PMID- 29504848 TI - Signalling pathways identified in salivary glands from primary Sjogren's syndrome patients reveal enhanced adipose tissue development. AB - A characteristic feature of primary Sjogren's syndrome (pSS) is the destruction of salivary and lacrimal glands mediated by mononuclear cell infiltration. Adipocytes can also occupy a large portion of the salivary gland (SG) tissue area, although little is known about their significance in pSS. We have previously investigated adipose tissue infiltration in SG biopsies from pSS patients and non-SS sicca controls. Our findings indicated the distinct incidence of adipose tissue replacement in pSS patients, where adipocytes were detected in interleukin (IL) 6 rich regions. We now aimed to examine the development of adipocytes in the SG microenvironment, and delineate their possible involvement in immune reactions. A microarray analysis was performed on SG from 6 pSS patients and 6 non-SS controls, where the expression levels of genes involved in adipose tissue development, inflammatory responses, and lymphoma development were assessed. Real-time PCR was carried out on SG from 14 pSS patients and 15 non-SS controls to account for IL6, IL10, and IL17 mRNA levels. Immunohistochemical staining of frozen SG tissue using IL17 was also conducted. Our results indicate signalling pathways identified in SG of pSS patients displayed genes leading to prominent adipose tissue development and reduced mitochondrial fatty acid beta oxidation (ARID5B, OXCT1, BDH1, SOX8, HMGCS2, FTO, ECHS1, PCCA, ACADL and ACADVL), inflammatory responses (IL1R1, IL7R, IL10RA, IL15, IL18RAP, CCL2, CCL5, CCL22, CXCR6, CD14, and CD48), and lymphoma development via JAK-STAT signalling (STAT2, TYK2, EBI3, FAS, TNFRSF1B, MAP3K8, HMOX1, LTB, TNF, STAT1, and BAK1). Genes involved in interferon production and signalling were also detected (IRF1, IRF9, and IRF7), in addition to IL6, IL10, and IL17. Higher mRNA levels of IL6, IL17 and IL10 were observed in the SG of pSS patients compared to controls. Moreover, IL17 positive cells were detected mostly interstitially in the SG and around adipocytes, also within the focal infiltrates. In conclusion, adipocyte development seems to be more prominent in the SG of pSS patients, where adipose tissue replacement is also evident. Whether this is due to disease progression, or the repair process, remains to be investigated. Detection of IL17 positive adipocytes in the target organ suggests their involvement in immune reactions. PMID- 29504849 TI - Evaluation of the clinical effects of diet and physical rehabilitation in dogs following tibial plateau leveling osteotomy. AB - OBJECTIVE To assess clinical effects of an omega-3 fatty acid and protein enriched diet, physical rehabilitation, or both in dogs following tibial plateau leveling osteotomy (TPLO) and arthroscopic surgery for cranial cruciate ligament (CCL) disease. DESIGN Randomized, prospective clinical trial. ANIMALS 48 dogs with unilateral CCL disease. PROCEDURES Dogs were randomly assigned to receive a dry omega-3 fatty acid and protein-enriched dog food formulated to support joint health (test food [TF]), a dry food formulated for maintenance of adult dogs (control food [CF]), TF plus rehabilitation (TF-R), or CF plus rehabilitation (CF R). Data collected over 6 months included body weight, body condition score, ground reaction force data, tibial plateau angle, limb circumference measurements, subjective pain and lameness scores assigned by surgeons and dog owners, and daily activity measured by accelerometry. RESULTS Peak vertical force and vertical impulse were greater after surgery for dogs in the TF groups than in the CF groups; peak vertical force was greater after surgery in dogs that underwent rehabilitation than in those that did not. Owner scores indicated lower frequencies of lameness and signs of pain during some activities for the TF group, compared with other groups, and for the TF-R and CF-R groups, compared with the CF group. Sedentary time decreased and time spent in light-to-moderate or vigorous activity increased in all groups over time. Rehabilitation was significantly associated with greater time spent in light-to-moderate activity, regardless of diet. CONCLUSIONS AND CLINICAL RELEVANCE Feeding the TF and providing physical rehabilitation during the first 6 months after TPLO were associated with improvements in some indices of clinical outcome and function in dogs. Significant interactions between time and some outcome variables were observed, indicating further research is warranted. PMID- 29504850 TI - JAVMA Book Reviewers 2017. PMID- 29504851 TI - Pathology in Practice. PMID- 29504852 TI - JAVMA Reviewers 2017. PMID- 29504853 TI - In This Issue * March 15, 2018. PMID- 29504854 TI - Letters to the Editor. PMID- 29504855 TI - Assessment of the effects of diet and physical rehabilitation on radiographic findings and markers of synovial inflammation in dogs following tibial plateau leveling osteotomy. AB - OBJECTIVE To determine the effects of an omega-3 fatty acid and protein-enriched diet, physical rehabilitation, or both on radiographic findings and markers of synovial inflammation in dogs following tibial plateau leveling osteotomy and arthroscopic surgery for treatment of cranial cruciate ligament disease. DESIGN Randomized, prospective clinical trial. ANIMALS 48 dogs with unilateral cranial cruciate ligament disease. PROCEDURES Dogs were randomly assigned to receive a dry omega-3 fatty acid and protein-enriched dog food formulated to support joint health (test food [TF]), a dry food formulated for adult canine maintenance (control food [CF]), TF plus rehabilitation, or CF plus rehabilitation after surgery. Synovial fluid prostaglandin (PG) E2 and interleukin-1beta concentrations, radiographic osteoarthritis scores, osteotomy site healing, and patellar ligament thickness were assessed at predetermined time points up to 6 months after surgery. RESULTS Dogs that received CF had significantly higher PGE2 concentrations over time following surgery than did dogs that received TF, regardless of rehabilitation status. Synovial fluid interleukin-1beta concentrations did not change over time in any groups. Diet and rehabilitation were both associated with osteoarthritis scores, with significantly lower scores over time for dogs that received TF versus CF and for dogs that underwent rehabilitation versus those that did not. Proportions of dogs with complete osteotomy healing 8 and 24 weeks after surgery were significantly lower for dogs that received TF than for dogs that received CF, regardless of rehabilitation status. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that feeding the TF can result in lower synovial fluid PGE2 concentrations and that both the TF and rehabilitation can reduce progression of osteoarthritis in the 6 months following tibial plateau leveling osteotomy; clinical relevance of slower osteotomy healing in dogs fed the TF was unclear. PMID- 29504856 TI - Treatment of pyonephrosis with a subcutaneous ureteral bypass device in four cats. AB - CASE DESCRIPTION 4 cats were examined because of ureteral obstruction. CLINICAL FINDINGS Clinical and clinicopathologic abnormalities were nonspecific and included anorexia, lethargy, weight loss, anemia, leukocytosis, neutrophilia, lymphopenia, and azotemia. A diagnosis of pyonephrosis was made in all cats. The presence of bacteriuria was confirmed by means of urinalysis in 2 cats, bacterial culture of a urine sample obtained by means of preoperative cystocentesis in 2 cats, and bacterial culture of samples obtained from the renal pelvis intraoperatively in 3 cats. Ureteral obstruction was caused by a urolith in 3 cats; ureteral stricture associated with a circumcaval ureter was identified in 1 cat. TREATMENT AND OUTCOME All 4 cats underwent renal pelvis lavage and placement of a subcutaneous ureteral bypass (SUB) device for treatment of obstructive pyonephrosis. Postoperatively, the cystostomy tube became occluded with purulent material in 1 cat, requiring exchange. The procedure was successful in relieving the obstruction and pyonephrosis in all cats. Three of 4 cats had documented resolution of urinary tract infection. One cat had persistent bacteriuria without clinical signs 1 month after SUB device placement. CLINICAL RELEVANCE Results of this small series suggested that renal pelvis lavage with placement of an SUB device may be a treatment option for cats with obstructive pyonephrosis. PMID- 29504858 TI - Theriogenology Question of the Month. PMID- 29504859 TI - Survival analysis to evaluate associations between periodontal disease and the risk of development of chronic azotemic kidney disease in cats evaluated at primary care veterinary hospitals. AB - OBJECTIVE To examine potential associations between periodontal disease (PD) and the risk of development of chronic azotemic kidney disease (CKD) among cats and determine whether the risk of CKD increases with severity of PD. DESIGN Retrospective cohort study. ANIMALS 169, 242 cats. PROCEDURES Cats were evaluated >= 3 times at any of 829 hospitals from January 1, 2002, through June 30, 2013. Cats with an initial diagnosis of PD of any stage (n = 56,414) were frequency matched with cats that had no history or evidence of PD (112,828) by age and year of study entry. Data on signalment, PD, and other conditions potentially related to CKD were extracted from electronic medical records. Cox proportional hazards modeling was used to estimate the association of PD with CKD after controlling for covariates. RESULTS PD was associated with increased risk of CKD; risk was highest for cats with stage 3 or 4 PD. Risk of CKD increased with age. Purebred cats had greater risk of CKD than mixed-breed cats. General anesthesia within the year before study exit and diagnosis of cystitis at any point prior to study exit (including prior to study entry) were each associated with increased CKD risk. Diagnosis of diabetes mellitus or hepatic lipidosis at any point prior to study exit was associated with decreased CKD risk. CONCLUSIONS AND CLINICAL RELEVANCE The findings supported the benefit of maintaining good oral health and can be useful to veterinarians for educating owners on the importance of preventing PD in cats. PMID- 29504860 TI - Surgical and endoscopic treatment of bladder exstrophy-epispadias complex in a female dog. AB - CASE DESCRIPTION A 14-week-old 7.7-kg (16.9-lb) sexually intact female Golden Retriever was evaluated because of urine dripping from the caudoventral aspect of the abdomen. CLINICAL FINDINGS Ultrasonography, radiography, excretory CT urography, and vaginocystourethroscopy were performed. Results indicated eversion of the bladder through the ventral abdominal wall with exposure of the ureterovesicular junctions, pubic diastasis, and an open vulva and clitoral fossa. Clinical findings were suggestive of bladder exstrophy, a rare congenital anomaly. TREATMENT AND OUTCOME The dog was anesthetized and bilateral ileal osteotomies were performed. Two ureteral catheters were passed retrograde into the renal pelves under fluoroscopic guidance. The lateral margins of the bladder, bladder neck, and urethra were surgically separated from the abdominal wall, and the bladder was closed, forming a hollow viscus. The symphysis pubis was closed on midline with horizontal mattress sutures. The defects in the vestibule and clitoral fossa were closed. Lastly, the iliac osteotomies were stabilized. The dog was initially incontinent with right hind limb sciatic neuropraxia and developed pyelonephritis. Over time, the dog became continent with full return to orthopedic and neurologic function, but had recurrent urinary tract infections, developed renal azotemia likely associated with chronic pyelonephritis, and ultimately was euthanized 3.5 years after surgery because of end-stage kidney disease. CLINICAL RELEVANCE Bladder exstrophy and epispadias is a treatable but rare congenital abnormality. The procedure described could be considered for treatment of this condition, but care should be taken to monitor for urinary tract infections and ascending pyelonephritis. PMID- 29504861 TI - Outcome of ureteral stent placement for treatment of benign ureteral obstruction in dogs: 44 cases (2010-2013). AB - OBJECTIVE To describe the technique and short- and long-term outcomes for dogs undergoing double-pigtail ureteral stent placement for treatment of benign ureteral obstruction. DESIGN Retrospective case series. ANIMALS 44 dogs (57 ureters). PROCEDURES Medical records of dogs that underwent ureteral stenting for treatment of benign ureteral obstruction between 2010 and 2013 were reviewed. Signal-ment, history, pertinent diagnostic imaging results, endourologic and post procedural details, duration of hospitalization, complications, and outcome (short term, 7 to 30 days; long term, > 30 days) were recorded. Ureteral stent placement was performed endoscopically, surgically, or both, with fluoroscopic guidance. RESULTS 57 ureters (44 dogs) underwent stenting because of obstructive ureterolithiasis (n = 48 [84%]), stricture (5 [9%]), or both (4 [7%]). Endoscopic or surgical techniques were successful for stent placement in 45 of 55 and 12 of 12 ureters (34/42 and 10/10 dogs), respectively. Median hospitalization time was 1 day. Median creatinine concentration was 2 mg/dL prior to stenting and 1.3 mg/dL 3 months after the procedure. Urinary tract infections were present in 26 of 44 (59%) dogs prior to stenting and in 11 of 43 dogs (26%) after stenting. One of the 44 (2%) dogs died after undergoing stenting, but the cause of death was not related to the procedure. Median follow-up time was 1,158 days (range, 3 to > 1,555 days), with 30 of 44 dogs alive at the time of last follow-up. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that ureteral stenting may be a viable option for first-line treatment of dogs with benign ureteral obstruction. However, patients should be monitored for urinary tract infection following stenting. PMID- 29504863 TI - Pathology in Practice. PMID- 29504862 TI - What Is Your Diagnosis? PMID- 29504865 TI - Novel effect of alpha-lactalbumin on the yohimbine-induced hot flush increase of the tail skin temperature in ovariectomized rats. AB - 5-Hydroxytryptamine (5-HT) and noradrenaline have been thought to play important roles in the mechanism of hot flush. Then, to clarify the relation between serotonergic and adrenergic nervous systems on the mechanism of hot flush, the effect of paroxetine, 5-HT reuptake inhibitor (SSRI) was evaluated on the yohimbine-induced hot flush increase of tail skin temperature in ovariectomized female rats. Yohimbine (adrenaline alpha2 antagonist) significantly increased the tail skin temperature in course of time. Clonidine (adrenaline alpha2 agonist) significantly attenuated this effect. Paroxetine also significantly inhibited the increase of tail skin temperature by yohimbine. alpha-Lactalbumin having SSRI activity in vitro study also significantly inhibited the increase of tail skin temperature, but not significantly decreased the initial temperature. This difference may explain the different mechanism between paroxetine (SSRI) and alpha-lactalbumin, suggesting new mechanism of hot flush. PMID- 29504866 TI - Diagnostic challenges of adult T-cell leukemia/lymphoma in North America - a clinical, histological, and immunophenotypic correlation with a workflow proposal. AB - Adult T-cell leukemia-lymphoma (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1) and little is known about ATLL endemic to the Caribbean basin and Latin America, designated as western ATLL (W-ATLL). Due to extensive systemic involvement and nonspecific clinical presentation, the initial diagnosis in this cohort can be very challenging. We have diagnosed 60 patients with W-ATLL over a 14-year period. ATLL involves the peripheral blood, bone marrow, and cerebrospinal fluid (CSF) in 98, 87, and 52% cases, respectively; while lymphadenopathy, pulmonary infiltrates, splenomegaly, and hepatomegaly was present in 90, 82, 48, and 45% patients, respectively. While 87% patients developed hypercalcemia only 28% had lytic bone lesions. We propose that any diagnosis of a peripheral T-lymphoproliferative disorder should result in a comprehensive review of the patient's endemic, laboratory information, HTLV-1 testing for proper diagnosis, and identification due to the varied manifestations of this disease. PMID- 29504867 TI - Efficacy of antimicrobial agents incorporated in orthodontic bonding systems: a systematic review and meta-analysis. AB - AIMS: The purpose of this study was to evaluate the efficacy of orthodontic bonding systems containing different antimicrobial agents, as well as the influence of antimicrobial agent incorporation in the bonding properties of these materials. METHODS: Eight databases were searched: PubMed (Medline), Web of Science, Scopus, Lilacs, Ibecs, BBO, Scielo and Google Scholar. Any study that evaluated antimicrobial activity in experimental or commercial orthodontic bonding systems was included. DATA EXTRACTION: Data were tabulated independently and in duplicated by two authors on pre-designed data collection form. DATA SYNTHESIS: The global analysis was carried out using a random-effects model, and pooled-effect estimates were obtained by comparing the standardised mean difference of each antimicrobial orthodontic adhesive with the respective control group. A p-value < .05 was considered as statistically significant. RESULTS: Thirty-two studies were included in the qualitative analysis; of these, 22 studies were included in the meta-analysis. Antimicrobial agents such as silver nanoparticles, benzalkonium chloride, chlorhexidine, triclosan, cetylpyridinium chloride, Galla chinensis extract, acid ursolic, dimethylaminododecyl methacrylate, dimethylaminohexadecyl methacrylate, 2-methacryloyloxyethyl phosphorylcholine, 1,3,5-triacryloylhexahydro-1,3,5-triazine, zinc oxide and titanium oxide have been incorporated into orthodontic bonding systems. The antimicrobial agent incorporation in orthodontic bonding systems showed higher antimicrobial activity than the control group in agar diffusion (overall standardised mean difference: 3.71; 95% CI 2.98 to 4.43) and optical density tests (0.41; 95% CI -0.05 to 0.86) (p < .05). However, for biofilm, the materials did not present antimicrobial activity (6.78; 95% CI 4.78 to 8.77). Regarding bond strength, the global analysis showed antimicrobial orthodontic bonding systems were statistically similar to the control. CONCLUSIONS: Although there is evidence of antibacterial activity from in vitro studies, clinical and long-term studies are still necessary to confirm the effectiveness of antibacterial orthodontic bonding systems in preventing caries disease. PMID- 29504868 TI - Enhancing hospital care of patients with cognitive impairment. AB - Purpose The patient-centred management of people with cognitive impairment admitted to acute health care facilities can be challenging. The TOP5 intervention utilises carers' expert biographical and social knowledge of the patient to facilitate personalised care. The purpose of this paper is to explore whether involvement of carers in the TOP5 initiative could improve patient care and healthcare delivery. Design/methodology/approach A small-scale longitudinal study was undertaken in two wards of one acute teaching hospital. The wards admitted patients with cognitive impairment, aged 70 years and over, under geriatrician care. Data for patient falls, allocation of one-on-one nurses ("specials"), and length-of-stay (LOS) over 38 months, including baseline, pilot, and establishment phases, were analysed. Surveys of carers and nursing staff were undertaken. Findings There was a significant reduction in number of falls and number of patients allocated "specials" over the study period, but no statistically significant reduction in LOS. A downward trend in complaints related to communication issues was identified. All carers ( n=43) completing the feedback survey were satisfied or very satisfied that staff supported their role as information provider. Most carers (90 per cent) felt that the initiative had a positive impact and 80 per cent felt that their loved one benefitted. Six months after implementation of the initiative, 80 per cent of nurses agreed or strongly agreed that it was now easier to relate to carers of patients with cognitive impairment. At nine-ten months, this increased to 100 per cent. Originality/value Actively engaging carers in management of people with cognitive impairment may improve the patient, staff, and carer journeys, and may improve outcomes for patient care and service delivery. PMID- 29504869 TI - An interdisciplinary approach to improve surgical antimicrobial prophylaxis. AB - Purpose The purpose of this paper is to improve surgical antimicrobial prophylaxis (SAP) prescribing in orthopaedic surgery using the model for improvement framework. Design/methodology/approach Orthopaedic patients receiving joint replacements, hip fracture repairs or open-reduction internal-fixation procedures were included. Antimicrobial(s); dose, time of administration and duration of SAP were evaluated for appropriateness based on the local SAP guidelines. After baseline data collection, a driver diagram was constructed with interventions devised for plan-do-study-act cycles. Data were fed back weekly using a point prevalence design (PPD). Interventions included SAP guideline changes, reminders and tools to support key messages. Findings SAP in 168 orthopaedic surgeries from 15 June 2016 to 31 January 2017 was studied. Prescribing appropriateness improved from 20 to 78 per cent. Junior doctor changeover necessitated additional education and reminders. Practical implications Due to constant staff changeover; continuous data collection, communication, education and reminders are essential to ensure continuous compliance with clinical guidance. Patients with hip fractures are difficult to weigh, requiring weight estimation for weight-based antimicrobial dosing. Unintended consequences of interventions included the necessity to change pre operative workflow to accommodate reconstitution time of additional antimicrobials and inadvertent continuation of new antimicrobials post operatively. Originality/value Rather than perform the traditional retrospective focused audit, we established a prospective, continuous, interventional quality improvement (QI) project focusing on internal processes within the control of the project team with rapid cyclical changes and interventions. The weekly PPD was pragmatic and enabled the QI project to be sustained with no additional resources. PMID- 29504870 TI - Measuring patient satisfaction with medical services using social media generated data. AB - : Purpose The purpose of this paper is to discuss the results of an effort to use social media generated data for measuring patient satisfaction with medical care services. Traditionally, scientifically designed patient satisfaction surveys are used to provide such measurements. The goal here is to evaluate the possibility of supplementing patient satisfaction surveys with social media generated patient satisfaction measurements such that the later can be used either as validation or replacement for the former. Although surveys are scientifically designed to yield dependable results, recent studies have revealed multiple factors relating to the methods currently used for survey data collection, that may be contributing to the limitations of many survey results. In light of such criticisms, this study explored the possibility of using the increasing popular and proactively generated consumer ratings through the pervasive social media as data source for satisfaction measurement. The average satisfaction scores created from such data are then used to compare levels of satisfaction among five types of health service businesses. Design/methodology/approach The data used in this research are garnered from the consumer review social media site called "Yelp!". Ratings and reviews that are related to health and medical services were extracted from the "Yelp!" DATABASE: The types of services that are identified by consumers are standardized to typologies that are traditionally used in health service research. Five types of services were targeted - general practice physician offices, physician specialty services, dentists, hospitals and physical therapy services. The "five-star" rating systems were re-coded to form a five-point ordinal scale variable to represent "satisfaction score". Findings The Yelp! data based measurement of patient satisfaction produced an overall satisfaction score of 3.8 (SD=1.7) for the sampled services. The average satisfaction score per type of service ranged from 3.16 (SD=1.83) for specialty physicians to 4.52 (SD=1.57) for physical therapists. In general, dentists and physical therapists received higher average satisfaction scores as compared to the other medical services. Research limitations/implications Because this study was meant to evaluate the utility of social media generated data to measure satisfaction, in general, the estimates cannot be construed as representative of any underlying geographically defined population. They, however, do have a "cohort" interpretability. This limitation is not inherent to the use of the data source. If some geographically identifiable representation of the measurement data is desired, identifiable business data can be generated from the Yelp! system to specifically target relevant populations following the method that are tested in this study. Practical implications Under certain circumstances, such as the size and maturity of the gathered data, social media generated data can be a useful as a "fortuitous" alternative to satisfaction surveys for evaluating patient satisfaction with medical care. This is propitious as there have been some indication by studies that the advent of communication media in the twenty-first century may be undermining the reliability of scientifically designed surveys. Originality/value The use of social media generated data as "alternative" or "secondary" data source for research use is currently being widely investigated. To the author's knowledge, this is the only paper that evaluated the use of "Yelp!" data as a possible source for population-based formal satisfaction measurement for healthcare services. PMID- 29504871 TI - Implementation of a nationwide electronic health record (EHR). AB - Purpose The purpose of this paper is to identify the best practices applied during the implementation process of a national electronic health record (EHR) system. Furthermore, the main goal is to explore the knowledge gained by experts from leading countries in the field of nationwide EHR system implementation, focusing on some of the main success factors and difficulties, or failures, of the various implementation approaches. Design/methodology/approach To gather the necessary information, an international survey has been conducted with expert participants from 13 countries (Denmark, Austria, Sweden, Norway, the UK, Germany, the Netherlands, Switzerland, Canada, the USA, Israel, New Zealand and South Korea), who had been playing varying key roles during the implementation process. Taking into consideration that each system is unique, with each own (different) characteristics and many stakeholders, the methodological approach followed was not oriented to offer the basis for comparing the implementation process, but rather, to allow us better understand some of the pros and cons of each option. Findings Taking into account the heterogeneity of each country's financing mechanism and health system, the predominant EHR system implementation option is the middle-out approach. The main reasons which are responsible for adopting a specific implementation approach are usually political. Furthermore, it is revealed that the most significant success factor of a nationwide EHR system implementation process is the commitment and involvement of all stakeholders. On the other hand, the lack of support and the negative reaction to any change from the medical, nursing and administrative community is considered as the most critical failure factor. Originality/value A strong point of the current research is the inclusion of experts from several countries (13) spanning in four continents, identifying some common barriers, success factors and best practices stemming from the experience obtained from these countries, with a sense of unification. An issue that should never be overlooked or underestimated is the alignment between the functionality of the new EHR system and users' requirements. PMID- 29504872 TI - The NHS Bowel cancer screening programme achieves the anticipated survival improvement, but participation must be improved. AB - Purpose The NHS Bowel cancer screening programme (NHSBCSP) aims to reduce colorectal cancer (CRC) cumulative mortality by up to 23 per cent; long-term outcomes at national level are not yet known. The purpose of this paper is to examine a local population of CRC patients of screening age for their characteristics and long-term survival in relation to their presentation, including through the NHSBCSP. Design/methodology/approach Retrospective analysis of a prospectively maintained CRC database for the years 2009-2014 in a single district hospital providing bowel cancer screening and tertiary rectal cancer services. Findings Of 528 CRC patients diagnosed in the screening age range, 144(27.3 per cent) presented through NHSBCSP, 308(58.3 per cent) electively with symptoms and 76(14.4 per cent) as emergency. NHSBCSP-diagnosed patients were younger (median 66 vs 68 and 69 years, respectively, p=0.001), had more often left-sided cancers (59(41.0 per cent) vs 82(26.6 per cent) and 24(31.6 per cent), respectively, p=0.001), more UICC-stage I (42(29.2 per cent) vs 49(15.9 per cent) and 2(2.6 per cent)), stage III (59(41.0 per cent) vs 106(34.4 per cent) and 20(26.3 per cent)) and less stage IV disease (8(5.6 per cent) vs 61(19.8 per cent) and 34 (44.7 per cent), respectively, p<0.001). Three-year overall survival was best for NHSBCSP and worst for emergency patients (87.5 per cent vs 69.0 per cent and 35.3 per cent, respectively, LogRank p<0.001). Originality/value Patients diagnosed within the NHSBCSP have improved outcome compared to both symptomatic elective and emergency presentations. A reduction in overall cumulative mortality in order of 25 per cent may well be achieved, but continuing high levels of emergency presentations and undetected right-sided disease emphasise need for further improvement in public participation in the NHSBCSP and research into more sensitive and acceptable alternative screening methods. PMID- 29504873 TI - Implementation of a multimodal patient safety improvement program "SafetyLEAP" in intensive care units. AB - Purpose Patient safety remains a top priority in healthcare. Many organizations have developed systems to monitor and prevent harm, and have invested in different approaches to quality improvement. Despite these organizational efforts to better detect adverse events, efficient resolution of safety problems remains a significant challenge. The authors developed and implemented a comprehensive multimodal patient safety improvement program called SafetyLEAP. The term "LEAP" is an acronym that highlights the three facets of the program including: a Leadership and Engagement approach; Audit and feedback; and a Planned improvement intervention. The purpose of this paper is to evaluate the implementation of the SafetyLEAP program in the intensive care units (ICUs) of three large hospitals. Design/methodology/approach A comparative case study approach was used to compare and contrast the adherence to each component of the SafetyLEAP program. The study was conducted using a convenience sample of three ( n=3) ICUs from two provinces. Two reviewers independently evaluated major adherence metrics of the SafetyLEAP program for their completeness. Analysis was performed for each individual case, and across cases. Findings A total of 257 patients were included in the study. Overall, the proportion of the SafetyLEAP tasks completed was 64.47, 100, and 26.32 percent, respectively. ICU nos 1 and 2 were able to identify opportunities for improvement, follow a quality improvement process and demonstrate positive changes in patient safety. The main factors influencing adherence were the engagement of a local champion, competing priorities, and the identification of appropriate resources. Practical implications The SafetyLEAP program allowed for the identification of processes that could result in patient harm in the ICUs. However, the success in improving patient safety was dependent on the engagement of the care teams. Originality/value The authors developed an evidence-based approach to systematically and prospectively detect, improve, and evaluate actions related to patient safety. PMID- 29504874 TI - Forwards, backwards or paddling nowhere.... PMID- 29504875 TI - Improving flow in the OR. AB - Purpose The purpose of this paper is to increase efficiency in ORs without affecting quality of care by improving the workflow processes. Administrative processes independent of the surgical act can be challenging and may lead to clinical impacts such as increasing delays. The authors hypothesized that a Lean project could improve efficiency of surgical processes by reducing the length of stays in the recovery ward. Design/methodology/approach Two similar Lean projects were performed in the surgery departments of two hospitals of the Centre Hospitalier Universitaire de Quebec: Hotel Dieu de Quebec (HDQ) and Hopital de l'Enfant Jesus (HEJ). The HDQ project designed around a Define, Measure, Analyse, Improve and Control process revision and a Kaizen workshop focused on patients who were hospitalized in a specific care unit after surgery and the HEJ project targeted patients in a post-operative ambulatory context. The recovery ward output delay was measured retrospectively before and after project. Findings For the HDQ Lean project, wasted time in the recovery ward was reduced by 62 minutes (68 percent reduction) between the two groups. The authors also observed an increase of about 25 percent of all admissions made in the daytime after the project compared to the time period before the project. For the HEJ Lean project, time passed in the recovery ward was reduced by 6 min (29 percent reduction). Originality/value These projects produced an improvement in the flow of the OR without targeting clinical practices in the OR itself. They demonstrated that change in administrative processes can have a great impact on the flow of clinical pathways and highlight the need for comprehensive and precise monitoring of every step of the elective surgery patient trajectory. PMID- 29504876 TI - Clinicians' perception of the preventability of inpatient mortality. AB - Purpose The purpose of this paper is to assess whether clinicians have an accurate perception of the preventability of their patients' mortality. Case note review estimates that approximately 5 percent of inpatient deaths are preventable. Design/methodology/approach The design involved in the study is a prospective audit of inpatient mortality in a single NHS hospital trust. The case study includes 979 inpatient mortalities. A number of outcome measures were recorded, including a Likert scale of the preventability of death- and NCEPOD based grading of care quality. Findings Clinicians assessed only 1.4 percent of deaths as likely to be preventable. This is significantly lower than previously published values ( p<0.0001). Clinicians were also more likely to rate the quality of care as "good," and less likely to identify areas of substandard clinical or organizational management. Research limitations/implications The implications of objective assessment of the preventability of mortality are essential to drive quality improvement in this area. Practical implications There is a wide disparity between independent case note review and clinicians assessing the care of their own patients. This may be due to a "knowledge gap" between reviewers and treating clinicians, or an "objectivity gap" meaning clinicians may not recognize preventability of death of patients under their care. Social implications This study gives some insight into deficiencies in clinical governance processes. Originality/value No similar study has been performed. This has significant implications for the idea of the preventability of mortality. PMID- 29504877 TI - A Multicenter Randomized Double-blind Controlled Clinical Trial of Fiber Post Cementation Strategies. AB - OBJECTIVES: The aim of this prospective randomized multicenter clinical trial was to evaluate the survival rate of glass fiber-reinforced posts cemented with self adhesive or regular resin cements. METHODS: The sample was comprised of 152 teeth randomized within two centers and in accordance with the adhesive strategies for RelyX U100/U200 (3M ESPE) or Single Bond and RelyX ARC (3M ESPE). The cementation procedures were standardized and performed by previously trained operators. The primary outcome evaluated was post debonding. A trained evaluator, one for each center, assessed all subjects at intervals of 12 months for up to 6 years. Statistical analysis was performed using the Kaplan-Meier method. RESULTS: There was no statistically significant difference in survival rates between the two strategies assessed ( p=0.991), with a 92.7% survival rate for the self-adhesive cement and 93.8% for the regular cement. CONCLUSION: Both the self-adhesive and the regular resin cements are good alternatives for glass fiber post cementation. PMID- 29504878 TI - Effect of Chlorhexidine Treatment Prior to Fiber Post Cementation on Long-Term Resin Cement Bond Strength. AB - The purpose of this study was to evaluate the push-out bond strength of two different adhesive cements (total etch and self-adhesive) for glass fiber post (GFP) cementation in simulated, long-term service (thermocycling) when the root canal is treated with chlorhexidine before cementation. One hundred twenty premolar specimens with a single root canal were selected, endodontically treated, and shaped for GFP cementation (n=120). The specimens were randomly placed into one of 12 groups (10 specimens each) according to cement (T = total etch RelyX ARC or S = self-adhesive RelyX Unicem), treatment with chlorhexidine (N or Y: without or with), and number of thermal cycles (00, 20, or 40: 0, or 20,000 or 40,000 cycles): 1. TN00, 2. TN20, 3. TN40, 4. TY00, 5. TY20, 6. TY40, 7. SN00, 8. SN20, 9. SN40, 10. SY00, 11. SY20, 12. SY40. The root of each specimen was cut perpendicular to the vertical axis, yielding six 1.0 mm-thick sections. A push-out bond strength test was performed followed by statistical analysis using a factorial analysis of variance. Pairwise comparisons of significant factor interactions were adjusted using the Tukey test. Significant differences of push-out bond strengths were found in the four main effects (resin cement [ p<0.0001], treatment with chlorhexidine [ p<0.0001], number of cycles [ p<0.0001], and root third [ p<0.0001]) and all interactions ( p<0.05 for all). Both resin cements produced higher bond strength in the cervical third followed by the middle third, and lower values were detected in the apical third. Additionally, the results suggest that the use of an additional disinfection treatment with chlorhexidine before the cement application produced the highest push-out bond strength regardless of root third. Further, the thermocycling simulation decreased the bond strength for both resin cements long-term when the chlorhexidine was not applied before cementation. However, when the root canal was treated with chlorhexidine and the fiber post was cemented with self-adhesive cement, the bond strength increased after 0, 20,000 and 40,000 cycles. PMID- 29504879 TI - Does Classification of Composites for Network Meta-analyses Lead to Erroneous Conclusions? AB - OBJECTIVES: Composites can be classified differently, according to manufacturer information, filler particle size, resin-monomer base, or viscosity, for example. Using clinical trial data, network meta-analyses aim to rank different composite material classes. Dentists then use these ranks to decide whether to use specific materials. Alternatively, annual failure rates (AFRs) of materials can be assessed, not requiring any classification for synthesis. It is unclear whether different classification systems lead to different rankings of the same material (ie, erroneous conclusions). We aimed to evaluate the agreement of material rankings between different classification systems. METHODS: A systematic review was performed via MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. Randomized controlled trials published from 2005-2015 that investigated composite restorations placed in load-bearing cavitated lesions in permanent teeth were included. Network meta-analyses were performed to rank combinations of composite classes (according to manufacturer, filler particle size, resin monomers, viscosity) and adhesives. Material combinations were additionally ranked using AFRs. RESULTS: A total of 42 studies (6088 restorations, 2325 patients) were included. The ranking of most material class combinations showed significant agreement between classifications ( R2 ranged between 0.03 and 0.56). Comparing material combinations using AFRs had low precision and agreement with other systems. AFRs were significantly correlated with follow-up periods of trials. CONCLUSION: There was high agreement between rankings of identical materials in different classification systems. Such rankings thus allow cautious deductions as to the performance of a specific material. Syntheses based on AFRs might lead to erroneous results because AFRs are determined by follow-up periods and have low precision. PMID- 29504880 TI - Combination of Acetaminophen/Codeine Analgesics Does Not Avoid Bleaching-Induced Tooth Sensitivity: A Randomized, Triple-Blind Two-Center Clinical Trial. AB - : Bleaching-induced tooth sensitivity (TS) is highly prevalent. OBJECTIVE: This study aimed to determine if the combination of opioids and nonopioids analgesics (Tylex) may provide a better analgesic effect. METHOD: A triple-blind, parallel, randomized two-center clinical trial was conducted with 105 healthy patients who received either a placebo or a combination of acetaminophen/codeine. The first dose of Tylex 30 mg (acetaminophen 500 mg/codeine 30 mg) or placebo was administered one hour before the in-office bleaching (35% hydrogen peroxide), and extra doses were administered every six hours for 48 hours. The TS was recorded using a visual analog scale of 0 to 10 and a numeric rating scale of 0 to 4 in different periods: during bleaching, one hour up to 24 hours, and 24 hours up to 48 hours postbleaching. The color was measured before and one month after dental bleaching with a visual shade guide (Vita Classical), Vita Bleachedguide 3D MASTER, and the spectrophotometer Vita Easyshade. The absolute risk of TS was evaluated using the Fisher exact test. Data of TS intensity with numeric rating scale of the two groups were compared with the Mann-Whitney U-test and the Friedman test, while data from the visual analog scale were evaluated by two-way repeated measures analysis of variance and the Tukey test for pairwise comparison. The color changes between groups were compared using the Student t test (alpha=0.05). RESULTS: No significant differences between the groups were observed in the risk and intensity of TS. The overall absolute risk of TS was approximately 96%. No significant differences between groups were observed in terms of color change ( p>0.05) for any scale. CONCLUSION: The use of an acetaminophen/codeine combination prior to in-office bleaching does not reduce the risk and intensity of bleaching-induced TS. PMID- 29504881 TI - Faculty Posting. PMID- 29504883 TI - Online Only Articles. AB - On occasion we receive manuscripts that we would like to publish, but do not have the page room to include in the print journal. For the full article, please go to www.jopdentonline.org or enter the provided address into your address bar. PMID- 29504882 TI - Degradation of Multimode Adhesive System Bond Strength to Artificial Caries Affected Dentin Due to Water Storage. AB - The purpose of this study was to evaluate the influence of water storage on bond strength of multimode adhesive systems to artificially induced caries-affected dentin. One hundred twelve sound bovine incisors were randomly assigned to 16 groups (n=7) according to the dentin condition (sound; SND, artificially induced caries-affected dentin; CAD, cariogenic challenge by pH cycling for 14 days); the adhesive system (SU, Scotchbond Universal Adhesive; AB, All-Bond Universal; PB, Prime & Bond Elect; SB, Adper Single Bond 2; and CS, Clearfil SE Bond), and the etching strategy (etch-and-rinse and self-etch). All adhesive systems were applied under manufacturer's instructions to flat dentin surfaces, and a composite block was built up on each dentin surface. After 24 hours of water storage, the specimens were sectioned into stick-shaped specimens (0.8 mm2) and submitted to a microtensile test immediately (24 hours) or after six months of water storage. Bond strength data (MPa) were analyzed using three-way repeated measures analysis of variance and post hoc Tukey test (alpha=5%), considering each substrate separately (SND and CAD). The etching strategy did not influence the bond strength of multimode adhesives, irrespective of the dentin condition. Water storage only reduced significantly the bond strength to CAD. The degradation of bond strength due to water storage was more pronounced in CAD, regardless of the etching strategy. PMID- 29504885 TI - Two-year Effects of Chlorhexidine-containing Adhesives on the In Vitro Durability of Resin-dentin Interfaces and Modeling of Drug Release. AB - OBJECTIVES: To evaluate the effects of addition of diacetate chlorhexidine (CHX) at different concentrations into two etch-and-rinse adhesive systems on CHX release, as well as the immediate (IM) and two-year (2-Y) resin-dentin microtensile bond strength (MUTBS) and nanoleakage (NL). METHODS: CHX was added to XP Bond (XP) and Ambar (AM) at concentrations of 0.0 wt% (control); 0.01 wt%; 0.05 wt%; and 0.1 to 0.2 wt%. To assess the cumulative CHX release, adhesive disks were made in a metallic matrix and after light-curing were stored in water. Ultraviolet spectrophotometric measurements of the storage solution were performed to examine the release kinetics of CHX. For MUTBS and NL, the occlusal enamel of molars was removed and the adhesives were applied to the dentin surface after acid etching. After composite resin build-up, specimens were sectioned to obtain MUTBS sticks. The specimens were subjected to MUTBS and NL at IM and after 2-Y. In addition, specimens underwent examination for CHX using micro-Raman spectroscopy. All data were submitted to statistical analysis (alpha=0.05). RESULTS: With regard to CHX release, AM showed a slower and gradual release of CHX while XP released CHX more quickly ( p<0.05), and CHX was still present in the hybrid layers after 2-Y. Both adhesives showed CHX release at 2-Y water storage. Both CHX-containing adhesives showed higher MUTBS values than did the control group ( p<0.05). PMID- 29504886 TI - Fatigue Failure Load of Restored Premolars: Effect of Etching the Intaglio Surface of Ceramic Inlays With Hydrofluoric Acid at Different Concentrations. AB - The aim of this study was to evaluate the effect of etching, with different hydrofluoric acid concentrations at the intaglio surface of feldspathic ceramic inlays, on the fatigue failure load of restored premolars. A total of 60 upper premolars were embedded in plastic cylinders with acrylic resin (up to 3 mm below the cement-enamel junction) and prepared using a device specially designed for that purpose. Teeth were randomly assigned to three groups (n=20): HF1, HF5, and HF10 (etching with hydrofluoric acid for 60 seconds at concentrations of 1%, 5%, and 10%, respectively). Preparations were scanned and restorations were milled by a computer-aided design / computer-aided manufacturing system. The inner surfaces of the inlays were etched and received an application of a silane coupling agent; the dentin and enamel were treated appropriately for the luting system (RelyX ARC, 3M-ESPE). The restorations were cemented and the fatigue failure load (in N) was determined using the staircase method (10 Hz; 105 cycles in each step). The initial load (585.5 N) was applied on the slopes of the cusps (labial and palatal/lingual, simultaneously) through a cylinder attached to the test machine (Instron ElectroPuls E3000). The tested samples were analyzed under a stereomicroscope for failure analysis. Fatigue data were analyzed by one-way analysis of variance. There was no statistical difference among the fatigue failure loads (in N): HF1 (448.5+/-79.1), HF5 (360.7+/-55.4), and HF10 (409.5+/ 121.1). Regarding the fracture mode, there was a predominance of interfacial fracture (50%), followed by cusp fracture (34.6%). It may be concluded that the etching with hydrofluoric acid at the tested concentrations (1%, 5%, and 10%) does not influence the fatigue failure load of feldspathic ceramic inlays cemented on premolars. PMID- 29504887 TI - Effect of Toothpaste Use Against Mineral Loss Promoted by Dental Bleaching. AB - AIM: To investigate the effect of different toothpaste formulations used prior to dental bleaching with 35% hydrogen peroxide (HP) on the mineral content and surface morphology of enamel. METHODS: Seventy bovine enamel blocks (4*4*2 mm) were submitted to in vitro treatment protocols using a toothbrushing machine prior to dental bleaching or a placebo procedure (n=10) as proposed in the following groups: unbleached control (PLA), bleached control (HP), and brushing with differing toothpastes prior to HP bleaching, including: potassium nitrate toothpaste containing sodium fluoride (PN), sodium monofluorophosphate/MFP toothpaste (FT), arginine-carbonate (8% arginine) (PA) or arginine-carbonate (1.5% arginine) toothpaste (SAN), and toothpaste containing bioactive glass (NM). Phosphorus concentration in gel ([P]) was evaluated (MUg of P/mg of gel), and the elemental levels (wt%) of Ca, P, and Na as well as the proportion between Ca and P and spectra graphics were determined using an energy-dispersive X-ray spectrometer (EDS). The surface morphology was assessed using scanning electron microscopy (SEM). The data were subjected to analysis of variance and the Tukey test (alpha=0.05). RESULTS: HP demonstrated the greatest [P] values in gel, being statistically different from PLA. The [P] of NM was statistically similar to PLA. HP showed a significant decrease in the Ca% and Ca/P values when compared to PLA in EDS analysis. PA showed Ca/P values statistically different from HP. In accordance with SEM analysis, the PA, SAN, and NM groups presented a smooth and uniform enamel surface, while HP and FT demonstrated some alterations in morphology. CONCLUSION: The toothpastes containing bioactive glass or arginine carbonate used prior to dental bleaching were effective in protecting enamel against mineral loss promoted by the whitening procedure. PMID- 29504889 TI - Editorial: Neonatal Clinical Pharmacology: A Rapidly Maturing Discipline. PMID- 29504890 TI - Editorial: Novel Perspectives in the Treatment of Epilepsy. PMID- 29504891 TI - Better ILP models for haplotype assembly. AB - BACKGROUND: The haplotype assembly problem for diploid is to find a pair of haplotypes from a given set of aligned Single Nucleotide Polymorphism (SNP) fragments (reads). It has many applications in association studies, drug design, and genetic research. Since this problem is computationally hard, both heuristic and exact algorithms have been designed for it. Although exact algorithms are much slower, they are still of great interest because they usually output significantly better solutions than heuristic algorithms in terms of popular measures such as the Minimum Error Correction (MEC) score, the number of switch errors, and the QAN50 score. Exact algorithms are also valuable because they can be used to witness how good a heuristic algorithm is. The best known exact algorithm is based on integer linear programming (ILP) and it is known that ILP can also be used to improve the output quality of every heuristic algorithm with a little decline in speed. Therefore, faster ILP models for the problem are highly demanded. RESULTS: As in previous studies, we consider not only the general case of the problem but also its all-heterozygous case where we assume that if a column of the input read matrix contains at least one 0 and one 1, then it corresponds to a heterozygous SNP site. For both cases, we design new ILP models for the haplotype assembly problem which aim at minimizing the MEC score. The new models are theoretically better because they contain significantly fewer constraints. More importantly, our experimental results show that for both simulated and real datasets, the new model for the all-heterozygous (respectively, general) case can usually be solved via CPLEX (an ILP solver) at least 5 times (respectively, twice) faster than the previous bests. Indeed, the running time can sometimes be 41 times better. CONCLUSIONS: This paper proposes a new ILP model for the haplotype assembly problem and its all-heterozygous case, respectively. Experiments with both real and simulated datasets show that the new models can be solved within much shorter time by CPLEX than the previous bests. We believe that the models can be used to improve heuristic algorithms as well. PMID- 29504892 TI - Comparing miRNA structure of mirtrons and non-mirtrons. AB - BACKGROUND: MicroRNAs proceeds through the different canonical and non-canonical pathways; the most frequent of the non-canonical ones is the splicing-dependent biogenesis of mirtrons. We compare the mirtrons and non-mirtrons of human and mouse to explore how their maturation appears in the precursor structure around the miRNA. RESULTS: We found the coherence of the overhang lengths what indicates the dependence between the cleavage sites. To explain this dependence we suggest the 2-lever model of the Dicer structure that couples the imprecisions in Drosha and Dicer. Considering the secondary structure of all animal pre-miRNAs we confirmed that single-stranded nucleotides tend to be located near the miRNA boundaries and in its center and are characterized by a higher mutation rate. The 5' end of the canonical 5' miRNA approaches the nearest single-stranded nucleotides what suggests the extension of the loop-counting rule from the Dicer to the Drosha cleavage site. A typical structure of the annotated mirtron pre miRNAs differs from the canonical pre-miRNA structure and possesses the 1- and 2 nt hanging ends at the hairpin base. Together with the excessive variability of the mirtron Dicer cleavage site (that could be partially explained by guanine at its ends inherited from splicing) this is one more evidence for the 2-lever model. In contrast with the canonical miRNAs the mirtrons have higher snp densities and their pre-miRNAs are inversely associated with diseases. Therefore we supported the view that mirtrons are under positive selection while canonical miRNAs are under negative one and we suggested that mirtrons are an intrinsic source of silencing variability which produces the disease-promoting variants. Finally, we considered the interference of the pre-miRNA structure and the U2snRNA:pre-mRNA basepairing. We analyzed the location of the branchpoints and found that mirtron structure tends to expose the branchpoint site what suggests that the mirtrons can readily evolve from occasional hairpins in the immediate neighbourhood of the 3' splice site. CONCLUSION: The miRNA biogenesis manifests itself in the footprints of the secondary structure. Close inspection of these structural properties can help to uncover new pathways of miRNA biogenesis and to refine the known miRNA data, in particular, new non-canonical miRNAs may be predicted or the known miRNAs can be re-classified. PMID- 29504893 TI - Novel read density distribution score shows possible aligner artefacts, when mapping a single chromosome. AB - BACKGROUND: The use of artificial data to evaluate the performance of aligners and peak callers not only improves its accuracy and reliability, but also makes it possible to reduce the computational time. One of the natural ways to achieve such time reduction is by mapping a single chromosome. RESULTS: We investigated whether a single chromosome mapping causes any artefacts in the alignments' performances. In this paper, we compared the accuracy of the performance of seven aligners on well-controlled simulated benchmark data which was sampled from a single chromosome and also from a whole genome. We found that commonly used statistical methods are insufficient to evaluate an aligner performance, and applied a novel measure of a read density distribution similarity, which allowed to reveal artefacts in aligners' performances. We also calculated some interesting mismatch statistics, and constructed mismatch frequency distributions along the read. CONCLUSIONS: The generation of artificial data by mapping of reads generated from a single chromosome to a reference chromosome is justified from the point of view of reducing the benchmarking time. The proposed quality assessment method allows to identify the inherent shortcoming of aligners that are not detected by conventional statistical methods, and can affect the quality of alignment of real data. PMID- 29504894 TI - Isoform specific gene expression analysis of KRAS in the prognosis of lung adenocarcinoma patients. AB - BACKGROUND: Aberrant mutations in KRAS play a critical role in tumor initiation and progression, and are a negative prognosis factor in lung adenocarcinoma (LUAD). RESULTS: Using genomic analysis for K-Ras isoforms (K-Ras4A and K-Ras4B) and large-scale multi-omics data, we inspected the overall survival (OS) and disease-free survival (DFS) of LUAD patients based on the abundance of transcript variants by analyzing RNA expression and somatic mutation data from The Cancer Genome Atlas (n = 516). The expression of the minor transcript K-Ras4A and its proportion were positively correlated with the presence of KRAS mutations in LUAD. We found that both K-Ras4A abundance measures (expression and proportion) have a strong association with poor OS (p = 0.0149 and p = 3.18E-3, respectively) and DFS (p = 3.03E-4 and p = 0.0237, respectively), but only in patients harboring KRAS mutations. A Cox regression analysis showed significant results in groups with low expression (hazard ratio (HR) = 2.533, 95% confidence interval (CI) = 1.380-4.651, p = 2.72E-3) and low proportion (HR = 2.549, 95% CI = 1.387 4.684, p = 2.58E-3) of K-Ras4A. CONCLUSIONS: Based on the above results, we report the possible use of abundance measures for K-Ras4A for predicting the survival of LUAD patients with KRAS mutations. PMID- 29504895 TI - FunGeneNet: a web tool to estimate enrichment of functional interactions in experimental gene sets. AB - BACKGROUND: Estimation of functional connectivity in gene sets derived from genome-wide or other biological experiments is one of the essential tasks of bioinformatics. A promising approach for solving this problem is to compare gene networks built using experimental gene sets with random networks. One of the resources that make such an analysis possible is CrossTalkZ, which uses the FunCoup database. However, existing methods, including CrossTalkZ, do not take into account individual types of interactions, such as protein/protein interactions, expression regulation, transport regulation, catalytic reactions, etc., but rather work with generalized types characterizing the existence of any connection between network members. RESULTS: We developed the online tool FunGeneNet, which utilizes the ANDSystem and STRING to reconstruct gene networks using experimental gene sets and to estimate their difference from random networks. To compare the reconstructed networks with random ones, the node permutation algorithm implemented in CrossTalkZ was taken as a basis. To study the FunGeneNet applicability, the functional connectivity analysis of networks constructed for gene sets involved in the Gene Ontology biological processes was conducted. We showed that the method sensitivity exceeds 0.8 at a specificity of 0.95. We found that the significance level of the difference between gene networks of biological processes and random networks is determined by the type of connections considered between objects. At the same time, the highest reliability is achieved for the generalized form of connections that takes into account all the individual types of connections. By taking examples of the thyroid cancer networks and the apoptosis network, it is demonstrated that key participants in these processes are involved in the interactions of those types by which these networks differ from random ones. CONCLUSIONS: FunGeneNet is a web tool aimed at proving the functionality of networks in a wide range of sizes of experimental gene sets, both for different global networks and for different types of interactions. Using examples of thyroid cancer and apoptosis networks, we have shown that the links over-represented in the analyzed network in comparison with the random ones make possible a biological interpretation of the original gene/protein sets. The FunGeneNet web tool for assessment of the functional enrichment of networks is available at http://www-bionet.sscc.ru/fungenenet/ . PMID- 29504896 TI - Transcriptome analysis reveals mechanisms of geroprotective effects of fucoxanthin in Drosophila. AB - BACKGROUND: We have previously showed that the carotenoid fucoxanthin can increase the lifespan in Drosophila melanogaster and Caenorhabditis elegans. However, the molecular mechanisms of the geroprotective effect of fucoxanthin have not been studied so far. RESULTS: Here, we studied the effects of fucoxanthin on the Drosophila aging process at the molecular and the whole organism levels. At the organismal level, fucoxanthin increased the median lifespan and had a positive effect on fecundity, fertility, intestinal barrier function, and nighttime sleep. Transcriptome analysis revealed 57 differentially expressed genes involved in 17 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. Among the most represented molecular pathways induced by fucoxanthin, a significant portion is related to longevity, including MAPK, mTOR, Wnt, Notch, and Hippo signaling pathways, autophagy, translation, glycolysis, oxidative phosphorylation, apoptosis, immune response, neurogenesis, sleep, and response to DNA damage. CONCLUSIONS: Life-extending effects of fucoxanthin are associated with differential expression of longevity-associated genes. PMID- 29504897 TI - Improving prediction of heterodimeric protein complexes using combination with pairwise kernel. AB - BACKGROUND: Since many proteins become functional only after they interact with their partner proteins and form protein complexes, it is essential to identify the sets of proteins that form complexes. Therefore, several computational methods have been proposed to predict complexes from the topology and structure of experimental protein-protein interaction (PPI) network. These methods work well to predict complexes involving at least three proteins, but generally fail at identifying complexes involving only two different proteins, called heterodimeric complexes or heterodimers. There is however an urgent need for efficient methods to predict heterodimers, since the majority of known protein complexes are precisely heterodimers. RESULTS: In this paper, we use three promising kernel functions, Min kernel and two pairwise kernels, which are Metric Learning Pairwise Kernel (MLPK) and Tensor Product Pairwise Kernel (TPPK). We also consider the normalization forms of Min kernel. Then, we combine Min kernel or its normalization form and one of the pairwise kernels by plugging. We applied kernels based on PPI, domain, phylogenetic profile, and subcellular localization properties to predicting heterodimers. Then, we evaluate our method by employing C-Support Vector Classification (C-SVC), carrying out 10-fold cross-validation, and calculating the average F-measures. The results suggest that the combination of normalized-Min-kernel and MLPK leads to the best F-measure and improved the performance of our previous work, which had been the best existing method so far. CONCLUSIONS: We propose new methods to predict heterodimers, using a machine learning-based approach. We train a support vector machine (SVM) to discriminate interacting vs non-interacting protein pairs, based on informations extracted from PPI, domain, phylogenetic profiles and subcellular localization. We evaluate in detail new kernel functions to encode these data, and report prediction performance that outperforms the state-of-the-art. PMID- 29504898 TI - On Burkholderiales order microorganisms and cystic fibrosis in Russia. AB - BACKGROUND: Microbes infecting cystic fibrosis patients' respiratory tract are important in determining patients' functional status. Representatives of Burkholderiales order are the most dangerous. The goal of our investigation was to reveal the diversity of Burkholderiales, define of their proportion in the microbiome of various parts of respiratory tract and determine the pathogenicity of the main representatives. RESULTS: In more than 500 cystic fibrosis patients, representing all Federal Regions of Russia, 34.0% were infected by Burkholderia cepacia complex (Bcc), 21.0% by Achromobacter spp. and 12.0% by Lautropia mirabilis. B. cenocepacia was the most numerous species among the Bcc (93.0%), and A. ruhlandii was the most numerous among Achromobacter spp. (58.0%). The most abundant genotype in Bcc was sequence type (ST) 709, and in Achromobacter spp. it was ST36. These STs constitute Russian epidemic strains. Whole genome sequencing of strains A. ruhlandii SCCH3:Ach33-1365 ST36 and B. cenocepacia GIMC4560:Bcn122 ST709 revealed huge resistomes and many virulence factors, which may explain the difficulties in eradicating these strains. An experience of less dangerous B. cenocepcia ST710 elimination was described. Massively parallel sequencing of 16S rDNA amplicons, including V1-V4 hypervariable regions, was used to definite "healthy" microbiome characteristics. Analysis of maxillary sinus lavage of 7 patients revealed infection with Proteobacteria of the same ST as pathogens from sputum, suggesting that the maxillary sinus is a source of infection in cystic fibrosis patients. CONCLUSIONS: Characterization of the Russian epidemic bacterial strains in the sputum and sinuses of cystic fibrosis patients have better defined the importance of Burkholderiales bacteria. This information may aid in the development of effective approaches for treatment of this disease. PMID- 29504900 TI - Primary microcephaly case from the Karachay-Cherkess Republic poses an additional support for microcephaly and Seckel syndrome spectrum disorders. AB - BACKGROUND: Primary microcephaly represents an example of clinically and genetically heterogeneous condition. Here we describe a case of primary microcephaly from the Karachay-Cherkess Republic, which was initially diagnosed with Seckel syndrome. CASE PRESENTATION: Clinical exome sequencing of the proband revealed a novel homozygous single nucleotide deletion in ASPM gene, c.1386delC, resulting in preterm termination codon. Population screening reveals allele frequency to be less than 0.005. Mutations in this gene were not previously associated with Seckel syndrome. CONCLUSIONS: Our case represents an additional support for the clinical continuum between Seckel Syndrome and primary microcephaly. PMID- 29504901 TI - Association of cerebrovascular dysfunction with the development of Alzheimer's disease-like pathology in OXYS rats. AB - BACKGROUND: Cerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD): the most common cause of dementia in the elderly. The involvement of neurovasculature disorders in the progression of AD is now increasingly appreciated, but whether they represent initial factors or late stage pathological changes during the disease is unclear. Using senescence accelerated OXYS rats, which simulate key characteristics of sporadic AD, we evaluated contributions of cerebrovascular alterations to the disease development. At preclinical, early, and advanced stages of AD-like pathology, in the hippocampus of OXYS and Wistar (control) rats, we evaluated (i) the blood vessel state by histological and electron-microscopic analyses; (ii) differences in gene expression according to RNA sequencing (RNA-Seq) to identify the metabolic processes and pathways associated with blood vessel function; (iii) the amount of vascular endothelial growth factor (VEGF) by western blot and immunohistochemical analysis. RESULTS: We observed a loss of hippocampal blood vessel density and ultrastructural changes of those blood vessels in OXYS rats at the early stage of AD-like pathology. There were significant alterations in the vessels and downregulation of VEGF with an increased amount of amyloid beta1-42 there at the advanced stage of the disease. According to RNA-Seq data analysis, major alterations in cerebrovascular processes of OXYS rats were associated with blood vessel development, circulatory system processes, the VEGF signaling pathway, and vascular smooth muscle contraction. At preclinical and early stages of the AD-like pathology, these processes were upregulated and then downregulated with age. At the advanced stage in OXYS rats, differentially expressed genes (DEGs) were associated with downregulation of cerebrovascular function as compared to Wistar rats. Among the 46 DEGs at the preclinical stage of the disease, 28 DEGs at the early stage, and among 85 DEGs at the advanced stage, using functional analysis and gene network construction, we identified genes (Nos1, P2rx4, Pla2g6, and Bdkrb2) probably playing a significant role in the development of cerebrovascular dysfunction in OXYS rats. CONCLUSIONS: Changes in expression of the genes functionally associated with cerebrovascular processes already in the early period of life may contribute to the development of AD-like pathology in OXYS rats. PMID- 29504902 TI - TERIUS: accurate prediction of lncRNA via high-throughput sequencing data representing RNA-binding protein association. AB - BACKGROUND: LncRNAs are long regulatory non-coding RNAs, some of which are arguably predicted to have coding potential. Despite coding potential classifiers that utilize ribosome profiling data successfully detected actively translated regions, they are less sensitive to lncRNAs. Furthermore, lncRNA annotation can be susceptible to false positives obtained from 3' untranslated region (UTR) fragments of mRNAs. RESULTS: To lower these limitations in lncRNA annotation, we present a novel tool TERIUS that provides a two-step filtration process to distinguish between bona fide and false lncRNAs. The first step successfully separates lncRNAs from protein-coding genes showing enhanced sensitivity compared to other methods. To eliminate 3'UTR fragments, the second step takes advantage of the 3'UTR-specific association with regulator of nonsense transcripts 1 (UPF1), leading to refined lncRNA annotation. Importantly, TERIUS enabled the detection of misclassified transcripts in published lncRNA annotations. CONCLUSIONS: TERIUS is a robust method for lncRNA annotation, which provides an additional filtration step for 3'UTR fragments. TERIUS was able to successfully re-classify GENCODE and miTranscriptome lncRNA annotations. We believe that TERIUS can benefit construction of extensive and accurate non-coding transcriptome maps in many genomes. PMID- 29504903 TI - HiComet: a high-throughput comet analysis tool for large-scale DNA damage assessment. AB - BACKGROUND: DNA damage causes aging, cancer, and other serious diseases. The comet assay can detect multiple types of DNA lesions with high sensitivity, and it has been widely applied. Although comet assay platforms have improved the limited throughput and reproducibility of traditional assays in recent times, analyzing large quantities of comet data often requires a tremendous human effort. To overcome this challenge, we proposed HiComet, a computational tool that can rapidly recognize and characterize a large number of comets, using little user intervention. RESULTS: We tested HiComet with real data from 35 high throughput comet assay experiments, with over 700 comets in total. The proposed method provided unprecedented levels of performance as an automated comet recognition tool in terms of robustness (measured by precision and recall) and throughput. CONCLUSIONS: HiComet is an automated tool for high-throughput comet assay analysis and could significantly facilitate characterization of individual comets by accelerating its most rate-limiting step. An online implementation of HiComet is freely available at https://github.com/taehoonlee/HiComet/ . PMID- 29504904 TI - Medical genomics at Belyaev Conference - 2017. PMID- 29504899 TI - Candidate SNP markers of reproductive potential are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters. AB - BACKGROUND: The progress of medicine, science, technology, education, and culture improves, year by year, quality of life and life expectancy of the populace. The modern human has a chance to further improve the quality and duration of his/her life and the lives of his/her loved ones by bringing their lifestyle in line with their sequenced individual genomes. With this in mind, one of genome-based developments at the junction of personalized medicine and bioinformatics will be considered in this work, where we used two Web services: (i) SNP_TATA_Comparator to search for alleles with a single nucleotide polymorphism (SNP) that alters the affinity of TATA-binding protein (TBP) for the TATA boxes of human gene promoters and (ii) PubMed to look for retrospective clinical reviews on changes in physiological indicators of reproductive potential in carriers of these alleles. RESULTS: A total of 126 SNP markers of female reproductive potential, capable of altering the affinity of TBP for gene promoters, were found using the two above mentioned Web services. For example, 10 candidate SNP markers of thrombosis (e.g., rs563763767) can cause overproduction of coagulation inducers. In pregnant women, Hughes syndrome provokes thrombosis with a fatal outcome although this syndrome can be diagnosed and eliminated even at the earliest stages of its development. Thus, in women carrying any of the above SNPs, preventive treatment of this syndrome before a planned pregnancy can reduce the risk of death. Similarly, seven SNP markers predicted here (e.g., rs774688955) can elevate the risk of myocardial infarction. In line with Bowles' lifespan theory, women carrying any of these SNPs may modify their lifestyle to improve their longevity if they can take under advisement that risks of myocardial infarction increase with age of the mother, total number of pregnancies, in multiple pregnancies, pregnancies under the age of 20, hypertension, preeclampsia, menstrual cycle irregularity, and in women smokers. CONCLUSIONS: According to Bowles' lifespan theory-which links reproductive potential, quality of life, and life expectancy the above information was compiled for those who would like to reduce risks of diseases corresponding to alleles in own sequenced genomes. Candidate SNP markers can focus the clinical analysis of unannotated SNPs, after which they may become useful for people who would like to bring their lifestyle in line with their sequenced individual genomes. PMID- 29504905 TI - Closha: bioinformatics workflow system for the analysis of massive sequencing data. AB - BACKGROUND: While next-generation sequencing (NGS) costs have fallen in recent years, the cost and complexity of computation remain substantial obstacles to the use of NGS in bio-medical care and genomic research. The rapidly increasing amounts of data available from the new high-throughput methods have made data processing infeasible without automated pipelines. The integration of data and analytic resources into workflow systems provides a solution to the problem by simplifying the task of data analysis. RESULTS: To address this challenge, we developed a cloud-based workflow management system, Closha, to provide fast and cost-effective analysis of massive genomic data. We implemented complex workflows making optimal use of high-performance computing clusters. Closha allows users to create multi-step analyses using drag and drop functionality and to modify the parameters of pipeline tools. Users can also import the Galaxy pipelines into Closha. Closha is a hybrid system that enables users to use both analysis programs providing traditional tools and MapReduce-based big data analysis programs simultaneously in a single pipeline. Thus, the execution of analytics algorithms can be parallelized, speeding up the whole process. We also developed a high-speed data transmission solution, KoDS, to transmit a large amount of data at a fast rate. KoDS has a file transfer speed of up to 10 times that of normal FTP and HTTP. The computer hardware for Closha is 660 CPU cores and 800 TB of disk storage, enabling 500 jobs to run at the same time. CONCLUSIONS: Closha is a scalable, cost-effective, and publicly available web service for large-scale genomic data analysis. Closha supports the reliable and highly scalable execution of sequencing analysis workflows in a fully automated manner. Closha provides a user-friendly interface to all genomic scientists to try to derive accurate results from NGS platform data. The Closha cloud server is freely available for use from http://closha.kobic.re.kr/ . PMID- 29504906 TI - Features of the organization of bread wheat chromosome 5BS based on physical mapping. AB - BACKGROUND: The IWGSC strategy for construction of the reference sequence of the bread wheat genome is based on first obtaining physical maps of the individual chromosomes. Our aim is to develop and use the physical map for analysis of the organization of the short arm of wheat chromosome 5B (5BS) which bears a number of agronomically important genes, including genes conferring resistance to fungal diseases. RESULTS: A physical map of the 5BS arm (290 Mbp) was constructed using restriction fingerprinting and LTC software for contig assembly of 43,776 BAC clones. The resulting physical map covered ~ 99% of the 5BS chromosome arm (111 scaffolds, N50 = 3.078 Mb). SSR, ISBP and zipper markers were employed for anchoring the BAC clones, and from these 722 novel markers were developed based on previously obtained data from partial sequencing of 5BS. The markers were mapped using a set of Chinese Spring (CS) deletion lines, and F2 and RICL populations from a cross of CS and CS-5B dicoccoides. Three approaches have been used for anchoring BAC contigs on the 5BS chromosome, including clone-by-clone screening of BACs, GenomeZipper analysis, and comparison of BAC-fingerprints with in silico fingerprinting of 5B pseudomolecules of T. dicoccoides. These approaches allowed us to reach a high level of BAC contig anchoring: 96% of 5BS BAC contigs were located on 5BS. An interesting pattern was revealed in the distribution of contigs along the chromosome. Short contigs (200-999 kb) containing markers for the regions interrupted by tandem repeats, were mainly localized to the 5BS subtelomeric block; whereas the distribution of larger 1000 3500 kb contigs along the chromosome better correlated with the distribution of the regions syntenic to rice, Brachypodium, and sorghum, as detected by the Zipper approach. CONCLUSION: The high fingerprinting quality, LTC software and large number of BAC clones selected by the informative markers in screening of the 43,776 clones allowed us to significantly increase the BAC scaffold length when compared with the published physical maps for other wheat chromosomes. The genetic and bioinformatics resources developed in this study provide new possibilities for exploring chromosome organization and for breeding applications. PMID- 29504909 TI - Introducing difference recurrence relations for faster semi-global alignment of long sequences. AB - BACKGROUND: The read length of single-molecule DNA sequencers is reaching 1 Mb. Popular alignment software tools widely used for analyzing such long reads often take advantage of single-instruction multiple-data (SIMD) operations to accelerate calculation of dynamic programming (DP) matrices in the Smith-Waterman Gotoh (SWG) algorithm with a fixed alignment start position at the origin. Nonetheless, 16-bit or 32-bit integers are necessary for storing the values in a DP matrix when sequences to be aligned are long; this situation hampers the use of the full SIMD width of modern processors. RESULTS: We proposed a faster semi global alignment algorithm, "difference recurrence relations," that runs more rapidly than the state-of-the-art algorithm by a factor of 2.1. Instead of calculating and storing all the values in a DP matrix directly, our algorithm computes and stores mainly the differences between the values of adjacent cells in the matrix. Although the SWG algorithm and our algorithm can output exactly the same result, our algorithm mainly involves 8-bit integer operations, enabling us to exploit the full width of SIMD operations (e.g., 32) on modern processors. We also developed a library, libgaba, so that developers can easily integrate our algorithm into alignment programs. CONCLUSIONS: Our novel algorithm and optimized library implementation will facilitate accelerating nucleotide long-read analysis algorithms that use pairwise alignment stages. The library is implemented in the C programming language and available at https://github.com/ocxtal/libgaba . PMID- 29504907 TI - HK3 overexpression associated with epithelial-mesenchymal transition in colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is a common cancer worldwide. The main cause of death in CRC includes tumor progression and metastasis. At molecular level, these processes may be triggered by epithelial-mesenchymal transition (EMT) and necessitates specific alterations in cell metabolism. Although several EMT related metabolic changes have been described in CRC, the mechanism is still poorly understood. RESULTS: Using CrossHub software, we analyzed RNA-Seq expression profile data of CRC derived from The Cancer Genome Atlas (TCGA) project. Correlation analysis between the change in the expression of genes involved in glycolysis and EMT was performed. We obtained the set of genes with significant correlation coefficients, which included 21 EMT-related genes and a single glycolytic gene, HK3. The mRNA level of these genes was measured in 78 paired colorectal cancer samples by quantitative polymerase chain reaction (qPCR). Upregulation of HK3 and deregulation of 11 genes (COL1A1, TWIST1, NFATC1, GLIPR2, SFPR1, FLNA, GREM1, SFRP2, ZEB2, SPP1, and RARRES1) involved in EMT were found. The results of correlation study showed that the expression of HK3 demonstrated a strong correlation with 7 of the 21 examined genes (ZEB2, GREM1, TGFB3, TGFB1, SNAI2, TWIST1, and COL1A1) in CRC. CONCLUSIONS: Upregulation of HK3 is associated with EMT in CRC and may be a crucial metabolic adaptation for rapid proliferation, survival, and metastases of CRC cells. PMID- 29504908 TI - Exome analysis of carotid body tumor. AB - BACKGROUND: Carotid body tumor (CBT) is a form of head and neck paragangliomas (HNPGLs) arising at the bifurcation of carotid arteries. Paragangliomas are commonly associated with germline and somatic mutations involving at least one of more than thirty causative genes. However, the specific functionality of a number of these genes involved in the formation of paragangliomas has not yet been fully investigated. METHODS: Exome library preparation was carried out using Nextera(r) Rapid Capture Exome Kit (Illumina, USA). Sequencing was performed on NextSeq 500 System (Illumina). RESULTS: Exome analysis of 52 CBTs revealed potential driver mutations (PDMs) in 21 genes: ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, SDHA, SDHB, SDHC, SDHD, SETD2, TP53BP1, TP53BP2, and TP53I13. In many samples, more than one PDM was identified. There are also 41% of samples in which we did not identify any PDM; in these cases, the formation of CBT was probably caused by the cumulative effect of several not highly pathogenic mutations. Estimation of average mutation load demonstrated 6-8 mutations per megabase (Mb). Genes with the highest mutation rate were identified. CONCLUSIONS: Exome analysis of 52 CBTs for the first time revealed the average mutation load for these tumors and also identified potential driver mutations as well as their frequencies and co-occurrence with the other PDMs. PMID- 29504910 TI - BRCA-Pathway: a structural integration and visualization system of TCGA breast cancer data on KEGG pathways. AB - BACKGROUND: Bioinformatics research for finding biological mechanisms can be done by analysis of transcriptome data with pathway based interpretation. Therefore, researchers have tried to develop tools to analyze transcriptome data with pathway based interpretation. Over the years, the amount of omics data has become huge, e.g., TCGA, and the data types to be analyzed have come in many varieties, including mutations, copy number variations, and transcriptome. We also need to consider a complex relationship with regulators of genes, particularly Transcription Factors(TF). However, there has not been a system for pathway based exploration and analysis of TCGA multi-omics data. In this reason, We have developed a web based system BRCA-Pathway to fulfill the need for pathway based analysis of TCGA multi-omics data. RESULTS: BRCA-Pathway is a structured integration and visual exploration system of TCGA breast cancer data on KEGG pathways. For data integration, a relational database is designed and used to integrate multi-omics data of TCGA-BRCA, KEGG pathway data, Hallmark gene sets, transcription factors, driver genes, and PAM50 subtypes. For data exploration, multi-omics data such as SNV, CNV and gene expression can be visualized simultaneously in KEGG pathway maps, together with transcription factors-target genes (TF-TG) correlation and relationships among cancer driver genes. In addition, 'Pathways summary' and 'Oncoprint' with mutual exclusivity sort can be generated dynamically with a request by the user. Data in BRCA-Pathway can be downloaded by REST API for further analysis. CONCLUSIONS: BRCA-Pathway helps researchers navigate omics data towards potentially important genes, regulators, and discover complex patterns involving mutations, CNV, and gene expression data of various patient groups in the biological pathway context. In addition, mutually exclusive genomic alteration patterns in a specific pathway can be generated. BRCA-Pathway can provide an integrative perspective on the breast cancer omics data, which can help researchers discover new insights on the biological mechanisms of breast cancer. PMID- 29504912 TI - Analysis of microbial sequences in plasma cell-free DNA for early-onset breast cancer patients and healthy females. AB - BACKGROUND: Cell-free circulating DNA (cfDNA) is becoming a useful biopsy for noninvasive diagnosis of diseases. Microbial sequences in plasma cfDNA may provide important information to improve prognosis and treatment. We have developed a stringent method to identify microbial species via microbial cfDNA in the blood plasma of early-onset breast cancer (EOBC) patients and healthy females. Empirically, microbe-originated sequence reads were identified by mapping non-human PE reads in cfDNA libraries to microbial databases. Those mapped concordantly to unique microbial species were assembled into contigs, which were subsequently aligned to the same databases. Microbial species uniquely aligned were identified and compared across all individuals on MCRPM (Microbial CfDNA Reads Per Million quality PE reads) basis. RESULTS: The predominant microbial cfDNAs in all plasma samples examined are originated from bacteria and these bacteria were limited to only a few genera. Among those, Acinetobacter johnsonii XBB1 and low levels of Mycobacterium spp. were commonly found in all healthy females, but also present in an EOBC patient. Compared to those in healthy counterparts, bacterial species in EOBC patients are more diverse and more likely to present at high levels. Among these three EOBC patients tested, a patient who has record high titer (2,724 MCRPM) of Pseudomonas mendocina together with 8.82 MCRPM of Pannonibacter phragmitetus has passed away; another patient infected by multiple Sphingomonas species remains alive; while the third patient who has similar microbial species (Acinetobacter johnsonii XBB1) commonly seen in normal controls is having a normal life. CONCLUSIONS: Our preliminary data on the profiles of microbial cfDNA sequences suggested that it may have some prognostic value in cancer patients. Validation in larger number of patients is warranted. PMID- 29504911 TI - Consequences of early life stress on genomic landscape of H3K4me3 in prefrontal cortex of adult mice. AB - BACKGROUND: Maternal separation models in rodents are widely used to establish molecular mechanisms underlying prolonged effects of early life adversity on neurobiological and behavioral outcomes in adulthood. However, global epigenetic signatures following early life stress in these models remain unclear. RESULTS: In this study, we carried out a ChIP-seq analysis of H3K4 trimethylation profile in the prefrontal cortex of adult male mice with a history of early life stress. Two types of stress were used: prolonged separation of pups from their mothers (for 3 h once a day, maternal separation, MS) and brief separation (for 15 min once a day, handling, HD). Adult offspring in the MS group demonstrated reduced locomotor activity in the open field test accompanied by reduced exploratory activity, while the HD group showed decreased anxiety-like behavior only. In a group of maternal separation, we have found a small number (45) of slightly up regulated peaks, corresponding to promoters of 70 genes, while no changes were observed in a group of handling. Among the genes whose promoters have differential enrichment of H3K4me3, the most relevant ones participate in gene expression regulation, modulation of chromatin structure and mRNA processing. For two genes, Ddias and Pip4k2a, increased H3K4me3 levels were associated with the increased mRNA expression in MS group. CONCLUSION: The distribution of H3K4me3 in prefrontal cortex showed relatively low variability across all individuals, and only some subtle changes were revealed in mice with a history of early life stress. It is possible that the observed long-lasting behavioral alterations induced by maternal separation are mediated by other epigenetic mechanisms, or other brain structures are responsible for these effects. PMID- 29504913 TI - Circadian succession of molecular processes in living tissues. AB - BACKGROUND: Oscillations of different origin, period and amplitude play an important role in the regulation of cellular processes. Most widely studied is the circadian or approximately daily variation in gene expression activity. Timing of gene expression is controlled by internal molecular clock keeping steady periodic expression. In this study, we shift attention towards a broad range of periodically expressed genes involved in multiple cellular functions which may or may not be under direct control of the intrinsic circadian clock. Are all molecular functions represented in expressed genes at all times? Alternatively, are different molecular functions performed at different times? Is there a pattern of succession for molecular processes and functions throughout their daily activity period? RESULTS: To answer these questions, we re-analyzed a number of mouse circadian gene expression data available from public sources. These data represent the normal function of metabolically active peripheral tissues (white adipose tissue, brown adipose tissue, liver). We applied novel methods for the estimation of confidence in phase assignment to identify groups of synchronous genes peaking at the same time regardless of the amplitude or the absolute intensity of expression. Each synchronous group has been annotated to identify Gene Ontology (GO) terms and molecular pathways. Our analysis identified molecular functions specific to a particular time of the day in different tissues. CONCLUSION: Improved methodology for datamining allowed for the discovery of functions and biological pathways in groups of genes with synchronized peak expression time. In particular, such functions as oxidative phase of energy metabolism, DNA repair, mRNA processing, lipid biosynthesis and others are separated in time. This timewise compartmentalization is important for understanding the cellular circuitry and can be used to optimize the time of intervention with drug or genome medication. PMID- 29504915 TI - Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks. AB - BACKGROUND: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. RESULTS: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension - 713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system. CONCLUSIONS: The application of methods of reconstruction and analysis of gene networks is a productive tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance to the comorbid condition of asthma and hypertension was employed that resulted in prediction of 10 genes, playing the key role in the development of the comorbid condition. The results can be utilised to plan experiments for identification of novel candidate genes along with searching for novel pharmacological targets. PMID- 29504914 TI - Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complicates its analysis with conventional methods. METHODS: We conducted next-generation sequencing (NGS) in a cohort of 89 adult patients negative for p.Phe508del homozygosity. Complete clinical and demographic information were available for 84 patients. RESULTS: By combining MLPA with NGS, we identified disease-causing alleles in all the CF patients. Importantly, in 10% of cases, standard bioinformatics pipelines were inefficient in identifying causative mutations. Class IV-V mutations were observed in 38 (45%) cases, predominantly ones with pancreatic sufficient CF disease; rest of the patients had Class I-III mutations. Diabetes was seen only in patients homozygous for class I-III mutations. We found that 12% of the patients were heterozygous for more than two pathogenic CFTR mutations. Two patients were observed with p.[Arg1070Gln, Ser466*] complex allele which was associated with milder pulmonary obstructions (FVC 107 and 109% versus 67%, CI 95%: 63-72%; FEV 90 and 111% versus 47%, CI 95%: 37-48%). For the first time p.[Phe508del, Leu467Phe] complex allele was reported, observed in four patients (5%). CONCLUSION: NGS can be a more information-gaining technology compared to standard methods. Combined with its equivalent diagnostic performance, it can therefore be implemented in the clinical practice, although careful validation is still required. PMID- 29504916 TI - Cumulative prognostic power of laminin genes in colorectal cancer. AB - BACKGROUND: Laminins are a major family of extracellular matrix proteins and the main component of basement membranes. Laminins are involved in many if not all stages of cancer progression, and expression of laminin genes has prognostic value in various types of cancer, including colorectal. Only single laminin genes or components of a single laminin trimer with significant differential expression have been regarded as potential biomarkers to date. RESULTS: Here we compared prognostic power of classifiers constructed from sets of laminin genes with that of any single laminin gene. The analysis showed that cumulative prognostic power of sets of laminin genes was higher and was achieved already with pairs and triples of the genes. Interestingly, components of the pairs and the triples did not belong to any known laminin trimer, but, taken together with the gene weights, suggested higher LAMA4/LAMA5 expression ratio in patients with poor prognosis. CONCLUSIONS: Analysis of the laminin expression profile rather than expression of the single genes or components of laminin trimers is useful for colorectal cancer prognosis in patients. High LAMA4/LAMA5 ratio is associated with increased permeability of basement membranes suggesting that basement membranes produced by colorectal tumors might be an important hindrance to their own dissemination in patients. PMID- 29504917 TI - Capturing alternative secondary structures of RNA by decomposition of base pairing probabilities. AB - BACKGROUND: It is known that functional RNAs often switch their functions by forming different secondary structures. Popular tools for RNA secondary structures prediction, however, predict the single 'best' structures, and do not produce alternative structures. There are bioinformatics tools to predict suboptimal structures, but it is difficult to detect which alternative secondary structures are essential. RESULTS: We proposed a new computational method to detect essential alternative secondary structures from RNA sequences by decomposing the base-pairing probability matrix. The decomposition is calculated by a newly implemented software tool, RintW, which efficiently computes the base pairing probability distributions over the Hamming distance from arbitrary reference secondary structures. The proposed approach has been demonstrated on ROSE element RNA thermometer sequence and Lysine RNA ribo-switch, showing that the proposed approach captures conformational changes in secondary structures. CONCLUSIONS: We have shown that alternative secondary structures are captured by decomposing base-paring probabilities over Hamming distance. Source code is available from http://www.ncRNA.org/RintW . PMID- 29504918 TI - Genomics at Belyaev conference - 2017. PMID- 29504919 TI - Computational master-regulator search reveals mTOR and PI3K pathways responsible for low sensitivity of NCI-H292 and A427 lung cancer cell lines to cytotoxic action of p53 activator Nutlin-3. AB - BACKGROUND: Small molecule Nutlin-3 reactivates p53 in cancer cells by interacting with the complex between p53 and its repressor Mdm-2 and causing an increase in cancer cell apoptosis. Therefore, Nutlin-3 has potent anticancer properties. Clinical and experimental studies of Nutlin-3 showed that some cancer cells may lose sensitivity to this compound. Here we analyze possible mechanisms for insensitivity of cancer cells to Nutlin-3. METHODS: We applied upstream analysis approach implemented in geneXplain platform ( genexplain.com ) using TRANSFAC(r) database of transcription factors and their binding sites in genome and using TRANSPATH(r) database of signal transduction network with associated software such as MatchTM and Composite Module Analyst (CMA). RESULTS: Using genome-wide gene expression profiling we compared several lung cancer cell lines and showed that expression programs executed in Nutlin-3 insensitive cell lines significantly differ from that of Nutlin-3 sensitive cell lines. Using artificial intelligence approach embed in CMA software, we identified a set of transcription factors cooperatively binding to the promoters of genes up-regulated in the Nutlin-3 insensitive cell lines. Graph analysis of signal transduction network upstream of these transcription factors allowed us to identify potential master regulators responsible for maintaining such low sensitivity to Nutlin-3 with the most promising candidate mTOR, which acts in the context of activated PI3K pathway. These finding were validated experimentally using an array of chemical inhibitors. CONCLUSIONS: We showed that the Nutlin-3 insensitive cell lines are actually highly sensitive to the dual PI3K/mTOR inhibitor NVP-BEZ235, while no responding to either PI3K -specific LY294002 nor Bcl-XL specific 2,3-DCPE compounds. PMID- 29504920 TI - Reclassification of Arthrobacter nasiphocae (Collins et al. 2002) as Falsarthrobacter nasiphocae gen. nov., comb. nov. AB - The original description of Arthrobacter nasiphocae M597/99/10T demonstrated that it is distantly related to the type species of the genus Arthrobacter, Arthrobacter globiformis, and that this phylogenetic relationship is reflected by the distinct peptidoglycan type [Lys-Ala2-Gly2-3-Ala(Gly)] and the features of the quinone system, which is composed of menaquinones MK-9(H2) and MK-8(H2). Here, we report a re-evaluation of the taxonomic status of A. nasiphocae. Phylogenetically, it was observed to be only distantly related to the genus Arthrobacter and to the type species of related genera. Re-analysis confirmed the quinone system menaquinones MK-9(H2) and MK-8(H2) in A. nasiphocae. Analysis of cell polar lipids showed a profile consisting of the predominant lipids diphosphatidylglycerol, phosphatidylglycerol, dimannosylglyceride, an unidentified phospholipid and an unidentified aminophosphoglycolipid, and several minor unidentified lipids. This profile clearly is different from that of Arthrobacter species. The cell fatty acid profile also showed characteristics that distinguished A. nasiphocae from Arthrobacter species. The phylogenetic distance of A. nasiphocae from any type species of genera within the family Micrococcaceae and the distinct chemotaxonomic traits warrant the reclassification of A. nasiphocae within a novel genus, for which we propose the name Falsarthrobacter nasiphocae gen. nov., comb. nov. The type strain is M597/99/10T (=CCUG 42953T=CIP 107054T=DSM 13988T=JCM 11677T). PMID- 29504921 TI - Aestuariibius insulae gen. nov., sp. nov., isolated from a tidal flat sediment. AB - A Gram-stain-negative, non-motile and ovoid or rod-shaped bacterial strain, DBTF 13T, which was isolated from a tidal flat sediment of the Yellow Sea in South Korea, was characterized taxonomically. Strain DBTF-13T grew optimally at 25-30 degrees C and pH 7.0-8.0, and in the presence of 2.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences revealed that strain DBTF-13T formed an evolutionary lineage independent of other genera, including the genera Pseudooctadecabacter and Octadecabacter. Strain DBTF-13T exhibited 16S rRNA gene sequence similarity values of 96.9 % to the type strain of Pseudooctadecabacter jejudonensis, and of 95.8-96.5 % to the type strains of Octadecabacter species. Strain DBTF-13T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c and C16 : 0 as the major fatty acids. The major polar lipids of strain DBTF-13T were phosphatidylcholine, phosphatidylglycerol, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain DBTF-13T was 61.6 mol%. The chemotaxonomic data and other differential phenotypic properties made it reasonable to differentiate strain DBTF-13T from the genera Pseudooctadecabacter and Octadecabacter. On the basis of the data presented, strain DBTF-13T constitutes a new genus and species within the class Alphaproteobacteria, for which the name Aestuariibius insulae gen. nov., sp. nov. is proposed. The type strain is DBTF-13T (=KACC 19432T=NBRC 113038T). PMID- 29504922 TI - Evaluation of in-vitro antimicrobial activity of Artemisia apiacea H. and Scutellaria baicalensis G. extracts. AB - PURPOSE: In traditional Korean medicine, Artemisia apiacea H. (ART) and Scutellaria baicalensis G. (SCU) are combined for the treatment of malaria and other malaria-like diseases. Because SCU is well-known as an antibacterial agent, the antimicrobial effect of a mixture of ART and SCU was investigated. METHODOLOGY: Plant samples were purchased from Kyungdong mart and extracted with 70 % ethanol. The in vitro antimicrobial activity of ART and SCU against pathogenic fungi (Aspergillus niger, Aspergillus oryzae, Candida albicans, Candida tropicalis and Candida glabrata), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) was evaluated using a broth microdilution assay, modified-disc diffusion and agar dilution methods with further CH2Cl2 fractionated ART, SCU and a mixture of ART/SCU (at a ratio of 3 : 5) (THAN-1). RESULTS: ART and SCU were effective against A. niger, C. albicans, B. subtilis and S. aureus. The range of minimum inhibitory concentration (MIC) values was 0.03125 to 4 mg ml-1 in the ART and SCU treatments. ART exhibited stronger activity than SCU. Interestingly, a 3 : 5 ratio mixture of ART and SCU (THAN-1) showed stronger antimicrobial activity than ART or SCU used individually. CONCLUSION: A treatment using a mixture of herbs such as THAN-1 would be useful in the suppression of the growth of pathogenic bacterial and fungal strains. PMID- 29504923 TI - Deinococcus lacus sp. nov., a gamma radiation-resistant bacterium isolated from an artificial freshwater pond. AB - A Gram-stain-negative, pink-coloured, non-motile and gamma radiation-resistant bacterium, designated strain IMCC1711T, was isolated from a freshwater sample collected from an artificial pond (Inkyong Pond). The 16S rRNA gene sequence analysis showed that strain IMCC1711T was most closely related to Deinococcus piscis 3axT (94.2 %) and formed a robust phylogenetic clade with other species of the genus Deinococcus. Optimal growth of strain MCC1711T was observed at 25 degrees C and pH 7.0 without NaCl. Strain IMCC1711T exhibited high resistance to gamma radiation. The DNA G+C content of strain IMCC1711T was 59.1 mol% and MK-8 was the predominant isoprenoid quinone. Major fatty acid constituents of the strain were C17 : 1omega8c, C16 : 0, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) and C15 : 1omega6c. The major polar lipids constituted phosphatidylethanolamine, one unidentified phosphoglycolipid and two unidentified glycolipids. On the basis of taxonomic data obtained in this study, it was concluded that strain IMCC1711T represented a novel species of the genus Deinococcus, for which the name Deinococcus lacus sp. nov. is proposed. The type strain of Deinococcus lacus is IMCC1711T (KCTC 52494T=KACC 18979T=NBRC 112440T). PMID- 29504924 TI - Role of p53/NF-kappaB functional balance in respiratory syncytial virus-induced inflammation response. AB - The interplay between respiratory syncytial virus (RSV) and the p53 pathway has only been reported in a limited number of studies, yet the underlying abrogation mechanisms of p53 activity during the time course of infection, possibly involving viral proteins, remained unclear. Here, we demonstrate that RSV infection impairs global p53 transcriptional activity, notably via its proteasome dependent degradation at late stages of infection. We also demonstrate that NS1 and NS2 contribute to the abrogation of p53 activity, and used different experimental strategies (e.g. siRNA, small molecules) to underline the antiviral contribution of p53 in the context of RSV infection. Notably, our study highlights a strong RSV-induced disequilibrium of the p53/NF-kappaB functional balance, which appears to contribute to the up-regulation of the expression of several proinflammatory cytokines and chemokines. PMID- 29504925 TI - The Gram-positive model organism Bacillus subtilis does not form microscopically detectable cardiolipin-specific lipid domains. AB - Rather than being homogenous diffusion-dominated structures, biological membranes can exhibit areas with distinct composition and characteristics, commonly termed as lipid domains. Arguably the most comprehensively studied examples in bacteria are domains formed by cardiolipin, which have been functionally linked to protein targeting, the cell division process and the mode of action of membrane-targeting antimicrobials. Cardiolipin domains were originally identified in the Gram negative model organism Escherichia coli based on preferential staining by the fluorescent membrane dye nonylacridine orange (NAO), and later reported to also exist in other Gram-negative and -positive bacteria. Recently, the lipid specificity of NAO has been questioned based on studies conducted in E. coli. This prompted us to reanalyse cardiolipin domains in the Gram-positive model organism Bacillus subtilis. Here we show that logarithmically growing B. subtilis does not form microscopically detectable cardiolipin-specific lipid domains, and that NAO is not a specific stain for cardiolipin in this organism. PMID- 29504926 TI - Whole-genome sequencing reveals that Shewanella haliotis Kim et al. 2007 can be considered a later heterotypic synonym of Shewanella algae Simidu et al. 1990. AB - Previously, experimental DNA-DNA hybridization (DDH) between Shewanellahaliotis JCM 14758T and Shewanellaalgae JCM 21037T had suggested that the two strains could be considered different species, despite minimal phenotypic differences. The recent isolation of Shewanella sp. MN-01, with 99 % 16S rRNA gene identity to S. algae and S. haliotis, revealed a potential taxonomic problem between these two species. In this study, we reassessed the nomenclature of S. haliotis and S. algae using available whole-genome sequences. The whole-genome sequence of S. haliotis JCM 14758T and ten S. algae strains showed >=97.7 % average nucleotide identity and >78.9 % digital DDH, clearly above the recommended species thresholds. According to the rules of priority and in view of the results obtained, S. haliotis is to be considered a later heterotypic synonym of S. algae. Because the whole-genome sequence of Shewanella sp. strain MN-01 shares >99 % ANI with S. algae JCM 14758T, it can be confidently identified as S. algae. PMID- 29504927 TI - Role of CovR phosphorylation in gene transcription in Streptococcus mutans. AB - Streptococcus mutans, the primary aetiological agent of dental caries, is one of the major bacteria of the human oral cavity. The pathogenicity of this bacterium is attributed not only to the expression of virulence factors, but also to its ability to respond and adapt rapidly to the ever-changing conditions of the oral cavity. The two-component signal transduction system (TCS) CovR/S plays a crucial role in virulence and stress response in many streptococci. Surprisingly, in S. mutans the response regulator CovR appears to be an orphan, as the cognate sensor kinase, CovS, is absent in all the strains. We found that acetyl phosphate, an intracellular phosphodonor molecule known to act in signalling, might play a role in CovR phosphorylation in vivo. We also found that in vitro, upon phosphorylation by potassium phosphoramide (a high-energy phophodonor) CovR formed a dimer and showed altered electrophoretic mobility. As expected, we found that the conserved aspartic acid residue at position 53 (D53) was the site of phosphorylation, since neither phosphorylation nor dimerization was seen when an alanine-substituted CovR mutant (D53A) was used. Surprisingly, we found that the ability of CovR to act as a transcriptional regulator does not depend upon its phosphorylation status, since the D53A mutant behaved similarly to the wild-type protein in both in vivo and in vitro DNA-binding assays. This unique phosphorylation-mediated inhibition of CovR function in S. mutans sheds light on an unconventional mechanism of the signal transduction pathway. PMID- 29504928 TI - Hymenobacter rivuli sp. nov., isolated from a freshwater creek. AB - A bright-red bacterial strain, TAPP3T, was isolated from a freshwater sample taken from the Wanan Creek in Taiwan. Phylogenetic analyses based on 16S rRNA gene sequences revealed that TAPP3T represented a member of the genus Hymenobacter and showed the highest levels of sequence similarity to Hymenobacter ginsengisoli DCY57T (97.0 %) and Hymenobacter marinus KJ035T (96.5 %) and less than 96.2 % with other members of the genus. Cells of TAPP3T were Gram-stain negative, aerobic, motile by gliding, rods that were surrounded by a thick capsule. Growth occurred at 20-35 degrees C (optimum, 25-30 degrees C), at pH 6.5-7.5 (optimum, pH 7) and with 0-1 % NaCl (optimum, 0 %). TAPP3T contained iso C15 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 1omega5c as the predominant fatty acids. The major isoprenoid quinone was MK-7. The polar lipid profile consisted of phosphatidylethanolamine, six uncharacterized aminophospholipids and four uncharacterized lipids. The major polyamine was homospermidine. The DNA G+C content of the genomic DNA was 62.8 mol%. The DNA-DNA relatedness of TAPP3T with respect to Hymenobacter ginsengisoli DCY57T was less than 40 %. On the basis of the phylogenetic inference and phenotypic data, TAPP3T should be classified as representing a novel species, for which the name Hymenobacter rivuli sp. nov. is proposed. The type strain is TAPP3T (=BCRC 80979T=LMG 29559T=KCTC 52236T). PMID- 29504929 TI - Pseudomaribius aestuariivivens gen. nov., sp. nov., isolated from a tidal flat sediment. AB - A Gram-stain-negative, non-motile and ovoid or rod-shaped bacterial strain, DBTF 15T, was isolated from a tidal flat sediment on the Yellow Sea in South Korea. Strain DBTF-15T grew optimally at 25-30 degrees C, at pH 7.0-8.0 and in the presence of 2.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences revealed that strain DBTF-15T joined the cluster comprising the type strains of species of the genus Palleronia. Strain DBTF-15T exhibited higher 16S rRNA gene sequence similarity values to the type strains (96.5-96.7 %) of Maribius pelagius and Maribius salinus than to those (94.6-96.1 %) of the three species of the genus Palleronia. It exhibited 16S rRNA gene sequence similarity values of less than 93.9 % to the type strains of the other recognized species. Strain DBTF-15T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids of strain DBTF-15T were phosphatidylcholine, phosphatidylglycerol and one unidentified aminolipid. The DNA G+C content of strain DBTF-15T was 68.7 mol%. The chemotaxonomic data and other differential phenotypic properties made it possible to distinguish strain DBTF-15T from the genera Maribius and Palleronia. On the basis of the data presented, strain DBTF-15T constitutes a novel genus and species within the class Alphaproteobacteria, for which the name Pseudomaribius aestuariivivens gen. nov., sp. nov. is proposed. The type strain is DBTF-15T (=KACC 19431T=NBRC 113039T). PMID- 29504930 TI - Changes in antimicrobial resistance of clinical isolates of Acinetobacter baumannii group isolated in Greece, 2010-2015. AB - In recent years, hospitals in southeastern Europe have faced dramatically high rates of antibiotic-resistant Acinetobacter baumannii. We analysed the evolution of resistance among clinical isolates of A. baumannii group obtained from nine tertiary hospitals throughout Greece over 6 years (2010-2015). Identification and antimicrobial susceptibility testing were performed using Vitek 2 or Microscan walkaway automated systems. Between 2010 and 2015, resistance to ampicillin/sulbactam increased from 46.2 to 88.2 % (P=0.021), resistance to gentamicin increased from 69.3 to 86.4 % (P=0.014) and resistance to tobramycin increased from 59.8 to 76.8 % (P=0.011). Imipenem resistance rates were consistently very high, ranging from 90.3 % in 2010 to 94.5 % in 2015 (P=0.198), while meropenem resistance rates increased from 82.6 % in 2010 to 94.8 % in 2015 (P=0.006). Resistance rates to trimethoprim/sulfamethoxazole showed a remarkable decreasing trend, declining from 90.2 % in 2010 to 69.1 % in 2015 (P=0.035). These evolutions render the treatment of A. baumannii infections particularly challenging and underline the need for enhanced infection control measures. PMID- 29504931 TI - Aestuariimonas insulae gen. nov., sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated OITF-44T, was isolated from a tidal flat in Oido, an island of the Republic of Korea. Strain OITF-44T grew optimally at 25 degrees C and in the presence of 2.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences revealed that strain OITF-44T formed an independent lineage within the clade comprising the genera Lutimonas, Taeania, Actibacter and Namhaeicola. The novel strain exhibited 16S rRNA gene sequence similarity values of 93.9-95.7 % to the type strains of the species of the genera Lutimonas, Taeania, Actibacter and Namhaeicola, and of less than 93.5 % to the type strains of other recognized species. Strain OITF-44T contained MK-6 as the predominant menaquinone and iso C15 : 0, iso-C15 : 1 G, iso-C16 : 1 H and iso-C16 : 0 3-OH as the major fatty acids. The major polar lipids of strain OITF-44T were phosphatidylethanolamine, one unidentified lipid and one unidentified phospholipid. The DNA G+C content of strain OITF-44T was 33.9 mol%. The chemotaxonomic data and other differential phenotypic properties made it reasonable to distinguish strain OITF-44T from the type strains of the type species of the genera Lutimonas, Taeania, Actibacter and Namhaeicola. On the basis of the data presented here, strain OITF-44T is considered to constitute a new genus and species within the family Flavobacteriaceae, for which the name Aestuariimonas insulae gen. nov., sp. nov. is proposed. The type strain of Aestuariimonas insulae is OITF-44T (=KACC 19569T=KCTC 62197T=DSM 105891T=NBRC 113118T). PMID- 29504932 TI - The inhibition of Caco-2 proliferation by astaxanthin from Xanthophyllomyces dendrorhous. AB - PURPOSE: To investigate the efficiency of natural astaxanthin that has been extracted from Xanthophyllomyces dendrorhous in inhibiting the proliferation and viability of colorectal adenocarcinoma cell line (Caco-2; colon cancer cells). METHODOLOGY: Caco-2 cells and normal human oralkeratinocytes (NOKs) were treated with different concentrations of extracted astaxanthin, ranging from 0.075 to 10 mg ml-1, for 24, 48 and 72 h. The number of cells was determined via MTS assay and the proliferating cells were investigated by bromodeoxyuridine (BrdU) assay.Results/Key findings. Of the Caco-2 cells, 30-50 % remained viable, while the NOKs showed 110-120 % survival when treated with 5 mg ml-1 astaxanthin. The Caco-2 cells showed distinct structural shrinkage when treated with the same concentration of astaxanthin. Fluorescent labelling of the DNA of the proliferative cells with BrdU showed a significant decrease in the number of the proliferative Caco-2 cells when the concentration of astaxanthin was increased to 5 mg ml-1. CONCLUSION: The natural astaxanthin from X. dendrorhous, at an appropriate concentration, is effective in terminating the viability of, or retarding the proliferative activity of, Caco-2 cells, without harmful effects on NOKs. PMID- 29504933 TI - SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation. AB - Glycogen synthase kinase 3 (GSK3) is a critical regulator of diverse cellular functions involved in the maintenance of structure and function. Enzymatic activity of GSK3 is inhibited by N-terminal serine phosphorylation. However, alternate post-translational mechanism(s) responsible for GSK3 inactivation are not characterized. Here, we report that GSK3alpha and GSK3beta are acetylated at Lys246 and Lys183, respectively. Molecular modeling and/or molecular dynamics simulations indicate that acetylation of GSK3 isoforms would hinder both the adenosine binding and prevent stable interactions of the negatively charged phosphates. We found that SIRT2 deacetylates GSK3beta, and thus enhances its binding to ATP. Interestingly, the reduced activity of GSK3beta is associated with lysine acetylation, but not with phosphorylation at Ser9 in hearts of SIRT2 deficient mice. Moreover, GSK3 is required for the anti-hypertrophic function of SIRT2 in cardiomyocytes. Overall, our study identified lysine acetylation as a novel post-translational modification regulating GSK3 activity. PMID- 29504934 TI - Mechanochemical coupling and bi-phasic force-velocity dependence in the ultra fast ring ATPase SpoIIIE. AB - Multi-subunit ring-shaped ATPases are molecular motors that harness chemical free energy to perform vital mechanical tasks such as polypeptide translocation, DNA unwinding, and chromosome segregation. Previously we reported the intersubunit coordination and stepping behavior of the hexameric ring-shaped ATPase SpoIIIE (Liu et al., 2015). Here we use optical tweezers to characterize the motor's mechanochemistry. Analysis of the motor response to external force at various nucleotide concentrations identifies phosphate release as the likely force generating step. Analysis of SpoIIIE pausing indicates that pauses are off pathway events. Characterization of SpoIIIE slipping behavior reveals that individual motor subunits engage DNA upon ATP binding. Furthermore, we find that SpoIIIE's velocity exhibits an intriguing bi-phasic dependence on force. We hypothesize that this behavior is an adaptation of ultra-fast motors tasked with translocating DNA from which they must also remove DNA-bound protein roadblocks. Based on these results, we formulate a comprehensive mechanochemical model for SpoIIIE. PMID- 29504935 TI - Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity. AB - Building arborisations of the right size and shape is fundamental for neural network function. Live imaging in vertebrate brains strongly suggests that nascent synapses are critical for branch growth during development. The molecular mechanisms underlying this are largely unknown. Here we present a novel system in Drosophila for studying the development of complex arborisations live, in vivo during metamorphosis. In growing arborisations we see branch dynamics and localisations of presynaptic proteins very similar to the 'synaptotropic growth' described in fish/frogs. These accumulations of presynaptic proteins do not appear to be presynaptic release sites and are not paired with neurotransmitter receptors. Knockdowns of either evoked or spontaneous neurotransmission do not impact arbor growth. Instead, we find that axonal branch growth is regulated by dynamic, focal localisations of Neurexin and Neuroligin. These adhesion complexes provide stability for filopodia by a 'stick-and-grow' based mechanism wholly independent of synaptic activity. PMID- 29504936 TI - Efficient termination of nuclear lncRNA transcription promotes mitochondrial genome maintenance. AB - Most DNA in the genomes of higher organisms does not code for proteins. RNA Polymerase II (Pol II) transcribes non-coding DNA into long non-coding RNAs (lncRNAs), but biological roles of lncRNA are unclear. We find that mutations in the yeast lncRNA CUT60 result in poor growth. Defective termination of CUT60 transcription causes read-through transcription across the ATP16 gene promoter. Read-through transcription localizes chromatin signatures associated with Pol II elongation to the ATP16 promoter. The act of Pol II elongation across this promoter represses functional ATP16 expression by a Transcriptional Interference (TI) mechanism. Atp16p function in the mitochondrial ATP-synthase complex promotes mitochondrial DNA stability. ATP16 repression by TI through inefficient termination of CUT60 therefore triggers mitochondrial genome loss. Our results expand the functional and mechanistic implications of non-coding DNA in eukaryotes by highlighting termination of nuclear lncRNA transcription as mechanism to stabilize an organellar genome. PMID- 29504937 TI - Tandem riboswitches form a natural Boolean logic gate to control purine metabolism in bacteria. AB - Gene control systems sometimes interpret multiple signals to set the expression levels of the genes they regulate. In rare instances, ligand-binding riboswitch aptamers form tandem arrangements to approximate the function of specific two input Boolean logic gates. Here, we report the discovery of riboswitch aptamers for phosphoribosyl pyrophosphate (PRPP) that naturally exist either in singlet arrangements, or occur in tandem with guanine aptamers. Tandem guanine-PRPP aptamers can bind the target ligands, either independently or in combination, to approximate the function expected for an IMPLY Boolean logic gate to regulate transcription of messenger RNAs for de novo purine biosynthesis in bacteria. The existence of sophisticated all-RNA regulatory systems that sense two ancient ribonucleotide derivatives to control synthesis of RNA molecules supports the hypothesis that RNA World organisms could have managed a complex metabolic state without the assistance of protein regulatory factors. PMID- 29504940 TI - Doped Sc2C(OH)2 MXene: new type s-pd band inversion topological insulator. AB - The electronic structures of Si and Ge substitutionally doped Sc2C(OH)2 MXene monolayers are investigated in density functional theory. The doped systems exhibit band inversion, and are found to be topological invariants in Z 2 theory. The inclusion of spin orbit coupling results in band gap openings. Our results point out that the Si and Ge doped Sc2C(OH)2 MXene monolayers are topological insulators. The band inversion is observed to have a new mechanism that involves s and pd states. PMID- 29504939 TI - The Association between Lifelong Greenspace Exposure and 3-Dimensional Brain Magnetic Resonance Imaging in Barcelona Schoolchildren. AB - BACKGROUND: Proponents of the biophilia hypothesis believe that contact with nature, including green spaces, has a crucial role in brain development in children. Currently, however, we are not aware of evidence linking such exposure with potential effects on brain structure. OBJECTIVE: We determined whether lifelong exposure to residential surrounding greenness is associated with regional differences in brain volume based on 3-dimensional magnetic resonance imaging (3D MRI) among children attending primary school. METHODS: We performed a series of analyses using data from a subcohort of 253 Barcelona schoolchildren from the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) project. We averaged satellite-based normalized difference vegetation index (NDVI) across 100-m buffers around all residential addresses since birth to estimate each participant's lifelong exposure to residential surrounding greenness, and we used high-resolution 3D MRIs of brain anatomy to identify regional differences in voxel-wise brain volume associated with greenness exposure. In addition, we performed a supporting substudy to identify regional differences in brain volume associated with measures of working memory (d' from computerized n-back tests) and inattentiveness (hit reaction time standard error from the Attentional Network Task instrument) that were repeated four times over one year. We also performed a second supporting substudy to determine whether peak voxel tissue volumes in brain regions associated with residential greenness predicted cognitive function test scores. RESULTS: Lifelong exposure to greenness was positively associated with gray matter volume in the left and right prefrontal cortex and in the left premotor cortex and with white matter volume in the right prefrontal region, in the left premotor region, and in both cerebellar hemispheres. Some of these regions partly overlapped with regions associated with cognitive test scores (prefrontal cortex and cerebellar and premotor white matter), and peak volumes in these regions predicted better working memory and reduced inattentiveness. CONCLUSION: Our findings from a study population of urban schoolchildren in Barcelona require confirmation, but they suggest that being raised in greener neighborhoods may have beneficial effects on brain development and cognitive function. https://doi.org/10.1289/EHP1876. PMID- 29504938 TI - Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum. AB - The onset of abnormal movements in DYT1 dystonia is between childhood and adolescence, although it is unclear why clinical manifestations appear during this developmental period. Plasticity at corticostriatal synapses is critically involved in motor memory. In the Tor1a+/Deltagag DYT1 dystonia mouse model, long term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded. Analysis of dendritic spines showed an increase of both spine width and mature mushroom spines in Tor1a+/Deltagag neurons, paralleled by an enhanced AMPA receptor (AMPAR) accumulation. BDNF regulates AMPAR expression during development. Accordingly, both proBDNF and BDNF levels were significantly higher in Tor1a+/Deltagag mice. Consistently, antagonism of BDNF rescued synaptic plasticity deficits and AMPA currents. Our findings demonstrate that early loss of functional and structural synaptic homeostasis represents a unique endophenotypic trait during striatal maturation, promoting the appearance of clinical manifestations in mutation carriers. PMID- 29504941 TI - Low-energy electron inelastic mean free paths for liquid water. AB - We improve the Mermin-Penn algorithm (MPA) for determining the energy loss function (ELF) within the dielectric formalism. The present algorithm is applicable not only to real metals, but also to materials that have an energy gap in the excitation spectrum. Applying the improved MPA to liquid water, we show that the present algorithm is able to address the ELF overestimation at the energy gap, and the calculated results are in good agreement with experimental data. PMID- 29504942 TI - Machine learning & artificial intelligence in the quantum domain: a review of recent progress. AB - Quantum information technologies, on the one hand, and intelligent learning systems, on the other, are both emergent technologies that are likely to have a transformative impact on our society in the future. The respective underlying fields of basic research-quantum information versus machine learning (ML) and artificial intelligence (AI)-have their own specific questions and challenges, which have hitherto been investigated largely independently. However, in a growing body of recent work, researchers have been probing the question of the extent to which these fields can indeed learn and benefit from each other. Quantum ML explores the interaction between quantum computing and ML, investigating how results and techniques from one field can be used to solve the problems of the other. Recently we have witnessed significant breakthroughs in both directions of influence. For instance, quantum computing is finding a vital application in providing speed-ups for ML problems, critical in our 'big data' world. Conversely, ML already permeates many cutting-edge technologies and may become instrumental in advanced quantum technologies. Aside from quantum speed-up in data analysis, or classical ML optimization used in quantum experiments, quantum enhancements have also been (theoretically) demonstrated for interactive learning tasks, highlighting the potential of quantum-enhanced learning agents. Finally, works exploring the use of AI for the very design of quantum experiments and for performing parts of genuine research autonomously, have reported their first successes. Beyond the topics of mutual enhancement-exploring what ML/AI can do for quantum physics and vice versa-researchers have also broached the fundamental issue of quantum generalizations of learning and AI concepts. This deals with questions of the very meaning of learning and intelligence in a world that is fully described by quantum mechanics. In this review, we describe the main ideas, recent developments and progress in a broad spectrum of research investigating ML and AI in the quantum domain. PMID- 29504943 TI - Phononic thermal conductivity in silicene: the role of vacancy defects and boundary scattering. AB - We calculate the thermal conductivity of free-standing silicene using the phonon Boltzmann transport equation within the relaxation time approximation. In this calculation, we investigate the effects of sample size and different scattering mechanisms such as phonon-phonon, phonon-boundary, phonon-isotope and phonon vacancy defect. We obtain some similar results to earlier works using a different model and provide a more detailed analysis of the phonon conduction behavior and various mode contributions. We show that the dominant contribution to the thermal conductivity of silicene, which originates from the in-plane acoustic branches, is about 70% at room temperature and this contribution becomes larger by considering vacancy defects. Our results indicate that while the thermal conductivity of silicene is significantly suppressed by the vacancy defects, the effect of isotopes on the phononic transport is small. Our calculations demonstrate that by removing only one of every 400 silicon atoms, a substantial reduction of about 58% in thermal conductivity is achieved. Furthermore, we find that the phonon-boundary scattering is important in defectless and small-size silicene samples, especially at low temperatures. PMID- 29504944 TI - A novel metastable state magnetic phase of monolayer FeSe. AB - We found a novel metastable magnetic phase by systematically calculating total energy of monolayer FeSe in various antiferromagnetic (AFM) orders using first principles method. The new metastable magnetic phase named as QAFM is a magnetic state with short-range magnetic structure which can be regarded as a transitional state between checkerboard-like AFM state and collinear AFM state. Both magnetic moments with important fluctuation and charge density difference with a 2 * 4 reconstruction of orbitals breaks C 4 symmetry and possibly commonly corresponds to the nematic phase in recent transmission electron microscopy and neutron scattering experiment observations. Its electronic band displays a Dirac-like band structure along Gamma-X in the folding Brillouin zone of the supercell. The QAFM phase of FeSe holds metallic feature with d xz , d yz and [Formula: see text] band crossing Fermi level even including spin-orbit coupling. Additionally, the weight of 3d orbitals varies as the applied expansion strain which may be directly correlated with the emerging nematic phase and superconducting state of strained monolayer FeSe. The finding of novel magnetic order may provide important clues to elucidate the relationship of antiferromagnetism and superconductivity for unconventional Fe-based superconductor. PMID- 29504945 TI - Pressure-jump induced rapid solidification of melt: a method of preparing amorphous materials. AB - By using a self-designed pressure-jump apparatus, we investigated the melt solidification behavior in rapid compression process for several kinds of materials, such as elementary sulfur, polymer polyether-ether-ketone (PEEK) and poly-ethylene-terephthalate, alloy La68Al10Cu20Co2 and Nd60Cu20Ni10Al10. Experimental results clearly show that their melts could be solidified to be amorphous states through the rapid compression process. Bulk amorphous PEEK with 24 mm in diameter and 12 mm in height was prepared, which exceeds the size obtained by melt quenching method. The bulk amorphous sulfur thus obtained exhibited extraordinarily high thermal stability, and an abnormal exothermic transition to liquid sulfur was observed at around 396 K for the first time. Furthermore, it is suggested that the glass transition pressure and critical compression rate exist to form the amorphous phase. This approach of rapid compression is very attractive not only because it is a new technique of make bulk amorphous materials, but also because novel properties are expected in the amorphous materials solidified by the pressure-jump within milliseconds or microseconds. PMID- 29504947 TI - Unleashing the therapeutic potential of oncolytic viruses. AB - Oncolytic viruses (OVs) are a versatile new class of therapeutic agents based on native or genetically modified viruses that selectively replicate in tumor cells and can express therapeutic transgenes designed to target cells within the tumor microenvironment and/or host immunity. To date, however, confirmation of the underlying mechanism of action and an understanding of innate and acquired drug resistance for most OVs have been limited. In this issue of the JCI, Zamarin et al. report a comprehensive analysis of an oncolytic Newcastle disease virus (NDV) using both murine melanoma tumor models and human tumor explants to explore how the virus promotes tumor eradication and details of the mechanisms involved. These findings have implications for the optimization of oncolytic immunotherapy, at least that based on NDV, and further confirm that specific combinatorial approaches are promising for clinical development. PMID- 29504946 TI - Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function. AB - We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and beta cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose stimulated insulin secretion and decreased beta cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased alpha cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered beta cell action potential (AP) firing and decreased alpha cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin-sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity. PMID- 29504948 TI - PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. AB - Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents. PMID- 29504949 TI - Osteoclast-secreted SLIT3 coordinates bone resorption and formation. AB - Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating beta-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases. PMID- 29504950 TI - Opening windows for bone remodeling through a SLIT. AB - Bone formation and resorption are tightly coupled, and dysfunction of either process leads to bone diseases, such as osteoporosis. Bone-forming agents have been explored clinically to increase bone density; however, long-term efficacy of these strategies is limited due to the accompanying increase in resorption in response to increased bone formation. Axonal guidance molecules have recently been shown to regulate formation-resorption coupling and thus have the potential for osteoporosis therapy. In this issue of the JCI, Kim et al. demonstrate that osteoclast-secreted SLIT3 influences bone formation and resorption by promoting osteoblast migration and suppressing osteoclast differentiation. Activation of SLIT3/ROBO signaling in ovariectomized mice increased bone mass, suggesting that SLIT3 should be further explored as a therapeutic target. PMID- 29504951 TI - Videographic Assessment of Pediatric Tracheal Intubation Technique During Emergency Airway Management. AB - OBJECTIVES: To examine technical aspects of pediatric tracheal intubation using video recording and to determine the association between tracheal intubation technique and procedural outcomes. DESIGN: Prospective observational study. SETTING: Emergency department resuscitation bay in single tertiary pediatric center. PATIENTS: Children undergoing emergent tracheal intubation under videorecorded conditions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A published scoring tool for characterizing patient positioning, intubator kinematics, and adjunctive maneuvers during tracheal intubation was applied to videorecorded pediatric resuscitations when tracheal intubation was performed. Procedural outcomes were measured from video review. Seventy-one children underwent 109 tracheal intubation attempts with an overall first attempt success rate of 69% and a median laryngoscopy duration of 34 seconds (interquartile range, 24-47 s). A significant subset of tracheal intubation attempts were made with the patient's bed at a height below the level of intubator's umbilicus (61%), the patient in a supine position without head elevation (55%), the intubator bent at the waist to greater than 45 degrees (66%), less than 1 cm of mouth opening by the intubator's right hand prior to laryngoscopy (46%), and with the intubator's face less than 12 inches away from the patient's mouth (65%). Adjunctive maneuvers were used in a minority of attempts (cricoid pressure 48%, external laryngeal manipulation 11%, retraction of the right corner of the patient's mouth 26%). On multivariate analysis, including controlling for patient age category and intubator background, retraction of the right corner of the patient's mouth by an assistant showed an independent association with successful tracheal intubation. No other technical aspects were associated with tracheal intubation success. CONCLUSIONS: Intubators commonly exhibited suboptimal technique during tracheal intubation such as bending deeply at the waist, having their eyes close to the patient's mouth, failing to widely open the patient's mouth, and not elevating the occiput in older children. Retraction of the right corner of the patient's mouth by an assistant during laryngoscopy and intubation was associated with TI success. PMID- 29504952 TI - Age-Related Changes in Tissue Value Properties in Children: Simultaneous Quantification of Relaxation Times and Proton Density Using Synthetic Magnetic Resonance Imaging. AB - OBJECTIVES: The properties of brain tissue undergo dynamic changes during maturation. T1 relaxation time (T1), T2 relaxation time (T2), and proton density (PD) are now simultaneously quantifiable within a clinically acceptable time, using a synthetic magnetic resonance imaging (MRI) sequence. This study aimed to provide age-specific reference values for T1, T2, and PD in children, using synthetic MRI. MATERIALS AND METHODS: We included 89 children (median age, 18 months; range, 34 weeks of gestational age to 17 years) who underwent quantitative MRI, using a multidynamic, multiecho sequence on 3 T MRI, between December 2015 and November 2016, and had no abnormal MRI/neurologic assessment findings. T1, T2, and PD were simultaneously measured in each of the 22 defined white matter and gray matter regions of interest. The measured values were plotted against age, and a curve fitting model that best explained the age dependence of tissue values was identified. Age-specific regional tissue values were calculated using a fit equation. RESULTS: The tissue values of all brain regions, except cortical PD, decreased with increasing age, and the robust negative association was best explained by modified biexponential model of the form Tissue values = T1 * exp (-C1 * age) + T2 * exp (-C2 * age). The quality of fit to the modified biexponential model was high in white matter and deep gray matter (white matter, R = 97%-99% [T1], 88%-95% [T2], 88%-97% [PD]; deep gray matter, R = 96%-97% [T1], 96% [T2], 49%-88% [PD]; cortex, 70%-83% [T1], 87%-90% [T2], 5%-27% [PD]). The white matter and deep gray matter changed the most dynamically within the first year of life. CONCLUSIONS: Our study provides age specific regional reference values, from the neonate to adolescent, of T1, T2, and PD, which could be objective tools for assessment of normal/abnormal brain development using synthetic MRI. PMID- 29504953 TI - Epidemiology of Persistent Dry Eye-Like Symptoms After Cataract Surgery. AB - PURPOSE: To evaluate the frequency and risk factors for persistent postsurgical pain (PPP) after cataract surgery, defined as mild or greater dry eye (DE)-like symptoms 6 months after surgery. METHODS: This single-center study included 86 individuals who underwent cataract surgery between June and October 2016 and had DE symptom information available 6 months after surgery. Patients were divided into 2 groups: controls were defined as those without DE symptoms 6 months after surgery (defined by a Dry Eye Questionnaire 5 (DEQ5) score <6), cases were defined as those with mild or greater DE-like symptoms 6 months after surgery (DEQ5 >=6). RESULTS: Mean age of the study population was 71 +/- 8.6 years; 95% (n = 82) were men. DE-like symptoms were reported in 32% (n = 27) of individuals 6 months after cataract surgery; 10% (n = 8) reported severe symptoms (DEQ5 >=12). Patients with DE-like symptoms after cataract extraction also had higher ocular pain scores and specific ocular complaints (ocular burning, sensitivity to wind and light) compared with controls with no symptoms. A diagnosis of nonocular pain increased the risk of DE-like symptoms after cataract surgery (odds ratio 4.4, 95% confidence interval 1.58-12.1, P = 0.005). CONCLUSIONS: Mild or greater PPP occurred in approximately 1/3 of individuals after cataract surgery. Prevalence of severe PPP is in line with that of refractive surgery, dental implants, and genitourinary procedures. PMID- 29504954 TI - Utility of Novel Autoantibodies in the Diagnosis of Sjogren's Syndrome Among Patients With Dry Eye. AB - PURPOSE: To investigate the value of 3 novel autoantibodies [salivary protein 1 (SP1), carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP)] in differentiating Sjogren's syndrome (SS)-related dry eye from non-SS dry eye. METHODS: Forty-six dry eye patients with SS (SS dry eye), 14 dry eye patients without SS (non-SS dry eye), and 25 controls were included. The 2012 American College of Rheumatology classification criteria were used for the diagnosis of SS. After a detailed review of systems, the Ocular Surface Disease Index questionnaire, Schirmer test without anesthesia, tear film breakup time, and ocular surface staining were performed to assess dry eye. All participants underwent serological testing using a commercially available finger prick kit. RESULTS: Thirty-seven patients with SS (80.4%) had a positive traditional autoantibody and 28 (60.9%) had a positive novel autoantibody. Traditional autoantibodies were absent in all non-SS dry eye patients and controls. Novel autoantibodies were present in 7/14 (50%) non-SS dry eye patients and 4/25 (16%) controls. Among 3 novel autoantibodies, anti-CA6 was significantly more prevalent in the SS and non-SS dry eye groups than in controls (52.2% vs. 42.9% vs. 8.0%, P = 0.001). Dry eye patients with positive anti-CA6 alone were significantly younger than patients with only traditional autoantibodies. Anti-CA6 was associated with worse dry eye signs and symptoms. CONCLUSIONS: Anti-CA6 was the most prevalent novel autoantibody in patients with dry eye, and was associated with younger age and more severe disease. Longitudinal studies are needed to determine whether anti-CA6 is a marker for early SS or perhaps another form of an autoimmune dry eye disease. PMID- 29504955 TI - Meibography of Eyes With Sequelae of Trachoma. AB - PURPOSE: To study the effect of trachoma on meibomian glands using infrared meibography and to correlate the results with tear film parameters. METHODS: This is a prospective cohort study in which 86 eyes of healthy volunteers and 90 eyes with trachoma were included. Clinical assessment was performed including the following: slit-lamp examination looking for signs of sequelae of trachoma, tear breakup time (TBUT), superficial punctate keratopathy (SPK), Schirmer II test (with anesthesia), and meibum score. Noncontact meibography was performed on both upper and lower eyelids separately using the meibograde system, which involved distortion of the meibomian gland, shortening, and dropout. RESULTS: Lid margin abnormalities (telangiectasia, lid margin swelling, and hyperemia) were all significantly higher in the trachoma group. The mean SPK (1.36), meibum score (1.76), meibography dropout, distortion, shortening, and total meibography (8.19 for upper eyelids and 3.81 for lower eyelids) were all significantly higher in the trachoma group (P < 0.001) compared with the normal group were SPK (0.88), meibum score (0.16), and total meibography (1.24 for upper eyelids and 0.92 for lower eyelids). Mean TBUT (4.2 s) was significantly shorter in the trachoma group than in the normal group (10.3 s) (P < 0.001). There was no significant difference between both groups in the Schirmer II test. CONCLUSIONS: Meibography of patients with sequelae of trachoma was in agreement with the histopathologic studies. Upper eyelids were much more affected than the lower eyelids. TBUT, SPK, and meibum score were correlated with the status of meibomian glands and meibography, which were significantly different in the trachoma group. PMID- 29504958 TI - Reduced anticoagulation is safe in high-risk patients with the On-X mechanical aortic valve. AB - PURPOSE OF REVIEW: The goal of anticoagulation in patients with mechanical aortic valve replacement (AVR) is to maintain an optimal international normalized ratio (INR) that minimizes both the risk of bleeding and thromboembolic events. Here, we review the published data on anticoagulation with bileaflet mechanical prostheses, with a focus on the On-X valve (On-X Life Technologies, Austin, TX), which was designed to function with less anticoagulation or, in some cases, antiplatelet therapy only. RECENT FINDINGS: Several long-term follow-up studies with the On-X valve demonstrate low rates of bleeding and thromboembolism with standard and low-dose anticoagulation. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) compared the safety of less aggressive anticoagulation (INR 1.5-2.0) with standard anticoagulation (INR 2.0-3.0) after implantation of On-X aortic prostheses for patients at high risk of thromboembolic events. The updated 5-year data confirm that low-dose warfarin is associated with lower major bleeding (1.6 vs. 3.9%/patient-year; P = 0.007) with no difference in thromboembolic events (0.11 vs. 0.52%/patient-year; P = 0.2). SUMMARY: Nonrandomized studies and the PROACT data support the safety and efficacy of maintaining the On-X bileaflet mechanical aortic valve prosthesis at a lower target INR than current guideline recommendations for patients at high risk of thromboembolic events. These results offer the promise of a valve prosthesis with excellent durability combined with reduced anticoagulation related complications. PMID- 29504956 TI - Hypoxia and the Prolyl Hydroxylase Inhibitor FG-4592 Protect Corneal Endothelial Cells From Mechanical and Perioperative Surgical Stress. AB - PURPOSE: To determine whether hypoxia preconditioning can protect corneal endothelial cells from mechanical stress and perioperative procedures mimicking Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: Preconditioning was delivered by 2 hours of 0.5% oxygen incubation in a hypoxia chamber or by exposure to the prolyl hydroxylase inhibitor FG-4592, which prevents hypoxia-inducible factor-1 alpha degradation. Damage to whole corneas was produced by brief sonication. To mimic use with DSAEK, FG-4592-preconditioned and control donor corneas were dissected with a microkeratome, and the posterior donor button was pulled through a transplant insertion device (Busin glide). The area of endothelial damage was determined by trypan blue staining. RESULTS: In all cases, hypoxia preconditioning or incubation with FG-4592 protected corneal endothelial cells from death by mechanical stress. Hypoxia-preconditioned human and rabbit corneas showed 19% and 29% less cell loss, respectively, relative to controls, which were both significant at P < 0.05. FG-4592 preconditioning reduced endothelial cell loss associated with preparation and insertion of DSAEK grafts by 23% relative to the control (P < 0.01). CONCLUSIONS: These results support the hypothesis that preconditioning by hypoxia or exposure to FG-4592 improves corneal endothelial cell survival and may also provide protection during surgical trauma. PMID- 29504959 TI - Grand Canyon South Rim. PMID- 29504960 TI - Edward Nathaniel Hanley, Jr, MD: 2014 ISSLS Wiltse Lifetime Achievement Award, Sponsored by Nuvasive. PMID- 29504961 TI - Long-term Outcomes of 2-Level Total Disc Replacement Using ProDisc-L: Nine- to 10 Year Follow-up. AB - STUDY DESIGN: A prospective clinical data analysis. OBJECTIVE: To determine the long-term clinical success of 2-level total disc replacement (TDR) in patients with degenerative disc disease. SUMMARY OF BACKGROUND DATA: Early successful clinical results of 2-level TDR have been reported. Few studies exist that have described this procedure's durability in the long term. METHODS: Fifteen patients underwent 2-level lumbar TDR with the ProDisc-L as part of a randomized trial, 13 of whom were available for follow-up. The patients were assessed preoperatively and at 2 years, 5 years, and more than 9 years postoperatively using visual Oswestry Disability Index. At the last follow-up visit, 2 additional questions were asked: satisfaction with surgery and willingness to undergo the same treatment. Finally, clinical success was assessed using a previously described definition. RESULTS: Mean follow-up time was 9.6 years (range, 9.2-10.3 yr). Postoperatively there was a significant improvement in Oswestry Disability Index score from baseline (70.0 vs. 15.7 at 2 yr, P = 0.002) that remained unchanged during the period of follow-up (19.8 at 5 yr, P = 0.003 and 12.9 at 9-10 yr, P = 0.002). Ninety-two percent of patients were "satisfied" or "somewhat satisfied" with treatment and the same number would undergo treatment again. Eighty-five percent of patients achieved clinical success. CONCLUSION: This prospective study demonstrates the durable clinical success of 2-level lumbar TDR as assessed at more than 9 years postoperatively. LEVEL OF EVIDENCE: 4. PMID- 29504962 TI - The Findings on Bone Scintigraphy in Patients With Suspected Tumor-Induced Osteomalacia Should Not Be Overlooked. AB - : Tumor-induced osteomalacia (TIO) is a chronic, devastating disease. The causative tumor is usually a small benign one that is very difficult to localize. Because the presenting symptoms include diffuse bone pain, a bone scintigraphy is commonly performed to determine the cause of the pain before TIO is suspected. In this retrospective investigation, we tried to assess whether bone scintigraphy acquired will be helpful in the eventual identification of the culprit tumor. METHODS: The images of bone scan and clinical charts of total 91 patients with confirmed TIO were retrospectively reviewed. The image findings were compared with the results of other imaging studies, surgical notes, histopathologic examinations and clinical follow-ups. RESULTS: In 76.9% (70 of 91) of the patients, the findings of bone scintigraphy did not correspond to the sites of the causative tumors, which were subsequently located. However, in 23.1% of the patients (21 of 91), the sites of the causative tumors corresponded to one of the abnormal technetium 99m-methyl diphosphonate activity on bone scintigraphy. More importantly, 6 tumors corresponded to the dominant activity on bone scintigraphy. CONCLUSIONS: Although findings of whole-body scintigraphy are nonspecific in patients with TIO, careful evaluation of bone scintigraphy results can be helpful in guiding further evaluation in some patients. PMID- 29504963 TI - Asthmatic Exacerbation as a Cause of False-Positive Whole-Body Iodine Scan in a Patient With Treated Papillary Thyroid Carcinoma. AB - A 44-year-old woman was found to have new diffuse lung uptake on a follow-up whole-body I scan 1 year after being treated with surgery and radioactive iodine for papillary thyroid cancer. However, subsequent CT thorax and thyroglobulin levels were both unremarkable. Shortly after, she presented with respiratory symptoms, exhibiting end-expiratory wheezing on auscultation. Metacholine challenge test confirmed asthma. Symptoms improved under inhaled corticosteroids and beta-2 agonists. Resolution of lung uptake was confirmed on a second I imaging 6 months later. PMID- 29504964 TI - Active Bone Marrow With Focal FDG Accumulation Mimicking Bone Metastasis With a Case of Early Esophageal Cancer. AB - A 68-year-old man underwent F-FDG PET/CT for the staging of esophageal carcinoma discovered by a medical checkup. Increased focal accumulation in some vertebrae, right humerus, and right femoral bone was noted on FDG-PET, whereas CT showed relatively high attenuation, and MRI showed hypointense lesions on T1- and T2 weighted imaging. A bone biopsy revealed mildly hypercellular bone marrow in the thoracic spine with FDG accumulation and markedly hypocellular bone marrow in the pelvic bone without an increased uptake. InCl scintigraphy showed a similar distribution and confirmed the diagnosis of bone marrow reconversion. PMID- 29504965 TI - Amyloid PET Positivity in Different Primary Progressive Aphasia Phenotypes. AB - PURPOSE: Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" F-florbetapir scans. Then, we compare the quantification and distribution of F-florbetapir uptake with those of typical, predominantly amnestic AD patients. METHODS: We conducted a PET study with F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. RESULTS: Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were F-florbetapir positive. A significantly higher F-florbetapir uptake was observed in PPA F florbetapir-positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. CONCLUSIONS: These results suggest that F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome. PMID- 29504966 TI - White matter structure in loneliness: preliminary findings from diffusion tensor imaging. AB - A pilot study was carried out to determine individual differences in perceived loneliness using diffusion tensor imaging. To the best of our knowledge, this is the first preliminary diffusion tensor imaging evidence that the ventral attention network, generally activated by attentional reorienting, was also related to loneliness. Image reconstruction results indicated significantly decreased fractional anisotropy of white matter fibers and that associated nodes of the ventral attention network are highly correlated with increased loneliness ratings. By providing evidence on the structural level, our findings suggested that attention-reorienting capabilities play an important role in shaping an individual's loneliness. PMID- 29504967 TI - Bilateral abducens nerve palsies and urinary retention caused by the rupture of a vertebral artery aneurysm: A case report and literature review. AB - RATIONALE: Bilateral abducens nerve deficits caused by vertebral artery (VA) aneurysm have been reported, but there have been no reports regarding accompanying urinary retention. PATIENT CONCERNS: In this report, we describe an unusual case with bilateral abducens nerve palsy and urinary retention due to rupture of a vertebral aneurysm. DIAGNOSES: Subarachnoid hemorrhage caused by the rupture of a left VA aneurysm. INTERVENTIONS: The VA aneurysm was successfully controlled by coil embolization. OUTCOMES: Urinary retention was improved after embolization and recovered by the day the patient left hospital. The bilateral abducens nerve palsy gradually recovered 6 months later. LESSONS: This case emphasizes the importance of maintaining a broad, open mind in approaching the diagnosis and management of urinary retention associated with cranial nerve symptoms and reacting quickly to the clinical developments. PMID- 29504968 TI - Repair of deep tissue defects in the posterior talocrural region using a superficial temporal fascia free flap plus thin split-skin grafting in extensively burned patients: A retrospective case series. AB - The aim of this study was to describe the scheme, surgical procedures, and clinical outcomes for the early repair of deep wounds of the posterior talocrural region in extensively burned patients with a method combining a superficial temporal fascia free flap with thin split-skin grafting.From January 2013 to February 2016, 9 extensively burned patients with deep tissue defects of the posterior talocrural region were treated in our department (2 patients had bilateral deep tissue defects of the posterior talocrural region). All 11 wounds were repaired using a superficial temporal fascia free flap and thin split-skin grafting. After the operation, survival of the fascia flaps and grafted skin was observed, and the appearance and functional recovery of the grafts were evaluated. Follow-up information was reviewed, and complications were documented.All 11 fascia flaps survived completely. Two cases of partial skin necrosis healed after the second application of skin grafts. The appearance and function of recipient sites were well restored in all patients over a follow-up period of 5 to 14 months.Deep tissue defects of the posterior talocrural region can be effectively repaired with our method combining a superficial temporal fascia free flap with thin split-skin grafting. This method offers the advantages of a good appearance, strong resistance to infection, minimal damage at the donor site, short course of disease, and good prognosis. PMID- 29504969 TI - Synergistic interaction between prolonged increased glycemic exposure and mildly increased urinary albumin excretion on diabetic retinopathy. AB - The association of mild increase in urinary albumin excretion with diabetic retinopathy (DR) in clinical studies is controversial. The aim of this study is to clarify the interaction between increased glycemic exposure and mild increase in urinary albumin excretion on risk of DR.Data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2012. Overall, data from 953 participants without microalbuminuria (477 men and 476 women) were assessed. Logistic regression analysis was constructed to evaluate the association between DR and related clinical parameters, including urinary albumin creatinine ratio (UACR, mg/g creatinine). The biological interaction of glycemic status and UACR on DR was evaluated by 3 indices: RERI, the relative excess risk due to the interaction; AP, the attributable proportion due to the interaction; and S, the additive interaction index of synergy.We found that UACR, glycated hemoglobin (HbA1c), and diabetic duration were deeply associated with increased risk of DR (UACR, odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.02 1.07; HbA1c, OR = 1.16, 95% CI = 1.04-1.30; diabetic duration, OR = 1.06, 95% CI = 1.04-1.07). Furthermore, our interaction analysis demonstrated that synergistic interaction between HbA1c and UACR on development of DR was prominent in participants with diabetic duration of >=10 years (adjusted RERI = 0.92, 95% CI = 0.10-1.74; adjusted AP = 0.29, 95% CI = -0.82-1.41; adjusted S = 1.76, 95% CI = 1.27-2.25), but not subjects with shorter diabetic duration.These findings imply that there is the interaction between prolonged hyperglycemic exposure and increased urinary albumin excretion may exert additive synergistic effect on vascular endothelial dysfunction in the eye, even before the appearance of overt diabetic nephropathy. PMID- 29504970 TI - Application of vascularized fibular graft for reconstruction and stabilization of multilevel cervical tuberculosis: A case report. AB - Multilevel cervical reconstruction and fusion after cervical tuberculosis has always been a challenge. The current implantation materials for cervical fusion, including titanium mesh, cage, and plate are limited by its inferior biological mechanical characteristics and the properties of the metallic material. This has led to the increased risk of recurrent infection after surgery. In addition, the unique nature of tuberculosis infection results in the low rate of cervical fusion and high risk of recurrence. This case report presents 1 patient who suffered from long segmental cervical tuberculosis and had reconstruction surgery using a vascularized fibula graft. The patient had successful graft incorporation 3 months postsurgery and was followed-up for 30 months. In this review, we detail the advantages of using vascularized fibular grafts and compare it with other types of grafts. PMID- 29504971 TI - Synchronous Hodgkin lymphoma and gastric adenocarcinoma: A rare case report and literature review. AB - Hodgkin lymphoma (HL) is a lymphoproliferative disease arising in the lymphoid tissue, which is characterized by Reed-Sternberg cells. Adenocarcinoma is the most frequent pathological type of stomach cancer. Improved survival in HL patients leads to the development of secondary malignancies. However, synchronous occurrence of these 2 malignancies is extremely rare. Here, we present a 45-year old male complaining of a lymph node mass in the neck, without any abdominal symptoms, diagnosed as HL and gastric adenocarcinoma with hepatitis B carrier status. We treated the patient with 8 courses of pirarubicin bleomycin, vincristine, and dacarbazine (modified ABVD), and 4 courses of capecitabine therapy concurrently along with oral entecavir, as the patient survived longer than 20 months.The prognosis of multiple primary malignancies is poor because therapy is difficult, without a standard treatment. The frequency of multiple primary malignancies is increasing in recent years, and second malignancies in patients with cancer should be taken into consideration. PMID- 29504972 TI - Ablative fractional carbon dioxide laser combined with intense pulsed light for the treatment of photoaging skin in Chinese population: A split-face study. AB - Intense pulsed light (IPL) is effective for the treatment of lentigines, telangiectasia, and generalized erythema, but is less effective in the removal of skin wrinkles. Fractional laser is effective on skin wrinkles and textural irregularities, but can induce postinflammatory hyperpigmentation (PIH), especially in Asians. This study evaluated the safety and efficacy of ablative fractional laser (AFL) in combination with IPL in the treatment of photoaging skin in Asians.This study included 28 Chinese women with Fitzpatrick skin type III and IV. The side of the face to be treated with IPL alone (3 times) or AFL in combination with IPL (2 IPL treatments and 1 AFL treatment) was randomly selected. Skin conditions including hydration, transepidermal water loss, elasticity, spots, ultraviolet spots, brown spots, wrinkle, texture, pore size and red areas, as well as adverse effects were evaluated before the treatment and at 30 days after the treatment.Compared with IPL treatment alone, AFL in combination with IPL significantly increased elasticity, decreased pore size, reduced skin wrinkles, and improved skin texture (P = .004, P = .039, P = .015, and P = .035, respectively). Both treatment protocols produced similar effects in relation to the improvement of photoaging-induced pigmentation. The combined therapy did not impair epidermal barrier function. No postoperative infection, hypopigmentation, or scarring occurred after IPL and AFL treatments. PIH occurred at 1 month after AFL treatment and disappeared at 30 days after completion of the combined therapy.AFL in combination with IPL is safe and effective for photoaging skin in Asians. PMID- 29504973 TI - The role of procalcitonin in the diagnosis of bacterial infection after major abdominal surgery: Advantage from daily measurement. AB - Postsurgical infections represent an important cause of morbidity after abdominal surgery. The microbiological diagnosis is not achieved in at least 30% of culture with consequent worsening of patient outcome. In this study, procalcitonin measurement, during the first 3 days after abdominal surgery, has been evaluated for the early diagnosis of postsurgical infection.Ninety consecutive patients subjected to major abdominal surgery at the University Campus Bio-Medico of Rome, have been included. PCT concentrations were measured by time-resolved amplified cryptate emission (TRACE) assay at admission and at the first, second, and third day after surgery. PCT levels were compared using the Mann-Whitney test and by ANOVA test for variance analysis. Receiver operating characteristic (ROC) analysis was performed to define the diagnostic ability of PCT in case of postsurgical infections.PCT values resulted significantly different between patients developing or not developing postsurgical infections. PCT >1.0 ng/mL at first or second day after surgery and >0.5 ng/mL at third day resulted diagnostic for infectious complication, whereas a value <0.5 ng/mL at the fifth day after surgery was useful for early and safety discharge of patients.In conclusion, PCT daily measurement could represent a useful diagnostic tool improving health care in the postsurgical period following major abdominal surgery and should be recommended. PMID- 29504974 TI - Three-dimensional brain arteriovenous malformation models for clinical use and resident training. AB - BACKGROUND: To fabricate three-dimensional (3D) models of brain arteriovenous malformation (bAVM) and report our experience with customized 3D printed models of patients with bAVM as an educational and clinical tool for patients, doctors, and surgical residents. METHODS: Using computerized tomography angiography (CTA) or digital subtraction angiography (DSA) images, the rapid prototyping process was completed with specialized software and "in-house" 3D printing service. Intraoperative validation of model fidelity was performed by comparing to DSA images of the same patient during the endovascular treatment process. 3D bAVM models were used for preoperative patient education and consultation, surgical planning, and resident training. RESULTS: 3D printed bAVM models were successful made. By neurosurgeons' evaluation, the printed models precisely replicated the actual bAVM structure of the same patients (n = 7, 97% concordance, range 95%-99% with average of < 2 mm variation). The use of 3D models was associated shorter time for preoperative patient education and consultation, higher acceptable of the procedure for patients and relatives, shorter time between obtaining intraoperative DSA data and the start of endovascular treatment. Thirty surgical residents from residency programs tested the bAVM models and provided feedback on their resemblance to real bAVM structures and the usefulness of printed solid model as an educational tool. CONCLUSIONS: Patient-specific 3D printed models of bAVM can be constructed with high fidelity. 3D printed bAVM models were proven to be helpful in preoperative patient consultation, surgical planning, and resident training. PMID- 29504975 TI - CT measurements of central pulmonary vasculature as predictors of severe exacerbation in COPD. AB - To identify a predictive value for the exacerbation status of chronic obstructive pulmonary disease (COPD) subjects, we evaluated the relationship between pulmonary vascular measurements on chest CT and severe COPD exacerbation.Six hundred three subjects enrolled in the COPDGene population were included and divided into nonexacerbator (n = 313) and severe exacerbator (n = 290) groups, based on whether they had an emergency room visit and/or hospitalization for COPD exacerbation. We measured the diameter of the main pulmonary artery (MPA) and ascending aorta (AA) at 2 different sites of the MPA (the tubular midportion and bifurcation) on both axial images and multiplanar reconstructions. Using multiple logistic regression analyses, we evaluated the relationship between each CT measured pulmonary vasculature and exacerbation status.Axial and multiplanar MPA to AA diameter ratios (PA:AA ratios) at the tubular midportion and the axial PA:AA ratios at the bifurcation indicated significant association with severe exacerbation. The strongest association was found with the axial PA:mean AA ratio at the bifurcation (adjusted odds ratio [OR] = 12.53, 95% confidence interval [CI] = 2.35-66.74, P = .003) and the axial PA:major AA ratio at the tubular midportion (adjusted OR = 10.72, 95% CI = 1.99-57.86, P = .006). No differences were observed in the MPA diameter. Receiver operating characteristic analysis of these variables indicates that they may serve as a good predictive value for severe exacerbation (area under the curve, 0.77-0.78). The range of cut-off value for PA:AA ratio was 0.8 to 0.87.CT-measured PA:AA ratios at either the bifurcation or the tubular site, measured either on axial or multiplanar images, are useful for identification of the risk of severe exacerbation, and consequently can be helpful in guiding the management of COPD. Although CT measurement was used at the level of pulmonary bifurcation in previous studies, we suggest that future studies should monitor the tubular site of the MPA for maximum diagnostic value of CT in pulmonary hypertension or severe COPD exacerbation, as the tubular site of the MPA remains relatively constant on CT images. PMID- 29504976 TI - Herbal medicine (Bojungikki-tang) for allergic rhinitis: A protocol for a systematic review of controlled trials. AB - BACKGROUND: Bojungikki-tang, a herbal medicine for strengthening the digestive system, has been widely used in East Asian countries since the Yuan Dynasty in China. Moreover, Bojungikki-tang has reportedly exhibited anti-allergy effects in many clinical trials. This systematic review will assess the effectiveness and safety of Bojungikki-tang for allergic rhinitis (AR). METHODS AND ANALYSIS: Eleven databases, including Asian databases, will be searched for studies conducted through October 2017. We will include randomized controlled trials (RCTs) assessing Bojungikki-tang for AR. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool, and confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and will also be disseminated electronically and in print. The review will be updated to inform and guide health care practices. REGISTRATION: The protocol for this systematic review has been registered in PROSPERO (https://www.crd.york.ac.uk/PROSPERO) under number CRD42017068993. PMID- 29504977 TI - Biatrial myxoma floating like a butterfly: A case report and review of the literature. AB - RATIONALE: Myxoma is the most common type of primary benign cardiac tumor in adults. The left atrium is the most frequent site of origin followed by the right atrium. Biatrial myxoma is extremely rare. PATIENT CONCERNS: We present a case of a 60-year-old woman with biatrial myxoma, who presented with palpitations for one month. DIAGNOSES: Echocardiography revealed an irregular homogeneous mass in the left atrium and in the right atrium, and were connected via the fossa ovalis suspiciously. Computed tomography angiography revealed a hypo-intense mass in both atria. INTERVENTIONS: The tumors were successfully removed by surgical excision and histological analysis confirmed the diagnosis. OUTCOMES: The patient was discharged one week after surgery, and did not experience recurrence during the two years follow-up period. LESSONS: Biatrial myxoma is rare. Surgical resection is the mainstay of treatment and there is no recurrence reported. The clinical data and the features on echocardiogram of biatrial myxoma are reviewed, providing important clinical information for the pre-operative diagnosis and intraoperative removal of biatrial myxoma. PMID- 29504978 TI - Lupus erythematosus panniculitis in a 10-year-old female child with severe systemic lupus erythematosus: A case report. AB - RATIONALE: Lupus erythematosus panniculitis (LEP) is a rare subset of lupus erythematosus. The incidence of LEP in systemic lupus erythematosus (SLE) ranges from 2% to 5%. In the previous literature, most LEP patients were women aged from 20 to 60 years, while pediatric cases were rare, all of whom appeared on their own without SLE.A rare LEP in a 10-year-old female child with severe SLE is presented. PATIENT CONCERNS: A 10-year-old girl was admitted to our hospital for marasmus and fatigue without other typical manifestations of SLE well before the appearance of skin lesions. The only proof to support the SLE is that we observed a weakly positive antinuclear antibody (ANA) in serum at the onset. DIAGNOSES: A 10-year-old girl diagnosed to the Division of Nephrology, Department of Pediatrics, the Second Xiangya Hospital, Central South University, for LEP with severe SLE. INTERVENTIONS: The patient was administered with high-dose corticosteroids and cyclophosphamide. OUTCOME: The patient died of severe lung involvement despite the use of high-dose corticosteroids and cyclophosphamide. LESSONS: This report highlights an unusual manifestation of LEP associated with SLE in a child. It also suggests that pediatricians should be aware of occult onset of SLE, such as unclear marasmus and fatigue found in this case. Repeat tests of antinuclear antibody and anti-double strand DNA antibody (anti-dsDNA) as well as renal biopsy in a timely manner will be effective to achieve early recognition and immediate treatment for saving lives. PMID- 29504979 TI - Autoimmune encephalitis positive for both anti-gamma-aminobutyric acid B receptor and anticollapsin response-mediator protein 5 antibodies: A case report. AB - RATIONALE: Autoimmune encephalitis (AE) is a heterogeneous group of recently identified disorders. Despite severe and even prolonged neurologic deficits, dramatic improvements may occur with proper immunotherapy in some patients with AE. Antineuronal antibodies have been discovered in patients' serum and cerebrospinal fluid (CSF). However, AE with multiple antineuronal antibodies is rare. To date, there are no published reports of AE with both anti-gamma aminobutyric acid B receptor (GABABR) and anticollapsin response-mediator protein 5 (CV2) antibodies. PATIENT CONCERNS: We describe a 46-year-old man who presented with seizures, working memory deficits, and visual hallucinations. We detected anti-CV2 and anti-GABABR antibodies in his serum and CSF. Brain magnetic resonance imaging (MRI) revealed patchy abnormal signals in his left temporal lobe and hippocampus. The patient's symptoms improved after receiving intravenous immunoglobulin injections and glucocorticoids, but his condition relapsed within 4 months, and he was readmitted to our hospital. Repeated MRI scans revealed new lesions in his right temporal lobe and hippocampus. DIAGNOSIS: The AE diagnosis was established from the results of the preliminary physical examination, the laboratory tests, and the imaging findings. INTERVENTIONS: The patient received intravenous immunoglobulins and glucocorticoids. OUTCOMES: We followed the patient for 9 months from the date of the patient's second hospital discharge. He experienced no seizures during this period, but his short-term memory deficits and visual hallucinations were not completely alleviated. LESSONS: Coexisting anti-CV2 and anti-GABABR antibodies may have synergistic effects and worsen the clinical syndrome. AE with multiple antineuronal antibodies may be relapse-prone. Further studies investigating the relationship between anti-CV2 and anti-GABABR antibodies are warranted. PMID- 29504980 TI - Efficacy of percutaneous vertebroplasty treatment of spinal tumors: A meta analysis. AB - OBJECTIVE: To evaluate the function of percutaneous vertebroplasty (PVP) treatment to pain relief and life quality for patients with spinal tumors. METHODS: Articles about the researches on the treatment of spinal tumors by PVP in PubMed, Embase, and the Chinese Biomedical Literature database from January 1, 2015 to December 31, 2013. The keywords "spinal tumors," "efficacy," and "vertebroplasty" were firstly scanned to exclude all irrelevant articles. Then, the final inclusion of studies was determined by reading the full text of the remaining articles. The citation lists of all retrieved articles were scanned to identify other potentially relevant reports. RevMan5.2 was used to analyze pain intensity visual analog scale (VAS) and Karnofsky performance scores (KPS) within each research. Combined HRs (hazard ratio) were calculated using fixed- or random effects models according to the heterogeneity. RESULTS: Twenty-six studies involving 1351 patients met our selection criteria. Meta-analysis results among 10 case-control studies showed that the combined HR was -2.83 [95% confidence interval (CI) -2.92, -2.73; P < .0001], indicating a 2.83-fold decrease of pain in PVP group. For 12 single-arm studies, a significantly decrease of pain after PVP treatment (HR = -4.79, 95% CI -5.00, -4.57, P < .0001) was also found in PVP group. In addition, for KPS analysis, the combined HR was 16.31 (95% CI 14.31, 18.31; P < .0001), which indicated that PVP treatment was associated with a 16.31 fold increase of KPS. The combined HR was 0.58 (95% CI 0.35, 0.96; P = .04) for complication analysis. CONCLUSIONS: PVP treatment of spinal tumor is significantly associated with better pain relief and life quality, which could improve the outcome in metastatic spinal tumor patients. PMID- 29504981 TI - A new clinical decision support tool for improving the adequacy of anticoagulant therapy and reducing the incidence of stroke in nonvalvular atrial fibrillation: A randomized clinical trial in primary care. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia and increases the risk of ischemic stroke 4 to 5-fold. The first choice of anticoagulant therapy (AT) is the vitamin K antagonist (VKA). Contraindication to VKA or poor control of the International Normalized Ratio leads to the administration of direct-acting oral anticoagulants. There is a trend toward inadequate AT in nonvalvular AF (NVAF) patients. AIM: To evaluate the impact of the implementation of a decision support tool linked to the digital clinical history on the adequacy of AT, the incidence of complications, and the mortality in patients with NVAF in primary care centers (PCCs) of the Catalan Institute of Health (ICS). METHODS AND ANALYSIS: Randomized clinical trial in 287 PCCs, formed by 2 groups (intervention and control). POPULATION: patients controlled in PCCs, diagnosed with NVAF 1 year before the implementation of the decision support tool and with VKA treatment over a minimum of 1 year. A simple randomization method will be performed at a sector level. The decision support tool will be available for 1 year. The time in therapeutic range (TTR) will be available in the digital clinical history only to professionals of the intervention group. The information system for primary care research development database will be used for the data extraction. Statistical analysis will be done at 3 time points: before the implementation of the tool, at 1 year, and at 2 years after the beginning of the intervention. Multilevel (patient and professional levels) logistic regression models will be used to estimate the effect of the intervention. ETHICS AND DISSEMINATION: This study protocol was approved by the Ethical Committee of Clinical Investigation of the Institut Universitari d'Investigacio en Atencio Primaria Jordi Gol (code P17/091). Articles will be published in scientific journals. TRIAL REGISTRATION: Clinical-Trials.gov: NCT03367325. PMID- 29504982 TI - Extramedullary plasmacytoma of the trachea: A case report and review of the literature. AB - RATIONALE: Extramedullary plasmacytomas (EMPs) are rare solitary soft tissue tumors characterized by monoclonal proliferation of plasma cells. Most lesions occur in the head and neck, but primary tracheal lesions are very rare. PATIENT CONCERNS: In this report, we describe a case of tracheal EMP discovered in a 48 year-old man who presented with a history of progressive dyspnea. DIAGNOSES: Computed tomography (CT) revealed a well-defined nodular mass in the posterior wall of trachea without signs of invasion of the tracheal walls. Then, a reddish mass occluding approximately 90% of the trachea was evidenced by bronchoscopic examination. INTERVENTIONS: The patient was treated with surgery followed by adjuvant radiotherapy to achieve better local control. OUTCOMES: After the surgery, there was immediate symptomatic relief. There was no recurrence or metastasis during a 6-month follow-up. LESSONS: This study presents a rare case of tracheal EMP occluding approximately 90% of the lumen that was successfully managed by surgery followed by radiotherapy. PMID- 29504983 TI - Peripheral mucous gland adenoma of the lung with parenchymal involvement and smooth muscle in the stroma: A rare case report and literature review. AB - RATIONALE: Mucous gland adenoma is an extremely rare benign tumor predominately presented in central bronchus. Thus far, only six cases located in the periphery have been reported in English literature. PATIENT CONCERNS: Herein, we report a case located in periphery of the lung with parenchymal involvement in a 59-year old female. Histologically, the tumor appeared as peripheral lobulated and solid mass with the pushing border. The tumor was composed of abundant irregular glands, mucus-filled acini and tubules lined by bland cuboidal to columnar mucus secreting epithelial cells lacking cellular atypia and mitotic activities. Moreover, the tumor contained fibromyxoid stroma with smooth muscular bundles and prominent lymph follicles, which has not been reported in previous cases. DIAGNOSIS: Based on the morphological profile and immunohistochemical staining, the tumor was diagnosed as a mucous gland adenoma. INTERVENTION: The patient then underwent wedge resection in our hospital. OUTCOMES: The patient was alive with no tumor recurrence or metastasis within 16 months of follow-up. LESSONS: We report a peculiar case of mucous gland adenoma that occurred in the periphery of the lung and involved the parenchyma. The present case reported the smooth muscular bundles presenting in the stroma, which could broaden the histologic profile of the tumor. PMID- 29504984 TI - Are phosphodiesterase type 5 inhibitors associated with increased risk of melanoma?: A systematic review and meta-analysis. AB - Phosphodiesterase type 5 (PDE5) inhibitors are recommended for patients with erectile dysfunction by American Urological Association and European Association Urology guidelines. However, recent researches have shown that PDE5 inhibitors may lead to increased melanoma risk. Thus, we aimed to explore whether PDE5 inhibitors are associated with increased melanoma risk based on published literatures.We conducted a systematic online search on PubMed, EMBASE, Cochrane Library, Chinese Biochemical Literature, China National Knowledge Infrastructure, and Chinese Science and Technology Periodical databases to identify the related studies. Odds ratios (ORs), risk ratios, and hazard ratios with 95% confidence intervals (CIs) were extracted and calculated to assess the strength of associations between PDE5 inhibitors and melanoma risk. We also extracted the basal cell carcinoma (BCC) to validate the association in this study.We included 5 studies containing 100,932 participants in our systematic review and meta analysis. The calculated results suggested positive results of PDE5 inhibitors on melanoma risk (OR: 1.13; 95%CI: 1.04-1.23). For localized and nonlocalized melanoma, the results were different (OR: 1.22; 95%CI: 1.04-1.43 for localized melanoma) (OR: 0.62; 95%CI: 0.39-0.98 for nonlocalized melanoma). It also showed that PDE5 inhibitors were associated with increased BCC risk (OR: 1.18; 95%CI: 1.11-1.27).The association between PDE5 inhibitors and melanoma might not be causal due to potential bias (patient selection, and so on) and limitations. PMID- 29504985 TI - Effectiveness and neural mechanisms of home-based telerehabilitation in patients with stroke based on fMRI and DTI: A study protocol for a randomized controlled trial. AB - BACKGROUND: Stroke is one of leading diseases causing adult death and disability worldwide. Home-based telerehabilitation has become a novel approach for stroke patients as effective as conventional rehabilitation, and more convenient and economical than conventional rehabilitation. However, there is no study assessing the mechanism of home-based telerehabilitation in promoting motor recovery among stroke patients with hemiplegic. AIMS: This study is designed to determine the efficacy and explore the mechanism of motor recovery after home-based telerehabilitation in stroke patients with motor deficits. METHODS/DESIGN: In a single-blinded randomized controlled pilot study, patients with acute subcortical stroke (n = 40) are assigned to receive home-based telerehabilitation or conventional rehabilitation. Task-based or resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI), and Fugl-Meyer assessment (FMA) score will acquired before and after rehabilitation. Activation volume of bilateral primary motor (M1), supplementary motor area (SMA), premotor cortex (PMC); lateralization index (LI) of interhemispheric M1, SMA, and PMC; functional connectivity of bilateral M1, SMA, PMC; fractional anisotropy (FA) will be measured; correlation analyses will be performed between neuroimaging biomarkers and FMA score pre- and postrehabilitation. DISCUSSION: We present a study design and rationale to explore the effectiveness and neural mechanism of home-based rehabilitation for stroke patients with motor deficits. The study limitations related to the small-amount sample. Moreover, home-based rehabilitation may provide an alternative means of recovery for stroke patients. Ultimately, results of this trial will help to understand the neural mechanism of home-based telerehabilitation among stroke patients with hand movement disorder. PMID- 29504986 TI - Impending thyroid storm in a pregnant woman with undiagnosed hyperthyroidism: A case report and literature review. AB - RATIONALE: Thyroid storm is a rare complication during caesarean section of patients with hyperthyroidism. It occurs abruptly, with a high mortality rate if not recognized immediately and aggressively treated. Herein, we reported a case of impending thyroid storm during a caesarean section. PATIENT CONCERNS: A healthy 23-year-old woman with undiagnosed hyperthyroidism underwent an emergency caesarean section under general anesthesia. After tracheal extubation, the patient exhibited abnormal tachycardia, agitation, sweating, and hyperpyrexia. DIAGNOSES: The clinical manifestation and the following thyroid function test indicate a high index of suspicion for impending thyroid storm. INTERVENTIONS: Hydrocortisone and esmolol were intravenously administered immediately. Propylthiouracil and propranolol were orally administered after the patient regained complete consciousness. OUTCOMES: Due to our immediate recognition and aggressive treatment, more serious manifestations of thyroid storm were avoided. LESSONS: Good antenatal care is very important for pregnant women, and they should be generally screened for thyroid disorders, especially if the resting heart rate is >100 beats/min and weight increases are inconsistent with gestational age. When hyperthyroidism is suspected, drugs that excite the sympathetic nerves or promote the release of histamine should not be used during caesarean section. PMID- 29504987 TI - Isolated skeletal muscle recurrence of an originally nodal diffuse large B cell lymphoma: A case report and review of the literature. AB - RATIONALE: Diffuse large B cell lymphoma (DLBCL) is a malignancy of the B cells with extranodal primary involvement being estimated at 30% to 40% of cases. Primary skeletal muscle presentation of DLBCL is extremely rare, with an estimated incidence of about 0.5% of extranodal lymphomas, presenting mostly in the lower extremities. The possible mechanisms of muscle involvement of DLBCL include primary extranodal disease, extension from adjacent organs (such as lymph nodes) or disseminated disease. PATIENT CONCERNS: We report a case of a 70-year old woman with an advanced initially nodal DLBCL, treated with R-CHOP, that presented with an enlargement of her left thigh and restricted mobility 3 months after completion of chemotherapy. Imaging studies were performed, which showed possible infiltration of the muscles of the left thigh, without any nodal disease present. DIAGNOSES: Muscle biopsy documented the recurrence of the lymphoma at the left thigh. INTERVENTIONS: The patient started second-line treatment with gemcitabine and vinorelbine. OUTCOMES: A partial response was achieved after the first cycle. LESSONS: The remarkable element lies in the reappearance of the lymphoma at the left thigh muscles, with no radiographic or clinical evidence of involvement of lymph nodes, despite the extensive lymph node disease at initial presentation. The further management of such recurrences remains to be clarified, as the odd biological behavior of the malignant cells dictates a special handling of the disease. PMID- 29504988 TI - Clinical and urodynamic characteristics of underactive bladder: Data analysis of 1726 cases from a single center. AB - There have no universally accepted criteria and have been established for classification of underactive bladder (UAB) at present. Thus, the study described the comprehensive clinical and urodynamic characteristics of UAB in patients with lower urinary tract symptoms.A total of 1726 patients (1259 men and 467 women; 6 88 years old) who were admitted to our center with a diagnosis of UAB were included in this retrospective study. It was due to the type of rehabilitation hospital, so higher percentage of neurological patients were included. The demographics, clinical characteristics, and urodynamic recordings were reviewed. The clinical characteristics and urodynamic findings of UAB were further classified.For the etiologic analysis, UAB with aging and without clear causes accounted for 11.5% of cases (199/1726), UAB with bladder outflow obstruction accounted for 2.6% (45/1726), and UAB acting on the nerve pathway of the voiding reflex accounted for 84.6% (1460/1726). There were a number of cases (1.3% [22/1726]) which had >2 factors assigned. For studies involving urodynamic findings and clinical symptoms, the percentage of patients with detrusor hyperreflexia with impaired contractility (DHIC), detrusor underactivity (DU), and acontractile detrusor (AcD) was 0.7%, 5.6%, and 93.7%, respectively.UAB can be classified into 4 types based on possible etiologic mechanisms (idiopathic, myogenic, neurogenic, and integrative). Based on urodynamic findings and symptoms, UAB can be classified into 3 types (DU, AcD, and DHIC). The classification of UAB can provide a reasonable basis for the future research. PMID- 29504989 TI - Induced abortion and breast cancer: An updated meta-analysis. AB - Different epidemiological studies have indicated conflicting information about the association of induced abortion (IA) with breast cancer risk. A recent meta analysis with prospective evidences did not support the positive association between IA and breast cancer risk. Thus, we in our meta-analysis study have tried to analyze this specific association.We searched all relevant articles from an English-language literature using Pubmed, Embase, and Cochrane databases, until December 10, 2016. All the statistical analyses were performed on case-control studies, using Review Manager Software 5.3 (Cochrane Collaboration, Oxford, UK).Our meta-analysis results based on 25 studies, including 5 studies with Chinese patients, indicated that there was no association of IA with breast cancer (OR = 1.08, 95% CI 0.98-1.19, P = .1). However, significant heterogeneity was observed, and thus further subgroup analyses were conducted. The combined OR of subjects with only 1-time IA was 1.03, 95% CI 0.90 to 1.18, P = .63, while for subjects with 2 or more IAs, it was 1.06, 95% CI 0.86 to 1.30, P = .58. In addition, the ORs of subjects, with 1st IA age either less than 30 or older than 30, were 1.05, 95% CI 0.88 to 1.26, P = .59, and 1.18, 95% CI 0.93 to 1.49, P = .17, respectively. These observations indicated that number of IAs and the age of 1st IA were not associated with breast cancer risk. Due to lack of dose-response relationships, it is difficult to say if number of IAs contributed into statistical heterogeneity. But after subgroup analysis, the age at the 1st IA appeared to impact the statistical heterogeneity. The different reproductive history appears to account for the high heterogeneity among individual studies. Also analysis of nulliparous women showed no significant difference in the association of IA and breast cancer (OR = 1.02, 95% CI 0.86-1.21, P = .85). However, parous women had higher IA rate in case group than control group (OR = 1.11, 95% CI 1.02-1.20, P = .01). Ethnicities might also result in high heterogeneity; thus, we conducted subgroup analyses on Chinese subjects, importantly, with 5 studies having Chinese patients, and did not observe any difference in the incidence of IA and its association with breast cancer between case and control groups (OR = 1.05, 95% CI 0.97-1.13, P = .21).After subgroup analysis, our study showed that IA might increase the risk of breast cancer in parous women, but in the nulliparous, IA was not significantly associated with an increased risk of breast cancer. PMID- 29504990 TI - Prognostic significance of circulating soluble programmed death ligand-1 in patients with solid tumors: A meta-analysis. AB - BACKGROUND: The prognostic significance of circulating soluble programmed death ligand-1 (sPD-L1) in patients with solid tumors remains unclear. We performed a meta-analysis to address this issue. METHODS: Several electronic databases were searched from January 1970 to May 2017. The hazard ratios (HRs) and 95% confidence interval (95% CI) were calculated to determine the relationship between the level of soluble PD-L1 in peripheral blood and patient overall survival. RESULTS: A total of 1040 patients with solid tumors from 8 eligible studies were included in the present meta-analysis. The pooled HR suggested that a high level of soluble PD-L1 (sPD-L1) in peripheral blood was significantly correlated with a worse overall survival (HR = 2.26, 95% 1.83-2.80, Z = 7.51, P < .001). CONCLUSION: The present meta-analysis demonstrated that a high level of soluble PD-L1 in peripheral blood significantly predicts poor prognosis in patients with solid tumors, suggesting that high level of sPD-L1 may serve as a predictive biomarker for poor prognosis. PMID- 29504991 TI - Delayed retroperitoneal arterial hemorrhage after inferior vena cava filter deployment: A case report. AB - RATIONALE: Pulmonary embolization is a life-threatening condition. The deployment of inferior vena cava (IVC) filter is the first choice for preventing embolus from the lower extremity. However, IVC filter complications are rare but not to be neglected. Penetration of the arterial wall may result in catastrophic damages. This case report describes a woman who suffered from retroperitoneal hemorrhage after placement of an IVC filter due to a pulmonary embolization. Her filter was found to have penetrated the right lumbar artery and caused the massive bleeding. She was successfully treated with endovascular coil embolization. PATIENT CONCERNS: A 47-year old woman presenting with pulmonary embolization was admitted to our hospital. An IVC filter was deployed. Twenty days after her operation, she suffered from an intolerable lumbago when bending over. Contrast-enhanced computed tomography at the local hospital showed a massive retroperitoneal hematoma adjacent to the IVC filter. DIAGNOSES: Contrast enhanced CT at the local hospital showed a massive retroperitoneal hematoma adjacent to the IVC filter. Thereafter, she was transferred to our hospital. Her hemoglobin and INR were 7.1 g/dl and 3.4, respectively. Her systolic blood pressure decreased to 70 mmHg with heart rate increasing to 110 beats/min. The shock index was greater than 1.5. INTERVENTIONS: Angiography of the abdominal aorta showed extravasation of contrast medium from the right third lumbar artery. Embolization of the lumbar arteries was performed with coils. OUTCOMES: Several days later, she recovered with hematoma shrinking in size and was discharged from the hospital with stable condition. LESSONS: It highlights that appropriate monitoring of patients with IVC filters is an essential part during the long-term management. Endovascular treatment showed a safe and effective way to treat arterial perforation caused by hooks of inferior vena cava filters. PMID- 29504992 TI - Overexpression of NEK3 is associated with poor prognosis in patients with gastric cancer. AB - The NIMA-related kinase 3 (NEK3) plays an important role in cell migration, cell proliferation, and cell viability. Recently, NEK3 was reported to enhance the malignancy of breast cancer. However, its role in gastric cancer has not been completely characterized. In this study, we explored the prognostic significance of NEK3 in human gastric cancer. Reverse transcription-polymerase chain reaction and western blot were performed to detect the NEK3 mRNA and protein expression in 6 paired fresh human gastric cancer tissues and surrounding normal tissues. NEK3 levels in gastric cancer and its adjacent normal samples of 168 cases were detected by immunohistochemistry, and the relationships between the NEK3 level and various clinicopathological features were analyzed. NEK3 mRNA and protein were significantly overexpressed in gastric cancer tissues, compared with adjacent normal tissues. Immunohistochemistry staining assay showed the percentage of high NEK3 expression in gastric cancer samples was higher than that in adjacent normal samples. NEK3 overexpression was significantly correlated with pT stage, pathologic TNM stage, lymph node metastasis, and poor prognosis of gastric cancer. Cox multivariate regression analyses suggested that NEK3 was an independent prognostic factor for survival of patients with gastric cancer. The data demonstrate that NEK3 is overexpressed in gastric cancer, which promotes the malignancy of gastric cancer. NEK3 may be as a prognostic biomarker and a potential therapeutic target for gastric cancer. PMID- 29504993 TI - The genetic diversity of hepatitis A genotype I in Bulgaria. AB - The purpose of this study was to analyze sequences of hepatitis A virus (HAV) Ia and Ib genotypes from Bulgarian patients to investigate the molecular epidemiology of HAV genotype I during the years 2012 to 2014. Around 105 serum samples were collected by the Department of Virology of the National Center of Infectious and Parasitic Diseases in Bulgaria. The sequenced region encompassed the VP1/2A region of HAV genome. The sequences obtained from the samples were 103. For the phylogenetic analyses, 5 datasets were built to investigate the viral gene in/out flow among distinct HAV subpopulations in different geographic areas and to build a Bayesian dated tree, Bayesian phylogenetic and migration pattern analyses were performed. HAV Ib Bulgarian sequences mostly grouped into a single clade. This indicates that the Bulgarian epidemic is partially compartmentalized. It originated from a limited number of viruses and then spread through fecal-oral local transmission. HAV Ia Bulgarian sequences were intermixed with European sequences, suggesting that an Ia epidemic is not restricted to Bulgaria but can affect other European countries. The time-scaled phylogeny reconstruction showed the root of the tree dating in 2008 for genotype Ib and in 1999 for genotype Ia with a second epidemic entrance in 2003. The Bayesian skyline plot for genotype Ib showed a slow but continuous growth, sustained by fecal-oral route transmission. For genotype Ia, there was an exponential growth followed by a plateau, which suggests better infection control. Bidirectional viral flow for Ib genotype, involving different Bulgarian areas, was observed, whereas a unidirectional flow from Sofia to Ihtiman for genotype Ia was highlighted, suggesting the fecal-oral transmission route for Ia. PMID- 29504994 TI - Evaluation of frailty and influencing factors in old people in hospital institution: Evidence for a phenotype of frailty. AB - We assessed the frailty status of inpatients and analyzed the factors influencing frailty status to explore the reasons for frailty and identify feasible intervention strategies.A total of 1494 geriatric patients aged >=60 years were recruited as subjects. All patients were hospitalized between September 2014 and August 2015 in the internal medicine units of 3 hospitals in Chongqing and Zunyi in the southwestern area of China. Patients' frailty status was evaluated using the Phenotype of Frailty scale, via face-to-face interviews coupled with physical examinations using simple equipment.Of the 1494 cases, 1400 (93.71%) were eligible for analysis. Participants' mean age was 75.52 +/- 9.28 years. The overall prevalence of frailty was 18.0%, and was higher for frail females (9.4%) than males (8.6%). Increasing age and body mass index, low income (<1000 Ren Min Bi for per month), poor self-rated health, cognitive impairment, depression, polypharmacy (>=5 medications), disability, and a history of fall in the past 1 year were independently significantly correlated with frailty (P < .05 for each comparison).Numerous factors were associated with frailty. As treatment for frailty is focused on prevention in this study, intervention strategies should target a comprehensive list of physiological and psychological aspects of the older people. PMID- 29504995 TI - Necessity of adjuvant postoperative radiotherapy for diffuse pigmented villonodular synovitis of the knee: A case report and literature review. AB - RATIONALE: Pigmented villonodular synovitis (PVNS) is an idiopathic, proliferative disorder lesion of synovial tissue, which is regarded as a benign disease, but has a local invasion. Up to now, these are no consensus about the etiology and pathogenesis of PVNS. Because of the lack of typical clinical features, misdiagnosis and delayed diagnosis are not uncommon, magnetic resonance imaging (MRI) can assist diagnosis and histopathological examination is recognized as the gold standard for the final diagnosis. Because this disease is so rare, there is no standard treatment. Surgical resection of the lesion is considered the preferred treatment, but postoperative recurrence is a problem that cannot be ignored. Postoperative radiotherapy is necessary, especially for patients with diffuse PVNS of the knee. PATIENT CONCERNS: A 27-year-old female teacher presented with 3 years chronic pain of the right knee, and progressive swelling aggravated for 1 week. The range of motion of the knee was limited. DIAGNOSES: Clinical and laboratory examination failed to provide definitive diagnosis. Imaging can assist in diagnosis, and pathology is the gold standard. Erythrocyte sedimentation rate (ESR), antihemolytic streptococcus O (ASO), and rheumatoid factors (RF) were all negative. Joint puncture revealed giant cell tumor of the synovial membrane. PVNS was confirmed by postoperative pathology. The characteristic T2 weighted low signal of MRI suggests the recurrence of PVNS. INTERVENTIONS: The patient underwent 2 stages of treatment: open synovectomy was performed in the first place and postoperative external radiotherapy was not considered. After 2 years of disease-free remission, she was diagnosed with a recurrence of the disease by MRI. Further, arthroscopic total synovectomy of the right knee was performed and external beam radiotherapy was carried out after the operation. OUTCOMES: Up to now, the patient was followed up for 3 years without any sign of recurrence. LESSONS: Adjuvant postoperative radiotherapy can improve the local control rate, it is a reliable treatment method for diffused PVNS. PMID- 29504996 TI - Influence of proton pump inhibitors on clinical outcomes in coronary heart disease patients receiving aspirin and clopidogrel: A meta-analysis. AB - BACKGROUND: Proton pump inhibitors (PPIs) are usually prescribed to protect against gastrointestinal bleeding in patients on dual antiplatelet therapy. This meta-analysis reviewed clinical outcomes in patients taking aspirin and clopidogrel, with and without concomitant PPIs to address concerns of adverse reactions. METHODS: We searched PubMed, Embase, and the Cochrane Library for articles published between January 1, 2010 and April 11, 2017. The primary end points were major adverse cardiovascular events and gastrointestinal bleeding. Secondary end points were myocardial infarction, stent thrombosis, revascularization, cardiogenic death, and all-cause mortality. RESULTS: The meta analysis included 33,492 patients in 4 randomized controlled trials and 8 controlled observational studies. Overall, patients taking PPIs had statistical differences in major adverse cardiovascular events [odds ratio (OR) 1.17 (95% confidence interval [CI] 1.07-1.28); P = .001; I = 28.3%], gastrointestinal bleeding [OR 0.58 (95% CI 0.36-0.92); P = .022; I = 80.6%], stent thrombosis [OR 1.30 (95% CI 1.01-1.68); P = .041; I = 0%], and revascularization [OR 1.20 (95% CI 1.04-1.38); P = .011; I = 5.1%], compared those not taking PPIs. There were no significant differences in myocardial infarction [OR 1.03 (95% CI 0.87-1.22); P = .742; I = 0%], cardiogenic death [OR 1.09 (95% CI 0.83-1.43); P = .526; I = 0%], or all-cause mortality [OR 1.08 (95% CI 0.93-1.25); P = .329; I = 0%). CONCLUSIONS: Among the patients taking aspirin and clopidogrel, the results indicated that the combined use of PPIs increased the rates of major adverse cardiovascular events, stent thrombosis, and revascularization. PMID- 29504997 TI - Clinicopathological features of combined hepatocellular-cholangiocarcinoma with sarcomatous change: Case report and literature review. AB - RATIONALE: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver malignancy comprising <1.5% of all primary liver tumors. Sarcomatoid changes in cHCC-CC are even rarer. Due to the rarity of this subtype, its clinicopathological feature is poorly understood. Therefore, here we report 2 tumors. PATIENT CONCERNS: The first patient was a 44-year-old man with 5-year history of hepatitis B-induced cirrhosis. The resection of right liver revealed a 2.5 * 2.5 * 2 cm tumor mass. Histologically, the tumor showed areas of the typical moderately differentiated HCC. An intermingled adenocarcinoma with pleomorphic and spindle-shaped cells was also identified. The second case involved a 54-year-old man with a history of hepatitis B-induced cirrhosis. A 3.5 * 3 * 3 cm mass was found in the middle left of falciform ligament. Microscopically, the tumor consisted of spindle-shaped sarcomatoid carcinoma cells mixed with typical well-differentiated HCC and well-differentiated CC. DIAGNOSES: According to the clinicopathological features, diagnosis of cHCC-CC with sarcomatous change was made. INTERVENTIONS: In the first case, right lobectomy of the liver was performed. The second patient underwent laparoscopic, hepatic left lateral lobectomy. OUTCOMES: The first patient was alive and well 10 years after the surgical resection without additional treatment. In second case, at 8 months after surgical resection, there was no evidence of recurrence or metastasis. LESSONS: In this report, we describe 2 rare cases of cHCC-CC with sarcomatous change, and findings are helpful for the pathologists would like to further identify the clinicopathological features of this rare tumor. PMID- 29504998 TI - Elevated red blood cell distribution width contributes to poor prognosis in patients undergoing resection for nonmetastatic rectal cancer. AB - Several studies have reported that elevated red blood cell distribution width (RDW) was associated with the poor prognosis of different kinds of cancers. The aim of this study was to investigate the prognostic role of RDW in patients undergoing resection for nonmetastatic rectal cancer.We retrospectively reviewed a database of 625 consecutive patients who underwent curative resection for nonmetastatic rectal cancer at our institution from January 2009 to December 2014. The cutoff value of RDW was calculated by receiver-operating characteristic curve.The results demonstrated that patients in high RDW-cv group had a lower overall survival (OS) (P = .018) and disease-free survival (P = .004). We also observed that patients in high RDW-sd group were associated with significantly lower OS (P = .033), whereas the disease-free survival (DFS) was not significantly different (P = .179).In multivariate analysis, we found elevated RDW-cv was associated poor DFS (hazard ratio [HR] = 1.56, P = .010) and RDW-sd can predict a worse OS (HR = 1.70, P = .009).We confirmed that elevated RDW can be an independently prognostic factor in patients undergoing resection for nonmetastatic rectal cancer. So more intervention or surveillance might be paid to the patients with nonmetastatic rectal cancer and elevated RDW values in the future. PMID- 29504999 TI - Salivary matrix metalloproteinase (MMP)-8 as a biomarker for periodontitis: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Salivary matrix metalloproteinase (MMP)-8 is currently considered to be one of the most promising biomarkers for early diagnosis of periodontitis, however, several recent studies showed conflicting results. OBJECTIVE: To determine the salivary matrix metalloproteinase (MMP)-8 levels between periodontitis patients and healthy individuals, and to assess its diagnostic value in periodontitis. METHODS: Literatures were searched on PubMed and Embase databases up to August 2017, for articles reporting salivary MMP-8 levels between periodontitis patients and health controls with the data of means +/- standard deviation (SD). Methodological quality was assessed by the Newcastle Ottawa scale (NOS). Standard mean differences (SMDs), heterogeneity, and publication bias were assessed by Stata 13.0 software. RESULTS: A total of 10 studies including 485 periodontitis patients and 379 healthy controls that met the preset inclusion criteria were included, the qualities of these studies were either good (n = 7) or moderate (n = 3). Eight studies showed salivary MMP-8 levels were higher in periodontitis patients compared with healthy controls (P < .05), while 2 studies showed opposite results (P > .05). The pooled SMD was 1.195 (95% CI: 0.720 1.670), with I of 89.3%, indicating high heterogeneity. Funnel plot showed publication bias existed. CONCLUSION: Our meta-analysis showed that salivary MMP 8 levels were significantly higher in periodontitis patients compared with healthy controls overall. Due to the heterogeneity and publication bias of included studies, further high quality studies are still needed to verify the conclusion. PMID- 29505000 TI - Biliary exploration via the left hepatic duct orifice versus the common bile duct in left-sided hepatolithiasis patients with a history of biliary tract surgery: A randomized controlled trial. AB - BACKGROUND: Hepatectomy and additional common bile duct exploration are required for the treatment of left-sided hepatolithiasis (LSH). METHODS: Eligible LSH patients (n = 62) scheduled for open left lateral segmentectomy or left hemihepatectomy with intraoperative biliary exploration via the left hepatic duct orifice (LHD group, n = 35) or the common bile duct (CBD group, n = 27) were retrospectively studied. T-tube insertion was performed on selected patients. Primary outcome measures included overall operative time, length of hospital stay, intraoperative complications, residual stones, and postoperative bile leaks. RESULTS: There were no residual stones observed in the 2 groups. Ten patients in the CBD group received T-tube placement, whereas no patients in the LHD group received T-tube placement. There were more patients in the CBD group suffered intraoperative complications and postoperative bile leakage than LHD group (P < .05). The LHD group had a significantly shorter operative time and hospitalization than the CBD group (P < .05). CONCLUSION: For left-sided hepatolithiasis patients with a history of biliary tract surgery, LHD cholangioscopy is an accessible technique that simplifies the operation procedure by avoiding choledochotomy and subsequent T-tube insertion, which results in lower complication rates as well as shorter operative duration and length of hospitalization. PMID- 29505001 TI - Acute lymphoblastic leukemia arising after treatment of Ewing sarcoma was misdiagnosed as bone marrow metastasis of Ewing sarcoma: A case report. AB - RATIONALE: Both acute lymphoblastic leukemia (ALL) and Ewing sarcoma (ES) are small round cell tumors, and it is difficult to differential diagnose them because of overlapping clinical, radiographic, histologic, and immunophenotypic features. PATIENT'S CONCERNS: A 5-year-old boy was admitted to our hospital because of pains in his left leg without obvious inducement and lameness worsening with walking over a two 2-month period. DIAGNOSES: Based on the comprehensive analysis of radiography, magnetic resonance imaging (MRI), pathology biopsy and immunohistochemistry, the lesion was confirmed to be ES. INTERVENTIONS: The patient received neoadjuvant chemotherapy with 2 cycles of VAC (vincristine 1 mg/m, adriamycin 50 mg/m, cyclophosphamide 800 mg/m) and 2 cycles of IE (ifosfamide 1.2 g/m, etoposide 70 mg/m, mesna 1.2 g/m) regimens. OUTCOMES: After 16 months, the results of routine blood tests showed reduced hemoglobin levels and decreased platelet counts. In addition, blast-like cells were found in a peripheral blood smear. All of the results suggested that the patient should undergo bone marrow aspiration and biopsy, which showed blast-like cells similar to that observed in cases of ES. Thus, a diagnosis of bone marrow metastasis of ES was established. However, when combined with immunohistochemistry data and medical history, the patient was eventually diagnosed as ALL arising after treatment of ES. LESSONS: When there was an abnormality in peripheral blood, it was easily misdiagnosed as bone marrow metastasis of ES after ES patient received neoadjuvant chemotherapy. We should jointly analyze bone marrow aspiration smear, bone marrow biopsy, immunohistochemistry, analysis of the medical history, even cytogenetic and molecular analysis for differential diagnosis. PMID- 29505002 TI - Case report of primary intestinal lymphangiectasia diagnosed in an octogenarian by ileal intubation and by push enteroscopy after missed diagnosis by standard colonoscopy and EGD. AB - RATIONALE: Primary intestinal lymphangiectasia (PIL) is a rare, presumably congenital lesion that is usually diagnosed in patients < 3 years old, is rarely first diagnosed in adulthood, and when first diagnosed in adulthood typically presents with symptoms for many years. Although PIL is often identified by endoscopic abnormalities, it must be emphasized that the jejunoileum/distal duodenum must be intubated for diagnosis because the lesions are present in these regions. This work demonstrates that 1)-PIL can occur in an octogenarian; 2) shows that the characteristic endoscopic findings are not found at colonoscopy without terminal ileal intubation; and 3)-may be missed at standard EGD without distal duodenal intubation. DIAGNOSES: A patient initially presented at age 83 with symptoms of watery diarrhea, abdominal distention, 5-Kg-weight-gain, and weakness for one month, and had typical clinical findings of PIL including chylous ascites, pleural effusions, bilateral pitting leg edema, hypoalbuminemia, borderline lymphopenia, hypovitaminosis-D, and hypocalcemia. Protein-losing enteropathy was demonstrated by positive stool tests for alpha-1-antitrypsin. Standard colonoscopy revealed no significant lesions, but terminal ileal intubation during colonoscopy demonstrated creamy-white, punctate, mucosal lesions in terminal ileum, characteristic of lymphangiectasia. EGD with intubation to mid-descending duodenum revealed no significant lesions, but subsequent enteroscopy demonstrated lesions in distal duodenum/proximal jejunum similar to those in terminal ileum characteristic of lymphangiectasia. Histopathologic analysis of lesions of terminal ileum/distal duodenum demonstrated dilated mucosal vessels, confirmed as lymphatic vessels by immunohistochemistry. PIL was diagnosed after excluding secondary causes of intestinal lymphangiectasia. INTERVENTIONS/OUTCOMES: Patient placed on standard PIL diet: oral supplements of medium-chain triglycerides, a high protein diet, supplements of fat-soluble vitamins, and avoiding long-chain fatty acids, with marked clinical improvement. LESSONS: This work shows that: 1)-standard EGD and colonoscopy may miss characteristic lesions of PIL, 2)-enteroscopy or terminal ileal intubation at colonoscopy may be required for the diagnosis because lesions are typically located in distal duodenum/jejunoileum; and 3)-PIL can first present in the very elderly even with symptoms of short duration. PMID- 29505003 TI - Successful revascularization of noninfarct related artery with chronic total occlusion among acute myocardial infarction patients: A systematic review and meta-analysis. AB - BACKGROUND: Randomized trials and meta-analyses demonstrated that chronic total occlusion (CTO) in noninfarct related artery (n-IRA) was associated with increased all-cause mortality. Recently, several observational studies suggested that the successful revascularization of n-IRA with CTO decreased all-cause mortality. METHODS: A systematic search was performed in Cochrane Controlled Trials Registry, PubMed, MEDLINE, and EMBASE databases for relevant studies. Article assessing the prognostic role of revascularization of n-IRA with CTO was enrolled in this meta-analysis. Data and characteristics of each study were extracted. A meta-analysis was performed to generate pooled odds ratio (OR) and 95% confidence intervals (95% CIs) for outcomes. The primary outcome was major adverse cardiac events (MACE). Beg funnel plot was used to evaluate publication bias. RESULTS: Four observational studies and one randomized controlled trial involving 1083 patients were enrolled for analysis. Compared with nonreperfusion, the successful percutaneous coronary intervention (PCI) of n-IRA with CTO was related to decreased all-cause mortality (OR was 0.34, and 95% CI was 0.2-0.59; P = .0001). CONCLUSIONS: Successful PCI of n-IRA with CTO could significantly decrease all-cause mortality, cardiac mortality, MACE, and stroke in acute myocardial infarction patients. In addition, it was not associated with the increased risk of repeat revascularization and myocardial infarction. PMID- 29505004 TI - Fungemia caused by Penicillium marneffei in an immunocompetent patient with COPD: A unique case report. AB - RATIONALE: This report describes a rare case in Wenzhou city of Zhejiang province that a non-HIV infected male recovering from fungemia caused by Penicillium marneffei (P. marneffei). Interestingly, it's very easy to misdiagnose with aspergillosis, a fungal disease prevalent in Wenzhou, during the whole procedure. PATIENT CONCERNS: An 80-year-old Chinese male subject with pre-existing chronic obstructive pulmonary disease (COPD) presented with symptoms of chest tightness and high fever for a month. DIAGNOSES: Fungal culture from the blood isolated P marneffei. Naturally, the patient was diagnosed with P marneffei fungemia. However, he was proven serologically to be negative for human immunodeficiency virus (HIV). INTERVENTIONS: The patient was treated with voriconazole at 200mg/dL every 12 hours via intravenous administration. OUTCOMES: The fever returned to normal and chest tightness disappeared gradually after a week of voriconazole treatment. LESSONS: A high level of clinical suspicion and awareness is necessary for early diagnosis of P marneffei fungemia, especially in elder patients with underlying diseases. PMID- 29505005 TI - Diaphragmatic hernia as a rare complication of colonoscopy: Case report and literature review. AB - RATIONALE: Diaphragmatic Hernia is rare as complication of Colonoscopy. Diaphragmatic hernia as a complication of colonoscopy has been reported only few cases. Additionally, it is often misdiagnosed as other disease by clinicians due to their lack of related knowledge, which delays diagnosis of Diaphragmatic hernia and thus exacerbates the prognosis. PATIENT CONCERNS: We report the case of a 66-year-old man with fecal occult blood. In the case, sudden epigastric pain after colonoscopy owing to diaphragmatic hernia in a left hemidiaphragm. DIAGNOSES: The diagnoses made by a CT scan without delay. It showed marked protrusion of the large bowel into the left thoracic cavity along with elevation of the left diaphragm. INTERVENTIONS: The diaphragmatic defect was repaired by simple closure and intestinal adhesions release surgery. OUTCOMES: Five days after surgery, the patient was discharged in good condition. LESSONS: Most of diaphragmatic hernia is congenital with high mortality. However, there are a few cases of Diaphragmatic hernia caused by previous trauma or surgery. We herein report an unusual case of diaphragmatic hernia related to colonoscopy but usually life-threatening complication. PMID- 29505006 TI - Clinically suspected anaphylaxis induced by sugammadex in a patient with Weaver syndrome undergoing restrictive mammoplasty surgery: A case report with the literature review. AB - RATIONALE: Sugammadex is a cylodextrin derivate that encapsulates steroidal neuromuscular blocker agents and is reported as a safe and well-tolerated drug. In this case report, we present a patient who developed grade 3 anaphylaxis just after sugammadex administration. PATIENT CONCERNS: A 22-year-old woman with diagnosis of Weaver syndrome was scheduled for bilateral mammoplasty and resection of unilateral accessory breast tissue resection. Anesthesia was induced and maintained by propofol, rocuronium, and remifentanil. At the end of the operation, sugammadex was administered and resulted in initially hypotension and bradycardia then the situation worsened by premature ventricular contraction and bigeminy with tachycardia, bronchospasm, and hypoxia. DIAGNOSIS: The Ring and Messmer clinical severity scale grade 3 anaphylactic reaction occurred just after sugammadex injection and the patient developed prolonged hypotension with recurrent cardiac arrhythmias in postoperative 12 hours. INTERVENTIONS: Treatment was initiated bolus injections of ephedrine, epinephrine, lidocaine, steroids and antihistaminic and continued with lidocaine bolus dosages and norepinephrine infusion for the postoperative period. OUTCOMES: The general condition of the patient improved to normal 3 hours after the sugammadex injection, and she was moved to the intensive care unit. At 2nd and 8th hours of intensive care unit follow-up, she developed premature ventricular contraction and bigeminy with the heart rate of 130 to 135 beats/min, which returned to sinus rhythm with 50 mg lidocaine. After that, no symptoms were observed and the patient was discharged to plastic surgery clinic at the following day. LESSONS: Sugammadex may result in life-treating anaphylactic reaction even in a patient who did not previously expose to drug. Moreover, prolonged cardiovascular collapse and cardiac arrhythmias may occur. PMID- 29505007 TI - Severe malnutrition evaluated by patient-generated subjective global assessment results in poor outcome among adult patients with acute leukemia: A retrospective cohort study. AB - To evaluate nutritional status in adult patients with acute leukemia (AL) using patient-generated subjective global assessment (PG-SGA) and to investigate the influence of nutritional status on prognosis.We observationally investigated 68 adult patients with newly diagnosed AL who received PG-SGA at the First Hospital of Jilin University between May 2013 and July 2015. Clinical features, chemotherapy regimens, biochemical indexes, body composition, complete remission (CR) rate, minimal residual disease (MRD), survival time, and side-effects of chemotherapy were compared between patients with and without severe malnutrition.Mean PG-SGA scores of the total patients were 6.1 +/- 4.0, and 19 of 68 (27.9%) patients had severe malnutrition (PG-SGA score >=9). Patients with acute myeloid leukemia (AML) had higher scores than those with acute lymphocytic leukemia (ALL; P = .011) and high-risk patients had higher scores regardless of whether they had AML or ALL (AML, P = .012; ALL, P = .043). Univariate analysis showed that severe malnutrition was correlated with age (P = .041), transferrin (P = .042), Karnofsky Performance Status score (P = .006), and C-reactive protein (CRP) (P = .018). Multivariate analysis demonstrated that severe malnutrition was associated with CRP (hazard ratio [HR] = 1.020, 95% confidence interval [CI]: 1.002-1.039, P = .026). No difference was found in CR rate (P = .831) between patients with and without malnutrition, but those who were severely malnourished had higher MRD (P = .048 in AML patients, P = .036 in ALL patients) and more gastrointestinal side-effects (P = .014). Severe malnutrition was also associated with inferior overall survival (HR = 0.243, 95% CI: 0.063-0.945, P = .041) but not with event-free survival (HR = 0.808, 95% CI: 0.338-1.934, P = .663).Severe malnutrition defined by PG-SGA in adult patients with de novo AL may result in poor outcome. PMID- 29505008 TI - Is the ratio superior to the number of metastatic lymph nodes in addressing the response in patients with papillary thyroid cancer? AB - CONTEXT: The number of metastatic lymph nodes (LNs) and the ratio of metastatic LN (LR) have been reported as predictors of recurrence in papillary thyroid carcinoma (PTC), while the role of LR or the number of metastatic LNs on the clinical response remains unclear. OBJECTIVE: We aimed to compare the prognostic value of LR and the number of metastatic LNs on clinical response in PTC. DESIGN/SETTING/PATIENTS: A total of 384 PTC patients with LN metastases were enrolled in this study, all of whom underwent total or near total thyroidectomy and subsequent radioiodine ablation. MAIN OUTCOME MEASURES: After a mean follow up of 25.7 months, response to initial therapy was classified as excellent response (ER), indeterminate, biochemical incomplete or structural incomplete response. The scatter diagram and receiver operating characteristic (ROC) curve were respectively employed to identify and compare the clinical value of the number of metastatic LNs and LR for predicting ER in different number of dissected LNs (DLNs). Multivariate analyses were further performed to explore the indicator for ER. RESULTS: ER tended to be more concentrate in patients with lower LR and lower number of metastatic LNs in scatter diagram. Although in patients with <=10 DLNs, LR presented higher area under the ROC curve than the number of metastatic LNs in predicting ER (LR: 0.687, LNs, 0.556, P = .02), whereas it turns opposite in those with >10 DLNs. In the multivariate analysis, LR (odds ratio [OR] = 1.037, P = .001) rather than the number metastatic LNs (OR = 0.752, P = .09) was an independent indicator for ER in addition to preablative stimulated thyroglobulin (ps-Tg; OR = 1.056, P = .01) among patients with <=10 DLNs. Although in patients with >10 DLNs, the number of metastatic LNs (OR = 1.062, P = .04) turned to be independent factor for ER, apart from ps-Tg (OR = 1.071, P = .00) and sex (OR = 0.570, P = .02). CONCLUSIONS: LR appears to be a better negative predictor for ER than the number of metastatic LNs in PTC patients with <=10 DLNs, whereas the number of metastatic LNs is superior to LR in those with >10 DLNs. PMID- 29505009 TI - Laparoscopic surgery for primary ovarian and retroperitoneal hydatid disease: A case report. AB - RATIONALE: Cystic echinococcosis (CE) is a parasitic zoonosis caused by echinococcus larvae. Manifestations of the disease include a severe damage to the liver and lung. Damages to the mesentery, omentum, spleen, brain, heart, bone, thyroid, kidney, and uterus are rarely observed. Moreover, primary ovarian and retroperitoneal hydatid disease is extremely rare, and is easily ignored or misdiagnosed. PATIENT CONCERNS: We present a case of CE in a 34-year-old female who presented with an adnexal mass detected by B-ultrasound. Adnexal and retroperitoneal masses were removed by laparoscopic surgery. Postoperative pathological report (retroperitoneal cyst) Echinococcus granulosus. DIAGNOSES: Primary ovarian and retroperitoneal hydatid disease. INTERVENTIONS: The patient received intravenous injection of dexamethasone (10 mg) before cyst resection to prevent allergic reactions and oral albendazole (600 mg BID) for 14 days to prevent relapse postsurgery. OUTCOMES: The patient revealed no recurrence of disease and no reportable significant changes in 3 months. LESSONS: We present here a case report of CE. This case described herein inhabited a nonendemic region. Gentle and careful operation, and avoiding cyst rupture is the key to insuring success of the surgery. For safety, dexamethasone may be used before cyst resection to prevent anaphylaxis, and mebendazole can be used postoperatively to prevent relapse. PMID- 29505010 TI - Anterolateral tibial plateau osteotomy as a new approach for the treatment of posterolateral tibial plateau fracture: A case report. AB - RATIONALE: It is challenging to visualize and reduce a posterolateral tibial plateau fracture through an anterolateral approach as the tibial plateau fragments are often covered by the fibular head and ligamentous structures. PATIENT CONCERNS: In this case report, we describe a patient with a depression fracture of the posterolateral quadrant combined with a split fracture of the posteromedial quadrant and an avulsion fracture of the tibial intercondylar eminence. DIAGNOSES: Tibial plateau fracture(AO type 41-B3). INTERVENTIONS: A posteromedial approach combined with an anterolateral approach and an osteotomy involving the proximal tibiofibular joint of the tibial plateau was used to expose, reduce, and fix the fracture. OUTCOMES: There was no risk of injury to the common peroneal nerve or ligaments. The patient is recovering well and is satisfied with the function of the injured knee. LESSONS: We recommend anterolateral tibial plateau osteotomy for the treatment of posterolateral tibial plateau fractures in clinical practice. PMID- 29505011 TI - Anti epidermal growth factor receptor therapy in small bowel adenocarcinoma: Case report and literature review. AB - RATIONALE: Small bowel adenocarcinoma (SBA) is an uncommon gastrointestinal cancer, thus limited data about treatment for advanced disease are available. The lack of specific guidelines has justified the use of therapeutic protocols usually applied in advanced colorectal cancer. Few and preliminary data have suggested possible clinical benefit from the use of target therapy such as bevacizumab and cetuximab. PATIENT CONCERNS: We present the case of a young woman who was admitted to the emergency department for acute abdominal pain, nausea, and vomiting related to a jejunal stenosis. DIAGNOSES: An enteroscopy with jejunal biopsy showed poorly differentiated cancerous cells suggestive for primary intestinal cancer. There were no signs of metastatic disease at radiological evaluation. A jejunal resection was subsequently carried out and the diagnosis of mucinous adenocarcinoma of the jejunum was confirmed. INTERVENTIONS: The computed tomography scan performed 1 month after surgery showed metastatic disease. Therefore, the patient received combined protocols of chemotherapy and either bevacizumab or the anti-epidermal growth factor receptor (EGFR) panitumumab. OUTCOMES: A partial response (PR) was achieved with Folfox plus panitumumab and a maintenance therapy with panitumumab is being conducted with a mild toxicity and a progression free survival of 19 months since the beginning of panitumumab. LESSONS: This is, to the best of our knowledge, the first report in the literature of a patient with SBA who has benefitted from panitumumab with an overall survival of 83 months. PMID- 29505012 TI - Case report of a novel maneuver to facilitate wire access to the side branch in bifurcation intervention-balloon block and support technique. AB - BACKGROUND: Despite advancements in the devices and techniques used for percutaneous coronary intervention, side branch (SB) wiring remains highly challenging in certain complex bifurcation intervention cases. METHODS AND RESULTS: In this report, we demonstrate the efficacy and safety of the balloon block and support technique (BBST), which comprises inflation of an appropriately sized balloon 1-2 mm distal from the carina in the distal main branch to facilitate wire access to the SB. Between June 2012 and July 2017, we utilized the BBST as a bail-out strategy for six bifurcation cases with difficult SB wiring. In this report, we present in detail the oldest and the most recent of those cases to illustrate the use of the BBST. As a bail-out strategy, the BBST successfully facilitated SB wiring. No BBST-related complications were observed. CONCLUSIONS: The BBST may be an efficient and safe method for facilitating SB wiring in complex bifurcation intervention cases and could be used as a bail-out technique. PMID- 29505013 TI - Vaginal atresia and cervical agenesis combined with asymmetric septate uterus: A case report of a new genital malformation and literature review. AB - RATIONALE: A combination of Vaginal atresia and septate uterus as a novel genital malformation has been reported the first time. It offers a support for the bidirectional theory. PATIENT CONCERNS: A 23-year-old woman presented with the inability to perform intercourse. The unprecedented variant was misdiagnosed by magnetic resonance imaging and ultrasonography as low vaginal atresia associated with complete septate uterus with functional endometrium in both the cavities. DIAGNOSES: The correct diagnosis was made and confirmed intraoperatively as a genital malformation, vaginal atresia and cervical agenesis associated with septate uterus. INTERVENTION: laparoscopic and hysteroscopic diagnosis the novel malformation never been reported and a vaginal stent was recommended postoperatively. OUTCOMES: This rare clinical variant made misdiagnosis. Intraoperatively, unprecedented genital malformation was confirmed. There are no vaginal atresia cases in the literature with a septate functional uterus and single agenesis cervix. LESSONS: Confirmed diagnosed by operation instead of depending on the imaging should be used for rare genital anomaly. PMID- 29505014 TI - Development of a postoperative occlusive thrombus at the site of an implanted inferior vena cava filter: A case report. AB - RATIONALE: Although an inferior vena cave (IVC) filter is placed to prevent fatal pulmonary embolism (PE), several complications associated with an IVC filter have been reported. We describe a case with symptomatic PE, of which the origin was an occlusive IVC thrombus that developed from the placement of an IVC filer after a laparoscopy-assisted total gastrectomy (LATG). PATIENT CONCERNS: A 71-year-old man underwent LATG under general anesthesia alone. He had an IVC filter implanted 13 years ago. An intravenous infusion of unfractionated heparin was substituted for the discontinuation of oral warfarin four days before the surgery. The proposed operation was performed and took a total of 404 minutes including the total duration of pneumoperitoneum that took 374 minutes. After the surgery, he experienced severe shivering reactions that required frequent bolus infusions of antihypertensive drugs. On the third postoperative day, he complained of dyspnea after taking a short walk, and subsequently lost consciousness. While he spontaneously recovered without requiring any resuscitation efforts, we performed computed tomography (CT) examination for suspected PE. DIAGNOSES: The CT showed that a massive thrombus was occupying the intravenous space from the IVC filter to the left common iliac vein with several embolic defects in the peripheral pulmonary arteries present. INTERVENTIONS: An anticoagulant therapy was established with 10 mg of oral apixaban given twice a day for the first four days, followed by a reduction to 5 mg. OUTCOMES: On the 17th postoperative day, an ultrasound vascular examination confirmed the complete disappearance of deep venous thrombus (DVT). LESSONS: As an IVC filter itself may be a potential source of DVT, we should carefully manage patients with a previously implanted IVC filter throughout the perioperative period. PMID- 29505015 TI - Longitudinally extensive transverse myelitis with pulmonary tuberculosis: Two case reports. AB - RATIONALE: Longitudinally extensive transverse myelitis (LETM) is characterized by contiguous inflammatory lesions of spinal cord extending to >=3 vertebral segments. The etiology of LETM is complicated, including various infection, autoimmune disease, and so on. Neuromyelitis optic spectrum disorder (NMOSD) is the most common cause of LETM. Several case reports have suggested the associations between NMOSD and pulmonary tuberculosis (PTB). PATIENT CONCERNS: Patient 1, a 20-year-old woman who had a past history of PTB, presented with weakness, numbness, and pain in the limbs. The serum anti-aquaporin-4 antibody (AQP4-Ab) was strongly positive, and the magnetic resonance imaging (MRI) scan of cervical and thoracic spinal cord after admission to the hospital revealed hyperintensity lesions extending from C3 to T8 on T2-weighted (T2W) image, T1 weighted (T1W) image, and fluid-attenuated inversion recovery (FLAIR) image. Patient 2, a 21-year-old woman who had a past medical history of PTB without receiving any treatment, presented for numbness in bilateral lower limbs and in the chest. The anti-AQP4-Ab was negative both in the serum and in the cerebral spinal fluid (CSF) of the patient. The MRI scan during hospitalization of cervical and thoracic spinal cord revealed diffuse hyperintense signal extending C3 to T11 on T2W and FLAIR images and hypointense signal on T1W image. DIAGNOSIS: The first patient was diagnosed with anti-AQP4-Ab positive NMOSD, while the second case was an anti-AQP4-Ab negative LETM patient. INTERVENTIONS: Both of the patients received a combination of corticosteroid and anti-tuberculosis (isonicotinyl hydrazide 0.3 g/d, rifampin 0.45 g/d, pyrazinamide 1 g/d, and ethambutol 1 g/d) treatment. OUTCOMES: The patients were followed up for up to 1 year. The Expanded Disability Status Scale (EDSS) of both patients were decreased and the lesion size in the spinal cord was significantly reduced at the time point of the follow-up. LESSONS: Combination of anti-tuberculosis and corticosteroid treatment may have better prognosis for patient of LETM with PTB. PMID- 29505016 TI - Targeted next-generation sequencing identifies a novel nonsense mutation in SPTB for hereditary spherocytosis: A case report of a Korean family. AB - RATIONALE: Hereditary spherocytosis (HS) is an inherited disorder characterized by the presence of spherical-shaped red blood cells (RBCs) on the peripheral blood (PB) smear. To date, a number of mutations in 5 genes have been identified and the mutations in SPTB gene account for about 20% patients. PATIENT CONCERNS: A 65-year-old female had been diagnosed as hemolytic anemia 30 years ago, based on a history of persistent anemia and hyperbilirubinemia for several years. She received RBC transfusion several times and a cholecystectomy roughly 20 years ago before. Round, densely staining spherical-shaped erythrocytes (spherocytes) were frequently found on the PB smear. Numerous spherocytes were frequently found in the PB smears of symptomatic family members, her 3rd son and his 2 grandchildren. DIAGNOSIS: One heterozygous mutation of SPTB was identified by targeted next generation sequencing (NGS). The nonsense mutation, c.1956G>A (p.Trp652*), in exon 13 was confirmed by Sanger sequencing and thus the proband was diagnosed with HS. INTERVENTIONS: The proband underwent a splenectomy due to transfusion refractory anemia and splenomegaly. OUTCOMES: After the splenectomy, her hemoglobin level improved to normal range (14.1 g/dL) and her bilirubin levels decreased dramatically (total bilirubin 1.9 mg/dL; direct bilirubin 0.6 mg/dL). LESSONS: We suggest that NGS of causative genes could be a useful diagnostic tool for the genetically heterogeneous RBC membrane disorders, especially in cases with a mild or atypical clinical manifestation. PMID- 29505018 TI - The effectiveness, safety, and economic evaluation of Korean medicine for unexplained infertile women: A multi-center, prospective, observational study protocol: Erratum. PMID- 29505019 TI - Investigation of an anatomically variant isolated bicuspid pulmonary valve: A case report: Erratum. PMID- 29505017 TI - Household tuberculosis contact investigation in a tuberculosis-prevalent country: Are the tuberculin skin test and interferon-gamma release assay enough in elderly contacts? AB - The high background rates of positive results on the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) sometimes confuse the investigation of tuberculosis (TB) contact in TB-prevalent countries, particularly in elderly contacts. The aim was to investigate the predictive value of TST and IGRA for diagnosing latent TB infection (LTBI) in elderly household contacts in South Korea.In this retrospective study, TST and IGRA results of household contacts of suspected pulmonary TB patients were reviewed according to the index patient's final diagnosis (TB group: culture-confirmed pulmonary TB, non-TB group: pulmonary disease other than TB).A total of 249 contacts were included in the analysis (188 in the TB group and 61 in the non-TB group). In the TB group, TST and IGRA were positive in 42.6% and 45.7% of contacts, respectively. In the non TB group, TST and IGRA were positive in 32.8% and 23.0% of contacts, respectively. TST did not show any differences between the TB and non-TB groups for any age group, whereas IGRA showed differences between the 2 groups for those ages 18 to 39 and 40 to 59 years. However, there were no significant differences between the groups for the >=60 years old group.In elderly contacts, neither TST nor IGRA showed clear discrimination of positivity between the groups. Further studies are needed to predict which elderly contacts are at risk for progression to active TB as well as to accurately detect recent Mycobacterium tuberculosis infection in this vulnerable population. PMID- 29505020 TI - Low Serum Fetuin-A as a Biomarker to Predict Pneumococcal Necrotizing Pneumonia and Hemolytic Uremic Syndrome in Children: Erratum. PMID- 29505021 TI - Dynamic risk stratification in medullary thyroid carcinoma: Single institution experiences. AB - Recently, dynamic risk stratification has been found to be more valuable than static anatomic staging system in nonmedullary thyroid cancer and this strategy has also been accepted in medullary thyroid cancer (MTC). The present study was designed to compare the clinical usefulness of response to initial therapy stratification with a traditional anatomic staging system.From August 1982 to December 2012, a total of 144 MTC patients underwent thyroidectomy in Yonsei University Hospital. Among them, 117 (82.2%) patients with complete clinical data and sustained follow-up were enrolled in this study. Clinicopathological features and surgical outcomes were analyzed by retrospective medical chart review. Mean follow-up duration was 85.78 +/- 62.51 months.In this study, mean tumor size was 1.94 +/- 1.40 cm and 22 (18.9%) patients had hereditary MTC; 95 (81.1%) patients had sporadic MTC. Stage I patients had highest probability of excellent response to initial therapy (92.1%). Stage IV patients had highest probability of biochemical and structural incomplete response to initial therapy (57.5% and 30.3%) and lowest probability of excellent response to initial therapy (12.1%). Both response to initial therapy stratification and TNM staging system offered useful prognostic information in this study. The TNM staging system provided risk stratification pertaining to disease-free survival (DFS), disease-specific survival (DSS), and the probability of having no evidence of disease at final outcome, but did not provide risk stratification pertaining to the probability of having biochemical persistent/recurrence disease at final outcome. However, response to initial therapy stratification provided risk stratification pertaining to not only DFS, DSS, and the probability of having no evidence of disease at final outcome but also the probability of having biochemical persistent/recurrence disease at final outcome.In this study, we demonstrated that dynamic risk stratification with adjusted response to initial therapy system can offer more useful prognostic information than anatomic staging system in MTC. PMID- 29505022 TI - Skipped multifocal extensive spinal tuberculosis involving the whole spine: A case report and literature review. AB - RATIONALE: Skipped multifocal extensive spinal tuberculosis (TB) involving the whole spine is very rare. So far, only 3 cases have been reported. PATIENT CONCERNS: We report a rare case of skipped multifocal extensive TB involving the whole spine of a 33-year-old Chinese male. The patient had been asymptomatic until his symptom was significantly aggravated, which caused him to have difficulty in walking and sleeping. The whole spinal computed tomography (CT) scan showed multifocal worm-eaten and osteolytic bony destruction spread over noncontiguous multilevel vertebral involvement in cervical, thoracic, lumbar, and sacral. In addition, the patient presented with low back pain, progressive fever, night sweats, and weight loss. An open biopsy was undergone indicating granulomatous inflammation after thorough radiographic examinations and laboratory investigations, which to our knowledge have been rarely reported by the published medical reference literature. DIGNOSES: It was initially diagnosed as lymphoma, multiple myeloma, or a metastatic disease by the radiologist. Final pathology confirmed it as an atypical form of spinal TB, which is extremely rare. INTERVENTIONS: The patient with no progressive severe neurological symptoms, spinal deformity, or a huge abscess was put on a combination of anti-TB treatment and discharged in an improved state to continue medication for a total of 12 months. OUTCOMES: This article is a case report, no outcomes. LESSONS: Multifocal extensive spinal TB involving the whole spine is rarely reported in the literature, which presents with atypical presentations and imaging features. It is noticeable that the possibility of TB is considered for any skip lesions involving the spine cautiously. Meanwhile, careful physical examination, trials of anti-TB treatment, and using the whole spine MRI routinely also play an important role in the diagnosis and treatment of this disease. PMID- 29505023 TI - Prevalence of posttraumatic stress disorder among road traffic accident survivors: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Involvement in road traffic accidents (RTAs) may put individuals at increased risk for a wide range of psychiatric disorders, among which posttraumatic stress disorder (PTSD) presents a public health issue. However, a great disparity was observed among studies exploring the prevalence of PTSD among RTA survivors. This meta-analysis aimed to explore the pooled prevalence of PTSD among RTA survivors. METHODS: Electronic databases of PubMed, Embase, Web of Science, PsycARTICLES, PsycINFO, and CINAHL were searched to identify relevant studies. Study selection and data extraction were conducted independently by 2 investigators, and a meta-analysis was performed to synthesize the data. Heterogeneity among studies was evaluated using the Cochran Q test and quantified using the I statistic. Subgroup analyses were performed to identify the source of the heterogeneity. The possibility of publication bias was assessed using Egger linear test. RESULTS: Fifteen eligible studies containing 6804 RTA survivors were identified in this meta-analysis, of which 1489 were identified with PTSD. The pooled prevalence of PTSD among RTA survivors was 22.25% (95% confidence interval: 16.71%-28.33%). A high degree of heterogeneity was observed across studies (I = 97.1%, P < .001), with reported PTSD prevalence ranging from 6.3% to 58.3%. Subgroup analyses found that the prevalence of PTSD among RTA survivors varied significantly across studies in relation to the instrument used to assess PTSD, country, race, gender, and education level (P < .05). CONCLUSION: The high pooled prevalence of PTSD among RTA survivors found in this study significantly underscores the need for providing timely and effective intervention strategies for RTA survivors. PMID- 29505024 TI - Clinical significance of ubiquilin 1 in gastric cancer. AB - Ubiquilin 1 (UBQLN1) plays an essential role in the regulation of protein degradations which is involved in the pathophysiology of neurodegenerative diseases and cancer. This study aimed to investigate the expression level of UBQLN1 in gastric cancer and evaluated the relationship between its expression and clinicopathological characteristics, as well as prognostic of patients with gastric cancer. Immunohistochemistry (IHC) was used to detect the expression levels of UBQLN1 in 179 pairs of gastric cancer and adjacent normal tissues. The UBQLN1 was significantly upregulated in gastric cancer tissue. High UBQLN1 expression was associated with high histological grade, invasion, lymph node metastasis, and tumor node metastasis (TNM) stage III (P < .001). Multivariate Cox analysis showed that larger tumor size (HR = 3.125, 95%CI: 2.031-4.808, P < .001), histological grade 3 (HR = 15.313, 95%,CI: 8.075-29.041, P < .001), pT3 + pT4 (HR = 3.224, 95%CI: 1.389-7.483, P = .006), LNM (HR = 4.467, 95%CI: 2.404 8.302, P < .001), TNM stage III (HR = 2.152, 95%CI: 1.289-3.594, P = .003), and high UBQLN1 expression (HR = 2.547, 95%CI: 1.511-4.292, P < .001) were significantly associated with worse prognosis of patients with gastric cancer. In conclusion, high UBQLN1 expression was an independent worse prognostic factor for patients with gastric cancer. PMID- 29505025 TI - Prognostic value of fibrosis ratio in metastatic lymph nodes of node-positive advanced gastric cancer. AB - Lymph node metastasis plays a crucial role in predicting prognosis in advanced gastric cancer (AGC). In the present study, we formulated a fibrosis ratio (FR), defined as the number of metastatic lymph nodes with fibrosis divided by the total number of lymph nodes, and sought to determine whether it can be used to predict the prognosis of patients with AGC and improve on existing node staging. We retrospectively analyzed 161 patients who underwent curative resection for node-positive AGC between 2001 and 2010, evaluating the association between FR, lymph node ratio (LNR), and micrometastasis, and the relationship between FR and clinicopathologic findings, overall survival (OS) and disease-free survival (DFS). A high FR was significantly related to T stage (P < .001), N stage (P < .001), tumor stage (P < .001), lymphatic invasion (P < .001), and venous invasion (P = .007). FR was significantly correlated with an increased number of metastatic lymph nodes (P = .001, R = 0.869) and LNR (P = .001, R = 0.943), but not with total harvested lymph nodes. Patients with micrometastases had a lower FR, compared with those without micrometastases (P < .001). A survival analysis showed poor OS for patients in the entire cohort (P < .001); N1 (P = .002), N2 (P = .004), N3a (P = .010), and N3b (P = .003) stages; and groups with high LNR (P = .013) and low LNR (P = .001). DFS was also poor for the entire cohort (P < .001) and the N2 (P = .013), N3b (P = .002), high-LNR (P = .036), and low-LNR (P = .001) groups, but not the N1 or N3a group. Univariate and multivariate analyses revealed that high FR was an independent prognostic factor for OS (hazard ratio [HR], 2.780; CI, 1.655-4.670; P < .001) and DFS (HR, 2.051; CI, 1.199-3.508; P = .009) in AGC. Collectively, our findings indicate that high FR is associated with adverse clinicopathologic parameters in AGC, clearly establishing nodal fibrosis as a pathological finding with value in predicting poor prognosis of patients with AGC. Thus, combining current N stage and LNR diagnostics with FR could improve prognostic prediction in AGC. PMID- 29505026 TI - Efficacy and Safety of apatinib in patients with intermediate/advanced hepatocellular carcinoma: A prospective observation study. AB - This prospective study aimed to evaluate the efficacy and safety of apatinib in patients with intermediate/advanced hepatocellular carcinoma (HCC).The patients with intermediate/advanced HCC, who met predetermined inclusion and exclusion criteria, underwent oral treatment of apatinib 500 mg daily. The drug-related adverse effects were monitored by regular follow-up and workup including laboratory tests and imaging examinations. Tumor response was assessed by response evaluation criteria in solid tumor criteria. The time to tumor progression (TTP) and overall survival rate (OS) were calculated using the Kaplan Meier method.A total of 31 patients were enrolled in the study from October 28, 2015 to December 28, 2016. The number of patients with intermediate and advanced HCC was 4 (12.90%) and 27 (87.10%), respectively. The mean tumor size was 9.47 +/ 5.48 cm (range: 1.2-19 cm). Vascular invasion was seen in 14 patients (45.16%). A total of 21 (67.74%) patients exhibited extrahepatic metastases. On the basis of first follow-up computed tomography and magnetic resonance imaging at 6 weeks after treatment, 10 (32.26%), 15 (48.39%), and 6 (19.35%) of 31 patients achieved a partial response, stable disease, and progression of disease, respectively. Response rate and disease control rate were 32.26% and 80.65%, respectively. The median TTP was 4.8 months (95% confidence interval: 3.75-5.86 months). Furthermore, 6- and 12-month OS rates were 73.8% and 55.4%, respectively. Grade 3 thrombocytopenia (6.45%) and hypertension (48.39%) were the most common hematologic and nonhematologic toxicities. Grade 3 elevation of either serum total bilirubin or aminotransferase (6.45%) was observed as the top incidence among important indexes of liver function.Our preliminary findings suggest apatinib is a safe and effective therapy in intermediate/advanced HCC patients with high tumor response and survival rates. PMID- 29505027 TI - Effects of age and sex on epigenetic modification induced by an acute physical exercise: Retraction. PMID- 29505028 TI - IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. AB - Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors is crucial for tumor clearance. We engineered CAR-T cells to express interleukin (IL)-7 and CCL19 (7 * 19 CAR-T cells), as these factors are essential for the maintenance of T-cell zones in lymphoid organs. In mice, 7 * 19 CAR-T cells achieved complete regression of pre-established solid tumors and prolonged mouse survival, with superior anti-tumor activity compared to conventional CAR-T cells. Histopathological analyses showed increased infiltration of dendritic cells (DC) and T cells into tumor tissues following 7 * 19 CAR-T cell therapy. Depletion of recipient T cells before 7 * 19 CAR-T cell administration dampened the therapeutic effects of 7 * 19 CAR-T cell treatment, suggesting that CAR-T cells and recipient immune cells collaborated to exert anti tumor activity. Following treatment of mice with 7 * 19 CAR-T cells, both recipient conventional T cells and administered CAR-T cells generated memory responses against tumors. PMID- 29505029 TI - Using deep learning to model the hierarchical structure and function of a cell. AB - Although artificial neural networks are powerful classifiers, their internal structures are hard to interpret. In the life sciences, extensive knowledge of cell biology provides an opportunity to design visible neural networks (VNNs) that couple the model's inner workings to those of real systems. Here we develop DCell, a VNN embedded in the hierarchical structure of 2,526 subsystems comprising a eukaryotic cell (http://d-cell.ucsd.edu/). Trained on several million genotypes, DCell simulates cellular growth nearly as accurately as laboratory observations. During simulation, genotypes induce patterns of subsystem activities, enabling in silico investigations of the molecular mechanisms underlying genotype-phenotype associations. These mechanisms can be validated, and many are unexpected; some are governed by Boolean logic. Cumulatively, 80% of the importance for growth prediction is captured by 484 subsystems (21%), reflecting the emergence of a complex phenotype. DCell provides a foundation for decoding the genetics of disease, drug resistance and synthetic life. PMID- 29505030 TI - Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. AB - Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4 methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy. PMID- 29505031 TI - Nociceptor sensory neurons suppress neutrophil and gammadelta T cell responses in bacterial lung infections and lethal pneumonia. AB - Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1+ nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1+-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung gammadelta T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1+ afferents mediated immunosuppression through release of the neuropeptide calcitonin gene-related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia. PMID- 29505032 TI - Single-cell developmental classification of B cell precursor acute lymphoblastic leukemia at diagnosis reveals predictors of relapse. AB - Insight into the cancer cell populations that are responsible for relapsed disease is needed to improve outcomes. Here we report a single-cell-based study of B cell precursor acute lymphoblastic leukemia at diagnosis that reveals hidden developmentally dependent cell signaling states that are uniquely associated with relapse. By using mass cytometry we simultaneously quantified 35 proteins involved in B cell development in 60 primary diagnostic samples. Each leukemia cell was then matched to its nearest healthy B cell population by a developmental classifier that operated at the single-cell level. Machine learning identified six features of expanded leukemic populations that were sufficient to predict patient relapse at diagnosis. These features implicated the pro-BII subpopulation of B cells with activated mTOR signaling, and the pre-BI subpopulation of B cells with activated and unresponsive pre-B cell receptor signaling, to be associated with relapse. This model, termed 'developmentally dependent predictor of relapse' (DDPR), significantly improves currently established risk stratification methods. DDPR features exist at diagnosis and persist at relapse. By leveraging a data driven approach, we demonstrate the predictive value of single-cell 'omics' for patient stratification in a translational setting and provide a framework for its application to human cancer. PMID- 29505033 TI - SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. AB - Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK independent mechanisms underlying resistance. PMID- 29505035 TI - On falsification of the binary instrumental variable model. AB - Instrumental variables are widely used for estimating causal effects in the presence of unmeasured confounding. The discrete instrumental variable model has testable implications for the law of the observed data. However, current assessments of instrumental validity are typically based solely on subject-matter arguments rather than these testable implications, partly due to a lack of formal statistical tests with known properties. In this paper, we develop simple procedures for testing the binary instrumental variable model. Our methods are based on existing techniques for comparing two treatments, such as the [Formula: see text]-test and the Gail-Simon test. We illustrate the importance of testing the instrumental variable model by evaluating the exogeneity of college proximity using the National Longitudinal Survey of Young Men. PMID- 29505036 TI - White Dwarfs in Cataclysmic Variables: An Update. AB - In this review, we summarize what is currently known about the surface temperatures of accreting white dwarfs in non-magnetic and magnetic cataclysmic variables (CVs) based upon synthetic spectral analyses of far ultraviolet data. We focus only on white dwarf surface temperatures, since in the area of chemical abundances, rotation rates, WD masses and accretion rates, relatively little has changed since our last review, pending the results of a large HST GO program involving 48 CVs of different CV types. The surface temperature of the white dwarf in SS Cygni is re-examined in the light of its revised distance. We also discuss new HST spectra of the recurrent nova T Pyxidis as it transitioned into quiescence following its April 2011 nova outburst. PMID- 29505034 TI - Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia. AB - Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR 126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML. PMID- 29505037 TI - Corrigendum to 'Intravitreal ranibizumab for treatment of choroidal neovascularization secondary to a bilateral choroidal osteoma' [Am. J. Ophthalmol. Case Reports (4) (2016) 7-10]. AB - [This corrects the article DOI: 10.1016/j.ajoc.2016.06.009.]. PMID- 29505038 TI - Exploring Symmetric and Asymmetric Bimanual Eating Detection with Inertial Sensors on the Wrist. AB - Motivated by health applications, eating detection with off-the-shelf devices has been an active area of research. A common approach has been to recognize and model individual intake gestures with wrist-mounted inertial sensors. Despite promising results, this approach is limiting as it requires the sensing device to be worn on the hand performing the intake gesture, which cannot be guaranteed in practice. Through a study with 14 participants comparing eating detection performance when gestural data is recorded with a wrist-mounted device on (1) both hands, (2) only the dominant hand, and (3) only the non-dominant hand, we provide evidence that a larger set of arm and hand movement patterns beyond food intake gestures are predictive of eating activities when L1 or L2 normalization is applied to the data. Our results are supported by the theory of asymmetric bimanual action and contribute to the field of automated dietary monitoring. In particular, it shines light on a new direction for eating activity recognition with consumer wearables in realistic settings. PMID- 29505039 TI - Corrigendum to "Ipsilateral supraorbital nerve transfer in a case of recalcitrant neurotrophic keratopathy with an intact ipsilateral frontal nerve: A novel surgical technique" [Am J Ophthalmol Case Rep 4 2016 14-17]. AB - [This corrects the article DOI: 10.1016/j.ajoc.2016.07.001.]. PMID- 29505040 TI - Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: results of monotherapy and combination therapy trials. PMID- 29505041 TI - Depolymerization of sodium polyphosphates on an iron oxide surface at high temperature. AB - Density functional theory (DFT) and first principles molecular dynamics (FPMD) studies of pyrophosphate cluster Na4P2O7 and triphosphate cluster Na5P3O10 absorbed and decomposed on an Fe2O3(0001) surface have been conducted. Comparative analyses of the structure properties and adsorption processes during the simulation at elevated temperature have been carried out. The results depict the key interactions including the covalent P-O bonds, pure ionic Na-O or Fe-O interactions. The iron oxide surface plays an important role in the bridging bond decomposition scheme which can both promote and suppress phosphate depolymerization. It is found that the chain length of polyphosphates does not have considerable effects on the decomposition of phosphate clusters. This study provides detailed insights into the interaction of a phosphate cluster on an iron oxide surface at high temperature, and in particular the depolymerization/polymerization of an inorganic phosphate glass lubricant, which has an important behavior under hot metal forming conditions. PMID- 29505042 TI - Coalescence between Au nanoparticles as induced by nanocurvature effect and electron beam athermal activation effect. AB - The coalescence of two single-crystalline Au nanoparticles on surface of amorphous SiOx nanowire, as induced by electron beam irradiation, was in situ studied at room temperature in a transmission electron microscope. It was observed that along with shrinkage of the SiOx nanowire during irradiation, adjacent Au nanoparticles moved around and migrated close to each other. Once the two nanoparticles contacted with each other, a fast, massive atom transportation took place along their contact surface, where a neck region was created. With a further irradiation, the two nanoparticles rotated, aligning their crystal orientations, and gradually coalesced into a larger single-crystalline nanoparticle. The above coalescence process demonstrated an intriguing surface nanowetting ability and nanograin boundary dislocation climb and slip of Au NPs at room temperature as driven by the non-uniformly distributed nanocurvature over the surface of the two contacting nanoparticles as well as the beam-induced instability and soft mode of atomic vibration, which have been underestimated or neglected in the existing theoretical descriptions or simulations. PMID- 29505043 TI - DMPC vesicle structure and dynamics in the presence of low amounts of the saponin aescin. AB - Vesicle shape and bilayer parameters are studied by small-angle X-ray (SAXS) and small-angle neutron (SANS) scattering in the presence of the saponin aescin. We confirm successful incorporation of aescin molecules by analysis of the radii of gyration RG and study furthermore the impact of aescin incorporation on bilayer thickness parameters from the neutron and X-ray perspective. Additionally, the bending elasticity (kappa) of these 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicle bilayers is studied in the presence of aescin. Neutron spin-echo spectroscopy (NSE) allows to detect subtle changes in the dynamics and kappa of lipid membranes. Changes of kappa are detectable at temperatures below and above the main phase transition temperature Tm of the lipid. The impact of aescin is much more significant below Tm. It has been found that below Tm the addition of aescin to the vesicles decreases the value of kappa and softens the bilayer. Above Tm the value of kappa increases with increasing aescin content and the bilayer becomes more rigid. Altogether, we demonstrate by analysis of the structure and dynamics of the vesicles that the impact of aescin strongly depends on the lipid state. Below Tm the membrane becomes fluidized and softer, above Tm solidified and stiffer compared to a DMPC membrane without additive at similar conditions. PMID- 29505044 TI - Enhanced measurement of residual chemical shift anisotropy for small molecule structure elucidation. AB - A method is introduced to measure residual chemical shift anisotropies conveniently and accurately in the mesophase of poly-gamma-(benzyl-l-glutamate). The alignment amplitude is substantially enhanced over common methods which greatly benefits measurements particularly on sp3 carbons. The approach offers significant improvements in data accuracy and utility for small molecule structure determination. PMID- 29505045 TI - Correction: Sumanene derivatives functionalized at the internal carbon. AB - Correction for 'Sumanene derivatives functionalized at the internal carbon' by Niti Ngamsomprasert et al., Chem. Commun., 2017, 53, 697-700. PMID- 29505046 TI - Hybrid mesoporous organosilicas with molecularly imprinted cavities: towards extended exposure of active amino groups in the framework wall. AB - Hybrid molecularly imprinted mesoporous silicas were synthesized by co condensation of tetraethoxysilane and functional organosilica precursors of HQP and BPAP, in which hydroquinone (HQ) and bisphenol A (BPA) were linked as imprinting molecules. Owing to the existence of a thermally reversible covalent bond of carbamate (-NH-COO-), the imprinting molecules could be eliminated under thermal treatment and molecularly imprinted cavities were formed in the framework wall. All of these materials were used to catalyze heterogeneous Knoevenagel reactions and proved to exhibit higher catalytic conversion and turnover frequency (TOF) number compared with the materials with imprinting molecules, which is attributed to the presence of amino groups with higher basicity and molecularly imprinted cavities. Importantly, compared with amino functionalized SBA-15 materials, the decisive role of molecularly imprinted cavities in the enhanced accessibility of amino groups in a mesoporous framework was further confirmed. Moreover, the size of imprinting molecules has an influence on the catalytic conversion and TOF values: imprinting molecules with relatively bulkier size tend to provide higher accessibility to the active sites. The amino groups in the framework are extremely stable during the reaction procedure and recycling process. PMID- 29505047 TI - New hydrogen-rich ammonium metal borohydrides, NH4[M(BH4)4], M = Y, Sc, Al, as potential H2 sources. AB - Three metal-ammonium borohydrides, NH4[M(BH4)4] M = Y, Sc, Al, denoted 1, 2, 3, respectively, were prepared via a low temperature mechanochemical synthesis and characterized using PXRD, FTIR and TGA/DSC/MS. The compounds 1 and 2 adopt the P21/c space group while the compound 3 crystallizes in an orthorhombic unit cell (Fddd). The first decomposition step of all three derivatives of ammonium borohydride has the maximum rate at 48 degrees C, 53 degrees C and 35 degrees C for 1, 2 and 3, respectively, which are comparable to that for NH4BH4 (53 degrees C). The thermal decomposition of these metal-ammonium borohydrides is a multistep process, with predominantly exothermic low-temperature stages. The compound 1 decomposes via known Y(BH4)3, however, some of the solid decomposition products of the other two compounds have not been fully identified. In the system containing compound 2, a new, more dense polymorph of the previously reported LiSc(BH4)4 has been detected as the intermediate of slow decomposition at room temperature. PMID- 29505048 TI - Correction: Metallacyclopentadienes: synthesis, structure and reactivity. AB - Correction for 'Metallacyclopentadienes: synthesis, structure and reactivity' by Wangyang Ma et al., Chem. Soc. Rev., 2017, 46, 1160-1192. PMID- 29505049 TI - Rhenium(i) based irregular pentagonal-shaped metallacavitands. AB - Neutral ditopic flexible N-donor ligands (Ln = bis(4-(naphtho[2,3-d]imidazol-1 ylmethyl)phenyl)methane, L1 bis(4-(benzimidazol-1-ylmethyl)phenyl)methane, L2 or bis(4-(2-nonylbenzimidazol-1-ylmethyl)phenyl)methane, L3) possessing a bis(4 methylphenyl)methane spacer with two imidazolyl donor units were designed and synthesized. The ligands were utilized to develop metallacavitands analogous to irregular pentagonal-shaped metallacavitands with larger cavities. The metallacavitands 1-4 were assembled from Re2(CO)10, a rigid bis-chelating donor (1,4-dihydroxy-9,10-anthraquinone or chloranilic acid) and Lnvia a solvothermal approach. The ligands and the metallacavitands were characterized by analytical and spectroscopic methods. The molecular structures of 1 and 4 were further confirmed by single crystal X-ray diffraction analysis which revealed that a toluene molecule resides in the hydrophobic cavity. Ln and 1-4 are emissive in DMSO at room temperature. The internal cavity of the metallacavitand acts as a host for aromatic guest molecules. The host-guest interaction properties of 1 with anthracene, naphthalene, nitrobenzene, 2-nitrotoluene, 4-nitrotoluene and 2,4-dinitrotoluene were studied by an emission spectroscopic method. PMID- 29505050 TI - Dinucleating Schiff base ligand in Zn/4f coordination chemistry: synthetic challenges and catalytic activity evaluation. AB - Four Zn/4f polynuclear coordination clusters (PCCs) formulated as [ZnII2DyIII2L2(CO3)2(NO3)2] (1), [ZnIIYIIIL(NO3)2(o-van) (MeOH)] (MeOH) [2 (MeOH)] and [ZnIILnIIIL(NO3)2Cl(EtOH)] where Ln is Dy (3) and Y (4) and where H2L is the dinucleating Schiff base ligand N,N'-bis(3-methoxysalicylidene)cyclohexane 1,2-diamine and o-van is ortho-vanillin, were prepared and fully characterised for the first time. These air-stable heterometallic PCCs, obtained in high yields from commercially available materials, were shown to remain stable in solution in their dinuclear [ZnIILnIIIL] form. Their catalytic activity was evaluated in various catalytic transformations including the Friedel-Crafts alkylation of 2 acyl imidazoles with indoles. PMID- 29505052 TI - Ruthenium-catalyzed hydrogen isotope exchange of C(sp3)-H bonds directed by a sulfur atom. AB - We present here the first example of C(sp3)-H activation directed by a sulfur atom. Based on this transformation catalyzed by Ru/C, we have developed a hydrogen isotope exchange reaction for the deuterium and tritium labelling of thioether substructures in complex molecules. PMID- 29505055 TI - One-step synthesis of nonstoichiometric TiO2 nanorod films for enhanced photocatalytic H2 evolution. AB - The realization of one-dimensional nanostructures or Ti3+ self-doping in TiO2 photocatalysts has proven to be an effective approach for significantly improving their photocatalytic performance. Herein, a series of nonstoichiometric anatase TiO2 nanorod films were deposited at 50-500 degrees C by a facile one-step magnetron sputtering method. The correlation between the microstructures and the photocatalytic H2 production abilities of the films was studied. It is found that, by increasing the deposition temperature, the as-sputtered TiO2 grains transformed from quasi-spherical to rod-like structures while the concentration of the Ti3+ species decreased gradually. Thus, by virtue of the collaboration between nanostructure engineering and defect engineering, the sample deposited at 300 degrees C showed a maximum H2 generation rate of 1874 MUmol m-2 h-1, which was about 134 times higher than that of a Degussa P25 powder film (14 MUmol m-2 h 1). Furthermore, the stoichiometric TiO2 shell formed on the surface of TiO2 nanograins protected the defective TiO2-x core from further oxidation, resulting in an excellent photocatalytic stability of the films. The possible film growth and photocatalytic reaction mechanisms over the Ti3+ doped TiO2 nanorod films have been investigated. Our work provides a facile route to fabricating a high efficiency defect-based TiO2 or other transition metal oxide nanostructures with a controlled morphology for solar energy conversion. PMID- 29505056 TI - Impact of junction formation processes on single molecular conductance. AB - We have investigated the electric conductance and atomic structure of single molecular junctions of pyrazine (Py), 4,4'-bipyridine (BiPy), fullerene (C60), and 1,4-diaminobutane (DAB). The single molecular junctions were fabricated by breaking Au contacts between an Au tip and the Au electrode surface in the presence of the target molecules (breaking process) or approaching the Au tip to the Au electrode surface covered by the molecules (making process). In the making process, no major conductance state was observed in the conductance histogram for DAB, while single conductance states were observed for the pi-conjugated molecules of Py (10 mG0, G0~ 77.45 MUOmega-1), BiPy (3 mG0), and C60 (5 mG0). In contrast to the making process, two major conductance states were observed for Py (1 mG0 and 0.3 mG0), BiPy (0.6 mG0 and 0.2 mG0), and C60 (30 mG0 and 3 mG0) in the breaking process. The observed conductance behavior could be explained by the characters of the anchoring unit of molecules. In the making process, anchoring of molecules cannot be established by the point contact between the Au electrode and the localized lone pair of the N atom of DAB, Py, and BiPY, while molecules anchor on the Au electrode by using the plane-like contact between the Au electrode and the delocalized pi electrons in the aromatic ring of Py, BiPY, and C60, which explains the difference in the observed conductance behavior between DAB and the pi conjugated molecules of Py, BiPY, and C60 in the making process. In the breaking process, the delocalized pi-electrons of Py, BiPY, and C60 can make a contact with the Au electrode surface and the lone pair on the N atom of DAB as well as Py and BiPY can bind to Au atoms, and therefore, single molecular junctions were formed for all systems. The present results indicate that the pi plane is important for making metal-molecule contacts and for the formation of the single molecular junction in the making process. PMID- 29505057 TI - [Ru3(6-NHC)(CO)10]: synthesis, characterisation and reactivity of rare 46 electron tri-ruthenium clusters. AB - [Ru3(CO)12] reacts at room temperature with N-alkyl substituted 6-membered ring N heterocyclic carbenes (6-NHC) to form [Ru3(6-NHC)(CO)10] (6-NHC = 6-iPr 1, 6-Et 2 and 6-Me 4), rare examples of coordinatively unsaturated (46-electron) ruthenium clusters. Complexes 1, 2 and 4 have been structurally characterised, along with the tetranuclear ruthenium cluster [Ru4(6-Et)2(CO)11] 3 that is formed along with 2. The degradation of the 6-iPr derivative 1 by pyrimidinium salt elimination helped to explain the poor activity of the complex in the catalytic acylation of pyridine. PMID- 29505059 TI - Synthesis and antioxidant capacity of novel stable 5-tellurofuranose derivatives. AB - Novel stable tellurium-containing carbohydrate derivatives are prepared from hexitols and pentitols through a double nucleophilic substitution with NaHTe in PEG-400. These tellurosugars react at very high rates with two-electron oxidants, including hypochlorous and peroxynitrous acid, formed at sites of inflammation, and show considerable promise as protective agents against oxidative damage. PMID- 29505061 TI - 1D-2D hybrids as efficient optoelectronic materials: a study on graphitic carbon nitride nanosheets wrapped with zinc oxide rods. AB - Zinc oxide (ZnO) nanorods (NRs) wrapped with graphitic carbon nitride (GCN) nanosheet (NS) hybrids have been synthesized by a simple chemical process. The as prepared samples are characterized by X-ray diffraction, field emission scanning electron microscopy, high resolution transmission electron microscopy, Fourier transformed infrared spectroscopy, UV-Vis spectroscopy and photoluminescence spectroscopy. The images obtained from the transmission electron microscopic study and the existence of C-N stretching modes as observed from Fourier transform infrared spectroscopy confirm the successful attachment of GCN NSs onto the ZnO NRs. It is seen that hybrid samples show broad photoluminescence (PL) emission with enhanced defect related emission along with a quenching effect due to the charge transfer mechanism. The results have been explained by taking into consideration the three different types of electron transitions occurring within the type-II band structure of the hybrid samples. Moreover a study on the conductivity of the samples is carried out under dark conditions and also under ultraviolet (UV) light irradiation. It is observed that the hybrid samples show significantly improved conductivity under both dark and UV irradiated conditions. The absorbance of the samples in the UV range shows better conductivity under UV conditions as compared to dark conditions. PMID- 29505062 TI - Holobionts and their hologenomes: Evolution with mixed modes of inheritance. AB - Symbioses are ubiquitous and have played an influential role in the evolution of life on Earth. Genomic studies are now revealing a huge diversity of associations among hosts and their microbiotas, allowing us to characterize their complex ecological and evolutionary dynamics. The different transmission modes and the asynchronous cell proliferation of the numerous symbionts associated with one host generate a genomic conflict ought to be solved. Two disputing views have been used to model and predict the outcome of such conflicts. The traditional view is based on community ecology, and considers that selection at the level of individuals is sufficient to explain longstanding associations among species. A new perspective considers that the host and its associated microbiota constitute a biological entity called holobiont, and that regarding it as a higher-level unit of selection is unavoidable to understand phenotypic evolution. Novel extended phenotypes are often built through symbiotic interactions, allowing the holobiont to explore and survive in distinct environmental conditions, and may evolve in a Lamarckian fashion. PMID- 29505063 TI - Cytological and genome size data analyzed in a phylogenetic frame: Evolutionary implications concerning Sisyrinchium taxa (Iridaceae: Iridoideae). AB - Sisyrinchium is the largest genus of Iridaceae in the Americas and has the greatest amount of cytological data available. This study aimed at investigating how genomes evolved in this genus. Chromosome number, genome size and altitude from species of sect. Viperella were analyzed in a phylogenetic context. Meiotic and pollen analyses were performed to assess reproductive success of natural populations, especially from those polyploid taxa. Character optimizations revealed that the common ancestor of sect. Viperella was probably diploid (2n = 2x =18) with two subsequent polyplodization events. Total DNA content (2C) varied considerably across the phylogeny with larger genomes detected mainly in polyploid species. Altitude also varied across the phylogeny, however no significant relationship was found between DNA content changes and altitude in our data set. All taxa presented regular meiosis and pollen viability (> 87%), except for S. sp. nov. aff. alatum (22.70%), suggesting a recent hybrid origin. Chromosome number is mostly constant within this section and polyploidy is the only source of modification. Although 2C varied considerably among the 20 taxa investigated, the diversity observed cannot be attributed only to polyploidy events because large variations of DNA content were also observed among diploids. PMID- 29505065 TI - Ageing with HIV - a periodontal perspective. AB - The importance of oral microflora composition in HIV-infected patients is well recognized. However, no studies so far have dealt with age-related changes in periodontal pathogens occurrence in HIV+ individuals. The aim of the present study was to assess and compare temporal changes of bacteria frequency in younger (<=35 years) and older (>=50 years) HIV-infected and non-infected individuals. Bacterial DNA was isolated from buccal swabs of 30 younger and 30 older subjects in both HIV+ and HIV- groups. By means of PCR the following microorganisms were detected: Aggregatibacter actinomycetemcomitans, Eikenella corrodens, Peptostreptococcus micros, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia and Treponema denticola. Oral and periodontal examinations were performed in all subjects. The prevalence of microorganisms was significantly higher in HIV+ patients compared to controls, and their distribution showed a notable shift. The decreasing incidence in HIV- subjects was: Pi>Pm>Pg>Aa>Ec>Tf>Td whilst in HIV+ it was: Pi>Pm>Ec>Pg>Tf>Aa>Td. Oral manifestations of HIV infection were more frequent in older compared to younger patients. All measured values of clinical periodontal parameters were significantly higher in older compared to younger HIV+ patients. Ageing in HIV+ subjects is accompanied with a substantial increase and rearrangements of periodontal microflora, potentially aggravating oral and systemic health. PMID- 29505064 TI - IS1598 (IsPg4) distributed to abscess-forming strains of Porphyromonas gingivalis may enhance virulence through upregulation of nrdD-like gene expression. AB - An insertion sequence, IS1598 (IsPg4) has been found in virulent strains of Porphyromonas gingivalis in a murine abscess model. The present study was performed to investigate the effects of genetic rearrangements by IS1598 on the phenotypic characteristics of the virulent strains. For this purpose, we searched for a common insertion site of IS1598 among the virulent strains. Through cloning and database search, a common insertion site was identified beside an nrdD-like gene in the virulent FDC 381, W83 and W50 strains. In this region, predicted promoters of the nrdD-like gene and IS1598 are located in tandem, and accumulation of nrdD-like gene mRNA was 5-fold higher in virulent strains (W83, W50, FDC 381) than avirulent strains (ATCC33277, SU63, SUNY1021, ESO59 without IS1598). The role of the nrdD-like gene in virulence of P. gingivalis was investigated by constructing a nrdD-deficient mutant. In the murine abscess model, the parental W83 strain produced necrotic abscesses, while the nrdD deficient mutant had almost lost this ability. Insertion of IS1598 into the nrdD like gene promoter region may be related to the phenotypic differences in virulence among P. gingivalis strains through upregulation of the expression of this gene. PMID- 29505066 TI - Evaluation of Real Time PCR Aspergillus spp. in bronchoalveolar lavage samples. AB - The present study investigated the improvement in the diagnosis of invasive pulmonary aspergillosis (IPA) adding a molecular test on bronchoalveolar lavage (BAL) to the routine diagnostic approach including microscopy, culture and galactomannan (GM) immunoassay. A total of 133 BAL samples were retrospectively tested for the Aspergillus DNA: 112 samples were from immunocompromised patients at risk of invasive fungal infection and 21 were from patients not at risk and without clinical evidence of IPA. The latter samples were used to identify the cut-off of positivity for the molecular test. Applying the cut-off quantity of 50 copies/reaction, the PCR test had 90% sensitivity and 97% specificity and resulted the most sensitive, specific and accurate among those evaluated. The statistical analysis showed that the probability that a patient is not affected by IPA is 99% when the three tests (PCR, GM and culture) are concordantly negative. PMID- 29505067 TI - Emergence of novel recombinant GII.P16_GII.2 and GII. P16_GII.4 Sydney 2012 norovirus strains in Italy, winter 2016/2017. AB - In the winter season 2014/15, the GII.P17_GII.17 norovirus strain Kawasaki 2014 emerged in Italy, cocirculating with pandemic GII.4 strains. In March 2016, molecular investigation identified novel GII.P16 recombinant noroviruses in children with gastroenteritis in Italy. In 43.10% of the genotyped noroviruses GII.P16 strains were identified: 12 were characterized as GII.2 and 13 as GII.4 Sydney 2012 capsid genotypes. The GII.P16 genotype became predominant in January- February 2017 along with an increase in norovirus activity. The capsid gene was characterized as GII.2 or GII.4 Sydney 2012 variant. The emergence of two different recombinant GII.P16 viruses, of which one harboring a pandemic GII.4 capsid sequence, suggests the potential for a future pandemic. PMID- 29505068 TI - Regional spread of contact lens-related Acanthamoeba keratitis in Italy. AB - Acanthamoeba ocular infections, known as Acanthamoeba keratitis, are an emerging problem among contact lens wearers. Infections mediated by Acanthamoeba are uncommon, but they can be underestimated due to poor awareness and delayed diagnosis. The routine use of rapid and cost-effective molecular methods like Real Time PCR for the diagnosis of this important pathogen could improve diagnosis and therapy outcome. This report describes the detection by Real Time PCR assay of six T4 and one T3 Acanthamoeba infections, as the first reported cases in Tuscany, Italy. PMID- 29505069 TI - Educating Our Students for Everyday Leadership. PMID- 29505070 TI - Review of State Boards of Nursing Rules and Regulations for Nurse Preceptors. AB - BACKGROUND: The clinical education of undergraduate nursing students relies heavily on the use of staff nurses who assume the preceptor role. The best and most efficient utilization of preceptors is unknown. METHOD: This study reviewed Board of Nursing rules and regulations for all 50 states, the District of Columbia, and the U.S. territories for their published requirements regarding preceptors. Specifically, this review focused on preceptor-student and faculty student ratios, role responsibilities, and requirements of preceptors and faculty in undergraduate precepted clinical experiences. RESULTS: Although some commonalities were noted, such as eligibility (RN licensure), degree requirements (baccalaureate), and years of experience (1 to 3), 11 states had no documented regulations. The existing documents appear to lack depth, specificity, and consistency. CONCLUSION: Because preceptors are utilized to such a great extent, the eligibility, selection, preparation, and expectations of preceptors and faculty who work with them should be more explicit. [J Nurs Educ. 2018;57(3):134 141.]. PMID- 29505071 TI - Predictors of Underrepresented Nursing Students' School Satisfaction, Success, and Future Education Intent. AB - BACKGROUND: The United States is steadily becoming more diverse. If current trends continue, the minority population will be the majority by 2043. In contrast to the U.S. population, nursing (the largest health care workforce) is composed of a nearly 76% White population. The literature reports that underrepresented minorities (URM) in nursing programs encounter multiple barriers to academic success. METHOD: A secondary data analysis of a national cohort of URM accelerated nursing students was conducted to examine three factors associated with microaggression-predictors of academic (NCLEX) success, satisfaction, and intent to pursue advanced education-among a cohort of URM accelerated nursing students who had received a national diversity scholarship (n = 2,250). RESULTS: These three factors were predicted by institutional climate, mentoring, social interactions, the prematriculation preparation program, and other psychological, social, and cultural barriers. CONCLUSION: To increase nursing diversity and ensure a culturally competent profession, programs must attend to these factors. [J Nurs. Educ. 2018;57(3):142-149.]. PMID- 29505072 TI - Using Critical Creativity to Reveal Nursing Student Learning in Long-Term Care. AB - BACKGROUND: The use of teaching-learning strategies that emphasize critical reflection aids students in making sense of complex clinical placement settings, such as those in long-term care (LTC) settings. METHOD: A qualitative descriptive research design was used to explore the assumptions, anticipations, and realizations of six undergraduate nursing students regarding aging, gerontological nursing, and LTC as they engaged in facilitated critical reflection activities during a 12-week LTC placement. RESULTS: The content analysis process revealed four main categories describing the student learning experience: Exploring the Therapeutic Nurse-Resident Relationship, Navigating Preceptor Relationships, Expanding Awareness of Context, and Embracing Many Feelings. CONCLUSION: Students placed in LTC were challenged by the realization of LTC as a complex setting, especially with minimal support from preceptors. Educators should present LTC as a challenging environment, rich with complex issues. There is potential in easing the strain on preceptors by leveraging the faculty educator role in facilitating student learning through critically creative approaches. [J Nurs Educ. 2018;57(3):150-153.]. PMID- 29505073 TI - Using Student-Produced Video to Validate Head-to-Toe Assessment Performance. AB - BACKGROUND: This study explored third-semester baccalaureate nursing students' perceptions of the value of using student-produced video as an approach for learning head-to-toe assessment, an essential clinical nursing skill taught in the classroom. METHOD: A cognitive apprenticeship model guided the study. The researchers developed a 34-item survey. A convenience sample of 72 students enrolled in an applied assessment and nursing fundamentals course at a university in the western United States provided the data. RESULTS: Most students reported a videotaping process that worked, supportive faculty, valuable faculty review of their work, confidence, a sense of performance independence, the ability to identify normal assessment findings, and few barriers to learning. CONCLUSION: The results suggested that a student-produced video approach to learning head-to toe assessment was effective. Further, the study demonstrated how to leverage available instructional technology to provide meaningful, personalized instruction and feedback to students about an essential nursing skill. [J Nurs Educ. 2018;57(3):154-158.]. PMID- 29505074 TI - Being Invisible: Stereotype Threat in an Undergraduate Nursing Program. AB - BACKGROUND: Nursing programs continue to be challenged to increase recruitment and retention of ethnic minority nursing students to meet the needs of a diversifying population. Ethnic minority students face a cadre of barriers, one of which is the negative implications of their own identity. This article describes a qualitative study that explored the experiences of stereotype threat among a group of ethnic minority nursing students at a large urban university. METHOD: Semistructured, one-time in-depth interviews were conducted. RESULT: Three themes emerged: A Sense of Uncertainty About Abilities, Avoidance, and Vigilance for Signs of Failure. CONCLUSION: Nursing faculty and administrators may better support ethnic minority nursing students through graduation by having an awareness of the implications of stereotype threat. [J Nurs Educ. 2018;57(3):159-162.]. PMID- 29505075 TI - Flipped Classroom: Do Students Perceive Readiness for Advanced Discussion? AB - BACKGROUND: Use of the flipped classroom model is recognized as a popular method of instruction. Effective preclass preparation methods can create more time for instructors to reinforce application, evaluation, and analysis of information using active learning strategies. METHOD: This quasi-experimental study used a convenience sample of 42 third-year baccalaureate nursing students. Students were randomized into two groups and received either a narrated video (vodcast) or guided readings for the preclass preparation. A quiz was administered to assess preparation prior to class, and students completed a survey following the classroom activities. RESULTS: Students preferred media preparation to guided readings. This preference translated to higher quiz scores. Positive correlations were noted between quiz scores and students' understanding and increased confidence. CONCLUSION: Students' preference for the vodcast translated to the perception of an increase in confidence and understanding of the material. [J Nurs Educ. 2018;57(3):163-165.]. PMID- 29505076 TI - Testing Off the Clock: Allowing Extended Time for All Students on Tests. AB - BACKGROUND: Standardized time allotments are typically imposed for administration of nursing tests. There is little evidence to guide the determination of time allotment. When time allotted for tests is too limited, construct irrelevant variance in test scores may be introduced and the reliability of tests may be negatively impacted. METHOD: For test administration, we establish a standard time allotment and offer all students the option of extended time. RESULTS: Many of the students use extended time, reporting that extended time reduces stress. Program outcomes have not been negatively affected. Data are provided to guide calculation of time allotment. CONCLUSION: Extended time may help relieve test anxiety and facilitate success for students with undiagnosed learning disabilities or non-native English speakers. Time allotment should be based on the item composition of tests using published mean item response times. Further research is needed. [J Nurs Educ. 2018;57(3):166-169.]. PMID- 29505077 TI - Mobile Devices: A Distraction, or a Useful Tool to Engage Nursing Students? AB - BACKGROUND: Engaging nursing students in theoretical courses, such as research, can be challenging. Innovative instructional strategies are essential to engage nursing students in theoretical nursing courses. METHOD: This article describes an educational innovation using technology as a tool in an undergraduate nursing research class. All students in the course received iPads for the semester. Lecture material was presented in class using Nearpod, an interactive presentation embedded with slides, multimedia components, and learning activities. RESULT: Students reported that using the mobile technology helped them minimize off-task activities, interact more with each other and the instructor, solve problems in the class, and develop skills and confidence related to their career. CONCLUSION: Allowing device use in the classroom, such as iPads and interactive mobile applications, can be a useful learning tool. Intentional use of technology and pedagogy can increase engagement and interaction with students. [J Nurs Educ. 2018;57(3):170-173.]. PMID- 29505078 TI - Instructor-Created Activities to Engage Undergraduate Nursing Research Students. AB - BACKGROUND: In flipped or blended classrooms, instruction intentionally shifts to a student-centered model for a problem-based learning approach, where class time explores topics in greater depth, creating meaningful learning opportunities. METHOD: This article describes instructor-created activities focused on research processes linked to evidence-based practice that engage undergraduate nursing research students. In the classroom, these activities include individual and team work to foster critical thinking and stimulate student discussion of topic material. RESULTS: Six activities for small and large student groups are related to quantitative, qualitative, and both research processes, as well as applying research evidence to practice. Positive student outcomes included quantitative success on assignments and robust student topic discussions, along with instructor-noted overall group engagement and interest. CONCLUSION: Using these activities can result in class time for the construction of meaning, rather than primarily information transmission. Instructors may adopt these activities to involve and stimulate students' critical thinking about research and evidence based practice. [J Nurs Educ. 2018;57(3):174-177.]. PMID- 29505079 TI - New Careers in Nursing: An Effective Model for Increasing Nursing Workforce Diversity. AB - BACKGROUND: The Robert Wood Johnson Foundation and the American Association of Colleges of Nursing developed the New Careers in Nursing (NCIN) program to address the nursing shortage, increase workforce diversity, and raise the profession's educational level. The program provided scholarships to second degree underrepresented or economically disadvantaged (UED) students attending an accelerated nursing program to earn a Bachelor of Science in Nursing degree. METHOD: A midwestern university received three academic-year cycles of NCIN funding. The program's model, resources, and functioning are described. RESULTS: The NCIN provided exceptional financial and program support that received high marks from participants. During the three award cycles, 20 UED scholars graduated with a Bachelor of Science in Nursing degree. Nineteen of the 20 scholars passed the NCLEX-RN on the first attempt. CONCLUSION: While the NCIN program has ended, nursing school administrators and faculty wishing to promote UED student success should consider using the program's model and resources as the basis for their own program. [J Nurs Educ. 2018;57(3):178-183.]. PMID- 29505080 TI - Escape Room Recruitment Event: Description and Lessons Learned. AB - BACKGROUND: The U.S. nursing workforce is facing a severe shortage of professionals due to an anticipated retirement of more than 500,000 RNs in the next 5 years. METHOD: An Escape to Nursing event was created and delivered in a rural medical center college of nursing in the spring of 2017. This faculty team developed four distinct rooms that were designed with key nursing concepts and patient health conditions. Recruits worked in teams to solve the patient health care puzzle, which then enabled them to proceed to the next room. RESULTS: Feedback was positive from the recruits, including comments about expanding the game to more health care scenarios and reaching out to more recruits. Additional recruitment may lead to better turnout of recruits. CONCLUSION: Linear, sequential formatting for the escape room game design is recommended for use with recruits into nursing. The use of escape rooms for recruitment is a positive activity. [J Nurs Educ. 2018;57(3):184-187.]. PMID- 29505081 TI - Cinema in Nursing Education: Tapping into the Affective Domain. PMID- 29505083 TI - Analyzing Social Media Imagery for Health Messages. PMID- 29505082 TI - An Innovative Simulation for Teaching Debridement to Nurse Practitioner Students. PMID- 29505085 TI - FDA-Approved Drugs to Treat ADHD. PMID- 29505084 TI - Protecting Our Patients From Sexual Assault. PMID- 29505086 TI - Obsessive-Compulsive Disorder in Children and Adolescents. AB - Obsessive-compulsive disorder (OCD) can be a disabling condition for children, adolescents, and their families. The majority of children and adolescents with OCD have poor academic functioning and a comorbid diagnosis. Many patients will respond with exposure and response prevention therapy. However, for those who are unable, unwilling, or do not fully respond to conservative treatment, it is essential that advanced practice nurses are able to appropriately evaluate and prescribe for OCD in their young patients. [Journal of Psychosocial Nursing and Mental Health Services, 56(3), 15-18.]. PMID- 29505087 TI - Pregnancy and the Opioid Epidemic. AB - Opioid use disorder (OUD) in pregnancy is increasing, which often results in poor maternal and neonatal outcomes including neonatal abstinence syndrome (NAS) as a result of lack of prenatal care and inadequate substance use disorder management. Practice guidelines have been developed to manage OUD during and after pregnancy for mother and baby, but barriers exist, limiting comprehensive implementation. To reduce the impact of OUD in pregnancy and associated maternal and neonatal sequela, implementing compassionate evidence-based care and a non-punitive response is needed. A stigma-free approach, substance use disorder screening, medication-assisted treatment, screening and treatment of mental health disorders, and an after-birth environment that promotes maternal-child bonding are recommended. [Journal of Psychosocial Nursing and Mental Health Services, 56(3), 19-23.]. PMID- 29505088 TI - Diurnal fluctuations in chloroplast GSH redox state regulate susceptibility to oxidative stress and cell fate in a bloom-forming diatom. AB - Diatoms are one of the key phytoplankton groups in the ocean, forming vast oceanic blooms and playing a significant part in global primary production. To shed light on the role of redox metabolism in diatom's acclimation to light-dark transition and its interplay with cell fate regulation, we generated transgenic lines of the diatom Thalassiosira pseudonana that express the redox-sensitive green fluorescent protein targeted to various subcellular organelles. We detected organelle-specific redox patterns in response to oxidative stress, indicating compartmentalized antioxidant capacities. Monitoring the GSH redox potential (EGSH ) in the chloroplast over diurnal cycles revealed distinct rhythmic patterns. Intriguingly, in the dark, cells exhibited reduced basal chloroplast EGSH but higher sensitivity to oxidative stress than cells in the light. This dark-dependent sensitivity to oxidative stress was a result of a depleted pool of reduced glutathione which accumulated during the light period. Interestingly, reduction in the chloroplast EGSH was observed in the light phase prior to the transition to darkness, suggesting an anticipatory phase. Rapid chloroplast EGSH re-oxidation was observed upon re-illumination, signifying an induction of an oxidative signaling during transition to light that may regulate downstream metabolic processes. Since light-dark transitions can dictate metabolic capabilities and susceptibility to a range of environmental stress conditions, deepening our understanding of the molecular components mediating the light dependent redox signals may provide novel insights into cell fate regulation and its impact on oceanic bloom successions. PMID- 29505089 TI - Malassezia species retrieved from skin with pityriasis versicolor, seborrhoeic dermatitis and skin free of lesions: a comparison of two sampling methods. PMID- 29505090 TI - Astrocyte elevated gene-1 participates in the production of pro-inflammatory cytokines in dental pulp cells via NF-kappaB signalling pathway. AB - AIM: To identify the role of astrocyte elevated gene-1 (AEG-1) and the mechanism underlying the inflammatory response in dental pulp cells. METHODOLOGY: Astrocyte elevated gene-1 expression was detected at different stages of pulpitis in a rat model using immunohistochemistry. RT-qPCR and Western blot were used to assess AEG-1 expression in human dental pulp cells stimulated by lipopolysaccharide (LPS). The LPS-induced expression of inflammatory cytokine genes was quantified by RT-qPCR in cells transfected with AEG-1 or negative control (NC) siRNA. Immunofluorescence and Western blot were utilized to evaluate the activation of NF-kappaB signalling in AEG-1 knockdown cells. AEG-1 expression was also investigated by Western blot in dental pulp cells pre-treated with inhibitors of NF-kappaB and PI-3K signalling before the addition of LPS. Data were analysed statistically using one-way anova. RESULTS: The exposure of dental pulp tissue to LPS resulted in acute inflammation with necrosis and AEG-1 expression in the pulp tissue beneath the perforation. In LPS-stimulated dental pulp cells, AEG-1 mRNA and protein were significantly up-regulated (P < 0 .05) in a time- and dose dependent manner. In AEG-1 knockdown cells, the synthesis of IL-1, IL-6 and TNF alpha mRNA was suppressed significantly (P < 0.05) upon LPS induction. AEG-1 knockdown also inhibited nuclear translocation of p65. Suppression of NF-kappaB and PI-3K abrogated the LPS-induced up-regulation of AEG-1. CONCLUSION: Astrocyte elevated gene-1 participated in inflammatory cytokine synthesis via NF-kappaB signalling in the dental pulp. Both NF-kappaB and PI-3K signalling are involved in LPS-induced AEG-1 expression in dental pulp cells. PMID- 29505091 TI - The role of imaging in women with ischemic heart disease. AB - Substantial advances and insights in medical technology and treatment strategies, and the focus on sex-specific research have contributed to a reduction in cardiovascular mortality in women. Despite these advances, ischemic heart disease (IHD) remains the leading cause of cardiovascular morbidity and mortality of women in the Western world. Advances in cardiovascular imaging, over the past 4 decades, have significantly improved the evaluation and management of the full spectrum of coronary atherosclerosis, which contributes to ischemic heart disease. The development of contemporary and novel diagnostic imaging techniques and tools have assumed an expanded role in the evaluation of symptomatic women to detect not only flow-limiting epicardial coronary stenosis and nonobstructive atherosclerosis, but also ischemia resulting from microvascular dysfunction. IHD is now diagnosed early and with greater accuracy, leading to improved risk assessment and timely therapies in women. In this article, we review the available evidence on the role of contemporary diagnostic imaging techniques in the evaluation of women with suspected IHD. PMID- 29505092 TI - MiR221 promotes precursor B-cell retention in the bone marrow by amplifying the PI3K-signaling pathway in mice. AB - Hematopoietic stem cells and lineage-uncommitted progenitors are able to home to the bone marrow upon transplantation and reconstitute the host with hematopoietic progeny. Expression of miR221 in B-lineage committed preBI-cells induces their capacity to home to the bone marrow. However, the molecular mechanisms underlying miR221-controlled bone marrow homing and retention remain poorly understood. Here, we demonstrate, that miR221 regulates bone marrow retention of such B-cell precursors by targeting PTEN, thus enhancing PI3K signaling in response to the chemokine CXCL12. MiR221-enhanced PI3K signaling leads to increased expression of the anti-apoptotic protein Bcl2 and VLA4 integrin-mediated adhesion to VCAM1 in response to CXCL12 in vitro. Ablation of elevated PI3K activity abolishes the retention of miR221 expressing preBI-cells in the bone marrow. These results suggest that amplification of PI3K signaling by miR221 could be a general mechanism for bone marrow residence, shared by miR221-expressing hematopoietic cells. PMID- 29505093 TI - Disease-Drug Interactions in Inflammatory States via Effects on CYP-Mediated Drug Clearance. AB - The human inflammatory response can result in the alteration of drug clearance through effects on drug-metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)-mediated drug clearance and alter plasma protein binding. Also examined is how albumin, alpha-1-acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation. PMID- 29505094 TI - Phenotypic and functional heterogeneity of human intermediate monocytes based on HLA-DR expression. AB - Human blood monocytes are subclassified as classical, intermediate and nonclassical. In this study, it was shown that conventionally defined human intermediate monocytes can be divided into two distinct subpopulations with mid- and high-level surface expression of HLA-DR (referred to as DRmid and DRhi intermediate monocytes). These IM subpopulations were phenotypically and functionally characterized in healthy adult blood by flow cytometry, migration assays and lipoprotein uptake assays. Their absolute numbers and proportions were then compared in blood samples from obese and nonobese adults. DRmid and DRhi intermediate monocytes differentially expressed several proteins including CD62L, CD11a, CX3CR1 and CCR2. Overall, the DRmid intermediate monocytes surface profile more closely resembled that of classical monocytes while DRhi intermediate monocytes were more similar to nonclassical. However, in contrast to classical monocytes, DRmid intermediate monocytes migrated weakly to CCL2, had reduced intracellular calcium flux following CCR2 ligation and favored adherence to TNFalpha-activated endothelium over transmigration. In lipid uptake assays, DRmid intermediate monocytes demonstrated greater internalization of oxidized and acetylated low-density lipoprotein than DRhi intermediate monocytes. In obese compared to nonobese adults, proportions and absolute numbers of DRmid , but not DRhi intermediate monocytes, were increased in blood. The results are consistent with phenotypic and functional heterogeneity within the intermediate monocytes subset that may be of specific relevance to lipoprotein scavenging and metabolic health. PMID- 29505095 TI - T-cell lymphomas associated gene expression signature: Bioinformatics analysis based on gene expression Omnibus. AB - OBJECTIVES: Due to the low incidence and the heterogeneity of subtypes, the biological process of T-cell lymphomas is largely unknown. Although many genes have been detected in T-cell lymphomas, the role of these genes in biological process of T-cell lymphomas was not further analyzed. METHODS: Two qualified datasets were downloaded from Gene Expression Omnibus database. The biological functions of differentially expressed genes were evaluated by gene ontology enrichment and KEGG pathway analysis. The network for intersection genes was constructed by the cytoscape v3.0 software. Kaplan-Meier survival curves and log rank test were employed to assess the association between differentially expressed genes and clinical characters. RESULTS: The intersection mRNAs were proved to be associated with fundamental processes of T-cell lymphoma cells. These intersection mRNAs were involved in the activation of some cancer-related pathways, including PI3K/AKT, Ras, JAK-STAT, and NF-kappa B signaling pathway. PDGFRA, CXCL12, and CCL19 were the most significant central genes in the signal net analysis. The results of survival analysis are not entirely credible. CONCLUSIONS: Our findings uncovered aberrantly expressed genes and a complex RNA signal network in T-cell lymphomas and indicated cancer-related pathways involved in disease initiation and progression, providing a new insight for biotargeted therapy in T-cell lymphomas. PMID- 29505096 TI - The influence of environmental features in the content of mycosporine-like amino acids in red marine algae along the Brazilian coast. AB - Mycosporine-like amino acids (MAA) are ultraviolet screen substances synthesized by marine algae. The physiological function of these substances is related to cellular protection against UV radiation and as a protective mechanism against oxidative stress. These substances can be found mainly in the ocean, among red seaweeds. Its concentration in organisms has been related to ultraviolet radiation and availability of inorganic nitrogen in the environment. We start our study of MAA content in different species to understand if environmental conditions influence the concentration of MAAs in red seaweeds. The Brazilian coast presents abiotic factors that interact to create different physical chemical features in the environment. We collected 441 samples from 39 species of red seaweed easily found in the intertidal zone, in low tide, during the summer of 2015. The sampling encompassed a latitudinal gradient (3 degrees S to 28 degrees 5' S) at 23 points along the coast. We quantified and identified the content of MAAs in species through the method of high performance liquid chromatography. We detected for the first time the occurrence of MAAs in certain species of red algae that have not been reported to contain MAAs before. We confirmed that some environmental factors influenced the content of MAAs. Enhanced MAA contents, for example, were found in environments with a basic pH, a high ultraviolet index, and high concentrations of phosphate and nitrate. Salinity, dissolved oxygen and variations of sea surface temperature also influenced, in a secondary way, MAA content in algae in their natural environments. PMID- 29505097 TI - Issues facing families of infants discharged after cardiac surgery: the perceptions of charity helpline staff. AB - AIM: To elicit the perceptions of helpline staff who talk to parents of children discharged after cardiac surgery in infancy about parents' key concerns. METHODS: A qualitative study involving semistructured interviews with 10 staff at four heart charities. Interviews were recorded, transcribed and analysed using Framework analysis. RESULTS: Staff identified the knowledge, communication and support needs of parents which they described in terms of the impact of patient and family factors, sources of support and systems. Staff perceptions of helplines, in terms of the function of a helpline and the roles of its staff, together with staff's personal views based on their experience of multiple encounters with many families, influenced how they viewed families' needs and responded to their requests. CONCLUSION: Helpline staff provided important, previously uncaptured evidence about the challenges faced by parents of children discharged after cardiac surgery in infancy. Staff have an important role in supporting communication, in terms of speaking to families about how to talk to professionals and talking to professionals directly to get or give information when parents are unable to do so. Capturing the perspective of helpline staff about communication issues has highlighted the need for interventions with professionals as well as parents. PMID- 29505098 TI - The effectiveness of an emotion-focused educational programme in reducing diabetes distress in adults with Type 2 diabetes mellitus (VEMOFIT): a cluster randomized controlled trial. AB - AIMS: To evaluate the effectiveness of a brief, value-based emotion-focused educational programme (VEMOFIT) in Malay adults with Type 2 diabetes mellitus compared with a programme of active listening to participants' emotional experiences, social support and their opinion on the health clinic diabetes care services (attention control). METHODS: Malay adults with severe diabetes distress [Diabetes Distress Scale (DDS-17) mean score >= 3] were included. VEMOFIT consisted of four biweekly group sessions, a booster session after 3 months and a follow-up 6 months post intervention. The attention control programme consisted of three sessions over the same period. Outcomes included diabetes distress, depressive symptoms, self-efficacy and disease control. Required total sample size was 165. RESULTS: Participants (n = 124) were randomized to either VEMOFIT (n = 53) or the attention control programme (n = 71). Participants had a mean (sd) age of 55.7 (9.7) years, median diabetes duration of 7.0 (8.0) years and mean HbA1c level of 82 mmol/mol (9.7%). The mean DDS-17 level decreased significantly in both the VEMOFIT and the attention control programmes (3.4 to 2.9 vs. 3.1 to 2.7, respectively). The adjusted between-group DDS-17 difference was not significant [-0.01, 95% confidence interval (CI) -0.38, 0.35]. The proportion of individuals with severe diabetes distress decreased in both groups, from 89% to 47% vs. 69% to 39% (odds ratio 0.88; 95% CI 0.26, 2.90). Other outcomes did not differ between groups. CONCLUSIONS: Both interventions decreased diabetes distress significantly. The theory-based VEMOFIT programme was not superior to the attention control programme. The latter approach is a simpler way to decrease severe diabetes distress (Trial registration: NCT02730078; NMRR-15 1144-24803). PMID- 29505099 TI - Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer's disease. AB - Women seem to have a higher vulnerability to Alzheimer's disease (AD), but the underlying mechanisms of this sex dichotomy are not well understood. Here, we first determined the influence of sex on various aspects of Alzheimer's pathology in transgenic CRND8 mice. We demonstrate that beta-amyloid (Abeta) plaque burden starts to be more severe around P180 (moderate disease stage) in female transgenics when compared to males and that aging aggravates this sex-specific difference. Furthermore, we show that female transgenics suffer from higher levels of neurovascular dysfunction around P180, resulting in impaired Abeta peptide clearance across the blood-brain-barrier at P360. Female transgenics show also higher levels of diffuse microgliosis and inflammation, but the density of microglial cells surrounding Abeta plaques is less in females. In line with this finding, testosterone compared to estradiol was able to improve microglial viability and Abeta clearance in vitro. The spatial memory of transgenics was in general poorer than in wildtypes and at P360 worse in females irrespective of their genotype. This difference was accompanied by a slightly diminished dendritic complexity in females. While all the above-named sex-differences emerged after the onset of Abeta pathology, kallikrein-8 (KLK8) protease levels were, as an exception, higher in female than in male brains very early when virtually no plaques were detectable. In a second step, we quantified cerebral KLK8 levels in AD patients and healthy controls, and could ascertain, similar to mice, higher KLK8 levels not only in AD-affected but also in healthy brains of women. Accordingly, we could demonstrate that estradiol but not testosterone induces KLK8 synthesis in neuronal and microglial cells. In conclusion, multiple features of AD are more pronounced in females. Here, we show for the first time that this sex-specific difference may be meditated by estrogen-induced KLK8 overproduction long before AD pathology emerges. PMID- 29505100 TI - Liquid chromatography-tandem MS/MS method for simultaneous quantification of paracetamol, chlorzoxazone and aceclofenac in human plasma: An application to a clinical pharmacokinetic study. AB - A facile, fast and specific method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous quantitation of paracetamol, chlorzoxazone and aceclofenac in human plasma was developed and validated. Sample preparation was achieved by liquid-liquid extraction. The analysis was performed on a reversed-phase C18 HPLC column (5 MUm, 4.6 * 50 mm) using acetonitrile-10 mM ammonium formate pH 3.0 (65:35, v/v) as the mobile phase where atrovastatin was used as an internal standard. A very small injection volume (3 MUL) was applied and the run time was 2.0 min. The detection was carried out by electrospray positive and negative ionization mass spectrometry in the multiple-reaction monitoring mode. The developed method was capable of determining the analytes over the concentration ranges of 0.03-30.0, 0.015-15.00 and 0.15-15.00 MUg/mL for paracetamol, chlorzoxazone and aceclofenac, respectively. Intraday and interday precisions (as coefficient of variation) were found to be <=12.3% with an accuracy (as relative error) of +/-5.0%. The method was successfully applied to a pharmacokinetic study of the three analytes after being orally administered to six healthy volunteers. PMID- 29505101 TI - Evaluating Potential QT Effects of JNJ-54861911, a BACE Inhibitor in Single- and Multiple-Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration-QTc Analysis. AB - Nonclinical assays with JNJ-54861911, a beta-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (Cmax ) comparable to those in the SAD study (~750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation. PMID- 29505102 TI - Bending strategies of convergently evolved, articulated coralline algae. AB - The evolution of uncalcified genicula in upright calcified corallines has occurred at least three times independently, resulting in articulated corallines within Corallinoideae, Lithophylloideae, and Metagoniolithoideae. Genicula confer flexibility to otherwise rigid thalli, and the localization of bending at discrete intervals amplifies bending stress in genicular tissue. Genicular morphology must, therefore, be balanced between maintaining flexibility while mitigating or resisting stress. Genicula in the three articulated lineages differ in both cellular construction and development, which may result in different constraints on morphology. By studying the interaction between flexibility and morphological variation in multiple species, we investigate whether representatives of convergently evolving clades follow similar strategies to generate mechanically successful articulated fronds. By using computational models to explore different bending strategies, we show that there are multiple ways to generate flexibility in upright corallines but not all morphological strategies are mechanically equivalent. Corallinoids have many joints, lithophylloids have pliant joints, and metagoniolithoids have longer joints-while these strategies can lead to comparable thallus flexibility, they also lead to different levels of stress amplification in bending. Moreover, genicula at greatest risk of stress amplification are typically the strongest, universally mitigating the trade-off between flexibility and stress reduction. PMID- 29505104 TI - Electron contamination in 60 Co gamma-ray beams. AB - All radiotherapy photon beams are accompanied to some extent by secondary electrons which originate in interactions with source hardware, collimator, shadow tray, and/or the air through which the beam passes. Skin sparing, the shape of the dose buildup curve, and the depth of the dose maximum are all influenced by this electron "contamination." The present study of a 60 Co source employs a flat ion chamber to measure dose buildup curves in polystyrene at source distances of 72 to 200 cm, with an open beam or a filter of Lucite, Cu, Pb loaded acrylic, or Ba- or Pb-loaded nonbrowning glass placed 57 cm from the source, using 5*5, 20*20, and 35*35-cm2 beams as defined at 80 cm SSD. The effect of electron generation in the air was studied by placing a He-gas-filled plastic bag in the beam. A value of about 12% is estimated for the lowest relative dose obtainable with a polystyrene phantom in a "clear" 60 Co gamma-ray beam of 1-cm diameter. PMID- 29505103 TI - Interventions for eye movement disorders due to acquired brain injury. AB - BACKGROUND: Acquired brain injury can cause eye movement disorders which may include: strabismus, gaze deficits and nystagmus, causing visual symptoms of double, blurred or 'juddery' vision and reading difficulties. A wide range of interventions exist that have potential to alleviate or ameliorate these symptoms. There is a need to evaluate the effectiveness of these interventions and the timing of their implementation. OBJECTIVES: We aimed to assess the effectiveness of any intervention and determine the effect of timing of intervention in the treatment of strabismus, gaze deficits and nystagmus due to acquired brain injury. We considered restitutive, substitutive, compensatory or pharmacological interventions separately and compared them to control, placebo, alternative treatment or no treatment for improving ocular alignment or motility (or both). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (containing the Cochrane Eyes and Vision Trials Register) (2017, Issue 5), MEDLINE Ovid, Embase Ovid, CINAHL EBSCO, AMED Ovid, PsycINFO Ovid, Dissertations & Theses (PQDT) database, PsycBITE (Psychological Database for Brain Impairment Treatment Efficacy), ISRCTN registry, ClinicalTrials.gov, Health Services Research Projects in Progress (HSRProj), National Eye Institute Clinical Studies Database and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The databases were last searched on 26 June 2017. No date or language restrictions were used in the electronic searches for trials. We manually searched the Australian Orthoptic Journal, British and Irish Orthoptic Journal, and ESA, ISA and IOA conference proceedings. We contacted researchers active in this field for information about further published or unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any intervention for ocular alignment or motility deficits (or both) due to acquired brain injury. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We used standard methods expected by Cochrane. We employed the GRADE approach to interpret findings and assess the quality of the evidence. MAIN RESULTS: We found five RCTs (116 participants) that were eligible for inclusion. These trials included conditions of acquired nystagmus, sixth cranial nerve palsy and traumatic brain injury-induced ocular motility defects. We did not identify any relevant studies of restitutive interventions.We identified one UK-based trial of a substitutive intervention, in which botulinum toxin was compared with observation in 47 people with acute sixth nerve palsy. At four months after entry into the trial, people given botulinum toxin were more likely to make a full recovery (reduction in angle of deviation within 10 prism dioptres), compared with observation (risk ratio 1.19, 95% CI 0.96 to 1.48; low-certainty evidence). These same participants also achieved binocular single vision. In the injection group only, there were 2 cases of transient ptosis out of 22 participants (9%), and 4 participants out of 22 (18%) with transient vertical deviation; a total complication rate of 24% per injection and 27% per participant. All adverse events recovered. We judged the certainty of evidence as low, downgrading for risk of bias and imprecision. It was not possible to mask investigators or participants to allocation, and the follow-up between groups varied.We identified one USA-based cross-over trial of a compensatory intervention. Oculomotor rehabilitation was compared with sham training in 12 people with mild traumatic brain injury, at least one year after the injury. We judged the evidence from this study to be very low-certainty. The study was small, data for the sham training group were not fully reported, and it was unclear if a cross-over study design was appropriate as this is an intervention with potential to have a permanent effect.We identified three cross-over studies of pharmacological interventions for acquired nystagmus, which took place in Germany and the USA. These studies investigated two classes of pharmacological interventions: GABAergic drugs (gabapentin, baclofen) and aminopyridines (4-aminopyridines (AP), 3,4-diaminopyridine (DAP)). We judged the evidence from all three studies as very low-certainty because of small numbers of participants (which led to imprecision) and risk of bias (they were cross-over studies which did not report data in a way that permitted estimation of effect size).One study compared gabapentin (up to 900 mg/day) with baclofen (up to 30 mg/day) in 21 people with pendular and jerk nystagmus. The follow-up period was two weeks. This study provides very low certainty evidence that gabapentin may work better than baclofen in improving ocular motility and reducing participant-reported symptoms (oscillopsia). These effects may be different in pendular and jerk nystagmus, but without formal subgroup analysis it is unclear if the difference between the two types of nystagmus was chance finding. Quality of life was not reported. Ten participants with pendular nystagmus chose to continue treatment with gabapentin, and one with baclofen. Two participants with jerk nystagmus chose to continue treatment with gabapentin, and one with baclofen. Drug intolerance was reported in one person receiving gabapentin and in four participants receiving baclofen. Increased ataxia was reported in three participants receiving gabapentin and two participants receiving baclofen.One study compared a single dose of 3,4-DAP (20 mg) with placebo in 17 people with downbeat nystagmus. Assessments were made 30 minutes after taking the drug. This study provides very low-certainty evidence that 3,4-DAP may reduce the mean peak slow-phase velocity, with less oscillopsia, in people with downbeat nystagmus. Three participants reported transient side effects of minor perioral/distal paraesthesia.One study compared a single dose of 4-AP with a single dose of 3,4-DAP (both 10 mg doses) in eight people with downbeat nystagmus. Assessments were made 45 and 90 minutes after drug administration. This study provides very low-certainty evidence that both 3,4-DAP and 4-AP may reduce the mean slow-phase velocity in people with downbeat nystagmus. This effect may be stronger with 4-AP. AUTHORS' CONCLUSIONS: The included studies provide insufficient evidence to inform decisions about treatments specifically for eye movement disorders that occur following acquired brain injury. No information was obtained on the cost of treatment or measures of participant satisfaction relating to treatment options and effectiveness. It was possible to describe the outcome of treatment in each trial and ascertain the occurrence of adverse events. PMID- 29505105 TI - Reply. PMID- 29505107 TI - Comments on "Optimal photon energies with respect to absorbed dose for visualization of soft tissue masses within adipose tissue". PMID- 29505108 TI - A targeted approach for routine viral load monitoring in Malawian adults on antiretroviral therapy. AB - OBJECTIVES: WHO recommends HIV viral load (VL) testing 6 months after antiretroviral therapy (ART) initiation and every 12 months thereafter, but cost prohibits routine, universal VL testing in many developing countries. We sought to devise a targeted approach to routine VL monitoring that could reduce cost and identify those at low risk for virologic failure (VF). METHODS: We analysed screening data from a clinical trial enrolling adults on ART in Malawi. We identified risk factors associated with VF and employed the Knill-Jones method to assign summary score identifying persons at lower risk for VF. RESULTS: Among 957 adults, prevalence of VF was 9.4%. Factors independently associated with VF included age <38 years (OR 3.44, 95% CI 2.01-5.89), ART duration >2.5 years (OR 2.98, 95% CI 1.79-4.96), ART adherence <95% (OR 1.76, 95% CI 1.06-2.94), CD4 count <200 cells/MUl (OR 5.94, 95% CI 3.27-10.78), haemoglobin <13 g/dl (OR 2.76, 95% CI 1.70-4.50) and CD8 count >885 cells/MUl (OR 2.10, 95% CI 1.28-3.44). Our VF prediction summary score included all factors above except CD8 count and was fairly accurate with validated area under receiver operating characteristic curve of 0.76. Implementation could reduce VL testing by 65%. CONCLUSION: A simple score incorporating age, ART duration and adherence, and CD4 count can accurately identify adults at low risk for VF in a sub-Saharan African setting. In areas with high ART utilisation and limited VL testing capacity, a targeted approach could optimise routine VL monitoring while identifying adults in need of alternate ART regimens. PMID- 29505109 TI - PD-L1 expression by tumor cell lines: A predictive marker in melanoma. AB - Prognostic biomarkers for patients with melanoma after lymph node resection are of clinical relevance and could thus enable the identification of patients who therefore would most benefit from adjuvant treatment. The aim of this work was to determine, using an in vitro model, whether immune-related biomarkers, such as MHC-class I and II, melanoma-associated antigens, IDO1 and PD-L1, could also be relevant to predict the risk of relapse of patients with stage III melanoma after lymph node resection. We established tumor cell lines from metastatic lymph nodes of 50 patients with melanoma. The expression of investigated biomarkers was determined on untreated and IFN-gamma treated melanoma cell lines using flow cytometry. Among the selected biomarkers, the IFN-gamma-induced expression of PD L1 and IDO1 was associated with an increased risk of relapse (P = .0001 and P = .013, respectively) and was also associated with death for IDO1 (P = .0005). In the future, this immunologic signature could permit the identification of patients at higher risk of relapse and justifying an adjuvant treatment using immunotherapy. PMID- 29505110 TI - Processed kaolin affects the probing and settling behavior of Diaphorina citri (Hemiptera: Lividae). AB - BACKGROUND: Alternative methods that have the potential to reduce the entry of Diaphorina citri Kuwayama (Hemiptera: Liviidae), the major citrus pest worldwide, into commercial groves could be a viable approach for huanglongbing management. Kaolin is an aluminum silicate that when sprayed on plants forms a white particle film that interferes with host recognition by the insects. Diaphorina citri orients towards the host plants by visual and olfactory cues. The purpose of the study was to determine the effect of processed kaolin on D. citri settling (no choice) and probing behavior [electrical penetration graph (EPG) technique] under laboratory conditions, and to study its host plant finding ability and dispersal under field conditions in the absence and presence of young shoots. RESULTS: Under laboratory conditions, kaolin caused an overall reduction of 40% in the number of psyllids settled on treated seedlings; furthermore, the proportion of individuals that were able to reach the phloem was 50% lower on kaolin-treated plants than on untreated plants. In the field, the plant finding ability of D. citri was disrupted on kaolin-treated trees (overall reduction of 96%), regardless of the vegetative condition, and psyllid dispersal was slower in kaolin-treated plots than in the untreated control. CONCLUSION: This study clearly demonstrates that processed kaolin interferes negatively with different aspects of the host plant finding ability of D. citri. These findings suggest that processed kaolin has a high potential to reduce huanglongbing primary infection. (c) 2018 Society of Chemical Industry. PMID- 29505112 TI - Hybrid Interfaces in Molecular Spintronics. AB - Molecular/inorganic multilayer heterostructures are gaining attention in molecular electronics and more recently in new generation spintronic devices. The intrinsic properties of molecular materials as low cost, tuneability, or long spin lifetimes were the original reasons behind their implementation. However, the non-innocent role played by these hybrid interfaces is a determinant factor in the device performance. In this account we will give an overview about different types of hybrid molecular system/ferromagnet interfaces, which can be of direct application in molecular spintronics. This includes the insertion of a 2D material in between the molecular system and the ferromagnet. As perspective, new hybrid interfaces able to tune the spin properties under an external stimulus, are proposed. These smart interfaces, based on switchable magnetic molecules or flexible MOFs, can open the way to new multifunctional spintronic devices able to couple the spin with a second property. PMID- 29505111 TI - A Toxoplasma gondii locus required for the direct manipulation of host mitochondria has maintained multiple ancestral functions. AB - The Toxoplasma gondii locus mitochondrial association factor 1 (MAF1) encodes multiple paralogs, some of which mediate host mitochondrial association (HMA). Previous work showed that HMA was a trait that arose in T. gondii through neofunctionalization of an ancestral MAF1 ortholog. Structural analysis of HMA competent and incompetent MAF1 paralogs (MAF1b and MAF1a, respectively) revealed that both paralogs harbor an ADP ribose binding macro-domain, with comparatively low (micromolar) affinity for ADP ribose. Replacing the 16 C-terminal residues of MAF1b with those of MAF1a abrogated HMA, and we also show that only three residues in the C-terminal helix are required for MAF1-mediated HMA. Importantly these same three residues are also required for the in vivo growth advantage conferred by MAF1b, providing a definitive link between in vivo proliferation and manipulation of host mitochondria. Co-immunoprecipitation assays reveal that the ability to interact with the mitochondrial MICOS complex is shared by HMA competent and incompetent MAF1 paralogs and mutants. The weak ADPr coordination and ability to interact with the MICOS complex shared between divergent paralogs may represent modular ancestral functions for this tandemly expanded and diversified T. gondii locus. PMID- 29505113 TI - Accuracy of syndromic management in targeting vaginal and cervical infections among symptomatic women of reproductive age attending primary care clinics in Dakar, Senegal. AB - OBJECTIVE: To assess the effectiveness of the WHO syndromic algorithm in the management of vaginal discharge among women of reproductive age in Dakar. METHODS: Cross-sectional study of consecutive female patients (aged 18-49 years) presenting with vaginal symptoms at six selected study sites in Dakar; of these, 276 patients were included in the analysis. Vaginal and cervical swab samples were collected and analysed to establish an aetiological diagnosis of any infection. Syndrome-based diagnosis was compared with the laboratory results to evaluate its accuracy based on sensitivity, specificity and positive and negative predictive values. The degree of agreement between the two approaches was assessed using the Cohen's kappa concordance analysis. RESULTS: Overall prevalence of vaginal infections was 56.9% (157/276); 5.4% (15/276) of the patients had cervical infection. Using the syndromic approach, 51% of patients were correctly managed for Trichomonas vaginalis (TV)/Gardnerella vaginalis (GV); 61% for Candida albicans (CA) and 54% for Chlamydia trachomatis (CT)/Neisseria gonorrhoea (NG) infections. Consequently, 31% of patients with TV/GV, 51% with CA and 53% with CT/NG infections would have missed treatment. Further, the kappa value was <0.20, indicating that there was no agreement or only slight agreement between the syndromic approach and laboratory-based diagnosis. CONCLUSION: This study highlights the limitations of the applicability of the WHO syndromic approach in settings with low prevalence of sexually transmitted infections (STIs) and calls for affordable and accurate rapid tests for STIs. PMID- 29505114 TI - Title X-Funded Health Center Staff Members' Perspectives on Barriers to Insurance Use For Confidential Family Planning Services. AB - CONTEXT: Under the Affordable Care Act (ACA), the number of patients who have health insurance among those receiving family planning and reproductive health services at Title X-funded health centers has grown. However, billing some patients' insurance for services may be difficult because of Title X's extensive confidentiality protections. Little is known about health centers' experiences in addressing these difficulties. METHODS: Eight focus group discussions were conducted with a convenience sample of 54 Title X-funded health center staff members and state program administrators in January and April 2015. Transcripts were examined through thematic analysis. RESULTS: Participants identified five key barriers to centers' ability to bill patients' health insurance. Insurance providers' policyholder communications (e.g., explanations of benefits or patient portal postings) can threaten confidentiality for patients insured as dependents. Patients and providers are sometimes confused about insurance providers' confidentiality protections; centers are hesitant to bill insurance when protections are unclear. Changes in Medicaid family planning waiver coverage in some states have added to this uncertainty. Health centers can encounter significant administrative burdens when billing insurance while trying to protect patients' confidentiality. Finally, patients sometimes hesitate to use their insurance because of financial or other concerns. CONCLUSIONS: Title X-funded health centers face several barriers to their ability to bill patients' health insurance while maintaining confidentiality protections. As a result, they are likely to continue relying on Title X funds to cover services for some insured patients despite the expansion of health insurance under the ACA. PMID- 29505117 TI - An update on clinical biochemical RIs of rabbits with special consideration for age, gender, and size. AB - BACKGROUND: Literature regarding the impact of age and breed size on clinical biochemical measurands in rabbits is scarce. OBJECTIVES: We aimed to establish clinical biochemical measurand RIs for rabbits bred and kept under standard conditions and to evaluate the impact of gender, age, and breed size on the results using a Nova CRT8 analyzer (Nova Biomedical GmbH) and an ABX Pentra 400 analyzer (ABX Horiba, Axonlab). METHODS: Serum samples were available from 122 adult rabbits (56 males, 66 females) of 10 different breeds and crossbreds with a mean age of 264 +/- 21 days. The impact of age was evaluated by sampling 48 rabbits at weaning (8 weeks of age) and when they reached adulthood. RESULTS: Significantly higher median values were obtained for ALT, glutamate dehydrogenase (GLDH), and potassium in adult males compared with adult female rabbits. Total bilirubin, cholesterol, creatinine, and urea were significantly higher in adult females than adult males. Juvenile animals at weaning revealed significantly higher median values for ALP, cholesterol, GGT, GLDH, glucose, phosphate, and triglycerides compared with their adulthood values. In contrast, lower median albumin, ALT, chloride, creatinine, globulin, ionized calcium, magnesium, potassium, total protein, urea, and calcium-phosphate ratios were seen at the time of weaning compared with adulthood values. Significantly lower median CK, creatinine, and ALT were found in dwarf/small rabbit breeds compared with intermediate/large breeds. CONCLUSIONS: These RIs are especially useful for rabbit production and experimental studies. Age should be considered when evaluating clinical biochemical measurands. Creatinine, CK, and ALT are affected by organ mass. PMID- 29505116 TI - A new high-resolution melting assay for genotyping Alternaria species causing citrus brown spot. AB - BACKGROUND: Alternaria brown spot is one of the most important diseases of tangerines and their hybrids worldwide. To set up effective control strategy, the accurate detection and identification of the species responsible for the diseases is crucial. However, characterization based on morphology and/or multilocus genetic approaches is time consuming, requires great expertise and sometimes is not conclusive. Therefore, the set-up of a rapid and efficient DNA-based assay might be of paramount importance. High-resolution melting (HRM) analysis represents an interesting tool for the uncovering of nucleotide variations as small as one base difference and, as such, relevant to species characterization. RESULTS: In the present investigation, an HRM assay based on the Alternaria barcoding region OPA1-3 was set up. Specimen strains of the main citrus associated Alternaria species and morphotypes generated distinct and normalized profiles, allowing their differentiation when HRM-tested. Moreover, when the assay was used to screen an Alternaria collection from citrus fruit and leaves, it distributed the 180 isolates in three independent clusters, readily and consistently resolved. Isolates were identified as belonging to the species Alternaria alternata and the species complex A. arborescens. Within A. alternata, the morphotypes alternata (77% of the collection) and limoniasperae (17% of the collection) were present. CONCLUSIONS: Although further validation experiments will be performed to optimize the assay for a diagnostic use, this HRM approach might represent a rapid, sensitive and specific method for the detection and identification of Alternaria spp. responsible for citrus brown spot disease. (c) 2018 Society of Chemical Industry. PMID- 29505118 TI - Reference intervals for the activity of lactate dehydrogenase and its isoenzymes in the serum and cerebrospinal fluid of healthy canines. AB - BACKGROUND: Lactate dehydrogenase (LD) exists as 5 isoenzymes (LD-1 through LD-5) that are expressed throughout the body and can be detected in both serum and cerebrospinal fluid (CSF). LD and its isoenzymes have been relatively unstudied in veterinary medicine, although studies in human medicine have demonstrated that changes in total LD activity and atypical isoenzyme patterns can indicate disease processes, including neurologic abnormalities. OBJECTIVES: The purpose of this study was to establish RIs for LD and its isoenzymes in the serum and CSF of clinically healthy dogs. By establishing a definitive RI for this enzyme in healthy canines, further study of the clinical and diagnostic usefulness of LD can be undertaken. METHODS: Serum and atlantoaxial CSF were collected from clinically healthy dogs. Total LD activity was measured spectrophotometrically immediately after collection. Isoenzyme distributions were also determined within 8 hours of collection using the QuickGel LD Isoenzyme technique and a densitometric scanner. RESULTS: The median serum total LD in healthy canines was 69.0 U/L (n = 41; range: 21.0-217.0 U/L), while the median CSF total LD was 10.0 U/L (n = 40; range: 6.0-19.3 U/L). LD-5 is the predominant isoenzyme in canine serum (n = 40), contributing over half of the total enzyme activity. Conversely, in canine CSF (n = 42), LD-1 is the predominant isoenzyme, followed by LD-2 and LD-3. CONCLUSIONS: Knowledge of the distribution and concentration of LD in the serum and CSF of healthy dogs will set the foundation for future studies of canine LD as a potentially clinically useful biomarker. PMID- 29505115 TI - Macrophage-derived GPNMB accelerates skin healing. AB - Healing is a vital response important for the re-establishment of the skin integrity following injury. Delayed or aberrant dermal wound healing leads to morbidity in patients. The development of therapies to improve dermal healing would be useful. Currently, the design of efficient treatments is stalled by the lack of detailed knowledge about the cellular and molecular mechanisms involved in wound healing. Recently, using state-of-the-art technologies, it was revealed that macrophages signal via GPNMB to mesenchymal stem cells, accelerating skin healing. Strikingly, transplantation of macrophages expressing GPNMB improves skin healing in GPNMB-mutant mice. Additionally, topical treatment with recombinant GPNMB restored mesenchymal stem cells recruitment and accelerated wound closure in the diabetic skin. From a drug development perspective, this GPNMB is a new candidate for skin healing. PMID- 29505119 TI - Exposure of Nursed Infants to Maternal Treatment with Ethambutol and Rifampicin. AB - Mycobacterial diseases remain a significant cause of morbidity and mortality worldwide. Rifampicin and ethambutol are among the drugs recommended by WHO as first-line treatment. In this work, we addressed the question whether doses of the two anti-tuberculosis agents ethambutol and rifampicin transferred to a nursed infant could be of health concerns when the mother is under treatment. We used the approach of pharmacokinetic modelling using a structural model with two interconnected organisms: the first one being the organism of the nursing mother and the second one being the organism of the nursed child. Physiological data were taken from the literature. The models were parameterised by data from the literature concerning clearance, absorption and plasma/milk ratio. Distribution into the tissues was calculated by an algorithm. The predictive power of the model was tested by comparing the predicted plasma concentrations in the mothers with measured data from the literature. Comparison with measured data after direct infant treatment was performed for the rifampicin plasma concentrations predicted in the nursed infant. Both comparisons confirmed the appropriateness of the modelling results. The transfer of 0.08 mg/kg bw/day ethambutol via breast milk to the nursed infant, the dose we have estimated, when the mother received a therapeutic dose of 24.5 mg/kg bw, can be judged as being without health concern. Likewise, for rifampicin, the transferred dose of 0.4 mg/kg bw to the nursed infant resulting from a therapeutic dose of 10.9 mg/kg bw to the mother does not raise health concerns. PMID- 29505120 TI - Finnish-born children of immigrants are more likely to be diagnosed with developmental disorders related to speech and language, academic skills and coordination. AB - AIM: We examined the association between having at least one parent born abroad and being diagnosed with a developmental disorder related to speech and language, academic skills or coordination. METHODS: This nested case-control study was based on Finnish population records for 1996-2007. Cases from the Finnish Hospital Discharge Register were diagnosed with developmental disorders of speech and language, academic skills and coordination by the end of 2012. We identified 28 192 cases and 106 616 matched controls. RESULTS: Children were more likely to be diagnosed with developmental disorders if they had an immigrant mother than children with two Finnish-born parents, with an adjusted odds ratio (aOR) of 1.3 and 95% confidence interval (95% CI) of 1.2-1.4, an immigrant father (aOR 1.2, 95% CI 1.1-1.3) or two immigrant parents (aOR 1.5, 95% CI 1.3-1.6). The level of development of the parental country of origin was not associated with receiving a diagnosis. CONCLUSION: Children of immigrant parents were more likely to be diagnosed with developmental disorders and the association was strongest with regard to speech and language disorders. There were similar adjusted odds ratios for mothers, fathers and both parents. The development level of the country of origin was irrelevant. PMID- 29505121 TI - Detection and function of lipopolysaccharide and its purified lipid A after treatment with auxiliary chemical substances and calcium hydroxide dressings used in root canal treatment. AB - AIM: To investigate the influence of auxiliary chemical substances (ACSs) and calcium hydroxide [Ca(OH)2 ] dressings on lipopolysaccharides (LPS)/lipid A detection and its functional ability in activating Toll-like receptor 4 (TLR4). METHODOLOGY: Fusobacterium nucleatum pellets were exposed to antimicrobial agents as following: (i) ACS: 5.25%, 2.5% and 1% sodium hypochlorite solutions (NaOCl), 2% chlorhexidine (CHX) (gel and solution) and 17% ethylenediaminetetraacetic acid (EDTA); (ii) intracanal medicament: Ca(OH)2 paste for various periods (1 h, 24 h, 7 days, 14 days and 30 days); (iii) combination of substances: (a) 2.5% NaOCl (1 h), followed by 17% EDTA (3 min) and Ca(OH)2 (7 days); (b) 2% CHX (1 h), afterwards, 17% EDTA (3 min) followed by Ca(OH)2 (7 days). Saline solution was the control. Samples were submitted to LPS isolation and lipid A purification. Lipid A peaks were assessed by matrix-assisted laser desorption ionization time of-flight mass spectrom (MALDI-TOF MS) whilst LPS bands by SDS-PAGE separation and silver staining. TLR4 activation determined LPS function activities. Statistical comparisons were carried out using one-way anova with Tukey-Kramer post-hoc tests at the 5% significance level. RESULTS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis of control lipid A demonstrated the ion cluster at mass/charge (m/z) 1882 and an intense band in SDS-PAGE followed by silver staining of control LPS. In parallel, LPS control induced a robust TLR4 activation when compared to ACS (P <= .001). 5.25% NaOCl treatment led to the absence of lipid A peaks and LPS bands, whilst no changes occurred to lipid A/LPS after treatment with others ACS. Concomitantly, 5.25% NaOCl-treated LPS did not activate TLR4 (P < .0001). As for Ca(OH)2 , lipid A was not detected by MALDI-TOF nor by gel electrophoresis within 24 h. LPS treated with Ca(OH)2 was a weak TLR4 activator (P < .0001). From 24 h onwards, no significant differences were found amongst the time periods tested (P > 0.05). The addition of Ca(OH)2 for 7 days to cells treated either with 2.5% NaOCl or 2% CHX led to the absence of lipid A peaks and LPS bands, leading to a lower activation of TLR4. CONCLUSION: 5.25% NaOCl and Ca(OH)2 dressings from 24 h onwards were able to induce both, loss of lipid A peaks and no detection of LPS bands, rendering a diminished immunostimulatory activity through TLR4. PMID- 29505122 TI - An evolutionarily conserved P-subfamily pentatricopeptide repeat protein is required to splice the plastid ndhA transcript in the moss Physcomitrella patens and Arabidopsis thaliana. AB - Pentatricopeptide repeat (PPR) proteins are known to play important roles in post transcriptional regulation in plant organelles. However, the function of the majority of PPR proteins remains unknown. To examine their functions, Physcomitrella patens PpPPR_66 knockout (KO) mutants were generated and characterized. The KO mosses exhibited a wild-type-like growth phenotype but showed aberrant chlorophyll fluorescence due to defects in chloroplast NADH dehydrogenase-like (NDH) activity. Immunoblot analysis suggested that disruption of PpPPR_66 led to a complete loss of the chloroplast NDH complex. To examine whether the loss of PpPPR_66 affects the expression of plastid ndh genes, the transcript levels of 11 plastid ndh genes were analyzed by reverse transcription PCR. This analysis indicated that splicing of the ndhA transcript was specifically impaired while mRNA accumulation levels as well as the processing patterns of other plastid ndh genes were not affected in the KO mutants. Complemented PpPPR_66 KO lines transformed with the PpPPR_66 full-length cDNA rescued splicing of the ndhA transcript. Arabidopsis thaliana T-DNA tagged lines of a PPR_66 homolog (At2 g35130) showed deficient splicing of the ndhA transcript. This indicates that the two proteins are functionally conserved between bryophytes and vascular plants. An in vitro RNA-binding assay demonstrated that the recombinant PpPPR_66 bound preferentially to the region encompassing a part of exon 1 to a 5' part of the ndhA group II intron. Taken together, these results indicate that PpPPR_66 acts as a specific factor to splice ndhA pre-mRNA. PMID- 29505123 TI - Molecular beacon-based real-time PCR method for detection of porcine DNA in gelatin and gelatin capsules. AB - BACKGROUND: The pharmaceutical industry has boosted gelatin consumption worldwide. This is supported by the availability of cost-effective gelatin production from porcine by-products. However, cross-contamination of gelatin materials, where porcine gelatin was unintentionally included in the other animal sources of gelatin, has caused significant concerns about halal authenticity. The real-time polymerase chain reaction (PCR) has enabled a highly specific and sensitive animal species detection method in various food products. Hence, such a technique was employed in the present study to detect and quantify porcine DNA in gelatin using a molecular beacon probe, with differences in performance between mitochondrial (cytochrome b gene) and chromosomal DNA-(MPRE42 repetitive element) based porcine-specific PCR assays being compared. RESULTS: A higher sensitivity was observed in chromosomal DNA (MPRE-PCR assay), where this assay allows the detection of gelatin DNA at amounts as as low as 1 pg, whereas mitochondrial DNA (CBH-PCR assay) can only detect at levels down to 10 pg of gelatin DNA. When an analysis with commercial gelatin and gelatin capsule samples was conducted, the same result was observed, with a significantly more sensitive detection being provided by the repetitive element of chromosomal DNA. CONCLUSION: The present study has established highly sensitive DNA-based porcine detection systems derived from chromosomal DNA that are feasible for highly processed products such as gelatin and gelatin capsules containing a minute amount of DNA. This sensitive detection method can also be implemented to assist the halal authentication process of various food products available on the market. (c) 2018 Society of Chemical Industry. PMID- 29505125 TI - UHPLC-HRMS/MS Based Profiling of Algerian Lichens and Their Antimicrobial Activities. AB - Lichens are complex symbiotic organisms able to produce a vast array of compounds. The Algerian lichen diversity has only prompted little interest even given the 1085 species listed. Herein, the chemodiversity of four Algerian lichens including Cladonia rangiformis, Ramalina farinaceae, R. fastigiata, and Roccella phycopsis was investigated. A dereplication strategy, using ultra high performance liquid chromatography-high resolution-electrospray ionization-mass spectrometry (UHPLC-HRMS/MS), was carried out for a comprehensive characterization of their substances including phenolics, depsides, depsidones, depsones, dibenzofurans, and aliphatic acids. Some known compounds were identified for the first time in some species. Additionally, the lichenic extracts were evaluated for their antifungal and antimicrobial activities on human pathogenic strains (Candida albicans, C. glabrata, Aspergillus fumigatus, Staphylococcus aureus, and Escherichia coli). Cyclohexane extracts were found particularly active against human pathogenic fungi with MIC80 values ranging from 8 to 62.5 MUg/mL, without cytotoxicity. This study highlights the therapeutic and prophylactic potential of lichenic extracts as antibacterial and antifungal agents. PMID- 29505127 TI - Erratum: to Med. Phys. 22, 809-819 (1995) and Med. Phys. 22, 821-829 (1995). PMID- 29505128 TI - Erratum: "Contrast-detail analysis of image degradation due to lossy compression" [Med. Phys. 22, 715-721 (1995)]. PMID- 29505129 TI - Quantitative verification of 192 Ir PDR and HDR source structure by pin-hole autoradiography. AB - For precise localization of the center and determination of the dimensions of the radioactive material within the capsule of brachytherapy sources, we have developed a method based on simultaneous pin-hole autoradiography of two sources. We constructed a variable magnification pin-hole camera consisting of two telescopically fitted Plexiglas cylinders which can accommodate two radioactive sources on the plate covering the top cylinder. The 192 Ir pulsed and high dose rate sources were studied and an 192 Ir seed was used as a reference source. The magnification factor was determined from the dimensions of the 192 Ir seed image, which was geometrically well defined by a separate transmission radiography experiment. The observed position for the center of radioactivity in the PDR and the HDR source capsules are in agreement with the vendor specifications. The distance from the tip of the PDR capsule to its center of radioactivity was found in this way to be 0.79+/-0.21 mm, which agrees with the position (0.85 mm) of the pellet situated closer to the tip as specified by the vendor. Quantitative verification of the internal source structure using this method enhances the accuracy with which the dose distribution near brachytherapy sources can be predicted by three-dimensional Monte Carlo calculations. PMID- 29505130 TI - Photoelectrons facilitate autoradiography for 192 Ir remote afterloaders. PMID- 29505131 TI - Erratum: "Dosimetry of Auger electron-emitting-radionuclides: Report No. 3 of AAPM Nuclear Medicine Task Group No. 6" [Med. Phys. 21, 1901-1915 (1994)]. PMID- 29505132 TI - Influence of implant neck surface and placement depth on crestal bone changes and soft tissue dimensions around platform-switched implants: A histologic study in dogs. AB - OBJECTIVES: To analyse bone remodelling and peri-implant soft tissues around platform-switching implants with and without a machined collar placed at different levels in relation to bone crest. MATERIAL AND METHODS: All mandibular premolars and the first molars were extracted in five dogs. At 6 months, six implants with and without a machined neck (MACH and GBAE implants, respectively) were randomly inserted in each hemimandible positioning the implant-abutment interface in either a supracrestal (+1.5 mm), equicrestal, or subcrestal (-1.5 mm) position. After 6 months, animals were killed for histomorphometric analysis. RESULTS: When net bone loss (primary outcome variable) was compared between MACH and GBAE groups, the multivariable regression analysis revealed no significant differences between implants inserted at the same vertical position. The dimensions of the peri-implant mucosa were greater in MACH implants compared with GBAE implants; however, these differences failed to reach statistical significance. Regarding the number of inflammatory cells and collagen fibre orientation, no statistically significant differences were found between MACH and GBAE groups. CONCLUSIONS: The surface treatment of the implant neck does not seem to have an influence on net bone loss, and there were no statistically significant differences in the peri-implant soft tissues between platform switching implants with and without a machined neck. PMID- 29505133 TI - Differences in the Synthesis and Elimination of Phosphatidylethanol 16:0/18:1 and 16:0/18:2 After Acute Doses of Alcohol. AB - BACKGROUND: The purpose of this study was to examine the synthesis and elimination of phosphatidylethanol (PEth) 16:0/18:1 and 16:0/18:2 following the consumption of alcohol among 56 light and heavy drinkers. METHODS: A transdermal alcohol monitor was used to promote alcohol absence 7 days prior, and 14 days after, alcohol consumption in the laboratory. Participants consumed a 0.4 or 0.8 g/kg dose of alcohol in 15 minutes. Blood and breath samples were collected before, at various times up to 360 minutes postconsumption, and 2, 4, 7, 11, and 14 days after alcohol consumption. Initial rates of PEth synthesis, 360 minutes area under the PEth pharmacokinetic curves (AUCs), and elimination half-lives were determined. RESULTS: (i) Nonzero PEth levels were observed before alcohol dosing for most participants, despite 7 days of alcohol use monitoring; (ii) 0.4 and 0.8 g/kg doses of alcohol produced proportional increases in PEth levels in all but 1 participant; (iii) the initial rate of synthesis of both PEth homologues did not differ between the 2 doses, but was greater for PEth 16:0/18:2 than PEth 16:0/18:1 at both doses; (iv) the mean AUC of both PEth homologues was higher at 0.8 g/kg than at 0.4 g/kg; (v) the mean AUC of 16:0/18:2 was greater than that of PEth 16:0/18:1 at both alcohol doses; (vi) the mean half-life of PEth 16:0/18:1 was longer than that of PEth 16:0/18:2 (7.8 +/- 3.3 [SD] days and 6.4 +/- 5.0 [SD] days, respectively); and (vii) there were no sex differences in PEth 16:0/18:1 or 16:0/18:2 pharmacokinetics. CONCLUSIONS: The results of this study support the use of PEth 16:0/18:1 and 16:0/18:2 as biomarkers for alcohol consumption. Because of consistent pharmacokinetic differences, the levels of these 2 PEth homologues may provide more information regarding the quantity and recentness of alcohol consumption than either alone. PMID- 29505134 TI - One-third of children with lactose intolerance managed to achieve a regular diet at the three-year follow-up point. AB - AIM: This study described outcomes following treatment for lactose intolerance, which is common in children. METHODS: The medical records of children aged 6-18 years who underwent lactose hydrogen breath testing at Dana-Dwek Children's Hospital, Tel Aviv, Israel, from August 2012 to August 2014 were analysed. We compared 154 children with gastrointestinal symptoms and positive lactose hydrogen breath tests to 49 children with negative test results. RESULTS: Of the 154 children in the study group, 89 (57.8%) were advised to follow a lactose restricted diet, 32 (20.8%) were advised to avoid lactose completely, 18 (11.7%) were instructed to use substitute enzymes, and 15 (9.7%) did not receive specific recommendations. Only 11 patients (7.1%) received recommendations to add calcium rich foods or calcium supplements to their diet. Lactose reintroduction was attempted in 119 of 154 patients (77.3%), and 65 of 154 (42.2%) experienced clinical relapses. At the final follow-up of 3.3 years, 62.3% of the study children were still observing a restricted diet. Older children and those who were symptomatic during lactose hydrogen breath testing were more likely to be on a prolonged restricted diet. CONCLUSION: Our long-term follow-up of lactose intolerant children showed that only a third were able to achieve a regular diet. PMID- 29505135 TI - Impact of Early Initiation of Enteral Nutrition on Survival During Pediatric Extracorporeal Membrane Oxygenation. AB - INTRODUCTION: Pediatric data related to safety, tolerance, and outcomes of enteral nutrition (EN) for patients requiring extracorporeal membrane oxygenation (ECMO) are lacking. The objectives of this study were to evaluate early nutrition status and timing of EN initiation on survival during pediatric ECMO. METHODS: A single center institutional review board-approved retrospective chart review was performed on all pediatric patients requiring ECMO from October 2008 through December 2013. Demographics, ECMO variables, laboratory values, vasoactive inotropic score (VIS), and nutrition data on day 5 (d5) were collected. Patients receiving parenteral nutrition (PN) were compared with those receiving any EN on d5. Analyses were conducted to identify factors influencing survival to completion of ECMO and to discharge. RESULTS: Forty-nine patients aged 53 +/- 76 months met inclusion criteria. Kaplan-Meier curves demonstrated greater survival to discharge in patients receiving any EN, compared with only receiving PN (P = .031). EN on d5 of ECMO support (P = .040) and a higher percentage of daily energy intake achieved (P = .013) were protective, whereas a higher VIS was associated with increased mortality (P = .010). Multivariable analysis demonstrated EN was no longer associated with survival to discharge (P = .139), whereas energy intake (P = .021) and VIS (P = .013) remained significant. CONCLUSIONS: Pediatric patients who received nutrition that was closer to goal energy intake, as well as those who received any EN early during ECMO, had improved survival to hospital discharge. PMID- 29505136 TI - Establishing Decision Trees for Predicting Successful Postpyloric Nasoenteric Tube Placement in Critically Ill Patients. AB - BACKGROUND: Despite the use of prokinetic agents, the overall success rate for postpyloric placement via a self-propelled spiral nasoenteric tube is quite low. METHODS: This retrospective study was conducted in the intensive care units of 11 university hospitals from 2006 to 2016 among adult patients who underwent self propelled spiral nasoenteric tube insertion. Success was defined as postpyloric nasoenteric tube placement confirmed by abdominal x-ray scan 24 hours after tube insertion. Chi-square automatic interaction detection (CHAID), simple classification and regression trees (SimpleCart), and J48 methodologies were used to develop decision tree models, and multiple logistic regression (LR) methodology was used to develop an LR model for predicting successful postpyloric nasoenteric tube placement. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of these models. RESULTS: Successful postpyloric nasoenteric tube placement was confirmed in 427 of 939 patients enrolled. For predicting successful postpyloric nasoenteric tube placement, the performance of the 3 decision trees was similar in terms of the AUCs: 0.715 for the CHAID model, 0.682 for the SimpleCart model, and 0.671 for the J48 model. The AUC of the LR model was 0.729, which outperformed the J48 model. CONCLUSION: Both the CHAID and LR models achieved an acceptable discrimination for predicting successful postpyloric nasoenteric tube placement and were useful for intensivists in the setting of self-propelled spiral nasoenteric tube insertion. PMID- 29505137 TI - Malnutrition in Patients With Cancer: Comparison of Perceptions by Patients, Relatives, and Physicians-Results of the NutriCancer2012 Study. AB - BACKGROUND: Malnutrition is a critical predictor of toxicity and outcome in patients with cancer and may be perceived differently by patients, relatives, and physicians. AIMS: To assess the prevalence of malnutrition in oncology departments and to compare it with the perceptions of nutrition status by patients themselves, their closest relatives, and attending physicians. MATERIALS AND METHODS: A 1-day multicentric cross-sectional survey on the prevalence of malnutrition was conducted in different oncology departments using patient-, relative-, and physician-specific questionnaires. Malnutrition was defined by a weight loss >=5% within 1 month or >=10% within 6 months, a body mass index <=18.5 kg/m2 in patients aged <70 years or <=21 kg/m2 in patients aged >=70 years, and/or albuminemia <35 g/L. Questionnaires for assessing medical condition, knowledge of nutrition status, and perceptions of the impact of malnutrition on daily life were distributed to consenting patients, attending physicians, and closest relatives. RESULTS: A total of 2197 patients were included, and 2071 and 976 questionnaires were collected from patients and relatives, respectively. Prevalence of malnutrition was 39%. Physicians overestimated malnutrition (44%), whereas patients and relatives underestimated it (22% and 23%, respectively, P < .001). Conversely, malnutrition-associated symptoms were underestimated by physicians compared with patients and relatives. CONCLUSION: We found a prevalence of malnutrition of 39%: it was underestimated by patients and relatives and overestimated by physicians. PMID- 29505138 TI - Obesity: Risk Factor for Increased Resource Utilization at Bidirectional Glenn. AB - BACKGROUND: Underweight infants with single-ventricle cardiac physiology have been shown to have increased morbidity, mortality, and resource utilization. The purpose of this study was to determine whether patients who were overweight, as defined by weight-for-length z score >90th percentile, were similarly at risk for increased resource utilization, as defined by mechanical ventilation hours (VHs) and intensive care unit length of stay (ICU LOS). METHODS: We evaluated resource utilization for 109 patients from our institution who underwent bidirectional Glenn surgery from January 2010 to June 2015 and met prespecified inclusion criteria. Patients were divided into 3 groups: underweight (z score, <5th percentile), normal weight (z score, 5th-90th percentile), and overweight (z score, >90th percentile). RESULTS: ICU LOS was longer in the overweight group (median, 18.5 days) when compared with the under- and normal-weight groups (median LOS, 11 and 9 days, respectively) but did not reach statistical significance. VHs were also increased in the overweight group (median, 72 hours) when compared with the underweight (median, 27 hours) and normal weight (median, 25 hours) groups. This increase in VHs was statistically significant (P = .03). CONCLUSIONS: This study suggests that patients with single-ventricle physiology who are overweight at the time of their bidirectional Glenn surgery may be at risk for increased resource utilization as compared with those who meet or fail to meet their caloric recommendations. These findings represent an underappreciated risk factor in this already-vulnerable patient population, providing potential opportunity for intervention and improved outcomes. PMID- 29505139 TI - Underweight Status Is an Independent Predictor of In-Hospital Mortality in Pediatric Patients on Extracorporeal Membrane Oxygenation. AB - BACKGROUND: Malnutrition is associated with an increased risk of mortality in patients admitted to the intensive care unit. Children requiring extracorporeal membrane oxygenation (ECMO) support represent an extremely ill subset of this population. There is a lack of data on the impact of nutrition state on survival in this cohort. We examined the association between being underweight and in hospital mortality among children supported with ECMO. MATERIALS AND METHODS: This article reports on an observational retrospective cohort study performed among neonatal and pediatric patients supported with ECMO in a tertiary children's hospital from May 1996 through June 2013. Nutrition status on intensive care unit admission was defined with z scores on weight for length and body mass index. RESULTS: Patients (N = 491) had a median age of 31 days (interquartile range, 2-771): 24.4% were underweight, and 8.9% were obese. During ECMO support, 88.3% received total parenteral nutrition, and 30.3% received enteral nutrition. Median maximum energy intake while receiving ECMO was 82 kcal/kg/d (interquartile range, 54.7-105). Multiple logistic regression showed that underweight status was associated with increased predicted odds of in hospital mortality when compared with normal weight (odds ratio: 1.99, 95% confidence interval: 1.21-3.25, P = .006). Other factors associated with increased odds of mortality included extracorporeal cardiopulmonary resuscitation and the need for continuous renal replacement therapy. CONCLUSION: Underweight status was an independent predictor for in-hospital mortality in our cohort of pediatric ECMO patients. Prospective studies evaluating the impact of metabolic state of children on ECMO should further define this relationship. PMID- 29505140 TI - Effects and Tolerance of Protein and Energy-Enriched Formula in Infants Following Congenital Heart Surgery: A Randomized Controlled Trial. AB - BACKGROUND: Nutrition support is important for clinical management to improve outcomes of infants following congenital heart surgery. Protein-enriched and energy-enriched formula (PE-formula) may help provide adequate nutrition and promote wound healing. However, the effects and tolerance of increased protein and energy intakes of these infants have not been well defined. OBJECTIVE: To evaluate nutrition effects and tolerance of a PE-formula compared with the standard formula (S-formula) in infants in the first 5 days after congenital heart surgery. METHODS: Fifty infants were randomly assigned to S-formula (S group, n = 24) or PE-formula (PE-group, n = 26). Daily nutrient intakes and tolerance were recorded. Plasma amino acid concentrations were measured. Cumulative energy balance and nitrogen balance were calculated. RESULTS: Nutrient intakes were significantly higher in the PE-group after day 1, and all met the adequate intakes as early as day 2. Nitrogen balance in the PE-group met positive balance from day 2, whereas in the S-group, this was not until day 5. The PE group also had a significantly higher increase in many essential amino acids. With the exception of tolerable diarrhea (multivariate adjusted hazard ratio, 3.16; 95% confidence interval, 1.24-8.01), the PE-group did not have a significantly higher incidence of intolerable events. CONCLUSIONS: In infants during the early postoperative period after congenital heart surgery, early administration of PE-formula was as well tolerated as S-formula and effective in achieving higher nutrition intakes and earlier nitrogen balance. Further research is warranted to support the use of PE-formula in this special group of infants. PMID- 29505141 TI - High Rates of Positive Severe Combined Immunodeficiency Screening Among Newborns with Severe Intestinal Failure. AB - PURPOSE: Severe combined immunodeficiency (SCID) screening by T-cell receptor excision circles (TREC) has been part of Massachusetts routine newborn screening since 2009. Tetratricopeptide repeat domain 7A gene (TTC7A) mutations responsible for hereditary multiple intestinal atresia with combined immunodeficiency (MIA CID) were also recently identified. We reviewed newborn SCID screening among infants with intestinal failure and correlated results with patient characteristics and outcomes. METHODS: Records of infants with severe intestinal failure and available newborn screen results treated at a single center 2009-2016 were reviewed retrospectively. Patients with 1 or more positive SCID screens (<252 TREC copies/MUL) were compared with those without positive screens. TREC copies/MUL were compared with population norms. RESULTS: Of 70 included infants, 34% had newborn screens with TREC <252 copies/MUL, compared with 0.3% of the general population; TREC levels for the cohort were lower than the general population (p<0.001). Of those with positive screens, 42% had prior or subsequent negative screening, 8% had no further workup, and 50% had flow cytometry showing: severe T-cell lymphopenia (absolute CD3+ <1500 cells/mcL) in 8, 3 of whom had TTC7A mutation-associated MIA-CID. Four had CD3+ >1500 cells/mcL. MIA-CID patients had the lowest serum citrulline in the cohort; 4 of the 8 patients with CD3+ <1500 cells/mcL on flow cytometry had newborn screening notable for severe hypocitrullinemia (<3 MUM). CONCLUSION: Infants with intestinal failure have lower TREC copies/MUL than the general population; one-third had levels concerning for SCID, and 11% were diagnosed with severe T-cell lymphopenia. The clinical implications and etiology of this phenomenon remain unknown, but may be related to hypocitrullinemia. PMID- 29505142 TI - The Relationship Between Parenteral Nutrition and Central Line-Associated Bloodstream Infections: 2009-2014. AB - BACKGROUND: Parenteral nutrition (PN) administered via central venous catheter has been identified as an independent risk factor for central line-associated bloodstream infections (CLABSIs). The aim of this study was to provide an updated description of the relationship between PN and CLABSI and assess temporal trends in CLABSI rates for individuals who received PN from 2009-2014, after the Centers for Medicare & Medicaid declared CLABSI a "never event." METHODS: Using data obtained from all adult patient discharges between January 1, 2009, and December 31, 2014, from 2 affiliated hospitals in a large health system in New York City, univariate and multivariate analyses were performed to examine the relationship between PN and CLABSIs as well as temporal trends. RESULTS: Among 38,674 patients with central lines, 3517 developed CLABSIs and 767 patients were prescribed PN. PN was an independent risk factor for developing CLABSI among our patients (odds ratio [OR], 2.65; 95% confidence interval [CI], 2.20-3.19). The incidence of CLABSI among patients who were prescribed PN was not significantly different across the years of this study, even after adjusting for severity of illness. CONCLUSION: PN remains a significant risk factor for CLABSIs; further work is needed to identify effective strategies to reduce rates of CLABSI among patients receiving PN. PMID- 29505143 TI - Malnutrition Identified by the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition Consensus Criteria and Other Bedside Tools Is Highly Prevalent in a Sample of Individuals Undergoing Treatment for Head and Neck Cancer. AB - BACKGROUND: Using the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (Academy/ASPEN) Consensus malnutrition definition, we estimated malnutrition prevalence in a sample of individuals with head and neck cancer (HNC) and compared it with the Patient-Generated Subjective Global Assessment (PG-SGA). We also investigated the utility of the 50-kHz phase angle (PA) and 200-kHz/5-kHz impedance ratio (IR) to identify malnutrition. MATERIALS AND METHODS: Nineteen individuals (18 males, 1 female) scheduled to undergo chemoradiotherapy were seen at 5 time points during and up to 3 months after treatment completion. Multiple-frequency bioelectrical impedance analysis, PG-SGA, nutrition-focused physical examination, anthropometry, dietary intake, and handgrip strength data were collected. RESULTS: Using the Consensus, 67% were found to be malnourished before treatment initiation; these criteria diagnosed malnutrition with overall good sensitivity (94%) and moderate specificity (43%) compared with PG-SGA. Over all pooled observations, "malnourished" (by Consensus but not PG-SGA category) had a lower mean PA (5.2 vs 5.9; P = .03) and higher IR (0.82 vs 0.79; P = .03) than "well-nourished" categorizations, although the clinical relevance of these findings is unclear. PA and IR were correlated with higher PG-SGA score (r = -0.35, r = 0.36; P < .01) and handgrip strength (r = 0.48, r = -0.47; P < .01). CONCLUSION: The Academy/ASPEN Consensus and the PG-SGA were in good agreement. It is unclear whether PA and IR can be used as surrogate markers of nutrition status or muscle loss. PMID- 29505144 TI - Computed Tomography-Measured Psoas Density Predicts Outcomes After Enterocutaneous Fistula Repair. AB - BACKGROUND: Low muscle mass and quality are associated with poor surgical outcomes. We evaluated computed tomography (CT)-measured psoas muscle density as a marker of muscle quality and physiologic reserve and hypothesized that it predicts poor outcomes after enterocutaneous fistula repair (ECF). METHODS: We conducted a retrospective cohort study of patients 18-90 years old with ECF who failed nonoperative management, requiring elective operative repair at The Ohio State University (2005-2016), and who received preoperative abdomen/pelvis CT scan with intravenous contrast within 3 months of the operation. Psoas Hounsfield unit average calculations were measured at the L3 level. One-year leak rate, mortality (90 days, 1 years, and 3 years), complication risk, length of stay, dependent discharge, and 30-day readmission were compared with Hounsfield unit average calculation (HUAC). RESULTS: One hundred patients met inclusion criteria. Patients were stratified into interquartile ranges based on HUAC. The lowest HUAC interquartile was our low muscle quality (LMQ) cutoff, which was associated with 1-year leak (relative risk [RR] = 2.10, P < .005), 1-year mortality (RR = 2.22, P < .04) and 3-year mortality (RR = 2.13, P < .007), complication risk (RR = 1.54, P < .001), and dependent discharge (RR = 2.50, P < .004) compared to patients without LMQ. CONCLUSIONS: Psoas muscle density is a significant predictor of poor outcomes in ECF repair. This readily available measure of physiologic reserve can identify patients with ECF who have increased risk and may benefit from additional interventions and recovery time before operative repair. PMID- 29505146 TI - Unique Patterns of Body Composition and Anthropometric Measurements During Maturation in Neonatal Intensive Care Unit Neonates: Opportunities for Modifying Nutritional Therapy and Influencing Clinical Outcomes. AB - BACKGROUND: Body composition is an important predictor of long-term outcomes in neonates and may be altered by several factors. Innovative methods like air displacement plethysmography (ADP) can safely and reliably measure body composition, potentially assisting in individualization of nutrition therapy. OBJECTIVES: 1) To characterize patterns of body composition change in convalescing neonates in the neonatal intensive care unit (NICU) and examine factors leading to variation. 2) To evaluate if the time interval between 2 measurements via ADP can detect significant changes. METHODS: NICU infants underwent anthropometry and body composition measurements by ADP at 37.5+/-0.7 weeks (Time 1) and 41.0+/-0.7 weeks (Time 2) postmenstrual age. Nutrition data were recorded. Data were analyzed using paired t-tests and linear regression models, presented as mean+/-SE, median (IQR), or %. RESULTS: Twenty-two neonates (54% males, 32.2+/-0.9 weeks gestation) were evaluated with a median interval of 3.6 (2.9-4.0) weeks between studies. Mean weight and % body fat increased significantly. There was no significant difference between mean weight and mean % body fat compared with normal references. Abdominal girth increased and mid-arm circumference decreased (p<0.01). Preterm group had higher mean % body fat (10.1) than term infants (6.5), p = 0.03. CONCLUSION: Longitudinal assessment of body composition can effectively assess nutrition status of fragile NICU infants. Although, an interval of 2.9-4.0 weeks between consecutive measurements detected significant changes in body composition, more frequent measurements are needed to determine nutrition factors responsible for body composition changes. PMID- 29505145 TI - High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults: A Pilot Double Blind, Randomized, Placebo-Controlled Trial. AB - BACKGROUND: Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. MATERIALS AND METHODS: Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. RESULTS: At enrollment, >75% of participants in all groups had plasma 25 hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup * time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup * time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. CONCLUSION: In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies. PMID- 29505147 TI - Parenteral Protein Decision Support System Improves Protein Delivery in Preterm Infants: A Randomized Clinical Trial. AB - BACKGROUND: Management of neonatal parenteral protein intake for preterm infants is challenging and requires daily modifications of the dose to account for the infant's postnatal age, birth weight, current weight, and the volume and protein concentration of concurrent enteral nutrition. The objective of this study was to create and evaluate the Parenteral Protein Calculator (PPC), a clinical decision support system to improve the accuracy of protein intake for preterm infants who require parenteral nutrition (PN). MATERIALS AND METHODS: We integrated the PPC into the computerized provider order entry system and tested it in a randomized controlled trial (routine or PPC). Infants were eligible if they were <=3 days old, had a birth weight <=1500 g, and had no inborn error of metabolism. The primary outcome was the appropriate total protein intake, defined as target protein dose +/-0.5 g/kg. RESULTS: We randomly allocated 42 infants for 221 PN days in the control group and 211 in the PPC group. Total protein intake in the PPC group was more accurate as compared with the control group (appropriate protein dosing: odds ratio = 5.8; 95% CI, 2.7-12.4). Absolute deviation from protein target was 0.41 g/kg (0.24-0.58) lower in the PPC group. CONCLUSION: The PPC improved appropriate protein dosing for premature infants receiving PN. Further studies are needed to test whether clinical decision support systems will reduce uremia and improve growth and to replicate similar findings in the cases of other PN nutrients. PMID- 29505148 TI - Response to "Pediatric Intensive Care Nutrition Guidelines 2017: Key Questions Remain Unanswered". PMID- 29505149 TI - Pediatric Intensive Care Nutrition Guidelines 2017: Key Questions Remain Unanswered. PMID- 29505150 TI - Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure: Catheter-Related Complications Over 4 Decades at the Main Danish Tertiary Referral Center. AB - BACKGROUND/AIMS: Catheter-related complications (CRCs) cause mortality and morbidity in patients dependent on parenteral support at home (HPN) due to intestinal failure (IF). This study describes the incidences of CRCs in an adult IF cohort over 40 years. It illustrates the evolution and consequences of CRCs, their association to demographic characteristics, and potential risk factors in an effort to provide the rationale for preventive precautions to the relevant patients with IF at risk. METHODS: All patients with IF discharged with HPN from 1970-2010 were included. Patient and treatment characteristics were extracted from the Copenhagen IF database. The incidences were given per 1000 central venous catheter (CVC) days. RESULTS: The 1715 CRCs occurred in 70% of the 508 patients with IF (56% of the 2191 CVCs). The incidence of catheter-related bloodstream infections (CRBSIs) was 1.43. Higher age, HPN administration by community home nurses, and prior CRBSIs significantly raised the hazard for CRBSIs. In the 1970s, catheters were generally replaced following CRBSIs, whereas catheter salvage was the norm in the 2000s. The incidences of mechanical complications, tunnel infections, and catheter-related venous thromboses were 0.80, 0.25, and 0.11, respectively. The overall CRC incidence was 2.58, decreasing the first 3 decades but peaking in the last (2.84). The deaths related to CRCs were low (0.018). CONCLUSION: Even in an experienced IF center of excellence, the incidence of CRCs increased over the 4 decades. This increase could be explained by the expansion of the indication of HPN to a more elderly and frail patient population. PMID- 29505151 TI - Single-Center Experience with the Use of Teduglutide in Adult Patients with Short Bowel Syndrome. AB - BACKGROUND: Teduglutide is a glucagon-like peptide 2 (GLP-2) analog that has been approved for the treatment of adult short bowel syndrome (SBS)-associated intestinal failure (IF; SBS-IF). Teduglutide increases villus height and crypt depth in the small bowel mucosa, promoting nutrition absorption and enteral independence from parenteral nutrition (PN). We aim to report our single-center experience with teduglutide in adult patients with SBS to provide real-world context to its use. METHOD: We conducted a retrospective analysis on patients managed within our tertiary-level intestinal rehabilitation program to identify patients with SBS-IF treated with teduglutide from 2009-2015. The current report includes all patients at our center who had any exposure to teduglutide, including those who received commercial drug after approval by the Food and Drug Administration (FDA) and outside the scope of clinical trials. RESULTS: A total of 18 patients were treated with teduglutide. Eleven patients (61%) achieved complete enteral independence from PN and/or intravenous fluids (IV) at a median time of 10 months (range: 3-36 months). PN/IV volume requirement was reduced in all patients except two. Ten of the 11 patients (91%) who achieved enteral autonomy had colon. All patients off PN/IV required additional oral vitamins and electrolyte supplementations. CONCLUSION: Our preliminary experience is consistent with prior reports of successful partial or complete weaning from PN/IV with teduglutide treatment in adult patients with SBS. The presence of colon appears to be favorable in obtaining enteral independence from PN/IV, regardless of residual small bowel length. Patients on teduglutide may remain at high risk of micronutrient deficiencies. PMID- 29505152 TI - Early Protein Inadequacy Is Associated With Longer Intensive Care Unit Stay and Fewer Ventilator-Free Days: A Retrospective Analysis of Patients With Prolonged Surgical Intensive Care Unit Stay. AB - BACKGROUND: Failure to provide adequate nutrition in the intensive care unit (ICU) may be particularly harmful for patients with prolonged critical illness. We hypothesized that early nutrition inadequacy is more influential for those requiring a longer ICU stay versus those requiring a shorter stay. METHODS: We enrolled 280 adult patients with prolonged surgical ICU stay who were receiving enteral nutrition for >72 hours. Subjects were divided into 2 groups: shortICU (<14 days) and longICU (>=14 days). Nutrition deficits at ICU days 3 and 7 were calculated. To investigate whether early nutrient deficit was associated with ICU length of stay (LOS), hospital LOS, 28-day ventilator-free days, and discharge disposition (home/rehabilitation vs death/nursing home), we performed linear and logistic regression analyses controlling for age, sex, body mass index, and APACHE II (Acute Physiology and Chronic Health Evaluation). RESULTS: While the shortICU (n = 163) and longICU (n = 117) groups were similar in age, APACHE II, Injury Severity Score, energy/protein prescription, and enteral nutrition initiation within 48 hours, the longICU group was more commonly male (76% vs 61%, P = .007) and had higher body mass index (27.4 vs 25.6, P = .007). Significant interactions occurred: in the longICU group but not the shortICU group, protein deficits were associated with longer ICU stay and fewer 28-day ventilator-free days. CONCLUSIONS: Early protein deficits accumulating at ICU days 3 and 7 are associated with worse clinical outcomes among patients requiring longer ICU stays. Additional studies are required to confirm these findings. PMID- 29505153 TI - Feeding Tube Insertion and Placement Confirmation Using Electromagnetic Guidance: A Team Review. AB - BACKGROUND: Challenges for bedside placement of small-bore feeding tube (SBFT) include iatrogenic injury, multiple exposures to x-rays, and prolonged placement times. In 2011, the study facility began a feeding tube placement team (FTPT) using the CORTRAK system (CS) in the adult intensive care unit (ICU) and medical surgical populations. In 2013, a protocol was implemented using the CS to determine final SBFT location. METHODS: Serial retrospective reviews were done of patients with SBFT placement by the FTPT during July 2011-December 2012 and 2015. Measures included pulmonary deviation, tube location, placement agreement beyond chance for CS tracing and confirmation radiography (CR), x-ray frequency, and placement time intervals. RESULTS: A total of 6290 SBFT placements were completed for 4239 patients. First-attempt SBFT locations were 12.78% gastric, 13.39% first through fourth portion of duodenum, and 73.83% ligament of Treitz/jejunum, with zero placements in esophagus or lung. In 2015, staff avoided 68 lung placements by recognizing proximal pulmonary deviation. X-ray preprotocol vs protocol (mean [SD]: 1.02 [0.15] vs 0.26 [0.44]) resulted in 74% x-ray reduction and cost avoidance of $346,000. Time intervals (mean [SD]; N = 6290) were 14.90 (12.74) minutes for insertion, 46.04 (13.80) minutes for placement event, and 3.85 (2.23) hours for consult conclusion. Agreement for n = 1692 placements was 85.28%, with k score of 0.622 (95% confidence limit: 0.582, 0.661; P = .0005). CONCLUSIONS: Team management of SBFT placement using the CS optimizes patient safety, standardizes practice, and decreases cost. Using the CS to determine final SBFT location is a safe alternative to CR. PMID- 29505154 TI - Characterization of Fatty Acid Profiles in Infants With Intestinal Failure Associated Liver Disease. AB - BACKGROUND: The purpose of this study was to characterize fatty acid profiles (FAPs) in parenteral nutrition (PN)-dependent infants with intestinal failure associated liver disease (IFALD) receiving soybean oil-based lipid emulsion (SO) doses of ~3 and ~1 g/kg/d. METHODS: Prospectively collected data were retrospectively reviewed. Serum FAPs of patients <1 year old who experienced development of IFALD while receiving standard PN with SO were examined before transitioning to a fish oil-based lipid emulsion for IFALD treatment. Time on SO, dose, gestational age, and weight- and length-for-age z scores were also reviewed. RESULTS: Among the 49 patients analyzed, there were no differences in demographics or anthropometrics between patients who received standard SO (SO-S) (n = 14, range of dosage 2.06-3.31 g/kg/d) and reduced SO (SO-R) (n = 35, range of dosage 0.90-1.34 g/kg/d). Patients received SO for a median of 53 days (interquartile range 39, 73) before FAP measurement. Patients who received SO-R had significantly higher Mead acid and lower alpha-linolenic, eicosapentaenoic, linoleic, stearic, total omega-3, and total omega-6 fatty acid levels than patients who received SO-S (P < .01). Triene:tetraene ratios were higher in patients who received SO-R (P = .0009), and no patients experienced biochemical essential fatty acid deficiency (EFAD). CONCLUSION: PN-dependent infants with IFALD receiving SO-R have different FAPs than patients receiving SO-S. No patients in either group had biochemical EFAD. PMID- 29505155 TI - Laboratory Monitoring of Children on Home Parenteral Nutrition: A Prospective Study. AB - BACKGROUND: The primary hypothesis of this article is that a team approach in creating a protocolized laboratory monitoring schedule for home parenteral nutrition (PN) patients improves patient safety by decreasing the occurrence of nutrition deficiencies and is cost-effective. METHODS: In this prospective cohort study of home PN patients, each patient followed an established protocol of laboratory monitoring and weekly review by an interdisciplinary team of dietitians, nurses, and physicians. Data collected included anthropometric measurements, laboratory results, deviations from laboratory protocols, laboratory charges, PN shortage information, and means of ameliorating such shortages. Cost-effectiveness analysis was only performed for nonmicronutrient laboratory tests. RESULTS: Fifteen children (male, n = 6) with a median age of 59 months (range, 19-216) were included in this study. Primary diagnoses included short bowel syndrome (47%) and intestinal pseudo-obstruction (40%). Patients received PN mixtures from 6 different infusion companies and experienced 60 different shortages in the PN formulation requiring adjustments or substitutions (mean, 4 shortages per patient). All patients had appropriate growth and complete micronutrient monitoring. No patient experienced any clinical symptoms due to shortages. The median number of laboratory draws/patient per month was 2.9 preprotocol compared with 1.14 postprotocol (P = .003). The median per patient per month charges were $2014 (interquartile range [IQR], 1471-2780) preprotocol compared with $792 (IQR, 435-1140) postprotocol (P = .002). CONCLUSIONS: A structured team approach to laboratory monitoring of home PN patients can simplify PN management, significantly decrease monthly laboratory costs, and lead to fewer laboratory draws while improving micronutrient monitoring and preventing deficiencies. PMID- 29505157 TI - Severely biased review of studies assessing the risk of venous thrombosis in users of drospirenone-containing oral contraceptives. PMID- 29505156 TI - A Rapid Colorimetric Method to Visualize Protein Interactions. AB - As key molecules in most biological pathways, proteins physically contact one or more biomolecules in a highly specific manner. Several driving forces (i.e., electrostatic and hydrophobic) facilitate such interactions and a variety of methods have been developed to monitor these processes both in vivo and in vitro. In this work, a new method is reported for the detection of protein interactions by visualizing a color change of a cyanine compound, a supramolecule complex of 3,3-di-(3-sulfopropyl)-4,5,4',5'-dibenzo-9-methyl-thiacarbocyanine triethylammonium salt (MTC). Nuclear magnetic resonance (NMR) studies suggest that the hydrophobic nature of the protein surfaces drives MTC into different types of aggregates with distinct colors. When proteins interact with other biomolecules, the hydrophobic surface of the complex differs, resulting in a shift in the form of MTC aggregation, which results in a color change. As a result, this in vitro method has the potential to become a rapid tool for the confirmation of protein-biomolecule interactions, without the requirements for sophisticated instrumentation or approaches. PMID- 29505158 TI - ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes. AB - Mutations in the ATP-binding cassette subfamily A member 3 (ABCA3) gene are the most common monogenetic cause of surfactant dysfunction disorders in newborns and interstitial lung diseases in children and young adults. Although the effect of mutations resulting in truncated or incomplete proteins can be predicted, the consequences of missense variants cannot be as easily. Our aim was to investigate the intracellular handling and disturbance of the cellular surfactant system in a stable cell model with several different clinically relevant ABCA3 missense mutations. We found that the investigated missense mutations within the ABCA3 gene affect surfactant homeostasis in different ways: first by disrupting intracellular ABCA3 protein localization (c.643C > A, p.Q215K; c.2279T > G, p.M760R), second by impairing the lipid transport of ABCA3 protein (c.875A > T, p.E292V; c.4164G > C, p.K1388N), and third by yet undetermined mechanisms predisposing for the development of interstitial lung diseases despite correct localization and normal lipid transport of the variant ABCA3 protein (c.622C > T, p.R208W; c.863G > A, p.R288K; c.2891G > A, p.G964D). In conclusion, we classified cellular consequences of missense ABCA3 sequence variations leading to pulmonary disease of variable severity. The corresponding molecular pathomechanisms of such ABCA3 variants may specifically be addressed by targeted treatments. PMID- 29505159 TI - Physician burnout: contributors, consequences and solutions. AB - Physician burnout, a work-related syndrome involving emotional exhaustion, depersonalization and a sense of reduced personal accomplishment, is prevalent internationally. Rates of burnout symptoms that have been associated with adverse effects on patients, the healthcare workforce, costs and physician health exceed 50% in studies of both physicians-in-training and practicing physicians. This problem represents a public health crisis with negative impacts on individual physicians, patients and healthcare organizations and systems. Drivers of this epidemic are largely rooted within healthcare organizations and systems and include excessive workloads, inefficient work processes, clerical burdens, work home conflicts, lack of input or control for physicians with respect to issues affecting their work lives, organizational support structures and leadership culture. Individual physician-level factors also play a role, with higher rates of burnout commonly reported in female and younger physicians. Effective solutions align with these drivers. For example, organizational efforts such as locally developed practice modifications and increased support for clinical work have demonstrated benefits in reducing burnout. Individually focused solutions such as mindfulness-based stress reduction and small-group programmes to promote community, connectedness and meaning have also been shown to be effective. Regardless of the specific approach taken, the problem of physician burnout is best addressed when viewed as a shared responsibility of both healthcare systems and individual physicians. Although our understanding of physician burnout has advanced considerably in recent years, many gaps in our knowledge remain. Longitudinal studies of burnout's effects and the impact of interventions on both burnout and its effects are needed, as are studies of effective solutions implemented in combination. For medicine to fulfil its mission for patients and for public health, all stakeholders in healthcare delivery must work together to develop and implement effective remedies for physician burnout. PMID- 29505160 TI - Management of Type 1 diabetes should be different from Type 2 diabetes at hospital admission. PMID- 29505161 TI - Flavonol rhamnosylation indirectly modifies the cell wall defects of RHAMNOSE BIOSYNTHESIS1 mutants by altering rhamnose flux. AB - Rhamnose is required in Arabidopsis thaliana for synthesizing pectic polysaccharides and glycosylating flavonols. RHAMNOSE BIOSYNTHESIS1 (RHM1) encodes a UDP-l-rhamnose synthase, and rhm1 mutants exhibit many developmental defects, including short root hairs, hyponastic cotyledons, and left-handed helically twisted petals and roots. It has been proposed that the hyponastic cotyledons observed in rhm1 mutants are a consequence of abnormal flavonol glycosylation, while the root hair defect is flavonol-independent. We have recently shown that the helical twisting of rhm1 petals results from decreased levels of rhamnose-containing cell wall polymers. In this study, we found that flavonols indirectly modify the rhm1 helical petal phenotype by altering rhamnose flux to the cell wall. Given this finding, we further investigated the relationship between flavonols and the cell wall in rhm1 cotyledons. We show that decreased flavonol rhamnosylation is not responsible for the cotyledon phenotype of rhm1 mutants. Instead, blocking flavonol synthesis or rhamnosylation can suppress rhm1 defects by diverting UDP-l-rhamnose to the synthesis of cell wall polysaccharides. Therefore, rhamnose is required in the cell wall for normal expansion of cotyledon epidermal cells. Our findings suggest a broad role for rhamnose-containing cell wall polysaccharides in the morphogenesis of epidermal cells. PMID- 29505162 TI - Influenza-like illness in healthcare personnel at a paediatric referral hospital: Clinical picture and impact of the disease. AB - INTRODUCTION: Healthcare personnel (HP) are frequently exposed to influenza and can be a source of transmission to patients and other workers, resulting in high cost outbreaks for healthcare institutions. OBJECTIVES: To analyse the presentation of HP with influenza-like illness (ILI) and the differences between individuals with influenza confirmed by polymerase chain reaction (PCR) and those with a negative test. The secondary objective was to evaluate the duration of symptomatology and work absenteeism as well as the vaccination rate of HP at a paediatric referral hospital. METHODS: A cross-sectional, descriptive study was conducted at a paediatric referral hospital. Clinical and epidemiological data on HP with ILI were collected between January and April 2016. Nasopharyngeal swab for influenza PCR was obtained from one in every three workers with ILI. Telephone follow-up was conducted to document duration of symptoms, complications and absenteeism. RESULTS: A total of 164 ILI episodes were evaluated in 162 HP. A swab was obtained in 59 cases, and influenza was detected in 30 cases. The clinical picture of HP with confirmed influenza was similar to that of HP with a negative PCR. Arthralgia was more common in those with influenza (90% vs 58%), with a tendency towards statistical significance. No HP required hospitalization, and 78.5% were absent from work at least 1 day. CONCLUSIONS: Influenza causes significant morbidity and absenteeism among HP. Influenza infection was confirmed in only half of HP with an ILI on whom a PCR was performed, suggesting that other respiratory viruses can cause a similar pattern. PMID- 29505163 TI - Generation of novel neuroinvasive prions following intravenous challenge. AB - Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection. PMID- 29505164 TI - Enoxaparin does not affect network formation of adipose tissue-derived microvascular fragments. AB - Dermal substitutes are frequently used for the initial coverage of extensive skin defects. The seeding of these implants with adipose tissue-derived microvascular fragments (ad-MVF) has recently been shown to accelerate their vascularization and incorporation. In the present study we analyzed whether these processes are affected by a thromboprophylactic therapy with the low molecular weight heparin (LMWH) enoxaparin (enox). Green fluorescent protein (GFP)+ ad-MVF were isolated from enox- (8 mg/kg s.c.) and vehicle-treated (0.9% NaCl s.c.) (C57BL/6-Tg(CAG EGFP)1Osb/J mice and seeded onto Integra matrices. Subsequently, these were implanted into full-thickness skin defects within dorsal skinfold chambers of enox- and vehicle-treated C57BL/6 wild-type mice. Repetitive stereomicroscopy and intravital fluorescence microscopy over 2 weeks as well as histological and immunohistochemical analyses on day 14 revealed that enox does not inhibit the reassembly of ad-MVF into new microvascular networks. In addition, treatment with the anticoagulative compound did not promote implant-induced hemorrhage formation. Accordingly, Integra matrices in enox- and vehicle-treated animals exhibited a comparable final microvessel density, fraction of GFP+ blood vessels originating from seeded ad-MVF, collagen fiber content, and epithelialization. These novel findings demonstrate that the seeding of dermal substitutes with ad MVF may be applied also during thromboprophylactic therapy without affecting implant vascularization and bleeding risk. PMID- 29505165 TI - Synthesis and Characterization of the Perthiatriarylmethyl Radical and Its Dendritic Derivatives with High Sensitivity and Selectivity to Superoxide Radical. AB - EPR spectroscopy, coupled with the use of tetrathiatriarylmethyl (TAM) radicals, has been a reliable method to detect the superoxide radical (O2.- ). However, the specificity and biocompatibility of TAM radicals need to be further improved. Although derivatization may overcome the drawbacks of current TAM radicals, esterification or amidation through the carboxylic groups greatly changes their redox properties and makes them inert to O2.- . Herein, the synthesis of a perthiatriarylmethyl (PST) radical and its dendritic derivatives, PST-TA and PST NA, in which PST is covalently linked with dendrons containing three (TA) and nine (NA) carboxylic acids, respectively. The results show that PST rapidly reacts with O2.- to yield a unique quinone methide product. Dendritic modification of PST slightly decreases the reactivities of PST-TA and PST-NA, but notably increases their biostability toward various oxidoreductants. The detection limit of PST-NA to O2.- was estimated to be 2.1 nm min-1 over 60 min of detection. Importantly, PST-NA shows threefold higher sensitivity to O2.- in the presence and absence of ascorbic acid than that of the classic spin-trapping technique. In addition, the application of PST-NA to detect extracellular O2.- generation in stimulated RAW 264.7 macrophages was also explored. This study demonstrates that PST-NA has great potential for specific detection and quantitation of O2.- in extracellular sites. PMID- 29505166 TI - Improved detection sensitivity of elements in solids via laser postionization in laser desorption time-of-flight mass spectrometry. AB - A newly constructed laser desorption (532 nm, 5 ns) and laser postionization (266 nm, 5 ns) time-of-flight mass spectrometer (LD-LPI-TOFMS) has been applied for improving the detection sensitivity of elements in solid samples. This method affords to acquire the information of the elemental impurities in solid standards as well as limit of detection (LOD) down to 10-8 g/g for some elements. Neutral atoms of solids are generated by low-irradiance laser desorption (< 108 W/cm2 ), followed by high-irradiance laser postionization (~ 109 W/cm2 ) of the desorbed atoms, facilitating to decouple the desorption and ionization processes in spatial and temporal domain. This non-interacting feature overcomes the discrimination between deteriorating spectral resolution at high irradiance (109 1011 W/cm2 ) and limited detectable elemental species and high LOD at low or medium irradiance (below 109 W/cm2 ). The utilization of originally "wasted" neutral atoms by laser postionization will help improve atom utilization and instrumental sensitivity. In this work, getting the utmost out of the consumed neutral atoms instead of an increment in sampling amounts is given attention with high priority for achieving high sensitivity and low LOD, which is especially useful on the occasions where very low sample consumption is desired. PMID- 29505167 TI - Hierarchical Co-Assembly Enhanced Direct Ink Writing. AB - Integrating intelligent molecular systems into 3D printing materials and transforming their molecular functions to the macroscale with controlled superstructures will unleash great potential for the development of smart materials. Compared to macromolecular 3D printing materials, self-assembled small molecule-based 3D printing materials are very rare owing to the difficulties of facilitating 3D printability as well as preserving their molecular functions macroscopically. Herein, we report a general approach for the integration of functional small molecules into 3D printing materials for direct ink writing through the introduction of a supramolecular template. A variety of inorganic and organic small-molecule-based inks were 3D-printed, and their superstructures were refined by post-printing hierarchical co-assembly. Through spatial and temporal control of individual molecular events from the nano- to the macroscale, fine tuned macroscale features were successfully installed in the monoliths. PMID- 29505168 TI - Evaluating oseltamivir prescriptions in Centers for Medicare and Medicaid Services medical claims records as an indicator of seasonal influenza in the United States. AB - BACKGROUND: Over 34 million residents of the United States aged 65 years and older are also Medicare prescription drug beneficiaries. Medical claims records for this age group potentially provide a wealth of data for better understanding influenza epidemiology. OBJECTIVE: The purpose of this study was to evaluate data on oseltamivir dispensing extracted from medical claims records as an indicator of influenza activity in the United States for the 2010-11 through 2014-15 influenza seasons. METHODS: We used Centers for Medicare and Medicaid Services (CMS) medical claims data to evaluate the weekly number of therapeutic oseltamivir prescriptions dispensed following a rapid influenza diagnostic test among beneficiaries 65 years old and older as an indicator of influenza timing and intensity. We compared the temporal changes in this indicator to changes in the proportion of influenza-like illnesses among outpatient visits in the US Outpatient Influenza-like Illness Surveillance Network (ILINet) by administrative regions defined by the US Department of Health and Human Services. Using the moving epidemic method, we determined intensity thresholds and categorized the severity of seasons for both CMS and ILINet data. RESULTS: Centers for Medicare and Medicaid Services oseltamivir data and ILINet data were strongly correlated by administrative region (median Spearman's rho = 0.78; interquartile range = 0.73-0.80). CMS oseltamivir data and ILINet data substantially agreed (Cohen's weighted kappa = 0.62) as to the seasonal severity across administrative regions. CONCLUSIONS: Our results support the use of oseltamivir dispensing in medical claims data as an indicator of US influenza activity. PMID- 29505169 TI - Effects of let-7e on LPS-Stimulated THP-1 Cells Assessed by iTRAQ Proteomic Analysis. AB - PURPOSE: Previous studies have demonstrated that let-7e is associated with inflammatory responses. To date, the roles and mechanisms of let-7e have not been completely revealed.Therefore, we aim to identify proteins associated with let-7e overexpression and explore their functions in the immune responses, including in cytokine production. EXPERIMENTAL DESIGN: High-throughput isobaric tag for relative and absolute quantitation (iTRAQ) technology is used to provide the first genome-wide study of THP-1 cells transfected with let-7e mimic followed by lipopolysaccharide (LPS) stimulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and KEGG pathway enrichment analyses are used to analyze a large number of differentially expressed proteins (DEPs) associated with let-7e overexpression or LPS stimulation. Quantitative reverse transcription PCR (qRT PCR) and 50% tissue culture infective dose (TCID50) assays are processed to confirm the relationship of let-7e and dengue virus replication. RESULTS: iTRAQ results show that let-7e is associated with the expression of anti-viral proteins. What's more, calcineurin subunit B type 1, an anti-tumor factor, is upregulated by let-7e after LPS stimulation. KEGG analyses identify that some DEPS associated with let-7e overexpression are involved in the measles and influenza A pathways, and LPS-stimulated proteins in THP-1 cells are mainly enriched in transcriptional misregulation in cancer pathway and hippo signaling pathway (multiple species). The results of qRT-PCRand TCID50 show that let-7e promotes dengue virus replication, which is in agreement with the iTRAQ results. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide molecular insights into the regulatory mechanisms of let-7e in cytokine expression, virus replication, and anti-tumor function. PMID- 29505170 TI - Drought consistently alters the composition of soil fungal and bacterial communities in grasslands from two continents. AB - The effects of short-term drought on soil microbial communities remain largely unexplored, particularly at large scales and under field conditions. We used seven experimental sites from two continents (North America and Australia) to evaluate the impacts of imposed extreme drought on the abundance, community composition, richness, and function of soil bacterial and fungal communities. The sites encompassed different grassland ecosystems spanning a wide range of climatic and soil properties. Drought significantly altered the community composition of soil bacteria and, to a lesser extent, fungi in grasslands from two continents. The magnitude of the fungal community change was directly proportional to the precipitation gradient. This greater fungal sensitivity to drought at more mesic sites contrasts with the generally observed pattern of greater drought sensitivity of plant communities in more arid grasslands, suggesting that plant and microbial communities may respond differently along precipitation gradients. Actinobateria, and Chloroflexi, bacterial phyla typically dominant in dry environments, increased their relative abundance in response to drought, whereas Glomeromycetes, a fungal class regarded as widely symbiotic, decreased in relative abundance. The response of Chlamydiae and Tenericutes, two phyla of mostly pathogenic species, decreased and increased along the precipitation gradient, respectively. Soil enzyme activity consistently increased under drought, a response that was attributed to drought-induced changes in microbial community structure rather than to changes in abundance and diversity. Our results provide evidence that drought has a widespread effect on the assembly of microbial communities, one of the major drivers of soil function in terrestrial ecosystems. Such responses may have important implications for the provision of key ecosystem services, including nutrient cycling, and may result in the weakening of plant-microbial interactions and a greater incidence of certain soil-borne diseases. PMID- 29505171 TI - Chemical modifications of Tonda Gentile Trilobata hazelnut and derived processing products under different infrared and hot-air roasting conditions: a combined analytical study. AB - BACKGROUND: For the processing industry, it is crucial to know what effect the roasting process and conditions have on hazelnut quality. The present study investigates, for the first time, the effects of hot-air and infrared (IR) roasting at different time-temperature combinations on Tonda Gentile Trilobata hazelnut: whole kernels and derived processing products (paste and oil). RESULTS: The nutritional and physical characteristics of hazelnuts and processing products were investigated to determine the influence of the different roasting conditions as a function of intended use. The antioxidant profile (2.2-diphenyl-1 picrylhydrazyl radical, oxygen radical absorbance capacity and total phenolic content) were analyzed on roasted hazelnut and paste extracts. For a comprehensive understanding of the complex biochemical phenomena occurring during roasting, E-nose and near-IR spectroscopy were also applied. All analytical data were processed using univariate and multivariate data analyses. Hazelnuts derived from IR roasting at higher temperatures (195 degrees C) showed a richer antioxidant profile and a more intense flavour. On the other hand, the yield associated with the oil extraction under the same conditions was unsatisfactory, making this process completely inadequate for oil production. Oil obtained by hot air roasting and IR roasting at lower temperature (135 degrees C) was found to be of good quality, showing rather similar acidity grade, peroxide number and acidic composition. In particular, a slightly but significantly lower acidity was related to lower roasting temperatures (0.21-0.22% versus 0.27% for higher temperatures). All roasting conditions tested allowed the quantitative homogeneous hazelnut paste to be obtained and, from a rheological point of view, a higher roasting temperatures resulted in pastes characterized by higher density and viscosity values. CONCLUSION: The use of IR was found to be a promising alternative method for hazelnut roasting, as a result of its capability with respect to preserving nutritional values and enhancing organoleptic quality. (c) 2018 Society of Chemical Industry. PMID- 29505172 TI - Repeat patient testing shows promise as a quality control method for veterinary hematology testing. AB - BACKGROUND: Repeat patient testing-based quality control (RPT-QC) is a potential method for veterinary laboratories (eg, that have a limited budget for quality commercial control material [QCM] or that wish to use material with a species specific matrix). OBJECTIVES: To determine whether total error (TEa ), probability of error detection (Ped), and probability of false rejection (Pfr) similar to that achievable with QC materials can be controlled using RPT-QC METHODS: Control limits (WBC, RBC, HGB, HCT, MCV, and PLT) for the Advia 120 (n = 23) and scil Vet ABC (n = 22) were calculated using data from normal canine specimens from a routine caseload. Specimens were measured at accession and again after 24 hours. Control limits were validated using 23 additional canine specimens tested similarly. Achievable TEa, Ped, and Pfr were investigated using the Westgard EZRules3 and compared to those achievable with commercial QCM. RESULTS: Theoretical performance of RPT-QC and commercial QCM-QC are similar for 1-3s with both n = 1 and 1-3s with n = 2 for all measurands and both instruments. Achievable TEa values for RPT-QC were close to ASVCP recommendations for most measurands; exceptions were PLT (both instruments) and WBC (scil Vet ABC). CONCLUSIONS: Repeat patient testing-based quality control advantages include a species-specific matrix, low-cost, and absence of QC material deterioration over time (since a fresh specimen is used each day). A potential disadvantage is daily access to normal canine specimens. A challenge is determining control limits, which has a subjective element. Further study is needed to confirm actual RPT-QC performance and to determine if RPT-QC with abnormal patient specimens is feasible. PMID- 29505173 TI - The effectiveness of various irrigation protocols on organic tissue removal from simulated internal resorption defects. AB - AIM: To evaluate the effectiveness of NaOCl, NaOCl-EDTA and NaOCl + HEBP activated by ultrasonics and XP-endo Finisher on organic tissue removal from simulated internal root resorption cavities. METHODOLOGY: The root canals of 144 single-rooted teeth were instrumented. The teeth were split longitudinally, and semicircular cavities were prepared in the canal walls on each half of the roots. Samples obtained from ground bovine muscle tissue were weighed and adapted into the semicircular cavities. The root fragments were reassembled and cemented to create a circular simulated resorption cavity within the canal. Teeth were divided into twelve groups (n = 12) according to the irrigation protocols: group 1: NaOCl, no activation; group 2: NaOCl, passive ultrasonic irrigation (PUI); group 3: NaOCl, XP-endo Finisher; group 4: NaOCl-EDTA, no activation; group 5: NaOCl-EDTA, PUI; group 6: NaOCl-EDTA, XP-endo Finisher; group 7: NaOCl + HEBP, no activation; group 8: NaOCl + HEBP, PUI; group 9: NaOCl + HEBP, XP-endo Finisher; group 10: distilled water, no activation; group 11: distilled water, PUI; and group 12: distilled water, XP-endo Finisher. The teeth were disassembled, and the tissue remaining inside the resorption cavities were weighed. The data were analysed statistically using two-way anova and Fisher's LSD tests with a significance level of 0.05. RESULTS: The use of XP-endo Finisher with the experimental solutions resulted in the greatest tissue weight loss compared to the other activation protocols (P < 0.001). There was no significant difference between NaOCl and NaOCl + HEBP in terms of tissue removal. CONCLUSION: The use of a NaOCl + HEBP mixture activated with XP-endo Finisher was an effective irrigation regimen for removing simulated organic tissues from artificial internal root resorption cavities in the straight root canals of single-rooted teeth. PMID- 29505174 TI - Activation of an Aquareovirus, Chum Salmon Reovirus (CSV), by the Ciliates Tetrahymena thermophila and T. canadensis. AB - For the first time, ciliates have been found to activate rather than inactivate a virus, chum salmon reovirus (CSV). Activation was seen as an increase in viral titre upon incubation of CSV at 22 degrees C with Tetrahymena canadenesis and two strains of T. thermophila: wild type (B1975) and a temperature conditional mutant for phagocytosis (NP1). The titre increase was not likely due to replication because CSV had no visible effects on the ciliates and no vertebrate virus has ever been shown unequivocally to replicate in ciliates. When incubated with B1975 and NP1 at 30 degrees C, CSV was activated only by B1975. Therefore, activation required CSV internalization because at 30 degrees C only B1975 exhibited phagocytosis. CSV replicated in fish cells at 18 to 26 degrees C but not at 30 degrees C. Collectively, these observations point to CSV activation being distinct from replication. Activation is attributed to the CSV capsid being modified in the ciliate phagosomal-lysosomal system and released in a more infectious form. When allowed to swim in CSV-infected fish cell cultures, collected, washed, and transferred to uninfected cultures, T. canadensis caused a CSV infection. Overall the results suggest that ciliates could have roles in the environmental dissemination of some fish viral diseases. PMID- 29505176 TI - Animal behaviour and algal camouflage jointly structure predation and selection. AB - Trait variation can structure interactions between individuals, thus shaping selection. Although antipredator strategies are an important component of many aquatic systems, how multiple antipredator traits interact to influence consumption and selection remains contentious. Here, I use a common larval dragonfly (Epitheca canis) and its predator (Anax junius) to test for the joint effects of activity rate and algal camouflage on predation and survival selection. I found that active and poorly camouflaged Epitheca were more likely to be consumed, and thus, survival selection favoured inactive and well camouflaged individuals. Notably, camouflage dampened selection on activity rate, likely by reducing attack rates when Epitheca encountered a predator. Correlational selection is therefore conferred by the ecological interaction of traits, rather than by opposing selection acting on linked traits. I suggest that antipredator traits with different adaptive functions can jointly structure patterns of consumption and selection. PMID- 29505175 TI - A single liquid chromatography-quadrupole time-of-flight mass spectrometric method for the quantification of total antibody, antibody-conjugated drug and free payload of antibody-drug conjugates. AB - A single hybrid affinity-captured-LC-TOF-MS/MS method was developed and applied for the quantification of total antibody, antibody conjugated drug and free payload of antibody drug conjugate (ADC). Adcetris(r), a valine-citrulline monomethyl auristatin E conjugated ADC, was used as a model ADC compound. A quadratic regression (weighted 1/concentration) was used to fit calibration curves over the concentration range 30.65-613.00 ng/mL with an equation y = ax2 + bx + c for the antibody-conjugated drug of Adcetris(r). The qualification run met the acceptance criteria of +/-25% accuracy and precision values for quality control samples. For the analysis of total antibody, a signature peptide (TTPPVLDSDGSFFLYSK, molecular weight 1874) was used after affinity capture using magnetic beads and on-bead trypsin digestion. A quadratic regression (weighted 1/concentration) was used to fit calibration curves over the concentration range 5.00-100.00 MUg/mL with an equation y = ax2 + bx + c for total antibody. For free payload analysis of monomethyl auristatin E, a protein precipitation method followed by LC-TOF-MS/MS analysis was used. A quadratic regression (weighted 1/concentration) was used to fit calibration curves over the concentration range 1.01-2200 ng/mL with an equation y = ax2 + bx + c for free payload. Pharmacokinetic study samples and in vitro stability samples in rat were successfully analyzed by this a hybrid affinity-captured-LC-TOF-MS/MS method. This single platform method is a useful complementary method for the pharmacokinetics study of ADC with valine-citrulline linker at the early drug discovery stage. PMID- 29505177 TI - Patient Preferences for Diagnostic Testing in the Emergency Department: A Cross sectional Study. AB - BACKGROUND: Diagnostic testing is common during emergency department (ED) visits. Little is understood about patient preferences for such testing. We hypothesized that a patient's willingness to undergo diagnostic testing is influenced by the potential benefit, risk, and personal cost. METHODS: We conducted a cross sectional survey among ED patients for diagnostic testing in two hypothetical scenarios: chest pain (CP) and mild traumatic brain injury (mTBI). Each scenario defined specific risks, benefits, and costs of testing. The odds of a participant desiring diagnostic testing were calculated using a series of nested multivariable logistic regression models. RESULTS: Participants opted for diagnostic testing 68.2% of the time, including 69.7% of CP and 66.7% of all mTBI scenarios. In the CP scenario, 81% of participants desired free testing versus 59% when it was associated with a $100 copay (difference = 22%, 95% confidence interval [CI] = 16% to 28%). Similarly, in the mTBI scenario, 73% of adult participants desired free testing versus 56% when charged a $100 copayment (difference = 17%, 95% CI = 11% to 24%). Benefit and risk had mixed effects across the scenarios. In fully adjusted models, the association between cost and desire for testing persisted in the CP (odds ratio [OR] = 0.33, 95% CI = 0.23 to 0.47) and adult mTBI (OR = 0.47, 95% CI = 0.33 to 0.67) scenarios. CONCLUSIONS: In this ED-based study, patient preferences for diagnostic testing differed significantly across levels of risk, benefit, and cost of diagnostic testing. Cost was the strongest and most consistent factor associated with decreased desire for testing. PMID- 29505178 TI - A Note From the ASCP President. PMID- 29505179 TI - Adverse Gestational Outcomes Associated With Attention-Deficit/Hyperactivity Disorder Medication Exposure During Pregnancy. AB - The use of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy has increased in recent years. An earlier article in this column examined whether psychostimulant medications, used to treated ADHD and related disorders, increase the risk of major congenital malformations in pregnancies with first trimester exposure to these drugs. This article examines whether amphetamines, methylphenidate, and atomoxetine exposure during early and late pregnancy are associated with other adverse gestational outcomes. One large and 4 small studies provided data relevant to the inquiry. In unadjusted analyses, amphetamines and methylphenidate were associated with an increased risk of most of the adverse outcomes under study. However, in analyses adjusted for potential confounds, amphetamine exposure during early pregnancy was associated only with an increased risk of preeclampsia; otherwise, amphetamine and methylphenidate exposure was not associated with the risk of preeclampsia, placental abruption, small for gestational age, or preterm birth. Late gestational exposure to psychostimulants was associated with an increased risk of preterm birth but not with the other adverse outcomes. In sensitivity analyses, such as one that examined exposure during weeks 8-18 of gestation, amphetamines were associated with an increased risk of preeclampsia, placental abruption, and preterm birth, and methylphenidate, with an increased risk of preeclampsia. For reasons explained in the text, it may be prudent to err on the side of caution, but in the worst case scenario, the number needed to harm is about 63 for amphetamines exposure and preeclampsia and larger (eg, > 500, indicating less risk) for other adverse outcomes. Atomoxetine was not associated with any adverse gestational outcome, but it is not clear whether this is a true finding or a result of underpowered analyses. In conclusion, women need to weigh the benefits of the ADHD medication that they are using against potential gestational risks when deciding whether or not to continue treatment during pregnancy. PMID- 29505180 TI - Correction. Treating Prolonged Grief Disorder: A 2-Year Follow-Up of a Randomized Controlled Trial PMID- 29505181 TI - Consensus Recommendations for rTMS in Depression: Not Entirely Correct! PMID- 29505183 TI - Roles and Qualifications of TMS Treatment Team Members. PMID- 29505182 TI - Dr McClintock and Colleagues Reply. PMID- 29505184 TI - Dr McClintock and Colleagues Reply. PMID- 29505185 TI - Lessons From the Latest US Military Suicide Surveillance Data. PMID- 29505186 TI - Effects of Rapastinel (Formerly GLYX-13) on Serum Brain-Derived Neurotrophic Factor in Obsessive-Compulsive Disorder. PMID- 29505187 TI - Discussing the Risk of Tardive Dyskinesia With Patients and Screening for Signs. AB - Your patients taking antipsychotics may be at risk for developing tardive dyskinesia. In this Case and Comment activity, follow Martha, a 60-year-old woman being treated with an antipsychotic medication for her treatment-resistant depression. PMID- 29505188 TI - Assessing and Treating Insomnia in Patients With Psychiatric Disorders, Part 1. AB - Listen to this podcast as experts discuss 2 patient cases focusing on diagnosing and treating co-occurring insomnia and mental illness. The first case features a 32-year-old man with bipolar disorder who is experiencing psychiatric symptoms and poor sleep, and the second case involves a 27-year-old man with schizophrenia who is having auditory hallucinations as well as chronic issues with insomnia. PMID- 29505189 TI - Assessing and Treating Insomnia in Patients With Psychiatric Disorders, Part 2. AB - Tune in to this podcast as experts discuss 2 patient cases-one involving co occurring insomnia and depression and another comprising PTSD, substance abuse, insomnia, and nightmares. Drs Benca and Buysse explain how to effectively diagnose and manage these complex cases based on the latest diagnostic criteria and evidence from clinical trials. PMID- 29505190 TI - Evidence-Based Strategies for Managing Tardive Dyskinesia. AB - Do you know how to manage tardive dyskinesia symptoms? In this Case and Comment activity, consider the case of John, a 25-year-old project manager diagnosed with bipolar disorder who has begun exhibiting symptoms of uncontrollable movement. PMID- 29505191 TI - What You Should Know About Tardive Dyskinesia: Screening, Causes, and New Treatment Options. AB - Do you know which of your patients are at risk for developing tardive dyskinesia? Watch this Webcast to learn about how to prevent tardive dyskinesia in your patients and new treatment strategies for your patients who have already been diagnosed. PMID- 29505192 TI - Improving Remission Rates in Major Depressive Disorder: A Case-Based Approach. AB - How many of your patients achieve remission from depression with their first treatment? In this CME Health Spectrum activity, enter a virtual office to follow 2 patient cases about inadequate response to treatment. Learn as an expert describes strategies based on recent evidence-based guidelines. PMID- 29505193 TI - Long-Acting Injectable Antipsychotics: Where Do They Fit in the Treatment Plan? AB - Long-acting injectable (LAI) antipsychotics have the potential to improve adherence and outcomes for patients with serious mental illness but are underused. Watch this Webcast to learn how to identify patients who may benefit from using LAIs, monitor treatment adherence, and use LAIs safely and effectively in patients with schizophrenia and related disorders. PMID- 29505194 TI - Cognitive Impairment in Major Depressive Disorder: A Case Discussion Illustrating Impact, Assessment, and Management. AB - How can you help your patients who are experiencing both depression and cognitive dysfunction? Tune in to this CME podcast to hear experts in psychiatry discuss 2 patient cases that illustrate the burden of cognitive impairment in major depressive disorder as well as effective assessment tools and management strategies. PMID- 29505195 TI - Child Benefits, Maternal Employment, and Children's Health: Evidence from Canadian Child Benefit Expansions. AB - Industrial countries typically provide income transfers to families with young children. Traditionally, these family benefit programs were motivated by distributional concerns--families with children faced higher expenditure needs than other families, and a concern for horizontal equity led to transfers. Throughout the 1990s, however, many countries introduced benefits aimed at improving labor market incentives for mothers with young children. In the United States, the Earned Income Tax Credit (EITC) has played this role, but similar programs exist in Europe, Canada, and elsewhere. Much effort has been expended on evaluating the labor market impact of child benefits. However, less work has examined the impact of these programs on broader outcomes such as the mental and physical health of both the children and the parents, outcomes that follow from the traditional equity motivation for child benefits. In this paper, we review and extend some recent results studying the expansion of family benefits in Canada. In particular, we exploit a change that occurred in the province of Manitoba to highlight the effects of child benefits on both labor supply and family outcomes. PMID- 29505196 TI - One on One with Guillermo Chacon. AB - Since its founding in 1990, the Latino Commission on AIDS has become the largest organization in the U.S. advocating for the health needs of the Latino community in response to the HIV/AIDS epidemic. Also known as Latino AIDS, the commission works with community organizations in developing HIV education, prevention programs, and capacity building. The commission, which began in New York City, now serves Latino communities in more than 40 states and Puerto Rico. Guillermo Chacon has been president of Latino AIDS since 2009. PMID- 29505197 TI - A New Era in the Face of Old Barriers. AB - Longtime national HIV treatment advocate Moises Agosto, a native of Puerto Rico, says the challenges facing Latinos in the epidemic haven't changed much over the decades. Problems with housing, jobs, and education, along with other social determinants of health, continue to hurt prevention and treatment: Immigration status. Language barriers. Access to physical and mental health care. Access to food. PMID- 29505198 TI - Average Earnings and Long-Term Mortality: Evidence from Administrative Data. AB - In this paper we exploit a unique database that merges longitudinal earnings data on Pennsylvanian workers with national death records to study the detailed nature of the correlation between earnings and mortality. We findthat the estimates typically reported in the literature, which are based on single years of earnings data, are likely to understate substantially the strength of the association between income and mortality. In particular, relative to a singleyear of earnings, the average of earnings over a six-year period predicts a 70 percent greater impact of income on mortality. In addition, controlling for the mean level of earnings over a period, we find that greater earnings volatility isassociated with higher mortality. We also examine the lag structure of the relationship between earnings and mortality. We find that conditional on a small number of years of recent earning levels, there is little or no correlation between earnings levels in earlier years and current mortality. This runs counter to the interpretation of the earnings-mortality correlation that views workers as "buying health" by allocating a steady fraction of their earnings to the accumulation of a health stock. It is also inconsistent with interpretations of the earnings- mortality link emphasizing the correlationof both variables with an unobserved, time-invariant trait, such as the rate at which workers discount the future. We find that explaining the patterns of correlation appears to require a relatively complex theory that we leave to future research. PMID- 29505199 TI - Prep for Latinx Communities. AB - During a holiday break in 2013, I told my mother about my decision to start taking Truvada as PrEP (pre-exposure prophylaxis). I sat on her couch and also explained that I was going to share my PrEP-taking journey on Facebook to educate more people like myself. I waited for an argument to erupt. Discussion about sexual health and freedom were usually met with negative feelings in our household. PMID- 29505200 TI - Live with HIV in Cuba: From quarantine camps to medical accomplishments. PMID- 29505201 TI - Unanticipated consequences of AIDS survival. PMID- 29505202 TI - In the eye of the storm. PMID- 29505203 TI - A Second Case of Infection PMID- 29505204 TI - Back to the Future. PMID- 29505205 TI - Strategies for Promoting Healthier Food Choices. PMID- 29505206 TI - Why co-infection may no longer be 'special'. PMID- 29505207 TI - Hepatitis C Awareness for Gay Man. PMID- 29505208 TI - Aging, and Thriving, with HIV. PMID- 29505209 TI - The Power of Being Positive with an HIV-Negative Status. PMID- 29505210 TI - Facing Stigma. PMID- 29505211 TI - Mindless Eating and Healthy Heuristics for the Irrational. AB - Food choice decisions are not the same as intake volume decisions. The former determine what we eat (soup or salad); the latter determine how much we eat (half of the bowl or all of it). Large amounts of money, time, and intelligencehave been invested in understanding the physiological mechanisms that influence food choice (James O. Hill, forthcoming). Much less has been invested in understanding how and why our environment influences food consumption volume. Yet environmental factors (such as package size, plate shape, lighting, variety, or the presence of others) affect our food consumption volume far more than we realize (Wansink 2006). Whereas people can acknowledge that environmental factors influence others, they wrongly believe they are unaffected. Perhaps they are influenced at a basic level of which they are not aware. A better understanding of these drivers of consumption volume will have immediateimplications for research, policy, and personal interventions. There are three objectives of this paper: (1) explain why environmental factors may unknowingly influence food consumption; (2) identify resulting myths that may lead to is specified models or misguided policy recommendations; and (3) offer clear direction for future research, policy, and personal dietary efforts. PMID- 29505212 TI - Voluntary Compliance, Pollution Levels, and Infant Mortality in Mexico. AB - The increasing body of evidence from high income countries linking pollution to health outcomes (Ken Chay and Michael Greenstone 2003; Janet Currie and Matthew Neidell 2004), has raised concerns about the health impact of adverse air quality in developing countries, where, in general, environmental regulation is less stringent and health monitoring and treatment are less accessible. These concerns have, in turn, encouraged consideration of the effectiveness of alternative mechanisms for improving air quality while limiting the adverse impact on economic growth. However, the analysis ofboth the effects of pollution on health and the effectiveness of pollution abatement policies faces particular empirical challenges in low- and middle-income contexts, given the scarcity of reliable measures of pollution concentrations.The primary source of good quality data on air quality, ground monitoring, tends to be limited to larger metropolitan areas with monitors placed at sentinel sites that may or may not yield a representative picture of population exposure.This paper calls attention to, and makes use of, newly available procedures for extracting measures of air quality from satellite imagery. In particular, satellite-based measures of aerosol optical depth (AOD) are used to obtain estimates of air quality for the whole Mexican territory at a detailed geographic scale, and these estimates are related to measures of participation in a voluntary certification program at the level of the county. The resulting estimates are then combined with estimates of the relationship between participation in the certification program and infant mortality due to respiratory causes to obtain a rough estimate of the relationship between air quality and infant health in Mexico. PMID- 29505213 TI - Climate Change and Birth Weight. PMID- 29505217 TI - What Matters (and What Does Not) in Households' Decision to Invest in Malaria Prevention? PMID- 29505218 TI - Commitment Mechanisms and Compliance with Health-Protecting Behavior: Preliminary Evidence from Orissa, India. PMID- 29505220 TI - Weathering storms, learning lessons. AB - In an article based on a presentation at last month's Institute of Hospital Engineering Australia (IHEA) Management Conference in Brisbane, Kim Bruton, chief engineer, MIHEA, NZIHE, CHCFM, of Northeast Health Wangaratta (NHW) in Victoria, describes some of the interesting experiences, challenges, and wider lessons learned, during his first five years as facility manager at the major referral health service for the north-east Victoria region. This serves some 28 townships beyond the boundaries of the Rural City of Wangaratta, and has a catchment population of approximately 90,000 people. PMID- 29505219 TI - Urbanization, Mortality, and Fertility in Malthusian England. PMID- 29505221 TI - Townsville project's key lesson outlined. AB - In an article that first appeared in The Australian Hospital Engineer, Michael Ward, facilities engineer, Building, Engineering & Maintenance Services (BEMS), Townsville Hospital and Health Service, Queensland Health, Mark Fasiolo, hospital engineer within the same organization and service (both work at Townsville Hospital), and Jeffrey Turner, now client services manager, BEMS, at Metro South Hospital and Health Service, Queensland Health (but formerly hospital engineer at Townsville Hospital), describe a complex redevelopment project at Townsville Hospital in Queensland. A key element of the project, which is still ongoing, was the significant reconfiguration of the site's power supply and building engineering services. PMID- 29505222 TI - Hospital steam: a tiger facing extinction? AB - Despite advances in technology, the importance of steam in NHS hospitals cannot be undervalued. Nevertheless, according to steam system specialist, Gary Sowerby CEng FDI, 'it is becoming a feature which, like the tiger, is facing extinction'. However, as he puts it, 'it is still of vital importance when we discuss the central role of steam in the hospital steriliser'. In this article, he aims to provide what he dubs 'a vital understanding of the provision of efficient and good quality steam to the sterilizer plant'. PMID- 29505223 TI - L8--consider the ventilation aspects. AB - The HSE's ACOP (Approved Code of Practice) L8 and supporting HSG274 Parts 1-3 Guidance set the minimum standards by which everyone should work to manage the risks from waterborne microbiological pathogens. The NHS also has further supporting guidance on the subject in the form of HTM core standards 00, 04-01 (three parts), and HTM 03-01 (two parts). However, argues Andrew Poplett IEng, MIHEEM, ACIBSE, an experienced engineer with over 28 years' healthcare building services engineering experience--18 in the NHS--'even with all of this available guidance, some elements of healthcare building services engineering are all too often overlooked'. Here, 'to stimulate discussion and raise awareness of the issues', he sets out some of the key points to consider. PMID- 29505224 TI - Water and fire safety issues addressed. AB - One of the four conference streams at last month's Healthcare Estates 2014 event focused on some of the key engineering challenges and opportunities facing healthcare estates managers and healthcare engineers. Mike Arrowsmith, HEJ's technical editor, provides an overview of the engineering sessions at this year's IHEEM conference. PMID- 29505225 TI - Valvular Heart Disease Epidemics. AB - BACKGROUND AIM OF THE STUDY: The real burden of valvular heart disease (VHD) is scarcely known, as several factors may potentially lead to its increased prevalence. The study aim was to assess the prevalence of VHD and its treatment in the authors' environment to plan the healthcare requisites for optimal management of the condition.METHODS: A retrospective analysis was conducted of data acquired from patients who had been assessed at different consultation levels for cardiovascular disorders during a six-month period between January and June 2014 in public health referral area of 500,00 inhabitants. Patients included were those admitted to hospital cardiology, cardiac surgery and geriatric care units (n = 1,083), as well as ambulatory patients attending cardiology-specific outpatient clinics at the authors' hospital or at two ascribed primary care centers (n = 852). Data were registered regarding the epidemiology, etiology, echocardiography and treatment of patients in whom VHD was detected.RESULTS: Among a total of 1,935 adult patients, moderate or severe valve disease was identified in 453 cases (23.4%) who were evaluated for cardiovascular disease. The prevalence of VHD increased with age. Multivalvular moderate-severe dysfunction was present in two valves in 33% and in three valves in 5.7% of patients. Significant mitral valve disease was present in 39% and aortic valve disease in 48% of patients. The etiology of the valvular lesions was degenerative in 60%, functional in 15.5%, rheumatic in almost 10%, congenital in 6%, due to endocarditis in only 3%. Patients with VHD represented up to 24.2% of the in hospital admissions. An interventional treatment was required in 55% of the patients (mostly surgical valve procedures). CONCLUSION: The present study results showed that VHD is a frequent occurrence and is increasingly prevalent with age, constituting up to one-fourth of all in-hospital admissions for cardiovascular disease. VHD is a growing public health problem that should be addressed with appropriate resources to improve research into its nature, diagnosis and treatment. PMID- 29505226 TI - Engaging staff 'The Leeds Way'. AB - Giving the keynote presentation on the first day of this year's Healthcare Estates conference, Julian Hartley, chief executive of Leeds Teaching Hospitals NHS Trust, discussed some of his key experiences and learnings since he began his NHS career as a management trainee in north-east England. Subsequently describing a momentous first year in post as CEO at the Leeds Trust, he stressed the importance of 'engaging staff' in the quest to improve patient services, and highlighted the vital role that estates and facilities personnel play, both in maintaining a clean, safe, and high quality care environment, and supporting their Board and management colleagues in dealing with the media, regulators, and other external organisations, following 'crisis' events. He also explained the five key tenets which underpin 'The Leeds Way'--a recently implemented approach to optimizing patient care, managing staff, and indeed improving every aspect of the way that a large acute NHS Trust operates. PMID- 29505227 TI - Property company's sustainability goals. AB - In a keynote presentation on the second morning of this year's Healthcare Estates conference, Kim Ormsby (pictured), national corporate social responsibility (CSR) and sustainability manager at NHS Property Services, discussed how, as part of its broader goals of 'supporting the NHS in delivering clinical services', and 'helping to enhance the experience' of patients visiting its buildings, the organization would continue to pursue and embed in its activities sustainable policies wherever and whenever possible, encouraging both its staff and tenants to take a similar approach. In an informative address, she highlighted some of the key steps the property company had already taken to encourage a proactive approach. Echoing the sentiments of Day One keynote speaker, Julian Hartley (see pages 55-60), she argued that one of the fundamentals to success was wide-ranging staff engagement. PMID- 29505228 TI - M13 Bacteriophage/Silver Nanowire Surface-Enhanced Raman Scattering Sensor for Sensitive and Selective Pesticide Detection. AB - A surface-enhanced Raman scattering (SERS) sensor comprising silver nanowires (AgNWs) and genetically engineered M13 bacteriophages expressing a tryptophan histidine-tryptophan (WHW) peptide sequence (BPWHW) was fabricated by simple mixing of BPWHW and AgNW solutions, followed by vacuum filtration onto a glass fiber filter paper (GFFP) membrane. The AgNWs stacked on the GFFP formed a high density of SERS-active hot spots at the points of nanowire intersections, and the surface-coated BPWHW functioned as a bioreceptor for selective pesticide detection. The BPWHW-functionalized AgNW (BPWHW/AgNW) sensor was characterized by scanning electron microscopy, confocal scanning fluorescence microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy. The Raman signal enhancement and the selective pesticide SERS detection properties of the BPWHW/AgNW sensor were investigated in the presence of control substrates such as wild-type M13 bacteriophage-decorated AgNWs (BPWT/AgNW) and undecorated AgNWs (AgNW). The BPWHW/AgNW sensor exhibited a significantly higher capture capability for pesticides, especially paraquat (PQ), than the control SERS substrates, and it also showed a relatively higher selectivity for PQ than for other bipyridylium pesticides such as diquat and difenzoquat. Furthermore, as a field application test, PQ was detected on the surface of PQ-pretreated apple peels, and the results demonstrated the feasibility of using a paper-based SERS substrate for on site residual pesticide detection. The developed M13 bacteriophage-functionalized AgNW SERS sensor might be applicable for the detection of various pesticides and chemicals through modification of the M13 bacteriophage surface peptide sequence. PMID- 29505229 TI - Influences of W Content on the Phase Transformation Properties and the Associated Stress Change in Thin Film Substrate Combinations Studied by Fabrication and Characterization of Thin Film V1- xW xO2 Materials Libraries. AB - The mechanical stress change of VO2 film substrate combinations during their reversible phase transformation makes them promising for applications in micro/nanoactuators. V1- xW xO2 thin film libraries were fabricated by reactive combinatorial cosputtering to investigate the effects of the addition of W on mechanical and other transformation properties. High-throughput characterization methods were used to systematically determine the composition spread, crystalline structure, surface topography, as well as the temperature-dependent phase transformation properties, that is, the hysteresis curves of the resistance and stress change. The study indicates that as x in V1- xW xO2 increases from 0.007 to 0.044 the crystalline structure gradually shifts from the VO2 (M) phase to the VO2 (R) phase. The transformation temperature decreases by 15 K/at. % and the resistance change is reduced to 1 order of magnitude, accompanied by a wider transition range and a narrower hysteresis with a minimal value of 1.8 K. A V1- xW xO2 library deposited on a Si3N4/SiO2-coated Si cantilever array wafer was used to study simultaneously the temperature-dependent stress change sigma( T) of films with different W content through the phase transformation. Compared with sigma( T) of ~700 MPa of a VO2 film, sigma( T) in V1- xW xO2 films decreases to ~250 MPa. Meanwhile, sigma( T) becomes less abrupt and occurs over a wider temperature range with decreased transformation temperatures. PMID- 29505230 TI - Bessel-Beam Hyperspectral CARS Microscopy with Sparse Sampling: Enabling High Content High-Throughput Label-Free Quantitative Chemical Imaging. AB - Microscopy-based high-content and high-throughput analysis of cellular systems plays a central role in drug discovery. However, for contrast and specificity, the majority of assays require a fluorescent readout which always comes with the risk of alteration of the true biological conditions. In this work, we demonstrate a label-free imaging platform which combines chemically specific hyperspectral coherent anti-Stokes Raman scattering microscopy with sparse sampling and Bessel beam illumination. This enabled us to screen multiwell plates at high speed, while retaining the high-content chemical analysis of hyperspectral imaging. To demonstrate the practical applicability of the method we addressed a critical side effect in drug screens, namely, drug-induced lipid storage within hepatic tissue. We screened 15 combinations of drugs and neutral lipids added to human HepG2 liver cells and developed a high-content quantitative data analysis pipeline which extracted the spectra and spatial distributions of lipid and protein components. We then used their combination to train a support vector machine discriminative algorithm. Classification of the drug responses in terms of phospholipidosis versus steatosis was achieved in a completely label free assay. PMID- 29505231 TI - Unusual Na+ Ion Intercalation/Deintercalation in Metal-Rich Cu1.8S for Na-Ion Batteries. AB - A key issue with Na-ion batteries is the development of active materials with stable electrochemical reversibility through the understanding of their sodium storage mechanisms. We report a sodium storage mechanism and properties of a new anode material, digenite Cu1.8S, based on its crystallographic study. It is revealed that copper sulfides (Cu xS) can have metal-rich formulas ( x >= 1.6), due to the unique oxidation state of +1 found in group 11 elements. These phases enable the unit cell to consist of all strong Cu-S bonds and no direct S-S bonds, which are vulnerable to external stress/strain that could result in bond cleavage as well as decomposition. Because of its structural rigidness, the Cu1.8S shows an intercalation/deintercalation reaction mechanism even in a low potential window of 0.1-2.2 V versus Na/Na+ without irreversible phase transformation, which most of the metal sulfides experience through a conversion reaction mechanism. It uptakes, on average, 1.4 Na+ ions per unit cell (~250 mAh g-1) and exhibits ~100% retention over 1000 cycles at 2C in a tuned voltage range of 0.5 2.2 V through an overall solid solution reaction with negligible phase separation. PMID- 29505232 TI - Vacuum Ultraviolet Spectroscopy and Mass Spectrometry: A Tandem Detection Approach for Improved Identification of Gas Chromatography-Eluting Compounds. AB - For wide class characterizations of volatile organic compounds (VOCs), conventional gas chromatography mass spectrometry (GC-MS)-based techniques are utilized. These GC-MS-based chemical identification approaches typically rely on library searches against ion fragmentation patterns of known compounds. Although MS library searches can often provide correct chemical identities, erroneous chemical assignments of structurally similar unknown compounds are also possible. Other detection systems, such as absorption spectrometers, have been used for VOC analysis and can provide complementary absorption data. Here, we demonstrate the analytical advantages of coupling vacuum ultraviolet (VUV) absorption spectroscopy and MS in tandem for the improved characterization of structurally similar VOCs. We also discuss technical considerations and limitations of coupling a VUV spectrometer to a quadrupole mass spectrometer. Moreover, we show that combining the isomer selectivity of VUV spectroscopy, as a nondestructive analyte detection approach, with the mass selectivity of MS in a VUV-MS detection system improves characterization of GC-eluting compounds. Utilizing GC/VUV-MS data, we demonstrate that orthogonal VUV and MS library searches improve identification of VOCs present in complex mixtures such as a mixed standard sample, a commercial perfume product, and an essential oil sample. PMID- 29505233 TI - Rapid Quantitative Profiling of Lipid Oxidation Products in a Food Emulsion by 1H NMR. AB - Lipid oxidation is one of the most important reasons for the compromised shelf life of food emulsions. A major bottleneck in unravelling the underlying mechanisms is the lack of methods that provide a rapid, quantitative, and comprehensive molecular view on lipid oxidation in these heterogeneous systems. In this study, the unbiased and quantitative nature of 1H NMR was exploited to assess lipid oxidation products in mayonnaise, a particularly oxidation-prone food emulsion. An efficient and robust procedure was implemented to produce samples where the 1H NMR signals of oxidation products could be observed in a well resolved and reproducible manner. 1H NMR signals of hydroperoxides were assigned in a fatty acid and isomer specific way. Band-selective 1H NMR pulse excitation allowed immediate and precise (RSDR = 5.9%) quantification of both hydroperoxides and aldehydes with high throughput and large dynamic range at levels of 0.03 mmol/kg. Explorative multivariate data modeling of the quantitative 1H NMR profiles revealed that shelf life temperature has a significant impact on lipid oxidation mechanisms. PMID- 29505234 TI - DNA Based Hybrid Material for Interface Engineering in Polymer Solar Cells. AB - A new solution processable electron transport material (ETM) is introduced for use in photovoltaic devices, which consists of a metallic conjugated polyelectrolyte, poly(4-(2,3-dihydrothieno[3,4- b][1,4]dioxin-2-yl-methoxy)-1 butanesulfonic acid (PEDOT-S), and surfactant-functionalized deoxyribonucleic acid (DNA) (named DNA:CTMA:PEDOT-S). This ETM is demonstrated to effectively work for bulk-heterojunction organic photovoltaic devices (OPV) based on different electron acceptor materials. The fill factor, the open circuit voltage, and the overall power conversion efficiency of the solar cells with a DNA:CTMA:PEDOT-S modified cathode are comparable to those of devices with a traditional lithium fluoride/aluminum cathode. The new electron transport layer has high optical transmittance, desired work function and selective electron transport. A dipole effect induced by the use of the surfactant cetyltrimethylammonium chloride (CTMA) is responsible for lowering the electrode work function. The DNA:CTMA complex works as an optical absorption dilutor, while PEDOT-S provides the conducting pathway for electron transport, and allows thicker layer to be used, enabling printing. This materials design opens a new pathway to harness and optimize the electronic and optical properties of printable interface materials. PMID- 29505236 TI - Endosomal Size and Membrane Leakiness Influence Proton Sponge-Based Rupture of Endosomal Vesicles. AB - In gene therapy, endosomal escape represents a major bottleneck since nanoparticles often remain entrapped inside endosomes and are trafficked toward the lysosomes for degradation. A detailed understanding of the endosomal barrier would be beneficial for developing rational strategies to improve transfection and endosomal escape. By visualizing individual endosomal escape events in live cells, we obtain insight into mechanistic factors that influence proton sponge based endosomal escape. In a comparative study, we found that HeLa cells treated with JetPEI/pDNA polyplexes have a 3.5-fold increased endosomal escape frequency compared to ARPE-19 cells. We found that endosomal size has a major impact on the escape capacity. The smaller HeLa endosomes are more easily ruptured by the proton sponge effect than the larger ARPE-19 endosomes, a finding supported by a mathematical model based on the underlying physical principles. Still, it remains intriguing that even in the small HeLa endosomes, <10% of the polyplex-containing endosomes show endosomal escape. Further experiments revealed that the membrane of polyplex-containing endosomes becomes leaky to small compounds, preventing effective buildup of osmotic pressure, which in turn prevents endosomal rupture. Analysis of H1299 and A549 cells revealed that endosomal size determines endosomal escape efficiency when cells have comparable membrane leakiness. However, at high levels of membrane leakiness, buildup of osmotic pressure is no longer possible, regardless of endosomal size. Based on our findings that both endosomal size and membrane leakiness have a high impact on proton sponge-based endosomal rupture, we provide important clues toward further improvement of this escape strategy. PMID- 29505235 TI - Direct n- to p-Type Channel Conversion in Monolayer/Few-Layer WS2 Field-Effect Transistors by Atomic Nitrogen Treatment. AB - We present a method for substitutional p-type doping in monolayer (1L) and few layer (FL) WS2 using highly reactive nitrogen atoms. We demonstrate that the nitrogen-induced lattice distortion in atomically thin WS2 is negligible due to its low kinetic energy. The electrical characteristics of 1L/FL WS2 field-effect transistors (FETs) clearly show an n-channel to p-channel conversion with nitrogen incorporation. We investigate the defect formation energy and the origin of p-type conduction using first-principles calculations. We reveal that a defect state appears near the Fermi level, leading to a shallow acceptor level at 0.24 eV above the valence band maximum in nitrogen-doped 1L/FL WS2. This doping strategy enables a substitutional p-type doping in intrinsically n-type 1L/FL transition metal dichalcogenides (TMDCs) with tunable control of dopants, offering a method for realizing complementary metal-oxide-semiconductor FETs and optoelectronic devices on 1L/FL TMDCs by overcoming one of the major limits of TMDCs, that is, their n-type unipolar conduction. PMID- 29505237 TI - Sn-Based Nanocomposite for Li-Ion Battery Anode with High Energy Density, Rate Capability, and Reversibility. AB - To design an easily manufactured, large energy density, highly reversible, and fast rate-capable Li-ion battery (LIB) anode, Co-Sn intermetallics (CoSn2, CoSn, and Co3Sn2) were synthesized, and their potential as anode materials for LIBs was investigated. Based on their electrochemical performances, CoSn2 was selected, and its C-modified nanocomposite (CoSn2/C) as well as Ti- and C-modified nanocomposite (CoSn2/ a-TiC/C) was straightforwardly prepared. Interestingly, the CoSn2, CoSn2/C, and CoSn2/ a-TiC/C showed conversion/nonrecombination, conversion/partial recombination, and conversion/full recombination during Li insertion/extraction, respectively, which were thoroughly investigated using ex situ X-ray diffraction and extended X-ray absorption fine structure analyses. As a result of the interesting conversion/full recombination mechanism, the easily manufactured CoSn2/ a-TiC/C nanocomposite for the Sn-based Li-ion battery anode showed large energy density (first reversible capacity of 1399 mAh cm-3), high reversibility (first Coulombic efficiency of 83.2%), long cycling behavior (100% capacity retention after 180 cycles), and fast rate capability (appoximately 1110 mAh cm-3 at 3 C rate). In addition, degradation/enhancement mechanisms for high capacity and high-performance Li-alloy-based anode materials for next-generation LIBs were also suggested. PMID- 29505238 TI - Tunable Pt-MoS x Hybrid Catalysts for Hydrogen Evolution. AB - Platinum (Pt)-based materials are inevitably among the best-performing electrocatalysts for hydrogen evolution reaction (HER). MoS2 was suggested to be a potent HER catalyst to replace Pt in this reaction by theoretical modeling; however, in practice, this dream remains elusive. Here we show a facile one-pot bottom-up synthesis of Pt-MoS x composites using electrochemical reduction in an electrolytic bath of Pt precursor and ammonium tetrathiomolybdate under ambient conditions. By modifying the millimolar concentration of Pt precursors, composites of different surface elemental composition are fabricated; specifically, Pt1.8MoS2, Pt0.1MoS2.5, Pt0.2MoS0.6, and Pt0.3MoS0.8. All electrodeposited Pt-MoS x hybrids showcase low overpotentials and small Tafel slopes that outperform MoS2 as an electrocatalyst. Tantamount to electrodeposited Pt, the rate-limiting process in the HER mechanism is determined to be the Heyrovsky desorption across Pt-MoS x hybrids and starkly swings from the rate determining Volmer adsorption step in MoS2. The Pt-MoS x composites are equipped with catalytic performance that closely mirrors that of electrodeposited Pt, in particular the HER kinetics for Pt1.8MoS2 and Pt0.1MoS2.5. This work advocates electrosynthesis as a cost-effective method for catalyst design and fabrication of competent composite materials for water splitting applications. PMID- 29505239 TI - Unraveling the Rapid Performance Decay of Layered High-Energy Cathodes: From Nanoscale Degradation to Drastic Bulk Evolution. AB - Lithium-rich layered oxides are promising cathode candidates because of their exceptional high capacity. The commercial application of these high-energy cathodes, however, is thwarted by the undesired rapid performance decay during cycling. Surface degradation has been widely considered to correlate with the performance decay of the cathodes, whereas, in this work, we demonstrate that the degradation of Li-rich high-energy Li1.2Ni0.13Mn0.54Co0.13O2 (HENMC) cathode material not only takes place at surfaces but also proceeds from its internal structure. In addition to demonstrating the surface reconstruction and the formation of a cathode-electrolyte interphase (CEI) layer of cycled HENMC cathode, this study uncovers the irreversible bulk phase transition from a Li excess monoclinic ( C2/ m) solid solution into a conventional "layered" ( R3 m) phase, accompanied by complete loss of Li+ from the TM layers during cycling. Furthermore, the internal grains of HENMC bear lattice distortions, leading to the formation of "nano-defect" domains, which could limit the Li+ diffusion inside the grains. More prominently, the layered-to-spinel transition in the form of large spinel grains ( Fd3 m), hundreds of nanometers across, is discovered, and their detailed atomic arrangement is studied. The findings suggest that, instead of attributing the overall capacity fade to the surface degradation, these drastic bulk evolutions would be the main degradation mechanisms at the source of the rapid failure of Li-rich cathodes. PMID- 29505240 TI - A Multifunctional Polypeptide via Ugi Reaction for Compact and Biocompatible Quantum Dots with Efficient Bioconjugation. AB - The growing application of quantum dots (QDs) in biomedical research necessitates, in turn, continuous development of surface functionalizing ligands to optimize their performance for ever more challenging and diverse biological applications. Here, we demonstrate the novel multifunctional polypeptide ligands for compact and biocompatible QDs. The target ligand preparation exploits the efficient, activating agent-free Ugi reaction of four functional components to incorporate lipoic acid, pyridine, zwitterion motifs, and reactive functionalities in a one-pot procedure under mild conditions. Cap exchange with these multifunctional polypeptide ligands generates hydrophilic QD dispersions, which are colloidally stable for prolonged periods of time. The zwitterionic ligation delivers compact and small QDs, and the existence of reactive functionalities enables coupling of the QDs to biologics through bio-orthogonal coupling chemistry, such as ligation of azide-modified QDs to DNA. Therefore, this QD functionalization strategy via Ugi reaction is believed to be a viable approach for compact and biocompatible QDs with efficient bioconjugation. PMID- 29505241 TI - Expanding the Coverage of the Metabolome with Nitrogen-Based NMR. AB - Isotopically labeling a metabolite and tracing its metabolic fate has provided invaluable insights about the role of metabolism in human diseases in addition to a variety of other issues. 13C-labeled metabolite tracers or unlabeled 1H-based NMR experiments are currently the most common application of NMR to metabolomics studies. Unfortunately, the coverage of the metabolome has been consequently limited to the most abundant carbon-containing metabolites. To expand the coverage of the metabolome and enhance the impact of metabolomics studies, we present a protocol for 15N-labeled metabolite tracer experiments that may also be combined with routine 13C tracer experiments to simultaneously detect both 15N- and 13C-labeled metabolites in metabolic samples. A database consisting of 2D 1H 15N HSQC natural-abundance spectra of 50 nitrogen-containing metabolites are also presented to facilitate the assignment of 15N-labeled metabolites. The methodology is demonstrated by labeling Escherichia coli and Staphylococcus aureus metabolomes with 15N1-ammonium chloride, 15N4-arginine, and 13C2-acetate. Efficient 15N and 13C metabolite labeling and identification were achieved utilizing standard cell culture and sample preparation protocols. PMID- 29505242 TI - Synergy of Two Highly Specific Biomolecular Recognition Events: Aligning an AT Hook Peptide in DNA Minor Grooves via Covalent Conjugation to 2'-Amino-LNA. AB - Two highly specific biomolecular recognition events, nucleic acid duplex hybridization and DNA-peptide recognition in the minor groove, were coalesced in a miniature ensemble for the first time by covalently attaching a natural AT-hook peptide motif to nucleic acid duplexes via a 2'-amino-LNA scaffold. A combination of molecular dynamics simulations and ultraviolet thermal denaturation studies revealed high sequence-specific affinity of the peptide-oligonucleotide conjugates (POCs) when binding to complementary DNA strands, leveraging the bioinformation encrypted in the minor groove of DNA duplexes. The significant cooperative DNA duplex stabilization may pave the way toward further development of POCs with enhanced affinity and selectivity toward target sequences carrying peptide-binding genetic islands. PMID- 29505243 TI - Near-Infrared Fluorescent Dye-Decorated Nanocages to Form Grenade-like Nanoparticles with Dual Control Release for Photothermal Theranostics and Chemotherapy. AB - Recently, nanoparticles (NPs) have been widely investigated for delivery of anticancer drugs. Here, a dual control drug-release modality was developed that uses naturally occurring protein apoferritin loaded with doxorubicin (DOX) and ADS-780 near-infrared (NIR) fluorescent dye-decorated NPs (ADNIR NPs). ADNIR NPs act as a grenade to detonate the targeted tumor site following laser irradiation (photothermal therapy, PTT) and explode into cluster warheads (apoferritin-loaded DOX nanocages, AF-DOX NCs) that further destroy the tumor cells (chemotherapy). Light was shown to disrupt the grenade-like structure of NPs to release AF-DOX NCs as well as DOX from NCs in low-pH intercellular environments. In vitro and in vivo studies showed that the structure of AF-DOX NCs was disassembled to release DOX, which then killed the cancer cells in organelles with acidic environments. In vivo studies showed that the ADNIR NP-decorated with NIR dye facilitated tracking of the accumulated NPs at the tumor site using an IVIS imaging system. Overall, targeted ADNIR NPs with dual-release mechanisms were developed for use in photothermal theranostic and chemotherapy. This modality has high potential for application in cancer treatment and clinical translation for drug delivery and imaging. PMID- 29505244 TI - Single-Cell Mass Spectrometry of Subpopulations Selected by Fluorescence Microscopy. AB - Specific subpopulations in a heterogeneous collection of cells, for example, cancer stem cells in a tumor, are often associated with biological or medical conditions. Fluorescence microscopy, based on biomarkers labeled with fluorescent probes, is a widely used technique for the visualization and selection of such cells. Phenotypic differences for these subpopulations at the molecular level can be identified by their untargeted analysis by single-cell mass spectrometry (MS). Here, we combine capillary microsampling MS with fluorescence microscopy for the analysis of metabolite and lipid levels in single cells to discern the heterogeneity of subpopulations corresponding to mitotic stages. The distributions of ATP, reduced glutathione (GSH), and UDP- N-acetylhexosamine (UDP HexNAc) levels in mitosis reveal the presence of 2-3 underlying subpopulations. Cellular energy is found to be higher in metaphase compared to prometaphase and slightly declines in anaphase, telophase, and cytokinesis. The [GTP]/[GDP] ratio in cytokinesis is significantly higher than in prometaphase and anaphase. Pairwise correlations between metabolite levels show that some molecules within a group, including certain amino acids and nucleotide sugars, are strongly correlated throughout mitosis, but this is not related to their pathway distances. Correlations are observed between monophosphates (AMP and GMP), diphosphates (ADP and GDP), and triphosphates (ATP and GTP) of different nucleosides. In contrast, there is low correlation between diphosphates and triphosphates of the same nucleoside (ADP and ATP). PMID- 29505245 TI - Biocompatible Nanocoatings of Fluorinated Polyphosphazenes through Aqueous Assembly. AB - Nonionic fluorinated polyphosphazenes, such as poly[bis(trifluoroethoxy)phosphazene] (PTFEP), display superb biocompatibility, yet their deposition to surfaces has been limited to solution casting from organic solvents or thermal molding. Herein, hydrophobic coatings of fluorinated polyphosphazenes are demonstrated through controlled deposition of ionic fluorinated polyphosphazenes (iFPs) from aqueous solutions using the layer-by layer (LbL) technique. Specifically, the assemblies included poly[(carboxylatophenoxy)(trifluoroethoxy)phosphazenes] with varied content of fluorine atoms as iFPs (or poly[bis(carboxyphenoxy)phosphazene] (PCPP) as a control nonfluorinated polyphosphazene) and a variety of polycations. Hydrophobic interactions largely contributed to the formation of LbL films of iFPs with polycations, leading to linear growth and extremely low water uptake. Hydrophobicity-enhanced ionic pairing within iFP/BPEI assemblies gave rise to large-amplitude oscillations in surface wettability as a function of capping layer, which were the largest for the most fluorinated iFP, while control PCPP/polycation systems remained hydrophilic regardless of the film top layer. Neutron reflectometry (NR) studies indicated superior layering and persistence of such layering in salt solution for iFP/BPEI films as compared to control PCPP/polycation systems. Hydrophobicity of iFP-capped LbL coatings could be further enhanced by using a highly porous polyester surgical felt rather than planar substrates for film deposition. Importantly, iFP/polycation coatings displayed biocompatibility which was similar to or superior to that of solution cast coatings of a clinically validated material (PTFEP), as demonstrated by the hemolysis of the whole blood and protein adsorption studies. PMID- 29505246 TI - Disilaruthena- and Ferracyclic Complexes Containing Isocyanide Ligands as Effective Catalysts for Hydrogenation of Unfunctionalized Sterically Hindered Alkenes. AB - Disilaferra- and disilaruthenacyclic complexes containing mesityl isocyanide as a ligand, 3' and 4', were synthesized and characterized by spectroscopy and crystallography. Both 3' and 4' showed excellent catalytic activity for the hydrogenation of alkenes. Compared with iron and ruthenium carbonyl analogues, 1' and 2', the isocyanide complexes 3' and 4' were more robust under the hydrogenation conditions, and were still active even at higher temperatures (~80 degrees C) under high hydrogen pressure (~20 atm). The iron complex 3' exhibited the highest catalytic activity toward hydrogenation of mono-, di-, tri-, and tetrasubstituted alkenes among currently reported iron catalysts. Ruthenium complex 4' catalyzed hydrogenation under very mild conditions, such as room temperature and 1 atm of H2. The remarkably high catalytic activity of 4' for hydrogenation of unfunctionalized tetrasubstituted alkenes was especially notable, because it was comparable to the activity of iridium complexes reported by Crabtree and Pfaltz, which are catalysts with the highest activity in the literature. DFT calculations suggested two plausible catalytic cycles, both of which involved activation of H2 assisted by the metal-silicon bond through sigma bond metathesis of late transition metals (oxidative hydrogen migration). The linear structure of M-C=N-C (ipso carbon of the mesityl group) played an essential role in the efficient hydrogenation of sterically hindered tetrasubstituted alkenes. PMID- 29505247 TI - Threshold Concentrations of Silver Ions Exist for the Sunlight-Induced Formation of Silver Nanoparticles in the Presence of Natural Organic Matter. AB - Sunlight-induced photoformation of silver nanoparticles (nAg), mediated by natural organic matter (NOM), is significantly affected by the concentration of Ag(I) and chloride. The initial photoformation rates of nAg in Suwannee River humic acid (SRHA) and Suwannee River natural organic matter (SRNOM) solutions were examined under simulated sunlight irradiation. A critical induction concentration (CIC) of Ag(I) (10 mg/L for SRHA and 5 mg/L for SRNOM, respectively) was observed, below which the nAg formation was minimal. The threshold is attributed to the interplay of reduction and oxidation reactions mediated by NOM, reflecting the need to achieve sufficiently fast growth of silver clusters to outcompete oxidative dissolution. The CIC can be reduced by scavenging oxidative radicals or be increased by promoting singlet oxygen and hydrogen peroxide generation. The presence of chloride effectively reduced the CIC by forming AgCl, which facilitates reduction reactions and provides deposition surfaces. SRNOM is more efficient in mediating photoformation of nAg than SRHA, owing to their differed phototransient generation. These results highlight prerequisites for the photoformation of nAg mediated by NOM, in which the photochemistry and solution chemistry are both important. PMID- 29505248 TI - Sulfur Isotope Fractionation by Sulfate-Reducing Microbes Can Reflect Past Physiology. AB - Sulfur (S) isotope fractionation by sulfate-reducing microorganisms is a direct manifestation of their respiratory metabolism. This fractionation is apparent in the substrate (sulfate) and waste (sulfide) produced. The sulfate-reducing metabolism responds to variability in the local environment, with the response determined by the underlying genotype, resulting in the expression of an "isotope phenotype". Sulfur isotope phenotypes have been used as a diagnostic tool for the metabolic activity of sulfate-reducing microorganisms in the environment. Our experiments with Desulfovibrio vulgaris Hildenborough (DvH) grown in batch culture suggest that the S isotope phenotype of sulfate respiring microbes may lag environmental changes on time scales that are longer than generational. When inocula from different phases of growth are assayed under the same environmental conditions, we observed that DvH exhibited different net apparent fractionations of up to -90/00. The magnitude of fractionation was weakly correlated with physiological parameters but was strongly correlated to the age of the initial inoculum. The S isotope fractionation observed between sulfate and sulfide showed a positive correlation with respiration rate, contradicting the well-described negative dependence of fractionation on respiration rate. Quantitative modeling of S isotope fractionation shows that either a large increase (~50*) in the abundance of sulfate adenylyl transferase (Sat) or a smaller increase in sulfate transport proteins (~2*) is sufficient to account for the change in fractionation associated with past physiology. Temporal transcriptomic studies with DvH imply that expression of sulfate permeases doubles over the transition from early exponential to early stationary phase, lending support to the transport hypothesis proposed here. As it is apparently maintained for multiple generations (~1-6) of subsequent growth in the assay environment, we suggest that this fractionation effect acts as a sort of isotopic "memory" of a previous physiological and environmental state. Whatever its root cause, this physiological hysteresis effect can explain variations in fractionations observed in many environments. It may also enable new insights into life at energetic limits, especially if its historical footprint extends deeper than generational. PMID- 29505249 TI - Application of SourceTracker for Accurate Identification of Fecal Pollution in Recreational Freshwater: A Double-Blinded Study. AB - The efficacy of SourceTracker software to attribute contamination from a variety of fecal sources spiked into ambient freshwater samples was investigated. Double blinded samples spiked with <=5 different sources (0.025-10% vol/vol) were evaluated against fecal taxon libraries characterized by next-generation amplicon sequencing. Three libraries, including an initial library (17 nonlocal sources), a blinded source library (5 local sources), and a composite library (local and nonlocal sources), were used with SourceTracker. SourceTracker's predictions of fecal compositions in samples were made, in part, based on distributions of taxa within abundant genera identified as discriminatory by discriminant analyses but also using a large percentage of low abundance taxa. The initial library showed poor ability to characterize blinded samples, but, using local sources, SourceTracker showed 91% accuracy (31/34) at identifying the presence of source contamination, with two false positives for sewage and one for horse. Furthermore, sink predictions of source contamination were positively correlated (Spearman's rho >= 0.88, P < 0.001) with spiked source volumes. Using the composite library did not significantly affect sink predictions ( P > 0.79) compared to those made using the local sources alone. Results of this study indicate that geographically associated fecal samples are required for SourceTracker to assign host sources accurately. PMID- 29505250 TI - Comparative Persistence of Engineered Nanoparticles in a Complex Aquatic Ecosystem. AB - During nanoparticle environmental exposure, presence in the water column is expected to dominate long distance transport as well as initial aquatic organism exposure. Much work has been done to understand potential ecological and toxicological effects of these particles. However, little has been done to date to understand the comparative persistence of engineered particles in realistic environmental systems. Presented here is a study of the water column lifetimes of 3 different classes of nanoparticles prepared with a combination of surface chemistries in wetland mesocosms. We find that, when introduced as a single pulse, all tested nanoparticles persist in the water column for periods ranging from 36 h to 10 days. Specifically, we found a range of nanoparticle residence times in the order Ag > TiO2 > SWCNT > CeO2. We further explored the hypothesis that heteroaggregation was the primary driving factor for nanoparticle removal from the water column in all but one case, and that values of surface affinity (alpha) measured in the laboratory appear to predict relative removal rates when heteroaggregation dominates. Though persistence in the water column was relatively short in all cases, differences in persistence may play a role in determining nanoparticle fate and impacts and were poorly predicted by currently prevailing benchmarks such as particle surface preparation. PMID- 29505251 TI - Diversity of Sporosarcina-like Bacterial Strains Obtained from Meter-Scale Augmented and Stimulated Biocementation Experiments. AB - Microbially Induced Calcite Precipitation (MICP) is a biomediated soil cementation process that offers an environmentally conscious alternative to conventional geotechnical soil improvement technologies. This study provides the first comparison of ureolytic bacteria isolated from sand cemented in parallel, meter-scale, MICP experiments using either biostimulation or bioaugmentation approaches, wherein colonies resembling the augmented strain ( Sporosarcina pasteurii ATCC 11859) were interrogated. Over the 13 day experiment, 47 of the 57 isolates collected were strains of Sporosarcina and the diversity of these strains was high, with 20 distinct strains belonging to 5 species identified. Although the S. pasteurii inoculant used for augmentation was recovered immediately after introduction in the augmented specimen, the strain was not recovered after 8 days in either augmented or stimulated soils, suggesting that it competes poorly with indigenous bacteria. Past studies on the physiological properties of S. pasteurii ATCC 11859 suggest that close relatives may have selective advantages under the biogeochemical conditions employed during MICP; however, the extent to which these properties apply to isolates of the current study is unknown. Whole cell urease kinetic properties were investigated for representative isolates and suggest up to 100-fold higher rates of carbonate production when compared to other biomediated processes proposed for MICP. PMID- 29505252 TI - Structures, Thermodynamic Relations, and Magnetism of Stable and Metastable Ni(NCS)2 Coordination Polymers. AB - Reaction of Ni(NCS)2 with 4-aminopyridine in different solvents leads to the formation of compounds with the compositions Ni(NCS)2(4-aminopyridine)4 (1), Ni(NCS)2(4-aminopyridine)2(H2O)2 (2), [Ni(NCS)2(4-aminopyridine)3(MeCN)].MeCN (3), and [Ni(NCS)2(4-aminopyridine)2] n (5-LT). Compounds 1, 2, and 3 form discrete complexes, with octahedral metal coordination. In 5-LT the Ni cations are linked by single thiocyanate anions into chains, which are further connected into layers by half of the 4-aminopyridine coligands. Upon heating, 1 transforms into an isomer of 5-LT with a 1D structure (5-HT), that on further heating forms a more condensed chain compound [Ni(NCS)2(4-aminopyridine)] n (6) that shows a very unusual chain topology. If 3 is heated, a further compound with the composition Ni(NCS)2(4-aminopyridine)3 (4) is formed, which presumably is a dimer and which on further heating transforms into 6 via 5-HT as intermediate. Further investigations reveal that 5-LT and 5-HT are related by enantiotropism, with 5-LT being the thermodynamic stable form at room-temperature. Magnetic and specific heat measurements reveal ferromagnetic exchange through thiocyanate bridges and magnetic ordering due to antiferromagnetic interchain interactions at 5.30(5) K and 8.2(2) K for 5-LT and 6, respectively. Consecutive metamagnetic transitions in the spin ladder compound 6 are due to dipolar interchain interactions. A convenient formula for susceptibility of the ferromagnetic Heisenberg chain of isotropic spins S = 1 is proposed, based on numerical DMRG calculations, and used to determine exchange constants. PMID- 29505253 TI - High Pressure and High Temperature Synthesis of the Iron Pernitride FeN2. AB - The high pressure chemistry of transition metals and nitrogen was recently discovered to be richer than previously thought, due to the synthesis of several transition metal pernitrides. Here, we explore the pressure-temperature domain of iron with an excess of nitrogen up to 91 GPa and 2200 K. Above 72 GPa and 2200 K, the iron pernitride FeN2 is produced in a laser-heated diamond anvil cell. This iron-nitrogen compound is the first with a N/Fe ratio greater than 1. The FeN2 samples were characterized from the maximum observed pressure down to ambient conditions by powder X-ray diffraction and Raman spectroscopy measurements. The crystal structure of FeN2 is resolved to be a Pnnm marcasite structure, analogously to other transition metal pernitrides. On the basis of the lattice's axial ratios and the recorded N-N vibrational modes of FeN2, a bond order of 1.5 for the nitrogen dimer is suggested. The bulk modulus of the iron pernitride is determined to be of K0 = 344(13) GPa, corresponding to an astounding increase of about 208% from pure iron. Upon decompression to ambient conditions, a partial structural phase transition to the theoretically predicted R3 m FeN2 is detected. PMID- 29505254 TI - Gibbs Adsorption Impact on a Nanodroplet Shape: Modification of Young-Laplace Equation. AB - We present an efficient technique for the evaluation of the Gibbs adsorption of a liquid on a solid substrate. The behavior of a water nanodroplet on a silicon surface is simulated with molecular dynamics. An external field with varying strength is applied on the system to tune the solid-liquid interfacial contact area. A linear dependence of droplet's volume as a function of the contact area is observed. We introduce a modified Young-Laplace equation to explain the influence of the Gibbs adsorption on the nanodroplet volume contraction. Fitting of the molecular dynamics results with the analytical approach allows us to evaluate the number of atoms per unit area adsorbed on the substrate, which quantifies the Gibbs adsorption. Thus, a threshold of a droplet size is obtained, for which the impact of the adsorption is crucial. For instance, a water droplet with 5 nm radius has 3% of its molecules adsorbed on silicon substrate, while for droplets less than 1 nm this amount is more than 10%. The presented results could be beneficial for the evaluation of the adsorption impact on the physical chemical properties of nanohybrid systems with large surface-to-volume ration. PMID- 29505255 TI - Antibiotic Resistant Bacteria in Municipal Wastes: Is There Reason for Concern? AB - Recently, there has been increased concern about the presence of antibiotic resistant bacteria (ARB) and antibiotic resistant genes (ARG), in treated domestic wastewaters, animal manures and municipal biosolids. The concern is whether these additional sources of ARB contribute to antibiotic resistance levels in the environment, that is, "environmental antibiotic resistance." ARB and ARG occur naturally in soil and water, and it remains unclear whether the introduction of ARB in liquid and solid municipal and animal wastes via land application have any significant impact on the background levels of antibiotic resistance in the environment, and whether they affect human exposure to ARB. In this current review, we examine and re-evaluate the incidence of ARB and ARG resulting from land application activities, and offer a new perspective on the threat of antibiotic resistance to public health via exposure from nonclinical environmental sources. Based on inputs of ARBs and ARGs from land application, their fate in soil due to soil microbial ecology principles, and background indigenous levels of ARBs and ARGs already present in soil, we conclude that while antibiotic resistance levels in soil are increased temporally by land application of wastes, their persistence is not guaranteed and is in fact variable, and often contradictory based on application site. Furthermore, the application of wastes may not produce the most direct impact of ARGs and ARB on public health. Further investigation is still warranted in agriculture and public health, including continued scrutiny of antibiotic use in both sectors. PMID- 29505256 TI - Carbon-Hydrogen Activation in Zerovalent Bis(1,5-cyclooctadiene) Complexes of the First Row Transition Metals: A Theoretical Study. AB - Stepwise interaction of first row transition metal atoms with 1,5-cyclooctadiene to give (C8H12)2M complexes is studied using the M06-L/DZP density functional method. The experimentally known (C8H12)2Ni is the thermodynamically most favorable complex, with a predicted geometry consistent with its experimental structure as determined by X-ray crystallography. The other transition metal atoms from scandium to zinc also interact exothermically with 1,5-cyclooctadiene to give (C8H12)2M derivatives, but these exhibit lower symmetry than the S4 symmetry exhibited by (C8H12)2Ni. Carbon-hydrogen activation of CH2 groups in a C8H12 ligand is predicted for most systems. Thus, conversion of (eta2,2-C8H12)2M to (eta3,2-C8H11)(eta2,1-C8H13)M, through a hydride intermediate (eta3,2 C8H11)(eta2,2-C8H12)MH, is predicted for scandium, vanadium, chromium, manganese, and cobalt. For titanium with a low-lying empty orbital, further C-H activation through a hydride intermediate (eta6-C8H10)(eta2,1-C8H13)TiH is predicted, leading ultimately to (eta6-C8H10)(eta1,1-C8H14)Ti, in which the hexahapto eta6 C8H10 ligand is shown by NICS to be aromatic. These two C-H activation processes on a titanium center represent the dehydrogenation of 1,5-cyclooctadiene to 1,3,5 cyclooctatriene with the second 1,5-cyclooctadiene ligand as the hydrogen acceptor. For zinc C-H activation terminates at (eta1-C8H11)(C8H12)ZnH, which has a C-Zn-H three-center bond. No energetically favorable C-H activation processes are predicted for the iron, nickel, and copper (eta2,2-C8H12)2M derivatives. PMID- 29505257 TI - Bioregeneration of Chabazite During Nitrification of Centrate from Anaerobically Digested Livestock Waste: Experimental and Modeling Studies. AB - Nitrification of high total ammonia nitrogen-strength wastewaters is challenging due to free ammonia (FA) inhibition of nitrification. FA inhibition can potentially be alleviated by temporarily adsorbing ammonium (NH4+) to natural zeolite, such as chabazite, followed by direct zeolite bioregeneration via nitrification. In this research, the effectiveness of chabazite addition for reducing nitrification inhibition during treatment of centrate from anaerobic digestion of swine waste was quantified. A mathematical model was developed that accounts for ion exchange of NH4+ and sodium at the chabazite surface, surface diffusion of adsorbed NH4+ within the chabazite grains, sequential nitrification of aqueous NH4+ to nitrite and nitrate, and inhibition of nitritation and nitratation rates by NH4+. The model was calibrated using results of abiotic ion exchange and nitrification studies. Subsequently, nitrification tests were carried out with synthetic wastewater with a NH4+-N concentration of 1000 mg L-1, with and without chabazite. A chabazite dose of 150 g L-1 decreased the FA concentration to below the inhibitory level and increased the nitrification rate from 0.16 to 0.36 mg-N (g-VSS)-1 h-1. Following calibration, the model could predict the experimental data with no additional fitting parameters or parameter adjustment, in both the presence and absence of chabazite. The results suggest that the mathematical model provides a theoretically sound conceptual understanding of ion exchange assisted nitrification. PMID- 29505258 TI - External Oxidant-Free Dehydrogenative Lactonization of 2-Arylbenzoic Acids via Visible-Light Photocatalysis. AB - An external oxidant-free C-H functionalization/C-O bond formation reaction for constructing benzo-3,4-coumarins accompanied by quantitative H2 evolution has been developed. High functional group tolerance and excellent reaction efficiency are shown in this transformation. Meanwhile, the substrates containing heterocyclic substituents such as thienyl-, pyridinyl-, and pyrrolylbenzoic acids displayed good performance. Importantly, this reaction can be performed with good efficiency on a gram scale. A cyclic voltammetry study and density functional theory calculations could provide insight into the mechanism of this reaction. PMID- 29505259 TI - Theoretical Investigation into Rate-Determining Factors in Electrophilic Aromatic Halogenation. AB - The halogenation of monosubstituted benzenes in aqueous solvent was studied using density functional theory at the PCM-M06-2 X/6-311G(d,p) level. The reaction with Cl2 begins with the formation of C atom coordinated pi-complex and is followed by the formation of the sigma-complex, which is rate-determining. The final part proceeds via the abstraction of the proton by a water molecule or a weak base. We evaluated the use of the sigma-complex as a model for the rate-determining transition state (TS) and found that this model is more accurate the later the TS comes along the reaction coordinate. This explains the higher accuracy of the model for halogenations (late TS) compared to nitrations (early TS); that is, the more deactivated the substrate the later the TS. The halogenation with Br2 proceeds with a similar mechanism as the corresponding chlorination, but the bromination has a very late rate-determining TS that is similar to the sigma complex in energy. The iodination with ICl follows a different mechanism than chlorination and bromination. After the formation of the pi-complex, the reaction proceeds in a concerted manner without a sigma-complex. This reaction has a large primary hydrogen kinetic isotope effect in agreement with experimental observations. PMID- 29505260 TI - Interstitial Water Enhances Sliding Friction. AB - This study examines how surfaces with different water contact angles (wettability) affect dry and underwater adhesion and friction. These studies were conducted by bringing a deformable hydrophobic poly(dimethylsiloxane) lens in contact with surfaces of gradient wettability. On the basis of our adhesion and friction results, we divide the results in three regions. In region I (water contact angles greater than 80 degrees ), the dry adhesion is lower than underwater adhesion. In contrast, in region III, (water contact angles less than 50 degrees ), the dry adhesion is higher than underwater adhesion. For surfaces with water contact angles between 50 and 80 degrees (region II), the dry and wet adhesion values are comparable. Interestingly, in this region II, the underwater coefficient of friction (COF) values are higher than those in regions I and III. We have used surface-sensitive sum frequency generation (SFG) spectroscopy to probe whether the contact interface in static conditions and during dynamic sliding is dry or wet. The SFG results reveal that the contact is dry in region I. If this dry contact is maintained, the underwater COF follows the trend of adhesion hysteresis in dry conditions (adhesion hysteresis decreases with an increase in water contact angles). In region III, the contact is wet and the underwater COF follows the trend for adhesion hysteresis in wet conditions (adhesion hysteresis increases with an increase in water contact angles). By knowing whether the contact interfaces are dry or wet, we can relate the trends in COF with the trends in adhesion hysteresis. For conditions where the contact interfaces have both dry and wet patches (region II), the COF values are higher than those in completely dry conditions, suggesting that a partially lubricated system can exhibit a higher COF. PMID- 29505261 TI - Using Atomic Force Microscopy to Predict Tumor Specificity of ICAM1 Antibody Directed Nanomedicines. AB - Atomic force microscopy (AFM) is a powerful tool to detect in vitro antibody antigen interactions. To date, however, AFM-measured antibody-antigen interactions have yet to be exploited to predict in vivo tumor specificity of antibody-directed nanomedicines. In this study, we have utilized AFM to directly measure the biomechanical interaction between live triple negative breast cancer (TNBC) cells and an antibody against ICAM1, a recently identified TNBC target. For the first time, we provide proof-of-principle evidence that in vitro TNBC cell-ICAM1 antibody binding force measured by AFM on live cells more precisely correlates with in vivo tumor accumulation and therapeutic efficacy of ICAM1 antibody-directed liposomes than ICAM1 gene and surface protein overexpression levels. These studies demonstrate that live cell-antibody binding force measurements may be used as a novel in vitro metric for predicting the in vivo tumor recognition of antibody-directed nanomedicines. PMID- 29505262 TI - Liquid Superlubricity of Polyethylene Glycol Aqueous Solution Achieved with Boric Acid Additive. AB - Boric acid is a weak acid and has been used as a lubrication additive because of its special structure. In this study, we report that boric acid could achieve a robust superlubricity (MU < 0.01) as an additive in polyethylene glycol (PEG) aqueous solution at the Si3N4/SiO2 interfaces. The superlow and steady friction coefficient of approximately 0.004-0.006 could be achieved with boric acid under neutral conditions (pH of approximately 6.4), which is different from the acidic conditions leading to superlubricity. The influence of various factors, including boric acid concentration, sliding speed, applied load, PEG molecular weight, and the volume of lubricant on the superlubricity, were investigated. The results reveal that the PEG aqueous solution with the boric acid additive could achieve superlubricity under a wide range of conditions. The surface composition analysis shows that the synergy effect between boric acid and PEG provides sufficient H+ ions to realize the running-in process. Moreover, a composite tribochemical film composed of silica and ammonia-containing compounds were formed on the ball surface, contributing to the superlubricity. The film thickness calculation shows that superlubricity was achieved in a mixed lubrication region, and therefore, the superlubricity state was dominated by both the composite tribochemical film formed via the tribochemical reaction on the contact surfaces and the hydrodynamic lubricating film between the contact surfaces. Such a liquid superlubricity achieved under neutral conditions is of importance for both scientific understanding and engineering applications. PMID- 29505263 TI - Making Nonsticky Surfaces of Sticky Materials: Self-Organized Microtexturing of Viscoelastic Elastomeric Layers by Tearing. AB - Fabrication of large area, multiscale microtextured surfaces engineered for antiadhesion properties remains a challenge. Compared to an elastic surface, viscoelastic solids show much higher surface stickiness, tack, and adhesion owing to the increased contact area and energy dissipation. Here, we show a simple, low cost, large-area and high throughput method with roll-to-roll compatibility to fabricate multiscale, rough microstructures resistant to adhesion in a viscoelastic layer by controlled tearing of viscous film. Even a high adhesive strength viscoelastic solid layer, such as partially cured PDMS, is made nonsticky simply by its controlled tearing. The torn surface shows a fracture induced, self-organized leaflike micropattern resistant to sticking. The topography and adhesion strength of these structures are readily tuned by changing the tearing speed and the film thickness. The microtexture displays a springlike recovery, low adhesive strength, and easy release properties even under the high applied loads. PMID- 29505264 TI - Toward Achieving Highly Ordered Fluorinated Surfaces of Spin-Coated Polymer Thin Films by Optimizing the Air/Liquid Interfacial Structure of the Casting Solutions. AB - Thin polymer films with well-assembled fluorinated groups on their surfaces are not easily achieved via spin-coating film-fabrication methods because the solution solidifies very rapidly during spin-coating, which hinders the fluorinated moieties from segregating and organizing on the film surface. In this contribution, we have proposed a comprehensive strategy toward achieving well ordered fluorinated thin films surfaces by optimizing the molecular organization at air/liquid interface of the film-formation solutions. To validate such a route, poly(methyl methacrylate) (PMMA) end-capped with several 2 perfluorooctylethyl methacrylate (FMA) units was employed as the model polymer for investigations. The air/solution interfacial structures were optimized by systematically changing the polymer chain structures and properties of the casting solvents. It was found that the polymers that form loosely associated aggregates (e.g., FMA1- ec-PMMA65- ec-FMA1) and a solvent with better solubility to FMA while having not too low surface tension (i.e., toluene) can combine to produce solutions with well-assembled FMA at the interfaces. By spin-coating the solutions with well-organized interfaces, an ultrathin film with perfluorinated groups that were highly oriented toward the film surface was readily achieved, exhibiting surface energies as low as 7.2 mJ/m2, which is among the lowest reported so far for the spin-coated thin films, and a very high F/C ratio (i.e., 0.98). PMID- 29505265 TI - Single Ag Nanoparticle Electro-oxidation: Potential-Dependent Current Traces and Potential-Independent Electron Transfer Kinetic. AB - Potential-dependent current traces were first observed for the same sized nanoparticles (NPs) during the dynamic electro-oxidation process of single AgNPs. In this work, we demonstrated that the motion trajectories of NPs, coupled with electrochemical kinetics parameters, qualitatively predicted from the series of the experimentally observed current traces obtained single AgNPs collision behaviors. Based on the Poisson-Boltzmann equation for a general electrochemical reaction, a rate constant of Ag oxidation could be further estimated to be 1 * 10 6 mol.cm-2.s-1 for electron transfer between AgNPs and the Au electrode by comparing the experimental results. Our method provided a meaningful attempt to test electron transfer kinetics and motion behaviors of single NPs using the high resolution electrochemical signal. PMID- 29505266 TI - Systematic Protein Prioritization for Targeted Proteomics Studies through Literature Mining. AB - There are more than 3.7 million published articles on the biological functions or disease implications of proteins, constituting an important resource of proteomics knowledge. However, it is difficult to summarize the millions of proteomics findings in the literature manually and quantify their relevance to the biology and diseases of interest. We developed a fully automated bioinformatics framework to identify and prioritize proteins associated with any biological entity. We used the 22 targeted areas of the Biology/Disease-driven (B/D)-Human Proteome Project (HPP) as examples, prioritized the relevant proteins through their Protein Universal Reference Publication-Originated Search Engine (PURPOSE) scores, validated the relevance of the score by comparing the protein prioritization results with a curated database, computed the scores of proteins across the topics of B/D-HPP, and characterized the top proteins in the common model organisms. We further extended the bioinformatics workflow to identify the relevant proteins in all organ systems and human diseases and deployed a cloud based tool to prioritize proteins related to any custom search terms in real time. Our tool can facilitate the prioritization of proteins for any organ system or disease of interest and can contribute to the development of targeted proteomic studies for precision medicine. PMID- 29505267 TI - Direct Selection of Fluorescence-Enhancing RNA Aptamers. AB - RNA aptamers that generate a strong fluorescence signal upon binding a nonfluorescent small-molecule dye offer a powerful means for the selective imaging of individual RNA species. Unfortunately, conventional in vitro discovery methods are not efficient at generating such fluorescence-enhancing aptamers, because they primarily exert selective pressure based on target affinity-a characteristic that correlates poorly with fluorescence enhancement. Thus, only a handful of fluorescence-enhancing aptamers have been reported to date. In this work, we describe a method for converting DNA libraries into "gene-linked RNA aptamer particles" (GRAPs) that each display ~105 copies of a single RNA sequence alongside the DNA that encodes it. We then screen large libraries of GRAPs in a high-throughput manner using the FACS instrument based directly on their fluorescence-enhancing properties. Using this strategy, we demonstrate the capability to generate fluorescence-enhancing aptamers that produce a variety of different emission wavelengths upon binding the dye of interest. PMID- 29505268 TI - Effect of Solids Retention Time on Effluent Dissolved Organic Nitrogen in the Activated Sludge Process: Studies on Bioavailability, Fluorescent Components, and Molecular Characteristics. AB - Wastewater-derived dissolved organic nitrogen (DON) should be minimized by municipal wastewater treatment plants (MWWTPs) to reduce its potential impact on receiving waters. Solids retention time (SRT) is a key control parameter for the activated sludge (AS) process; however, knowledge of its impact on effluent DON is limited. This study investigated the effect of SRT on the bioavailability, fluorescent components, and molecular characteristics of effluent DON in the AS process. Four lab-scale AS reactors were operated in parallel at different SRTs (5, 13, 26, and 40 days) for treatment of primary treated wastewater collected from an MWWTP. Results showed the positive effect of prolonged SRT on DON removal. AS reactors during longer SRTs, however, cannot sequester the bioavailable DON (ABDON) and occasionally contribute to greater amounts of ABDON in the effluents. Consequently, effluent DON bioavailability increased with SRT ( R2 = 0.619, p < 0.05, ANOVA). Analysis of effluent DON fluorescent components and molecular characteristics indicated that the high effluent DON bioavailability observed at long SRTs is contributed by the production of microbially derived nitrogenous organics. The results presented herein indicate that operating an AS process with a longer SRT cannot control the DON forms that readily stimulate algal growth. PMID- 29505269 TI - Reply to Fernandez Perez: Diagnostic Decision-Making in Hypersensitivity Pneumonitis: Toward a Consensus Statement. PMID- 29505270 TI - A Rare Hemodynamic Cause of Airway Obstruction. PMID- 29505271 TI - Diagnostic Decision-Making in Hypersensitivity Pneumonitis: Toward a Consensus Statement. PMID- 29505272 TI - Does the Tempo of Music Impact Human Behavior Behind the Wheel? AB - OBJECTIVE: Assess the influence of background music tempo on driving performance. BACKGROUND: Music with a fast tempo is known to increase the level of arousal, whereas the reverse is observed for slow music. The relationship between driving performance and level of arousal was expected to take the form of an inverted U curve. METHOD: Three experiments were undertaken to manipulate the musical background during driving. In Experiment 1, the driver's preferred music track played at its original and modified (plus or minus 30%) tempo were used together with the simple ticking of a metronome. In Experiment 2, music tracks of different tempos were played during driving. In Experiment 3, music tracks were categorized as arousing or relaxing based on the associated perceived level of arousal. RESULTS: Listening to music tended to influence drivers' performances in a car-following task by improving coherence and gain adjustments relative to the followed vehicle but simultaneously shortened the intervehicular time. Although the tempo of the music per se did not directly affect driving behavior, arousing music tracks improved drivers' adjustments to the followed vehicle (Experiment 3). CONCLUSION: The tempo of the music listened to behind the wheel was not found to influence driving behaviors. However, arousing music improved drivers' responsiveness to changes in the speed of the followed vehicle. However, this benefit was canceled out by a reduction in the drivers' intervehicle safety margin. APPLICATION: Listening to arousing music while driving cannot be considered to improve road safety, at least in a car-following task without attentional impairments. PMID- 29505275 TI - Identifying Potential Mass Shooters and Suicide Terrorists With Warning Signs of Suicide, Perceived Victimization, and Desires for Attention or Fame. AB - In the United States and Europe, the distinction between public mass shooters and suicide terrorists no longer seems particularly meaningful. A number of public mass shooters have considered using bombs and claimed to be sacrificing themselves for an ideological cause, and many suicide terrorists have attacked without organizational support, using firearms, for what appear to be largely personal reasons. Previous research has also documented several common factors in these offenders' lives, including (a) suicidal motives and life indifference, (b) perceived victimization, and (c) desires for attention or fame. These factors are not always easy for observers to recognize in advance, so mental health professionals, the public, and law enforcement officials might need help from experts to more successfully identify at-risk individuals. This article reviews the evidence of each factor, provides a list of specific warning signs, and offers recommendations for future research. Ultimately, an evidence-based approach to prevention could help save both the lives of many potential victims and the lives of the would-be attackers themselves. PMID- 29505276 TI - Stereotype Deduction About Bisexual Women. AB - Bisexuals are an invisible sexual minority. However, at the same time, bisexuals are stereotypically associated with confusion and promiscuity. Stereotype learning theories suggest that individuals who are unfamiliar with a social group are less likely to have stereotypical beliefs about its members. In contrast, it has been recently hypothesized that stereotypes about bisexuality are not necessarily learned but rather deduced based on common conceptualizations of sexuality. Because stereotypes are suppressed only if they are recognized as offensive, lack of knowledge regarding bisexual stereotypes should actually enhance their adoption. To assess the strength of the two competing accounts, we examined the relationship between explicit knowledge of bisexual stereotypes and stereotypical evaluation of bisexual individuals. Heterosexual participants (N = 261) read a description of two characters on a date and evaluated one of them. Bisexual women were evaluated as more confused and promiscuous relative to nonbisexual women. Moreover, the stereotypical evaluations of bisexual women were inversely related to knowledge about these stereotypes. The findings support the notion that bisexual stereotypes are not learned but rather deduced from shared assumptions about sexuality. Consequently, public invisibility not only exists alongside bisexual stereotypes but might also exacerbate their uninhibited adoption. PMID- 29505280 TI - Reply to Fernandez Perez: Diagnostic Decision-Making in Hypersensitivity Pneumonitis: Toward a Consensus Statement. PMID- 29505281 TI - Genome-wide identification and analysis of elongase of very long chain fatty acid genes in the silkworm, Bombyx mori. AB - Very long chain fatty acids (VLCFAs), such as sphingolipids, are components of cellular lipids, which are essential for cell proliferation. Mutations in the genes that encode proteins participating in VLCFA biosynthesis may cause inherited diseases, such as macular degeneration. Elongases of very long chain fatty acid (ELOVL) are enzymes that are involved in the biosynthesis of VLCFAs. Here, a total of 13 ELOVL genes, distributed across three chromosomes, were identified in the silkworm genome; all the ELOVL members contain a distinct ELO domain and a conserved HXXHH motif. Phylogenetic reconstruction was performed to analyze the evolutionary relationships among different species and to predict gene functions. The 13 ELOVL genes were assigned to the ELOVL3/6, ELOVL1/7, and ELOVL4 clades. Microarray and semiquantitative PCR analyses indicated that these genes are differentially expressed among various tissues, in turn suggesting functional divergence in the growth and development of each tissue. Further investigation showed that the expression level of the BGIBMGA000424 gene is significantly negatively correlated with the cocoon-shell weight among different silkworm strains. Taken together, the present study is the first comprehensive analysis of ELOVL genes in silkworm, and the results may serve as a foundation for further analysis of the physiological functions of ELOVL genes in silkworm. PMID- 29505282 TI - It's not that Difficult: An Interrater Reliability Study of the DSM-5 Section III Alternative Model for Personality Disorders. AB - The Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2013 ) Section III Alternative Model for Personality Disorders (AMPD) represents a novel approach to the diagnosis of personality disorder (PD). In this model, PD diagnosis requires evaluation of level of impairment in personality functioning (Criterion A) and characterization by pathological traits (Criterion B). Questions about clinical utility, complexity, and difficulty in learning and using the AMPD have been expressed in recent scholarly literature. We examined the learnability, interrater reliability, and clinical utility of the AMPD using a vignette methodology and graduate student raters. Results showed that student clinicians can learn Criterion A of the AMPD to a high level of interrater reliability and agreement with expert ratings. Interrater reliability of the 25 trait facets of the AMPD varied but showed overall acceptable levels of agreement. Examination of severity indexes of PD impairment showed the level of personality functioning (LPF) added information beyond that of global assessment of functioning (GAF). Clinical utility ratings were generally strong. The satisfactory interrater reliability of components of the AMPD indicates the model, including the LPF, is very learnable. PMID- 29505283 TI - South African Men Who Have Sex With Both Men and Women and How They Differ From Men Who Have Sex With Men Exclusively. AB - The label "men who have sex with men" (MSM) is used to categorize a diverse population exclusively on the basis of its sexual behavior. Understanding the diversity that this label comprises is critical for the development of health interventions that effectively reach the various populations subsumed under this label. In this cross-sectional study of South African MSM (N = 480) recruited through respondent-driven sampling (RDS), we explored differences between men who had sex with both men and women (MSMW) and men who had sex with men exclusively (MSME). We found significant differences between these two groups in terms of sexual attraction, sexual identity, sexual preferences, sexual histories, and current sexual practices. MSMW were more likely to be confused about their same sex attraction, to experience internalized homophobia, and to have paid for sex in the previous year, while MSME were more gender nonconforming and more likely to have been forced to have sex in the previous year. These findings underscore that the MSM label comprises a diverse population and that exclusive sexual engagement with other men is a critical distinction to take into account in understanding this diversity and fully grasping the lived experiences of men who have sex with men. PMID- 29505286 TI - Effects of Resolution, Range, and Image Contrast on Target Acquisition Performance. AB - OBJECTIVE: We sought to determine the joint influence of resolution, target range, and image contrast on the detection and identification of targets in simulated naturalistic scenes. BACKGROUND: Resolution requirements for target acquisition have been developed based on threshold values obtained using imaging systems, when target range was fixed, and image characteristics were determined by the system. Subsequent work has examined the influence of factors like target range and image contrast on target acquisition. METHOD: We varied the resolution and contrast of static images in two experiments. Participants (soldiers) decided whether a human target was located in the scene (detection task) or whether a target was friendly or hostile (identification task). Target range was also varied (50-400 m). In Experiment 1, 30 participants saw color images with a single target exemplar. In Experiment 2, another 30 participants saw monochrome images containing different target exemplars. RESULTS: The effects of target range and image contrast were qualitatively different above and below 6 pixels per meter of target for both tasks in both experiments. CONCLUSION: Target detection and identification performance were a joint function of image resolution, range, and contrast for both color and monochrome images. APPLICATION: The beneficial effects of increasing resolution for target acquisition performance are greater for closer (larger) targets. PMID- 29505298 TI - Response. PMID- 29505294 TI - Assessing Level of Personality Organization With the Psychodiagnostic Chart: A Validity Study. AB - Heterogeneity within diagnostic types and comorbidity across diagnostic groups render a specific personality disorder anything but specific, leading researchers and clinicians to increasingly focus on the general severity of personality pathology. Personality pathology severity is reflected in one's level of personality organization (LPO) and research has demonstrated that LPO is a significant predictor of treatment response. This investigation examined the reliability and validity of the Psychodiagnostic Chart (PDC) in assessing the LPO dimension of the Psychodynamic Diagnostic Manual (PDM; PDM Task Force, 2006). Among a sample of 88 urban-dwelling women seeking primary medical care, the LPO dimension of the PDC received fair to good interrater reliability among 6 psychodynamic psychologists. Convergent validity was demonstrated with contrast analysis and individual correlations that yielded statistically significant associations between LPO scores and conceptually related psychodynamic variables (e.g., defensive functioning, object relations) and self-reported personality pathology scores. Support for discriminant validity was limited by the modest power associated with the sample size. Exploratory analyses examining LPO scores and measures of physical health and intimate partner violence were conducted. Our results supported the reliability, validity, and practical use of the LPO dimension of the PDC. PMID- 29505299 TI - Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients. AB - Multiple sclerosis (MS) is an autoimmune pathology leading to neurodegeneration. Because of the complexity and heterogenic etiology of this disease, diagnosis and treatment for individual patients are challenging. Exosome-associated microRNAs (miRNAs) have recently emerged as a new class of diagnostic biomarkers involved in both autoimmune and neurologic disorders. Interesting new evidence has emerged showing that circulating miRNAs are dysregulated in MS body fluids, including serum, plasma, and cerebrospinal fluid. We hypothesized that exosome-associated miRNAs could present a readily accessible blood-based assay for MS disease. We detected expression of miRNAs by quantitative PCR on a small cohort of MS patients. We analyzed circulating exosome-associated miRNAs of MS patients before and after therapy and found that 14 exosome-associated miRNAs were significantly down-regulated, while 2 exosome-associated miRNAs were significantly up-regulated in IFN-beta-treated relapsing-remitting MS patients with response to therapy compared to those without response. We identified a serum miRNA panel that could be used to monitor the response to IFN-beta therapy. Overall, these data suggest that circulating exosome-associated miRNA profiling could represent an easily detectable biomarker of disease and treatment response.-Manna, I., Iaccino, E., Dattilo, V., Barone, S., Vecchio, E., Mimmi, S., Filippelli, E., Demonte, G., Polidoro, S., Granata, A., Scannapieco, S., Quinto, I., Valentino, P., Quattrone, A. Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients. PMID- 29505300 TI - The fifth subunit in alpha3beta4 nicotinic receptor is more than an accessory subunit. AB - The alpha3beta4 subtype is the predominant neuronal nicotinic acetylcholine receptor present in the sensory and autonomic ganglia and in a subpopulation of brain neurons. This subtype can form pentameric receptors with either 2 or 3 beta4 subunits that have different pharmacologic and functional properties. To further investigate the role of the fifth subunit, we coexpressed a dimeric construct coding for a single polypeptide containing the beta4 and alpha3 subunit sequences, with different monomeric subunits. With this strategy, which allowed the formation of single populations of receptors with unique stoichiometry, we demonstrated with immunofluorescence and biochemical and functional assays that only the receptors with 3 beta4 subunits are efficiently expressed at the plasma membrane. Moreover, the LFM export motif of beta4 subunit in the fifth position exerts a unique function in the regulation of the intracellular trafficking of the receptors, their exposure at the cell surface, and consequently, their function, whereas the same export motif present in the beta4 subunits forming the acetylcholine binding site is dispensable.-Crespi, A., Plutino, S., Sciaccaluga, M., Righi, M., Borgese, N., Fucile, S., Gotti, C., Colombo, S. F. The fifth subunit in alpha3beta4 nicotinic receptor is more than an accessory subunit. PMID- 29505301 TI - NEDD4L limits cAMP signaling through ubiquitination of CREB-regulated transcription coactivator 3. AB - The transcription factor cAMP-responsive element-binding protein (CREB) is involved in a variety of physiologic processes. Although its activity appears to be largely correlated with its phosphorylation status, cAMP-mediated dephosphorylation and the subsequent nuclear migration of the CREB-regulated transcription factors (CRTCs) are required to stimulate CREB transcriptional activity. Among the 3 identified mammalian homologs of CRTCs, CRTC3 has been shown to be expressed predominantly in adipose tissues in response to catecholamine signals that regulate lipid metabolism. Here, we show that prolonged cAMP signaling down-regulates CRTC3 in a proteasome-dependent manner and that neural precursor cell-expressed developmentally down-regulated gene 4 like (NEDD4L), a specific ubiquitin ligase for CRTC3, is responsible for this process. By recognizing the PY motif of CRTC3, NEDD4L interacts with CRTC3 and promotes its polyubiquitination. Interaction between NEDD4L and CRTC3 is further boosted by cAMP signaling, and this enhanced interaction appears to be dependent on the cAMP-mediated phosphorylation of NEDD4L at the Ser448 site. Furthermore, we show that food withdrawal stimulates NEDD4L phosphorylation in mice, which then show a decrease of adipose tissue CRTC3 protein levels. Together, these results suggest that NEDD4L plays a key role in the feedback regulation of cAMP signaling by limiting CRTC3 protein levels.-Kim, Y.-H., Yoo, H., Hong, A.-R., Kwon, M., Kang, S.-W., Kim, K., Song, Y. NEDD4L limits cAMP signaling through ubiquitination of CREB-regulated transcription coactivator 3. PMID- 29505302 TI - AMPK/GSK3beta/beta-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming. AB - Prostate cancer (PCa) represents one of the most common solid neoplasms, and metastasis is the second leading cause of death in adult males. Anoikis is a programmed cell death that is induced upon cell detachment from the extracellular matrix (ECM), which behaves as a critical protective mechanism for anchorage independent cell growth and metastasis formation. However, in the absence of ECM attachment, shift of metabolic pattern and tolerance to anoikis facilitate the survival of aggressive cancer cells in the circulatory system as well as their metastasis to distant sites. Few molecular targets in PCa have thus far been reported to prevent anoikis resistance, metabolic reprogramming, and metastasis simultaneously. In the present study, elevated migration, invasion, pyruvate production, lactate generation, ATP level, and impaired detachment-induced apoptosis were found in anoikis-resistant PCa cells, and genome microarray analysis demonstrated that the cell migration-inducing protein (CEMIP) was a potential molecular target for the regulation of the aforementioned malignant behaviors. Additional investigation revealed that the AMPK/glycogen synthase kinase 3beta (GSK3beta)/beta-catenin cascade-triggered CEMIP overexpression in anoikis-resistant PCa cells might be implicated in local progression, metabolic shift, and cellular migration and invasion, whereas knockout of CEMIP by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 in anoikis-resistant PCa cells reversed the described bioeffects by reducing expressions of matrix metalloproteinase 2 (MMP2), VEGF, pyruvate dehydrogenase kinase isoform 4 (PDK4), and lactate dehydrogenase A. In addition, inhibition of glycolysis by CEMIP-mediated PDK4 down-regulation impaired the migration and invasion of anoikis-resistant PCa cells by attenuating MMP2 and VEGF expressions. Our findings establish that AMPK/GSK3beta/beta-catenin cascade-triggered CEMIP overexpression might promote migration and invasion in anoikis-resistant PCa cells by enhancing PDK4-associated metabolic reprogramming, which may provide a novel, promising therapeutic target for the treatment of advanced PCa.-Zhang, P., Song, Y., Sun, Y., Li, X., Chen, L., Yang, L., Xing, Y. AMPK/GSK3beta/beta-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming. PMID- 29505303 TI - Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. AB - Most general anesthetics enhance GABA type A (GABAA) receptor activity at clinically relevant concentrations. Sites of action of volatile anesthetics on the GABAA receptor remain unknown, whereas sites of action of many intravenous anesthetics have been identified in GABAA receptors by using photolabeling. Here, we used photoactivatable analogs of isoflurane (AziISO) and sevoflurane (AziSEVO) to locate their sites on alpha1beta3gamma2L and alpha1beta3 GABAA receptors. As with isoflurane and sevoflurane, AziISO and AziSEVO enhanced the currents elicited by GABA. AziISO and AziSEVO each labeled 10 residues in alpha1beta3 receptors and 9 and 8 residues, respectively, in alpha1beta3gamma2L receptors. Photolabeled residues were concentrated in transmembrane domains and located in either subunit interfaces or in the interface between the extracellular domain and the transmembrane domain. The majority of these transmembrane residues were protected from photolabeling with the addition of excess parent anesthetic, which indicated specificity. Binding sites were primarily located within alpha+/beta- and beta+/alpha- subunit interfaces, but residues in the alpha+/gamma- interface were also identified, which provided a basis for differential receptor subtype sensitivity. Isoflurane and sevoflurane did not always share binding sites, which suggests an unexpected degree of selectivity.-Woll, K. A., Zhou, X., Bhanu, N. V., Garcia, B. A., Covarrubias, M., Miller, K. W., Eckenhoff, R. G. Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. PMID- 29505304 TI - Decision to Return to Sport After Anterior Cruciate Ligament Reconstruction, Part I: A Qualitative Investigation of Psychosocial Factors. AB - CONTEXT: Return-to-sport criteria after anterior cruciate ligament (ACL) injury are often based on "satisfactory" functional and patient-reported outcomes. However, an individual's decision to return to sport is likely multifactorial; psychological and physical readiness to return may not be synonymous. OBJECTIVE: To determine the psychosocial factors that influence the decision to return to sport in athletes 1 year post-ACL reconstruction (ACLR). DESIGN: Qualitative study. SETTING: Academic medical center. PATIENTS OR OTHER PARTICIPANTS: Twelve participants (6 males, 6 females) were purposefully chosen from a large cohort. Participants were a minimum of 1-year postsurgery and had been active in competitive athletics preinjury. DATA COLLECTION AND ANALYSIS: Data were collected via semistructured interviews. Qualitative analysis using a descriptive phenomenologic process, horizontalization, was used to derive categories and themes that represented the data. The dynamic-biopsychosocial model was used as a theoretical framework to guide this study. RESULTS: Six predominant themes emerged that described the participants' experiences after ACLR: (1) hesitation and lack of confidence led to self-limiting tendencies, (2) awareness was heightened after ACLR, (3) expectations and assumptions about the recovery process influenced the decision to return to sport after ACLR, (4) coming to terms with ACL injury led to a reprioritization, (5) athletic participation helped reinforce intrinsic personal characteristics, and (6) having a strong support system both in and out of rehabilitation was a key factor in building a patient's confidence. We placed themes into components of the dynamic biopsychosocial model to better understand how they influenced the return to sport. CONCLUSIONS: After ACLR, the decision to return to sport was largely influenced by psychosocial factors. Factors including hesitancy, lack of confidence, and fear of reinjury are directly related to knee function and have the potential to be addressed in the rehabilitation setting. Other factors, such as changes in priorities or expectations, may be independent of physical function but remain relevant to the patient-clinician relationship and should be considered during postoperative rehabilitation. PMID- 29505308 TI - Verbal and visual cognition: Individual differences in the lab, in the brain, and in the classroom. AB - In many ways, individuals vary in their thought processes, and in their cognitive strengths and weaknesses. Among the findings revealed by individual differences research, one major dividing line highlighted recurrently by decades of experimental studies is that between linguistically-mediated cognitive operations (verbal cognition), versus cognition, which primarily operates on visual - or visuospatial - representations (visual cognition). In this article, we review findings from three research areas-cognitive abilities, working memory, and task strategies-focusing on individual differences in verbal and visual cognition. In each area we highlight behavioral, neuroimaging, and classroom-based findings, bridging the perspectives of these different methodologies. PMID- 29505309 TI - What gestures reveal about cognitive deficits in Williams Syndrome. AB - Gestures have a central role in speaking and thinking about spatial information. The goal of the present study is to examine the function of gestures in Williams Syndrome (WS), a genetic disorder characterized by spatial impairments and a preservation of communication. The study's subjects were 11 WS individuals and 22 typically-developing controls who performed a narrative task. We analyzed offline gesture production and its relation with language and spatial information. Compared to the control groups, WS individuals produced more representational gestures that anticipated, supplemented, or gesture-only communication. Gestures produced by WS participants serve a compensatory role particularly in representing spatial contents. PMID- 29505310 TI - Intradermal tranexamic acid injections to prevent post-inflammatory hyperpigmentation after solar lentigo removal with a Q-switched 532-nm Nd:YAG laser. AB - INTRODUCTION: Post-inflammatory hyperpigmentation (PIH) after solar lentigo removal using a Q-switched (QS) 532-nm Nd:YAG laser is a cause for concern. This study aimed to evaluate the efficacy and safety of intradermal injections of tranexamic acid (TA) at reducing the risk of PIH after QS 532-nm Nd:YAG laser treatment of solar lentigines. METHODS: Twenty-five patients with 50 solar lentigines on forearms underwent QS 532-nm Nd:YAG laser treatment. Then, TA (50 mg/mL) was injected randomly into one lesion and 0.9% normal saline was injected intradermally into another lesion. Two blinded dermatologists and a Mexameter(r) evaluated photographs at baseline, and at weeks 2, 4, 8, and 12. RESULTS: At the end of the study, the mean melanin index (MI) had decreased significantly in both groups. The TA group showed a significant reduction in the mean MI compared with that in the control group at week 4 (p = 0.025). The overall PIH rates were 16% and 28% in the TA and control groups, respectively. The side effects of TA were minimal and they were resolved within 1 h. CONCLUSION: Single dose of intradermal TA (50 mg/mL) injected can reduce the risk of developing PIH 4 weeks after 532-nm QS Nd:YAG laser treatment of solar lentigines. PMID- 29505311 TI - Modeling Nonstationary Emotion Dynamics in Dyads using a Time-Varying Vector Autoregressive Model. AB - Emotion dynamics are likely to arise in an interpersonal context. Standard methods to study emotions in interpersonal interaction are limited because stationarity is assumed. This means that the dynamics, for example, time-lagged relations, are invariant across time periods. However, this is generally an unrealistic assumption. Whether caused by an external (e.g., divorce) or an internal (e.g., rumination) event, emotion dynamics are prone to change. The semi parametric time-varying vector-autoregressive (TV-VAR) model is based on well studied generalized additive models, implemented in the software R. The TV-VAR can explicitly model changes in temporal dependency without pre-existing knowledge about the nature of change. A simulation study is presented, showing that the TV-VAR model is superior to the standard time-invariant VAR model when the dynamics change over time. The TV-VAR model is applied to empirical data on daily feelings of positive affect (PA) from a single couple. Our analyses indicate reliable changes in the male's emotion dynamics over time, but not in the female's-which were not predicted by her own affect or that of her partner. This application illustrates the usefulness of using a TV-VAR model to detect changes in the dynamics in a system. PMID- 29505312 TI - Reprogramming the virulence: Insect defense molecules navigating the epigenetic landscape of Metarhizium robertsii. AB - Metarhizium species are the leading bio-control agents well characterized regarding pathogenicity to agricultural, forest, public health, stored grains and urban insect pests. They infect the target host through the tight conidial adherence with the insect cuticle. Conidial binding to the insect cuticle drive the systematic integrated disease development events in target host to impart pathogenesis. However, there is growing evidence that virulence of the pathogen is directly related with proteolytic enzymes including metalloproteinases, chymotrypsin-like proteinases and subtilisin-like proteinases. Successful host pathogenesis is the selection of right set of virulence-related proteinases, which evolved as a result of host-pathogen coevolution. PMID- 29505313 TI - Pharmacological management of late-onset hypogonadism. AB - INTRODUCTION: The frequency of late-onset hypogonadism (LOH) ranges between 2 and 15%. Up to 85% of LOH is due to a functional impairment of the hypothalamus pituitary-testicular axis, mostly secondary to metabolic conditions. Areas covered: This paper provides a comprehensive review of all the available medications for treating LOH, including antiestrogens, gonadotropins and testosterone therapy (TTh). In addition, the evidence on clinical outcomes of these treatments is provided by meta-analyzing the results from the available randomized clinical trials. Expert commentary: The present data indicate that antiestrogens are able to increase testosterone levels without changing gonadotropins or even increasing them. Therefore, they may maintain, and even to stimulate spermatogenesis. However, their efficacy in treating LOH-associated symptoms has been scarcely tested and their use in LOH is off-label. In contrast, gonadotropins are indicated for hypogonadism, in particular when fertility is required. Information on the effects of gonadotropins on LOH is scanty and the impractical administration limits their use. TTh can be administered with different modalities, making it a suitable option for LOH, when fertility is not desired. The available meta-analyses show that TTh is able to improve sexual function and body composition, with more evident results obtained with transdermal and injectable preparations. PMID- 29505314 TI - Neuroprotection of Transplanting Human Umbilical Cord Mesenchymal Stem Cells in a Microbead Induced Ocular Hypertension Rat Model. AB - PURPOSE: The purpose of this study is to investigate the potential therapeutic benefits of intravitreally transplanted human umbilical cord mesenchymal stem cells (UC-MSCs) in an animal model of microbead-injection-induced ocular hypertension (OHT). METHODS: UC-MSCs were isolated from human umbilical cords and then cultured. The OHT model was induced via intracameral injection of polystyrene microbeads in Sprague-Dawley adult rat eyes. Fifty-four healthy adult rats were randomly divided into three groups: normal control, OHT model treated with intravitreal transplantation of UC-MSCs, or phosphate-buffered saline (PBS). Two days after OHT was induced, either 5 ul 105 UC-MSCs suspension or PBS was injected into the vitreous cavity of rats. UC-MSCs localization and integration were examined via immunohistochemistry. Neuroprotection was quantified by counting retinal ganglion cells (RGCs) and axons 2 weeks following transplantation. The expression levels of glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) were assessed via immunohistochemistry and Western blot. Functional recovery was assessed 2 weeks after transplantation via scotopic threshold response (STR) electroretinography. RESULTS: Elevated IOP levels were sustained at least 3 weeks after intracameral microbead injection and the number of beta-III-tubulin+ RGCs significantly declined compared to PBS-injected eyes. UC-MSCs survived for at least 2 weeks after intravitreal transplantation and predominantly located in the vitreous cavity. A fraction of cells migrated into the ganglion cell layer of host retina, but without differentiation. Intravitreal UC-MSC transplantation resulted in increased number of RGCs, axons, and increased expression of GDNF and BDNF but decreased expression of GFAP. Intravitreal delivery of UC-MSCs significantly improved the recovery of the positive STR. CONCLUSIONS: Intravitreal transplantation of UC-MSCs revealed the neuroprotection in the microbead-injection induced OHT. The effects could be related to the secretion of tropic factors (BDNF and GDNF) and the modulation of glial cell activation. PMID- 29505315 TI - A putative role for Discoidin Domain Receptor 1 in cancer chemoresistance. AB - The Discoidin Domain Receptor 1 (DDR1) receptor tyrosine kinase performs pleiotropic functions in the control of cell adhesion, proliferation, survival, migration, and invasion. Aberrant DDR1 function as a consequence of either mutations or increased expression has been associated with various human diseases including cancer. Pharmacological inhibition of DDR1 results in significant therapeutic benefit in several pre-clinical cancer models. Here, we discuss the potential implication of DDR1-dependent pro-survival functions in the development of cancer resistance to chemotherapeutic regimens and speculate on the molecular mechanisms that might mediate such important feature. PMID- 29505316 TI - Nurses' Experiences in using Physical Activity as Complementary Treatment in Patients with Schizophrenia. AB - INTRODUCTION: Schizophrenia is a common disease with a high risk of comorbidity in both psychiatric and somatic diseases. Physical activity is proven effective in reducing symptoms of schizophrenia and increasing overall health. Still it is not used systematically in the care of persons with schizophrenia. AIM: The aim of this study is to describe nurses' experience, including personal motivation, in using physical activity as complementary treatment in patients with schizophrenia. METHOD: Interviews in three focus groups with 12 participating nurses were conducted. Qualitative content analysis was used to analyze data. RESULTS: Physical activity was commonly used. Although several nurses signaled positive patient response, i.e. less anxiety and better quality of sleep, the overall consensus was an uncertainty regarding the benefits. It was perceived as non-evidence based form of intervention. CONCLUSION: The uncertainty of the benefits of physical activity is evident in nursing staff and poses a resistance to implement systematic physical activity as a complementary treatment in schizophrenia. A new awareness of evidence based nursing is suggested to promote a wider and more receptive attitude to reduce patient vulnerability in persons with schizophrenia. PMID- 29505317 TI - Genital warts treatment: Beyond imiquimod. AB - Genital warts are one of the most common sexually transmitted diseases worldwide. The disease is a result of infection with low-risk types of human papillomaviruses, mostly type 6 and 11. Current therapies for genital warts are mainly ablative, or alternatively topical application of imiquimod cream and sinecatechin (polyphenon E) ointment to the warts. However, low patient compliance and high recurrence rate are significant problems for the treatment of genital warts by imiquimod and ablative therapies. We summarise recent literature in this area and propose combining imiquimod with other therapies to increase the efficacy of imiquimod. PMID- 29505318 TI - A safety comparison of LABA+LAMA vs LABA+ICS combination therapy for COPD. AB - INTRODUCTION: LABA+LAMA and LABA+ICS combinations are key pharmacological approaches to the treatment of COPD. However, both combination types can induce adverse events (AEs). Areas covered: Current literature on LABA+LAMA and LABA+ICS combinations has been reviewed with a specific focus on their safety profile in the treatment of COPD. Expert opinion: Several meta-analyses have compared the pooled safety data from randomized clinical trials (RCTs) of LABA+LAMA combinations with LABA+ICS combinations. LABA+LAMA caused significantly less AEs and SAEs. However, this evidence in real life is less solid because of the lack of appropriate studies. A statistically significant reduction in the risk for pneumonia with LABA+LAMA compared with LABA+ICS has been repeatedly documented by various meta-analyses. The meta-analytic signal indicates that an equal number of patients would die or have cardiac SAEs on LABA+LAMA or LABA+ICS, and in an observational, real-life study the LABA+LAMA combination had similar or lower risk of these events in comparison to LABA+ICS. Nonetheless, since RCTs are conducted under widely varying conditions and, consequently, AE rates of a drug observed in a RCT cannot be directly compared with rates in the RCTs of another drug and may not reflect the rates observed in practice, we need more specific data. PMID- 29505319 TI - Mild Traumatic Brain Injury and Aggression, Impulsivity, and History of Other- and Self-Directed Aggression. AB - Mild traumatic brain injury (mTBI) is highly prevalent, with an estimated occurrence in the United States of more than 1.3 million per year. While one consequence of mTBI is impulsive aggressive behavior, very few studies have examined the relationship between history of mTBI and aggressive behavior in impulsively aggressive individuals. The authors examined the relationship between history of mTBI in a healthy control group (HC; N=453), a control group with psychiatric disorders (PC; N=486), and individuals with intermittent explosive disorder (IED; N=695), a disorder of primary impulsive aggression. Results demonstrated that IED study participants were significantly more likely to have a history of mTBI (with or without history of a brief loss of consciousness [LOC]) compared with both HC and PC participants. A similar observation was made with regard to self-directed aggression (i.e., suicidal or self-injurious behavior), although group differences were only among those with mTBI with LOC. For both other- and self-directed aggression variables, the authors observed a stepwise increase in dimensional aggression and impulsivity scores across participants as a function of mTBI history. Given that impulsive aggressive behavior begins very early in life, these data are consistent with the hypothesis that lifelong presence of an impulsive aggressive temperament places impulsive aggressive individuals in circumstances that put them at greater risk for mTBI compared with other individuals with and without nonimpulsive aggressive psychopathology. PMID- 29505320 TI - Pseudobulbar Affect Correlates With Mood Symptoms in Parkinsonian Disorders but Not Amyotrophic Lateral Sclerosis. AB - Pseudobulbar affect (PBA) is a syndrome of affective disturbance associated with inappropriate laughter and crying, independent of mood. PBA is common in amyotrophic lateral sclerosis (ALS) and increasingly recognized in Parkinson's disease (PD) and atypical parkinsonism (aP). Correlates of PBA have not been systematically studied. The purpose of this study was to determine whether cognitive and psychiatric comorbidities correlated with patient-reported symptoms of PBA by using the Center for Neurological Study-Lability Scale among patients with ALS, PD, and aP. A total of 108 patients (PD, N=53; aP, N=29; ALS, N=26) completed a cognitive screener and self-reported measures of lability, depression, anxiety, apathy, and quality of life. Statistical analyses included one- and two-way analyses of covariance to evaluate group differences, Pearson's correlations to determine relationships between PBA symptoms and comorbidities, multiple regression for predicting PBA symptom severity in clinical correlates, and chi-square t tests for predicting demographic variables. PBA symptom severity did not vary between the three groups. Younger age and worse anxiety correlated with PBA symptom severity in all three groups, whereas depression and poor mental health/quality of life only correlated with PBA symptom severity in the PD and aP groups. PD and aP patients may be more likely to benefit from treatment with antidepressants. Increased PBA symptoms were associated with declines in cognitive functioning in the aP group, but sufficient numbers of PD and ALS patients with cognitive dysfunction may not have been recruited. The results suggest the possibility of an alternate pathophysiologic mechanism for PBA, which may vary between neurological disorders and disease progression. Mood and cognition are of particular relevance and should be evaluated when symptoms of PBA are suspected. PMID- 29505321 TI - Functional measures show improvements after a home exercise program following supervised balance training in older adults with elevated fall risk. AB - Supervised balance training shows immediate benefit for older adults at fall risk. The long-term effectiveness of such training can be enhanced by implementing a safe and simple home exercise program (HEP). We investigated the effects of a12-week unsupervised HEP following supervised clinic-based balance training on functional mobility, balance, fall risk, and gait. Six older adults with an elevated fall risk obtained an HEP and comprised the HEP group (HEPG) and five older adults who were not given an HEP comprised the no HEP group (NoHEPG). The HEP consisted of three static balance exercises: feet-together, single-leg stance, and tandem. Each exercise was to be performed twice for 30-60 s, once per day, 3 days per week for 12 weeks. Participants were educated on proper form, safety, and progression of exercises. Pre- and post-HEP testing included Berg Balance Scale (BBS), Timed Up and Go, Short Physical Performance Battery (SPPB) assessments, Activities-Balance Confidence, Late-Life Functional Disability Instrument and instrumented assessments of balance and gait (Limits of Stability, modified Clinical Test of Sensory Interaction on Balance, Gait). A healthy control group (HCG; n = 11) was also tested. For most of the measures, the HEPG improved to the level of HCG. Though task-specific improvements like BBS and SPPB components were seen, the results did not carry over to more dynamic assessments. Results provide proof of concept that a simple HEP can be independently implemented and effective for sustaining and/or improving balance in older adults at elevated fall-risk after they have undergone a clinic-based balance intervention. PMID- 29505322 TI - Activation of Stimulator of Interferon Genes (STING) and Sjogren Syndrome. AB - Sjogren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-gamma, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-beta production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS. PMID- 29505323 TI - Our Ultimate Fellow Travelers: A Pilot Exploration of Sibling Support for Adults with Developmental Disabilities. AB - People with developmental disabilities often experience needs for support that extend beyond the caregiving capacity of their aging parents and their siblings tend to be looked to as next-generation support providers. Yet, sibling support relationships are distinct for their simultaneously obligatory and voluntary nature. This pilot exploration, using in-depth focus group data from five siblings of people with developmental disabilities, is aimed at enriching understandings of the nature of, and expectations surrounding, sibling support for brothers and sisters with developmental disabilities. Findings reflect how sibling support evolves over time and can manifest in siblings assuming roles of: 1-companion and protector, 2-follower, 3-caregiver, and 4-within family protector. Siblings are a vital resource, yet not one that can be assumed as automatically forthcoming. PMID- 29505324 TI - Hispanic Mothers' Experiences with School-Based Emotional Health Curriculum and Perspectives of their Own Mental Health Needs. AB - An Emotional Health Curriculum (EHC) was developed to promote positive mental health in primarily Hispanic elementary school-aged children. In order to further expand the EHC, the mothers' experiences with the curriculum were examined. Eighteen mothers participated in two focus groups. Mothers reported that they valued this curriculum as a preventive program. Importantly, all mothers wished to extend their involvement to not only assisting their child in completing the curriculum homework but also attending a proposed parenting program. This study provides preliminary evidence that mothers embraced the EHC as an accessible community mental health service for their children and sought greater involvement. PMID- 29505325 TI - Safety of treatment options for spondyloarthritis: a narrative review. AB - INTRODUCTION: Spondyloarthritis (SpA) are chronic inflammatory diseases with overlapping pathogenic mechanisms and clinical features. Treatment armamentarium against SpA includes non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs, including sulfasalazine, methotrexate, leflunomide, cyclosporine), targeted synthetic DMARDs (apremilast) and biological DMARDs (TNF inhibitors, anti-IL 12/23 and anti IL-17 agents). Areas covered: A narrative review of published literature on safety profile of available SpA treatment options was performed. Readers will be provided with a comprehensive overview on frequent and rare adverse events associated with each drug listed in current SpA treatment recommendations. Expert opinion: The overall safety profile of such molecules is good and serious adverse events are rare but need to be promptly recognized and treated. However, the monitoring of adverse events is a major challenge for clinicians because it is not adequately addressed by current treatment recommendations. A tailored treatment is crucial and rheumatologists must accurately select patients in order to identify those more susceptible to develop adverse events. PMID- 29505326 TI - Adult Children and the Transition of Aging Parents. AB - This study explores the experiences of adult children as they transition their functionally and/or cognitively declining aging parents from independent living to supervised housing. A qualitative grounded theory approach was used to chronicle the experiences of adult children as their caregiving responsibilities intensified and their parents' health declined. Purposive, snowball sampling was used to enlist adult children (n = 16) who were in the process of transitioning an aging parent from an independent living situation to one providing assistance with everyday care and tasks. Semi-structured telephone interviews were conducted and designed to follow a pattern of increased frailty of the parent(s) and escalating involvement of the adult child. Two major themes emerged from the data: Changing places and everlasting love. Adult children began to intervene when cognitive or physical declines compromised the safety and well-being of the older adult and began to assume responsibility for day-to-day needs. As disabilities intensified, adult children relied on siblings, friends, social services, and health care providers to assist in planning and implementing caregiving responsibilities. Deep respect and abiding love of the aging parent(s) sustained the adult child throughout the caregiving experience. PMID- 29505327 TI - Transcatheters for closure of patent foramen ovales. AB - INTRODUCTION: Nowadays patent foramen ovale (PFO) closure is considered clinically beneficial and even cost-effective over medical therapy in secondary prevention of stroke due to paradoxical embolism. Areas covered: In this review, the authors discuss both anatomical and technical details and constructive concepts of current devices used for PFO closure. Expert commentary: Right atrial and interatrial septum anatomy is more complex than usually thought and a unique prosthesis that fits properly to all the possible morphologies is far from being designed. Existing devices can be classified into suture-like devices, metal disk occluders and mixed metal/tissue occluders depending on the mechanism of closure and the amount of metal/tissue components. Moreover, during recent years, nothing behind technology has been introduced and will be closely watched as a future option. PMID- 29505328 TI - Development of Vignettes to Explore Workplace Bullying. AB - Incivility and bullying in healthcare can impact care delivery and quality. There are challenges in research to making a direct link between the behaviors and patient outcomes. One way to address the challenges is through the creation of bullying vignettes that induce mood changes that reflect a feeling of being bullied. The purpose of this study was to develop workplace bullying textual vignettes and to test content validity. Cognitive interviewing was used by engaging content experts to rate 21 author-created vignettes for relevance, realism, and severity. Eleven vignettes were identified and have potential use in research, education, and practice. PMID- 29505333 TI - Video laryngoscopy-assisted tracheal intubation in airway management. AB - INTRODUCTION: Video laryngoscopy-assisted tracheal intubation devices have become alternatives to traditional laryngoscopes in recent years. This review will provide information on commonly used video laryngoscopes and their clinical applications in airway management. Areas covered: In this review, the differences between video laryngoscopy and direct laryngoscopy, and the utilization of video laryngoscopes in specific clinical settings are discussed. Expert commentary: Video laryngoscopy should be embraced as an initial approach to intubation in patients with suspected difficult airway. Acute care providers should be familiar with more than one intubation techniques so that a rescue attempt can be applied promptly. Continual practice and familiarity with new video laryngoscopes are still essential to maximize the effectiveness and minimize the complications of using these devices. PMID- 29505334 TI - The times they are a-changing: Self-directed long-term services and supports and gerontological social work. AB - The Partnerships for Person-Centered (PC) and Participant-Directed (PD) Long-Term Services and Supports (LTSS) Project (Partnerships Project) was a three-year effort funded by the New York Community Trust to develop and implement social work curriculum that would better prepare students for the changing practice demands of the aging and disability services network for self-directed LTSS (SD LTSS). This article first describes the growth of SD-LTSS and the need for trained social workers on this service delivery model. The paper then describes the Partnerships Project that involved schools of social work along and aging and disability network organization partners in nine states. This description includes the major activities of the project including the creation of SD-LTSS competencies for social work education, the infusion of these competencies in beginning and advanced social work classes, and student assessment of their attainment of these competencies. This article then discusses the challenges to institutionalizing such curricular changes within social work programs and the need for a national strategy to train social workers for the demands of SD-LTSS. PMID- 29505335 TI - "A Focus on Topics Related to Smoking and PTSD". PMID- 29505336 TI - Contamination of table salts from Turkey with microplastics. AB - Microplastics (MPs) pollution has become a problem that affects all aquatic, atmospheric and terrestial environments in the world. In this study, we looked into whether MPs in seas and lakes reach consumers through table salt. For this purpose, we obtained 16 brands of table salts from the Turkish market and determined their MPs content with microscopic and Raman spectroscopic examination. According to our results, the MP particle content was 16-84 item/kg in sea salt, 8-102 item/kg in lake salt and 9-16 item/kg in rock salt. The most common plastic polymers were polyethylene (22.9%) and polypropylene (19.2%). When the amounts of MPs and the amount of salt consumed by Turkish consumers per year are considered together, if they consume sea salt, lake salt or rock salt, they consume 249-302, 203-247 or 64-78 items per year, respectively. This is the first time this concerning level of MPs content in table salts in the Turkish market has been reported. PMID- 29505339 TI - To What Extent and Under Which Circumstances Are Growth Mind-Sets Important to Academic Achievement? Two Meta-Analyses. AB - Mind-sets (aka implicit theories) are beliefs about the nature of human attributes (e.g., intelligence). The theory holds that individuals with growth mind-sets (beliefs that attributes are malleable with effort) enjoy many positive outcomes-including higher academic achievement-while their peers who have fixed mind-sets experience negative outcomes. Given this relationship, interventions designed to increase students' growth mind-sets-thereby increasing their academic achievement-have been implemented in schools around the world. In our first meta analysis ( k = 273, N = 365,915), we examined the strength of the relationship between mind-set and academic achievement and potential moderating factors. In our second meta-analysis ( k = 43, N = 57,155), we examined the effectiveness of mind-set interventions on academic achievement and potential moderating factors. Overall effects were weak for both meta-analyses. However, some results supported specific tenets of the theory, namely, that students with low socioeconomic status or who are academically at risk might benefit from mind-set interventions. PMID- 29505340 TI - Stereotype activation and self-regulation by conservatives and liberals in political encounters. AB - We examined stereotyping and its effect on self-regulation in preparation for inter-ideological interactions. Turkish conservative and liberal students anticipated interacting with a political outgroup (vs. ingroup) member and the accessibility of outgroup and ingroup stereotypes was measured. Conservatives in both outgroup and ingroup interaction conditions showed higher accessibility for outgroup stereotypes. Liberals, however, showed lower accessibility for both outgroup and ingroup stereotypes in both conditions. Liberals' suppression of stereotypes about the anticipated partner led to worse self-regulation when the anticipated partner was conservative but better self-regulation when the partner was liberal. Conservatives' stereotype accessibility did not affect their self regulation. These findings show that liberals may tend to rely on self-regulatory resources to suppress their stereotypes while anticipating inter-ideological interactions while conservatives rely on stereotypes to navigate such interactions. PMID- 29505341 TI - Call to action: Better care, better health, and greater value in college health. AB - It is time for action by leaders across higher education to strengthen quality improvement (QI) in college health, in pursuit of better care, better health, and increased value - goals closely linked to students' learning and success. The size and importance of the college student population; the connections between wellbeing, and therefore QI, and student success; the need for improved standards and greater accountability; and the positive contributions of QI to employee satisfaction and professionalism all warrant a widespread commitment to building greater capacity and capability for QI in college health. This report aims to inspire, motivate, and challenge college health professionals and their colleagues, campus leaders, and national entities to take both immediate and sustainable steps to bring QI to the forefront of college health practice - and, by doing so, to elevate care, health, and value of college health as a key pathway to advancing student success. PMID- 29505342 TI - Frailty Syndrome in Association with Depressive Symptoms and Functional Disability among Hospitalized Elderly. AB - We sought to examine the frailty association with depression and functional disability in hospitalized older adults. In particular, we compared non-frail, pre-frail, and frail elderly hospitalized individuals. We performed a cross sectional study with 255 hospitalized Brazilian elderly patients. We used a structured instrument to assess socio-economic data, the Fried frailty phenotype and used morbidity scales (Geriatric Depression; Katz; Lawton and Brody). The adjusted analysis revealed that frail elderly exhibit increased odds ratios (OR) for depressive symptoms (OR = 2.72, 95% CI: 1.12-6.62), disability related to basic activities (OR = 3.50, 95% CI: 1.26-9.60), and instrumental daily living (OR = 2.70, 95% CI: 1.12-6.44). Frailty in hospitalized older adults is associated with depressive symptomatology and functional disability. PMID- 29505343 TI - Older Adults' Experiences with Audiovisual Virtual Reality: Perceived Usefulness and Other Factors Influencing Technology Acceptance. AB - OBJECTIVE: This study explores how older adults respond to audiovisual virtual reality (VR) and perceive its usefulness to their lives. METHOD: Focus groups were conducted with residents of a retirement community after they viewed two audiovisual VR simulations (n = 41). Thematic analysis was used to identify patterns in responses. RESULTS: Older adults described positive and negative emotional reactions to aspects of the VR experience, articulated content preferences, shared ideas to improve the usability of the equipment, and identified facilitators and barriers that influenced perceived usefulness. Recommendations for improving this technology include maximizing the positive aspects of VR through increasing interactivity, facilitating socializing with friends or family, and enhancing older adults' ease of use. Desired content of simulations involved travel, continuing education, reminiscence, and self care/therapy. CONCLUSION: Virtual reality was reviewed positively, yet modifications are necessary to facilitate optimal user experience and potential benefit for this population. CLINICAL IMPLICATIONS: As older adults are interested in using VR, especially if poor health prevents the continuation of desirable activities or new experiences, it is important to respond to older adults' preferences and remove barriers that limit use and enjoyment. PMID- 29505344 TI - Distress and worry as mediators in the relationship between psychosocial risks and upper body musculoskeletal complaints in highly automated manufacturing. AB - As a result of changes in manufacturing including an upward trend in automation and the advent of the fourth industrial revolution, the requirement for supervisory monitoring and consequently, cognitive demand has increased in automated manufacturing. The incidence of musculoskeletal disorders has also increased in the manufacturing sector. A model was developed based on survey data to test if distress and worry mediate the relationship between psychosocial factors (job control, cognitive demand, social isolation and skill discretion), stress states and symptoms of upper body musculoskeletal disorders in highly automated manufacturing companies (n = 235). These constructs facilitated the development of a statistically significant model (RMSEA 0.057, TLI 0.924, CFI 0.935). Cognitive demand was shown to be related to higher distress in employees, and distress to a higher incidence of self-reported shoulder and lower back symptoms. The mediation model incorporating stress states (distress, worry) as mediators is a novel approach in linking psychosocial risks to musculoskeletal disorders. Practitioners' Summary With little requirement for physical work in many modern automated manufacturing workplaces, there is often minimal management focus on Work-Related Musculoskeletal Disorders (WRMSDs) as important occupational health problems. Our model provides evidence that psychosocial factors are important risk factors in symptoms of WRMSD and should be managed. PMID- 29505345 TI - Marine Leech Anticoagulant Diversity and Evolution. AB - Leeches (Annelida: Hirudinea) possess powerful salivary anticoagulants and, accordingly, are frequently employed in modern, authoritative medicine. Members of the almost exclusively marine family Piscicolidae account for 20% of leech species diversity, and they feed on host groups (e.g., sharks) not encountered by their freshwater and terrestrial counterparts. Moreover, some species of Ozobranchidae feed on endangered marine turtles and have been implicated as potential vectors for the tumor-associated turtle herpesvirus. In spite of their ecological importance and unique host associations, there is a distinct paucity of data regarding the salivary transcriptomes of either of these families. Using next-generation sequencing, we profiled transcribed, putative anticoagulants and other salivary bioactive compounds that have previously been linked to blood feeding from 7 piscicolid species (3 elasmobranch feeders; 4 non-cartilaginous fish feeders) and 1 ozobranchid species (2 samples). In total, 149 putative anticoagulants and bioactive loci were discovered in varying constellations throughout the different samples. The putative anticoagulants showed a broad spectrum of described antagonistic pathways, such as inhibition of factor Xa and platelet aggregation, which likely have similar bioactive roles in marine fish and turtles. A transcript with homology to ohanin, originally isolated from king cobras, was found in Cystobranchus vividus but is otherwise unknown from leeches. Estimation of selection pressures for the putative anticoagulants recovered evidence for both positive and purifying selection along several isolated branches in the gene trees, and positive selection was also estimated for a few select codons in a variety of marine species. Similarly, phylogenetic analyses of the amino acid sequences for several anticoagulants indicated divergent evolution. PMID- 29505346 TI - Cumulative Childhood Trauma and Therapeutic Alliance: The Moderator Role of Attachment in Adult Patients Consulting in Sex Therapy. AB - While it is documented that clients consulting in sex therapy tend to report high rates of childhood interpersonal traumas (e.g., physical, psychological and sexual abuse), which are associated to insecure attachment and poorer therapeutic alliance, the interrelations of these variables have not yet been evaluated in this specific population. This study examined the associations between attachment, cumulative trauma and therapeutic alliance in 278 sex therapy patients who filled out self-report questionnaires. Results revealed that avoidant attachment acted as a moderator between cumulative trauma and the agreement on tasks dimension of therapeutic alliance. Results suggests the relevance for sex therapists to investigate past traumas and current attachment representations to guide interventions and optimize treatment benefits. PMID- 29505347 TI - Dose-Rate Effects in Breaking DNA Strands by Short Pulses of Extreme Ultraviolet Radiation. AB - In this study, we examined dose-rate effects on strand break formation in plasmid DNA induced by pulsed extreme ultraviolet (XUV) radiation. Dose delivered to the target molecule was controlled by attenuating the incident photon flux using aluminum filters as well as by changing the DNA/buffer-salt ratio in the irradiated sample. Irradiated samples were examined using agarose gel electrophoresis. Yields of single- and double-strand breaks (SSBs and DSBs) were determined as a function of the incident photon fluence. In addition, electrophoresis also revealed DNA cross-linking. Damaged DNA was inspected by means of atomic force microscopy (AFM). Both SSB and DSB yields decreased with dose rate increase. Quantum yields of SSBs at the highest photon fluence were comparable to yields of DSBs found after synchrotron irradiation. The average SSB/DSB ratio decreased only slightly at elevated dose rates. In conclusion, complex and/or clustered damages other than cross-links do not appear to be induced under the radiation conditions applied in this study. PMID- 29505348 TI - Financial Capability: Clinicians' Assessment of Beneficiaries with Dual Diagnoses. AB - INTRODUCTION: Adults with mental health disorders whose ability to work is sufficiently impeded are entitled to financial supports from the Social Security Administration. Beneficiaries determined to be incapable of managing these funds are supposed to be assigned a representative payee to assist beneficiaries in meeting their needs. However, patterns of payee assignment suggest that payee assignment is impacted by factors other than those the Social Security Administration instructs clinicians to consider. In this study, we tested the association between clinicians' judgments of their clients' financial capability and hypothesized predictors (demographic characteristics, psychiatric diagnosis, recent alcohol and other substance use, self-rated money mismanagement, recent homelessness, and provider characteristics). We posited that predictors might act indirectly on capability judgment, via their impact on beneficiaries' money management. METHODS: Altogether, 261 people receiving intensive mental health care who did not have payees or fiduciaries were enrolled after providing written informed consent. These beneficiaries completed in-person assessment interviews, reporting demographic characteristics, treatment history, substance use, and homelessness. Mental health clinicians identified by the beneficiaries were enrolled in the study and asked to judge their clients' financial capability with standard Social Security instructions for determining capability. Bivariate associations between hypothesized predictors and clinicians' determinations of incapability were tested. In multivariate probit regression models, incapability determination was modeled as a function of all beneficiary and clinician characteristics that had significant bivariate associations with the outcome. RESULTS: Providers identified 24% of their clients as financially incapable. Determinations of financial incapability were unrelated to any beneficiary or provider demographic characteristics, but were positively associated with money mismanagement, homelessness and having a psychotic disorder. Alcohol and other substance use were only significantly associated with capability determinations indirectly, through their effects on money mismanagement. CONCLUSION: Providers' judgments of beneficiaries' capability to manage their funds were associated with factors that were consistent with Social Security Administration guidelines, and were, importantly, not associated with personal characteristics. This finding suggests that guidelines can be fairly applied by clinicians, and that reported inconsistencies in payee assignment are accounted for by other factors. Social Security Administration is currently considering other approaches to standardize capability determinations. PMID- 29505351 TI - Turner's syndrome and the H-Y antigen: A response to Silvers, Gasser, and Eicher (1982). PMID- 29505350 TI - Assessment of women's empowerment: An exploratory study to develop a valid and reliable Persian-version tool. AB - Lack of a valid and reliable women's empowerment tool was reported by previous studies in Iran. The authors of this paper, accordingly, intended to fill this gap by developing a valid questionnaire. 600 women in Dezful city, southeast of Iran, took part in the study in 2014-2015. Multistage sampling method was used to recruit the participants. Our exploratory factor analysis revealed that 18 items of the model loaded on 4 factors. Internal consistency of the questionnaire was suitable as Cronbach's alpha coefficient was 0.77. Considering high validity and shortness of the questionnaire, it can be used as a trustful and comprehensive tool to measure women's empowerment in future studies. PMID- 29505349 TI - Low 25-Hydroxyvitamin D Concentrations and Risk of Incident Cognitive Impairment in Black and White Older Adults: The Health ABC Study. AB - Using data from the Health, Aging, and Body Composition study, we examined whether low 25-hydroxyvitamin D (25[OH]D) concentrations were associated with prevalent or incident cognitive impairment. Serum 25(OH)D concentrations were measured in 2,786 older adults and categorized as <20 ng/mL, 20 to <30 ng/mL, or >=30 ng/mL. Cognitive impairment was defined as a score >1.5 standard deviations below race and education specific means on either digit symbol substitution test or modified mini-mental state test. Logistic regression determined the odds of cognitive impairment at baseline and year 5 by 25(OH)D category. 25(OH)D concentrations were <30 ng/mL in 57.3% of whites and 84.6% of blacks. After excluding participants with baseline cognitive impairment (n = 340), 13% of whites and 13% of blacks developed cognitive impairment by year 5. In whites, 25(OH)D concentrations <30 ng/mL were not associated with prevalent or incident cognitive impairment. Black participants with 25(OH)D concentrations <20 ng/mL had a higher odds of prevalent, but not incident cognitive impairment (OR (95% CI): 2.05 (1.08-3.91), p = 0.03) compared to participants with 25(OH)D concentrations >=30 ng/mL. Low 25(OH)D concentrations were associated with twofold higher odds of prevalent cognitive impairment in blacks. PMID- 29505352 TI - Sexual evaluation of women with feminist attitudes. AB - A study was conducted to investigate whether subjects make inferences about a female's sexuality based on her attitudes toward feminist issues. Based on the idea that both attitudes toward feminist issues and toward sexual traits are components of prototypes about females, it was hypothesized that females who expressed nontraditional attitudes on various feminist issues would be rated higher on a number of sexual traits than females who expressed more traditional attitudes. Male and female subjects were given information about a 19-year-old, single, female's attitudes on a number of issues related to women's occupational and domestic roles. The target's answers were manipulated so that in one condition she expressed traditional attitudes, and in a second condition she expressed nontraditional or feminist attitudes. The respondents were then asked to rate the target on traits reflecting a sexual and an evaluative dimension. As predicted, it was found that the female expressing nontraditional attitudes was rated higher in the sexual traits and was evaluated more negatively. The results were discussed in terms of the perceived incongruity between feminist attitudes and the traditional female prototype. PMID- 29505353 TI - The commencement of bisexual activity in swinging married women over age thirty. AB - The commencement of bisexual behavior and the ontogenesis of a bisexual orientation was studied in order to aid in the better understanding of how sexual behavior patterns begin and change. The investigation was conducted through in depth interviews held in California, Oregon, and Washington with the first 50 female volunteers gathered from a variety of sources who met the study requirements. Those requirements were that each subject, at the time of her first sexual contact with another female, (a) was married; (b) was at least 30 years of age; (c) was engaged in swinging; (d) was enjoying sex with males; and (e) had no history, prior to age 30, of a sexual attraction to females. "Multi-female" and "multi-male" sexual activity are terms introduced to remove the ambiguity and mislabeling which results from defining sexual activity between all persons of the same sex as necessarily homosexual. Subjects typically revealed a high incidence of early and continuing autosexual and heterosexual activity and current high frequencies of sexual activity with each sex. Influences facilitating a typical subject's initial and subsequent sexual activity with females were found to be her husband, other swingers, and the general swinging environment-the husband's influence usually being of paramount importance. It was concluded that those influences, perhaps together with a predisposition toward gaining perceived fulfillment of felt needs through sexual activity, will result in some heterosexual females engaging in multi-female sexual activity and eventually adopting a self-identified bisexual orientation. PMID- 29505354 TI - The ego-analytic approach to individual body-work sex therapy: Five case examples. AB - The term individual body-work sex therapy is proposed to refer to a subfield of the larger field of sex therapy in which paraprofessionals take a variety of roles, from partner surrogate to sensory guide to body-work cotherapist, working from a variety of therapeutic models. To convey the unique and generally unfamiliar dimensions of this treatment modality, as identified through 10 years of experience with it, five cases are presented, each embodying one or more critical incidents. An ideographic method of reporting clinical work is offered in which these case presentations are chosen to represent five levels of therapeutic outcome. Since these cases also illustrate an application of the ego analytic model, this approach is discussed and is compared with other approaches to body-work therapy in relation to the way the body work is used, the way the role of the paraprofessional is conceived, the structure of the therapy, and the patient populations treated. PMID- 29505355 TI - Sex-role orientation, mother's expression of affection toward spouse, and college women's attitudes toward sexual behaviors. AB - The relative importance of women's sex-role orientation and their observation of maternal sexual affection in predicting college women's attitudes toward 18 sexual behaviors were examined in this investigation. A sample of 122 single female college students from intact families was administered three questionnaires: the Attitudes Toward Women Scale, the Mother's Expression of Affection Scale, and the Sexual Attitude Questionnaire. Stepwise regression analysis was used to determine the relative contribution of sex-role orientation and maternal expression of affection to attitudes toward each of the sexual behaviors. Findings revealed that sex-role orientation was a significant predictor of attitudes toward 14 of the 18 specific items. More egalitarian views of women were associated with more positive attitudes toward engaging in a variety of sexual behaviors and taking steps to ensure one's own contraceptive security. Mother's expression of sexual affection toward her spouse was a significant predictor of only two behavioral items. Greater exposure to an affectionate mother was associated with more positive attitudes toward speaking affectionately to men and behaving assertively in a sexual relationship. Implications of the findings for family practitioners are discussed. PMID- 29505356 TI - Can there be positive effects of participation in pornography experiments? AB - This two-phase experiment was conducted in response to recent ethical concerns about the possible antisocial effects of exposing research subjects to pornographic rape portrayals. In Phase 1, subjects were randomly assigned to read either an "acquaintance" rape depiction, a "stranger" rape depiction, or to read control materials. Subjects who read the rape depictions were then given a rape debriefing. This debriefing included a communication about the undesirable desensitizing effects of pairing sexual violence with other highly explicit and pleasing sexual stimuli. It was also designed to dispel a number of myths about rape. Half of the subjects who read the control materials were also given the rape debriefing, whereas the other half were given a control debriefing. This design enabled the assessment of the independent and interactive effects of the rape depictions and of the rape debriefing (although ethical considerations did not enable the use of a fully crossed factorial design). In Phase 2, subjects were presented with a number of newspaper articles (in which a newspaper report of a rape was embedded) and asked to give their opinions. The results indicated that the rape debriefing generally increased subjects' perceptions of pornography as a cause of rape. Subjects in the rape debriefing conditions also gave the rapist in the newspaper report a higher sentence, and saw the rape victim as less responsible, than did subjects in the control conditions. This latter effect, however, only occurred under conditions where subjects had earlier been exposed to an example of a rape depiction which was relevant to both the rape myths discussed in the rape debriefing and the newspaper report of the rape. These data suggest that participation in pornography experiments employing pornographic rape depictions can have an educational impact on subjects' postexperimental attitudes, if the debriefing is appropriately constructed to dispel any rape myths that may be portrayed in the rape depictions. PMID- 29505357 TI - Debriefing effectiveness following exposure to pornographic rape depictions. AB - Data are presented concerning the ethics of exposing undergraduate students to pornographic rape portrayals followed by a debriefing designed to dispel a number of rape myths. One hundred fifty males and females were randomly assigned to read pornographic stories. Some of these depicted a rape, whereas others depicted mutually consenting intercourse. Afterwards, those exposed to the rape version were given a debriefing which included statements concerning the true horror of rape and the existence of rape myths. About 10 days later, a "Public Survey" ostensibly conducted by a local committee of citizens was given to subjects in their classes. A postexperimental questionnaire confirmed that participants were not aware that this survey was related to the earlier phase of the research. As part of the survey, subjects were presented with actual newspaper articles about which their opinions were solicited. One of these articles, the dependent measure of the study, concerned rape. Subjects indicated their reactions to this article and their opinions about the general causes of rape. The results indicated that those exposed to the rape depictions followed by a "rape debriefing" were less accepting of certain rape myths than subjects exposed to mutually consenting intercourse depictions. Implications of the data for future research in this area are discussed both in terms of work focusing on the potential antisocial impact of violent pornography and of research specifically designed to identify the conditions most likely to change acceptance of rape myths. PMID- 29505358 TI - Reviews and abstracts. AB - : CASES OF THE REINCARNATION TYPE (VOL. 4). Twelve Cases in Thailand and Burma. Ian Stevenson. Charlottesville, VA: University Press of Virginia, 1983; 308 pages; $20.00. MALEDICTA: THE INTERNATIONAL JOURNAL OF VERBAL AGGRESSION. Reinhold Aman (Ed.). Published by the Editor, 331 South Greenfield Avenue, Waukesha, WI 53186, Vol. 1, No. 1, Summer 1977-Vol. 5, Nos. 1 & 2, Summer & Winter 1981, Annual, S22.50 (prepaid)/$24.00. SEXUALITY AND AGING: AN ANNOTATED BIBLIOGRAPHY. George F. Wharton, III. Metuchen, New Jersey & London: Scarecrow Press, 1981; 259 pages; $15.00. INCEST: THE LAST TABOO: AN ANNOTATED BIBLIOGRAPHY. Rick Rubin and Greg Byerly. New York: Garland Publishing, 1983; 180 pages; $25.00. PMID- 29505359 TI - An Unconditional Prenatal Income Supplement Reduces Population Inequities In Birth Outcomes. AB - The Commission on Social Determinants of Health, sponsored by the World Health Organization, has identified measuring health inequities and evaluating interventions to reduce them as important priorities. We examined whether an unconditional prenatal income supplement for low-income women was associated with reduced population-level inequities in birth outcomes. We identified all mother newborn pairs from the period 2003-10 in Manitoba, Canada, and divided them into the following three groups: low income exposed (received the supplement); low income unexposed (did not receive the supplement); and not low income unexposed (ineligible for the supplement). We measured inequities in low-birthweight births, preterm births, and breast-feeding initiation among these groups. The findings indicated that the socioeconomic gap in birth outcomes between low income and other women was significantly smaller when the low-income women received the income supplement than when they did not. The prenatal income supplement may be an important driver in attaining population-level equity in birth outcomes; its success could inform strategies seeking to improve maternal and child health. PMID- 29505362 TI - Advancing Health Equity. PMID- 29505360 TI - Household Immigration Status Had Differential Impact On Medicaid Enrollment In Expansion And Nonexpansion States. AB - Recent research has shown that concern about the apprehension and deportation of undocumented immigrants can affect how members of their households who are eligible for public benefits choose to participate in public programs. The extent to which this "chilling effect" broadly affects adults' Medicaid enrollment nationally remains unclear, in part because of the difficulty of isolating undocumented immigrants in survey data. In this study we identified households that likely included undocumented immigrants and then examined whether gains in health care coverage due to the expansion of Medicaid eligibility under the Affordable Care Act (ACA) were dampened for eligible people living in households with mixed immigration status. We found no significant differences in coverage gains for people in mixed- relative to non-mixed-status households in expansion states. Coverage gains were significantly lower, however, for people in mixed status households relative to those in non-mixed-status households in nonexpansion states. These findings suggest that household immigration status may have dampened the "woodwork effect," whereby the ACA enhanced knowledge about program availability, in turn increasing Medicaid enrollment in nonexpansion states among people previously eligible for the program but not enrolled in it. PMID- 29505364 TI - Funders' Support Of Health Equity. PMID- 29505363 TI - Promoting Health Equity And Eliminating Disparities Through Performance Measurement And Payment. AB - Current approaches to health care quality have failed to reduce health care disparities. Despite dramatic increases in the use of quality measurement and associated payment policies, there has been no notable implementation of measurement strategies to reduce health disparities. The National Quality Forum developed a road map to demonstrate how measurement and associated policies can contribute to eliminating disparities and promote health equity. Specifically, the road map presents a four-part strategy whose components are identifying and prioritizing areas to reduce health disparities, implementing evidence-based interventions to reduce disparities, investing in the development and use of health equity performance measures, and incentivizing the reduction of health disparities and achievement of health equity. To demonstrate how the road map can be applied, we present an example of how measurement and value-based payment can be used to reduce racial disparities in hypertension among African Americans. PMID- 29505365 TI - Quality Of Breast Cancer Care In The US Territories: Insights From Medicare. AB - The quality of breast cancer care among Medicare beneficiaries in the US territories-where federal spending for health care is lower than in the continental US-is unknown. We compared female Medicare beneficiaries who were residents of the US territories and had surgical treatment for breast cancer in 2008-14 to those in the continental US in terms of receipt of recommended breast cancer care (diagnostic needle biopsy and adjuvant radiation therapy [RT] following breast-conserving surgery) and the timeliness (time from needle biopsy to surgery and from surgery to adjuvant RT) of that care. Residents of the US territories were less likely to receive recommended care (24 percent lower odds of receiving diagnostic needle biopsy and 34 percent lower odds of receiving adjuvant RT) and to receive timely care (45 percent lower odds of receiving surgery and 82 percent lower odds of receiving adjuvant RT, both within three months). Further research is needed to identify barriers to the provision of adequate and timely breast cancer care in this unique population. PMID- 29505366 TI - Addressing Social Determinants Of Health Through Medical-Legal Partnerships. AB - The US health care system needs effective tools to address complex social and environmental issues that perpetuate health inequities, such as food insecurity, education and employment barriers, and substandard housing conditions. The medical-legal partnership is a collaborative intervention that embeds civil legal aid professionals in health care settings to address seemingly intractable social problems that contribute to poor health outcomes and health disparities. More than three hundred health care organizations are home to medical-legal partnerships. This article draws upon national survey data and field research to identify three models of the medical-legal partnership that health care organizations have adopted and the core elements of infrastructure that they share. Financing and commitment from health care organizations are key considerations for sustaining and scaling up the medical-legal partnership as a health equity intervention. PMID- 29505367 TI - How Community Organizing Promotes Health Equity, And How Health Equity Affects Organizing. AB - Public health scholarship increasingly recognizes community organizing as a vehicle for unleashing the collective power necessary to uproot socioeconomic inequities at the core of health disparities. In this article we reverse the analytical focus from how organizing can affect health equity, and we consider how the frame of health equity has shaped grassroots organizing. Using evidence from a range of cases in California, we suggest that the health equity frame can guide and justify grassroots groups' efforts to improve the health outcomes of marginalized populations; connect issues such as housing and school discipline to health; and provide a rationale for community organizing groups to directly address the trauma experienced by their own members and staff, who often come from communities at risk for poor health outcomes. PMID- 29505368 TI - Social Pension Income Associated With Small Improvements In Self-Reported Health Of Poor Older Men In Colombia. AB - The countries of Latin American are aging rapidly. Because most countries in the region lack adequate social protection systems, many Latin American governments have introduced noncontributory pension programs to reduce poverty and food shortages. This study assessed the effects of a large national noncontributory pension program on the health and health care use of older people in Colombia. Using an instrumental variables approach that exploited differential rollout of the program across municipalities, we found evidence that the program led to significant but small improvements in self-reported health and reductions in hospitalizations among men. No significant effects were found among women or among men for other health and health care use outcomes. A small noncontributory pension was associated with improvements in self-reported measures of health for vulnerable older men, but these effects are small in magnitude. Researchers and policy makers should assess ways to maximize the health benefits of cash transfers to poor older people. PMID- 29505369 TI - Project HOPE Honors 60 Years Of Volunteers. PMID- 29505370 TI - Nearly Half Of Small Employers Using Tobacco Surcharges Do Not Provide Tobacco Cessation Wellness Programs. AB - The Affordable Care Act (ACA) allowed employer plans in the small-group marketplace to charge tobacco users up to 50 percent more for premiums-known as tobacco surcharges-but only if the employer offered a tobacco cessation program and the employee in question failed to participate in it. Using 2016 survey data collected by the Henry J. Kaiser Family Foundation and Health Research and Educational Trust on 278 employers eligible for Small Business Health Options Program, we examined the prevalence of tobacco surcharges and tobacco cessation programs in the small-group market under this policy and found that 16.2 percent of small employers used tobacco surcharges. Overall, 47 percent of employers used tobacco surcharges but failed to offer tobacco cessation counseling. Wellness program prevalence was lower in states that allowed tobacco surcharges, and 10.8 percent of employers in these states were noncompliant with the ACA by charging tobacco users higher premiums without offering cessation programs. Efforts should be undertaken to improve the monitoring and enforcement of ACA tobacco rating rules. PMID- 29505372 TI - Health Equity. AB - Many factors that affect health can have disproportionate effects on vulnerable groups, such as those with low socioeconomic status, women, racial and ethnic minorities, people who are disabled, and those who are LGBTQ. Factors such as educational opportunity, geography, food and housing security, safety, and environmental conditions are often beyond a person's direct control. Exploring these determinants of health, the disparities that arise from them, and policies that attempt to improve equity by addressing them are active areas of research. PMID- 29505371 TI - Oregon's Emphasis On Equity Shows Signs Of Early Success For Black And American Indian Medicaid Enrollees. AB - In 2012 Oregon transformed its Medicaid program, providing coverage through sixteen coordinated care organizations (CCOs). The state identified the elimination of health disparities as a priority for the CCOs, implementing a multipronged approach that included strategic planning, community health workers, and Regional Health Equity Coalitions. We used claims-based measures of utilization, access, and quality to assess baseline disparities and test for changes over time. Prior to the CCO intervention there were significant white black and white-American Indian/Alaska Native disparities in utilization measures and white-black disparities in quality measures. The CCOs' transformation and implementation of health equity policies was associated with reductions in disparities in primary care visits and white-black differences in access to care, but no change in emergency department use, with higher visit rates persisting among black and American Indian/Alaska Native enrollees, compared to whites. States that encourage payers and systems to prioritize health equity could reduce racial and ethnic disparities for some measures in their Medicaid populations. PMID- 29505373 TI - From Payday Loans To Pawnshops: Fringe Banking, The Unbanked, And Health. AB - The fringe banking industry, including payday lenders and check cashers, was nearly nonexistent three decades ago. Today it generates tens of billions of dollars in annual revenue. The industry's growth accelerated in the 1980s with financial deregulation and the working class's declining resources. With Current Population Survey data, we used propensity score matching to investigate the relationship between fringe loan use, unbanked status, and self-rated health, hypothesizing that the material and stress effects of exposure to these financial services would be harmful to health. We found that fringe loan use was associated with 38 percent higher prevalence of poor or fair health, while being unbanked (not having one's own bank account) was associated with 17 percent higher prevalence. Although a variety of policies could mitigate the health consequences of these exposures, expanding social welfare programs and labor protections would address the root causes of the use of fringe services and advance health equity. PMID- 29505374 TI - For People With Disabilities, A Fight For Access To Housing. AB - The City of Los Angeles continues to struggle to make available housing that is both affordable and accessible. PMID- 29505375 TI - What 'Merle' Taught Me About Energy Insecurity And Health. AB - Being unable to meet basic household energy needs can have dire health consequences and merits more attention and resources. PMID- 29505376 TI - The Arc Of History Bends Toward Coverage: Health Policy At A Crossroads. AB - There is a formidable historical arc to health care policy: Every modern US president has sought to expand coverage. Democrats eagerly placed the issue on the agenda. Republicans vociferously opposed Democratic proposals but countered with creative ways to expand coverage on their own terms. Democrats eventually absorbed elements of the latest Republican plan-which Republicans, in turn, attacked, and the cycle began anew. The dynamic interaction between the parties slowly, often haphazardly, expanded health insurance as each sought to extend coverage in its own way. We speculate about whether the recent Republican efforts to repeal the Affordable Care Act constitute a sharp break with the past, perhaps because opposition to government, exacerbated by racial anxieties, has changed the Republican calculus. Alternatively, there are still some reasons to conclude that the arc of health policy continues to bend toward increasing coverage. PMID- 29505378 TI - Identifying Gender Minority Patients' Health And Health Care Needs In Administrative Claims Data. AB - Health care utilization patterns for gender minority Medicare beneficiaries (those who are transgender or gender nonbinary people) are largely unknown. We identified gender minority beneficiaries using a diagnosis-code algorithm and compared them to a 5 percent random sample of non-gender minority beneficiaries from the period 2009-14 in terms of mental health and chronic diseases, use of preventive and mental health care, hospitalizations, and emergency department (ED) visits. Gender minority beneficiaries experienced more disability and mental illness. When we adjusted for age and mental health, we found that they used more mental health care. And when we adjusted for age and chronic conditions, we found that they were more likely to be hospitalized and to visit the ED. There were several small but significant differences in preventive care use. Findings were similar for disabled and older cohorts. These findings underscore the need to capture gender identity in health data to better address this population's health needs. PMID- 29505379 TI - Parent Mentoring Program Increases Coverage Rates For Uninsured Latino Children. AB - Latinos have the highest US childhood uninsurance rate of any race/ethnicity, but little is known about effective ways to eliminate this disparity. We evaluated the effects of parent mentors-Latino parents with children covered by Medicaid or the Children's Health Insurance Program-on insuring Latino children in a randomized, controlled, community-based trial of 155 uninsured children conducted in the period 2011-15. Parent mentors were trained to assist families in getting insurance coverage, accessing health care, and addressing social determinants of health. We found that parent mentors were more effective than traditional methods in insuring children (95 percent versus 69 percent), achieving faster coverage and greater parental satisfaction, reducing unmet health care needs, providing children with primary care providers, and improving the quality of well-child and subspecialty care. Children in the parent-mentor group had higher quality of overall and specialty care, lower out-of-pocket spending, and higher rates of coverage two years after the end of the intervention (100 percent versus 70 percent). Parent mentors are highly effective in insuring uninsured Latino children and eliminating disparities. PMID- 29505380 TI - Accumulation Of Chronic Conditions At The Time Of Death Increased In Ontario From 1994 To 2013. AB - With falling mortality rates for several diseases, patients are living longer with complex multimorbidities. We explored the burden of multimorbidity at the time of death, how it varies by socioeconomic status, and trends over time in Ontario, Canada. We calculated the proportions of decedents with varying degrees of multimorbidity and types of conditions at death, and we analyzed the trend from 1994 to 2013 in the number of conditions at the time of death. The prevalence of multimorbidity at death increased from 79.6 percent in 1994 to 95.3 percent in 2013. An upward trend in the number of conditions per person at death was observed for all chronic conditions except chronic coronary syndrome, congestive heart failure, and stroke. Chronic respiratory diseases and diabetes were disproportionately represented in low-income and deprived neighborhoods. The trend toward greater multimorbidity burden over time and the existence of steep socioeconomic gradients underscore the importance of integrated health care planning for preventing and managing multiple complex conditions. PMID- 29505381 TI - Conditional Cash Transfers And Health Of Low-Income Families In The US: Evaluating The Family Rewards Experiment. AB - Opportunity NYC-Family Rewards was the first conditional cash transfer, randomized controlled trial for low-income families in the United States. From 2007 to 2010, Family Rewards offered 2,377 New York City families cash transfers that were conditional upon their investments in education, preventive health care, and parental employment. Their health and other outcomes were compared to those of a control group of 2,372 families. The experiment led to a modest improvement in health insurance coverage and a large increase in the use of preventive dental care. It improved parents' perception of their own health and levels of hope, mainly through improvements in reported financial well-being. While the program's impacts on physical health were weaker, our study might not have captured effects on chronic disease risk that take longer to accrue. In the context of New York City's operating social-safety-net programs, conditional cash transfers may have led to positive, albeit modest, improvements in the health of poor families. PMID- 29505382 TI - Examining Whether The Health-In-All-Policies Approach Promotes Health Equity. AB - Scholars and public health advocates have expressed optimism about the potential for the health-in-all-policies approach to address social disparities in health, but little research has been done on whether it promotes health equity in practice. Based on sixty-five in-depth interviews with US officials in the public and private sectors conducted in five states in 2016-17, we found a relationship between the use of the approach and the prominence of health equity as a policy concern. In emphasizing the social determinants of health, the approach gives public officials and policy entrepreneurs a framework for promoting this goal. In some areas, we found a gradual transition in focus from health generally to health equity. Overall, we found that practitioners of the approach introduce equity selectively and strategically. PMID- 29505383 TI - Categorical and Dimensional Conceptions of Personality Pathology in DSM-5: Toward a Model-Based Synthesis. AB - Symptom-based models, typically operationalized through diagnostic interview, and trait models, typically operationalized via questionnaire inventories, reflect historically competing conceptions of personality disorder (PD). DSMD-5 includes models of both types, in Sections II and III, respectively. In this study, we sought to synthesize these alternative conceptualizations by fitting bifactor models to data for both Section II PD symptoms (assessed using the SCID-II interview protocol) and dimensional traits for the six PDs retained in Section III (assessed using the Personality Inventory for DSM-5). Bifactor models fit the data effectively for all six PDs, and trait and symptom indicators both loaded appreciably on general factors reflecting cross-domain PD constructs. These results provide the basis for a principled, quantitative synthesis of categorical/interview and dimensional/self-report approaches to operationalizing and studying PDs, with considerable implications for diagnosis, research, and practice. PMID- 29505384 TI - Emotional Intelligence in Incarcerated Female Offenders With Psychopathic Traits. AB - Emotional impairment is a core feature of psychopathy, and the disorder has been linked to an inability to recognize and regulate emotion, leading to deficiencies in empathy and difficulties in social functioning. This study investigated associations among psychopathic traits and ability-based emotional intelligence (EI) in female offenders and integrated data with previously published male offender data (Ermer, Kahn, Salovey, & Kiehl, 2012) to examine gender differences in relationships. Results showed that female offenders were impaired in the understanding and management of emotion relative to the general population, and that female offenders scored higher than male offenders in EI. Affective psychopathic traits (e.g., callousness) yielded a small relationship with difficulties in managing emotion in female offenders, and few gender differences in relationships between psychopathy and EI were found. Findings contribute to literature on emotional functioning in females with psychopathic traits and further understanding of gender differences in emotional abilities among offenders. PMID- 29505385 TI - A Randomized Controlled Trial of Group Psychoeducation for Carers of Persons With Borderline Personality Disorder. AB - Carers of persons with borderline personality disorder (BPD) experience high burden. Treatment guidelines advocate involving carers in comprehensive therapy approaches. This study is a randomized controlled trial of group psychoeducation, compared to waitlist. Group psychoeducation involved 6-8 carers per group and focused on improving relationship patterns between carers and relatives with BPD, psychoeducation about the disorder, peer support and self-care, and skills to reduce burden. Carers were randomized into intervention (N = 33) or waitlist (N = 35). After 10 weeks, those in the intervention reported improvements in dyadic adjustment with their relative, greater family empowerment, and reduced expressed emotion, sustained after 12 months. There were also improvements in carers' perceptions of being able to play a more active role, such as interacting with service providers. This study demonstrates that providing structured group programs for carers can be an effective way of extending interventions to a group experiencing high burden. PMID- 29505386 TI - Relationships Among Avoidant Personality Disorder, Social Anxiety Disorder, and Normative Personality Traits: A Twin Study. AB - Avoidant personality disorder (AvPD) and social anxiety disorder (SAD) share risk factors to a substantial degree, and both are characterized by the experience of anxiety in social situations. The authors investigated whether these disorders are differentially related to the Big Five personality traits. They also examined the underlying genetic and environmental influences on these associations. A population-based sample of 1,761 female twins was interviewed at baseline, and 1,471 of these were re-interviewed 10 years later. Associations between AvPD, SAD, and personality traits were investigated with multivariate biometric analyses. The authors found that AvPD and SAD are differentially related to several personality traits at the phenotypic, genetic, and environmental level. The genetic and environmental liability to AvPD could be fully accounted for by the genetic and environmental factors influencing SAD and personality. The findings may increase current etiological understanding of these disorders and inform future classification and treatment efforts. PMID- 29505387 TI - Low Vocational Outcome Among People Diagnosed With Borderline Personality Disorder During First Admission to Mental Health Services in Denmark: A Nationwide 9-Year Register-Based Study. AB - Earlier studies report that although people with borderline personality disorder (BPD) experience symptom reduction in the long term, they continue to have difficulties in work recovery. This nationwide 9-year register-based study (N = 67,075) investigated the long-term labor-market attachment of all individuals diagnosed with BPD during first admission to Danish mental health services in comparison with other psychiatric disorders. Controlling for baseline characteristics and co-occurring secondary psychiatric diagnoses, the BPD group had 32% lower odds (OR = 0.68; 95% CI [0.61, 0.76]) of being in work/under education after 9 years. Individuals diagnosed with BPD also showed more impairment in long-term vocational outcome than other personality disorders, and lower labor-market attachment than other psychiatric disorders except for schizophrenia, schizotypal and delusional disorders, and mental and behavioral disorders due to psychoactive substance use. Intervention programs addressing social psychiatric aspects of BPD in terms of work functioning is henceforth an important area for future research. PMID- 29505388 TI - Externalizing Behavior and Psychopathy: A Social Relations Analysis. AB - Most conceptualizations of psychopathy emphasize its interpersonal consequences, yet most research on psychopathy has been conducted at the individual level. In small groups, well-acquainted members of sororities and fraternities (N = 111) rated one another and themselves on a variety of externalizing behaviors (e.g., cheating, risky sex), and completed a self-report measure of psychopathy. There was consensus about the extent to which members of the groups engaged in these behaviors. The associations between these target effects and respondents' self reports suggest that these consensual judgments were reasonably accurate. Individuals who reported higher levels of psychopathic personality traits were seen as more likely to engage in externalizing behaviors, with self-centered impulsivity most strongly associated with these behaviors. Although fearless dominance was unrelated to self-reported externalizing behaviors, it was related to peers' ratings of marijuana use, academic dishonesty, and future legal troubles, suggesting that individuals high in fearless dominance may underreport their problem behaviors. PMID- 29505389 TI - Predictors of Slower Time-to-Cessation of Individual Therapy for Borderline Patients Over 16 Years of Prospective Follow-Up. AB - The current study assesses time-to-cessation of individual therapy for patients with borderline personality disorder (BPD) and comparison subjects with other personality disorders (OPD) after 16 years of prospective follow-up. It also details the multivariate factors that predict this outcome for those with BPD. At baseline, 290 patients met criteria for BPD and 72 met criteria for OPD. Individuals with BPD had a significantly slower time-to-cessation of individual therapy than OPD comparison subjects. Seven baseline variables were found to be significant multivariate predictors of a slower time-to-cessation of individual therapy: older age, being white, severity of childhood neglect, history of a mood disorder, an IQ less than 90, poor vocational record prior to index admission, and higher level of trait neuroticism. The results of this study suggest that prediction of slower time-to-cessation of individual therapy is multifactorial in nature, involving factors related to demographics, childhood adversity, comorbidity, individual competence, and temperament. PMID- 29505390 TI - Borderline Personality Disorder: Associations Between Dimensional Personality Profiles and Self-Destructive Behaviors. AB - Ongoing research is shifting towards a dimensional understanding of borderline personality disorder (BPD). Aim of this study was to identify personality profiles in BPD that are predictive of self-destructive behaviors. Personality traits were assessed (n = 130) according to the five-factor model of personality (i.e., Neuroticism, Extraversion, Openness to Experience, Agreeableness, Conscientiousness) and an additional factor called Risk Preference. Self destructive behavior parameters such as non-suicidal self-injury (NSSI) and other borderline typical dyscontrolled behaviors (e.g., drug abuse) were assessed by self-report measures. Canonical correlation analyses demonstrated that Neuroticism, Extraversion, and Conscientiousness are predictors of NSSI. Further, Neuroticism, Agreeableness, and Risk Preference were associated with dyscontrolled behaviors. Our results add further support on personality-relevant self-destructive behaviors in BPD. A combined diagnostic assessment could offer clinically meaningful insights about the causes of self-destruction in BPD to expand current therapeutic repertoires. PMID- 29505392 TI - Barriers to care for women with breast cancer symptoms in rural Bangladesh. AB - Breast cancer survival rates in lower-income countries like Bangladesh are approximately 50%, versus over 80% in high income countries. Anecdotal reports suggest that, beyond economic and health system barriers, sociocultural factors may influence a woman's care-seeking behavior and resultant early stage diagnoses. To understand these barriers, we conducted 63 interviews (43 women with breast cancer symptoms and 20 men) in Khulna, Bangladesh. We identified socio-cultural barriers like neglect and indifference toward women, women's lack of power to use resources, and reduced support from family due to stigma. Interventions must address these barriers and improve the status of women in Bangladesh. PMID- 29505391 TI - Detecting the Presence of a Personality Disorder Using Interpersonal and Self Dysfunction. AB - Calls have increased to place interpersonal and self-disturbance as defining features of personality disorders (PDs). Findings from a methodologically diverse set of studies suggest that a common factor undergirds all PDs. The nature of this core of PDs, however, is not clear. In the current study, interviews were completed for DSM-IV PD diagnosis and interpersonal dysfunction independently with 272 individuals (PD = 191, no-PD = 91). Specifically, we evaluated interpersonal dysfunction across social domains. In addition, we empirically assessed the structure of self-dysfunction in PDs. We found dysfunction in work and romantic domains, and unstable identity uniquely predicted variance in the presence of a PD. Using receiver operating characteristic analysis, we found that the interpersonal dysfunction and self-dysfunction scales each predicted PDs with high accuracy. In combination, the scales resulted in excellent sensitivity (.90) and specificity (.88). The results support interpersonal and self-dysfunction as general factors of PD. PMID- 29505393 TI - Quality of life as a mediator of leisure activity and perceived health among older women. AB - Despite consistent evidence to suggest that participating in leisure is associated with perceived health status among older adults, there have been few attempts to determine the possible underlying mechanisms in this relationship, including the role of quality of life (QoL). This study examined the role of perceived quality of life in the relationship between leisure and perceived health in older women. Correlations, regression, and mediation analysis were conducted on data from the Woman's College Alumnae Women's Health Study. Results indicate that QoL partially mediates the relationship between leisure and perceived health in older women. Findings further establish the link between leisure and perceived health with QoL playing an important role in the relationship. PMID- 29505394 TI - Measuring Nutrition-Related Unmet Needs in Recently Hospital-Discharged Homebound Older Adults. AB - Functional limitations in homebound older adults may cause difficulties with obtaining and preparing adequate healthy food. Services exist to help with these difficulties, however, not all individuals who could benefit receive them. This secondary analysis of observational data, obtained via questionnaires from homebound, recently hospital discharged older adults (n = 566), aimed to identify the prevalence and correlates of unmet need for such services, and to examine the disagreement between self-reported need for a service and functional limitation that could be addressed by that service. One-fifth of respondents reported unmet need for vision services and oral health services, and one-tenth reported unmet need for transportation services and physical therapy. There was a significant association between reported need and functional limitation (p < 0.001) for all services, except mental health and grocery delivery. However, for each service there were participants who under-reported need, compared with functional ability indicators. More research is required to determine the best methods for measuring these needs to ensure that nutritional vulnerability is detected and addressed in those returning from hospital. PMID- 29505396 TI - Impulsivity and Comorbid PTSD-Binge Drinking. AB - OBJECTIVE: Trauma exposure is common, with estimates of 28 to 90% of adults reporting at least one traumatic event over their lifetime. Those exposed to traumatic events are at risk for alcohol misuse (i.e., binge drinking), posttraumatic stress disorder (PTSD), or both. A potential underlying mechanism for this comorbidity is increased impulsivity-the tendency to act rashly. Little work to date has examined the impact of different impulsogenic traits on this comorbidity. METHODS: This study (n = 162) investigated trauma-exposed young adults (age 21-30) who had endorsed a lifetime interpersonal trauma. Additionally, three impulsogenic traits (motor, non-planning, and attentional) were measured. RESULTS: Over and above the covariates for age, gender, race, and traumatic events, greater attentional impulsivity was associated with greater likelihood of meeting criteria for PTSD and binge drinking, compared to meeting criteria for PTSD, binge drinking, or neither. Neither non-planning impulsivity nor motor impulsivity exerted unique effects. CONCLUSIONS: Young adults who report difficulty attending to immediate stimuli within their environment may be unable to think about and/or process the traumatic event, potentially increasing risk for PTSD and maladaptive coping skills to manage this distress (e.g., alcohol misuse, binge drinking). PMID- 29505395 TI - There's no place like OM: Vesicular sorting and secretion of the peptidylarginine deiminase of Porphyromonas gingivalis. AB - The oral pathogen Porphyromonas gingivalis is one of the major periodontal agents and it has been recently hailed as a potential cause of the autoimmune disease rheumatoid arthritis. In particular, the peptidylarginine deiminase enzyme of P. gingivalis (PPAD) has been implicated in the citrullination of certain host proteins and the subsequent appearance of antibodies against citrullinated proteins, which might play a role in the etiology of rheumatoid arthritis. The aim of this study was to investigate the extracellular localization of PPAD in a large panel of clinical P. gingivalis isolates. Here we show that all isolates produced PPAD. In most cases PPAD was abundantly present in secreted outer membrane vesicles (OMVs) that are massively produced by P. gingivalis, and to minor extent in a soluble secreted state. Interestingly, a small subset of clinical isolates showed drastically reduced levels of the OMV-bound PPAD and secreted most of this enzyme in the soluble state. The latter phenotype is strictly associated with a lysine residue at position 373 in PPAD, implicating the more common glutamine residue at this position in PPAD association with OMVs. Further, one isolate displayed severely restricted vesiculation. Together, our findings show for the first time that neither the major association of PPAD with vesicles, nor P. gingivalis vesiculation per se, are needed for P. gingivalis interactions with the human host. PMID- 29505397 TI - Challenges of Dealing with Financial Concerns during Life-Threatening Illness: Perspectives of Health Care Practitioners. AB - The costs of serious medical illness and end of life care are often a heavy burden for patients and families (Collins, Stepanczuk, Williams, & Rich, 2016 ; Kim, 2007 ; May et al., 2014 ; Zarit, 2004 ). Twenty-six practitioners, including social workers, managers/administrators, supervisors, and case managers from five health care settings, participated in qualitative semistructured interviews about financial challenges patients encountered. Seven practitioners took part in a focus group. Practitioners were recruited from hospice (n = 5), long-term care (n = 5), intensive care (n = 5), dialysis (n = 6), and oncology (n = 5). Interview and focus group questions focused on financial challenges patients encountered when facing life-threatening illness. Interview data were transcribed and thematically coded and trustworthiness of data was established with peer debriefing, member checking, and agreement on themes among the authors. Practitioners described interacting micro, meso, and macroinfluences on the financial well-being and challenges patients encountered. Microlevel influences involved patient characteristics, such as their demographic profile and/or health status that set them up for financial aptitude or challenges. Macrolevel influences involved the larger health care/safety net system, which provided valuable resources for some patients but not others. Practitioners also discussed the mesolevel of influence, the local setting where they worked to match available resources with patients' individual needs given the constraints emerging from the micro and macrolevels. Practitioners described how they navigated the interplay of these three areas to meet patients' needs and cope with financial challenges. Implications for practice point to directly addressing the kind of financial concerns that patients and families facing financial burden from serious medical illness have, and identifying ways to bridge knowledge and resource access gaps at the individual, organizational, and societal levels. PMID- 29505398 TI - Bayesian Optimization of Personalized Models for Patient Vital-Sign Monitoring. AB - Gaussian process regression (GPR) provides a means to generate flexible personalized models of time series of patient vital signs. These models can perform useful clinical inference in ways that population-based models cannot. A challenge for the use of personalized models is that they must be amenable to a wide range of parameterizations, to accommodate the plausible physiology of any patient in the population. Additionally, optimal performance is typically achieved when models are regularized in light of the knowledge of the physiology of the individual patient. In this paper, we describe a method to build GP models with varying complexity (via covariance kernels) and regularization (via fixed priors over hyperparameters) on a patient-specific level, for the purpose of robust vital-sign forecasting. To this end, our results present evidence in support of two main hypotheses: 1) the use of patient-specific models can outperform population-based models for useful clinical tasks, such as vital-sign forecasting; and 2) the optimal values of (hyper)parameters of these models are best determined by sophisticated methods of optimization, due to high correlation between dimensions of the search space. The resulting models are sufficiently robust to inform clinicians of a patient's vital-sign trajectory and warn of imminent deterioration. PMID- 29505399 TI - Platform for Automated Real-Time High Performance Analytics on Medical Image Data. AB - Biomedical data are quickly growing in volume and in variety, providing clinicians an opportunity for better clinical decision support. Here, we demonstrate a robust platform that uses software automation and high performance computing (HPC) resources to achieve real-time analytics of clinical data, specifically magnetic resonance imaging (MRI) data. We used the Agave application programming interface to facilitate communication, data transfer, and job control between an MRI scanner and an off-site HPC resource. In this use case, Agave executed the graphical pipeline tool GRAphical Pipeline Environment (GRAPE) to perform automated, real-time, quantitative analysis of MRI scans. Same-session image processing will open the door for adaptive scanning and real-time quality control, potentially accelerating the discovery of pathologies and minimizing patient callbacks. We envision this platform can be adapted to other medical instruments, HPC resources, and analytics tools. PMID- 29505400 TI - Tempo-Spatial Compressed Sensing of Organ-on-a-Chip for Pervasive Health. AB - As a micro-engineered biomimetic system to replicate key functions of living organs, organ-on-a-chip (OC) technology provides a high-throughput model for investigating complex cell interactions with both high temporal and spatial resolutions in biological studies. Typically, microscopy and high-speed video cameras are used for data acquisition, which are expensive and bulky. Recently, compressed sensing (CS) has increasingly attracted attentions due to its extremely low-complexity structure and low sampling rate. However, there is no CS solution tailored for tempo-spatial information acquisition. In this paper, we propose tempo-spatial CS (TS-CS), a unified CS architecture for OC stream, which achieves significant cost reduction and truly combines sensing with compression along the temporal and spatial domains. We point out that TS-CS can consistently achieve better performance by exploiting tempo-spatial compressibility in OC data. To this end, we comprehensively evaluate the system performance by employing four different bases for CS. With comparison to the traditional way, we show that TS-CS always obtains better recovery result with a throughput bound and can achieve around throughput improvement under a reconstruction demand by applying discrete cosine transform matrix as the basis. PMID- 29505401 TI - Modeling Clinically Validated Physical Activity Assessments Using Commodity Hardware. AB - Consumer-grade wearable activity devices such as Fitbits are increasingly being used in research settings to promote physical activity (PA) due to their low-cost and widespread popularity. However, Fitbit-derived measures of activity intensity are consistently reported to be less accurate than intensity estimates obtained from research-grade accelerometers (i.e., ActiGraph). As such, the potential for using a Fitbit to measure PA intensity within research contexts remains limited. This study aims to model ActiGraph-based intensity estimates from the validated Freedson vector magnitude (VM3) algorithm using measures of steps, metabolic equivalents, and intensity levels obtained from Fitbit. Minute-level data collected from 19 subjects, who concurrently wore the ActiGraph GT3X and Fitbit Flex devices for an average of 1.8 weeks, were used to generate the model. After testing several modeling methods, a naive Bayes classifier was chosen based on the lowest achieved error rate. Overall, the model reduced Fitbit to ActiGraph errors from 19.97% to 16.32%. Moreover, the model reduced misclassification of Fitbit-based estimates of moderate-to-vigorous physical activity (MVPA) by 40%, eliminating a statistically significant difference between MVPA estimates derived from ActiGraph and Fitbit. Study findings support the general utility of the model for measuring MVPA with the Fitbit Flex in place of the more costly ActiGraph GT3X accelerometer for young healthy adults. PMID- 29505402 TI - On the Accuracy and Scalability of Probabilistic Data Linkage Over the Brazilian 114 Million Cohort. AB - Data linkage refers to the process of identifying and linking records that refer to the same entity across multiple heterogeneous data sources. This method has been widely utilized across scientific domains, including public health where records from clinical, administrative, and other surveillance databases are aggregated and used for research, decision making, and assessment of public policies. When a common set of unique identifiers does not exist across sources, probabilistic linkage approaches are used to link records using a combination of attributes. These methods require a careful choice of comparison attributes as well as similarity metrics and cutoff values to decide if a given pair of records matches or not and for assessing the accuracy of the results. In large, complex datasets, linking and assessing accuracy can be challenging due to the volume and complexity of the data, the absence of a gold standard, and the challenges associated with manually reviewing a very large number of record matches. In this paper, we present AtyImo, a hybrid probabilistic linkage tool optimized for high accuracy and scalability in massive data sets. We describe the implementation details around anonymization, blocking, deterministic and probabilistic linkage, and accuracy assessment. We present results from linking a large population-based cohort of 114 million individuals in Brazil to public health and administrative databases for research. In controlled and real scenarios, we observed high accuracy of results: 93%-97% true matches. In terms of scalability, we present AtyImo's ability to link the entire cohort in less than nine days using Spark and scaling up to 20 million records in less than 12s over heterogeneous (CPU+GPU) architectures. PMID- 29505403 TI - Ultrasound Imaging From Sparse RF Samples Using System Point Spread Functions. AB - Upcoming phased-array 2-D sensors will soon enable fast high-definition 3-D ultrasound imaging. Currently, the communication of raw radio-frequency (RF) channel data from the probe to the computer for digital beamforming is a bottleneck. For reducing the amount of transferred data samples, this paper investigates the design of an adapted sparse sampling technique for image reconstruction inspired by the compressed sensing framework. Echo responses from isolated points are generated using a physically based simulation of ultrasound wave propagation through tissues. These point spread functions form a dictionary of shift-variant bent waves, which depend on the specific sound excitation and acquisition protocols. Speckled ultrasound images can be approximately decomposed in this dictionary where sparsity is enforced at the system matrix design. The Moore-Penrose pseudoinverse is precomputed and used at the reconstruction stage for fast minimum-norm recovery from nonuniform pseudorandom sampled raw RF data. Results on simulated and acquired phantoms demonstrate the benefits of an optimized basis function design for high-quality B-mode image recovery from few RF channel data samples. PMID- 29505404 TI - Ultrafast Ultrasound Imaging as an Inverse Problem: Matrix-Free Sparse Image Reconstruction. AB - Conventional ultrasound (US) image reconstruction methods rely on delay-and-sum (DAS) beamforming, which is a relatively poor solution to the image reconstruction problem. An alternative to DAS consists in using iterative techniques, which require both an accurate measurement model and a strong prior on the image under scrutiny. Toward this goal, much effort has been deployed in formulating models for US imaging, which usually require a large amount of memory to store the matrix coefficients. We present two different techniques, which take advantage of fast and matrix-free formulations derived for the measurement model and its adjoint, and rely on sparsity of US images in well-chosen models. Sparse regularization is used for enhanced image reconstruction. Compressed beamforming exploits the compressed sensing framework to restore high-quality images from fewer raw data than state-of-the-art approaches. Using simulated data and in vivo experimental acquisitions, we show that the proposed approach is three orders of magnitude faster than non-DAS state-of-the-art methods, with comparable or better image quality. PMID- 29505405 TI - Robust Short-Lag Spatial Coherence Imaging. AB - Short-lag spatial coherence (SLSC) imaging displays the spatial coherence between backscattered ultrasound echoes instead of their signal amplitudes and is more robust to noise and clutter artifacts when compared with traditional delay-and sum (DAS) B-mode imaging. However, SLSC imaging does not consider the content of images formed with different lags, and thus does not exploit the differences in tissue texture at each short-lag value. Our proposed method improves SLSC imaging by weighting the addition of lag values (i.e., M-weighting) and by applying robust principal component analysis (RPCA) to search for a low-dimensional subspace for projecting coherence images created with different lag values. The RPCA-based projections are considered to be denoised versions of the originals that are then weighted and added across lags to yield a final robust SLSC (R SLSC) image. Our approach was tested on simulation, phantom, and in vivo liver data. Relative to DAS B-mode images, the mean contrast, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) improvements with R-SLSC images are 21.22 dB, 2.54, and 2.36, respectively, when averaged over simulated, phantom, and in vivo data and over all lags considered, which corresponds to mean improvements of 96.4%, 121.2%, and 120.5%, respectively. When compared with SLSC images, the corresponding mean improvements with R-SLSC images were 7.38 dB, 1.52, and 1.30, respectively (i.e., mean improvements of 14.5%, 50.5%, and 43.2%, respectively). Results show great promise for smoothing out the tissue texture of SLSC images and enhancing anechoic or hypoechoic target visibility at higher lag values, which could be useful in clinical tasks such as breast cyst visualization, liver vessel tracking, and obese patient imaging. PMID- 29505406 TI - Receiver-Operating Characteristic Analysis of Eigen-Based Clutter Filters for Ultrasound Color Flow Imaging. AB - The eigen-based filter has theoretically established itself as a potent solution in ultrasound color flow imaging (CFI) for combating against clutter arising from moving tissues. Yet, it remains poorly understood on how much gain in flow detection sensitivity and specificity can be delivered by this adaptive clutter filter. Here, we investigated the receiver operating characteristic (ROC) of the eigen-based clutter filter to statistically evaluate its efficacy. Our investigation was conducted using a new vascular phantom testbed that incorporated both intrinsic tissue motion (vessel pulsation: 7.58 cm/s peak velocity) and extrinsic tissue motion (vibration: 5-Hz frequency, 2.98 cm/s peak velocity), as well as pulsatile flow (pulse rate: 60 beats/min; systolic flow rate: 6.5 mL/s). The eigen-filter (single-ensemble formulation) was applied to CFI raw data sets obtained from the phantom's short-axis view (slow-time ensemble size: 12; pulse repetition frequency: 2 kHz; and ultrasound frequency: 5 MHz), and post-filter Doppler power was compared between flow and tissue regions. Results show that, in the presence of vessel pulsation and tissue vibration, the eigen-filter yielded a high true positive rate in depicting flow pixels in CFI frames (0.945 and 0.917, respectively, during peak systole and end diastole at 60 degrees beam-flow angle), while maintaining a low false alarm rate (0.10) in rendering tissue pixels. Also, the eigen-filter posed ROC curves whose area under curve was higher than those for the polynomial regression filter (statistically significant; t-test p values were less than 0.05). These findings serve well to substantiate the merit of using eigen-filters to enhance the vascular visualization capability of CFI. PMID- 29505407 TI - Investigation of Physical Phenomena Underlying Temporal-Enhanced Ultrasound as a New Diagnostic Imaging Technique: Theory and Simulations. AB - Temporal-enhanced ultrasound (TeUS) is a novel noninvasive imaging paradigm that captures information from a temporal sequence of backscattered US radio frequency data obtained from a fixed tissue location. This technology has been shown to be effective for classification of various in vivo and ex vivo tissue types including prostate cancer from benign tissue. Our previous studies have indicated two primary phenomena that influence TeUS: 1) changes in tissue temperature due to acoustic absorption and 2) micro vibrations of tissue due to physiological vibration. In this paper, first, a theoretical formulation for TeUS is presented. Next, a series of simulations are carried out to investigate micro vibration as a source of tissue characterizing information in TeUS. The simulations include finite element modeling of micro vibration in synthetic phantoms, followed by US image generation during TeUS imaging. The simulations are performed on two media, a sparse array of scatterers and a medium with pathology mimicking scatterers that match nuclei distribution extracted from a prostate digital pathology data set. Statistical analysis of the simulated TeUS data shows its ability to accurately classify tissue types. Our experiments suggest that TeUS can capture the microstructural differences, including scatterer density, in tissues as they react to micro vibrations. PMID- 29505408 TI - Realistic Vendor-Specific Synthetic Ultrasound Data for Quality Assurance of 2-D Speckle Tracking Echocardiography: Simulation Pipeline and Open Access Database. AB - Two-dimensional (2-D) echocardiography is the modality of choice in the clinic for the diagnosis of cardiac disease. Hereto, speckle tracking (ST) packages complement visual assessment by the cardiologist by providing quantitative diagnostic markers of global and regional cardiac function (e.g., displacement, strain, and strain-rate). Yet, the reported high vendor-dependence between the outputs of different ST packages raises clinical concern and hampers the widespread dissemination of the ST technology. In part, this is due to the lack of a solid commonly accepted quality assurance pipeline for ST packages. Recently, we have developed a framework to benchmark ST algorithms for 3-D echocardiography by using realistic simulated volumetric echocardiographic recordings. Yet, 3-D echocardiography remains an emerging technology, whereas the compelling clinical concern is, so far, directed to the standardization of 2-D ST only. Therefore, by building upon our previous work, we present in this paper a pipeline to generate realistic synthetic sequences for 2-D ST algorithms. Hereto, the synthetic cardiac motion is obtained from a complex electromechanical heart model, whereas realistic vendor-specific texture is obtained by sampling a real clinical ultrasound recording. By modifying the parameters in our pipeline, we generated an open-access library of 105 synthetic sequences encompassing: 1) healthy and ischemic motion patterns; 2) the most common apical probe orientations; and 3) vendor-specific image quality from seven different systems. Ground truth deformation is also provided to allow performance analysis. The application of the provided data set is also demonstrated in the benchmarking of a recent academic ST algorithm. PMID- 29505410 TI - Investigation on the Effect of Spatial Compounding on Photoacoustic Images of Carotid Plaques in the In Vivo Available Rotational Range. AB - Photoacoustic imaging (PAI) is a promising imaging modality due to its high optical specificity. However, the low signal-to-noise ratio (SNR) and contrast-to noise ratio (CNR) of in vivo PA images are major challenges that prevent PAI from finding its place in clinics. This paper investigates the merit of spatial compounding of PA images in arterial phantoms and the achievable improvements of SNR, when in vivo conditions are mimicked. The analysis of the compounding technique was performed on a polyvinyl alcohol vessel phantom with black threads embedded in its wall. The in vivo conditions were mimicked by limiting the rotation range in +/-30 degrees , adding turbid surrounding medium, and filling the lumen with porcine blood. Finally, the performance of the technique was evaluated in ex vivo human carotid plaque samples. Results showed that spatial compounding elevates the SNR by 5-10 dB and CNR by 1-5 dB, depending on the location of the absorbers. This paper elucidates prospective in vivo PA characterization of carotid plaques by proposing a method to enhance PA image quality. PMID- 29505409 TI - Robust Phase Velocity Dispersion Estimation of Viscoelastic Materials Used for Medical Applications Based on the Multiple Signal Classification Method. AB - Ultrasound shear wave elastography (SWE) is emerging as a promising imaging modality for the noninvasive evaluation of tissue mechanical properties. One of the ways to explore the viscoelasticity is through analyzing the shear wave velocity dispersion curves. To explore the dispersion, it is necessary to estimate the shear wave velocity at each frequency. An increase of the available spectrum to be used for phase velocity estimation is significant for a tissue dispersion analysis in vivo. A number of available methods suffer because the available spectrum that one can work with is limited. We present an alternative method to the classical 2-D Fourier transform (2D-FT) that uses the multiple signal classification (MUSIC) technique to provide robust estimation of the space and phase velocity dispersion curves. We compared results from the MUSIC method with the 2D-FT technique twofold: by searching for maximum peaks and gradient-based strategy. We tested this method on digital phantom data created using finite-element methods (FEMs) in viscoelastic media as well as on the experimental phantoms used in the Radiological Society of North America Quantitative Imaging Biomarker Alliance effort for the standardization of shear wave velocity in liver fibrosis applications. In addition, we evaluated the algorithm with different levels of added noise for FEMs. The MUSIC algorithm provided dispersion curves estimation with lower errors than the conventional 2D FT method. The MUSIC method can be used for the robust evaluation of shear wave velocity dispersion curves in viscoelastic media. PMID- 29505411 TI - Strategies to Obtain Subpitch Precision in Lateral Motion Estimation in Ultrasound Elastography. AB - In elastography, conventional linear array (CLA)-based RF data acquisition provides more accurate displacement measurements in the direction of beam propagation (axial direction) when compared to the perpendicular direction (lateral). Obtaining good quality lateral displacement estimates in ultrasound (US) elastography will lead to several benefits such as obtaining accurate inverse solutions, improving shear strain elastogram quality, getting good quality poroelastograms, and obtaining reliable rotation elastograms. For accomplishing high-precision lateral displacement estimation (LDE), one of the popular methods is by interpolating additional A-lines in between neighboring RF A-lines. We describe a method wherein true RF A-lines (not interpolated) are acquired and augmented at subpitch locations using CLA transducer, instead of interpolating the data, and using this new frame data for further image formation and/or processing to yield better lateral resolution and LDE. We demonstrate the proposed method by translating the US beam of CLA transducer in subpitch range by the following two approaches: 1) actuator-assisted beam translation and 2) electronic translation of subaperture of a CLA by activating odd and even number of consecutive elements sequentially, referred to as electronic beam translation. The performances of the different methods were studied through simulations and experiments on phantoms. The results demonstrate that these methods yield better quality LDE compared to those obtained from interpolation of RF A-lines. These methods may provide affordable ways to obtain subpitch precision LDE using CLA. PMID- 29505412 TI - Piezoelectric Nanotube Array for Broadband High-Frequency Ultrasonic Transducer. AB - Piezoelectric materials are vital in determining ultrasonic transducer and imaging performance as they offer the function for conversion between mechanical and electrical energy. Ultrasonic transducers with high-frequency operation suffer from performance degradation and fabrication difficulty of the demanded piezoelectric materials. Hence, we propose 1-D polymeric piezoelectric nanostructure with controlled nanoscale features to overcome the technical limitations of high-frequency ultrasonic transducers. For the first time, we demonstrate the integration of a well-aligned piezoelectric nanotube array to produce a high-frequency ultrasonic transducer with outstanding performance. We find that nanoconfinement-induced polarization orientation and unique nanotube structure lead to significantly improved piezoelectric and ultrasonic transducing performance over the conventional piezoelectric thin film. A large bandwidth, 126% (-6 dB), is achieved at high center frequency, 108 MHz. Transmission sensitivity of nanotube array is found to be 46% higher than that of the monolithic thin film transducer attributed to the improved electromechanical coupling effectiveness and impedance match. We further demonstrate high resolution scanning, ultrasonic imaging, and photoacoustic imaging using the obtained nanotube array transducers, which is valuable for biomedical imaging applications in the future. PMID- 29505413 TI - Monolithic Multiband CMUTs for Photoacoustic Computed Tomography With In Vivo Biological Tissue Imaging. AB - Among the biomedical imaging modalities, photoacoustic computed tomography (PACT) was one of the emerging hybrid techniques in recent years. In designing the PACT imaging system, a finite-bandwidth transducer is one of the limited factors for the overall performance. As the target size is inversely proportional to the dominant frequency components of the generated photoacoustic (PA) signal, a broad bandwidth transducer is desired for different scales' imaging. In this paper, a monolithic multiband capacitive micromachined ultrasonic transducer (CMUT) array was designed and fabricated for the reception of the wideband PA signals so as to provide high-resolution images with high-frequency CMUT arrays and present the high signal-to-noise-ratio major structure with low-frequency CMUT arrays. To demonstrate its performance, a phantom experiment was conducted to show and evaluate the various qualities of multiresolution images. In addition, an in vivo mouse model experiment was also carried out for revealing the multiscale PA imaging capability with the multiband CMUTs on biological tissues. From the obtained results, the images from different CMUT arrays could show the structures of the mouse brain in different scales. In addition, the images from the high frequency CMUT arrays were able to reveal the major blood vasculatures, whereas the images from low-frequency CMUT arrays showed the gross macroscopic anatomy of the brain with higher contrast. PMID- 29505414 TI - A General Analytical Formulation for the Motional Parameters of Piezoelectric MEMS Resonators. AB - This paper reports on a general analytical expression for the motional resistance ( ) of an arbitrary mode in a piezoelectric microelectromechanical system resonator with parallel plate electrode geometry. After applying simplifying assumptions and using analytical modes shapes, expressions for the of modes with out-of-plane flexure as the primary displacement are presented. These modes include free-free transverse beam flexure (TBF), unclamped disk flexure resonators (DFRs), and antisymmetric Lamb modes. For verification, is extracted from resonators fabricated in a lead zirconate titanate on silicon process. Predicted of TBF and DFR modes is validated using on-wafer extracted constants, analytical modal properties, and independently measured material properties. PMID- 29505415 TI - A Comparison of Two Configurations for a Dual-Resonance Cymbal Transducer. AB - The ability to design tuned ultrasonic devices that can be operated in the same mode at two different frequencies has the potential to benefit a range of applications, such as surgical cutting procedures where the penetration through soft then hard tissues could be enhanced by switching the operating frequency. The cymbal transducer has recently been adapted to form a prototype ultrasonic surgical cutting device that operates at a single frequency. In this paper, two different methods of configuring a dual-resonance cymbal transducer are detailed. The first approach relies on transducer fabrication using different metals for the two endcaps, thereby forming a dual-resonance transducer. The second employs transducer endcaps composed from a shape memory alloy, superelastic Nitinol. The resonance frequency of the Nitinol transducer depends on the phase microstructure of the material, switchable through the temperature or stress dependence of the Nitinol endcaps. The vibration response of each transducer is measured through electrical impedance measurements and laser Doppler vibrometry, and finite element analysis is used to show the sensitivity of transducer modal response to the fabrication processes. Through this paper, two viable dual-resonance cymbal transducers are designed and characterized and compared to illustrate the advantages and disadvantages of the two different approaches. PMID- 29505416 TI - The Application of the Factorization Method to the Subsurface Imaging of Surface Breaking Cracks. AB - A common location for cracks to appear is at the surface of a component; at the near surface, many nondestructive evaluation techniques are available to inspect for these, but at the far surface this is much more challenging. Ultrasonic imaging is proposed to enable far surface defect detection, location, and characterization. One specific challenge here is the presence of a strong reflection from the backwall, which can often mask the relatively small response from a defect. In this paper, the factorization method (FM) is explored for the application of subsurface imaging of the surface-breaking cracks. In this application, the component has two parallel surfaces, the crack is initiated from the far side and the phased array is attached on the near side. Ideally, the pure scattered field from a defect is needed for the correct estimation of the scatterer through the FM algorithm. However, the presence of the backwall will introduce a strong specular reflection into the measured data which should be removed before applying the FM algorithm. A novel subtraction method was developed to remove the backwall reflection. The performance of the FM algorithm and this subtraction method were tested with the simulated and experimental data. The experimental results showed a good consistency with the simulated results. It is shown that the FM algorithm can generate high-quality images to provide a good detection of the crack and an accurate sizing of the crack length. The subtraction method was able to provide a good backwall reflection removal in the case of small cracks (1-3 wavelengths). PMID- 29505417 TI - Low-Temperature Co-Fired Unipoled Multilayer Piezoelectric Transformers. AB - The reliability of piezoelectric transformers (PTs) is dependent upon the quality of fabrication technique as any heterogeneity, prestress, or misalignment can lead to spurious response. In this paper, unipoled multilayer PTs were investigated focusing on high-power composition and co-firing profile in order to provide low-temperature synthesized high-quality device measured in terms of efficiency and power density. The addition of 0.2 wt% CuO into Pb0.98Sr0.02(Mg1/3Nb2/3)0.06(Mn1/3Nb2/3)0.06(Zr0.48Ti0.52)0.88O3 (PMMnN-PZT) reduces the co-firing temperature from 1240 degrees C to 930 degrees C, which allows the use of Ag/Pd inner electrode instead of noble Pt inner electrode. Low temperature synthesized material was found to exhibit excellent piezoelectric properties ( , , %, pC/N, and degrees C). The performance of the PT co-fired with Ag/Pd electrode at 930 degrees C was similar to that co-fired at 1240 degrees C with Pt electrode (25% reduction in sintering temperature). Both high- and low-temperature synthesized PTs demonstrated 5-W output power with >90% efficiency and 11.5 W/cm3 power density. PMID- 29505418 TI - Reorganized Force Control in Elbow Pain Patients During Isometric Wrist Extension. AB - INTRODUCTION: Reorganized force control may be an important adaptation following painful traumas. In this study, force control adaptations were assessed in elbow pain patients. Increasing the contraction demand may overcome pain interference on the motor control and as such act as an internal control. It was hypothesized that elbow pain patients compared with controls would present greater change in the direction of force when increasing the demand of the motor task. METHODS: Elbow pain patients (n=19) and asymptomatic participants (n=21) performed isometric wrist extensions at 5% to 70% of maximum voluntary contraction. Pressure pain thresholds were recorded at the lateral epicondyle and tibialis anterior muscle. Contraction force was recorded using a 3-directional force transducer. Participants performed contractions according to visual feedback of the task-related force intensity (main direction of wrist extension) and another set of contractions with feedback of the 3 force directions. Going from the simple to the detailed force feedback will increase the demand of the motor task. Force steadiness in all 3 dimensions and force directions were extracted. RESULTS: Compared with controls, elbow pain patients presented lower pressure pain thresholds at both sites (P<0.05). Force steadiness was not significantly different between groups or feedback methods. The change in force direction when providing simple visual feedback in contrast with feedback of all force components at all contraction levels was greater for patients compared with controls (P<0.05). CONCLUSION: The larger change in force direction in pain patients implies redistribution of loads across the arm as an associated effect of pain. PMID- 29505419 TI - Depression Effects on Long-term Prescription Opioid Use, Abuse, and Addiction. AB - OBJECTIVES: Treatment guidelines discourage long-term opioid treatment for patients with chronic pain and major depression, but this treatment occurs commonly, producing higher daily doses, longer duration, and more adverse events. MATERIALS AND METHODS: Review of prospective cohort, retrospective cohort, and other observational studies of the relation between depression and opioid use, abuse, and addiction. RESULTS: Depressed patients initiate opioid therapy slightly more often than nondepressed patients, but are twice as likely to transition to long-term use. This adverse selection of high-risk patients with depression into long-term high-dose opioid therapy seems to be a process of self selection. Opioids may be used by patients with chronic pain and depression to compensate for a reduced endogenous opioid response to stressors. Depressed patients seem to continue opioid use at lower pain intensity levels and higher levels of physical function than do nondepressed patients. In studies that carefully control for confounding by indication, it has been shown that long-term opioid therapy increases the risk of incident, recurrent, and treatment-resistant depression. Depressed patients may tend to overuse opioids because they use them to treat insomnia and stress. Depression also seems to increase the risk of abuse or nonmedical use of prescription opioids among adults and adolescents. This increased rate of nonmedical opioid use may be the path through which depression increases the risk of opioid use disorder among patients with chronic pain. DISCUSSION: It is not possible to understand long-term opioid therapy for chronic pain without understanding the close and multifaceted relationship of this therapy with depression. PMID- 29505420 TI - Reducing Maternal Mortality and Severe Maternal Morbidity Through State-based Quality Improvement Initiatives. AB - State Perinatal Quality Collaboratives (PQCs) represent a major advance for scaling up quality improvement efforts for reducing maternal mortality and severe maternal morbidity. The critical roles of partners, rapid-cycle low-burden data systems, and linkage to maternal mortality review committees are reviewed. The choice of measures is also explored. California's experience with its PQC, data center, quality improvement efforts, and promising results for reduction of maternal mortality and morbidity from hemorrhage are presented. Early data from other states is also shared. PMID- 29505421 TI - Long Fusion Arthrodesis Stopping at L5 for Adult Scoliosis: Fate of L5-S1 Disk and Risk Factors for Subsequent Disk Degeneration. AB - STUDY DESIGN: This is retrospective study. OBJECTIVE: Our purpose is to examine the state of the L5-S1 disk after long fusion arthrodesis stopping at L5 in adult scoliosis, and to identify the risk factors for disk degeneration. SUMMARY OF BACKGROUND DATA: The long fusion arthrodesis surgery for adult scoliosis has shown to have good clinical results. However, there is still some controversy with reference to the potential caudal extents of the fusion, that is, L5 or S1. One of the most common problems related to the L5 fusion is whether subsequent L5 S1 disk degenerations occurs because of stress concentration. In this study, 1.5 T MRI was used to evaluate the L5-S1 disk degeneration according to Pfirrmann classification. MATERIALS AND METHODS: In total, 43 patients with adult scoliosis after posterior long fusions arthrodesis surgery were reviewed retrospectively with the average follow-up period of 4.17+/-1.55 years (range, 2-9 y). The 1.5 T MRI and standing long x-ray were performed preoperatively and at last follow-up visit. Clinical outcomes were evaluated according to Japanese Orthopedic Association (JOA) scores and Oswestry Disability Index (ODI). RESULTS: Subsequent L5-S1 disk degeneration was observed in 33 patients (51.56%). Preoperative average Pfirrmann grade was 1.98+/-0.58, whereas during last follow-up average Pfirrmann grade was 2.63+/-0.83 (P<0.001). Preoperative Pfirrmann grade in patients with subsequent disk degeneration was 1.94+/-0.66, and in patients without subsequent disk degeneration was 2.06+/-0.51 (P=0.278). Greater ODI showed in patients with subsequent degeneration (P=0.008). Multivariate logistic regression analysis revealed that long follow-up period, heavy labor, and preoperative imbalance were the risk factors. CONCLUSIONS: Subsequent L5-S1 disk degeneration was common after long fusions arthrodesis was stopped at L5. The recovery of neurological status was similar in patients with or without subsequent L5-S1 disk degeneration, whereas patients with subsequent degeneration complained more about low back pain. Patients with long follow-up period, heavy labor, and preoperative imbalance were more likely to suffer subsequent L5-S1 disk degeneration. PMID- 29505422 TI - Prevalence, Risk Factors, and Outcomes of Financial Stress in Survivors of Critical Illness. AB - OBJECTIVES: Little is known about the experience of financial stress for patients who survive critical illness or their families. Our objective was to describe the prevalence of financial stress among critically ill patients and their families, identify clinical and demographic characteristics associated with this stress, and explore associations between financial stress and psychologic distress. DESIGN: Secondary analysis of a randomized trial comparing a coping skills training program and an education program for patients surviving acute respiratory failure and their families. SETTING: Five geographically diverse hospitals. PARTICIPANTS: Patients (n = 175) and their family members (n = 85) completed surveys within 2 weeks of arrival home and 3 and 6 months after randomization. MEASUREMENTS AND MAIN RESULTS: We used regression analyses to assess associations between patient and family characteristics at baseline and financial stress at 3 and 6 months. We used path models and mediation analyses to explore relationships between financial stress, symptoms of anxiety and depression, and global mental health. Serious financial stress was high at both time points and was highest at 6 months (42.5%) among patients and at 3 months (48.5%) among family members. Factors associated with financial stress included female sex, young children at home, and baseline financial discomfort. Experiencing financial stress had direct effects on symptoms of anxiety (beta = 0.260; p < 0.001) and depression (beta = 0.048; p = 0.048). CONCLUSIONS: Financial stress after critical illness is common and associated with symptoms of anxiety and depression. Our findings provide direction for potential interventions to reduce this stress and improve psychologic outcomes for patients and their families. PMID- 29505423 TI - The Heat Is On: Clinical Implications of Intraoperative Thermoregulation Research. PMID- 29505424 TI - Histopathologic Features of Postablation Tubal Sterilization Syndrome. AB - Postablation tubal sterilization syndrome (PATSS) is an uncommon complication of endometrial ablation in patients with antecedent tubal ligation characterized by cyclic pelvic pain. Recurrent tubal distention resulting from retrograde menstruation into occluded proximal fallopian tube segments by residual/regenerated cornual endometrial tissue is postulated to be the cause. Reports of PATSS have largely focused on the clinicoradiologic and operative findings. Detailed descriptions of the gross pathologic findings of PATSS are sparse and rarer still are examples in which the histologic manifestations are discussed. Three patients with a history of tubal ligation and subsequent endometrial ablation who underwent hysterectomy and bilateral salpingo oophorectomy for pelvic pain were identified. A clinical suspicion of PATSS was conveyed to the pathologist at the time of initial pathologic examination in only 2 of the 3 cases. Pathologic findings in all 3 cases were similar and included hematosalpinx of the proximal fallopian tubes, intraluminal hemosiderotic material, mural hemosiderosis, and pseudoxanthomatous salpingitis featuring plical and mural lipofuscin-laden macrophages, along with inactive to attenuated endometrium with variable submucosal myometrial hyalinization/scarring compatible with postablative changes. The pathologic features, in conjunction with the appropriate clinicoradiologic findings, were interpreted as consistent with PATSS. PATSS complicates an estimated 5% to 10% of endometrial ablations, but is likely underreported due to a lack of awareness. Pathologists should consider PATSS in hysterectomy specimens that show postablative endometrial changes accompanied by hematosalpinx and pseudoxanthomatous salpingitis of the proximal segments of ligated fallopian tubes. To our knowledge, this is the first study to depict the histopathologic features of PATSS. PMID- 29505426 TI - Intralymphatic Spread is a Rare Finding Associated With Poor Prognosis in Diffuse Large B-Cell Lymphoma With Extranodal Involvements. AB - Intralymphatic spread is common in solid cancers, but has been rarely studied in lymphomas. Review of 635 extranodal specimens from 475 diffuse large B-cell lymphoma (DLBCL) patients revealed intralymphatic spread in 10 surgical resection specimens from 10 patients including 9 de novo DLBCLs and 1 Richter transformation. The prevalence in de novo DLBCL with extranodal involvements was 1.65%. The most common involved site of intralymphatic spread was the gastrointestinal tract, followed by the female genital tract and breasts. Lymphatic vessels, lined by D2-40-positive endothelial cells, were expanded by lymphoma cells, reminiscent of intravascular lymphoma or tumor emboli. None of the involved lymphatic vessels were located in the mucosa. Patients with intralymphatic spread had a trend of lower overall response rate and a trend of higher progressive disease than those without intralymphatic spread. Compared with patients without intralymphatic spread, those patients with intralymphatic spread had a shorter median overall survival (14.3 vs. 96.2 mo; P=0.004) and a shorter median progression-free survival (11.2 vs. 64.2 mo; P=0.01), respectively. Multivariate analyses showed that intralymphatic spread was an independent poor prognostic factor for overall survival (hazard ratio, 3.029; 95% confidence interval, 1.315-6.978; P=0.009), irrespective of the National Comprehensive Cancer Network-International Prognostic Index, B symptoms, and serum albumin levels. Among patients who underwent surgical resection, intralymphatic spread was still an independent prognostic factor. In conclusion, our study demonstrated extranodal intralymphatic spread in DLBCL. Inspiringly, this rare morphologic finding may serve as a new negative prognostic indicator in DLBCL with extranodal involvements. PMID- 29505425 TI - Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix. AB - Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor. PMID- 29505427 TI - Inflammatory Myofibroblastic Tumor Associated With the Placenta: Short Tandem Repeat Genotyping Confirms Uterine Site of Origin. AB - Inflammatory myofibroblastic tumor (IMT) is a neoplasm of intermediate malignant potential that only rarely involves the gynecologic tract. Several cases of IMT arising in various locations including the lung, bladder, trachea, and breast in association with pregnancy have been reported in the literature, and 3 cases involving the placenta have been previously described. We report 2 cases of IMT identified in association with pregnancy; the first was an intrauterine mass delivered entirely separate from the placenta and fetus, and the second was an incidental mass identified within the placental parenchyma following delivery. Short tandem repeat genotyping was used to compare tissue from the tumor and the placenta for both cases. Both tumors were determined to be of maternal origin, confirming that uterine IMTs may present within the placenta or as a separate mass following delivery. This demonstrates the utility of short tandem repeat genotyping in determining the origin of tumors presenting in association with the placenta. PMID- 29505429 TI - Differentiated Vulvar Intraepithelial Neoplasia-like and Lichen Sclerosus-like Lesions in HPV-associated Squamous Cell Carcinomas of the Vulva. AB - Most human papillomavirus (HPV)-associated vulvar squamous cell carcinomas (VSCCs) originate from high-grade squamous intraepithelial lesions, also named usual type vulvar intraepithelial neoplasia. However, growing evidence suggests that morphologic studies have limitations in predicting HPV status in vulvar lesions. We aimed to evaluate adjacent intraepithelial lesions in a series of DNA HPV-positive VSCCs, focusing on unusual histologic patterns mimicking differentiated vulvar intraepithelial neoplasia (dVIN) or lichen sclerosus (LS). We identified 326 DNA HPV-positive VSCC with at least 1 cm of skin adjacent to the invasive tumor and analyzed HPV typing, HPV E6*I mRNA, and p16 immunohistochemistry in all cases. A careful histologic evaluation was conducted. A conclusive association with HPV was based on a positive p16 or HPV E6*I mRNA result or both in addition to the HPV DNA, whereas cases negative for both markers were classified as nonconclusively associated with HPV. One hundred twenty-one tumors (37.1%) had normal adjacent skin, 191 (58.6%) had only high grade squamous intraepithelial lesions, also named usual type vulvar intraepithelial neoplasia, and unusual intraepithelial lesions were identified in 14 (4.3%) tumors. Seven cases showed dVIN-like features, 5 showed adjacent LS like lesion, and in 2 cases dVIN-like and LS-like lesions were identified simultaneously. Six of them were conclusively associated with HPV (3 dVIN-like, 2 LS-like, 1 with combined dVIN/LS-like features). All 6 tumors were associated with HPV16 and were positive for both p16 and HPV mRNA, and p16 was also positive in the dVIN-like and LS-like lesions. In summary, a small subset of VSCCs conclusively associated with HPV may arise on intraepithelial lesions, mimicking precursors of HPV-independent VSCC. PMID- 29505428 TI - Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. AB - Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications. PMID- 29505430 TI - One-dimensional Spatial Distributions of Gamma-ray Emitting Contaminants in Field Lysimeters Using a Collimated Gamma-ray Spectroscopy System. AB - One-dimensional scans of gamma-ray emitting contaminants were conducted on lysimeters from the RadFLEX facility at the Savannah River Nationals Laboratory (SRNL). The lysimeters each contained a contamination source that was buried in SRNL soil. A source consisted of Cs, Co, Ba, and Eu incorporated either into a solid waste form (Portland cement and reducing grout) or applied to a filter paper for direct soil exposure. The lysimeters were exposed to natural environmental conditions for 3 to 4 y. The initial contaminant activities range from 4.0 to 9.0 MBq for the solid wasteforms and 0.25 to 0.47 MBq for the soil incorporated source. The measurements were performed using a collimated high purity germanium gamma-ray spectrometer with a spatial resolution of 2.5 mm. These scans showed downward mobility of Co and Ba when the radionuclides were incorporated directly into the SRNL soil. When radionuclides were incorporated into the solid waste forms positioned in the SRNL soil, Cs exhibited both upward and downward dispersion while the other radionuclides showed no movement. This dispersion was more significant for the Portland cement than the reducing grout wasteform. Europium-152 was the only radionuclide of those studied that showed no movement within the spatial resolution of the scanner from the original placement within the lysimeter. Understanding radionuclide movement in the environment is important for developing strategies for waste management and disposal. PMID- 29505431 TI - Health Physics Society Comments to U.S. Environmental Protection Agency Regulatory Reform Task Force. AB - The Health Physics Society (HPS) provided comment to the U.S. Environmental Protection Agency (EPA) on options to consider when developing an action plan for President Trump's Executive Order to evaluate regulations for repeal, replacement, or modification. The HPS recommended that the EPA reconsider their adherence to the linear no-threshold (LNT) model for radiation risk calculations and improve several documents by better addressing uncertainties in low-dose, low dose-rate (LDDR) radiation exposure environments. The authors point out that use of the LNT model near background levels cannot provide reliable risk projections, use of the LNT model and collective-dose calculations in some EPA documents is inconsistent with the recommendations of international organizations, and some EPA documents have not been exposed to the public comment rule-making process. To assist in establishing a better scientific basis for the risks of low dose rate and low dose radiation exposure, the EPA should continue to support the "Million Worker Study," led by the National Council on Radiation Protection and Measurement. PMID- 29505432 TI - Alpha Air Sample Counting Efficiency Versus Dust Loading: Evaluation of a Large Data Set. AB - Dust loading on air sample filters is known to cause a loss of efficiency for direct counting of alpha activity on the filters, but the amount of dust loading and the correction factor needed to account for attenuated alpha particles is difficult to assess. In this paper, correction factors are developed by statistical analysis of a large database of air sample results for a uranium and plutonium processing facility at the Savannah River Site. As is typically the case, dust-loading data is not directly available, but sample volume is found to be a reasonable proxy measure; the amount of dust loading is inferred by a combination of the derived correction factors and a Monte Carlo model. The technique compares the distribution of activity ratios [beta/(beta + alpha)] by volume and applies a range of correction factors on the raw alpha count rate. The best-fit results with this method are compared with MCNP modeling of activity uniformly deposited in the dust and analytical laboratory results of digested filters. A linear fit is proposed to evenly-deposited alpha activity collected on filters with dust loading over a range of about 2 mg cm to 1,000 mg cm. PMID- 29505433 TI - Usage and Usability of a Web-based Program for Family Caregivers of Older People in Three European Countries: A Mixed-Methods Evaluation. AB - InformCare is a European Web platform that supports informal caregivers of older people by providing access to online information and professional and peer support. The aim of this study was to assess the usage and usability of a psychosocial Web-based program carried out in three European countries (Italy, Sweden, and Germany). A mixed-methods sequential explanatory design was adopted, comprising baseline and postintervention assessments, as well as combined thematic content analysis of results and focus group findings. A convenience sample of 118 caregivers was enrolled, of whom 94 used the services offered by the program at least once. The subsamples in the three countries used the platform in different ways, with a predominance of passive strategies (eg, seeking information and reading other people's comments) for Italian caregivers, and more active usage by Swedish and German caregivers. The usability assessment showed that the platform was perceived well by Italian and German caregivers, whereas technical problems affected the Swedish sample's experiences. Focus group data highlighted user satisfaction with the online support and reliability of the environment. Recommendations for practitioners are to ensure digital training for caregivers who have lower confidence in use of the Internet, to involve different healthcare professionals in the provision of professional support, and to adequately manage online community building. PMID- 29505434 TI - Ocular Impression-Taking-Which Material Is Best? AB - OBJECTIVES: To assess the efficacy and effect on clinical signs of a polyvinylsiloxane (Tresident; Shutz Dental Group GmbH, Germany) compared with an irreversible hydrocolloid (Orthoprint; Zhermack SpA, Badia Polesine, Italy) for ocular impression-taking. METHODS: Twenty subjects were recruited (13 female and 7 male), with mean age 31.1+/-4.6 years (SD) (range 25.8-39.7). Subjects attended for 2 sessions, each of 1-hr duration, on 2 separate days. Each session was scheduled at the same time on each day. At each visit, the subject underwent an ocular impression procedure, using either Tresident or Orthoprint, in random order and to one eye only. Investigator 2 was blind to this assignment. Two experienced practitioners conducted the study, investigator 1 performed the ocular impression procedures and investigator 2 observed and assessed the clinical signs: logMAR visual acuity, ocular surface staining, tear break-up time (TBUT), and ocular hyperemia. RESULTS: Visual acuity was unaffected by either material; TBUT was marginally disrupted by both materials, but was not clinically significant according to published criteria; ocular redness increased with both materials; and corneal staining was significantly greater after Orthoprint impression. Less redness and clinically insignificant staining after impression taking, with fewer clinical complications, was found after use of Tresident. CONCLUSIONS: Tresident offers a quicker, more effective, and clinically viable method of obtaining ocular impression topography compared with the traditional Orthoprint, and Orthoprint causes significantly more superficial punctuate staining of the corneal epithelium than Tresident. PMID- 29505435 TI - Effects of Intraneural Injection of Dexmedetomidine in Combination With Ropivacaine in Rat Sciatic Nerve Block. AB - BACKGROUND AND OBJECTIVES: Dexmedetomidine is known to have neural protection effect via attenuation of inflammatory responses induced by local anesthetics. We investigated whether intraneural dexmedetomidine is effective for attenuating or preventing neural injury resulting from inadvertent intraneural injection of local anesthetic. METHODS: Rats were randomly divided, and left sciatic nerve was surgically exposed. The rats received no injection (control group) or intraneural injections of 0.2 mL of normal saline (saline group), 0.2 mL of 0.5% ropivacaine (ropivacaine group), or 0.2 mL of 0.5% ropivacaine and 0.5 MUg/kg of dexmedetomidine (ropivacaine plus dexmedetomidine group). Interleukin (IL)-6 and IL-1beta messenger RNA (mRNA) levels were detected at 60 minutes after intraneural injection in experiment 1 (5 per group). Sensory and motor functions were assessed until the return of normal sensory and motor functions, and histopathological and ultrastructure analysis were performed at 4 weeks after intraneural injection in experiment 2 (8 per group). RESULTS: Dexmedetomidine with ropivacaine better enhanced sensory and motor blockade than ropivacaine alone. IL-6 (3.2 +/- 1.0 vs 5.9 +/- 2.1), IL-1beta (1.1 +/- 0.1 vs 2.2 +/- 0.7) levels, scores of axon and myelinated fiber degeneration (1 [0-2] vs 2 [1-3]), and demyelinated fiber percentages (20.1 +/- 10.4 vs 48.3 +/- 12.7) were lower in the ropivacaine plus dexmedetomidine group than in the ropivacaine group. No animals showed any signs of permanent neurological deficit. CONCLUSIONS: Intraneural dexmedetomidine has sensory and motor blockade-enhancing effects, anti-inflammatory properties, and protective effects against neural injury. These findings suggest that dexmedetomidine as an adjuvant has beneficial effects in rat when intraneural injection of local anesthetic occurs. PMID- 29505436 TI - Intramedullary Percutaneous Fixation of Extra-Articular Proximal and Middle Phalanx Fractures. AB - Multiple methods have been described for treating unstable proximal and middle phalangeal fractures. Irrespective of using an open or closed technique of fixation, stiffness and extensor lag at the proximal/distal interphalangeal joint almost always occur. This issue can be avoided by allowing the patients to mobilize the fingers out of plaster or splint as early as possible from the day of surgery. We describe a technique of intramedullary percutaneous fixation of extra-articular proximal and middle phalanx fractures allowing immediate mobilization of fingers, concurrent stabilization with progressive healing and thus preventing such complications. PMID- 29505437 TI - Development of an Epilepsy Nursing Communication Tool: Improving the Quality of Interactions Between Nurses and Patients With Seizures. AB - BACKGROUND: Nurses have become increasingly involved in overseeing the management of patients with complex medical conditions, including those with epilepsy. Nurses who are not specialists in epilepsy can play a central role in providing optimal care, education, and support to their patients with epilepsy, given the proper tools. OBJECTIVE: Our objective was to create a tool that can be used by nurses in the clinic setting to help facilitate discussion of topics relevant to enhancing medical care and management of patients with epilepsy. To address this need, a panel of epilepsy nursing experts used a patient-centered care approach to develop an Epilepsy Nursing Communication Tool (ENCT). METHODS: An initial set of topics and questions was created based on findings from a literature review. Eight nurse experts reviewed and revised the ENCT using focus groups and discussion forums. The revised ENCT was provided to nurses who care for patients with epilepsy but had not been involved in ENCT development. Nurses were asked to rate the usability and feasibility on a 5-point scale to assess whether the tool captured important topics and was easy to use. RESULTS: Ten nurses provided usability and feasibility assessments. Results indicated strong tool utility, with median scores of 4.5, 4, and 4 for usefulness, ease of use, and acceptability, respectively. CONCLUSIONS: The preliminary ENCT shows promise in providing a tool that nurses can use in their interactions with patients with epilepsy to help address the complexity of disease management, which may help improve overall patient care. PMID- 29505438 TI - Association of Postoperative Topical Prostaglandin Analog or Beta-Blocker Use and Incidence of Pseudophakic Cystoid Macular Edema. AB - PURPOSE: The purpose of this article is to determine the association of postoperative topical prostaglandin analog (PGA) or topical beta-blocker use and the incidence of pseudophakic cystoid macular edema (CME). METHODS: This was a nested case-control study. All adult patients who underwent cataract surgery between January 1, 2006 and December 31, 2016 and who were enrolled in the PharMetrics Plus database were eligible for inclusion. The association between postoperative topical PGAs (bimatoprost, latanoprost, and travoprost/travoprost z) or beta-blocker (betaxolol, levobunolol, and timolol) use and the incidence of pseudophakic CME was assessed by conditional logistic regression. RESULTS: Five hundred eight cases and 5080 controls were included in the analyses. Incidence of pseudophakic CME was found to be statistically significantly associated with the current postoperative use of both topical PGAs [relative risk (RR), 1.86; 95% confidence interval (CI), 1.04-3.32] and topical beta-blockers (RR, 2.64; 95% CI, 1.08-6.49). Postoperative use of each of bimatoprost (RR, 2.73; 95% CI, 1.35% 5.53%) and travoprost/travoprost-z (RR, 3.16; 95% CI, 1.42-7.03) in the year before diagnosis was demonstrated to be statistically significantly associated with the incidence of pseudophakic CME. This association was not observed to be statistically significant with the postoperative use of latanoprost (RR, 1.55; 95% CI, 0.84-2.88). CONCLUSIONS: To the best of our knowledge this is the largest study that has investigated the association between postoperative topical PGA or topical beta-blocker use and the incidence of pseudophakic CME. Postoperative use of both topical PGAs and topical beta-blockers was found to be associated with the incidence of pseudophakic CME. PMID- 29505439 TI - Surgical Outcomes of a New Low-Cost Nonvalved Glaucoma Drainage Device in Refractory Glaucoma: Results at 1 Year. AB - PURPOSE: The purpose of this study was to report the early outcomes in terms of efficacy and safety of a new, indigenously manufactured, low-cost nonvalved drainage device [AADI (Aurolab Aqueous Drainage Implant)] in the management of refractory glaucoma in the Indian population. METHODS: Retrospective review of consecutive patients older than 12 years, who underwent glaucoma drainage device surgery (GDD) using AADI, by a single fellowship-trained surgeon, between January 2014 and December 2016, who had at least 3 months of documented post-op follow up. OUTCOME MEASURES: Primary-intraocular pressure (IOP).Secondary-number of antiglaucoma medication (AGM), LogMAR best corrected visual acuity (BCVA), and complications.Complete success was defined as IOP >=5 mm Hg and <=21 mm Hg or reduction of IOP by >=20% from baseline without AGM; qualified success with use of AGM. Failure was defined as inability to meet IOP criteria, loss of perception of light, explantation or any additional glaucoma surgery. RESULTS: A total of 54 eyes of 51 patients were included. Mean follow up was 12.1+/-6.3 months. The IOP and number of AGM required was significantly lower at every visit postoperatively (P<0.001). Median LogMAR BCVA remained unchanged (P=0.5). Complications occurred in 22 patients (40.7%). Complete success was seen in 66.6%; overall success was 92.6%. CONCLUSIONS: New nonvalved GDD (AADI) surgery is effective in reducing IOP and need for AGM with a safety profile similar to published reports of prevailing GDDs. It thus has the ability to breach the cost barrier in low-to-middle income countries; further follow-up is required to determine sustainability over time. PMID- 29505440 TI - INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR EXUDATIVE RETINAL ARTERIAL MACROANEURYSMS. AB - PURPOSE: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective multicenter interventional study of anti-vascular endothelial growth factor in symptomatic RAMs. Central macular thickness in MUm and best-corrected visual acuity in logMar were correlated with the RAM size and distance to the macula. Statistical analyses were performed using paired comparisons and Pearson correlation. RESULTS: Thirty-two eyes (32 patients) were treated with a mean of 2.7 injections over a mean follow-up of 16.6 months. Initial best-corrected visual acuity correlated with the RAM size and distance to the macula (P = 0.02). Central macular thickness decreased by 131,180, and 211 MUm at 1, 2, and 3 months after the first injection (P < 0.001). Best-corrected visual acuity improved by 0.47 and 0.38 Early Treatment Diabetic Retinopathy Study lines at 2 and 3 months (P = 0.005). Anti-vascular endothelial growth factor response correlated with the RAM size (P = 0.04) and the distance to the macula (P = 0.009). CONCLUSION: Symptomatic RAMs can be treated successfully with anti-vascular endothelial growth factor injections, leading to a decrease in macular edema. PMID- 29505441 TI - WIDEFIELD SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING OF PERIPHERAL ROUND RETINAL HOLES WITH OR WITHOUT RETINAL DETACHMENT. AB - PURPOSE: To describe the widefield spectral-domain optical coherence tomography features of peripheral round retinal holes, with or without associated retinal detachment (RD). METHODS: Retrospective, observational study of 28 eyes with peripheral round retinal holes, with and without RD. Patients underwent imaging with a widefield 50-degree spectral-domain optical coherence tomography (Heidelberg Engineering, Germany) and Optos ultra-widefield imaging systems (Optos, United Kingdom). RESULTS: Vitreous attachment at the site of the retinal hole was detected in 27/28 (96.4%) cases. Cases were split into three groups: RHs with RD (n = 12); RHs with subretinal fluid (n = 5), and flat RHs (n = 11), with minimal or no subretinal fluid. 91.6% retinal holes associated with subretinal fluid or RD had vitreous attachment at the site of the hole. Eighty percent had vitreous attachment at both edges of the retinal hole, in a U-shape configuration, which appeared to exert traction. By contrast, flat retinal holes had visible vitreous attachment only at one edge of the retinal hole in 45.4%. CONCLUSION: Vitreous attachment was commonly seen at the site of round retinal holes. Vitreous attachment at both edges of the retinal hole in a U-shape configuration was more commonly seen at holes associated with subretinal fluid or RD. PMID- 29505442 TI - The Association Between Timing of Routine Preoperative Blood Testing and a Composite of 30-Day Postoperative Morbidity and Mortality. AB - BACKGROUND: Laboratory testing is a common component of preanesthesia evaluation and is designed to identify medical abnormalities that might otherwise remain undetected. While blood testing might optimally be performed shortly before surgery, it is often done earlier for practical reasons. We tested the hypothesis that longer periods between preoperative laboratory testing and surgery are associated with increased odds of having a composite of 30-day morbidity and mortality. METHODS: We obtained preoperative data from 2,320,920 patients in the American College of Surgeons National Surgical Quality Improvement Program who were treated between 2005 and 2012. Our analysis was restricted to relatively healthy patients with American Society of Anesthesiology physical status I-II who had elective surgery and normal blood test results (n = 235,010). The primary relationship of interest was the odds of 30-day morbidity and mortality as a function of delay between preoperative testing and surgery. A multivariable logistic regression model was used for the 10 pairwise comparisons among the 5 laboratory timing groups (laboratory blood tests within 1 week of surgery; 1-2 weeks; 2-4 weeks; 1-2 months; and 2-3 months) on 30-day morbidity, adjusting for any imbalanced baseline covariables and type of surgery. RESULTS: A total of 4082 patients (1.74%) had at least one of the component morbidities or died within 30 days after surgery. The observed incidence (unadjusted) was 1.7% when the most recent laboratory blood tests measured within 1 week of surgery, 1.7% when it was within 1-2 weeks, 1.8% when it was within 2-4 weeks, 1.7% when it was between 1 and 2 months, and 2.0% for patients with most recent laboratory blood tests measured 2-3 months before surgery. None of the values within 2 months differed significantly: estimated odds ratios for patients within blood tested within 1 week were 1.00 (99.5% confidence interval, 0.89-1.12) as compared to 1-2 weeks, 0.88 (0.77-1.00) for 2-4 weeks, and 0.95 (0.79-1.14) for 1-2 months, respectively. The estimated odds ratio comparing 1-2 weeks to each of 2-4 weeks and 1-2 months were 0.88 (0.76-1.03) and 0.95 (0.78-1.16), respectively. Blood testing 2-3 months before surgery was associated with increased odds of outcome compared to patients whose most recent test was within 1 week (P = .002) and 1-2 weeks of the date of surgery. CONCLUSIONS: In American Society of Anesthesiologists physical status I and II patients, risk of 30-day morbidity and mortality was not different with blood testing up to 2 months before surgery, suggesting that it is unnecessary to retest patients shortly before surgery. PMID- 29505443 TI - Renal Interstitial Exhaustion and SGLT2 Blockers. PMID- 29505444 TI - Pulse Pressure and Carotid Artery Doppler Velocimetry as Indicators of Maternal Volume Status: A Prospective Cohort Study. AB - BACKGROUND: Narrow pulse pressure has been demonstrated to indicate low central volume status. In critically ill patients, volume status can be qualitatively evaluated using Doppler velocimetry to assess hemodynamic changes in the carotid artery in response to autotransfusion with passive leg raise (PLR). Neither parameter has been prospectively evaluated in an obstetric population. The objective of this study was to determine if pulse pressure could predict the response to autotransfusion using carotid artery Doppler in healthy intrapartum women. We hypothesized that the carotid artery Doppler response to PLR would be greater in women with a narrow pulse pressure, indicating relative hypovolemia. METHODS: Intrapartum women with singleton gestations >=35 weeks without acute or chronic medical conditions were recruited to this prospective cohort study. Participants were grouped by admission pulse pressure as <45 mm Hg (narrow) or >=50 mm Hg (normal). Maternal carotid artery Doppler assessment was then performed in all patients before and after PLR using a standard technique where carotid blood flow (mL/min) = pi * (carotid artery diameter/2) * (velocity time integral) * (60 seconds). The velocity time integral was calculated from the Doppler waveform. The primary outcome was the change in the carotid Doppler parameters (carotid artery diameter, velocity time integral, and carotid blood flow) after PLR. Outcomes were compared between study groups with univariable and multivariable analyses with adjustment for potential confounding factors. RESULTS: Thirty-three women consented to participation, including 18 in the narrow and 15 in the normal pulse pressure groups (mean and standard deviation initial pulse pressure, 38.3 +/- 4.4 vs 57.3 +/- 4.1 mm Hg). The 2 groups demonstrated similar characteristics except for initial pulse pressure, systolic and diastolic blood pressure, and race. In response to PLR, the narrow pulse pressure group had a significantly greater increase in carotid artery diameter (0.08 vs 0.02 cm; standardized difference, 2.0; 95% confidence interval [CI], 1.16-2.84), carotid blood flow (79.4 vs 16.0 mL/min; standardized difference, 2.23; 95% CI, 1.36-3.10), and percent change in carotid blood flow (47.5% vs 8.7%; standardized difference, 2.52; 95% CI, 1.60-3.43) compared with the normal pulse pressure group. In multivariable analysis with adjustment for potential confounding factors, women with narrow admission pulse pressure had a significantly larger carotid diameter (0.66 vs 0.62 cm; P < .0001) and greater carotid flow (246.7 vs 219.3 cm/s; P = .001) after PLR compared to women with a normal pulse pressure. Initial pulse pressure was strongly correlated with the change in carotid flow after PLR (r = 0.60; P < .0001). CONCLUSIONS: The hemodynamic response of the carotid artery to autotransfusion after PLR is significantly greater in women with narrow pulse pressure. Pulse pressure correlates with the physiological response to autotransfusion and provides a qualitative indication of intravascular volume in term and near-term pregnant women. PMID- 29505445 TI - The Effect of Repeated Versus Initial Procalcitonin Measurements on Diagnosis of Infection in the Intensive Care Setting: A Prospective Observational Study. AB - Procalcitonin (PCT) measurement has been proposed to direct antibiotic use. We examined whether repeated PCT measurements (0, 6, and/or 12 hours) versus the initial measurement only (time 0) increased the sensitivity and specificity of PCT for diagnosing infection in intensive care unit patients. Infection was identified in 67/176 (38%) patients. The sensitivity of repeated versus the initial PCT measurement (with a cutoff value 0.5 ng/mL) was 52/67 (77%; 95% confidence interval [CI], 66%-87%) vs 46/67 (69%; 95% CI, 56%-79%; P = .04) and specificity 60/109 (55%; 95% CI, 45%-65%) vs 59/109 (54%; 95% CI, 44%-64%; P = 1.0). Repeat PCT evaluations over 12 hours did not provide a clinically significant improvement in diagnostic accuracy when compared to the initial single test. PMID- 29505446 TI - Description of a Novel Set-up for Functional Echocardiographic Assessment of Left Ventricular Performance During Ex Vivo Heart Perfusion. AB - Ex vivo heart perfusion (EVHP) is a new technology aimed at decreasing cold ischemia time and evaluating cardiac function before transplanting a donor heart. In an experimental EVHP swine model, we tested a 3D-printed custom-made set-up to perform surface echocardiography on an isolated beating heart during left ventricular loading. The views obtained at any time point were equivalent to standard transesophageal and transthoracic views. A decrease in left ventricular function during EVHP was observed in all experiments. PMID- 29505447 TI - The Association of Targeted Cell Salvage Blood Transfusion During Cesarean Delivery With Allogeneic Packed Red Blood Cell Transfusions in a Maternity Hospital in China. AB - BACKGROUND: Autologous transfusion of intraoperative cell salvage blood may be a potential method to decrease the need for allogeneic packed red blood cell transfusions after cesarean delivery, although there are limited data on the benefits of this method. This study evaluated the implementation of targeted intraoperative cell salvage during cesarean delivery in women at increased risk for hemorrhage at the Women's and Children's Hospital in Ningbo, China. METHODS: All women who underwent cesarean delivery >28 weeks of gestation were included in the study. The period before intraoperative cell collection (October 1, 2010, to August 31, 2012, n = 11,322) was compared with the postimplementation period (September 1, 2012, to June 30, 2015, n = 17,456) using an interrupted time series analysis. In the postimplementation period, women suspected to be at increased risk of the need for a blood transfusion (1604, 9.2%) underwent intraoperative cell salvage collection. The primary outcomes were the monthly rate of allogeneic packed red blood cell use and the incidence of clinical manifestation of acute blood transfusion reactions. RESULTS: The mean (standard deviation) estimated monthly allogeneic packed blood cell transfusion rate at the end of the 57-month study was 2.2% +/- 0.7% with the implementation compared with 2.7% +/- 0.9% without, difference -0.5%, 95% CI, -1.4% to 0.3%; P = .22. The mean number of allogeneic units transfused per patient was 4.1 +/- 0.4 units with implementation and 3.9 +/- 0.9 units without, difference 0.2, 95% CI, -1.7 to 1.1 units; P = .69. Intraoperative cell salvage blood was reinfused in 757 (47%) and wasted in 847 (53%) cases. The monthly intraoperative allogeneic packed red blood cells use rate was lower after implementation (difference -0.7%, 95% CI, -0.1% to -1.4%; P = .03); however, the monthly postpartum allogeneic packed red blood cell use rate was unchanged (difference -0.2%, 95% CI, -0.4% to 0.7%; P = .56). The clinical manifestation of acute blood transfusion reactions rate was unchanged (difference -2%, 99% CI, -9% to 5%; P = .55) between the periods. CONCLUSIONS: Our findings suggest that targeted intraoperative cell salvage in women undergoing cesarean delivery was associated with less allogeneic blood exposure in the operating room, but not in the postoperative period. Intraoperative cell salvage in targeted cesarean deliveries was not associated with a lesser allogeneic red blood cell exposure over the hospital admission period. The lack of adverse events associated with intraoperative cell salvage supports the safety of intraoperative cell salvage in cesarean delivery. PMID- 29505448 TI - Predicting Persistent Pain After Surgery: Can Predicting the Weather Serve as an Example? PMID- 29505449 TI - Excipients in Anesthesia Medications. AB - Medications used in anesthesiology contain both pharmacologically active compounds and additional additives that are usually regarded as being pharmacologically inactive. These additives, called excipients, serve diverse functions. Despite being labeled inert, excipients are not necessarily benign substances. Anesthesiologists should have a clear understanding of their chemical properties and the potential for adverse reactions. This report catalogs the excipients found in drugs commonly used in anesthesiology, provides a brief description of their function, and documents examples from the literature regarding their adverse effects. PMID- 29505450 TI - A Device for the Quantification of Oxygen Consumption and Caloric Expenditure in the Neonatal Range. AB - BACKGROUND: The accurate measurement of oxygen consumption (VO2) and energy expenditure (EE) may be helpful to optimize the treatment of critically ill patients. However, current techniques are limited in their ability to accurately quantify these end points in infants due to a low VO2, low tidal volume, and rapid respiratory rate. This study describes and validates a new device intended to perform in this size range. METHODS: We created a customized device that quantifies inspiratory volume using a pneumotachometer and concentrations of oxygen and carbon dioxide gas in the inspiratory and expiratory limbs. We created a customized algorithm to achieve precise time alignment of these measures, incorporating bias flow and compliance factors. The device was validated in 3 ways. First, we infused a certified gas mixture (50% oxygen/50% carbon dioxide) into an artificial lung circuit, comparing measured with simulated VO2 and carbon dioxide production (VCO2) within a matrix of varying tidal volume (4-20 mL), respiratory rate (20-80 bpm), and fraction of inspired oxygen (0.21-0.8). Second, VO2, VCO2, and EE were measured in Sprague Dawley rats under mechanical ventilation and were compared to simultaneous Douglas bag collections. Third, the device was studied on n = 14 intubated, spontaneously breathing neonates and infants, comparing measured values to Douglas measurements. In all cases, we assessed for difference between the device and reference standard by linear regression and Bland-Altman analysis. RESULTS: In vitro, the mean +/- standard deviation difference between the measured and reference standard VO2 was +0.04 +/ 1.10 (95% limits of agreement, -2.11 to +2.20) mL/min and VCO2 was +0.26 +/- 0.31 (-0.36 to +0.89) mL/min; differences were similar at each respiratory rate and tidal volume measured, but higher at fraction of inspired oxygen of 0.8 than at 0.7 or lower. In rodents, the mean difference was -0.20 +/- 0.55 (-1.28 to +0.89) mL/min for VO2, +0.16 +/- 0.25 (-0.32 to +0.65) mL/min for VCO2, and -0.84 +/- 3.29 (-7.30 to +5.61) kcal/d for EE. In infants, the mean VO2 was 9.0 +/- 2.5 mL/kg/min by Douglas method and was accurately measured by the device (bias, +0.22 +/- 0.87 [-1.49 to +1.93] mL/kg/min). The average VCO2 was 8.1 +/- 2.3 mL/kg/min, and the device exhibited a bias of +0.33 +/- 0.82 (-1.27 to +1.94) mL/kg/min. Mean bias was +2.56% +/- 11.60% of the reading for VO2 and +4.25% +/- 11.20% of the reading for VCO2; among 56 replicates, 6 measurements fell outside of the 20% error range, and no patient had >1 of 4 replicates with a >20% error in either VO2 or VCO2. CONCLUSIONS: This device can measure VO2, VCO2, and EE with sufficient accuracy for clinical decision-making within the neonatal and pediatric size range, including in the setting of tachypnea or hyperoxia. PMID- 29505451 TI - In Response. PMID- 29505452 TI - Questions Regarding Perioperative Surgical Home by Kim et al. PMID- 29505453 TI - In Response. PMID- 29505454 TI - A newborn diagnosed with van Maldergem syndrome. PMID- 29505455 TI - Expanding Nursing Approaches to Address Addiction: Mobile Health Technology. PMID- 29505456 TI - Relational Health and Recovery: Adolescent Girls in Chemical Dependency Treatment. AB - Adolescent substance use (SU) endures as a priority concern to communities. The increasing risk of SU in young women has been a rising concern, and the needs of young women may be unique. The importance of relationships and "connectedness" as aberrant behavior protective factors has been validated extensively in the literature of several disciplines over the past decade. Less well described are the components and qualities of relational engagement among adolescents involved in SU treatment. This multimethod study was a broad analysis of the nature of relational health in adolescent girls, so as to determine whether understanding components of relational health could inform SU treatment options. The survey tool, the Relational Health Indices (Liang et al., 2002), was used to measure dimensions and domains of relational health in adolescent girls and informed qualitative methods in the study. It is clear from this research that adolescent girls in SU treatment care deeply about but are confused regarding their relationships with others, particularly their romantic partners and their mothers. They have a desire to help others, specifically their siblings and others struggling with addiction. This article describes the multimethod study and implications for treatment, research, and education. PMID- 29505457 TI - The Relationship Between Emotional Intelligence and Internet Addiction Among Youth and Adults. AB - This study aimed to compare emotional intelligence (EI) levels and Internet addiction (IA) by gender and age groups and to assess the predictive relationship between EI and IA. One thousand four hundred thirteen young people and adults participated in the study. Participants were between 17 and 81 years old (M = 38.70 years old, SD = 13.72 years old); 42.2% were male, whereas 57.5% were female. We used a sociodemographic questionnaire, the Schutte Emotional Intelligence Scale (Schutte, Malouff, & Bhullar, 2009), and the Internet Addiction Test (Young, 1998) as data collection instruments. Results showed that there is a weak, but statistically significant, negative relationship between EI and IA. We found higher levels of EI in older people and in women than in the youngest participants and in men. No relevant prevalence of IA was found in the participants of this study. PMID- 29505458 TI - Prevalence and Correlates of Substance Use in Homeless Youth and Young Adults. AB - Substance use is higher among homeless youth than among the general population. Although substance use has been well studied, little is known about the risk factors associated with specific substances used by homeless youth, particularly in the Houston, Texas, area. Therefore, we conducted this study to examine the rates of lifetime and past-month substance use in a sample of homeless youth in Harris County, Texas, and examine the relations between substance type and race/ethnicity, age, gender identity, sexual orientation, shelter status, stress, and trauma history. Participants were recruited during October and November 2014 as part of the study YouthCount 2.0! and completed a survey to assess demographics, stress, abuse, substance use, and risk behaviors. The sample (N = 416) was predominantly young adult (13-17 years old: 55 and 18-24 years old: 361), African American (54.5%), and male (55.9%). Nearly one quarter identified as lesbian, gay, bisexual, or questioning (n = 102). Over a third of youth had used alcohol (38%) or marijuana (36%) in the past month, and 36% had ever used synthetic marijuana. Bivariate analyses showed that substance use was significantly associated with race/ethnicity, age, gender identity, sexual orientation, shelter status, stress, and trauma scores. Youth in this study had lower rates of alcohol and some substance use than other samples of homeless youth, although use still exceeded national rates for housed youth. Substance use prevention interventions for homeless youth should be trauma informed and include housing navigation and stress management strategies. The most at-risk subgroups included street-dwelling and lesbian, gay, bisexual, or questioning youth. PMID- 29505459 TI - Bariatric Outcomes: Self-Management for Sustained Surgical Success: A Multicomponent Treatment for Dysregulated Overeating in Bariatric Surgery Patients. AB - Binge eating disorder, food addiction, and dysregulated overeating are common among people with severe obesity and prevalent among bariatric surgery populations. These problematic eating habits share commonalities with other addictions. Effective, holistic self-management is needed to promote long-term weight loss and psychosocial adjustment among patients who are severely obese who undergo surgery, especially those with clinically remarkable levels of binge eating, food addiction, or dysregulated overeating.This article aims to briefly review binge eating disorder, food addiction, and obesity-as well as issues surrounding surgery for individuals who are severely obese-and introduce the Bariatric Outcomes: Self-management for Sustained Surgical Success (BOSSSS) program. The BOSSSS program is holistic, skill based, and designed to promote weight loss, prevent weight regain, and improve well-being in patients with severe obesity with a history of bariatric surgery.Preliminary survey data suggest that bariatric surgery patients report a lack of skill-based emotional and behavioral support designed to help them over the long term. The BOSSSS program is rooted in self-determination theory, integrating mobile health technology across program components. Self-determination theory-based interventions are personalized and encourage autonomy, competence, and social support among participating patients and providers. The behavioral self regulation training within BOSSSS is energy balance self-monitoring and titration. Emotional self-regulation is addressed via a specialized version of dialectical behavior skills therapy, emphasizing promotion of coping skills and use of adaptive, healthy substances in immediate environments. The BOSSSS program has been well received by patients and could be implemented by nurses and other health professionals with minimal support. PMID- 29505460 TI - Evaluation of a School-Based Program for Internet Addiction of Adolescents in Turkey. AB - This study aimed to evaluate a school-based program for Internet addiction, the Healthy Internet Use Program, with adolescents in Turkey. Forty-one students were included in the intervention group, and the control group was composed of 43 students. All students were from two primary schools. Students in the intervention group participated in the Healthy Internet Use Program, which was developed in accordance with the literature. The intervention group was given eight training sessions over a 3-month period, and their parents were given two training and consultancy sessions. Data were collected using a data collection form and the Internet Addiction Scale. The third evaluation of the Internet Addiction Scale scores showed a significant difference between the intervention group and the control group (p < .05). The fourth evaluation of the Internet Addiction Scale points showed a highly significant difference between the two groups (p < .001). The findings suggest that use of the Healthy Internet Use Program decreases the rate of Internet addiction among adolescents. PMID- 29505461 TI - Brazilian Public Policies on Drugs: An Analysis Considering the Aspects of Assistance, Prevention, and Supply Control. AB - Since 2004, Brazilian policy makers have been making some changes in the drug policies. It has prioritized a harm reduction perspective instead of a prohibitionist one. Nevertheless, this latter perspective also persists in some parts of the policies and strategies used to deal with this phenomenon in Brazil. This study aims to analyze the structure of the drug policies in Brazil. It is a documental search of Brazilian mental health legislation (laws, decrees, and ordinances) regarding alcohol and other drugs since 2001. The analysis focused on prevention, assistance, and supply control axes. There was a predominance of assistance, which focuses on development of treatment services. Documents have focused more on crack cocaine than on other drugs which have more impact on public health. Scientific evidence competes with partisan political issues and values and the opinions of different actors. The results suggest that it is necessary to have a solid scientific foundation, clearer technical operational aspects, and an evaluation strategy for mental health services to systematize and analyze the implemented policies. PMID- 29505462 TI - Opiate Dependence or Addiction?: A Review of the Centers for Disease Control and Prevention Guidelines for Management of Chronic Pain. AB - In the wake of epidemic of opioid overdoses in the United States, patients who are receiving treatment for chronic pain with opioid have come under increasing scrutiny. The Centers for Disease Control and Prevention issued a guideline for managing chronic pain in 2016, which makes recommendations for opioids based on current evidence. This review will highlight key components of the guideline including differentiating addiction from dependence to assist nurses to better inform patient care in managing chronic pain. PMID- 29505463 TI - One Nurse's Experience.... PMID- 29505464 TI - Racialized Mass Incarceration and the War on Drugs: A Critical Race Theory Appraisal. AB - The purpose of this column is to summarize important aspects of the racialized War on Drugs, including (a) the school-to-prison pipeline, (b) the for-profit prison system ("prison industrial complex"), (c) racialized mass incarceration, and (d) the disproportionately negative impact of the War on Drugs on families and communities of color. Analysis of critical race theory (CRT), the study of the relationships between race, racism, and power, will provide a cohesive framework for examining these four aspects. CRT maintains that American laws, including antidiscrimination laws, are structured to maintain White privilege (Alexander, 2010; Capers, 2014; Delgado & Stefancic, 2017; Nyika & Murray-Orr, 2017). Proponents of CRT are committed to progressive race consciousness and view CRT as a mechanism for analyzing and addressing racial inequity (Capers, 2014). We cannot incarcerate our way out of the drug epidemic. The War on Drugs is a war on individuals who experience a treatable medical condition and on the communities in which they reside. It should more properly be called "The War on Our Own People." The failed War on Drugs and the current administration's efforts to revive and strengthen it provide examples of how the dominant society allows, and perhaps even actively promotes, the destruction of minority communities. Addictions nurses object to the conditions that perpetuate the War on Drugs and racialized mass incarceration. We view it our ethical responsibility to advocate for social justice and healthy sociopolitical environments for all members of society, regardless of race, class, or creed. PMID- 29505465 TI - Prevalence and Correlates of Substance Use in Homeless Youth and Young Adults. PMID- 29505466 TI - Measurement of Medial Wall Bowing and Clinical Associations in Thyroid Eye Disease. AB - PURPOSE: To propose and validate a measure of medial wall bowing in thyroid eye disease (TED) and to assess the clinical correlates of bowing in TED. METHODS: In this cross-sectional cohort study, all patients affected with TED seen by a single specialist over a 2-year period were screened for study entry. Eligible participants were adults with clinical evidence of TED and either CT or MRI of the orbits. Exclusion criteria included prior history of decompression surgery and/or medical or other ophthalmic conditions that could alter the orbital anatomy. The primary outcome measure was prevalence of medial wall bowing. Secondary outcomes included the associations between medial wall bowing and exophthalmometry, diplopia, rectus muscle restriction, dysthyroid optic neuropathy (DON), strabismus, and quality of life. Medial wall bowing was defined as medial divergence of the medial wall from a straight line drawn between the anterior lacrimal crest and the middle of the optic canal and measured radiographically using axial images of the orbits. Volumetric analysis of bowing was performed on a sample of orbits with and without bowing. Volumetric and axial single slice measurements were compared. Bivariate statistics were performed. RESULTS: The final sample included 112 orbital images from 56 patients with TED. Medial wall bowing was found to be evident in 11.6% (n = 13/112) of orbits. Medial wall bowing was significantly associated with greater Hertel measurements, horizontal and vertical muscle restriction, ocular surface symptoms and Clinical Activity Score, as well as lower quality of life scores. Patients with demonstrable medial wall bowing were more likely to be affected by optic neuropathy, diplopia (Gorman score >= 1), strabismus, or horizontal muscle restriction. Analysis of the volume for medial wall bowing demonstrated that the height of the arc at the peak of bowing on an axial image of a 2-dimensional CT scan correlated highly with the total volume of bowing (r = 0.90, p < 0.001). CONCLUSIONS: The identification of medial wall bowing on CT or MRI is associated with clinical measures of disease severity, including diplopia and DON. PMID- 29505467 TI - Biopsy-Proven Metastatic Merkel Cell Carcinoma to the Orbit: Case Report and Review of Literature. AB - Merkel cell carcinoma is a rare neuroendocrine tumor of subspecialized dermal mechanoreceptors, associated with immunosuppression. The usual ophthalmic presentation is an eyelid lesion. The authors present a case of biopsy-proven orbital metastatic Merkel cell carcinoma in the absence of any eyelid lesion, in an immunosuppressed patient with a history of multiple cancers. There are to the authors' knowledge only 2 other case reports of presumed metastatic Merkel cell carcinoma to the orbit, though neither were biopsied. Despite its rarity, metastatic Merkel cell carcinoma should be included in the differential of a metastatic orbital lesion, in the patient with a known or suspected cutaneous primary. The patient has had an excellent response to combined radiotherapy and programmed death-1 inhibitor pembrolizumab, and this case highlights the potential benefit of an exciting new biologic therapy. PMID- 29505468 TI - Bilateral Limbal Keratin-Associated Amyloidosis. AB - Conjunctival amyloid is usually of the immunoglobulin light chain (AL) variety. The authors report an exceptional case of bilateral limbal amyloid deposits that were identified by mass spectrometry as keratin-related specifically regarding to basal keratinocyte keratins 5 and 14. Cytokeratin-related amyloid has been described by immunohistochemical analysis of formalin-fixed cutaneous and mucous membrane lesions but not ocular tissues. The conjunctival lesion in the right eye contained intraepithelial dyskeratotic cells that extended to the surface, causing a lacy leukoplakia on clinical examination. The authors excluded the diagnosis of hereditary benign intraepithelial dyskeratosis in this patient. Collection of patient data and all protected patient health information was compliant with the Health Insurance Portability and Accountability Act. PMID- 29505469 TI - Nasal Glioma: A Rare Cause of Congenital Inner Canthal Swelling. AB - Nasal glioma, encephalocele, and ectopic brain are rare congenital anomalies. The terminology applied to these entities has been historically confusing. In many cases, the terms overlap and may be employed synonymously although some authors emphasize their differences. The authors describe herein a child with an inner canthal mass of brain-like tissue that they interpret as nasal glioma, a variety of encephalocele that has lost its connection to the intracranial contents. This research was conducted in conformity with the Helsinki Declaration and Health Insurance Portability and Accountability Act regulations. PMID- 29505470 TI - alpha7 Nicotinic Acetylcholine Receptor: A Potential Target in Treating Cognitive Decline in Schizophrenia. AB - PURPOSE: The aim of this article is to review the recent trials of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists and positive allosteric modulators (PAMs) on the treatment of cognitive decline in schizophrenia. alpha7 Nicotinic acetylcholine receptor abnormalities in schizophrenia and clinical implications of alpha7 nAChR agonists and PAMs are also discussed. PROCEDURES: Studies were searched on PubMed with keywords "nicotinic," "alpha7," and "schizophrenia" over a 2-year period: January 1, 2016, to December 1, 2017. Cognition was not included in key terms in order to broaden the results. Inclusion criteria included (1) article categorization as a clinical study, review, or journal article; (2) schizophrenia diagnosis based on Diagnostic and Statistical Manual of Mental Disorders criteria; (3) article in English; (4) objective measure of cognition from effects of alpha7 nAChR agonists/PAMs; and (5) article currently published. FINDINGS: A total of 76 studies were found over the past 2 years. Fifteen of these studies were included in this review. Human studies were limited. Cognitive-related improvements in rodent models were found across the 6 cognitive constructs: perception, executive functioning, social and affective processes, working memory, and long-term memory. IMPLICATIONS: These results support the potential of nAChR agonists and PAMs to improve cognitive decline in patients with schizophrenia as an adjunct treatment to antipsychotics. However, these results were found primarily in rodent models of schizophrenia, and further primate/human studies are necessary to support this conclusion in humans. PMID- 29505472 TI - Cutaneous T-Cell Lymphoma, a Novel Manifestation of PDGFRA-Rearranged Neoplasm. AB - Patients with PDGFRA-rearranged hematopoietic neoplasms typically present with chronic eosinophilic leukemia and rarely with acute myeloid leukemia or T lymphoblastic lymphoma. However, mature T-cell lymphoma has not been previously associated with PDGFRA aberrations. We report a patient who presented with simultaneous T-lymphoblastic lymphoma, focal myeloid proliferation, and cutaneous cytotoxic T-cell lymphoma refractory to chemotherapy. The presence of myeloid and lymphoid lineages prompted genetic and molecular studies. A PDGFRA rearrangement was identified in all compartments: cutaneous, lymph node, and bone marrow. Treatment with imatinib resulted in an excellent response in cutaneous and systemic disease. We report the first case of a mature cutaneous T-cell lymphoma with PDGFRA rearrangement, expanding the spectrum of neoplasms associated with this genetic abnormality. Our case underscores the great importance of recognizing PDGFRA rearrangement in unusual cases of cutaneous T-cell lymphoma, systemic lymphoid, and myeloid neoplasms. These patients may respond well to tyrosine kinase inhibitors, despite resistance to conventional chemotherapy. PMID- 29505471 TI - Placebo Effects Across Self-Report, Clinician Rating, and Objective Performance Tasks Among Women With Post-Traumatic Stress Disorder: Investigation of Placebo Response in a Pharmacological Treatment Study of Post-Traumatic Stress Disorder. AB - PURPOSE/BACKGROUND: For a drug to acquire Food and Drug Administration approval, it must significantly outperform placebo treatment. In recent years, the placebo effect seems to be increasing in neuropsychiatric conditions. Here, we examine placebo effects across self-reported, clinically rated, and performance-based data from a trial using a corticotropin-releasing hormone receptor type 1 (CRHR1) antagonist for treatment of post-traumatic stress disorder (PTSD). METHODS/PROCEDURES: Women with chronic PTSD were randomized to treatment with either GSK561679, a CRHR1 antagonist, or placebo. Before randomization, participants completed self-report scales, clinician-rated measures of PTSD and depression symptoms, and objective tests of cognition and functioning. Differences in change scores on measures were compared between GSK561679 and placebo-treated participants. FINDINGS/RESULTS: GSK561679 failed to produce any significant improvement in the participants. A substantial placebo effect was observed in both self-report and clinical rating scales, with effect sizes up to 1.5 SD. No single variable predicted placebo-related changes. Notably, there was an improvement on objective performance measures of cognition that exceeded previous standards for practice effects. IMPLICATIONS/CONCLUSIONS: Participants in this trial manifested retest effects on performance-based measures of cognition. Notably, they had minimal prior experience with performance-based assessments. Experiencing the structure and support of a clinical trial may have contributed to significant reductions in subject-reported and clinician-rated PTSD symptom levels. The improvement seen across all assessment domains was consistent with that seen in previous studies where the active treatments separated from placebo. Investigators conducting clinical trials treating PTSD patients should expect placebo effects and design studies accordingly. PMID- 29505473 TI - Stony Hard Skin During Early Infancy. AB - Stiff skin syndrome is a rare disease causing stony hard induration of skin usually in early childhood. We report a case of 12 years old boy who presented to our clinic with biopsy showing adipocyte entrapment which we believe is an unrecognized key pathological finding in diagnosis of this entity. PMID- 29505474 TI - Periumbilical Papule: Challenge. PMID- 29505475 TI - De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients. AB - OBJECTIVE: Patients who have undergone transplantation often develop metabolic syndrome (MetS) and de-novo nonalcoholic fatty liver disease (NAFLD). Our aim was to evaluate the impact of metabolic disease on cardiovascular and neoplastic risk and survival. PATIENTS AND METHODS: Data from patients who underwent transplantation between 2000 and 2005 in two Italian transplant centers were analyzed. Cox regression analysis was carried out for predictors of de-novo NAFLD and nonalcoholic steatohepatitis (NASH), cardiovascular events, de-novo extrahepatic cancers, and survival. Survival analysis was completed using the Kaplan-Meier method. A P value less than 0.05 was considered significant for all tests. RESULTS: De-novo NAFLD was found in one-fifth of 194 patients. Patients with de-novo NAFLD fulfilled the criteria of MetS in 74.4% of cases, while patients without de-novo NAFLD in 29.8% (P=0.000). On multivariate analysis, MetS correlated independently with de-novo NAFLD and this emerged as an independent predictor of cardiovascular events and as a relevant risk factor for solid extrahepatic cancer. Data on smoking habits, which represent a consolidated risk factor for cardiovascular events and cancer in both the general population and patients who have undergone transplantation, are not available. In the subset of histologically proven NASH, it was the strongest predictor of long-term survival (hazard ratio=4.133, 95% confidence interval: 1.385-12.331, P=0.011). CONCLUSION: Post-transplant NAFLD represented a strong risk factor for cardiovascular atherosclerotic disease and solid extrahepatic cancer, whereas de novo histologically proven NASH was an independent predictor of long-term mortality. PMID- 29505476 TI - Homocysteine: a new diagnostic marker in spontaneous bacterial peritonitis. AB - BACKGROUND AND AIMS: The diagnosis of spontaneous bacterial peritonitis (SBP) depends primarily on a polymorphonuclear leukocyte cell count more than 250/mm. This method is invasive, and not diagnostic in all variants of SBP; we aimed to assess serum homocysteine as a precise indicative marker for the diagnosis of all variants of SBP. PATIENTS AND METHODS: A total 323 consecutive ascitic patients were registered in this prospective work. Serum and ascitic fluid of homocysteine were evaluated utilizing an enzyme-linked immunosorbent assay. RESULTS: Participants were classified into a non-SBP group, including 262 participants and 61 patients with SBP. Serum and ascitic homocysteine were considerably elevated in the SBP group than in the non-SBP group (17.94+/-7.57 vs. 11.75+/-5.68 MUmol/l; P<0.001 and 14.70+/-5.45 vs. 9.75+/-4.55 MUmol/l; P<0.001). At a cutoff value of 17.79 MUmol/l, serum homocysteine had 89.3% specificity and 95.1% sensitivity for distinguishing SBP (area under the curve: 0.932) and, at a cutoff value of 16.1 MUmol/l, ascitic homocysteine had 84.4% specificity and 92.7% sensitivity for distinguishing SBP (area under the curve: 0.901). Both were positively correlated with the polymorphonuclear count, C-reactive protein, Child Pugh score, and Model For End-Stage Liver Disease score as well as negatively correlated with the protein content in the ascitic fluid and estimated glomerular filtration rate. After SBP therapy, there was a marked reduction in serum and ascitic homocysteine levels. CONCLUSION: This study demonstrates that serum and ascitic homocysteine are considerably higher in SBP participants versus non-SBP patients. Serum homocysteine may provide a reliable and noninvasive diagnostic marker for all variants of SBP. PMID- 29505477 TI - Transparent cap-assisted endoscopic sclerotherapy in esophageal varices: a randomized-controlled trial. AB - BACKGROUND AND AIM: Endoscopic treatment is widely accepted as the first-line therapy selection for esophageal variceal bleeding. Nevertheless, endoscopic injection sclerotherapy requires experienced endoscopists and is associated with a high risk of bleeding. Our study evaluates the feasibility and efficacy of transparent cap-assisted endoscopic sclerotherapy in the management of esophageal varices. PATIENTS AND METHODS: A randomized-controlled trial was conducted in a tertiary referral center from April 2015 to May 2016. Patients who received endoscopic sclerotherapy were randomized in a blinded manner into two groups: the transparent cap-assisted group (n=59) and the control group (n=61). RESULTS: The average injection sites were reduced in the transparent cap-assisted group compared with the control group (1.2+/-0.4 vs. 1.4+/-0.05, P=0.000), whereas no difference was observed in the dosage of lauromacrogol (16.97+/-4.91 vs. 16.85+/ 4.57, P=0.662) and the hemorrhage that occurred during injection made no difference (50.8 vs. 61.0%, P=0.276); yet, salvage hemostasis methods were used in only nine patients in the transparent cap-assisted group compared with 17 patients in the control group (25.0 vs. 38.7%, P=0.0936). The cost of each procedure in the cap-assisted group was Y2578 (1878-4202), whereas it was Y3691 for the control group (2506-5791) (P=0.023). Moreover, in both groups, no esophageal constriction was observed during the 6-month follow-up period, whereas the rebleeding rate between two groups showed no statistical significance in 6 months (89.8 vs. 93.4%, P=0.563). CONCLUSION: Transparent cap-assisted sclerotherapy provided a clear field of vision and helped to fix the targeted veins, thus significantly reducing the use of the salvage hemostasis method during sclerotherapy injection hemorrhage. It is also associated with reduced injection sites and endoscopic therapy cost. PMID- 29505478 TI - Retrospective analysis of children with alpha-1 antitrypsin deficiency. AB - BACKGROUND: alpha-1 Antitrypsin (AAT) deficiency is the most frequently occurring genetic liver disorder. The association among classical alpha-1 antitrypsin deficiency (AATD), chronic liver disease, and cirrhosis is common in adult patients but rare in children. AIM: To assess the clinical characteristics of children with AATD and to compare symptoms between homozygous and heterozygous children. MATERIALS AND METHODS: The study included 20 children who were found to have mutant Pi alleles. AAT phenotyping was conducted on patients with a low serum AAT level. The exclusion criteria included infectious, anatomic, and metabolic conditions. Symptoms on presentation, physical examination findings, laboratory values, liver biopsy results, and follow-up periods were recorded for each patient. RESULTS: The patients included six (30%) girls and 14 (70%) boys, with a mean age of 6.3+/-5.1 (1-16) years. The PiZZ phenotype was present in eight (40%) and PiMZ in 12 (60%) patients. The most frequent symptom was elevated liver function test results. Three patients were referred with neonatal cholestasis and one with compensated cirrhosis. Eight patients underwent liver biopsy; all patients except one had periodic acid-Schiff-positive diastase resistant globules in the hepatocytes. The mean follow-up period was 34+/-33 (12 101) months. At the end of follow-up, all patients with PiZZ were found to have chronic hepatitis, and one with cirrhosis. On the contrary, two patients with PiMZ were found to have chronic hepatitis. CONCLUSION: Children with classical AATD commonly have chronic liver disease. In heterozygous (PiMZ) children with AATD, enzyme levels can normalize with occasional fluctuations, sometimes causing delayed diagnosis. PMID- 29505479 TI - Pneumonia in HIV-exposed and Infected Children and Association With Malnutrition. AB - We evaluated the association between HIV exposed-uninfected (HEU) status, malnutrition and risk of death in Ugandan children hospitalized with pneumonia. Both HIV exposure and infection were associated with lower anthropometric indices on univariate analysis, and mid-upper arm circumference was significantly associated with overall mortality (odds ratio (OR), 0.96) in a multivariable model. HIV infection (OR 5.0) but not HEU status was associated with overall mortality. Malnutrition may contribute to poor pneumonia outcomes among HIV infected and HEU children requiring hospitalization. PMID- 29505480 TI - Linking Health and Education: Commentary on "Childhood Infections and Subsequent School Achievement Among 598,553 Danish Children". PMID- 29505481 TI - Adult Caregiver Influenza Vaccination Through Administration in Pediatric Outpatient Clinics: A Cocooning Healthcare Improvement Project. AB - BACKGROUND: Pediatric exposure to influenza-infected adult caregivers (AC) is a significant risk factor for developing influenza. Poor access to vaccines contributes to low adult vaccination rates. We offered adult vaccination at regularly scheduled pediatric office visits and examined barriers to improve future vaccination rates. METHODS: Via a retrospective chart review, we identified ACs who received an influenza vaccination at 1 of 3 pediatric clinics within an academic center from August 2015 to May 2016. We screened for demographics of ACs and their children. Rates of AC vaccination and AC refusal were not measured. RESULTS: A total of 297 ACs representing 518 children received their influenza vaccine at their child's pediatric office. The mean age of ACs was 35.9 years (range, 22-70 years) and 68.5% were mothers. Most ACs (n = 294, 99%) receiving the vaccine had private insurance. Almost all ACs received their vaccination on the day of the child's visit (n = 250, 84%). A total of 49.6% of AC's children had high-risk illnesses. Parents of children with Medicaid were under-represented because of high parental copays (n = 3, 1%). The highest clinic vaccine participation was noted at the clinics with lowest Medicaid populations. CONCLUSIONS: ACs readily accepted influenza vaccination at their child's pediatric primary care office. Increased vaccination acceptance occurred when ACs were female, had private insurance, if their child had a chronic illness and if the vaccination was offered the same day as their child's appointment. Likely reason for low acceptance in ACs with Medicaid insurance is high cost; thus, staff, well-aware of Medicaid's nonreimbursement, likely offered the vaccine less to these parents. PMID- 29505482 TI - A comparison of four-sample slope-intercept and single-sample 51Cr-EDTA glomerular filtration rate measurements. AB - The aim of this study was to verify, with a large dataset of 1394 Cr-EDTA glomerular filtration rate (GFR) studies, the equivalence of slope-intercept and single-sample GFR. Raw data from 1394 patient studies were used to calculate four sample slope-intercept GFR in addition to four individual single-sample GFR values (blood samples taken at 90, 150, 210 and 270 min after injection). The percentage differences between the four-sample slope-intercept and each of the single-sample GFR values were calculated, to identify the optimum single-sample time point. Having identified the optimum time point, the percentage difference between the slope-intercept and optimal single-sample GFR was calculated across a range of GFR values to investigate whether there was a GFR value below which the two methodologies cannot be considered equivalent. It was found that the lowest percentage difference between slope-intercept and single-sample GFR was for the third blood sample, taken at 210 min after injection. The median percentage difference was 2.5% and only 6.9% of patient studies had a percentage difference greater than 10%. Above a GFR value of 30 ml/min/1.73 m, the median percentage difference between the slope-intercept and optimal single-sample GFR values was below 10%, and so it was concluded that, above this value, the two techniques are sufficiently equivalent. This study supports the recommendation of performing single-sample GFR measurements for GFRs greater than 30 ml/min/1.73 m. PMID- 29505484 TI - Medication Reconciliation. PMID- 29505483 TI - A novel method to assess subchondral bone formation using [18F]NaF-PET in the evaluation of knee degeneration. AB - PURPOSE: Fluorine-18-sodium fluoride-PET ([F]NaF-PET) facilitates direct assessment of subchondral bone formation to evaluate degeneration in articulating joints. No standards exist for the quantification of joint activity using [F]NaF PET, and many techniques rely on focal uptake to characterize an entire region of interest. This study proposes a novel method of quantitative global knee analysis to assess regions of expected bone remodeling in the evaluation of knee degeneration. PATIENTS AND METHODS: The study population consisted of 18 patients with rheumatoid arthritis who underwent [F]NaF-PET/computed tomography imaging. The maximum standardized uptake value (knee SUVmax) in addition to a target-to background ratio (TBR) that represents global knee activity adjusted for systemic bone formation measured at the lateral femoral neck (global knee TBR) were calculated. A radiologist scored standard radiographs of the knee in nine patients using the Kellgren-Lawrence grading system. RESULTS: Patients with greater [F]NaF uptake demonstrated greater knee deterioration, which was corroborated by the radiograph findings. Average Kellgren-Lawrence grading was strongly associated with both global knee TBR (Spearman rho=0.69, P=0.04) and knee SUVmax scores (Spearman rho=0.93, P=0.0003). CONCLUSION: Assessment of global activity within the joint is a feasible and clinically useful technique for characterizing disease activity with a single value. Furthermore, a ratio based on systemic bone turnover in a nonarticulating, weight-bearing site adjusts for differences in bone formation related to bodyweight or metabolic bone diseases. We hypothesize that a global knee TBR score may be more sensitive at detecting changes in disease progression, as new spatially distinct lesions with a lower SUV that develop within an region of interest would not be detected by the SUVmax methodology. Longitudinal studies assessing sensitivity with larger patient cohorts are needed to further validate this methodology. PMID- 29505485 TI - Off-label antidepressant prescription in pediatric outpatients based on China Food and Drug Administration and Food and Drug Administration regulations: a Chinese retrospective study. AB - The objective of this study was to evaluate the prevalence and relative risk of off-label prescription of antidepressants in Chinese pediatric outpatients according to China Food and Drug Administration (C-FDA) and USFDA regulations. Medical records of 18 459 pediatric outpatients were identified between 2013 and 2015. Patient characteristics, prevalence of off-label antidepressant prescriptions, and relative risk factors associated with off-label prescribing were analyzed. The results indicate that patients aged from 12 to 17 years account for 88.1% of antidepressant prescriptions, with the most commonly prescribed being sertraline (41.4%). In total, 90.0 and 84.1% of antidepressant prescriptions were off-labeled according to C-FDA and USFDA, respectively, and off-label indications was the most frequent type in this study. Depression was the most common indication for antidepressant treatment, followed by bipolar disorder and schizophrenia. Patients aged 12-17 years diagnosed with bipolar affective disorder have a high risk of off-label antidepressant prescription according to C-FDA regulations. Patients diagnosed with obsessive-compulsive disorder have a low risk of off-label antidepressant prescription according to both regulations. Therefore, future studies are recommended to collect evidence to safeguard appropriate prescribing of off-label antidepressants among pediatric patients. PMID- 29505486 TI - Adapting the Consolidated Framework for Implementation Research to Create Organizational Readiness and Implementation Tools for Project ECHO. AB - The Project Extension for Community Healthcare Outcomes (ECHO) model expands primary care provider (PCP) capacity to manage complex diseases by sharing knowledge, disseminating best practices, and building a community of practice. The model has expanded rapidly, with over 140 ECHO projects currently established globally. We have used validated implementation frameworks, such as Damschroder's (2009) Consolidated Framework for Implementation Research (CFIR) and Proctor's (2011) taxonomy of implementation outcomes, combined with implementation experience to (1) create a set of questions to assess organizational readiness and suitability of the ECHO model and (2) provide those who have determined ECHO is the correct model with a checklist to support successful implementation. A set of considerations was created, which adapted and consolidated CFIR constructs to create ECHO-specific organizational readiness questions, as well as a process guide for implementation. Each consideration was mapped onto Proctor's (2011) implementation outcomes, and questions relating to the constructs were developed and reviewed for clarity. The Preimplementation list included 20 questions; most questions fall within Proctor's (2001) implementation outcome domains of "Appropriateness" and "Acceptability." The Process Checklist is a 26-item checklist to help launch an ECHO project; items map onto the constructs of Planning, Engaging, Executing, Reflecting, and Evaluating. Given that fidelity to the ECHO model is associated with robust outcomes, effective implementation is critical. These tools will enable programs to work through key considerations to implement a successful Project ECHO. Next steps will include validation with a diverse sample of ECHO projects. PMID- 29505487 TI - Pulmonary Function Diagnosis Based on Respiratory Changes in Lung Density With Dynamic Flat-Panel Detector Imaging: An Animal-Based Study. AB - OBJECTIVES: The aims of this study were to address the relationship between respiratory changes in image density of the lungs and tidal volume, to compare the changes between affected and unaffected lobes, and to apply this new technique to the diagnosis of atelectasis. MATERIALS AND METHODS: Our animal care committee approved this prospective animal study. Sequential chest radiographs of 4 pigs were obtained under respiratory control with a ventilator using a dynamic flat-panel detector system. Porcine models of atelectasis were developed, and the correlation between the tidal volume and changes in pixel values measured in the lungs were analyzed. The mean difference in respiratory changes in pixel values between both lungs was tested using paired t tests. To facilitate visual evaluation, respiratory changes in pixel values were visualized in the form of a color display, that is, as changes in color scale. RESULTS: Average pixel values in the lung regions changed according to forced respiration. High linearity was observed between changes in pixel values and tidal volume in the normal models (r = 0.99). Areas of atelectasis displayed significantly reduced changes in pixel values (P < 0.05). Of all atelectasis models with air trapping and air inflow restriction, 92.7% (19/20) were visualized as color-defective or color-marked areas on functional images, respectively. CONCLUSION: Dynamic chest radiography allows for the relative evaluation of tidal volume, the detection of ventilation defects in the lobe unit, and a differential diagnosis between air trapping and air inflow restriction, based on respiratory changes in image density of the lungs, even without the use of contrast media. PMID- 29505488 TI - The Introduction of a Preoperative MRI Protocol Significantly Reduces Unplanned Return to the Operating Room in the Treatment of Pediatric Osteoarticular Infections. AB - BACKGROUND: Pediatric osteoarticular infection can cause severe morbidity. Some infectious loci may be difficult to identify clinically, and there may be more than one. There is little agreement regarding the appropriate use of preoperative magnetic resonance imaging (MRI) in this setting. After noting an unacceptably high rate of unplanned returns to the operating room for recurrent infection, clinicians at a tertiary care children's hospital noticed many patients had adjacent foci of infection on postoperative MRI. As a result, patients experienced prolonged treatment courses and multiple surgeries. An interdisciplinary team instituted practice guidelines whereby all patients with suspected osteoarticular infection underwent MRI for planned debridement during a reserved morning slot with a surgical suite on hold to proceed directly to surgery if indicated. Images were reviewed in real time to form the surgical plan. Young patients that required sedation for MRI were taken to surgery under the same anesthetic used for MRI without being awakened. The purpose of our retrospective study is to determine if implementing the practice guidelines for acute management of osteoarticular infection reduced unplanned returns to the operating room. METHODS: A total of 93 patients with osteoarticular infection were included in this study. A total of 40 cases, group A, were treated before implementing practice guidelines; 53 cases, group B, were treated after implementing practice guidelines. Our primary outcomes of interest were the identification of adjacent infections prior to surgery and need for repeat surgery, either planned or unplanned. RESULTS: Implementation of these guidelines reduced repeat surgery from 50% of patients to <27% (P=0.0099). Of patients requiring repeat surgery, 85% (n=17) were unplanned in group A versus 60% (n=9) in group B (P=0.0099). Adjacent infections were identified in 47.5% (n=19) of patients in group A, versus 60% (n=32) in group B. Adjacent infections were known before surgery in 32% (n=6) of patients in group A versus 72% (n=23) in group B. There were no statistically significant differences in initial patient characteristics or sites of infection. CONCLUSIONS: Implementing these guidelines reduced the need for repeat surgery in this population. It is difficult to predict with sufficient accuracy which patients need preoperative MRI. While resource intensive, preoperative MRI appears to offer substantial benefit in preoperative planning. PMID- 29505489 TI - RETINAL CAVERNOUS HEMANGIOMA WITH INTRALESIONAL PHLEBOLITHS. AB - PURPOSE: To report a case of retinal cavernous hemangioma with intralesional phleboliths, simulating retinoblastoma. METHODS: A healthy 5-month-old girl developed left esotropia and was noted to have atraumatic vitreous hemorrhage with underlying partially calcified mass, suspicious for retinoblastoma. RESULTS: On examination, the visual acuity was fix and follow in the right eye and absent fixation in the left eye. Evaluation of the right eye revealed normal findings. The left eye demonstrated healthy anterior segment and dense vitreous hemorrhage with no view of the postequatorial structures, but with hazy view of the flat peripheral retina and a superonasal retinal mass, covered with fresh hemorrhage. Three white intralesional flecks, consistent with calcification, each measuring 300 MUm, were visualized. B-scan ultrasonography confirmed the dense mass with several foci of calcification, suspicious for retinoblastoma, despite poor visualization on funduscopy. Prophylactic intravenous chemotherapy was delivered for globe salvage and systemic protection. At 12-month follow-up, the hemorrhage showed resolution, revealing a superonasal dark blue multilobulated mass with saccular aneurysms, measuring 16 mm in diameter, and with 3 phleboliths (intralesional calcification). Fluorescein angiography demonstrated early and midphase hypofluorescence with late-phase filling and with plasma-erythrocyte separation in some larger aneurysms, characteristic of retinal cavernous hemangioma. CONCLUSION: Retinal cavernous hemangioma can be associated with intralesional calcification (phleboliths). PMID- 29505491 TI - Severe Acute Kidney Injury After Single-Dose Injection of Zoledronic Acid in an Elderly Patient. PMID- 29505490 TI - Clozapine Rechallenge After Major Adverse Effects: Clinical Guidelines Based on 259 Cases. AB - BACKGROUND: Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines. STUDY QUESTIONS: How safe is the clozapine rechallenge after life-threatening adverse effects? STUDY DESIGN: The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%. RESULTS: A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%-69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%-44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%-84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1% 100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency. CONCLUSION: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects. PMID- 29505492 TI - Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Antipsychotics: Drawbacks of Its Clinical Application. AB - BACKGROUND: Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug monitoring of antipsychotics. To facilitate implementation in clinical practice, the aim of this study was to perform a clinical validation study of a DBS method for quantification of risperidone, aripiprazole, pipamperone, and their major metabolites 9-OH risperidone and dehydro-aripiprazole in a real-life, clinical setting. METHODS: Paired DBS and venous plasma samples were analyzed (n = 35 for risperidone, n = 21 for aripiprazole, n = 21 for pipamperone). Estimated plasma concentrations were calculated from DBS concentrations based on hematocrit and/or Deming regression formulas. Deming regression and Bland-Altman analyses were used to determine the agreement between the calculated and measured plasma concentrations. For Bland Altman analysis, the following acceptance limit was used: for a minimum of 67% of the samples, the difference of the 2 measurements should be within 20% of their mean. RESULTS: The median venous plasma levels were 0.9 mcg/L for risperidone, 14.8 mcg/L for 9-OH risperidone, 135.4 mcg/L for aripiprazole, 54.9 mcg/L for dehydro-aripiprazole, and 56.4 mcg/L for pipamperone. All antipsychotics required different correction formulas of DBS concentrations for best agreement. Subsequently, no constant or proportional bias was observed using Deming regression analysis. With Bland-Altman analyses, for risperidone, 45% of the samples were within the 20% limits; for 9-OH risperidone, 36%; for aripiprazole, 45%; for dehydro-aripiprazole, 35%; and for pipamperone, 43%. CONCLUSIONS: The DBS method to quantify risperidone, aripiprazole, pipamperone, and their major metabolites did not meet the acceptance criteria in the Bland-Altman analyses. Therefore, this DBS method was not clinically valid. This study shows the importance of a clinical validation study with use of Bland-Altman plots before clinical implementation. PMID- 29505493 TI - Pharmacokinetic Therapeutic Drug Monitoring of Advagraf in More Than 500 Adult Renal Transplant Patients, Using an Expert System Online. AB - BACKGROUND: Immunosuppressant Bayesian dose adjustment (ISBA) is an online expert system, routinely used by approximately 140 transplantation centers in the world for the dose adjustment of immunosuppressive drugs in transplant patients. This system determines the area under the curve (AUC) of the drug by pharmacokinetic modeling and Bayesian estimation. The purpose of this study was to analyze tacrolimus exposure after administration of its modified-release formulation (Advagraf) in kidney allograft recipients, to optimize its therapeutic drug monitoring. METHODS: This is a retrospective study of exposure indices measured locally [trough tacrolimus concentration (C0), C0/dose] or estimated through ISBA (AUC, AUC/dose, AUC/C0), of their evolution over posttransplantation time, and of the correlations between them. RESULTS: A total of 922 requests posted by 28 different centers for routine Advagraf adjustment in 530 different patients treated with Advagraf were studied. The exposure to, and dose requirement of, tacrolimus significantly increased across the first posttransplant months before reaching steady state. The AUC:C0 ratio (on which C0 monitoring is implicitly based) was stable across the different posttransplant periods, although with high interindividual variability. C0-AUC correlation was stronger in the late than in the early posttransplant period (r = 0.75 versus 0.63; P = 0.0075). Using the regression equations obtained, AUC ranges corresponding to different applicable C0 target ranges were calculated to guide dose adjustment. When one of the doses recommended was administered, the following AUC was significantly more often in the predicted target ranges (P < 0.0001). CONCLUSIONS: This study improves our knowledge of Advagraf pharmacokinetic variability and relations between exposure indices and the scientific background of the expert service provided through the ISBA Web site. PMID- 29505494 TI - Alpha-Fetoprotein Slope >7.5 ng/mL per Month Predicts Microvascular Invasion and Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma. AB - BACKGROUND: Rising alpha-fetoprotein (AFP) is a potential marker of worse prognosis after liver transplant (LT) for hepatocellular carcinoma (HCC), but prior studies relied on only 2 data points and were imprecise in assessing AFP slope. The aim of this study was to examine the association between AFP slope and post-LT HCC recurrence, with AFP slope estimated from multiple data points over time. METHODS: Our cohort included 336 patients undergoing LT with Model for End Stage Liver Disease exception for HCC within Milan criteria from 2003 to 2013. Most (98%) had pre-LT locoregional therapy. AFP slope was estimated by fitting a regression line to the AFP levels over time. RESULTS: The 1- and 5-year post-LT survivals were 94% and 77% and 1- and 5-year recurrence-free probabilities were 95% and 86%, respectively. In univariate analysis, HCC recurrence was significantly associated with microvascular invasion (hazard ratio [HR], 13.1; P<0.001), tumor grade (HR, 1.8; P<0.001), pathologic stage >Milan criteria (HR, 8.9; P<0.001), 3 tumor nodules (HR, 5.5; P=0.002), AFP slope greater than 7.5 ng/mL per month (HR, 3.9; P=0.005), and female sex (HR, 2.3; P=0.01). In multivariable analysis of factors known before LT, 3 tumor nodules (HR, 7.6; P<0.001), female sex (HR, 2.5; P=0.01), and AFP slope >7.5 (HR, 3.0; P=0.03) were significantly associated with HCC recurrence. AFP slope greater than 7.5 was also associated with microvascular invasion (odds ratio, 6.8; P=0.008). CONCLUSIONS: AFP slope increasing greater than 7.5 ng/mL per month despite locoregional therapy is associated with post-LT HCC recurrence and may serve as a surrogate for microvascular invasion. These findings support incorporating changes in the AFP into candidate selection for LT. PMID- 29505495 TI - Intraoperative Neuromonitoring During Sciatic Nerve Schwanomma Excision: Utility of Evoked Potentials. PMID- 29505496 TI - Value Affordances in Students' Probability of Persisting as a Nursing Major. AB - This study investigated how perceptions of agentic and communal values attract students to major in and persist in nursing. Participants reported a potential major and why they were attracted to that major. Transcripts were coded for declaration and graduating with a nursing major. Results showed that students who reported being attracted to a major for communal and agentic reasons were more likely to report nursing as a potential major, declare nursing as a major, and graduate with a nursing degree. Departments are encouraged to recruit students by highlighting the communal and agentic values that nursing affords. PMID- 29505497 TI - Universal Design for Instruction in Nursing Education: An Integrative Review. AB - AIM: The aim of the study was to explore the use of universal design for instruction (UDI) in nursing education. BACKGROUND: Educators seek to employ innovative pedagogies accessible to diverse learners across learning environments. UDI, an inclusive strategy for meeting this goal is not well known in nursing education. METHOD: An integrative review was used to meet the study's aim. Five databases were searched for literature published between 2000 and 2013. RESULTS: Of 45 articles retrieved, only three studies and 14 feature articles met the inclusion criteria. A literature matrix was used to synthesize major concepts to create theme labels: marginalized students as a vulnerable population, faculty lack of knowledge of UDI, reactive versus proactive instructional design, and best teaching practices. CONCLUSION: The lack of UDI knowledge by educators is a barrier to its usage. Implications and recommendations for adopting universal design in nursing education are discussed. PMID- 29505498 TI - Statewide At-Risk Tracking and Intervention for Nurses: Identifying and Intervening With Nursing Students at Risk of Attrition in Texas. AB - AIM: The purpose of this study was to identify students at risk of attrition and implement interventions to decrease the risk. BACKGROUND: The ability to identify and intervene with students deemed at risk of attrition can be a valuable tool for increasing the RN workforce. "Statewide At-Risk Tracking and Interventions for Nurses" (SATIN) involved students from 27 initial RN licensure nursing programs in Texas. METHOD: At-risk status of each nursing student was identified, and each nursing program provided interventions based on students' needs. RESULTS: The Weaver Reading Program was the most effective of the six intervention strategies used with SATIN participants. Lack of utilization of the interventions was the number one limitation of the study. CONCLUSION: Use of the Weaver Reading Program as well as personal engagement with students, one-on-one mentoring, and continued time investment are recommended to all programs. PMID- 29505499 TI - You're Teaching Evidence-Based Practice to BSN Students...But Are They Learning? AB - Although baccalaureate nursing programs often teach evidence-based practice (EBP), the effectiveness of targeted education to facilitate progressive EBP knowledge development is unclear. Rigorous, objective evaluation is vital for faculty to determine if students' EBP knowledge is advancing, stagnating, or declining as they progress toward program completion. In a study across multiple campuses of one traditional baccalaureate nursing program, EBP knowledge significantly improved between sophomore and junior levels, but not between junior and senior levels. These results highlight the importance of using evaluation to gauge the impact of curriculum on students' learning and progressive EBP knowledge development. PMID- 29505500 TI - Test Anxiety and Academic Procrastination Among Prelicensure Nursing Students. AB - Test anxiety may cause nursing students to cope poorly with academic demands, affecting academic performance and attrition and leading to possible failure on the National Council Licensure Examination for Registered Nurses (NCLEX-RN(r)). Test-anxious nursing students may engage academic procrastination as a coping mechanism. The Test Anxiety Inventory and the Procrastination Assessment Scale for Students were administered to 202 prelicensure nursing students from diploma, associate, and baccalaureate nursing programs in southwestern Pennsylvania. Statistically significant correlations between test anxiety and academic procrastination were found. The majority of participants reported procrastinating most on weekly reading assignments. Students with higher grade point averages exhibited less academic procrastination. PMID- 29505501 TI - A Comparison Study of the Effect of Type of Grading on Clinical Simulation Performance. AB - The purpose of this study was to determine whether student performance in a simulation varied according to which grading method was used: pass/fail versus numerical grading with calculation into a course grade. Results showed that student performances were not significantly different when the pass/fail graded group was compared to the numerically graded group, even though students knew which grading schema would be used in their evaluation. The study challenges the opinion that students perform better when they know that they will be numerically graded in simulation. PMID- 29505502 TI - Trends in Research on Simulation in the Teaching of Nursing: An Integrative Review. AB - AIM: The aim of the study was to identify and reflect on evidence regarding the use of simulation in nursing education. BACKGROUND: The use of simulation as a teaching strategy in nursing is expanding. It is important to check the evidence deriving from research. METHOD: Departing from a guiding question, an international literature search was undertaken between January 2008 and March 2014 in Portuguese, English, and Spanish. RESULTS: Out of 160 articles, 68.1 percent used simulated teaching to develop clinical reasoning; 31.9 percent used it to train skills. Most (about 91.8 percent) discussed positive aspects related to the use of simulation, including support for the teaching process and increased self-efficacy and self-confidence. CONCLUSION: The studies indicate that appropriate tools are needed to measure the true impact of the strategy on the teaching of nursing care and the training needed to use simulation as a teaching strategy. PMID- 29505503 TI - A Factor Analysis of the Perceived Value of Certification Tool for Nurse Educators: Evidence for Construct Validity. AB - AIM: The purpose of this study was to examine construct validity of the Perceived Value of Certification Tool for Nurse Educators (PVCT-NE). BACKGROUND: Preliminary testing of the PVCT-NE demonstrated content validity and strong evidence of internal consistency reliability. Construct validity evidence for the tool is lacking. METHOD: Using data from a descriptive study about nurses' perceived value of nurse educator certification, exploratory factor analysis was used to examine whether the factor structure of the PVCT-NE was consistent with the two-factor structure reported for the original PVCT. RESULTS: Data (n = 221) were analyzed using principal components analysis to identify factors. The observed two-factor solution and individual item loadings in this sample were consistent with the original PVCT's intrinsic and extrinsic value subscales and accounted for 64 percent of the total instrument variance. CONCLUSION: Overall, the PVCT-NE is a valid tool to measure perceived value of certification in nurse educators. PMID- 29505504 TI - Intraoperative burn from a grounding pad of electrosurgical device during breast surgery: A CARE-compliant case report. AB - RATIONAL: Burns at the site of the return electrode (i.e., grounding pad) are possible effects of electrosurgery. Despite this knowledge, however, ignorance or negligence with regards to proper handling of the grounding pads still often occurs. Burn injuries can be easily prevented by taking the necessary precautions; thus, during plastic surgery, careful attention should to be paid. PATIENT CONCERNS: A 38-year-old female patient was admitted to our ward to be performed augmentation mammoplasty. Before the start of the procedure, the grounding pad was placed on the surgical table and the left calf of the patient was placed on the grounding pad. Before using the endoscope, we found a burn on patient's left calf, where the grounding pad had been placed. DIAGNOSIS: It was a 3-cm-by-3-cm-sized full thickness burn. The surrounding areas had no painful sensation with noninfectious sign. INTERVENTION: Debridement and direct closure was performed with elliptical incision of eschar. OUTCOMES: The patient did not require additional surgical procedure anymore and satisfied with the scar. LESSONS: Through this case, we present the appropriate management of electrical burns from a grounding pad, and emphasize the understanding of the mechanism of burn because of electrosurgery, and how to use the grounding pad optimally to minimize the patient's risk. PMID- 29505505 TI - A case report with shock induced by tolvaptan in an elderly patient with congestive heart failure. AB - RATIONALE: Tolvaptan (TLV) is a new vasopressin type 2 receptor antagonist effective in patients with heart failure (HF). Accumulating evidences have revealed that treatment with TLV does not alter the blood pressure significantly. PATIENT CONCERNS: An 84-year-old man was diagnosed with acute exacerbation of chronic HF due to ischemic cardiomyopathy, arrhythmia, mitral and aortic regurgitation. Treatment with TLV increased the urine volume and improved the dyspnea. After 4 days use of TLV (3.75 mg QD, 7.5 mg QD, 7.5 mg QD, and 15 mg QD, respectively), decrease in blood pressure to less than 90/60 mmHg was observed continuously and the lowest blood pressure was 80/37 mmHg. He was apyretic and felt only thirsty. Central venous pressure was 12 cmH2O. DIAGNOSES: Because no other medications were changed and no signs of hypovolemic, septic, allergic, or cardiac shock were detected, we suspected an adverse reaction to TLV. INTERVENTION: Intravenous hydration was performed with 250 mL of normal saline. OUTCOMES: His blood pressure increased gradually and the statue of hypotention lasted for 14 hours. The dose of TLV was decreased to 7.5 mg/d from the next day to discharge. During this period, his blood pressure was stable at about 125/60 mmHg. LESSONS: TLV has side effect of severe hypotension that is consistent with its physiological activity. The dose should be increased gradually to achieve the desired effect, while attention should be paid to potential drug interactions. PMID- 29505506 TI - Efficacy, safety, and mechanisms of herbal medicines used in the treatment of obesity: A protocol for systematic review. AB - INTRODUCTION: This systematic review protocol aims to perform a protocol for assessing the effectiveness, safety, and mechanism of herbal medicines for the treatment of obesity and metabolic syndrome. Some systematic reviews conducted earlier have evaluated the efficacy of herbal medicine to treat obesity and metabolic syndrome. Owing to the huge burden imposed by obesity in the recent years, a need is felt for conducting new systematic reviews on the topic of obesity with a focus on randomized clinical trials, we felt the need. METHODS AND ANALYSIS: All relevant clinical trials that examine the effectiveness of herbal medicines for the treatment of obesity and metabolic syndrome without restrictions on publication status will be applied.Four electronic databases will be searched: PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials. The main outcome is expected to be an improvement in the body weight, body mass index, waist circumference, waist-to-hip ratio, body fat (weight or mass of visceral adipose tissue, fat mass or percent), and appetite.Selection studies, data extraction, and risk of bias will be assessed independently by 2 authors. ETHICS AND DISSEMINATION: In this study, ethical approval is not required because the data that will be used are not subjects and the results will be discussed through peer-reviewed publications. TRIAL REGISTRATION NUMBER: PROSPEROCRD42016049753. PMID- 29505507 TI - Effective assessment of low times MET amplification in pleural effusion after epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance: Cases report. AB - RATIONALE: The mechanism of the first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance included T790M mutation, cellular-mesenchymal to epithelial transition factor (MET) or EGFR amplification, PIK3CA mutation, and transformation to small cell lung cancer. MET amplification accounted for only about 5% of the resistance cases. PATIENTS CONCERNS: Few report detected MET amplification in pleural effusion. Here, we reported 2 lung adenocarcinoma cases with MET amplification in pleural effusion rapidly responded to crizotinib after EGFR-TKIs acquired resistance. DIAGNOSES: Biopsy via bronchoscopy, next-generation sequencing (NGS) in pleural effusion. INTERVENTIONS: EGFR-TKIs (Icotinib), MET inhibitor crizotinib. OUTCOMES: After a progression-free survival of 9 months and 23months, respectively, both cases progressed accompanying with pleural effusion. Results of NGS in pleural effusion showed MET amplification (2-3 times) in both cases. The 2 patients were treated with a MET inhibitor crizotinib and rapidly responded. CONCLUSION: MET amplification in pleural effusion could predict a perfect response to crizotinib after EGFR-TKIs acquired resistance, even only a low times gene amplification. PMID- 29505508 TI - Association between serum 25-hydroxyvitamin D concentration and pulmonary infection in children. AB - We assessed the relationship between serum 25-hydroxyvitamin D (25(OH)D) level and community-acquired pneumonia (CAP) among Chinese children.This observational study examined children aged 3 days to 14 years (n = 1582) from the Capital Institute of Pediatrics in 2009 to 2011. There were 797 children in the CAP group and 785 controls. The CAP group was divided into 2 groups: a pneumonia group and pneumonia-induced sepsis group. The serum 25(OH)D level was estimated using micro whole blood chemiluminescence.The average serum 25(OH)D level in all samples was 25.32 +/- 14.07 ng/mL, with the CAP group showing a lower value than the control group (P < .001). There were also significant differences between the pneumonia group and pneumonia-induced sepsis group (P < .001). In the pneumonia-induced sepsis group, significant differences in serum 25(OH)D levels were observed in children who received mechanical ventilation or presenting with multiple organ dysfunction (P < .01).All serum 25(OH)D levels in the pneumonia group and pneumonia-induced sepsis group were below normal levels, particularly in the sepsis group. A lower serum 25(OH)D level was associated with more serious symptoms in CAP children. Children with low serum 25(OH)D levels may be at higher risk of receiving mechanical ventilation and presenting with multiple organ dysfunction. These findings suggest that vitamin D supplements are beneficial for the treatment and prevention of CAP. PMID- 29505509 TI - Nursing care of a boy seriously infected with Steven-Johnson syndrome after treatment with azithromycin: A case report and literature review. AB - RATIONALE: Stevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. SJS in children is not common but potentially serious disease. But the epidemiology of SJS in China is not well defined. PATIENT CONCERNS: A 6-year-old boy was initially diagnosed as pneumonia admitted to hospital after admission, and the body appears red rash with blisters, skin damage, lip debaucjed, repeated high fever, and rapid progression. DIAGNOSES: SJS often results from an allergy reaction response to a range of drugs. It is a clinical diagnosis suggested by fever and malaise followed by an extensive painful, nonblanching, macular rash that commonly progresses to blistering or sloughing, and mucositis. INTERVENTIONS: The boy was treated with continuous renal replacement therapy, anti-infection therapy, high-dose glucocorticoid treatment, and symptomatic treatment. OUTCOMES: The patient was recovered after 33 days of treatment. LESSONS: The current treatment is mainly symptomatic treatment, and for the patient, it is important to make skin care related well, included early out blisters at effusion, reducing skin ulceration of the mucosa area, keeping skin clean, removing mucosa secretion and blood clots, doing eye care related, preventing the complications, ensuring adequate intake of nutrition and warm and so on. PMID- 29505510 TI - Efficacy and safety of image-guidance radiotherapy by helical tomotherapy in patients with lung cancer. AB - This study aimed to explore the efficacy and toxicity of image-guided stereotactic body radiotherapy (IGSBR) by helical tomotherapy in patients with lung cancer among Chinese Han population.A total of 21 patients with stage I lung cancer were included. They received a total of 60 Gy factions IGSBR. The outcomes included complete response (CR), partial response (PR), stable disease (SD), progress disease (PD), overall response rate (ORR), and overall survival (OS). In addition, toxicities were also recorded in this study.Three-year CR, PR, SD, PD, ORR, and OS were 47.6%, 38.1%, 9.5%, 4.8%, 85.7%, and 48.0 months, respectively. Additionally, mild toxicities were found in this study.This study demonstrated that IGSBR is efficacious for patients with stage I lung cancer with mild toxicities among Chinese Han population. PMID- 29505511 TI - Cardiovascular risk factors in patients with combined central retinal vein occlusion and cilioretinal artery occlusion: Case report. AB - RATIONALE: To analyze cardiovascular risk factors and comorbidity of acute unilateral visual loss due to combined central retinal vein occlusion (CRVO) and cilioretinal artery occlusion (CLRAO). PATIENT CONCERNS: Among patients with retinal vein or artery occlusion hospitalized at the Department of Ophthalmology between January 2011 and August 2017, subjects with combined CRVO/CLRAO were selected. All of them underwent ophthalmologic and cardiologic examination, including fluorescein angiography, optical coherence tomography, 12-lead electrocardiogram, transthoracic and transesophageal echocardiography, carotid Doppler sonography, cerebral magnetic resonance imaging, and a panel of laboratory tests. DIAGNOSES: Four subjects with coexisting CRVO and CLRAO were found among 146 patients with retinal vein or artery occlusion. There were no other types of concomitance of CRVO and retinal artery occlusion. INTERVENTIONS: All patients were treated with low molecular heparin in a full dose for 2 weeks, then with 1 mg/kg once daily for the next 2 weeks, followed by acetylsalicylic acid 75 mg/kg/d. Other medication included long-term statins, angiotensin converting-enzyme inhibitor in 3 patients and beta-blocker in one patient. OUTCOMES: All patients with CRVO/CLRAO presented multiple cardiovascular risk factors, including hypertension, obesity, hyperlipidemia, chronic nicotine addiction, and a positive family history of coronary artery disease or stroke. In all of them, echocardiography revealed left ventricular hypertrophy and atherosclerotic lesions in the descending aorta; in addition, 3 patients had insignificant atherosclerotic plaques in the carotid artery. Also, in 3 subjects, focal ischemic cerebral changes were diagnosed. LESSONS: Patients with combined CRVO and CLRAO present numerous cardiovascular risk factors and abnormalities on imaging examinations, which should be routinely evaluated and treated. PMID- 29505512 TI - A demonstration area for type 2 diabetes prevention in Barranquilla and Juan Mina (Colombia): Baseline characteristics of the study participants. AB - : Type 2 diabetes (T2D) imposes a heavy public health burden in both developed and developing countries. It is necessary to understand the effect of T2D in different settings and population groups. This report aimed to present baseline characteristics of study participants in the demonstration area for the "Type 2 Diabetes Prevention in Barranquilla and Juan Mina" (DEMOJUAN) project after randomization and to compare their fasting and 2-hour glucose levels according to lifestyle and T2D risk factor levels.The DEMOJUAN project is a randomized controlled field trial. Study participants were recruited from study sites using population-wide screening using the Finnish Diabetes Risk Score (FINDRISC) questionnaire. All volunteers with FINDRISC of >=13 points were invited to undergo an oral glucose tolerance test (OGTT). Participant inclusion criteria for the upcoming field trial were either FINDRISC of >=13 points and 2-hour post challenge glucose level of 7.0 to 11.0 mmol/L or FINDRISC of >=13 points and fasting plasma glucose level of 6.1 to 6.9 mmol/L. Lifestyle habits and risk factors for T2D were assessed by trained interviewers using a validated questionnaire.Among the 14,193 participants who completed the FINDRISC questionnaire, 35% (n = 4915) had a FINDRISC score of >=13 points and 47% (n = 2306) agreed to undergo the OGTT. Approximately, 33% (n = 772) of participants underwent the OGTT and met the entry criteria; these participants were randomized into 3 groups. There were no statistically significant differences found in anthropometric or lifestyle risk factors, distribution of the glucose metabolism categories, or other diabetes risk factors between the 3 groups (P > .05). Women with a past history of hyperglycaemia had significantly higher fasting glucose levels than those without previous hyperglycaemia (103 vs 99 mg/dL; P < .05).Lifestyle habits and risk factors were evenly distributed among the 3 study groups. No differences were found in fasting or 2-hour glucose levels among different lifestyle or risk factor categories with the exception of body mass index, past history of hyperglycaemia, and age of >=64 years in women. TRIAL REGISTRATION: NCT01296100 (2/12/2011; Clinical trials.gov). PMID- 29505513 TI - Impact of inhalational anesthetics on postoperative cognitive function: Study protocol of a systematic review and meta-analysis. AB - BACKGROUND: Conflict findings of the impact of inhalational anesthetics on postoperative cognitive function are reported. No systematic review has been performed to solve the problem. The aim of the study was to assess the effect of different inhalational anesthetics on postoperative cognitive function in a network meta-analysis. METHODS: We will search MEDLINE, EMBASE, the Central Register of Controlled Trials in the Cochrane library, and CINAHL for randomized controlled trials or cohort studies assessing the short-term or long-term cognitive function of elderly patients (over 60 years) receiving major surgeries and inhalational anesthetics (desflurane, isoflurane, sevoflurane, halothane, and nitrous oxide) during surgery. Two reviewers will independently screen study eligibility, extract information from eligible studies, and appraise study quality. The impact of inhalational anesthetics will be assessed through: incidence of postoperative cognitive dysfunction at 1 week, 3 months, 1 year, and over 1 year after surgery; incidence of post-operative delirium; test of postoperative cognitive function. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: To our knowledge, this systematic review will be the first to evaluate existing research on the incidence of postoperative cognitive function after inhalational anesthetics. Our study will assess the effect of different inhalational anesthetics on postoperative cognitive function. ETHICS AND DISSEMINATION: The review will be finished in December 2017, and the result will be published in a peer-reviewed journal or disseminated through conference posters or abstracts. REVIEW REGISTRATION NUMBER: CRD42017056675 (www.crd.york.ac.uk/PROSPERO). PMID- 29505514 TI - Lumbar laminotomy and replantation for the treatment of adult spinal epidermoid cyst: A case report. AB - RATIONALE: Adult spinal epidermoid cyst (SEC) is a rare tumor. Lumbar laminectomy and tumor removal was a routine surgical procedure for adult spinal epidermoid cyst according to the literature, but postoperative lumbar instability and intractable low back pain may occur. In this study, we presented a brief report of an adult lumbar epidermoid cyst and introduced another surgical approach. PATIENT CONCERNS: This 28-year-old woman has been complaining of the severe right buttock pain and right thigh radiating pain for half a year. She had been diagnosed as sacroiliitis, spinal arthritis, and lumbar disc herniation at 3 different hospitals before coming to our hospital. And she received a variety of conservative treatments, including non-steroidal anti-inflammatory drugs, aspirin, acetaminophen, glucocorticoids, acupuncture, physical therapy, and so on. However, her pain did not diminish at all. Finally, we find a space-occupying lesion in her lumbar magnetic resonance images (MRI). The lesion was slightly low, equal, and uneven equal-low signals on T1WI. T2WI showed slightly higher, equal, and uneven equal-high signals. And a thin-rim enhancement was observed on Gd-DTPA-enhanced MRI. DIAGNOSES: Adult spinal epidermoid cyst. INTERVENTIONS: The patient underwent a surgery of lumbar laminectomy, tumor excision, and spinous process-vertebral plate in situ replantation. OUTCOMES: Postoperative pathology prompted that the tumor was cystoid. The patient's symptoms were completely removed 1 week after surgery. Three-month postoperative MRI confirmed that the spinal epidermoid cyst had been completely removed and three-dimensional CT prompted lumbar lamina in situ. Bony fusion occurred at 6 months after the surgery. LESSONS: Lumbar laminotomy and replantation provides an ideal option to treat adult spinal epidermoid cyst because it can completely remove the cyst and simultaneously reduce the risk of iatrogenic lumbar instability. PMID- 29505515 TI - Persistent fever and destructive arthritis caused by dialysis-related amyloidosis: A case report. AB - RATIONALE: Dialysis-related amyloidosis (DRA) can present rheumatic manifestations in patients on long-term hemodialysis. Typical articular symptoms with DRA involve carpal-tunnel syndrome, effusion in large joints, spondyloarthropathy, or cystic bone lesions, which are usually with non inflammatory processes. PATIENT CONCERNS: A 64-year-old man on hemodialysis for >30 years was admitted because of intermittent fever, polyarthritis, and elevated serum C-reactive protein (CRP) level, which was continuous for 2 years. Several antibiotics were ineffective for 3 months before his admission. On physical examination, joint swelling was observed at bilateral wrists, knees, ankles, and hip joints. Laboratory tests revealed elevation of serum inflammatory markers and beta2-microglobulin (beta2-MG). Synovial fluid showed predominant infiltration of polymorphonuclear leukocytes and the increase of beta2-MG level. DIAGNOSIS: Significant deposition of beta2-MG with inflammatory cell infiltration was found in biopsied samples from synovium, skin, and ileum. INTERVENTIONS: We decided to switch to the hemodialysis column with membrane that can effectively absorb beta2 MG in circulation. OUTCOMES: The relief of symptoms and a decrease of CRP level by changing the membrane lead to the final diagnosis of DRA. LESSONS: Our case demonstrates that DRA arthropathy can be inflammatory and destructive, and also develop systemic inflammatory signs and symptoms. In such cases, aggressive absorption of beta2-MG in circulation might help the amelioration of symptoms. PMID- 29505516 TI - Heterotopic pancreatic cyst in the adrenal gland: A case report and review of literature. AB - RATIONALE: The incidence of heterotopic pancreas (HP) is relatively rare and mainly found in the upper gastrointestinal tract, and no case of HP cyst in the adrenal gland has been reported. Informed consent has been obtained from the patient for the publication of the case details. PATIENT CONCERNS: A 21-year-old woman who presented with chronic lower back pain for a week without urinary disturbance or gastrointestinal discomfortable. DIAGNOSES: Ultrasound (US) revealed a left renal cyst, and computed tomography (CT) showed a cyst in the area of the adrenal gland. INTERVENTIONS: Cystectomy was successfully performed laparoscopically. Histopathologic examination of the removed cyst wall showed heterotopic pancreatic cyst accompanied by cystic degeneration. OUTCOMES: No unusual drainage or abdominal signs were observed during the 6-month follow-up. LESSONS: Despite of its rarity, HP accompanied by cyst formation in the adrenal gland area can present with waist pain. Therefore, the possibility of such disease needs to be considered. For thorough evaluation, in addition to abdominal US, CT, and/or magnetic resonance imaging, histopathological examination should sometimes be performed to make a definite diagnosis. Total excision and regular follow-up is necessary for such cases due to the potential risk of complications or recurrent cyst formation. PMID- 29505517 TI - Evaluation of HVHF for the treatment of severe acute pancreatitis accompanying MODS. AB - Systemic inflammatory response syndrome (SIRS) prevention is key to severe acute pancreatitis (SAP) treatment and the assessment of high-volume hemofiltration (HVHF) for treating SAP accompanying multiple organ dysfunction syndromes.In this prospective controlled study, 40 SAP patients were divided into 2 groups: control (n = 22, treated with fasting, decompression, and intravenous somatostatin) and HVHF (n = 18, HVHF administration in addition to the treatment in the control group) groups; and were assessed for serum and urine amylase, WBC, C-reactive protein (CRP), and hepatic and renal functions. Vital signs and abdominal symptoms were recorded, and complications and mortality were analyzed.APACHE II scores in the HVHF group were significantly lower than in the control group at 3 and 7 days (6.3 +/- 1.7 vs 9.2 +/- 2.1 and 3.3 +/- 0.8 vs 6.2 +/- 1.7, respectively). Compared with controls, serum, and urine amylase, WBC, CRP, and organ functions significantly improved after HVHF treatment. Meanwhile, mortality (16.7% vs 31.8%) and complication (11.1% vs 40.9%) rates were significantly reduced.The other clinical parameters were significantly ameliorated by HVHF. HVHF rapidly reduces abdominal symptoms and improves prognosis, reducing mortality in SAP patients; and is likely through systemic inflammatory response syndrome attenuation in the early disease stage. PMID- 29505518 TI - Effectiveness and safety of an optimized blood management program in total hip and knee arthroplasty: A large, single-center, retrospective study. AB - Little has been published on blood management in total hip and knee arthroplasty (THA and TKA, respectively) patients focusing on both hematopoiesis and hemostasis. Our aim was to explore the effectiveness and safety of an optimized blood management program in THA and TKA patients in a large, single-center, retrospective study.We retrospectively reviewed consecutive primary unilateral THA and TKA patients' data at our institution through the National Health Database. They were divided into 3 groups according to an optimized blood management program: group A-combined use of intravenous and topical tranexamic acid (TXA); group B-use of recombinant human erythropoietin (rHuEPO) and iron supplements in addition to treatments in group A; group C-use of additional multiple boluses of TXA in addition to treatments in group B. The primary outcomes were hemoglobin (Hb) drop and calculated total blood loss (TBL). Other outcome measurements such as transfusion rate, postoperative length of stay (PLOS), venous thromboembolism (VTE), and mortality were also compared.From 2014 to 2016, a total of 1907 unilateral THA (986 in group A, 745 in group B, and 176 in group C) and 1505 unilateral TKA (795 in group A, 556 in group B, and 154 in group C) procedures were conducted at our institution. The Hb drop, calculated TBL, and PLOS in group C were significantly lower than those in groups A and B for THA and TKA patients. The transfusion rate in group C was also significantly less than in groups A and B for THA patients, while it was similar in groups A and B for TKA patients. No patients in group C received a transfusion. A significant difference was not detected in the incidence of deep vein thrombosis. No episode of symptomatic pulmonary embolism or all-cause mortality occurred within 30 days postoperatively.The current retrospective study suggests that for patients receiving primary unilateral THA or TKA, multiple boluses of intravenous TXA combined with topical TXA, rHuEPO, and iron supplements can reduce the calculated TBL, Hb drop, transfusion rate, and PLOS without increasing the incidence of VTE or mortality. PMID- 29505519 TI - Association between cadmium exposure and urolithiasis risk: A systematic review and meta-analysis. AB - BACKGROUND: We performed a meta-analysis to determine whether a consistent relationship exists between cadmium exposure and urolithiasis in humans. Accordingly, we summarized and reviewed previously published quantitative studies. METHODS: Eligible studies with reference lists published before June 1, 2017 were obtained from searching several databases. Random effects models were used to summary the overall estimate of the multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Six observational studies involving 88,045 participants were identified and stratified into the following categories according to cadmium assessment results: occupational (n = 4) and dietary (n = 2). The findings of the meta-analysis suggested that the risk of urolithiasis increases significantly by 1.32 times at higher cadmium exposure (OR = 1.32; 95% CI = 1.08-1.62; for highest vs lowest category urinary cadmium values). The summary OR in occupational exposure (OR = 1.56; 95% CI = 1.13-2.14) increased at the same condition. Meanwhile, no association was observed between cadmium exposure and urolithiasis risk in dietary exposure (OR = 1.13; 95% CI = 0.87-1.47). A significant association remained consistent, as indicated by subgroup analyses and sensitivity analyses. CONCLUSIONS: The meta-analysis indicated that increased risk of urolithiasis is associated with high cadmium exposure, and this association is higher in occupational exposure than in dietary exposure. Nevertheless, well-designed observational studies with different ethnic populations are still needed. PMID- 29505520 TI - Ultrasonographic manifestations of a rare granular cell tumor of the accessory breast: A case report. AB - RATIONALE: The ultrasound manifestations of granular cell tumor (GCT) is a consequence of the histopathological characteristic of the tumor and can be distinguished from breast cancer. PATIENT CONCERNS: A GCT is a rare, benign, hyperplasia-based lesion. Approximately 1% to 2% of GCTs are malignant. About 5% to15% of the cases occur in the breast, and it is relatively rare in the axillary accessory breast. There are no effective preventive measures for GCTs, early detection combined with a thorough and wide complete resection of the tumor remains the best treatment for a favorable outcome. DIAGNOSES: A 45-year-old female patient with an axillary mass of more than 3 months duration was examined through physical examination, color Doppler ultrasound and postoperative pathology. INTERVENTIONS: A provisional diagnosis of left axillary lymph node enlargement was made and necessary investigations were advised. OUTCOMES: A differential diagnosis of accessory breast in the left arm pit, possibly malignant, or a solid mass in the left arm pit secondary to chronic inflammation. Postoperative pathology: GCT of axillary accessory breast, with tumor-free margins. Immunohistochemical staining showed strong S-100 positivity, CD68 positivity, and negative periodic acid-Schiff staining. LESSONS: The ultrasound examination can detect GCT mass in the breast/accessory breast and is not easy to misdiagnosis. PMID- 29505521 TI - The relationship of sit-to-stand tests with 6-minute walk test in healthy young adults. AB - The aim of this study was to evaluate the timed sit-to-stand (STS) test performances of healthy young adults and to investigate the relationship of timed STS tests with 6-minute walk test (6MWT). A cross-sectional study was performed. A total of 40 healthy volunteers (mean age: 21.7 +/- 1.2 years) were evaluated with 10, 30, and 60 seconds STS tests and 6MWT. Fatigue and shortness of breath were rated using Borg category-ratio scale (CR10) before and after each test. Weekly energy expenditures of volunteers were calculated using International Physical Activity Questionnaire. 30 and 60 seconds STS tests were moderately (r = 0.611 and r = 0.647, respectively) (P < .001) and 10 seconds STS test was weakly (r = 0.344) (P = .028) correlated with 6MWT. Among correlations of each STS test with 6MWT, none of them was statistically stronger to one another (P > .05). Borg fatigue scores after 10, 30, and 60 seconds STS tests were weakly correlated with fatigue score after 6MWT (r = 0.321, r = 0.378, and r = 0.405, respectively) (P < .05). Weekly energy expenditure (MET-min/week) was moderately correlated with 10, 30, and 60 seconds STS tests and 6MWT (r = 0.533, r = 0.598, r = 0.598, and r = 0.547, respectively) (P < .001). Considering the statistically significant relationship between timed STS tests and 6MWT, any of the timed STS tests may be used for a quick and alternative measurement of physical performance and functional capacity in healthy young adults. PMID- 29505522 TI - The effects of one-lung ventilation mode on lung function in elderly patients undergoing esophageal cancer surgery. AB - The objective of the present study was to explore the effects of different one lung ventilation (OLV) modes on lung function in elderly patients undergoing esophageal cancer surgery. A total of 180 consecutive elderly patients (ASA Grades I-II, with OLV indications) undergoing elective surgery were recruited in the study. Patients were randomly divided into 4 groups (n = 45). In Group A, patients received low tidal volume (VT < 8 mL/kg) + pressure controlled ventilation (PCV), low tidal volume (VT < 8 mL/kg) + volume-controlled ventilation (VCV) in Group B, high tidal volume (VT >= 8 mL/kg) + PCV in Group C and high tidal volume (VT >= 8 mL/kg) + VCV in Group D. Two-lung ventilation involved routine tidal volume (8-10 mL/kg) at a frequency of 12 to 18 times/min, and VCV mode. Clinical efficacy among 4 groups was compared. The partial pressure of end-tidal carbon dioxide (PetCO2) did not significantly differ among 4 groups (all P > .05), and the oxygenation index and SO2 in Group A were significantly higher than in the other groups (P < .05). The PetCO2, peak airway pressure (Ppeak), platform airway pressure (Pplat), and mean airway pressure (Pmean) in Group A were significantly lower than those in the other groups (all P < .05). However, airway resistance (Raw) among 4 groups did not significantly differ (all P > .05). The incidence of pulmonary infection, anastomotic fistula, ventilator induced lung injury, lung dysfunction, difficulty weaning from mechanical ventilation, and multiple organ dysfunction in Groups A and B were lower than that in Groups C and D (all P < .05). The expression levels of IL-6, tumor necrosis factor-alpha, and C-reactive protein in lavage fluid in Group A were significantly lower than those in the other groups (all P < .05). OLV with low tidal volume (VT < 8 mL/kg) + PCV (5 cmH2O PEEP) improved lung function and mitigated inflammatory responses in elderly patients undergoing esophageal cancer surgery. PMID- 29505523 TI - Aberrations and clinical significance of BRAF in malignant melanoma: A series of 60 cases in Chinese Uyghur. AB - Malignant melanoma (MM) is a highly malignant melanocytic tumor, it occurs mostly in the skin, the mucous membrane close to the skin, but also in the tunicae rhagoides and the pia mater. The Uyghur is the largest ethnic group living in the Xinjiang Uyghur Autonomous Region of China, accounting for 46% of the total population of 20 million. Large-scale studies on MMs in Asian countries are limited. This study aimed to investigate BRAF mRNA expression and mutations in Chinese Uyghur patients with MMs and to identify the clinical features associated with these parameters.Formalin-fixed, paraffin wax-embedded tumor sections from 60 MMs were analyzed for BRAF expression using reverse transcription polymerase chain reaction (RT-PCR). Exons 11 and 15 of BRAF were analyzed for the presence of mutations using PCR and DNA sequencing. Sixty MMs were followed by mobile phone for survival analysis.BRAF mRNA expression was higher in MMs than in pigmented moles and normal skin tissues. Fourteen of 60 MMs had BRAF mutations. The frequency of BRAF mutations was significantly higher in patients younger than 60 years (10/28, 4/32, P = .02). A significant difference was observed in the frequency of BRAF mutations among specimens of mucosal, acral, chronic sun induced damage (CSD), and non-CSD MMs (2/10, 3/19, 8/25, 1/6, P = .002). No significant association was found among BRAF mutations, sex, ulceration, or lymph node metastasis. MMs lymph node metastasis (hazard ratio 2.54 [95% confidence interval 1.062 - 6.066], P = .01) affected survival.This study indicated that BRAF mutations and expression might serve as independent adverse prognostic factors in melanoma. PMID- 29505524 TI - Retracted: Serum 25-hydroxyvitamin D and risk of type 2 diabetes in older adults: A dose-response meta-analysis of prospective cohort studies. AB - Lower serum level of 25-hydroxyvitamin D is common in older adults and associated with several negative outcomes. However, previous studies have indicated that 25 hydroxyvitamin D is associated with risk of type 2 diabetes, but presented controversial results.Studies in PubMed and EMBASE were searched update to June 2017 to identify and quantify the potential dose-response association between low 25-hydroxyvitamin D and risk of type 2 diabetes in older adults.Nine eligible studies involving a total of 34,511 participants with 2863 incident cases were included in this meta-analysis. Our results showed statistically significant association between lower 25-hydroxyvitamin D and type 2 diabetes in older adults [odds ratio (OR) = 1.19, 95% confidence interval (95% CI): 1.08-1.32, P = .001]. In addition, we obtained the best fit at an inflection point of decrease 10 ng/mL in piecewise regression analysis; the summary relative risk of type 2 diabetes in older adults for a decrease of 10 ng/mL 25-hydroxyvitamin D was 1.06 (95% CI: 1.02-1.13, P < .001). Furthermore, subgroups analysis indicated that lower 25 hydroxyvitamin D was associated with a significant increment risk of type 2 diabetes in older adults in female (OR = 1.21, 95% CI: 1.04-1.40, P = .014) but not in male (OR = 1.11, 95% CI: 0.75-1.63, P = .615). Subgroup meta-analyses in study design, duration of follow-up, number of participants, and number of cases showed consistent with the primary findings.Lower 25-hydroxyvitamin D is associated with type 2 diabetes in older adults risk increment. PMID- 29505525 TI - Survival benefits of pelvic lymphadenectomy versus pelvic and para-aortic lymphadenectomy in patients with endometrial cancer: A meta-analysis. AB - BACKGROUND: Despite that pelvic and para-aortic lymphadenectomy (PPaLND) is recommended as part of accurate surgical staging by International Federation of Gynecology and Obstetrics (FIGO) in endometrial cancer, the impact of para-aortic lymphadenectomy on survival remains controversial. The aim of this work is to evaluate the survival benefits or risks in endometrial cancer patients who underwent surgical staging with or without para-aortic lymphadenectomy using meta analysis. METHODS: Literature search was undertaken using PubMed, Embase, and Cochrane Library databases for relevant articles published between January 1, 1990, and January 1, 2017, without language restriction. The primary outcome was overall survival (OS); progression-free survival (PFS)/recurrence-free survival (RFS)/disease-free survival (DFS)/disease-related survival (DRS) was also analyzed. Subgroup analysis and sensitivity analysis were conducted to investigate the source of heterogeneity. Quality assessments were performed by Newcastle-Ottawa Quality Assessment Scale (NOS). Publication bias was evaluated by using Begg and Egger tests. The hazard ratio (HR) was pooled with random effects or fixed-effects model as appropriate. RESULTS: Eight studies with a total of 2793 patients were included. OS was significantly longer in PPaLND group than in pelvic lymphadenectomy (PLND) group for patients with endometrial cancer [HR 0.68; 95% confidence interval (CI) 0.55-0.84, P < .001, I = 12.2%]. Subgroup analysis by recurrence risk explored the same association in patients at intermediate- or high-risk (HR 0.52; 95% CI 0.39-0.69, P < .001, I = 41.4%), but not for low-risk patients (HR 0.48; 95% CI 0.21-1.08, P = .077, I = 0). PPaLND with systematic resection of all para-aortic nodes up to renal vein also improved PFS/RFS/DFS/DRS, compared with PLND (HR 0.52, 95% CI 0.37-0.72, P < .001, I = 0). No publication bias was observed among included studies. CONCLUSION: PPaLND is associated with favorable survival outcomes in endometrial cancer patients with intermediate- or high-risk of recurrence compared with PLND, particularly with regards to OS. PPaLND with systematic resection of all para-aortic nodes up to renal vein also improve PFS compared with PLND. Further large-scale randomized clinical trials are required to validate our findings. PMID- 29505527 TI - Modified transprepancreatic septotomy reduces postoperative complications after intractable biliary access. AB - This study aimed to assess the clinical value of transprepancreatic septotomy indwelling guide wire or pancreatic duct stent in intractable endoscopic retrograde cholangiopancreatography (ERCP) for bile duct cannulation.Of the 2107 patients treated by ERCP, a total of 81 cases with difficult bile duct cannulation underwent transprebiliopancreatic septotomy (referred to as the septotomy group, 37 cases) and transprepancreatic septotomy with pancreatic duct stent (modified septotomy group, 44 cases). Success rates of cannulation and postoperative complications for both methods were compared.Among them, 77 cases were successfully administered bile duct cannulation. The success rates of the septotomy and modified septotomy groups were 91.89% and 97.73%, respectively, with no significant difference (P = .489). Of the 77 patients, 12 cases had complications. The septotomy group included 7 acute pancreatitis, 1 bleeding, and 1 biliary tract infection cases; while in the modified septotomy group, there were 1 acute pancreatitis, 1 bleeding, and 1 biliary tract infection cases. The occurrence rate of acute pancreatitis in the modified septotomy group was lower than that of the septotomy group (2.33% vs 20.59%) with a significant difference (P = .026).These findings indicate that transprepancreatic septotomy with pancreatic duct stent seems to be a safe and feasible operation with reducing complication rates. PMID- 29505526 TI - Encephalopathy associated with propofol infusion syndrome: A case report. AB - INTRODUCTION: Propofol infusion syndrome (PRIS) is a rare but potentially fatal complication of propofol infusion. It is clinically characterized by metabolic acidosis, refractory bradycardia, rhabdomyolysis, renal failure, hyperlipidemia, and hepatomegaly. Brain lesion was only reported once in a pediatric patient. We present the 1st adult case with colon polyp and cancer who was diagnosed with PRIS. Her brain magnetic resonance imaging (MRI) and computed tomography (CT) scans reveal prominent bilateral brain lesions, matching with the proposed pathophysiologic mechanism of the syndrome. The patient received prompt acidosis correction and cardiorespiratory support. At last, she died from refractory circulatory failure. CONCLUSION: It may be necessary to order a prompt neuroimaging examination in patients suspected with PRIS to judge whether brain lesions exist or not. PMID- 29505528 TI - Recombinant human erythropoietin for treating severe traumatic brain injury. AB - BACKGROUND: This study aimed to explore the efficacy and safety of recombinant human erythropoietin (RHE) for the treatment of severe traumatic brain injury (STBI). METHODS: One hundred and twenty eligible patients with STBI were randomly divided into an intervention group or a control group equally. Patients in the intervention group received RHE. The participants in the control group received 0.9% saline. The outcome measurements included the Glasgow Outcome Scale (GOS) scores, mortality, and any adverse events. RESULTS: At the end of 10-week follow up after treatment, RHE neither showed greater efficacy in GOS scores (1-2, P = .43; 3-4, P = .25; 5-6, P = .58; 7-8, P = .23), nor the lower mortality in the intervention group than those in the control group (P = .47). In addition, both groups had similar safety profile. CONCLUSION: This study found that RHE did not improve the neurological outcomes in patients with STBI. PMID- 29505529 TI - High EMP3 expression might independently predict poor overall survival in glioblastoma and its expression is related to DNA methylation. AB - In this study, we analyzed the prognostic value of epithelial membrane protein 3 (EMP3) in terms of overall survival (OS) in glioblastoma multiforme (GBM) and the association between its expression and DNA methylation.Bioinformatic analysis was performed by using data from the Cancer Genome Atlas (TCGA) database.EMP3 expression was markedly higher in GBM tissues than in normal brain tissues. High EMP3 expression was associated with significantly worse OS in patients with GBM. Univariate and multivariate analysis showed that EMP3 expression was an independent prognostic factor of poor OS no matter converting its expression into categorical variables (Hazard Ratio [HR] = 1.359, 95%CI: 1.118-1.652, P = .002) or setting it as a continuous variable (HR = 1.178, 95%CI: 1.101-1.260, P < .001). Among different subtypes of GBM, proneural subtype had the lowest EMP3 expression. The lowest EMP3 expression was observed in cluster 5 DNA methylation, which all belong to G-CIMP phenotype. Regression analysis confirmed a moderate negative correlation between EMP3 expression and its DNA methylation (Pearson's r = -0.61).Based on these findings, we infer that high EMP3 expression might be an independent indicator of unfavorable OS in GBM. EMP3 expression might be repressed by DNA methylation. PMID- 29505530 TI - Noncystoscopic removal of retained ureteral stents in children: A retrospective study from a single-center. AB - Cystoscopic technique is the current common method of retrieving double J ureteral stent in most pediatric urological centers. In this study, we evaluated the feasibility and efficacy of a novel noncystoscopic method to remove retained ureteral stents in pediatric patients.We reviewed all medical records from a total of 102 patients who were treated in our hospital between January 2013 and December 2016 to remove the double J ureteral stent retained into the ureter. The pediatric patients were divided into 2 groups based on different surgical options: cystoscopic group and noncystoscopic group. The surgery time (including time for instrument preparation), operation time, expenses, postoperative urination discomfort, and hospitalization were compared between the 2 groups.The noncystoscopic group took significantly less time for surgery and operation than the cystoscopic group (surgery time:7.40 +/- 3.75 vs 18.42 +/- 2.77 min, P <.05; operation time: 3.54 +/- 2.03 vs 4.48 +/- 2.04 min, P <.05). The mean spending for patients in the noncystoscopic group were less than that in the cystoscopic group ($736.70 +/- 105.96 vs $618.23 +/- 110.31, P <.05). There were less children with postoperative urination discomforts in the noncystoscopic group than that in the cystoscopic group (8 vs 20 cases, chi = 4.241, P <.05). The mean hospitalization of the noncystoscopic group was shorter than that of the cystoscopic group (3.20 +/- 1.25 vs 4.13 +/- 1.63 d, P <.05). The differences in all comparison projects were significant.The noncystoscopic procedure is a safe and viable technique that may be used successfully in pediatric urology. This novel procedure which is much safer and more affordable provides an alternative solution to remove retained ureteral stents in child patients. PMID- 29505531 TI - Primary, cardiac, fibroblastic osteosarcoma: A case report. AB - RATIONALE: Primary cardiac osteosarcoma is a rare tumor. To our knowledge, only 15 cases have been reported in the literature in the past 10 years. We describe a case of primary, cardiac, fibroblastic osteosarcoma in a 42-year-old woman. PATIENT CONCERNS: A 42-year-old woman with a 10-day history of chest pain. Intraoperatively, a mass was found originating from the ostium of the left inferior pulmonary vein in the left atrium, extending to the mitral orifice. Histologically, the tumor contained variable amounts of spindle cells and osseous differentiation in different areas. Primary, cardiac fibroblastic osteosarcoma had the typical appearance of interlacing hyperchromatic spindle-shaped stromal cells associated with osseous matrix. DIAGNOSES: According to the clinicopathological features, diagnosis of primary, cardiac fibroblastic osteosarcoma was made. INTERVENTIONS: Wide surgical excision of the mass was performed. OUTCOMES: Three months after the operation, transthoracic echocardiography demonstrated a 3.2 cm * 2 cm recurrent mass in the wall of the left atrium (LA). She died shortly afterwards as a result of the local disease recurrence. LESSONS: In this report, we describe a rare case of primary, cardiac fibroblastic osteosarcoma, and findings are helpful for the pathologists would like to further identify the clinicopathological features of this rare tumor. PMID- 29505532 TI - Case report of a pituitary thyrotropin-secreting macroadenoma with Hashimoto thyroiditis and infertility. AB - RATIONALE: Thyrotropin-secreting adenoma (TSHoma) is rare, diagnosis and treatment are often delayed if the condition coexists with Hashimoto thyroiditis. The enlarged pituitary adenoma may eventually induce panhypopituitarism, infertility, or the compression of optic nerves and optic chiasma. PATIENT CONCERNS: This patient was a 36-year-old man who had been referred to the pituitary disease multidisciplinary team (MDT) of the West China Hospital, due to infertility. DIAGNOSES: Examinations revealed pituitary thyrotropin-secreting macroadenoma. INTERVENTIONS: We conducted trans-sphenoidal surgery. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were used for reproductive reconstruction after surgery. OUTCOMES: This patient successfully fathered a child. LESSONS: To date, the multidisciplinary team treatment of TSHoma was rare, TSHomas are often misdiagnosed as macroadenomas, because the clinical features are varied and it often takes a long time to be diagnosed. So the purpose of this case report is to attract attention to the manifestation of increased thyroid stimulating hormone (TSH) concentration and discuss MDT treatment for TSH-secreting adenoma. PMID- 29505533 TI - Familial Mediterranean fever mimicking Crohn disease: A case report. AB - RATIONALE: Familial Mediterranean fever (FMF) is the most common form of autoinflammatory disease. We report a rare case of FMF with gastrointestinal lesions mimicking Crohn disease. PATIENT CONCERNS: A 21-year-old Japanese man was referred to our institution, complaining of refractory diarrhea and weight loss of 14 kg during the past two years. He had presented with recurrent fever, abdominal pain, anal fistula and stomatitis. His father and one of his brothers had ulcerative colitis. Colonoscopy revealed longitudinal ulcers in the terminal ileum and aphthous erosions in the colorectum. Esophagogastroduodenoscopy revealed multiple linear erosions in the gastric corpus and circular erosions in the duodenal second portion. Biopsy from these lesions failed to detect epithelioid cell granulomas. DIAGNOSES: Analysis of the genomic DNA revealed compound heterozygous mutations of E148Q/L110P in exon 2 of MEFV gene, suggesting a diagnosis of FMF. INTERVENTIONS: The patient was subsequently given 0.5 mg of colchicine per day. OUTCOMES: Follow-up colonoscopy 6 months later demonstrated that both the longitudinal ulcers in the terminal ileum and aphthous lesions in the colorectum had completely disappeared. LESSONS: Our case suggests that patients with FMF possibly manifest gastrointestinal lesions mimicking Crohn disease. PMID- 29505534 TI - Obesity was an independent risk factor for febrile infection after prostate biopsy: A 10-year single center study in South China. AB - To detect the best antibiotic protocol for prostate biopsy and to assess the potential risk factors postbiopsy in Chinese patients.A total of 1526 patients underwent biopsy were assessed retrospectively. The effect of 3 antibiotic protocols was compared, including fluoroquinolone (FQ) monotherapy, third generation cephalosporin combined with FQ and targeted antibiotics according to the prebiopsy rectal swab culture result. Postbiopsy infection (PBI) was defined as fever and/or active urinary tract symptoms such as dysuria or frequency with pyuria and/or leucocytosis, sepsis is defined as the presence of clinically or microbiologically documented infection in conjunction with systemic inflammatory response syndrome. The relationship between infections and clinical characteristics of patients was assessed. Data were first picked out in univariate analysis and then enter multivariate logistic regression.Thirty-three (2.2%) patients developed febrile infection. The combination antibiotic prophylaxis could significantly decrease the rate of PBI than FQ monotherapy (1.0% vs 4.0%, P = .000). The infection rate of the targeted antibiotic group was 1.1%, but there was no significant statistic difference compared with FQ alone (P = .349). Escherichia coli was the most predominant pathogen causing infection. Rectal swab revealed as high as 47.1% and 36.0% patients harbored FQ resistant and ESBL-producing organisms, respectively. In univariate analysis, overweight (BMI between 25 and 28 kg/m), obesity (BMI > 28 kg/m), diabetes were picked out as potential risk factors. Obesity remained as risk factor (OR = 12.827, 95% CI: 0.983-8.925, P = .001) while overweight and diabetes were close to significance (P = .052, .053, respectively).The combined cephalosporin with FQ prophylaxis could significantly decrease the risk of infectious complications. Obesity was an independent risk factor for PBI. PMID- 29505536 TI - Diagnostic accuracy of colposcopy with dynamic spectral imaging for cytology negative/high-risk HPV positive (failed test of cure) after large loop excision of the transformation zone (LLETZ) of the cervix: Results of the DySIS colposcopy 1 study. AB - After treatment for cervical intraepithelial neoplasia (CIN), in the UK women who are cytology-negative, high-risk (HR) human papilloma virus (HPV) positive are referred to colposcopy. This pilot study assessed the incidence of residual/recurrent CIN and the diagnostic accuracy of colposcopy with dynamic spectral imaging (DSI) mapping in their detection.This was a prospective service evaluation carried out in a UK National Health Service (NHS) colposcopy clinic. All women, referred with negative cytology/HR-HPV positive result following treatment for CIN from March 2013 until November 2014, who were examined with the DSI digital colposcope were included. We excluded 3 cases because of poor-quality imaging from user errors. Everyday clinical practice was followed. Initial colposcopic impression, DSI map indication, and biopsy site selections were recorded. CIN2+ was considered the primary outcome and CIN of any grade a secondary outcome.A total of 105 women were included of which 5 (4.8%) had CIN2+ histology and 24 (22.9%) had CIN1. Pre-DSI map colposcopy suggested normal/low grade in all 5 of the CIN2+ cases and DSI suggested high-grade (HG) CIN in 4 of the 5 cases. Sensitivity of standard colposcopy for CIN2+ was 0%, improving to 80% with the incorporation of the DSI map.The CIN burden in this population is higher than previously expected. Colposcopic identification of HG CIN appears to improve significantly with DSI in this cohort leading to refinement in patient management. A larger, multicentric prospective study (DySIS colposcopy 2) is planned to confirm these initial findings. PMID- 29505535 TI - Dentist's distress in the management of chronic pain control: The example of TMD pain in a dental practice-based research network. AB - We aimed to obtain greater understanding of dentists' distress when they diagnose and treat patients with temporomandibular disorders (TMD), and to explore ways in which TMD can be better treated.We conducted a cross-sectional study based on a questionnaire survey of dentists (n = 148). Dentists were queried using an open ended questionnaire about distress they experienced when treating patients with TMD. Survey responses were analyzed using mixed methods. Associations between specific dentist and patient characteristics and types of distress were analyzed by one way analysis of variance and residual analysis.One hundred thirteen clinicians responded to the questionnaire, giving a 76% response rate. Thematic analysis identified 6 major themes: difficulty in predicting therapeutic effect and prognosis; difficulty in diagnosis; difficulty in the decision about whether to do occlusal adjustment; difficulty in specifying a cause; difficulty in communicating with patients and mental factors; and health insurance system barriers. Clinicians who reported difficulty in deciding whether to do occlusal adjustment saw significantly more patients who experienced shoulder stiffness and headache (P = .008 and P = .022, respectively). Dentists' knowledge of TMD guidelines was associated with a lower percentage of difficulty in predicting therapeutic effect and prognosis (residual analysis; P = .010).These findings provide important insights into clinician's perception of difficulties with patients experiencing TMD-related pain. Knowledge of the existence of TMD clinical practice guidelines may lower dentist distress, particularly with regard to prognosis. Further studies are needed to decrease dentist's distress and to overcome the evidence-practice gap in TMD treatment. PMID- 29505537 TI - Physicians as well as nonphysician health care professionals in Taiwan have higher risk for lumbar herniated intervertebral disc than general population. AB - Physicians in Taiwan have long working hours and are at risk for inappropriate posture when handling patients, which may contribute to lumbar herniated intervertebral disc (L-HIVD). This study was conducted to delineate this issue, which is still unknown. This nationwide population-based cohort study was based on Taiwan National Health Insurance Research Database. We identified 25,428 physicians, 32,316 nonphysician health care professionals (HCPs), and an identical number of age- and sex-matched individuals from the general population. All individuals who had L-HIVD before 2007 were excluded. We compared the L-HIVD risk between physicians and general population, nonphysician HCPs and general population, and physicians and nonphysician HCPs by tracing their medical histories between 2007 and 2011. A comparison among physician specialties was also performed. Physicians and nonphysician HCPs had higher L-HIVD risk than the general population [odds ratio (OR): 1.149; 95% confidence interval (CI): 1.011 1.307 and OR: 1.220; 95% CI: 1.080-1.378, respectively]. Physicians did not have higher L-HIVD risk than nonphysician HCPs [adjusted OR (AOR): 0.912; 95% CI: 0.795-1.046]. Physician specialties of orthopedics and obstetrics and gynecology had a trend of higher L-HIVD risk than other specialties (AOR: 1.538; 95% CI: 0.805-2.939, and AOR: 1.306; 95% CI: 0.967-1.764, respectively). Physicians as well as nonphysician health care professionals in Taiwan have higher L-HIVD risk than the general population, which could be attributed to a probable role of long working hours. This result provides an important reference for the government to promote occupational health in health care professionals; however, further studies are warranted for the underlying mechanisms. PMID- 29505538 TI - Imaging appearance of renal epithelioid angiomyolipoma: A case report and literature review. AB - RATIONALE: Epithelioid angiomyolipoma (EAML) is an extremely rare disease. It commonly occurs in middle-aged females and mainly involves the kidney. Histological and immunohistochemical examination play important roles in differentiating EAML from renal cell carcinoma (RCC) and poor-fat angiomyolipoma (AML). PATIENT CONCERNS: Here, We report the imaging phenotype, as well as the pathological findings of a case of EAML in a 39-year-old female. DIAGNOSES: Preoperative noncontrast computed tomography (CT) scan revealed a 6.0 * 5.2 * 7.0 cm soft tissue mass with necrosis, located in the left kidney. On contrast enhanced CT images, aprogressive enhancement pattern was observed. CT angiography did not show any enlarged vessels or vascular malformation. Abdominal MRI showed a well-circumscribed solid mass with a heterogeneous signal on T1-weighted and T2 weighted images. Ultrasonography of the abdomen demonstrated a hypoechoic mass with abundant blood flow. This patient underwent radical nephrectomy. The pathologic diagnosis was EAML. INTERVENTIONS: This patient underwent operative resection of the tumor. The resection margins were negative for the neoplastic proliferation and no distant metastases were found. The patient did not receive advanced radiotherapy or chemotherapy. OUTCOMES: Four months after surgery, the follow-up CT scan did not reveal any local recurrence or distant metastases. LESSONS: This case adds to the experience with EAML by summarizing its imaging characteristics as well as reviewing the literature. Additionally, we described the state-of-the-art management of the management of this rare tumor. PMID- 29505539 TI - Neuroprotective effect of ethanol in acute carbon monoxide intoxication: A retrospective study. AB - In acute carbon monoxide (CO) intoxication, treatment of neurologic injury and prevention of neurological sequelae are primary concerns. Ethanol is the one of the frequent substances which is co-ingested in intentional CO poisoning. Neuroprotective effect of ethanol was highlighted and demonstrated in isolated brain injury recently. We assessed the neuroprotective effect of ethanol in acute CO intoxication using magnetic resonance imaging (MRI).We retrospectively reviewed medical records for patients who visited an emergency medical center of a university-affiliated hospital during a period of 73 months, from March 2009 to April 2015. Enrolled patients were divided into 2 groups, patients with or without abnormal brain lesion in brain MRI. Multivariate logistic regression analysis was performed to assess the factors associated with brain injury in MRI.A total of 109 patients with acute CO intoxication were evaluated of which 66 (60.55%) tested positive in brain MRI. MRI lesion-positive patients were more likely to have electrocardiogram change, elevation of serum troponin I and s100 protein level and lower serum ethanol level. Serum ethanol positivity was an independent factor for prevalence of brain injury in MRI in acute CO poisoning.This study revealed that ethanol which is co-ingested in acute CO intoxication may work the neuroprotective effect and could consequence more favorable neurological outcome in acute CO intoxication. PMID- 29505541 TI - Bone mineral density after treatment for gastric cancer: Endoscopic treatment versus gastrectomy. AB - Changes in bone metabolism among gastric cancer survivors have long been recognized. The aim of our study was to clarify the changes of bone mineral density (BMD) among gastric cancer survivors who underwent endoscopic resection or gastrectomy. Forty-nine patients diagnosed with tumor, node, and metastasis (TNM) stage 1 gastric cancer with pathologic confirmation, who underwent BMD measurement just before the procedure, and had no prior osteoporosis treatment, were studied. BMD was measured with dual energy x-ray absorptiometry before and after treatment. Laboratory tests were performed using fresh serum, and serum levels of alkaline phosphatase, albumin, calcium, and phosphorus were measured. We used a nested case-control design to compare groups. Of the 49 patients, 34 underwent gastrectomy and 15 underwent endoscopic treatment. There were no differences in baseline clinical characteristics, including BMD, and biochemical data between groups. The mean and median follow-up intervals for BMD measurement were 32.6 months (standard deviation, 16.5) and 31.0 months (interquartile range: 21.5, 41.0), respectively. The follow-up BMDs of the femoral neck and total hip were lower in the gastrectomy group (P = .010 and .011, respectively). The percentage changes in BMD for the lumbar spine, femoral neck, and total hip were 3.30%, -1.52%, and 0.40%, respectively, in the endoscopic treatment group, and 7.17%, -6.30%, and -3.49%, respectively, in the gastrectomy group. Bone loss of the lumbar spine and femoral neck were greater in the gastrectomy group (P = .028 and .022, respectively). BMD is lower after gastrectomy than after endoscopic treatment among early stage gastric cancer survivors. PMID- 29505543 TI - Apatinib in refractory radiation-induced brain Edema: A case report: Erratum. PMID- 29505544 TI - Identifications of potential therapeutic targets and drugs in angiotensin II induced hypertension: Erratum. PMID- 29505542 TI - The clinical manifestation, survival outcome and predictive prognostic factors of 137 patients with primary gastrointestinal lymphoma (PGIL): Strobe compliant. AB - This retrospective study aimed to investigate clinical characteristics and prognostic factors in patients with primary gastrointestinal lymphoma (PGIL) of Chinese population.From January 2001 to December 2015, 137 patients diagnosed with PGIL were recruited. The clinical features, treatment, and follow-up information were analysed.The median patient age was 62.3 years. With 18.47 months follow-up, the 2-year progress-free survival and overall survival rate was 74.9% and 75.5%, respectively. The overall response rate was 33.6%. Age>=60 years, advanced Lugano staging (>=stage IIE), elevated lactate dehydrogenase (LDH) levels, >=2 extra-nodal involved sites, National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI)>=4, Ki-67>=50% were associated with worse prognosis in univariate analysis (P < .05). By multivariate analyses, we determined that the involvement of extra-nodal involved sites was the only statistically significant poor prognostic factor in PGIL.Age, staging, LDH levels, NCCN-IPI, Ki-67 especially involvement of multiple extra-nodal sites were associated with poor overall survival of PGIL. PMID- 29505545 TI - Systematic Review and Meta-Analysis of Carotid Artery Stenting Versus Endarterectomy for Carotid Stenosis: A Chronological and Worldwide Study: Erratum. PMID- 29505546 TI - Is cerebral glucose metabolism related to blood-brain barrier dysfunction and intrathecal IgG synthesis in Alzheimer disease? A 18F-FDG PET/CT study: Erratum. PMID- 29505547 TI - A PRISMA-compliant systematic review and meta-analysis of the relationship between thyroid disease and different levels of iodine intake in mainland China: Erratum. PMID- 29505548 TI - Concomitant endometrial and cervical adenocarcinoma: A case report and literature review. AB - RATIONALE: Concomitant malignancy of the endometrium and cervix is extremely rare. PATIENT CONCERNS: A 56-year-old female presented to the Women's Hospital, School of Medicine, Zhejiang University, complaining of irregular vaginal bleeding. The human papillomavirus test (type 18/45) was positive. We performed dilation and curettage; pathology revealed moderately differentiated endometrial carcinoma exhibiting squamous differentiation. The epithelium of the cervical uterus was atypical upon biopsy. DIAGNOSES: Histological and immunochemical tests confirmed a diagnosis of endometrial carcinoma concomitant with cervical adenocarcinoma. INTERVENTIONS: She underwent laparoscopic staging surgery. OUTCOMES: The patient fully recovered with only surgery. LESSONS: Endometrial carcinoma concomitant with cervical adenocarcinoma is very rare. It is imperative to schedule adequate examination, and to perform careful preoperative diagnosis and appropriate treatment to minimize relapse. PMID- 29505550 TI - Unilateral Versus Bilateral Lung Transplantation: Do Different Esophageal Risk Factors Predict Chronic Allograft Failure? AB - GOALS: To assess the effect of unilateral versus bilateral lung transplantation (LTx) on esophageal motility and gastroesophageal reflux, and the association with the development of obstructive chronic lung allograft dysfunction (o-CLAD). BACKGROUND: We have shown that esophagogastric junction outflow obstruction, incomplete bolus transit, and proximal reflux are all independent risk factors for the development of chronic allograft failure. However, it remains unclear whether these factors are influenced by the type of surgery and how this relates to allograft failure. STUDY: Patients post-LTx (n=48, 24 female; aged 20 to 73 y) completed high-resolution impedance manometry and 24-hour pH/impedance. RESULTS: Patients who had undergone unilateral LTx were more likely to exhibit esophagogastric junction outflow obstruction (47% vs. 18%; P=0.046) and less likely to exhibit hypocontractility (0% vs. 21%; P=0.058) than those who had undergone bilateral LTx. Although the proportion of patients exhibiting gastroesophageal reflux was no different between groups (33% vs. 39%; P=0.505), those undergoing bilateral LTx were more likely to exhibit proximal reflux (8% vs. 37%; P=0.067). Univariate Cox proportion hazards regression analysis did not show a difference between unilateral versus bilateral LTx in the development of o CLAD (hazard ratio=1.17; 95% confidence interval, 0.48-2.85; P=0.723). CONCLUSION: The type of LTx performed seems to lead to different risk factors for the development of o-CLAD. Physicians should be aware of these differences, as they may need to be taken into account when managing patient's post-LTx. PMID- 29505549 TI - Effect of intralipid on myocardial injury during valve replacement surgery with concomitant radiofrequency ablation: A randomized controlled trial. AB - BACKGROUND: This study aimed to evaluate the effect of intralipid postconditioning (ILPC) on myocardial damage in patients undergoing valve replacement surgery with concomitant radiofrequency ablation (RFA) for atrial fibrillation (AF). METHODS: Randomized patient and assessor-blind controlled trial conducted in adult patients undergoing valve replacement surgery with concomitant RFA. Sixty-nine patients were randomly assigned to ILPC group (n = 34) or control group (n = 35): ILPC group received an intravenous infusion of 20% intralipid (2 mL/kg) just 10 minutes before aortic cross-unclamping, and control group received an equivalent volume of normal saline. Serum cardiac troponin-T (cTnT) and creatine kinase-MB (CK-MB) was measured before surgery and at 4, 12, 24, 48, and 72 hours after surgery. The primary endpoints were the 72-hour area under the curve (AUC) for cTnT and CK-MB. RESULTS: The total 72-hour AUC of cTnT (P = .33) and CK-MB (P = .52) were comparable between 2 groups. The left ventricle ejection fraction at discharge (P = .011) was higher in the ILPC group than that in the control group, while the AF recurrence did not differ significantly between 2 groups. CONCLUSIONS: There was no observed beneficial effect of ILPC on myocardial injury documented by the cardiac biomarkers in patients undergoing valve replacement surgery with concomitant RFA, and the effect of intralipid against myocardial I/R injury is undetectable within the background of massive biomarker release following ablation owing to localized myocardial necrosis. Besides, there are no other published data about the cardioprotective role of intralipid in patients undergoing this procedure and benefits of this protection need further studies to validate. PMID- 29505551 TI - Dietary Factors and Mucosal Immune Response in Celiac Disease Patients Having Persistent Symptoms Despite a Gluten-free Diet. AB - GOALS: The aim of this study was to investigate the role of dietary factors, distinct small-bowel mucosal immune cell types, and epithelial integrity in the perpetuation of gastrointestinal symptoms in treated celiac disease patients. BACKGROUND: For unexplained reasons, many celiac disease patients suffer from persistent symptoms, despite a strict gluten-free diet (GFD) and recovered intestinal mucosa. STUDY: We compared clinical and serological data and mucosal recovery in 22 asymptomatic and 25 symptomatic celiac patients on a long-term GFD. The density of CD3 and gammadelta intraepithelial lymphocytes (IELs), CD25 and FOXP3 regulatory T cells, and CD117 mast cells, and the expression of tight junction proteins claudin-3 and occludin, heat shock protein 60, interleukin 15, and Toll-like receptor 2 and 4 were evaluated in duodenal biopsies. RESULTS: All subjects kept a strict GFD and had negative celiac autoantibodies and recovered mucosal morphology. The asymptomatic patients had higher mean fiber intake (20.2 vs. 15.2 g/d, P=0.028) and density of CD3 IELs (59.3 vs. 45.0 cell/mm, P=0.045) than those with persistent symptoms. There was a similar but nonsignificant trend in gammadelta IELs (17.9 vs. 13.5, P=0.149). There were no differences between the groups in other parameters measured. CONCLUSIONS: Low fiber intake may predispose patients to persistent symptoms in celiac disease. There were no differences between the groups in the markers of innate immunity, epithelial stress or epithelial integrity. A higher number of IELs in asymptomatic subjects may indicate that the association between symptoms and mucosal inflammation is more complicated than previously thought. PMID- 29505552 TI - Water Exchange Produces Significantly Higher Adenoma Detection Rate Than Water Immersion: Pooled Data From 2 Multisite Randomized Controlled Trials. AB - GOALS: To test the hypothesis that water exchange (WE) significantly increases adenoma detection rates (ADR) compared with water immersion (WI). BACKGROUND: Low ADR was linked to increased risk for interval colorectal cancers and related deaths. Two recent randomized controlled trials of head-to-head comparison of WE, WI, and traditional air insufflation (AI) each showed that WE achieved significantly higher ADR than AI, but not WI. The data were pooled from these 2 studies to test the above hypothesis. STUDY: Two trials (5 sites, 14 colonoscopists) that randomized 1875 patients 1:1:1 to AI, WI, or WE were pooled and analyzed with ADR as the primary outcome. RESULTS: The ADR of AI (39.5%) and WI (42.4%) were comparable, significantly lower than that of WE (49.6%) (vs. AI P=0.001; vs. WI P=0.033). WE insertion time was 3 minutes longer than that of AI (P<0.001). WE showed significantly higher detection rate (vs. AI) of the >10 mm advanced adenomas. Right colon combined advanced and sessile serrated ADR of AI (3.4%) and WI (5%) were comparable and were significantly lower than that of WE (8.5%) (vs. AI P<0.001; vs. WI P=0.039). CONCLUSIONS: Compared with AI and WI, the superior ADR of WE offsets the drawback of a significantly longer insertion time. For quality improvement focused on increasing adenoma detection, WE is preferred over WI. The hypothesis that WE could lower the risk of interval colorectal cancers and related deaths should be tested. PMID- 29505553 TI - Prediction of Liver Steatosis Applying a New Score in Subjects from the Brazilian Longitudinal Study of Adult Health. AB - GOALS: To develop a noninvasive algorithm for diagnosis of liver steatosis and to compare its diagnostic value with available predictive models. BACKGROUND: Liver steatosis represents the most frequent liver disease worldwide. STUDY: This cross sectional study analyzed data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Patients were randomly divided into training (n=6571) and validation (n=3286) cohort. Abdominal ultrasound (US), used to grade steatosis, and overnight fasting blood tests were performed at the same day. Fatty Liver Index (FLI), Hepatic Steatosis Index, and Nonalcoholic Fatty Liver Disease-Liver Fat Score were calculated. A backward stepwise multivariate logistic regression analysis was used to develop the new predictive model, Steato-ELSA. RESULTS: In total, 9857 subjects [58% female, age=51 (interquartile range, 45 to 58) years, body mass index=26.4 (23.9 to 29.6) Kg/m] were included. Body mass index, waist circumference, homeostasis model of assessment of insulin resistance, transaminases, and triglycerides were independently associated with steatosis in the multivariate model (Hosmer-Lemeshow P=0.279). In the validation cohort, the area under the receiver-operator characteristics (95% confidence interval) for prediction of mild and moderate steatosis were: (i) 0.768 (0.751-0.784) and 0.829 (0.810-0.848) for Steato-ELSA; (ii) 0.762 (0.745-0.779) and 0.819 (0.799-0.838) for Fatty Liver Index; (iii) 0.743 (0.727-0.761) and 0.800 (0.779-0.822) for Hepatic Steatosis Index; and (iv) 0.719 (0.701-0.737) and 0.769 (0.747-0.791) for Nonalcoholic Fatty Liver Disease-Liver Fat Score. Steato-ELSA performed significantly better than other models and yielded sensitivity (Se)/specificity (Sp) (95% confidence interval): (i) for mild steatosis (score >=0.386): Se=65.6% (63.0-68.3) and Sp=73.7% (71.8-75.6); (ii) for moderate steatosis (score >=0.403): Se=83.5% (80.0-86.9) and Sp=68.7% (67.0-70.4). CONCLUSIONS: Steato-ELSA is an accurate and inexpensive tool that uses simple parameters to identify individuals at high risk of liver steatosis. PMID- 29505554 TI - Editor's Introduction: Know Your Audience. PMID- 29505555 TI - Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES). AB - BACKGROUND Recently, mutations in several genes have been described to be associated with sporadic ASD, but some genetic variants remain to be identified. The aim of this study was to use whole-exome sequencing (WES) combined with bioinformatics analysis to identify novel genetic variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing. MATERIAL AND METHODS Five Han patients with secundum ASD were recruited, and their tissue samples were analyzed by WES, followed by verification by Sanger sequencing of tissue and blood samples. Further evaluation using blood samples included 452 additional patients with sporadic secundum ASD (212 male and 240 female patients) and 519 healthy subjects (252 male and 267 female subjects) for further verification by a multiplexed MassARRAY system. Bioinformatic analyses were performed to identify novel genetic variants associated with sporadic ASD. RESULTS From five patients with sporadic ASD, a total of 181,762 genomic variants in 33 exon loci, validated by Sanger sequencing, were selected and underwent MassARRAY analysis in 452 patients with ASD and 519 healthy subjects. Three loci with high mutation frequencies, the 138665410 FOXL2 gene variant, the 23862952 MYH6 gene variant, and the 71098693 HYDIN gene variant were found to be significantly associated with sporadic ASD (P<0.05); variants in FOXL2 and MYH6 were found in patients with isolated, sporadic ASD (P<5*10^-4). CONCLUSIONS This was the first study that demonstrated variants in FOXL2 and HYDIN associated with sporadic ASD, and supported the use of WES and bioinformatics analysis to identify disease associated mutations. PMID- 29505556 TI - Development of a surface tension mediated technique for dry stabilization of mammalian cells. AB - Dry state preservation at ambient temperatures (lyopreservation) is a biomimetic alternative to low temperature stabilization (cryopreservation) of biological materials. Lyopreservation is hypothesized to rely upon the creation of a glassy environment, which is commonly observed in desiccation-tolerant organisms. Non uniformities in dried samples have been indicated as one of the reasons for instability in storage outcome. The current study presents a simple, fast, and uniform surface tension based technique that can be implemented for lyopreservation of mammalian cells. The technique involves withdrawing cells attached to rigid substrates to be submerged in a solution of lyoprotectant and then withdrawing the samples at a specific rate to an inert environment. This creates a uniform thin film of desiccated lyoprotectant due to sudden change of surface tension. The residual moisture contents at different locations in the desiccated film was quantified using a spatially resolved Raman microspectroscopy technique. Post-desiccation cellular viability and growth are quantified using fluorescent microscopy and dye exclusion assays. Cellular injury following desiccation is evaluated by bioenergetic quantification of metabolic functions using extracellular flux analysis and by a Raman microspectroscopic analysis of change in membrane structure. The technique developed here addresses an important bottleneck of lyoprocessing which requires the fast and uniform desiccation of cellular samples. PMID- 29505557 TI - Genotypic analysis of clinical and environmental Cryptococcus neoformans isolates from Brazil reveals the presence of VNB isolates and a correlation with biological factors. AB - Cryptococcal infections are mainly caused by members of the Cryptococcus neoformans species complex (molecular types VNI, VNII, VNB, VNIV and the AD hybrid VNIII). PCR of the mating type loci and MLST typing using the ISHAM-MLST consensus scheme were used to evaluate the genetic relationship of 102 (63 clinical and 39 environmental) C. neoformans isolates from Uberaba, Brazil and to correlate the obtained genotypes with clinical, antifungal susceptibility and virulence factor data. All isolates were mating type alpha. MLST identified 12 known and five new sequence types (ST). Fourteen STs were identified within the VNI isolates, with ST93 (57/102, 56%) and ST77 (19/102, 19%) being the most prevalent. From the nine VNII isolates previously identify by URA5-RFLP only four (ST40) were confirmed by MLST. The remaining five grouped within the VNB clade in the phylogenetic analysis corresponding to the sequence type ST504. Other two environmental isolates also grouped within VNB clade with the new sequence type ST527. The four VNII/ST40 isolates were isolated from CSF. The two VNIV sequence types (ST11 and ST160) were isolated from blood cultures. Two of six patients evaluated with more than one isolates had mixed infections. Amongst the VNI isolates 4 populations were identified, which showed differences in their susceptibility profiles, clinical outcome and virulence factors. These results reinforce that ST93 is the most prevalent ST in HIV-infected patients in the Southeastern region of Brazil. The finding of the VNB molecular type amongst environmental Brazilian isolates highlights that this genotype is not restricted to the African continent. PMID- 29505558 TI - Synchronous termination of replication of the two chromosomes is an evolutionary selected feature in Vibrionaceae. AB - Vibrio cholerae, the causative agent of the cholera disease, is commonly used as a model organism for the study of bacteria with multipartite genomes. Its two chromosomes of different sizes initiate their DNA replication at distinct time points in the cell cycle and terminate in synchrony. In this study, the time delayed start of Chr2 was verified in a synchronized cell population. This replication pattern suggests two possible regulation mechanisms for other Vibrio species with different sized secondary chromosomes: Either all Chr2 start DNA replication with a fixed delay after Chr1 initiation, or the timepoint at which Chr2 initiates varies such that termination of chromosomal replication occurs in synchrony. We investigated these two models and revealed that the two chromosomes of various Vibrionaceae species terminate in synchrony while Chr2-initiation timing relative to Chr1 is variable. Moreover, the sequence and function of the Chr2-triggering crtS site recently discovered in V. cholerae were found to be conserved, explaining the observed timing mechanism. Our results suggest that it is beneficial for bacterial cells with multiple chromosomes to synchronize their replication termination, potentially to optimize chromosome related processes as dimer resolution or segregation. PMID- 29505559 TI - Cytosolic proteins can exploit membrane localization to trigger functional assembly. AB - Cell division, endocytosis, and viral budding would not function without the localization and assembly of protein complexes on membranes. What is poorly appreciated, however, is that by localizing to membranes, proteins search in a reduced space that effectively drives up concentration. Here we derive an accurate and practical analytical theory to quantify the significance of this dimensionality reduction in regulating protein assembly on membranes. We define a simple metric, an effective equilibrium constant, that allows for quantitative comparison of protein-protein interactions with and without membrane present. To test the importance of membrane localization for driving protein assembly, we collected the protein-protein and protein-lipid affinities, protein and lipid concentrations, and volume-to-surface-area ratios for 46 interactions between 37 membrane-targeting proteins in human and yeast cells. We find that many of the protein-protein interactions between pairs of proteins involved in clathrin mediated endocytosis in human and yeast cells can experience enormous increases in effective protein-protein affinity (10-1000 fold) due to membrane localization. Localization of binding partners thus triggers robust protein complexation, suggesting that it can play an important role in controlling the timing of endocytic protein coat formation. Our analysis shows that several other proteins involved in membrane remodeling at various organelles have similar potential to exploit localization. The theory highlights the master role of phosphoinositide lipid concentration, the volume-to-surface-area ratio, and the ratio of 3D to 2D equilibrium constants in triggering (or preventing) constitutive assembly on membranes. Our simple model provides a novel quantitative framework for interpreting or designing in vitro experiments of protein complexation influenced by membrane binding. PMID- 29505560 TI - Reading the tea leaves: Dead transposon copies reveal novel host and transposon biology. AB - Transposable elements comprise a huge portion of most animal genomes. Unlike many pathogens, these elements leave a mark of their impact via their insertion into host genomes. With proper teasing, these sequences can relay information about the evolutionary history of transposons and their hosts. In a new publication, Larson and colleagues describe a previously unappreciated density of long interspersed element-1 (LINE-1) sequences that have been spliced (LINE-1 and other reverse transcribing elements are necessarily intronless). They provide data to suggest that the retention of these potentially deleterious splice sites in LINE-1 results from the sites' overlap with an important transcription factor binding site. These spliced LINE-1s (i.e., spliced integrated retrotransposed elements [SpiREs]) lose their ability to replicate, suggesting they are evolutionary dead ends. However, the lethality of this splicing could be an efficient means of blocking continued replication of LINE-1. In this way, the record of inactive LINE-1 sequences in the human genome revealed a new, though infrequent, event in the LINE-1 replication cycle and motivates future studies to test whether splicing might be another weapon in the anti-LINE-1 arsenal of host genomes. PMID- 29505561 TI - Association between institutional procedural preference and in-hospital outcomes in laparoscopic surgeries; Insights from a retrospective cohort analysis of a nationwide surgical database in Japan. AB - OBJECTIVE: To assess the use of laparoscopic surgeries (LS) and the association between its performance and hospitals' preference for LS over open surgeries. SUMMARY BACKGROUND DATA: LS is increasingly used in many abdominal surgeries, albeit both with and without solid guideline recommendations. To date, the hospitals' preference (LS vs. open surgeries) and its association with in hospital outcomes has not been evaluated. METHODS: We enrolled patients undergoing 8 types of gastrointestinal surgeries in 2011-2013 in the Japanese National Clinical Database. We assessed the use of LS and the occurrences of surgery-related morbidity and mortality during the study period. Further, for 4 typical LS procedures, we assessed the hospitals' preference for LS by modeling the propensity to perform LS (over open surgeries) from patient-level factors, and estimating each institution's observed/expected (O/E) ratio for LS use. Institutions with O/E>2 were defined as LS-dominant. Using hierarchical logistic regression models, we assessed the association between LS preference and in hospital outcomes. RESULTS: Among 1,377,118 patients undergoing gastrointestinal procedures in 2,336 participating hospitals, use of LS increased in all 8 procedures (35.1% to 44.7% for distal gastrectomy (DG), and 27.5% to 43.2% for right hemi colectomy (RHC)). Those operated at LS-dominant hospitals were at an increased risk of operative death (OR 1.83 [95%CI, 1.37-2.45] for DG, 1.79 [95%CI, 1.43-2.25] for RHC) compared to standard O/E level hospitals (0.5<=O/E<2.0). CONCLUSIONS: LS use widely increased during 2011-2013 in Japan. Facilities with higher than expected LS use had higher mortality compared to other hospitals, suggesting a need for careful patient selection and dissemination of the procedure. PMID- 29505563 TI - A reference interval for serum IgG subclasses in Chinese children. AB - BACKGROUND: Reference intervals (RIs) for serum IgG subclasses vary greatly among different geographical regions. The present study aimed to establish RIs for serum IgG subclasses in Chinese children, which is essential for interpretation of laboratory findings and making clinical decisions. METHODS: This study was performed in accordance with guideline C28-A3, proposed by the International Federation of Clinical Chemistry and the Clinical and Laboratory Standards Institute. In total, 607 apparently healthy Chinese children were enrolled, and serum levels of IgG subclasses were measured. Individuals were stratified by age and the RIs were determined through statistical analysis. RESULTS: Following were the median values of RIs for serum IgG subclasses in Chinese children: IgG1, 2.78 g/L; IgG2, 0.85 g/L; IgG3, 0.13 g/L; IgG4, 0.06 g/L at 1-6 months of age; IgG1, 3.64 g/L; IgG2, 0.73 g/L; IgG3, 0.19 g/L; IgG4, 0.03 g/L at 6-12 months of age; IgG1, 5.15 g/L; IgG2, 0.87 g/L; IgG3, 0.19 g/L; IgG4, 0.07 g/L at 1-2 years of age; IgG1, 5.26 g/L; IgG2, 1.23 g/L; IgG3, 0.14 g/L; IgG4, 0.11 g/L at 2-3 years of age; IgG1, 6.33 g/L; IgG2, 1.8 g/L; IgG3, 0.2 g/L; IgG4, 0.21 g/L at age 3-4 years; IgG1, 7.05 g/L; IgG2, 1.87 g/L; IgG3, 0.25 g/L; IgG4, 0.29 g/L at 4-6 years of age; IgG1, 6.19 g/L; IgG2, 1.93 g/L; IgG3, 0.2 g/L; IgG4, 0.28 g/L at 6 9 years of age; IgG1, 6.76 g/L; IgG2, 2.29 g/L; IgG3, 0.27 g/L; IgG4, 0.37 g/L at 10-12 years of age; IgG1, 7.45 g/L; IgG2, 2.92 g/L; IgG3, 0.28 g/L; IgG4, 0.38 g/L at 13-16 years of age. CONCLUSION: To our knowledge, this study is the first to establish RIs for serum IgG subclasses exclusively in Chinese children. PMID- 29505562 TI - SUMO E3 ligase Mms21 prevents spontaneous DNA damage induced genome rearrangements. AB - Mms21, a subunit of the Smc5/6 complex, possesses an E3 ligase activity for the Small Ubiquitin-like MOdifier (SUMO). Here we show that the mms21-CH mutation, which inactivates Mms21 ligase activity, causes increased accumulation of gross chromosomal rearrangements (GCRs) selected in the dGCR assay. These dGCRs are formed by non-allelic homologous recombination between divergent DNA sequences mediated by Rad52-, Rrm3- and Pol32-dependent break-induced replication. Combining mms21-CH with sgs1Delta caused a synergistic increase in GCRs rates, indicating the distinct roles of Mms21 and Sgs1 in suppressing GCRs. The mms21-CH mutation also caused increased rates of accumulating uGCRs mediated by breakpoints in unique sequences as revealed by whole genome sequencing. Consistent with the accumulation of endogenous DNA lesions, mms21-CH mutants accumulate increased levels of spontaneous Rad52 and Ddc2 foci and had a hyper activated DNA damage checkpoint. Together, these findings support that Mms21 prevents the accumulation of spontaneous DNA lesions that cause diverse GCRs. PMID- 29505564 TI - Purification and characterization of the first gamma-phospholipase inhibitor (gammaPLI) from Bothrops jararaca snake serum. AB - Phospholipases A2 (PLA2) are enzymes acting on the cell membrane phospholipids resulting in fatty acids and lysophospholipids and deconstructing the cell membrane. This protein is commonly found in snake venoms, causing tissue inflammation in the affected area. Evidence indicates that snakes have natural resistance to their own venom due to protective properties in plasma, that inhibit the action of proteins present in their venom. Given that, this study aimed to purify and characterize a gammaPLI from Bothrops jararaca serum, named gammaBjPLI. PLA2 inhibitor was isolated using two chromatographic steps: an ion exchange column (DEAE), followed by an affinity column (crotoxin coupled to a CNBr-activated Sepharose resin). The purity and biochemical characterization of the isolated protein were analyzed by RP-HPLC, SEC, SDS-PAGE, circular dichroism and mass spectrometry. The ability to inhibit PLA2 was determined by enzymatic activity, neutralization of paw edema and myonecrosis. The protein purity was confirmed by RP-HPLC and SEC, whilst an apparent molecular mass of 25 kDa and 20 kDa was obtained by SDS-PAGE, under reducing and non-reducing conditions, respectively. According to mass spectrometry analysis, this protein showed 72% and 68% of coverage when aligned to amino acid sequences of two proteins already described as PLIs. Thus, the inhibitory activity of enzymatic, edema and myonecrotic activities by gammaBjPLI suggests a role of this inhibitor for protection of these snakes against self-envenomation. PMID- 29505565 TI - Pheromone expression reveals putative mechanism of unisexuality in a saprobic ascomycete fungus. AB - Homothallism (self-fertility) describes a wide variety of sexual strategies that enable a fungus to reproduce in the absence of a mating partner. Unisexual reproduction, a form of homothallism, is a process whereby a fungus can progress through sexual reproduction in the absence of mating genes previously considered essential for self-fertility. In this study, we consider the molecular mechanisms that allow for this unique sexual behaviour in the saprotrophic ascomycete; Huntiella moniliformis. These molecular mechanisms are also compared to the underlying mechanisms that control sex in Huntiella omanensis, a closely related, but self-sterile, species. The main finding was that H. omanensis displayed mating-type dependent expression of the a- and alpha-pheromones. This was in contrast to H. moniliformis where both pheromones were co-expressed during vegetative growth and sexual development. Furthermore, H. moniliformis also expressed the receptors of both pheromones. Consequently, this fungus is likely able to recognize and respond to the endogenously produced pheromones, allowing for self-fertility in the absence of other key mating genes. Overall, these results are concomitant with those reported for other unisexual species, but represent the first detailed study considering the unisexual behaviour of a filamentous fungus. PMID- 29505566 TI - Blood concentration of bupivacaine and duration of sensory and motor block following ultrasound-guided femoral and sciatic nerve blocks in dogs. AB - Peripheral nerve blocks are becoming increasingly popular for perioperative use as anesthetics and analgesics in small animals. This prospective study was performed to investigate the duration of motor and sensory blockade following use of bupivacaine for ultrasound-guided femoral and sciatic nerve blocks in dogs and to measure the plasma concentrations of bupivacaine that result from these procedures. Six dogs were anesthetized twice using a randomized cross-over design. At the first anesthetic, dogs were assigned to receive either an ultrasound-guided femoral nerve block or sciatic nerve block with 0.15 mL kg-1 of bupivacaine 0.5%. Two months later, the other nerve block was performed during a second anesthetic. At 5, 10, 15, 20, 30 and 60 minutes after injection, arterial blood samples were collected for laboratory measurement of bupivacaine. After 60 minutes, dogs were recovered from anesthesia. Starting at two hours post injection, video-recordings of the dogs were made every two hours for 24 hours. The videos were randomized and the degree of motor and sensory blockade was evaluated using a three-point scoring system (0 = no effect, 1 = mild effect, 2 = complete blockade) by two blinded assessors. The median (range) times to full recovery from motor blockade were 11 (6-14) hours (femoral) and 12 (4-18) hours (sciatic), and 15 (10-18) hours (femoral) and 10 (4-12) hours (sciatic) for sensory blockade. There were no differences in the median times to functional recovery for the two techniques. Plasma concentrations of bupivacaine were no different following the blocks and were less than 0.78 MUg mL-1 at all times. These results suggest that these ultrasound-guided nerve blocks do not result in potentially toxic systemic levels of local anesthetic and that their duration of action is useful for providing anesthesia and analgesia for pelvic limb procedures. PMID- 29505567 TI - Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3. AB - BACKGROUND: Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed. METHODOLOGY: Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions. RESULTS: Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16 22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families. CONCLUSIONS: This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood. PMID- 29505569 TI - Ways to increase precision and accuracy of wound area measurement using smart devices: Advanced app Planimator. AB - INTRODUCTION: Wound surface area measurement is important as therapeutic decisions may depend on the change of wound surface area over time. Digital planimetry is a popular technique in wound area measurement. It is accurate and repeatable when calibration is performed with 2 rulers placed at opposite sides of a wound. The aim of the current study was improving accuracy and precision of wound area measurement using capabilities of smart devices. METHODS: The correction of area measurement based on calculated camera tilt angle and the calculation of calibration coefficient of linear dimensions as weighted average were proposed. These and other improvements were applied in the Planimator app for Android, which was then used in the study. Accuracy and precision of the Planimator app were compared to the Visitrak device, the SilhouetteMobile device, the AreaMe software, and to the digital planimetry based on 2-ruler calibration with pictures taken by the smartphone, compact, and D-SLR cameras. Areas of 40 wound shapes of area ranged from 0.14 to 31.72 cm2 were measured with each device. Medians of relative errors (REs) were compared in the accuracy tests and standard deviations (SDs) of relative differences (RDs) were compared in the tests of precision. RESULTS: The median of REs for the Planimator app was not significantly different from the medians of REs for the digital planimetry based on pictures from the compact or D-SLR cameras, but it was significantly lower than the medians of REs for the Visitrak and SilhouetteMobile devices, the AreaMe software and the digital planimetry based on pictures from a smartphone camera. The SD of RDs for the Planimator app was not significantly different from the SDs of RDs for the digital planimetry based on pictures from the compact or D-SLR cameras, but it was significantly lower than the SDs of RDs for the Visitrak and SilhouetteMobile devices, the AreaMe software and the digital planimetry based on pictures from a smartphone camera. The Planimator app installed at a smartphone revealed to be 2-fold more accurate and 1.5-fold more precise than the measurements with using ImageJ software based on pictures taken with the same smartphone. CONCLUSIONS: The Planimator app occurred to have the same accuracy and precision as measurements with digital planimetry with 2-ruler calibration and based on pictures from a compact camera or a D-SLR camera. This app showed better accuracy and precision than the Visitrak and SilhouetteMobile devices, the AreaMe software and the digital planimetry based on pictures from a smartphone camera. PMID- 29505568 TI - Spliced integrated retrotransposed element (SpIRE) formation in the human genome. AB - Human Long interspersed element-1 (L1) retrotransposons contain an internal RNA polymerase II promoter within their 5' untranslated region (UTR) and encode two proteins, (ORF1p and ORF2p) required for their mobilization (i.e., retrotransposition). The evolutionary success of L1 relies on the continuous retrotransposition of full-length L1 mRNAs. Previous studies identified functional splice donor (SD), splice acceptor (SA), and polyadenylation sequences in L1 mRNA and provided evidence that a small number of spliced L1 mRNAs retrotransposed in the human genome. Here, we demonstrate that the retrotransposition of intra-5'UTR or 5'UTR/ORF1 spliced L1 mRNAs leads to the generation of spliced integrated retrotransposed elements (SpIREs). We identified a new intra-5'UTR SpIRE that is ten times more abundant than previously identified SpIREs. Functional analyses demonstrated that both intra-5'UTR and 5'UTR/ORF1 SpIREs lack Cis-acting transcription factor binding sites and exhibit reduced promoter activity. The 5'UTR/ORF1 SpIREs also produce nonfunctional ORF1p variants. Finally, we demonstrate that sequence changes within the L1 5'UTR over evolutionary time, which permitted L1 to evade the repressive effects of a host protein, can lead to the generation of new L1 splicing events, which, upon retrotransposition, generates a new SpIRE subfamily. We conclude that splicing inhibits L1 retrotransposition, SpIREs generally represent evolutionary "dead ends" in the L1 retrotransposition process, mutations within the L1 5'UTR alter L1 splicing dynamics, and that retrotransposition of the resultant spliced transcripts can generate interindividual genomic variation. PMID- 29505570 TI - Free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA. AB - The eukaryotic genome is packaged into a nucleus in the form of chromatin. The fundamental structural unit of chromatin is a protein-DNA complex, the nucleosome, where 146 or 147 base pairs of DNA wrap 1.75 times around a histone core. To function in cellular processes, however, nucleosomal DNA must be unwrapped. Although this unwrapping has been experimentally investigated, details of the process at an atomic level are not yet well understood. Here, we used molecular dynamics simulation with an enhanced sampling method to calculate the free energy profiles for unwrapping the outer superhelical turn of nucleosomal DNA. A free energy change of about 11.5 kcal/mol for the unwrapping agrees well with values obtained in single molecule experiments. This simulation revealed a variety of conformational states, indicating there are many potential paths to outer superhelicdal turn unwrapping, but the dominant path is likely asymmetric. At one end of the DNA, the first five bps unwrap, after which a second five bps unwrap at the same end with no increase in free energy. The unwrapping then starts at the other end of the DNA, where 10 bps are unwrapped. During further unwrapping of 15 bps, the unwrapping advances at one of the ends, after which the other end of the DNA unwraps to complete the unwrapping of the outer superhelical turn. These results provide insight into the construction, disruption, and repositioning of nucleosomes, which are continuously ongoing during cellular processes. PMID- 29505571 TI - Altered vector competence in an experimental mosquito-mouse transmission model of Zika infection. AB - Few animal models of Zika virus (ZIKV) infection have incorporated arthropod borne transmission. Here, we establish an Aedes aegypti mosquito model of ZIKV infection of mice, and demonstrate altered vector competency among three strains, (Orlando, ORL, Ho Chi Minh, HCM, and Patilas, PAT). All strains acquired ZIKV in their midguts after a blood meal from infected mice, but ZIKV transmission only occurred in mice fed upon by HCM, and to a lesser extent PAT, but not ORL, mosquitoes. This defect in transmission from ORL or PAT mosquitoes was overcome by intrathoracic injection of ZIKV into mosquito. Genetic analysis revealed significant diversity among these strains, suggesting a genetic basis for differences in ability for mosquito strains to transmit ZIKV. The intrathoracic injection mosquito-mouse transmission model is critical to understanding the influence of mosquitoes on ZIKV transmission, infectivity and pathogenesis in the vertebrate host, and represents a natural transmission route for testing vaccines and therapeutics. PMID- 29505572 TI - A computational model for how cells choose temporal or spatial sensing during chemotaxis. AB - Cell size is thought to play an important role in choosing between temporal and spatial sensing in chemotaxis. Large cells are thought to use spatial sensing due to large chemical difference at its ends whereas small cells are incapable of spatial sensing due to rapid homogenization of proteins within the cell. However, small cells have been found to polarize and large cells like sperm cells undergo temporal sensing. Thus, it remains an open question what exactly governs spatial versus temporal sensing. Here, we identify the factors that determines sensing choices through mathematical modeling of chemotactic circuits. Comprehensive computational search of three-node signaling circuits has identified the negative integral feedback (NFB) and incoherent feedforward (IFF) circuits as capable of adaptation, an important property for chemotaxis. Cells are modeled as one dimensional circular system consisting of diffusible activator, inactivator and output proteins, traveling across a chemical gradient. From our simulations, we find that sensing outcomes are similar for NFB or IFF circuits. Rather than cell size, the relevant parameters are the 1) ratio of cell speed to the product of cell diameter and rate of signaling, 2) diffusivity of the output protein and 3) ratio of the diffusivities of the activator to inactivator protein. Spatial sensing is favored when all three parameters are low. This corresponds to a cell moving slower than the time it takes for signaling to propagate across the cell diameter, has an output protein that is polarizable and has a local-excitation global-inhibition system to amplify the chemical gradient. Temporal sensing is favored otherwise. We also find that temporal sensing is more robust to noise. By performing extensive literature search, we find that our prediction agrees with observation in a wide range of species and cell types ranging from E. coli to human Fibroblast cells and propose that our result is universally applicable. PMID- 29505573 TI - Clonorchis sinensis adult-derived proteins elicit Th2 immune responses by regulating dendritic cells via mannose receptor. AB - BACKGROUND: Clonorchis sinensis (C. sinensis) is the most widespread human liver fluke in East Asia including China and Korea. Clonorchiasis as a neglected tropical zoonosis, leads to serious economic and public health burden in China. There are considerable evidences for an etiological relation between chronic clonorchiasis and liver fibrosis in human beings. Liver fibrosis is a highly conserved and over-protected response to hepatic tissue injury. Immune cells including CD4+ T cell as well as dendritic cell (DC), and pro-fibrogenic cytokines like interleukin 4 (IL-4), IL-13 have been identified as vital manipulators in liver fibrogenesis. Our previous studies had a mere glimpse of T helper type 2 (Th2) dominant immune responses as key players in liver fibrosis induced by C. sinensis infection, but little is known about the involved mechanisms in this pathological process. METHODOLOGY/PRINCIPAL FINDINGS: By flow cytometry (FACS), adult-derived total proteins of C. sinensis (CsTPs) down regulated the expression of surface markers CD80, CD86 and major histocompatibility complex class II (MHC-II) on lipopolysaccharide (LPS) induced DC. ELISA results demonstrated that CsTPs inhibited IL-12p70 release from LPS treated bone marrow-derived dendritic cells (BMDC). IL-10 level increased in a time-dependent manner in LPS-treated BMDCs after incubation with CsTPs. CD4+ T cells incubated with LPS-treated BMDCs plus CsTPs could significantly elevate IL 4 level by ELISA. Meanwhile, elevated expression of pro-fibrogenic mediators including IL-13 and IL-4 were detected in a co-culture system of LPS-activated BMDCs and naive T cells containing CsTPs. In vivo, CsTPs-immunized mice enhanced expression of type 2 cytokines IL-13, IL-10 and IL-4 in both splenocytes and hepatic tissue. Exposure of BMDCs to CsTPs activated expression of mannose receptor (MR) but not toll like receptor 2 (TLR2), TLR4, C-type lectin receptor DC-SIGN and Dectin-2 on the cell surface by RT-PCR and FACS. Blockade of MR almost completely reversed the capacity of CsTPs to suppress LPS-induced BMDCs surface markers CD80, CD86 and MHC-II expression, and further made these BMDCs fail to induce a Th2-skewed response as well as Th2 cell-associated cytokines IL 13 and IL-4 release in vitro. CONCLUSIONS/SIGNIFICANCE: Collectively, we validated that CsTPs could suppress the maturation of BMDCs in the presence of LPS via binding MR, and showed that the CsTPs-pulsed BMDCs actively polarized naive T helper cells to Th2 cells though the production of IL-10 instead of IL 12. CsTPs endowed host with the capacity to facilitate Th2 cytokines production including IL-13 and IL-4 in vitro and vivo. The study might provide useful information for developing potential therapeutic targets against the disease. PMID- 29505574 TI - Treatment of infected lungs by ex vivo perfusion with high dose antibiotics and autotransplantation: A pilot study in pigs. AB - The emergence of multi-drug resistant bacteria threatens to end the era of antibiotics. Drug resistant bacteria have evolved mechanisms to overcome antibiotics at therapeutic doses and further dose increases are not possible due to systemic toxicity. Here we present a pilot study of ex vivo lung perfusion (EVLP) with high dose antibiotic therapy followed by autotransplantation as a new therapy of last resort for otherwise incurable multidrug resistant lung infections. Severe Pseudomonas aeruginosa pneumonia was induced in the lower left lungs (LLL) of 18 Mini-Lewe pigs. Animals in the control group (n = 6) did not receive colistin. Animals in the conventional treatment group (n = 6) received intravenous application of 2 mg/kg body weight colistin daily. Animals in the EVLP group (n = 6) had their LLL explanted and perfused ex vivo with a perfusion solution containing 200 MUg/ml colistin. After two hours of ex vivo treatment, autotransplantation of the LLL was performed. All animals were followed for 4 days following the initiation of treatment. In the control and conventional treatment groups, the infection-related mortality rate after five days was 66.7%. In the EVLP group, there was one infection-related mortality and one procedure related mortality, for an overall mortality rate of 33.3%. Moreover, the clinical symptoms of infection were less severe in the EVLP group than the other groups. Ex vivo lung perfusion with very high dose antibiotics presents a new therapeutic option of last resort for otherwise incurable multidrug resistant pneumonia without toxic side effects on other organs. PMID- 29505575 TI - An improved anonymous authentication scheme for roaming in ubiquitous networks. AB - With the evolution of communication technology and the exponential increase of mobile devices, the ubiquitous networking allows people to use our data and computing resources anytime and everywhere. However, numerous security concerns and complicated requirements arise as these ubiquitous networks are deployed throughout people's lives. To meet the challenge, the user authentication schemes in ubiquitous networks should ensure the essential security properties for the preservation of the privacy with low computational cost. In 2017, Chaudhry et al. proposed a password-based authentication scheme for the roaming in ubiquitous networks to enhance the security. Unfortunately, we found that their scheme remains insecure in its protection of the user privacy. In this paper, we prove that Chaudhry et al.'s scheme is vulnerable to the stolen-mobile device and user impersonation attacks, and its drawbacks comprise the absence of the incorrect login-input detection, the incorrectness of the password change phase, and the absence of the revocation provision. Moreover, we suggest a possible way to fix the security flaw in Chaudhry et al's scheme by using the biometric-based authentication for which the bio-hash is applied in the implementation of a three factor authentication. We prove the security of the proposed scheme with the random oracle model and formally verify its security properties using a tool named ProVerif, and analyze it in terms of the computational and communication cost. The analysis result shows that the proposed scheme is suitable for resource constrained ubiquitous environments. PMID- 29505576 TI - Reproducible preclinical research-Is embracing variability the answer? AB - Translational failures and replication issues of published research are undermining preclinical research and, if the outcomes are questionable, raise ethical implications over the continued use of animals. Standardization of procedures, environmental conditions, and genetic background has traditionally been proposed as the gold standard approach, as it reduces variability, thereby enhancing sensitivity and supporting reproducibility when the environment is defined precisely. An alternative view is that standardization can identify idiosyncratic effects and hence decrease reproducibility. In support of this alternative view, Voelkl and colleagues present evidence from resampling a large quantity of research data exploring a variety of treatments. They demonstrate that by implementing multi-laboratory experiments with as few as two sites, we can increase reproducibility by embracing variation without increasing the sample size. PMID- 29505577 TI - The non-canonical Notch signaling is essential for the control of fertility in Aedes aegypti. AB - The Notch signaling pathway is a highly evolutionarily-conserved cell-cell signaling pathway that regulates many events during development. It plays a pivotal role in the regulation of fundamental cellular processes, such as cell proliferation, stem cell maintenance, and differentiation during embryonic and adult development. However, functions of Notch signaling in Aedes aegypti, the major mosquito vector for dengue, are largely unknown. In this study, we identified a unique feature of A. aegypti Notch (AaNotch) in the control of the sterile-like phenotype in female mosquitoes. Silencing AaNotch with a reverse genetic approach significantly reduced the fecundity and fertility of the mosquito. Silencing AaNotch also resulted in the prevention of micropyle formation, which led to impaired fertilization. In addition, JNK phosphorylation (a signaling molecule in the non-canonical Notch signaling pathway) was inhibited in the absence of AaNotch. Furthermore, treatment with a JNK inhibitor in the mosquito resulted in impaired fecundity and fertility. Taken together, our results demonstrate that non-canonical Notch signaling is essential for controlling fertility in the A. aegypti mosquito. PMID- 29505578 TI - Optimal mode for delivery of seasonal malaria chemoprevention in Ouelessebougou, Mali: A cluster randomized trial. AB - BACKGROUND: Seasonal malaria chemoprevention (SMC), the administration of complete therapeutic courses of antimalarials to children aged 3-59 months during the malaria transmission season, is a new strategy recommended by the World Health Organization (WHO) for malaria control in Sahelian countries such as Mali with seasonal transmission. The strategy is a highly cost-effective approach to reduce malaria burden in these areas. Despite the substantial benefits of SMC on malaria infection and disease, the optimal approach to deliver SMC remains to be determined. While fixed-point delivery (FPD) and non-directly observed treatment (NDOT) by community health workers are logistically attractive, these need to be evaluated and compared to other modes of delivery for maximal coverage. METHODS: To determine the optimal mode fixed-point (FPD) vs door-to-door delivery (DDD); directly observed treatment (DOT) vs. non- directly observed treatment (NDOT)), 31 villages in four health sub-districts were randomized to receive three rounds of SMC with Sulfadoxine-pyrimethamine plus Amodiaquine (SP+AQ) at monthly intervals using one of the following methods: FPD+DOT; FPD+NDOT; DDD+DOT; DDD+NDOT. The primary endpoint was SMC coverage assessed by cross-sectional survey of 2,035 children at the end of intervention period. RESULTS: Coverage defined as the proportion of children who received all three days of SMC treatment during the three monthly rounds based information collected by interview (primary endpoint) was significantly higher in children who received SMC using DDD 74% (95% CI 69% - 80%) compared to FPD 60% (95% CI 50% - 70%); p = 0.009. It was similar in children who received SMC using DOT or NDOT 65%, (95% CI 55% - 76%) versus 68% (95% CI 57% - 79%); p = 0.72. CONCLUSIONS: In summary, door to-door delivery of SMC provides better coverage than FPD. Directly observed therapy, which requires more time and resources, did not improve coverage with SMC. TRIAL REGISTRATION: ClinicalTrials.gov NCT02646410. PMID- 29505579 TI - Rift Valley Fever: A survey of knowledge, attitudes, and practice of slaughterhouse workers and community members in Kabale District, Uganda. AB - BACKGROUND: Rift Valley Fever virus (RVF) is a zoonotic virus in the Phenuiviridae family. RVF outbreaks can cause significant morbidity and mortality in humans and animals. Following the diagnosis of two RVF cases in March 2016 in southern Kabale district, Uganda, we conducted a knowledge, attitudes and practice (KAP) survey to identify knowledge gaps and at-risk behaviors related to RVF. METHODOLOGY/PRINCIPAL FINDINGS: A multidisciplinary team interviewed 657 community members, including abattoir workers, in and around Kabale District, Uganda. Most participants (90%) had knowledge of RVF and most (77%) cited radio as their primary information source. Greater proportions of farmers (68%), herdsmen (79%) and butchers (88%) thought they were at risk of contracting RVF compared to persons in other occupations (60%, p<0.01). Participants most frequently identified bleeding as a symptom of RVF. Less than half of all participants reported fever, vomiting, and diarrhea as common RVF symptoms in either humans or animals. The level of knowledge about human RVF symptoms did not vary by occupation; however more farmers and butchers (36% and 51%, respectively) had knowledge of RVF symptoms in animals compared to those in other occupations (30%, p<0.01). The use of personal protective equipment (PPE) when handling animals varied by occupation, with 77% of butchers using some PPE and 12% of farmers using PPE. Although most butchers said that they used PPE, most used gumboots (73%) and aprons (60%) and less than 20% of butchers used gloves or eye protection when slaughtering. CONCLUSIONS: Overall, knowledge, attitudes and practice regarding RVF in Kabale District Uganda could be improved through educational efforts targeting specific populations. PMID- 29505580 TI - Onchocerca volvulus infection in Tihama region - west of Yemen: Continuing transmission in ivermectin-targeted endemic foci and unveiled endemicity in districts with previously unknown status. AB - BACKGROUND: Onchocerciasis in Yemen is one of the most neglected diseases, where baseline estimates of onchocerciasis and monitoring of the impact of ivermectin regularly administered to the affected individuals on its transmission are lacking. Therefore, this study aimed to determine the anti-Ov16 IgG4 seroprevalence among local communities of Hodeidah and Al-Mahwit governorates of Tihama region. The factors possibly associated with previous exposure to infection were also studied. METHODOLOGY/PRINCIPAL FINDINGS: This cross-sectional study was conducted in two ivermectin-targeted districts endemic for onchocerciasis in Hodeidah and Al-Mahwit and two untargeted districts with unknown previous endemicity in Hodeidah between February and July 2017. For 508 residents sampled by a multi-stage random approach, data were collected and blood specimens were screened for anti-Ov16 IgG4 using the SD BIOLINE Onchocerciasis IgG4 rapid tests. The study revealed an overall anti-Ov16 IgG4 rate of 18.5% (94/508) in all surveyed districts, with 10.2% (12/118) of children aged <=10 years being seropositive. Moreover, rates of 8.0% (4/50) and 6.1% (4/66) were found in districts not officially listed as endemic for the disease. Multivariable analysis confirmed the age of more than ten years and residing within a large family as the independent predictors of exposure to infection. CONCLUSIONS/SIGNIFICANCE: Onchocerciasis transmission is still ongoing as supported by the higher anti-Ov16 IgG4 seroprevalence rate among children aged <=10 years compared to that (<0.1%) previously set by the World Health Organization as a serologic criterion for transmission interruption. Further large-scale studies combining serologic and entomologic criteria are recommended for the mapping of O. volvulus in human and blackfly populations in endemic foci and their neighboring areas of uncertain endemicity. In addition, ivermectin distribution, coverage and impact on disease transmission need to be continually assessed. PMID- 29505581 TI - Parkinson disease related ATP13A2 evolved early in animal evolution. AB - Several human P5-type transport ATPases are implicated in neurological disorders, but little is known about their physiological function and properties. Here, we investigated the relationship between the five mammalian P5 isoforms ATP13A1-5 in a comparative study. We demonstrated that ATP13A1-4 isoforms undergo autophosphorylation, which is a hallmark P-type ATPase property that is required for substrate transport. A phylogenetic analysis of P5 sequences revealed that ATP13A1 represents clade P5A, which is highly conserved between fungi and animals with one member in each investigated species. The ATP13A2-5 isoforms belong to clade P5B and diversified from one isoform in fungi and primitive animals to a maximum of four in mammals by successive gene duplication events in vertebrate evolution. We revealed that ATP13A1 localizes in the endoplasmic reticulum (ER) and experimentally demonstrate that ATP13A1 likely contains 12 transmembrane helices. Conversely, ATP13A2-5 isoforms reside in overlapping compartments of the endosomal system and likely contain 10 transmembrane helices, similar to what was demonstrated earlier for ATP13A2. ATP13A1 complemented a deletion of the yeast P5A ATPase SPF1, while none of ATP13A2-5 could complement either the loss of SPF1 or that of the single P5B ATPase YPK9 in yeast. Thus, ATP13A1 carries out a basic ER function similar to its yeast counterpart Spf1p that plays a role in ER related processes like protein folding and processing. ATP13A2-5 isoforms diversified in mammals and are expressed in the endosomal system where they may have evolved novel complementary or partially redundant functions. While most P5 type ATPases are widely expressed, some P5B-type ATPases (ATP13A4 and ATP13A5) display a more limited tissue distribution in the brain and epithelial glandular cells, where they may exert specialized functions. At least some P5B isoforms are of vital importance for the nervous system, since ATP13A2 and ATP13A4 are linked to respectively Parkinson disease and autism spectrum disorders. PMID- 29505582 TI - CD39 and immune regulation in a chronic helminth infection: The puzzling case of Mansonella ozzardi. AB - BACKGROUND: Chronic helminth infections typically induce an immunoregulatory environment, with markedly reduced immune responses to both parasite-specific and unrelated bystander antigens. Here we tested whether these changes are also observed in human infections with Mansonella ozzardi, a neglected filarial nematode widely distributed across Latin America. METHODS: CD4+ T cell populations from microfilaremic (Fil+) and uninfected (Fil-) inhabitants in M. ozzardi-endemic riverine communities in Brazil were characterized by flow cytometry analysis. Plasma concentrations of a wide range of cytokines and chemokines were measured. We examined whether M. ozzardi infection is associated with suppressed in vitro lymphoproliferative and inflammatory cytokine responses upon stimulation with filarial antigen, unrelated antigens or mitogens. PRINCIPAL FINDINGS/CONCLUSIONS: Fil+ subjects had lower plasma levels of selected inflammatory cytokines, such as TNF-alpha, IL-8, and IL-6, than their Fil- counterparts. However, we found no evidence for attenuated T-cell responses to filarial antigens or co-endemic pathogens, such as malaria parasites and Toxoplasma gondii. CD4+ T cells expressing CD39, an ectonucleosidase involved in the generation of the anti-inflammatory molecule adenosine, were increased in frequency in Fil+ subjects, compared to uninfected controls. Significantly, such an expansion was directly proportional to microfilarial loads. Surprisingly, CD39 blocking with a neutralizing antibody suppressed antigen-driven lymphoproliferation in vitro, while decreasing inflammatory cytokine responses, in Fil+ and Fil- individuals. These findings suggest that circulating CD4+ CD39+ T cells comprise subsets with both regulatory and stimulatory roles that contribute to the immune homeostasis in chronic M. ozzardi infection. PMID- 29505583 TI - Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study. AB - Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35-94% of the simulation time, depending on the basket's position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes; increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures. PMID- 29505585 TI - Design of limited-stop service based on the degree of unbalance of passenger demand. AB - This paper presents a limited-stop service for a bus fleet to meet the unbalanced demand of passengers on a bus route and to improve the transit service of the bus route. This strategy includes two parts: a degree assessment of unbalanced passenger demand and an optimization of the limited-stop service. The degree assessment of unbalanced passenger demand, which is based on the different passenger demand between stations and the unbalance of passengers within the station, is used to judge whether implementing the limited-stop service is necessary for a bus route. The optimization of limited-stop service considers the influence of stop skipping action and bus capacity on the left-over passengers to determine the proper skipping stations for the bus fleet serving the entire route by minimizing both the waiting time and in-vehicle time of passengers and the running time of vehicles. A solution algorithm based on genetic algorithm is also presented to evaluate the degree of unbalanced passenger demand and optimize the limited-stop scheme. Then, the proper strategy is tested on a bus route in Changchun city of China. The threshold of degree assessment of unbalanced passenger demand can be calibrated and adapted to different passenger demands. PMID- 29505584 TI - Prescribing patterns and associated factors of antibiotic prescription in primary health care facilities of Kumbo East and Kumbo West Health Districts, North West Cameroon. AB - BACKGROUND: Inappropriate use of antibiotics is a global public health challenge and has been associated with antibiotic resistance. WHO reports show that efforts to promote rational antibiotic use in developing countries are poor. With the growing number of infections with antibiotic resistant bacteria, rational drug use becomes imperative and studies that promote rational drug use are highly necessary. Considering this, we investigated prescribing patterns and predictors of antibiotic prescription in primary health care facilities in Kumbo East (KE) and Kumbo West (KW) health districts in North West Cameroon, to contribute data which could influence policy on antibiotic use. METHODS AND FINDINGS: A cross sectional retrospective study was conducted from April 2014 to April 2015 in 26 randomly selected primary care facilities. Questionnaires were administered to 59 antibiotic prescribers to determine factors that predict antibiotic prescribing. Data on antibiotic prescription were collected by review of consultation registers. Prescription rates and demographics, prescriber and institution factors were analyzed using ANOVA. The best predictor of prescription was determined using multiple linear regression analysis. RESULTS: A total of 30,096 prescriptions were reviewed. Overall antibiotic prescription rate was 36.71%, with a mean of 1.14 antibiotics prescribed per patient. Amoxicillin was the most prescribed (29.9%). The most prevalent indications for prescribing were respiratory tract infections (21.27%). All antibiotics prescribed were broad spectrum. Antibiotics were prescribed for patients with malaria and also in situations where diagnosis was uncertain. Prescribing by generic name was 98.36% while 99.87% was from Essential Drug List. Use of laboratory results, patient turnout and Performance Based Financing (PBF) were significantly associated with antibiotic prescribing rates (p < 0.05). PBF moderated prescribing. CONCLUSION: There was misuse of antibiotics in primary care facilities in study area. We recommend all primary care health facilities in study area to be included in the PBF scheme and that prescribing should only be done by physicians as the have adequate training. PMID- 29505587 TI - Preference and strategy in proposer's prosocial giving in the ultimatum game. AB - The accumulation of findings that most responders in the ultimatum game reject unfair offers provides evidence that humans are driven by social preferences such as preferences for fairness and prosociality. On the other hand, if and how the proposer's behavior is affected by social preferences remains unelucidated. We addressed this question for the first time by manipulating the knowledge that the proposer had about the responder's belief concerning the intentionality of the proposer. In a new game called the "ultimatum game with ambiguous intentions of the proposer (UGAMB)," we made the intentionality of the proposer ambiguous to the recipient. We expected and found that the proposer would make more unfair offers in this new game than in the standard ultimatum game. This expectation can be derived from either the preference-based model or the strategy model of the proposer's giving decision. The additional finding that more unfair giving in the UGAMB was not mediated by the proposer's expectation that the recipient would be more willing to accept unfair offers provided support for the preference-based model. Using a psychological measure of cognitive control, the preference-based model received additional support through a conceptual replication of the previous finding that cognitive control of intuitive drive for prosociality in the dictator game, rather than mind reading in the ultimatum game, is responsible for the difference in giving between the two games. PMID- 29505586 TI - A pathway-directed positive growth restoration assay to facilitate the discovery of lipid A and fatty acid biosynthesis inhibitors in Acinetobacter baumannii. AB - Acinetobacter baumannii ATCC 19606 can grow without lipooligosaccharide (LOS). Lack of LOS can result from disruption of the early lipid A biosynthetic pathway genes lpxA, lpxC or lpxD. Although LOS itself is not essential for growth of A. baumannii ATCC 19606, it was previously shown that depletion of the lipid A biosynthetic enzyme LpxK in cells inhibited growth due to the toxic accumulation of lipid A pathway intermediates. Growth of LpxK-depleted cells was restored by chemical inhibition of LOS biosynthesis using CHIR-090 (LpxC) and fatty acid biosynthesis using cerulenin (FabB/F) and pyridopyrimidine (acetyl-CoA carboxylase). Here, we expand on this by showing that inhibition of enoyl-acyl carrier protein reductase (FabI), responsible for converting trans-2-enoyl-ACP into acyl-ACP during the fatty acid elongation cycle also restored growth during LpxK depletion. Inhibition of fatty acid biosynthesis during LpxK depletion rescued growth at 37 degrees C, but not at 30 degrees C, whereas rescue by LpxC inhibition was temperature independent. We exploited these observations to demonstrate proof of concept for a targeted medium-throughput growth restoration screening assay to identify small molecule inhibitors of LOS and fatty acid biosynthesis. The differential temperature dependence of fatty acid and LpxC inhibition provides a simple means by which to separate growth stimulating compounds by pathway. Targeted cell-based screening platforms such as this are important for faster identification of compounds inhibiting pathways of interest in antibacterial discovery for clinically relevant Gram-negative pathogens. PMID- 29505588 TI - Development of a multiple-gene-loading method by combining multi-integration system-equipped mouse artificial chromosome vector and CRISPR-Cas9. AB - Mouse artificial chromosome (MAC) vectors have several advantages as gene delivery vectors, such as stable and independent maintenance in host cells without integration, transferability from donor cells to recipient cells via microcell-mediated chromosome transfer (MMCT), and the potential for loading a megabase-sized DNA fragment. Previously, a MAC containing a multi-integrase platform (MI-MAC) was developed to facilitate the transfer of multiple genes into desired cells. Although the MI system can theoretically hold five gene-loading vectors (GLVs), there are a limited number of drugs available for the selection of multiple-GLV integration. To overcome this issue, we attempted to knock out and reuse drug resistance genes (DRGs) using the CRISPR-Cas9 system. In this study, we developed new methods for multiple-GLV integration. As a proof of concept, we introduced five GLVs in the MI-MAC by these methods, in which each GLV contained a gene encoding a fluorescent or luminescent protein (EGFP, mCherry, BFP, Eluc, and Cluc). Genes of interest (GOI) on the MI-MAC were expressed stably and functionally without silencing in the host cells. Furthermore, the MI-MAC carrying five GLVs was transferred to other cells by MMCT, and the resultant recipient cells exhibited all five fluorescence/luminescence signals. Thus, the MI-MAC was successfully used as a multiple-GLV integration vector using the CRISPR-Cas9 system. The MI-MAC employing these methods may resolve bottlenecks in developing multiple-gene humanized models, multiple-gene monitoring models, disease models, reprogramming, and inducible gene expression systems. PMID- 29505589 TI - Proton range verification in inhomogeneous tissue: Treatment planning system vs. measurement vs. Monte Carlo simulation. AB - In particle radiotherapy, range uncertainty is an important issue that needs to be overcome. Because high-dose conformality can be achieved using a particle beam, a small uncertainty can affect tumor control or cause normal-tissue complications. From this perspective, the treatment planning system (TPS) must be accurate. However, there is a well-known inaccuracy regarding dose computation in heterogeneous media. This means that verifying the uncertainty level is one of the prerequisites for TPS commissioning. We evaluated the range accuracy of the dose computation algorithm implemented in a commercial TPS, and Monte Carlo (MC) simulation against measurement using a CT calibration phantom. A treatment plan was produced for eight different materials plugged into a phantom, and two dimensional doses were measured using a chamber array. The measurement setup and beam delivery were simulated by MC code. For an infinite solid water phantom, the gamma passing rate between the measurement and TPS was 97.7%, and that between the measurement and MC was 96.5%. However, gamma passing rates between the measurement and TPS were 49.4% for the lung and 67.8% for bone, and between the measurement and MC were 85.6% for the lung and 100.0% for bone tissue. For adipose, breast, brain, liver, and bone mineral, the gamma passing rates computed by TPS were 91.7%, 90.6%, 81.7%, 85.6%, and 85.6%, respectively. The gamma passing rates for MC for adipose, breast, brain, liver, and bone mineral were 100.0%, 97.2%, 95.0%, 98.9%, and 97.8%, respectively. In conclusion, the described procedure successfully evaluated the allowable range uncertainty for TPS commissioning. The TPS dose calculation is inefficient in heterogeneous media with large differences in density, such as lung or bone tissue. Therefore, the limitations of TPS in heterogeneous media should be understood and applied in clinical practice. PMID- 29505590 TI - Varicella zoster virus transmission dynamics in Vojvodina, Serbia. AB - This study aimed at establishing baseline key epidemiological parameters for varicella zoster virus (VZV) infection in Vojvodina, Serbia, with the ultimate goal to quantify the VZV transmission potential in the population. Seroprevalence data generated during the first large cross-sectional VZV serosurvey were modelled, using a two-tiered modelling approach to calculate age-specific forces of infection (FOI), the basic reproduction number (R0) and herd immunity threshold (H). Seroprevalence and modelling data were compared with corresponding pre-vaccination epidemiological parameters from 11 countries participating in the European Sero-Epidemiology Network 2 (ESEN2) project. Serbia fits into the general dynamic VZV transmission patterns in Europe in the pre-vaccine era, with estimated R0 = 4.12, (95% CI: 2.69-7.07) and H = 0.76 (95% CI: 0.63-0.86). The highest VZV transmission occurs among preschool children, as evidenced by the estimation of the highest FOI (0.22, 95% CI: 0.11-0.34) in the 0.5-4 age group, with a peak FOI of 0.25 at 2.23 years. Seroprevalence was consistently lower in 5 14 year-olds, resulting in considerable shares of VZV-susceptible adolescents (7.3%), and young adults (6%), resembling the situation in a minority of European countries. The obtained key epidemiological parameters showed most intense VZV transmission in preschool children aged <4 years, justifying the consideration of universal childhood immunization in the future. National immunization strategy should consider programs for VZV serologic screening and immunization of susceptible groups, including adolescents and women of reproductive age. This work is an important milestone towards the evaluation of varicella immunization policy options in Serbia. PMID- 29505591 TI - Development of an immunoaffinity chromatography and LC-MS/MS method for the determination of 6 zearalenones in animal feed. AB - A novel and simple method for detecting 6 zearalenones in animal feed using liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS) and immunoaffinity columns (IAC) was developed. The chromatographic peaks of the 6 zearalenones were successfully identified by comparing their retention times and mass spectrum with reference standards. The mobile phase was composed of mobile phase A (water) and B (0.5% formic acid in ACN). Method validation was performed with linearity, sensitivity, selectivity, accuracy and precision. The limits of detection (LODs) for the instrument used to study zearalenones ranged from 0.3 to 1.1 MUg/kg, and the limits of quantification (LOQs) ranged from 1.0 to 2.2 MUg/kg. Average recoveries of the 6 zearalenones ranged from 82.5% to 106.4%. Method replication resulted in intra-day and inter-day peak area variation of <3.8%. The developed method was specific and reliable and is suited for the routine analysis of zearalenones in animal feed. PMID- 29505592 TI - The skills related to the early reading acquisition in Spain and Peru. AB - This paper deals with the skills related to the early reading acquisition in two countries that share language. Traditionally on reading readiness research there is a great interest to find out what factors affect early reading ability, but differ from other academic skills that affect general school learnings. Furthermore, it is also known how the influence of pre-reading variables in two countries with the same language, affect the development of the reading. On the other hand, several studies have examined what skills are related to reading readiness (phonological awareness, alphabetic awareness, naming speed, linguistic skills, metalinguistic knowledge and basic cognitive processes), but there are no studies showing whether countries can also influence the development of these skills.Our main objective in this study was to establish whether there were differences in the degree of acquisition of these skills between Spanish (119 children) and Peruvian (128 children), five years old children assessed in their own countries and after controlling Economic, Social and Cultural Status (ESCS). The results show that there are significant differences in the degree of acquisition of these skills between these two samples. It's especially relevant, in these results, that the main predictor in a regression study was the country of origin, explaining a higher percentage of variance than other variables such as age differences, in months, or gender. These findings corroborate the results obtained in other studies with migrant population. PMID- 29505593 TI - Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections. AB - There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10MUg/ml total for bnAbs and combinations, and 5MUg/ml for bispecifics. We used IC80 breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (~98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95-97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8 iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa. PMID- 29505594 TI - Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance. AB - Every year in the United States, more than 300,000 infants are admitted to neonatal intensive care units (NICU) where they are exposed to a chemical intensive hospital environment during a developmentally vulnerable period. The neurodevelopmental impact of environmental exposure to phthalates during the NICU stay is unknown. As phthalate exposure during the third trimester developmental window has been implicated in neurobehavioral deficits in term-born children that are strikingly similar to a phenotype of neurobehavioral morbidity common among children born premature, the role of early-life phthalate exposure on the neurodevelopmental trajectory of premature infants may be clinically important. In this study, premature newborns with birth weight <1500g were recruited to participate in a prospective environmental health cohort study, NICU-HEALTH (Hospital Exposures and Long-Term Health), part of the DINE (Developmental Impact of NICU Exposures) cohort of the ECHO (Environmental influences on Child Health Outcomes) program. Seventy-six percent of eligible infants enrolled in the study. Sixty-four of 81 infants survived and are included in this analysis. 164 urine specimens were analyzed for phthalate metabolites using high-performance liquid chromatography/tandem mass spectrometry. The NICU Network Neurobehavioral Scale (NNNS) was performed prior to NICU discharge. Linear and weighted quantile sum regression quantified associations between phthalate biomarkers and NNNS performance, and between phthalate biomarkers and intensity of medical intervention. The sum of di(2-ethylhexyl) phthalate metabolites (?DEHP) was associated with improved performance on the Attention and Regulation scales. Specific mixtures of phthalate biomarkers were also associated with improved NNNS performance. More intense medical intervention was associated with higher ?DEHP exposure. NICU-based exposure to phthalates mixtures was associated with improved attention and social response. This suggests that the impact of phthalate exposure on neurodevelopment may follow a non-linear trajectory, perhaps accelerating the development of certain neural networks. The long-term neurodevelopmental impact of NICU-based phthalate exposure needs to be evaluated. PMID- 29505596 TI - Bayesian optimization for computationally extensive probability distributions. AB - An efficient method for finding a better maximizer of computationally extensive probability distributions is proposed on the basis of a Bayesian optimization technique. A key idea of the proposed method is to use extreme values of acquisition functions by Gaussian processes for the next training phase, which should be located near a local maximum or a global maximum of the probability distribution. Our Bayesian optimization technique is applied to the posterior distribution in the effective physical model estimation, which is a computationally extensive probability distribution. Even when the number of sampling points on the posterior distributions is fixed to be small, the Bayesian optimization provides a better maximizer of the posterior distributions in comparison to those by the random search method, the steepest descent method, or the Monte Carlo method. Furthermore, the Bayesian optimization improves the results efficiently by combining the steepest descent method and thus it is a powerful tool to search for a better maximizer of computationally extensive probability distributions. PMID- 29505595 TI - Molecular taxonomy and evolutionary relationships in the Oswaldoi-Konderi complex (Anophelinae: Anopheles: Nyssorhynchus) from the Brazilian Amazon region. AB - Recent studies have shown that Anopheles oswaldoi sensu lato comprises a cryptic species complex in South America. Anopheles konderi, which was previously raised to synonymy with An. oswaldoi, has also been suggested to form a species complex. An. oswaldoi has been incriminated as a malaria vector in some areas of the Brazilian Amazon, Colombia, Peru and Venezuela, but was not recognized as a vector in the remaining regions in its geographic distribution. The role of An. konderi as a malaria vector is unknown or has been misattributed to An. oswaldoi. The focus of this study was molecular identification to infer the evolutionary relationships and preliminarily delimit the geographic distribution of the members of these complexes in the Brazilian Amazon region. The specimens were sampled from 18 localities belonging to five states in the Brazilian Amazon and sequenced for two molecular markers: the DNA barcode region (COI gene of mitochondrial DNA) and Internal Transcribed Spacer 2 (ITS2 ribosomal DNA). COI (83 sequences) and ITS2 (27 sequences) datasets generated 43 and 10 haplotypes, respectively. Haplotype networks and phylogenetic analyses generated with the barcode region (COI gene) recovered five groups corresponding to An. oswaldoi s.s., An. oswaldoi B, An. oswaldoi A, An. konderi and An. sp. nr. konderi; all pairwise genetic distances were greater than 3%. The group represented by An. oswaldoi A exhibited three strongly supported lineages. The molecular dating indicated that the diversification process in these complexes started approximately 2.8 Mya, in the Pliocene. These findings confirm five very closely related species and present new records for these species in the Brazilian Amazon region. The paraphyly observed for the An. oswaldoi complex suggests that An. oswaldoi and An. konderi complexes may comprise a unique species complex named Oswaldoi-Konderi. Anopheles oswaldoi B may be a potential malaria vector in the extreme north of the Brazilian Amazon, whereas evidence of sympatry for the remaining species in other parts of the Brazilian Amazon (Acre, Amazonas, Para and Rondonia) precluded identification of probable vectors in those areas. PMID- 29505597 TI - A novel ex vivo Huntington's disease model for studying GABAergic neurons and cell grafts by laser microdissection. AB - Organotypic brain slice cultures have been recently used to study neurodegenerative disorders such as Parkinson's disease and Huntington's disease (HD). They preserve brain three-dimensional architecture, synaptic connectivity and brain cells microenvironment. Here, we developed an innovative model of Huntington's disease from coronal rat brain slices, that include all the areas involved in the pathology. HD-like neurodegeneration was obtained in only one week, in a single step, during organotypic slice preparation, without the use of neurotoxins. HD-like histopathology was analysed and after one week, a reduction of 40% of medium spiny neurons was observed. To analyse new therapeutic approaches in this innovative HD model, we developed a novel protocol of laser microdissection to isolate and analyse by RT-qPCR, grafted cells as well as surrounding tissue of fresh organotypic slices. We determined that laser microdissection could be performed on a 400MUm organotypic slice after alcohol dehydration protocol, allowing the analysis of mRNA expression in the rat tissue as well as in grafted cells. In conclusion, we developed a new approach for modeling Huntington's disease ex vivo, and provided a useful innovative method for screening new potential therapies for neurodegenerative diseases especially when associated with laser microdissection. PMID- 29505598 TI - Physical activity and sedentary behavior in patients with Systemic Lupus Erythematosus. AB - INTRODUCTION: The aim of this study was to evaluate the proportion of patients with Systemic Lupus Erythematosus (SLE) who did not met the WHO recommendations for physical activity and to evaluate the amount of time spent in sedentary behavior. METHODS: SLE patients were consecutively enrolled in a cross sectional study. The type and the time spent in physical activity and sedentary behavior were evaluated using the IPAQ short form questionnaire. The adequate physical activity was defined according to the 2010 WHO recommendations for health and the sedentary behavior according to the 2017 SBRN consensus. We also assessed quality of life using SF-36, mood disorders using BDI and HAM-H, fatigue using Facit Fatigue and sleep disorders using PSQI scores. RESULTS: Physical activity was not sufficient to meet WHO recommendations in 56 of 93 SLE patients (60%). SLE patients spent a median (95% range) of 180 (0-600) minutes everyday in sedentary activities. The length of daily sedentary time was more than 6 hours in 25% of SLE patients. In multivariable analysis, the factors associated to the probability of not meeting WHO criteria was only the time of exposure to antimalarials (OR 0.88, p 0.03) and the factors related to the probability of being in the upper tertile of sedentary time (more than 270 minutes) were age (OR 1.04, p 0.02), disease activity expressed by SELENA-SLEDAI score (OR 1.2, p 0.01) and Facit-fatigue score (OR 0.94, p 0.04). CONCLUSION: A relevant proportion of SLE patients were inadequately physically active. It is essential to improve the awareness of the importance of increase physical activity and reduce sedentary time. A better control of disease activity and fatigue and a prolonged use of antimalarials could help to reach this notable goal. PMID- 29505599 TI - Phosphoethanolamine-N-methyltransferase is a potential biomarker for the diagnosis of P. knowlesi and P. falciparum malaria. AB - BACKGROUND: Plasmodium knowlesi is recognised as the main cause of human malaria in Southeast Asia. The disease is often misdiagnosed as P. falciparum or P. malariae infections by microscopy, and the disease is difficult to eliminate due to its presence in both humans and monkeys. P. knowlesi infections can rapidly cause severe disease and require prompt diagnosis and treatment. No protein biomarker exists for the rapid diagnostic test (RDT) detection of P. knowlesi infections. Plasmodium knowlesi infections can be diagnosed by PCR. METHODS AND PRINCIPAL FINDINGS: Phosphoethanolamine-N-methyltransferase (PMT) is involved in malaria lipid biosynthesis and is not found in the human host. The P. falciparum, P. vivax and P. knowlesi PMT proteins were recombinantly expressed in BL21(DE3) Escherichia coli host cells, affinity purified and used to raise antibodies in chickens. Antibodies against each recombinant PMT protein all detected all three recombinant proteins and the native 29 kDa P. falciparum PMT protein on western blots and in ELISA. Antibodies against a PMT epitope (PLENNQYTDEGVKC) common to all three PMT orthologues detected all three proteins. Antibodies against unique peptides from each orthologue of PMT, PfCEVEHKYLHENKE, PvVYSIKEYNSLKDC, PkLYPTDEYNSLKDC detected only the parent protein in western blots and P. falciparum infected red blood cell lysates or blood lysates spiked with the respective proteins. Similar concentrations of PfPMT and the control, PfLDH, were detected in the same parasite lysate. The recombinant PfPMT protein was detected by a human anti-malaria antibody pool. CONCLUSION: PMT, like the pan-specific LDH biomarker used in RDT tests, is both soluble, present at comparable concentrations in the parasite and constitutes a promising antimalarial drug target. PMT is absent from the human proteome. PMT has the potential as a biomarker for human malaria and in particular as the first P. knowlesi specific protein with diagnostic potential for the identification of a P. knowlesi infection. PMID- 29505601 TI - Influence of water temperature and food on the last stages of cultured pearl mineralization from the black-lip pearl oyster Pinctada margaritifera. AB - Environmental parameters, such as food level and water temperature, have been shown to be major factors influencing pearl oyster shell growth and molecular mechanisms involved in this biomineralization process. The present study investigates the effect of food level (i.e., microalgal concentration) and water temperature, in laboratory controlled conditions, on the last stages of pearl mineralization in order to assess their impact on pearl quality. To this end, grafted pearl oysters were fed at different levels of food and subjected to different water temperatures one month prior to harvest to evaluate the effect of these factors on 1) pearl and shell deposition rate, 2) expression of genes involved in biomineralization in pearl sacs, 3) nacre ultrastructure (tablet thickness and number of tablets deposited per day) and 4) pearl quality traits. Our results revealed that high water temperature stimulates both shell and pearl deposition rates. However, low water temperature led to thinner nacre tablets, a lower number of tablets deposited per day and impacted pearl quality with better luster and fewer defects. Conversely, the two tested food level had no significant effects on shell and pearl growth, pearl nacre ultrastructure or pearl quality. However, one gene, Aspein, was significantly downregulated in high food levels. These results will be helpful for the pearl industry. A wise strategy to increase pearl quality would be to rear pearl oysters at a high water temperature to increase pearl growth and consequently pearl size; and to harvest pearls after a period of low water temperature to enhance luster and to reduce the number of defects. PMID- 29505602 TI - Magnitude of glycemic control and its associated factors among patients with type 2 diabetes at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. AB - BACK GROUND: Diabetes is increasing at an alarming rate throughout the world and about 80% of diabetic cases live in low and middle income countries. Glycemic control is the most important predictor for diabetic related complications and deaths. Identifying factors associated with glycemic control help health care providers and patients to work in the areas that reduce risks of diabetic related complications and deaths. OBJECTIVES: The aim of this study is to assess the magnitude and factors associated with glycemic control among type 2 diabetic patients at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. METHODS: Hospital-based cross sectional study was conducted on 412 type 2 diabetic patients who were attending in diabetic clinics at Tikur Anbessa Specialized Hospital. Data were collected through structured interview questionnaire, and data abstraction format to collect information from each patient's medical records from March to April, 2015. Data were entered and analyzed using SPSS version 20 statistical software. Both descriptive and inferential statistics were used to determine magnitude of glycemic control and factors associated with poor glycemic control. RESULT: Median age of participants was 52 years old (IQR = 40 60 years old). From the study participants,51.7% were females. Median duration of living with diabetes since diagnosis was 10 years (IQR: 5-16 years). About 80% of the respondents had uncontrolled fasting blood glucose level. The factors which are significantly associated with poor glycemic control were longer duration of diabetes (AOR = 2.72 95%CI:1.16-6.32), and being on insulin therapy (AOR = 3.01 95% CI: 1.5-5.9). CONCLUSION: A high proportion of patients had poor glycemic control. Longer duration of the disease, and being on drug regimen of insulin were associated with poor glycemic control. Appropriate attention should be given to patients with longer duration of disease and those who are on insulin therapy. PMID- 29505600 TI - A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function. AB - TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trial NCT00594880. PMID- 29505603 TI - The Fear Avoidance Model predicts short-term pain and disability following lumbar disc surgery. AB - OBJECTIVE: To examine the prognostic value of the Fear Avoidance Model (FAM) variables when predicting pain intensity and disability 10-weeks postoperative following lumbar disc surgery. METHODS: We recruited patients scheduled for first time, single level lumbar disc surgery. The following aspects of the FAM were assessed at preoperative baseline and after 10 postoperative weeks: numeric pain rating scale (0-10) for leg and back pain intensity separately, Pain Catastrophizing Scale (PCS), Fear Avoidance Beliefs Questionnaire (FABQ), Beck Depression Inventory (BDI), Oswestry Disability Questionnaire (ODI), and the International Physical Activity Questionnaire (IPAQ). Multivariate regression models were used to examine the best combination of baseline FAM variables to predict the 10-week leg pain, back pain, and disability. All multivariate models were adjusted for age and sex. RESULTS: 60 patients (30 females, mean [SD] age = 40.4 [9.5]) were enrolled. All FAM measures correlated with disability at baseline. Adding FAM variables to each of the stepwise multiple linear regression model explained a significant amount of the variance in disability (Adj. R2 = .38, p < .001), leg pain intensity (Adj. R2 = .25, p = .001), and back pain intensity Adj. R2 = .32, p < .001 at 10-weeks). After adjusting for age and gender, BDI and FABQ-work subscale were the only significant predictors added to each of the prediction models for the 10-week clinical outcome (leg pain, back pain, and ODI). CONCLUSION: BDI and FABQ-work subscale variables are associated with baseline pain intensity and disability and predict short-term pain and disability following lumbar disc surgery. Measuring these variables in patients being considered for lumbar disc surgery may improve patient outcome. PMID- 29505604 TI - Hereditary cancer genes are highly susceptible to splicing mutations. AB - Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing. PMID- 29505606 TI - Correction: Comparisons of management practices and farm design on Australian commercial layer and meat chicken farms: Cage, barn and free range. AB - [This corrects the article DOI: 10.1371/journal.pone.0188505.]. PMID- 29505605 TI - Plasma miR-199a-5p is increased in neutrophilic phenotype asthma patients and negatively correlated with pulmonary function. AB - OBJECTIVE: We investigated the relationship between plasma miRNAs levels and inflammatory characteristics in asthmatic patients. METHODS: Eligible adults with untreated asthma (n = 35) underwent a clinical assessment, sputum induction, and assessment of pulmonary function test and Asthma Control Test (ACT) scores. Asthma phenotypes were defined using the sputum cell count. miR-199a-5p expression was measured using quantitative real-time polymerase chain reaction (qPCR). Lipopolysaccharide (LPS) stimulation was used to detect miR-199a-5p secretion from peripheral blood-derived neutrophil, lymphocyte, macrophage and BEAS-2B cells. The correlation of miR-199a-5p expression with clinical parameters was analyzed using multiple linear regression analysis. In silico analysis predicted the target genes and signaling pathway of miR-199a-5p. Transfection of miR-199a-5p mimics in human airway smooth muscle cells (HASMCs) was performed in vitro. RESULTS: The miRNA-199a-5p levels in plasma and sputum increased significantly in patients with neutrophilic asthma compared to healthy subjects (ps = 0.014 and 0.006, respectively). Expression of miR-199a-5p in the plasma of asthmatic patients positively correlated with sputum miR-199a-5p expression (r = 0.511, p = 0.021). The miR-199a-5p level was only elevated with LPS stimulation in neutrophils but not macrophages, lymphocytes, or epithelial cells from healthy controls (p < 0.01). miR-199a-5p expression increased in response to LPS (p = 0.005) and LPS combined with IL-4 (p = 0.003), but not IL-4 alone. However, peripheral neutrophils from eosinophilic asthma patients did not respond to LPS with increased miR-199a-5p expression (n = 5, p > 0.05) in contrast to the significant response from neutrophilic patients (n = 4, p < 0.0001). miR-199a-5p negatively correlated with FEV1, FVC and PEF (r = -0.377, p = 0.026; r = -0.419, p = 0.012; and r = -0.392, p = 0.024, respectively). Multivariate correlation analysis confirmed that the plasma miR-199a-5p levels negatively correlated with FEV1 in patients with asthma (Adjusted R2 = 0.164, p = 0.015). In silico analysis suggested that the WNT signaling pathway participates in miR-199a-5p mediation of smooth muscle cell hypertrophy. In vitro experiment, miR-199a-5p mimics inhibited the protein expressions of WNT2 and WNT4, decreased the c-myc expression and dramatically increased the Sm-MHC expression in HASMCs. CONCLUSION: Plasma miR 199a-5p was increased in neutrophilic asthma and negatively correlated with pulmonary function, which suggests that miR-199a-5p actively contributes to disease pathogenesis by modulating the inflammatory process and transferring the signal from inflammatory cells to structure cells. PMID- 29505607 TI - Myeloperoxidase mediated HDL oxidation and HDL proteome changes do not contribute to dysfunctional HDL in Chinese subjects with coronary artery disease. AB - High density lipoprotein (HDL) cholesterol levels and cholesterol efflux capacity (CEC) are inversely correlated with coronary artery disease (CAD) risk. Myeloperoxidase (MPO) derived oxidants and HDL proteome changes are implicated in HDL dysfunction in subjects with CAD in the United States; however, the effect of MPO on HDL function and HDL proteome in ethnic Chinese population is unknown. We recruited four matched ethnic Chinese groups (20 patients each): subjects with 1) low HDL levels (HDL levels in men <40mg/dL and women <50mg/dL) and non-CAD (identified by coronary angiography or cardiac CT angiography); 2) low HDL and CAD; 3) high HDL (men >50mg/dL; women >60mg/dL) with no CAD; and 4) high HDL with CAD. Serum cytokines, serum MPO levels, serum CEC, MPO-oxidized HDL tyrosine moieties, and HDL proteome were assessed by mass spectrometry individually in the four groups. The cytokines, MPO levels, and HDL proteome profiles were not significantly different between the four groups. As expected, CEC was depressed in the entire CAD group but more specifically in the CAD low-HDL group. HDL of CAD subjects had significantly higher 3-nitrotyrosine than non-CAD subjects, but the MPO-specific 3-chlorotyrosine was unchanged; CEC in the CAD low-HDL group did not correlate with either HDL 3-chlorotyrosine or 3-nitrotyrosine levels. Neither 3-chlorotyrosine, which is MPO-specific, nor 3-nitrotyrosine generated from MPO or other reactive nitrogen species was associated with CEC. MPO mediated oxidative stress and HDL proteome composition changes are not the primary cause HDL dysfunction in Chinese subjects with CAD. These studies highlight ethnic differences in HDL dysfunction between United States and Chinese cohorts raising possibility of unique pathways of HDL dysfunction in this cohort. PMID- 29505608 TI - Evidence of embodied social competence during conversation in high functioning children with autism spectrum disorder. AB - Even high functioning children with Autism Spectrum Disorder (ASD) exhibit impairments that affect their ability to carry out and maintain effective social interactions in multiple contexts. One aspect of subtle nonverbal communication that might play a role in this impairment is the whole-body motor coordination that naturally arises between people during conversation. The current study aimed to measure the time-dependent, coordinated whole-body movements between children with ASD and a clinician during a conversational exchange using tools of nonlinear dynamics. Given the influence that subtle interpersonal coordination has on social interaction feelings, we expected there to be important associations between the dynamic motor movement measures introduced in the current study and the measures used traditionally to categorize ASD impairment (ADOS-2, joint attention and theory of mind). The study found that children with ASD coordinated their bodily movements with a clinician, that these movements were complex and that the complexity of the children's movements matched that of the clinician's movements. Importantly, the degree of this bodily coordination was related to higher social cognitive ability. This suggests children with ASD are embodying some degree of social competence during conversations. This study demonstrates the importance of further investigating the subtle but important bodily movement coordination that occurs during social interaction in children with ASD. PMID- 29505609 TI - Phosphorylated vasodilator-stimulated phosphoprotein (P-VASPSer239) in platelets is increased by nitrite and partially deoxygenated erythrocytes. AB - Nitrite is recognized as a bioactive nitric oxide (NO) metabolite. We have shown that nitrite inhibits platelet activation and increases platelet cGMP levels in the presence of partially deoxygenated erythrocytes. In this study, we investigated the effect of nitrite on phosphorylation of vasodilator-stimulated phosphoprotein on residue serine 239 (P-VASPSer239), a marker of protein kinase G (PKG) activation, in human platelets. In platelet-rich plasma (PRP), nitrite itself had no effect on levels of P-VASPSer239 while DEANONOate increased P VASPSer239. Deoxygenation of PRP + erythrocytes (20% hematocrit) raised baseline P-VASPSer239 in platelets. At 20% hematocrit, nitrite (10 MUM) increased P VASPSer239 in platelets about 31% at 10-20 minutes of incubation while the levels of P-VASPSer157, a marker of protein kinase A (PKA) activation, were not changed. Nitrite increased P-VASPSer239 in platelets in the presence of deoxygenated erythrocytes at 20-40% hematocrit, but the effects were slightly greater at 20% hematocrit. In conclusion, our data confirm that nitrite increases P-VASPSer239 in platelets in the presence of deoxygenated erythrocytes. They also further support the idea that partially deoxygenated erythrocytes may modulate platelet activity, at least in part, via the NO/sGC/PKG pathway from NO formed by reduction of circulating nitrite ions. PMID- 29505610 TI - The technical reliability and biotemporal stability of cerebrospinal fluid biomarkers for profiling multiple pathophysiologies in Alzheimer's disease. AB - OBJECTIVE: Alzheimer's disease (AD) is a complex neurodegenerative disease driven by multiple interacting pathophysiological processes that ultimately results in synaptic loss, neuronal death, and dementia. We implemented a fit-for-purpose modeled approach to qualify a broad selection of commercially available immunoassays and evaluate the biotemporal stability of analytes across five pathophysiological domains of interest in AD, including core amyloid-beta (Abeta) and tau AD biomarkers, neurodegeneration, inflammation/immune modulation, neurovascular injury, and metabolism/oxidative stress. METHODS: Paired baseline and eight-week CSFs from twenty participants in a clinical drug trial for mild cognitive impairment (MCI) or mild dementia due to AD were used to evaluate sensitivity, intra-assay precision, inter-assay replicability, and eight-week biotemporal stability for sixty unique analytes measured with commercially available single- and multi-plex ELISA assays. Coefficients of variation (CV) were calculated, and intraclass correlation and Wilcoxon signed rank tests were applied. RESULTS: We identified 32 biomarker candidates with good to excellent performance characteristics according to assay technical performance and CSF analyte biotemporal stability cut-off criteria. These included: 1) the core AD biomarkers Abeta1-42, Abeta1-40, Abeta1-38, and total tau; 2) non-Abeta, non-tau neurodegeneration markers NfL and FABP3; 3) inflammation/immune modulation markers IL-6, IL-7, IL-8, IL-12/23p40, IL-15, IL-16, MCP-1, MDC, MIP-1beta, and YKL-40; 4) neurovascular markers Flt-1, ICAM-1, MMP-1, MMP-2, MMP-3, MMP-10, PlGF, VCAM-1, VEGF, VEGF-C, and VEGF-D; and 5) metabolism/oxidative stress markers 24-OHC, adiponectin, leptin, soluble insulin receptor, and 8-OHdG. CONCLUSIONS: Assays for these CSF analytes demonstrate consistent sensitivity, reliability, and biotemporally stability for use in a multiple pathophysiological CSF biomarker panel to profile AD. Their qualification enables further investigation for use in AD diagnosis, staging and progression, disease mechanism profiling, and clinical trials. PMID- 29505611 TI - A FRET-based biosensor for measuring Galpha13 activation in single cells. AB - Forster Resonance Energy Transfer (FRET) provides a way to directly observe the activation of heterotrimeric G-proteins by G-protein coupled receptors (GPCRs). To this end, FRET based biosensors are made, employing heterotrimeric G-protein subunits tagged with fluorescent proteins. These FRET based biosensors complement existing, indirect, ways to observe GPCR activation. Here we report on the insertion of mTurquoise2 at several sites in the human Galpha13 subunit, aiming to develop a FRET-based Galpha13 activation biosensor. Three fluorescently tagged Galpha13 variants were found to be functional based on i) plasma membrane localization and ii) ability to recruit p115-RhoGEF upon activation of the LPA2 receptor. The tagged Galpha13 subunits were used as FRET donor and combined with cp173Venus fused to the Ggamma2 subunit, as the acceptor. We constructed Galpha13 biosensors by generating a single plasmid that produces Galpha13-mTurquoise2, Gbeta1 and cp173Venus-Ggamma2. The Galpha13 activation biosensors showed a rapid and robust response when used in primary human endothelial cells that were exposed to thrombin, triggering endogenous protease activated receptors (PARs). This response was efficiently inhibited by the RGS domain of p115-RhoGEF and from the biosensor data we inferred that this is due to GAP activity. Finally, we demonstrated that the Galpha13 sensor can be used to dissect heterotrimeric G protein coupling efficiency in single living cells. We conclude that the Galpha13 biosensor is a valuable tool for live-cell measurements that probe spatiotemporal aspects of Galpha13 activation. PMID- 29505612 TI - Epidemiological survey in single-species flocks from Poland reveals expanded genetic and antigenic diversity of small ruminant lentiviruses. AB - Small ruminant lentivirus (SRLV) infections are widespread in Poland and circulation of subtypes A1, A12, A13, B1 and B2 was detected. The present work aimed at extending previous study based on the analysis of a larger number of animals from single-species flocks. Animals were selected for genetic analysis based on serological reactivity towards a range of recombinant antigens derived from Gag and Env viral proteins. Phylogenetic analysis revealed the existence of subtypes B2 and A12 in both goats and sheep and subtypes A1 and B1 in goats only. In addition, two novel subtypes, A16 and A17, were found in goats. Co-infections with strains belonging to different subtypes within A and B groups were detected in 1 sheep and 4 goats originating from four flocks. Although the reactivity of serum samples towards the recombinant antigens confirmed immunological relatedness between Gag epitopes of different subtypes and the cross-reactive nature of Gag antibodies, eleven serum samples failed to react with antigens representing all subtypes detected up-to-date in Poland, highlighting the limitations of the serological diagnosis. These data showed the complex nature of SRLV subtypes circulating in sheep and goats in Poland and the need for improving SRLV-related diagnostic capacity. PMID- 29505613 TI - TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities. AB - Once considered a phenotypically monomorphic bacterium, there is a growing body of work demonstrating heterogeneity among Mycobacterium tuberculosis (Mtb) strains in clinically relevant characteristics, including virulence and response to antibiotics. However, the genetic and molecular basis for most phenotypic differences among Mtb strains remains unknown. To investigate the basis of strain variation in Mtb, we performed genome-wide transposon mutagenesis coupled with next-generation sequencing (TnSeq) for a panel of Mtb clinical isolates and the reference strain H37Rv to compare genetic requirements for in vitro growth across these strains. We developed an analytic approach to identify quantitative differences in genetic requirements between these genetically diverse strains, which vary in genomic structure and gene content. Using this methodology, we found differences between strains in their requirements for genes involved in fundamental cellular processes, including redox homeostasis and central carbon metabolism. Among the genes with differential requirements were katG, which encodes the activator of the first-line antitubercular agent isoniazid, and glcB, which encodes malate synthase, the target of a novel small-molecule inhibitor. Differences among strains in their requirement for katG and glcB predicted differences in their response to these antimicrobial agents. Importantly, these strain-specific differences in antibiotic response could not be predicted by genetic variants identified through whole genome sequencing or by gene expression analysis. Our results provide novel insight into the basis of variation among Mtb strains and demonstrate that TnSeq is a scalable method to predict clinically important phenotypic differences among Mtb strains. PMID- 29505614 TI - High-normal estimated glomerular filtration rate and hyperuricemia positively correlate with metabolic impairment in pediatric obese patients. AB - BACKGROUND: Childhood obesity represents a major health concern worldwide due to its well established detrimental effect on cardiovascular and its potential negative effect on kidney functions. However, biomarkers that can help diagnose early stages of kidney damage in obese children represent an unmet clinical need. OBJECTIVES: In this study, we asked whether the prevalence of microalbuminuria, estimated glomerular filtration rate (eGFR) or hyperuricemia recorded in a wide cohort of obese children and adolescents would positively correlate with cardiometabolic dysfunction in these subjects. METHODS: We carried out a cross sectional study on 360 obese children and adolescents between the ages of 3-18 years, enrolled in a tertiary care center. Clinical and biochemical evaluations including oral glucose tolerance tests (OGTTs) were performed on all patients. Microalbuminuria was defined as urinary albumin-to-creatinine ratio (u-ACR) of 30 300 mg/g. All data are expressed as mean +/- standard deviation (SD), absolute values or percentages. Sex age-specific and eGFR SDs were used for statistical analyses. Serum uric acid >= 5.5 mg/dL was considered abnormal. RESULTS: The prevalence of microalbuminuria was 6.4%. Except for a lower insulinogenic-index, no correlations between microalbuminuria and cardiometabolic risk factors were detected. eGFR was < -1 SD and > 1 SD in 1.4% and 60.8% of subjects, respectively. Subjects with an eGFR > 1 SD had higher systolic blood pressure, liver enzymes, insulin resistance, glucose and insulin during OGTT, lower insulin sensitivity and a more prevalent microalbuminuria. Hyperuricemia (27.5%) increased the odds of hypertension, HDL <= 10th percentile and glucose >= 155.0 mg/dL after 60 minutes of OGTT. CONCLUSIONS: A worse cardiometabolic profile was observed in subjects with an eGFR > 1 SD compared to other subgroups. Therefore, pediatric obese patients with eGFR > 1 SD or hyperuricemia should be closely monitored for microalbuminuria and post-challenge glucose and insulin secretion, all potential indicators of renal dysfunction in these young patients. PMID- 29505616 TI - Correction: Rhesus macaques form preferences for brand logos through sex and social status based advertising. AB - [This corrects the article DOI: 10.1371/journal.pone.0193055.]. PMID- 29505615 TI - Circulating miRNAs, isomiRs and small RNA clusters in human plasma and breast milk. AB - Circulating small RNAs, including miRNAs but also isomiRs and other RNA species, have the potential to be used as non-invasive biomarkers for communicable and non communicable diseases. This study aims to characterize and compare small RNA profiles in human biofluids. For this purpose, RNA was extracted from plasma and breast milk samples from 15 healthy postpartum mothers. Small RNA libraries were prepared with the NEBNext(r) small RNA library preparation kit and sequenced in an Illumina HiSeq2000 platform. miRNAs, isomiRs and clusters of small RNAs were annotated using seqBuster/seqCluster framework in 5 plasma and 10 milk samples that passed the initial quality control. The RNA yield was 81 ng/mL [standard deviation (SD): 41] and 3985 ng/mL (SD: 3767) for plasma and breast milk, respectively. Mean number of good quality reads was 4.04 million (M) (40.01% of the reads) in plasma and 12.5M (89.6%) in breast milk. One thousand one hundred eighty two miRNAs, 12,084 isomiRs and 1,053 small RNA clusters that included piwi interfering RNAs (piRNAs), tRNAs, small nucleolar RNAs (snoRNA) and small nuclear RNAs (snRNAs) were detected. Samples grouped by biofluid, with 308 miRNAs, 1,790 isomiRs and 778 small RNA clusters differentially detected. In summary, plasma and milk showed a different small RNA profile. In both, miRNAs, piRNAs, tRNAs, snRNAs, and snoRNAs were identified, confirming the presence of non-miRNA species in plasma, and describing them for the first time in milk. PMID- 29505621 TI - Disruptive Physician Behavior: The Importance of Recognition and Intervention and Its Impact on Patient Safety. AB - Professional misconduct by physicians is a significant problem with negative implications in the healthcare environment and has been termed "disruptive physician behavior" (DPB) in the United States. In recent years, hospitals and healthcare organizations have begun to better understand and formally address DPB, including its management and repercussions. Policy statements by the Joint Commission and the American Medical Association (AMA) have acknowledged that DPB may pose a threat to patient and provider safety. The purpose of this article is to raise awareness about the etiology of disruptive behavior in physicians, describe the consequences and the need for early recognition, and discuss potential interventions. PMID- 29505619 TI - Single seed precise sowing of maize using computer simulation. AB - In order to test the feasibility of computer simulation in field maize planting, the selection of the method of single seed precise sowing in maize is studied based on the quadratic function model Y = A*(D-Dm)2+Ym, which depicts the relationship between maize yield and planting density. And the advantages and disadvantages of the two planting methods under the condition of single seed sowing are also compared: Method 1 is optimum density planting, while Method 2 is the ideal seedling emergence number planting. It is found that the yield reduction rate and yield fluctuation of Method 2 are all lower than those of Method 1. The yield of Method 2 increased by at least 0.043 t/hm2, and showed more advantages over Method 1 with higher yield level. Further study made on the influence of seedling emergence rate on the yield of maize finds that the yields of the two methods are both highly positively correlated with the seedling emergence rate and the standard deviations of their yields are both highly negatively correlated with the seedling emergence rate. For the study of the break-up problem of sparse caused by the method of single seed precise sowing, the definition of seedling missing spots is put forward. The study found that the relationship between number of hundred-dot spot and field seedling emergence rate is as the parabola function y = -189.32x2 + 309.55x - 118.95 and the relationship between number of spot missing seedling and field seedling emergence rate is as the negative exponent function y = 395.69e-6.144x. The results may help to guide the maize seeds production and single seed precise sowing to some extent. PMID- 29505617 TI - Pathogenesis of bat rabies in a natural reservoir: Comparative susceptibility of the straw-colored fruit bat (Eidolon helvum) to three strains of Lagos bat virus. AB - Rabies is a fatal neurologic disease caused by lyssavirus infection. People are infected through contact with infected animals. The relative increase of human rabies acquired from bats calls for a better understanding of lyssavirus infections in their natural hosts. So far, there is no experimental model that mimics natural lyssavirus infection in the reservoir bat species. Lagos bat virus is a lyssavirus that is endemic in straw-colored fruit bats (Eidolon helvum) in Africa. Here we compared the susceptibility of these bats to three strains of Lagos bat virus (from Senegal, Nigeria, and Ghana) by intracranial inoculation. To allow comparison between strains, we ensured the same titer of virus was inoculated in the same location of the brain of each bat. All bats (n = 3 per strain) were infected, and developed neurological signs, and fatal meningoencephalitis with lyssavirus antigen expression in neurons. There were three main differences among the groups. First, time to death was substantially shorter in the Senegal and Ghana groups (4 to 6 days) than in the Nigeria group (8 days). Second, each virus strain produced a distinct clinical syndrome. Third, the spread of virus to peripheral tissues, tested by hemi-nested reverse transcriptase PCR, was frequent (3 of 3 bats) and widespread (8 to 10 tissues positive of 11 tissues examined) in the Ghana group, was frequent and less widespread in the Senegal group (3/3 bats, 3 to 6 tissues positive), and was rare and restricted in the Nigeria group (1/3 bats, 2 tissues positive). Centrifugal spread of virus from brain to tissue of excretion in the oral cavity is required to enable lyssavirus transmission. Therefore, the Senegal and Ghana strains seem most suitable for further pathogenesis, and for transmission, studies in the straw-colored fruit bat. PMID- 29505620 TI - The ratio of pre-dialysis vancomycin trough serum concentration to minimum inhibitory concentration is associated with treatment outcomes in methicillin resistant Staphylococcus aureus bacteremia. AB - BACKGROUND: Vancomycin is a standard treatment for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and its efficacy is closely linked to the recommended serum trough concentration of 15-20 mg/L. However, it is unknown how the pre-dialysis trough serum concentration (Cpre-HD) correlates with MRSA eradication in renal failure patients undergoing intermittent hemodialysis (HD). OBJECTIVE: To evaluate the relationship between Cpre-HD and the treatment outcomes in this population. MATERIALS AND METHODS: A retrospective study was conducted to enroll renal failure patients undergoing HD who had received vancomycin treatment for MRSA bacteremia during January 2013 to June 2016. Treatment failure was defined as persistent bacteremia after >= 7 days of vancomycin therapy or recurrent MRSA infection within 30 days. Patient characteristics, vancomycin dosing regimen, Cpre-HD, vancomycin minimum inhibitory concentration (MIC), and subsequent culture data were reviewed. The receiver operating characteristic (ROC) curve was used to find the optimal cut off point of Cpre-HD. RESULTS: 42 patients were enrolled and 64% had treatment failure. Although there were no significant differences in demographics or Cpre HD between the two groups, Cpre-HD/MIC was significantly higher in the success group than that in the failure group (22.80+/-10.90 vs. 14.94+/-6.11, p = 0.019). The area under the ROC curve was 0.74, while the sensitivity, specificity, positive predictive value, and negative predictive value were 67%, 78%, 62.5%, and 81%, respectively, at the optimal Cpre-HD/MIC of ? 18.6. CONCLUSIONS: Cpre HD/MIC was associated with vancomycin treatment outcome in MRSA bacteremia, and targeting to achieve a Cpre-HD/MIC of ? 18.6 may improve treatment outcomes in renal failure patients who are on intermittent HD. PMID- 29505622 TI - In the Hospital: Series Introduction. PMID- 29505618 TI - A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism. AB - Amino-acid coevolution can be referred to mutational compensatory patterns preserving the function of a protein. Viral envelope glycoproteins, which mediate entry of enveloped viruses into their host cells, are shaped by coevolution signals that confer to viruses the plasticity to evade neutralizing antibodies without altering viral entry mechanisms. The functions and structures of the two envelope glycoproteins of the Hepatitis C Virus (HCV), E1 and E2, are poorly described. Especially, how these two proteins mediate the HCV fusion process between the viral and the cell membrane remains elusive. Here, as a proof of concept, we aimed to take advantage of an original coevolution method recently developed to shed light on the HCV fusion mechanism. When first applied to the well-characterized Dengue Virus (DENV) envelope glycoproteins, coevolution analysis was able to predict important structural features and rearrangements of these viral protein complexes. When applied to HCV E1E2, computational coevolution analysis predicted that E1 and E2 refold interdependently during fusion through rearrangements of the E2 Back Layer (BL). Consistently, a soluble BL-derived polypeptide inhibited HCV infection of hepatoma cell lines, primary human hepatocytes and humanized liver mice. We showed that this polypeptide specifically inhibited HCV fusogenic rearrangements, hence supporting the critical role of this domain during HCV fusion. By combining coevolution analysis and in vitro assays, we also uncovered functionally-significant coevolving signals between E1 and E2 BL/Stem regions that govern HCV fusion, demonstrating the accuracy of our coevolution predictions. Altogether, our work shed light on important structural features of the HCV fusion mechanism and contributes to advance our functional understanding of this process. This study also provides an important proof of concept that coevolution can be employed to explore viral protein mediated-processes, and can guide the development of innovative translational strategies against challenging human-tropic viruses. PMID- 29505623 TI - Denah Joseph: "In the Hospital". PMID- 29505624 TI - Relationship between Hospital 30-Day Mortality Rates for Heart Failure and Patterns of Early Inpatient Comfort Care. AB - BACKGROUND: The Centers for Medicare & Medicaid Services rewards hospitals that have low 30-day riskstandardized mortality rates (RSMR) for heart failure (HF). OBJECTIVE: To describe the use of early comfort care for patients with HF, and whether hospitals that more commonly initiate comfort care have higher 30-day mortality rates. DESIGN: A retrospective, observational study. SETTING: Acute care hospitals in the United States. PATIENTS: A total of 93,920 fee-for-service Medicare beneficiaries admitted with HF from January 2008 to December 2014 to 272 hospitals participating in the Get With The Guidelines-Heart Failure registry. EXPOSURE: Early comfort care (defined as comfort care within 48 hours of hospitalization) rate. MEASUREMENTS: A 30-day RSMR. RESULTS: Hospitals' early comfort care rates were low for patients admitted for HF, with no change over time (2.5% to 2.6%, from 2008 to 2014, P = .56). Rates varied widely (0% to 40%), with 14.3% of hospitals not initiating comfort care for any patients during the first 2 days of hospitalization. Risk-standardized early comfort care rates were not correlated with RSMR (median RSMR = 10.9%, 25th to 75th percentile = 10.1% to 12.0%; Spearman's rank correlation = 0.13; P = .66). CONCLUSIONS: Hospital use of early comfort care for HF varies, has not increased over time, and on average, is not correlated with 30-day RSMR. This suggests that current efforts to lower mortality rates have not had unintended consequences for hospitals that institute early comfort care more commonly than their peers. PMID- 29505625 TI - Atomic structure and electronic properties of A2B2XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) inorganic double helices: first principles calculations. AB - We study the structural stability and electronic properties of new classes of DNA like inorganic double helices of the type A2B2XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) by employing first principles density functional theory (DFT) calculations including van der Waals interactions. In these quaternary double helices PN or SiS forms the inner helix while the AB helix wraps around the inner helix and the two are interconnected. We find that the bromides and iodides of Ge, Sn, and Pb as well as Pb2Cl2PN form structurally stable double helices while Ge2I2SiS as well as bromides and iodides of Sn and Pb have stable double helices. The atomic structures of different double helices have been analyzed in detail to understand the stability of these systems as there is up to about 80% difference in the interatomic distances in the two helices which is remarkable. Also in these new classes of double helices there is polar covalent bonding in the inner helix due to heteroatoms. We have calculated the DDEC6 partial atomic charges and bond orders which suggest strong covalent bonding in the inner helix. The electronic structure reveals that these double helices are semiconducting and in many cases the band gap is direct. Furthermore, we have studied the effects of doping and found that hole doping is the most appropriate way to tuning their electronic properties. PMID- 29505626 TI - Chaotization of internal motion of excitons in ultrathin layers by spin-orbit coupling. AB - We show that Rashba spin-orbit coupling (SOC) can generate chaotic behavior of excitons in two-dimensional semiconductor structures. To model this chaos, we study a Kepler system with spin-orbit coupling and numerically obtain a transition to chaos at a sufficiently strong coupling. The chaos emerges since the SOC reduces the number of integrals of motion as compared to the number of degrees of freedom. Dynamically, the dependence of the exciton energy on the spin orientation in the presence of SOC produces an anomalous spin-dependent velocity resulting in chaotic motion. We observe numerically the critical dependence of the dynamics on the initial conditions, where the system can return to and exit a stability domain through very small changes in the initial spin orientation. This chaos can have a strong influence on the lifetime of optically injected carriers in semiconductors and organometallic perovskites. Hence, this effect should be taken into account while designing structures for photovoltaic and optical spintronics applications, where excitons play a significant role. PMID- 29505627 TI - Genetic Diversity, Population Structure, and Genetic Correlation with Climatic Variation in Chickpea (Cicer arietinum) Landraces from Pakistan. AB - Chickpea ( L.) production in arid regions, such as those predominant in Pakistan, faces immense challenges of drought and heat stress. Addressing these challenges is made more difficult by the lack of genetic and phenotypic characterization of available cultivated varieties and breeding materials. Genotyping-by-sequencing offers a rapid and cost-effective means to identify genome-wide nucleotide variation in crop germplasm. When combined with extended crop phenotypes deduced from climatic variation at sites of collection, the data can predict which portions of genetic variation might have roles in climate resilience. Here we use 8113 single nucleotide polymorphism markers to determine genetic variation and compare population structure within a previously uncharacterized collection of 77 landraces and 5 elite cultivars, currently grown in situ on farms throughout the chickpea growing regions of Pakistan. The compiled landraces span a striking aridity gradient into the Thal Desert of the Punjab. Despite low levels of variation across the collection and limited genetic structure, we found some differentiation between accessions from arid, semiarid, irrigated, and coastal areas. In a subset of 232 markers, we found evidence of differentiation along gradients of elevation and isothermality. Our results highlight the utility of exploring large germplasm collections for nucleotide variation associated with environmental extremes, and the use of such data to nominate germplasm accessions with the potential to improve crop drought tolerance and other environmental traits. PMID- 29505628 TI - Rice TCM1 Encoding a Component of the TAC Complex is Required for Chloroplast Development under Cold Stress. AB - Transcriptionally active chromosome (TAC) is a component of protein-DNA complexes with RNA polymerase activity, expressed in the plastid. However, the function of rice TAC proteins is still poorly understood. In this paper, we first report the identification of a new rice ( L.) mutant () in the gene encoding TAC. The mutant displayed an albino phenotype and malformed chloroplasts before the three-leaf stage when grown at low temperatures (20 degrees C) and a normal phenotype at higher temperatures (>28 degrees C). Map-based cloning revealed that encodes a novel chloroplast-targeted TAC protein in rice. In addition, the transcript levels of all examined plastid-encoded polymerase (PEP)-dependent genes were clearly downregulated in mutants at low temperatures, although partially recovering levels were obtained at high temperatures, comparable to wild-type plants. Furthermore, the transcripts were ubiquitously expressed in all examined tissues, with high expression levels in green tissues. The data suggest that the rice nuclear-encoded TAC protein TCM1 is essential for proper chloroplast development and maintaining PEP activity under cold stress. PMID- 29505629 TI - Genome-Wide Association and Metabolic Pathway Analysis of Corn Earworm Resistance in Maize. AB - Maize ( L.) is a staple crop of economic, industrial, and food security importance. Damage to the growing ears by corn earworm [ (Boddie)] is a major economic burden and increases secondary fungal infections and mycotoxin levels. To identify biochemical pathways associated with native resistance mechanisms, a genome-wide association analysis was performed, followed by pathway analysis using a gene-set enrichment-based approach. The gene-set enrichment exposed the cumulative effects of genes in pathways to identify those that contributed the most to resistance. Single nucleotide polymorphism-trait associations were linked to genes including transcription factors, protein kinases, hormone-responsive proteins, hydrolases, pectinases, xylogluconases, and the flavonol synthase gene (in the maysin biosynthesis pathway). The most significantly associated metabolic pathways identified included those that modified cell wall components, especially homogalacturonan, wax esters, and fatty acids; those involved in antibiosis, especially 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), flavonoids, and phenolics; and those involved in plant growth, including N uptake and energy production. The pathways identified in this study, and especially the cell wall associated pathways, identified here for the first time, provide clues to resistance mechanisms that could guide the identification of new resistant ideotypes and candidate genes for creation of resistant maize germplasm via selection of natural variants or gene editing. PMID- 29505630 TI - Genome-Wide Association Analysis of Grain Yield-Associated Traits in a Pan European Barley Cultivar Collection. AB - A collection of 379 Hordeum vulgare cultivars, comprising all combinations of spring and winter growth habits with two and six row ear type, was screened by genome wide association analysis to discover alleles controlling traits related to grain yield. Genotypes were obtained at 6,810 segregating gene-based single nucleotide polymorphism (SNP) loci and corresponding field trial data were obtained for eight traits related to grain yield at four European sites in three countries over two growth years. The combined data were analyzed and statistically significant associations between the traits and regions of the barley genomes were obtained. Combining this information with the high resolution gene map for barley allowed the identification of candidate genes underlying all scored traits and superposition of this information with the known genomics of grain trait genes in rice resulted in the assignation of 13 putative barley genes controlling grain traits in European cultivated barley. Several of these genes are associated with grain traits in both winter and spring barley. PMID- 29505631 TI - Verticillium dahliae Disease Resistance and the Regulatory Pathway for Maturity and Tuberization in Potato. AB - Kleb. is a pathogenic fungus causing wilting, chlorosis, and early dying in potato ( L.). Genetic mapping of resistance to was done using a diploid population of potato. The major quantitative trait locus (QTL) for resistance was found on chromosome 5. The gene, controlling earliness of maturity and tuberization, was mapped within the interval. Another QTL on chromosome 9 co localized with the wilt resistance gene marker. Epistasis analysis indicated that the loci on chromosomes 5 and 9 had a highly significant interaction, and that functioned downstream of The alleles were sequenced and found to encode StCDF1.1 and StCDF1.3. Interaction between the resistance allele and the was demonstrated, but not for Genome-wide expression QTL (eQTL) analysis was performed and genes with eQTL at the and loci were both found to have similar functions involving the chloroplast, including photosynthesis, which declines in both maturity and wilt. Among the gene ontology (GO) terms that were specific to genes with eQTL at the , but not the locus, were those associated with fungal defense. These results suggest that controls fungal defense and reduces early dying in wilt through affecting genetic pathway controlling tuberization timing. PMID- 29505633 TI - Recipient of 2017 CSSA Editor's Citation for Excellence Named. PMID- 29505632 TI - A Genome-Wide Association Study of Apple Quality and Scab Resistance. AB - The apple ( * Borkh.) is an economically and culturally important crop grown worldwide. Growers of this long-lived perennial must produce fruit of adequate quality while also combatting abiotic and biotic stress. Traditional apple breeding can take up to 20 yr from initial cross to commercial release, but genomics-assisted breeding can help accelerate this process. To advance genomics assisted breeding in apple, we performed genome-wide association studies (GWAS) and genomic prediction in a collection of 172 apple accessions by linking over 55,000 single nucleotide polymorphisms (SNPs) with 10 phenotypes collected over 2 yr. Genome-wide association studies revealed several known loci for skin color, harvest date and firmness at harvest. Several significant GWAS associations were detected for resistance to a major fungal pathogen, apple scab ( [Cke.] Wint.), but we demonstrate that these hits likely represent a single ancestral source. Using genomic prediction, we show that most phenotypes are sufficiently predictable using genome-wide SNPs to be candidates for genomic selection. Finally, we detect a signal for firmness retention after storage on chromosome 10 and show that it may not stem from variation in , a gene repeatedly identified in bi-parental mapping studies and widely believed to underlie a major QTL for firmness on chromosome 10. We provide evidence that this major QTL is more likely due to variation in a neighboring ethylene response factor (ERF) gene. The present study showcases the superior mapping resolution of GWAS compared to bi parental linkage mapping by identifying a novel candidate gene underlying a well studied, major QTL involved in apple firmness. PMID- 29505634 TI - Regional Heritability Mapping Provides Insights into Dry Matter Content in African White and Yellow Cassava Populations. AB - The HarvestPlus program for cassava ( Crantz) fortifies cassava with beta carotene by breeding for carotene-rich tubers (yellow cassava). However, a negative correlation between yellowness and dry matter (DM) content has been identified. We investigated the genetic control of DM in white and yellow cassava. We used regional heritability mapping (RHM) to associate DM with genomic segments in both subpopulations. Significant segments were subjected to candidate gene analysis and candidates were validated with prediction accuracies. The RHM procedure was validated via a simulation approach and revealed significant hits for white cassava on chromosomes 1, 4, 5, 10, 17, and 18, whereas hits for the yellow were on chromosome 1. Candidate gene analysis revealed genes in the carbohydrate biosynthesis pathway including plant serine-threonine protein kinases (SnRKs), UDP (uridine diphosphate)-glycosyltransferases, UDP-sugar transporters, invertases, pectinases, and regulons. Validation using 1252 unique identifiers from the SnRK gene family genome-wide recovered 50% of the predictive accuracy of whole-genome single nucleotide polymorphisms for DM, whereas validation using 53 likely genes (extracted from the literature) from significant segments recovered 32%. Genes including an acid invertase, a neutral or alkaline invertase, and a glucose-6-phosphate isomerase were validated on the basis of an a priori list for the cassava starch pathway, and also a fructose-biphosphate aldolase from the Calvin cycle pathway. The power of the RHM procedure was estimated as 47% when the causal quantitative trait loci generated 10% of the phenotypic variance (sample size = 451). Cassava DM genetics are complex and RHM may be useful for complex traits. PMID- 29505636 TI - Characterizing and Validating Stripe Rust Resistance Loci in US Pacific Northwest Winter Wheat Accessions (Triticum aestivum L.) by Genome-wide Association and Linkage Mapping. AB - Stripe rust resistance is a critical need for wheat cultivars in the US Pacific Northwest (PNW). Our previous genome-wide association study (GWAS) for stripe rust resistance in a set of PNW winter wheat accessions (Panel-2) identified multiple marker-trait associations (MTAs) for both all-stage and field resistance. In this study, we conducted additional GWAS using a different set of PNW winter wheat accessions (Panel-1) that contained recently bred soft white winter wheat breeding lines and cultivars. A total of 12 all-stage resistance MTAs and eight field resistance MTAs were identified. Within these MTAs, nine MTAs for all-stage resistance and two MTAs for field resistance were located distinctly from previously characterized genes and likely represent novel loci. Markers IWB60567 (1B), IWB24342 (2A), and IWB46564 (2B) explained the largest phenotypic variances for disease responses. The analysis confirmed that MTAs on chromosome 1B were indeed the same as identified in Panel-2 and that MTAs on chromosome 2A were likely and closely linked to another field resistance QTL, (Panel-2). Haplotypes for MTAs on chromosome 1B, , and linked loci on chromosome 2A provide useful information for marker development and introgression of these QTL into wheat breeding programs. PMID- 29505638 TI - Quantitative Trait Loci Controlling Fruit Size and Other Horticultural Traits in Bell Pepper (Capsicum annuum). AB - Bell pepper ( L.) is a group of fruit vegetables that has large variation in fruit shape, fruit size, and horticultural traits. Using unadapted sources of germplasm to bring in novel alleles while maintaining favorable quality and horticultural traits is challenging for breeding in pepper. A genetic map with 318 loci from genotype-by-sequencing (GBS) and single nucleotide polymorphism assays was generated from a recombinant inbred line population derived from a cultivated bell-type 'Maor' and a landrace highly resistant to , 'Criollo de Morelos-334'. Forty-nine quantitative trait loci (QTLs) were detected for fruit, leaf, and horticultural traits with the scantwo permutation and stepwiseqtl methods from R/qtl. With the availability of a pepper reference genome and GBS data, candidate genes for pepper organ size and other horticultural traits were predicted. , , and genes were candidate genes for controlling organ sizes on chromosome 1, 2, and 3, respectively. Two candidate genes controlling trichome formation in pepper are located at chromosome 10: and . The locus on chromosome 10, which encodes a member of the R2R3 MYB-domain family of proteins, has a function in anthocyanin accumulation. These QTL results and the candidate genes for each trait emphasize the genetic basis of the important traits for breeding with unadapted parents in bell pepper. PMID- 29505639 TI - Resistance to Multiple Temperate and Tropical Stem and Sheath Diseases of Rice. AB - Stem rot and aggregated sheath spot are the two major stem and sheath diseases affecting rice (Oryza sativa L.) in temperate areas. A third fungal disease, sheath blight, is a major disease in tropical areas. Resistance to these diseases is a key objective in rice breeding programs but phenotyping is challenged by the confounding effects of phenological and morphological traits such as flowering time (FT) and plant height (PH). This study sought to identify quantitative trait loci (QTL) for resistance to these three diseases after removing the confounding effects of FT and PH. Two populations of advanced breeding germplasm, one with 316 tropical japonica and the other with 325 indica genotypes, were evaluated in field and greenhouse trials for resistance to the diseases. Phenotypic means for field and greenhouse disease resistance, adjusted by FT and PH, were analyzed for associations with 29,000 single nucleotide polymorphisms (SNPs) in tropical japonica and 50,000 SNPs in indica. A total of 29 QTL were found for resistance that were not associated with FT or PH. Multilocus models with selected resistance-associated SNPs were fitted for each disease to estimate their effects on the other diseases. A QTL on chromosome 9 accounted for more than 15% of the phenotypic variance for the three diseases. When resistance-associated SNPs at this locus from both the tropical japonica and indica populations were incorporated into the model, resistance was improved for all three diseases with little impact on FT and PH. PMID- 29505640 TI - Genetic Architecture of Dietary Fiber and Oligosaccharide Content in a Middle American Panel of Edible Dry Bean. AB - Common bean ( L.) is the most consumed edible grain legume worldwide and contains a wide range of nutrients for human health including dietary fiber. Diets high in beans are associated with lower rates of chronic diseases such as obesity and type 2 diabetes, and the content of dietary fibers varies among different market classes of dry bean. In this study, we evaluated the dietary fiber content in a Middle American diversity panel (MDP) of common bean and evaluated the genetic architecture of the various dietary fiber components. The dietary fiber components included insoluble and soluble dietary fibers as well as the antinutritional raffinose family of oligosaccharides (RFOs; raffinose, stachyose, and verbascose). All variables measured differed among market classes and entries. Colored bean seeds had higher levels of insoluble dietary fibers with the black market class showing also the highest raffinose and stachyose content. Cultivars and lines released since 1997 had higher insoluble dietary fibers and RFO content in race Durango. Higher levels of RFOs were also observed in cultivars with type II growth habit that was a recent breeding target in Durango race germplasm. Candidate genes for dietary fiber traits, especially homologs to two main genes in the RFO biosynthesis pathway, were identified. The knowledge of diversity of dietary fibers in the MDP accompanied with the identification of candidate genes could effectively improve dietary fiber components in common bean. PMID- 29505641 TI - Combining High-Throughput Phenotyping and Genomic Information to Increase Prediction and Selection Accuracy in Wheat Breeding. AB - Genomics and phenomics have promised to revolutionize the field of plant breeding. The integration of these two fields has just begun and is being driven through big data by advances in next-generation sequencing and developments of field-based high-throughput phenotyping (HTP) platforms. Each year the International Maize and Wheat Improvement Center (CIMMYT) evaluates tens-of thousands of advanced lines for grain yield across multiple environments. To evaluate how CIMMYT may utilize dynamic HTP data for genomic selection (GS), we evaluated 1170 of these advanced lines in two environments, drought (2014, 2015) and heat (2015). A portable phenotyping system called 'Phenocart' was used to measure normalized difference vegetation index and canopy temperature simultaneously while tagging each data point with precise GPS coordinates. For genomic profiling, genotyping-by-sequencing (GBS) was used for marker discovery and genotyping. Several GS models were evaluated utilizing the 2254 GBS markers along with over 1.1 million phenotypic observations. The physiological measurements collected by HTP, whether used as a response in multivariate models or as a covariate in univariate models, resulted in a range of 33% below to 7% above the standard univariate model. Continued advances in yield prediction models as well as increasing data generating capabilities for both genomic and phenomic data will make these selection strategies tractable for plant breeders to implement increasing the rate of genetic gain. PMID- 29505642 TI - Single Nucleotide Polymorphism Markers Associated with Seed Quality Characteristics of Cultivated Lentil. AB - The dimensions of lentil ( Medik.) seeds are important quality parameters that are major determinants of market preference, cooking time, and post-harvest milling quality. Knowledge of the genetic control of traits related to seed dimensions would be useful for crop improvement. The principal aim of this study was to identify single nucleotide polymorphism (SNP) markers linked to genes that control seed diameter, seed thickness, and seed plumpness. Association mapping analysis with SNP markers was used to study the seed dimensions of 138 diverse cultivated lentil accessions grown at two locations in Saskatchewan, Canada, in 2011 and 2012. Six marker-trait associations were shown to be significant for the studied seed dimension characteristics. Two SNP markers closely associated with seed diameter across locations and years identified in previous work were validated in this study. Three additional marker-seed thickness associations were identified. Using the association mapping strategy, we confirmed the presence of two genomic regions controlling seed diameter and plumpness. This information can be used worldwide as a resource for lentil seed quality improvement programs. PMID- 29505643 TI - Extensive Genetic Diversity is Present within North American Switchgrass Germplasm. AB - Switchgrass ( is a perennial native North American grass present in two ecotypes: upland, found primarily in the northern range of switchgrass habitats, and lowland, found largely in the southern reaches of switchgrass habitats. Previous studies focused on a diversity panel of primarily northern switchgrass, so to expand our knowledge of genetic diversity in a broader set of North American switchgrass, exome capture sequence data were generated for 632 additional, primarily lowland individuals. In total, over 37 million single nucleotide polymorphisms (SNPs) were identified and a set of 1.9 million high-confidence SNPs were obtained from 1169 individuals from 140 populations (67 upland, 65 lowland, 8 admixed) were used in downstream analyses of genetic diversity and population structure. Seven separate population groups were identified with moderate genetic differentiation [mean fixation index (Fst) estimate of 0.06] between the lowland and the upland populations. Ecotype-specific and population specific SNPs were identified for use in germplasm evaluations. Relative to rice ( L.), maize ( L.), soybean [ (L.) Merr.], and Gaertn., analyses of nucleotide diversity revealed a high degree of genetic diversity (0.0135) across all individuals, consistent with the outcrossing mode of reproduction and the polyploidy of switchgrass. This study supports the hypothesis that repeated glaciation events, ploidy barriers, and restricted gene flow caused by flowering time differences have resulted in distinct gene pools across ecotypes and geographic regions. These data provide a resource to associate alleles with traits of interest for forage, restoration, and biofuel feedstock efforts in switchgrass. PMID- 29505644 TI - Genetic Analysis of Gossypium Fiber Quality Traits in Reciprocal Advanced Backcross Populations. AB - In mapping populations segregating for many loci, the large amount of variation among genotypes often masks small-effect quantitative trait loci (QTL). This problem can be reduced by development of populations with fewer chromosome segments segregating. Here, we report early QTL detection in reciprocal advanced backcross populations from crosses between elite Gossypium hirsutum L. 'Acala Maxxa' (GH) and G. barbadense L. 'Pima S6' (GB). A total of 297 BCF and BCF progeny rows-127 segregating for GB chromosome segments in GH background and 170 segregating for GH chromosome segments in GB background-were evaluated in three environments. Totals of 3186 and 3026 polymorphic single-nucleotide polymorphisms (SNPs) in GH and GB backgrounds, respectively, were identified and used for trait mapping. Small-effect QTL (<10% variance explained) made up 87 and 100% of QTL in GH and GB backgrounds, respectively. In both species, favorable alleles were found with effects being masked or neutralized by unfavorable alleles, with greater scope for improvement of GH than GB by introgressive breeding. A total of three stable QTL-two in GH background for fiber elongation (ELO) and micronaire (MIC) and one in GB background for upper-half mean length (UHM)-were identified in two out of three environments. Curiously, only four QTL-three for UHM and one for ELO-showed the expected opposite effects in reciprocal backgrounds, perhaps reflecting the combined consequences of epistasis, small phenotypic effects, and low coverage of some genomic regions. Along with new information for marker assisted breeding, this study adds to knowledge that can be used to unravel complex genetic networks governing fiber quality traits. PMID- 29505645 TI - Standardized Hypertension Management to Reduce Cardiovascular Disease Morbidity and Mortality Worldwide. PMID- 29505646 TI - Prevalence of HCV Infection in Adults with Congenital Heart Disease and Treatment with Direct Antiviral Agents. AB - OBJECTIVES: Hepatitis C virus (HCV) infection affects >3% of the US population, which over time can lead to cirrhosis and hepatocellular carcinoma. The lack of a reliable screening method for HCV before 1992 resulted in a higher prevalence of the virus in adults with congenital heart disease who underwent corrective surgery that required blood transfusions. Direct-acting antiviral agents such as sofosbuvir/ledipasvir have significantly increased the efficacy of HCV therapy, although use of these medications in adults with congenital heart disease has not been described. METHODS: Ours was a retrospective study of 188 adults with congenital heart conditions who had cardiac surgery before 1992. These patients were screened for HCV using HCV antibody followed by HCV RNA if the screening test was positive. RESULTS: Of the 188 adults, 116 (43% male patients, 24-70 years) were screened for the HCV antibody, demonstrating that 104 individuals were negative and 12 subjects were positive for the virus. Subsequently, further testing for the presence of HCV demonstrated 11 of 12 were infected, with an overall prevalence of 9.5%. Five individuals chose to be treated with sofosbuvir/ledipasvir and 5 of 5 have successfully cleared the virus and are considered cured. CONCLUSIONS: Adults with congenital heart disease who underwent cardiac surgery before 1992 warrant being screened for HCV, and, if testing positive, may be considered for therapy using direct-acting antiviral agents with close monitoring for cardiac complications. PMID- 29505647 TI - Commentary on "Prevalence of HCV Infection in Adults with Congenital Heart Disease and Treatment with Direct Antiviral Agents". PMID- 29505648 TI - Diverticular Disease: The Old, the New, and the Ever-Changing View. AB - Our understanding of diverticular disease has evolved significantly during the last 25 years, and as such, a reexamination is in order. We performed a literature search for the years 1960-2017 of PubMed, Medline, and Google Scholar for updates regarding the epidemiology, risk factors, and therapies for traditional diverticulitis as well as the recently described subtypes of diverticular disease, segmental colitis associated with diverticulosis, and symptomatic uncomplicated diverticular disease. Although the prevalence of diverticulosis is still extremely common in the general population, the literature suggests that the incidence of diverticulitis is much less than previously believed and occurrences do not necessarily increase with age. In addition, the commonly held beliefs that low-fiber diets alone contribute to the development of diverticulosis and diverticulitis have not been verified; however, the combination of a low-fiber diet and a high red meat/high-fat diet is a risk factor for diverticulitis. Surgery continues to be the treatment for severe complications of diverticulitis, but new literature suggests that it has a poor utility in preventing a recurrence of diverticulitis in the long term; therefore, elective surgery after two episodes of diverticulitis is no longer the standard. PMID- 29505649 TI - Endobronchial Lesions in Patients Presenting with Hemoptysis. AB - OBJECTIVES: The aim of this study was to determine the incidence of endobronchial lesions in patients presenting with hemoptysis. We also aimed to characterize features that would predict whether bronchoscopy would be useful. METHODS: A retrospective chart review was conducted on 185 consecutive patients who presented with hemoptysis from January 1, 2006 to December 31, 2015 at Methodist Le Bonheur Healthcare-affiliated hospitals in Memphis, Tennessee. Data collection included demographic information, description of hemoptysis, imaging results, bronchoscopy results, and the final diagnosis. RESULTS: A total of 185 patients presented with hemoptysis during our study period. Of these, 14 patients were excluded because of age (younger than 18 years) and incomplete data (inadequate information about the procedure performed, lack of imaging studies, incorrect International Classification of Diseases, Ninth Revision coding). The final analysis was performed in 171 patients; 87 underwent bronchoscopy either to determine etiology or to aid in management. Most patients (73%) had mild hemoptysis, with approximately half of the patients having hemoptysis for <=1 day. Of 87 people who underwent bronchoscopy, 12 (13.8%) were found to have endobronchial lesions, and 35 (51.7%) patients were found to have either active bleeding or had fresh blood in their airway during bronchoscopy. Final diagnoses included pneumonia/bronchitis in 30 (18.9%) patients, malignancy in 24 (15.1 %), and anticoagulation toxicity in 23 (14.5%) patients. CONCLUSIONS: Bronchoscopy should be strongly considered in patients presenting with hemoptysis, especially if it is frank blood, of >1 week's duration, or both, because the information obtained can be vital for management. This appears to hold true even for patients who have no abnormalities seen on computed tomography chest imaging upon initial workup. PMID- 29505650 TI - Awareness and Knowledge Among Internal Medicine Resident Trainees for Dose Adjustment of Analgesics and Neuropsychotropic Medications in CKD. AB - OBJECTIVES: Errors in drug dosing lead to poor patient outcomes and are common in patients with chronic kidney disease (CKD). Because the majority of patients with CKD are being treated by physicians specializing in internal medicine, we studied the awareness and knowledge that internal medicine resident trainees (IMRTs) have regarding the correct dosage of commonly used analgesic and neuropsychotropic medications for patients with CKD. METHODS: We surveyed 353 IMRTs about their awareness of whether a medication needs dose adjustment in patients with CKD and knowledge for medication adjustment by level of glomerular filtration rate. RESULTS: There were high percentages for lack of awareness and knowledge. For analgesics, this lack of awareness/knowledge was highest for acetaminophen (awareness 83.0%, knowledge 90.9%). For neuropsychotropics, this was highest for paroxetine (awareness 74.5%, knowledge 91.5%). Analyses for postgraduate year (PGY) -1 trainees and PGY-2 trainees for analgesics showed higher odds for lack of awareness for tramadol (PGY-1 odds ratio [OR] 2.37, 95% confidence interval [CI] 1.2-4.62, P < 0.05; PGY-2 OR 2.34, 95% CI 1.16-4.72, P < 0.05) and for lack of knowledge for meperedine (PGY-1 OR 4.01, 95% CI 1.81-8.89, P < 0.05; PGY-2 OR 3.30, 95% CI 1.44-7.59, P < 0.05). Nephrology residency rotation for the neuropsychotropic medication of gabapentin showed lower odds for both lack of awareness (OR 0.56, 95% CI 0.32-0.97, P < 0.05) and knowledge (OR 0.52, 95% CI 0.27-0.997, P < 0.05). CONCLUSIONS: Awareness and knowledge are poor among IMRTs for dose adjustments of analgesics and neuropsychotropic medication classes in patients with CKD. There should be a renewed focus during IMRTs' residency on additional nephrology exposure and formal didactic educational training to help them better manage complex treatment regimens to prevent medication dosing errors. PMID- 29505651 TI - Commentary on "Awareness and Knowledge Among Internal Medicine Resident Trainees for Dose Adjustment of Analgesics and Neuropsychotropic Medications in CKD". PMID- 29505652 TI - Video Decision Aids in End-of-Life Care: Is There a Role with Older Adult Patients? PMID- 29505653 TI - The Inaccuracy of Accuracy. PMID- 29505654 TI - Delayed Emergence in Pediatric Patients with Neurologic Disease Presenting for Ambulatory Surgery. AB - OBJECTIVES: Management of pediatric patients with neurological diagnoses can be challenging for anesthesiologists. We sought to determine whether preexisting neurologic disease could serve as an intrinsic risk factor for prolonged emergence. METHODS: Following institutional review board approval, we conducted a database search from 2012 to 2015. Included were patients aged 0 to 18 years undergoing ambulatory procedures, and carrying neurological diagnoses that profoundly affected their development. Patients were excluded if they received a total intravenous anesthetic, were not managed with an endotracheal tube, or were extubated deep. A healthy case-control group also was obtained for comparison. The primary outcome was emergence from anesthesia: time from anesthetic cessation to extubation. Our secondary outcome was time from extubation to discharge. Descriptive statistics were calculated for demographic data, outcomes were analyzed for differences using the Student t test, and regression analysis was performed. RESULTS: Data from 69 patients and 169 controls met criteria. There were no differences between study and control groups for age, sex, procedural length, or intraoperative temperatures. The study group had higher American Society of Anesthesiologists scores (2.4 vs 1.4). The primary outcome of time to emergence was longer in the study group (15.2 vs 11.0 min), and time to discharge also was prolonged (101.0 vs 86.1 min). Regression analysis on most differing variables did not yield a correlation to primary/secondary outcomes, but neurologic disease did correlate to both. CONCLUSIONS: In this case-controlled retrospective study, there was a prolongation of anesthetic emergence and hospital discharge times for pediatric patients with severe neurologic disease, mostly independent of external factors. PMID- 29505655 TI - Risk-Reducing Salpingectomy Versus Standard Tubal Sterilization: Lessons From Offering Women Options for Interval Sterilization. AB - OBJECTIVES: In women receiving sterilization, the removal of the entire fallopian tube, a procedure referred to as a risk-reducing salpingectomy (RRS), reduces subsequent ovarian cancer risk compared with standard tubal sterilization procedures. There are limited data on which surgical procedure women will choose when educated about the benefits of an RRS. Our objective was to study the proportion of women desiring sterilization that would choose an RRS. METHODS: This cohort study included women 30 years of age and older with a living biological child who requested laparoscopic sterilization at a tertiary academic hospital. Participants were given a decision aid and offered an RRS or a standard tubal sterilization procedure with titanium clips. The primary outcome was to determine the proportion of women who would choose an RRS. Other outcomes included estimated blood loss and operative time, which was compared between groups, along with complications. RESULTS: Fourteen of the 18 (78%) women who participated in our study chose RRS. Estimated blood loss and operating time were similar among women who underwent RRS and standard tubal sterilizations. There were no significant complications in either group. The study was ended early based on emerging data and a change in national practice patterns. CONCLUSIONS: Because of the elective nature of sterilization and the complexities of cancer risk reduction, a patient-centered approach is beneficial for sterilization counseling. Our results support offering RRS as an alternative to standard tubal sterilization. PMID- 29505656 TI - Association of the Length of the Third Stage of Labor and Blood Loss Following Vaginal Delivery. AB - OBJECTIVES: The length of the third stage of labor is correlated with blood loss following a vaginal delivery. We aimed to accurately measure blood loss following a vaginal delivery and examine the relation between blood loss and length of the third stage of labor. METHODS: This was a prospective observational study of singleton pregnancies >=24 weeks undergoing a vaginal delivery. Blood loss was meticulously measured and the length of the third stage of labor was recorded. RESULTS: The median blood loss of the 600 women was 125 mL (interquartile range 175) and the median length of the third stage of labor was 5 minutes (interquartile range 4). Total blood loss (P = 0.0263) and length of the third stage of labor (P = 0.0120) were greater in pregnancies >=37 weeks versus <37 weeks. Women with a third stage of labor >=15 minutes had a significantly greater risk of blood loss >500 mL (relative risk 5.8, 95% confidence interval 8.36 29.88). CONCLUSIONS: The median blood loss following a vaginal delivery is 125 mL and the median length of the third stage of labor is 5 minutes. Total blood loss and the length of the third stage of labor are greater in pregnancies >37 weeks. Women with a third stage of labor >15 minutes are 15.8 times more likely to have total blood loss >=500 mL. As such, it is prudent to consider manual extraction of the placenta at 15 minutes rather than 30 minutes to minimize the risk of excessive blood loss. PMID- 29505657 TI - Women's Health Curriculum for Medical Students. AB - OBJECTIVES: Knowledge of women's health is important for physicians in various specialties, but training often is inadequate. The objective of this project was to develop, implement, and evaluate a women's health curriculum for medical students at the University of Florida College of Medicine in Gainesville. METHODS: After reviewing previous pertinent literature and assessing institutional factors, we developed an interdisciplinary women's health elective for medical students. We present the curricular design for the course. The 2-week elective explores women's health topics such as disease prevention, screening, breast health, osteoporosis, and cardiovascular health. Teaching methodology includes case-based lectures, reading assignments, and clinic sessions at multiple sites. RESULTS: Senior medical students worked in a variety of clinical settings and were assigned a women's health project, a pretest before starting the elective, and a posttest after completion of the course. A statistically significant increase was seen in the students' mean posttest (98.8%) versus pretest (85.6%) scores (difference 13.1%; 95% confidence interval 7.3-19.0, P < 0.0001). CONCLUSIONS: Designing curricula that promote lifelong professional competency in the field of women's health can be challenging. At the University of Florida, we have successfully created and implemented a medical student elective in women's health using local resources and expertise. This elective satisfies important women's health training requirements, has been well received by our students, and has resulted in increased women's health-specific knowledge. The experience at our institution may be useful for other programs interested in developing a women's health curriculum geared toward medical students utilizing minimal resources. PMID- 29505658 TI - Two- and four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation in the diagnosis of fetal isolated partial anomalous pulmonary venous connection. AB - Partial anomalous pulmonary venous connection (PAPVC) is a rare malformation. We describe a case of PAPVC, in which the left pulmonary veins coursed to the left innominate vein through a vertical vein and finally drained into the right superior vena cava; the right pulmonary veins were connected to the left atrium. Tracing the origin and destination of abnormal vessels presented at the three vessel and trachea view is useful for the diagnosis. Four-dimensional echocardiography with high-definition flow imaging and spatiotemporal image correlation facilitates the identification of the drainage of fetal pulmonary veins, which should be considered as a complementary modality in obstetric ultrasonic examination when cardiac abnormalities are suspected. PMID- 29505659 TI - Utility of postural change in differentiating sludge from thrombus in the left atrial appendage: A case report. AB - We detected symptomatic atrial fibrillation in a 64-year-old man who had undergone mitral valvuloplasty. While performing transesophageal echocardiography (TEE) in the left lateral decubitus position, we detected an isoechoic mass lesion at the bottom of the left atrial appendage (LAA). After changing the patient's position from left to right, the mass lesion dropped down from the bottom of the LAA, spread out into the left atrium, and appeared as a spontaneous echocardiographic contrast with mobility. We therefore diagnosed the mass lesion as not a thrombus but sludge. Changing the patient's position during TEE is useful for distinguishing sludge from thrombi. PMID- 29505660 TI - An evaluation of the objective quality and perceived usefulness of maternity clinical practice guidelines at a tertiary maternity unit. AB - BACKGROUND: Compliance with maternity clinical practice guidelines developed by National Women's Health has been found to be low at audit. OBJECTIVE: To explore the reasons for poor compliance with maternity guidelines by evaluating the quality of a sample of National Women's Health guidelines using a validated instrument and assessing local guideline users' perceptions of and attitudes toward guidelines. DESIGN: Five independent reviewers evaluated the quality of 10 purposively selected guidelines for adherence to the Appraisal of Guidelines Research & Evaluation (AGREE) II instrument standards. A self-administered questionnaire for staff was undertaken regarding views of and barriers to guideline use. RESULTS: None of the guidelines attained a score over 50% for the following domains: stakeholder involvement, rigour of development, applicability, editorial independence. The highest scoring domain was clarity of presentation (mean 69%). All guidelines scored the minimum possible for editorial independence. Survey respondents had positive attitudes toward guidelines, believed that their use could improve quality of care within the service, and felt that encouragement from senior staff members and peers would encourage their use. Accessibility was the most commonly cited of many barriers identified. CONCLUSION: The National Women's Health guidelines evaluated in this study cannot be considered to be high quality, and could be improved by reporting on methodology of the development process. Although poor guideline development may contribute to failure of the local maternity guidelines, it appears that accessibility is a major barrier to their use and implementation. PMID- 29505661 TI - Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients. AB - Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. PMID- 29505662 TI - Exogenous melatonin protects small-for-size liver grafts by promoting monocyte infiltration and releases interleukin-6. AB - Defective regeneration of small-for-size (SFS) liver remnants and partial grafts remains a key limiting factor in the application of liver surgery and transplantation. Exogenous melatonin (MLT) has protective effects on hepatic ischemia-reperfusion injury (IRI), but its influence on graft regeneration is unknown. The aim of the study is to investigate the role of MLT in IRI and graft regeneration in settings of partial liver transplantation. We established three mouse models to study hepatic IRI and regeneration associated with partial liver transplantation: (I) IR+PH group: 60 minutes liver ischemia (IR) plus 2/3 hepatectomy (PH); (II) IR+exPH group: 60 minutes liver IR plus extended hepatectomy (exPH) associated with the SFS syndrome; (III) SFS-LT group: Arterialized 30% SFS liver transplant. Each group was divided into MLT or vehicle treated subgroups. Hepatic injury, inflammatory signatures, liver regeneration, and animal survival rates were assessed. MLT reduced liver injury, enhanced liver regeneration, and promoted interleukin (IL) 6, IL10, and tumor necrosis factor alpha release by infiltrating, inflammatory Ly6C+ F4/80+ monocytes in the IR+PH group. MLT-induced IL6 significantly improved hepatic microcirculation and survival in the IR+exPH model. In the SFS-LT group, MLT promoted graft regeneration and increased recipient survival along with increased IL6/GP130 STAT3 signaling. In IL6-/- mice, MLT failed to promote liver recovery, which could be restored through recombinant IL6. In the IR+exPH and SFS-LT groups, inhibition of the IL6 co-receptor GP130 through SC144 abolished the beneficial effects of MLT. MLT ameliorates SFS liver graft IRI and restores regeneration through monocyte-released IL6 and downstream IL6/GP130-STAT3 signaling. PMID- 29505663 TI - The right ventricular outflow tract in pediatric pulmonary hypertension-Data from the European Pediatric Pulmonary Vascular Disease Network. AB - OBJECTIVE: The right ventricular outflow tract (RVOT) is pivotal for adequate RV function and known to be adversely affected by elevated pulmonary arterial pressure (PAP) in adults with pulmonary hypertension (PH). Aim of this study was to determine the effects of increased RV pressure afterload in children with PH on RVOT size, function, and flow parameters. METHODS: We conducted a transthoracic echocardiographic study in 51 children with PH (median age: 5.3 years; range 1.5 months to 18 years) and determined the following RVOT variables: RVOT diameter, RVOT velocity time integral (VTI), ratio of tricuspid regurgitation velocity (TRV)/RVOT VTI, and RVOT systolic excursion (SE). RESULTS: In our pediatric PH cohort, the age-specific RVOT diameter z-score was higher compared to normal values. Deviation from normal RVOT diameter values increased with age, disease severity, and New York Heart Association functional class. Significant correlations were found between RVOT diameter and the RV end diastolic area and right atrial area. The age-specific RVOT VTIz-score values were significantly lower in children with PH vs healthy controls. The TRV/RVOT VTI ratio increased with rising systolic RV pressure, while the RVOT SE was similar between PH children and control subjects. CONCLUSIONS: In pediatric PH cohort, the RVOT VTI is decreased, and the TRV/RVOT VTI ratio and the RVOT diameter increased compared to healthy subjects. Assessment of RVOT variables, together with established RV parameters, allows for a comprehensive assessment of global right heart size and performance in children with PH. PMID- 29505664 TI - Higher versus lower amino acid intake in parenteral nutrition for newborn infants. AB - BACKGROUND: Sick newborn and preterm infants frequently are not able to be fed enterally, necessitating parenteral fluid and nutrition. Potential benefits of higher parenteral amino acid (AA) intake for improved nitrogen balance, growth, and infant health may be outweighed by the infant's ability to utilise high intake of parenteral AA, especially in the days after birth. OBJECTIVES: The primary objective is to determine whether higher versus lower intake of parenteral AA is associated with improved growth and disability-free survival in newborn infants receiving parenteral nutrition.Secondary objectives include determining whether:* higher versus lower starting or initial intake of amino acids is associated with improved growth and disability-free survival without side effects;* higher versus lower intake of amino acids at maximal intake is associated with improved growth and disability-free survival without side effects; and* increased amino acid intake should replace non-protein energy intake (glucose and lipid), should be added to non-protein energy intake, or should be provided simultaneously with non-protein energy intake.We conducted subgroup analyses to look for any differences in the effects of higher versus lower intake of amino acids according to gestational age, birth weight, age at commencement, and condition of the infant, or concomitant increases in fluid intake. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (2 June 2017), MEDLINE (1966 to 2 June 2017), Embase (1980 to 2 June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 2 June 2017). We also searched clinical trials databases, conference proceedings, and citations of articles. SELECTION CRITERIA: Randomised controlled trials of higher versus lower intake of AAs as parenteral nutrition in newborn infants. Comparisons of higher intake at commencement, at maximal intake, and at both commencement and maximal intake were performed. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality, and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs) and assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Thirty-two studies were eligible for inclusion. Six were short-term biochemical tolerance studies, one was in infants at > 35 weeks' gestation, one in term surgical newborns, and three yielding no usable data. The 21 remaining studies reported clinical outcomes in very preterm or low birth weight infants for inclusion in meta-analysis for this review.Higher AA intake had no effect on mortality before hospital discharge (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14; I2 = 0%; quality of evidence: low). Evidence was insufficient to show an effect on neurodevelopment and suggest no reported benefit (quality of evidence: very low). Higher AA intake was associated with a reduction in postnatal growth failure (< 10th centile) at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3; I2 = 22%; typical RD -0.15, 95% CI -0.27 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 50; quality of evidence: very low). Subgroup analyses found reduced postnatal growth failure in infants that commenced on high amino acid intake (> 2 to <= 3 g/kg/day); that occurred with increased amino acid and non protein caloric intake; that commenced on intake at < 24 hours' age; and that occurred with early lipid infusion.Higher AA intake was associated with a reduction in days needed to regain birth weight (MD -1.14, 95% CI -1.73 to -0.56; participants = 950; studies = 13; I2 = 77%). Data show varying effects on growth parameters and no consistent effects on anthropometric z-scores at any time point, as well as increased growth in head circumference at discharge (MD 0.09 cm/week, 95% CI 0.06 to 0.13; participants = 315; studies = 4; I2 = 90%; quality of evidence: very low).Higher AA intake was not associated with effects on days to full enteral feeds, late-onset sepsis, necrotising enterocolitis, chronic lung disease, any or severe intraventricular haemorrhage, or periventricular leukomalacia. Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4; I2 = 31%; quality of evidence: very low) but no difference in severe retinopathy of prematurity.Higher AA intake was associated with an increase in positive protein balance and nitrogen balance. Potential biochemical intolerances were reported, including risk of abnormal blood urea nitrogen (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7; I2 = 6%; typical RD 0.26, 95% CI 0.20 to 0.32; number needed to treat for an additional harmful outcome (NNTH) 4; 95% CI 3 to 5; quality of evidence: high). Higher amino acid intake in parenteral nutrition was associated with a reduction in hyperglycaemia (> 8.3 mmol/L) (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5; I2 = 68%), although the incidence of hyperglycaemia treated with insulin was not different. AUTHORS' CONCLUSIONS: Low-quality evidence suggests that higher AA intake in parenteral nutrition does not affect mortality. Very low-quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure. Evidence was insufficient to show an effect on neurodevelopment. Very low-quality evidence suggests that higher AA intake reduces retinopathy of prematurity but not severe retinopathy of prematurity. Higher AA intake was associated with potentially adverse biochemical effects resulting from excess amino acid load, including azotaemia. Adequately powered trials in very preterm infants are required to determine the optimal intake of AA and effects of caloric balance in parenteral nutrition on the brain and on neurodevelopment. PMID- 29505665 TI - Suicide among nursing home residents in Australia: A national population-based retrospective analysis of medico-legal death investigation information. AB - OBJECTIVES: Suicide among nursing home residents is a growing public health concern, currently lacking in empirical research. This study aims to describe the frequency and nature of suicide among nursing home residents in Australia. METHODS: This research comprised a national population-based retrospective analysis of suicide deaths among nursing home residents in Australia reported to the Coroner between July 2000 and December 2013. Cases were identified using the National Coronial Information System, and data collected from paper-based coroners' records on individual, incident, and organizational factors, as well as details of the medico-legal death investigation. Data analysis comprised univariate and bivariate descriptive statistical techniques; ecological analysis of incidence rates using population denominators; and comparison of age and sex of suicide cases to deaths from other causes using logistic regression. RESULTS: The study identified 141 suicides among nursing home residents, occurring at a rate of 0.02 deaths per 100 000 resident bed days. The ratio of deaths from suicide to deaths from any other cause was higher in males than females (OR = 3.56, 95%CI = 2.48-5.12, P = <0.001). Over half of the residents who died from suicide had a diagnosis of depression (n = 93, 66.0%) and had resided in the nursing home for less than 12 months (n = 71, 50.3%). Common major life stressors identified in suicide cases included the following: health deterioration (n = 112, 79.4%); isolation and loneliness (n = 60, 42.6%); and maladjustment to nursing home life (n = 42, 29.8%). CONCLUSIONS: This research provides a foundational understanding of suicide among nursing home residents in Australia and contributes important new information to the international knowledge base. PMID- 29505667 TI - Oral myiasis in older adult with severe Alzheimer's disease. AB - AIMS: Myiasis is a disease caused by the invasion of tissues by larvae of flies. The aim of this study was to carry out a review of reported cases of oral and maxillofacial myiasis in older adults and to show a case report of oral myiasis in a 95-year-old frail man with severe Alzheimer's disease from Brazil. METHODS AND RESULTS: Between 1988 and 2017, 35 oral and maxillofacial myiasis cases were reported in older adults in English-language studies from PubMed and Lilacs databases. CONCLUSIONS: Oral and maxillofacial myiasis in older adults showed low incidence and good prognosis of cure, when there were no systemic complications. Weakness, frailty, dementia, oral lesions, labial incompetence, poor oral hygiene, and bad breath were associated with this disease in reported cases. Preferential therapy choices were debridement alone or combined with Ivermectin. In this case report, debridement and Ivermectin prescription was an effective therapy for an older adult with severe Alzheimer's disease. PMID- 29505666 TI - E/e' ratio and left atrial area are predictors of atrial fibrillation in patients with hypertrophic cardiomyopathy. AB - INTRODUCTION: Atrial fibrillation (AF) occurs in about 20%-25% of patients with hypertrophic cardiomyopathy and is associated with increased risk of cardioembolism and heart failure impacting on patients' morbidity and mortality. The aim of this study was to identify echocardiographic predictors of AF in a cohort of patients with hypertrophic cardiomyopathy (HCM). METHODS: Patients were recruited from 2 centers: Buenos Aires Cardiovascular Institute and the Hospital Vall d'Hebron of Barcelona which were analyzed together. Retrospective study using electronic charts. RESULTS: A total of 321 patients with HCM and no documented history of AF were included. Median follow-up was 3 years. Mean age was 54 +/- 16 years. Obstructive HCM was present in 41% of the patients, and 94.2% had preserved systolic function. Thirty-eight patients developed AF during the follow-up period (11.8%). Univariate analysis showed that age, maximum myocardial thickness, atrial area, an E/e' ratio >= 17, and systolic pulmonary pressure estimated by echocardiography were associated with new-onset AF. Multivariate analysis showed that E/e' >= 17 ratio {HR 3.27 ([1.10-9.27] P = .033)} and atrial area {HR 1.06 ([1.01-1.13] P = .037)} remained predictors of AF. CONCLUSIONS: An E/e' ratio >= 17, as an expression of left ventricular filling pressures with impact on the left atrium, and left atrial area >=28 cm2 are strong predictors of AF in patients with HCM. PMID- 29505668 TI - Altered expression of IL-18 binding protein and IL-18 receptor in basophils and mast cells of asthma patients. AB - IL-18 is likely to contribute to asthma. However, little is known regarding the role of IL-18 binding protein (BP) and IL-18 receptor (R) in asthma. Because the action of IL-18 in the body is regulated by IL-18BP and mast cells and basophils are key cell types involved in asthma, we investigated the expression of IL-18, IL-18BP and IL-18R in basophils and mast cells using flow cytometry and a mouse asthma model. We found that among basophils, approximately 53% and 51% were IL 18+ , 85% and 81% were IL-18BP+ basophils, and 19.8% and 8.6% were IL-18R+ in healthy control (HC) and asthmatic blood, respectively. The allergens tested had little effect on the expression of IL-18 and related factors. Only 3.5%, 14.3% and 2.4% of dispersed mast cells expressed IL-18, IL-18BP and IL-18R, respectively, in asthmatic sputum. In a mouse asthma model, OVA-sensitized mice exhibited decreased IL-18BP+ but increased IL-18R+ basophils in their blood. IL 18 increased the number of basophils but eliminated IL-18BP+ basophils in mouse blood. IL-18 increased the number of mast cells and IL-18R+ mast cells in the lung as well as increased the mast cell numbers and IL-18BP+ mast cells in the bronchoalveolar lavage fluid (BALF) of OVA-sensitized mice. Thus, basophils and mast cells may be involved in asthma pathogenesis via an IL-18-associated mechanism. PMID- 29505669 TI - Multicentre emergency department study found that paracetamol and ibuprofen were inappropriately used in 83% and 63% of paediatric cases. AB - AIM: The Pain Practice in Italian Paediatric Emergency Departments assessed how appropriately analgesic drugs were being used by Italian clinicians, based on national paediatric pain guidelines. METHODS: This was a retrospective study that involved 17 Italian members of the Pain In Pediatric Emergency Rooms group. It comprised patients up to the age of 14 years who came to hospital emergency departments with pain and were treated with paracetamol, ibuprofen or opioids, such as codeine, tramadol and morphine. RESULTS: We studied 1471 patients who were given 1593 doses of analgesics. The median time to administration of analgesia was 25 minutes. Opioids were used in 13.5% of the children, and usage increased with age and with more severe clinical conditions, such as trauma: 1.6% of children under two years, 5.9% aged 3-10 and 8.0% aged 11-14. Inappropriate doses of paracetamol, ibuprofen and opioids were used in 83%, 63% and 33% of cases, respectively. The patient's age was a critical determinant of the correct analgesic dosage; for every one-year increase in the patient's age, the probability of appropriate prescriptions rose 14.8%. CONCLUSION: The appropriate use of paracetamol and ibuprofen for paediatric pain in Italian emergency departments was very poor, but improved with age. PMID- 29505670 TI - Clinical and economic burden associated with stage III to IV triple-negative breast cancer: A SEER-Medicare historical cohort study in elderly women in the United States. AB - BACKGROUND: The current study was performed to describe patient characteristics, treatment patterns, survival, health care resource use (HRU), and costs among older women in the United States with advanced (American Joint Committee on Cancer stage III/IV) triple-negative breast cancer (TNBC) in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. METHODS: Women who were aged >=66 years at the time of diagnosis and diagnosed with advanced TNBC between January 1, 2007, and January 1, 2011, in the SEER-Medicare database and who were followed for survival through December 31, 2013, were eligible. Patient demographic and clinical characteristics at the time of diagnosis, subsequent treatment patterns, and survival outcomes were analyzed. HRU and costs for the first 3 months after diagnosis, the last 3 months of life, and the time in between are summarized. All analyses were stratified by American Joint Committee on Cancer stage of disease. RESULTS: There were 1244 patients newly diagnosed with advanced TNBC; the majority were aged >=75 years (61% with stage III disease and 57.4% with stage IV disease) and white (>70% of patients in both disease stage groups). The most common treatment approaches were surgery combined with chemotherapy for patients for stage III disease (50.6%) and chemotherapy alone or with radiotherapy for patients with stage IV disease (31.3%). Diverse chemotherapy regimens were administered for each line of therapy; nevertheless, the medications used were consistent with national guidelines. Patients with stage III and stage IV disease were found to have a similar mean number of hospitalizations and outpatient visits, but mean monthly costs were greater for patients with stage IV disease at all 3 time points. The mean cost per patient month (in 2013 US dollars) was $4810 for patients with stage III disease and $9159 for patients with stage IV disease. CONCLUSIONS: Among older women with advanced TNBC, significant treatment variations and considerable HRU and costs exist. Further research is needed to find effective treatments with which to reduce the clinical and economic burden of this disease. Cancer 2018;124:2104-14. (c) 2018 American Cancer Society. PMID- 29505671 TI - Late stillbirth post mortem examination in New Zealand: Maternal decision-making. AB - BACKGROUND: For parents who experience stillbirth, knowing the cause of their baby's death is important. A post mortem examination is the gold standard investigation, but little is known about what may influence parents' decisions to accept or decline. AIM: We aimed to identify factors influencing maternal decision-making about post mortem examination after late stillbirth. METHODS: In the New Zealand Multicentre Stillbirth Study, 169 women with singleton pregnancies, no known abnormality at recruitment, and late stillbirth (>=28weeks gestation), from seven health regions were interviewed within six weeks of birth. The purpose of this paper was to explore factors related to post mortem examination decision-making and the reasons for declining. We asked women if they would make the same decision again. RESULTS: Maternal decision to decline a post mortem (70/169, 41.4%) was more common among women of Maori (adjusted odds ratio (aOR) 4.99 95% confidence interval (CI) 1.70-14.64) and Pacific (aOR 3.94 95% CI 1.47-10.54) ethnicity compared to European, and parity two or more (aOR 2.95 95% CI 1.14-7.62) compared to primiparous. The main reason for declining was that women 'did not want baby to be cut'. Ten percent (7/70) who declined said they would not make this decision again. No woman who consented regretted her decision. CONCLUSION: Ethnic differences observed in women's post mortem decision making should be further explored in future studies. Providing information of the effect of post mortem on the baby's body and the possible emotional benefits of a post mortem may assist women faced with this decision in the future. PMID- 29505672 TI - Human secreted proteins SLURP-1 and SLURP-2 control the growth of epithelial cancer cells via interactions with nicotinic acetylcholine receptors. AB - BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nAChRs) are a promising target for development of new anticancer therapies. Here we have investigated the effects of the endogenous human proteins SLURP-1 and SLURP-2, antagonists of nAChRs, on human epithelial cancer cells. EXPERIMENTAL APPROACH: Growth of epithelial cancer cells (A431, SKBR3, MCF-7, A549, HT-29) exposed to SLURP-1, SLURP-2, mecamylamine, atropine, timolol and gefitinib was measured by the WST-1 test. Expression levels of SLURP-1, alpha7-nAChR and EGF receptors and their distribution in cancer cells were studied by confocal microscopy and flow cytometry. Secretion of endogenous SLURP-1 by A431 cells under treatment with recombinant SLURP-1 was analysed by Western-blotting. KEY RESULTS: SLURP-1 and SLURP-2 significantly inhibited growth of A431, SKBR3, MCF-7 and HT-29 cells at concentrations above 1 nM, to 40-70% of the control, in 24 h. Proliferation of A549 cells was inhibited only by SLURP-1. The anti-proliferative activity of SLURPs on A431 cells was associated with nAChRs, but not with beta-adrenoceptors or EGF receptors. Action of gefitinib and SLURPs was additive and resulted almost complete inhibition of A431 cell proliferation during 24 h. Exposure of A431 cells to recombinant SLURP-1 down-regulated alpha7-nAChR expression and induced secretion of endogenous SLURP-1 from intracellular depots, increasing its concentration in the extracellular media. CONCLUSIONS AND IMPLICATIONS: SLURPs inhibit growth of epithelial cancer cells in vitro and merit further investigation as potential agents for anticancer therapy. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 29505673 TI - Multiple pharmacological approaches on Fibigia eriocarpa extracts by in vitro and computational assays. AB - The ethyl acetate, methanolic, and water extracts of Fibigia eriocarpa were assessed for a panoply of bioactivities. Total phenolic and flavonoid content were quantified as well as individual phenolic compounds by HPLC-DAD. The in vitro antioxidant and enzyme (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, alpha-amylase, and alpha-glucosidase) inhibitory potential of the extracts were evaluated. In silico molecular docking was used to investigate possible interaction between dominant compounds and selected enzymes. Vanillin (303 MUg/g extract), apigenin (270 MUg/g extract), and kaempferol (180 MUg/g extract) were the main compounds in the ethyl acetate extract, while the methanolic extract was characterized by the presence of vanillin, rutin, and apigenin (616, 616 and 252 MUg/g extract, respectively). (+)-catechin (1422 MUg/g extract) was the main compound in the water extracts. The ethyl acetate extract was found to be a superior source of antioxidant compounds and enzyme inhibitors against above-mentioned enzymes. Docking studies revealed that p-hydroxybenzoic and (+)-catechin have the best scores for tyrosinase, while kaempferol and apigenin showed the best binding pose for alpha-glucosidase, AChE, and BChE. Results amassed herein are the first report on the phytochemical and biological attributes of F. eriocarpa, which tend to validate the pharmacological uses of this plant as an alternative medicine. PMID- 29505674 TI - Outcomes of left split graft transplantation in Europe: report from the European Liver Transplant Registry. AB - Split liver transplantation (SLT) has been widely adopted across Europe, resulting in remarkable reduction in the paediatric waiting-list mortality. Left split graft (LSG) is commonly used for paediatric recipients; however, deceased donor criteria selection are not universal. The aim of this study was to analyse the LSG outcome from the European Liver Transplant Registry and to identify risk factors for graft failure. Data from 1500 children transplanted in 2006-2014 with LSG from deceased donors were retrospectively analysed. Overall, graft losses were 343(22.9%) after 5 years from transplantation, 240(70.0%) occurred within the first 3 months. Estimated patient survival was 89.1% at 3 months and 82.9% at 5 years from SLT. Re-transplantation rate was 11.5%. At multivariable analysis, significant risk factors for graft failure at 3 months included the following: urgent SLT (HR = 1.73, P = 0.0012), recipient body weight <=6 kg (HR = 1.91, P = 0.0029), donor age >50 years (HR = 1.87, P = 0.0039), and cold ischaemic time (CIT) [HR = 1.07 per hour, P = 0.0227]. LSG has good outcomes and SLT is excellent option for paediatric recipients in the current organ shortage era. We identified practical guidelines for LSG donor and recipient selection criteria: donor age may be safely extended up to 50 years in the absence of additional risk factors; thus, children <6 kg and urgent transplantation need CIT <6 h and appropriate graft/recipient size-matching to achieve good outcomes. PMID- 29505675 TI - Lipid nanoparticles (SLN & NLC) for delivery of vitamin E: a comprehensive review. AB - The antioxidative and photoprotective properties of vitamin E have caused it to be included as an active agent in various pharmaceutical and cosmetic products. However, its lipophilicity, chemical instability and poor skin penetration have limited the effectiveness of these formulations. For that reason, many attempts to include it in different drug delivery systems have been made. In recent decades, lipid nanoparticles have received special attention due to their advantages of compatibility with the skin, ability to enhance penetration of drugs in the stratum corneum, protection of the encapsulated substance against degradation induced by the external medium and control of drug release. This work reviews the current status of the encapsulation of vitamin E in lipid nanoparticles. We describe the most important methods for obtaining and characterizing lipid nanoparticles containing vitamin E (LNP-VE), various techniques for the evaluation of vitamin E's properties after encapsulation, the main in vitro and in vivo studies of the potential effectiveness or toxicity of LNP-VE, the formulations and stability studies of this delivery system, the commercial products based on LNP-VE and the regulatory aspects related to lipid nanoparticles. Finally, we discuss the most relevant advantages of encapsulating vitamin E in such particles and critical aspects that still demand attention to enhance the potential of solid lipid nanoparticles to deliver vitamin E. PMID- 29505676 TI - On the paper "Notes on the overlap measure as an alternative to the Youden index". PMID- 29505677 TI - Response to comments by Pablo Martinez-Camblor on "Notes on Overlap Measure as an Alternative to Youden Index: How are they related?" PMID- 29505678 TI - Analyzing Approaches to the Backlog of Untested Sexual Assault Kits in the U.S.A. AB - Motivated by the debate over how to deal with the huge backlog of untested sexual assault kits in the U.S.A., we construct and analyze a mathematical model that predicts the expected number of hits (i.e., a new DNA profile matches a DNA sample in the criminal database) as a function of both the proportion of the backlog that is tested and whether the victim-offender relationship is used to prioritize the kits that are tested. Refining the results in Ref. (Criminol Public Policy, 2016, 15, 555), we use data from Detroit, where government funding was used to process ~15% of their backlog, to predict that prioritizing stranger kits over nonstranger kits leads to only a small improvement in performance (a 0.034 increase in the normalized area under the curve of the hits vs. proportion of backlog tested curve). Two rough but conservative cost-benefit analyses-one for testing the entire backlog and a marginal one for testing kits from nonstranger assaults-suggest that testing all sexual assault kits in the backlog is quite cost-effective: for example, spending ~$1641 to test a kit averts sexual assaults costing ~$133,484 on average. PMID- 29505679 TI - Second-harmonic imaging microscopy for identifying colorectal intraepithelial neoplasia. AB - In this study, second-harmonic imaging microscopy was used to monitor precancerous colorectal lesions at different stages. It was found that the morphology of glands and lamina propria in mucosa changes with the progression of colorectal diseases from normal to low-grade intraepithelial neoplasia to high grade intraepithelial neoplasia and this microscopy has the ability of direct visualization of these warning symptoms. Furthermore, two morphologic variables were quantified to determine the changes of glands and collagen in lamina propria during the development of colorectal intraepithelial neoplasia. These results suggest that second-harmonic imaging microscopy has the potential in label-freely and effectively distinguishing between normal and precancerous colorectal tissues, and will be helpful for early diagnosis and treatment of colorectal diseases. PMID- 29505680 TI - Impact of hemophilia B on quality of life in affected men, women, and caregivers Assessment of patient-reported outcomes in the B-HERO-S study. AB - INTRODUCTION: Health-related quality of life (HRQoL) is impaired in patients with hemophilia; however, the impact in mild/moderate hemophilia B and affected women is not well characterized. OBJECTIVE: To evaluate factors that affect HRQoL in adults with hemophilia B and caregivers of affected children. METHODS: US adult patients and caregivers of affected children completed distinct ~1-hour online surveys including patient-reported outcome instruments. RESULTS: In total, 299 adult patients and 150 caregivers participated. Adults with moderate hemophilia reported poorer health status (median EQ-5D-5L index score, 0.63) than those with mild (0.73) or severe (0.74) hemophilia. Women reported greater pain severity than men on the Brief Pain Inventory v2 Short Form (median, 7.00 vs 5.00). Based on the Patient Health Questionnaire, mild or worse depression was observed in >50% of adult respondents, and depression was reported more often in those with moderate and severe hemophilia vs those with mild hemophilia. Most caregivers reported at least mild depression. CONCLUSION: Pain, functional impairment, and depression/anxiety are present at higher-than-expected levels in individuals with hemophilia B. The large proportion of individuals with mild/moderate hemophilia and women with reduced health status suggests significant unmet needs in this population. PMID- 29505681 TI - Cell cycle arrest and cell death correlate with the extent of ischaemia and reperfusion injury in patients following kidney transplantation - results of an observational pilot study. AB - A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7 days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10 days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors. PMID- 29505682 TI - The impact of cohort substance use upon likelihood of transitioning through stages of alcohol and cannabis use and use disorder: Findings from the Australian National Survey on Mental Health and Wellbeing. AB - INTRODUCTION AND AIMS: We used population-level Australian data to estimate prevalence, age of onset and speed of transitions across stages of alcohol and cannabis use, abuse and dependence, and remission from disorder, and consider the potential impacts that an individual's age cohort's level of substance use predicted transitions into and out of substance use. DESIGN AND METHODS: Data on use, DSM-IV use disorders, and remission from these disorders were collected from participants (n = 8463) in the 2007 Australian National Survey of Mental Health and Wellbeing using the Composite International Diagnostic Interview. RESULTS: Lifetime prevalence (95% confidence interval) of alcohol use, regular use, abuse and dependence were 94.1% (93.3-94.8%), 64.5% (62.9-66.2%), 18.7% (17.4-19.9%) and 4.0% (3.4-4.6%). Lifetime prevalence of cannabis use, abuse and dependence were 19.8% (18.6-20.9%), 4.4% (3.8-5.0%) and 1.9% (1.5-2.4%). Among those with the disorder, rates of remission from cannabis abuse, alcohol abuse, cannabis dependence and alcohol dependence were 90.5% (87.4-93.6%), 86.2% (83.8-88.7%), 79.6% (71.1-88.1%) and 53.8% (46.6-61.0%). Increases in the estimated proportion of people in the respondent's age cohort who used alcohol/cannabis as of a given age were significantly associated with most transitions from use through to remission beginning at the same age. DISCUSSION AND CONCLUSIONS: Clear associations were documented between cohort-level prevalence of substance use and personal risk of subsequent transitions of individuals in the cohort from use to greater substance involvement. This relationship remained significant over and above associations involving the individual's age of initiation. These findings have important implications for our understanding of the causal pathways into and out of problematic substance use. PMID- 29505683 TI - Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts. AB - Amidation of unprotected amino acids has been investigated using a variety of 'classical" coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions. PMID- 29505684 TI - Accuracy of left atrial bipolar voltages obtained by ConfiDENSE multielectrode mapping in patients with persistent atrial fibrillation. AB - INTRODUCTION: The ConfiDENSETM module (Carto3 v4) allows rapid annotation of endocardial electrograms acquired by multielectrode (ME) mapping. However, its accuracy in assessing atrial voltages is unknown. METHODS AND RESULTS: Two ConfiDENSETM left atrial voltage maps were created during continuous pacing in 20 patients undergoing catheter ablation for persistent AF using a ME lasso catheter and a contact force (CF) sensing ablation catheter. The automated tissue proximity indicator (TPI) filter was then applied to the ME map to yield a TPI map. Reference maps (RM) were created offline by a blinded observer by manually assessing all points against fidelity criteria. Bipolar voltages and proportion of low voltage points (< 0.5 mV) derived from the ME, CF, and TPI maps were compared with those derived from the RM. Note that 853 +/- 365 points, 252 +/- 184 points, and 144 +/- 73 were collected for ME, TPI, and CF maps, respectively, and 429 +/- 153 points were included in the RM. Voltages with CF and TPI maps were similar to those with RM (1.57 +/- 0.47 mV vs. 1.63 +/- 0.31 mV, P = 0.57 and 1.50 +/- 0.38 mV vs. 1.63 +/- 0.31 mV, P = 0.07, respectively), whereas ME maps showed a significantly lower mean voltage (1.00 +/- 0.22 mV, P < 0.001). As compared to RM maps (17 +/- 8%), low voltage points were significantly overestimated by the ME maps (50 +/- 9% (P < 0.001) and TPI maps (28 +/- 13% (P < 0.001), but not by the CF maps (22 +/- 14%, P = 0.17). CONCLUSION: Application of the TPI filter to ConfiDENSE maps significantly increases the quality of the voltage data, conserving a reasonable point density, but still overestimates low voltage points as compared to CF-sensing maps or maps reviewed manually. PMID- 29505685 TI - A narrow QRS irregular tachycardia: What is the mechanism? PMID- 29505686 TI - Orchid seed removal by ants in Neotropical ant-gardens. AB - Most plants that inhabit ant-gardens (AGs) are cultivated by the ants. Some orchids occur in AGs; however, it is not known whether their seeds are dispersed by AG ants because most orchid seeds are tiny and dispersed by wind. We performed in situ seed removal experiments, in which we simultaneously provided Azteca gnava ants with seeds of three AG orchid species and three other AG epiphyte species (Bromeliaceae, Cactaceae and Gesneriaceae), as well as the non-AG orchid Catasetum integerrimum. The seeds most removed were those of the bromeliad Aechmea tillandsioides and the gesneriad Codonanthe uleana, while seeds of AG orchids Coryanthes picturata, Epidendrum flexuosum and Epidendrum pachyrachis were less removed. The non-AG orchid was not removed. Removal values were positively correlated with the frequency of the AG epiphytes in the AGs, and seeds of AG orchids were larger than those of non-AG orchids, which should favour myrmecochory. Our data show that Azt. gnava ants discriminate and preferentially remove seeds of the AG epiphytes. We report for the first time the removal of AG orchid seeds by AG ants in Neotropical AGs. PMID- 29505687 TI - An Argon-Oxygen Covalent Bond in the ArOH+ Molecular Ion. AB - The OH+ cation is a well-known diatomic for which the triplet (3 Sigma- ) ground state is 50.5 kcal mol-1 more stable than its corresponding singlet (1 Delta) excited state. However, the singlet forms a strong donor-acceptor bond to argon with a bond energy of 66.4 kcal mol-1 at the CCSDT(Q)/CBS level, making the singlet ArOH+ cation 3.9 kcal mol-1 more stable than the lowest energy triplet complex. Both singlet and triplet isomers of this molecular ion were prepared in a cold molecular beam using different ion sources. Infrared photodissociation spectroscopy in combination with messenger atom tagging shows that the two spin isomers exhibit completely different spectral signatures. The ground state of ArOH+ is the predicted singlet with a covalent Ar-O bond. PMID- 29505688 TI - Improving the Activity and Stability of Human Galactokinase for Therapeutic and Biotechnological Applications. AB - Galactokinase catalyses the site- and stereospecific phosphorylation of alpha-d galactose. As such it has attracted interest as a biocatalyst for the introduction of phosphate groups into monosaccharides. However, attempts to broaden the substrate range of human galactokinase have generally resulted in substantially reduced activity. The enzyme also has biotechnological potential in enzyme replacement therapy (ERT) for type II galactosaemia. The return-to consensus approach can be used to identify residues that can be altered to increase protein stability and enzyme activity. This approach identified six residues of potential interest in human galactokinase. Some of the single consensus variants (M60V, D268E, A334S and G373S) increased the catalytic turnover of the enzyme, but none resulted in improved stability. When all six changes were introduced into the protein (M60V/M180V/D268E/A334S/R366Q/G373S), thermal stability was increased. Molecular dynamics simulations suggested that these changes altered the protein's conformation at key sites. The number of salt bridges and hydrogen bonds was also increased. Combining the six consensus variations with Y379W (a variant with greater substrate promiscuity) increased the stability of this variant and its turnover towards some substrates. Thus, the six consensus variants can be used to stabilise catalytically interesting variants of human galactokinase and might also be useful if the protein were to be used in ERT. PMID- 29505689 TI - Prolonged Reduction in Shoulder Strength after Transcutaneous Electrical Nerve Stimulation Treatment of Exercise-Induced Acute Muscle Pain. AB - OBJECTIVES: Transcutaneous electrical nerve stimulation (TENS) is commonly used for reducing musculoskeletal pain to improve function. However, peripheral nerve stimulation using TENS can alter muscle motor output. Few studies examine motor outcomes following TENS in a human pain model. Therefore, this study investigated the influence of TENS sensory stimulation primarily on motor output (strength) and secondarily on pain and disability following exercise-induced delayed-onset muscle soreness (DOMS). METHODS: Thirty-six participants were randomized to a TENS treatment, TENS placebo, or control group after completing a standardized DOMS protocol. Measures included shoulder strength, pain, mechanical pain sensitivity, and disability. TENS treatment and TENS placebo groups received 90 minutes of active or sham treatment 24, 48, and 72 hours post-DOMS. All participants were assessed daily. RESULTS: A repeated measures analysis of variance and post-hoc analysis indicated that, compared to the control group, strength remained reduced in the TENS treatment group (48 hours post-DOMS, P < 0.05) and TENS placebo group (48 hours post-DOMS, P < 0.05; 72 hours post-DOMS, P < 0.05). A mixed-linear modeling analysis was conducted to examine the strength (motor) change. Randomization group explained 5.6% of between-subject strength variance (P < 0.05). Independent of randomization group, pain explained 8.9% of within-subject strength variance and disability explained 3.3% of between-subject strength variance (both P < 0.05). DISCUSSION: While active and placebo TENS resulted in prolonged strength inhibition, the results were nonsignificant for pain. Results indicated that higher pain and higher disability were independently related to decreased strength. Regardless of the impact on pain, TENS, or even the perception of TENS, may act as a nocebo for motor output. PMID- 29505690 TI - Involvement of transient receptor potential vanilloid 2 in intra-oral incisional pain. AB - OBJECTIVE: To examine whether transient receptor potential vanilloid 2 (TRPV2) contributes to the changes in intra-oral thermal and mechanical sensitivity following the incision of buccal mucosa. MATERIALS AND METHODS: Buccal mucosal pain threshold was measured after the incision. Changes in the number of TRPV2 immunoreactive (IR) trigeminal ganglion (TG) neurons which innervate the whisker pad skin and buccal mucosa, changes in the number of isolectin B4 negative/isolectin B4-positive TRPV2-IR TG neurons which innervate the whisker pad skin and the buccal mucosa, and the effect of peripheral TRPV2 antagonism on the pain threshold of incisional whisker pad skin and buccal mucosa were examined after these injuries. RESULTS: Buccal mucosal pain hypersensitivities were induced on day 3 following the incision. The total number of TRPV2-IR TG neurons and the number of isolectin B4-negative TRPV2-IR TG neurons which innervate the whisker pad skin and buccal mucosa were increased. Buccal mucosal TRPV2 antagonism completely suppressed the heat and mechanical hypersensitivities, but not cold hypersensitivity. TRPV2 antagonist administration to the incisional whisker pad skin only partially suppressed pain hypersensitivities. CONCLUSION: The increased expression of TRPV2 in peptidergic TG neurons innervating the incisional buccal mucosa is predominantly involved in buccal mucosal heat hyperalgesia and mechanical allodynia following buccal mucosal incision. PMID- 29505691 TI - Elucidating the sponge stress response; lipids and fatty acids can facilitate survival under future climate scenarios. AB - Ocean warming (OW) and ocean acidification (OA) are threatening coral reef ecosystems, with a bleak future forecast for reef-building corals, which are already experiencing global declines in abundance. In contrast, many coral reef sponge species are able to tolerate climate change conditions projected for 2100. To increase our understanding of the mechanisms underpinning this tolerance, we explored the lipid and fatty acid (FA) composition of four sponge species with differing sensitivities to climate change, experimentally exposed to OW and OA levels predicted for 2100, under two CO2 Representative Concentration Pathways. Sponges with greater concentrations of storage lipid, phospholipids, sterols and elevated concentrations of n-3 and n-6 long-chain polyunsaturated FA (LC PUFA), were more resistant to OW. Such biochemical constituents likely contribute to the ability of these sponges to maintain membrane function and cell homeostasis in the face of environmental change. Our results suggest that n-3 and n-6 LC PUFA are important components of the sponge stress response potentially via chain elongation and the eicosanoid stress-signalling pathways. The capacity for sponges to compositionally alter their membrane lipids in response to stress was also explored using a number of specific homeoviscous adaptation (HVA) indicators. This revealed a potential mechanism via which additional CO2 could facilitate the resistance of phototrophic sponges to thermal stress through an increased synthesis of membrane-stabilizing sterols. Finally, OW induced an increase in FA unsaturation in phototrophic sponges but a decrease in heterotrophic species, providing support for a difference in the thermal response pathway between the sponge host and the associated photosymbionts. Here we have shown that sponge lipids and FA are likely to be an important component of the sponge stress response and may play a role in facilitating sponge survival under future climate conditions. PMID- 29505692 TI - Graft-derived exosomes. When small vesicles play a big role in transplant rejection. PMID- 29505693 TI - Predicting ion mobility collision cross sections directly from standard quantum chemistry software. AB - A method is proposed to predict ions' collision cross-sectional area from properties that are already evaluated in standard quantum chemistry software. Computed molecular isodensity surface areas recover the predictions of existing projection approximations. Computed solvent cavity areas give comparable accuracy. This provides a simplified workflow for assigning ion-mobility mass spectra. PMID- 29505694 TI - Risk assessment, dissipation behavior and persistence of quinalphos in/on green pea by gas chromatography with electron capture detector. AB - Chemical investigation was carried out to examine the risk assessment, dissipation behavior, persistence, and half-life period of quinalphos in/on green pea fruit by spraying quinalphos at fruiting stage followed by another application after 10-day interval. The samples were extracted by using the quick, easy, cheap, effective, rugged, and safe method, and the residues of quinalphos were analyzed by gas chromatography with electron capture detector. Herein, we report a novel, accurate, and cost-effective gas chromatography method for the determination of average deposits of quinalphos in/on green pea. The initial deposits and half-life of quinalphos were found to be 1.20 mg/kg and 2.77 days, respectively, following the application of insecticide. Residues of quinalphos reached below detection limit of 0.05 mg/kg after 10 days at recommended dosage. For risk assessment studies, the tenth day will be safe for consumers for consumption of green pea. The developed method is simple, selective, and repeatable, and it can be extended for quinalphos-based standardization of herbal formulations containing green pea and its use in pesticide industries. PMID- 29505695 TI - Age-adjusted D-dimer cut-off leads to more efficient diagnosis of venous thromboembolism in the emergency department: a comparison of four assays. AB - : Essentials Age-adjusted D-dimer cut-offs decrease the false positives in the elderly. Four D-dimer assays were compared in venous thromboembolism outpatients in an emergency ward. Age-adjusted cut-off resulted in improved specificity with maintained sensitivity for all assays. There was a substantial decrease in false positive results, especially in the older population. SUMMARY: Background The study compares different D-dimer assays and age-adjusted cut-offs in outpatients with suspected venous thromboembolism (VTE). The plasma concentration of this sensitive biomarker is increased by activated coagulation, but also by several conditions that are linked to an increased risk of VTE. One such condition is old age, which poses a common clinical problem where many prefer not to analyze D dimer in elderly patients. Age-adjusted cut-offs have been validated for both deep venous thrombosis (DVT) and pulmonary embolism, aiming to increase specificity without notably decreasing sensitivity. Objectives We evaluated four common D-dimer assays in parallel, with and without applying age-adjusted cut offs for VTE. Patients/methods The prospective single-center study was conducted in 940 outpatients attending the emergency department with clinically suspected pulmonary embolism or DVT. Four automated D-dimer assays were compared (Siemens INNOVANCE(r) , Roche Tina-quant, Medirox MRX and STA(r) -Liatest(r) D-Di PLUS). Results All assays performed with areas under the ROC curve (AUC) > 0.9 and maintained their sensitivities after implementation of age-adjusted cut-offs. Specificities increased by 6-7% and number needed to test decreased by < 0.3. The rate of false positive results decreased by 6% overall and by 10-20% for patients >= 70. Conclusions Age-adjusted cut-offs resulted in maintained high sensitivity and a modest improvement in specificity and number needed to test for all evaluated D-dimer assays. There was a significant reduction in false positive results, which reflects avoidable unnecessary imaging without any compromise of clinical safety. This suggests a potential to benefit the management of VTE in elderly patients, both clinically and economically. PMID- 29505696 TI - Histone Modification Patterns Using RPPA-Based Profiling Predict Outcome in Acute Myeloid Leukemia Patients. AB - Posttranslational histone tail modifications are known to play a role in leukemogenesis and are therapeutic targets. A global analysis of the level and patterns of expression of multiple histone-modifying proteins (HMP) in acute myeloid leukemia (AML) and the effect of different patterns of expression on outcome and prognosis has not been investigated in AML patients. Here we analyzed 20 HMP by reverse phase protein array (RPPA) in a cohort of 205 newly diagnosed AML patients. Protein levels were correlated with patient and disease characteristics, including survival and mutational state. We identified different protein clusters characterized by higher (more on) or lower (more off) expression of HMP, relative to normal CD34+ cells. On state of HMP was associated with poorer outcome compared to normal-like and a more off state. FLT3 mutated AML patients were significantly overrepresented in the more on state. DNA methylation related mutations showed no correlation with the different HMP states. In this study, we demonstrate for the first time that HMP form recurrent patterns of expression and that these significantly correlate with survival in newly diagnosed AML patients. PMID- 29505697 TI - Trends of hospitalizations for syncope/collapse in the United States from 2004 to 2013-An analysis of national inpatient sample. AB - INTRODUCTION: Syncope/collapse is a common reason for emergency department visits, and approximately 30-40% of these individuals are hospitalized. We examined changes in hospitalization rates, in-hospital mortality, and cost of syncope/collapse-related hospital care in the United States from 2004 to 2013. METHODS: We used the US Nationwide Inpatient Sample (NIS) from 2004 to 2013 to identify syncope/collapse-related hospitalizations using ICD-9, code 780.2, as the principal discharge diagnosis. Data are presented as mean +/- SEM. RESULTS: From 2004 to 2013, there was a 42% reduction in hospitalizations with a principal discharge diagnosis of syncope/collapse from 54,259 (national estimate 253,591) in 2004 to 31,427 (national estimate 156,820) in 2013 (P < 0.0001). The mean length of hospital stays decreased (2.88 +/- 0.04 days in 2004 vs. 2.54 +/- 0.02 in 2013; P < 0.0001), while in-hospital mortality did not change (0.28% in 2004 vs. 0.18% in 2013; P = 0.12). However, mean charges (inflation adjusted) for syncope/collapse-related hospitalization increased by 43.6% from $17,514 in 2004 to $25,160 in 2013 (P < 0.0001). The rates of implantation of permanent pacemakers and implantable cardioverter defibrillator remained low during these hospitalizations, and decreased over time (P for both < 0.0001). CONCLUSIONS: Hospitalization rates for syncope/collapse have decreased significantly in the US from 2004 to 2013. Despite a modest reduction in length of stay, the cost of syncope/collapse-related hospital care has increased. PMID- 29505698 TI - Crystal structure of the nitrosuccinate lyase CreD in complex with fumarate provides insights into the catalytic mechanism for nitrous acid elimination. AB - : Enzymes belonging to the aspartase/fumarase superfamily catalyze elimination of various functional groups from succinate derivatives and play an important role in primary metabolism and aromatic compound degradation. Recently, an aspartase/fumarase superfamily enzyme, CreD, was discovered in cremeomycin biosynthesis. This enzyme catalyzes the elimination of nitrous acid from nitrosuccinate synthesized from aspartate by CreE, a flavin-dependent monooxygenase. Nitrous acid generated by this pathway is an important precursor of the diazo group of cremeomycin. CreD is the first aspartase/fumarase superfamily enzyme that was reported to catalyze the elimination of nitrous acid, and therefore we aimed to analyze its reaction mechanism. The crystal structure of CreD was determined by the molecular replacement native-single anomalous diffraction method at 2.18 A resolution. Subsequently, the CreD-fumarate complex structure was determined at 2.30 A resolution by the soaking method. Similar to other aspartase/fumarase superfamily enzymes, the crystal structure of CreD was composed of three domains and formed a tetramer. Two molecules of fumarate were observed in one subunit of the CreD-fumarate complex. One of them was located in the active site pocket formed by three different subunits. Intriguingly, no histidine residue, which usually functions as a catalytic acid in aspartase/fumarase superfamily enzymes, was found around the fumarate molecule in the active site. Based on the mutational analysis, we propose a catalytic mechanism of CreD, in which Arg325 acts as a catalytic acid. DATABASES: The crystal structures of CreD and the CreD-fumarate complex were deposited to PDB under the accession numbers 5XNY and 5XNZ, respectively. ENZYMES: Nitrosuccinate lyase CreD, EC4.3. PMID- 29505700 TI - The association between patient-professional partnerships and self-management of chronic back pain: A mixed methods study. AB - BACKGROUND: Self-management is recommended for patients with chronic back pain. Health professionals' support for self-management can be more effective when working in partnership with patients. The aim of this study was to investigate the associations between patient-professional partnerships and the self management of chronic back pain. METHODS: An explanatory sequential mixed methods study was undertaken. Adults with chronic back pain referred to pain management clinics participated at baseline and 3-month follow-up. Their pain severity, partnerships with health professionals and self-management ability were measured. Hierarchical linear regression was undertaken to examine the strength of the associations between partnerships and self-management. A subsample was interviewed about experiences of the impact of patient-professional partnerships on their self-management ability, using a grounded theory approach. RESULTS: A total of 147 patients were recruited and 103 (70%) patients completed the follow up. A strong association (p < 0.001) was detected between patient-professional partnerships and all dimensions of self-management ability. This was validated by interviews with a subsample of 26 patients. Four themes emerged as follows: connecting with health professionals, being supported through partnerships, feeling positive and making progress towards self-management, and acknowledging the impact but feeling no difference. CONCLUSIONS: Developing a partnership in care may improve patients' ability to gain knowledge, manage side effects and symptoms and adhere to treatment. It helped strengthen health professionals' support and produce a sense of safety for patients. Guiding health professionals in building partnerships where expectations are acknowledged and tailored information and support are provided could be considered as part of the standard education and training. SIGNIFICANCE: This study identified and validated strong associations between patient-professional partnerships and self-management. Support for self-management alone may not be sufficient, and building partnerships where patients and professionals work together towards agreed goals make an essential contribution to helping increase patients' ability to self manage chronic back pain. PMID- 29505699 TI - Translating Immunopeptidomics to Immunotherapy-Decision-Making for Patient and Personalized Target Selection. AB - Immunotherapy is revolutionizing cancer treatment and has shown success in particular for tumors with a high mutational load. These effects have been linked to neoantigens derived from patient-specific mutations. To expand efficacious immunotherapy approaches to the vast majority of tumor types and patient populations carrying only a few mutations and maybe not a single presented neoepitope, it is necessary to expand the target space to non-mutated cancer associated antigens. Mass spectrometry enables the direct and unbiased discovery and selection of tumor-specific human leukocyte antigen (HLA) peptides that can be used to define targets for immunotherapy. Combining these targets into a warehouse allows for multi-target therapy and accelerated clinical application. For precise personalization aimed at optimally ensuring treatment efficacy and safety, it is necessary to assess the presence of the target on each individual patient's tumor. Here we show how LC-MS paired with gene expression data was used to define mRNA biomarkers currently being used as diagnostic test IMADETECTTM for patient inclusion and personalized target selection within two clinical trials (NCT02876510, NCT03247309). Thus, we present a way how to translate HLA peptide presentation into gene expression thresholds for companion diagnostics in immunotherapy considering the peptide-specific correlation to its encoding mRNA. PMID- 29505701 TI - Telediagnosis of oral lesions in primary care: The EstomatoNet Program. AB - OBJECTIVE: The diagnosis of oral lesions is often challenging for primary healthcare providers, which explains the high number of referrals to specialist care. This favors increases in waiting lines and delays in diagnosis, contributing to high mortality rates from oral cancer. This study aimed to summarize the experience of the EstomatoNet, a telediagnosis program catering to primary care dentists and physicians from southern Brazil. STUDY DESIGN: This exploratory study included all queries received by EstomatoNet from June 2015 to December 2016. Health providers (71 dentists and 18 physicians from primary care) submitted requests including clinical information and photographs of oral lesions by means of a cloud-based platform. Specialized oral medicine teleconsultants received the data, conveyed a diagnostic hypothesis, and conveyed management recommendations. RESULTS: Actinic cheilitis (n = 41, 15.8%), squamous cell carcinoma (n = 22, 8.5%), and inflammatory hyperplasia (21, 8.1%) were the most frequent diagnoses. Teleconsultants recommended referral to specialists in 42.9% of the cases, total biopsy in 23.6%, and follow-up in 16.2%. After the EstomatoNet use, the intention to refer the patients to face-to-face consultation reduced from 96.9% to 35.1%. CONCLUSION: Telediagnosis for oral lesions is feasible and has potential to improve the quality of primary health care by bridging the gap between primary and specialized health care. PMID- 29505702 TI - Fibrinolytic abnormality associated with progression of pediatric solid tumor. AB - BACKGROUND: Thrombosis and hemorrhage are serious complications of pediatric solid tumor, and enhanced fibrinolysis associated with disseminated intravascular coagulation (DIC) is often observed. Fibrinolytic enzymes also play an important role in metastasis. Limited information is available, however, on the assessment of overall hemostatic function in children with malignant solid tumor. METHODS: We have investigated the comprehensive hemostatic potential in these circumstances using simultaneous thrombin/plasmin generation assay (T/P-GA). Endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) were measured using T/P-GA in six children newly diagnosed with solid tumor at regular intervals during chemotherapy at the present hospital from 2013 to 2016. Four patients with metastasis were defined as the advanced group, and the other patients were defined as the non-advanced group. RESULTS: In the advanced group, the ratio of P-Peak to normal was higher than the slightly increased ratio of T EP to normal (range, 1.2-2.1 vs 1.1-1.5, respectively). In the non-advanced group, however, the P-Peak ratio was relatively lower than the slightly increased T-EP ratio (range, 1.0-1.5 vs 1.1-1.5, respectively). Fibrin-fibrinogen degradation product was elevated in all patients except in one non-advanced brain tumor patient during this induction therapy (maximum, 11.6-161 MUg/mL). CONCLUSIONS: Uncontrolled fibrinolysis together with an imbalance between coagulation and fibrinolytic potential might lead to DIC. Further research is warranted to clarify comprehensive hemostatic function in pediatric patients with solid tumors to establish optimal supportive therapy, and possibly limit tumor progression in these critical disorders. PMID- 29505703 TI - Comorbidity of mitochondrial disease and dementia in patients with idiopathic polyneuropathy. AB - BACKGROUND AND PURPOSE: Studying the comorbidities of chronic idiopathic axonal polyneuropathy (CIAP) might help to better understand its etiopathogenesis. We aimed to assess the associations of mitochondrial disease (MD), Alzheimer's disease (AD) and vascular dementia (VD) with CIAP. METHODS: In this nested case control study we included 2659 patients with CIAP identified from the Swedish Patient Register and 13 295 age- and sex-matched controls to assess the associations of MD, AD and VD with the subsequent risk of CIAP. We also conducted a follow-up study of the cases and controls to assess the risk of MD, AD or VD among patients with CIAP in comparison to individuals without CIAP. RESULTS: Individuals with MD had an increased risk of subsequent CIAP [odds ratio (OR), 4.17; 95% confidence intervals (CI), 1.27-13.65], whereas individuals with AD and VD had a decreased risk (OR, 0.18; 95% CI, 0.06-0.59 and OR, 0.17; 95% CI, 0.04 0.69). Patients with CIAP had a ninefold increased risk of subsequent MD [hazard ratio (HR), 9.37; 95% CI, 4.00-21.93], twofold increased risk of VD (HR, 1.97; 95% CI, 1.23-3.16), but no increased risk of AD (HR, 1.33; 95% CI, 0.89-1.98) compared with individuals without CIAP. CONCLUSIONS: We found a higher risk of MD among patients with CIAP, both before and after the diagnosis of CIAP. We found a higher risk of VD, but not AD, after the diagnosis of CIAP. The lower risks of AD and VD before CIAP might be due to a reduced surveillance of CIAP symptoms among patients with dementia. PMID- 29505704 TI - From laboratory to the field: consistent effects of experience on host location by the fruit fly parasitoid Diachasmimorpha kraussii (Hymenoptera: Braconidae). AB - Associative learning is well documented in Hymenopteran parasitoids, where it is thought to be an adaptive mechanism for increasing successful host location in complex environments. Based on this learning capacity, it has been suggested that providing prerelease training to parasitoids reared for inundative release may lead to a subsequent increase in their efficacy as biological control agents. Using the fruit fly parasitoid Diachasmimorpha krausii we tested this hypothesis in a series of associative learning experiments which involved the parasitoid, two host fruits (tomatoes and nectarine), and one host fly (Bactrocera tryoni). In sequential Y-tube olfactometer studies, large field-cage studies, and then open field studies, naive wasps showed a consistent preference for nectarines over tomatoes. The preference for nectarines was retained, but not significantly increased, for wasps which had prior training exposure to nectarines. However, and again consistently at all three spatial scales, prior experience on tomatoes led to significantly increased attraction to this fruit by tomato-trained wasps, including those liberated freely in the environment. These results, showing consistency of learning at multiple spatial scales, gives confidence to the many laboratory-based learning studies which are extrapolated to the field without testing. The experiment also provides direct experimental support for the proposed practice of enhancing the quality of inundatively released parasitoids through associative learning. PMID- 29505705 TI - Have reducing tonsillectomy rates in England led to increasing incidence of invasive Group A Streptococcus infections in children? AB - OBJECTIVES: To determine whether there is a correlation between falling tonsillectomy numbers and increasing numbers of tonsillitis admissions and invasive Group A beta-haemolytic streptococcus (iGAS) infection in children aged 14 and under in England. DESIGN: An observational cross-sectional study was performed. SETTING: The data extracted covered the period from 1991 until 2014. PARTICIPANTS: Hospital admissions for tonsillectomies, tonsillitis/pharyngitis and all diagnoses of iGAS in children aged 14 and under who had a tonsillectomy. MAIN OUTCOME MEASURES: Correlation between trends in tonsillectomies, tonsillitis/pharyngitis and iGAS. RESULTS: Across all age groups, there was a dramatic reduction in the total number of tonsillectomies performed in England from 28 309 in 1990/1991, down to 6327 in 2013/2014 (77.7% reduction). The numbers of hospital admissions for management of acute tonsillitis and pharyngitis have risen dramatically. iGAS numbers have increased steadily over this time period and more than doubled in children aged 14 and under. There are significant negative correlations between the trend in iGAS infections and numbers of tonsillectomies in all ages. There are also strong positive correlations between the trend in numbers of tonsillitis episodes and the number of iGAS infections in all under 14-year groups; the strongest correlation was seen in the 1- to 4-year age group (+0.92 Pearson correlation coefficient). CONCLUSIONS: There appears to be a correlation between falling tonsillectomy numbers, increasing hospital admissions with tonsillitis and rising iGAS infection in England. Further studies are required to assess the aetiological role of tonsillitis in predisposing to iGAS infection and the potential societal benefit of tonsillectomies. PMID- 29505706 TI - Pseudohalogenogermylenes versus Halogenogermylenes: Difference in their Complexation Behavior towards Group 6 Metal Carbonyls. AB - Pseudohalogenogermylenes [(iBu)2 ATI]GeY (Y=NCO 4, NCS 5) show different coordination behavior towards group 6 metal carbonyls in comparison to the corresponding halogenogermylenes [(iBu)2 ATI]GeX (X=F 1, Cl 2, Br 3) (ATI=aminotroponiminate). The reactions of compounds 4-5 and 1-3 with cis-[M(CO)4 (COD)] (M=Mo, W, COD=cyclooctadiene) gave trans-germylene metal complexes {[(iBu)2 ATI]GeY}2 M(CO)4 (Y=NCO, M=Mo 6, W 11; Y=NCS, M=Mo 7) and cis-germylene metal complexes {[(iBu)2 ATI]GeX}2 M(CO)4 (M=Mo, X=F 8, Cl 9, Br 10; M=W, X=Cl 12), respectively. Theoretical studies on compounds 7 and 9 reveal that donor acceptor interactions from Mo to Ge atoms are better stabilized in the observed trans and cis geometries than in the hypothetical cis and trans structures, respectively. PMID- 29505707 TI - Biovolatilization of Arsenic as Arsines from Seawater. AB - Marine sources of arsenic to the atmosphere are normally dismissed as minor. Here we show that arsenic can be biovolatilized from seawater, and that biovolatilzation is based on organic arsenic species present in the seawater. Even though inorganic arsenic is in great excess in seawaters, it is trimethylarsine (TMA) that is the primary biovolatilized product, with dimethylarsine (DMA) also observed if dimethylarsinic acid (DMAA) is spiked into seawaters. With respect to budgets, 0.04% of the total arsenic in the seawater was biovolatilized over a 2-week incubation period. To test the environmental significance of this finding, wet deposition was analyzed for arsenic species at coastal locations, one of which was the origin of the seawater. It was found that the oxidized product of TMA, trimethylarsine oxide (TMAO), and to a less extent DMAA were widely present. When outputs for arsines (0.9 nmol/m2/d) from seawater and inputs from wet deposition (0.3-0.5 nmol/m2/d) were compared, they were of the same order of magnitude. These findings provide impetus to reexamining the global arsenic cycle, as there is now a need to determine the flux of arsines from the ocean to the atmosphere. PMID- 29505708 TI - Insight into the Aggregation Capacity of Anammox Consortia during Reactor Start Up. AB - Anammox aggregates have been extensively observed in high-efficiency nitrogen removal reactors, yet the variation and inherent cause of its aggregation capacity related to reactor operation are still unknown. Here, we used microbial detection, metabolomics, extended Derjaguin-Landau-Verwey-Overbeek theory, and multivariate statistical analysis to address this issue. The aggregation capacity of anammox consortia varied periodically during reactor operation, which was determined by the hydrophobic force and the ratio of extracellular protein (PN) to extracellular polysaccharides (PS). Fundamentally, it related to the variation of polysaccharides degradation bacteria abundance and the discrepancy of consortia metabolism. Specifically, the distinguishable up-regulation of the amino acids Phe, Leu, Ala, Thr, Gly, Glu, and Val potentially contributed to the high biosynthesis of extracellular PN. Together with the reduced extracellular PS production that was regulated via the uridine diphosphate (UDP)- N-acetyl-d glucosamine and UDP- N-acetyl-d-galactosamine pathways, the elevated extracellular PN-to-PS ratio resulted in the obviously increased extracellular hydrophobicity and aggregation capacity. Additionally, the overtly enriched phosphatidylethanolamine biosynthesis pathway was also vital to increasing extracellular hydrophobicity to accelerate aggregation. Understanding aggregation capacity variation is useful for advancing anammox aggregation for its application in wastewater treatment. PMID- 29505709 TI - Patterning of Structurally Anisotropic Composite Hydrogel Sheets. AB - Compositional and structural patterns play a crucial role in the function of many biological tissues. In the present work, for nanofibrillar hydrogels formed by chemically cross-linked cellulose nanocrystals (CNC) and gelatin, we report a microextrusion-based 3D printing method to generate structurally anisotropic hydrogel sheets with CNCs aligned in the direction of extrusion. We prepared hydrogels with a uniform composition, as well as hydrogels with two different types of compositional gradients. In the first type of gradient hydrogel, the composition of the sheet varied parallel to the direction of CNC alignment. In the second hydrogel type, the composition of the sheet changed orthogonally to the direction of CNC alignment. The hydrogels exhibited gradients in structure, mechanical properties, and permeability, all governed by the compositional patterns, as well as cytocompatibility. These hydrogels have promising applications for both fundamental research and for tissue engineering and regenerative medicine. PMID- 29505710 TI - Field-Induced Antipolar-Polar Structural Transformation and Giant Electrostriction in Organic Crystal. AB - The field-induced antipolar-polar structural transition in an organic antiferroelectric 2-trifluoromethylnaphthimidazole crystal is investigated by performing synchrotron X-ray diffraction. The polarities of all of the hydrogen bonded chains become parallel with each other in the presence of an external electric field. The switching is accompanied by a giant electrostriction, which provides 1 order of magnitude larger strain than the piezoelectric strain of the organic ferroelectrics: croconic acid and poly(vinylidene fluoride); however, it is comparable to those of typical commercial piezoelectric ceramics. The crystal structure analysis with electric field shows that the origin of the observed giant electrostriction can be attributed to the shear strain that emerges from the polarity switching of the hydrogen-bonded chains. The antipolar-polar structural transition in antiferroelectrics could be employed for the development of high-performance electrostrictive organic materials. PMID- 29505711 TI - mPEG5k- b-PLGA2k/PCL3.4k/MCT Mixed Micelles as Carriers of Disulfiram for Improving Plasma Stability and Antitumor Effect in Vivo. AB - The clinical application of disulfiram (DSF) in cancer treatments is hindered by its rapid degradation in the blood circulation. In this study, methoxy poly(ethylene glycol)- b-poly(lactide- co-glycolide)/poly(epsilon-caprolactone) (mPEG5k- b-PLGA2k/PCL3.4k) micelles were developed for encapsulation of DSF by using the emulsification-solvent diffusion method. Medium chain triglyceride (MCT) was incorporated into the mixed polymeric micelles to improve drug loading by reducing the core crystallinity. Differential scanning calorimetry (DSC) results implied that DSF is likely present in an amorphous form within the micelles, and is well dispersed. DSF is encapsulated within the core and the reservoir is stabilized by the hydrophilic shell to prevent rapid diffusion of DSF from the core. The DSF mixed micelles (DSF-MMs) showed good drug loading (5.90%) and a well-controlled particle size (86.4 +/- 13.2 nm). The mixed micelles efficiently protected DSF from degradation in plasma, with 58% remaining after 48 h, while almost 90% of DSF was degraded after the same period for the DSF solution (DSF-sol), which was used as a control. The pharmacokinetics study showed that the maximum plasma concentration and bioavailability of DSF were improved by using the DSF-MMs (2 and 2.5 times that of the DSF-sol). The TIRs (tumor inhibition rates) of 5-FU, DSF-sol, and DSF-MMs were 63.46, 19.57, and 69.98%, respectively, implying that DSF-MMs slowed the growth of a H22 xenograft tumor model effectively. PMID- 29505712 TI - Design of Free Triblock Polylysine- b-Polyleucine- b-Polylysine Chains for Gene Delivery. AB - Mixing cationic polymer chains with anionic DNA chains in solution results in the polymer/DNA complexes (also known as polyplexes). We recently confirmed that it is those noncomplexed cationic chains free in the mixture that promote the gene transfection, leading to a hypothesis: free cationic chains adsorbed on various anionic membranes interfere with the signal protein interaction, disrupt the intervesicular fusion, and block the endolysosome pathway so that the plasmid DNA (pDNA) chains have a higher chance to enter the nucleus. Accordingly, we design and synthesize linear cationic-hydrophobic-cationic triblock polylysine (K)- b polyleucine (L)- b-polylysine (K) as free cationic chains by using natural protamine to condense the pDNA. The hydrophobic middle L-block helps its insertion into the membrane, while the interaction of the two cationic side K blocks with the signal proteins helps the escape of the polyplexes from the lysosome entrapment. We studied the transfection efficiency of these copolymers with different block lengths. We found the optimal length of blocks K and L that allows the free triblock cationic copolymer chains to effectively enhance the gene transfection process. A combination of copolypeptides and protamine provides a new kind of biocompatible and nontoxic gene vectors made of only nontoxic peptides. PMID- 29505713 TI - Consensus Classification Using Non-Optimized Classifiers. AB - Classifying samples into categories is a common problem in analytical chemistry and other fields. Classification is usually based on only one method, but numerous classifiers are available with some being complex, such as neural networks, and others are simple, such as k nearest neighbors. Regardless, most classification schemes require optimization of one or more tuning parameters for best classification accuracy, sensitivity, and specificity. A process not requiring exact selection of tuning parameter values would be useful. To improve classification, several ensemble approaches have been used in past work to combine classification results from multiple optimized single classifiers. The collection of classifications for a particular sample are then combined by a fusion process such as majority vote to form the final classification. Presented in this Article is a method to classify a sample by combining multiple classification methods without specifically classifying the sample by each method, that is, the classification methods are not optimized. The approach is demonstrated on three analytical data sets. The first is a beer authentication set with samples measured on five instruments, allowing fusion of multiple instruments by three ways. The second data set is composed of textile samples from three classes based on Raman spectra. This data set is used to demonstrate the ability to classify simultaneously with different data preprocessing strategies, thereby reducing the need to determine the ideal preprocessing method, a common prerequisite for accurate classification. The third data set contains three wine cultivars for three classes measured at 13 unique chemical and physical variables. In all cases, fusion of nonoptimized classifiers improves classification. Also presented are atypical uses of Procrustes analysis and extended inverted signal correction (EISC) for distinguishing sample similarities to respective classes. PMID- 29505714 TI - Hot-Pressing Method To Prepare Imidazole-Based Zn(II) Metal-Organic Complexes Coatings for Highly Efficient Air Filtration. AB - Particulate matters (PMs) air pollution has become a serious environmental issue due to its great threat to human health. Herein, metal-organic complexes PBM-Zn1 and PBM-Zn2 coatings (noted as PBM-Zn-Filter) have been produced by the hot pressing method on various substrates for the first time. Layer-by-layer PBM-Zn Filters were also obtained through varying hot-pressing cycles. The obtained PBM Zn-Filters with high robustness show excellent performance in PMs removal. In particular, benefiting from thelarger conjugation system, micropore structure, lower pressure drop, higher electrostatic potential zeta, and electron cloud exposed metal center of PBM-Zn2 (DFT calculations), PBM-Zn2@melamine foam-4 gives the highest removal rates, PM2.5:99.5% +/- 1.2% and PM10:99.3% +/- 1.1%, and the removal efficiency for capture PM2.5 and PM10 particles in cigarette smoke were both retained at high levels (>95.5%) after 24 h tests. More importantly, a homemade mask is made up by imbedding the PBM-Zn2@melamine foam-4 into a commercial breathing mask, which shows higher removal efficiency, lower pressure drop, smaller thickness, and higher quality factor than two commercial breathing masks, the PMs removal efficiencies for both PM2.5 and PM10 are 99.6% +/- 0.5% and 99.4% +/- 0.8%, and acceptable air resistance are demonstrated. PMID- 29505715 TI - Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information. AB - Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability, and high protein binding, however, did not allow reaching of the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD). Lacking structural information on the receptor-ligand complex, we implemented a group efficiency (GE) based strategy and identified a new fragment like lead (60) with more balanced profile. Significant improvement achieved on the druglike properties nominated the compound for in vivo proof of concept studies that revealed the chemotype being a promising PAM lead targeting mGluR2 receptors. PMID- 29505716 TI - Air Quality and Health Impacts of an Aviation Biofuel Supply Chain Using Forest Residue in the Northwestern United States. AB - Forest residue is a major potential feedstock for second-generation biofuel; however, little knowledge exists about the environmental impacts of the development and production of biofuel from such a feedstock. Using a high resolution regional air quality model, we estimate the air quality impacts of a forest residue based aviation biofuel supply chain scenario in the Pacific Northwestern United States. Using two potential supply chain regions, we find that biomass and biofuel hauling activities will add <1% of vehicle miles traveled to existing traffic, but the biorefineries will add significant local sources of NO x and CO. In the biofuel production scenario, the regional average increase in the pollutant concentration is small, but 8-hr maximum summer time O3 can increase by 1-2 ppb and 24-hr average maximum PM2.5 by 2 MUg/m3. The alternate scenario of slash pile burning increased the multiday average PM2.5 by 2-5 MUg/m3 during a winter simulation. Using BenMAP, a health impact assessment tool, we show that avoiding slash pile burning results in a decrease in premature mortality as well as several other nonfatal and minor health effects. In general, we show that most air quality and health benefits result primarily from avoided slash pile burning emissions. PMID- 29505717 TI - Kinetic Modeling of Accelerated Stability Testing Enabled by Second Harmonic Generation Microscopy. AB - The low limits of detection afforded by second harmonic generation (SHG) microscopy coupled with image analysis algorithms enabled quantitative modeling of the temperature-dependent crystallization of active pharmaceutical ingredients (APIs) within amorphous solid dispersions (ASDs). ASDs, in which an API is maintained in an amorphous state within a polymer matrix, are finding increasing use to address solubility limitations of small-molecule APIs. Extensive stability testing is typically performed for ASD characterization, the time frame for which is often dictated by the earliest detectable onset of crystal formation. Here a study of accelerated stability testing on ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, has been conducted. Under the condition for accelerated stability testing at 50 degrees C/75%RH and 40 degrees C/75%RH, ritonavir crystallization kinetics from amorphous solid dispersions were monitored by SHG microscopy. SHG microscopy coupled by image analysis yielded limits of detection for ritonavir crystals as low as 10 ppm, which is about 2 orders of magnitude lower than other methods currently available for crystallinity detection in ASDs. The four decade dynamic range of SHG microscopy enabled quantitative modeling with an established (JMAK) kinetic model. From the SHG images, nucleation and crystal growth rates were independently determined. PMID- 29505718 TI - Computer-Aided Formulation Design for a Highly Soluble Lutein-Cyclodextrin Multiple-Component Delivery System. AB - Cyclodextrin (CD) complexation is widely used for the solubilization of poorly soluble drugs in the pharmaceutical industry. Current research was to develop a highly soluble lutein-cyclodextrin multiple-component delivery system (lutein-CD MCDS) by combined modeling and experimental approaches. Both phase solubility diagram and molecular dynamics (MD) simulation results revealed that the interactions between lutein and CDs were very weak, which confirmed the insignificant solubility improvement of lutein-CD binary system. On the basis of theoretical calculation and preliminary CD studies, lutein-CD-MCDS was developed with over 400-fold solubility improvement after formulation screening. MD simulation indicated that the auxiliary polymers of TWEEN 80 and poloxamer 188 in the lutein-CD-MCDS introduced bridged interaction between lutein and gamma-CD to increase the solubility, dissolution rate, and stability of the complex. The lutein-CD-MCDS was characterized by in vitro dissolution test, differential scanning colorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and powder X-ray diffraction (PXRD). Moreover, lutein-CD-MCDS had significantly higher uptake in Caco-2 cells than free lutein. The relative bioavailability of the lutein-CD-MCDS increased to 6.6 fold compared to pure lutein, and to 1.2-fold compared with commercial lutein soft capsules. In conclusion, the highly soluble lutein-CD-MCDS with significant improvement in both the solubility and bioavailability was developed and characterized by combined modeling and experimental approaches. Our research indicates that computer-aided formulation design is a promising approach for future formulation development. PMID- 29505719 TI - The Oxygenic Photogranule Process for Aeration-Free Wastewater Treatment. AB - This study presents the oxygenic photogranule (OPG) process, a light-driven process for wastewater treatment, developed based on photogranulation of filamentous cyanobacteria, nonphototrophic bacteria, and microalgae. Unlike other biogranular processes requiring airlift or upflow-based mixing, the OPG process was operated in stirred-tank reactors without aeration. Reactors were seeded with hydrostatically grown photogranules and operated in a sequencing-batch mode for five months to treat wastewater. The new reactor biomass propagated with progression of photogranulation under periodic light/dark cycles. Due to effective biomass separation from water, the system was operated with short settling time (10 min) with effective decoupling of hydraulic and solids retention times (0.75 d vs 21-42 d). During quasi-steady state, the diameter of the OPGs ranged between 0.1 and 4.5 mm. The reactors produced effluents with average total chemical oxygen demand less than 30 mg/L. Nitrogen removal (28-71%) was achieved by bioassimilation and nitrification/denitrification pathways. Oxygen needed for the oxidation of organic matter and nitrification was produced by OPGs at a rate of 12.6 +/- 2.4 mg O2/g biomass-h. The OPG system presents a new biogranule process, which can potentially use simple mixing and natural light to treat wastewater. PMID- 29505720 TI - A Novel Mechanism for Calmodulin-Dependent Inactivation of Transient Receptor Potential Vanilloid 6. AB - The paralogues TRPV5 and TRPV6 belong to the vanilloid subfamily of the transient receptor potential (TRP) superfamily of ion channels, and both play an important role in overall Ca2+ homeostasis. The functioning of the channels centers on a tightly controlled Ca2+-dependent feedback mechanism in which the direct binding of the universal Ca2+-binding protein calmodulin (CaM) to the channel's C terminal tail is required for channel inactivation. We have investigated this interaction at the atomic level and propose that under basal cellular Ca2+ concentrations CaM is constitutively bound to the channel's C-tail via CaM C-lobe only contacts. When the cytosolic Ca2+ concentration increases charging the apo CaM N-lobe with Ca2+, the CaM:TRPV6 complex rearranges and the TRPV6 C-tail further engages the CaM N-lobe via a crucial interaction involving L707. In a cellular context, mutation of L707 significantly increased the rate of channel inactivation. Finally, we present a model for TRPV6 CaM-dependent inactivation, which involves a novel so-called "two-tail" mechanism whereby CaM bridges two TRPV6 monomers resulting in closure of the channel pore. PMID- 29505721 TI - Uniform Ordered Two-Dimensional Mesoporous TiO2 Nanosheets from Hydrothermal Induced Solvent-Confined Monomicelle Assembly. AB - Two-dimensional (2D) nanomaterials have been the focus of substantial research interest recently owing to their fascinating and excellent properties. However, 2D porous materials have remained quite rare due to the difficulty of creating pores in 2D nanostructures. Here, we have synthesized a novel type of single layered 2D mesoporous TiO2 nanosheets with very uniform size and thickness as well as ordered mesostructure from an unprecedented hydrothermal-induced solvent confined assembly approach. The F127/TiO2 spherical monomicelles are first formed and redispersed in ethanol and glycerol, followed by a hydrothermal treatment to assemble these subunits into single-layered 2D mesostructure owing to the confinement effect of highly adhered glycerol solvent. The obtained 2D mesoporous TiO2 nanosheets have a relative mean size at around 500 * 500 nm and can be randomly stacked into a bulk. The TiO2 nanosheets possess only one layer of ordered mesopores with a pore size of 4.0 nm, a very high surface area of 210 m2 g-1 and a uniform thickness of 5.5 nm. The thickness can be further manipulated from 5.5 to 27.6 nm via simply tuning precursor concentration or solvent ratio. Due to the well-defined 2D morphology and large mesoporosity as well as crystalline anatase mesopore walls, these uniform TiO2 nanosheets are capable of providing large accessible voids for sodium ion adsorption and intercalation as well as preventing volume expansion. As expected, these mesoporous TiO2 nanosheets have exhibited an excellent reversible capacity of 220 mAh g-1 at 100 mA g-1 as sodium-ion battery anodes, and they can retain at 199 mAh g-1 after numerous cycles at different current densities. The capacity is retained at 44 mAh g-1 even at a large current density of 10 A g-1 after 10 000 cycles, demonstrating a remarkable performance for energy storage. PMID- 29505722 TI - Stability of Polydopamine Coatings on Gold Substrates Inspected by Surface Plasmon Resonance Imaging. AB - Polydopamine (PDA)-based surface modification has been used in a variety of fields. However, a vague impression on the stability of PDA still exists due to a lack of systematic studies. To ascertain the issue and make better use of this surface modification method, a technique of surface plasmon resonance imaging (SPRi) was exploited to study the stability of PDA coated on gold surface. The results showed that PDA-coating stability was largely dependent on the pH of aqueous solutions, giving detachment ratios up to 66% and 80% at pH 1.0 and pH 14.0, respectively. However, increasing the ionic strength of aqueous solutions could reduce the detachment of PDA in strong acid and strong alkali conditions. Besides, organic solvents also made a difference on the PDA-coating stability. Among the tested 10 kinds of organic solvents, including n-hexane, toluene, ethyl ether, tetrahydrofuran, ethyl acetate, isopropanol, acetone, acetonitrile, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), DMSO caused the most serious detachment of PDA, up to 56%, followed by DMF with a detachment ratio of 31%. Ultrasonication caused less than 10% detachment of the coated PDA. It should be mentioned that the PDA coatings deposited on gold surface were not detached completely in all the test conditions, even at pH 14.0 (ca. 20% PDA retained). In alkaline conditions, detachment competes with further polymerization, which gave a slight increase of the SPRi signals at pH 9.0-11.0. Based on the obtained information about PDA-coating stability, thickness-controllable and alkali resistant PDA coatings were prepared. Moreover, the alkali-resistant PDA coatings remained reactive to biomolecules, supporting further functionalization of PDA coatings. PMID- 29505724 TI - Transition-Metal-Free C-Vinylation of Ketones with Acetylenes: A Quantum-Chemical Rationalization of Similarities and Differences in Catalysis by Superbases MOH/DMSO and tBuOM/DMSO (M = Na, K). AB - Transition-metal-free C-vinylation of acetone with phenylacetylene catalyzed by superbases MOH/DMSO and tBuOM/DMSO (M = Na, K) has been theoretically evaluated in the B3LYP/6-311++G**//B3LYP/6-31+G* approach to rationalize similarities and differences in activity of the above catalytic systems. The close solvate surroundings of sodium and potassium tert-butoxides have been studied. Formation of tBuOM. nDMSO complexes and their structure and thermodynamic stability are discussed in comparison with similar complexes of alkali-metal hydroxides MOH. nDMSO. Activation barriers of the title reaction in the presence of tBuOM. nDMSO complexes are found to be less than those with MOH. nDMSO complexes participating. PMID- 29505725 TI - Macromolecule-Network Electrostatics Controlling Delivery of the Biotherapeutic Cell Modulator TIMP-2. AB - Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an endogenous 22 kDa proteinase inhibitor, demonstrating antitumorigenic, antimetastatic and antiangiogenic activities in vitro and in vivo. Recombinant TIMP-2 is currently undergoing preclinical testing in multiple, murine tumor models. Here we report the development of an inert, injectable peptide hydrogel matrix enabling encapsulation and sustained release of TIMP-2. We studied the TIMP-2 release profile from four beta-hairpin peptide gels of varying net electrostatic charge. A negatively charged peptide gel (designated AcVES3) enabling encapsulation of 4 mg/mL of TIMP-2, without effects on rheological properties, facilitated the slow sustained release (0.9%/d) of TIMP-2 over 28 d. Released TIMP-2 is structurally intact and maintains the ability to inhibit MMP activity, as well as suppress lung cancer cell proliferation in vitro. These findings suggest that the AcVES3 hydrogel will be useful as an injectable vehicle for systemic delivery of TIMP-2 in vivo for ongoing preclinical development. PMID- 29505723 TI - Detection and Quantification of Graphene-Family Nanomaterials in the Environment. AB - An increase in production of commercial products containing graphene-family nanomaterials (GFNs) has led to concern over their release into the environment. The fate and potential ecotoxicological effects of GFNs in the environment are currently unclear, partially due to the limited analytical methods for GFN measurements. In this review, the unique properties of GFNs that are useful for their detection and quantification are discussed. The capacity of several classes of techniques to identify and/or quantify GFNs in different environmental matrices (water, soil, sediment, and organisms), after environmental transformations, and after release from a polymer matrix of a product is evaluated. Extraction and strategies to combine methods for more accurate discrimination of GFNs from environmental interferences as well as from other carbonaceous nanomaterials are recommended. Overall, a comprehensive review of the techniques available to detect and quantify GFNs are systematically presented to inform the state of the science, guide researchers in their selection of the best technique for the system under investigation, and enable further development of GFN metrology in environmental matrices. Two case studies are described to provide practical examples of choosing which techniques to utilize for detection or quantification of GFNs in specific scenarios. Because the available quantitative techniques are somewhat limited, more research is required to distinguish GFNs from other carbonaceous materials and improve the accuracy and detection limits of GFNs at more environmentally relevant concentrations. PMID- 29505727 TI - The Molecular Origin of Enthalpy/Entropy Compensation in Biomolecular Recognition. AB - Biomolecular recognition can be stubborn; changes in the structures of associating molecules, or the environments in which they associate, often yield compensating changes in enthalpies and entropies of binding and no net change in affinities. This phenomenon-termed enthalpy/entropy (H/S) compensation-hinders efforts in biomolecular design, and its incidence-often a surprise to experimentalists-makes interactions between biomolecules difficult to predict. Although characterizing H/S compensation requires experimental care, it is unquestionably a real phenomenon that has, from an engineering perspective, useful physical origins. Studying H/S compensation can help illuminate the still murky roles of water and dynamics in biomolecular recognition and self-assembly. This review summarizes known sources of H/ S compensation (real and perceived) and lays out a conceptual framework for understanding and dissecting-and, perhaps, avoiding or exploiting-this phenomenon in biophysical systems. PMID- 29505726 TI - Methods of Measuring Enzyme Activity Ex Vivo and In Vivo. AB - Enzymes catalyze a variety of biochemical reactions in the body and, in conjunction with transporters and receptors, control virtually all physiological processes. There is great value in measuring enzyme activity ex vivo and in vivo. Spatial and temporal differences or changes in enzyme activity can be related to a variety of natural and pathological processes. Several analytical approaches have been developed to meet this need. They can be classified broadly as methods either based on artificial substrates, with the goal of creating images of diseased tissue, or based on natural substrates, with the goal of understanding natural processes. This review covers a selection of these methods, including optical, magnetic resonance, mass spectrometry, and physical sampling approaches, with a focus on creative chemistry and method development that make ex vivo and in vivo measurements of enzyme activity possible. PMID- 29505728 TI - The Influence of Ruptured Scar Pattern on the Healing Potential of Anterior Cruciate Ligament Remnant Cells. AB - BACKGROUND: Vascular CD34+ cells in anterior cruciate ligament (ACL) tissues have a potential for high proliferation and multilineage differentiation, which can accelerate tendon-bone healing after ACL reconstruction. To predict outcomes of ACL reconstruction with remnant preservation or ruptured tissue incorporation, patient characteristics should be considered. However, the influence of ACL remnant morphologic pattern on healing potential remains unknown. HYPOTHESIS: The healing potential of ACL remnants could differ among their morphologic patterns. STUDY DESIGN: Descriptive laboratory study. METHODS: ACL remnant tissues were harvested from patients aged <35 years who received primary ACL reconstruction within 3 months after injury. The tissues were evaluated according to the Crain classification (4 patterns). The patterns were divided into 2 groups: the reattachment group (Crain I-III) and the nonreattachment group (Crain IV). ACL remnant cells were characterized via fluorescence-activated cell sorting. The potential for proliferation and multilineage differentiation was assessed and compared between the groups. RESULTS: The ratio of CD34+ cells was significantly higher in the nonreattachment group than in the reattachment group. In early passages, the nonreattachment group had a significantly higher expansion potential than the reattachment group. In the evaluation of osteogenic and endothelial differentiation potential, the nonreattachment group showed a higher potential in immunohistochemical/histochemical staining and quantitative real time polymerase chain reaction analysis as compared with the reattachment group. CONCLUSION: In the subacute phase, ACL remnant tissue of the nonreattachment group possibly has a higher healing potential than that of the reattachment group. CLINICAL RELEVANCE: If healing potential differs among the morphologic patterns of ACL remnants, surgeons may expect the healing potential when preserving remnants. PMID- 29505729 TI - Advanced Endoscopic Navigation: Surgical Big Data, Methodology, and Applications. AB - Interventional endoscopy (e.g., bronchoscopy, colonoscopy, laparoscopy, cystoscopy) is a widely performed procedure that involves either diagnosis of suspicious lesions or guidance for minimally invasive surgery in a variety of organs within the body cavity. Endoscopy may also be used to guide the introduction of certain items (e.g., stents) into the body. Endoscopic navigation systems seek to integrate big data with multimodal information (e.g., computed tomography, magnetic resonance images, endoscopic video sequences, ultrasound images, external trackers) relative to the patient's anatomy, control the movement of medical endoscopes and surgical tools, and guide the surgeon's actions during endoscopic interventions. Nevertheless, it remains challenging to realize the next generation of context-aware navigated endoscopy. This review presents a broad survey of various aspects of endoscopic navigation, particularly with respect to the development of endoscopic navigation techniques. First, we investigate big data with multimodal information involved in endoscopic navigation. Next, we focus on numerous methodologies used for endoscopic navigation. We then review different endoscopic procedures in clinical applications. Finally, we discuss novel techniques and promising directions for the development of endoscopic navigation. PMID- 29505730 TI - Descriptive Epidemiology of the MOON Shoulder Instability Cohort. AB - BACKGROUND: Shoulder instability is a common diagnosis among patients undergoing shoulder surgery. PURPOSE: To perform a descriptive analysis of patients undergoing surgery for shoulder instability through a large multicenter consortium. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All patients undergoing surgery for shoulder instability who were enrolled in the MOON Shoulder Instability Study were included. Baseline demographics included age, sex, body mass index, and race. Baseline patient-reported outcomes (PROs) included the American Shoulder and Elbow Surgeons (ASES) score, Shoulder Activity Score, Western Ontario Shoulder Instability Index (WOSI), 36-Item Health Survey (RAND-36), and Single Assessment Numeric Evaluation (SANE). The preoperative physician examination included active range of motion (ROM) and strength testing. Preoperative imaging assessments with plain radiography, magnetic resonance imaging (MRI), and computed tomography were also included and analyzed. RESULTS: Twenty-six surgeons had enrolled 863 patients (709 male, 154 female) across 10 clinical sites. The mean age for the cohort was 24 years (range, 12-63 years). Male patients represented 82% of the cohort. The primary direction of instability was anterior for both male (74%) and female (73%) patients. Football (24%) and basketball (13%) were the most common sports in which the primary shoulder injury occurred. No clinically significant differences were found in preoperative ROM between the affected and unaffected sides for any measurement taken. Preoperative MRI scans were obtained in 798 patients (92%). An anterior labral tear was the most common injury found on preoperative MRI, seen in 66% of patients, followed by a Hill-Sachs lesion in 41%. Poor PRO scores were recorded preoperatively (mean: ASES, 72.4; WOSI, 43.3; SANE, 46.6). CONCLUSION: The MOON Shoulder Instability Study has enrolled the largest cohort of patients undergoing shoulder stabilization to date. Anterior instability is most common among shoulder instability patients, and most patients undergoing shoulder stabilization are in their early 20s or younger. The results of this study provide important epidemiological information for patients undergoing shoulder stabilization surgery. PMID- 29505731 TI - Does Capsular Laxity Lead to Microinstability of the Native Hip? AB - BACKGROUND: Hip "microinstability" is commonly cited as the cause of symptoms that occur in the presence of translation of the femoral head away from conformity with the acetabular fossa. However, there is still no consistent objective criteria defining its presence and biomechanical basis. One hypothesis is that abnormal motion of the articular surfaces occurs because of capsular laxity, ultimately leading to clinical symptoms. PURPOSE: To determine the relationship between capsular laxity and abnormal rotation and translation of the hip. STUDY DESIGN: Controlled laboratory study. METHODS: Eight cadaveric hips were dissected down to the capsule and mounted in a customized multiaxial hip activity simulator. Each specimen was loaded with 5 N.m of internal and external rotational torque in full extension and 0 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion. During testing, the relative position and rotation of the femur and the pelvis were monitored in real time with a 6-camera motion analysis system. The testing was repeated after capsular laxity was generated by placing a regular array of incisions ("pie crusting") in the iliofemoral, pubofemoral, and ischiofemoral ligaments. Joint rotation and femoral head translation were calculated with specimen-specific models. A hip microinstability index was defined as the ratio between the length of the locus of the femoral head center and the radius of the femoral head during rotation from extension to 90 degrees of flexion. RESULTS: In intact hips, the components of femoral head translation were within 0.5 mm in positions close to neutral (<30 degrees of flexion). Capsular modification led to significant increases in internal and external rotation ( P < .01) and in the translation of the femoral head center at different positions ( P < .05). Compared with intact hips, the femoral head was inferiorly displaced during external rotation and anteroinferiorly during internal rotation. The length of the locus of the femoral head center increased from 3.61 +/- 1.30 mm to 5.35 +/- 1.83 mm for external rotation ( P < .05) and from 6.24 +/- 1.48 mm to 8.21 +/- 1.42 mm for internal rotation ( P < .01). The correlations between rotational laxity and the total translation of the femoral head were not significant, with coefficients of 0.093 and 0.006 in external and internal rotation, respectively. In addition, the hip microinstability index increased from 0.40 +/- 0.08 for intact hips to 0.55 +/- 0.09 for modified hips ( P < .01). CONCLUSION: The native hip approximates a concentric ball-and-socket joint within 30 degrees of flexion; however, beyond 30 degrees of flexion, the femoral head translation reached as high as 4 mm. Capsular laxity leads to microinstability of the hip, as indicated by significantly increased joint rotations and femoral head translations and an abnormal movement path of the femoral head center. However, there was no correlation between rotational laxity and the increase in femoral head translation. CLINICAL RELEVANCE: Capsular laxity alters normal kinematics (joint rotation and femoral head translation) of the hip, potentially leading to abnormal femoral-acetabular contact and joint degeneration. PMID- 29505732 TI - Transovarial transmission of dengue 1 virus in Aedes aegypti larvae: real-time PCR analysis in a Brazilian city with high mosquito population density. AB - Transovarial transmission is among the reported factors able to influence environmental maintenance of dengue virus (DENV). Endemic areas with active transmission of dengue are suitable for studying transovarial transmission. Brazil is a country where dengue is endemic and where DENV-1 is the most common disease-related virus serotype. This study aimed to identify transovarial transmission of DENV-1 in Aedes aegypti larvae by reverse-transcriptase nested real-time polymerase chain reaction. Between March and October 2016, Culicidae larvae were collected using traps in 3 locations in Taubate, Sao Paulo, Brazil, which has a high occurrence of dengue. The collected larvae were sacrificed in the 3rd or 4th larval stage, classified, and stored at -20 degrees C. The A. aegypti larvae samples (n = 910) were separated into 91 pools of 10 specimens each from which RNA was extracted, reverse transcribed into cDNA, and analyzed by nested qPCR. None of the pools tested positive for DENV-1. Due to the absence of detectable virus in the evaluated samples, we concluded that transovarial transmission may not be the primary mechanism for maintenance of DENV-1 in this particular environment. PMID- 29505733 TI - Physical Activity Preferences and Attitudes of Individuals with Substance Use Disorders: A Review of the Literature. AB - Substance use disorders (SUDs) are prevalent in the United States and costly to society. SUDs contribute significantly to decreased quality of life and overdose deaths. Physical activity (PA) interventions may be one efficacious method to improve recovery and long-term abstinence from substance use; although PA interventions have resulted in positive physical and psychological outcomes, their adherence and attrition rates have been problematic. To address lack of adherence and high attrition rates, it is important to understand the preferences and attitudes for PA among patients in SUD treatment. We, therefore, conducted a literature review to examine preferences and attitudes for PA among adults with SUDs. Five articles met inclusion and exclusion criteria. The findings from this small sample of studies suggest that adults with SUDs are interested in PA. Walking, strength training, and cycling were the activities preferred most frequently. Participants said that they would like to engage in these activities either alone or with small groups and would prefer their exercise options to be located at facilities they already frequented, such as treatment clinics. Nurses are well positioned to assess patient preferences and attitudes and to enhance recovery efforts in this population. Further exploration of this population's unique preferences and attitudes regarding PA may lay the groundwork for efficacious PA interventions with improved adherence and attrition rates, which may lead to improved recovery outcomes. PMID- 29505734 TI - Efficacy of Pseudomonas fluorescens for control of Mucor rot of apple during commercial storage and potential modes of action. AB - The ability of Pseudomonas fluorescens isolates 1-112, 2-28, and 4-6, to control Mucor piriformis (Mucor rot) on Gala, McIntosh, Ambrosia, and Spartan apple cultivars in commercial cold storage and their possible mechanisms of action were investigated. Isolates 1-112 and 2-28 provided significant levels of disease control on McIntosh and Spartan apples, while isolate 4-6 provided control of Mucor rot on Gala and Spartan apples, compared with control fruits after 15 weeks of storage at 0 degrees C. Mycelial growth of M. piriformis was markedly inhibited by cell-free supernatant and volatile organic compounds produced by P. fluorescens isolates, in vitro. In filter-sterilized apple juice, living cells of all 3 P. fluorescens isolates or their metabolites significantly inhibited spore germination by 99.8% and 61.6%, on average, respectively. Electron microscopy indicated that all 3 isolates of P. fluorescens colonized the hyphae of M. piriformis, but only isolate 1-112 was observed to colonize M. piriformis spores in vitro. In the wounds of apple, all 3 isolates formed a biofilm on the fungal hyphae and on the fruit tissue. Potential mechanisms of antagonism utilized by P. fluorescens against M. piriformis may include competition for nutrients and space, production of inhibitory metabolites and volatiles, and biofilm formation, leading to inhibition of spore germination and mycelial growth. PMID- 29505735 TI - Quantitative Algorithm-Based Paired Imaging Measurement for Antibody-Triggered Endocytosis in Cultured Cells. AB - Antibody-triggered endocytosis (ATE) is a biological mechanism on which many therapeutic strategies are grounded, such as delivery of antibody-drug conjugates (ADCs). Current methods monitoring ATE include confocal Z-stack analysis, acid wash, antibody quenching, and pH-sensitive dye labeling. However, those generate less quantifiable results with low throughput. Here we report a new method referred to as "paired imaging measurement" to analyze ATE using a quantitative algorithm in conjunction with high-content imaging. With two sequential measurements of cell surface antibody employing live cell staining and total antibody by immunostaining before and after cell permeabilization, intracellular antibody undergoing endocytosis can be quantified indirectly. Antibodies against CD98 and transferrin receptor were tested on hCMEC/D3 and hiPSC-derived endothelial cells. The maximal response and potency of endocytosed antibodies were generated with good assay robustness (Z' > 0.6) and >5-fold signal/background ratio. Antibody endocytosis response ranking is consistent between batches ( R2 > 0.9). The obtained results were confirmed by other traditional methods. In conclusion, we have developed a novel method using a quantitative imaging algorithm in conjunction with live cell staining for high throughput investigation of ATE. PMID- 29505736 TI - Transforming growth factor-beta1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways. AB - Transgenic mice constitutively overexpressing the cytokine transforming growth factor-beta1 (TGF-beta1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-beta1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-beta1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID. PMID- 29505737 TI - When Two Rights Make a Wrong: The Evolutionary Genetics of Plant Hybrid Incompatibilities. AB - Hybrids between flowering plant species often exhibit reduced fitness, including sterility and inviability. Such hybrid incompatibilities create barriers to genetic exchange that can promote reproductive isolation between diverging populations and, ultimately, speciation. Additionally, hybrid breakdown opens a window into hidden molecular and evolutionary processes occurring within species. Here, we review recent work on the mechanisms and origins of hybrid incompatibility in flowering plants, including both diverse genic interactions and chromosomal incompatibilities. Conflict and coevolution among and within plant genomes contributes to the evolution of some well-characterized genic incompatibilities, but duplication and drift also play important roles. Inversions, while contributing to speciation by suppressing recombination, rarely cause underdominant sterility. Translocations cause severe F1 sterility by disrupting meiosis in heterozygotes, making their fixation in outcrossing sister species a paradox. Evolutionary genomic analyses of both genic and chromosomal incompatibilities, in the context of population genetic theory, can explicitly test alternative scenarios for their origins. PMID- 29505738 TI - Diversity of Chlorophototrophic Bacteria Revealed in the Omics Era. AB - Because of recent advances in omics methodologies, knowledge of chlorophototrophy (i.e., chlorophyll-based phototrophy) in bacteria has rapidly increased. Chlorophototrophs currently are known to occur in seven bacterial phyla: Cyanobacteria, Proteobacteria, Chlorobi, Chloroflexi, Firmicutes, Acidobacteria, and Gemmatimonadetes. Other organisms that can produce chlorophylls and photochemical reaction centers may still be undiscovered. Here we summarize the current status of the taxonomy and phylogeny of chlorophototrophic bacteria as revealed by genomic methods. In specific cases, we briefly describe important ecophysiological and metabolic insights that have been gained from the application of genomic methods to these bacteria. In the 20 years since the completion of the Synechocystis sp. PCC 6803 genome in 1996, approximately 1,100 genomes have been sequenced, which represents nearly the complete diversity of known chlorophototrophic bacteria. These data are leading to new insights into many important processes, including photosynthesis, nitrogen and carbon fixation, cellular differentiation and development, symbiosis, and ecosystem functionality. PMID- 29505739 TI - Heterogeneity and Robustness in Plant Morphogenesis: From Cells to Organs. AB - Development is remarkably reproducible, producing organs with the same size, shape, and function repeatedly from individual to individual. For example, every flower on the Antirrhinum stalk has the same snapping dragon mouth. This reproducibility has allowed taxonomists to classify plants and animals according to their morphology. Yet these reproducible organs are composed of highly variable cells. For example, neighboring cells grow at different rates in Arabidopsis leaves, sepals, and shoot apical meristems. This cellular variability occurs in normal, wild-type organisms, indicating that cellular heterogeneity (or diversity in a characteristic such as growth rate) is either actively maintained or, at a minimum, not entirely suppressed. In fact, cellular heterogeneity can contribute to producing invariant organs. Here, we focus on how plant organs are reproducibly created during development from these highly variable cells. PMID- 29505740 TI - The role of microRNA-146a in regulating the expression of IRAK1 in cerebral ischemia-reperfusion injury. AB - MicroRNA-146a (miR-146a) is reportedly implicated in the pathogenesis of ischemia reperfusion (I/R) injury; however, its role in cerebral I/R injury is unclear and requires further investigation. In this study, cerebral I/R injury was established in mice via middle cerebral artery occlusion, and the expression of miR-146a was detected in the brain tissue via quantitative real-time PCR. We found that the expression of miR-146a was upregulated. Furthermore, the endogenous miR-146a was antagonized by its specific inhibitor. The results indicated that the inhibition of miR-146a deteriorated I/R-induced neurobehavioral impairment, exaggerated the infarct size, and exacerbated blood brain barrier leakage. Cerebral I/R injury-induced generation of inflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, was further promoted by miR-146a inhibitor. The expression of interleukin-1 receptor associated kinase 1 (IRAK1), a target of miR-146a, was upregulated upon miR-146a inhibition. In addition, the nuclear factor kappaB (NF-kappaB) signaling pathway was over-activated when miR-146a was antagonized as manifested by the increased levels of phospho-NF-kappaB inhibitor alpha and nuclear p65. In summary, our findings demonstrate that the elevation of miR-146a may be one of the compensatory responses after the cerebral I/R injury and suggest miR-146a as a potential therapeutic target for cerebral I/R injury. PMID- 29505741 TI - The Role of the Paratenon in Achilles Tendon Healing: A Study in Rats. AB - BACKGROUND: The role of the paratenon in tendon healing is unknown. The present study compares healing in the presence or absence of the paratenon in an Achilles tendon defect model in rats. HYPOTHESIS: Resection of the paratenon impairs tendon healing. STUDY DESIGN: Controlled laboratory study. METHODS: Sixty skeletally mature Sprague Dawley rats were randomly assigned to either a resected paratenon (RP) group or an intact paratenon (IP) group. In all animals, a 4-mm portion of the Achilles tendon was resected in the midsubstance. In the RP group, the paratenon was resected completely. In the IP group, the paratenon was opened longitudinally and closed again after the tendon defect had been created. One, 2, and 4 weeks after surgery, 7 animals per group were tested biomechanically and 3 animals per group examined histologically. RESULTS: The recovery of mechanical strength was much more rapid in IP tendons. Tear resistance was significantly increased for IP tendons (41.3 +/- 8.8 N and 47.3 +/- 14.1 N, respectively) compared with RP tendons (19.3 +/- 9.1 N and 33.2 +/- 6.4 N, respectively) after 1 and 2 weeks. The cross-sectional area was larger in the IP group after 1 and 2 weeks (8.2 +/- 2.3 mm2 and 11.3 +/- 3.1 mm2 vs 5.0 +/- 2.4 mm2 and 5.9 +/- 2.0 mm2, respectively) compared with the RP group. Tendon stiffness was greater in the IP group after 1 week (10.4 +/- 1.9 N/mm vs 4.5 +/- 1.6 N/mm, respectively) compared with the RP group. In comparison, normal contralateral tendons had a maximal tear resistance of 56.6 +/- 7.2 N, a cross-sectional area of 3.6 +/- 0.7 mm2, and stiffness of 17.3 +/- 3.8 N/mm. Hematoxylin and eosin staining revealed slightly delayed healing of RP tendons. Early collagen formation was seen in the IP group already after 1 week, whereas in the RP group, this only occurred after 2 weeks. After 4 weeks, the IP tendons showed more collagen crimp formation than the RP tendons. CONCLUSION: An intact paratenon promotes healing of the Achilles tendon. CLINICAL RELEVANCE: Although incision or resection of the paratenon has been advocated when repairing injured or degenerative tendons, our data suggest that the integrity of the paratenon should be preserved. PMID- 29505742 TI - When Should We Repair Partial-Thickness Rotator Cuff Tears? Outcome Comparison Between Immediate Surgical Repair Versus Delayed Repair After 6-Month Period of Nonsurgical Treatment. AB - BACKGROUND: Patients with partial-thickness rotator cuff tears (PTRCTs) can be treated nonoperatively and/or undergo operative treatment, but the ideal time for surgical intervention is unclear. PURPOSE: To compare the results of immediate arthroscopic rotator cuff repair with repair after 6 months of nonoperative care of PTRCTs involving more than 50% of the tendon thickness. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: The authors prospectively randomized and analyzed 78 consecutive patients diagnosed with either isolated bursal-side or articular-side PTRCTs (supraspinatus only). Group 1 (n = 44) received immediate rotator cuff repair. Group 2 (n = 34) received delayed rotator cuff repair after 6 months of nonoperative treatment. The American Shoulder and Elbow Surgeons (ASES) Score, Constant score, visual analog scale (VAS) for pain, and range of motion at initial visit; months 3, 6, and 12 postoperatively; and the last visit after 24 months were used for the evaluation. Cuff integrity was assessed with magnetic resonance imaging at 12 months postoperatively. RESULTS: There were no significant differences in age, sex (18/26 vs 13/21, male/female), symptom duration, composition of PTRCTs, or clinical outcomes between groups 1 and 2 ( P > .05). In group 2, 10 patients voluntarily dropped out from the study due to improvement of symptoms during the 6 months of preoperative nonoperative treatment. The mean follow-up period in groups 1 and 2 was 31.9 +/- 1.5 months and 37.0 +/- 2.2 months, respectively. At the end of the study, both groups showed significant improvements in terms of functional scores and pain VAS scores compared with the initial period. There were no significant differences between the 2 groups, except for lower pain VAS score and higher ASES Score in group 2 at 6 months postoperatively. At 12 months postoperatively, 1 patient from group 1 and 2 patients from group 2 experienced a retear. CONCLUSION: Both immediate surgical repair and delayed repair after nonsurgical care for PTRCTs were effective in improving clinical outcomes, and there was a very low incidence of retears in both groups. However, at 6 months postoperatively, superior functional outcomes were observed in the delayed repair group compared with the immediate repair group. A trial period of preoperative nonsurgical care is reasonable, and immediate surgical repair is not crucial for the treatment of PTRCT. PMID- 29505743 TI - A genetic method for sex determination in Ovis spp. by interruption of the zinc finger protein, Y-linked (ZFY) gene on the Y chromosome. AB - The mammalian Y chromosome plays a critical role in spermatogenesis. However, the exact functions of each gene on the Y chromosome have not been completely elucidated, due, in part, to difficulties in gene targeting analysis of the Y chromosome. The zinc finger protein, Y-linked (ZFY) gene was first proposed to be a sex determination factor, although its function in spermatogenesis has recently been elucidated. Nevertheless, ZFY gene targeting analysis has not been performed to date. In the present study, RNA interference (RNAi) was used to generate ZFY interrupted Hu sheep by injecting short hairpin RNA (shRNA) into round spermatids. The resulting spermatozoa exhibited abnormal sperm morphology, including spermatozoa without tails and others with head and tail abnormalities. Quantitative real-time polymerase chain reaction analysis showed that ZFY mRNA expression was decreased significantly in Hu sheep with interrupted ZFY compared with wild-type Hu sheep. The sex ratio of lambs also exhibited a bias towards females. Together, the experimental strategy and findings of the present study reveal that ZFY also functions in spermatogenesis in Hu sheep and facilitate the use of RNAi in the control of sex in Hu sheep. PMID- 29505744 TI - Virtual Reality Rehabilitation With Functional Electrical Stimulation Improves Upper Extremity Function in Patients With Chronic Stroke: A Pilot Randomized Controlled Study. AB - OBJECTIVE: To compare virtual reality (VR) combined with functional electrical stimulation (FES) with cyclic FES for improving upper extremity function and health-related quality of life in patients with chronic stroke. DESIGN: A pilot, randomized, single-blind, controlled trial. SETTING: Stroke rehabilitation inpatient unit. PARTICIPANTS: Participants (N=48) with hemiplegia secondary to a unilateral stroke for >3 months and with a hemiplegic wrist extensor Medical Research Council scale score ranging from 1 to 3. INTERVENTIONS: FES was applied to the wrist extensors and finger extensors. A VR-based wearable rehabilitation device was used combined with FES and virtual activity-based training for the intervention group. The control group received cyclic FES only. Both groups completed 20 sessions over a 4-week period. MAIN OUTCOME MEASURES: Primary outcome measures were changes in Fugl-Meyer Assessment-Upper Extremity and Wolf Motor Function Test scores. Secondary outcome measures were changes in Box and Block Test, Jebsen-Taylor Hand Function Test, and Stroke Impact Scale scores. Assessments were performed at baseline (t0) and at 2 weeks (t1), 4 weeks (t4), and 8 weeks (t8). Between-group comparisons were evaluated using a repeated measures analysis of variance. RESULTS: Forty-one participants were included in the analysis. Compared with FES alone, VR-FES produced a substantial increase in Fugl-Meyer Assessment-distal score (P=.011) and marginal improvement in Jebsen Taylor Hand Function Test-gross score (P=.057). VR-FES produced greater, although nonsignificant, improvements in all other outcome measures, except in the Stroke Impact Scale-activities of daily living/instrumental activities of daily living score. CONCLUSIONS: FES with VR-based rehabilitation may be more effective than cyclic FES in improving distal upper extremity gross motor performance poststroke. PMID- 29505745 TI - Cardioprotective effect of paeonol against epirubicin-induced heart injury via regulating miR-1 and PI3K/AKT pathway. AB - Cardiotoxicity is a dose-dependent side effect of epirubicin that restricts its clinical utility in cancer chemotherapy. Paeonol is an active constituent with various biological activities, including the protection of antineoplastic-induced toxicities. In the present study, we investigated the protective effect of paeonol on epirubicin-induced cardiotoxicity and explored the underlying mechanism. A series of methods were used including a MTT assay, flow cytometry, echocardiography, TUNEL staining, a dual-luciferase reporter assay, immunofluorescence, RT-PCR and Western blotting. The results indicate that paeonol improves cardiac dysfunction, relieves histopathological changes, alleviates inflammation, reduces myocardial apoptosis and increases autophagy. Further studies suggest that paeonol upregulates the decreased expression of miR 1 caused by epirubicin and thus inhibits the activation of PI3K/AKT/mTOR and NF kappaB pathways. In conclusion, paeonol effectively ameliorates myocardial injury by increasing miR-1 expression to suppress the PI3K/AKT/mTOR and NF-kB signalling pathways. PMID- 29505746 TI - Association of N-acetyltransferase-2 and glutathione S-transferase polymorphisms with idiopathic male infertility in Vietnam male subjects. AB - N-acetyltransferase-2 (NAT2) and Glutathione S-transferases (GSTs) are phase-II xenobiotic metabolizing enzymes participating in detoxification of toxic arylamines, aromatic amines, hydrazines and reactive oxygen species (ROS), which are produced under oxidative and electrophile stresses. The purpose of this research was to investigate whether two common single-nucleotide polymorphisms (SNP) of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) associated with susceptibility to idiopathic male infertility. A total 300 DNA samples (150 infertile patients and 150 healthy control) were genotyped for the polymorphisms by ARMS - PCR. We revealed a significant association between the NAT2 variant genotypes (CT + TT (rs1799929), (OR: 3.74; p < 0.001)) and (GA + AA (rs1799930), (OR: 3.75; p < 0.001)) or GSTP1 variant genotypes (GA + AA (rs1695), (OR: 5.11; p < 0,001)) and (CT + TT (rs1138272), (OR: 7.42; p < 0,001) with idiopathic infertility risk. Our findings rate the effect of single-nucleotide polymorphisms of GSTP1 and/or NAT2 in modulation of the risk of male infertility in subjects from Vietnam. This pilot study is the first (as far as we know) to reveal that polymorphisms of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) are some novel genetic markers for susceptibility to idiopathic male infertility. PMID- 29505747 TI - The prevalence and impacts of crisis pregnancy center visits among a population of pregnant women. AB - OBJECTIVES: Investigations into Crisis Pregnancy Centers (CPCs) have documented the provision of deceptive information about abortion, but it is unclear how many pregnant women actually visit CPCs and what impact visits have on their pregnancy decision-making. STUDY DESIGN: We conducted a mixed-methods study. We surveyed patients at one of two local abortion clinics and three prenatal clinics in Southern Louisiana about whether they had visited a CPC for this pregnancy and conducted in-depth interviews with prenatal patients who reported a CPC visit about their experience. RESULTS: We surveyed 114 abortion patients and 269 prenatal patients, and interviewed 12 prenatal patients about their CPC visit. Just 6% of abortion patients (n=7) and 5% of prenatal patients (n=14) visited a CPC for this pregnancy. Prenatal patients went to CPCs primarily for free pregnancy tests and reported receiving information about abortion from CPC staff that was inaccurate. They also generally recognized the CPC was antiabortion, ideologically Christian, and not a medical establishment. Only three had been considering abortion at the time of their visit and reported that the visit impacted their plan for the pregnancy. However, all three also faced additional barriers to abortion, including inability to find an abortion provider, difficulty securing funding, gestational limits, ambivalence about choosing abortion, and opposition to abortion from family members. CONCLUSIONS: We do not find evidence that pregnant women regularly seek CPC services or that CPCs persuade women who are certain abortion is the right decision for them to continue their pregnancies. IMPLICATIONS: Given little evidence that CPCs impact pregnant women's decision-making on a broad scale, future research should examine other aspects of CPCs, such as their role in the antiabortion movement and/or the impact of CPC visits on maternal health and birth outcomes among women who continue their pregnancies. PMID- 29505749 TI - Metastatic Lung Cancer Diagnosed by Colonoscopy and Presented With Hematochezia. PMID- 29505750 TI - Worming Your Way Through the Gastrointestinal Tract: A Case of Strongyloidiasis. PMID- 29505752 TI - A Congenital Culprit: Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery. PMID- 29505748 TI - Neuronal Transforming Growth Factor beta Signaling via SMAD3 Contributes to Pain in Animal Models of Chronic Pancreatitis. AB - BACKGROUND & AIMS: Chronic pancreatitis (CP) is characterized by pancreatic inflammation and fibrosis, associated with increased pancreatic expression of transforming growth factor beta (TGFB). It is not clear how these might contribute to pain. We investigated whether TGFB signaling via SMAD induces sensitization of pancreatic sensory neurons to increase nociception. METHODS: CP was induced in Sprague-Dawley rats by infusion of trinitrobenzene sulfonic acid; some rats were given intrathecal infusions of TGFB1. CP was induced in control mice by administration of cerulein; we also studied beta1glo/Ptf1acre-ER mice, which on induction overexpress TGFB1 in pancreatic acinar cells, and TGFBr1f/f CGRPcreER mice, which have inducible disruption of TGFBr1 in calcitonin gene related peptide-positive neurons. Dominant negative forms of human TGFBR2 and SMAD3 were overexpressed from viral vectors in rat pancreas. Some rats were given the SMAD3 inhibitors SIS3 or halofuginone. After induction of CP, mice were analyzed for pain in behavior tests or electrophysiologic studies of sensory neurons. Pancreatic nociceptor excitability was examined by patch-clamp techniques and nociception was measured by Von Frey Filament tests for referred somatic hyperalgesia and behavioral responses to pancreatic electrical stimulation. Pancreata were collected from mice and rats and analyzed histologically and by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Overexpression of TGFB in pancreatic acinar cells of mice and infusion of TGFB1 into rats resulted in sensory neuron hyperexcitability, SMAD3 activation, and increased nociception. This was accompanied by a reduction in the transient A-type current in pancreas-specific sensory neurons in rats, a characteristic of nociceptive sensitization in animal models of CP. Conversely, pancreata from TGFBr1f/f-CGRPcreER mice, rats with pancreatic expression of dominant negative forms of human TGFBR2 or SMAD3, and rats given small molecule inhibitors of SMAD3 had attenuated neuronal sensitization and pain behavior following induction of CP. In contrast to findings from peripheral administration of TGFB1, intrathecal infusion of TGFB1 reduced hyperalgesia in rats with CP. CONCLUSIONS: In pancreata of mice and rats, TGFB promotes peripheral nociceptive sensitization via a direct effect on primary sensory neurons mediated by intra neuronal SMAD3. This is distinct from the central nervous system, where TGFB reduces nociception. These results provide an explanation for the link between fibrosis and pain in patients with CP. This signaling pathway might be targeted therapeutically to reduce pain in patients with CP. PMID- 29505751 TI - Dexamethasone intravitreal implant downregulates PDGFR-alpha and upregulates caveolin-1 in experimental branch retinal vein occlusion. AB - A dexamethasone (DEX) intravitreal implant (OZURDEX) provides an effective treatment of inflammation secondary to branch retinal vein occlusion (BRVO). Retinal proteome changes which mediate the beneficial effects of the implant remain poorly understood. To study retinal proteome changes in BRVO following an intervention with a DEX implant this study combined an experimental model of BRVO with proteomic techniques. In eight Danish Landrace pigs experimental BRVO was induced in both eyes using argon laser. After inducing BRVO a DEX implant was injected into the right eye of each animal while the left control eye was given an identical injection without an implant. Fifteen days after BRVO and DEX implant intervention the retinas were excised and analyzed with tandem mass tag based mass spectrometry. A total of 26 significantly changed proteins were identified. DEX intervention reduced the retinal levels of platelet-derived growth factor receptor-alpha (PDGFR-alpha) and vascular endothelial growth factor receptor 2 (VEGFR-2). DEX treatment resulted in increased levels of caveolin-1, peptidyl-prolyl cis-trans isomerase FKBP5 and transgelin. Changes in PDGFR-alpha and caveolin-1 were confirmed with immunohistochemistry. In BRVO treated with the DEX implant a strong reaction for caveolin-1 was observed in the innermost retinal layers. DEX implant intervention may inhibit PDGF signaling by decreasing the retinal level of PDGFR-alpha while an increased content of caveolin-1 may help maintain the integrity of the blood-retinal barrier. PMID- 29505753 TI - No Ordinary Back Pain: Malignant Spinal Cord Compression. PMID- 29505754 TI - Segmental Arterial Mediolysis: An Important but Often Overlooked Cause of Multi Vessel Thrombosis. PMID- 29505755 TI - Meta-Analysis of the Effect of Gum Chewing After Gynecologic Surgery. AB - OBJECTIVE: To describe the scientific evidence related to gum chewing to reduce ileus after gynecologic surgery. DATA SOURCES: A literature search was performed using Ovid Medline, Embase, Cochrane Library, CINAHL, Scopus, and Web of Science databases. STUDY SELECTION: Inclusion criteria included randomized controlled trials (RCTs) on the use of gum chewing after gynecologic surgery in which the main outcomes measured were time to first flatus, time to defecation, and length of hospital stay. DATA EXTRACTION: Data on authors, country, randomization method, the type of disease, surgical and anesthetic methods, sample characteristics such as age and body mass index, gum chewing program, and study results were extracted from selected articles. DATA SYNTHESIS: Of 493 publications, eight RCTs conducted between 2013 and 2017 involving 1,077 women were included in our meta-analysis. Weighted mean differences (WMDs) with 95% confidence intervals were calculated for the eight studies with the use of Cochrane Review Manager Version 5.3 (RevMan; 2014). The pooled results showed that gum chewing was superior to no gum chewing, with a reduction in WMD for time to first flatus of -6.20 hours (95% confidence interval [CI] [-9.51, -2.88]), WMD for time to first defecation of -9.03 hours (95% CI [-14.02, -4.04]), and WMD for length of hospital stay of -0.36 days (95% CI [-0.72, -0.01]). CONCLUSION: Gum chewing significantly reduced the time to first flatus and defecation after gynecologic surgery and should be recommended by health care providers. PMID- 29505756 TI - Transient Acceleration of Epidermal Growth Factor Receptor Dynamics Produces Higher-Order Signaling Clusters. AB - Cell signaling depends on spatiotemporally regulated molecular interactions. Although the movements of signaling proteins have been analyzed with various technologies, how spatial dynamics influence the molecular interactions that transduce signals is unclear. Here, we developed a single-molecule method to analyze the spatiotemporal coupling between motility, clustering, and signaling. The analysis was performed with the epidermal growth factor receptor (EGFR), which triggers signaling through its dimerization and phosphorylation after association with EGF. Our results show that the few EGFRs isolated in membrane subdomains were released by an EGF-dependent increase in their diffusion area, facilitating molecular associations and producing immobile clusters. Using a two color single-molecule analysis, we found that the EGF-induced state transition alters the properties of the immobile clusters, allowing them to interact for extended periods with the cytoplasmic protein, GRB2. Our study reveals a novel correlation between this molecular interaction and its mesoscale dynamics, providing the initial signaling node. PMID- 29505757 TI - Lyar-Mediated Recruitment of Brd2 to the Chromatin Attenuates Nanog Downregulation Following Induction of Differentiation. AB - During development, cellular differentiation programs need tight regulation for proper display of the activity of multiple factors in time and space. Chromatin adaptors of the BET family (Brd2, Brd3, Brd4 and Brdt in vertebrates) are transcription co-regulators tightly associated with the progression of the cell cycle. A key question regarding their function is whether they work as part of the general transcription machinery or, on the contrary, they are precisely recruited to the chromatin through specific transcription factors. Here, we report the selective recruitment of Brd2 to the chromatin by the transcription factor Lyar. We show that Lyar downregulation results in Brd2 dissociation from a number of promoters studied. On the contrary, dissociation of BET proteins from the chromatin has no effect on Lyar occupancy. Under differentiation conditions, the absence of Lyar leads to impaired downregulation of the pluripotency gene Nanog, with concomitant reduction in the upregulation of differentiation markers. Interestingly, following the induction of differentiation, Brd2 depletion exhibits the same effects as expressing a truncated Lyar molecule lacking the Brd2 interacting domain. Both approaches result in stronger Nanog repression, indicating that Lyar-mediated recruitment of Brd2 moderates Nanog downregulation when differentiation is triggered. Moreover, expression of truncated Lyar leads to impaired differentiation and increased apoptosis. Thus, Lyar-mediated recruitment of Brd2 would participate in preserving a proper timing for Nanog silencing ensuring the appropriate establishment of the differentiation program. PMID- 29505758 TI - Genome-Wide Association of PVT1 with Vitiligo. PMID- 29505759 TI - Risk of Serious Infection, Opportunistic Infection, and Herpes Zoster among Patients with Psoriasis in the United Kingdom. AB - The risk of infection among patients with psoriasis of varying severity in a broadly representative population remains poorly understood. Using The Health Improvement Network (THIN), an electronic medical records database representative of the general UK population, we performed a cohort study to determine the risks of serious infection, opportunistic infection, and herpes zoster among patients with versus without psoriasis and according to psoriasis severity. We identified 187,258 patients with mild and 12,442 patients with moderate to severe psoriasis based on treatment patterns. Using Cox proportional hazards regression, the adjusted hazard ratios (95% confidence intervals) for serious infection were 1.18 (1.16-1.21) and 1.63 (1.52-1.75) for the mild and moderate to severe psoriasis groups, respectively. Among a nested cohort of 8,569 psoriasis patients with disease severity classified by body surface area involvement, similar results were obtained with the exception of an attenuated but significantly increased risk of serious infection among the moderate to severe psoriasis group (1.27 [1.10-1.47]). Overall, the risks of opportunistic infection and herpes zoster were significantly increased only among the moderate to severe psoriasis group and were associated with immunosuppressive therapy. Our analyses suggest that psoriasis is associated with an increased risk of serious infection, and psoriasis severity is a predictor of serious infection risk. PMID- 29505760 TI - Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations. PMID- 29505761 TI - Proteomic analysis of labial saliva of the generalist cabbage looper (Trichoplusia ni) and its role in interactions with host plants. AB - Insect saliva is one of the first secretions to come in contact with plants during feeding. The composition and role of caterpillar saliva has not been as thoroughly studied as that of sucking insects. This study focuses on characterizing the proteome of the cabbage looper (Trichoplusia ni) saliva using iTRAQ labeling and LC-MS/MS. We also measured how the saliva proteome changed when larvae were reared on different diets - cabbage, tomato, and an artificial pinto bean diet. We identified 254 proteins in the saliva out of which 63 were differentially expressed. A large percentage (56%) of the proteins identified function in protein metabolism, followed by proteins involved in vesicle transport (6%) and oxidoreductase activity (5%), among other categories. Several proteins identified are antioxidants or reactive oxygen species (ROS) scavengers. Among these ROS scavengers, we identified a catalase and further analyzed its gene expression and enzymatic activity. We also applied commercial, purified catalase on tomato and measured the activity of defensive proteins - trypsin proteinase inhibitor, polyphenol oxidase and peroxidase. Catalase gene expression was significantly higher in the salivary glands of larvae fed on tomato. Also, catalase suppressed the induction of tomato trypsin proteinase inhibitor levels, but not the induction of polyphenol oxidase or peroxidase. These results add to our understanding of proteomic plasticity in saliva and its role in herbivore offense against plant defenses. PMID- 29505762 TI - Genetic and epigenetic regulatory mechanisms of the oxytocin receptor gene (OXTR) and the (clinical) implications for social behavior. AB - Oxytocin and the oxytocin receptor (OXTR) play an important role in a large variety of social behaviors. The oxytocinergic system interacts with environmental cues and is highly dependent on interindividual factors. Deficits in this system have been linked to mental disorders associated with social impairments, such as autism spectrum disorder (ASD). This review focuses on the modulation of social behavior by alterations in two domains of the oxytocinergic system. We discuss genetic and epigenetic regulatory mechanisms and alterations in these mechanisms that were found to have clinical implications for ASD. We propose possible explanations how these alterations affect the biological pathways underlying the aberrant social behavior and point out avenues for future research. We advocate the need for integration studies that combine multiple measures covering a broad range of social behaviors and link these to genetic and epigenetic profiles. PMID- 29505765 TI - Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-associated extracavitary primary effusion lymphoma presenting as multiple lymphomatous polyposis. AB - Primary effusion lymphoma (PEL) is a distinct clinicopathological entity usually characterized by presentation as a lymphomatous body cavity effusion in the absence of solid tumor mass or dissemination during its clinical course. PEL can also rarely occur as a solid lymphoma involving nodal and extranodal sites and is referred to as extracavitary PEL. Here we report a unique case of extracavitary PEL in a 49-year-old HIV-seropositive patient who presented with vague abdominal pain and 20-lb weight loss. Esophagogastroduodenoscopy and colonoscopy revealed more than 100 broad-based intestinal polyps ranging from 2 mm to 3 cm in size, spreading from the duodenum to the rectum as a typical impression of "intestinal polyposis syndrome." Multiple biopsies demonstrated sheets of large lymphoid cells with characteristic features of extracavitary PEL with strong Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 virus positivity by immunohistochemistry. Extracavitary PEL presenting as distinctive multiple lymphomatous polyposis as manifested in the case has not been described previously. PMID- 29505763 TI - Interactions between estrogen receptors and metabotropic glutamate receptors and their impact on drug addiction in females. AB - Contribution to Special Issue on Fast effects of steroids. Estrogen receptors alpha and beta (ERalpha and ERbeta) have a unique relationship with metabotropic glutamate receptors (mGluRs) in the female rodent brain such that estradiol is able to recruit intracellular G-protein signaling cascades to influence neuronal physiology, structure, and ultimately behavior. While this association between ERs and mGluRs exists in many cell types and brain regions, its effects are perhaps most striking in the nucleus accumbens (NAc). This review will discuss the original characterization of ER/mGluR signaling and how estradiol activity in the NAc confers increased sensitivity to drugs of abuse in females through this mechanism. PMID- 29505764 TI - Heligmosomoides polygyrus Venom Allergen-like Protein-4 (HpVAL-4) is a sterol binding protein. AB - Heligmosomoides polygyrus bakeri is a model parasitic hookworm used to study animal and human helminth diseases. During infection, the parasite releases excretory/secretory products that modulate the immune system of the host. The most abundant protein family in excretory/secretory products comprises the venom allergen-like proteins (VALs), which are members of the SCP/TAPS (sperm-coating protein/Tpx/antigen 5/pathogenesis related-1/Sc7) superfamily. There are >30 secreted Heligmosomoides polygyrus VAL proteins (HpVALs) and these proteins are characterised by having either one or two 15 kDa CAP (cysteine-rich secretory protein (CRISP)/antigen 5/pathogenesis related-1) domains. The first known HpVAL structure, HpVAL-4, refined to 1.9 A is reported. HpVAL-4 was produced as a homogeneously glycosylated protein in leaves of Nicotiana benthamiana infiltrated with recombinant plasmids, making this plant expression platform amenable for the production of biological products. The overall topology of HpVAL-4 is a three layered alphabetaalpha sandwich between a short N-terminal loop and a C-terminal cysteine rich extension. The C-terminal cysteine rich extension has two strands stabilized by two disulfide bonds and superposes well with the previously reported extension from the human hookworm Necator americanus Ancylostoma secreted protein-2 (Na-ASP-2). The N-terminal loop is connected to alpha helix 2 via a disulfide bond previously observed in Na-ASP-2. HpVAL-4 has a central cavity that is more similar to the N-terminal CAP domain of the two CAP Na-ASP-1 from Necator americanus. Unlike Na-ASP-2, mammalian CRISP, and the C-terminal CAP domain of Na-ASP-1, the large central cavity of HpVAL-4 lacks the two histidines required to coordinate divalent cations. HpVAL-4 has both palmitate-binding and sterol-binding cavities and is able to complement the in vivo sterol export phenotype of yeast mutants lacking their endogenous CAP proteins. More studies are required to determine endogenous binding partners of HpVAL-4 and unravel the possible impact of sterol binding on immune-modulatory functions. PMID- 29505766 TI - A case of syphilitic hepatitis in an HIV-infected patient. AB - While the incidence of syphilis has been persistently on the rise in the United States, hepatitis as a complication of early syphilis is relatively uncommon. We present a case of a 51-year-old homosexual, HIV-positive man who presented with acute cholestatic hepatitis with a predominantly elevated alkaline phosphatase. After laboratory studies and imaging were unrevealing, a liver biopsy was performed that showed expanded portal tracts with a predominantly lymphoplasmacytic infiltrate and prominent bile ductular proliferation with periductal neutrophils. Testing revealed a positive rapid plasma reagin, and a subsequent Warthin-Starry stain of the liver tissue demonstrated the presence of scattered spirochetes, confirmed as Treponema pallidum spirochetes on immunohistochemistry testing. These findings confirmed a diagnosis of syphilitic hepatitis. With therapy, symptoms and liver enzymes rapidly normalized. Given the persistent rise in syphilis incidence along with the morbidity and mortality associated with a missed diagnosis, keen suspicion, early identification, and treatment are crucial. PMID- 29505767 TI - High glucose induces dysfunction of human umbilical vein endothelial cells by upregulating miR-137 in gestational diabetes mellitus. AB - Recent studies have revealed considerable dysfunction of vascular endothelial cells (VECs) and abnormal expression of microRNA (miR)-137 in women with gestational diabetes mellitus (GDM), and the aim of this study was to clarify the underlying mechanism and possible role of microRNA (miR)-137 in dysfunction of VECs during GDM. We found increased levels of miR-137 in the plasma of GDM women and high-glucose (HG)-exposed HUVECs. Upregulating miR-137 in HUVECs elevated the chemokine (C-C motif) ligand 2 (CCL2) secretion and enhanced the chemotaxis and adhesion of U937 and THP-1 (two human acute monocytic leukemia cell lines) cells to HUVECs in a co-culture system. Moreover, HG stimulation and/or overexpression of miR-137 inhibited the viability, upregulated the expression levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM 1), E-selectin, and inflammatory cytokine interleukin (IL)-6, and downregulated the production of IL-8, vascular endothelial growth factor (VEGF), and angiogenesis of HUVECs in vitro. These results imply that up-regulated miR-137 by HG can restrict the viability and angiogenesis, promote the activation and inflammatory cytokine secretion of VECs, and stimulate the monocyte chemotaxis and adhesion to VECs. Ultimately, we have concluded that miR-137 is crucial to HG induced VEC dysfunction and may be involved in pathology of GDM. PMID- 29505768 TI - Young scientists and Clinical Biochemists need to develop superior negotiating skills. PMID- 29505769 TI - Regulation of phase boundaries and phase-segregated patterns in model membranes. AB - Demixing of components has long been described in model membranes. It is a consequence of non-ideal lateral interactions between membrane components, and it causes the presence of segregated phases, forming patches (domains) of different properties, thus introducing heterogeneity into the membrane. In the present review we first describe the processes through which domains are generated, how they grow, and why they are rounded, striped or fractal-like, as well as why they get distributed forming defined patterns. Next, we focus on the effect of an additive on a lipid mixture, which usually induces shifts in demixing points, thus stabilizing or destabilizing the phase-segregated state. Results found for different model membranes are summarized, detailing the ways in which phase segregation and the generated patterns may be modulated. We focus on which are, from our viewpoint, the most relevant regulating factors affecting the surface texture observed in model membranes. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo. PMID- 29505770 TI - Perinatal outcomes associated with abnormal cardiac remodeling in women with treated chronic hypertension. AB - BACKGROUND: Adverse maternal outcomes associated with chronic hypertension include accelerated hypertension and resultant target organ damage. One example is long-standing hypertension leading to maternal cardiac dysfunction. Our group has previously identified that features of such injury manifest as cardiac remodeling with left ventricular hypertrophy. Moreover, these features of cardiac remodeling identified in women with chronic hypertension during pregnancy were associated with adverse perinatal outcomes. Recent definitions of maternal cardiac remodeling using echocardiography have been expanded to include measurements of wall thickness. We hypothesized that these new features characterizing cardiac remodeling in women with chronic hypertension may also be associated with adverse perinatal outcomes. OBJECTIVE: There were 3 aims in this study of women with treated chronic hypertension during pregnancy: to (1) apply the updated definitions of maternal cardiac remodeling; (2) elucidate whether these features of cardiac remodeling were associated with adverse perinatal outcomes; and (3) determine which, if any, of the newly defined cardiac remodeling strata were most damaging when compared to women with normal cardiac geometry. STUDY DESIGN: This was a retrospective study of women with treated chronic hypertension during pregnancy delivered from January 2009 through January 2016. Cardiac remodeling was categorized by left ventricular mass index and relative wall thickness into 4 groups determined using the 2015 American Society of Echocardiography guidelines: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Perinatal outcomes were analyzed according to each category of cardiac remodeling compared with outcomes in women with normal geometry. RESULTS: A total of 314 women with treated chronic hypertension underwent echocardiography at a mean gestational age of 17.9 weeks. There were no differences between maternal age (P = .896), habitus (P = .36), or duration of chronic hypertension (P = .212) among the 4 groups. Abnormal cardiac remodeling was found in 51% and was significantly associated with increased rates of superimposed preeclampsia (P = .015), preterm birth (P < .001), and neonatal intensive care admission (P = .003). These outcomes reached the greatest significance when comparisons were made between eccentric hypertrophy and normal geometry. CONCLUSION: Using current American Society of Echocardiography guidelines, 51% of women with treated chronic hypertension during pregnancy have some degree of abnormal cardiac remodeling. Any suggestion of maternal cardiac remodeling, regardless of subtype, was associated with increased risks for superimposed preeclampsia and preterm birth with its resultant perinatal sequelae. Eccentric ventricular hypertrophy, previously thought to mimic exercise physiology, appears to be the most associated with adverse perinatal outcomes. Despite evidence of cardiac remodeling, ejection fraction was preserved. PMID- 29505771 TI - Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin on length of stay in the neonatal intensive care unit. AB - BACKGROUND: Preeclampsia is a major pregnancy complication with adverse short- and long-term implications for both the mother and baby. Screening for preeclampsia at 11-13 weeks' gestation by a combination of maternal demographic characteristics and medical history with measurements of biomarkers can identify about 75% of women who develop preterm preeclampsia with delivery at <37 weeks' gestation and 90% of those with early preeclampsia at <32 weeks, at a screen positive rate of 10%. A recent trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) has reported that in women identified by first-trimester screening as being at high risk for preeclampsia, use of aspirin (150 mg/d from the first to the third trimester), compared to placebo, reduced the incidence of preterm preeclampsia, which was the primary outcome, by 62% (95% confidence interval, 26 80%) and the incidence of early preeclampsia by 89% (95% confidence interval, 53 97%). The surprising finding of the trial was that despite the reduction in preeclampsia the incidence of admission to the neonatal intensive care unit, which was one of the secondary outcomes, was not significantly affected (odds ratio, 0.93; 95% confidence interval, 0.62-1.40). OBJECTIVE: We sought to examine the effect of prophylactic use of aspirin during pregnancy in women at high risk of preeclampsia on length of stay in the neonatal intensive care unit. STUDY DESIGN: This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial to assess evidence of differences in the effect of aspirin on length of stay in neonatal intensive care. Bootstrapping was used for the comparison of mean length of stay between the aspirin and placebo groups. Logistic regression was used to assess treatment effects on stay in the neonatal intensive care unit. RESULTS: In the trial there were 1620 participants and 1571 neonates were liveborn. The total length of stay in neonatal intensive care was substantially longer in the placebo than aspirin group (1696 vs 531 days). This is a reflection of significantly shorter mean lengths of stay in babies admitted to the neonatal intensive care unit from the aspirin than the placebo group (11.1 vs 31.4 days), a reduction of 20.3 days (95% confidence interval, 7.0-38.6; P = .008). Neonatal intensive care of babies born at <32 weeks' gestation contributed 1856 (83.3%) of the total of 2227 days in intensive care across both treatment arms. These occurred in 9 (1.2%) of the 777 livebirths in the aspirin group and in 23 (2.9%) of 794 in the placebo group (odds ratio, 0.42; 95% confidence interval, 0.19-0.93; P = .033). Overall, in the whole population, including 0 lengths of stay for those not admitted to the neonatal intensive care unit, the mean length of stay was longer in the placebo than aspirin group (2.06 vs 0.66 days; reduction of 1.4 days; 95% confidence interval, 0.45-2.81; P = .014). This corresponds to a reduction in length of stay of 68% (95% confidence interval, 20 86%). CONCLUSION: In pregnancies at high risk of preeclampsia administration of aspirin reduces the length of stay in the neonatal intensive care unit by about 70%. This reduction could essentially be attributed to a decrease in the rate of births at <32 weeks' gestation, mainly because of prevention of early preeclampsia. The findings have implications for both short- and long-term health care costs as well as infant survival and handicap. PMID- 29505772 TI - Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: a double-masked, randomized controlled trial. AB - BACKGROUND: Nonsteroidal antiinflammatory drug use has been shown to increase blood pressure in nonpregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. OBJECTIVE: Our goal was to test the hypothesis that nonsteroidal antiinflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. STUDY DESIGN: At delivery, we randomized women with preeclampsia with severe features to receive around-the-clock oral dosing with either 600 mg of ibuprofen or 650 mg of acetaminophen every 6 hours. Dosing began within 6 hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses, and physicians were masked to study allocation. Exclusion criteria were serum aspartate aminotransferase or alanine aminotransferase >200 mg/dL, serum creatinine >1.0 mg/dL, infectious hepatitis, gastroesophageal reflux disease, age <18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours) from delivery to the last blood pressure >=160/110 mm Hg. Secondary outcomes were time from delivery to last blood pressure >=150/100 mm Hg, mean arterial pressure, need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. RESULTS: We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first line pain control. Seven patients crossed over or did not receive their allocated study drug, and 93 completed the study protocol in their assigned groups. We found no differences in baseline characteristics between groups, including mode of delivery, body mass index, parity, race, chronic hypertension, and maximum blood pressure prior to delivery. We did not find a difference in the duration of severe-range hypertension in the ibuprofen vs acetaminophen groups (35.3 vs 38.0 hours, P = .30). There were no differences between groups in the secondary outcome measures of time from delivery to last blood pressure >=150/100 mm Hg, postpartum mean arterial pressure, maximum postpartum systolic or diastolic blood pressures, any postpartum blood pressure >=160/110 mm Hg, short-acting antihypertensive use for acute blood pressure control, length of postpartum stay, need to extend postpartum stay for blood pressure control, antihypertensive use at discharge, or opioid use for inadequate pain control. In a subgroup analysis of patients who experienced severe-range hypertension, the mean time to blood pressure control in the acetaminophen group was 68.4 hours and ibuprofen group was 56.7 hours (P = .26). At 6 weeks postpartum, there were no differences between groups in the rates of obstetric triage visits, hospital readmissions, continued opioid use, or continued antihypertensive use. CONCLUSION: The first line use of ibuprofen rather than acetaminophen for postpartum pain did not lengthen the duration of severe-range hypertension in women with preeclampsia with severe features. PMID- 29505774 TI - Subtarsal Fibrosis Is Associated With Ocular Surface Epitheliopathy in Graft Versus-Host Disease. AB - PURPOSE: To evaluate occurrence of subtarsal fibrosis in patients with graft-vs host disease (GVHD) and to determine its association with ocular surface epitheliopathy. DESIGN: Cross-sectional study. METHODS: We enrolled 40 patients with moderate or severe dry eye disease, including 20 patients with chronic ocular GVHD and 20 patients without (as the control group). All patients had a comprehensive ophthalmic assessment including evaluation for subtarsal fibrosis, corneal and conjunctival staining, tear break-up time (TBUT), and Schirmer test. Furthermore, meibomian gland drop-out area and densities of epithelial and stromal immune cells were measured using meibography and in vivo confocal microscopy, respectively. RESULTS: Subtarsal fibrosis was not seen in any eye of the non-GVHD group. However, 16 eyes (40%) of 10 patients (50%) in the GVHD group had subtarsal fibrosis (P < .001) with an average involvement of 28.9% +/- 13.7% of the tarsal area. Fibrosis was more frequent in the upper lids (35%) than in the lower lids (5%). Regression analyses showed that corneal fluorescein staining was significantly associated with the extent of fibrosis (P < .001, beta = 0.14) and TBUT (P < .001, beta = -0.53) but not with other clinical or imaging parameters. Conjunctival lissamine green staining also had a statistically significant association with the extent of fibrosis (P = .04, beta = 0.12) but not other clinical or imaging parameters. Eyes with subtarsal fibrosis had a more severe ocular surface epitheliopathy compared with eyes without fibrosis. CONCLUSIONS: Subtarsal fibrosis is present in a significant percentage of patients with chronic ocular GVHD, likely contributing to the ocular surface damage in these patients. PMID- 29505773 TI - Impact of contraceptive initiation on vaginal microbiota. AB - BACKGROUND: Data evaluating the impact of contraceptives on the vaginal microbiome are limited and inconsistent. OBJECTIVE: We hypothesized that women initiating copper intrauterine device use would have increased bacterial vaginosis and bacterial vaginosis-associated microbes with use compared to women initiating and using hormonal contraceptive methods. STUDY DESIGN: Vaginal swabs (N = 1047 from 266 participants seeking contraception) for Nugent score determination of bacterial vaginosis and quantitative polymerase chain reaction analyses for assessment of specific microbiota were collected from asymptomatic, healthy women aged 18-35 years in Harare, Zimbabwe, who were confirmed to be free of nonstudy hormones by mass spectrometry at each visit. Contraception was initiated with an injectable (depot medroxyprogesterone acetate [n = 41], norethisterone enanthate [n = 44], or medroxyprogesterone acetate and ethinyl estradiol [n = 40]), implant (levonorgestrel [n = 45] or etonogestrel [n = 48]), or copper intrauterine device (n = 48) and repeat vaginal swabs were collected after 30, 90, and 180 days of continuous use. Self-reported condom use was similar across all arms at baseline. Quantitative polymerase chain reaction was used to detect Lactobacillus crispatus, L jensenii, L gasseri/johnsonii group, L vaginalis, L iners, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera like bacterium phylotype I from swabs. Modified Poisson regression and mixed effects linear models were used to compare marginal prevalence and mean difference in quantity (expressed as gene copies/swab) prior to and during contraceptive use. RESULTS: Bacterial vaginosis prevalence increased in women initiating copper intrauterine devices from 27% at baseline, 35% at 30 days, 40% at 90 days, and 49% at 180 days (P = .005 compared to marginal prevalence at enrollment). Women initiating hormonal methods had no change in bacterial vaginosis prevalence over 180 days. The mean increase in Nugent score was 1.2 (95% confidence interval, 0.5-2.0; P = .001) in women using copper intrauterine devices. Although the frequency and density of beneficial lactobacilli did not change among intrauterine device users over 6 months, there was an increase in the log concentration of G vaginalis (4.7, 5.2, 5.8, 5.9; P = .046) and A vaginae (3.0, 3.8, 4.6, 5.1; P = .002) between baseline and 30, 90, and 180 days after initiation. Among other contraceptive groups, women using depot medroxyprogesterone acetate had decreased L iners (mean decrease log concentration = 0.8; 95% confidence interval, 0.3-1.5; P = .004) and there were no significant changes in beneficial Lactobacillus species over 180 days regardless of contraceptive method used. CONCLUSION: Copper intrauterine device use may increase colonization by bacterial vaginosis-associated microbiota, resulting in increased prevalence of bacterial vaginosis. Use of most hormonal contraception does not alter vaginal microbiota. PMID- 29505775 TI - Autoimmunity, Autoinflammation, and Infection in Uveitis. AB - PURPOSE: To review the pathogenesis of uveitis in light of recent advances in our understanding of innate and adaptive immune responses and their regulation. DESIGN: Perspective. METHODS: Methods included a review of prevailing views on the pathogenesis of uveitis and an analysis of developments in immunology that impact on its conceptual basis, particularly the concept of immunologic tolerance and its loss in autoimmunity. Importantly, the role of infection in the pathogenesis of uveitis is evaluated. RESULTS: The results comprise a reappraisal of the pathogenesis of anterior vs posterior uveitis in the context of the blood retinal barrier and its relation to autoimmune, autoinflammatory, and infectious uveitis. Autoimmunity is seen as a possible cause of certain forms of uveitis but definitive proof is lacking. Autoinflammatory disease, involving activated innate immune mechanisms, is considered causative in a second set of uveitis conditions. A place for infection in uveitis generally is proposed within a unifying concept for the pathogenesis of uveitis. CONCLUSION: Infection may be implicated directly or indirectly in many forms of noninfectious or undifferentiated uveitis. In addition to the growing recognition that foreign antigen, including reactivatable infectious agents, might hide within ocular tissues, the possibility that a dysregulated microbiome might generate T cells that cause immune-mediated ocular inflammation has now been demonstrated experimentally. An uncontrolled, overexuberant host immune response may cause continuing irreversible tissue damage even after the infection has been cleared. PMID- 29505776 TI - Macular Displacement After Vitrectomy in Eyes With Idiopathic Macular Hole Determined by Optical Coherence Tomography Angiography. AB - PURPOSE: To determine whether the macula is displaced after vitrectomy with internal limiting membrane (ILM) peeling in eyes with an idiopathic macular hole. DESIGN: A retrospective, observational case series. METHODS: Optical coherence tomography angiography was used to obtain 3 mm * 3 mm en face images before and 2, 4, and 8 weeks after the vitrectomy with ILM peeling for 20 eyes of 20 patients with an idiopathic macular hole. The displacements of easily identifiable retinal vessel bifurcations were measured relative to the fovea and the optic disc. RESULTS: The distance between the optic disc and vessel bifurcations was significantly shorter in all 4 quadrants throughout the postoperative period (P < .001). This distance was significantly greater in the temporal quadrant (P < .001). The distance of the bifurcations was significantly correlated with the preoperative distance from the optic disc (r = -0.579, P < .001). A significantly greater downward displacement was observed in the superior quadrant (P < .001). The change in the angle of bifurcations was significantly correlated with the preoperative angle to the optic disc (r = -0.632, P < .001). The change in the distance in the inner region was significantly greater than that in the outer region in all quadrants. A significant reduction was observed in the mean foveal avascular zone area during the follow-up period. CONCLUSIONS: The retina in the macular region was displaced nasally, probably owing to movement of the retina toward the optic disc because of a contraction after the ILM removal. There is also a possibility of a rotation downward by buoyancy from gas tamponade, and centripetal contraction during the process of hole closure. PMID- 29505777 TI - Editorial Comment. PMID- 29505778 TI - Rapid quantification of tyrosine sulfation in therapeutic proteins. AB - Protein tyrosine sulfation (Tyr-O-SO3) is a common post-translational modification (PTM), which is important for protein function. Absolute quantitation of Tyr-O-SO3 in recombinant therapeutic proteins has been challenging. We report here an MRM method used for absolute quantitation of Tyr-O SO3 in the hydrolysate of a recombinant Fc-fusion protein. Quantitation is achieved by monitoring the sum of two transitions: the loss of carboxylic acid from tyrosine sulfate (major transition) and sulfate group from tyrosine sulfate sodium salt. The method exhibits a good sensitivity with a limit of quantitation of 1.4 ng/mL, linearity over three orders of magnitude, good repeatability, precision and accuracy. PMID- 29505779 TI - Methods for imaging mammalian mitochondrial morphology: A prospective on MitoGraph. AB - Mitochondria are found in a variety of shapes, from small round punctate structures to a highly interconnected web. This morphological diversity is important for function, but complicates quantification. Consequently, early quantification efforts relied on various qualitative descriptors that understandably reduce the complexity of the network leading to challenges in consistency across the field. Recent application of state-of-the-art computational tools have resulted in more quantitative approaches. This prospective highlights the implementation of MitoGraph, an open-source image analysis platform for measuring mitochondrial morphology initially optimized for use with Saccharomyces cerevisiae. Here Mitograph was assessed on five different mammalian cells types, all of which were accurately segmented by MitoGraph analysis. MitoGraph also successfully differentiated between distinct mitochondrial morphologies that ranged from entirely fragmented to hyper elongated. General recommendations are also provided for confocal imaging of labeled mitochondria (using mito-YFP, MitoTracker dyes and immunostaining parameters). Widespread adoption of MitoGraph will help achieve a long-sought goal of consistent and reproducible quantification of mitochondrial morphology. PMID- 29505780 TI - Complete solubilization of cartilage using the heat-stable protease thermolysin for comprehensive GAG analysis. AB - Articular cartilage comprises collagens, proteoglycans, and glycosaminoglycans (GAGs) together with water, in hyaline matrixes. Articular cartilage is resistant to proteolytic solubilization for comprehensive GAG analyses partly because of assemblies of collagen fibers with thermolabile hydrogen bonds. In this study, we used the heat-stable protease thermolysin to digest collagen in solid articular cartilage at 70 degrees C and compared the efficiencies of collagen digestion and GAG extraction to those with collagenase digestion at 50 degrees C. Overnight digestion with thermolysin completely solubilized cartilage, whereas collagenase with >10-times higher proteolytic activity digested <20% of collagen. Following thermolysin treatments, almost all GAGs were extracted from the cartilage, whereas only 56% of GAGs were extracted after collagenase digestion. Disaccharide analyses of extracted GAG chains revealed >98% extraction efficiencies of several GAG classes from thermolysin-treated cartilage, compared with <60% extraction efficiencies using collagenase, depending on GAG classes. These results indicate that thermolysin allows complete GAG extraction from solid articular cartilage and that complete solubilization is required for accurate and reproducible analyses of cartilage GAGs. Hence, thermolysin offers a tool for complete solubilization of cartilage prior to comprehensive GAGomic analysis, and is likely applicable to other collagen-rich tissues such as ligaments, skin, and blood vessels. PMID- 29505781 TI - Analyzing mitochondrial function in human peripheral blood mononuclear cells. AB - Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for producing most of the adenosine triphosphate required by eukaryotic cells. Lymphocytes make up the majority of the peripheral blood mononuclear cells. Peripheral blood mononuclear cells are readily obtainable, providing an ideal sample to monitor systemic changes and understand molecular signaling mechanisms in disease processes. Mitochondrial energy metabolism of lymphocyte has been used to screen for OXPHOS disorders. While there are increasing studies of lymphocyte OXPHOS, few studies examined activity of electron transport chain of lymphocyte mitochondria. We present an optimal protocol to harvest fresh peripheral blood mononuclear cells from human whole blood, determine integrated mitochondrial function, and analyze electron transport chain complex activity. Analyzing integrated mitochondrial function using OXPHOS provides data to uncover defects in the transport of substrates into the mitochondria, generation of reducing equivalents, the electron transport chain, and coupling to the production of adenosine triphosphate. The optimal conditions to harvest peripheral blood mononuclear cells were using blood anticoagulated with ethylenediaminetetraacetic acid, processed utilizing LymphoprepTM, and washed in phosphate buffered saline, all at room temperature. Using isolated peripheral blood mononuclear cells, integrated mitochondrial function and the activities of electron transport chain were determined. PMID- 29505782 TI - Therapeutic mild hypothermia improves early outcomes in rats subjected to severe sepsis. AB - AIMS: Therapeutic hypothermia has shown beneficial effects in sepsis. This study focused on its mechanism. MAIN METHODS: Sixteen male Sprague-Dawley rats underwent cecal ligation and perforation and subsequently were treated with either hypothermia (HT; body temperature cooled and maintained at 34 degrees C by ice pad for 10 h; n = 8) or normothermia (NT; n = 8). Three additional rats underwent sham surgery. The body temperatures of the sham-operated and NT groups were maintained at 38 degrees C with a thermal pad. After the hypothermia treatment, the HT rats were rewarmed for 2 h. The groups were compared for circulating cytokines (IL-6, IL-10), lactate, high mobility group box-1 protein (HMGB1), and lung and intestinal lesions. Animals were observed for 24 h. KEY FINDINGS: Compared with the sham-operated group, the 2 sepsis group rats had significantly higher circulating IL-6, HMGB1, and lactate levels, and tissue injury. In the HT rats, the levels of IL-6, HMGB1, and lactate, the lung wet-to dry ratio, and lung and intestinal damage were significantly lower than that of the NT group. Circulating IL-10 levels increased significantly after 12 h in the sepsis groups compared with sham animals, while that of the NT and HT groups were comparable. The survival rates of the NT and HT rats were also comparable. SIGNIFICANCE: Therapeutic hypothermia in a rat model of sepsis was associated with lower levels of circulating IL-6 and HMGB1, and less capillary leakage and tissue edema. These results suggest that mild hypothermia has potential as a therapy in sepsis. PMID- 29505783 TI - Sesamin induces ER stress-mediated apoptosis and activates autophagy in cervical cancer cells. AB - AIMS: Sesamin, a major lignan of sesame oil, has demonstrated anticancer properties. However, its anticancer effects on cervical cancer have not been studied. Here, we investigated the effects of sesamin on cervical cancer (HeLa) cell line and explored the underlying mechanisms. MAIN METHODS: HeLa cells were cultured with sesamin. CCK-8 and scratch wound test were applied to detect the proliferation and migration ability, while flow cytometry and TUNEL staining were applied to detect apoptosis. The expression of Bax and Bcl-2 was assessed by Western blotting. Further observe the ultrastructure using transmission electron microscopy (TEM) and detect the expression of caspase-12, GRP78, GADD153, IRE1alpha, p-IRE1alpha, JNK, p-JNK, LC3I/II and beclin-1. In addition, HeLa cells were treated with 3-MA (an autophagy inhibitor) and/or sesamin. Then detect the expression of LC3I/II and cell viability. KEY FINDINGS: CCK-8 and scratch wound test revealed that sesamin inhibits HeLa cells proliferation and migration, while flow cytometry and TUNEL staining indicated that sesamin induces apoptosis in these cells. In sesamin group, the expression of Bax, caspase-12, GRP78, GADD153, p-IRE1alpha, p-JNK, LC3I/II and beclin-1 was up-regulated while Bcl-2 was down regulated compared to control group. Further research revealed that sesamin also induces Hela cells autophagy and inhibition of autophagy increases cell viability of sesamin-treated HeLa cells. SIGNIFICANCE: Sesamin inhibits proliferation/migration of HeLa cells and induces ER stress-mediated apoptosis through IRE1alpha/JNK pathway, and that it activates autophagy and autophagic death in these cells, further validate the anticancer effect of sesamin. PMID- 29505784 TI - Hypolipidemic, antioxidant and antiatherogenic property of sardine by-products proteins in high-fat diet induced obese rats. AB - AIMS: Fish by-products valorization on account of their richness in bioactive compounds may represent a better alternative to marine products with a view to economic profitability and sustainable development. In this study, we compared the effect of sardine by-product proteins (SBy-P), with those of the fillets (SF P) or casein (Cas), on growth parameters, serum leptin level, lipids disorders, lipid peroxidation and reverse cholesterol transport, in diet-induced obese rats. MAIN METHODS: Obesity was induced by feeding rats a high-fat diet (20% sheep fat), during 12 weeks. At body weight (BW) of 400 +/- 20 g, eighteen obese rats were divided into three homogenous groups and continue to consume the high-fat diet for 4 weeks containing either, 20% SBy-P, SF-P or Cas. KEY FINDINGS: The results showed that SBy-P, compared to SF-P and Cas, efficiently reduced food intake (FI), BW gain and serum leptin level, and improved blood lipids levels and reverse cholesterol transport by reducing total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-HDL1-C) serum levels, increasing the level of high-density lipoprotein cholesterol (HDL2-C and HDL3-C), and enhancing lecithin: cholesterol acyltransferase (LCAT) activity. Furthermore, they attenuated lipid peroxidation by increasing atheroprotective activity of the paraoxonase-1 (PON-1). SIGNIFICANCE: Sardine by-product proteins due to their richness in certain essential amino acids, highlight weight-loss, lipid-lowering, antioxidant and anti-atherogenic potentials, contributing to the improvement of the complications associated with obesity. PMID- 29505785 TI - Striatal GluN2B involved in motor skill learning and stimulus-response learning. AB - Although the striatum has a well-documented role in procedural learning and memory, the underlying mechanisms remain poorly understood. GluN2B subunit is abundantly expressed in striatum, however, the function of striatal GluN2B subunit in striatum-related learning is also unclear. In the present study, using transgenic mice with forebrain-specific overexpression of the GluN2B subunit, we observed that up-regulation of GluN2B subunit expression results in enhanced dorsal striatum-related motor skill learning and stimulus-response (S-R) learning as well as cortico-dorsomedial striatal (cortico-DMS) long-term potentiation (LTP). Consistent with the above results, we also found that GluN2B transgenic mice exhibited a remarkable increase in N-methyl-d-aspartic acid receptor (NMDAR) mediated currents in the dorsomedial striatum. In addition, in order to further verify that striatal GluN2B is involved in the dorsal striatum-related cognitive function, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of GluN2B gene in the dorsomedial striatum. As a consequence of down regulation of dorsomedial striatal GluN2B subunit expression, defective motor skill learning and S-R learning were observed in the GluN2B-shRNA mice. Furthermore, the impaired cortico-DMS LTP, as well as decreased NMDAR mediated currents in the dorsomedial striatum were also detected. Taken together, our findings demonstrate for the first time that striatal GluN2B subunit plays an important role in the dorsal striatum-related motor skill learning and S-R learning and provide further evidence that the cortico-DMS LTP underlies dorsal striatum-related motor skill learning and S-R learning. PMID- 29505786 TI - Deep brain stimulation and fluoxetine exert different long-term changes in the serotonergic system. AB - Both selective serotonin reuptake inhibitors (SSRIs) and ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) modulate serotonergic activity. We compared the acute (1 day) and long-term (12 days) effects of vmPFC stimulation and fluoxetine on serotonin (5-HT) release and receptor expression in rats. Samples to measure serotonin levels were collected from the hippocampus using microdialysis. Serotonin transporter (SERT), 5-HT1A and 5-HT1B mRNA were measured using in situ hybridization. [3H]8-OH-DPAT and [125I]cyanopindolol autoradiography were used to measure 5-HT1A and 5-HT1B binding. Our results show that after fluoxetine injections serotonin levels were approximately 150% higher than at baseline. Twelve days later, pre-injection 5-HT extracellular concentration was substantially higher than on day 1. In contrast, serotonin levels following DBS were only 50% higher than at baseline. While pre-stimulation 5-HT on day 12 was significantly higher than on treatment day 1, no stimulation induced 5-HT peak was recorded. SERT expression in the dorsal raphe was increased after acute fluoxetine and decreased following a single day of DBS. Neither fluoxetine nor DBS administered acutely substantially changed 5-HT1A or 5-HT1B binding. Chronic fluoxetine treatment, however, was associated with a decrease in [3H]8-OH-DPAT prefrontal cortex and hippocampus expression. In contrast, chronic DBS induced a significant increase in [125I]cyanopindolol binding in the prefrontal cortex, globus pallidus, substantia nigra and raphe nuclei. mRNA expression of 5-HT1A and 5-HT1B in raphe nuclei was not altered by either treatment. These results suggest that fluoxetine and DBS modulate activity of the serotonergic system but likely exert their effects through different mechanisms. PMID- 29505787 TI - Thrombolytic therapies for ischemic stroke: Triumphs and future challenges. AB - Acute stroke therapy has significantly evolved over the last two decades. The two main advances have been the approval of intravenous chemical thrombolysis in 1995, and the approval of intra-arterial mechanical thrombectomy in 2015. This has led to significant improvement of functional outcomes in a disease known to be the first cause of disability worldwide. Subsequent studies have focused on identifying pre-treatment predictors of good treatment candidates, by developing biochemical and imaging biomarkers. Different doses and agents of thrombolysis are also being tested. In this review article, we explain the fundamentals of stroke therapy focusing on the time, recanalization and collateral perfusion factors. We then review recent advances in stroke thrombolysis, the most significant of which is the recent trials on a novel rtPA agent, tenecteplase, and approval of endovascular treatment as a standard of care. Looking ahead, defining the benefits and limitations of bridging chemical with mechanical thrombolysis is a key area of current interest. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 29505788 TI - Metabotropic glutamate receptor subtype 7 in the dorsal striatum oppositely modulates pain in sham and neuropathic rats. AB - The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N'-bis(diphenylmethyl)-1,2 ethanediamine (AMN082), a selective mGluR7 positive allosteric modulator, into the dorsal striatum, facilitated pain, increased the activity of the ON cells and inhibited the activity of the OFF cells in the rostral ventromedial medulla, and decreased glutamate levels in the dorsal striatum. Conversely, AMN082 inhibited pain and the activity of the ON cells while increased the activity of the OFF cells in rats with spared nerve injury (SNI) of the sciatic nerve. AMN082 also decreased glutamate levels in the dorsal striatum of SNI rats. The effect of AMN082 on mechanical allodynia and glutamate release was blocked by 6-(2,4 dimethylphenyl)-2-ethyl-6,7-dihydro-4(5H)-benzoxazolone (ADX71743), a selective mGluR7 negative allosteric modulator. Moreover, in the sham rats, AMN082 increased the activity of total nociceptive convergent neurons in the dorsal reticular nucleus while in the SNI rats, such activity was decreased. The administration of lidocaine into the subthalamic nucleus abolished the effect of AMN082 on the total nociceptive convergent neurons in the sham rats but not in the SNI rats. Thus, the dual effect of mGluR7 in facilitating or inhibiting pain responses may be due to the recruitment of different pathways of the basal ganglia, the indirect or direct pathway, in physiological or pathological conditions, respectively. PMID- 29505789 TI - Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons. AB - Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5 min) and long exposures (1h) in rat hippocampal cultures. Notably, the consequence of TLR3 activation on neuronal function was reproduced in iPSC-derived cortical neurons, with poly I:C (25 MUg/ml, 1h) significantly inhibiting sAP firing. We examined the mechanisms underlying these effects, with poly I:C significantly reducing peak sodium current, an effect dependent on the MyD88-independent TRIF dependent pathway. Furthermore, poly I:C (25 MUg/ml, 1h) resulted in a significant reduction in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude and significantly reduced surface AMPAR expression. These novel findings reveal that TLR3 activation inhibits neuronal excitability and synaptic activity through multiple mechanisms, with this being observed in both rat and human iPSC-derived neurons. These data might provide further insight into how TLR3 activation may contribute to neurodevelopmental disorders following maternal infection and in patients with increased susceptibility to herpes simplex encephalitis. PMID- 29505790 TI - Berberine alleviates hepatic lipid accumulation by increasing ABCA1 through the protein kinase C delta pathway. AB - Abnormal lipid metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). The ATP-binding cassette transporter A1 (ABCA1) protein mediates the transport of cholesterol and phospholipids from cells to apolipoprotein A-I (apoA-I) to generate nascent HDL particles. Previous studies revealed that the overexpression of ABCA1 alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effect of berberine (BBR) on ABCA1 in QSG-7701 hepatocytes and in mice. BBR decreased hepatic cholesterol and triglyceride levels. It also increased ABCA1 protein levels but not mRNA levels in a time- and dose-dependent manner. The PKCdelta inhibitor rottlerin and PKCdelta siRNA completely abolished the effect of BBR on ABCA1. BBR also decreased the phosphorylation of ABCA1 serine residues and PKCdelta Tyr 311. The inhibition of ABCA1 with its siRNA abolished the reduction in cellular cholesterol levels by BBR. BBR administration to mice fed a methionine choline deficient diet also significantly increased ABCA1 protein levels and reduced hepatic lipid levels. These results suggest that BBR can reduce steatosis by increasing ABCA1 protein levels through PKCdelta to reduce the phosphorylation of serine residues in ABCA1. PMID- 29505791 TI - Hypothermia-induced RNA-binding motif protein 3 (RBM3) stimulates osteoblast differentiation via the ERK signaling pathway. AB - The RNA-binding motif protein 3 (RBM3) belongs to a small group of proteins whose synthesis increases during hypothermia while global protein production is slowed down. Bone homeostasis is maintained by a balance between bone resorption and bone formation. Osteoblasts are key components of the bone and have an important role in bone remodeling cycle. However, hypothermia-induced RBM3 between osteoblasts remains unclear. At 32 degrees C, expression of RBM3 and Runx2 was increased in a time-dependent manner and mineralization was also increased. RBM3 was also increased in a time-dependent manner under osteogenic conditions. Overexpression of RBM3 increased the expression of osteogenic genes such as Runx2 and OC. The osteogenic condition-induced expressions of RBM3, Runx2 and OC gene were decreased by RBM3 siRNA. Moreover, RBM3 promoted ERK and p38 phosphorylation. The inhibitor of ERK decreased the expression of Runx2 but did not affect the expression of RBM3. Taken together, these results demonstrate that RBM3 stimulates osteoblast differentiation via the ERK signaling pathway. PMID- 29505792 TI - Evodiamine induces apoptosis and promotes hepatocellular carcinoma cell death induced by vorinostat via downregulating HIF-1alpha under hypoxia. AB - Hypoxia promotes HCC progression and therapy resistance, and there is no systemic treatment for HCC patients after sorafenib resistance. Thus, it is urgent to develop potential therapeutic regimens for HCC patients by targeting hypoxia signaling. In this study, we showed that evodiamine might be a potential therapeutic medicine for HCC by suppressing HIF-1alpha. In addition, evodiamine could sensitize the anti-HCC effect of vorinostat in HCC cells under hypoxia. Furthermore, evodiamine plus vorinostat accelerated the degradation of HIF-1alpha in HCC cells under hypoxia. In general, evodiamine might be a potential therapeutic candidate for HCC patients, and evodiamine combining with vorinostat might be an attractive chemotherapy strategy for HCC treatment. PMID- 29505793 TI - Evaluation of the toxic effects of celecoxib on Xenopus embryo development. AB - Celecoxib is a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 and is prescribed for severe pain and inflammation. The excellent therapeutic effects of celecoxib mean that it is frequently used clinically, including for women of child-bearing age. However, the prenatal effects of this compound have not been studied extensively in vertebrates. The present study examined the developmental toxicity of celecoxib using a frog embryo teratogenic assay-Xenopus (FETAX). In addition, we examined its effects on cell migration using co-cultures of human umbilical vein endothelial cells and 10T1/2 cells. These studies revealed that celecoxib induced concentration dependent mortality and various malformations of the Xenopus internal organs, including gut miscoiling, haemorrhage, and oedema. Celecoxib also downregulated the expression of vascular wall markers (Msr and alpha smooth muscle actin) and other organ-specific markers (Nkx2.5, Cyl104 and IFABP). In vitro co-culture studies revealed that celecoxib inhibited pericyte migration and differentiation into vascular smooth muscle cells. In conclusion, celecoxib was both toxic and teratogenic in Xenopus embryos, where it produced serious heart and vessel malformation by inhibiting vascular wall maturation and vascular network formation. PMID- 29505794 TI - Characterizing ISI and sub-threshold membrane potential distributions: Ensemble of IF neurons with random squared-noise intensity. AB - A theoretical investigation is presented that characterizes the emerging sub threshold membrane potential and inter-spike interval (ISI) distributions of an ensemble of IF neurons that group together and fire together. The squared-noise intensity sigma2 of the ensemble of neurons is treated as a random variable to account for the electrophysiological variations across population of nearly identical neurons. Employing superstatistical framework, both ISI distribution and sub-threshold membrane potential distribution of neuronal ensemble are obtained in terms of generalized K-distribution. The resulting distributions exhibit asymptotic behavior akin to stretched exponential family. Extensive simulations of the underlying SDE with random sigma2 are carried out. The results are found to be in excellent agreement with the analytical results. The analysis has been extended to cover the case corresponding to independent random fluctuations in drift in addition to random squared-noise intensity. The novelty of the proposed analytical investigation for the ensemble of IF neurons is that it yields closed form expressions of probability distributions in terms of generalized K-distribution. Based on a record of spiking activity of thousands of neurons, the findings of the proposed model are validated. The squared-noise intensity sigma2 of identified neurons from the data is found to follow gamma distribution. The proposed generalized K-distribution is found to be in excellent agreement with that of empirically obtained ISI distribution of neuronal ensemble. PMID- 29505795 TI - Psychoeducational Intervention for Symptom Management of Fatigue, Pain, and Sleep Disturbance Cluster Among Cancer Patients: A Pilot Quasi-Experimental Study. AB - OBJECTIVES: To assess the feasibility of conducting a trial of a psychoeducational intervention involving the provision of tailored information and coaching to improve management of a cancer-related symptom cluster (fatigue, pain, and sleep disturbance) and reduce symptom cluster impacts on patient health outcomes in the Vietnamese context and to undertake a preliminary evaluation of the intervention. METHODS: A parallel-group single-blind pilot quasi-experimental trial was conducted with 102 cancer patients in one Vietnamese hospital. The intervention group received one face-to-face session and two phone sessions delivered by a nurse one week apart, and the comparison group received usual care. Patient outcomes were measured at baseline before the chemotherapy cycle and immediately preceding the next chemotherapy cycle. Separate linear mixed models were used to evaluate the impact of the intervention on total symptom cluster severity, symptom scores, functional status, depressive symptoms, and health-related quality of life. RESULTS: The study design was feasible with a recruitment rate of 22.6% and attrition rate of 9.8%. Compared to the control group, the intervention group showed a significant reduction in symptom cluster severity, fatigue severity, fatigue interference, sleep disturbance, depression, and anxiety. Significant differences were not observed for pain severity, pain interference, functional status, and health-related quality of life. The intervention was acceptable to the study population, with a high attendance rate of 78% and adherence rate of 95.7%. CONCLUSION: On the basis of the present study findings, future randomized controlled trials are needed to test the effectiveness of a symptom cluster psychoeducational intervention in Vietnam. PMID- 29505796 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin can alter the sex ratio of embryos with decreased viability of Y spermatozoa in mice. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a reproductive and developmental toxicant that can alter the sex ratio of offspring (proportion of male offspring). We hypothesized that the alteration of sex ratio is associated with sex chromosome ratio of live spermatozoa affected by exposure to TCDD. After exposure to TCDD we analyzed simultaneously sperm sex chromosome constitution and viability, and evaluated sperm sex chromosome ratio association with embryo sex ratio in mice. Short-term exposure to TCDD affects the decreased sperm motility and viability, and the increased acrosome reaction. Interestingly, Y spermatozoa survived shorter than X spermatozoa at high concentrations of TCDD. Moreover, the decreased sex ratio of embryos was associated with the short lifespan of Y spermatozoa. Our results suggest that TCDD may affect the fertility of Y spermatozoa more than X spermatozoa. Further studies are needed to compare the difference of fertilizing capability between X and Y spermatozoa by the effect of TCDD. PMID- 29505798 TI - In-silico study of toxicokinetics and disease association of chemicals present in smokeless tobacco products. AB - Smokeless tobacco (SLT) products are consumed by millions of people in over 130 countries around the world. Consumption of SLT has been estimated to cause a number of diseases accounting to more than 0.65 million deaths per year. There is sufficient epidemiological evidence on the association of SLT products with nicotine addiction, cancers of oral cavity and digestive systems but there is a lack of understanding of the role of toxic chemicals in these diseases. We provide the first comprehensive in-silico analysis of chemical compounds present in different SLT products used worldwide. Many of these compounds are found to have good absorption, solubility and permeability along with mutagenic and toxic properties. They are also found to target more than 350 human proteins involved in a plethora of human biological processes and pathways. Along with all the previously known diseases, the present study has identified the association of compounds of SLT products with a number of unknown diseases like neurodegenerative, immune and cardiac diseases (Left ventricular non compaction, dilated cardiomyopathy etc). These findings indicate far-reaching impact of SLT products on human health than already known which needs further validations using epidemiological, in-vitro and in-vivo methodologies. Thus, this study will provide one stop information for the policy makers in development of regulatory policies on toxic contents of SLT products. PMID- 29505799 TI - Pre-pregnancy consumption of starchy vegetables and legumes and risk of gestational diabetes mellitus among Tehranian women. AB - AIMS: The aim of this study was to investigate the association between legumes and starchy vegetables, including 1. potatoes and 2. other starchy vegetables (corn, squash, green pea, and green lima beans), and GDM among Tehranian women. METHODS: Our study included 1026 pregnant women, aged 18-45 years, who consecutively attended prenatal clinics in five hospitals affiliated to universities of medical sciences in Tehran. The diagnosis of GDM was based on the criteria set by the American Diabetes Association. Dietary intakes were assessed during gestational age <=6 weeks with a validated food frequency questionnaire. RESULTS: Of the 1026 pregnant women, 6.9% developed GDM. With respect to potato, higher consumption was negatively associated with GDM risk; OR for those who consumed >=2.1 servings/week was 0.53 (95% CI 0.29-0.97), an association which disappeared after adjustment for confounding factors. For legumes, higher consumption was negatively associated with GDM; OR for those who consumed >=3.3 servings/week was 0.38 (95% CI 0.19-0.74), also an association that did not change appreciably after adjustment for confounding factors. There was no significant association with the consumption of total starchy or other starchy vegetables with GDM. CONCLUSIONS: Higher consumption of legumes during reproductive age decrease the risk of GDM during pregnancy. PMID- 29505797 TI - Changes in gene expression following long-term in vitro exposure of Macaca mulatta trophoblast stem cells to biologically relevant levels of endocrine disruptors. AB - Trophoblast stem cells (TSCs) are crucial for embryo implantation and placentation. Environmental toxicants that compromise TSC function could impact fetal viability, pregnancy, and progeny health. Understanding the effects of low, chronic EDC exposures on TSCs and pregnancy is a priority in developmental toxicology. Differences in early implantation between primates and other mammals make a nonhuman primate model ideal. We examined effects of chronic low-level exposure to atrazine, tributyltin, bisphenol A, bis(2-ethylhexyl) phthalate, and perfluorooctanoic acid on rhesus monkey TSCs in vitro by RNA sequencing. Pathway analysis of affected genes revealed negative effects on cytokine signaling related to anti-viral response, most strongly for atrazine and tributyltin, but shared with the other three EDCs. Other affected processes included metabolism, DNA repair, and cell migration. Low-level chronic exposure of primate TSCs to EDCs may thus compromise trophoblast development in vivo, inhibit responses to infection, and negatively affect embryo implantation and pregnancy. PMID- 29505801 TI - The rearranged mitochondrial genome of Podagrion sp. (Hymenoptera: Torymidae), a parasitoid wasp of mantis. AB - The complete sequence of the mitochondrial genome of Podagrion sp. (Hymenoptera: Torymidae) is described. The mitogenome was 15,845 bp in size, and contained typical sets of mitochondrial genes. The base composition of the Podagrion sp. mitogenome was also biased toward A + T bases (81.8%). The mitochondrial genome of Podagrion sp. has a weak AT skew (0.07) and a strong GC skew (-0.26). Podagrion sp. exhibits a novel rearrangement compared with the ancestral order, including six protein-coding genes (nad3, cox3, atp6, atp8, cox2 and cox1), which have inverted to the minor strand from the major strand. The A + T-rich region of Podagrion sp., which is located between trnN and trnI, have five tandem repeats. The apomorphic rearrangements, including the conserved block "cox3-atp6-atp8-cox2 cox1-nad5-nad4-nad4l-nad6-cob" and the special locations of trnV and trnA, were mapped onto the phylogeny of Proctotrupomorpha. PMID- 29505800 TI - Rab7a modulates ER stress and ER morphology. AB - The Endoplasmic Reticulum (ER) is a membranous organelle with diverse structural and functional domains. Peripheral ER includes interconnected tubules, and dense tubular arrays called "ER matrices" together with bona fide flat cisternae. Transitions between these states are regulated by membrane-associated proteins and cytosolic factors. Recently, the small GTPases Rab10 and Rab18 were reported to control ER shape by regulating ER dynamics and fusion. Here, we present evidence that another Rab protein, Rab7a, modulates the ER morphology by controlling the ER homeostasis and ER stress. Indeed, inhibition of Rab7a expression by siRNA or expression of the dominant negative mutant Rab7aT22 N, leads to enlargement of sheet-like ER structures and spreading towards the cell periphery. Notably, such alterations are ascribable neither to a direct modulation of the ER shaping proteins Reticulon-4b and CLIMP63, nor to interactions with Protrudin, a Rab7a-binding protein known to affect the ER organization. Conversely, depletion of Rab7a leads to basal ER stress, in turn causing ER membrane expansion. Both ER enlargement and basal ER stress are reverted in rescue experiments by Rab7a re-expression, as well as by the ER chemical chaperone tauroursodeoxycholic acid (TUDCA). Collectively, these findings reveal a new role of Rab7a in ER homeostasis, and indicate that genetic and pharmacological ER stress manipulation may restore ER morphology in Rab7a silenced cells. PMID- 29505802 TI - Emission of categorized 50-kHz ultrasonic vocalizations in rats repeatedly treated with amphetamine or apomorphine: Possible relevance to drug-induced modifications in the emotional state. AB - The emission of 50-kHz ultrasonic vocalizations (USVs) is increasingly emerging as a potential behavioral marker of the subjective effects that psychoactive drugs elicit in rats. However, multiple categories of 50-kHz USVs have been identified, which are thought to possess different behavioral significance. Besides, limited information is available on how psychoactive drugs affect the emission of categorized 50-kHz USVs. To further elucidate this issue, we evaluated the numbers of multiple categories of 50-kHz USVs emitted by rats repeatedly treated with amphetamine (1 or 2 mg/kg, i.p.) or apomorphine (2 or 4 mg/kg, i.p.), two drugs that elicit similar and dissimilar subjective effects. Amphetamine- and apomorphine-treated rats emitted patterns of categorized 50-kHz USVs that varied according to the drug administered, drug dose, and number of drug administrations. Nevertheless, the numbers of several categories of 50-kHz USVs were positively correlated with the number of total calls emitted (i.e., the sum of categorized 50-kHz USVs). Moreover, a marked interindividual variability in the emission of categorized 50-kHz USVs was observed. Taken together, the present results may be relevant to further elucidating the interplay between calling of the 50-kHz USVs group and psychopharmacological profile of drugs. PMID- 29505803 TI - Excitatory repetitive transcranial magnetic stimulation applied to the right inferior frontal gyrus has no effect on motor or cognitive impulsivity in healthy adults. AB - BACKGROUND: Impulsivity is a multi-faceted concept. It is a crucial feature of many neuropsychiatric disorders. Three subtypes of impulsivity have been identified: motor, temporal, and cognitive impulsivity. Existing evidence suggests that the right inferior frontal gyrus (rIFG) plays a crucial role in impulsivity, and such a role has been elucidated using inhibitory repetitive transcranial magnetic stimulation (rTMS). There is a dearth of studies using excitatory rTMS at the rIFG, an important gap in the literature this study aimed to address. METHODS: Twenty healthy male adults completed a single-blind sham controlled randomised crossover study aimed at assessing the efficacy of rTMS in the neuromodulation of impulsivity. This involved delivering 10-Hz excitatory rTMS to the rIFG at the intensity of 100% motor threshold with 900 pulses per session. Trait impulsivity was measured at baseline using the Barrett Impulsiveness Scale and UPPS-P Impulsiveness Scale. The Stop Signal Task (SST) and Information Sampling Task (IST), administered before and after rTMS sessions, were used as behavioural measures of impulsivity. RESULTS: No significant changes on any measures from either SST or IST after active rTMS at the rIFG compared to the sham-controlled condition were found. CONCLUSIONS: Excitatory rTMS applied to the rIFG did not have a statistically significant effect on response inhibition and reflective/cognitive impulsivity. Further research is required before drawing firm conclusions. This may involve a larger sample of highly impulsive individuals, a different stimulation site or a different TMS modality such as theta burst stimulation. PMID- 29505804 TI - Outcome of a three-phase treatment algorithm for inpatients with melancholic depression. AB - BACKGROUND: In patients suffering from major depressive disorder, non-response to initial antidepressant monotherapy is relatively common. The use of treatment algorithms may optimize and enhance treatment outcome. METHODS: A single-center 3 phase treatment algorithm was evaluated for inpatients with major depressive disorder, i.e. phase I (n = 85): 7 weeks optimal antidepressant monotherapy (imipramine or venlafaxine); phase II (n = 39): 4 weeks subsequent plasma level targeted dose lithium addition in case of insufficient improvement of antidepressant monotherapy; and phase III (n = 8): subsequent electroconvulsive therapy in case of insufficient improvement of antidepressant-lithium treatment. Overall feasibility of the 3-phase algorithm was determined by the number of dropouts, and overall efficacy was evaluated using weekly scores on the 17-item Hamilton Rating Scale for Depression (HAM-D) during the treatment phases of the algorithm. This paper is based on an RCT comparing the two antidepressants in phase I and adding lithium in phase II. RESULTS: Of the 85 patients analyzed, overall dropout during the 3-phase treatment algorithm was 24 (28%) patients. When analyzing the 3-phase treatment algorithm on a modified intention-to-treat basis, 39 (46%) patients achieved complete remission (HAM-D score <= 7) by the end of the algorithm. Regarding response (HAM-D score reduction >=50%): of the 85 patients, 60 (71%) were responders by the end of the algorithm. CONCLUSION: The favorable outcome of the 3-phase treatment algorithm emphasizes the importance of pursuing stepwise antidepressant treatment in patients who are nonresponsive to the first antidepressant. CLINICAL TRIAL REGISTRATION: This study protocol is registered at http://www.controlled-trials.com, "Pharmacological Treatment of Depression" (identifier: ISRCTN73221288). PMID- 29505805 TI - Analysis of promoter polymorphism in monoamine oxidase A (MAOA) gene in completed suicide on Slovenian population. AB - Suicide is a well-defined public health problem and is a complex phenomenon influenced by a number of different risk factors, including genetic ones. Numerous studies have examined serotonin system genes. Monoamine oxidase A (MAO A) is an outer mitochondrial membrane enzyme which is involved in the metabolic pathway of serotonin degradation. Upstream variable number of tandem repeats (uVNTR) in the promoter region of MAOA gene affects the activity of transcription. In the present study we genotyped MAOA-uVNTR polymorphism in 266 suicide victims and 191 control subjects of Slovenian population, which ranks among the European and world populations with the highest suicide rate. Genotyping was performed with polymerase chain reaction and agarose gel electrophoresis. Using a separate statistical analysis for female and male subjects we determined the differences in genotype distributions of MAOA-uVNTR polymorphism between the studied groups. Statistical analysis showed a trend towards 3R allele and suicide, and associated 3R allele with non-violent suicide method on stratified data (20 suicide victims). This is the first study associating highly suicidal Slovenian population with MAOA-uVNTR polymorphism. PMID- 29505806 TI - Social marketing and community mobilisation to reduce underage alcohol consumption in Australia: A cluster randomised community trial. AB - BACKGROUND AND AIMS: In many countries adolescent alcohol use is a major health problem. To supplement national policies, it is important to trial community interventions as a potential strategy to prevent adolescent alcohol use. METHODS: This study evaluated a multicomponent community intervention that included community mobilisation, social marketing, and the monitoring of alcohol sales to minors. Evaluation was a clustered randomised trial design with 14 intervention and 14 control communities. Prior to randomisation, communities were matched on socioeconomic status and location. Intervention communities were not blinded. PARTICIPANTS: 3545 Year 8 students (M = 12 years) were surveyed at baseline from 75 schools; 3377 students were surveyed post intervention in 2013 from 54 schools. OUTCOMES: It was hypothesised that the primary outcome, individual alcohol consumption in last 30 days, after the intervention would be 15% lower in intervention communities. Secondary outcomes were consumption in the past year and intention not to drink before age 18. RESULTS: The intervention communities showed larger relative reductions compared to the controls in last 30-day consumption and past year (10%), but not significantly different. A significantly lower proportion of participants in the intervention community (63%), compared to the controls (71%), reported intending to drink before 18 years old. Subgroup analysis identified regional and state differences for some secondary measures. CONCLUSIONS: Intervention assignment was associated with lower adolescent intention to drink before the age of 18. However, more intensive and longer-term intervention may be required to measure significant differences in behaviour change. TRIAL REGISTRATION: ACTRN12612000384853. PROTOCOL: Rowland B, Toumbourou JW, Osborn A, et al. BMJ Open 2013;3:e002423. doi:10.1136/bmjopen-2012-002423. PMID- 29505807 TI - Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle. AB - Treatment of many posterior-segment ocular indications would benefit from improved targeting of drug delivery to the back of the eye. Here, we propose the use of iontophoresis to direct delivery of negatively charged nanoparticles through the suprachoroidal space (SCS) toward the posterior pole of the eye. Injection of nanoparticles into the SCS of the rabbit eye ex vivo without iontophoresis led to a nanoparticle distribution mostly localized at the site of injection near the limbus and <15% of nanoparticles delivered to the most posterior region of SCS (>9 mm from the limbus). Iontophoresis using a novel microneedle-based device increased posterior targeting with >30% of nanoparticles in the most posterior region of SCS. Posterior targeting increased with increasing iontophoresis current and increasing application time up to 3 min, but further increasing to 5 min was not better, probably due to the observed collapse of the SCS within 5 min after injection ex vivo. Reversing the direction of iontophoretic flow inhibited posterior targeting, with just ~5% of nanoparticles reaching the most posterior region of SCS. In the rabbit eye in vivo, iontophoresis at 0.14 mA for 3 min after injection of a 100 MUL suspension of nanoparticles resulted in ~30% of nanoparticles delivered to the most posterior region of the SCS, which was consistent with ex vivo findings. The procedure was well tolerated, with only mild, transient tissue effects at the site of injection. We conclude that iontophoresis in the SCS using a microneedle has promise as a method to target ocular drug delivery within the eye, especially toward the posterior pole. PMID- 29505808 TI - Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats. AB - Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders. PMID- 29505809 TI - Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood. AB - BACKGROUND: Humoral immunocompetence develops stepwise throughout life and contributes to individual susceptibility to infection, immunodeficiency, autoimmunity, and neoplasia. Immunoglobulin heavy chain (IgH) isotype serum levels can partly explain such age-related differences, but their relationship with the IgH isotype distribution within memory B-cell (MBC) and plasma cell (PCs) compartments remains to be investigated. OBJECTIVE: We studied the age related distribution of MBCs and PCs expressing different IgH isotypes in addition to the immature/transitional and naive B-cell compartments. METHODS: B cell and PC subsets and plasma IgH isotype levels were studied in cord blood (n = 19) and peripheral blood (n = 215) from healthy donors aged 0 to 90 years by using flow cytometry and nephelometry, respectively. RESULTS: IgH-switched MBCs expressing IgG1, IgG2, IgG3, IgA1, and IgA2 were already detected in cord blood and newborns at very low counts, whereas CD27+IgM++IgD+ MBCs only became detectable at 1 to 5 months and remained stable until 2 to 4 years, and IgD MBCs peaked at 2 to 4 years, with both populations decreasing thereafter. MBCs expressing IgH isotypes of the second immunoglobulin heavy chain constant region (IGHC) gene block (IgG1, IgG3, and IgA1) peaked later during childhood (2-4 years), whereas MBCs expressing third IGHC gene block immunoglobulin isotypes (IgG2, IgG4, and IgA2) reached maximum values during adulthood. PCs were already detected in newborns, increasing in number until 6 to 11 months for IgM, IgG1, IgG2, IgG3, IgA1, and IgA2; until 2 to 4 years for IgD; and until 5 to 9 years for IgG4 and decreasing thereafter. For most IgH isotypes (except IgD and IgG4), maximum plasma levels were reached after PC and MBC counts peaked. CONCLUSIONS: PC counts reach maximum values early in life, followed by MBC counts and plasma IgH isotypes. Importantly, IgH isotypes from different IGHC gene blocks show different patterns, probably reflecting consecutive cycles of IgH isotype switch recombination through life. PMID- 29505810 TI - Is eating pleasure compatible with healthy eating? A qualitative study on Quebecers' perceptions. AB - Given that traditional interventions promoting the adoption of a healthy diet are having limited impacts on the population's food choices and eating behaviours, researchers and health practitioners could explore alternative strategies such as the use of eating pleasure to promote healthy eating. To inform future interventions using this approach, this study aimed to explore how a sample of Quebecers perceives and defines eating pleasure and healthy eating. Specific objectives were to verify what commonalities can be found between their definitions of eating pleasure and healthy eating, and what differences can be observed in their answers based on their sex and body mass index (BMI). Twelve focus groups were conducted in Quebec City, Canada, among women and men with a normal weight and with obesity (n = 92). Verbatim transcripts were double-coded using NVivo10. Participants mostly defined eating pleasure through food characteristics related to sensory qualities and psychosocial contexts. In contrast, they mostly mentioned food characteristics related to nutritional quality and ways to regulate eating behaviours to define healthy eating. Most salient perceptions were similar among subgroups based on sex or BMI. Results showed that in participants' perceptions, the concepts of eating pleasure and healthy eating were different, but appeared to be mostly compatible, which makes the integration of eating pleasure a promising avenue for interventions promoting healthy eating. PMID- 29505811 TI - Genetically elevated gamma-glutamyltransferase and Alzheimer's disease. AB - Observational epidemiological evidence supports a linear and independent association between serum gamma-glutamyltransferase (GGT) concentrations and the risk of Alzheimer's disease (AD). However, the causality of this association has not been previously investigated. We sought to assess the causal nature of this association using a Mendelian randomization (MR) approach. Using inverse-variance weighted MR analysis, we assessed the association between GGT and AD using summary statistics for single nucleotide polymorphism (SNP)-AD associations obtained from the International Genomics of Alzheimer's Project of 17,008 individuals with AD and 37,154 controls. We used 26 SNPs significantly associated with GGT in a previous genome-wide association study on liver enzymes as instruments. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR. The odds ratio of AD was 1.09 (95% confidence interval, 0.98 to 1.22; p = 0.10) per one standard deviation genetically elevated GGT based on all 26 SNPs. The results were similar in both MR-Egger and weighted median MR methods. Overall, our findings cannot confirm a strong causal effect of GGT on AD risk. Further MR investigations using individual-level data are warranted to confirm or rule out causality. PMID- 29505812 TI - Stress evokes stronger medial posterior cingulate deactivations during emotional distraction in slower paced aging. AB - INTRODUCTION: Middle-aged offspring from long-lived families are thought to have a slower pace of aging, possibly related to HPA-axis function. Here, we investigated the neural and behavioral effects of social stress in offspring compared to their regular aging partners on emotional distraction during working memory (WM). METHODS: 104 middle-aged participants (53 males) consisting of offspring and their partners underwent the Trier Social Stress Test or a control procedure. Hereafter, a WM task with emotional distracters was performed using fMRI. Saliva cortisol levels were obtained during the procedure. RESULTS: Partners had higher overall cortisol levels than offspring. In addition, partners had decreased deactivations compared to offspring in the medial posterior cingulate cortex (mPCC) during emotional distraction, which were significantly correlated with lower accuracy during emotional distraction. DISCUSSION: mPCC deactivations are known to be modulated by chronological aging, with more deactivations in the young than in the old. Here we show the same pattern in familial longevity versus regular aging after mild stress, with more deactivations related to better accuracy during emotional distraction. Functional mPCC deactivations might thus be related to pace of aging, and can be revealed by inducing mild stress. PMID- 29505813 TI - Lysosomal response in relation to alpha-synuclein pathology differs between Parkinson's disease and multiple system atrophy. AB - Intracellular deposition of pathologically altered alpha-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic alpha-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of alpha-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/alpha-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated alpha-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of alpha-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with alpha-synuclein pre aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated alpha-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated alpha-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of alpha-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous alpha-synuclein in MSA. PMID- 29505814 TI - Effect of pH and leucine concentration on aerosolization properties of carrier free formulations of levofloxacin. AB - The aim of this study was to evaluate the effect of leucine at different pH values preferred for inhalation on particle characteristics and aerosolization performance of spray dried carrier-free formulations of levofloxacin. A full factorial design was applied to optimize the formulation containing levofloxacin with or without leucine in different pH values and the optimum condition was determined. Particle size and morphology, crystallinity state, electrostatic charge and surface composition of the particles were determined. Aerodynamic properties of the powders were also assessed by an Andersen cascade impactor after aerosolization through an Aerolizer(r) at an air flow rate of 60 L/min. The pH of initial solution affected various physical properties of the drug containing particles and hence their in vitro deposition. The profound effect of pH was on water content, electrostatic charge and surface composition of the particles. The negative effect of water content on in vitro deposition of the drug was covered by preferred surface accumulation of leucine at pH 6. Optimum formulation which obtained by co-spray drying of the drug with 21.79% leucine at pH 5.98 presented a fine particle fraction equal to 54.38. In conclusion, changing pH of the initial solution influenced the effect of leucine on aerosolization of levofloxacine spray dried particles by modification of their physical properties. PMID- 29505815 TI - Effects of dissolving microneedle fabrication parameters on the activity of encapsulated lysozyme. AB - Dissolving microneedle (DMN) is referred to a microscale needle that encapsulates drug(s) within a biodegradable polymer matrix and delivers it into the skin in a minimally invasive manner. Although vast majority of studies have emphasized DMN as an efficient drug delivery system, the activity of DMN-encapsulated proteins or antigens can be significantly affected due to a series of thermal, physical and chemical stress factors during DMN fabrication process and storage period. The objective of this study is to evaluate the effects of DMN fabrication parameters including polymer type, polymer concentration, fabrication and storage temperature, and drying conditions on the activity of the encapsulated therapeutic proteins by employing lysozyme (LYS) as a model protein. Our results indicate that a combination of low temperature fabrication, mild drying condition, specific polymer concentration, and addition of protein stabilizer can maintain the activity of encapsulated LYS up to 99.8 +/- 3.8%. Overall, findings of this study highlight the importance of optimizing DMN fabrication parameters and paves way for the commercialization of an efficient delivery system for therapeutics. PMID- 29505816 TI - TGF-beta1 acts as mediator in fluoride-induced autophagy in the mouse osteoblast cells. AB - It is well known that excess fluoride intake can result in fluorosis, which is a serious public health problem. TGF-beta1 affects a wide variety of cellular activities and plays an important role in fluorosis. Recent literature proved that fluoride induces autophagy, however, the mechanism is still unclear, and the role of TGF-beta1 in the fluoride-induced autophagy should be further illustrated. Therefore, in this study, plasmids and small interfering RNA (siRNA) were used to overexpress and silence the TGF-beta1 expression in the osteoblasts cells. Our results demonstrated that sodium fluoride (NaF) (2.26 mg/L F-) exposure lead to a significant decrease in proliferation rate of mouse osteoblast cells in a dose-dependent manner with a concomitant increase in the expression levels of TGF-beta1 and autophagic markers. Overexpression of TGF-beta1 significantly increased the fluorescence intensity of MDCstained cells, the mRNA and protein expression levels of Beclin1 and LC3-II/I, with a concomitant decrease in p62. However, TGF-beta1 silencing resulted in vice versa. In summary, we concluded that TGF-beta1 plays a mediator role in NaF-induced autophagy of mouse osteoblast cells. In the future, TGF-beta1-autophagy signaling network could be a new idea for the investigation of skeletal fluorosis. PMID- 29505817 TI - Assessment of the impact of aerosol from a potential modified risk tobacco product compared with cigarette smoke on human organotypic oral epithelial cultures under different exposure regimens. AB - Cigarette smoke (CS) is affecting considerably the oral mucosa. Heating, instead of burning, tobacco reduces consistently the amount of toxic compounds and may exert a lower impact on oral health than combusted cigarettes. The carbon-heated tobacco product 1.2 (CHTP1.2) is a potential modified risk tobacco product (MRTP) based on heat-not-burn technology. Using a systems toxicology assessment framework, we compared the effects of exposure to CHTP1.2 aerosol with those of CS from a reference cigarette (3R4F). Human organotypic cultures derived from buccal and gingival epithelia were exposed acutely (28-min) or repeatedly (28 min/day for 3 days), respectively, to two matching concentrations of CHTP1.2 aerosol or 3R4F CS, and a non-diluted (100%) CHTP1.2 aerosol. The results showed an absence of cytotoxicity, reduction in pathophysiological alterations, toxicological marker proteins, and inflammatory mediators following exposure to CHTP1.2 aerosol compared with 3R4F CS. Changes in mRNA and miRNA expression were linked by an integrative analysis approach, suggesting a regulatory role of miRNAs in several smoke/disease-relevant biological processes induced by 3R4F CS. The identification of mechanisms by which potential MRTPs can reduce the impact of tobacco use on biological systems is of great importance in understanding the molecular basis of the smoking harm reduction paradigm. PMID- 29505818 TI - Characterization of Botrytis cinerea isolates collected on pepper in Southern Turkey by using molecular markers, fungicide resistance genes and virulence assay. AB - Botrytis cinerea is a polyphagous fungal pathogen causing gray mold disease. Moreover, it is one of the most destructive infections of small fruit crops such as pepper (Capsicum annnum L.). C. sativum is a species belonging to the Solanaceae family and Turkey is one of the main producers in the World. In the present work, aiming to obtain information useful for pest management, fifty B. cinerea isolates collected from Turkey and a reference isolate (B05.10) were characterized using molecular markers and fungicide resistance genes. Morphological and molecular (ITS1-ITS4) identification of B. cinerea isolates, the degree of virulence and mating types were determined. Since one or several allelic mutations in the histidine kinase (Bos1) and beta-tubulin genes generally confer the resistance to fungicides, the sequences of these target genes were investigated in the selected isolates, which allowed the identification of two different haplotypes. Mating types were also determined by PCR assays using primer specific for MAT1-1 alpha gene (MAT1-1-1) and MAT1-2 HMG (MAT1-2-1) of B. cinerea. Twenty-two out of 50 isolates (44%) were MAT1-2, while 38% were MAT1-1. Interestingly, out of whole studied samples, 9 isolates (18%) were heterokaryotic or mixed colonies. In addition, cluster and population structure analyses identified five main groups and two genetic pools, respectively, underlining a good level of variability in the analysed panel. The results highlighted the presence of remarkable genetic diversity in B. cinerea isolates collected in a crucial economical area for pepper cultivation in Turkey and the data will be beneficial in view of future gray mold disease management. PMID- 29505819 TI - The role of TonB-dependent copper receptor in virulence of Acinetobacter baumannii. AB - Acinetobacter baumannii is an opportunistic gram negative pathogen that can adhere to different surfaces and cause different nosocomial infections. To investigate the role of TonB-dependent copper receptor, an outer membrane protein, in virulence of A. baumannii, we deleted this receptor from A. baumannii chromosome. There was a significant decrease in biofilm formation by copper receptor deficient mutant strain. Similarly, the adherence to human epithelial cell and the hydrophobicity were declined. The survival rate of the mutant strain in human sera was reduced while no change was observed in motility of strains. In murine pneumonia model, the bacterial lethal dose 0 (LD0), LD50 and LD100 were increased for mutant strain. Moreover, in vivo and in vitro experiments revealed changes in growth rate and dissemination of mutant strain; so that the bacterial load of the mutant was significantly reduced in the spleen and lung. The findings suggest a critical role for TonB-dependent copper receptor in virulence of A. baumannii. PMID- 29505820 TI - Accuracy of patient-specific guided implantation of the glenoid component in reversed shoulder arthroplasty. AB - BACKGROUND: The aim of this study was to assess the accuracy of patient-specific guided glenoid component implantation in reverse shoulder arthroplasty. MATERIALS AND METHODS: 32 reverse shoulder arthroplasties were done using preoperative 3D planning and 4 patient-specific guides to prepare the glenoid and position the glenoid component. Baseplate version, inclination and entry point as well as angulation of the screws were compared to the preoperative plan measured on CT by independent observers. RESULTS: The mean deviation in baseplate version from the preoperative plan was 4.4 degrees +3.1 degrees (range, 0.3 degrees -13.7 degrees ), in baseplate inclination 5.0 degrees +4.2 degrees (range, 0.1 degrees to 14.5 degrees ) and in baseplate entry point 2.4mm+1.4mm (range, 0.4 degrees to 6.3 degrees ). The average screw superior-inferior angulation deviation for the superior screw was 2.8 degrees +2.6 degrees (range, 0.0 degrees -10.1 degrees ) and 2.8+2.6 degrees in the antero-posterior plane (range, 0.1 degrees -11.6 degrees ). For the inferior screw the superior-inferior angle deviation was 5.3 degrees +3.8 degrees (range, 0.1 degrees -15.2 degrees ); the antero-posterior angle deviation was 4.1 degrees +3.1 degrees (range, 0.0 degrees -9.8 degrees ). CONCLUSIONS: Patient-specific instrumentation (PSI) for the glenoid component in reverse shoulder arthroplasty allows the shoulder surgeon to accurately execute the preoperative 3D plan. LEVEL OF EVIDENCE: Level 3. PMID- 29505821 TI - Early Reconstitution of NK and gammadelta T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. AB - Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Natural killer (NK) cells and gammadelta T cells reconstitute early after allo-HSCT, contribute to tumor immunosurveillance via major histocompatibility complex-independent mechanisms and do not induce graft-versus-host disease. Here we performed a quantitative and qualitative analysis of the NK and gammadelta T cell repertoire in healthy individuals, recipients of HLA-matched sibling or unrelated donor allo-HSCT (MSD/MUD-HSCT) and umbilical cord blood-HSCT (UCB-HSCT). NK cells are present at high frequencies in all allo-HSCT recipients. Immune reconstitution (IR) of vdelta2+ cells depended on stem cell source. In MSD/MUD-HSCT recipients, vdelta2+ comprise up to 8% of the total lymphocyte pool, whereas vdelta2+ T cells are barely detectable in UCB-HSCT recipients. Vdelta1+ IR was driven by CMV reactivation and was comparable between MSD/MUD-HSCT and UCB-HSCT. Strategies to augment NK cell mediated tumor responses, similar to IL-15 and antibodies, also induced vdelta2+ T cell responses against a variety of different tumor targets. Vdelta1+ gammadelta T cells were induced less by these same stimuli. We also identified elevated expression of the checkpoint inhibitory molecule TIGIT (T cell Ig and ITIM domain), which is also observed on tumor-infiltrating lymphocytes and epidermal gammadelta T cells. Collectively, these data show multiple strategies that can result in a synergized NK and gammadelta T cell antitumor response. In the light of recent developments of low-toxicity allo-HSCT platforms, these interventions may contribute to the prevention of early relapse. PMID- 29505822 TI - An autoregulatory loop controls the expression of the transcription factor NF-Y. AB - The heterotrimeric NF-Y complex is a pioneer factor that binds to CCAAT-genes and regulates their transcription. NF-Y cooperates with multiple transcription factors and co-regulators in order to positively or negatively influence gene transcription. The recruitment of NF-Y to CCAAT box is significantly enriched in cancer-associated gene promoters loci and positively correlates with malignancy. NF-Y subunits, in particular the DNA-binding subunit NF-YA and the histone-fold subunit NF-YC, appear overexpressed in specific types of cancer. Here we demonstrate that NF-Y subunits expression is finely regulated through transcriptional and post-translational mechanisms thus allowing control over basal expression levels. NF-Y negatively regulates the transcription of the genes encoding for its subunits. DNA pull-down/affinity purification assay coupled with Mass Spectrometry identified putative co-regulators, such as Lamin A, involved in NF-YA gene transcription level. We also evidentiate how the stability of the complex is severely affected by the absence of one subunit. Our results identified for the first time one of the mechanisms responsible for NF-Y expression, which may be involved in the aberrant expression and activity observed in tumor cells and other pathological conditions. PMID- 29505823 TI - Microbiome Medicine: This Changes Everything. PMID- 29505824 TI - Porcelain Gallbladder: Is Observation a Safe Option in Select Populations? AB - BACKGROUND: Management of gallbladder wall calcifications has been controversial for many decades. Although the traditionally perceived strong association with gallbladder cancer mandated prophylactic cholecystectomy, newer evidence suggests a much lesser association and might indicate an observational approach. STUDY DESIGN: A retrospective cohort study of 113 patients with gallbladder wall calcifications diagnosed between 2004 and 2016 at a single institution was conducted. Radiographic re-review identified patients with definitive (n = 70) and highly probable (n = 43) gallbladder wall calcifications. Patients were categorized according to their designated treatment plan. RESULTS: In the observation group (n = 90), delayed cholecystectomy for gallbladder-related symptoms was necessary in 4 patients (4%). None of the patients in this group were diagnosed with a gallbladder malignancy during a mean of 3.2 +/- 3.2 years follow-up. In the operative group (n = 23), peri-operative complications occurred in 13%, and gallbladder malignancy was found in 2 patients. In comparison, although patients in the observation group were older and had more comorbidities, the rate of adverse events was not significantly different (4% vs 13%; p = 0.15) with an overall low risk for potentially life-threatening complications to the patient when observed clinically. CONCLUSIONS: For management of gallbladder wall calcifications, observation appears to provide no significant difference in adverse events, including the risk of gallbladder malignancy developing, compared with an operative approach. Although there is a need for intervention in the presence of symptoms and findings suggestive of malignancy, prophylactic cholecystectomy should be avoided in patients with limited life expectancy and significant comorbidities. PMID- 29505825 TI - Cost Evaluation of a Donation after Cardiac Death Program: How Cost per Organ Compares to Other Donor Types. AB - BACKGROUND: Donation after cardiac death (DCD) is one method of organ donation. Nationally, more than half of evaluated DCD donors do not yield transplantable organs. There is no algorithm for predicting which DCD donors will be appropriate for organ procurement. Donation after cardiac death program costs from an organ procurement organization (OPO) accounting for all evaluated donors have not been reported. STUDY DESIGN: Hospital, transportation, and supply costs of potential DCD donors evaluated at a single OPO from January 2009 to June 2016 were collected. Mean costs per donor and per organ were calculated. Cost of DCD donors that did not yield a transplantable organ were included in cost analyses resulting in total cost of the DCD program. Donation after cardiac death donor costs were compared with costs of in-hospital donation after brain death (DBD) donors. RESULTS: There were 289 organs transplanted from 264 DCD donors evaluated. Mean cost per DCD donor yielding transplantable organs was $9,306. However, 127 donors yielded no organs, at a mean cost of $8,794 per donor. The total cost of the DCD program was $32,020 per donor and $15,179 per organ. Mean cost for an in-hospital DBD donor was $33,546 and $9,478 per organ transplanted. Mean organ yield for DBD donors was 3.54 vs 2.21 for DCD donors (p < 0.0001), making the cost per DBD organ 63% of the cost of a DCD organ. CONCLUSIONS: Mean cost per DCD donor is comparable with DBD donors, however, individual cost of DCD organs increases by almost 40% when all costs of an entire DCD program are included. PMID- 29505826 TI - Phylogeny, molecular dating and zoogeographic history of the titi monkeys (Callicebus, Pitheciidae) of eastern Brazil. AB - The titi monkeys belong to a genus of New World primates endemic to South America, which were recently reclassified in three genera (Cheracebus, Plecturocebus and Callicebus). The genus Callicebus, which currently includes five species, is endemic to eastern Brazil, occurring in the Caatinga, Savanna, and Atlantic Forest biomes. In the present study, we investigated the validity of these species and inferred their phylogenetic relationships, divergence times, and biogeographic patterns based on the molecular analysis of a concatenated sequence of 11 mitochondrial and nuclear DNA markers, derived from 13 specimens. We ran Maximum Likelihood (ML) and Bayesian Inference (BI) analyses, and estimated genetic distances, divergence times. Ancestral areas were estimated on BioGeoBears. Our results suggest that at about twelve million years ago, the ancestor of all titi monkeys inhabited a wide area that extended from the Amazon forest to the South of the Atlantic forest. A first vicariant event originated Cheracebus in the West of the Amazon and the ancestor of Callicebus and Plectorocebus which, later were separated by a second one. The diversification of Callicebus occurred during the Plio-Pleistocene (beginning at 5 Ma) probably influenced by climatic fluctuations and geological events. Therefore, the results of the present work confirmed the existence of five species that currently inhabit forested areas under increasing threat from human activities. Thus, a reliable diagnosis of the taxonomic status of species living in endangered environments is extremely important for the development of conservation measures. PMID- 29505827 TI - Left ventricular lead implantation in cardiac resynchronization therapy (CRT): A challenging procedure. PMID- 29505828 TI - Detection and treatment of chronic thromboembolic pulmonary hypertension: Still a lot of homework to do. PMID- 29505829 TI - Structural basis for partition of the cyclodipeptide synthases into two subfamilies. AB - Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides that can be further used for the synthesis of diketopiperazines. It was shown that CDPSs fall into two subfamilies, NYH and XYP, characterized by the presence of specific sequence signatures. However, current understanding of CDPSs only comes from studies of enzymes from the NYH subfamily. The present study reveals the crystal structures of three CDPSs from the XYP subfamily. Comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold. This gives a structural basis for the partition of CDPSs into two subfamilies. Despite these differences, the catalytic residues adopt similar positioning regardless of the subfamily suggesting that the XYP and NYH motifs correspond to two structural solutions to facilitate the reactivity of the catalytic serine residue. PMID- 29505830 TI - Additional travel recommendations for babies and pregnant women after the recent Zika and Chikungunya outbreaks. PMID- 29505831 TI - Continuous manganese delivery via osmotic pumps for manganese-enhanced mouse MRI does not impair spatial learning but leads to skin ulceration. AB - Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique in rodent neuroimaging studies. Traditionally, Mn2+ is delivered to animals via a systemic injection; however, this can lead to toxic effects at high doses. Recent studies have shown that subcutaneously implanted mini-osmotic pumps can be used to continuously deliver manganese chloride (MnCl2), and that they produce satisfactory contrast while circumventing many of the toxic side effects. However, neither the time-course of signal enhancement nor the effect of continuous Mn2+ delivery on behaviour, particularly learning and memory, have been well-characterized. Here, we investigated the effect of MnCl2 dose and route of administration on a) spatial learning in the Morris Water Maze and b) tissue signal enhancement in the mouse brain. Even as early as 3 days after pump implantation, infusion of 25-50 mg/kg/day MnCl2 via osmotic pump produced signal enhancement as good as or better than that achieved 24 h after a single 50 mg/kg intraperitoneal injection. Neither route of delivery nor MnCl2 dose adversely affected spatial learning and memory on the water maze. However, especially at higher doses, mice receiving MnCl2 via osmotic pumps developed skin ulceration which limited the imaging window. With these findings, we provide recommendations for route and dose of MnCl2 to use for different study designs. PMID- 29505832 TI - EL1-like Casein Kinases Suppress ABA Signaling and Responses by Phosphorylating and Destabilizing the ABA Receptors PYR/PYLs in Arabidopsis. AB - Unveiling the signal transduction of phytohormone abscisic acid (ABA) and its regulatory mechanisms is critical for developing the strategies toward improving plant responses to stressful environments. ABA signaling is perceived and mediated by multiple PYR/PYL receptors, whose post-translational modifications, especially phosphorylation, remain largely unknown. In this study, we demonstrate that Arabidopsis EL1-like (AEL) protein, a casein kinase that regulates various physiological processes, phosphorylate PYR/PYLs to promote their ubiquitination and degradation, resulting in suppressed ABA responses. Arabidopsis ael triple mutants display hypersensitive responses to ABA treatment, which is consistent with the suppressed degradation of PYR/PYL proteins. PYR/PYLs are phosphorylated in vivo and mutation of the conserved AEL phosphorylation sites results in reduced phosphorylation, ubiquitination, and degradation of PYR/PYLs, and hence enhanced ABA responses. Taken together, these results demonstrate that AEL mediated phosphorylation plays crucial roles in regulating the stability and function of PYR/PYLs, providing significant insights into the post-translational regulation of PYR/PYL receptors and ABA signaling. PMID- 29505833 TI - Knee flexion strength is significantly reduced following competition in semi professional Australian Rules football athletes: Implications for injury prevention programs. AB - OBJECTIVES: To evaluate strength and flexibility measures pre- and post- Australian Football (AF) competition to determine their potential utility as secondary prevention measures. DESIGN: Cohort study. SETTING: Semi-professional AF club. PARTICIPANTS: Ten male AF athletes (mean +/- SD; age, 21.3 +/- 2.2 years; height, 186.1 +/- 6.3 cm; weight, 83.5 +/- 8.6 kg). MAIN OUTCOME MEASURES: Maximal unilateral isometric knee flexion strength performed in 45 degrees of hip flexion and 30 degrees of knee flexion, flexibility measures of hip and knee extension and ankle dorsiflexion. All outcome measures were evaluated pre-match to determine baseline measurements and repeated acutely post-match and at 26, 50 and 74 h following. Comparisons were made between baseline measures and all other time points. RESULTS: Knee flexion strength was significantly reduced at a group level acutely (-122.8N, 95%CI -156.2 to -89.4, p = 0.000) and at 26 h (-89.6N, 95%CI -122.9 to -56.2, p = 0.000) following competition. Hamstring flexibility was significantly reduced at all time periods following competition (all p < 0.05), however these values were not clinically meaningful. CONCLUSIONS: Knowledge that unilateral isometric knee flexion strength returns to pre competition levels by 50 h following match-play in AF athletes is valuable for planning recovery time frames and may inform implementation of secondary prevention strategies. PMID- 29505834 TI - Specific intron-dependent loading of DAZAP1 onto the cox6c transcript suppresses pre-mRNA splicing efficacy and induces cell growth retardation. AB - DAZAP1 is an evolutionarily conserved RNA-binding protein expressed in many tissues in mice and humans. DAZAP1-knockout mice carrying a partial loss-of function (hypomorphic) allele exhibited severe deficiencies in spermatogenesis and cell growth, indicating that DAZAP1 plays a pivotal role in the development of germ and somatic cells. We have identified cox6c mRNA, which encodes a subunit of complex IV of the mitochondrial respiratory chain, as a target transcript regulated by DAZAP1. We found that DAZAP1 bound to cox6c mRNA derived from either the genomic DNA or a genome-type expression vector in cells, but not to cox6c mRNA derived from an intronless expression vector. Interestingly, the presence of the last intron was sufficient for DAZAP1 binding to the mRNA, suggesting specific intron dependent DAZAP1 loading onto cox6c mRNA. Overexpression of DAZAP1 resulted in the accumulation of cox6c pre-mRNA for all introns, implying that DAZAP1 reduces pre-mRNA splicing efficiency. In addition, the reduction of mature cox6c mRNA levels led to decreases in the COX6C protein levels. Both DAZAP1 knockdown and COX6C overexpression retarded cell growth. The lines of evidence presented here reveal that DAZAP1 is a negative regulator of pre-mRNA splicing and may control energy production in mitochondria by regulating COX6C expression. The DAZAP1 functions described in this study may also account for the phenotypes observed in the DAZAP1 hypomorphic mice. PMID- 29505835 TI - Selection and validation of reference genes for quantitative real-time PCR in Artemisia sphaerocephala based on transcriptome sequence data. AB - Artemisia sphaerocephala, a dicotyledonous perennial semi-shrub belonging to the Artemisia genus of the Compositae family, is widely distributed in northwestern China. This shrub is one of the most important pioneer plants which is capable of protecting rangelands from wind erosion. It therefore plays a vital role in maintaining desert ecosystem stability. In addition, to its use as a forage grass, it has excellent prospective applications as a source of plant oil and as a plant-based fuel. The use of internal genes is the basis for accurately assessing Real time quantitative PCR. In this study, based on transcriptome data of A. sphaerocephala, we analyzed 21 candidate internal genes to determine the optimal internal genes in this shrub. The stabilities of candidate genes were evaluated in 16 samples of A. sphaerocephala. Finally, UBC9 and TIP41-like were determined as the optimal reference genes in A. sphaerocephala by Delta Ct and three various programs. There were GeNorm, NormFinder and BestKeeper. PMID- 29505836 TI - microRNA-520f inhibits hepatocellular carcinoma cell proliferation and invasion by targeting TM4SF1. AB - microRNAs (miRNAs) are reported to play crucial roles in tumorigenesis. Dysregulation of miR-520f has been implicated to be involved in several cancer progressions. However, the biological functions of miR520f in hepatocellular carcinoma (HCC) remain unclear. Thus, the molecular mechanism underlying miR-520f on HCC development was investigated in this study. Here, we found that miR-520f was remarkably down-regulated in human HCC samples and cell lines compared to paired normal tissues and cell lines as detected by qRT-PCR. Furthermore, the deregulated miR-520f was strongly associated with larger tumor size, advanced TNM stage, and metastasis in HCC patients. Functional investigations revealed that overexpression of miR-520f significantly suppressed cell proliferation, invasion and migration, caused cell cycle arrested at G0/G1 phase, and promoted cell apoptosis in HCC cells according to MTT, colony formation, transwell, and flow cytometry assays, respectively, whereas, downregulation of miR-520f exhibited inverse effects. Transmembrane-4 L-Six family member-1 (TM4SF1) was identified as a direct target of miR-520f, and an inverse relationship was found between miR 520f and TM4SF1 mRNA levels in HCC specimens. Rescue experiments suggested that restoration of TM4SF1 partially abolished miR-520f-meidated cell proliferation and invasion inhibition in HCC cells through regulating P13K/AKT and p38 MAPK signaling pathways. In conclusion, these data indicated that miR-520f acted as tumor suppressor in HCC proliferation and invasion by targeting TM4SF1, which might provide potential therapeutic evidence for HCC patients. PMID- 29505839 TI - Reduced brain volumes in children of women with epilepsy: A neuropsychological and voxel based morphometric analysis in pre-adolescent children. AB - BACKGROUND AND PURPOSE: Children of Women with Epilepsy with antenatal exposure to antiepileptic drugs (CAED) have reduced neuropsychological functions. We aimed to explore the anatomical basis for this impairment by comparing the brain volumes of CAED with that of matched healthy children without antenatal AED exposure (COAED). MATERIALS AND METHODS: CAED aged 8-12 years were recruited from the Kerala Registry of epilepsy and pregnancy that prospectively follows up children of women with epilepsy and COAED from children attending the imaging department for minor illnesses. Maternal clinical details and the neuropsychological data including IQ of CAED and COAED were obtained. Total intracranial volume (TBV), grey matter volume (GMV), white matter volume (WMV) and volumes of deep grey matter were measured by Voxel Based Morphometry. RESULTS: We studied 30 CAED (mean age 10.8+1.11 years) and 35 COAED (mean age 10.64+1.26). The antenatal AED exposure for the CAED was monotherapy for 8 children and polytherapy for 22 children. The CAED had significantly lower (P<0.001) IQ (77.5+13.8), TBV(1259.55+/-169.85mL) and GMV (672.51+/-85.42 mL) compared to the IQ (87.0+13.5), TBV(1405.37+/-161mL) and GMV (745.427+/-86.69 mL) of COAED. CAED had lower volumes for Lt Inferior Triangular Gyrus, and hippocampi on both sides, when compared to COAED. Group analysis CAED showed less GMV (P<0.05) for left inferior and middle frontal gyri relative to COAED. CONCLUSIONS: These observations point towards an anatomical basis of lower GMV for the lower neuropsychological functions in children with antenatal AED exposure. PMID- 29505837 TI - Expression profiles of mRNA and long noncoding RNA in the ovaries of letrozole induced polycystic ovary syndrome rat model through deep sequencing. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-aged women. However, the exact pathophysiology of PCOS remains largely unclear. We performed deep sequencing to investigate the mRNA and long noncoding RNA (lncRNA) expression profiles in the ovarian tissues of letrozole induced PCOS rat model and control rats. A total of 2147 mRNAs and 158 lncRNAs were differentially expressed between the PCOS models and control. Gene ontology analysis indicated that differentially expressed mRNAs were associated with biological adhesion, reproduction, and metabolic process. Pathway analysis results indicated that these aberrantly expressed mRNAs were related to several specific signaling pathways, including insulin resistance, steroid hormone biosynthesis, PPAR signaling pathway, cell adhesion molecules, autoimmune thyroid disease, and AMPK signaling pathway. The relative expression levels of mRNAs and lncRNAs were validated through qRT-PCR. LncRNA-miRNA-mRNA network was constructed to explore ceRNAs involved in the PCOS model and were also verified by qRTPCR experiment. These findings may provide insight into the pathogenesis of PCOS and clues to find key diagnostic and therapeutic roles of lncRNA in PCOS. PMID- 29505838 TI - Lead exposure inhibits expression of SV2C through NRSF. AB - Lead (Pb) exposure has been shown to affect presynaptic neurotransmitter release in the animal and cell models. The mechanism by which Pb exposure impairs neurotransmitter release remains unknown. In this study, we aimed to investigate the effect of Pb exposure on synaptic vesicle protein 2C (SV2C) and its molecular mechanism. SV2C promoter region contains a neuron-restrictive silencer element (NRSE) binding motif. Neuron-restrictive silencer factor (NRSF) is a transcription repressor that regulates gene expression by binding to NRSE. We also observed whether Pb exposure regulates the transcriptional level of SV2C by influencing the expression of NRSF. Pregnant female rats were exposed to 0, 0.5 and 2.0 g/L lead acetate (PbAc) via drinking water from the first day of gestation until postnatal week 3. Neuro-2a (N2a) cells were divided into 3 groups: 0 MUM (control group), 1 MUM and 100 MUM PbAc. Our data revealed that the ability of learning and memory in Pb-exposed rats were decreased, Pb exposure decreased SV2C expression and increased NRSF expression in the rat hippocampus and N2a cell. Silencing NRSF can reverse the down-regulation of Pb exposure on SV2C. These results indicate that Pb exposure can inhibit the transcription level of SV2C by up regulating the expression of NRSF. Decreased expression of SV2C can affect neurotransmitter release and synaptic transmission, which affect synaptic plasticity and then result in impairment of learning and memory. PMID- 29505840 TI - Historadiological correlations in high-grade glioma with the histone 3.3 G34R mutation. AB - BACKGROUND AND PURPOSE: Molecular alterations were recently added to the World Health Organization (WHO) 2016 classification of central nervous system (CNS) tumors. We correlated the histological and radiological features of G34R mutant high-grade gliomas, a recently described hemispheric and supratentorial glioma of children and young adults. MATERIALS AND METHODS: We performed a retrospective multicenter study on the histopathological and MRI results of 12 patients. RESULTS: All tumors were supratentorial. Several radiological aspects were observed. Height over 12 were bulky and well delineated tumors, without visible peritumoral infiltration on MRI and pathologically characterized by highly cellular tissue associated with a moderate peritumoral infiltrative component. Two tumors were ill-defined and hyperintense on T2 sequences and pathologically characterized by diffuse tumoral infiltration. Two tumors were bulky and well delineated with an infiltrative component, both radiologically and histopathologically. CONCLUSIONS: These different patterns may correspond to different pathological mechanisms and a potential link with prognosis should be assessed in further studies. PMID- 29505841 TI - Evaluation of prospective motion correction of high-resolution 3D-T2-FLAIR acquisitions in epilepsy patients. AB - T2-FLAIR is the single most sensitive MRI contrast to detect lesions underlying focal epilepsies but 3D sequences used to obtain isotropic high-resolution images are susceptible to motion artefacts. Prospective motion correction (PMC) - demonstrated to improve 3D-T1 image quality in a pediatric population - was applied to high-resolution 3D-T2-FLAIR scans in adult epilepsy patients to evaluate its clinical benefit. Coronal 3D-T2-FLAIR scans were acquired with a 1mm isotropic resolution on a 3T MRI scanner. Two expert neuroradiologists reviewed 40 scans without PMC and 40 with navigator-based PMC. Visual assessment addressed six criteria of image quality (resolution, SNR, WM-GM contrast, intensity homogeneity, lesion conspicuity, diagnostic confidence) on a seven-point Likert scale (from non-diagnostic to outstanding). SNR was also objectively quantified within the white matter. PMC scans had near-identical scores on the criteria of image quality to non-PMC scans, with the notable exception that intensity homogeneity was generally worse. Using PMC, the percentage of scans with bad image quality was substantially lower than without PMC (3.25% vs. 12.5%) on the other five criteria. Quantitative SNR estimates revealed that PMC and non-PMC had no significant difference in SNR (P=0.07). Application of prospective motion correction to 3D-T2-FLAIR sequences decreased the percentage of low-quality scans, reducing the number of scans that need to be repeated to obtain clinically useful data. PMID- 29505842 TI - Radiotherapy in acromegaly: Long-term brain parenchymal and vascular magnetic resonance changes. AB - BACKGROUND: Radiation therapy (RT) effectiveness on hormonal reduction is proven in acromegaly; however, collateral long-term effects are still undetermined. This transversal neuroimaging study on a large cohort of acromegalic patients aimed to investigate the rate of parenchymal and vascular changes after RT. MATERIALS AND METHODS: Thirty-six acromegalic patients underwent RT (RT+) after unsuccessful surgery and were compared to RT- acromegalic patients matched for age, gender, adenoma features, clinical and surgical history. All patients underwent magnetic resonance angiography (MRA) to investigate intracranial artery abnormalities and FLAIR sequence to assess white matter changes according to the Wahlund scale. RESULTS: RT+ acromegalic patients had a higher rate of controlled disease (29/36 vs. 12/36, P<0.001). RT+ acromegalic patients had MRI/MRA evaluation 15.3+/-9.6 years after RT. RT+ acromegalic patients had a significantly higher Wahlund score than RT- acromegalic patients (6.03+/-6.41 vs. 2.53+/-3.66, P=0.006) due to increased white matter signal abnormalities at the level of the temporal lobes, the basal ganglia (insula) and the infratentorial regions, bilaterally. Among RT+ patients one died because of temporo-polar anaplastic astrocytoma, one suffered from a stroke due to right internal carotid artery occlusion, one presented with cystic degeneration of the temporal poles. Long-dated RT (>10 years before MR evaluation) was associated with a higher rate of RT-related white matter changes (P=0.0004). CONCLUSIONS: RT seems to have created a cohort of patients with brain parenchymal changes whose clinical and cognitive impact is still unknown. These patients might require a prolonged MRI and MRA follow-up to promptly detect delayed RT-related complications and minimize their clinical consequences. PMID- 29505843 TI - The role of molecular enrichment on future therapies in hepatocellular carcinoma. AB - Hepatocellular carcinomas (HCCs) are characterised by considerable phenotypic and molecular heterogeneity. Treating HCC and designing clinical trials are particularly challenging because co-existing liver disease, present in most patients, limits aggressive therapeutic options. Positive results in recent phase III clinical trials have confirmed the high value of anti-angiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities. However, failure of several large randomised controlled clinical trials over the last 10 years underlines the necessity for innovative treatment strategies and implementation of translational findings to overcome the unmet clinical need. Furthermore, the promising results from novel immunotherapies are likely to complement the landscape of active compounds for HCC and will require a completely different approach to patients, as well as the development of prognostic/predictive biomarkers. Given our increasing understanding of the most abundant molecular alterations in HCC, effective enrichment of patients based on clinical and molecular biomarkers, as well as adaptive clinical trials, are now feasible and should be implemented. Herein, we aim to review important aspects of precision medicine approaches in HCC that might contribute to improving the molecular subclassification of patients in a clinical trial setting and pave the way for novel therapeutic strategies. PMID- 29505844 TI - Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. AB - BACKGROUND AND AIMS: Recent studies suggest an association between hepatitis C virus (HCV) infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct-acting antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis. MATERIALS AND METHODS: One hundred eighty-two consecutive patients with HCV and advanced fibrosis or compensated cirrhosis were evaluated. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT >=1 mm) and carotid plaques, defined as focal thickening of >=1.5 mm at the level of the common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. Fifty-six percent of patients were male, mean age 63.1 +/- 10.4 years, and 65.9% had compensated cirrhosis. One in five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. At baseline, mean IMT was 0.94 +/- 0.29 mm, 42.8% had IMT >=1 mm, and 42.8% had carotid plaques. RESULTS: All patients achieved a 12-week sustained virological response. IMT significantly decreased from baseline to follow-up (0.94 +/- 0.29 mm vs. 0.81 +/- 0.27, p <0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p <0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p = 0.34). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity. CONCLUSION: HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis with or without additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term. LAY SUMMARY: Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis. The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors. Hepatitis C virus eradication by direct-acting antiviral agents also lead to improvement in glucose homeostasis and increased cholesterol levels. PMID- 29505845 TI - Assessment of the risk of alcohol relapse following liver transplantation for alcoholic hepatitis using a meta-analysis approach. PMID- 29505846 TI - Reply to: "Assessment of the risk of alcohol relapse following liver transplantation for alcoholic hepatitis using a meta-analysis approach". PMID- 29505848 TI - Psychophysiological assessment and correction of spatial disorientation during simulated Orion spacecraft re-entry. AB - The National Aeronautics and Space Administration (NASA) has identified a potential risk of spatial disorientation, motion sickness, and degraded performance to astronauts during re-entry and landing of the proposed Orion crew vehicle. The purpose of this study was to determine if a physiological training procedure, Autogenic-Feedback Training Exercise (AFTE), can mitigate these adverse effects. Fourteen men and six women were assigned to two groups (AFTE, no treatment Control) matched for motion sickness susceptibility and gender. All subjects received a standard rotating chair test to determine motion sickness susceptibility; three training sessions on a manual performance task; and four exposures in the rotating chair (Orion tests) simulating angular accelerations of the crew vehicle during re-entry. AFTE subjects received 2 h of training before Orion tests 2, 3, and 4. Motion sickness symptoms, task performance, and physiological measures were recorded on all subjects. Results showed that the AFTE group had significantly lower symptom scores when compared to Controls on test 2 (p = .05), test 3 (p = .03), and test 4 (p = .02). Although there were no significant group differences on task performance, trends showed that AFTE subjects were less impaired than Controls. Heart rate change scores (20 rpm minus baseline) of AFTE subjects indicated significantly less reactivity on Test 4 compared to Test 1 (10.09 versus 16.59, p = .02), while Controls did not change significantly across tests. Results of this study indicate that AFTE may be an effective countermeasure for mitigating spatial disorientation and motion sickness in astronauts. PMID- 29505847 TI - Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic beta-Catenin, PIK3CA and MET. AB - BACKGROUND & AIMS: Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), beta-catenin and PIK3CA. METHODS: We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and DeltaN90-beta-catenin (MET/CAT), or c-Met and PIK3CAH1047R (MET/PIK), into WT and Shp2hep-/- mice. We compared liver tumor loads and investigated the pathogenesis and molecular mechanisms involved using multidisciplinary approaches. RESULTS: Despite the induction of oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins MET/CAT or MET/PIK. Shp2 loss inhibited proliferative signaling from c-Met, Wnt/beta-catenin, Ras/Erk and PI3K/Akt pathways, but triggered cell senescence following exogenous expression of the oncogenes. CONCLUSIONS: Shp2, acting downstream of RTKs, is positively required for hepatocyte-intrinsic tumorigenic signaling from these oncoproteins, even if Shp2 deficiency induces a tumor-promoting hepatic microenvironment. These data suggest a new and more effective therapeutic strategy for HCCs driven by oncogenic RTKs and other upstream molecules, by inhibiting Shp2 and also suppressing any tumor-enhancing stromal factors produced because of Shp2 inhibition. LAY SUMMARY: Primary liver cancer is a malignant disease with poor prognosis, largely because there are limited systemic therapies available. We show here that a cytoplasmic tyrosine phosphatase Shp2 is required for liver tumorigenesis. This tumorigenesis is driven by two oncoproteins that are implicated in human liver cancer. This, together with our previous studies, uncovers the complexity of liver tumorigenesis, by elucidating the pro- and anti tumor effects of Shp2 in mouse models. This data can be used to guide new therapies. PMID- 29505849 TI - Resting beta activation and trait motivation: Neurophysiological markers of motivated motor-action preparation. AB - Based on Reinforcement Sensitivity Theory (Gray and McNaughton 2000), human behavior is influenced by systems of approach motivation, avoidance motivation, and a third regulatory system presiding over the other two. These systems mediate action and are likely related to neurophysiological markers of motor-action preparation. Previous research has found that lower levels of beta activity over the motor cortex are associated with greater motor-action preparation. The current study sought to test whether trait approach, avoidance, and regulatory control would relate to resting beta activity over the motor cortex, a measure of motor-action preparation. One hundred twenty-eight individuals completed measures of trait behavioral approach motivation and trait behavioral avoidance motivation (BIS/BAS; Carver and White 1994), as well as regulatory control (UPPS-P Impulsive Behaviour Scale; Whiteside et al. 2005). Then, resting EEG was recorded. Greater trait approach was negatively associated with resting beta activity. In contrast, greater trait impulsivity was associated with greater resting beta activity. Lower levels of resting beta activity in the motor cortex appear to be associated with traits related to deliberate motivated motor behaviors. Trait motor-action preparation seems to be an indicator of tendencies toward planful motivated behavior. PMID- 29505850 TI - Heart rate variability is associated with thermal heat pain threshold in males, but not females. AB - Previous research has suggested that heart rate variability (HRV; the variability in the interval between successive heartbeats) can predict the perception of experimentally-induced pain (i.e., pain sensitivity). However, little research has sought to investigate sex-specific associations between HRV and pain sensitivity. This is an important consideration, given that sex differences in resting HRV have been observed, and there has been extensive debate about sex differences in sensitivity to experimentally-induced pain. We examined whether the association between resting HRV and sensitivity to experimentally-induced pain differed in men and women. Fifty-one pain free individuals (26 women, mean age = 21.9 years) participated. Resting electrocardiography (ECG) was collected during a paced breathing task (15 cycles per minute), and measures of HRV were extracted via Fast Fourier Transformation. Thermal heat pain threshold (i.e., the point at which the sensation was first perceived as painful, rather than warm) was measured with a Medoc Pathway Pain and Sensory Evaluation System. There were no sex differences in resting HRV or thermal heat pain threshold, nor did sex moderate the relationship between HRV and thermal heat pain threshold. However, there were significant positive relationships between thermal heat pain threshold and LF-HRV (r = 0.47), and HF-HRV (r = 0.43) in men, but not in women. The results suggest that higher pain threshold appears to be related to greater engagement of the inhibitory parasympathetic nervous system in men only, and that other biopsychosocial mechanisms may contribute to experimental pain experience in women. Future research is needed to study these mechanisms further, accounting for other factors known to influence nociceptive and cardiovascular regulatory processes (e.g., ethnicity, hormones). PMID- 29505851 TI - Rewarding images do not invoke the reward positivity: They inflate it. AB - Increasing evidence suggests that the reward positivity conforms to an axiomatic reward prediction error - that is, it closely follows the rule-like encoding of surprising reinforcers. However, a major limitation in these EEG studies is the over-reliance on a single class of secondary rewards like points or money, constraining dimensionality and limiting generalizability. In the current suite of studies we address this limitation by leveraging different classes of rewards outcomes, specifically emotionally pleasant pictures. Over a series of three experiments, participants were able to choose idiosyncratically preferred pictures as rewards. During the first two experiments, participants were rewarded with either high or low points or high or low preferred pictures. The reward positivity was modulated by points, but not by pictures (regardless of preference), which instead evoked enhanced N2 amplitudes. In a third study that paired high/low points and preferred/non-preferred pictures, the point-induced reward positivity was inflated by the presence of a preferred picture. In line with past research stating the reward positivity is primarily sensitive to positive reward prediction error, this report finds that it is also influenced by a liking dimension, which possibly acts as an affective state to frame the motivational aspect of extrinsic rewards. PMID- 29505852 TI - Does practicing a skill with the expectation of teaching alter motor preparatory cortical dynamics? AB - Recent evidence suggests practicing a motor skill with the expectation of teaching it enhances learning by increasing information processing during motor preparation. However, the specific motor preparatory processes remain unknown. The present study sought to address this shortcoming by employing EEG to assess participants' motor preparatory processes while they completed a golf putting pretest, and then practiced putting with the expectation of (a) teaching another participant how to putt the next day (teach group, n = 30), or (b) being tested on their putting the next day (test group, n = 30). Participants' EEG during the 3-s prior to and 1-s after initiating putter movement was analyzed. All participants completed posttests 1 day after the practice session. The teach group exhibited better posttest performance (superior learning) relative to the test group, but no group differences in motor preparatory processing (EEG) emerged. However, participants in both groups exhibited linear decreases in both theta power at frontal midline and upper-alpha power over motor areas during putt initiation. These results suggest a decrease in working memory and action monitoring (frontal midline theta), and an increase in motor programming (motor upper-alpha) during putt initiation. Further, participants in both groups exhibited increased frontal midline theta from pretest to practice, but decreases in both upper motor-alpha and upper-alpha coherence between left/right temporal and motor planning regions. These results suggest participants utilized working memory and action monitoring to a greater extent during practice relative to pretest, while refining their motor programming and verbal-analytic/visuospatial involvement in motor programming. PMID- 29505853 TI - Use of motor evoked potentials during lateral lumbar interbody fusion reduces postoperative deficits. AB - BACKGROUND CONTEXT: Intraoperative neurophysiological monitoring (IONM) has gained rather widespread acceptance as a method to mitigate risk to the lumbar plexus during lateral lumbar interbody fusion (LLIF) surgery. The most common approach to IONM involves using only electromyography (EMG) monitoring, and the rate of postoperative deficit remains unacceptably high. Other test modalities, such as transcranial electric motor-evoked potentials (tcMEPs) and somatosensory evoked potentials, may be more suitable for monitoring neural integrity, but they have not been widely adopted during LLIF. Recent studies have begun to examine their utility in monitoring LLIF surgery with favorable results. PURPOSE: This study aimed to evaluate the efficacy of different IONM paradigms in the prevention of iatrogenic neurologic sequelae during LLIF and to specifically evaluate the utility of including tcMEPs in an IONM strategy for LLIF surgery. STUDY DESIGN/SETTING: A non-randomized, retrospective analysis of 479 LLIF procedures at a single institution over a 4-year period was conducted. During the study epoch, three different IONM strategies were used for LLIF procedures: (1) surgeon-directed T-EMG monitoring ("SD-EMG"), (2) neurophysiologist-controlled T EMG monitoring ("NC-EMG"), and (3) neurophysiologist-controlled T-EMG monitoring supplemented with MEP monitoring ("NC-MEP"). PATIENT SAMPLE: The patient population comprised 254 men (53.5%) and 221 women (46.5%). Patient age ranged from a minimum of 21 years to a maximum of 89 years, with a mean of 56.6 years. OUTCOME MEASURES: Physician-documented physiological measures included manual muscle test grading of hip-flexion, hip-adduction, or knee-extension, as well as hypo- or hyperesthesia of the groin or anterolateral thigh on the surgical side. Self-reported measures included numbness or tingling in the groin or anterolateral thigh on the surgical side. METHODS: Patient progress notes were reviewed from the postoperative period up to 12 months after surgery. The rates of postoperative sensory-motor deficit consistent with lumbar plexopathy or peripheral nerve palsy on the surgical side were compared between the three cohorts. RESULTS: Using the dependent measure of neurologic deficit, whether motor or sensory, patients with NC-MEP monitoring had the lowest rate of immediate postoperative deficit (22.3%) compared with NC-EMG monitoring (37.1%) and SD-EMG monitoring (40.4%). This result extended to sensory deficits consistent with lumbar plexopathy (pure motor deficits being excluded); patients with NC-MEP monitoring had the lowest rate (20.5%) compared with NC-EMG monitoring (34.3%) and SD-EMG monitoring (36.9%). Additionally, evaluation of postoperative motor deficits consistent with peripheral nerve palsy (pure sensory deficits being excluded) revealed that the NC-MEP group had the lowest rate (5.7%) of motor deficit compared with the SD-EMG (17.0%) and NC-EMG (17.1%) cohorts. Finally, when assessing only those patients whose last follow-up was greater than or equal to 12 months (n=251), the rate of unresolved motor deficits was significantly lower in the NC-MEP group (0.9%) compared with NC-EMG (6.9%) and SD-EMG (11.0%). A comparison of the NC-MEP versus NC-EMG and SD-EMG groups, both independently and combined, was statistically significant (>95% confidence level) for all analyses. CONCLUSIONS: The results of the present study indicate that preservation of tcMEPs from the adductor longus, quadriceps, and tibialis anterior muscles are of paramount importance for limiting iatrogenic sensory and motor injuries during LLIF surgery. In this regard, the inclusion of tcMEPs serves to compliment EMG and allows for the periodic, functional assessment of at risk nerves during these procedures. Thus, tcMEPs appear to be the most effective modality for the prevention of both transient and permanent neurologic injury during LLIF surgery. We propose that the standard paradigm for protecting the nervous system during LLIF be adapted to include tcMEPs. PMID- 29505854 TI - Clinical features and treatment outcomes of Langerhans cell histiocytosis of the spine. AB - BACKGROUND CONTEXT: Langerhans cell histiocytosis (LCH) of the spine is a relatively rare condition with unknown etiology. The diagnosis and treatment protocols for spine LCH remain controversial. PURPOSE: In this study, we evaluated the efficacy and safety of our proposed diagnosis and treatment protocol introduced in 2009. STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: A total of 110 patients with spine LCH who had been diagnosed and treated in our hospital from October 1997 to November 2015 were included in this study. OUTCOME MEASURES: The age, gender, symptoms, neurologic function, lesion distribution, radiological features, pathology, treatment, outcome, and treatment complications of the patients were collected. Visual analog scale (VAS) for pain and Frankel scale for neurologic status were also documented. METHODS: We retrospectively reviewed 110 patients with spine LCH who had been diagnosed and treated in our hospital from October 1997 to November 2015. The indications for computed tomography (CT)-guided biopsy and surgery for spine LCH have become more stringent since 2009. In cases of a solitary spinal lesion, immobilization and observation were usually first suggested. Chemotherapy was suggested for cases with multifocal LCH lesions, and low-dosage radiotherapy was restricted to recurrent solitary lesion. This project was supported by our hospital (No. Y71508 01) (Y 400,000). RESULT: This series included 69 male and 41 female patients (age range, 1-52 years). Pain was the most common symptom (93.6%, 103/110). Pathologic diagnosis was achieved in 72 cases (65.5%). CT-guided biopsies were performed in 91.3% (42/46) and 73.2% (41/56) of cases before and after 2009, respectively (p=.02). Ninety-eight cases (89.1%) were followed up for a mean 66.3 (range, 24 159) months. Immobilization and observation were performed in 25.9% (14/54) and 75.0% (42/56) of cases before and after 2009, respectively (p<.001). Approximately 35.2% (19/54) and 10.7% (6/56) of cases had surgery (p=.002) before and after 2009, respectively. During the follow-up, no significant difference was found in the outcomes between the two groups treated before and after 2009 (p=.64). CONCLUSION: Biopsy is not mandatory for typical spine lesions of LCH. Given the self-healing tendency of spine LCH, immobilization and observation remain the first-choice treatments for LCH lesions. Conservative biopsy and treatment protocols might be more appropriate for spinal LCH. PMID- 29505856 TI - In Vivo Comparison of "V-Loc 90 Wound Closure Device" With "Vicryl" and "Monocryl" in Regard to Tissue Reaction in a Rabbit Bladder Model. AB - OBJECTIVE: To compare the barbed polyglyconate suture (BPS) with 2 commonly used conventional sutures, this prospective randomized trial was designed. The sutures applied in the urinary collecting system, in terms of long-term histopathologic and macroscopic suture material features. MATERIALS AND METHODS: Eight female and 6 male New Zealand rabbits were included in the study. Each animal served as its own control and was subjected to cystotomy. Watertight running cystorrhaphies were performed using 3 different sutures in a randomized fashion, namely Monocryl, Vicryl, and V-Loc 90. Seven animals were sacrificed after the third and 7 after the sixth week. Macroscopic and histopathologic examinations were performed. Tissue reaction, like inflammation and fibrosis, around the sutures were evaluated. Friedman and Wilcoxon signed ranks test was used for the statistical analysis. RESULTS: The BPS demonstrated no adhesion. However, in the six-week group, stone formation was recorded on 4 BPS and 1 Vicryl thread, a difference being statistically significant (P = .039). Additionally, in the third and in the sixth-week group, 1 (P = .368) and 3 (P = .050) BPS threads migrated, respectively. The histopathologic analysis revealed less inflammation and fibrosis associated with the BPS thread in both the third and the sixth-week groups (P = .010 and P = .002, respectively). CONCLUSION: The BPS appears to be superior to conventional sutures in terms of local inflammation and fibrosis. However, suture migration and stone formation following collecting system closure could be potential predicaments. PMID- 29505855 TI - The Immunome of Colon Cancer: Functional In Silico Analysis of Antigenic Proteins Deduced from IgG Microarray Profiling. AB - Characterization of the colon cancer immunome and its autoantibody signature from differentially-reactive antigens (DIRAGs) could provide insights into aberrant cellular mechanisms or enriched networks associated with diseases. The purpose of this study was to characterize the antibody profile of plasma samples from 32 colorectal cancer (CRC) patients and 32 controls using proteins isolated from 15,417 human cDNA expression clones on microarrays. 671 unique DIRAGs were identified and 632 were more highly reactive in CRC samples. Bioinformatics analyses reveal that compared to control samples, the immunoproteomic IgG profiling of CRC samples is mainly associated with cell death, survival, and proliferation pathways, especially proteins involved in EIF2 and mTOR signaling. Ribosomal proteins (e.g., RPL7, RPL22, and RPL27A) and CRC-related genes such as APC, AXIN1, E2F4, MSH2, PMS2, and TP53 were highly enriched. In addition, differential pathways were observed between the CRC and control samples. Furthermore, 103 DIRAGs were reported in the SEREX antigen database, demonstrating our ability to identify known and new reactive antigens. We also found an overlap of 7 antigens with 48 "CRC genes." These data indicate that immunomics profiling on protein microarrays is able to reveal the complexity of immune responses in cancerous diseases and faithfully reflects the underlying pathology. PMID- 29505857 TI - Genital Mobilization of Intravesical Phallus Associated With Covered Cloacal Exstrophy: A Case Report. AB - Cloacal exstrophy is the most severe form of the exstrophy-epispadias complex, occurring in approximately 1 of every 200,000 to 400,000 live births. Variant such as covered cloacal exstrophy presentations are only one-tenth as common. Although exstrophy-epispadias complexes include genital anomalies, intravesical phallus is very rare. We report an extremely rare case of intravesical phallus with covered cloacal exstrophy that was successfully treated by phallic mobilization. PMID- 29505858 TI - Characteristics of Female Genital Restoration Surgery for Congenital Adrenal Hyperplasia Using a Large-scale Administrative Database. AB - OBJECTIVE: To analyze nationwide information on the timing of surgical procedures, cost of surgery, hospital length of stay following surgery, and surgical complications of female genital restoration surgery (FGRS) in females with congenital adrenal hyperplasia (CAH). MATERIALS AND METHODS: We used the Pediatric Health Information System database to identify patients with CAH who underwent their initial FGRS in 2004-2014. These patients were identified by an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for adrenogenital disorders (255.2) in addition to a vaginal ICD-9 procedure code (70.x, excluding vaginoscopy only) or perineal ICD-9 procedure code (71.x), which includes clitoral operations (71.4). RESULTS: A total of 544 (11.8%) females underwent FGRS between 2004 and 2014. Median age at initial surgery was 9.9 months (interquartile range 6.8-19.1 months). Ninety-two percent underwent a vaginal procedure, 48% underwent a clitoral procedure, and 85% underwent a perineal procedure (non-clitoral). The mean length of stay was 2.5 days (standard deviation 2.5 days). The mean cost of care was $12,258 (median $9,558). Thirty day readmission rate was 13.8%. Two percent underwent reoperation before discharge, and 1 (0.2%) was readmitted for a reoperation within 30 days. Four percent had a perioperative surgical complication. CONCLUSION: Overall, 12% of girls with CAH underwent FGRS at one of a national collaborative of freestanding children's hospitals. The majority underwent a vaginoplasty as a part of their initial FGRS for CAH. Clitoroplasty was performed on less than half the patients. Overall, FGRS for CAH is performed at a median age of 10 months and has low 30 day complication and immediate reoperation rates. PMID- 29505859 TI - Systematic reviews do not adequately report or address missing outcome data in their analyses: a methodological survey. AB - OBJECTIVES: To describe how systematic review authors report and address categories of participants with potential missing outcome data of trial participants. STUDY DESIGN AND SETTING: Methodological survey of systematic reviews reporting a group-level meta-analysis. RESULTS: We included a random sample of 50 Cochrane and 50 non-Cochrane systematic reviews. Of these, 25 reported in their methods section a plan to consider at least one of the 10 categories of missing outcome data; 42 reported in their results, data for at least one category of missing data. The most reported category in the methods and results sections was "unexplained loss to follow-up" (n = 34 in methods section and n = 6 in the results section). Only 19 reported a method to handle missing data in their primary analyses, which was most often complete case analysis. Few reviews (n = 9) reported in the methods section conducting sensitivity analysis to judge risk of bias associated with missing outcome data at the level of the meta-analysis; and only five of them presented the results of these analyses in the results section. CONCLUSION: Most systematic reviews do not explicitly report sufficient information on categories of trial participants with potential missing outcome data or address missing data in their primary analyses. PMID- 29505861 TI - Patients prioritize local recurrence risk over other attributes for surgical treatment of facial melanomas-Results of a stated preference survey and choice based conjoint analysis. AB - BACKGROUND: Surgical treatment options for facial melanomas include conventional excision with postoperative margin assessment, Mohs micrographic surgery (MMS) with immunostains (MMS-I), and slow MMS. Patient preferences for these surgical options have not been studied. OBJECTIVES: To evaluate patient preferences for surgical treatment of facial melanoma and to determine how patients value the relative importance of different surgical attributes. METHODS: Participants completed a 2-part study consisting of a stated preference survey and a choice based conjoint analysis experiment. RESULTS: Patients overwhelmingly (94.3%) rated local recurrence risk as very important and ranked it as the most important attribute of surgical treatment for facial melanoma. Via choice-based conjoint analysis, patients ranked the following surgical attributes from highest to lowest in importance: local recurrence rate, out-of-pocket cost, chance of second surgical visit, timing of reconstruction, travel time, and time in office for the procedure. Consistent with their prioritization of low local recurrence rates, more than 73% of respondents selected MMS-I or slow MMS as their preferred treatment option for a facial melanoma. LIMITATIONS: Data were obtained from a single health system. CONCLUSION: Patients prefer surgical treatment options that minimize risk for local recurrence. Logistics for travel and treatment have less influence on patient preferences. Most survey participants chose MMS-I to maximize local cure and convenience of care. PMID- 29505862 TI - Inflammatory response and cytokine levels induced by intralesional photodynamic therapy and 630-nm laser in a case series of basal cell carcinoma. PMID- 29505863 TI - Impact of topical fluorouracil cream on costs of treating keratinocyte carcinoma (nonmelanoma skin cancer) and actinic keratosis. AB - BACKGROUND: It is unknown whether treatment costs for keratinocyte carcinoma (KC) and actinic keratosis (AK) can be lowered by spending more on chemoprevention. OBJECTIVE: To examine the impact of 1-course treatment with topical fluorouracil (5-FU) on the face and ears on KC and AK treatment costs over 3 years. METHODS: The Veterans Affairs Keratinocyte Carcinoma Chemoprevention trial compared the efficacy of topical 5-FU 5% with that of vehicle control cream for reducing KC risk. Trial data and administrative data on costs and utilization were analyzed to measure postrandomization encounters and treatment costs for KC and AK care. Adjusted models were used to test for statistically significant differences between treatment arms for number of treatment encounters and costs. RESULTS: One year after randomization, the control arm had a higher mean number of treatment encounters for squamous cell carcinoma (0.04) than the intervention arm (0.01) (P < .01). At 1 year, the intervention arm had lower treatment and dermatologic costs: $2106 (standard deviation, $2079) compared with $2444 (standard deviation, $2716) for the control patients (P = .02). After 3 years, the intervention arm incurred a cost of $771 less per patient. LIMITATIONS: Care not provided or paid for by the Department of Veterans Affairs was not included. Results may not be generalizable to other payers. CONCLUSION: We found significant cost savings for patients treated with 5-FU. PMID- 29505860 TI - An observational study showed that explaining randomization using gambling related metaphors and computer-agency descriptions impeded randomized clinical trial recruitment. AB - OBJECTIVES: To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. STUDY DESIGN AND SETTING: Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. RESULTS: One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was "best for them". Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. CONCLUSIONS: The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation. PMID- 29505864 TI - Modified purse-string closure: a lymphatic channel and tissue sparing technique for biopsy of suspicious pigmented lesions on extremities. PMID- 29505866 TI - Periodic benefit-risk assessment using Bayesian stochastic multi-criteria acceptability analysis. AB - Benefit-risk (BR) assessment is essential to ensure the best decisions are made for a medical product in the clinical development process, regulatory marketing authorization, post-market surveillance, and coverage and reimbursement decisions. One challenge of BR assessment in practice is that the benefit and risk profile may keep evolving while new evidence is accumulating. Regulators and the International Conference on Harmonization (ICH) recommend performing periodic benefit-risk evaluation report (PBRER) through the product's lifecycle. In this paper, we propose a general statistical framework for periodic benefit-risk assessment, in which Bayesian meta-analysis and stochastic multi-criteria acceptability analysis (SMAA) will be combined to synthesize the accumulating evidence. The proposed approach allows us to compare the acceptability of different drugs dynamically and effectively and accounts for the uncertainty of clinical measurements and imprecise or incomplete preference information of decision makers. We apply our approaches to two real examples in a post-hoc way for illustration purpose. The proposed method may easily be modified for other pre and post market settings, and thus be an important complement to the current structured benefit-risk assessment (sBRA) framework to improve the transparent and consistency of the decision-making process. PMID- 29505865 TI - Three-Year Results of the Endurant Stent Graft System Post Approval Study. AB - BACKGROUND: Long-term data following endovascular aneurysm repair (EVAR) exist but are limited to endografts that are no longer in use. The aim of the ENGAGE Post Approval Study is to describe the long-term safety and effectiveness data following EVAR using the Endurant stent graft system. METHODS: From August 2011 to June 2012, 178 patients were enrolled and treated with the Endurant stent graft system. Clinical and radiologic data were prospectively collected and analyzed. The primary end point was abdominal aortic aneurysm (AAA)-related mortality, and secondary end points were overall mortality, endoleak, secondary interventions, and device-related complications. Kaplan-Meier estimates were used for late outcomes. RESULTS: A total of 178 patients underwent EVAR with the Endurant stent graft across 24 centers (82% men; median age 71, interquartile range [IQR] 66-79). Median aortic diameter was 55 mm (IQR 51-58 mm). There was a 98.9% technical success rate. Three-year clinical and radiographic follow-up data were available for 87% and 74% of patients, respectively. Median follow-up was 37 months (IQR 30-38 months). Three-year aneurysm-related mortality rate was 1.1%, with 2 deceased patients in the perioperative period. All-cause mortality rate at 3 years was 13%. No patients suffered from aneurysm rupture or underwent conversion to open repair through 3 years of follow-up. Only 11 patients (6.2%) had undergone reintervention at 3 years. Younger age was associated with reintervention (HR 3.3 per younger decade, 95% confidence interval 1.3-7.6, P < 0.01), but neck diameter, length, and angulation were not significantly associated with reintervention. CONCLUSIONS: The Endurant stent graft system provides a safe, durable approach to treating infrarenal AAA. No patients experienced late rupture or aneurysm-related mortality, and only 1 in 16 patients underwent reintervention by 3 years. The rate of reintervention with the Endurant graft appears to be lower than other contemporary grafts, despite more liberal "Instructions For Use" parameters, but further research including direct graft comparisons will be necessary to guide appropriate graft selection. PMID- 29505867 TI - HOMBRE: A randomized controlled trial to compare two approaches to weight loss for overweight and obese Latino men (Hombres con Opciones para Mejorar el Bienestar y bajar el Riesgo de Enfermedades cronicas; men with choices to improve well-being and decrease chronic disease risk). AB - Latino men bear a disproportionate burden of obesity, diabetes, and cardiovascular disease.However, limited behavioral lifestyle intervention research has focused on Latino men. This trial compares two approaches to weight loss for overweight and obese Latino men: 1) HOMBRE is a culturally adapted intervention that provides individual choice of either self-directed online videos, coach-facilitated in-person groups, and coach-facilitated online groups; and 2) a minimal intensity intervention that uses online videos with a coach available, if solicited by the participant.Latino men with a Body Mass Index (BMI) of >=27 kg/m2 and one or more cardiometabolic risk factors (n = 424) will be randomly assigned to receive one of the two approaches.The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework guides the planned evaluations.The primary aim is to determine the effectiveness of the HOMBRE intervention (the "E" in RE-AIM) on clinically significant weight loss (>=5% of baseline weight) at 18 months. We hypothesize that a significantly higher proportion of HOMBRE participants will maintain >=5% of weight loss compared with those in the minimal intensity intervention.Secondary aims are to determine the effectiveness of HOMBRE on cardiometabolic risk factors (e.g., blood pressure, waist circumference), health behaviors (e.g., diet and physical activity), and psychosocial well-being (e.g., quality of life and depressive symptoms) and to evaluate the other attributes of RE-AIM. These findings have real word applicability with value to clinicians, patients, and other decision makers considering effective diabetes prevention programs for Latino men in primary care. PMID- 29505868 TI - Structural insights into a multifunctional inhibitor, 'AMTIN' from tubers of Alocasia macrorrhizos and its possible role in dengue protease (NS2B-NS3) inhibition. AB - Protease inhibitors from plants play major role in defensive mechanism against various pathogenic organisms. AMTIN from the tubers of Alocasia macrorrhiza has been purified and characterized as multi-functional Kunitz type protease inhibitor. AMTIN is varied from other KTIs by having three different loops specific for binding to trypsin/amylase and subtilisin that are located approximately 30A away from one another as evidenced from crystallographic efforts. Biochemical studies on AMTIN reveal simultaneous binding of protease/amylase and have been cross validated using in-silico tools to model Amylase - AMTIN - Trypsin complex without any steric clashes. Apart from multi functionality, the remarkable structural and functional stability of AMTIN at high temperature, presence of many phosphorylation, myristoylation and glycosylation sites and molecular docking studies with dengue viral protease (NS2B-NS3) makes this protein interesting. Hence AMTIN can be considered as a template to design effective antivirals against dengue virus. PMID- 29505869 TI - Tumor-targeting and pH-responsive nanoparticles from hyaluronic acid for the enhanced delivery of doxorubicin. AB - In this study, intracellular pH-responsive nanoparticles (NPs) of hyaluronic acid hydrazone linkage-doxorubicin (HA-hyd-DOX) were designed and prepared for acid triggered release of doxorubicin through a hydrazone linkage. A series of amphiphilic polymeric prodrugs were obtained, which can be self-assembled in aqueous media, the formed NPs exhibited a spherical core-shell type and the uniform size was ranging from 167 to 220nm. Moreover, the HA-hyd-DOX NPs exhibited a good stability in vitro and the drug release profiles showed that the DOX release was obviously mediated by pH gradient. Additionally, the cell counting assay kit-8 (CCK-8) demonstrated that the drug delivery system in this study performed a lower cytotoxicity on normal cells (Mouse fibroblast cells, L929) and higher inhibition ratio on tumor cells (Human cervical cancer cells, HeLa) in response to drug release with the intracellular pH environment. Furthermore, confocal laser scanning microscopy (CLSM) images and flow cytometric profiles of HeLa cells showed an efficiently cellular uptake due to the receptor mediated affinity of CD44 for HA with high specificity. These results suggest that this pH dependent drug delivery system based on HA will provide insights into the design of potential prodrugs for the cancer therapy. PMID- 29505870 TI - Incorporating allylated lignin-derivatives in thiol-ene gel-polymer electrolytes. AB - Growing environmental and economic concerns as well as the uncertainty that accompanies finite petrochemical resources contributes to the increase in research and development of bio-based, renewable polymers. Concurrently, industrial and consumer demand for smaller, safer, and more flexible technologies motivates a global research effort to improve electrolytic polymer separators in lithium-ion batteries. To incorporate the aromatic structural advantages of lignin, a highly abundant and renewable resource, into gel-polymer electrolytes, lignin-derived molecules, vanillyl alcohol and gastrodigenin are functionalized and UV-polymerized with multi-functional thiol monomers. The resulting thin, flexible, polymer films possess glass transition temperatures ranging from -42.1 degrees C to 0.3 degrees C and storage moduli at 25 degrees C ranging from 1.90MPa to 10.08MPa. The crosslinked polymer films swollen with electrolyte solution impart conductivities in the range of 7.04*10-7 to 102.73*10-7Scm-1. Thiol molecular weight has the most impact on the thermo-mechanical properties of the resulting films while polymer crosslink density has the largest effect on conductivity. The conducting abilities of the bio-based gel-polymer electrolytes in this study prove the viability of lignin-derived feedstock for use in lithium ion battery applications and reveal structurally and thermally desirable traits for future work. PMID- 29505871 TI - Sesbania gum based hydrogel as platform for sustained drug delivery: An 'in vitro' study of 5-Fu release. AB - The purpose of this study is to fabricate 5-Fluorouracil sustained release matrix based on a novel, nontoxic, eco-friendly modified biopolymer. The sesbania gum based hydrogel has been prepared by microwave assisted method using acrylamide as a monomer and N,N Methylenebisacrylamide as a crosslinker. The crosslink copolymerization has been confirmed by several modern techniques such as FTIR, SEM, XRD, TGA, DSC, elemental analysis etc. The bioactive 5-Fluorouracil has been encapsulated via solvent swelling method and its release rate has been investigated in various pH dissolution medium through USP standard protocol. The synthesized hydrogel with higher degree of crosslinking exhibited slower release rate than that of hydrogel having lower degree of crosslinking. Thus, resulting higher t25 value, the release rate increases with increase in pH of the medium. Release kinetics suggests the non-Fickian release behaviour of the hydrogel. PMID- 29505872 TI - One-step procedure for enhancing the antibacterial and antioxidant properties of a polysaccharide polymer: Kojic acid grafted onto chitosan. AB - The purpose of this work was to develop a nontoxic bioactive material based on a natural pyrone compound (kojic acid, KA) and chitosan oligosaccharides (COS). The bioactive material, chitosan oligosaccharide-N-kojic acid polymer (COS-N-KA), was prepared by one-step environmentally friendly approach. Then, the physicochemical properties and biological activities of COS-N-KA as a prepared water-soluble COS derivative were evaluated. The polymer was characterized by using UV-vis, FTIR, 1H NMR, and 13C NMR spectroscopy, Mw, PID, TGA, water solubility, hemolysis assay, and animal toxicity studies. Particularly, the antioxidant and antimicrobial assays revealed that COS-N-KA significantly enhanced the antimicrobial and antioxidant activities, which remarkably stronger than that of free COS and KA. Hence, the low hemolytic activity to human red blood cells, and nontoxic to female mice of SLAC KM strain made this novel polymer material a promising and effective compound for food and pharmaceutical industries. PMID- 29505873 TI - Optimization of antioxidant and antiglycated activities of polysaccharides from Arthrocnemum indicum leaves. AB - Central composite design was performed to optimize uronic acid rate, esterification degree, total antioxidant ability and antiglycation capacity of carbohydrates from Arthrocnemum indicum leaves. Three independent variables were opted: extraction temperature, time and ratio (solvent/material). The optimal settings were: extraction temperature of 80 degrees C, time of 288min and (solvent/solid) ratio of 40mL/g. Under these settings, uronic acid rate and esterification degree were 49.29%, 30.24%, respectively, whereas total antioxidant activity and antiglycation capacity was 35.81mg ascorbic acid equivalents/g matter and 69.81%, respectively. Colorimetric assays showed that total sugar and uronic acid contents for polysaccharide were 71.78% and 49.24%, respectively. Furthermore, Preliminary structure study was performed via various methods including FT-IR, NMR and UV-vis analysis. SEC analyzes revealed that polysaccharide had an average molecular weight of 2179kDa. Moreover, GC-MS analyzes showed that extracted polysaccharide was a pectic polysaccharide which formed of arabinose, mannose, galactose, rhamnose, glucose and xylose in the molar percentage of 66.68%, 3.93%, 12.71%, 6.31%, 6.08% and 4.29%, respectively. This results revealed that extracted polysaccharide can be employed as source of natural antioxidants and as possible antiglycated agents. PMID- 29505874 TI - Allantoin and hydantoin as new protein aggregation suppressors. AB - Allantoin is widely used in pharmaceutical and cosmetic products, and is composed of a hydantoin ring and a ureido group. Recent reports showed that allantoin suppresses thermal aggregation of hen egg white lysozyme (LYZ). However, structural insight into the properties of allantoin on protein aggregation and whether allantoin controls the aggregation of other proteins under different stress conditions remain unclear. Here we studied the structural properties of allantoin in terms of its effects on protein aggregation by comparing allantoin with urea and hydantoin. Furthermore, we analyzed the effects of allantoin and its derivatives on the aggregation of LYZ, carbonic anhydrase from bovine erythrocytes (BCA), albumin from chicken egg white (OVA), and immunoglobulin G (IgG) by various stresses in comparison with arginine. These four proteins are widely different in charged state and molecular size. Allantoin suppressed the aggregation and inactivation of LYZ comparing to arginine without affecting the melting temperature of proteins, and was responsible for the slightly improved formation of soluble oligomers and insoluble aggregates of IgG with thermal and acidic stresses. In contrast, hydantoin increased the solubility of aromatic amino acids more effectively than arginine and allantoin. The structural properties underlying the observed effects of allantoin as an aggregation suppressor include hydrophobic interactions between hydantoin moiety and aromatic ring on the surface of proteins, which is reflected on the difference between allantoin and arginine. These results show that the backbone of hydantoin ring may be a new category of additives for development of small aggregation suppressors. PMID- 29505875 TI - The smaller heparin fragments bind non-specifically through the IAPP sequence: An in silico study. AB - The diminishing beta-cell mass of pancreas in type II diabetes mellitus (TIIDM) is intricately linked with high fibrillation propensity of islet amyloid polypeptide (IAPP, aka amylin). IAPP is one of the most amyloidogenic peptide secreted by pancreatic beta-cells. In the autopsy of TIIDM patients, IAPP rich amyloid plaques are found containing different components of extracellular matrix (ECM), including heparin. For a positively charged IAPP, interaction with heparin which has accessible high density negatively charged functional groups is anticipated to moderate the fibrillation kinetics. Hence, the heparin has shown to affect the amyloidogenicity and cytotoxicity of IAPP depending upon its polymer length; short polymer inhibited the amyloidogenicity and longer fragment enhanced the propensity. Here using docking and molecular dynamic (MD) simulations studies, the work investigates key interactions between IAPP and different heparin fragments, those are likely involved in moderating IAPP fibrillation kinetics in presence of different length heparin fragments. The findings indicate that the heparin fragments of longer length, >dp7, predominantly interact with IAPP N- and C-termini, resulting in a stable complex with solvent accessible self-recognition element (SRE) of IAPP sequence. However, shorter fragment non-specifically binds through the IAPP sequence, including N terminus residues and SRE sequences. PMID- 29505876 TI - Structural characterization of a polysaccharide from the flower buds of Tussilago farfara, and its effect on proliferation and apoptosis of A549 human non-small lung cancer cell line. AB - In present study, we purified a polysaccharide, TFPB1, from the flower buds of Tussilago farfara using DEAE-cellulose 52 anion-exchange and Sephacryl S-300 HR gel filtration chromatography. TFPB1 was a homogeneous polysaccharide with a molecular weight of 37.8kDa and composed of rhamnose, galacturonic acid, glucose, galactose, and arabinose, in a ratio of 13:13:1:7:12. Methylation and NMR results demonstrated that TFPB1 contained a rhamnogalacturonan I backbone consisting of a repeat disaccharide unit ->4)-alpha-D-GalAp-(1->2)-alpha-L-Rhap-(1->, substituted by various type II arabinogalactan branches including terminal galactose, (1->3) beta-D-galactan and (1->5)-alpha-L-arabinan, attached to the O-4 of (1->2)-alpha L-Rhap. TFPB1 was found to inhibit cell proliferation of A549 cells and induce cell apoptosis in vitro. Furthermore, TFPB1 downregulated the phosphorylation of Akt, and upregulated caspase-3, Fas, FasL, and Bax expression, but downregulated Bcl-2 expression. Therefore, TFPB1 exhibited anti-proliferative and anti apoptotic effect partly depending on the suppression of Akt signaling pathway. These findings provided us a potential chemotherapeutic strategy for the treatment of human non-small cell lung cancer. PMID- 29505877 TI - Polyhydroxybutyrate and phenolic compounds microalgae electrospun nanofibers: A novel nanomaterial with antibacterial activity. AB - Polymer nanofibers produced by electrospinning are promising for use in food packaging because of their nanometric diameter, which provides a barrier to external conditions above the possible incorporation of the active compounds. The microalga Spirulina sp. LEB 18 synthesizes bioproducts, such as polyhydroxybutyrate (PHB), which is biodegradable and has similar mechanical and thermal properties to polymers of petrochemical origin. Moreover, phenolic compounds of microalgae have antibacterial, antifungal, and antioxidant activities, which is a differential for the development of packaging. The objective of the study was to develop a nanomaterial with antibacterial action from bioproducts of microalgal origin. PHB nanofibers containing phenolic compounds presented average diameter of 810+/-85nm exhibited hydrophobicity, which gave protection to the food relative to the moisture outside the package. These nanofibers showed inhibition of the growth of Staphylococcus aureus ATCC 25923 with a zone of 7.5+/-0.4mm. Thermal and mechanical properties have confirmed the potential applicability of this material as food packaging. This new nanomaterial combines a packaging function to protect products and to be biodegradable with the antibacterial activity that prevents the proliferation of microorganisms and ensures the quality and preservation of food. PMID- 29505878 TI - European Commission guidelines for the prudent use of antimicrobials in human health: a missed opportunity to embrace nursing participation in stewardship. PMID- 29505880 TI - Comparison of phenoxymethylpenicillin, amoxicillin, and doxycycline for erythema migrans in general practice. A randomized controlled trial with a 1-year follow up. AB - OBJECTIVES: To compare the three most commonly used antibiotics for erythema migrans (EM) in Norwegian primary care. METHODS: A randomized, parallel, controlled trial was carried out. Treatments were open to the patients, but blinded for the GPs and investigators. Patients eligible for inclusion were aged >=18 years and clinically diagnosed with EM. Block randomization was processed in blocks of six. Patients were assigned to receive one of three antibiotic treatments for 14 days: phenoxymethylpenicillin (PCV), amoxicillin, or doxycycline. The primary outcome was the duration of EM in days in the three treatment groups. Patients kept a diary for the 14 days of treatment, in which they registered concomitant symptoms and side effects. The patients consulted their GP after 14 days of treatment and had a 1-year follow-up to monitor any development of disseminated Lyme borreliosis (LB). EMs with a duration of more than 14 days were followed until resolution. ClinicalTrials.govNCT01368341 and EU Clinical Trials Register 2010-023747-15. RESULTS: One hundred and eighty eight patients (PCV: n = 56, amoxicillin: n = 64, doxycycline: n = 68) were included by 44 Norwegian general practitioners (GPs) from June 2011 to November 2013. Follow up was completed by December 2014. The median duration of EM was altogether 14 days (range 3-293). For the PCV group median duration was 14 days (range 5-91), for amoxicillin 13 days (range 4-179) and for doxycycline 14 days (range 3-293). The duration of EM did not differ significantly between the three antibiotic groups (p 0.277). None of the patients developed disseminated LB within the 1 year follow-up. CONCLUSIONS: We did not find 14 days of PCV, doxycycline, and amoxicillin treatments to differ in effectiveness or safety in the treatment of clinically diagnosed EM in primary care. PMID- 29505879 TI - Guidance document for prevention of Clostridium difficile infection in acute healthcare settings. AB - SCOPE: Clostridium difficile infection (CDI) is the most important infective cause of healthcare-associated diarrhoea in high income countries and one of the most important healthcare-associated pathogens in both Europe and the United States. It is associated with high morbidity and mortality resulting in both societal and financial burden. A significant proportion of this burden is potentially preventable by a combination of targeted infection prevention and control measures and antimicrobial stewardship. The aim of this guidance document is to provide an update on recommendations for prevention of CDI in acute care settings to provide guidance to those responsible for institutional infection prevention and control programmes. METHODS: An expert group was set up by the European society of clinical microbiology and infectious diseases (ESCMID) Study Group for C. difficile (ESGCD), which performed a systematic review of the literature on prevention of CDI in adults hospitalized in acute care settings and derived respective recommendations according to the GRADE approach. Recommendations are stratified for both outbreak and endemic settings. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: This guidance document provides thirty-six statements on strategies to prevent CDI in acute care settings, including 18 strong recommendations. No recommendation was provided for three questions. PMID- 29505881 TI - Multicentre determination of rezafungin (CD101) susceptibility of Candida species by the EUCAST method. AB - OBJECTIVES: Rezafungin (CD101) is a new long-acting echinocandin allowing weekly dosing, currently undergoing phase-II clinical trials for invasive candidiasis. The aim of this study was to assess rezafungin's in vitro activity against the most frequent Candida species following the EUCAST methodology. METHODS: The susceptibility of 2018 clinical Candida isolates was determined at four European laboratories. In parallel, six control strains were repeatedly tested. Wild-type upper limits (WT-ULs), defined as the MIC value where the wild-type distribution ends, were determined following the principles for EUCAST ECOFF-setting. RESULTS: The lowest rezafungin MICs (geometric MIC (GM-MIC), MIC range (mg/L)) were observed for C. albicans (0.016, 0.002-0.125) and the highest for C. parapsilosis (1.657, 0.063->4). MICs for the remaining species were in between these values (GM-MICs 0.048-0.055). Visual and statistical WT-ULs were identical for C. glabrata (0.125), C. krusei (0.125), C. parapsilosis (4), and C. tropicalis (0.25). If adopting these WT-ULs for classification into WT and non-WT populations, 1/413 C. glabrata, 1/402 C. krusei, 1/398 C. parapsilosis, and 1/402 C. tropicalis isolates were categorized as non-WT, all of which derived from Laboratory 1. For C. albicans unexplained laboratory variation was observed (WT UL: 0.063-0.125 in Laboratories 1 and 2 versus 0.016 in Laboratories 3 and 4). A similar systematic difference was observed comparing the MICs for the three C. albicans QC strains, specifically, obtained in Laboratories 1and 2 with those in Laboratories 3 and 4. DISCUSSION: Rezafungin displayed species-specific activity similar to other echinocandins. Interlaboratory variation was observed for the most susceptible species C. albicans clinical and QC strains, an observation that warrants further investigation. PMID- 29505882 TI - Early diagnosis of HIV infection among men who have sex with men in Lima (Peru). A prospective cohort study. PMID- 29505883 TI - The pitfalls of laboratory diagnostics of Clostridium difficile infection. PMID- 29505884 TI - Understanding the experience of "burnout" in first-episode psychosis carers. AB - BACKGROUND: The first onset of psychosis can exert a significant negative impact on the functioning and positive wellbeing of family carers. Carer reports of "burnout" have recently been recorded in early psychosis carers, though the literature is scarce detailing our understanding of how burnout relates to the primary experience of caregiving. The current study investigated reports of burnout and its relationship with beliefs about caregiving and wellbeing in a large group of early psychosis carers who were routinely assessed within an early intervention team. METHODS AND MATERIALS: Using a cross-sectional design, 169 early psychosis carers completed the Maslach Burnout Inventory alongside measures of caregiving experiences, affect and wellbeing. RESULTS: The mean illness length for patients with psychosis was 18 months. Their mean age was 24.4 years and most was male (65%). The majority of carer participants were parental caregivers and living with their relative with psychosis. Across the three key burnout dimensions, 58% of the sample reported high levels of emotional exhaustion; 31% endorsed high levels of depersonalization; and 43% reported low levels personal accomplishment. The most severe level of burnout, reflecting elevated rates across all three dimensions, was observed in 16% of the sample. Carer burnout was positively associated with negative caregiving experiences (i.e. burden), poor affect, and reduced levels of positive wellbeing and perception of being in good health. CONCLUSIONS: Reports by early psychosis carers of exhaustion, feeling inadequate and expressing negativity towards the relative they care for is not uncommon and are closely associated with their overall negative appraisals of caregiving. The results underscore the importance of developing targeted interventions during the early phase, which are designed to reduce the development and entrenchment of burnout responses in carers, but to also mitigate its negative sequelae. PMID- 29505885 TI - Emergence of multidrug-resistant sequence type 45 strains among mecA-positive borderline oxacillin-resistant Staphylococcus aureus causing bacteraemia in a medical centre in Taiwan. AB - Clinical data related to bacteraemia caused by mecA-positive borderline oxacillin resistant Staphylococcus aureus (BORSA) isolates [minimum inhibitory concentrations (MICs) of 0.5-4 mg/L] are limited. Patients aged >=15 years with bacteraemia due to BORSA who were admitted to the emergency department of a Taiwanese tertiary hospital between January 2001 and December 2015 were evaluated. Clinical characteristics of patients with bacteraemia caused by BORSA, methicillin-susceptible S. aureus and methicillin-resistant S. aureus (MRSA) were compared. MICs of 12 antibiotics were determined by agar dilution. Genetic characteristics of 64 available BORSA isolates were analysed by detection of the SCCmec gene, the mecA promoter region sequence and multilocus sequence typing (MLST). Pulsed-field gel electrophoresis (PFGE) was performed to identify the clonality of the emerging ST isolates. The quinolone resistance genes were analysed for the emerging ciprofloxacin-resistant ST45 clone isolates. Among the 65 BORSA bacteraemic patients, in-hospital mortality was 24.6%, significantly lower than that of MRSA patients (38.5%) (P = 0.03). Underlying conditions were similar between BORSA and MRSA patients, but with less dialysis in the former (P = 0.01). Multivariate analysis revealed that septic shock [odds ratio (OR) = 15.95] and bacteraemia originating from lower respiratory tract infection (OR = 5.78) were two independent risk factors for 30-day mortality. The ST45 clone with high-level ciprofloxacin resistance (MICs of 8-128 mg/L) replaced ST59 as the predominant clone since 2012, although no major clustering was detected. In conclusion, the emerging multidrug-resistant ST45 clone has replaced ST59 as the most common among BORSA isolates. PMID- 29505886 TI - Oleanolic acid acetate attenuates polyhexamethylene guanidine phosphate-induced pulmonary inflammation and fibrosis in mice. AB - Oleanolic acid acetate (OAA), triterpenoid compound isolated from Vigna angularis (azuki bean), has been revealed anti-inflammatory in several studies. We investigated the effects of OAA against polyhexamethylene guanidine phosphate (PHMG-P)-induced pulmonary inflammation and fibrosis in mice. OAA treatment effectively alleviated PHMG-P-induced lung injury, including the number of total and differential cell in BAL fluid, histopathological lesions and hydroxyproline content in a dose dependent manner. Moreover, OAA treatment significantly decreased the elevations of IL-1beta, IL-6, TNF-alpha, TGF-beta1, and fibronectin, and the activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the lungs of PHMG-P-treated mice. Cytokines are known to be key modulators in the inflammatory responses that drive progression of fibrosis in injured tissues. The activation of NLRP3 inflammasome has been reported to be involved in induction of inflammatory cytokines. These results indicate that OAA may mitigate the inflammatory response and development of pulmonary fibrosis in the lungs of mice treated with PHMG-P. PMID- 29505887 TI - Effect of incubation temperature on neuropeptide Y and neuropeptide Y receptors in turkey and chicken satellite cells. AB - Neuropeptide Y (NPY) is an appetite stimulating peptide released from the central nervous system and impacts the function of many different cell types. A recent transcriptome study showed that NPY expression was altered when turkey breast muscle satellite cells were incubated at low or high temperatures, suggesting NPY may mediate temperature effects on satellite cells. However, to date minimal information exists describing the expression and function of NPY in satellite cells. The objective of this study was to determine how temperature impacts NPY and NPY receptor gene expression in satellite cells isolated from turkeys and chickens with differing genetic lineages. Two broiler and two turkey breast muscle satellite cell lines were incubated at 35, 38 or 41 degrees C during proliferation and differentiation. In both turkey lines, NPY, and receptors NPY2R and NPY5R expression increased at elevated temperatures after 72 h of proliferation. During differentiation NPY and NPY5R expression increased in both turkey lines with higher temperatures, whereas NPY2R was minimally affected by temperature. In contrast, in both chicken cell lines there were few significant differences for NPY and NPY receptor expression across temperature during proliferation. During differentiation, the temperature effect was different in the two chicken cell lines. In the BPM8 chicken line, there were few differences in NPY and NPY receptors across temperature; whereas elevated temperatures increased NPY, NPY2R, and NPY5R expression in the 708 line. The differences between turkey and chicken lines suggest NPY has species specific satellite cell functions in response to heat stress. PMID- 29505888 TI - Puncturing of lyophilized tissue engineered vascular matrices enhances the efficiency of their recellularization. AB - : Data on in vitro engineered "off the shelf" matrices support the concept of endogenous cellular repopulation driving the graft's remodeling via immune mediated response. This seems important to further accelerate the cell reconstitution and may play a crucial role when mononuclear cells are used. Nevertheless, studies on decellularized xenogeneic grafts showed only limited host cell repopulation post-implantation. This study aims at a systematic comparison of reseeding methods (dripping, injection, bathing in a cell suspension and combined puncturing-dripping method) to define the most efficient technique enhancing recellularization of tissue engineered vascular matrices (patches, vessels, small diameter and standard size valves) prior implantation. The constructs were analyzed histologically, biochemically and biomechanically. Various preconditioning treatments (wet, lyophilized and air-dried) combined with reseeding methods demonstrated the highest cell loading efficiency, despite applied crimping and flow stress, of lyophilization followed by puncturing dripping technique. This novel seeding method allows for an efficient, time saving graft reseeding that can be used within a one-step cardiovascular clinical intervention. STATEMENT OF SIGNIFICANCE: The concept of living tissue engineered, self-repairing, autologous cardiovascular replacements, was proposed alternatively to existing synthetic/xenogeneic prostheses. Recent studies in animal models demonstrate faster in vivo recellularization after grafts pre seeding with cells prior implantation. Pre-seeded cells hold either, the ability to differentiate directionally or attract host cells, crucial for graft integration and remodeling. It is unclear, however, how efficient the pre-loading is and how well cells withstand the flow. The study presents a systematic overview of cell loading techniques of different cardiovascular constructs, tested under static and dynamic conditions. Comparison illustrates a significantly higher efficiency of cells loading in lyophilized tissues punctured before their standard seeding. This technique may beneficially accelerate remodeling of cardiovascular grafts in further in vivo studies. PMID- 29505889 TI - Recovery of low volumes of wear debris from rat stifle joint tissues using a novel particle isolation method. AB - : Less than optimal particle isolation techniques have impeded analysis of orthopaedic wear debris in vivo. The purpose of this research was to develop and test an improved method for particle isolation from tissue. A volume of 0.018 mm3 of clinically relevant CoCrMo, Ti-6Al-4V or Si3N4 particles was injected into rat stifle joints for seven days of in vivo exposure. Following sacrifice, particles were located within tissues using histology. The particles were recovered by enzymatic digestion of periarticular tissue with papain and proteinase K, followed by ultracentrifugation using a sodium polytungstate density gradient. Particles were recovered from all samples, observed using SEM and the particle composition was verified using EDX, which demonstrated that all isolated particles were free from contamination. Particle size, aspect ratio and circularity were measured using image analysis software. There were no significant changes to the measured parameters of CoCrMo or Si3N4 particles before and after the recovery process (KS tests, p > 0.05). Titanium particles were too few before and after isolation to analyse statistically, though size and morphologies were similar. Overall the method demonstrated a significant improvement to current particle isolation methods from tissue in terms of sensitivity and efficacy at removal of protein, and has the potential to be used for the isolation of ultra-low wearing total joint replacement materials from periprosthetic tissues. STATEMENT OF SIGNIFICANCE: This research presents a novel method for the isolation of wear particles from tissue. Methodology outlined in this work would be a valuable resource for future researchers wishing to isolate particles from tissues, either as part of preclinical testing, or from explants from patients for diagnostic purposes. It is increasingly recognised that analysis of wear particles is critical to evaluating the safety of an orthopaedic device. PMID- 29505890 TI - The in vitro effects of macrophages on the osteogenic capabilities of MC3T3-E1 cells encapsulated in a biomimetic poly(ethylene glycol) hydrogel. AB - : Poly(ethylene glycol) PEG-based hydrogels are promising for cell encapsulation and tissue engineering, but are known to elicit a foreign body response (FBR) in vivo. The goal of this study was to investigate the impact of the FBR, and specifically the presence of inflammatory macrophages, on encapsulated cells and their ability to synthesize new extracellular matrix. This study employed an in vitro co-culture system with murine macrophages and MC3T3-E1 pre-osteoblasts encapsulated in a bone-mimetic hydrogel, which were cultured in transwell inserts, and exposed to an inflammatory stimulant, lipopolysaccharide (LPS). The co-culture was compared to mono-cultures of the cell-laden hydrogels alone and with LPS over 28 days. Two macrophage cell sources, RAW 264.7 and primary derived, were investigated. The presence of LPS-stimulated primary macrophages led to significant changes in the cell-laden hydrogel by a 5.3-fold increase in percent apoptotic osteoblasts at day 28, 4.2-fold decrease in alkaline phosphatase activity at day 10, and 7-fold decrease in collagen deposition. The presence of LPS-stimulated RAW macrophages led to significant changes in the cell laden hydrogel by 5-fold decrease in alkaline phosphatase activity at day 10 and 4-fold decrease in collagen deposition. Mineralization, as measured by von Kossa stain or quantified by calcium content, was not sensitive to macrophages or LPS. Elevated interleukin-6 and tumor necrosis factor-alpha secretion were detected in mono-cultures with LPS and co-cultures. Overall, primary macrophages had a more severe inhibitory effect on osteoblast differentiation than the macrophage cell line, with greater apoptosis and collagen I reduction. In summary, this study highlights the detrimental effects of macrophages on encapsulated cells for bone tissue engineering. STATEMENT OF SIGNIFICANCE: Poly(ethylene glycol) (PEG)-based hydrogels are promising for cell encapsulation and tissue engineering, but are known to elicit a foreign body response (FBR) in vivo. The impact of the FBR on encapsulated cells and their ability to synthesize tissue has not been well studied. This study utilizes thiol-ene click chemistry to create a biomimetic, enzymatically degradable hydrogel system with which to encapsulate MC3T3-E1 pre osteoblasts. The osteogenic capabilities and differentiation of these cellswerestudied in co-culture with macrophages, known drivers of the FBR.This study demonstrates that macrophages reduce osteogenic capabilities of encapsulated cellsin vitroand suggestthat the FBR should be considered for in vivo tissue engineering. PMID- 29505891 TI - Long-term in vivo evolution of high-purity Mg screw degradation - Local and systemic effects of Mg degradation products. AB - : Magnesium (Mg) based materials are the focus of research for use as degradable materials in orthopedics and cranio-maxillofacial surgery. However, corrosion rate control and biosecurity are still the key issues that need to be solved prior to their clinical applications. In the present study, as-rolled high-purity magnesium (HP Mg, 99.99 wt%) screws were implanted in rabbit tibiae for up to 52 weeks in order to investigate their long-term in vivo degradation and the local and systemic effects of their degradation products. A series of long-term monitoring were performed at various time points (4w, 12w, 26w and 52w) after implantation using numerous investigations such as micro-CT assay, histomorphometric analysis, local micro-environment testing and biochemical analysis of serum and urine. It was revealed that HP Mg screws had a uniform degradation morphology and a slow degradation rate in vivo during the period of 52 weeks. Their degradation products not only increased the local pH values but also changed the local Mg2+ ions concentration and gas cavity area in the peri implant tissues in a dynamic manner. More importantly, both the new bone formation and bone-implant contact rate were increased at bone-implant interfaces at 26 weeks and 52 weeks post-implantation. Furthermore, neither abnormal elevation of serum magnesium and urine magnesium level, nor liver and kidney dysfunction were detected during the monitoring period of 26 weeks. All these results of long-term investigation suggest that HP Mg screws possess a slow degradation rate, desirable bone repair capacity and long-term local/systemic biosafety, and consequently may have good potential for application as bone fixation devices. STATEMENT OF SIGNIFICANCE: The corrosion resistance control and biosecurity issues of Mg alloys limited their clinical applications in some extent. Mg purification is another effective way to improve corrosion resistance of Mg-based materials. However, the long-term in vivo degradation of high-purity magnesium (HP Mg) and the local and systemic effects of its degradation products have not been fully investigated yet, which are the key factors to determine the clinical application prospect of HP Mg. Especially the changes in peri-implant microenvironment may greatly influence the local physiological response and bone repair. In this study, the long-term evolution tendency of in vivo degradation behavior of HP Mg screws was discovered from the view of space-time. Furthermore, not only the dynamic changes of local microenvironment and the long-term evolution process of bone repair, but also the dynamic systemic responses were systematically revealed. Conclusions of this study may help us to further understand the long-term in vivo evolution of HP Mg degradation and the local/systemic effects of its degradation products and help to guide the design of biodegradable bone fixation material. PMID- 29505893 TI - Electrofabrication of functional materials: Chloramine-based antimicrobial film for infectious wound treatment. AB - : Electrical signals can be imposed with exquisite spatiotemporal control and provide exciting opportunities to create structure and confer function. Here, we report the use of electrical signals to program the fabrication of a chloramine wound dressing with high antimicrobial activity. This method involves two electrofabrication steps: (i) a cathodic electrodeposition of an aminopolysaccharide chitosan triggered by a localized region of high pH; and (ii) an anodic chlorination of the deposited film in the presence of chloride. This electrofabrication process is completed within several minutes and the chlorinated chitosan can be peeled from the electrode to yield a free-standing film. The presence of active NCl species in this electrofabricated film was confirmed with chlorination occurring first on the amine groups and then on the amide groups when large anodic charges were used. Electrofabrication is quantitatively controllable as the cathodic input controls film growth during deposition and the anodic input controls film chlorination. In vitro studies demonstrate that the chlorinated chitosan film has antimicrobial activities that depend on the chlorination degree. In vivo studies with a MRSA infected wound healing model indicate that the chlorinated chitosan film inhibited bacterial growth, induced less inflammation, developed reorganized epithelial and dermis structures, and thus promoted wound healing compared to a bare wound or wound treated with unmodified chitosan. These results demonstrate the fabrication of advanced functional materials (i.e., antimicrobial wound dressings) using controllable electrical signals to both organize structure through non-covalent interactions (i.e., induce chitosan's reversible self-assembly) and to initiate function-conferring covalent modifications (i.e., generate chloramine bonds). Potentially, electrofabrication may provide a simple, low cost and sustainable alternative for materials fabrication. STATEMENT OF SIGNIFICANCE: We believe this work is novel because this is the first report (to our knowledge) that electronic signals enable the fabrication of advanced antimicrobial dressings with controlled structure and biological performance. We believe this work is significant because electrofabrication enables rapid, controllable and sustainable materials construction with reduced adverse environmental impacts while generating high performance materials for healthcare applications. More specifically, we report an electrofbrication of antimicrobial film that can promote wound healing. PMID- 29505892 TI - Crystallinity of hydroxyapatite drives myofibroblastic activation and calcification in aortic valves. AB - : Calcific aortic valve disease (CAVD) is an inexorably degenerative pathology characterized by progressive calcific lesion formation on the valve leaflets. The interaction of valvular cells in advanced lesion environments is not well understood yet highly relevant as clinically detectable CAVD exhibits calcifications composed of non-stoichiometric hydroxyapatite (HA). In this study, Fourier transform infrared spectroscopic imaging was used to spatially analyze mineral properties as a function of disease progression. Crystallinity (size and perfection) increased with increased valve calcification. To study the relationship between crystallinity and cellular behavior in CAVD, valve cells were seeded into 3D mineral-rich collagen gels containing synthetic HA particles, which had varying crystallinities. Lower crystallinity HA drove myofibroblastic activation in both valve interstitial and endothelial cells, as well as osteoblastic differentiation in interstitial cells. Additionally, calcium accumulation within gels depended on crystallinity, and apoptosis was insufficient to explain differences in HA-driven cellular activity. The protective nature of endothelial cells against interstitial cell activation and calcium accumulation was completely inhibited in the presence of less crystalline HA particles. Elucidating valve cellular behavior post-calcification is of vital importance to better predict and treat clinical pathogenesis, and mineral containing hydrogel models provide a unique 3D platform to evaluate valve cell responses to a later stage of valve disease. STATEMENT OF SIGNIFICANCE: We implement a 3D in vitro platform with embedded hydroxyapatite (HA) nanoparticles to investigate the interaction between valve interstitial cells, valve endothelial cells, and a mineral-rich extracellular environment. HA nanoparticles were synthesized based on analysis of the mineral properties of calcific regions of diseased human aortic valves. Our findings indicate that crystallinity of HA drives activation and differentiation in interstitial and endothelial cells. We also show that a mineralized environment blocks endothelial protection against interstitial cell calcification. Our HA-containing hydrogel model provides a unique 3D platform to evaluate valve cell responses to a mineralized ECM. This study additionally lays the groundwork to capture the diversity of mineral properties in calcified valves, and link these properties to progression of the disease. PMID- 29505895 TI - Neural Foraminal Lesions: An Imaging Overview. PMID- 29505894 TI - Human iPSC-derived mesenchymal stem cells encapsulated in PEGDA hydrogels mature into valve interstitial-like cells. AB - : Despite recent advances in tissue engineered heart valves (TEHV), a major challenge is identifying a cell source for seeding TEHV scaffolds. Native heart valves are durable because valve interstitial cells (VICs) maintain tissue homeostasis by synthesizing and remodeling the extracellular matrix. This study demonstrates that induced pluripotent stem cells (iPSC)-derived mesenchymal stem cells (iMSCs) can be derived from iPSCs using a feeder-free protocol and then further matured into VICs by encapsulation within 3D hydrogels. The differentiation efficiency was characterized using flow cytometry, immunohistochemistry staining, and trilineage differentiation. Using our feeder free differentiation protocol, iMSCs were differentiated from iPSCs and had CD90+, CD44+, CD71+, alphaSMA+, and CD45- expression. Furthermore, iMSCs underwent trilineage differentiation when cultured in induction media for 21 days. iMSCs were then encapsulated in poly(ethylene glycol)diacrylate (PEGDA) hydrogels grafted with adhesion peptide (RGDS) to promote remodeling and further maturation into VIC-like cells. VIC phenotype was assessed by the expression of alpha-smooth muscle actin (alphaSMA), vimentin, and collagen production after 28 days. When MSC-derived cells were encapsulated in PEGDA hydrogels that mimic the leaflet modulus, a decrease in alphaSMA expression and increase in vimentin was observed. In addition, iMSCs synthesized collagen type I after 28 days in 3D hydrogel culture. Thus, the results from this study suggest that iMSCs may be a promising cell source for TEHV. STATEMENT OF SIGNIFICANCE: Developing a suitable cell source is a critical component for the success and durability of tissue engineered heart valves. The significance of this study is the generation of iPSCs-derived mesenchymal stem cells (iMSCs) that have the capacity to mature into valve interstitial-like cells when introduced into a 3D cell culture designed to mimic the layers of the valve leaflet. iMSCs were generated using a feeder-free protocol, which is one major advantage over other methods, as it is more clinically relevant. In addition to generating a potential new cell source for heart valve tissue engineering, this study also highlights the importance of a 3D culture environment to influence cell phenotype and function. PMID- 29505896 TI - Effect on Passive Range of Motion and Functional Correlates After a Long-Term Lower Limb Self-Stretch Program in Patients With Chronic Spastic Paresis. AB - BACKGROUND: In current health care systems, long-duration stretching, performed daily, cannot be obtained through prescriptions of physical therapy. In addition, the short-term efficacy of the various stretching techniques is disputed, and their long-term effects remain undocumented. OBJECTIVE: To evaluate changes in extensibility in 6 lower limb muscles and in ambulation speed after a >=1-year self-stretch program, the Guided Self-rehabilitation Contract (GSC), in individuals with chronic spastic paresis. DESIGN: Retrospective study. SETTING: Neurorehabilitation clinic. PARTICIPANTS: Patients diagnosed with hemiparesis or paraparesis at least 1 year before the initiation of a GSC and who were then involved in the GSC program for at least 1 year. INTERVENTIONS: For each patient, specific muscles were identified for intervention among the following: gluteus maximus, hamstrings, vastus, rectus femoris, soleus, and gastrocnemius. Prescriptions and training for a daily, high-load, prolonged, home self stretching program were primarily based on the baseline coefficient of shortening, defined as CSH = [(XN -XV1)/XN] (XV1 = PROM, passive range of motion; XN = normally expected amplitude). MAIN OUTCOME MEASUREMENTS: Six assessments were performed per year, measuring the Tardieu XV1 or maximal slow stretch range of motion angle (PROM), CSH, 10-m ambulation speed, and its functional ambulation category (Perry's classification: household, limited, or full). Changes from baseline in self-stretched and nonself-stretched muscles were compared, with meaningful XV1 change defined as DeltaXV1 >5 degrees for plantar flexors and >10 degrees for proximal muscles. Correlation between the composite XV1 (mean PROM for the 6 muscles) and ambulation speed also was evaluated. RESULTS: Twenty-seven GSC participants were identified (14 women, mean age 44 years, range 29-59): 18 with hemiparesis and 9 with paraparesis. After 1 year, 47% of self-stretched muscles showed meaningful change in PROM (DeltaXV1) versus 14% in nonself stretched muscles (P < .0001, chi2). DeltaCSH was -31% (95% confidence interval [95% CI] -41.5 to -15.2) in self-stretched versus -7% (95% CI -11.9 to -2.1) in nonself-stretched muscles (P < .0001, t-test). Ambulation speed increased by 41% (P < .0001) from 0.81 m/s (95% CI 0.67-0.95) to 1.15 m/s (95% CI 1.01-1.29). Eight of the 12 patients (67%) who were in limited or household categories at baseline moved to a higher functional ambulation category. There was a trend for a correlation between composite XV1 and ambulation speed (r = 0.44, P = .09) in hemiparetic patients. CONCLUSION: Therapists should consider prescribing and monitoring a long-term lower limb self-stretch program using GSC, as this may increase muscle extensibility in adult-onset chronic paresis. LEVEL OF EVIDENCE: III. PMID- 29505897 TI - Problem Behaviors and Psychological Distress Among Teens Seen in a National Sample of Emergency Departments. AB - BACKGROUND: Problem behaviors, such as substance use and peer aggression, frequently coexist and are common among youth seen in emergency departments (EDs). EDs are increasingly urged to screen for both psychological distress and problem behaviors. OBJECTIVE: To inform screening and intervention efforts, we aimed to identify classes of problematic substance use and peer aggression in a sample of adolescents from 16 pediatric EDs, and to examine the relative prevalence of psychological distress in identified classes. METHODS: We completed a cross-sectional survey of youth (n = 5001) presenting for any reason to 16 pediatric EDs across the United States, with the use of validated measures of demographics, alcohol and substance use, and peer aggression. We used standard latent class analysis techniques to create behavioral risk classes of adolescents based on violence and substance use variables; then we conducted logistic regression to examine the relationship between psychological distress and the latent classes. RESULTS: Three classes of problem behaviors were identified: low risk (few problem behaviors, 91.2% of sample), medium risk (high cigarette smoking; moderate violence, alcohol/substance use; 5.2%), and high risk (high levels of all problem behaviors, 3.5%). A significant directional association (P < .001) between worse psychological distress and higher-risk behavior classes was noted, even after adjusting for demographics. CONCLUSIONS: Youth seen in the ED for any reason who report higher levels of past-year substance use and peer aggression are significantly more likely to report negative mood symptoms. Targeted screening and interventions for this population may be indicated. PMID- 29505898 TI - A Randomized Controlled Trial of an Eczema Care Plan. AB - OBJECTIVE: To test whether an eczema care plan (ECP) would improve provider documentation and management, decrease eczema severity, and increase patient quality of life (QOL) in the pediatric primary care setting. METHODS: We conducted a randomized controlled trial from June 2015 to September 2016 at a large hospital-based pediatric primary care clinic. Participants included children from 1 month to 16 years of age with a diagnosis of eczema. The intervention group received the ECP and the control group received usual care. Both groups completed a validated eczema severity scale (Patient-Oriented Eczema Measure [POEM]) and a QOL scale (Infant's Dermatitis Quality of Life Index [IDQOL]) or Children's Dermatology Life Quality Index [CDLQI]) before the visit and again ~1 month later. RESULTS: A total of 211 caregivers completed both the pre- and postintervention surveys (100 control group and 111 intervention group [94% completion]). Intervention group providers were more likely to recommend a comprehensive "step-up" plan (88%) vs 28%; P < .001, bleach baths (45%) vs 9%; P < .001, and wet wraps (50%) vs 7%; P < .001. They were also more likely to document providing a written plan to families (80%) vs 2%; P < .001. In the intervention and control groups, eczema severity and QOL improved between the pre and postintervention periods. However, there was not a significant difference between the groups on either measure: POEM difference -0.8, 95% confidence interval (CI) -3.2 to 1.7; IDQOL difference -0.1, 95% CI -1.8 to 1.6; CDLQI difference 0.8, 95% CI -0.9 to 2.6. CONCLUSIONS: Intervention group providers documented more comprehensive eczema care than control group providers. Although patients improved on all measures in the postintervention period, the ECP did not augment that improvement. PMID- 29505899 TI - The evaluation of endpoint variability and implications for study statistical power and sample size in conscious instrumented dogs. AB - INTRODUCTION: The sensitivity of a given test to detect a treatment-induced effect in a variable of interest is intrinsically related to the variability of that variable observed without treatment and the number of observations made in the study (i.e. number of animals). To evaluate test sensitivity to detect drug induced changes in myocardial contractility using the variable LVdP/dtmax, a HESI supported consortium designed and conducted studies in chronically instrumented, conscious dogs using telemetry. This paper evaluated the inherent variability of the primary endpoint, LVdP/dtmax, over time in individual animals as well as the variability between animals for a given laboratory. An approach is described to evaluate test system variability and thereby test sensitivity which may be used to support the selection of the number of animals for a given study, based on the desired test sensitivity. METHODS: A double 4 * 4 Latin square study design where eight animals each received a vehicle control and three dose levels of a test compound was conducted at six independent laboratories. LVdP/dtmax was assessed via implanted telemetry systems in Beagle dogs (N = 8) using the same protocol and each of the six laboratories conducted between two and four studies. Vehicle data from each study was used to evaluate the between-animal and within-animal variability in different time averaging windows. Simulations were conducted to evaluate statistical power and type I error for LVdP/dtmax based on the estimated variability and assumed treatment effects in hourly-interval, bi-hourly interval, or drug-specific super interval. RESULTS: We observe that the within-animal variability can be reduced by as much as 30% through the use of a larger time averaging window. Laboratory is a significant source of animal-to-animal variability as between-animal variability is laboratory-dependent and is less impacted by the use of different time averaging windows. The statistical power analysis shows that with N = 8, the double Latin square design has over 90% power to detect a minimal time profile with a maximum change of up to 15% or approximately 450 mm Hg/s in LVdP/dtmax. With N = 4, the single Latin square design has over 80% power to detect a minimal time profile with a maximum change of up to 20% or approximately 600 mm Hg/s in LVdP/dtmax. DISCUSSION: We describe a statistical procedure to quantitatively evaluate the acute cardiac effects from studies conducted across six sites and objectively examine the variability and sensitivity that were difficult or impossible to calculate consistently based on previous works. Although this report focuses on the evaluation on LVdP/dtmax, this approach is appropriate for other variables such as heart rate, arterial blood pressure, or variables derived from the ECG. PMID- 29505900 TI - A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer. AB - INTRODUCTION: We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC. METHODS: In an open-label multicenter trial, patients with pathological stage IB to IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) plus carboplatin (area under the curve 5) every 3 weeks for four cycles (arm A) or a group receiving orally administered UFT (250 mg/m2) daily for 2 years (arm B). The primary and secondary end points were overall survival and relapse-free survival and toxicity, respectively. RESULTS: Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in each arm). The median follow-up period was 6.5 years. The 5-year overall survival rate was 70% (95% confidential interval [CI]: 63-76] in arm A versus 73% (95% CI: 66-78) in arm B (hazard ratio = 0.92, 95% CI: 0.55-1.41, p = 0.69). There was no significant difference in the 5-year relapse-free survival rate between arms A and B (56% versus 57% [hazard ratio = 0.92, 95% CI: 0.63 1.34, p = 0.50]). Toxicities were well tolerated and there was no treatment related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than in the UFT group (76.5% and 1.0%, respectively [p < 0.0001 in both]). CONCLUSIONS: As adjuvant chemotherapy, paclitaxel plus carboplatin was no better than UFT in terms of survival among patients with stage IB to IIIA NSCLC tumors who underwent complete resection (UMIN000000810). PMID- 29505901 TI - Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC. AB - INTRODUCTION: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non-small-cell lung cancer who have been pre-treated with EGFR tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. METHODS: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated non-small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. RESULTS: T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1-12.1). Median survival was not reached and the 1 year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (>=10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92-3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89-5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. CONCLUSION: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib. PMID- 29505902 TI - The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder. AB - Considerable evidence suggests that autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive-compulsive disorder (OCD) share a common molecular aetiology, despite their unique clinical diagnostic criteria. The aim of this study was therefore to determine and characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD. Gene lists were obtained from previously published studies for ASD, BD, SCZ and for OCD. Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using the web-server tool Enrichr. Ten genes were identified to be commonly associated with the aetiology of ASD, SCZ, BD and OCD. Enrichment analyses determined that these genes are predominantly involved in the dopaminergic and serotonergic pathways, the voltage-gated calcium ion channel gene network, folate metabolism, regulation of the hippo signaling pathway, and the regulation of gene silencing and expression. In addition to well-characterised and previously described pathways, regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders. In contrast, a large number of previously associated genes were shown to be disorder-specific. And unique disorder-specific pathways and biological processes were presented for ASD, BD, SCZ and OCD aetiology. Considering the current global incidence and prevalence rates of mental health disorders, focus should be placed on cross-disorder commonalities in order to realise actionable and translatable results to combat mental health disorders. PMID- 29505903 TI - Hardened Liver Due to Fibrolamellar Hepatocellular Carcinoma. PMID- 29505904 TI - 36-Year-Old Man With Acute Epigastric Pain After Breakfast. PMID- 29505905 TI - Effects of Treatment of Chronic Hepatitis B Virus Infection on Patient-Reported Outcomes. AB - BACKGROUND & AIMS: Chronic infection with hepatitis B virus (HBV) causes liver disease and cirrhosis. It is not clear how treatment of chronic HBV infection affects patient-reported outcomes (PROs). We aimed to assess changes in PROs in patients treated for chronic HBV infection. METHODS: We collected and analyzed PRO data from 242 patients with chronic HBV infection (without advanced fibrosis or cirrhosis) enrolled in 2 international phase 2 blinded controlled clinical trials from 2015 through 2017. In these trials, patients were treated with an approved oral antiviral regimen (tenofovir, entecavir, adefovir, lamivudine, or telbivudine) and then randomly assigned to groups given vesatolimod (an oral agonist of Toll-like receptor 7) or placebo. PROs were collected using the Short Form-36, the Chronic Liver Disease Questionnaire, and the Work Productivity and Activity Impairment: Specific Health Problem questionnaires before treatment and during treatment weeks 12, 24, and 48. RESULTS: We did not observe significant differences in PROs between patients receiving vesatolimod vs placebo. At baseline, patients with viral suppression (HBV DNA level, <20 IU/mL) had higher PRO scores (by up to +10.6% of a PRO range size). During treatment, there were significant increases in scores for some domains of the Chronic Liver Disease Questionnaire and in General Health scores of Short Form-36 (increases of up to 4.9%; P < .05). Patients with a decrease of at least 2.7 log10 IU/mL in level of HBV DNA had substantially larger increases in PRO scores (P < .05 for 10 of 22 studied PROs). In multivariate analysis, a reduction in viral load was independently associated with increases in PROs (beta values up to 1.6% per log10 IU/mL decrease; P < .05). CONCLUSIONS: In an analysis of data from phase 2 trials, we associated active treatment of chronic HBV infection with increased PRO scores. These findings support inclusion of PRO end points in assessments of efficacy and safety in clinical trials of treatments for HBV infection. PMID- 29505906 TI - Utility of Endoscopic Ultrasound in Evaluating Local Recurrence After Surgery for Pancreatic Cancer. AB - Pancreatic adenocarcinoma recurrence after surgery (PARaS) is associated with poor outcomes. PARaS is locoregional in 50%-80%, effecting the resection bed and adjacent lymphatics.1-3 Detection of PARaS via endoscopic ultrasound (EUS) is challenging because recurrent malignancy is difficult to distinguish from normal postoperative changes. Diagnosing PARaS is important, because salvage chemotherapy/radiation improves survival.4,5 The purpose of this investigation is to determine the clinical utility of EUS fine-needle aspiration (FNA) in patients with suspected PARaS. PMID- 29505907 TI - Innumerable Nodular Lesions in the Duodenum. PMID- 29505908 TI - New Causes for the Old Problem of Bile Reflux Gastritis. PMID- 29505909 TI - Outcomes of Endoscopic Balloon Dilation vs Surgical Resection for Primary Ileocolic Strictures in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Few studies have compared endoscopic balloon dilation (EBD) with ileocolic resection (ICR) in the treatment of primary ileocolic strictures in patients with Crohn's disease (CD). METHODS: We performed a retrospective study to compare postprocedure morbidity and surgery-free survival among 258 patients with primary stricturing ileo(colic) CD (B2, L1, or L3) initially treated with primary EBD (n = 117) or ICR (n = 258) from 2000 through 2016. Patients with penetrating disease were excluded from the study. We performed multivariate analyses to evaluate factors associated with surgery-free survival. RESULTS: Postprocedural complications occurred in 4.7% of patients treated with EBD and salvage surgery was required in 44.4% of patients. Factors associated with reduced surgery-free survival among patients who underwent EBD included increased stricture length (hazard ratio, 2.0; 95% CI, 1.3-3.3), ileocolonic vs ileal disease (hazard ratio, 10.9; 95% CI, 2.6-45.4), and decreased interval between EBD procedures (hazard ratio, 1.2; 95% CI, 1.1-1.4). There were no significant differences in sex, age, race, or CD duration between EBD and ICR groups. Patients treated with ICR were associated with more common postoperative adverse events (32.2%; P < .0001), but a reduced need for secondary surgery (21.7%; P < .0001) and significantly longer surgery-free survival (11.1 +/- 0.6 vs 5.4 +/- 0.6 y; P < .001). CONCLUSIONS: In this retrospective study, we found that although EBD is initially successful with minimal adverse events, there is a high frequency of salvage surgery. Initial ICR is associated with a higher morbidity but a longer surgery-free interval. The risks and benefits should be balanced in selecting treatments for individual patients. PMID- 29505910 TI - Appropriateness of Combination Therapy for Patients With Inflammatory Bowel Diseases: One Size Still Does Not Fit All. AB - Randomized controlled trials (RCTs) have demonstrated that therapies targeting tumor necrosis factor (TNF) and alpha4beta7 integrin are effective when given as monotherapy in inducing and/or maintaining remission in patients with ulcerative colitis (UC) or Crohn's disease (CD), but data from RCTs are less clear on whether concomitant immunomodulator (IM) therapy confers additional benefit. In CD, RCT data are mixed,1,2 as are results of systematic reviews and meta analyses, showing no benefit overall,3 minimal benefit with individual agents,4 and comparative benefit over some monotherapies but not others.5 For example, concomitant azathioprine with infliximab is more effective than either drug alone in patients with CD naive to both drugs,2 but whether combination therapy is more effective than monotherapy with infliximab in nonnaive patients, or with other approved biologic drugs in any population, remains unknown. In UC, RCTs have shown that the benefit may be limited to specific populations,6 whereas systematic reviews suggest no benefit at all.7. PMID- 29505911 TI - Cholangioscopy Is Safe and Feasible in Elderly Patients. AB - BACKGROUND & AIMS: Although cholangioscopy is widely used during endoscopic retrograde cholangiopancreatiography (ERCP), its safety and feasibility for elderly patients are not well established. We aimed to evaluate the safety and feasibility of cholangioscopy in elderly patients. METHODS: We performed a retrospective study of all ERCPs with single-operator cholangioscopy (SOC) performed at 3 tertiary referral hospitals from March 2012 through October 2015. We collected data on patient demographics, procedure indications, findings, complications, and success rates (complete success was achieved if all intended diagnostic and therapeutic procedures were performed, such as tissue sample collection or complete removal of stones). The cohort was divided into 3 groups: patients younger than 65 years (group 1, n = 178), patients 65-75 years old (group 2, n = 86), and patients older than 75 years (group 3, n = 77). We used 1 way ANOVA, the chi2 test, and the Wilcoxon sum rank test to compare study variables. The primary aim was to assess rates of complications from ERCP with SOC in elderly patients compared with younger patients. RESULTS: Baseline clinical features were similar among groups, except for a higher prevalence of co morbidities in group 3. The indication for and findings from ERCP with SOC differed among the groups; stricture or tumor was the most common indication in groups 1 and 3-the most common findings were strictures and masses, respectively. In group 2, choledocholithiasis was the most common indication and finding. The success rate, analyzed in a subset of 209 patients, was 88.5% overall and did not differ significantly among groups. The overall rate of complication was 7.33% with no significant difference among groups (7.30% for group 1, 6.98% for group 2, and 7.79% for group 3) (P < .17). CONCLUSIONS: In a retrospective analysis of ERCPs with SOCs, we found this procedure to be safe for elderly patients (older than 75 years), who had rates of complications and hospital admission similar to those of younger patients. PMID- 29505912 TI - Modelling survival of Salmonella Enteritidis during storage of yoghurt at different temperatures. AB - The aim of this study was to evaluate the behaviour of Salmonella Enteritidis during the storage of yoghurt at different temperatures (4, 12, 20, and 25 degrees C), and to develop mathematical models to predict the behaviour of this bacterium as a function of storage temperature. Results indicated that Salmonella was able to survive longer during storage when temperature was low (e.g. 304 h at 4 degrees C, 60 h at 25 degrees C). The Geeraerd model with log-decrease and tailing was selected as the most suitable model to describe survival. To evaluate the effect of storage temperature on kinetic parameters such as death rate (kmax) secondary models were developed. The kmax was maximum at 25 degrees C and minimum at 4 degrees C with kmax = 0.28 and 0.039 h-1, respectively. The residual population (Nres) ranged 0.5 and 1.8 log CFU/g but there was no temperature dependency of this parameter. A probabilistic example was conduced based on the developed model to assess the exposure to Salmonella by consumption of traditional Turkish yoghurt. PMID- 29505913 TI - Occurrence of blaCMY-42 on an IncI1 plasmid in multidrug-resistant Escherichia coli from a tertiary referral hospital in India. AB - OBJECTIVES: Plasmids of different replicon types are believed to be associated with the carriage and transmission of antimicrobial resistance genes. The present study was undertaken to examine the association of blaCIT with particular plasmid types and to identify Escherichia coli strains involve in the maintenance of this resistance determinant in the plasmid. METHODS: Phenotypic screening of AmpC beta lactamases was performed by the modified three-dimensional extract method, followed by antimicrobial susceptibility testing and determination of minimum inhibitory concentrations (MICs). Genotyping screening of beta-lactamase genes was performed by PCR assay, followed by sequencing. Transferability of the blaCMY gene was performed by transformation and conjugation experiments. Plasmid incompatibility typing and DNA fingerprinting by enterobacterial repetitive intergenic consensus (ERIC)-PCR were performed. RESULTS: Among 203 E. coli obtained from different clinical specimens (pus, urine, stool and sputum), 37 were detected as harbouring the blaCIT gene and sequencing of this gene showed nucleotide sequence similarity with the blaCMY-42 variant. This study revealed IncI1-type plasmids as carriers of blaCMY-42 and its propagation within E. coli ST5377, ST361 and ST672. According to the stability results, the blaCMY-42 encoding plasmid can be maintained in E. coli strains for a longer duration without any antimicrobial pressure. CONCLUSIONS: These finding document blaCMY-42 on IncI1-type plasmids, which are considered to be the main vehicles for the spread of blaCMY-42 in this hospital setting. Thus, a proper strategy should be developed to curb the expansion of IncI1-type plasmids in the hospital and community environment. PMID- 29505914 TI - Awareness levels of prevention of cardiac diseases in general population of rawalpindi and requirement of health education. AB - OBJECTIVES: To assess the level of awareness in population about cardiac diseases prevention and suggestion of recommendations. STUDY DESIGN: Descriptive cross sectional survey was carried out in Rawalpindi Cantonment in Oct 2016. METHODS: 100 respondents were selected through convenience sampling. Data was collected through questionnaire. RESULTS: Results indicated low levels of awareness as only 30% of the population knew that cardiac diseases can be prevented to certain extent by lifestyle changes. 46% population knew about importance of physical activity and 34% knew that excess of fried and salty food can cause cardiac diseases. Only 22% population knew that red meat use in excess can cause cardiac diseases. 20% population were aware that lack of sleep can cause cardiac disease. 13% (for sodas), 15% (for sweets) 13% (for consuming egg yolk daily) and 28% (for stress) were the statistics for remaining modifiable risk factors. 80% of the population was aware of smoking hazards which shows the success of anti-smoking campaigns. CONCLUSION: These levels of awareness indicate that there is dire need of policy making for health education to make people aware of lifestyle modifications necessary to prevent cardiac diseases. PMID- 29505915 TI - The influence of betamethasone on fetal heart rate variability, obtained by non invasive fetal electrocardiogram recordings. AB - BACKGROUND: Betamethasone is widely used to enhance fetal lung maturation in case of threatened preterm labour. Fetal heart rate variability is one of the most important parameters to assess in fetal monitoring, since it is a reliable indicator for fetal distress. AIM: To describe the effect of betamethasone on fetal heart rate variability, by applying spectral analysis on non-invasive fetal electrocardiogram recordings. STUDY DESIGN: Prospective cohort study. SUBJECTS: Patients that require betamethasone, with a gestational age from 24 weeks onwards. OUTCOME MEASURES: Fetal heart rate variability parameters on day 1, 2, and 3 after betamethasone administration are compared to a reference measurement. RESULTS: Following 68 inclusions, 12 patients remained with complete series of measurements and sufficient data quality. During day 1, an increase in absolute fetal heart rate variability values was seen. During day 2, a decrease in these values was seen. All trends indicate to return to pre-medication values on day 3. Normalised high- and low-frequency power show little changes during the study period. CONCLUSIONS: The changes in fetal heart rate variability following betamethasone administration show the same pattern when calculated by spectral analysis of the fetal electrocardiogram, as when calculated by cardiotocography. Since normalised spectral values show little changes, the influence of autonomic modulation seems minor. PMID- 29505916 TI - Influence of rest interval on foot-tibia coordination with chronic ankle instability during the Star Excursion Balance Test. AB - The purpose of this study was to determine whether different rest intervals affect performance on the Star Excursion Balance Test (SEBT) associated with chronic ankle instability (CAI) and whether foot-tibia coordination can be associated factors that may help discriminate between individuals with and without CAI during the SEBT. Participants included forty-eight individuals with (n = 24) and without CAI (n = 24). Subjects completed 3 trials in each of the 3 reach directions (anteromedial, medial, posteromedial) in random order. A total of three visits were required to complete the 3 rest interval conditions (10, 20, 40 s). Coupling angles (CA) of tibial internal rotation/dorsiflexion (TIR/DF) and tibial internal rotation/eversion (TIR/EV) were calculated and compared between groups in each direction for each rest interval. Individuals with CAI showed greater CAs of TIR/DF in the M direction (p = 0.01) and of TIR/EV in the P direction (p = 0.04) than healthy individuals in 20 s rest interval time. Overall, joint CAs were different between healthy individuals and those with CAI during the SEBT regardless of rest interval. Based on these results, rest interval and a natural result of CAI could alter ankle joint coordination in comparison of healthy individuals when performing the SEBT. PMID- 29505917 TI - Association between stride time fractality and gait adaptability during unperturbed and asymmetric walking. AB - Human locomotion is an inherently complex activity that requires the coordination and control of neurophysiological and biomechanical degrees of freedom across various spatiotemporal scales. Locomotor patterns must constantly be altered in the face of changing environmental or task demands, such as heterogeneous terrains or obstacles. Variability in stride times occurring at short time scales (e.g., 5-10 strides) is statistically correlated to larger fluctuations occurring over longer time scales (e.g., 50-100 strides). This relationship, known as fractal dynamics, is thought to represent the adaptive capacity of the locomotor system. However, this has not been tested empirically. Thus, the purpose of this study was to determine if stride time fractality during steady state walking associated with the ability of individuals to adapt their gait patterns when locomotor speed and symmetry are altered. Fifteen healthy adults walked on a split-belt treadmill at preferred speed, half of preferred speed, and with one leg at preferred speed and the other at half speed (2:1 ratio asymmetric walking). The asymmetric belt speed condition induced gait asymmetries that required adaptation of locomotor patterns. The slow speed manipulation was chosen in order to determine the impact of gait speed on stride time fractal dynamics. Detrended fluctuation analysis was used to quantify the correlation structure, i.e., fractality, of stride times. Cross-correlation analysis was used to measure the deviation from intended anti-phasing between legs as a measure of gait adaptation. Results revealed no association between unperturbed walking fractal dynamics and gait adaptability performance. However, there was a quadratic relationship between perturbed, asymmetric walking fractal dynamics and adaptive performance during split-belt walking, whereby individuals who exhibited fractal scaling exponents that deviated from 1/f performed the poorest. Compared to steady state preferred walking speed, fractal dynamics increased closer to 1/f when participants were exposed to asymmetric walking. These findings suggest there may not be a relationship between unperturbed preferred or slow speed walking fractal dynamics and gait adaptability. However, the emergent relationship between asymmetric walking fractal dynamics and limb phase adaptation may represent a functional reorganization of the locomotor system (i.e., improved interactivity between degrees of freedom within the system) to be better suited to attenuate externally generated perturbations at various spatiotemporal scales. PMID- 29505918 TI - DDT poisoning of big brown bats, Eptesicus fuscus, in Hamilton, Montana. AB - Dichlorodiphenyltrichloroethane (DDT) is an insecticidal organochlorine pesticide with; known potential for neurotoxic effects in wildlife. The United States Environmental Protection Agency (US EPA) registration for this pesticide has been cancelled and there are currently no federally active products that contain this ingredient in the U.S. We present a case of a colony of big brown bats (E. Fuscus) found dead in the attic roost of an administrative building; in the city of Hamilton, Montana from unknown cause. DDT and its metabolites; dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) were detected in bat tissues by gas chromatography/mass spectrometry (GC-MS) and quantified by gas chromatography tandem quadrupole mass spectrometry (GC-MS/MS). Concentrations of 4081 ppm DDT and 890 ppm DDE wet weight were found in the brain of one bat and are the highest reported concentrations in such a mortality event to date. This case emphasizes the importance of testing wildlife mortalities against a comprehensive panel of toxicologic agents including persistent organic pollutants in the absence of other more common disease threats. PMID- 29505919 TI - Combined polyhydroxyalkanoates (PHA) and 1,3-propanediol production from crude glycerol: Selective conversion of volatile fatty acids into PHA by mixed microbial consortia. AB - Crude glycerol is an important by-product of the biodiesel industry, which can be converted into volatile fatty acids (VFA) and/or 1,3-propanediol (1,3-PDO) by fermentation. In this study, a selective conversion of VFA to polyhydroxyalkanoates (PHA) was attained while leaving 1,3-PDO in the supernatant by means of mixed microbial consortia selection strategies. The process showed highly reproducible results in terms of PHA yield, 0.99 +/- 0.07 Cmol PHA/Cmol S (0.84 g COD PHA/g COD S), PHA content (76 +/- 3.1 g PHA/100 g TSS) and 1,3-PDO recovery (99 +/- 2.1%). The combined process had an ultimate yield from crude glycerol of 0.19 g COD PHA and 0.42 g COD 1,3-PDO per g of input COD. The novel enrichment strategy applied for selectively transforming fermentation by-products into a high value product (PHA) demonstrates the significance of the enrichment process for targeting specific bio-transformations and could potentially prove valuable for other biotechnological applications as well. PMID- 29505921 TI - Encouraging effects of a short-term, adapted Nordic diet intervention on skin microvascular function and skin oxygen tension in younger and older adults. AB - OBJECTIVES: The microvascular benefits of regional diets appear in the literature; however, little is known about Nordic-type diets. We investigated the effects of a short-term, adapted, Nordic diet on microvascular function in younger and older individuals at rest and during activity. METHODS: Thirteen young (mean age: 28 y; standard deviation: 5 y) and 15 older (mean age: 68 y; standard deviation: 6 y) participants consumed a modified Nordic diet for 4 wk. Laser Doppler flowmetry and transcutaneous oxygen monitoring were used to assess cutaneous microvascular function and oxygen tension pre- and postintervention; blood pressure, body mass, body fat percentage, ratings of perceived exertion, and peak heart rate during activity were examined concurrently. RESULTS: Axon mediated vasodilation improved in older participants (1.17 [0.30] to 1.30 [0.30]; P < 0.05). Improvements in endothelium-dependent vasodilation were noted in both young (1.67 [0.50] to 2.03 [0.62]; P < 0.05) and older participants (1.49 [0.37] to 1.63 [0.39]; P < 0.05). Reduced peak heart rate during activity was noted in older participants only (36.5 [8.9] to 35.3 [8.5]; P < 0.05) and reduced body fat percentage in young participants only (young = 27.2 [8.3] to 25.2 [8.8]; P < 0.05). No other variables reached statistical significance; however, trends were observed. CONCLUSIONS: We observed statistically significant improvements in microvascular function, peak heart rate, and body composition. An adapted Nordic diet might improve microvascular health. PMID- 29505920 TI - Selective cytotoxicity of the herbal substance acteoside against tumor cells and its mechanistic insights. AB - Natural products are characterized by extreme structural diversity and thus they offer a unique source for the identification of novel anti-tumor agents. Herein, we report that the herbal substance acteoside being isolated by advanced phytochemical methods from Lippia citriodora leaves showed enhanced cytotoxicity against metastatic tumor cells; acted in synergy with various cytotoxic agents and it sensitized chemoresistant cancer cells. Acteoside was not toxic in physiological cellular contexts, while it increased oxidative load, affected the activity of proteostatic modules and suppressed matrix metalloproteinases in tumor cell lines. Intraperitoneal or oral (via drinking water) administration of acteoside in a melanoma mouse model upregulated antioxidant responses in the tumors; yet, only intraperitoneal delivery suppressed tumor growth and induced anti-tumor-reactive immune responses. Mass-spectrometry identification/quantitation analyses revealed that intraperitoneal delivery of acteoside resulted in significantly higher, vs. oral administration, concentration of the compound in the plasma and tumors of treated mice, suggesting that its in vivo anti-tumor effect depends on the route of administration and the achieved concentration in the tumor. Finally, molecular modeling studies and enzymatic activity assays showed that acteoside inhibits protein kinase C. Conclusively, acteoside holds promise as a chemical scaffold for the development of novel anti-tumor agents. PMID- 29505922 TI - Involvement of growth factors in diabetes mellitus and its complications: A general review. AB - Diabetes mellitus (DM) is a major endocrine metabolic disease and is marked by a lack of insulin. The complication of DM is one of the most difficult problems in medicine. The initial translational studies revealed that growth factors have a major role in integrating tissue physiology and in embryology as well as in growth, maturation and tissue repair. In some tissues affected by diabetes, growth factors are induced by a relative deficit or excess. Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor and is implicated in both of these complications in diabetes. Increase or decrease in the production of transforming growth factor-beta1 (TGF-beta1) has been associated with diabetic nephropathy and retinopathy. The insulin-like growth factor-I (IGF-I) is a naturally-occurring single chain polypeptide which has been widely used in the treatment of diabetic glomerular and renal tubular injuries. This review summarizes the recent evidences for an involvement of growth factors in diabetic complications, focusing on their emergence in sequence of events leading to vascular complications or their potential therapeutic role in these diseases. Growth factor therapy in diabetic foot ulcers is already a clinical reality. As methods to finely regulate growth factors in a tissue and time-specific manner are further developed and tested, regulation of the growth factor to normal level in vivo may well become a therapy to prevent and treat diabetic complications. PMID- 29505923 TI - MiR-204-5p regulates C2C12 myoblast differentiation by targeting MEF2C and ERRgamma. AB - Myogenic differentiation, which occurs in the process of muscle development, is a highly ordered process. Increasing evidence indicates that microRNAs (miRNAs) are important regulators in myogenic processes. In this study, we found that miR-204 5p expression gradually decreased when myoblasts were induced to differentiate. Our results suggested that miR-204-5p blunted myoblast differentiation, which was accompanied with a decreased proportion of myosin heavy chain (MyHC)-positive cells in myoblasts with augmented expression of miR-204-5p. Furthermore, overexpression of miR-204-5p significantly decreased the MyHC composition of slow twitch fibers in myoblasts. Luciferase activity assays confirmed that miR-204-5p directly targeted the 3'-untranslated region (3'-UTR) of myocyte enhancer factor 2C (MEF2C) and estrogen-related receptor gamma (ERRgamma). Small interfering RNA (siRNA) technology successfully inhibited the expression of MEF2C and ERRgamma. Interference with MEF2C or ERRgamma inhibited myoblast differentiation and the formation of slow-twitch fibers. Meanwhile, co-transfection of either si-MEF2C or si-ERRgamma with miR-204-5p mimics resulted in a more severe attenuation of myogenic differentiation. In summary, this study demonstrates that miR-204-5p inhibits myoblast differentiation by targeting MEF2C and ERRgamma. Our findings suggest that miR-204-5p is a potential regulator that could influence myogenesis. PMID- 29505924 TI - LncRNA-MALAT1 contributes to the cisplatin-resistance of lung cancer by upregulating MRP1 and MDR1 via STAT3 activation. AB - Multiple drug resistance is the main reason for chemotherapeutic failure in lung cancer patients with complex molecular mechanisms. LncRNA-MALAT1 plays functional roles in the progression of carcinomas and development of drug resistance. We aimed to identify the role of MALAT1 in DDP-resistant non-small cell lung cancer as well as potential mechanisms. Human lung cancer cell line A549 and the DDP resistant cell line A549/DDP were used. Cell transfection was performed to establish A549/MALAT1 and A549/DDP/shMALAT1 cells. The qRT-PCR analysis was performed to detect lncRNA-MALAT1 level. Cell viability, colony formation assay, apoptosis analysis, western blot analysis, immunohistochemistry, and animal study were carried out. MALAT1 was upregulated in DDP-resistant A549 cell line. MALAT1 decreased DDP sensitivity in vitro and in vivo by upregulating MRP1 and MDR1 via STAT3 activation. Overexpression of MALAT1 contributed to the DDP resistance and might confer a potently poor prognosis. PMID- 29505925 TI - Dihydromyricetin ameliorates foam cell formation via LXRalpha-ABCA1/ABCG1 dependent cholesterol efflux in macrophages. AB - As the most abundant flavonoid in Ampelopsis grossedentata, the protective effects of dihydromyricetin on atherosclerosis have been well established, yet the detailed mechanisms are not fully understood. The aim of the present study was to examine the effect of dihydromyricetin on lipid accumulation and the underlying molecular mechanisms in macrophages and ApoE-/- mice. Incubation with dihydromyricetin significantly attenuated oxidized low-density lipoprotein (ox LDL)-mediated cholesterol and lipid accumulation in THP-1-derived macrophages, which was due to increased cholesterol efflux. In addition, dihydromyricetin increased mRNA and protein expressions of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 but had no effect on the mRNA and protein expressions of SR-A, CD36, or SR-BI involved in cholesterol homeostasis. Furthermore, the upregulation of ABCA1 and ABCG1 by dihydromyricetin depended on liver X receptor alpha (LXRalpha), as evidenced by an increase in the nuclear level of LXRalpha and its prevention of the expression of ABCA1 and ABCG1 after inhibition of LXRalpha activity by knockdown of LXRalpha expression with small interfering RNA (siRNA). Accordingly, dihydromyricetin-mediated suppression of cholesterol and lipid accumulation in macrophages was also abrogated by LXRalpha siRNA. Moreover, the lesion size of atherosclerosis was smaller in dihydromyricetin-treated ApoE-/- mice compared with the vehicle-treated mice, and the protein expression of CD36, SR-A, ABCA1, ABCG1 and LXRalpha in aortas was modulated similar to that observed in THP-1-derived macrophages. These data suggest that promotion of LXRalpha ABCA1/ABCG1-dependent cholesterol efflux is crucial event in suppression of lipid accumulation by dihydromyricetin in the transformation of macrophage foam cells. PMID- 29505926 TI - Analysis and toxicity of 59 PAH in petrogenic and pyrogenic environmental samples including dibenzopyrenes, 7H-benzo[c]fluorene, 5-methylchrysene and 1 methylpyrene. AB - In this study 59 PAH were analyzed in samples of petrogenic and pyrogenic sources as well as mixed environmental matrices. Among the analytes, PAH of molecular weights from 128 Da to 302 Da in alkylated and in native form were included. Results show that non-EPA PAH make up 69.3-95.1% of the overall toxic equivalents (TEQ) as based on the toxic equivalent factors (TEF) of 24 PAH. Particularly 7H benzo[c]fluorene, dibenzopyrene isomers and alkylated PAH (in particular 5 methylchrysene and 1-methylpyrene) turned out to have a huge impact on the toxicity and must not be neglected in future risk assessment. In detail, dibenzopyrenes have a high impact on toxicity predominantly in pyrogenic materials (21% to 84%; mean: 59%) whereas 7H-benzo[c]fluorene dominates toxicity of petrogenic materials (up to 80%; mean: 26%). However, in the studied mixed environmental samples the toxic impact of both groups together is as high as about 80%. Many non-EPA PAH are not considered in risk assessment and amongst them there are some very toxic ones. This needs to be carefully evaluated in future studies. PMID- 29505927 TI - Electrically enhanced adsorption and green regeneration for fluoride removal using Ti(OH)4-loaded activated carbon electrodes. AB - An electrically enhanced fluoride removal method was developed that blended the merits of electrosorption and adsorbent adsorption. This method has the advantages of high adsorption selectivity and capacity for fluoride. The saturated adsorption capacity of Ti(OH)4 for fluoride in the electrode of Ti(OH)4 loaded activated carbon reached 115.2 mg/g when a voltage of +1.2 V was applied to the electrode. The electrode was easily and cleanly regenerated in a short time in aqueous solution with high fluoride concentrations when a voltage of -1.6 V was applied. The adsorption capacity of the Ti(OH)4-loaded electrode for fluoride did not decrease after multiple cycles of electrically enhanced adsorption and regeneration. Excellent adsorption selectivity for fluoride was achieved. The electrically enhanced adsorption method showed potential for fluoride removal. PMID- 29505928 TI - Evaluation of biological properties and fate in the environment of a new class of biosurfactants. AB - Selected sophorolipid quaternary ammonium salts (SQAS), being a new class of modified biosurfactants, were studied in this work for the first time with regard to their biodegradability and fate in the environment. It was made to find whether environment-friendly bioproducts like biosurfactants are still safe to the environment after their chemical modification. The susceptibility of these SQAS for biodegradation was estimated together with the evaluation of their influence on activated sludge microorganisms. Additionally, the mechanisms of removal of the SQAS from wastewater and from the aquatic environment, were analysed. The evaluated SQAS were potentially biodegradable, although none of them could be classified as readily biodegradable. The biodegradation degrees after 28 days ranged from 4 to 42%, dependent on the SQAS tested, i.e. below the required OECD 301D Closed Bottle Test level of 60%. Simultaneously, the analysis of the mass spectra revealed the presence of the breakdown products of each SQAS studied. Biodegradation was preceded by sorption of the SQAS on sludge particles, which occurred to be a main mechanism of the removal of these newly synthesized biosurfactants from wastewater. The mean degree of sorption calculated on the basis of SQAS determination was from 75 to 96%, dependent on the studied SQAS. The presence of SQAS in wastewater did not deteriorate the operation of the activated sludge system, although the products of the SQAS biodegradation remained in the liquid phase and might contribute to the increase of COD of the effluent to be introduced to the environment. PMID- 29505929 TI - Urinary metabolites of phosphate flame retardants in workers occupied with e waste recycling and incineration. AB - Urinary metabolites of phosphate flame retardants (PFRs) were determined in workers from an electronic waste (e-waste) recycling site and an incineration plant, in order to assess the PFR exposure risks of workers occupied with e-waste recycling and incineration. Bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro 2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP) were the most frequently detected chemicals (82-93%). The median concentrations of BCEP, BDCIPP, and DPHP were 1.77, 0.23, and 0.70 ng/mL, and 1.44, 0.22, and 0.11 ng/mL in samples from the e-waste site and the incineration plant, respectively. Dibutyl phosphate (DBP) was detected in all samples from the incineration plant, with a median level of 0.30 ng/mL. The concentrations of BDCIPP (r = -0.31, p < 0.05) were significantly correlated with the occupational exposure time rather than age in workers from the e-waste site. Negative and significant correlations were also observed between the concentrations of BCEP (r = -0.42, p < 0.05), BDCIPP (r = -0.37, p < 0.05), and DPHP (r = -0.37, p < 0.05) and occupational exposure time rather than age in workers from the incineration plant. No gender differences were observed in levels of PFR metabolites in urine samples (p > 0.05). Concentrations of BDCIPP in female were significantly correlated with occupational exposure time (r = -0.507, p < 0.01). Concentrations of PFR metabolites in male were not significantly correlated with age or occupational exposure time (p > 0.05). Overall, the workers with occupational exposure to PFRs had different profiles of urinary PFR metabolites. The age, occupational exposure time, and gender seemed not to be main factors mediating the exposure to PFRs for workers occupied with e-waste recycling and incineration. PMID- 29505930 TI - Hydrogeochemical and isotopic evaluation of groundwater with elevated arsenic in alkaline aquifers in Eastern Punjab, Pakistan. AB - Geochemical investigation was carried out for delineating factors responsible for the mobilization of arsenic (As) from aquifer material into the groundwater. Four sites along Ravi River, (Samada, Sarai Chimba, Kot Maiga and Chah Fatehwala), were selected based on the blanket survey. Groundwater-rock interaction and evaporation were the key phenomena controlling groundwater chemistry, as shown by the hydrogeochemical data. Groundwater was predominantly Na-Cl type, with other principle facies being Na-HCO3, Na-Ca-HCO3 and Ca-Mg-Cl. The groundwater As concentration ranged between below detection level (2 MUg/L) to 548 MUg/L with 59% samples exceeding the World Health Organization (WHO) guidelines for As in drinking water (10 MUg/L) and 31% having higher concentrations than the National Environmental Quality Standard (NEQS, 50 MUg/L). Moderate to high concentrations of SO4-2 averaged at 244 mg/L and moderate NO3- concentrations averaged at 8 mg/L, together with alkaline pH (7.3-8.8) and high Eh values (113-402 mV) suggest partial oxidizing nature of the aquifers. The values for delta 18O and delta 2H in groundwater varied between -9.14 and -5.510/00, and -56.57 to -39.50/00 respectively, and suggests meteoric origin of the groundwater with some evaporative loss. This effect could be partly responsible for elevated levels of pH and salinity in groundwater. Based on geochemical and isotopic composition of groundwater, desorption of As from metal surfaces under alkaline environment might be the factor causing As enrichment in study area. PMID- 29505931 TI - Metal contamination in a riparian wetland: Distribution, fractionation and plant uptake. AB - Heavy metal pollution in aquatic system is of concern due its ecologic risk. In this study, we investigated the distribution, fractionation and plant uptake of heavy metals (As, Cd, Cr, Co, Cu, Ni, Pb and Zn) in a riparian wetland impacted by mining activities in Yunnan, southwest China. The results showed that excluding Cr, metal contents in sediment were higher than the background values, especially for As, which was 100-fold higher. While Cd showed high levels in the acid-soluble fraction with high availability, As, Cr, Cu, Ni and Pb mainly existed in the residual fraction with low availability. Two native aquatic plants including Phragmites australis (common reed) and Typha orientalis (bullrush) showed different uptake ability. T. orientalis accumulated more As, while P. australis accumulated more other metals. Based on geoaccumulation index (Igeo), As, Cd and Zn were more contaminated (Igeo> 3), followed by Cu, Pb and Co (Igeo<3), with Cr and Ni being slightly polluted (Igeo<1). According to risk assessment code, Cd showed high availability, followed by Zn and Co, with As exhibiting the lowest. The data suggested that both total and bioavailable metals should be considered for risk assessment of metal pollution in a wetland. PMID- 29505932 TI - P44/42 MAPK signal pathway-mediated hyperphosphorylation of paxillin and redistribution of E-cadherin was involved in microcystin-LR-reduced cellular adhesion in a human liver cell line. AB - Microcystin-LR (MC-LR) is the most common and toxic variant of microcystins. We hypothesize that p44/42 MAPK (ERK1/2) signal pathway is involved in MC-LR-induced cell adhesion alteration in a human liver cell line-HL7702. We identified that MC LR constantly activated MEK1/2-ERK1/2 signal pathway for 24 h, 48 h and 72 h in vitro. MC-LR reduced hepatocytes adhesion efficiency. Furthermore, as the focal adhesion biomarker, hyperphosphorylation of paxillin (ser83) was induced by MC LR, which can be blocked by ERK1/2 pathway inhibitor (U0126) and was enhanced after hepatocytes transfected with pCMV6-MAPK plasmid. E-cadherin, as a biomarker which reflects the dynamic of cell-cell adhesion, its redistribution in hepatocytes was induced by MC-LR, and these redistribution and colocalization can be attenuated by U0126. Furthermore, MC-LR increased the co-localization efficiency of p-ERK1/2 with E-cadherin and paxillin. Finally, MC-LR-induced adhesive alteration of hepatocytes can be blocked by ERK1/2 signal pathway inhibitor. These data suggest ERK1/2-phospho-paxillin (ser83)/E-cadherin axis is involved in MC-LR toxic mechanism, which probably provides adaptive protection against MC-LR-induced hepatocytes adhesion changes. PMID- 29505933 TI - Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2 ([18F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N diethylacetamide in a preclinical model of neuroinflammation. AB - Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [18F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2 [18F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N diethylacetamide ([18F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [18F]DPA-714. We evaluated the performance of [18F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BPND), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [18F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging. PMID- 29505934 TI - Design and synthesis of furyl/thineyl pyrroloquinolones based on natural alkaloid perlolyrine, lead to the discovery of potent and selective PDE5 inhibitors. AB - Based on perlolyrine (1), a natural alkaloid with weak PDE5 potency from the traditional Chinese aphrodisiac plant Tribulus terrestris L., a series alpha substituted tetrahydro-beta-carboline (THbetaC) derivatives were synthesized via T+BF4--mediated oxidative C-H functionalization of N-aryl THbetaCs with diverse potassium trifluoroborates. Following Winterfeldt oxidation afforded the corresponding furyl/thienyl pyrroloquinolones, of which 5 ethylthiophene/ethylfuran derivatives 20a-b were identified as the most potent and selective PDE5 inhibitors. Among the enantiomers, (S)-20a and (S)-20b (IC50 = 0.52 and 0.39 nM) were found to be more effective than their (R)-antipode, display favorable pharmacokinetic profiles, exert in vitro vasorelaxant effects on the isolated thoracic aorta, and exhibit in vivo efficacy in the anesthetized rabbit erectile model. PMID- 29505935 TI - Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. AB - The indole scaffold is one of the most widespread heterocycles in the naturally occurring and synthetic bioactive compounds including anticancer agents. Due to its biodiversity and versatility, it has been a highly privileged motif for the target-based design and development of anticancer agents. In the last decade, many researchers have reported various indole-based compounds with distinct mechanisms involved in producing potential anticancer activities, indicating the importance of indole motif in the anticancer drug development. The present article aims to review the current application of indole core in the design of new anticancer agents that may act via various targets such as histone deacetylases (HDACs), sirtuins, PIM kinases, DNA topoisomerases and sigma receptors. Targeting these enzymes or receptors in cancer cells by indole-derived compounds can be a powerful tool for the management of cancer. PMID- 29505937 TI - Children's education and parental old age survival - Quasi-experimental evidence on the intergenerational effects of human capital investment. AB - While a large literature has investigated the role of parental human capital on children's well-being, relatively little is known regarding the effects of human capital investment in children on long run outcomes of parents. In this study we explore the human capital variations created by the 1974 Tanzania education reform to estimate the effect of children's primary schooling attainment on parental survival. Using 5,026,315 census records from 1988, 2002, and 2012, we show that the 1974 reform resulted in an additional 1.1 years (31%) of educational attainment among exposed cohorts. Using the reform as instrument for child education we find that each additional year of primary schooling in children resulted in a 3.7 percentage point reduction (p < .001) in the probability of maternal death, and a 0.8 percentage point reduction (p = .011) in the probability of paternal death by the time exposed child cohorts reach age 50. The results suggest that-at least in a setting where social security coverage is largely absent-a substantial fraction of human capital gains generated by reforms are shared with the parental generation. PMID- 29505936 TI - Insights into protein structure, stability and function from saturation mutagenesis. AB - Where convenient phenotypic readouts are available, saturation mutagenesis coupled to deep sequencing provides a rapid and facile method to infer sequence determinants of protein structure, stability and function. We provide brief descriptions and currently available options for the various steps involved, and mention limitations of current implementations. We also highlight recent applications such as estimating relative stabilities and affinities of protein variants, mapping epitopes, protein model discrimination and prediction of mutant phenotypes. Most mutational scans have so far been applied to single genes and proteins. Additional methodological improvements are required to expand the scope to study intergenic epistasis and intermolecular interactions in macromolecular complexes. PMID- 29505939 TI - Influence of alkali metal cations/type of activator on the structure of alkali activated fly ash - ATR-FTIR studies. AB - Coal fly ash as a secondary aluminosiliceous raw material that is commonly used in the so-called geopolymerization process has been activated with different alkali hydroxides solutions: LiOH, NaOH and KOH. Changes in the aluminosilicate structure of the material during alkali-activation have been analyzed in detail on the basis of ATR/FT-IR spectra. These changes mainly affect both the integral intensity and FWHM of bands in the range of 1200-950cm-1, however dehydration and carbonation process can be also analyzed based on obtaining results. PMID- 29505938 TI - Genome-wide association study of depressive symptoms in the Hispanic Community Health Study/Study of Latinos. AB - Although genome-wide association studies (GWAS) have identified several variants linked to depression, few GWAS of non-European populations have been performed. We conducted a genome-wide analysis of depression in a large, population-based sample of Hispanics/Latinos. Data came from 12,310 adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Past-week depressive symptoms were assessed using the 10-item Center for Epidemiological Studies of Depression Scale. Three phenotypes were examined: a total depression score, a total score modified to account for psychiatric medication use, and a score excluding anti depressant medication users. We estimated heritability due to common variants (h2SNP), and performed a GWAS of the three phenotypes. Replication was attempted in three independent Hispanic/Latino cohorts. We also performed sex-stratified analyses, analyzed a binary trait indicating probable depression, and conducted three trans-ethnic analyses. The three phenotypes exhibited significant heritability (h2SNP = 6.3-6.9%; p = .002) in the total sample. No SNPs were genome-wide significant in analyses of the three phenotypes or the binary indicator of probable depression. In sex-stratified analyses, seven genome-wide significant SNPs (one in females; six in males) were identified, though none were supported through replication. Four out of 24 loci identified in prior GWAS were nominally associated in HCHS/SOL. There was no evidence of overlap in genetic risk factors across ancestry groups, though this may have been due to low power. We conducted the largest GWAS of depression-related phenotypes in Hispanic/Latino adults. Results underscore the genetic complexity of depressive symptoms as a phenotype in this population and suggest the need for much larger samples. PMID- 29505940 TI - Synthesis and characterization of new unsymmetrical Schiff base Zn (II) and Co (II) complexes and study of their interactions with bovin serum albumin and DNA by spectroscopic techniques. AB - Two novel tetra-coordinated Cobalt(II) and Zinc (II) chelate series with the general formula of [Co (L).2H2O] (1) and [Zn (L)] (2) [L=N-2-hydroxyacetophenon N'-2-hydroxynaphthaldehyde-1,2 phenylenediimine)] with biologically active Schiff base ligands were synthesized and recognized by elemental analysis and multi nuclear spectroscopy (IR and 1H and 13C NMR); then, their biological activities including DNA and protein interactions were studied. The interaction of the synthesized compounds with bovine serum albumin (BSA) was investigated via fluorescence spectroscopy, showing the affinity of the complexes for these proteins with relatively high binding constant values and the changed secondary BSA structure in the presence of the complexes. The interaction of these compounds with CT-DNA was considered by UV-Vis technique, emission titration, viscosity measurements, helix melting methods, and circular dichroism (CD) spectroscopy, confirming that the complexes were bound to CT-DNA by the intercalation binding mode. Furthermore, the complexes had the capability to displace the DNA-bound MB, as shown by the competitive studies of these complexes with methylene blue (MB), thereby suggesting the intercalation mode for the competition. Finally, the theoretical studies carried out by the docking method were performed to calculate the binding constants and recognize the binding site of the BSA and DNA by the complexes. In addition, in vitro and in silico studies showed that the compounds were degradable by bacterial and fungal biodegradation activities. PMID- 29505941 TI - Distributed fluorescent optical fiber proximity sensor: Towards a proof of concept. AB - Fluorescent fibers are optical fibers which emit light as a response to an incident phenomenon, usually an incident light. Operation depends on the doping dyes, which determine specific fluorescence and optical characteristics useful in the development of optical sensors. In this work we propose a low-cost distributed proximity sensor implemented using a red fluorescent fiber, to provide a security option for a surface plasmon resonance system. Operation of the proposed sensor relies on having the incident illumination intensity varied by the presence or absence of an obstacle in the vicinity of the sensing element. This will influence the radiated fluorescence accordingly. The proposed setup for the implementation of the optical proximity sensor assumes having a high brightness LED deployed for axial fiber illumination and a blue LED for side illumination. Electronic processing then accounts for gain and digitization. Measurement results of the prototype validate the proposed concept. PMID- 29505942 TI - Hippocampal dependent neuropsychological tests and their relationship to measures of cardiac and self-report interoception. AB - The hippocampus is involved in interoceptive processing (i.e., perceiving internal bodily states), with much of this evidence relating to hunger and fullness. Here we examine whether cardiac and self-report measures of interoception are related to two measures of hippocampal dependent learning and memory (HDLM) - the Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory. Healthy adults completed a neuropsychological test battery including all of these measures, along with assessments of intelligence and executive function. Biographical, medical and psychological-related data that might confound detecting an HDLM-interoception relationship was also collected. Both measures of HDLM were associated with cardiac interoception after controlling for confounding variables. More accurate cardiac interoception was linked to better HDLM performance. On the self-report measure of interoception, better performance on the RAVLT was associated with better-reported attention regulation, consistent with the hippocampus's known role in mindfulness. Overall, these findings suggest hippocampal involvement in cardiac and self-report interoceptive capacity. The broader functional role of the hippocampus in interoception is discussed. PMID- 29505943 TI - fMRI during Transcendental Meditation practice. AB - This study used a within group design to investigate blood flow patterns (fMRI) in 16 long-term practitioners of Transcendental Meditation (mean practice: 34.3 years with each having over 36,000 h of meditation practice). During Transcendental Meditation practice, blood flow patterns were significantly higher in executive and attention areas (anterior cingulate and dorsolateral prefrontal cortices) and significantly lower in arousal areas (pons and cerebellum). This pattern supports the understanding that Transcendental Meditation practice requires minimal effort. During Transcendental Meditation, the attentional system was active (heightened blood flow in anterior cingulate and dorsolateral prefrontal cortices) in an automatic manner-decreased blood flow in the pons and cerebellum. This pattern of heightened blood flow in attentional areas and decreased blood flow in arousal areas has not been reported during other meditation practices. Future research should investigate blood flow patterns in different meditation practices in the same study. PMID- 29505944 TI - The mental simulation of state/psychological verbs in the adolescent brain: An fMRI study. AB - This fMRI study investigated mental simulation of state/psychological and action verbs during adolescence. Sixteen healthy subjects silently read verbs describing a motor scene or not (STIMULUS: motor, state/psychological verbs) and they were explicitly asked to imagine the situation or they performed letter detection preventing them from using simulation (TASK: imagery vs. letter detection). A significant task by stimuli interaction showed that imagery of state/psychological verbs, as compared to action stimuli (controlled by the letter detection) selectively increased activation in the right supramarginal gyrus/rolandic operculum and in the right insula, and decreased activation in the right intraparietal sulcus. We compared these data to those from a group of older participants (Tomasino et al. 2014a). Activation in the left supramarginal gyrus decreased for the latter group (as compared to the present group) for imagery of state/psychological verbs. By contrast, activation in the right superior frontal gyrus decreased for the former group (as compared to the older group) for imagery of state/psychological verbs. PMID- 29505945 TI - Implementation of a childbirth preparation program in the maternal and child health centres in Jordan. AB - OBJECTIVE: To investigate the feasibility and outcomes of introducing childbirth preparation programs in a sample of Maternal and Child Health centres in Jordan. DESIGN: An exploratory, descriptive design, and practice- research engagement was used to implement and evaluate the proposed childbirth preparation program. Face to face interviews and field notes were used to collect data. Outcomes of pregnancy and birth were collected from interviews with women using a structured format. SETTING AND PARTICIPANTS: Three Maternal and Child Health centres were randomly selected from the three main regions of Jordan. A convenience sample of 107 primigravid women was recruited for the implementation process. Six health staff (3 doctors and 3 midwives) also participated. FINDINGS: The practice- research engagement approach assisted the researchers and care providers in dealing with problems that arose during the implementation of the program. Out of the 107 women initially recruited, only 36 women completed the implementation program, with attrition rate of 65%. The main reasons for poor attendance included: difficulty in keeping contact with participants, transportation difficulties, duration of the program, health problems, antenatal follow up at a private clinic, and not having permission from husbands to attend. The effectiveness of the program was noticed through some improved pregnancy outcomes for the participants and the high satisfaction of the health professionals and women who participated. The program was effective in increasing knowledge and understanding of women regarding the different aspects of pregnancy, birth, and postnatal periods. It helped promote a trusting relationship between health professionals and women; and increased staff self confidence in providing specific and essential information to women. Women seemed to have an increased sense of control over the childbirth process, and it reinforced benefits and duration of breastfeeding and knowledge of family planning. Challenges identified by health professionals and women included: women's commitment and capacity to attend the scheduled sessions and shortage of qualified staff. KEY CONCLUSIONS: Implementing a childbirth preparation program in a developing country appears possible, successful, and effective if logistical and cultural requirements can be better addressed. This was evidenced with a high rate of participants' satisfaction (women and health care providers), and suggestions of improved pregnancy outcomes. IMPLICATIONS FOR PRACTICE: It is necessary to address some logistical issues of delivery and recognise the importance and limitations of current human resources. Policy makers in the Ministry of Health should consider implementation of a childbirth preparation program, as there are no existing programs. Clinical leaders, supported by researchers, should jointly consider reframing the program into a shorter more logistically acceptable delivery mode. This could be tested and evaluated. PMID- 29505946 TI - Introducing sensitive issues and self-care strategies to first year midwifery students. AB - OBJECTIVE: first year midwifery students learn early in semester about situations in midwifery where a high level of emotion is expressed, such as taking a sexual history, being faced with the body image changes of pregnancy and working with women in the extreme pain of labour. Commencing students usually have not had exposure to the realities of studying and working in midwifery, and often have an idealised view of midwifery that may lead to attrition from the course. We aimed to equip students with personal and professional tools to discuss sensitive issues in midwifery and promote self-care through the development of two workshops. The first workshop focussed on sensitive issues in midwifery and the second on self-care strategies. DESIGN: quantitative and qualitative data were collected pre and post workshops using a survey. SETTING: the workshops were developed at one university in New South Wales, Australia. PARTICIPANTS: Beginning first year midwifery students MEASUREMENTS: feeling more comfortable, confident and knowledgeable was measured using a paired t-test from the responses on a pre and post workshop survey. Content analysis was performed on the qualitative survey responses. FINDINGS: there were significant increases in the students feeling more comfortable to discuss sensitive issues in midwifery following the first workshop. They found meeting new people, respecting opinions, normalizing confronting topics to be valuable and useful. The second workshop found significant differences in being more confident and knowledgeable to access and try new self-care strategies in both their personal and professional life. Students discussed learning to be more mindful in order to prepare for stressful situations. They became aware of their feeling and thoughts when under stress and said they would practice techniques including meditation. CONCLUSION: the workshops assisted the students to develop peer support, self-care strategies and coping mechanisms when faced with the intimate and sometimes confronting nature of midwifery practice. Through embedding these first year workshops early in the degree we hope to address attrition rates and facilitate the students' to become the compassionate, caring, woman-centred midwives that they envisioned. IMPLICATIONS FOR PRACTICE: the workshops have the potential for replication in other universities to support and nurture beginning midwifery students. PMID- 29505947 TI - Online approximation of the multichannel Wiener filter with preservation of interaural level difference for binaural hearing-aids. AB - This work presents an online approximation method for the multichannel Wiener filter (MWF) noise reduction technique with preservation of the noise interaural level difference (ILD) for binaural hearing-aids. The steepest descent method is applied to a previously proposed MWF-ILD cost function to both approximate the optimal linear estimator of the desired speech and keep the subjective perception of the original acoustic scenario. The computational cost of the resulting algorithm is estimated in terms of multiply and accumulate operations, whose number can be controlled by setting the number of iterations at each time frame. Simulation results for the particular case of one speech and one-directional noise source show that the proposed method increases the signal-to-noise ratio SNR of the originally acquired speech by up to 16.9 dB in the assessed scenarios. As compared to the online implementation of the conventional MWF technique, the proposed technique provides a reduction of up to 7 dB in the noise ILD error at the price of a reduction of up 3 dB in the output SNR. Subjective experiments with volunteers complement these objective measures with psychoacoustic results, which corroborate the expected spatial preservation of the original acoustic scenario. The proposed method allows practical online implementation of the MWF ILD noise reduction technique under constrained computational resources. Predicted SNR improvements from 12 dB to 16.9 dB can be obtained in application specific integrated circuits for hearing-aids and state-of-the-art digital signal processors. PMID- 29505948 TI - The biological and behavioral computations that influence dopamine responses. AB - Phasic dopamine responses demonstrate remarkable simplicity; they code for the differences between received and predicted reward values. Yet this simplicity belies the subtle complexity of the psychological, computational, and contextual factors that influence this signal. Advances in behavioral paradigms and models, in monkeys and rodents, have demonstrated that phasic dopamine responses reflect numerous behavioral computations and factors including choice, subjective value, confidence, and context. The application of optogenetics has provided evidence that dopamine reward prediction error responses cause value learning. Furthermore, studies using advanced circuit tracing techniques have begun to uncover the biological network implementation of the reward learning algorithm. The purpose of this review is to summarize the recent advances in dopamine neurophysiology and synthesize an updated account of the behavioral function of dopamine signals. PMID- 29505949 TI - Plant growth regulator interactions in physiological processes for controlling plant regeneration and in vitro development of Tulbaghia simmleri. AB - The endogenous auxin and cytokinin contents of in vitro regenerated Tulbaghia simmleri maintained on applied plant growth regulators in Murashige and Skoog (MS) medium were investigated using UHPLC-MS analysis. The highest number of shoots (27.6 per leaf) were produced in MS medium supplemented with 2.5 MUM thidiazuron. A higher number of these shoots were rooted with 10 MUM 6-(2-hydroxy 3-methylbenzylamino) purine (PI-55, cytokinin antagonist). Production of somatic embryos (SEs: 16.4-4.6, globular to cotyledonary stages) improved significantly with liquid MS medium containing 2.5 MUM picloram, 2.5 MUM phloroglucinol (PG) and 1.5 MUM gibberellic acid or 1.5 MUM PI-55 and 1.0 MUM trans-zeatin. SEs (torpedo and cotyledonary stages) germinated (100%) in plant growth regulator free MS medium. The plantlets were acclimatized and all survived in the greenhouse. Higher levels of endogenous auxin, 2-oxindole-3-acetic acid (oxIAA, 371.52 pmol/g DW) and indole-3-acetylaspartate (IAAsp, 141.56 pmol/g DW) were detected in shoots from PG treatments. The roots of garden-grown mother plants possessed the highest level of indole-3-acetic acid (IAA, 630.54 pmol/g DW) and oxIAA (515.26 pmol/g DW). Cytokinins [CKs: trans-zeatin-O-glucoside (tZOG), cis zeatin (cZ) and N6-isopentenyladenosine-5'-monophosphate (iPRMP)] levels were relatively high in shoots and roots of plantlets in vitro. However, PI-55 treatments influenced the development of plantlets promoting a higher biosynthesis level of iPRMP (418.06 pmol/g DW in root) and cZRMP (904.61 pmol/g DW in roots and 1427.83 pmol/g DW in shoots). The presented protocols offer organogenesis and somatic organogenesis systems for rapid plant regeneration of T. simmleri. In addition, the importance of exogenous and endogenous hormonal effects on in vitro plant growth and development as well as endogenous hormone metabolism signalling and transport related to the physiological processes of CK metabolism and transport are illustrated for in vitro development of T. simmleri. PMID- 29505950 TI - Legal decision-making in child sexual abuse investigations: A mixed-methods study of factors that influence prosecution. AB - Prosecution of child sexual abuse cases is an important aspect of a community's response for holding perpetrators accountable and protecting children. Differences in charging rates across jurisdictions may reflect considerations made in prosecutors' decision-making process. This mixed-methods, multiphase study used data from a Children's Advocacy Center in a suburban county in the Southern United States to explore the factors associated with child sexual abuse cases that are accepted for prosecution and the process followed by prosecutors. Data were sequentially linked in three phases (qualitative-quantitative qualitative), incorporating 1) prosecutor perceptions about what case characteristics affect charging potential, 2) 100 case records and forensic interviews, and 3) in-depth reviews of cases prosecuted. Content analysis was used to identify influential case elements, logistic regression modeling was used to determine factors associated with a decision to prosecute, and framework analysis was used to further confirm and expand upon case factors. Overall, findings indicate that prosecution is most strongly predicted by caregiver support and the availability of other evidence. The decision to prosecute was found to include a process of ongoing evaluation of the evidence and determination of a balanced approach to justice. The decision to prosecute a case can be influenced by strong and supportive investigative practices. An important implication is that interaction among multidisciplinary professionals promotes communication and efforts, further enhancing discretion about potential legal actions. PMID- 29505951 TI - Linking testosterone and antisocial behavior in at-risk transitional aged youth: Contextual effects of parentification. AB - Parentification refers to parents bestowing adult-like roles on children within families, and studies have linked parentification to individual differences in risk and resilience. The depth of our understanding of the pathways that translate parentification into risk for negative developmental outcomes remains shallow. This study examined whether parentification has a contextual effect moderating the expression of links between testosterone and antisocial behavior. Eighty-three participants (M age = 21.37 years, SD = 1.87; 48% Black; 60% female) were interviewed initially and one year later. Audio Computer Assisted Self Interview methods were used to measure parentification and antisocial behavior. Saliva was sampled on multiple occasions and later assayed for testosterone. Results revealed, for both sexes, testosterone was positively associated with antisocial behavior at baseline and at follow-up when participants scored low on perceived benefits of parentification. This relationship became weaker as levels of perceived benefits of parentification increased. At the highest levels of perceived benefits of parentification, testosterone and antisocial behavior were inversely related. The findings suggest a potentially important role for perceptions of parentification as a moderator for the expression of hormone behavior relationships and are discussed in terms of implications for the biosocial model of the family. PMID- 29505952 TI - Reduced substantia innominata volume mediates contributions of microvascular and macrovascular disease to cognitive deficits in Alzheimer's disease. AB - The relationships between cholinergic system damage and cerebrovascular disease are not entirely understood. Here, we investigate associations between atrophy of the substantia innominata (SI; the origin of cortical cholinergic projections) and measures of large and small vessel disease; specifically, elongation of the juxtaposed internal carotid artery termination and Cholinergic Pathways Hyperintensity scores (CHIPS). The study (n = 105) consisted of patients with Alzheimer's disease (AD) and/or subcortical ischemic vasculopathy, and elderly controls. AD and subcortical ischemic vasculopathy groups showed greater impingement of the carotid termination on the SI and smaller SI volumes. Both carotid termination elongation and CHIPS were associated independently with smaller SI volumes in those with and without AD. Atrophy of the SI mediated effects of carotid termination elongation on language and memory functions and the effect of CHIPS on attention/working memory. In conclusion, SI atrophy was related to cerebrovascular disease of the large and small vessels and to cognitive deficits in people with and without AD. PMID- 29505954 TI - White matter hyperintensities and vascular risk factors in monozygotic twins. AB - Cerebral white matter hyperintensities (WMHs) have been associated with vascular risk factors, both of which are under genetic influence. We examined in a monozygotic twin sample whether the association between vascular risk and WMHs is influenced by overlapping genetic factors. We included 195 cognitively normal monozygotic twins (age = 70 +/- 7 years), including 94 complete pairs. Regional WMH load was estimated using an automated algorithm. Vascular risk was summarized with the Framingham score. The within-twin pair correlation for total WMHs was 0.76 and for Framingham score was 0.77. Within participants, Framingham score was associated with total and periventricular WMHs (r = 0.32). Framingham score in 1 twin was also associated with total WMHs in the co-twin (r = 0.26). Up to 83% of the relation between both traits could be explained by shared genetic effects. In conclusion, monozygotic twins have highly similar vascular risk and WMH burden, confirming a genetic background for these traits. The association between both traits is largely driven by overlapping genetic factors. PMID- 29505953 TI - Multimodal neuroimaging and behavioral assessment of alpha-synuclein polymorphism rs356219 in older adults. AB - The single-nucleotide polymorphism rs356219 in the alpha-synuclein (SNCA) gene has been shown to significantly contribute to an earlier age at onset of Parkinson's disease (PD), and regulates SNCA expression in PD brain regions, blood, and plasma. Here, we used multimodal magnetic resonance imaging (MRI) to study healthy adults with and without the rs356219 risk genotype. Motor and cognitive tests were administered, and all participants underwent functional and structural MRI. Imaging analyses included (1) task-based functional MRI; (2) task based functional connectivity; (3) free-water diffusion MRI of the substantia nigra; (4) voxel-based morphometry; and (5) surface-based morphometry. There were no differences between the 2 groups in motor and cognitive performance, or brain structure. However, carrying a PD risk variant was associated with reduced functional activity in the posterior putamen and primary motor cortex. Moreover, the posterior putamen had reduced functional connectivity with the motor cortex during motor control in those with a risk genotype compared to those without. These findings point to functional abnormalities in the striatocortical circuit of rs356219 risk genotype carriers. PMID- 29505955 TI - Genetic and phenotypic analysis of carbohydrate metabolism and transport in Lactobacillus reuteri. AB - Lactobacilli derive metabolic energy mainly from carbohydrate fermentation. Homofermentative and heterofermentative lactobacilli exhibit characteristic differences in carbohydrate transport and regulation of metabolism, however, enzymes for carbohydrate transport in heterofermentative lactobacilli are poorly characterized. This study aimed to identify carbohydrate active enzymes in the L. reuteri strains LTH2584, LTH5448, TMW1.656, TMW1.112, 100-23, mlc3, and lpuph by phenotypic analysis and comparative genomics. Sourdough and intestinal isolates of L. reuteri displayed no difference in the number and type of carbohydrate active enzymes encoded in the genome. Predicted sugar transporters encoded by genomes of L. reuteri strains were secondary carriers and most belong to the major facilitator superfamily. The quantification of gene expression during growth in sourdough and in chemically defined media corresponded to the predicted function of the transporters MalT, ScrT and LacS as carriers for maltose, sucrose, and lactose or raffinose, respectively. The genotype for sugar utilization matched the fermentation profile of 39 sugars for L. reuteri strains, and indicated preference for maltose, sucrose, raffinose and (iso)-malto oligosaccharides, which are available in sourdough and in the upper intestine of rodents. Pentose utilization in L. reuteri species was strain-specific but independent of the origin or phylogenetic position of isolates. Two glycosyl hydrolases, licheninase (EC 3.2.1.73) and endo-1, 4-beta-galactosidase (EC 3.2.1.89) were identified based on conserved domains. In conclusion, the study identified the lack of PTS systems, preference for secondary carriers for carbohydrate transport, and absence of carbon catabolite repression as characteristic features of the carbohydrate metabolism in the heterofermentative L. reuteri. PMID- 29505956 TI - Influence of ochratoxin A on adaptation of Penicillium nordicum on a NaCl-rich dry-cured ham-based medium. AB - Iberian dry-cured ham is an important meat product with high consumption worldwide. The special ecological conditions occurring throughout its ripening favour surface colonisation of filamentous fungi. Normally, moulds contribute to the development of the sensory qualities of the ham; however, some toxigenic species, such as Penicillium nordicum, are able to successfully adapt to the NaCl rich environment found in dry-cured ham and produce ochratoxin A (OTA) in this product. Moreover, it was suggested that the biosynthesis of OTA by P. nordicum itself may support the adaptation to this food environment. However, this mechanism has not been completely elucidated yet. The objective of this work was to evaluate the influence of different concentrations of commercial OTA (cOTA, at 0, 0.2, 1 and 5 ppb) on growth rate, biosynthetic- and stress-related gene expression and OTA production by two P. nordicum strains (Pn15 and Pn69) on dry cured ham based-media. Two NaCl conditions (0% and 10%) were evaluated for each cOTA level. In general, no intra-strain and inter-strain differences in growth rates were found among the conditions tested. The stress-related Hog1 gene expression of the strain Pn15 was affected by cOTA and NaCl concentration whilst the strain Pn69 was not affected by these variables. The expression of OTA related otapks and otanps genes of the strain Pn15 was affected by several NaCl and cOTA combinations. However, the strain Pn69 showed no differences in relative gene expression. Regarding to OTA production, different behaviours were displayed by the two strains. The strain Pn15, which produced high OTA amounts by itself, produced OTA without the necessity of the presence of NaCl or cOTA as stressors. However, the presence of cOTA triggers OTA production by the weak OTA producing Pn69 in the absence of NaCl. In addition, although a moderate correlation was found between the expression of the OTA-related genes and mycotoxin produced by P. nordicum in the absence of NaCl, none was obtained between Hog1 gene expression and mycotoxin production. This study is a step forward for a better understanding of the ability of P. nordicum producers of OTA to colonise NaCl rich habitats such as Iberian ham for proposing actions to minimise OTA contamination in this meat product. PMID- 29505957 TI - COX-2 Forms Regulatory Loop with YAP to Promote Proliferation and Tumorigenesis of Hepatocellular Carcinoma Cells. AB - COX-2 and YAP are shown to be highly associated with hepatocellular carcinoma (HCC) and frequently upregulated during tumor formation. However, despite their importance, whether there is a mutual interaction between COX-2 and YAP and how they regulate each other are not clear. In this paper, we showed that COX-2 overexpression in HCC cell lines resulted in increased levels of YAP mRNA, protein, and its target genes. COX-2 promoted proliferation of HCC cell lines, and knockdown of YAP antagonized this effect. In addition, our results indicated that EP2 and Wnt/beta-Catenin mediate the transcriptional induction of YAP by COX 2. On the other hand, YAP increased COX-2 expression at the level of transcription requiring intact TEAD binding sites in the COX-2 promoter. Collectively, these findings indicated that COX-2 is not only a stimulus of YAP but also a target of Hippo-YAP pathway, thus forming a positive feedback circuit, COX-2-PGE2-EP2-Galphas-beta-catenin-YAP-COX-2. In a further study, we showed that inhibition of YAP and COX-2 acted synergistically and more efficiently reduced the growth of HCC cells and tumor formation than either of them alone, suggesting that dual governing of YAP and COX-2 may lead to the discovery of promising therapeutic strategies for HCC patients via blocking this positive feedback loop. PMID- 29505959 TI - Wrong-site nerve blocks: A systematic literature review to guide principles for prevention. AB - STUDY OBJECTIVE: Wrong-site nerve blocks (WSBs) are a significant, though rare, source of perioperative morbidity. WSBs constitute the most common type of perioperative wrong-site procedure reported to the Pennsylvania Patient Safety Authority. This systematic literature review aggregates information about the incidence, patient consequences, and conditions that contribute to WSBs, as well as evidence-based methods to prevent them. DESIGN: A systematic search of English language publications was performed, using the PRISMA process. MAIN RESULTS: Seventy English-language publications were identified. Analysis of four publications reporting on at least 10,000 blocks provides a rate of 0.52 to 5.07 WSB per 10,000 blocks, unilateral blocks, or "at risk" procedures. The most commonly mentioned potential consequence was local anesthetic toxicity. The most commonly mentioned contributory factors were time pressure, personnel factors, and lack of site-mark visibility (including no site mark placed). Components of the block process that were addressed include preoperative nerve-block verification, nerve-block site marking, time-outs, and the healthcare facility's structure and culture of safety. DISCUSSION: A lack of uniform reporting criteria and divergence in the data and theories presented may reflect the variety of circumstances affecting when and how nerve blocks are performed, as well as the infrequency of a WSB. However, multiple authors suggest three procedural steps that may help to prevent WSBs: (1) verify the nerve-block procedure using multiple sources of information, including the patient; (2) identify the nerve block site with a visible mark; and (3) perform time-outs immediately prior to injection or instillation of the anesthetic. Hospitals, ambulatory surgical centers, and anesthesiology practices should consider creating site-verification processes with clinician input and support to develop sustainable WSB-prevention practices. PMID- 29505958 TI - Wnt Signalling Drives Context-Dependent Differentiation or Proliferation in Neuroblastoma. AB - Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of beta-catenin immunohistochemistry shows high levels of beta catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation. PMID- 29505960 TI - A rapid, LC-MS/MS assay for quantification of piperacillin and tazobactam in human plasma and pleural fluid; application to a clinical pharmacokinetic study. AB - Piperacillin, in combination with tazobactam is a common first-line antibiotic used for the treatment of pleural infection, however its pleural pharmacokinetics and penetration has not previously been reported. The objective of this work was to develop and validate a rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay for quantification of piperacillin (PIP) and tazobactam (TAZ). PIP and TAZ were extracted from both human plasma and pleural fluid samples by protein precipitation in methanol containing the internal standards (IS) piperacillin-d5 (PIP-d5) and sulbactam (SUL). Briefly, 5 MUL of sample was mixed with 125 MUL of methanol containing IS, vortexed and centrifuged. Supernatant (50 MUL) was diluted into 500 MUL of mobile phase containing 10 mM of ammonium bicarbonate in LCMS grade water and transferred to the autosampler tray. Electrospray ionization in positive mode and multiple reaction monitoring (MRM) were used for PIP and PIP-d5 at the transitions m/z 518.2 -> 143.2 and m/z 523.2 -> 148.2 respectively, and electrospray ionization in negative mode and MRM were used for TAZ and SUL at the transitions m/z 299.1 > 138.1 and m/z 232.4 -> 140.1. The chromatographic separation was achieved using an Acquity BEH C-18 column with gradient elution of mobile phase containing 10 mmol/L ammonium bicarbonate in water and methanol. A linear range was observed over the concentration range of 0.25-352 mg/L and 0.25-50.5 mg/L for PIP and TAZ respectively. Complete method validation was performed according to US FDA guidelines for selectivity, specificity, precision and accuracy, LLOQ, matrix effects, recovery and stability, with all results within acceptable limits. This method was successfully applied to two patients with pleural infection and is suitable for further pharmacokinetic studies and therapeutic drug monitoring. PMID- 29505961 TI - Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span. AB - 3',5'-Cyclic nucleotide phosphodiesterases (PDEs) degrade 3',5' cyclic adenonosine monophosphate (cAMP) and 3',5' cyclic guanosine monophosphate (cGMP), with PDE9A having the highest affinity for cGMP. We show PDE9A6 and 3 novel PDE9 isoforms (PDE9X-100, PDE9X-120, and PDE9X-175) are reliably detected in the brain and lung of mice, whereas PDE9A2 and other isoforms are found elsewhere. PDE9A localizes to the membrane in all organs except the bladder, where it is cytosolic. Brain additionally shows PDE9 in the nuclear fraction. PDE9A mRNA expression/localization dramatically changes across neurodevelopment in a manner that is strikingly consistent between mice and humans (i.e., decreased expression in the hippocampus and cortex and inverted-U in the cerebellum). Study of the 4 PDE9 isoforms in the mouse brain from postnatal day 7 through 24 months similarly identifies dramatic effects of age on expression and subcellular compartmentalization that are isoform specific and brain region specific. Finally, PDE9A mRNA is elevated in the aged human hippocampus with dementia when there is a history of traumatic brain injury. Thus, brain PDE9 is localized to preferentially regulate nuclear- and membrane-proximal pools of cGMP, and its function likely changes across the life span. PMID- 29505962 TI - Polymorphisms in the ICOS/CD28-ICOSL pathway are related to capecitabine-based chemotherapy response in advanced colon cancer patients. AB - Polymorphisms within a gene's 3'-UTR may modulate posttranscriptional regulation of gene expression, and may explain individual sensitivity of chemotherapy. To investigate the correlation between single nucleotide polymorphisms (SNPs) in 3' UTRs of B7/CD28 family genes and the response of capecitabine-based chemotherapy in colon cancer, 16 SNPs were identified in 274 advanced colon cancer patients. Statistical analysis indicated that ICOS rs1559931, rs4404254, and rs4675379 were in complete linkage disequilibrium and significantly associated with chemotherapy response. Heterozygous patients with rs1559931 G/A (31.34% vs 48.29%; P = 0.016), rs4404254 T/C (30.43% vs 48.77%; P = 0.011), or rs4675379 G/C (28.13% vs 49.04%; P = 0.004) genotypes showed poorer response to chemotherapy compared to wildtype patients. Moreover, three SNPs, including ICOSL rs15927, ICOSL rs3804033 and CD28 rs3181113, were significantly associated with the occurrence of side effects of chemotherapy. In addition, patients with ICOSL rs15927 G/G (78.26%), ICOSL rs3804033 G/G (76.00%), or CD28 rs3181113 T/T (82.05%) were more prone to enduring adverse events compared to patients bearing other polymorphisms. Taken together, our findings demonstrated that polymorphisms in the 3'-UTRs of genes in the ICOS/CD28-ICOSL pathway may influence the efficacy and occurrence of adverse events of capecitabine-based chemotherapy in advanced colon cancer patients. PMID- 29505964 TI - Transposable element activity, genome regulation and human health. AB - A convergence of novel genome analysis technologies is enabling population genomic studies of human transposable elements (TEs). Population surveys of human genome sequences have uncovered thousands of individual TE insertions that segregate as common genetic variants, i.e. TE polymorphisms. These recent TE insertions provide an important source of naturally occurring human genetic variation. Investigators are beginning to leverage population genomic data sets to execute genome-scale association studies for assessing the phenotypic impact of human TE polymorphisms. For example, the expression quantitative trait loci (eQTL) analytical paradigm has recently been used to uncover hundreds of associations between human TE insertion variants and gene expression levels. These include population-specific gene regulatory effects as well as coordinated changes to gene regulatory networks. In addition, analyses of linkage disequilibrium patterns with previously characterized genome-wide association study (GWAS) trait variants have uncovered TE insertion polymorphisms that are likely causal variants for a variety of common complex diseases. Gene regulatory mechanisms that underlie specific disease phenotypes have been proposed for a number of these trait associated TE polymorphisms. These new population genomic approaches hold great promise for understanding how ongoing TE activity contributes to functionally relevant genetic variation within and between human populations. PMID- 29505965 TI - Promoting physical activity, healthy eating and gross motor skills development among preschoolers attending childcare centers: Process evaluation of the Healthy Start-Depart Sante intervention using the RE-AIM framework. AB - BACKGROUND: The Healthy Start-Depart Sante intervention was developed to promote physical activity, gross motor skills and healthy eating among preschoolers attending childcare centers. This process evaluation aimed to report the reach, effectiveness, adoption, implementation and maintenance of the Healthy Start Depart Sante intervention. METHODS: The RE-AIM framework was used to guide this process evaluation. Data were collected across 140 childcare centers who received the Healthy Start-Depart Sante intervention in the provinces of Saskatchewan and New Brunswick, Canada. Quantitative data were collected through director questionnaires at 10 months and 2 years after the initial training and analyzed using descriptive statistics. Qualitative data were collected throughout the intervention. RESULTS: The intervention was successful in reaching a large number of childcare centres and engaging both rural and urban communities across Saskatchewan and New Brunswick. Centres reported increasing opportunities for physical activity and healthy eating, which were generally low-cost, easy and quick to implement. However, these changes were rarely transformed into formal written policies. A total of 87% of centers reported using the physical activity resource and 68% using the nutrition resource on a weekly basis. Implementation fidelity of the initial training was high. Of those centers who received the initial training, 75% participated in the mid-point booster session training. Two year post-implementation questionnaires indicated that 47% of centers were still using the Active Play Equipment kit, while 42% were still using the physical activity resource and 37% were still using the nutrition resource. Key challenges to implementation and sustainability identified during the evaluation were consistent among all of the REAIM elements. These challenges included lack of time, lack of support from childcare staff and low parental engagement. CONCLUSIONS: Findings from this study suggest the implementation of Healthy Start Depart Sante may be improved further by addressing resistance to change and varied levels of engagement among childcare staff. In addition, further work is needed to provide parents with opportunities to engage in HSDS with their children. PMID- 29505963 TI - Horizontal acquisition of transposable elements and viral sequences: patterns and consequences. AB - It is becoming clear that most eukaryotic transposable elements (TEs) owe their evolutionary success in part to horizontal transfer events, which enable them to invade new species. Recent large-scale studies are beginning to unravel the mechanisms and ecological factors underlying this mode of transmission. Viruses are increasingly recognized as vectors in the process but also as a direct source of genetic material horizontally acquired by eukaryotic organisms. Because TEs and endogenous viruses are major catalysts of variation and innovation in genomes, we argue that horizontal inheritance has had a more profound impact in eukaryotic evolution than is commonly appreciated. To support this proposal, we compile a list of examples, including some previously unrecognized, whereby new host functions and phenotypes can be directly attributed to horizontally acquired TE or viral sequences. We predict that the number of examples will rapidly grow in the future as the prevalence of horizontal transfer in the life cycle of TEs becomes even more apparent, firmly establishing this form of non-Mendelian inheritance as a consequential facet of eukaryotic evolution. PMID- 29505966 TI - Analysis of forensic odontological examinations at the National Forensic Service of Korea from 2011 to 2015. AB - The National Forensic Service (NFS) of Korea is a government agency responsible for examining and evaluating evidence obtained at crime scenes. The Section of Forensic Odontology of the Medical Examiner's Office conducts forensic odontological analyses of human remains, and mainly criminal cases are handled. In this study, 588 forensic odontological cases referred to NFS during 2011-2015 were analyzed for referral pattern, evidence material, examination criteria, and other factors and were compared with respective data from 2007 to 2010. Majority of the requests were internal (further dental examinations after autopsy) rather than external (direct requests from other agencies such as police departments). Regarding evidence materials, "Teeth" (including teeth and resected jaws) were dominant evidences. Due to the seasonal effects in Korea, the highest number of requests was in September of each year, but the number of requests in April has recently increased. Evidence materials were mostly found in suburban and rural area, especially in mountainous area due to the geographic characteristics of Korea. Regarding specific examinations, profiling, including age estimation, accounted for majority of the requests; this number had increased relative to the findings of a previous study, whereas the number of requests for dental identification and bite mark analysis had decreased. With this analysis, trends in forensic odontology can be observed, and we expect that these trends would be served as a reference for designing study and making training protocol for forensic odontology. PMID- 29505967 TI - Intermediate prognosis in metastatic germ cell tumours-outcome and prognostic factors. AB - BACKGROUND: For metastatic germ cell tumour patients with intermediate prognosis (IPGCT) according to the IGCCCG classification 5-year overall survival (OS) rates of 79% were described, but recent data suggest significant changes. PATIENTS AND METHODS: To compare the outcome of current IPGCT with former patients and to find new prognosticators a retrospective observational study was performed. Eligibility criteria were: age >=16 years, diagnosed between 1979 and 2014. Primary end-point was the 5-year OS rate. RESULTS: This database includes 707 IPGCT: group 1 was diagnosed 1979-1996 (n = 237), and group 2 1997-2014 (n = 470). Median follow-up was 8.6 years (IQR: 14.4). Group 1 and 2 received first line treatment with BEP (median 4 cycles; range 1-6) in 99% (group 1) and 95% (group 2), respectively. The proportion of first-line chemotherapy responders (CR and marker negative PR) was similar: 94% (group 1) and 96% (group 2), respectively (P = 0.290), but OS was superior in group 2 with a 5-year OS rate of 89% compared with 83% in group 1 (P = 0.035). In refractory disease, high-dose chemotherapy and treatment beyond second line was performed more often in group 2. A lactate dehydrogenase (LDH) cut-off value of 2 ULN (P = 0.002; HR 2.121) and alpha-fetoprotein (AFP) levels of 6200 IU/ml (P = 0.032; HR 2.155) pre chemotherapy were independent prognosticators for OS in a multivariate analysis. CONCLUSION: Outcome of IPGCT has improved and is now closer to the good prognosis category. LDH and AFP levels represent potential markers to stratify IPGCT before treatment initiation. PMID- 29505968 TI - Management of hyperbilirubinaemia in pancreatic cancer patients. AB - Development of hyperbilirubinaemia is common in patients with advanced pancreatic adenocarcinoma, both at diagnosis as well throughout disease evolution. For this reason, hyperbilirubinaemia determines chemotherapy treatment selection, and therefore it should be considered one of the most relevant conditions. There is very little evidence for the use of chemotherapy in this setting. This article summarises the main causes of hyperbilirubinaemia, how to treat them as well as their differential diagnosis. The current clinical evidence of the available drugs as well as the recommendations of use different combinations in the context of hyperbilirubinaemia are also reviewed. PMID- 29505969 TI - Short-term nighttime wind turbine noise and cardiovascular events: A nationwide case-crossover study from Denmark. AB - AIMS: The number of people exposed to wind turbine noise (WTN) is increasing. WTN is reported as more annoying than traffic noise at similar levels. Long-term exposure to traffic noise has consistently been associated with cardiovascular disease, whereas effects of short-term exposure are much less investigated due to little day-to-day variation of e.g. road traffic noise. WTN varies considerably due to changing weather conditions allowing investigation of short-term effects of WTN on cardiovascular events. METHODS AND RESULTS: We identified all hospitalisations and deaths from stroke (16,913 cases) and myocardial infarction (MI) (17,559 cases) among Danes exposed to WTN between 1982 and 2013. We applied a time-stratified, case-crossover design. Using detailed data on wind turbine type and hourly wind data at each wind turbine, we simulated mean nighttime outdoor (10-10,000 Hz) and nighttime low frequency (LF) indoor WTN (10-160 Hz) over the 4 days preceding diagnosis and reference days. For indoor LF WTN between 10 and 15 dB(A) and above 15 dB(A), odds ratios (ORs) for MI were 1.27 (95% confidence interval (CI): 0.97-1.67; cases = 198) and 1.62 (95% CI: 0.76-3.45; cases = 21), respectively, when compared to indoor LF WTN below 5 dB(A). For stroke, corresponding ORs were 1.17 (95% CI: 0.95-1.69; cases = 166) and 2.30 (95% CI: 0.96-5.50; cases = 15). The elevated ORs above 15 dB(A) persisted across sensitivity analyses. When looking at specific lag times, noise exposure one day before MI events and three days before stroke events were associated with the highest ORs. For outdoor WTN at night, we observed both increased and decreased risk estimates. CONCLUSION: This study did not provide conclusive evidence of an association between WTN and MI or stroke. It does however suggest that indoor LF WTN at night may trigger cardiovascular events, whereas these events seemed largely unaffected by nighttime outdoor WTN. These findings need reproduction, as they were based on few cases and may be due to chance. PMID- 29505970 TI - H2O2 homeostasis in wild-type and ethylene-insensitive Never ripe tomato in response to salicylic acid treatment in normal photoperiod and in prolonged darkness. AB - Ethylene proved to be an important modulator of salicylic acid (SA) signalling pathway. Since SA may regulate both the production and scavenging of hydrogen peroxide (H2O2), which show light-dependency, the aim of this study was to compare H2O2 metabolism in the leaves of SA-treated wild-type (WT) tomato (Solanum lycopersicum L. cv. Ailsa Craig) and in ethylene receptor Never-ripe (Nr) mutants grown in normal photoperiod or in prolonged darkness. H2O2 accumulation was higher in the WT than in the mutants in normal photoperiod after 1 mM SA treatment, while Nr leaves contained more H2O2 after light deprivation. The expression of certain superoxide dismutase (SOD) genes and activity of the enzyme followed the same tendency as H2O2, which was scavenged by different enzymes in the two genotypes. Catalase (CAT, EC 1.11.1.6) activity was inhibited by SA in WT, while the mutants maintained enhanced enzyme activity in the dark. Thus, in WT, CAT inhibition was the major component of the H2O2 accumulation elicited by 1 mM SA in a normal photoperiod, since the expression and/or activity of ascorbate (APX, EC 1.11.1.11) and guaiacol peroxidases (POD, EC 1.11.1.7) were induced in the leaves. The absence of APX and POD activation in mutant plants suggests that the regulation of these enzymes by SA needs functional ethylene signalling. While the block of ethylene perception in Nr mutants was overwritten in the transcription and activity of certain SOD and CAT isoenzymes during prolonged darkness, the low APX and POD activities led to H2O2 accumulation in these tissues. PMID- 29505971 TI - Validation of Adolescent Suicide Assessment Protocol-20 (ASAP-20) to Sri Lankan adolescents. AB - PURPOSE: Youth suicide rates are rising worldwide, including Sri Lanka, where 46.5/100,000 among 15-19yrs was reported in 1986. Identifying high risk adolescents is vital. Dearth of trained professionals, demands an instrument utilizable by non-psychiatrists. Such was not available in Sinhalese. Adolescent Suicide Assessment Protocol (ASAP-20) and its' manual was translated and validated to Sri Lankan adolescents. METHOD: A validation study. Forward/back translations followed by cultural adaptation. Face validity, operational equivalence were assessed. Panel of Psychiatrists assessed semantics, conceptual, content/construct validity using external criticism. Final Sinhalese version was applied to 100 Sinhalese speaking 10-19yr olds referred to Psychiatry units of two Teaching Hospitals following a suicide attempt or with suicidal ideation (cases) excluding psychotic disorder, acute emergencies or special needs and compared with same aged adolescents on treatment for respiratory problems as controls. Discriminant ability was calculated using area under the Receiver Operating Curve (AUC). Reliability was calculated using Cronbach's alpha. RESULTS: Sinhalese version showed satisfactory face/contents/construct validity and operational equivalence. Median suicide risk score was 18 and mean 17.99 (SD = 7.56) for cases, median = 4 and mean = 4.86 (SD = 2.41) for controls. AUC was 0.969 (SE = 0.11), indicating a high ability to discriminate moderate/high from low suicidal risk. Cut off value, 8.5 was lower than original tool at a sensitivity of 91% and a specificity of 91%. Cronbach's alpha was 0.811 indicating high reliability and consistency. CONCLUSION: Sinhalese version of ASAP-20 is a successful screening instrument to detect high suicide risk among adolescents in clinical and non clinical settings. PMID- 29505972 TI - Epidemiology of substance use and dependence in the state of Punjab, India: Results of a household survey on a statewide representative sample. AB - BACKGROUND: Despite its political sensitivity, little scientifically valid evidence on the prevalence, pattern and treatment need of substance use in the northern border state of Punjab, India is available till date. METHODOLOGY: The 'universe' for the survey was the entire house-dwelling population of Punjab, of both genders, aged 11-60 years. Stratified multistage sampling technique was used. Following a pilot study, data were collected by trained research workers by face-to-face interview using pre-tested survey instruments. RESULTS: From 6398 households, 13,925 respondents were interviewed. Prevalence of lifetime and current (12 month) dependence on any substance were 15.8% (95% confidence interval [CI] 15.1-16.4%) and 14.7% (95% CI 14.1-15.3%) respectively. Of the specific substances, current dependence was the highest on alcohol (10.9%; 95% CI 10.3-11.4%), followed by tobacco (8.1%; 95% CI 7.7-8.6%). Regarding opioids, lifetime use was 1.9% (95% CI 1.6-2.1%) and current dependence 0.8% (95%CI 0.7 1.0%). Use of and dependence on natural opioids was the highest. After projecting these figures to the entire source population of the state, number of currently dependent alcohol, tobacco and opioid users were 2.2, 1.6, and 0.17 million, respectively. Overall, substance use was predominant in men and significantly more common in rural areas. Majority (81%) of the tobacco users, and 51% each of alcohol and opioid users needed intervention. However, merely one in six subjects sought any professional help. CONCLUSION: Punjab has a substantive problem related to substance use. Though alcohol and tobacco are by far the major substances of use and dependence, the large number of opioid users also raises concern. Treatment services need scaling-up. PMID- 29505973 TI - Light-dependent processes on the cathode enhance the electrical outputs of sediment microbial fuel cells. AB - In this study, we explored in details the influence of the light irradiation on the SMFCs electrical outputs. The experiments at both natural and artificial illumination firmly show that during the photoperiods the current grows up. The intensity of the current increase depends on the duration of the photoperiod as well as on the wavelength of the monochromatic light source applied. The highest influence of the light irradiation has been obtained at wavelengths, corresponding to the absorption peaks of essential pigments in the light harvesting system of oxygenic photosynthesizing microorganisms. The decreased values as well as the discontinued fluctuations of the current as a result of suppressed illumination or substitution of the biocathode with a new one suggest that photosynthesizing microorganisms, co-existing in the cathodic biofilm consortium, contribute to the overall SMFC performance. The microscopic observations confirm the existence of chlorophyll-containing microorganisms on the cathode surface. Though the performed metagenomics DNA analysis has not certified a dominance of photosynthesizing microorganisms, all other results support the hypothesis that the current enhance during the photoperiods is due to the in situ bio-oxygen production on the cathode surface, thus lowering the mass transport limitations for the oxygen reduction reaction. PMID- 29505974 TI - How beginning handwriting is influenced by letter knowledge: Visual-motor coordination during children's form copying. AB - Even with recent technological advances, handwriting remains the developmental foundation from which communication via written language unfolds. Despite the importance of handwriting to academic success, previous research with beginning school-age children has only indirectly measured the processes of handwriting using post hoc assessments of legibility and accuracy. We adapted new head mounted eye-tracking methods to directly measure visual-motor coordination of preschool and early elementary school children (N = 40) as they copied familiar (English letters) and unfamiliar (Cyrillic symbols) letter-like forms in real time. Results indicated that younger children needed more time to visually process a letter or symbol and initiate a writing action compared with older children despite children of all ages writing letters in a similar amount of time. Analyses also revealed that children copied familiar English letters more efficiently than they copied unfamiliar Cyrillic symbols: They spent more time on and made more visual fixations to the Cyrillic symbols compared with the English letters during the copying task. Finally, children made more visual fixations to less frequently occurring English letters than to more frequently occurring ones. Results are considered in relation to how letter recognition influences the development of automaticity in early handwriting. PMID- 29505975 TI - DNA methylation as a genomic marker of exposure to chemical and environmental agents. AB - Recent progress in interpreting comprehensive genetic and epigenetic profiles for human cellular states has contributed new insights into the developmental origins of disease, elucidated novel signalling pathways and enhanced drug discovery programs. A similar comprehensive approach to decoding the epigenetic readouts from chemical challenges in vivo would yield new paradigms for monitoring and assessing environmental exposure in model systems and humans. PMID- 29505976 TI - Illuminating developmental biology with cellular optogenetics. AB - In developmental biology, localization is everything. The same stimulus-cell signaling event or expression of a gene-can have dramatically different effects depending on the time, spatial position, and cell types in which it is applied. Yet the field has long lacked the ability to deliver localized perturbations with high specificity in vivo. The advent of optogenetic tools, capable of delivering highly localized stimuli, is thus poised to profoundly expand our understanding of development. We describe the current state-of-the-art in cellular optogenetic tools, review the first wave of major studies showcasing their application in vivo, and discuss major obstacles that must be overcome if the promise of developmental optogenetics is to be fully realized. PMID- 29505977 TI - External fixation and surgical fusion for pediatric cervical spine injuries: Short-term outcomes. AB - OBJECTIVE: To compare in-hospital complication rates in pediatric patients with atlantoaxial and subaxial injuries undergoing either external fixation or surgical fusion. PATIENTS AND METHODS: Baseline and outcome data were obtained from the 2002-2011 Nationwide Inpatient Sample (NIS) for patients under the age of 18 with a diagnosis of cervical spine fracture without spinal cord injury or cervical spine subluxation. Patients who underwent external immobilization or internal fixation were included for analysis. Variables analyzed included length of stay, in-hospital mortality, discharge disposition, total hospital charges, and development of at least one in-hospital complication. RESULTS: A total of 2878 pediatric patients with cervical spine injury were identified; 1462 patients (50.8%) with atlantoaxial (C1-2) injury and 1416 (49.2%) with subaxial (C3-7) injury. Among atlantoaxial injury patients, external fixation was associated with lower total charges ($73,786 vs. $98,158, p = .040) and a lower likelihood of developing at least one complication (1.9% vs. 6.8%, p = .029) compared to surgical fusion, and was a more common treatment for subluxation alone (16.4% vs. 2.6%, p < .001). Among subaxial injury patients, there were no significant differences in age (p = .262), length of stay (p = .196), occurrence of at least one complication (p = .334), or total charges (p = .142). Subaxial subluxation injuries alone were treated more often with surgical fusion (2.2% vs. 1.2%, p < .001). CONCLUSION: Optimal treatment of patients with cervical injury may vary by location of injury. Our findings warrant further investigation into the difference in clinical outcomes between surgical and non-surgical management of atlantoaxial and subaxial injury. PMID- 29505978 TI - Clinical and radiological outcomes after stand-alone ALIF for single L5-S1 degenerative discopathy using a PEEK cage filled with hydroxyapatite nanoparticles without bone graft. AB - OBJECTIVE: Recent improvements in cage designs with integral fixation and screw attachments have made stand-alone ALIF a viable option with several possible advantages. The aim of this study was to confirm the efficacy and safety of a PEEK cage filled with hydroxyapatite nanoparticles without adding a bone graft for stand-alone ALIF in the treatment of L5-S1 isolated degenerative disc discopathy (DDD). PATIENTS AND METHODS: Sixty-five patients who required surgery for DDD were evaluated. Clinical outcome evaluations included back and leg pain (VAS), disability (Oswestry Disability Index), and patient satisfaction (Macnab's criteria). Radiological outcomes include the assessment of disc height, the L5-S1 intervertebral disc angle, and anterior intervertebral fusion through standard and functional sagittal X-rays of the lumbar spine. Clinical and radiological measurements were assessed 2, 6, 12, and 24 months after surgery. RESULTS: Clinical outcomes improved progressively and stabilized from 12- to 24-month follow-up. Final postoperative ODI scores showed a notable improvement (95%CI = 36.1-48.9 points; p < .001). Similarly, 24-month postoperative VAS scores revealed a significant decrease in pain (95%CI = 5.4-6.2; p < .001). The fusion rate was 95.4%. Anterior disc height was restored from 4.1 +/- 3.2 mm at baseline to 9.5 +/- 1.6 mm in the immediate postoperative period (p < .001). A small collapse (17.9%) of the disc height was detected from the 2- and 24-month follow ups. Cage subsidence (more than 3 mm collapse) was detected in 4 cases (6.2%) and was related to cage size (more than 11 mm height; P < .05). There were no serious bone substitute-related adverse events and no revision surgeries. CONCLUSION: Stand-alone anterior lumbar interbody fusion using hydroxyapatite nanoparticles without an autologous bone graft is an effective and safe treatment option for L5 S1 degenerative pathology. Clinical outcomes were very satisfactory with a high fusion rate. PMID- 29505979 TI - Stacking of microbial fuel cells with continuous mode operation for higher bioelectrogenic activity. AB - The effect of stacking multiple microbial fuel cells for stable power output was evaluated in continuous mode operation. Three single chambered air cathode CMFCs with Nafion (CMFCN), Terry cotton (CMFCT) as membranes and one without membrane (CMFCML) were operated in continuous mode. Maximum power density (PD) and COD removal efficiency was obtained for CMFCN (0.1 W/m2, 50%) followed by CMFCML (0.062 W/m2, 47%) and CMFCT (0.025 W/m2, 39%) and were stable throughout the operation. To increase the power output further, stacking of CMFCs was carried in series/parallel circuitry, which yielded high power density in parallel (2.0 W/m2; 7.2 W/m3) and high voltage in series (1.1 V). Study also evidenced that stacking resulted in high and stable bioelectricity by minimizing the electron losses in comparison to individual CMFCs operation. Stable and high power output signifies the impact of continuous mode operation that constantlty replenishes the substrate. PMID- 29505980 TI - Bio-plasticizer production by hybrid acetone-butanol-ethanol fermentation with full cell catalysis of Candida sp. 99-125. AB - Hybrid process that integrated fermentation, pervaporation and esterification was established aiming to improve the economic feasibility of the conventional acetone-butanol-ethanol (ABE) fermentation process. Candida sp 99-125 cells were used as full-cell catalyst. The feasibility of batch and fed-batch esterification using the ABE permeate of pervaporation (ranging from 286.9 g/L to 402.9 g/L) as substrate were compared. Valuable butyl oleate was produced along with ethyl oleate. For the batch esterification, due to severe inhibition of substrate to lipase, the yield of butyl oleate and ethyl oleate were only 24.9% and 3.3%, respectively. In contrast, 75% and 11.8% of butyl oleate and ethyl oleate were obtained, respectively, at the end of the fed-batch esterification. The novel integration process provides a promising strategy for in situ upgrading ABE products. PMID- 29505981 TI - Production of xylitol by expressing xylitol dehydrogenase and alcohol dehydrogenase from Gluconobacter thailandicus and co-biotransformation of whole cells. AB - In the present study, recombinant strains were constructed for xylitol production by cloning and expressing the novel xylitol dehydrogenase (xdh) and alcohol dehydrogenase (adh) genes in E. coli BL21 (DE3) from Gluconobacter thailandicus CGMCC1.3748. The optimum pH, temperature, specific activity and kinetic parameters were further investigated for purified XDH. The co-culture of G. thailandicus (30 g/L), BL21-xdh (20 g/L) and BL21-adh (20 g/L) produced 34.34 g/L of xylitol after 48 h in the presence of 40 g/L d-arabitol and 2% ethanol. The concentration of xylitol produced in this co-biotransformation was found to be 2.7-folds higher than the xylitol yield of G. thailandicus alone, while the yield was increased by 4.8% when compared to that of G. thailandicus mixed with BL21 xdh under the similar experimental conditions. PMID- 29505982 TI - Evaluation of copper toxicity using site specific algae and water chemistry: Field validation of laboratory bioassays. AB - Studies of metal toxicity to microalgae have predominantly been conducted using single non-target algae species and without due regard for the chemistry of the treated waters, leading to ineffective or excessive algaecide treatments. In this study, indigenous multi-algal species (Scenedesmus quadricauda, and Scenedesmus subspicatus and Oscillatoria agardhii) were used in laboratory toxicity bioassays under simulated field water chemistry (pH = 7.2, hardness = 196 mg L-1 as CaCO3, and alkalinity = 222 mg L-1 as CaCO3) to determine the optimum copper sulfate treatment dose to control algae growth in an irrigation canal. Toxicity bioassays were conducted using copper sulfate in chelated (with EDTA) and non-chelated (without EDTA) forms to assess the influence of the use of synthetic chelators in toxicity studies. Also, copper toxicity to the indigenous algae species was measured in the non-modified EPA test medium (pH = 7.5, hardness = 92 mg L-1 as CaCO3, alkalinity = 10 mg L-1 as CaCO3 and EDTA= 300 ug L-1) to assess the impact of the water chemistry on algae inhibitory algal dosages. Under simulated water chemistry conditions, lower toxicity was measured in the test flasks with the chelated form of copper (96 h- EC50= 386.67 ug L-1 as Cu) as compared to those with the non-chelated metal (96 h-EC50= 217.17 ug L-1 as Cu). In addition, higher copper toxicity was measured in the test flasks prepared with the non-modified EPA medium using chelated copper (96 h-EC50 = 65.93 ug L-1 as Cu) as compared to their analogous microcosms with modified water chemistry (96 h-EC50= 386.67 ug L 1 as Cu), the increased water hardness and alkalinity in the latter case contributing to the decrease of the metal bioavailability. Results from laboratory experiments showed good correlation with copper dosages used in a small scale field testing to control algae growth, increasing confidence in laboratory bioassays. PMID- 29505983 TI - From a common progenitor to distinct liver epithelial phenotypes. AB - The vertebrate liver presents a fascinating case study for how cell form is optimized for function. To execute its duties the liver assembles two distinct lumen-forming epithelial phenotypes: Firstly, cords with a branched, capillary like luminal network formed between hepatocytes (bile canaliculi); and secondly, tubular ducts formed by biliary epithelial cells arranged around a central cavity and connected to the bile canaliculi. How these remarkably different epithelial polarity phenotypes are generated and joined into a contiguous luminal network are major unresolved questions. Recent studies have characterized the divergence of the two epithelial lineages from common progenitors, described the coordination of bile canaliculi formation with bile duct branching during biliary tree morphogenesis and implicated RhoA-dependent E-cadherin adhesion in the decision to polarize with hepatocytic or biliary phenotype. PMID- 29505984 TI - Ecotoxicological effects of the herbicide glyphosate in non-target aquatic species: Transcriptional responses in the mussel Mytilus galloprovincialis. AB - Glyphosate has been the most widely used herbicide worldwide over the last three decades, raising increasing concerns for its potential impacts on environmental and human health. Recent studies revealed that glyphosate occurs in soil, surface water, and groundwater, and residues are found at all levels of the food chain, such as drinking water, plants, animals, and even in humans. While research has demonstrated that glyphosate can induce a broad range of biological effects in exposed organisms, the global molecular mechanisms of action still need to be elucidated, in particular for marine species. In this study, we characterized for the first time the molecular mechanisms of action of glyphosate in a marine bivalve species after exposure to environmentally realistic concentrations. To reach such a goal, Mediterranean mussels Mytilus galloprovincialis, an ecologically and economically relevant species, were exposed for 21 days to 10, 100, and 1000 MUg/L and digestive gland transcriptional profiles were investigated through RNA-seq. Differential expression analysis identified a total of 111, 124, and 211 differentially regulated transcripts at glyphosate concentrations of 10, 100, and 1000 MUg/L, respectively. Five genes were found consistently differentially expressed at all investigated concentrations, including SERP2, which plays a role in the protection of unfolded target proteins against degradation, the antiapoptotic protein GIMAP5, and MTMR14, which is involved in macroautophagy. Functional analysis of differentially expressed genes reveals the disruption of several key biological processes, such as energy metabolism and Ca2+ homeostasis, cell signalling, and endoplasmic reticulum stress response. Together, the results obtained suggest that the presence of glyphosate in the marine ecosystem should raise particular concern because of its significant effects even at the lowest concentration. PMID- 29505985 TI - Population-level predictions from cannabis risk perceptions to active cannabis use prevalence in the United States, 1991-2014. AB - INTRODUCTION: A mosaic of evidence links risk perceptions with drug use in adolescence, including population summaries to guide public health campaigns, as well as subject-specific estimates on preventing an adolescent's drug use by manipulating that individual's prior risk perceptions. We re-visit these issues with a public health perspective, asking whether population-level cannabis risk perceptions of school-attending adolescents at one grade level might predict cannabis use prevalence two and four grade levels later. METHODS: From 1991 to 2014, each year's United States "Monitoring the Future" (MTF) study population included 8th-, 10th-, & 12th-graders. Two and four years later, statistically independent school samples of the same cohorts were drawn and assessed (n ~ 16,000/year). Population-level modeling estimated cannabis use prevalence at time "t" (12th-grade) regressed on that same cohort's cannabis risk perceptions as had been measured at time "t-4" (8th-grade) and time "t-2" (10th-grade). RESULTS: Higher cannabis risk perception levels for 10th-graders predict lower cannabis use prevalence when 10th-graders have become 12th-graders (beta=-0.12), and higher cannabis risk perception levels of 8th-graders predict lower cannabis prevalence when 8th-graders have become 10th-graders (beta=-0.27); p-values < 0.05. Across four-year spans, the prediction is null (p-value = 0.619). CONCLUSIONS: This within-cohort across-grade population-level prediction prompts questions for drug prevention specialists, including "Would a relatively small upward shift in a local area population's appraisal of risk perceptions be followed, two years later, by reduced population prevalence of cannabis use?" Future randomized trial designs, health education, or prevention efforts focused on altering early adolescent cannabis risk perceptions might provide the most convincing and definitive evidence. PMID- 29505986 TI - Shame mediates the relationship between depression and addictive behaviours. AB - BACKGROUND: Alcohol and gambling problems are common in young adults. Self medication theory states that young adults with depression drink and/or gamble to escape negative emotions. Research shows that depression is a risk factor for drinking/gambling problems, but more work is needed to examine mediators underlying these associations. One potential mediator is shame. Shame is a self directed emotion that follows a negative life event and is characterized by intense feelings of inferiority, worthlessness, and embarrassment. Depressed individuals are especially susceptible to shame (and associated emotions). Shame has also been implicated in risk for addiction. Accordingly, we predicted that elevated shame would explain why depression is associated with both alcohol and gambling problems. METHODS: A longitudinal design was used to examine this hypothesis. Undergraduates (N = 210) completed self-reports of depression at baseline (Time 1) and then completed self-reports of shame, alcohol misuse, gambling problems one month later (Time 2). RESULTS: Results showed that individuals with elevated depression at Time 1 endorsed high levels of shame at Time 2, which in turn predicted more gambling (beta = .038, 95% CI [.010, .087]) and alcohol problems (beta = .249, 95% CI [.123, .435]) at Time 2. We found that increased levels of shame explained the effects of depression on problem drinking and gambling. CONCLUSIONS: Study findings improve our understanding of the depressive pathway to addiction by providing evidence for shame as a potential mechanism of this pathway. IMPACT: Reducing shame can be a target of clinical interventions for young adults with depression and alcohol/gambling problems. PMID- 29505987 TI - Effect of pH on the microstructure of beta-Ga2O3 and its enhanced photocatalytic activity for antibiotic degradation. AB - Semiconductor photocatalysis has become the focus of recent research on antibiotic treatment because it is a green and efficient technology. In this study, alpha-GaOOH with several novel microstructures has been synthesized at a low temperature and its subsequent thermal transformation. The influence of pH on the synthesis of alpha-GaOOH is studied, and the results indicate that pH played an important role in the microstructures of alpha-GaOOH and beta-Ga2O3. All Ga2O3 samples possess macro-mesoporous network structures and exhibits a remarkable photocatalytic activity for antibiotic degradation. The photoelectron chemical tests show that the separation efficiency of photogenerated charge carriers of Ga2O3-7.0 is higher than that of other Ga2O3. The enhanced photocatalytic activity of Ga2O3-7.0 is mainly ascribed to its morphology and oxygen vacancy. The active species trapping and photoluminescence measurement experiments indicate that OH and O2- are the major active species contributing to the photocatalytic process. This study will bring about the potential application in treatment of the antibiotic pollutants. PMID- 29505988 TI - Ionic liquid-induced double regulation of carbon quantum dots modified bismuth oxychloride/bismuth oxybromide nanosheets with enhanced visible-light photocatalytic activity. AB - The efficient separation of photoexcited electron-hole pairs acts as a significant factor and challenge for the enhanced photocatalytic activity of the photocatalyst. To pursue higher photocatalytic activity, carbon quantum dots (CQDs) modified bismuth oxychloride (BiOCl)/bismuth oxybromide (BiOBr) nanosheet photocatalyst has first been synthesized via an in situ ionic liquid-induced strategy. The bridge function of the ionic liquid ensures the uniform dispersal of CQDs on the surface of the BiOCl/BiOBr material. After the introduction of CQDs, the CQDs/BiOCl/BiOBr composite photocatalyst displayed enhanced photocatalytic activity for the photodegradation of several different types of organic contaminants such as rhodamine B, tetracycline hydrochloride, ciprofloxacin, and bisphenol A under the irradiation of visible light, and the BiOCl/BiOBr material loading with 5 wt% CQDs showed the best photocatalytic performance. The characterization results revealed that the introduction of CQDs could simultaneously improve the visible light absorption properties and separation efficiency of photoexcited electron-hole pairs. The electron spin resonance and radical quenching experiments demonstrated that during the photocatalytic reactions, holes and superoxide radicals were the main active species involved in the degradation of the contaminants, and the possible photocatalytic mechanism is presented. Therefore, this work provides an efficient pathway for the improved activity of the photocatalyst. PMID- 29505989 TI - Simultaneously efficient adsorption and photocatalytic degradation of tetracycline by Fe-based MOFs. AB - Recently, Fe-based metal-organic frameworks (MOFs) have attracted increasing attention and been widely used. To date, however, it is unknown whether they can be employed to degrade tetracycline, one of the most widely used antibiotics. This work therefore aims to provide such support by comparing the performance of three Fe-based MOFs (namely, Fe-MIL-101, Fe-MIL-100, and Fe-MIL-53) in removing tetracycline. Experimental results showed that Fe-MIL-101 exhibited the best performance in tetracycline removal, with 96.6% of tetracycline being removed (initial tetracycline concentration at 50 mg/L) while Fe-MIL-100 and Fe-MIL-53 removed 57.4% and 40.6% under the same conditions. Additionally, the effects of adding dosage, adsorption time, and initial concentration of tetracycline on degradation efficiency were examined. It was found that the adsorption and photocatalytic degradation effect was better with the increase of time, the optimum dosage of Fe-MIL-101 was 0.5 g/L and the removal efficiency decreased with the increasing of initial tetracycline concentrations. Moreover, the trapping experiments and ESR tests indicated that O2-, OH and h+ were the main active species in photocatalytic degradation process of tetracycline. Due to its high removal efficiency and simple synthesis, it could be used as a potential catalyst for degradation of tetracycline and other antibiotics. PMID- 29505990 TI - Interfacing superhydrophobic silica nanoparticle films with graphene and thermoplastic polyurethane for wear/abrasion resistance. AB - HYPOTHESIS: Nanoparticle films are one of the most suitable platforms for obtaining sub-micrometer and nanometer dual-scale surface texture required for liquid repellency. The assembly of superhydrophobic nanoparticles into conformal and strongly adherent films having abrasion-induced wear resistance still poses a significant challenge. Various techniques have been developed over the years to render nanoparticle films with good liquid repellent properties and transparency. However, forming abrasion resistant superhydrophobic nanoparticle films on hard surfaces is challenging. One possibility is to partially embed or weld nanoparticles in thin thermoplastic primers applied over metals. EXPERIMENTS: Hexamethyldisilazane-functionalized fumed silica nanoparticle films spray deposited on aluminum surfaces were rendered abrasion resistant by thermally welding them into thermoplastic polyurethane (TPU) primer applied a priori over aluminum. Different solvents, nanoparticle concentrations and annealing temperatures were studied to optimize nanoparticle film morphology and hydrophobicity. FINDINGS: Thermal annealing at 150 degrees C enhanced stability and wear resistance of nanoparticle films. A thin thermal interface layer of graphene nanoplatelets (GnPs) between the primer and the nanoparticle film significantly improved superhydrophobic wear resistance after annealing. As such, superhydrophobic nanocomposite films with the GnPs thermal interface layer displayed superior abrasion-induced wear resistance under 20 kPa compared to films having no GnPs-based thermal interface. PMID- 29505991 TI - Advances in colloidal manipulation and transport via hydrodynamic interactions. AB - In this review article, we highlight many recent advances in the field of micromanipulation of colloidal particles using hydrodynamic interactions (HIs), namely solvent mediated long-range interactions. At the micrsocale, the hydrodynamic laws are time reversible and the flow becomes laminar, features that allow precise manipulation and control of colloidal matter. We focus on different strategies where externally operated microstructures generate local flow fields that induce the advection and motion of the surrounding components. In addition, we review cases where the induced flow gives rise to hydrodynamic bound states that may synchronize during the process, a phenomenon essential in different systems such as those that exhibit self-assembly and swarming. PMID- 29505992 TI - Acute epiploic appendigitis: Diagnostic and laparoscopic approach. AB - INTRODUCTION: Acute epiploic appendagitis is a relatively rare disease that mimics a varied number of diseases. PRESENTATION OF CASE: In this paper we report a 24-year-old male who presented with epiploic appendagitis that might have been misdiagnosed by physicians due to its equivocal presentation imitating more common acute abdominal conditions like acute appendicitis or acute diverticulitis depending on the site of the inflamed appendage. DISCUSSION: The clinical presentation, investigations findings and both conservative and surgical interventions of the patient are mentioned within the report. CONCLUSION: Radiological imaging like enhanced CT scan of the abdomen has an important role in differentiating acute epiploic appendigitis from other acute abdominal conditions along with the proper physical examination, thus promoting conservative management and avoiding surgery. However, failure of conservative management might lead to the surgical intervention. PMID- 29505993 TI - Hydrological controls on nitrogen (ammonium versus nitrate) fluxes from river to coast in a subtropical region: Observation and modeling. AB - Increased anthropogenic nutrient input and losses has caused eutrophication problems in freshwater and coastal ecosystems worldwide. High-frequency observations and modeling of river fluxes in subtropical regions are required to understand nutrient cycling and predict water quality and ecological responses. In 2014, a normal hydrologic year, we carried out daily sampling of the North Jiulong River in southeast China, which drains an agricultural watershed and experiences the Asian monsoon climate. We focused on the distinct characteristics of two important inorganic nitrogen forms (ammonium and nitrate). Our results show contrasting hydrological controls on the seasonal timing and magnitude of ammonium and nitrate concentrations and loads, likely due to differing sources and transport pathways (surface runoff versus baseflow) to the river. Both nitrogen concentrations were enriched in the dry season and diluted in the wet season. Arrival of rains in the pre-wet period in March caused a "first flush" peak event with the highest concentrations of the year, during which ammonium peaked two weeks earlier than nitrate. In contrast, the majority of nitrogen transport occurred during the lower concentrations of the wet season, with seven storms inducing flood events that lasted 24% of the time, contributed 52% of the runoff, and exported 47% of the ammonium and 42% of the nitrate. We found that seasonally piecewise LOADEST models (for pre-wet, wet and post-wet periods) performed better (5-8% error) than a year-round model (12-24% error) in estimating monthly nitrogen loads. However, not all nitrogen dynamics are easily synthesized by this approach, and extreme floods might produce a greater deviation in estimating nitrogen loads. These findings represent important implications for coastal ecology and provide opportunity on improving observation and modeling. PMID- 29505994 TI - A novel system of MnO2-mullite-cordierite composite particle with NaClO for Methylene blue decolorization. AB - The MnO2-mullite-cordierite composite particle (MnO2-MCP) was prepared and firstly was applied as catalyst with sodium hypochlorite (NaOCl) as oxidant in heterogeneous Fenton-like system for methylene blue (MB) decolorization. The MnO2 MCP was characterized by XRD, SEM, EDS and BET analysis. The decolorization efficiencies of MB/MnO2-MCP, MB/NaClO, (MB after filtrating MnO2-MCP)/NaClO and MB/MnO2-MCP/NaClO were compared, which confirmed the interaction ability between MnO2-MCP and NaClO. After evaluating the role of adsorption of MB by MnO2-MCP, the catalytic oxidation effects of MnO2-MCP with NaClO on MB were exploited. The adsorption results showed that the new porous catalyst had certain adsorption capacity for MB and the adsorption fit best with Langmuir model. The central composite rotatable design (CCD) of response surface methodology (RSM) was used to design catalytic oxidation experiments of MB/MnO2-MCP/NaClO system, with influencing factors of catalyst dose, NaClO concentration, pH and initial MB concentration. The optimum conditions were 5.97 mM of NaClO, 37.9 g/L of catalyst dose, 5.74 of pH value and 100.71 mg/L of initial MB concentration, which could ensure nearly 100% MB decolorization. The effect of radical scavengers elucidated that superoxide anion (O2-) was the main species to decolorize MB. Then the possible degradation mechanism and pathway of MB were proposed in this MnO2 MCP/NaClO system. PMID- 29505995 TI - Pyrolysis production of fruit peel biochar for potential use in treatment of palm oil mill effluent. AB - Fruit peel, an abundant waste, represents a potential bio-resource to be converted into useful materials instead of being dumped in landfill sites. Palm oil mill effluent (POME) is a harmful waste that should also be treated before it can safely be released to the environment. In this study, pyrolysis of banana and orange peels was performed under different temperatures to produce biochar that was then examined as adsorbent in POME treatment. The pyrolysis generated 30.7 47.7 wt% yield of a dark biochar over a temperature ranging between 400 and 500 degrees C. The biochar contained no sulphur and possessed a hard texture, low volatile content (<=34 wt%), and high amounts of fixed carbon (>=72 wt%), showing durability in terms of high resistance to chemical reactions such as oxidation. The biochar showed a surface area of 105 m2/g and a porous structure containing mesopores, indicating its potential to provide many adsorption sites for use as an adsorbent. The use of the biochar as adsorbent to treat the POME showed a removal efficiency of up to 57% in reducing the concentration of biochemical oxygen demand (BOD), chemical oxygen demand COD, total suspended solid (TSS) and oil and grease (O&G) of POME to an acceptable level below the discharge standard. Our results indicate that pyrolysis shows promise as a technique to transform banana and orange peel into value-added biochar for use as adsorbent to treat POME. The recovery of biochar from fruit waste also shows advantage over traditional landfill approaches in disposing this waste. PMID- 29505996 TI - How do marine and coastal citizen science experiences foster environmental engagement? AB - Citizen science programs enable community involvement in scientific research. In addition to fostering greater science literacy, some citizen science programs aim to foster engagement in environmental issues. However, few data are available to indicate whether and how citizen science programs can achieve greater environmental engagement. We survey individuals choosing to attend one of seventeen reef citizen science events and examine the extent to which attendees reported three indicators of greater environmental engagement: (i) willingness to share information, (ii) increased support for marine conservation and citizen science, and (iii) intentions to adopt a new behavior. Most participants reported being willing to share information about reef conservation (91%) and described increased support for marine science and conservation (87%). Half of participants (51%) reported intentions to adopt a new conservation behavior. We found that key elements of the citizen science experience associated with these outcomes were learning about actions to protect reefs and coasts (procedural learning), experiencing surprise, and experiencing negative emotions about environmental problems. Excitement was also associated with positive outcomes, but only in participants who were less likely to see themselves as environmental, or were less frequent visitors to reefs and coasts. Importantly, the association between factual learning and environmental engagement outcomes was limited or negative. These findings suggest that the way citizen science experiences make people feel, may be more important for fostering future environmental engagement than factual based learning. When designing citizen science programs for community members, these findings provide a reminder to not focus on provision of factual information alone, but to highlight environmental impacts while providing meaningful experiences and building environmental skills. PMID- 29505997 TI - A case study of odour nuisance evaluation in the context of integrated urban planning. AB - Odour nuisance poses a serious problem in many urban areas, yet its evaluation and mitigation is often omitted in the urban planning process. By identifying its range and spatio-temporal variations, it could be taken into consideration by planners in urban development strategies and land use decisions. The aim of the study was to present the application of odour evaluation techniques in the improvement of the quality of life in the built environment. The problem of odours is discussed in regard to human health, social aspects and current practices in the management of spatial development. The application possibilities of field olfactometry are demonstrated based on a case study of a municipal landfill which is a major source of odour nuisance for the adjacent areas. The results of odour nuisance measurements were field olfactometry combined with topographical and meteorological data. Using dispersion modelling (non-steady state Lagrangian Gaussian puff model CALPUFF with dedicated meteorological pre processor CALMET) it was possible to calculate odour concentrations and to place the measured odour concentrations in a specific spatial context. The obtained results were juxtaposed with local development strategies and discussed in the context of environmental-based planning. We suggest that odour evaluation and dispersion modelling are valid tools in managing the dynamics of urban growth. PMID- 29505998 TI - Assessing influences on social vulnerability to wildfire using surveys, spatial data and wildfire simulations. AB - A growing body of research focuses on identifying patterns among human populations most at risk from hazards such as wildfire and the factors that help explain performance of mitigations that can help reduce that risk. Emerging policy surrounding wildfire management emphasizes the need to better understand such social vulnerability-or human populations' potential exposure to and sensitivity from wildfire-related impacts, including their ability to reduce negative impacts from the hazard. Studies of social vulnerability to wildfire often pair secondary demographic data with a variety of vegetation and wildfire simulation models to map potential risk. However, many of the assumptions made by those researchers about the demographic, spatial or perceptual factors that influence social vulnerability to wildfire have not been fully evaluated or tested against objective measures of potential wildfire risk. The research presented here utilizes self-reported surveys, GIS data, and wildfire simulations to test the relationships between select perceptual, demographic, and property characteristics of property owners against empirically simulated metrics for potential wildfire related damages or exposure. We also evaluate how those characteristics relate to property owners' performance of mitigations or support for fire management. Our results suggest that parcel characteristics provide the most significant explanation of variability in wildfire exposure, sensitivity and overall wildfire risk, while the positive relationship between income or property values and components of social vulnerability stands in contrast to typical assumptions from existing literature. Respondents' views about agency or government management helped explain a significant amount of variance in wildfire sensitivity, while the importance of wildfire risk in selecting a residence was an important influence on mitigation action. We use these and other results from our effort to discuss updated considerations for determining social vulnerability to wildfire and articulate alternative means to collect such information. PMID- 29505999 TI - Multiple flood vulnerability assessment approach based on fuzzy comprehensive evaluation method and coordinated development degree model. AB - Flood is a serious challenge that increasingly affects the residents as well as policymakers. Flood vulnerability assessment is becoming gradually relevant in the world. The purpose of this study is to develop an approach to reveal the relationship between exposure, sensitivity and adaptive capacity for better flood vulnerability assessment, based on the fuzzy comprehensive evaluation method (FCEM) and coordinated development degree model (CDDM). The approach is organized into three parts: establishment of index system, assessment of exposure, sensitivity and adaptive capacity, and multiple flood vulnerability assessment. Hydrodynamic model and statistical data are employed for the establishment of index system; FCEM is used to evaluate exposure, sensitivity and adaptive capacity; and CDDM is applied to express the relationship of the three components of vulnerability. Six multiple flood vulnerability types and four levels are proposed to assess flood vulnerability from multiple perspectives. Then the approach is applied to assess the spatiality of flood vulnerability in Hainan's eastern area, China. Based on the results of multiple flood vulnerability, a decision-making process for rational allocation of limited resources is proposed and applied to the study area. The study shows that multiple flood vulnerability assessment can evaluate vulnerability more completely, and help decision makers learn more information about making decisions in a more comprehensive way. In summary, this study provides a new way for flood vulnerability assessment and disaster prevention decision. PMID- 29506000 TI - Differential transcriptome modulation leads to variation in arsenic stress response in Arabidopsis thaliana accessions. AB - Arsenic (As) is a ubiquitous metalloid and a health hazard to millions of people worldwide. The presence of As in groundwater poses a threat as it not only affects crop productivity but also contaminates food chain. Therefore, it is essential to understand molecular mechanisms underlying uptake, transport and accumulation of As in plants. In recent past, natural variation in Arabidopsis thaliana has been utilized to understand molecular and genetic adaptation under different stresses. In this study, responses of Arabidopsis accessions were analyzed at biochemical and molecular levels towards arsenate [As(V)] stress. On the basis of reduction in root length, accessions were categorized into tolerant and sensitive ones towards As(V). Root length analysis led to the identification of Col-0 (<10% reduction) and Slavi-1 (>60% reduction) as the most tolerant and sensitive accessions, respectively. Comparative genome-wide expression analysis revealed differential expression of 168 and 548 genes in Col-0 and Slavi-1, respectively, with 120 common differentially expressed genes. A number of genes associated with defense and stress-response, transport system, regulatory mechanisms and biochemical processes showed differential expression in contrasting accessions. The study provides an insight into the molecular mechanisms associated with stress response and processes involved in adaptation strategies towards As stress. PMID- 29506001 TI - A novel ion-exchange strategy for the fabrication of high strong BiOI/BiOBr heterostructure film coated metal wire mesh with tunable visible-light-driven photocatalytic reactivity. AB - Visible-light-driven (VLD) BiOI/BiOBr heterostructure films with hierarchical microstructure have been firstly fabricated on 304 stainless steel wire mesh (304SSWM) substrates through a novel ion-exchange method using the BiOI film as precursor. The concentration of tetrabutylammonium bromide (TBAB) is the key factor to control the composition and microstructure of BiOI/BiOBr films. Physical, chemical, and optical properties of BiOI/BiOBr heterostructure films were characterized by X-ray diffraction, scanning electron microscope, energy dispersive X-ray spectroscopy, high resolution transmittance electron microscopy, X-ray photoelectron spectroscopy, UV-vis diffuse reflectance absorption, and fluorescence spectrophotometer, respectively. The VLD photocatalytic ability of the BiOI/BiOBr heterostructure film coated 304SSWM was studied by degrading rhodamine B and pIRES2-EGFP plasmid as target water organic pollutants and pathogenic bacteria genetic materials. The BiOI/BiOBr heterostructure film coated 304SSWM fabricated with 50 mM TBAB has excellent photocatalytic activity, stability, and reusability in the cycled experiments. The reasons for these unique features can be ascribed to the formation of heterojuction structure and the open framework structure of the 304SSWM. The current work can provide new strategies to construct novel VLD photoactive functional films for water purification and disinfection. PMID- 29506002 TI - Toxicity of contaminants of emerging concern to Dugesia japonica: QSTR modeling and toxicity relationship with Daphnia magna. AB - Freshwater planarian Dugesia japonica has a critical ecological importance owing to its unique properties. This study presents for the first time an in silico approach to determine a priori the acute toxicity of contaminants of emerging concern towards D. japonica. Quantitative structure-toxicity/toxicity-toxicity relationship (QSTR/QTTR) models provided here allow producing reliable information using the existing data, thus, reducing the demand of in vivo and in vitro experiments, and contributing to the need for a more holistic approach to environmental safety assessment. Both models are promising for being notably simple and robust, meeting rigorous validation metrics and the OECD criteria. The QTTR model based on the available Daphnia magna data might also contribute to the US EPA Interspecies Correlation Estimation web application. Moreover, the proposed models were applied on hundreds of environmentally significant chemicals lacking experimental D. japonica toxicity data and predicted toxicity values were reported for the first time. The models presented here can be used as potential tools in toxicity assessment, screening and prioritization of chemicals and development of risk management measures in a scientific and regulatory frame. PMID- 29506003 TI - Washable antimicrobial polyester/aluminum air filter with a high capture efficiency and low pressure drop. AB - Here, we introduce a reusable bifunctional polyester/aluminum (PET/Al) air filter for the high efficiency simultaneous capture and inactivation of airborne microorganisms. Both bacteria of Escherichia coli and Staphylococcus epidermidis were collected on the PET/Al filter with a high efficiency rate (~99.99%) via the electrostatic interactions between the charged bacteria and fibers without sacrificing pressure drop. The PET/Al filter experienced a pressure drop approximately 10 times lower per thickness compared with a commercial high efficiency particulate air filter. As the Al nanograins grew on the fibers, the antimicrobial activity against airborne E. coli and S. epidermidis improved to ~94.8% and ~96.9%, respectively, due to the reinforced hydrophobicity and surface roughness of the filter. Moreover, the capture and antimicrobial performances were stably maintained during a cyclic washing test of the PET/Al filter, indicative of its reusability. The PET/Al filter shows great potential for use in energy-efficient bioaerosol control systems suitable for indoor environments. PMID- 29506004 TI - Cryptosporidium occultus sp. n. (Apicomplexa: Cryptosporidiidae) in rats. AB - Cryptosporidium parvum VF383 has been reported in humans, domesticated ruminants, and wild rats worldwide and described under several names including Cryptosporidium suis-like, based on its close phylogenetic relationship to C. suis. Unlike C. suis, however, it has never been detected in pigs. In the present work, C. parvum VF383 originating from wild brown rats was not infectious for piglets or calves but was infectious for laboratory brown rats, BALB/c mice, and Mongolian gerbils. The prepatent period was 4-5 days for all rodents. The patent period was longer for rats (>30 days) than other rodents (<20 days). None of the rodents developed clinical signs of infection. In all rodents, life cycle stages were detected in the colon by histology and electron microscopy. Oocysts were morphometrically similar to those of C. parvum and smaller than those of C. suis, measuring 5.20 * 4.94 MUm. Phylogenetic analyses of 18S rRNA, actin, and HSP70 gene sequences revealed C. parvum VF383 to be genetically distinct from, C. suis, and other described species of Cryptosporidium. Morphological, genetic, and biological data support the establishment of C. parvum VF383 as a new species, and we propose the name Cryptosporidium occultus sp. n. PMID- 29506005 TI - Simultaneous determination of columbianetin-beta-d-glucopyranoside and columbianetin in a biological sample by high-performance liquid chromatography with fluorescence detection and identification of other columbianetin-beta-d glucopyranoside metabolites by ultra high-performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry. AB - Columbianetin-beta-d-glucopyranoside (CBG) and its metabolite columbianetin (CBN) are the bioactive constituents of Angelicae pubescentis radix (APR). They exhibit the anti-platelet aggregation, anti-inflammatory and analgesic properties. The absorption, distribution, metabolism and excretion (ADME) of CBG has not been reported to date. Both high-performance liquid chromatography with fluorescence detection and ultra high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry methods were developed and validated for the study of ADME of CBG. It was found that CBG could be catabolized into its active metabolite CBN in vivo. The absolute bioavailability of columbianetin-beta d-glucopyranoside was 5.63 +/- 4.42%. The other co-existing constituents from the APR ethanol extract could enhance the absorption of CBG. CBG and CBN were rapidly and broadly distributed in the stomach, ovary, kidney, liver, spleen, lung, muscles, heart and brain. Higher levels of accumulation of CBG and CBN were detected in the ovary and kidney tissues. Eight metabolites of CBG were tentatively identified in blood, urine, bile and faeces of rats after oral administration of pure CBG. It was also found that CBG and CBN were mainly excreted through the faecal route. It can be concluded that the validated methods were successfully applied for absorption, distribution, metabolism and excretion study of CBG. PMID- 29506006 TI - Acetylcholinesterase affinity-based screening assay on Lippia gracilis Schauer extracts. AB - The use of affinity-based protein assay produced by covalently linking acetylcholinesterase to magnetic beads, followed by chemical characterization of the selective binders using Liquid Chromatography with tandem High-Resolution Mass Spectrometry (LC-HRMS) is herein described for profiling crude aqueous natural product extracts. The fishing assay was first modulated using galanthamine as a reference ligand and then, the assay condition was adjusted for the aqueous leaves extracts obtained from Lippia gracilis Schauer (genotype 201) that was used as the natural combinatory library. From the experiments, a selective binder has been undisclosed with an accurate mass of 449.1131 m/z and identified as eriodictyol 2'-O-glucoside or eriodictyol 3'-O-glucoside. The selectivity of the binding assay was demonstrated, as much as, that erydictiol 7 O-glucoside was not fished, although it was present in the crude aqueous extract. The binding assay platform exhibited high specificity and did not require any sample pretreatment, making it appropriate for profiling binders at natural libraries. PMID- 29506007 TI - Surface electromyography can quantify temporal and spatial patterns of activation of intrinsic human foot muscles. AB - Intrinsic foot muscles (IFM) are a crucial component within the human foot. Investigating their functioning can help understand healthy and pathological behaviour of foot and ankle, fundamental for everyday activities. Recording muscle activation from IFM has been attempted with invasive techniques, mainly investigating single muscles. Here we present a novel methodology, to investigate the feasibility of recording physiological surface EMG (sEMG) non-invasively and quantify patterns of activation across the whole plantar region of the foot. sEMG were recorded with a 13 * 5 array from the sole of the foot (n = 25) during two foot stance, two-foot tiptoe and anterior/posterior sways. Physiological features of sEMG were analysed. During anterior/posterior epochs within the sway task, sEMG patterns were analysed in terms of signal amplitude (intensity) and structure (Sample Entropy) distribution, by evaluating the centre of gravity (CoG) of each topographical map. Results suggest signals are physiological and not affected by loading. Both amplitude and sample entropy CoG coordinates were grouped in one region and overlapped, suggesting that the region with highest amplitude corresponds with the most predictable signal. Therefore, both spatial and temporal features of IFM activation may be recorded non-invasively, providing opportunity for more detailed investigation of IFM function in healthy and patient populations. PMID- 29506008 TI - A Commentary on Caries Detection, Validity, Reliability, and Outcomes of Care. PMID- 29506009 TI - Evaluation of Prolidase Activity, Oxidative Stress, and Antioxidant Enzyme Levels in Testicular and Penile Tissues after Human Chorionic Gonadotropin Treatment in Rats by Predicting Infertility and Erectile Dysfunction. AB - OBJECTIVES: Prolidase plays a vital role in collagen turnover, matrix remodeling, and cell growth. We aimed to evaluate the association between treatment with chorionic gonadotropin and infertility and erectile dysfunction by investigating tissue prolidase activity, oxidative stress, and levels of antioxidant enzymes. MATERIALS AND METHODS: The 16 male Wistar albino rats used in this study were randomly divided into 2 groups: rats treated with human chorionic gonadotropin (hCG) and control rats (n = 8 in each group). The rats in the hCG group were subcutaneously injected with 50 IU hCG daily for 15 days, while the rats in the control group were subcutaneously injected isotonic saline. All of the rats were sacrificed by a lethal overdose of sodium pentobarbital at the first month after hCG administration. Prolidase activity and levels of malonyl aldehyde, glutathione reductase, superoxide dismutase (SOD), glutathione peroxidase (GSH Px), and catalase (CAT) were estimated in the testicular and penile tissue. The testicles and penis were transversely dissected and placed in formalin. RESULTS: Levels of prolidase and malonyl aldehyde in the testicular and penile tissues were significantly higher in the hCG group than in the control group (p < 0.001), while levels of glutathione reductase, SOD, GSH-Px, and CAT were significantly lower in the hCG group than in the control group (p < 0.001). CONCLUSIONS: In this study, we observed that treatment with hCG increased prolidase activity and oxidative stress and decreased the antioxidant capacity of penile and testicular tissues; therefore, this may affect fertility and erectile function. PMID- 29506010 TI - Nyvad Criteria for Caries Lesion Activity and Severity Assessment: A Validated Approach for Clinical Management and Research. AB - The Nyvad classification is a visual-tactile caries classification system devised to enable the detection of the activity and severity of caries lesions with special focus on low-caries populations. The criteria behind the classification reflect the entire continuum of caries, ranging from clinically sound surfaces through noncavitated and microcavitated caries lesions in enamel, to frank cavitation into the dentin. Lesion activity at each severity stage is discriminated by differences in surface topography and lesion texture. The reliability of the Nyvad criteria is high to excellent when used by trained examiners in the primary and permanent dentitions. The Nyvad criteria have construct validity for lesion activity assessments because of their ability to reflect the well-known caries-controlling effect of fluoride. Predictive validity was demonstrated by showing that active noncavitated lesions are at higher risk of progressing to a cavity or filled state than do inactive noncavitated lesions. Lesion activity assessment performed successfully as a screening tool to identify individuals with a poor caries prognosis. Because of their predictive validity, the Nyvad criteria are superior to other current caries lesion descriptors for the detection of changes in the lesion activity status over time. The Nyvad criteria fulfill all the formal requirements for a robust caries lesion classification and are recommended for evidence-based caries management in clinical practice and in research. PMID- 29506011 TI - Drug Resistance-Associated Mutations in Antiretroviral Treatment-Experienced Patients in Kuwait. AB - OBJECTIVES: To investigate the prevalence of nonpolymorphic resistance-associated mutations (RAM) in HIV-1 patients on first-line antiretroviral therapy in Kuwait. SUBJECTS AND METHODS: Total RNA was isolated from plasma samples of 42 patients who received a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI) based regimen. HIV-1 protease and reverse transcriptase genetic regions were then amplified by nested reverse transcription-polymerase chain reaction and directly sequenced. The HIV-1 subtype was identified using the Bayesian phylogenetic method, and RAM were identified using the Stanford University genotypic resistance interpretation algorithm. RESULTS: The HIV-1 viral load at sampling ranged from < 20 to 8.25 * 104 copies/ml. CRF01_AE, C, and B were the most predominant HIV-1 subtypes. Nonpolymorphic mutations associated with resistance to antiretroviral drugs were detected in 11 (26.2%) of the 42 patients; 5 (11.9%) patients had mutations associated with a high-level resistance to nucleoside reverse transcriptase inhibitors (NRTI), 4 (9.5%) patients had mutations associated with resistance to NNRTI, 1 (2.4%) patient had mutations associated with resistance to both NRTI and NNRTI, and 1 (2.4%) patient had mutations potentially associated with low-level resistance to both protease inhibitors and NNRTI. All patients with RAM had a detectable plasma HIV-1 RNA level. CONCLUSION: Our results indicate the development of RAM during an NNRTI-based regimen and highlight the importance of considering other regimens to avoid treatment failure. PMID- 29506012 TI - Clinical Diagnosis of Dental Caries in the 21st Century: Introductory Paper - ORCA Saturday Afternoon Symposium, 2016. AB - Classifications employed to measure dental caries should first of all reflect the dynamics of the disease, in order to provide a solid basis for subsequent treatment decisions and for further monitoring of dental health of individual patients and populations. The contemporary philosophy of dental caries management implies that nonoperative treatment of caries lesions should be implemented whenever possible, limiting operative interventions to the severe and irreversible cases. The ORCA Saturday Afternoon Symposium 2016, held back-to-back to the 63rd ORCA Congress in Athens, Greece, was intended to provide an update on general requirements for clinical caries diagnosis and to overview caries diagnostic classifications including their rationale, validation, advantages, and limitations. Clinical caries diagnostic criteria and caries management outcomes are interrelated, and any diagnostic classification disregarding this concept is outdated, according to the current understanding of oral health care. Choosing clinical caries diagnostic classifications that assess the activity status of detected lesions should be a priority for dental professionals since these classifications favor the best clinical practice directed towards nonoperative interventions. The choice of clinical caries diagnostic classifications in research, in clinical practice, and in public health services should be guided by the best available scientific evidence. The clinical caries diagnostic classifications should be universally applicable in all these fields. Policy making in oral health care and the underlying policy analyses should follow the same standards. Any clinical caries diagnostic classification disregarding the universality of its use is of limited or no interest in the context of the clinical caries diagnosis of today. PMID- 29506013 TI - Influence of Sleep Stage on LH Pulse Initiation in the Normal Late Follicular Phase and in Polycystic Ovary Syndrome. AB - OBJECTIVE: During the early follicular phase, sleep-related luteinizing hormone (LH) pulse initiation is positively associated with brief awakenings but negatively associated with rapid eye movement (REM) sleep. The relationship between sleep architecture and LH pulse initiation has not been assessed in other cycle stages or in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: We performed concomitant frequent blood sampling (LH pulse analysis) and polysomnography on 8 normal women (cycle day 7-11) and 7 women with PCOS (at least cycle day 7). RESULTS: In the normal women, the 5 min preceding LH pulses contained more wake epochs and fewer REM epochs than the 5 min preceding randomly determined time points (wake: 22.3 vs. 9.1%, p = 0.0111; REM: 4.4 vs. 18.8%, p = 0.0162). However, LH pulse initiation was not related to wake or REM epochs in PCOS; instead, the 5 min preceding LH pulses contained more slow-wave sleep (SWS) than the 5 min before random time points (20.9 vs. 6.7%, p = 0.0089). Compared to the normal subjects, the women with PCOS exhibited a higher REM-associated LH pulse frequency (p = 0.0443) and a lower proportion of wake epochs 0-5 min before LH pulses (p = 0.0205). CONCLUSIONS: Sleep-related inhibition of LH pulse generation during the later follicular phase is normally weakened by brief awakenings and strengthened by REM sleep. In women with PCOS, LH pulse initiation is not appropriately discouraged by REM sleep and may be encouraged by SWS; these abnormalities may contribute to a high sleep-related LH pulse frequency in PCOS. PMID- 29506015 TI - NG2-Glia, a New Player in Energy Balance. AB - There is increasing evidence that glia act not only as neuronal support cells, but that they can also influence physiological outcomes via effects on neural signalling. The role of NG2-glia in this regard is especially enigmatic, as they are known to interact with neural circuits but their precise functions other than as oligodendrocyte progenitor cells remain elusive. Here, we summarise recent evidence suggesting that NG2-glia play a role in the maintenance of energy homeostasis, most notably via the support of leptin-sensing neural circuits. We also discuss the potential clinical implication of these findings specifically in the context of cranial radiation therapy. PMID- 29506014 TI - Effect of Milking Maneuver in Preterm Infants: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the short and medium-term effects of milking maneuver (MM) compared with early cord clamping for infants born before 37 weeks of pregnancy. MATERIAL AND METHODS: 138 infants between 24+0 and 36+6 weeks of gestation were allocated to MM or early cord clamping. Primary outcomes were the requirement of red blood cell transfusions or phototherapy. RESULTS: Initial hemoglobin was significantly higher in the MM group by 1.675 g/dL (p < 0.05) and initial hematocrit by 5.36% (p < 0.05), but no differences in the need of transfusion during the first 30 days after delivery were found (RR 0.8; 95% CI 0.22-2.85). Peak serum bilirubin was similar in both groups (11,097 +/- 3.21 vs. 11,247 +/- 3.56 mg/dL, p = 0.837). Phototherapy requirements were higher in the MM group (RR 1.62; 95% CI 1.1-2.38). No differences regarding the need of oral iron supplementation, platelet transfusion, respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, meconium aspiration syndrome, use of surfactant, days of oxygen supplementation, need of vasopressors, length of stay in the neonatal intensive care unit, or postpartum hemorrhage were found. CONCLUSION: MM does not reduce the need for red blood cell transfusions and increases phototherapy requirements in preterm infants. PMID- 29506016 TI - Validation of Oral Health Impact Profile-14 and its association with Hypossialia in a Sjogren Syndrome Portuguese Population. AB - AIMS: The objective of this study was to perform the Portuguese transcultural adaptation of the original Brazilian version of the Oral Health Impact Profile-14 (OHIP-14) while evaluating the association between hyposalivation and quality of life in a Sjogren's Syndrome population. METHODS: The original Brazilian version of the Oral Health Impact Profile-14 was culturally adapted following the guidelines for cross-cultural adaptation of health-related quality of life measures. The questionnaires were administered by trained and calibrated dental doctors to 86 patients with Sjogren's Syndrome. Oral Health Impact Profile-14 properties were examined including reliability, internal consistency and test retest reliability, using Cronbach's alpha, total and inter-item correlation, and intra-class correlation coefficients, respectively. Whole saliva secretion rates and hyposalivation-related variables were collected and statistically analyzed. Spearman's rho correlations were obtained between salivary flows and OHIP -14 domains and total score. Alpha was set at 0.05. Informed consents and local ethical committee clearance were obtained. RESULTS: Each question of the questionnaire performed adequately. Cronbach alpha values for the 14 questions were 0.89 for both test administrations and were lower if item removed. Scores for both questionnaire administration and ICC results presented good to excellent reliability with ICC ranging from 84% to 92%. Mean salivary flow rate was 0.05 (SD: 0.03) ml/min and mean stimulated salivary flow was 0.57 (SD: 0.44) ml/min, which are within expected values in a population with hyposalivation. The results describe a negative and significant correlation between total OHIP-14-PT score, physical pain, physical disability domain and stimulated and differential salivary flows. There was a negative and significant correlation between unstimulated salivary flow with physical pain. CONCLUSION: Within the limitations of this study, the OHIP-14-PT seems to be a valid and reliable instrument for measuring oral health related quality of life in patients with Sjogren's Syndrome. Both differential and stimulated salivary flows seem to correlate negatively with age and the quality of life is significantly diminished by lower stimulated salivary flow rates. PMID- 29506018 TI - Corrigendum. PMID- 29506017 TI - Effectiveness of a Referral Program for rheumatoid arthritis and axial spondyloarthritis Diagnosis at Primary Care Centers in Portugal - SIARA STUDY. AB - OBJECTIVES: Early diagnosis and treatment of Rheumatoid Arthritis (RA) and axial Spondylarthritis (axial SpA) can limit the impact of disease outcomes. This study evaluated the effectiveness of a referral program on the identification of patients with RA and axial SpA. METHODS: This was an observational, prospective, randomized (by clusters) study conducted in Portugal to evaluate the impact of the implementation of a set of referral support actions (RSA). The study was divided in two sub-studies, the RA sub-study and the axial SpA sub-study. 28 participating primary care units were randomly (by clusters) assigned to RSA or control group (with no intervention). Both RSA and control groups identified and referred patients with suspected RA or axial SpA to the rheumatology unit of the reference hospital. The primary objective was to evaluate the correct diagnosis of RA or axial SpA cases confirmed by the rheumatologist of the reference hospital. RESULTS: RA-Substudy: A total of 340 patients were recruited (144 in the RSA-exposed group; 196 in the control). RA diagnosis confirmation was 7.3% (95%CI, 2.1-12.5%) in RSA group versus 2.7% (95%CI, 0.0-5.7%) in control group RSA effect was positive but moderate (4.6%) and not statistically significant (95% CI, 0.0%-11.8%; p=0.222, adjusted for clustering effect). Rate of confirmed arthritis of any type was 16.9% (n=14/83) in the RSA group and 6.0% (n=5/83) in the control group. This difference was statistically significant and favorable to RSA group (OR=3.2; 95% CI 1.1-9.2; p=0.028). Axial SpA-Substudy: A total of 231 patients were recruited (108 in the RSA-exposed group; 123 in the control). Axial SpA diagnosis confirmation was 8.7% (95% CI, 2.1-15.4%) in RSA group versus 5.6% (95% CI, 0.0-11.73%) in control group. RSA effect was positive (3.1%) but not statistically significant (95% CI, -7.5- 12.9%; p=0.568, adjusted for clustering effect). CONCLUSIONS: This study showed a positive tendency for the RSA program, most relevantly on the diagnosis of patients with any type of arthritis in the RA sub-study. It is possible that a referral program more comprehensive than the one herein tested might improve early diagnosis of RA and SpA. PMID- 29506019 TI - Parallelization of MAFFT for large-scale multiple sequence alignments. AB - Summary: We report an update for the MAFFT multiple sequence alignment program to enable parallel calculation of large numbers of sequences. The G-INS-1 option of MAFFT was recently reported to have higher accuracy than other methods for large data, but this method has been impractical for most large-scale analyses, due to the requirement of large computational resources. We introduce a scalable variant, G-large-INS-1, which has equivalent accuracy to G-INS-1 and is applicable to 50 000 or more sequences. Availability and implementation: This feature is available in MAFFT versions 7.355 or later at https://mafft.cbrc.jp/alignment/software/mpi.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29506020 TI - MIRA: an R package for DNA methylation-based inference of regulatory activity. AB - Summary: DNA methylation contains information about the regulatory state of the cell. MIRA aggregates genome-scale DNA methylation data into a DNA methylation profile for a given region set with shared biological annotation. Using this profile, MIRA infers and scores the collective regulatory activity for the region set. MIRA facilitates regulatory analysis in situations where classical regulatory assays would be difficult and allows public sources of region sets to be leveraged for novel insight into the regulatory state of DNA methylation datasets. Availability and implementation: http://bioconductor.org/packages/MIRA. PMID- 29506021 TI - Updating the 97% identity threshold for 16S ribosomal RNA OTUs. AB - Motivation: The 16S ribosomal RNA (rRNA) gene is widely used to survey microbial communities. Sequences are often clustered into Operational Taxonomic Units (OTUs) as proxies for species. The canonical clustering threshold is 97% identity, which was proposed in 1994 when few 16S rRNA sequences were available, motivating a reassessment on current data. Results: Using a large set of high quality 16S rRNA sequences from finished genomes, I assessed the correspondence of OTUs to species for five representative clustering algorithms using four accuracy metrics. All algorithms had comparable accuracy when tuned to a given metric. Optimal identity thresholds were ~99% for full-length sequences and ~100% for the V4 hypervariable region. Availability and implementation: Reference sequences and source code are provided in the Supplementary Material. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29506022 TI - Movement is medicine: the Scandinavian way. PMID- 29506023 TI - Prognostic relevance of mitral and tricuspid regurgitation in patients with severe aortic stenosis. AB - Aims: Although concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) are frequently present in patients with aortic stenosis (AS), outcome data are scarce and treatment strategies are controversial. The aim of the present study was to assess the presentation and outcome of patients with AS and coexisting MR and TR. Methods and results: Eighty-nine consecutive patients with severe AS and at least moderate MR (72 functional and 17 degenerative) were included and followed. Seventy-five patients were symptomatic at presentation. Sixty of these had severe symptoms (New York Heart Association class >=3). Nine additional patients had an indication for valve procedures during follow-up. However, 35 patients were managed conservatively. Isolated aortic valve intervention was performed in 29 patients (22 valve replacement and 7 transcatheter aortic valve replacement) and concomitant mitral valve surgery in 20 patients. For the assessment of outcome, overall survival (i.e. time from study entry to death from any cause) was assessed: adjusted survival was significantly higher for patients undergoing any valve procedure as compared with patients managed conservatively (P = 0.032). Surgical treatment of severe concomitant MR was associated with improved survival in an unadjusted population but did not reach statistical significance after propensity adjustment. 14 of 36 patients who had concomittant moderate-to-severe tricuspid regurgitation (TR) underwent surgery of which 7 (50 %) died within 3 months postoperatively. On the other hand, only 1 of 35 (3%) with no or mild TR undergoing surgery died within 3 months post-operatively (P < 0.001). Conclusion: Presence of MR in patients with severe AS characterizes a high-risk population. Timely aortic valve intervention confers a survival benefit and concomitant mitral valve surgery should be considered according to operative risk. The additional presence of significant TR is associated with dismal outcomes, regardless of the treatment strategy. PMID- 29506024 TI - Effect of the proximal anastomosis site on mid-term radial artery patency in off pump coronary artery bypass. AB - OBJECTIVES: The purpose of this study was to evaluate mid-term patency and clinical outcomes according to the proximal anastomosis site after off-pump coronary artery bypass using the radial artery (RA). METHODS: From January 2001 to December 2015, 1124 patients who underwent isolated off-pump coronary artery bypass using the RA were reviewed and divided into 2 groups: the composite Y graft (n = 1014, Y group) and aortocoronary graft (n = 110, Aorta group). Graft patency was assessed by computed tomography or coronary angiography. RESULTS: Patients receiving Y-grafts had a greater number of RA anastomoses (1.79 +/- 0.68 per patient vs 1.40 +/- 0.51 per patient, P < 0.001), more sequential grafts (55.6% vs 37.3%, P < 0.001) and a higher incidence of total arterial revascularization (77.9% vs 54.5%, P < 0.001). Postoperative graft patency at a mean of 3.1 +/- 3.5 years was assessed in 1944 distal RA anastomoses (Y group: 1811, Aorta group: 133). No significant differences were observed in RA graft patency rate (P = 0.705), overall survival (P = 0.987) and major cardiac event free survival (P = 0.830) between groups. Multivariable analysis demonstrated that the independent predictors of graft occlusion were age [hazard ratio (HR) 1.025, confidence interval (CI) 1.007-1.044; P = 0.007], female gender (HR 1.391, CI 1.007-1.924; P = 0.047), target of the right coronary artery territory (HR 2.135, CI 1.347-3.382; P = 0.001) and target vessel stenosis >=90% (HR 0.478, CI 0.291-0.785; P = 0.004). The proximal anastomosis site was not significantly associated with graft occlusion (P = 0.705). CONCLUSIONS: When target vessel territory and stenosis are appropriately considered, the RA as a secondary conduit can be effectively used for myocardial revascularization, regardless of the proximal anastomosis site. PMID- 29506025 TI - The therapeutic 'make-over' of dementias-an introduction. AB - The online themed collection of 15 papers recently published provides an update on the advances of pharmacological and non-pharmacological interventions in dementia over the last 15 years. The published studies reflect the efficacy of the current anti-dementia treatments, preventive treatments of cardio and cerebrovascular incidents (known to be risk factors for dementia), alongside the use of antidepressant medication and non-pharmacological interventions for treatment of behavioural and psychopathological symptoms of dementia. We also address the future preventative steps and therapeutic strategies currently in development to combat the devastating consequences of dementia. PMID- 29506026 TI - Comparing Data from the Poisons Information Centre with Employers' Accident Reports Reveal Under-Recognized Hazards at the Workplace. AB - Records of injuries and incidents provide an important basis for injury prevention related to hazardous substances at the workplace. The present study aimed to review available data on injuries and incidents involving hazardous substances and investigate how data from the Poisons Information Centre could complement the records of the Swedish Work Environment Authority. We found two major obstacles for using injury/incident data based on employers' mandatory reporting. First, it was not possible to quickly and reliably identify injuries caused by hazardous substances, and second, data identifying substances or products are not systematically included. For two out of five investigated injuries with lost working days likely due to chemical injuries, we could not identify substances and/or products involved. The records based on calls to the Poisons Information Centre allow better understanding of chemical hazards and products. Besides the large share of unidentified chemical hazards in the injury statistics, the most striking difference was found for cleaning agents. Cleaning agents were implicated in one-third of the occupational cases that the consulting Poisons Information Centre expert judged to pose a major risk and in need of immediate healthcare. Only one in 10 injuries with lost days reported by employers was related to this type of product. The identification of exposures and symptoms by the Poisons Information Centre allow recognition of chemicals with problematic occupational uses. Hence, these records may serve as an important complement to official injury statistics related to incidents with hazardous substances at work. PMID- 29506027 TI - Cell-type-specific disturbance of DNA methylation pattern: a chance to get more benefit from and to minimize cohorts for epigenome-wide association studies. AB - Background: Both genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) are aiming to discover molecular signs for diseases, which possibly can be helpful for future therapeutic intervention strategies. The most prominently used tissue in association studies on humans is venous blood. In contrast to the unchangeable genotype, epigenetic DNA methylation is more variable. Methylation is affected not only by a subject's constitution such as age, gender, ethnicity, genotype, lifestyle and health status, but is also determined by tissue-specific cell types. Methods: PubMed, published before 2017, was researched, documenting the importance of epigenetic analyses on single cell types instead of whole blood in EWAS. Results: Initial studies documented that stressor-induced, mostly marginal, DNA methylation changes in whole-blood samples (< 5% methylation difference) may rely not on uniform distribution of that methylation shift among each blood cell type, but on strongly altered methylation (> 20%) in single cell types. The effect size in single cell types enables the performance of epigenome-wide studies on replicated smaller cohorts, in contrast to the requirement of larger international consortium-based approaches. Conclusions: Therefore, the identification of a specific cell type that is responsible for association between DNA methylation in whole blood with the phenotype of interest, has to be a prioritized experimental approach in association studies. This is a key prerequisite for constructive interpretation of epigenetic signs in the context of diverse biological function of the tissue blood, for detection of causality link between methylation and phenotype and for establishment of valuable clinical biomarkers and therapeutic targets. PMID- 29506028 TI - Cohort Profile: The China Hainan Centenarian Cohort Study (CHCCS). PMID- 29506029 TI - Hospitalization from the patient perspective: a data linkage study of adults in Australia. AB - Objective: Evidence of the patient experience of hospitalization is an essential component of health policy and service improvement but studies often lack a representative population sample or do not examine the influence of patient and hospital characteristics on experiences. We address these gaps by investigating the experiences of a large cohort of recently hospitalized patients aged 45 years and over in New South Wales (NSW), Australia who were identified using data linkage. Design: Cross-sectional survey. Setting: Hospitals in NSW, Australia. Participants: The Picker Patient Experience Survey (PPE-15) was administered to a random sample of 20 000 patients hospitalized between January and June 2014. Main outcome measure: Multivariable negative binomial regression was used to investigate factors associated with a higher PPE-15 score. Results: There was a 40% response rate (7661 completed surveys received). Respondents often reported a positive experience of being treated with dignity and respect, yet almost 40% wanted to be more involved in decisions about their care. Some respondents identified other problematic aspects of care such as receiving conflicting information from different care providers (18%) and feeling that doctors spoke in front of them as if they were not there (14%). Having an unplanned admission or having an adverse event were both very strongly associated with a poorer patient experience (P < 0.001). No other factors were found to be associated. Conclusions: Patient involvement in decision-making about care was highlighted as an important area for improvement. Further work is needed to address the challenges experienced by patients, carers and health professionals in achieving a genuine partnership model. PMID- 29506030 TI - Perioral Rejuvenation: A Prospective, Quantitative Dynamic Three-Dimensional Analysis of a Dual Modality Treatment. AB - Background: The perioral region is the most dynamic anatomic area of the face and subject to complex and dramatic changes during aging. Successful treatment for perioral rejuvenation has yet to be identified, and prior studies have reported only subjective outcomes. Objectives: The purpose of this study was to utilize our validated dynamic 3-dimensional imaging technology to determine whether conservative neuromodulation combined with hyaluronic acid filler volumization can decrease perioral strain and increase volume with significant patient satisfaction. Methods: An IRB-approved prospective study of a dual modality treatment for perioral rhytids was performed on females with perioral aging who had not had prior facial treatment within the past year. Eighteen (18) units of Dysport were injected into the upper and lower orbicularis oris and 1 cc of Restylane Silk was injected in volume-depleted perioral regions in each patient. Each patient underwent imaging with digital image correlation (DIC) and completed the FACE-Q survey prior to injection and at 14 days and 90 days postinjection. Results: Thirty-two female patients were recruited. A significant reduction in perioral strain was observed at both day 14 and day 90. This was concomitant with a significant increase in perioral volume at day 14 that at 90 days was significantly retained in the marionette lines. Further, there was a significant improvement in patient satisfaction with overall facial appearance at day 14 that was maintained at 90 days. Conclusions: Conservative neuromodulation and hyaluronic acid filler volumization of the perioral region produces a significant reduction in strain correlating with high patient satisfaction, even at 90 days. This dual modality treatment is effective in rejuvenating the perioral region, and its future optimization will provide greater therapeutic options for this anatomically complex area. Level of Evidence 4: PMID- 29506032 TI - Host Plant Selection by the Wheat Bug, Nysius huttoni (Hemiptera: Lygaeidae) on a Range of Potential Trap Plant Species. AB - The wheat bug, Nysius huttoni L. is an endemic New Zealand pest. The seedlings of forage brassicas are highly susceptible to direct feeding damage by this insect, and this can reduce plant establishment. Prophylactic use of pesticides is the usual practice for N. huttoni management. These practices have been linked to environmental pollution, biodiversity loss, and pollinator population declines in brassicas and other crops. Habitat management of the bug utilizing potential trap crops can be a better option for its management. A series of choice, no-choice, and paired-choice tests were conducted in a controlled-temperature room to evaluate the pest's preferences on seedlings of eight plant species. Kale plants (Brassica oleracea) were used as a potentially susceptible control, and seven non kale plants were compared with kale as potential trap-plant species. These were: Lobularia maritima (L.) Desvaux (alyssum), Triticum aestivum L. (wheat), Phacelia tanacetifolia Bentham (phacelia), Fagopyrum esculentum Moench (buckwheat), Coriandrum sativum L. (coriander), Trifolium repens L. (white clover), and Medicago sativa L. (lucerne). In choice tests, wheat was the most suitable followed by alyssum, buckwheat, and phacelia, all significantly more favored than kale. In no-choice tests, alyssum was significantly more favored than kale and the other plant species except wheat and phacelia. First feeding damage was recorded on alyssum in both the above test conditions. For paired-choice tests including kale, wheat, and alyssum were significantly more suitable than brassica. These findings are important for developing agro-ecological management strategies. Alyssum followed by wheat were the most suitable trap plants for N. huttoni. These two plant species can be deployed in and around brassica fields either independently or as in a multiple trap-cropping system to reduce bug damage, minimizing or avoiding pesticides, and delivering a range of ecosystem services. PMID- 29506033 TI - A Laboratory Curse: Variation in Temperature Stimulates Embryonic Development and Shortens Diapause. AB - An ongoing biological debate concerns the difference in trait expression in continuous versus cycling temperature regimes, but are even daily cycling temperatures sufficient to generate natural expression of traits? We compared embryonic development and the duration of diapause for Mormon cricket Anabrus simplex Haldeman (Orthoptera: Tettigoniidae) eggs incubated in a daily cycling temperature constant in both amplitude and thermoperiod with those in a cycling temperature that was patterned after natural fluctuations in ambient temperature. Although the proportion of eggs developing did not differ between treatments, 128 d of vernalization was required to hatch after incubation in the constant cycling treatment relative to 42 d in the more variable cycle. We then compared these same development and diapause traits for eggs incubated in a daily cycling temperature that was constant in amplitude but varied in thermoperiod with those in the cycling temperature patterned after natural fluctuations in ambient temperature. The proportion of eggs developing in this constant cycling treatment was nearly half that in the variable treatment, and 128 d was insufficient time to break diapause following the constant cycling treatment even though the thermoperiods were now more similar. We have found that variation in the cycling temperature to mimic natural fluctuations in amplitude and period broadens the time when eggs can be warmed up for hatching and improves hatching success. Daily cycling temperatures that are constant over the season are insufficient to generate natural trait expression. PMID- 29506031 TI - Cognition and dementia in older patients with epilepsy. AB - With advances in healthcare and an ageing population, the number of older adults with epilepsy is set to rise substantially across the world. In developed countries the highest incidence of epilepsy is already in people over 65 and, as life expectancy increases, individuals who developed epilepsy at a young age are also living longer. Recent findings show that older persons with epilepsy are more likely to suffer from cognitive dysfunction and that there might be an important bidirectional relationship between epilepsy and dementia. Thus some people with epilepsy may be at a higher risk of developing dementia, while individuals with some forms of dementia, particularly Alzheimer's disease and vascular dementia, are at significantly higher risk of developing epilepsy. Consistent with this emerging view, epidemiological findings reveal that people with epilepsy and individuals with Alzheimer's disease share common risk factors. Recent studies in Alzheimer's disease and late-onset epilepsy also suggest common pathological links mediated by underlying vascular changes and/or tau pathology. Meanwhile electrophysiological and neuroimaging investigations in epilepsy, Alzheimer's disease, and vascular dementia have focused interest on network level dysfunction, which might be important in mediating cognitive dysfunction across all three of these conditions. In this review we consider whether seizures promote dementia, whether dementia causes seizures, or if common underlying pathophysiological mechanisms cause both. We examine the evidence that cognitive impairment is associated with epilepsy in older people (aged over 65) and the prognosis for patients with epilepsy developing dementia, with a specific emphasis on common mechanisms that might underlie the cognitive deficits observed in epilepsy and Alzheimer's disease. Our analyses suggest that there is considerable intersection between epilepsy, Alzheimer's disease and cerebrovascular disease raising the possibility that better understanding of shared mechanisms in these conditions might help to ameliorate not just seizures, but also epileptogenesis and cognitive dysfunction. PMID- 29506034 TI - Safety and Effectiveness of Repeat Treatment With VYC-15L for Lip and Perioral Enhancement: Results From a Prospective Multicenter Study. AB - Background: VYC-15L (Juvederm Volbella XC) is a non-animal crosslinked hyaluronic acid (HA) gel with lidocaine. Objective: To evaluate safety and effectiveness of repeat treatment with VYC-15L administered 1 year after treatment for lip and perioral enhancement. Methods: In this prospective multicenter study, 124 subjects with minimal, mild, or moderate lip fullness on the validated 5-point Allergan Lip Fullness Scale (LFS) who received initial/touch-up treatment with VYC-15L received repeat treatment with VYC-15L 1 year after initial treatment. Effectiveness endpoints included LFS responder rates (>=1-point improvement from baseline) and scores on the FACE-Q Satisfaction With Lips and Appraisal of Lip Lines scales at 1 month after repeat treatment. Subjects completed safety diaries for 30 days after repeat treatment. Results: LFS responder rates were 86.2%, 80.3%, and 61.8% at months 1 and 3 and 1 year, respectively, after initial/touch up treatment. The responder rate improved to 94.3% 1 month after repeat treatment with VYC-15L and required less median volume vs initial/touchup treatment (1.5 vs 2.6 mL). FACE-Q scores doubled from baseline at 3 months, remained high through 1 year, and doubled from baseline after repeat treatment. At 1 month after repeat treatment, 96.7% and 89.3% of subjects showed improvement over baseline in FACE-Q Satisfaction With Lips and Appraisal of Lip Lines, respectively. Severe injection site responses were less frequent after repeat treatment than initial/touch-up treatment. Conclusion: Repeat treatment with VYC-15L at 1 year was safe and effective for lip and perioral enhancement, and required less product volume to achieve similar effectiveness to initial/touch-up treatment. PMID- 29506035 TI - Interaction Between Chrysocharis flacilla and Diglyphus isaea (Hymenoptera: Eulophidae), Two Parasitoids of Liriomyza Leafminers. AB - Agromyzid Liriomyza leafminer flies are a major threat to horticultural production in East Africa with low natural control reported. The endoparasitoid Chrysocharis flacilla (Walker; Hymenoptera: Eulophidae) was introduced from Peru into quarantine facilities at ICIPE in Kenya for a leafminer classical biological control program. Interaction assays with one of the dominant local parasitoids, Diglyphus isaea (Walker; Hymenoptera: Eulophidae), using Liriomyza huidobrensis (Blanchard; Diptera: Agromyzidae) was assessed through sole, simultaneous and sequential releases. C. flacilla resulted to superior host parasitism rates over D. isaea. When used separately, specific parasitism rates of D. isaea and C. flacilla were 26.33 +/- 2.07% and 60.27 +/- 2.53% respectively but, when simultaneously used, the total parasitism rose to 72.96 +/- 4.12%. Presence of C. flacilla after D. isaea reduced significantly parasitism rate of D. isaea. Both parasitoids caused separately and simultaneously additionally significant nonreproductive host mortalities of between 48.33 +/- 3.75% and 69.33 +/- 3.92 for D. isaea and C. flacilla respectively. Sex ratios of C. flacilla and D. isaea F1 progenies were female biased and were not affected by interspecific interactions. Implications of these results for subsequent combined use of C. flacilla and D. isaea against Liriomyza leafminers in East Africa are discussed. PMID- 29506036 TI - Rates and Patterns of Laboratory Adaptation in (Mostly) Insects. AB - Insects and other invertebrates can readily adapt to a range of environmental conditions and these include conditions used in artificial rearing. This can lead to problems when mass rearing insects and mites for release as biocontrol agents or in sterile insect control programs, and when using laboratory strains to understand field population dynamics. Laboratory adaptation experiments also help to understand potential rates of trait evolution and repeatability of evolutionary changes. Here, we review evidence for laboratory adaptation across invertebrates, contrasting different taxonomic groups and providing estimates of the rate of evolutionary change across trait classes. These estimates highlight rapid changes in the order of 0.033 (median) haldanes and up to 2.4 haldanes, along with proportional changes in traits of more than 10% per generation in some cases. Traits tended to change in the direction of increased fitness for Coleoptera, Diptera and Hymenoptera, but changes in Lepidoptera were often in the opposite direction. Laboratory-adapted lines tend to be more sensitive to stress, likely reflecting relaxed selection for stress-related traits. Morphological traits show smaller changes under laboratory conditions than other types of traits. Estimates of evolutionary rates slowed as more generations were included in comparisons, perhaps reflecting nonlinear dynamics although such patterns may also reflect variance differences among trait classes. The rapid rate of laboratory adaptation in some cultures reinforces the need to develop guidelines for maintaining quality during mass rearing and highlights the need for caution when using laboratory lines to represent the performance of species in vulnerability assessments. PMID- 29506037 TI - Body Mass Index, Falls, and Hip Fractures Among Nursing Home Residents. AB - Background: To examine the association between body mass index (BMI) and the risk for falls and hip fractures among nursing home (NH) residents. Methods: A cohort study of newly admitted NH residents, excluding those with a prior history of hip fracture. Using the Minimum Data Set 2.0 (2006-2010), we determined the occurrence of new falls and hip fractures among NH residents during their first 3 months of stay. Residents were categorized as underweight (BMI < 18.5), normal-to overweight (18.5 <= BMI < 30), mildly obese (30 <= BMI < 35), and moderately-to severely obese (BMI >= 35). Results: Among newly admitted NH residents over the first 3 months, 51.1% of underweight residents, 53.1% of normal-to-overweight residents, 49.1% of residents with mild obesity, and 43.1% of residents with moderate-to-severe obesity experienced a fall; 3.1% of underweight residents, 2.5% of normal-to-overweight residents, 1.5% of residents with mild obesity, and 1.1% of residents with moderate-to-severe obesity experienced a hip fracture. In comparison with normal-to-overweight residents, after adjustment for resident level and facility-level characteristics, mildly obese residents (odds ratio [OR] = 0.94, 95% confidence interval [CI] = [0.91-0.93]), and moderately-to-severely obese residents (OR = 0.84 [95% CI = 0.83-0.85]) were less likely to experience a fall; Mildly obese residents (OR = 0.65 [95% CI = 0.63-0.68]), and moderately-to severely obese residents (OR = 0.84 [95% CI = 0.83-0.85]) were less likely, and underweight residents were more likely (OR = 1.22 [95% CI = 1.18-1.26]) to experience a hip fracture. Conclusion: Obesity is associated with reduced risks for falls and hip fractures among newly admitted NH residents. Future studies are needed to explore possible explanations for these associations. PMID- 29506038 TI - Surgical left subclavian artery revascularization for thoracic aortic stent grafting: a single-centre experience in 101 patients. AB - OBJECTIVES: To evaluate the indications, perioperative strategy and postoperative outcome of surgical left subclavian artery (LSA) revascularization combined with thoracic endovascular aortic repair (TEVAR) covering the LSA. METHODS: Between 2000 and 2017, a total of 101 consecutive patients underwent surgical revascularization of the LSA prior to, concomitant or following TEVAR. Revascularization was performed through a small supraclavicular incision and consisted of a transposition or bypass graft, using intraoperative transcranial Doppler monitoring. Data regarding indication, procedural details and postoperative results were retrospectively analysed. RESULTS: In total, 63 subclavian-carotid bypass grafts and 38 subclavian-carotid transpositions were performed in the context of TEVAR. The majority was performed prior to stent grafting to reduce the risk of stroke (n = 50), spinal cord ischaemia (n = 20), left arm malperfusion (n = 10) or to preserve a patent left internal mammary artery coronary bypass graft (n = 2). Secondary revascularization was performed in 14 patients, 2 times immediately due to acute left arm malperfusion and 12 times to treat invalidating left arm claudication. No in-hospital mortality and permanent spinal cord ischaemia occurred. Two (2%) ischaemic strokes were observed in patients with concomitant procedures, and none when separate, staged procedures were performed. Additional complications observed were permanent peripheral nerve palsies (9%), chyle leakage requiring diet (6%) and 1 bypass occlusion requiring a redo procedure. CONCLUSIONS: In patients predominantly selected upon the anticipated risk of (posterior) stroke, spinal cord ischaemia and left arm malperfusion, surgical revascularization of the LSA proved to be a safe treatment option to preserve antegrade LSA flow in the context of TEVAR. PMID- 29506039 TI - Commentary on Piumatti et al. 2018. PMID- 29506040 TI - Factors Affecting Population Dynamics of Thrips Vectors of Soybean vein necrosis virus. AB - Thrips-infesting soybeans were considered of minor economic importance, but recent evidence of their ability to transmit a newly identified soybean virus, Soybean vein necrosis virus (SVNV), has raised their profile as pests. Season long surveys were conducted using suction traps to determine the effects of temperature and precipitation on the spatiotemporal patterns of three vector species of SVNV, Neohydatothrips variabilis (Beach) (Thysanoptera: Thripidae) (soybean thrips), Frankliniella tritici (Fitch) (Thysanoptera: Thripidae) (eastern flower thrips), and Frankliniella fusca (Hinds) (Thysanoptera: Thripidae) (tobacco thrips) in soybean fields in Indiana in 2013 and 2014. In addition, soybean fields were surveyed for presence of SVNV in both years. We found that the magnitude and timing of thrips activity varied greatly for the three species. N. variabilis activity peaked in mid-August each year. The peak activity for F. tritici occurred between late-June, and a second peak in activity was observed in early-August, while F. fusca activity remained more or less the same with no peak. There was no gradient in thrips populations from southern to northern locations. This suggests that these insects are not migratory and may overwinter in soil or perennial noncrop host plants and other weed hosts in Indiana. The capture rates of N. variabilis and F. tritici were only related to temperature, and capture rates of F. fusca were not related to either variable. SVNV was first detected in mid-late August, which coincided with the peak of the primary vector, N. variabilis. The virus was not detected earlier in the season despite peaks in F. tritici activity. Our results may be used in weather-based models to predict both thrips dynamics as well as SVNV outbreaks. PMID- 29506041 TI - Medical research using governments' health claims databases: with or without patients' consent? AB - Taking advantage of its single-payer, universal insurance system, Taiwan has leveraged its exhaustive database of health claims data for research purposes. Researchers can apply to receive access to pseudonymized (coded) medical data about insured patients, notably their diagnoses, health status and treatments. In view of the strict safeguards implemented, the Taiwanese government considers that this research use does not require patients' consent (either in the form of an opt-in or in the form of an opt-out). A group of non-governmental organizations has challenged this view in the Taiwanese Courts, but to no avail. The present article reviews the arguments both against and in favor of patients' consent for re-use of their data in research. It concludes that offering patients an opt-out would be appropriate as it would best balance the important interests at issue. PMID- 29506043 TI - A national quality incentive scheme to reduce antibiotic overuse in hospitals: evaluation of perceptions and impact. AB - Background: In 2016/2017, a financially linked antibiotic prescribing quality improvement initiative Commissioning for Quality and Innovation (AMR-CQUIN) was introduced across acute hospitals in England. This aimed for >1% reductions in DDDs/1000 admissions of total antibiotics, piperacillin/tazobactam and carbapenems compared with 2013/2014 and improved review of empirical antibiotic prescriptions. Objectives: To assess perceptions of staff leading antimicrobial stewardship activity regarding the AMR-CQUIN, the investments made by hospitals to achieve it and how these related to achieving reductions in antibiotic use. Methods: We invited antimicrobial stewardship leads at acute hospitals across England to complete a web-based survey. Antibiotic prescribing data were downloaded from the PHE Antimicrobial Resistance Local Indicators resource. Results: Responses were received from 116/155 (75%) acute hospitals. Owing to yearly increases in antibiotic use, most trusts needed to make >5% reductions in antibiotic consumption to achieve the AMR-CQUIN goal of 1% reduction. Additional funding was made available at 23/113 (20%) trusts and, in 18 (78%), this was <10% of the AMR-CQUIN value. Nationally, the annual trend for increased antibiotic use reversed in 2016/2017. In 2014/2015, year-on-year changes were +3.7% (IQR -0.8%, +8.4%), +9.4% (+0.2%, +19.5%) and +5.8% (-6.2%, +18.2%) for total antibiotics, piperacillin/tazobactam and carbapenems, respectively, and +0.1% (-5.4%, +4.0%), 4.8% (-16.9%, +3.2%) and -8.0% (-20.2%, +4.0%) in 2016/2017. Hospitals where staff believed they could reduce antibiotic use were more likely to do so (P < 0.001). Conclusions: Introducing the AMR-CQUIN was associated with a reduction in antibiotic use. For individual hospitals, achieving the AMR-CQUIN was associated with favourable perceptions of staff and not availability of funding. PMID- 29506044 TI - Echinocandin resistance among Candida isolates at an academic medical centre 2005 15: analysis of trends and outcomes. AB - Objectives: To identify the frequency of micafungin resistance among clinically significant isolates of Candida stored at our institution from 2005 to 2015. Chart review of patients with resistant isolates then informed the clinical setting and outcomes associated with these infections. Methods: Clinical Candida isolates had been stored at -80 degrees C in Brucella broth with 20% glycerol from 2005. Isolates were tested using broth microdilution to determine micafungin MICs. All Candida glabrata isolates and all isolates demonstrating decreased susceptibility to micafungin were screened for FKS mutations using a Luminex assay. Results: In total, 3876 Candida isolates were tested for micafungin resistance, including 832 C. glabrata isolates. Of those, 33 isolates from 31 patients were found to have either decreased susceptibility to micafungin and/or an FKS mutation. C. glabrata accounted for the majority of these isolates. While bloodstream infections were found to have a very high mortality rate, isolates from other sites were uncommonly associated with 30-day mortality. Overall resistance rates were very low. Conclusions: Echinocandin resistance in C. glabrata has been increasingly reported but rates at our institution remain very low. We hypothesize that a focus on antifungal stewardship may have led to these observations. Knowledge of local resistance patterns is key to appropriate empirical treatment strategies. PMID- 29506042 TI - GCN5 contributes to stem cuticular wax biosynthesis by histone acetylation of CER3 in Arabidopsis. AB - Cuticular wax is a major component of the surface cuticle of plants, which performs crucial functions in optimizing plant growth. Histone acetylation regulates gene expression in diverse biological processes, but its role in cuticular wax synthesis is not well understood. In this study, we observed that mutations of the Arabidopsis thaliana histone acetyltransferase GENERAL CONTROL NON-REPRESSED PROTEIN5 (GCN5) impaired the accumulation of stem cuticular wax. Three target genes of GCN5, ECERIFERUM3 (CER3), CER26, and CER1-LIKE1 (CER1-L1), were identified by RNA-seq and ChIP assays. H3K9/14 acetylation levels at the promoter regions of CER3, CER26, and CER1-L1 were consistently and significantly decreased in the gcn5-2 mutant as compared to the wild-type. Notably, overexpression of CER3 in the gcn5-2 mutant rescued the defect in stem cuticular wax biosynthesis. Collectively, these data demonstrate that GCN5 is involved in stem cuticular wax accumulation by modulating CER3 expression via H3K9/14 acetylation, which underlines the important role of histone acetylation in cuticular wax biosynthesis. PMID- 29506045 TI - Impact of Minimal Extra-Thyroid Extension in Differentiated Thyroid Cancer: Systematic Review and Meta-analysis. AB - Background: Minimal extra-thyroid extension (mETE) in differentiated thyroid cancer (DTC) patients was defined as an intermediate risk feature in the 2015 American Thyroid Association guidelines. However, controversy persists as several studies suggested mETE has little effect on disease outcome. Objective: To assess the impact of mETE on DTC patients' outcome. Methods: Meta-analysis of controlled trials comparing DTC patients with and without mETE. Data Extraction and Synthesis: Thirteen retrospective studies including 23,816 patients were included, with a median follow-up of 86 months. mETE in patients without lymph node involvement (N0 disease) was associated with increased risk of recurrence (7 studies, OR 1.73, 95%CI 1.03-2.92). The absolute risk of recurrence was 2.2% in patients without extension and 3.5% in patients with mETE (p=0.04). In studies including patients with and without lymph-node involvement (N1/N0 disease), mETE resulted in a significantly higher risk of recurrence (8 studies, OR 1.82, 95%CI 1.14-2.91). The absolute risk of recurrence was 6.2% in patients without extension and 7% in patients with mETE (p=0.01). In patients with micro-papillary carcinoma (<1cm) the impact of mETE was non-significant (OR 2.40, 95%CI 0.95 6.03). Minimal ETE had no impact on disease-related mortality (8 studies, OR 0.5, 95%CI 0.11-2.21). Conclusion: mETE increases risk of recurrence in DTC patients. However, the absolute increase in risk is small, and in patients with N0 disease the risk is within the low-risk of recurrence category at 3.5%. Minimal ETE has no impact on disease-related mortality, and should not change tumor stage. PMID- 29506046 TI - Effects of reduced dietary energy and amino acid density on Pectoralis major myopathies in broiler chickens at 36 and 49 days of age1. AB - Two experiments (Exp) were conducted to determine if reductions in the incidence and severity of wooden breast (WB) and white striping (WS) may be obtained by reducing dietary nutrient density. In each Exp, Yield Plus * Ross 708 male broiler chicks were placed into 63 pens (22 birds/pen). All birds received an identical prestarter diet until 7 d of age, after which time each pen was randomly assigned to 1 of the following 7 dietary treatments (TRT) for the starter (8 to 14 d), grower (15 to 24 d), finisher 1 (Exp 1: 26 to 35 d; Exp 2: 26 to 42 d), and withdrawal (Exp 2: 43 to 48 d) phases: 1) 100% of primary breeder recommendations for digestible amino acid and metabolizable energy density throughout Exp; 2) 95% of TRT 1 until 14 d of age, then as TRT 1; 3) 95% of TRT 1 until 24 d of age, then as TRT 1; 4) 95% of TRT 1 throughout Exp; 5) 90% of TRT 1 until 14 d of age, then as TRT 1; 6) 90% of TRT 1 until 24 d of age, then as TRT 1; 7) 90% of TRT 1 throughout Exp. At 36 d (Exp 1) and 49 d (Exp 2), 18 birds per pen were processed and evaluated for WS and WB. In Exp 1, reduced dietary density in the starter phase (TRT 2 and TRT 5) resulted in increased (P <= 0.05) incidences of severe WB (32.9% and 34.7%) relative to TRT 1 (18.2%). In Exp 2, broilers assigned to TRT 7 had reduced (P < 0.01) incidences of severe WB (20.8%) and WS (42.3%) relative to the control (WB: 36.5%; WS: 64.5%). In both Exp, plasma creatine kinase and lactate dehydrogenase increased (P <= 0.05) with increasing scores for WB and WS. Reducing dietary nutrient density from 8 to 14 d may exacerbate fillet myopathies in broilers reared to 35 d of age. Although reducing dietary energy and amino acid density to 90% of recommendations from 1 to 48 d reduced the severity of myopathies, these reductions occurred with compromises in live performance. Altogether, these results indicated that concurrent manipulation of dietary amino acid and energy density is not a viable practical solution for breast myopathies. PMID- 29506048 TI - Comparison of Capsule Endoscopy and Magnetic Resonance Enterography for the Assessment of Small Bowel Lesions in Crohn's Disease. AB - Background and Aims: Diagnostic yield of Small Bowel Capsule Endoscopy (SBCE) for the assessment of small bowel (SB) lesions is higher than radiologic imaging techniques. However, magnetic resonance enterography (MRE) data are scarce and inconclusive. Colon Capsule Endoscopy (CCE) is a new capsule modality. The primary aim of our study was to compare MRE and capsule endoscopy (CE) for the assessment of Crohn's disease (CD). The secondary objectives were to compare the diagnostic accuracy of both CE modalities and changes in Montreal classification after each examination. Methods: We included 47 patients with established (n = 32) or suspected CD (n = 15). MRE was performed first to rule out strictures. In patients with a suspected stricture by MRE, an Agile Patency Capsule was performed. SB disease activity was measured by MaRIA score (MRE) and Lewis Index (CE). Results: SB lesions were found in 36 of47 patients with CE and in 21 of47 patients with MRE (76.6% vs 44.7%, P = 0.001). Jejunal inflammation was detected by CE in 31.9% of patients and by MRE in 6.4% of patients (15/47 vs 3/47; P = 0.03); lesions in ileum were detected in 57.4% of patients by CE, and in 21.3% of patients by MRE (27/ 47 vs 10/ 47; P = 0.04). Finally, in terminal ileum, CE showed lesions in 68.1% (32/47) of patients, whereas MRE detected lesions in 38.3% (18/ 47 patients), (P = 0.001). The original Montreal classification was changed in 53.1% of patients (25/ 47) based on CE findings and in 12.7% of patients (6/47) based on MRE findings (P < 0.05). Conclusions: In our cohort CE was significantly superior to MRE for detecting SB lesions, mainly superficial and proximal lesions. CE is useful for a appropriate patients' classification according to Montreal classification. PMID- 29506047 TI - Phytase supplementation in diets rich in fiber from rapeseed enhances phosphorus and calcium digestibility but not retention in broiler chickens. AB - Two experiments were conducted on broilers to assess the effect of dietary fiber from 00-rapeseed meal (RSM) on phosphorus (P) and calcium (Ca) apparent ileal digestibility (AID) and retention (AR) during the growing (Exp1: 10 to 21 d) or finishing period (Exp2: 21 to 31 d) in diets supplemented or not with microbial phytase. Each experiment involved 144 male Cobb 500 fed one of 8 diets. Fiber content was modulated by incorporating whole RSM, RSM from dehulled rapeseeds, either raw or supplemented with 2 levels of defatted rapeseed hulls. Diets were supplemented or not with 750 phytase units of microbial phytase per kg. Excreta were collected from d 14 to d 17 (Exp1) and from d 27 to d 30 (Exp2) to measure AR. At the end of experiments, digestive tracts were sampled and weighed. The distal ileum and tibias were collected to measure AID and bone mineralization, respectively. Age did not significantly alter the response of birds to the addition of dietary fiber. Inclusion of hulls decreased growth performance (P < 0.05). The weight of the proventriculus-gizzard (PG) increased with the dietary fiber content in Exp1: The decreased weight observed using dehulled RSM was reversed following the inclusion of hulls. In both trials, while the presence of phytase increased the AID of P (P < 0.001) but not Ca, the inclusion of hulls with phytase improved the AID of P and Ca [linear (Lin), P < 0.05]. This effect could depend on the effect of fiber on PG development and physiology. Hulls decreased the moisture content of excreta (P < 0.01), suggesting higher water retention or lower water consumption with fiber. The AR of P was lower than AID of P with hulls, contrary to Ca, suggesting a metabolic imbalance. The decrease of AR together with the decrease of bone characteristics indicates a lack of Ca in diets with hulls and suggests that P and Ca provision should be adapted to the level and the origin of fiber inclusion. PMID- 29506049 TI - Trends in the quality assurance process indicators for Japanese colorectal cancer screening during 2003-13. AB - Background: Recently, the importance of quality assurance (QA) for cancer screening has gained increasing attention in Japan. This study aimed to evaluate QA process indicators for population-based colorectal cancer screening during 2003-13. Methods: A national cancer screening database was used to evaluate the following process indicators: the positivity rate, diagnostic follow-up rate, unidentified results rate, non-compliance with diagnostic follow-up rate, cancer detection rate and positive predictive value (PPV). Results: The positivity rate remained constant at 6.5% until 2011, and then increased slightly thereafter. During 2003-13, the cancer detection rate increased from 0.15% to 0.21%, and the PPV increased from 2.2% to 3.1%. Although the diagnostic follow-up rate increased from 58% to 67%, the non-compliance with diagnostic follow-up rate decreased from 24% to 16% and the unidentified results rate decreased from 18% to 17%. Conclusions: During the study period, the QA process indicators for colorectal cancer screening in Japan generally improved. However, the recent increase in the positivity rate requires careful observation. Innovative solutions are needed to increase the diagnostic follow-up rate. PMID- 29506050 TI - Amplifying the Population Health Benefits of PrEP for HIV Prevention. PMID- 29506051 TI - GSK-3beta/mTORC1 Couples Synaptogenesis and Axonal Repair to Reduce Hypoxia Ischemia-Mediated Brain Injury in Neonatal Rats. AB - Glycogen synthase kinase 3 beta (GSK-3beta) plays an important role in neurological outcomes after brain injury. However, its roles and mechanisms in hypoxia-ischemia (HI) are unclear. Activation of mTOR complex 1 (mTORC1) has been proven to induce the synthesis of proteins associated with regeneration. We hypothesized that GSK-3beta inhibition could activate the mTORC1 signaling pathway, which may reduce axonal injury and induce synaptic protein synthesis and functional recovery of synapses after HI. By analyzing a P7 rat model of cerebral HI and an in vitro ischemic (oxygen glucose deprivation) model, we found that GSK 3beta inhibitors (GSK-3beta siRNA or lithium chloride) activated mTORC1 signaling, leading to increased expression of synaptic proteins, including synapsin 1, PSD95, and GluR1, and the microtubule-associated protein Tau and decreased expression of the axonal injury-associated protein amyloid precursor protein. These changes contributed to attenuated axonal injury (decreased amyloid precursor protein staining and axonal loss by silver staining), improved electrophysiological properties of synapses, and enhanced spatial memory performance in the Morris water maze. However, inhibition of mTORC1 by rapamycin blocked the benefits induced by GSK-3beta inhibition, suggesting that GSK-3beta inhibition induces synaptogenesis and axonal repair via mTORC1 signaling, which may benefit neonatal rats subjected to HI. PMID- 29506052 TI - The Risk of Skin Necrosis Following Hyaluronic Acid Filler Injection in Patients With a History of Cosmetic Rhinoplasty. AB - Background: As the number of patients using dermal filler for face augmentation increases, the number of adverse events associated with injection may increase. Unpredictable repositioning of blood vessels and a more tenuous blood supply in the operated nose may increase the risk of ischemia, necrosis, and vascular embolism following the filler injection. Objectives: To highlight the importance of the patient's history of previous cosmetic procedures including rhinoplasty in the emergence of vascular complications. Methods: Our medical records over a two year period were reviewed retrospectively to identify all patients who were treated at our center for vascular complications associated with facial hyaluronic acid filler injections. In each case, the subject's demographic data (gender and age), habitual status, past medical and surgical history, the symptoms and clinical presentation at the first visit, the time interval between the injection and the onset of symptoms, injected filler material and brand, injection sites, the introduced treatment, and photographs were reviewed carefully. Results: A total of seven patients were identified, each developing skin necrosis following injection of the hyaluronic acid filler. All patients reported a cosmetic rhinoplasty more than three years ago. Conclusions: Our finding confirms the conjecture previously made in the literature and suggests that the distinctive vascularity of the nose and the surrounding area may cause filler augmentation induced vascular complications in patients whose vascular circulation has already been compromised by a previous nose surgery. Level of Evidence 5: PMID- 29506053 TI - MicroRNAs in Peripheral Mononuclear Cells as Potential Biomarkers in Hypertensive Patients With Heart Failure With Preserved Ejection Fraction. AB - BACKGROUND: MicroRNAs (miRs) regulate gene expression and play an important role in ventricular and vascular remodeling. However, there are limited data regarding their role in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to assess gene expression of miR-1, miR-133a, miR-21, miR-208b, miR-499, and miR-26b in peripheral blood mononuclear cells (PBMCs) in hypertensive patients with HFpEF and to evaluate their association with their exercise capacity. METHODS: We included 56 hypertensive patients with HFpEF (age 67.29 +/- 7.75 years). Forty-two hypertensive patients without HFpEF (age 66.83 +/- 7.17 years) served as controls. All subjects underwent a cardiopulmonary exercise test (CPXT). PBMCs were isolated and levels of miRs were determined by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: For hypertensive patients with HFpEF, higher expression levels in PBMCs were found only for miR-26b (7.6 +/- 7.3 vs. 4.0 +/- 3.6, P = 0.002), miR-208b (28.8 +/- 35.3 vs. 7.5 +/- 13.3, P < 0.001), and miR-499 (14.2 +/- 22.4 versus 3.5 +/- 2.9, P = 0.001). The strongest correlations with CPXT parameters were found for miR-208b levels, which had a positive correlation with maximal oxygen uptake (peakVO2) (r = 0.671, P < 0.001), exercise duration (r = 0.445, P = 0.001), and minute ventilation-carbon dioxide production relationship (VE/VCO2) (r = 0.437, P = 0.001) in the HFpEF group. CONCLUSIONS: miR-26b, miR-208b, and miR-499 show a distinct in profile in hypertensive patients with HFpEF that is related with functional capacity. Further studies are needed to assess the role of miRs as prognostic tools or as therapeutic targets in those patients. PMID- 29506055 TI - Changes in expression of special AT-rich sequence binding protein 1 and phosphatase and tensin homologue in kidneys of diabetic rats during ageing. AB - Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM). We studied the expression of special AT-rich sequence binding protein 1 (SATB1) and phosphatase and tensin homologue (PTEN) in the kidneys of diabetic rats during ageing. Methods: Male Sprague Dawley rats were injected with 55 mg/kg streptozotocin (STZ) (DM group) or with citrate buffer (control group). Kidneys were collected after 2 weeks, 6 months and 12 months, and were analysed in three different kidney structures: glomeruli, proximal (PCT) and distal convoluted tubules (DCT). Sections were stained immunohistochemically, using SATB1 and PTEN. Results: Significant differences in marker expression were observed after 2 weeks, with higher SATB1 expression and lower PTEN expression in diabetic rats. PTEN was more highly expressed in controls after 6 and 12 months. After 12 months, there was higher SATB1 expression in diabetic rats. In the glomeruli, control rats had higher PTEN expression, whereas diabetic rats had higher SATB1 expression, after 12 months. PTEN expression increased from 2 weeks to 12 months in both the PCT and DCT of control rats. SATB1 was expressed exclusively in the PCT of diabetic rats after 2 weeks, and its expression in the DCT was higher in controls. After 6 months, both the PCT and DCT showed higher SATB1 expression in diabetic rats. Conclusions: The major changes in expression of SATB1 and PTEN occur after 2 weeks of DM onset, particularly in the PCT, implying an early onset of pathophysiological changes in diabetic kidneys, which would normally occur with ageing. These findings help to contribute to our understanding of changes associated with DN and guide towards possible appropriate treatment modalities. PMID- 29506054 TI - Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes. AB - Context: Efforts to preserve beta-cell mass in the preclinical stages of type 1 diabetes (T1D) are limited by few blood-derived biomarkers of beta-cell destruction. Objective: Platelets are proposed sources of blood-derived biomarkers for a variety of diseases, and they show distinct proteomic changes in T1D. Thus, we investigated changes in the exocytosis protein, double C2 domain protein-beta (DOC2B) in platelets and islets from T1D humans, and prediabetic nonobese diabetic (NOD) mice. Design, Patients, and Main Outcome Measure: Protein levels of DOC2B were assessed in platelets and islets from prediabetic NOD mice and humans, with and without T1D. Seventeen new-onset T1D human subjects (10.3 +/ 3.8 years) were recruited immediately following diagnosis, and platelet DOC2B levels were compared with 14 matched nondiabetic subjects (11.4 +/- 2.9 years). Furthermore, DOC2B levels were assessed in T1D human pancreatic tissue samples, cytokine-stimulated human islets ex vivo, and platelets from T1D subjects before and after islet transplantation. Results: DOC2B protein abundance was substantially reduced in prediabetic NOD mouse platelets, and these changes were mirrored in the pancreatic islets from the same mice. Likewise, human DOC2B levels were reduced over twofold in platelets from new-onset T1D human subjects, and this reduction was mirrored in T1D human islets. Cytokine stimulation of normal islets reduced DOC2B expression ex vivo. Remarkably, platelet DOC2B levels increased after islet transplantation in patients with T1D. Conclusions: Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of beta-cell mass and an early biomarker of T1D. PMID- 29506056 TI - Doppler assessment of intra-renal vasculature as a predictor of contrast-induced nephropathy - a pilot investigation. PMID- 29506057 TI - Preexposure Prophylaxis Initiation and Retention in Care Over 5 Years, 2012-2017: Are Quarterly Visits Too Much? AB - Retention in preexposure prophylaxis (PrEP) care is critical to elimination of human immunodeficiency virus. We reviewed all Howard Brown Health patients receiving PrEP (n = 5583) from 2012 to 2017. Among those with 12 months of follow up, 43% remained in care, yet only 15% had all 4 quarters with a PrEP visit. Insurance status and comorbid conditions were drivers of retention in care. PMID- 29506058 TI - Host-Acceptance Behavior of Trissolcus japonicus (Hymenoptera: Scelionidae) Reared on the Invasive Halyomorpha halys (Heteroptera: Pentatomidae) and Nontarget Species. AB - Trissolcus japonicus (Ashmead) (Hymenoptera: Scelionidae) is an egg parasitoid wasp from East Asia. It is considered to be an important natural enemy of the brown marmorated stink bug, Halyomorpha halys (Stal) (Hemiptera: Pentatomidae). Ongoing efforts to evaluate the physiological host range of this potential classical biological control agent have demonstrated that the wasp can parasitize at least 11 genera of nontarget Pentatomoidea in North America in no-choice tests. However, factors such as host-acceptance behavior that might affect nontarget parasitism in the field are poorly understood. We evaluated the preference of T. japonicus females provided with egg clusters of H. halys, Thyanta custator accerra McAtee (Hemiptera: Pentatomidae), Podisus maculiventris (Say) (Hemiptera: Pentatomidae), and Euschistus variolarius (Palisot de Beauvois) (Hemiptera: Pentatomidae) when wasps were reared on the target pest, H. halys, and the nontarget species, T.c. accerra and P. maculiventris. When reared on H. halys, T. japonicus showed a strong preference for H. halys, and frequently rejected nontarget hosts after inspection. When T. japonicus was reared on nontarget hosts, females showed reduced host-specificity, but were significantly smaller and produced a lower number of offspring. These results suggest that innate host-acceptance behavior is likely to reduce parasitism on some nontarget Pentatomoidea which T. japonicus will encounter in the field. Future efforts should be made to examine the ability of the wasp to reproduce long term on nontarget species when H. halys eggs are limited. PMID- 29506059 TI - Response. PMID- 29506061 TI - SYNTHESIS, OPTICAL PROPERTIES AND THERMOLUMINESCENCE DOSIMETRY FEATURES OF MANGANESE DOPED Li2B4O7 NANOPARTICLES. AB - Lithium tetraborate (Li2B4O7) nanoparticles (NPs) doped with manganese (Mn) were prepared for the first time by the solid-state sintering method. NPs were characterized using X-ray diffraction, scanning electron microscopy, photoluminescence and thermoluminescence (TL) techniques. The synthesized NPs exhibited highest TL response at 0.3 wt% of Mn dopant under gamma irradiation. TL dose response is linear for the absorbed dose from 1 Gy to 20 kGy and beyond this range behaves sub-linear. Such feature makes the synthesized nanophosphor as a promising material for high-dose dosimetry applications. Low fading and good reusability were obtained for the synthesized NPs. Tm-Tstop and computerized glow curve deconvolution procedures were utilized to identify the component TL glow peaks and kinetic parameters of the produced phosphor. Other TL dosimetry features of the prepared NPs are also presented and discussed. PMID- 29506060 TI - Social, motor, and cognitive development through the lens of sleep network dynamics in infants and toddlers between 12 and 30 months of age. AB - Widespread change in behavior and the underlying brain network substrate is a hallmark of early development. Sleep plays a fundamental role in this process. Both slow waves and spindles are key features of nonrapid eye movement sleep (NREM) that exhibit pronounced developmental trajectories from infancy to adulthood. Yet, these prominent features of NREM sleep are poorly understood in infants and toddlers in the age range of 12 to 30 months. Moreover, it is unknown how network dynamics of NREM sleep are associated with outcomes of early development. Addressing this gap in our understanding of sleep during development will enable the subsequent study of pathological changes in neurodevelopmental disorders. The aim of the current study was to characterize the sleep topography with high-density electroencephalography in this age group. We found that delta, theta, and beta oscillations and sleep spindles exhibited clear developmental changes. Low delta and high theta oscillations correlated with motor, language, and social skills, independent of age. These findings suggest an important role of network dynamics of NREM sleep in cortical maturation and the associated development of skills during this important developmental period. PMID- 29506062 TI - The 2017 ESC Guidelines on PADs: what's new? PMID- 29506063 TI - The 'Ten Commandments' of 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases. PMID- 29506064 TI - Cardiologists and management of vascular diseases. PMID- 29506065 TI - The re-birth of an ESC Working Group. PMID- 29506066 TI - Cardiovascular Research Institute Basel. PMID- 29506067 TI - Ulrich Laufs, EHJ International Associate Editor. PMID- 29506068 TI - Responding to the Opioid Epidemic in the United States. PMID- 29506069 TI - Thank You for Supporting the Foundation at CSM. PMID- 29506071 TI - Peripouch Fat Area Measured on MRI Image and Its Association With Adverse Pouch Outcomes. AB - Background: There are no published studies on the impact of peripouch fat on pouch outcomes in inflammatory bowel disease (IBD) patients. Methods: Patients with pelvic MRI-DIXON scans from our prospectively maintained Pouch Database between 2002 and 2016 were evaluated. Peripouch fat area was measured on MRI DIXON-F images at the middle height level of the pouch (area M) and the highest level of the pouch (area H). Results: Of all 1863 patients in the database, 197 eligible patients were included in this study. The median of area M was 52.4 cm2, so the 197 patients were classified into 2 groups: group 1 (Area-M <52.4 cm2) and group 2 (Area-M >=52.4 cm2). Compared with group 1, group 2 was found to have thicker perianal fat, more Caucasian and more males. Group 2 also had a higher Area-H, more weight, height, and body mass index, along with greater age at IBD diagnosis, age at pouch construction and pouch age, and a higher frequency of total pouch complication (86.7% versus 66.7%, P = 0.001), chronic pouch complication (68.4% versus 51.5%, P = 0.016), and chronic antibiotic-refractory pouchitis (16.3% versus 7.1%, P = 0.043). Multivariate logistic analysis showed that Area-M was an independent risk factor for chronic antibiotic-refractory pouchitis (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.007-1.042, P = 0.005). The 22 patients with 2 or more pelvic MRI-DIXON scans were further classified into 2 groups by the change from the initial to latest MRI-DIXON scans. Patients with Area-M increase >=10% and Area-M/height increase >=10% were found to have shorter pouch survivals than those with increase <10%. Conclusions: A new method was established for measuring peripouch fat using pelvic MRI-DIXON-F image. Our study suggests that accumulation of peripouch fat may be associated with poor outcomes in selected IBD patients suspected of inflammatory or mechanical disorders of the pouch. Whether this association is causal warrants further investigation. PMID- 29506072 TI - Training reproductive health providers to talk about intimate partner violence and reproductive coercion: an exploratory study. AB - To explore the effect of provider communication-skills training on frequency of intimate partner violence (IPV) and reproductive coercion (RC) assessment, four family planning clinics were randomized to IPV/RC communication-skills building workshop or standard knowledge-based IPV/RC training and compared to historical controls from the same clinics (before any training). Female patients aged 16-29 completed after-visit surveys. Primary outcomes included provider discussion about IPV/RC, receipt of safety card with IPV/RC resources and patient disclosure of IPV/RC. Chi-square tests were used to compare groups that received training and historical controls. Participants (training: n = 103; historical control: n = 576) were predominantly white with mean age of 22. More patients reported discussion about healthy relationships in both training groups (78-90%) compared to historical controls (49-52%, P < 0.001 for both). Discussion on birth control sabotage and pregnancy coercion was infrequent with patient-participants in both groups (6-17 and 4-13%, respectively). More patients in the clinics that received training reported receiving a safety card (72-84%) as compared to historical controls (9%, P < 0.001 for both). Overall, in this exploratory study, both communication-skills and standard training improved frequency of IPV communication when compared to historical controls but with few differences when compared to each other. PMID- 29506073 TI - Host-specific differences in the contribution of an ESBL IncI1 plasmid to intestinal colonization by Escherichia coli O104:H4. AB - Objectives: To assess stability and contribution of a large ESBL-encoding IncI1 plasmid to intestinal colonization by Escherichia coli O104:H4 in two different mammalian hosts. Methods: Specific-pathogen-free 3-4-day-old New Zealand White rabbits and conventionally reared 6-week-old weaned lambs were orally infected with WT E. coli O104:H4 or the ESBL-plasmid-cured derivative, and the recovery of bacteria in intestinal homogenates and faeces monitored over time. Results: Carriage of the ESBL plasmid had differing impacts on E. coli O104:H4 colonization of the two experimental hosts. The plasmid-cured strain was recovered at significantly higher levels than WT during late-stage colonization of rabbits, but at lower levels than WT in sheep. Regardless of the animal host, the ESBL plasmid was stably maintained in virtually all in vivo passaged bacteria that were examined. Conclusions: These findings suggest that carriage of ESBL plasmids has distinct effects on the host bacterium depending upon the animal species it encounters and demonstrates that, as for E. coli O157:H7, ruminants could represent a potential transmission reservoir. PMID- 29506075 TI - Risk of HIV Acquisition During Pregnancy and Postpartum: A Call for Action. PMID- 29506074 TI - Morpholino oligomers tested in vitro, in biofilm and in vivo against multidrug resistant Klebsiella pneumoniae. AB - Background: Klebsiella pneumoniae is an opportunistic pathogen and many strains are multidrug resistant. KPC is one of the most problematic resistance mechanisms, as it confers resistance to most beta-lactams, including carbapenems. A promising platform technology for treating infections caused by MDR pathogens is the nucleic acid-like synthetic oligomers that silence bacterial gene expression by an antisense mechanism. Objectives: To test a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) in a mouse model of K. pneumoniae infection. Methods: PPMOs were designed to target various essential genes of K. pneumoniae and screened in vitro against a panel of diverse strains. The most potent PPMOs were further tested for their bactericidal effects in broth cultures and in established biofilms. Finally, a PPMO was used to treat mice infected with a KPC-expressing strain. Results: The most potent PPMOs targeted acpP, rpmB and ftsZ and had MIC75s of 0.5, 4 and 4 MUM, respectively. AcpP PPMOs were bactericidal at 1-2 * MIC and reduced viable cells and biofilm mass in established biofilms. In a mouse pneumonia model, therapeutic intranasal treatment with ~30 mg/kg AcpP PPMO improved survival by 89% and reduced bacterial burden in the lung by ~3 logs. Survival was proportional to the dose of AcpP PPMO. Delaying treatment by 2, 8 or 24 h post-infection improved survival compared with control groups treated with PBS or scrambled sequence (Scr) PPMOs. Conclusions: PPMOs have the potential to be effective therapeutic agents against KPC-expressing, MDR K. pneumoniae. PMID- 29506076 TI - Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling. AB - Context: WNT signaling is fundamental to bone health, and its aberrant activation leads to skeletal pathologies. The heterozygous missense mutation p.C218G in WNT1, a key WNT pathway ligand, leads to severe early-onset and progressive osteoporosis with multiple peripheral and spinal fractures. Despite the severe skeletal manifestations, conventional bone turnover markers are normal in mutation-positive patients. Objective: This study sought to explore the circulating microRNA (miRNA) pattern in patients with impaired WNT signaling. Design and Setting: A cross-sectional cohort study at a university hospital. Participants: Altogether, 12 mutation-positive (MP) subjects (median age, 39 years; range, 11 to 76 years) and 12 mutation-negative (MN) subjects (35 years; range, 9 to 59 years) from two Finnish families with WNT1 osteoporosis due to the heterozygous p.C218G WNT1 mutation. Methods and Main Outcome Measure: Serum samples were screened for 192 miRNAs using quantitative polymerase chain reaction. Findings were compared between WNT1 MP and MN subjects. Results: The pattern of circulating miRNAs was significantly different in the MP subjects compared with the MN subjects, with two upregulated (miR-18a-3p and miR-223-3p) and six downregulated miRNAs (miR-22-3p, miR-31-5p, miR-34a-5p, miR-143-5p, miR 423-5p, and miR-423-3p). Three of these (miR-22-3p, miR-34a-5p, and miR-31-5p) are known inhibitors of WNT signaling: miR-22-3p and miR-34a-5p target WNT1 messenger RNA, and miR-31-5p is predicted to bind to WNT1 3'UTR. Conclusions: The circulating miRNA pattern reflects WNT1 mutation status. The findings suggest that the WNT1 mutation disrupts feedback regulation between these miRNAs and WNT1, providing insights into the pathogenesis of WNT-related bone disorders. These miRNAs may have potential in the diagnosis and treatment of osteoporosis. PMID- 29506077 TI - Reduction of Mosquito Abundance Via Indoor Wall Treatments: A Mathematical Model. AB - Insecticidal indoor residual wall treatment is a major tool for the control of malaria, with the goals of reducing indoor vector density and vector life span, in addition to reducing transmission rates of disease. Dynamics of the malaria vector, Anopheles gambiae, in the Emutete region in the Western Kenya highlands are based on an already existing model in the literature. In this paper, the framework is used to predict vector reduction due to four types of indoor wall treatments: two cases of indoor residual spraying of DDT and two types of pyrethrin-based INESFLY insecticidal paint. These treatments differ primarily in the duration of their persistence on walls. The model shows the extent of suppression of vector abundance over time due to each of the four treatments. It predicts that indoor residual spraying may have no noticeable effect at all if the percent coverage is not high enough or the persistence of the mortality effect is low, but will have a substantial effect at higher coverage rates and/or higher persistence. For treatments with longer persistence of mortality, the model predicts a coverage threshold above which extra treatment has little to no effect. For treatments of short persistence of mortality, the seasonal timing of treatment has a noticeable effect on the duration of vector suppression. Overall, the model supports claims in the literature that wall treatments have the capacity to reduce the vector burden. PMID- 29506078 TI - SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. AB - The methyltransferase like 3 (METTL3) is a key component of the large N6 adenosine-methyltransferase complex in mammalian responsible for N6 methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1 specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization and interaction with METTL14 and WTAP, but significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs. Consistently with this, the abundance of m6A in mRNAs is increased with re expression of the mutant METTL3-4KR compared to that of wild-type METTL3 in human non-small cell lung carcinoma (NSCLC) cell line H1299-shMETTL3, in which endogenous METTL3 was knockdown. The alternation of m6A in mRNAs and subsequently change of gene expression profiles, which are mediated by SUMOylation of METTL3, may directly influence the soft-agar colony formation and xenografted tumor growth of H1299 cells. Our results uncover an important mechanism for SUMOylation of METTL3 regulating its m6A RNA methyltransferase activity. PMID- 29506079 TI - The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers. AB - Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic. PMID- 29506080 TI - Which supplements can I recommend to my osteoarthritis patients? AB - OA is a chronic and disabling joint disease with limited evidence-based pharmacological treatment options available that improve outcomes for patients safely. Faced with few effective pharmacological treatments, the use has grown of dietary supplements and complementary medicines for symptomatic relief among people living with OA. The aim of this review is to provide a summary of existing evidence and recommendations supporting the use of supplements for OA. Systematic reviews and randomized controlled trials investigating oral supplements for treating OA were identified. Limited research evidence supports recommendations for the oral use of Boswellia serrata extract and Pycnogenol, curcumin and methylsulfonylmethane in people with OA despite the poor quality of the available studies. Few studies adequately reported possible adverse effects related to supplementation, although the products were generally recognized as safe. Further high quality trials are needed to improve the strength of evidence to support this recommendation and better guide optimal treatment of people living with OA. PMID- 29506081 TI - Association between work role stressors and sleep quality. AB - Background: Work-related stressors are associated with low sleep quality. However, few studies have reported an association between role stressors and sleep quality. Aims: To elucidate the association between role stressors (including role conflict and ambiguity) and sleep quality. Methods: Cross sectional study of daytime workers whose sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Work-related stressors, including role stressors, were assessed using the Generic Job Stress Questionnaire (GJSQ). The association between sleep quality and work-related stressors was investigated by logistic regression analysis. Results: A total of 243 participants completed questionnaires were received (response rate 71%); 86 participants reported poor sleep quality, based on a global PSQI score >=6. Multivariable logistic regression analysis revealed that higher role ambiguity was associated with global PSQI scores >=6, and that role conflict was significantly associated with sleep problems, including sleep disturbance and daytime dysfunction. Conclusions: These results suggest that high role stress is associated with low sleep quality, and that this association should be considered an important determinant of the health of workers. PMID- 29506083 TI - Addition of Questions on Parental Factors to the WHO (Integrated Management of Childhood Illnesses) IMCI-HIV Algorithm Improves the Utility of the Algorithm for Diagnosis of HIV Infection in Children. AB - The WHO Integrated Management of Childhood Illnesses-HIV (IMCI-HIV) algorithm and its regional adaptation have shown variable performance in clinically identifying HIV-infected children with lack of validation in low prevalence areas. Addition of certain 'parental factors' (proxy indicators of parental HIV) may improve its utility. In this study, children aged 2 months to 5 years were enrolled into Group A (n = 1000, 'suspected symptomatic HIV infected' children as per the IMNCI HIV algorithm) and group B (n = 50, children newly diagnosed with HIV infection). Parental factors were asked and HIV infection was tested for in Group A. For Group B, retrospective data were collected regarding IMNCI-HIV algorithm signs and parental factors. Utility of individual and various combinations of IMNCI-HIV signs and parental factors to predict HIV status was evaluated. Results showed that incorporating parental factors to IMNCI-HIV algorithm improved its sensitivity and positive predictive value in identifying HIV-infected children while maintaining the same sensitivity. PMID- 29506082 TI - Evaluating Within-Person Change in Implicit Measures of Alcohol Associations: Increases in Alcohol Associations Predict Increases in Drinking Risk and Vice Versa. AB - Aims: Implicit measures of alcohol associations (i.e. measures designed to assess associations that are fast/reflexive/impulsive) have received substantial research attention. Alcohol associations related to the self (drinking identity), the effects of alcohol (alcohol excite) and appetitive inclinations (alcohol approach) have been found to predict drinking cross-sectionally and over time. A critical next step in this line of research and the goal of this study is to evaluate whether increases in the strength of these associations predict increases in drinking and vice versa. These hypotheses were tested in a sample of first- and second-year US university students: a sample selected because this time period is associated with initiation and escalation of drinking, peak levels of alcohol consumption and severe alcohol-related negative consequences. Short summary: This study's purpose was to evaluate whether increases in the strength of alcohol associations with the self (drinking identity), excitement (alcohol excite) and approach (alcohol approach) as assessed by implicit measures predicted subsequent increases in drinking risk and vice versa using a longitudinal, university student sample. Results were consistent with hypotheses. Methods: A sample of 506 students' (57% women) alcohol associations and alcohol consumption were assessed every 3 months over a 2-year period. Participants' consumption was converted to risk categories based on NIAAA's criteria: non drinkers, low-risk drinkers and high-risk drinkers. A series of cross-lagged panel models tested whether changes in alcohol associations predicted subsequent change in drinking risk (and vice versa). Results: Across all three measures of alcohol associations, increases in the strength of alcohol associations were associated with subsequent increases in drinking risk and vice versa. Conclusion: Results from this study indicate bi-directional relationships between increases in alcohol associations (drinking identity, alcohol excite and alcohol approach) and subsequent increases in drinking risk. Intervention and prevention efforts may benefit from targeting these associations. PMID- 29506085 TI - Corrigendum to: An integrative review exploring black men of African and Caribbean backgrounds, their fears of prostate cancer and their attitudes towards screening. PMID- 29506084 TI - Higher Anti-Cytomegalovirus Immunoglobulin G Concentrations Are Associated With Worse Neurocognitive Performance During Suppressive Antiretroviral Therapy. AB - Background: Cytomegalovirus (CMV) has been linked to higher risk of cardiovascular disease and mortality. We aimed to determine if CMV is associated with neurocognitive performance in adults infected with human immunodeficiency virus (HIV). Methods: In this cross-sectional analysis, anti-CMV immunoglobulin G (IgG) concentrations in blood and CMV DNA copies in blood and cerebrospinal fluid (CSF) were measured in stored specimens of 80 HIV-infected adults who were previously assessed with a comprehensive neurocognitive test battery. Thirty eight were taking suppressive antiretroviral therapy (ART) and 42 were not taking ART. A panel of 7 soluble biomarkers was measured by immunoassay in CSF. Results: Anti-CMV IgG concentrations ranged from 5.2 to 46.1 IU/mL. CMV DNA was detected in 7 (8.8%) plasma specimens but in no CSF specimens. Higher anti-CMV IgG levels were associated with older age (P = .0017), lower nadir CD4+ T-cell count (P < .001), AIDS (P < .001), and higher soluble CD163 (P = .009). Higher anti-CMV IgG levels trended toward an association with worse neurocognitive performance overall (P = .059). This correlation was only present in those taking suppressive ART (P = .0049). Worse neurocognitive performance remained associated with higher anti-CMV IgG levels after accounting for other covariates in multivariate models (model P = .0038). Detectable plasma CMV DNA was associated with AIDS (P = .05) but not with neurocognitive performance. Conclusions: CMV may influence neurocognitive performance in HIV-infected adults taking suppressive ART. Future clinical trials of anti-CMV therapy should help to determine whether the observed relationships are causal. PMID- 29506086 TI - Effect of varying trace mineral supplementation of steers with or without hormone implants on growth and carcass characteristics. AB - To determine the effects of trace mineral (TM) supplementation and hormone implant strategy on growth and carcass characteristics of cattle, 72 Angus-cross steers (388 +/- 17 kg) were blocked by body weight (six steers per pen) to a 2 * 3 factorial. Factors included growth-stimulating implant (GS): day 0 with Component TE-IS, reimplanted day 56 with Component TE-200 (IMP) or no implant (NoIMP), and TM supplementation (TM): no supplemental TM (CON), TM supplemented at national (NASEM, 2016). Nutrient requirements of beef cattle. 8th ed. Washington, DC: The National Academics Press) recommendations of 10 Cu, 30 Zn, 20 Mn, 0.10 Se, 0.15 Co, and 0.50 I (mg/kg; REC), or TM supplemented at feedlot consultant recommendations of 20 Cu, 100 Zn, 50 Mn, 0.30 Se, 0.20 Co, and 0.50 I (mg/kg; IND). Steers received a finishing diet for 124 d in GrowSafe bunks and were harvested on day 125. Data were analyzed in SAS as a 2 * 3 factorial with steer as the experimental unit (n = 12 per combination). Day -7 liver trace mineral concentrations were used as a covariate in analysis. There were no GS * TM effects for liver Zn, Mn, Se, or Co (P >= 0.11) on day 70 or 125. Implanted steers had lesser liver Cu and Mn on day 70 (P <= 0.05) and day 125 compared with NoIMP. There was a GS * TM interaction for liver Cu on day 125 (P = 0.05) where IMP/REC, IMP/IND, and NoIMP/REC had greater liver Cu than NoIMP/CON, which had greater liver Cu than IMP/CON. There was a TM effect for liver Cu on day 70 (P < 0.01) with IND having greater liver Cu than REC and CON. There was a TM effect (P <= 0.01) for liver Mn and Se on day 70 where IND had greater Mn and Se than CON, with REC being intermediate. There was a TM effect (P < 0.01) on liver Mn on day 125 where IND had greater liver Mn than CON and greater (P < 0.01) liver Se than CON and REC on day 125, whereas day 125 liver Se was greater in REC vs. CON. Implanted steers had greater (P < 0.01) dry matter intake (DMI), final body weight (BW), overall average daily gain (ADG), G:F, and hot carcass weight (HCW) than NoIMP. Overall DMI was affected by TM (P < 0.01) with REC and IND being greater than CON. There was a TM effect for carcass-adjusted final BW, ADG, and DMI (P >= 0.03) and a tendency for TM to affect adjusted G:F (P = 0.07). There was a TM effect (P = 0.03) for HCW where IND was greater than CON and REC. There was a GS * TM (P = 0.02) for ribeye area (REA); within IMP, CON were greater than IND, whereas REC were intermediate while NoIMP had smaller REA, regardless of TM supplementation. Additional research is needed to better determine trace mineral requirements of finishing beef steers for optimal performance. PMID- 29506087 TI - Forearm Cephalic Vein Graft for Short, "Middle"-Flow, Internal Maxillary Artery to Middle Cerebral Artery Bypass. AB - BACKGROUND: The cervical carotid system has been used as a source of donor vessels for radial artery or saphenous vein grafts in cerebral bypass. Recently, internal maxillary artery to middle cerebral artery bypass has been described as an alternative, with reduction of graft length potentially correlating with improved patency. OBJECTIVE: To describe our experience using the forearm cephalic vein grafts for short segment internal maxillary artery to middle cerebral artery bypasses. METHODS: All vein grafts were harvested from the volar forearm between the proximal cubital fossa where the median cubital vein is confluent with the cephalic vein and the distal wrist. RESULTS: Six patients were treated with internal maxillary artery to middle cerebral artery bypass. In 4, the cephalic vein was used. Postoperative angiography demonstrated good filling of the grafts with robust distal flow. There were no upper extremity vascular complications. All but 1 patient (mortality) tolerated the procedure well. The other 3 patients returned to their neurological baseline with no new neurological deficit during follow-up. CONCLUSION: The internal maxillary artery to middle cerebral artery "middle" flow bypass allows for shorter graft length with both the proximal and distal anastomoses within the same microsurgical field. These unique variable flow grafts represent an ideal opportunity for use of the cephalic vein of the forearm, which is more easily harvested than the wider saphenous vein graft and which has good match size to the M1/M2 segments of the middle cerebral artery. The vessel wall is supple, which facilitates handling during anastomosis. There is lower morbidity potential than utilization of the radial artery. Going forward, the cephalic vein will be our preferred choice for external carotid-internal carotid transplanted conduit bypass. PMID- 29506088 TI - The Lateral Triangle of the Middle Fossa: Surgical Anatomy and a Novel Technique for Transcranial Exposure of the Internal Maxillary Artery. AB - BACKGROUND: The challenge of locating and isolating the internal maxillary artery (IMA) hinders its potential use as an arterial donor for extracranial-to intracranial bypass surgery. OBJECTIVE: To introduce a new approach through the middle cranial fossa for easy access and safe exposure of the IMA. METHODS: Ten specimens were prepared for surgical simulation. After the pterional craniotomy, a 2-step drilling technique was performed (lateral triangle). First, a triangular craniectomy was completed anterolateral to the foramen spinosum. By following the middle meningeal artery and dividing the lateral pterygoid muscle, the proximal part of IMA was located. Second, a bone slot was drilled in a posterior-to anterior direction from the anterior aspect of the first craniectomy. By tracing of the proximal part, the main trunk of the IMA was obtained. The size of the 2 craniectomies, the depth of IMA from the surface of the middle fossa, and the length of exposed IMA were measured. RESULTS: Drilling within the lateral triangle allowed safe exposure of both the trunk and the branches of the mandibular nerve of the IMA. The total craniectomy measured 27.8 +/- 4.2 mm in the anterior-posterior direction, and the posterior portion measured 13.3 +/- 1.5 mm in the lateral-medial direction. The depth from the middle fossa to the IMA (16.8 +/- 3.2 mm, mean +/- SD) was equal to the length of IMA exposed (17.6 +/- 3.3 mm, mean +/- SD; P > .05). CONCLUSION: This new approach provides an efficient and safe method to consistently find and isolate a segment of the IMA suitable for extracranial-to-intracranial bypass. PMID- 29506089 TI - Minimum Transpetrosal Retrolabyrinthine Approach for Revascularization of Posterior Cerebral Artery: Operative Nuance. AB - BACKGROUND: Revascularization of the posterior cerebral artery (PCA) can be essential for treating complex cerebral aneurysms in the posterior circulation, and it is considered technically challenging. To help decrease the difficulty of this technique, we developed the minimum transpetrosal approach (MTPA). OBJECTIVE: The technical nuances of the MTPA were innovated by cadaver head dissections and an actual clinical case. METHODS: Four sides of the formalin fixed cadaver heads were used to investigate if the posterior cerebral artery could be exposed with this minimum retraction of the temporal lobe in the subtemporal approach and the MTPA. By using the MTPA, 1 patient harboring a ruptured PCA aneurysm underwent superficial temporal artery-PCA anastomosis followed by isolation of the aneurysm. RESULTS: In the cadaver head dissections, we noticed that the PCAs were difficult to expose with gentle retraction of the temporal lobe in the subtemporal approach. By performing an additional retrolabyrinthine mastoidectomy, performed as the MTPA, all 4 PCAs were easily exposed in the 4 wide surgical fields. The maximum widths of the surgical fields above and below the PCA could be successfully measured in 2 cases, which were 13.3 mm and 11.2 mm, respectively (mean, 12.3 mm). Additionally, in the actual live surgery using MTPA, the PCAs were relative easy to expose with a surgical field wide enough to perform PCA bypass, which was performed without complication. CONCLUSION: The MTPA may be the most favorable approach for PCA bypass that can be performed easily with minimal temporal lobe retraction. PMID- 29506090 TI - Monteris AXiiiS Stereotactic Miniframe for Intracranial Biopsy: Precision, Feasibility, and Ease of Use. AB - BACKGROUND: Stereotactic biopsy is an important and minimally invasive technique used for a variety of indications in neurosurgery. Initially, this technique required a frame, but recently there have been a number of newer, less cumbersome approaches to biopsy including robotic arms, fixed arms, and, more recently, skull-mounted miniframes. Miniframes are attractive because they are disposable and low profile. However, the relatively limited degree of freedom offered by currently available devices necessitates a preplanned burr hole, which in turn limits flexibility and multiple trajectories. The AXiiiS device is a skull mounted, magnetic resonance imaging-compatible miniframe that provides a similar degree of freedom with a frame while maintaining a low-profile, disposable platform. OBJECTIVE: To assess the image-guided trajectory alignment accuracy using AXiiiS stereotactic miniframe biopsy of intracranial lesions. The accuracy of the AXiiiS device is compared with the Navigus Trajectory Guide as platforms. METHODS: After approval by our institutional review board, medical records of 10 neurosurgical patients with intracranial pathologies were chosen for AXiiiS stereotactic miniframe biopsy, and histological correlation was obtained. RESULTS: Ten reported cases demonstrate the precision and ease of using the AXiiiS stereotactic miniframe for biopsy of intracranial lesions in conjunction with preoperative magnetic resonance imaging. Multiple trajectories and angles have been used with precision and safety. CONCLUSION: The AXiiiS stereotactic miniframe is a feasible, safe, and disposable platform for multitrajectory intracranial biopsies. Compared with existing platforms, this novel device provides a more stable base and wider limits of trajectory angles with comparable accuracy and precision. PMID- 29506091 TI - Transsellar Ultrasound in Pituitary Surgery With a Designated Probe: Early Experiences. AB - BACKGROUND: Anatomic orientation in transsphenoidal surgery can be difficult, and residual tumors are common. A major limitation of both direct microscopy and endoscopic visualization is the inability to see below the surface of the surgical field to confirm the location of vessels, nerves, tumor remnants, and normal pituitary tissue. OBJECTIVE: To present our initial experience with a new forward-looking, custom-designed ultrasound probe for transsellar imaging. METHODS: The center frequency of the prototype tightly curved linear array, bayonet-shaped probe is 12 MHz. Twenty-four patients with pituitary adenomas were included after informed consent. RESULTS: With the use of transsellar ultrasound, we could confirm the location of important neurovascular structures and improve the extent of resection in 4 of 24 cases, as rated subjectively by the operating surgeons. Image quality was good. In 17 patients (71%), biochemical cures and/or complete resections were confirmed at 3 months. CONCLUSION: We found the images from our custom-designed ultrasound probe to be clinically helpful for anatomic orientation during surgery, and the technology is potentially helpful for improving the extent of resection during transsphenoidal surgery. This quick and flexible form of intraoperative imaging in transsphenoidal surgery could be of great support for surgeons in both routine use and difficult cases. The concept of transsellar intraoperative ultrasound imaging can be further refined and developed. PMID- 29506092 TI - Safety and Efficacy of Preoperative Embolization of Intracranial Hemangioblastomas. AB - BACKGROUND: Intracranial hemangioblastomas are highly vascular tumors that account for 1% to 2% of all central nervous system tumors. Preoperative embolization has been proposed to limit the often significant intraoperative blood loss associated with resection and potentially make the tumor more soft/necrotic and thus more amenable to gross total resection. The safety and efficacy of preoperative embolization of intracranial hemangioblastomas, however, are not well characterized. OBJECTIVE: To evaluate the safety and efficacy of preoperative endovascular embolization of intracranial hemangioblastomas using a variety of embolic agents. METHODS: A retrospective review of all surgically resected intracranial hemangioblastomas treated with preoperative embolization between 1999 and 2014 at 2 high-volume centers was performed. Clinical and radiographic criteria, including von Hippel-Lindau status, magnetic resonance imaging tumor characteristics, embolization-related complications, degree of angiographic devascularization, intraoperative blood loss, ability to obtain gross total resection, transfusion requirements, and operative time, were analyzed. RESULTS: A total of 54 patients underwent surgery, with 24 undergoing preoperative embolization followed by surgical resection, and 30 patients undergoing surgical resection alone. Embolization-related neurological complications were seen in 6 patients (25%), including 3 hemorrhages when polyvinyl alcohol particles (P = .04) were used and 3 infarctions when liquid embolic agents were used (P = .27). Permanent neurological deficits were seen in 15%. CONCLUSION: Preoperative embolization of intracranial hemangioblastomas should be performed with caution, given the potential for neurological morbidity. Further studies are needed to help guide patient and embolic agent selection. PMID- 29506093 TI - Ventral and Dorsal Persistent Primitive Ophthalmic Arteries. AB - BACKGROUND: Before the development of the adult ophthalmic artery (OA), the primitive maxillary artery (MA), the primitive dorsal OA, and the primitive ventral OA contribute to the vascularization of early ocular structures, whereas the primitive olfactory artery (OlfA) forms in the vicinity of the optic vesicle. These vessels are involved in several OA origin variants. OBJECTIVE: To clarify the developmental history of the OA, emphasizing in particular the criteria used to define persistent primitive OAs. METHODS: Eight rare variants relevant to the discussion of aberrant OA origins are presented. RESULTS: Five abnormal anatomic configurations are described including (1) OAs branching from the cavernous internal carotid artery (ICA) involving a persistent primitive MA, (2) OAs originating from the distal supraclinoid ICA involving persistent primitive ventral or dorsal OAs, (3) an OA originating from the anterior cerebral artery (ACA) involving a persistent primitive OlfA, (4) a persistent primitive OlfA, and (5) infraoptic ACAs involving the persistent primitive MA, OlfA, and OA. CONCLUSION: Discrepancies regarding the identification of persistent primitive OAs appear to result from a misinterpretation of the literature. Notably, an OA arising from the cavernous segment of the ICA derives from a primitive MA, whereas an OA arising from the ACA represents the partial persistence of a primitive OlfA; neither corresponds to a persistent primitive OA. Two new observations of this latter variant, which is exceptional, are presented. PMID- 29506094 TI - Endoscopic Endonasal Transclival Transcondylar Approach for Foramen Magnum Meningiomas: Surgical Anatomy and Technical Note. AB - BACKGROUND: The endoscopic endonasal approach provides a direct route to ventral foramen magnum (FM) lesions like meningiomas, which are difficult to access. Endonasal access at the FM is limited laterally by the occipital condyles and inferiorly by the C1 anterior arch and the odontoid process, which may need partial resection. OBJECTIVE: We investigated the surgical anatomy and technical nuances for endonasally increasing the surgical corridor at the FM region both laterally and inferiorly. Unique to our report, we quantified the amount of required medial condyle resection to obtain exposure of the lateral aspects of the FM. METHODS: Five fresh human head silicone-injected specimens underwent endonasal inferior transclival, transcondylar approaches. The lateral limit of medial condyle resection was defined using a vertical line extending inferiorly from foramen lacerum and its intersection with the occipital condyle. The condylectomy was limited posteriorly by the cortical bone surrounding the hypoglossal canal. The volume of the resected condyle (cubic centimeters) for 10 sides was measured using the pre- and postdissection computed tomography volumetric analysis. RESULTS: The mean percentage condylar volume resected during a unilateral medial condylectomy was 18% (9.7%-28.3%). The surgical corridor was extended inferiorly in all specimens without violating the transverse ligament by drilling the superior aspects of C1 anterior arch and the exposed odontoid tip. These operative nuances were successfully applied in the operating room. CONCLUSION: Anatomical landmarks can reliably guide an endonasal anteromedial condyle resection. Minimal condyle resection is required to widen lateral access at the FM, which minimizes the risk of craniocervical instability. PMID- 29506095 TI - Anastomosis Between the Ascending Pharyngeal Artery and the Posterior Inferior Cerebellar Artery Through the Jugular Foramen: A Cadaveric Observation. AB - BACKGROUND: The ascending pharyngeal artery (APA) may, in very rare cases, supply the posterior inferior cerebellar artery (PICA). In reported cases, when such is the case, the ipsilateral vertebral artery (VA) does not supply the PICA, and most of the time it is hypoplastic. OBJECTIVE: To describe a unique cadaveric observation of a direct anastomosis between the posterior division (neuromeningeal) of the jugular branch of the APA and the PICA, where the PICA is also supplied by a normal-size VA. METHODS: A direct connection between the APA and the PICA was examined in a cadaveric specimen using a 3-dimensional endoscope and a surgical microscope. RESULTS: The enlarged jugular branch of the posterior division of the APA entered intracranially via the jugular foramen in its pars vascularis. It then connected directly with the lateral medullary segment of the PICA. The first segment of the PICA originated from a left vertebral artery of normal size and continued its normal course beyond the junction with the jugular branch of the APA. CONCLUSION: Both the VA and the jugular branch of the APA may simultaneously supply the PICA territory. Recognition of this anatomic variant is relevant when planning surgical or endovascular treatments. PMID- 29506096 TI - Anatomy of the Spinal Meninges. AB - BACKGROUND: The spinal meninges have received less attention than the cranial meninges in the literature, although several points remain debatable and poorly understood, like their phylogenesis, their development, and their interactions with the spinal cord. Their constancy among the chordates shows their crucial importance in central nervous system homeostasis and suggests a role far beyond mechanical protection of the neuraxis. OBJECTIVE: This work provides an extensive study of the spinal meninges, from an overview of their phylogenesis and embryology to a descriptive and topographic anatomy with clinical implications. It examines their involvement in spinal cord development, functioning, and repair. METHODS: This work is a review of the literature using PubMed as a search engine on Medline. RESULTS: The stages followed by the meninges along the phylogenesis could not be easily compared with their development in vertebrates for methodological aspects and convergence processes throughout evolution. The distinction between arachnoid and pia mater appeared controversial. Several points of descriptive anatomy remain debatable: the functional organization of the arterial network, and the venous and lymphatic drainages, considered differently by classical anatomic and neuroradiological approaches. Spinal meninges are involved in neurodevelopment and neurorepair producing neural stem cells and morphogens, in cerebrospinal fluid dynamics and neuraxis functioning by the synthesis of active molecules, and the elimination of waste products of central nervous system metabolism. CONCLUSION: The spinal meninges should be considered as dynamic functional formations evolving over a lifetime, with ultrastructural features and functional interactions with the neuraxis remaining not fully understood. PMID- 29506097 TI - The Lurking Catastrophic Complication of an Equally Catastrophic Disease: The Lesson Learned. AB - BACKGROUND: Medullary-bridging vein dural arteriovenous fistula (DAVF) is an uncommon type of DAVF with an aggressive clinical course due to direct fistulous shunting into medullary and brainstem veins. Important considerations need to be given to retrograde embolic migration or perforator involvement while treating these fistulas endovascularly with a liquid embolic agent. We report a lateral spinal artery feeding the DAVF, the recognition of which is important to avoid potential catastrophic complications during definitive therapy, and which has not been described before. OBJECTIVE: To discuss the anatomy of the lateral spinal artery (LSA) and its communications with pial arteries such as the posterior inferior cerebellar artery (PICA) that may have important implications in the management of neurovascular diseases in and around the foramen magnum. METHODS: A retrospective analysis of cerebral angiograms and 3-dimensional rotational angiograms of a patient with medullary-bridging vein DAVF treated by transarterial embolization under balloon protection was performed after the patient developed lateral medullary syndrome in the postoperative period. RESULTS: Detailed analysis revealed a dural branch from the LSA feeding the DAVF which anastomosed with rudimentary PICA. CONCLUSION: LSA has important anastomoses with perforating arteries of the medulla and cervical cord and, hence, it is important to recognize and identify LSA prospectively in the vascular pathologies of the foramen magnum to avoid fatal neurological complications during endovascular therapy. This is especially important while treating neurovascular pathologies using liquid embolic agents such as Onyx or SQUID, because they can percolate retrogradely through the anastomoses into PICA or other vertebrobasilar perforators. PMID- 29506098 TI - Microsurgical Clipping of Bilateral Superior Hypophyseal Artery Aneurysms Through Unilateral Pterional Craniotomy: 3-Dimensional Operative Video. PMID- 29506099 TI - V3 Vertebral Artery to M2 Middle Cerebral Artery Bypass: 3-Dimensional Operative Video. PMID- 29506100 TI - Two Distal Posterior Inferior Cerebellar Artery Aneurysms Treated With Trapping Reanastomosis and Clipping: 3-Dimensional Operative Video. PMID- 29506101 TI - Reduction in Syrinx Size and Severity After Venous Sinus Stenting in a Patient With Pseudotumor Cerebri and Chiari Malformation: Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Pseudotumor cerebri and Chiari I malformation are found to coexist in a subset of patients. Surgical cranial decompression has been the mainstay of Chiari malformation management, whereas venous sinus stenting has emerged as an effective treatment modality for pseudotumor cerebri. Gaps in our current understanding of cerebrospinal fluid (CSF) circulation and the pathophysiology behind CSF-related disorders present difficulties in the simultaneous management of these conditions. A case is presented of the successful management of both conditions with venous sinus stenting, with sustained improvement in symptoms and structural abnormalities of the Chiari malformation and associated syrinxes. CLINICAL PRESENTATION: An obese woman in her 20s with a history of occipital headaches who presented with progressively worsening intermittent visual obscurations was diagnosed with pseudotumor cerebri, Chiari I malformation, and associated spinal syrinxes. Magnetic resonance venography demonstrated right transverse sinus narrowing with an elevated pressure gradient. Successful endovascular intervention with venous sinus stenting achieved normalization of the venous sinus pressure gradient and symptomatic improvement. After stenting, the cervical syrinx was observed to have decreased in size, with a decrease in the extent of cerebellar tonsillar herniation and an increase in CSF signal around the cerebellar tonsils. CONCLUSION: Venous sinus stenting for treatment of concomitant pseudotumor cerebri and Chiari I malformation can be effective in patients demonstrating transverse sinus stenosis. PMID- 29506102 TI - Monteris AXiiiS Stereotactic Miniframe for Intracranial Biopsy: Precision, Feasibility, and Ease of Use: Erratum. PMID- 29506104 TI - Early Results in Flow Diverter Sizing by Computational Simulation: Quantification of Size Change and Simulation Error Assessment. PMID- 29506103 TI - Prevalence of Tick-Borne Pathogens in Two Species of Peromyscus Mice Common in Northern Wisconsin. AB - Two species of mice, the white-footed mouse, Peromyscus leucopus (Rafinesque; Rodentia: Cricetidae) and the woodland deer mouse, Peromyscus maniculatus (Wagner; Rodentia: Cricetidae), serve as reservoirs of tick-borne pathogens in many parts of North America. However, the role P. maniculatus plays in the amplification and maintenance of Anaplasma phagocytophilum (Rickettsiales: Ehrlichiaceae) and Borrelia burgdorferi (Spirochaetales: Spirochaetaceae) is not well understood. In northern Wisconsin, from 2012 to 2014, 560 unique mice were captured at 83 sites distributed across five forests. P. leucopus was more likely infested with immature Ixodes scapularis compared to P. maniculatus (60.1 vs. 28.3%). Abundance of immature I. scapularis on P. leucopus (M = 2.69; SD = 3.53) was surprisingly low and even lower for P. maniculatus (M = 0.717; SD = 1.44). Both P. leucopus and P. maniculatus were infected with B. burgdorferi, 24.0 and 16.8%, respectively. The prevalence of A. phagocytophilum infection in P. leucopus (1.69%) was similar to that observed in P. maniculatus (4.73%). Nine of 10 mice co-infected with both pathogens were P. maniculatus, and there were more co-infections in this species than expected by chance (3.07 vs. 0.82%). Differences in the behavior and biology between these two mice species may contribute to the variation observed in the abundance of host-attached ticks and pathogen prevalence. These differences highlight a potential hazard of the failure to differentiate between these visually similar mice, but there is evidence that these two mice species can each serve as reservoirs for tick-borne pathogens that cause human disease in Wisconsin. PMID- 29506105 TI - Changes in Disease Behaviour and Location in Patients With Crohn's Disease After Seven Years of Follow-Up: A Danish Population-based Inception Cohort. AB - Background and Aim: Crohn's disease [CD] is a progressive inflammatory bowel disease that can lead to complications such as strictures or penetrating disease, and ultimately surgery. Few population-based studies have investigated the predictors for disease progression and surgery in CD according to the Montreal classification. We aimed to identify clinical predictors associated with complicated CD in a Danish population-based inception cohort during the biologic era. Methods: All incident patients with CD in a well-defined Copenhagen area, between 2003 and 2004, were followed prospectively until 2011. Disease progression was defined as the development of bowel stricture [B2] or penetrating disease [B3] in patients initially diagnosed with non-stricturing/non-penetrating disease [B1]. Associations between disease progression and/or resection, and multiple covariates, were investigated by Cox regression analyses. Results: In total, 213 CD patients were followed. A total of 177 [83%] patients had B1 at diagnosis. Patients who changed location had increased risk of disease progression (hazard ratio [HR] = 3.1, 95% CI: 1.12,8.52). Biologic treatment was associated with lower risk of change in location [HR = 0.3, 95% CI: 0.1-0.7]. Colonic involvement [L2 or L3 vs L1] was associated with a lower risk of surgery (HR = 0.34/0.22, 95% CI: [0.13,0.86]/[0.08,0.60]). All CD patients who progressed in behaviour or changed location had an increased risk of surgery [p < 0.05]. Conclusions: This population-based inception cohort study demonstrates that changes in disease location or behaviour in patients with CD increase their risk of resection. Our findings highlight the protective effect of biologic treatment with regard to change in disease location, which might ultimately improve the disease course for CD patients. PMID- 29506106 TI - DigR: a generic model and its open source simulation software to mimic three dimensional root-system architecture diversity. AB - Background and Aims: Many studies exist in the literature dealing with mathematical representations of root systems, categorized, for example, as pure structure description, partial derivative equations or functional-structural plant models. However, in these studies, root architecture modelling has seldom been carried out at the organ level with the inclusion of environmental influences that can be integrated into a whole plant characterization. Methods: We have conducted a multidisciplinary study on root systems including field observations, architectural analysis, and formal and mathematical modelling. This integrative and coherent approach leads to a generic model (DigR) and its software simulator. Architecture analysis applied to root systems helps at root type classification and architectural unit design for each species. Roots belonging to a particular type share dynamic and morphological characteristics which consist of topological and geometric features. The DigR simulator is integrated into the Xplo environment, with a user interface to input parameter values and make output ready for dynamic 3-D visualization, statistical analysis and saving to standard formats. DigR is simulated in a quasi-parallel computing algorithm and may be used either as a standalone tool or integrated into other simulation platforms. The software is open-source and free to download at http://amapstudio.cirad.fr/soft/xplo/download. Key Results: DigR is based on three key points: (1) a root-system architectural analysis, (2) root type classification and modelling and (3) a restricted set of 23 root type parameters with flexible values indexed in terms of root position. Genericity and botanical accuracy of the model is demonstrated for growth, branching, mortality and reiteration processes, and for different root architectures. Plugin examples demonstrate the model's versatility at simulating plastic responses to environmental constraints. Outputs of the model include diverse root system structures such as tap-root, fasciculate, tuberous, nodulated and clustered root systems. Conclusions: DigR is based on plant architecture analysis which leads to specific root type classification and organization that are directly linked to field measurements. The open source simulator of the model has been included within a friendly user environment. DigR accuracy and versatility are demonstrated for growth simulations of complex root systems for both annual and perennial plants. PMID- 29506107 TI - Intervertebral Micro Access Surgery for Transforaminal Lumbar Interbody Fusion. AB - BACKGROUND: Minimally invasive spine surgery (MIS) has undergone tremendous progress in the past 2 decades. The intervertebral micro access surgery (iMAS) technique represents a hybrid of both open and minimally invasive techniques. OBJECTIVE: To describe the surgical technique and operative nuances of the iMAS technique. METHODS: We describe a novel operative approach for the standard transforaminal lumbar interbody fusion with pedicle screw fixation. Described are the preoperative planning, incision and approach, pedicle screw insertion, facetectomy and discectomy, transforaminal interbody placement, and direct decompression. RESULTS: Early experience suggests that iMAS is well suited for the same degenerative conditions currently treated with open or MIS transforaminal lumbar interbody fusion, including grade I spondylolisthesis, unilateral synovial cysts with instability, unilateral disc herniations with instability, and recurrent disc herniations. CONCLUSION: The novel integration of both open and MIS techniques makes iMAS an attractive approach for select degenerative lumbar disease processes. Similar to other MIS procedures, minimal tissue disruption may allow for more rapid patient recovery, reduced blood loss, and reduced length of hospital stay. PMID- 29506108 TI - Anterior Longitudinal Ligament Release From the Minimally Invasive Lateral Retroperitoneal Transpsoas Approach: Technical Note. AB - BACKGROUND: The technique for minimally invasive anterior longitudinal ligament release is a major advancement in lateral access surgery. This method provides hypermobility of lumbar segments to allow for aggressive lordosis restoration while maintaining the benefits of indirect decompression and minimally invasive access. OBJECTIVE: To provide video demonstration of the lateral retroperitoneal transpsoas approach with anterior longitudinal ligament sectioning. METHODS: A detailed surgical technique of the minimally invasive anterior column release is described and illustrated in an elderly patient with adult spinal deformity and low back pain (visual analog scale, 8 of 10) refractory to conservative measures. The 3-foot standing radiographs demonstrated a lumbar lordosis of 54.4 degrees , pelvic incidence of 63.7 degrees , and pelvic tilt of 17.5 degrees . Computed tomography and magnetic resonance imaging showed generalized lumbar spondylosis and degenerative disc changes from L2 to L5. RESULTS: The patient underwent a multilevel minimally invasive deformity correction with an anterior longitudinal ligament release at the L3/L4 level through the lateral retroperitoneal transpsoas approach. Lumbar lordosis increased from 54.4 degrees to 77 degrees with a global improvement in sagittal vertical axis from 4.37 cm to 0 cm. Total blood loss was less than 25 mL, and there were no major neurological or vascular complications. CONCLUSION: The anterior longitudinal ligament release using the minimally invasive lateral approach allows for deformity correction without the morbidity and blood loss encountered by traditional open posterior approaches. However, the risk of major vascular/visceral complication warrants only experts in minimally invasive lateral surgery to attempt this technique. PMID- 29506110 TI - Three-Dimensional Simulation of Collision-Free Paths for Combined Endoscopic Third Ventriculostomy and Pineal Region Tumor Biopsy: Implications for the Design Specifications of Future Flexible Endoscopic Instruments. AB - BACKGROUND: Recent innovations to expand the scope of intraventricular neuroendoscopy have focused on transitioning multiple-incision procedures into single-corridor approaches. However, the successful adoption of these combined procedures requires minimizing the unwanted torques applied to surrounding healthy structures. OBJECTIVE: To define the geometry of relevant anatomical structures in endoscopic third ventriculostomy (ETV) and pineal region tumor biopsy (ETB). Second, to determine the optimal instrument shaft path required for collision-free single burr hole combined ETV/ETB. METHODS: Magnetic resonance and computed tomography data from 15 pediatric patients who underwent both ETV and ETB procedures between 2006 and 2014 was segmented by using the 3DSlicer software package to create virtual 3-D patient models. Anatomical regions of interest were measured including the foramen of Monro, the massa intermedia, the floor of the third ventricle, and the tumor margin. Utilizing the MATLAB software package, virtual dexterous instruments were inserted into the models and optimal dimensions were calculated. RESULTS: The diameters of the foramen of Monro, massa intermedia (anterior-posterior, superior-inferior), anterior third ventricle, and tumor margin are 6.85, 4.01, 5.05, 14.2, and 28.5 mm, respectively. The average optimal burr placement was determined to be 22.5 mm anterior to the coronal and 30 mm lateral to the sagittal sutures. Optimal flexible instrument geometries for novel instruments were calculated. CONCLUSION: We have established a platform for estimating the shape of novel curved dexterous instruments for collision-free targeting of multiple intraventricular points, which is both patient and tool specific and can be integrated with image guidance. These data will aid in developing novel dexterous instruments. PMID- 29506109 TI - Endoscopic Transnasal Odontoidectomy With Anterior C1 Arch Preservation and Anterior Vertebral Column Reconstruction in Patients With Irreducible Bulbomedullary Compression by Complex Craniovertebral Junction Abnormalities: Operative Nuance. AB - BACKGROUND: During the past decades, the transoral transpharyngeal approach has been advocated as the standard route for the removal of odontoid causing an irreducible symptomatic neural compression. However, it may be potentially associated with a significant built-in morbidity because of the splitting of the soft palate for an adequate working angle, tracheostomy, and incision of the oral mucosa, causing exposure to a higher risk of infection by oral flora. OBJECTIVE: To describe our experience with the minimally invasive pure endoscopic transnasal odontoidectomy in patients with bulbomedullary compression affected by complex anterior craniovertebral junction abnormalities. METHODS: Five patients underwent a pure endoscopic neuronavigation-assisted transnasal odontoidectomy with anterior C1 arch preservation. Moreover, the anterior cervical spine column was reconstructed by filling the gap between the C1 arch and the residual C2 body with autologous/artificial bone. Neither tracheostomy nor enteral tube feeding were needed in any case. RESULTS: A postoperative neurological improvement was observed in all patients. Postoperative imaging confirmed a satisfactory spinal cord decompression with cervical anterior column arthrodesis, and without evidence of instability at follow-up, so far. CONCLUSION: The endoscopic transnasal approach seems to represent an efficient and safe alternative to the transoral route for the resection of odontoid process causing irreducible bulbomedullary compression. It provides a straightforward and minimally invasive natural surgical corridor to the anterior craniocervical junction, allowing a better working angle with preservation of spine biomechanics, while minimizing potential comorbidities. PMID- 29506111 TI - Complex Alterations of Intracranial 4-Dimensional Hemodynamics in Vein of Galen Aneurysmal Malformations During Staged Endovascular Embolization. AB - BACKGROUND: Vein of Galen aneurysmal malformations (VGAMs) are rare congenital cerebral arteriovenous shunts often treated by staged endovascular embolization early in life. Treatment-induced changes in intracranial hemodynamics and their impact on the clinical management of VGAM patients remain unclear. OBJECTIVE: To evaluate hemodynamic alterations in the cerebral arterial and venous network in pediatric patients with VGAMs during staged embolizations. METHODS: Serial 4 dimensional flow magnetic resonance imaging (21 scans) was performed in 6 VGAM patients (3 female; mean age, 2.1 +/- 4.0 years) undergoing staged embolization. Time-integrated pathlines were used to visualize 3-dimensional blood flow changes in intracranial arterial and venous systems. Total cerebral arterial inflow (flow in bilateral internal carotid arteries plus basilar artery), arteriovenous shunt flow, and blood flow in other major cerebral arteries (middle cerebral artery; posterior cerebral artery) were quantified for all patients. RESULTS: Intracranial 3-dimensional blood flow visualization demonstrated marked reduction of arteriovenous shunting and distinct hemodynamic alterations after embolization. From baseline to endpoint embolization, total cerebral arterial inflow dropped by 40.2% (from 22.70 +/- 6.54 mL/s to 13.57 +/- 4.87 mL/s), corresponding to arteriovenous shunt flow reduction of 73.5% (from 9.69 +/- 6.16 mL/s to 2.57 +/- 3.79 mL/s). In addition, the ipsilateral posterior cerebral artery/middle cerebral artery flow ratio decreased by 86.9% (from 4.20 +/- 6.28 to 0.55 +/- 0.23). CONCLUSION: Hemodynamic alterations in VGAMs after embolization can be visualized and quantified using 4-dimensional flow magnetic resonance imaging. Cerebral arterial inflow and arteriovenous shunt flow reduction and complex flow redistribution after embolization illustrate the potential of 4-dimensional flow magnetic resonance imaging to better evaluate the efficacy of interventions and monitor treatment effects. PMID- 29506112 TI - Stent Retriever-Assisted Mechanical Thrombectomy for Acute Basilar Artery Occlusion: Single US Institution Experience. AB - BACKGROUND: Acute basilar artery occlusion causes devastating strokes that carry high mortality and morbidity. OBJECTIVE: To report the outcomes of mechanical thrombectomy in the posterior circulation with a focus on safety and efficacy of stent retrievers. METHODS: We retrospectively reviewed our endovascular database for all patients treated with stent retrievers for posterior circulation stroke between June 2012 and June 2014. Twelve patients were identified. The following data were analyzed: thrombus location, previous stroke or transient ischemic attack, thrombus etiology, comorbidities, time from presentation to initiation of endovascular treatment, time from start of angiography to revascularization, and whether intravenous tissue plasminogen activator was administered pre thrombectomy. Outcome was considered poor when modified Rankin Scale score was >2. RESULTS: Mean patient age was 63.42 years (median, 64.5; range, 28-83 years); 7 were women. Successful recanalization (Thrombolysis in Cerebral Infarction grade 2b or 3) was achieved in 11 of 12 patients (91.7%). Mean discharge modified Rankin Scale score was 2.3 (median, 2.0; standard deviation 1.96; range, 0-6), with a favorable discharge outcome in 9 of 12 (75%) patients. Two patients died as inpatients. Mean follow-up modified Rankin Scale score was 1.4 (median, 1.00; standard deviation 1.075; range, 0-4). Good outcome was achieved in 9 of 10 (90%) patients at last follow-up (mean follow-up duration, 132.42 days [median, 90.50; standard deviation 80.2; range, 8-378 days]). CONCLUSION: Our single-institution study has shown that good clinical outcomes and successful recanalization with acceptable mortality can be achieved with current stent retrievers. PMID- 29506113 TI - Intraoperative Identification of a Normal Pituitary Gland and an Adenoma Using Near-Infrared Fluorescence Imaging and Low-Dose Indocyanine Green. AB - BACKGROUND: The intraoperative distinction between normal and abnormal pituitary tissue is crucial during pituitary adenoma surgery to obtain a complete tumor resection while preserving endocrine function. Near-infrared (NIR) fluorescence imaging is a technique to intraoperatively visualize tumors by using indocyanine green (ICG), a contrast agent allowing visualization of differences in tissue vascularization. Although NIR fluorescence imaging has been described in pituitary surgery, it has, in contrast to other surgical areas, never become widely used. OBJECTIVE: To evaluate NIR fluorescence imaging in pituitary surgery, both qualitatively and quantitatively, and to assess the additional value of resecting adenoma tissue under NIR fluorescence guidance. METHODS: We included 10 patients planned to undergo transnasal transsphenoidal selective adenomectomy. Patients received multiple intravenous administrations of 5 mg ICG, up to a maximum of 15 mg per patient. Endoscopic NIR fluorescence imaging was performed at multiple points in time. The NIR fluorescent signal in both the adenoma and pituitary gland was obtained, and the fluorescence contrast ratio was assessed. RESULTS: Four patients had Cushing disease, 1 had acromegaly, and 1 had a prolactinoma. Four patients had a nonfunctioning macroadenoma. In 9 of 10 patients with a histologically proven pituitary adenoma, the normal pituitary gland showed a stronger fluorescent signal than the adenoma. A fluorescence contrast ratio of normal pituitary gland to adenoma of 1.5 +/- 0.2 was obtained. In 2 patients; adenoma resection was actually performed under NIR fluorescence guidance instead of under white light. CONCLUSION: NIR fluorescence imaging can easily and safely be implemented in pituitary surgery. The timing of ICG administration is important for optimal results and warrants further study. It appears that injection of ICG can best be postponed until some part of the normal pituitary gland is identified. Subsequent repeated low-dose ICG administrations improved the distinction between adenoma and gland. PMID- 29506114 TI - Microsurgical and Fiber Tract Anatomy of the Nucleus Accumbens. AB - BACKGROUND: The nucleus accumbens (NAc) has been a target for deep brain stimulation (DBS) in the treatment of depression and obsessive-compulsive disorder (OCD). OBJECTIVE: To examine the anatomy and connections of the NAc using a fiber dissection technique. METHODS: Ten human brains and 2 whole cadaveric heads were examined by fiber dissection technique and *6 to *40 surgical magnification. The NAc was examined from the lateral, medial, superior, and inferior sides to define its fiber connections and relationships with adjacent cortical and subcortical structures. Magnetic resonance imaging (MRI) with 1-mm slices was used to define its neuronavigation coordinates. RESULTS: Eight tracts, the uncinate fasciculus, cingulum, stria medullaris thalami, fornix, diagonal band of Broca, stria terminalis, medial olfactory stria, and forceps minor, form a capsule around the anterior, inferior, and medial sides of the NAc. The uncinate fasciculus connects along the inferior and adjacent part of the medial side of the NAc, the cingulum and diagonal band along the medial surface, the medial olfactory stria along the posteromedial and adjacent part of the inferior surface, the forceps minor along the anteromedial surface, and the stria terminalis, fornix, and stria medullaris along the posterosuperior surface. The subcortical gray matter related to the NAc includes the septal nuclei, indusium griseum, substantia innominata, caudate nucleus, and hypothalamus. The cortical areas communicating with and overlying the NAc are reviewed. CONCLUSION: An increased understanding of the fiber connections and neural relationships of the NAc should allow more accurate DBS targeting for the treatment of psychiatric disorders. PMID- 29506115 TI - Anatomical Variations of the Anterior Clinoid Process: A Study of 597 Skull Base Computerized Tomography Scans. AB - BACKGROUND: The anterior clinoid process (ACP) is surrounded by a complex anatomy; variations include pneumatization and the formation of bone bridges with the middle and posterior clinoid, which complicate surgery. The key to avoiding microsurgical complications is a perfect understanding of this anatomy. OBJECTIVE: To explore the anatomic variations of the ACP. METHODS: Between January 1, 2013, and September 6, 2014, 597 skull base computed tomography scans were performed to evaluate inner ear disease in patients with no history of paranasal sinus disease or endonasal surgery. The base width and length of the ACP, complete carotid-clinoid foramen and sella turcica bridge, and sphenoid sinus pneumatization volume were assessed. ACP pneumatization was assessed with the use of a novel classification system. RESULTS: The scans were derived from a population of 343 female patients (57.5%), with a mean age of 38.6 years (0.2-90 years). ACP base width and length were 7.7 +/- 1.73 and 10.31 +/- 2.1 mm, respectively. Anatomic variations were present in 38.7% of scans. ACP pneumatization was present in 25.5% of scans, and carotid-clinoid foramen and sella turcica bridge were present in 14.2% and 14.4% of scans, respectively. There was no pneumatization of the ACP in patients <10 years of age and no progression of the pneumatization of the sphenoid sinus in patients >10 years old. CONCLUSION: At least 1 variation in ACP anatomy was found in 38.7% of cases with this simple method. Thus, a preoperative computed tomography scan could improve surgical procedures that involve removal of the anterior clinoid process. PMID- 29506116 TI - Incidence, Management, and Outcome of Symptomatic Postoperative Posterior Fossa Pseudomeningocele: A Retrospective Single-Institution Experience. AB - BACKGROUND: Pseudomeningocele is a source of considerable morbidity after posterior fossa surgery, but incidence and optimal management strategies are unclear. OBJECTIVE: To define risk factors, evaluate management strategies, and identify predictors of resolution. METHODS: A prospectively maintained database of 687 consecutive posterior fossa operations at a single institution was analyzed to identify cases of symptomatic postoperative pseudomeningocele. Retrospective analysis of treatment strategies and outcome was performed. RESULTS: Overall rate of symptomatic postoperative pseudomeningocele was 14.1% (97 cases). The highest rate was for midline posterior fossa surgery (16.5%), and the lowest rate was for retrosigmoid surgery (11.9%). Multivariate logistic regression analysis revealed that the presence of increased ventricle size on postoperative imaging predicted significantly higher risk of failure of lumbar drainage (odds ratio, 6.57; 95% confidence interval [CI], 1.18-36.59; P < .05). Cox proportional hazards analysis revealed that time to clinical resolution was significantly associated only with use of temporary lumbar drainage (hazards ratio, 2.28; 95% CI, 1.04-5.00; P < .05), and time to radiographic resolution was associated only with placement of a ventricular shunt (hazards ratio, 2.84; 95% CI, 1.19-6.78; P < .05). CONCLUSION: Pseudomeningocele is a common complication after posterior fossa surgery, but incidence is not related to age or medical comorbidity. Postoperative ventriculomegaly portends failure of temporary cerebrospinal fluid diversion, and early consideration of shunting might be appropriate in such cases. In the absence of ventriculomegaly, temporary use of a lumbar drain leads to earlier clinical resolution, but complete radiographic resolution is rare when a permanent shunt is not implanted. Further research should be performed to establish the most effective treatment strategy. PMID- 29506117 TI - Revascularization of the Posterior Inferior Cerebellar Artery With Contralateral Reimplantation of Right Posterior Inferior Cerebellar Artery to Left Posterior Inferior Cerebellar Artery: 3-Dimensional Operative Video. PMID- 29506118 TI - Simultaneous Microsurgical Treatment of a Cerebellar Arteriovenous Malformation and a Distal Superior Cerebellar Artery Aneurysm: 3-Dimensional Operative Video. PMID- 29506119 TI - Delayed Spinal Cord Herniation After a Swordfish Attack. PMID- 29506120 TI - Granulosa cells from human primordial and primary follicles show differential global gene expression profiles. AB - STUDY QUESTION: Can novel genetic candidates involved in follicle dormancy, activation and integrity be identified from transcriptomic profiles of isolated granulosa cells from human primordial and primary follicles? SUMMARY ANSWER: The granulosa cell compartment of the human primordial and primary follicle was extensively enriched in signal transducer and activator of transcription 3 (STAT3) and cAMP-response element binding protein (CREB) signalling, and several other putative signalling pathways that may also be mediators of follicle growth and development were identified. WHAT IS KNOWN ALREADY: Mechanistic target of rapamycin kinase (mTOR) signalling and the factors Forkhead Box L2 (FOXL2) and KIT proto-oncogene receptor tyrosine kinase (KITL) may be involved in defining the early steps of mammalian follicular recruitment through complex bidirectional signalling between the oocyte and granulosa cells. cAMP/protein kinase K (PKA)/CREB signalling is a feature of FSH-induced regulation of granulosa cell steroidogenesis that is essential to normal human fertility. STUDY DESIGN, SIZE, DURATION: A class comparison study was carried out on primordial follicles (n = 539 follicles) and primary follicles (n = 261) follicles) donated by three women having ovarian tissue cryopreserved before chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA samples from isolates of laser capture micro-dissected oocytes and follicles from the primordial and primary stage, respectively, were sequenced on the HiSeq Illumina platform. Data mapping, quality control, filtering, FPKM (fragments per kilobase of exon per million) normalization and comparisons were performed. The granulosa cell contribution in whole follicle isolates was extracted in silico. Modelling of complex biological systems was performed using Ingenuity Pathway Analysis (IPA). For validation of transcriptomic findings, we performed quantitative RT-PCR of selected candidate genes. Furthermore, we interrogated the in situ localization of selected corresponding proteins using immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE: Our differentially expressed gene analysis revealed a number of transcripts in the granulosa cells to be significantly down- (736 genes) or up- (294 genes) regulated during the human primordial-to-primary follicle transition. The IPA analysis revealed enriched canonical signalling pathways not previously associated with granulosa cells from human primordial and primary follicles. Immunofluorescent staining of human ovarian tissue explored the intra-ovarian localization of FOG2, and FOXL2, which revealed the presence of forkhead box L2 (FOXL2) in both oocytes and granulosa cells in primary follicles, with a more enriched staining in the granulosa cells in primary follicles. Friend of GATA 2 (FOG2) stained strongly in oocytes in primordial follicles, with a shift towards granulosa cell as follicle stage advanced. LARGE SCALE DATA: http://users birc.au.dk/biopv/published_data/ernst_et_al_GC_2017/. LIMITATIONS REASONS FOR CAUTION: This is a descriptive study, and no functional assays were employed. The study was based on a limited number of patients, and it is acknowledged that natural biological variance exists in human samples. Strict filters were applied to accommodate the in silico extraction of the granulosa cell contribution. In support of this, quantitative RT-PCR was used to confirm selected candidate genes, and immunofluorescent staining was employed to interrogate the intra ovarian distribution of selected corresponding proteins. Moreover, it is unknown whether the primordial follicles analysed represent those still in the resting pool, or those from the cohort that have entered the growing pool. WIDER IMPLICATIONS OF THE FINDINGS: We present, for the first time, a detailed description of global gene activity in the human granulosa cell compartment of primordial and primary follicles. These results may be utilized in the development of novel clinical treatment strategies aimed at improving granulosa cell function. STUDY FUNDING/COMPETING INTEREST(S): E.H.E. was supported by the Health Faculty, Aarhus University and Kong Christian Den Tiendes Fond. K.L.H. was supported by a grant from Fondens til Laegevidenskabens Fremme and Kong Christian Den Tiendes Fond. No authors have competing interests to declare. PMID- 29506121 TI - Natural Occurrence of Secondary Bacterial Symbionts in Aphids from Tunisia, with a Focus on Genus Hyalopterus. AB - Aphids (Hemiptera: Aphididae) can harbor two types of bacterial symbionts. In addition to the obligate endosymbiont Buchnera aphidicola Munson, Baumann and Kinsey 1991 (Enterobacteriales: Enterobacteriaceae), several facultative symbiotic bacteria, called secondary (S) symbionts, have been identified among many important pest aphid species. To determine interpopulational diversity of S symbionts, we carried out a survey in a total of 18 populations of six aphid species collected from six localities in Tunisia, by performing a diagnostic polymerase chain reaction analysis of partial 16S-23S rRNA operon sequences. While 61.7% of individuals contained only Buchnera, three S-symbionts were found at different frequencies. Arsenophonus sp. Gherna et al. 1991 (Enterobacteriales: Enterobacteriaceae) was found in all species under study except for Acyrtosiphon pisum (Harris 1776) (Aphidinae: Macrosiphini); Serratia symbiotica Moran et al. 2005 (Enterobacteriales: Enterobacteriaceae) was present in all analyzed individuals of A. pisum but only sporadically in Aphis spiraecola (Patch 1914) (Aphidinae: Aphidini) and Hyalopterus amygdali (Blanchard 1840) (Aphidinae: Aphidini), while Hamiltonella defensa Moran et al. 2005 (Enterobacteriales: Enterobacteriaceae) was found in all analyzed individuals of one population of Aphis gossypii (Glover 1877) (Aphidinae: Aphidini) and sporadically in two populations of Hyalopterus. The lysogenic bacteriophage APSE-1 (A. pisum secondary endosymbiont, type 1) was detected in the three populations infected with H. defensa. This bacteriophage has been associated with moderate protection against braconid parasitoids in pea aphids. The high prevalence of Arsenophonus sp. in our samples is in accordance with previous studies indicating that, among gammaproteobacteria, this genus is one of the most widespread insect facultative symbionts. PMID- 29506122 TI - Profiles of circular RNAs in human placenta and their potential roles related to preeclampsia. AB - To identify the profiles of circular RNAs (circRNAs) in human placental tissues and to explore the potential roles of dysregulated circRNAs in the pathological genesis of preeclampsia, expression profiles of circRNAs in human placentas were performed in this study. Utilizing high-throughput technology, based on fold changes and P values, 300 circRNAs that are differentially expressed between preeclampsia and normal placental tissues were identified. Among them, hg38_circ_0014736 and hsa_circ_0015382 were validated as significantly upregulated by real-time quantitative PCR with divergent primers. At the same time, hsa_circ_0007121 was significantly downregulated. GO analysis revealed that the three altered circRNAs had a relationship with transcription regulation, proliferation, protein binding, and response to hypoxia. KEGG analysis yielded that apoptosis, Wnt signaling, and HIF-1 pathways were significantly enriched. Interestingly, hsa_circ_0007121 was found to be expressed differently in plasma between preeclampsia and normal pregnancy and this difference could be detected before 20 gestational weeks. Besides, addition receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve of hsa_circ_0007121 reached 0.72 ([0.59-0.85], P = 0.004) with a sensitivity of 0.77 and specificity of 0.70. Collectively, this study demonstrates the existence of dysregulated circRNAs in the placenta of preeclampsia patients and annotates their potential roles in the pathogenesis of the disease. Encouragingly, hsa_circ_0007121 was found to be a potential noninvasive biomarker for the prediction of preeclampsia. PMID- 29506123 TI - Meta-analysis of lamb birth weight as influenced by pregnancy nutrition of multiparous ewes. AB - Across the literature, there is large variation in lamb birth weight responses to changes in the ewe pregnancy nutrition. Much of this heterogeneity has been attributed to several factors inherent to each experiment; however, the relative contribution of these experimental factors has not yet been quantified. This meta analysis aimed to systematically review the variation in lamb birth weight responses across nutritional studies involving adult multiparous ewes. Effect sizes for individual studies were estimated using the unbiased estimator Hedges' g, whereby positive and negative values indicate heavier and lighter treatment lambs vs. controls, respectively. Heterogeneity varied between early-, mid- and late-pregnancy undernutrition studies (I2total [early pregnancy] = 19.90%, I2total [midpregnancy] = 52.10%, I2total [late pregnancy] = 68.70%). The small average effects for early- (0.04, highest posterior density [HPD] interval = 0.22, 0.28) and mid-pregnancy undernutrition (-0.15, HPD interval = -0.35, 0.05) suggest that if farmers anticipate a potential feed shortage, ewes can be allowed to lose weight providing nutrition is resumed to adequate levels later in pregnancy. On the contrary, late-pregnancy undernutrition was associated with a significant decrease in lamb birth weight (-0.72, HPD interval = -0.86, -0.55). Thus, management practices should focus on ensuring adequate nutrition in late pregnancy. Increasing lamb birth weight could be possible by feeding ewes above their pregnancy maintenance requirement (0.23, HPD interval = 0.002, 0.48), though the number of studies is limited and further research is needed. PMID- 29506124 TI - Clinical Response and Complications are not Associated with Drug Levels in Patients with Severe Ulcerative Colitis on IV Cyclosporine Induction Therapy. AB - Background: IV ciclosporin therapy is effective in steroid-refractory ulcerative colitis. The optimal drug level to achieve response and minimize complications during induction therapy is not known. Aim: The primary aim was to evaluate if serum ciclosporin drug levels are associated with increased risk of colectomy within 90 days of hospitalization. Secondary aims were to determine if ciclosporin levels are associated with avoidance of colectomy at 7 and 30 days, if ciclosporin levels are associated with drug-related and postoperative complications, and if patient-specific factors are associated with response to ciclosporin. Methods: We conducted a retrospective analysis of 81 hospitalized patients with steroid-refractory ulcerative colitis treated with ciclosporin. Risk factors for colectomy within 7, 30, and 90 days, medication-specific and postoperative complications were compared by first, mean, and peak ciclosporin level during IV induction therapy. Results: There were 47 patients (58%) who underwent surgery. There were no differences between initial, mean, and peak ciclosporin levels among responders and nonresponders and treatment-related or postoperative complications. Responders within 90 days had lower C-reactive protein levels (20mg/L vs. 38mg/L, P = 0.01), lower serum albumin concentrations (3.4g/dL vs. 3.7g/dL, P = 0.03), and higher rates of kidney injury (50% vs 17%, P = 0.002). Conclusion: Initial, mean, and peak serum levels of ciclosporin did not correlate with response or toxicity. However, C-reactive-protein levels levels and kidney injury may be helpful in predicting clinical response to ciclosporin. PMID- 29506125 TI - The future of continuing medical education: the roles of medical professional societies and the health care industry: Position paper prepared with contributions from the European Society of Cardiology Committees for Advocacy, Education and Industry Relations, Endorsed by the Board of the European Society of Cardiology. AB - In recent years, wide ranging biomedical innovation has provided powerful new approaches for prevention, diagnosis and management of diseases. In order to translate such innovation into effective practice, physicians must frequently update their knowledge base and skills through continuing medical education and training. Medical Professional Societies, run as not-for-profit organizations led by peers, are uniquely placed to deliver balanced, disease oriented and patient centred education. The medical industry has a major role in the development of new, improved technology, devices and medication. In fact, the best innovations have been achieved through collaboration with scientists, clinical academics and practicing physicians. Industry has for many years been committed to ensure the optimal and safe application of its products by providing unrestricted support of medical education developed and delivered by international and national learned societies. Recently adopted Codes of Practice for the Pharmaceutical and Device industry were intended to enhance public trust in the relationship between biomedical industry and physicians. Unexpectedly, changes resulting from adoption of the Codes have limited the opportunity for unconditional industry support of balanced medical education in favour of a more direct involvement of industry in informing physicians about their products. We describe the need for continuing medical education in Cardiovascular Medicine in Europe, interaction between the medical profession and medical industry, and propose measures to safeguard the provision of high quality, balanced medical education. PMID- 29506126 TI - A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula. AB - Purpose: Chemicals with hormonelike activity, such as estrogenic isoflavones, may perturb human development. Infants exclusively fed soy-based formula are highly exposed to isoflavones, but their physiologic responses remain uncharacterized. Estrogen-responsive postnatal development was compared in infants exclusively fed soy formula, cow-milk formula, and breast milk. Methods: We enrolled 410 infants born in Philadelphia-area hospitals between 2010 and 2014; 283 were exclusively fed soy formula (n = 102), cow-milk formula (n = 111), or breast milk (n = 70) throughout the study (birth to 28 or 36 weeks for boys and girls, respectively). We repeatedly measured maturation index (MI) in vaginal and urethral epithelial cells using standard cytological methods, uterine volume and breast-bud diameter using ultrasound, and serum estradiol and follicle-stimulating hormone levels. We estimated MI, organ-growth, and hormone trajectories by diet using mixed-effects regression splines. Results: Maternal demographics did not differ between cow milk-fed and soy-fed infants but did differ between formula-fed and breastfed infants. Vaginal-cell MI trended higher (P = 0.01) and uterine volume decreased more slowly (P = 0.01) in soy-fed girls compared with cow-milk-fed girls; however, their trajectories of breast-bud diameter and hormone concentrations did not differ. We observed no significant differences between boys fed cow-milk vs soy formula; estradiol was not detectable. Breastfed infants differed from soy formula-fed infants in vaginal-cell MI, uterine volume, and girls' estradiol and boys' breast-bud diameter trajectories. Conclusions: Relative to girls fed cow milk formula, those fed soy formula demonstrated tissue- and organ-level developmental trajectories consistent with response to exogenous estrogen exposure. Studies are needed to further evaluate the effects of soy on child development. PMID- 29506127 TI - Pharmacodynamics and cellular accumulation of amphotericin B and miltefosine in Leishmania donovani-infected primary macrophages. AB - Objectives: We examined the in vitro pharmacodynamics and cellular accumulation of the standard anti-leishmanial drugs amphotericin B and miltefosine in intracellular Leishmania donovani amastigote-macrophage drug assays. Methods: Primary mouse macrophages were infected with L. donovani amastigotes. In time kill assays infected macrophages were exposed to at least six different concentrations of serially diluted drugs and the percentage of infected macrophages was determined after 6, 12, 24, 48, 72 and 120 h of exposure. Cellular drug accumulation was measured following exposure to highly effective drug concentrations for 1, 6, 24, 48 and 72 h. Data were analysed through a mathematical model, relating drug concentration to the percentage of infected cells over time. Host cell membrane damage was evaluated through measurement of lactate dehydrogenase release. The effect of varying the serum and albumin concentrations in medium on the cellular accumulation levels of miltefosine was measured. Results: Amphotericin B was more potent than miltefosine (EC50 values of 0.65 and 1.26 MUM, respectively) and displayed a wider therapeutic window in vitro. The kinetics of the cellular accumulation of amphotericin B was concentration- and formulation-dependent. At an extracellular concentration of 10 MUM miltefosine maximum cellular drug levels preceded maximum anti-leishmanial kill. Miltefosine induced membrane damage in a concentration-, time- and serum dependent manner. Its cellular accumulation levels increased with decreasing amounts of protein in assay medium. Conclusions: We have developed a novel approach to investigate the cellular pharmacology of anti-leishmanial drugs that serves as a model for the characterization of new drug candidates. PMID- 29506129 TI - A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases. AB - A priority for the National Institute of Allergy and Infectious Diseases is development of a universal influenza vaccine providing durable protection against multiple influenza strains. NIAID will use this strategic plan as a foundation for future investments in influenza research. PMID- 29506128 TI - Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. AB - Background: Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. Methods: Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. Results: PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. Conclusions: PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes. PMID- 29506130 TI - A single-cell epigenetic model for paternal psychological stress-induced transgenerational reprogramming in offspring. AB - Experimental evidence shows that parental psychological stress affects the long term health of offspring in an inheritable fashion. Although epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, are involved in transgenerational programming, the underlining mechanisms of transgenerational inheritance remain unsolved. Here, we present a single-cell based computational model for transgenerational inheritance for investigating the long-term dynamics of phenotype changes in response to parental stress. The model is based on a recent study that has identified the imprinted sperm gene Sfmbt2 as a key target, and incorporates crosstalks among drastically different time scales in mammalian development, including DNA methylation, transcription, cell division, and population dynamics. Computational analysis of the model suggests a positive feedback to DNA methylation in the promoter region of sperm Sfmbt2 gene that provides a possible mechanism to mediate the parental psychological stress reprogramming in offspring. This approach provides a modeling framework for the understanding of the roles that epigenetics play in transgenerational inheritance. PMID- 29506132 TI - Beyond aesthetic consequences: congestive hepatopathy caused by pectus excavatum. AB - Pectus excavatum can lead to right ventricle compression. Although extremely rare, congestive hepatopathy should be considered when patients with severe pectus excavatum present with cardiovascular involvement. PMID- 29506131 TI - Comparative biochemical analysis of UHRF proteins reveals molecular mechanisms that uncouple UHRF2 from DNA methylation maintenance. AB - UHRF1 is a histone- and DNA-binding E3 ubiquitin ligase that functions with DNMT1 to maintain mammalian DNA methylation. UHRF1 facilitates DNMT1 recruitment to replicating chromatin through a coordinated mechanism involving histone and DNA recognition and histone ubiquitination. UHRF2 shares structural homology with UHRF1, but surprisingly lacks functional redundancy to facilitate DNA methylation maintenance. Molecular mechanisms uncoupling UHRF2 from DNA methylation maintenance are poorly defined. Through comprehensive and comparative biochemical analysis of recombinant human UHRF1 and UHRF2 reader and writer activities, we reveal conserved modes of histone PTM recognition but divergent DNA binding properties. While UHRF1 and UHRF2 diverge in their affinities toward hemi methylated DNA, we surprisingly show that both hemi-methylated and hemi hydroxymethylated DNA oligonucleotides stimulate UHRF2 ubiquitin ligase activity toward histone H3 peptide substrates. This is the first example of an E3 ligase allosterically regulated by DNA hydroxymethylation. However, UHRF2 is not a productive histone E3 ligase toward purified mononucleosomes, suggesting UHRF2 has an intra-domain architecture distinct from UHRF1 that is conformationally constrained when bound to chromatin. Collectively, our studies reveal that uncoupling of UHRF2 from the DNA methylation maintenance program is linked to differences in the molecular readout of chromatin signatures that connect UHRF1 to ubiquitination of histone H3. PMID- 29506134 TI - New Initiative Aims to Decrease Cardiovascular Risk for Rheumatoid Arthritis Sufferers. PMID- 29506133 TI - Tree root dynamics in montane and sub-alpine mixed forest patches. AB - Background and Aims: The structure of heterogeneous forests has consequences for their biophysical environment. Variations in the local climate significantly affect tree physiological processes. We hypothesize that forest structure also alters tree root elongation and longevity through temporal and spatial variations in soil temperature and water potential. Methods: We installed rhizotrons in paired vegetation communities of closed forest (tree islands) and open patches (canopy gaps), along a soil temperature gradient (elevations of 1400, 1700 and 2000 m) in a heterogeneous mixed forest. We measured the number of growing tree roots, elongation and mortality every month over 4 years. Key Results: The results showed that the mean daily root elongation rate (RER) was not correlated with soil water potential but was significantly and positively correlated with soil temperature between 0 and 8 degrees C only. The RER peaked in spring, and a smaller peak was usually observed in the autumn. Root longevity was dependent on altitude and the season in which roots were initiated, and root diameter was a significant factor explaining much of the variability observed. The finest roots usually grew faster and had a higher risk of mortality in gaps than in closed forest. At 2000 m, the finest roots had a higher risk of mortality compared with the lower altitudes. Conclusions: The RER was largely driven by soil temperature and was lower in cold soils. At the treeline, ephemeral fine roots were more numerous, probably in order to compensate for the shorter growing season. Differences in soil climate and root dynamics between gaps and closed forest were marked at 1400 and 1700 m, but not at 2000 m, where canopy cover was more sparse. Therefore, heterogeneous forest structure and situation play a significant role in determining root demography in temperate, montane forests, mostly through impacts on soil temperature. PMID- 29506135 TI - 'Choosing Wisely' culture among Brazilian cardiologists. AB - Objective: (i) To describe how aligned the 'Choosing Wisely' concept is with the medical culture among Brazilian cardiologists and (ii) to identify predictors for physicians' preference for avoiding wasteful care. Design: Cross-sectional study. Setting: Brazilian Society of Cardiology. Participants: Cardiologists who agree to fill a web questionary. Intervention: A task force of 12 Brazilian cardiologists prepared a list of 13 'do not do' recommendations, which were made available on the Brazilian Society of Cardiology website for affiliates to assign a supported score of 1 to 10 to each recommendation. Main Outcome Measurement: Score average for supporting recommendations. Results: Of 14 579 Brazilian cardiologists, 621 (4.3%) answered the questionnaire. The top recommendation was 'do not perform routine percutaneous coronary intervention in asymptomatic individuals' (mean score = 8.0 +/- 2.9) while the one with the lowest support was 'do not use an intra-aortic balloon pump in infarction with cardiogenic shock' (5.8 +/- 3.2). None of the 13 recommendations presented a mean grade >9 (strong support); 7 recommendations averaged 7-8 (moderate support) followed by 6 recommendations with an average of 5-7 (modest support). Multivariate analysis independently identified predictors of the score attributed to the top recommendation; being an interventionist and time since graduation were both negatively associated with support. Conclusions: (i) The support of Brazilian cardiologists for the 'Choosing Wisely' concept is modest to moderate, and (ii) older generations and enthusiasm towards the procedure one performs may be factors against the 'Choosing Wisely' philosophy. PMID- 29506136 TI - Spatial Analysis of Seasonal Dynamics and Overwintering of Drosophila suzukii (Diptera: Drosophilidae) in the Okanagan-Columbia Basin, 2010-2014. AB - Spotted wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), was monitored from 2010 to 2014 in 314-828 sites located in interior fruit growing regions of OR and WA, United States, and BC, Canada, using traps baited with apple cider vinegar or sugar-water-yeast. Seasonal population dynamics and sex ratios were summarized for berry, cherry, stone fruit, grape, non-crop host plants, non-host sites, and for conventional IPM, certified organic, backyard, and feral sites, by region and year. Overwintering was detected in all regions and years, despite winter temperatures below -17 degrees C. A spatial analysis was conducted using a Geographic Information System (GIS), daily weather data, geomorphometric measures of terrain, distance to water, and other variables, at each site. Overwintering success at a site, measured as Julian week of first capture of D. suzukii, was significantly related (R2 = 0.49) in cherry habitats to year, agronomic treatment, and number of winter days with temperatures >-5 degrees C. In berry, cherry, stone fruit and grape habitats, 2011-2014, it was significantly related (R2 = 0.42) to year, agronomic treatment, the logarithm of peak population of D. suzukii in the prior autumn, latitude, elevation, and topographic wetness index. The results show that D. suzukii has adapted to exploit a succession of irrigated crops and feral habitats in mixed landscapes of a semi-arid region with cold winters and hot dry summers, and are shaping strategies for pest management and for biological control. PMID- 29506137 TI - Fecal Calprotectin During Pregnancy in Women With Moderate-Severe Inflammatory Bowel Disease. AB - Background: Fecal calprotectin (FC) is a biomarker used for assessing disease activity among IBD patients. Sparse knowledge exists as to whether FC correlates with clinical disease activity during pregnancy. Our aim was to assess FC and selected biomarkers in women with moderate-severe IBD and correlate them with clinical disease activity scores in pregnant women. Methods: We identified a nationwide cohort of 219 singleton pregnancies in women with moderate-severe disease (all treated with anti-tumor recrosis factor-alpha [anti-TNF-alpha] therapy during pregnancy), and we reviewed the medical records to extract clinical details and information on biomarkers. FC, C-reactive protein (CRP), hemoglobin, and albumin were collected according to each trimester. Results: A total of 346 FC measurements were obtained throughout the gestational periods. FC values were between 80-120, 259-349, and 778-1277 mg/kg in women with clinically inactive, mild, and moderate-severe disease activity, respectively, and were significantly higher among the women with clinical disease activity. ROC curves for disease activity were computed according to the preconception period: 0.81 (95% confidence interval [CI], 0.69-0.93), first trimester: 0.73 (95% CI, 0.60 0.86), second trimester: 0.74 (95% CI, 0.62-0.86), and third trimester: 0.76 (95% CI, 0.64-0.88), respectively. We found a sensitivity of 69.7%-80.0%, a specificity of 66.7%-73.3%, and a positive predictive value of 66.7%-74.4% over the 4 gestational periods when a cutoff of 200 mg/kg was used. We found no clinically significant differences in CRP, albumin, or hemoglobin. Conclusions: FC in pregnant women with moderate-severe IBD treated with anti-TNF-alpha therapy was significantly higher in women with clinical disease activity compared with the women without. FC correlated with the level of clinical disease activity in all gestational periods. PMID- 29506138 TI - A ddPCR Assay for Identification of Autographa gamma (Noctuidae: Plusiinae) in Bulk Trap Samples. AB - The silver Y moth [Autographa gamma (Linneaus) (Noctuidae: Plusiinae)] is a pervasive crop pest in its native range but has not been found in moth surveys in the United States. Specimens of A. gamma are often intercepted at U.S. ports of entry, so the risk of introduction of this invasive species is high. Currently, identification of Plusiinae adults captured in domestic surveys is done by morphlogical comparison; however, this method is time consuming and misidentifications have occurred in the past. A recent study outlined a real-time PCR assay capable of rapidly identifying individual A. gamma specimens using CO1. This same study provided preliminary data for a droplet digital PCR (ddPCR) assay capable of processing bulk trap samples. Here, we develop and test a ddPCR assay for detecting a single A. gamma in a trap sample of 200 individual moths. This assay will drastically reduce the time and cost needed to screen domestic trap samples for A. gamma. PMID- 29506139 TI - Resistance Training Augments Cerebral Blood Flow Pulsatility: Cross-Sectional Study. AB - BACKGROUND: Increased central arterial stiffness and/or decreased compliance reduces buffer function and increases cerebral blood flow (CBF) pulsatility, which leads to increased cerebral microvascular damage, resulting in the augmentation of the risk of cerebrovascular diseases. Resistance-trained men showed higher central arterial stiffness and lower arterial compliance than age matched, sedentary men. This study examined the effect of increased central arterial stiffness and/or decreased arterial compliance on CBF pulsatility. METHODS: The study participants included 31 young healthy men (15 resistance trained men, aged 21 +/- 1 years; and 16 controls, aged 23 +/- 1 years). beta Stiffness index and arterial compliance were measured in the right carotid artery as index of central arterial stiffness and compliance, respectively. The pulsatility index (PI) was measured in the middle cerebral artery as index of CBF pulsatility. RESULTS: beta-Stiffness index and PI were significantly higher in the resistance-trained group than in the control group (beta-stiffness index: 5.3 +/- 0.3 vs. 3.5 +/- 0.3 a.u., P < 0.05, PI: 0.80 +/- 0.02 vs. 0.70 +/- 0.02, P < 0.05). The resistance-trained group showed significantly lower arterial compliance than the control group (0.16 +/- 0.01 vs. 0.23 +/- 0.01 mm2/mm Hg, P < 0.05). Positive and negative correlations were observed between beta-stiffness index and PI (r = 0.39, P < 0.05), and between arterial compliance and PI (r = 0.59, P < 0.05), respectively. CONCLUSIONS: The resistance-trained group showed higher central arterial stiffness and PI and lower arterial compliance. Central arterial stiffness and arterial compliance were associated with PI. Increased arterial stiffness and decreased arterial compliance with resistance training impair buffer function, resulting in increased CBF pulsatility. CLINICAL TRIAL REGISTRATION: Trial Number UMIN000023816 URL: http://www.umin.ac.jp/icdr/index.html Official scientific title of the study: effect of increase arterial stiffness by resistance training on cerebral hemodynamic. PMID- 29506140 TI - Role of cerium oxide nanoparticle-induced autophagy as a safeguard to exogenous H2O2-mediated DNA damage in tobacco BY-2 cells. AB - The effect of cerium oxide nanoparticle (CeNP) in plants has elicited substantial controversy. While some investigators have reported that CeNP possesses antioxidant properties, others observed CeNP to induce reactive oxygen species (ROS). In spite of considerable research carried out on the effects of CeNP in metazoans, fundamental studies that can unveil its intracellular consequences linking ROS production, autophagy and DNA damage are lacking in plants. To elucidate the impact of CeNP within plant cells, tobacco BY-2 cells were treated with 10, 50 and 250 ug ml-1 CeNP (Ce10, Ce50 and Ce250), for 24 h. Results demonstrated concentration-dependent accumulation of Ca2+ and ROS at all CeNP treatment sets. However, significant DNA damage and alteration in antioxidant defence systems were noted prominently at Ce50 and Ce250. Moreover, Ce50 and Ce250 induced DNA damage, analysed by comet assay and DNA diffusion experiments, complied with the concomitant increase in ROS. Furthermore, to evaluate the antioxidant property of CeNP, treated cells were washed after 24 h (to minimise CeNP interference) and challenged with H2O2 for 3 h. Ce10 did not induce genotoxicity and H2O2 exposure to Ce10-treated cells showed lesser DNA breakage than cells treated with H2O2 only. Interestingly, Ce10 provided better protection over N-acetyl-L-cysteine against exogenous H2O2 in BY-2 cells. CeNP exposure to transgenic BY-2 cells expressing GFP-Atg8 fusion protein exhibited formation of autophagosomes at Ce10. Application of vacuolar protease inhibitor E-64c and fluorescent basic dye acridine orange, further demonstrated accumulation of particulate matters in the vacuole and occurrence of acidic compartments, the autophagolysosomes, respectively. BY-2 cells co-treated with CeNP and autophagy inhibitor 3-methyladenine exhibited increased DNA damage in Ce10 and cell death at all assessed treatment sets. Thus, current results substantiate an alternative autophagy-mediated, antioxidant and geno-protective role of CeNP, which will aid in deciphering novel phenomena of plant-nanoparticle interaction at cellular level. PMID- 29506141 TI - Assessing the Associations of Blood Metabolites With Osteoporosis: A Mendelian Randomization Study. AB - Context: Osteoporosis is a metabolic bone disease. The effect of blood metabolites on the development of osteoporosis remains elusive. Objective: To explore the relationship between blood metabolites and osteoporosis. Design and Methods: We used 2286 unrelated white subjects for the discovery samples and 3143 unrelated white subjects from the Framingham Heart Study (FHS) for the replication samples. The bone mineral density (BMD) was measured using dual energy X-ray absorptiometry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using Affymetrix Human SNP Array 6.0 (for discovery samples) and Affymetrix SNP 500K and 50K array (for FHS replication samples). The SNP sets significantly associated with blood metabolites were obtained from a reported whole-genome sequencing study. For each subject, the genetic risk score of the metabolite was calculated from the genotype data of the metabolite associated SNP sets. Pearson correlation analysis was conducted to evaluate the potential effect of blood metabolites on the variations in bone phenotypes; 10,000 permutations were conducted to calculate the empirical P value and false discovery rate. Results: We analyzed 481 blood metabolites. We identified multiple blood metabolites associated with hip BMD, such as 1,5-anhydroglucitol (Pdiscovery < 0.0001; Preplication = 0.0361), inosine (Pdiscovery = 0.0018; Preplication = 0.0256), theophylline (Pdiscovery = 0.0048; Preplication = 0.0433, gamma-glutamyl methionine (Pdiscovery = 0.0047; Preplication = 0.0471), 1 linoleoyl-2-arachidonoyl-GPC (18:2/20:4n6; Pdiscovery = 0.0018; Preplication = 0.0390), and X-12127 (Pdiscovery = 0.0002; Preplication = 0.0249). Conclusions: Our results suggest a modest effect of blood metabolites on the variations of BMD and identified several candidate blood metabolites for osteoporosis. PMID- 29506142 TI - A miRNA-145/TGF-beta1 negative feedback loop regulates the cancer-associated fibroblast phenotype. AB - The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-beta1 and acquires an altered, heterogeneous phenotype (cancer associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-beta1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-beta signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-beta1 induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome. PMID- 29506144 TI - Toxic effect of visible light on Drosophila lifespan depending upon diet protein content. AB - We investigated the toxic effect of visible light on Drosophila lifespan in both sexes. The toxic effect of ultraviolet (UV) light on organisms is well known. However, the effects of illumination with visible light remain unclear. Here, we found that visible light could be toxic to Drosophila survival, depending on the protein content in diet. In addition, further analysis revealed significant interaction between light and sex, and showed that strong light shortened life span by causing opposite direction changes in mortality rate parameters in females versus males. Our findings suggest that photoageing may be a general phenomenon, and support the theory of sexual antagonistic pleiotropy in aging intervention. The results caution that exposure to visible light could be hazardous to life span and suggest that identification of the underlying mechanism would allow better understanding of aging intervention. PMID- 29506145 TI - Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses. AB - Background: High-dose radiotherapy (>8-10 Gy) causes rapid endothelial cell death via acid sphingomyelinase (ASMase)-induced ceramide production, resulting in biologically significant enhancement of tumor responses. To further augment or solicit similar effects at low radiation doses, we used genetic and chemical approaches to evaluate mechano-acoustic activation of the ASMase-ceramide pathway by ultrasound-stimulated microbubbles (USMB). Methods: Experiments were carried out in wild-type and acid sphingomyelinase (asmase) knockout mice implanted with fibrosarcoma xenografts. A cohort of wild-type mice received the ASMase-ceramide pathway inhibitor sphingosine-1-phosphate (S1P). Mice were treated with varying radiation doses, with or without a priori USMB exposure at different microbubble concentrations. Treatment response was assessed with quantitative 3D Doppler ultrasound and immunohistochemistry at baseline, and at three, 24, and 72 hours after treatment, with three to five mice per treatment group at each time point. All statistical tests were two-sided. Results: Results confirmed an interaction between USMB and ionizing radiation at 24 hours (P < .001), with a decrease in tumor perfusion of up to 46.5% by three hours following radiation and USMB. This peaked at 24 hours, persisting for up to 72 hours, and was accompanied by extensive tumor cell death. In contrast, statistically nonsignificant and minimal tumor responses were noted in S1P-treated and asmase knockout mice for all treatments. Conclusions: This work is the first to confirm the involvement of the ASMase-ceramide pathway in mechanotransductive vascular targeting using USMB. Results also confirm that an acute vascular effect is driving this form of enhanced radiation response, and that it can be elicited at low radiation doses (<8-10 Gy) by a priori USMB exposure. PMID- 29506143 TI - mTOR pathway is activated in endothelial cells from patients with Takayasu arteritis and is modulated by serum immunoglobulin G. AB - Objectives: Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis. Methods: We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients on mTOR pathway activation and cell proliferation. Results: IF analyses on tissues revealed that both mTORC1 and mTORC2 are activated specifically in ECs from TA patients but not in ECs from GCA patients and healthy controls (HCs). Using IIF and ELISA, we observed higher levels of antibodies binding to ECs in TA patients compared with GCA patients and HCs. Using western blot, we demonstrated that purified IgG from TA patients caused mTORC1 activation in ECs, whereas this effect was not observed with purified IgG from GCA patients or HCs. Purified IgG from TA patients induced a significant EC proliferation compared with to GCA and HC IgG, and this effect was decreased after EC exposure with sirolimus, a specific mTOR inhibitor and PI3K inhibitor. Conclusion: Our results suggest that antibodies targeting ECs drive endothelial remodelling in TA through activation of the mTOR pathway, but not in GCA. Inhibition of the mTOR pathway could represent a therapeutic option in TA. PMID- 29506147 TI - Good-quality support for the homeless is good for everyone. PMID- 29506146 TI - Assessing the influence of knowledge translation platforms on health system policy processes to achieve the health millennium development goals in Cameroon and Uganda: a comparative case study. AB - There is a scarcity of empirical data on the influence of initiatives supporting evidence-informed health system policy-making (EIHSP), such as the knowledge translation platforms (KTPs) operating in Africa. To assess whether and how two KTPs housed in government-affiliated institutions in Cameroon and Uganda have influenced: (1) health system policy-making processes and decisions aiming at supporting achievement of the health millennium development goals (MDGs); and (2) the general climate for EIHSP. We conducted an embedded comparative case study of four policy processes in which Evidence Informed Policy Network (EVIPNet) Cameroon and Regional East African Community Health Policy Initiative (REACH-PI) Uganda were involved between 2009 and 2011. We combined a documentary review and semi structured interviews of 54 stakeholders. A framework-guided thematic analysis, inspired by scholarship in health policy analysis and knowledge utilization was used. EVIPNet Cameroon and REACH-PI Uganda have had direct influence on health system policy decisions. The coproduction of evidence briefs combined with tacit knowledge gathered during inclusive evidence-informed stakeholder dialogues helped to reframe health system problems, unveil sources of conflicts, open grounds for consensus and align viable and affordable options for achieving the health MDGs thus leading to decisions. New policy issue networks have emerged. The KTPs indirectly influenced health policy processes by changing how interests interact with one another and by introducing safe-harbour deliberations and intersected with contextual ideational factors by improving access to policy-relevant evidence. KTPs were perceived as change agents with positive impact on the understanding, acceptance and adoption of EIHSP because of their complementary work in relation to capacity building, rapid evidence syntheses and clearinghouse of policy-relevant evidence. This embedded case study illustrates how two KTPs influenced policy decisions through pathways involving policy issue networks, interest groups interaction and evidence-supported ideas and how they influenced the general climate for EIHSP. PMID- 29506148 TI - SubRecon: ancestral reconstruction of amino acid substitutions along a branch in a phylogeny. AB - Summary: Existing ancestral sequence reconstruction techniques are ill-suited to investigating substitutions on a single branch of interest. We present SubRecon, an implementation of a hybrid technique integrating joint and marginal reconstruction for protein sequence data. SubRecon calculates the joint probability of states at adjacent internal nodes in a phylogeny, i.e. how the state has changed along a branch. This does not condition on states at other internal nodes and includes site rate variation. Simulation experiments show the technique to be accurate and powerful. SubRecon has a user-friendly command line interface and produces concise output that is intuitive yet suitable for subsequent parsing in an automated pipeline. Availability and implementation: SubRecon is platform independent, requiring Java v1.8 or above. Source code, installation instructions and an example dataset are freely available under the Apache 2.0 license at https://github.com/chrismonit/SubRecon. PMID- 29506149 TI - Role of bacterial efflux pumps in biofilm formation. AB - Efflux pumps are widely implicated in antibiotic resistance because they can extrude the majority of clinically relevant antibiotics from within cells to the extracellular environment. However, there is increasing evidence from many studies to suggest that the pumps also play a role in biofilm formation. These studies have involved investigating the effects of efflux pump gene mutagenesis and efflux pump inhibitors on biofilm formation, and measuring the levels of efflux pump gene expression in biofilms. In particular, several key pathogenic species associated with increasing multidrug resistance, such as Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, have been investigated, whilst other studies have focused on Salmonella enterica serovar Typhimurium as a model organism and problematic pathogen. Studies have shown that efflux pumps, including AcrAB-TolC of E. coli, MexAB-OprM of P. aeruginosa, AdeFGH of A. baumannii and AcrD of S. enterica, play important roles in biofilm formation. The substrates for such pumps, and whether changes in their efflux activity affect biofilm formation directly or indirectly, remain to be determined. By understanding the roles that efflux pumps play in biofilm formation, novel therapeutic strategies can be developed to inhibit their function, to help disrupt biofilms and improve the treatment of infections. This review will discuss and evaluate the evidence for the roles of efflux pumps in biofilm formation and the potential approaches to overcome the increasing problem of biofilm-based infections. PMID- 29506150 TI - Pharmacokinetics of piperacillin in critically ill patients with acute kidney injury receiving sustained low-efficiency diafiltration. AB - Background: Piperacillin is a beta-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections. However, knowledge regarding the effect of sustained low-efficiency diafiltration (SLED f), a technique increasingly being used in ICUs, on piperacillin pharmacokinetics (PK) and dosing in critically ill patients is lacking. Objectives: To describe the PK of piperacillin during SLED-f and compare the results with those reported for other forms of renal replacement therapies. Methods: Serial blood samples were collected at pre- and post-filter ports within the SLED-f circuit during SLED-f in one session and from an arterial catheter during sampling without SLED f. Piperacillin concentrations were measured using a validated chromatography method. Non-compartmental PK analysis of the data was performed. Results: The median clearance and area under the concentration-time curve during SLED-f were 6 L/h and 532 mg.h/L, respectively. Fifty-eight percent of piperacillin was cleared by a single SLED-f session (6 h) compared with previous reports of 30%-45% clearance by a 3.5 h intermittent haemodialysis session. Clearance, half-life and area under the concentration-time curve during SLED-f obtained from this study were comparable with those reported in the post-dilution mode of continuous veno venous haemodiafiltration studies. Conclusions: As it can be challenging to accurately predict when SLED-f will be initiated in the critically ill, a maintenance dose of at least 4 g every 12 h with at least a 2 g replacement dose post-SLED-f would be a practical approach to piperacillin dosing in ICU patients with anuria receiving SLED-f with a duration similar to the current study. PMID- 29506151 TI - Unraveling Saproxylic Insect Interactions in Tree Hollows from Iberian Mediterranean Forest. AB - Tree hollows are complex microhabitats in which a variety of abiotic and biotic factors shape the community assembly of saproxylic insects. Detecting non-random species co-occurrence patterns is a fundamental goal in ecology in order to understand the assembly mechanisms of communities. We study association patterns of species of Coleoptera and Diptera (Syrphidae), belonging to different trophic guilds, on 72 tree hollows at a local and regional scale in three protected areas in Mediterranean forests using a fixed-fixed null model. Our matrix-level analysis shows a tendency for segregation in species association (species exclusion) at the regional and site levels. However, the high complexity of tree hollow habitats, offering different resources for a more or less specialized fauna, makes it difficult to prove competition interactions. Indeed, pairwise analysis shows a dominance of non-random aggregation patterns (species coexistence) at the local and regional levels. Both aggregation and segregation of non-random patterns were more common among species from different trophic guilds than within the same guilds, with predators being a common denominator for a high percentage of the inter-guild pairs. Our results suggest that predation and facilitation interactions, together with habitat segregation, are the main factors shaping tree-hollow assemblages, while competition seems to be less important. We conclude that species interactions take an important part of the process of assemblage structuration and special attention should be paid to 'ecosystem engineers' and threatened species in the conservation of tree hollow assemblages. PMID- 29506152 TI - Corrigendum to "Resistance to Selected Pyrethroid Insecticides in the Malaria Mosquito, Anopheles stephensi (Diptera: Culicidae), From Punjab, Pakistan". PMID- 29506154 TI - Sarcoma of the heart: survival after surgery. AB - OBJECTIVES: Malignant intracardiac tumours are rare, and consensus concerning the optimal therapeutic approach is lacking. We performed a retrospective medical analysis, identifying 9 patients having been operated for cardiac sarcomas. All of them had a complete postoperative long-term follow-up. To enhance understanding of the best therapeutic approach for future patients, it is crucial to reveal special medical problems and to analyse the potential impact they may have on disease course and survival rate in this specific patient group. METHODS: Cardiac tumours operated on 2000 to the end of 2015 were reviewed. Late mortality during the follow-up period was determined. The impact of tumour extension, tumour localization, resection status (complete versus partial) and histopathological diagnosis on survival was analysed retrospectively. RESULTS: Of all cardiac malignant tumours resected, sarcomas were, with an incidence of 0.14% (9 patients), the most frequent histological group admitted to cardiac surgery. All of the patients presented with cardiac symptoms. All of the patients survived the operation and all had relief or improvement of cardiac symptoms. The mean follow-up period was 17 +/- 13 months. Five patients died after 6, 8, 12, 12 and 15 months, respectively. Four survivors (3 with a pulmonary artery tumour sarcoma and 1 with a left atrial sarcoma) had a mean follow-up of 26 +/- 17 months. Macroscopically complete tumour resection, absence of metastatic spread and histological sarcoma type had an impact on follow-up survival. CONCLUSIONS: Although cardiac sarcomas are rare, surgeons occasionally encounter them. A 1 year mortality rate of 44% reflects an unfavourable prognosis, but surgery seems to be a secure, reliable option in selected patients for treating cardiac symptoms and avoiding early cardiac-related deaths. PMID- 29506153 TI - Interleukin-7 Unveils Pathogen-Specific T Cells by Enhancing Antigen-Recall Responses. AB - Background: Interleukin (IL)-7 promotes the generation, expansion, and survival of memory T cells. Previous mouse and human studies showed that IL-7 can support immune cell reconstitution in lymphopenic conditions, expand tumor-reactive T cells for adoptive immunotherapy, and enhance effector cytokine expression by autoreactive T cells. Whether pathogen-reactive T cells also benefit from IL-7 exposure remains unknown. Methods: In this study, we investigated this issue in cultures of peripheral blood mononuclear cells (PBMCs) derived from patients infected with various endemic pathogens. After short-term exposure to IL-7, we measured PBMC responses to antigens derived from pathogens, such as Mycobacterium tuberculosis, Candida albicans, and cytomegalovirus, and to the superantigen Staphylococcus aureus enterotoxin B. Results: We found that IL-7 favored the expansion and, in some instances, the uncovering of pathogen-reactive CD4 T cells, by promoting pathogen-specific interferon-gamma, IL-2, and tumor necrosis factor recall responses. Conclusions: Our findings indicate that IL-7 unveils and supports reactivation of pathogen-specific T cells with possible diagnostic, prognostic, and therapeutic significance of clinical value, especially in conditions of pathogen persistence and chronic infection. PMID- 29506155 TI - Work-leave rotation pattern and incidence of offshore workplace injury. AB - Background: Studies on work-leave rotation pattern and work place injuries among offshore oil and gas workers have been few and limited to a 2- or 3-week rotation schedule. Aims: To examine incidence of workplace injury in relation to the duration of time into work rotation for extended work schedules up to 24 weeks. Methods: Six-year injury data on four offshore installations were extracted. Data were analysed for incidence of injury over time and relative risk using linear trend lines and regression. Results: In total, 311 injuries for 1302 workers were analysed, 39% with rotation schedule of 4 weeks work and 4 weeks rest, 27% 8 weeks work and 4 weeks rest, 23% 16 weeks work and 4 weeks rest and 10% 24 weeks work and 4 weeks rest. Incidence of injury decreased as duration of time into the work rotation increased, corrected for exposure, and this was statistically significant for all rotations in first 4 weeks (P < 0.01). Negative correlation between time offshore and injury was observed in all schedules and consistent for age groups, categories of work, shifts and severity of injury. There was no difference in relative risk of injuries between the four schedules, when corrected for exposure and occupational risk of injury. Conclusions: These results are at variance with previous studies, although no prior study has looked beyond 3-week rotation schedule. Longer offshore schedules are safely possible and this could help decrease manpower and logistics costs for oil and gas companies coping with unprecedented low oil prices. PMID- 29506156 TI - The IL-4/STAT6/PPARgamma signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages. AB - Retinoid X receptor (RXR) is an obligate heterodimeric partner of several nuclear receptors (NRs), and as such a central component of NR signaling regulating the immune and metabolic phenotype of macrophages. Importantly, the binding motifs of RXR heterodimers are enriched in the tissue-selective open chromatin regions of resident macrophages, suggesting roles in subtype specification. Recent genome wide studies revealed that RXR binds to thousands of sites in the genome, but the mechanistic details how the cistrome is established and serves ligand-induced transcriptional activity remained elusive. Here we show that IL-4-mediated macrophage plasticity results in a greatly extended RXR cistrome via both direct and indirect actions of the transcription factor STAT6. Activation of STAT6 leads to chromatin remodeling and RXR recruitment to de novo enhancers. In addition, STAT6 triggers a secondary transcription factor wave, including PPARgamma. PPARgamma appears to be indispensable for the development of RXR-bound de novo enhancers, whose activities can be modulated by the ligands of the PPARgamma:RXR heterodimer conferring ligand selective cellular responses. Collectively, these data reveal the mechanisms leading to the dynamic extension of the RXR cistrome and identify the lipid-sensing enhancer sets responsible for the appearance of ligand-preferred gene signatures in alternatively polarized macrophages. PMID- 29506157 TI - Bone Turnover Markers in Patients With Nonalcoholic Fatty Liver Disease and/or Type 2 Diabetes During Oral Glucose and Isoglycemic Intravenous Glucose. AB - Context: Nonalcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes (T2D) and vice versa, and both conditions are associated with an increased risk of fractures and altered bone turnover. Although patients with NAFLD typically suffer from decreased bone mineral density (BMD), T2D is associated with normal to high BMD. The pathophysiology is uncertain but may involve the gut-bone axis. Objective: We investigated the influence of the gut on glucose-induced changes in plasma bone turnover markers in healthy controls and patients with T2D and/or biopsy-verified NAFLD. Design: Cross-sectional cohort study. Patients: Patients with NAFLD with normal glucose tolerance, patients with NAFLD and T2D, patients with T2D without liver disease, and healthy controls. Interventions: Four-hour 50-g oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI). Main Outcome Measures: Collagen type 1 C-telopeptide (CTX), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone. Results: Plasma glucose levels achieved during OGTTs were successfully matched on corresponding IIGI days. Patients with NAFLD and T2D exhibited similar CTX suppression during the two glucose challenges (P = 0.46) and pronounced suppression of P1NP during IIGI compared with OGTT. Conversely, remaining groups showed greater (P < 0.05) CTX suppression during OGTT and similar suppression of bone formation markers during IIGI and OGTT. Conclusions: OGTT-induced CTX suppression seems to be impaired in patients with NAFLD and T2D, but preserved in patients with either NAFLD or T2D, suggesting that coexistence of T2D and NAFLD may affect gut-bone axis. PMID- 29506158 TI - Predictors and outcome of conversion to cardiac surgery during transcatheter aortic valve implantation. AB - OBJECTIVES: Due to increasing clinical experience with transcatheter aortic valve implantation (TAVI) procedures, sophisticated imaging and advanced device technology, TAVI complication rates are low; however, patients requiring conversion to surgery are confronted with an increased mortality risk. In this retrospective study, we evaluated the predictors for conversion and the outcomes of these patients. METHODS: We analysed the records of all patients undergoing TAVI in our centre from 2011 to 2016 and focused on cases that required conversion to sternotomy. We investigated reasons and risk factors for conversion as well as 30-day and 1-year outcomes. RESULTS: During the study period, 32 (2.1%) of 1775 patients undergoing TAVI required immediate conversion to sternotomy. Annular rupture (5 of 32; 16%), device embolization (9 of 32; 28%) and pericardial tamponade (15 of 32; 47%) were the most common reasons for conversion. Usage of a self-expandable valve showed to be the only predictor for conversion (odds ratio 0.38, 95% confidence interval 0.16-0.90; P = 0.03). Survival at 30 days and 1 year was 56% and 41%, respectively. Patients who survived 30 days after conversion showed higher preoperative ejection fraction, shorter duration of surgery and shorter perfusion time. CONCLUSIONS: In this high volume, single-centre experience, conversion to sternotomy during TAVI occurred in about 2%, with annular rupture, device embolization and pericardial tamponade being the most common causes. Complications requiring conversion showed to be unpredictable. However, in view of these life-threatening complications, the 30 day survival rate exceeding 50% emphasizes the importance of an experienced and well-attuned heart team providing immediate access to surgical bailout procedures. PMID- 29506159 TI - Endoscopic and Gravity-Assisted Resection of Medial Temporo-occipital Lesions Through a Supracerebellar Transtentorial Approach: Technical Notes With Case Illustrations. AB - BACKGROUND: Traditional approaches to medial temporo-occipital intra-axial brain tumors carry the risk of visual or language deficits related to brain retraction or transgression of deep fiber tracts. To reduce these risks, the microscopic supracerebellar transtentorial approach with the patient in the sitting position has been previously described for lesions in relative proximity to the tentorium. OBJECTIVE: We describe this approach performed with endoscopic tumor resection to allow better visualization and a more ergonomic operating position. METHODS: Four consecutive patients harboring a medial temporo-occipital lesion are reported. All were operated on while in the sitting position using frameless navigation and a supracerebellar transtentorial approach. Tumor resection was performed by 2 surgeons with endoscopic visualization. RESULTS: Pathologies included intraparenchymal metastatic melanoma, cavernous hemangioma, and ganglioglioma, as well as an intraventricular metastatic tumor. The distance from the tentorium to the lesion ranged from 1 to 4 mm. Gross total resection was achieved in 3 of the 4 patients. The patient with a metastatic melanoma had an intentional near-total resection given the tumor encasing a branch of the posterior cerebral artery. The patient with the intraventricular tumor sustained a small but symptomatic infarct of the lateral geniculate region, resulting in a visual field deficit. CONCLUSION: This small series suggests that the endoscopic supracerebellar transtentorial approach with the patient in the sitting position can be a safe and effective approach for removing medial temporo-occipital lesions. It allows excellent tumor visualization, eliminates the need for brain retraction, minimizes parenchymal transgression, and improves surgical ergonomics. Significant experience in endoscopy and excellent neuroanesthesia support are recommended before undertaking this approach. PMID- 29506160 TI - Simultaneous Image-Guided Skull Bone Tumor Resection and Reconstruction With a Preconstructed Prosthesis Based on an OsiriX Virtual Resection. AB - BACKGROUND: Skull reconstruction can be challenging due to the complex 3 dimensional shape of some structures, such as the orbital walls, and for cases involving a large cranial vault. In such situations, computer-assisted design and modeling of prostheses is especially helpful to achieve an adequate reconstruction. Simultaneous tumor resection and skull defect reconstruction are also challenging because the preoperative imaging does not display the anticipated defect. Currently, sophisticated methods based on physical prototypes and templates are required to enable simultaneous resection and reconstruction techniques. OBJECTIVE: To report a new technique for simultaneous tumor resection and skull reconstruction with a custom-made prosthesis. METHODS: Using OsiriX software, virtual bone resection was performed using preoperative images by carefully delimiting the tumor on each slice. The modified images were integrated to predict the defect and also served as a basis for prosthesis construction. At the time of surgery, the images were projected onto the patient's skull using a surgical navigation system to delimit the area of the craniectomy. RESULTS: The virtual planning method was simple and accurate and provided a precise preoperative definition of important structures that needed to be spared, such as the frontal sinus. Using this method, simultaneous tumor resection and prosthetic skull reconstruction was successfully achieved for a patient with a wide skull tumor. CONCLUSION: Simultaneous skull tumor resection and prosthetic reconstruction are possible when a virtual preoperative tumor resection is performed, and a corresponding customized prosthesis subsequently is manufactured and used. PMID- 29506161 TI - Thoracoscopic-Assisted Ventriculo-Azygous Shunt Placement for the Treatment of Hydrocephalus. AB - BACKGROUND: Cerebrospinal fluid diversion is one of the most frequent neurosurgical procedures across the world and can be challenging in select patients who fail standard distal drainage sites. OBJECTIVE: To present the case of a woman after failing peritoneal, pleural, and atrial distal drainage sites who underwent a thoracoscopic-assisted ventriculo-azygous vein shunt placement. METHODS: A 32-year-old woman presented to our hospital with long-standing history of hydrocephalus and shunt dependence. She had failed peritoneal and atrial shunts secondary to infection, scarring, and clot formation. At presentation, she had a pleural shunt in place and developed a large pleural effusion with shortness of breath. RESULTS: She was taken to the operating room where a thoracoscopic-assisted ventriculo-azygous vein shunt was placed through a mini thoracotomy. Postoperatively, she has not required a shunt revision in >2 years of follow-up. CONCLUSION: When other distal sites fail, our case report illustrates a novel surgical technique capable of being performed through a multidisciplinary approach. PMID- 29506162 TI - The Subtemporal Approach to Retroinfundibular Craniopharyngiomas: A New Look at an Old Approach. AB - BACKGROUND: Retrochiasmatic, retroinfundibular craniopharyngiomas are surgically challenging tumors. Anterolateral, posterolateral, and endoscopic endonasal approaches represent the most commonly used techniques to access these tumors, but all require an extensive exposure time, and each has its own risks and limitations. The subtemporal approach is a well-known neurosurgical approach that is rarely described for craniopharyngiomas. OBJECTIVE: To assess the feasibility, advantages, and disadvantages of a subtemporal approach for craniopharyngiomas. METHODS: Five patients with retrochiasmatic craniopharyngiomas where the majority of the tumor extended behind the dorsal clival line underwent a subtemporal approach for resection. Extent of resection, degree of temporal lobe injury, visual and endocrine outcomes, and time to recurrence were analyzed. RESULTS: Average tumor volume was 6.4 cm3. Near-total resection was achieved in 80% (4/5) and subtotal in 20% (1/5). All patients had stable or improved vision. There was 1 new permanent endocrine deficiency. Minimal temporal lobe edema was observed in 80% (4/5) of patients. Three patients required postoperative radiation. CONCLUSION: The subtemporal approach represents a feasible approach for retrochiasmatic, retroinfundibular craniopharyngiomas when gross total resection is not mandatory. It provides rapid access to the tumor and a caudal-to-cranial visualization that promotes minimal manipulation of critical neurovascular structures, particularly the optic apparatus. PMID- 29506163 TI - Video-Assisted Navigation for Adjustment of Image-Guidance Accuracy to Slight Brain Shift. AB - BACKGROUND: Information supplied by an image-guidance system can be superimposed on the operating microscope oculars or on a screen, generating augmented reality. Recently, the outline of a patient's head and skull, injected in the oculars of a standard operating microscope, has been used to check the registration accuracy of image guidance. OBJECTIVE: To propose the use of the brain surface relief and superficial vessels for real-time intraoperative visualization and image-guidance accuracy and for intraoperative adjustment for brain shift. METHODS: A commercially available image-guidance system and a standard operating microscope were used. Segmentation of the brain surface and cortical blood vessel relief was performed manually on preoperative computed tomography and magnetic resonance images. The overlay of segmented digital and real operating-microscope images was used to monitor image-guidance accuracy. Adjustment for brain shift was performed by manually matching digital images on real structures. RESULTS: Experimental manipulation on a phantom proved that the brain surface relief could be used to restore accuracy if the primary registration shifted. Afterward, the technique was used to assist during surgery of 5 consecutive patients with 7 deep-seated brain tumors. The brain surface relief could be successfully used to monitor registration accuracy after craniotomy and during the whole procedure. If a certain degree of brain shift occurred after craniotomy, the accuracy could be restored in all cases, and corticotomies were correctly centered in all cases. CONCLUSION: The proposed method was easy to perform and augmented image-guidance accuracy when operating on small deep-seated lesions. PMID- 29506164 TI - The Use of an Aspirating/Resecting Device to Reduce Stoma Closure Following Endoscopic Third Ventriculostomy for Aqueductal Stenosis. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) is commonly used to treat obstructive hydrocephalus. Closure of the stoma can be associated with symptom recurrence and need for further surgical intervention. OBJECTIVE: To describe the use of a side-cutting aspiration device for treatment of aqueductal stenosis in patients undergoing ETV. METHODS: A retrospective review of 30 consecutive adults with aqueductal stenosis treated with ETV using an adjunct side-cutting aspiration device between 2011 and 2013 was performed. Patients included in the study ranged from 35 to 64 years of age. ETV success was determined by the absence of stoma closure (aqueductal and cisternal flow assessed by high resolution, gradient-echo magnetic resonance imaging), post-ETV symptom recurrence, and need for subsequent surgical intervention. RESULTS: Patients treated by using a side-cutting aspirator had no observed stoma closure (0%) and a 10% (n = 3) rate of post-ETV symptom recurrence. Three patients (10%) demonstrated a need for surgical revision following initial ETV with the side cutting aspirator. CONCLUSION: Adult patients with obstructive hydrocephalus secondary to aqueductal stenosis exhibited a low rate of stoma closure with the use of a side-cutting aspiration device, and a rate of complications comparable to the known literature. Likewise, patients treated with a side-cutting aspirator may have lower symptom recurrence post-ETV and require fewer revisions in comparison with the known literature. As such, a side-cutting aspirator may be considered as a useful adjunct to traditional ETV for the treatment of obstructive hydrocephalus secondary to aqueductal stenosis. PMID- 29506165 TI - Microsurgical Pontine Descending Tractotomy in Cases of Intractable Trigeminal Neuralgia. AB - BACKGROUND: Current treatment strategies in patients with trigeminal neuralgia (TN) include trials of medical therapy and surgical intervention, when necessary. In some patients, pain is not adequately managed with these existing strategies. OBJECTIVE: To present a novel technique, ventral pontine trigeminal tractotomy via retrosigmoid craniectomy, as an adjunct treatment in TN when there is no significant neurovascular compression. METHODS: We present a nonrandomized retrospective comparison between 50 patients who lacked clear or impressive arterial neurovascular compression of the trigeminal nerve as judged by preoperative magnetic resonance imaging and intraoperative observations. These patients had intractable TN unresponsive to previous treatment. Trigeminal tractotomy was performed either alone or in conjunction with microvascular decompression. Stereotactic neuronavigation was used during surgery to localize the descending tract via a ventral pontine approach for descending tractotomy. RESULTS: Follow-up was a mean of 44 months. At first follow-up, 80% of patients experienced complete relief of their pain, and 18% had partial relief. At the most recent follow-up, 74% of patients were considered a successful outcome. Only 1 (2%) patient had no relief after trigeminal tractotomy. Of those with multiple sclerosis-related TN, 87.5% experienced successful relief of pain at their latest follow-up. CONCLUSION: While patient selection is a significant challenge, this procedure represents an option for patients with TN who have absent or equivocal neurovascular compression, multiple sclerosis-related TN, or recurrent TN. PMID- 29506166 TI - Percutaneous Minimally Invasive (MIS) Guide Wire-less Self-Tapping Pedicle Screw Placement in the Thoracic and Lumbar Spine: Safety and Initial Clinical Experience: Technical Note. AB - BACKGROUND: Multiple methods for minimally invasive (MIS) thoracic and lumbar pedicle screw placement exist. The guide wire is almost universally used for most insertion techniques; however, its use is not without complication and potentially prolongs surgical procedures. OBJECTIVE: To evaluate the safety of percutaneous MIS guide wire-less pedicle screw placement in the thoracic and lumbar spine at a single institution over a 3-year experience. METHODS: Forty-one patients who underwent posterior instrumentation with 110 transpedicular MIS thoracic and lumbar screws by a single surgeon from 2011 to 2014 were analyzed. The mean age was 63 years at the time of surgery. Etiological diagnoses were adult spinal deformity, trauma, spondylosis/spondylolisthesis, and other spinal diseases. Pedicle screws were inserted with the use of a guide wire-free technique in which anatomy-specific entry sites and fluoroscopic landmarks were used to guide the surgeon. A square, sharp-tipped pedicle screw was carefully advanced under biplanar fluoroscopic image (anteroposterior and lateral) down the pedicle into the body. No tapping or any type of electromonitoring was performed. An independent spine surgeon using medical records and thoracic/lumbar computed tomography taken during the postoperative period reviewed all patients. RESULTS: The number of the screws inserted at each level was as follows: total, 110; thoracic, 30; and lumbar, 80. All screws were evaluated by computed tomography to assess screw position. Seven screws (6.3%) were inserted with moderate cortical perforation, including 3 screws (2.7%) that violated the medial wall. There were no neurological, vascular, or visceral complications with up to 3 years of follow up. CONCLUSION: The percutaneous MIS guide wire-less technique of lumbar and thoracic pedicle screw placement performed using a biplanar fluoroscopic guidance in a stepwise, consistent manner is an accurate, safe, and reproducible method of insertion to treat a variety of spinal disorders. PMID- 29506167 TI - Prospective Evaluation of a Low-Dose Radiation Fluoroscopy Protocol for Minimally Invasive Transforaminal Lumbar Interbody Fusion. AB - BACKGROUND: Recent research on radiation exposure in minimally invasive surgery for transforaminal lumbar interbody fusion (MIS TLIF) has led to the development of a low-dose radiation fluoroscopy protocol, with resulting reductions in fluoroscopy times and radiation exposures. OBJECTIVE: To prospectively evaluate a previously reported low-dose radiation fluoroscopy protocol for MIS TLIF. METHODS: A prospective evaluation of the low-dose radiation fluoroscopy protocol for MIS TLIF was performed for 65 consecutive patients. Total fluoroscopy time, radiation dose, and operative times were prospectively analyzed for all enrolled patients. RESULTS: Sixty-five consecutive patients (43 women; 22 men) who underwent an MIS TLIF were prospectively enrolled in this study of the low-dose fluoroscopy protocol. A total of 260 pedicle screws were placed. The mean age of the patients was 63 years (range, 46-82 years). They had a mean operative time of 178.7 minutes (range, 119-247 minutes), a mean fluoroscopic time of 10.43 seconds (range, 5-24 seconds), and a mean radiation dose of 0.295 mGy * m2 (range, 0.092 0.314 mGy * m2). CONCLUSION: The combination of low-dose pulsed images and digital spot images in a low-dose protocol decreases fluoroscopy times and radiation doses in patients undergoing MIS TLIF without compromising visualization of the bony anatomy or the safety and efficiency of the procedure. The application of this low-dose protocol uncouples the otherwise linear relationship between fluoroscopy times and radiation dose. This is due primarily to the use of the digital spot technique. Equal emphasis should be placed on radiation dose and acquisition time to optimize this protocol. PMID- 29506168 TI - Use of a Dermal Regeneration Template in Complicated Craniotomy Wounds: Review of a Series. AB - BACKGROUND: Surgical wounds after craniotomy heal with primary closure in most cases; however, significant comorbidities, multiple procedures, and history of tumor increase the risk of wound breakdown. Craniotomy wounds often require sophisticated coverage by a plastic surgeon using regional or microvascular flaps to address exposed intracranial contents. Unfortunately, timely treatment of craniotomy wounds may be difficult as a result of limitations of plastic surgery consultation, specialized operating room staffing, and operating room time. Infected wounds may need serial debridement and antibiotic therapy before definitive closure, and patients with dehisced or infected craniotomy wounds may need medical and nutritional optimization. OBJECTIVE: To present the first case series of 7 neurosurgical patients with craniotomy wound complications who underwent closure with dermal regeneration template (DRT) at the time of urgent surgical debridement. METHODS: Seven adult patients underwent placement of DRT for dehisced or infected craniotomy wounds after treatment for tumor or trauma. Patients had an average of 5.5 operations before definitive closure. Six patients ultimately underwent delayed free flap transfer after DRT placement, and 1 patient had DRT as definitive coverage. RESULTS: All patients had healed craniotomy wounds. CONCLUSION: DRT has a role in treating complicated craniotomy wounds in patients with cancer or trauma either as a bridge or as definitive coverage. Its ease of application does not require advanced or time-consuming techniques. In some cases, it may even be used as a definitive means of closure in surgical wounds. PMID- 29506169 TI - Accuracy of Laser Placement With Frameless Stereotaxy in Magnetic Resonance Guided Laser-Induced Thermal Therapy. AB - BACKGROUND: As magnetic resonance-guided laser-induced thermal therapy (MRgLITT) becomes more accepted, there needs to be an evaluation of the techniques required to achieve accurate laser placement. OBJECTIVE: To report our experience with frameless stereotaxy and the ability to achieve accurate laser placements. We also evaluate the variables associated with proper placement. METHODS: We performed a retrospective analysis from 3 years of MRgLITT. Demographics and operational parameters, including trajectory length, target alignment error, registration error, and radial error were recorded and compared. Blinded review was used for completeness of ablation. RESULTS: In the study, 90 laser placements were evaluated for 72 cases. Trajectory length and target alignment error was 95.3 +/- 26.0 mm and 0.7 +/- 0.3 mm, respectively. Significant differences existed in registration error between 4 (0.6 +/- 0.3 mm) and 5 (0.5 +/- 0.2 mm) skull pins (P = .04), but no significant decreases in registration error as additional skull pins were registered. Fifteen laser placements resulted in subtotal ablations. The overall radial error using frameless stereotaxy was 0.9 +/- 1.6 mm. In the study, 65% of lasers were exactly on the planned trajectory. Of the 30 that were not, the radial error = 2.6 +/- 1.9 mm. Radial error of subtotal laser ablations was 0.5 +/- 0.9 (range, 0-2.8 mm) and was not significantly different from 0.8 +/- 1.7 (range, 0-7.1 mm) radial error of lasers with total ablations (P = .52). Lasers with radial error >0 mm resulted in an incomplete ablation in 26.7% of cases. CONCLUSION: Skull pin-based frameless stereotaxy for MRgLITT results in consistent accuracy, with the majority of cases resulting in complete ablations. A significant proportion of lasers with RE >0 mm still result in complete ablations. PMID- 29506170 TI - Dual Origin of Extradural Posterior Inferior Cerebellar Artery From Vertebral and Occipital Arteries: Anatomic Case Report. AB - BACKGROUND: Small anastomotic channels exist between the occipital artery (OA) and muscular branches of the vertebral artery; however, no direct connection has been reported between an extradural origin of the posterior inferior cerebellar artery (PICA) and the OA. OBJECTIVE: To describe a rare anatomic connection between the extradural PICA and the OA. METHODS: A far lateral exposure was completed on a cadaveric head prepared for surgical simulation. The course and branches of the OA were followed, and the relations to their immediate anatomic structures were studied. RESULTS: The origin of the PICA was found at the second segment of the vertebral artery, between the C1 and C2 transverse foramina. There was a large anastomotic connection between the superficial descending branch of the occipital artery and the PICA 12 mm proximal to the dural entrance of the artery. CONCLUSION: Awareness of the angioarchitecture of the suboccipital region and the existence of patent vertebrocarotid anastomotic connections is important to avoid complications during surgical or endovascular interventions. When present, a pre-existing OA-PICA anastomosis can be exploited to facilitate treatment in certain vascular pathologies (eg, vertebral artery aneurysms). Awareness of the existence of both an extradural origin of the PICA and a direct connection of this vessel with the OA is of great relevance to the muscular stage of surgical approaches to the posterior craniovertebral junction. PMID- 29506171 TI - Alternative Detachment Technique for Electrically Detachable Coils: Rescue From an Unintended Complication. AB - BACKGROUND: Embolization of intracranial aneurysms with the use of detachable coils has become the most widely used therapy for this condition. However, unexpected device failure can lead to critical complications. OBJECTIVE: To describe an alternative detachment technique for various electrically detachable coils (eg, Target of Stryker Neurovascular, Presidio and Microphere of Codman Neurovascular, and MicroPlex and Hydrocoil of MicroVention Terumo) that can be used when standard troubleshooting techniques are not effective and the physician is not able to remove a coil. METHODS: The alternative detachment method involved the restoration of the current pathway with the use of an alligator clip wire and the distal end of a new coil delivery wire of the same type. The detachment mechanism used in this method is the same as that normally used for each system. RESULTS: We found that this alternative maneuver was both feasible and reproducible. Moreover, an electrically detachable coil was successfully detached with the use of this method, especially when detachment failure was the result of distal delivery wire and connector damage. No additional complications were noted. CONCLUSION: An alternative detachment technique involving the reconstruction of the electric circuit could be a safe method of rescue in the potentially risky situation caused by detachment failure during embolization of cerebral aneurysms with electrically detachable coils. PMID- 29506172 TI - Aneurysm Transection and Intra-aneurysmal Clipping of a Giant Ophthalmic Artery Aneurysm: 3-Dimensional Operative Video. PMID- 29506173 TI - Microsurgical Treatment of Thalamic Cavernous Malformation: 3-Dimensional Operative Video. PMID- 29506174 TI - Awake Craniotomy and Intraoperative MRI for Maximal Safe Resection in a Case of an Extensive Left Frontal and Insular Low-grade Glioma: 3-Dimensional Operative Video. PMID- 29506175 TI - An Unusual Case of an Ethmoidal Arteriovenous Fistula Draining Into the Superior Ophthalmic Vein: Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Ethmoidal arteriovenous fistulae (AVF) are uncommon and are characterized by an aggressive clinical course. Typical venous drainage is into the frontal cortical veins. We present the case of a 76-year-old male patient who was found to have a right ethmoidal AVF draining directly into the superior ophthalmic vein (SOV), with no cavernous sinus involvement and an associated SOV aneurysm and was successfully treated using surgical cutdown of the SOV followed by endovascular embolization. CLINICAL PRESENTATION: A 76-year old man presented with chemosis, proptosis, and lid lag with occasional diplopia. Based on the clinical presentation, there was a suspicion of a carotid cavernous fistula. Cerebral angiography demonstrated a right ethmoidal to SOV fistula, without any involvement of the cavernous sinus, and a SOV aneurysm. Transarterial embolization of the fistula was attempted but was unsuccessful. An SOV approach was performed using SOV cutdown followed by endovascular embolization of the fistula from a transocular route using coils and Onyx embolic agent. There was complete obliteration of the fistula and associated venous aneurysm. The patient had a remarkable recovery. CONCLUSION: In rare cases, ethmoidal AVFs can present with an unusual venous drainage. Clinical presentation may be similar to carotid cavernous fistulae, and proper identification of the lesion using an angiogram is essential to guide treatment. In cases in which other approaches fail to treat the fistula, direct surgical exposure of the SOV followed by embolization using coiling and Onyx may be successful in achieving AVF occlusion. PMID- 29506176 TI - Single-Staged Multilevel Spondylectomy for En Bloc Resection of an Epithelioid Sarcoma With Intradural Extension in the Cervical Spine: Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Occurrence of spinal epithelioid sarcomas is rare, with few cases reported in the literature. Although wide local resection is the recommended treatment, this technique is challenging in the spine. CLINICAL PRESENTATION: The case of a 17-year-old male with a recurrent epithelioid sarcoma with intradural extension in the cervical spine is presented. Because of nerve root involvement, the patient presented with right upper extremity weakness. The patient underwent a posterior C1-C4 spondylectomy to achieve an en bloc resection, followed by reconstruction from the occiput to T4. The right vertebral artery and C1-C4 nerve roots were sacrificed because of tumor involvement. After 3 years of follow-up the patient is disease-free but has persistent right deltoid weakness. CONCLUSION: Cervical spondylectomy via a single-staged posterior approach is a challenging yet feasible procedure for the treatment of epithelioid sarcomas. To the best of the authors' knowledge, this is the first report of complete resection of an epithelioid sarcoma with intradural extension in the cervical spine. Although neurovascular structures may warrant sacrifice, this procedure may provide improved long-term prognosis. PMID- 29506177 TI - Mitigating the adverse impact of batch effects in sample pattern detection. AB - Motivation: It is well known that batch effects exist in RNA-seq data and other profiling data. Although some methods do a good job adjusting for batch effects by modifying the data matrices, it is still difficult to remove the batch effects entirely. The remaining batch effect can cause artifacts in the detection of patterns in the data. Results: In this study, we consider the batch effect issue in the pattern detection among the samples, such as clustering, dimension reduction and construction of networks between subjects. Instead of adjusting the original data matrices, we design an adaptive method to directly adjust the dissimilarity matrix between samples. In simulation studies, the method achieved better results recovering true underlying clusters, compared to the leading batch effect adjustment method ComBat. In real data analysis, the method effectively corrected distance matrices and improved the performance of clustering algorithms. Availability and implementation: The R package is available at: https://github.com/tengfei-emory/QuantNorm. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29506179 TI - The relationship between socioeconomic status and trauma outcomes. AB - Background: The burden of trauma is not equally distributed among all groups of societies and often disproportionately affects poor populations. This study aimed to examine the relationship of socioeconomic status (SES) and trauma outcomes. Methods: In this cohort study, 600 trauma patients in Kashan, Iran were studied. Data were gathered by demographic and trauma-related questionnaires, a socioeconomic assessment scale, the Hospital Care Index and the World Health Organization Disability Assessment Schedule-II. The concentration index was done for measuring socioeconomic inequalities. Results: About 49.7% of the patients received high level of hospital care. After 3 months from trauma incidence, 64.2% of the patients reported some levels of disability and 71.4% returned to their work or activities of daily living. Most cases of high level of hospital care and return to work (RTW) were among patients with high SES while most instances of death and disability occurred among patients with low SES. Inequality analysis also revealed that patients with low and high SES differed significantly from each other in terms of hospital care and RTW. Conclusion: Patients with low SES are at greater risk for receiving low level of hospital care and experiencing non RTW and needs to stronger post-discharge social supports. PMID- 29506178 TI - Can we prevent OA? Epidemiology and public health insights and implications. AB - This narrative review discusses the potential of prevention of OA in different stages of the disease. The theoretical background for primary prevention (i.e. prevention of occurrence of definite structural or clinical OA in subjects free of the disease) and secondary prevention (i.e. prevention of progression of the disease in subjects with pre-clinical pathological changes to the joint) is provided and evidence for effective strategies is discussed. Since direct evidence for the prevention of OA development and progression is scarce, indirect evidence enhancing our current knowledge on the potential of OA prevention is additionally discussed. Also, implications of preventive strategies for study design and public health are considered. Prevention of OA has great potential, but as deliberated in the current review, there are still large gaps in our current knowledge and the implications of preventive strategies for the development and progression of OA require consideration. PMID- 29506180 TI - Branching out: a new era of investigating physiological processes in forest trees using genomic tools. PMID- 29506181 TI - Quality of care and variability in lung cancer management across Belgian hospitals: a population-based study using routinely available data. AB - Objective: To evaluate the quality of care for all patients diagnosed with lung cancer in Belgium based on a set of evidence-based quality indicators and to study the variability of care between hospitals. Design, Setting, Participants: A retrospective study based on linked data from the cancer registry, insurance claims and vital status for all patients diagnosed with lung cancer between 2010 and 2011. Evidence-based quality indicators were identified from a systematic literature search. A specific algorithm to attribute patients to a centre was developed, and funnel plots were used to assess variability of care between centres. Intervention: None. Main outcome measure: The proportion of patients who received appropriate care as defined by the indicator. Secondary outcome included the variability of care between centres. Results: Twenty indicators were measured for a total of 12 839 patients. Good results were achieved for 60-day post surgical mortality (3.9%), histopathological confirmation of diagnosis (93%) and for the use of PET-CT before treatment with curative intent (94%). Areas to be improved include the reporting of staging information to the Belgian Cancer Registry (80%), the use of brain imaging for clinical stage III patients eligible for curative treatment (79%), and the time between diagnosis and start of first active treatment (median 20 days). High variability between centres was observed for several indicators. Twenty-three indicators were found relevant but could not be measured. Conclusion: This study highlights the feasibility to develop a multidisciplinary set of quality indicators using population-based data. The main advantage of this approach is that not additional registration is required, but the non-measurability of many relevant indicators is a hamper. It allows however to easily point to areas of large variability in care. PMID- 29506182 TI - Consecutive operative procedures in patients with Marfan syndrome up to 28 years after initial aortic root surgery. AB - OBJECTIVES: Most patients (75%) with Marfan syndrome present with aortic root dilatation that may require surgical intervention. However, associated cardiovascular disorders are not limited to the aortic root. These patients frequently require consecutive operations on the remaining thoracic aorta or the heart valves. Our intent was to characterize the spectrum of such procedures. METHODS: Data from all patients with Marfan syndrome undergoing aortic root surgery at our centre between 1988 and 2016 were analysed retrospectively. RESULTS: Overall, 73 patients (26 women) were selected for the study. The median age at 1st operation was 30 years (3-68 years). Indications for aortic root surgery were aneurysm (78%) and dissection (22%). Initially, 33 Bentall procedures and 40 valve-sparing root replacement procedures were performed, with a 97% rate of follow-up completion. The median follow up was 8 years (0-28 years). Survival at 1, 10 and 15 years was 100%, 85% and 82%, respectively. During follow-up monitoring, 48 subsequent procedures were performed in 33 patients (aorta, 23; aortic valve, 11; mitral valve, 7 and combined procedures, 7). The 30-day mortality rate after subsequent procedures was 4.2%. Freedom from subsequent operation and death (combined end-point) after 5, 10 and 15 years was 70%, 53% and 34%, respectively. CONCLUSIONS: After the initial surgery, subsequent procedures required in the setting of Marfan syndrome most often involve the remaining native aorta, followed by the aortic and mitral valves. The continued need for additional operative procedures remains high, even decades after the initial surgeries are undertaken. Therefore, long-term patient monitoring at specialized centres is imperative. PMID- 29506183 TI - Characterization of metabolic responses to healthy diets and association with blood pressure: application to the Optimal Macronutrient Intake Trial for Heart Health (OmniHeart), a randomized controlled study. AB - Background: Interindividual variation in the response to diet is common, but the underlying mechanism for such variation is unclear. Objective: The objective of this study was to use a metabolic profiling approach to identify a panel of urinary metabolites representing individuals demonstrating typical (homogeneous) metabolic responses to healthy diets, and subsequently to define the association of these metabolites with improvement of risk factors for cardiovascular diseases (CVDs). Design: 24-h urine samples from 158 participants with pre-hypertension and stage 1 hypertension, collected at baseline and following the consumption of a carbohydrate-rich, a protein-rich, and a monounsaturated fat-rich healthy diet (6 wk/diet) in a randomized, crossover study, were analyzed by proton (1H) nuclear magnetic resonance (NMR) spectroscopy. Urinary metabolite profiles were interrogated to identify typical and variable responses to each diet. We quantified the differences in absolute excretion of metabolites, distinguishing between dietary comparisons within the typical response groups, and established their associations with CVD risk factors using linear regression. Results: Globally all 3 diets induced a similar pattern of change in the urinary metabolic profiles for the majority of participants (60.1%). Diet-dependent metabolic variation was not significantly associated with total cholesterol or low-density lipoprotein (LDL) cholesterol concentration. However, blood pressure (BP) was found to be significantly associated with 6 urinary metabolites reflecting dietary intake [proline-betaine (inverse), carnitine (direct)], gut microbial co metabolites [hippurate (direct), 4-cresyl sulfate (inverse), phenylacetylglutamine (inverse)], and tryptophan metabolism [N-methyl-2-pyridone 5-carboxamide (inverse)]. A dampened clinical response was observed in some individuals with variable metabolic responses, which could be attributed to nonadherence to diet (<=25.3%), variation in gut microbiome activity (7.6%), or a combination of both (7.0%). Conclusions: These data indicate interindividual variations in BP in response to dietary change and highlight the potential influence of the gut microbiome in mediating this relation. This approach provides a framework for stratification of individuals undergoing dietary management. The original OmniHeart intervention study and the metabolomics study were registered at www.clinicaltrials.gov as NCT00051350 and NCT03369535, respectively. PMID- 29506184 TI - Limestone particle size fed to pullets influences subsequent bone integrity of hens. AB - This study was conducted to evaluate limestone particle size (LPS) in 2 strains of laying hens housed in conventional cages or aviaries on bone integrity. Lohmann Brown and Bovan White pullet chicks were started in equal numbers on the floor or in battery brooders and were intermingled throughout all subsequent housing systems. At 5 wk of age, 432 floor-raised pullets were moved to 8 aviary cages. At 10 wk, 256 battery-raised pullets were transferred to 64 conventional layer cages. Pullets were given diets containing fine (LPS-FINE, 0.431 mm) or a blend of fine and coarse (LPS-BLEND, 0.879 mm) LPS from 7 to 17 weeks. Data were analyzed as a split plot factorial design with strain as subplot and with 4 replicates for each treatment combination. Body weight, feed intake, egg production, and eggshell breaking strength and percentage were measured. Tibia bone mineral density (BMD) was determined using a dual energy x-ray absorptiometry. Presence of keel indentations, curvatures, or fractures was recorded. LPS-BLEND increased BMD (0.215 vs. 0.208, P = 0.03) at 18 weeks. During the pullet phase, the odds of pullets fed LPS-FINE displaying keel curvatures were 2.8 times the odds of those fed LPS-BLEND (P = 0.04). At 54 wk, hens fed LPS BLEND as pullets had lower odds of keel indentations (P = 0.02). Brown aviary hens fed LPS-BLEND as pullets had the lowest egg production compared to the rest of the treatment combinations (P = 0.004). Taken together, feeding LPS-BLEND to pullets improved bone mineralization at the onset of sexual maturity and reduced keel damage during the pullet and layer phases, regardless of strain; however, LPS-BLEND was associated with lower egg production in Brown hens housed in aviaries compared to all others. PMID- 29506185 TI - Comparative Effectiveness and Injury to Tomato Plants of Three Neotropical Mirid Predators of Tuta absoluta (Lepidoptera: Gelechiidae). AB - Tuta absoluta (Meyrick; Lepidoptera: Gelechiidae) is a key pest of tomato and is quickly spreading over the world. We conducted an experiment aimed at evaluating the control capacity and risk for plant damage of three Neotropical mirid species, Campyloneuropsis infumatus (Carvalho; Hemiptera: Miridae), Engytatus varians (Distant; Hemiptera: Miridae) and Macrolophus basicornis (Stal; Hemiptera: Miridae) on T. absoluta infested tomato plants in large cages in an experimental greenhouse. During three successive periods of 9 wk each, we followed population development of the three mirids when exposed to T. absoluta, and of T. absoluta alone in separate cages in the greenhouse. We determined weekly the numbers of T. absoluta eggs and larvae per leaf, the number of mirid predators per leaf, the percentage of damaged leaves and fruits by T. absoluta, and the weight of fruits. Two of the mirid predators, C. infumatus and M. basicornis, successfully established on T. absoluta infested tomato plants and significantly reduced T. absoluta numbers, which ultimately resulted in an increased yield. These two mirid species hardly injured tomato plants or fruits as a result of plant feeding. Surprisingly, the species E. varians, which showed high predation rates in laboratory experiments, did not establish and reduce pest populations in any of the tests. PMID- 29506187 TI - Interactions between transcription factors and chromatin regulators in the control of flower development. AB - Chromatin modifiers and remodelers are involved in generating dynamic changes at the chromatin, which allow differential and specific readouts of the genome. While genetic evidence indicates that several chromatin factors play a key role in controlling basic developmental programs for inflorescence and flower morphogenesis, it remained unknown until recently how they exert their specificity toward gene expression, both temporally and spatially. An emerging topic is the recruitment or eviction of chromatin factors through the activity of sequence-specific DNA-binding domains, present in the chromatin factors themselves or in partnering transcription factors. Here we summarize recent progress that has been made in this regard in the model plant Arabidopsis thaliana. We further outline the different possible modes through which chromatin complexes specifically target genes involved in flower development. PMID- 29506186 TI - Chondroitin sulfate proteoglycans as novel drivers of leucocyte infiltration in multiple sclerosis. AB - Multiple sclerosis presents with profound changes in the network of molecules involved in maintaining central nervous system architecture, the extracellular matrix. The extracellular matrix components, particularly the chondroitin sulfate proteoglycans, have functions beyond structural support including their potential interaction with, and regulation of, inflammatory molecules. To investigate the roles of chondroitin sulfate proteoglycans in multiple sclerosis, we used the experimental autoimmune encephalomyelitis model in a time course study. We found that the 4-sulfated glycosaminoglycan side chains of chondroitin sulfate proteoglycans, and the core protein of a particular family member, versican V1, were upregulated in the spinal cord of mice at peak clinical severity, correspondent with areas of inflammation. Versican V1 expression in the spinal cord rose progressively over the course of experimental autoimmune encephalomyelitis. A particular structure in the spinal cord and cerebellum that presented with intense upregulation of chondroitin sulfate proteoglycans is the leucocyte-containing perivascular cuff, an important portal of entry of immune cells into the central nervous system parenchyma. In these inflammatory perivascular cuffs, versican V1 and the glycosaminoglycan side chains of chondroitin sulfate proteoglycans were observed by immunohistochemistry within and in proximity to lymphocytes and macrophages as they migrated across the basement membrane into the central nervous system. Expression of versican V1 transcript was also documented in infiltrating CD45+ leucocytes and F4/80+ macrophages by in situ hybridization. To test the hypothesis that the chondroitin sulfate proteoglycans regulate leucocyte mobility, we used macrophages in tissue culture studies. Chondroitin sulfate proteoglycans significantly upregulated pro inflammatory cytokines and chemokines in macrophages. Strikingly, and more potently than the toll-like receptor-4 ligand lipopolysaccharide, chondroitin sulfate proteoglycans increased the levels of several members of the matrix metalloproteinase family, which are implicated in the capacity of leucocytes to cross barriers. In support, the migratory capacity of macrophages in vitro in a Boyden chamber transwell assay was enhanced by chondroitin sulfate proteoglycans. Finally, using brain specimens from four subjects with multiple sclerosis with active lesions, we found chondroitin sulfate proteoglycans to be associated with leucocytes in inflammatory perivascular cuffs in all four patients. We conclude that the accumulation of chondroitin sulfate proteoglycans in the perivascular cuff in multiple sclerosis and experimental autoimmune encephalomyelitis boosts the activity and migration of leucocytes across the glia limitans into the central nervous system parenchyma. Thus, chondroitin sulfate proteoglycans represent a new class of molecules to overcome in order to reduce the inflammatory cascades and clinical severity of multiple sclerosis. PMID- 29506189 TI - Corrigendum to: "Effective biological control depends on life history strategies of both parasitoid and its host: evidence from Aphidius colemani-Myzus persicae System". PMID- 29506188 TI - Evaluating the effectiveness of the Emergency Neurological Life Support educational framework in low-income countries. AB - Background: The Emergency Neurological Life Support (ENLS) is an educational initiative designed to improve the acute management of neurological injuries. However, the applicability of the course in low-income countries in unknown. We evaluated the impact of the course on knowledge, decision-making skills and preparedness to manage neurological emergencies in a resource-limited country. Methods: A prospective cohort study design was implemented for the first ENLS course held in Asia. Knowledge and decision-making skills for neurological emergencies were assessed at baseline, post-course and at 6 months following course completion. To determine perceived knowledge and preparedness, data were collected using surveys administered immediately post-course and 6 months later. Results: A total of 34 acute care physicians from across Nepal attended the course. Knowledge and decision-making skills significantly improved following the course (p=0.0008). Knowledge and decision-making skills remained significantly improved after 6 months, compared with before the course (p=0.02), with no significant loss of skills immediately following the course to the 6-month follow up (p=0.16). At 6 months, the willingness to participate in continuing medical education activities remained evident, with 77% (10/13) of participants reporting a change in their clinical practice and decision-making, with the repeated use of ENLS protocols as the main driver of change. Conclusions: Using the ENLS framework, neurocritical care education can be delivered in low-income countries to improve knowledge uptake, with evidence of knowledge retention up to 6 months. PMID- 29506190 TI - Molecular techniques in infective endocarditis. PMID- 29506191 TI - Nitric oxide buffering and conditional nitric oxide release in stress response. AB - Nitric oxide (NO) has emerged as an essential biological messenger in plant biology that usually transmits its bioactivity by post-translational modifications such as S-nitrosylation, the reversible addition of an NO group to a protein cysteine residue leading to S-nitrosothiols (SNOs). In recent years, SNOs have risen as key signalling molecules mainly involved in plant response to stress. Chief among SNOs is S-nitrosoglutathione (GSNO), generated by S nitrosylation of the key antioxidant glutathione (GSH). GSNO is considered the major NO reservoir and a phloem mobile signal that confers to NO the capacity to be a long-distance signalling molecule. GSNO is able to regulate protein function and gene expression, resulting in a key role for GSNO in fundamental processes in plants, such as development and response to a wide range of environmental stresses. In addition, GSNO is also able to regulate the total SNO pool and, consequently, it could be considered the storage of NO in cells that may control NO signalling under basal and stress-related responses. Thus, GSNO function could be crucial during plant response to environmental stresses. Besides the importance of GSNO in plant biology, its mode of action has not been widely discussed in the literature. In this review, we will first discuss the GSNO turnover in cells and secondly the role of GSNO as a mediator of physiological and stress-related processes in plants, highlighting those aspects for which there is still some controversy. PMID- 29506192 TI - Modern Paradigm for Peritoneal Catheter Insertion: Single Port Optical Access Laparoscopic Shunt Insertion: Erratum. PMID- 29506193 TI - Variability and interaction of some egg physical and eggshell quality attributes during the entire laying hen cycle. AB - The aim of this study was to investigate the variability and relationships between some egg physical (egg weight, width, length, shape index, and surface area) and eggshell parameters (weight and percentage, thickness, breaking strength, and L*, a*, and b* values) during the entire laying hen cycle. A total of 8,000 eggs was collected every 5 wk, from 30 to 81 wk of hen age (10 samplings of 400 eggs/house), in 2 identical poultry houses equipped with enriched cages. For the statistical analysis, ANOVA, Bivariate Correlation, Principal Component Analysis (PCA), and Hierarchical Cluster Analysis were used. An increase of egg weight, length, and eggshell lightness (L*) associated with a reduction of eggshell percentage, breaking strength, and redness (a*) was observed as the hen aged (P < 0.05). Overall, the coefficients of variation resulted in <5% in width, length, shape index, and egg surface area; from 5 to 10% of egg weight, shell weight, shell percentage, shell thickness, L*, and b*; and >10% of eggshell breaking strength and a*. According to the PCA, the highest changes during the laying cycle are related to egg physical parameters (32%) and to eggshell breaking strength, percentage, and thickness (26%). The egg physical parameters appeared to be strongly correlated to each other, whereas a slight correlation between eggshell breaking strength and color attributes were evidenced (-0.231 and 0.289, respectively, for L* and a*; P < 0.01). Hierarchical cluster analysis, based on principal components of the overall egg attributes, is hereby considered, and evidenced dissimilarities for eggs laid from peak production up for 39 wk of hen age from the eggs laid afterwards. The latter group could also be divided into 2 subgroups, one comprising eggs laid from 44 and 53 wk of hen age and the other from 58 wk to the end. In conclusion, the large dataset created in this study allowed to extrapolate some robust information regarding the variability and correlations of the egg physical and eggshell quality attributes throughout the entire laying hen cycle. PMID- 29506194 TI - Influence of diluent volume of colistimethate sodium on aerosol characteristics and pharmacokinetics in ventilator-associated pneumonia caused by MDR bacteria. AB - Objectives: Nebulized colistimethate sodium (CMS) can be used to treat ventilator associated pneumonia caused by MDR bacteria. The influence of the diluent volume of CMS on aerosol delivery has never been studied. The main objectives of the study were to compare aerosol particle characteristics and plasma and urine pharmacokinetics between two diluent volumes in patients treated with nebulized CMS. Methods: A crossover study was conducted in eight patients receiving nebulized CMS every 8 h. After inclusion, nebulization started with 4 million international units (MIU) of CMS diluted either in 6 mL (experimental dilution) or in 12 mL (recommended dilution) of normal saline in a random order. For each diluent volume, CMS aerosol particle sizes were measured and plasma and urine samples were collected every 2 h. Nebulization time and stability of colistin in normal saline were assessed. Results: The mass median aerodynamic diameters were 1.4 +/- 0.2 versus 0.9 +/- 0.2 MUm (P < 0.001) for 6 and 12 mL diluent volumes, respectively. The plasma area under the concentration-time curve from 0 to 8 h (AUC0-8) of colistinA+B was 6.6 (4.3-17.0) versus 6.7 (3.6-14.0) MUg.h/mL (P = 0.461) for each dilution. The total amount of colistin and CMS eliminated in the urine represented, respectively, 17% and 13% of the CMS initially placed in the nebulizer chamber for 6 and 12 mL diluent volumes (P = 0.4). Nebulization time was shorter [66 (58-75) versus 93 (69-136) min, P = 0.042] and colistin stability was better with the 6 mL diluent volume. Conclusions: Nebulization with a higher concentration of CMS in saline (4 MIU in 6 mL) decreases nebulization time and improves colistin stability without changing plasma and urine pharmacokinetics or aerosol particle characteristics for lung deposition. PMID- 29506195 TI - Demographic and Operational Factors Predicting Study Completion in a Multisite Case-Control Study of Preschool Children. AB - Participant attrition can limit inferences drawn from study results and inflate research costs. We examined factors associated with completion of the Study to Explore Early Development (2007-2011), a multiple-component, case-control study of risk factors for autism spectrum disorder in preschoolers, conducted in California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania. Participants (n = 3,769) were asked to complete phone interviews, questionnaires, an in-person evaluation, and biologic sampling. We examined whether participant demographic and administrative factors predicted completion using mixed-effects logistic regression models. Completion of individual key study components was generally 70% or higher. However, 58% of families completed all per-protocol data elements (defined a priori as key study components). Per-protocol completion differed according to mother's age, race, educational level, driving distance to clinic, number of contact attempts to enroll, and number of telephone numbers provided (all P < 0.05). Case status was not associated with completion, despite additional data collection for case-confirmation. Analysis of a subset that completed an early interview revealed no differences in completion by household factors of income, primary language spoken, number of adults, or number of children with chronic conditions. Differences in completion by race and education were notable and need to be carefully considered in developing future recruitment and completion strategies. PMID- 29506197 TI - RE: "HORMONE THERAPY USE AND RISK OF CHRONIC DISEASE IN THE NURSES' HEALTH STUDY: A COMPARATIVE ANALYSIS WITH THE WOMEN'S HEALTH INITIATIVE". PMID- 29506196 TI - The Role of Mobile Genetic Elements in the Spread of Antimicrobial-Resistant Escherichia coli From Chickens to Humans in Small-Scale Production Poultry Operations in Rural Ecuador. AB - Small-scale production poultry operations are increasingly common worldwide. To investigate how these operations influence antimicrobial resistance and mobile genetic elements (MGEs), Escherichia coli isolates were sampled from small-scale production birds (raised in confined spaces with antibiotics in feed), household birds (no movement constraints; fed on scraps), and humans associated with these birds in rural Ecuador (2010-2012). Isolates were screened for genes associated with MGEs as well as phenotypic resistance to 12 antibiotics. Isolates from small scale production birds had significantly elevated odds of resistance to 7 antibiotics and presence of MGE genes compared with household birds (adjusted odds ratio (OR) range = 2.2-87.9). Isolates from humans associated with small scale production birds had elevated odds of carrying an integron (adjusted OR = 2.0; 95% confidence interval (CI): 1.06, 3.83) compared with humans associated with household birds, as well as resistance to sulfisoxazole (adjusted OR = 1.9; 95% CI: 1.01, 3.60) and trimethoprim/sulfamethoxazole (adjusted OR = 2.1; 95% CI: 1.13, 3.95). Stratifying by the presence of MGEs revealed antibiotic groups that are explained by biological links to MGEs; in particular, resistance to sulfisoxazole, trimethoprim/sulfamethoxazole, or tetracycline was highest among birds and humans when MGE exposures were present. Small-scale production poultry operations might select for isolates carrying MGEs, contributing to elevated levels of resistance in this setting. PMID- 29506198 TI - anexVis: visual analytics framework for analysis of RNA expression. AB - Summary: Although RNA expression data are accumulating at a remarkable speed, gaining insights from them still requires laborious analyses, which hinder many biological and biomedical researchers. This report introduces a visual analytics framework that applies several well-known visualization techniques to leverage understanding of an RNA expression dataset. Our analyses on glycosaminoglycan related genes have demonstrated the broad application of this tool, anexVis (analysis of RNA expression), to advance the understanding of tissue-specific glycosaminoglycan regulation and functions, and potentially other biological pathways. Availability and implementation: The application is accessible at https://anexvis.chpc.utah.edu/, source codes deposited on GitHub. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29506199 TI - Efficacy of tapentadol for first-line opioid-resistant neuropathic pain in Japan. AB - Background: Cancer-related neuropathic pain is sometimes unresponsive to multidrug treatment. Novel drugs are required to treat such severe pain without necessitating the use of adjuvant analgesics. Tapentadol is a new drug that has a dual mechanism as both an opioid agonist and noradrenalin reuptake inhibitor. The study objective was to investigate the effectiveness of oral tapentadol for relieving cancer-related neuropathic pain. Methods: A retrospective, single center, open, non-randomized study was conducted at the Nagoya City University Hospital. The study included 38 Japanese patients with advanced cancer who received opioids, such as tramadol, oral oxycodone and transdermal fentanyl, with or without adjuvant analgesics. Eastern Cooperative Oncology Group performance status, Numerical Rating Scale, primary tumor type, primary opioid and tapentadol doses, adjuvant analgesic prescriptions, outcomes and adverse events of opioid switching were assessed for 7 days. Results: Eighteen (47.3%) out of 38 patients were enrolled in this study. The average performance status was 2.13 +/- 0.94 (mean +/- standard deviation). After switching to oral tapentadol, the pain score decreased from 3.78 to 2.78. The patients who had clinically improved effective pain scores had a higher percentage of prior opioid use for more than 2 months. After switching to tapentadol, adverse events were usually mild, with a grade of 1-2 by the Common Terminology Criteria for Adverse Events v4.03. Conclusions: Tapentadol appears to have an acceptable safety margin and promising efficacy to relieve cancer-related neuropathic pain that is refractory to first-line opioid treatment. PMID- 29506200 TI - Atlas of the normal intracranial electroencephalogram: neurophysiological awake activity in different cortical areas. AB - : In contrast to scalp EEG, our knowledge of the normal physiological intracranial EEG activity is scarce. This multicentre study provides an atlas of normal intracranial EEG of the human brain during wakefulness. Here we present the results of power spectra analysis during wakefulness. Intracranial electrodes are placed in or on the brain of epilepsy patients when candidates for surgical treatment and non-invasive approaches failed to sufficiently localize the epileptic focus. Electrode contacts are usually in cortical regions showing epileptic activity, but some are placed in normal regions, at distance from the epileptogenic zone or lesion. Intracranial EEG channels defined using strict criteria as very likely to be in healthy brain regions were selected from three tertiary epilepsy centres. All contacts were localized in a common stereotactic space allowing the accumulation and superposition of results from many subjects. Sixty-second artefact-free sections during wakefulness were selected. Power spectra were calculated for 38 brain regions, and compared to a set of channels with no spectral peaks in order to identify significant peaks in the different regions. A total of 1785 channels with normal brain activity from 106 patients were identified. There were on average 2.7 channels per cm3 of cortical grey matter. The number of contacts per brain region averaged 47 (range 6-178). We found significant differences in the spectral density distributions across the different brain lobes, with beta activity in the frontal lobe (20-24 Hz), a clear alpha peak in the occipital lobe (9.25-10.25 Hz), intermediate alpha (8.25-9.25 Hz) and beta (17-20 Hz) frequencies in the parietal lobe, and lower alpha (7.75 8.25 Hz) and delta (0.75-2.25 Hz) peaks in the temporal lobe. Some cortical regions showed a specific electrophysiological signature: peaks present in >60% of channels were found in the precentral gyrus (lateral: peak frequency range, 20 24 Hz; mesial: 24-30 Hz), opercular part of the inferior frontal gyrus (20-24 Hz), cuneus (7.75-8.75 Hz), and hippocampus (0.75-1.25 Hz). Eight per cent of all analysed channels had more than one spectral peak; these channels were mostly recording from sensory and motor regions. Alpha activity was not present throughout the occipital lobe, and some cortical regions showed peaks in delta activity during wakefulness. This is the first atlas of normal intracranial EEG activity; it includes dense coverage of all cortical regions in a common stereotactic space, enabling direct comparisons of EEG across subjects. This atlas provides a normative baseline against which clinical EEGs and experimental results can be compared. It is provided as an open web resource (https://mni-open ieegatlas. RESEARCH: mcgill.ca). PMID- 29506201 TI - Comparison of graft patency following coronary artery bypass grafting in the left versus the right coronary artery systems: a systematic review and meta-analysis. AB - Although coronary artery bypass grafting has been the standard of care for patients with complex coronary artery disease for over 50 years, the evolution of graft patency over time in the left versus the right coronary systems remains poorly documented. This systematic review and meta-analysis aimed to characterize the evolution of graft patency over time comparing the left (excluding left anterior descending artery) and right coronary systems, with an emphasis on the comparison of venous versus arterial grafts and symptomatic versus asymptomatic patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to August 2016. We also searched clinical trials registers and reference lists of relevant studies. We included randomized clinical trials and observational studies comparing graft patency in the left versus the right coronary systems. Our outcome was graft patency defined as a binary variable according to whether grafts were reported as patent or failed at the time of angiogram. Data collection and analysis were performed according to the methodological recommendations of the Cochrane Collaboration. From a total 2275 papers, 52 studies were included in the qualitative analysis and 48 studies (including 36 006 grafts) in the meta-analysis. There was a 3.3% significant difference between the left-sided and right-sided graft patency, and the difference appeared to increase over time. Furthermore, patency of arterial grafts was higher in the left coronary system, while venous grafts performed similarly irrespective of the coronary circulation. Symptom recurrence also seemed related to a higher failure rate in the right coronary circulation. However, the high degree of heterogeneity precluded drawing definite conclusions. This meta-analysis suggested that graft patency might be better for left-sided vessels and that this difference might be driven by the better performance of arterial grafts in the left coronary system. However, evidence currently available is limited, and further research is warranted to understand whether certain grafts achieve better patency in the right versus the left coronary circulations. PMID- 29506202 TI - Applications of a highly alpha2,6-selective pseudosialidase. AB - Within human biology, combinations of regioisomeric motifs of alpha2,6- or alpha2,3-sialic acids linked to galactose are frequently observed attached to glycoconjugates. These include glycoproteins and glycolipids, with each linkage carrying distinct biological information and function. Microbial linkage-specific sialidases have become important tools for studying the role of these sialosides in complex biological settings, as well as being used as biocatalysts for glycoengineering. However, currently, there is no alpha2,6-specific sialidase available. This gap has been addressed herein by exploiting the ability of a Photobacterium sp. alpha2,6-sialyltransferase to catalyze trans-sialidation reversibly and in a highly linkage-specific manner, acting as a pseudosialidase in the presence of cytidine monophosphate. Selective, near quantitative removal of alpha2,6-linked sialic acids was achieved from a wide range of sialosides including small molecules conjugates, simple glycan, glycopeptide and finally complex glycoprotein including both linkages. PMID- 29506203 TI - Effect of knowledge and perceptions of risks on Ebola-preventive behaviours in Ghana. AB - Background: Limited studies exist on the effects of knowledge and risk perceptions in Ebola-preventive behaviours in Ghana. Methods: Using data collected from 800 respondents in 40 randomly selected communities in the Greater Accra Region of Ghana, this study employed hierarchical linear modelling to examine the effects of individual- and community-level factors on Ebola preventive behaviours. Results: The study found individual- and community-level factors are significantly associated with Ebola-preventive behaviours. Respondents with greater knowledge about Ebola were more likely to engage in Ebola-preventive behaviours. In addition, there were significant changes in risk perception from the time the disease had peaked in neighbouring countries to the time data were collected. Most importantly, respondents who perceived themselves to have a high risk of contracting Ebola at the time of the survey were significantly less likely to engage in Ebola-preventive behaviours. Compared with Christians, Muslims were significantly less likely to engage in Ebola-preventive behaviours. Findings from the multilevel analysis indicated significant differences across communities. Communities expressing worry about a potential Ebola outbreak were more likely to engage in Ebola-preventive behaviours. Conclusion: The findings suggest the importance of adopting behaviour change interventions that address Ebola at both the individual and community level, especially in the event of a future outbreak in Ghana. PMID- 29506204 TI - The role of inorganic nitrate and nitrite in cardiovascular disease risk factors: a systematic review and meta-analysis of human evidence. AB - Context: Depleted nitric oxide levels in the human body play a major role in cardiovascular disease pathogenesis. Inorganic nitrate/nitrite (rich dietary sources include beetroot and spinach) can act as a nitric oxide donor because nitrate/nitrite can be metabolized to produce nitric oxide. Objective: This review and meta-analysis sought to investigate the role of inorganic nitrate/nitrite in preventing or treating cardiovascular disease risk factors in humans. Data Sources: Electronic databases, including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane, and Scopus, were searched. Data Extraction: Experimental trials examining the effect of oral inorganic nitrate/nitrite intake on cardiovascular disease risk factors were included for systematic analysis. Results: Thirty-four studies were included for qualitative synthesis, 23 of which were eligible for meta-analysis. Included studies measured the following outcomes: blood pressure, endothelial function, arterial stiffness, platelet aggregation, and/or blood lipids. Inorganic nitrate intake was found to significantly reduce resting blood pressure (systolic blood pressure: -4.80 mmHg, P < 0.0001; diastolic blood pressure: -1.74 mmHg, P = 0.001), improve endothelial function (flow-mediated dilatation: 0.59%, P < 0.0001), reduce arterial stiffness (pulse wave velocity: -0.23 m/s, P < 0.0001; augmentation index: -2.1%, P = 0.05), and reduce platelet aggregation by 18.9% (P < 0.0001). Conclusions: Inorganic nitrate consumption represents a simple strategy for targeting cardiovascular disease risk factors. Future studies investigating the long-term effects of inorganic nitrate on cardiovascular disease outcomes are warranted. PMID- 29506205 TI - The Montreal Augmentation Mammaplasty Operation (MAMO) Simulator: An Alternative Method to Train and Assess Competence in Breast Augmentation Procedures. AB - Background: Surgical residents' exposure to aesthetic procedures remains limited in residency training. The development of the Montreal augmentation mammaplasty operation (MAMO) simulator aims to provide an adjunctive training method and assessment tool to complement the evolving competency-based surgical curriculum. Objectives: To perform face, content, and construct validations of the MAMO simulator for subpectoral breast augmentation procedures and assess the reliability of the assessment scales used. Methods: Plastic surgery staff and residents were recruited to perform a subpectoral breast augmentation on the simulator. Video recordings of their performance were blindly evaluated using the objective structured assessment of technical skills (OSATS) system consisting of the global rating scale (GRS), mammaplasty objective assessment tool (MOAT), and a surgery-specific Checklist score. Results: Fourteen plastic surgery residents and seven expert plastic surgeons were enrolled. Experts' performance was significantly higher than residents' according to each of GRS, MOAT, and Checklist scores. Mean values of residents and experts were 23.4 (2.5) vs 36.9 (3.1) (P < 0.0001) for GRS score, 30.4 (2.2) vs 40 (3.2) (P < 0.0001) for MOAT scores, and 9.7 (1.5) vs 12 (1) (P < 0.001) for Checklist scores, respectively. Face and content validations showed excellent results among parameters evaluated, with an overall mean score of 4.8 (0.3) on 5. Cronbach's alpha was 0.96 and 0.83 for GRS and MOAT scores, respectively. Intraclass correlation coefficients for interrater reliability were excellent at 0.93, 0.92, and 0.89 for the GRS, MOAT, and Checklist scores, respectively. Conclusions: This study proves the construct simulator to be valid and the assessment scales to be reliable. PMID- 29506206 TI - Extrema-weighted feature extraction for functional data. AB - Motivation: Although there is a rich literature on methods for assessing the impact of functional predictors, the focus has been on approaches for dimension reduction that do not suit certain applications. Examples of standard approaches include functional linear models, functional principal components regression and cluster-based approaches, such as latent trajectory analysis. This article is motivated by applications in which the dynamics in a predictor, across times when the value is relatively extreme, are particularly informative about the response. For example, physicians are interested in relating the dynamics of blood pressure changes during surgery to post-surgery adverse outcomes, and it is thought that the dynamics are more important when blood pressure is significantly elevated or lowered. Results: We propose a novel class of extrema-weighted feature (XWF) extraction models. Key components in defining XWFs include the marginal density of the predictor, a function up-weighting values at extreme quantiles of this marginal, and functionals characterizing local dynamics. Algorithms are proposed for fitting of XWF-based regression and classification models, and are compared with current methods for functional predictors in simulations and a blood pressure during surgery application. XWFs find features of intraoperative blood pressure trajectories that are predictive of postoperative mortality. By their nature, most of these features cannot be found by previous methods. Availability and implementation: The R package 'xwf' is available at the CRAN repository: https://cran.r-project.org/package=xwf. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29506207 TI - Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model. AB - Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT>MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. Methods: Dose fractionation was conducted over 24 h in a dynamic one compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). Results: Bacterial killing of no more than ~3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2 = 0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. Conclusions: Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically. PMID- 29506208 TI - The effect of chair-based pedal exercises for older people admitted to an acute hospital compared to standard care: a feasibility study. AB - Background: chair-based pedal exercises potentially offer a simple method of improving physical activity in older people admitted to hospital. Objective: to assess the feasibility of using chair-based pedal exercisers on acute medical wards for older people. To study if there is any effect on muscle strength, mobility and time spent physically active. Subjects: fifty participants >=65 years who were able to pedal admitted to acute medical wards for older people in a UK hospital. Methods: participants were randomised to either pedal for 5 min three times a day with minimal supervision; or standard care. Outcome data (compliance with exercise and change in lower limb muscle strength, mobility and level of physical activity) were collected on day 7 or on discharge, whichever came 1st. Results: there were no significant differences in baseline characteristics between the intervention and standard care group. Participants remained in the study for an average of 5 days. None in the intervention group adhered to the prescribed exercise duration. The intervention group completed a median of 152 revolutions, or a median total pedal time of 5 min during the entire study period. There were no differences in change in lower limb muscle strength, mobility score or the percentage of time spent active between the two groups. Conclusion: pedal exercises with minimal supervision are not feasible as a single intervention to improve physical activity in older people admitted to hospital. There may be a role for it as part of a multifaceted strategy to improve physical activity in hospital. PMID- 29506209 TI - Are physical activity interventions for healthy inactive adults effective in promoting behavior change and maintenance, and which behavior change techniques are effective? A systematic review and meta-analysis. AB - Physical inactivity and sedentary behavior relate to poor health outcomes independently. Healthy inactive adults are a key target population for prevention. This systematic review and meta-analysis aimed to evaluate the effectiveness of physical activity and/or sedentary behavior interventions, measured postintervention (behavior change) and at follow-up (behavior change maintenance), to identify behavior change techniques (BCT) within, and report on fidelity. Included studies were randomized controlled trials, targeting healthy inactive adults, aiming to change physical activity and/or sedentary behavior, with a minimum postintervention follow-up of 6 months, using 16 databases from 1990. Two reviewers independently coded risk of bias, the "Template for Intervention Description and Replication" (TIDieR) checklist, and BCTs. Twenty six studies were included; 16 pooled for meta-analysis. Physical activity interventions were effective at changing behavior (d = 0.32, 95% confidence intervals = 0.16-0.48, n = 2,346) and maintaining behavior change after 6 months or more (d = 0.21, 95% confidence intervals = 0.12-0.30, n = 2,190). Sedentary behavior interventions (n = 2) were not effective. At postintervention, physical activity intervention effectiveness was associated with the BCTs "Biofeedback," "Demonstration of the behavior," "Behavior practice/rehearsal," and "Graded tasks." At follow-up, effectiveness was associated with using "Action planning," "Instruction on how to perform the behavior," "Prompts/cues," "Behavior practice/rehearsal," "Graded tasks," and "Self-reward." Fidelity was only documented in one study. Good evidence was found for behavior change maintenance effects in healthy inactive adults, and underlying BCTs. This review provides translational evidence to improve research, intervention design, and service delivery in physical activity interventions, while highlighting the lack of fidelity measurement. PMID- 29506210 TI - Low-Temperature Fumigation of Harvested Lettuce Using a Phosphine Generator. AB - A research-scale phosphine generator, QuickPHlo-R, from United Phosphorus Ltd. (Mumbai, India) was tested to determine whether it was suitable for low temperature fumigation and oxygenated phosphine fumigation of harvested lettuce. Vacuum cooled Iceberg and Romaine lettuce (Lactuca sativa) were fumigated in 442 liter chambers at 2 degrees C for 24 and 72 h for control of western flower thrips [Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae)] and lettuce aphid [Nasonovia ribisnigri (Mosely) (Homoptera: Aphididae)]. Oxygenated phosphine fumigation for 48 h under 60% O2 was also conducted at 2 degrees C with Iceberg and Romaine lettuce for control of lettuce aphid. The generator completed phosphine generation in 60-90 min. Complete control of western flower thrips was achieved in 24-h treatment, and the 48-h oxygenated fumigation, and 72-h regular fumigation treatments completely controlled lettuce aphid. Lettuce quality was evaluated 14 d after fumigation. There was increased incidence of brown stains on fumigated Iceberg lettuce, and the increases were more obvious in longer (>=48 h) treatments. Both Iceberg and Romaine lettuce from all treatments and controls had good visual quality even though there was significantly higher brown stain incidence on fumigated Iceberg lettuce in >=48-h treatment and significant differences in quality score for both Iceberg and Romaine lettuce in the 72-h treatment. The brown stains were likely due to the high sensitivity of lettuce to carbon dioxide. The study indicated that QuiPHlo-R phosphine generator has potential in low-temperature phosphine fumigation due to the quick establishment of desired phosphine levels, efficacy in pest control, and reasonable safety to product quality. PMID- 29506211 TI - Bronchopulmonary sequestrations in a paediatric centre: ongoing practices and debated management. AB - OBJECTIVES: Bronchopulmonary sequestration (BPS) is the second most common congenital lung malformation, with an estimated incidence ranging from 0.15% to 1.8%. Surgical treatment is elective in patients with symptoms, but the management of asymptomatic patients remains controversial. METHODS: We retrospectively reviewed the medical records of 99 patients treated for BPS in our institution from January 2000 to December 2015. BPS was diagnosed prenatally in 86 (87%) cases. Management throughout this 16-year period was based on 3 interventions: resection by open surgery, resection by thoracoscopy and embolization. RESULTS: Among the 86 patients with a prenatal diagnosis of BPS, 14% had symptoms at birth and 10% had delayed symptoms at a median delay of 8 months (4.5-42 months). For the other 13 patients, symptoms occurred at a median age of 34 months (range 3-96 months). Embolization of the feeding vessel was performed in 46 patients with 6 secondary surgical resections (13%). A total of 59 patients were operated on: 23 cases by open surgery and 36 cases by thoracoscopy. The mean hospitalization stay was significantly longer for open surgery: 4.8 +/- 1.3 days vs 4.1 +/-1.5 days, respectively (P = 0.03). Differences in hospitalization stay were also found between asymptomatic and symptomatic patients: 3.5 +/- 1.2 vs 5.1 +/-1.6 days, respectively (P = 0.002). Two of the operated patients died. CONCLUSIONS: When surgery is chosen, thoracoscopy appears to be a valuable procedure. A better understanding of the natural history of BPS is still needed to define the optimal management and the respective roles of surgery, embolization or non-interventional follow-up. PMID- 29506212 TI - Fooling the Harlequin Bug (Hemiptera: Pentatomidae) Using Synthetic Volatiles to Alter Host Plant Choice. AB - Harlequin bug, Murgantia histrionica (Hahn) (Hemiptera: Pentatomidae), is a widespread pest that feeds on a variety of brassicaceous crops and other plants. To understand olfactory cues that mediate host-finding, and their possible utility in pest management, we deployed aggregation pheromone (mixed murgantiols = 10,11-epoxy-1-bisabolen-3-ols) and/or isothiocyanate (ITC) host plant volatiles with potted host plants and nonhost soybean, in field choice bioassays. Adults of both sexes were strongly attracted (10-31*) to collard host plants baited with pheromone lures, compared with unbaited collards, as were nymphs. Collard plants baited with lures containing allyl and/or benzyl-ITC showed a 1.3* and 1.9* increase in attractiveness, respectively, neither differing by life-stage nor sex; multiple lures showed additive attraction. Nonhost soybean, baited with pheromone lure, was 4.6-7.5* more attractive to adults than unbaited collard; conversely, baited collard was 124* more attractive than unbaited soybean. The stark difference in observed effect of pheromone lure between unpoisoned plants, and those poisoned with imidacloprid, indicated that attraction was underestimated by circa-daily counts of unpoisoned plants, presumably because if not poisoned, bugs rapidly abandoned the baited nonhost soybean plant. Results indicate that harlequin bugs can be misled to encounter and feed on nonhosts by their aggregation pheromone, but additional means may be needed to retain them. Attraction to hosts is increased both by the aggregation pheromone, and at least two host plant volatiles, allyl and benzyl-ITC. These results contribute to our knowledge of host finding in harlequin bug, and to possible trapping and trap cropping schemes for pest management. PMID- 29506213 TI - Probing binding specificity of the sucrose transporter AtSUC2 with fluorescent coumarin glucosides. AB - The phloem sucrose transporter, AtSUC2, is promiscuous with respect to substrate recognition, transporting a range of glucosides in addition to sucrose, including naturally occurring coumarin glucosides. We used the inherent fluorescence of coumarin glucosides to probe the specificity of AtSUC2 for its substrates, and determined the structure-activity relationships that confer phloem transport in vivo using Arabidopsis seedlings. In addition to natural coumarin glucosides, we synthesized new compounds to identify key structural features that specify recognition by AtSUC2. Our analysis of the structure-activity relationship revealed that the presence of a free hydroxyl group on the coumarin moiety is essential for binding by AtSUC2 and subsequent phloem mobility. Structural modeling of the AtSUC2 substrate-binding pocket explains some important structural requirements for the interaction of coumarin glucosides with the AtSUC2 transporter. PMID- 29506215 TI - Corrigendum. PMID- 29506214 TI - Predictive value of genetic analysis for pathological complete response to preoperative treatment in HER2 positive, HR negative early breast cancer (PASSION trial). AB - We previously reported a potential predictive value of HSD17B4 hypermethylation for pathological complete response after preoperative trastuzumab plus chemotherapy in HER2-positive breast cancer. We will prospectively evaluate the predictive performance of HSD17B4 hypermethylation in patients with HER2 positive/HR-negative breast cancer treated with sequential chemo-radiotherapy. The primary endpoint is the rate of pathological complete response, defined as the absence of invasive and intraductal tumor cells in the breast at surgery, in breast cancer with HSD17B4 hypermethylation. If the pCR rates are extremely high, the ultimate breast-conserving treatment excluding the need for surgery could be a future treatment option. A total of 200 patients will be enrolled. This trial is registered at the UMIN Clinical Trials Registry as UMIN000028065 and is financially supported by the Japan Agency for Medical Research and Development, AMED. PMID- 29506216 TI - Localization of dimethylated histone three lysine four in the Rattus norvegicus sperm genome. AB - We examined the precise localization of dimethylated histone three lysine four (H3K4me2) in mature rat sperm. Within nonintergenic-enriched regions, half of the DNA peaks associated with H3K4me2 retention fell in gene bodies and the other half in promoter regions. The most significant peaks near annotated DNA regions in the composite data included loci known to be associated with RNA metabolism, cell cycle regulation, and spermatogenesis. Regions associated with differential retention of H3K4me2 within gene bodies were significantly enriched for housekeeping gene and cell-cycle functionality. Proximal promoter-associated peaks were enriched for viral reproduction and cell cycle regulation genes, while Promoter1k and Promoter3k peaks were enriched for RNA metabolism functions. Further, homeobox- and kruppel-like factor motifs were among the most significantly enriched de novo and known motifs discovered within gene-associated H3K4me2 peaks. Motif analysis and native chromatin immunoprecipitation followed by sequencing (nChIP-seq) peak calling indicated an instructive role for retained paternal histones in the epigenetic regulation of early embryonic development in the rat. PMID- 29506217 TI - IBD-INFO Questionnaire: A Multicenter French Up-to-Date Survey of Patient Knowledge in Inflammatory Bowel Disease. AB - Background: It has been demonstrated in many chronic conditions, including inflammatory bowel disease (IBD), that better patient knowledge about pathology and treatment improves the course and management of disease. The aim of this study was to develop an updated self-questionnaire to assess patients' level of knowledge of IBD. Methods: The IBD-INFO included 3 parts: an original part (Q1) and 2 parts from the translation of the preexisting questionnaires Crohn's and Colitis Knowledge score (CCKNOW) (Q2) and Crohn's and Colitis Pregnancy Knowledge score (CCPKNOW) (Q3). The reliability and discriminatory ability of the questionnaire were validated in 3 groups of non-IBD volunteers with various theoretical knowledge levels. The final questionnaire (64 validated questions) was then tested on 364 in- and out- IBD patients from 4 French university hospitals. The score for each part of the questionnaire was calculated, and factors associated with low scores were identified by univariate and multivariate logistic regression analyses. Results: The scores obtained by the 3 non-IBD volunteer groups differed significantly (P < 0.0001), and the IBD-INFO questionnaire showed excellent internal reliability and consistency (alpha = 0.98). The median total score obtained by the IBD patients was 27/64 (range, 0 59), and scores for Q1, Q2, and Q3 were, respectively, 10/23 (range, 0-21), 11/24 (range, 0-23), and 4/17 (range, 0-16). In multivariate analysis, lack of a university degree, not being a member of a patient association, not receiving anti-tumor necrosis factor alpha (anti-TNFalpha) treatment, duration of IBD <=3 years, male sex, and age >38 years were independent risk factors of a poor IBD INFO knowledge score. The areas of knowledge least mastered were vaccination, IBD related cancers, treatments, and pregnancy. Conclusions: Using the IBD-INFO, an updated self-administered questionnaire built to assess IBD patients' knowledge, several risk factors have been highlighted that allow better targeting of patients and areas requiring an improvement in the level of information. PMID- 29506218 TI - A survey of healthcare-seeking practices and related stigma among community- and street-based children in Cambodia. AB - Background: Globally, street children comprise a growing population of vulnerable children. Understanding how they interact with healthcare systems is fundamental to efforts to improve their health and well-being. Methods: We surveyed 75 street and community-based children in Battambang, Cambodia regarding their healthcare seeking practices and related stigma. Results: For demographically similar street and community children, hospitals and pharmacies were preferred healthcare institutions, with this choice being motivated by the caretaker's decision or cost. Street children reported increased fear of being refused treatment. Conclusions: Street children and demographically similar community children have similar healthcare-seeking practices and preferences, although street children face increased stigmatization. PMID- 29506219 TI - Plant-based diets for children as a means of improving adult cardiometabolic health. AB - Cardiovascular disease (CVD) is the largest contributor to global mortality, and this trend is expected to continue. Although mortality rates have been falling, adverse developments in obesity and diabetes threaten to reverse this. It has been estimated that the only viable strategy to reduce the epidemic is to focus on population-wide risk factor reduction. Primordial prevention, a strategy aimed at avoiding the development of risk factors before the disease onset, has been shown to reduce the CVD epidemic substantially. Plant-based diets appear beneficial for prevention of cardiometabolic diseases, with adult vegetarians and vegans having lower CVD risk than omnivores. Atherosclerosis starts in childhood and progresses in relation to classical CVD risk factors, which, along with dietary habits, track to adulthood. Based on this evidence, it is proposed that plant-based diets in childhood could promote cardiometabolic health in adults and thereby reduce CVD and promote longevity and health. However, the need for additional research to establish the safety of predominantly or exclusively plant based diets in children is noted. PMID- 29506220 TI - Identification of Trophectoderm-Derived Cripto as an Essential Mediator of Embryo Implantation. AB - Cripto-1 (TDGF1) is a multifunctional signaling factor that stimulates cellular effects, including proliferation, migration, survival, epithelial-to-mesenchymal transition, and angiogenesis, to regulate embryogenesis, tissue homeostasis, and tumorigenesis. Those cell behaviors are also associated with implantation of the embryo into the uterine wall, and this led us to investigate the role of embryo derived Cripto in embryo attachment and implantation. In this study, we show that Cripto and its signaling mediator GRP78 are uniquely localized to embryo implantation sites. We knocked down Cripto expression specifically in trophoblast cells and found that this resulted in a corresponding decrease in the levels of its downstream signaling mediators, phosphorylated (phospho-)SMAD2, phospho-SRC, phospho-extracellular signal-regulated kinase, and phospho-AKT, which are also known mediators of embryo implantation. We then transplanted Cripto knockdown and control embryos into uteri of pseudopregnant female mice and found that embryos with Cripto-depleted trophoblast cells had dramatically impaired capacity to attach to the uterine wall when compared with controls. This loss of appropriate embryo attachment following Cripto knockdown in trophoblast cells was associated with abnormally enlarged implantation sites that were almost completely devoid of microvessels. A role for Cripto in embryo implantation was further supported by our demonstration that attachment of trophoblast-derived spheroids to endometrial cells in vitro was stimulated by Cripto treatment and diminished by treatment with either of two mechanistically distinct Cripto blocking agents. Collectively, our findings identify Cripto as a novel and critical embryo attachment factor and suggest that modulation of Cripto signaling may have significant therapeutic potential for the treatment of infertility and other related disorders. PMID- 29506221 TI - Effect of short- and long-term feed restriction on ghrelin concentrations in turkeys. AB - One-day-old broad-breasted white turkeys (Meleagris gallopavo) were reared as recommended by industry standards. In Experiment 1, starting at 5 wk of age (WOA), birds were placed in individual cages with free access to feed and water. Blood samples were taken after 18 h of fasting (FASTING) and at 90 +/- 5 min after feeding (1.5 h after feeding). In Experiment 2, birds were weighed, randomly assigned to 2 treatments, and placed in individual cages. In treatment 1 (n = 10), birds were fed ad libitum (FF), while birds in treatment 2 (n = 11) were placed on a restricted diet to allow for an average daily gain of 10.0 g per d from 4 to 11 WOA (RES). In Experiment 1, concentrations of ghrelin (P = 0.012) and glucose (P < 0.001) were increased 1.5 h after feeding compared with concentration during FASTING, whereas concentrations of adrenocorticotropic hormone (ACTH) (P < 0.001) and corticosterone (P = 0.002) were decreased 1.5 h after feeding. Concentration of insulin, free fatty acids, and ketone bodies followed a normal physiological response to fasting and feeding. Similarly, in Experiment 2, concentrations of ghrelin (P < 0.001) and glucose (P = 0.038) were increased in FF birds, whereas concentrations of corticosterone were decreased (P = 0.002) in FF birds. It could be concluded that in turkeys, preprandial (18 h of fasting) and long-term feed restriction is associated with decreased concentration of ghrelin-thus, the opposite effect of that reported in chickens and mammalian species. PMID- 29506222 TI - Serum Sclerostin and Bone Turnover in Latent Autoimmune Diabetes in Adults. AB - Purpose: Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA. Methods: This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed. Results: Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (rho = 0.29; P = 0.0001), high-density lipoprotein (rho = -0.23; P = 0.003), triglycerides (rho = 0.19; P = 0.002), and time since diagnosis (rho = 0.32; P < 0.0001). Conclusions: Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only. PMID- 29506223 TI - Molecular Identification of Thrips Species Infesting Cotton in the Southeastern United States. AB - Traditional identification of thrips species based on morphology is difficult, laborious, and especially challenging for immature thrips. To support monitoring and management efforts of thrips as consistent and widespread pests of cotton (Gossypium hirsutum L.), a probe-based quantitative PCR (qPCR) assay with crude DNA extraction was developed to allow efficient and specific identification of the primary species of thrips infesting cotton. The assay was applied to identify over 5,000 specimens of thrips (including 3,366 immatures) collected on cotton seedlings from Alabama, Georgia, North Carolina, South Carolina, and Virginia in 2016. One half of all adult samples were examined by morphological identification, which provided a statistically equivalent species composition as the qPCR method. Frankliniella fusca (Hinds) (Thysanoptera: Thripidae) was the dominant species across all the locations (76.8-94.3% of adults and 81.6-98.0% of immatures), followed by Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) in Georgia, North Carolina, and Virginia (4.6-19% of adults and 1.7 17.3% of immatures) or Frankliniella tritici (Fitch) (Thysanoptera: Thripidae) in South Carolina (10.8% of adults and 7.8% of immatures). Thrips tabaci (Lindeman) (Thysanoptera: Thripidae) and Neohydatothrips variabilis (Beach) (Thysanoptera: Thripidae) were occasionally found among adults but were rarely present among immature thrips. These five species of thrips represented 98.2-100% of samples collected across the Southeast. The qPCR assay was demonstrated to be a valuable tool for large-scale monitoring of species composition of thrips at different life stages in cotton. The tool will contribute to a better understanding of thrips population structure in cotton and could assist with development and application of improved management strategies. PMID- 29506224 TI - Learning from errors for continuously improving patient safety. PMID- 29506225 TI - Overlapping and differential roles of plasma membrane calcium ATPases in Arabidopsis growth and environmental responses. AB - Plant cells have multiple plasma membrane (PM)-localized calcium ATPases (ACAs) pumping calcium ions out of the cytosol. Although the involvement of some of these ACAs in plant growth and immunity has been reported, their individual and combined functions have not been fully examined. Here, we analysed the effects of single and combined mutations of four ACA genes, ACA8, ACA10, ACA12, and ACA13, in a number of processes. We found that these four genes had both overlapping and differential involvements in vegetative growth, inflorescence growth, seeds setting, disease resistance and stomatal movement. Disruption of any of these four genes reduces seed setting, indicating their contribution to the overall fitness of the plants. While ACA10 and ACA8 play major roles in vegetative growth and immunity, ACA13 and ACA12 are also involved in these processes especially when the function of ACA10 and/or ACA8 is compromised. The loss of ACA13 and ACA10 function in combination with a reduction in function of ACA8 leads to seedling death at bolting, revealing the essential role of their collective function in plant growth. Taken together, this study indicates a highly tuned calcium system involving these PM-localized calcium pumps in plant growth and environmental responses. PMID- 29506226 TI - RE: Effectiveness of Pharmaceutical Smoking Cessation Aids in a Nationally Representative Cohort of American Smokers. PMID- 29506227 TI - Muscle protein anabolism in advanced cancer patients: response to protein and amino acids support, and to physical activity. AB - In the field of oncology, it is well recognized that a decrease in mass, density, strength, or function of skeletal muscle is associated to increased treatment toxicities and postoperative complications, as well as poor progression-free survival and overall survival. The ability of amino acids to stimulate protein synthesis in cancer patients is reduced. Considering nutritional intervention, this anabolic resistance could be in a part counteracted by increasing protein or by giving specific amino acids. In particular, Leucine might counteract this anabolic resistance not only by increasing substrate availability, but also by directly modulating the anabolic signal pathway. Few studies showed the possibility of increasing muscle protein synthesis by specific nutriments and/or by increasing amino acids or protein administration. In addition, whereas many studies provide evidence of a benefit of adapted physical activity in advanced cancer patients, it is difficult to specify the most appropriate type of exercise, and the optimum rhythm and intensity. Moreover, the benefits of physical activities and of protein support seem greater when it is started at the precachexia stage rather than at the cachexia stage, and their benefits are limited or nonexistent at the stage of refractory cachexia. Future approaches should integrate the combination of several complementary treatments in order to prevent (or improve) cachexia and/or sarcopenia in cancer patients. PMID- 29506228 TI - Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy. AB - Body composition, defined as the proportions and distribution of lean and fat tissues in the human body, is an emergent theme in clinical oncology. Severe muscle depletion (sarcopenia) is most easily overlooked in obese patients; the advent of secondary analysis of oncologic images provides a precise and specific assessment of sarcopenia. Here, we review the definitions, prevalence and clinical implications of sarcopenic obesity (SO) in medical and surgical oncology. Reported prevalence of SO varies due to the heterogeneity in the definitions and the variability in the cut points used to define low muscle mass and high fat mass. Prevalence of SO in advanced solid tumor patient populations average 9% (range 2.3%-14.6%) overall, and one in four (24.7%, range 5.9%-39.2%) patients with body mass index >= 30 kg/m2 are sarcopenic. SO is independently associated with higher mortality and higher rate of complications in systemic and surgical cancer treatment, across multiple cancer sites and treatment plans. These associations remain unexplained, however, it has been hypothesized that patients with sarcopenia are generally unfit and unable to tolerate stress. Another proposed mechanism relates to increased exposure to antineoplastic therapy, i.e. a large fat mass would be expected to inflate drug dose in BSA based treatments, causing an increased rate of dose-limiting toxicity. Pharmacokinetic data are needed to confirm or refute this hypothesis. Old age, deconditioning, cancer progression, acute or chronic nonmalignant disease and drug side-effects are suggested causes of muscle loss, and it is unknown the degree to which this can be reversed. Sarcopenia can be readily detected before start of cancer treatment, however, clinical management protocols for SO patients require development. Studies of cancer treatment dose-modulation are in progress. PMID- 29506229 TI - Insulin resistance and body composition in cancer patients. AB - Cancer cachexia, weight loss with altered body composition, is a multifactorial syndrome propagated by symptoms that impair caloric intake, tumor byproducts, chronic inflammation, altered metabolism, and hormonal abnormalities. Cachexia is associated with reduced performance status, decreased tolerance to chemotherapy, and increased mortality in cancer patients. Insulin resistance as a consequence of tumor byproducts, chronic inflammation, and endocrine dysfunction has been associated with weight loss in cancer patients. Insulin resistance in cancer patients is characterized by increased hepatic glucose production and gluconeogenesis, and unlike type 2 diabetes, normal fasting glucose with high, normal or low levels of insulin. Cancer cachexia results in altered body composition with the loss of lean muscle mass with or without the loss of adipose tissue. Alteration in visceral adiposity, accumulation of intramuscular adipose tissue, and secretion of adipocytokines from adipose cells may play a role in promoting the metabolic derangements associated with cachexia including a proinflammatory environment and insulin resistance. Increased production of ghrelin, testosterone deficiency, and low vitamin D levels may also contribute to altered metabolism of glucose. Cancer cachexia cannot be easily reversed by standard nutritional interventions and identifying and treating cachexia at the earliest stage of development is advocated. Experts advocate for multimodal therapy to address symptoms that impact caloric intake, reduce chronic inflammation, and treat metabolic and endocrine derangements, which propagate the loss of weight. Treatment of insulin resistance may be a critical component of multimodal therapy for cancer cachexia and more research is needed. PMID- 29506230 TI - Broiler responses to increasing selenium supplementation using Zn-L selenomethionine with special attention to breast myopathies. AB - A study was conducted to evaluate growth performance, carcass and breast yields, and the occurrence and severity of white striping (WS) and wooden breast (WB) myopathies of broilers fed diets supplemented with increasing dietary levels of an organic source of selenium (Zn-L-SeMet). Broilers were fed 6 treatments with 12 replications of 26 birds in a 4-phase feeding program from 1 to 42 days. Corn soy-based diets were supplemented with 0, 0.2, 0.4, 0.6, 0.8, and 1.0 ppm of Zn-L SeMet. At 42 d, 6 birds were randomly selected from each pen (n = 72) and processed for carcass and breast yields. Breast fillets were scored for WS and WB at 42 days. Increasing Zn-L-SeMet led to quadratic responses (P < 0.05) for FCR from 1 to 7 d, BWG from 22 to 35 d, and for both responses from 8 to 21 d and 36 to 42 d, as well as in the overall period of 42 days. Carcass and breast yields presented a quadratic improvement (P < 0.01) with increasing Zn-L-SeMet supplementation and Se requirements were estimated at 0.85 and 0.86 ppm, respectively. In the overall period, estimates of Se requirements were 0.64 ppm for BWG and 0.67 ppm for FCR. White striping and WB scores presented quadratic increases (P < 0.01), and maximum scores were observed at 0.68 and 0.67 ppm, respectively. Broilers fed diets formulated without Se supplementation had a higher percentage of normal fillets compared to other Se supplementation levels (quadratic, P < 0.05). In conclusion, increasing Se supplementation to reach maximum growth performance led to higher degrees of severity of WS and WB. Selenium requirements determined in the present study were significantly higher than the present commercial recommendations. PMID- 29506235 TI - Management of Barrett's esophagus with low-grade dysplasia. AB - Barrett's esophagus progresses to esophageal adenocarcinoma in a stepwise histological fashion of no dysplasia, low grade dysplasia, high grade dysplasia and cancer. Hence the progression to cancer from various histological stages is different. Progression to cancer from low grade dysplasia is highly variable in the literature due to high inter-observer variability between pathologists in diagnosing it. Studies have shown the utility of having confirmation of low grade dysplasia by expert pathologists or documenting its persistence on two subsequent endoscopies in order to unify the diagnosis. The treatment of low grade dysplasia is variable. In this article we summarize the diagnosis, evaluation and management of low grade dysplasia in Barrett's Esophagus. PMID- 29506236 TI - Retinal gene therapy. AB - Introduction: Inherited retinal diseases are the leading cause of sight impairment in people of working age in England and Wales, and the second commonest in childhood. Gene therapy offers the potential for benefit. Sources of data: Pubmed and clinicaltrials.gov. Areas of agreement: Gene therapy can improve vision in RPE65-associated Leber Congenital Amaurosis (RPE65-LCA). Potential benefit depends on efficient gene transfer and is limited by the extent of retinal degeneration. Areas of controversy: The magnitude of vision improvement from RPE65-LCA gene therapy is suboptimal, and its durability may be limited by progressive retinal degeneration. Growing points: The safety and potential benefit of gene therapy for inherited and acquired retinal diseases is being explored in a rapidly expanding number of trials. Areas timely for developing research: Developments in vector design and delivery will enable greater efficiency and safety of gene transfer. Optimization of trial design will accelerate reliable assessment of outcomes. PMID- 29506238 TI - Influence of empirical double-active combination antimicrobial therapy compared with active monotherapy on mortality in patients with septic shock: a propensity score-adjusted and matched analysis-authors' response. PMID- 29506237 TI - Determination of an effective scoring function for RNA-RNA interactions with a physics-based double-iterative method. AB - RNA-RNA interactions play fundamental roles in gene and cell regulation. Therefore, accurate prediction of RNA-RNA interactions is critical to determine their complex structures and understand the molecular mechanism of the interactions. Here, we have developed a physics-based double-iterative strategy to determine the effective potentials for RNA-RNA interactions based on a training set of 97 diverse RNA-RNA complexes. The double-iterative strategy circumvented the reference state problem in knowledge-based scoring functions by updating the potentials through iteration and also overcame the decoy-dependent limitation in previous iterative methods by constructing the decoys iteratively. The derived scoring function, which is referred to as DITScoreRR, was evaluated on an RNA-RNA docking benchmark of 60 test cases and compared with three other scoring functions. It was shown that for bound docking, our scoring function DITScoreRR obtained the excellent success rates of 90% and 98.3% in binding mode predictions when the top 1 and 10 predictions were considered, compared to 63.3% and 71.7% for van der Waals interactions, 45.0% and 65.0% for ITScorePP, and 11.7% and 26.7% for ZDOCK 2.1, respectively. For unbound docking, DITScoreRR achieved the good success rates of 53.3% and 71.7% in binding mode predictions when the top 1 and 10 predictions were considered, compared to 13.3% and 28.3% for van der Waals interactions, 11.7% and 26.7% for our ITScorePP, and 3.3% and 6.7% for ZDOCK 2.1, respectively. DITScoreRR also performed significantly better in ranking decoys and obtained significantly higher score-RMSD correlations than the other three scoring functions. DITScoreRR will be of great value for the prediction and design of RNA structures and RNA-RNA complexes. PMID- 29506239 TI - The Importance of Umbilical Blood Supply and Umbilical Delay in Secondary Abdominoplasty: A Case Report. AB - Level of Evidence 5: PMID- 29506240 TI - Longitudinal nailfold capillaroscopy tracking of microangiopathic changes in systemic sclerosis. PMID- 29506242 TI - Improvements in Behavior and Immune Function and Increased Life Span of Old Mice Cohabiting With Adult Animals. AB - The social environment can affect the regulatory systems, and cohabitation with sick subjects is a negative factor for the nervous and immune systems, compromising the life span. Nevertheless, the possible beneficial effects of a positive social environment on nervous and immune functions and longevity have not yet been studied. The aim of this study was to analyze several behavioral and immune function parameters and life span in old mice after their cohabitation with adult animals. Old and adult ICR-CD1 female mice were divided into three experimental groups: adult controls, old controls, and a social environment experimental group. The latter contained two old mice with five adult mice. After 2 months in these conditions, mice were submitted to a behavioral battery of tests to analyze their sensorimotor abilities, anxiety-like behaviors, and exploratory capacities. Peritoneal leukocytes were then collected, and several immune functions as well as oxidative and inflammatory stress parameters were assessed. The animals were maintained in the same conditions until natural death occurred. The results showed that old animals, after cohabitation with adult mice, presented an improvement of behavioral capacities, immune functions, and a lower oxidative and inflammatory stress. Consequently, they exhibited a higher life span. PMID- 29506243 TI - Operative Neurosurgery: The Surgeon's Armamentarium. PMID- 29506241 TI - PITX2 deficiency and associated human disease: insights from the zebrafish model. AB - The PITX2 (paired-like homeodomain 2) gene encodes a bicoid-like homeodomain transcription factor linked with several human disorders. The main associated congenital phenotype is Axenfeld-Rieger syndrome, type 1, an autosomal dominant condition characterized by variable defects in the anterior segment of the eye, an increased risk of glaucoma, craniofacial dysmorphism and dental and umbilical anomalies; in addition to this, one report implicated PITX2 in ring dermoid of the cornea and a few others described cardiac phenotypes. We report three novel PITX2 mutations-c.271C > T, p.(Arg91Trp); c.259T > C, p.(Phe87Leu); and c.356delA, p.(Gln119Argfs*36)-identified in independent families with typical Axenfeld-Rieger syndrome characteristics and some unusual features such as corneal guttata, Wolf-Parkinson-White syndrome, and hyperextensibility. To gain further insight into the diverse roles of PITX2/pitx2 in vertebrate development, we generated various genetic lesions in the pitx2 gene via TALEN-mediated genome editing. Affected homozygous zebrafish demonstrated congenital defects consistent with the range of PITX2-associated human phenotypes: abnormal development of the cornea, iris and iridocorneal angle; corneal dermoids; and craniofacial dysmorphism. In addition, via comparison of pitx2M64* and wild-type embryonic ocular transcriptomes we defined molecular changes associated with pitx2 deficiency, thereby implicating processes potentially underlying disease pathology. This analysis identified numerous affected factors including several members of the Wnt pathway and collagen types I and V gene families. These data further support the link between PITX2 and the WNT pathway and suggest a new role in regulation of collagen gene expression during development. PMID- 29506244 TI - Traumatic Intraconal Foreign Body: Report of an Injury Corrected With Combined Surgical and Endoscopic Treatment. AB - BACKGROUND: Management of penetrating ocular splinter injuries is very controversial. Penetrating wounds of the orbit represent a complex therapeutic problem that requires a multidisciplinary approach. Endoscopic approaches to the orbit are currently performed through the lamina papyracea to access the medial part, or through large orbitotomies to access the lateral part. OBJECTIVE: To describe a novel combined approach to the lateral part of the orbit. METHODS: Clinical and surgical findings of intraorbital foreign body removal are presented. A minimal supraorbital osteotomy was performed, combined with endoscopic intraorbital dissection. RESULTS: The foreign body was removed, no postoperative complications were reported, and visual acuity increased from 2/10 preoperatively, to 8/10 one month after surgery. CONCLUSION: The present technique can be considered a safe and novel surgical approach to access the retrobulbar space and to treat the pathology of this anatomic region. PMID- 29506245 TI - Portable Intraoperative Computed Tomography Scan in Image-Guided Surgery for Brain High-grade Gliomas: Analysis of Technical Feasibility and Impact on Extent of Tumor Resection. AB - BACKGROUND: Intraoperative magnetic resonance imaging is the gold standard among image-guided techniques for glioma surgery. Scant data are available on the role of intraoperative computed tomography (i-CT) in high-grade glioma (HGG) surgery. OBJECTIVE: To verify the technical feasibility and usefulness of portable i-CT in image-guided surgical resection of HGGs. METHODS: This is a retrospective series control analysis of prospectively collected data. Twenty-five patients (Group A) with HGGs underwent surgery using i-CT and 5-aminolevulinic acid (5-ALA) fluorescence. A second cohort of 25 patients (Group B) underwent 5-ALA fluorescence-guided surgery but without i-CT. We used a portable 8-slice CT scanner and, in both groups, neuronavigation. Extent of tumor resection (ETOR) and pre- and postoperative Karnofsky performance status (KPS) scores were measured; the impact of i-CT on overall survival (OS) and progression-free survival (PFS) was also analyzed. RESULTS: In 8 patients (32%) in Group A, i-CT revealed residual tumor, and in 4 of them it helped to also resect pathological tissue detached from the main tumor. EOTR in these 8 patients was 97.3% (96% 98.6%). In Group B, residual tumor was found in 6 patients, whose tumor's mean resection was 98% (93.5-99.7). The Student t test did not show statistically significant differences in EOTR in the 2 groups. The KPS score decreased from 67 to 69 after surgery in Group A and from 74 to 77 in Group B (P = .07 according to the Student t test). Groups A and B did not show statistically significant differences in OS and PFS (P = .61 and .46, respectively, by the log-rank test). CONCLUSION: No statistically significant differences in EOTR, KPS, PFS, and OS were observed in the 2 groups. However, i-CT helped to verify EOTR and to update the neuronavigator with real-time images, as well as to identify and resect pathological tissue in multifocal tumors. i-CT is a feasible and effective alternative to intraoperative magnetic resonance imaging. Portable i-CT can provide useful real-time information during brain surgery and can be easily introduced in neurosurgical theaters in daily practice. PMID- 29506246 TI - A Compaction Bone Grafting Technique Leads to Early Bone Fusion in Cases of Posterior Lumbar Interbody Fusion. AB - BACKGROUND: The impaction bone grafting technique is a popular approach for achieving complete bone fusion during hip surgery or total knee arthroplasty. We hypothesized that compaction bone grafting (CBG), a modified version of impaction bone grafting, could be applied to lumbar fusion surgery. OBJECTIVE: To compare the bone fusion rates and durations achieved using the CBG technique and a conventional loose bone grafting technique. METHODS: We retrospectively reviewed 89 patients who underwent single-level posterior lumbar interbody fusion at the university hospital; 35 other posterior lumbar interbody fusion recipients were excluded due to undergoing multilevel fusion, prior lumbar surgery, trauma, infection, or inadequate computed tomographic data. Computed tomographic-based bone fusion assessments were obtained using the Brantigan, Steffee, and Fraser criteria at 1 and 2 years after surgery. RESULTS: The baseline characteristics of the CBG (n = 42) and loose bone grafting (n = 47) groups did not significantly differ. Fusion assessments indicated that significantly superior bone fusion rates were achieved at 1 year after surgery in the CBG group than in the loose bone grafting group (P = .04, chi2 test). However, the bone fusion rates of the 2 groups at 2 years after surgery did not significantly differ (P = .3). A nonsymptomatic surgical complication occurred in the CBG group when a spacer was inserted into the intervertebral space; specifically, the spacer slipped out of the right psoas muscle because a large quantity of compaction bone grafts disrupted the cage's pathway. CONCLUSION: In posterior lumbar interbody fusion surgeries, bone fusion was achieved more quickly with the CBG technique than with the conventional technique. PMID- 29506247 TI - Volumetric Measurements of Brain Shift Using Intraoperative Cone-Beam Computed Tomography: Preliminary Study. AB - BACKGROUND: Cerebrospinal fluid leakage and ventricular compression during open surgery may lead to brain deformation called brain shift. Brain shift may affect intraoperative navigation that is based on image-based preoperative planning. Tools to correct or predict these anatomic modifications can be important to maintain precision during open guided neurosurgery. OBJECTIVE: To obtain a reliable intraoperative volumetric deformation vector field describing brain shift during intracranial neurosurgical procedures. METHODS: We acquired preoperative and intraoperative cone-beam computed tomography enhanced with intravenous injection of iodine contrast. These data sets were preprocessed and elastically registered to obtain the volumetric brain shift deformation vector fields. RESULTS: We obtained the brain shift deformation vector field in 9 cases. The deformation fields proved to be highly nonlinear, particularly around the ventricles. Interpatient variability was considerable, with a maximum deformation ranging from 8.1 to 26.6 mm and a standard deviation ranging from 0.9 to 4.9 mm. CONCLUSION: Contrast-enhanced cone-beam computed tomography provides a feasible technique for intraoperatively determining brain shift deformation vector fields. This technique can be used perioperatively to adjust preoperative planning and coregistration during neurosurgical procedures. PMID- 29506248 TI - Face, Content, and Construct Validity of Brain Tumor Microsurgery Simulation Using a Human Placenta Model. AB - BACKGROUND: Brain tumors are complex 3-dimensional lesions. Their resection involves training and the use of the multiple microsurgical techniques available for removal. Simulation models, with haptic and visual realism, may be useful for improving the bimanual technical skills of neurosurgical residents and neurosurgeons, potentially decreasing surgical errors and thus improving patient outcomes. OBJECTIVE: To describe and assess an ex vivo placental model for brain tumor microsurgery using a simulation tool in neurosurgical psychomotor teaching and assessment. METHODS: Sixteen human placentas were used in this research project. Intravascular blood remnants were removed by continuous saline solution irrigation of the 2 placental arteries and placental vein. Brain tumors were simulated using silicone injections in the placental stroma. Eight neurosurgeons and 8 neurosurgical residents carried out the resection of simulated tumors using the same surgical instruments and bimanual microsurgical techniques used to perform human brain tumor operations. Face and content validity was assessed using a subjective evaluation based on a 5-point Likert scale. Construct validity was assessed by analyzing the surgical performance of the neurosurgeon and resident groups. RESULTS: The placenta model simulated brain tumor surgical procedures with high fidelity. Results showed face and content validity. Construct validity was demonstrated by statistically different surgical performances among the evaluated groups. CONCLUSION: Human placentas are useful haptic models to simulate brain tumor microsurgical removal. Results using this model demonstrate face, content, and construct validity. PMID- 29506249 TI - Microsurgical Anatomy of the Precuneal Artery: Does It Really Exist? Clarifying an Ambiguous Vessel Under the Microscope. AB - BACKGROUND: The ambiguous term precuneal artery (PA) has several synonyms and anatomic definitions. OBJECTIVE: To examine the arteries of the precuneus and describe the PA and its branching pattern. We defined the PA as the principal arterial supplier of the precuneus. METHODS: Twenty formalin-fixed, colored latex injected cadaveric heads were studied with the aid of an operating microscope and microsurgical instrumentation. After removal of the cerebrum from the cranial vault, we examined this vessel's anatomy. Anatomic features of the PA were investigated and assessed in relation to demographic and anthropometric variables. RESULTS: The PA was always a pericallosal artery branch and, more specifically, the superior internal parietal artery (SIPA) in 86.84%, the inferior internal parietal artery in 2.63%, and their common stem in 10.53% of specimens. Anastomosing interhemispheric branches between the PAs were present in 20% of cases. Compared with the right PA, the left anastomosed nearly 3 times more often with the ipsilateral posterior cerebral artery. The average distance of the PA's origin from the posterior limit of the splenium was shown to be 9.4 mm longer in elderly individuals compared with younger ones. CONCLUSION: The term PA complex (rather than PA) can better describe the principal arterial supplier of the precuneus, and the SIPA, inferior internal parietal artery, and their common stem were shown as the 3 contributing arteries, with the SIPA predominating. The average distance of the PA complex origin from the splenium's posterior limit shows significant variation with respect to age. PMID- 29506250 TI - Pseudoaneurysm of Distal Anterior Cerebral Artery Branch Following External Ventricular Drain Placement. AB - BACKGROUND: External ventricular drains (EVDs) are routinely placed as part of the management of intracranial hypertension. Pseudoaneurysm formation after EVD placement is a rare complication that can occur as a result of direct trauma to the cerebral vasculature. Prompt recognition and treatment may prevent future rupture. OBJECTIVE: To present our management strategy of a unique case of pseudoaneurysm formation in the context of the medical literature on these rare complications. METHODS: An EVD was placed in a 58-year-old female patient who presented with intracranial hypertension after subarachnoid hemorrhage secondary to a ruptured posterior communicating artery aneurysm before coiling of the aneurysm. On postbleed day 10, a pseudoaneurysm was identified in the distal anterior cerebral artery adjacent to the EVD tract. RESULTS: The pseudoaneurysm was successfully treated with surgical resection. CONCLUSION: Pseudoaneurysm formation after EVD placement is a rare but serious complication. We do not recommend routine screening for this complication; however, further investigation may be warranted when a delayed EVD tract hemorrhage is encountered. Prompt treatment of pseudoaneurysms is necessary to prevent future hemorrhage. PMID- 29506251 TI - Delayed Collapse of a Pipeline Embolization Device. AB - BACKGROUND: The Pipeline Embolization Device (PED) is a treatment modality for wide-neck complex intracranial aneurysms. There have been recent reports for the use of PEDs in dissecting pseudoaneurysms of the cervical carotid arteries. The use of this flow diversion technology has emerged as a promising alternative; however, there are various risks and complications that one should be aware of. OBJECTIVE: To report a rare postoperative complication, identified during follow up, in a patient initially treated for an internal carotid artery dissection with multiple overlapping PEDs. METHODS: A 53-year-old male with unremarkable history presented with acute Horner's syndrome, and imaging findings revealing internal carotid artery dissection and pseudoaneurysm with significant flow-limiting stenosis. He underwent treatment with a PED. RESULTS: At 3 months post-operation, a cerebral angiogram demonstrated that one of his pipeline stents in the posterior cavernous segment had collapsed at its central portion. Flow was preserved around the outside of the collapsed device. We performed 4 rounds of balloon angioplasty with modest, but not complete, re-expansion of the stent. The patient has been doing well in the postoperative period with no complications. CONCLUSION: The PED's role in the management of aneurysms and other intra- and extra-cranial vascular pathologies continues to expand, and new complications are bound to be discovered, similar to our case. As the use of these devices becomes routine and widespread, the frequency of these complications will increase. The management of unforeseen complications of PEDs, such as a collapsed stent, will need to be determined on an individual basis. PMID- 29506252 TI - Microsurgical Management of Recurrent Anterior Communicating Artery Aneurysms After Endovascular Coiling: 3-Dimensional Operative Video. PMID- 29506253 TI - Middle Cerebral Artery-to-A1 Anterior Cerebral Artery Intracranial-Intracranial Bypass for Ruptured Dissecting Pseudoaneurysm: 3-Dimensional Operative Video. PMID- 29506254 TI - Clipping of Ruptured Residual Anterior Communicating Artery Aneurysm After Endovascular Coiling: 3-Dimensional Operative Video. PMID- 29506255 TI - Fenestra Obscura: Flow Diverter Reconstruction of a Complex Vertebrobasilar Aneurysm Through an Obscured Fenestration Limb: Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Basilar fenestration aneurysms are rare, challenging intracranial vascular lesions with atypical anatomy. The posterior circulation represents a difficult therapeutic dilemma because of the close proximity of crucial life-sustaining brainstem structures. The use of flow diverter technology has been very limited in posterior circulation vessels. CLINICAL PRESENTATION: We present the case of a 49-year-old female patient, who was diagnosed with a symptomatic large vertebrobasilar junction aneurysm, which was initially thought to be a proximal basilar dilatation. The aneurysm was later verified to arise from the proximal end of a basilar fenestration, distended by the aneurysm fundus. The small-caliber fenestration limbs were the only connection to the distal basilar artery, but were stretched laterally and concealed by the aneurysm fundus. This complex lesion was successfully treated by flow diverter deployment through one of the fenestration limbs, followed by coiling of the aneurysm fundus, and sacrificing the contralateral vertebral artery. A 6-month follow-up angiogram showed remodeling of the basilar artery and complete occlusion of the aneurysm with good clinical outcome. Careful diagnostic workup, multidisciplinary discussions, and the innovative use of versatile endovascular technology were crucial to achieve an optimal result in this case. CONCLUSION: This is the first report of a successful basilar artery reconstruction for the treatment of a large atypical vertebrobasilar junction fenestration aneurysm by deployment of a flow diverter device directly in a small, obscured fenestration limb. PMID- 29506256 TI - Society of Behavioral Medicine (SBM) position statement: Increasing funding for the NIH OBSSR to promote timely and effective behavioral medicine research. AB - Chronic diseases are a leading cause of morbidity and mortality in the USA. Most chronic diseases have behavioral risk factors that can improve health and quality of life and reduce financial burdens. Improved methods of measurement and behavioral interventions are rapidly progressing. These changes require sufficient funding to maximize effectiveness. The National Institutes of Health (NIH) Office of Behavioral and Social Sciences Research (OBSSR) helps to coordinate and support behavioral and social science research initiatives that are designed to promote public health and reduce chronic disease burden throughout the NIH. OBSSR's budget has not increased for the past 5 years. The goals of this policy paper are to promote awareness of the OBSSR Strategic Plan FY 2017-2021's three priority areas and encourage increased and sustained funding for OBSSR to support these priority areas. Priority area 1 involves improving the quality and integration of behavioral and social science research, which can increase speed of funding natural experiments. Priority area 2 encourages the use and improvement of new technology to create methods and infrastructures to analyze big behavioral data, ensuring that health behavior interventions keep pace with the substantial data generated from new technology. Priority area 3 supports translational research between scientific data and real-world practice, ensuring the delivery of research findings to patients and populations. Adequate and sustained resources are needed to address these priority areas. Without such resources, disparities in health outcomes and the costs of treating preventable chronic diseases will continue to grow. Society of Behavioral Medicine (SBM) recommends and supports an increase for OBSSR's budget. PMID- 29506257 TI - Influences of Species Interactions With Aggressive Ants and Habitat Filtering on Nest Colonization and Community Composition of Arboreal Twig-Nesting Ants. AB - Ant community assembly is driven by many factors including species interactions (e.g., competition, predation, parasitism), habitat filtering (e.g., vegetation differences, microclimate, food and nesting resources), and dispersal. Canopy ant communities, including dominant and twig-nesting ants, are structured by all these different factors, but we know less about the impacts of species interactions and habitat filters acting at the colonization or recruitment stage. We examined occupation of artificial twig nests placed in shade trees in coffee agroecosystems. We asked whether species interactions-aggression from the dominant canopy ant, Azteca sericeasur Longino (Hymenoptera: Formicidae)-or habitat filtering-species of tree where nests were placed or surrounding vegetation-influence colonization, species richness, and community composition of twig-nesting ants. We found 20 species of ants occupying artificial nests. Nest occupation was lower on trees with A. sericeasur, but did not differ depending on tree species or surrounding vegetation. Yet, there were species-specific differences in occupation depending on A. sericeasur presence and tree species. Ant species richness did not vary with A. sericeasur presence or tree species. Community composition varied with A. sericeasur presence and surrounding vegetation. Our results suggest that species interactions with dominant ants are important determinants of colonization and community composition of twig-nesting ants. Habitat filtering at the level of tree species did not have strong effects on twig-nesting ants, but changes in coffee management may contribute to differences in community composition with important implications for ant conservation in agricultural landscapes, as well as biological control of coffee pests. PMID- 29506258 TI - Effect of a single dose of meloxicam prior to band or knife castration in 1-wk old beef calves: I. Acute pain. AB - In Western Canada, approximately half of the calves produced are castrated before 1 wk of age. Therefore, it is important to identify effective analgesic drugs to mitigate pain associated with castration and consequently improve animal welfare. The aim of this study was to assess the efficacy of a single s.c. dose of meloxicam at mitigating pain associated with knife and band castration in 1-wk old calves. Seventy-two Angus crossbred bull calves (47.3 +/- 6.70 kg of body weight (BW), 1 wk old) were used in a 3 * 2 factorial design where main factors included castration method-sham (CT), band (BA) or knife (KN) castration- and medication-lactate ringer (NM) or 0.5 mg/kg BW of meloxicam (M). Measurements included different physiological and behavioral parameters. Samples were collected on day -1, immediately before castration (T0); and 60, 90, and 120 min and 1, 2, 3, and 7 d after castration except for visual analog scale (VAS) which was collected at the time of castration. The salivary cortisol concentrations were greater (P = 0.04) in KN and BA calves than CT calves 60 min after castration, while 90 min after castration BA had greater concentrations than CT calves. Substance P concentrations were greater (P = 0.04) in NM calves than M calves on d 3 and 7 after castration. The serum amyloid-A (SAA) concentrations were greater (P = 0.05) in KN calves than BA and CT calves on days 0, 2, and 3, while BA calves had greater SAA concentrations on day 7 than KN and CT calves. The visual analog scores were greater (P < 0.01) in KN calves than BA, and in BA compared to CT calves. The KN calves tail flicked more (P < 0.01) than BA and CT calves, and NM calves tail flicked more (P = 0.03) than M calves. No castration or medication effect (P > 0.10) was observed for stride length, walking, standing, lying ventral, eating, foot stamping, head turning, lying and standing percentage, performance, platelets, or body temperature. Overall, knife castrated calves exhibited a greater acute pain response than band castrated calves. Meloxicam was able to reduce substance P concentrations, white blood cell counts and number of tail flicks after castration, suggesting that the drug was able to mitigate acute pain to some extent. However, meloxicam did not have an effect on the other physiological and behavioral parameters assessed. PMID- 29506260 TI - External aortic clamping versus endoaortic balloon occlusion in minimally invasive cardiac surgery: a systematic review and meta-analysis. AB - OBJECTIVES: Minimally invasive cardiac valve surgery is safe, effective and increasingly popular. It is performed worldwide with the use of either external aortic clamping or endoaortic balloon occlusion. METHODS: We conducted a literature search using MEDLINE, EMBASE, Scopus and Web of Science. Primary outcomes included aortic dissection, conversion to sternotomy, mortality, stroke and cross-clamp time. Secondary outcomes included atrial fibrillation, acute kidney injury, reoperation for bleeding, cardiopulmonary bypass times, myocardial infarction, use of intra-aortic balloon pump and length of hospital stay. The random effects model was used to calculate the outcomes of both binary and continuous data. RESULTS: Thirty retrospective studies were included in the meta analysis. The incidence of aortic dissection (pooled odds ratio = 3.88, 95% confidence interval = 1.06-14.18; P =0.04) and conversion to sternotomy (pooled odds ratio = 3.07, 95% confidence interval = 1.33-7.10; P = 0.009) was higher in the endoaortic balloon occlusion group than in the external aortic clamping group, in whom a direct comparison was possible. The remaining observational studies did not show any significant differences in either group. There was no significant difference in 30-day mortality (P = 0.37), stroke (P = 0.26), cross clamp time (P = 0.20), atrial fibrillation (P = 0.18), acute kidney injury (P = 0.49), reoperation for bleeding (P = 0.24), cardiopulmonary bypass time (P = 0.06), myocardial infarction (P = 0.74), use of intra-aortic balloon pump (P = 0.11) or length of hospital stay (P = 0.47). CONCLUSIONS: External aortic clamping may be safer than endoaortic balloon occlusion with respect to aortic dissection and conversion to sternotomy. However, mortality, length of stay, stroke, cross-clamp time and other cardiovascular complication rates were similar between the 2 techniques. PMID- 29506259 TI - The future of genomics in polar and alpine cyanobacteria. AB - In recent years, genomic analyses have arisen as an exciting way of investigating the functional capacity and environmental adaptations of numerous micro-organisms of global relevance, including cyanobacteria. In the extreme cold of Arctic, Antarctic and alpine environments, cyanobacteria are of fundamental ecological importance as primary producers and ecosystem engineers. While their role in biogeochemical cycles is well appreciated, little is known about the genomic makeup of polar and alpine cyanobacteria. In this article, we present ways that genomic techniques might be used to further our understanding of cyanobacteria in cold environments in terms of their evolution and ecology. Existing examples from other environments (e.g. marine/hot springs) are used to discuss how methods developed there might be used to investigate specific questions in the cryosphere. Phylogenomics, comparative genomics and population genomics are identified as methods for understanding the evolution and biogeography of polar and alpine cyanobacteria. Transcriptomics will allow us to investigate gene expression under extreme environmental conditions, and metagenomics can be used to complement tradition amplicon-based methods of community profiling. Finally, new techniques such as single cell genomics and metagenome assembled genomes will also help to expand our understanding of polar and alpine cyanobacteria that cannot readily be cultured. PMID- 29506265 TI - Urinary and serum soluble CD25 complements urinary soluble CD163 to detect active renal anti-neutrophil cytoplasmic autoantibody-associated vasculitis: a cohort study. AB - Background: Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV. Methods: sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4+ T and CD4+ T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serum soluble CD25 (ssCD25) add utility to usCD163. Results: usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163-positive patients. usCD25 correlated positively with urinary CD4+ T and CD4+ TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4+ T and CD4+ TEM cells. Conclusion: Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis. PMID- 29506266 TI - A putative RND-type efflux pump, H239_3064, contributes to colistin resistance through CrrB in Klebsiella pneumoniae. AB - Background: Colistin is one of the last-resort antibiotics used to treat carbapenem-resistant Klebsiella pneumoniae infection. Our previous studies indicated that clinical strains encoding CrrB with amino acid substitutions exhibited higher colistin resistance (MICs >=512 mg/L) than did colistin resistant strains encoding mutant MgrB, PmrB or PhoQ. Objectives: CrrAB may regulate another unknown mechanism(s) contributing to colistin resistance, besides modifications of LPS with 4-amino-4-deoxy-l-arabinose and phosphoethanolamine. Methods: To identify these potential unknown mechanism(s), a transposon mutant library of A4528 crrB(N141I) was constructed. Loci that might contribute to colistin resistance and were regulated by crrB were confirmed by deletion and complementation experiments. Results: Screening of 2976 transposon mutants identified 47 mutants in which the MICs of colistin were significantly decreased compared with that for the parent. Besides crrAB, crrC and pmrHFIJKLM operons, these 47 transposon insertion mutants included another 13 loci. Notably, transcript levels of one of these insertion targets, H239_3064 (encoding a putative RND-type efflux pump), were significantly increased in A4528 crrB(N141I) compared with the A4528 parent strain. Deletion of H239_3064 in the A4528 crrB(N141I) background resulted in an 8-fold decrease in the MIC of colistin; complementation of the deletion mutant with H239_3064 restored resistance to colistin. Susceptibilities of A4528-derived strains to other antibiotics were also tested. Mutations of crrB resulted in decreased susceptibility to tetracycline and tigecycline, and deletion of H239_3064 in A4528 crrB(N141I) attenuated this phenomenon. Conclusions: This study demonstrated that missense mutations of K. pneumoniae crrB lead to increased expression of H239_3064, leading in turn to decreased susceptibility to colistin, tetracycline and tigecycline. PMID- 29506267 TI - Type 2 Diabetes and Adiposity Induce Different Lipid Profile Disorders: A Mendelian Randomization Analysis. AB - Context: Type 2 diabetes and obesity often coexist, so it is difficult to judge whether diabetes or obesity induce certain types of hyperlipidemia due to mutual confounds and reverse causation. We used Mendelian randomization analyses to explore the causal relationships of diabetes and adiposity with lipid profiles. Design, Setting, and Main Outcome Measures: From 23 sites in East China, 9798 participants were enrolled during 2014 to 2016. We calculated two weighted genetic risk scores as instrumental variables for type 2 diabetes and body mass index (BMI). These scores were used to measure the causal relationships of diabetes and BMI with lipid profiles that included total cholesterol, high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), and triglycerides (TGs). Results: The causal regression coefficients (betaIV) of genetically determined diabetes for the total cholesterol, LDL-C, and log10TG were 0.130 [95% confidence interval (CI): 0.020, 0.240; P = 0.014], 0.125 (96% CI: 0.041, 0.209; P = 0.001), and 0.019 (95% CI: -0.001, 0.039; P = 0.055), respectively. The betaIV for HDL-C was -0.008 (95% CI: -0.032. 0.016), which was not significant (P = 0.699). The causal regression coefficients of a genetically determined 10 kg/m2 increase in BMI for HDL-C and log10TG were -0.409 (96% CI: 0.698, -0.120; P = 0.004) and 0.227 (95% CI: 0.039, 0.415; P = 0.026), respectively. The betaIVs for TGs and LDL-C were not significant. Conclusions: This study has provided evidence for the biologically plausible causal effects of diabetes and adiposity by BMI on different elements of the lipid profile using Mendelian randomization analyses. PMID- 29506268 TI - Things I Do Not Like. PMID- 29506269 TI - Molecular Epidemiology of HIV-1 Subtype B Reveals Heterogeneous Transmission Risk: Implications for Intervention and Control. AB - Background: The impact of HIV pre-exposure prophylaxis (PrEP) depends on infections averted by protecting vulnerable individuals as well as infections averted by preventing transmission by those who would have been infected if not receiving PrEP. Analysis of HIV phylogenies reveals risk factors for transmission, which we examine as potential criteria for allocating PrEP. Methods: We analyzed 6912 HIV-1 partial pol sequences from men who have sex with men (MSM) in the United Kingdom combined with global reference sequences and patient-level metadata. Population genetic models were developed that adjust for stage of infection, global migration of HIV lineages, and changing incidence of infection through time. Models were extended to simulate the effects of providing susceptible MSM with PrEP. Results: We found that young age <25 years confers higher risk of HIV transmission (relative risk = 2.52 [95% confidence interval, 2.32-2.73]) and that young MSM are more likely to transmit to one another than expected by chance. Simulated interventions indicate that 4-fold more infections can be averted over 5 years by focusing PrEP on young MSM. Conclusions: Concentrating PrEP doses on young individuals can avert more infections than random allocation. PMID- 29506270 TI - Development and Validation of a Novel RNA Sequencing-Based Prognostic Score for Acute Myeloid Leukemia. AB - Background: Recent progress in sequencing technologies allows us to explore comprehensive genomic and transcriptomic information to improve the current European LeukemiaNet (ELN) system of acute myeloid leukemia (AML). Methods: We compared the prognostic value of traditional demographic and cytogenetic risk factors, genomic data in the form of somatic aberrations of 25 AML-relevant genes, and whole-transcriptome expression profiling (RNA sequencing) in 267 intensively treated AML patients (Clinseq-AML). Multivariable penalized Cox models (overall survival [OS]) were developed for each data modality (clinical, genomic, transcriptomic), together with an associated prognostic risk score. Results: Of the three data modalities, transcriptomic data provided the best prognostic value, with an integrated area under the curve (iAUC) of a time dependent receiver operating characteristic (ROC) curve of 0.73. We developed a prognostic risk score (Clinseq-G) from transcriptomic data, which was validated in the independent The Cancer Genome Atlas AML cohort (RNA sequencing, n = 142, iAUC = 0.73, comparing the high-risk group with the low-risk group, hazard ratio [HR]OS = 2.42, 95% confidence interval [CI] = 1.51 to 3.88). Comparison between Clinseq-G and ELN score iAUC estimates indicated strong evidence in favor of the Clinseq-G model (Bayes factor = 26.78). The proposed model remained statistically significant in multivariable analysis including the ELN and other well-known risk factors (HRos = 2.34, 95% CI = 1.30 to 4.22). We further validated the Clinseq-G model in a second independent data set (n = 458, iAUC = 0.66, adjusted HROS = 2.02, 95% CI = 1.33 to 3.08; adjusted HREFS = 2.10, 95% CI = 1.42 to 3.12). Conclusions: Our results indicate that the Clinseq-G prediction model, based on transcriptomic data from RNA sequencing, outperforms traditional clinical parameters and previously reported models based on genomic biomarkers. PMID- 29506271 TI - In vitro synergism and anti-biofilm activity of ampicillin, gentamicin, ceftaroline and ceftriaxone against Enterococcus faecalis. AB - Background: Enterococci frequently cause severe biofilm-associated infections such as endocarditis. The combination of ampicillin/ceftriaxone has recently been clinically evaluated as non-inferior compared with the standard therapy of ampicillin/gentamicin for treatment of Enterococcus faecalis endocarditis. Ceftaroline is a novel cephalosporin with enhanced activity against Gram-positive bacteria. Objectives: To compare the in vitro effectiveness of the ceftaroline/ampicillin combination with those of gentamicin/ampicillin and ceftriaxone/ampicillin in planktonic and biofilm cultures of clinical E. faecalis isolates. Methods: Synergistic effects at the planktonic level were analysed by chequerboard assays in 20 E. faecalis isolates. Biofilm-eradicating and biofilm preventing activities of the antibiotics and their combinations were determined by confocal laser scanning microscopy with quantification by quantitative biofilm analysis (qBA) algorithm and cfu/mL determination. Results: Comparable synergistic effects were observed for both beta-lactam combinations in most isolates, in contrast to gentamicin/ampicillin. However, none of the antibiotic combinations succeeded in eradicating mature biofilms. Gentamicin showed promising biofilm-preventing activity, but at concentrations above those clinically tolerable. The beta-lactams showed a U-shape dose-response relationship in biofilm prevention. Only exposure to cephalosporins caused alterations in cell morphology, which resulted in cell elongation and reclustering in a concentration-dependent manner. Reclustering was associated with high occurrences of small colony variants (SCVs), especially at high ceftriaxone concentrations. Conclusions: This study suggests that combinations of cephalosporins or gentamicin with ampicillin may be advantageous only while bacteraemia persists, whereas combinations have no advantage over monotherapy regarding the treatment of mature biofilms. The selection of SCVs at high ceftriaxone concentrations is worth further study. PMID- 29506272 TI - Inhibition of MicroRNA-23b Attenuates Immunosuppression During Late Sepsis Through NIK, TRAF1, and XIAP. AB - Background: microRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis-induced immunosuppression. Methods: Mice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)-induced sepsis. Apoptosis in spleens and apoptotic signals were investigated, and survival was monitored. T-cell immunoreactivities were examined during late sepsis. Nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK), tumor necrosis factor (TNF)-receptor associated factor 1 (TRAF1), and X-linked inhibitor of apoptosis protein (XIAP), the putative targets of miR 23b, were identified by a dual-luciferase reporter assay. Results: miR-23b expression is upregulated and sustained during sepsis. The activation of the TLR4/TLR9/p38 MAPK/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased the number of spleen cells positive by terminal deoxynucleotidyl transferase dUTP nick-end labeling and improved survival. miR-23b inhibitor restored the immunoreactivity by alleviating the development of T-cell exhaustion and producing smaller amounts of immunosuppressive interleukin 10 and interleukin 4 during late sepsis. We demonstrated that miR-23b mediated immunosuppression during late sepsis by inhibiting the noncanonical NF-kappaB signal and promoting the proapoptotic signal pathway by targeting NIK, TRAF1, and XIAP. Conclusions: Inhibition of miR 23b reduces late-sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression. PMID- 29506273 TI - DNA sliding in nucleosomes via twist defect propagation revealed by molecular simulations. AB - While nucleosomes are highly stable structures as fundamental units of chromatin, they also slide along the DNA, either spontaneously or by active remodelers. Here, we investigate the microscopic mechanisms of nucleosome sliding by multiscale molecular simulations, characterizing how the screw-like motion of DNA proceeds via the formation and propagation of twist defects. Firstly, coarse grained molecular simulations reveal that the sliding dynamics is highly dependent on DNA sequence. Depending on the sequence and the nucleosome super helical location, we find two distinct types of twist defects: a locally under twisted DNA region, previously observed in crystal structures, and a locally over twisted DNA, an unprecedented feature. The stability of the over-twist defect was confirmed via all-atom simulations. Analysis of our trajectories via Markov state modeling highlights how the sequence-dependence of the sliding dynamics is due to the different twist defect energy costs, and in particular how nucleosome regions where defects cannot easily form introduce the kinetic bottlenecks slowing down repositioning. Twist defects can also mediate sliding of nucleosomes made with strong positioning sequences, albeit at a much lower diffusion coefficient, due to a high-energy intermediate state. Finally, we discuss how chromatin remodelers may exploit these spontaneous fluctuations to induce unidirectional sliding of nucleosomes. PMID- 29506274 TI - Editorial: Nucleic Acids Research and Nucleic Acid Therapeutics. PMID- 29506275 TI - The Mini-Open Pedicle Subtraction Osteotomy for Flat-Back Syndrome and Kyphosis Correction: Operative Technique. AB - BACKGROUND: The pedicle subtraction osteotomy (PSO) has been a mainstay treatment for flat-back syndrome. The morbidity of open deformity correction can be high, and minimally invasive applications may reduce such morbidity. OBJECTIVE: To describe an operative technique of the mini-open PSO. METHODS: Two patients underwent percutaneous fixation above and below the PSO, and the PSO was performed in a mini-open fashion. The correction was obtained by cantilever. RESULTS: The patient who underwent the L3 PSO had a prior fusion from T11 to L4 for scoliosis 35 years ago. On presentation at 62 years of age, he had a pelvic incidence of 54 degrees , lumbar lordosis of 23 degrees , sagittal vertical axis of +14 cm, and pelvic tilt of 25 degrees . He underwent an anterior lumbar interbody fusion at L5-S1 followed by a min-open L3 PSO. He had a postoperative lumbar lordosis of 64 degrees (correction of 41 degrees ), and his sagittal vertical axis went to +3 cm. His Oswestry Disability Index and visual analog scale scores decreased after surgery. The second patient was 64 years of age and underwent an L1 PSO. He had 43 degrees of kyphosis from T10 to L2. He had a preoperative pelvic incidence of 63 degrees , lumbar lordosis of 35 degrees , pelvic tilt of 24 degrees , and sagittal vertical axis of 3 cm. His postoperative kyphosis improved from 43 degrees to 32 degrees . CONCLUSION: The mini-open PSO can achieve significant lordosis, although it is heavily reliant on anterior arthrodesis. Larger studies are needed to compare this approach with an open PSO. PMID- 29506276 TI - Gravity-Dependent Supine Position for the Lateral Supracerebellar Infratentorial Approach: An Alternative to the Prone and Sitting Positions: Operative Nuance. AB - BACKGROUND: The supracerebellar infratentorial (SCIT) approach has been used for a variety of intracranial pathologies. Positioning has traditionally involved the sitting, lateral, or prone position. The sitting position allows gravity retraction of the cerebellum, with less cerebellar swelling and venous congestion compared with the prone position. There is less need for cerebellar retraction away from the tentorium with the sitting position compared with the prone and lateral positions. However, the sitting position involves disadvantages related to surgeon comfort and fatigue in protracted cases, as well as possible venous air emboli. OBJECTIVE: To describe an operative technique of gravity-dependent supine (GDS) positioning to avoid certain drawbacks of sitting, lateral, and prone positions for the lateral SCIT approach. METHODS: We present this positioning technique in 2 illustrative cases using the GDS approach. The first patient underwent surgical resection of a right cerebellar arteriovenous malformation that drained superiorly with the draining vein adjacent to the tentorium after a ventricular/subarachnoid hemorrhage. The second patient underwent surgical resection of a brainstem cavernous malformation in the left pontomesencephalic region with the GDS supracerebellar approach. RESULTS: Postoperative imaging demonstrated complete resection in both patients. There were no perioperative complications related to positioning or the surgical resections postoperatively, with an uneventful hospital course in both cases. CONCLUSION: The GDS lateral SCIT approach allows natural cerebellar relaxation via gravity without the need for lumbar drainage and is a novel, straightforward operative technique with inherent advantages over the prone, lateral decubitus, and sitting positions. PMID- 29506277 TI - Three-Dimensional Printed Model Used to Teach Skull Base Anatomy Through a Transsphenoidal Approach for Neurosurgery Residents. AB - BACKGROUND: Skull base anatomy through a transsphenoidal approach is challenging for the neurosurgical resident to conquer. OBJECTIVE: To demonstrate that stereolithography, or 3-dimensional (3-D) printing, is a useful educational tool for neurosurgery residents to learn skull base anatomy. METHODS: Before any formal teaching, residents were brought into the operating room where they were asked to identify key structures seen through an endoscopic transsphenoidal approach. Scoring was based on correctly naming the anatomical structures. After the initial testing, all residents participated in a didactic lecture reviewing this anatomy by using 2-dimensional pictures. Residents were then divided into 2 groups: A and B. Group B residents were additionally taught through neurosurgical simulation using a 3-D printed model and an endoscope. Following all formal teaching, residents were retested in the operating room. RESULTS: A maximum score of 8 points was possible if all structures were identified correctly. Group A had mean scores of 2.75 on initial testing compared with 5 after the lecture (P = .041 using 2-tailed t test). Group B had mean scores of 2.75 on initial testing compared with 7.5 after the lecture and 3-D model simulation (P = .002). When comparing mean scores after formal teaching in groups A and B, 5 vs 7.5 were obtained for lecture only vs lecture and 3-D model simulation, respectively (P = .031). CONCLUSION: Three-dimensional models used in neurosurgical simulation to teach skull base anatomy through a transsphenoidal approach showed objective and subjective improvement in testing scores in neurosurgery residents. This study confirms that 3-D models are a useful educational tool. PMID- 29506278 TI - Susceptibility Sensitive Magnetic Resonance Imaging Displays Pallidofugal and Striatonigral Fiber Tracts. AB - BACKGROUND: The pallidofugal and striatonigral fiber tracts form a functional part of the basal ganglionic neuronal networks. For deep brain stimulation, a surgical procedure applied in the treatment of Parkinson disease and dystonia, precise localization of pallidofugal pathways may be of particular clinical relevance for correct electrode positioning. OBJECTIVE: To investigate whether the pallidofugal and striatonigral pathways can be visualized with magnetic resonance imaging in vivo by exploiting their intrinsic magnetic susceptibility. METHODS: Three-dimensional gradient-echo imaging of 5 volunteers was performed on a 7 T magnetic resonance imaging system. To demonstrate that the displayed tubular structures in the vicinity of the subthalamic nucleus and substantia nigra truly represent fiber tracts rather than veins, gradient-echo data of a formalin-fixated brain and a volunteer during inhalation of ambient air and carbogen were collected at 3 T. Susceptibility weighted images, quantitative susceptibility maps, and effective transverse relaxation maps were reconstructed and the depiction of fiber tracts was qualitatively assessed. RESULTS: High resolution susceptibility-based magnetic resonance imaging contrasts enabled visualization of pallidofugal and striatonigral fiber tracts noninvasively at 3 T and 7 T. We verified that the stripe-like pattern observed on susceptibility sensitive images is not caused by veins crossing the internal capsule but by fiber tracts traversing the internal capsule. CONCLUSION: Pallidofugal and striatonigral fiber tracts have been visualized in vivo for the first time by using susceptibility-sensitive image contrasts. Considering the course of pallidofugal pathways, in particular for deep brain stimulation procedures in the vicinity of the subthalamic nucleus, could provide landmarks for optimal targeting during stereotactic planning. PMID- 29506279 TI - Percutaneous Lumbar Transfacet Screw Fixation: A Technique Analysis of 176 Screws in 83 Patients With Assessment of Radiographic Accuracy, Hardware Failure, and Complications. AB - BACKGROUND: Transfacet screw fixation can be used to supplement varying techniques of lumbar interbody fusion. The percutaneous placement of transfacet screws represents an alternative to pedicle screws for select cases, which can potentially minimize morbidity. OBJECTIVE: To analyze our experience with respect to accuracy, hardware failure, and neurologic compromise. METHODS: Clinical records gathered from August 2009 to January 2014 were retrospectively reviewed. We identified 83 patients who underwent placement of 176 consecutive percutaneous transfacet screws while in the prone or lateral position. Accuracy of screw placement was assessed on computed tomography (CT) by entry point and end point. Hardware failure was assessed by radiography or CT. Clinical complications were assessed during regular follow-up visits. RESULTS: Entry point accuracy was 91.4%. Seven cases of intra-articular screw placement and 1 para-articular screw placement were detected on CT. End-point accuracy was 82.8%. There were 16 cases of pedicle breach from 1 to 3 mm on CT. There were 2 screw fractures and 1 case of a Kirschner-wire fracture that were clinically inconsequential. One patient had new nondisabling leg numbness. One patient with new radicular leg pain required removal of a screw. CONCLUSION: The technique of percutaneous lumbar transfacet screw fixation can be performed accurately and safely with patients in the prone and lateral positions. Entry point inaccuracies were more common at rostral levels due to facet orientation. End-point inaccuracies (pedicle breaches) were more common in the intervertebral foramen where 2 clinical complications occurred. PMID- 29506280 TI - Early Localization of the Third Segment of the Vertebral Artery: The Atlanto Mastoid Line. PMID- 29506281 TI - Translateral Orbital Wall Approach to the Orbit and Cavernous Sinus: Anatomic Study. AB - BACKGROUND: Surgical approaches to lesions in either the orbit or cavernous sinus have been well documented; however, approaching lesions involving both areas remains challenging. OBJECTIVE: To examine the microsurgical and endoscopic anatomy of the orbit and cavernous sinus as seen through the orbitozygomatic and translateral orbital wall approaches. METHODS: Seven orbits and cavernous sinuses of formalin-fixed adult cadaveric heads were dissected and examined with the aid of the surgical microscope and 0 degrees endoscope. RESULTS: The orbitozygomatic approach exposes the superior and lateral surfaces of the orbit, optic canal, superior orbital fissure, and cavernous sinus and offers a range of visibility and enough space for manipulation in both the horizontal and vertical planes. The translateral orbital wall approach exposes the lateral surface of the orbit, optic canal, and superior orbital fissure and can be extended to the lateral wall of the cavernous sinus. However, the surgical corridor to the orbital apex and adjacent cavernous sinus is narrow and deep. Endoscopic assistance may increase the exposure, especially around the anterior clinoid process and as far back as V3. CONCLUSION: The translateral orbital wall approach with endoscopic assistance provides access to the orbit and cavernous sinus, making it a good alternative to the orbitozygomatic approach for biopsy of unresectable lesions and removal of selected small lesions limited to the lateral aspect of the orbit and cavernous sinus. PMID- 29506282 TI - Anatomic Understanding of Vertical Hemispherotomy With Cadaveric Brains and Intraoperative Photographs. AB - BACKGROUND: Vertical hemispherotomy is performed in hemispheric epilepsy to disconnect commissural fibers, projecting fibers, and limbic system from the affected side of the brain with minimal parenchyma removal. However, anatomic understanding of this surgery is generally difficult. OBJECTIVE: To present the vertical hemispherotomy procedures using cadaveric brains and intraoperative photographs. METHODS: Two formalin-fixed adult cadaveric brains were used to demonstrate vertical hemispherotomy. Intraoperative photographs were taken of a 19-year-old man with intractable epilepsy due to head trauma in infancy. RESULTS: After coronal skin incision along the coronal suture, bifrontal craniotomy and a C-shaped dural incision from lateral to medial to the midline are performed. The interhemispheric fissure is dissected from anterior to posterior. Interhemispheric total corpus callosotomy is performed to disconnect commissural fibers. Corticotomy on the cingulate gyrus is performed to approach the lateral ventricle. The lateral border of the thalamus is cut from posterior to anterior until exposing the inferior horn of the lateral ventricle and hippocampal head to disconnect projecting fibers. At the anteromedial side of the hippocampus, the inferior part of the amygdala and uncal gyrus is removed, exposing the basal cistern to disconnect the hippocampus and amygdala. The posterior column of the fornix at the trigone of the lateral ventricle is resected to disconnect the limbic system. Projecting fibers from the anterior frontal lobe are disconnected. CONCLUSION: A step-by-step procedure using cadaveric brains and intraoperative photographs provide a better anatomic understanding of vertical hemispherotomy. PMID- 29506283 TI - Acute Ischemic Stroke During Deep Brain Stimulation Surgery of Globus Pallidus Internus: Report of 5 Cases. AB - BACKGROUND: Cerebrovascular accident (CVA) is a potentially devastating complication of deep brain stimulation (DBS) surgery. Although there are substantial data reporting the incidence and cause of hemorrhagic CVA, reports of acute ischemic infarctions during DBS implantation surgery are rare. OBJECTIVE: To present a series of 5 patients who experienced clinically significant ischemic CVA during microelectrode-guided globus pallidus internus (GPi) DBS, and evaluate the potential risk factors and mechanisms. METHODS: A retrospective analysis of GPi DBS surgeries performed between June 2010 and February 2015 at UCLA Medical Center and June 2010 and February 2014 at Cedars-Sinai Medical Centers was performed to identify stroke risk factors. Statistical analysis was performed, comparing the stroke group with all patients undergoing GPi DBS. RESULTS: All 5 patients developed acute onset of lethargy, dysarthria, and contralateral facial and/or hemibody weakness intraoperatively. Computed tomographic scans in all cases were negative for hemorrhage. Magnetic resonance images obtained in 3 patients revealed infarction in the posterior limb of the internal capsule. During the time period analyzed, a total of 234 GPi leads were placed in 129 patients, yielding a 2.14% rate of ischemic stroke per lead. No statistically significant risk factors were identified in the stroke group. Given the variability of symptom onset during surgery, the mechanism is not clear, but it could be related to compression, compromise, or vasospasm of lenticulostriate arteries and/or anterior choroidal branches near the GPi target. CONCLUSION: Ischemic stroke in GPi DBS is a significant complication for clinicians to be aware of and discuss with their patients preoperatively. PMID- 29506284 TI - Microsurgical Management of Galenic Dural Arteriovenous Fistula: 3-Dimensional Operative Video. PMID- 29506285 TI - Management of Complex Pediatric Chordoma: Transnasal and Bilateral Far-Lateral Approach for Resection With O-C4 Fusion: 3-Dimensional Operative Video. PMID- 29506286 TI - Left Transtemporal Approach for Resection of Cranial Nerve VI and VII Neurofibroma Tumors With Reconstruction of Cranial Nerve VII Using a Sural Nerve Interposition Graft: 3-Dimensional Operative Video. PMID- 29506287 TI - Interhemispheric Approach for Excision of Callosal Marginal Dissecting Aneurysm With End-to-End Anastomosis: 3-Dimensional Operative Video. PMID- 29506288 TI - Letter: Microsurgical and Fiber Tract Anatomy of the Nucleus Accumbens. PMID- 29506289 TI - In Reply: Microsurgical and Fiber Tract Anatomy of the Nucleus Accumbens. PMID- 29506290 TI - The Posterior Transcallosal Approach to the Pineal Region and Posterior Third Ventricle: Intervenous and Paravenous Variants: Erratum. PMID- 29506291 TI - INVESTIGATION OF A PRACTICAL PATIENT DOSE INDEX FOR ASSESSMENT OF PATIENT ORGAN DOSE FROM CONE-BEAM COMPUTED TOMOGRAPHY IN RADIATION THERAPY USING A MONTE CARLO SIMULATION. AB - The purpose of this study was to investigate a practical patient dose index for assessing the patient organ dose from a cone-beam computed tomography (CBCT) scan by comparing eight dose indices, i.e. CTDI100, CTDIIEC, CTDIinfinity, midpoint doses f(0)PMMA for a cylindrical polymethyl methacrylate (PMMA) phantom, f(0)Ap for an anthropomorphic phantom and f(0)Pat for a prostate cancer patient, as well as the conventional size specific dose estimations (SSDEconv) and modified SSDE (SSDEmod), with organ dose for the prostate (ODprost) obtained via Monte Carlo (MC) simulation. The ODprost was the reference dose used to find the practical dose index at the center of the pelvic region of a prostate cancer patient. The smallest error rate with respect to the ODprost of 19.3 mGy (reference) among eight dose indices was 5% for f(0)Pat. The practical patient dose index was the f(0)Pat, which showed the smallest error with respect to the reference dose. PMID- 29506292 TI - DETERMINATION AND DOSE CONTRIBUTION OF URANIUM ISOTOPES AND 210Po ACTIVITY CONCENTRATIONS OF NATURAL SPRING WATERS IN THE PROVINCE OF GRANADA, SPAIN. AB - The activity concentrations of alpha-emitters comprising isotopes of uranium (238, 234, 235U) and polonium (210Po) were measured using alpha-particle spectrometry in natural spring waters in the province of Granada, Spain. These water are consumed by the population of the zone who live in villages. This is almost half of the population of the whole region. Mean values of activity concentrations found are 42.61 +/- 2.66; 49.55 +/- 3.03; 1.64 +/- 0.28 and 1.74 +/- 0.15 mBq L-1 for 238U, 234U, 235U and 210Po, respectively. Finally, the radiological impact of the analysed waters has been determined, in terms of the estimation of the committed annual effective dose due to the ingestion of the water. The assessment has been carried out for five age groups with the aim to cover all the population. The calculated annual effective doses are observed to be below the prescribed dose limit of 100 MUSv y-1 recommended by WHO. PMID- 29506293 TI - Ginkgo biloba Food Supplements on the European Market - Adulteration Patterns Revealed by Quality Control of Selected Samples. AB - The aim of this study was to prove whether Ginkgo biloba food supplements on the European market comply with pharmaceutical quality, and whether their composition satisfies the European Pharmacopoeia criteria. Medicinal products containing a standardised Ginkgo leaf extract are used for the improvement of cognitive impairment and quality of life in mild dementia. Further, Ginkgonis folium is used for the treatment of peripheral circulation disorders. Pharmacopoeial Ginkgo dry extract contains 22.0 - 27.0% flavonoids and 5.4 - 6.6% terpene lactones (ginkgolides, bilobalide). In addition to its widespread use as an herbal medicine (herbal medicinal product), the same extract can be an ingredient in food supplements. The content of active secondary metabolites was quantified in a number of European food supplements containing Ginkgo dry extract or Ginkgo leaf. Flavonoids were quantified using a modified pharmacopoeial HPLC-UV method, and terpene lactones (ginkgolides A, B, C, and bilobalide) using LC-MS/MS. Some Ginkgo leaf supplement samples were also analysed by microscopy. The quality of food supplements on the European market is dubious. In this paper, we present selected examples of several methods of adulteration and falsification, including higher/lower doses of Ginkgo dry extract or Ginkgo leaf than declared and the addition of undeclared extraneous materials. These examples reveal several patterns in the manufacturing of adulterated products. PMID- 29506294 TI - Plants and Natural Products for the Treatment of Skin Hyperpigmentation - A Review. AB - Skin hyperpigmentation is caused by several factors that upregulate melanogenesis. Plants and natural products with skin-whitening effects are gaining interest among consumers and researchers because they are perceived to be milder, safer, and healthier than synthetic alternatives. This review extensively summarizes the status of plants and natural products currently used in skin whitening cosmetics as well as potential candidates for future use, because the scope of natural choices for efficient treatment of skin hyperpigmentation is rapidly widening. Biological activities of plants and natural extracts are therefore available for cosmetic formulators and dermatologists interested in naturally derived ingredients for skin hyperpigmentation treatment and in accordance with the consumers' preferences and expectations upon natural cosmetic products. PMID- 29506295 TI - [Living With and After Cancer]. PMID- 29506296 TI - [18-Year-Old Man with Recurrent Swelling Attacks]. PMID- 29506297 TI - [Exercise and Physical Activity During and after Cancer - Who Benefits most, What is Proven?] AB - A growing number of literature reports positive effects of physical activity and exercise. These effects concern prevention, mortality and progress of cancer. Furthermore they show a reduction of disease- and treatment-specific side effects, which implies a better patients' quality of life. Evidence shows a decreased mortality risk in patients with physically active cancer of colon, breast, ovaries and prostate. Activity recommendations for patients with cancer do not differ from those for healthy persons. However, a decrease in physical activity can be observed in many cancer patients after diagnosis, and this fact concludes to a reduced physical capacity - although just physical capacity helps to overcome the burden of medical treatment and to recover. In fact, tailored exercise programs can counteract a decrease in physical capacity successfully. Further they reduce side effects such as fatigue, incontinence and lymphedema. Moreover, first studies report a positive influence on: chemotherapy-induced polyneuropathies, cancer-related cognitive impairments, bone health and sleep. Finally, an enormous number of investigations showed that exercise interventions can improve psychosocial factors (e. g. mood and self-esteem). Except for very few conditions, such as extremely impaired blood cell counts and days when cardio or nephrotoxic drugs are given, physical activity should be recommended. Especially during medical treatment, physicians and therapists are prompted to interact closely in order to prevent general activity prohibitions. Physical activity and exercise programs represent a unique and low-cost chance for cancer patients to influence the course of their own disease positively. More effort is necessary to improve professional activity offers for cancer patients and survivors and to specify activity recommendations. PMID- 29506299 TI - [Surveillance after Treatment of Gastrointestinal Cancer]. AB - Treatment for gastrointestinal malignancies has evolved over the past two decades. Long-term outcomes have considerably improved, however a high rate of recurrence persists. With the exception of colon cancer, clear consensus strategies with regards to post-treatment surveillance are lacking. Current surveillance practices in non-colon cancer cases are inadequately based on retrospective case analyses and expert recommendations which are not uniformly consistent.This article presents the key follow-up aspects such as recurrence frequency, timing, localization, and therapeutic efficacy for the most common gastrointestinal tumors, and summarizes current recommendations for early detection of recurrence. In particular, we compare and contrast the recommendations of the German S3 guideline, the European Society for Medical Oncology (ESMO) and the American National Comprehensive Cancer Network (NCCN). PMID- 29506298 TI - [Psychooncological Care: A Challenge]. AB - Cancer patients and their relatives suffer from multiple psychological and social problems associated with the illness itself and its treatment. The major challenge for an excellent psychooncological support is the further development and nationwide implementation of effective, patient-centered, quality assured, and affordable concepts of treatment and care. PMID- 29506300 TI - [Follow-up Care in Cancer: Selected Solid Tumors and Hematological Neoplasias]. AB - More and more follow-up care gets important in the treatment of oncological patients. In addition to detection of recurrent and secondary diseases, the focus should be put particularly on identifying and medicating sequelae associated with therapy. Anamnesis and clinical examination remain at the centre of follow-up treatment. Further contents of follow-up care are based on the disease situation, previous therapies and individual risk factors. For most entities there is no recommendation for routine radiological diagnosis in asymptomatic patients. However, imaging measures are indicated especially when symptoms require clarification. The increasing rate of oral long-term and permanent therapies implies new tasks in after-care. Here, potential side effects have to be registered specifically. Furthermore, treatment success should be monitored regularly. PMID- 29506301 TI - [Beneficial Effect of Medical Cannabis in the Treatment of a Pharmacoresistant Nausea Associated with a Somatoform Disorder in a Patient with Post-Polio Syndrome]. AB - HISTORY AND CLINICAL FINDINGS: We report a 79-year-old patient with post-polio syndrome (PPS). In the course of this disease, recurrent upper abdominal pain and a therapy-resistant nausea developed without vomiting. In addition, the patient was limited by the combination of muscular weakness, obesity, dietary-treated diabetes and a degenerative spinal cord injury significantly in its mobility and physical capacity. INVESTIGATIONS AND DIAGNOSIS: Despite extensive diagnostics, no somatic cause could be found neither for the nausea nor for the upper abdominal pain. Due to the psychological stress within the scope of the PPS, the development of a somatoform autonomic function disorder of the upper gastrointestinal tract may have occurred. TREATMENT AND COURSE: Even under combination therapy of antiemetic and pain-modulating drugs, no adequate symptom control could be achieved. In the absence of therapy alternatives and increasing psychological strain the patient was prescribed medical cannabis. Under the therapy there was a relief of the nausea symptoms and decreased pain. CONCLUSION: Cannabis is a treatment option for treatment-resistant symptoms as part of a PPS. PMID- 29506302 TI - [Patent foramen ovele, good reasons to close it]. AB - A patent foramen ovale (PFO) is not to be considered a disease as it is present in about 25 % of people. Yet, it is the prime reason for paradoxical embolism that can cause serious problems, such as death, stroke, myocardial infarction, and peripheral ischemia. The frequency of such events is probably underestimated as other causes tend to be blamed for them. Device PFO closure can be easily accomplished as outpatient procedure with minimal discomfort and risk and it has been referred to as mechanical vaccination. Randomized trials have proved its value for reduction of recurrent stroke. There is also good evidence that PFO closure solves problems like platypnoea orthodeoxia and exercise desaturation, improves migraine, and is helpful in sleep apnoea. In addition, it renders diving and high altitude climbing safer. The absolute risk of a PFO is dependent on its size and its association with an atrial septal aneurysm, a Eustachian valve, or a Chiari network. The number needed to treat to prevent one stroke by PFO closure may be as low as 2 over lifetime in selected patients. PMID- 29506303 TI - [Closure of Patent Foramen Ovale after Ischemic Stroke: an Update]. AB - The value of interventional closure of patent foramen ovale (PFO) after cryptogenic stroke has been controversial. Recently, two randomized controlled trials showed a benefit of interventional closure of PFO compared to antiplatelet therapy only. We give a survey of the current literature and express questions that still remain unacknowledged. PMID- 29506304 TI - Impact of Chronic Cannabis Use on Auditory Mismatch Negativity Generation in Schizophrenia Patients. AB - INTRODUCTION: Cannabis use disorders (CUD) are highly prevalent among patients with schizophrenia (SCZ). Deficient mismatch negativity (MMN) generation is a characteristic finding in SCZ patients and cannabis users. This study therefore examined the effects of CUD on MMN generation in SCZ patients. METHODS: Twenty SCZ - CUD patients, 21 SCZ+CUD patients, and 20 healthy controls (HC) were included in this study. MMN to frequency and duration deviants was elicited within an auditory oddball paradigm and recorded by 32 channel EEG. RESULTS: As expected, SCZ - CUD patients showed reduced frontocentral MMN amplitudes to duration deviants compared to HC. Interestingly, SCZ+CUD patients demonstrated greater MMN amplitudes to duration deviants compared to SCZ - CUD patients at central electrodes with no differences compared to HC. DISCUSSION: These results demonstrate that comorbid cannabis use in SCZ patients might be associated with superior cognitive functioning. It can be assumed that the association between cannabis use and better cognitive performance may be due to a subgroup of cognitively less impaired SCZ patients characterized by lower genetic vulnerability for psychosis. PMID- 29506305 TI - Comparative Efficacy and Safety of Antipsychotic Drugs for Tic Disorders: A Systematic Review and Bayesian Network Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of antipsychotic drugs for tic disorders (TDs) in a network meta-analysis. METHODS: PubMed, Embase, Cochrane Library, and 4 Chinese databases were searched. Randomized controlled trials (RCTs) evaluating the efficacy of antipsychotic drugs for TDs were included. RESULTS: Sixty RCTs were included. In terms of tic symptom score, compared with placebo, haloperidol, risperidone, aripiprazole, quetiapine, olanzapine, and ziprasidone can significantly improve tic symptom score (standardized mean differences [SMD] ranged from -12.32 to -3.20). Quetiapine was superior to haloperidol, pimozide, risperidone, tiapride, aripiprazole, and penfluridol for improving tic symptom score (SMD ranged from 28.24 to -7.59). Compared with tiapride, aripiprazole could significantly improve tic symptom score (SMD=-4.27). Compared with all other drugs, penfluridol was not effective. Atypical antipsychotics were generally well tolerated. CONCLUSIONS: Atypical antipsychotics (risperidone and aripiprazole) appear to be the most robust evidence-based options for the treatment of TDs. Quetiapine may be a promising therapy. Ziprasidone and olanzapine are also effective, but the evidence is lacking. Further high-quality directly comparing different pharmacological treatment studies are justified. PMID- 29506306 TI - The Relation Between Stretching Typology and Stretching Duration: The Effects on Range of Motion. AB - Different stretching strategies and protocols are widely used to improve flexibility or maintain health, acting on the muscle tendon-unit, in order to improve the range of motion (ROM) of the joints. This review aims to evaluate the current body of literature in order to understand the relation between stretching typology and ROM, and secondly to evaluate if a relation exists between stretching volume (either as a single training session, weekly training and weekly frequency) and ROM, after long-term stretching. Twenty-three articles were considered eligible and included in the quantitative synthesis. All stretching typologies showed ROM improvements over a long-term period, however the static protocols showed significant gains (p<0.05) when compared to the ballistic or PNF protocols. Time spent stretching per week seems fundamental to elicit range of movement improvements when stretches are applied for at least or more than 5 min, whereas the time spent stretching within a single session does not seem to have significant effects for ROM gains. Weekly frequency is positively associated to ROM. Evaluated data indicates that performing stretching at least 5 days a week for at least 5 min per week using static stretching may be beneficial to promote ROM improvements. PMID- 29506307 TI - Effect of Muscular Strength, Asymmetries and Fatigue on Kicking Performance in Soccer Players. AB - The aim of this study was to determine the effect of muscular strength, strength asymmetries, and fatigue on the speed and accuracy of an instep kick in soccer players. We measured ball velocity (BV) and kicking accuracy (KA) in the preferred (PL) and non-preferred leg (NPL) before (PRE) and after (POST) physical load in the PL. Maximum peak muscle torque of the knee extensors and flexors in the PL and NPL as well as ipsilateral knee flexors and knee extensors ratio (H:Q ratio) for both legs were assessed. BV was significantly decreased in POST physical load (5.82%, BVPRE=30.79+/-1.70 m.s-1, BVPOST=29.00+/-1.70 m.s-1, t19=3.67, p=0.00, d=1.05). Instep kick accuracy after the physical load worsened by an average of 10% in the most accurate trials. Results revealed a significant decrease in instep kick accuracy after physical loading (KAPRE=2.74+/-0.70 m, KAPOST=3.85+/-1.24 m, t19=-3.31, p=0.00, d=1.10). We found an insignificant correlation between H:Q ratio and KA in PRE test value, whereas a lower ipsilateral ratio (higher degree of strength asymmetry) in the POST physical load significantly correlated with KA in all angular velocities (r=-0.63 up to -0.67, p=0.00). PMID- 29506308 TI - One-stage wound healing of fingertip injuries induced by treatment of artificial dermis. AB - BACKROUND: Fingertip injuries are common in both adults and children. Many operative and non-operative management techniques have been reported to restore the function and cosmetic shape of fingertips after injuries. Although these methods may be used for different indications in clinical settings, few of them can treat all kinds of fingertip injuries. In addition, there is controversy as to whether the surgical approach or the conservative approach is the optimal management for fingertip injuries. METHODS: Thirty-six fingers of 33 patients with fingertip injuries were included in the study. All wounds were treated with surgical debridement and artificial dermis coverage without further surgical treatment. Follow-up duration was 24.5 months on average. RESULTS: All injuries were categorised into four types - Allen's classification of fingertip injury type II, type III, type IV, and transverse amputations proximal to the lunula and close to the level of the distal interphalangeal (DIP) joint - and 28 of them had bone exposure. The defects of all fingers were restored in one stage within an average of 8 weeks. Although the length and width of the new fingertips were less than those of the contralateral fingertips, almost all patients were satisfied with the functional and cosmetic outcomes of their regenerated fingers. CONCLUSIONS: One-stage wound healing of fingertip injuries induced by artificial dermis treatment is an easy and effective approach to restoring defects after injury with excellent functional and cosmetic results. Nearly all kinds of fingertip injuries can be managed with this method without any further surgical treatment. Therefore, this is a good alternative for the management of fingertip injuries. PMID- 29506309 TI - LHCGR Gene Analysis in Girls with Non-Classic Central Precocious Puberty. AB - BACKGROUND: Luteinizing hormone (LH) is a useful parameter in diagnosing precocious puberty. The pubertal response of serum LH to a GnRH stimulation test is varied, and clinical symptoms of precocious puberty are sometimes disproportionate with serum LH concentrations. Many patients present in a state of precocious puberty that advances rapidly, but the post-GnRH peak LH remains prepubertal. LH receptor mutations are suspected of involvement in the non classic type of central precocious puberty (CPP). OBJECTIVE: To examine the association between LHCGR polymorphism and non-classic CPP in subjects exhibiting a peak LH<5 IU/L on a GnRH stimulation test. METHODS: In total, 102 girls with non-classic CPP and 100 normal adult women were enrolled. All subjects underwent LHCGR gene analysis by the Sanger method, and patients and controls were compared. Auxological data and gonadotropin concentrations were analyzed in the 102 patients. Of these patients, 75 completed GnRH agonist treatment, and the treatment outcomes were analyzed. RESULTS: A total of seven variants were identified, including two missense mutations (g.48698754 G/A and g.48688613 G/A) that were found in the patient group (no patients contained both mutations). In silico analysis of these missense mutations suggested the possibility of damaging the LHCGR. However, no significant association was found between the identified LHCGR variants and non-classic CPP. GnRH agonist treatment decreased bone age advancement and increased predicted adult height. CONCLUSIONS: LHCGR gene polymorphisms do not appear to be a major causative factor for the relatively low concentration of LH in patients with non-classic CPP. GnRH agonist treatment improved clinical parameters in these patients. PMID- 29506310 TI - First Line Sorafenib Treatment for Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis. AB - BACKGROUND: Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers. METHODS: Ten consecutive patients with progressive or symptomatic metastatic MTC were included and started sorafenib 400 mg twice a day between June 2012 and March 2016. The primary end point was median progression-free survival (mPFS). Secondary endpoints included disease control rate, biochemical response, symptomatic response and toxicity. RESULTS: Four patients achieved partial remission (40%) according to RECIST 1.1 evaluation. Five patients had stable disease beyond 12 months (50%) and one patient had progressive disease (10%). Median PFS was 19.1 months. The disease control rate was 90%. Association between radiologic response and biochemical or symptomatic response was inconsistent. Most common side effects were Grade 1-2 fatigue (60%), palmar-plantar erythrodysesthesia, rash/dermatitis 50-50%, alopecia 40%. CONCLUSIONS: In our prospective case series in patients with MTC first-line sorafenib showed at least similar efficacy as in other small phase II trials and case reports. Based on comparable efficacy with registered tyrosine kinase inhibitors and it's manageable toxicity profile, we believe that sorafenib has role in the sequential treatment of MTC. PMID- 29506311 TI - The Beneficial Effects of Trimetazidine on Reperfusion-Induced Arrhythmia in Diabetic Rats. AB - Trimetazidine (TMZ), as an anti-ischemic drug, plays a critical role in protecting against cardiovascular complications induced by diabetes. This study was therefore aimed to evaluate the protective effects of TMZ on reperfusion induced arrhythmias in the diabetic rats. Male Sprague-Dawley rats (250+/-20 g) were randomly assigned to four (n=8): control rats (C), alloxan induced diabetic rats (D), diabetic rats treated with TMZ (10 mg/kg, D+T10), diabetic rats treated with TMZ (30 mg/kg, D+T30). TMZ was treated orally once daily for 8 weeks. Diabetes was induced by a single intraperitoneal injection of alloxan (120 mg/kg). Ischemia-reperfusion (I/R) was carried out via 30 min of ischemia and following120-min reperfusion. The magnitude and score of arrhythmia, the left ventricular function, infarct size, lactate dehydrogenase (LDH), myocardial creatine kinase (CK-MB) and troponin (cTnI) were measured. The findings were evaluated by two-way repeated measures and one-way ANOVA followed by LSD post hoc test and Fisher's exact test for incidence percentage. The duration, incidence and score of arrhythmia (p<0.001), infarct size (p<0.01) were significantly increased, the cardiac contractility (+/-dp/dt), LDH, CK-MB (p<0.001) and cTnI (p<0.05) were significantly decreased in the diabetic rats in comparison with the control group. However, treatment with TMZ in the diabetic rats was significantly improved the duration (p<0.001), incidence and score of arrhythmia,+/-dp/dt LDH, CK-MB, cTnI (p<0.05) and infarct size (p<0.01) in comparison with the untreated diabetic group. The present study indicates anti-arrhythmic effect of TMZ in reducing arrhythmias induced by reperfusion in the diabetic rats. PMID- 29506312 TI - Seasonal Variation in Month of Diagnosis of Polish Children with Type 1 Diabetes A Multicenter Study. AB - AIM: The seasonal variation of incidence of type 1 diabetes (T1D) theory supports the hypothesis that environmental factors play a role in the onset of the disease. The aim of this study is to assess seasonality of month of diagnosis in children with T1D in Poland. MATERIAL AND METHODS: the study group consisted of 2174 children from eastern and central Poland diagnosed with T1D between 2010 and 2014. Analysis was performed in different age groups, based on place of residence (rural/urban area) and depending on sex. RESULTS: We noted significant seasonality in the incidence of T1D with a peak in diagnosis of diabetes in January and the minimum rate in June. A total of 423 (19%) children were diagnosed in the warmest months (June to August with a mean temperature of 16.8 degrees C) compared to 636 (29%) recognised in the coldest months (December to February with a mean temperature of -1.6 degrees C), OR 0.57 95%CI [0.51-0.67], p<0.0001. We noted a more flat seasonal pattern in children 0-4 years of age compared with subjects 5-17 years old with a week correlation of trend comparison between both groups, r=0.69, p=0.001. Similar seasonal variation in the incidence of T1D was noted in children from urban and rural setting. For girls, seasonal pattern peaks were observed one month earlier as compared to boys. CONCLUSIONS: Seasonal variation in incidence of T1D diagnosis of Polish children supports the role of different environmental factors in diabetes onset. The majority of children were diagnosed with diabetes in autumn and winter. PMID- 29506313 TI - Impact of Autoimmune Thyroiditis on Reproductive and Metabolic Parameters in Patients with Polycystic Ovary Syndrome. AB - BACKGROUND: Autoimmune thyroiditis (AIT) has been found to be associated with polycystic ovary syndrome (PCOS). The aim of this retrospective cohort study using data from a fertility clinic, with patients recruited from 2009 to 2010, was to confirm the higher prevalence of AIT in PCOS and to evaluate the impact of AIT on reproductive and metabolic parameters of PCOS patients. METHODS: Patients comprised 827 PCOS subjects seen for reproductive or metabolic complaints. Patients presenting primarily for thyroid problems were excluded. All patients were tested for the presence of AIT by laboratory testing and thyroid ultrasound. The impact of AIT on PCOS was evaluated by determination of reproductive and metabolic parameters. RESULTS: Patients with PCOS and AIT as compared to those only with PCOS, had a lower prevalence of elevated testosterone (45 vs. 61%; p=0,0001), free androgen index (5,96+/-5,41 vs. 7,02+/-7,6; p<0,001) and hyperandrogenemia (66 vs. 78%; p<0,001). Also testosterone levels were lower in PCOS patients with AIT (0,50+/-0,30 vs. 0,63+/-0,71; p=0,0006). Consequently, in these patients, hirsutism was less frequent (51 vs. 66%; p=0,0021). There was no difference in the prevalence of acne, alopecia, a-/ or oligomenorrhea or PCO morphology in the two patient groups. Patients with PCOS and AIT were more obese by 2 kg/m2 BMI on average. A higher BMI correlated with a higher TSH value, although all patients were euthyroid. CONCLUSIONS: AIT is more prevalent in PCOS than in controls. PCOS patients with AIT have less severe hyperandrogenemia and hyperandrogenism but are likely to suffer from an elevated metabolic risk. PMID- 29506314 TI - Dual role for inositol-requiring enzyme 1alpha in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice. AB - : Obesity is associated with both endoplasmic reticulum (ER) stress and chronic metabolic inflammation. ER stress activates the unfolded protein response (UPR) and has been implicated in a variety of cancers, including hepatocellular carcinoma (HCC). It is unclear whether individual UPR pathways are mechanistically linked to HCC development, however. Here we report a dual role for inositol-requiring enzyme 1alpha (IRE1alpha), the ER-localized UPR signal transducer, in obesity-promoted HCC development. We found that genetic ablation of IRE1alpha in hepatocytes not only markedly reduced the occurrence of diethylnitrosamine (DEN)-induced HCC in liver-specific IRE1alpha knockout (LKO) mice when fed a normal chow (NC) diet, but also protected against the acceleration of HCC progression during high-fat diet (HFD) feeding. Irrespective of their adiposity states, LKO mice showed decreased hepatocyte proliferation and signal transducer and activator of transcription 3 (STAT3) activation, even in the face of increased hepatic apoptosis. Furthermore, IRE1alpha abrogation blunted obesity-associated activation of hepatic inhibitor of nuclear factor kappa B kinase subunit beta (IKKbeta)-nuclear factor kappa B (NF-kappaB) pathway, leading to reduced production of the tumor-promoting inflammatory cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6). Importantly, higher IRE1alpha expression along with elevated STAT3 phosphorylation was also observed in the tumor tissues from human HCC patients, correlating with their poorer survival rate. CONCLUSION: IRE1alpha acts in a feed-forward loop during obesity-induced metabolic inflammation to promote HCC development through STAT3-mediated hepatocyte proliferation. (Hepatology 2018). PMID- 29506315 TI - Magic mirror on the wall: Which is the best biomarker for hepatocellular carcinoma? PMID- 29506316 TI - Hand gestures support word learning in patients with hippocampal amnesia. AB - Co-speech hand gesture facilitates learning and memory, yet the cognitive and neural mechanisms supporting this remain unclear. One possibility is that motor information in gesture may engage procedural memory representations. Alternatively, iconic information from gesture may contribute to declarative memory representations mediated by the hippocampus. To investigate these alternatives, we examined gesture's effects on word learning in patients with hippocampal damage and declarative memory impairment, with intact procedural memory, and in healthy and in brain-damaged comparison groups. Participants learned novel label-object pairings while producing gesture, observing gesture, or observing without gesture. After a delay, recall and object identification were assessed. Unsurprisingly, amnesic patients were unable to recall the labels at test. However, they correctly identified objects at above chance levels, but only if they produced a gesture at encoding. Comparison groups performed well above chance at both recall and object identification regardless of gesture. These findings suggest that gesture production may support word learning by engaging nondeclarative (procedural) memory. PMID- 29506317 TI - Quantitative determination of meloxicam in dog plasma by high performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. AB - A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine meloxicam in beagle dog plasma. Sample pretreatment involved a one-step protein precipitation with methanol of 0.1 mL plasma. Analysis was performed on a Venusil ASB-C18 column with mobile phase consisting of methanol-water (containing 0.1% formic acid) (75:25, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization source. Each plasma sample was chromatographed within 4.1 min. The linear calibration curves for meloxicam was obtained in the concentration range of 10.3-4.12 * 103 ng/mL (r >= 0.99). The intra- and inter-day precisions (relative standard deviation) were <= 15%, and accuracy (relative error) was within +/-7.3%. The method herein described was fully validated and successfully applied to the pharmacokinetic study of meloxicam tablets in beagle dog. PMID- 29506318 TI - The Stapedial Artery in the Mongolian Gerbil (Meriones unguiculatus). AB - The persistent stapedial artery is a component of the main arterial roads of the head in some animal groups (Frackowiak: Roczn Akad Roln Poznan 336 (2003) 1-81). This type of vascularization occurs in the Mongolian gerbil, among others. The stapedial artery is common in a variety of forms in rodents. It has been described, for example, in Sciuridae, Muridae, Heteromyidae, Geomyidae, Splacidae, Cricetidae, Arvicolinae, and in genus Jaculus (Cox and Hautier: Evolution of the Rodents: Advances in phylogeny, Functional Morphology and Development, 2015). The aim of this study was the analysis of morphology, and of course, of the stapedial artery in this species. Investigations were performed on 10 animals of both sexes, weighing 50-60 g. After lethal anesthesia, the vascular system of every animal was filled with colored latex. After latex coagulation and decalcification of skull bones, fixed tissues were delicately prepared, and the head vascular system was exposed. The stapedial artery separates from the internal carotid artery, runs toward the auditory bulb and passes through the stapes. After the branching of the medial meningeal artery, the stapedial artery runs rostrally, forming its infraorbital branch. This branch, in the further course, gives the branch forming the short trunk of the ophthalmic artery, which supplies orbital structures (muscles, lacrimal gland, Harderian gland, and eyeball). The performed investigations revealed that the maintained infraorbital branch of the stapedial artery is the only source of arterial supply of the orbit in this species. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29506319 TI - Reply. PMID- 29506320 TI - Evaluating the validity and reliability of the V-scale instrument (Turkish version) used to determine nurses' attitudes towards vital sign monitoring. AB - AIM: The aim of this study was to determine the validity and reliability of the Turkish version of the V-scale, which measures nurses' attitudes towards vital signs monitoring in the detection of clinical deterioration. METHODS: This validity and reliability study was conducted at a tertiary hospital in Ankara, Turkey, in 2016. A total of 169 ward nurses participated in the study. Exploratory factor analysis, Cronbach's alpha coefficient, and the intraclass correlation coefficient were used to determine the validity and reliability of the scale. RESULTS: A 5-factor, 16-item scale explained 60.823% of the total variance according to the validity analysis. Our version matched the original scale in terms of the number of items and factor structure. Cronbach's alpha coefficient of the Turkish version of the V-scale was 0.764. The test-retest reliability results were 0.855 for the overall intraclass correlation coefficient, and the t-test result was P > 0.05. CONCLUSION: The V-scale is a reliable and valid instrument to measure Turkish nurses' attitudes towards vital signs monitoring in the detection of clinical deterioration. PMID- 29506321 TI - Modified images reflecting effects of age-related macular degeneration on perception of everyday scenes. AB - BACKGROUND: Depictions of vision with age-related macular degeneration (AMD) in public information material typically show a central region of absolute vision loss. Patients with early and moderate disease frequently do not report this. We aimed to measure how a group of people with AMD perceive everyday scenes in order to produce accurate depictions. METHODS: We report on six people aged 65-82 years with monocular AMD (visual acuity +0.04 to +1.64 logMAR) and normal vision in the fellow eye. Participants viewed four images monocularly, alternating between eyes. The image was digitally altered to approximate participants' descriptions of their perception with the affected eye. The altered image was viewed with the unaffected eye, and compared with the original image viewed with the affected eye. This was repeated iteratively until a perceptual match was achieved between the modified image/unaffected eye and the original image/affected eye. RESULTS: For five AMD participants with visual acuity +0.04 to +0.50 logMAR the modified images did not resemble those in current public information material. Image modifications required to achieve perceptual similarity with the affected eyes included localised distortion, contrast reduction and blur. Widespread colour desaturation was also required in some cases. One participant with advanced geographic atrophy reported an absolute positive scotoma, similar to existing depictions. CONCLUSIONS: Vision in people with AMD may not conform to the common depiction of a central region of absolute vision loss. The accurate representations of AMD patients' vision produced in this study will enable better understanding of the visual consequences of AMD. PMID- 29506322 TI - Bacillus Calmette-Guerin strain differences as the basis for immunotherapies against bladder cancer. AB - In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guerin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non-muscle-invasive bladder cancer. Bacillus Calmette-Guerin is a family of vaccines derived in 1921 by the in vitro attenuation of Mycobacterium bovis. Subsequently, bacillus Calmette Guerin seed lots were spread around the world, and both phenotypic and genotypic differences among the strains have been compiled. In recent genomic comparisons, the evolution of the different bacillus Calmette-Guerin substrains has begun to emerge. However, some of these genetic alterations in bacillus Calmette-Guerin strains have yet to be shown to affect the therapeutic effects and/or adverse effects. There are thus ongoing research efforts to assess the effects of these genetic alterations on the properties of bacillus Calmette-Guerin strains, with the ultimate goal of identifying an ideal bacillus Calmette-Guerin strain for treatment of non-muscle-invasive bladder cancer and providing clues for the improvement of bacillus Calmette-Guerin strains. The present review provides a history of bacillus Calmette-Guerin immunotherapy, and discusses the genetic differences among bacillus Calmette-Guerin strains, the different clinical outcomes afforded by bacillus Calmette-Guerin strains and possible future developments. PMID- 29506323 TI - Variability in acceptance of organ offers by pediatric transplant centers and its impact on wait-list mortality. AB - Recent data have suggested that pediatric patients wait-listed for a liver transplantation frequently have liver offers declined. However, factors associated with liver offer decisions and center-level variability in practice patterns have not been explored. We evaluated United Network for Organ Sharing data on all match runs from May 1, 2007 to December 31, 2015 in which the liver was offered to >=1 pediatric patient; the transplant recipient was ranked in the first 40 positions for the organ offer; and the donor was brain-dead and <50 years of age. We used multilevel mixed effects models to evaluate factors associated with organ offer acceptance, among-center variability, and the association between center-level acceptance and wait-list mortality. There were 4088 unique pediatric patients during the study period, comprising 27,094 match runs. Initial Model for End-Stage Liver Disease or Pediatric End-Stage Liver Disease score, history of exception points, recipient region, rank on match run, and geographic share type were all associated with probability of offer acceptance. There was significant among-center variation (P < 0.001) in adjusted liver offer acceptance rates, accounting for donor, recipient, and match-related factors (adjusted acceptance rates: median, 8.9%; range, 5.1%-14.6%). Center level acceptance rates were associated with wait-list mortality, with a >10% increase in the risk of wait-list mortality for every 1% decrease in a center's adjusted liver offer acceptance rate (odds ratio, 1.10; 95% confidence interval, 1.01-1.19). In conclusion, there is significant among-center variability in liver offer acceptance rates for pediatric patients that is not explained by donor and recipient factors. A center's liver acceptance behavior significantly impacts whether a pediatric patient will be transplanted or die on the waiting list. Liver Transplantation 24 803-809 2018 AASLD. PMID- 29506324 TI - Reply. PMID- 29506325 TI - The impact of continuous positive airway pressure on radiation dose to heart and lung during left-sided postmastectomy radiotherapy when deep inspiration breath hold technique is not applicable: a case report. AB - Deep inspiration breathing hold (DIBH) compared to free-breathing (FB) during radiotherapy (RT) has significantly decreased radiation dose to heart and has been one of the techniques adopted for patients with breast cancer. However, patients who are unable to make suitable deep inspiration breath may not be eligible for DIBH, yet still need to spare the heart and lung during breast cancer RT (left-sided RT in particular). Continuous positive airway pressure (CPAP) is a positive airway pressure ventilator, which keeps the airways continuously open and subsequently inflates the thorax resembling thoracic changes from DIBH. In this report, authors applied CPAP instead of FB during left sided breast cancer RT including internal mammary node in a patient who was unable to tolerate DIBH, and substantially decreased radiation dose the heart and lung with CPAP compared to FB. PMID- 29506326 TI - Prognostic significance of adjuvant radiation therapy in adenocarcinoma of the cecum. AB - PURPOSE: Local recurrence is a common failure pattern in adenocarcinoma of the cecum. This study aimed to investigate the potential role of adjuvant radiation therapy on oncologic outcomes of patients with adenocarcinoma of the cecum. MATERIALS AND METHODS: This retrospective study was carried out at three large tertiary university hospitals. We analyzed the characteristics, prognostic factors, and survival of 162 patients with adenocarcinoma of the cecum that were treated and followed up between 2000 and 2013. All the patients had undergone a right hemicolectomy and received chemotherapy with (n = 48) or without (n = 114) adjuvant radiation therapy. RESULTS: The subjects were 65 females and 97 males with a median age of 56 years (range, 17 to 90 years) at diagnosis. The 5-year local control (LC), disease free survival (DFS), and overall survival (OS) rates were 72.7%, 57.2%, and 62.6% respectively. In a multivariate analysis, age, tumor stage, node stage, and adjuvant radiation therapy were determined to be independent prognostic factors. Age more than 55 years (hazard ratio [HR] = 1.0; 95% confidence interval [CI], 0.06-0.32; p = 0.003], T4 stage (HR = 6.8; 95% CI, 3.07-15.36; p < 0.001), node positive disease (HR = 4.2; 95% CI, 1.94-9.13; p < 0.001), and the absence of adjuvant radiation therapy (HR = 3.0; 95% CI, 1.39 6.46; p = 0.005) had a negative influence on OS. CONCLUSION: Adjuvant radiation therapy significantly improves DFS and OS in patients with adenocarcinoma of the cecum. PMID- 29506327 TI - Re-Engineering the Cleft Craft Surgery: Function is an Essential Element of the Repair. PMID- 29506328 TI - Endoscopic transaxillary prepectoral conversion for submuscular breast implants. AB - BACKGROUND: During breast augmentation, the transaxillary approach provides the advantage of allowing the mammary prosthesis to be placed through incisions that are remote from the breast itself, thereby reducing the visibility of postoperative scars. For patients experiencing capsular contracture who do not want additional scars, the previous transaxillary scar can be used for site change and implant exchange. METHODS: This study analyzed 17 patients (34 breasts) with submuscular breast implants with grade III-IV capsular contracture who received treatment from 2010 to 2015. The mean age of the patients was 29 years (range, 20-38 years). The inclusion criterion was a pinch test of more than 3 cm at the upper pole of the breast. Previous axillary scars were used to expose the pectoralis fascia, and submuscular breast implants were removed carefully. The dissection underneath the pectoralis fascia was performed with endoscopic assistance, using electrocautery under direct visualization. RESULTS: The mean follow-up period was 14 months (range, 6-24 months). The entire dissection plane was changed from the submuscular plane to the subfascial plane. Round textured gel implants were used, with a mean implant size of 220 mL (range, 160-300 mL). Two patients developed grade II capsular contracture. There were no cases of malposition or asymmetry. Three patients complained of minor implant palpability. None of the patients required additional surgery. CONCLUSIONS: Endoscopic subfascial conversion may be an effective technique for treating capsular contracture and avoiding scarring of the breast in selected patients. PMID- 29506329 TI - How to deal with revisions? PMID- 29506330 TI - In vivo tracking of adipose tissue grafts with cadmium-telluride quantum dots. AB - BACKGROUND: Fat grafting, or lipofilling, represent frequent clinically used entities. The fate of these transplants is still not predictable, whereas only few animal models are available for further research. Quantum dots (QDs) are semiconductor nanocrystals which can be conveniently tracked in vivo due to photoluminescence. METHODS: Fat grafts in cluster form were labeled with cadmium telluride (CdTe)-QD 770 and transplanted subcutaneously in a murine in vivo model. Photoluminescence levels were serially followed in vivo. RESULTS: Tracing of fat grafts was possible for 50 days with CdTe-QD 770. The remaining photoluminescence was 4.9%+/-2.5% for the QDs marked fat grafts after 30 days and 4.2%+/- 1.7% after 50 days. There was no significant correlation in the relative course of the tracking signal, when vital fat transplants were compared to non vital graft controls. CONCLUSIONS: For the first-time fat grafts were tracked in vivo with CdTe-QDs. CdTe-QDs could offer a new option for in vivo tracking of fat grafts for at least 50 days, but do not document vitality of the grafts. PMID- 29506331 TI - Safety of long-term subcutaneous free flap skin banking after skin-sparing mastectomy. AB - BACKGROUND: A persistent problem in autologous breast reconstruction in skin sparing mastectomies is skin restoration after skin necrosis or secondary oncological resection. As a solution to facilitate reconstruction, skin banking of free-flap skin has been proposed in cases where the overlying skin envelope must be resected, as this technique spares the patient an additional donor site. Herein, we present the largest series to date in which this method was used. We investigated its safety and the possibility of skin banking for prolonged periods of time. METHODS: All skin-sparing mastectomies and immediate autologous breast reconstructions from December 2009 until June 2013 at our institution were analysed. RESULTS: We identified 31 patients who underwent 33 free flap reconstructions in which skin banking was performed. Our median skin banking period was 7 days, with a maximum duration of 171 days. In 22.5% of cases, the banked skin was used to reconstruct overlying skin defects, and in 9.6% of cases to reconstruct the nipple-areolar complex. Microbiological and histological investigations of the banked skin revealed neither clinical infections nor malignancies. CONCLUSIONS: In situ skin banking, even for prolonged periods of time, is a safe and cost-effective method to ensure that skin defects due to necrosis or secondary oncological resection can be easily reconstructed. PMID- 29506332 TI - The vertical orbicularis oculi muscle turn-over procedure for the correction of paralytic ectropion of the lower eyelid. AB - BACKGROUND: Static reconstruction surgery that tightens the tension of the inferior tarsus, thereby raising the lax lower eyelid, is a common treatment for paralytic ectropion of the lower eyelid. We present one such operative procedure, in which an orbicularis oculi muscle flap was used. METHODS: The surgical technique involves partial resection of the tarsus and the skin, as well as a superior-based orbicularis oculi muscle flap that is sutured to the firm tissue present on the Whitnall tubercle. The muscle flap is approximately 7 mm in width and 15 mm in length, with a superior pedicle that is attached to the tarsus at the medial point of the resected tarsus. The procedure results in contact between the ocular surface and the lower eyelid. RESULTS: The procedure was performed in 11 patients with lower eyelid ectropion due to facial paralysis. Ten cases showed a favorable outcome following surgery, with stable results seen over an average follow-up period of 4.5 years. In one case, recurrence of ectropion was observed 2 months after surgery due to an insufficient correction, and the patient required repeat surgery. CONCLUSIONS: The orbicularis oculi muscle flap was an effective means of suspension and was able to maintain long-term traction tension. This procedure can therefore be considered a favorable treatment option for lower eyelid ectropion due to facial paralysis. PMID- 29506333 TI - A rare approach? Microsurgical breast reconstruction after severe burns. AB - Breast deformity, in post-burn patients, is a common problem leading to lower self-esteem and reclusive behavior that impairs quality of life. The authors present the course of treatment of an 18-year-old immigrant girl who suffered second- to third-degree burns over approximately 20% of her total body surface area in her early childhood. The second- to third-degree burns were located on her right trunk and abdomen, as well as her right shoulder, neck, and right groin area. Since it was not offered in her home country, reconstructive surgery, including microsurgical breast reconstruction, was sought abroad. Due to the lack of available skin and soft tissue, a bilateral breast reconstruction with free transverse myocutaneous gracilis flaps was offered. This case illustrates one method of using microsurgery to address post-burn breast deformities in order to alleviate psychological suffering and improve quality of life. PMID- 29506334 TI - Cranially-based nasolabial flaps for the reconstruction of nasal surgical defects. AB - BACKGROUND: Cranially-based nasolabial flaps are a good alternative for the reconstruction of nasal defects. METHODS: A cranially-based nasolabial flap was used in 18 patients to reconstruct defects of the nose from 2010 to 2016, and the long-term results are presented in this report. RESULTS: Fifteen of the flaps completely survived. All the patients had a bulky appearance, but they did not want to undergo a second operation for cosmesis. The dissection of the flap took approximately 20 minutes, and the total operation lasted for 1 hour. The patients were hospitalized for 1-7 days, and the postoperative follow-up period was 1-28 months (mean, 17 months). CONCLUSIONS: The cranially-based nasolabial flap possesses all the advantages of the traditional forehead flap, and can safely be used in selected cases. PMID- 29506335 TI - A decision-making method for breast augmentation based on 25 years of practice. PMID- 29506336 TI - Early definitive treatment of partial-thickness alkali burns with tangential excision and biobrane. PMID- 29506337 TI - Superficial temporal artery flap for reconstruction of complex facial defects: A new algorithm. AB - BACKGROUND: A variety of island flaps can be based on the superficial temporal artery with variable tissue composition. They can be used for defect reconstruction, cavity resurfacing, facial hair restoration, or contracture release. METHODS: Seventy-two patients underwent facial reconstruction using a superficial temporal artery island flap from October 2010 to October 2014. The defects had various etiologies, including trauma, burns, tumors, exposed hardware, and congenital causes. We classified the patients by indication into 5 groups: cavity resurfacing, contracture release, facial hair restoration, skin coverage, and combined. The demographic data of the patients, defect characteristics, operative procedures, postoperative results, and complications were retrospectively documented. The follow-up period ranged from 24 to 54 months. RESULTS: A total of 24 females and 48 males were included in this study. The mean age of the patients was 33.7+/-15.6 years. The flaps were used for contracture release in 13 cases, cavity resurfacing in 10 cases, skin coverage in 17 cases, facial hair restoration in 19 cases, and combined defects in 13 cases. No major complications were reported. Conclusion: Based on our experiences with the use of superficial temporal artery island flaps, we have developed a detailed approach for the optimal management of patients with composite facial defects. The aim of this article is to provide the reader with a systematic algorithm to use for such patients. PMID- 29506338 TI - A child with type I ulnar ray deficiency. PMID- 29506339 TI - New techniques for wound management: A systematic review of their role in the management of chronic wounds. AB - Debridement is a crucial component of wound management. Recent technologies such as hydrosurgery (Versajet), ultrasound therapy (the MIST therapy device), or plasma-mediated bipolar radio-frequency ablation therapy (Coblation) seem to represent interesting alternatives for wound debridement. The purpose of this systematic review was to describe, evaluate, and compare these three recently developed methods for the management of chronic wounds. In January 2016, an electronic database search was conducted of MEDLINE, PubMed Central, and Embase for articles concerning these three innovative methods for the management of chronic wounds. A total of 389 references were identified by our search strategy, and 15 articles were included. We extracted data regarding the number and age of patients, indications, operating time, number of procedures, costs, wound healing time, decrease in exudation, perioperative blood loss, bacterial load, and the occurrence of complications. The 15 articles included studies that involved 563 patients who underwent hydrosurgery (7 studies), ultrasound therapy (6 studies), or Coblation (2 studies). Six randomized controlled trials were included that compared the use of a scalpel or curette to hydrosurgery (2 studies) or ultrasound therapy (6 studies). Hydrosurgery, in addition to being a very precise and selective tool, allows significantly faster debridement. Ultrasound therapy provides a significant reduction of exudation, and improves the wound healing time. No comparative study dedicated to Coblation was identified. Despite the obvious clinical interest of the topic, our review of the current literature revealed a lack of prospective randomized studies comparing these devices with each other or with standard techniques, particularly for Coblation and hydrosurgery. PMID- 29506340 TI - Case of late hematoma after breast augmentation. AB - We present a case report of a patient who experienced a late, spontaneous breast hematoma 26 years after primary breast augmentation. Late hematomas are a rare complication of breast augmentation with uncertain etiology. In this case, there was no trauma, calcifications, or implant rupture. We believe the patient's hematoma was secondary to erosion of a capsular vessel due to capsular contracture. PMID- 29506341 TI - Retention Esophagitis as a Significant Clinical Predictor of Progression to Esophageal Cancer in Achalasia. AB - BACKGROUND/AIMS: Chronic liquid and/or food stasis caused by retention esophagitis (RE) in achalasia is a notable endoscopic finding because of the presence of a thickened or whitish esophageal mucosa and histologically altered squamous hyperplasia. We aimed to identify the clinical features of RE associated with achalasia and to clarify the clinical definition of RE in achalasia as a precancerous lesion identified by analyzing biomarker expressions. METHODS: From 2006 to 2015, we retrospectively reviewed 37 patients with achalasia without previous treatment. Among them, 21 patients had diagnostic findings of RE (RE+) and 16 patients had no diagnostic findings of RE (RE-). Immunohistochemical staining of p53, p16, and Ki-67 was performed on the endoscopic biopsy tissues from the patients with achalasia and 10 control patients with non-obstructive dysphagia. RESULTS: The symptom duration and transit delay were significantly longer in the RE+ group than in the RE- group. We found particularly high p53 positivity rates in the RE+ group (p<0.001). The rate of p16 expression was also significantly higher in the RE+ group than in the other two groups (p=0.003). CONCLUSIONS: A high p53 expression rate was more frequently found in the RE+ group than in the other two groups. RE could be a meaningful clinical feature of achalasia for predicting esophageal carcinogenesis. PMID- 29506342 TI - Kidney transplantation in patients with diabetes: better than nothing. PMID- 29506343 TI - Epidemiology and treatment of antimicrobialresistant gram-negative bacteria in Korea. AB - Antimicrobial resistance is becoming one of the greatest challenges to public health worldwide. Infections by antimicrobial-resistant organisms could result in the failure of treatment, increased medical costs, prolonged hospital stays, and an increased socioeconomic burden. Antimicrobial usage in Korea remains heavy, even after much effort to reduce their use. According to the Korean antimicrobial resistance surveillance system, the resistance rates of many bacteria are increasing. The resistance rate of Acinetobacter baumannii to imipenem in Korea increased to 85% in 2015, representing a major public threat. The reports of increased carbapenem resistance in Enterobacteriaceae are worrisome. More importantly, some carbapenem-resistant Enterobacteriaceae may result from the production of carbapenemases, which break down carbapenems. There are relatively few treatment options for extensively drug-resistant A. baumannii and carbapenem resistant Enterobacteriaceae. Most reports are retrospective observational studies. Because there are little published data from randomized controlled trials, more data assessing antimicrobial treatment for extensively drug resistant A. baumannii and carbapenem-resistant Enterobacteriaceae are needed to make treatment recommendations. PMID- 29506344 TI - Middle East respiratory syndrome: what we learned from the 2015 outbreak in the Republic of Korea. AB - Middle East Respiratory Syndrome coronavirus (MERS-CoV) was first isolated from a patient with severe pneumonia in 2012. The 2015 Korea outbreak of MERSCoV involved 186 cases, including 38 fatalities. A total of 83% of transmission events were due to five superspreaders, and 44% of the 186 MERS cases were the patients who had been exposed in nosocomial transmission at 16 hospitals. The epidemic lasted for 2 months and the government quarantined 16,993 individuals for 14 days to control the outbreak. This outbreak provides a unique opportunity to fill the gap in our knowledge of MERS-CoV infection. Therefore, in this paper, we review the literature on epidemiology, virology, clinical features, and prevention of MERS-CoV, which were acquired from the 2015 Korea outbreak of MERSCoV. PMID- 29506346 TI - Bedside endoscopy of patients with gastrointestinal bleeding: early does not mean hurried. PMID- 29506347 TI - Skin Mast Cell Promotion in Random Skin Flaps in Rats using Bone Marrow Mesenchymal Stem Cells and Amniotic Membrane AB - Background: Skin flap procedures are employed in plastic surgery, but failure can lead to necrosis of the flap. Studies have used bone marrow mesenchymal stem cells (BM-MSCs) to improve flap viability. BM-MSCs and acellular amniotic membrane (AAM) have been introduced as alternatives. The objective of this study was to evaluate the effect of BM-MSCs and AAM on mast cells of random skin flaps (RSF) in rats. Methods: RSFs (80 * 30 mm) were created on 40 rats that were randomly assigned to one of four groups, including (I) AAM, (II) BM-MSCs, (III) BM-MSCs/AAM, and (IV) saline (control). Transplantation was carried out during the procedure (zero day). Flap necrosis was observed on day 7, and skin samples were collected from the transition line of the flap to evaluate the total number and types of mast cells. The development and the total number of mast cells were related to the development of capillaries. Results: The results of one-way ANOVA indicated that there was no statistically significant difference between the mean numbers of mast cell types for different study groups. However, the difference between the total number of mast cells in the study groups was statistically significant (p = 0.001). Conclusion: The present study suggests that the use of AAM/BM-MSCs can improve the total number of mast cells and accelerate the growth of capillaries at the transient site in RSFs in rats. PMID- 29506345 TI - Infectious complications after hematopoietic stem cell transplantation: current status and future perspectives in Korea. AB - Hematopoietic stem cell transplantation (HSCT) is a treatment for hematologic malignancies, immune deficiencies, or genetic diseases, ect. Recently, the number of HSCTs performed in Korea has increased and the outcomes have improved. However, infectious complications account for most of the morbidity and mortality after HSCT. Post-HSCT infectious complications are usually classified according to the time after HSCT: pre-engraftment, immediate post-engraftment, and late post-engraftment period. In addition, the types and risk factors of infectious complications differ according to the stem cell source, donor type, conditioning intensity, region, prophylaxis strategy, and comorbidities, such as graft versushost disease and invasive fungal infection. In this review, we summarize infectious complications after HSCT, focusing on the Korean perspectives. PMID- 29506348 TI - [Vaccines: first and foremost, a matter of public health]. PMID- 29506349 TI - [Scientific directors' reply to the letter of Paolo D'Argenio et al.] PMID- 29506350 TI - [Investigation of enteric viruses in wastewater of Milan area (Lombardy Region, Northern Italy)]. PMID- 29506351 TI - [Migrants, health and healthcare: the new epidemiology we need]. PMID- 29506352 TI - [For an epidemiology of migration in Italy: the opportunity of new partnerships]. PMID- 29506353 TI - [Anna Frank]. PMID- 29506354 TI - [A tribute to Gianfranco Domenighetti]. PMID- 29506355 TI - [Precarious workers, precarious research, precarious epidemiology]. PMID- 29506356 TI - [Four years of Epichange: first evaluation]. PMID- 29506358 TI - [Residential cohort study on mortality and hospitalization in Viggiano and Grumento Nova Municipalities in the framework of HIA in Val d'Agri (Basilicata Region, Southern Italy)]. AB - OBJECTIVES: to evaluate the associations among the emissions produced by "Centro olio Val d'Agri" (COVA), with mortality and hospitalization of residents in the Viggiano and Grumento Nova Municipalities, located in Val d'Agri (Basilicata Region, Southern Italy). DESIGN: residential cohort study. SETTINGS AND PARTICIPANTS: Lagrangians dispersion models to estimate the level of exposure at the address of residence to NOX concentrations as tracers of COVA emissions. Based on the tertile of NOX distribution, individual exposure was classified and a Cox model analysis was performed (hazard ratio, HR, trend with relative 95%CI). The association among exposure to NOX and the cohort mortality/hospitalization was evaluated considering age, socioeconomic status, and distance from the high traffic density road. The cohort included 6,795 residents (73,270 person-years) in the period 2000-2014. MAIN OUTCOME MEASURES: causes of mortality and hospitalization due to cardio-respiratory diseases, recognised as associated to air pollution, with medium-short latency induction period, consistent with the period of operation at the COVA. RESULTS: increasing trends were observed on three exposure classes for mortality due to circulatory system diseases (HR trend: 1.19; 95%CI 1.02-1.39), stronger considering women (HR trend: 1.19; 95%CI 1.02-1.39). From hospitalizations results, an increased risk emerges for respiratory diseases (HR trend: 1.12; 95%CI 1.01-1.25) and, for women, for diseases of the circulatory system (HR trend: 1.19; 95%CI 1.03-1.38), for ischemic diseases (HR trend: 1.33; 95%CI 1.02-1.74) and respiratory diseases (HR trend: 1.22; 95%CI 1.03-1.46). CONCLUSIONS: the excesses of mortality and hospitalization emerged in areas most exposed to pollutants of industrial origin are relevant for preventive actions. It is recommended to define and implement a surveillance system for the entire resident population based on indicators of environmental pollution and related health outcomes on the basis of the scientific literature and the results achieved by the present study. PMID- 29506357 TI - [Recommendations from a health impact assessment in Viggiano and Grumento Nova (Basilicata Region, Southern Italy)]. AB - In Europe, Health Impact Assessment (HIA) is a consolidated practice aimed at predicting health impacts supporting the predisposition of plans and projects subjected to authorization procedures. In Italy, further developments are needed to harmonize the practice and consolidate methodologies in order to extend the HIA application in different fields. The recent HIA conducted in Val d'Agri (Basilicata) on the impacts of a first crude oil treatment plant represents an opportunity to illustrate its tools, methods and fields of application. In this experience, participation methods in impact assessment have been adapted to the context, emphasizing aspects of ethics, equity and democracy. Environmental and epidemiological studies were included in the HIA Val d'Agri in order to characterize the environment and assess the health status of the resident population. On the basis of the results public health recommendations have been elaborated, shared with the stakeholders and shared with local and regional administrators. The experience in Val d'Agri introduces elements of reflection on the potential of HIA at local level in order to support the public health and the environmental control systems in the area, as well as planning based on preventive environment and HIA. PMID- 29506360 TI - [Phisycal activity and primary prevention: lifestyle analysis in young people]. AB - OBJECTIVES: to assess physical activity and overweight in a young population as factors associated with well-being. DESIGN: cross-sectional study. SETTING AND PARTICIPANTS: data collection was performed in primary and secondary schools of a district located in Florence (Tuscany Region, Central Italy) by a validated questionnaire; 1,776 subjects were enrolled. MAIN OUTCOME MEASURES: physical activity levels and overweight. RESULTS: an overweight or obese condition in 14,4% of the study population was observed. Vigorous physical activity prevailed in normal weight children, while the time spent in a sitting position was higher in overweight subjects. CONCLUSIONS: physical activity levels do not follow the guidelines for youth people. Educational programmes, also at schools, are recommended in order to prevent the risk of developing chronic diseases in adulthood. PMID- 29506359 TI - [Accurate compiling of the hospital discharge records according to clinicians' perception: critical issues and perspectives]. AB - OBJECTIVES: to explore clinicians vision on hospital discharge records in order to identify useful elements to foster a more accurate compiling. DESIGN: qualitative research with phenomenological approach. SETTING AND PARTICIPANTS: participants were selected through purposive sampling among clinicians of two hospitals located in Sardinia; the sample included 76 people (32 medical directors and 44 doctors in training). MAIN OUTCOME MEASURES: identified codes for themes under investigation: vision of accurate compiling, difficulties, and proposals. RESULTS: collected data highlighted two prevailing visions, respectively focused on the importance of an accurate compiling and on the burden of such activity. The accurate compiling is hindered by the lack of motivation and training, by the limits of the registration system and the information technology, by the distortions induced by the prominent role of the hospital discharge records in the evaluation processes. Training, timely updating of the information system accompanied by a proper cross-cultural validation process, improvement of the computer system, and activation of support services could promote more accurate compiling. CONCLUSIONS: the implementation of services, unconnected with evaluation and control processes, dedicated to training and support in the compiling of the hospital discharge records and in the conduction of related epidemiological studies would facilitate the compliance to the compilation. Such services will make tangible the benefits obtainable from this registration system, increasing skills, motivation, ownership, and facilitating greater accuracy in compiling. PMID- 29506361 TI - [Big data in environmental epidemiology. Satellite and land use data for the estimation of environmental exposures at national level]. AB - OBJECTIVES: to define a national geographic domain, with high spatial (1 km2) and temporal (daily) resolution, and to build a list of georeferenced environmental and temporal indicators useful for environmental epidemiology applications at national level. DESIGN: geographic study. SETTING AND PARTICIPANTS: study domain: Italian territory divided into 307,635 1-km2 grid cells; study period: 2006-2012, divided into 2,557 daily time windows. MAIN OUTCOME MEASURES: for each grid cell and day, an extensive number of indicators has been computed. These indicators include spatial (administrative layers, resident population, presence of water bodies, climatic zones, land use variables, impervious surfaces, orography, viability, point and areal emissions of air pollutants) and spatio-temporal predictors (particulate matter data from monitoring stations, meteorological parameters, desert dust advection episodes, aerosol optical depth, normalized difference vegetation index, planetary boundary layer) potentially useful to characterize population environmental exposures and to estimate their health effects, at national level. RESULTS AND CONCLUSIONS: this study represents the first example of relational big data in environmental epidemiology at national level, where multiple sources of data (satellite, environmental, meteorology, land use, population) have been linked on a common spatial and temporal domain, aimed at promoting environmental epidemiology applications at national and local level. PMID- 29506362 TI - [Hygienic and sanitary aspects in urban planning: contradiction in national and local urban legislation regarding public health]. AB - Nowadays, the majority of world population lives in urban areas and this portion is going to increase in the coming decades. The health impact of urban areas is well established and described in scientific literature. Italian health and hygiene legislation dealing with urban health is fragmented and not coordinated with the regulation about environment and city planning. The overlapping of legal competences between different authorities and the conflict of attribution between the Central State and Regional Governments deeply contributed to generate uncertainty. The authors here analyse the Italian regulatory framework and depict its lacks in terms of public health protection. PMID- 29506363 TI - [Varicella vaccination: scientific reasons for a different strategic approach]. AB - The Italian Parliament has recently introduced 10 mandatory immunisations, including the one against varicella. For this vaccination, the obligation starts with the birth cohort of 2017, but it is offered free of charge to subjects with a negative history and not previously vaccinated. This paper presents up-to-date evidence on this issue and illustrates a number of critical arguments that may question the opportunity of this choice. Particularly, while the disease is relatively mild in children aged between 1 and 9 years, the risk of worsening its consequences is progressive with age, becoming worst in the elderly, so the vaccination of children may increase the age of the cases. Some vaccine side effects are not trivial and the duration of protection is still uncertain, as well as the cost-effectiveness of mass vaccination and its long-term effects, referring to virus reactivation and to the incidence of Herpes zoster in the general population, which could be increased and anticipated in the long run. Varicella vaccination is not included in international eradication goals and very few Europeans Countries have considered it as a public health priority. A different rational choice could have been to offer a selective vaccination only to adolescents with a negative history of chickenpox; or at least to delay the beginning of the universal campaign in the Italian regions that had not started the mass vaccination yet, evaluating the results over time. Lastly, this paper lists a number of preventive interventions of proven effectiveness and cost effectiveness, with extraordinary margins of improvement, whose mandatory introduction in the population have never been considered, even as a matter of debate. PMID- 29506364 TI - [Tobacco cultivationin Salento (Apulia Region, Southern Italy) from 1929 to 1993: possible health implications]. AB - The Province of Lecce (Apulia Region, Southern Italy) is one of the Italian areas where the prevalence of respiratory disease and cancer of the respitartory tract is very high. Through a descriptive analysis of the historical series of tobacco culture indicators, a historical reconstruction of the development of tobacco cultivation in Salento (the area where the Province of Lecce is located) is here presented, in order to provide an additional element of knowledge on potential risk factors for respiratory diseases and cancers. Data regarding extensions in hectares and crop productions in the province of Lecce, in Apulia, and in Italy are from the Chamber of commerce of Lecce province and from the Italian National Institute of Statistics (Istat). From 1929 to 1993, the province of Lecce provided between 75% and 94% of the tobacco cultivated in Apulia Region and 25% of the national tobacco until 1945. Since the late Sixties, a growing increase in annual average production was observed, reaching 21.5 quintals per hectare in 1991 in Salento. This large tobacco production, associated with intensive use of pesticides, could be an element to be observed in analytical studies as a determining potential for the high prevalence of respiratory diseases and pulmonary cancers in the male population of the province of Lecce. PMID- 29506365 TI - [ERRATA CORRIGE bis: Epidemiol Prev 2016; 40(3-4): 205-214]. AB - [This corrects the article Epidemiol Prev 2016;40(3-4): 205-214]. Article's PDF can be found at www.epiprev.it/articolo_scientifico/mortalita-mesotelioma pleurico-italia-ricostruzione-dellaserie-storica-1970-20. PMID- 29506369 TI - [Give voice to different cultures for a stronger idea of prevention]. PMID- 29506370 TI - [Being born in Italy today]. PMID- 29506371 TI - [Towards a national strategy addressing inequalities]. PMID- 29506372 TI - [High prices and low clinical benefit: anomalies of the drug market]. PMID- 29506373 TI - [Epigenetics and air pollution: a "hot" topic]. PMID- 29506375 TI - [Using large current databases to analyze mental health services]. PMID- 29506374 TI - [An epidemiology of research to avoid dissipation of resources of the Italian national health service]. PMID- 29506376 TI - [The place of prevention]. PMID- 29506378 TI - Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder. AB - Expanded CAG trinucleotide repeats in Huntington's disease (HD) are causative for neurotoxicity. The mutant CAG repeat RNA encodes neurotoxic polyglutamine proteins and can lead to a toxic gain of function by aberrantly recruiting RNA binding proteins. One of these is the MID1 protein, which induces aberrant Huntingtin (HTT) protein translation upon binding. Here we have identified a set of CAG repeat binder candidates by in silico methods. One of those, furamidine, reduces the level of binding of HTT mRNA to MID1 and other target proteins in vitro. Metadynamics calculations, fairly consistent with experimental data measured here, provide hints about the binding mode of the ligand. Importantly, furamidine also decreases the protein level of HTT in a HD cell line model. This shows that small molecules masking RNA-MID1 interactions may be active against mutant HTT protein in living cells. PMID- 29506379 TI - Deterministic Ratchet for Sub-micrometer (Bio)particle Separation. AB - Resolving the heterogeneity of particle populations by size is important when the particle size is a signature of abnormal biological properties leading to disease. Accessing size heterogeneity in the sub-micrometer regime is particularly important to resolve populations of subcellular species or diagnostically relevant bioparticles. Here, we demonstrate a ratchet migration mechanism capable of separating sub-micrometer sized species by size and apply it to biological particles. The phenomenon is based on a deterministic ratchet effect, is realized in a microfluidic device, and exhibits fast migration allowing separation in tens of seconds. We characterize this phenomenon extensively with the aid of a numerical model allowing one to predict the speed and resolution of this method. We further demonstrate the deterministic ratchet migration with two sub-micrometer sized beads as model system experimentally as well as size-heterogeneous mouse liver mitochondria and liposomes as model system for other organelles. We demonstrate excellent agreement between experimentally observed migration and the numerical model. PMID- 29506380 TI - Supported Au Nanoparticles with N-Heterocyclic Carbene Ligands as Active and Stable Heterogeneous Catalysts for Lactonization. AB - Attachment of N-heterocyclic carbenes (NHCs) on the surface of metal nanoparticle (NP) catalysts permits fine-tuning of catalytic activity and product selectivity. Yet, NHC-coated Au NPs have been seldom used in catalysis beyond hydrogenation chemistry. One challenge in this field has been to develop a platform that permits arbitrary ligand modification without having to compromise NP stability toward aggregation or leaching. Herein, we exploit the strategy of supported dendrimer-encapsulated metal clusters (DEMCs) to achieve aggregation-stable yet active heterogeneous Au NP catalysts with NHC ligands. Dendrimers function as aggregation-inhibitors during the NP synthesis, and NHCs, well-known for their strong attachment to the gold surface, provide a handle to modify the stereochemistry, stereoelectronics, and chemical functionality of the NP surface. Indeed, compared to "ligandless" Au NPs which are virtually inactive below 80 degrees C, the NHC-ligated Au NP catalysts enable a model lactonization reaction to proceed at 20 degrees C on the same time scale (hours). Based on Eyring analysis, proto-deauration is the turnover-limiting step accelerated by the NHC ligands. Furthermore, the use of chiral NHCs led to asymmetric induction (up to 16% enantiomeric excess) in the lactonization transformations, which demonstrates the potential of supported DEMCs with ancillary ligands in enantioselective catalysis. PMID- 29506377 TI - [Italian Cystic Fibrosis Registry. Report 2011-2014]. AB - INTRODUCTION: The Italian Cystic Fibrosis Registry (ICFR) is based on a new agreement about the data flow towards the Registry signed on October, 4th 2016 by the Centre for Rare Diseases of the Italian National Institute of Health (NIH), the clinicians of the Italian National Referral and Support Centres for Cystic Fibrosis, the Paediatric Hospital "Bambino Gesu" (Rome), the Italian Cystic Fibrosis Society, and the Italian League for Cystic Fibrosis. OBJECTIVES: The aim of the present Report is to improve the knowledge on cystic fibrosis (CF) through the epidemiological description of Italian patients. The members of the Scientific and Technical Committee have to write a report on data collected by ICFR, in order to contribute to achieve the aims of ICFR itself, i.e., to improve the care of CF patients. In particular, the Report should contribute to the following objectives: - to analyze the medium and long-term clinical and epidemiological trends of the disease; - to identify the main healthcare needs at regional and national level in order to contribute to the healthcare programmes and to the distribution of resources; - to compare Italian data with the international ones. DESIGN: Analyses and results described in the present Report are referred to patients in charge to the Italian National Referral and Support Centres for Cystic Fibrosis in the period 2011-2014. Data were sent by Centres by means of a specific software (Camilla, Ibis Informatica) and has undergone a double quality control (QC): the first by NIH and the second at a European level (before the inclusion of the Italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and accuracy of data as well as their consistency with European core data. SETTING AND PARTICIPANTS: A total of 29 different CF centres (referral, support, and Paediatric Hospital "Bambino Gesu") sent their data to ICFR; data referred to the period 2011-2014. Data regarding Sardinia Region (Southern Italy) are missing; data from Molise (Southern Italy) CF centre refer only to 2014. RESULTS: The present Report has been organized into 10 sections. 1. Demography - number of Italian patients with cystic fibrosis (CF) in 2014 was 4,981 and their median age was 20.4 years; estimated 2014 CF prevalence was 8.2/100,000 residents in Italy; on average, 52.1% of the patients were male and CF distribution showed higher frequency in patients aged from 7 to 35 years. On average, 53.7% of CF patients are aged more than 18 years. 2. Diagnoses - most of the CF patients were diagnosed before two years of age (around 66%); a significant proportion of patients (on average, 12%) was diagnosed in adult age. 3. New diagnoses - new diagnoses were 187 in 2011, 200 in 2012, 160 in 2013, and 135 in 2014. Estimated incidence was 1/4,052 live births in 2011; 1/4,313 in 2012; 1/5,189 in 2013 and 1/8,243 in 2014. 4. Genetics - 99.5% of patients was studied at the molecular level, with identification of 90.1% of Cystic Fibrosis Transmembrane Regulator CFTR mutations; [delta]508F was the most frequent mutation (44.8% in 2014). 5. Lung function - FEV1 (Forced Expiratory Volume in the first second) scores progressively decreased shortly before the start of adult age, in accordance with the natural history of the disease. Most of the patients between 6 and 17 years of age reported a FEV1 % >= 70% of the predicted value, while the proportion of patients with severe lung disease (FEV1 % <40% of the predicted value) is <2% over the period 2011-2014. 6. Nutrition - most critical periods come out during the first 6 months of life and during adolescence. Prevalence of malnourished male aged 12-17 years decreases over the period 2011-2014; an increasing percentage of patient (both male and female) with a suboptimal body mass index value is observed among patients aged more than 18 years 7. Complications - the presence of missing data represents an obstacle in the correct evaluation of prevalence value of complications related to Italian patients within ICFR. Nevertheless, it was estimated that, in 2014, the principal complication in patients aged <18 years was hepatopathies (15%), while in patients aged more than 18 years the principal complications were due to hepatopathies (25%) and diabetes (22%). 8. Transplantation - during the period 2011-2014, 135 patients ageed between 7 and 53 years received a double lung transplant; median age at transplantation was 32.5 years. Median duration of waiting list for transplantation is estimated in 11 months. 9. Microbiology - analyses were referred to test performed in 2014. Prevalence of adult patients with Pseudomonas aeruginosa chronic infection is 49.4% compared to 14.5% of paediatric patients; Staphylococcus aureus chronic infection is present in 48% of adult patients and 45.6% of paediatric patients; Burkholderia Cepacia complex is present almost exclusively in adult patients (4.9%); Nontuberculous mycobacteria is present in 0.9% and 0.3% of adult and paediatric patients, respectively; Stenotrophomonas maltophilia infection is present in 4.6% of patients (both adults and paediatric). 10. Mortality - RIFC data show that 176 patients (median age 32 years; 81 males and 95 females) died in the period 2011-2014. CONCLUSIONS: The present Report shows that CF population is growing (median age), so paediatric mortality is decreasing. A very low percentage of paediatric population is characterized by complication of pulmonary functions; adult patients are characterized by an increase of age at death (more than 30 years of age). ICFR Report may represent an important tool to analyze clinical and epidemiological trends of the disease as well as to identify the main healthcare needs at regional and national level to contribute to the healthcare programmes and to the distribution of the resources. PMID- 29506381 TI - Direct Electrochemiluminescence Imaging of a Single Cell on a Chitosan Film Modified Electrode. AB - Single-cell imaging is essential for elucidating the biological mechanism of cell function because it accurately reveals the heterogeneity among cells. The electrochemiluminescence (ECL) microscopy technique has been considered a powerful tool to study cells because of its high throughput and zero cellular background light. However, since cells are immobilized on the electrode surface, the steric hindrance and the insulation from the cells make it difficult to obtain a luminous cell ECL image. To solve this problem, direct ECL imaging of a single cell was investigated and achieved on chitosan and nano-TiO2 modified fluoride-doped tin oxide conductive glass (FTO/TiO2/CS). The permeable chitosan film is not only favorable for cell immobilization but also increases the space between the bottom of cells and the electrode; thus, more ECL reagent can exist below the cells compared with the cells on a bare electrode, which guarantees the high sensitivity of quantitative analysis. The modification of nano-TiO2 strengthens the ECL visual signal in luminol solution and effectively improves the signal-to-noise ratio. The light intensity is correlated with the H2O2 concentration on FTO/TiO2/CS, which can be applied to analyze the H2O2 released from cells at the single-cell level. As far as we know, this is the first work to achieve cell ECL imaging without the steric hindrance effect of the cell, and it expands the applications of a modified electrode in visualization study. PMID- 29506382 TI - Solution Self-Assemblies of Sequence-Defined Ionic Peptoid Block Copolymers. AB - A series of amphiphilic ionic peptoid block copolymers where the total number (1 or 3) and position of ionic monomers along the polymer chain are precisely controlled have been synthesized by the submonomer method. Upon dissolution in water at pH = 9, the amphiphilic peptoids self-assemble into small spherical micelles having hydrodynamic radius in ~5-10 nm range and critical micellar concentration (CMC) in the 0.034-0.094 mg/mL range. Small-angle neutron scattering (SANS) analysis of the micellar solutions revealed unprecedented dependence of the micellar structure on the number and position of ionic monomers along the chain. It was found that the micellar aggregation number ( Nagg) and the micellar radius ( Rm) both increase as the ionic monomer is positioned progressively away from the junction of the hydrophilic and hydrophobic segments along the polymer chain. By defining an ionic monomer position number ( n) as the number of monomers between the junction and the ionic monomer, Nagg exhibited a power law dependence on n with an exponent of ~1/3 and ~3/10 for the respective singly and triply charged series. By contrast, Rm exhibited a weaker dependence on the ionic monomer position by a power law relationship with an exponent of ~1/10 and ~1/20 for the respective singly and triply charged series. Furthermore, Rm was found to scale with Nagg in a power-law relationship with an exponent of 0.32 for the singly charged series, consistent with a weakly charged ionic star like polymer model in the unscreened regime. This study demonstrated a unique method to precisely tailor the structure of small spherical micelles based on ionic block copolymers by controlling the sequence and position of the ionic monomer. PMID- 29506383 TI - Bimodal Electrochemiluminescence of G-CNQDs in the Presence of Double Coreactants for Ascorbic Acid Detection. AB - How to improve the accuracy of target detection substance in low-content and complex of real sample, which is still a major challenge in the analysis field. There is no doubt that the internal standard method is the best choice in the analysis methods. The internal standard method of ECL strategy can furnish more accurate detection results in the changeable complex environment, and it can dispel the primary vaguest interference in the system through the self calibration of two emission spectra. Herein, we effectually explored a strong and stable bimodal ECL system based on graphitic carbon nitride quantum dots (g CNQDs) as single luminophore in the presence of double coreactants potassium persulfate (K2S2O8) and tetrabutylammonium bromide (TBAB) under the optimized conditions. ECL-1 at 2.82 V and ECL-2 at 1.73 V were observed when the potential was scanned between -3 and 3 V at the scan rate of 0.2 V.s-1. The ECL-1 was responding to the analyte, that is, ascorbic acid (AA) and the ECL-2 was not for a certain concentration of AA; hence, the developed bimodal ECL system was used as internal standard method for quantitative AA in human serum due to the different sensitivity of the double-peak ECL signals to the target analytes. The linear relationships were obtained based on the ln I (ECL-1/ECL-2) against the concentration of AA in the concentration range of 3.5 to 330 nM, with a detection limit of 110 pM (S/N = 3). PMID- 29506385 TI - SLTCAP: A Simple Method for Calculating the Number of Ions Needed for MD Simulation. AB - An accurate depiction of electrostatic interactions in molecular dynamics requires the correct number of ions in the simulation box to capture screening effects. However, the number of ions that should be added to the box is seldom given by the bulk salt concentration because a charged biomolecule solute will perturb the local solvent environment. We present a simple method for calculating the number of ions that requires only the total solute charge, solvent volume, and bulk salt concentration as inputs. We show that the most commonly used method for adding salt to a simulation results in an effective salt concentration that is too high. These findings are confirmed using simulations of lysozyme. We have established a web server where these calculations can be readily performed to aid simulation setup. PMID- 29506384 TI - Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening. AB - Heme-based tryptophan dioxygenases are established immunosuppressive metalloproteins with significant biomedical interest. Here, we synthesized two mechanistic probes to specifically test if the alpha-amino group of the substrate directly participates in a critical step of the O atom transfer during catalysis in human tryptophan 2,3-dioxygenase (TDO). Substitution of the nitrogen atom of the substrate to a carbon (probe 1) or oxygen (probe 2) slowed the catalytic step following the first O atom transfer such that transferring the second O atom becomes less likely to occur, although the dioxygenated products were observed with both probes. A monooxygenated product was also produced from probe 2 in a significant quantity. Analysis of this new product by HPLC coupled UV-vis spectroscopy, high-resolution mass spectrometry, 1H NMR, 13C NMR, HSQC, HMBC, and infrared (IR) spectroscopies concluded that this monooxygenated product is a furoindoline compound derived from an unstable epoxyindole intermediate. These results prove that small molecules can manipulate the stepwise O atom transfer reaction of TDO and provide a showcase for a tunable mechanism by synthetic compounds. The product analysis results corroborate the presence of a substrate based epoxyindole intermediate during catalysis and provide the first substantial experimental evidence for the involvement of the substrate alpha-amino group in the epoxide ring-opening step during catalysis. This combined synthetic, biochemical, and biophysical study establishes the catalytic role of the alpha amino group of the substrate during the O atom transfer reactions and thus represents a substantial advance to the mechanistic comprehension of the heme based tryptophan dioxygenases. PMID- 29506386 TI - Singlet Fission and Triplet Transfer to PbS Quantum Dots in TIPS-Tetracene Carboxylic Acid Ligands. AB - Singlet exciton fission allows for the generation of two triplet excitons for each photon absorbed within an organic semiconductor. Efficient harvesting of these triplets could allow for the Shockley-Queisser limit on the power conversion efficiency of single-junction photovoltaics to be broken. Here, we show that singlet fission molecules bound directly to PbS quantum dots as ligands can undergo singlet fission with near unity efficiency and can transfer triplets sequentially into the PbS with near unity efficiency. Within the PbS, the excitations recombine, giving rise of the emission of photons. This allows for the doubling of the quantum dot photoluminescence quantum efficiency when photons are absorbed by the singlet fission ligand, as compared to when directly absorbed in the quantum dot. Our approach demonstrates that it is possible to convert the exciton multiplication process of singlet fission into a photon multiplication process and provides a new path to harness singlet fission with photovoltaics. PMID- 29506387 TI - ESIgen: Electronic Supporting Information Generator for Computational Chemistry Publications. AB - Electronic supporting information (ESI) occupies a fundamental position in the way scientists report their work. It is a key element in lightening the writing of the core manuscript and makes concise communication easier for the authors. Computational chemistry, as all fields related to structural studies of molecules, tends to generate huge amounts of data that should be inserted in the ESI. ESI reports originating from computational chemistry works generally reach tens of sheets long and include 3D depictions, coordinates, energies, and other characteristics of the structures involved in the molecular process understudy. While most experienced users end up building scripts that dig throughout the output files searching for the relevant data, this is not the case for users without programming experience or time. Here we present an automated ESI generator supported by both web-based and command line interfaces. Focused on quantum mechanics calculations outputs so far, we trust that the community would find this tool useful. Source code is freely available at https://github.com/insilichem/esigen . A web app public demo can be found at http://esi.insilichem.com . PMID- 29506388 TI - Catalyst-Free Synthesis of Aryl Diamines via a Three-Step Reaction Process. AB - The formation of C-N bonds with aryl amines is one of the most widely studied reactions in organic chemistry. Despite this, it is still highly challenging, often requiring expensive, precious metal-based catalysts. Here we report an easy catalyst-free methodology for constructing C-N bonds. The method, which proceeds via the in situ formation of closed ring amidinium ions, allows the preparation of a series of symmetrical and/or unsymmetrical aryl diamines in notably high yields (82-98%) and purity and with a variety of different substituents. The methodology is shown successful for the preparation of aryl diamines having para- and/or meta-substituted carboxyl, nitro, bromo, methoxy, or methyl groups. This green synthetic pathway, which is catalyst free, requires only three steps, and proceeds without the need for purification. Further, it is a new sustainable, economically viable method to achieve an otherwise challenging bond formation. PMID- 29506389 TI - Bending Lipid Bilayers: A Closed-Form Collective Variable for Effective Free Energy Landscapes in Quantitative Biology. AB - Curvature-related processes are of major importance during protein-membrane interactions. The illusive simplicity of membrane reshaping masks a complex molecular process crucial for a wide range of biological functions like fusion, endo- and exocytosis, cell division, cytokinesis, and autophagy. To date, no functional expression of a reaction coordinate capable of biasing molecular dynamics simulations to produce membrane curvature has been reported. This represents a major drawback given that the adequate identification of proper collective variables to enhance sampling is fundamental for restrained dynamics techniques. In this work, we present a closed-form equation of a collective variable that induces bending in lipid bilayers in a controlled manner, allowing for straightforward calculation of free energy landscapes of important curvature related events, using standard methods such as umbrella sampling and metadynamics. As a direct application of the collective variable, we calculate the bending free energies of a ternary lipid bilayer in the presence and the absence of a Bin/Amphiphysin/Rvs domain with an N-terminal amphipathic helix (N BAR), a well-known peripheral membrane protein that induces curvature. PMID- 29506390 TI - Tectona grandis (teak) - A review on its phytochemical and therapeutic potential. AB - Tectona grandis Linn (Teak), is locally known as Sagwan, belongs to Lamiaceae family. It is one of the most valuable timber in the world, due to its beautiful surface and its resistance to termite and fungal damage. The main active ingredient compounds that are responsible for these action are tectoquinone, lapachol and deoxylapachol. Naphthoquinones, anthraquinones and isoprenoid quinones are abundant metabolites in teak. In addition to these, teak contains several other phytochemicals such as triterpenoids, steroids, lignans, fatty esters and phenolic compounds. Pharmacologically, the plant has been investigated for antioxidant, anti-inflammatory, anti-pyretic, cytotoxic, analgesic, hypoglycemic, wound healing and antiplasmodial activities. The present review highlights the phytochemical and pharmacological aspects of teak. PMID- 29506392 TI - Background and rationale of the eXalt3 trial investigating X-396 in the treatment of ALK+ non-small-cell lung cancer. AB - Despite significant advancements in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) since the advent of crizotinib, the development of acquired resistance and poor CNS efficacy have necessitated the search for novel and more robust therapies. Ensartinib (X-396) is a novel second-generation ALK-tyrosine kinase inhibitor (TKI) that holds much clinical promise. Preclinical data have demonstrated increased potency of the drug as compared with crizotinib and other second-generation ALK-TKI therapies such as alectinib and ceritinib. This review highlights the first- and second-generation ALK inhibitors approved for the treatment of ALK-positive NSCLC and discusses the clinical trial protocol for the eXalt3 trial (NCT02767804) comparing the efficacy and safety of ensartinib to crizotinib in patients diagnosed with ALK-positive NSCLC who are naive to prior ALK-TKI treatment. PMID- 29506391 TI - Increased kynurenine plasma concentrations and kynurenine-tryptophan ratio in mild-to-moderate chronic obstructive pulmonary disease patients. AB - AIM: Since an increase in kynurenine (Kyn) plasma concentrations has been proposed as marker of immune system activation, we studied the associations between the Kyn levels and presence and severity of chronic obstructive pulmonary disease (COPD). METHODS & RESULTS: Plasma Kyn, tryptophan (Trp) and Kyn/Trp ratio were measured in 43 COPD patients with clinically defined mild (n = 29) or moderate (n = 14) disease and 43 age- and sex-matched healthy controls. When compared with controls, COPD patients had significantly higher plasma Kyn concentrations and Kyn/Trp ratios. In multiple logistic regression analysis, after adjusting for clinical and demographic confounders, the Kyn/Trp ratio was independently associated with COPD severity. DISCUSSION & CONCLUSION: Kyn and Kyn/Trp ratio might represent a new, sensitive, biomarker of systemic inflammation in COPD patients. PMID- 29506393 TI - Psychosocial predictors of mammography history among Chinese American women without a recent mammogram. AB - Chinese American women have lower rates of mammography screening compared with non-Hispanic White women. Although the extent of perceived barriers, as conceptualized by the Health Belief Model, have been shown to distinguish between currently non-adherent Chinese American women who have ever and never had a mammogram, it is less clear which types of perceived barriers differentiate them. One hundred twenty-eight Chinese American women in the New York metropolitan area who had not had a mammogram in the past year completed baseline assessments for a mammography framing intervention study. Demographics, medical access variables, and perceived barriers to mammography (lack of access, lack of need for screening, and modesty) were used to predict mammography history (ever versus never screened). Fifty-five women (43%) reported having been screened at least once. A sequential logistic regression showed that English speaking ability and having health insurance significantly predicted mammography history. However, these control variables became non-significant when the three barrier factors were included in the final model. Women who reported a greater lack of access (OR = 0.36, p < .05) and greater lack of need (OR = 0.27, p < .01) were less likely to be ever screeners. Unexpectedly, women who reported greater modesty were more likely to be ever screeners (OR = 4.78, p < .001). The results suggest that interventions for Chinese American women should identify and target specific perceived barriers with consideration of previous adherence. PMID- 29506394 TI - Rolled Tendon Allograft Interposition Arthroplasty for Salvage Surgery of the Hallux Metatarsophalangeal Joint. AB - BACKGROUND: Hallux rigidus is a common osteoarthritic disease of the first metatarsophalangeal joint (MTPJ). Few salvage treatment options exist that preserve motion for patients who have failed an initial procedure and who are not amenable to fusion, typically patients who are active or who would like to wear high heels. Allograft tendon interpositional arthroplasty is an unconventional salvage treatment option that may preserve motion and prevent bone loss. METHODS: A retrospective chart review is reported of 19 patients who failed previous procedures and refused fusion who underwent allograft tendon interpositional arthroplasty of the hallux MTPJ by a single surgeon between 2012 and 2015. Outcomes included the American Orthopaedic Foot & Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal scale assessment as well as measurement of apparent joint space on anterior to posterior and lateral views. RESULTS: The cumulative average AOFAS score for all patients was 68.5 preoperatively and 74.1 postoperatively. The average AOFAS pain subscore was 24.7 preoperatively and 26.8 postoperatively (SD = 7.7 and 13.8, respectively). Radiographically, patients had an increase in apparent joint space from pre- to postoperatively, most notable on the lateral view (0.6 to 4.7 mm; SD = 0.7 and 3.2 mm). Five patients required a second operative procedure, for an overall 26% reoperation rate. One patient underwent hallux MTPJ fusion after the interpositional arthroplasty. An additional 4 patients (21%) had symptoms requiring a steroid injection, and another 3 patients (16%) were recommended to undergo a revision procedure based on their symptoms. CONCLUSION: Rolled allograft tendon interposition arthroplasty performed poorly as a salvage strategy for failed previous hallux MTPJ surgery for hallux rigidus because of a high rate of complication and minimal benefits. The senior author has abandoned the technique. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29506395 TI - Opioid Consumption Following Foot and Ankle Surgery. AB - : Background Orthopedic surgeons frequently prescribe pain medications during the postoperative period. The efficacy of these medications at alleviating pain after foot/ankle surgery and the quantity of medication required (and conversely, leftover) are unknown. METHODS: Patients undergoing foot/ankle surgery during a 3 month period who met inclusion criteria were surveyed at their first postoperative visit. Information collected included gender, number of prescribed pills remaining, satisfaction with pain control, and willingness to surrender leftover opioids to a Drug Enforcement Administration (DEA) disposal center. Additional data, including utilization of a perioperative nerve block and type (bony versus nonbony) and anatomic region of procedure, were collected through review of the medical record. All data were analyzed in a retrospective fashion. A total of 171 patients with a mean age of 53.1 +/- 15.5 years (range, 18-81 years) were included in the study. RESULTS: The mean number of opioids taken was 27.2 +/- 17.5 pills (range, 0-70). The mean number of short-acting opioids and long-acting opioids taken was 21.4 +/- 14.8 and 9.2 +/- 5.0 pills, respectively. Most (73.5%) patients were satisfied with their pain control. Patients who underwent ankle/hindfoot surgery took more long-acting opioids on average than others ( P = .047). There was not a significant difference in opioid usage between bony and nonbony procedures. Of those with leftover opioids, 63% were willing to surrender them to a DEA disposal center. Patients willing to surrender leftover medications had both more short-acting ( P < .001) and long-acting ( P = .015) opioids leftover than those not willing to surrender them. CONCLUSION: Most patients undergoing foot/ankle surgery had opioids leftover at the first postoperative visit, and most were willing to surrender them. We can adequately treat patients' pain and decrease the number of opioid pills available in the community by decreasing the number of pills prescribed and encouraging disposal of leftovers. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29506396 TI - Role of Antiplatelet/Anticoagulant Medications and Blood-Clotting Tests in Prediction of Traumatic Foot Compartment Syndrome. AB - BACKGROUND: Although intracompartmental bleeding is one cause of traumatic compartment syndrome, no previous studies have defined the role of hemostatic stability in the development of traumatic compartment syndrome. Therefore, to investigate this issue, we identified the relationship between antiplatelet/anticoagulant medications and the development of traumatic foot compartment syndrome. In addition, as a possible predictor of compartment syndrome, we evaluated the utility of blood-clotting tests in the prediction of traumatic foot compartment syndrome. METHODS: Retrospective review of patients diagnosed with isolated foot injury in our institution between 2008 and 2016 was used to identify patients who had traumatic foot compartment syndrome. Potential predictors, including medication history for antiplatelet/anticoagulant agents and blood-clotting test results, were analyzed using logistic regression analysis. The present study included 789 feet, and 29 (3.7%) had traumatic foot compartment syndrome. RESULTS: The antiplatelet medication and the blood-clotting test results were not significantly associated with the development of traumatic foot compartment syndrome. Among other variables, damage caused by heavy objects as the injury mechanism was the only significant predictor in the development of traumatic foot compartment syndrome ( P < .05). CONCLUSION: Our results showed that antiplatelet medication and blood-clotting tests did not predict the development of traumatic foot compartment syndrome. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 29506397 TI - Prospective Cohort Study on the Employment Status of Working Age Patients After Recovery From Ankle Arthritis Surgery. AB - BACKGROUND: People who are affected by end-stage ankle arthritis are as disabled as those suffering from arthritis in other main articulations of the lower extremity. Once these patients become unable to perform their job duties, they leave the workforce and require financial aid from government agencies, which represents a considerable economic burden. Regardless of whether arthrodesis or arthroplasty is performed, we hypothesized that patients younger than 55 years at the time of surgery should be able to return to work within 2 years and require less social assistance. METHODS: Patients from 2002 to 2014 included in the nationwide prospective Ankle Reconstruction Database treated for end-stage ankle arthritis with a total ankle replacement or an ankle arthrodesis and younger than 55 years at the time of surgery were included. This study used a standard preoperative survey (AAOS, SF-36) along with the same survey filled by patients in intervals up to 2 years postoperatively. Their employment status was determined at each time point. Participation in third-party wage assistance programs was recorded. This cohort had 194 patients with an average age of 47.0 +/- 7.2 years and was balanced in terms of sex (104 female) and side (94 left). RESULTS: The employment rate prior to surgery was 56%, which increased to 62% at the 2-year postoperative mark. With regards to worker's compensation, disability, and social security, 20% of patients left all subsidized programs whereas 4% entered at least 1 which is significant (P < .05). CONCLUSION: The 2-year follow up after tibiotalar arthrodesis/arthroplasty in patients younger than 55 years showed that significantly more people were able to leave subsidized work assistance programs than enroll in them. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 29506398 TI - Tardive dyskinesia responsive to deep brain stimulation. PMID- 29506400 TI - Prevention of mental disorders requires action on adverse childhood experiences. AB - The increased availability of treatment has not reduced the prevalence of mental disorders, suggesting a need for a greater emphasis on prevention. With chronic physical diseases, successful prevention efforts have focused on reducing the big risk factors. If this approach is applied to mental disorders, the big risk factors are adverse childhood experiences, which have major effects on most classes of mental disorder across the lifespan. While the evidence base is limited, there is support for a number of interventions to reduce adverse childhood experiences, including an important role for mental health professionals. Taking action on adverse childhood experiences may be our best chance of emulating the success of public health action to prevent chronic physical diseases and thereby reduce the large global burden of mental disorders. PMID- 29506399 TI - Guidelines on treatment of perinatal depression with antidepressants: An international review. AB - OBJECTIVE: Several countries have developed Clinical Practice Guidelines regarding treatment of perinatal depressive symptoms and perinatal use of antidepressant. We aimed to compare guidelines to guide clinicians in best clinical practice. METHODS: An extensive search in guideline databases, MEDLINE and PsycINFO was performed. When no guidelines were (publicly) available online, we contacted psychiatric-, obstetric-, perinatal- and mood disorder societies of all first world countries and the five largest second world countries. Only Clinical Practice Guidelines adhering to quality criteria of the Appraisal of Guidelines for Research and Evaluation instrument and including a systematic review of evidence were included. Data extraction focussed on recommendations regarding continuation or withdrawal of antidepressants and preferred treatment in newly depressed patients. RESULTS: Our initial search resulted in 1094 articles. After first screening, 40 full-text articles were screened. Of these, 24 were excluded for not being an official Clinical Practice Guidelines. In total, 16 Clinical Practice Guidelines were included originating from 12 countries. Eight guidelines were perinatal specific and eight were general guidelines. CONCLUSION: During pregnancy, four guidelines advise to continue antidepressants, while there is a lack of evidence supporting this recommendation. Five guidelines do not specifically advise or discourage continuation. For new episodes, guidelines agree on psychotherapy (especially cognitive behavioural therapy) as initial treatment for mild to moderate depression and antidepressants for severe depression, with a preference for sertraline. Paroxetine is not preferred treatment for new episodes but switching antidepressants for ongoing treatment is discouraged (three guidelines). If mothers use antidepressants, observation of the neonate is generally recommended and breastfeeding encouraged. PMID- 29506405 TI - National evaluation of policies governing funding for wheelchairs and scooters in Canada: Evaluation nationale des politiques regissant le financement des fauteuils roulants, des triporteurs et des quadriporteurs au Canada. AB - BACKGROUND: Wheelchairs, scooters, and related equipment are essential for the well-being of individuals with limited mobility and impact participation, health, and quality of life. PURPOSE: Our objective was to identify and evaluate policies governing equipment funding for Canadian adults. We reviewed funding legislation and program documentation for adult Canadians (>=18 years of age) covered by their provincial, territorial, or federal health care plan. Documents were obtained online or through administrative staff. Policy evaluation was guided by the Disability Policy Lens from the Canadian Disability Policy Alliance. KEY ISSUES: Coverage ranges from full funding for all individuals within the jurisdiction to programs limited by strict eligibility criteria. Each jurisdiction defines "disability" or "basic/essential need" differently, contributing to further funding disparities. IMPLICATIONS: Funding policies differ substantially across Canada, resulting in unequal access to equipment dependent on province or territory. We identified eligibility, funding, definitions of mobility, repair and replacement, and prescriber requirement benchmarks that represent policy targets for improved access. PMID- 29506406 TI - La spiritualite et la metaphore de la voiture autonome. PMID- 29506407 TI - Spirituality and the metaphorical self-driving car. PMID- 29506408 TI - Occupational transition in the process of becoming housed following chronic homelessness: La transition occupationnelle liee au processus d'obtention d'un logement a la suite d'une itinerance chronique. AB - BACKGROUND: Studying the occupations of formerly homeless persons as they transition to becoming housed following long-term homelessness has the potential to offer a meaningful contribution to the ongoing dialogue on homelessness. PURPOSE: Occupational transition was explored with a sample of persons with a history of chronic homelessness to contribute an occupational perspective to current scholarship on homelessness and to inform the practice of occupational therapists who support this population. METHOD: Interpretive phenomenology guided the study. Eleven persons with a history of chronic homelessness were engaged in semistructured interviews 3 to 24 months after becoming housed. FINDINGS: Six themes emerged that highlighted occupation as a means of promoting social and psychological integration, and the meaning and experience of occupational transition. IMPLICATIONS: A more comprehensive support strategy acknowledging the occupations of chronically homeless persons is essential to incorporate into future research and practice aimed at promoting community inclusion and housing retention. PMID- 29506409 TI - College students' experiences of hedonia and eudaimonia in their everyday activities: Degres d'hedonisme et d'eudemonisme eprouves par des etudiants du niveau universitaire au fil de leurs activites quotidiennes. AB - BACKGROUND: Experiences of hedonia (i.e., seeking pleasure) and eudaimonia (i.e., actualizing human potential in pursuit of meaningful goals) are central to the study of human well-being. PURPOSE: This study sought to examine levels of hedonia (pleasure) and eudaimonia (productivity) in a convenience sample of college (university) students' ( n = 264) daily activities, controlling for levels of perceived stress. METHOD: Data were gathered using a 24-hr time-use recall diary designed to assess objective and subjective information about everyday activities. Descriptions of self-reported everyday activities were coded into 20 activity types. FINDINGS: Activities reported high in pleasure were eating, listening to music/watching movies, and exercise. Activities reported as high in productivity were studying and working. Activities reported as high in both pleasure and productivity were reported less frequently and often had a recognizable outcome or provided social connection. IMPLICATIONS: Developing a greater understanding of how college students experience their daily activities could strengthen programs designed to enable students to manage stress and sustain their well-being. PMID- 29506410 TI - ? PMID- 29506411 TI - Fall determinants and home modifications by occupational therapists to prevent falls: Facteurs determinants des chutes et modifications du domicile effectuees par les ergotherapeutes pour prevenir les chutes. AB - BACKGROUND: Approximately one third of older people over 65 years fall each year. Home modifications may decrease occurrence of falls. PURPOSE: This study aims to determine the risk factors of falls for frail older persons and to evaluate the impact of home modifications by an occupational therapist on the occurrence of falls. METHOD: We conducted a longitudinal study using a quasiexperimental design to examine occurrence of falls. All participants 65 years of age and older and were assessed at baseline and 6 months after the intervention. Bivariate analysis and logistic regression models were used to study the risk factors of falls and the effect of home modifications on the incidence of falls. FINDINGS: The main predictors of falls were vision problems, distress of informal caregiver, and insufficient informal support. Home modifications provided by an occupational therapist showed a significant reduction of falls. IMPLICATIONS: Informal caregivers and their health status had an impact on the fall risk of frail older persons. Home modifications by an occupational therapist reduced the fall risk of frail older persons at 6-months follow-up. PMID- 29506414 TI - Pharmacokinetics of multiple doses of teicoplanin in Chinese elderly critical patients. AB - BACKGROUND: The dose-effect relationship of teicoplanin has been a hot topic of clinical concern, but there was lack of the evidence of Chinese patients to optimize dosage, especially in elderly critical patients, whose plasma protein, liver and kidney function are greatly different from ordinary patients. METHODS: Elderly critical patients were divided into high-dose(800mg), medium-dose (600mg) and low-dose (400mg) groups, which consisted of 6 cases of each group. Three groups were taken intravenous blood at different times after the last administration of teicoplanin to measure teicoplanin plasma concentration. RESULTS: The t1/2 of high-dose, middle-dose and low-dose groups were 70.76 +/- 11.72h, 73.60 +/- 9.48h, 80.24 +/- 6.75h, respectively; CL were 0.14 +/- 0.09mL ? h-1 ? kg-1, 0.11 +/- 0,05mL ? h-1 ? kg-1, 0.12 +/- 0.06mL ? h-1 ? kg-1 respectively. The Cmax and AUC0-t of the three dose groups were linearly correlated with the dose. CONCLUSIONS: In Chinese elderly critical patients, t1/2 of teicoplanin was consistent with that of literatures published, however, CL were higher. The pharmacokinetics of teicoplanin at the range of 400 ~ 800mg is linear pharmacokinetics, indicating that the dosage regimens for patients were more simply and accurately adjusted according to therapeutic drug monitoring. PMID- 29506415 TI - Neophyte experiences of football (soccer) match analysis: a multiple case study approach. AB - Performance analysis is extensively used in sport, but its pedagogical application is little understood. Given its expanding role across football, this study explored the experiences of neophyte performance analysts. Experiences of six analysis interns, across three professional football clubs, were investigated as multiple cases of new match analysis. Each intern was interviewed after their first season, with archival data providing background information. Four themes emerged from qualitative analysis: (1) "building of relationships" was important, along with trust and role clarity; (2) "establishing an analysis system" was difficult due to tacit coach knowledge, but analysis was established; (3) the quality of the "feedback process" hinged on coaching styles, with balance of feedback and athlete engagement considered essential; (4) "establishing effect" was complex with no statistical effects reported; yet enhanced relationships, role clarity, and improved performances were reported. Other emic accounts are required to further understand occupational culture within performance analysis. PMID- 29506416 TI - Precise nanoinjection delivery of plasmid DNA into a single fibroblast for direct conversion of astrocyte. AB - Direct conversion is a powerful approach to safely generate mature neural lineages with potential for treatment of neurological disorders. Astrocytes play a crucial role in neuronal homeostasis and their dysfunctions contribute to several neurodegenerative diseases. Using a single-cell approach for precision, we describe here a robust method using optimized DNA amounts for the direct conversion of mouse fibroblasts to astrocytes. Controlled amount of the reprogramming factors Oct4, Sox2, Klf4 and cMyc was directly delivered into a single fibroblast cell. Consequently, 2500 DNA molecules, no more or less, were found to be the optimal amount that dramatically increased the expression levels of the astrocyte-specific markers GFAP and S100b and the demethylation gene TET1, the expression of which was sustained to maintain astrocyte functionality. The converted astrocytes showed glutamate uptake ability and electrophysiological activity. Furthermore, we demonstrated a potential mechanism whereby fibroblast was directly converted into astrocyte at a single-cell level; this was achieved by activating BMP2 pathway through direct binding of Sox2 protein to BMP2 gene. This study suggests that nanotechnology for directly injecting plasmid DNAs into cell nuclei may help understand such a conversion at single-cell level. PMID- 29506417 TI - Building a Tribal-Academic Partnership to Address PTSD, Substance Misuse, and HIV Among American Indian Women. AB - OBJECTIVES: To describe our partnership and research infrastructure development strategies and discuss steps in developing a culturally grounded framework to obtain data and identify a trauma-informed evidence-based intervention. METHOD: We present funding strategies that develop and maintain the partnership and tools that guided research development. We share how a community research committee was formed and the steps taken to clarify the health concern and develop a culturally tailored framework. We present results from our needs/assets assessment that led to the selection of a trauma-informed intervention. Finally, we describe the agreements and protocols developed. RESULTS: We produced a strong sustainable research team that brought program and research funding to the community. We created a framework and matrix of program objectives grounded in community knowledge. We produced preliminary data and research and publication guidelines that have facilitated program and research funding to address community-driven concerns. CONCLUSIONS: This study highlights the importance of bidirectional collaboration with American Indian communities, as well as the time and funding needed to maintain these relationships. A long-term approach is necessary to build a sustainable research infrastructure. Developing effective and efficient ways to build culturally based community research portfolios provides a critical step toward improving individual and community health outcomes. PMID- 29506418 TI - HCV in Egypt, prevention, treatment and key barriers to elimination. AB - INTRODUCTION: Currently, direct-acting antivirals (DAAs) are considered the ideal choice for the treatment of chronic HCV patients due to their proven efficacy (SVR> 90%), and minimal adverse effects. Egypt launched a large treatment program aimed at providing treatment coverage for Egyptian HCV- infected patients. Areas covered: This review covers the treatment and prevention efforts made by the Egyptian National Committee for the Control of Viral Hepatitis (NCCVH) with the available model of care for HCV patients in Egypt, in addition to the barriers that prevent elimination of HCV from Egypt. Expert commentary: Egypt could provide a model for establishing the largest HCV management system aimed at eliminating HCV from the country with the highest worldwide prevalence. Despite the huge efforts and achieved results in combating the HCV epidemic in Egypt, certain improvements are needed in order to attain HCV elimination, such as the development of an enhanced screening program working in parallel to the present treatment options. PMID- 29506420 TI - Maternal serum advanced glycation end products level as an early marker for predicting preterm labor/PPROM: a prospective preliminary study. AB - OBJECTIVE: To evaluate the value of maternal serum advanced glycation end products (AGEs) level at 11-13 weeks' gestation for the prediction of preterm labor and or preterm premature rupture of membranes (PPROM). MATERIALS AND METHODS: This prospective cross-sectional study is performed in a university affiliated hospital between February and April 2016. The participants of this study are low-risk pregnant women. Blood samples for maternal AGEs level were collected in the first trimester of pregnancy and all women completed their antenatal follow-up and delivered in our center. During the follow-up 21 women developed preterm labor/PPROM. The first trimester maternal AGEs levels of preterm labor/PPROM cases were compared with uncomplicated cases (n = 25) matched for age-parity and BMI. The predictive value of AGEs levels for preterm labor/PPROM was also assessed. RESULTS: First-trimester AGEs levels were significantly higher in cases complicated with preterm labor/PPROM (1832 (415 6682) versus 1276 (466-6445) ng/L, p = .001 and 1722 (804-6682) versus 1343 (466 6445) ng/L, p = .025). According to receiver-operating characteristic curve analysis, the calculated cut off value of AGEs was 1538 ng/L with the sensitivity 91.7%, specificity 73.8%; and the negative and positive predictive values were 91.6% and 29.5%, respectively. CONCLUSIONS: For the prediction of preterm labor/PPROM, the relatively high AGEs levels in the first trimester might be a useful marker. PMID- 29506421 TI - Factors influencing thermal injury to skin and abdominal wall structures in HIFU ablation of uterine fibroids. AB - OBJECTIVE: To investigate the factors which may cause thermal injury of abdominal wall structures in ultrasound-guided high-intensity focussed ultrasound (USgHIFU) ablation of uterine fibroids. METHOD: A total of 892 patients with uterine fibroids diagnosed on contrast-enhanced magnetic resonance imaging (MRI) scans received HIFU ablation and follow-up MRI scanning. After therapy, thermal injury to the skin was assessed via measurement of skin redness, blisters, subcutaneous nodules and to the abdominal wall structures via measurement of signal intensity on T2-weighted MRI images. A total of 151 patients were assigned to the injury group, 741 patients were assigned to the non-injury group. The relationship between patient and treatment parameters and injury were analysed using univariate and multiple logistic regression analyses. RESULTS: Univariate logistic regression revealed that sonication time, sonication time per hour, total energy deposited, distance from uterine fibroid ventral side to skin, volume of uterine fibroids, abdominal wall scar, abdominal wall thickness and body mass index (BMI) all affected whether thermal injury occurred (p < 0.05). Subsequently, multiple logistic regression analysis revealed that total energy (p = 0.000, OR = 2.228, 95% CI 1.831-2.712), abdominal wall scar (p = 0.019, OR = 1.639, 95% CI 1.085-2.477) and abdominal wall thickness (p = 0.000, OR = 1.562, 95% CI 1.313-1.857) were significantly correlated with thermal injury. CONCLUSION: Multiple logistic regression analysis revealed that abdominal wall thickness, total energy and abdominal wall scar were the most significant influencing factors that influenced minimal thermal injury of abdominal wall structures in USgHIFU ablation of uterine fibroids. PMID- 29506419 TI - Lowering minimum eye height to increase peak knee and hip flexion during landing. AB - The purpose was to determine the effect of lowering minimum eye height through an externally focused object on knee and hip flexion and impact forces during jump landing. Kinematics and ground reaction forces were collected when 20 male and 19 female participants performed jump-landing trials with their natural minimum eye height, and trials focusing on lowering their minimum eye height to an external object, which was set at 5% or 10% of standing height lower. Participants demonstrated decreased minimum eye height and increased peak knee and hip flexion during early-landing and stance phase when focusing on lowering eye height to the external object (p < 0.01). Peak vertical ground reaction forces during early landing also decreased for the greater force group (p < 0.001). Jump-landing training through manipulating eye height provides a strategy that involves an external focus and intrinsic feedback, which may have advantages in promoting learning and practical application. PMID- 29506422 TI - DEFB1 polymorphisms and HIV-1 mother-to-child transmission in Zambian population. AB - INTRODUCTION: Human Beta Defensin-1 (hBD-1) is a component of the innate immune system, the first line of defence against pathogens, already reported as involved in the susceptibility to HIV-1 infection and HIV-1 mother-to-child transmission (MTCT) in different populations. We investigated the role of DEFB1 gene (encoding for hBD-1) functional polymorphisms in the susceptibility to HIV-1 MTCT in a population from Zambia. METHODS: Four selected polymorphisms within DEFB1 gene, three at the 5' untranslated region (UTR), namely -52G > A (rs1799946), -44C > G (rs1800972) and -20G > A (rs11362) and one in the 3'UTR, c.*87A > G (rs1800972), were genotyped in 101 HIV-1 positive mothers (26 transmitters -27% and 75 not transmitters -73%) and 331 infants born to HIV-1 infected mothers (85 HIV-1 positive -26% and 246 exposed but not infected -74%). RESULTS: DEFB1 c.*87-A allele was more frequent among HIV- children with respect to HIV+ (with intrauterine MTCT). Concerning DEFB1 haplotypes, GCGA haplotype resulted more represented in HIV- than HIV+ infants and DEFB1 ACGG haplotype presented increased frequency in HIV- children respect to HIV+ (with intra-partum MTCT) (p = .02, p = .002 and p = .006, respectively). CONCLUSIONS: DEFB1 polymorphisms were significantly associated with decreased risk of HIV-1 infection acquisition in the studied Zambian population suggesting that they may play a role in HIV-1 MTCT. PMID- 29506423 TI - Muscle strength characteristics of the hamstrings and quadriceps in players from a high-level youth football (soccer) Academy. AB - The objective of this study was to investigate knee muscle strength characteristics in players from a high-level youth football Academy. In total, 110 players (aged 8-15 years) underwent muscle strength assessments carried out by a research physiotherapist using a computer-linked hand-held dynamometer. Results indicated that isometric hamstrings and quadriceps strength increased with age, whereas the isometric hamstring to quadriceps (H/Q) ratio decreased with age. A number of youth football players (n = 20; 18%; 95% CI: 11-27%) demonstrated isometric H/Q ratios of less than 0.60, as well as muscle strength asymmetries between limbs for the hamstrings (n = 40, 36%; 95% CI: 27-46%) and quadriceps (n = 51, 46%; 95% CI 37-56%), potentially increasing injury risk. This study provides new evidence that the isometric H/Q ratio reduces with advancing age during adolescence which may have important implications for junior athlete development and long-term injury prevention in football. PMID- 29506425 TI - Challenges of breastfeeding in China under its universal two-child policy. PMID- 29506424 TI - Local recurrence rate in patients with colorectal cancer liver metastasis after wedge resection or percutaneous radiofrequency ablation. AB - PURPOSE: To compare local recurrence (LR) rate in patients with colorectal cancer liver metastasis (CRCLM) after surgical wedge resection (WR) or radiofrequency ablation (RFA) and to investigate predictive factors of LR. MATERIALS AND METHODS: This single-centre, retrospective, institutional review board-approved study including 43 consecutive patients with 121 metastases treated by WR and 60 patients with 110 metastases treated by RFA between 2007 and 2014 with 23 and 18.5 months of follow-up, respectively. Demographics and tumour characteristics were compared using the unpaired t-test and chi-square test. Predictive factors for LR (lesion size, depth, relation to hepatic vessels, intervention, margin status) were investigated in uni- and multivariate analyses. RESULTS: Patient and CRCLM characteristics were similar in both groups. Mean lesion size and depth in the WR and RFA groups were 18 mm and 15 mm (p = 0.03), and 19 mm and 26 mm (p < 0.001), respectively. LR showed a trend towards difference in favour of RFA (19% and 10% in the WR and RFA groups, respectively, p = 0.06). Positive margins and lesion depth were predictive factors of LR in the WR group (p = 0.03 and p = 0.02, respectively, on uni- and multivariable analyses). Lesion depth and proximity to a vein increased the risk of positive margins on pathology after WR (p = 0.04 and p < 0.001, respectively). Our analysis did not identify any predictive factors of LR following RFA. CONCLUSION: Our study showed a trend towards a lower LR rate with RFA compared to WR. Lesions located deep in the liver and/or close to large vessels are at high risk of LR following WR, while curative treatment can be obtained with RFA. PMID- 29506426 TI - Which criteria should be used for starting pharmacologic therapy for management of gestational diabetes in pregnancy? Evidence from randomized controlled trials. AB - INTRODUCTION: There is inconclusive evidence to support any specific criteria for starting pharmacologic therapy after diet in women with gestational diabetes mellitus (GDM). We aimed to analyze the most used criteria for starting pharmacologic treatment for patients with GDM. MATERIAL AND METHODS: Electronic databases were searched from their inception to September 2017. We included all the randomized controlled trials (RCTs) of GDM managed initially by diet and exercise reporting criteria for starting pharmacologic therapy. RCTs in women with pregestational diabetes were excluded. Data regarding glucose values used for starting pharmacologic therapy were extracted and carefully reviewed. RESULTS: We included 15 RCTs (4307 women) in the meta-analysis. For fasting glucose target, 8/14 (57%) used a value lower or equal to 90 mg/dL and the remainder used values <99 mg/dL. Of the 10 RCTs targeting 2-h postprandial values, the majority (9/10, 90%) used 120 mg/dL. The majority of RCTs (13/15, 87%) recommended pharmacologic therapy if either 1 or 2 values per 1- or 2-week period were higher than the target values: 7/13 (54%) used 1 value and 6/13 (46%) used 2 values higher than target values. One RCT (7%) used >50% of the values higher than the target values and another one (7%) used >30%. CONCLUSION: The majority of RCTs (87%) used very tight criteria of either 1 or 2 values over the target values in the 1 or 2-week period for starting pharmacologic treatment for patients with GDM; more than 50% used 2 values. Key Message Pharmacologic therapy should be considered in women with gestational diabetes when, despite an adequate diet and exercise, 1 or 2 blood glucose values are over the target values of 90mg/dL fasting or 120mg/dL 2-hour postprandial over 1 or 2 weeks. PMID- 29506427 TI - Skin mechanical properties and modeling: A review. AB - The mechanical properties of the skin are important for various applications. Numerous tests have been conducted to characterize the mechanical behavior of this tissue, and this article presents a review on different experimental methods used. A discussion on the general mechanical behavior of the skin, including nonlinearity, viscoelasticity, anisotropy, loading history dependency, failure properties, and aging effects, is presented. Finally, commonly used constitutive models for simulating the mechanical response of skin are discussed in the context of representing the empirically observed behavior. PMID- 29506428 TI - Targeted sequencing analysis of ACVR2A gene identifies novel risk variants associated with preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is the most common complication of pregnancy that remains to be a major cause of maternal and fetal mortality. Prediction and early diagnosis of PE would allow for timely initiation of preventive therapy. According to recent studies of ACVR2A gene polymorphism is associated with PE, but it is still unclear whether these findings reflect specific pathogenetic mechanisms of this disease. METHODS: We performed targeted next-generation sequencing (NGS) sequencing of ACVR2A gene by means of Ion Torrent Personal Genome machine (PGM) Sequencer. A genetic analysis of patients with PE and control group was performed. Bioinformatics analysis using Polyphen2 (Boston, MA), SIFT (La Jolla, CA), and SnpSift software were used. To select genetic markers in PE patients two additive models and score analysis were applied. RESULTS: Based on the score analysis, we detected two substitutions (rs145399059 and rs17692648) and one insertion insAA at position 148642724 that were associated with PE in our cohorts. We also detected a variant rs17742573 that can be considered as protective against preeclampsia. CONCLUSIONS: Our data suggest that some variants in ACVR2A gene are associated with PE. But more studies are required to reveal the role of ACVR2A gene in the pathogenesis of this disease during pregnancy. PMID- 29506429 TI - Parent ratings of working memory are uniquely related to performance-based measures of secondary memory but not primary memory. AB - INTRODUCTION: Existing evidence suggests that performance- and rating-based measures of working memory (WM) correlate poorly. Although some researchers have interpreted this evidence as suggesting that these measures may be assessing distinct cognitive constructs, another possibility is that rating-based measures are related to some but not all theoretically motivated performance-based measures. The current study distinguished between performance-based measures of primary memory (PM) and secondary memory (SM), and examined the relation between each of these components of WM and parent-ratings on the WM subscale of the Behavior Rating Inventory of Executive Function (BRIEF-WM). Because SM and BRIEF WM scores have both been associated with group differences in attention deficit/hyperactivity disorder (ADHD), it was hypothesized that SM scores would be uniquely related to parent-rated BRIEF-WM scores. METHOD: Participants were a sample of 77 adolescents with and without an ADHD diagnosis, aged 11 to 15 years, from a midwestern school district. Participant scores on verbal and spatial immediate free recall tasks were used to estimate both PM and SM capacities. Partial correlation analyses were used to evaluate the extent to which estimates of PM and SM were uniquely related parent-rated BRIEF-WM scores. RESULTS: Both verbal and spatial SM scores were significantly related to parent-rated BRIEF-WM scores, when corresponding PM scores were controlled. Higher verbal and spatial SM scores were associated with less frequent parent-report of WM-related failures in their child's everyday life. However, neither verbal nor spatial PM scores significantly related to parent-rated BRIEF-WM scores, when corresponding SM scores were controlled. CONCLUSION: The current study suggested that previously observed low correlations between performance- and rating-based measures of WM may result from use of performance-based WM measures that do not capture the unique contributions of PM and SM components of WM. PMID- 29506430 TI - Pregnancy and hemodialysis access: A case for patient satisfaction in favor of a tunneled dialysis catheter. AB - While an arteriovenous fistula is the best available access, many patients continue to rely on a tunneled hemodialysis catheter for dialysis therapy. Despite the highest risk of catheter-related bacteremia and associated morbidity and mortality, patients often prefer tunneled hemodialysis catheter to avoid pain associated with cannulation of an arteriovenous access. We report three tunneled hemodialysis catheter-dependent end-stage renal disease patients (age: 38, 35, 33 years), who became pregnant. Pregnancy was discovered at 10, 12 and 10 weeks of gestation. All three patients were switched to daily hemodialysis (six sessions/week) as soon as the pregnancy was discovered. The three patients had refused the placement of an arteriovenous access and expressed their strong preference for tunneled hemodialysis catheter. All had been educated about the risks and benefits of catheter, grafts, and fistulas. Patient preference was acknowledged and dialysis therapy was continued with tunneled hemodialysis catheter. Pregnancy was uneventful in two patients with the delivery of a healthy baby. The third patient had a miscarriage. Patient preference for tunneled hemodialysis catheter and satisfaction is important and can result in a successful outcome in pregnant patients. Nonetheless, in keeping with the National Kidney Foundation guidelines as well as the Fistula First, an arteriovenous fistula should be offered to hemodialysis patients. At the same time, patient's preference and wish should be respected and followed. PMID- 29506431 TI - The relationship between resilience and quality of life in patients with a drainage enterostomy. AB - Impact and adjustment to a drainage enterostomy are measured mainly through health indicators. To investigate the relationship between resilience and adaptation to the placement of a drainage enterostomy. Prospective observational study with a sample of 125 patients (64 men/36 women) with a temporary or permanent drainage enterostomy and a mean age of 66.72 years. High quality of life (mean, 80.5) and resilience (mean, 79.57) scores and a positive relationship between both were found. There seems to be a positive relationship with general quality of life and health-related quality of life. The logistic regression model shows that the main predictor as regards health-related quality of life is resilience. PMID- 29506437 TI - Adult-onset Still's disease with prominent polyserositis. AB - Adult-onset Still's disease is a systemic autoinflammatory disease the presentation of which can often mimic infection. As a consequence, there is often a delay in diagnosis. Serositis is a recognised but less common clinical feature that can result in complications including cardiac tamponade and constrictive pericarditis. We describe a case of adult-onset Still's disease without the hallmark rash or significant arthritis, presenting with polyserositis that showed a good response to initial steroid treatment and sustained remission with anakinra. An elevated procalcitonin level was due to active adult-onset Still's disease, not bacterial infection. PMID- 29506436 TI - High-throughput tool to discriminate effects of NMs (Cu-NPs, Cu-nanowires, CuNO3, and Cu salt aged): transcriptomics in Enchytraeus crypticus. AB - The current testing of nanomaterials (NMs) via standard toxicity tests does not cover many of the NMs specificities. One of the recommendations lays on understanding the mechanisms of action, as these can help predicting long-term effects and safe-by-design production. In the present study, we used the high throughput gene expression tool, developed for Enchytraeus crypticus (4 * 44k Agilent microarray), to study the effects of exposure to several copper (Cu) forms. The Cu treatments included two NMs (spherical and wires) and two copper salt treatments (CuNO3 spiked and Cu salt field historical contamination). To relate gene expression with higher effect level, testing was done with reproduction effect concentrations (EC20, EC50), using 3 and 7 days as exposure periods. Results showed that time plays a major role in the transcriptomic response, most of it occurring after 3 days. Analysis of gene expression profiles showed that Cu-salt-aged and Cu-nanowires (Nwires) differed from CuNO3 and Cu nanoparticles (NPs). Functional analysis revealed specific mechanisms: Cu-NPs uniquely affected senescence and cuticle pattern formation, which can result from the contact of the NPs with the worms' tegument. Cu-Nwires affected reproduction via male gamete generation and hermaphrodite genitalia development. CuNO3 affected neurotransmission and locomotory behavior, both of which can be related with avoidance response. Cu salt-aged uniquely affected phagocytosis and reproductive system development (via different mechanisms than Cu-Nwires). For the first time for Cu (nano)materials, the adverse outcome pathways (AOPs) drafted here provide an overview for common and unique effects per material and linkage with apical effects. PMID- 29506438 TI - West Nile Virus Infection in American Singer Canaries: An Experimental Model in a Highly Susceptible Avian Species. AB - This study investigated the susceptibility of American singer canaries ( Serinus canaria) to West Nile virus (WNV) infection. Adult canaries were inoculated with 105, 102, and 101 plaque forming units (PFU) of WNV. All birds became infected and mortality occurred by 5 days postinoculation. The load of viral RNA as determined by RT-qPCR was dose dependent, and was higher at all doses than the level of viral RNA detected in American crows ( Corvus brachyrhynchos) challenged with 105 PFU of WNV. In a subset of birds, viremia was detected by virus isolation; canaries inoculated with 101 PFU of WNV developed viremia exceeding 1010 PFU/mL serum, a log higher than American crows inoculated with 105 PFU of virus. In canaries euthanized at 3 days postinoculation, WNV was isolated at >107 PFU of virus/100 mg of lung, liver, heart, spleen, and kidney tissues. Pallor of the liver and splenomegaly were the most common macroscopic observations and histologic lesions were most severe in liver, spleen, and kidney, particularly in canaries challenged with 102 and 101 PFU. Immunoreactivity to WNV was pronounced in the liver and spleen. IgG antibodies to WNV were detected in serum by enzyme immunoassay in 11 of 21 (52%) challenged canaries and, in 4 of 5 (20%) of these sera, neutralization antibodies were detected at a titer >= 1:20. American singer canaries provide a useful model as this bird species is highly susceptible to WNV infection. PMID- 29506439 TI - Ecologies of security: On the everyday security tactics of female sex workers in Nairobi, Kenya. AB - This paper highlights important environmental dimensions of HIV vulnerability by describing how the sex trade operates in Nairobi, Kenya. Although sex workers there encounter various forms of violence and harassment, as do sex workers globally, we highlight how they do not merely fall victim to a set of environmental risks but also act upon their social environment, thereby remaking it, as they strive to protect their health and financial interests. In so doing, we illustrate the mutual constitution of 'agency' and 'structure' in social network formations that take shape in everyday lived spaces. Our findings point to the need to expand the focus of interventions to consider local ecologies of security in order to place the local knowledges, tactics, and capacities that communities might already possess on centre stage in interventions. Planning, implementing, and monitoring interventions with a consideration of these ecologies would tie interventions not only to the risk reduction goals of global public health policy, but also to the very real and grounded financial priorities of what it means to try to safely earn a living through sex work. PMID- 29506440 TI - Pseudo-aneurysm caused from banding failure. AB - BACKGROUND: To present a case of banding failure with vessel wall erosion and pseudo-aneurysm creation caused by the suture. CASE REPORT: A 75-year-old male patient was operated for a high-flow fistula (>2 L/min). This was overall the third time that the patient was operated for the same indication since he started dialysis 5 years ago. Standard banding technique with perioperative flow measurements was used, and three separate Prolene sutures tied over 5 and 4.5 mm probes to achieve flow reduction. The operation was successful and first few weeks were uneventful. However, 5-6 weeks postoperatively, the patient felt locally an acute pain that lasted only few seconds and a voluminous aneurysm occurred progressively within the next few weeks. He was observed 2 months after the first operation where a recurrent high-flow fistula was diagnosed and ultrasound examination revealed that the sutures used for banding were into the vessel lumen while a pseudo-aneurysm had occurred at the same level. The patient was re-operated for excision of the aneurysm and flow reduction with tapering of the anastomosis. CONCLUSION: Under certain conditions, the suture used for banding may erode through the vessel wall and get into the lumen. This will result in recurrence of a high-flow fistula. While this has been previously described, the phenomenon was otherwise uneventful. In contrary, in the case presented herein, a potentially threatening pseudo-aneurysm has occurred. PMID- 29506441 TI - Three-dimensional Visualization of Ultrasound Backscatter Statistics by Window modulated Compounding Nakagami Imaging. AB - In this study, the window-modulated compounding (WMC) technique was integrated into three-dimensional (3D) ultrasound Nakagami imaging for improving the spatial visualization of backscatter statistics. A 3D WMC Nakagami image was produced by summing and averaging a number of 3D Nakagami images (number of frames denoted as N) formed using sliding cubes with varying side lengths ranging from 1 to N times the transducer pulse. To evaluate the performance of the proposed 3D WMC Nakagami imaging method, agar phantoms with scatterer concentrations ranging from 2 to 64 scatterers/mm3 were made, and six stages of fatty liver (zero, one, two, four, six, and eight weeks) were induced in rats by methionine-choline-deficient diets (three rats for each stage, total n = 18). A mechanical scanning system with a 5 MHz focused single-element transducer was used for ultrasound radiofrequency data acquisition. The experimental results showed that 3D WMC Nakagami imaging was able to characterize different scatterer concentrations. Backscatter statistics were visualized with various numbers of frames; N = 5 reduced the estimation error of 3D WMC Nakagami imaging in visualizing the backscatter statistics. Compared with conventional 3D Nakagami imaging, 3D WMC Nakagami imaging improved the image smoothness without significant image resolution degradation, and it can thus be used for describing different stages of fatty liver in rats. PMID- 29506442 TI - The Impact of an Aging Population in the Workplace. AB - : According to the Centers for Disease Control and Prevention, the number of people 65 years of age or older living in the United States is projected to double by 2030 to 72 million adults, representing 20% of the total U.S. POPULATION: Evidence suggests that older Americans are working longer and spending more time on the job than their peers did in previous years. The increased number of older adults working longer is observed not only in the Unites States but also worldwide. There are numerous ramifications associated with the changing demographics and the expanding prevalence of an aging population in the workforce. Dynamics that arise include stereotyping and discrimination, longevity and on-site expert knowledge, variances in workplace behavior, a multigenerational employee pool, chronic disease management, occupational safety, and the application of adaptive strategies to reduce injury occurrences. Occupational health nurses play a pivotal role in implementing best practices for an aging-friendly workplace. PMID- 29506443 TI - Adaptive Changes in the Self-Concept During a Life Transition. AB - Theories about the self-concept suggest that different aspects of the self are organized according to importance, or psychological centrality. The ways in which psychological centrality can change and how these changes are associated with psychological well-being were investigated in a sample of aging women who had experienced community relocation. The self-concept was measured before and after the move, with regard to five life domains (health, family, friends, economics, and daily activities). It was hypothesized that well-being is maximized by increasing the psychological centrality of life domains in which one is doing well and by lowering the psychological centrality of life domains in which one is doing poorly. The hypothesized, adaptive psychological centrality shifts emerged in the health and friends domains for select outcome measures. Centrality shifts with different patterns of directionality were observed for the other three domains and are interpreted as reflecting problem-focused coping. PMID- 29506444 TI - Dispositional Attributions Require the Joint Application of the Methods of Difference and Agreement. AB - Denis J. Hilton, Richard H. Smith, and Sung Hee Kim proposed in 1995 that making dispositional inferences requires the use of John Stuart Mill's method of agreement. However, their data were based on "incomplete"information that may have obscured the use of Mill's method of difference. Consistent with this suspicion, a study with "complete" information revealed the joint operation of both Mill's methods. Dispositions to the actor required not only low distinctiveness but also low consensus, whereas dispositions to the stimulus required not only high consensus but also high distinctiveness. In contrast, causal explanations to the person, stimulus, or occasion were determined by the method of difference only. PMID- 29506445 TI - Implementation Intentions and the Theory of Planned Behavior. AB - This study concerns the implications of Peter Gollwitzer's concept of implementation intentions for Icek Ajzen's theory of planned behavior. Attitude, subjective norm, perceived behavioral control, and intentions were assessed before an intervention that required subjects to make implementation intentions concerning when and where they would perform breast self-examination during the next month. Behavior was assessed by self-report 1 month later. Results supported Gollwitzer's contention that goal intentions that have been supplemented by implementation intentions concerning where and when the behavior is to be performed are more likely to be enacted. Evidence suggested that implementation intentions were effective because they provided a mechanism that facilitated the retrieval of intentions in memory. Implementation intentions also reduced the capacity of past behavior to predict future behavior, suggesting that implementation intentions mimic the effect of habit in human action. Implications for applications of models of attitude-behavior relations are outlined. PMID- 29506446 TI - Thinking about Choking? Attentional Processes and Paradoxical Performance. AB - When pressure to perform is increased, individuals commonly perform worse than if there were no pressure ("choking under pressure'). Two mechanisms have been proposed to account for this effect-distraction (cognitive load), wherein pressure distracts attention from the task, and self focus, wherein attention shifts inward interfering with performance. To distinguish between these two competing explanations, the current experiment manipulated pressure by offering performance-contingent rewards. For half the participants, cognitive load was increased by requiring participants to count backward from 100. Additionally, adaptation to self awareness was manipulated by videotaping half the participants during practice trials. Results show that pressure caused choking when participants were not distracted and had not been adapted to self awareness. This effect was attenuated when cognitive load was increased or when self-awareness adaptation had occurred. These results support self focus mediated misregulation as the mechanism for choking and disconfirm the distraction hypothesis. PMID- 29506447 TI - Attention-Grabbing Vocal Signals: Impact on Information Processing and Expectations. AB - Adults listened to children's verbalizations that differed in fundamental frequency (fo) or pitch, a vocal quality that has potential attention-eliciting properties. Undergraduate women listened to child messages in anticipation of a teaching interaction. As predicted, higher recall was shown for child messages accompanied by high fo than low fo; this advantage was, however, limited to younger children. Additionally, listeners showed differential expectations for their teaching success on the combined basis of child fo and their own perceptions of perceived social control (PC). As predicted, low-PC teachers expected that interactions with high-fo children would be relatively unsuccessful, whereas interactions with low-fo children would be relatively easy. Results are interpreted as reflecting differential reactions to the demands of dependent others based on cognitive representations of such relationships. PMID- 29506448 TI - Collective Self-Esteem as a Mediator of the Relationship between Allocentrism and Subjective Well-Being. AB - The present studies examined the relationship between allocentrism and subjective well-being. In addition, the mediational role of collective self-esteem for ascribed and acquired groups was tested. Study 1 showed that the reliable relation between allocentrism and life satisfaction was mediated by private, public, and membership collective self-esteem. Study 2 showed that once personal self-esteem was controlled, only private and public collective self-esteem mediated the relation between allocentrism and subjective well-being. PMID- 29506449 TI - Romantic Popularity and Mate Preferences: A Peer-Nomination Study. AB - In their quest to understand romantic relationships, researchers have extensively examined mate preferences. Self-report methods have been most commonly employed. In this study, the authors used a methodology not employed in other studies to date. First, they used peer reports of dating popularity to assess the extent to which individuals of varying qualities are romantically pursued by opposite-sex individuals. Second, the authors obtained peer nominations of a variety of qualities that self-report studies of mate preferences indicate may be important. Results revealed that romantically popular men are physically attractive, outgoing, and seen as trendsetters. Romantically popular women were also viewed as physically attractive and as trendsetters. In contrast to the self-report literature, men who were seen as having most potential for financial success were not particularly popular. Results are discussed with respect to the self-reported preferences literature. PMID- 29506450 TI - Avoidance Personal Goals and Subjective Well-Being. AB - The present research comprises two studies designed to investigate both antecedents and consequences of pursuing avoidance (relative to approach) personal goals over the course of a semester-long period. Results revealed that neuroticism was positively related to the adoption of avoidance personal strivings (Study 1), and participants with low perceptions of their life skills were more likely to adopt avoidance personal projects (Study 2). Avoidance regulation proved deleterious to both retrospective and longitudinal subjective well-being (SWB), as participants with a greater proportion of avoidance goals reported lower SWB over the course of the semester and evidenced a decrease in SWB from the beginning to the end of the semester. Ancillary analyses attested to the robustness of these results across a variety of alternative predictor variables. Path analyses validated perceived progress as a mediator of the direct relationships observed. PMID- 29506451 TI - Purulent Pericarditis Due to Paronychia in a 16-Month-Old Child: A Nail-Biting Story. AB - Purulent pericarditis is a rare infectious disease with significant mortality, even in the modern antibiotic era. The presenting signs can often be subtle and patients can deteriorate rapidly with cardiac tamponade. We report a previously healthy 16-month-old female who developed purulent pericarditis associated with paronychia and sepsis caused by methicillin-sensitive Staphylococcus aureus. In addition to antibiotic treatment, she required emergent pericardiocentesis for cardiac tamponade, followed by two surgical interventions including full median sternotomy incision and partial pericardiectomy. At 4-month follow-up, she did well with no evidence of constrictive pericarditis on echocardiogram. PMID- 29506452 TI - Atypical Left Ventricular Myxoma: Unusual Echocardiographic and Histopathological Features. AB - Cardiac myxomas are the most common primary cardiac tumors and are typically attached to the interatrial septum. Left ventricular myxomas are exceedingly rare and presentation in children is all the more uncommon. We report a case of left ventricular myxoma with very atypical cystic appearance raising an initial suspicion of a hydatid cyst. Subsequently, cardiac magnetic resonance imaging was done, which ruled out the diagnosis of hydatid cyst. Complete surgical excision was done through transaortic and transmitral route. Histopathological examination revealed it to be a cardiac myxoma with vascular proliferation, which on echocardiography had appeared as a polycystic lesion. This is a very unusual histopathological presentation of cardiac myxoma. PMID- 29506453 TI - Left Superior Vena Cava Draining Into Left Atrium in Tetralogy of Fallot-Four Cases of a Rare Association. AB - Persistent left superior vena cava is a common congenital anomaly of the thoracic venous system. Left superior vena cava draining into left atrium is a malformation of sinus venosus and caval system. The anomaly may be a cause of unexplained hypoxia even in adults. It may give rise to various diagnostic and technical challenges during cardiac catheterization and open-heart surgery. It is often detected serendipitously during diagnostic workup. Isolated left superior vena cava opening into left atrium is very commonly associated with other congenital heart defects. But tetralogy of Fallot is very rarely associated with persistent left superior vena cava which drains into left atrium. We report four such cases who underwent surgical correction successfully. PMID- 29506454 TI - Benzoquinone induces ROS-dependent mitochondria-mediated apoptosis in HL-60 cells. AB - Benzene exposure affects the hematopoietic system and leads to the occurrence of various types of leukemia and hematotoxicity. It has been confirmed that active metabolites of benzene, including 1,4-benzoquinone (1,4-BQ), can induce reactive oxygen species (ROS) and apoptosis in the bone marrow, and recent studies have also suggested that benzene exposure can affect mitochondrial function in both experimental animals and cell lines. However, the potential relationship among ROS production, mitochondrial damages, and subsequent apoptosis following benzene exposure has not been well studied in detail. In the present study, we utilized HL-60 cells, a well-characterized human myeloid cell line, as an in vitro model and examined the effects of 1,4-BQ on intracellular ROS formation, mitochondria damage, and the occurrence of apoptotic events with or without using the ROS scavenger N-acetyl-l-cysteine (NAC). The results demonstrated that 1,4-BQ could dose-dependently induce production of ROS and mitochondrial damage as characterized by mitochondrial membrane potential disruption, mitochondrial ultrastructure alteration, and induced apoptosis and activated caspase-3 and caspase-9. Preincubation of HL-60 cells with NAC prior to 1,4-BQ treatment could block 1,4-BQ-induced production of ROS and the occurrence of apoptosis. These results demonstrated that 1,4-BQ induced apoptosis in HL-60 cells through a ROS dependent mitochondrial-mediated pathway. PMID- 29506455 TI - Exposure and nephrotoxicity concern of bismuth with the occurrence of autophagy. AB - Metal nanoparticles or metal-based compounds have drawn attention in various fields ranging from industry to medicine because of their unique physicochemical properties. Bismuth (Bi) compounds and nanomaterials have been commonly used in alloys, electronic industry, batteries, and as flame retardants as well as for anti- Helicobacter pylori therapy, while the nanomaterial form has great potential for computed tomography imaging and thermotherapy, both of which will be introduced in this review. Although Bi was used for several decades, there is a lack of detailed information concerning their toxicity and mechanisms on human health. We described the toxicity of Bi on the kidney that seemed to be relatively known by researchers, while the mechanisms remain unclear. Recently, our group has found that Bi compounds, including bismuth nitrate (BN) and Bi nanomaterials, can induce autophagy in kidney cells. We also extended our findings by selecting five Bi compounds, and the results showed that BN, bismuth oxychloride, bismuth citrate, colloidal bismuth subcitrate, and Bi nanomaterials all induced slight cytotoxicity accompanied with autophagy. Although the role of autophagy in Bi-induced cytotoxicity and kidney injury is under investigation by us, autophagy may help with the exploration of the mechanisms of nephrotoxicity by Bi. PMID- 29506456 TI - Antigonadal and endocrine-disrupting activities of lambda cyhalothrin in female rats and its attenuation by taurine. AB - Lambda cyhalothrin (LCT) is a type II pyrethroid with a wide range of agricultural, industrial, and household uses. Taurine is a nonprotein sulfur containing amino acid as well as a well-known antioxidant and has valuable clinical applications in the detoxification of xenobiotics. The present study evaluated the effect of LCT on the reproductive and endocrine systems of female rats and determined whether taurine might alter these effects. Sexually mature female rats were administered LCT at two different dosages (6.3 mg/kg BW and 11.33 mg/kg BW) once daily by oral gavage for 14 consecutive days with the pretreatment of taurine (50 mg kg-1 BW). LCT treatment resulted in diminished adrenal cholesterol, ovarian 3beta- and 17beta-hydroxysteroid dehydrogenase (HSD) activity with increased ovarian cholesterol, adrenal 3beta- and 17beta-HSD activity. Furthermore, protein and mRNA expressions of ovarian 17beta-HSD and steroidogenic acute regulatory protein were also decreased. Hormonal imbalance was evident by concurrent reduction in the gonadotropic hormone, estradiol, and progesterone levels in LCT-treated rats. These rats also demonstrated the histopathological evidence of degenerative changes in the ovaries. Pretreatment of taurine attenuated the LCT-induced changes. PMID- 29506458 TI - Toxicity of carbon nanotubes: A review. AB - Carbon nanotubes (CNTs) are widely used in the aerospace, automotive, and electronics industries because of their stability, enhanced metallic, and electrical properties. CNTs are also being investigated for biomedical applications such as drug delivery systems and biosensors. However, the toxic potential of CNTs was reported in various cell lines and animal models. The toxicity depends on diverse properties of the CNTs, such as length, aspect ratio, surface area, degree of aggregation, purity, concentration, and dose. In addition, CNTs and/or associated contaminants were well known for oxidative stress, inflammation, apoptosis, pulmonary inflammation, fibrosis, and granuloma in lungs. The increased production of CNTs likely enhanced the possibility of its exposure in people. Studies on the toxicity of CNTs are mainly focused on the pulmonary effects after intratracheal administration, and only a few studies are reported about the toxicity of CNTs via other routes of exposure. So, it is essential to consider the chronic toxicity of CNTs before using them for various biomedical applications. This review focuses on the potential toxicities of CNTs. PMID- 29506457 TI - Effects of volatile organic compounds and carbon monoxide mixtures on learning and memory, oxidative stress, and monoamine neurotransmitters in the brains of mice. AB - In this study, we investigated the effect of inhaled mixtures of volatile organic compounds (VOCs) and carbon monoxide (CO) on neuroethology. Fifty 6-week-old male Kunming mice were exposed in five similar static chambers; zero (control) and four different doses of VOC and CO mixtures (G1-G4) for 10 consecutive days and 2 h/day. The compounds and concentrations were as follows: formaldehyde, benzene, toluene, xylene, and CO as 0.10 + 0.11 + 0.20 + 0.20 + 10.00 mg/m3, 0.20 + 0.22 + 0.40 + 0.40 + 20.00 mg/m3, 1.00 + 1.10 + 2.00 + 2.00 + 100.00 mg/m3, and 5.00 + 5.50 + 10.00 + 10.00 + 500.00 mg/m3, respectively, which corresponded to 1, 2, 10, and 50 times the indoor air quality standard in China. Morris water maze and grip strength tests were performed during the exposure experiment. One day following the final exposure, oxidative damage levels, monoamine neurotransmitters, monoamine oxidase (MAO), and morphology of mice brain were analyzed. Escape latency, dopamine, norepinephrine (NE), and serotonin decreased significantly, while total antioxidant capacity, glutathione peroxidase, and MAO increased significantly in G3 and G4. In addition, there were morphological changes and degeneration of neurons in the dentate gyrus regions of the hippocampus in G4. Results showed that the inhaled mixtures of VOCs and CO affected learning and memory of mice. The impairment of monoamine neurotransmitter associated with MAO may be one of the mechanisms of learning and memory impairment of the mice induced by the mixtures of VOCs and CO. PMID- 29506459 TI - A pilot study: a teaching electronic medical record for educating and assessing residents in the care of patients. AB - OBJECTIVE: We tested a novel, web-based teaching electronic medical record to teach and assess residents' ability to enter appropriate admission orders for patients admitted to the intensive care unit. The primary objective was to determine if this tool could improve the learners' ability to enter an evidence based, comprehensive initial care plan for critically ill patients. METHODS: The authors created three modules using de-identifed real patient data from selected patients that were admitted to the intensive care unit. All senior residents (113 total) were invited to participate in a dedicated two-hour educational session to complete the modules. Learner performance was graded against gold standard admission order sets created by study investigators based on the latest evidence based medicine and guidelines. RESULTS: The session was attended by 39 residents (34.5% of invitees). There was an average improvement of at least 20% in users' scores across the three modules (Module 3-Module 1 mean difference 22.5%; p = 0.001 and Module 3-Module 2 mean difference 20.3%; p = 0.001). Diagnostic acumen improved in successive modules. Almost 90% of the residents reported the technology was an effective form of teaching and would use it autonomously if more modules were provided. CONCLUSIONS: In this pilot project, using a novel educational tool, users' patient care performance scores improved with a high level of user satisfaction. These results identify a realistic and well-received way to supplement residents' training and assessment on core clinical care and patient management in the face of duty hour restrictions. PMID- 29506461 TI - A medical student perspective on sexual history-taking: doing it for the first time. PMID- 29506460 TI - Clinical pulmonary infection score and a spot serum procalcitonin level to guide discontinuation of antibiotics in ventilator-associated pneumonia: a study in a single institution with high prevalence of nonfermentative gram-negative bacilli infection. AB - : Background We wanted to determine the impact of combined Clinical Pulmonary Infection Score (CPIS) and a spot serum procalcitonin (PCT)-guided protocol to shorten the duration of antibiotic treatment in patients with ventilator associated pneumonia (VAP), mainly caused by nonfermentative gram-negative bacilli (NF-GNB). Methods Patients with VAP who received appropriate antibiotics for 7 days, temperature ? 37.8 degrees C, without shock, and CPIS ? 6 were allocated to the PCT group or conventional group according to the treating physicians' decisions. In the PCT group, antibiotics were stopped if the PCT level on day 8 < 0.5 ng/ml. In the conventional group, antibiotics were stopped according to physicians' discretion. Results There were 24 patients in the PCT group and 26 patients in the conventional group. NF-GNB were responsible for VAP in 79.2% of the PCT group and 65.4% of the conventional group. PCT group had a greater number of antibiotic-free days alive during the 28 days after VAP onset than the conventional group (14.6 +/- 5.4 days versus 5.9 +/- 5.7 days, respectively; p <.001). In the multivariate, propensity score-adjusted analysis, the PCT group [coefficient = -9.1 (-12.2 to -6); p <.001] and extrapulmonary infections [coefficient = 6.4 (3.3-9.5); p <.001] were independent predictors of total antibiotic exposure days. There was no relapse in both groups. Meanwhile, 12.5% of the PCT group and 26.9% of the conventional group subsequently developed recurrent VAP compatible with superinfections. Conclusions CPIS and a spot serum PCT level appeared effective and safe to guide discontinuation of antibiotic treatment in patients with VAP caused by NF-GNB. TRIAL REGISTRATION: TCTR20160726002. PMID- 29506462 TI - Child anthropometry data quality from Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and National Nutrition Surveys in the West Central Africa region: are we comparing apples and oranges? PMID- 29506463 TI - Motorcycle helmets and cervical spine injuries: a 5-year experience at a Level 1 trauma center. AB - OBJECTIVE Motorcycle helmets have been shown to decrease the incidence and severity of traumatic brain injury due to motorcycle crashes. Despite this proven efficacy, some previous reports and speculation suggest that helmet use is associated with a higher likelihood of cervical spine injury (CSI). In this study, the authors examine 1061 cases of motorcycle crash victims who were treated during a 5-year period at a Level 1 trauma center to investigate the association of helmet use with the incidence and severity of CSI. The authors hypothesized that wearing a motorcycle helmet during a motorcycle crash is not associated with an increased risk of CSI and may provide some protective advantage to the wearer. METHODS The authors performed a retrospective review of all cases in which the patient had been involved in a motorcycle crash and was evaluated at a single Level 1 trauma center in Wisconsin between January 1, 2010, and January 1, 2015. Biometric, clinical, and imaging data were obtained from a trauma registry database. The patients were then divided into 2 distinct groups based on whether or not they were wearing helmets at the time of the accident. Baseline and functional characteristics were compared between the 2 groups. The Student t-test was used for continuous variables, and Pearson's chi-square analysis was used for categorical variables. RESULTS In total, 1061 patient charts were examined containing data on 738 unhelmeted (69.6%) and 323 helmeted (30.4%) motorcycle riders. On average, helmeted riders had a much lower Injury Severity Score (p < 0.001). Cervical spine injury occurred in 114 unhelmeted riders (15.4%) compared with only 24 helmeted riders (7.4%) (p < 0.001), with an adjusted odds ratio of 2.3 (95% CI 1.44-3.61, p = 0.0005). In the unhelmeted group, 10.8% of patients were found to have a cervical spine fracture compared with only 4.6% of patients in the helmeted group (p = 0.001). Additionally, ligamentous injury occurred more frequently in unhelmeted riders (1.9% vs 0.3%, p = 0.04). No difference was found in the occurrence of cervical strain, cord contusion, or nerve root injury (all p > 0.05). CONCLUSIONS The results of this study demonstrate a statistically significant lower likelihood of suffering a CSI among helmeted motorcyclists. Unhelmeted riders sustained a statistically significant higher number of vertebral fractures and ligamentous injuries. The study findings reported here confirm the authors' hypothesis that helmet use does not increase the risk of developing a cervical spine fracture and may provide some protective advantage. PMID- 29506464 TI - A Rare Case Report of Toxic Epidermal Necrolysis Due to Ofloxacin. AB - BACKGROUND: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), also known as Lyell's syndrome, are rare and life-threatening conditions, for which etiopathogenesis, as well as pharmacotherapy, is yet unclear. CASE REPORT: A 45-year-old male patient by chance on re-exposure to Ofloxacin developed Severe Cutaneous Adverse Drug Reaction (SCADR), diagnosed with toxic epidermal necrolysis. His comorbid conditions and systemic complications of TEN lead him to death. In developing countries, where antibiotics especially fluoroquinolones are widely prescribed, a physician should be now vigilant for such kind of SCADRs because of increasing numbers of such kind of reports. PMID- 29506465 TI - Natural language processing in text mining for structural modeling of protein complexes. AB - BACKGROUND: Structural modeling of protein-protein interactions produces a large number of putative configurations of the protein complexes. Identification of the near-native models among them is a serious challenge. Publicly available results of biomedical research may provide constraints on the binding mode, which can be essential for the docking. Our text-mining (TM) tool, which extracts binding site residues from the PubMed abstracts, was successfully applied to protein docking (Badal et al., PLoS Comput Biol, 2015; 11: e1004630). Still, many extracted residues were not relevant to the docking. RESULTS: We present an extension of the TM tool, which utilizes natural language processing (NLP) for analyzing the context of the residue occurrence. The procedure was tested using generic and specialized dictionaries. The results showed that the keyword dictionaries designed for identification of protein interactions are not adequate for the TM prediction of the binding mode. However, our dictionary designed to distinguish keywords relevant to the protein binding sites led to considerable improvement in the TM performance. We investigated the utility of several methods of context analysis, based on dissection of the sentence parse trees. The machine learning based NLP filtered the pool of the mined residues significantly more efficiently than the rule-based NLP. Constraints generated by NLP were tested in docking of unbound proteins from the DOCKGROUND X-ray benchmark set 4. The output of the global low-resolution docking scan was post-processed, separately, by constraints from the basic TM, constraints re-ranked by NLP, and the reference constraints. The quality of a match was assessed by the interface root-mean-square deviation. The results showed significant improvement of the docking output when using the constraints generated by the advanced TM with NLP. CONCLUSIONS: The basic TM procedure for extracting protein-protein binding site residues from the PubMed abstracts was significantly advanced by the deep parsing (NLP techniques for contextual analysis) in purging of the initial pool of the extracted residues. Benchmarking showed a substantial increase of the docking success rate based on the constraints generated by the advanced TM with NLP. PMID- 29506466 TI - Characterization and visualization of RNA secondary structure Boltzmann ensemble via information theory. AB - BACKGROUND: The nearest neighbor model and associated dynamic programming algorithms allow for the efficient estimation of the RNA secondary structure Boltzmann ensemble. However because a given RNA secondary structure only contains a fraction of the possible helices that could form from a given sequence, the Boltzmann ensemble is multimodal. Several methods exist for clustering structures and finding those modes. However less focus is given to exploring the underlying reasons for this multimodality: the presence of conflicting basepairs. Information theory, or more specifically mutual information, provides a method to identify those basepairs that are key to the secondary structure. RESULTS: To this end we find most informative basepairs and visualize the effect of these basepairs on the secondary structure. Knowing whether a most informative basepair is present tells us not only the status of the particular pair but also provides a large amount of information about which other pairs are present or not present. We find that a few basepairs account for a large amount of the structural uncertainty. The identification of these pairs indicates small changes to sequence or stability that will have a large effect on structure. CONCLUSION: We provide a novel algorithm that uses mutual information to identify the key basepairs that lead to a multimodal Boltzmann distribution. We then visualize the effect of these pairs on the overall Boltzmann ensemble. PMID- 29506467 TI - ToxPi Graphical User Interface 2.0: Dynamic exploration, visualization, and sharing of integrated data models. AB - BACKGROUND: Drawing integrated conclusions from diverse source data requires synthesis across multiple types of information. The ToxPi (Toxicological Prioritization Index) is an analytical framework that was developed to enable integration of multiple sources of evidence by transforming data into integrated, visual profiles. Methodological improvements have advanced ToxPi and expanded its applicability, necessitating a new, consolidated software platform to provide functionality, while preserving flexibility for future updates. RESULTS: We detail the implementation of a new graphical user interface for ToxPi (Toxicological Prioritization Index) that provides interactive visualization, analysis, reporting, and portability. The interface is deployed as a stand-alone, platform-independent Java application, with a modular design to accommodate inclusion of future analytics. The new ToxPi interface introduces several features, from flexible data import formats (including legacy formats that permit backward compatibility) to similarity-based clustering to options for high resolution graphical output. CONCLUSIONS: We present the new ToxPi interface for dynamic exploration, visualization, and sharing of integrated data models. The ToxPi interface is freely-available as a single compressed download that includes the main Java executable, all libraries, example data files, and a complete user manual from http://toxpi.org . PMID- 29506468 TI - Who is the gate keeper for treatment in a fertility clinic in Germany? -baseline results of a prospective cohort study (PinK study). AB - BACKGROUND: It is estimated that 5-15% of all couples in industrialised nations are infertile. A perceived unfulfilled desire for a child or self-identification as infertile can lead to psychological strain and social isolation. About 53.000 women underwent assisted reproduction treatments in Germany in 2014. Little is known about the first medical consultation and patient needs prior to the first visit in a fertility clinic in Germany. The baseline survey of the prospective cohort study on couples undergoing fertility treatment in Germany (PinK Study) provides first results on this topic for Germany. METHODS: The baseline survey was conducted between 2012 and 2013. Self-administered questionnaires were handed out to patients of six fertility clinics at the beginning of treatment by clinic staff. At a participation rate of 31.0%, we were able to analyse data on 323 women and 242 men. RESULTS: 92.6% of the women had their initial medical consultation on their unfulfilled desire for a child with a gynaecologist. After the urologist (44.2%), the general practitioner (12.0%) was the second most approached initial contact person for men. 36.4% of all men had no medical consultation on the unfulfilled desire for a child before visiting a fertility clinic. 46.9% of the respondents expressed the wish that the conversation about infertility should be initiated by a physician. Prior to their first visit to a fertility clinic, 11.2% of the men and 24.8% of the women were informed by a physician that infertility treatment can cause emotional strain. CONCLUSION: While almost all women consult a gynaecologist prior to the first visit in a fertility centre, one out of three men do not consult any physician at that stage. For the remaining group of men, urologists and general practitioners are the most important contact persons. Gender-specific health care needs are evident. In order to close the health care gap for men in Germany, more opportunities for discreet access to consultation should be offered. Due to its low threshold and family-oriented approach, general practice could make an important contribution to this effect. PMID- 29506470 TI - Alignment-free clustering of large data sets of unannotated protein conserved regions using minhashing. AB - BACKGROUND: Clustering of protein sequences is of key importance in predicting the structure and function of newly sequenced proteins and is also of use for their annotation. With the advent of multiple high-throughput sequencing technologies, new protein sequences are becoming available at an extraordinary rate. The rapid growth rate has impeded deployment of existing protein clustering/annotation tools which depend largely on pairwise sequence alignment. RESULTS: In this paper, we propose an alignment-free clustering approach, coreClust, for annotating protein sequences using detected conserved regions. The proposed algorithm uses Min-Wise Independent Hashing for identifying similar conserved regions. Min-Wise Independent Hashing works by generating a (w,c) sketch for each document and comparing these sketches. Our algorithm fits well within the MapReduce framework, permitting scalability. We show that coreClust generates results comparable to existing known methods. In particular, we show that the clusters generated by our algorithm capture the subfamilies of the Pfam domain families for which the sequences in a cluster have a similar domain architecture. We show that for a data set of 90,000 sequences (about 250,000 domain regions), the clusters generated by our algorithm give a 75% average weighted F1 score, our accuracy metric, when compared to the clusters generated by a semi-exhaustive pairwise alignment algorithm. CONCLUSIONS: The new clustering algorithm can be used to generate meaningful clusters of conserved regions. It is a scalable method that when paired with our prior work, NADDA for detecting conserved regions, provides a complete end-to-end pipeline for annotating protein sequences. PMID- 29506469 TI - Analysis of MAPK and MAPKK gene families in wheat and related Triticeae species. AB - BACKGROUND: The mitogen-activated protein kinase (MAPK) family is involved in signal transduction networks that underpin many different biological processes in plants, ranging from development to biotic and abiotic stress responses. To date this class of enzymes has received little attention in Triticeae species, which include important cereal crops (wheat, barley, rye and triticale) that represent over 20% of the total protein food-source worldwide. RESULTS: The work presented here focuses on two subfamilies of Triticeae MAPKs, the MAP kinases (MPKs), and the MAPK kinases (MKKs) whose members phosphorylate the MPKs. In silico analysis of multiple Triticeae sequence databases led to the identification of 152 MAPKs belonging to these two sub-families. Some previously identified MAPKs were renamed to reflect the literature consensus on MAPK nomenclature. Two novel MPKs, MPK24 and MPK25, have been identified, including the first example of a plant MPK carrying the TGY activation loop sequence common to mammalian p38 MPKs. An EF hand calcium-binding domain was found in members of the Triticeae MPK17 clade, a feature that appears to be specific to Triticeae species. New insights into the novel MEY activation loop identified in MPK11s are offered. When the exon-intron patterns for some MPKs and MKKs of wheat, barley and ancestors of wheat were assembled based on transcript data in GenBank, they showed deviations from the same sequence predicted in Ensembl. The functional relevance of MAPKs as derived from patterns of gene expression, MPK activation and MKK-MPK interaction is discussed. CONCLUSIONS: A comprehensive resource of accurately annotated and curated Triticeae MPK and MKK sequences has been created for wheat, barley, rye, triticale, and two ancestral wheat species, goat grass and red wild einkorn. The work we present here offers a central information resource that will resolve existing confusion in the literature and sustain expansion of MAPK research in the crucial Triticeae grains. PMID- 29506472 TI - A case of anterior spinal cord syndrome in a patient with unruptured thoracic aortic aneurysm with a mural thrombus. AB - BACKGROUND: Spinal cord infarction is an uncommon condition. Anterior cord syndrome present with paraparesis or quadriparesis with sparing of vibration and proprioceptive senses. The common causes of anterior cord syndrome are aortic dissection and aortic surgical interventions. Spontaneous unruptured nondissected aortic aneurysms with intramural thrombus can rarely cause anterior cord infarctions. CASE PRESENTATION: We report a case of anterior spinal cord syndrome due to aneurysm of the thoracic aorta with a mural thrombus. A 64 year old male presented with sudden onset paraparesis with a sensory level at T1 with preserved sense of proprioception and vibration. The MRI panspine revealed increased T2 intensity in the anterior portion of the spinal cord from C5 to T10 level with characteristic 'owl eye' appearance on axial imaging. The CT aortogram detected aneurysmal dilatation of the ascending aortic, arch and descending thoracic aorta with significant intimal irregularities, calcified atherosclerotic plaques and a small mural thrombus. CONCLUSION: The possible mechanisms postulated are occlusion of ostia of radicular arteries by the atherosclerotic plaques and mural thrombus or thromboembolism to the anterior spinal artery. Nondissected atherosclerotic aortic aneurysms should be considered in patients presenting with spinal cord infarctions especially in the presence of vascular risk factors and smoking. PMID- 29506471 TI - A population-based analysis of germline BRCA1 and BRCA2 testing among ovarian cancer patients in an era of histotype-specific approaches to ovarian cancer prevention. AB - BACKGROUND: Identifying female carriers of BRCA1 and BRCA2 mutations is imperative for prevention of ovarian cancer and breast cancer. There are five major histologic subtypes of ovarian cancer and high grade serous cancer (the most common) is reported in 75-100% of BRCA1 and BRCA2 mutation carriers. We examined histology-based referral to the Hereditary Cancer Program following an educational prevention campaign recommending BRCA1 and BRCA2 mutation screening for all high-grade serous cancer patients. METHODS: We conducted a population based retrospective study in the province of British Columbia, Canada that included all patients visiting the Hereditary Cancer Program for genetic counselling for BRCA1 and BRCA2 mutation between 2001 and 2014. We examined the difference in rates of BRCA1 and BRCA2 testing between serous cancer patients and endometrioid and clear cell cancer patients using a differences in differences analysis. We also calculated the mean number of family members tested for every BRCA1 and BRCA2 identified ovarian cancer patient before and after the educational campaign. RESULTS: There were 5712 women tested for a BRCA1 and BRCA2 mutation at the HCP between 2001 and 2014, 887 of which had previously received a diagnosis of ovarian cancer. By 2013, 43% of serous cancer patients were being tested for BRCA1 and BRCA2 mutations compared with 20% of endometrioid and clear cell patients (p < 0.001). The mean number of family members tested for each BRCA1 and BRCA2 positive ovarian cancer patient increased after the educational campaign from 2.54 to 3.27 (p = 0.071), and the number of family members identified as BRCA positive also increased significantly. CONCLUSIONS: Recommendations for histology-based referral significantly increased the likelihood of serous cancer patients being tested for BRCA mutations. There was also an increase in the number of carrier tests performed for each BRCA1 and BRCA2 index ovarian cancer patient. PMID- 29506473 TI - Three endoplasmic reticulum-associated fatty acyl-coenzyme a reductases were involved in the production of primary alcohols in hexaploid wheat (Triticum aestivum L.). AB - BACKGROUND: The cuticle covers the surface of the polysaccharide cell wall of leaf epidermal cells and forms an essential diffusion barrier between the plant and the environment. The cuticle is composed of cutin and wax. Cuticular wax plays an important role in the survival of plants by serving as the interface between plants and their biotic and abiotic environments, especially restricting nonstomatal water loss. Leaf cuticular waxes of hexaploid wheat at the seedling stage mainly consist of primary alcohols, aldehydes, fatty acids, alkane and esters. Primary alcohols account for more than 80% of the total wax load. Therefore, we cloned several genes encoding fatty acyl-coenzyme A reductases from wheat and analyzed their function in yeast and plants. We propose the potential use of these genes in wheat genetic breeding. RESULTS: We reported the cloning and characterization of three TaFARs, namely TaFAR6, TaFAR7 and TaFAR8, encoding fatty acyl-coenzyme A reductases (FAR) in wheat leaf cuticle. Expression analysis revealed that TaFAR6, TaFAR7 and TaFAR8 were expressed at the higher levels in the seedling leaf blades, and were expressed moderately or weakly in stamen, glumes, peduncle, flag leaf blade, sheath, spike, and pistil. The heterologous expression of three TaFARs in yeast (Saccharomyces cerevisiae) led to the production of C24:0 and C26:0 primary alcohols. Transgenic expression of the three TaFARs in tomato (Solanum lycopersicum) and rice (Oryza sativa) led to increased accumulation of C24:0-C30:0 primary alcohols. Transient expression of GFP protein-tagged TaFARs revealed that the three TaFAR proteins were localized to the endoplasmic reticulum (ER), the site of wax biosynthesis. The three TaFAR genes were transcriptionally induced by drought, cold, heat, powdery mildew (Blumeria graminis) infection, abscisic acid (ABA) and methyl jasmonate (MeJa) treatments. CONCLUSIONS: These results indicated that wheat TaFAR6, TaFAR7 and TaFAR8 are involved in biosynthesis of very-long-chain primary alcohols in hexaploid wheat and in response to multiple environmental stresses. PMID- 29506474 TI - Anti-apoptotic effects of IGF-I on mortality and dysmorphogenesis in tbx5 deficient zebrafish embryos. AB - BACKGROUND: Tbx5 deficiency in zebrafish causes several abnormal phenotypes of the heart and pectoral fins. It has been reported that exogenous human growth hormone can enhance expression of downstream mediators in the growth hormone and insulin-like growth factor I (IGF-I) pathway and partially restore dysmorphogenesis in tbx5 morphants. This study aimed to further evaluate the effects of IGF-I on cell apoptosis and dysmorphogenesis in zebrafish embryos deficient for tbx5. RESULTS: Among the five studied groups of zebrafish embryos (wild-type embryos [WT], tbx5 morphants [MO], mismatched tbx5 morpholino-treated wild-type embryos [MIS], IGF-I-treated wild-type embryos [WTIGF1], and IGF-I treated tbx5 morphants [MOIGF1]), the expression levels of the ifg1, igf1-ra, ifg rb, erk1, and akt2 genes as well as the ERK and AKT proteins were significantly reduced in the MO group, but were partially restored in the MOIGF1 group. These expression levels remained normal in the WT, MIS, and WTIGF1 groups. Exogenous human IGF-I also reduced the incidence of phenotypic anomalies, decreased the expression levels of apoptotic genes and proteins, suppressed cell apoptosis, and improved survival of the MOIGF1 group. CONCLUSIONS: These results suggest that IGF-I has an anti-apoptotic protective effect in zebrafish embryos with tbx5 deficiency. PMID- 29506476 TI - AmpuBase: a transcriptome database for eight species of apple snails (Gastropoda: Ampullariidae). AB - BACKGROUND: Gastropoda, with approximately 80,000 living species, is the largest class of Mollusca. Among gastropods, apple snails (family Ampullariidae) are globally distributed in tropical and subtropical freshwater ecosystems and many species are ecologically and economically important. Ampullariids exhibit various morphological and physiological adaptations to their respective habitats, which make them ideal candidates for studying adaptation, population divergence, speciation, and larger-scale patterns of diversity, including the biogeography of native and invasive populations. The limited availability of genomic data, however, hinders in-depth ecological and evolutionary studies of these non-model organisms. RESULTS: Using Illumina Hiseq platforms, we sequenced 1220 million reads for seven species of apple snails. Together with the previously published RNA-Seq data of two apple snails, we conducted de novo transcriptome assembly of eight species that belong to five genera of Ampullariidae, two of which represent Old World lineages and the other three New World lineages. There were 20,730 to 35,828 unigenes with predicted open reading frames for the eight species, with N50 (shortest sequence length at 50% of the unigenes) ranging from 1320 to 1803 bp. 69.7% to 80.2% of these unigenes were functionally annotated by searching against NCBI's non-redundant, Gene Ontology database and the Kyoto Encyclopaedia of Genes and Genomes. With these data we developed AmpuBase, a relational database that features online BLAST functionality for DNA/protein sequences, keyword searching for unigenes/functional terms, and download functions for sequences and whole transcriptomes. CONCLUSIONS: In summary, we have generated comprehensive transcriptome data for multiple ampullariid genera and species, and created a publicly accessible database with a user-friendly interface to facilitate future basic and applied studies on ampullariids, and comparative molecular studies with other invertebrates. PMID- 29506475 TI - IntLIM: integration using linear models of metabolomics and gene expression data. AB - BACKGROUND: Integration of transcriptomic and metabolomic data improves functional interpretation of disease-related metabolomic phenotypes, and facilitates discovery of putative metabolite biomarkers and gene targets. For this reason, these data are increasingly collected in large (> 100 participants) cohorts, thereby driving a need for the development of user-friendly and open source methods/tools for their integration. Of note, clinical/translational studies typically provide snapshot (e.g. one time point) gene and metabolite profiles and, oftentimes, most metabolites measured are not identified. Thus, in these types of studies, pathway/network approaches that take into account the complexity of transcript-metabolite relationships may neither be applicable nor readily uncover novel relationships. With this in mind, we propose a simple linear modeling approach to capture disease-(or other phenotype) specific gene metabolite associations, with the assumption that co-regulation patterns reflect functionally related genes and metabolites. RESULTS: The proposed linear model, metabolite ~ gene + phenotype + gene:phenotype, specifically evaluates whether gene-metabolite relationships differ by phenotype, by testing whether the relationship in one phenotype is significantly different from the relationship in another phenotype (via a statistical interaction gene:phenotype p-value). Statistical interaction p-values for all possible gene-metabolite pairs are computed and significant pairs are then clustered by the directionality of associations (e.g. strong positive association in one phenotype, strong negative association in another phenotype). We implemented our approach as an R package, IntLIM, which includes a user-friendly R Shiny web interface, thereby making the integrative analyses accessible to non-computational experts. We applied IntLIM to two previously published datasets, collected in the NCI-60 cancer cell lines and in human breast tumor and non-tumor tissue, for which transcriptomic and metabolomic data are available. We demonstrate that IntLIM captures relevant tumor-specific gene-metabolite associations involved in known cancer-related pathways, including glutamine metabolism. Using IntLIM, we also uncover biologically relevant novel relationships that could be further tested experimentally. CONCLUSIONS: IntLIM provides a user-friendly, reproducible framework to integrate transcriptomic and metabolomic data and help interpret metabolomic data and uncover novel gene-metabolite relationships. The IntLIM R package is publicly available in GitHub ( https://github.com/mathelab/IntLIM ) and includes a user-friendly web application, vignettes, sample data and data/code to reproduce results. PMID- 29506477 TI - Impact of a vaccination programme in children vaccinated with ProQuad, and ProQuad-specific effectiveness against varicella in the Veneto region of Italy. AB - BACKGROUND: Monovalent varicella vaccines have been available in the Veneto Region of Italy since 2004. In 2006, a single vaccine dose was added to the immunisation calendar for children aged 14 months. ProQuad(r), a quadrivalent measles-mumps-rubella-varicella vaccine, was introduced in May 2007 and used, among other varicella vaccines, until October 2008. This study aimed to evaluate the effectiveness of a single dose of ProQuad, and the population impact of a vaccination program (VP) against varicella of any severity in children who received a first dose of ProQuad at 14 months of age in the Veneto Region, METHODS: All children born in 2006/2007, i.e., eligible for varicella vaccination after ProQuad was introduced, were retrospectively followed through individual level data linkage between the Pedianet database (varicella cases) and the Regional Immunization Database (vaccination status). The direct effectiveness of ProQuad was estimated as the incidence rate of varicella in ProQuad-vaccinated children aged < 6 years compared to children with no varicella vaccination from the same birth cohort. The impact of the VP on varicella was measured by comparing children eligible for the VP to an unvaccinated historical cohort from 1997/1998. The vaccine impact measures were: total effect (the combined effect of ProQuad vaccination and being covered by the Veneto VP); indirect effect (the effect of the VP on unvaccinated individuals); and overall effect (the effect of the VP on varicella in the entire population of the Veneto Region, regardless of their vaccination status). RESULTS: The adjusted direct effectiveness of ProQuad was 94%. The vaccine impact measures total, indirect, and overall effect were 97%, 43%, and 90%, respectively. CONCLUSIONS: These are the first results on the effectiveness and impact of ProQuad against varicella; data confirmed its high effectiveness, based on immunological correlates for protection. Direct effectiveness is our only ProQuad-specific measure; all impact measures refer at least partially to the VP and should be interpreted in the context of high vaccine coverage and the use of various varicella vaccines in this region. The Veneto Region offered a unique opportunity for this study due to an individual data linkage between Pedianet and the Regional Immunization database. PMID- 29506478 TI - A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Oxaliplatin is a platinum derivative that has shown efficacy in advanced hepatocellular carcinoma. S-1 is an oral fluoropyrimidine that has substituted for 5-fluorouracil in many cancers. This was a multicenter, open label, single-arm phase II trial that evaluated the efficacy of S-1 and oxaliplatin (SOX) in advanced hepatocellular carcinoma. All patients included in the present study were systemic treatment-naive. Prior treatment with sorafenib was allowed, but other treatments were not. METHODS: Patients received S-1 (40 mg/m2 twice daily from day 1-14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. The primary end point was time to progression (TTP). Secondary end points included progression-free survival, overall survival (OS), response rate, and safety profile. RESULTS: Thirty six patients with advanced hepatocellular carcinoma were included in this study. The median TTP was 3.0 months (95% confidence interval (CI), 0.75-5.25), and the median OS was 10.3 months (95% CI, 6.4-14.3). Bone metastasis was associated with poorer TTP and OS. The efficacy of SOX was unaffected by prior sorafenib or locoregional therapy. The objective response rate was 13.9%. No grade 4 toxicity or death from adverse events occurred. The most common grade 3 toxicities were neutropenia (13.9%), thrombocytopenia (13.9%), and diarrhea (8.3%). CONCLUSIONS: Although this trial did not meet its primary end point, the SOX regimen showed comparable efficacy and safety to the 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen. As the SOX regimen is easier for patients, SOX may be a reasonable substitute for FOLFOX in hepatocellular carcinoma. TRIAL REGISTRATION: Clinicaltrials.gov NCT01429961 . Registered 7 September 2011. PMID- 29506479 TI - A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing. AB - BACKGROUND: Adrenal hypoplasia is a rare congenital disorder, which can be classified into a non-syndromic form, without extra-adrenal features, and a syndromic form, with such features. Despite biochemical and molecular genetic evaluation, etiologic diagnosis cannot be performed in many patients with adrenal hypoplasia. CASE PRESENTATION: The patient in this case was a boy born at 31 weeks of gestation with a weight of 882 g (< 3rd percentile) to non consanguineous parents. Genital examination showed micropenis and bilateral cryptorchidism. On the third day of life, he manifested hypotension with high urine output, hyponatremia, hyperkalemia, hypernatriuria, high plasma adrenocorticotropic hormone level, and high plasma renin activity, suggesting acute adrenal insufficiency. The serum 17alpha-hydroxyprogesterone level was normal. Adrenal insufficiency improved following administration of hydrocortisone and 9alpha-fludrocortisone, but the patient died of recurrent infection at 4 months of age. He was suspected as IMAGE (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) syndrome. However, no mutation in CDKN1C was identified. Targeted exome sequencing using the TruSight One Sequencing Panel (Illumina) identified a heterozygous mutation of c.2944C > T (p.R982C) in exon 3 in SAMD9. CONCLUSION: This report describes the first Korean case of MIRAGE syndrome. The patient presented with severe primary adrenal insufficiency, intrauterine growth retardation, and recurrent infection. SAMD9 mutation should be considered in patients who present with adrenal hypoplasia and extra-adrenal phenotypes. PMID- 29506480 TI - Treatment outcomes and factors affecting unsuccessful outcome among new pulmonary smear positive and negative tuberculosis patients in Anqing, China: a retrospective study. AB - BACKGROUND: Monitoring the treatment outcomes of tuberculosis and determining the specific factors associated with unsuccessful treatment outcome are essential to evaluate the effectiveness of tuberculosis control program. This study aimed to assess treatment outcomes and explore the factors associated with unsuccessful outcomes among new pulmonary smear positive and negative tuberculosis patients in Anqing, China. METHODS: A nine-year retrospective study was conducted using data from Anqing Center for Diseases Prevention and Control. New pulmonary tuberculosis patients treated with two six-month regimens were investigated. Non conditional logistic regression was performed to calculate odds ratios and 95% confidence intervals for factors associated with unsuccessful outcomes. RESULTS: Among 22,998 registered patients (16,939 males, 6059 females), 64.54% were smear positive patients. The treatment success rates was 95.02% for smear-positive patients and 95.00% for smear-negative patients. Characteristics associated with an higher risk of unsuccessful treatment among smear-positive patients included aged above 35 years, treatment management model of self-medication, full-course management and supervision in intensive phase, unchecked chest X-ray, cavity in chest X-ray, and miliary shadow in chest X-ray, while normal X-ray was negative factor. Unsuccessful treatment among smear-negative patients was significantly associated with age over 45 years, treatment management model of full-course management, unchecked chest X-ray, presence of miliary shadow in chest X-ray and delay over 51 days. CONCLUSIONS: Tuberculosis treatment in Anqing area was successful and independent of treatment regimens. Special efforts are required for patients with unsuccessful outcomes. PMID- 29506481 TI - Does sarcopenia predict change in mobility after hip fracture? a multicenter observational study with one-year follow-up. AB - BACKGROUND: Patients with hip fracture frequently have sarcopenia and are at great risk of loss of mobility. We have investigated if sarcopenia predicts change in mobility after hip fracture. METHODS: This is a prospective, multicenter observational study with one-year follow-up. Patients with hip fracture who were community-living and capable of walking before the fracture were included at three hospitals in Norway (2011-2013). The primary outcome of the study was change in mobility, measured by the New Mobility Score (NMS). Sarcopenia was determined postoperatively by anthropometry, grip strength, and NMS. RESULTS: We included 282 participants and sarcopenia status was determined in 201, of whom 38% (77/201) had sarcopenia, 66% (128/194) had low muscle mass, 52% (116/222) had low grip strength and 8% (20/244) had low pre-fracture mobility (NMS < 5). Sarcopenia did not predict change in mobility (effect 0.2 points; 95% CI -0.5 to 0.9, P = 0.6), but it was associated with having lower mobility at one year (NMS 5.8 (SD 2.3) vs. 6.8 (SD 2.2), P = 0.003), becoming a resident of a nursing home (odds ratio 3.2, 95% CI 0.9 to 12.4, P = 0.048), and the combined endpoint of becoming a resident of a skilled nursing home or death (odds ratio 3.6, 95% CI 1.2 to 12.2, P = 0.02). CONCLUSIONS: Sarcopenia did not predict change in mobility in the year after hip fracture. PMID- 29506482 TI - Increased circulating bioactive C-type natriuretic peptide is associated with reduced heart rate variability in patients with chronic kidney disease. AB - BACKGROUND: C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family and have been implicated to be involved in maintaining vascular homeostasis and acting as a cardiac chronotropic agent in experimental studies. However, clinical evidence of its participation in cardiovascular regulation is lacking, especially in patients with chronic kidney disease (CKD). We aimed to explore the association of circulating CNP with cardiovascular alterations in CKD. METHODS: Seventy-six subjects with CKD were recruited. Plasma CNP-22, the bioactive form of CNP in the circulation, was measured by an enzyme immunoassay. The patients also underwent several cardiovascular evaluations including measurement of blood pressure, endothelial function, heart rate variability (HRV) and pulse wave velocity. RESULTS: Mean (+/-standard deviation) age of the patients were 59.9 (+/-14.9) years and 56.6% were male. Average plasma CNP level was 790.8 +/- 309.1 pg/ml. Plasma CNP level was not increased as estimated glomerular filtration rate declined. There was no significant difference of CNP between patients with or without endothelial dysfunction (with vs. without endothelial dysfunction: 844.6 +/- 365.5 pg/ml vs. 738.3 +/- 231.8 pg/ml, p = 0.14). Plasma CNP showed no association with blood pressure or pulse wave velocity, but was negatively associated with time-domain HRV parameters (SDNN, RMSSD, Triangular Index). The association of CNP with HRV persisted after adjustment for potential covariates. CONCLUSIONS: Our data highlights a possible link between circulating CNP and autonomic dysfunction in CKD patients. Further studies are warranted to explore the mechanisms underlying this association, as well as evaluate the ability of circulating CNP in predicting adverse cardiovascular event in CKD patients. PMID- 29506483 TI - Morbidity from in-hospital complications is greater than treatment failure in patients with Staphylococcus aureus bacteraemia. AB - BACKGROUND: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. METHODS: Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12 months. Data were available for 222 patients recruited from February 2011 to December 2012. RESULTS: Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score >= 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. CONCLUSIONS: This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications. PMID- 29506484 TI - Lymphnode tuberculosis in a 4-year-old boy with relapsed ganglioneuroblastoma: a case report. AB - BACKGROUND: Mycobacterium tuberculosis (M. tuberculosis) disease is a generally well-known problem among immunocompromised adults and children. In pediatric oncology, only few cases of M. tuberculosis disease are reported so far. CASE PRESENTATION: We report a case of concomitant lymphnode tuberculosis in a 4-year old German boy with relapsed ganglioneuroblastoma. 18 months after the initial diagnosis, relapse with new paravertebral lesions and new lesions in the left lower lobe of the lung and in the perihilar lymphnodes suspicious of metastases of the ganglioneuroblastoma were detected. While relapse in the tumor was confirmed, unexpectedly, pathologic examination revealed morphological diagnosis of lymphnode tuberculosis. The boy was of German background without previous history of tuberculosis exposure. Both, antituberculostatic and relapse treatment were immediately initiated. Three months on, MRI revealed regressive findings in the lung and lymphnodes and partial response in the tumor. The patient underwent second MiBG therapy and haploidentical stem cell transplantation. CONCLUSION: The diagnosis of lymphnode tuberculosis in a 4-year-old German boy with relapsed ganglioneuroblastoma was only made by chance, but most likely saved his life. Pediatric oncologist should be aware of tuberculosis as the incidence might increase over time and the timely diagnosis of a potentially preventable M. tuberculosis disease is irreplaceable. Further studies are needed to explore the incidence of M. tuberculosis infections and the value of IGRA, testing for latent tuberculosis infection prior to chemotherapy in children with underlying malignancies. PMID- 29506485 TI - Transcriptional profiling of liver in riboflavin-deficient chicken embryos explains impaired lipid utilization, energy depletion, massive hemorrhaging, and delayed feathering. AB - BACKGROUND: A strain of Leghorn chickens (rd/rd), unable to produce a functional riboflavin-binding protein, lays riboflavin-deficient eggs, in which all embryos suddenly die at mid-incubation (days 13-15). This malady, caused by riboflavin deficiency, leads to excessive lipid accumulation in liver, impaired beta oxidation of lipid, and severe hypoglycemia prior to death. We have used high density chicken microarrays for time-course transcriptional scans of liver in chicken embryos between days 9-15 during this riboflavin-deficiency-induced metabolic catastrophe. For comparison, half of rd/rd embryos (n = 16) were rescued from this calamity by injection of riboflavin just prior to incubation of fertile eggs from rd/rd hens. RESULTS: No significant differences were found between hepatic transcriptomes of riboflavin-deficient and riboflavin-rescued embryos at the first two ages (days 9 and 11). Overall, we found a 3.2-fold increase in the number of differentially expressed hepatic genes between day 13 (231 genes) and day 15 (734 genes). Higher expression of genes encoding the chicken flavoproteome was more evident in rescued- (15 genes) than in deficient embryos (4 genes) at day 15. Diminished activity of flavin-dependent enzymes in riboflavin-deficient embryos blocks catabolism of yolk lipids, which normally serves as the predominant source of energy required for embryonic development. CONCLUSIONS: Riboflavin deficiency in mid-stage embryos leads to reduced expression of numerous genes controlling critical functions, including beta oxidation of lipids, blood coagulation and feathering. Surprisingly, reduced expression of feather keratin 1 was found in liver of riboflavin-deficient embryos at e15, which could be related to their delayed feathering and sparse clubbed down. A large number of genes are expressed at higher levels in liver of riboflavin-deficient embryos; these up-regulated genes control lipid storage/transport, gluconeogenesis, ketogenesis, protein catabolism/ubiquitination and cell death. PMID- 29506486 TI - Determinants of cancer screening awareness and participation among Indonesian women. AB - BACKGROUND: Cancer screening awareness and participation may be lower in low- and middle-income countries that lack established national screening programmes compared with those that do. We evaluated potential determinants of awareness about and participation in breast and cervical cancer screening, and breast self examination (BSE) in women using survey data from Indonesia. METHODS: From the fifth Indonesian Family Life Survey (2014-2015), a total of 5397 women aged 40 and older without any history of cancer who responded to questionnaires concerning Pap smears, mammography, and BSE were included. Multilevel modelling was used to assess potential determinants in relation to awareness about Pap smears and mammography, and participation in Pap smears and BSE practice. Multivariable analyses were performed to identify independent predictors of cancer screening. RESULTS: Of the 5397 respondents, 1058 (20%) women were aware of Pap smears, of which 297 had never had the procedure. Only 251 (5%) participants were aware of mammography. A total of 605 (12%) of women reported they performed BSE. Higher education and household expenditure were consistently associated with higher odds of awareness about Pap smears and mammography (e.g. odds ratio [OR] of being aware of Pap smear and mammography: 7.82 (95% CI: 6.30 9.70) and 7.70 (6.19-9.58), respectively, for high school graduates compared to women with less educational attainment in the multivariable models), and participation in Pap smears and BSE. We also identified enabling factors linked with greater cancer screening awareness and participation, including health insurance, shorter distance to health services, and social participation. CONCLUSION: There are socioeconomic disparities in cancer screening awareness and participation among Indonesian women. Our findings may help inform targeted health promotion and screening for cancer in the presence of limited resources. PMID- 29506487 TI - Detection and interval cancer rates during the transition from screen-film to digital mammography in population-based screening. AB - BACKGROUND: Between 2003 and 2010 digital mammography (DM) gradually replaced screen-film mammography (SFM) in the Dutch breast cancer screening programme (BCSP). Previous studies showed increases in detection rate (DR) after the transition to DM. However, national interval cancer rates (ICR) have not yet been reported. METHODS: We assessed programme sensitivity and specificity during the transition period to DM, analysing nationwide data on screen-detected and interval cancers. Data of 7.3 million screens in women aged 49-74, between 2004 and 2011, were linked to the Netherlands Cancer Registry to obtain data on interval cancers. Age-adjusted DRs, ICRs and recall rates (RR) per 1000 screens and programme sensitivity and specificity were calculated by year, age and screening modality. RESULTS: 41,662 screen-detected and 16,160 interval cancers were analysed. The DR significantly increased from 5.13 (95% confidence interval (CI):5.00-5.30) in 2004 to 6.34 (95% CI:6.15-6.47) in 2011, for both in situ (2004:0.73;2011:1.24) and invasive cancers (2004:4.42;2011:5.07), whereas the ICR remained stable (2004: 2.16 (95% CI2.06-2.25);2011: 2.13 (95% CI:2.04-2.22)). The RR changed significantly from 14.0 to 21.4. Programme sensitivity significantly increased, mainly between ages 49-59, from 70.0% (95% CI:68.9-71.2) to 74.4% (95% CI:73.5-75.4) whereas specificity slightly declined (2004:99.1% (95% CI:99.09 99.13);2011:98.5% (95% CI:98.45-98.50)). The overall DR was significantly higher for DM than for SFM (6.24;5.36) as was programme sensitivity (73.6%;70.1%), the ICR was similar (2.19;2.20) and specificity was significantly lower for DM (98.5%;98.9%). CONCLUSIONS: During the transition from SFM to DM, there was a significant rise in DR and a stable ICR, leading to increased programme sensitivity. Although the recall rate increased, programme specificity remained high compared to other countries. These findings indicate that the performance of DM in a nationwide screening programme is not inferior to, and may be even better, than that of SFM. PMID- 29506488 TI - Household contact non-attendance of clinical evaluation for tuberculosis: a pilot study in a high burden district in South Africa. AB - BACKGROUND: In 2012, the World Health Organization launched guidelines for systematically investigating contacts of persons with infectious tuberculosis (TB) in low- and middle-income countries. As such, it is necessary to understand factors that would influence successful scale-up. This study targeted household contacts of newly-diagnosed infectious TB patients in the Mangaung Metropolitan district to explore factors associated with non-attendance of clinical evaluation. METHOD: In September-October 2016, a pilot study of household contacts was conducted. At each of the 40 primary health care (PHC) facilities in the district, at least one out of four types of TB index cases were purposefully selected. These included children <5 years, smear-positive cases, HIV co-infected cases, and multidrug-resistant TB (MDR-TB) cases. Trained fieldworkers administered questionnaires and screened contacts for TB symptoms. Those with TB symptoms as well as children <5 years were referred for clinical evaluation at the nearest PHC facility. Contacts' socio-demographic and clinical characteristics, TB knowledge and perception about TB-related discrimination are described. Logistic regression analysis was used to investigate factors associated with non-attendance of clinical evaluation. RESULTS: Out of the 259 participants, approximately three in every five (59.5%) were female. The median age was 20 (interquartile range: 8-41) years. While the large majority (87.3%) of adult contacts correctly described TB aetiology, almost three in every five (59.9%) thought that it was hereditary, and almost two-thirds (65.5%) believed that it could be cured by herbal medicine. About one-fifth (22.9%) of contacts believed that TB patients were subjected to discrimination. Two in every five (39.4%) contacts were referred for clinical evaluation of whom more than half (52.9%) did not attend the clinic. Non-attendance was significantly associated with inter alia male gender (AOR: 3.4; CI: 1.11-10.24), prior TB diagnosis (AOR: 5.6; CI: 1.13-27.90) and sharing of a bedroom with the index case (AOR: 3.4: CI: 1.07-10.59). CONCLUSION: The pilot study identified gaps in household contacts' knowledge of TB. Further research on important individual, clinical and structural factors that can influence and should be considered in the planning, implementation and scale-up of household contact TB investigation is warranted. PMID- 29506490 TI - Rubinstein-Taybi 2 associated to novel EP300 mutations: deepening the clinical and genetic spectrum. AB - BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces. RSTS is caused by mutations in CREBBP and in EP300 genes in 50-60% and 8%, respectively. Up to now, 76 RSTS-EP300 patients have been described. We present the clinical and molecular characterization of a cohort of RSTS patients carrying EP300 mutations. METHODS: Patients were selected from a cohort of 72 individuals suspected of RSTS after being negative in CREBBP study. MLPA and panel-based NGS EP300 were performed. RESULTS: Eight patients were found to carry EP300 mutations. Phenotypic characteristics included: intellectual disability (generally mild), postnatal growth retardation, infant feeding problems, psychomotor and language delay and typical facial dysmorphisms (microcephaly, downslanting palpebral fissures, columella below the alae nasi, and prominent nose). Broad thumbs and/or halluces were common, but angulated thumbs were only found in two patients. We identified across the gene novel mutations, including large deletion, frameshift mutations, nonsense, missense and splicing alterations, confirming de novo origin in all but one (the mother, possibly underdiagnosed, has short and broad thumbs and had learning difficulties). CONCLUSIONS: The clinical evaluation of our patients corroborates that clinical features in EP300 are less marked than in CREBBP patients although it is difficult to establish a genotype-phenotype correlation although. It is remarkable that these findings are observed in a RSTS-diagnosed cohort; some patients harbouring EP300 mutations could present a different phenotype. Broadening the knowledge about EP300-RSTS phenotype may contribute to improve the management of patients and the counselling to the families. PMID- 29506489 TI - AKT1 restricts the invasive capacity of head and neck carcinoma cells harboring a constitutively active PI3 kinase activity. AB - BACKGROUND: In mammals, the AKT/PKB protein kinase family comprises three members (AKT1-3). PI3-Kinase (PI3K), a key oncogene involved in a wide variety of cancers, drives AKT activity. Constitutive activation of the PI3K/AKT pathway has been associated with tumorigenic properties including uncontrolled cell proliferation and survival, angiogenesis, promotion of cellular motility, invasiveness and metastasis. However, AKT1 activity has also been recently shown to repress the invasive properties of breast cancer cells in specific contexts. METHODS: This study used both pharmacological and shRNA approaches to inhibit AKT function, microscopy to characterize the cellular morphology, 3D spheroid models to assess migratory and invasive cellular capacities and a phenotypic screening approach based on electrical properties of the cells. RESULTS: Here we demonstrate that the alternative action of AKT1 on invasive properties of breast cancers can be extended to head and neck carcinomas, which exhibit constitutive activation of the PI3K/AKT pathway. Indeed, inhibition of AKT1 function by shRNA or a specific pharmacological inhibitor resulted in cellular spreading and an invasive phenotype. A phenotypic screening approach based on cellular electrical properties corroborated microscopic observations and provides a foundation for future high-throughput screening studies. This technique further showed that the inhibition of AKT1 signaling is phenocopied by blocking the mTORC1 pathway with rapamycin. CONCLUSION: Our study suggests that the repressive action of PI3K/AKT1 on cellular invasive properties may be a mechanism common to several cancers. Current and future studies involving AKT inhibitors must therefore consider this property to prevent metastases and consequently to improve survival. PMID- 29506491 TI - Cilostazol-induced acute tubulointerstitial nephritis accompanied by IgA nephropathy: a case report. AB - BACKGROUND: Cilostazol is an antiplatelet drug that is widely prescribed for the prevention of secondary stroke. Adverse reactions to cilostazol include headaches, palpitations, and diarrhea. Little is known about the nephrotoxicity of cilostazol, such as acute kidney injury. We report a biopsy-proven case of diffuse tubulointerstitial nephritis induced by cilostazol. CASE PRESENTATION: A 69-year-old woman prescribed cilostazol was hospitalized for acute kidney injury. On admission, her renal function deteriorated, with an increased serum creatinine level. Urinalysis showed hematuria, proteinuria, and hyper-beta2 microglobulinuria. A renal biopsy revealed diffuse tubulointerstitial nephritis associated with IgA nephropathy, and gallium-67 scintigraphy showed uptake in the bilateral kidneys. A drug lymphocyte stimulation test for cilostazol was positive, and the patient was diagnosed with cilostazol-induced acute tubulointerstitial nephritis. Despite discontinuation of cilostazol, her renal function rapidly worsened and steroid pulse therapy was initiated, followed by oral high-dose glucocorticoid therapy. After steroid treatment, her serum creatinine level normalized in parallel with urine beta2-microglobulin. CONCLUSION: Cilostazol can induce acute tubulointerstitial nephritis. PMID- 29506492 TI - Threat of biographical disruption: the gendered construction and experience of infertility following cancer for women and men. AB - BACKGROUND: Infertility is a major concern for people with cancer and their partners. There have been calls for further research on the gendered nature of psychosocial, emotional and identity concomitants of fertility post-cancer across women and men. METHOD: The gendered construction and experience of infertility following cancer was examined through a survey of 693 women and 185 men, and in depth one-to-one interviews with a subsample of survey respondents, 61 women and 17 men, purposively selected across cancer types and age groups. Thematic decomposition was used to examine the open ended survey responses and interviews. The chi square test for independence was used to test for group differences between women and men on closed survey items. RESULTS: In the thematic decomposition, infertility was identified as providing a 'Threat of Biographical Disruption' which impacted on life course and identity, for both women and men. Subthemes identified were: 'Parenthood as central to adulthood'; 'Infertility as a threat to gender identity'; ' Unknown fertility status and delayed parenthood'; 'Feelings of loss and grief'; 'Absence of understanding and support'; 'Benefit finding and renegotiation of identity'. In the closed survey items, the majority of women and men agreed that they had always 'wanted to be a parent' and that 'parenthood was a more important life goal than a satisfying career'. 'It is hard to feel like a true adult until you have a child' and impact upon 'my feelings about myself as a man or a woman' was reported by both women and men, with significantly more women reporting 'I feel empty because of fertility issues'. Many participants agreed they 'could visualise a happy life without a child' and there is 'freedom without children'. Significantly more men than women reported that they had not discussed fertility with a health care professional. CONCLUSION: The fear of infertility following cancer, or knowledge of compromised fertility, can have negative effects on identity and psychological wellbeing for both women and men, serving to create biographical disruption. Support from family, partners and health care professionals can facilitate renegotiation of identity and coping. PMID- 29506493 TI - Mixed response on regorafenib treatment for GIST (gastro-intestinal stromal tumor) according to 18F-FDG-PET/CT. AB - BACKGROUND: Gastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET. CASE PRESENTATION: A 37-year-old male with lower abdominal pain and weight loss was referred to our hospital. Abdominal ultrasound and computed tomography (CT) showed diffuse peritoneal implants. Surgical specimen histology showed a GIST with c-KIT exon 11 deletion (c.1708_1728del) and treatment with imatinib 400 mg/day was initiated. Due to disease progression illustrated on baseline versus follow-up 18F-FDG-PET/CT scans therapy was switched to imatinib 800 mg/day and later to sunitinib 50 mg/day. Upon further disease progression 10 months later, third line treatment with regorafenib 160 mg/day was initiated. 18F-FDG-PET/CT showed the metabolic responses after 4 months regorafenib treatment ranging from complete response to the appearance of a new lesion in the liver. The new hypermetabolic lesion was only seen on the non attenuation-corrected images because of breathing motion artifact. CONCLUSION: This case illustrates that metabolic response can occur in GIST lesions without morphological response after third line regorafinib treatment. Furthermore this is the first case in literature to show regorafinib response on PET. PMID- 29506494 TI - Targeted next generation sequencing identified clinically actionable mutations in patients with esophageal sarcomatoid carcinoma. AB - BACKGROUND: Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor. Its genetic background and mechanisms of oncogenesis remain largely unknown. METHODS: Here we performed targeted next generation sequencing (NGS) on a pan-cancer gene panel in 15 ESC tumors to explore their genetic alterations, and aimed to identify clinically actionable mutations for future treatment instructions. RESULTS: TP53 alterations were identified in all patients. Alterations in receptor tyrosine kinases (RTK) were identified in 10 out of 15 patients. Members of downstream RAS and PI3-kinase pathways are also mutated in 10 patients, and PIK3CA is the top mutated gene in these pathways. In addition, we identified mutations on histone modification genes in 5 patients, including histone acetyltransferase gene EP300 and its homologue CREBBP, lysine methyltransferase genes KMT2A and KMT2B, and lysine demethylase gene KDM5A. Finally, mismatch repair (MMR) genes and proofreading gene POLE all together were mutated in one third of the ESC patients. CONCLUSIONS: This is the first study to unravel the mutational profile of ESC tumors. Our findings could match 9 patients to the targeted therapies currently available in clinical practice or in active clinical trials, suggesting the potential utility of targeted therapies for this rare disease in the future. PMID- 29506495 TI - CMR stress testing in a patient with morbid obesity (BMI 58 kg/m2) and suspected coronary artery disease. AB - BACKGROUND: Severe obesity is asscociated with an increased risk of coronary artery disease (CAD) but non-invasive cardiac imaging modalities have important technical limits. CASE PRESENTATION: We report a case of a 58-year old patient with suspected CAD and severely elevated BMI of 58 kg/m2. CONCLUSIONS: Stress-CMR was able to non-invasively stratify risk with good imaging quality despite the body dimensions of the patient. PMID- 29506496 TI - Extragonadal germ cell tumor of the posterior mediastinum in a child complicated with spinal cord compression: a case report. AB - BACKGROUND: Germ cell tumors (GCTs) in children are rare neoplasms with diverse pathological findings according to the site and age of presentation. The most common symptoms in children with mediastinal GCTs, which are nonspecific, are dyspnea, chest pain, cough, hemoptysis, vena cava occlusion syndrome, and fatigue/weakness. Because of these nonspecific symptoms, it is difficult to suspect a mediastinal mass. A posterior mediastinal tumor causing spinal cord compression is an important example of an oncologic emergency arising from a neurogenic tumor. CASE PRESENTATION: Children with posterior mediastinum GCTs can be easily mistaken as having a neurogenic tumor because of site of tumor origin. We treated our 7-year-old patient with emergency decompression surgery and high dose steroid pulse therapy to prevent secondary injury to the spinal cord. Primary injury was a result of spinal cord compression due to the initial manifestation of GCT in the posterior mediastinum. Cisplatin-based chemotherapy was also administered. The patient was followed up regularly for 3 years and is undergoing rehabilitation without any signs of recurrence. CONCLUSIONS: We present an extremely rare case of a child with paraparesis caused by extradural spinal cord compression as the initial manifestation of GCT in the posterior mediastinum. The child was treated with emergency decompression surgery and high dose pulse steroid therapy to prevent secondary injury to the spinal cord. PMID- 29506497 TI - A novel surgical technique for punctal stenosis: placement of three interrupted sutures after rectangular three-snip punctoplasty. AB - BACKGROUND: We developed a novel surgical technique to treat punctal stenosis involving the placement of three interrupted sutures after rectangular three-snip punctoplasty (TSP). METHODS: Retrospective chart review of forty-eight eyes of 44 patients who underwent rectangular TSP with three interrupted sutures was performed. We investigated whether anatomical recurrences (re-stenosis) occurred during the follow-up period. The subjective symptoms of patients were surveyed. RESULTS: The mean patient age was 64.1 years, and the mean follow-up time was 17.4 months. The placement of three interrupted sutures after rectangular TSP afforded satisfactory outcomes. Regarding subjective symptoms, 91.7% of the eyes (44/48) were reported as improved. Among 4 eyes determined as symptomatic failure, anatomical recurrence (re-stenosis of the punctum) was observed in only one eye. The other three (6.25%, 3/48 eyes) showed functional nasolacrimal obstruction, namely epiphora with patent tear duct. CONCLUSIONS: Placement of three interrupted sutures after rectangular TSP to treat punctal stenosis showed promising results. Notably anatomical success rate was about 98%. Further comparisons between the novel surgical technique and conventional techniques are required. PMID- 29506498 TI - High incidence of rainbow glare after femtosecond laser assisted-LASIK using the upgraded FS200 femtosecond laser. AB - BACKGROUND: To compare the incidence of rainbow glare (RG) after femtosecond laser assisted-LASIK (FS-LASIK) using the upgraded FS200 femtosecond laser with different flap cut parameter settings. METHODS: A consecutive series of 129 patients (255 eyes) who underwent FS-LASIK for correcting myopia and/or astigmatism using upgraded WaveLight FS200 femtosecond laser with the original settings was included in group A. Another consecutive series of 129 patients (255 eyes) who underwent FS-LASIK using upgraded WaveLight FS200 femtosecond laser with flap cut parameter settings changed (decreased pulse energy, spot and line separation) was included in group B. The incidence and fading time of RG, confocal microscopic image and postoperative clinical results were compared between the two groups. RESULTS: There were no differences between the two groups in age, baseline refraction, excimer laser ablation depth, postoperative uncorrected visual acuity and refraction. The incidence rate of RG in group A (35/255, 13.73%) was significantly higher than that in group B (4/255, 1.57%) (P < 0.05). The median fading time was 3 months in group A and 1 month in group B (P > 0.05).The confocal microscopic images showed wider laser spot spacing in group A than group B. The incidence of RG was significantly correlated with age and grouping (P < 0.05). CONCLUSIONS: The upgraded FS200 femtosecond laser with original flap cut parameter settings could increase the incidence of RG. The narrower grating size and lower pulse energy could ameliorate this side effect. PMID- 29506499 TI - Clinical and laboratory findings in 503 cattle with traumatic reticuloperitonitis. AB - BACKGROUND: The study evaluated the results of clinical examination and haematological and serum biochemical analyses in 503 cattle with traumatic reticuloperitonitis (TRP). RESULTS: The most common clinical findings were abnormal demeanour and general condition (87%), decreased rumen motility (72%), poorly digested faeces (57%), decreased rumen fill (49%), fever (43%) and tachycardia (26%). In 58% of the cattle, at least one of three tests for reticular foreign bodies (pinching of the withers, pressure on the xiphoid and percussion of the abdominal wall) was positive, and in 42% all three tests were negative. The most common haematological findings were decreased haematocrit in 45% of cattle and leukocytosis in 42%. An increase in the concentration of fibrinogen in 69% of cattle and total protein in 64% were the main biochemical findings. The glutaraldehyde test time was decreased with coagulation occurring within 6 min in 75% of cattle. CONCLUSIONS: In many cases, a diagnosis of TRP is not possible based on individual clinical or laboratory findings because even the most common abnormalities are not seen in all cattle with TRP. PMID- 29506500 TI - Community-based maternal, newborn, and child health surveillance: perceptions and attitudes of local stakeholders towards using mobile phone by village health volunteers in the Kenge Health Zone, Democratic Republic of Congo. AB - BACKGROUND: In early 2016, we implemented a community-based maternal, newborn, and child health (MNCH) surveillance using mobile phones to collect, analyze, and use data by village health volunteers (VHV) in Kenge Health Zone (KHZ), in the Democratic Republic of Congo (DRC). The objective of this study was to determine the perceptions of households, attitudes of community health volunteers, and opinions of nurses in Health center and administrative authorities towards the use of mobile phones for MNCH surveillance in the rural KHZ in the DRC. METHODS: We used mixed methods combining phenomenological and descriptive cross-sectional study. Between 3 and 24 March 2016, we collected the data through focus group discussions (FGD) with households, and structured interviews with VHV, local health and administrative authority, and nurses to explore the perceptions on MNCH surveillance using mobile phone. Data from the FGD and interviews were analyzed using thematic analysis techniques and descriptive statistics respectively. RESULTS: Health issues and services for under-five children were well known by community; however, beliefs and cultural norms contributed to the practices of seeking behavior for households. Mobile phones were perceived as devices that render quick services for people who needed help; and the community's attitudes towards the mobile phone use for collection of data, analysis, and use activities were good. Although some of community members did not see a direct linkage between this surveillance approach and health benefits, majority believed that there would be better MNCH services with the use of mobile phone. In addition, VHV will benefit from free healthcare for households and some material benefits and training. The best time to undertake these activities were in the afternoon with mother of the child, being the best respondent at the household. CONCLUSION: Health issues and services for under-five children are well known and MNCH surveillance using mobile phone by VHV in which the mother can be involved as respondent is accepted. PMID- 29506501 TI - Morbidity and mortality related to pneumonia and TRACHEOBRONCHITIS in ICU after lung transplantation. AB - BACKGROUND: Bacterial respiratory infections (BRI) are major complications contributing to increased morbidity and mortality after lung transplantation (LT). This study analyzed epidemiology and outcome of 175 consecutive patients developing BRI in ICU after LT between 2006 and 2012. METHODS: Three situations were described: colonization determined in donors and recipients, pneumonia and tracheobronchitis during the first 28 postoperative days. Severity score, demographic, bacteriologic and outcome data were collected. RESULTS: 26% of donors and 31% of recipients were colonized. 92% of recipients developed BRI, including at least one episode of pneumonia in 19% of recipients. Only 21% of recipients developed BRI with an organism cultured from the donor's samples, while 40% of recipients developed BRI with their own bacteria cultured before LT. Purulent sputum appears to be an important factor to discriminate tracheobronchitis from pneumonia. When compared to patients with tracheobronchitis, those with pneumonia had longer durations of mechanical ventilation (13 [3-27] vs 3 [29], p = 0.0005) and ICU stay (24 [16-34] vs 14 [9 22], p = 0.002). Pneumonia was associated with higher 28-day (11 (32%) vs 9 (7%), p = 0.0004) and one-year mortality rates (21 (61%) vs 24 (19%), p <= 0.0001). CONCLUSIONS: These data confirm the high frequency of BRI right from the early postoperative period and the poor prognosis of pneumonia after LT. PMID- 29506502 TI - Effects of subclinical inflammation on C-reactive protein and haptoglobin levels as well as specific humoral immunity in dogs vaccinated against canine distemper and parvovirus. AB - BACKGROUND: The aim of the present study was to assess the effects of subclinical inflammation on specific humoral immunity in dogs vaccinated with Nobivac(r) DHP based on serum levels of CRP and Hp. Dogs from the group I were administered Nobivac(r) DHP, the vaccine against distemper, infectious hepatitis and parvovirus whereas group II animals received subcutaneous turpentine oil to induce subclinical inflammation, followed by Nobivac(r) DHP after 24 h. Animals in group III received only turpentine oil in the way and amount identical to that as in group II. RESULTS: Nobivac DHP relatively poorly induced the immune inflammatory response showing good immunogenic properties, which was evidenced by only a double increase in mean CRP and Hp levels associated with antigenic stimulation in group I. In group II, serum neutralization (SN) and haemagglutination inhibition (HI) results were quite closely correlated with serum levels of CPR and Hp. CONCLUSIONS: Our findings suggest that the efficacy of vaccinations in dogs can be significantly affected by subclinical inflammations, which is indicated by a correlation between serum CRP and Hp levels versus antibody titres for canine distemper and parvovirus in both experimental groups of dogs (group I and II). The correlation of mean CRP and Hp values in dogs with subclinical inflammation and after vaccination with the kinetics of increasing antibody titres against distemper and parvovirus in group II dogs reflects the severity of inflammatory response and the extent of specific humoral immunity. Routine determinations of serum CRP and Hp levels as the indices of inflammation severity can be the essential biochemical markers for assessment of dogs' health in the period preceding specific immunoprophylaxis and efficacy of the vaccine. PMID- 29506503 TI - The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study. AB - BACKGROUND: Klotho, a protein linked to aging, has emerged as a pivotal player in mineral bone metabolism and might explain the relationship between chronic kidney disease (CKD) and cardiovascular disease (CVD). The present study aimed to investigate the association between serum klotho and cardiac parameters from a large-scale Korean CKD cohort. METHODS: We analyzed 2101 participants from KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort who had been measured for serum klotho levels. Left ventricular hypertrophy evaluated by left ventricular mass index (LVMI) and arterial stiffness measured by brachial-to-ankle pulse wave velocity (baPWV) were explored as cardiovascular parameters. RESULTS: Patients were 53.6 +/- 12.2 years old and 61.1% were male. The mean estimated glomerular filtration rate (eGFR) was 53.0 +/ 30.7 mL/min/1.73m2. The median serum klotho level was 536 (interquartile range [IQR]: 420-667) pg/mL. Advanced CKD stages were associated with lower serum klotho levels (P < 0.001, P for linear trend < 0.001). Ascending quartiles of klotho were significantly associated with decreased LMVI (P < 0.001, P for linear trend< 0.001). A multivariable linear regression model showed serum klotho had a significant inverse association with LVMI (beta - 0.04; 95% CI [confidence interval] -0.004, - 0.00007; P = 0.041). However, there was no significant association between serum klotho and baPWV after adjustment (beta 0.003; 95% CI 0.04, 0.05; P = 0.876). TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 28 June 2012 ( NCT01630486 ). CONCLUSIONS: Serum klotho was an independent biomarker of LVMI, but not arterial stiffness. PMID- 29506504 TI - A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD. AB - BACKGROUND: Long-acting muscarinic antagonist (LAMA) and long-acting beta2 agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies. METHODS: In this randomized, double blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 MUg, 14.4 MUg, 7.2 MUg, and 3.6 MUg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 MUg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h (AUC0-12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study. RESULTS: All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 MUg and 14.4 MUg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 MUg versus placebo MDI for the proportion of patients achieving >=12% improvement in FEV1. No nominally significant differences were observed between GP MDI 28.8 MUg and GP MDI 14.4 MUg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings. CONCLUSIONS: This study indicated that there was no advantage of GP MDI 28.8 MUg compared with GP MDI 14.4 MUg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 MUg as the most appropriate dose for use in the Phase III clinical studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01350128). Registered May 09, 2011. PMID- 29506505 TI - Pathology of carbon monoxide poisoning in two cats. AB - BACKGROUND: Carbon monoxide (CO), a common cause of poisoning in human beings has also been implicated in the death of animals. Though there are multiple studies on CO poisoning and relevant lethal blood COHb concentrations in humans, there are no reliable reports of diagnostic lethal carboxyhemoglobin percentage of saturation (COHb%) in cats. Additionally, due to shared housing environments, exposures to companion animals can be a surrogate for lethal exposures in human beings and provide valuable information in concurrent forensic investigations. CASE PRESENTATION: Two adult Singapura brown ticked cats were submitted to the California Animal Health and Food Safety Laboratory (CAHFS) for necropsy and diagnostic work-up. These animals were found dead along with their two deceased owners. Similar lesions were observed in both cats. At necropsy, gross lesions consisted of multifocal, large, irregular, bright red spots on the skin of the abdomen and the inner surface of ear pinnae, bright red muscles and blood. The carcasses, and tissues fixed in formalin retained the bright red discoloration for up to two weeks. Microscopic lesions included diffuse pulmonary congestion and edema, and multifocal intense basophilia of cardiomyocytes mostly affecting whole fibers or occasionally a portion of the fiber. Based on the clinical history,gross and microscopic changes, cyanide or carbon monoxide poisoning was suspected. Blood samples analyzed for carbon monoxide showed 57 and 41% carboxyhemoglobin COHb%. Muscle samples were negative for cyanide. CONCLUSION: There are no established reference values for lethal COHb concentration in cats. The COHb % values detected in this case which fell within the lethal range reported for other species, along with the gross lesions and unique histological findings in the heart suggest a helpful criteria for diagnosis of CO intoxication associated death in cats. This case demonstrates that since pets share the same environment as human beings and often are a part of their activities, they can be useful adjuncts in potential forensic investigations to help solve human cases. PMID- 29506507 TI - Ki-67 expression predicts biochemical recurrence after radical prostatectomy in the setting of positive surgical margins. AB - BACKGROUND: Positive surgical margin (PSM) is a predictor of biochemical recurrence (BCR) following radical prostatectomy (RP). Attempts to stratify PSM based on linear length, Gleason score, location and number have failed to add to predictive models using margin status alone. We evaluated the prognostic significance of Ki-67 expression in this setting. METHODS: Immunohistochemical staining for Ki-67 was done on prostatectomy specimens from 117 patients who had a PSM. Ki67 expression was measured at the margin and in the index lesion. Patients were dichotomized based on Ki-67 expression into three groups. Group 1 with no Ki-67 expression, Group 2 with Ki-67 <= 2%, and Group 3 with Ki-67 >= 3%. To eliminate the impact of the adjuvant treatment (AT) on the outcome, data were analyzed by the Cox proportional hazards in which AT was Considered as a time dependent covariate. RESULTS: The discordance rate of Ki-67 expression between matched index lesion and margin specimens was 44/117 (37.6%). There was a trend for higher risk of BCR (HR:2.06, (0.97-4.43), P = 0.06) in patients expressing high Ki67 at the surgical margin although this was not statistically significant. However High Ki-67 expression in the index lesion was an independent predictive factor for BCR in this subset of patients. (HR:4, (1.64-9.80), P = 0.002). CONCLUSION: High Ki67 expression in the index prostate cancer lesion is an independent predictor of BCR in patients with positive surgical margin following radical prostatectomy. Our findings need to be validated in a larger cohort. PMID- 29506508 TI - Petri net-based prediction of therapeutic targets that recover abnormally phosphorylated proteins in muscle atrophy. AB - BACKGROUND: Muscle atrophy, an involuntary loss of muscle mass, is involved in various diseases and sometimes leads to mortality. However, therapeutics for muscle atrophy thus far have had limited effects. Here, we present a new approach for therapeutic target prediction using Petri net simulation of the status of phosphorylation, with a reasonable assumption that the recovery of abnormally phosphorylated proteins can be a treatment for muscle atrophy. RESULTS: The Petri net model was employed to simulate phosphorylation status in three states, i.e. reference, atrophic and each gene-inhibited state based on the myocyte-specific phosphorylation network. Here, we newly devised a phosphorylation specific Petri net that involves two types of transitions (phosphorylation or de phosphorylation) and two types of places (activation with or without phosphorylation). Before predicting therapeutic targets, the simulation results in reference and atrophic states were validated by Western blotting experiments detecting five marker proteins, i.e. RELA, SMAD2, SMAD3, FOXO1 and FOXO3. Finally, we determined 37 potential therapeutic targets whose inhibition recovers the phosphorylation status from an atrophic state as indicated by the five validated marker proteins. In the evaluation, we confirmed that the 37 potential targets were enriched for muscle atrophy-related terms such as actin and muscle contraction processes, and they were also significantly overlapping with the genes associated with muscle atrophy reported in the Comparative Toxicogenomics Database (p-value < 0.05). Furthermore, we noticed that they included several proteins that could not be characterized by the shortest path analysis. The three potential targets, i.e. BMPR1B, ROCK, and LEPR, were manually validated with the literature. CONCLUSIONS: In this study, we suggest a new approach to predict potential therapeutic targets of muscle atrophy with an analysis of phosphorylation status simulated by Petri net. We generated a list of the potential therapeutic targets whose inhibition recovers abnormally phosphorylated proteins in an atrophic state. They were evaluated by various approaches, such as Western blotting, GO terms, literature, known muscle atrophy-related genes and shortest path analysis. We expect the new proposed strategy to provide an understanding of phosphorylation status in muscle atrophy and to provide assistance towards identifying new therapies. PMID- 29506509 TI - Development of a new valid and reliable microsurgical skill assessment scale for ophthalmology residents. AB - BACKGROUND: More and more concerns have been arisen about the ability of new medical graduates to meet the demands of today's practice environment. In this study, we wanted to develop a valid, reliable and standardized assessment tool for evaluating the basic microsurgical skills of residents in a microsurgery laboratory, to get them well prepared before entering the surgical realm of ophthalmology. METHODS: Twenty-three experts who have teaching experience reviewed the assessment scale. Constructive comments were incorporated to ensure face and content validity. Twenty-one attendings from different specialties then graded eight corneal rupture suturing videos with the scale to investigate interrater reliability. Fourteen of them graded the same videos 3 months later to investigate intrarater reliability (repeatability). RESULTS: A total of 280 assessment scales were completed. All the ICC values of interrater reliability were greater than 0.8 with 75% data greater than 0.9 (range 0.860-0.976). All the ICC values of intrarater reliability (repeatability) were also greater than 0.8 with 63% data greater than 0.9 (range 0.833-0.954). CONCLUSIONS: The assessment scale we developed is valid and reliable. This tool could be useful to ensure that junior residents achieve a certain level of microsurgical technique in a laboratory environment before training in the operation room. Hopefully, this tool will provide a structured template for other residency programs to assess their residents for basic microsurgical skills. PMID- 29506510 TI - Predictive multi-imaging biomarkers relevant for visual acuity in idiopathic macular telangiectasis type 1. AB - BACKGROUND: To evaluate the structural changes associated with visual acuity (VA) in patients with idiopathic macular telangiectasia (MT) type 1 using multimodal imaging modalities. METHODS: A retrospective study of 14 patients with MT type 1 and of 10 eyes from 10 healthy individuals as age-matched controls was conducted. The medical records of patients who had undergone colour fundus photography, spectral domain optical coherence tomography (OCT), fluorescein angiography and OCT angiography were reviewed. Central macular thickness (CMT), the areas of macular oedema and ellipsoid zone (EZ) disruption, EZ length, disorganization of the retinal inner layers (DRIL) and external limiting membrane (ELM) disruption, as measured by spectral domain OCT; and vascular density and the foveal avascular zones (FAZ) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP), as measured by OCT angiography, were assessed in MT type 1 eyes and correlated with VA. RESULTS: The mean baseline best-corrected VA of MT type 1 eyes was 0.45 +/- 0.28. The mean CMT was 385.19 +/- 75.21 MUm in MT type 1 eyes and 252.43 +/- 15.77 MUm in contralateral eyes (Z = - 4.113, p < 0.001). The mean vessel density of the DCP was lower in MT type 1 eyes (47.25 +/- 4.69%) than in contralateral eyes (53.93 +/- 2.94%) and normal eyes (59.37 +/- 2.50%) (Z = - 3.492, - 4.099; p < 0.001, < 0.001). The baseline logMAR VA was correlated with CMT (r = 0.682, p = 0.007), SCP density (r = - 0.652, p = 0.012), DCP density (r = - 0.700, p = 0.005), total area of EZ disruption (r = 0.649, p = 0.012); and total lengths of EZ (r = 0.681, p = 0.007), ELM (r = 0.699, p = 0.005) and DRIL (r = 0.707, p = 0.005) disruption in the 1-mm-diameter foveal region in MT type 1 eyes. CONCLUSIONS: Decreased DCP density and the presence of DRIL may be predictive biomarkers of VA in MT type 1. CMT, SCP density, total area of EZ disruption, and lengths of EZ and ELM disruption within the 1-mm-diameter central region were strongly associated with VA. PMID- 29506506 TI - Cancer stem cells as key drivers of tumour progression. AB - BACKGROUND: Cancer stem cells (CSCs) are subpopulations of cancer cells sharing similar characteristics as normal stem or progenitor cells such as self-renewal ability and multi-lineage differentiation to drive tumour growth and heterogeneity. Throughout the cancer progression, CSC can further be induced from differentiated cancer cells via the adaptation and cross-talks with the tumour microenvironment as well as a response from therapeutic pressures, therefore contributes to their heterogeneous phenotypes. Challengingly, conventional cancer treatments target the bulk of the tumour and are unable to target CSCs due to their highly resistance nature, leading to metastasis and tumour recurrence. MAIN BODY: This review highlights the roles of CSCs in tumour initiation, progression and metastasis with a focus on the cellular and molecular regulators that influence their phenotypical changes and behaviours in the different stages of cancer progression. We delineate the cross-talks between CSCs with the tumour microenvironment that support their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation in response to therapeutic pressure. An insight into the distinct roles of CSCs in promoting angiogenesis and metastasis has been captured based on in vitro and in vivo evidences. CONCLUSION: Given dynamic cellular events along the cancer progression and contributions of resistance nature by CSCs, understanding their molecular and cellular regulatory mechanism in a heterogeneous nature, provides significant cornerstone for the development of CSC-specific therapeutics. PMID- 29506512 TI - Euthanasia and assisted suicide for people with an intellectual disability and/or autism spectrum disorder: an examination of nine relevant euthanasia cases in the Netherlands (2012-2016). AB - BACKGROUND: Euthanasia and assisted suicide (EAS) have been legally possible in the Netherlands since 2001, provided that statutory due care criteria are met, including: (a) voluntary and well-considered request; (b) unbearable suffering without prospect of improvement; (c) informing the patient; (d) lack of a reasonable alternative; (e) independent second physician's opinion. 'Unbearable suffering' must have a medical basis, either somatic or psychiatric, but there is no requirement of limited life expectancy. All EAS cases must be reported and are scrutinised by regional review committees (RTE). The purpose of this study was to investigate whether any particular difficulties arise when the EAS due care criteria are applied to patients with an intellectual disability and/or autism spectrum disorder. METHODS: The 416 case summaries available on the RTE website (2012-2016) were searched for intellectual disability (6) and autism spectrum disorder (3). Direct content analysis was used on these nine cases. RESULTS: Assessment of decisional capacity was mentioned in eight cases, but few details given; in two cases, there had been uncertainty or disagreement about capacity. Two patients had progressive somatic conditions. For most, suffering was due to an inability to cope with changing circumstances or increasing dependency; in several cases, suffering was described in terms of characteristics of living with an autism spectrum disorder, rather than an acquired medical condition. Some physicians struggled to understand the patient's perspective. Treatment refusal was a common theme, leading physicians to conclude that EAS was the only remaining option. There was a lack of detail on social circumstances and how patients were informed about their prognosis. CONCLUSIONS: Autonomy and decisional capacity are highly complex for patients with intellectual disabilities and difficult to assess; capacity tests in these cases did not appear sufficiently stringent. Assessment of suffering is particularly difficult for patients who have experienced life-long disability. The sometimes brief time frames and limited number of physician-patient meetings may not be sufficient to make a decision as serious as EAS. The Dutch EAS due care criteria are not easily applied to people with intellectual disabilities and/or autism spectrum disorder, and do not appear to act as adequate safeguards. PMID- 29506511 TI - Hospital readmissions with acute infectious diseases in New Zealand children < 2 years of age. AB - BACKGROUND: Infectious diseases are the leading cause of hospital admissions in young children. Hospitalisation with an infectious disease is a recurrent event for some children. Our objective was to describe risk factors for infectious disease readmission following hospital admission with an infectious disease in the first two years of life. METHODS: We performed a national cohort study of New Zealand children, born 2005-2009, with an infectious disease admission before age 24 months. Children readmitted with an infectious disease within 12 months of the first infectious disease admission were identified. Every infectious disease admission was categorised as a respiratory, enteric, skin and soft tissue, urinary or other infection. Independent associations of demographic and child health factors with infectious disease readmission were determined using multiple variable logistic regression. RESULTS: From 2005 to 2011, there were 69,902 infectious disease admissions for 46,657 children less than two years old. Of these 46,657 children, 10,205 (22%) had at least one infectious disease readmission within 12 months of their first admission. The first infectious disease admission was respiratory (54%), enteric (15%), skin or soft tissue (7%), urinary (4%) or other (20%). Risk of infectious disease readmission was increased if the first infectious disease admission was respiratory (OR = 1.87, 95% CI 1.78 1.95) but not if it was in any other infectious disease category. Risk factors for respiratory infectious disease readmission were male gender, Pacific or Maori ethnicity, greater household deprivation, presence of a complex chronic condition, or a first respiratory infectious disease admission during autumn or of >=3 days duration. Fewer factors (younger age, male gender, presence of a complex chronic condition) were associated with enteric infection readmission. The presence of a complex chronic condition was the only factor associated with urinary tract infection readmission and none of the factors were associated with skin or soft tissue infection readmission. CONCLUSIONS: In children less than two years old, infectious disease readmission risk is increased if the first infectious disease admission is a respiratory infectious disease but not if it is another infectious disease category. Risk factors for respiratory infectious disease readmission are different from those for other infectious disease readmissions. PMID- 29506513 TI - Risk assessment of occupational exposure to heavy metal mixtures: a study protocol. AB - BACKGROUND: Sfax is a very industrialized city located in the southern region of Tunisia where heavy metals (HMs) pollution is now an established matter of fact. The health of its residents mainly those engaged in industrial metals-based activities is under threat. Indeed, such workers are being exposed to a variety of HMs mixtures, and this exposure has cumulative properties. Whereas current HMs exposure assessment is mainly carried out using direct air monitoring approaches, the present study aims to assess health risks associated with chronic occupational exposure to HMs in industry, using a modeling approach that will be validated later on. METHODS: To this end, two questionnaires were used. The first was an identification/descriptive questionnaire aimed at identifying, for each company: the specific activities, materials used, manufactured products and number of employees exposed. The second related to the job-task of the exposed persons, workplace characteristics (dimensions, ventilation, etc.), type of metals and emission configuration in space and time. Indoor air HMs concentrations were predicted, based on the mathematical models generally used to estimate occupational exposure to volatile substances (such as solvents). Later on, and in order to validate the adopted model, air monitoring will be carried out, as well as some biological monitoring aimed at assessing HMs excretion in the urine of workers volunteering to participate. Lastly, an interaction-based hazard index HIint and a decision support tool will be used to predict the cumulative risk assessment for HMs mixtures. DISCUSSION: One hundred sixty-one persons working in the 5 participating companies have been identified. Of these, 110 are directly engaged with HMs in the course of the manufacturing process. This model-based prediction of occupational exposure represents an alternative tool that is both time-saving and cost-effective in comparison with direct air monitoring approaches. Following validation of the different models according to job processes, via comparison with direct measurements and exploration of correlations with biological monitoring, these estimates will allow a cumulative risk characterization. PMID- 29506514 TI - Development and validation of the quality care questionnaire -palliative care (QCQ-PC): patient-reported assessment of quality of palliative care. AB - BACKGROUND: In this study, we aimed to develop and validate an instrument that could be used by patients with cancer to evaluate their quality of palliative care. METHODS: Development of the questionnaire followed the four-phase process: item generation and reduction, construction, pilot testing, and field testing. Based on the literature, we constructed a list of items for the quality of palliative care from 104 quality care issues divided into 14 subscales. We constructed scales of 43 items that only the cancer patients were asked to answer. Using relevance and feasibility criteria and pilot testing, we developed a 44-item questionnaire. To assess the sensitivity and validity of the questionnaire, we recruited 220 patients over 18 years of age from three Korean hospitals. RESULTS: Factor analysis of the data and fit statistics process resulted in the 4-factor, 32-item Quality Care Questionnaire-Palliative Care (QCQ PC), which covers appropriate communication with health care professionals (ten items), discussing value of life and goals of care (nine items), support and counseling for needs of holistic care (seven items), and accessibility and sustainability of care (six items). All subscales and total scores showed a high internal consistency (Cronbach alpha range, 0.89 to 0.97). Multi-trait scaling analysis showed good convergent (0.568-0.995) and discriminant (0.472-0.869) validity. The correlation between the total and subscale scores of QCQ-PC and those of EORTC QLQ-C15-PAL, MQOL, SAT-SF, and DCS was obtained. CONCLUSION: This study demonstrates that the QCQ-PC can be adopted to assess the quality of care in patients with cancer. PMID- 29506515 TI - A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy. AB - BACKGROUND: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. METHODS: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. RESULTS: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. CONCLUSIONS: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH. PMID- 29506516 TI - miR-221-5p enhances cell proliferation and metastasis through post transcriptional regulation of SOCS1 in human prostate cancer. AB - BACKGROUND: To investigate the effect of miR-221-5p on cell proliferaton and metastasis of human prostate cancer in vitro and vivo. METHODS: We established PC3 cell lines with stable overexpression or silencing of miRNA-221-5p via lentivirus infection. miRNA-221-5p and its target gene SOCS1 expression levels in the stable cells were analyzed by real-time polymerase chain reaction (RT-PCR) and western blotting. Using luciferase reporter assays to study the relationship between miR-221-5p and SOCS1. Cell proliferative activity was measured using the MTT assay and colony formation assay. Migration ability was assessed using wound healing assay and transwell assay. To further study the function of miR-221-5p in human prostate cancer we established nude mice xenograft model in vivo. RESULTS: miR-221-5p regulates the proliferation, migration of prostate cancer cells in vitro and tumorigenesis in vivo by regulating socs1 expression through targeted its 3'UTR, and miR-221-5p regulates MAPK/ERK signaling pathway and EMT features in prostate cancer cells. CONCLUSIONS: Up-regulation and silencing of miR-221-5p expression in prostate cancer cells are correlated with cell proliferation, migration and tumorigenesis, which suggest that miR-221-5p plays an important role in prostate cancer progression. PMID- 29506517 TI - Rhaponticum acaule (L) DC essential oil: chemical composition, in vitro antioxidant and enzyme inhibition properties. AB - BACKGROUND: alpha-glucosidase is a therapeutic target for diabetes mellitus (DM) and alpha-glucosidase inhibitors play a vital role in the treatments for the disease. Furthermore, xanthine oxidase (XO) is a key enzyme that catalyzes hypoxanthine and xanthine to uric acid which at high levels can lead to hyperuricemia which is an important cause of gout. Pancreatic lipase (PL) secreted into the duodenum plays a key role in the digestion and absorption of fats. For its importance in lipid digestion, PL represents an attractive target for obesity prevention. METHODS: The flowers essential oil of Rhaponticum acaule (L) DC (R. acaule) was characterized using gas chromatography-mass spectrometry (GC-MS). The antioxidant activities of R. acaule essential oil (RaEO) were also determined using 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), reducing power, phosphomolybdenum, and DNA nicking assays. The inhibitory power of RaEO against alpha-glucosidase, xanthine oxidase and pancreatic lipase was evaluated. Enzyme kinetic studies using Michaelis-Menten and the derived Lineweaver-Burk (LB) plots were performed to understand the possible mechanism of inhibition exercised by the components of this essential oil. RESULTS: The result revealed the presence of 26 compounds (97.4%). The main constituents include germacrene D (49.2%), methyl eugenol (8.3%), (E)-beta-ionone (6.2%), beta caryophyllene (5.7%), (E,E)-alpha-farnesene (4.2%), bicyclogermacrene (4.1%) and (Z)-alpha-bisabolene (3.7%). The kinetic inhibition study showed that the essential oil demonstrated a strong alpha-glucosidase inhibiton and it was a mixed inhibitor. On the other hand, our results evidenced that this oil exhibited important xanthine oxidase inhibitory effect, behaving as a non-competitive inhibitor. The essential oil inhibited the turkey pancreatic lipase, with maximum inhibition of 80% achieved at 2 mg/mL. Furthermore, the inhibition of turkey pancreatic lipase by RaEO was an irreversible one. CONCLUSION: The results revealed that the RaEO is a new promising potential source of antioxidant compounds, endowed with good practical applications for human health. PMID- 29506518 TI - Educational status and beliefs regarding non-communicable diseases among children in Ghana. AB - BACKGROUND: Increasing prevalence of non-communicable diseases (NCDs) has been observed in Ghana as in other developing countries. Past research focused on NCDs among adults. Recent researches, however, provide evidence on NCDs among children in many countries, including Ghana. Beliefs about the cause of NCDs among children may be determined by the socioeconomic status of parents and care givers. This paper examines the relationship between educational status of parents and/or care givers of children with NCDs on admission and their beliefs regarding NCDs among children. METHODS: A total of 225 parents and/or care givers of children with NCDS hospitalized in seven hospitals in three regions (Greater Accra, Ashanti and Volta) were selected for the study. Statistical techniques, including the chi-square and multinomial logistic regression, were used for the data analysis. RESULTS: Educational status is a predictor of care giver's belief about whether enemies can cause NCDs among children or not. This is the only belief with which all the educational categories have significant relationship. Also, post-secondary/polytechnic (p-value =0.029) and university (p-value = 0.009) levels of education are both predictors of care givers being undecided about the belief that NCDs among children can be caused by enemies, when background characteristics are controlled for. Significant relationship is found between only some educational categories regarding the other types of beliefs and NCDs among children. For example, those with Middle/Juniour Secondary School (JSS)/Juniour High School (JHS) education are significantly undecided about the belief that the sin of parents can cause NCDs among children. CONCLUSIONS: Education is more of a predictor of the belief that enemies can cause NCDs among children than the other types of beliefs. Some categories of ethnicity, residential status and age have significant relationship with the beliefs when background characteristics of the parents and/or care givers were controlled for. PMID- 29506520 TI - Prevalence of metabolic syndrome in Saudi Arabia - a cross sectional study. PMID- 29506519 TI - RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs. AB - BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes. RESULTS: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3% 89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes. CONCLUSIONS: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis. PMID- 29506521 TI - Water extract of Semecarpus parvifolia Thw. leaves inhibits cell proliferation and induces apoptosis on HEp-2 cells. AB - BACKGROUND: Semecarpus parvifolia Thw is used as an ingredient of poly herbal decoctions to treat cancer in traditional medicine. The present study aims to investigate the antiproliferative activity on HEp 2 cells by the water extract of S. parvifolia leaves and to evaluate potential mechanisms. METHODS: The plant extract was exposed to S. parvifolia for 24 hours and antiproliferative activity was quantified by Sulforhodamine B (SRB), 3-(4, 5-dimethythiazol-2-yl)-2, 5 diphenyl tetrazolium bromide (MTT) and Lactate dehydrogenase (LDH) assays. Morphological changes were observed after staining cells with ethidium bromide/acridine orange (EB/AO) and Giemsa dye. Comet assay was performed to evaluate the DNA damage. The toxicity of the plant extract was determined by brine shrimp lethality assay. RESULTS: S. parvifolia leaves reduced the cell proliferation in a dose and time dependent manner. A two fold increase in NO level was observed at higher concentrations. Morphological changes characteristic to apoptosis were observed in light microscopy, Giemsa and EB/AO stained cells. Fragmented DNA further confirmed its capacity to induce apoptosis. No lethality was observed with brine shrimps. CONCLUSION: The results suggest that Semecarpus parvifolia Thw induces apoptosis in HEp-2 cells through a NO dependent pathway. PMID- 29506522 TI - Assessing short evolution brucellosis in a highly brucella endemic cattle keeping population of Western Uganda: a complementary use of Rose Bengal test and IgM rapid diagnostic test. AB - BACKGROUND: Brucellosis is a worldwide and zoonotic disease often sadly misdiagnosed in endemic areas. Challenges of availability and accessibility of diagnostic tools are common in resource constrained populations where the most vulnerable are found, surveillance and diagnosis are limited too. METHODS: A cross-sectional study using a simple two stage cluster sampling method was conducted to measure short evolution brucellosis burden among cattle keeping households that are one of the highest risk populations to be exposed to Brucella infection. A total of 216 households were randomly selected from 18 rural villages from the Western Region of Uganda. Household blood samples were tested for Brucella antibodies using the highly sensitive Rose Bengal test (RBT) and IgM ELISA Lateral Flow Assay (LFA). RESULTS: Among the total tested population, 58.8% did not react with any of the tests, 13.4% reacted with both tests. Among those that reacted with both (N = 29), 62.1% had weak (+ 1) LFA staining, 34.5% had moderate (2+) LFA staining. Altogether, both weak and moderate staining (96.5%) are consistent with sub-acute disease, while only one (3.4%) had strong (3+) LFA staining consistent with acute infection. 19.4% of the samples tested positive only with RBT, consistent with chronic infection, eighteen samples (8.3%) reacted exclusively with IgM LFA. CONCLUSION: We identified a high prevalence of short evolution brucellosis in the cattle keeping household members. Prevalence of chronic infection diagnosed with RBT only was higher than the prevalence of short evolution brucellosis. IgM LFA results depict possible cases of cross reaction with Salmonella spp., Plasmodium etc. Ultimately, we identified a consistent prevalence of short evolution brucellosis in the cattle keeping household members. Indeed, the use of a combined diagnostic with LFA and RBT is easy and amenable for an active disease surveillance and accurate diagnosis in rural settings. PMID- 29506523 TI - Cardiovascular magnetic resonance measures of aortic stiffness in asymptomatic patients with type 2 diabetes: association with glycaemic control and clinical outcomes. AB - BACKGROUND: We aimed to investigate in patients with type 2 diabetes whether aortic stiffness is: (i) associated with glycaemic control, (ii) associated with adverse outcomes and (iii) can be reversed on treatment with RAAS inhibition. METHODS: Patients with type 2 diabetes (N = 94) and low vascular risk underwent assessment of cardiovascular risk and CMR assessment of ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (PWV). Of these patients a subgroup with recent onset microalbuminuria (N = 25) were treated with renin-angiotensin-aldosterone system (RAAS) inhibition and imaging repeated after 1 year. All 94 patients were followed up for 2.4 years for major adverse cardiovascular disease (CVD) events including myocardial infarction detected on late gadolinium enhancement CMR. RESULTS: Ascending aortic distensibility, DAD and PWV all had a significant association with age and 24 h systolic blood pressure but only AAD had a significant association with glycaemic control, measured as HbA1c (Beta - 0.016, P = 0.04). The association between HbA1c and AAD persisted even after correction for age and hypertension. CVD events occurred in 19/94 patients. AAD, but not DAD or PWV, was associated with CVD events (hazard ratio 0.49, 95% confidence interval 0.25-0.95, P = 0.01). On treatment with RAAS inhibition, AAD, but not DAD or PWV, showed significant improvement from 1.51 +/- 1.15 to 1.97 +/- 1.07 10 3 mmHg-1, P = 0.007. CONCLUSIONS: Ascending aortic distensibility measured by CMR is independently associated with poor glycaemic control and adverse cardiovascular events. Furthermore it may be reversible on treatment with RAAS inhibition. AAD is a promising marker of cardiovascular risk in asymptomatic patients with type 2 diabetes and has potential use as a surrogate cardiovascular endpoint in studies of novel hypoglycaemic agents. Clinical trials registration https://clinicaltrials.gov/ct2/show/NCT01970319. PMID- 29506524 TI - Crossed beaks in a local Swiss chicken breed. AB - BACKGROUND: Crossed beaks have been reported to occur in Appenzeller Barthuhn, a local Swiss chicken breed. The assumed causes for this beak deformity which are also seen in other bird species including domestic chickens, range from environmental influences to genetic factors. The aim of this project was to characterize the prevalence, the phenotype, and the underlying genetics of crossed beaks in Appenzeller Barthuhn chickens. RESULTS: The estimated prevalence of 7% crossed beaks in Appenzeller Barthuhn was significantly higher compared to two other local Swiss chicken breeds. A breeding trial showed significantly higher prevalence of offspring with deformed beaks from mating of affected parents compared to mating of non-affected parents. Examination of 77 Appenzeller Barthuhn chickens with crossed beaks showed a variable phenotype presentation. The deviation of the beak from the median plane through the head ranged from 1 degrees to 61 degrees . In more than 60% of the cases, the upper and lower beak were bent in the same direction, whereas the remaining cases showed different forms of crossed beaks. Computed tomographic scans and bone maceration of the head of two chickens with crossed beaks revealed that the maxilla and the mandibula were affected, while other parts of the skull appeared to be normal. The gene LOC426217, a member of the keratin family, was postulated as a candidate gene for beak deformity in domestic chickens. Sequencing of the coding region revealed two significantly associated synonymous variants for crossed beaks in Appenzeller Barthuhn chickens. A genome-wide association study and a comparative analysis of runs of homozygosity based on high-density SNP array genotyping data of 53 cases and 102 controls showed no evidence of association. CONCLUSIONS: The findings suggest a hereditary cause of crossed beaks in Appenzeller Barthuhn chickens. However, the observed variation in the phenotype, together with the inconclusive molecular genetic results indicates the need for additional research to unravel the genetic architecture of this beak deformity. PMID- 29506525 TI - Serum lipids as an indicator for the alteration of liver function in patients with hepatitis B. AB - BACKGROUND: Hepatitis B virus (HBV) exerts an intense impact on host lipid metabolism. Hence the aim of present study is to determine metabolic derangement that occurred in subjects suffering from hepatitis B patients. METHODS: The fasting blood samples were collected from hepatitis B patients (n = 50) attended in Taluka hospital TandoAdam, Sindh with age and gender matched controls (n = 50). Serum lipid profile and fatty acid (FA) composition were analyzed by micro lab and gas chromatography. RESULTS: The hepatitis B patients have significantly lower level (p < 0.01) of lipid profile including total cholesterol (TC), triacylglyceride (TAG), high density lipoprotein-C (HDL-C) very low density lipoprotein-cholesterol (VLDL-C), low density lipoprotein-cholesterol (LDL-C), and total lipid (TL) in comparison to controls, indicating hypolipidemia in patients. The result of total FA composition of HBV patients in comparison to controls reveal that myristic, palmitic, docosahexaenoic acids were significantly (p < 0.05) higher, while linoleic, eicosatrienoic, arachidonic, eicosapentaenoic acids were lower in HBV patients in comparison to controls. The elongase, ?5 and ?6-desaturase enzymes activities were found lower, while ?9-desaturase activity was higher in hepatitis B patients as compared to controls, which indicates the impaired lipid metabolism. CONCLUSION: The serum saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) were increased while polyunsaturated fatty acid (PUFA) was reduced in both total and free form in hepatitis B patients due to altered activities of enzyme desaturases with impaired PUFA metabolism and non enzymatic oxidation. PMID- 29506526 TI - Racial disparities of differentiated thyroid carcinoma: clinical behavior, treatments, and long-term outcomes. AB - BACKGROUND: The incidence of thyroid cancer in black Americans is significantly lower than that in white Americans, and the impact of race on the prognosis of thyroid cancer remains controversial. The purpose of this study was to determine the risk factors for survival in black and white patients and to compare the survival of differentiated thyroid carcinoma subtypes between these two races. We further investigated the association of lymph node and distant metastases with races. METHODS: This is a retrospective analysis using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A total of 70,346 cases were included in our study. Patients' demographics and cancer- and treatment-related characteristics were compared between the black and white Americans using chi-square and Fisher's exact tests. For multivariate analysis, Cox proportional hazards regression were used to assess the association between potential risk factors and the survival in black and white patients. RESULT: Black Americans had a worse overall survival than white Americans (HR = 1.127, P = 0.002). While disease-specific survival (DSS) was comparable, the risk factors for DSS were different between white and black Americans. Black Americans had less lymph node metastasis of classical variant papillary thyroid carcinoma (CPTC, OR = 0.476, P < 0.001) and follicular variant papillary thyroid carcinoma (FVPTC, OR = 0.522, P < 0.001), but not follicular thyroid carcinoma (FTC). However, black Americans with FVPTC, but not CPTC or FTC, had a higher potential of distant metastasis (OR = 1.715, P = 0.026). Furthermore, only white patients with tumor > 2 cm and lymph node metastasis benefited from radioactive iodine. CONCLUSIONS: The risk factors for DSS were significantly different in white and black patients. The impact of race should be considered in treatment strategy for thyroid cancer. PMID- 29506527 TI - Analysis of polymorphisms in the circumsporozoite protein gene of Plasmodium vivax isolates from Henan Province, China. AB - BACKGROUND: Plasmodium vivax malaria has historically been a major source of disease in Henan, China. In the 1970s, the morbidity of malaria was highest in the country. With support from the government and the efforts of healthcare personnel, the reported malaria cases have declined dramatically and a national elimination programme was launched in 2010. To achieve the goal, it is essential to study the diversity of autochthonous malaria and transmission of Plasmodium parasites, which will provide baseline data for disease control and management. METHODS: Thirty-two P. vivax isolates from Henan province were collected from 2008 to 2011, and circumsporozoite protein (csp) genes were analysed to estimate the genetic diversity of this parasite. RESULTS: The assessment of csp sequences indicated that all the isolates were the VK210 type, however, none of them was identical to the VK210 strain. The sequences displayed variations in the central region, and eight sub-types were observed. Among the sub-types, HN7 was the most prevalent (37.5%), followed by HN3 (34.4%). A total of 653 repeat units were discovered in 32 Henan isolates. Nucleotide sequences were grouped in 13 unique repeat nucleotide sequence allotypes that coded for 7 different repeated amino acid allotypes. B (GNGAGGQAA) and D (GDRAAGQPA) were more frequent based on the results; they represented 53.9% (352/653) of the total. In comparison to the basic repeat units of VK210, more than 75% of the central repeat units had at least one non-synonymous nucleotide change. CONCLUSIONS: Recent P. vivax populations in Henan province showed some degree of genetic diversity in csp, with 8 sub-types among 32 samples. Meantime, the results also suggested its relative conserved parasite populations. This could provide interesting baseline data that allow identifying whether potential new cases differ from the parasites already circulating in the area. PMID- 29506529 TI - Tearing down the walls: FDA approves next generation sequencing (NGS) assays for actionable cancer genomic aberrations. AB - The United States Food and Drug Administration (FDA) recently approved the clinical use of two comprehensive 'mid-size' Next Generation Sequencing (NGS) panels calling actionable genomic aberrations in cancer. This is the first endorsement, by a regulatory body, of a new standard of care in oncology. Herein, we argue that besides its many practice-changing implications, this approval tears down the conceptual walls dividing system biology from clinical practice, diagnosis from research, prevention from therapy, cancer genetics from cancer genomics, and computational biology from empirical therapy assignment. PMID- 29506528 TI - The promising future of microalgae: current status, challenges, and optimization of a sustainable and renewable industry for biofuels, feed, and other products. AB - Microalgae have recently attracted considerable interest worldwide, due to their extensive application potential in the renewable energy, biopharmaceutical, and nutraceutical industries. Microalgae are renewable, sustainable, and economical sources of biofuels, bioactive medicinal products, and food ingredients. Several microalgae species have been investigated for their potential as value-added products with remarkable pharmacological and biological qualities. As biofuels, they are a perfect substitute to liquid fossil fuels with respect to cost, renewability, and environmental concerns. Microalgae have a significant ability to convert atmospheric CO2 to useful products such as carbohydrates, lipids, and other bioactive metabolites. Although microalgae are feasible sources for bioenergy and biopharmaceuticals in general, some limitations and challenges remain, which must be overcome to upgrade the technology from pilot-phase to industrial level. The most challenging and crucial issues are enhancing microalgae growth rate and product synthesis, dewatering algae culture for biomass production, pretreating biomass, and optimizing the fermentation process in case of algal bioethanol production. The present review describes the advantages of microalgae for the production of biofuels and various bioactive compounds and discusses culturing parameters. PMID- 29506530 TI - The effects of gait training using powered lower limb exoskeleton robot on individuals with complete spinal cord injury. AB - BACKGROUND: Powered exoskeleton can improve the mobility for people with movement deficits by providing mechanical support and facilitate the gait training. This pilot study evaluated the effect of gait training using a newly developed powered lower limb exoskeleton robot for individuals with complete spinal cord injury (SCI). METHODS: Two participants with a complete SCI were recruited for this clinical study. The powered exoskeleton gait training was 8 weeks, 1 h per session, and 2 sessions per week. The evaluation was performed before and after the training for (1) the time taken by the user to don and doff the powered exoskeleton independently, (2) the level of exertion perceived by participants while using the powered exoskeleton, and (3) the mobility performance included the timed up-and-go test, 10-m walk test, and 6-min walk test with the powered exoskeleton. The safety of the powered exoskeleton was evaluated on the basis of injury reports and the incidence of falls or imbalance while using the device. RESULTS: The results indicated that the participants were donning and doffing the powered lower limb exoskeleton robot independently with a lower level of exertion and walked faster and farther without any injury or fall incidence when using the powered exoskeleton than when using a knee-ankle-foot orthosis. Bone mineral densities was also increased after the gait training. No adverse effects, such as skin abrasions, or discomfort were reported while using the powered exoskeleton. CONCLUSIONS: The findings demonstrated that individuals with complete SCI used the powered lower limb exoskeleton robot independently without any assistance after 8 weeks of powered exoskeleton gait training. TRIAL REGISTRATION: Trial registration: National Taiwan University Hospital. TRIAL REGISTRATION NUMBER: 201210051RIB . Name of registry: Hui-Fen Mao. URL of registry: Not available. Date of registration: December 12th, 2012. Date of enrolment of the first participant to the trial: January 3rd, 2013. PMID- 29506531 TI - Group antenatal care models in low- and middle-income countries: a systematic evidence synthesis. AB - In high-income countries, group antenatal care (ANC) offers an alternative to individual care and is associated with improved attendance, client satisfaction, and health outcomes for pregnant women and newborns. In low- and middle-income country (LMIC) settings, this model could be adapted to address low antenatal care uptake and improve quality. However, evidence on key attributes of a group care model for low-resource settings remains scant. We conducted a systematic review of the published literature on models of group antenatal care in LMICs to identify attributes that may increase the relevance, acceptability and effectiveness of group ANC in such settings. We systematically searched five databases and conducted hand and reference searches. We also conducted key informant interviews with researchers and program implementers who have introduced group antenatal care models in LMICs. Using a pre-defined evidence summary template, we extracted evidence on key attributes-like session content and frequency, and group composition and organization-of group care models introduced across LMIC settings. Our systematic literature review identified nine unique descriptions of group antenatal care models. We supplemented this information with evidence from 10 key informant interviews. We synthesized evidence from these 19 data sources to identify attributes of group care models for pregnant women that appeared consistently across all of them. We considered these components that are fundamental to the delivery of group antenatal care. We also identified attributes that need to be tailored to the context in which they are implemented to meet local standards for comprehensive ANC, for example, the number of sessions and the session content. We compiled these attributes to codify a composite "generic" model of group antenatal care for adaptation and implementation in LMIC settings. With this combination of standard and flexible components, group antenatal care, a service delivery alternative that has been successfully introduced and implemented in high-income country settings, can be adapted for improving provision and experiences of care for pregnant women in LMIC. Any conclusions about the benefits of this model for women, babies, and health systems in LMICs, however, must be based on robust evaluations of group antenatal care programs in those settings. PMID- 29506532 TI - CADM2, as a new target of miR-10b, promotes tumor metastasis through FAK/AKT pathway in hepatocellular carcinoma. AB - BACKGROUND: Cell adhesion molecules (CADMs) comprise of a protein family whose functions include maintenance of cell polarity and tumor suppression. Hypo expression of CADM2 gene expression has been observed in several cancers including hepatocellular carcinoma (HCC). However, the role and mechanisms of CADM2 in HCC remain unclear. METHODS: The expression of CADM2 and miRNA-10b (miR 10b) in HCC tissues and cell lines were detected using real-time PCR and Western blotting. Immunofluorescence was used to detect Epithelial-mesenchymal transition (EMT) progression in HCC cell lines. Dual-luciferase reporter assay was used to determine miR-10b binding to CADM2 3'UTR. Wound healing assay and Transwell assay were performed to examine the migration and invasion of HCC cells. RESULTS: We report the effect of CADM2 as a tumor suppressor in HCC. Firstly, we confirmed that CADM2 expression was significantly down regulated in HCC tissues compared to normal tissues according to TCGA data analysis and fresh HCC sample detection. Secondly, overexpression of CADM2 could inhibit EMT process, migratory and invasion ability of HCC cells. Furthermore, the results indicated that CADM2 is a direct target of miR-10b in HCC cells and miR-10b/CADM2 modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC. CONCLUSIONS: Our study demonstrates that miR-10b-CADM2-FAK/AKT axis plays an important role in HCC metastasis, which might be a novel potential therapeutic option for HCC treatment. PMID- 29506533 TI - A software tool 'CroCo' detects pervasive cross-species contamination in next generation sequencing data. AB - BACKGROUND: Multiple RNA samples are frequently processed together and often mixed before multiplex sequencing in the same sequencing run. While different samples can be separated post sequencing using sample barcodes, the possibility of cross contamination between biological samples from different species that have been processed or sequenced in parallel has the potential to be extremely deleterious for downstream analyses. RESULTS: We present CroCo, a software package for identifying and removing such cross contaminants from assembled transcriptomes. Using multiple, recently published sequence datasets, we show that cross contamination is consistently present at varying levels in real data. Using real and simulated data, we demonstrate that CroCo detects contaminants efficiently and correctly. Using a real example from a molecular phylogenetic dataset, we show that contaminants, if not eliminated, can have a decisive, deleterious impact on downstream comparative analyses. CONCLUSIONS: Cross contamination is pervasive in new and published datasets and, if undetected, can have serious deleterious effects on downstream analyses. CroCo is a database independent, multi-platform tool, designed for ease of use, that efficiently and accurately detects and removes cross contamination in assembled transcriptomes to avoid these problems. We suggest that the use of CroCo should become a standard cleaning step when processing multiple samples for transcriptome sequencing. PMID- 29506534 TI - Research gaps and emerging priorities in sexual and reproductive health in Africa and the eastern Mediterranean regions. AB - BACKGROUND: In-country research capacity is key to creating improvements in local implementation of health programs and can help prioritize health issues in a landscape of limited funding. Research prioritization has shown to be particularly useful to help answer strategic and programmatic issues in health care, including sexual and reproductive health (SRH). The purpose of this paper is to present the results of a priority setting exercise that brought together researchers and program managers from the WHO Africa and Eastern Mediterranean regions to identify key SRH issues. METHODS: In June 2015, researchers and program managers from the WHO Africa and Eastern Mediterranean regions met for a three-day meeting to discuss strategies to strengthen research capacity in the regions. A prioritization exercise was carried out to identify key priority areas for research in SRH. The process included five criteria: answerability, effectiveness, deliverability and acceptability, potential impact of the intervention/program to improve reproductive, maternal and newborn health substantially, and equity. RESULTS: The six main priorities identified include: creation and investment in multipurpose prevention technologies, addressing adolescent violence and early pregnancy (especially in the context of early marriage), improved maternal and newborn emergency care, increased evaluation and improvement of adolescent health interventions including contraception, further focus on family planning uptake and barriers, and improving care for mothers and children during childbirth. CONCLUSION: The setting of priorities is the first step in a dynamic process to identify where research funding should be focused to maximize health benefits. The key elements identified in this exercise provides guidance for decision makers to focus action on identified research priorities and goals. Prioritization and identifying/acting on research gaps can have great impact across multiple sectors in the regions for improved reproductive, maternal and children health. PMID- 29506535 TI - Nitrosative damage during retrovirus infection-induced neuropathic pain. AB - BACKGROUND: Peripheral neuropathy is currently the most common neurological complication in HIV-infected individuals, occurring in 35-50% of patients undergoing combination anti-retroviral therapy. Data have shown that distal symmetric polyneuropathy develops in mice by 6 weeks following infection with the LP-BM5 retrovirus mixture. Previous work from our laboratory has demonstrated that glial cells modulate antiviral T-cell effector responses through the programmed death (PD)-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. METHODS: Using the MouseMet electronic von Frey system, we assessed hind-paw mechanical hypersensitivity in LP-BM5-infected wild-type (WT) and PD-1 KO animals. Using multi-color flow cytometry, we quantitatively assessed cellular infiltration and microglial activation. Using real-time RT-PCR, we assessed viral load, expression of IFN gamma, iNOS, and MHC class II. Using western blotting, we measured protein nitrosylation within the lumbar spinal cord (LSC) and dorsal root ganglion (DRG). Histochemical staining was performed to analyze the presence of CD3, ionized calcium binding adaptor molecule (Iba)-1, MHCII, nitrotyrosine, isolectin B4 (IB4) binding, and neurofilament 200 (NF200). Statistical analyses were carried out using graphpad prism. RESULTS: Hind-paw mechanical hypersensitivity observed in LP-BM5-infected animals was associated with significantly increased lymphocyte infiltration into the spinal cord and DRG. We also observed elevated expression of IFN-gamma (in LSC and DRG) and MHC II (on resident microglia in LSC). We detected elevated levels of 3-nitrotyrosine within the LSC and DRG of LP-BM5 infected animals, an indicator of nitric oxide (NO)-induced protein damage. Moreover, we observed 3-nitrotyrosine in both small (IB4+) and large (NF200+) DRG sensory neurons. Additionally, infected PD-1 KO animals displayed significantly greater mechanical hypersensitivity than WT or uninfected mice at 4 weeks post infection (p.i.). Accelerated onset of hind-paw hypersensitivity in PD-1 KO animals was associated with significantly increased infiltration of CD4+ and CD8+ T lymphocytes, macrophages, and microglial activation at early time points. Importantly, we also observed elevated levels of 3-nitrotyrosine and iNOS in infected PD-1 KO animals when compared with WT animals. CONCLUSIONS: Results reported here connect peripheral immune cell infiltration and reactive gliosis with nitrosative damage. These data may help elucidate how retroviral infection induced neuroinflammatory networks contribute to nerve damage and neuropathic pain. PMID- 29506536 TI - A case of adrenocortical carcinoma accompanying secondary acute adrenal hypofunction postoperation. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. ACCs are classified as functioning and non-functioning. The pathogenesis of ACC remains elusive, and diagnosis of ACC is currently based on pathology. In the absence of other effective approaches, surgical resection is the preferred treatment option. CASE PRESENTATION: Here, we report a case of ACC in the retroperitoneum. The patient underwent radical adrenalectomy and remained disease-free throughout a 6-month follow-up. CONCLUSIONS: Radical surgical resection is an efficient therapy for ACC, and hydrocortisone can be used to alleviate symptoms of secondary acute adrenal hypofunction. PMID- 29506537 TI - A mini-review of quality of life as an outcome in prostate cancer trials: patient centered approaches are needed to propose appropriate treatments on behalf of patients. AB - BACKGROUND: Patients with prostate cancer (PC) may be ready to make trade-offs between their quantity and their quality of life. For instance, elderly patients may prefer the absence of treatment if it is associated with a low-risk of disease progression, compared to treatments aiming at preventing disease progression but with a substantial deterioration of their Health-Related Quality of Life (HRQoL). Therefore, it seems relevant to compare the treatments by considering both survival and HRQoL. In this mini-review, the aim was to question whether the potential trade-offs between survival and HRQoL are considered in high impact factor journals. METHODS: The study was conducted from the PubMed database for recent papers published between May 01, 2013, and May 01, 2015. We also restricted our search to nine medical journals with 2013 impact factor > 15. RESULTS: Among the 30 selected studies, only six collected individual HRQoL as a secondary endpoint by using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. In four studies, the time to HRQoL change was analyzed, but its definitions varied. In two studies, the mean changes in HRQoL between the baseline and the 12- or 16-week follow-up were analyzed. None of the six studies reported in a single endpoint both the quantity and the quality of life. CONCLUSIONS: Our mini-review, which only focused on recent publications in journals with high-impact, suggests moving PC clinical research towards patient centered outcomes-based studies. This may help physicians to propose the most appropriate treatment on behalf of patients. We recommend the use of indicators such as Quality-Adjusted Life-Years (QALYs) as principal endpoint in future clinical trials. PMID- 29506538 TI - Another frontier for harm reduction: contraceptive needs of females who inject drugs in Estonia, a cross-sectional study. AB - BACKGROUND: Despite increasing contraceptive availability, unintended pregnancy remains a global problem. Developing strategies to reverse this trend and increasing occurrence of withdrawal syndrome among newborn children of females currently injecting drugs warrants special attention. The knowledge base on the uptake of effective contraception among females who inject drugs (FWID) is scant. We aimed to examine the prevalence of and factors associated with the use of non condom contraceptives among sexually active FWID with the focus on effective contraception. METHODS: In a series of cross-sectional studies (2007-2013), 265 current FWID were recruited through respondent-driven sampling (RDS), interviewed, and tested for HIV. RDS weights were used to estimate the prevalence of effective contraception (hormonal contraception, intrauterine device, sterilization) use in the last 6 months. RESULTS: Of the sexually active women with main partners (n = 196) 4.8% (95% CI 2.3-9.7) were using effective contraception, 52.7% (95% CI 42.5-62.7) less-effective or no contraception. 42.5% (95% CI 32.7-52.9) relied on condoms for contraception. The odds for using effective contraception were higher among women with > 10 years of education (OR 7.29, 95% CI 1.4-38.8). None of the women lacking health insurance (n = 84) were using effective contraception. CONCLUSIONS: The very low coverage with effective contraception highlights the need to improve contraceptive services for FWID. Reproductive health service including contraception should be considered essential components of harm reduction and of comprehensive prevention and care for HIV among persons who use drugs. PMID- 29506539 TI - Linac-based VMAT radiosurgery for multiple brain lesions: comparison between a conventional multi-isocenter approach and a new dedicated mono-isocenter technique. AB - BACKGROUND: Linac-based stereotactic radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) of multiple brain lesions using volumetric modulated arc therapy (VMAT) is typically performed by a multiple-isocenter approach, i.e. one isocenter per lesion, which is time-demanding for the need of independent setup verifications of each isocenter. Here, we present our initial experience with a new dedicated mono-isocenter technique with multiple non-coplanar arcs (HyperArcTM, Varian Inc.) in terms of a plan comparison with a multiple-isocenter VMAT approach. METHODS: From August 2017 to October 2017, 20 patients with multiple brain metastases (mean 5, range 2-10) have been treated by HyperArc in 1 3 fractions. The prescribed doses (Dp) were 18-25 Gy in single-fraction, and 21 27 Gy in three-fractions. Planning Target Volume (PTV), defined by a 2 mm isotropic margin from each lesion, had mean dimension of 9.6 cm3 (range 0.5-27.9 cm3). Mono-isocenter HyperArc VMAT plans (HA) with 5 non-coplanar 180 degrees arcs (couch at 0 degrees , +/-45 degrees , +/-90 degrees ) were generated and compared to multiple-isocenter VMAT plans (RA) with 2 coplanar 360 degrees -arcs per isocenter. A dose normalization of 100%Dp at 98%PTV was adopted, while D2%(PTV) < 150%Dp was accepted. All plans had to respect the constraints on maximum dose to the brainstem (D0.5cm3 < 18 Gy) as well as to the optical nerves/chiasm, eyes and lenses (D0.5cm3 < 15 Gy). HA and RA plans were compared in terms of dose-volume metrics, by Paddick conformity (CI) and gradient (GI) index and by V12 and mean dose to the brain-minus-PTV, and in terms of MU and overall treatment time (OTT) per fraction. OTT was measured for HA treatments, whereas for RA plans OTT was estimated by assuming 3 min. For initial patient setup plus 5 min. For each CBCT-guided setup correction per isocenter. RESULTS: Significant variations in favour of HA plans were computed for both target dose indexes, CI (p < .01) and GI (p < .01). The lower GI in HA plans was the likely cause of the significant reduction in V12 to the brain-minus-PTV (p = .023). Although at low doses, below 2-5 Gy, the sparing of the brain-minus-PTV was in favour of RA plans, no significant difference in terms of mean doses to the brain minus-PTV was observed between the two groups (p = .31). Finally, both MU (p < .01) and OTT (p < .01) were significantly reduced by HyperArc plans. CONCLUSIONS: For linac-based SRS/FSRT of multiple brain lesions, HyperArc plans assured a higher CI and a lower GI than standard multiple-isocenter VMAT plans. This is consistent with the computed reduction in V12 to the brain-minus-PTV. Finally, HyperArc treatments were completed within a typical 20 min. time slot, with a significant time reduction with respect to the expected duration of multiple isocenters VMAT. PMID- 29506541 TI - Efficacy of naproxen prophylaxis for the prevention of heterotopic ossification after hip surgery: a meta-analysis. AB - BACKGROUND: This meta-analysis aimed to assess whether the specific nonsteroidal anti-inflammatory drug (NSAID) naproxen has a role in reducing the occurrence of heterotopic ossification after hip surgery. METHODS: Potential studies were identified in the following electronic databases: PubMed, EMBASE, Web of Science, Cochrane Library, and Google. We included studies involving hip surgery patients in which the intervention group received naproxen and the control group received placebo. The occurrence of heterotopic ossification and complications were the final outcomes. Stata 13.0 was used for the meta-analysis. RESULTS: Four randomized controlled trials (RCTs) involving 269 patients were ultimately included in this meta-analysis. The use of naproxen was associated with a significant reduction in the occurrence of heterotopic ossification at 1.5-, 3-, 6-, and 12-month follow-ups (P < 0.05). There was no significant difference in the occurrence of complications between treatment and control groups (P > 0.05). CONCLUSION: Our analysis indicates that naproxen can decrease the occurrence of heterotopic ossification without increasing complications in hip surgery patients. Due to the limited number of studies included, more high-quality RCTs are needed to identify the optimal dose of naproxen. PMID- 29506540 TI - Pigmentary mosaicism: a review of original literature and recommendations for future handling. AB - BACKGROUND: Pigmentary mosaicism is a term that describes varied patterns of pigmentation in the skin caused by genetic heterogeneity of the skin cells. In a substantial number of cases, pigmentary mosaicism is observed alongside extracutaneous abnormalities typically involving the central nervous system and the musculoskeletal system. We have compiled information on previous cases of pigmentary mosaicism aiming to optimize the handling of patients with this condition. Our study is based on a database search in PubMed containing papers written in English, published between January 1985 and April 2017. The search yielded 174 relevant and original articles, detailing a total number of 651 patients. RESULTS: Forty-three percent of the patients exhibited hyperpigmentation, 50% exhibited hypopigmentation, and 7% exhibited a combination of hyperpigmentation and hypopigmentation. Fifty-six percent exhibited extracutaneous manifestations. The presence of extracutaneous manifestations in each subgroup varied: 32% in patients with hyperpigmentation, 73% in patients with hypopigmentation, and 83% in patients with combined hyperpigmentation and hypopigmentation. Cytogenetic analyses were performed in 40% of the patients: peripheral blood lymphocytes were analysed in 48%, skin fibroblasts in 5%, and both analyses were performed in 40%. In the remaining 7% the analysed cell type was not specified. Forty-two percent of the tested patients exhibited an abnormal karyotype; 84% of those presented a mosaic state and 16% presented a non-mosaic structural or numerical abnormality. In patients with extracutaneous manifestations, 43% of the cytogenetically tested patients exhibited an abnormal karyotype. In patients without extracutaneous manifestations, 32% of the cytogenetically tested patients exhibited an abnormal karyotype. CONCLUSION: We recommend a uniform parlance when describing the clinical picture of pigmentary mosaicism. Based on the results found in this review, we recommend that patients with pigmentary mosaicism undergo physical examination, highlighting with Wood's light, and karyotyping from peripheral blood lymphocytes and skin fibroblasts. It is important that both patients with and without extracutaneous manifestations are tested cytogenetically, as the frequency of abnormal karyotype in the two groups seems comparable. According to the results only a minor part of patients, especially those without extracutaneous manifestations, are tested today reflecting a need for change in clinical practice. PMID- 29506542 TI - Values clarification workshops to improve abortion knowledge, attitudes and intentions: a pre-post assessment in 12 countries. AB - BACKGROUND: Women's access to abortion care is often denied or hampered due to a range of barriers, many of which are rooted in abortion stigma. Abortion values clarification and attitude transformation (VCAT) workshops are conducted with abortion providers, trainers, and policymakers and other stakeholders to mitigate the effects of abortion stigma and increase provision of and access to abortion care. This study assesses changes in knowledge, attitudes, and behavioral intentions of VCAT workshop participants. METHODS: Pre- and post-workshop surveys from 43 VCAT workshops conducted in 12 countries in Asia, Africa, and Latin America between 2006 and 2011 were analyzed to assess changes in three domains: knowledge, attitudes and behavioral intentions related to abortion care. A score was created for each domain (range: 0-100), and paired t-tests or Wilcoxon matched-pairs signed-ranks tests were used to test for significant differences between the pre- and post-workshop scores overall and by region and participant type (providers, trainers, and policymakers/other stakeholders). We also assessed changes in pre- and post-workshop scores for participants with the lowest knowledge and negative attitudes on the pre-workshop survey. RESULTS: Overall, the mean knowledge score increased significantly from 49.0 to 67.1 (p < 0.001) out of a total possible score of 100. Attitudes and behavioral intentions showed more modest, but still statistically significant improvements between the pre- and post-workshop surveys. The mean attitudes score increased from 78.2 to 80.9 (p < 0.001), and the mean behavioral intentions score rose from 82.2 to 85.4 (p = 0.03). Among participants with negative attitudes pre-workshop, most shifted to positive attitudes on the post-workshop survey, ranging from 35.2% who switched to supporting unrestricted access to second-trimester abortion to 90.9% who switched to feeling comfortable working to increase access to contraceptive services in their country. Participants who began the workshop with the lowest level of knowledge experienced the greatest increase in mean knowledge score from 20.0 to 55.0 between pre- and post-workshop surveys (p < 0.001). CONCLUSIONS: VCAT workshop participants demonstrated improvements in knowledge, attitudes, and behavioral intentions related to abortion care. Participants who entered the workshops with the lowest levels of knowledge and negative attitudes had the greatest gains in these domains. PMID- 29506543 TI - An extremely patient-friendly and efficient stimulation protocol for assisted reproductive technology in normal and high responders. AB - BACKGROUND: The use of oral progestin has been shown to effectively prevent luteining hormone (LH) surge during ovarian stimulation with daily human menopausal gonadotropin injections. This study was aimed to investigate the efficacy of long-acting follicle stimulating hormone (long-acting FSH; corifollitropin alfa, Elonva(r)) use in progestin-primed ovarian stimulation for normal and high responders undergoing IVF/ICSI. METHODS: This is a retrospective and proof-of-concept study. We developed an extremely patient-friendly protocol to be applied to forty-five normal or high responders, in which a single injection of corifollitropin alfa (Elonva(r)) was administered and medroxyprogesterone acetate (MPA) was taken orally every day from the day after Elonva injection to the day of trigger. Seven days after Elonva injection, folliculometry and hormone tests were performed, followed by short-acting daily FSH/LH injections, if needed, until the day before trigger. Duration of stimulation, number of injections and visits before trigger, incidence of premature LH surge, the number of oocytes retrieved, fertilization rate, cleavage rate, the rate of day 2 good embryos available, and cumulative ongoing pregnancy rate per retrieval were assessed. RESULTS: The average age of the population was 34.7 years. Duration of stimulation was 9.4 days in average. Before trigger, only 3.6 injection shots and 1.4 visits were needed on average. There was no case of premature LH surge. Number of oocytes retrieved was 13.7, fertilization rate was 79.04%, cleavage rate was 91.11%, and day 2 good embryo rate was 64.34%, in average respectively. There was no case of ovarian hyperstimulation syndrome. The cumulative ongoing pregnancy rate per oocyte retrieval achieved a satisfactory level as 53.1%. CONCLUSIONS: Our protocol consisting of long-acting FSH injection and oral MPA preventing LH surge reduces the number of injections and visits to an extreme and achieves a satisfactory reproductive outcome, and, therefore, is a really patient-friendly and effective approach to ovarian stimulation. PMID- 29506544 TI - Experimental malaria-associated acute respiratory distress syndrome is dependent on the parasite-host combination and coincides with normocyte invasion. AB - BACKGROUND: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a complication of malaria with a lethality rate of up to 80% despite anti-malarial treatment. It is characterized by a vast infiltration of leukocytes, microhaemorrhages and vasogenic oedema in the lungs. Previously, a mouse model for MA-ARDS was developed by infection of C57BL/6 mice with the Edinburgh line NK65-E of Plasmodium berghei. RESULTS: Here, both host and parasite factors were demonstrated to play crucial roles in the development and severity of lung pathology. In particular, the genetic constitution of the host was an important determinant in the development of MA-ARDS. Both male and female C57BL/6, but not BALB/c, mice developed MA-ARDS when infected with P. berghei NK65-E. However, the New York line of P. berghei NK65 (NK65-NY) did not induce demonstrable MA-ARDS, despite its accumulation in the lungs and fat tissue to a similar or even higher extent as P. berghei NK65-E. These two commonly used lines of P. berghei differ in their red blood cell preference. P. berghei NK65-NY showed a stronger predilection for reticulocytes than P. berghei NK65-E and this appeared to be associated with a lower pathogenicity in the lungs. The pulmonary pathology in the C57BL/6/P. berghei NK65-E model was more pronounced than in the model with infection of DBA/2 mice with P. berghei strain ANKA. The transient lung pathology in DBA/2 mice infected with P. berghei ANKA coincided with the infection phase in which parasites mainly infected normocytes. This phase was followed by a less pathogenic phase in which P. berghei ANKA mainly infected reticulocytes. CONCLUSIONS: The propensity of mice to develop MA-ARDS during P. berghei infection depends on both host and parasite factors and appears to correlate with RBC preference. These data provide insights in induction of MA-ARDS and may guide the choice of different mouse-parasite combinations to study lung pathology. PMID- 29506545 TI - Antidepressant-like effects of translocator protein (18 kDa) ligand ZBD-2 in mouse models of postpartum depression. AB - The 18 kDa translocator protein (TSPO) is primarily localized in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. One of the protein's main functions is transporting substrate cholesterol into the mitochondria in a prerequisite process for steroid synthesis. Clinical trials have indicated that TSPO ligands might be valuable in treating some neuropathies and psychopathies. However, limited information is known about the role of TSPO in postpartum depression (PPD). The TSPO ligand ZBD 2, a derivative of XBD173, was synthesized in our laboratory. Behavioral tests, enzyme linked immunosorbent assay, and Western blot were employed to evaluate ZBD 2's efficacy against PPD and to elucidate the potential underlying molecular mechanism. The TSPO levels significantly decreased in the basolateral amygdala of PPD models. After treatment for 2 weeks, ZBD-2 alleviated depression-like behaviors and enhanced the TSPO level in a PPD animal model. The underlying mechanisms of ZBD-2 were related to regulate the hypothalamic-pituitary-adrenal axis, enhance 5-HT and BDNF secretion, and maintain the excitatory and inhibitory synaptic protein expression to normal levels. Our results directly confirm that ZBD-2 exerts a therapeutic effect on PPD, which provides a new target for anti PPD drug development. PMID- 29506546 TI - Analysis of prognostic factors of patients with malignant peritoneal mesothelioma. AB - BACKGROUND: The study aims to find out independent prognostic factors for patients with malignant peritoneal mesothelioma (MPeM). METHODS: Patients with pathologically proven MPeM were retrospectively reviewed. Potential prognostic factors were analyzed, including age, gender, asbestos exposure, body mass index (BMI), treatment, and laboratory results, such as blood routine examination and liver functions. The influences of various risk factors on the prognoses were analyzed by univariate analysis. A Cox regression model analysis established independent factors for the survival prognosis of the patients. RESULTS: Seventy MPeM patients, including 33 patients who received intraperitoneal chemotherapy with cisplatin, 14 patients who received systemic chemotherapy with cisplatin + pemetrexed, and 21 untreated patients were included in this study. The 1-year survival was 32.9%, the 2-year survival was 10%, and the 3-year survival was 2.9%. The median age of MPeM was 62 years, and the female-to-male ratio was 1:0.56. The univariate and multivariate analyses showed that treatment, albumin (ALB), and blood neutrophil-to-lymphocyte ratio (NLR) were independent factors that affected the overall survival (OS) of MPeM patients. CONCLUSION: High blood NLR and hypoalbuminemia are adverse prognostic factors for MPeM patients. Systemic chemotherapy and intraperitoneal chemotherapy can prolong the survival period. PMID- 29506547 TI - Programmed Sports Therapy (PST) in People with Haemophilia (PwH) "Sports Therapy Model for Rare Diseases". AB - Sports and exercise therapy becomes more and more integrated in the treatment plan of different diseases. Although the benefits of this therapy are of high quality evidence, e.g. in cardiovascular diseases, no concepts of sports therapy are available as a treatment option for rare diseases.During the last eighteen years, we analyzed the situation as well as necessity, and developed a model, contents and the concept of the "Programmed Sports Therapy (PST)" for the treatment of PwH (people with haemophilia) as our model of rare disease. Many studies have shown that motoric skills are depressed in PwH, and that this gap to healthy people increases during age. The only way to reduce this progression is an appropriate therapy, adapted to the necessities of PwH. In haemophilia, in particular, physio- and sports therapy treatments should go hand in hand, the first in the acute phase after bleeding, the second later, after the acute phase has finished. One model, which considers all the different challenges, can be the cogwheel model presented here. Since haemophilia is a rare disease, new training concepts are necessary because classical group therapies are often impossible. PST based on the combination of sports therapy camps together with a supervised autonomous home training helps to directly bring the training to the trainee, in order to enhance key competences and improve the individual situation in PwH, and perhaps in patients with other rare diseases.The experience and scientific data substantiate the success of "Programmed Sports Therapy (PST)" and even this can be a model for other rare diseases. PMID- 29506548 TI - Reprogramming Tumor-Immune Cell Interface in Solid and Hematological Malignancies to Enhance Response to Therapy. PMID- 29506549 TI - Lipid profiles in French West Indies sickle cell disease cohorts, and their general population. AB - BACKGROUND: The pathophysiology of sickle cell disease (SCD) and the variability of its clinical expression remain not fully understood, whether within or between different SCD genotypes. Recent studies have reported associations between lipid levels and several SCD complications. If lipid levels have been previously described as low in sickle cell anemia (SCA), few data have been provided for sickle cell SC disease (SCC). We designed our epidemiological study to isolate lipid levels and profiles by genotype in Guadeloupian cohorts of SCA and SCC adult patients, at steady state. We compared SCD lipid levels with those of the Guadeloupian general population (GGP), and analyzed potential associations between lipid levels and SCD complications (vaso-occlusive crises, acute chest syndrome and osteonecrosis). METHODS: Lipids, apolipoproteins, biological variables and anthropometric evaluation, were collected at steady state from medical files for 62 SCC and 97 SCA adult patients. Clinical SCD complications were collected from the clinical files. Analysis was conducted by genotype for all variables. RESULTS: Different SCC and SCA lipid profiles, both distinct from their GGP's, were identified. Compared to SCC and GGP, higher triglyceride (TG) levels were observed in SCA patients, independent of hydroxyurea, hemolysis, gender, age, body mass index (BMI), abdominal obesity and clinical nutritional status. Our survey highlights also subsequent anthropometrical phenotypes, with an over-representation of abdominal obesity with normal BMI in SCA patients, and affecting almost exclusively females in both genotypes. Moreover, more frequent positive history of acute chest syndrome (ACS) was observed in SCA patients with TG level higher than 1.50 g/l, and of osteonecrosis in SCC patients having non high-density lipoprotein-cholesterol level (Non HDL-C) higher than 1.30 g/l. CONCLUSIONS: This study reveals that SCA and SCC patients exhibit distinct lipid profiles and suggests that high TG and Non HDL-C levels are associated with past histories of ACS and osteonecrosis in SCA and SCC patients, respectively. PMID- 29506550 TI - Early life Triclosan exposure and child adiposity at 8 Years of age: a prospective cohort study. AB - BACKGROUND: Triclosan is an antimicrobial agent that may affect the gut microbiome and endocrine system to influence adiposity. However, little data from prospective studies examining prenatal and childhood exposures exist. We investigated the relationship between multiple, prospective early life measure of triclosan exposure and child adiposity. METHODS: In a prospective cohort of 220 mother-child pairs from Cincinnati, OH (enrolled 2003-2006), we quantified triclosan in urine samples collected twice during pregnancy, annually from 1 to 5 years of age, and once at 8 years. We assessed child adiposity at age 8 years using body mass index (BMI), waist circumference, and bioelectric impedance. We estimated covariate-adjusted associations of child adiposity with a 10-fold increase in average prenatal, average early childhood (average of 1-5 years), and 8-year triclosan concentrations. RESULTS: Among all children, there was no association between triclosan and child adiposity. While urinary triclosan concentrations at all three time periods were weakly, imprecisely, and inversely associated with all three measures of adiposity among girls, these associations did not differ significantly from those in boys (sex x triclosan p-values> 0.35). Among girls, the strongest associations were generally observed for prenatal triclosan when we adjusted for all three triclosan concentrations and covariates in the same model; BMI z-score (beta: -0.13; 95% CI: -0.42, 0.15), waist circumference (beta: - 1.7 cm; 95% CI: -4.2, 0.7), and percent body fat (beta : 0.6; 95% CI: -2.7, 1.3). In contrast, the associations between triclosan concentrations and adiposity measures were inconsistent among boys. CONCLUSION: We did not observe evidence of an association of repeated urinary triclosan concentrations during pregnancy and childhood with measures of child adiposity at age 8 years in this cohort. PMID- 29506551 TI - Serum obestatin level strongly correlates with lipoprotein subfractions in non diabetic obese patients. AB - BACKGROUND: Obestatin is a ghrelin-associated peptide, derived from preproghrelin. Although many of its effects are unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. To date, level of obestatin and its correlations to the lipid subfractions in non diabetic obese (NDO) patients have not been investigated. METHODS: Fifty NDO patients (BMI: 41.96 +/- 8.6 kg/m2) and thirty-two normal-weight, age- and gender matched healthy controls (BMI: 24.16 +/- 3.3 kg/m2) were enrolled into our study. Obestatin level was measured by ELISA. Low-density lipoprotein (LDL) and high density lipoprotein (HDL) subfractions, intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) levels and mean LDL size were detected by nongradient polyacrylamide gel electrophoresis (Lipoprint). RESULTS: Serum level of obestatin was significantly lower in NDO patients compared to controls (3.01 +/- 0.5 vs. 3.29 +/- 0.6 MUg/ml, p < 0.05). We found significant negative correlations between the level of obestatin and BMI (r = - 0.33; p < 0.001), level of serum glucose (r = - 0.27, p < 0.05), HbA1c (r = - 0.38; p < 0.001) and insulin (r = - 0.34; p < 0.05). Significant positive correlation was found between obestatin level and the levels of ApoA1 (r = 0.25; p < 0.05), large HDL subfraction ratio and level (r = 0.23; p < 0.05 and r = 0.24; p < 0.05), IDL (r = 0.25 p < 0.05) and mean LDL size (r = 0.25; p < 0.05). Serum VLDL ratio and level negatively correlated with obestatin (r = - 0.32; p < 0.01 and r = - 0.21; p = 0.05). In multiple regression analysis obestatin was predicted only by VLDL level. CONCLUSIONS: Based on our data, measurement of obestatin level in obesity may contribute to understand the interplay between gastrointestinal hormone secretion and metabolic alterations in obesity. PMID- 29506552 TI - First installation of a dual-room IVR-CT system in the emergency room. AB - Computed tomography (CT) embedded in the emergency room has gained importance in the early diagnostic phase of trauma care. In 2011, we implemented a new trauma workflow concept with a sliding CT scanner system with interventional radiology features (IVR-CT) that allows CT examination and emergency therapeutic intervention without relocating the patient, which we call the Hybrid emergency room (Hybrid ER). In the Hybrid ER, all life-saving procedures, CT examination, damage control surgery, and transcatheter arterial embolisation can be performed on the same table. Although the trauma workflow realized in the Hybrid ER may improve mortality in severe trauma, the Hybrid ER can potentially affect the efficacy of other in/outpatient diagnostic workflow because one room is occupied by one severely injured patient undergoing both emergency trauma care and CT scanning for long periods. In July 2017, we implemented a new trauma workflow concept with a dual-room sliding CT scanner system with interventional radiology features (dual-room IVR-CT) to increase patient throughput. When we perform emergency surgery or interventional radiology for a severely injured or ill patient in the Hybrid ER, the sliding CT scanner moves to the adjacent CT suite, and we can perform CT scanning of another in/outpatient. We believe that dual room IVR-CT can contribute to the improvement of both the survival of severely injured or ill patients and patient throughput. PMID- 29506553 TI - Correction to: Protective and therapeutic role of 2-carbacyclic phosphatidic acid in demyelinating disease. AB - After publication of the article [1], it was brought to our attention that an acknowledgement was missing from the original version. PMID- 29506554 TI - Effects of dexamethasone on the Li-pilocarpine model of epilepsy: protection against hippocampal inflammation and astrogliosis. AB - BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is accompanied, in one third of cases, by resistance to antiepileptic drugs (AED). Most AED target neuronal activity modulated by ionic channels, and the steroid sensitivity of these channels has supported the use of corticosteroids as adjunctives to AED. Assuming the importance of astrocytes in neuronal activity, we investigated inflammatory and astroglial markers in the hippocampus, a key structure affected in TLE and in the Li-pilocarpine model of epilepsy. METHODS: Initially, hippocampal slices were obtained from sham rats and rats subjected to the Li-pilocarpine model of epilepsy, at 1, 14, and 56 days after status epilepticus (SE), which correspond to the acute, silent, and chronic phases. Dexamethasone was added to the incubation medium to evaluate the secretion of S100B, an astrocyte-derived protein widely used as a marker of brain injury. In the second set of experiments, we evaluated the in vivo effect of dexamethasone, administrated at 2 days after SE, on hippocampal inflammatory (COX 1/2, PGE2, and cytokines) and astroglial parameters: GFAP, S100B, glutamine synthetase (GS) and water (AQP-4), and K+ (Kir 4.1) channels. RESULTS: Basal S100B secretion and S100B secretion in high-K+ medium did not differ at 1, 14, and 56 days for the hippocampal slices from epileptic rats, in contrast to sham animal slices, where high-K+ medium decreased S100B secretion. Dexamethasone addition to the incubation medium per se induced a decrease in S100B secretion in sham and epileptic rats (1 and 56 days after SE induction). Following in vivo dexamethasone administration, inflammatory improvements were observed, astrogliosis was prevented (based on GFAP and S100B content), and astroglial dysfunction was partially abrogated (based on Kir 4.1 protein and GSH content). The GS decrease was not prevented by dexamethasone, and AQP-4 was not altered in this epileptic model. CONCLUSIONS: Changes in astroglial parameters emphasize the importance of these cells for understanding alterations and mechanisms of epileptic disorders in this model. In vivo dexamethasone administration prevented most of the parameters analyzed, reinforcing the importance of anti-inflammatory steroid therapy in the Li-pilocarpine model and possibly in other epileptic conditions in which neuroinflammation is present. PMID- 29506556 TI - TNFalpha induces Ca2+ influx to accelerate extrinsic apoptosis in hepatocellular carcinoma cells. AB - BACKGROUND: Tumor necrosis factor-alpha has been proven an effective anticancer agent in preclinical studies. However, the translation of TNFalpha from research to clinic has been blocked by significant systemic toxicity and limited efficacy at maximal tolerated dose, which need urgently to be solved. METHODS: The level of cytosolic Ca2+ was assessed by Fura-2 in HCC cells. After changing cytosolic Ca2+ level by using agonists or inhibitors, cell apoptosis was detected by flow cytometry. We also detected the effect of ionomycin or parvalbumin on the anti tumor activity of TNFalpha in a mice model. Lastly, we studied the roles of cytosolic Ca2+ in the mitochondrial-dependent intrinsic apoptosis pathway. RESULTS: Here, we demonstrated that TNFalpha induced extracellular Ca2+ influx into cytoplasm through transient receptor potential channel in HCC cells. Both cytosolic Ca2+ scavenger and Ca2+-binding protein PV effectively desensitized hepatocellular carcinoma cells to TNFalpha, whereas combination ionomycin or 1,4,5-inositol triphosphate significantly sensitized HCC cells to TNFalpha, indicating that the increased level of cytosolic Ca2+ was positively correlated with the TNFalpha-induced cell apoptosis in vitro. In a nude mice xenograft model, our data revealed that TNFalpha combined with ionomycin remarkably synergized the anti-tumor effect of TNFalpha. Furthermore, we found that TNFalpha mediated extracellular Ca2+ influx accelerated TNFalpha-induced extrinsic apoptosis through activating calpain/IAP/caspase3 pathway. CONCLUSIONS: Our study provides the evidence supporting a novel mechanism by which TNFalpha induces extracellular Ca2+ influx to enhance cell apoptosis and suggests that increasing the level of cytosolic Ca2+ might be an alternative strategy to improve the pro apoptotic activity of TNFalpha in HCC cells, although suitable chemical or biological reagents need to be further tested. PMID- 29506555 TI - Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer. AB - BACKGROUND: T-cell immunoglobulin mucin 3 (TIM3) is a negative immune checkpoint and plays a crucial part in tumor-induced immune suppression. However, the mechanism of TIM3 in regulating immunosuppression in head and neck squamous cell carcinoma (HNSCC) was still not quite clear. METHODS: We carried out the immunohistochemistry staining of HNSCC tissue microarrays. Through quantification of the histoscore, we performed the correlation analysis among the TIM3, Galectin 9, Foxp3, CD68 and CD163. The effects of TIM3 on regulatory T cells (Tregs) and macrophages were detected by utilizing the Tgfbr1/Pten 2cKO HNSCC mouse model. Flow cytometry were used to analysis the percent of Tregs, macrophages and IFN gamma. RESULTS: We demonstrated the close association among TIM3/Galectin-9 pathway, regulatory T cell marker (Foxp3) and macrophage marker (CD68, CD163) in human HNSCC. In the transgenic HNSCC mouse model, blockade of TIM3 by the anti TIM3 monoclonal antibody induced a reduction of CD4+CD25+Foxp3+ Tregs. Meanwhile, the population of TIM3+ Tregs was also decreased. However, the population of CD206+ macrophages was not significantly declined. The increased IFN-gamma production on CD8+ T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors. CONCLUSIONS: The present study demonstrated that TIM3 was associated with the immunosuppression in HNSCC. And targeting TIM3 can enhance anti-tumor immune response by decreasing Tregs in HNSCC. PMID- 29506557 TI - Attitudes of stakeholders in psychiatry towards the inclusion of children in genomic research. AB - BACKGROUND: Genomic sequencing of children in research raises complex ethical issues. This study aims to gain more knowledge on the attitudes towards the inclusion of children as research subjects in genomic research and towards the disclosure of pertinent and incidental findings to the parents and the child. METHODS: Qualitative data were collected from interviews with a wide range of informants: experts engaged in genomic research, clinical geneticists, persons with mental disorders, relatives, and blood donors. Quantitative data were collected from a cross-sectional web-based survey among 1227 parents and 1406 non parents who were potential stakeholders in psychiatric genomic research. RESULTS: Participants generally expressed positive views on children's participation in genomic research. The informants in the qualitative interviews highlighted the age of the child as a critical aspect when disclosing genetic information. Other important aspects were the child's right to an autonomous choice, the emotional burden of knowing imposed on both the child and the parents, and the possibility of receiving beneficial clinical information regarding the future health of the child. Nevertheless, there was no consensus whether the parent or the child should receive the findings. A majority of survey stakeholders agreed that children should be able to participate in genomic research. The majority agreed that both pertinent and incidental findings should be returned to the parents and to the child when of legal age. Having children does not affect the stakeholder's attitudes towards the inclusion of children as research subjects in genomic research. CONCLUSION: Our findings illustrate that both the child's right to autonomy and the parents' interest to be informed are important factors that are found valuable by the participants. In future guidelines governing children as subjects in genomic research, it would thus be essential to incorporate the child's right to an open future, including the right to receive information on adult-onset genetic disorders. PMID- 29506558 TI - Fatal visceral disseminated varicella zoster infection during initial remission induction therapy in a patient with lupus nephritis and rheumatoid arthritis possible association with mycophenolate mofetil and high-dose glucocorticoid therapy: a case report. AB - BACKGROUND: Visceral disseminated varicella zoster viral (VZV) infection is a rare but severe complication with a high mortality rate in immunosuppressed individuals, and an increased susceptibility to VZV has been reported in kidney transplant recipients who are treated with mycophenolate mofetil (MMF). In Japan, MMF is currently approved for patients with lupus nephritis (LN) and data to indicate its optimal dosage are still insufficient. CASE PRESENTATION: A 46-year old Japanese woman with rheumatoid arthritis was diagnosed as having systemic lupus erythematosus (SLE) and LN class III (A/C). Although initial remission induction therapy with prednisolone and tacrolimus was started, her serum creatinine level and urinary protein excretion were elevated. Methylprednisolone pulse therapy was added, and tacrolimus was switched to MMF. Two months after admission when she was taking 40 mg of PSL and 1500 mg of MMF daily, she suddenly developed upper abdominal pain and multiple skin blisters, and disseminated visceral VZV infection was diagnosed. Laboratory examinations demonstrated rapid exacerbation of severe acute liver failure and coagulation abnormalities despite immediate multidisciplinary treatment, and she died of hemorrhagic shock 7 days after the onset of abdominal pain. A serum sample collected at the time of admission revealed that she had recursive VZV infection. CONCLUSIONS: MMF together with high-dose glucocorticoid therapy may increase the risk of VZV infection in Asian patients with SLE. Accumulation of evidence for parameters of safety, such as the area under the blood concentration-time curve of mycophenolic acid, should be urgently considered in order to establish a safer protocol for remission induction therapy in Asian patients with LN. PMID- 29506559 TI - Patient and provider determinants for receipt of three dimensions of respectful maternity care in Kigoma Region, Tanzania-April-July, 2016. AB - BACKGROUND: Lack of respectful maternity care (RMC) is increasingly recognized as a human rights issue and a key deterrent to women seeking facility-based deliveries. Ensuring facility-based RMC is essential for improving maternal and neonatal health, especially in sub-Saharan African countries where mortality and non-skilled delivery care remain high. Few studies have attempted to quantitatively identify patient and delivery factors associated with RMC, and none has modeled the influence of provider characteristics on RMC. This study aims to help fill these gaps through collection and analysis of interviews linked between clients and providers, allowing for description of both patient and provider characteristics and their association with receipt of RMC. METHODS: We conducted cross-sectional surveys across 61 facilities in Kigoma Region, Tanzania, from April to July 2016. Measures of RMC were developed using 21-items in a Principal Components Analysis (PCA). We conducted multilevel, mixed effects generalized linear regression analyses on matched data from 249 providers and 935 post-delivery clients. The outcomes of interest included three dimensions of RMC Friendliness/Comfort/Attention; Information/Consent; and Non-abuse/Kindness developed from the first three components of PCA. Significance level was set at p < 0.05. RESULTS: Significant client-level determinants for perceived Friendliness/Comfort/Attention RMC included age (30-39 versus 15-19 years: Coefficient [Coef] 0.63; 40-49 versus 15-19 years: Coef 0.79) and self-reported complications (reported complications versus did not: Coef - 0.41). Significant provider-level determinants included perception of fair pay (Perceives fair pay versus unfair pay: Coef 0.46), cadre (Nurses/midwives versus Clinicians: Coef - 0.46), and number of deliveries in the last month (11-20 versus < 11 deliveries: Coef - 0.35). Significant client-level determinants for Information/Consent RMC included labor companionship (Companion versus none: Coef 0.37) and religiosity (Attends services at least weekly versus less often: Coef - 0.31). Significant provider-level determinants included perception of fair pay (Perceives fair pay versus unfair: Coef 0.37), weekly work hours (Coef 0.01), and age (30-39 versus 20-29 years: Coef - 0.34; 40-49 versus 20-29 years: Coef - 0.58). Significant provider-level determinants for Non-abuse/Kindness RMC included the predictors of age (age 50+ versus 20-29 years: Coef 0.34) and access to electronic mentoring (Access to two mentoring types versus none: Coef 0.37). CONCLUSIONS: These findings illustrate the value of including both client and provider information in the analysis of RMC. Strategies that address provider-level determinants of RMC (such as equitable pay, work environment, access to mentoring platforms) may improve RMC and subsequently address uptake of facility delivery. PMID- 29506560 TI - Intravenous injection of beta-amyloid seeds promotes cerebral amyloid angiopathy (CAA). AB - Seeding and spread of beta-amyloid (Abeta) pathologies have been considered to be based on prion-like mechanisms. However, limited transmissibility of Abeta seeding activity upon peripheral exposure would represent a key difference to prions, not only in terms of pathogenesis but also in terms of potential transmission of disease. We partially characterized the seeded Abeta amyloidosis after intracerebral injection of various brain homogenates in APP/PS1 mice. One particularly seed-laden homogenate was selected to investigate the development of Abeta pathologies after intravenous exposure. We report here that a single intravenous injection of an Alzheimer disease patient's-brain extract into APP/PS1 recipient mice led to cerebral amyloid angiopathy within 180 days post injection. Thus, vascular proteinopathies such as CAA are transmissible in mice via the intravenous route of peripheral exposure. PMID- 29506561 TI - Improved adherence adjustment in the Coronary Drug Project. AB - BACKGROUND: The survival difference between adherers and non-adherers to placebo in the Coronary Drug Project has been used to support the thesis that adherence adjustment in randomized trials is not generally possible and, therefore, that only intention-to-treat analyses should be trusted. We previously demonstrated that adherence adjustment can be validly conducted in the Coronary Drug Project using a simplistic approach. Here, we re-analyze the data using an approach that takes full advantage of recent methodological developments. METHODS: We used inverse-probability weighted hazards models to estimate the 5-year survival and mortality risk when individuals in the placebo arm of the Coronary Drug Project adhere to at least 80% of the drug continuously or never during the 5-year follow up period. RESULTS: Adjustment for post-randomization covariates resulted in 5 year mortality risk difference estimates ranging from - 0.7 (95% confidence intervals (CI), - 12.2, 10.7) to 4.5 (95% CI, - 6.3, 15.3) percentage points. CONCLUSIONS: Our analysis confirms that appropriate adjustment for post randomization predictors of adherence largely removes the association between adherence to placebo and mortality originally described in this trial. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT00000482 . Registered retrospectively on 27 October 1999. PMID- 29506562 TI - BetaMe: impact of a comprehensive digital health programme on HbA1c and weight at 12 months for people with diabetes and pre-diabetes: study protocol for a randomised controlled trial. AB - BACKGROUND: Long-term conditions (LTCs) are the biggest contributor to health loss in New Zealand. The economic cost and burden on the health system is substantial and growing. Self-management strategies offer a potential way to reduce the pressure on health services. This study evaluates a comprehensive self management programme (the BetaMe programme) delivered by mobile and web-based technologies for people with Type 2 diabetes (T2DM) and pre-diabetes. The primary aim of this study is to evaluate the effectiveness of the BetaMe programme versus usual care among primary care populations in improving the control of T2DM and pre-diabetes, as measured by change in HbA1c and weight over 12 months. METHODS: Participants will be recruited through two primary healthcare organisations and a Maori healthcare provider in New Zealand (n = 430). Eligible participants will be 18 to 75 years old, with T2DM or pre-diabetes, with an HbA1c of 41-70 mmol/mol up to 2 years prior to study commencement. Eligible participants who consent to participate will be individually randomised to the control arm (usual care) or intervention arm (usual care and BetaMe). The programme consists of a 16-week core followed by a maintenance period of 36 weeks. It incorporates (1) individualised health coaching, (2) goal setting and tracking, (3) peer support in an online forum and (4) educational resources and behaviour-change tools. The primary outcome measures are change in HbA1c and weight at 12 months. Secondary outcomes are changes in waist circumference, blood pressure, patient activation and diabetes-specific behaviours. All outcomes will be assessed at 4 and 12 months for the total study population and for Maori and Pacific participants specifically. All primary analyses will be based on intention-to-treat. Primary analysis will use linear mixed models comparing mean outcome levels adjusted for initial baseline characteristics at 12 months. DISCUSSION: This is a randomised controlled trial of a comprehensive self-management intervention for people with diabetes and pre-diabetes. If effective, this programme would allow healthcare providers to deliver an intervention that is person-centred and supports the self care of people with T2DM, pre-diabetes and potentially other LTCs. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ID: ACTRN12617000549325 . Registered on 19 April 2017. PMID- 29506563 TI - Evaluation of community-level interventions to increase early initiation of antenatal care in pregnancy: protocol for the Community REACH study, a cluster randomised controlled trial with integrated process and economic evaluations. AB - BACKGROUND: The provision of high-quality maternity services is a priority for reducing inequalities in health outcomes for mothers and infants. Best practice includes women having their initial antenatal appointment within the first trimester of pregnancy in order to provide screening and support for healthy lifestyles, well-being and self-care in pregnancy. Previous research has identified inequalities in access to antenatal care, yet there is little evidence on interventions to improve early initiation of antenatal care. The Community REACH trial will assess the effectiveness and cost-effectiveness of engaging communities in the co-production and delivery of an intervention that addresses this issue. METHODS/DESIGN: The study design is a matched cluster randomised controlled trial with integrated process and economic evaluations. The unit of randomisation is electoral ward. The intervention will be delivered in 10 wards; 10 comparator wards will have normal practice. The primary outcome is the proportion of pregnant women attending their antenatal booking appointment by the 12th completed week of pregnancy. This and a number of secondary outcomes will be assessed for cohorts of women (n = approximately 1450 per arm) who give birth 2-7 and 8-13 months after intervention delivery completion in the included wards, using routinely collected maternity data. Eight hospitals commissioned to provide maternity services in six NHS trusts in north and east London and Essex have been recruited to the study. These trusts will provide anonymised routine data for randomisation and outcomes analysis. The process evaluation will examine intervention implementation, acceptability, reach and possible causal pathways. The economic evaluation will use a cost-consequences analysis and decision model to evaluate the intervention. Targeted community engagement in the research process was a priority. DISCUSSION: Community REACH aims to increase early initiation of antenatal care using an intervention that is co-produced and delivered by local communities. This pragmatic cluster randomised controlled trial, with integrated process and economic evaluation, aims to rigorously assess the effectiveness of this public health intervention, which is particularly complex due to the required combination of standardisation with local flexibility. It will also answer questions about scalability and generalisability. TRIAL REGISTRATION: ISRCTN registry: registration number 63066975 . Registered on 18 August 2015. PMID- 29506564 TI - Treatment of early stage Supraglottic squamous cell carcinoma: meta-analysis comparing primary surgery versus primary radiotherapy. AB - OBJECTIVES: For early stage supraglottic squamous cell carcinoma (SCC), single modality treatment either in the form of primary organ preservation surgery alone or radiation alone is recommended. Thus, a definite treatment strategy for early stage supraglottic SCC remains undefined. The primary objective of this study was to conduct a systematic review and meta-analysis comparing the oncologic outcomes of surgery and radiotherapy in early stage (Stage I and II) T1 N0 and T2 N0 supraglottic SCC. METHODS: Systematic methods were used to identify published and unpublished data. Two reviewers independently screened all titles, abstracts and articles for relevance using predefined criteria. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Five studies met the inclusion criteria for disease specific mortality with a total of 2864 pooled patients. 5-year disease specific mortality was lower in the surgery group (ORs 0.43, 95% CI 0.31-0.60). Four studies met the inclusion criteria for 5-year overall mortality with a total of 2790 pooled patients. Five-year overall mortality was lower in surgery group (ORs 0.40, 95% CI 0.29-0.55). CONCLUSIONS: This is the first study to examine the management of early stage supraglottic SCC using meta-analytic methodology. Our results suggest that primary surgery may result in decreased disease specific and overall mortality compared to primary radiotherapy. PMID- 29506565 TI - TREE2FASTA: a flexible Perl script for batch extraction of FASTA sequences from exploratory phylogenetic trees. AB - OBJECTIVE: The body of DNA sequence data lacking taxonomically informative sequence headers is rapidly growing in user and public databases (e.g. sequences lacking identification and contaminants). In the context of systematics studies, sorting such sequence data for taxonomic curation and/or molecular diversity characterization (e.g. crypticism) often requires the building of exploratory phylogenetic trees with reference taxa. The subsequent step of segregating DNA sequences of interest based on observed topological relationships can represent a challenging task, especially for large datasets. RESULTS: We have written TREE2FASTA, a Perl script that enables and expedites the sorting of FASTA formatted sequence data from exploratory phylogenetic trees. TREE2FASTA takes advantage of the interactive, rapid point-and-click color selection and/or annotations of tree leaves in the popular Java tree-viewer FigTree to segregate groups of FASTA sequences of interest to separate files. TREE2FASTA allows for both simple and nested segregation designs to facilitate the simultaneous preparation of multiple data sets that may overlap in sequence content. PMID- 29506566 TI - Laparoscopic inguinal ligament suspension versus laparoscopic sacrocolpopexy in the treatment of pelvic organ prolapse: study protocol for a randomized controlled trial. AB - BACKGROUND: Pelvic organ prolapse (POP) is a common health problem. The lifetime risk of undergoing surgery for prolapse is 11%. POP significantly affects the effects on quality of life and activities of daily living. Laparoscopic sacrocolpopexy (LSC) has been viewed as the gold standard treatment for women with POP who desire reconstructive surgery. However, LSC is associated with technical difficulties, resulting in a long learning curve and operative time. Recently, our team introduced a new laparoscopic technique of inguinal ligament suspension (LILS) and had confirmed its safety and efficacy in treating vaginal vault prolapse. As a new surgical technique for POP, a prospective randomized controlled trial comparing the LILS with the standard technique of LSC is necessary. Therefore, we will conduct a trial. METHODS: The trial is a randomized controlled trial. It compares LILS with LSC in women with stage 2 or higher uterine prolapse. The primary outcomes of this study are perioperative parameters, including surgical time, blood loss, intraoperative complications, and hospital stay as well as surgical anatomical results using the pelvic organ prolapse questionnaire (POP-Q) classification at 6 weeks, 6 months, 12 months, and annually till 5 years after surgery. Secondary outcomes are subjective improvement in urogenital symptoms and quality of life, postoperative complications, postoperative recovery, sexual functioning, and cost-effectiveness at each follow-up point. Validated questionnaires will be used and the data will be analyzed according to the intention-to-treat principle. Based on an objective success rate of 90%, a noninferiority margin of 15%, and a dropout of 20%, 107 patients are needed in each arm to prove the hypothesis with a 95% confidence interval. DISCUSSION: The trial is a randomized controlled, multicenter, noninferiority trial that will provide evidence whether the efficacy and safety of LILS is noninferior to LSC in women with symptomatic stage 2 or higher uterine prolapse. TRIAL REGISTRATION: China Trial Register (CTR): ChiCTR-INR-15007408 . Registered on 9 November 2015. PMID- 29506567 TI - Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling. AB - BACKGROUND: Castor zinc finger 1 (CASZ1) plays critical roles in various biological processes and pathologic conditions, including cancer. However, the prognostic importance and biologic functions of CASZ1 in hepatocellular carcinoma (HCC) are still unclear. METHODS: qRT-PCR, western blot and immunohistochemistry analyses were used to determine CASZ1 expression in HCC samples and cell lines. The clinical significance of CASZ1 was assessed in two independent study cohorts containing 232 patients with HCC. A series of in vitro and in vivo experiments were performed to explore the role and molecular mechanism of CASZ1 in HCC progression. RESULTS: Here we report that CASZ1 expression was downregulated in HCC tissues and cell lines. Low CASZ1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes and early recurrence of HCC patients. Moreover, overexpression of CASZ1 in HCCLM3 cells significantly inhibited cell proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo, whereas silencing CASZ1 significantly enhanced the above abilities of PLC/PRF/5 cells. Further mechanism study indicated that these phenotypic changes were mediated by MAPK/ERK signaling pathway and involved altered expression of MMP2, MMP9 and cyclinD1. Finally, we proved that CASZ1 exerted its tumor-suppressive effect by directly interacting with RAF1 and reducing the protein stability of RAF1. CONCLUSIONS: Our study for the first time demonstrated that CASZ1 is a tumor suppressor in HCC, which may serve as a novel prognostic predictor and therapeutic target for HCC patients. PMID- 29506568 TI - Digital storytelling as a method in health research: a systematic review protocol. AB - BACKGROUND: Digital storytelling is an arts-based research method with potential to elucidate complex narratives in a compelling manner, increase participant engagement, and enhance the meaning of research findings. This method involves the creation of a 3- to 5-min video that integrates multimedia materials including photos, participant voices, drawings, and music. Given the significant potential of digital storytelling to meaningfully capture and share participants' lived experiences, a systematic review of its use in healthcare research is crucial to develop an in-depth understanding of how researchers have used this method, with an aim to refine and further inform future iterations of its use. METHODS: We aim to identify and synthesize evidence on the use, impact, and ethical considerations of using digital storytelling in health research. The review questions are as follows: (1) What is known about the purpose, definition, use (processes), and contexts of digital storytelling as part of the research process in health research? (2) What impact does digital storytelling have upon the research process, knowledge development, and healthcare practice? (3) What are the key ethical considerations when using digital storytelling within qualitative, quantitative, and mixed method research studies? Key databases and the grey literature will be searched from 1990 to the present for qualitative, quantitative, and mixed methods studies that utilized digital storytelling as part of the research process. Two independent reviewers will screen and critically appraise relevant articles with established quality appraisal tools. We will extract narrative data from all studies with a standardized data extraction form and conduct a thematic analysis of the data. To facilitate innovative dissemination through social media, we will develop a visual infographic and three digital stories to illustrate the review findings, as well as methodological and ethical implications. DISCUSSION: In collaboration with national and international experts in digital storytelling, we will synthesize key evidence about digital storytelling that is critical to the development of methodological and ethical expertise about arts-based research methods. We will also develop recommendations for incorporating digital storytelling in a meaningful and ethical manner into the research process. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number CRD42017068002 . PMID- 29506569 TI - Does the primary route of spread have a prognostic significance in stage III non serous epithelial ovarian cancer? AB - BACKGROUND: The purpose of this retrospective study was to determine the prognosis of non-serous epithelial ovarian cancer (EOC) patients with exclusively retroperitoneal lymph node (LN) metastases, and to compare the prognosis of these women to that of patients who had abdominal peritoneal involvement. METHODS: A multicenter, retrospective department database review was performed to identify patients with stage III non-serous EOC at 7 gynecologic oncology centers in Turkey. Demographic, clinicopathological and survival data were collected. The patients were divided into three groups based on the initial sites of disease: 1) the retroperitoneal (RP) group included patients who had positive pelvic and /or para-aortic LNs only. 2) The intraperitoneal (IP) group included patients with > 2 cm IP dissemination outside of the pelvis. These patients all had a negative LN status, 3) The IP / RP group included patients with > 2 cm IP dissemination outside of the pelvis as well as positive LN status. Survival data were compared with regard to the groups. RESULTS: We identified 179 women with stage III non serous EOC who were treated at 7 participating centers during the study period. The median age of the patients was 53 years, and the median duration of follow-up was 39 months. There were 35 (19.6%) patients in the RP group, 72 (40.2%) in the IP group and 72 (40.2%) in the IP/RP group. The 5-year disease-free survival (DFS) rates for the RP, the IP, and IP/RP groups were 66.4%, 37.6%, and 25.5%, respectively (p = 0.002). The 5-year overall survival (OS) rate for the RP group was significantly longer when compared to those of the IP, and the IP/RP groups (74.4% vs. 54%, and 36%, respectively; p = 0.011). However, we were not able to define "RP only disease" as an independent prognostic factor for increased DFS or OS. CONCLUSIONS: Primary non-serous EOC patients with node-positive-only disease seem to have better survival when compared to those with extra-pelvic peritoneal involvement. PMID- 29506570 TI - Fine-scale spatial and temporal variation of clinical malaria incidence and associated factors in children in rural Malawi: a longitudinal study. AB - BACKGROUND: Spatio-temporal variations in malaria burden are currently complex and costly to measure, but are important for decision-making. We measured the spatio-temporal variation of clinical malaria incidence at a fine scale in a cohort of children under five in an endemic area in rural Chikhwawa, Malawi, determined associated factors, and monitored adult mosquito abundance. METHODS: We followed-up 285 children aged 6-48 months with recorded geolocations, who were sampled in a rolling malaria indicator survey, for one year (2015-2016). Guardians were requested to take the children to a nearby health facility whenever ill, where health facility personnel were trained to record malaria test results and temperature on the child's sick-visit card; artemisinin-based combination therapy was provided if indicated. The cards were collected and replaced 2-monthly. Adult mosquitoes were collected from 2-monthly household surveys using a Suna trap. The head/thorax of adult Anopheles females were tested for presence of Plasmodium DNA. Binomial logistic regression and geospatial modelling were performed to determine predictors of and to spatially predict clinical malaria incidence, respectively. RESULTS: Two hundred eighty two children, with complete results, and 267.8 child-years follow-up time were included in the analysis. The incidence rate of clinical malaria was 1.2 cases per child-year at risk; 57.1% of the children had at least one clinical malaria case during follow-up. Geographical groups of households where children experienced repeated malaria infections overlapped with high mosquito densities and high entomological inoculation rate locations. CONCLUSIONS: Repeated malaria infections within household groups account for the majority of cases and signify uneven distribution of malaria risk within a small geographical area. PMID- 29506571 TI - Microclimatic temperatures at Danish cattle farms, 2000-2016: quantifying the temporal and spatial variation in the transmission potential of Schmallenberg virus. AB - BACKGROUND: Microclimatic temperatures provide better estimates of vector-borne disease transmission parameters than standard meteorological temperatures, as the microclimate represent the actual temperatures to which the vectors are exposed. The objectives of this study were to quantify farm-level geographic variations and temporal patterns in the extrinsic incubation period (EIP) of Schmallenberg virus transmitted by Culicoides in Denmark through generation of microclimatic temperatures surrounding all Danish cattle farms. METHODS: We calculated the hourly microclimatic temperatures at potential vector-resting sites within a 500 m radius of 22,004 Danish cattle farms for the months April to November from 2000 to 2016. We then modeled the daily EIP of Schmallenberg virus at each farm, assuming vectors choose resting sites either randomly or based on temperatures (warmest or coolest available) every hour. The results of the model output are presented as 17-year averages. RESULTS: The difference between the warmest and coolest microhabitats at the same farm was on average 3.7 degrees C (5th and 95th percentiles: 1.0 degrees C to 7.8 degrees C). The mean EIP of Schmallenberg virus (5th and 95th percentiles) for all cattle farms during spring, summer, and autumn was: 23 (18-33), 14 (12-18) and 51 (48-55) days, respectively, assuming Culicoides select resting sites randomly. These estimated EIP values were considerably shorter than those estimated using standard meteorological temperatures obtained from a numerical weather prediction model for the same periods: 43 (39-52), 21 (17-24) and 57 (55-58) days, respectively. When assuming that vectors actively select the coolest resting sites at a farm, the EIP was 2.3 (range: 1.1 to 4.1) times longer compared to that of the warmest sites at the same farm. CONCLUSIONS: We estimated a wide range of EIP in different microclimatic habitats surrounding Danish cattle farms, stressing the importance of identifying the specific resting sites of vectors when modeling vector-borne disease transmission. We found a large variation in the EIP among different farms, suggesting disease transmission may vary substantially between regions, even within a small country. Our findings could be useful for designing risk-based surveillance, and in the control and prevention of emerging and re emerging vector-borne diseases. PMID- 29506572 TI - Efficacy and safety of electrical moxibustion for knee osteoarthritis: study protocol for a randomized controlled trial. AB - BACKGROUND: Knee osteoarthritis (KOA) is a significant health issue because it causes pain and functional limitation. Many studies have reported that moxibustion, a treatment in traditional Korean medicine, is effective in treating KOA. However, conventional moxibustion produces smoke, harmful gases, and odors that can adversely affect the eyes, skin, and throat. It is also difficult to control the intensity of stimulation in conventional moxibustion. An electrical moxibustion device was developed to circumvent these problems, but there are few studies of that device. We will evaluate the efficacy and safety of electrical moxibustion as a treatment for KOA, and compare it with traditional indirect moxibustion and usual care. METHODS: This is a multicenter, randomized, open, assessor-blinded, parallel-group clinical trial. A total of 138 eligible participants with KOA will be randomly allocated into three groups (electrical moxibustion, traditional indirect moxibustion, or usual care) with a 1:1:1 ratio. Participants in each moxibustion group will receive 12 sessions of moxibustion treatment at 6 acupoints (ST36, ST35, ST34, SP9, EX-LE4, SP10) plus up to 2 points of "ashi", if needed, over a period of 6 weeks (2 sessions per week). A specifically designed device that provides thermal stimulation using electrical energy will be used for the electrical moxibustion group. Participants in the usual care group will receive usual treatment and self-care. The primary outcome measure is change in pain on a numerical rating scale (NRS) from week 1 to week 6. The secondary outcome measures are pain assessed on a visual analog scale (VAS), the Korean version of the Western Ontario and McMaster osteoarthritis index (K-WOMAC), patient global assessment (PGA), and the European quality of life five dimension five level scale (EQ-5D-5 L). Safety will be assessed by monitoring adverse events at each visit. Follow-up measurements will be performed at 12 weeks after baseline measurements. DISCUSSION: This trial will provide evidence on the efficacy and safety of electrical moxibustion as a treatment for KOA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03287570 . Registered on 19 September 2017. PMID- 29506573 TI - Developing indicators for measuring low-value care: mapping Choosing Wisely recommendations to hospital data. AB - OBJECTIVE: Low-value health care refers to interventions where the risk of harm or costs exceeds the likely benefit for a patient. We aimed to develop indicators of low-value care, based on selected Choosing Wisely (CW) recommendations, applicable to routinely collected, hospital claims data. RESULTS: We assessed 824 recommendations from the United States, Canada, Australia and the United Kingdom CW lists regarding their capacity to be measured in administrative hospital admissions datasets. We selected recommendations if they met the following criteria: the service occurred in the hospital setting (observable in setting); a claim recorded the use of the service (record of service); the appropriate/inappropriate use of the service could be mapped to information within the hospital claim (indication); and the service is consistently recorded in the claims (consistent documentation). We identified 17 recommendations (15 services) as measurable. We then developed low-value care indicators for two hospital datasets based on the selected recommendations, previously published indicators, and clinical input. PMID- 29506574 TI - Fever with pancytopenia: unusual presentation of extrapulmonary tuberculosis: a case report. AB - BACKGROUND: Tuberculosis is a major health problem in the developing world. Diagnosis of extrapulmonary tuberculosis is delayed because the presentation is nonspecific. Extrapulmonary tuberculosis can present with various hematological manifestations, including pancytopenia. Pancytopenia could be due to hypersplenism, maturation arrest, hemophagocytic lymphohistiocytosis, or infiltration of the bone marrow by caseating or noncaseating granulomas causing reversible or irreversible fibrosis. CASE PRESENTATION: We report a case of a 56 year-old Sri Lankan Sinhalese man who presented with pyrexia of known origin with significant loss of weight and loss of appetite. He had mild pallor with mild hepatosplenomegaly. He had high inflammatory markers with pancytopenia in a peripheral blood smear. His chest radiograph was unremarkable, and he had a negative Mantoux test result. A diagnosis of disseminated tuberculosis was made on the basis of caseating tuberculous granulomas in the bone marrow. CONCLUSIONS: Disseminated tuberculosis remains a diagnostic challenge because the presentation is vague and nonspecific. In case of pyrexia of unknown origin with peripheral cytopenia, the possibility of disseminated tuberculosis should be considered, particularly in endemic areas. Simultaneous culture and histopathological examination of the bone marrow is important in such instances, because results of common tests such as chest radiography or Mantoux tests can be negative. PMID- 29506575 TI - Evaluation of a spot-on imidacloprid-moxidectin formulation (Advocate(r)) for the treatment of naturally occurring esophageal spirocercosis in dogs: a double blinded, placebo-controlled study. AB - BACKGROUND: Dogs are the definitive hosts of Spirocerca lupi. Spirocercosis is treated by prolonged avermectin administration by injection or daily oral doses. In this prospective, double-blinded, placebo-controlled, clinical trial, the efficacy of imidacloprid and moxidectin spot-on formulation (Advocate(r)) was compared to injectable doramectin (Dectomax(r)). Dogs diagnosed with benign esophageal spirocercosis were divided randomly into doramectin (400 MUg/kg IM) or moxidectin and imidacloprid spot-on (2.5-6.25 mg/kg and 10-25 mg/kg, respectively) groups and treated weekly for 12 consecutive weeks. Dogs were followed for 20 weeks by physical examination, owners' questionnaire, blood work, fecal floatation, PCR and endoscopy. RESULTS: All the doramectin group dogs (n = 10) completed the treatment and follow-up, and the disease had completely resolved in all by week 12. Of the Advocate(r) group (n = 10), four had complete resolution at week 12, four had partial resolution, one dog did not respond to treatment, and one dog was switched to the doramectin protocol on week 5 due to persistent severe clinical signs. PCR analysis was more sensitive in detecting S. lupi eggs compared to fecal floatation. Discrepancies were detected on 22 occasions, of which on 20 occasions, the PCR was positive while fecal floatation was negative, and only on two occasions the PCR results were negative while fecal flotation was positive. CONCLUSIONS: The present results indicate that weekly Advocate(r) spot-on administration may be effective for treating benign esophageal spirocercosis, but is less effective than the currently used injectable doramectin therapy at the dose and duration used herein. PMID- 29506577 TI - Atherogenic index of plasma is a novel and better biomarker associated with obesity: a population-based cross-sectional study in China. AB - BACKGROUND: Atherogenic index of plasma (AIP) has been reported to be associated with cardiovascular diseases. However no study has yet systematically evaluated the association between AIP and obesity and its advantage in obesity prediction compared with conventional lipid components. METHODS: A total of 6465 participants aged over 30 years were included in this study. Blood lipid components including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured, and AIP was calculated as log10(TG/HDL-C). Pearson correlation analyses, multivariable logistic analyses and predictive analyses were used to evaluate the association and discrimination ability between AIP, four conventional lipid profiles and obesity. RESULTS: Subjects in the higher quartiles of AIP all had a significantly increased risk of obesity compared with those in the lowest quartile (P for trend< 0.01). AIP showed a stronger association with obesity than the conventional lipid components as the pearson coefficient reached up to 0.372 and the adjusted odds ratio was 5.55. Using AIP rather than HDL-C and TG significantly improved risk prediction for obesity (AUC improvement = 0.011, P = 0.011; Continuous net reclassification index = 29.55%, P < 0.01; Category net reclassification index = 6.06%; Integrated discrimination improvement = 0.68%, P < 0.01). CONCLUSIONS: Higher AIP level was positively and strongly associated with obesity. AIP is a novel and better biomarker associated with obesity. Controlling the AIP level would be more helpful for the prevention of obesity. PMID- 29506576 TI - Effects of isoflurane, sevoflurane, propofol and alfaxalone on brain metabolism in dogs assessed by proton magnetic resonance spectroscopy (1H MRS). AB - BACKGROUND: The purpose of this study was to determine the effects of isoflurane, sevoflurane, propofol and alfaxalone on the canine brain metabolite bioprofile, measured with single voxel short echo time proton magnetic resonance spectroscopy at 3 Tesla. Ten adult healthy Beagle dogs were assigned to receive isoflurane, sevoflurane, propofol and alfaxalone at 3 different dose rates each in a randomized cross-over study design. Doses for isoflurane, sevoflurane, propofol and alfaxalone were FE'Iso 1.7 vol%, 2.1 vol%, 2.8 vol%, FE'Sevo 2.8 vol%, 3.5 vol% and 4.7 vol%, 30, 45 and 60 mg kg- 1 h- 1 and 10, 15 and 20 mg kg- 1 h- 1 respectively. A single voxel Point Resolved Spectroscopy Sequence was performed on a 3 T MRI scanner in three brain regions (basal ganglia, parietal and occipital lobes). Spectral data were analyzed with LCModel. Concentration of total N-acetylaspartate (tNAA), choline, creatine, inositol and glutamine and glutamate complex (Glx) relative to water content was obtained. Plasma concentration of lactate, glucose, triglycerides, propofol and alfaxalone were determined. Statistics were performed using repeated measures ANOVA or Wilcoxon Sign Rank test with alpha = 5%. RESULTS: Plasma glucose increased with isoflurane, sevoflurane and alfaxalone but decreased with propofol. Plasma lactate increased with all anesthetics (isoflurane > sevoflurane > propofol > alfaxalone). Cerebral lactate could not be detected. Only minor changes in cerebral metabolite concentrations of tNAA, choline, inositol, creatine and Glx occurred with anesthetic dose changes. CONCLUSION: The metabolomic profile detected with proton magnetic resonance spectroscopy at 3 Tesla of canine brain showed only minor differences between doses and anesthetics related to tNAA, choline, creatine, inositol and Glx. PMID- 29506578 TI - Collagen IX gene polymorphisms and lumbar disc degeneration: a systematic review and meta-analysis. AB - BACKGROUND: An increasing number of studies have investigated associations between collagen IX alpha 2 chain (COL9A2) and collagen IX alpha 3 chain (COL9A3) gene polymorphisms and the risk of lumbar disc degeneration (LDD). However, these studies have yielded contradictory results. The purpose of this meta-analysis is to investigate the association between the collagen IX gene polymorphisms (rs12077871, rs12722877, rs7533552 in COL9A2; rs61734651 in COL9A3) and LDD. METHODS: All relevant articles were collected from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI). The last electronic search was performed on September 1, 2017. The allele/genotype frequencies were extracted from each study. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of associations under the five comparison genetic models. Statistical analysis was performed by Review Manager (RevMan) 5.31 software. RESULTS: The meta-analysis of 10 case-control studies, including 2102 LDD cases and 2507 controls, indicated that COL9A2 gene (rs12077871, rs12722877, rs7533552) and COL9A3 gene (rs61734651) polymorphisms were not associated with LDD (rs12077871: T vs. C, OR = 1.85, 95% CI = 0.87-3.91, P = 0.11; rs12722877: G vs. C, OR = 0.83, 95% CI = 0.69-1.01, P = 0.06; rs7533552: G vs. A, OR = 1.11, 95% CI = 0.98-1.25, P = 0.09; rs61734651: T vs. C, OR = 1.57, 95% CI = 0.51-4.84, P = 0.43). The Egger text and the Begg funnel plot did not show any evidence of publication bias. CONCLUSION: rs12077871, rs12722877, and rs7533552 variants in COL9A2 and rs61734651 variant in COL9A3 were not significantly associated with a predisposition to LDD. Large-scale and well-designed studies are needed to confirm this conclusion. PMID- 29506579 TI - High-flow nasal oxygen vs. standard oxygen therapy in immunocompromised patients with acute respiratory failure: study protocol for a randomized controlled trial. AB - BACKGROUND: Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in immunocompromised patients. High-flow nasal oxygen (HFNO) therapy is an alternative to standard oxygen. By providing warmed and humidified gas, HFNO allows the delivery of higher flow rates via nasal cannula devices, with FiO2 values of nearly 100%. Benefits include alleviation of dyspnea and discomfort, decreased respiratory distress and decreased mortality in unselected patients with acute hypoxemic respiratory failure. However, in preliminary reports, HFNO benefits are controversial in immunocompromised patients in whom it has never been properly evaluated. METHODS/DESIGN: This is a multicenter, open-label, randomized controlled superiority trial in 30 intensive care units, part of the Groupe de Recherche Respiratoire en Reanimation Onco Hematologique (GRRR-OH). Inclusion criteria will be: (1) adults, (2) known immunosuppression, (3) ARF, (4) oxygen therapy >= 6 L/min, (5) written informed consent from patient or proxy. Exclusion criteria will be: (1) imminent death (moribund patient), (2) no informed consent, (3) hypercapnia (PaCO2 >= 50 mmHg), (4) isolated cardiogenic pulmonary edema, (5) pregnancy or breastfeeding, (6) anatomical factors precluding insertion of a nasal cannula, (7) no coverage by the French statutory healthcare insurance system, and (8) post-surgical setting from day 1 to day 6 (patients with ARF occurring after day 6 of surgery can be included). The primary outcome measure is day-28 mortality. Secondary outcomes are intubation rate, comfort, dyspnea, respiratory rate, oxygenation, ICU length of stay, and ICU-acquired infections. Based on an expected 30% mortality rate in the standard oxygen group, and 20% in the HFNO group, error rate set at 5%, and a statistical power at 90%, 389 patients are required in each treatment group (778 patients overall). Recruitment period is estimated at 30 months, with 28 days of additional follow-up for the last included patient. DISCUSSION: The HIGH study will be the largest multicenter, randomized controlled trial seeking to demonstrate that survival benefits from HFNO reported in unselected patients also apply to a large immunocompromised population. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02739451 . Registered on 15 April 2016. PMID- 29506582 TI - Early childhood onset of high-grade atrioventricular block in Hunter syndrome. AB - Cardiac involvement has been reported in various mucopolysaccharidoses syndromes. Cardiac valve pathology is the most prominent cardiac manifestation of patients with these syndromes. To date, there have been no reports of early childhood onset of high-grade atrioventricular block in patients with Hunter syndrome. We present a case of a 3-year-old boy with Hunter syndrome who was found to have various degrees of atrioventricular block. This case highlights the importance of early routine cardiac screening for conduction abnormalities and close follow-up in patients with mucopolysaccharidoses syndromes. PMID- 29506581 TI - Transcatheter aortic valve implantation with a mechanically expandable prosthesis: a learning experience for permanent pacemaker implantation rate reduction. AB - BACKGROUND: Permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI) remains an issue open for criticism. Aim of this study is to investigate a strategy to reduce PPMI rate after TAVI in general and more specifically after implantation of the LOTUS(r) prosthesis. METHODS: Through our learning curve, we have developed a structured protocol to reduce PPMI rate. The protocol includes: shallow implantation depth within the native annulus, strict adherence to the international guidelines for PPMI, PPMI not earlier than 5 days after TAVI, and intravenous chronotropic and steroidal treatment (orciprenaline 0.6-1.7 mg/h i.v. and dexamethasone 25 mg/day i.v. for a maximum of 5 days) in case of acute onset of intraventricular and/or atrio-ventricular conduction disturbances after TAVI. RESULTS: The first 35 patients (group A) were managed as per routine in our early stage experience with the LOTUS valve. The PPMI reduction protocol was applied in the second phase on the last 31 patients (group B). The PPMI rate was reduced from 34.3% (12/35) to 9.7% (3/31) (p = 0.02). At logistic regression analysis being treated in the second phase of our experience (group B) had a protective effect against PPMI (p = 0.05; OR = 0.1; CI = 0.01 1.0). Prosthesis implantation depth was directly related to PPMI (p = 0.005; OR = 2.0; CI = 1.2-3.2). Receiver operating characteristic curve analysis confirmed that a LOTUS implantation depth > 4.8 mm was the cut-off to predict PPMI (AUC = 0.8; p = 0.003; CI = 0.6-0.9) with maximal sensitivity (78.6%) and specificity (73.2%). CONCLUSIONS: PPMI rate after LOTUS can be reduced with experience by applying specific clinical and operative strategies. PMID- 29506583 TI - Diagnosis of schistosomiasis mansoni: an evaluation of existing methods and research towards single worm pair detection. AB - The inadequacy of current diagnostics for the detection of low worm burdens in humans means that schistosomiasis mansoni is more widespread than previously acknowledged. With the inception of mass drug treatment programmes aimed at disease elimination and the advent of human vaccine trials, the need for more sensitive diagnostics is evident. In this review, we evaluate the merits and limitations of the principal diagnostic methods, namely detection of eggs in faeces; anti-schistosome antibodies in serum; parasite-derived proteins and glycans in serum or urine; parasite DNA in blood, faeces or urine. Only in the baboon model, where actual worm burden is determined by portal perfusion, have faecal smear and circulating antigen methods been calibrated, and shown to have thresholds of detection of 10-19 worm pairs. There is scope for improvement in all the four methods of detection, e.g. the identification of single targets for host antibodies to improve the specificity of enzyme linked immunosorbent assay. Despite recent advances in the definition of the schistosome secretome, there have been no comprehensive biomarker investigations of parasite products in the urine of infected patients. Certainly, the admirable goal of eliminating schistosomiasis will not be achieved unless individuals with low worm burdens can be diagnosed. PMID- 29506584 TI - Core beliefs in healthy youth and youth at ultra high-risk for psychosis: Dimensionality and links to depression, anxiety, and attenuated psychotic symptoms. AB - Cognitive theory posits that core beliefs play an active role in developing and maintaining symptoms of depression, anxiety, and psychosis. This study sought to comprehensively examine core beliefs, their dimensionality, and their relationships to depression, anxiety, and attenuated psychotic symptoms in two groups of community youth: a group at ultrahigh risk for psychosis (UHR; n = 73, M age = 18.7) and a matched healthy comparison group (HC; n = 73, M age = 18.1). UHR youth reported significantly more negative beliefs about self and others, and significantly less positive beliefs about self and others. HC youth rarely endorsed negative self-beliefs. Exploratory factor analyses found that HC negative self-beliefs did not cohere as a single factor. We hypothesized specific links between core beliefs and symptoms based on cognitive models of each disorder, and tested these links through regression analyses. The results in the HC group were consistent with the proposed models of depression and anxiety. The results in the UHR group were consistent with proposed models of depression and negative psychotic symptoms, somewhat consistent with a proposed model of positive psychotic symptoms, and not at all consistent with a proposed model of anxiety. These findings add to a growing developmental literature on core beliefs and psychopathology, with important clinical implications. PMID- 29506586 TI - WOMEN'S EMPOWERMENT AND INTIMATE PARTNER VIOLENCE IN BANGLADESH: INVESTIGATING THE COMPLEX RELATIONSHIP. AB - The aim of this study was to assess whether women's empowerment ensures reduced intimate partner violence (IPV). The differential relationship between women's empowerment and IPV among married women in Bangladesh was investigated using 2007 Demographic and Health Survey data. Logistic regression models were used to assess whether women's empowerment had any influence on their likelihood of experiencing IPV while controlling for other covariates. The analyses revealed that older cohorts of women, who were more empowered, were more vulnerable to physical violence than less-empowered, younger women. The likelihood of being affected by physical violence among less-empowered, childless women was greater than that of more-empowered women with only male children. Less-empowered, uneducated women were more likely to experience physical violence than more empowered, primary-educated women. Less-empowered women who had been married for less than 5 years were more likely to suffer from physical violence than more empowered women who had been married for more than 19 years. The likelihood of experiencing sexual violence was not found to have any significant association with women's empowerment. The findings suggest that although women's empowerment in Bangladesh is gradually improving, some sub-groups of empowered women are still susceptible to IPV. PMID- 29506585 TI - Feasibility and relative validity of a digital photo-based dietary assessment: results from the Nutris-Phone study. AB - OBJECTIVE: For dietary assessment, mobile devices with a camera can be used as an alternative to hand-written paper records. The Nutritional Tracking Information Smartphone (Nutris-Phone) study aimed to examine relative validity and feasibility of a photo-based dietary record in everyday life. DESIGN: Parallel to the photo-based technique, a weighed record was performed. Participant satisfaction was assessed by questionnaire. A trained nutrition scientist evaluated portion sizes and nutrient content was calculated (DGExpert). Spearman correlation and Bland-Altman analyses were applied. SETTING: Healthy, non pregnant volunteers (>=18 years) without intent to lose weight recruited at Ulm University, Germany. SUBJECTS: Sixty-six participants (36 % males, median age 22.0 (interquartile range 20.0-25.0) years) took pictures of foods and beverages consumed with a commercially available mobile phone. RESULTS: Significant correlation between the photo-based and weighed record was observed: energy (r=0.991), carbohydrate (r=0.980), fat (r=0.972), protein (r=0.988), fibre (r=0.941). Bland-Altman analyses indicated comparable means and acceptable 95 % limits of agreement (energy: -345.2 to 302.9 kJ (-82.5 to 72.4 kcal); carbohydrate: -15.2 to 13.1 g; fat: -6.4 to 6.4 g; protein: -5.9 to 5.6 g; fibre: -2.7 to 2.5 g). However, with increasing intake level, underestimation by the digital method was present (except for fat, all P<0.01). Over 80 % of participants were satisfied with the photo-based record. In nearly 90 %, technical implementation was without major problems. CONCLUSIONS: Compared with a weighed record, the photo-based dietary record seems to be valid, feasible and user-friendly to estimate energy, macronutrient and fibre intakes, although a systematic bias with increasing levels of intake should be kept in mind. PMID- 29506587 TI - Hepatitis E: we have seen the footprint in the sand, let us hunt the beast. PMID- 29506589 TI - Cost-effectiveness of digoxin, pacing, and direct current cardioversion for conversion of atrial flutter in neonates. AB - : IntroductionNewborn atrial flutter can be treated by medications, pacing, or direct current cardioversion. The purpose is to compare the cost-effectiveness of digoxin, pacing, and direct current cardioversion for the treatment of atrial flutter in neonates.Materials and methodsA decision tree model was developed comparing the efficacy and cost of digoxin, pacing, and direct current cardioversion based on a meta-analysis of published studies of success rates of cardioversion of neonatal atrial flutter (age<2 months). Patients who failed initial attempt at cardioversion progressed to the next methodology until successful. Data were analysed to assess the cost-effectiveness of these methods with cost estimates obtained from 2015 Medicare reimbursement rates. RESULTS: The cost analysis for cardioversion of atrial flutter found the most efficient method to be direct current cardioversion at a cost of $10 304, pacing was next at $11 086, and the least cost-effective was digoxin at $14 374. The majority of additional cost, regardless of method, was from additional neonatal ICU day either owing to digoxin loading or failure to covert. Direct current cardioversion remains the most cost-effective strategy by sensitivity analyses performed on pacing conversion rate and the cost of the neonatal ICU/day. Direct current cardioversion remains cost-effective until the assumed conversion rate is below 64.6%. CONCLUSION: The most cost-efficient method of cardioverting a neonate with atrial flutter is direct current cardioversion. It has the highest success rates based on the meta-analysis, shorter length of stay in the neonatal ICU owing to its success, and results in cost-savings ranging from $800 to $4000 when compared with alternative approaches. PMID- 29506590 TI - Differences in meal patterns and timing with regard to central obesity in the ANIBES ('Anthropometric data, macronutrients and micronutrients intake, practice of physical activity, socioeconomic data and lifestyles in Spain') Study - CORRIGENDUM. PMID- 29506588 TI - Rationalising the use of cardiac catheterisation before Glenn completion. AB - Previous studies have shown that cardiac MRI can be used to evaluate the suitability for infants to undergo the Glenn operation after having undergone the Norwood procedure. We sought to analyse our institutional data retrospectively to identify whether such a policy would be advisable in the current era. We reviewed patients who underwent the Norwood procedure between 1 January, 2006 and 1 January, 2016. All patients undergoing evaluation for the Glenn procedure received clinical evaluation, echocardiography, and cardiac catheterisation. A total of 179 patients were identified; 154 patients (86%) survived to undergo cardiac catheterisation as part of evaluation for the Glenn, and all who were evaluated did not eventually receive the Glenn. Using said algorithm, if cardiac MRI or CT were to be used to rationalise the use of catheterisation, 26 of 154 patients would have required catheterisation after cross-sectional imaging identified vascular obstruction; 83 of 154 patients would have received cross sectional imaging only; and 45 of 154 would have had catheterisation only. All cases that required intervention, excluding aortopulmonary collaterals, and all cases that were not suitable to progress would have been correctly identified using clinical and echocardiographic criteria in addition to cardiac cross sectional imaging to rationalise the use of catheterisation. Thus, in cases with acceptable clinical, echocardiographic, and angiographic findings, the additional haemodynamic information from catheterisation is rarely of use for decision making, and interventions can largely be predicted by angiographic imaging modalities. PMID- 29506591 TI - Forty years of the Law 180: the aspirations of a great reform, its successes and continuing need. AB - AIM: Italy pioneered deinstitutionalisation over the past 60 years and enforced a famous mental health (MH) reform law in 1978. Deinstitutionalisation has been completed with the very closure of all psychiatric hospitals over two decades. METHODS: After 40 years of implementation, this article presents the main achievements and challenges of the Italian MH reform law, including its long-term effect and impact in Italy and abroad. RESULTS: The Legislation of 1978 was based on the discovery of rights as a key tool in mental healthcare. At the climax of crisis of psychiatric hospitals as total institutions in this country, through the new community-based system of care, it has fostered the lowest rate of involuntary care and gave back the full citizenship to people with MH disorders. This act was also part of a social movement for expanding civil and social rights, and a promise of a true paradigm shift not only in psychiatry, but also in the way of providing an adequate welfare community for all citizens. According to the WHO, the Italian city of Trieste, together with its region, is a practical example of how the Italian movement achieved deinstitutionalisation, intended as a complex process resulting in the gradual relocation of the economic and human resources and subsequent creation of 24 h services together with the development of social inclusion programmes. CONCLUSIONS: Even if the great principles of the Italian reform law were anticipatory (e.g., the UN Convention on Rights of Persons with Disabilities - CRPD), the law application has been poorly provided with resources and did not follow those avant-garde experiences as models. Limitations are evident today especially at the organisational levels, such as services capable to take up the challenge and transforming the field, left free from the imprint of total institutions. These endemic critical aspects concerning to implementation policies, together with the financial crisis of the Italian healthcare system, must be taken into consideration for a re-launch of this historical law. The rights-based approach opened by the Law 180 should now take into consideration the new legal situation caused by the CRPD worldwide in the area of individuals' human rights, especially about the issue of legal capacity and related involuntary care. PMID- 29506592 TI - Quantity and species of fish consumed shape breast-milk fatty acid concentrations around Lake Victoria, Kenya. PMID- 29506593 TI - The global nutrition transition: trends, disease burdens and policy interventions. AB - Non-communicable diseases (NCD) have increased dramatically in developed and developing countries. Unhealthy diet is one of the major factors contributing to NCD development. Recent evidence has identified deterioration in aspects of dietary quality across many world regions, including low- and middle-income countries (LMIC). Most burdens of disease attributable to poor diet can be prevented or delayed as they occur prematurely. Therefore, it is important to identify and target unhealthy dietary behaviours in order to have the greatest impact. National dietary-related programmes have traditionally focused on micronutrient deficiency and food security and failed to acknowledge unhealthy dietary intakes as a risk factor that contributes to the development of NCD. Inadequate intakes of healthy foods and nutrients and excess intakes of unhealthy ones are commonly observed across the world, and efforts to reduce the double burden of micronutrient deficiency and unhealthy diets should be a particular focus for LMIC. Interventions and policies targeting whole populations are likely to be the most effective and sustainable, and should be prioritized. Population based approaches such as health information and communication campaigns, fiscal measures such as taxes on sugar-sweetened beverages, direct restrictions and mandates, reformulation and improving the nutrient profile of food products, and standards regulating marketing to children can have significant and large impacts to improve diets and reduce the incidence of NCD. There is a need for more countries to implement population-based effective approaches to improve current diets. PMID- 29506594 TI - Blood Eosinophil Count and Metabolic, Cardiac and Pulmonary Outcomes: A Mendelian Randomization Study. AB - Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results. PMID- 29506595 TI - Inverse association of calcium intake with abdominal adiposity and C-reactive protein in Brazilian children. AB - OBJECTIVE: To evaluate Ca intake and its association with cardiometabolic risk factors during childhood. DESIGN: A cross-sectional study with a representative sample. Food consumption was assessed through three 24 h dietary recalls. Anthropometry, body composition and biochemical measurements were also conducted. SETTING: Vicosa, Minas Gerais, Brazil. SUBJECTS: Children between 8 and 9 years old (n 350) enrolled in public and private schools in the urban area of the municipality of Vicosa. RESULTS: Almost all children had inadequate intake of Ca (97.4 %), especially those with low income, non-white and who studied in public schools. Foods that contributed most to Ca intake were 'milk' and 'cheeses and yoghurts' (R 2=0.66 and 0.13, respectively), and intake of 'milk' was correlated with 'chocolate milk powder' intake (r=0.538, P<0.01). Children with lower Ca intake had a higher prevalence of increased C-reactive protein (prevalence ratio=2.93; 95 % CI 1.21, 7.07), increased waist circumference (prevalence ratio=2.86; 95 % CI 1.01, 8.13) and a lower prevalence of high LDL cholesterol (prevalence ratio=0.64; 95 % CI 0.41, 0.99). CONCLUSIONS: Lower Ca intake was associated with excess abdominal adiposity and subclinical inflammation in Brazilian children. Monitoring of adequate Ca intake is important, especially in poorer communities. PMID- 29506596 TI - Persistent social inequality in low intake of vegetables among adolescents, 2002 2014. AB - OBJECTIVE: To examine the trend in social inequality in low intake of vegetables among adolescents in Denmark from 2002 to 2014 using occupational social class (OSC) as socio-economic indicator. DESIGN: Repeated cross-sectional school surveys including four waves of data collection in 2002-2014. The analyses focused on absolute social inequality (difference between high and low OSC in low vegetable intake) as well as relative social inequality (OR for low vegetable intake by OSC). SETTING: The nationally representative Health Behaviour in School aged Children (HBSC) study in Denmark. SUBJECTS: The study population was 11-15 year olds (n 17 243). RESULTS: Low intake of vegetables was defined as less than weekly intake measured by food frequency items. OSC was measured by student reports of parents' occupation. The proportion of participants who reported eating vegetables less than once weekly was 8.9 %, with a notable decrease from 11.9 % in 2002 to 5.9 % in 2014. The OR (95 % CI) for less than weekly vegetable intake was 2.28 (1.98, 2.63) in the middle compared with high OSC and 3.12 (2.67, 3.66) in the low compared with high OSC. The absolute social inequality in low vegetable intake decreased from 2002 to 2014 but the relative social inequality remained unchanged. CONCLUSIONS: The study underscores that it is important to address socio-economic factors in future efforts to promote vegetable intake among adolescents. The statistical analyses of social inequality in vegetable intake demonstrate that it is important to address both absolute and relative social inequality as these two phenomena may develop differently. PMID- 29506597 TI - School achievement as a predictor of depression and self-harm in adolescence: linked education and health record study. AB - BACKGROUND: Mental disorders in children and adolescents have an impact on educational attainment. Aims To examine the temporal association between attainment in education and subsequent diagnosis of depression or self-harm in the teenage years. METHOD: General practitioner, hospital and education records of young people in Wales between 1999 and 2014 were linked and analysed using Cox regression. RESULTS: Linked records were available for 652 903 young people and of these 33 498 (5.1%) developed depression and 15 946 (2.4%) self-harmed after the age of 12 but before the age of 20. Young people who developed depression over the study period were more likely to have achieved key stage 1 (age 7 years) but not key stage 2 (age 11) (hazard ratio (HR) = 0.79, 95% CI 0.74-0.84) milestones, indicating that they were declining in academic attainment during primary school. Conversely, those who self-harmed were achieving as well as those who did not self-harm in primary school, but showed a severe decline in their attainment during secondary school (HR = 0.72, 95% CI 0.68-0.78). CONCLUSIONS: Long-term declining educational attainment in primary and secondary school was associated with development of depression in the teenage years. Self-harm was associated with declining educational attainment during secondary school only. Incorporating information on academic decline with other known risk factors for depression/self-harm (for example stressful life events, parental mental health problems) may improve risk profiling methods. Declaration of interest None. PMID- 29506598 TI - Headache in Guillain-Barre Syndrome: Diagnostic and Management Implications. AB - Headache is an uncommon symptom in Guillain-Barre syndrome (GBS). We review four clinical settings related to GBS in which headache may be present. We focus on pathophysiological explanations, alerting the clinician to further potential investigations and treatment. Most reports of headache in GBS occur in the context of the posterior reversible encephalopathy syndrome, an increasingly recognized dysautonomia-related GBS complication. Less frequent is headache in the setting of increased intracranial pressure and papilledema (secondary intracranial hypertension), Miller Fisher syndrome, and cerebral venous sinus thrombosis. Rarely, headache can occur secondary to aseptic meningitis from IVIg use. PMID- 29506599 TI - Evidence for Cholinergic Dysfunction in Autosomal Dominant Kufs Disease. AB - OBJECTIVE: Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. METHODS: We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. RESULTS: Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection fibers were spared, but there was a profound loss of choline acetyltransferase within the caudate, putamen, and basal forebrain. This suggests a loss of choline acetyltransferase as opposed to a loss of the neurons. CONCLUSIONS: This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain. PMID- 29506601 TI - Effects of Ginkgo Biloba Extract on A53T alpha-Synuclein Transgenic Mouse Models of Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) is a degenerative disorder of the central nervous system mainly affecting the motor system. Presently, there is no effective and safe drug to treat patients with PD. Ginkgo biloba extract (GBE), obtained from leaves of the Ginkgo biloba tree, is a complex mixture of ingredients primarily containing two active components: flavonoids and terpenoids. In this study, we investigated the effects of GBE on A53T alpha synuclein transgenic mice, a PD model that has better simulated the progression of PD patients than other models such as the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced PD model. METHODS: Fifty alpha-synuclein A53T transgenic mice were fed and treated with GBE, and locomotor activity was detected by pole test, forced swim test, and wire-hang test. The expression of tyrosine hydroxylase and dopamine transporters was detected using immunohistochemistry. Superoxide dismutase activity, glutathione peroxidase activity, and malondialdehyde expression were detected using an assay kit. RESULTS: Our results show that GBE treatment improved locomotor activity and that superoxide dismutase and glutathione peroxidase inhibited the expression of methane dicarboxylic aldehyde and recovered the expression of tyrosine hydroxylase and dopamine transporters. CONCLUSIONS: The GBE treatment improved locomotor activity and inhibited the development of PD in the A53T alpha synuclein transgenic mice, which may be partly responsible for decreased oxidative damage and maintain the normal dopamine homeostasis. PMID- 29506600 TI - Secondary Abnormal CSF Neurotransmitter Metabolite Profiles in a Pediatric Tertiary Care Centre. AB - BACKGROUND: Secondary neurotransmitter deficiencies have been reported in several reviews. Our primary aim was to assess the relationship among epilepsy, antiseizure medications, and specific neurotransmitter abnormalities. We also evaluated movement disorders and brain abnormalities via magnetic resonance imaging scans in patients with secondary neurotransmitter defects. METHODS: This is a retrospective case series of 376 patients who underwent neurotransmitter analysis at BC Children's Hospital between 2009 and 2013, for a variety of neurological presentations. The biochemical genetics laboratory database was interrogated for results of cerebrospinal fluid neurotransmitter analyses. Clinical data for patients with abnormal results were collected from the hospital charts. Statistical analysis included one-way analysis of variance, chi-square, and a two-way contingency table. RESULTS: Abnormal neurotransmitter values were identified in 67 (17.8%) patients, two (0.53%) of which were attributable to a congenital neurotransmitter disorder and 11 (16.9%) secondary to other genetic diagnoses. Of 64 patients with secondary abnormal neurotransmitter values, 38 (59%) presented with epilepsy and 20 (31%) with movement disorders. A combination of epilepsy and movement disorder was less frequent. DISCUSSION: Acknowledging the limitations of this retrospective chart review, we conclude that, in our cohort, in addition to patients with movement disorders, a considerable number of patients with epilepsy and epileptic encephalopathy also showed secondary neurotransmitter mono-amine abnormalities. There is no clear relation, however, between clinical phenotype and type of neurotransmitter affected. In addition, no association was identified between the type of antiseizure medications and affected neurotransmitter type. We outline the need for prospective studies to further enrich our understanding of the relation between epilepsy and neurotransmitters with a focus on improving treatments and patient outcomes. PMID- 29506602 TI - Cerebrovascular Neurosurgery in Canada: An Historical Review. AB - Canadian contributions to cerebrovascular neurosurgery have been disproportionately large and, with some exceptions, relatively unrecognized. In this review, some of the efforts in the advancement of cerebrovascular neurosurgery by Canadian neurologists and neurosurgeons are described. PMID- 29506604 TI - Associations of vegetable and fruit consumption with metabolic syndrome. A meta analysis of observational studies. AB - OBJECTIVE: To examine the associations of vegetable and/or fruit consumption with metabolic syndrome (MetS). DESIGN: Meta-analysis of observational studies. SETTING: The electronic databases of PubMed, Web of Science and EMBASE were searched up to September 2017 for observational studies concerning the associations of vegetable and/or fruit consumption with MetS. The pooled relative risk (RR) of MetS for the highest v. the lowest category of vegetable and/or fruit consumption, as well as their corresponding 95 % CI, were calculated. RESULTS: A total of twenty-six observational studies (twenty cross-sectional, one case-control and five cohort studies) were included in the meta-analysis. Specifically, sixteen studies were related to vegetable consumption and the overall multivariable-adjusted RR evidenced a negative association between vegetable consumption and MetS (RR=0.89, 95 % CI 0.85, 0.93; P<0.001). For fruit consumption, sixteen studies were included and the overall multivariable-adjusted RR demonstrated that fruit consumption was inversely associated with MetS (RR=0.81, 95 % CI 0.75, 0.88; P<0.001). For vegetable and fruit consumption, eight studies were included; the overall multivariable-adjusted RR showed that vegetable and fruit consumption was also negatively associated with MetS (RR=0.75, 95 % CI 0.63, 0.90; P=0.002). CONCLUSIONS: The existing evidence suggests that vegetable and/or fruit consumption is negatively associated with MetS. More well-designed prospective cohort studies are needed to elaborate the concerned issues further. PMID- 29506605 TI - Has compassionate use ever sunk a drug? PMID- 29506606 TI - Mission impossible: the End TB strategy. PMID- 29506607 TI - Ringing the alarm bells about migrants' health. PMID- 29506609 TI - People- and patient-centred care for tuberculosis: models of care for tuberculosis. AB - SETTING: The first pillar in the World Health Organisation's (WHO's) End TB strategy is 'Integrated, patient-centred tuberculosis (TB) care and prevention'. However, what are patient- and people-centred care, and why are they important for TB care and prevention? OBJECTIVE AND RATIONALE: To define the concept of patient-centred care, the rationale for it, and its evolution into people-centred care; and to explore evidence on whether people-centred approaches work for TB and present key areas where continuous efforts are needed to support their implementation. RESULTS: Based on the reasoning and the evidence presented, we propose four areas where further action is needed to ensure that people-centred TB care and prevention can achieve their potential: 1) reaching consensus on definitions and terminology; 2) strengthening research; 3) using and evaluating new technology; and 4) nurturing country leadership and advocacy. CONCLUSION: Integrated, people-centred TB care and prevention should be a guiding light for all those involved in the quest to eliminate TB. However, much still needs to be done to bridge the gaps between the potential and actual performance of national programmes. PMID- 29506608 TI - Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. AB - Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. The duration of treatment required for all forms of tuberculosis (TB) put existing regimens at risk of failure because of early discontinuations and treatment loss to follow-up. Long-acting injections, for example, administered every month, could improve patient adherence and treatment outcomes. We review the state of the science for potential long-acting formulations of existing tuberculosis drugs, and propose a target product profile for new formulations to treat latent tuberculous infection (LTBI). The physicochemical properties of some anti-tuberculosis drugs make them unsuitable for long-acting formulation, but there are promising candidates that have been identified through modeling and simulation, as well as other novel agents and formulations in preclinical testing. An efficacious long-acting treatment for LTBI, particularly for those co-infected with HIV, and if coupled with a biomarker to target those at highest risk for disease progression, would be an important tool to accelerate progress towards TB elimination. PMID- 29506610 TI - Recurrent tuberculosis in the pre-elimination era. AB - Recurrent tuberculosis (TB), defined as TB that recurs after a patient has been considered cured, constitutes a challenge to TB control. In low TB burden countries, the underlying causes and consequences of recurrent TB are poorly understood. We conducted a literature review to summarise the evidence of recurrent TB in low-burden settings and to address current gaps in knowledge. We included peer-reviewed publications on studies conducted in countries with an estimated TB incidence of <100 cases per 100 000 population. The Newcastle-Ottawa scale was used to assess study quality. The review yielded 44 manuscripts, 39 of which were reports of observational studies and 5 of clinical trials. The median percentage of TB patients experiencing an episode of recurrent TB after treatment completion was 3.4% (interquartile range [IQR] 1.6-6.0, range 0.4-16.7) in studies with a median follow-up of 7.8 years (IQR 5-12, range 2-33). The median percentage of recurrences attributable to endogenous reactivation (rather than exogenous reinfection) was 81% (IQR 73.1-85.5, range 49-100). Commonly identified risk factors for recurrence in low-burden settings included infection by the human immunodeficiency virus, low socio-economic status, foreign birth and infection with drug-resistant TB. Current understanding of recurrence in low burden settings is limited, in part due to substantial methodological differences between studies. Further research is required to delineate the mechanisms of TB recurrence, its health and clinical impact, as well as the implications for TB elimination efforts in low-burden countries. PMID- 29506611 TI - Policies and practices on the programmatic management of LTBI: a survey in the African Region. AB - BACKGROUND: Although the management of latent tuberculous infection (LTBI) is a core component of the End TB Strategy, there is limited information about the status of implementation of such interventions in most African countries. METHODS: A web-based survey involving the 47 countries of the African Region was conducted between November 2016 and April 2017. RESULTS: The questionnaire was completed by 32/47 (68.1%) National TB Programme managers or their delegates. LTBI guidelines were available in four countries (12.5%), while 13 (40.6%) had an LTBI section in their national TB guidelines; there was no significant association with socio-economic conditions and funding allocation. LTBI diagnosis was mostly based on clinical evaluation to rule out active disease, rather than on systematic use of the tuberculin skin test. Respectively 23 (71.8%) and 17 countries (53.1%) reported providing treatment to child contacts aged <5 years and people living with the human immunodeficiency virus (PLHIV). Over two thirds of respondent countries had ongoing activities targeting at least one of the aforementioned high-risk groups. A recording and reporting system for LTBI related data on child contacts and PLHIV was available in respectively 14 and 12 countries; 7 countries had an LTBI monitoring and evaluation plan. CONCLUSIONS: These data suggest that greater effort is needed to appropriately scale up LTBI policies in the African Region. PMID- 29506580 TI - The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial. AB - BACKGROUND: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. METHODS/DESIGN: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). DISCUSSION: Final results of RESTART will be analysed and disseminated in 2019. TRIAL REGISTRATION: ISRCTN71907627 ( www.isrctn.com/ISRCTN71907627 ). Prospectively registered on 25 April 2013. PMID- 29506612 TI - Spatial clusters of latent tuberculous infection, Connecticut, 2010-2014. AB - SETTING: In the United States, tuberculosis (TB) control is increasingly focusing on the identification of persons with latent tuberculous infection (LTBI). OBJECTIVE: To characterize the local epidemiology of LTBI in Connecticut, USA. METHODS: We used spatial analyses 1) to identify census tract-level clusters of reported LTBI and TB disease in Connecticut, 2) to compare persons and populations in clusters with those not in clusters, and 3) to compare persons with LTBI to those with TB disease. RESULTS: Significant census tract-level spatial clusters of LTBI and TB disease were identified. Compared with persons with LTBI in non-clustered census tracts, those in clustered census tracts were more likely to be foreign-born and less likely to be of white non-Hispanic ethnicity. Populations in census tract clusters of high LTBI prevalence had greater crowding, persons living in poverty, and persons lacking health care insurance than populations not in clustered census tracts. Persons with LTBI were less likely than those with TB disease to be of Asian ethnicity, and persons with LTBI were more likely than those with TB disease to reside in a clustered census tract. CONCLUSIONS: Characterizing fine-scale populations at risk for LTBI supports effective and culturally accessible screening and treatment programs. PMID- 29506613 TI - Spatial distribution of tuberculosis in Manaus and its social determinants, 2008 2013. AB - SETTING: Brazil ranks eighteenth worldwide in annual numbers of new tuberculosis (TB) cases. The municipality of Manaus, Amazonas State, has the highest incidence of TB in Brazil. OBJECTIVE: To evaluate the quality of TB epidemiological surveillance, and to describe the spatial distribution pattern of TB incidence in Manaus and its social determinants. DESIGN: An ecological study was performed based on secondary data from TB epidemiological surveillance reports. RESULTS: An index was developed to classify neighborhoods in terms of the quality of surveillance and suspected underreporting. Based on data from neighborhoods with better surveillance performance, we observed that the average number of residents per room, the unemployment rate and the proportion of households connected to a sewage system were significant predictors of TB incidence. Seven neighborhoods in the south and west of the city had clusters of high TB transmission. CONCLUSION: Our results suggest that the association between TB and social vulnerability is obscured by the poor quality of TB surveillance data. We identified priority areas that require immediate TB control interventions and those where local surveillance efforts should be improved, and generated information useful for formulating more effective actions. PMID- 29506616 TI - Tuberculosis notification and treatment outcome among migrant boat arrivals in Malta, 2007-2011. AB - The annual incidence of tuberculosis (TB) in Malta has remained low, at <20 per 100 000 population per year. However, TB notification among vulnerable groups is on the rise and is a matter of public health concern. We measured the TB notification rate, which ranged from 470 to 880/100 000 among migrant boat arrivals 1 year after arrival, highlighting the need to maintain high treatment success rates. Early case detection and high treatment success were observed due to post-arrival screening; however, the need for pragmatic, patient-friendly approaches that will encourage self-referral and access to treatment among migrant groups could play a significant role in preventing the re-emergence of TB in low-incidence settings. PMID- 29506615 TI - Systematic case finding for tuberculosis in HIV-infected people who inject drugs: experience from Pakistan. AB - SETTING: Pakistan is a high tuberculosis (TB) burden country, moving from low human immunodeficiency virus (HIV) prevalence to a concentrated epidemic driven primarily by people who inject drugs (PWID). The Antiretroviral Treatment Adherence Unit (AAU) in Islamabad, Pakistan, is a residential facility that offers combined treatment for opioid dependence and HIV. OBJECTIVE AND DESIGN: This retrospective study was conducted to assess TB prevalence among HIV-infected PWID referred to the AAU and to evaluate the diagnostic value of cough as a screening symptom. A single sputum sample was collected regardless of symptoms, and examined using smear, Xpert(r) MTB/RIF and culture. RESULTS: Of 888 PWID, 71.5% submitted a sputum sample. More TB cases were detected using Xpert (n = 25) than with smear (n = 10) or culture (n = 20). A TB prevalence of 6141 per 100 000 was estimated based on seven cases already identified as being on anti tuberculosis treatment and 32 newly diagnosed bacteriologically confirmed TB cases. Both cough and smoking (?10 pack-years) were associated with increased TB prevalence. Only half of the TB cases reported cough. Rifampicin resistance was reported among 10% (3/29) of newly identified cases. CONCLUSION: TB prevalence in HIV-infected PWID was 15 times higher than in the general adult population. As a screening symptom, cough has low diagnostic value. PMID- 29506617 TI - Alarming levels of multidrug-resistant tuberculosis in Ukraine: results from the first national survey. AB - SETTING: The true prevalence of multidrug-resistant tuberculosis (MDR-TB) in Ukraine is not known. Available data are a decade old and limited to only one province. OBJECTIVE: To determine the prevalence of MDR-TB among new and previously treated TB cases in Ukraine and explore the risk factors associated with drug resistance. METHODS: A total of 1550 sputum smear-positive pulmonary TB patients were recruited from 40 clusters throughout Ukraine. Sputum specimens were examined using culture, drug susceptibility testing and pncA gene sequencing. RESULTS: The proportion of MDR-TB among new and previously treated TB cases was respectively 24.1% (95%CI 20.7-27.6) and 58.1% (95%CI 52.1-64.1). More than one third (38.0%) of MDR-TB or rifampicin (RMP) resistant cases showed resistance to either a fluoroquinolone (FQ) or a second-line injectable agent or both. Resistance to pyrazinamide and FQs was low in patients with RMP-susceptible TB. Among new TB cases, the odds of MDR-TB were higher among patients who were younger, female and living in south-eastern provinces, as well as among human immunodeficiency virus-positive patients who belonged to a low socio-economic group. CONCLUSIONS: Our study showed that the burden of MDR-TB in Ukraine was much greater than previously assumed. Urgent actions are needed to prevent further spread of drug-resistant TB in Ukraine. PMID- 29506614 TI - Socio-economic status and risk of tuberculosis: a case-control study of HIV infected patients in Asia. AB - SETTING: Tuberculosis (TB) is the most common human immunodeficiency virus (HIV) related opportunistic infection and cause of acquired immune-deficiency syndrome related death. TB often affects those from a low socio-economic background. OBJECTIVE: To assess the socio-economic determinants of TB in HIV-infected patients in Asia. DESIGN: This was a matched case-control study. HIV-positive, TB positive cases were matched to HIV-positive, TB-negative controls according to age, sex and CD4 cell count. A socio-economic questionnaire comprising 23 questions, including education level, employment, housing and substance use, was distributed. Socio-economic risk factors for TB were analysed using conditional logistic regression analysis. RESULTS: A total of 340 patients (170 matched pairs) were recruited, with 262 (77.1%) matched for all three criteria. Pulmonary TB was the predominant type (n = 115, 67.6%). The main risk factor for TB was not having a university level education (OR 4.45, 95%CI 1.50-13.17, P = 0.007). Burning wood or coal regularly inside the house and living in the same place of origin were weakly associated with TB diagnosis. CONCLUSIONS: These data suggest that lower socio-economic status is associated with an increased risk of TB in Asia. Integrating clinical and socio-economic factors into HIV treatment may help in the prevention of opportunistic infections and disease progression. PMID- 29506618 TI - Multidrug-resistant tuberculosis in Queensland, Australia: an ongoing cross border challenge. AB - : SETTINGp: Multidrug-resistant tuberculosis (MDR-TB) is a growing concern worldwide. In Australia, although the incidence of MDR-TB remains low, Queensland is at an increased risk due to its proximity to Papua New Guinea (PNG). OBJECTIVE: To examine the epidemiology, clinical features and outcomes of MDR-TB in Queensland, with a comparison between cross-border PNG and non-cross-border patients. DESIGN: Retrospective case series of all MDR-TB patients in Queensland between 1 January 2000 and 31 December 2014. RESULTS: Ninety-six patients were diagnosed with MDR-TB in Queensland between 2000 and 2014. The majority were cross-border PNG nationals diagnosed within the Torres Straight Protected Zone (n = 73, 76%). Cross-border patients were younger (27.4 vs. 36.3 years, P = 0.02), had spent less time in Australia before diagnosis (<1 vs. 19 months, P < 0.01), had higher rates of smear positivity (67.1% vs. 40%, P = 0.04) and were less likely to have received a second-line injectable agent (45.8% vs. 71.4%, P = 0.05). Cross-border patients had significantly lower rates of treatment success than non-cross-border patients (47.9% vs. 85.7%; P < 0.01). CONCLUSION: MDR-TB cases in Queensland are largely a result of cross-border PNG nationals, with poorer outcomes seen in this cohort. Continued strengthening of the region's TB programmes, with a focus on cross-border patients, is required. PMID- 29506619 TI - Enhanced expression of TNF-alpha type-1 receptors by immune cells in active pulmonary tuberculosis. AB - BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) and its inhibitors are involved in both defence against tuberculosis (TB) and damage to the host by TB. Notably, the change in receptor expression on cell density is a key mechanism in regulation of the biological properties of cytokines. OBJECTIVE: To study the differences in TNF-alpha receptor (TNFR) expression in patients with active pulmonary tuberculosis (aPTB) in correlation with the parameters of disease severity. METHODS: TNFR1/2 levels on peripheral blood mononuclear cells (PBMCs) from 45 patients with aPTB and 150 healthy controls were analysed by flow cytometry using monoclonal antibodies and QuantiBRITE beads. Soluble TNFR1/2 and TNF-alpha in serum were measured using an enzyme-linked immunosorbent assay. RESULTS: TNFR1 expression in aPTB patients was increased in the main populations of immune cells. Patients who were Mycobacterium tuberculosis culture-positive on bronchoscopy had higher levels of the soluble forms of TNFR1 (sTNFR1) than M. tuberculosis-negative patients. CONCLUSION: Active TB was shown to cause activation of different immune cell types by increasing TNFR1 expression on cells and reducing sTNFR1 expression compared with healthy controls. M. tuberculosis positive patients with disseminated infection had the highest sTNFR1 serum level compared with other patients, but did not differ in receptor expression on PBMCs. PMID- 29506620 TI - Allergen sensitisation among chronic respiratory diseases in urban and rural areas of the south of Viet Nam. AB - OBJECTIVE: To evaluate the prevalence of and risk factors for allergen sensitisation among patients with chronic respiratory disease (CRD) in southern Viet Nam. DESIGN: An environmental questionnaire and skin prick tests for airborne and food allergens were administered to patients with CRD, defined as individuals with respiratory symptoms and lung function defects. RESULTS: Of 610 CRD patients, 56% had chronic obstructive pulmonary disease and 31% were asthma patients; 80% were males. The most frequent sensitisers were dust mites (Dermatophagoides farinae 22%, Blomia tropicalis 19%, D. pteronyssinus 18%) and cockroach droppings (13%). Among study participants, 37% were from rural settings and 36% from urban areas, whereas 27% had migrated from rural to urban areas. Compared with people from rural areas, being born in an urban area was a risk factor for sensitisation to mites (OR 1.56, 95%CI 1.11-2.20, P < 0.02). In multivariate analysis, place of birth remained a risk factor for mite sensitisation. Compared with the native urban population, the risk of mite sensitisation was not significantly different among patients born in rural areas and those migrating to urban areas. CONCLUSION: Dust mites and cockroach droppings were the most frequent allergens among people with CRD in the south of Viet Nam. Compared with the urban population, being native to a rural area was protective against mite sensitisation, but this effect ceased to be significant after migration from rural to urban areas. PMID- 29506621 TI - Risk factors contributing to early and late recurrence of haemoptysis after bronchial artery embolisation. AB - OBJECTIVE: To identify the risk factors for early and late relapse of haemoptysis after bronchial artery embolisation (BAE). DESIGN: We performed a retrospective study of 255 patients with haemoptysis who underwent BAE from January 2009 to June 2016 at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Using a Cox regression model, risk factors contributing to early (within the first month) and late (>1 month) recurrence were analysed. We censored recurrence-free patients at 1 month and patients without rebleeding after 1 month. RESULTS: The cumulative recurrence rate at 1, 6, 12, 24 and 48 months was respectively 14.9%, 16.9%, 20.6%, 31.0% and 39.9%, with a median follow-up of 574 days. Early relapse occurred in 38 of 255 patients, while late recurrence was found in 45 of the remaining 217 patients. The risk factors related to early recurrence were lung destruction on computed tomography of the chest and involvement of non-bronchial systemic arteries. The risk factors associated with late recurrence were tuberculosis sequelae, the presence of shunts and the use of gelfoam as an embolisation material. CONCLUSIONS: The variables related to incomplete embolisation were the risk factors for early rebleeding. The variables associated with same-vessel recanalisation and formation of a new collateral circulation influenced late recurrence. PMID- 29506622 TI - Professor Massimo Amicosante, 1968-2017. PMID- 29506623 TI - The effects of zinc and melatonin on muscle ischaemi-reperfusion injury in rat. AB - Ischemia-reperfusion leads to damage in cell or tissue due to insufficient blood flow. The aim of present study was to determine the effect of zinc, melatonin and zinc + melatonin supplementations during 3 weeks on muscle tissue and plasma MDA and GSH levels. This study was performed on 38 male Wistar-Albino rats. Experiments groups were designed as sham-control, ischemia-reperfusion (I/R), zinc + I/R, melatonin + I/R and zinc + melatonin + I/R Ischemia-reperfusion was induced by left femoral artery occlusion (1 hour) and reopening (1 hour). At the end of experiments tissue and blood samples were analysed for MDA and GSH. MDA levels were increased, GSH levels decreased in I/R groups. However, zinc and melatonin supplementation inhibited MDA and increased GSH levels in I/R groups. The results of present study show that increased lipid peroxidation in muscle tissue by ischemia-reperfusion may be prevented by zinc and melatonin or zinc plus melatonin supplementation. PMID- 29506624 TI - CCN3, a key matricellular protein, distinctly inhibits TGFbeta1-mediated Smad1/5/8 signalling in human podocyte culture. AB - Growth factors like TGFbeta and CTGF (CCN2) plays a vital role in various cellular functions. TGFbeta and CTGF are overexpressed in renal fibrosis. CTGF act as profibrotic stimuli to TGFbeta. CCN3 is a member of CCN family which also comprises CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP 3). CCN3 has been shown to antagonise CTGF. In this study, we investigated the role of CCN3 in TGFbeta1-mediated signalling in human podocytes culture. This study describes the novel function of CCN3 in regulation of TGFbeta1 mediated non canonical Smad signalling in human podocytes culture. Experiments were conducted on conditionally immortalised human podocytes incubated with TGFbeta1 (1.25ng/ml and 2.5ng/ml) and CCN3 (360ng/ml). Western blot study was performed to study signalling proteins. RT-PCR was performed to study alternative splicing of Fibronectin (Fn). Real time PCR was performed to look for gene expression of Fn and collagen IV and collagen I. TGFbeta1 induced the Smad1/5/8, Smad3 and p38 phosphorylation and CCN3 downregulated the TGFbeta1 induced Smad1/5/8 phosphorylation and did not affect Smad3 and p38 phosphorylation. In addition to this CCN3 induced alternative splicing of Extra domain A Fibronectin (EDA+Fn). CCN3 also induced collagen IV, Collagen I and Fn gene expression. This is the first evidence of downregulation of TGFbeta-mediated activation of a Smad1/5/8 signalling pathway by CCN3 in human podocytes and in any cell type. Targeting CCN3-mediated events could provide exciting outcomes in the understanding of molecular mechanism of fibrosis. PMID- 29506625 TI - VDBP, VDR Mutations and Other Factors Related With Vitamin D Metabolism May Be Associated With Type 1 Diabetes Mellitus. AB - Type 1 diabetes mellitus (T1DM) is an insulin dependent autoimmune disorder resulting the progressive destruction of pancreatic beta cells. Another possible factor considered to be related with T1DM is vitamin D deficiency. Therefore in this study it was aimed to investigate the associations between T1DM, vitamin D binding protein (VDBP) and vitamin D receptor (VDR) gene mutations which are related with vitamin D metabolism. Fifty five T1DM paitents and 40 healthy volunteers were recruited to the study. FokI (rs2228570), BsmI (rs1544410) mutations in VDR; rs4588 and rs7041 polymorphisms in VDBP were investigated with real-time polymerase chain reaction (RT-PCR). Other risk factors related with T1DM were also investigated. Results were evaluated statistically. Statistically significant relations were found in glucose, HbA1c, TSH, higher 25[OH]D, free vitamin D, calcium, albumin, log25[OH]D, retinopathy, higher than 30 mg/day microalbuminuria in T1DM patients. Also statistically significant association was found between C allele in Fok1 and T1DM in patients. When the relation between the risk factors and mutations were investigated, it was found that VDBP, free vitamin D and bioactive vitamin D were significantly associated with rs7041 mutation in VDBP whereas HDL was significantly associated with rs2228570 mutation in VDR. Other studies with larger data sets may demonstrate more reliable statistical results to rule out genotype-phenotype correlations of the disease. PMID- 29506626 TI - TGFbeta1-mediated expression and alternative splicing of Fibronectin Extra Domain A in human podocyte culture. AB - Alternative splicing is a fundamental phenomenon to build protein diversity in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin protein present in the extra cellular matrix (ECM) in renal fibrosis. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM proteins in renal physiology and pathology. TGFbeta1 is a strong stimulator of ECM proteins in renal injury. In this study, we have investigated alternative splicing of EDA+ Fn in human podocytes in response to TGFbeta1. We have performed western blotting and immunofluorescence to characterise the expression of the EDA+Fn protein, real-time PCR for RNA expression and RT-PCR to look for alternative splicing of EDA+Fn in conditionally immortalised human podocytes culture.We used TGFbeta1 as a stimulator and SB431542 and SRPIN340 for inhibitory studies. In this work, for the first time we have demonstrated in human podocytes culture EDA+Fn is expressed in the basal condition and TGFbeta1 2.5ng/ml induced the Fn mRNA and EDA+Fn protein expression demonstrated by real-time PCR, western blotting and immunofluorescence. TGFbeta1 2.5ng/ml induced the alternative splicing of EDA+Fn shown by conventional RT-PCR. Studies with ALK5 inhibitor SB431542 and SRPIN340 show that TGFbeta1 induced alternative splicing of EDA+Fn was by the ALK5 receptor and the SR proteins. In human podocytes culture, alternative splicing of EDA+Fn occurs at basal conditions and TGFbeta1 further induced the alternative splicing of EDA+Fn via ALK5 receptor activation and SR proteins. This is the first evidence of basal and TGFbeta1 mediated alternative splicing of EDA+Fn in human podocytes culture. PMID- 29506627 TI - Evaluation of anticancer, antioxidant activity and phenolic compounds of Artemisia absinthium L. Extract. AB - In the treatment of cancer, which remains a fatal disease, increasingly successful treatment rates of alternative therapies using the power of plants have directed the scientific world towards natural plant resources. This study aimed to examine the anti-cancer and antioxidant properties and identify the phenolic content of the methanolic extract obtained from Artemisia absinthium L. (AR) species, which is used as folk-medicine. The antioxidant activity of the extract was investigated using total phenolics, flavonoids, ABTS and CUPRAC methods. Phenolic component analysis of the plant extract was performed by LC MS/MS. The anti-cancer property of AR extract was investigated on human colon (DLD-1), endometrium (ECC-1) cancer cells and embryonic kidney (HEK-293) cells. Cytotoxic effects were defined with MTT, apoptotic activity with DNA fragmentation ELISA and AO/EB fluorescent staining, the genotoxic effect with the comet assay and the intracellular oxidative status with TAS and TOS methods. As a result of the study, it was determined that AR extract showed an antioxidant effect, and as a result of the content analysis made with LC-MS/MS, phenolic components were determined, the most abundant being chlorogenic acid, followed by quinic acid, cinnamic acid, rhoifolin and malic acide. AR extract showed cytotoxic activity on DLD-1 and ECC-1 cancer cells, while the cytotoxic effect on HEK-293 cells was determined to be low. It was determined that by increasing the intracellular amount of free radicals on cancer cells, this led to DNA damage, which consequently led to apoptosis of the cancer cells. PMID- 29506628 TI - The determination of the effect of some 1,3,4 thiadiazole derivatives on biochemical content (Fatty Acids, Sterols, Lipophilic Vitamins) in rat liver. AB - Thiadiazole derivatives and its metal compounds have antibacterial, antifungal, antitumoral, antiproliferative and antioxidant properties. In the study, the effects caused by thiadiazole ligand and its metal complexes upon the fatty acids and lipophilic vitamins in livers of rats were examined. The fatty acids in liver were specified by GC while the lipophilic vitamins were specified by HPLC. It was observed that the amounts of oleic acids (18:1, n-9) and monounsaturated fatty acids (MUFA) notably increased in the Mn complex group while the amounts of arachidonic acid (20:4, n-6) notably increased in the ligand group, compared to control group. The amounts of vitamin K2, vitamin D3 and alpha-tocopherol considerably increased in all groups compared to control group. It was noted that the amounts of alpha-tocopherol were elevated in both the Mn and Cr complex groups compared to control group. However, this elevation was matching with the amount in the same groups. Nevertheless, the amount of retinol was determined to be lower in the Mn complex group compared to other groups. Accordingly, it can be considered that thanks to the utilization of toxic metals such as manganese, cadmium and chrome, unsaturated fatty acids influenced the activities of the enzymes in liver tissue, which are in charge of fatty acid chain elongation. PMID- 29506629 TI - The prevalence of CMY-2, OXA-48 and KPC-2 genes in clinical isolates of Klebsiella spp. AB - Klebsiella pneumoniae is a Gram-negative bacterium which causes several human infections. Treatment of infections related to K. pneumoniae has become problematic, because of increasing trend of extended spectrum beta-lactamases producing (ESBLs) strains. The present study was aimed to detect the prevalence of ESBL-producing Klebsiella spp. and KPC-2, CMY-2 and OXA-48 beta-lactamase encoding genes in clinical isolates of Klebsiella spp. isolated from hospitalized patients. In this cross-sectional study carried out from February to August 2014, 144 isolates of Klebsiella spp. were collected from different clinical specimens in hospitals in the North of Iran. Klebsiella isolates were identified using standard microbiological procedure. Antimicrobial susceptibility patterns were determined using disk diffusion method in accordance with CLSI recommendation. The presence of antibiotic resistance genes were investigated by PCR method. Among 144 Klebsiella spp., 118 isolates were identified as K. pneumoniae and 26 isolates as Klebsiella oxytoca. Antibiotic susceptibility test showed the most resistance rates were against amoxicillin (96.5%) and ampicillin (95.8%). On the other hand, the most effective antibiotic was revealed to be imipenem with resistance rate of 4.9% (Table 2). Among 144 isolated Klebsiella strains, 57 cases (39.6%) were ESBL producers. The OXA-48 and KPC-2 genes were not detected among Klebsiella spp. during the present study, but 21.1% of isolates contained CMY-2 gene. This is the first report of CMY-2 gene detection in Klebsiella spp. in Iran. The homology between CMY-2 genes identified in isolates from Northern Iran and in other countries showed the wide dispersion of this gene around the world. PMID- 29506630 TI - Human podocytes responses to alternatively spliced Extra domain A Fibronectin in culture. AB - The interactions of the extracellular matrix (ECM) proteins with cells strongly regulate cell behaviour. The glomerular basement membrane (GBM) is a dynamic structure made up of protein secreted by endothelial cells and podocyte. These proteins could regulate the behaviour of these cells in health and diseases. Extra Domain A + Fn (EDA+Fn) is an alternatively spliced form of Fibronectin (Fn) recently identified in GBM and a recognised marker of various pathologies. In this study for the first time, we have investigated the responses of human podocytes cultured on different composition of GBM proteins which are cellular Fn (EDA+), plasma Fn (EDA-) and collagen IV. Conditionally immortalised human podocyte were grown on the dishes coated with different matrices; collagen IV (Col IV), cellular fibronectin (CFn) containing the EDA Exon, plasma fibronectin (PFn), which lacks the EDA Exon (EDA-Fn). We have performed western blotting to characterise the expression of the different proteins, real time PCR and RT-PCR to look for gene expression and alternative splicing of EDA+Fn. We have used TGFbeta1 as a stimulator. We have used HEK-Blue-hTLR4 cells to determine the biological activity of cellular Fn. Conditionally immortalised human podocyte show marked differences in their morphology grown on the dishes coated with different matrices; Col IV, CFn, and PFn. CFn was biologically active as it activated the TLR4 signalling in HEK-Blue-hTLR4 cells. Different matrices effects basal as well as TGFbeta1 mediated alternative splicing of EDA+Fn. TGFbeta1 was active on different matrices as it induced phosphorylation of pSmad3 however it did not affect phosphorylation of pAkt and p38. Interestingly, different cellular matrices affected basal phosphorylation of pAkt. CFn downregulated gene expression of synaptopodin and increased gene expression of collagen I and Fn. CFn increased cell death in detached human podocytes. Alteration of the constituents of the GBM is likely to significantly alter podocyte cellular responses to growth factors involved in podocytopathies, such as TGFbeta. PMID- 29506631 TI - The osmolyte type affects cartilage associated pathologic marker expression during in vitro mesenchymal stem cell chondrogenesis under hypertonic conditions. AB - Stem cells' fate during in vitro differentiation is influenced by biophysicochemical cues. Osmotic stress has proved to enhance chondrocyte marker expression, however its potent negative impacts had never been surveyed. We questioned whether specific osmotic conditions, regarding the osmolyte agent, could benefit chondrogenesis while dampening undesired concomitant hypertrophy and inflammatory responses. To examine the potential side effects of hypertonicity, we assessed cell proliferation as well as chondrogenic and hypertrophic marker expression of human Adipose Derived-MSC after a two week induction in chondrogenic media with either NaCl or Sorbitol, as the osmolyte agent to reach a +100 mOsm hypertonic condition. Calcium deposition and TNF-alpha secretion as markers associated with hypertrophy and inflammation were then assayed. While both hyperosmotic conditions upregulated chondrogenic markers, sorbitol had a nearly three times higher chondro-promotive effect and a lesser hypertrophic effect compared to NaCl. Also, a significantly lesser calcium deposition was observed in sorbitol hypertonic group. NaCl showed an anti proinflammatory effect while sorbitol had no effect on inflammatory markers. The ossification potential and cartilage associated pathologic markers were affected differentially by the type of the osmolyte. Thus, a vigilant application of the osmotic agent is inevitable in order to avoid or reduce undesired hypertrophic and inflammatory phenotype acquisition by MSC during chondrogenic differentiation. Our findings are a step towards developing a more reliable chondrogenic regimen using external hypertonic cues for MSC chondrogenesis with potential applications in chondral lesions cell therapy. PMID- 29506632 TI - Cytotoxic effects of new-generation bulk-fill composites on human dental pulp stem cells. AB - This study was performed to evaluate possible DNA damage in cells of human origin exposed to dental composites in vitro using a cytotoxic assay. Five bulk-fill composites were filled in molds and irradiated for 20 s. DPSCs were inoculated into 24-well plates. After the insert membrane was inserted and composites were added and the experiment was continued for 24/72 hours. In order to investigate the effects of the materials on DPSCs; its effect on apoptosis-regulating Bcl-2 gene, Human Beta-Defensins (HBDs 1-2) gene, Interleukin 6, 8, 10 expression level was examined. Also in order to check the cellular viability and stress factors; MTT assay, Total Antioxidant and Oxidant Status kits were used. At both irradiation times, all composites significantly affected analyses parameters used in primary DNA damage assessment or induced significant formation of cellular death. Cytotoxicity was detected in TEA, rs2735940 T>C, rs2853669 A>G, rs2736098 G>A, and rs2736100 T>G) on susceptibility to BC in Turkish population. The genotype frequency of hTERT rs2736109 G>A, rs2735940 T>C, rs2853669 A>G, rs2736098 G>A, and rs2736100 T>G polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan methods in 123 subjects with GC and 122 healthy control subjects. The mean age value of the BC patients was 51.58+/-11.28 (among them 8 subjects <=35 and 115 subjects >35). In this study, it was found that there was no statistical difference between hTERT rs2736109 G>A, rs2735940 T>C, rs2853669 A>G, rs2736098 G>A, and rs2736100 T>G polymorphisms that can be associated with risk of BC. PMID- 29506640 TI - A rare case of complicated pericardial effusion with Elizabethkingia meningoseptica from Iran. AB - Infections due to Elizabethkingia meningoseptica, a Gram-negative oxidative bacterium are frequently founded in neonatal and immunocompromised individuals. The notable characteristic of this organism is its multi-drug resistance to common antibiotics used for infections caused by Gram-negative bacteria. We report a rare case of complicated pericardial effusion due to E. meningoseptica in a 2-year-old boy, who was admitted with chief complaints of fever and tachypnea (mentioned by his parents) and suffered from a rare lung malignancy (lymphangioleiomyomatosis). He was successfully treated with vancomycin. E. meningoseptica infection is a rare situation in immunocompetent hosts, and we concluded that this infection was probably originated from device medicine or even hands of healthcare workers. PMID- 29506642 TI - Leveraging a relationship-based sexual health framework for sexual risk prevention in adolescent men in the United States. AB - : Background Studies link sexual health to lower sexual risk in adolescent women, yet no empirical literature evaluates these associations in adolescent men. METHODS: Data were drawn from a longitudinal cohort study of sexual relationships and sexual behaviour among adolescent men (n=72; 14-16 years) in the US. Participants contributed quarterly partner-specific interviews, from which sexual health information and partnered sexual behaviours were drawn. A multidimensional measure of sexual health was constructed and linked to partnered outcomes, including oral-genital, vaginal and anal sex, condom use, partner concurrency and intimate partner violence. Random intercept, mixed-effects linear, ordinal logistic or binary logistic regression were for analyses. Models controlled for participant age, race/ethnicity and relationship length. RESULTS: Adolescent men contributed 651 unique partner-specific interviews. A higher sexual health score with partners was significantly associated with more frequent oral-genital and vaginal sex, as well as higher condom use, lower partner concurrency and lower received and perpetuated intimate partner violence. CONCLUSION: Positive sexually related experiences in adolescent men contribute to a core of sexual wellbeing, which in turn is linked to lower levels of sexual risk with partners. The present study data support both developmental and public health applications of sexual health, with attention on promoting healthy sexuality as well as risk reduction. Higher sexual health among adolescent men from the US is associated with more frequent condom use, lower partner concurrency and less frequent intimate partner violence. Young men's exercising the skills associated with healthy sexuality may also reinforce the skills needed to both enjoy sexuality with partners and to avoid adverse sexual outcomes. PMID- 29506641 TI - Comparing Australian gay and bisexual men with undiagnosed and recently diagnosed HIV infection to those in the National HIV Registry. AB - : Background Gay and bisexual men (GBM) with recent HIV infection are a key population to inform HIV-prevention. The National HIV Registry (NHR) provides details about all individuals diagnosed with HIV, but it is unclear how. METHODS: Basic sociodemographic characteristics of GBM in the NHR who were diagnosed between 2010 and 2014 were compared with three samples of GBM: men with undiagnosed HIV infection from the Community-Based Study of Undiagnosed HIV and Testing (COUNT) study of HIV prevalence and undiagnosed infection that was conducted during 2013-14; men in the Australian Gay Community Periodic Surveys (GCPS) who were diagnosed with HIV between 2010 and 2014; and men in the HIV Seroconversion Study (SCS) who were also diagnosed in those years. RESULTS: The NHR identified 3629 men who reported male-to-male sex as the exposure risk for their diagnosis between 2010 and 2014. COUNT identified 19 (8.9% of all men who tested HIV positive) men as having undiagnosed HIV. In the GCPS sample, 185 (2.5%) reported being diagnosed with HIV in 2010-14. In total, 367 men in the SCS received their diagnosis during 2010-14. The mean age of men in the NHR (36.8 years) was similar to that in GCPS (36.3 years) and SCS (35.1 years), while undiagnosed men in COUNT were younger (32.6 years), with no other significant differences between the samples. CONCLUSIONS: The undiagnosed men were somewhat younger than diagnosed men. To achieve earlier diagnosis of new HIV infections, improved HIV testing frequency is needed among younger men. PMID- 29506643 TI - [Diagnosis and treatment of primary antibody deficiency syndromes]. AB - Primary antibody deficiencies (PAD) make up more than half of primary immunodeficiencies. PAD is characterized by low levels of one or more immunoglobulin (Ig) classes or impaired vaccine response. Recurrent infections are the predominant presenting symptoms, but autoimmune disorders are also frequent. Onset of symptoms is often after the age of six. Screening for PAD with measurement of the levels of serum IgG, IgM, and IgA is simple and can be done in general practice. Replacement therapy with Ig is the cornerstone in treatment of PAD and reduces the frequency of infections and mortality. PMID- 29506644 TI - [Primary antibody deficiency syndromes]. AB - Primary antibody deficiency syndromes (PAD) are a group of primary immunodeficiencies (PID) characterized by reduced production of immunoglobulins and recurrent respiratory tract infections. PAD varies from rare but life threatening agammaglobulinaemias to frequent but often asymptomatic conditions such as selective immunoglobulin(Ig)A deficiency or IgG subclass deficiency. Common variable immunodeficiency is the clinically most important PAD. Hypogammaglobulinaemia may be associated with other PID or may be drug-induced or caused by infectious diseases, haematological malignancies or protein loss. PMID- 29506645 TI - [Cannabinoids for neuropathic pain management]. AB - Pharmacological treatment of neuropathic pain is associated with side effects and limited efficacy. Recently, the interest in cannabis-based medicine has led to legalisation of medical cannabis in some countries. The aim of this review is to evaluate the evidence of cannabinoids in neuropathic pain. Seventeen trials were identified; eight reported an analgesic efficacy of cannabis-based medicine, and the remaining trials showed no analgesic efficacy. Conclusions were limited by design of studies and short duration of treatment. Overall, the reduction in pain was minimal. PMID- 29506646 TI - [Fistula construction in a late anastomotic leakage]. AB - Post-operative bowel perforation is often a consequence of an anastomotic leakage. In most cases of major anastomotic leakage with generalised peritonitis a stoma formation at the point of perforation is recommended. In some cases, however, stoma formation is not possible. In this case report an artificial fistula was made. The edge of the defect in the anastomosis was sutured to an incision in the iliac fossa to provide source control in a difficult case of anastomotic leakage. The abdominal cavity was found without faecal contamination on the fourth post-operative day. PMID- 29506647 TI - [Oral and verbal dyspraxia in an otherwise healthy child]. AB - In the absence of any known neurological condition, dyspraxia is the inability to plan and execute movement. This case report describes a girl with swallowing difficulties, who was diagnosed with oral dyspraxia, as all other possible explanations had been ruled out. A percutaneous endoscopic gastrostomy was performed at the age of 6.5 months, and as a five-year-old she was still dependent on supplementary nutrition through the tube, even though she had gradually learned to swallow. Her difficulties to correctly pronounce syllables and words were later diagnosed as childhood apraxia of speech, another subtype of dyspraxia. PMID- 29506648 TI - [Acupuncture-induced bilateral pneumothorax in a 16-year-old boy]. AB - Acupuncture is a well-known form of alternative medicine, it is becoming increasingly popular in Denmark for a wide variety of uses, and is also practiced on children. However, there is a risk of serious complications. This is a case report of acupuncture-induced bilateral pneumothorax in a 16-year-old boy, who had been admitted to the emergency department with chest pain. Treatment included a unilateral chest tube in the left lung and conservative treatment in the right lung. Physicians must be aware of pneumothorax as a serious complication of acupuncture in the thoracic region. PMID- 29506650 TI - Individual crop loads provide local control for collective food intake in ant colonies. AB - Nutritional regulation by ants emerges from a distributed process: food is collected by a small fraction of workers, stored within the crops of individuals, and spread via local ant-to-ant interactions. The precise individual-level underpinnings of this collective regulation have remained unclear mainly due to difficulties in measuring food within ants' crops. Here we image fluorescent liquid food in individually tagged Camponotus sanctus ants and track the real time food flow from foragers to their gradually satiating colonies. We show how the feedback between colony satiation level and food inflow is mediated by individual crop loads; specifically, the crop loads of recipient ants control food flow rates, while those of foragers regulate the frequency of foraging trips. Interestingly, these effects do not rise from pure physical limitations of crop capacity. Our findings suggest that the emergence of food intake regulation does not require individual foragers to assess the global state of the colony. PMID- 29506649 TI - Neutrophil-generated HOCl leads to non-specific thiol oxidation in phagocytized bacteria. AB - Phagocytic immune cells kill pathogens in the phagolysosomal compartment with a cocktail of antimicrobial agents. Chief among them are reactive species produced in the so-called oxidative burst. Here, we show that bacteria exposed to a neutrophil-like cell line experience a rapid and massive oxidation of cytosolic thiols. Using roGFP2-based fusion probes, we could show that this massive breakdown of the thiol redox homeostasis was dependent on phagocytosis, presence of NADPH oxidase and ultimately myeloperoxidase. Interestingly, the redox mediated fluorescence change in bacteria expressing a glutathione-specific Grx1 roGFP2 fusion protein or an unfused roGFP2 showed highly similar reaction kinetics to the ones observed with roGFP2-Orp1, under all conditions tested. We recently observed such an indiscriminate oxidation of roGFP2-based fusion probes by HOCl with fast kinetics in vitro. In line with these observations, abating HOCl production in immune cells with a myeloperoxidase inhibitor significantly attenuated the oxidation of all three probes in bacteria. PMID- 29506653 TI - Has the Gloom Lifted on Genome-wide Association Studies? PMID- 29506651 TI - Energetics and conformational pathways of functional rotation in the multidrug transporter AcrB. AB - The multidrug transporter AcrB transports a broad range of drugs out of the cell by means of the proton-motive force. The asymmetric crystal structure of trimeric AcrB suggests a functionally rotating mechanism for drug transport. Despite various supportive forms of evidence from biochemical and simulation studies for this mechanism, the link between the functional rotation and proton translocation across the membrane remains elusive. Here, calculating the minimum free energy pathway of the functional rotation for the complete AcrB trimer, we describe the structural and energetic basis behind the coupling between the functional rotation and the proton translocation at atomic resolution. Free energy calculations show that protonation of Asp408 in the transmembrane portion of the drug-bound protomer drives the functional rotation. The conformational pathway identifies vertical shear motions among several transmembrane helices, which regulate alternate access of water in the transmembrane as well as peristaltic motions that pump drugs in the periplasm. PMID- 29506652 TI - Pupillometry reveals perceptual differences that are tightly linked to autistic traits in typical adults. AB - The pupil is primarily regulated by prevailing light levels but is also modulated by perceptual and attentional factors. We measured pupil-size in typical adult humans viewing a bistable-rotating cylinder, constructed so the luminance of the front surface changes with perceived direction of rotation. In some participants, pupil diameter oscillated in phase with the ambiguous perception, more dilated when the black surface was in front. Importantly, the magnitude of oscillation predicts autistic traits of participants, assessed by the Autism-Spectrum Quotient AQ. Further experiments suggest that these results are driven by differences in perceptual styles: high AQ participants focus on the front surface of the rotating cylinder, while those with low AQ distribute attention to both surfaces in a more global, holistic style. This is the first evidence that pupillometry reliably tracks inter-individual differences in perceptual styles; it does so quickly and objectively, without interfering with spontaneous perceptual strategies. PMID- 29506654 TI - Neural Circuits Regulating Social Behavior: Highlighting the Causal Contribution of the Lateral Habenula. PMID- 29506655 TI - Out of the Cave, Into the Light? Modeling Mental Illness With Organoids. PMID- 29506657 TI - Legacies begun, legacies continued. PMID- 29506656 TI - Pharmacy technicians-A critical element to facilitate implementation of pharmacist-provided services. PMID- 29506658 TI - Legacies begun, legacies continued. PMID- 29506659 TI - Legacies begun, legacies continued. PMID- 29506660 TI - Appointment-based models: A comparison of three model designs in a large chain community pharmacy setting. AB - OBJECTIVES: To compare the effects of 3 different appointment-based model (ABM) designs on medication adherence and medication use outcomes controlling for patient and pharmacy characteristics. METHODS: This study was a retrospective cohort analysis in a large grocery store chain from January 1, 2012, to October 31, 2015. A total of 500 comparison and 613 intervention patients in 3 different model designs were analyzed. The outcome measures were proportion of days covered for selected medication classes, number of fills, administered vaccinations, number of trips, statin use in persons with diabetes, use of high-risk medications in older adults, and medication therapy for persons with asthma. RESULTS: After adjusting for relevant covariates, the authors found that all of the ABM designs significantly increased the number of fills after enrollment. Model designs 1 and 3 also significantly reduced the number of trips after enrollment: 4.5 fewer trips (95% CI -5.3 to -3.8; P < 0.05) for model 1 and 1.9 fewer trips (95% CI -3 to -0.9; P < 0.05) for model 3. Models 1 and 3 increased the percentage of patients considered to be adherent for diabetes medications and increased the number of vaccinations patients received. Models 1 and 2 significantly increased the percentage of patients considered to be adherent for statins. No model design was significantly associated with statin use in diabetes, high-risk medication use in older adults, nor percentage of patients considered to be adherent for the hypertension measure. CONCLUSION: All of the ABM designs were effective at increasing the number of fills after enrollment. This paralleled an increase in percentage of patients considered to be adherent to diabetes and statin therapies after enrollment. Models that included face-to face delivery of the appointment and telephonic synchronization, or face-to-face delivery for all components, increased the number of vaccinations that patients received after enrollment and significantly reduced the number of trips a patient made to the pharmacy. PMID- 29506661 TI - Vaccine adjuvants: Key components of some new vaccines. PMID- 29506663 TI - MTM Economics 101: Supply vs. demand. PMID- 29506662 TI - Delafloxacin meglumine, Meropenem trihydrate/vaborbactam, Secnidazole, and Benznidazole. PMID- 29506664 TI - RETRACTED: Beyond the PGY-1 community pharmacy residency: Characterizing career pathways of residency graduates. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article was retracted by the authors because of data errors discovered after publication. PMID- 29506665 TI - [Gaceta Sanitaria in 2017. Improving the quality of our journal]. PMID- 29506666 TI - Exploring Stem Cell Heterogeneity in Chronic Myeloid Leukemia. AB - Until very recently, understanding the complexity of the stem cell (SC) compartment in both normal and leukemic hematopoiesis has been challenging due to the inability to separate and study normal and leukemic SCs at the single-cell level. Recent advances in cell-sorting techniques and single-cell technologies now make this possible, with the identification of a population of highly quiescent chronic myeloid leukemia (CML) SCs that is enriched following therapy with tyrosine kinase inhibitors (TKIs). PMID- 29506667 TI - Cancer Is Not (Only) a Senescence Problem. AB - Age is one of the strongest predictors of cancer and risk of death from cancer. Cancer is therefore generally viewed as a senescence-related malady. However, cancer also exists at subclinical levels in humans and other animals, but its earlier effects on the body are poorly known by comparison. We argue here that cancer is a significant but ignored burden on the body and is likely to be a strong selective force from early during the lifetime of an organism. It is time to adopt this novel view of malignant pathologies to improve our understanding of the ways in which oncogenic phenomena influence the ecology and evolution of animals long before their negative impacts become evident and fatal. PMID- 29506668 TI - CSB: An Emerging Actionable Target for Cancer Therapy. AB - The DNA repair protein Cockayne syndrome group B (CSB) is frequently found overexpressed in cancer cells. High CSB levels favor tumor cell proliferation whilst inhibiting apoptosis. Conversely, the suppression of CSB has significant anticancer effects. In this manuscript we describe CSB downregulation as a potential new therapeutic approach in cancer. PMID- 29506669 TI - The Evolving Landscape of Brain Metastasis. AB - Metastasis, involving the spread of systemic cancer to the brain, results in neurologic disability and death. Current treatments are largely palliative in nature; improved therapeutic approaches represent an unmet clinical need. However, recent experimental and clinical advances challenge the bleak long-term outcome of this disease. Encompassing key recent findings in epidemiology, genetics, microenvironment, leptomeningeal disease, neurocognition, targeted therapy, immunotherapy, and prophylaxis, we review preclinical and clinical studies to provide a comprehensive picture of contemporary research and the management of secondary brain tumors. PMID- 29506670 TI - Resistance to Ibrutinib in B Cell Malignancies: One Size Does Not Fit All. AB - Ibrutinib resistance, as a result of coordinated rewiring of signaling networks and enforced tumor microenvironment (TME)-lymphoma interactions, drives unrestrained proliferation and disease progression. To combat resistance mechanisms, we must identify the compensatory resistance pathways and the central modulators of reprogramming events. Targeting the transcriptome and kinome reprogramming of lymphoma cells represents a rational approach to mitigate ibrutinib resistance in B cell malignancies. However, with the apparent heterogeneity and plasticity of tumors shown in therapy response, a one size fits all approach may be unattainable. To this end, a reliable and real-time drug screening platform to tailor effective individualized therapies in patients with B cell malignancies is warranted. Here, we describe the complexity of ibrutinib resistance in B cell lymphomas and the current approaches, including a drug screening assay, which has the potential to further explore the mechanisms of ibrutinib resistance and to design effective individualized combination therapies to overcome resistance and disable aggressive lymphomas (see Outstanding Questions). PMID- 29506671 TI - Deciphering the Epitranscriptome in Cancer. AB - Technological and methodological advancements have recently revolutionized our understanding of widespread epitranscriptome including RNA modifications and editing. N6-methyladenosine (m6A) represents the most prevalent internal modification in mammalian RNAs. Adenosine to inosine (A-to-I) RNA editing is an important mechanism underlying RNA generation and protein diversity through the post-transcriptional modification of single nucleotides in RNA sequences. In this review, we attempt to summarize its functional importance in various fundamental bioprocesses of m6A and A-to-I editing. We also highlight some of the key findings that have helped shape our understanding of epitranscriptome in tumorigenesis, tumor progression, and metastasis. Finally, we discuss conceivable targets and future directions of m6A and A-to-I editing in cancer therapeutics. PMID- 29506672 TI - MicroRNA-Based Drugs for Brain Tumors. AB - MicroRNAs (miRNAs) are key regulatory elements encoded by the genome. A single miRNA can downregulate the expression of multiple genes involved in diverse functions. Because cancer is a disease with multiple gene aberrations, developing novel approaches to identify and modulate miRNA pathways may result in a breakthrough for cancer treatment. With a special focus on glioblastoma (GBM), this review provides an up-to-date summary of miRNA biogenesis, the role of miRNA in cancer resistance, and essential tools for modulating miRNA expression, as well as of clinically promising RNAi delivery systems and how they can be adapted for therapy. PMID- 29506673 TI - Desmoplastic Tumor Microenvironment and Immunotherapy in Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a dismal disease which often is diagnosed at a late stage where the tumor is locally advanced, metastatic, and, as a result, is associated with low resectability. The heterogeneity of this cancer type is a major reason why the majority of patients fail to respond to therapy, and surgery remains their only curative option. Among patients who undergo surgical intervention, such tumors typically recur in 50% of cases within 1year. Thus, CCA is among the most aggressive and chemoresistant malignancies. CCA is characterized by marked tumor reactive stroma, a fibrogenic connective tissue which surrounds and infiltrates the tumor epithelium. This desmoplastic environment presents a clinical challenge, limiting drug delivery and supporting the growth of the tumor mass. In this review we attempt to highlight key pathways involved in cell to cell communication between the tumor epithelium and stroma, the immune components, and opportunities for novel strategies to improve patient outcome. PMID- 29506675 TI - AF stroke risk stratification-can we do better? PMID- 29506676 TI - Left atrial fibrosis provides a new means of identifying patients with higher risk of new-onset heart failure among patients with atrial fibrillation. PMID- 29506674 TI - The EUROpean and Chinese cardiac and renal Remote Ischemic Preconditioning Study (EURO-CRIPS CardioGroup I): A randomized controlled trial. AB - BACKGROUND: The potential protective effects of remote ischemic preconditioning (RIPC) on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) remain to be defined. METHODS AND RESULTS: A double blind, randomized, placebo controlled multicenter study was performed. Patients younger than 85years old, with a renal clearance of 30-60ml/min/1.73m2, who were candidates for PCI for all clinical indications except for primary PCI, were allocated 1:1 to RIPC or to standard therapy. The primary endpoint was incidence of CIN. The secondary endpoint was incidence of peri-procedural myocardial infarction (PMI). From February 2013 to April 2014, 3108 patients who were scheduled for coronary angiography were screened for the study. 442 fulfilled the inclusion criteria and 223 received PCI. These patients were randomized to sham RIPC (n=107) or treatment group (n=116). The only pre-specified subgroup of diabetic patients included 85 (38%) cases. RIPC significantly reduced CIN incidence in the overall population (12.1% vs. 26.1%, p=0.01, with a NNT=9) and in non-diabetic patients (9.2% vs. 25.0%, p=0.02), but showed no benefit in diabetics (16.7% vs. 28.2%, p=0.21). A trend for lower PMI was seen in the intervention arm (creatine kinase - muscle brain >5 URL; 8.4% vs. 16.4%, p=0.07; troponin T >5 URL; 27% vs. 38%, p=0.21). CONCLUSIONS: Remote ischemic preconditioning significantly reduces the incidence of acute kidney injury in non diabetic patients undergoing PCI. Larger sample size is presumably needed to assess the effect of RIPC for patients with diabetes mellitus. Clinical Trial number:NCT02195726https://www.clinicaltrial.gov/. PMID- 29506677 TI - Left atrial fibrosis provides a new means of identifying patients with higher risk of new-onset heart failure among patients with atrial fibrillation. PMID- 29506678 TI - Torsade de Pointes: The tip of the iceberg. PMID- 29506679 TI - Comments on clinical predictors of challenging atrioventricular node ablation procedure for rate control in patients with atrial fibrillation. PMID- 29506680 TI - Comment on "Alcohol and incident atrial fibrillation-A systematic review and meta analysis". PMID- 29506681 TI - Association of diuretic treatment at hospital discharge in patients with heart failure with all-cause short- and long-term mortality: A propensity score-matched analysis from SwedeHF. AB - AIMS: Diuretics are recommended for treating congestive symptoms in heart failure (HF). The short- and long-term prognostic effects of diuretic treatment at hospital discharge have not been studied in randomized clinical trials or in a Western world population. We aimed to determine the association of diuretic treatment at discharge with the risk of short-and long-term all-cause mortality in real-life patients in Sweden with HF irrespective of EF. METHODS AND RESULTS: From a Swedish nationwide HF register 26,218 patients discharged from hospital were included in the present study. A total of 87% of patients were treated with and 13% were not treated with diuretics at hospital discharge. In a 1:1 propensity score-matched cohort of 6564 patients, the association of diuretic treatment at hospital discharge with the risk of 90-day all-cause mortality was neutral (HR 0.89, 95% CI 0.74-1.07, p=0.21) whereas the risk of long-term all cause mortality (median follow-up: 2.85years) was increased (HR 1.15, 95% CI 1.06 1.24, p<0.001). CONCLUSION: Diuretic treatment at hospital discharge was not associated with short-term mortality whereas it was associated with increased long-term mortality. Although we accounted for a wide range of clinical features, measured or unmeasured factors could still explain this increase in risk. However, our results suggest that diuretic treatment at hospital discharge may be regarded as a marker of increased long-term mortality. PMID- 29506682 TI - Obtaining a follow-up appointment before discharge protects against readmission for patients with acute coronary syndrome and heart failure: A quality improvement project. AB - BACKGROUND: Cardiac patients have a high risk of readmission following hospital discharge. The aim of our project was to examine the factors associated with increased readmission rate, with a view to eventually decrease the rate of readmission for patients admitted to the hospital due to acute coronary syndrome (ACS) or heart failure. METHODS: Patients admitted to the cardiac step-down unit at a single private hospital from 2015 to 2016 were included in our study. Interventions that were employed included: (1) improved pre-discharge follow-up appointment scheduling, (2) medication education by a pharmacist, and (3) timely discharge planning. Our primary outcome of interest was all-cause rate of hospital readmission within 30days. We conducted a multivariate analysis to determine the factors that were predictive of readmission rate. RESULTS: 578 patients were included in the study and 402 were diagnosed with ACS (69.9%). The rate of readmission was 14.2% for patients with heart failure, compared to 7.5% for patients with ACS. Following the bundle of interventions, patients were significantly more likely to receive an appointment (45.6% vs. 75.4%, p<0.001), medication education from a pharmacist (38.5% vs. 56.7%, p=0.006), and a timely discharge (47.1% vs. 76.0%, p<0.001). Readmission rate was comparable following the intervention (8.6% vs. 9.7%), but patients that received an appointment had 0.374 times lower odds of being readmitted (p=0.004). CONCLUSIONS: While our package of interventions did not lead to a significant decline in our readmission rate, patients who received a follow-up appointment prior to discharge were strongly protected against readmission. PMID- 29506683 TI - Joint effects of obstructive sleep apnea and resistant hypertension on chronic heart failure: A cross-sectional study. AB - BACKGROUND: Obstructive sleep apnea (OSA) and resistant hypertension (RHTN) are two major risk factors of chronic heart failure (CHF) and limited information is available about the joint effects of OSA and RHTN on CHF. METHODS: Baseline data of participants who had completed polysomnography were used in the current study. The relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP) were calculated, and RERI >0 or AP >0 indicates joint effect of OSA and RHTN on CHF is greater than the sum of estimated effects of OSA alone and RHTN alone. Due to significant interaction between coronary heart disease (CHD) and both OSA and RHTN, participants were stratified into with and without CHD subgroups. RESULTS: Among 1157 participants, 33.1% had OSA. The prevalence of RHTN in OSA participants was 18.3%. The apnea-hypopnea index (AHI), pulse pressure and CHF were significantly associated with RHTN. In the CHD subgroup, participants with OSA and RHTN were associated with >3-fold increased odds of prevalent CHF. RERI was 2.66 and AP was 0.75. The odds of prevalent CHF with left ventricular ejection fraction (LVEF) >=45% in participants with OSA+RHTN were >2-fold higher compared to those without, or with either OSA or RHTN, and RERI was 1.50 and AP was 0.72. CONCLUSION: Presence of CHF, increased AHI and pulse pressure are independently associated with RHTN. OSA and RHTN have significant joint effects on CHF, especially in patients with concurrent CHD and preserved LVEF. PMID- 29506684 TI - A cost effectiveness study establishing the impact and accuracy of implementing the NICE guidelines lowering plasma NTproBNP threshold in patients with clinically suspected heart failure at our institution. AB - AIMS: The 2014 National Institute of Clinical Excellence (NICE) guidelines on the management of acute heart failure recommended using a plasma NT-proBNP threshold of 300pg/ml to assist in ruling out the diagnosis of heart failure (HF), updating previous guidelines recommending using a threshold of 400pg/ml. NICE based their recommendations on 6 studies performed in other countries. This study sought to determine the diagnostic and economic implications of using these thresholds in a large unselected UK population. METHODS: Patient and clinical demographics were recorded for all consecutive suspected HF patients over 12months, as well as clinical outcomes including time to HF hospitalisation and time to death (follow up 15.8months). RESULTS: Of 1995 unselected patients admitted with clinically suspected HF, 1683 (84%) had a NTproBNP over the current NICE recommended threshold, of which 35% received a final diagnosis of HF. Lowering the threshold from 400 to 300pg/ml would have involved screening an additional 61 patients and only would have identified one new patient with HF (sensitivity 0.985, NPV 0.976, area under the curve (AUC) at 300pg/ml 0.67; sensitivity 0.983, NPV 0.977, AUC 0.65 at 400pg/ml). The economic implications of lowering the threshold would have involved additional costs of L42,842.04 (L702.33 per patient screened, or L 42,824.04 per new HF patient). CONCLUSION: Applying the recent updated NICE guidelines to an unselected real world population increases the AUC but would have a significant economic impact and only identified one new patient with heart failure. PMID- 29506685 TI - The effectiveness of remote monitoring of elderly patients after hospitalisation for heart failure: The renewing health European project. AB - Background: The effectiveness of remote monitoring (RM) in the management of the elderly after hospitalisation for heart failure (HF) is uncertain. Methods and results: Randomized trial (2:1 design) comparing RM with usual care (UC) in patients >65 years old, hospitalised in the previous 3 months for HF with left ventricular ejection fraction <40% or >40% plus BNP > 400 (or NT-proBNP >1500); the primary end-point (PE) was the combined 12-month incidence of death by any cause or at least one hospital readmission for HF. Overall, 229 and 110 pts were enrolled in the RM and UC group, respectively; in the intention-to-treat analysis, the PE was reached in 101 (44.1%) and 51 (46.4%) patients in the RM and UC group respectively (p = 0.78), with no difference in mortality (24.0% vs 21.8%, p = 0.097) or in the proportion of patients with at least one rehospitalisation for HF (34.5% vs 39.1%, p = 0.48). Quality of life, secondary end-point measured by SF36v2 scores, was significantly improved in the RM group, both in physical (2.63 score difference, p < 0.0001) and mental (1.69 score difference, p = 0.04) components. In the on-treatment analysis comparing 190 patients that ultimately received RM with the 149 remaining patients, the primary end-point was reached in 40.0% vs 51.0% (p = 0.055), respectively. Conclusion: In the intention-to-treat analysis, during the 12-month follow up of elderly patients hospitalised for HF, remote monitoring had no impact on the primary end point but it significantly improved patients' quality of life. In the on treatment analysis a trend for improving the PE was observed in the RM group. PMID- 29506686 TI - Mismatch between right- and left-sided filling pressures in heart failure patients with preserved ejection fraction. AB - BACKGROUND: Mismatch between right- and left-sided filling pressures is poorly understood in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We retrospectively analyzed 170 patients with HFpEF (EF>=40%) who underwent right heart catheterization. Low match (right atrial pressure [RAP] < 10 mm Hg and pulmonary capillary wedge pressure [PCWP] < 22 mm Hg) was 76%, high match (RAP >= 10 mm Hg and PCWP >= 22 mm Hg) was 6.5%, high-R mismatch (RAP >= 10 mm Hg and PCWP < 22 mm Hg) was 12%, and high-L mismatch (RAP < 10 mm Hg and PCWP >= 22 mm Hg) was 5.9%. Elevated PCWP was a significant predictor of the composite endpoint of death or HF hospitalization within 12months (hazard ratio 5.40, 95% confidence interval 2.17-12.5, p<0.001). Elevated RAP was not significantly associated with worse outcomes. Pulmonary artery systolic pressure (PASP) and diastolic pressure (PADP) showed strong correlations with PCWP (PASP, r=0.738, p<0.001; PADP, r=0.834, p<0.001; RAP, r=0.638, p<0.001, respectively). CONCLUSIONS: Discordance exists between right- and left-sided filling pressures in HFpEF. Physicians may utilize pulmonary artery pressure to evaluate left-sided filling pressure, which is a significant predictor of prognosis. PMID- 29506687 TI - ALDH2 protects against alcoholic cardiomyopathy through a mechanism involving the p38 MAPK/CREB pathway and local renin-angiotensin system inhibition in cardiomyocytes. AB - BACKGROUND: Angiotensin II (Ang II) in the local cardiac renin-angiotensin system (RAS) is closely associated with alcoholic cardiomyopathy (ACM). Inhibition of local cardiac RAS has great significance in the treatment of ACM. Although aldehyde dehydrogenase 2 (ALDH2) has been demonstrated to protect against ACM through detoxification of aldehydes, the precise mechanisms are largely unknown. In the present study, we determined whether ALDH2 improved cardiac damage by inhibiting the local RAS in ACM and investigated the related regulatory mechanisms. METHODS AND RESULTS: Adult male mice were fed with 5% ethanol or a control diet for 2months, with or without the ALDH2 activator Alda-1. Heavy ethanol consumption induced cardiac damage, increased angiotensinogen (AGT) and Ang II and decreased myocardial ALDH2 activity in hearts. ALDH2 activation improved ethanol-induced cardiac damage and decreased AGT and Ang II in hearts. In vitro, ALDH2 activation or overexpression decreased AGT and Ang II in cultured cardiomyocytes treated with 400mmol/L ethanol for 24h. Furthermore, p38 MAP kinase (p38 MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) pathway activation by ethanol increased AGT and Ang II in cardiomyocytes. In addition, ALDH2 activation or overexpression inhibited the p38 MAPK/CREB pathway leading to decreased AGT and Ang II in cardiomyocytes. We also found that p38 MAPK activation effectively mitigated Alda-1-decreased AGT and Ang II, the effect of which was reversed by inhibition of CREB. CONCLUSIONS: ALDH2 decreased AGT and Ang II in the local cardiac RAS via inhibiting the p38 MAPK/CREB pathway in ACM, thus improving ethanol-induced cardiac damage. PMID- 29506688 TI - Exercise electrocardiogram in middle-aged and older leisure time sportsmen: 100 exercise tests would be enough to identify one silent myocardial ischemia at risk for cardiac event. AB - BACKGROUND: The importance of exercise electrocardiogram (ECG) has been controversial in the prevention of cardiac events among sportsmen. The aim of this study was to determine the frequency of silent myocardial ischemia (SMI) from an exercise ECG and its relationship with induced coronary angiographic assessment and potentially preventable cardiac events. METHODS: This prospective cohort study included leisure time asymptomatic sportsmen over 35years old, referred from 2011 to 2014 in the Sports Medicine Unit of the University Hospital of Saint-Etienne. RESULTS: Of the cohort of 1500 sportsmen (1205 men; mean age 50.7+/-9.4years; physical activity level 32.8+/-26.8MET-h/week), 951 (63%) had at least one cardiovascular disease (CVD) risk factor. Family history, medical examination and standard resting 12-lead were collected. A total of 163 exercise ECGs (10.9%) were defined as positive, most of them due to SMI (n=129, 8.6%). SMI was an indication for coronary angiography in 23 cases, leading to 17 documented SMIs (1.1%), including 11 significant stenoses requiring revascularization. In multivariate logistic regression analysis, a high risk of CVD (OR=2.65 [CI 95%: 1.33-5.27], p=0.005) and an age >50years (OR=2.71 [CI 95%: 1.65-4.44], p<0.0001) were independently associated with confirmed SMI. CONCLUSIONS: The association of positive exercise ECG with significant coronary stenosis was stronger among sportsmen with CVD risk factors and older than 50years. Screening by exercise ECG can lower the risk of cardiac events in middle-aged and older sportsmen. One hundred tests would be enough to detect one silent myocardial ischemia at risk for cardiac event. PMID- 29506689 TI - Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D). AB - BACKGROUND: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A mutations have been linked to the clinical entity multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy. METHODS & RESULTS: A family with a uniform MEPPC-like phenotype, associated with complex atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency of ventricular ectopy was clinically assessed. Screening of the SCN5A gene revealed a missense mutation in the linker between segments 3 and 4 in domain 1 of the Nav1.5 protein, resulting in a glycine to aspartate substitution at position 213 (G213D). The phenotype co segregated with the missense mutation. Electrophysiological studies of wild type (WT) hNav1.5 and hNav1.5_G213D expressed in CHO-K cells showed that the voltage of half-maximal activation (V1/2) was significantly more negative for hNav1.5_G213D compared to WT (V1/2=-38.7+/-0.5mV for WT and V1/2=-42.4+/-0.5mV for G213D; P<0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V1/2 of steady-state inactivation was significantly shifted towards more positive values for Nav1.5_G213D (V1/2=-86.7+/-0.2mV for WT and 82.2+/-0.3mV for G213D; P<0.001), also contributing to a gain-of-function phenotype. Flecainide and amiodarone markedly reduced premature atrial and ventricular contractions in four patients. CONCLUSION: The Nav1.5_G213D mutation is associated with a gain-of-function phenotype, multifocal atrial and ventricular ectopy and dilated cardiomyopathy. Since patients with a MEPPC-like phenotype may specifically benefit from Class-1 antiarrhythmic drugs or amiodarone, clinical identification of this disease entity is important. PMID- 29506690 TI - Effects of angiotensin receptor blocker at discharge in patients with heart failure with reduced ejection fraction: Korean Acute Heart Failure (KorAHF) registry. AB - BACKGROUND: After introduction of up-titration strategy, there are limited data on comparison between the effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) in patients with heart failure with reduced ejection fraction (HFrEF). The study sought to investigate the association between treatment with ARB at discharge and clinical outcomes in patients with HFrEF compared with treatment with ACEI or no renin angiotensin system blocker (RASB). METHODS: The KorAHF registry is a prospective multicenter cohort and included patients who were hospitalized for acute heart failure (AHF). We studied 3005 patients with HFrEF (<40%), and divided into ARB (n=1190), ACEI (n=1090), and no RASB (n=725) groups. Propensity score matching was performed. RESULTS: All-cause death occurred in 346 patients (29.1%) in the ARB group, 315 patients (28.9%) in the ACEI group, and 305 (42.1%) in the no RASB group. After propensity score matching (ARB vs. ACEI, 827 pairs), there was no significant difference between the two groups in the rate of death (HR 0.91, 95% CI 0.76 1.09, p=0.32). All-cause death was significantly lower in the ARB group than in the no RASB group (ARB vs. no RASB, 538 pairs, HR 0.69, 95% CI 0.56-0.83, p<0.001). The ARB group had a significantly lower discontinuation rate than the ACEI group (20.8% vs. 33.6%, p<0.001). CONCLUSIONS: For treatment of AHF with reduced EF after hospitalization, ARB at discharge shows a mortality benefit comparable to that of ACEI. In addition, tolerability of medication was greater for ARB than for ACEI. PMID- 29506691 TI - Impaired left atrial systolic function and inter-atrial dyssynchrony may contribute to symptoms of heart failure with preserved left ventricular ejection fraction: A comprehensive assessment by echocardiography. AB - AIMS: To assess LA diastolic and systolic function and atrial dyssynchrony in patients with heart failure with preserved ejection fraction (HFpEF) and to examine whether LA dysfunction and dyssynchrony account for the patients' symptoms of HFpEF. METHODS: Fifty-five patients with HFpEF, 31 asymptomatic patients with left ventricular diastolic dysfunction (LVDD) and 33 healthy individuals were enrolled in the study. The LA active ejection fraction (LAAEF) was calculated. The peak atrial longitudinal systolic strain (PALS) and peak atrial contraction strain (PACS) were measured using speckle tracking echocardiography (STE). Atrial dyssynchrony including inter-atrial dyssynchrony, LA dyssynchrony and right atrial dyssynchrony were calculated by tissue Doppler imaging (TDI). RESULTS: The PALS and PACS were deteriorated, whereas inter-atrial dyssynchrony was prolonged in patients with HFpEF (20.41+/-7.41%, 10.83+/-4.19%, 31+/-15ms, respectively) compared with the values obtained in asymptomatic LVDD patients (26.61+/-6.30%, 13.23+/-4.52%, 19+/-12ms, respectively) and those found in normal individuals (33.51+/-6.74%, 14.17+/-2.88%, 17+/-12ms, respectively) (P<0.05). However, PACS and inter-atrial dyssynchrony did not reach statistical significance between asymptomatic LVDD and normal individuals (P>0.05). Moreover, patients with deteriorated clinical symptoms (NYHA>II) presented worse LA systolic function and prolonged dyssynchrony compared with those with NYHA=II. Inter-atrial dyssynchrony and LAAEF are independently associated with worse NYHA functional classes in patients with HFpEF. CONCLUSIONS: LA diastolic and systolic function were significantly impaired, and inter-atrial dyssynchrony was prolonged in patients with HFpEF. Decreased LA systolic function and prolonged inter-atrial dyssynchrony were possibly associated with deteriorated clinical symptoms. PMID- 29506692 TI - Impact of aerobic interval training and continuous training on left ventricular geometry and function: a SAINTEX-CAD substudy. AB - BACKGROUND: Increase of exercise capacity (peak VO2) after cardiac rehabilitation improves outcome in patients with coronary artery disease (CAD). Systolic and diastolic function have been associated with peak VO2, but their role towards improvement of exercise capacity remains unclear. It is unknown which exercise intensity has the most beneficial impact on left ventricular (LV) geometry and function in CAD patients without heart failure. METHODS: 200 stable CAD patients without heart failure were randomized to 3months of aerobic interval training (AIT) or aerobic continuous training (ACT). Cardiopulmonary exercise test and transthoracic echocardiography were scheduled before and after 3months of training. RESULTS: At baseline, a higher peak VO2 correlated with lower LV posterior wall thickness (p=0.002), higher LV ejection fraction (p=0.008), better LV global longitudinal strain (p=0.043) and lower E/e' (0=0.001). After multivariate stepwise regression analysis only E/e remained an independent predictor of peak VO2 (p=0.042). Improvement of peak VO2 after 3months of training correlated with reverse remodeling of the interventricular septum (p=0.005), enlargement of LV diastolic volume (p=0.007) and increase of LV stroke volume (p=0.018) but not with other indices of systolic or diastolic function. Significant reduction of the interventricular septum thickness after cardiac rehabilitation was observed (p=0.012), with a trend towards more reverse remodeling after ACT compared to AIT (p=0.054). In contrast, there were no changes in other parameters of LV geometry, diastolic or systolic function. CONCLUSION: Systolic and diastolic function are determinants of baseline exercise capacity in CAD patients without heart failure, but do not seem to mediate improvement of peak VO2 after either AIT or ACT. PMID- 29506694 TI - When right is wrong in heart failure with preserved ejection fraction. PMID- 29506693 TI - Heart failure in sub-Saharan Africa: A contemporaneous systematic review and meta analysis. AB - OBJECTIVE: To summarise available data on the prevalence, aetiology, treatment and prognosis of heart failure (HF) in sub-Saharan Africa (SSA). SETTING: This systematic review and meta-analysis included data from individuals recruited in primary to tertiary health facilities in SSA. PARTICIPANTS: All published and unpublished literatures between January 1, 1996 and June 23, 2017, of individuals aged 12years and older and residing in sub-Saharan Africa. They must be of African descent. OUTCOME: Number of heart failure admissions into general wards or HF clinics; number of cases of the different aetiologies of HF; number of participants on the different medications for HF; number of cases of all-cause mortality in participants with HF, and the predictors of all-cause mortality. Due to a limited word count, only results on the aetiologies of HF will be presented in the abstract. RESULTS: Thirty five full text articles were selected after screening of an initial 3785 titles and abstract. Hypertensive heart disease (HHD) (39.2% [95% CI=32.6-45.9]) was the commonest cause of HF in SSA, followed by cardiomyopathies (CMO) (21.4% [95% CI=16.0-27.2]) and rheumatic heart disease (RHD) (14.1% [95% CI=10.0-18.8]). Ischaemic heart disease (7.2% [95% CI=4.1 11.0]) was rare. CONCLUSION: HHD, CMO and RHD are the most common causes of HF in SSA, with HHD and CMO responsible for over 50% of the cases. Also, the last two decades have witnessed a relative reduction in the prevalence of RHD below 15.0%. PMID- 29506695 TI - Multifocal ectopic Purkinje-related premature contractions: Sorting the wheat from the chaff. PMID- 29506696 TI - Alcohol puts the heart under pressure: Acetaldehyde activates a localized renin angiotensin aldosterone system within the myocardium in alcoholic cardiomyopathy. PMID- 29506697 TI - Left atrial function and dyssynchrony: Main characters and not actor appearances in heart failure with preserved ejection fraction. PMID- 29506698 TI - Analysing registries in heart failure: The case of angiotensin receptor blockers in Asians with heart failure with reduced ejection fraction. PMID- 29506699 TI - Could the CHA2DS2-VASc schema help stratify risk of ischemic stroke for individual patients with congestive heart failure? PMID- 29506700 TI - Changes of late gadolinium enhancement extension compared with native T1 mapping early after acute myocarditis. PMID- 29506701 TI - JDP2 and ATF3 - bZIP repressors in cardiac remodeling. PMID- 29506702 TI - Neural cell adhesion molecule-1 may be a new biomarker of coronary artery disease. AB - BACKGROUND: Patients with coronary artery disease (CAD) are often asymptomatic and their condition can go largely untreated, resulting in severe outcomes. Therefore, there is an urgent need for new biomarkers of CAD. METHODS: In this cross-sectional study, 540 patients were recruited. We performed a preliminary study, which included nine CAD-positive and nine CAD-negative patients, wherein the biomarker NCAM-1 was identified using label-free mass spectrometry. We then validated the efficacy of NCAM-1 in 429 CAD-positive and 93 CAD-negative patients. RESULTS: In the preliminary study, we found 204 different proteins in the two groups, of which seven were found in all samples; from these, we decided to explore the use of neural cell adhesion molecule (NCAM)-1 as a biomarker for CAD. We found NCAM-1 levels to be 53.22ng/ml lower in CAD patients (161.76+/ 105.50ng/ml) than in control samples (214.98+/-146.55ng/ml; p=0.0011). Spearman correlation analysis showed NCAM-1 was significantly correlated with Troponin T (cTnT), and N-terminal B-type natriuretic peptide (NT-proBNP) in CAD-positive patients, and with homocysteine in CAD-negative controls. Moreover, in multivariable logistic regression analysis, decreased plasma NCAM-1 was significantly associated with increased risk of CAD (multivariable-adjusted odds ratios: 0.728; 95% confidence interval, 0.599-0.884, p=0.001), adjusting for age, gender, current smoking status, cholesterol, triglyceride, glucose, creatine, homocysteine, cTnT, and NT-proBNP. CONCLUSIONS: These findings suggested that NCAM-1 may be a potential biomarker of CAD. PMID- 29506703 TI - Droplet digital PCR as a novel detection method for quantifying microRNAs in acute myocardial infarction. AB - BACKGROUND: micro-RNAs have shown promise as potential biomarkers for acute myocardial infarction and ischemia-reperfusion injury (I/R). Most recently droplet digital polymerase chain reaction (ddPCR) has been introduced as a more reliable and reproducible method for detecting micro-RNAs. AIMS: We aimed to demonstrate the improved technical performance and diagnostic potential of ddPCR by measuring micro-RNAs in ST-elevation myocardial infarction (STEMI). METHODS: A dilution series was performed in duplicate on synthetic Caenorrhabditis elegans miR-39, comparing quantitative real-time PCR (qRT-PCR) and ddPCR. We used ddPCR and qRT-PCR to quantify the serum levels of miR-21, miR-208a and miR-499 between STEMI patients (n=24) and stable coronary artery disease (CAD) patients (n=20). In STEMI, I/R injury was assessed via measurement of ST-segment resolution. RESULTS: In the dilution series, ddPCR demonstrated superior coefficient of variation (12.1%vs.32.9%) and limit of detection (0.9325 vs.2.425copies/MUl). In the patient cohort, ddPCR demonstrated greater differences in miR-21 levels (2190.5 vs. 484.7copies/MUl; p=0.0004 for ddPCR and 136.4 vs. 122.8copies/MUl; p=0.2273 for qRT-PCR) and in miR-208a (0 vs. 24.1copies/MUl, p=0.0013 for ddPCR and 0 vs. 0copies/MUl, p=0.0032 for qRT-PCR), with similar differences observed in miR-499 levels (9.4 vs. 81.5copies/MUl, p<0.0001 for ddPCR and 0 vs. 19.41copies/MUl, p<0.0001 for qRT-PCR). ddPCR also more accurately defined STEMI for all miRNAs (area under the curve (AUC) of 0.8021/0.7740/0.9063 for miR 21/208a/499 with ddPCR vs. AUC of 0.6083/0.6917/0.8417 with qRT-PCR). However, there was no association between miR-21/208a/499 levels and ischemia-reperfusion injury. CONCLUSION: ddPCR demonstrates superiority in both technical performance and diagnostic potential compared to qRT-PCR. Ultimately, this supports its use as a diagnostic method for quantifying micro-RNAs, particularly in large multi center trials. PMID- 29506704 TI - Ivabradine does not acutely affect open-loop baroreflex static characteristics and spares sympathetic heart rate control in rats. AB - AIMS: To assess the acute effects of intravenous ivabradine, a selective bradycardic agent, on carotid sinus baroreflex-mediated sympathetic arterial pressure (AP) and heart rate (HR) responses. METHODS AND RESULTS: In anesthetized and vagotomized Wistar-Kyoto rats (n=6), carotid sinus baroreceptor regions were isolated. Changes in splanchnic sympathetic nerve activity (SNA), AP, and HR in response to a step-wise pressure input were examined before and after intravenous ivabradine (2mg/kg). Ivabradine did not affect the response range of SNA (91.8+/ 6.5 vs. 93.5+/-9.8%) or AP (89.6+/-10.6 vs. 91.0+/-9.7mmHg). Ivabradine significantly reduced the minimum HR from 369.4+/-8.4 to 223.3+/-13.2 (P<0.001) but did not attenuate the HR response range (69.1+/-7.0 vs. 82.5+/-9.6beats/min). CONCLUSIONS: Ivabradine does not acutely affect baroreflex-mediated sympathetic AP regulation and also spares the magnitude of the sympathetic HR response, despite significant bradycardia. The preserved sympathetic HR response, which could not be afforded by beta-blockers, may contribute to some beneficial clinical effects of ivabradine. PMID- 29506705 TI - Mobilizing EPCs: It is not just an acute issue. PMID- 29506706 TI - Authors' reply to Dr. Schmitz and Dr. Brand comments on "Epigenetics and Cardiovascular Regenerative Medicine in the Elderly". PMID- 29506707 TI - Pathogenic effect of PI3K/Akt signaling inhibition by miR-1 and miR-29b on adverse post-infarct ventricular remodeling. PMID- 29506709 TI - Engaging patients for their opinions regarding research of abdominal aortic aneurysms. PMID- 29506708 TI - Venous thromboembolism therapy with rivaroxaban in daily-care patients: Results from the Dresden NOAC registry. AB - The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be confirmed in daily care. To confirm the positive results of phase-III VTE treatment trials with rivaroxaban in daily care, we used data from the ongoing, prospective, non interventional Dresden NOAC Registry. For this analysis, only patients with acute VTE who started rivaroxaban within 14days after diagnosis of VTE and who were enrolled within these 14days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes. Between December 1st 2011 and 30th September 2016, 418 patients with acute VTE and rivaroxaban treatment were enrolled. During rivaroxaban treatment (median rivaroxaban exposure 206d; median follow-up 862d) rates of recurrent VTE and ISTH major bleeding were 1.9% and 3.8%, respectively. At 6months. 58.3% of patients were still taking rivaroxaban, 28.2% had a scheduled end of treatment, 7.2% were switched to other anticoagulants, 1.7% had withdrawn their consent and the remaining 3.6% of patients had unplanned complete discontinuation of anticoagulation. After permanent discontinuation of rivaroxaban, 20 patients experienced a recurrent VTE (7 pulmonary embolism+/-deep vein thrombosis, 13 deep vein thrombosis) with a mean time between last intake of rivaroxaban and VTE recurrence of 374.3+/-247.6days (range 28-927d). In daily care patients with acute VTE, rivaroxaban demonstrated high effectiveness with acceptable major bleeding rates. Initial dosing was according to label in over 90% of patients and persistence to rivaroxaban therapy was adequate with low rates of unplanned complete discontinuation. PMID- 29506710 TI - CHA2DS2-VASc: An eligible score for atrial fibrillation prediction in chronic obstructive pulmonary disease? PMID- 29506711 TI - EURO-CRIPS: Another piece of evidence for systemic cardiovascular protection by remote ischemic conditioning. PMID- 29506712 TI - Predictors of 10-year changes in levels of N-terminal pro B-type natriuretic peptide and cardiac troponin I in the elderly. AB - BACKGROUND: Measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) might be useful for monitoring of cardiovascular disease in the elderly. However, it is not clear whether changes in these biomarkers are associated with changes in the cardiovascular risk profile and if this pattern could be modified by changes in lifestyle habits or medications. METHODS: We measured levels of NT-proBNP and cTnI in community-dwelling subjects (PIVUS study) upon visits scheduled at age 70 (n=1007), 75 (n=825) and 80 (n=602). The associations of these biomarkers with repeated measurements of clinical variables (risk factors, lifestyle habits, echocardiographic data and medications) were investigated using sex-adjusted linear mixed random effect models. RESULTS: NT-proBNP and cTnI were positively associated with increasing age. NT-proBNP, but not cTnI, was affected by changes of renal function and the degree of obesity. NT-proBNP was more closely related than cTnI to changes in echocardiographic estimates of cardiac geometry and function. Biomarker levels and/or their changes were inversely associated with a physically more active lifestyle (both NT-proBNP and cTnI) and statin treatment at age 70 (only cTnI). Changes in smoking status or antihypertensive treatment had no effect on biomarker levels. CONCLUSIONS: Changes in NT-proBNP and cTnI levels are associated with different patterns of cardiovascular disease burden when using a longitudinal approach. However, levels of both biomarkers and their changes also reflect changes in the cardiovascular risk profile that might be modifiable. This is an important aspect for the use of any cardiovascular biomarker in an elderly population. PMID- 29506713 TI - Relationship between Syntax Score and prognostic localization of coronary artery lesions with conventional risk factors, plasma profile markers, and carotid atherosclerosis (CAPP Study 2). AB - BACKGROUND: Data concerning the relationship between cardiovascular risk factors, plasmatic markers, carotid disease and extent of coronary lesions are lacking. OBJECTIVES: To evaluate the role of cardiovascular risk factors, plasmatic levels of high sensitivity C-reactive protein (hs-CRP), fibrinogen, lipoprotein(a), and carotid plaque extension in predicting the severity of coronary artery disease (CAD). METHODS: We analyzed 574 subjects undergoing first coronary angiography. For angiographic analysis, we used the Syntax Score and we defined the prognostic localization of CAD as a critical stenosis of the left main and/or proximal segment of left anterior descending artery. Levels of hs-CRP >3mg/L, lipoprotein(a) plasma levels >30mg/dL and plasma fibrinogen >300mg/dL were considered critical. Significant carotid disease (SCD) was defined by the presence of lesions producing a 50% diameter stenosis with a peak systolic velocity >125cm/s. A mean carotid intima media thickness (IMT) >0.9mm was considered abnormal. RESULTS: In the adjusted analysis the presence of SCD was found to be an independent predictor of high Syntax Score (p<0.001), while high fibrinogen levels were independently associated with the presence of CAD in prognostic localization (p=0.04). In the sub-group of patients without SCD, IMT >0.9mm was found to be an independent predictor of the presence of CAD (p<0.001). CONCLUSIONS: SCD strongly predicts high Syntax Score, while IMT shows excellent positive predictive value for the presence of CAD. In addition, high plasma fibrinogen levels are associated with coronary stenoses in prognostic localization. PMID- 29506714 TI - Coronary artery disease severity, its predictors, and the increasingly important role of noninvasive imaging. PMID- 29506715 TI - Response to Drs. Rasmussen and Pareek regarding our paper in Int. J. Cardiol. 2018; 250: 247-252: Hs-cTroponins for the prediction of recurrent cardiovascular events in patients with established CHD - A comparative analysis from the KAROLA study. PMID- 29506716 TI - Revisited the place for B-type natriuretic peptide in patients with muscular dystrophy in the area of mechanical ventilation. PMID- 29506717 TI - Comments on adding markers of organ damage to risk score models improves cardiovascular risk assessment: Prospective analysis of a large cohort of adult outpatients. PMID- 29506718 TI - The utility of cardiovascular biomarkers in patients with coronary artery disease. PMID- 29506720 TI - Comments on association of sST2 and hs-CRP levels with new-onset atrial fibrillation in coronary artery disease. PMID- 29506719 TI - Elevations in neutrophils with obstructive sleep apnea: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Obstructive sleep apnea (OSA) associates with increased risk of cardiovascular diseases (CVD). Immune abnormalities and surges in sympathetic activity accompany OSA and CVD. We hypothesized that OSA associates with leukocytosis partially by abnormalities in autonomic nervous system (ANS) function that would suggest a pathway linking OSA and CVD. METHODS: Participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort of individuals initially without overt CVD, underwent polysomnography and assays for white blood cells (WBC) and subsets. Heart rate (HR) and heart rate variability (HRV), indirect measurements of ANS, were obtained from overnight electrocardiography. A formal statistical mediation analysis tested the indirect effect that mean HR and HRV measures contribute to associations between OSA and leukocytosis. RESULTS: The analytical sample consisted of 1298 participants (54% female), ages 54-93years, 14% with severe OSA (apnea-hypopnea-index, AHI>=30). Severe OSA associated with a higher prevalence of obesity, diabetes, and increased levels of WBC total and subsets. Neutrophil count associated with severe OSA after adjusting for confounders (p=0.017). Mean HR positively associated with OSA indices and neutrophils. A mediation analysis revealed an "indirect" effect of mean HR that explained an estimated 11% of the association between AHI and neutrophils. Overnight hypoxia also associated with neutrophil count (p=0.009), and mean HR explained 14% of the association between neutrophils and hypoxia. CONCLUSIONS: In the MESA cohort, OSA measures associate with elevated neutrophil counts and increases in overnight mean HR. These data link innate immune dysregulation with OSA and provide a potential pathophysiologic pathway between CVD and OSA. PMID- 29506721 TI - Comment on "Epigenetics and cardiovascular regenerative medicine in the elderly". PMID- 29506722 TI - Diagnostic performance of coronary CT angiography carried out with a novel whole heart coverage high-definition CT scanner in patients with high heart rate. AB - BACKGROUND: Aim of the study was to evaluate image quality, radiation exposure and diagnostic accuracy of coronary CT angiography (CCTA) performed with a novel cardiac CT scanner in patients with very high heart rate (HR). METHODS: We prospectively enrolled 202 patients (111 men, mean age 66+/-8years) with suspected coronary artery disease who underwent CCTA with a whole-organ volumetric CT scanner. The HR during the scan was >=80bpm in 100 patients (Group 1), while it was <=65bpm in the remaining 102 patients (Group 2). In all patients, image quality score and coronary interpretability were evaluated and effective dose (ED) was recorded. In 86 of the 202 enrolled patients (40 patients in Group 1, 46 patients in Group 2) who were referred for a clinically indicated invasive coronary angiography (ICA) within 6months, diagnostic accuracy of CCTA vs. ICA was evaluated. RESULTS: Mean image quality and coronary interpretability were very high in both Groups (Likert=3.35 vs. 3.39 and 97.3% [1542/1584 segments] and 98% [1569/1600 segments] in Group 1 and Group 2, respectively). Mean ED was lower in Group 2 (1.1+/-0.5mSv) compared to Group 1 (2.9+/-1.6mSv). In Group 1, sensitivity and specificity of CCTA for detection of >50% stenosis vs. ICA were 95.2% and 98.9% in a segment-based analysis and 100% and 81.8% in a patient-based analysis, respectively. CONCLUSIONS: The whole organ high definition CT scanner allows evaluating coronary arteries in patients with high HR with excellent image quality, coronary interpretability and low radiation exposure. PMID- 29506723 TI - The role of the ST resolution ratio on in-hospital complications in patients with Takotsubo syndrome. PMID- 29506724 TI - Implications of cardiac variability with cardiovascular magnetic resonance imaging for calculating trial sample size in pulmonary arterial hypertension. AB - BACKGROUND: Normally, morbidity precedes mortality in pulmonary arterial hypertension (PAH) and is assessed with recognized surrogate measures of survival. Cardiovascular magnetic resonance (CMR) can assess right ventricular (RV) structure and function which is directly related to survival in PAH. This study describes CMR-assessed weekly cardiac variability in PAH, allowing calculation of sample sizes for trials comparing PAH targeted treatment effects and optimal methods for individual monitoring. METHODS: Ten clinically stable patients with PAH and ten healthy controls had three CMR examinations at weekly intervals. Stroke volume (SV) and cardiac output (CO) measured at six locations with two CMR-methods were, together with the right and left ventricular volumes and systolic function, assessed for variability, which allowed the calculation of sample sizes for clinically relevant changes. RESULTS: Variability (SD/mean) for SV and CO was lower in PAH patients than in control subjects (SV=5.7% vs. 8.9% [p=0.002]; CO=6.1% vs. 10.2% [p=0.003]), allowing a total sample size of 6 patients for a clinically relevant 10mL change in SV or 4 patients for a 10% increase in CO. For the lowest variability, SV is best measured with cine imaging in the left ventricle, and CO is best measured with flow imaging in the aorta. The RV volumes varied more than did the left ventricular volumes. For systolic function, the RV ejection fraction had the lowest variability (9.7%). CONCLUSIONS: Low cardiac variability measured with CMR in PAH enables the statistically strong detection of clinically relevant changes with a small trial sample size. PMID- 29506725 TI - Precision medicine in pulmonary hypertension: Start with the end (point). PMID- 29506726 TI - In depth understanding of adverse ventricular remodeling after acute myocardial infarction. PMID- 29506728 TI - Transforming care for rare and inherited cardiovascular diseases through education and training. PMID- 29506727 TI - T1-mapping provides superior diagnostic accuracy than late gadolinium enhancement imaging in patients with acute myocarditis. PMID- 29506729 TI - Common presentation of rare diseases: Left ventricular hypertrophy and diastolic dysfunction. AB - Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of several diseases affecting different structural and functional proteins of cardiomyocytes. Among these, sarcomeric hypertrophic cardiomyopathy (HCM) represents the most frequent cause. In addition, several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases). The recognition of these rare causes of myocardial hypertrophy is important for family screening strategies, risk assessment, and treatment. Moreover, as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy. Diastolic dysfunction is a key feature of HCM and its phenocopies. Its assessment is complex and requires evaluation of several functional parameters and structural changes. Severe diastolic dysfunction carries a negative prognostic implication and its value in differential diagnosis is limited. PMID- 29506730 TI - Operators' experience with radial access for cardiac catheterization in patients with acute coronary syndromes. PMID- 29506731 TI - Common presentation of rare cardiac diseases: Arrhythmias. AB - Ventricular or supraventricular ectopic beats or atrial fibrillation may be the first presentation of uncommon cardiac disease, both acquired and genetically determined. In some patients, these manifestations can be the first sign of the underlying cardiac disorder. In others, however, they are also important as prognostic indicators, reflecting electrical instability and risk. Most cardiology clinics are busy environments where the implementation of complex diagnostic algorithms is not feasible. However, it is equally impossible to reach a final diagnosis, among the thousands of rare diseases that involve the heart, moving from a first line clinical and instrumental examination. Cardiac and extra cardiac red flags, an accurate family and clinical history and ECG interpretation may be of help in identifying a rare disease. Advanced imaging and laboratory testing at experienced referral centers is then necessary to reach a final diagnosis, but the first step in the right direction, based on these simple elements, is the most important. We here review arrhythmic presentations of rare or relatively rare diseases, and suggest a simple "rule out-rule in" approach to help direct clinical suspicion and minimize risk of neglect. PMID- 29506732 TI - Common presentation of rare diseases: Aortic aneurysms & valves. AB - The concept "common presentation of rare diseases" implies that rare diseases are masked by common phenotypic manifestations. This concept applies to both aneurysmal and valvular diseases that can be syndromic and non-syndromic. Syndromic disorders include genetic connective tissue diseases and chromosomal disorders that are diagnosed independently from the aneurysm or valve disease. Non-syndromic diseases, on the other hand, are defined by the presence of aneurysm or valve disease or both. The reasons for suspecting these rare diseases include young age, the absence of risk factors, a positive family history for aortic or valvular disease/event, and extra-cardiovascular traits for syndromes. The probands should receive genetic counseling, genetic testing [single gene in case of precise phenotyping addressing the gene to be tested, or multigene panels, in case of diseases with genetic heterogeneity], post-test counseling, clinical family screening and cascade genetic testing in relatives after the identification of a causative mutation. Segregation studies are essential in case of novel mutations, in particular non-truncation predicting variants. Clinical family screening of syndromic diseases is facilitated by the evaluation of non cardiovascular traits; this supports early diagnosis and geno-phenotype correlation. Vice versa, family screening studies in non-syndromic aneurysmal and valvular diseases exclusively relies on CV imaging screening of relatives. In this context, conditions such as BAV and related aortopathy are easy to diagnose because BAV is present at birth while aortopathy usually develops during the life course. PMID- 29506733 TI - GDF-15 levels and atherosclerosis. PMID- 29506734 TI - "Primary" dilated hearts. AB - Dilated cardiomyopathy is part of the spectrum of heart failure which is a syndrome with certain morphological and functional characteristics. Although significant progress in the management of those patients has been achieved, seems that risk stratification and future treatments will be related to the specific pathological substrate. PMID- 29506735 TI - SGLT1: A potential target for human ischemic and hypertrophic heart? PMID- 29506736 TI - Common presentation of rare diseases: Arrhythmogenic right ventricular cardiomyopathy and its mimics. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is the most common phenotype described within the spectrum of arrhythmogenic cardiomyopathies. It usually presents in early adolescence with severe ventricular arrhythmias along with cardiac structural and functional alterations mainly of the right ventricular myocardium. Though the estimated prevalence of ARVC in the general population is only 1:5000, it represents one of the most common causes of juvenile sudden death. However, detection of early RV dysfunction in ARVC may be challenging requiring high clinical suspicion and an algorithmic approach. A thorough family history of juvenile sudden death, ventricular arrhythmias and ICD implants should always be sought. Diagnosis usually requires electrocardiographic interpretation as well as cardiac imaging. In this article, the key diagnostic steps in the assessment of ARVC and diagnostic red flags that aid its differential diagnosis are discussed. PMID- 29506737 TI - Reply to the "Letter to the Editor" Ma Z-G, Yuan Y-P, Zhang X, Tang Q-Z. SGLT1: A potential target for human ischemic and hypertrophic heart? Int J Cardiol (2017). PMID- 29506738 TI - ST-elevation magnitude and evolution in Takotsubo syndrome. PMID- 29506739 TI - Chronic kidney damage in the adult Fontan population. AB - OBJECTIVES: 1) To determine the accuracy of estimated GFR (eGFR) as compared to directly measured GFR (mGFR) in the adult Fontan population; 2) to determine the true prevalence of chronic kidney damage (CKD) as determined by uACR AND eGFR. METHODS: Prospective study of 81 patients Fontan patients (>=18years) followed at St. Paul's Hospital, University of British Columbia. CKD-EPI and MDRD equations used to calculate eGFR, mGFR determined by 99mTc-DTPA renal dynamic imaging and urine albumin to creatinine ratios were calculated. RESULTS: The mGFR was 93+/ 27ml/min/1.73m2: 28 (53%) had an mGFR<90ml/min/1.73m2 and 1 (2%) had an mGFR <60ml/min/1.73m2. There was a modest correlation between mGFR and eGFR (EPI/MDRD) (r=0.50, p<0.0001 and r=0.54, p<0.0001 respectively). Both eGFR (EPI) (bias 27.0; 95% CI 18.0-27.7ml/min/m2, p<0.0001) and eGFR (MDRD) (bias 15.5; 95% CI 7.6 17.4ml/min/m2, p<0.0001) overestimated GFR as compared to mGFR. Among patients with an eGFR (EPI)/(MDRD) >90ml/min/1.73m2, 50% and 46% respectively had an mGFR <90ml/min/1.73m2. Significant albuminuria (>3mg/mmol) was present in 33% and upwards of 32% of patients with a normal eGFR (MDRD/EPI) had evidence of CKD with uACR >3mg/mmol. Using combined criteria of eGFR <90ml/min/1.73m2 and/or uACR >3mg/mmol, 46% of patients had evidence of CKD. CONCLUSIONS: This study draws attention to the need for stringent CKD screening as an important proportion of CKD is currently not being detected. Mild undetected CKD, an early marker of end organ damage, may also be an early sign of Fontan failure that requires warrants further research. PMID- 29506740 TI - Oral anticoagulant therapy in adults with congenital heart disease and atrial arrhythmias: Implementation of guidelines. AB - BACKGROUND: Current guidelines on oral anticoagulation (OAC) in adults with congenital heart disease (ACHD) and atrial arrhythmias (AA) consist of heterogeneous and divergent recommendations with limited level of evidence, possibly leading to diverse OAC management and different outcomes. Therefore, we aimed to evaluate real-world implementation and outcome of three guidelines on OAC management in ACHD patients with AA. METHODS: The ESC GUCH 2010, PACES/HRS 2014 and ESC atrial fibrillation (AF) 2016 guidelines were assessed for implementation. ACHD patients with recurrent or sustained non-valvular AA from 5 tertiary centers were identified using a national ACHD registry. After two years of prospective follow-up, thromboembolism, major bleeding and death were assessed. RESULTS: In total, 225 adults (mean age 54+/-15years, 55% male) with various defects (simple 43%; moderate 37%; complex 20%) and AA were included. Following the most strict indication (OAC is recommended in all three guidelines), one should treat a mere 37% of ACHD patients with AA, whereas following the least strict indication (OAC is recommended in any one of the three guidelines), one should treat 98% of patients. The various guidelines were implemented in 54-80% of patients. From all recommendations, Fontan circulation, CHA2DS2-VASc>=1 and AF were independently associated with OAC prescription. Superiority of any guideline in identifying outcome (n=15) could not be demonstrated. CONCLUSIONS: The implementation of current guidelines on OAC management in ACHD patients with AA is low, probably due to substantial heterogeneity among guidelines. OAC prescription in daily practice was most consistent in patients with AF and CHA2DS2-VASc>=1 or Fontan circulation. PMID- 29506742 TI - The Fontan circulation: An alternative physiology. PMID- 29506741 TI - Effect of coronary artery spasm on long-term outcomes in survivors of acute myocardial infarction. AB - BACKGROUND: The prevalence of coronary artery spasm (CAS) inducible by intracoronary injection of acetylcholine (ACh) is high in survivors of acute myocardial infarction (AMI). Although there is a potential risk of sudden cardiac death in patients with CAS, the prognostic value of CAS was not clear. Thus, this study examined the effect of CAS on long-term prognosis in survivors of AMI in a prospective manner. METHODS: The study included a total of 437 patients with AMI who underwent a CAS provocation test using ACh. All patients were followed prospectively for 5years or until the occurrence of the primary composite endpoint that consisted of cardiac death and acute coronary syndrome (ACS). RESULTS: CAS was induced in 195 (45%) of the study patients. During the follow-up period, 30 patients had a recurrent event (4 had cardiac death and 26 had ACS). Kaplan-Meier estimates in time-to-first-event analysis demonstrated a similar probability of the primary endpoint in patients with and without inducible CAS (p=0.13, log-rank test). The rate of each component of the composite endpoint was also comparable between the 2 patient groups. In Cox proportional hazards risk analysis, treatment with calcium channel blockers (CCBs) negatively predicted the primary endpoints in patients with inducible CAS (HR, 0.21; 95% CI, 0.08-0.55, p<0.01). CONCLUSIONS: The presence of inducible CAS did not increase the incidence of the cardiac events in AMI survivors. Treatment with CCBs may improve outcomes in AMI survivors with inducible CAS. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021340, unique identifier: UMIN000018432. PMID- 29506743 TI - Net clinical benefit of rivaroxaban compared with warfarin in atrial fibrillation: Results from ROCKET AF. AB - AIMS: The aim of this study was to determine the net clinical benefit (NCB) of rivaroxaban compared with warfarin in patients with atrial fibrillation. METHODS: This was a retrospective analysis of 14,236 patients included in ROCKET AF who received at least one dose of study drug. We analyzed NCB using four different methods: (1) composite of death, stroke, systemic embolism, myocardial infarction, and major bleeding; (2) method 1 with fatal or critical organ bleeding substituted for major bleeding; (3) difference between the rate of ischemic stroke or systemic embolism minus 1.5 times the difference between the rate of intracranial hemorrhage; and (4) weighted sum of differences between rates of death, ischemic stroke or systemic embolism, intracranial hemorrhage, and major bleeding. RESULTS: Rivaroxaban was associated with a lower risk of the composite outcome of death, myocardial infarction, stroke, or systemic embolism (rate difference per 10,000 patient-years [RD]=-86.8 [95% CI -143.6 to -30.0]) and fatal or critical organ bleeding (-41.3 [-68 to -14.7]). However, rivaroxaban was associated with a higher risk of major bleeding other than fatal or critical organ bleeding (55.9 [14.7 to 97.2]). Method 1 showed no difference between treatments (-35.5 [-108.4 to 37.3]). Methods 2-4 favored treatment with rivaroxaban (2: -96.8 [-157.0 to -36.8]; 3: -65.2 [-112.3 to -17.8]; 4: -54.8 [ 96.0 to -10.2]). CONCLUSIONS: Rivaroxaban was associated with favorable NCB compared with warfarin. The NCB was attributable to lower rates of ischemic events and fatal or critical organ bleeding. PMID- 29506744 TI - Gender differences in electro-mechanical characteristics of left bundle branch block: Potential implications for selection and response of cardiac resynchronization therapy. AB - BACKGROUND: Female patients are underrepresented in cardiac resynchronization therapy (CRT) trials, although they show better CRT response compared to males and at shorter QRS durations. We hypothesized that differences in left bundle branch block (LBBB) characteristics and mechanical dyssynchrony might explain this gender disparity. METHODS: Patients presenting with true LBBB-morphology (including mid-QRS notching) on surface electrocardiograms (ECG) were selected. LBBB QRS duration (QRSDLBBB) was measured automatically on the ECG. Left ventricular dimensions were assessed by two-dimensional echocardiography. Mechanical dyssynchrony was assessed by the presence of septal flash (SF) on echocardiography. RESULTS: The study enrolled 1037 patients (428 females). Female LBBB patients had smaller QRSDLBBB compared to male LBBB patients (142 [22]ms versus 156 [24]ms, p<0.001). In a multivariate analysis, sex and left ventricular end-diastolic diameter (LVEDD) were independent predictors of QRSDLBBB. QRSDLBBB can be corrected for sex and LVEDD using a simplified formula: corrected QRSDLBBB=QRSDLBBB+0.5*(50-LVEDD)-10 (if male). SF was more prevalent in females compared to males (60% versus 43%, p<0.001). Women revealed significantly more SF in narrow QRSDLBBB groups compared to men: 65% versus 13% (p<0.001) with QRSDLBBB 120-129ms, 66% versus 18% (p<0.001) with QRSDLBBB 130-139ms and 63% versus 31% (p<0.001) with QRSDLBBB 140-149ms. At QRSDLBBB>150ms, there were no differences in SF prevalence between females and males. CONCLUSION: Female patients show true LBBB morphology at shorter QRSD and have more frequent mechanical dyssynchrony at shorter QRSD compared to males. This might explain the better CRT response rates at shorter QRSD in females. PMID- 29506745 TI - The CHA2DS2-VASc score: Not as simple as it seems. AB - The CHA2DS2-VASc score has been widely adopted as a risk stratification tool for strokes in patients with atrial fibrillation and to help in deciding when anticoagulation therapy for stroke prophylaxis may be beneficial. The score as a whole has been well validated and has been included in the current major practice guidelines. An advantage of the CHA2DS2-VASc score is its ease of use, allowing clinicians to quickly estimate risk based on a short set of criteria. However, the benefit of simplicity may also be a weakness. Studies on individual components of the score suggest that only a subset of patients deemed to be at risk based on the current definition are actually at risk for stroke. Thus, users of the score should be aware of the nuances based on available evidence and avoid over-generalization. Accurate assessment of stroke risk has important clinical implications as it influences decision-making on initiation of anticoagulation. PMID- 29506747 TI - The problem of detecting long-term forgetting: Evidence from the Crimes Test and the Four Doors Test. AB - While most individuals who have problems acquiring new information forget at a normal rate, there have been reports of patients who show much more rapid forgetting, particularly comprising a subsample of patients with temporal lobe epilepsy. Currently available tests are generally not designed to test this since it requires multiple different tests of the same material. We describe two tests that aim to fill this gap, one verbal, the Crimes Test, the other visual, the Four Doors Test. Each test involves four scenes comprising five features. In each case, this allows four tests of 20 different questions to be produced and used at four different delays. Two experiments were run, each comprising a multi-test condition in which immediate testing was followed by retesting after 24 h, one week and one month, and a second condition involving a single test after one month. Both the visual and verbal tests showed clear evidence of forgetting in the single test condition, together with little evidence of forgetting in the multi-test conditions. We suggest that the testing of individual features encourages participants to remember the whole episode which then acts as a further reminder. Further research is needed to decide whether this serendipitous lack of forgetting in healthy individuals (decelerated long-term forgetting) will provide an ideal test of accelerated long-term forgetting by avoiding the danger of floor effects, or whether it will simply prove to be a further complication. Theoretical implications are discussed, as well as possible ways ahead in further investigating the surprisingly neglected field of long-term forgetting. PMID- 29506746 TI - Left atrial low-voltage areas predict atrial fibrillation recurrence after catheter ablation in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: Association between the presence of left atrial low-voltage areas and atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) has been shown mainly in persistent AF patients. We sought to compare the AF recurrence rate in paroxysmal AF patients with and without left atrial low-voltage areas. METHODS: This prospective observational study included 147 consecutive patients undergoing initial ablation for paroxysmal AF. Voltage mapping was performed after PVI during sinus rhythm, and low-voltage areas were defined as regions where bipolar peak-to-peak voltage was <0.50mV. RESULTS: Left atrial low-voltage areas after PVI were observed in 22 (15%) patients. Patients with low-voltage areas were significantly older (72+/-6 vs. 66+/-10, p<0.0001), more likely to be female (68% vs. 32%, p=0.002), and had higher CHA2DS2-VASc score (2.5+/-1.5 vs. 1.8+/-1.3, p=0.028). During a mean follow-up of 22 (18, 26) months, AF recurrence was observed in 24 (16%) and 16 (11%) patients after the single and multiple ablation procedures, respectively. AF recurrence rate after multiple ablations was higher in patients with low-voltage areas than without (36% vs. 6%, p<0.001). Low-voltage areas were independently associated with AF recurrence even after adjustment for the other related factors (Hazard ratio, 5.89; 95% confidence interval, 2.16 to 16.0, p=0.001). CONCLUSION: The presence of left atrial low voltage areas after PVI predicts AF recurrence in patients with paroxysmal AF as well as in patients with persistent AF. PMID- 29506748 TI - [Unexplained diffuse arteriosclerosis in a 26-year-old patient]. AB - Arteriosclerosis is an alteration of the blood vessels whose walls calcify, lose their elasticity and thicken. The result is a decrease in circulating blood flow and ischemic manifestations. Calcification of the arteries is a physiological phenomenon in the elderly but young subjects may also be affected. Indeed, certain risk factors can favor the formation of plaques at the level of the vessels. These include classic cardiovascular risk factors, as well as systemic inflammatory diseases, connective tissue diseases, chronic hypercalcemia... We report the case of a 26-year-old female patient with diffuse arteriosclerosis discovered accidentally, and whose exhaustive etiological investigation remained negative. PMID- 29506749 TI - Tardive syndromes. AB - Tardive syndromes are a group of hyperkinetic and hypokinetic movement disorders that occur after some delay following exposure to dopamine receptor blocking agents such as antipsychotic and anti-emetic drugs. The severity of these disorders ranges from mild to disabling or even life-threatening. There is a wide range of recognized tardive phenomenologies that may occur in isolation or in combination with each other. These phenomenologies include stereotypy, dystonia, chorea, akathisia, myoclonus, tremor, tics, gait disorders, parkinsonism, ocular deviations, respiratory dyskinesia, and a variety of sensory symptoms. Recognition of the various tardive phenomenologies may not only lead to early diagnosis but also to appropriate therapeutic intervention. This review focuses on the diagnosis and clinical course of tardive syndromes and how to distinguish between the various phenomenologies as well as how to differentiate them from other, similar but etiologically different, movement disorders. PMID- 29506750 TI - Response to: High-grade squamous intraepithelial lesion (HSIL) of the cervix with bizarre cytological appearances ('pleomorphic HSIL'): author reply. PMID- 29506751 TI - BRAF gene rearrangements can be identified by FISH studies in pancreatic acinar cell carcinoma. PMID- 29506752 TI - Sensitive method for glycosaminoglycan analysis of tissue sections. AB - A simple, isocratic HPLC method based on HILIC-WAX separation, has been developed for analyzing sulfated disaccharides of glycosaminoglycans (GAGs). To our best knowledge, this is the first successful attempt using this special phase in nano HPLC-MS analysis. Mass spectrometry was based on negative ionization, improving both sensitivity and specificity. Detection limit for most sulfated disaccharides were approximately 1 fmol; quantitation limits 10 fmol. The method was applied for glycosaminoglycan profiling of tissue samples, using surface digestion protocols. This novel combination provides sufficient sensitivity for GAG disaccharide analysis, which was first performed using prostate cancer tissue microarrays. Preliminary results show that GAG analysis may be useful for identifying cancer related changes in small amounts of tissue samples (ca. 10 MUg). PMID- 29506753 TI - The use of IRE in multi-modality treatment for oligometastatic pancreatic cancer. AB - INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) often presents late with only 20% of patients being candidates for resection while majority already have advanced metastases with median overall survival of 3-6 months. Currently, the role of oligometastasectomy and local therapy options in PDAC is unknown in patients who have favorable response to systemic chemotherapy. The aim of this study is to analyze the survival outcome of oligometastasectomy and local IRE therapy in select patients who are treated with systemic chemotherapy for PDAC metastases. METHODS: We utilized a prospective database from 2010 to 2016 to identify patients with local surgical therapy after induction systemic chemotherapy for oligometastatic PDAC (Stage 4). The initial local therapy treatment of distant metastatic lesions was followed by adjuvant chemotherapy. Subsequently, resection of the primary PDAC in conjunction with irreversible electroporation (IRE) was performed after favorable response by RECIST criteria. RESULTS: Seven patients were identified with metastatic PDAC treated with oligometastasectomy and/or local therapy. There was single metastatic lesion in 43% (3/7) of which 57% (4/7) were localized in the liver. The treatment of the primary pancreatic cancer was performed utilizing IRE in situ in 6/7 (86%) of patients in our study with resection or radiation of oligometastasis. The median survival in our study group was 16 months with 28% (2/7) patients who remain NED (range 16-41 months). CONCLUSION: Combination of systemic chemotherapy and oligometastasectomy with adjunctive local IRE therapy is a feasible treatment strategy in highly select patients with oligometastatic PDAC that demonstrate favorable tumor biology with objective response to systemic therapy. PMID- 29506754 TI - Discussion of "Oncoplastic reduction mammaplasty, an effective and safe method of breast conservation". PMID- 29506755 TI - LaSalle D. Leffall Jr., M.D. The Man and the Mission. AB - On March 19-20, 2017; Howard University hosted a Festschrift inspired by Dr. Leffall's writings (Fig. 1). The celebrants highlighted the broad spectrum of Dr. Leffall's contributions in mentorship, leadership in American Surgery, breast cancer, endocrine cancer, pancreatic cancer, and familial polyposis coli. Perhaps most inspirational was the awe inspiring consistency the presenters demonstrated in describing the personal characteristics Dr. Leffall brings to his academic discourse: his encyclopedic knowledge and recall, his charm, eloquence, humility, and his total dedication to the patient, his students, and trainees. We are greatly indebted to Kirby Bland M.D., FACS for offering the pages of The American Journal of Surgery to illuminate this celebration. PMID- 29506756 TI - Defining the pattern of initiation of monomorphic ventricular tachycardia using the beat-to-beat intervals recorded on implantable cardioverter defibrillators from the RAFT study: A computer-based algorithm. AB - Arrhythmia onset pattern may have important implications on morbidity, recurrent implantable cardioverter defibrillator (ICD) shocks, and mortality, given the proposed correlation between initiation pattern and arrhythmia mechanism. Therefore, we developed and tested a computer-based algorithm to differentiate the pattern of initiation based on the beat-to-beat intervals of the ventricular tachycardia (VT) episodes in ICD recordings from the Resynchronization Defibrillation for Ambulatory Heart Failure Trial (RAFT). Intervals on intracardiac electrograms from ICDs were analyzed backwards starting from the marker of VT detection, comparing each interval with the average tachycardia cycle length. If the morphology of the beat initiating the VT was similar to the morphology of the VT itself, the episode was considered sudden. If the morphology of the beat initiating the VT was not similar to the morphology of the VT itself, the episode was considered non-sudden. The capability of the algorithm to classify the pattern of initiation based only on the beat-to-beat intervals allows for the classification and analysis of large datasets to further investigate the clinical importance of classifying VT initiation. If analysis of the VT initiation proves to be of clinical value, this algorithm could potentially be integrated into ICD software, which would make it easily accessible and potentially helpful in clinical decision-making. PMID- 29506757 TI - Linking stroke-induced heart injury and neurogenic atrial fibrillation: a hypothesis to be proven. PMID- 29506758 TI - Oscillating devices for airway clearance in people with cystic fibrosis. PMID- 29506759 TI - Modulation of shoulder muscle and joint function using a powered upper-limb exoskeleton. AB - Robotic-assistive exoskeletons can enable frequent repetitive movements without the presence of a full-time therapist; however, human-machine interaction and the capacity of powered exoskeletons to attenuate shoulder muscle and joint loading is poorly understood. This study aimed to quantify shoulder muscle and joint force during assisted activities of daily living using a powered robotic upper limb exoskeleton (ArmeoPower, Hocoma). Six healthy male subjects performed abduction, flexion, horizontal flexion, reaching and nose touching activities. These tasks were repeated under two conditions: (i) the exoskeleton compensating only for its own weight, and (ii) the exoskeleton providing full upper limb gravity compensation (i.e., weightlessness). Muscle EMG, joint kinematics and joint torques were simultaneously recorded, and shoulder muscle and joint forces calculated using personalized musculoskeletal models of each subject's upper limb. The exoskeleton reduced peak joint torques, muscle forces and joint loading by up to 74.8% (0.113 Nm/kg), 88.8% (5.8%BW) and 68.4% (75.6%BW), respectively, with the degree of load attenuation strongly task dependent. The peak compressive, anterior and superior glenohumeral joint force during assisted nose touching was 36.4% (24.6%BW), 72.4% (13.1%BW) and 85.0% (17.2%BW) lower than that during unassisted nose touching, respectively. The present study showed that upper limb weight compensation using an assistive exoskeleton may increase glenohumeral joint stability, since deltoid muscle force, which is the primary contributor to superior glenohumeral joint shear, is attenuated; however, prominent exoskeleton interaction moments are required to position and control the upper limb in space, even under full gravity compensation conditions. The modeling framework and results may be useful in planning targeted upper limb robotic rehabilitation tasks. PMID- 29506760 TI - An ocular biomechanic model for dynamic simulation of different eye movements. AB - Simulating and analysing eye movement is useful for assessing visual system contribution to discomfort with respect to body movements, especially in virtual environments where simulation sickness might occur. It can also be used in the design of eye prosthesis or humanoid robot eye. In this paper, we present two biomechanic ocular models that are easily integrated into the available musculoskeletal models. The model was previously used to simulate eye-head coordination. The models are used to simulate and analyse eye movements. The proposed models are based on physiological and kinematic properties of the human eye. They incorporate an eye-globe, orbital suspension tissues and six muscles with their connective tissues (pulleys). Pulleys were incorporated in rectus and inferior oblique muscles. The two proposed models are the passive pulleys and the active pulleys models. Dynamic simulations of different eye movements, including fixation, saccade and smooth pursuit, are performed to validate both models. The resultant force-length curves of the models were similar to the experimental data. The simulation results show that the proposed models are suitable to generate eye movement simulations with results comparable to other musculoskeletal models. The maximum kinematic root mean square error (RMSE) is 5.68 degrees and 4.35 degrees for the passive and active pulley models, respectively. The analysis of the muscle forces showed realistic muscle activation with increased muscle synergy in the active pulley model. PMID- 29506761 TI - Addressing paediatric surgical care on World Birth Defects Day. PMID- 29506762 TI - Systematic review of hearing loss after traumatic brain injury without associated temporal bone fracture. AB - OBJECTIVE: While hearing loss following temporal bone fracture is a well described phenomenon, few data exist on auditory dysfunction in patients with traumatic brain injury (TBI) without temporal bone fracture. Herein, we aim to systematically review hearing loss after TBI without bony fracture and describe its etiologies. DATA SOURCES: Pubmed, Embase, Cochrane databases. REVIEW METHODS: A systematic review of the literature from 1966 to January 2017 was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. Data were obtained from studies that investigated hearing loss in TBI without skull fracture according to an a priori protocol with inclusion and exclusion criteria. Variables included type and severity of hearing loss, as well as pathophysiology of hearing loss. RESULTS: There were 13 studies with 773 patients that met study criteria. Overall, there was one prospective cohort study, four retrospective cohort studies, two case-control studies, and six case reports. The studies with the highest level of evidence report a change in hearing of at least 10-15 dB across a range of frequencies in as many as 58% percent of TBI patients without bony fracture, which was transient or chronic. The mechanism/severity of injury may impact the rate of hearing loss. CONCLUSIONS: Hearing loss after TBI in the absence of bony injury appears to be a clinically significant but poorly characterized phenomenon. PMID- 29506763 TI - Intramural atrial hematoma complicating transesophageal echocardiography during cardiac arrest. AB - BACKGROUND: Adequate strategies using either transthoracic (TTE) or transesophageal (TEE) echocardiography in patients receiving cardiopulmonary resuscitation (CPR) is an ongoing area of research. OBJECTIVES: As transthoracic point-of-care ultrasound (POCUS) during cardiac arrest resuscitation might result in an increased duration of interruptions in the delivery of chest compressions; the use of TEE has been proposed as an alternative. METHODS: No technical complications of either TTE nor TEE are so far being reported in the literature. RESULTS: We report the case of a left intramural atrial hematoma complicating TEE procedure during cardiac arrest. This highlights a unique and to our knowledge, first-in-man, described complicating TEE procedure during CPR. CONCLUSIONS: Further research on the safety of transesophageal echo during CRP is mandatory and the question about any potential harm of particular interest. PMID- 29506764 TI - Association Between the Brain-derived Neurotrophic Factor Val66Met Polymorphism and Overweight/Obesity in Pediatric Population. AB - BACKGROUND: The brain-derived neurotrophic factor (BDNF) rs6265 (G196A; Val66Met) single nucleotide polymorphism has been associated with BMI and obesity in distinct populations, both adult and pediatric, with contradictory results involving either Val or Met as the risk variant. AIM OF THE STUDY: To determine the association between the BDNF Val66Met polymorphism and BMI in Mexican children and adolescents. METHODS: BDNF Val66Met genotyping by restriction fragment length polymorphism and nutritional status characterized by their BMI for-age z-scores (BAZ) from pediatric volunteers (n = 498) were analyzed by Fisher's exact test association analysis. Standardized residuals (R) were used to determine which genotype/allele had the major influence on the significant Fisher's exact test statistic. Odds ratios were analyzed to measure the association between genotype and normal weight (>=-2 SD < + 1 SD) and overweight (>= + 1 SD, including obesity, Ow + Ob) status with 95% confidence intervals to estimate the precision of the effect as well as 95% credible intervals to obtain the most probable estimate. RESULTS: Comparisons between GG (Val/Val), GA (Val/Met) and AA (Met/Met) genotypes or Met homozygotes vs. Val carriers (combination of GG and GA genotypes) showed significant differences (p = 0.034 and p = 0.037, respectively) between normal weight and the combined overweight and obese pediatric subjects. Our data showed that children/adolescents homozygous for the A allele have increased risk of overweight compared to the Val carriers (Bayes OR = 4.2, 95% CI**[1.09-33.1]). CONCLUSION: This is the first study showing the significant association between the BDNF rs6265 AA (Met/Met) genotype and overweight/obesity in Mexican pediatric population. PMID- 29506765 TI - Creatine kinase (CK) and its association with aggressive behavior in patients with schizophrenia. AB - OBJECTIVE: To study the association between the serum creatine kinase (CK) level and aggressive behavior in patients with schizophrenia. METHOD: This retrospective study recruited 2780 Chinese patients with schizophrenia from January 2009 to December 2013 at the psychiatric inpatient units of West China Hospital. The diagnosis was made according to the DSM-IV criteria. The serum level of CK was checked. RESULTS: Aggressive behavior was positively correlated with the serum CK level (r=0.262, p=0.000). The OR value is 8.084 when comparing the high CK group and normal CK group prior to admission. The aggressive behavior rate in the 5 times group (serum level>=1130U/L) after admission (28.2%) is higher than the rate prior to admission (16.5%). CONCLUSION: The aggressive patients with schizophrenia displayed increased serum CK level. It may be useful to include a lab test of CK level in patients with schizophrenia and history of aggression. It would help the staff to take precautions to protect the patients and others. PMID- 29506766 TI - The association between schizophrenia and violence. PMID- 29506767 TI - Triple advantages of injectable long acting second generation antipsychotics: Relapse prevention, neuroprotection, and lower mortality. PMID- 29506768 TI - Prognostic factors and benefits of adjuvant therapy after pancreatoduodenectomy for ampullary adenocarcinoma: Mayo Clinic experience. AB - INTRODUCTION: Ampullary adenocarcinoma is a rare entity with limited data on prognostic factors. The aim of this study is to identify prognostic factors and assess the benefit of adjuvant therapy in patients with ampullary adenocarcinoma who underwent pancreatoduodenectomy. METHODS: A cohort of 121 consecutive patients underwent pancreatoduodenectomy for ampullary adenocarcinoma from 2006 to 2016 at Mayo Clinic in Rochester, MN. All patients were confirmed by independent pathologic review to have ampullary carcinoma. Patient survival and its correlation with patient and tumor variables were evaluated by univariate and multivariate analysis. RESULTS: Fifty three patients (45%) received adjuvant therapy (34 patients had chemotherapy alone, while 19 patients received both chemotherapy and radiation therapy). Fifty seven percent of the patients were diagnosed with advanced stage disease (Stage IIB or higher). Nearly all patients (98.3%) had negative surgical margins. Median overall survival (OS) was 91.8 months (95% CI:52.6 months-not reached). In multivariate analysis, excellent performance status (ECOG: 0), adjuvant therapy, and advanced stage remained statistically significant. Adjuvant therapy was independently associated with improved disease free survival (Hazard ratio [HR]:0.52, P = 0.04) and overall survival (HR:0.45, P = 0.03) in patients with advanced disease. CONCLUSIONS: Adjuvant therapy was associated with improved survival in patients with resected ampullary cancer, especially with advanced stage disease. A multi-institutional randomized trial is needed to further assess the role of adjuvant therapy in ampullary adenocarcinoma. PMID- 29506769 TI - Risk factors for surgical site infection following spinal instrumentation surgery. AB - BACKGROUND: In spinal instrumentation surgeries, surgical site infection (SSI) is one of the complications to be avoided. However, spinal instrumentation surgeries have a higher rate of SSI than other clean orthopedic surgeries. The purpose of this study was to investigate the risk factors for SSI following spinal instrumentation surgeries and contribute to the prevention of SSIs by identifying high-risk patients. METHODS: Records of 431 patients who underwent spinal instrumentation surgeries from 2011 to 2014 with a minimum follow-up period of 90 days were retrospectively reviewed. Associations of SSI with various preoperative, operative, and postoperative factors were statistically analyzed with univariate and stepwise multivariate logistic regression analysis. RESULTS: Deep or superficial SSIs were observed in 15 patients (3.5%). Univariate analysis revealed significant association of SSI with diabetes mellitus (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.5-14.4; p = 0.012) and serum albumin <=3.5 g/dl (OR 3.35, 95% CI 1.1-10.38, p = 0.012). The number of regular medications prescribed in patients with SSI (8.2 +/- 5.4) was significantly more than that in patients without SSI (3.8 +/- 4.4) (p = 0.001), and the cut-off value of the number of medications was 7, as derived from receiver operating characteristics analysis. Multivariate analysis revealed that the number of regular medications >=7 was an independent risk factor significantly associated with SSIs (OR 7.3, 95% CI 2.3-24.0, p = 0.001). CONCLUSIONS: Our study demonstrated that an important risk factor for SSI after spinal instrumentation surgery was number of regular medications >=7. Number of regular medications is a simple and valuable risk index for SSI, which reflects the influence of medications and comorbidities. PMID- 29506770 TI - Direct detection and characterization of bioinorganic peroxo moieties in a vanadium complex by 17O solid-state NMR and density functional theory. AB - Electronic and structural properties of short-lived metal-peroxido complexes, which are key intermediates in many enzymatic reactions, are not fully understood. While detected in various enzymes, their catalytic properties remain elusive because of their transient nature, making them difficult to study spectroscopically. We integrated 17O solid-state NMR and density functional theory (DFT) to directly detect and characterize the peroxido ligand in a bioinorganic V(V) complex mimicking intermediates non-heme vanadium haloperoxidases. 17O chemical shift and quadrupolar tensors, measured by solid state NMR spectroscopy, probe the electronic structure of the peroxido ligand and its interaction with the metal. DFT analysis reveals the unusually large chemical shift anisotropy arising from the metal orbitals contributing towards the magnetic shielding of the ligand. The results illustrate the power of an integrated approach for studies of oxygen centers in enzyme reaction intermediates. PMID- 29506771 TI - Electrophysiologic Features of Radial Neuropathy in Childhood and Adolescence. AB - BACKGROUND: We analyzed the clinical and electrophysiologic patterns of nerve injury in pediatric patients with radial neuropathy. METHODS: This is a retrospective analysis of 19 children and adolescents with radial neuropathy. RESULTS: The mean subject age was 12 years (range one month to 19 years), 56% were female, and 53% had traumatic etiologies. Weakness in the finger and wrist extensors was the prevailing complaint (82%). Predominant localization was at the posterior interosseous nerve (37%), followed by the radial nerve below the spiral groove (32%), the radial nerve at the spiral groove (26%), and the radial nerve above the spiral groove (5%). Extensor indicis proprius compound muscle action potential amplitude was reduced in 86% of cases when tested, with a median axon loss estimate of 78%. The radial sensory nerve action potential amplitude was reduced in 53% of all cases, and in 83% of cases affecting the main radial trunk with a median axon loss estimate of 100%. For neuropathy affecting the main radial trunk, there was a high correlation of extensor indicis proprius median axon loss estimate and radial sensory nerve action potential median axon loss estimate (r = 0.72, P = 0.02). Neurogenic changes were seen in the extensor indicis proprius, extensor digitorum communis, extensor carpi radialis, and brachioradialis in 88%, 94%, 60%, and 44% of cases, respectively. Pathophysiology was demyelinating in 10%, axonal in 58%, and mixed in 32%. CONCLUSIONS: In contrast to adults, where localization at the spiral groove predominates, radial neuropathy in children and adolescents is commonly localized at the posterior interosseous nerve or at the distal main radial trunk. Pediatric radial neuropathy is frequently of traumatic etiology and axonal pathophysiology. PMID- 29506772 TI - Intracavitary amphotericin B in the treatment of intracranial aspergillosis. AB - Intracranial aspergillosis is a rare infectious disease of the central nervous system with high mortality rates. Our aim is to present 3 cases of intracranial aspergillosis who were surgically treated with intracavitary amphotericin B administration. First case was a 21-year-old male patient. Allogeneic stem cell transplantation treatment was performed because of aplastic anemia and vocal cord paralysis developed 10 days after treatment. Multiple aspergillosis abscesses were observed in the cranial magnetic resonance imaging (MRI). Cerebral lesions were excised and 0.3 cc of amphotericin B was applied locally. Second case was a 18-year-old male patient treated for acute lymphocytic leukemia. MRI was performed on the development of consciousness change during treatment and right frontal abscess was detected. The abscess was excised and amphotericin B was applied locally. Third case was a 45-year-old woman with mastectomy. She had chemotherapy after surgery and had blood stem cell transplantation because of pancytopenia. Two months after treatments, MRI was performed on the development of ataxia and a cerebellar abscess was detected. The abscess was surgically excised and local amphotericin B was applied. The first case deceased 2 weeks after surgery and the second case died 2.5 years later due to multi-organ failure. The third case is stil alive and neurologically stable after 14 years of surgical treatment. In intracranial aspergillosis, intracavitary amphotericin B therapy may be used as an adjunct after the surgical excision of abscess. This procedure may contributes to the regression of abscess or prevention of the recurrence. But comparative clinical studies are needed for more accurate conclusions. PMID- 29506773 TI - Quality markers based on biological activity: A new strategy for the quality control of traditional Chinese medicine. AB - BACKGROUND: The quality and quality evaluation system of traditional Chinese medicine (TCM) are crucial in the safety and effectiveness assessment of TCM. However, they are also the major bottlenecks that restrict the quality control of TCM. Given the nature of Chinese medicine and the limitations of science and technology, the quality evaluation of TCM involves a few difficulties. Therefore, scholars have conducted considerable amount of research on this topic and obtained promising results. Biological potency and biomarkers have been used to evaluate the quality of TCM. Previous studies provided new strategies and methods to establish a system on quality evaluation. PURPOSE: This review aims to provide a new strategy for the quality control of Chinese herbal medicine by combining biological potency and biomarkers based on biological effects. METHODS: We reviewed the quality evaluation system of Chinese herbal medicine, focusing on quality markers (Q-markers) based on biological effects and the application of these markers in the quality evaluation of Chinese herbal medicine. We also reviewed the factors affecting quality, the difficulties related to the quality evaluation system and the attempt of researchers to improve the quality control of TCM. RESULTS: We propose Q-biomarkers by integration of biological potency and biomarkers to evaluate the quality of TCM. The quality markers provided us significant insights in the process of definition. We further optimised the concept of Q-markers and summarised their definition and properties (including quantification, specificity and related to biological response) in accordance with the requirement of the quality evaluation of TCM. CONCLUSION: We propose the use of Q-biomarkers in vivo related to specific diseases as a new strategy for the quality evaluation of Chinese herbal medicine. The quality evaluation system of Q-biomarkers would provide a new perspective to standardise and globalise TCM. PMID- 29506774 TI - Use of Video-consultation is Feasible During Follow-up Care of Patients with a Neuroendocrine Tumour. PMID- 29506775 TI - Separation of mixed waste plastics via magnetic levitation. AB - Separation becomes a bottleneck of dealing with the enormous stream of waste plastics, as most of the extant methods can only handle binary mixtures. In this paper, a novel method that based on magnetic levitation was proposed for separating multiple mixed plastics. Six types of plastics, i.e., polypropylene (PP), acrylonitrile butadiene styrene (ABS), polyamide 6 (PA6), polycarbonate (PC), polyethylene terephthalate (PET), and polytetrafluoroethylene (PTFE), were used to simulate the mixed waste plastics. The samples were mixed and immersed into paramagnetic medium that placed into a magnetic levitation configuration with two identical NdFeB magnets with like-poles facing each other, and Fourier transform infrared (FTIR) spectroscopy was employed to verify the separation outputs. Unlike any conventional separation methods such as froth flotation and hydrocyclone, this method is not limited by particle sizes, as mixtures of different size fractions reached their respective equilibrium positions in the initial tests. The two-stage separation tests demonstrated that the plastics can be completely separated with purities reached 100%. The method has the potential to be industrialised into an economically-viable and environmentally-friendly mass production procedure, since quantitative correlations are determined, and the paramagnetic medium can be reused indefinitely. PMID- 29506776 TI - Recycled wind turbine blades as a feedstock for second generation composites. AB - With an increase in renewable wind energy via turbines, an underlying problem of the turbine blade disposal is looming in many areas of the world. These wind turbine blades are predominately a mixture of glass fiber composites (GFCs) and wood and currently have not found an economically viable recycling pathway. This work investigates a series of second generation composites fabricated using recycled wind turbine material and a polyurethane adhesive. The recycled material was first comminuted via a hammer-mill through a range of varying screen sizes, resinated and compressed to a final thickness. The refined particle size, moisture content and resin content were assessed for their influence on the properties of recycled composites. Static bending, internal bond and water sorption properties were obtained for all composites panels. Overall improvement of mechanical properties correlated with increase in resin content, moisture content, and particle size. The current investigation demonstrates that it is feasible and promising to recycle the wind turbine blade to fabricate value-added high-performance composite. PMID- 29506777 TI - Measurement of Blood Loss in Cardiac Surgery: Still Too Much. AB - BACKGROUND: Cardiac surgery is associated with a significant decrease in hematocrit. It is unclear whether that occurs from hemodilution, loss of red cells, or both. Hematocrit is a major determinant of transfusion decisions although transfusion is associated with increased morbidity and mortality. Physicians must determine whether this anemia is the result of hemodilution or red blood cell loss as the former would be treated with packed red blood cell transfusions and the latter by diuresis. We hypothesize that the decrease in hematocrit observed in cardiac surgery is due to hemodilution. METHODS: Blood volume (BV), plasma volume (PV), and red blood cell volume (RBCV) were measured in 54 patients undergoing coronary artery bypass graft surgery, valve surgery, or coronary artery bypass graft/valve surgery. Measurements were made preoperatively, immediately postoperatively, and 2 hours after surgery utilizing a dilution tracer method and hematocrit measurements. RESULTS: Preoperative average BV was 6,094 mL (SD 1,904 mL), RBCV was 2,024 mL (SD 720 mL), and PV was 4,070 mL (SD 1,339 mL). Postoperative average BV was 4,834 mL (SD 1,432 mL), RBCV 1,226 mL (SD 527 mL), and PV 3,607 mL (SD 993 mL). Blood volume decreased 18% (p < 0.0001), RBCV decreased 38% (p < 0.001), and PV decreased 8% (p < 0.012). There were no significant changes between postoperative values and those 2 hours later in the cardiac surgery intensive care unit. CONCLUSIONS: Decreases in hematocrit observed in cardiac surgery patients are due to significant red blood cell losses and not to hemodilution. Red blood cell losses averaged 38%. Plasma volume also decreased. PMID- 29506778 TI - Corrigendum to "Cytological analyses of the karyotypes and chromosomes of three Colletotrichum species, C. orbiculare, C. graminicola and C. higginsianum" [Fungal Genet. Biol. 82 (2015) 238-250]. PMID- 29506779 TI - Risks of diabetic foot syndrome and amputation associated with sodium glucose co transporter 2 inhibitors: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: The U.S. Food and Drug Administration recently issued a safety communication requiring new warnings of increased leg and foot amputation risk be added to canagliflozin drug labelling. However, the risk associated with other sodium-glucose co-transporter 2 inhibitors (SGLT2i) remains uncertain. AIM: This meta-analysis aimed to evaluate the potential risks of diabetic foot syndrome (DFS) and amputation associated with SGLT2i. METHODS: Relevant databases were searched from inception to June 14, 2017 to identify randomized controlled trials (RCTs) that evaluated risks of DFS and amputation associated with SGLT2i use. A random effects model was performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) using STATA 14. RESULTS: Fourteen RCTs involving 26,167 patients were eligible for this meta-analysis. SGLT2i were not significantly associated with increased risk of DFS compared with placebo (OR 1.05, 95% CI: 0.58-1.89). No significant association was observed in the subgroup and sensitivity analysis on DFS risk either. Although SGLT2i, as a class, were not significantly associated with amputation risk (OR 1.40, 95% CI: 0.81-2.41), subgroup analysis showed an increased incidence of amputation in participants using canagliflozin (OR 1.89, 95% CI: 1.37-2.60), compared with oral anti diabetic drugs and placebo, but not in those using empagliflozin (OR 1.02, 95% CI: 0.71-1.48). CONCLUSION: Current evidence from RCTs suggests that canagliflozin may be positively associated with an increased risk of amputation. Due to limited data, large-scale studies are required to further clarify the association between amputation and individual SGLT2i drugs. PMID- 29506780 TI - Effect of Race on the Incidence of Aortic Stenosis and Outcomes of Aortic Valve Replacement in the United States. AB - OBJECTIVE: To assess the effect of race on the incidence of aortic stenosis (AS) and utilization and outcomes of aortic valve replacement (AVR). PATIENTS AND METHODS: Patients older than 60 years hospitalized with a primary diagnosis of AS and those who underwent AVR between 2003 and 2014 were included. Adjusted and unadjusted incidence of AS-related hospitalizations, utilization rates of AVR, in hospital morbidity and mortality, and resource utilization was compared between whites and African Americans (AAs). RESULTS: Between January 1, 2003, and December 31, 2014, the incidence of AS-related admissions increased from 13 (95% CI, 12.8-13.2) to 26 (95% CI, 25.7-26.4) cases per 100,000 patient-years in whites and from 3 (95% CI, 3.5-3.8) to 9.5 (95% CI, 9.4-9.8) cases per 100,000 patient-years in AAs (P<.001). The incidence density ratio decreased from 4.3 (95% CI, 2.27-6.6) in 2003 to 2.7 (95% CI, 1.1-3.8) in 2014. The ratio of AVR to AS-related admissions was 11.3% in whites and 6.7% in AAs (P<.001). Crude in hospital mortality after AVR was higher in AAs (6.4% vs 4.7%; P<.001). However, after propensity score matching, in-hospital morality after isolated AVR was not significantly different between AAs and whites (4.7% vs 3.7%; P=.12). African Americans also had longer hospitalizations (12+/-12 days vs 10+/-9 days; P<.001), higher rates of nonhome discharge (32.1% vs 27.2%; P=.004), and higher cost of hospitalization ($55,631+/-$37,773 vs $52,521+/-$38,040; P<.001). CONCLUSIONS: African Americans undergo AVR less than whites. The underlying etiology of this disparity is multifactorial, but may be related to a lower incidence of AS in AAs. Aortic valve replacement is associated with similar risk-adjusted in hospital mortality but higher cost and longer hospitalizations in AAs than in whites. PMID- 29506781 TI - The Importance of Vigorous-Intensity Leisure-Time Physical Activity in Reducing Cardiovascular Disease Mortality Risk in the Obese. AB - OBJECTIVE: To investigate the role of vigorous-intensity leisure-time physical activity in reducing cardiovascular disease (CVD) mortality risk in the obese. PARTICIPANTS AND METHODS: Trained interviewers assessed physical activity and body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) in 59,005 adult participants (mean +/- SD age, 57+/-12 years; 46.5% male) in 2 household-based surveillance studies: Health Survey for England and Scottish Health Survey. Mortality was ascertained from death certificates. Data were collected from January 1, 1994, through March 31, 2011. Cox proportional hazards models were adjusted for age, sex, smoking habit, total physical activity, long-standing illness, prevalent CVD, and occupation. RESULTS: There were 2302 CVD deaths during 532,251 person-years of follow-up (mean +/- SD, 9+/-4 years). A total of 15,002 (25%) participants were categorized as obese (BMI >=30). Leisure-time physical activity was inversely associated and BMI was positively associated with CVD mortality. Compared with those who reported meeting physical activity guidelines including some vigorous-intensity physical activity and who had a normal BMI (18.5-24.9) (reference group), the CVD mortality hazard ratio was not significantly different in the obese who also reported meeting physical activity guidelines including some vigorous-intensity physical activities (1.25; 95% CI, 0.50-3.12). Compared with the reference group, the CVD mortality hazard ratio was more than 2-fold in the obese who reported meeting physical activity guidelines, including only moderate-intensity physical activities (2.52; 95% CI, 1.15-2.53). CONCLUSION: This large, statistically powerful study suggests that vigorous-intensity leisure-time physical activity is important in reducing CVD mortality risk in the obese. PMID- 29506782 TI - The ontogeny of cultural learning. AB - All primates engage in one or another form of social learning. Humans engage in cultural learning. From very early in ontogeny human infants and young children do not just learn useful things from others, they conform to others in order to affiliate with them and to identify with the cultural group. The cultural group normatively expects such conformity, and adults actively instruct children so as to ensure it. Young children learn from this instruction how the world is viewed and how it works in their culture. These special forms of cultural learning enable powerful and species-unique processes of cumulative cultural evolution. PMID- 29506783 TI - Self-construal: a cultural framework for brain function. AB - Humans have created complex cultures that provide frameworks for our lives, guiding our behavior and thoughts. Recent brain imaging studies have uncovered cultural influences on brain activity in multiple tasks. We review recent cultural neuroscience findings that illustrate that (a) self-construal, a cultural trait that differentiates between East Asian and Western societies, mediates group differences in brain activity between East Asians and Westerners; and (b) priming interdependent/independent self-construals modulates brain activity engaged in sensory/motor and cognitive/affective processes. These findings provide new insights on human brain function and suggest that self construals provide a cultural framework that constrains brain activity underlying multiple cognitive and affective processes. PMID- 29506784 TI - Culture and cognition. AB - In this paper, we review the latest developments in cultural influences on attention, perception, categorization, memory and cognitive heuristics. We then explore the origin of these cultural differences, and highlight the implications of such culture-specific thinking styles for people's judgment and decision making processes. We conclude this review by discussing some of the future research directions to further advance our understanding in culture and cognition. PMID- 29506785 TI - Culture-gene coevolutionary psychology: cultural learning, language, and ethnic psychology. AB - While most psychologists recognize the importance of genes and culture in shaping human cognition, few theoretical perspectives in the field offer a framework for understanding their relationship and for deriving predictions about the structure of the variation we see across space and time. Here we argue that culture-gene coevolutionary (CGC) frameworks have such potential, and can unite disparate fields across the social sciences and sub-fields within psychology. We illustrate the power of this functionalist evolutionary approach by reviewing recent research on three interlinked topics; cultural learning rules, language cognition, and reasoning about ethnic social groups. We show how CGC approaches complement, and contrast with, traditional approaches in psychology on these topics. Furthermore, this theoretical framework has already been fruitful in drawing new predictions and pointing to new directions of inquiry. PMID- 29506786 TI - Social niche construction. AB - Humans are niche constructors who create physical and social environments to which they adapt. The social niche construction approach to human behavior analyzes behavior as a strategy to further long-term self-interest given a specific institution-that is, a set of stable and predictable responses from others to one's own behavior. We illustrate the logic of social niche construction analysis using examples of individualist and collectivist institutions, and explain how independent and interdependent self-construal can be viewed as strategies adapting to and collectively sustaining individualist or collectivist institutions. We discuss how the social niche construction approach is related to similar approaches used in cultural psychology, namely the socio ecological approach, intersubjective approach, equilibrium approach, and gene culture co-evolution approach. PMID- 29506787 TI - Cultural differences in moral judgment and behavior, across and within societies. AB - We review contemporary work on cultural factors affecting moral judgments and values, and those affecting moral behaviors. In both cases, we highlight examples of within-societal cultural differences in morality, to show that these can be as substantial and important as cross-societal differences. Whether between or within nations and societies, cultures vary substantially in their promotion and transmission of a multitude of moral judgments and behaviors. Cultural factors contributing to this variation include religion, social ecology (weather, crop conditions, population density, pathogen prevalence, residential mobility), and regulatory social institutions such as kinship structures and economic markets. This variability raises questions for normative theories of morality, but also holds promise for future descriptive work on moral thought and behavior. PMID- 29506788 TI - Cultural influences in mental health treatment. AB - Research on mental health treatments from 2010 to 2015 has continued to highlight the critical role of culture on treatment services, processes, and outcomes for racial/ethnic minority groups. Studies showed that factors such as acculturation and phenotypic appearance were associated with risk for psychopathology. Issues such as face concern and acculturation level were associated with the quality of client-therapist relationships and the amount of information clients disclosed in sessions. While racial/ethnic minority clients generally preferred same-ethnicity therapists, findings showed relatively small effects for racial/ethnic match and positive treatment outcomes. Several studies provided additional evidence for the effectiveness of culturally-adapted, evidence-based treatments compared to non adapted treatments for minority clients, and more researchers are beginning to delineate the processes involved in making these successful adaptations. PMID- 29506789 TI - Culture and teams. AB - We first review research on culture effects in teams, illustrating that mean levels of team cultural values have main (i.e. direct) effects, indirect effects (i.e. mediated by intervening variables), and moderating influences on team processes and outcomes. Variance in team cultural values or on country of origin (i.e. nationality diversity) also has main effects on team functioning, and we highlight contextual variables that strengthen or weaken these main effects. We next review research examining the effect of variance in team cultural values on global virtual teams, specifically. Finally, we review research on how cultural values shape employees' receptivity to empowering leadership behavior in teams. We conclude by discussing critical areas for future research. PMID- 29506790 TI - Culture and psychopathology. AB - Recent work on culture and psychopathology is beginning to unpack the cognitive, developmental and interactional processes through which social contexts shape illness onset, experience, course and outcome. New conceptual models, tools, and technologies, along with better data, lend support to an ecosocial view of mental disorders that emphasizes the way that cultural contexts influence developmental processes and exposure to social adversity to increase risk for specific types of psychopathology. This contextual view has implications for research design and clinical practice. Recognizing the importance of culture, DSM-5 now includes a discussion of cultural concepts of mental disorders as well as a Cultural Formulation Interview to help clinicians explore the context of mental health symptoms and disorders. PMID- 29506791 TI - Cultural diffusion in humans and other animals. AB - Recent years have seen an enormous expansion and progress in studies of the cultural diffusion processes through which behaviour patterns, ideas and artifacts are transmitted within and between generations of humans and other animals. The first of two main approaches focuses on identifying, tracing and understanding cultural diffusion as it naturally occurs, an essential foundation to any science of culture. This endeavor has been enriched in recent years by sophisticated statistical methods and surprising new discoveries particularly in humans, other primates and cetaceans. This work has been complemented by a growing corpus of powerful, purpose-designed cultural diffusion experiments with captive and natural populations that have facilitated the rigorous identification and analysis of cultural diffusion in species from insects to humans. PMID- 29506793 TI - What moves people to action? Culture and motivation. AB - The study of motivation answers the question: what moves people to action in particular situations. A large volume of research provides compelling evidence that the answer to this question depends on the cultural context. In the individualist West, particularly in middle-class, college educated North America, the motivation for 'good' actions such as persistent productive performance is commonly understood to come from preferences and values inside the person. Yet in most contexts (those of the majority world), motivation takes form as being receptive to specific others, realizing expectations, and following culturally inscribed norms. Explaining the actions of people with a mismatched model of motivation can lead to inferences of irrationality, deficiency or immorality and is a barrier to intercultural communication. PMID- 29506792 TI - Values: the dynamic nexus between biology, ecology and culture. AB - Values are motivational goals that influence attitudes, behaviors and evaluations. Cross-cultural evidence suggests that values show a systematic structure. Personal and cultural variations in the value structure, value priorities and value links to attitudes, behavior and well-being reflect contextual constraints and affordances in the environment, suggesting that values function as broadly adaptive psychological structures. The internal structure of values (the descriptive value system) becomes more clearly differentiated in more economically developed contexts. Value priorities shift toward more autonomous, self-expressive and individualistic orientations with greater economic resources and less ecological stress. In addition to systematic changes in internal structure, value links to attitudes, behaviors and well-being are influenced by economic, ecological and institutional contexts. Values are more likely to be expressed in attitudes and behavior if individuals have greater access to economic resources, experience less institutional and ecological stress or when the values reinforce culturally normative behavior. Frontiers for further value research include a greater examination of the neural underpinnings of values in specific ecological contexts and across the lifespan; and an examination of how values are behaviorally instantiated in different environments. PMID- 29506794 TI - From one mind to many: the emerging science of cultural norms. AB - Cultural norms permeate human existence. They shape our view of reality and the evolution of culture. In this review, we discuss the benefits of a cultural science that studies norms as well as values, and review research on (a) whether cultural norms are distinctly human, (b) when people will follow cultural norms, and (c) what factors shape the content and strength of cultural norms. We argue that studying cultural norms represents a critical cross-disciplinary, multi level approach that is ideal for both understanding culture and tapping its potential for positive change. PMID- 29506795 TI - Culture and participation: a paradigm shift. AB - The present article makes the case that the study of culture would do well to shift the notion of culture to 'ways of life,' rather than treating culture as static characteristics of groups (e.g. ethnicity). This would entail a paradigm shift, to focus on people's participation in cultural communities, across generations. The shift fits a transactional worldview, contrasting with the interactional worldview that is common in mainstream research and everyday life in the US. The article focuses on a way of organizing children's learning that fits the participation paradigm-Learning by Observing and Pitching In to the activities of family and community-that appears to be common in Indigenous and Indigenous-heritage communities of the Americas. PMID- 29506796 TI - Intentional cultural change. AB - As a process of blind variation and selective retention, evolution lacks intentionality. Nevertheless, intentional processes can be a product of evolution and can double back to effect evolution. This article briefly describes how intentional processes evolve, how they figure in human cultural evolution, and how future cultural evolution needs to become more intentional. PMID- 29506797 TI - Culture and the natural environment. AB - The way individuals relate to the natural environment is culturally patterned. In this article we review and discuss cross-cultural differences and similarities in a number of important domains including environmental concern, environmental risk perception, and pro-environmental behaviour. Three possible psychological universals (future thinking, self-transcendent orientation, and psychological distance) in association with pro-environmental attitudes and behaviour are proposed, and cultural variations are also discussed. We highlight evidence including new analyses of cross-cultural data-indicating that an overwhelming majority of the world's population supports environmental protection, and identifies with the value of 'looking after the environment.' PMID- 29506798 TI - Personality traits across cultures. AB - Current questions in the study of personality traits across cultures include (a) the universality versus cultural uniqueness of trait structure, (b) cultural differences in trait levels, (c) the consistency and validity of traits and their measures across cultures, and (d) the evolutionary, ecological, and cultural contexts of personality. Although the Five Factor Model (FFM) of personality continues to find cross-cultural support, new research suggests that the model may be difficult to replicate in less educated or preliterate groups and that indigenous social-relational concepts may be distinguishable from the FFM in some cultures. In lexical studies, two or three broad dimensions may replicate better across cultures than alternative models. Substantial evidence suggests that mean trait profiles of cultures may be reasonably accurate. Nonetheless, research on response styles and measurement invariance raises questions about cross-cultural trait comparisons. Findings regarding cultural differences in trait-related consistency and validity are mixed. Researchers are offering innovative theory and research on the evolutionary, ecological, and cultural contexts of personality. PMID- 29506799 TI - The cultural construction of emotions. AB - A large body of anthropological and psychological research on emotions has yielded significant evidence that emotional experience is culturally constructed: people more commonly experience those emotions that help them to be a good and typical person in their culture. Moreover, experiencing these culturally normative emotions is associated with greater well-being. In this review, we summarize recent research showing how emotions are actively constructed to meet the demands of the respective cultural environment; we discuss collective as well as individual processes of construction. By focusing on cultural construction of emotion, we shift the focus toward how people from different cultures 'do' emotions and away from which emotions they 'have'. PMID- 29506800 TI - The cultural evolution of language. AB - Human language has unusual structural properties that enable open-ended communication. In recent years, researchers have begun to appeal to cultural evolution to explain the emergence of these structural properties. A particularly fruitful approach to this kind of explanation has been the use of laboratory experiments. These typically involve participants learning and interacting using artificially constructed communication systems. By observing the evolution of these systems in the lab, researchers have been able to build a bridge between individual cognition and population-wide emergent structure. We review these advances, and show how cultural evolution has been used to explain the origins of structure in linguistic signals, and in the mapping between signals and meanings. PMID- 29506801 TI - Globalization and psychology. AB - In globalized societies, people often encounter symbols of diverse cultures in the same space at the same time. Simultaneous exposure to diverse cultures draws people's attention to cultural differences and promotes catergorical perceptions of culture. Local cultural identification and presence of cultural threat increase the likelihood of resisting inflow of foreign cultures (exclusionary reactions). When cultures are seen as intellectual resources, foreign cultural exposure affords intercultural learning and enhances individual creativity (integrative reactions). Psychological studies of globalization attest to the utility of treating cultures as evolving, interacting systems, rather than static, independent entities. PMID- 29506802 TI - Multicultural identity processes. AB - The study of multicultural identity has gained prominence in recent decades and will be even more urgent as the mobility of individuals and social groups becomes the 'new normal'. This paper reviews the state-of-the-art theoretical advancements and empirical discoveries of multicultural identity processes at the intrapersonal, interpersonal, and collective (e.g., organizational, societal) levels. First, biculturalism has more benefits for individuals' psychological and sociocultural adjustment than monoculturalism. Bicultural individuals' racial essentialist beliefs and Bicultural Identity Integration affect cultural frame switching, racial categorization, and creativity. Second, identity denial and identity-based discrimination by other people or groups threaten multicultural individuals' psychological health and performance. Third, multiculturalism and interculturalism policies are associated with different conceptions of and attitudes toward diversity, and have distinct outcomes for multicultural individuals and societies. PMID- 29506803 TI - Beyond East vs. West: social class, region, and religion as forms of culture. AB - In this article we seek to further broaden the focus of the psychological study of cultural differences beyond the predominant focus on ethnicity and nationality. We highlight ways that other forms of culture, including social class, region, and religion, sometimes have psychological consequences that parallel those of ethnicity and nationality, and are sometimes more unique. For example, we review recent work that working class culture is more interdependent, holistic, empathic, and vigilant; that regional cultures vary in honor, individualism, conformity, and tightness-looseness; and that religions differ in attributions, cognition, working styles, and the bases of morality. We conclude with some recommendations for future work on culture, including the origins of cultures, the multiple forms of culture, the uniqueness and similarities of cultures, and how multiple forms of culture interact. PMID- 29506804 TI - Current and future directions in culture and happiness research. AB - Once believed to be universal, a growing body of research shows that both the conception and predictors of happiness vary cross-culturally. First, the meaning and importance of happiness varies both across time and between nations. Americans, for instance, tend to define happiness in terms of pleasure or enjoyment and view happiness as universally positive, whereas East Asian and Middle Eastern cultures may highlight the transient and socially disruptive nature of happiness and be ambivalent about whether it is good. Second, predictors of happiness vary between cultures. Recent work highlights new mediators (e.g., relational mobility), individual predictors (e.g., person culture fit), societal factors (e.g., good governance and wealth), within-culture variations (e.g., at the state or city level), and interventions (e.g., practicing gratitude) that differ cross-culturally or help explain cultural differences in happiness. Though many questions remain, this review highlights how these recent advances broaden and revise our understanding of culture and happiness. PMID- 29506805 TI - Attachment. A pancultural need but a cultural construct. AB - Attachment theory can be considered as the most important theory for children's socioemotional development during the first years of life with substantial implications also for the application in clinical and educational fields. Attachment theory has been developed out of the prevailing Euro-American childcare philosophy and based on a selective review of knowledge available from different disciplines, including evolutionary theory, ethology, and systems theory. What is left out is systematic evidence for relationship formation beyond the exclusive dyadic Western mother-child format. Recent evidence published by cultural anthropologists, psychologists, and evolutionary theorists is discussed in this paper especially with respect to caregiving arrangements with multiple caregivers. It is concluded that there is not one model of relationship formation that is adaptive for all of the world's population. PMID- 29506806 TI - Cross-cultural leadership: leading around the world. AB - Situational models of leadership have been discussed since the mid-1960s. In this paper, we review the evidence concerning one such contextual variable, societal culture. The traditional cross-cultural literature shows how culture affects the kind of leadership characteristics, attributes, and behaviors desired and believed to be important in a society. The research also shows that culture moderates the outcomes resulting from different styles of leadership. The newly emerging global leadership literature focuses on leadership when followers are culturally diverse. We review the current state of these literatures and provide research suggestions. PMID- 29506807 TI - The relation between language, culture, and thought. AB - The relationship between culture, language, and thought has long been one of the most important topics for those who wish to understand the nature of human cognition. This issue has been investigated for decades across a broad range of research disciplines. However, there has been scant communication across these different disciplines, a situation largely arising through differences in research interests and discrepancies in the definitions of key terms such as 'culture,' 'language,' and 'thought.' This article reviews recent trends in research on the relation between language, culture and thought to capture how cognitive psychology and cultural psychology have defined 'language' and 'culture,' and how this issue was addressed within each research discipline. We then review recent research conducted in interdisciplinary perspectives, which directly compared the roles of culture and language. Finally, we highlight the importance of considering the complex interplay between culture and language to provide a comprehensive picture of how language and culture affect thought. PMID- 29506808 TI - The science of culture and negotiation. AB - Recent negotiation research has produced a groundswell of insights about the effects of culture on negotiation. Yet, few frameworks exist to organize the findings. This review integrates recent research using a two-dimensional framework: The first dimension organizes the research into that which has taken: (1) a comparative intracultural approach, versus (2) an intercultural approach. The second dimension organizes the research by its emphasis on: (1) inputs into negotiation, (2) processes of negotiating, and (3) outcomes of negotiation. This framework helps to organize extant research and produces novel insights about the connections between disparate research streams, revealing both commonalities and culture-specificities in negotiation strategy and outcomes and suggesting that intercultural negotiations are difficult but not insurmountable. We conclude by discussing several areas in which more research on culture and negotiation is urgently needed in today's globalizing world. PMID- 29506809 TI - Social change, cultural evolution, and human development. AB - Social change has accelerated globally. Greenfield's interdisciplinary and multilevel theory of social change and human development provides a unified framework for exploring implications of these changes for cultural values, learning environments/socialization processes, and human development/behavior. Data from societies where social change has occurred in place (US, China, and Mexico) and a community where it has occurred through international migration (Mexican immigrants in the US) elucidate these implications. Globally dominant sociodemographic trends are: rural to urban, agriculture to commerce, isolation to interconnectedness, less to more education, less to more technology, lesser to greater wealth, and larger to smaller families/households. These trends lead to both cultural losses (e.g., interdependence/collectivism, respect, tradition, contextualized thinking) and cultural gains (e.g., independence/individualism, equality, innovation, abstraction). PMID- 29506810 TI - Cultural dynamics. AB - Cultural dynamics can be characterized as macro-level phenomena of the stability and change in distribution of cultural information within a human population, and the micro-level mechanisms about the social transmission of cultural information that drive the trajectory of cultural formation, maintenance, and transformation. This article focuses on the micro-level mechanisms, which consist of the intrapersonal and interpersonal processes of production, grounding, interpretation, and memory of cultural information. The review of recent empirical research suggests that the cultural transmission tends to favour the retention of cultural information beneficial for the individual survival in the hunter-gatherer ecosystem, and collective action that supports a group living. PMID- 29506811 TI - Advancing acculturation theory and research: the acculturation process in its ecological context. AB - Continued intercultural contact leads to challenges and changes. As part of this process, the acculturating individual deals with acculturative stressors whose negative effects on well-being can be buffered or exacerbated by coping reactions. A second component of the acculturation process involves the acquisition, maintenance, and change of cultural behaviors, values and identities associated with heritage and settlement cultures. Both acculturative stress and acculturative change unfold in an ecological context. Within the family, acculturation discrepancies between parents and children affect acculturation trajectories and outcomes. At the institutional level, the school and workplace exert significant influences on the acculturation of young people and working adults, respectively. At the societal level attitudes, policies and prejudice affect the acculturation experiences of sojourners and immigrants and influence their psychological and socio-cultural adaptation. PMID- 29506812 TI - Editorial overview: Culture: Advances in the science of culture and psychology. PMID- 29506813 TI - Parallels in safety between aviation and healthcare. AB - Aviation and healthcare are complex industries and share many similarities: the cockpit and the operating theater, the captain and the surgeon. While North American commercial aviation currently enjoys a tremendous safety record, it was not always this way. A spike of accidents in 1973 caused 3214 aviation-related fatalities. Over the past 20years, the rate of fatal accidents per million flights fell by a factor of five, while air traffic increased by more than 86%. There have been no fatalities on a U.S. carrier for over 12years. Last year, there were 251,454 deaths in the United States owing to medical error. Pilots pioneered ways to address risks through crew resource management (CRM), and threat and error management (TEM). Both strategies, which are aimed at minimizing risk and optimizing safety, are applicable to surgery and the healthcare industry. These strategies as well as the Swiss Cheese Model, Checklists and the Normalization of Deviance will be reviewed in this article. PMID- 29506815 TI - Evaluating complication rates and outcomes among infants less than 5kg undergoing traditional percutaneous endoscopic gastrostomy insertion: A retrospective chart review. AB - PURPOSE: Percutaneous endoscopic gastrostomy (PEG) enables enteral nutrition for patients with inadequate oral intake. Laparoscopic guidance of PEG insertion is used for high-risk populations, including in infants less than 5kg at insertion. This study aimed to assess complication rates with traditional PEG tube insertion in infants less than 5kg at a single tertiary care center. METHODS: A retrospective review of patients less than 5kg who underwent PEG insertion was conducted. PEG insertion-related complications, up to four years following insertion, were collected. Outcomes were reported as counts and percentages, or median with minimum and maximum values. RESULTS: 480 pediatric gastrostomy procedures between January 1, 2009 and February 1, 2017, were screened, with 129 included for analysis. Median weight at PEG insertion was 3800g. Superficial surgical site infection (SSI) occurred in 6 (4.7%) patients, and 1 (0.8%) required readmission for intravenous antibiotics. One (0.8%) required endoscopic management for retained foreign body, 1 (0.8%) required operative management for gastrocolic fistula, and 1 (0.8%) for persistent gastrocutaneous fistula. No deep space SSI, procedure-related hemorrhage requiring readmission or transfusion, buried bumper syndrome, or procedure-related mortality occurred. CONCLUSION: Traditional PEG tube insertion in infants less than 5kg results in complication rates comparable to pediatric literature standards. LEVEL OF EVIDENCE: Level II, retrospective prognosis study. PMID- 29506814 TI - A simulated training model for laparoscopic pyloromyotomy: Is 3D printing the way of the future? AB - BACKGROUND: Hypertrophic pyloric stenosis (HPS) is a common neonatal condition treated with open or laparoscopic pyloromyotomy. 3D-printed organs offer realistic simulations to practice surgical techniques. The purpose of this study was to validate a 3D HPS stomach model and assess model reliability and surgical realism. METHODS: Medical students, general surgery residents, and adult and pediatric general surgeons were recruited from a single center. Participants were videotaped three times performing a laparoscopic pyloromyotomy using box trainers and 3D-printed stomachs. Attempts were graded independently by three reviewers using GOALS and Task Specific Assessments (TSA). Participants were surveyed using the Index of Agreement of Assertions on Model Accuracy (IAAMA). RESULTS: Participants reported their experience levels as novice (22%), inexperienced (26%), intermediate (19%), and experienced (33%). Interrater reliability was similar for overall average GOALS and TSA scores. There was a significant improvement in GOALS (p<0.0001) and TSA scores (p=0.03) between attempts and overall. Participants felt the model accurately simulated a laparoscopic pyloromyotomy (82%) and would be a useful tool for beginners (100%). CONCLUSION: A 3D-printed stomach model for simulated laparoscopic pyloromyotomy is a useful training tool for learners to improve laparoscopic skills. The GOALS and TSA provide reliable technical skills assessments. LEVEL OF EVIDENCE: II. PMID- 29506816 TI - Gastrocutaneous fistulae in children - A systematic review and meta-analysis of epidemiology and treatment options. AB - BACKGROUND: Gastrostomy tubes are a common adjunct to the care of vulnerable pediatric patients. This study systematically evaluates the epidemiology and risk factors for gastrocutaneous fistulae (GCF) after gastrostomy removal in children and reviews treatment options focusing on nonoperative management (NOM). METHODS: After protocol registration (CRD-42017059565), multiple databases were searched. Studies describing epidemiology in children and GCF treatment at any age were included. Critical appraisal was performed (MINORS risk-of-bias assessment tool). One-sided meta-analysis was executed to estimate efficacy of therapeutic adjuncts using a random-effects model. RESULTS: Sixteen articles evaluating pediatric GCF were identified. 44% defined GCF as persistence >1month which occurred in 31+/-7% of cases. Risk factors for pediatric GCF include age at gastrostomy, timing of removal, open technique, and fundoplication. Mean MINORS score was 0.60+/-0.16. Seventeen additional studies were identified reporting 142 patients undergoing NOM (endoscopic, systemic, and local therapies), and one pediatric comparative study was identified. Overall aggregate proportion of GCF closure after any NOM is 77% (80% success rate in local/systemic therapies; 75% success rate in endoscopic approaches). No adverse events were reported. CONCLUSION: Persistent GCF complicates the management of gastrostomies in 1/3 of children with predictable risk factors. Several treatment options exist that obviate the need for general anesthesia. Their efficacy is unclear. Further prospective investigations are clearly warranted. LEVEL OF EVIDENCE: III - Systematic Review and Meta-Analysis Based on Retrospective Case Control Studies. PMID- 29506818 TI - Metabolomic profiling of women with gestational diabetes mellitus and their offspring: Review of metabolomics studies. AB - BACKGROUND: Gestational diabetes mellitus (GDM) reflects an increased risk of developing type 2 diabetes (T2D) after pregnancy in women. Offspring born to mothers with GDM are at an elevated risk of obesity and T2D at a young age. Currently, there are lack of ways for identifying women in early pregnancy who are at risk of developing GDM. As a result, both mothers and fetus are not treated until late in the second trimester when GDM is diagnosed. The recent advance in metabolomics, a new approach of systematic investigation of the metabolites, provides an opportunity for early detection of GDM, and classifying the risk of subsequent chronic diseases among women and their offspring. METHODS: We reviewed the literatures published in the past 20 years on studies using high throughput metabolomics technologies to investigate women with GDM and their offspring. CONCLUSIONS: Despite the inconsistent results, previous studies have identified biomarkers that involved in specific metabolite groups and several pathways, including amino acid metabolism, steroid hormone biosynthesis, glycerophospholipid metabolism, and fatty acid metabolism. However, most studies have small sample sizes. Further research is warranted to determine if metabolomics will result in new indicators for the diagnosis, management, and prognosis of GDM and related complications. PMID- 29506817 TI - Results after laparoscopic partial splenectomy for children with hereditary spherocytosis: Are outcomes influenced by genetic mutation? AB - BACKGROUND: Laparoscopic partial splenectomy (LPS) theoretically maintains long term splenic immune function for children with hereditary spherocytosis (HS). Our goal was to review our results after LPS and to determine if specific genetic mutations influence outcome. METHODS: All children with HS undergoing LPS between 2005 and 2016 were reviewed. RESULTS: Thirty-one children underwent LPS (16 male) at a median age of 9 (range 2-18) years. All experienced an increase in hemoglobin and decrease in reticulocyte count early after LPS and at last follow up. Twenty-two were sent for genetic analysis. Mutations in alpha-spectrin, beta spectrin, and Ankyrin were identified in 6, 5, and 11 patients, respectively. Gene mutation was not correlated with complications, perioperative transfusion, length of hospital stay, or median hemoglobin, platelet, or reticulocyte counts. Three children required completion splenectomy at 10.9, 6.9, and 3.2years post LPS, each with a different gene mutation. CONCLUSIONS: LPS is effective in reversing anemia and reducing reticulocytosis. So far less than 10% have required completion splenectomy, and those children did benefit from delaying the risks of asplenia. In this preliminary analysis, genetic mutation did not influence outcome after LPS. A larger multicenter study is necessary to further investigate potential correlations with specific genetic mutations. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: IV. PMID- 29506819 TI - The Value of Supine Chest X-Ray in the Diagnosis of Pneumonia in the Basal Lung Zones. AB - RATIONALE AND OBJECTIVES: Basal lung opacities are frequently observed on supine chest x-ray (SCXR) of intensive care patients, causing insecurity among clinicians and radiologists. We sought to determine the diagnostic accuracy of SCXR for basal pneumonia. MATERIALS AND METHODS: We identified 172 patients who received both SCXR and computed tomography within 1 hour. Two readers examined the SCXR and rated findings in both basal zones according to the following scale: 0 = "no pneumonia," 1 = "possible pneumonia," 2 = "highly suspected pneumonia." Computed tomography served as standard of reference. Sensitivity, specificity, and positive and negative predictive values (PPV/NPV) were calculated once pooling 0 and 1 as negative and once pooling 1 and 2 as positive finding. RESULTS: When pooling 0 and 1 as negative, sensitivity was 0.45 (right)/0.38 (left), specificity was 0.94/0.97, PPV was 0.76/0.79, and NPV was 0.81/0.84. When pooling 1 and 2 as positive, sensitivity was 0.80/0.75, specificity was 0.62/0.58, PPV was 0.45/0.35, and NPV was 0.88/0.89. The most common findings in false-positive cases were combined pleural effusions and lower lobe atelectasis. CONCLUSIONS: Interpreting only highly suspicious basal opacities as pneumonia considerably increases the PPV with almost constant NPV. Clinicians and radiologists should be aware of the limitations of SCXR regarding basal pneumonia. PMID- 29506820 TI - Tandem repeated expression of lunasin gene in Pichia pastoris and its anti inflammatory activity in vitro. AB - Lunasin is a novel promising health-beneficial peptide derived from soybean. However, the application of lunasin is limited by its high cost. In this study, we developed a successful protocol for expression of a dimer formation protein containing 4 tandem repeated lunasin analogs (lunasin-4) in Pichia pastoris. The expression level at the optimal condition (initial pH 7.0, 1.0% final methanol concentration and induction for 72 h at 26 degrees C) was 0.24 mg/mL cell-free broth. Lunasin analog, obtained from purified lunasin-4 protein through enterokinase digestion and ultrafiltration, significantly decreased (p < 0.05) the release of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in a dose-dependent manner. In addition, intracellular signaling array analysis demonstrated down-regulated levels of phosphorylated Akt, mechanistic target of rapamycin (mTOR) and p70 s6 kinase (p70s6k) and an up-regulated level of glycogen synthase kinase-3beta (GSK-3beta) after lunasin analog treatment. These results suggest that lunasin analog exerted anti-inflammatory activities in LPS stimulated RAW264.7 cells partly via inhibiting the activation of Akt/mTOR/p70s6k signaling pathway. In conclusion, this study provides a potential strategy for recombinant production of bioactive lunasin in industry. PMID- 29506821 TI - Movement disorders associated with neurocysticercosis. PMID- 29506822 TI - Restlessness restricted to the perianal region in a patient with Parkinson's disease. PMID- 29506823 TI - Are submarine groundwater discharges affecting the structure and physiological status of rocky intertidal communities? AB - This study evaluated the impacts of submarine groundwater discharges (SGD) on a rocky intertidal community of South Portugal, during April-November 2011. Chlorophyll-a concentration was higher at the SGD site in respect to the Reference site. Epibenthic community structure differed between sites, with an increase in Chthamalus spp. and a decrease in macroalgae coverage at the SGD site. The abundance and body size of Mytilus galloprovincialis were consistently higher at the SGD site. During mid-spring, under potentially higher SGD and less favorable conditions for coastal phytoplankton, the ecophysiological condition of M. galloprovincialis and G. umbilicalis was also higher at the SGD site. These beneficial effects on filter-feeders and herbivores probably resulted from local increases in prey availability, supported by SGD-driven nutrient inputs. Conversely, P. depressa was not favoured by SGD, probably due to a lower dependency on algae as food. The analysis of epibenthic community structure and ecophysiological condition represents a promising approach to disentangle the ecological impacts of SGD on intertidal ecosystems. PMID- 29506824 TI - Single-site robotic cholecystectomy and robotics training: should we start in the junior years? AB - BACKGROUND: It has become increasingly important to expose surgical residents to robotic surgery as its applications continue to expand. Single-site robotic cholecystectomy (SSRC) is an excellent introductory case to robotics. Resident involvement in SSRC is known to be feasible. Here, we sought to determine whether it is safe to introduce SSRC to junior residents. MATERIALS AND METHODS: A total of 98 SSRC cases were performed by general surgery residents between August 2015 and August 2016. Cases were divided into groups based on resident level: second- and third-years (juniors) versus fourth- and fifth-years (seniors). Patient age, gender, race, body mass index, and comorbidities were recorded. The number of prior laparoscopic cholecystectomies completed by participating residents was noted. Outcomes including operative time, console time, rate of conversion to open cholecystectomy, and complication rate were compared between groups. RESULTS: Juniors performed 54 SSRC cases, whereas seniors performed 44. There were no significant differences in patient age, gender, race, body mass index, or comorbidities between the two groups. Juniors had less experience with laparoscopic cholecystectomy. There was no significant difference in mean operative time (92.7 min versus 98.0 min, P = 0.254), console time (48.7 min versus 50.8 min, P = 0.639), or complication rate (3.7% versus 2.3%, P = 0.68) between juniors and seniors. CONCLUSIONS: SSRC is an excellent way to introduce general surgery residents to robotics. This study shows that with attending supervision, SSRC is feasible and safe for both junior and senior residents with very low complication rates and no adverse effect on operative time. PMID- 29506825 TI - Neighborhood socioeconomic disadvantage is not associated with wound healing in diabetic foot ulcer patients treated in a multidisciplinary setting. AB - BACKGROUND: Socioeconomic deprivation is associated with poor glycemic control and higher hospital admission rates in patients with diabetes. We sought to quantify the effects of neighborhood socioeconomic deprivation on wound healing among a cohort of patients with diabetic foot ulceration (DFU) treated in a multidisciplinary setting. METHODS: Socioeconomic disadvantage was calculated for all patients using the area deprivation index (ADI) stratified by quartile (from ADI-0: least through ADI-3: most). Predictors of wound healing were assessed using Cox proportional hazards models accounting for patient demographics, wound characteristics, and ADI category. RESULTS: Six hundred twenty-one wounds were evaluated, including 59% ADI-0, 7% ADI-1, 12% ADI-2, and 22% ADI-3. After accounting for patient demographics and wound characteristics, the likelihood of wound healing was similar between groups (ADI-3 versus ADI-0: hazards ratio [HR] 1.03 [95% confidence interval 0.76-1.41]). Independent predictors of poor wound healing included peripheral arterial disease (HR 0.75), worse wound stage (stage 4: HR 0.48), larger wound area (HR 0.99), and partially dependent functional status (HR 0.45) (all, P < 0.05). CONCLUSIONS: In a multidisciplinary setting, wound healing was largely dependent on wound characteristics and vascular status rather than patient demographics or neighborhood socioeconomic disadvantage. Use of a multidisciplinary approach to the management of DFU may overcome the negative effects of socioeconomic disadvantage frequently described in the diabetic population. PMID- 29506826 TI - Nonresponse bias in survey research: lessons from a prospective study of breast reconstruction. AB - BACKGROUND: Survey-based research is essential for evaluating the outcomes of health care in an era of patient-centered care. However, many such studies are hampered by poor response rates in completion of study questionnaires, thus limiting the generalizability of any findings. The objectives of this analysis were to identify independent variables associated with nonresponse to surveys following breast reconstruction to improve future patient-reported outcomes research. MATERIALS AND METHODS: The Mastectomy Reconstruction Outcomes Consortium is a prospective cohort study involving 11 leading medical centers from the United States and Canada. Nonresponse rates for surveys assessing satisfaction with breast, satisfaction with care (BREAST-Q), depression (Patient Health Questionnaire-9), and anxiety (Generalized Anxiety Disorder-7) were measured at 1 y and 2 y postoperatively. Clinical complication rates were compared between responders and nonresponders, and multivariable models were used to assess predictors of nonresponse. RESULTS: Among 2856 women in the analytic cohort, 1882 (65.9%) underwent implant-based, 817 (28.6%) received autologous, and 157 (5.5%) underwent latissimus dorsi myocutaneous flap breast reconstructions. Nonresponse rates to surveys at 1 y and 2 y were 27.8% and 34.4%, respectively. Race, ethnicity, and annual household income were associated with nonresponse to surveys. Women who underwent implant-based procedures were less likely to complete long-term surveys. CONCLUSIONS: As survey-based research plays an increasingly prominent role in evaluating the outcomes of breast reconstruction, we found socioeconomic and procedure-related differences in survey response rates. Investigators must consider systematic differences in response rates among particular groups of women on the generalizability and validity of findings and perform rigorous nonresponse bias analyses. PMID- 29506828 TI - Effect of the vascularized bone components on the survival of vascularized composite allografts. AB - BACKGROUND: Vascularized composite allograft (VCA), such as hand and face allograft, contains a vascularized bone component that may provide an immunologic benefit and induce tolerance for the simultaneous inclusion of marrow cells and a marrow microenvironment. We developed a chimeric groin cutaneous/femur flap to investigate the effect of vascularized bone marrow on VCA survival and its ability to induce chimerism. METHODS: Brown Norway and Lewis rats were used as donors and recipients, respectively. The experimental groups were as follows: groin flap transplantation alone, flap plus intravenous donor bone marrow cells and flap plus simultaneous femur transplantation. Animals received a nonmyeloablative conditioning regimen that consisted of 7-Gy thymic irradiation, 0.75-mL antilymphocyte serum, and 8-mg-1kg-1d cyclosporine A. The flap survival time, peripheral blood chimerism, and the bone marrow of transplanted femurs were analyzed and compared between groups. RESULTS: Our data showed that the conditioning regimen was effective in T cell ablation. Simultaneous femur transplantation significantly prolonged the median flap survival time (78.8 +/- 13.0 d, n = 8) compared with the intravenous bone marrow infusion group (60.9 +/- 2.2 d, n = 7) and the control group (58.6 +/- 1.3 d, n = 5). Peripheral blood chimerism of 5.81% +/- 1.98% was persistently detected for 60 d in recipients of femur transplants but not in the other two groups. Viable bone marrow was confirmed within the transplanted femur on postoperative d 60, but it was gradually replaced by recipient origin cells and eventually developed rejection and fibrosis. CONCLUSIONS: Vascularized bone component plays some protective roles on VCA survival but fails to provide a continuous source of donor cells. PMID- 29506829 TI - Response to Letter to the Editor: the use of high-flow nasal cannula during extubation. PMID- 29506827 TI - Characterizing the relationship between flow-mediated vasodilation and radial artery tonometry in peripheral artery disease. AB - BACKGROUND: Arterial stiffness, measured by the augmentation index (AIX) from radial artery tonometry, and endothelial dysfunction, measured by brachial-artery flow-mediated vasodilation (FMD), have each been associated with increased risk of cardiovascular events. However, their interrelationship in peripheral artery disease (PAD) patients is poorly understood. MATERIALS AND METHODS: In a cross sectional analysis of 123 vascular surgery outpatients, the association between FMD and AIX was examined in controls with atherosclerotic risk factors (n = 32) and patients with PAD (n = 91). PAD was defined as claudication symptoms with an ankle-brachial index of <0.9 or a history of revascularization for symptomatic PAD. Controls had an ankle-brachial index >=0.9 and no history of atherosclerotic vascular disease. RESULTS: Compared to controls, patients with PAD had lower FMD (6.3 +/- 3.8 versus 8.4 +/- 3.7, P = 0.008), while central AIX normalized to 75 beats per minute (25.5 +/- 9.0 versus 19.3 +/- 8.6, P = 0.001) and peripheral AIX (91.3 +/- 14.5 versus 81.3 +/- 11.4, P = 0.001) were higher. FMD was not significantly correlated with either central or peripheral AIX (central AIX: P = 0.58; peripheral AIX: P = 0.89) across the entire cohort, or in either the patients with PAD (central AIX: P = 0.48; peripheral AIX: P = 0.23) or controls (central AIX: P = 0.43; peripheral AIX: P = 0.92). In a multivariate model including FMD, higher AIX remained independently associated with PAD. CONCLUSIONS: In an analysis of vascular surgery outpatients, no correlation between FMD and AIX was detected. Larger prospective studies are needed to determine whether the inclusion of both parameters improves predictive models for the early identification and potential risk stratification of PAD patients. PMID- 29506830 TI - Impact of early positive cultures in the elderly with traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States, especially in the elderly, who have the highest rates of TBI-related hospitalizations and deaths among all age groups. Sepsis is one of many risk factors that is associated with higher mortality and longer length of hospital stay in this population partially due to the immunosuppressive effects of TBI. The significance of early indicators of infection, such as a positive blood, sputum, or urine culture, is not well described. The purpose of this study was to determine if early positive cultures predict higher mortality in elderly patients with TBI. METHODS: All trauma patients aged >=65 years with TBI, admitted between January 1, 2009 and December 31, 2013 to the surgical intensive care unit, were retrospectively reviewed. Clinical data including results from sputum, blood, and urine cultures were reviewed. RESULTS: Overall, 288 elderly patients with TBI were identified, and 92 (32%) had a positive culture. Patients with positive cultures had longer intensive care unit (median 6.0 versus 2.0 days, P < 0.001) and ventilation days (median 7.0 versus 2.0 days, P < 0.001). Patients who had positive cultures within 2-3 days of admission had a higher adjusted hazard ratio for mortality than those patients who had positive cultures after 6 or more days. CONCLUSIONS: In elderly patients with TBI, early positive cultures are associated with a higher risk of mortality. Further research is required to determine the role of obtaining cultures on admission in this subpopulation of trauma patients. PMID- 29506831 TI - The use of high-flow nasal cannula during extubation. PMID- 29506832 TI - Umbilical mesenchymal stromal cells provide intestinal protection through nitric oxide dependent pathways. AB - BACKGROUND: Umbilical-derived mesenchymal stromal cells (USCs) have shown promise in the protection of ischemic organs. We hypothesized that USCs would improve mesenteric perfusion, preserve intestinal histological architecture, and limit inflammation by nitric oxide-dependent mechanisms following intestinal ischemia/reperfusion (IR) injury. METHODS: Adult wild-type C57BL/6J (WT) and endothelial nitric oxide synthase knock out (eNOS KO) mice were used: (1) WT IR + vehicle, (2) WT IR + USC, (3) eNOS KO IR + vehicle, and (4) eNOS KO IR + USC. Mice were anesthetized, and a midline laparotomy was performed. The superior mesenteric artery was clamped with a nonoccluding clamp for 60-min. Following IR, mice were treated with an injection of 250 MUL phosphate buffered saline or 2 * 106 USCs suspended in 250-MUL phosphate buffered saline solution. Mesenteric perfusion images were acquired using laser Doppler imaging. Perfusion was analyzed as a percentage of baseline. At 24 h, mice were euthanized, and intestines were harvested. Intestines were evaluated for injury, and data were analyzed using the Mann-Whitney or Kruskal-Wallis tests. RESULTS: Intestinal mesenteric perfusion was significantly improved in WT mice treated with USC therapy compared with eNOS KOs. Intestinal histological architecture was preserved with USC therapy in WT mice. However, in eNOS KO mice, this benefit was abolished. Finally, the presence of several cytokines and growth factors were significantly improved in WT mice compared with eNOS KO mice treated with USCs. CONCLUSIONS: The benefits of USC-mediated therapy following intestinal IR injury likely occur via nitric oxide-dependent pathways. Further studies are required to define the molecular mechanisms by which USCs activate endothelial nitric oxide synthase to bring about their protective effects. PMID- 29506833 TI - Subcutaneous cefazolin to reduce surgical site infections in a porcine model. AB - BACKGROUND: Surgical site infections (SSIs) pose a significant health and financial burden. A key aspect of appropriate prophylaxis is the administration of antibiotics intravenously (IV). However, subcutaneous administration of antibiotics is not well described in the literature. During surgery, we hypothesize that subcutaneous injection may provide better protection against SSIs. To better understand the kinetics after subcutaneous injection, we describe the serum concentrations of cefazolin in a porcine model. MATERIALS AND METHODS: Juvenile mini-Yucatan pigs were administered 20 mL of 25 mg/kg cefazolin subcutaneously, and serial blood samples were taken for 3 h. Blood samples were analyzed for cefazolin concentration using chromatography. Pharmacokinetic data were calculated based on the blood serum concentrations. RESULTS: Maximum serum concentrations of cefazolin were achieved 42.6 +/- 2.0 min after the time of injection and were found to be 18.8 +/- 7.4 MUg/mL. The elimination rate constant was 0.0033 +/- 0.0016 min-1 and the half-life was 266 +/- 149 min. The area under the curve was 4940 +/- 1030 MUg * min/mL. The relative bioavailability of subcutaneous injection was 95% +5%/-20%. CONCLUSIONS: Subcutaneous administration of cefazolin achieves a significantly lower maximum serum concentration than IV injection. As a result, higher doses of antibiotic can be injected locally without incurring systemic toxicity. Subcutaneous administration will therefore result in higher concentrations of antibiotic for a longer time at the incision site compared with standard IV administration. This strategy of antibiotic delivery may be more effective in preventing SSIs. Further studies are needed to detail the exact effect of subcutaneous antibiotic injection on SSI rates. PMID- 29506834 TI - Socioeconomic disparities in the thoracic trauma population. AB - BACKGROUND: Health-care disparities based on socioeconomic status have been well documented in the trauma literature; however, there is a paucity of data on how these factors affect outcomes in patients experiencing severe thoracic trauma. This study aims to identify the effect of insurance status and race on patient mortality and disposition after thoracic trauma. METHODS: The National Trauma Data Bank was queried from 2007 to 2012 for patients with sternal fractures, rib fractures, and flailed chest. Demographics data were examined for the cohort based on insurance status. Univariate and multivariate logistic regression models were used, controlling for patient comorbidities, age, injury severity score, and associated injuries, to determine the impact of race and insurance status on length of stay, mortality, and discharge disposition. RESULTS: A total of 152,655 thoracic traumas were included in our analysis. As compared to privately insured patients, uninsured patients with thoracic trauma were 1.9 times more likely to die (odds ratio [OR]: 1.91, confidence interval [CI]: 1.76-2.09) and 4.6 times more likely to leave against medical advice (OR: 4.61, CI: 3.14-6.79). When compared to Caucasians, Hispanics had slightly higher in-hospital mortality (OR: 1.14, CI: 1.02-1.27), but there was no survival difference seen in black patients (OR: 0.95, CI: 0.86-1.05). CONCLUSIONS: Insurance status appears to have a more significant effect on thoracic trauma patient outcomes than race, but substantial socioeconomic disparities were seen in this patient population. Further studies are needed to show reproducibility of our findings and to investigate the impact of universal health care and expansion of insurance availability on thoracic trauma outcomes. LEVEL OF EVIDENCE: Level 3, economic/decision. PMID- 29506835 TI - Attrition in general surgery residency: can global and rural surgery shift the paradigm? AB - General surgery is one of the more popular career choices among medical students worldwide. An alarming one in five general surgery residents, however, abandon residency training-a rate that is much higher than most other medical and surgical specialities. We believe that additional measures are needed to decrease attrition and increase "grit" among house staff. Specifically, the diversification of the surgery training experience to include global and rural surgery may help mitigate burnout among surgical house staff. PMID- 29506836 TI - Parathyroidectomy decreases neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios. AB - BACKGROUND: Systemic inflammation has been implicated in complications and heightened mortality of patients with secondary hyperparathyroidism. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are widely available surrogate markers of inflammation. This study sought to delineate the changes in NLR and PLR after parathyroidectomy. METHODS: A total of 213 patients undergoing initial parathyroidectomy from 2010 to 2015 for secondary hyperparathyroidism were identified from a prospectively maintained clinical database. Among 183 patients free of persistent or recurrent disease, follow-up NLR and PLR were available for analysis in 85 patients. RESULTS: In the whole study population, the baseline NLR was positively correlated with male sex, total white blood cell count, height, serum phosphorus, and calcium-phosphorus product levels. The baseline PLR was positively correlated with platelet count, serum phosphorus, and calcium-phosphorus product levels and negatively associated with patient age. Postoperative parathyroid hormone levels were positively correlated with NLR and PLR at follow-up. For patients who had successful parathyroidectomy, there was a decrease in NLR (P = 0.0006), PLR (P = 0.0003), and platelet count (P = 0.033), whereas hemoglobin significantly increased (P = 0.0002) after surgery. Those with persistent or recurrent hyperparathyroidism had no change in NLR, PLR, hemoglobin, total white blood cell, or platelet count. CONCLUSIONS: Successful parathyroidectomy is associated with a decrease in NLR and PLR. The modulatory effects of parathyroidectomy on systemic inflammation may partially explain the benefits of surgery in secondary hyperparathyroidism. PMID- 29506837 TI - Predictors of 30-day readmissions after gastrectomy for malignancy. AB - BACKGROUND: The objective of this study is to identify risk factors associated with readmission after gastrectomy to potentially identify potential areas for targeted improvements. Hospital readmission after surgery is a topic of interest in health-care policy among hospitals, payers, and providers. Readmissions are associated with increased costs, morbidity, and mortality. Readmission rates have been proposed as a quality metric for hospitals and quality indicator of individual surgeon's performance. In addition, the Centers for Medicare and Medicaid Services has reduced payments to hospitals with excessive readmissions for certain diagnoses. MATERIALS AND METHODS: All gastrectomy procedures for malignancy in patients aged >=18 y from 2005 to 2011 were queried from the California State Inpatient Database. Patients who died during index admission were excluded. Descriptive statistics were examined between all baseline variables and readmission status. Logistic regression models were adjusted for age, race, sex, and insurance status. RESULTS: A total of 6985 patients underwent gastrectomy for malignancy; 16.5% of the patients were readmitted after postoperative discharge. Readmission rate did not change significantly over time. Multivariable analysis demonstrated that the occurrence of any postoperative complications, postoperative length of stay greater than 10 d, discharge to skilled nursing facility or home health care, combined resection with distal pancreatectomy and/or splenectomy, and patient comorbidities like diabetes mellitus and renal failure were independently associated with readmissions. CONCLUSIONS: The findings suggest that focusing on quality improvement efforts by targeting reduction of postoperative complications may reduce readmission rates. PMID- 29506838 TI - Safety of long-distance transfers of patients on acute mechanical circulatory support. AB - BACKGROUND: Acute mechanical circulatory support (aMCS) can be a lifesaving therapy for patients with refractory cardiogenic shock. As device safety and technology improve, so will the ability to extend aMCS to patients at remote hospitals. The Intermountain West is unique because of the large geographical area, making transport of critically ill patients a logistical challenge. METHODS: We reviewed our experience of transporting patients in cardiogenic shock over long distances who had already been placed on aMCS: Impella and extracorporeal membrane oxygenator devices. Survival data was compared to international benchmark data published by the Extracorporeal Life Support Organization. RESULTS: A total of 11 patients (91% male; mean age 56 +/- 5.4 y) were transported via fixed-wing aircraft to our center. The etiology of cardiogenic shock was ST-elevation myocardial infarction (n = 4), acutely decompensated chronic systolic heart failure (n = 4), postcardiotomy shock (n = 2), and acute myocarditis (n = 1). Average transport distance was 364 +/- 139 miles (585 +/- 264 km) and flight time was 170 +/- 29 min. All patients were safely transported with no in-transit adverse events. The average duration of aMCS was 6.4 +/- 3.3 d. Six patients (54.5%) survived to device explantation and 3 (27.2%) survived to hospital discharge. For comparison, Extracorporeal Life Support Organization benchmark data for adult cardiogenic shock patients report 56% survival to device explantation and 41% to hospital discharge. CONCLUSIONS: Patient transport with aMCS over long distances can be done safely without serious adverse events using good protocols and well-trained personnel. Although survival data are slightly below benchmark data, they appear reasonable, given the severity of illness and challenges of transferring critically ill patients to an expert center. PMID- 29506839 TI - Does industry funding mean more publications for subspecialty academic plastic surgeons? AB - BACKGROUND: Conflict of interest among physicians in the context of private industry funding led to the introduction of the Physician Payments Sunshine Act in 2010. This study examined whether private industry funding correlated with scholarly productivity in the respective subspecialties of plastic surgery and the wider academic plastic surgery community. MATERIALS AND METHODS: Full-time plastic surgeons and their academic attributes were identified via institutional websites. Fellowship-trained individuals were segregated into subspecialties of microsurgery, craniofacial surgery, hand surgery, esthetic surgery, and burn surgery. The Center for Medicare and Medicaid Services Open Payment database was used to extract industry funding information. Each individual's bibliometric data were then collected through Scopus to determine the correlation between selected surgeon characteristics, academic productivity, and industry funding. RESULTS: Nine hundred and thirty-five academic plastic surgeons were identified, with 532 having defined subspecialty training. Academic bibliometrics among subspecialty surgeons were comparable among the five groups with esthetic and craniofacial surgeons displaying a preponderance of attaining more industry funding (P = 0.043) and career publications respectively, with the latter not attaining statistical significance (P = 0.12). Overall, research-specific funding (P = 0.014) and higher funding amounts (P < 0.0001) correlated with higher Hirsch indices in tandem with higher academic rank. A funding level of $2000 appeared to be the approximate cutoff above which scholastic productivity became apparent. CONCLUSIONS: Our study demonstrated in detail the association between industry funding and academic bibliometrics in academic plastic surgery of every subspecialty. Even at modest amounts, industry support, especially when research designated, positively influenced research and therefore, academic output. PMID- 29506840 TI - Analysis of factors affecting successful microcoil localization for pulmonary nodules. AB - BACKGROUND: This study aimed to investigate the factors affecting successful microcoil localization for subsequent thoracoscopic resection of pulmonary small nodules and ground-glass nodules. Microcoil has been useful for preoperative localization. Nevertheless, microcoil may dislocate before video-assisted thoracoscopic surgery. METHODS: The medical data of patients with pulmonary solid nodules and ground-glass nodules, who underwent computed tomography-guided microcoil localization before thoracoscopic surgery, were retrospectively reviewed. Factors including clinical data, imaging data, surgical data, and technical data of microcoil localization were collected for stepwise logistic regression analysis. RESULTS: A total of 206 nodules in 192 patients were included in this study. Microcoil dislocation was identified on video-assisted thoracoscopic surgery exploration in six patients (2.9%), resulting in a successful localization rate of 97.1%. The insertion depth of Chiba needle, transfissure needle tract, and pneumothorax after localization were implicated as significant factors for successful microcoil localization. Based on logistic regression, the insertion depth of Chiba needle and pneumothorax after localization were identified as the independent factors for successful microcoil localization. CONCLUSIONS: The insertion depth of Chiba needle and pneumothorax after localization were the independent factors affecting successful microcoil localization for subsequent thoracoscopic resection. Special care should be taken in terms of the sufficient insertion depth of Chiba needle during microcoil localization and the risk of dislocation. PMID- 29506841 TI - Impact of angiotensin-converting enzyme 2 levels on postoperative pneumonia after esophagectomy. AB - BACKGROUND: Pulmonary complications after esophagectomy are often fatal. The prediction of postoperative pulmonary complications remains a challenge. Accumulating evidence demonstrates a physiological and pathological role for angiotensin-converting enzyme 2 (ACE2) in the respiratory system. The purpose of this study was to evaluate the predictive value of ACE2 levels for the development of postoperative pneumonia. METHODS: To evaluate the association between serum ACE2 levels and pneumonia after esophagectomy, we retrospectively reviewed the medical records of 80 patients who underwent thoracoscopic esophagectomy for esophageal cancer from 2009 to 2014. RESULTS: Nineteen patients (23.8%) developed pneumonia after esophagectomy. Patients with pneumonia had significantly higher levels of ACE2 from the preoperative day to postoperative day (POD) 3, white blood cell count (POD7), and C-reactive protein (POD3, POD5, and POD7) than patients without pneumonia. Patients with postoperative pneumonia had higher serum ACE2 levels on POD3 than patients without pneumonia. CONCLUSIONS: The elevation of ACE2 levels on POD3 may predict the incidence of pneumonia. PMID- 29506842 TI - Evaluation of the fluid responsiveness in patients with septic shock by ultrasound plus the passive leg raising test. AB - BACKGROUND: Prompt, accurate, and noninvasive prediction of fluid responsiveness is still lacking in intensive care unit. This study is to investigate the value of the Doppler ultrasound evaluation of variation in brachial artery peak velocity (VVpeakbrach) and passive leg raising (PLR)-induced changes in the brachial artery peak velocity (DeltaVpeakPLR) in predicting the fluid responsiveness in mechanically ventilated patients with severe sepsis or septic shock. METHODS: A prospective study was conducted involving 62 patients. Semirecumbent positioning, PLR, and a return to the semirecumbent position were performed with all patients before volume expansion. VVpeakbrach, DeltaVpeakPLR, and stroke volume were observed by Doppler ultrasound. A patient with an increase of >=15% in the stroke volume on volume expansion was defined as a responder. The predictive value was evaluated on the receiver operating characteristic curve analysis. RESULTS: A total of 28 patients were classified as responders. The area under the receiver operating characteristic curve of DeltaVpeakPLR and VVpeakbrach was 0.898 and 0.891, respectively. A DeltaVpeakPLR value of more than 10.6% predicted the fluid responsiveness with a sensitivity of 82.1% and a specificity of 88.2%. A VVpeakbrach value of more than 10.95% predicted the fluid responsiveness with a sensitivity of 78.6% and a specificity of 91.2%. The positive predictive value was 94.4% when both were positive. In contrast, the negative predictive value was 96.6%. CONCLUSIONS: Doppler ultrasound evaluation of VVpeakbrach and DeltaVpeakPLR could be a feasible method for the noninvasive assessment of fluid responsiveness in mechanically ventilated patients with severe sepsis or septic shock. The combination of two indicators can improve the predictive value. PMID- 29506843 TI - Pathologic response following treatment for locally advanced rectal cancer: Does location matter? AB - BACKGROUND: Despite advances in the treatment of rectal adenocarcinoma, the management of locally advanced disease remains a challenge. The standard of care for patients with stages II and III rectal cancer includes neoadjuvant chemoradiation followed by total mesorectal excision and postoperative chemotherapy. Much effort has been dedicated to the identification of predictive factors associated with pathologic complete response (pCR). The aim of our study was to examine our institutional experience and determine whether any association exists between anatomic tumor location and the rate of pCR. We hypothesized that lesions more than 6 cm from the anal verge are more likely to achieve a pCR. METHODS: Using data from our prospectively maintained tumor registry, a query was completed to identify all patients with locally advanced rectal adenocarcinoma who underwent treatment at Fox Chase Cancer Center from 2002 to 2015. Demographics, pretreatment, posttreatment, and final pathologic TNM staging data were collected as well as treatment intervals in days, recurrence status, overall survival, and disease-free survival. Patients with incomplete endoscopic data, staging information, survival, or recurrence status were excluded. The primary outcome measured was the degree of pathologic response. Logistic regression was used to adjust for covariates. RESULTS: Of the 135 patients eligible in the study cohort, 39% were female and 61% were male. Regarding initial clinical stage, 43% were stage II and 57% were stage III. A total of 29% had a pCR, 43% had partial pathologic response, and 28% had no response to neoadjuvant treatment. Tumor location ranged from 0 to 13 cm from the anal verge. Longitudinal tumor length was recorded in 111 patients, facilitating the calculation of mean tumor distance from the anal verge. This ranged from 0 to 15.5 cm. Univariate and multivariable analyses were completed using pCR as a primary outcome. No statistically significant difference was noted based on tumor location, regardless of measurement approach. CONCLUSIONS: Anatomic location of cancer of the rectum does not affect pCR after neoadjuvant therapy and subsequent surgical resection. PMID- 29506844 TI - Time course study of intestinal epithelial barrier disruption in acute mesenteric venous thrombosis. AB - BACKGROUND: Acute superior mesenteric venous thrombosis (ASMVT) is an abdominal vascular condition. Early recanalization is essential to successful treatment. The aim of the study was to establish rabbit models of ASMVT and assess the time course of intestinal epithelial barrier disruption. METHODS: After surgical exposure of superior mesenteric vein (Sham group), large-vessel (L-group) and small-vessel (S-group) models were established by endothelium damage, stenosis creation, and thrombin injection. At baseline, 6, 9, and 12 h, hemodynamic and serum parameters were tested. Serum from ASMVT patients diagnosed at 24, 36, 48, and 60 h from symptom onset was collected. Intestinal barrier disruption was assessed by tight junction (TJ) protein expression, morphology changes, and bacterial translocation. Mesenteric arteriospasm was measured by flow velocity and intestinal wet/dry weight ratio. The serum level of intestinal fatty acid binding protein and endotoxin in patients was also measured as an indicator for intestinal barrier function. RESULTS: Severe acidosis and lacticemia were observed in both the groups. The L-group experienced greater hemodynamic alteration than the S-group. Intestinal barrier disruption was detected by significantly decreased TJ protein expression, histology and ultrastructure injury of TJ, increased permeability, and bacterial translocation, at 9 h in the S-group and 12 h in the L-group. Secondary mesenteric arteriospasm occurred at the same time of complete intestinal barrier disruption and could be a significant cause of bowel necrosis. Significant increased level of intestinal fatty acid-binding protein and endotoxin was found in patients at 48 h in the S group type and 60 h in the L-group type. CONCLUSIONS: The ASMVT animal models of both the types were first established. The loss of intestinal barrier function occurred at 6 h in the S-group model and 9 h in the L-group model. For clinical patients, the time window extended to 36 h in the S-group type and 48 h in the L group type. PMID- 29506845 TI - Transplantation of genetically modified hepatocytes after liver preconditioning in Watanabe heritable hyperlipidemic rabbit. AB - BACKGROUND: Hepatocyte transplantation is a potentially less invasive alternative to liver transplantation for treating inherited metabolic liver diseases. We developed an autotransplantation protocol of ex vivo genetically modified hepatocytes combining lentiviral transduction and transplantation after liver preconditioning by partial portal vein embolization. We investigated the metabolic efficiency of this approach in Watanabe rabbits, animal model of familial hypercholesterolemia. METHODS: Our autotransplantation experimental protocol was used in two groups of rabbits (n = 10), experimental and sham, receiving transduced and control hepatocytes, respectively. Isolated hepatocytes from left liver lobes were transduced using recombinant lentiviruses. Median lobe portal branches were embolized under fluoroscopic control. Functional measurement of low-density lipoprotein (LDL) receptor expression was assessed by LDL internalization assays. Cholesterol level evolution was monitored. Rabbits were killed 20 wk after the procedure. RESULTS: Three rabbits of each group died several hours after hepatocyte transplantation; autopsy revealed portal vein thrombosis in two rabbits from each group. The protocol was therefore modified with hepatocytes being transplanted through splenic injection. Lentiviral hepatocyte transduction efficacy was 64.5%. Fluorescence microscopy revealed Dil LDL internalization of transduced hepatocytes. Seven rabbits in each group were considered for lipid analysis. Four weeks after autotransplantation, median total cholesterol level decreased in the experimental group, without reaching statistical significance (8.9 [8.0-9.8] g/L versus 6.3 [0.5-8.3]; P = 0.171). In the experimental group, enzyme-linked immunosorbent assay detected significant antibody expression against human low-density lipoprotein receptor. CONCLUSIONS: Autotransplantation protocol allowed a nonstatistically significant improvement of the lipid profile in Watanabe rabbits. Further experiments involving a larger number of animals are necessary to confirm or refute our findings. PMID- 29506846 TI - Assessing quality of randomized trials supporting guidelines for laparoscopic and endoscopic surgery. AB - BACKGROUND: Recent studies have highlighted the risk of bias and the fragility of results in randomized controlled trials (RCTs). The aim of our study was to evaluate the clinical practice guidelines created by the Society for Gastrointestinal and Endoscopic Surgeons (SAGES) for fragility, statistical power, and risk of bias. MATERIALS AND METHODS: We screened the SAGES clinical practice guideline references for qualifying RCTs. RCTs were assessed for risk of bias using the Cochrane Collaboration Risk of Bias tool 2.0. We used the fragility index and fragility quotient to evaluate the robustness of trial results and conducted a power analysis using G*Power to determine if trials were adequately powered. RESULTS: Twenty-two (40.7%) of the 54 trials that we assessed were rated as having a high risk of bias, 17 (31.5%) were rated as having a low risk of bias, and 15 (27.8%) were rated as having some concerns. The median fragility index was 2.5 (interquartile range 1-7). The median fragility quotient was 0.021 (interquartile range 0.003-0.045). Mean sample size was 108, and the mean loss to follow-up was eight patients. Eight of 33 trials (24.2%) were found to be underpowered according to the sample size used in the primary outcome. CONCLUSIONS: Guidelines created by SAGES are supported by RCTs that are frequently fragile or underpowered or have a high risk of bias. Future RCTs should utilize the Consolidated Standards of Reporting Trials statement, implement strategies to minimize loss to follow-up, and use properly powered sample sizes. PMID- 29506847 TI - Postoperative outcomes of open versus laparoscopic pyloromyotomy for hypertrophic pyloric stenosis. AB - BACKGROUND: Hypertrophic pyloric stenosis (HPS) is one of the most common indications for non-elective surgery in the neonatal population. Multiple small prospective trials have shown that postoperative outcomes for laparoscopic versus open pyloromyotomy are equivalent or slightly better with the minimally invasive approach. This study uses a prospective national database to compare postoperative complications and length of stay for infants undergoing laparoscopic versus open pyloromyotomy. METHODS: Infants undergoing either open or laparoscopic pyloromyotomy for HPS were identified from the 2013 National Surgical Quality Improvement Project-Pediatric Participant Use File. Post operative complication rates for an open versus laparoscopic approach were compared using chi square or Fisher's exact test as appropriate. Operative time and post-operative length of stay were compared using the Wilcoxon two-sample test. RESULTS: A total of 3256 infants were identified from the 2013 and 2014 American College of Surgeons National Surgical Quality Improvement Project Pediatric Participant Use File who underwent pyloromyotomy for HPS. Of these, 1182 were open and 2074 were laparoscopic. Postoperative outcomes are depicted in Table 2. Laparoscopic pyloromyotomy was associated with statistically significant decrease in overall morbidity (2.4% versus 1.2%, P = 0.007). CONCLUSIONS: We have demonstrated that post-operative outcomes after laparoscopic pyloromyotomy are equivalent or superior to an open approach. The minimally invasive approach to pyloromyotomy is a safe and feasible option in the treatment of HPS in infants. PMID- 29506848 TI - Cost-effectiveness of laparoscopic versus open appendectomy in developing nations: a Colombian analysis. AB - BACKGROUND: Colombia is a developing nation in need for efficient resource administration in fields such as health care, where innovation is constant. Since the introduction of laparoscopic appendectomy (LA), direct costs have been increasing without definitive results in terms of clinical outcomes. The objective of this study is to determine the cost-effectiveness of open appendectomy (OA) versus LA and thereby help surgeons in clinical decision-making in a limited resource setting. METHODS: A retrospective cost-effectiveness analysis comparing OA versus multiport LA during 2013 in a third-level university hospital (Hospital Universitario San Ignacio) in Bogota, Colombia was performed. Effectiveness was determined as the number of days in additional length of stay (LOS) due to the complications saved. A total of 377 clinical histories were collected by the authors and analyzed for the following variables: surgery type, conversion to open laparotomy, complications (surgical site infection, reintervention, and readmission), hospital LOS, and total cost of hospitalization for initial surgery and subsequent complications-related hospitalizations. The total accumulative costs and LOS for OA and LA plus complications were estimated. The cost-effectiveness threshold was set at US $46 (139,000 Colombian Peso [COP]), the cost of an additional day in LOS. An incremental cost-effectiveness ratio was calculated for OA as the comparator and LA as the intervention. RESULTS: The number of LA was 130 and of OA was 247. The two groups were balanced in terms of population characteristics. Complication rate was 13.7 % for OA and 10.4% for LA (P < 0.05), and LOS was 2 days for LA and OA (P = 0.9). No conversions from LA to OA were recorded. The total costs for complications for OA were US $8523 (25,569,220 COP) and US 3385 (10,157,758 COP) for LA. Cumulative costs including cost of surgery and complications and LOS for OA were US $65,753 (197,259,310 COP) and 297, respectively. Similarly, for LA were US $66,425 (199,276,948 COP) and 271, respectively. The incremental cost-effectiveness ratio was US $25.86 (77,601 COP) making LA a cost-effective alternative with a difference of US $20.76 (62,299 COP) under the cost-effectiveness threshold. CONCLUSIONS: LA is a cost-effective alternative over OA with an increasing cost of $25.85 per day of additional hospitalization due to complications saved. This is accounting the low cost of surgical interventions and complications in developing nations such as Colombia. PMID- 29506849 TI - Disparities in fertility-sparing surgery in adolescent and young women with stage I ovarian dysgerminoma. AB - BACKGROUND: In many cancers, racial and socioeconomic disparities exist regarding the extent of surgery. For ovarian dysgerminoma, fertility-sparing (FS) surgery is recommended whenever possible. The aim of this study was to investigate rates of FS versus non-fertility-sparing (NFS) procedures for stage I ovarian dysgerminoma in adolescents and young adults (AYAs) by ethnicity/race and socioeconomic status. MATERIALS AND METHODS: The National Cancer Data Base was queried for patients with ovarian dysgerminoma from 1998 to 2012. After selecting patients aged 15-39 y with stage I disease, a multivariate regression analysis was performed, and rates of FS and NFS procedures were compared, first according to ethnicity/race, and then by socioeconomic surrogate variables. RESULTS: Among the 687 AYAs with stage I ovarian dysgerminoma, there was no significant difference in rates of FS and NFS procedures based on ethnicity/race alone (P = 0.17), but there was a significant difference in procedure type for all three socioeconomic surrogates. The uninsured had higher NFS rates (30%) than those with government (21%) or private (19%) insurance (P = 0.036). Those in the poorest ZIP codes had almost twice the rate of NFS procedures (31%) compared with those in the most affluent ZIP codes (17%). For those in the least-educated regions, 24% underwent NFS procedures compared to 14% in the most-educated areas (P = 0.027). CONCLUSIONS: AYAs with stage I ovarian dysgerminoma in lower socioeconomic groups were more likely to undergo NFS procedures than those in higher socioeconomic groups, but there was no difference in rates of FS versus NFS procedures by ethnicity/race. Approaches aimed at reducing socioeconomic disparities require further examination. PMID- 29506850 TI - Retroperitoneal lymph node staging in paratesticular rhabdomyosarcoma-are we meeting expectations? AB - BACKGROUND: Staging retroperitoneal lymph node dissection (RPLND) for paratesticular rhabdomyosarcoma (RMS) is recommended for all patients aged >=10 y. The purpose of this study was to evaluate adherence with surgical resection guidelines for RPLND in patients with paratesticular RMS as a measure for surgical quality. MATERIALS AND METHODS: All patients with paratesticular RMS were identified in the Surveillance, Epidemiology, and End Results database from 1973 to 2012. Patients were divided into two eras to reflect before (1973-2002) and after (2003-2012) the release and dissemination of the 2001 surgical guidelines for staging ipsilateral RPLND in all patients aged >=10 y with paratesticular RMS. Survival outcomes associated with lymph node dissection were calculated using the Kaplan-Meier method and Cox proportional hazards analysis. RESULTS: Two hundred thirty-five patients with paratesticular RMS were identified and included in the study, among whom 111 were adolescents aged 10-20. RPLND did not significantly increase after 2003 among adolescents (45%-61%, P = 0.09). The benefit of RPLND on improved 5-y overall survival was evident among adolescents (92% versus 64%, P = 0.003). Adjusting for histology, age, stage at diagnosis, and race/ethnicity, RPLND was associated with improved overall survival among patients aged >=10 y (hazard ratio 0.37, 95% confidence interval 0.17-0.83). CONCLUSIONS: Despite surgical guidelines recommending RPLND in pediatric patients aged >=10 y, nearly one-third of adolescent patients did not undergo RPLND. These findings are disturbing considering the survival benefit associated with RPLND among adolescent patients and indicate an opportunity for improvement in surgical quality. PMID- 29506851 TI - Metabolic acidosis and the role of unmeasured anions in critical illness and injury. AB - Acid-base disorders are frequently present in critically ill patients. Metabolic acidosis is associated with increased mortality, but it is unclear whether as a marker of the severity of the disease process or as a direct effector. The understanding of the metabolic component of acid-base derangements has evolved over time, and several theories and models for precise quantification and interpretation have been postulated during the last century. Unmeasured anions are the footprints of dissociated fixed acids and may be responsible for a significant component of metabolic acidosis. Their nature, origin, and prognostic value are incompletely understood. This review provides a historical overview of how the understanding of the metabolic component of acid-base disorders has evolved over time and describes the theoretical models and their corresponding tools applicable to clinical practice, with an emphasis on the role of unmeasured anions in general and several specific settings. PMID- 29506852 TI - Chemotherapy can promote liver metastasis by enhancing metastatic niche formation in mice. AB - BACKGROUND: Some chemotherapeutic agents have been reported to promote lung metastasis. However, there have been no reports regarding chemotherapy-induced liver metastasis. We hypothesized that chemotherapy might also enhance liver metastasis. The present study aimed to create a chemotherapy-enhanced liver metastasis mouse model and investigate its mechanism. MATERIALS AND METHODS: Mice were pretreated with cisplatin, vincristine, or saline by intraperitoneal injection. Next, B16F10 mouse melanoma cells and BE(2)-C human neuroblastoma cells were injected into the spleens of C57BL/6 and BALB/c nu/nu mice, respectively, to induce experimental liver metastasis, and the number of liver nodules was determined. We also analyzed the effect of chemotherapy on changes of the liver tissue regarding representative metastasis-promoting factors using real time quantitative polymerase chain reaction and immunohistochemical and histological analysis. RESULTS: Cisplatin increased the number of nodules by 4.7 fold in the B16F10 liver metastasis model. Vincristine increased the number of nodules by 3.8-fold in the BE(2)-C liver metastasis model. Cisplatin increased mRNA levels of matrix-metalloproteinase (MMP)-2 and periostin, while vincristine increased MMP-9 and S100A8/9 levels in liver tissues. Cisplatin induced fibrosis, whereas vincristine induced neutrophil recruitment in liver tissues according to histological and immunohistochemical analysis. CONCLUSIONS: We concluded that cisplatin or vincristine could enhance liver metastasis of mouse melanoma cells or human neuroblastoma cells, respectively. In addition, the mRNA expression of MMP-2 and periostin, or MMP-9 and S100A8/9 is increased by cisplatin or vincristine pretreatment, possibly resulting in fibrosis or neutrophil recruitment, respectively. These niche factors might be associated with increased liver metastasis. PMID- 29506853 TI - Plasma microRNAs reflecting cardiac and inflammatory injury in coronary artery bypass grafting surgery. AB - BACKGROUND: Circulating microRNAs (miRs) may act as diagnostic and prognostic biomarkers for cardiovascular events in coronary artery bypass graft (CABG) surgery patients. This study measured changes in cardiac- and muscle-related miRs and cardiac and inflammatory biomarkers in acute coronary syndrome patients undergoing CABG surgery as well as investigated the correlations between these indicators. METHODS: Creatine kinase-MB (CK-MB), brain natriuretic peptide (BNP), cardiac troponin T (cTnT), interleukin-6 (IL-6), IL-8, IL-10, high-sensitivity C reactive protein, and tumor necrosis factor-alpha were measured, and real-time quantitative polymerase chain reaction was performed to determine the plasma levels of miR-1, miR-133a, miR-208a, and miR-499 before and after surgery in 27 acute coronary syndrome patients. Left ventricular ejection fraction was also analyzed in a 3-month follow-up. RESULTS: miR-1, miR-133a, and miR-208a increased significantly (P = 0.0011; P = 0.0057; P = 0.0197, respectively) and the CK-MB, cTnT, BNP, and IL-6 levels were augmented after surgery. miR-133a, miR-208a, and miR-499 positively correlated with cTnT (r = 0.302, P = 0.027; r = 0.326, P = 0.016; r = 0.298, P = 0.029, respectively), but only miR-208a significantly correlated with CK-MB (r = 0.278, P = 0.041). miR-133a and miR-208a were significantly related to IL-6 (r = 0.287, P = 0.036; r = 0.292, P = 0.032, respectively). However, there were no significant associations between miRs and BNP or 3-month left ventricular ejection fraction. CONCLUSIONS: CABG surgery induced myocardial reperfusion damage and subsequent inflammation were related to changes in miR-1, miR-133a, and miR-208a. Notably, miR-208a was the only indicator associated with CK-MB, cTnT, and IL-6, which may reflect heart injury and inflammation in these patients. PMID- 29506854 TI - Spectral analysis of heart rate variability predicts mortality and instability from vascular injury. AB - BACKGROUND: Spectral analysis of continuous blood pressure and heart rate variability provides a quantitative assessment of autonomic response to hemorrhage. This may reveal markers of mortality as well as endpoints of resuscitation. METHODS: Fourteen male Yorkshire pigs, ranging in weight from 33 to 36 kg, were included in the analysis. All pigs underwent laparotomy and then sustained a standardized retrohepatic inferior vena cava injury. Animals were then allowed to progress to class 3 hemorrhagic shock and where then treated with abdominal sponge packing followed by 6 h of crystalloid resuscitation. If the pigs survived the 6 h resuscitation, they were in the survival (S) group, otherwise they were placed in the nonsurvival (NS) group. Fast Fourier transformation calculations were used to convert the components of blood pressure and heart rate variability into corresponding frequency classifications. Autonomic tones are represented as the following: high frequency (HF) = parasympathetic tone, low frequency (LF) = sympathetic, and very low frequency (VLF) = renin-angiotensin aldosterone system. The relative sympathetic to parasympathetic tone was expressed as LF/HF ratio. RESULTS: Baseline hemodynamic parameters were equal for the S (n = 11) and NS groups. LF/HF was lower at baseline for the NS group but was higher after hemorrhage and the resuscitation period indicative of a predominately parasympathetic response during hemorrhagic shock before mortality. HF signal was lower in the NS group during the resuscitation indicating a relatively lower sympathetic tone during hemorrhagic shock, which may have contributed to mortality. Finally, the NS group had a lower VLF signal at baseline (e.g., [S] 16.3 +/- 2.5 versus [NS] 4.6 +/- 2.9 P < 0.05,) which was predictive of mortality and hemodynamic instability in response to a similar hemorrhagic injury. CONCLUSIONS: An increased LF/HF ratio, indicative of parasympathetic predominance following injury and during resuscitation of hemorrhagic shock was a marker of impending death. Spectral analysis of heart rate variability can also identify autonomic lability following hemorrhagic injuries with implications for first responder triage. Furthermore, a decreased VLF signal at baseline indicates an additional marker of hemodynamic instability and marker of mortality following a hemorrhagic injury. These data indicate that continuous quantitative assessment of autonomic response can be a predictor of mortality and potentially guide resuscitation of patients in hemorrhagic shock. PMID- 29506855 TI - Robotic versus standard laparoscopic elective colectomy: where are the benefits? AB - BACKGROUND: Robotic approaches for colorectal surgery have been growing in popularity as experience with the new technology develops, but are frequently associated with longer operative time. It is unclear whether prolonged operative duration in robotic cases translates to increased morbidity. This study aims to compare the outcomes of non-emergent laparoscopic and robotic colon resections. METHODS: Patients undergoing non-emergent laparoscopic (LC) or robotic (RC) colon resections were identified in National Surgical Quality Improvement Project (2013 2015). Patients were matched 1:1 between cohorts using propensity score matching. To account for the prolonged operative time associated with robotic cases, operative times were stratified into approach-specific (LC or RC) tertiles (low, medium, and high) as covariates in the matching algorithm. RESULTS: RC increased significantly over time and had lower conversion rates (6.0% among RC versus 11.5% among LC, P < 0.001). RC cases were longer (226 min versus 178 min, P < 0.001). Unadjusted complication rates were higher in the LC cohort (17.5% versus 15.2%, P < 0.001). After propensity score matching, RC was not associated with a significant difference in postoperative morbidity (15.2% among RC versus 15.9% among LC, P = 0.434). The robotic approach was associated with a one-half day shorter length of stay (4.6 d versus 5.2 d, P < 0.001), but similar 30-day readmission rates (8.9% versus 8.3%, P = 0.368). CONCLUSIONS: After controlling for operative duration and patient covariates, RC was associated with similar rates of postoperative morbidity, but decreased conversion rates and shorter length of stay. Further studies examining costs are needed to evaluate whether these benefits offset the increased costs associated with robotic approaches. PMID- 29506856 TI - Short-term and family-reported long-term outcomes of simple versus complicated gastroschisis. AB - BACKGROUND: Our goal is to determine short- and long-term outcomes of simple gastroschisis (SG) and complicated gastroschisis (CG) patients including quality of life (QoL) measures, surgical reoperation rates, and residual gastrointestinal symptom burden. MATERIALS AND METHODS: Retrospective chart review of patients who underwent surgical repair of gastroschisis between January 1, 2009, and December 31, 2012, was performed at a quaternary children's hospital. Parent telephone surveys were conducted to collect information on subsequent operations and current health status as well as to assess QoL using two validated tools. RESULTS: Of 143 patients identified, 45 (31.5%) were reached and agreed to participate with a median follow-up age of 4.7 y. Although CG was associated with short-term outcomes such as longer length of stay, longer days to feeds, and higher complication rates, there were no major differences in long-term QoL outcomes when comparing SG and CG. Children with CG experienced abdominal pain/gas/diarrhea more often than those with SG and required more major abdominal procedures than those with SG (15% versus 0%, P = 0.009). CONCLUSIONS: Despite worse short-term outcomes, presence of certain gastrointestinal symptoms, and need for more surgical interventions for patients with CG, and overall QoL scores were reassuringly similar to those with SG. PMID- 29506857 TI - The first postesophagectomy chest X-ray predicts respiratory failure and the need for tracheostomy. AB - BACKGROUND: Esophagectomy is a major surgical procedure associated with high rates of morbidity. The purpose of this study was to determine if the immediate first postesophagectomy chest X-ray (pCXR) is associated with morbidity or mortality. METHODS: This was a single-institution analysis of patients undergoing esophagectomy, 2005-2015. A pCXR was routinely performed. A pCXR score was developed based on the number of objective abnormal findings. A statistical analysis was performed using patient/tumor variables and the pCXR score to derive adjusted odds ratios (ORs) on short-term outcomes. RESULTS: One hundred eighty two patients had pCXRs. Scores ranged from 0 (normal) to 4 depending on the number of abnormalities, with a mean score of 1.6. The mean patient age was 60.7 y. Within the cohort, 92.9% had adenocarcinoma, 39.6% had T3/T4 tumors, and 48.4% were node positive. Open surgeries were performed in 51.6%, and 74.2% had chest anastomoses. The 30- and 90-d mortality rates were 2.2% and 3.9%, respectively. Increasing pCXR scores were associated with increased risk of prolonged intubation (OR: 1.67, 95% confidence interval [CI]: 1.21-2.36, P = 0.002) and tracheostomy (OR: 2.12, 95% CI: 1.08-4.16, P = 0.029). Multivariable analysis adjusting for age, comorbidities and performance status, histology, pathologic stage, surgical approach, and operative time confirmed a statistically significant association with the pCXR score and respiratory failure requiring tracheostomy (OR: 2.13, 95% CI: 1.03-4.39, P = 0.041). CONCLUSIONS: This is the first study to show an association between the first pCXR and respiratory failure, providing new evidence that the first pCXR has important implications for pulmonary care after esophagectomy. PMID- 29506858 TI - Computed tomography in ventral hernia diagnosis: have we improved? A quality improvement initiative. AB - BACKGROUND: Previous studies suggest that agreement between readers of computed tomography (CT) scans for the diagnosis of a ventral hernia (VH) is poor (32% agreement, kappa = 0.21). Recommendations were developed by surgeons and radiologists after determining common reasons for disagreement among CT reviewers; however, the long-term effect of adoption of these recommendations has not been assessed. The aim of this quality improvement (QI) project was to determine whether the incorporation of recommendations developed by surgeons and radiologists improves agreement among reviewers of CT scans in diagnosing a VH. METHODS: A prospective cohort of patients, with a CT scan of the abdomen and pelvis in the past 1 y, attending a surgery clinic at a single institution was enrolled. Enrolled subjects underwent a standardized physical examination by a trained hernia surgeon to determine the likelihood of a clinical VH (no, indeterminate, or yes). The QI intervention was the distribution and implementation of previously described recommendations. After a year of intervention, independent radiologists assessed patients' CT scans for the presence or absence of a VH. Percent agreement and kappa were calculated to determine interobserver reliability. In-person discussion on scans with disagreement was held, and the results were used as a "gold standard" to calculate sensitivity, specificity, positive, and negative predictive values for CT scan diagnosis of a VH. RESULTS: A total of 79 patients were included in the study. After QI intervention, seven radiologists agreed on 43% of the scans, and kappa was 0.50 (P < 0.001). Agreement was highest among patients with a high clinical likelihood of a VH and lowest among patients with an indeterminate clinical likelihood. Sensitivity and specificity were 0.369 and 0.833, respectively. CONCLUSIONS: After the implementation of recommendations, there is improved agreement among radiologists reading CT scans for the diagnosis of a VH. However, there is substantial room for improvement, and CT scans for the diagnosis of VH is not ready for widespread use. PMID- 29506859 TI - Comparison of acid-base and electrolyte changes following administration of 6% hydroxyethyl starch 130/0.42 in a saline and a polyionic solution in anaesthetized dogs. AB - OBJECTIVE: To evaluate the effects of a 6% hydroxyethyl starch (130/0.42) in either a buffered, electrolyte-balanced (HES-BAL) or saline (HES-SAL) carrier solution on electrolyte concentrations and acid-base parameters in healthy anaesthetized dogs. STUDY DESIGN: Prospective randomised clinical study. ANIMALS: A group of 40 client-owned dogs undergoing general anaesthesia for elective surgical procedures or diagnostic imaging. METHODS: During anaesthesia, dogs were intravenously administered 15 mL kg-1 of either HES-SAL (n = 20) or HES-BAL (n = 20) over 30-40 minutes. Jugular blood samples were analysed before (T0) and 5 minutes (T5), 1 hour (T60) and 3 hours (T180) after fluid administration. Sodium, potassium, chloride, ionised calcium, phosphate, albumin, pH, venous pCO2, base excess (BE), bicarbonate and anion gap were determined and strong ion difference (SID) and total quantity of weak nonvolatile acids were calculated for each time point. RESULTS: Chloride was significantly increased at T5, T60 and T180 compared with T0 after HES-SAL, and was significantly greater after HES-SAL than after HES BAL at T5 (p = 0.042). Ionised calcium was significantly decreased at T5 compared with T0 after HES-SAL, and was significantly lower after HES-SAL than after HES BAL at T5 (p < 0.001). Bicarbonate was significantly lower after HES-SAL than after HES-BAL at T5 (p = 0.004) and T60 (p = 0.032). BE was significantly lower after HES-SAL than after HES-BAL at T5 (p < 0.001) and T60 (p = 0.007). SID was significantly decreased after HES-SAL at T5 and T60 compared with T0, and was significantly lower after HES-SAL than after HES-BAL at T5 (p = 0.027). Mean electrolyte and acid-base parameters remained within or marginally outside of reference intervals. CONCLUSIONS AND CLINICAL RELEVANCE: Changes in both groups were minor and short-lived with either fluid in healthy individuals, but might become clinically relevant with higher fluid doses or in critically ill dogs. PMID- 29506860 TI - [Anesthesia for cesarean delivery in a patient with Klippel-Trenaunay syndrome]. AB - INTRODUCTION: Klippel-Trenaunay syndrome is a rare congenital vascular disease characterized by cutaneous hemangiomas, varicosities, and limb asymmetry, which may evolve with coagulation disorders and hemorrhage as those more frequent complications in pregnant patients. Pregnancy is not advised in women with this syndrome due to increased obstetrical risk. CASE REPORT: Female patient, 29 years old, 99kg, 167cm, BMI 35.4kg.m-2, physical status ASA III, with 27 weeks of gestational age and diagnosis of Klippel-Trenaunay syndrome. She was admitted to attempt inhibition of preterm labor. As manifestations of Klippel-Trenaunay syndrome, the patient presented with cerebral and cutaneous hemangioma mainly in the trunk and lumbar region, paresis in the left upper and lower limbs, and limb asymmetry requiring the use of a walking stick. Physical examination revealed absence of airway vascular malformations and Mallampati class 3. Laboratory tests were normal and abdominal angiotomography showed irregular uterus, with multiple varices and vessels of arterial origin and bilateral periadnexal varices. She evolved with failure in preterm labor inhibition, and cesarean section under total intravenous anesthesia was indicated. Monitoring, central and peripheral venous access, radial artery catheterization, and diuresis were secured. Cesarean section was performed with median incision and longitudinal uterine body section for fetal extraction. Two episodes of arterial hypotension were seen intraoperatively. The postoperative evolution was uneventful. The choice of anesthesia was dependent on the clinical manifestations and the lack of imaging tests proving the absence of neuraxial hemangiomas. PMID- 29506861 TI - Prospective assessment of follicular growth and the oocyte cohort after ovarian stimulation for fertility preservation in 90 cancer patients versus 180 matched controls. AB - A lower number of metaphase II oocytes eligible for vitrification after controlled stimulation in cancer patients has recently been reported, suggesting that cancer may impair the dynamics and quality of follicular growth. In this prospective, non-interventional study, the pattern of follicular growth and oocyte cohort after ovarian stimulation in cancer patients was analysed. Ninety cancer patients, recruited before starting chemotherapy, were compared with 180 time- and age-matched healthy controls undergoing intracytoplasmic sperm injection. Primary outcome was total number of metaphase II oocytes and metaphase II /total oocytes rate. Basal anti-Mullerian hormone levels (P < 0.05) and antral follicle count (P < 0.0001) were significantly lower in cancer patients. Recombinant FSH total dose was significantly higher in the cancer group (P < 0.0001). No differences were found in duration of stimulation, mean number of mature follicles on day of ovulation induction and total oocyte number after retrieval; the number of metaphase II oocytes retrieved (6.2 +/- 4.7 versus 8.8 +/- 4.2; P < 0.0001) and number of metaphase II oocytes-total oocytes ratio were significantly lower in cancer patients (56% versus 78%, P < 0.0001). Fewer metaphase II oocytes were eligible for vitrification and lower maturation rate in the cancer group. PMID- 29506863 TI - Efficacy of a Deep Learning System for Detecting Glaucomatous Optic Neuropathy Based on Color Fundus Photographs. AB - PURPOSE: To assess the performance of a deep learning algorithm for detecting referable glaucomatous optic neuropathy (GON) based on color fundus photographs. DESIGN: A deep learning system for the classification of GON was developed for automated classification of GON on color fundus photographs. PARTICIPANTS: We retrospectively included 48 116 fundus photographs for the development and validation of a deep learning algorithm. METHODS: This study recruited 21 trained ophthalmologists to classify the photographs. Referable GON was defined as vertical cup-to-disc ratio of 0.7 or more and other typical changes of GON. The reference standard was made until 3 graders achieved agreement. A separate validation dataset of 8000 fully gradable fundus photographs was used to assess the performance of this algorithm. MAIN OUTCOME MEASURES: The area under receiver operator characteristic curve (AUC) with sensitivity and specificity was applied to evaluate the efficacy of the deep learning algorithm detecting referable GON. RESULTS: In the validation dataset, this deep learning system achieved an AUC of 0.986 with sensitivity of 95.6% and specificity of 92.0%. The most common reasons for false-negative grading (n = 87) were GON with coexisting eye conditions (n = 44 [50.6%]), including pathologic or high myopia (n = 37 [42.6%]), diabetic retinopathy (n = 4 [4.6%]), and age-related macular degeneration (n = 3 [3.4%]). The leading reason for false-positive results (n = 480) was having other eye conditions (n = 458 [95.4%]), mainly including physiologic cupping (n = 267 [55.6%]). Misclassification as false-positive results amidst a normal-appearing fundus occurred in only 22 eyes (4.6%). CONCLUSIONS: A deep learning system can detect referable GON with high sensitivity and specificity. Coexistence of high or pathologic myopia is the most common cause resulting in false-negative results. Physiologic cupping and pathologic myopia were the most common reasons for false-positive results. PMID- 29506862 TI - Impact of hospital volume on racial disparities and outcomes for endometrial cancer. AB - OBJECTIVE: Little is known about the influence of hospital procedural volume on racial disparities for uterine cancer. We examined whether the magnitude of the survival differential between black and white women varied based on hospital procedural volume for endometrial cancer. METHODS: We utilized the National Cancer Data Base to examine women with endometrial cancer from 1998 to 2012. Annualized hospital procedural volume was calculated and hospitals grouped into volume-based quartiles. Multivariable models were developed to examine differences in two and five-year survival between black and white women across the hospital volume categories. Patients were classified as early or advanced stage and as type I (low grade, endometrioid) or type II (high grade endometrioid, other histologies) cancers. RESULTS: We identified 243,422 (75.0%) white and 27,764 (8.6%) black women treated at 1059 hospitals. Regardless of hospital volume, black women had decreased survival. For each tumor class, the absolute difference in adjusted two-year survival between black and white women decreased with increasing hospital volume. For example, for women with early stage, type I tumors, the adjusted two-year survival differential between blacks and whites was -1.4% (95%CI, -2.4 to -0.5%) at low volume centers and decreased to -0.5% (95%CI, -0.9 to 0%) at high-volume hospitals (P<0.0001). For advanced stage, type I tumors, the adjusted survival differential decreased from -12.4% (95%CI, -24.0 to -0.9%) to 1.2% (95%CI, -2.9 to 5.3%) at high volume hospitals (P<0.0001). CONCLUSION: Black race is an independent predictor of mortality. The impact of race on mortality is mitigated, albeit not eliminated, by increasing hospital volume. PMID- 29506865 TI - Corrigendum to "Netrin-1 promotes metastasis of gastric cancer by regulating YAP activity" [Biochem. Biophys. Res. Commun. 496 (1) (2018 Jan 29) 76-82]. PMID- 29506864 TI - Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH-JAPAN study. AB - BACKGROUND: The effect of very high or extremely high levels of high-density lipoprotein cholesterol (HDL-C) on cardiovascular disease (CVD) is not well described. Although a few recent studies have reported the adverse effects of extremely high levels of HDL-C on CVD events, these did not show a statistically significant association between extremely high levels of HDL-C and cause-specific CVD mortality. In addition, Asian populations have not been studied. OBJECTIVE: We examine the impact of extremely high levels of HDL-C on cause-specific CVD mortality using pooled data of Japanese cohort studies. METHODS: We performed a large-scale pooled analysis of 9 Japanese cohorts including 43,407 participants aged 40-89 years, dividing the participants into 5 groups by HDL-C levels, including extremely high levels of HDL-C >=2.33 mmol/L (>=90 mg/dL). We estimated the adjusted hazard ratio of each HDL-C category for all-cause death and cause specific deaths compared with HDL-C 1.04-1.55 mmol/L (40-59 mg/dL) using a cohort stratified Cox proportional hazards model. RESULTS: During a 12.1-year follow-up, 4995 all-cause deaths and 1280 deaths due to overall CVD were identified. Extremely high levels of HDL-C were significantly associated with increased risk of atherosclerotic CVD mortality (hazard ratio = 2.37, 95% confidence interval: 1.37-4.09 for total) and increased risk for coronary heart disease and ischemic stroke. In addition, the risk for extremely high HDL-C was more evident among current drinkers. CONCLUSION: We showed extremely high levels of HDL-C had an adverse effect on atherosclerotic CVD mortality in a pooled analysis of Japanese cohorts. PMID- 29506866 TI - Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta analysis. AB - INTRODUCTION: It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population. MATERIALS AND METHODS: We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality. RESULTS: We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42-1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05-2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85-6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85 1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis. CONCLUSIONS: DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2-3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs. PMID- 29506867 TI - Characterization of circulating gamma-delta T cells in relapsing vs remission multiple sclerosis. AB - We characterized circulating gamma-delta T cells in relapsing-remitting multiple sclerosis (RRMS) patients, during remission and relapse phases. In relapse, we observed a decrease of circulating CCR5+ gammadelta TEMRA cell subset, together with a decrease in EOMES and granzyme B mRNA expression in gammadelta T cells, suggesting a reduction of the cytotoxic potential of this subset. Moreover, we also found a higher frequency of IFNgamma+ gammadelta T cells, which may indicate that these cells are assuming a more regulatory function associated to a Th1 profile. These results suggest a specific release from the periphery of a particular gammadelta T cell subset, expressing CCR5 and belonging to an effector compartment, supporting the idea that gammadelta T cells could play a role in MS relapse. PMID- 29506869 TI - UK and Irish Y-STR population data-A catalogue of variant alleles. AB - A total of 3128 Y-STR profiles from three UK and one Irish population have been analysed with the PowerPlex Y23 system and are reported here. Instances of haplotype sharing between apparently unrelated individuals were identified and further investigated with the use of the 5 additional markers within the Yfiler Plus kit, resulting in a reduction by 76% in the number of shared haplotypes. Furthermore, Yfiler Plus was also employed to verify locus deletions and duplications observed in Y23 genotypes while inconsistencies between the two kits were sequenced, revealing underlying Y23 primer binding site mutations in loci DYS392 and DYS576. Finally, the mechanism behind a previously reported population specific peak shift observed in DYS481 in South Asian samples has been evaluated and further investigated in a novel case of this phenomenon seen in a Black British individual featuring a different flanking region mutation. PMID- 29506868 TI - Associations of Physical and Psychologic Symptom Burden in Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms. AB - BACKGROUND: The physical symptom burden of patients with myeloproliferative neoplasms (MPNs) may last for extended periods during their disease trajectories and lead to psychologic distress, anxiety, or depression or all of these. OBJECTIVE: This study evaluated the relationship between physical symptom burden captured by the Physical Problem List (PPL) on the Distress Thermometer and Problem List and psychologic outcomes (distress, anxiety, and depression) in the MPN setting. METHODS: Patients (N = 117) with MPNs completed questionnaires containing the Distress Thermometer and Problem List and the Hospital Anxiety and Depression Scale in a dedicated MPN clinic within an academic medical center. They reported symptoms from any of 22 physical problems on the PPL. Items endorsed by more than 10% of participants were assessed for their associations with distress (Distress Thermometer and Problem List), anxiety (Hospital Anxiety and Depression Scale-Anxiety), and depression (Hospital Anxiety and Depression Scale-Depression). The total number of endorsed PPL items per participant was also evaluated. RESULTS: Nine of 22 PPL items (fatigue, sleep, pain, dry skin/pruritus, memory/concentration, feeling swollen, breathing, and sexual) were reported by >10% of participants. In univariate analyses, all PPL items but one were associated with distress and depression, and all but 2 were associated with anxiety. In multivariate analyses, the total number of PPL items was associated with depression only (p < 0.001) when controlling for covariates. CONCLUSION: Physical symptom burden in MPN patients was clearly associated with psychologic symptoms. Depression was uniquely associated with overall physical symptom burden. As such, the endorsement of multiple PPL items on the Distress Thermometer and Problem List should prompt an evaluation for psychologic symptoms to improve MPN patients' overall morbidity and quality of life. PMID- 29506870 TI - Lower pulse frequency, and not longer stimulus duration, helps reduce seizure threshold in ECT. PMID- 29506871 TI - Corrigendum to "NF-kappaB signaling is key in the wound healing processes of silk fibroin" [Acta Biomater. 67 (2018), 183-195]. PMID- 29506872 TI - Ophthalmological injuries associated with fractures of the orbitozygomaticomaxillary complex. AB - Our aim was to evaluate ophthalmological injuries associated with fractures of the orbitozygomaticomaxillary complex that required operative treatment, and we collected data retrospectively over a period of five years (2012-2016 inclusive). Of the 190 patients, 162 were male with a median age of 31 (IQR 25 -39) years. Assault was the most common mechanism of injury (125/190, 66%). Minor ophthalmic injuries (those unlikely to cause permanent visual disturbance) and major ophthalmic injuries (those with the potential to cause permanent visual disturbance) were recorded. The common minor ophthalmic injuries were: diplopia, enophthalmos, proptosis, subconjunctival haemorrhage, and restriction of the extraocular muscles. Commotio retinae, traumatic mydriasis, retro-orbital haemorrhage, and hyphaema were the common major ophthalmic injuries. All 13 different major ophthalmic injuries were recorded in the group who had had orbital fractures reconstructed, which suggested that more intraocular damage can be caused by this type of fracture than by others. Visual acuity was reduced in 26/190 patients with only four having persistent postoperative changes at six weeks. The odds ratio for those patients who had a major ophthalmological injury and were unable to drive was 0.07 (95% CI 0.02 to 0.21, p=0.001), which was highly significant. Ophthalmological assessment is strongly recommended for patients with fractures of the orbitozygomaticomaxillary complex. PMID- 29506873 TI - Retrobulbar abscess: rare complication after repair of an oroantral communication. AB - We present the case of a retrobulbar abscess that developed secondary to the repair of an oroantral communication. Orbital abscesses have been described in relation to odontogenic infections, facial injury, sinusitis, and after dental extractions but, to the best of our knowledge, none has been reported in these circumstances. Retrobulbar abscess is a rare complication, but early clinical and radiological diagnosis, and urgent decompression are vital because it comes with considerable risk of irreversible visual impairment. PMID- 29506875 TI - Age at First Presentation for Erectile Dysfunction: Analysis of Changes over a 12 yr Period. AB - BACKGROUND: The awareness regarding erectile dysfunction (ED) may have increased over the past decade due to the widespread availability of phosphodiesterase type 5 inhibitors and the growing knowledge of a link between ED and men's overall health. OBJECTIVE: We examined whether the increased awareness of ED has led to observable changes in patient characteristics among first-time assessments for ED. DESIGN, SETTING, AND PARTICIPANTS: Data was collected from 1586 men seeking their first medical attention for ED at a single academic center during 2005 2017. INTERVENTION: Patients completed the International Index of Erectile Function (IIEF) to assess ED. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Local polynomial regression models explored the relationship between patient characteristics and the year of first-time assessment. Linear and logistic regression models estimated the association between the time at first assessment and the investigated outcomes. Restricted cubic splines tested the nonlinearity for continuous variables. RESULTS AND LIMITATIONS: We observed a nonlinear correlation between age and year of assessment (p=0.0003); the probability that a patient aged <40 yr presented for ED increased from 13.5% in 2006 to 21.7% in 2017 (p=0.002). Patients assessed over the last period were significantly healthier (Charlson Comorbidity Index>=1; odds ratio [OR]: 0.96; 95% confidence interval [CI]: 0.92-0.99, p=0.02). We observed an increase in the rate of smokers (OR: 1.19, 95% CI: 1.14-1.23, p<0.0001) and in regularly physically active men (OR: 1.05; 95% CI: 1.01-1.08, p=0.008) over the same period. No changes were observed in terms of baseline IIEF-Erectile function scores over time. The single center design is the main limitation of the study. CONCLUSIONS: Age at first presentation for ED significantly decreased over the past decade. Physicians should carefully assess EF even at younger age groups, suggesting lifestyle modifications and relevant treatments for comorbid conditions as soon as possible. PATIENT SUMMARY: Patients presenting for erectile dysfunction (ED) are younger than they were 10 yr ago. These findings may suggest an increase in ED awareness. Likewise, this age reduction could represent a worrisome increase in terms of ED incidence in young men. PMID- 29506876 TI - In-depth statistical analysis of the use of a website providing patients' narratives on lifestyle change when living with chronic back pain or coronary heart disease. AB - OBJECTIVE: To investigate the use of lebensstil-aendern.de ("lifestyle change"), a website providing peer narratives of experiences with successful lifestyle change, and to analyze whether peer model characteristics, clip content, and media type have an influence on the number of visitors, dwell time, and exit rates. METHODS: An in-depth statistical analysis of website use with multilevel regression analyses. RESULTS: In two years, lebensstil-aendern.de attracted 12,844 visitors. The in-depth statistical analysis of usage rates demonstrated that audio clips were less popular than video or text-only clips, longer clips attracted more visitors, and clips by younger and female interviewees were preferred. User preferences for clip content categories differed between heart and back pain patients. Clips about stress management drew the smallest numbers of visitors in both indication modules. CONCLUSIONS: Patients are interested in the experiences of others. Because the quality of information for user-generated content is generally low, healthcare providers should include quality-assured patient narratives in their interventions. User preferences for content, medium, and peer characteristics need to be taken into account. PRACTICE IMPLICATIONS: If healthcare providers decide to include patient experiences in their websites, they should plan their intervention according to the different needs and preferences of users. PMID- 29506874 TI - MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load. AB - Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5.4months-37years, IQR=17.9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C. PMID- 29506877 TI - Early changes in vitamin B12 uptake and biomarker status following Roux-en-Y gastric bypass and sleeve gastrectomy. AB - BACKGROUND & AIMS: Bariatric surgery increases the risk of micronutrient deficiencies, including vitamin B12 (B12) deficiency. We analysed early changes in biomarkers of B12 status following bariatric surgery. METHODS: We prospectively included adult patients (n = 27) referred for either Roux-en-Y Gastric Bypass (RYGB) (n = 19) or Sleeve Gastrectomy (SG) (n = 8). Blood samples were drawn before surgery and 2 and 6 months following surgery for measurement of B12, holotranscobalamin (holoTC), and methylmalonic acid (MMA). The B12 absorption capacity was estimated from the increase in plasma holoTC two days after a standardised oral B12 challenge. RESULTS: B12 status decreased following both RYBG and SG. While a decrease in plasma B12 was not evident until 6 months postoperatively, we observed a statistically significant decrease in plasma holoTC and increase in MMA already 2 months postoperatively. These changes were more pronounced at 6 months post surgery. Correspondingly, the B12 absorption capacity was decreased following surgery. CONCLUSIONS: HoloTC and MMA were superior to B12 to detect early changes in B12 status following bariatric surgery. Our data challenge the current concept that liver B12 stores secure long term maintenance of B12 status. They indicate that B12 treatment in pharmacological doses may be warranted immediately after surgery. PMID- 29506878 TI - Up-regulated expression of SNHG6 predicts poor prognosis in colorectal cancer. AB - Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumor formation and development. Small nucleolar RNA host gene 6 (SNHG6) is a recently identified cancer-related lncRNA, and its role in colorectal cancer (CRC) remains to be explored. The aim of this study was to evaluate the expression and function of SNHG6 in CRC. The expression of SNHG6 was detected by real time quantitative RT-PCR (qRT-PCR) in 74 CRC tissues and matched noncancerous tissues (NCTs). Relationships between the expression levels of SNHG6 and various clinicopathological features were analyzed by Chi-square test. The Kaplan-Meier method and log-rank test were applied to compare the survival distribution between different groups. CCK8 assay and colony formation assay were used to measure the effect of SNGH6 on cell proliferation. Flow cytometric analysis was performed to measure the effect of SNHG6 on cell cycle and apoptosis. Our results showed that SNHG6 was up-regulated more than 1.5-fold in 50.0% (37/74) of CRC tissues compared with paired NCTs (P < 0.0001). High level of SNHG6 expression was strongly associated with advanced tumor stage (P = 0.026) and predicted poor prognosis of CRC (P = 0.0215). The Cox proportional hazards model demonstrated that SNHG6 expression was an independent prognostic factor for CRC (HR, 2.568; 95% CI, 1.055-6.252; P = 0.038). Furthermore, SNHG6 knockdown by siRNA could inhibit cell proliferation, cell cycle progression, and induce apoptosis. Taken together, SNHG6 functions as an oncogene in CRC and appears as a novel prognositic factor for CRC patients. PMID- 29506879 TI - Ring Ring Ring! Characterising Telephone Interruptions During Radiology Reporting and How to Reduce These. AB - BACKGROUND: Telephone calls remain one of the most frequent interruptions in radiology reporting rooms, despite modern electronic order communication systems. A call received by a radiology trainee during the hour before completing a report may increase the chance of a discrepancy by 12%. AIM: To characterise telephone calls to radiology reporting rooms and identify ways to reduce these interruptions. METHODS AND MATERIALS: An observational study over five working days (10 programmed activity reporting sessions equivalent) was conducted across 2 large teaching hospital reporting rooms. Radiologists were requested to record all calls between 9a.m and 5p.m on a preprepared Excel proforma and indicate their initial rating of call appropriateness. RESULTS: A total of 288 calls recorded, 92% (266/288) interrupted reporting. Reasons for calls were 48% (139/288) ask for a request to be vetted, 17% (50/288) ask for a study to be reported, 17% (45/288) "other," 7% (19/288) discuss choice of study, 6% (16/288) review a report, 3% (9/288) wrong number, 2% (7/288) returning a bleep, and 1% (3/288) provide further explanation in addition to the electronic request form. CONCLUSION: Radiologists and referrers remain over reliant on telephone interruptions for their workflow. Attempts to educate referrers previously reduced calls to a computed tomography reporting room by 28%. Our recommendations include (1) defining protected activities, (2) adhering to fully electronic requesting and vetting processes, other than in time critical or exceptional circumstances, (3) electronic critical report alerts and review of report priority triaging to reduce calls for reports, (4) revising duty radiologist timetables to tackle nonreporting responsibilities, and (5) improving new doctor induction in the organization to improve radiology request practice. PMID- 29506880 TI - Fine-Tuning Limited Proteolysis: A Major Role for Regulated Site-Specific O Glycosylation. AB - Limited proteolytic processing is an essential and ubiquitous post-translational modification (PTM) affecting secreted proteins; failure to regulate the process is often associated with disease. Glycosylation is also a ubiquitous protein PTM and site-specific O-glycosylation in close proximity to sites of proteolysis can regulate and direct the activity of proprotein convertases, a disintegrin and metalloproteinases (ADAMs), and metalloproteinases affecting the activation or inactivation of many classes of proteins, including G-protein-coupled receptors (GPCRs). Here, we summarize the emerging data that suggest O-glycosylation to be a key regulator of limited proteolysis, and highlight the potential for crosstalk between multiple PTMs. PMID- 29506881 TI - Extended antibiotic therapy versus placebo after laparoscopic cholecystectomy for mild and moderate acute calculous cholecystitis: A randomized double-blind clinical trial. AB - BACKGROUND: Acute calculous cholecystitis (ACC) is the most common complication of cholelithiasis. Laparoscopic cholecystectomy (LC) is the gold standard treatment in mild and moderate forms. Currently there is consensus for the use of antibiotics in the preoperative phase of ACC. However, the need for antibiotic therapy after surgery remains undefined with a low level of scientific evidence. METHODS: The CHART (Cholecystectomy Antibiotic Randomised Trial) study is a single-center, prospective, double blind, and randomized trial. Patients with mild to moderate ACC operated by LC were randomly assigned to receive antibiotic (amoxicillin/clavulanic acid) or placebo treatment for 5 consecutive days. The primary endpoint was postoperative infectious complications. Secondary endpoints were as follows: (1) duration of hospital stay, (2) readmissions, (3) reintervention, and (4) overall mortality. RESULTS: In the per-protocol analysis, 6 of 104 patients (5.8%) in the placebo arm and 6 of 91 patients (6.6%) in the antibiotic arm developed postoperative infectious complications (absolute difference 0.82 (95% confidence interval, -5.96 to 7.61, P = .81). The median hospital stay was 3 days. There was no mortality. There were no differences regarding readmissions and reoperations between the 2 groups. CONCLUSION: Although this trial failed to show noninferiority of postoperative placebo compared to antibiotic treatment after LC for mild and moderate ACC within a noninferiority margin of 5%, the use of antibiotics in the postoperative period does not seem justified, because it was not associated with a decrease in the incidence of infectious and other types of morbidity in the present study. PMID- 29506882 TI - Chronic pain after mesh versus nonmesh repair of inguinal hernias: A systematic review and a network meta-analysis of randomized controlled trials. AB - BACKGROUND: Chronic pain affects 10%-12% of patients after inguinal hernia repairs. Some have suggested that less foreign material may theoretically prevent pain. If the prevalence of chronic pain is less after nonmesh repairs, selected hernias might be repaired without mesh. Our aim was to clarify if nonmesh repairs are superior to mesh repairs regarding chronic pain. METHODS: For this systematic review, searches were conducted in five databases. The main outcome was chronic pain reported a minimum of six months after mesh and nonmesh repair in adult patients with a primary inguinal hernia. Only randomized controlled trials (RCTs) were included. RESULTS: A total of 23 RCTs with 5,444 patients were included. The median follow up was 1.4 years (range 0.5-10). Twenty-one studies reported crude chronic pain rates, and when considering moderate and severe pain, the prevalences of pain after nonmesh repairs and mesh repairs were similar: median 3.5% (0%-16.2%) versus median 2.9% (0%-27.6%), respectively. Both the meta analyses and the network meta-analysis indicated no difference in chronic pain rates when comparing nonmesh repairs with open- and laparoscopic mesh repairs. CONCLUSION: Mesh may be used without fear of causing a greater rate of chronic pain. PMID- 29506883 TI - Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation. AB - Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome. PMID- 29506884 TI - Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma. AB - PURPOSE: Distant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPCs); yet, there are few reliable predictors of DM in this disease. The role of quantitative imaging (ie, radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that are associated with a higher risk of DM developing. METHODS AND MATERIALS: Radiation therapy planning computed tomography scans were retrieved for all nonmetastatic p16-positive OPC patients treated with radiation therapy or chemoradiation therapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume. The biomarkers included 4 representative radiomic features from tumor first-order statistics, shape, texture, and wavelet groups, as well as a combined 4-feature signature. Univariable Cox proportional hazards models for DM risk were identified. The discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed. RESULTS: There were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up period of 5 years. On univariable analysis, top results included the 4 representative radiomic features (C-index, 0.670-0.686; P < .001), the radiomic signature (C-index, 0.670; P < .001), tumor stage (C-index, 0.633; P < .001), tumor diameter (C-index, 0.653; P < .001), and tumor volume (C-index, 0.674; P < .001), which demonstrated moderate discrimination of DM risk. Combined clinical radiomic models yielded significantly improved performance (C-index, 0.701-0.714; P < .05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index, 0.663-0.796), such as patients with stage III disease. CONCLUSIONS: Radiomic biomarkers appear to classify DM risk for patients with nonmetastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in the assignment of DM risk in future HPV-related OPC clinical trials. PMID- 29506885 TI - Patient-Side Appraisal of Late Radiation-Induced Oral Microvascular Changes. AB - PURPOSE: To determine the clinical feasibility of examining and measuring late irradiation changes in the oral microcirculation of head and neck (HN) cancer patients using the novel CytoCam video microscope system. METHODS AND MATERIALS: In 30 HN cancer patients and 30 age-matched controls, bilateral video images were recorded noninvasively of the oral microcirculation of the buccal mucosa and mandibular gingiva. Tissue perfusion parameters, such as functional capillary density (FCD), buccal blood vessel diameter, and microcirculatory flow index, were analyzed. RESULTS: No difference was observed for mean buccal mucosa FCD in irradiated versus healthy tissue, whereas a lower mean gingival FCD in irradiated versus healthy tissue was observed (34 +/- 17 capillaries per millimeter squared [cpll/mm2] vs 68 +/- 19 cpll/mm2; P < .001). A significant difference in mean buccal blood vessel diameter of 16 +/- 3 MUm was measured, compared with 14 +/- 1 MUm in control buccal mucosa (P < .001). No significant difference in microcirculatory flow index was observed between the 2 groups. CONCLUSIONS: Quantifying oral microcirculatory injury associated with late irradiation effects using the CytoCam was feasible in HN cancer patients. Results indicate that marked differences in tissue-specific microcirculatory measurements of angioarchitecture, diminished capillary density, and extensively dilated blood vessel diameters are associated with late irradiation effects in HN cancer patients. PMID- 29506886 TI - Is Eye Color Related to Dental Injection Pain? A Prospective, Randomized, Single blind Study. AB - INTRODUCTION: Recent studies have investigated the relationship between pain perception and specific phenotypes such as red hair color and various eye colors. Further investigations into biomarkers as they relate to pain could be useful in understanding underlying genetic components involved in these pathways. Additionally, it would be clinically useful to determine if a patient would be more likely to experience pain during dental treatment based on eye color. The purpose of this study was to investigate a link between eye color and perceived injection pain in healthy, asymptomatic white women. METHODS: Three hundred healthy, adult, white female patients were included, 133 with dark eyes and 167 with light eyes. Dental anxiety was assessed with the Corah Dental Anxiety Scale. Subjects with their eye color masked by dark glasses received a right maxillary lateral incisor infiltration of 1 cartridge of 2% lidocaine with 1:100,000 epinephrine. Patients rated their injection pain on a 170-mm Heft-Parker visual analog scale. Photographs of the subjects' eyes were taken after the infiltrations and categorized into dark- and light-eyed groups by 3 independent observers. Comparisons for injection pain were analyzed using analysis of variance and the Tukey-Kramer test. RESULTS: No significant differences were found for pain of injection between dark- or light-eyed subjects. CONCLUSIONS: Eye color was not shown to be a predictor for injection pain in white women. Therefore, eye color would not be clinically useful in determining if a patient would be more likely to experience pain during dental treatment. PMID- 29506887 TI - Hydrogen production from algal biomass - Advances, challenges and prospects. AB - Extensive effort is being made to explore renewable energy in replacing fossil fuels. Biohydrogen is a promising future fuel because of its clean and high energy content. A challenging issue in establishing hydrogen economy is sustainability. Biohydrogen has the potential for renewable biofuel, and could replace current hydrogen production through fossil fuel thermo-chemical processes. A promising source of biohydrogen is conversion from algal biomass, which is abundant, clean and renewable. Unlike other well-developed biofuels such as bioethanol and biodiesel, production of hydrogen from algal biomass is still in the early stage of development. There are a variety of technologies for algal hydrogen production, and some laboratory- and pilot-scale systems have demonstrated a good potential for full-scale implementation. This work presents an elucidation on development in biohydrogen encompassing biological pathways, bioreactor designs and operation and techno-economic evaluation. Challenges and prospects of biohydrogen production are also outlined. PMID- 29506888 TI - Assessing the influence of chin prominence on profile esthetics: A survey study. AB - PURPOSE: The aim of this survey study was to assess the influence of chin prominence on the perception of profile esthetics between genders by orthodontists, oral and maxillofacial surgeons (OMF), plastic surgeons, orthognathic patients and laypersons. MATERIALS AND METHODS: A total of 731 observers participated in this study. Profile photographs of one female and one male showing ideal soft tissue values, skeletal class 1 relationship, and normodivergent facial type were modified with photo editing program (Adobe Photoshop CC software), so that the chin was moved posteriorly up to 10 mm and anteriorly up to 8 mm at 2-mm intervals. Participants were asked to rate 11 female and 11 male profile images and to assess whether surgery was needed. RESULTS: Within the limits of this study, ideal, slightly concave and slightly convex profiles for females, and ideal and slightly concave profiles for males were found more acceptable. Surgery was desired for 50.9% of retrusive profiles and 57.3% of protrusive profiles. Female participants had a higher rate of desire for surgery than male participants, and clinicians desired surgery significantly less than others. Desire for surgery started from 4 mm in males and females for all groups, from -6 mm in orthodontists and OMFs, from -4 mm in other groups in females, and from -6 mm in males for all groups. CONCLUSION: Clinicians tend to operate more pronounced cases when compared to laypeople. A significantly higher rate of surgery was desired for protrusive chin profiles, and female participants had a higher desire for surgery. PMID- 29506890 TI - Survival Outcomes Among Lung Cancer Patients Treated Using a Multidisciplinary Team Approach. AB - BACKGROUND: Evidence favoring a multidisciplinary team (MDT) approach in the treatment of lung cancer is scarce, especially in the United States. The purpose of the present investigation was to evaluate survival outcomes of lung cancer patients treated with an MDT compared with a traditional care model. PATIENTS AND METHODS: The Stony Brook Cancer Center Registry was used to identify all lung cancer cases diagnosed between 2002 and 2016. We compared survival outcomes among 1956 lung cancer patients participating in our institution's Lung Cancer Evaluation Center's (LCEC) MDT program and 2315 lung cancer patients receiving traditional care. Log-ranks tests were used to evaluate differences in the 1-, 3 , 5-, and 10-year survival outcomes between the 2 groups. To address inherent biases, Cox proportional hazard models were used to estimate the effects on survival outcomes and adjust for possible confounders. Propensity matching was also performed to account for the effects of selection bias. RESULTS: The 5-year survival rates in the propensity-matched sample were one third greater among LCEC patients compared with those receiving a traditional care approach (33.6% vs. 23.0%; P < .001). After adjusting for potential confounders in the multivariable propensity-matched analyses, the LCEC model demonstrated a significant beneficial effect on 5-year survival outcomes compared with the standard treatment model (hazard ratio, 0.65; 95% confidence interval, 0.54-0.77). CONCLUSION: The results of the present investigation suggest an improved survival benefit from usage of an MDT model versus a traditional care model in the treatment of lung cancer. Despite the use of sophisticated statistical methods to mitigate bias in a nonrandomized study, additional research is needed to determine the extent to which an MDT approach for lung cancer influences patient outcomes. PMID- 29506889 TI - Targeted treatment of primary aldosteronism - The consensus of Taiwan Society of Aldosteronism. AB - BACKGROUND/PURPOSE: Even with the increasing recognition of primary aldosteronism (PA) as a cause of refractory hypertension and an issue of public health, the consensus of its optimal surgical or medical treatment in Taiwan has not been reached. Our objective was to develop a clinical practice guideline that is feasible for real-world management of PA patients in Taiwan. METHODS: The Taiwan Society of Aldosteronism (TSA) Task Force recognized the above-mentioned issues and reached this Taiwan PA consensus at its inaugural meeting, in order to provide updated information of internationally acceptable standards, and also to incorporate our local disease characteristics and constraints into PA management. RESULTS: In patients with lateralized PA, including aldosterone producing adenoma (APA), laparoscopic adrenalectomy is the 'gold standard' of treatment. Mini laparoscopic and laparoendoscopic single-site approaches are feasible only in highly experienced surgeons. Patients with bilateral adrenal hyperplasia or those not suitable for surgery should be treated by mineralocorticoid receptor antagonists. The outcome data of PA patient management from the literature, especially from PA patients in Taiwan, are reviewed. Mental health screening is helpful in early detection and management of psychopathology among PA patients. CONCLUSION: We hope this consensus will provide a guideline to help medical professionals to manage PA patients in Taiwan to achieve a better quality of care. PMID- 29506891 TI - Intubations in elderly patients have decreased from 1999 through 2014-Results of a multi-center cohort study. AB - BACKGROUND: Advances in pharmacologic therapy, non-invasive positive pressure ventilation (NIPPV) and advanced directives may have decreased the intubations of dyspneic elderly (>=65years old) patients in the emergency department (ED). OBJECTIVE: To determine if the percentage of elderly ED patients intubated has decreased in recent years. METHODS: Design: Retrospective multihospital cohort. SETTING: Consecutive ED patients in nine NJ hospitals (1/1/1999 to 9/30/2014). PROTOCOL: We identified patients intubated in the ED by CPT codes. DATA ANALYSIS: We calculated the annual percentage of patients >=65 intubated and the percentage intubated by diagnosis along with 95% confidence intervals (CIs). RESULTS: Of the 5,693,380 total patients in the database there were 1,065,371 visits for patients>=65. Their average age was 80+/-8years; 54% were female. Of these, 6297 were intubated (0.59%). From 1999 to 2014 the percent intubated decreased from 0.73% to 0.52%, a relative decrease of 29% (95% CI: 17%, 38%). The specific diagnoses with >500 intubations were congestive heart failure (CHF), pneumonia and cardiac arrest, accounting for 37% of the total. Of these three, CHF was the only diagnosis with a statistically significant change from 1999 to 2014: a relative decrease of 70% (95% CI: 53%, 81%). If all diagnoses without CHF are analyzed the overall relative decrease is 14% (95% CI: 3%, 24%). CONCLUSION: Intubation rates for patients>=65 decreased from 1999 through 2014, particularly in CHF patients. We speculate that these findings reflect wider implementation of NIPPV, other therapeutic modalities and advanced directives. PMID- 29506892 TI - Low-level troponin elevations following a reduced troponin I cutoff: Increased resource utilization without improved outcomes. AB - OBJECTIVE: The study sought to evaluate changes in mortality and resource utilization in patients with low level troponin elevations following a reduction in the cutoff for normal troponin I (TnI) from 0.5 ng/mL to the 99th percentile (0.06 ng/mL). METHODS: This was an interrupted time series comparing emergency department (ED) patients with possible acute coronary syndrome (ACS) and TnI values 0.06-0.5 ng/mL before and after an institutional decrease in the TnI cutoff. The primary outcome was overall mortality at 90 days. Secondary outcomes included rates of rehospitalization, subsequent ACS, and coronary intervention within 90 days, as well as rates of anticoagulation, cardiology consultation, cardiac testing, and coronary intervention during the index visit. Outcomes for the pre-cutoff change group (control) and post-cutoff change group (post) were compared using tests of proportions and odds ratios. RESULTS: The study included a total of 1058 subjects with 529 in each cohort. No significant differences in 90 day outcomes were observed between groups, including mortality (13.2% post vs 14.1% control, OR 0.93 [95% CI: 0.65-1.34], p = 0.705). During the index visit, the post-group demonstrated higher rates of cardiology consultation (55.4% vs 41.2%, OR 1.77 [1.39-2.26], p < 0.0001) and cardiac stress testing (16.4% vs 10.6%, OR 1.66 [1.16-2.38], p = 0.006), but no significant differences in coronary intervention or short-term mortality were observed. CONCLUSION: A reduction in the TnI cutoff to the 99th percentile did not change mortality or rates of coronary intervention in ED patients with low level troponin elevations, but significantly increased the use of cardiology resources. PMID- 29506893 TI - Perioperative Risk Factors Associated With Postoperative Unplanned Intubation After Lung Resection. AB - OBJECTIVE: Postoperative respiratory failure requiring reintubation is associated with a significant increase in mortality. However, perioperative risk factors and their effects on unplanned 30-day reintubation and postoperative outcomes after unplanned reintubation following lung resection are not described well. The aim of this study was to determine whether certain comorbidities, demographic factors, and postoperative outcomes are associated with 30-day reintubation after thoracic surgery. DESIGN: This was a retrospective observational study using multivariable logistic regression to identify preoperative risk factors and consequences of unplanned 30-day reintubation. SETTING: Multi-institutional, prospective, surgical outcome-oriented database study. PARTICIPANTS: Using the American College of Surgeons National Surgical Quality Improvement Program database, video-assisted thorascopic surgery and thoracotomy lung resections (lobectomy, wedge resection, segmentectomy, bilobectomy, pneumonectomy) were analyzed by Common Procedural Terminology codes from the years 2007 to 2016 in 16,696 patients undergoing thoracic surgery. INTERVENTION: None. MEASUREMENT AND MAIN RESULTS: The final analysis included 16,696 patients, of who 593 (3.5%) underwent unplanned reintubation. Among the final study population, 137 (23%) of unplanned intubations occurred within 24 hours postoperatively and the median (25%, 75% quartile) day of reintubation was day 3 (2, 8 days). The final multivariable logistic regression analysis suggested that age, American Society of Anesthesiologists physical status classification score >=4, dyspnea with moderate exertion and at rest, history of chronic obstructive pulmonary disease, male sex, smoking, functional dependence, steroid use, open thoracotomies, increased operation time, and preoperative laboratory results (albumin and hematocrit) were associated with unplanned intubation after lung resection (p < 0.05). Unplanned intubation was associated significantly with 30-day mortality, reoperation, postoperative blood transfusion, and increased hospital length of stay (p < 0.05). CONCLUSIONS: Nonmodifiable and modifiable preoperative risk factors were associated with increased odds of unplanned reintubation. Patients who experienced unplanned intubation were at considerable risk for 30-day mortality, reoperation, postoperative blood transfusion, and increased hospital length of stay. PMID- 29506894 TI - Anesthesia Matters: In Pursuit of the Interventions that Affect Outcomes in Transcatheter Aortic Valve Replacement. PMID- 29506895 TI - The DRIHEMATO PT-S Test in Cardiac Surgery, a Tulip Mania Problem? PMID- 29506896 TI - Strain for Relaxation in the Operating Room? PMID- 29506897 TI - Success With VV ECMO for Respiratory Failure: Is it the Device, the Center, or Both? PMID- 29506898 TI - Breakthrough Pain: A Qualitative Study of Patients with Advanced Cancer in Northwest China. AB - BACKGROUND: Breakthrough pain is an extremely painful symptom that impairs quality of life in cancer patients. It negatively impacts their emotional wellbeing, physical function, and mental health. The aim of this study is to use a qualitative methodology to examine the perception of cancer patients with breakthrough pain in the Northwest of China. METHODS: A semi-structured, face-to face interview was conducted with nine cancer patients who experienced breakthrough pain; and a qualitative content analysis was performed. RESULTS: Five themes were generated: (1) sufferings from breakthrough cancer pain, (2) hopelessness and helplessness, (3) perception of breakthrough cancer pain and analgesia, (4) strong as a Chinese, and (5) support needed from health care system. CONCLUSION: Although certain traditional cultural worldviews increase patients' acceptance of pain, healthcare providers need proper treatment guidelines to improve the quality of cancer patient care in Northwest China. We recommend that healthcare workers and hospital managers place cancer pain management in higher priority. Relevant pain management education programs should be provided to both healthcare providers and patients to improve their knowledge in these area. Healthcare professionals need to establish a mutual communication channel between patients and healthcare workers to meet patients' needs during breakthrough pain episodes in order to improve pain management. Nevertheless, the government and the healthcare system need to recognize the importance and urgency of palliative care services. PMID- 29506899 TI - Respiratory Tract Infections and Voice Quality in 4-Year-old Children in the STEPS Study. AB - OBJECTIVES: Health-related factors are part of the multifactorial background of dysphonia in children. Respiratory tract infections affect the same systems and structures that are used for voice production. The purpose of this study was to investigate if the number of respiratory tract infections or the viral etiology were significant predictors for a more hoarse voice quality. METHODS: The participants were 4-year-old children who participated in the multidisciplinary STEPS study (Steps to the Healthy Development and Well-being of Children) where they were followed up from pregnancy or birth to 4 years of age. Data were collected through questionnaires and a health diary filled in by the parents. Some of the children were followed up more intensively for respiratory tract infections during the first 2 years of life, and nasal swab samples were taken at the onset of respiratory symptoms. Our participants were 489 of these children who had participated in the follow-up for at least 1 year and for whom data on respiratory tract infections and data on voice quality were available. RESULTS: The number of hospitalizations due to respiratory tract infections was a significant predictor for a more hoarse voice quality. Neither the number of rhinovirus infections nor the number of respiratory syncytial virus infections was statistically significant predictors for a more hoarse voice quality. CONCLUSIONS: Based on our results, we would suggest including questions on the presence of respiratory tract infections that have led to hospitalization in the pediatric voice anamnesis. Whether the viral etiology of respiratory tract infections is of importance or not requires further research. PMID- 29506900 TI - A review of the conundrum of mild hypoxic-ischemic encephalopathy: Current challenges and moving forward. AB - A review of the conundrum called mild hypoxic-ischemic encephalopathy (HIE) is provided. During the past decades, the definition of HIE has evolved to accommodate the short window of time required for the initiation of therapeutic hypothermia. Also, neurological evaluations have changed with the use of simpler staging systems that can be applied within the first 6 h of life. In this review, we discuss the challenges in the identification of newborns with "mild HIE" within 6 h after birth, the limitations in the existing early biomarkers of brain injury, and the current knowledge gaps in the long term neurodevelopmental outcomes of infants diagnosed with mild HIE. Progress in the understanding of mild HIE and its sequelae continues to be hindered by the lack of a standardized definition for mild HIE that will reliably identify at-risk infants who may benefit from neuroprotective strategies. PMID- 29506901 TI - Corrigendum to "Omega-3 and -6 fatty acid supplementation and sensory processing in toddlers with ASD symptomology born preterm: A randomized controlled trial" [Early Hum. Dev. 115 (2017) 64-70]. PMID- 29506902 TI - Comparison of Double-Freeze versus Modified Triple-Freeze Pulmonary Cryoablation and Hemorrhage Volume Using Different Probe Sizes in an In Vivo Porcine Lung. AB - PURPOSE: To determine size of ablation zone and pulmonary hemorrhage in double freeze (DF) vs modified triple-freeze (mTF) cryoablation protocols with different probe sizes in porcine lung. MATERIALS AND METHODS: In 10 healthy adult pigs, 20 pulmonary cryoablations were performed using either a 2.4-mm or a 1.7-mm probe. Either conventional DF or mTF protocol was used. Serial noncontrast CT scans were performed during ablations. Ablation iceball and hemorrhage volumes were measured and compared between protocols and probe sizes. RESULTS: With 1.7-mm probe, greater peak iceball volume was observed with DF compared with mTF, although difference was not statistically significant (16.1 mL +/- 1.9 vs 8.8 mL +/- 3.6, P = .07). With 2.4-mm probe, DF and mTF produced similar peak iceball volumes (14.0 mL +/- 2.8 vs 14.6 mL +/- 2.7, P = .88). Midcycle hemorrhage was significantly larger with DF with the 1.7-mm probe (94.3 mL +/- 22.2 vs 19.6 mL +/- 2.1, P = .02) and with both sizes combined (93.2 mL +/- 17.5 vs. 50.9 mL +/- 12.6, P = .048). Rate of hemorrhage increase was significantly higher in DF (10.4 mL/min vs 5.1 mL/min, P = .003). End-cycle hemorrhage was visibly larger in DF compared with mTF across probe sizes, although differences were not statistically significant (P = .14 for 1.7 mm probe, P = .18 for 2.4 mm probe, and P = .07 for both probes combined). Rate of increase in hemorrhage during the last thaw period was not statistically different between DF and mTF (3.0 mL/min vs 2.8 mL/min, P = .992). CONCLUSIONS: mTF reduced rate of midcycle hemorrhage compared with DF. With mTF, midcycle hemorrhage was significantly smaller with 1.7-mm probe; although noticeably smaller with 2.4-mm probe, statistical significance was not achieved. Iceball size was not significantly different across both protocols and probe types. PMID- 29506903 TI - A Comparison of Bleeding Complications in Patients Undergoing Percutaneous Renal Cryoablation Using Cryoprobes with and without Heat-Based Track Ablation. AB - PURPOSE: To determine if the use of heat-based track ablation with new-generation cryoprobes is associated with decreased renal cryoablation bleeding complications. MATERIALS AND METHODS: Eighty-nine patients who underwent percutaneous cryoablation for treatment of a solitary renal mass with the use of cryoprobes with track ablation (CwTA) from October 29, 2015, to May 18, 2017, were compared with a propensity score-matched control group of 178 patients who underwent treatment with the use of cryoprobes without track ablation (Cw/oTA) from January 5, 2012, to October 28, 2015. Bleeding complications were assessed with the use of the Clavien-Dindo classification system and compared between the matched patient groups by means of conditional logistic regression, both univariately and in a multivariate model to adjust for imbalanced covariates. Change in patient hemoglobin was evaluated as a secondary measure of periprocedural bleeding. RESULTS: Seven of the 89 patients (7.9%) who underwent percutaneous renal cryoablation with the use of CwTA developed major (grade >=3) bleeding complications, versus 13 of the 178 patients (7.3%) treated with the use of Cw/oTA. Conditional logistic regression analysis adjusted for potential confounders showed that major, minor, and overall bleeding complications were not associated with the type of cryoprobes used for treatment (P values .727, .370, and .733, respectively). There was also no significant difference in postprocedural change in hemoglobin for patients treated with the use of CwTA compared with Cw/oTA (P = .909). Furthermore, total duration of track ablation in patients with bleeding complications (mean 169 seconds, SD 68, range 60-240) was not significantly different than in patients without bleeding complications (mean 171 seconds, SD 86, range 30-360; P = .940). CONCLUSIONS: The use of cryoprobes with heat-based track ablation did not decrease the incidence of bleeding complications after renal cryoablation compared with procedures performed without track ablation. PMID- 29506906 TI - Application of unfolding transformation in the random matrix theory to analyze in vivo neuronal spike firing during awake and anesthetized conditions. AB - General anesthetics decrease the frequency and density of spike firing. This effect makes it difficult to detect spike regularity. To overcome this problem, we developed a method utilizing the unfolding transformation which analyzes the energy level statistics in the random matrix theory. We regarded the energy axis as time axis of neuron spike and analyzed the time series of cortical neural firing in vivo. Unfolding transformation detected regularities of neural firing while changes in firing densities were associated with pentobarbital. We found that unfolding transformation enables us to compare firing regularity between awake and anesthetic conditions on a universal scale. PMID- 29506904 TI - Lunate excision with capitohamate fusion in the treatment of stage IIIB and IIIC Kienbock's disease. AB - OBJECTIVE: The aim of this study was to report our results of lunate excision combined with capitohamate fusion in the treatment of Kienbock's stage IIIB/IIIC disease. METHODS: A total of 7 patients with a mean age 35.2 (SD 11.5) years were enrolled in the study. Pain was the principal reason for surgery. All operations were carried out by the same senior surgeon. Patients were evaluated in terms of range of motion, DASH and VAS scores, satisfaction, and grip/tip/palmar/key pinch strength compared with contralateral sides. Preoperative carpal height indexes and findings of osteoarthritis were determined radiographically and compared with postoperative evaluations. RESULTS: Mean duration of follow up was 15.2 months. Mean DASH and VAS scores were 13.8 2.7 and 2 1.1 respectively. The mean patient satisfaction score was 3.2 0.4 over 4 points. The mean grip strength in the operated hands was 66.4%, palmar pinch was 75.1%, tip pinch was 71.8% and key pinch was 70.4% when compared to the contralateral unaffected sides. The mean flexion range in the operated hands was 58.8%, extension range was 60.3%, radial deviation range was 65.2% and ulnar deviation range was 65.7% when compared to the contralateral sides. There was no significant difference between preoperative and postoperative carpal height ratios (p = 0.086). CONCLUSIONS: Our early term results indicate that lunate excision combined with capitohamate fusion may be an alternative treatment option in patients with stage IIIB and IIIC Kienbock's disease. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 29506907 TI - What is the evidence for the role of therapeutic apheresis in the management of complement-associated thrombotic microangiopathies? AB - Thrombotic microangiopathies (TMAs) are disorders characterized by endothelial cell activation, microangiopathic hemolytic anemia, thrombocytopenia and organ failure of variable intensity. The pathophysiology of various types of TMAs have become an interesting field of study. Alternative complement system activation plays an important role in several pathophysiological conditions. Complement activation is also described in an increasing number of TMAs. Inherited defects in complement regulatory genes and acquired autoantibodies against complement regulatory proteins have been described. Atypical hemolytic uremic synrome (HUS) is caused by uncontrolled activation of the alternative complement system, now called complement-mediated TMAs. Recently, application of a monoclonal antibody that specifically binds to C5 became available to treat patients with complement mediated TMAs. Eculizumab is a humanized monoclonal antibody that blocks complement C5 activation. Empiric therapeutic apheresis is also recommended in all forms of complement-mediated TMAs. The justification for therapeutic apheresis use in all forms of complement-mediated TMAs is that it can effectively remove the autoantibodies or mutated circulating complement regulators while replacing absent or defective complement regulators. Currently, therapeutic apheresis and eculizumab are the available treatment options for complement mediated TMAs. In this paper, we review the evidence for the role of therapeutic apheresis in the management of complement-associated TMAs. PMID- 29506905 TI - Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study. AB - PURPOSE: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome. METHODS: Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment. RESULTS: There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. CONCLUSION: In our small patient cohort, there seems to be no phenotype-genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype. PMID- 29506909 TI - VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans. AB - OBJECTIVE: Reduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD related regulation and association of VEGF and GLUT1 (SLC2A1) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study. METHODS: 92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance. RESULTS: In this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ~39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 * 10-11) but higher SLC2A1 expression (P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes. CONCLUSIONS: The results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance. CLINICAL TRIAL REGISTRATION NUMBER: NCT01631123. PMID- 29506910 TI - GPR142 prompts glucagon-like Peptide-1 release from islets to improve beta cell function. AB - OBJECTIVE: GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets are limited to regulating insulin secretion. The current study expands research on its action. METHODS AND RESULTS: We demonstrated by in situ hybridization and immunostaining that GPR142 is expressed not only in beta cells but also in a subset of alpha cells. Stimulation of GPR142 by a selective agonist increased glucagon secretion in both human and mouse islets. More importantly, the GPR142 agonist also potentiated glucagon-like peptide-1 (GLP-1) production and its release from islets through a mechanism that involves upregulation of prohormone convertase 1/3 expression. Strikingly, stimulation of insulin secretion and increase in insulin content via GPR142 engagement requires intact GLP-1 receptor signaling. Furthermore, GPR142 agonist increased beta cell proliferation and protected both mouse and human islets against stress-induced apoptosis. CONCLUSIONS: Collectively, we provide here evidence that local GLP-1 release from alpha cells defines GPR142's beneficial effects on improving beta cell function and mass, and we propose that GPR142 agonism may have translatable and durable efficacy for the treatment of type 2 diabetes. PMID- 29506908 TI - Single Intramuscular Injection of AAV-shRNA Reduces DNM2 and Prevents Myotubular Myopathy in Mice. AB - Myotubular myopathy, or X-linked centronuclear myopathy, is a severe muscle disorder representing a significant burden for patients and their families. It is clinically characterized by neonatal and severe muscle weakness and atrophy. Mutations in the myotubularin (MTM1) gene cause myotubular myopathy, and no specific curative treatment is available. We previously found that dynamin 2 (DNM2) is upregulated in both Mtm1 knockout and patient muscle samples, whereas its reduction through antisense oligonucleotides rescues the clinical and histopathological features of this myopathy in mice. Here, we propose a novel approach targeting Dnm2 mRNA. We screened and validated in vitro and in vivo several short hairpin RNA (shRNA) sequences that efficiently target Dnm2 mRNA. A single intramuscular injection of AAV-shDnm2 resulted in long-term reduction of DNM2 protein level and restored muscle force, mass, histology, and myofiber ultrastructure and prevented molecular defects linked to the disease. Our results demonstrate a robust DNM2 knockdown and provide an alternative strategy based on reduction of DNM2 to treat myotubular myopathy. PMID- 29506912 TI - Transient Ischemic Attack while Injecting Intravenous Saline Contrast in a Patient with Persistent Left Superior Vena Cava. AB - In this case report, we describe a patient who has a persistent left superior vena cava (PLSVC) manifesting as a transient ischemic attack (TIA) and a remote brain abscess. PLSCV, when draining in the left atrium, is a cause of right to left shunt, and it has been related to brain abscesses and, as reported in a few cases, to ischemic stroke. After admission, our patient experienced 2 new episodes of TIA while being injected with agitated saline contrast through the left arm, producing echocardiographic images of right to left shunt, which gave the clue to the diagnosis. PMID- 29506911 TI - Results from the second year of a collaborative effort to forecast influenza seasons in the United States. AB - Accurate forecasts could enable more informed public health decisions. Since 2013, CDC has worked with external researchers to improve influenza forecasts by coordinating seasonal challenges for the United States and the 10 Health and Human Service Regions. Forecasted targets for the 2014-15 challenge were the onset week, peak week, and peak intensity of the season and the weekly percent of outpatient visits due to influenza-like illness (ILI) 1-4 weeks in advance. We used a logarithmic scoring rule to score the weekly forecasts, averaged the scores over an evaluation period, and then exponentiated the resulting logarithmic score. Poor forecasts had a score near 0, and perfect forecasts a score of 1. Five teams submitted forecasts from seven different models. At the national level, the team scores for onset week ranged from <0.01 to 0.41, peak week ranged from 0.08 to 0.49, and peak intensity ranged from <0.01 to 0.17. The scores for predictions of ILI 1-4 weeks in advance ranged from 0.02-0.38 and was highest 1 week ahead. Forecast skill varied by HHS region. Forecasts can predict epidemic characteristics that inform public health actions. CDC, state and local health officials, and researchers are working together to improve forecasts. PMID- 29506913 TI - Determinants of survival following hepatocellular carcinoma in Egyptian patients with untreated chronic HCV infection in the pre-DAA era. AB - BACKGROUND AND STUDY AIMS: In this study we assessed rates and determinants of survival in people with untreated chronic HCV infection and hepatocellular carcinoma (HCC) in an Egyptian liver clinic setting. PATIENTS AND METHODS: This is a prospective cohort study of patients diagnosed with HCV-related HCC and undergoing HCC management at a national liver centre in Egypt in 2013-2014 and with a follow-up through 2016. RESULTS: A total of 345 patients diagnosed with HCV-related liver cirrhosis complicated by HCC were included. Median age at diagnosis was 57 years (IQR = 52, 62), the majority were male (78%) and Child Turcotte-Pugh (CTP) class A (64%). At diagnosis Barcelona Clinic Liver Cancer staging (BCLC) was 0 (8%), A (48%), B (20%), C (17%), and D (7%). Most common HCC management modalities were transarterial chemoembolization (TACE) (42%), and radiofrequency ablation (RFA) (21%). Median survival following HCC was 22.8 months. Factors associated with poorer survival in adjusted analyses were INR (HR = 1.81, p = 0.01), alpha-foeto protein (AFP) >=200 (HR = 1.41, p = 0.02), higher CTP score (HR = 2.48, p < 0.01), and advanced BCLC stage (HR = 1.85, p < 0.01). One year survival in patients with CTP A, B, and C was 85%, 71% and 32%, respectively. One year survival following RFA, TACE, combination RFA/TACE, and sorafenib was 93%, 79%, 80% and 60%, respectively. CONCLUSION: Survival following HCV-HCC in Egyptian patients undergoing HCC management in a specialised clinic setting is poor, although similar to high income country settings. CTP score is a key determinant of survival, even following adjustment for BCLC stage and HCC management. PMID- 29506915 TI - Current practice in provision of alcohol assessment and support for patients following alcohol related facial fractures. AB - OBJECTIVES: The algorithm for maxillofacial trauma management is well defined; however, provision of alcohol assessment for patients after trauma is not widely practiced. This study aims to investigate the rate of alcohol assessment achieved within the demographic characteristics of patients with facial trauma and the circumstances where this intervention was implemented. STUDY DESIGN: This study retrospectively examined the Victorian Admitted Episodes Data Set (VAED) from 2004 to 2013. RESULTS: Of a total of 54,730 presentations with facial fractures to all Victorian hospitals, 0.9% in the non-alcohol-involved group and 4.3% in the alcohol-involved group received alcohol assessment during their inpatient stay (P < .001). Among patients with alcohol involvement, the likelihood of assessment was significantly different with regard to length of stay, age, trauma mechanism, and gender. Positive blood alcohol test did not relate to probability of assessment. Those with acute alcohol intoxication were less likely to be assessed (P < .001), whereas those with harmful alcohol use, alcohol dependence, or alcohol withdrawal state were much more likely to be assessed (P < .001). CONCLUSIONS: This study found no consistent practice of alcohol support to patients following alcohol-related facial fractures. Post-trauma alcohol support may optimize perioperative management of patients and education regarding alcohol harm and may reduce future trauma risk. Development and refinement of such practice is an area for further research. PMID- 29506914 TI - Successful replacement of a metallic hepaticogastrostomy stent dislocated during endoscopic retrograde cholangiography. AB - In the present case with lower bile duct cancer, an endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) was placed because of repeated obstructions of biliary metallic stent. However, when the HGS was occluded, transpapillary duodenoscopic procedure was again required. During this transpapillary procedure, including biliary balloon cleaning and metallic stent deployment, the HGS stent was dislocated into the stomach. Fortunately, due to the complete fistulization, no bile peritonitis was recognized and an HGS stent could be replaced from the gastric wall three days later. Current case report alarms a risk of HGS stent dislocation when conducting endoscopic retrograde cholangiopancreatography (ERCP) associated procedures after the placement of an HGS stent. PMID- 29506916 TI - Prevalence of primary open-angle glaucoma among patients with obstructive sleep apnea. AB - OBJECTIVE: Our objective was to determine primary open-angle glaucoma (POAG) prevalence among obstructive sleep apnea (OSA) patients because the perioperative environment risks further damaging the optic nerve. STUDY DESIGN: We analyzed a "convenience sample" referred by Sleep Medicine for oral appliances because of continuous positive airway pressure intolerance. We determined the aggregate prevalence of the 3 POAG subtypes-"classic" open-angle glaucoma (COAG), normal tension glaucoma (NTG), and open-angle glaucoma suspect (OAGS)-among the index population and compared it with that of same hospital's general population. Similarly determined were associations between OSA severity levels (apnea hypopnea index [AHI]) and POAG subtypes. RESULTS: Among the study sample of 225 patients with OSA (96.4% male; mean age 58.5 +/- 12.3 years), 47 (20.9%) had POAG, with a subtype distribution of COAG: 12 (25.5%), NTG: 8 (17.0%), and OAGS: 27 (57.4%). The POAG prevalence rate among medical center's general population was 2.5%, which was significantly less (P < .00001) than among those with comorbid OSA. Severity of the breathing disorder (AHI) failed to identify a significant correlation to any POAG subtype (P > .05). CONCLUSION: The significant prevalence of POAG among OSA sufferers suggests need for preoperative consultations from an ophthalmologist to determine eye health and possibly an anesthesiologist to avoid potential vision loss. PMID- 29506917 TI - Multidetector computed tomography imaging characteristics of asymptomatic palatine tonsilloliths: a retrospective study on 3886 examinations. AB - OBJECTIVE: This study aimed to estimate the prevalence of palatine tonsilloliths and analyze their multidetector computed tomography (CT) imaging features. STUDY DESIGN: The CT images of 3886 patients (1654 men, 2232 women; mean age, 35.8 years) were reviewed. The distribution, dimension, morphology, and location of each tonsillolith was assessed. The correlation between participant demographic characteristics and the characteristics (prevalence, number, size) of tonsilloliths was determined. RESULTS: The prevalence of palatine tonsilloliths was 30.3%; we identified significant differences in the prevalence and size between men and women. The prevalence of tonsilloliths significantly increased with age (P < .001). The mean number of tonsilloliths per participant was 2.7, and 64.7% of patients had 1 to 2 tonsilloliths. Ovoid-shaped tonsilloliths were the most common (approximately 80%). The centers of the tonsillar crypts contained the majority of the tonsilloliths, 50.3% of which had sizes of 1 to 2 mm. CONCLUSION: The results, based on a larger sample size compared with previous studies, can be applied as guidelines for the diagnosis of tonsilloliths on CT images. PMID- 29506918 TI - Prognostic indicators of improved survival and quality of life in surgically treated oral cancer. AB - OBJECTIVE: No published study has analyzed the prognostic factors of surgically treated oral squamous cell carcinoma (OSCC) in relation to both survival and quality of life (QoL). The aim of this study was to analyze postoperative QoL in relation to survival to identify which parameters can predict the long-term outcome allowing the best QoL. STUDY DESIGN: This retrospective cohort study considered 167 patients affected by OSCC treated surgically at the Otolaryngology Department of Cattinara Hospital (Trieste, Italy) by a single surgeon. We collected data about the main prognostic factors and the postoperative QoL 12 month after surgery. RESULTS: The 5-year overall survival rate was equal to 68.1%, and the 5-year disease-specific survival was 77.8%. In this sample, 32% of patients also underwent adjuvant chemoradiotherapy. On stepwise Cox regression, the best predictors of disease-specific survival were the N stage (P < .001) and tumor depth of invasion (P < .001). QoL was affected by N stage, depth of invasion, invasive surgical approach, radiotherapy, and neck dissection (P < .05). CONCLUSION: The prognostic factors that affect both survival rates and residual QoL are the surgical approach, the neck stage, and the depth of invasion, all of which can be minimized by early diagnosis. PMID- 29506919 TI - Impact of a Structured Reporting Template on Adherence to Prostate Imaging Reporting and Data System Version 2 and on the Diagnostic Performance of Prostate MRI for Clinically Significant Prostate Cancer. AB - PURPOSE: The aim of this study was to assess the impact of a structured reporting template on adherence to the Prostate Imaging Reporting and Data System (PI-RADS) version 2 lexicon and on the diagnostic performance of prostate MRI to detect clinically significant prostate cancer (CS-PCa). METHODS: An imaging database was searched for consecutive patients who underwent prostate MRI followed by MRI ultrasound fusion biopsy from October 2015 through October 2017. The initial MRI reporting template used included only subheadings. In July 2016, the template was changed to a standardized PI-RADS-compliant structured template incorporating dropdown menus. Lesion, patient characteristics, pathology, and adherence to the PI-RADS lexicon were extracted from MRI reports and patient charts. Diagnostic performance of prostate MRI to detect CS-PCa using combined ultrasound-MRI fusion and systematic biopsy as a reference standard was assessed. RESULTS: Three hundred twenty-four lesions in 202 patients (average age, 67 years; average prostate-specific antigen level, 5.9 ng/mL) were analyzed, including 217 MRI peripheral zone (PZ) lesions, 84 MRI non-PZ lesions, and 23 additional PZ lesions found on systematic biopsy but missed on MRI. Thirty-three percent (106 of 324) were CS-PCa. Adherence to the PI-RADS lexicon improved from 32.9% (50 of 152) to 88.4% (152 of 172) (P < .0001) after introduction of the structured template. The sensitivity of prostate MRI for CS-PCa in the PZ increased from 53% to 70% (P = .011). There was no significant change in specificity (60% versus 55%, P = .458). CONCLUSIONS: A structured template with dropdown menus incorporating the PI-RADS lexicon and classification rules improves adherence to PI-RADS and may increase the diagnostic performance of prostate MRI for CS-PCa. PMID- 29506920 TI - ECFS best practice guidelines: the 2018 revision. AB - Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe. PMID- 29506921 TI - Elucidating the associations between sleep disturbance and depression, fatigue, and pain in older adults with cancer. AB - OBJECTIVES: Sleep disturbance is prevalent and often coexists with depression, fatigue, and pain in the cancer population. The aim of this study was to describe the prevalence of sleep disturbance with co-existing depression, fatigue, and pain in older patients with cancer. We also examined the associations of several socio-demographic and clinical variables with sleep disturbance. METHODS: This cross-sectional study consisted of 389 older patients with solid and hematologic malignancies who were referred to the Specialized Oncology Care & Research in the Elderly (SOCARE) clinics at the Universities of Rochester and Chicago between May 2011 and October 2015 and completed a sleep and geriatric assessment (that inquires about fatigue, pain, and depression). Multivariate logistic regression was used to identify variables associated with sleep disturbance. RESULTS: The prevalence of sleep disturbance was 40%. Of those with sleep disturbance (n = 154), 84% also had at least one of the other three symptoms (25% had one symptom, 38% had two symptoms, and 21% had three symptoms). Sleep disturbance was more likely to be reported in those with comorbidities (45% vs. 28%, P = 0.002), depression (49% vs. 36%, P = 0.015), fatigue (49% vs. 23%, P < 0.001), and pain (45% vs. 31%, P = 0.010). On multivariable analysis, only fatigue (adjusted odds ratio (AOR) 1.90, 95% CI 1.10-3.30, P = 0.020) was independently associated with sleep disturbance. CONCLUSIONS: Sleep disturbance is prevalent and often co occurs with depression, fatigue, or pain in older patients with cancer. Fatigue was significantly associated with sleep disturbance and future studies should explore interventions that target sleep disturbance and fatigue. PMID- 29506923 TI - Why France is making eight new vaccines mandatory. AB - France is one of the countries with the highest prevalence of vaccine hesitancy in the world. In an attempt to raise vaccination coverages, the French government made on January 1, 2018 eight more vaccines mandatory in addition to the three required until then. The process that led to this policy choice is of particular interest. We describe how vaccines became contentious in France and how French authorities came to view mandatory vaccination as the solution to the rise in vaccine hesitancy. In a bold move, French public health authorities turned to a new type of institutional device grounded in the ideal of democracy and public participation to political decision-making: "a citizen consultation". This consultation anchored the idea that legal coercion could be the solution to France's crisis with vaccines. Time will tell whether the French extension of mandatory vaccination will reduce tensions around vaccines. PMID- 29506922 TI - Efficacy of a high-potency multivalent foot-and-mouth disease virus vaccine in cattle against heterologous challenge with a field virus from the emerging A/ASIA/G-VII lineage. AB - In 2015, outbreaks of foot-and-mouth disease (FMD) in the Middle East were discovered to be caused by a viral lineage (A/ASIA/G-VII), which has recently emerged from the Indian sub-continent. In vitro vaccine matching data generated by the World Reference Laboratory (WRLFMD) indicated that A/ASIA/G-VII field viruses were poorly matched with vaccines (A-SAU-95, A22 IRQ and A-IRN-05) that are already used in the region. In order to assess the likely performance of one of these commercially available FMD vaccines, sixteen cattle were vaccinated with a polyvalent vaccine which contained two serotype A components (A-SAU-95 and A IRN-05) with a homologous potency of at least 6PD50, and two cattle were left unvaccinated as controls. Twenty-one days later, all 18 cattle were challenged by tongue inoculation with an FMDV field isolate A/IRN/22/2015 from the A/ASIA/G-VII lineage, in line with the European Pharmacopeia PPG test conditions. The two control animals developed generalised FMD, and 7/16 vaccinated animals developed at least one foot lesion, thus only 56.3% were defined as protected. For the vaccine components, there was a significant increase in the probability of protection with increasing serological titres for A-SAU-95 (p = 0.03), but not for A-IRN-05 (p = 0.42). Analysis of FMDV in blood and nasal swabs suggested that vaccination reduced shedding and potential onward spread of FMD virus even if the animal developed foot lesions. In summary, the results from this study suggest that whilst this vaccine would not be appropriate for use in an emergency situation (in previously FMD-free countries), it may be partially effective in the field in endemic countries where repeat prophylactic vaccination is practiced. For emergency reactive vaccination, the findings from this study support the idea that a new vaccine strain should be developed that is tailored to the A/ASIA/G-VII lineage. PMID- 29506924 TI - Killed but metabolically active Pseudomonas aeruginosa-based vaccine induces protective humoral- and cell-mediated immunity against Pseudomonas aeruginosa pulmonary infections. AB - Pseudomonas aeruginosa (Pa) is a significant cause of morbidity and mortality, especially in cystic fibrosis patients. Its eradication is difficult due to a wide phenotypic adaptability and an increase of its resistance to antibiotics. After the failure of several recombinant vaccines which mainly triggered humoral response, live-attenuated vaccines received attention thanks to their ability to elicit a broad immunity with both humoral- and cell-mediated responses, essential to fight this pathogen. In this study, we developed an innovative and safer live attenuated Pa vaccine based on a Killed But Metabolically Active (KBMA) attenuation method. KBMA Pa has been further rationally designed to overexpress beneficial effectors like the type 3 secretion system apparatus. We demonstrated that KBMA Pa elicits a high and broad humoral response in mice against several antigens of particular interest such as OprF and PcrV proteins. Moreover, we assessed cytokines in the serum of immunized mice and showed that KBMA Pa elicits Th1, Th2 and especially Th17 pathways of cell-mediated immune responses. Th17 pathway involvement was also confirmed after specific stimulation of helper T cells in immunized mice. Finally, we showed that this vaccine is safe and has a protective effect in a murine acute pulmonary infectious challenge. In conclusion, KBMA Pa is a new platform with high potential for the development of a vaccine against Pa. PMID- 29506925 TI - Treated Versus Untreated Depression in Total Joint Arthroplasty Impacts Outcomes. AB - BACKGROUND: To determine if there was a difference in the change in patient reported physical function (PF) between nondepressed and medically treated depressed or untreated depressed total joint arthroplasty (TJA) patients. METHODS: This is an Institutional Review Board exempt retrospective review of 280 TJA cases from March 2014 to May 2016. Patient-reported PF was measured as part of the routine care via the Patient Reported Outcomes Measurement Information System PF computerized adaptive test. Linear generalized estimating equation regression analyses were used. RESULTS: Untreated depressed cases demonstrated much smaller gains in PF scores compared to nondepressed patients (P = .020). Additionally, although treated and untreated depressed patients had statistically similar preoperative and postoperative PF scores (P > .05), untreated depressed cases experienced a lower magnitude of change (P = .015). CONCLUSION: Medically treated depressed patients may have similar PF gains as nondepressed patients. Larger prospective studies may help identify whether screening for untreated depression and subsequent treatment leads to improved outcomes. PMID- 29506926 TI - Robotic Arm-Assisted Total Knee Arthroplasty. AB - BACKGROUND: Robotic arm-assisted total knee arthroplasty (RATKA) has a number of potential advantages. Therefore, in order to more comprehensively assess this technology, we reviewed the (1) accuracy and precision; (2) soft-tissue protection; (3) patient satisfaction; (4) learning curve; and (5) its other potential benefits. METHODS: A literature review was conducted using PubMed search database for studies reporting clinical outcomes, cadaver results, radiographic outcomes, surgeon experience, and robotic accuracy. Forty articles were included for the final analysis. RESULTS: Advantages of RATKA may include greater component accuracy and precision, soft-tissue protection, increased patient satisfaction, a short learning curve, optimal ergonomic design, and less surgeon and surgical team fatigue. The aforementioned advantages might help improve clinical, surgical, and patient-reported outcomes. CONCLUSION: Although there are a number of studies that highlight the potential advantages of RATKA, most of these studies report of short-term outcomes. It is hoped that longer term studies will continue to support the use of this technology in providing higher patient satisfaction and other clinical outcomes. PMID- 29506927 TI - Cost Efficacy of Methicillin-Resistant Staphylococcus aureus Decolonization With Intranasal Povidone-Iodine. AB - BACKGROUND: With increasing rates of virulent drug resistant organisms, MRSA (methicillin-resistant Staphylococcus aureus) decolonization has been demonstrated to decrease infection rates. Recent research has shown the antiseptic povidone-iodine to be equally effective and potentially cost saving compared to intranasal mupirocin. This study's purpose is to evaluate the incidence of MRSA colonization in a more rural community-based population, rates of infection on a mupirocin decolonization protocol, and develop a cost analysis model to compare costs of utilizing povidone-iodine. METHODS: Utilizing over 4 years of data, the incidence of MRSA decolonization of consecutive total knee and hip arthroplasties, as well as the rates of infection of patients uncolonized, colonized with successful decolonization, and unsuccessful decolonization were evaluated. Utilizing these data, cost data, and known infection rate utilizing povidone-iodine decolonization, a cost analysis model was developed. RESULTS: Of the 5584 cases with MRSA data at a single institution, only 3.5% tested positive for intranasal MRSA. Of those patients, 69% were successfully decolonized. Of the 3864 cases with infection data, 21 sustained a surgical site infection within 90 days (0.54%). Of these patients, all tested negative for intranasal MRSA initially and therefore did not undergo the decolonization protocol. The cost analysis predicts a potential savings of $74.72 per patient at our institution to use a global intranasal povidone-iodine protocol prior to total joint arthroplasty. CONCLUSION: Even with a lower incidence of MRSA than typically reported, utilization of intranasal povidone-iodine would potentially save $74.42 per patient. PMID- 29506928 TI - Hip Fractures and the Bundle: A Cost Analysis of Patients Undergoing Hip Arthroplasty for Femoral Neck Fracture vs Degenerative Joint Disease. AB - BACKGROUND: The purpose of this study is to determine whether episode Target Prices in the Bundled Payment for Care Improvement (BPCI) initiative sufficiently match the complexities and expenses expected for patients undergoing hip arthroplasty for femoral neck fracture (FNF) as compared to hip degenerative joint disease (DJD). METHODS: Claims data under BPCI Model 2 were collected for patients undergoing hip arthroplasty at a single institution over a 2-year period. Payments from the index hospitalization to 90 days postoperatively were aggregated by Medicare Severity Diagnosis-Related Group (469 or 470), indication (DJD vs FNF), and categorized as index procedure, postacute services, and related hospital readmissions. Actual episode costs and Target Prices were compared in both the FNF and DJD cohorts undergoing hip arthroplasty to gauge the cost discrepancy in each group. RESULTS: A total of 183 patients were analyzed (31 with FNFs, 152 with DJD). In total, the FNF cohort incurred a $415,950 loss under the current episode Target Prices, whereas the DJD cohort incurred a $172,448 gain. Episode Target Prices were significantly higher than actual episode prices for the DJD cohort ($32,573 vs $24,776, P < .001). However, Target Prices were significantly lower than actual episode prices for the FNF cohort ($32,672 vs $49,755, P = .021). CONCLUSION: Episode Target Prices in the current BPCI model fall dramatically short of the actual expenses incurred by FNF patients undergoing hip arthroplasty. Better risk-adjusting Target Prices for this fragile population should be considered to avoid disincentives and delays in care. PMID- 29506929 TI - Quality of Recovery, Postdischarge Hospital Utilization, and 2-Year Functional Outcomes After an Outpatient Total Knee Arthroplasty Program. AB - BACKGROUND: Outpatient total knee arthroplasty (TKA) has been made possible with advances in perioperative care and standardized clinical inpatient pathways. While many studies report on benefits of outpatient programs, none explore patient-reported outcome measures. As such, our goals were to compare the short term quality of recovery; highlight postdischarge hospital resources utilization; and report on 2-year functional outcomes scores. METHODS: This was a prospective comparative cohort study of 43 inpatients (43 TKAs) and 43 outpatients (43 TKAs) operated on by a single surgeon between September 28, 2010 and May 5, 2015. All patients were given a diary to complete at 1, 3, 7, 14, and 28 days postoperatively; we collected 90-day complications, readmissions, and emergency department visits; Knee Injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index scores were completed preoperatively and 2 years postoperatively. SPSS (IBM, version 22.0) was used for all statistical analyses. RESULTS: Quality of recovery (QoR-9) was similar in the outpatient TKA group compared with the inpatient group. No statistically significant differences were observed for Knee Injury and Osteoarthritis Outcome Score and Western Ontario and McMaster Universities Osteoarthritis Index subscores (P > .05). There was 1 readmission in both outpatient and inpatient groups. Six inpatients and 8 outpatients returned to the emergency department for any reason within 90 days, with no statistical significance observed between the 2 groups (P = .771). CONCLUSION: Outpatient TKA in selected patients produced similar short-term and 2-year patient-reported outcome measures and a comparable 90-day postdischarge hospital resource utilization when compared to an inpatient cohort, supporting further investigation into outpatient TKA. PMID- 29506930 TI - Joint Line Modification in Kinematically Aligned Total Knee Arthroplasty Improves Functional Activity but Not Patient Satisfaction. AB - BACKGROUND: Joint line modification in kinematically aligned total knee arthroplasty (KA-TKA) is attracting attention in expectation of optimizing patient satisfaction after TKA. This study aimed to examine the effects of joint line modification on Pain Catastrophizing Scale (PCS), painDETECT score, and new Knee Society Score (KSS) 2011, all of which are robustly related to patient satisfaction. METHODS: The study enrolled 45 knees of 45 patients undergoing KA TKA and a matched group of 45 knees of 45 patients undergoing mechanically aligned (MA) TKA as controls. At a mean of 31.6 months after TKA, new KSS 2011, PCS, and painDETECT score were assessed and compared between KA- and MA-TKA. Data from all 90 patients were pooled into one group for secondary multiple regression analysis to identify postoperative variables affecting patient satisfaction. RESULTS: Assessment with new KSS 2011 showed no significant differences between the 2 TKAs preoperatively, but functional activity score was significantly higher with KA-TKA than with MA-TKA postoperatively (P = .047). Among the 4 categories of functional activity score, advanced activity score was significantly higher with KA-TKA than with MA-TKA (P = .003). Of the 5 advanced activities, the score for climbing ladder/step stool was significantly greater with KA-TKA (P = .004). KA-TKA failed to influence patient satisfaction score. Multiple regression analysis revealed that standard activity score and PCS affected patient satisfaction positively and negatively, respectively. CONCLUSION: Joint line modification in KA-TKA improved functional activity but not patient satisfaction. PCS was a key element negatively affecting patient satisfaction. PMID- 29506931 TI - Maximizing Physician-Hospital Alignment: Lessons Learned From Effective Models of Joint Arthroplasty Care. AB - BACKGROUND: With recent healthcare reform efforts focusing on rewarding value instead of volume, it has become important for orthopedic surgeons to partner and align with their hospitals. We report our experience in aligning clinical and financial incentives with 6 health systems in our geographic area. METHODS: By managing the entire episode-of-care continuum for total hip and total knee arthroplasty patients, our standardized, evidence-based protocols have improved the quality of care for our joint arthroplasty patients. While most studies focus on cost through insurance claims data, we have been able to accurately determine the costs to our practice and each facility through time-driven activity-based costing. RESULTS: We have also achieved measureable claims and actual cost reduction by reducing unnecessary care, inappropriate variation in care, and avoidable complications through demand matching, risk stratification, and our nurse navigator program. Our joint ventures with our hospital partners in both specialty hospitals and our ambulatory surgery centers have also been critical to our success. CONCLUSION: Our experience demonstrates that large private practice groups can successfully align both clinical and financial incentives with healthcare systems to provide quality joint arthroplasty care at a lower cost. PMID- 29506932 TI - Current Role of Computer Navigation in Total Knee Arthroplasty. AB - BACKGROUND: Computer-assisted surgical (CAS) navigation has been developed with the aim of improving the accuracy and precision of total knee arthroplasty (TKA) component positioning and therefore overall limb alignment. The historical goal of knee arthroplasty has been to restore the mechanical alignment of the lower limb by aligning the femoral and tibial components perpendicular to the mechanical axis of the femur and tibia. Despite over 4 decades of TKA component development and nearly 2 decades of interest in CAS, the fundamental question remains; does the alignment goal and/or the method of achieving that goal affect the outcome of the TKA in terms of patient-reported outcome measures and/or overall survivorship? The quest for reliable and reproducible achievement of the intraoperative alignment goal has been the primary motivator for the introduction, development, and refinement of CAS navigation. Numerous proprietary systems now exist, and rapid technological advancements in computer processing power are stimulating further development of robotic surgical systems. Three categories of CAS can be defined: image-based large-console navigation; imageless large-console navigation, and more recently, accelerometer-based handheld navigation systems have been developed. CONCLUSION: A review of the current literature demonstrates that there are enough well-designed studies to conclude that both large-console CAS and handheld navigation systems improve the accuracy and precision of component alignment in TKA. However, missing from the evidence base, other than the subgroup analysis provided by the Australian Orthopaedic Association National Joint Replacement Registry, are any conclusive demonstrations of a clinical superiority in terms of improved patient-reported outcome measures and/or decreased cumulative revision rates in the long term. Few authors would argue that accuracy of alignment is a goal to ignore; therefore, in the absence of clinical evidence, many of the arguments against the use of large console CAS navigation center on the prohibitive cost of the systems. The utilization of low-cost, handheld CAS navigation systems may therefore bridge this important gap, and over time, further clinical evidence may emerge. PMID- 29506933 TI - Extrinsic Factors as Component Positions to Bone and Intrinsic Factors Affecting Postoperative Rotational Limb Alignment in Total Knee Arthroplasty. AB - BACKGROUND: This study aimed to identify the factors affecting postoperative rotational limb alignment of the tibia relative to the femur. We hypothesized that not only component positions but also several intrinsic factors were associated with postoperative rotational limb alignment. METHODS: This study included 99 knees (90 women and 9 men) with a mean age of 77 +/- 6 years. A three dimensional (3D) assessment system was applied under weight-bearing conditions to biplanar long-leg radiographs using 3D-to-2D image registration technique. The evaluation parameters were (1) component position; (2) preoperative and postoperative coronal, sagittal, and rotational limb alignment; (3) preoperative bony deformity, including femoral torsion, condylar twist angle, and tibial torsion; and (4) preoperative and postoperative range of motion (ROM). RESULTS: In multiple linear regression analysis using a stepwise procedure, postoperative rotational limb alignment was associated with the following: (1) rotation of the component position (tibia: beta = 0.371, P < .0001; femur: beta = -0.327, P < .0001), (2) preoperative rotational limb alignment (beta = 0.253, P = .001), (3) postoperative flexion angle (beta = 0.195, P = .007), and (4) tibial torsion (beta = 0.193, P = .010). CONCLUSION: In addition to component positions, the intrinsic factors, such as preoperative rotational limb alignment, ROM, and tibial torsion, affected postoperative rotational limb alignment. On a premise of correct component positions, the intrinsic factors that can be controlled by surgeons should be taken care. In particular, ROM is necessary to be improved within the possible range to acquire better postoperative rotational limb alignment. PMID- 29506934 TI - Risk Factors for Surgical Site Infection Following Lower Limb Arthroplasty: A Retrospective Cohort Analysis of 3932 Lower Limb Arthroplasty Procedures in a High Volume Arthroplasty Unit. AB - BACKGROUND: Surgical site infection (SSI) is a debilitating complication of lower limb arthroplasty with significant morbidity and increased costs. Numerous risk factors are associated with SSI. METHODS: In an effort to identify novel risk factors for SSI, we undertook a retrospective cohort study of 1832 primary total hip arthroplasties and 2100 primary total knee arthroplasties performed in our high volume arthroplasty unit over a 2-year period. RESULTS: Two risk factors were identified for SSI following total hip arthroplasty: body mass index >=30 and peri-operative blood transfusion. Eight risk factors were identified for SSI following total knee arthroplasty: hypertension, peri-operative blood transfusion, skin closure using 2-octyl cyanoacrylate, use of oral steroids, reduced serum mean cell volume, reduced mean cell hemoglobin, elevated serum neutrophil count, and use of warfarin or rivaroxaban for venous thromboembolism prophylaxis. CONCLUSIONS: Our work proposes a number of previously undocumented risk factors in relation to SSI. Further investigation is required to ascertain the magnitude of their effect. PMID- 29506935 TI - Prognostic Biomarkers in the Progression From MGUS to Multiple Myeloma: A Systematic Review. AB - Multiple myeloma (MM), characterized by malignant plasma cells in the bone marrow, is consistently preceded by asymptomatic premalignant stage monoclonal gammopathy of undetermined significance (MGUS). These MGUS patients have an annual risk of 1% to progress to MM. Clinical, imaging, and genomic (genetic and epigenetic) factors were identified, whose presence increased the risk of progression from MGUS to MM. In this systematic review we summarize the currently identified clinical, imaging, and genomic biomarkers suggested to increase the progression risk or shown to be differentially expressed/present between both cohorts of patients. Despite the wide range of proposed markers, there are still no reliable biomarkers to individually predict which MGUS patient will progress to MM and which will not. Research on biomarkers in the progression from MGUS to MM will give more insight in the unknown pathogenesis of this hematological malignancy. This would improve research by elucidating new pathways and potential therapeutic targets as well as clinical management by closer follow-up and earlier treatment of high-risk MGUS patients. PMID- 29506936 TI - Quantitative and qualitative assessment of acute myocardial injury by CMR at multiple time points after acute myocardial infarction. AB - BACKGROUND: Recent experimental studies have shown a dynamic time course of myocardial edema with an initial wave of edematous reaction within hours after reperfusion which almost resolved at 24 h. However, this dynamic pattern appears to be absent in clinical cohort studies. Thus far, no studies have combined a quantitative and qualitative assessment of acute myocardial injury in a large clinical cohort to explain these divergent findings. METHODS: A cohort of 225 patients (59 +/- 11 years, 83% men) with successfully reperfused STEMI within 12 h of symptom onset were included. Quantitative measurements of myocardial damage such as T1 mapping and T2 triple short-tau inversion recovery (STIR), contrast-to noise ratio (CNR) and their impact on area-at-risk (AAR), infarct size (IS), and myocardial salvage index (MSI) were assessed at different time points. One-way analysis of variance (ANOVA) and linear regression analysis was used to compare myocardial damage at the different time points. RESULTS: A small fraction of patients underwent CMR within 24 h of reperfusion (17/225, 7.6%). No significant variations in AAR, IS, MSI, T2 STIR CNR, or native T1 maps were observed between the different time points after reperfusion. Time of CMR was not a significant predictor of AAR (P = 0.90), IS (P = 0.27), MSI (P = 0.23) or T2 STIR CNR (P = 0.23). CONCLUSIONS: The majority of CMR exams in STEMI patients are performed outside the dynamic time window of early post-MI edema. The stable pattern of markers of acute myocardial damage at different time points suggests these markers are reliable for the prognostication of patients after STEMI. PMID- 29506937 TI - Dual chemotactic factors-secreting human amniotic mesenchymal stem cells via TALEN-mediated gene editing enhanced angiogenesis. AB - BACKGROUND: Even though mesenchymal stem cells (MSCs) have angiogenic property, their cytokine secretory capacity is limited to treat ischemic vascular disorders. In present study, we produced genome-edited MSCs that secreted dual chemokine granulocyte chemotactic protein-2 (GCP-2) and stromal-derived factor 1alpha (SDF-1alpha) and determined their therapeutic potential in the context of experimental ischemia. METHODS: GCP-2 and SDF-1alpha genes were integrated into safe harbor site at the safe harbor genomic locus of amniotic mesenchymal stem cells (AMM) via transcription activator-like effector nucleases (TALEN). GCP-2 and SDF-1alpha gene-edited AMM (AMM/GS) were used for quantitative (q)-PCR, Matrigel tube formation, cell migration, Matrigel plug assays and in vivo therapeutic assays using hindlimb ischemia mouse model. RESULTS: AMM/GS-derived culture media (CM) induced significantly higher tube lengths and branching points as compared to AMM/S CM and AMM CM. Interestingly, Matrigel plug assays revealed that significantly higher levels of red blood cells were found in AMM/GS than AMM/S and AMM Matigel plugs and exhibited micro-vascular like formation. Cells was transplanted into ischemic mouse hindlimbs and compared with control groups. AMM/GS injection prevented limb loss and augmented blood perfusion, suggesting that enhances neovascularization in hindlimb ischemia. In addition, transplanted AMM/GS revealed high vasculogenic potential in vivo compared with transplanted AMM/S. CONCLUSION: Taken together, genome-edited MSCs that express dual chemokine GCP-2 and SDF-1alpha might be alternative therapeutic options for the treatment of ischemic vascular disease. PMID- 29506938 TI - Computed tomography detection and quantification of left atrial appendage residual patency as collateral finding after percutaneous closure. PMID- 29506939 TI - Temporal trends between association of evidence-based treatment and outcomes in patients with non-ST-elevation myocardial infarction. PMID- 29506940 TI - Conditional analyses of recurrence and progression in patients with TaG1 non muscle-invasive bladder cancer. AB - OBJECTIVE: To determine conditional recurrence-free survival (RFS) and progression-free survival (PFS) and improve decision-making toward surveillance protocols and scheduling. Furthermore, evaluating the evolution of predictors for disease recurrence over time, because TaG1 non-muscle-invasive bladder cancer harbors a risk of disease recurrence and progression. MATERIAL AND METHODS: The retrospective multicenter design study includes 1,245 TaG1 bladder cancer patients with median follow-up of 62.7 (interquartile range: 34.3-91.1) months. Conditional RFS and PFS estimates were calculated using the Kaplan-Meier method. Multivariable Cox regression model was calculated proportional for the prediction of recurrence and progression (covariables: age, tumor size, multiple tumors, prior recurrence, and immediate postoperative instillation of chemotherapy). RESULTS: After 3 months without event, the conditional RFS and PFS (to >=pT2) rates for 5 additional years without event were 57.5% and 93.4%, respectively. Given a 1-, 2-, 3-, and 5-year survival, the conditional RFS rates for 5 additional years without event improved by +9.8 (67.3%), +5.2 (72.5%), +6.5 (79.0%), +2.0 (81.0%), and +1.0% (82.0%), respectively. In contrast, the 5-year conditional PFS rates were more or less stable with 94.3% after 1 year to 94.1% after 5 years. Multivariable analyses showed decreasing impact of risk parameters on RFS estimates over time. Based on these findings, we suggest a risk stratification to individualize follow-up for intermediate risk TaG1. Main limitation was the retrospective design. CONCLUSIONS: Conditional-survival analyses demonstrates that the patient risk profile changes over time. RFS rates rise with increasing survival whereas PFS rates were stable. The impact of prognostic features decreases over time. Our findings can be used for patient counseling and planning of personalized follow-up. PMID- 29506941 TI - Accurate prediction of progression to muscle-invasive disease in patients with pT1G3 bladder cancer: A clinical decision-making tool. AB - PURPOSE: To improve current prognostic models for the selection of patients with T1G3 urothelial bladder cancer who are more likely to fail intravesical therapy and progress to muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We performed a retrospective analysis of 1,289 patients with pT1G3 urothelial bladder cancer who were treated with transurethral resection of the bladder (TURB) and adjuvant intravesical bacillus-Calmette-Guerin (BCG). Random-split sample data and competing-risk regression were used to identify the independent impact of lymphovascular invasion (LVI) and variant histology (VH) on progression to MIBC. We developed a nomogram for predicting patient-specific probability of disease progression at 2 and 5 years after TURB. Decision curve analysis (DCA) was performed to evaluate the clinical benefit associated with the use of our nomogram. RESULTS: In the development cohort, within a median follow-up of 51.6 months (IQR: 19.3-92.5), disease progression occurred in 89 patients (13.8%). A total of 84 (13%) patients were found to have VH and 57 (8.8%) with LVI at TURB. Both factors were independently associated with disease progression on multivariable competing-risk analysis (HR: 4.4; 95% CI: 2.8-6.9; P<0.001 and HR: 3.5; 95% CI: 2.1-5.8; P<0.001, respectively). DCA showed superior net benefits for the nomogram within a threshold probability of progression between 5% and 55%. Limitations are inherent to the retrospective design. CONCLUSIONS: We demonstrated the clinical value of the integration of LVI and VH in a prognostic model for the prediction of MIBC. Indeed, our tool provides superior individualized risk estimation of progression facilitating decision-making regarding early RC. PMID- 29506943 TI - Response to "Re. Nutcracker Syndrome: An Update on Current Diagnostic Criteria and Management Guidelines". PMID- 29506942 TI - Prevalence of Abdominal Aortic Aneurysms in the General Population and in Subgroups at High Cardiovascular Risk in Italy. Results of the RoCAV Population Based Study. AB - OBJECTIVES: Prevalence data on abdominal aortic aneurysm (AAA) in women, subjects younger than 65 years and in subgroups carrying specific risk factors are scarce. AAA prevalence was evaluated in an Italian population including women and younger subjects, stratifying for the presence of cardiovascular disease (CVD) risk factors and CVD risk score. MATERIALS AND METHODS: A population based cross sectional study was conducted between 2013 and 2016. Men aged 50-75 and women aged 60-75 years, resident in the city of Varese (northern Italy), were randomly selected from the civil registry. A vascular surgeon performed an abdominal aortic ultrasound scan at four sites using the leading edge to leading edge method. CVD risk score was computed using the ESC-SCORE algorithm. The age and gender specific prevalence was estimated, stratifying by the presence of CVD and cardiovascular risk factors. RESULTS: Among the 3755 subjects with a valid ultrasound measurement, 63 subjects with an AAA were identified (5 referred for surgical intervention), among whom 34 were not previously known (30 men 1.3%, 95% CI 0.9-1.8; 4 women 0.3%, 95% CI 0.1-0.8). Considering age classes in men only, the highest prevalence of screen detected AAA was found in subjects aged 65-70 (1.2%; 95% CI 0.4-2.5) and 70-75 (2.5%; 95% CI 1.4-4.0) years. Among 65-75 year old men, the highest AAA prevalence was found in subjects with a previous myocardial infarction (MI 4.9%, 95% CI 2.0-9.9) and in ever-smokers reporting more than 15 pack years of smoking (4.1%, 95% CI 2.5-6.3). Among the younger subjects, those having an ESC-SCORE higher than 5% or a previous CVD (MI or stroke) showed a prevalence of 1.4% (95% CI 0.3-4.2; prevalence including subaneurysms 6.7%, 95% CI 3.7-11.0%). CONCLUSIONS: In the study population, both a general screening program in 65-75 year old men and an approach targeted to subgroups at higher risk merit evaluation in a cost-effectiveness study. In 50-64 year old men, strategies for population selection should consider CVD risk stratification tools. PMID- 29506944 TI - Meta-analysis of Renal Function Following Infrarenal EVAR using Suprarenal or Infrarenal Fixation Devices. AB - OBJECTIVE/BACKGROUND: The effect of suprarenal (SR) as opposed to infrarenal (IR) fixation on renal outcomes post-endovascular aneurysm repair (EVAR) remains controversial. This meta-analysis aims to update current understanding of this issue. METHODS: A prior meta-analysis was updated through a Preferred Reporting Items for Systematic reviews and Meta-Analyses search for additional studies published in the last 3 years reporting on renal dysfunction or related outcomes post-EVAR. Random effects meta-analysis was undertaken using SPSS. RESULTS: A total of 25 non-randomised studies comparing SR with IR fixation were included, totalling 54,832 patients. In total, 16,634 underwent SR and 38,198 IR. Baseline characteristics, including age, baseline estimated glomerular filtration rate, diabetes, cardiac disease, and smoking, were similar between the groups. There was a small but significant difference in outcomes for renal dysfunction at the study end point (SR 5.98% vs. IR 4.83%; odds ratio [OR] 1.29, 95% confidence interval [CI] 1.18-1.40 [p < .001]); however, at 30 days and 12 months there was no significant difference, and this did not hold up to sensitivity analysis. Incidence of renal infarcts (SR 6.6% vs. IR 2.3%; OR 2.78, 95% CI 1.46-5.29 [p = .002]), renal stenosis (SR 2.4% vs. IR 0.8%; OR 2.89, 95% CI 1.00-8.38 [p = .05]), and renal artery occlusion (SR 2.4% vs. IR 1.2%; OR 2.21, 95% CI 1.15-4.25 [p = 0.02]) favoured IR fixation; however, there was no difference in haemodialysis rates. CONCLUSION: This meta-analysis has identified small but significantly worse renal outcomes in patients having SR fixation devices compared with IR; however, there was no difference in dialysis rates and a small effect on renal dysfunction, which did not stand up to rigorous sensitivity analysis. This should be taken into consideration during graft selection, and further studies must assess renal outcomes in the longer term, and in those with pre-existing renal dysfunction. PMID- 29506945 TI - National trends in admissions, repair, and mortality for thoracic aortic aneurysm and type B dissection in the National Inpatient Sample. AB - OBJECTIVE: The advent of endovascular repair for both thoracic aortic aneurysm and type B dissection has transformed the management of these disease processes. This study was undertaken to better define, compare, and contrast the national trends in hospital admissions, invasive treatments, and inpatient mortality of patients with thoracic aortic aneurysm and type B dissection in the National Inpatient Sample. METHODS: The cohort was derived from International Classification of Diseases, Ninth Revision diagnosis codes for thoracic aortic dissection and thoracic aortic or thoracoabdominal aortic aneurysm. Patients receiving type A dissection or ascending aortic repair during their index admission were excluded using International Classification of Diseases, Ninth Revision procedure codes. A total of 155,187 patients were available for analysis from 2000 to 2012. RESULTS: Admissions for thoracic aortic aneurysm outnumbered the admissions for type B dissection (69.8% vs 30.2%; P < .001), and the number of admissions for aneurysm grew more rapidly during this time (132% vs 63%; P < .001). Thoracic endovascular aortic repair (TEVAR) for aneurysm experienced an increase in 2005, concordant with Food and Drug Administration approval of TEVAR for thoracic aortic aneurysm indication, then superseded open repair for thoracic aortic aneurysm from 2006 onward. Despite this, the rate of thoracic aortic aneurysm repair has remained relatively stable over time. TEVAR for dissection increased in 2006, superseded open repair in 2010, and continues to account for 50.5% of all dissection repairs. Overall, the number of type B dissection repairs has increased (P < .001), over and above the increase in number of admissions for type B dissection. Despite the increased trends of utilization of TEVAR for both aneurysm and type B dissection, the overall in-hospital mortality rate among patients admitted for either disease state has decreased steadily over time (P < .001). CONCLUSIONS: Whereas admissions for thoracic aortic aneurysm disease have increased over time, the rate of aneurysm repair has been stable, although TEVAR has supplanted a proportion of open repairs. In contrast, whereas admissions for type B dissection have experienced a more modest increase, there has been a disproportionate increase in type B dissection repair, largely due to increased use of TEVAR. These results show embracing of endovascular technology for dissection through expansion of indication. Despite the increase in rate of repair for type B dissection, inpatient mortality rate was reduced in both aneurysm and dissection patients, influenced by appropriate selection of patients for intervention. PMID- 29506946 TI - Readmissions after thoracic endovascular aortic repair. AB - OBJECTIVE: The care of patients undergoing thoracic endovascular aortic repair (TEVAR) can be resource intensive, which can be driven by readmissions. Our objective was to characterize index readmissions at 30, 90, and 180 days after TEVAR. METHODS: A retrospective analysis of the Nationwide Readmissions Database was performed for patients who underwent TEVAR in 2013. Multivariable analysis identified independent predictors for index readmission at 30, 90, and 180 days. RESULTS: There were 4045 TEVARs performed for descending thoracic aortic dissection (37.7%), nonruptured aneurysm (56%), and ruptured aneurysm (6.3%). There were 419 (11.1%) index readmissions at 30 days, 895 (23.6%) at 90 days, and 1131 (29.8%) at 180 days. The most frequent reason for index readmission was heart related at 30 days (15.5%) and aorta related at 90 days (18%) and 180 days (19.6%). Reinterventions were performed at 6.4%, 9.5%, and 9.7% of 30-, 90-, and 180-day readmissions, respectively. The majority of these included additional endovascular stent graft placement (51.9% of reinterventions at 30 days, 67.7% at 90 days, and 65.9% at 180 days). In multivariable analysis, 30-day index readmission was associated with initial ruptured presentation (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.1-3.5; P = .023) and diagnosis-related group (DRG) severity grades of moderate (OR, 1.42; 95% CI, 0.74-2.73), major (OR, 2.47; 95% CI, 1.28-4.74), and extreme (OR, 1.60; 95% CI, 0.76-3.36; P = .009). Index readmission at 90 days was independently associated with initial ruptured presentation (OR, 1.88; 95% CI, 1.18-3.01; P = .008), urgent/emergent TEVAR (OR, 1.41; 95% CI, 1.08-1.85; P = .014), and DRG severity grades of moderate (OR, 1.53; 95% CI, 0.95-2.47), major (OR, 2.27; 95% CI, 1.39-3.7), and extreme (OR, 2.45; 95% CI, 1.43-4.18; P = .002). Finally, at 180 days, initial ruptured presentation (OR, 1.66; 95% CI, 1.05-2.62; P = .029), urgent/emergent TEVAR (OR, 1.37; 95% CI, 1.08-1.79; P = .013), and DRG severity grades of moderate (OR, 1.55; 95% CI, 1.01-2.38), major (OR, 2.15; 95% CI, 1.38-3.33), and extreme (OR, 2.39; 95% CI, 1.47-3.89; P = .002) were, again, independently associated with index readmission. CONCLUSIONS: A large portion of patients treated with TEVAR were readmitted most commonly for heart-related reasons at 30 days and aorta related reasons at 90 and 180 days. TEVAR performed to treat initial aortic rupture and greater DRG severity grade were independently associated with an index readmission at 30, 90, and 180 days. Urgent/emergent TEVAR was independently associated with an index readmission at 90 and 180 days. These factors are important to consider in using readmissions as a quality measure. PMID- 29506948 TI - Is the Midterm Progress of Pediatric and Adolescent Talus Fractures Stratified by Age? AB - The outcomes of pediatric talus fractures have been minimally reported in published studies. The purpose of the present retrospective study was to determine the clinical and radiographic outcomes after talus fractures in pediatric and adolescent patients and to define the differences among the different age groups in this population. A total of 52 children and adolescents (54 fractures) with 24 type 1 (44.44%), 13 type 2 (24.07%), 8 type 3 (14.81%), and 9 type 4 (16.67%) Marti-Weber fractures were considered. Of the 52 patients, 19 (35.19%; 21 talus fractures) with follow-up data available for >12 months were included in the final study population. Of the 21 fractures, 9 (42.86 %) were type 1, 4 (19.05%) were type 2, 1 (4.76%) was type 3, and 7 (33.33%) were type 4. The mean patient age was 14.7 (range 4 to 18) years. The patients were divided into 3 age groups: group 1, age <=11.9 years; group 2, age 12.0 to 15.8 years; and group 3, age 16.1 to 18.0 years. Of the 21 fractures, 3 (14.29%) were treated nonoperatively and 18 (85.71%) operatively. The overall mean follow-up duration was 40.3 (range 14 to 95) months. The outcomes of interest included fracture nonunion, talar avascular necrosis, ankle range of motion, pain, arthrosis, and arthrodesis. After treatment, the mean ankle range of motion was 20 degrees (range 0 degrees to 35 degrees ) of dorsiflexion and 40 degrees (range 0 degrees to 45 degrees ) of plantarflexion. Complications included persistent pain in 10 fractures (47.62%), 3 cases of nonunion (14.29%), 3 cases of avascular necrosis (14.29%; of which, 1 [4.76%] required ankle and subtalar fusion), and arthrosis developing in >=1 surrounding joint in 12 fractures (57.14%). Of the 12 fractures in group 3, 9 (75.00%) developed arthrosis and 2 (16.67%) subsequently required arthrodesis. Our observations suggest that the incidence of displaced talus fractures, as well as complications, increases with patient age. PMID- 29506949 TI - Comparison between burning mouth syndrome patients with and without psychological problems. AB - The purpose of this study was to compare clinical and socio-demographic characteristics between burning mouth syndrome (BMS) patients with and without psychological problems. Of 644 patients with symptoms of oral burning, 224 with primary BMS were selected on the basis of laboratory testing, medical history, and psychometric tests: 39 with psychological problems (age 62.5+/-11.5years) and 185 without psychological problems (age 58.4+/-11.4years). Comprehensive clinical and socio-demographic characteristics, including psychological profiles and salivary flow rates, were compared between the two groups. No significant difference in sex ratio, duration and diurnal pattern of symptoms, unstimulated whole saliva flow rate, or marital status was found between the groups. The patients with psychological problems had a significantly higher mean age, reduced stimulated whole saliva flow rate, and lower level of education than those without psychological problems. The patients with psychological problems also displayed higher rates and greater severity of various types of BMS-related symptom in most parts of the oral mucosa, higher rates of stress-related symptoms, and greater difficulties in daily activities. The severity of taste disturbance was the factor most significantly correlated with the level of psychometry. In conclusion, psychological problems in BMS patients are associated with an aggravation of BMS symptoms. PMID- 29506947 TI - The impact of current smoking on outcomes after infrainguinal bypass for claudication. AB - OBJECTIVE: Although smoking cessation is a benchmark of medical management of intermittent claudication, many patients require further revascularization. Currently, revascularization among smokers is a controversial topic, and practice patterns differ institutionally, regionally, and nationally. Patients who smoke at the time of revascularization are thought to have a poor prognosis, but data on this topic are limited. The purpose of this study was to evaluate the impact of smoking on outcomes after infrainguinal bypass for claudication. METHODS: Data from the national Vascular Quality Initiative from 2004 to 2014 were used to identify infrainguinal bypasses performed for claudication. Patients were categorized as former smokers (quit >1 year before intervention) and current smokers (smoking within 1 year of intervention). Demographic and comorbid differences of categorical variables were assessed. Significant predictors were included in adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) by smoking status for outcomes of major adverse limb event (MALE), amputation-free survival, limb loss, death, and MALE or death. Cumulative incidence curves were created using competing risks modeling. RESULTS: We identified 2913 patients (25% female, 9% black) undergoing incident infrainguinal bypass grafting for claudication. There were 1437 current smokers and 1476 former smokers in our study. Current smoking status was a significant predictor of MALE (HR, 1.27; 95% CI, 1.00-1.60; P = .048) and MALE or death (HR, 1.22; 95% CI, 1.03-1.44; P = .02). Other factors found to be independently associated with poor outcomes in adjusted models included black race, below-knee bypass grafting, use of prosthetic conduit, and dialysis dependence. CONCLUSIONS: Current smokers undergoing an infrainguinal bypass procedure for claudication experienced more MALEs than former smokers did. Future studies with longer term follow-up should address limitations of this study by identifying a data source with long-term follow-up examining the relationship of smoking exposure (pack history and duration) with outcomes. PMID- 29506950 TI - An Analysis of Staging and Treatment Trends for Upper Tract Urothelial Carcinoma in the National Cancer Database. AB - BACKGROUND: The purpose of this study was to analyze contemporary trends for diagnosis and treatment of upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: We identified all cases of UTUC in the National Cancer Database (NCDB) between 2004 and 2013. Data comprising tumor, patient, and facility factors were extracted. Treatment data for surgery and chemotherapy were also collected. Comparisons used chi2 testing. RESULTS: Over this 10-year period, the sex and age distribution of UTUC was stable at 60% male and median age of 72 years. Most tumors were < cT2 at diagnosis, with an upward trend over 10 years (66% to 72%; P < .001). However, presentation with clinical metastatic disease also rose, from 4.6% to 8.9% (P < .001). Primary tumor biopsy increased from 37% to 50%. Overall rate of nephroureterectomy decreased from 59.6% to 56.7% whereas endoscopic ablation increased from 9.8% to 11.5%. Ablation was much more common in < cT2 tumors than >= cT2 (18.3% vs. 3.7%) and for low-grade tumors than high-grade (22.6% vs. 5.9%). Neoadjuvant chemotherapy was significantly more used, but still at a low rate. CONCLUSION: Treatment of UTUC appears to be shifting toward conservative surgical management with tumor ablation, and increasing neoadjuvant chemotherapy use. More primary tumor biopsies are being performed, likely reflecting improved ureteroscopic instruments and training. The NCDB also reports an increase in metastatic disease, which must be interpreted cautiously and might be artifactual. PMID- 29506951 TI - An occurrence of apnea, bradycardia, and desaturation events resulting in a delay of discharge in late preterm and full term infants. PMID- 29506952 TI - Mediators and Moderators of Health-Related Quality of Life in People Living with HIV. AB - We examined whether social support moderated communication and self-management, and tested whether self-management mediated communication, instrumental and emotional social support (ISS, ESS), and health-related quality of life (HRQOL) in Korean people living with HIV (PLWH). A cross-sectional research design using a self-reported survey questionnaire was conducted. Data for 205 PLWH were collected at the outpatient divisions of seven hospitals. HRQOL was positively associated with communication, ISS, ESS, and self-management. ESS moderated the relationship between communication and self-management through a significant interaction with communication. Johnson-Neyman analysis indicated that the interaction effect of ESS was significant at the range from 4 to 14.4. However, the ISS did not moderate the relationship between communication and self management. Self-management mediated the relationship between communication, ESS, and HRQOL. The findings suggest that nursing interventions should be focused on providing interactive communication and ESS to improve self-management and HRQOL of PLWH. PMID- 29506953 TI - Neo-adjuvant radiotherapy (NART) in breast reconstruction - The future for autologous reconstruction in locally advanced disease? PMID- 29506954 TI - A fast and improved method of rapid prototyping for ear prosthesis using portable 3D laser scanner. PMID- 29506955 TI - Chronic diazoxide treatment decreases fat mass and improves endurance capacity in an obese mouse model of Prader-Willi syndrome. AB - Excess fat mass is a cardinal feature of Prader-Willi syndrome (PWS) that is recapitulated in the Magel2-null mouse model of this genetic disorder. There is a pressing need for drugs that can prevent or treat obesity in children with PWS. Recently, a clinical study of a controlled release form of the benzothiadiazine derivative diazoxide demonstrated improved metabolic parameters and decreased fat mass in obese children and adults with PWS. We tested whether chronic diazoxide administration can reduce fat mass and improve metabolism in mice lacking MAGEL2, a gene inactivated in PWS. Magel2-null and wild-type control mice were rendered obese by high fat diet feeding, then provided diazoxide while being maintained on a high fat diet. Treatment of obese mice with diazoxide reduced weight and body fat, lowered blood glucose and improved endurance capacity. Treatment with diazoxide partially normalizes obesity in children and adults with PWS and in a PWS mouse model, demonstrating that the biological pathways impacted by diazoxide may be rational pharmacological targets in PWS and other disorders diseases associated with obesity. PMID- 29506956 TI - Investigating the Effects of the Progressive Muscle Relaxation-Guided Imagery Combination on Patients with Cancer Receiving Chemotherapy Treatment: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Previous systematic reviews indicate that progressive muscle relaxation (PMR) and guided imagery (GI) are both effective interventions to decrease the psychological impact and to alleviate the adverse events in cancer patients undergoing chemotherapy treatment. To date, no review studies have investigated the effectiveness of a combination of PMR and GI. AIM: To systematically review the current state of knowledge regarding the effects of the PMR-GI combination on cancer patients receiving chemotherapy. METHODS: A search for relevant records was carried out in four electronic databases (AMED, Cochrane Library, Pubmed and Scopus). After removing the duplicates 342 publications were screened and 71 were considered as potentially relevant. The flow of information of this study was in line with the PRISMA statement. Original articles investigating the application of both PMR and GI through a randomized trial on patients receiving chemotherapy were included. Those using PMR or GI alone and those combining other techniques together with PMR and GI were excluded. The trials' quality was assessed using the Jadad Scale. RESULTS: Eight papers reporting the results of seven independent trials were finally included. All of them included only breast cancer patients, apart from a single trial using a mixed sample of breast and prostate cancer patients. Seven of the included trials reported beneficial effects on mental state (mood, anxiety, and depression) and on toxicity (nausea and vomiting). Three trials reported an effect on biomarkers (heart rate, blood pressure, cortisol, and immunity). Four trials scored three of five points on the Jadad Scale, two trials scored two points and a single trial scored zero. CONCLUSIONS: Independent trials indicate that the PMR-GI combination is an effective way to tackle the impact of nausea and vomiting and to improve patients' mental state. However, studies involving other types of primary tumors would be useful because seven of the eight clinical trials only included breast cancer patients. Future research on the identification of potential effects on disease-related parameters (e.g., cytokines and disease-recurrence) and on patient survival is highly needed. PMID- 29506957 TI - Prefabricated fibula free flap with dental implants for mandibular reconstruction. AB - Free fibula transplant is routinely used for mandibular reconstruction in head and neck cancer. Dental rehabilitation, the objective of mandibular reconstruction, requires the use of dental implants as supports for fixed or removable dentures. Positioning of fibular bone grafts and implants determines implant osseointegration and the possibilities of dental rehabilitation. Prefabrication of a fibula free flap with dental implants prior to harvesting as a free flap can promote implant osseointegration. The position of the implants must then be precisely planned. Virtual surgery and computer-assisted design and prefabrication techniques are used to plan the reconstruction and then reproduce this planning by means of tailored fibula and mandible cutting guides, thereby ensuring correct positioning of fibular bone fragments and implants. The prefabricated fibula free flap technique requires two surgical procedures (prefabrication and flap transfer) and precise preoperative planning. Prefabricated fibula free flap with dental implants, by improving the quality of osseointegration of the implants before flap transfer, extends the possibilities of prosthetic rehabilitation in complex secondary mandibular reconstructions. PMID- 29506958 TI - Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid proteases. AB - Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms. PMID- 29506959 TI - 2',3'-Dideoxyuridine triphosphate conjugated to SiO2 nanoparticles: Synthesis and evaluation of antiproliferative activity. AB - A conjugate of triphosphorylated 2',3'-dideoxyuridine (ddU) with SiO2 nanoparticles was obtained via the CuAAC click chemistry between a gamma-alkynyl ddU triphosphate and azido-modified SiO2 nanoparticles. Assessment of cytotoxicity in human breast adenocarcinoma MCF7 cells demonstrated that ddU triphosphate conjugated to SiO2 nanoparticles exhibited a 50% decrease in cancer cell growth at a concentration of 183 +/- 57 ug/mL, which corresponds to 22 +/- 7 uM of the parent nucleotide, whereas the parent nucleoside, nucleotide and alkynyl triphosphate precursor do not show any cytotoxicity. The data provide an example of remarkable potential of novel conjugates of SiO2 nanoparticles with phosphorylated nucleoside analogues, even those, which have not been used previously as therapeutics, for application as new anticancer agents. PMID- 29506960 TI - Genetics of endometriosis: State of the art on genetic risk factors for endometriosis. AB - Developments in high-throughput genotyping technology have driven discovery of genomic regions associated with an increased risk of endometriosis. In all, 16 genomic regions have been associated with risk of endometriosis in one or more populations. The latest meta-analysis including 17,045 endometriosis cases identified 14 genomic regions supported by results from multiple studies. No independent associations were identified from direct genotyping of common and low frequency protein-coding variants. This suggests that the most common genetic factors that contribute to endometriosis risk are located in regulatory DNA sequences and alter the regulation of gene transcription. Evidence from different methods is essential to identify the target genes and transcripts that contribute to altered disease risk. Potential target genes in three chromosome regions showing altered gene regulation include LINC00339 and CDC42 on chromosome 1, CDKN2A-AS1 on chromosome 9, and VEZT on chromosome 12. Further functional studies are needed to confirm the causal genes in these and other regions to understand pathways that increase endometriosis risk and help identify novel targets for interventions to improve diagnosis and treatment. PMID- 29506961 TI - Ultrasound diagnosis of endometriosis and adenomyosis: State of the art. AB - Transvaginal ultrasonography has become the primary test in the diagnosis of pelvic endometriosis and adenomyosis. A review of the literature on the diagnostic accuracy of ultrasonography in pelvic endometriosis and adenomyosis, as well as a comparison with magnetic resonance imaging, will be presented. Criteria for diagnosis of an endometrioma according to robust prospective data together with guidelines as to adequate reporting of the location of deep infiltrating endometriosis will be given. The sonographic features of adenomyosis including the differential diagnosis between focal adenomyosis and a uterine fibroid are reviewed. The available data in the literature on ultrasound diagnosis of pelvic endometriosis and adenomyosis, their clinical relevance, and their limitations are discussed. PMID- 29506962 TI - Immunology of endometriosis. AB - The pathophysiology of endometriosis is not completely understood, but an aberrant immune response in the peritoneal environment seems to be crucial for the proliferation of ectopic endometrial cells - as those cells escape apoptosis and peritoneal cavity immunosurveillance. The growth of endometrial implants leads to the recruitment of a large number and diversity of immune cells and intense inflammation with increased pro-inflammatory cytokines, growth factors, and angiogenesis. There is substantial evidence of aberrant function of almost all types of immune cells in women with endometriosis: decreased T cell reactivity and NK cytotoxicity, polyclonal activation of B cells and increased antibody production, increased number and activation of peritoneal macrophages, and changes in inflammatory mediators. New clinical treatments for endometriosis are an urgent need, especially nonhormonal drugs. The study of immunology may clarify its role in the pathogenesis of endometriosis and contribute to the development of new therapeutic strategies. PMID- 29506963 TI - Variability of forearm collateral circulation: An observational study of serial hand plethysmography testing. AB - OBJECTIVES: Evaluation of plethysmography as a reliable triage tool to access collateral circulation in the hand prior to transradial access. BACKGROUND: Hand plethysmographic testing has been used for access site triage prior to cardiac catheterization despite a lack of data supporting its result's stability. METHODS: Cohort of consecutive outpatients presenting for evaluation prior to cardiac catheterization underwent hand plethysmographic testing at the beginning of the office visit and before discharge. Demographics and clinical data was recorded. RESULTS: Hands (N = 887) in 445 patients were evaluated using the Barbeau plethysmography technique. Barbeau Test (BT) patterns A, B, C, and D were observed in 58%, 30%, 8% and 4% on initial evaluation. On preliminary evaluation, 780 (88%) hands had a "low-risk" pattern (A or B) and 107 (12%) hands had a "high risk" pattern (C or D). Repeat evaluation performed 50 +/- 26 min later revealed a 'low-risk' pattern in 809 (91%) hands with 78 (9%) of hands showing a persistent "high risk" pattern. In 29 (27%) high-risk hands, spontaneous conversion to pattern B within <1 h occurred. Reverse Barbeau Test (RBT) at baseline showed pattern A, B, C and D in 95.9%, 2.8%, 1% and .4% respectively. There was no significant change in RBT upon follow-up evaluation. Strength of the radial artery pulsation was significantly associated with the pattern of RBT and the strength of ulnar pulsation was associated with the results of the BT. CONCLUSIONS: Plethysmographic testing of forearm circulation demonstrates variability over short intervals suggesting poor reliability for access site triage. PMID- 29506965 TI - Percutaneous treatment of an anomalous left main arising from the opposite sinus with subpulmonic course. AB - Anomalous origin of a coronary artery from the opposite sinus of Valsalva (ACAOS) is a rare malformation traditionally considered "malignant" in cases of interarterial course. Recently, a protective effect of the low interarterial subtype (between the aorta and the right ventricle outflow tract) has been described. We present an IVUS-guided percutaneous intervention in a patient with anomalous origin of the left coronary artery from the right coronary sinus presenting with anterior ischemia. In patients with ACAOS, the integration of complementary image techniques is recommended, defining the anomalous course of the vessel and providing an accurate assessment of the individual risk for each patient. The use of IVUS may be advisable, emerging as a really useful tool to complete the study and guide the treatment. PMID- 29506964 TI - Minimizing the risk of contrast-induced nephropathy and hemodynamic collapse during chronic total occlusion percutaneous coronary intervention with a percutaneous left ventricular assist device. AB - Candidates for percutaneous coronary revascularization are becoming progressively older and more complex. A combination of factors related to the patient, lesion, and/or hemodynamic conditions may increase the risk of adverse events. Therefore, when a high-risk procedure is identified, it is crucial to provide the patient with adequate support in order to safely perform percutaneous coronary intervention (PCI). We report the case of a 77-year-old man with moderate left ventricular dysfunction and stage IV chronic kidney disease who underwent successful recanalization of a chronically occluded left anterior descending artery. The procedure was performed with a micro-axial percutaneous left ventricular assist device (Impella 2.5) in order to provide stable hemodynamics, and with minimal contrast medium administration (14 ml) to minimize the risk of acute kidney injury. Despite the use of aggressive techniques (including rotational atherectomy), the patients remained stable throughout the procedure and did not experience contrast-induced nephropathy or periprocedural myocardial infarction, and was discharged two days later. Moreover, we provide recommendations to assist interventional cardiologist safely perform complex and high-risk PCI, with particular attention to renal function preservation. PMID- 29506966 TI - Secure and Efficient Regression Analysis Using a Hybrid Cryptographic Framework: Development and Evaluation. AB - BACKGROUND: Machine learning is an effective data-driven tool that is being widely used to extract valuable patterns and insights from data. Specifically, predictive machine learning models are very important in health care for clinical data analysis. The machine learning algorithms that generate predictive models often require pooling data from different sources to discover statistical patterns or correlations among different attributes of the input data. The primary challenge is to fulfill one major objective: preserving the privacy of individuals while discovering knowledge from data. OBJECTIVE: Our objective was to develop a hybrid cryptographic framework for performing regression analysis over distributed data in a secure and efficient way. METHODS: Existing secure computation schemes are not suitable for processing the large-scale data that are used in cutting-edge machine learning applications. We designed, developed, and evaluated a hybrid cryptographic framework, which can securely perform regression analysis, a fundamental machine learning algorithm using somewhat homomorphic encryption and a newly introduced secure hardware component of Intel Software Guard Extensions (Intel SGX) to ensure both privacy and efficiency at the same time. RESULTS: Experimental results demonstrate that our proposed method provides a better trade-off in terms of security and efficiency than solely secure hardware-based methods. Besides, there is no approximation error. Computed model parameters are exactly similar to plaintext results. CONCLUSIONS: To the best of our knowledge, this kind of secure computation model using a hybrid cryptographic framework, which leverages both somewhat homomorphic encryption and Intel SGX, is not proposed or evaluated to this date. Our proposed framework ensures data security and computational efficiency at the same time. PMID- 29506967 TI - Mode Equivalence of Health Indicators Between Data Collection Modes and Mixed Mode Survey Designs in Population-Based Health Interview Surveys for Children and Adolescents: Methodological Study. AB - BACKGROUND: The implementation of an Internet option in an existing public health interview survey using a mixed-mode design is attractive because of lower costs and faster data availability. Additionally, mixed-mode surveys can increase response rates and improve sample composition. However, mixed-mode designs can increase the risk of measurement error (mode effects). OBJECTIVE: This study aimed to determine whether the prevalence rates or mean values of self- and parent-reported health indicators for children and adolescents aged 0-17 years differ between self-administered paper-based questionnaires (SAQ-paper) and self administered Web-based questionnaires (SAQ-Web), as well as between a single-mode control group and different mixed-mode groups. METHODS: Data were collected for a methodological pilot of the third wave of the "German Health Interview and Examination Survey for Children and Adolescents". Questionnaires were completed by parents or adolescents. A population-based sample of 11,140 children and adolescents aged 0-17 years was randomly allocated to 4 survey designs-a single mode control group with paper-and-pencil questionnaires only (n=970 parents, n=343 adolescents)-and 3 mixed-mode designs, all of which offered Web-based questionnaire options. In the concurrent mixed-mode design, both questionnaires were offered at the same time (n=946 parents, n=290 adolescents); in the sequential mixed-mode design, the SAQ-Web was sent first, followed by the paper questionnaire along with a reminder (n=854 parents, n=269 adolescents); and in the preselect mixed-mode design, both options were offered and the respondents were asked to request the desired type of questionnaire (n=698 parents, n=292 adolescents). In total, 3468 questionnaires of parents of children aged 0-17 years (SAQ-Web: n=708; SAQ-paper: n=2760) and 1194 questionnaires of adolescents aged 11-17 years (SAQ-Web: n=299; SAQ-paper: n=895) were analyzed. Sociodemographic characteristics and a broad range of health indicators for children and adolescents were compared by survey design and data collection mode by calculating predictive margins from regression models. RESULTS: There were no statistically significant differences in sociodemographic characteristics or health indicators between the single-mode control group and any of the mixed-mode survey designs. Differences in sociodemographic characteristics between SAQ-Web and SAQ-paper were found. Web respondents were more likely to be male, have higher levels of education, and higher household income compared with paper respondents. After adjusting for sociodemographic characteristics, only one of the 38 analyzed health indicators showed different prevalence rates between the data collection modes, with a higher prevalence rate for lifetime alcohol consumption among the online-responding adolescents (P<.001). CONCLUSIONS: These results suggest that mode bias is limited in health interview surveys for children and adolescents using a mixed-mode design with Web-based and paper questionnaires. PMID- 29506968 TI - The Impact of a Small Private Online Course as a New Approach to Teaching Oncology: Development and Evaluation. AB - BACKGROUND: Oncology involves complex care and multidisciplinary management of patients; however, misinformation and ineffective communication remain problematic. OBJECTIVE: The educational objective of our study was to develop a new teaching method to improve cancer treatment and management by emphasizing the link between hospitals (inpatients) and their surrounding communities (outpatients). METHODS: A team of 22 professionals from public and private institutions developed a small private online course (SPOC). Each offering of the course lasted 6 weeks and covered 6 topics: individual health care plans, cancer surgery, ionizing radiation, cancer medicines, clinical research, and oncological supportive care. For participants in the course, we targeted people working in the cancer field. The SPOC used an active teaching method with collaborative and multidisciplinary learning. A final examination was offered in each session. We evaluated participants' satisfaction rate through a questionnaire and the success of the SPOC by participants' completion, success, and commitment rates. RESULTS: Of the total participants (N=1574), 446 completed the evaluation form. Most participants were aged 31 to 45 years. Participants included 56 nurses, 131 pharmacists, 80 from the medical field (including 26 physicians), 53 from patients' associations, 28 health teachers, and 13 students (medical and paramedical). Among the participants, 24.7% (90/446) had an independent medical practice, 38.5% (140/446) worked in a public institution, and 36.8% (134/446) worked in a private institution. After completing the SPOC sessions, 85.9% (384/446) thought they had learned new information, 90.8% (405/446) felt their expectations were met, and 90.4% (403/446) considered that the information had a positive impact on their professional practice. The completion rate was 35.51% (559/1574), the success rate was 71.47% (1025/1574), and the commitment rate was 64.67% (1018/1574). Concerning the cost effectiveness of SPOC compared with a traditional classroom of 25 students, online education became more effective when there were more than 950 participants. CONCLUSIONS: SPOCs improved the management of oncology patients. This new digital learning technique is an attractive concept to integrate into teaching practice. It offered optimal propagation of information and met the students' expectations. PMID- 29506969 TI - Targeted Secure Messages to Facilitate Access to Tobacco Treatment Counseling for Veterans: Feasibility Study. AB - BACKGROUND: Studies show that combining nicotine replacement therapy (NRT) with tobacco treatment counseling is most effective for smoking cessation. However, tobacco treatment counseling has been underutilized across the nation. A secure email message sent to patients already taking NRT was hypothesized to increase the utilization of tobacco treatment counseling among Veterans in New Jersey. Secure messaging for communication between patients and providers was implemented through a web-based password-protected, secure messaging account, where veterans get notified through their personal email when they have a message awaiting them. OBJECTIVE: The main objective of this project was to determine if there was a significant increase in adoption of tobacco treatment counseling among Veterans who received a secure message describing the options for tobacco treatment counseling available to them. Secondary objectives were to demographically characterize Veterans who were and were not enrolled in secure messaging, as well as those who opened or did not open a message. Finally, because the language and content of the messages were changed across project phases, this project also sought to determine (by analysis of response rates) the type of language that was most effective at eliciting a response. METHODS: Over two phases, messages were sent to two samples of Veterans prescribed NRT within the prior 90 days of each phase. In phase 1, one message was sent in December 2015 (message 1). In phase 2, one message was sent in July 2016 (message 2) and the same message (message 3) was resent in August 2016 to persons who did not open message 2. Messages 2 and 3 were more directive than message 1. Response rates to message 1 versus message 2 were compared. A logistic regression analysis determined effect of age and gender on enrollment in secure messaging across both phases. The effectiveness of each phase at increasing tobacco treatment counseling was analyzed using a McNemar test. RESULTS: Message 2, sent to 423 Veterans, had a significantly higher response rate than message 1, sent to 348 Veterans (18%, 17/93 vs 8%, 6/78, P=.04). Phase 2 (ie, messages 2 and 3) significantly increased utilization of tobacco treatment counseling (net increase of six tobacco treatment counseling adopters, P=.04), whereas phase 1 (ie, message 1) did not (net increase of two tobacco treatment counseling adopters, P=.48). Women (odds ratio [OR] 1.6, 95% CI 1.1-2.3) and those aged 30 to 49 years (compared to other age groups) were more likely to be enrolled in secure messaging. Gender and age were not significant predictors of opening or replying to either message. CONCLUSIONS: Although the effect was small, secure messaging was a useful modality to increase tobacco treatment counseling. Directive content with a follow-up message appeared useful. Female Veterans and/or Veterans aged between 30 and 49 years are more likely to use secure messaging. PMID- 29506971 TI - Comment on: Clinical Validity, Understandability, and Actionability of Online Cardiovascular Disease Risk Calculators: Systematic Review. PMID- 29506972 TI - Anaesthetist is investigated over deaths of several patients. PMID- 29506970 TI - Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. OBJECTIVE: The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA. METHODS: A randomized, double-blind, placebo controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue. RESULTS: Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed. CONCLUSIONS: This is the first clinical trial evaluating creatine therapy in SBMA. Given that creatine serves as an energy source in skeletal muscles, recovery of intramuscular creatine concentration is expected to improve muscle strength. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000012503; https://upload.umin.ac.jp/cgi-open bin/ctr_e/ctr_view.cgi?recptno=R000014611 (Archived by WebCite at http://www.webcitation.org/6xOlbPkg3). PMID- 29506973 TI - Charting the Future of Cancer Health Disparities Research-Letter. PMID- 29506974 TI - Industry must cut calories in savoury food products by 20%, says Public Health England. PMID- 29506975 TI - A Role for Branched-Chain Amino Acids in the Pathophysiology of Diabetes: Using Data to Guide Discovery. PMID- 29506976 TI - Local approaches to the general practice recruitment crisis. PMID- 29506977 TI - Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomised controlled trial of PRISM (primary care streptococcal management). PMID- 29506978 TI - March 5th Question. PMID- 29506979 TI - Sam Guglani: Life, mortality, and poetry. PMID- 29506980 TI - Relaxation of the one child policy and trends in caesarean section rates and birth outcomes in China between 2012 and 2016: observational study of nearly seven million health facility births. AB - OBJECTIVE: To examine how the relaxation of the one child policy and policies to reduce caesarean section rates might have affected trends over time in caesarean section rates and perinatal and pregnancy related mortality in China. DESIGN: Observational study. SETTING: China's National Maternal Near Miss Surveillance System (NMNMSS). PARTICIPANTS: 6 838 582 births at 28 completed weeks or more of gestation or birth weight >=1000 g in 438 hospitals in the NMNMSS between 2012 and 2016. MAIN OUTCOME MEASURES: Obstetric risk was defined using a modified Robson classification. The main outcome measures were changes in parity and age distributions and relative frequency of each Robson group, crude and adjusted trends over time in caesarean section rates within each risk category (using Poisson regression with a robust variance estimator), and trends in perinatal and pregnancy related mortality over time. RESULTS: Caesarean section rates declined steadily between 2012 and 2016 (crude relative risk 0.91, 95% confidence interval 0.89 to 0.93), reaching an overall hospital based rate of 41.1% in 2016. The relaxation of the one child policy was associated with an increase in the proportion of multiparous births (from 34.1% in 2012 to 46.7% in 2016), and births in women with a uterine scar nearly doubled (from 9.8% to 17.7% of all births). Taking account of these changes, the decline in caesarean sections was amplified over time (adjusted relative risk 0.82, 95% confidence interval 0.81 to 0.84). Caesarean sections declined noticeably in nulliparous women (0.75, 0.73 to 0.77) but also declined in multiparous women without a uterine scar (0.65, 0.62 to 0.77). The decrease in caesarean section rates was most pronounced in hospitals with the highest rates in 2012, consistent with the government's policy of targeting hospitals with the highest rates. Perinatal mortality declined from 10.1 to 7.2 per 1000 births over the same period (0.87, 0.83 to 0.91), and there was no change in pregnancy related mortality over time. CONCLUSIONS: China is the only country that has succeeded in reverting the rising trends in caesarean sections. China's success is remarkable given that the changes in obstetric risk associated with the relaxation of the one child policy would have led to an increase in the need for caesarean sections. China's experience suggests that change is possible when strategies are comprehensive and deal with the system level factors that underpin overuse as well as the various incentives at work during a clinical encounter. PMID- 29506982 TI - Obesity Progression Between Young Adulthood and Midlife and Incident Diabetes: A Retrospective Cohort Study of U.S. Adults. AB - OBJECTIVE: Understanding how changes in weight over the life course shape risk for diabetes is critical for the prevention of diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), we investigated the association between self-reported weight change from young adulthood to midlife and incident diabetes. RESEARCH DESIGN AND METHODS: We categorized individuals into four weight-change groups: those who remained nonobese (stable nonobese), those who moved from an obese BMI to a nonobese BMI (losing), those who moved from a nonobese BMI to an obese BMI (gaining), and those who remained obese (stable obese). Diabetes status was determined by self-report of a prior diagnosis, and age at diagnosis was used to establish time of diabetes onset. Hazard ratios (HRs) relating weight change to incident diabetes over 10 years of follow-up were calculated using Cox models adjusting for covariates. RESULTS: Those who were obese and lost weight exhibited a significantly lower risk (HR 0.33; 95% CI 0.14, 0.76) of diabetes compared with those with stable obesity. We also observed lower risk among those who were stable nonobese (HR 0.22; 95% CI 0.18, 0.28) and those in the gaining category (HR 0.70; 95% CI 0.57, 0.87). Further, there was evidence of an increased incidence of diabetes among obese individuals who lost weight compared with individuals who were stable nonobese; however, weight loss was rare, and the association was not statistically significant. If those who were obese had become nonobese during the 10-year period, we estimate that 9.1% (95% CI 5.3, 12.8) of observed diabetes cases could have been averted, and if the population had maintained a normal BMI during the period, 64.2% (95% CI 59.4, 68.3) of cases could have been averted. CONCLUSIONS: The findings from this study underscore the importance of population-level approaches to the prevention and treatment of obesity across the life course of individuals. PMID- 29506983 TI - Liver Zonation Index of Drug Transporter and Metabolizing Enzyme Protein Expressions in Mouse Liver Acinus. AB - The purpose of the present study was to clarify the molecular basis of zonated drug distributions in mouse liver based on the protein expression levels of transporters and metabolizing enzymes in periportal (PP) and pericentral (PC) vein regions of mouse hepatic lobules. The distributions of sulforhodamine 101 (SR-101), a substrate of organic anion transporting polypeptides (Oatps), and ribavirin, a substrate of equilibrative nucleoside transporter 1 (Ent1), were elucidated in frozen liver sections of mice, to which each compound had been intravenously administered. Regions strongly positive for SR-101 (SR-101+) and regions weakly positive or negative for SR-101 (SR-101-) were separated by laser microdissection. The zonated distribution of protein expression was quantified in terms of the liver zonation index. Quantitative targeted absolute proteomics revealed the selective expression of glutamine synthetase in the SR-101+ region, indicating predominant distribution of SR-101 in hepatocytes of the PC vein region. The protein levels of Oatp1a1, Oatp1b2, organic cation transporter 1 (Oct1), and cytochrome P450 (P450) 2e1 were greater in the PC vein regions, whereas the level of organic anion transporter 2 (Oat2) was greater in the PP vein regions. Mouse Oatp1a1 mediated SR-101 transport. On the other hand, there were no statistically significant differences in expression of Ent1, Na+ taurocholate cotransporting polypeptide, several canalicular transporters, P450 enzymes, and UDP-glucuronosyltransferases between the PP and PC vein regions. This is consistent with the almost uniform distribution of ribavirin in the liver. In conclusion, sinusoidal membrane transporters such as Oatp1a1, Oatp1b2, Oct1, and Oat2 appear to be determinants of the zonated distribution of drugs in the liver. PMID- 29506981 TI - Reference values for peak oxygen uptake: cross-sectional analysis of cycle ergometry-based cardiopulmonary exercise tests of 10 090 adult German volunteers from the Prevention First Registry. AB - OBJECTIVE: This study aims to construct quantile reference values for peak oxygen uptake (VO2peak) measured by cycle ergometry-based incremental cardiopulmonary exercise tests. DESIGN: Cross-sectional study using quantile regressions to fit sex-specific and age-specific quantile curves. Exercise tests were conducted using cycle ergometry. Maximal effort in the exercise tests wass assumed when respiratory exchange ratio >=1.1 or lactate >=8 mmol/L or maximal heart rate >=90% of the age-predicted maximal heart rate. This was assessed retrospectively for a random subsample with an a priori calculated sample size of n=252 participants. SETTING: A network of private outpatient clinics in three German cities recorded the results of cycle ergometry-based cardiopulmonary exercise tests to a central database (Prevention First Registry) from 2001 to 2015. PARTICIPANTS: 10 090 participants (6462 men, 3628 women) from more than 100 local companies volunteered in workplace health promotion programmes. Participants were aged 21 to 83 years, were free of acute complaints and had primarily sedentary working environments. MAIN OUTCOME MEASURE: Peak oxygen uptake was measured as absolute VO2peak in litres of oxygen per minute and relative VO2peak in millilitres of oxygen per kilogram of body mass per minute. RESULTS: The mean age for both men and women was 46 years. Median relative VO2peak was 36 and 30 mL/kg/min at 40 to 49 years, as well as 32 and 26 mL/kg/min at 50 to 59 years for men and women, respectively. An estimated proportion of 97% of the participants performed the exercise test until exertion. CONCLUSIONS: Reference values and nomograms for VO2peak were derived from a large sample of preventive healthcare examinations of healthy white-collar workers. The presented results can be applied to participants of exercise tests using cycle ergometry who are part of a population that is comparable to this study. PMID- 29506984 TI - Impact of Novel Low-Density Lipoprotein-Cholesterol Assessment on the Utility of Secondary Non-High-Density Lipoprotein-C and Apolipoprotein B Targets in Selected Worldwide Dyslipidemia Guidelines. AB - BACKGROUND: Selected dyslipidemia guidelines recommend non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (apoB) as secondary targets to the primary target of low-density lipoprotein-cholesterol (LDL-C). After considering 2 LDL-C estimates that differ in accuracy, we examined: (1) how frequently non-HDL-C guideline targets could change management; and (2) the utility of apoB targets after meeting LDL-C and non-HDL-C targets. METHODS: We analyzed 2518 adults representative of the US population from the 2011 to 2012 National Health and Nutrition Examination Survey and 126 092 patients from the Very Large Database of Lipids study with apoB. We identified all individuals as well as those with high-risk clinical features, including coronary artery disease, diabetes mellitus, and metabolic syndrome who met very high- and high risk guideline targets of LDL-C <70 and <100 mg/dL using Friedewald estimation (LDL-CF) and a novel, more accurate method (LDL-CN). Next, we examined those not meeting non-HDL-C (<100, <130 mg/dL) and apoB (<80, <100 mg/dL) guideline targets. In those meeting dual LDL-C and non-HDL-C targets (<70 and <100 mg/dL, respectively, or <100 and <130 mg/dL, respectively), we determined the proportion of individuals who did not meet guideline apoB targets (<80 or <100 mg/dL). RESULTS: A total of 7% to 9% and 31% to 36% of individuals had LDL-C <70 and <100 mg/dL, respectively. Among those with LDL-CF<70 mg/dL, 14% to 15% had non-HDL-C >=100 mg/dL, and 7% to 8% had apoB >=80 mg/dL. Among those with LDL-CF<100 mg/dL, 8% to 10% had non-HDL-C >=130 mg/dL and 2% to 3% had apoB >=100 mg/dL. In comparison, among those with LDL-CN<70 or 100 mg/dL, only ~2% and ~1% of individuals, respectively, had non-HDL-C and apoB values above guideline targets. Similar trends were upheld among those with high-risk clinical features: ~0% to 3% of individuals with LDL-CN<70 mg/dL had non-HDL-C >=100 mg/dL or apoB >=80 mg/dL compared with 13% to 38% and 9% to 25%, respectively, in those with LDL CF<70 mg/dL. With LDL-CF or LDL-CN<70 mg/dL and non-HDL-C <100 mg/dL, 0% to 1% had apoB >=80 mg/dL. Among all dual LDL-CF or LDL-CN<100 mg/dL and non-HDL-C <130 mg/dL individuals, 0% to 0.4% had apoB >=100 mg/dL. These findings were robust to sex, fasting status, and lipid-lowering therapy status. CONCLUSIONS: After more accurately estimating LDL-C, guideline-suggested non-HDL-C targets could alter management in only a small fraction of individuals, including those with coronary artery disease and other high-risk clinical features. Furthermore, current guideline-suggested apoB targets provide modest utility after meeting cholesterol targets. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489. PMID- 29506985 TI - Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes. AB - Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for beta-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism. PMID- 29506986 TI - Opioid prescribing and adverse events in opioid-naive patients treated by emergency physicians versus family physicians: a population-based cohort study. AB - BACKGROUND: Emergency physicians provide primary care to patients and often prescribe opioids for acutely painful self-limiting conditions. The objective of this study was to describe patterns of opioid prescribing by emergency physicians and family physicians and to explore the relation between setting of initiation of opioid treatment and adverse events over the subsequent 2 years. METHODS: This was a population-based cohort study using administrative data from Ontario. Opioid-naive patients aged 15-64 years who received an opioid prescription for noncancer pain from an emergency or family physician between Apr. 1, 2008, and Mar. 31, 2012 were eligible for inclusion. RESULTS: A total of 34 713 and 45 952 patients were initiated on an opioid by an emergency physicians and family physicians, respectively. Both emergency and family physicians most commonly prescribed codeine-containing products (58.9% and 79.6% of prescriptions, respectively); however, emergency physicians were twice as likely as family physicians to prescribe higher-potency opioids (morphine, oxycodone, hydromorphone, fentanyl, meperidine) (both combination and single-agent preparations) (40.6% v. 19.9%, ? = 20.7, 95% confidence interval [CI] 20.0-21.3). Compared to patients in the family physician group, those in the emergency physician group received significantly higher daily dosages, a higher proportion were initiated on a daily dosage of 100 mg of morphine equivalents (MEQs) or more, and had a hospital admission for opioid toxicity within 2 years (0.5% v. 0.3%, ? = 0.2%, 95% CI 0.1%-0.3%). A higher proportion of patients in the family physician group than in the emergency physician group had dosage escalation beyond 199 mg MEQs within 2 years (0.7% v. 0.1%, ? = 0.6%, 95% CI 0.5%-0.7%). INTERPRETATION: Codeine was the most common opioid prescribed by emergency and family physicians. Compared to patients prescribed opioids by family physicians, those prescribed opioids by emergency physicians received higher initial daily dosages and had an increased likelihood of opioid toxicity. PMID- 29506987 TI - Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients. AB - Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.Experimental Design: We performed mutation profiling using targeted next generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified.Results:EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC50) of osimertinib in vitro, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS, and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations.Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo, and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097-107. (c)2018 AACR. PMID- 29506989 TI - Brexit will affect UK's supply of radioisotopes. PMID- 29506988 TI - Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer. AB - Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3.Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors.Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade >=3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab.Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276-84. (c)2018 AACR. PMID- 29506990 TI - Smartphone GP app service will divert funding from most needy, warns practice. PMID- 29506991 TI - Margaret McCartney: Direct patient care should be rewarded and cherished. PMID- 29506992 TI - Left Ventricular Biopsy in the Diagnosis of Myocardial Diseases. PMID- 29506993 TI - Unmeasured Interface in Emergency Cardiovascular Care: How Do Dispatch-Assisted Telephone Cardiopulmonary Resuscitation and Bystander Training Interact? PMID- 29506994 TI - Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials. PMID- 29506995 TI - Predicting the Future in Hypertrophic Cardiomyopathy. PMID- 29506998 TI - Highlights From the Circulation Family of Journals. PMID- 29506996 TI - Glucose-Lowering Therapies and Heart Failure in Type 2 Diabetes Mellitus: Mechanistic Links, Clinical Data, and Future Directions. AB - Diabetes mellitus independently increases the risk of and mortality from heart failure in a manner that is well established but inadequately understood. Glycemic optimization does not eliminate this risk, and measures of glycemic control are insufficient markers of cardiovascular risk. In response to a regulatory guidance from the US Food and Drug Administration, glucose-lowering agents are now routinely evaluated in large cardiovascular outcome trials. These recent trial experiences of novel and established glucose-lowering therapies have shown variable risks and benefits with respect to heart failure. Cardiovascular outcome trials have increasingly included heart failure events as either a component of the primary end point or a secondary adjudicated end point. We comprehensively review each established and novel currently marketed glucose lowering therapy, their biological targets, mechanisms of action, and relationships with heart failure. We then highlight gaps in available evidence and directions for future research regarding the ascertainment of heart failure related data in the evaluation of emerging glucose-lowering therapies. PMID- 29506999 TI - Unusual Rhythm Behind a Narrow Complex Tachycardia. PMID- 29507000 TI - Return-to-Play for Athletes With Genetic Heart Diseases. PMID- 29507001 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study". PMID- 29507002 TI - Letter by Hjuler et al Regarding Article, "Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study". PMID- 29507003 TI - Response by Lerman et al to Letters Regarding Article, "Coronary Plaque Characterization in Psoriasis Reveals High-Risk Features That Improve After Treatment in a Prospective Observational Study". PMID- 29507004 TI - Letter by Spartalis et al Regarding Article, "Cardiomyocyte Regeneration: A Consensus Statement". PMID- 29507005 TI - Association of Nonoxidized Parathyroid Hormone with Cardiovascular and Kidney Disease Outcomes in Chronic Kidney Disease. AB - BACKGROUND AND OBJECTIVES: In patients with CKD, elevated plasma parathyroid hormone (PTH) levels are associated with greater cardiovascular morbidity and mortality. However, the reference method for PTH measurement is disputed. It has been argued that measurement of nonoxidized PTH better reflects biologically active PTH than measurements with conventional assays. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: PTH and nonoxidized PTH levels were measured at study baseline in 535 patients with CKD with an eGFR range between 89 and 15 ml/min per 1.73 m2. Patients were followed over 5.1 years for the occurrence of acute heart failure, atherosclerotic events, CKD progression (doubling of serum creatinine or initiation of RRT), or all-cause death. RESULTS: Atherosclerotic events, acute heart failure, CKD progression, and deaths from any cause occurred in 116, 58, 73, and 85 patients, respectively. In Kaplan-Meier analyses, patients at the highest PTH and nonoxidized-PTH tertile (79-543 and 12-172 pg/ml, respectively) showed a higher rate of atherosclerotic events, acute heart failure, CKD progression, and death from any cause. After adjustment for eGFR and albuminuria, nonoxidized PTH was no longer associated with atherosclerotic events (hazard ratio third versus first tertile, 1.04 [95% confidence intervals, 0.62 1.75]), acute heart failure (hazard ratio third versus first tertile, 1.24 [95% confidence intervals, 0.59-2.62]), CKD progression (hazard ratio third versus first tertile, 0.93 [95% confidence intervals, 0.46-1.90]), and death from any cause (hazard ratio third versus first tertile, 1.23 [95% confidence intervals, 0.66-2.31]), and PTH lost its association with atherosclerotic events (hazard ratio third versus first tertile, 0.80 [95% confidence intervals, 0.46-1.38]) and CKD progression (hazard ratio third versus first tertile, 0.99 [95% confidence intervals, 0.46-2.10]), although it remained associated with acute heart failure (hazard ratio third versus first tertile, 2.76 [95% confidence intervals, 1.11 6.89]) and all-cause death (hazard ratio third versus first tertile, 2.35 [95% confidence intervals, 1.13-4.89]). After further adjustment for cardiovascular and kidney risk factors, PTH remained associated with all-cause death (hazard ratio third versus first tertile, 2.79 [95% confidence intervals, 1.32-5.89]), but with no other end point. CONCLUSIONS: In a cohort of patients with CKD, PTH was associated with all-cause mortality; there was no association of nonoxidized PTH with any of the clinical outcomes examined. PMID- 29507007 TI - Clear the Fog around Parathyroid Hormone Assays: What Do iPTH Assays Really Measure? PMID- 29507006 TI - Association between Duration of Predialysis Care and Mortality after Dialysis Start. AB - BACKGROUND AND OBJECTIVES: Early nephrology referral is recommended for people with CKD on the basis of observational studies showing that longer nephrology care before dialysis start (predialysis care) is associated with lower mortality after dialysis start. This association may be observed because predialysis care truly reduces mortality or because healthier people with an uncomplicated course of disease will have both longer predialysis care and lower risk for death. We examined whether the survival benefit of longer predialysis care exists after accounting for the potential confounding effect of disease course that may also be affected by predialysis care. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective cohort study and used data from 3152 adults with end stage kidney failure starting dialysis between 2004 and 2014 in five Canadian dialysis programs. We obtained duration of predialysis care from the earliest nephrology outpatient visit to dialysis start; markers of disease course, including inpatient or outpatient dialysis start and residual kidney function around dialysis start; and all-cause mortality after dialysis start. RESULTS: The percentages of participants with 0, 1-119, 120-364, and >=365 days of predialysis care were 23%, 8%, 10%, and 59%, respectively. When we ignored markers of disease course as in previous studies, longer predialysis care was associated with lower mortality (hazard ratio120-364 versus 0-119 days, 0.60; 95% confidence interval, 0.46 to 0.78]; hazard ratio>=365 versus 0-119 days, 0.60; 95% confidence interval, 0.51 to 0.71; standard Cox model adjusted for demographics and laboratory and clinical characteristics). When we additionally accounted for markers of disease course using the inverse probability of treatment weighted Cox model, this association was weaker and no longer significant (hazard ratio120-364 versus 0-119 days, 0.84; 95% confidence interval, 0.60 to 1.18; hazard ratio>=365 versus 0-119 days, 0.88; 95% confidence interval, 0.69 to 1.13). CONCLUSIONS: The association between longer predialysis care and lower mortality after dialysis start is weaker and imprecise after accounting for patients' course of disease. PMID- 29507009 TI - Beating the odds: a rare case of supracardiac total anomalous pulmonary venous return (TAPVR) in an adult patient. AB - Total anomalous pulmonary venous return (TAPVR) is a rare congenital heart defect, and patients are usually symptomatic at a very young age. Survival to adulthood without surgical correction is extremely rare. We report a 33-year-old woman with a heart murmur and a history of a successful pregnancy. Echocardiogram revealed a large atrial septal defect with suspicious pulmonary vein anomaly. Chest radiograph demonstrated classical 'snowman' configuration. Cardiac catheterisation was consistent with anomalous pulmonary venous drainage. Cardiac CT confirmed supracardiac TAPVR, whereby all the pulmonary veins drain into the anomalous vein and finally to the superior vena cava. She remained asymptomatic and underwent a successful surgical repair. PMID- 29507008 TI - Exploring the Clinical Relevance of Providing Increased Removal of Large Middle Molecules. AB - Dialysis technologies have continued to advance over recent decades; however, these advancements have not always been met with improved patient outcomes. In part, the high morbidity and mortality associated with dialysis have been attributed to a group of uremic toxins, which are described as "difficult to remove." With a new generation of hemodialysis membranes now making meaningful clearance of these molecules possible, it is an apt time to review the clinical relevance of these middle molecules. Our review describes the developments in membrane technology that enable the removal of large middle molecules (molecular mass >15 kD) that is limited with high-flux dialysis membranes. Of the known 58 middle molecules, a literature search identified 27 that have molecular mass >15 kD. This group contains cytokines, adipokines, hormones, and other proteins. These molecules are implicated in chronic inflammation, atherosclerosis, structural heart disease, and secondary immunodeficiency in the literature. Single-center safety and efficacy studies have identified that use of these membranes in maintenance dialysis populations is associated with limited loss of albumin and increased clearance of large middle molecules. Larger, robustly conducted, multicenter studies are now evaluating these findings. After completion of these safety and efficacy studies, the perceived clinical benefits of providing clearance of large middle molecules must be assessed in rigorously conducted, randomized clinical studies. PMID- 29507010 TI - Chronic lymphocytic leukaemia and spontaneous rupture of spleen. AB - Pathological or spontaneous splenic rupture is a rare but well-recognised complication of haematological malignancies. The authors present a clinical report of a 78-year-old woman with known clinical history of chronic lymphocytic leukaemia and atrial fibrillation under anticoagulation with apixaban which has spontaneous splenic rupture. Pathological examination revealed lymph node and splenic infiltration due to chronic lymphocytic leukaemia. The diagnosis of splenic rupture must be considered in all patients with haematological malignancies who experience acute abdomen. Given the severity, it requires a correct and timely diagnosis. PMID- 29507012 TI - SLE presenting as demyelinative autoimmune visual loss. AB - A healthy 38-year-old woman developed sudden unilateral vision loss due to retrobulbar optic neuritis in the wake of varicella-zoster virus infection. She had no further central nervous system (CNS) lesions. Antinuclear antibodies (ANA) and anti-aquaporin 4 antibodies were found, consistent with neuromyelitis optica (NMO). Later, serial MRIs showed dynamic short-segment and long-segment myelitis lesions, ANA titre increased and additional autoantibodies were found including anti-dsDNA, anti-chromatin/nucleosome and antiphospholipid antibodies. In that setting, NMO can be regarded a rare presenting manifestation of systemic lupus erythematosus (SLE). The relevant literature is reviewed and the implications of NMO spectrum disorder demyelinating syndromes as the first manifestation of SLE (with or without antiphospholipid syndrome) (APS) or their later development (in a patient diagnosed with SLE) as part of the spectrum of neuropsychiatric SLE are analysed in view of recent research developments in the field. PMID- 29507011 TI - Extramammary Paget's disease of the scrotum with complete response to imiquimod and photodynamic therapy. AB - Extramammary Paget's disease (EMPD) is a rare intraepithelial neoplasm with an extremely variable clinical course. The objective of this study was to determine if combination imiquimod and photodynamic therapy could induce remission of EMPD. A 69-year-old man with EMPD was treated with topical imiquimod 5% cream at night for 5 days per week for 1 month, followed by 2 months of 5% imiquimod for three nights a week. For the following 6 months, monthly 5-aminolevulinic acid photodynamic therapy was added. After 6 months, imiquimod was discontinued and the patient continued to be treated with quarterly photodynamic therapy. Treatment resulted in significant improvement in the appearance of the lesion, and pathology revealed no evidence of residual disease. The patient has had no clinical signs of disease for >5 years. We conclude that topical imiquimod 5% cream and photodynamic therapy may aid in the treatment of some patients with EMPD. PMID- 29507013 TI - More, less or both? AB - A 67-year-old Caucasian woman with no prior medical history was admitted to our hospital with complaints of generalised weakness, nausea, diarrhoea and weight loss. The patient suffered from tachycardia and hypotension. Blood tests revealed Graves' thyrotoxicosis and the patient was treated accordingly. However, patient's health continued to decline rapidly and further tests revealed a concomitant Addisonian crisis. Additional treatment with corticosteroids led to a full recovery. It is well known that autoimmune endocrine disorders tend to cluster. However, the presentation is usually sequential in time. This case reports the highly rare simultaneous presentation of Addison's disease and Graves' thyrotoxicosis. It also provides several suggestions to help establish the diagnoses. PMID- 29507014 TI - Placental abruption after amnioreduction for polyhydramnios caused by chorioangioma. AB - Placental chorioangioma is the most common type of a benign placental tumour that occurs in 1% of pregnancies. A large chorioangioma is associated with adverse pregnancy outcomes. We present a case of placental abruption necessitating preterm delivery after multiple amnioreductions for polyhydramnios caused by a large chorioangioma. If antenatal diagnosis of a significant chorioangioma is made as the cause of polyhydramnios, caution should be taken when performing rapid amnioreductions. PMID- 29507015 TI - The mass effect of a slowly growing GIST. AB - Gastrointestinal stromal tumours (GISTs) are typically defined as solid masses arising from the GI tract, most commonly from the stomach and small intestine. They seldom present in a cystic form. Management of cystic masses arising from the GI tract may pose a diagnostic predicament. We had one such case that presented itself with complaints of a slow growing intra-abdominal mass. An ultrasound scan demonstrated a thick-walled cystic lesion arising from the pelvis. Further imaging evaluations in the form of a CT scan revealed a complex large cystic mass arising from left upper quadrant (see Figure 1). Due to the uncertainty of origin of this mass and lack of invasion or lymphadenopathy, it was thought to be benign. After a multidisciplinary meeting, it was concluded that an urgent surgical excision of this benign mass was the best treatment. The surgical treatment of which entailed a 10 hours surgery to resect this 10 kg lesion, which comprised 7 L fluid and 3 kg solid mass. Histopathology aided in the diagnosis of this lesion as a CD117-positive and DOG1-positive GIST. PMID- 29507016 TI - Retropharyngeal abscess after chemotherapy. AB - Chemotherapy increases susceptibility to infection due to the effect on cell mediated and humoral immunity. Retropharyngeal abscess is a serious head and neck infection that rapidly progresses from toxicity, whether the patient is neutropenic or not. The risk should be carefully assessed with any chemotherapeutic agent, especially docetaxel. PMID- 29507017 TI - Metastatic MSSA infection of the spine and extremities. AB - Here, we present a rare case of metastatic methicillin sensitive Staphylococcus aureus (MSSA) infection arising from an unknown focus and spreading throughout the lumbar spine with associated pyomyositis of the paraspinal musculature, and septic arthritis of the knee, ankle and sternoclavicular joint. This case highlights the potential for missed aspects and delay in diagnosis in the care of metastatic S. aureus and the need for multispecialty intervention. Treatment of S. aureus infections requires a high index of suspicion and careful examination of multiple organ systems to identify the full extent of the disease. A discussion on metastatic S. aureus infection follows the report. PMID- 29507018 TI - Acute demyelinating neuropathy in a patient with neurolymphomatosis. AB - Peripheral neurological complications of lymphomas are rare and much less frequent than central complications. Nonetheless, on occasion, systemic non Hodgkin's lymphoma may directly infiltrate the peripheral nervous system at various levels. This report describes a man with non-Hodgkin's lymphoma and leptomeningeal disease who developed progressive areflexic quadraparesis. Initial electromyography (EMG) was consistent with a polyradiculopathy and a repeat EMG performed 1 month later for worsening symptoms showed evidence of demyelination. The patient expired due to systemic complications of his illness. Autopsy of the sural nerve showed moderately severe distal sensory axonal loss, direct infiltration of the brachial plexus by malignant lymphocytes and demyelination in brachial and lumbar plexus, most prominent in areas of neoplastic infiltration. Based on this patient's course and pathology, we suggest that widespread demyelination may accompany neurolymphomatosis and the clinical presentation may be indistinguishable from an acute demyelinating neuropathy. PMID- 29507019 TI - Whipple's disease: a rare case of malabsorption. AB - Whipple's disease is a chronic, rare, multisystemic, infectious entity, described for the first time in 1907. Its aetiological agent is the Gram-negative rod, Tropheryma whipplei, which was isolated for the first time in 2001 from a cardiac valve of a patient with endocarditis. We present the case of a 71-year-old man, who came into the emergency room complaining of anorexia, weakness, abdominal pain and diarrhoea with haematochezia and presented disseminated palpable purpuric lesions, predominantly in the lower limbs. The upper endoscopy showed a duodenal vasculitis and the biopsy of that location revealed aspects suggestive of Whipple's disease. We started him on antibiotics according to the recent orientations with progressive clinical and analytical improvement, although he developed an immune reconstitution syndrome, which lasted for 2 weeks. PMID- 29507020 TI - Successful faecal microbiota transplant for recurrent Clostridium difficile infection delivered by colonoscopy through a diverted ileostomy in a patient with severe perianal Crohn's disease. AB - We present the first reported case of successful treatment of recurrent Clostridium difficile infection with faecal microbiota transplantation delivered antegrade with a colonoscope through a diverting ileostomy. PMID- 29507021 TI - Meningococcal serogroup W135 epiglottitis in an adolescent patient. AB - Acute epiglottitis is a severe and potentially life-threatening condition. Since the implementation of Haemophilus influenzae vaccination, the number of cases of epiglottitis has decreased and the proportion of other infectious causes has increased. We report a case of acute epiglottitis in a teenager caused by Neisseria meningitidis, an unusual pathogen. PMID- 29507022 TI - Pregnancy in a patient with portal hypertension secondary to liver cirrhosis. AB - This case report is of a 32-year-old woman of African descent on follow-up for pregnancy in the background of portal hypertension due to liver cirrhosis. She had initially been treated for chronic hepatitis B infection with lamivudine and tenofovir, complicated by portal hypertension and variceal bleeding that thrice required banding. Her pregnancy was uneventful until 31 weeks gestation when she presented with dyspnoea. On examination and investigation, she had oedema, bilateral pleural effusions and ascites. Multidisciplinary discussions involving surgery, anaesthesia, obstetrics, neonatology and medicine were held. A consensus outpatient and inpatient management plan was implemented. At 36 weeks, following non-reassuring fetal cardiotocography, she underwent induction of labour. An assisted vacuum delivery was conducted in a controlled setting. She gave birth to a live female infant who had an APGAR score of 9 at 5 min. Both she and the baby had an uneventful postpartum period. PMID- 29507023 TI - Kingella kingae sternoclavicular osteoarthritis. AB - Sternoclavicular arthritis is an unusual osteoarticular infection and can be associated with severe complications. Cases in a paediatric population are infrequently reported, making this approach challenging. Kingella kingae is an agent of increasing recognition in paediatric invasive infections, principally below 2 years of age. A case of K. kingae osteoarthritis in a 17-month-old child is described with a review of the literature. PMID- 29507024 TI - Spontaneous splenic rupture due to rivaroxaban. AB - In the prevention and treatment of thromboembolic disease, novel oral anticoagulants have emerged as alternatives to warfarin. A major challenge continues to be the reversal of their anticoagulant effect in the case of life threatening haemorrhagic complications. We report a case of spontaneous splenic rupture treated by splenic artery embolisation in a 77-year-old woman who was anticoagulated with rivaroxaban. PMID- 29507025 TI - Cytomegalovirus ulcerative oesophagitis in a young healthy immunocompetent patient. AB - Cytomegalovirus (CMV) gastrointestinal disease usually arises in patients with immunodeficiency or immunosuppression, being rare in immunocompetent hosts. Although increasing in incidence, few cases of CMV gastrointestinal disease have been described among young healthy patients. Currently, there is uncertainty in approaching these patients, including the need for antiviral therapy that remains to be established. This case report describes a CMV ulcerative oesophagitis in a young healthy immunocompetent patient with good evolution with no need for antiviral therapy, the youngest case being reported in the literature until now. PMID- 29507026 TI - Multiorgan failure associated with severe ovarian hyperstimulation syndrome due to inadequate protocol optimisation: a rare but avoidable complication. AB - Ovarian hyperstimulation syndrome (OHSS) is a well-recognised iatrogenic complication following controlled ovarian stimulation (COS). Mild to moderate cases are mostly managed conservatively. Severe cases of OHSS can be potentially fatal. For this reason, UK clinics providing licensed fertility treatment are obliged to follow Human Fertilisation and Embryology Authority guidelines for reporting severe incidents. We present an unusually severe complication of OHSS resulting in significant morbidity. A nulligravida woman aged 25, with a 4-year history of subfertility and multiple risk factors for the development of OHSS, underwent COS. Immediately following oocyte retrieval, the patient developed symptoms of early-onset severe OHSS. The subsequent clinical deterioration of the patient precipitated multiple organ failure, including renal and hepatic dysfunction. Despite supportive management in an intensive care unit, the patient required transfer to a tertiary liver centre for specialist treatment. OHSS is a preventable complication; therefore, such an uncommon presentation of the syndrome provides important clinical lessons to be discussed. PMID- 29507027 TI - Uncommon cause for chest pain. PMID- 29507028 TI - Stroke thrombolysis complicated by ST elevation myocardial infarction (STEMI). AB - An 84-year-old male Jehovah's Witness presented to the emergency department 1 hour after onset of left facial droop and left upper limb weakness. Thrombolytic stroke treatment was commenced as per local thrombolytic protocol with intravenous recombinant tissue plasminogen activator (rtPA) at 2 hours and 25 min following onset of symptoms. Almost immediately after rtPA infusion the patient reported chest pain and had ECG changes consistent with a diagnosis of anterior ST elevation myocardial infarction. At angiogram, a graft study showed severe native coronary artery disease. The left internal mammary artery graft was patent to the left anterior descending artery (LAD); however, the apical LAD was occluded, with the appearance suggestive of embolic occlusion. PMID- 29507029 TI - Encephalopathy in an adult with cat-scratch disease. AB - We report the case of a 53-year-old healthy man, presenting with confusion. The patient had been clinically diagnosed with cat-scratch disease (CSD) and prescribed a 10-day course of doxycycline orally. Approximately a week after he had completed the treatment, he was admitted to our department with confusion. Neurological examination revealed expressive dysphasia with no motor or sensory deficits. Cerebrospinal fluid (CSF) examination showed only increased content. Imaging with CT and MRI of the brain did not reveal any abnormalities, and funduscopy was normal. Serology confirmed Bartonella henselae infection. CSD associated encephalopathy was confirmed based on the clinical manifestations, CSF findings and positive serology. The patient was treated with a combination of doxycycline and rifampin and he rapidly improved with complete neurological recovery within 7 days. Encephalopathy is an unusual manifestation of CSD in adults with excellent prognosis. PMID- 29507030 TI - Delayed diagnosis of chronic postoperative sternal infection: a rare case of sternal tuberculosis. AB - Sternal osteomyelitis secondary to mycobacterium tuberculosis (TB) is rare, with <1% of musculoskeletal TB cases reported. The recurrent scenario is unresolving infection and delayed diagnosis. A 75-year-old woman presented with a persistently discharging sternal wound 10 months after coronary artery bypass grafting. Multiple antibiotics, wound debridement and removal of sternal wires was attempted; however, progression to local osteomyelitis and sternoclavicular joint destruction occurred. Tissue biopsies were finally sent for mycobacterial culture testing positive for Mycobacterium tuberculosis High index of suspicion is necessary for diagnosis of sternal tuberculosis, confirmed through timely microbiological investigations. MRI may identify soft-tissue and bone oedema characteristic of TB osteomyelitis. This patient had no TB risk factors. The source of infection is unclear and warrants further investigation. Sternal TB osteomyelitis is uncommon and largely reported through case reports, thus management and indications for surgery remain undefined. If sensitive, standard TB four-drug regimen may be trialled. PMID- 29507031 TI - Methylprednisolone-induced acute liver injury in a patient treated for multiple sclerosis relapse. AB - Drug-induced liver injury is the fourth most common cause of liver disease in industrialised countries. Methylprednisolone is often considered to be a treatment with a low hepatotoxicity. We report a case of methylprednisolone induced liver injury in a 35-year-old woman. She was admitted to our department for acute liver injury 2 months after a treatment with high dose of methylprednisolone (1 g/day) for a multiple sclerosis relapse. No other cause of liver injury could be found (screening for hepatotropic viruses, autoimmune antibodies, ceruloplasmin, abdominal ultrasonography and liver biopsy). Liver function tests spontaneously improved and returned to normal range within 6 weeks. We also performed a brief review of the literature and identified 12 other cases of methylprednisolone-induced liver injury in patients treated for multiple sclerosis relapse. An immune rebound phenomenon could be responsible for rare but true hepatotoxicity of high-dose methylprednisolone therapy. PMID- 29507032 TI - Following leads: connecting dysphagia to mixed connective tissue disease. AB - Mixed connective tissue disease (MCDT) is a rare condition characterised by the presence of high titres of anti-U1 ribonucleoprotein antibodies and selected clinical features of systemic lupus erythematosus, systemic sclerosis and polymyositis/dermatomyositis. Early symptoms are non-specific, including easy fatigability, myalgia, arthralgia and Raynaud's phenomenon. Some reports emphasised the favourable outcome and excellent response to glucocorticoids, but there are contradictory studies reporting worse prognosis. Also, a subset of patients evolve into a clinical picture more consistent with a major diffuse connective tissue disease. We present the case of a 50-year-old black woman whose inaugural presentation of MCDT was oropharyngeal dysphagia, symmetrical proximal muscle weakness, tongue atrophy and skin sclerosis. High-dose corticosteroids and methotrexate were given with little improvement, maintaining disabling dysphagia leading to a percutaneous endoscopic gastrostomy tube placement. She was then started on intravenous immunoglobulin with progressive remission of symptoms. PMID- 29507033 TI - 'Pseudo-calcifications': detection of perfluorocarbon residue on a computed tomography scan 15 years after liquid ventilation therapy at 3 months of age. AB - Partial liquid ventilation using perfluorocarbons is a therapy that was once frequently used in paediatric populations for patients with severe respiratory distress. Perfluorocarbon is a non-toxic, insoluble and radiopaque vector through which improved gas exchange can occur. Two previous cases have been reported of persistent perfluorocarbon residua, identified on imaging years after receiving liquid ventilation therapy. We report a case of perfluorocarbon detection on a CT scan 15 years after liquid ventilation at 3 months of age, and propose the probable mechanism of its appearance. The importance of considering the imaging appearances of 'pseudo-calcifications' as a long-term sequela to perfluorocarbon liquid ventilation is emphasised. PMID- 29507034 TI - The forgotten electrolyte, when hypercalcaemia manifest as gait instability and altered mental status. AB - An altered mental status presents a diagnostic challenge for many clinicians. Described here is a case of primary hyperparathyroidism not initially suspected until after a thorough neurological and infectious cause were excluded. A 60-year old woman presented with altered mental status and gait instability. Her family noticed progressive gait instability and mood swings for the past 4 months. Initial imaging and laboratory values were unable to explain her symptoms. On transfer out of the intensive care unit, her corrected calcium was found to be 13.3 mg/dL with an elevated parathyroid hormone. Her hypercalcaemia was refractory to medical management. Ultrasound found a 2 cm nodule, which was surgically removed and found to be a parathyroid adenoma. Her calcium normalised and neurological deficits subsided. Hypercalcaemia can lead to a constellation of symptoms that include the classical 'stones, bones, abdominal moans and psychic groans' and electrolyte derangements should be considered in the differential of altered mental status. PMID- 29507035 TI - Unusual cause of neck pain. PMID- 29507036 TI - Blue nails: window to micronutrient deficiency. PMID- 29507037 TI - Uncommon skin cancer: pleomorphic dermal sarcoma. PMID- 29507038 TI - Eyes that cannot be seen: a rare case of ankyloblepharon filiforme adnatum (AFA) in a neonate. PMID- 29507039 TI - IgG4-related autoimmune pancreatitis complicated by splenic artery pseudoaneurysm. PMID- 29507041 TI - Prognosis prediction with two calculations of Palliative Prognostic Index: further prospective validation in hospice cancer patients with multicentre study. AB - OBJECTIVES: In palliative care settings, predicting prognosis is important for patients and clinicians. The Palliative Prognostic Index (PPI), a prognostic tool calculated using clinical indices alone has been validated within cancer population. This study was to further test the discriminatory ability of the PPI (ie, its ability to determine whether a subject will live more or less than a certain amount of time) in a larger sample but with a palliative care context and to compare predictions at two different points in time. METHODS: Multicentre, prospective, observational study in 10 inpatient hospices in the UK. The PPI score was calculated on the day of admission (PPI1) and again once on days 3-5 of inpatient stay (PPI2). Patients were followed up for 6 weeks or until death, whichever was earlier. RESULTS: Of the 1164 patients included in the study, 962 had both scores available. The results from PPI2 showed improved sensitivity, specificity, positive predictive value and negative predictive value compared with PPI1. For PPI1versus PPI2, area under receiver operator character curve (ROC) for <21 days were 0.73 versus 0.82 and for >=42 days prediction 0.72 versus 0.80. The median survival days for patients with PPI1 <=4, 4.5-6 and >6 were 38 (31 to 44), 17 (14 to 19) and 5 (4 to 7). CONCLUSION: This study showed improved discriminatory ability using the PPI score calculated between day 3and day5 of admission compared with that calculated on admission. This study further validated PPI as a prognostic tool within a palliative care population and showed recording at two time points improved accuracy. PMID- 29507042 TI - Is the concept of clinical equipoise still relevant to research? PMID- 29507043 TI - Lactobacillus acidophilus NS1 attenuates diet-induced obesity and fatty liver. AB - Obesity is a major threat to public health, and it is strongly associated with insulin resistance and fatty liver disease. Here, we demonstrated that administration of Lactobacillus acidophilus NS1 (LNS1) significantly reduced obesity and hepatic lipid accumulation, with a concomitant improvement in insulin sensitivity, in high-fat diet (HFD)-fed mice. Furthermore, administration of LNS1 inhibited the effect of HFD feeding on the SREBP-1c and PPARalpha signaling pathways and reduced lipogenesis with an increase in fatty acid oxidation in ex vivo livers from HFD-fed mice. These LNS1 effects were confirmed in HepG2 cells and ex vivo livers by treatment with LNS1 culture supernatant (LNS1-CS). Interestingly, AMPK phosphorylation and activity in the liver of HFD-fed mice were increased by administration of LNS1. Consistently, chemical inhibition of AMPK with compound C, a specific inhibitor of AMPK, dramatically reduced the effect of LNS1-CS on lipid metabolism in HepG2 cells and ex vivo livers by modulating the SREBP-1c and PPARalpha signaling pathways. Furthermore, administration of LNS1 to HFD-fed mice significantly improved insulin resistance and increased Akt phosphorylation in the liver, white adipose tissue and skeletal muscle. Together, these data suggest that LNS1 may prevent diet-induced obesity and related metabolic disorders by improving lipid metabolism and insulin sensitivity through an AMPK->SREBP-1c/PPARalpha signaling pathway. PMID- 29507045 TI - New consultant contract needs more flexibility for young doctors, senior leader says. PMID- 29507044 TI - Fructose bisphosphatase 2 overexpression increases glucose uptake in skeletal muscle. AB - Skeletal muscle is a major tissue for glucose metabolism and can store glucose as glycogen, convert glucose to lactate via glycolysis and fully oxidise glucose to CO2 Muscle has a limited capacity for gluconeogenesis but can convert lactate and alanine to glycogen. Gluconeogenesis requires FBP2, a muscle-specific form of fructose bisphosphatase that converts fructose-1,6-bisphosphate (F-1,6-bisP) to fructose-6-phosphate (F-6-P) opposing the activity of the ATP-consuming enzyme phosphofructokinase (PFK). In mammalian muscle, the activity of PFK is normally 100 times higher than FBP2 and therefore energy wasting cycling between PFK and FBP2 is low. In an attempt to increase substrate cycling between F-6-P and F-1,6 bisP and alter glucose metabolism, we overexpressed FBP2 using a muscle-specific adeno-associated virus (AAV-tMCK-FBP2). AAV was injected into the right tibialis muscle of rats, while the control contralateral left tibialis received a saline injection. Rats were fed a chow or 45% fat diet (HFD) for 5 weeks after which, hyperinsulinaemic-euglycaemic clamps were performed. Infection of the right tibialis with AAV-tMCK-FBP2 increased FBP2 activity 10 fold on average in chow and HFD rats (P < 0.0001). Overexpression of FBP2 significantly increased insulin stimulated glucose uptake in tibialis of chow animals (control 14.3 +/- 1.7; FBP2 17.6 +/- 1.6 umol/min/100 g) and HFD animals (control 9.6 +/- 1.1; FBP2 11.2 +/- 1.1umol/min/100 g). The results suggest that increasing the capacity for cycling between F-1,6-bisP and F-6-P can increase the metabolism of glucose by introducing a futile cycle in muscle, but this increase is not sufficient to overcome muscle insulin resistance. PMID- 29507046 TI - Targeting Zero Infections in Dialysis: New Devices, Yes, but also Guidelines, Checklists, and a Culture of Safety. PMID- 29507047 TI - Immune landscape of papillary thyroid cancer and immunotherapeutic implications. AB - Although papillary thyroid cancer (PTC) is curable with excellent survival rate, patients with dedifferentiated PTC suffer the recurrence or death. As cancer immune escape plays a critical role in cancer progression, we aimed to investigate the relationship between differentiation and immune landscape of PTC and its implications for immunotherapy. Using The Cancer Genome Atlas data, we estimated the immune cell enrichment scores and overall immune infiltration, ImmuneScore, to characterize the immune landscape of PTC. Thyroid differentiation score (TDS) was calculated from 16 thyroid function genes. We demonstrated that ImmuneScore had a significant negative correlation with TDS, and BRAFV600E+ tumors showed significantly low TDS and high ImmuneScore. Enrichment scores of myeloid cells and B-cells were negatively correlated with TDS, while those of plasma cells were positively correlated with TDS. In addition, the association between TDS, ImmuneScore and immunosuppressive markers (CTLA-4, PD-L1, HLA-G) were evaluated according to BRAFV600E status. All immunosuppressive markers expression had a significant negative correlation with TDS, and they were significantly higher in BRAFV600E+ status. Subgroups were divided by median values of TDS and ImmuneScore, and immunosuppressive markers of these subgroups were compared. The immunosuppressive markers expression was the highest in high ImmuneScore and low TDS subgroup. Furthermore, ImmuneScore had a significant association with recurrence-free survival, irrespective of clinicopathologic factors including BRAFV600E status. These findings based on gene expression data illuminate the immune landscape of PTC and its association with TDS, immunosuppressive markers and recurrence. Our results would be extended to investigate immunotherapeutic approaches in PTC. PMID- 29507049 TI - Collapse in the scrum. AB - CLINICAL INTRODUCTION: A 17-year-old male patient was brought by ambulance to the ED following a witnessed collapse while playing rugby. He denied any significant trauma, chest pain or breathlessness, and was alert and uncomplaining on arrival, with normal observations and a normal physical exam. Witnesses described a loss of consciousness, with a period of respiratory arrest requiring rescue breaths at the scene. Paramedics reported frequent ventricular extrasystoles on their arrival.The patient had no medical history and was on no medication, although admitted to 'fainting' some 3 weeks previously, again while playing rugby. A paternal uncle had died suddenly at the age of 45.His initial ECG is shown in figure 1.emermed;35/12/764/F1F1F1Figure 1Initial ECG. QUESTION: What is the most likely diagnosis?Pulmonary embolism (PE)Hypertrophic obstructive cardiomyopathy (HOCM)Arrhythmogenic right ventricular cardiomyopathy (ARVC)Right ventricular outflow tract tachycardia (RVOT). PMID- 29507048 TI - A Bayesian Framework for Generalized Linear Mixed Modeling Identifies New Candidate Loci for Late-Onset Alzheimer's Disease. AB - Recent technical and methodological advances have greatly enhanced genome-wide association studies (GWAS). The advent of low-cost, whole-genome sequencing facilitates high-resolution variant identification, and the development of linear mixed models (LMM) allows improved identification of putatively causal variants. While essential for correcting false positive associations due to sample relatedness and population stratification, LMMs have commonly been restricted to quantitative variables. However, phenotypic traits in association studies are often categorical, coded as binary case-control or ordered variables describing disease stages. To address these issues, we have devised a method for genomic association studies that implements a generalized LMM (GLMM) in a Bayesian framework, called Bayes-GLMM Bayes-GLMM has four major features: (1) support of categorical, binary, and quantitative variables; (2) cohesive integration of previous GWAS results for related traits; (3) correction for sample relatedness by mixed modeling; and (4) model estimation by both Markov chain Monte Carlo sampling and maximal likelihood estimation. We applied Bayes-GLMM to the whole genome sequencing cohort of the Alzheimer's Disease Sequencing Project. This study contains 570 individuals from 111 families, each with Alzheimer's disease diagnosed at one of four confidence levels. Using Bayes-GLMM we identified four variants in three loci significantly associated with Alzheimer's disease. Two variants, rs140233081 and rs149372995, lie between PRKAR1B and PDGFA The coded proteins are localized to the glial-vascular unit, and PDGFA transcript levels are associated with Alzheimer's disease-related neuropathology. In summary, this work provides implementation of a flexible, generalized mixed-model approach in a Bayesian framework for association studies. PMID- 29507051 TI - Chronic low back pain: a successful intervention for desk-bound workers. PMID- 29507050 TI - Proteomics of Aspergillus fumigatus Conidia-containing Phagolysosomes Identifies Processes Governing Immune Evasion. AB - Invasive infections by the human pathogenic fungus Aspergillus fumigatus start with the outgrowth of asexual, airborne spores (conidia) into the lung tissue of immunocompromised patients. The resident alveolar macrophages phagocytose conidia, which end up in phagolysosomes. However, A. fumigatus conidia resist phagocytic degradation to a certain degree. This is mainly attributable to the pigment 1,8-dihydroxynaphthalene (DHN) melanin located in the cell wall of conidia, which manipulates the phagolysosomal maturation and prevents their intracellular killing. To get insight in the underlying molecular mechanisms, we comparatively analyzed proteins of mouse macrophage phagolysosomes containing melanized wild-type (wt) or nonmelanized pksP mutant conidia. For this purpose, a protocol to isolate conidia-containing phagolysosomes was established and a reference protein map of phagolysosomes was generated. We identified 637 host and 22 A. fumigatus proteins that were differentially abundant in the phagolysosome. 472 of the host proteins were overrepresented in the pksP mutant and 165 in the wt conidia-containing phagolysosome. Eight of the fungal proteins were produced only in pksP mutant and 14 proteins in wt conidia-containing phagolysosomes. Bioinformatical analysis compiled a regulatory module, which indicates host processes affected by the fungus. These processes include vATPase-driven phagolysosomal acidification, Rab5 and Vamp8-dependent endocytic trafficking, signaling pathways, as well as recruitment of the Lamp1 phagolysosomal maturation marker and the lysosomal cysteine protease cathepsin Z. Western blotting and immunofluorescence analyses confirmed the proteome data and moreover showed differential abundance of the major metabolic regulator mTOR. Taken together, with the help of a protocol optimized to isolate A. fumigatus conidia-containing phagolysosomes and a potent bioinformatics algorithm, we were able to confirm A. fumigatus conidia-dependent modification of phagolysosomal processes that have been described before and beyond that, identify pathways that have not been implicated in A. fumigatus evasion strategy, yet.Mass spectrometry proteomics data are available via ProteomeXchange with identifiers PXD005724 and PXD006134. PMID- 29507052 TI - Artificial gametes, the unnatural and the artefactual. AB - In debates on the ethics of artificial gametes, concepts of naturalness have been used in a number of different ways. Some have argued that the unnaturalness of artificial gametes means that it is unacceptable to use them in fertility treatments. Others have suggested that artificial gametes are no less natural than many other tissues or processes in common medical use. We suggest that establishing the naturalness or unnaturalness of artificial gametes is unlikely to provide easy answers as to the acceptability of using them in fertility medicine. However, we also suggest that we should be cautious about repudiating any relationship between nature and moral evaluation. The property of being natural or man-made may not per se tell us anything about an entity's moral status, but it has an important impact on the moral relationship between the creator and the created organism. PMID- 29507053 TI - Genomics of cellular proliferation in periodic environmental fluctuations. AB - Living systems control cell growth dynamically by processing information from their environment. Although responses to a single environmental change have been intensively studied, little is known about how cells react to fluctuating conditions. Here, we address this question at the genomic scale by measuring the relative proliferation rate (fitness) of 3,568 yeast gene deletion mutants in out of-equilibrium conditions: periodic oscillations between two environmental conditions. In periodic salt stress, fitness and its genetic variance largely depended on the oscillating period. Surprisingly, dozens of mutants displayed pronounced hyperproliferation under short stress periods, revealing unexpected controllers of growth under fast dynamics. We validated the implication of the high-affinity cAMP phosphodiesterase and of a regulator of protein translocation to mitochondria in this group. Periodic oscillations of extracellular methionine, a factor unrelated to salinity, also altered fitness but to a lesser extent and for different genes. The results illustrate how natural selection acts on mutations in a dynamic environment, highlighting unsuspected genetic vulnerabilities to periodic stress in molecular processes that are conserved across all eukaryotes. PMID- 29507055 TI - Antitumor Activity of DLX1008, an Anti-VEGFA Antibody Fragment with Low Picomolar Affinity, in Human Glioma Models. AB - Angiogenesis mediated by vascular endothelial growth factor (VEGF) is a hallmark of glioblastoma. Based on the response rate and improved progression-free survival, although not on overall survival, the 149-kDa anti-VEGF-A IgG antibody bevacizumab (Avastin) has been approved in the United States and Japan for recurrent glioblastoma and in Japan for newly diagnosed glioblastoma; however, it is not approved in the EU. Here we characterize the biologic activity of DLX1008, a 26-kDa anti-VEGF-A single-chain antibody fragment that shows 30-fold stronger affinity to human VEGF-A than bevacizumab. The small molecular size of DLX1008 is predicted to result in improved target coverage over bevacizumab. DLX1008 showed superiority to bevacizumab in the inhibition of VEGF-A binding to VEGF receptor (VEGFR) 1 in enzyme-linked immunosorbent assay by a factor of around 10 and comparable efficacy for the inhibition of VEGF-A-stimulated VEGFR2 dimerization. In a tube-formation assay with human cerebral microvascular endothelial cells, DLX1008 was at least as active as bevacizumab. In vivo, DLX1008 delayed growth in a mouse subcutaneous U87 xenograft model (P = 0.0021) and improved survival in a mouse orthotopic U87 xenograft model (P = 0.00026). Given the exceptionally high affinity and small molecular size of DLX1008, these data warrant further clinical development of DLX1008 as an antiangiogenic agent in glioblastoma. PMID- 29507054 TI - Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors. AB - Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression. PMID- 29507056 TI - TAK1ng control: TAK1 restrains NLRP3 activation. AB - In this issue of JEM, Malireddi et al. (https://doi.org/10.1084/jem.20171922) demonstrate that macrophage-specific loss of TAK1 causes spontaneous NLRP3 inflammasome activation, driven by unregulated TNF secretion and signaling. This has implications for therapeutically targeting TAK1, enhancing its potential function as an anticancer drug treatment. PMID- 29507057 TI - The Molecular Chaperone HSP90 Promotes Notch Signaling in the Germline of Caenorhabditis elegans. AB - In a genetic screen to identify genes that promote GLP-1/Notch signaling in Caenorhabditis elegans germline stem cells, we found a single mutation, om40, defining a gene called ego-3. ego-3(om40) causes several defects in the soma and the germline, including paralysis during larval development, sterility, delayed proliferation of germline stem cells, and ectopic germline stem cell proliferation. Whole genome sequencing identified om40 as an allele of hsp-90, previously known as daf-21, which encodes the C. elegans ortholog of the cytosolic form of HSP90. This protein is a molecular chaperone with a central position in the protein homeostasis network, which is responsible for proper folding, structural maintenance, and degradation of proteins. In addition to its essential role in cellular function, HSP90 plays an important role in stem cell maintenance and renewal. Complementation analysis using a deletion allele of hsp 90 confirmed that ego-3 is the same gene. hsp-90(om40) is an I->N conservative missense mutation of a highly conserved residue in the middle domain of HSP-90 RNA interference-mediated knockdown of hsp-90 expression partially phenocopied hsp-90(om40), confirming the loss-of-function nature of hsp-90(om40) Furthermore, reduced HSP-90 activity enhanced the effect of reduced function of both the GLP-1 receptor and the downstream LAG-1 transcription factor. Taken together, our results provide the first experimental evidence of an essential role for HSP90 in Notch signaling in development. PMID- 29507058 TI - Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. AB - Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut-epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R2 = 0.5301, P<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R2 = 0.4608, P<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN. PMID- 29507059 TI - Thermokinetic profile of NDM-1 and its inhibition by small carboxylic acids. AB - The New Delhi metallo-beta-lactamase (NDM-1) is an important clinical target for antimicrobial research, but there are insufficient clinically useful inhibitors and the details of NDM-1 enzyme catalysis remain unclear. The aim of this work is to provide a thermodynamic profile of NDM-1 catalysed hydrolysis of beta-lactams using an isothermal titration calorimetry (ITC) approach and to apply this new method to the identification of new low-molecular-weight dicarboxylic acid inhibitors. The results reveal that hydrolysis of penicillin G and imipenem by NDM-1 share the same thermodynamic features with a significant intrinsic enthalpy change and the release of one proton into solution, while NDM-1 hydrolysis of cefazolin exhibits a different mechanism with a smaller enthalpy change and the release of two protons. The inhibitory constants of four carboxylic acids are found to be in the micromolar range. The compounds pyridine-2,6-dicarboxylic acid and thiazolidine-2,4-dicarboxylic acid show the best inhibitory potency and are confirmed to inhibit NDM-1 using a clinical strain of Escherichia coli The pyridine compound is further shown to restore the susceptibility of this E. coli strain to imipenem, at an inhibitor concentration of 400 MUM, while the thiazoline compound also shows a synergistic effect with imipenem. These results provide valuable information to enrich current understanding on the catalytic mechanism of NDM-1 and to aid the future optimisation of beta-lactamase inhibitors based on these scaffolds to tackle the problem of antibiotic resistance. PMID- 29507060 TI - The PLUTO plastidial nucleobase transporter also transports the thiamin precursor hydroxymethylpyrimidine. AB - In plants, the hydroxymethylpyrimidine (HMP) and thiazole precursors of thiamin are synthesized and coupled together to form thiamin in plastids. Mutants unable to form HMP can be rescued by exogenous HMP, implying the presence of HMP transporters in the plasma membrane and plastids. Analysis of bacterial genomes revealed a transporter gene that is chromosomally clustered with thiamin biosynthesis and salvage genes. Its closest Arabidopsis homolog, the plastidic nucleobase transporter (PLUTO), is co-expressed with several thiamin biosynthetic enzymes. Heterologous expression of PLUTO in Escherichia coli or Saccharomyces cerevisiae increased sensitivity to a toxic HMP analog, and disrupting PLUTO in an HMP-requiring Arabidopsis line reduced root growth at low HMP concentrations. These data implicate PLUTO in plastidial transport and salvage of HMP. PMID- 29507061 TI - Metabolism, Excretion, and Mass Balance of Solithromycin in Humans. AB - Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of solithromycin were studied in healthy male subjects after oral administration of a single 800-mg (~100-MUCi) dose of [14C]solithromycin. Solithromycin was well tolerated, and absorption from the solution occurred with a median time to peak concentration of 4.0 h. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole-blood total radioactivity was approximately 75% of the plasma total radioactivity. Recovery was essentially complete (mean, 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity area under the concentration-time curve [AUC]), with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl-CEM 101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly like that of the parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of the administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism, with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed. PMID- 29507062 TI - Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered? AB - Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fTMIC) and 0.125 mg/liter (100% fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.). PMID- 29507063 TI - Spread of Plasmid-Encoded NDM-1 and GES-5 Carbapenemases among Extensively Drug Resistant and Pandrug-Resistant Clinical Enterobacteriaceae in Durban, South Africa. AB - Whole-genome sequence analyses revealed the presence of blaNDM-1 (n = 31), blaGES 5 (n = 8), blaOXA-232 (n = 1), or blaNDM-5 (n = 1) in extensively drug-resistant and pandrug-resistant Enterobacteriaceae organisms isolated from in-patients in 10 private hospitals (2012 to 2013) in Durban, South Africa. Two novel NDM-1 encoding plasmids from Klebsiella pneumoniae were circularized by PacBio sequencing. In p19-10_01 [IncFIB(K); 223.434 bp], blaNDM-1 was part of a Tn1548 like structure (16.276 bp) delineated by IS26 The multireplicon plasmid p18-43_01 [IncR_1/IncFIB(pB171)/IncFII(Yp); 212.326 bp] shared an 80-kb region with p19 10_01, not including the blaNDM-1-containing region. The two plasmids were used as references for tracing NDM-1-encoding plasmids in the other genome assemblies. The p19-10_01 sequence was detected in K. pneumoniae (n = 7) only, whereas p18 43_01 was tracked to K. pneumoniae (n = 4), Klebsiella michiganensis (n = 1), Serratia marcescens (n = 11), Enterobacter spp. (n = 7), and Citrobacter freundii (n = 1), revealing horizontal spread of this blaNDM-1-bearing plasmid structure. Global phylogeny showed clustering of the K. pneumoniae (18/20) isolates together with closely related carbapenemase-negative ST101 isolates from other geographical origins. The South African isolates were divided into three phylogenetic subbranches, where each group had distinct resistance and replicon profiles, carrying either p19-10_01, p18-10_01, or pCHE-A1 (8,201 bp). The latter plasmid carried blaGES-5 and aacA4 within an integron mobilization unit. Our findings imply independent plasmid acquisition followed by local dissemination. Additionally, we detected blaOXA-232 carried by pPKPN4 in K. pneumoniae (ST14) and blaNDM-5 contained by a pNDM-MGR194-like genetic structure in Escherichia coli (ST167), adding even more complexity to the multilayer molecular mechanisms behind nosocomial spread of carbapenem-resistant Enterobacteriaceae in Durban, South Africa. PMID- 29507064 TI - Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime Avibactam Treatment Failures and Resistance among Patients with Carbapenem Resistant Enterobacteriaceae Infections. AB - Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; these rates were higher than those predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved for 55% of patients but differed by the site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia (P = 0.045) and receipt of renal replacement therapy (RRT) (P = 0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients and occurred more commonly among patients infected with KPC-3-producing CRE than among those infected with KPC-2-producing CRE (P = 0.002). Pneumonia was an independent predictor of microbiologic failure (P = 0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% of those infected with Klebsiella pneumoniae and 32% of those with microbiologic failure. RRT was an independent predictor of the development of resistance (P = 0.009). Resistance was identified exclusively among K. pneumoniae bacteria harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole-genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type 258 (ST258) clade II sublineage; resistant isolates from one patient clustered independently from other ST258 clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve on the poor outcomes among patients with pneumonia and those receiving RRT. PMID- 29507065 TI - P174E Substitution in GES-1 and GES-5 beta-Lactamases Improves Catalytic Efficiency toward Carbapenems. AB - GES-type beta-lactamases are a group of enzymes that have evolved their hydrolytic activity against carbapenems. In this study, the role of residue 174 inside the Omega-loop of GES-1 and GES-5 was investigated. GES-1P174E and GES 5P174E mutants, selected by site saturation mutagenesis, were purified and kinetically characterized. In comparison with GES-1 and GES-5 wild-type enzymes, GES-1P174E and GES-5P174E mutants exhibited lower kcat and kcat/Km values for cephalosporins and penicillins. Concerning carbapenems, GES-1P174E shared higher kcat values but lower Km values than those calculated for GES-1. The GES-1P174E and GES-5P174E mutants showed high hydrolytic efficiency for imipenem, with kcat/Km values 100- and 660-fold higher, respectively, than those of GES-1. Clavulanic acid and tazobactam are good inhibitors for both GES-1P174E and GES 5P174E Molecular dynamic (MD) simulations carried out for GES-1, GES-5, GES 1P174E, and GES-5P174E complexed with imipenem and meropenem have shown that mutation at position 174 induces a drastic increase of enzyme flexibility, in particular in the Omega-loop. The circular dichroism (CD) spectroscopy spectra of the four enzymes indicate that the P174E substitution in GES-1 and GES-5 does not affect the secondary structural content of the enzymes. PMID- 29507066 TI - Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids. AB - The incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active against Cryptococcus neoformansin vitro and had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents. PMID- 29507067 TI - Elevated MIC Values of Imidazole Drugs against Aspergillus fumigatus Isolates with TR34/L98H/S297T/F495I Mutation. AB - The use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in Aspergillus fumigatus Though widely used in agriculture, imidazole fungicides have not been linked to resistance in A. fumigatus This study showed that elevated MIC values of imidazole drugs were observed against A. fumigatus isolates with TR34/L98H/S297T/F495I mutation, but not among isolates with TR34/L98H mutation. Short-tandem-repeat (STR) typing analysis of 580 A. fumigatus isolates from 20 countries suggested that the majority of TR34/L98H/S297T/F495I strains from China were genetically different from the predominant major clade comprising most of the azole-resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14alpha-demethylase sequences suggested that F495I in A. fumigatus was orthologous to F506I in Penicillium digitatum and F489L in Pyrenophora teres, which have been reported to be associated with imidazole resistance. In vitro antifungal susceptibility testing of different recombinants with cyp51A mutations further confirmed the association of the F495I mutation with imidazole resistance. In conclusion, this study suggested that environmental use of imidazole fungicides might confer selection pressure for the emergence of azole resistance in A. fumigatus. PMID- 29507068 TI - Exploring the Pharmacokinetic/Pharmacodynamic Relationship of Relebactam (MK 7655) in Combination with Imipenem in a Hollow-Fiber Infection Model. AB - Resistance to antibiotics among bacterial pathogens is rapidly spreading, and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel beta-lactamase inhibitor relebactam (REL; MK-7655) in a hollow-fiber infection model. REL is intended for use with the carbapenem beta-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow-fiber infection model to confirm the efficacy of human exposures associated with the phase 2 doses (imipenem at 500 mg plus REL at 125 or 250 mg administered intravenously every 6 h as a 30-min infusion) against imipenem resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae Dose fractionation experiments confirmed that the pharmacokinetic parameter that best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between beta lactam antibiotics and beta-lactamase inhibitors is complex, as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the MIC of imipenem as dynamic: it changes with time, and this change is directly related to REL levels. For the strains tested, the percentage of the dosing interval time that the concentration remains above the dynamic MIC for imipenem was maintained at the carbapenem target of 30 to 40%, required for maximum efficacy, for imipenem at 500 mg plus REL at 250 mg. PMID- 29507069 TI - Native Human Monoclonal Antibodies with Potent Cross-Lineage Neutralization of Influenza B Viruses. AB - Although antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single-cell screening technology to identify rare monoclonal antibodies (MAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 MAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 MAbs, 3 exhibited low expression in a transient-transfection system, 4 were neutralizers that bound to the HA head region, 11 were stalk-binding nonneutralizers, and 5 were stalk-binding neutralizers, with 4 of these 5 having unique antibody sequences. Of these four unique stalk-binding neutralizing MAbs, all were broadly reactive and neutralizing against a panel of multiple strains spanning both IBV lineages as well as highly effective in treating lethal IBV infections in mice at both 24 and 72 h postinfection. The MAbs in this group were thermostable and bound different epitopes in the highly conserved HA stalk region. These characteristics suggest that these MAbs are suitable for consideration as candidates for clinical studies to address their effectiveness in the treatment of IBV-infected patients. PMID- 29507070 TI - Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection. AB - Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. A target area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 50 MUg . h/ml is recommended. The standard dose has resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization for this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach. The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC0-24 to ensure its efficacy. A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC0 24 after being given the standard dose. For all the subtherapeutic patients (achieving <80% of the target AUC) (n = 5), a model-based dosage adjustment was performed using the Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased by 28.6% to 60.0% in these five patients, and all adapted AUC0-24 values achieved the target (range, 48.6 to 66.1 MUg . h/ml). The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. The population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinically feasible method to adapt the ganciclovir dose in neonatal clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT03113344.). PMID- 29507071 TI - Heavy Metal Resistance Genes Are Associated with blaNDM-1- and blaCTX-M-15 Carrying Enterobacteriaceae. AB - The occurrence of heavy metal resistance genes in multiresistant Enterobacteriaceae possessing blaNDM-1 or blaCTX-M-15 genes was examined by PCR and pulsed-field gel electrophoresis with S1 nuclease. Compared with clinical susceptible isolates (10.0% to 30.0%), the pcoA, merA, silC, and arsA genes occurred with higher frequencies in blaNDM-1-positive (48.8% to 71.8%) and blaCTX M-15-positive (19.4% to 52.8%) isolates, and they were mostly located on plasmids. Given the high association of metal resistance genes with multidrug resistant Enterobacteriaceae, increased vigilance needs to be taken with the use of heavy metals in hospitals and the environment. PMID- 29507072 TI - Effect of Antimicrobial Agents on Inflammatory Cytokines in Acute Leptospirosis. AB - The aim of this study was to assess the inflammatory cytokine response and possible association with antimicrobial treatment with penicillin, ceftriaxone, and doxycycline in acute leptospirosis. In the early acute stage, interleukin-10 (IL-10) levels were higher in mild cases than in severe cases (P = 0.01). IL-6 and IL-8 levels were low in patients who received >5 antimicrobial doses (P < 0.01). IL-8 levels were negatively correlated with the number of ceftriaxone doses administered (r = -0.315; P = 0.031). Further studies are needed to evaluate the possible downregulation of proinflammatory cytokines by ceftriaxone in leptospirosis. PMID- 29507074 TI - Francica JR, Zak DE, Linde C, et al. Innate transcriptional effects by adjuvants on the magnitude, quality, and durability of HIV envelope responses in NHPs. Blood Adv. 2017;1(25):2329-2342. PMID- 29507073 TI - Topical Treatment for Cutaneous Leishmaniasis: Dermato-Pharmacokinetic Lead Optimization of Benzoxaboroles. AB - Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 MUM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 MUM < EC50 < 30 MUM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the in vitro evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that of para-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against Leishmania major was tested in vivo LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration. PMID- 29507075 TI - A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells. AB - Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRalphabeta, we combined an antibody-derived single-chain variable fragment specific for CD3epsilon with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3epsilon, blocking surface CD3 and TCRalphabeta expression. In 25 experiments, median TCRalphabeta expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRalphabeta cell depletion yielded virtually pure TCRalphabeta-negative T cells. Anti CD3epsilon PEBLs abrogated TCRalphabeta-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3epsilon PEBL-T cells, expression of an anti-CD19-41BB-CD3zeta CAR induced cytokine secretion, long-term proliferation, and CD19+ leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRalphabeta expression. In immunodeficient mice, anti-CD3epsilon PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRalphabeta expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies. PMID- 29507076 TI - Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia. AB - Recurrent chromosomal rearrangements carry prognostic significance in pediatric B lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (ETV6-ABL1: n = 1; FOXP1-ABL1: n = 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1-altered patients, irrespective of the presence of a kinase-activating fusion. PMID- 29507077 TI - Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. AB - This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30+ peripheral T cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5 year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789. PMID- 29507078 TI - Coagulopathy induced by traumatic brain injury: systemic manifestation of a localized injury. AB - Traumatic brain injury (TBI)-induced coagulopathy is a common and well-recognized risk for poor clinical outcomes, but its pathogenesis remains poorly understood, and treatment options are limited and ineffective. We discuss the recent progress and knowledge gaps in understanding this lethal complication of TBI. We focus on (1) the disruption of the brain-blood barrier to disseminate brain injury systemically by releasing brain-derived molecules into the circulation and (2) TBI-induced hypercoagulable and hyperfibrinolytic states that result in persistent and delayed intracranial hemorrhage and systemic bleeding. PMID- 29507079 TI - Zc3h10 is a novel mitochondrial regulator. AB - Mitochondria are the energy-generating hubs of the cell. In spite of considerable advances, our understanding of the factors that regulate the molecular circuits that govern mitochondrial function remains incomplete. Using a genome-wide functional screen, we identify the poorly characterized protein Zinc finger CCCH type containing 10 (Zc3h10) as regulator of mitochondrial physiology. We show that Zc3h10 is upregulated during physiological mitochondriogenesis as it occurs during the differentiation of myoblasts into myotubes. Zc3h10 overexpression boosts mitochondrial function and promotes myoblast differentiation, while the depletion of Zc3h10 results in impaired myoblast differentiation, mitochondrial dysfunction, reduced expression of electron transport chain (ETC) subunits, and blunted TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with increased body mass index, fat mass, fasting glucose, and triglycerides. Isolated peripheral blood mononuclear cells from individuals homozygotic for Cys105 display reduced oxygen consumption rate, diminished expression of some ETC subunits, and decreased levels of some TCA cycle metabolites, which all together derive in mitochondrial dysfunction. Taken together, our study identifies Zc3h10 as a novel mitochondrial regulator. PMID- 29507082 TI - Trio sequencing in pediatric cancer and clinical implications. PMID- 29507080 TI - Two distinct conformational states define the interaction of human RAD51-ATP with single-stranded DNA. AB - An essential mechanism for repairing DNA double-strand breaks is homologous recombination (HR). One of its core catalysts is human RAD51 (hRAD51), which assembles as a helical nucleoprotein filament on single-stranded DNA, promoting DNA-strand exchange. Here, we study the interaction of hRAD51 with single stranded DNA using a single-molecule approach. We show that ATP-bound hRAD51 filaments can exist in two different states with different contour lengths and with a free-energy difference of ~4 kBT per hRAD51 monomer. Upon ATP hydrolysis, the filaments convert into a disassembly-competent ADP-bound configuration. In agreement with the single-molecule analysis, we demonstrate the presence of two distinct protomer interfaces in the crystal structure of a hRAD51-ATP filament, providing a structural basis for the two conformational states of the filament. Together, our findings provide evidence that hRAD51-ATP filaments can exist in two interconvertible conformational states, which might be functionally relevant for DNA homology recognition and strand exchange. PMID- 29507081 TI - OST1-mediated BTF3L phosphorylation positively regulates CBFs during plant cold responses. AB - Cold stress is a major environmental factor that negatively affects plant growth and survival. OST1 has been identified as a key protein kinase in plant response to cold stress; however, little is known about the underlying molecular mechanism. In this study, we identified BTF3 and BTF3L (BTF3-like), beta-subunits of a nascent polypeptide-associated complex (NAC), as OST1 substrates that positively regulate freezing tolerance. OST1 phosphorylates BTF3 and BTF3L in vitro and in vivo, and facilitates their interaction with C-repeat-binding factors (CBFs) to promote CBF stability under cold stress. The phosphorylation of BTF3L at the Ser50 residue by OST1 is required for its function in regulating freezing tolerance. In addition, BTF3 and BTF3L proteins positively regulate the expression of CBF genes. These findings unravel a molecular mechanism by which OST1-BTF3-CBF module regulates plant response to cold stress. PMID- 29507083 TI - Chemotaxis allows bacteria to overcome host-generated reactive oxygen species that constrain gland colonization. AB - The epithelial layer of the gastrointestinal tract contains invaginations, called glands or crypts, which are colonized by symbiotic and pathogenic microorganisms and may function as designated niches for certain species. Factors that control gland colonization are poorly understood, but bacterial chemotaxis aids occupation of these sites. We report here that a Helicobacter pylori cytoplasmic chemoreceptor, TlpD, is required for gland colonization in the stomach. tlpD mutants demonstrate gland colonization defects characterized by a reduction in the percent of glands colonized, but not in number of bacteria per gland. Consistent with TlpD's reported role in reactive oxygen species (ROS) avoidance, tlpD mutants showed hallmarks of exposure to high ROS. To assess the role of host generated ROS in TlpD-dependent gland colonization, we utilized mice that lack either the ability to generate epithelial hydrogen peroxide or immune cell superoxide. tlpD gland colonization defects were rescued to wild-type H. pylori levels in both of these mutants. These results suggest that multiple types of innate immune generated ROS production limit gland colonization and that bacteria have evolved specific mechanisms to migrate through this gauntlet to establish in the glands. PMID- 29507084 TI - Interleukin-18 Is Critical for Mucosa-Associated Invariant T Cell Gamma Interferon Responses to Francisella Species In Vitro but Not In Vivo. AB - Mucosa-associated invariant T (MAIT) cells are a subset of innate T cells that express a semi-invariant Valpha chain paired with limited Vbeta chains. MAIT cells are activated by riboflavin metabolite derivatives presented by the nonpolymorphic major histocompatibility complex class I (MHC-I)-like molecule MR1. The precise mechanisms required to activate MAIT cells are an area of intense interest. Here we used two closely related intracellular pathogens with distinct inflammasome activation phenotypes to probe the role of innate cytokines in MAIT cell activation. Using an in vitro assay containing transgenic murine MAIT cells, we show that macrophages infected with Francisella novicida, a strong inflammasome activator, released high levels of interleukin-18 (IL-18) and stimulated high levels of MAIT cell gamma interferon (IFN-gamma) through a partially MR1-independent pathway. In contrast, macrophages infected with Francisella tularensis live vaccine strain (LVS), a weak inflammasome activator, generated little IL-18 and stimulated low MAIT cell IFN-gamma through an MR1 dependent pathway. By manipulating the quantities of IL-18 in these cultures, we show that the IL-18 concentration is sufficient to influence the magnitude of MAIT cell IFN-gamma production. Correspondingly, infected IL-18-deficient macrophages failed to induce substantial MAIT cell IFN-gamma. In contrast, we found that MAIT cell IFN-gamma production in the lungs of IL-18-deficient mice was not significantly different from that in WT mice during F. tularensis LVS pulmonary infection. Overall, we demonstrate that while IL-18 is essential for the MAIT cell IFN-gamma response in vitro, it is not essential for MAIT cell IFN gamma production during in vivo LVS pulmonary infection, suggesting that additional signals can drive MAIT cell IFN-gamma production in vivo. PMID- 29507085 TI - MyD88 Signaling in T Cells Is Critical for Effector CD4 T Cell Differentiation following a Transitional T Follicular Helper Cell Stage. AB - Activation of CD4 T cells by dendritic cells leads to their differentiation into various effector lineages. The nature of the effector lineage is determined by the innate cues provided by dendritic cells to newly primed T cells. Although the cytokines necessary for several effector lineages have been identified, the innate cues that drive T follicular helper (Tfh) lineage cell development remain unclear. Here we found that following priming, CD4 T cells undergoing clonal expansion acquire a transient Tfh-like phenotype before differentiating into other effector lineages. In addition, we found that T cell-intrinsic myeloid differentiation antigen 88 (MyD88) signaling, which occurs downstream of interleukin-1 (IL-1) and IL-18 receptors, is critical for the primed CD4 T cells to transition out of the temporary Tfh lineage. Mice with T cell-specific deletion of MyD88 have a higher proportion of Tfh cells and germinal center (GC) B cells. These exaggerated Tfh cell and GC B cell responses, however, do not lead to protective immunity against infections. We demonstrate that T cell-intrinsic MyD88 is critical for effector lineage differentiation as well as production of the cytokines that are necessary for class switching. Overall, our study establishes that following priming and clonal expansion, CD4 T cells undergo a transitional Tfh-like phase and that further differentiation into effector lineages is dictated by T cell-intrinsic MyD88-dependent cues. PMID- 29507086 TI - A Bacterial Microcompartment Is Used for Choline Fermentation by Escherichia coli 536. AB - Bacterial choline degradation in the human gut has been associated with cancer and heart disease. In addition, recent studies found that a bacterial microcompartment is involved in choline utilization by Proteus and Desulfovibrio species. However, many aspects of this process have not been fully defined. Here, we investigate choline degradation by the uropathogen Escherichia coli 536. Growth studies indicated E. coli 536 degrades choline primarily by fermentation. Electron microscopy indicated that a bacterial microcompartment was used for this process. Bioinformatic analyses suggested that the choline utilization (cut) gene cluster of E. coli 536 includes two operons, one containing three genes and a main operon of 13 genes. Regulatory studies indicate that the cutX gene encodes a positive transcriptional regulator required for induction of the main cut operon in response to choline supplementation. Each of the 16 genes in the cut cluster was individually deleted, and phenotypes were examined. The cutX, cutY, cutF, cutO, cutC, cutD, cutU, and cutV genes were required for choline degradation, but the remaining genes of the cut cluster were not essential under the conditions used. The reasons for these varied phenotypes are discussed.IMPORTANCE Here, we investigate choline degradation in E. coli 536. These studies provide a basis for understanding a new type of bacterial microcompartment and may provide deeper insight into the link between choline degradation in the human gut and cancer and heart disease. These are also the first studies of choline degradation in E. coli 536, an organism for which sophisticated genetic analysis methods are available. In addition, the cut gene cluster of E. coli 536 is located in pathogenicity island II (PAI-II536) and hence might contribute to pathogenesis. PMID- 29507087 TI - Two rsaM Homologues Encode Central Regulatory Elements Modulating Quorum Sensing in Burkholderia thailandensis. AB - The bacterium Burkholderia thailandensis possesses three N-acyl-l-homoserine lactone (AHL) quorum sensing (QS) systems designated BtaI1/BtaR1 (QS-1), BtaI2/BtaR2 (QS-2), and BtaI3/BtaR3 (QS-3). These QS systems are associated with the biosynthesis of N-octanoyl-homoserine lactone (C8-HSL), N-3-hydroxy-decanoyl homoserine lactone (3OHC10-HSL), and N-3-hydroxy-octanoyl-homoserine lactone (3OHC8-HSL), which are produced by the LuxI-type synthases BtaI1, BtaI2, and BtaI3 and modulated by the LuxR-type transcriptional regulators BtaR1, BtaR2, and BtaR3. The btaR1-btaI1 and btaR2-btaI2 gene clusters each carry an additional gene encoding a homologue of the QS repressor RsaM originally identified in the phytopathogen Pseudomonas fuscovaginae and thus here named rsaM1 and rsaM2, respectively. We have characterized the functions of these two conserved rsaM homologues and demonstrated their involvement in the regulation of AHL biosynthesis in B. thailandensis strain E264. We quantified the production of C8 HSL, 3OHC10-HSL, and 3OHC8-HSL by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the wild-type strain and in the rsaM1 and rsaM2 mutants, and we monitored btaI1, btaI2, and btaI3 expression using chromosomal mini-CTX-lux transcriptional reporters. The transcription of btaR1, btaR2, and btaR3 was also measured by quantitative reverse transcription-PCR (qRT-PCR). We observed that RsaM1 mainly represses the QS-1 system, whereas RsaM2 principally represses the QS-2 system. We also found that both rsaM1 and rsaM2 are QS controlled and negatively autoregulated. We conclude that RsaM1 and RsaM2 are an integral part of the QS circuitry of B. thailandensis and play a major role in the hierarchical and homeostatic organization of the QS-1, QS-2, and QS-3 systems.IMPORTANCE Quorum sensing (QS) is commonly involved in the coordination of gene transcription associated with the establishment of host-pathogen interactions and acclimatization to the environment. We present the functional characterization of two rsaM homologues in the regulation of the multiple QS systems coexisting in the nonpathogenic bacterium Burkholderia thailandensis, which is widely used as a model system for the study of the human pathogen Burkholderia pseudomallei We found that inactivation of these rsaM homologues, which are clustered with the other QS genes, profoundly affects the QS circuitry of B. thailandensis We conclude that they constitute essential regulatory components of the QS modulatory network and provide additional layers of regulation to modulate the transcription of QS-controlled genes, particularly those linked to environmental adaptation. PMID- 29507088 TI - The Pseudomonas aeruginosa PrrF1 and PrrF2 Small Regulatory RNAs Promote 2-Alkyl 4-Quinolone Production through Redundant Regulation of the antR mRNA. AB - Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that requires iron for growth and virulence. Under low-iron conditions, P. aeruginosa transcribes two highly identical (95%) small regulatory RNAs (sRNAs), PrrF1 and PrrF2, which are required for virulence in acute murine lung infection models. The PrrF sRNAs promote the production of 2-akyl-4(1H)-quinolone metabolites (AQs) that mediate a range of biological activities, including quorum sensing and polymicrobial interactions. Here, we show that the PrrF1 and PrrF2 sRNAs promote AQ production by redundantly inhibiting translation of antR, which encodes a transcriptional activator of the anthranilate degradation genes. A combination of genetic and biophysical analyses was used to define the sequence requirements for PrrF regulation of antR, demonstrating that the PrrF sRNAs interact with the antR 5' untranslated region (UTR) at sequences overlapping the translational start site of this mRNA. The P. aeruginosa Hfq protein interacted with UA-rich sequences in both PrrF sRNAs (Kd [dissociation constant] = 50 nM and 70 nM). Hfq bound with lower affinity to the antR mRNA (0.3 MUM), and PrrF was able to bind to antR mRNA in the absence of Hfq. Nevertheless, Hfq increased the rate of PrrF annealing to the antR UTR by 10-fold. These studies provide a mechanistic description of how the PrrF1 and PrrF2 sRNAs mediate virulence traits, such as AQ production, in P. aeruginosaIMPORTANCE The iron-responsive PrrF sRNAs play a central role in regulating P. aeruginosa iron homeostasis and pathogenesis, yet the molecular mechanisms by which PrrF regulates gene expression are largely unknown. In this study, we used genetic and biophysical analyses to define the interactions of the PrrF sRNAs with Hfq, an RNA annealer, and the antR mRNA, which has downstream effects on quorum sensing and virulence factor production. These studies provide a comprehensive mechanistic analysis of how the PrrF sRNAs regulate virulence trait production through a key mRNA target in P. aeruginosa. PMID- 29507089 TI - Fatty Acid Oxidation Is Required for Myxococcus xanthus Development. AB - Myxococcus xanthus cells produce lipid bodies containing triacylglycerides during fruiting body development. Fatty acid beta-oxidation is the most energy-efficient pathway for lipid body catabolism. In this study, we used mutants in fadJ (MXAN_5371 and MXAN_6987) and fadI (MXAN_5372) homologs to examine whether beta oxidation serves an essential developmental function. These mutants contained more lipid bodies than the wild-type strain DK1622 and 2-fold more flavin adenine dinucleotide (FAD), consistent with the reduced consumption of fatty acids by beta-oxidation. The beta-oxidation pathway mutants exhibited differences in fruiting body morphogenesis and produced spores with thinner coats and a greater susceptibility to thermal stress and UV radiation. The MXAN_5372/5371 operon is upregulated in sporulating cells, and its expression could not be detected in csgA, fruA, or mrpC mutants. Lipid bodies were found to persist in mature spores of DK1622 and wild strain DK851, suggesting that the roles of lipid bodies and beta-oxidation may extend to spore germination.IMPORTANCE Lipid bodies act as a reserve of triacylglycerides for use when other sources of carbon and energy become scarce. beta-Oxidation is essential for the efficient metabolism of fatty acids associated with triacylglycerides. Indeed, the disruption of genes in this pathway has been associated with severe disorders in animals and plants. Myxococcus xanthus, a model organism for the study of development, is ideal for investigating the complex effects of altered lipid metabolism on cell physiology. Here, we show that beta-oxidation is used to consume fatty acids associated with lipid bodies and that the disruption of the beta-oxidation pathway is detrimental to multicellular morphogenesis and spore formation. PMID- 29507090 TI - Iron and Zinc Regulate Expression of a Putative ABC Metal Transporter in Corynebacterium diphtheriae. AB - Corynebacterium diphtheriae, a Gram-positive, aerobic bacterium, is the causative agent of diphtheria and cutaneous infections. While mechanisms required for heme iron acquisition are well known in C. diphtheriae, systems involved in the acquisition of other metals such as zinc and manganese remain poorly characterized. In this study, we identified a genetic region that encodes an ABC type transporter (iutBCD) and that is flanked by two genes (iutA and iutE) encoding putative substrate binding proteins of the cluster 9 family, a related group of transporters associated primarily with the import of Mn and Zn. We showed that IutA and IutE are both membrane proteins with comparable Mn and Zn binding abilities. We demonstrated that the iutABCD genes are cotranscribed and repressed in response to iron by the iron-responsive repressor DtxR. Transcription of iutE was positively regulated in response to iron availability in a DtxR-dependent manner and was repressed in response to Zn by the Zn dependent repressor Zur. Electrophoretic mobility shift assays showed that DtxR does not bind to the iutE upstream region, which indicates that DtxR regulation of iutE is indirect and that other regulatory factors controlled by DtxR are likely responsible for the iron-responsive regulation. Analysis of the iutE promoter region identified a 50-bp sequence at the 3' end of the iutD gene that is required for the DtxR-dependent and iron-responsive activation of the iutE gene. These findings indicate that transcription of iutE is controlled by a complex mechanism that involves multiple regulatory factors whose activity is impacted by both Zn and Fe.IMPORTANCE Vaccination against diphtheria prevents toxin-related symptoms but does not inhibit bacterial colonization of the human host by the bacterium. Thus, Corynebacterium diphtheriae remains an important human pathogen that poses a significant health risk to unvaccinated individuals. The ability to acquire iron, zinc, and manganese is critical to the pathogenesis of many disease-causing organisms. Here, we describe a gene cluster in C. diphtheriae that encodes a metal importer that is homologous to broadly distributed metal transport systems, some with important roles in virulence in other bacterial pathogens. Two metal binding components of the gene cluster encode surface exposed proteins, and studies of such proteins may guide the development of second-generation vaccines for C. diphtheriae. PMID- 29507091 TI - Identification of a Direct Biosynthetic Pathway for UDP-N-Acetylgalactosamine from Glucosamine-6-Phosphate in Thermophilic Crenarchaeon Sulfolobus tokodaii. AB - Most organisms, from Bacteria to Eukarya, synthesize UDP-N-acetylglucosamine (UDP GlcNAc) from fructose-6-phosphate via a four-step reaction, and UDP-N acetylgalactosamine (UDP-GalNAc) can only be synthesized from UDP-GlcNAc by UDP GlcNAc 4-epimerase. In Archaea, the bacterial-type UDP-GlcNAc biosynthetic pathway was reported for Methanococcales. However, the complete biosynthetic pathways for UDP-GlcNAc and UDP-GalNAc present in one archaeal species are unidentified. Previous experimental analyses on enzymatic activities of the ST0452 protein, identified from the thermophilic crenarchaeon Sulfolobus tokodaii, predicted the presence of both a bacterial-type UDP-GlcNAc and an independent UDP-GalNAc biosynthetic pathway in this archaeon. In the present work, functional analyses revealed that the recombinant ST2186 protein possessed an glutamine:fructose-6-phosphate amidotransferase activity and that the recombinant ST0242 protein possessed a phosphoglucosamine-mutase activity. Along with the acetyltransferase and uridyltransferase activities of the ST0452 protein, the activities of the ST2186 and ST0242 proteins confirmed the presence of a bacterial-type UDP-GlcNAc biosynthetic pathway in S. tokodaii In contrast, the UDP-GlcNAc 4-epimerase homologue gene was not detected within the genomic data. Thus, it was expected that galactosamine-1-phosphate or galactosamine-6 phosphate (GalN-6-P) was provided by conversion of glucosamine-1-phosphate or glucosamine-6-phosphate (GlcN-6-P). A novel epimerase converting GlcN-6-P to GalN 6-P was detected in a cell extract of S. tokodaii, and the N-terminal sequence of the purified protein indicated that the novel epimerase was encoded by the ST2245 gene. Along with the ST0242 phosphogalactosamine-mutase activity, this observation confirmed the presence of a novel UDP-GalNAc biosynthetic pathway from GlcN-6-P in S. tokodaii Discovery of the novel pathway provides a new insight into the evolution of nucleotide sugar metabolic pathways.IMPORTANCE In this work, a novel protein capable of directly converting glucosamine-6-phosphate to galactosamine-6-phosphate was successfully purified from a cell extract of the thermophilic crenarchaeon Sulfolobus tokodaii Confirmation of this novel activity using the recombinant protein indicates that S. tokodaii possesses a novel UDP GalNAc biosynthetic pathway derived from glucosamine-6-phosphate. The distributions of this and related genes indicate the presence of three different types of UDP-GalNAc biosynthetic pathways: a direct pathway using a novel enzyme and two conversion pathways from UDP-GlcNAc using known enzymes. Additionally, Crenarchaeota species lacking all three pathways were found, predicting the presence of one more unknown pathway. Identification of these novel proteins and pathways provides important insights into the evolution of nucleotide sugar biosynthesis, as well as being potentially important industrially. PMID- 29507092 TI - Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration. AB - Recently, a new class of HIV-1 integrase (IN) inhibitors with a dual mode of action, called IN-LEDGF/p75 allosteric inhibitors (INLAIs), was described. Designed to interfere with the IN-LEDGF/p75 interaction during viral integration, unexpectedly, their major impact was on virus maturation. This activity has been linked to induction of aberrant IN multimerization, whereas inhibition of the IN LEDGF/p75 interaction accounts for weaker antiretroviral effect at integration. Because these dual activities result from INLAI binding to IN at a single binding site, we expected that these activities co-evolved together, driven by the affinity for IN. Using an original INLAI, MUT-A, and its activity on an Ala-125 (A125) IN variant, we found that these two activities on A125-IN can be fully dissociated: MUT-A-induced IN multimerization and the formation of eccentric condensates in viral particles, which are responsible for inhibition of virus maturation, were lost, whereas inhibition of the IN-LEDGF/p75 interaction and consequently integration was fully retained. Hence, the mere binding of INLAI to A125 IN is insufficient to promote the conformational changes of IN required for aberrant multimerization. By analyzing the X-ray structures of MUT-A bound to the IN catalytic core domain (CCD) with or without the Ala-125 polymorphism, we discovered that the loss of IN multimerization is due to stabilization of the A125-IN variant CCD dimer, highlighting the importance of the CCD dimerization energy for IN multimerization. Our study reveals that affinity for the LEDGF/p75 binding pocket is not sufficient to induce INLAI-dependent IN multimerization and the associated inhibition of viral maturation. PMID- 29507093 TI - Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats. AB - Hereditary tyrosinemia type I (HTI) is a metabolic genetic disorder caused by mutation of fumarylacetoacetate hydrolase (FAH). Because of the accumulation of toxic metabolites, HTI causes severe liver cirrhosis, liver failure, and even hepatocellular carcinoma. HTI is an ideal model for gene therapy, and several strategies have been shown to ameliorate HTI symptoms in animal models. Although CRISPR/Cas9-mediated genome editing is able to correct the Fah mutation in mouse models, WT Cas9 induces numerous undesired mutations that have raised safety concerns for clinical applications. To develop a new method for gene correction with high fidelity, we generated a Fah mutant rat model to investigate whether Cas9 nickase (Cas9n)-mediated genome editing can efficiently correct the Fah First, we confirmed that Cas9n rarely induces indels in both on-target and off target sites in cell lines. Using WT Cas9 as a positive control, we delivered Cas9n and the repair donor template/single guide (sg)RNA through adenoviral vectors into HTI rats. Analyses of the initial genome editing efficiency indicated that only WT Cas9 but not Cas9n causes indels at the on-target site in the liver tissue. After receiving either Cas9n or WT Cas9-mediated gene correction therapy, HTI rats gained weight steadily and survived. Fah-expressing hepatocytes occupied over 95% of the liver tissue 9 months after the treatment. Moreover, CRISPR/Cas9-mediated gene therapy prevented the progression of liver cirrhosis, a phenotype that could not be recapitulated in the HTI mouse model. These results strongly suggest that Cas9n-mediated genome editing is a valuable and safe gene therapy strategy for this genetic disease. PMID- 29507094 TI - Kruppel-like factor 4 (KLF4) induces mitochondrial fusion and increases spare respiratory capacity of human glioblastoma cells. AB - Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor critical for the regulation of many cellular functions in both normal and neoplastic cells. Here, using human glioblastoma cells, we investigated KLF4's effects on cancer cell metabolism. We found that forced KLF4 expression promotes mitochondrial fusion and induces dramatic changes in mitochondrial morphology. To determine the impact of these changes on the cellular functions following, we analyzed how KLF4 alters glioblastoma cell metabolism, including glucose uptake, glycolysis, pentose phosphate pathway, and oxidative phosphorylation. We did not identify significant differences in baseline cellular metabolism between control and KLF4 expressing cells. However, when mitochondrial function was impaired, KLF4 significantly increased spare respiratory capacity and levels of reactive oxygen species in the cells. To identify the biological effects of these changes, we analyzed proliferation and survival of control and KLF4-expressing cells under stress conditions, including serum and nutrition deprivation. We found that following serum starvation, KLF4 altered cell cycle progression by arresting the cells at the G2/M phase and that KLF4 protected cells from nutrition deprivation induced death. Finally, we demonstrated that methylation-dependent KLF4-binding activity mediates mitochondrial fusion. Specifically, the downstream targets of KLF4-mCpG binding, guanine nucleotide exchange factors, serve as the effector of KLF4-induced mitochondrial fusion, cell cycle arrest, and cell protection. Our experimental system provides a robust model for studying the interactions between mitochondrial morphology and function, mitochondrial dynamics and metabolism, and mitochondrial fusion and cell death during tumor initiation and progression. PMID- 29507095 TI - Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice. AB - Tendon is a dense connective tissue that transmits high mechanical forces from skeletal muscle to bone. The transcription factor scleraxis (Scx) is a highly specific marker of both precursor and mature tendon cells (tenocytes). Mice lacking scx exhibit a specific and virtually complete loss of tendons during development. However, the functional contribution of Scx to wound healing in adult tendon has not yet been fully characterized. Here, using ScxGFP-tracking and loss-of-function systems, we show in an adult mouse model of Achilles tendon injury that paratenon cells, representing a stem cell antigen-1 (Sca-1)-positive and Scx-negative progenitor subpopulation, display Scx induction, migrate to the wound site, and produce extracellular matrix (ECM) to bridge the defect, whereas resident tenocytes exhibit a delayed response. Scx induction in the progenitors is initiated by transforming growth factor beta (TGF-beta) signaling. scx deficient mice had migration of Sca-1-positive progenitor cell to the lesion site but impaired ECM assembly to bridge the defect. Mechanistically, scx-null progenitors displayed higher chondrogenic potential with up-regulation of SRY-box 9 (Sox9) coactivator PPAR-gamma coactivator-1alpha (PGC-1alpha) in vitro, and knock-in analysis revealed that forced expression of full-length scx significantly inhibited Sox9 expression. Accordingly, scx-null wounds formed cartilage-like tissues that developed ectopic ossification. Our findings indicate a critical role of Scx in a progenitor-cell lineage in wound healing of adult mouse tendon. These progenitor cells could represent targets in strategies to facilitate tendon repair. We propose that this lineage-regulatory mechanism in tissue progenitors could apply to a broader set of tissues or biological systems in the body. PMID- 29507096 TI - Not just heads and tails: The complexity of the sperm epigenome. AB - Transgenerational inheritance requires mechanisms by which epigenetic information is transferred via gametes. Canonical thought holds that mammalian sperm chromatin would be incapable of carrying epigenetic information as post translational modifications of histones because of their replacement with protamine proteins. Furthermore, compaction of the sperm genome would hinder DNA accessibility of proteins involved in transcriptional regulation and genome architecture. In this Minireview, we delineate the paternal chromatin remodeling events during spermatogenesis and fertilization. Sperm chromatin is epigenetically modified at various time points throughout its development. This allows for the addition of environment-specific modifications that can be passed from parents to offspring. PMID- 29507097 TI - Pioneer transcription factors shape the epigenetic landscape. AB - Pioneer transcription factors have the unique and important role of unmasking chromatin domains during development to allow the implementation of new cellular programs. Compared with those of other transcription factors, this activity implies that pioneer factors can recognize their target DNA sequences in so called compacted or "closed" heterochromatin and can trigger remodeling of the adjoining chromatin landscape to provide accessibility to nonpioneer transcription factors. Recent studies identified several steps of pioneer action, namely rapid but weak initial binding to heterochromatin and stabilization of binding followed by chromatin opening and loss of cytosine-phosphate-guanine (CpG) methylation that provides epigenetic memory. Whereas CpG demethylation depends on replication, chromatin opening does not. In this Minireview, we highlight the unique properties of this transcription factor class and the challenges of understanding their mechanism of action. PMID- 29507100 TI - Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II-Induced Atrial Fibrillation in Mice. AB - Angiotensin II (Ang II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II-induced AF in immunosubunit PSMB10 (also known as beta2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/min per kg). PSMB10 expression and trypsin like activity were increased in atrial tissues and serum from Ang II-treated mice or serum from patients with AF. Moreover, Ang II-infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10-treated mice. Administration of IKKbeta-specific inhibitor IMD 0354 reduced Ang II-induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-beta-Smad2/3 signaling leading to cardiac fibrosis but also induced IKKbeta activation and ubiquitin-mediated degradation of IkBalpha ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1beta, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF. PMID- 29507099 TI - Relation of Dietary Sodium (Salt) to Blood Pressure and Its Possible Modulation by Other Dietary Factors: The INTERMAP Study. AB - : Available data indicate that dietary sodium (as salt) relates directly to blood pressure (BP). Most of these findings are from studies lacking dietary data; hence, it is unclear whether this sodium-BP relationship is modulated by other dietary factors. With control for multiple nondietary factors, but not body mass index, there were direct relations to BP of 24-hour urinary sodium excretion and the urinary sodium/potassium ratio among 4680 men and women 40 to 59 years of age (17 population samples in China, Japan, United Kingdom, and United States) in the INTERMAP (International Study on Macro/Micronutrients and Blood Pressure), and among its 2195 American participants, for example, 2 SD higher 24-hour urinary sodium excretion (118.7 mmol) associated with systolic BP 3.7 mm Hg higher. These sodium-BP relations persisted with control for 13 macronutrients, 12 vitamins, 7 minerals, and 18 amino acids, for both sex, older and younger, blacks, Hispanics, whites, and socioeconomic strata. With control for body mass index, sodium-BP-but not sodium/potassium-BP-relations were attenuated. Normal weight and obese participants manifested significant positive relations to BP of urinary sodium; relations were weaker for overweight people. At lower but not higher levels of 24 hour sodium excretion, potassium intake blunted the sodium-BP relation. The adverse association of dietary sodium with BP is minimally attenuated by other dietary constituents; these findings underscore the importance of reducing salt intake for the prevention and control of prehypertension and hypertension. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005271. PMID- 29507098 TI - Ligand- and cation-induced structural alterations of the leukocyte integrin LFA 1. AB - In alphaI integrins, including leukocyte function-associated antigen 1 (LFA-1), ligand-binding function is delegated to the alphaI domain, requiring extra steps in the relay of signals that activate ligand binding and coordinate it with cytoplasmic signals. Crystal structures reveal great variation in orientation between the alphaI domain and the remainder of the integrin head. Here, we investigated the mechanisms involved in signal relay to the alphaI domain, including whether binding of the ligand intercellular adhesion molecule-1 (ICAM 1) to the alphaI domain is linked to headpiece opening and engenders a preferred alphaI domain orientation. Using small-angle X-ray scattering and negative-stain EM, we define structures of ICAM-1, LFA-1, and their complex, and the effect of activation by Mn2+ Headpiece opening was substantially stabilized by substitution of Mg2+ with Mn2+ and became complete upon ICAM-1 addition. These agents stabilized alphaI-headpiece orientation, resulting in a well-defined orientation of ICAM-1 such that its tandem Ig-like domains pointed in the opposite direction from the beta-subunit leg of LFA-1. Mutations in the integrin betaI domain alpha1/alpha1' helix stabilizing either the open or the closed betaI-domain conformation indicated that alpha1/alpha1' helix movements are linked to ICAM-1 binding by the alphaI domain and to the extended-open conformation of the ectodomain. The LFA-1-ICAM-1 orientation described here with ICAM-1 pointing anti parallel to the LFA-1 beta-subunit leg is the same orientation that would be stabilized by tensile force transmitted between the ligand and the actin cytoskeleton and is consistent with the cytoskeletal force model of integrin activation. PMID- 29507101 TI - Mechanistic Role of the Calcium-Dependent Protease Calpain in the Endothelial Dysfunction Induced by MPO (Myeloperoxidase). AB - MPO (myeloperoxidase) is a peroxidase enzyme secreted by activated leukocytes that plays a pathogenic role in cardiovascular disease, mainly by initiating endothelial dysfunction. The molecular mechanisms of the endothelial damaging action of MPO remain though largely elusive. Calpain is a calcium-dependent protease expressed in the vascular wall. Activation of calpains has been implicated in inflammatory disorders of the vasculature. Using endothelial cells and genetically modified mice, this study identifies the u-calpain isoform as novel downstream signaling target of MPO in endothelial dysfunction. Mouse lung microvascular endothelial cells were stimulated with 10 nmol/L MPO for 180 minutes. MPO denitrosylated u-calpain C-terminus domain, and time dependently activated u-calpain, but not the m-calpain isoform. MPO also reduced Thr172 AMPK (AMP-activated protein kinase) and Ser1177 eNOS (endothelial nitric oxide synthase) phosphorylation via upregulation of PP2A (protein phosphatase 2) expression. At the functional level, MPO increased endothelial VCAM-1 (vascular cell adhesion molecule 1) abundance and the adhesion of leukocytes to the mouse aorta. In MPO-treated endothelial cells, pharmacological inhibition of calpain activity attenuated expression of VCAM-1 and PP2A, and restored Thr172 AMPK and Ser1177 eNOS phosphorylation. Compared with wild-type mice, u-calpain deficient mice experienced reduced leukocyte adhesion to the aortic endothelium in response to MPO. Our data first establish a role for calpain in the endothelial dysfunction and vascular inflammation of MPO. The MPO/calpain/PP2A signaling pathway may provide novel pharmacological targets for the treatment of inflammatory vascular disorders. PMID- 29507102 TI - Calpain: A Novel Mediator of MPO (Myeloperoxidase)-Induced Endothelial Dysfunction. PMID- 29507103 TI - Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach. AB - Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases. PMID- 29507104 TI - MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease. AB - Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2 MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-kappaB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD. PMID- 29507106 TI - The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability. AB - Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I) based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2Db in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2Db/Trh4. Comparison of the crystal structures of the H-2Db/Trh4-p3P and H-2Db/Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur-pi interactions with H-2Db residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability. PMID- 29507105 TI - Associations of Simian Immunodeficiency Virus (SIV)-Specific Follicular CD8+ T Cells with Other Follicular T Cells Suggest Complex Contributions to SIV Viremia Control. AB - Follicular CD8+ T (fCD8) cells reside within B cell follicles and are thought to be immune-privileged sites of HIV/SIV infection. We have observed comparable levels of fCD8 cells between chronically SIV-infected rhesus macaques with low viral loads (LVL) and high viral loads (HVL), raising the question concerning their contribution to viremia control. In this study, we sought to clarify the role of SIV-specific fCD8 cells in lymph nodes during the course of SIV infection in rhesus macaques. We observed that fCD8 cells, T follicular helper (Tfh) cells, and T follicular regulatory cells (Tfreg) were all elevated in chronic SIV infection. fCD8 cells of LVL animals tended to express more Gag-specific granzyme B and exhibited significantly greater killing than did HVL animals, and their cell frequencies were negatively correlated with viremia, suggesting a role in viremia control. Env- and Gag-specific IL-21+ Tfh of LVL but not HVL macaques negatively correlated with viral load, suggesting better provision of T cell help to fCD8 cells. Tfreg positively correlated with fCD8 cells in LVL animals and negatively correlated with viremia, suggesting a potential benefit of Tfreg via suppression of chronic inflammation. In contrast, in HVL macaques, Tfreg and fCD8 cell frequencies tended to be negatively correlated, and a positive correlation was seen between Tfreg number and viremia, suggesting possible dysfunction and suppression of an effective fCD8 cell immune response. Our data suggest that control of virus-infected cells in B cell follicles not only depends on fCD8 cell cytotoxicity but also on complex fCD8 cell associations with Tfh cells and Tfreg. PMID- 29507107 TI - Clec9A+ Dendritic Cells Are Not Essential for Antitumor CD8+ T Cell Responses Induced by Poly I:C Immunotherapy. AB - In the steady state, tumors harbor several populations of dendritic cells (DCs) and myeloid cells that are key regulators of the intratumoral immune environment. Among these cells, migratory CD103+ cross-presenting DCs are thought to be critical for tumor-specific CTL responses and tumor resistance. However, it is unclear whether this prominent role also extends to immunotherapy. We used a murine orthotopic mammary tumor model, as well as Clec9A-diphtheria toxin receptor mice that can be depleted of the specialized cross-presenting CD8alpha+ and CD103+ DC1 subsets, to investigate the role of these DCs in immunotherapy. Treatment with monosodium urate crystals and mycobacteria at the tumor site delayed tumor growth and required DC1s for efficacy. In contrast, treatment with poly I:C was equally effective regardless of DC1 depletion. Neither treatment affected myeloid-derived suppressor cell numbers in the spleen or tumor. Similar experiments using subcutaneous B16 melanoma tumors in BATF3-knockout mice confirmed that CD103+ DCs were not necessary for successful poly I:C immunotherapy. Nevertheless, adaptive immune responses were essential for the response to poly I:C, because mice depleted of CD8+ T cells or all DC subsets were unable to delay tumor growth. In vivo experiments showed that DC1 and DC2 subsets were able to take up tumor Ags, with DC2s making up the larger proportion of lymph node DCs carrying tumor material. Both DC subsets were able to cross present OVA to OT-I T cells in vitro. Thus, immunotherapy with poly I:C enables multiple DC subsets to cross-present tumor Ag for effective antitumor immune responses. PMID- 29507108 TI - RGC32 Promotes Bleomycin-Induced Systemic Sclerosis in a Murine Disease Model by Modulating Classically Activated Macrophage Function. AB - Systemic sclerosis (SSc) is a multisystem autoimmune disorder that is characterized by inflammation and fibrosis in the skin and internal organs. Previous studies indicate that inflammatory cells and cytokines play essential roles in the pathogenesis of SSc; however, the mechanisms that underlie the inflammation-driven development of SSc are not fully understood. In this study, we show that response gene to complement 32 (RGC32) is abundantly expressed in mouse macrophages in the early stage of bleomycin-induced SSc. Importantly, RGC32 is required to induce the inflammatory response during the onset of SSc, because RGC32 deficiency in mice significantly ameliorates skin and lung sclerosis and inhibits the expression of inflammatory mediators inducible NO synthase (iNOS) and IL-1beta in macrophages. RGC32 appears to be a novel regulator for the differentiation of classically activated macrophages (M1 macrophages). IFN-gamma and LPS stimulation induces RGC32 expression in primary peritoneal macrophages and bone marrow-derived macrophages. RGC32 deficiency impairs the polarization of M1 macrophages and attenuates iNOS and IL-1beta production. Mechanistically, RGC32 interacts with NF-kappaB proteins and promotes iNOS and IL-1beta expression by binding to their promoters. Collectively, our data reveal that RGC32 promotes the onset of SSc by regulating the inflammatory response of M1 macrophages, and it may serve as a promising therapeutic target for treating SSc. PMID- 29507110 TI - Assessing the impact of a regional UK feline neutering campaign. AB - Neutering is key to feline population control. Neutering campaigns provide education and/or financial assistance to encourage neutering. This study assessed the impact of the Cats Protection East Midlands Neutering Campaign (CPEMNC) on the proportion and ages of cats neutered. The CPEMNC, comprising of an outreach programme and voucher-based subsidised neutering scheme, began in June 2014. A convenience sample of owners who had attended 12 regional veterinary practices to complete a cat vaccination course in June/July 2014, or to have their cat neutered in October 2014 (CAMPAIGN) were compared with an equivalent control period in 2013 (CONTROL). Data collected by postal questionnaire revealed that the proportion of cats neutered by six months of age was significantly higher and the age at neutering significantly lower in the CAMPAIGN (n=134) versus the CONTROL groups (n=100). Results of multivariable logistic regression indicated cats were significantly more likely to be neutered by six months of age if they were in the CAMPAIGN group (OR 2.44) and male (OR 2.17), compared with in the CONTROL group and female. Further work is needed to evaluate factors important for campaign success and to explore the effectiveness of campaigns within the wider community and across the UK. PMID- 29507109 TI - Epitope-Binding Characteristics for Risk versus Protective DRB1 Alleles for Visceral Leishmaniasis. AB - HLA-DRB1 is the major genetic risk factor for visceral leishmaniasis (VL). We used SNP2HLA to impute HLA-DRB1 alleles and SNPTEST to carry out association analyses in 889 human cases and 977 controls from India. NetMHCIIpan 2.1 was used to map epitopes and binding affinities across 49 Leishmania vaccine candidates, as well as across peptide epitopes captured from dendritic cells treated with crude Leishmania Ag and identified using mass spectrometry and alignment to amino acid sequences of a reference Leishmania genome. Cytokines were measured in peptide-stimulated whole blood from 26 cured VL cases and eight endemic healthy controls. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective and risk alleles, respectively, with specific residues at aa positions 11 and 13 unique to protective alleles. We observed greater peptide promiscuity in sequence motifs for 9-mer core epitopes predicted to bind to risk (*1404/*1301) compared with protective (*1501) DRB1 alleles. There was a higher frequency of basic amino acids in DRB1*1404/*1301-specific epitopes compared with hydrophobic and polar amino acids in DRB1*1501-specific epitopes at anchor residues pocket 4 and pocket 6, which interact with residues at DRB1 positions 11 and 13. Cured VL patients made variable, but robust, IFN-gamma, TNF, and IL-10 responses to 20-mer peptides based on captured epitopes, with peptides based on DRB1*1501-captured epitopes resulting in a higher proportion (odds ratio 2.23, 95% confidence interval 1.17-4.25, p = 0.017) of patients with IFN-gamma/IL-10 ratios > 2-fold compared with peptides based on DRB1*1301-captured epitopes. Our data provide insight into the molecular mechanisms underpinning the association of HLA-DRB1 alleles with risk versus protection in VL in humans. PMID- 29507113 TI - The Arf-GDP-regulated recruitment of GBF1 to Golgi membranes requires domains HDS1 and HDS2 and a Golgi-localized protein receptor. AB - We previously proposed a novel mechanism by which the enzyme Golgi-specific Brefeldin A resistance factor 1 (GBF1) is recruited to the membranes of the cis Golgi, based on in vivo experiments. Here, we extended our in vivo analysis on the production of regulatory Arf-GDP and observed that ArfGAP2 and ArfGAP3 do not play a role in GBF1 recruitment. We confirm that Arf-GDP localization is critical, as a TGN-localized Arf-GDP mutant protein fails to promote GBF1 recruitment. We also reported the establishment of an in vitro GBF1 recruitment assay that supports the regulation of GBF1 recruitment by Arf-GDP. This in vitro assay yielded further evidence for the requirement of a Golgi-localized protein because heat denaturation or protease treatment of Golgi membranes abrogated GBF1 recruitment. Finally, combined in vivo and in vitro measurements indicated that the recruitment to Golgi membranes via a putative receptor requires only the HDS1 and HDS2 domains in the C-terminal half of GBF1. PMID- 29507111 TI - Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG proteins in the heart. AB - Reduced levels of the cardiac human (h)ERG ion channel protein and the corresponding repolarizing current IKr can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. Here, we identified TRIOBP-1, an F-actin-binding protein previously associated with actin polymerization, as a putative hERG-interacting protein in a yeast-two hybrid screen of a cardiac library. We corroborated this interaction by performing Forster resonance energy transfer (FRET) in HEK293 cells and co-immunoprecipitation in HEK293 cells and native cardiac tissue. TRIOBP-1 overexpression reduced hERG surface expression and current density, whereas reducing TRIOBP-1 expression via shRNA knockdown resulted in increased hERG protein levels. Immunolabeling in rat cardiomyocytes showed that native TRIOBP-1 colocalized predominantly with myosin-binding protein C and secondarily with rat ERG. In human stem cell-derived cardiomyocytes, TRIOBP-1 overexpression caused intracellular co-sequestration of hERG signal, reduced native IKr and disrupted action potential repolarization. Ca2+ currents were also somewhat reduced and cell capacitance was increased. These findings establish that TRIOBP 1 interacts directly with hERG and can affect protein levels, IKr magnitude and cardiac membrane excitability. PMID- 29507114 TI - Hsp70-Hsp110 chaperones deliver ubiquitin-dependent and -independent substrates to the 26S proteasome for proteolysis in yeast. AB - During protein quality control, proteotoxic misfolded proteins are recognized by molecular chaperones, ubiquitylated by dedicated quality control ligases and delivered to the 26S proteasome for degradation. Proteins belonging to the Hsp70 chaperone and Hsp110 (the Hsp70 nucleotide exchange factor) families function in the degradation of misfolded proteins by the ubiquitin-proteasome system via poorly understood mechanisms. Here, we report that the Saccharomyces cerevisiae Hsp110 proteins (Sse1 and Sse2) function in the degradation of Hsp70-associated ubiquitin conjugates at the post-ubiquitylation step and are also required for ubiquitin-independent proteasomal degradation. Hsp110 associates with the 19S regulatory particle of the 26S proteasome and interacts with Hsp70 to facilitate the delivery of Hsp70 substrates for proteasomal degradation. By using a highly defined ubiquitin-independent proteasome substrate, we show that the mere introduction of a single Hsp70-binding site renders its degradation dependent on Hsp110. The findings define a dedicated and chaperone-dependent pathway for the efficient shuttling of cellular proteins to the proteasome with profound implications for understanding protein quality control and cellular stress management. PMID- 29507112 TI - Rap1, Canoe and Mbt cooperate with Bazooka to promote zonula adherens assembly in the fly photoreceptor. AB - In Drosophila epithelial cells, apical exclusion of Bazooka (the Drosophila Par3 protein) defines the position of the zonula adherens (ZA), which demarcates the apical and lateral membrane and allows cells to assemble into sheets. Here, we show that the small GTPase Rap1, its effector Canoe (Cno) and the Cdc42 effector kinase Mushroom bodies tiny (Mbt), converge in regulating epithelial morphogenesis by coupling stabilization of the adherens junction (AJ) protein E Cadherin and Bazooka retention at the ZA. Furthermore, our results show that the localization of Rap1, Cno and Mbt at the ZA is interdependent, indicating that their functions during ZA morphogenesis are interlinked. In this context, we find the Rap1-GEF Dizzy is enriched at the ZA and our results suggest that it promotes Rap1 activity during ZA morphogenesis. Altogether, we propose the Dizzy, Rap1 and Cno pathway and Mbt converge in regulating the interface between Bazooka and AJ material to promote ZA morphogenesis. PMID- 29507116 TI - Nuclear phosphatidylinositol 4,5-bisphosphate islets contribute to efficient RNA polymerase II-dependent transcription. AB - This paper describes a novel type of nuclear structure - nuclear lipid islets (NLIs). They are of 40-100 nm with a lipidic interior, and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] molecules comprise a significant part of their surface. Most of NLIs have RNA at the periphery. Consistent with that, RNA is required for their integrity. The NLI periphery is associated with Pol II transcription machinery, including the largest Pol II subunit, transcription factors and NM1 (also known as NMI). The PtdIns(4,5)P2-NM1 interaction is important for Pol II transcription, since NM1 knockdown reduces the Pol II transcription level, and the overexpression of wild-type NM1 [but not NM1 mutated in the PtdIns(4,5)P2-binding site] rescues the transcription. Importantly, Pol II transcription is dependent on NLI integrity, because an enzymatic reduction of the PtdIns(4,5)P2 level results in a decrease of the Pol II transcription level. Furthermore, about half of nascent transcripts localise to NLIs, and transcriptionally active transgene loci preferentially colocalise with NLIs. We hypothesize that NLIs serve as a structural platform that facilitates the formation of Pol II transcription factories, thus participating in the formation of nuclear architecture competent for transcription. PMID- 29507115 TI - Neurochondrin interacts with the SMN protein suggesting a novel mechanism for spinal muscular atrophy pathology. AB - Spinal muscular atrophy (SMA) is an inherited neurodegenerative condition caused by a reduction in the amount of functional survival motor neuron (SMN) protein. SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependent mobile vesicles rich in SMN and SNRPB, a member of the Sm family of small nuclear ribonucleoprotein (snRNP)-associated proteins, in neural cells. By comparing the interactomes of SNRPB and SNRPN, a neural-specific Sm protein, we now show that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites. NCDN has roles in protein localisation in neural cells and in maintenance of cell polarity. NCDN is required for the correct localisation of SMN, suggesting they may both be required for formation and transport of trafficking vesicles. NCDN may have potential as a therapeutic target for SMA together with, or in place of the targeting of SMN expression.This article has an associated First Person interview with the first author of the paper. PMID- 29507117 TI - CRL7SMU1 E3 ligase complex-driven H2B ubiquitylation functions in sister chromatid cohesion by regulating SMC1 expression. AB - Cullin-RING-type E3 ligases (CRLs) control a broad range of biological processes by ubiquitylating numerous cellular substrates. However, the role of CRL E3 ligases in chromatid cohesion is unknown. In this study, we identified a new CRL type E3 ligase (designated as CRL7SMU1 complex) that has an essential role in the maintenance of chromatid cohesion. We demonstrate that SMU1, DDB1, CUL7 and RNF40 are integral components of this complex. SMU1, by acting as a substrate recognition module, binds to H2B and mediates monoubiquitylation at the lysine (K) residue K120 through CRL7SMU1 E3 ligase complex. Depletion of CRL7SMU1 leads to loss of H2B ubiquitylation at the SMC1a locus and, thus, subsequently compromised SMC1a expression in cells. Knockdown of CRL7SMU1 components or loss of H2B ubiquitylation leads to defective sister chromatid cohesion, which is rescued by restoration of SMC1a expression. Together, our results unveil an important role of CRL7SMU1 E3 ligase in promoting H2B ubiquitylation for maintenance of sister chromatid cohesion during mitosis.This article has an associated First Person interview with the first author of the paper. PMID- 29507118 TI - Phosphorylation hotspot in the C-terminal domain of occludin regulates the dynamics of epithelial junctional complexes. AB - The apical junctional complex (AJC), which includes tight junctions (TJs) and adherens junctions (AJs), determines the epithelial polarity, cell-cell adhesion and permeability barrier. An intriguing characteristic of a TJ is the dynamic nature of its multiprotein complex. Occludin is the most mobile TJ protein, but its significance in TJ dynamics is poorly understood. On the basis of phosphorylation sites, we distinguished a sequence in the C-terminal domain of occludin as a regulatory motif (ORM). Deletion of ORM and expression of a deletion mutant of occludin in renal and intestinal epithelia reduced the mobility of occludin at the TJs. ORM deletion attenuated Ca2+ depletion, osmotic stress and hydrogen peroxide-induced disruption of TJs, AJs and the cytoskeleton. The double point mutations T403A/T404A, but not T403D/T404D, in occludin mimicked the effects of ORM deletion on occludin mobility and AJC disruption by Ca2+ depletion. Both Y398A/Y402A and Y398D/Y402D double point mutations partially blocked AJC disruption. Expression of a deletion mutant of occludin attenuated collective cell migration in the renal and intestinal epithelia. Overall, this study reveals the role of ORM and its phosphorylation in occludin mobility, AJC dynamics and epithelial cell migration. PMID- 29507120 TI - Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies. AB - The immunoregulatory and anti-infective properties of normal circulating polyclonal Abs have been exploited for the therapeutic purposes in the form of IVIG as well as several hyperimmune globulins. Current knowledge on the therapeutic use of normal Igs is based on the discoveries made by several pioneers of the field. In this paper, we review the evolution of IVIG over the years. More importantly, the process started as an s.c. replacement in gamma globulin-deficient patients, underwent metamorphosis into i.m. Ig, was followed by IVIG, and is now back to s.c. forms. Following successful use of IVIG in immune thrombocytopenic purpura, there has been an explosion in the therapeutic applications of IVIG in diverse autoimmune and inflammatory conditions. In addition to clinically approved pathological conditions, IVIG has been used as an off-label drug in more than 100 different indications. The current worldwide consumption of IVIG is over 100 tons per year. PMID- 29507121 TI - Recent Insights into CD4+ Th Cell Differentiation in Malaria. AB - CD4+ Th cell differentiation is crucial for protecting against blood-stage Plasmodium parasites, the causative agents of malaria. It has been known for decades that more than one type of Th cell develops during this infection, with early models proposing a biphasic Th1/Th2 model of differentiation. Over the past decade, a large body of research, in particular, reports over the past 2-3 y, have revealed substantial complexity in the Th differentiation program during Plasmodium infection. In this article, we review how several studies employing mouse models of malaria, and recent human studies, have redefined the process of Th differentiation, with a particular focus on Th1 and T follicular helper (Tfh) cells. We review the molecular mechanisms that have been reported to modulate Th1/Tfh differentiation, and propose a model of Th1/Tfh differentiation that accommodates observations from all recent murine and human studies. PMID- 29507119 TI - VASCULAR PLANT ONE-ZINC FINGER1 (VOZ1) and VOZ2 Interact with CONSTANS and Promote Photoperiodic Flowering Transition. AB - In plants, endogenous and environmental signals such as light control the timing of the transition to flowering. Two phytochrome B-interacting transcription factors, VASCULAR PLANT ONE-ZINC FINGER1 (VOZ1) and VOZ2, redundantly promote flowering in Arabidopsis (Arabidopsis thaliana). In the voz1 voz2 mutant, the expression of FLOWERING LOCUS C (FLC) was up-regulated and that of FLOWERING LOCUS T (FT) was down-regulated, which was proposed to be the cause of late flowering in voz1 voz2 However, the detailed mechanism by which the VOZ genes promote flowering is not well understood. Here, we show that neither the reduced FT expression nor the late-flowering phenotype of voz1 voz2 is suppressed in the voz1 voz2 flc triple mutant. Genetic interaction experiments between voz1 voz2 and constans-2 (co-2) mutants reveal that the VOZs and CO work in the same genetic pathway. Using in vitro pull-down, electrophoretic mobility shift, and bimolecular fluorescence complementation assays, we show that VOZ1 and VOZ2 interact with CO. The voz1 voz2 35S::CO:YFP plants show suppression of the early flowering phenotype induced by CO overexpression, suggesting that CO requires VOZ for the induction of flowering. Determination of the VOZ consensus-binding site followed by genome-wide sequence analysis failed to identify any VOZ-binding sites near known flowering time genes. Together, these results indicate that the VOZ genes regulate flowering primarily through the photoperiod pathway, independent of FLC, and suggest that VOZs modulate CO function to promote flowering. PMID- 29507122 TI - Impact of a national QI programme on reducing electronic health record notifications to clinicians. AB - BACKGROUND: Emerging evidence suggests electronic health record (EHR)-related information overload is a risk to patient safety. In the US Department of Veterans Affairs (VA), EHR-based 'inbox' notifications originally intended for communicating important clinical information are now cited by 70% of primary care practitioners (PCPs) to be of unmanageable volume. We evaluated the impact of a national, multicomponent, quality improvement (QI) programme to reduce low-value EHR notifications. METHODS: The programme involved three steps: (1) accessing daily PCP notification load data at all 148 facilities operated nationally by the VA; (2) standardising and restricting mandatory notification types at all facilities to a recommended list; and (3) hands-on training for all PCPs on customising and processing notifications more effectively. Designated leaders at each of VA's 18 regional networks led programme implementation using a nationally developed toolkit. Each network supervised technical requirements and data collection, ensuring consistency. Coaching calls and emails allowed the national team to address implementation challenges and monitor effects. We analysed notification load and mandatory notifications preintervention (March 2017) and immediately postintervention (June-July 2017) to assess programme impact. RESULTS: Median number of mandatory notification types at each facility decreased significantly from 15 (IQR: 13-19) to 10 (IQR: 10-11) preintervention to postintervention, respectively (P<0.001). Mean daily notifications per PCP decreased significantly from 128 (SEM=4) to 116 (SEM=4; P<0.001). Heterogeneity in implementation across sites led to differences in observed programme impact, including potentially beneficial carryover effects. CONCLUSIONS: Based on prior estimates on time to process notifications, a national QI programme potentially saved 1.5 hours per week per PCP to enable higher value work. The number of daily notifications remained high, suggesting the need for additional multifaceted interventions and protected clinical time to help manage them. Nevertheless, our project suggests feasibility of using large-scale 'de-implementation' interventions to reduce unintended safety or efficiency consequences of well intended electronic communication systems. PMID- 29507123 TI - The data of diagnostic error: big, large and small. PMID- 29507124 TI - Next-generation audit and feedback for inpatient quality improvement using electronic health record data: a cluster randomised controlled trial. AB - BACKGROUND: Audit and feedback improves clinical care by highlighting the gap between current and ideal practice. We combined best practices of audit and feedback with continuously generated electronic health record data to improve performance on quality metrics in an inpatient setting. METHODS: We conducted a cluster randomised control trial comparing intensive audit and feedback with usual audit and feedback from February 2016 to June 2016. The study subjects were internal medicine teams on the teaching service at an urban tertiary care hospital. Teams in the intensive feedback arm received access to a daily-updated team-based data dashboard as well as weekly inperson review of performance data ('STAT rounds'). The usual feedback arm received ongoing twice-monthly emails with graphical depictions of team performance on selected quality metrics. The primary outcome was performance on a composite discharge metric (Discharge Mix Index, 'DMI'). A washout period occurred at the end of the trial (from May through June 2016) during which STAT rounds were removed from the intensive feedback arm. RESULTS: A total of 40 medicine teams participated in the trial. During the intervention period, the primary outcome of completion of the DMI was achieved on 79.3% (426/537) of patients in the intervention group compared with 63.2% (326/516) in the control group (P<0.0001). During the washout period, there was no significant difference in performance between the intensive and usual feedback groups. CONCLUSION: Intensive audit and feedback using timely data and STAT rounds significantly increased performance on a composite discharge metric compared with usual feedback. With the cessation of STAT rounds, performance between the intensive and usual feedback groups did not differ significantly, highlighting the importance of feedback delivery on effecting change. CLINICAL TRIAL: The trial was registered with ClinicalTrials.gov (NCT02593253). PMID- 29507125 TI - IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic beta cells. AB - In mammalian pancreatic beta cells, the IRE1alpha-XBP1 pathway is constitutively and highly activated under physiological conditions. To elucidate the precise role of this pathway, we constructed beta cell-specific Ire1alpha conditional knockout (CKO) mice and established insulinoma cell lines in which Ire1alpha was deleted using the Cre-loxP system. Ire1alpha CKO mice showed the typical diabetic phenotype including impaired glycemic control and defects in insulin biosynthesis postnatally at 4-20 weeks. Ire1alpha deletion in pancreatic beta cells in mice and insulinoma cells resulted in decreased insulin secretion, decreased insulin and proinsulin contents in cells, and decreased oxidative folding of proinsulin along with decreased expression of five protein disulfide isomerases (PDIs): PDI, PDIR, P5, ERp44, and ERp46. Reconstitution of the IRE1alpha-XBP1 pathway restored the proinsulin and insulin contents, insulin secretion, and expression of the five PDIs, indicating that IRE1alpha functions as a key regulator of the induction of catalysts for the oxidative folding of proinsulin in pancreatic beta cells. PMID- 29507128 TI - What's Happening In Neurology(r). PMID- 29507129 TI - What's Happening In Neurology(r)Clinical Practice. PMID- 29507126 TI - VASP regulates leukocyte infiltration, polarization, and vascular repair after ischemia. AB - In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP-/- mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow-derived cells was sufficient to mimic the increased blood flow recovery of global VASP-/- mice. In chemotaxis experiments, VASP-/- neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and beta-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP-/- leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking. PMID- 29507127 TI - Branched actin networks push against each other at adherens junctions to maintain cell-cell adhesion. AB - Adherens junctions (AJs) are mechanosensitive cadherin-based intercellular adhesions that interact with the actin cytoskeleton and carry most of the mechanical load at cell-cell junctions. Both Arp2/3 complex-dependent actin polymerization generating pushing force and nonmuscle myosin II (NMII)-dependent contraction producing pulling force are necessary for AJ morphogenesis. Which actin system directly interacts with AJs is unknown. Using platinum replica electron microscopy of endothelial cells, we show that vascular endothelial (VE) cadherin colocalizes with Arp2/3 complex-positive actin networks at different AJ types and is positioned at the interface between two oppositely oriented branched networks from adjacent cells. In contrast, actin-NMII bundles are located more distally from the VE-cadherin-rich zone. After Arp2/3 complex inhibition, linear AJs split, leaving gaps between cells with detergent-insoluble VE-cadherin transiently associated with the gap edges. After NMII inhibition, VE-cadherin is lost from gap edges. We propose that the actin cytoskeleton at AJs acts as a dynamic push-pull system, wherein pushing forces maintain extracellular VE cadherin transinteraction and pulling forces stabilize intracellular adhesion complexes. PMID- 29507130 TI - What's Happening In Neurology(r)Genetics. PMID- 29507131 TI - What's Happening In Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29507133 TI - An extremely rare giant skin cirsoid angioma with brain compression. PMID- 29507132 TI - What's Happening In Innovations in Care Delivery. PMID- 29507134 TI - Pearls & Oy-sters: Ocular motor apraxia as essential differential diagnosis to supranuclear gaze palsy: Eyes up. PMID- 29507135 TI - Editors' note: Sleep architecture and the risk of incident dementia in the community. PMID- 29507136 TI - Reader response: Sleep architecture and the risk of incident dementia in the community. PMID- 29507137 TI - Author response: Sleep architecture and the risk of incident dementia in the community. PMID- 29507138 TI - Editors' note: The state of academic neurology departments in the United States, 2016: A national survey. PMID- 29507139 TI - Reader response: The state of academic neurology departments in the United States, 2016: A national survey. PMID- 29507140 TI - Author response: The state of academic neurology departments in the United States, 2016: A national survey. PMID- 29507141 TI - Clinical Reasoning: A teenager with left arm weakness. PMID- 29507142 TI - Teaching NeuroImages: Intradural, intramedullary spinal cord metastasis from primary renal cell carcinoma. PMID- 29507143 TI - Teaching NeuroImages: Gummatous neurosyphilis: An atypical presentation in a patient with HIV. PMID- 29507144 TI - Glutathione Conjugation at the Blood-CSF Barrier Efficiently Prevents Exposure of the Developing Brain Fluid Environment to Blood-Borne Reactive Electrophilic Substances. AB - Exposure of the developing brain to toxins, drugs, or deleterious endogenous compounds during the perinatal period can trigger alterations in cell division, migration, differentiation, and synaptogenesis, leading to lifelong neurological impairment. The brain is protected by cellular barriers acting through multiple mechanisms, some of which are still poorly explored. We used a combination of enzymatic assays, live tissue fluorescence microscopy, and an in vitro cellular model of the blood-CSF barrier to investigate an enzymatic detoxification pathway in the developing male and female rat brain. We show that during the early postnatal period the choroid plexus epithelium forming the blood-CSF barrier and the ependymal cell layer bordering the ventricles harbor a high detoxifying capacity that involves glutathione S-transferases. Using a functional knock-down rat model for choroidal glutathione conjugation, we demonstrate that already in neonates, this metabolic pathway efficiently prevents the penetration of blood borne reactive compounds into CSF. The versatility of the protective mechanism results from the multiplicity of the glutathione S-transferase isoenzymes, which are differently expressed between the choroidal epithelium and the ependyma. The various isoenzymes display differential substrate specificities, which greatly widen the spectrum of molecules that can be inactivated by this pathway. In conclusion, the blood-CSF barrier and the ependyma are identified as key cellular structures in the CNS to protect the brain fluid environment from different chemical classes of potentially toxic compounds during the postnatal period. This metabolic neuroprotective function of brain interfaces ought to compensate for the liver postnatal immaturity.SIGNIFICANCE STATEMENT Brain homeostasis requires a stable and controlled internal environment. Defective brain protection during the perinatal period can lead to lifelong neurological impairment. We demonstrate that the choroid plexus forming the blood-CSF barrier is a key player in the protection of the developing brain. Glutathione-dependent enzymatic metabolism in the choroidal epithelium inactivates a broad spectrum of noxious compounds, efficiently preventing their penetration into the CSF. A second line of detoxification is located in the ependyma separating the CSF from brain tissue. Our study reveals a novel facet of the mechanisms by which the brain is protected at a period of high vulnerability, at a time when the astrocytic network is still immature and liver xenobiotic metabolism is limited. PMID- 29507145 TI - TRPM2 Channel Aggravates CNS Inflammation and Cognitive Impairment via Activation of Microglia in Chronic Cerebral Hypoperfusion. AB - Chronic cerebral hypoperfusion is a characteristic seen in widespread CNS diseases, including neurodegenerative and mental disorders, and is commonly accompanied by cognitive impairment. Recently, several studies demonstrated that chronic cerebral hypoperfusion can induce the excessive inflammatory responses that precede neuronal dysfunction; however, the precise mechanism of cognitive impairment due to chronic cerebral hypoperfusion remains unknown. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable channel that is abundantly expressed in immune cells and is involved in aggravation of inflammatory responses. Therefore, we investigated the pathophysiological role of TRPM2 in a mouse chronic cerebral hypoperfusion model with bilateral common carotid artery stenosis (BCAS). When male mice were subjected to BCAS, cognitive dysfunction and white matter injury at day 28 were significantly improved in TRPM2 knock-out (TRPM2-KO) mice compared with wild-type (WT) mice, whereas hippocampal damage was not observed. There were no differences in blood-brain barrier breakdown and H2O2 production between the two genotypes at 14 and 28 d after BCAS. Cytokine production was significantly suppressed in BCAS-operated TRPM2-KO mice compared with WT mice at day 28. In addition, the number of Iba1 positive cells gradually decreased from day 14. Moreover, daily treatment with minocycline significantly improved cognitive perturbation. Surgical techniques using bone marrow chimeric mice revealed that activated Iba1-positive cells in white matter could be brain-resident microglia, not peripheral macrophages. Together, these findings suggest that microglia contribute to the aggravation of cognitive impairment by chronic cerebral hypoperfusion, and that TRPM2 may be a potential target for chronic cerebral hypoperfusion-related disorders.SIGNIFICANCE STATEMENT Chronic cerebral hypoperfusion is manifested in a wide variety of CNS diseases, including neurodegenerative and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms require clarification. Here, we used a chronic cerebral hypoperfusion mouse model to investigate whether TRPM2, a Ca2+-permeable cation channel highly expressed in immune cells, plays a destructive role in the development of chronic cerebral hypoperfusion-induced cognitive impairment, and propose a new hypothesis in which TRPM2-mediated activation of microglia, not macrophages, specifically contributes to the pathology through the aggravation of inflammatory responses. These findings shed light on the understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and are expected to provide a novel therapeutic molecule for cognitive impairment in CNS diseases. PMID- 29507147 TI - Activity-Dependent Myelination of Parvalbumin Interneurons Mediated by Axonal Morphological Plasticity. AB - Axonal myelination of neocortical pyramidal neurons is modulated dynamically by neuronal activity. Recent studies have shown that a substantial proportion of neocortical myelin content is contributed by fast-spiking, parvalbumin (PV) positive interneurons. However, it remains unknown whether the myelination of PV+ interneurons is also modulated by intrinsic activity. Here, we used cell-type specific Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in adult mice to activate a sparse population of medial prefrontal cortex (mPFC) PV+ interneurons. Using single-cell axonal reconstructions, we found that DREADD stimulated PV+ interneurons exhibited a nearly two-fold increase in total length of myelination, predominantly mediated by a parallel increase of axonal arborization and number of internodes. In contrast, the distribution of axonal interbranch segment distance and myelin internode length were not altered significantly. Topographical analysis revealed that myelination of DREADD stimulated cells extended to higher axonal branch orders while retaining a similar interbranch distance threshold for myelination. Together, our results demonstrate that chemogenetically induced neuronal activity increases the myelination of neocortical PV+ interneurons mediated at least in part by an elaboration of their axonal morphology.SIGNIFICANCE STATEMENT Myelination is the wrapping of an axon to optimize conduction velocity in an energy-efficient manner. Previous studies have shown that myelination of neocortical pyramidal neurons is experience and activity dependent. We now show that activity-dependent myelin plasticity in the adult neocortex extends to parvalbumin (PV)-expressing fast-spiking interneurons. Chemogenetic stimulation of PV interneurons in the medial prefrontal cortex (mPFC) significantly enhanced axonal myelination, which was paralleled by an increase in axonal arborization. This suggests that activity dependent axonal plasticity may involve changes in both structural morphology and myelination. Such multicomponent plasticity reveals an unexpected repertoire of anatomical parameters available for optimizing and adapting neuronal networks in response to experience. PMID- 29507146 TI - beta-Secretase BACE1 Promotes Surface Expression and Function of Kv3.4 at Hippocampal Mossy Fiber Synapses. AB - The beta-secretase beta-site APP-cleaving enzyme 1 (BACE1) is deemed a major culprit in Alzheimer's disease, but accumulating evidence indicates that there is more to the enzyme than driving the amyloidogenic processing of the amyloid precursor protein. For example, BACE1 has emerged as an important regulator of neuronal activity through proteolytic and, most unexpectedly, also through nonproteolytic interactions with several ion channels. Here, we identify and characterize the voltage-gated K+ channel 3.4 (Kv3.4) as a new and functionally relevant interaction partner of BACE1. Kv3.4 gives rise to A-type current with fast activating and inactivating kinetics and serves to repolarize the presynaptic action potential. We found that BACE1 and Kv3.4 are highly enriched and remarkably colocalized in hippocampal mossy fibers (MFs). In BACE1-/- mice of either sex, Kv3.4 surface expression was significantly reduced in the hippocampus and, in synaptic fractions thereof, Kv3.4 was specifically diminished, whereas protein levels of other presynaptic K+ channels such as KCa1.1 and KCa2.3 remained unchanged. The apparent loss of presynaptic Kv3.4 affected the strength of excitatory transmission at the MF-CA3 synapse in hippocampal slices of BACE1-/ mice when probed with the Kv3 channel blocker BDS-I. The effect of BACE1 on Kv3.4 expression and function should be bidirectional, as predicted from a heterologous expression system, in which BACE1 cotransfection produced a concomitant upregulation of Kv3.4 surface level and current based on a physical interaction between the two proteins. Our data show that, by targeting Kv3.4 to presynaptic sites, BACE1 endows the terminal with a powerful means to regulate the strength of transmitter release.SIGNIFICANCE STATEMENT The beta-secretase beta-site APP-cleaving enzyme 1 (BACE1) is infamous for its crucial role in the pathogenesis of Alzheimer's disease, but its physiological functions in the intact nervous system are only gradually being unveiled. Here, we extend previous work implicating BACE1 in the expression and function of voltage-gated Na+ and K+ channels. Specifically, we characterize voltage-gated K+ channel 3.4 (Kv3.4), a presynaptic K+ channel required for action potential repolarization, as a novel interaction partner of BACE1 at the mossy fiber (MF)-CA3 synapse of the hippocampus. BACE1 promotes surface expression of Kv3.4 at MF terminals, most likely by physically associating with the channel protein in a nonenzymatic fashion. We advance the BACE1-Kv3.4 interaction as a mechanism to strengthen the temporal control over transmitter release from MF terminals. PMID- 29507149 TI - Correction for Adonai et al., Ex vivo cell labeling with 64Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. PMID- 29507148 TI - The Encoding of Sound Source Elevation in the Human Auditory Cortex. AB - Spatial hearing is a crucial capacity of the auditory system. While the encoding of horizontal sound direction has been extensively studied, very little is known about the representation of vertical sound direction in the auditory cortex. Using high-resolution fMRI, we measured voxelwise sound elevation tuning curves in human auditory cortex and show that sound elevation is represented by broad tuning functions preferring lower elevations as well as secondary narrow tuning functions preferring individual elevation directions. We changed the ear shape of participants (male and female) with silicone molds for several days. This manipulation reduced or abolished the ability to discriminate sound elevation and flattened cortical tuning curves. Tuning curves recovered their original shape as participants adapted to the modified ears and regained elevation perception over time. These findings suggest that the elevation tuning observed in low-level auditory cortex did not arise from the physical features of the stimuli but is contingent on experience with spectral cues and covaries with the change in perception. One explanation for this observation may be that the tuning in low level auditory cortex underlies the subjective perception of sound elevation.SIGNIFICANCE STATEMENT This study addresses two fundamental questions about the brain representation of sensory stimuli: how the vertical spatial axis of auditory space is represented in the auditory cortex and whether low-level sensory cortex represents physical stimulus features or subjective perceptual attributes. Using high-resolution fMRI, we show that vertical sound direction is represented by broad tuning functions preferring lower elevations as well as secondary narrow tuning functions preferring individual elevation directions. In addition, we demonstrate that the shape of these tuning functions is contingent on experience with spectral cues and covaries with the change in perception, which may indicate that the tuning functions in low-level auditory cortex underlie the perceived elevation of a sound source. PMID- 29507150 TI - Correction for Wani et al., Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. PMID- 29507151 TI - Correction for Carkeet et al., Human vitamin B12 absorption measurement by accelerator mass spectrometry using specifically labeled 14C-cobalamin. PMID- 29507152 TI - Correction for LeGrande et al., Consistent simulations of multiple proxy responses to an abrupt climate change event. PMID- 29507153 TI - Who needs palliative care? PMID- 29507154 TI - Narrowing the treatment gap in managing opioid use disorder. PMID- 29507155 TI - Outcomes, experiences and palliative care in major stroke: a multicentre, mixed method, longitudinal study. AB - BACKGROUND: Case fatality after total anterior circulation stroke is high. Our objective was to describe the experiences and needs of patients and caregivers, and to explore whether, and how, palliative care should be integrated into stroke care. METHODS: From 3 stroke services in Scotland, we recruited a purposive sample of people with total anterior circulation stroke, and conducted serial, qualitative interviews with them and their informal and professional caregivers at 6 weeks, 6 months and 1 year. Interviews were transcribed for thematic and narrative analysis. The Palliative Care Outcome Scale, EuroQol-5D-5L and Caregiver Strain Index questionnaires were completed after interviews. We also conducted a data linkage study of all patients with anterior circulation stroke admitted to the 3 services over 6 months, which included case fatality, place of death and readmissions. RESULTS: Data linkage (n = 219) showed that 57% of patients with total anterior circulation stroke died within 6 months. The questionnaires recorded that the patients experienced immediate and persistent emotional distress and poor quality of life. We conducted 99 interviews with 34 patients and their informal and professional careers. We identified several major themes. Patients and caregivers faced death or a life not worth living. Those who survived felt grief for a former life. Professionals focused on physical rehabilitation rather than preparation for death or limited recovery. Future planning was challenging. "Palliative care" had connotations of treatment withdrawal and imminent death. INTERPRETATION: Major stroke brings likelihood of death but little preparation. Realistic planning with patients and informal caregivers should be offered, raising the possibility of death or survival with disability. Practising the principles of palliative care is needed, but the term "palliative care" should be avoided or reframed. PMID- 29507157 TI - Diffuse skin thickening, myalgias and joint stiffness in a 41-year-old man. PMID- 29507158 TI - Jamestown Canyon virus meningoencephalitis mimicking migraine with aura in a resident of Manitoba. PMID- 29507156 TI - Management of opioid use disorders: a national clinical practice guideline. PMID- 29507159 TI - Professional writers can help to improve clarity of medical writing. PMID- 29507160 TI - Opioids for chronic pain. PMID- 29507161 TI - Canada and US going opposite directions on conscientious objection for doctors. PMID- 29507162 TI - Deans of medicine urge provincial action on residency mismatch. PMID- 29507163 TI - Tough job market pushes more surgical specialists to extend training. PMID- 29507164 TI - Calculating the Real Costs of the Opioid Crisis. PMID- 29507166 TI - Opioid-Related Critical Care Resource Use in US Children's Hospitals. AB - BACKGROUND AND OBJECTIVES: There has been a rapid increase in the rate of pediatric opioid-related hospitalizations. It is unknown how this increase has impacted the use of pediatric critical care. Our objective in this study was to assess the trends in pediatric hospitalization for opioid ingestions in a cohort of US children's hospitals and, specifically, to evaluate the impact on pediatric critical care resource use. METHODS: A retrospective cohort study of the Pediatric Health Information System was performed to identify hospitalizations for opioid ingestions from 2004 to 2015. Admission to the PICU and the use of naloxone, vasopressors, and ventilation were assessed by using billing data. The primary outcome measure was the trend in the rate of PICU admission for opioid related ingestion over time, assessed by using Poisson regression. RESULTS: There were 3647 opioid-related hospitalizations in 31 hospitals; 42.9% required PICU care. The overall mortality was 1.6%, with annual deaths decreasing from 2.8% to 1.3% (P < .001). The number of opioid-related hospitalizations requiring PICU care doubled between 2004 and 2015. The rate of PICU admission for opioid-related hospitalization increased significantly, from 24.9 to 35.9 per 10 000 PICU admissions (P < .001). Among PICU admissions, 37.0% required mechanical ventilator support, and 20.3% required vasopressors. CONCLUSIONS: The US opioid crisis is negatively impacting children, and the rate of hospitalization and PICU admission for pediatric opioid ingestions is increasing. Current efforts to reduce adult opioid use have not curtailed the incidence of pediatric opioid ingestions, and additional efforts are needed to reduce preventable opioid exposure in children. PMID- 29507165 TI - Adolescent Exposure to Toxic Volatile Organic Chemicals From E-Cigarettes. AB - BACKGROUND: There is an urgent need to understand the safety of e-cigarettes with adolescents. We sought to identify the presence of chemical toxicants associated with e-cigarette use among adolescents. METHODS: Adolescent e-cigarette users (>=1 use within the past 30 days, >=10 lifetime e-cigarette use episodes) were divided into e-cigarette-only users (no cigarettes in the past 30 days, urine 4 [methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL] level <1 pg/mL of creatinine; n = 67), dual users (use of cigarettes in the past 30 days in addition to e cigarettes, NNAL level >30 pg/mL; n = 16), and never-using controls (N = 20). Saliva was collected within 24 hours of the last e-cigarette use for analysis of cotinine and urine for analysis of NNAL and levels of 8 volatile organic chemical compounds. Bivariate analyses compared e-cigarette-only users with dual users, and regression analyses compared e-cigarette-only users with dual users and controls on levels of toxicants. RESULTS: The participants were 16.4 years old on average. Urine excretion of metabolites of benzene, ethylene oxide, acrylonitrile, acrolein, and acrylamide was significantly higher in dual users versus e-cigarette-only users (all P < .05). Excretion of metabolites of acrylonitrile, acrolein, propylene oxide, acrylamide, and crotonaldehyde were significantly higher in e-cigarette-only users compared with controls (all P < .05). CONCLUSIONS: Although e-cigarette vapor may be less hazardous than tobacco smoke, our findings can be used to challenge the idea that e-cigarette vapor is safe, because many of the volatile organic compounds we identified are carcinogenic. Messaging to teenagers should include warnings about the potential risk from toxic exposure to carcinogenic compounds generated by these products. PMID- 29507167 TI - Electronic Cigarette Use and Progression From Experimentation to Established Smoking. AB - BACKGROUND: It has been shown that never-smoking adolescents who try electronic cigarettes (e-cigarettes) are at increased risk of subsequent conventional cigarette smoking. We evaluated associations between e-cigarette use and progression to established smoking among adolescents who had already tried cigarettes. METHODS: Among participants (age 12-17 years) in the nationally representative Population Assessment of Tobacco and Health survey who had smoked a cigarette (>=1 puff) but not yet smoked 100 cigarettes (N = 1295), we examined 3 outcomes at 1-year follow-up as a function of baseline e-cigarette use: (1) having smoked >=100 cigarettes (established smoking), (2) smoking during the past 30 days, and (3) both having smoked >=100 cigarettes and past 30-day smoking (current established smoking). Survey-weighted multivariable logistic regression models were fitted to obtain odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for smoking risk factors. RESULTS: Versus e-cigarette never use, having ever used e-cigarettes was positively associated with progression to established cigarette smoking (19.3% vs 9.7%), past 30-day smoking (38.8% vs 26.6%), and current established smoking (15.6% vs 7.1%). In adjusted models, e-cigarette ever use positively predicted current established smoking (OR: 1.80; 95% CI: 1.04 3.12) but did not reach statistical significance (alpha = .05) for established smoking (OR: 1.57; 95% CI: 0.99-2.49) and past 30-day smoking (OR: 1.32; 95% CI: 0.99-1.76). CONCLUSIONS: Among adolescent cigarette experimenters, using e cigarettes was positively and independently associated with progression to current established smoking, suggesting that e-cigarettes do not divert from, and may encourage, cigarette smoking in this population. PMID- 29507168 TI - Pulse dynamics in reaction-diffusion equations with strong spatially localized impurities. AB - In this article, a general geometric singular perturbation framework is developed to study the impact of strong, spatially localized, nonlinear impurities on the existence, stability and bifurcations of localized structures in systems of linear reaction-diffusion equations. By taking advantage of the multiple-scale nature of the problem, we derive algebraic conditions determining the existence and stability of pinned single- and multi-pulse solutions. Our methods enable us to explicitly control the spectrum associated with a (multi-)pulse solution. In the scalar case, we show how eigenvalues may move in and out of the essential spectrum and that Hopf bifurcations cannot occur. By contrast, even a pinned 1 pulse solution can undergo a Hopf bifurcation in a two-component system of linear reaction-diffusion equations with (only) one impurity.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507169 TI - Evans function computation for the stability of travelling waves. AB - In recent years, the Evans function has become an important tool for the determination of stability of travelling waves. This function, a Wronskian of decaying solutions of the eigenvalue equation, is useful both analytically and computationally for the spectral analysis of the linearized operator about the wave. In particular, Evans-function computation allows one to locate any unstable eigenvalues of the linear operator (if they exist); this allows one to establish spectral stability of a given wave and identify bifurcation points (loss of stability) as model parameters vary. In this paper, we review computational aspects of the Evans function and apply it to multidimensional detonation waves.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507170 TI - Stability of combustion waves in a simplified gas-solid combustion model in porous media. AB - We study the stability of the combustion waves that occur in a simplified model for injection of air into a porous medium that initially contains some solid fuel. We determine the essential spectrum of the linearized system at a travelling wave. For certain waves, we are able to use a weight function to stabilize the essential spectrum. We perform a numerical computation of the Evans function to show that some of these waves have no unstable discrete spectrum. The system is partly parabolic, so the linearized operator is not sectorial, and the weight function decays at one end. We use an extension of a recent result about partly parabolic systems that are stabilized by such weight functions to show nonlinear stability.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507171 TI - Consensus and clustering in opinion formation on networks. AB - Ideas that challenge the status quo either evaporate or dominate. The study of opinion dynamics in the socio-physics literature treats space as uniform and considers individuals in an isolated community, using ordinary differential equation (ODE) models. We extend these ODE models to include multiple communities and their interactions. These extended ODE models can be thought of as being ODEs on directed graphs. We study in detail these models to determine conditions under which there will be consensus and pluralism within the system. Most of the consensus/pluralism analysis is done for the case of one and two cities. However, we numerically show for the case of a symmetric cycle graph that an elementary bifurcation analysis provides insight into the phenomena of clustering. Moreover, for the case of a cycle graph with a hub, we discuss how having a sufficient proportion of zealots in the hub leads to the entire network sharing the opinion of the zealots.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507172 TI - Instability of pulses in gradient reaction-diffusion systems: a symplectic approach. AB - In a scalar reaction-diffusion equation, it is known that the stability of a steady state can be determined from the Maslov index, a topological invariant that counts the state's critical points. In particular, this implies that pulse solutions are unstable. We extend this picture to pulses in reaction-diffusion systems with gradient nonlinearity. In particular, we associate a Maslov index to any asymptotically constant state, generalizing existing definitions of the Maslov index for homoclinic orbits. It is shown that this index equals the number of unstable eigenvalues for the linearized evolution equation. Finally, we use a symmetry argument to show that any pulse solution must have non-zero Maslov index, and hence be unstable.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507173 TI - Periodic waves of the Lugiato-Lefever equation at the onset of Turing instability. AB - We study the existence and the stability of periodic steady waves for a nonlinear model, the Lugiato-Lefever equation, arising in optics. Starting from a detailed description of the stability properties of constant solutions, we then focus on the periodic steady waves which bifurcate at the onset of Turing instability. Using a centre manifold reduction, we analyse these Turing bifurcations, and prove the existence of periodic steady waves. This approach also allows us to conclude on the nonlinear orbital stability of these waves for co-periodic perturbations, i.e. for periodic perturbations which have the same period as the wave. This stability result is completed by a spectral stability result for general bounded perturbations. In particular, this spectral analysis shows that instabilities are always due to co-periodic perturbations.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507174 TI - On the vortices for the nonlinear Schrodinger equation in higher dimensions. AB - We consider the nonlinear Schrodinger equation in n space dimensions [Formula: see text]and study the existence and stability of standing wave solutions of the form [Formula: see text]and [Formula: see text]For n=2k, (rj ,thetaj ) are polar coordinates in [Formula: see text], j=1,2,...,k; for n=2k+1, (rj ,thetaj ) are polar coordinates in [Formula: see text], (rk ,thetak ,z) are cylindrical coordinates in [Formula: see text], j=1,2,...,k-1. We show the existence of functions phiw , which are constructed variationally as minimizers of appropriate constrained functionals. These waves are shown to be spectrally stable (with respect to perturbations of the same type), if 10. Using normal forms and spatial dynamics, we prove the existence of a family of steady-state solutions that represent a transition in space from a homogeneous state to a striped pattern state. The wavenumbers of these stripes are contained in a narrow band whose width grows linearly with the size of the jump. This represents a severe restriction from the usual constant parameter case, where the allowed band grows with the square root of the parameter. We corroborate our predictions using numerical continuation and illustrate implications on stability of growing patterns in direct simulations.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507176 TI - An energy-based stability criterion for solitary travelling waves in Hamiltonian lattices. AB - In this work, we revisit a criterion, originally proposed in Friesecke & Pego (Friesecke & Pego 2004 Nonlinearity17, 207-227. (doi:10.1088/0951715/17/1/013)), for the stability of solitary travelling waves in Hamiltonian, infinite dimensional lattice dynamical systems. We discuss the implications of this criterion from the point of view of stability theory, both at the level of the spectral analysis of the advance-delay differential equations in the co travelling frame, as well as at that of the Floquet problem arising when considering the travelling wave as a periodic orbit modulo shift. We establish the correspondence of these perspectives for the pertinent eigenvalue and Floquet multiplier and provide explicit expressions for their dependence on the velocity of the travelling wave in the vicinity of the critical point. Numerical results are used to corroborate the relevant predictions in two different models, where the stability may change twice. Some extensions, generalizations and future directions of this investigation are also discussed.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507177 TI - The phase structure of grain boundaries. AB - This article discusses numerical and analytical results on grain boundaries, which are line defects that separate roll patterns oriented in different directions. The work is set in the context of a canonical pattern-forming system, the Swift-Hohenberg (SH) equation, and of its phase diffusion equation, the regularized Cross-Newell equation. It is well known that, as the angle made by the rolls on each side of a grain boundary is decreased, dislocations appear at the core of the defect. Our goal is to shed some light on this transition, which provides an example of defect formation in a system that is variational. Numerical results of the SH equation that aim to analyse the phase structure of far-from-threshold grain boundaries are presented. These observations are then connected to properties of the associated phase diffusion equation. Outcomes of this work regarding the role played by phase derivatives in the creation of defects in pattern-forming systems, about the role of harmonic analysis in understanding the phase structure in such systems, and future research directions are also discussed.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507178 TI - Nonlinear modulation near the Lighthill instability threshold in 2+1 Whitham theory. AB - The dispersionless Whitham modulation equations in 2+1 (two space dimensions and time) are reviewed and the instabilities identified. The modulation theory is then reformulated, near the Lighthill instability threshold, with a slow phase, moving frame and different scalings. The resulting nonlinear phase modulation equation near the Lighthill surfaces is a geometric form of the 2+1 two-way Boussinesq equation. This equation is universal in the same sense as Whitham theory. Moreover, it is dispersive, and it has a wide range of interesting multi periodic, quasi-periodic and multi-pulse localized solutions. For illustration the theory is applied to a complex nonlinear 2+1 Klein-Gordon equation which has two Lighthill surfaces in the manifold of periodic travelling waves.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507179 TI - Partial differential systems with non-local nonlinearities: generation and solutions. AB - We develop a method for generating solutions to large classes of evolutionary partial differential systems with non-local nonlinearities. For arbitrary initial data, the solutions are generated from the corresponding linearized equations. The key is a Fredholm integral equation relating the linearized flow to an auxiliary linear flow. It is analogous to the Marchenko integral equation in integrable systems. We show explicitly how this can be achieved through several examples, including reaction-diffusion systems with non-local quadratic nonlinearities and the nonlinear Schrodinger equation with a non-local cubic nonlinearity. In each case, we demonstrate our approach with numerical simulations. We discuss the effectiveness of our approach and how it might be extended.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507180 TI - Spectral analysis of localized rotating waves in parabolic systems. AB - In this paper, we study the spectra and Fredholm properties of Ornstein-Uhlenbeck operators [Formula: see text]where [Formula: see text] is the profile of a rotating wave satisfying [Formula: see text] as [Formula: see text], the map [Formula: see text] is smooth and the matrix [Formula: see text] has eigenvalues with positive real parts and commutes with the limit matrix [Formula: see text] The matrix [Formula: see text] is assumed to be skew-symmetric with eigenvalues (lambda1,...,lambda d )=(+/-isigma1,...,+/-isigmak ,0,...,0). The spectra of these linearized operators are crucial for the nonlinear stability of rotating waves in reaction-diffusion systems. We prove under appropriate conditions that every [Formula: see text] satisfying the dispersion relation [Formula: see text]belongs to the essential spectrum [Formula: see text] in Lp For values Re lambda to the right of the spectral bound for [Formula: see text], we show that the operator [Formula: see text] is Fredholm of index 0, solve the identification problem for the adjoint operator [Formula: see text] and formulate the Fredholm alternative. Moreover, we show that the set [Formula: see text]belongs to the point spectrum [Formula: see text] in Lp We determine the associated eigenfunctions and show that they decay exponentially in space. As an application, we analyse spinning soliton solutions which occur in the Ginzburg Landau equation and compute their numerical spectra as well as associated eigenfunctions. Our results form the basis for investigating the nonlinear stability of rotating waves in higher space dimensions and truncations to bounded domains. This article is part of the themed issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507181 TI - Stability of nonlinear waves and patterns and related topics. AB - Periodic and localized travelling waves such as wave trains, pulses, fronts and patterns of more complex structure often occur in natural and experimentally built systems. In mathematics, these objects are realized as solutions of nonlinear partial differential equations. The existence, dynamic properties and bifurcations of those solutions are of interest. In particular, their stability is important for applications, as the waves that are observable are usually stable. When the waves are unstable, further investigation is warranted of the way the instability is exhibited, i.e. the nature of the instability, and also coherent structures that appear as a result of an instability of travelling waves. A variety of analytical, numerical and hybrid techniques are used to study travelling waves and their properties.This article is part of the theme issue 'Stability of nonlinear waves and patterns and related topics'. PMID- 29507182 TI - Transcription Activation Domains of the Yeast Factors Met4 and Ino2: Tandem Activation Domains with Properties Similar to the Yeast Gcn4 Activator. AB - Eukaryotic transcription activation domains (ADs) are intrinsically disordered polypeptides that typically interact with coactivator complexes, leading to stimulation of transcription initiation, elongation, and chromatin modifications. Here we examined the properties of two strong and conserved yeast ADs: Met4 and Ino2. Both factors have tandem ADs that were identified by conserved sequence and functional studies. While the AD function of both factors depended on hydrophobic residues, Ino2 further required key conserved acidic and polar residues for optimal function. Binding studies showed that the ADs bound multiple Med15 activator-binding domains (ABDs) with similar orders of micromolar affinity and similar but distinct thermodynamic properties. Protein cross-linking data show that no unique complex was formed upon Met4-Med15 binding. Rather, we observed heterogeneous AD-ABD contacts with nearly every possible AD-ABD combination. Many of these properties are similar to those observed with yeast activator Gcn4, which forms a large heterogeneous, dynamic, and fuzzy complex with Med15. We suggest that this molecular behavior is common among eukaryotic activators. PMID- 29507183 TI - AMPK Inhibits ULK1-Dependent Autophagosome Formation and Lysosomal Acidification via Distinct Mechanisms. AB - Autophagy maintains metabolism in response to starvation, but each nutrient is sensed distinctly. Amino acid deficiency suppresses mechanistic target of rapamycin complex 1 (MTORC1), while glucose deficiency promotes AMP-activated protein kinase (AMPK). The MTORC1 and AMPK signaling pathways converge onto the ULK1/2 autophagy initiation complex. Here, we show that amino acid starvation promoted formation of ULK1- and sequestosome 1/p62-positive early autophagosomes. Autophagosome initiation was controlled by MTORC1 sensing glutamine, leucine, and arginine levels together. In contrast, glucose starvation promoted AMPK activity, phosphorylation of ULK1 Ser555, and LC3-II accumulation, but with dynamics consistent with a block in autophagy flux. We studied the flux pathway and found that starvation of amino acid but not of glucose activated lysosomal acidification, which occurred independently of autophagy and ULK1. In addition to lack of activation, glucose starvation inhibited the ability of amino acid starvation to activate both autophagosome formation and the lysosome. Activation of AMPK and phosphorylation of ULK1 were determined to specifically inhibit autophagosome formation. AMPK activation also was sufficient to prevent lysosome acidification. These results indicate concerted but distinct AMPK-dependent mechanisms to suppress early and late phases of autophagy. PMID- 29507184 TI - Developmental Decline in the MicroRNA 199a (miR-199a)/miR-214 Cluster in Human Fetal Lung Promotes Type II Cell Differentiation by Upregulating Key Transcription Factors. AB - The major surfactant protein, SP-A (a product of the SFTPA gene), serves as a marker of type II pneumocyte differentiation and surfactant synthesis. SFTPA expression in cultured human fetal lung (HFL) epithelial cells is upregulated by hormones that increase cyclic AMP (cAMP) and activate TTF-1/NKX2.1 and NF-kappaB. To further define mechanisms for type II cell differentiation and induction of SP A, we investigated roles of microRNAs (miRNAs). Using microarray to identify differentially expressed miRNAs in HFL epithelial cells during type II cell differentiation in culture, we observed that members of the miRNA 199a (miR 199a)/miR-214 cluster were significantly downregulated during differentiation. Validated and predicted targets of miR-199a-3p/miR-199a-5p and miR-214, which serve roles in type II cell differentiation (COX-2, NF-kappaB p50/p65, and CREB1), and the CREB1 target, C/EBPbeta, were coordinately upregulated. Accordingly, overexpression of miR-199a-5p, miR-199a-3p, or miR-214 mimics in cultured HFL epithelial cells decreased COX-2, NF-kappaB p50/p65, CREB1, and C/EBPbeta proteins, with an associated inhibition of SP-A expression. Interestingly, overexpression of the EMT factor, ZEB1, which declines during cAMP induced type II cell differentiation, increased pri-miR-199a and reduced the expression of the targets NF-kappaB/p50 and COX-2. Collectively, these findings suggest that the developmental decline in miR-199a/miR-214 in HFL causes increased expression of critical targets that enhance type II cell differentiation and SP-A expression. PMID- 29507185 TI - LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis. AB - The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DC), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished LXR-dependent induction of DC chemotaxis. Using the LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for efficient emigration of DCs in response to chemotactic signals during inflammation. PMID- 29507186 TI - Increased O-GlcNAcylation of SNAP29 drives arsenic-induced autophagic dysfunction. AB - Environmental exposure to arsenic is linked to adverse health effects including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here, we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8-bearing lysosomes. Mechanistically, arsenic inhibits SNARE complex formation, at least in part, by enhancing O-GlcNAcylation of SNAP29. Transfection of O-GlcNAcylation defective, but not wild type, SNAP29 into CRISPR-mediated SNAP29 knockout cells abolishes arsenic-mediated autophagy inhibition. These findings reveal a mechanism by which low-levels of arsenic perturb proteostasis through inhibition of SNARE complex formation, providing a possible therapeutic target for disease intervention in the more than 200 million people exposed to unsafe levels of arsenic. PMID- 29507187 TI - Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells. AB - In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by beta catenin, which has previously been shown to associate with MED12. Importantly, beta-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4. PMID- 29507188 TI - Correction for D'Asaro et al., Ocean convergence and the dispersion of flotsam. PMID- 29507189 TI - MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) causes a zoonotic respiratory disease of global public health concern, and dromedary camels are the only proven source of zoonotic infection. Although MERS-CoV infection is ubiquitous in dromedaries across Africa as well as in the Arabian Peninsula, zoonotic disease appears confined to the Arabian Peninsula. MERS-CoVs from Africa have hitherto been poorly studied. We genetically and phenotypically characterized MERS-CoV from dromedaries sampled in Morocco, Burkina Faso, Nigeria, and Ethiopia. Viruses from Africa (clade C) are phylogenetically distinct from contemporary viruses from the Arabian Peninsula (clades A and B) but remain antigenically similar in microneutralization tests. Viruses from West (Nigeria, Burkina Faso) and North (Morocco) Africa form a subclade, C1, that shares clade-defining genetic signatures including deletions in the accessory gene ORF4b Compared with human and camel MERS-CoV from Saudi Arabia, virus isolates from Burkina Faso (BF785) and Nigeria (Nig1657) had lower virus replication competence in Calu-3 cells and in ex vivo cultures of human bronchus and lung. BF785 replicated to lower titer in lungs of human DPP4-transduced mice. A reverse genetics-derived recombinant MERS-CoV (EMC) lacking ORF4b elicited higher type I and III IFN responses than the isogenic EMC virus in Calu-3 cells. However, ORF4b deletions may not be the major determinant of the reduced replication competence of BF785 and Nig1657. Genetic and phenotypic differences in West African viruses may be relevant to zoonotic potential. There is an urgent need for studies of MERS-CoV at the animal-human interface. PMID- 29507190 TI - Long-term urban carbon dioxide observations reveal spatial and temporal dynamics related to urban characteristics and growth. AB - Cities are concentrated areas of CO2 emissions and have become the foci of policies for mitigation actions. However, atmospheric measurement networks suitable for evaluating urban emissions over time are scarce. Here we present a unique long-term (decadal) record of CO2 mole fractions from five sites across Utah's metropolitan Salt Lake Valley. We examine "excess" CO2 above background conditions resulting from local emissions and meteorological conditions. We ascribe CO2 trends to changes in emissions, since we did not find long-term trends in atmospheric mixing proxies. Three contrasting CO2 trends emerged across urban types: negative trends at a residential-industrial site, positive trends at a site surrounded by rapid suburban growth, and relatively constant CO2 over time at multiple sites in the established, residential, and commercial urban core. Analysis of population within the atmospheric footprints of the different sites reveals approximately equal increases in population influencing the observed CO2, implying a nonlinear relationship with CO2 emissions: Population growth in rural areas that experienced suburban development was associated with increasing emissions while population growth in the developed urban core was associated with stable emissions. Four state-of-the-art global-scale emission inventories also have a nonlinear relationship with population density across the city; however, in contrast to our observations, they all have nearly constant emissions over time. Our results indicate that decadal scale changes in urban CO2 emissions are detectable through monitoring networks and constitute a valuable approach to evaluate emission inventories and studies of urban carbon cycles. PMID- 29507192 TI - Acceleration of tropical cyclogenesis by self-aggregation feedbacks. AB - Idealized simulations of tropical moist convection have revealed that clouds can spontaneously clump together in a process called self-aggregation. This results in a state where a moist cloudy region with intense deep convection is surrounded by extremely dry subsiding air devoid of deep convection. Because of the idealized settings of the simulations where it was discovered, the relevance of self-aggregation to the real world is still debated. Here, we show that self aggregation feedbacks play a leading-order role in the spontaneous genesis of tropical cyclones in cloud-resolving simulations. Those feedbacks accelerate the cyclogenesis process by a factor of 2, and the feedbacks contributing to the cyclone formation show qualitative and quantitative agreement with the self aggregation process. Once the cyclone is formed, wind-induced surface heat exchange (WISHE) effects dominate, although we find that self-aggregation feedbacks have a small but nonnegligible contribution to the maintenance of the mature cyclone. Our results suggest that self-aggregation, and the framework developed for its study, can help shed more light into the physical processes leading to cyclogenesis and cyclone intensification. In particular, our results point out the importance of the longwave radiative cooling outside the cyclone. PMID- 29507191 TI - dCas9-targeted locus-specific protein isolation method identifies histone gene regulators. AB - Eukaryotic gene regulation is a complex process, often coordinated by the action of tens to hundreds of proteins. Although previous biochemical studies have identified many components of the basal machinery and various ancillary factors involved in gene regulation, numerous gene-specific regulators remain undiscovered. To comprehensively survey the proteome directing gene expression at a specific genomic locus of interest, we developed an in vitro nuclease-deficient Cas9 (dCas9)-targeted chromatin-based purification strategy, called "CLASP" (Cas9 locus-associated proteome), to identify and functionally test associated gene regulatory factors. Our CLASP method, coupled to mass spectrometry and functional screens, can be efficiently adapted for isolating associated regulatory factors in an unbiased manner targeting multiple genomic loci across different cell types. Here, we applied our method to isolate the Drosophila melanogaster histone cluster in S2 cells to identify several factors including Vig and Vig2, two proteins that bind and regulate core histone H2A and H3 mRNA via interaction with their 3' UTRs. PMID- 29507194 TI - Correction for Haines et al., New twist on artificial muscles. PMID- 29507193 TI - Biogeographical disparity in the functional diversity and redundancy of corals. AB - Corals are major contributors to a range of key ecosystem functions on tropical reefs, including calcification, photosynthesis, nutrient cycling, and the provision of habitat structure. The abundance of corals is declining at multiple scales, and the species composition of assemblages is responding to escalating human pressures, including anthropogenic global warming. An urgent challenge is to understand the functional consequences of these shifts in abundance and composition in different biogeographical contexts. While global patterns of coral species richness are well known, the biogeography of coral functions in provinces and domains with high and low redundancy is poorly understood. Here, we quantify the functional traits of all currently recognized zooxanthellate coral species (n = 821) in both the Indo-Pacific and Atlantic domains to examine the relationships between species richness and the diversity and redundancy of functional trait space. We find that trait diversity is remarkably conserved (>75% of the global total) along latitudinal and longitudinal gradients in species richness, falling away only in species-poor provinces (n < 200), such as the Persian Gulf (52% of the global total), Hawaii (37%), the Caribbean (26%), and the East-Pacific (20%), where redundancy is also diminished. In the more species-poor provinces, large and ecologically important areas of trait space are empty, or occupied by just a few, highly distinctive species. These striking biogeographical differences in redundancy could affect the resilience of critical reef functions and highlight the vulnerability of relatively depauperate, peripheral locations, which are often a low priority for targeted conservation efforts. PMID- 29507196 TI - Uranium isotope evidence for two episodes of deoxygenation during Oceanic Anoxic Event 2. AB - Oceanic Anoxic Event 2 (OAE 2), occurring ~94 million years ago, was one of the most extreme carbon cycle and climatic perturbations of the Phanerozoic Eon. It was typified by a rapid rise in atmospheric CO2, global warming, and marine anoxia, leading to the widespread devastation of marine ecosystems. However, the precise timing and extent to which oceanic anoxic conditions expanded during OAE 2 remains unresolved. We present a record of global ocean redox changes during OAE 2 using a combined geochemical and carbon cycle modeling approach. We utilize a continuous, high-resolution record of uranium isotopes in pelagic and platform carbonate sediments to quantify the global extent of seafloor anoxia during OAE 2. This dataset is then compared with a dynamic model of the coupled global carbon, phosphorus, and uranium cycles to test hypotheses for OAE 2 initiation. This unique approach highlights an intra-OAE complexity that has previously been underconstrained, characterized by two expansions of anoxia separated by an episode of globally significant reoxygenation coincident with the "Plenus Cold Event." Each anoxic expansion event was likely driven by rapid atmospheric CO2 injections from multiphase Large Igneous Province activity. PMID- 29507195 TI - Rare variants in axonogenesis genes connect three families with sound-color synesthesia. AB - Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound-color (auditory-visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes-COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2 associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences. PMID- 29507197 TI - B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. AB - Induced B7-H1 expression in the tumor microenvironment initiates adaptive resistance, which impairs immune functions and leads to tumor escape from immune destruction. Antibody blockade of the B7-H1/PD-1 interaction overcomes adaptive resistance, leading to regression of advanced human cancers and survival benefits in a significant fraction of patients. In addition to cancer cells, B7-H1 is expressed on dendritic cells (DCs), but its role in DC functions is less understood. DCs can present multiple antigens (Ags) to stimulate dominant or subdominant T cell responses. Here, we show that immunization with multiple tumor Ag-loaded DCs, in the absence of B7-H1, vastly enhances cytotoxic T lymphocyte (CTL) responses to dominant Ag. In sharp contrast, CTL responses to subdominant Ag were paradoxically suppressed, facilitating outgrowth of tumor variants carrying only subdominant Ag. Suppressed CTL responses to subdominant Ag are largely due to the loss of B7-H1-mediated protection of DCs from the lysis of CTL against dominant Ag. Therefore, B7-H1 expression on DCs may help maintain the diversity of CTL responses to multiple tumor Ags. Interestingly, a split immunization approach, which presents dominant and subdominant Ags with different DCs, promoted CTL responses to all Ags and prevented tumor escape in murine tumor models. These findings have implications for the design of future combination cancer immunotherapies. PMID- 29507198 TI - BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. AB - Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies. PMID- 29507199 TI - Antidepression action of BDNF requires and is mimicked by Galphai1/3 expression in the hippocampus. AB - Stress-related alterations in brain-derived neurotrophic factor (BDNF) expression, a neurotrophin that plays a key role in synaptic plasticity, are believed to contribute to the pathophysiology of depression. Here, we show that in a chronic mild stress (CMS) model of depression the Galphai1 and Galphai3 subunits of heterotrimeric G proteins are down-regulated in the hippocampus, a key limbic structure associated with major depressive disorder. We provide evidence that Galphai1 and Galphai3 (Galphai1/3) are required for the activation of TrkB downstream signaling pathways. In mouse embryonic fibroblasts (MEFs) and CNS neurons, Galphai1/3 knockdown inhibited BDNF-induced tropomyosin-related kinase B (TrkB) endocytosis, adaptor protein activation, and Akt-mTORC1 and Erk MAPK signaling. Functional studies show that Galphai1 and Galphai3 knockdown decreases the number of dendrites and dendritic spines in hippocampal neurons. In vivo, hippocampal Galphai1/3 knockdown after bilateral microinjection of lentiviral constructs containing Galphai1 and Galphai3 shRNA elicited depressive behaviors. Critically, exogenous expression of Galphai3 in the hippocampus reversed depressive behaviors in CMS mice. Similar results were observed in Galphai1/Galphai3 double-knockout mice, which exhibited severe depressive behaviors. These results demonstrate that heterotrimeric Galphai1 and Galphai3 proteins are essential for TrkB signaling and that disruption of Galphai1 or Galphai3 function could contribute to depressive behaviors. PMID- 29507200 TI - Integration of speed and time for estimating time to contact. AB - To coordinate movements with events in a dynamic environment the brain has to anticipate when those events occur. A classic example is the estimation of time to contact (TTC), that is, when an object reaches a target. It is thought that TTC is estimated from kinematic variables. For example, a tennis player might use an estimate of distance (d) and speed (v) to estimate TTC (TTC = d/v). However, the tennis player may instead estimate TTC as twice the time it takes for the ball to move from the serve line to the net line. This latter strategy does not rely on kinematics and instead computes TTC solely from temporal cues. Which of these two strategies do humans use to estimate TTC? Considering that both speed and time estimates are inherently uncertain and the ability of the human brain to combine different sources of information, we hypothesized that humans estimate TTC by integrating speed information with temporal cues. We evaluated this hypothesis systematically using psychophysics and Bayesian modeling. Results indicated that humans rely on both speed information and temporal cues and integrate them to optimize their TTC estimates when both cues are present. These findings suggest that the brain's timing mechanisms are actively engaged when interacting with dynamic stimuli. PMID- 29507201 TI - Dynamic patterns of cortical expansion during folding of the preterm human brain. AB - During the third trimester of human brain development, the cerebral cortex undergoes dramatic surface expansion and folding. Physical models suggest that relatively rapid growth of the cortical gray matter helps drive this folding, and structural data suggest that growth may vary in both space (by region on the cortical surface) and time. In this study, we propose a unique method to estimate local growth from sequential cortical reconstructions. Using anatomically constrained multimodal surface matching (aMSM), we obtain accurate, physically guided point correspondence between younger and older cortical reconstructions of the same individual. From each pair of surfaces, we calculate continuous, smooth maps of cortical expansion with unprecedented precision. By considering 30 preterm infants scanned two to four times during the period of rapid cortical expansion (28-38 wk postmenstrual age), we observe significant regional differences in growth across the cortical surface that are consistent with the emergence of new folds. Furthermore, these growth patterns shift over the course of development, with noninjured subjects following a highly consistent trajectory. This information provides a detailed picture of dynamic changes in cortical growth, connecting what is known about patterns of development at the microscopic (cellular) and macroscopic (folding) scales. Since our method provides specific growth maps for individual brains, we are also able to detect alterations due to injury. This fully automated surface analysis, based on tools freely available to the brain-mapping community, may also serve as a useful approach for future studies of abnormal growth due to genetic disorders, injury, or other environmental variables. PMID- 29507202 TI - Near-atomic cryo-EM imaging of a small protein displayed on a designed scaffolding system. AB - Current single-particle cryo-electron microscopy (cryo-EM) techniques can produce images of large protein assemblies and macromolecular complexes at atomic level detail without the need for crystal growth. However, proteins of smaller size, typical of those found throughout the cell, are not presently amenable to detailed structural elucidation by cryo-EM. Here we use protein design to create a modular, symmetrical scaffolding system to make protein molecules of typical size suitable for cryo-EM. Using a rigid continuous alpha helical linker, we connect a small 17-kDa protein (DARPin) to a protein subunit that was designed to self-assemble into a cage with cubic symmetry. We show that the resulting construct is amenable to structural analysis by single-particle cryo-EM, allowing us to identify and solve the structure of the attached small protein at near atomic detail, ranging from 3.5- to 5-A resolution. The result demonstrates that proteins considerably smaller than the theoretical limit of 50 kDa for cryo-EM can be visualized clearly when arrayed in a rigid fashion on a symmetric designed protein scaffold. Furthermore, because the amino acid sequence of a DARPin can be chosen to confer tight binding to various other protein or nucleic acid molecules, the system provides a future route for imaging diverse macromolecules, potentially broadening the application of cryo-EM to proteins of typical size in the cell. PMID- 29507204 TI - Physical and geometric constraints shape the labyrinth-like nasal cavity. AB - The nasal cavity is a vital component of the respiratory system that heats and humidifies inhaled air in all vertebrates. Despite this common function, the shapes of nasal cavities vary widely across animals. To understand this variability, we here connect nasal geometry to its function by theoretically studying the airflow and the associated scalar exchange that describes heating and humidification. We find that optimal geometries, which have minimal resistance for a given exchange efficiency, have a constant gap width between their side walls, while their overall shape can adhere to the geometric constraints imposed by the head. Our theory explains the geometric variations of natural nasal cavities quantitatively, and we hypothesize that the trade-off between high exchange efficiency and low resistance to airflow is the main driving force shaping the nasal cavity. Our model further explains why humans, whose nasal cavities evolved to be smaller than expected for their size, become obligate oral breathers in aerobically challenging situations. PMID- 29507203 TI - Enzymatic reconstitution of ribosomal peptide backbone thioamidation. AB - Methyl-coenzyme M reductase (MCR) is an essential enzyme found strictly in methanogenic and methanotrophic archaea. MCR catalyzes a reversible reaction involved in the production and consumption of the potent greenhouse gas methane. The alpha-subunit of this enzyme (McrA) contains several unusual posttranslational modifications, including the only known naturally occurring example of protein thioamidation. We have recently demonstrated by genetic deletion and mass spectrometry that the tfuA and ycaO genes of Methanosarcina acetivorans are involved in thioamidation of Gly465 in the MCR active site. Modification to thioGly has been postulated to stabilize the active site structure of MCR. Herein, we report the in vitro reconstitution of ribosomal peptide thioamidation using heterologously expressed and purified YcaO and TfuA proteins from M. acetivorans Like other reported YcaO proteins, this reaction is ATP-dependent but requires an external sulfide source. We also reconstitute the thioamidation activity of two TfuA-independent YcaOs from the hyperthermophilic methanogenic archaea Methanopyrus kandleri and Methanocaldococcus jannaschii Using these proteins, we demonstrate the basis for substrate recognition and regioselectivity of thioamide formation based on extensive mutagenesis, biochemical, and binding studies. Finally, we report nucleotide-free and nucleotide-bound crystal structures for the YcaO proteins from M. kandleri Sequence and structure-guided mutagenesis with subsequent biochemical evaluation have allowed us to assign roles for residues involved in thioamidation and confirm that the reaction proceeds via backbone O-phosphorylation. These data assign a new biochemical reaction to the YcaO superfamily and paves the way for further characterization of additional peptide backbone posttranslational modifications. PMID- 29507205 TI - Cyclin-dependent kinase activity is required for type I interferon production. AB - Recognition of nucleic acids results in the production of type I IFNs, which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes. In a search for modulators of this pathway, we discovered an unexpected requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and IFN stimulated gene expression. CDKs are not required for the initial nucleic acid sensing leading to IFN-beta mRNA induction, nor for the response to exogenous IFN alpha/beta, but are critical for IFN-beta release into culture supernatants, suggesting a posttranscriptional role for CDKs in type I IFN production. In the absence of CDK activity, we demonstrate a translational block specific for IFN beta, in which IFN-beta mRNA is removed from the actively translating polysomes, while the distribution of other cellular mRNAs or global translation rates are unaffected. Our findings reveal a critical role for CDKs in the translation of IFN-beta. PMID- 29507206 TI - Genetic signatures of microbial altruism and cheating in social amoebas in the wild. AB - Many microbes engage in social interactions. Some of these have come to play an important role in the study of cooperation and conflict, largely because, unlike most animals, they can be genetically manipulated and experimentally evolved. However, whereas animal social behavior can be observed and assessed in natural environments, microbes usually cannot, so we know little about microbial social adaptations in nature. This has led to some difficult-to-resolve controversies about social adaptation even for well-studied traits such as bacterial quorum sensing, siderophore production, and biofilms. Here we use molecular signatures of population genetics and molecular evolution to address controversies over the existence of altruism and cheating in social amoebas. First, we find signatures of rapid adaptive molecular evolution that are consistent with social conflict being a significant force in nature. Second, we find population-genetic signatures of purifying selection to support the hypothesis that the cells that form the sterile stalk evolve primarily through altruistic kin selection rather than through selfish direct reproduction. Our results show how molecular signatures can provide insight into social adaptations that cannot be observed in their natural context, and they support the hypotheses that social amoebas in the wild are both altruists and cheaters. PMID- 29507208 TI - Opinion: How to tackle the childcare-conference conundrum. PMID- 29507207 TI - How cognitive and reactive fear circuits optimize escape decisions in humans. AB - Flight initiation distance (FID), the distance at which an organism flees from an approaching threat, is an ecological metric of cost-benefit functions of escape decisions. We adapted the FID paradigm to investigate how fast- or slow-attacking "virtual predators" constrain escape decisions. We show that rapid escape decisions rely on "reactive fear" circuits in the periaqueductal gray and midcingulate cortex (MCC), while protracted escape decisions, defined by larger buffer zones, were associated with "cognitive fear" circuits, which include posterior cingulate cortex, hippocampus, and the ventromedial prefrontal cortex, circuits implicated in more complex information processing, cognitive avoidance strategies, and behavioral flexibility. Using a Bayesian decision-making model, we further show that optimization of escape decisions under rapid flight were localized to the MCC, a region involved in adaptive motor control, while the hippocampus is implicated in optimizing decisions that update and control slower escape initiation. These results demonstrate an unexplored link between defensive survival circuits and their role in adaptive escape decisions. PMID- 29507209 TI - Linking imaging to omics utilizing image-guided tissue extraction. AB - Phenotypic heterogeneity is commonly observed in diseased tissue, specifically in tumors. Multimodal imaging technologies can reveal tissue heterogeneity noninvasively in vivo, enabling imaging-based profiling of receptors, metabolism, morphology, or function on a macroscopic scale. In contrast, in vitro multiomics, immunohistochemistry, or histology techniques accurately characterize these heterogeneities in the cellular and subcellular scales in a more comprehensive but ex vivo manner. The complementary in vivo and ex vivo information would provide an enormous potential to better characterize a disease. However, this requires spatially accurate coregistration of these data by image-driven sampling as well as fast sample-preparation methods. Here, a unique image-guided milling machine and workflow for precise extraction of tissue samples from small laboratory animals or excised organs has been developed and evaluated. The samples can be delineated on tomographic images as volumes of interest and can be extracted with a spatial accuracy better than 0.25 mm. The samples remain cooled throughout the procedure to ensure metabolic stability, a precondition for accurate in vitro analysis. PMID- 29507210 TI - Conserved mechanism of cell-wall synthase regulation revealed by the identification of a new PBP activator in Pseudomonas aeruginosa. AB - Penicillin-binding proteins (PBPs) are synthases required to build the essential peptidoglycan (PG) cell wall surrounding most bacterial cells. The mechanisms regulating the activity of these enzymes to control PG synthesis remain surprisingly poorly defined given their status as key antibiotic targets. Several years ago, the outer-membrane lipoprotein EcLpoB was identified as a critical activator of Escherichia coli PBP1b (EcPBP1b), one of the major PG synthases of this organism. Activation of EcPBP1b is mediated through the association of EcLpoB with a regulatory domain on EcPBP1b called UB2H. Notably, Pseudomonas aeruginosa also encodes PBP1b (PaPBP1b), which possesses a UB2H domain, but this bacterium lacks an identifiable LpoB homolog. We therefore searched for potential PaPBP1b activators and identified a lipoprotein unrelated to LpoB that is required for the in vivo activity of PaPBP1b. We named this protein LpoP and found that it interacts directly with PaPBP1b in vitro and is conserved in many Gram-negative species. Importantly, we also demonstrated that PaLpoP-PaPBP1b as well as an equivalent protein pair from Acinetobacter baylyi can fully substitute for EcLpoB-EcPBP1b in E. coli for PG synthesis. Furthermore, we show that amino acid changes in PaPBP1b that bypass the PaLpoP requirement map to similar locations in the protein as changes promoting EcLpoB bypass in EcPBP1b. Overall, our results indicate that, although different Gram-negative bacteria activate their PBP1b synthases with distinct lipoproteins, they stimulate the activity of these important drug targets using a conserved mechanism. PMID- 29507211 TI - Strain-induced high-temperature perovskite ferromagnetic insulator. AB - Ferromagnetic insulators are required for many new magnetic devices, such as dissipationless quantum-spintronic devices, magnetic tunneling junctions, etc. Ferromagnetic insulators with a high Curie temperature and a high-symmetry structure are critical integration with common single-crystalline oxide films or substrates. So far, the commonly used ferromagnetic insulators mostly possess low symmetry structures associated with a poor growth quality and widespread properties. The few known high-symmetry materials either have extremely low Curie temperatures (<=16 K), or require chemical doping of an otherwise antiferromagnetic matrix. Here we present compelling evidence that the LaCoO3 single-crystalline thin film under tensile strain is a rare undoped perovskite ferromagnetic insulator with a remarkably high TC of up to 90 K. Both experiments and first-principles calculations demonstrate tensile-strain-induced ferromagnetism which does not exist in bulk LaCoO3 The ferromagnetism is strongest within a nearly stoichiometric structure, disappearing when the Co2+ defect concentration reaches about 10%. Significant impact of the research includes demonstration of a strain-induced high-temperature ferromagnetic insulator, successful elevation of the transition over the liquid-nitrogen temperature, and high potential for integration into large-area device fabrication processes. PMID- 29507212 TI - RNAi is a critical determinant of centromere evolution in closely related fungi. AB - The centromere DNA locus on a eukaryotic chromosome facilitates faithful chromosome segregation. Despite performing such a conserved function, centromere DNA sequence as well as the organization of sequence elements is rapidly evolving in all forms of eukaryotes. The driving force that facilitates centromere evolution remains an enigma. Here, we studied the evolution of centromeres in closely related species in the fungal phylum of Basidiomycota. Using ChIP-seq analysis of conserved inner kinetochore proteins, we identified centromeres in three closely related Cryptococcus species: two of which are RNAi-proficient, while the other lost functional RNAi. We find that the centromeres in the RNAi deficient species are significantly shorter than those of the two RNAi-proficient species. While centromeres are LTR retrotransposon-rich in all cases, the RNAi deficient species lost all full-length retroelements from its centromeres. In addition, centromeres in RNAi-proficient species are associated with a significantly higher level of cytosine DNA modifications compared with those of RNAi-deficient species. Furthermore, when an RNAi-proficient Cryptococcus species and its RNAi-deficient mutants were passaged under similar conditions, the centromere length was found to be occasionally shortened in RNAi mutants. In silico analysis of predicted centromeres in a group of closely related Ustilago species, also belonging to the Basidiomycota, were found to have undergone a similar transition in the centromere length in an RNAi-dependent fashion. Based on the correlation found in two independent basidiomycetous species complexes, we present evidence suggesting that the loss of RNAi and cytosine DNA methylation triggered transposon attrition, which resulted in shortening of centromere length during evolution. PMID- 29507214 TI - Biomass smoke from southern Africa can significantly enhance the brightness of stratocumulus over the southeastern Atlantic Ocean. AB - Marine stratocumulus clouds cover nearly one-quarter of the ocean surface and thus play an extremely important role in determining the global radiative balance. The semipermanent marine stratocumulus deck over the southeastern Atlantic Ocean is of particular interest, because of its interactions with seasonal biomass burning aerosols that are emitted in southern Africa. Understanding the impacts of biomass burning aerosols on stratocumulus clouds and the implications for regional and global radiative balance is still very limited. Previous studies have focused on assessing the magnitude of the warming caused by solar scattering and absorption by biomass burning aerosols over stratocumulus (the direct radiative effect) or cloud adjustments to the direct radiative effect (the semidirect effect). Here, using a nested modeling approach in conjunction with observations from multiple satellites, we demonstrate that cloud condensation nuclei activated from biomass burning aerosols entrained into the stratocumulus (the microphysical effect) can play a dominant role in determining the total radiative forcing at the top of the atmosphere, compared with their direct and semidirect radiative effects. Biomass burning aerosols over the region and period with heavy loadings can cause a substantial cooling (daily mean -8.05 W m-2), primarily as a result of clouds brightening by reducing the cloud droplet size (the Twomey effect) and secondarily through modulating the diurnal cycle of cloud liquid water path and coverage (the cloud lifetime effect). Our results highlight the importance of realistically representing the interactions of stratocumulus with biomass burning aerosols in global climate models in this region. PMID- 29507213 TI - Liver X receptor beta regulates the development of the dentate gyrus and autistic like behavior in the mouse. AB - The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor beta (LXRbeta) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRbeta in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRbeta-null mice. In addition, LXRbeta deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRbeta in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRbeta-deficient mice. PMID- 29507215 TI - Exploring modular allostery via interchangeable regulatory domains. AB - Most proteins comprise two or more domains from a limited suite of protein families. These domains are often rearranged in various combinations through gene fusion events to evolve new protein functions, including the acquisition of protein allostery through the incorporation of regulatory domains. The enzyme 3 deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS) is the first enzyme of aromatic amino acid biosynthesis and displays a diverse range of allosteric mechanisms. DAH7PSs adopt a common architecture with a shared (beta/alpha)8 catalytic domain which can be attached to an ACT-like or a chorismate mutase regulatory domain that operates via distinct mechanisms. These respective domains confer allosteric regulation by controlling DAH7PS function in response to ligand Tyr or prephenate. Starting with contemporary DAH7PS proteins, two protein chimeras were created, with interchanged regulatory domains. Both engineered proteins were catalytically active and delivered new functional allostery with switched ligand specificity and allosteric mechanisms delivered by their nonhomologous regulatory domains. This interchangeability of protein domains represents an efficient method not only to engineer allostery in multidomain proteins but to create a new bifunctional enzyme. PMID- 29507216 TI - Molecular mechanism of ATP versus GTP selectivity of adenylate kinase. AB - Enzymatic substrate selectivity is critical for the precise control of metabolic pathways. In cases where chemically related substrates are present inside cells, robust mechanisms of substrate selectivity are required. Here, we report the mechanism utilized for catalytic ATP versus GTP selectivity during adenylate kinase (Adk) -mediated phosphorylation of AMP. Using NMR spectroscopy we found that while Adk adopts a catalytically competent and closed structural state in complex with ATP, the enzyme is arrested in a catalytically inhibited and open state in complex with GTP. X-ray crystallography experiments revealed that the interaction interfaces supporting ATP and GTP recognition, in part, are mediated by coinciding residues. The mechanism provides an atomic view on how the cellular GTP pool is protected from Adk turnover, which is important because GTP has many specialized cellular functions. In further support of this mechanism, a structure function analysis enabled by synthesis of ATP analogs suggests that a hydrogen bond between the adenine moiety and the backbone of the enzyme is vital for ATP selectivity. The importance of the hydrogen bond for substrate selectivity is likely general given the conservation of its location and orientation across the family of eukaryotic protein kinases. PMID- 29507217 TI - High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism. AB - Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome. PMID- 29507218 TI - Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein coupled receptor. AB - Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular G-protein-coupling site, with a minimum rmsd of 2.48 A in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR-nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein-protein interactions. PMID- 29507219 TI - Manipulating thermal emission with spatially static fluctuating fields in arbitrarily shaped epsilon-near-zero bodies. AB - The control and manipulation of thermal fields is a key scientific and technological challenge, usually addressed with nanophotonic structures with a carefully designed geometry. Here, we theoretically investigate a different strategy based on epsilon-near-zero (ENZ) media. We demonstrate that thermal emission from ENZ bodies is characterized by the excitation of spatially static fluctuating fields, which can be resonantly enhanced with the addition of dielectric particles. The "spatially static" character of these temporally dynamic fields leads to enhanced spatial coherence on the surface of the body, resulting in directive thermal emission. By contrast with other approaches, this property is intrinsic to ENZ media and it is not tied to its geometry. This point is illustrated with effects such as geometry-invariant resonant emission, beamforming by boundary deformation, and independence with respect to the position of internal particles. We numerically investigate a practical implementation based on a silicon carbide body containing a germanium rod. PMID- 29507220 TI - Brief history of US debt limits before 1939. AB - Between 1776 and 1920, the US Congress designed more than 200 distinct securities and stated the maximum amount of each that the Treasury could sell. Between 1917 and 1939, Congress gradually delegated all decisions about designing US debt instruments to the Treasury. In 1939, Congress began imposing a limit on the par value of total federal debt outstanding. By summing Congressional borrowing authorizations outstanding each year for each bond, we construct a time series of implied federal debt limits before 1939. PMID- 29507221 TI - Discovery of a hexagonal ultradense hydrous phase in (Fe,Al)OOH. AB - A deep lower-mantle (DLM) water reservoir depends on availability of hydrous minerals which can store and transport water into the DLM without dehydration. Recent discoveries found hydrous phases AlOOH (Z = 2) with a CaCl2-type structure and FeOOH (Z = 4) with a cubic pyrite-type structure stable under the high pressure-temperature (P-T) conditions of the DLM. Our experiments at 107-136 GPa and 2,400 K have further demonstrated that (Fe,Al)OOH is stabilized in a hexagonal lattice. By combining powder X-ray-diffraction techniques with multigrain indexation, we are able to determine this hexagonal hydrous phase with a = 10.5803(6) A and c = 2.5897(3) A at 110 GPa. Hexagonal (Fe,Al)OOH can transform to the cubic pyrite structure at low T with the same density. The hexagonal phase can be formed when delta-AlOOH incorporates FeOOH produced by reaction between water and Fe, which may store a substantial quantity of water in the DLM. PMID- 29507222 TI - N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. AB - The conjugation of amino acids to the protein N termini is universally observed in eukaryotes and prokaryotes, yet its functions remain poorly understood. In eukaryotes, the amino acid l-arginine (l-Arg) is conjugated to N-terminal Asp (Nt Asp), Glu, Gln, Asn, and Cys, directly or associated with posttranslational modifications. Following Nt-arginylation, the Nt-Arg is recognized by UBR boxes of N-recognins such as UBR1, UBR2, UBR4/p600, and UBR5/EDD, leading to substrate ubiquitination and proteasomal degradation via the N-end rule pathway. It has been a mystery, however, why studies for the past five decades identified only a handful of Nt-arginylated substrates in mammals, although five of 20 principal amino acids are eligible for arginylation. Here, we show that the Nt-Arg functions as a bimodal degron that directs substrates to either the ubiquitin (Ub)-proteasome system (UPS) or macroautophagy depending on physiological states. In normal conditions, the arginylated forms of proteolytic cleavage products, D101-CDC6 and D1156-BRCA1, are targeted to UBR box-containing N-recognins and degraded by the proteasome. However, when proteostasis by the UPS is perturbed, their Nt-Arg redirects these otherwise cellular wastes to macroautophagy through its binding to the ZZ domain of the autophagic adaptor p62/STQSM/Sequestosome-1. Upon binding to the Nt-Arg, p62 acts as an autophagic N-recognin that undergoes self-polymerization, facilitating cargo collection and lysosomal degradation of p62-cargo complexes. A chemical mimic of Nt-Arg redirects Ub-conjugated substrates from the UPS to macroautophagy and promotes their lysosomal degradation. Our results suggest that the Nt-Arg proteome of arginylated proteins contributes to reprogramming global proteolytic flux under stresses. PMID- 29507223 TI - ATP-dependent substrate reduction at an [Fe8S9] double-cubane cluster. AB - Chemically demanding reductive conversions in biology, such as the reduction of dinitrogen to ammonia or the Birch-type reduction of aromatic compounds, depend on Fe/S-cluster-containing ATPases. These reductions are typically catalyzed by two-component systems, in which an Fe/S-cluster-containing ATPase energizes an electron to reduce a metal site on the acceptor protein that drives the reductive reaction. Here, we show a two-component system featuring a double-cubane [Fe8S9] cluster [{Fe4S4(SCys)3}2(MU2-S)]. The double-cubane-cluster-containing enzyme is capable of reducing small molecules, such as acetylene (C2H2), azide (N3-), and hydrazine (N2H4). We thus present a class of metalloenzymes akin in fold, metal clusters, and reactivity to nitrogenases. PMID- 29507224 TI - Measuring the potential for sustainable intensification of aquaculture in Bangladesh using life cycle assessment. AB - Food production is a major driver of global environmental change and the overshoot of planetary sustainability boundaries. Greater affluence in developing nations and human population growth are also increasing demand for all foods, and for animal proteins in particular. Consequently, a growing body of literature calls for the sustainable intensification of food production, broadly defined as "producing more using less". Most assessments of the potential for sustainable intensification rely on only one or two indicators, meaning that ecological trade offs among impact categories that occur as production intensifies may remain unaccounted for. The present study addresses this limitation using life cycle assessment (LCA) to quantify six local and global environmental consequences of intensifying aquaculture production in Bangladesh. Production data are from a unique survey of 2,678 farms, and results show multidirectional associations between the intensification of aquaculture production and its environmental impacts. Intensification (measured in material and economic output per unit primary area farmed) is positively correlated with acidification, eutrophication, and ecotoxicological impacts in aquatic ecosystems; negatively correlated with freshwater consumption; and indifferent with regard to global warming and land occupation. As production intensifies, the geographical locations of greenhouse gas (GHG) emissions, acidifying emissions, freshwater consumption, and land occupation shift from the immediate vicinity of the farm to more geographically dispersed telecoupled locations across the globe. Simple changes in fish farming technology and management practices that could help make the global transition to more intensive forms of aquaculture be more sustainable are identified. PMID- 29507225 TI - Long-term nutrient reductions lead to the unprecedented recovery of a temperate coastal region. AB - Humans strongly impact the dynamics of coastal systems, yet surprisingly few studies mechanistically link management of anthropogenic stressors and successful restoration of nearshore habitats over large spatial and temporal scales. Such examples are sorely needed to ensure the success of ecosystem restoration efforts worldwide. Here, we unite 30 consecutive years of watershed modeling, biogeochemical data, and comprehensive aerial surveys of Chesapeake Bay, United States to quantify the cascading effects of anthropogenic impacts on submersed aquatic vegetation (SAV), an ecologically and economically valuable habitat. We employ structural equation models to link land use change to higher nutrient loads, which in turn reduce SAV cover through multiple, independent pathways. We also show through our models that high biodiversity of SAV consistently promotes cover, an unexpected finding that corroborates emerging evidence from other terrestrial and marine systems. Due to sustained management actions that have reduced nitrogen concentrations in Chesapeake Bay by 23% since 1984, SAV has regained 17,000 ha to achieve its highest cover in almost half a century. Our study empirically demonstrates that nutrient reductions and biodiversity conservation are effective strategies to aid the successful recovery of degraded systems at regional scales, a finding which is highly relevant to the utility of environmental management programs worldwide. PMID- 29507226 TI - Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells. AB - The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1 Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma. PMID- 29507227 TI - Guanidinium export is the primal function of SMR family transporters. AB - The small multidrug resistance (SMR) family of membrane proteins is prominent because of its rare dual topology architecture, simplicity, and small size. Its best studied member, EmrE, is an important model system in several fields related to membrane protein biology, from evolution to mechanism. But despite decades of work on these multidrug transporters, the native function of the SMR family has remained a mystery, and many highly similar SMR homologs do not transport drugs at all. Here we establish that representative SMR proteins, selected from each of the major clades in the phylogeny, function as guanidinium ion exporters. Drug exporting SMRs are all clustered in a single minority clade. Using membrane transport experiments, we show that these guanidinium exporters, which we term Gdx, are very selective for guanidinium and strictly and stoichiometrically couple its export with the import of two protons. These findings draw important mechanistic distinctions with the notably promiscuous and weakly coupled drug exporters like EmrE. PMID- 29507228 TI - Solution NMR structure of yeast Rcf1, a protein involved in respiratory supercomplex formation. AB - The Saccharomyces cerevisiae respiratory supercomplex factor 1 (Rcf1) protein is located in the mitochondrial inner membrane where it is involved in formation of supercomplexes composed of respiratory complexes III and IV. We report the solution structure of Rcf1, which forms a dimer in dodecylphosphocholine (DPC) micelles, where each monomer consists of a bundle of five transmembrane (TM) helices and a short flexible soluble helix (SH). Three TM helices are unusually charged and provide the dimerization interface consisting of 10 putative salt bridges, defining a "charge zipper" motif. The dimer structure is supported by molecular dynamics (MD) simulations in DPC, although the simulations show a more dynamic dimer interface than the NMR data. Furthermore, CD and NMR data indicate that Rcf1 undergoes a structural change when reconstituted in liposomes, which is supported by MD data, suggesting that the dimer structure is unstable in a planar membrane environment. Collectively, these data indicate a dynamic monomer-dimer equilibrium. Furthermore, the Rcf1 dimer interacts with cytochrome c, suggesting a role as an electron-transfer bridge between complexes III and IV. The Rcf1 structure will help in understanding its functional roles at a molecular level. PMID- 29507229 TI - Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition. AB - Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression. PMID- 29507230 TI - Transmembrane E3 ligase RNF183 mediates ER stress-induced apoptosis by degrading Bcl-xL. AB - The accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and triggers the unfolded protein response (UPR). Failure to resolve ER stress leads to apoptotic cell death via a yet unclear mechanism. Here, we show that RNF183, a membrane-spanning RING finger protein, localizes to the ER and exhibits classic E3 ligase activities. Sustained ER stress induced by different treatments increases RNF183 protein levels posttranscriptionally in an IRE1alpha dependent manner. Activated IRE1 reduces the level of miR-7, which increases the stability of RNF183 transcripts. In addition, overexpression of RNF183 leads to increased apoptosis and its depletion alleviates ER stress-induced apoptosis. Furthermore, RNF183 interacts with Bcl-xL, an antiapoptotic member of the Bcl-2 family, and polyubiquitinates Bcl-xL for degradation. Thus, RNF183 plays an important role in executing programmed cell death upon prolonged ER stress, likely by inducing apoptosis through Bcl-xL. PMID- 29507231 TI - Conformational transitions of the sodium-dependent sugar transporter, vSGLT. AB - Sodium-dependent transporters couple the flow of Na+ ions down their electrochemical potential gradient to the uphill transport of various ligands. Many of these transporters share a common core structure composed of a five-helix inverted repeat and deliver their cargo utilizing an alternating-access mechanism. A detailed characterization of inward-facing conformations of the Na+ dependent sugar transporter from Vibrio parahaemolyticus (vSGLT) has previously been reported, but structural details on additional conformations and on how Na+ and ligand influence the equilibrium between other states remains unknown. Here, double electron-electron resonance spectroscopy, structural modeling, and molecular dynamics are utilized to deduce ligand-dependent equilibria shifts of vSGLT in micelles. In the absence and presence of saturating amounts of Na+, vSGLT favors an inward-facing conformation. Upon binding both Na+ and sugar, the equilibrium shifts toward either an outward-facing or occluded conformation. While Na+ alone does not stabilize the outward-facing state, gating charge calculations together with a kinetic model of transport suggest that the resting negative membrane potential of the cell, absent in detergent-solubilized samples, may stabilize vSGLT in an outward-open conformation where it is poised for binding external sugars. In total, these findings provide insights into ligand induced conformational selection and delineate the transport cycle of vSGLT. PMID- 29507232 TI - BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells. AB - Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Abeta42, an amyloid forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-betaH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-betaH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of Drosophila melanogaster results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes. PMID- 29507233 TI - Chirality-controlled spontaneous twisting of crystals due to thermal topochemical reaction. AB - Crystals that show mechanical response against various stimuli are of great interest. These stimuli induce polymorphic transitions, isomerizations, or chemical reactions in the crystal and the strain generated between the daughter and parent domains is transcribed into mechanical response. We observed that the crystals of modified dipeptide LL (N3-l-Ala-l-Val-NHCH2C=CH) undergo spontaneous twisting to form right-handed twisted crystals not only at room temperature but also at 0 degrees C over time. Using various spectroscopic techniques, we have established that the twisting is due to the spontaneous topochemical azide-alkyne cycloaddition (TAAC) reaction at room temperature or lower temperatures. The rate of twisting can be increased by heating, exploiting the faster kinetics of the TAAC reaction at higher temperatures. To address the role of molecular chirality in the direction of twisting the enantiomer of dipeptide LL, N3-d-Ala-d-Val NHCH2C=CH (DD), was synthesized and topochemical reactivity and mechanoresponse of its crystals were studied. We have found that dipeptide DD not only underwent TAAC reaction, giving 1,4-triazole-linked pseudopolypeptides of d-amino acids, but also underwent twisting with opposite handedness (left-handed twisting), establishing the role of molecular chirality in controlling the direction of mechanoresponse. This paper reports (i) a mechanical response due to a thermal reaction and (ii) a spontaneous mechanical response in crystals and (iii) explains the role of molecular chirality in the handedness of the macroscopic mechanical response. PMID- 29507234 TI - Allostery revealed within lipid binding events to membrane proteins. AB - Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein-lipid assemblies. Despite this inherent complexity, the identification of specific protein-lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as allostery [Monod J, Wyman J, Changeux JP (1965) J Mol Biol 12:88-118]. Here, we use native mass spectrometry to determine the allosteric nature of heterogeneous lipid binding events to membrane proteins. We monitored individual lipid binding events to the ammonia channel (AmtB) from Escherichia coli, enabling determination of their equilibrium binding constants. We found that different lipid pairs display a range of allosteric modulation. In particular, the binding of phosphatidylethanolamine and cardiolipin-like molecules to AmtB exhibited the largest degree of allosteric modulation, inspiring us to determine the cocrystal structure of AmtB in this lipid environment. The 2.45-A resolution structure reveals a cardiolipin-like molecule bound to each subunit of the trimeric complex. Mutation of a single residue in AmtB abolishes the positive allosteric modulation observed for binding phosphatidylethanolamine and cardiolipin-like molecules. Our results demonstrate that specific lipid-protein interactions can act as allosteric modulators for the binding of different lipid types to integral membrane proteins. PMID- 29507235 TI - Single-molecule analysis of phospholipid scrambling by TMEM16F. AB - Transmembrane protein 16F (TMEM16F) is a Ca2+-dependent phospholipid scramblase that translocates phospholipids bidirectionally between the leaflets of the plasma membrane. Phospholipid scrambling of TMEM16F causes exposure of phosphatidylserine in activated platelets to induce blood clotting and in differentiated osteoblasts to promote bone mineralization. Despite the importance of TMEM16F-mediated phospholipid scrambling in various biological reactions, the fundamental features of the scrambling reaction remain elusive due to technical difficulties in the preparation of a platform for assaying scramblase activity in vitro. Here, we established a method to express and purify mouse TMEM16F as a dimeric molecule by constructing a stable cell line and developed a microarray containing membrane bilayers with asymmetrically distributed phospholipids as a platform for single-molecule scramblase assays. The purified TMEM16F was integrated into the microarray, and monitoring of phospholipid translocation showed that a single TMEM16F molecule transported phospholipids nonspecifically between the membrane bilayers in a Ca2+-dependent manner. Thermodynamic analysis of the reaction indicated that TMEM16F transported 4.5 * 104 lipids per second at 25 degrees C, with an activation free energy of 47 kJ/mol. These biophysical features were similar to those observed with channels, which transport substrates by facilitating diffusion, and supported the stepping-stone model for the TMEM16F phospholipid scramblase. PMID- 29507236 TI - Layered dynamic regulation for improving metabolic pathway productivity in Escherichia coli. AB - Microbial production of value-added chemicals from biomass is a sustainable alternative to chemical synthesis. To improve product titer, yield, and selectivity, the pathways engineered into microbes must be optimized. One strategy for optimization is dynamic pathway regulation, which modulates expression of pathway-relevant enzymes over the course of fermentation. Metabolic engineers have used dynamic regulation to redirect endogenous flux toward product formation, balance the production and consumption rates of key intermediates, and suppress production of toxic intermediates until later in the fermentation. Most cases, however, have utilized a single strategy for dynamically regulating pathway fluxes. Here we layer two orthogonal, autonomous, and tunable dynamic regulation strategies to independently modulate expression of two different enzymes to improve production of D-glucaric acid from a heterologous pathway. The first strategy uses a previously described pathway-independent quorum sensing system to dynamically knock down glycolytic flux and redirect carbon into production of glucaric acid, thereby switching cells from "growth" to "production" mode. The second strategy, developed in this work, uses a biosensor for myo-inositol (MI), an intermediate in the glucaric acid production pathway, to induce expression of a downstream enzyme upon sufficient buildup of MI. The latter, pathway-dependent strategy leads to a 2.5-fold increase in titer when used in isolation and a fourfold increase when added to a strain employing the former, pathway-independent regulatory system. The dual-regulation strain produces nearly 2 g/L glucaric acid, representing the highest glucaric acid titer reported to date in Escherichia coli K-12 strains. PMID- 29507237 TI - Cholesterol provides nonsacrificial protection of membrane lipids from chemical damage at air-water interface. AB - The role of cholesterol in bilayer and monolayer lipid membranes has been of great interest. On the biophysical front, cholesterol significantly increases the order of the lipid packing, lowers the membrane permeability, and maintains membrane fluidity by forming liquid-ordered-phase lipid rafts. However, direct observation of any influence on membrane chemistry related to these cholesterol induced physical properties has been absent. Here we report that the addition of 30 mol % cholesterol to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1 palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) monolayers at the air-water interface greatly reduces the oxidation and ester linkage cleavage chemistries initiated by potent chemicals such as OH radicals and HCl vapor, respectively. These results shed light on the indispensable chemoprotective function of cholesterol in lipid membranes. Another significant finding is that OH oxidation of unsaturated lipids generates Criegee intermediate, which is an important radical involved in many atmospheric processes. PMID- 29507238 TI - Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates. AB - Recent evidence has shown that, in addition to rigidity, the viscous response of the extracellular matrix (ECM) significantly affects the behavior and function of cells. However, the mechanism behind such mechanosensitivity toward viscoelasticity remains unclear. In this study, we systematically examined the dynamics of motor clutches (i.e., focal adhesions) formed between the cell and a viscoelastic substrate using analytical methods and direct Monte Carlo simulation. Interestingly, we observe that, for low ECM rigidity, maximum cell spreading is achieved at an optimal level of viscosity in which the substrate relaxation time falls between the timescale for clutch binding and its characteristic binding lifetime. That is, viscosity serves to stiffen soft substrates on a timescale faster than the clutch off-rate, which enhances cell ECM adhesion and cell spreading. On the other hand, for substrates that are stiff, our model predicts that viscosity will not influence cell spreading, since the bound clutches are saturated by the elevated stiffness. The model was tested and validated using experimental measurements on three different material systems and explained the different observed effects of viscosity on each substrate. By capturing the mechanism by which substrate viscoelasticity affects cell spreading across a wide range of material parameters, our analytical model provides a useful tool for designing biomaterials that optimize cellular adhesion and mechanosensing. PMID- 29507239 TI - Simultaneous imaging and functional studies reveal a tight correlation between calcium and actin networks. AB - Tip-growing cells elongate in a highly polarized manner via focused secretion of flexible cell-wall material. Calcium has been implicated as a vital factor in regulating the deposition of cell-wall material. However, deciphering the molecular and mechanistic calcium targets in vivo has remained challenging. Here, we investigated intracellular calcium dynamics in the moss Physcomitrella patens, which provides a system with an abundant source of genetically identical tip growing cells, excellent cytology, and a large molecular genetic tool kit. To visualize calcium we used a genetically encoded cytosolic FRET probe, revealing a fluctuating tipward gradient with a complex oscillatory profile. Wavelet analysis coupled with a signal-sifting algorithm enabled the quantitative comparison of the calcium behavior in cells where growth was inhibited mechanically, pharmacologically, or genetically. We found that cells with suppressed growth have calcium oscillatory profiles with longer frequencies, suggesting that there is a feedback between the calcium gradient and growth. To investigate the mechanistic basis for this feedback we simultaneously imaged cytosolic calcium and actin, which has been shown to be essential for tip growth. We found that high cytosolic calcium promotes disassembly of a tip-focused actin spot, while low calcium promotes assembly. In support of this, abolishing the calcium gradient resulted in dramatic actin accumulation at the tip. Together these data demonstrate that tipward calcium is quantitatively linked to actin accumulation in vivo and that the moss P. patens provides a powerful system to uncover mechanistic links between calcium, actin, and growth. PMID- 29507240 TI - Surface chemical heterogeneity modulates silica surface hydration. AB - An in-depth knowledge of the interaction of water with amorphous silica is critical to fundamental studies of interfacial hydration water, as well as to industrial processes such as catalysis, nanofabrication, and chromatography. Silica has a tunable surface comprising hydrophilic silanol groups and moderately hydrophobic siloxane groups that can be interchanged through thermal and chemical treatments. Despite extensive studies of silica surfaces, the influence of surface hydrophilicity and chemical topology on the molecular properties of interfacial water is not well understood. In this work, we controllably altered the surface silanol density, and measured surface water diffusivity using Overhauser dynamic nuclear polarization (ODNP) and complementary silica-silica interaction forces across water using a surface forces apparatus (SFA). The results show that increased silanol density generally leads to slower water diffusivity and stronger silica-silica repulsion at short aqueous separations (less than ~4 nm). Both techniques show sharp changes in hydration properties at intermediate silanol densities (2.0-2.9 nm-2). Molecular dynamics simulations of model silica-water interfaces corroborate the increase in water diffusivity with silanol density, and furthermore show that even on a smooth and crystalline surface at a fixed silanol density, adjusting the spatial distribution of silanols results in a range of surface water diffusivities spanning ~10%. We speculate that a critical silanol cluster size or connectivity parameter could explain the sharp transition in our results, and can modulate wettability, colloidal interactions, and surface reactions, and thus is a phenomenon worth further investigation on silica and chemically heterogeneous surfaces. PMID- 29507241 TI - Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors. AB - The pH (low) insertion peptides (pHLIPs) target acidity at the surfaces of cancer cells and show utility in a wide range of applications, including tumor imaging and intracellular delivery of therapeutic agents. Here we report pHLIP constructs that significantly improve the targeted delivery of agents into tumor cells. The investigated constructs include pHLIP bundles (conjugates consisting of two or four pHLIP peptides linked by polyethylene glycol) and Var3 pHLIPs containing either the nonstandard amino acid, gamma-carboxyglutamic acid, or a glycine leucine-leucine motif. The performance of the constructs in vitro and in vivo was compared with previous pHLIP variants. A wide range of experiments was performed on nine constructs including (i) biophysical measurements using steady-state and kinetic fluorescence, circular dichroism, and oriented circular dichroism to study the pH-dependent insertion of pHLIP variants across the membrane lipid bilayer; (ii) cell viability assays to gauge the pH-dependent potency of peptide toxin constructs by assessing the intracellular delivery of the polar, cell impermeable cargo molecule amanitin at physiological and low pH (pH 7.4 and 6.0, respectively); and (iii) tumor targeting and biodistribution measurements using fluorophore-peptide conjugates in a breast cancer mouse model. The main principles of the design of pHLIP variants for a range of medical applications are discussed. PMID- 29507242 TI - hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons. AB - Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ~3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance. PMID- 29507243 TI - Stable iridium dinuclear heterogeneous catalysts supported on metal-oxide substrate for solar water oxidation. AB - Atomically dispersed catalysts refer to substrate-supported heterogeneous catalysts featuring one or a few active metal atoms that are separated from one another. They represent an important class of materials ranging from single-atom catalysts (SACs) and nanoparticles (NPs). While SACs and NPs have been extensively reported, catalysts featuring a few atoms with well-defined structures are poorly studied. The difficulty in synthesizing such structures has been a critical challenge. Here we report a facile photochemical method that produces catalytic centers consisting of two Ir metal cations, bridged by O and stably bound to a support. Direct evidence unambiguously supporting the dinuclear nature of the catalysts anchored on alpha-Fe2O3 is obtained by aberration corrected scanning transmission electron microscopy (AC-STEM). Experimental and computational results further reveal that the threefold hollow binding sites on the OH-terminated surface of alpha-Fe2O3 anchor the catalysts to provide outstanding stability against detachment or aggregation. The resulting catalysts exhibit high activities toward H2O photooxidation. PMID- 29507245 TI - Coherent Lagrangian swirls among submesoscale motions. AB - The emergence of coherent Lagrangian swirls (CLSs) among submesoscale motions in the ocean is illustrated. This is done by applying recent nonlinear dynamics tools for Lagrangian coherence detection on a surface flow realization produced by a data-assimilative submesoscale-permitting ocean general circulation model simulation of the Gulf of Mexico. Both mesoscale and submesoscale CLSs are extracted. These extractions prove the relevance of coherent Lagrangian eddies detected in satellite-altimetry-based geostrophic flow data for the arguably more realistic ageostrophic multiscale flow. PMID- 29507244 TI - Deciphering the reading of the genetic code by near-cognate tRNA. AB - Some codons of the genetic code can be read not only by cognate, but also by near cognate tRNAs. This flexibility is thought to be conferred mainly by a mismatch between the third base of the codon and the first of the anticodon (the so-called "wobble" position). However, this simplistic explanation underestimates the importance of nucleotide modifications in the decoding process. Using a system in which only near-cognate tRNAs can decode a specific codon, we investigated the role of six modifications of the anticodon, or adjacent nucleotides, of the tRNAs specific for Tyr, Gln, Lys, Trp, Cys, and Arg in Saccharomyces cerevisiae. Modifications almost systematically rendered these tRNAs able to act as near cognate tRNAs at stop codons, even though they involve noncanonical base pairs, without markedly affecting their ability to decode cognate or near-cognate sense codons. These findings reveal an important effect of modifications to tRNA decoding with implications for understanding the flexibility of the genetic code. PMID- 29507246 TI - The seasonality of nonpolio enteroviruses in the United States: Patterns and drivers. AB - Nonpolio enteroviruses are diverse and common viruses that can circulate year round but tend to peak in summer. Although most infections are asymptomatic, they can result in a wide range of neurological and other diseases. Many serotypes circulate every year, and different serotypes predominate in different years, but the drivers of their geographical and temporal dynamics are not understood. We use national enterovirus surveillance data collected by the US Centers for Disease Control and Prevention during 1983-2013, as well as demographic and climatic data for the same period, to study the patterns and drivers of the seasonality of these infections. We find that the seasonal pattern of enterovirus cases is spatially structured in the United States and similar to that observed for historical prevaccination poliomyelitis (1931-1954). We identify latitudinal gradients for the amplitude and the timing of the peak of cases, meaning that those are more regularly distributed all year-round in the south and have a more pronounced peak that arrives later toward the north. The peak is estimated to occur between July and September across the United States, and 1 month earlier than that for historical poliomyelitis. Using mixed-effects models, we find that climate, but not demography, is likely to drive the seasonal pattern of enterovirus cases and that the dew point temperature alone explains ~30% of the variation in the intensity of transmission. Our study contributes to a better understanding of the epidemiology of enteroviruses, demonstrates important similarities in their circulation dynamics with polioviruses, and identifies potential drivers of their seasonality. PMID- 29507248 TI - Low agreement among reviewers evaluating the same NIH grant applications. AB - Obtaining grant funding from the National Institutes of Health (NIH) is increasingly competitive, as funding success rates have declined over the past decade. To allocate relatively scarce funds, scientific peer reviewers must differentiate the very best applications from comparatively weaker ones. Despite the importance of this determination, little research has explored how reviewers assign ratings to the applications they review and whether there is consistency in the reviewers' evaluation of the same application. Replicating all aspects of the NIH peer-review process, we examined 43 individual reviewers' ratings and written critiques of the same group of 25 NIH grant applications. Results showed no agreement among reviewers regarding the quality of the applications in either their qualitative or quantitative evaluations. Although all reviewers received the same instructions on how to rate applications and format their written critiques, we also found no agreement in how reviewers "translated" a given number of strengths and weaknesses into a numeric rating. It appeared that the outcome of the grant review depended more on the reviewer to whom the grant was assigned than the research proposed in the grant. This research replicates the NIH peer-review process to examine in detail the qualitative and quantitative judgments of different reviewers examining the same application, and our results have broad relevance for scientific grant peer review. PMID- 29507247 TI - Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection. AB - Treatment of bacterial infections is becoming a serious clinical challenge due to the global dissemination of multidrug antibiotic resistance, necessitating the search for alternative treatments to disarm the virulence mechanisms underlying these infections. Uropathogenic Escherichia coli (UPEC) employs multiple chaperone-usher pathway pili tipped with adhesins with diverse receptor specificities to colonize various host tissues and habitats. For example, UPEC F9 pili specifically bind galactose or N-acetylgalactosamine epitopes on the kidney and inflamed bladder. Using X-ray structure-guided methods, virtual screening, and multiplex ELISA arrays, we rationally designed aryl galactosides and N acetylgalactosaminosides that inhibit the F9 pilus adhesin FmlH. The lead compound, 29beta-NAc, is a biphenyl N-acetyl-beta-galactosaminoside with a Ki of ~90 nM, representing a major advancement in potency relative to the characteristically weak nature of most carbohydrate-lectin interactions. 29beta NAc binds tightly to FmlH by engaging the residues Y46 through edge-to-face pi stacking with its A-phenyl ring, R142 in a salt-bridge interaction with its carboxylate group, and K132 through water-mediated hydrogen bonding with its N acetyl group. Administration of 29beta-NAc in a mouse urinary tract infection (UTI) model significantly reduced bladder and kidney bacterial burdens, and coadministration of 29beta-NAc and mannoside 4Z269, which targets the type 1 pilus adhesin FimH, resulted in greater elimination of bacteria from the urinary tract than either compound alone. Moreover, FmlH specifically binds healthy human kidney tissue in a 29beta-NAc-inhibitable manner, suggesting a key role for F9 pili in human kidney colonization. Thus, these glycoside antagonists of FmlH represent a rational antivirulence strategy for UPEC-mediated UTI treatment. PMID- 29507250 TI - Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis. AB - Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3'-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3' phosphoadenosine 5'-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF 2alpha. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis. PMID- 29507249 TI - Structural basis for the role of serine-rich repeat proteins from Lactobacillus reuteri in gut microbe-host interactions. AB - Lactobacillus reuteri, a Gram-positive bacterial species inhabiting the gastrointestinal tract of vertebrates, displays remarkable host adaptation. Previous mutational analyses of rodent strain L. reuteri 100-23C identified a gene encoding a predicted surface-exposed serine-rich repeat protein (SRRP100-23) that was vital for L. reuteri biofilm formation in mice. SRRPs have emerged as an important group of surface proteins on many pathogens, but no structural information is available in commensal bacteria. Here we report the 2.00-A and 1.92-A crystal structures of the binding regions (BRs) of SRRP100-23 and SRRP53608 from L. reuteri ATCC 53608, revealing a unique beta-solenoid fold in this important adhesin family. SRRP53608-BR bound to host epithelial cells and DNA at neutral pH and recognized polygalacturonic acid (PGA), rhamnogalacturonan I, or chondroitin sulfate A at acidic pH. Mutagenesis confirmed the role of the BR putative binding site in the interaction of SRRP53608-BR with PGA. Long molecular dynamics simulations showed that SRRP53608-BR undergoes a pH-dependent conformational change. Together, these findings provide mechanistic insights into the role of SRRPs in host-microbe interactions and open avenues of research into the use of biofilm-forming probiotics against clinically important pathogens. PMID- 29507251 TI - Communicating the nutritional value of sugar in Drosophila. AB - Sweet-insensitive Drosophila mutants are unable to readily identify sugar. In presence of wild-type (WT) flies, however, these mutant flies demonstrated a marked increase in their preference for nutritive sugar. Real-time recordings of starved WT flies revealed that these flies discharge a drop from their gut end after consuming nutritive sugars, but not nonnutritive sugars. We proposed that the drop may contain a molecule(s) named calorie-induced secreted factor (CIF), which serves as a signal to inform other flies about its nutritional value. Consistent with this, we observed a robust preference of flies for nutritive sugar containing CIF over nutritive sugar without CIF. Feeding appears to be a prerequisite for the release of CIF, given that fed flies did not produce it. Additionally, correlation analyses and pharmacological approaches suggest that the nutritional value, rather than the taste, of the consumed sugar correlates strongly with the amount (or intensity) of the released CIF. We observed that the release of this attractant signal requires the consumption of macronutrients, specifically nutritive sugars and l-enantiomer essential amino acids (l-eAAs), but it is negligibly released when flies are fed nonnutritive sugars, unnatural d enantiomer essential amino acids (d-eAAs), fatty acids, alcohol, or salts. Finally, CIF (i) is not detected by the olfactory system, (ii) is not influenced by the sex of the fly, and (iii) is not limited to one species of Drosophila. PMID- 29507253 TI - Correction for Muretta et al., A posttranslational modification of the mitotic kinesin Eg5 that enhances its mechanochemical coupling and alters its mitotic function. PMID- 29507252 TI - Structural basis for the alternating access mechanism of the cation diffusion facilitator YiiP. AB - YiiP is a dimeric antiporter from the cation diffusion facilitator family that uses the proton motive force to transport Zn2+ across bacterial membranes. Previous work defined the atomic structure of an outward-facing conformation, the location of several Zn2+ binding sites, and hydrophobic residues that appear to control access to the transport sites from the cytoplasm. A low-resolution cryo EM structure revealed changes within the membrane domain that were associated with the alternating access mechanism for transport. In the current work, the resolution of this cryo-EM structure has been extended to 4.1 A. Comparison with the X-ray structure defines the differences between inward-facing and outward facing conformations at an atomic level. These differences include rocking and twisting of a four-helix bundle that harbors the Zn2+ transport site and controls its accessibility within each monomer. As previously noted, membrane domains are closely associated in the dimeric structure from cryo-EM but dramatically splayed apart in the X-ray structure. Cysteine crosslinking was used to constrain these membrane domains and to show that this large-scale splaying was not necessary for transport activity. Furthermore, dimer stability was not compromised by mutagenesis of elements in the cytoplasmic domain, suggesting that the extensive interface between membrane domains is a strong determinant of dimerization. As with other secondary transporters, this interface could provide a stable scaffold for movements of the four-helix bundle that confers alternating access of these ions to opposite sides of the membrane. PMID- 29507255 TI - What Have We Learned from the CSIRO National NBN Telehealth Trial? AB - The CSIRO National NBN Telehealth Trial investigated the effects of introducing at home telemonitoring of vital signs for the management of a heterogeneous group of chronically ill patients. Patients suffering from a wide range of chronic conditions who were frequently admitted to hospital, were selected from nominated hospital lists. The impact of telemonitoring was analysed using a wide range of health and wellbeing outcomes as well as numerous health economic metrics derived from Medicare Medical Benefits Scheme (MBS) and Pharmaceutical Benefits Scheme (PBS) data and Hospital Health Roundtable data. Data was also recorded from the telemonitoring system used in the trial, and the administration of questionnaires. The impact of this intervention on the patients, carers and clinicians involved in their care was quantitatively and qualitatively analysed and documented. There were no significant differences between test and control patients at baseline. Test patients were monitored for an average of 276 days with 75% of patients monitored for more than 6 months. Test patients 1 year after the start of their intervention showed a 46.3% reduction in rate of predicted medical expenditure, a 25.5% reduction in the rate of predicted pharmaceutical expenditure, a 53.2% reduction in the rate of predicted unscheduled admission to hospital, a 67.9% reduction in the predicted rate of LOS when admitted to hospital, and a reduction in mortality of between 41.3% and 44.5% relative to control patients. Control patients did not demonstrate any significant change in their predicted trajectory for any of the above variables. In addition, this project reports on the effect of workplace culture and capacity for innovation and organizational change management in successfully integrating a new model of care with long established service models. PMID- 29507254 TI - Protein homology model refinement by large-scale energy optimization. AB - Proteins fold to their lowest free-energy structures, and hence the most straightforward way to increase the accuracy of a partially incorrect protein structure model is to search for the lowest-energy nearby structure. This direct approach has met with little success for two reasons: first, energy function inaccuracies can lead to false energy minima, resulting in model degradation rather than improvement; and second, even with an accurate energy function, the search problem is formidable because the energy only drops considerably in the immediate vicinity of the global minimum, and there are a very large number of degrees of freedom. Here we describe a large-scale energy optimization-based refinement method that incorporates advances in both search and energy function accuracy that can substantially improve the accuracy of low-resolution homology models. The method refined low-resolution homology models into correct folds for 50 of 84 diverse protein families and generated improved models in recent blind structure prediction experiments. Analyses of the basis for these improvements reveal contributions from both the improvements in conformational sampling techniques and the energy function. PMID- 29507256 TI - Telehealth in the Elderly with Chronic Heart Failure: What Is the Evidence? AB - BACKGROUND: In a series of studies over the past decade we have measured the effectiveness of telehealth for elderly heart failure patients (>70 years) on rehospitalisation, mortality, adherence, satisfaction, cost effectiveness, health related quality of life, age and types of technology. METHODS: Evidence has been derived from a Cochrane systematic review and meta-analysis (1 original and 2 updates: 2007-2016), two sub-analysis of this data and a large NHMRC funded multicentre randomised controlled trial (CHAT study 2010). RESULTS: Within the studies included in the meta-analysis the mean age was 70 or more years in eight of the 16 (n=2,659/5,613; 47%) involving structured telephone support studies and four of the 11 (n=894/2,710; 33%) Telemonitoring studies. Structured telephone support (RR 0.80; 95% CI=0.63-1.00) and Telemonitoring (RR 0.56; 95% CI=0.41 0.76) interventions reduced mortality. Structured telephone support interventions reduced heart failure-related hospitalizations (RR 0.81; 95% CI=0.67-0.99). Four different types of non-invasive remote monitoring technologies were identified, including structured telephone calls, videophone, interactive voice response devices, and Telemonitoring. Structured telephone calls and Telemonitoring were effective in reducing the risk of all-cause mortality (relative risk [RR]=0.87; 95% confidence interval [CI], 0.75-1.01; p=0.06; and RR=0.62; 95% CI, 0.50-0.77; p<0.0001, respectively) and heart failure-related hospitalizations (RR=0.77; 95% CI, 0.68-0.87;p<0.001; and RR=0.75; 95% CI, 0.63-0.91; p=0.003, respectively). Videophone and interactive voice response technologies were not effective. Only 3% of this elderly group (mean age 74.7+/-9.3 years) were unable to learn or competently use the technology. Adherence was reported between 55.1%and 98.5%. Participant satisfaction with Telehealth was reported between 76% and 97%. CONCLUSION: These studies show that elderly patients can adapt quickly to telehealth, find its use an acceptable part of their healthcare routine, and are able to maintain good adherence for at least 12 months. These findings support the use of telehealth as part of a comprehensive chronic heart failure management programme.goes here. PMID- 29507257 TI - Supporting Regional Aged Care Nursing Staff to Manage Residents' Behavioural and Psychological Symptoms of Dementia, in Real Time, Using the Nurses' Behavioural Assistant (NBA): A Pilot Site 'End-User Attitudes' Trial. AB - BACKGROUND: This regional pilot site 'end-user attitudes' study explored nurses' experiences and impressions of using the Nurses' Behavioural Assistant (NBA) (a knowledge-based, interactive ehealth system) to assist them to better respond to behavioural and psychological symptoms of dementia (BPSD) and will be reported here. METHODS: Focus groups were conducted, followed by a four-week pilot site 'end-user attitudes' trial of the NBA at a regional aged care residential facility (ACRF). Brief interviews were conducted with consenting nursing staff. RESULTS: Focus group feedback (N = 10) required only minor cosmetic changes to the NBA prototype. Post pilot site end-user interview data (N = 10) indicated that the regional ACRF nurses were positive and enthusiastic about the NBA, however several issues were also identified. CONCLUSIONS: Overall the results supported the utility of the NBA to promote a person centred care approach to managing BPSD. Slight modifications may be required to maximise its uptake across all ACRF nursing staff. PMID- 29507258 TI - Caring for Carers of People with Dementia: A Protocol for Harnessing Innovation Through Deploying Leading Edge Technologies to Enable Virtual Support Groups and Services. AB - In rural Australia, knowledge and utilisation of support by informal carers is lacking. During the caregiving period, socioemotional support from family and friends plays an important role in sustaining caregiving activities. Post-care, these social networks facilitate adjustment to role change and dealing with grief. Developing and improving access to peer support to enable carers to effectively cope with the challenges of caring may positively influence their caring experience. The primary objective of this project is to examine the response of isolated rural carers for older people with dementia to a videoconference (VC) based peer support and information program. Will participation in the program improve self-efficacy, quality of life, and mental health? Secondary objectives are to develop a VC based peer support program for isolated rural carers for older people with dementia, using a co-design approach; and to assess the feasibility of VC technology for enhancing social support to family caregivers in their homes. This project will collaboratively co-design and evaluate a facilitated VC peer support and information program to carers of people with dementia within rural areas. Carers will be recruited through community health and care providers. Program development will use an information sharing approach to facilitate social interaction. A focus of the project is to use off-the-shelf technology which will be more accessible than specialised bespoke solutions that are currently popular in this area of research. A mixed methods repeated measures randomized wait list design will be used to evaluate the project. The primary outcomes are self-efficacy, quality of life, and mental health. Secondary outcomes are perceived social support and user satisfaction with the technology, and intention to continue VC interaction. PMID- 29507259 TI - Consumer Wearable Information and Health Self Management by Older Adults. AB - BACKGROUND: The present study was undertaken to build an evidence base focusing on an ageing population who are using or have used consumer wearables to collect and manage information about their personal health status. The primary objective was to understand the health self-management requirements, frailty and age related changes, and the health information support provided by consumer wearable devices, specifically in the context of older adults living independently. METHOD: The study aimed to recruit older adults to respond to an online questionnaire. Inclusion criteria for the selection of study participants were: Aged 55 or over, independent living, and currently using or having used a wearable device or devices for health self-management in the past year. The online survey questionnaire represented a cross-section of variables in three sections: (1) Use of wearables for health monitoring, (2) Demographics and (3) Health, physical condition and wellness. A subset of the questions was drawn from the Tilburg Frailty Indicator. RESULTS: Summary findings from the completed questionnaires suggest the use of wearable health information supports aspects of health self-management activities among independent living seniors. Personal variations and user characteristics in the extent and consistency of the use of wearable information, and user experience in the process, was more difficult to extrapolate, for example, in health information sharing. CONCLUSION: Responses to the survey do not indicate widespread use of information from consumer wearables for health self-management among older adults. However, among the respondents, more than half were willing to participate in a follow-up interview by a researcher on their wearable health information use. Further research will explore what they have to say about this information use in relation to frailty and age related changes, and about the way that such information may be integrated into health and aged care support systems. PMID- 29507260 TI - Trial Implementation of a Telerehabilitation Exercise System in Residential Aged Care. AB - The 2011 Productivity Commission report, Caring for Older Australians, observed that as the number of older Australians rises and the demand for aged care services increases, there will be a commensurate increase in demand for a well trained aged care workforce. One of the significant issues impacting upon the ability of the aged services sector to respond to a growing number of older adults is to attract and retain sufficient numbers of staff. A number of factors are acknowledged to contribute to a failure of the aged care sector to attract and retain workers including: poor sector reputation, poor working conditions, including high client-staff ratios, a lack of career paths and professional development opportunities and low rates of remuneration. Poor perceptions about working in the aged care sector (e.g. that aged care nursing is less glamorous than nursing in the acute care sector) appear to develop early, with many nursing students indicating that they do not view aged care as an attractive career choice. Undergraduate nursing students have often found clinical placements in aged care unsatisfactory and unsettling, dissuading them from considering aged care as an employment option on graduation. In the following we describe one way we have attempted to address this issue by training undergraduate health sciences students (occupational therapy, nursing) to deliver a physical activity program to residents of an aged care facility using a novel telerehabilitation technology that enables remote prescription and monitoring of exercise programs. The main purpose of this quality assurance trial was to explore the feasibility and safety of supervised use of a novel telerehabilitation exercise system with older adults living in residential aged care. Four residents were recruited into the study and all displayed limitations in mobility, balance, strength and endurance. None had any had previous experience with computer games or interactive technologies. Resident diagnoses included multiple chronic health conditions and mild cognitive impairment. Over the six-week period, only one session was declined by a resident, providing an overall adherence rate of 98.5%. According to the resident's scores of perceived level of enjoyment, at the end of the first week the program was rated as always enjoyable by 75% of the residents. At the conclusion of the program, 100% responded as always enjoying the exercises and activities. Active sitting and standing time for residents across the program increased markedly. A novel finding from our study is that senior undergraduate students are capable of designing and delivering telerehabilitation programs to residents in aged care facilities. Whilst attention has been given to telesimulation in undergraduate preparation (where learners are off site and connected to simulated laboratory), our trial opens opportunities for a further paradigm shift towards teleplacement. PMID- 29507261 TI - Supporting Diverse Challenges of Ageing with Digital Enhanced Living Solutions. AB - By the 2050, it is estimated that the proportion of people over the age of 80 will have risen from 3.9% to 9.1% of population of Organisation for Economic Cooperation and Development countries. A large proportion of these people will need significant help to manage various chronic illnesses, including dementia, heart disease, diabetes, limited physical movement and many others. Current approaches typically focus on acute episodes of illness and are not well designed to provide adequately for daily living care support. In our rapidly ageing society, a critical need exists for effective, affordable, scalable and safe in home and in-residential care solutions leveraging a range of current and emerging sensor, interaction and integration technologies. Key aims are to support the ageing to live longer in their own homes; make daily challenges associated with ageing less limiting through use of technology supports; better support carers - both professional and family - in providing monitoring, proactive intervention, and community connectedness; enable in-home and in-residential care organisations to scale their support services and better use their workforces; and ultimately provide better quality of life. Deakin University researchers have been investigating a range of emerging technologies and platforms to realise this vision, which we in broad terms coin Digital Enhanced Living, in the ageing space but also supporting those with anxiety and depression, sleep disorders, various chronic diseases, recovery from injury, and various predictive analytics. A Smart Home solution, carried out in conjunction with a local start-up, has produced and trialled a novel sensor, interaction, and AI-based technology. Virtual Reality (VR) solutions have been used to support carers in the set-up of dementia friendly homes, in conjunction with Alzheimers Australia. Activity and nutrition solutions, including the use of conversational agents, have been used to build dialogue to engage and change behaviour. Predictive analytics, in conjunction with major hospitals, have been applied to large medical datasets to better support professionals making judgements around discharge outcomes. A set of lessons have been learned from the design, deployment and trialing of these diverse solutions and new development approaches have been crafted to address the challenges faced. In particular, we found that there is a need to consider user emotional expectations as first-class citizens and create methodologies that consider the user needs during the creation of the software solutions. We find that quality and emotional aspects have to be engineered into the solution, rather than added after a technical solution is deployed. PMID- 29507262 TI - Systems to Harness Digital Footprint to Elucidate and Facilitate Ageing in Place. AB - The rapid ageing of the population is a worldwide inexorable demographic transformation. At a time of immense social, political and economic change, the growing elderly population is at the forefront of global burden, placing an increasing strain on the federal, state, and local budgets. Many public policy responses to the impending ageing epidemic have begun, particularly with regards to dementia prevention and quality of life for older adults. However, to date, the fruition of such efforts remains to be discovered. Indeed, there is a need to find more novel and multifaceted ways of understanding the fragmentary changes and underlying mechanisms in the biopsychosocial contexts of ageing. Discovering better ways to measure these intricate domains will create better insight into how to improve clinical and public health information systems for the development of more personalisation support and services across the continuum of aged care. Technology now permeates all aspects of our everyday living. Digital footprints are data arising as a by-product of interactions we do as part of everyday living. The digital traces we live behind, be it on internet, social media, on mobile phone apps, as well as in health records (EHRs) could be used to infer how we behave and interact with environment, and how we feel in different situations. Commercial sector has very successfully used these footprints in the advertisement and marketing space. This type of information may provide clinicians with an unobtrusive way of monitoring older adults in their daily living, and provide an alternative means to traditional self-report and expert rated assessment. In this paper we present two innovative digital footprint applications, Actionable Intime Insights and the SAIL Mobile app, which aim to facilitate "Ageing in Place" through adaptive, dynamic, early intervention strategies. These systems are devised to unveil contextual indicators of how a person is functioning mentally, socially, behaviourally and physically in their own environment, as to as assist those with chronic conditions better self-manage by facilitating assistance with care and medication needs just in time. PMID- 29507263 TI - An Innovative Technology to Support Independent Living: The Smarter Safer Homes Platform. AB - Australian population aged over 65 years is 14% (3.3 million) and this expected to increase to 21% by 2053 (8.3 million), of which 1.9% to 4.2% is attributed to Australians over 85 years. With increase in ageing, there is high prevalence in long-term health conditions and more likely multiple visits to the doctors or the hospitals, particularly when one's functional condition declines. This adds burden to the already stretched health system such as the overcrowding of emergency departments in hospitals. This is partly due to many ageing patients with high care needs occupying significant number of hospital beds because they are waiting for entry to the limited placements in residential care. To address this increase in ageing population and its impact in the society, the Australian government has funded aged care reforms for initiatives for older community stay at home longer. Recently, this was implemented through consumer directed age care reform. Advances in information and communication technologies, particularly in the advancement of lifestyle technologies and its increased use, show promise in the uptake of telehealth approach to support older people to live longer in their homes. In 2011, CSIRO took the initiative to a develop consumer designed innovative platform that would assist and support the older community in their functional ability and health for day to day living in their home environment. This platform was called the Smarter Safer Homes technology. The Smarter Safer Homes platform infers the Activities of Daily Living information from a passive sensor-enabled environment and correlates the information with home-based health monitoring measurements. The use of sensors enables the information to be captured in an unobtrusive manner. This information is then provided to the individual in the household through an iPad application while information can also be shared with formal and informal carers. The platform has undergone a few pilot studies to explore an objective and individualised approach to Activities of daily living based on an individual's profile and its applicability in multi resident home setting in individual's in regional Queensland. Furthermore, the platform is being validated in a clinical study for its application in the aged care service in various geographical settings such as in urban and remote communities. This paper describes the platform, outcomes of pilot studies, and its future application. PMID- 29507264 TI - Maximising the Opportunity for Healthy Ageing: Online Mental Health Measurement and Targeted Interventions. AB - Longevity is a valuable resource for society, as older people are increasingly looking for new ways to contribute after retirement. Their contribution is however dependent upon their physical health, mental health and wellbeing. The potential role that mental health and wellbeing, two separate but interrelated constructs, play often are both under-recognised and insufficiently targeted. Positive ageing is a positive and constructive view of ageing, where older people actively work on maintaining a positive attitude, work towards keeping fit and healthy, and strive to maximize their wellbeing. Interventions stimulating positive ageing show promising results for both mental health and wellbeing, and telehealth can play an important role in improving the reach and effectiveness of positive ageing interventions. Telehealth solutions can also help researchers reliably measure and better understand the drivers of wellbeing at individual and population levels; results that can both form the basis for advancing the field of positive ageing and help inform public policy. PMID- 29507265 TI - Prediction of Freezing of Gait in Patients with Parkinson's Disease Using EEG Signals. AB - Freezing of gait (FOG) is an episodic gait disturbance affecting initiation and continuation of locomotion in many Parkinson's disease (PD) patients, causing falls and a poor quality of life. FOG can be experienced on turning and start hesitation, passing through doorways or crowded areas dual tasking, and in stressful situations. Electroencephalography (EEG) offers an innovative technique that may be able to effectively foresee an impending FOG. From data of 16 PD patients, using directed transfer function (DTF) and independent component analysis (ICA) as data pre-processing, and an optimal Bayesian neural network as a predictor of a transition of 5 seconds before the impending FOG occurs in 11 in group PD patients, we achieved sensitivity and specificity of 85.86% and 80.25% respectively in the test set (5 out-group PD patients). This study therefore contributes to the development of a non-invasive device to prevent freezing of gait in PD. PMID- 29507268 TI - What We Do and Do Not Know About Women and Kidney Diseases: Questions Unanswered and Answers Unquestioned: Reflection on World Kidney Day and International Woman's Day. AB - Chronic kidney disease affects approximately 10% of the world's adult population; it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. The World Kidney Day and the International Women's Day coincide in 2018, thus offering an opportunity to reflect on the importance of women's health, and specifically their kidney health, on the community and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, offering an opportunity for diagnosis of kidney disease, but also a state where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women, with profound consequences for child bearing and the fetus. Women have different complications on dialysis than men, and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women's kidney health and kidney disease, and what we might learn in the future to improve outcomes worldwide. PMID- 29507269 TI - A Systematic Review and Meta-analysis of Using Acupuncture and Acupressure for Uremic Pruritus. AB - INTRODUCTION: Uremic pruritus is characterized by an uncomfortable and unlimited sensation which leads to scratch, which strongly reduces the quality of life. Pruritus is a common symptom in patients with end-stage renal disease. Various clinical trial studies have examined the effects of acupuncture and acupressure on treatment of uremic pruritus. This systematic review meta-analysis aimed to evaluate the effectiveness based on published studies. MATERIALS AND METHODS: An electronic literature search was conducted to identify appropriate trial studies. The results for continuous outcomes were presented as weighted mean difference, with 95% confidence intervals. RESULTS: A total of 5 articles, including 6 trials, were enrolled in this systematic review. Only 3 of the six trial studies used a visual analogue scale score for assessing pruritus and acupressure for intervention regime, which were considered for meta-analysis. The combined results showed that acupuncture or acupressure was effective in treatment of uremic pruritus (pooled mean difference, -1.994; 95% confidence interval, -2.544 to -1.445). CONCLUSIONS: This study confirms that using acupuncture and acupressure is effective in treatment of uremic pruritus. However, further vigorous studies are needed to verify these findings. PMID- 29507270 TI - Antioxidative Effects of Tempol on Mitochondrial Dysfunction in Diabetic Nephropathy. AB - INTRODUCTION: Oxidative stress has a well-known role in diabetic nephropathy, and mitochondria are the major source of reactive oxygen species production. This study aimed to assess the effect of tempol, a superoxide dismutase mimetic agent, on mitochondrial antioxidant enzymes and cell viability in diabetic nephropathy. MATERIALS AND METHODS: Adult male Wistar rats were divided into 4 groups of 7 animals. Diabetes mellitus was induced by injection of streptozotocin in 2 groups, the rat in one of which were also treated with tempol for 4 weeks. Another group without diabetes mellitus received tempol, and the last group was the control. At the end of the treatment period, the kidney mitochondria were isolated and their antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, and catalase were assessed. Malondialdehyde, total antioxidant capacity, and kidney cells viability were studied, as well. RESULTS: The diabetic group was significantly different compared with the control group in malondialdehyde, catalase, and glutathione peroxidase activities. Superoxide dismutase and total antioxidative capacity did not show any significant differences among the four groups. Moreover, the diabetic group treated with tempol had significantly different glutathione peroxidase level and kidney cells viability, compared to the other diabetic group (P < .05) Conclusions. Diabetic nephropathy induces changes in mitochondrial antioxidative biomarkers and cells viability, some of which can be modified by tempol administration in rats. PMID- 29507271 TI - Clinical Characterization of Serum Docosahexaenoic Acid and Its Relationship With Inflammation Factors in Patients With Diabetic Nephropathy. AB - INTRODUCTION: A variety of molecular pathways, such as generation of advanced glycation end products, inflammation, and oxidative stress, are involved in the development of diabetic nephropathy (DN). Recently, a protective effect of omega 3 polyunsaturated fatty acids on the kidney has been reported. This study aimed to determine serum docosahexaenoic acid (DHA) level and its association with inflammation factors in patients with DN. MATERIALS AND METHODS: One hundred patients with type 2 diabetic mellitus were divided into 3 groups of non-DN, early DN, and clinical DN, based on 24-hour urinary albumin levels. Hemoglobin A1c, biochemical indicators, beta2-microglobulin, and 24-hour urine albumin levels were assessed. Enzyme linked immunosorbent assay was applied to determine the serum concentrations of DHA, advanced glycation end products, fractalkine, superoxide dismutase, and tumor necrosis factor-alpha. RESULTS: Lower serum DHA and superoxide dismutase and higher serum beta2-microglobulin and 24-hour urine albumin levels were associated with clinical DN, compared to no DN and early DN. The reductions in serum DHA levels were different among the patients with early and clinical DN, stratified by sex, body mass index, and serum lipid levels. Serum DHA significantly correlated positively with superoxide dismutase and negatively with fractalkine and tumor necrosis factor-alpha in the patients with DN. CONCLUSIONS: Docosahexaenoic acid may suppress the expression and secretion of fractalkine through inhibiting the tumor necrosis factor-alpha signaling pathway in DN patients, which improves inflammation and oxidative stress of the kidney, and in turn, delaying the development of DN. PMID- 29507272 TI - Protection Against Doxorubicin-induced Nephropathy by Plantago major in Rat. AB - INTRODUCTION: Nephropathy is an important side effect of doxorubicin. The aim of the current study was to investigate the protective effect of Plantago major extract against doxorubicin-induced functional and histological damage in rat's kidney. MATERIALS AND METHODS: Sixty Albino rats were randomly divided into 6 groups. Doxorubicin, 5 mg/kg, was injected intravenously on the 7th day of the study. Animals were treated with dexamethasone, 0.9 mg/kg, vitamin E, 100 mg/kg, and P major extract, 600 mg/kg and 1200 mg/kg, for 7 days before and 4 weeks after doxorubicin administration. Glomerular filtration rate, urea clearance, and urine glucose concentration were determined on the 1st day and 1, 2, 3 and 4 weeks after doxorubicin injection. Histological changes were also examined and the end of the study. RESULTS: Doxorubicin caused significant decreases in glomerular filtration rate and urea clearance and significant glycosuria and kidney damage. Urea clearance in the rats treated with P major showed no significant change between different days of the experiment. Administration of dexamethasone, vitamin E, and low- and high-dose P major significantly improved the glycosuria and kidney tissue damage. CONCLUSIONS: These findings suggested that hydroalcoholic extract of P major protected renal tissue against doxorubicin induced nephropathy. The protective effects of P major on renal lesions associated with doxorubicin may be due to its antioxidant and anti-inflammatory actions. PMID- 29507274 TI - Epidemiologic Association of Nonalcoholic Fatty Liver Disease and Urinary Calculi: a Population-based Cross-sectional Study in Southern China. AB - INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been reported to have effects on kidney diseases; however, a link between NAFLD and urinary calculi remains to be confirmed. This study was conducted on a male population based on our previous Fangchenggang Area Male Health and Examination Survey in Guangxi, China in order to estimate the frequency of urinary calculi and assess the association between NAFLD and urinary calculi while controlling for possible confounders. MATERIALS AND METHODS: This was a population-based cross-sectional study conducted in the Fangchenggang region in Guangxi, China. The diagnoses of NAFLD and urinary calculi were made by ultrasonography. Clinical and laboratory findings were analyzed to investigate whether NAFLD was a risk factor for urinary calculi. RESULTS: A total of 3719 men were enrolled (age range, 17 to 88 years). Slightly more than a quarter (26.5%) of the participants were diagnosed with NAFLD. The percentage of urinary calculi in all participants was 6.9%, and the percentage of NAFLD patients with urinary calculi (8.4%) was significantly higher than that among patients without NAFLD (6.4%, P < .05). Advanced age; high body mass index; elevated levels of blood glucose, cholesterol, triglycerides, and low density lipoprotein cholesterol; low education; lower or higher physical activity; and NAFLD were independent risk factors for urinary calculi (P < .05). CONCLUSIONS: Our results showed that NAFLD was associated with a higher incidence of urinary calculi in this cohort and NAFLD might represent a risk factor for urinary calculi. PMID- 29507273 TI - Urinary CD80 as a Replacement for Renal Biopsy for Diagnosis of Pediatric Minimal Change Disease. AB - INTRODUCTION: Early diagnosis of minimal change disease (MCD) is challenging in nephrotic children. CD80 is a protein expressed on the surface of podocytes associated with nephrotic syndrome and it is implicated in the induction of proteinuria. This study aimed to investigate the use of urinary CD80 for the diagnosis of MCD. MATERIALS AND METHODS: Urinary CD80 levels were evaluated in 36 children with nephrotic syndrome and normal glomerular filtration rate. They were divided into three groups of MCD (n = 21), focal segmental glomerulosclerosis (n = 9), and other glomerulopathies (n = 6). The MCD group was subdivided into 2 of those with remission (n = 11) and those in the active stage (n = 10). Forty healthy children were included as controls. RESULTS: The urinary CD80 level was significantly higher in the MCD group (3.5 +/- 2.1 ng/mg creatinine) than in the focal segmental glomerulosclerosis group (1.2 +/- 0.5 ng/mg creatinine, P < .001), the other glomerulopathies group (1.4 +/- 0.7 ng/mg creatinine, P < .001), and the control group (0.7 +/- 0.2 ng/mg creatinine, P < .001), while it showed no significant difference among the non-MCD groups. There was no significant difference between MCD in remission and MCD in relapse, either. A urinary CD80 cutoff value of 1.5 ng/gm creatinine showed a sensitivity of 100% and a specificity of 86% for diagnosis of MCD. CONCLUSIONS: Urinary CD80 levels were significantly higher in the children with MCD than in the controls and patients with other causes of nephrotic syndrome. PMID- 29507275 TI - Effect of Angiotensin II Receptor Type 1 Antibodies on Kidney Allograft Function. AB - INTRODUCTION: Non-human leukocyte antigen antibodies are an independent risk factor for acute rejection in kidney transplant recipients. Among them, angiotensin II receptor type 1 (ART1) antibodies can induce various effects, but their clinical importance in kidney transplant recipients has not been properly explained. This study aimed to evaluate the effect of ART1 antibodies on allograft function and hypertension in stable kidney transplant recipients. MATERIALS AND METHODS: Eighty-one kidney recipients from non- human leukocyte antigen antibodies-matched donors with stable allograft function were examined for estimated glomerular filtration rate (Chronic Kidney Disease-Epidemiology Collaboration formula) and ART1 antibodies (measured using an enzyme-linked immunosorbent assay method). The result was considered positive if the anti-ART1 level was greater than 17 U/mL. RESULTS: The mean age of the participant was 51.1 +/- 11.9 years with the mean time from transplantation was 83.5 +/- 6.5 months. Fifteen recipients (18.5%) had a high ART1 antibodies level. Those with low titers of ART1 antibodies had better allograft function. The mean estimated glomerular filtration rate was 63.0 +/- 13.7 mL/min in those with low ART1 antibodies and 42.3 +/- 13.9 mL/min in those with high ART1 antibodies (P < .001). There were no significant correlation between high ART1 antibodies levels and hypertension, cause of end-stage renal disease, age, sex, transplant and dialysis duration, cytomegalovirus infection, antihypertensive medication, or immunosuppressive agents. CONCLUSIONS: A high level of ART1 antibodies was a risk factor for allograft function; however this indicator was not correlated with hypertension in our study. PMID- 29507276 TI - Classification of Acute Rejection Episodes in Kidney Transplantation: a Proposal Based on Factor Analysis. AB - INTRODUCTION: Kidney transplantation is considered the ideal treatment for end stage renal disease. Acute rejection can influence graft survival. The aim of this study was to propose a classification system for acute rejection based on factor analysis. MATERIALS AND METHODS: Data were collected from kidney transplant recipients with acute rejection diagnosis based on standard histological variables, the presence of peritubular eosinophils, and immunolabeling for lysozyme and myeloperoxidase in kidney tissue. Factor analysis was employed for data reduction and generation of a new case classification, with orthogonal rotation as a strategy to simplify factors, and principal component analysis was used as an extraction method. RESULTS: Seventy-nine kidney biopsies were obtained from 74 patients. The total population was divided into humoral rejection (39.2%), cellular rejection (34.1%), and mixed acute rejection (26.7%). No significant differences were found between the three groups in clinical and biochemical variables. We extracted 4 factors using factor analysis. The 1st factor was characterized by the presence of capillaritis, plasma cells infiltration, tubulitis, and inflammation. The 2nd factor included positivity for lysozyme and myeloperoxidase, while the 3rd factor included the presence of eosinophils and glomerulitis. The 4th component consisted of the presence of C4d and endarteritis. The cases belonging to the 3rd factor showed the greatest increase in serum creatinine. The cases belonging to the 4th factor exhibited greater urinary excretion of proteins. CONCLUSIONS: This proposal of classification of acute rejection could contribute to evaluate the prognosis of kidney transplant recipients. PMID- 29507277 TI - Light Chain Deposition Disease Associated With Multiple Myeloma Developing in Late Pregnancy. AB - Preeclampsia is the most common cause of proteinuria with hypertension during pregnancy. Primary kidney disease and kidney disease secondary to systemic disorders may rarely occur during pregnancy, resulting in proteinuria. A 34-year old woman was admitted to our hospital with abdominal distention and lower extremity edema. The pregnancy was terminated at the 24th week of gestation due to preterm labor. Even after the delivery, proteinuria and renal deterioration continued to progress. The M-peak was not found on serum and urine protein electrophoresis. The serum free light chains assay showed absolute elevation of lambda chains at 1013.9 mg/L with a decreased kappa to lambda ratio of 0.05. Kidney biopsy revealed light chain deposition disease with lambda light chain deposits on immunofluorescence. Bone marrow examination was compatible with multiple myeloma. To our knowledge, this is the first reported case of light chain deposition disease associated with multiple myeloma during pregnancy. PMID- 29507278 TI - Amniotic Membrane Transplantation in Reconstructive and Regenerative Ophthalmology. AB - BACKGROUND The goal of this study was to investigate numbers, indications, surgical techniques, and experiences of amniotic membrane transplantation at the University Eye Hospital Tubingen over the last 16 years. MATERIAL AND METHODS Data from all amniotic membrane transplantations from January 2001 to December 2016 were retrospectively analyzed. Data was accessed from the electronic database and the annual reports of the Eye Bank at the University Eye Hospital Tubingen. RESULTS A total of 771 amniotic membrane transplantations were performed between 2001 and 2016 at the University Eye Hospital Tubingen. The mean number of amniotic membrane transplantations was 48 per year (range: 7-81). Overall, the mean number of amniotic membrane transplantations more than doubled, from 31 amniotic membrane transplantations per year during the first 8-year period to 66 amniotic membrane transplantations per year during the second 8-year period (p<0.0001). The most common surgical indications for amniotic membrane transplantation were corneal ulcers and persistent corneal epithelial defects. The inlay, overlay, and sandwich technique became the favored surgical methods for various disorders of the ocular surface. CONCLUSIONS Our study showed a significant increase of amniotic membrane transplantations from 2001 to 2016. This increase is likely influenced by the introduction of different surgical amniotic membrane transplantation techniques, the rising knowledge about containing growth factors, neurotrophins and cytokines, and the demographic change with aging of the population. PMID- 29507279 TI - Regression and Sentinel Lymph Node Status in Melanoma Progression. AB - BACKGROUND The purpose of this study was to assess the role of regression and other clinical and histological features for the prognosis and the progression of cutaneous melanoma. MATERIAL AND METHODS Between 2005 and 2016, 403 patients with melanoma were treated and followed at our Department of Dermatology. Of the 403 patients, 173 patients had cutaneous melanoma and underwent sentinel lymph node (SLN) biopsy and thus were included in this study. RESULTS Histological regression was found in 37 cases of melanoma (21.3%). It was significantly associated with marked and moderate tumor-infiltrating lymphocyte (TIL) and with negative SLN. Progression of the disease occurred in 42 patients (24.2%). On multivariate analysis, we found that a positive lymph node and a Breslow index higher than 2 mm were independent variables associated with disease free survival (DFS). These variables together with a mild TIL were significantly correlated with overall survival (OS). The presence of regression was not associated with DFS or OS. CONCLUSIONS We could not demonstrate an association between regression and the outcome of patients with cutaneous melanoma. Tumor thickness greater than 2 mm and a positive SLN were associated with recurrence. Survival was influenced by a Breslow thickness >2 mm, the presence of a mild TIL and a positive SLN status. PMID- 29507280 TI - Spinal Tuberculosis Mimicking Failed Back Surgery. AB - BACKGROUND The aim of this study was to draw attention to rare spinal infections in recurrent failed spinal surgeries. CASE REPORT A 59-year-old female was admitted to the hospital for back pain, which was assessed as a 9 on the visual analogue scale (VAS); the patient reported tiredness and night sweats. She had an operation for L3-4 far lateral disc herniation four years ago. Then another operation for L4-5 disc herniation six months ago and immediately three months later she has an operation with L3-4-5 fixation again. She had hypothyroidism, diabetes mellitus, and hypertension. Her daughter was cured of pulmonary tuberculosis 20 years ago. We performed an operation by L4-5 discectomy; all granulation formation with inflammatory processes were debrided and irrigated with antibiotics at levels of L3-5. The old fixation was controlled and replaced. Her back pain improved immediately after surgery; she had a score of 2 on the VAS. Two days after her surgery, our Infection Disease Department reported acid resistant bacillus (ARB+) in samples and began anti-tuberculosis medication. CONCLUSIONS Spinal infections should always be taken into consideration in recurrent failed back surgeries. PMID- 29507281 TI - Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania. AB - Mood disturbances seen in first-episode mania (FEM) are linked to disturbed functional connectivity of the striatum. Lithium and quetiapine are effective treatments for mania but their neurobiological effects remain largely unknown. We conducted a single-blinded randomized controlled maintenance trial in 61 FEM patients and 30 healthy controls. Patients were stabilized for a minimum of 2 weeks on lithium plus quetiapine then randomly assigned to either lithium (serum level 0.6 mmol/L) or quetiapine (dosed up to 800 mg/day) treatment for 12 months. Resting-state fMRI was acquired at baseline, 3 months (patient only) and 12 months. The effects of treatment group, time and their interaction, on striatal functional connectivity were assessed using voxel-wise general linear modelling. At baseline, FEM patients showed reduced connectivity in the dorsal (p = 0.05) and caudal (p = 0.008) cortico-striatal systems when compared to healthy controls at baseline. FEM patients also showed increased connectivity in a circuit linking the ventral striatum with the medial orbitofrontal cortex, cerebellum and thalamus (p = 0.02). Longitudinally, we found a significant interaction between time and treatment group, such that lithium was more rapid, compared to quetiapine, in normalizing abnormally increased functional connectivity, as assessed at 3-month and 12-month follow-ups. The results suggest that FEM is associated with reduced connectivity in dorsal and caudal corticostriatal systems, as well as increased functional connectivity of ventral striatal systems. Lithium appears to act more rapidly than quetiapine in normalizing hyperconnectivity of the ventral striatum with the cerebellum. The study was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12607000639426). http://www.anzctr.org.au. PMID- 29507282 TI - Intrinsic functional connectivity predicts remission on antidepressants: a randomized controlled trial to identify clinically applicable imaging biomarkers. AB - Default mode network (DMN) dysfunction (particularly within the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC)) has been implicated in major depressive disorder (MDD); however, its contribution to treatment outcome has not been clearly established. Here we tested the role of DMN functional connectivity as a general and differential biomarker for predicting treatment outcomes in a large, unmedicated adult sample with MDD. Seventy-five MDD outpatients completed fMRI scans before and 8 weeks after randomization to escitalopram, sertraline, or venlafaxine-XR. A whole-brain voxel-wise t-test identified profiles of pretreatment intrinsic functional connectivity that distinguished patients who were subsequently classified as remitters or non remitters at follow-up. Connectivity was seeded in the PCC, an important node of the DMN. We further characterized differences between remitters, non-remitters, and 31 healthy controls and characterized changes pretreatment to posttreatment. Remitters were distinguished from non-remitters by relatively intact connectivity between the PCC and ACC/mPFC, not distinguishable from healthy controls, while non-remitters showed relative hypo-connectivity. In validation analyses, we demonstrate that PCC-ACC/mPFC connectivity predicts remission status with >80% cross-validated accuracy. In analyses testing whether intrinsic connectivity differentially relates to outcomes for a specific type of antidepressant, interaction models did not survive the corrected threshold. Our findings demonstrate that the overall capacity to remit on commonly used antidepressants may depend on intact organization of intrinsic functional connectivity between PCC and ACC/mPFC prior to treatment. The findings highlight the potential utility of functional scans for advancing a more precise approach to tailoring antidepressant treatment choices. PMID- 29507283 TI - Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition. AB - Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha 2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits. PMID- 29507284 TI - Microhomology-assisted scarless genome editing in human iPSCs. AB - Gene-edited induced pluripotent stem cells (iPSCs) provide relevant isogenic human disease models in patient-specific or healthy genetic backgrounds. Towards this end, gene targeting using antibiotic selection along with engineered point mutations remains a reliable method to enrich edited cells. Nevertheless, integrated selection markers obstruct scarless transgene-free gene editing. Here, we present a method for scarless selection marker excision using engineered microhomology-mediated end joining (MMEJ). By overlapping the homology arms of standard donor vectors, short tandem microhomologies are generated flanking the selection marker. Unique CRISPR-Cas9 protospacer sequences nested between the selection marker and engineered microhomologies are cleaved after gene targeting, engaging MMEJ and scarless excision. Moreover, when point mutations are positioned unilaterally within engineered microhomologies, both mutant and normal isogenic clones are derived simultaneously. The utility and fidelity of our method is demonstrated in human iPSCs by editing the X-linked HPRT1 locus and biallelic modification of the autosomal APRT locus, eliciting disease-relevant metabolic phenotypes. PMID- 29507285 TI - Operando spectroscopy study of the carbon dioxide electro-reduction by iron species on nitrogen-doped carbon. AB - The carbon-carbon coupling via electrochemical reduction of carbon dioxide represents the biggest challenge for using this route as platform for chemicals synthesis. Here we show that nanostructured iron (III) oxyhydroxide on nitrogen doped carbon enables high Faraday efficiency (97.4%) and selectivity to acetic acid (61%) at very-low potential (-0.5 V vs silver/silver chloride). Using a combination of electron microscopy, operando X-ray spectroscopy techniques and density functional theory simulations, we correlate the activity to acetic acid at this potential to the formation of nitrogen-coordinated iron (II) sites as single atoms or polyatomic species at the interface between iron oxyhydroxide and the nitrogen-doped carbon. The evolution of hydrogen is correlated to the formation of metallic iron and observed as dominant reaction path over iron oxyhydroxide on oxygen-doped carbon in the overall range of negative potential investigated, whereas over iron oxyhydroxide on nitrogen-doped carbon it becomes important only at more negative potentials. PMID- 29507286 TI - Sea ice dynamics across the Mid-Pleistocene transition in the Bering Sea. AB - Sea ice and associated feedback mechanisms play an important role for both long- and short-term climate change. Our ability to predict future sea ice extent, however, hinges on a greater understanding of past sea ice dynamics. Here we investigate sea ice changes in the eastern Bering Sea prior to, across, and after the Mid-Pleistocene transition (MPT). The sea ice record, based on the Arctic sea ice biomarker IP25 and related open water proxies from the International Ocean Discovery Program Site U1343, shows a substantial increase in sea ice extent across the MPT. The occurrence of late-glacial/deglacial sea ice maxima are consistent with sea ice/land ice hysteresis and land-glacier retreat via the temperature-precipitation feedback. We also identify interactions of sea ice with phytoplankton growth and ocean circulation patterns, which have important implications for glacial North Pacific Intermediate Water formation and potentially North Pacific abyssal carbon storage. PMID- 29507287 TI - Robust singlet fission in pentacene thin films with tuned charge transfer interactions. AB - Singlet fission, the spin-allowed photophysical process converting an excited singlet state into two triplet states, has attracted significant attention for device applications. Research so far has focused mainly on the understanding of singlet fission in pure materials, yet blends offer the promise of a controlled tuning of intermolecular interactions, impacting singlet fission efficiencies. Here we report a study of singlet fission in mixtures of pentacene with weakly interacting spacer molecules. Comparison of experimentally determined stationary optical properties and theoretical calculations indicates a reduction of charge transfer interactions between pentacene molecules with increasing spacer molecule fraction. Theory predicts that the reduced interactions slow down singlet fission in these blends, but surprisingly we find that singlet fission occurs on a timescale comparable to that in pure crystalline pentacene. We explain the observed robustness of singlet fission in such mixed films by a mechanism of exciton diffusion to hot spots with closer intermolecular spacings. PMID- 29507289 TI - Life times of metastable states guide regulatory signaling in transcriptional riboswitches. AB - Transcriptional riboswitches modulate downstream gene expression by a tight coupling of ligand-dependent RNA folding kinetics with the rate of transcription. RNA folding pathways leading to functional ON and OFF regulation involve the formation of metastable states within well-defined sequence intervals during transcription. The kinetic requirements for the formation and preservation of these metastable states in the context of transcription remain unresolved. Here, we reversibly trap the previously defined regulatory relevant metastable intermediate of the Mesoplasma florum 2'-deoxyguanosine (2'dG)-sensing riboswitch using a photocaging-ligation approach, and monitor folding to its native state by real-time NMR in both presence and absence of ligand. We further determine transcription rates for two different bacterial RNA polymerases. Our results reveal that the riboswitch functions only at transcription rates typical for bacterial polymerases (10-50 nt s-1) and that gene expression is modulated by 40 50% only, while subtle differences in folding rates guide population ratios within the structural ensemble to a specific regulatory outcome. PMID- 29507288 TI - A diminutive perinate European Enantiornithes reveals an asynchronous ossification pattern in early birds. AB - Fossils of juvenile Mesozoic birds provide insight into the early evolution of avian development, however such fossils are rare. The analysis of the ossification sequence in these early-branching birds has the potential to address important questions about their comparative developmental biology and to help understand their morphological evolution and ecological differentiation. Here we report on an early juvenile enantiornithine specimen from the Early Cretaceous of Europe, which sheds new light on the osteogenesis in this most species-rich clade of Mesozoic birds. Consisting of a nearly complete skeleton, it is amongst the smallest known Mesozoic avian fossils representing post-hatching stages of development. Comparisons between this new specimen and other known early juvenile enantiornithines support a clade-wide asynchronous pattern of osteogenesis in the sternum and the vertebral column, and strongly indicate that the hatchlings of these phylogenetically basal birds varied greatly in size and tempo of skeletal maturation. PMID- 29507290 TI - Reagent-controlled regiodivergent ring expansions of steroids. AB - Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late stage natural product diversification programs. PMID- 29507291 TI - Nanoplanktonic diatoms are globally overlooked but play a role in spring blooms and carbon export. AB - Diatoms are one of the major primary producers in the ocean, responsible annually for ~20% of photosynthetically fixed CO2 on Earth. In oceanic models, they are typically represented as large (>20 um) microphytoplankton. However, many diatoms belong to the nanophytoplankton (2-20 um) and a few species even overlap with the picoplanktonic size-class (<2 um). Due to their minute size and difficulty of detection they are poorly characterized. Here we describe a massive spring bloom of the smallest known diatom (Minidiscus) in the northwestern Mediterranean Sea. Analysis of Tara Oceans data, together with literature review, reveal a general oversight of the significance of these small diatoms at the global scale. We further evidence that they can reach the seafloor at high sinking rates, implying the need to revise our classical binary vision of pico- and nanoplanktonic cells fueling the microbial loop, while only microphytoplankton sustain secondary trophic levels and carbon export. PMID- 29507292 TI - Fear extinction requires infralimbic cortex projections to the basolateral amygdala. AB - Fear extinction involves the formation of a new memory trace that attenuates fear responses to a conditioned aversive memory, and extinction impairments are implicated in trauma- and stress-related disorders. Previous studies in rodents have found that the infralimbic prefrontal cortex (IL) and its glutamatergic projections to the basolateral amygdala (BLA) and basomedial amygdala (BMA) instruct the formation of fear extinction memories. However, it is unclear whether these pathways are exclusively involved in extinction, or whether other major targets of the IL, such as the nucleus accumbens (NAc) also play a role. To address this outstanding issue, the current study employed a combination of electrophysiological and chemogenetic approaches in mice to interrogate the role of IL-BLA and IL-NAc pathways in extinction. Specifically, we used patch-clamp electrophysiology coupled with retrograde tracing to examine changes in neuronal activity of the IL and prelimbic cortex (PL) projections to both the BLA and NAc following fear extinction. We found that extinction produced a significant increase in the intrinsic excitability of IL-BLA projection neurons, while extinction appeared to reverse fear-induced changes in IL-NAc projection neurons. To establish a causal counterpart to these observations, we then used a pathway specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD) strategy to selectively inhibit PFC-BLA projection neurons during extinction acquisition. Using this approach, we found that DREADD-mediated inhibition of PFC BLA neurons during extinction acquisition impaired subsequent extinction retrieval. Taken together, our findings provide further evidence for a critical contribution of the IL-BLA neural circuit to fear extinction. PMID- 29507294 TI - One step fabrication of Silicon nanocones with wide-angle enhanced light absorption. AB - We report the fabrication of an array of random Silicon nanocones using a KrF excimer laser. A 370 nm thick amorphous Silicon layer deposited on a glass substrate was used in the process. The fabricated nanocones showed a large and broadband absorption enhancement over the entire visible wavelength range. An enhancement up to 350% is measured at lambda = 650 nm. Additionally, the laser irradiation caused the nanocones to crystallize. The effect of changing the laser parameters (i.e. energy density, time, and frequency) on the morphology and the absorption is studied and compared. Wide-angle anti-reflective properties have been observed for the fabricated nanocones with less than 10% reflection for angles up to 60 degrees . The major limitation of amorphous silicon thin film solar cells is the reduced absorption. This problem could be solved if light is trapped efficiently inside the thin film without the need of increasing the film thickness. The random array of nanocones presented in this work showed a substantial increase in absorption over a wide angle, were fabricated at a low cost and are easily scalable. This technique offers a fast approach which could significantly help in overcoming the absorption limitation. PMID- 29507293 TI - Dissecting super-enhancer hierarchy based on chromatin interactions. AB - Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants. Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape. As such, hub enhancers are the major constituents responsible for SE functional and structural organization. PMID- 29507295 TI - Uncovering the balance of forces driving microtubule aster migration in C. elegans zygotes. AB - Microtubule asters must be positioned precisely within cells. How forces generated by molecular motors such as dynein are integrated in space and time to enable such positioning remains unclear. In particular, whereas aster movements depend on the drag caused by cytoplasm viscosity, in vivo drag measurements are lacking, precluding a thorough understanding of the mechanisms governing aster positioning. Here, we investigate this fundamental question during the migration of asters and pronuclei in C. elegans zygotes, a process essential for the mixing of parental genomes. Detailed quantification of these movements using the female pronucleus as an in vivo probe establish that the drag coefficient of the male asters complex is approximately five times that of the female pronucleus. Further analysis of embryos lacking cortical dynein, the connection between asters and male pronucleus, or the male pronucleus altogether, uncovers the balance of dynein-driven forces that accurately position microtubule asters in C. elegans zygotes. PMID- 29507297 TI - Broadband multiresonator quantum memory-interface. AB - In this paper we experimentally demonstrated a broadband scheme of the multiresonator quantum memory-interface. The microwave photonic scheme consists of the system of mini-resonators strongly interacting with a common broadband resonator coupled with the external waveguide. We have implemented the impedance matched quantum storage in this scheme via controllable tuning of the mini resonator frequencies and coupling of the common resonator with the external waveguide. Proof-of-principal experiment has been demonstrated for broadband microwave pulses when the quantum efficiency of 16.3% was achieved at room temperature. By using the obtained experimental spectroscopic data, the dynamics of the signal retrieval has been simulated and promising results were found for high-Q mini-resonators in microwave and optical frequency ranges. The results pave the way for the experimental implementation of broadband quantum memory interface with quite high efficiency eta > 0.99 on the basis of modern technologies, including optical quantum memory at room temperature. PMID- 29507296 TI - Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder. AB - The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca2+ pathway, were significantly increased in SCZ and BD (p < 3 * 10-4). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders. PMID- 29507298 TI - Brain-specific functional relationship networks inform autism spectrum disorder gene prediction. AB - Autism spectrum disorder (ASD) is a neuropsychiatric disorder with strong evidence of genetic contribution, and increased research efforts have resulted in an ever-growing list of ASD candidate genes. However, only a fraction of the hundreds of nominated ASD-related genes have identified de novo or transmitted loss of function (LOF) mutations that can be directly attributed to the disorder. For this reason, a means of prioritizing candidate genes for ASD would help filter out false-positive results and allow researchers to focus on genes that are more likely to be causative. Here we constructed a machine learning model by leveraging a brain-specific functional relationship network (FRN) of genes to produce a genome-wide ranking of ASD risk genes. We rigorously validated our gene ranking using results from two independent sequencing experiments, together representing over 5000 simplex and multiplex ASD families. Finally, through functional enrichment analysis on our highly prioritized candidate gene network, we identified a small number of pathways that are key in early neural development, providing further support for their potential role in ASD. PMID- 29507299 TI - Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice. AB - Clinical and experimental studies have shown that sodium glucose co-transporter 2 inhibitors (SGLT2i) contribute to the prevention of diabetic kidney disease progression. In order to clarify its pharmacological effects on the molecular mechanisms underlying the development of diabetic kidney disease, we administered different doses of the SGLT2i, ipragliflozin, to type 2 diabetic mice. A high dose ipragliflozin treatment for 8 weeks lowered blood glucose levels and reduced urinary albumin excretion. High- and low-dose ipragliflozin both inhibited renal and glomerular hypertrophy, and reduced NADPH oxidase 4 expression and subsequent oxidative stress. Analysis of glomerular phenotypes using glomeruli isolation demonstrated that ipragliflozin preserved podocyte integrity and reduced oxidative stress. Regarding renal tissue hypoxia, a short-term ipragliflozin treatment improved oxygen tension in the kidney cortex, in which SGLT2 is predominantly expressed. We then administered ipragliflozin to type 1 diabetic mice and found that high- and low-dose ipragliflozin both reduced urinary albumin excretion. In conclusion, we confirmed dose-dependent differences in the effects of ipragliflozin on early diabetic nephropathy in vivo. Even low-dose ipragliflozin reduced renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, high-dose ipragliflozin exerted renoprotective effects by reducing oxidative stress in tubular epithelia and glomerular podocytes. PMID- 29507301 TI - Caudal autotomy as anti-predatory behaviour in Palaeozoic reptiles. AB - Many lizards can drop a portion of their tail in response to an attack by a predator, a behaviour known as caudal autotomy. The capacity for intravertebral autotomy among modern reptiles suggests that it evolved in the lepidosaur branch of reptilian evolution, because no such vertebral features are known in turtles or crocodilians. Here we present the first detailed evidence of the oldest known case of caudal autotomy, found only among members of the Early Permian captorhinids, a group of ancient reptiles that diversified extensively and gained a near global distribution before the end-Permian mass extinction event of the Palaeozoic. Histological and SEM evidence show that these early reptiles were the first amniotes that could autotomize their tails, likely as an anti-predatory behaviour. As in modern iguanid lizards, smaller captorhinids were able to drop their tails as juveniles, presumably as a mechanism to evade a predator, whereas larger individuals may have gradually lost this ability. Caudal autotomy in captorhinid reptiles highlights the antiquity of this anti-predator behaviour in a small member of a terrestrial community composed predominantly of larger amphibian and synapsid predators. PMID- 29507300 TI - A retrospective study of community-acquired Clostridium difficile infection in southwest China. AB - To identify the prevalence and characteristics of community-acquired Clostridium difficile infection (CA-CDI) in southwest China, we conducted a cross-sectional study. 978 diarrhea patients were enrolled and stool specimens' DNA was screened for virulence genes. Bacterial culture was performed and isolates were characterized by PCR ribotyping and multilocus sequence typing. Toxin genes tcdA and/or tcdB were found in 138/978 (14.11%) cases for fecal samples. A total of 55 C. difficile strains were isolated (5.62%). The positive rate of toxin genes and isolation results had no statistical significance between children and adults groups. However, some clinical features, such as fecal property, diarrhea times before hospital treatment shown difference between two groups. The watery stool was more likely found in children, while the blood stool for adults; most of children cases diarrhea <=3 times before hospital treatment, and adults diarrhea >3 times. Independent risk factor associated with CA-CDI was patients with fever. ST35/RT046 (18.18%), ST54/RT012 (14.55%), ST3/RT001 (14.55%) and ST3/RT009 (12.73%) were the most distributed genotype profiles. ST35/RT046, ST3/RT001 and ST3/RT009 were the commonly found in children patients but ST54/RT012 for adults. The prevalence of CA-CDI in Yunnan province was relatively high, and isolates displayed heterogeneity between children and adults groups. PMID- 29507302 TI - Reactivity of He with ionic compounds under high pressure. AB - Until very recently, helium had remained the last naturally occurring element that was known not to form stable solid compounds. Here we propose and demonstrate that there is a general driving force for helium to react with ionic compounds that contain an unequal number of cations and anions. The corresponding reaction products are stabilized not by local chemical bonds but by long-range Coulomb interactions that are significantly modified by the insertion of helium atoms, especially under high pressure. This mechanism also explains the recently discovered reactivity of He and Na under pressure. Our work reveals that helium has the propensity to react with a broad range of ionic compounds at pressures as low as 30 GPa. Since most of the Earth's minerals contain unequal numbers of positively and negatively charged atoms, our work suggests that large quantities of He might be stored in the Earth's lower mantle. PMID- 29507303 TI - Impacts of different methods of conception on the perinatal outcome of intrahepatic cholestasis of pregnancy in twin pregnancies. AB - Twin pregnancies have a higher prevalence of intrahepatic cholestasis of pregnancy (ICP) than single pregnancies. It is unknown whether in vitro fertilization-embryo transfer (IVF-ET) influences the fetal outcomes in twin pregnancies complicated by ICP. This study aimed to explore the impact of IVF-ET on the perinatal outcomes of ICP in twin pregnancy. Clinical data from 142 twin pregnant women complicated with ICP were retrospectively analyzed, including 51 patients who conceived through IVF-ET (IVF group) and 91 patients with spontaneous conception (SC group). Several biochemical indicators and perinatal outcomes were analyzed. Compared to the SC group, the IVF group had a higher incidence of early-onset ICP (P = 0.015) and more frequent clinical symptoms (P = 0.020), including skin pruritus, skin scratch, and jaundice. Furthermore, the IVF group had higher rates of neonatal asphyxia (IVF vs. SC, 9.80% vs. 1.10%, P = 0.023) and premature delivery (IVF vs. SC, 96.08% vs. 83.52%, P = 0.027) compared to the SC group. The IVF-conceived twin pregnancy group had a higher risk of early-onset ICP and suffered from clinical symptoms and poor perinatal outcomes. PMID- 29507304 TI - Observation of optic disc neovascularization using OCT angiography in proliferative diabetic retinopathy after intravitreal conbercept injections. AB - This study reports the short-term efficacy and safety of intravitreal conbercept injections for neovascularization at the disc (NVD) in patients with proliferative diabetic retinopathy (PDR). Conbercept is a recombinant fusion protein with a high affinity for all isoforms of vascular endothelial growth factor (VEGF)-A, placental growth factor and VEGF-B. A prospective case series study was conducted in 15 patients (15 eyes). Patients had complete ocular examinations and received a 0.5 mg intravitreal conbercept injection followed by supplemental pan-retinal photocoagulation (PRP). Optical coherence tomography angiography (OCTA) was performed before and after treatment. Before treatment, the mean NVD area was 1.05 +/- 0.33 mm2, and it decreased to 0.56 +/- 0.17 mm2 after an interval of 7.5 d (p = 0.000). One eye required vitrectomy during follow up. Recurrent NVD was observed in 2 eyes, which resolved after repeated injections. The remaining 12 eyes were stable over a mean follow-up period of 8.3 months. The mean area of the NVD in 14 patients without vitrectomy was 0.22 +/- 0.11 mm2 (p = 0.000) at the last visit. Intravitreal conbercept injections combined with intensive PRP are an effective and safe treatment for PDR with NVD. Quantitative information on NVD can be obtained with OCTA, which may be clinically useful in evaluating the therapeutic effect. PMID- 29507305 TI - Association between causes of peritoneal dialysis technique failure and all-cause mortality. AB - Technique failure is a frequent complication of peritoneal dialysis (PD), but the association between causes of death-censored technique failure and mortality remains unclear. Using Australian and New Zealand Dialysis and Transplant (ANZDATA) registry data, we examined the associations between technique failure causes and mortality in all incident PD patients who experienced technique failure between 1989-2014. Of 4663 patients, 2415 experienced technique failure attributed to infection, 883 to inadequate dialysis, 836 to mechanical failure and 529 to social reasons. Compared to infection, the adjusted hazard ratios (HR) for all-cause mortality in the first 2 years were 0.83 (95%CI 0.70-0.98) for inadequate dialysis, 0.78 (95%CI 0.66-0.93) for mechanical failure and 1.46 (95%CI 1.24-1.72) for social reasons. The estimates from the competing risk models were similar. There was an interaction between age and causes of technique failure (pinteraction < 0.001), such that the greatest premature mortality was observed in patients aged >60 years post social-related technique failure. There was no association between causes of technique failure and mortality beyond 2 years. In conclusion, infection and social-related technique failure are associated with premature mortality within 2 years post technique failure. Future studies examining the associations may help to improve outcomes in these patients. PMID- 29507306 TI - Sea urchin histamine receptor 1 regulates programmed cell death in larval Strongylocentrotus purpuratus. AB - Settlement is a rapid process in many marine invertebrate species, transitioning a planktonic larva into a benthic juvenile. In indirectly developing sea urchins, this ecological transition correlates with a morphological, developmental and physiological transition (metamorphosis) during which apoptosis is essential for the resorption and remodelling of larval and juvenile structures. While settlement is initiated by environmental cues (i.e. habitat-specific or benthic substrate cues), metamorphosis is regulated by developmental endocrine signals, such as histamine (HA), thyroid hormones (THs) and nitric oxide (NO). In the purple sea urchin, Strongylocentrotus purpuratus, we found that suH1R mRNA levels increase during larval development and peak during metamorphic competence. SuH1R positive cell clusters are prominently visible in the mouth region of sea urchin larvae, but the protein appears to be expressed at low levels throughout the larval arms and epidermis. SuH1R knock-down experiments in larval stages show that the function of suH1R is in inhibiting apoptosis. Our results therefore suggest that suH1R is regulating the metamorphic transition by inhibiting apoptosis. These results provide new insights into metamorphic mechanisms and have implications for our understanding of settlement and metamorphosis in the marine environment. PMID- 29507307 TI - A new electrospray method for targeted gene delivery. AB - A challenge for gene therapy is absence of safe and efficient local delivery of therapeutic genetic material. An efficient and reproducible physical method of electrospray for localized and targeted gene delivery is presented. Electrospray works on the principle of coulombs repulsion, under influence of electric field the liquid carrying genetic material is dispersed into micro droplets and is accelerated towards the targeted tissue, acting as a counter electrode. The accelerated droplets penetrate the targeted cells thus facilitating the transfer of genetic material into the cell. The work described here presents the principle of electrospray for gene delivery, the basic instrument design, and the various optimized parameters to enhance gene transfer in vitro. We estimate a transfection efficiency of up to 60% was achieved. We describe an efficient gene transfer method and a potential electrospray-mediated gene transfer mechanism. PMID- 29507308 TI - Circuit-specific and neuronal subcellular-wide E-I balance in cortical pyramidal cells. AB - We used ChR2-assisted circuit mapping (CRACM) to examine neuronal/compartmental excitatory and inhibitory synaptic balance (E-I balance) in pyramidal cells (PCs) located in several brain regions (including both neocortices and paleocortices). Within the vS1, different inputs on the same neurons, or the same inputs formed on different targets, induced different E/I ratios. E/I ratios in PCs from different regions were largely different. Chemogenetic silencing of somatostatin (SOM)- or parvalbumin (PV)-containing interneurons (INs) while optogenetically activating long-range M1 inputs demonstrated differential contribution of PV and SOM INs to the E/I ratios in a layer-specific manner in S1. Our results thus demonstrate that there are both universal subcellular-wide E-I balance within single PC and high specificity in the value of E/I ratios across different circuits (i.e. visual, somatosensory, piriform and hippocampal). Specificity of E/I balance are likely caused by unique glutamatergic innervation of interneurons. The dichotomy of high specificity and generalization of subcellular E-I balance in different circuits forms the basis for further understanding of neuronal computation under physiological conditions and various neuro-psychiatric disease-states. PMID- 29507309 TI - Recombinant RNA-Dependent RNA Polymerase Complex of Ebola Virus. AB - Here we report on the expression, purification and characterization of recombinant ebola virus RNA-dependent RNA polymerase (EBOV RdRp). Active protein complexes composed of the large L protein and viral protein VP35 were isolated from insect cells and analyzed using a short primer/template substrate that allowed benchmarking against related enzymes. RNA synthesis by multiprotein complexes of EBOV, influenza B, respiratory syncytial virus (RSV) and monomeric enzymes of hepatitis C and Zika (ZIKV) viruses required a 5'-phosporylated primer. The minimum length of the primer varied between two and three nucleotides in this system. The EBOV enzyme utilizes Mg2+ as a co-factor and the D742A substitution provides an active site mutant that likely affects binding of the catalytic metal ions. Selectivity measurements with nucleotide analogues translate our assay into quantitative terms and facilitate drug discovery efforts. The related EBOV and RSV enzymes are not able to efficiently discriminate against ara-cytidine-5'-triphosphate. We demonstrate that this compound acts like a non-obligate chain-terminator. PMID- 29507310 TI - Periostin blockade overcomes chemoresistance via restricting the expansion of mesenchymal tumor subpopulations in breast cancer. AB - Recent studies suggest a functional involvement of Epithelial-Mesenchymal Transition (EMT) in tumor chemoresistance. Specifically, EMT is associated with chemoresistance and poor prognosis in triple-negative breast cancer. However, no effective therapy targeting EMT has been developed. Here, we report that periostin, an extracellular matrix protein, was induced upon chemotherapy and tightly correlated with the EMT gene signature and poor prognosis in breast cancer. In triple-negative breast cancer xenografts, chemotherapy upregulated periostin expression in tumor cells, triggered expansion of mesenchymal tumor cells and promoted invasion in residual tumors. Knockdown of periostin inhibited outgrowth and invasion of mesenchymal tumor cells upon chemotherapy. Furthermore, chemotherapy upregulated cancer-specific variants of periostin and application of a blocking antibody specifically targeting those variants overcame chemoresistance and halted disease progression without toxicity. Together, these data indicate that periostin plays a key role in EMT-dependent chemoresistance and is a promising target to overcome chemoresistance in triple-negative breast cancer. PMID- 29507311 TI - Voxel-wise comparisons of cellular microstructure and diffusion-MRI in mouse hippocampus using 3D Bridging of Optically-clear histology with Neuroimaging Data (3D-BOND). AB - A key challenge in medical imaging is determining a precise correspondence between image properties and tissue microstructure. This comparison is hindered by disparate scales and resolutions between medical imaging and histology. We present a new technique, 3D Bridging of Optically-clear histology with Neuroimaging Data (3D-BOND), for registering medical images with 3D histology to overcome these limitations. Ex vivo 120 * 120 * 200 MUm resolution diffusion-MRI (dMRI) data was acquired at 7 T from adult C57Bl/6 mouse hippocampus. Tissue was then optically cleared using CLARITY and stained with cellular markers and confocal microscopy used to produce high-resolution images of the 3D-tissue microstructure. For each sample, a dense array of hippocampal landmarks was used to drive registration between upsampled dMRI data and the corresponding confocal images. The cell population in each MRI voxel was determined within hippocampal subregions and compared to MRI-derived metrics. 3D-BOND provided robust voxel wise, cellular correlates of dMRI data. CA1 pyramidal and dentate gyrus granular layers had significantly different mean diffusivity (p > 0.001), which was related to microstructural features. Overall, mean and radial diffusivity correlated with cell and axon density and fractional anisotropy with astrocyte density, while apparent fibre density correlated negatively with axon density. Astrocytes, axons and blood vessels correlated to tensor orientation. PMID- 29507312 TI - Analysis of the oligomeric states of nucleophosmin using size exclusion chromatography. AB - Nucleophosmin (NPM1) is a multifunctional phosphoprotein which plays important roles in diverse biological processes. NPM1 can form homo- or hetero-oligomers through its N-terminal region, and bind DNA and RNA through its C-terminal region. However, the monomer-oligomer distribution of NPM1, and the extent of NPM1 binding and unbinding to RNA in living cells, are not fully understood. In this work, we analysed molecular complexes of NPM1 using size exclusion chromatography. We found that a substantial fraction of NPM1 behaves as an oligomer in HeLa cells. Furthermore, we identified three distinct oligomeric states of NPM1 using molecular characterization techniques such as subcellular localization and RNA binding. Finally, we found that heterozygous expression of a leukemia-associated NPM1 mutant significantly decreases the RNA binding level. Our data demonstrate that size exclusion chromatography provides a powerful tool for analysing NPM1 oligomers. PMID- 29507313 TI - Shear Viscosity of Uniform Fermi Gases with Population Imbalance. AB - The shear viscosity has been an important topic in ultracold Fermi gases, and it has served as a diagnostic of various theories. Due to the complicated phase structures of population-imbalanced (polarized) Fermi gases with tunable attraction, past works on the shear viscosity mainly focused on unpolarized Fermi gases. Here we investigate the shear viscosity of homogeneous, population imbalanced Fermi superfluid at finite temperatures by a pairing fluctuation theory for thermodynamical quantities and a gauge-invariant linear response theory for transport coefficients. The Cooper pairs lead to the anomalous shear viscosity analogous to the shear viscosity. We derive an exact relation connecting certain thermodynamic quantities and transport coefficients at the mean-field level for polarized unitary Fermi superfluids. An approximate relation beyond mean-field is proposed and only exhibits mild deviations from our numerical results. In the unitary and Bose-Einstein condensation (BEC) regimes, the total shear viscosity increases with the polarization because the excess majority fermions cause gapless excitations acting like a normal fluid. Moreover, competition among the excess fermions, noncondensed pairs, and fermionic quasiparticles may lead to non-monotonic behavior of the ratio between the shear viscosity and relaxation time as the polarization increases. PMID- 29507314 TI - Linear Micro-patterned Drug Eluting Balloon (LMDEB) for Enhanced Endovascular Drug Delivery. AB - In-stent restenosis (ISR) often occurs after applying drug eluting stents to the blood vessels suffering from atherosclerosis or thrombosis. For treatment of ISR, drug eluting balloons (DEB) have been developed to deliver anti-proliferative drugs to the lesions with ISR. However, there are still limitations of DEB such as low drug delivery efficiency and drug loss to blood flow. Although most researches have focused on alteration of drug formulation for more efficient drug delivery, there are few studies that have attempted to understand and utilize the contact modality of DEB drug delivery. Here, we developed a linear micro patterned DEB (LMDEB) that applied higher contact pressure to enhance drug stamping to vascular tissue. Ex vivo and in vivo studies confirmed that higher contact pressure from micro-patterns increased the amount of drug delivered to the deeper regions of vessel. Finite element method simulation also showed significant increase of contact pressure between endothelium and micro-patterns. Quantitative analysis by high performance liquid chromatography indicated that LMDEBs delivered 2.3 times higher amount of drug to vascular tissue in vivo than conventional DEBs. Finally, efficacy studies using both atherosclerotic and ISR models demonstrated superior patency of diseased vessels treated with LMDEB compared to those treated with DEB. PMID- 29507315 TI - Lactobacillus rossiae strain isolated from sourdough produces putrescine from arginine. AB - This work reports a Lactobacillus rossiae strain (L. rossiae D87) isolated from sourdough that synthesizes putrescine - a biogenic amine that raises food safety and spoilage concerns - from arginine via the ornithine decarboxylase (ODC) pathway. The odc and potE genes were identified and sequenced. These genes respectively encode ornithine decarboxylase (Odc), which participates in the decarboxylation of ornithine to putrescine, and the ornithine/putrescine exchanger (PotE), which exchanges ornithine for putrescine. Transcriptional analysis showed that odc and potE form an operon that is regulated transcriptionally by ornithine in a dose-dependent manner. To explore the possible role of the ODC pathway as an acid stress resistance mechanism for this bacterium, the effect of acidic pHs on its transcriptional regulation and on putrescine biosynthesis was analysed. Acidic pHs induced the transcription of the odc-potE genes and the production of putrescine over that seen at neutral pH. Further, putrescine production via the ODC system improved the survival of L. rossiae D87 by counteracting the acidification of the cytoplasm when the cells were subjected to acidic conditions. These results suggest the ODC pathway of L. rossiae D87 provides a biochemical defence mechanism against acidic environments. PMID- 29507316 TI - LPS-primed CD11b+ leukocytes serve as an effective carrier of Shiga toxin 2 to cause hemolytic uremic syndrome in mice. AB - Shiga toxin (Stx)-induced hemolytic uremic syndrome (HUS) is a life-threatening complication associated with Stx-producing Escherichia coli infection. One critical barrier of understanding HUS is how Stx transports from infected intestine to kidney to cause HUS. Passive dissemination seems unlikely, while circulating blood cells have been debated to serve as the toxin carrier. Employing a murine model of Stx2-induced HUS with LPS priming (LPS-Stx2), we investigate how Stx causes HUS and identify possible toxin carrier. We show that peripheral white blood cells (WBC), but not other blood cells or cell-free plasma, carry Stx2 in LPS-Stx2-treated mice. The capability of WBC binding to Stx2 is confirmed in brief ex vivo Stx2 incubation, and adoptively transferring these Stx2-bound WBC into mice induces HUS. Cell separation further identifies a subpopulation in the CD11b+ myeloid leukocytes not the CD11b- lymphocytes group act as the toxin carrier, which captures Stx2 upon exposure and delivers the toxin in vivo. Interestingly, LPS-induced inflammation significantly augments these leukocytes for binding to Stx2 and enhances HUS toxicity. Our results demonstrate that a specific fraction of circulating leukocytes carry Stx2 and cause HUS in vivo, and that LPS priming enhances the carrier capacity and aggravates organ damage. PMID- 29507317 TI - Probing the localization of magnetic dichroism by atomic-size astigmatic and vortex electron beams. AB - We report localization of a magnetic dichroic signal on atomic columns in electron magnetic circular dichroism (EMCD), probed by beam distorted by four fold astigmatism and electron vortex beam. With astigmatic probe, magnetic signal to noise ratio can be enhanced by blocking the intensity from the central part of probe. However, the simulations show that for atomic resolution magnetic measurements, vortex beam is a more effective probe, with much higher magnetic signal to noise ratio. For all considered beam shapes, the optimal SNR constrains the signal detection at low collection angles of approximately 6-8 mrad. Irrespective of the material thickness, the magnetic signal remains strongly localized within the probed atomic column with vortex beam, whereas for astigmatic probes, the magnetic signal originates mostly from the nearest neighbor atomic columns. Due to excellent signal localization at probing individual atomic columns, vortex beams are predicted to be a strong candidate for studying the crystal site specific magnetic properties, magnetic properties at interfaces, or magnetism arising from individual atomic impurities. PMID- 29507318 TI - Prediction of pKa Values for Neutral and Basic Drugs based on Hybrid Artificial Intelligence Methods. AB - The pKa value of drugs is an important parameter in drug design and pharmacology. In this paper, an improved particle swarm optimization (PSO) algorithm was proposed based on the population entropy diversity. In the improved algorithm, when the population entropy was higher than the set maximum threshold, the convergence strategy was adopted; when the population entropy was lower than the set minimum threshold the divergence strategy was adopted; when the population entropy was between the maximum and minimum threshold, the self-adaptive adjustment strategy was maintained. The improved PSO algorithm was applied in the training of radial basis function artificial neural network (RBF ANN) model and the selection of molecular descriptors. A quantitative structure-activity relationship model based on RBF ANN trained by the improved PSO algorithm was proposed to predict the pKa values of 74 kinds of neutral and basic drugs and then validated by another database containing 20 molecules. The validation results showed that the model had a good prediction performance. The absolute average relative error, root mean square error, and squared correlation coefficient were 0.3105, 0.0411, and 0.9685, respectively. The model can be used as a reference for exploring other quantitative structure-activity relationships. PMID- 29507319 TI - Phenotype-driven identification of epithelial signalling clusters. AB - In metazoans, epithelial architecture provides a context that dynamically modulates most if not all epithelial cell responses to intrinsic and extrinsic signals, including growth or survival signalling and transforming oncogene action. Three-dimensional (3D) epithelial culture systems provide tractable models to interrogate the function of human genetic determinants in establishment of context-dependency. We performed an arrayed genetic shRNA screen in mammary epithelial 3D cultures to identify new determinants of epithelial architecture, finding that the key phenotype impacting shRNAs altered not only the data population average but even more noticeably the population distribution. The broad distributions were attributable to sporadic gene silencing actions by shRNA in unselected populations. We employed Maximum Mean Discrepancy concept to capture similar population distribution patterns and demonstrate here the feasibility of the test in identifying an impact of shRNA in populations of 3D structures. Integration of the clustered morphometric data with protein-protein interactions data enabled hypothesis generation of novel biological pathways underlying similar 3D phenotype alterations. The results present a new strategy for 3D phenotype-driven pathway analysis, which is expected to accelerate discovery of context-dependent gene functions in epithelial biology and tumorigenesis. PMID- 29507320 TI - Comparative efficacy of corticosteroid injection and non-invasive treatments for plantar fasciitis: a systematic review and meta-analysis. AB - The first choice of treatment for patients with plantar fasciitis is non-invasive treatment, rather than corticosteroid injection (CSI). However, no comprehensive study has compared the effectiveness of CSI with non-invasive treatments for plantar fasciitis. We conducted a meta-analysis comparing CSI and non-invasive treatment effects on plantar fasciitis. The primary outcome was pain reduction. Nine randomized controlled trials comparing CSI with 4 non-invasive treatment types were included. A trend favoring CSI over non-invasive treatments was indicated regarding reduction in the visual analogue scale (VAS) score at 1-1.5 (mean difference (MD), 1.70; 95% confidence interval (CI) = 0.39-3.01; P = 0.01) and 2-3 months (MD, 1.67; 95% CI = 0.58-2.76; P = 0.003). At 1.5-month follow-up, CSI was associated with improved VAS score compared with physical therapy (PT) (MD, 2.5; 95% CI = 0.1-4.9; P = 0.04). No significant differences in the VAS score reduction were observed between CSI and shock wave therapy within 3 months. In summary, CSI tends to be more effective for pain reduction than non-invasive treatments within 3 months. Moreover, CSI provides significant pain relief at 1.5 months after treatment compared with PT. This study provides important clinical information for selecting therapeutics. PMID- 29507321 TI - Marine spatial planning makes room for offshore aquaculture in crowded coastal waters. AB - Marine spatial planning (MSP) seeks to reduce conflicts and environmental impacts, and promote sustainable use of marine ecosystems. Existing MSP approaches have successfully determined how to achieve target levels of ocean area for particular uses while minimizing costs and impacts, but they do not provide a framework that derives analytical solutions in order to co-ordinate siting of multiple uses while balancing the effects of planning on each sector in the system. We develop such a framework for guiding offshore aquaculture (bivalve, finfish, and kelp farming) development in relation to existing sectors and environmental concerns (wild-capture fisheries, viewshed quality, benthic pollution, and disease spread) in California, USA. We identify > 250,000 MSP solutions that generate significant seafood supply and billions of dollars in revenue with minimal impacts (often < 1%) on existing sectors and the environment. We filter solutions to identify candidate locations for high-value, low-impact aquaculture development. Finally, we confirm the expectation of substantial value of our framework over conventional planning focused on maximizing individual objectives. PMID- 29507323 TI - Exposure of kale root to NaCl and Na2SeO3 increases isothiocyanate levels and Nrf2 signalling without reducing plant root growth. AB - A plant factory is a closed cultivation system that provides a consistent and modified environment for plant growth. We speculated that treatment of kale (Brassica oleracea) grown in a plant factory with NaCl, Na2SeO3, or both would increase the bioactive phytochemical levels including glucosinolates (GLSs) and isothiocyanates (ITCs), the key molecules in cancer prevention. The kale was harvested and analysed after treatment with NaCl and Na2SeO3 alone or in combination for 1 or 2 weeks. Exposure to NaCl alone but not Na2SeO3 increased plant root growth. Levels of sinigrin were increased by a 2-week exposure to Na2SeO3 alone or in combination with NaCl, whereas no changes were observed in glucoraphanin and gluconasturtiin gluconasturtiin levels. Importantly, the ITC concentration was affected by 2-week treatment with both compounds. To evaluate the bioactivity of kale, HepG2 human hepatoma cells were treated with plant extract for 6 h. Only the extract of kale roots exposed to a combination NaCl and Na2SeO3 for 2 weeks showed an increased expression of nuclear factor erythroid 2 related factor (Nrf2), which regulates genes encoding antioxidant proteins. These data suggest that co-treatment with NaCl and Na2SeO3 increased the ITC content and chemopreventive effects of kale root. PMID- 29507322 TI - The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target. AB - Apicomplexa form a phylum of obligate parasitic protozoa of great clinical and veterinary importance. These parasites synthesize glycoconjugates for their survival and infectivity, but the enzymatic steps required to generate the glycosylation precursors are not completely characterized. In particular, glucosamine-phosphate N-acetyltransferase (GNA1) activity, needed to produce the essential UDP-N-acetylglucosamine (UDP-GlcNAc) donor, has not been identified in any Apicomplexa. We scanned the genomes of Plasmodium falciparum and representatives from six additional main lineages of the phylum for proteins containing the Gcn5-related N-acetyltransferase (GNAT) domain. One family of GNAT domain containing proteins, composed by a P. falciparum sequence and its six apicomplexan orthologs, rescued the growth of a yeast temperature-sensitive GNA1 mutant. Heterologous expression and in vitro assays confirmed the GNA1 enzymatic activity in all lineages. Sequence, phylogenetic and synteny analyses suggest an independent origin of the Apicomplexa-specific GNA1 family, parallel to the evolution of a different GNA1 family in other eukaryotes. The inability to disrupt an otherwise modifiable gene target suggests that the enzyme is essential for P. falciparum growth. The relevance of UDP-GlcNAc for parasite viability, together with the independent evolution and unique sequence features of Apicomplexa GNA1, highlights the potential of this enzyme as a selective therapeutic target against apicomplexans. PMID- 29507324 TI - Monosulfonicpillar[5]arene: Synthesis, Characterization, and Complexation with Tetraphenylethene for Aggregation-Induced Emission. AB - A pillar[5]arene derivative with a hydrophilic sulfonic group, i.e., monosulfonicpillar[5]arene (MSP5), has been successfully synthesized for the first time, which exhibited strong binding affinity towards alcohol analogs. Significantly, fluorescent supramolecular ensemble was fabricated from the supramolecular complexation of MSP5 and a neutral guest with tetraphenylethene core. Enhanced fluorescent emission of this system can be detected both in dilute solution and the solid state, and its temperature and competitive guest multi responsive properties suggest its promising application as a chemical sensor towards alcohol analogs, ethylenediamine, and temperature variations. PMID- 29507325 TI - Identification of microRNAs involved in lipid biosynthesis and seed size in developing sea buckthorn seeds using high-throughput sequencing. AB - Sea buckthorn is a plant of medicinal and nutritional importance owing in part to the high levels of essential fatty acids, linoleic (up to 42%) and alpha linolenic (up to 39%) acids in the seed oil. Sea buckthorn can produce seeds either via the sexual pathway or by apomixis. The seed development and maturation programs are critically dependent on miRNAs. To understand miRNA-mediated regulation of sea buckthorn seed development, eight small RNA libraries were constructed for deep sequencing from developing seeds of a low oil content line 'SJ1' and a high oil content line 'XE3'. High-throughput sequencing identified 137 known miRNA from 27 families and 264 novel miRNAs. The potential targets of the identified miRNAs were predicted based on sequence homology. Nineteen (four known and 15 novel) and 22 (six known and 16 novel) miRNAs were found to be involved in lipid biosynthesis and seed size, respectively. An integrated analysis of mRNA and miRNA transcriptome and qRT-PCR identified some key miRNAs and their targets (miR164d-ARF2, miR168b-Delta9D, novelmiRNA-108-ACC, novelmiRNA 23-GPD1, novelmiRNA-58-DGAT1, and novelmiRNA-191-DGAT2) potentially involved in seed size and lipid biosynthesis of sea buckthorn seed. These results indicate the potential importance of miRNAs in regulating lipid biosynthesis and seed size in sea buckthorn. PMID- 29507326 TI - Thermal Expansion in Layered Na x MO2. AB - Layered oxide Na x MO2 (M: transition metal) is a promising cathode material for sodium-ion secondary battery. Crystal structure of O3- and P2-type Na x MO2 with various M against temperature (T) was systematically investigated by synchrotron x-ray diffraction mainly focusing on the T-dependences of a- and c-axis lattice constants (a and c) and z coordinate (z) of oxygen. Using a hard-sphere model with minimum Madelung energy, we confirmed that c/a and z values in O3-type Na x MO2 were reproduced. We further evaluated the thermal expansion coefficients (alpha a and alpha c ) along a- and c-axis at 300 K. The anisotropy of the thermal expansion was quantitatively reproduced without adjustable parameters for O3-type Na x MO2. Deviations of z from the model for P2-type Na x MO2 are ascribed to Na vacancies characteristic to the structure. PMID- 29507327 TI - Generation and characterization of a hypothyroidism rat model with truncated thyroid stimulating hormone receptor. AB - Thyroid stimulating hormone receptor (TSHR), a G-protein-coupled receptor, is important for thyroid development and growth. In several cases, frameshift and/or nonsense mutations in TSHR were found in the patients with congenital hypothyroidism (CH), however they have not been functionally studied in an animal model. In the present work, we generated a unique Tshr Df/Df rat model that recapitulates the phenotypes in TSHR Y444X patient by CRISPR/Cas genome editing technology. In this rat model, TSHR is truncated at the second transmembrane domain, leading to CH phenotypes as what was observed in the patients, including dwarf, thyroid aplasia, infertility, TSH resistant as well as low serum thyroid hormone levels. The phenotypes can be reversed, at least partially, by levothyroxine (L-T4) treatment after weaning. The thyroid development is severely impaired in the Tshr Df/Df rats due to the suppression of the thyroid specific genes, i.e., thyroperoxidase (Tpo), thyroglobulin (Tg) and sodium iodide symporter (Nis), at both mRNA and protein levels. In conclusion, the Tshr Df/Df rat serves as a brand new genetic model to study CH in human, and will greatly help to shed light into the development of terminal organs that are sensitive to thyroid hormones. PMID- 29507328 TI - In vivo imaging of T cell lymphoma infiltration process at the colon. AB - The infiltration and proliferation of cancer cells in the secondary organs are of great interest, since they contribute to cancer metastasis. However, cancer cell dynamics in the secondary organs have not been elucidated at single-cell resolution. In the present study, we established an in vivo model using two photon microscopy to observe how infiltrating cancer cells form assemblages from single T-cell lymphomas, EL4 cells, in the secondary organs. Using this model, after inoculation of EL4 cells in mice, we discovered that single EL4 cells infiltrated into the colon. In the early stage, sporadic elongated EL4 cells became lodged in small blood vessels. Real-time imaging revealed that, whereas more than 70% of EL4 cells did not move during a 1-hour observation, other EL4 cells irregularly moved even in small vessels and dynamically changed shape upon interacting with other cells. In the late stages, EL4 cells formed small nodules composed of several EL4 cells in blood vessels as well as crypts, suggesting the existence of diverse mechanisms of nodule formation. The present in vivo imaging system is instrumental to dissect cancer cell dynamics during metastasis in other organs at the single-cell level. PMID- 29507329 TI - Three dimensional-stacked complementary thin-film transistors using n-type Al:ZnO and p-type NiO thin-film transistors. AB - The three dimensional inverters were fabricated using novel complementary structure of stacked bottom n-type aluminum-doped zinc oxide (Al:ZnO) thin-film transistor and top p-type nickel oxide (NiO) thin-film transistor. When the inverter operated at the direct voltage (VDD) of 10 V and the input voltage from 0 V to 10 V, the obtained high performances included the output swing of 9.9 V, the high noise margin of 2.7 V, and the low noise margin of 2.2 V. Furthermore, the high performances of unskenwed inverter were demonstrated by using the novel complementary structure of the stacked n-type Al:ZnO thin-film transistor and p type nickel oxide (NiO) thin-film transistor. PMID- 29507330 TI - Association between sea lice (Lepeophtheirus salmonis) infestation on Atlantic salmon farms and wild Pacific salmon in Muchalat Inlet, Canada. AB - Growth in salmon aquaculture over the past two decades has raised concerns regarding the potential impacts of the industry on neighboring ecosystems and wild fish productivity. Despite limited evidence, sea lice have been identified as a major cause for the decline in some wild Pacific salmon populations on the west coast of Canada. We used sea lice count and management data from farmed and wild salmon, collected over 10 years (2007-2016) in the Muchalat Inlet region of Canada, to evaluate the association between sea lice recorded on salmon farms with the infestation levels on wild out-migrating Chum salmon. Our analyses indicated a significant positive association between the sea lice abundance on farms and the likelihood that wild fish would be infested. However, increased abundance of lice on farms was not significantly associated with the levels of infestation observed on the wild salmon. Our results suggest that Atlantic salmon farms may be an important source for the introduction of sea lice to wild Pacific salmon populations, but that the absence of a dose response relationship indicates that any estimate of farm impact requires more careful evaluation of causal inference than is typically seen in the extant scientific literature. PMID- 29507331 TI - Higher retinal vessel oxygen saturation: investigating its relationship with macular oedema in retinitis pigmentosa patients. AB - PURPOSE: Primary objective-to investigate the effect of retinal vessel oxygen saturation (SO2) on macular oedema (ME) in retinitis pigmentosa (RP) patients. Secondary objective-to link the presence of ME to metabolic (oxygen saturation of retinal vessels, SO2), functional (multifocal electroretinography, mfERG) and structural (Spectral Domain Optical Coherent Tomography, SD-OCT) alterations in RP. DESIGN: Prospective, cross-sectional, non-interventional study. SUBJECTS: Patients with typical RP (N = 37) and controls (N = 19), who underwent retinal vessel Oximetry (RO), SD-OCT and mfERG, were included. METHODS: A computer-based program of the retinal vessel analyser unit (IMEDOS Systems UG, Jena, Germany) was used to measure SO2. We evaluated the mean SO2, in all major retinal arterioles (oxygen saturation in retinal arterioles, A-SO2, %) and venules (oxygen saturation in retinal venules, V-SO2, %). MfERG responses were averaged in zones (zone 1 (0-3 degrees ), zone 2 (3-8 degrees ) and zone 3 (8-15 degrees )) and compared to corresponding areas of the OCT. The effect of ME on SO2 was evaluated dividing the RP in two subgroups: with clinical appearance of ME (ME RP) and without it (no-ME-RP). MAIN OUTCOME MEASURES: Parallel recording and juxtaposition of metabolic (SO2) to structural (OCT) and functional-(mfERG) measures. Mean ( +/- SD) A-SO2 and V-SO2 were higher in no-ME-RP (96.77% (+/ 6.31) and 59.93% (+/-7.76)) and even higher in the ME-RP (99.82% (+/-6.21) and 65.63% (+/-7.63)), compared to controls (93.15% (+/-3.76) and 53.77% (+/-3.70), p <= 0.006). RESULTS: The subgroup ME-RP differed significantly from the subgroup no-ME-RP by increased A-SO2 and V-SO2, p <= 0.026. The presence of ME confirmed a different relationship between the altered SO2 and the vessel diameters, against the functional and structural parameters. CONCLUSION: Based on our results, the presence of macular oedema indicates a tendency toward greater alteration of the metabolic function in RP patients. PMID- 29507332 TI - Convergent shifts in host-associated microbial communities across environmentally elicited phenotypes. AB - Morphological plasticity is a genotype-by-environment interaction that enables organisms to increase fitness across varying environments. Symbioses with diverse microbiota may aid in acclimating to this variation, but whether the associated bacteria community is phenotype specific remains understudied. Here we induce morphological plasticity in three species of sea urchin larvae and measure changes in the associated bacterial community. While each host species has unique bacterial communities, the expression of plasticity results in the convergence on a phenotype-specific microbiome that is, in part, driven by differential association with alpha- and gamma-proteobacteria. Furthermore, these results suggest that phenotype-specific signatures are the product of the environment and are correlated with ingestive and digestive structures. By manipulating diet quantity over time, we also show that differentially associating with microbiota along a phenotypic continuum is bidirectional. Taken together, our data support the idea of a phenotype-specific microbial community and that phenotypic plasticity extends beyond a genotype-by-environment interaction. PMID- 29507333 TI - A browser-based tool for visualization and analysis of diffusion MRI data. AB - Human neuroscience research faces several challenges with regards to reproducibility. While scientists are generally aware that data sharing is important, it is not always clear how to share data in a manner that allows other labs to understand and reproduce published findings. Here we report a new open source tool, AFQ-Browser, that builds an interactive website as a companion to a diffusion MRI study. Because AFQ-Browser is portable-it runs in any web-browser it can facilitate transparency and data sharing. Moreover, by leveraging new web visualization technologies to create linked views between different dimensions of the dataset (anatomy, diffusion metrics, subject metadata), AFQ-Browser facilitates exploratory data analysis, fueling new discoveries based on previously published datasets. In an era where Big Data is playing an increasingly prominent role in scientific discovery, so will browser-based tools for exploring high-dimensional datasets, communicating scientific discoveries, aggregating data across labs, and publishing data alongside manuscripts. PMID- 29507334 TI - Night Sleep Duration and Risk of Incident Anemia in a Chinese Population: A Prospective Cohort Study. AB - The purpose was to study the association between sleep duration and the prevalence of anemia in Chinese people. There were 84,791 participants (men: 79.1%; women: 20.9%) aged 18-98 years in the prospective study. We divided the participants into five categories based on the individual sleep duration: <=5 h, 6 h, 7 h(reference), 8 h, and >=9 h. Anemia was defined based on hemoglobin <12 g/dL for men and <11 g/dL for women. The Cox proportional hazards model was used to assess the association between sleep duration and anemia. During median follow up of 7.9 years, 2698 cases of anemia had occurred. The HRand (95% CI) of anemia (7 h as the reference group) for individuals reporting <=5 h, 6 h, 8 h, and >=9 h were 1.23(1.04-1.45), 1.26(1.11-1.44), 1.04(0.92-1.16) and 1.42(1.08-1.86), respectively. It showed that there was a significant interaction on the risk of anemia between sleep duration and sex in the secondary analysis (p < 0.001).The significant association between long sleepduration and anemia was found in women (HR, 2.29; 95% CI, 1.56-3.37), not in men(HR, 0.90; 95% CI, 0.60-1.34). Both short and long night sleep duration were associated with increased risk of anemia. PMID- 29507335 TI - Omnivore-herbivore interactions: thrips and whiteflies compete via the shared host plant. AB - Phytophagy is a common feature among pure herbivorous insects and omnivores that utilise both plant and prey as food resources; nevertheless, experimental evidence for factors affecting their interactions is restricted to intraguild predation and predator-mediated competition. We herein focused on plant-mediated effects that could result from plant defence activation or quality alteration and compared the performance of an omnivore, the western flower thrips Frankliniella occidentalis, and a pure herbivore, the greenhouse whitefly Trialeurodes vaporariorum, on cucumber plants previously infested with either species. Furthermore, we recorded their behavioural responses when given a choice among infested and clean plants. Whiteflies laid less eggs on plants previously exposed to thrips but more on whitefly-infested plants. Thrips survival was negatively affected on whitefly-infested than on thrips-infested or clean plants. Notably, whiteflies developed significantly faster on plants infested with conspecifics. In accordance, whiteflies avoided thrips-infested plants and preferred whitefly infested over clean plants. Thrips showed no preference for either infested or clean plants. Our study is a first report on the role of plant-mediated effects in shaping omnivore-herbivore interactions. Considering the factors driving such interactions we will likely better understand the ecology of the more complex relationships among plants and pest organisms. PMID- 29507337 TI - Cedratvirus getuliensis replication cycle: an in-depth morphological analysis. AB - The giant viruses are the largest and most complex viruses in the virosphere. In the last decade, new members have constantly been added to this group. Here, we provide an in-depth descriptive analysis of the replication cycle of Cedratvirus getuliensis, one of the largest viruses known to date. We tracked the virion entry, the early steps of virus factory and particles morphogenesis, and during this phase, we observed a complex and unique sequential organization of immature particle elements, including horseshoe and rectangular compartments, revealed by transverse and longitudinal sections, respectively, until the formation of the final ovoid-shaped striped virion. The genome and virion proteins are incorporated through a longitudinal opening in the immature virion, followed by the incorporation of the second cork and thickening of the capsid well. Moreover, many cell modifications occur during viral infection, including intense membrane trafficking important to viral morphogenesis and release, as evidenced by treatment using brefeldin A. Finally, we observed that Cedratvirus getuliensis particles are released after cellular lysis, although we obtained microscopic evidence that some particles are released by exocytosis. The present study provides new information on the unexplored steps in the life cycle of cedratviruses. PMID- 29507336 TI - Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue. AB - Inflammation, following injury, induces cellular plasticity as an inherent component of physiological tissue repair. The dominant fate of wound macrophages is unclear and debated. Here we show that two-thirds of all granulation tissue fibroblasts, otherwise known to be of mesenchymal origin, are derived from myeloid cells which are likely to be wound macrophages. Conversion of myeloid to fibroblast-like cells is impaired in diabetic wounds. In cross-talk between keratinocytes and myeloid cells, miR-21 packaged in extracellular vesicles (EV) is required for cell conversion. EV from wound fluid of healing chronic wound patients is rich in miR-21 and causes cell conversion more effectively compared to that by fluid from non-healing patients. Impaired conversion in diabetic wound tissue is rescued by targeted nanoparticle-based delivery of miR-21 to macrophages. This work introduces a paradigm wherein myeloid cells are recognized as a major source of fibroblast-like cells in the granulation tissue. PMID- 29507338 TI - Myocardial Effective Transverse Relaxation Time T 2* is Elevated in Hypertrophic Cardiomyopathy: A 7.0 T Magnetic Resonance Imaging Study. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium and bares the risk of progression to heart failure or sudden cardiac death. Identifying patients at risk remains an unmet need. Recognizing the dependence of microscopic susceptibility on tissue microstructure and on cardiac macromorphology we hypothesized that myocardial T2* might be altered in HCM patients compared to healthy controls. To test this hypothesis, myocardial T2* mapping was conducted at 7.0 Tesla to enhance T2*-contrast. 2D CINE T2*-mapping was performed in healthy controls and HCM patients. To ensure that T2* is not dominated by macroscopic magnetic field inhomogeneities, volume selective B0 shimming was applied. T2* changes in the interventricular septum across the cardiac cycle were analyzed together with left ventricular radius and ventricular septal wall thickness. The results show that myocardial T2* is elevated throughout the cardiac cycle in HCM patients compared to healthy controls. A mean septal T2* = 13.7 +/- 1.1 ms (end-systole: T2*,systole = 15.0 +/- 2.1, end diastole: T2*,diastole = 13.4 +/- 1.3 ms, T2*,systole/T2*,diastole ratio = 1.12) was observed in healthy controls. For HCM patients a mean septal T2* = 17.4 +/- 1.4 ms (end-systole: T2*,systole = 17.7 +/- 1.2 ms, end-diastole: T2*,diastole = 16.2 +/- 2.5 ms, T2*,systole/T2*,diastole ratio = 1.09) was found. Our preliminary results provide encouragement that assessment of T2* and its changes across the cardiac cycle may benefit myocardial tissue characterization in HCM. PMID- 29507339 TI - Socioeconomic Status and Race are both Independently associated with Increased Hospitalization Rate among Crohn's Disease Patients. AB - Racial disparities are observed clinically in Crohn's Disease (CD) with research suggesting African Americans (AA) have worse outcomes than Caucasian Americans (CA). The aim of this study is to assess whether socioeconomic status (SES) rather than race is the major predictor of worse outcomes. We designed a retrospective cohort study of 944 CD patients seen at our center. Patients' billing zip codes were collected and average income and percent of population living above or below poverty level (PL) for each zip code calculated. Patients were separated by quartiles using average state income level and federal PL. Demographics and hospitalization rates were collected. Poison regression models estimated incidence rate ratios (IRR) for CD-related hospitalizations. Incidence rate (IR) of hospitalization per 100-person years for the lowest income group was 118 (CI 91.4-152.3), highest income group was 29 (CI 21.7-38.9), Above PL was 26.9 (25.9-28.9), Below PL was 35.9 (33.1-38.9), CA was 25.3 (23.7-27), and AA was 51.4 (46.8-56.3). IRR for a CD-related hospitalization for lowest income group was 2.01 (CI 1.34-3.01), for Below PL was 1.26 (CI 1.12-1.42), and for AAs was 1.88 (CI 1.66-2.12). SES and race are both associated with hospitalization among CD patients and need further investigation. PMID- 29507341 TI - The relation between mental health, homosexual stigma, childhood abuse, community engagement, and unprotected anal intercourse among MSM in China. AB - The aim of the study was to explore the relation of various factors with unprotected anal intercourse (UAI) and provide some insight for HIV intervention on Chinese men who have sex with men (MSM). The current cross-sectional study recruited 365 MSM in Dalian, China. More than half of the respondents (117 respondents, 51.8% of the sample) had engaged in UAI. The multivariable logistic regression model suggested that poorer mental health (AOR: 7.16; 95% CI: 3.14 16.31), self-stigma (AOR: 1.53; 95% CI: 1.00-2.34), and experience(s) of physical abuse in childhood (AOR: 5.85; 95% CI: 1.77-19.30) were significantly and positively related to UAI. Community engagement was negatively associated with UAI (p < 0.05). It appears it is necessary to incorporate mental health services, eliminate the stigma against homosexuality, and facilitate MSM-related community engagement into intervention strategies to prevent UAI among Chinese MSM. Targeted UAI interventions in the subgroup with a history of childhood physical abuse should also be of great concern. PMID- 29507340 TI - MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB. AB - Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation dependent lysosomal localization of MAP4K3. We document that MAP4K3 physically interacts with TFEB and MAP4K3 inhibition is sufficient for TFEB nuclear localization, target gene transactivation, and autophagy, even when mTORC1 is activated. Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. Our results uncover a role for MAP4K3 in the control of autophagy and reveal MAP4K3 as a central node in nutrient-sensing regulation. PMID- 29507342 TI - Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells. AB - Tumours have developed strategies to interfere with most steps required for anti tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation. PMID- 29507343 TI - The Seasonality of Acute Attack of Primary Angle-Closure Glaucoma in Beijing, China. AB - In this study, the seasonality of acute attack of primary angle-closure glaucoma (PACG) was analysed. This retrospective case series included 283 patients (200 women, 83 men; mean age, 68.2 +/- 10.3 years; range, 37-96 years) with acute attack of PACG from a university-based clinic over 4 years. Patients' age and sex, and the date and season of onset of PACG attack, were analysed. Descriptive analysis and von Mises distribution were used for statistical analysis. The highest incidence of acute attack of PACG was observed in those aged 60-69 years (34.6%). Descriptive analysis showed that the incidence was greater in June and July for men, November for women, and November for the entire sample. An angular plot (using von Mises distribution) of the individual dates of onset revealed the estimated peak onset on September 11, November 8, and October 28 for men, women, and both, respectively. Integration of the results from the two analyses revealed the incidence to be higher in the summer and winter for men, and in the winter for women and for the entire sample. More females than males were affected. Monthly and seasonal variations in onset were observed, which might be related to weather changes. PMID- 29507344 TI - Effect of human very low-density lipoproteins on cardiotrophin-like cytokine factor 1 (CLCF1) activity. AB - The cytokines CLCF1 and CNTF are ligands for the CNTF receptor and the apolipoprotein E (ApoE) receptor sortilin. Both share structural similarities with the N-terminal domain of ApoE, known to bind CNTF. We therefore evaluated whether ApoE or ApoE-containing lipoproteins interact with CLCF1 and regulate its activity. We observed that CLCF1 forms complexes with the three major isoforms of ApoE in co-immunoprecipitation and proximity assays. FPLC analysis of mouse and human sera mixed with CLCF1 revealed that CLCF1 co-purifies with plasma lipoproteins. Studies with sera from ApoE-/- mice indicate that ApoE is not required for CLCF1-lipoprotein interactions. VLDL- and LDL-CLCF1 binding was confirmed using proximity and ligand blots assays. CLCF1-induced STAT3 phosphorylation was significantly reduced when the cytokine was complexed with VLDL. Physiological relevance of our findings was asserted in a mouse model of oxygen-induced retinopathy, where the beneficial anti-angiogenic properties of CLCF1 were abrogated when co-administrated with VLDL, indicating, that CLCF1 binds purified lipoproteins or lipoproteins in physiological fluids such as serum and behave as a "lipocytokine". Albeit it is clear that lipoproteins modulate CLCF1 activity, it remains to be determined whether lipoprotein binding directly contributes to its neurotrophic function and its roles in metabolic regulation. PMID- 29507345 TI - Inhibitory effects of superoxide dismutase 3 on Propionibacterium acnes-induced skin inflammation. AB - Propionibacterium acnes is a well-known commensal bacterium that plays an important role in the pathogenesis of acne and chronic inflammatory skin disease. In this study, we investigated the effect of superoxide dismutase 3 (SOD3) on P. acnes- or peptidoglycan (PGN)-induced inflammation in vitro and in vivo. Our data demonstrated that SOD3 suppressed toll-like receptor-2 (TLR-2) expression in P. acnes- or PGN-treated keratinocytes and sebocytes. Moreover, we found that SOD3 suppressed the expressions of phosphorylated nuclear factor-kappaB (NF-kappaB) and p38 in P. acnes- or PGN-treated cells. SOD3 also exhibited an anti inflammatory role by reducing the expression of inflammasome-related proteins (NLRP3, ASC, caspase-1) and inhibiting the expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta, interleukin 6, and interleukin-8. In addition, SOD3 reduced lipid accumulation and expression of lipogenic regulators in P. acnes-treated sebocytes. Recombinant SOD3-treated wild-type mice and SOD3 transgenic mice, which were subcutaneously infected with P. acnes, showed tolerance to inflammation through reducing inflammatory cell infiltration in skin, ear thickness, and expression of inflammatory mediators. Our result showed that SOD3 could suppress the inflammation through inhibition of TLR2/p38/NF-kappaB axis and NLRP3 inflammasome activation. Therefore, SOD3 could be a promising candidate for treatment of P. acnes-mediated skin inflammation. PMID- 29507346 TI - Experimental observation of photonic nodal line degeneracies in metacrystals. AB - Nodal line semimetals (NLS) are three-dimensional (3D) crystals that support band crossings in the form of one-dimensional rings in the Brillouin zone. In the presence of spin-orbit coupling or lowered crystal symmetry, NLS may transform into Dirac semimetals, Weyl semimetals, or 3D topological insulators. In the photonics context, despite the realization of topological phases, such as Chern insulators, topological insulators, Weyl, and Dirac degeneracies, no experimental demonstration of photonic nodal lines (NLs) has been reported so far. Here, we experimentally demonstrate NL degeneracies in microwave cut-wire metacrystals with engineered negative bulk plasma dispersion. Both the bulk and surface states of the NL metamaterial are observed through spatial Fourier transformations of the scanned near-field distributions. Furthermore, we theoretically show that the NL degeneracy can transform into two Weyl points when gyroelectric materials are incorporated into the metacrystal design. Our findings may inspire further advances in topological photonics. PMID- 29507347 TI - High-flux water desalination with interfacial salt sieving effect in nanoporous carbon composite membranes. AB - Freshwater flux and energy consumption are two important benchmarks for the membrane desalination process. Here, we show that nanoporous carbon composite membranes, which comprise a layer of porous carbon fibre structures grown on a porous ceramic substrate, can exhibit 100% desalination and a freshwater flux that is 3-20 times higher than existing polymeric membranes. Thermal accounting experiments demonstrated that the carbon composite membrane saved over 80% of the latent heat consumption. Theoretical calculations combined with molecular dynamics simulations revealed the unique microscopic process occurring in the membrane. When the salt solution is stopped at the openings to the nanoscale porous channels and forms a meniscus, the vapour can rapidly transport across the nanoscale gap to condense on the permeate side. This process is driven by the chemical potential gradient and aided by the unique smoothness of the carbon surface. The high thermal conductivity of the carbon composite membrane ensures that most of the latent heat is recovered. PMID- 29507349 TI - Anti-CRISPR proteins encoded by archaeal lytic viruses inhibit subtype I-D immunity. AB - Viruses employ a range of strategies to counteract the prokaryotic adaptive immune system, clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas), including mutational escape and physical blocking of enzymatic function using anti-CRISPR proteins (Acrs). Acrs have been found in many bacteriophages but so far not in archaeal viruses, despite the near ubiquity of CRISPR-Cas systems in archaea. Here, we report the functional and structural characterization of two archaeal Acrs from the lytic rudiviruses, SIRV2 and SIRV3. We show that a 4 kb deletion in the SIRV2 genome dramatically reduces infectivity in Sulfolobus islandicus LAL14/1 that carries functional CRISPR-Cas subtypes I-A, I-D and III-B. Subsequent insertion of a single gene from SIRV3, gp02 (AcrID1), which is conserved in the deleted fragment, successfully restored infectivity. We demonstrate that AcrID1 protein inhibits the CRISPR-Cas subtype I-D system by interacting directly with Cas10d protein, which is required for the interference stage. Sequence and structural analysis of AcrID1 show that it belongs to a conserved family of compact, dimeric alphabeta sandwich proteins characterized by extreme pH and temperature stability and a tendency to form protein fibres. We identify about 50 homologues of AcrID1 in four archaeal viral families demonstrating the broad distribution of this group of anti-CRISPR proteins. PMID- 29507348 TI - Global Gene Expression Analysis in an in vitro Fibroblast Model of Idiopathic Pulmonary Fibrosis Reveals Potential Role for CXCL14/CXCR4. AB - Idiopathic Pulmonary Fibrosis (IPF) is a progressive disorder that is marked by an over accumulation of activated fibroblast populations. Despite the improved understanding of many mechanisms within this disease, global gene expression analysis has few focused studies on the fibroblast, the central effector cell of progressive fibrosis. We present a unique analysis of IPF pulmonary fibroblasts as they transition through cell culture and identify in vitro altered cellular processes. Fibroblasts were isolated from diseased (n = 8) and non-diseased (n = 4) lungs. Global gene expression analysis was carried out at the initial point of isolation and after 3 weeks of culture. We identify several genes that are altered by removal of the fibroblast from the IPF environment. Comparison of this subset of genes to four previously published whole lung analyses refined our list to a small subset of key fibroblast specific genes important in IPF. Application of STRING database analysis and confirmation via in-vitro and histological assay highlights the CXCL14/CXCR4 chemokine axis with a possible role in the progression and/or activation of fibroblasts within the IPF lung. Our findings, present a possible therapeutic target for IPF and a model for the study and discovery of novel protein and processes in this terrible disease. PMID- 29507350 TI - Use of Ultrasonic Device in Cervical and Thoracic Laminectomy: a Retrospective Comparative Study and Technical Note. AB - Multilevel severe compressive myelopathy is a challenging disorder for the surgeons, the aim of this study is to assess the efficacy and safety of a newly designed ultrasonic burr as an assistant tool to the ultrasonic scalpel in laminectomy for this disease. This is a retrospective comparative study, the included subjects were patients who received cervical and thoracic laminectomy using ultrasonic device (LUD, n = 9, 10 surgeries) and controls with the high speed burr (LHB, n = 16). Fifteen patients (60.0%) showed severe cord occupancy and the average number of laminae operated was 3.5. Ultrasonic devices caused less blood loss (P = 0.02) and quicker operative time per level (P < 0.001) than LHB, and was associated with more operated laminae (P = 0.04). Preoperative JOA scores (P = 0.51), improvement rate (P = 0.47), and dural injury (P = 0.51) were not related to LUD. Our experience indicates ultrasonic devices are safe and effective for laminectomy treating multilevel and severe compressive myelopathy, the instrument could be used with ease especially for cases with ossified posterior longitudinal ligament and ossification of the ligamentum flavum, proper utility of the instrument is crucial to prevent complications. PMID- 29507351 TI - Night-time activation of the intrarenal renin-angiotensin system due to nocturnal hypertension is associated with renal arteriosclerosis in normotensive IgA nephropathy patients. AB - Intrarenal renin-angiotensin system (RAS) activation plays an important role in the development of hypertension and renal damage. However, the association between daytime and night-time intrarenal RAS activation and renal structural damage in normotensive IgA nephropathy patients is unclear. We investigated the relationships between urinary angiotensinogen (U-AGT) excretion, which reflects intrarenal RAS activity, and renal structural damage (i.e., endocapillary and mesangial cell hypercellularity, arteriolar hyalinosis and arteriosclerosis levels, and global glomerulosclerosis and tubulointerstitial fibrosis percentages) in 27 normotensive IgA nephropathy patients (age 39.2 +/- 13.6 years, 10 men and 17 women, estimated glomerular filtration rate (eGFR) 74.0 +/- 17.3 ml/min/1.73 m2, urinary protein excretion 0.58 +/- 0.50 g/day, and U-AGT excretion 64.9 +/- 100.6 MUg/day). The arteriosclerosis level had a significant positive association with the daytime and night-time U-AGT excretion levels. By contrast, the endocapillary and mesangial cell hypercellularity and arteriolar hyalinosis levels and global glomerulosclerosis and tubulointerstitial fibrosis percentages did not correlate with the daytime and night-time U-AGT excretion levels. The daytime and night-time U-AGT excretion levels were higher in patients with arteriosclerotic changes than in patients without these changes. Multiple linear regression analysis revealed that the arteriosclerosis levels had a significant positive association with the U-AGT excretion levels at night after adjusting for age, sex, body mass index, and the eGFR. However, when diastolic BP was added as an independent variable, the relationship between U-AGT excretion and arteriosclerosis at night disappeared. In normotensive IgA nephropathy patients, intrarenal RAS activation at night due to nocturnal hypertension may be associated with arteriosclerosis. PMID- 29507352 TI - Modulation of miRNA expression in aged rat hippocampus by buttermilk and krill oil. AB - The increasing incidence of age-induced cognitive decline justifies the search for complementary ways of prevention or delay. We studied the effects of concentrates of phospholipids, sphingolipids, and/or 3-n fatty acids on the expression of genes or miRNAs related to synaptic activity and/or neurodegeneration, in the hippocampus of aged Wistar rats following a 3-month supplementation. The combination of two phospholipidic concentrates of krill oil (KOC) and buttermilk (BMFC) origin modulated the hippocampal expression of 119 miRNAs (11 were common to both BMFC and BMFC + KOC groups). miR-191a-5p and miR 29a-3p changed significantly only in the BMFC group, whereas miR-195-3p and miR 148a-5p did so only in the combined-supplemented group. Thirty-eight, 58, and 72 differentially expressed genes (DEG) were found in the groups supplemented with KOC, BMFC and BMFC + KOC, respectively. Interaction analysis unveiled networks of selected miRNAs with their potential target genes. DEG found in the KOC and BMFC groups were mainly involved in neuroactive processes, whereas they were associated with lysosomes and mRNA surveillance pathways in the BMFC + KOC group. We also report a significant reduction in hippocampal ceramide levels with BMFC + KOC. Our results encourage additional in-depth investigations regarding the potential beneficial effects of these compounds. PMID- 29507353 TI - Correlation and shear bands in a plastically deformed granular medium. AB - Recent experiments (Le Bouil et al., Phys. Rev. Lett., 2014, 112, 246001) have analyzed the statistics of local deformation in a granular solid undergoing plastic deformation. Experiments report strongly anisotropic correlation between events, with a characteristic angle that was interpreted using elasticity theory and the concept of Eshelby transformations with dilation; interestingly, the shear bands that characterize macroscopic failure occur at an angle that is different from the one observed in microscopic correlations. Here, we interpret this behavior using a mesoscale elastoplastic model of solid flow that incorporates a local Mohr-Coulomb failure criterion. This differs from the interpretation of Le Bouil et al., which is based on purely elastic considerations ignoring the potential role of local friction on deformation patterns. We show that the angle observed in the microscopic correlations can be understood by combining the elastic interactions associated with Eshelby transformation with the local failure criterion. At large strains, we also induce permanent shear bands at an angle that is different from the one observed in the correlation pattern. We interpret this angle as the one that leads to the maximal instability of slip lines. PMID- 29507354 TI - First detection of a Sesamia nonagrioides resistance allele to Bt maize in Europe. AB - The Ebro Valley (Spain) is the only hotspot area in Europe where resistance evolution of target pests to Cry1Ab protein is most likely, owing to the high and regular adoption of Bt maize (>60%). The high-dose/refuge (HDR) strategy was implemented to delay resistance evolution, and to be effective it requires the frequency of resistance alleles to be very low (<0.001). An F2 screen was performed in 2016 to estimate the frequency of resistance alleles in Sesamia nonagrioides from this area and to evaluate if the HDR strategy is still working effectively. Out of the 137 isofemale lines screened on Cry1Ab maize leaf tissue, molted larvae and extensive feeding were observed for two consecutive generations in one line, indicating this line carried a resistance allele. The frequency of resistance alleles in 2016 was 0.0036 (CI 95% 0.0004-0.0100), higher but not statistically different from the value obtained in 2004-2005. Resistance does not seem to be evolving faster than predicted by a S. nonagrioides resistance evolution model, but the frequency of resistance is now triple the value recommended for an effective implementation of the HDR strategy. Owing to this, complementary measures should be considered to further delay resistance evolution in the Ebro Valley. PMID- 29507355 TI - Salivary factor LTRIN from Aedes aegypti facilitates the transmission of Zika virus by interfering with the lymphotoxin-beta receptor. AB - Pathogens have co-evolved with mosquitoes to optimize transmission to hosts. Mosquito salivary-gland extract is known to modulate host immune responses and facilitate pathogen transmission, but the underlying molecular mechanisms of this have remained unknown. In this study, we identified and characterized a prominent 15-kilodalton protein, LTRIN, obtained from the salivary glands of the mosquito Aedes aegypti. LTRIN expression was upregulated in blood-fed mosquitoes, and LTRIN facilitated the transmission of Zika virus (ZIKV) and exacerbated its pathogenicity by interfering with signaling through the lymphotoxin-beta receptor (LTbetaR). Mechanically, LTRIN bound to LTbetaR and 'preferentially' inhibited signaling via the transcription factor NF-kappaB and the production of inflammatory cytokines by interfering with the dimerization of LTbetaR during infection with ZIKV. Furthermore, treatment with antibody to LTRIN inhibited mosquito-mediated infection with ZIKV, and abolishing LTbetaR potentiated the infectivity of ZIKV both in vitro and in vivo. This study provides deeper insight into the transmission of mosquito-borne diseases in nature and supports the therapeutic potential of inhibiting the action of LTRIN to disrupt ZIKV transmission. PMID- 29507357 TI - TNFalpha and IL-1beta modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. AB - Astrocytes are known to be critical regulators of neuronal function. However, relatively few mediators of astrocyte to neuron communication have been identified. Recent advancements in the biology of extracellular vesicles have begun to implicate astrocyte derived extracellular vesicles (ADEV) as mediators of astrocyte to neuron communication, suggesting that alterations in the release and/or composition of ADEVs could influence gliotransmission. TNFalpha and IL 1beta are key mediators of glial activation and neuronal damage, but the effects of these cytokines on the release or molecular composition of ADEVs is unknown. We found that ADEVs released in response to IL-1beta (ADEV-IL-1beta) and TNFalpha (ADEV-TNFalpha) were enriched with miRNAs that target proteins involved in neurotrophin signaling. We confirmed that miR-125a-5p and miR-16-5p (both enriched in ADEV-IL-1beta and ADEV-TNFalpha) targeted NTKR3 and its downstream effector Bcl2. Downregulation of these targets in neurons was associated with reductions in dendritic growth, dendritic complexity, reduced spike rates, and burst activity. Molecular interference of miR-125a-5p and miR-16-5p prevented ADEV-IL-1beta from reducing dendritic complexity, spike, and burst rates. These findings suggest that astrocytes respond to inflammatory challenge by modifying the miRNA cargo of ADEVs to diminish the activity of target neurons by regulating the translational expression of proteins controlling programs essential for synaptic stability and neuronal excitability. PMID- 29507359 TI - Disturbance-Disturbance uncertainty relation: The statistical distinguishability of quantum states determines disturbance. AB - The Heisenberg uncertainty principle, which underlies many quantum key features, is under close scrutiny regarding its applicability to new scenarios. Using both the Bell-Kochen-Specker theorem establishing that observables do not have predetermined values before measurements and the measurement postulate of quantum mechanics, we propose that in order to describe the disturbance produced by the measurement process, it is convenient to define disturbance by the changes produced on quantum states. Hence, we propose to quantify disturbance in terms of the square root of the Jensen-Shannon entropy distance between the probability distributions before and after the measurement process. Additionally, disturbance and statistical distinguishability of states are fundamental concepts of quantum mechanics that have thus far been unrelated; however, we show that they are intermingled thereupon we enquire into whether the statistical distinguishability of states, caused by statistical fluctuations in the measurement outcomes, is responsible for the disturbance's magnitude. PMID- 29507358 TI - Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors. AB - Under homeostatic conditions the release of self-RNA from dying cells does not promote inflammation. However, following injury or inflammatory skin diseases such as psoriasis and rosacea, expression of the cathelicidin antimicrobial peptide LL37 breaks tolerance to self-nucleic acids and triggers inflammation. Here we report that LL37 enables keratinocytes and macrophages to recognize self non-coding U1 RNA by facilitating binding to cell surface scavenger receptors that enable recognition by nucleic acid pattern recognition receptors within the cell. The interaction of LL37 with scavenger receptors was confirmed in human psoriatic skin, and the ability of LL37 to stimulate expression of interleukin-6 and interferon-beta1 was dependent on a 3-way binding interaction with scavenger receptors and subsequent clathrin-mediated endocytosis. These results demonstrate that the inflammatory activity of LL37 is mediated by a cell-surface-dependent interaction and provides important new insight into mechanisms that drive auto inflammatory responses in the skin. PMID- 29507356 TI - Innate immune responses to trauma. AB - Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier. PMID- 29507360 TI - Effect of long-term fertilisation on the weed community of a winter wheat field. AB - Effects of fertilisation and other management techniques on a weed community were evaluated during wheat growth in a rice-wheat cropping system. Fertiliser treatments were C0 (C means chemical, C0 means zero chemical fertiliser.), CN (N fertiliser), CNK (N plus K fertiliser), CNPK (N plus P and K fertiliser), CNP (N plus P fertiliser), and CPK (P plus K fertiliser). Weed density, biomass, and bio diversity were determined. Redundancy analysis (RDA) was used to investigate the relationship between fertiliser management, weed species, and weed density. The overall weed densities in the C0 and CPK treatments were the greatest during wheat seeding and ripening periods and were significantly greater than densities in the other treatments. N, P and organic matter in soil were highly correlated with weed species and density, whereas K in soil was not significantly correlated with weed species and weed density. N fertiliser significantly reduced weed density. Balanced fertilisation maintained weed species richness and resulting in a high yield of wheat. CNPK application reduced weed damage and improved the productivity and stability of the farmland ecosystem. PMID- 29507361 TI - Changes in global translation elongation or initiation rates shape the proteome via the Kozak sequence. AB - The sequence context surrounding the AUG start codon of an open reading frame - the 'Kozak sequence' - affects the probability with which a scanning ribosome will recognize the start codon and start translating there. A significant number of transcripts in animals such as Drosophila contain weak Kozak sequences. This is predicted to cause constitutively low translation of these transcripts. We study here the additional possibility that these mRNAs have weak Kozak sequences to allow for the regulation of their translation in response to stress or altered cellular signaling. We find that transcripts with weak Kozak sequences are less sensitive to drops in global elongation rates and more sensitive to drops in global initiation rates compared to transcripts with strong Kozak sequences. This provides a mechanism by which changes in these global translation parameters differentially affect different pools of mRNAs depending on their Kozak sequence, thereby shaping the proteome. Interestingly, mRNAs with weak Kozak sequences are enriched for genes involved in neurobiology, suggesting that they constitute a functional group that can be translationally co-regulated. PMID- 29507362 TI - Insulin-signalling dysregulation and inflammation is programmed trans generationally in a female rat model of poor maternal nutrition. AB - Developmental programming phenotypes can be recapitulated in subsequent generations not directly exposed to the initial suboptimal intrauterine environment. A maternal low-protein diet during pregnancy and postnatal catch-up growth ('recuperated') alters insulin signaling and inflammation in rat offspring (F1-generation). We aimed to establish if this phenotype is also present in F2 generation females. Insulin-receptor-substrate-1 protein expression was decreased in para-ovarian adipose tissue at 3 months in offspring exposed to a grand maternal low-protein diet (F2-recuperated), vs. F2-control animals (p < 0.05). There was no effect of grand-maternal diet upon Insulin-receptor-substrate-1 mRNA. Protein-kinase C-zeta protein levels were increased at 3 and 6 months in F2 recuperated animals (p < 0.01 at both ages). Phosphorylated-Aktser473 levels were decreased in F2-recuperated animals (p < 0.001). Interleukin-1beta protein levels were increased at 3 (p < 0.01) and (p < 0.001) 6 months in F2-recuperated animals. Vastus-lateralis insulin-receptor-beta protein expression (p < 0.001) and pAktser473 (p < 0.01) were increased at 3 months in F2-recuperated animals compared to controls. At 6 months, PAktser473 was lower in F2-recuperated animals (p < 0.001). Aspects of insulin signalling dysregulation and inflammation present in offspring of low-protein fed dams can be transmitted to subsequent generations without further exposure to a suboptimal maternal diet. These findings contribute to our understanding of insulin-resistance in grandchildren of sub-optimally nourished individuals during pregnancy. PMID- 29507363 TI - Microbead-based spoligotyping of Mycobacterium tuberculosis from Ziehl-Neelsen stained microscopy preparations in Ethiopia. AB - The worldwide dissemination of Mycobacterium tuberculosis strains has led to the study of their genetic diversity. One of the most used genotyping methods is spoligotyping, based on the detection of spacers in the clustered regularly interspaced short palindromic repeats (CRISPR) locus. This study assessed the performance of a microbead-based spoligotyping assay using samples extracted from Ziehl-Neelsen-stained smear-microscopy preparations and described the genetic diversity of Mycobacterium tuberculosis among new TB patients in Southern Nations, Nationalities and Peoples' Region (SNNPR) in Ethiopia. Among the 91 samples analysed, 59 (64.8%) generated spoligotyping patterns. Fifty (84.7%) samples were classified into 12 clusters (mostly Lineage 4 or 3) comprising 2-11 samples and nine had unique spoligotyping patterns. Among the 59 spoligotyping patterns, 25 belonged to the T1 sublineage, 11 to the T3-ETH, 5 to the URAL, 4 to the H3 and 14 to other L4 sublineages. There was a remarkable variation in genetic distribution in SNNPR compared to other regions of the country. Microbead based spoligotyping is an easy-to-perform, high-throughput assay that can generate genotyping information using material obtained from smear microscopy preparations. The method provides an opportunity to obtain data of the M. tuberculosis genetic epidemiology in settings with limited laboratory resources. PMID- 29507364 TI - Allogeneic dendritic cells stimulated with antibodies against HLA class II polarize naive T cells in a follicular helper phenotype. AB - Follicular helper T cells (Tfh) are crucial for the production of high-affinity antibodies, such as alloantibodies, by providing the signals for B-cell proliferation and differentiation. Here, we demonstrate that human allogeneic dendritic cells (DC) stimulated with antibodies against HLA class II antigens preferentially differentiate human naive CD4+ T cells into Tfh cells. Following coculture with DCs treated with these antibodies, CD4+ T cells expressed CXCR5, ICOS, IL-21, Bcl-6 and phosphorylated STAT3. Blockade of IL-21 abrogated Bcl-6, while addition of the IL-12p40 subunit to the coculture increased CXCR5, Bcl-6, phosphorylated STAT3 and ICOS, indicating that they were both involved in Tfh polarization. We further phenotyped the peripheral T cells in a cohort of 55 kidney transplant recipients. Patients with anti-HLA-II donor-specific antibodies (DSA) presented higher blood counts of circulating Tfh cells than those with anti HLA-I DSAs. Moreover, there was a predominance of lymphoid aggregates containing Tfh cells in biopsies from patients with antibody-mediated rejection and anti-HLA II DSAs. Collectively, these data suggest that alloantibodies against HLA class II specifically promote the differentiation of naive T cells to Tfh cells following contact with DCs, a process that might appear in situ in human allografts and constitutes a therapeutic target. PMID- 29507365 TI - Kinetic effects in thermal explosion with oscillating ambient conditions. AB - Thermal explosion problem for a medium with oscillating ambient temperature at its boundaries is a new problem which was introduced in the preceding publication by the present author. It is directly applicable to a range of practical fire autoignition scenarios (e.g. in the storages of organic matter, explosives, propellants, etc.). Effects of kinetic mechanisms, however, need be further investigated as they are expected to alter critical conditions of thermal explosion. We consider several global kinetic mechanisms: first order reaction, second order reaction, and first order autocatalysis. It is demonstrated that kinetic effects related to reactants consumption do indeed shift respective critical boundaries. Effect of kinetics on oscillatory development of thermal explosion is of particular interest. In line with conclusions of the preceding publication, it is confirmed that temperature oscillations may develop during induction phase of thermal explosion when the effect of reactants consumption is properly taken into account. Moreover, development of thermal explosion instability through the prior oscillations is an inevitable and natural scenario. This fact is confirmed by a number of examples. Besides, effects of the other relevant parameter, Zeldovich number on critical conditions are also investigated. PMID- 29507366 TI - Control over phase separation and nucleation using a laser-tweezing potential. AB - Control over the nucleation of new phases is highly desirable but elusive. Even though there is a long history of crystallization engineering by varying physicochemical parameters, controlling which polymorph crystallizes or whether a molecule crystallizes or forms an amorphous precipitate is still a poorly understood practice. Although there are now numerous examples of control using laser-induced nucleation, the absence of physical understanding is preventing progress. Here we show that the proximity of a liquid-liquid critical point or the corresponding binodal line can be used by a laser-tweezing potential to induce concentration gradients. A simple theoretical model shows that the stored electromagnetic energy of the laser beam produces a free-energy potential that forces phase separation or triggers the nucleation of a new phase. Experiments in a liquid mixture using a low-power laser diode confirm the effect. Phase separation and nucleation using a laser-tweezing potential explains the physics behind non-photochemical laser-induced nucleation and suggests new ways of manipulating matter. PMID- 29507367 TI - Evolution of sequence-defined highly functionalized nucleic acid polymers. AB - The evolution of sequence-defined synthetic polymers made of building blocks beyond those compatible with polymerase enzymes or the ribosome has the potential to generate new classes of receptors, catalysts and materials. Here we describe a ligase-mediated DNA-templated polymerization and in vitro selection system to evolve highly functionalized nucleic acid polymers (HFNAPs) made from 32 building blocks that contain eight chemically diverse side chains on a DNA backbone. Through iterated cycles of polymer translation, selection and reverse translation, we discovered HFNAPs that bind proprotein convertase subtilisin/kexin type 9 (PCSK9) and interleukin-6, two protein targets implicated in human diseases. Mutation and reselection of an active PCSK9-binding polymer yielded evolved polymers with high affinity (KD = 3 nM). This evolved polymer potently inhibited the binding between PCSK9 and the low-density lipoprotein receptor. Structure-activity relationship studies revealed that specific side chains at defined positions in the polymers are required for binding to their respective targets. Our findings expand the chemical space of evolvable polymers to include densely functionalized nucleic acids with diverse, researcher-defined chemical repertoires. PMID- 29507368 TI - Efficient detection of Zika virus RNA in patients' blood from the 2016 outbreak in Campinas, Brazil. AB - Infection with Zika virus (ZIKV), a mosquito-borne flavivirus has been casually linked with increased congenital microcephaly in Brazil from 2015 through 2016. Sensitive and specific diagnosis of patients with Zika fever (ZIKF) remains critical for patient management. We developed a ZIKV NS5 qRT-PCR assay by combining primers described by Balm et al. and a new Taqman probe. The assay was evaluated and compared with another assay described by Lanciotti et al. (ZIKV 1107) using 51 blood and 42 urine samples from 54 suspected ZIKV patients. ZIKV NS5 performed better in terms of sensitivity with more samples detected as ZIKV positive (n = 37) than ZIKV 1107 (n = 34) for urine, and ZIKV-positive (n = 29) than ZIKV 1107 (n = 26) for blood. Both assays displayed good overall agreement for urine (kappaappa = 0.770) and blood (kappaappa = 0.825) samples. Improved availability of validated diagnostic tests, such ZIKV NS5 qRT-PCR, will be critical to ensure adequate and accurate ZIKV diagnosis. PMID- 29507369 TI - Elucidating anionic oxygen activity in lithium-rich layered oxides. AB - Recent research has explored combining conventional transition-metal redox with anionic lattice oxygen redox as a new and exciting direction to search for high capacity lithium-ion cathodes. Here, we probe the poorly understood electrochemical activity of anionic oxygen from a material perspective by elucidating the effect of the transition metal on oxygen redox activity. We study two lithium-rich layered oxides, specifically lithium nickel metal oxides where metal is either manganese or ruthenium, which possess a similar structure and discharge characteristics, but exhibit distinctly different charge profiles. By combining X-ray spectroscopy with operando differential electrochemical mass spectrometry, we reveal completely different oxygen redox activity in each material, likely resulting from the different interaction between the lattice oxygen and transition metals. This work provides additional insights into the complex mechanism of oxygen redox and development of advanced high-capacity lithium-ion cathodes. PMID- 29507370 TI - In situ atomic-scale observation of oxidation and decomposition processes in nanocrystalline alloys. AB - Oxygen contamination is a problem which inevitably occurs during severe plastic deformation of metallic powders by exposure to air. Although this contamination can change the morphology and properties of the consolidated materials, there is a lack of detailed information about the behavior of oxygen in nanocrystalline alloys. In this study, aberration-corrected high-resolution transmission electron microscopy and associated techniques are used to investigate the behavior of oxygen during in situ heating of highly strained Cu-Fe alloys. Contrary to expectations, oxide formation occurs prior to the decomposition of the metastable Cu-Fe solid solution. This oxide formation commences at relatively low temperatures, generating nanosized clusters of firstly CuO and later Fe2O3. The orientation relationship between these clusters and the matrix differs from that observed in conventional steels. These findings provide a direct observation of oxide formation in single-phase Cu-Fe composites and offer a pathway for the design of nanocrystalline materials strengthened by oxide dispersions. PMID- 29507371 TI - Thermochromic microcapsules with highly transparent shells obtained through in situ polymerization of urea formaldehyde around thermochromic cores for smart wood coatings. AB - In this paper, thermochromic microcapsules were synthesized in situ polymerization with urea formaldehyde as shell material and thermochromic compounds as core material. The effects of emulsifying agent and conditions on surface morphology and particle size of microcapsules were studied. It was found that the size and surface morphology of microcapsules were strongly depending on stirring rate and the ratio of core to shell. The stable and small size spherical microcapsules with excellent transparency can be obtained at an emulsifying agent to core to shell ratio as 1:5:7.5 under mechanical stirring at 12 krpm for 15 min. Finally, the thermochromic property was discussed by loading microcapsules in wood and wood coatings. Results indicate that microcapsules can realize the thermochromic property while incorporated with wood and coatings, and could have high potential in smart material fabrication. PMID- 29507372 TI - Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior. AB - The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction. PMID- 29507373 TI - The impact of creating mathematical formula to predict cardiovascular events in patients with heart failure. AB - Since our retrospective study has formed a mathematical formula, alpha = f(x1, ..., x252), where alpha is the probability of cardiovascular events in patients with heart failure (HF) and x1 is each clinical parameter, we prospectively tested the predictive capability and feasibility of the mathematical formula of cardiovascular events in HF patients. First of all, to create such a mathematical formula using limited number of the parameters to predict the cardiovascular events in HF patients, we retrospectively determined f(x) that formulates the relationship between the most influential 50 clinical parameters (x) among 252 parameters using 167 patients hospitalized due to acute HF; the nonlinear optimization could provide the formula of alpha = f(x1, ..., x50) which fitted the probability of the actual cardiovascular events per day. Secondly, we prospectively examined the predictability of f(x) in other 213 patients using 50 clinical parameters in 3 hospitals, and we found that the Kaplan-Meier curves using actual and estimated occurrence probabilities of cardiovascular events were closely correlated. We conclude that we created a mathematical formula f(x) that precisely predicted the occurrence probability of future cardiovascular outcomes of HF patients per day. Mathematical modelling may predict the occurrence probability of cardiovascular events in HF patients. PMID- 29507374 TI - Single-plane retroperitoneoscopic adrenalectomy: a new operative procedure for benign adrenal disease. AB - To evaluate the therapeutic effect of single-plane retroperitoneoscopic adrenalectomy. From February 2014 to March 2017, 251 patients underwent single plane retroperitoneoscopic adrenalectomy, and their operative outcomes were compared with those of 98 patients who underwent anatomical three-plane retroperitoneoscopic adrenalectomy. Among 35 patients with a body mass index (BMI) of >=30 kg/m2, their operative outcomes were compared between two operative procedures. The demographic data and perioperative outcomes of the patients were statistically analysed. The single-plane and three-plane groups were comparable in terms of estimated blood loss, time to oral intake, hospital stay, and incidence of complications among patients with similar baseline demographics. The single-plane group had a significantly shorter operation time (46.9 +/- 5.8 vs 54.8 +/- 7.0 mins, P < 0.0001) and lower analgesia requirement (56/251 vs 33/98, p = 0.03). For obese patients with a BMI of >=30 kg/m2, single-plane adrenalectomy was also associated with a significantly shorter operation time(48.1 +/- 6.2 vs 64.1 +/- 5.1 mins, p < 0.0001). Single-plane retroperitoneoscopic adrenalectomy is feasible, safe, and effective in the treatment of adrenal masses <5 cm in size and provides a shorter operation time and better pain control than anatomical retroperitoneal adrenalectomy, especially in obese patients. PMID- 29507375 TI - Low intensity repetitive transcranial magnetic stimulation modulates skilled motor learning in adult mice. AB - Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical plasticity in clinical and non-clinical populations. Clinically, rTMS is delivered to targeted regions of the cortex at high intensities (>1 T). We have previously shown that even at low intensities, rTMS induces structural and molecular plasticity in the rodent cortex. To determine whether low intensity rTMS (LI-rTMS) alters behavioural performance, daily intermittent theta burst LI rTMS (120 mT) or sham was delivered as a priming or consolidating stimulus to mice completing 10 consecutive days of skilled reaching training. Relative to sham, priming LI-rTMS (before each training session), increased skill accuracy (~9%) but did not alter the rate of learning over time. In contrast, consolidating LI-rTMS (after each training session), resulted in a small increase in the rate of learning (an additional ~1.6% each day) but did not alter the daily skill accuracy. Changes in behaviour with LI-rTMS were not accompanied with long lasting changes in brain-derived neurotrophic factor (BDNF) expression or in the expression of plasticity markers at excitatory and inhibitory synapses for either priming or consolidation groups. These results suggest that LI-rTMS can alter specific aspects of skilled motor learning in a manner dependent on the timing of intervention. PMID- 29507378 TI - Cutting edge analyses. PMID- 29507377 TI - Two million years of flaking stone and the evolutionary efficiency of stone tool technology. AB - Temporal variability in flaking stone has been used as one of the currencies for hominin behavioural and biological evolution. This variability is usually traced through changes in artefact forms and techniques of production, resulting overall in unilineal and normative models of hominin adaptation. Here, we focus on the fundamental purpose of flaking stone-the production of a sharp working edge-and model this behaviour over evolutionary time to reassess the evolutionary efficiency of stone tool technology. Using more than 19,000 flakes from 81 assemblages spanning two million years, we show that greater production of sharp edges was followed by increased variability in this behaviour. We propose that a diachronic increase in this variability was related to a higher intensity of interrelations between different behaviours involving the use and management of stone resources that gave fitness advantages in particular environmental contexts. The long-term trends identified in this study inform us that the evolutionary efficiency of stone tool technology was not inherently in advanced tool forms and production techniques, but emerged within the contingencies of hominin interaction with local environments. PMID- 29507376 TI - Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis. AB - The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Y to the plasma membrane was impaired and that the expression of BSEPC129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Y was also significantly lower than that via BSEPWT. The transport activity of BSEPC129Y may be conserved because the amount of membrane BSEPC129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis. PMID- 29507379 TI - Secondary foundation species enhance biodiversity. AB - It has long been recognized that primary foundation species (FS), such as trees and seagrasses, enhance biodiversity. Among the species facilitated are secondary FS, including mistletoes and epiphytes. Case studies have demonstrated that secondary FS can further modify habitat-associated organisms ('inhabitants'), but their net effects remain unknown. Here we assess how inhabitants, globally, are affected by secondary FS. We extracted and calculated 2,187 abundance and 397 richness Hedges' g effect sizes from 91 and 50 publications, respectively. A weighted meta-analysis revealed that secondary FS significantly enhanced the abundance and richness of inhabitants compared to the primary FS alone. This indirect facilitation arising through sequential habitat formation was consistent across environmental and experimental conditions. Complementary unweighted analyses on log response ratios revealed that the magnitude of these effects was similar to the global average strength of direct facilitation from primary foundation species and greater than the average strength of trophic cascades, a widely recognized type of indirect facilitation arising through sequential consumption. The finding that secondary FS enhance the abundance and richness of inhabitants has important implications for understanding the mechanisms that regulate biodiversity. Integrating secondary FS into conservation practice will improve our ability to protect biodiversity and ecosystem function. PMID- 29507380 TI - Genomics of habitat choice and adaptive evolution in a deep-sea fish. AB - Intraspecific diversity promotes evolutionary change, and when partitioned among geographic regions or habitats can form the basis for speciation. Marine species live in an environment that can provide as much scope for diversification in the vertical as in the horizontal dimension. Understanding the relevant mechanisms will contribute significantly to our understanding of eco-evolutionary processes and effective biodiversity conservation. Here, we provide an annotated genome assembly for the deep-sea fish Coryphaenoides rupestris and re-sequencing data to show that differentiation at non-synonymous sites in functional loci distinguishes individuals living at different depths, independent of horizontal spatial distance. Our data indicate disruptive selection at these loci; however, we find no clear evidence for differentiation at neutral loci that may indicate assortative mating. We propose that individuals with distinct genotypes at relevant loci segregate by depth as they mature (supported by survey data), which may be associated with ecotype differentiation linked to distinct phenotypic requirements at different depths. PMID- 29507381 TI - Publisher Correction: Gene-based predictive models of trophic modes suggest Asgard archaea are not phagocytotic. AB - In the version of this Article originally published, question marks appeared in Table 1; they should have been tick marks. This has now been corrected in all versions of the Article. PMID- 29507382 TI - Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. AB - Abdominal sepsis is associated with dysfunctional hemostasis. Thrombin generation (TG) is a rate-limiting step in systemic coagulation. Neutrophils can expell neutrophil extracellular traps (NETs) and/or microparticles (MPs) although their role in pathological coagulation remains elusive. Cecal ligation and puncture (CLP)-induced TG in vivo was reflected by a reduced capacity of plasma from septic animals to generate thrombin. Depletion of neutrophils increased TG in plasma from CLP mice. Sepsis was associated with increased histone 3 citrullination in neutrophils and plasma levels of cell-free DNA and DNA-histone complexes and administration of DNAse not only eliminated NET formation but also elevated TG in sepsis. Isolated NETs increased TG and co-incubation with DNAse abolished NET-induced formation of thrombin. TG triggered by NETs was inhibited by blocking factor XII and abolished in factor XII-deficient plasma but intact in factor VII-deficient plasma. Activation of neutrophils simultaneously generated large amount of neutrophil-derived MPs, which were found to bind to NETs via histone-phosphatidylserine interactions. These findings show for the first time that NETs and MPs physically interact, and that NETs might constitute a functional assembly platform for MPs. We conclude that NET-MP complexes induce TG via the intrinsic pathway of coagulation and that neutrophil-derived MPs play a key role in NET-dependent coagulation. PMID- 29507383 TI - Negative soil moisture-precipitation feedback in dry and wet regions. AB - Soil moisture-precipitation (SM-P) feedback significantly influences the terrestrial water and energy cycles. However, the sign of the feedback and the associated physical mechanism have been debated, leaving a research gap regarding global water and climate changes. Based on Koster's framework, we estimate SM-P feedback using satellite remote sensing and ground observation data sets. Methodologically, the sign of the feedback is identified by the correlation between monthly soil moisture and next-month precipitation. The physical mechanism is investigated through coupling precipitation and soil moisture (P SM), soil moisture ad evapotranspiration (SM-E) and evapotranspiration and precipitation (E-P) correlations. Our results demonstrate that although positive SM-P feedback is predominant over land, non-negligible negative feedback occurs in dry and wet regions. Specifically, 43.75% and 40.16% of the negative feedback occurs in the arid and humid climate zones. Physically, negative SM-P feedback depends on the SM-E correlation. In dry regions, evapotranspiration change is soil moisture limited. In wet regions, evapotranspiration change is energy limited. We conclude that the complex SM-E correlation results in negative SM-P feedback in dry and wet regions, and the cause varies based on the environmental and climatic conditions. PMID- 29507384 TI - MSeq-CNV: accurate detection of Copy Number Variation from Sequencing of Multiple samples. AB - Currently a few tools are capable of detecting genome-wide Copy Number Variations (CNVs) based on sequencing of multiple samples. Although aberrations in mate pair insertion sizes provide additional hints for the CNV detection based on multiple samples, the majority of the current tools rely only on the depth of coverage. Here, we propose a new algorithm (MSeq-CNV) which allows detecting common CNVs across multiple samples. MSeq-CNV applies a mixture density for modeling aberrations in depth of coverage and abnormalities in the mate pair insertion sizes. Each component in this mixture density applies a Binomial distribution for modeling the number of mate pairs with aberration in the insertion size and also a Poisson distribution for emitting the read counts, in each genomic position. MSeq-CNV is applied on simulated data and also on real data of six HapMap individuals with high-coverage sequencing, in 1000 Genomes Project. These individuals include a CEU trio of European ancestry and a YRI trio of Nigerian ethnicity. Ancestry of these individuals is studied by clustering the identified CNVs. MSeq-CNV is also applied for detecting CNVs in two samples with low coverage sequencing in 1000 Genomes Project and six samples form the Simons Genome Diversity Project. PMID- 29507385 TI - Lack of metabolism in (R)-ketamine's antidepressant actions in a chronic social defeat stress model. AB - Since the metabolism of (R,S)-ketamine to (2R,6R)-hydroxynorketamine (HNK) is reported to be essential for ketamine's antidepressant effects, there is an increasing debate about antidepressant effects of (2R,6R)-HNK. Using pharmacokinetic and behavioral techniques, we investigated whether intracerebroventricular (i.c.v.) infusion of (R)-ketamine or (2R,6R)-HNK show antidepressant effects in a chronic social defeat stress (CSDS) model of depression. Low levels of (2R,6R)-HNK in the brain after i.c.v. infusion of (R) ketamine were detected, although brain levels of (2R,6R)-HNK were markedly lower than those after i.c.v. infusion of (2R,6R)-HNK. Furthermore, high levels of (2R,6R)-HNK in the blood and liver after i.c.v. infusion of (R)-ketamine or (2R,6R)-HNK were detected. A single i.c.v. infusion of (R)-ketamine showed rapid and long-lasting (7 days) antidepressant effects in a CSDS model. In contrast, i.c.v. infusion of (2R,6R)-HNK did not show any antidepressant effect in the same model, although brain concentration of (2R,6R)-HNK was higher than after i.c.v. infusion of (R)-ketamine. This study suggest that (R)-ketamine in the periphery after washout from the brain is metabolized to (2R,6R)-HNK in the liver, and subsequently, (2R,6R)-HNK enters into brain tissues. Furthermore, it is unlikely that (2R,6R)-HNK is essential for the antidepressant actions of (R)-ketamine in a CSDS model. PMID- 29507387 TI - Folding against the wind. PMID- 29507388 TI - Chaperones convert the energy from ATP into the nonequilibrium stabilization of native proteins. AB - During and after protein translation, molecular chaperones require ATP hydrolysis to favor the native folding of their substrates and, under stress, to avoid aggregation and revert misfolding. Why do some chaperones need ATP, and what are the consequences of the energy contributed by the ATPase cycle? Here, we used biochemical assays and physical modeling to show that the bacterial chaperones GroEL (Hsp60) and DnaK (Hsp70) both use part of the energy from ATP hydrolysis to restore the native state of their substrates, even under denaturing conditions in which the native state is thermodynamically unstable. Consistently with thermodynamics, upon exhaustion of ATP, the metastable native chaperone products spontaneously revert to their equilibrium non-native states. In the presence of ATPase chaperones, some proteins may thus behave as open ATP-driven, nonequilibrium systems whose fate is only partially determined by equilibrium thermodynamics. PMID- 29507386 TI - Genetic profiling of poorly differentiated sinonasal tumours. AB - The sinonasal cavities harbour a variety of rare tumour types. Many carry a poor prognosis while therapeutic options are limited. Histopathological classification can be difficult, especially for poorly differentiated tumours such as olfactory neuroblastoma (ONB), sinonasal neuroendocrine carcinoma (SNEC) and sinonasal undifferentiated carcinoma (SNUC). We analysed Affymetrix OncoScan genome-wide copy number profiles of these three tumour types, both as originally diagnosed and as regrouped by their cytokeratin (Ck) and neuroendocrine (Ne) expression pattern, aiming to find a relation between phenotype and genotype. According to the original histopathological classification our series consisted of 24 ONB, 11 SNEC and 19 SNUC, while immunohistochemistry indicated 11 Ck-Ne+/ONB, 18 Ck+Ne+/SNEC, 24 Ck+Ne-/SNUC, and 1 Ck-Ne-/unclassified. As originally diagnosed, the three tumour types showed similar copy number profiles. However, when regrouped by Ck/Ne immunostaining we found a distinct set of gains and losses; Ck Ne+/ONB harboured few and predominantly whole chromosomes abnormalities, Ck+Ne+/SNEC carried both gains and losses in high frequency, and Ck+Ne-/SNUC showed mostly gains. In addition, each tumour carried a number of unique chromosomal deletions. Genome-wide copy number profiling supports the value of immunohistochemical CkNe staining of ONB, SNEC and SNUC for tumour classification, which is important for prognosis and therapeutic decision-making. PMID- 29507389 TI - A lanthipeptide library used to identify a protein-protein interaction inhibitor. AB - In this article we describe the production and screening of a genetically encoded library of 106 lanthipeptides in Escherichia coli using the substrate-tolerant lanthipeptide synthetase ProcM. This plasmid-encoded library was combined with a bacterial reverse two-hybrid system for the interaction of the HIV p6 protein with the UEV domain of the human TSG101 protein, which is a critical protein protein interaction for HIV budding from infected cells. Using this approach, we identified an inhibitor of this interaction from the lanthipeptide library, whose activity was verified in vitro and in cell-based virus-like particle-budding assays. Given the variety of lanthipeptide backbone scaffolds that may be produced with ProcM, this method may be used for the generation of genetically encoded libraries of natural product-like lanthipeptides containing substantial structural diversity. Such libraries may be combined with any cell-based assay to identify lanthipeptides with new biological activities. PMID- 29507390 TI - Regulation of apoptosis by an intrinsically disordered region of Bcl-xL. AB - Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two alpha-helices (alpha1-alpha2) of the antiapoptotic protein Bcl xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTMs within the alpha1-alpha2 IDR promote its interaction with the folded core of Bcl-xL that inhibits the proapoptotic activity of two types of regulatory targets, BH3-only proteins and p53. This autoregulation utilizes an allosteric pathway whereby, in one direction, the IDR induces a direct displacement of p53 from Bcl-xL coupled to allosteric displacement of simultaneously bound BH3-only partners. This pathway operates in the opposite direction when the BH3-only protein PUMA binds to the BH3 binding groove of Bcl-xL, directly displacing other bound BH3-only proteins, and allosterically remodels the distal site, displacing p53. Our findings show how an IDR enhances functional versatility through PTM dependent allosteric regulation of a folded protein domain. PMID- 29507392 TI - Glycome analysis of extracellular vesicles derived from human induced pluripotent stem cells using lectin microarray. AB - Glycans are one of the major building blocks of extracellular vesicles (EVs). However, their roles and applications have not been completely explored. Here, we analyzed the glycome of EVs derived from human induced pluripotent stem cells (hiPSCs) using high-density lectin microarray. The glycan profiles of hiPSC derived EVs were different from those of non-hiPSC-derived EVs. Moreover, rBC2LCN that shows specific binding to hiPSCs, showed strong specificity for hiPSC derived EVs but not non-hiPSCs-derived EVs. Further, other hiPSC-specific probes, such as anti-TRA-1-60, anti-SSEA4, and anti-R-10G, exhibited specific, but weaker binding to hiPSC-derived EVs than rBC2LCN. We then developed a sandwich assay using rBC2LCN and a phosphatidylserine receptor, Tim4, to specifically detect hiPSC-derived EVs. The Tim4-rBC2LCN sandwich assay allowed for specific detection of hiPSC-derived EVs but not non-hiPSC-derived EVs, indicating that rBC2LCN could also be used for the specific detection of hiPSC-derived EVs. Together, our findings demonstrate that the characteristic glycan signature of hiPSCs are retained by EVs derived from them. The EV glycome could be novel targets for the identification and characterization of stem cells for use in regenerative medicine. PMID- 29507391 TI - Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. AB - The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest. PMID- 29507393 TI - Plasma steroids, body composition, and fat distribution: effects of age, sex, and exercise training. AB - BACKGROUND/OBJECTIVES: Plasma steroid hormone levels vary between men and women, but their associations with BMI and adiposity are controversial. Furthermore, little is known about the role of exercise programs on the relationship between steroid hormones and adiposity. This report evaluates these relationships for plasma levels of adrenal, gonadal, and conjugated steroids with body composition and fat distribution in sedentary men and women, aged 17-65 years, and their responses to an exercise program. SUBJECTS/METHODS: In the sedentary state, 270 men (29% Blacks) and 304 women (34% Blacks) from the HERITAGE Family Study were available. Among them, 242 men and 238 women completed a 20-week fully standardized exercise program. Fourteen steroid hormones and SHBG concentrations were assayed in a fasted state and were compared for their associations with adiposity in men and women and in response to the exercise program. Covariates adjusted for in partial correlation analysis were age, ancestry, menopause status (women), and oral contraceptives/hormone replacement treatment status (women) at baseline, as well as baseline value of the trait for the training response. Differences among normal weight, overweight, and obese subjects were also considered. Statistical significance was set at P < 0.0001. RESULTS: Baseline levels of dihydrotesterone (DHT), 17 hydroxy progesterone (OHPROG), sex hormone binding globulin (SHBG), and testosterone (TESTO) were negatively associated with fat mass and abdominal fat (P < 0.0001) in men and for SHBG in women (P < 0.0001). TESTO was not correlated with fat-free mass in men or women, but was significantly associated with % fat-free mass in men. No association was detected between baseline steroid hormone levels and changes in adiposity traits in response to 20 weeks of exercise. CONCLUSION: In men, low DHT, OHPROG, SHBG, and TESTO were associated with higher adiposity and abdominal and visceral fat. A similar adiposity profile was observed in women with low SHBG. PMID- 29507394 TI - Ribothrypsis, a novel process of canonical mRNA decay, mediates ribosome-phased mRNA endonucleolysis. AB - mRNAs transmit the genetic information that dictates protein production and are a nexus for numerous pathways that regulate gene expression. The prevailing view of canonical mRNA decay is that it is mediated by deadenylation and decapping followed by exonucleolysis from the 3' and 5' ends. By developing Akron-seq, a novel approach that captures the native 3' and 5' ends of capped and polyadenylated RNAs, respectively, we show that canonical human mRNAs are subject to repeated cotranslational and ribosome-phased endonucleolytic cuts at the exit site of the mRNA ribosome channel, in a process that we term ribothrypsis. We uncovered RNA G quadruplexes among likely ribothrypsis triggers and show that ribothrypsis is a conserved process. Strikingly, we found that mRNA fragments are abundant in living cells and thus have important implications for the interpretation of experiments, such as RNA-seq, that rely on the assumption that mRNAs exist largely as full-length molecules in vivo. PMID- 29507395 TI - Pan-cancer analysis of somatic mutations across 21 neuroendocrine tumor types. PMID- 29507396 TI - A CRISPR screen identifies CDK7 as a therapeutic target in hepatocellular carcinoma. PMID- 29507397 TI - Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. AB - Misfolded proteins can be degraded by selective autophagy. The prevailing view is that ubiquitin-tagged misfolded proteins are assembled into aggregates by the scaffold protein p62, and the aggregates are then engulfed and degraded by autophagosomes. Here we report that p62 forms droplets in vivo which have liquid like properties such as high sphericity, the ability to undergo fusion, and recovery after photobleaching. Recombinant p62 does not undergo phase separation in vitro; however, adding a K63 polyubiquitin chain to p62 induces p62 phase separation, which results in enrichment of high-molecular weight ubiquitin signals in p62 droplets. Mixing recombinant p62 with cytosol from p62-/- cells also results in p62 phase separation in a polyubiquitination-dependent manner. Mechanistically, p62 phase separation is dependent on p62 polymerization, the interaction between p62 and ubiquitin, and the valence of the polyubiquitin chain. Moreover, p62 phase separation can be regulated by post-translational modifications such as phosphorylation. Finally, we demonstrate that disease associated mutations in p62 can affect phase separation. We propose that polyubiquitin chain-induced p62 phase separation drives autophagic cargo concentration and segregation. PMID- 29507398 TI - The earliest evidence for a supraorbital salt gland in dinosaurs in new Early Cretaceous ornithurines. AB - Supraorbital fossae occur when salt glands are well developed, a condition most pronounced in marine and desert-dwelling taxa in which salt regulation is key. Here, we report the first specimens from lacustrine environments of the Jehol Biota that preserve a distinct fossa above the orbit, where the salt gland fossa is positioned in living birds. The Early Cretaceous ornithurine bird specimens reported here are about 40 million years older than previously reported Late Cretaceous marine birds and represent the earliest described occurrence of the fossa. We find no evidence of avian salt gland fossae in phylogenetically earlier stem birds or non-avialan dinosaurs, even in those argued to be predominantly marine or desert dwelling. The apparent absence of this feature in more basal dinosaurs may indicate that it is only after miniaturization close to the origin of flight that excretory mechanisms were favored over exclusively renal mechanisms of salt regulation resulting in an increase in gland size leaving a bony trace. The ecology of ornithurine birds is more diverse than in other stem birds and may have included seasonal shifts in foraging range, or, the environments of some of the Jehol lakes may have included more pronounced periods of high salinity. PMID- 29507400 TI - Speed up to find the right ones: rapid discovery of functional nanobodies. PMID- 29507399 TI - Radiomics analysis at PET/CT contributes to prognosis of recurrence and survival in lung cancer treated with stereotactic body radiotherapy. AB - We sought to quantify contribution of radiomics and SUVmax at PET/CT to predict clinical outcome in lung cancer patients treated with stereotactic body radiotherapy (SBRT). 150 patients with 172 lung cancers, who underwent SBRT were retrospectively included. Radiomics were applied on PET/CT. Principal components (PC) for 42 CT and PET-derived features were examined to determine which ones accounted for most of variability. Survival analysis quantified ability of radiomics and SUVmax to predict outcome. PCs including homogeneity, size, maximum intensity, mean and median gray level, standard deviation, entropy, kurtosis, skewness, morphology and asymmetry were included in prediction models for regional control (RC) [PC4-HR:0.38, p = 0.02], distant control (DC) [PC4-HR:0.51, p = 0.02 and PC1-HR:1.12, p = 0.01], recurrence free probability (RFP) [PC1 HR:1.08, p = 0.04], disease specific survival (DSS) [PC2-HR:1.34, p = 0.03 and PC3-HR:0.64, p = 0.02] and overall survival (OS) [PC4-HR:0.45, p = 0.004 and PC3 HR:0.74, p = 0.02]. In combined analysis with SUVmax, PC1 lost predictive ability over SUVmax for RFP [HR:1.1, p = 0.04] and DC [HR:1.13, p = 0.002], while PC4 remained predictive of DC independent of SUVmax [HR:0.5, p = 0.02]. Radiomics remained the only predictors of OS, DSS and RC. Neither SUVmax nor radiomics predicted recurrence free survival. Radiomics on PET/CT provided complementary information for prediction of control and survival in SBRT-treated lung cancer patients. PMID- 29507402 TI - Rewriting the past: de novo activity of PRC2 restores global H3K27 methylation patterns. PMID- 29507401 TI - Turning the table on miRNAs. PMID- 29507403 TI - TAp63 as a guardian of female germ line integrity. PMID- 29507404 TI - The effects of oxygen in spinel oxide Li1+xTi2-xO4-delta thin films. AB - The evolution from superconducting LiTi2O4-delta to insulating Li4Ti5O12 thin films has been studied by precisely tuning the oxygen pressure in the sample fabrication process. In superconducting LiTi2O4-delta films, with the increase of oxygen pressure, the oxygen vacancies are filled gradually and the c-axis lattice constant decreases. When the oxygen pressure increases to a certain critical value, the c-axis lattice constant becomes stable, which implies that the sample has been completely converted to Li4Ti5O12 phase. The two processes can be manifested by the angular bright-field images of the scanning transmission electron microscopy techniques. The transition temperature (T ch ) of magnetoresistance from the positive to the negative shows a nonmonotonic behavior, i.e. first decrease and then increase, with the increase of oxygen pressure. We suggest that the decrease Tch can be attributed to the suppressing of orbital-related state, and the inhomogeneous phase separated regions contribute positive MR and thereby lead to the reverse relation between Tch and oxygen pressure. PMID- 29507405 TI - Author Correction: Basolateral protrusion and apical contraction cooperatively drive Drosophila germ-band extension. AB - In the version of this Article originally published, the authors cited the wrong articles for reference numbers 18, 30 and 31; the correct ones are listed below. Furthermore, four additional references have been inserted at numbers 37, 38, 39 and 40 as in the list below, and the original references 37-40 have been renumbered. These corrections have been made in the online versions of the Article. PMID- 29507406 TI - Publisher Correction: High-resolution myogenic lineage mapping by single-cell mass cytometry. AB - In the version of this Article originally published, the name of author Andrew Tri Van Ho was coded wrongly, resulting in it being incorrect when exported to citation databases. This has been corrected, though no visible changes will be apparent. PMID- 29507407 TI - Promises and limitations of human intracranial electroencephalography. AB - Intracranial electroencephalography (iEEG), also known as electrocorticography when using subdural grid electrodes or stereotactic EEG when using depth electrodes, is blossoming in various fields of human neuroscience. In this article, we highlight the potentials of iEEG in exploring functions of the human brain while also considering its limitations. The iEEG signal provides anatomically precise information about the selective engagement of neuronal populations at the millimeter scale and the temporal dynamics of their engagement at the millisecond scale. If several nodes of a given network are monitored simultaneously with implanted electrodes, the iEEG signals can also reveal information about functional interactions within and across networks during different stages of neural computation. As such, human iEEG can complement other methods of neuroscience beyond simply replicating what is already known, or can be known, from noninvasive lines of research in humans or from invasive recordings in nonhuman mammalian brains. PMID- 29507408 TI - A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing. AB - A three-dimensional single-cell-resolution mammalian brain atlas will accelerate systems-level identification and analysis of cellular circuits underlying various brain functions. However, its construction requires efficient subcellular resolution imaging throughout the entire brain. To address this challenge, we developed a fluorescent-protein-compatible, whole-organ clearing and homogeneous expansion protocol based on an aqueous chemical solution (CUBIC-X). The expanded, well-cleared brain enabled us to construct a point-based mouse brain atlas with single-cell annotation (CUBIC-Atlas). CUBIC-Atlas reflects inhomogeneous whole brain development, revealing a significant decrease in the cerebral visual and somatosensory cortical areas during postnatal development. Probabilistic activity mapping of pharmacologically stimulated Arc-dVenus reporter mouse brains onto CUBIC-Atlas revealed the existence of distinct functional structures in the hippocampal dentate gyrus. CUBIC-Atlas is shareable by an open-source web-based viewer, providing a new platform for whole-brain cell profiling. PMID- 29507409 TI - B-1a lymphocytes promote oligodendrogenesis during brain development. AB - During brain development, the immune system mediates neurogenesis, gliogenesis and synapse formation. However, it remains unclear whether peripheral lymphocytes contribute to brain development. Here we identified the subtypes of lymphocytes that are present in neonatal mouse brains and investigated their functions. We found that B-1a cells, a subtype of B cells, were abundant in the neonatal mouse brain and infiltrated into the brain in a CXCL13-CXCR5-dependent manner. B-1a cells promoted the proliferation of oligodendrocyte-precursor cells (OPCs) in vitro, and depletion of B-1a cells from developing brains resulted in a reduction of numbers of OPCs and mature oligodendrocytes. Furthermore, neutralizing Fcalpha/MUR, the receptor for the Fc region of IgM secreted by B-1a cells, inhibited OPC proliferation and reduced the proportion of myelinated axons in neonatal mouse brains. Our results demonstrate that B-1a cells infiltrate into the brain and contribute to oligodendrogenesis and myelination by promoting OPC proliferation via IgM-Fcalpha/MUR signaling. PMID- 29507410 TI - Cortical specialization for attended versus unattended working memory. AB - Items held in working memory can be either attended or not, depending on their current behavioral relevance. It has been suggested that unattended contents might be solely retained in an activity-silent form. Instead, we demonstrate here that encoding unattended contents involves a division of labor. While visual cortex only maintains attended items, intraparietal areas and the frontal eye fields represent both attended and unattended items. PMID- 29507411 TI - Nontoxic, double-deletion-mutant rabies viral vectors for retrograde targeting of projection neurons. AB - Recombinant rabies viral vectors have proven useful for applications including retrograde targeting of projection neurons and monosynaptic tracing, but their cytotoxicity has limited their use to short-term experiments. Here we introduce a new class of double-deletion-mutant rabies viral vectors that left transduced cells alive and healthy indefinitely. Deletion of the viral polymerase gene abolished cytotoxicity and reduced transgene expression to trace levels but left vectors still able to retrogradely infect projection neurons and express recombinases, allowing downstream expression of other transgene products such as fluorophores and calcium indicators. The morphology of retrogradely targeted cells appeared unperturbed at 1 year postinjection. Whole-cell patch-clamp recordings showed no physiological abnormalities at 8 weeks. Longitudinal two photon structural and functional imaging in vivo, tracking thousands of individual neurons for up to 4 months, showed that transduced neurons did not die but retained stable visual response properties even at the longest time points imaged. PMID- 29507412 TI - Developmentally primed cortical neurons maintain fidelity of differentiation and establish appropriate functional connectivity after transplantation. AB - Repair of complex CNS circuitry requires newly incorporated neurons to become appropriately, functionally integrated. One approach is to direct differentiation of endogenous progenitors in situ, or ex vivo followed by transplantation. Prior studies find that newly incorporated neurons can establish long-distance axon projections, form synapses and functionally integrate in evolutionarily old hypothalamic energy-balance circuitry. We now demonstrate that postnatal neocortical connectivity can be reconstituted with point-to-point precision, including cellular integration of specific, molecularly identified projection neuron subtypes into correct positions, combined with development of appropriate long-distance projections and synapses. Using optogenetics-based electrophysiology, experiments demonstrate functional afferent and efferent integration of transplanted neurons into transcallosal projection neuron circuitry. Results further indicate that 'primed' early postmitotic neurons, including already fate-restricted deep-layer projection neurons and/or plastic postmitotic neuroblasts with partially fate-restricted potential, account for the predominant population of neurons capable of achieving this optimal level of integration. PMID- 29507414 TI - Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. AB - Neuroinflammation and neurodegeneration may represent two poles of brain pathology. Brain myeloid cells, particularly microglia, play key roles in these conditions. We employed single-cell mass cytometry (CyTOF) to compare myeloid cell populations in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, the R6/2 model of Huntington's disease (HD) and the mutant superoxide dismutase 1 (mSOD1) model of amyotrophic lateral sclerosis (ALS). We identified three myeloid cell populations exclusive to the CNS and present in each disease model. Blood-derived monocytes comprised five populations and migrated to the brain in EAE, but not in HD and ALS models. Single-cell analysis resolved differences in signaling and cytokine production within similar myeloid populations in EAE compared to HD and ALS models. Moreover, these analyses highlighted alpha5 integrin on myeloid cells as a potential therapeutic target for neuroinflammation. Together, these findings illustrate how neuropathology may differ between inflammatory and degenerative brain disease. PMID- 29507413 TI - Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease. AB - Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles. Furthermore, we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD. PMID- 29507415 TI - Mechanical complications and outcomes following invasive emergency procedures in severely injured trauma patients. AB - This study aimes to determine the complication rates, possible risk factors and outcomes of emergency procedures performed during resuscitation of severely injured patients. The medical records of patients with an injury severity score (ISS) >15 admitted to the University Hospital Leipzig from 2010 to 2015 were reviewed. Within the first 24 hours of treatment, 526 patients had an overall mechanical complication rate of 26.2%. Multivariate analysis revealed out-of hospital airway management (OR 3.140; 95% CI 1.963-5.023; p < 0.001) and ISS (per ISS point: OR 1.024; 95% CI 1.003-1.045; p = 0.027) as independent predictors of any mechanical complications. Airway management complications (13.2%) and central venous catheter complications (11.4%) were associated with ISS >32.5 (p < 0.001) and ISS >33.5 (p = 0.005), respectively. Chest tube complications (15.8%) were associated with out-of-hospital insertion (p = 0.002) and out-of-hospital tracheal intubation (p = 0.033). Arterial line complications (9.4%) were associated with admission serum lactate >4.95 mmol/L (p = 0.001) and base excess <-4.05 mmol/L (p = 0.008). In multivariate analysis, complications were associated with an increased length of stay in the intensive care unit (p = 0.019) but not with 24 hour mortality (p = 0.930). Increasing injury severity may contribute to higher complexity of the individual emergency treatment and is thus associated with higher mechanical complication rates providing potential for further harm. PMID- 29507416 TI - A facile approach to enhance antigen response for personalized cancer vaccination. AB - Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumours in about 80% of mice and generated immunological memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumour growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumour models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination. PMID- 29507417 TI - A molecular cross-linking approach for hybrid metal oxides. AB - There is significant interest in the development of methods to create hybrid materials that transform capabilities, in particular for Earth-abundant metal oxides, such as TiO2, to give improved or new properties relevant to a broad spectrum of applications. Here we introduce an approach we refer to as 'molecular cross-linking', whereby a hybrid molecular boron oxide material is formed from polyhedral boron-cluster precursors of the type [B12(OH)12]2-. This new approach is enabled by the inherent robustness of the boron-cluster molecular building block, which is compatible with the harsh thermal and oxidizing conditions that are necessary for the synthesis of many metal oxides. In this work, using a battery of experimental techniques and materials simulation, we show how this material can be interfaced successfully with TiO2 and other metal oxides to give boron-rich hybrid materials with intriguing photophysical and electrochemical properties. PMID- 29507418 TI - Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner. AB - Since the identification of the antisense protein of HTLV-2 (APH-2) and the demonstration that APH-2 mRNA is expressed in vivo in most HTLV-2 carriers, much effort has been dedicated to the elucidation of similarities and/or differences between APH-2 and HBZ, the antisense protein of HTLV-1. Similar to HBZ, APH-2 negatively regulates HTLV-2 transcription. However, it does not promote cell proliferation. In contrast to HBZ, APH-2 half-life is very short. Here, we show that APH-2 is addressed to PML nuclear bodies in T-cells, as well as in different cell types. Covalent SUMOylation of APH-2 is readily detected, indicating that APH-2 might be addressed to the PML nuclear bodies in a SUMO-dependent manner. We further show that silencing of PML increases expression of APH-2, while expression of HBZ is unaffected. On the other hand, SUMO-1 overexpression leads to a specific loss of APH-2 expression that is restored upon proteasome inhibition. Furthermore, the carboxy-terminal LAGLL motif of APH-2 is responsible for both the targeting of the protein to PML nuclear bodies and its short half life. Taken together, these observations indicate that natural APH-2 targeting to PML nuclear bodies induces proteasomal degradation of the viral protein in a SUMO dependent manner. Hence, this study deciphers the molecular and cellular bases of APH-2 short half-life in comparison to HBZ and highlights key differences in the post-translational mechanisms that control the expression of both proteins. PMID- 29507419 TI - EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications. AB - The polycomb repressor complex 2 molecule EZH2 is now known to play a role in essential cellular processes, namely, cell fate decisions, cell cycle regulation, senescence, cell differentiation, and cancer development/progression. EZH2 inhibitors have recently been developed; however, their effectiveness and underlying molecular mechanisms in many malignancies have not yet been elucidated in detail. Although the functional role of EZH2 in tumorigenesis in neuroblastoma (NB) has been investigated, mutations of EZH2 have not been reported. A Kaplan Meier analysis on the event free survival and overall survival of NB patients indicated that the high expression of EZH2 correlated with an unfavorable prognosis. In order to elucidate the functional roles of EZH2 in NB tumorigenesis and its aggressiveness, we knocked down EZH2 in NB cell lines using lentivirus systems. The knockdown of EZH2 significantly induced NB cell differentiation, e.g., neurite extension, and the neuronal differentiation markers, NF68 and GAP43. EZH2 inhibitors also induced NB cell differentiation. We performed a comprehensive transcriptome analysis using Human Gene Expression Microarrays and found that NTRK1 (TrkA) is one of the EZH2-related suppression targets. The depletion of NTRK1 canceled EZH2 knockdown-induced NB cell differentiation. Our integrative methylome, transcriptome, and chromatin immunoprecipitation assays using NB cell lines and clinical samples clarified that the NTRK1 P1 and P2 promoter regions were regulated differently by DNA methylation and EZH2-related histone modifications. The NTRK1 transcript variants 1/2, which were regulated by EZH2-related H3K27me3 modifications at the P1 promoter region, were strongly expressed in favorable, but not unfavorable NB. The depletion and inhibition of EZH2 successfully induced NTRK1 transcripts and functional proteins. Collectively, these results indicate that EZH2 plays important roles in preventing the differentiation of NB cells and also that EZH2-related NTRK1 transcriptional regulation may be the key pathway for NB cell differentiation. PMID- 29507420 TI - How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations. AB - Chronic exposure to intraperitoneal asbestos triggered a marked response in the mesothelium well before tumor development. Macrophages, mesothelial precursor cells, cytokines, and growth factors accumulated in the peritoneal lavage. Transcriptome profiling revealed YAP/TAZ activation in inflamed mesothelium with further activation in tumors, paralleled by increased levels of cells with nuclear YAP/TAZ. Arg1 was one of the highest upregulated genes in inflamed tissue and tumor. Inflamed tissue showed increased levels of single-nucleotide variations, with an RNA-editing signature, which were even higher in the tumor samples. Subcutaneous injection of asbestos-treated, but tumor-free mice with syngeneic mesothelioma tumor cells resulted in a significantly higher incidence of tumor growth when compared to naive mice supporting the role of the environment in tumor progression. PMID- 29507421 TI - Three dimensional electron microscopy reveals changing axonal and myelin morphology along normal and partially injured optic nerves. AB - Following injury to the central nervous system, axons and myelin distinct from the initial injury site undergo changes associated with compromised function. Quantifying such changes is important to understanding the pathophysiology of neurotrauma; however, most studies to date used 2 dimensional (D) electron microscopy to analyse single sections, thereby failing to capture changes along individual axons. We used serial block face scanning electron microscopy (SBF SEM) to undertake 3D reconstruction of axons and myelin, analysing optic nerves from normal uninjured female rats and following partial optic nerve transection. Measures of axon and myelin dimensions were generated by examining 2D images at 5 um intervals along the 100 um segments. In both normal and injured animals, changes in axonal diameter, myelin thickness, fiber diameter, G-ratio and percentage myelin decompaction were apparent along the lengths of axons to varying degrees. The range of values for axon diameter along individual reconstructed axons in 3D was similar to the range from 2D datasets, encompassing reported variation in axonal diameter attributed to retinal ganglion cell diversity. 3D electron microscopy analyses have provided the means to demonstrate substantial variability in ultrastructure along the length of individual axons and to improve understanding of the pathophysiology of neurotrauma. PMID- 29507422 TI - A large electronic-health-record-based genome-wide study of serum lipids. AB - A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR) derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease. PMID- 29507423 TI - Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. AB - Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion. PMID- 29507425 TI - Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence. AB - Clustering of mutations has been observed in cancer genomes as well as for germline de novo mutations (DNMs). We identified 1,796 clustered DNMs (cDNMs) within whole-genome-sequencing data from 1,291 parent-offspring trios to investigate their patterns and infer a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these clusters consisted of more individual mutations with larger intermutational distances than those of paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in previously identified regions with accelerated maternal mutation rates. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G transversions. Finally, we found that maternal clusters were associated with processes involving double-strand-breaks (DSBs), such as meiotic gene conversions and de novo deletion events. This result suggested accumulation of DSB-induced mutations throughout oocyte aging as the mechanism underlying the formation of maternal mutation clusters. PMID- 29507424 TI - CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity. AB - Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases. PMID- 29507427 TI - Effect of patient-specific model scaling on hip joint reaction force in one legged stance - study of 356 hips. AB - PURPOSE: Estimation of hip joint loading is fundamental for understanding joint function, injury and disease. To predict patientspecific hip loading, a musculoskeletal model must be adapted to the patient's unique geometry. By far the most common and cost effective clinical images are whole pelvis plain radiographs. This study compared the accuracy of anisotropic and isotropic scaling of musculoskeletal model to hip joint force prediction by taking patient specific bone geometry from standard anteroposterior radiograms. METHODS: 356 hips from 250 radiograms of adult human pelvis were analyzed. A musculoskeletal model was constructed from sequential images of the Visible Human Male. The common body position of one-legged stance was substituted for the midstance phase of walking. Three scaling methods were applied: a) anisotropic scaling by interhip separation, ilium height, ilium width, and lateral and inferior position of the greater trochanter, b) isotropic scaling by pelvic width and c) isotropic scaling by interhip separation. Hip joint force in one-legged stance was estimated by inverse static model. RESULTS: Isotropic scaling affects all proportions equally, what results in small difference in hip joint reaction force among patients. Anisotropic hip scaling increases variation in hip joint force among patients considerably. The difference in hip joint force estimated by isotropic and anisotropic scaling may surpass patient's body weight. CONCLUSIONS: Hip joint force estimated by isotropic scaling depends mostly on reference musculoskeletal geometry. Individual's hip joint reaction force estimation could be improved by including additional bone geometrical parameters in the scaling method. PMID- 29507428 TI - Investigation of hydroxyapatite-titanium composite properties during heat treatment. AB - A biocompatible hydroxyapatite (HA) coating with a thickness of about 18-20 microns was successfully deposited by radiofrequency (RF) magnetron sputtering on titanium substrates VT1-0. The data obtained for the optimal composition and structure of hydroxyapatite can be used to create coating which will interact with a titanium substrate. Using the methods of optical and SEM, AFM, electron microprobe, FTIR and X-ray analysis, surface morphology, phase and elemental composition, structure of hydroxyapatite (HA) coatings were studied. Structural and phase transformations after heat treatment using X-ray diffraction and microscopic methods of analysis were studied. It was found that after annealing coating phase analysis showed the presence of not only hydroxyapatite (Ca5(PO4)3OH), but also compounds of tricalcium phosphate (Ca3(PO4)2) and titanium oxide. Adhesivetribological durability, friction and deformation characteristics of hydroxyapatite coating on titanium substrate were determined. The obtained coatings had high hardness, wear resistance and adhesion to the substrate and low modulus of elasticity and coefficient of friction. PMID- 29507426 TI - Exercise Ameliorates Motor Deficits and Improves Dopaminergic Functions in the Rat Hemi-Parkinson's Model. AB - To determine the influences of exercise on motor deficits and dopaminergic transmission in a hemiparkinson animal model, we measured the effects of exercise on the ambulatory system by estimating spatio-temporal parameters during walking, striatal dopamine (DA) release and reuptake and synaptic plasticity in the corticostriatal pathway after unilateral 6-OHDA lesions. 6-OHDA lesioned hemiparkinsonian rats were exercised on a fixed speed treadmill for 30 minutes per day. Controls received the same lesion but no exercise. Animals were subsequently analyzed for behavior including gait analysis, rotarod performance and apomorphine induced rotation. Subsequently, in vitro striatal dopamine release was analyzed by using FSCV and activity-dependent plasticity in the corticostriatal pathway was measured in each group. Our data indicated that exercise could improve motor walking speed and increase the apomorphine-induced rotation threshold. Exercise also ameliorated spatiotemporal impairments in gait in PD animals. Exercise increased the parameters of synaptic plasticity formation in the corticostriatal pathway of PD animals as well as the dynamics of dopamine transmission in PD animals. Fixed speed treadmill training 30 minutes per day could ameliorate spatial-temporal gait impairment, improve walking speed, dopamine transmission as well as corticostriatal synaptic plasticity in the unilateral 6-OHDA lesioned rat model. PMID- 29507429 TI - alphaBSM failed as a carrier of rhBMP-2 to enhance bone consolidation in a sheep model of distraction osteogenesis. AB - PURPOSE: One of the problems associated with callus distraction is a long time period needed for consolidation of the newly formed bone. The goal of this study was to determine whether percutaneous injections of rhBMP 2 in alphaBSM would enhance bone consolidation. METHODS: A unilateral tibial osteotomy combined with external stabilization was performed in 20 adult sheep. After a latency of four days, distraction was conducted for 20 days. Sheep were divided into three groups: group 1 received rhBMP-2/alphaBSM injections at day 23 and 30, group 2 buffer/alphaBSM injections at day 23 and 30 and group 3 did not receive any injection. The radiographs and in-vivo torsional stiffness measurements were obtained weekly during the following 50 days. Post-mortem bone densitometry (DXA) and mechanical testing were performed. RESULTS: In-vivo stiffness assessments, DXA values and the maximum torsional moment of the sheep tibia treated with two rhBMP-2 injections were not significantly greater than those of both control groups. CONCLUSIONS: Presented application of rhBMP-2 in alphaBSM failed to enhance bone consolidation in distraction osteogenesis. PMID- 29507430 TI - The biomechanical characteristics of elite deaf and hearing female soccer players: comparative analysis. AB - PURPOSE: The aim of this study was to examine the differences in body composition, strength and power of lower limbs, height of jump measured for the akimbo counter movement jumps, counter movement jump and spike jumps between deaf and hearing elite female soccer players. METHODS: Twenty deaf (age: 23.7+/-5.0 years, hearing loss: 96+/-13.9 dB) and 25 hearing (age: 20.3+/-3.8 years) participated in the study. Their WHR and BMI were calculated. Body fat was measured using the BIA method. The maximal power and height of jump were measured by force plate. Biodex dynamometer was used to evaluate isokinetic isometric strength of the hamstrings and quadriceps. RESULTS: Significant differences between hearing and deaf soccer players in anthropometric values were for the waist and calf circumferences and the WHR index ( p < 0.01, effect size 0.24 0.79). Statistically significant differences were observed for flexion of the lower limb in the knee joint for the relative joint torque and relative power obtained for the angular velocity of 300 deg?s-1 for both lower limbs (p < 0.01, effect size 0.19-0.48) and for 180 deg?s-1 during flexion of the left limb (p = 0.02, effect size 0.13). The hearing female football players developed significantly greater MVC in all the cases. Statistically significant differences between deaf and hearing athletes were found for spike jump for maximal power (1828.6 +/- 509.4 W and 2215.2 +/- 464.5 W, respectively; p = 0.02, effect size 0.14). CONCLUSIONS: Hearing impairment does not limit the opportunities for development of physical fitness in the population of deaf women. PMID- 29507431 TI - Postural stability in Parkinson's disease patients. AB - PURPOSE: The aim of the study was to analyze postural stability in Parkinson's disease patients. A total of 32 subjects were tested, including 26 (81.25%) women and 6 (18.75%) men. These were patients with advanced, idiopathic Parkinson's disease. The disease duration was over 5 years. METHODS: The study was conducted in the Posturology Laboratory at the Department of Medicine and Health Sciences, Jan Kochanowski University in Kielce (Poland). The Biodex Balance System was used for evaluation of postural stability. Postural Stability Testing was performed with both feet positioned on a stable surface with the eyes open. RESULTS: The Overall Stability Index in the whole group was 0.5 degrees . The higher Overall Stability Index in women is indicative of slightly worse postural stability compared to men, although in both groups, it was within norms (Z = 2.0545, p = 0.0399). Anterior-Posterior Overall Stability Index (A/P) was an average of 0.35 degrees . The Medial-Lateral Overall Stability Index (M/L) was an average of 0.27 degrees . Both women and men were observed to have higher postural sway in the sagittal plane than the frontal plane. The vast majority of the subjects maintained in Zone A during testing (99.94%), and was slightly bent backwards to the right and in Quadrant IV (61.53%). CONCLUSIONS: Regular control of postural stability in Parkinson's disease patients is significant due to the risk of falls. PMID- 29507432 TI - Biomechanics of diving: the influence of the swimming speed on the kinematics of lower limbs of professional divers. AB - PURPOSE: The aim of this study is to evaluate the influence of the swimming speed during diving on the biomechanical parameters describing the movement of selected measurement points of the lower limb in professional divers. METHODS: The study involved a group of 4 professional divers whose movement was recorded during underwater swimming at slow (approx. 0.4 m.s-1), medium (approx. 0.5 m.s-1), and fast (approx. 0.8 m.s-1) pace. RESULTS: During swimming at medium speed, the divers made a smaller displacement (along the axes Y) of the midpoint of fin than during swimming at fast speed. The range of motion in the ankle joint increased in fast speed in comparison with low and medium swimming speed. The same relationship was noted for the obtained velocity and angular acceleration in the hip, knee and ankle joints. The authors observed that during swimming at slow pace the divers choose movement ensuring high swimming comfort while the efficiency of motion is a secondary factor. On the other hand, during swimming at higher pace, the applied movement pattern ensures far greater efficiency rather than swimming comfort. CONCLUSION: The conducted analysis showed that divers adjust the movement of their lower limbs to the swimming pace. PMID- 29507433 TI - Elastic constants influence on the L4-L5-S1 annuli fibrosus behavior, a probabilistic finite element analysis. AB - PURPOSE: A probabilistic finite element (FE) analysis of the L4-L5 and L5-S1 human annulus fibrosus (AF) was conducted to obtain a better understanding of the biomechanics of the AF and to quantify its influence on the range of motion (ROM) of the L4-L5 and L5-S1 segments. METHODS: The FE models were composed of the AF and the upper and lower endplates. The AF was represented as a continuous material composed of a hyperelastic isotropic Yeoh matrix reinforced with two families of fibers described with an exponential energy function. The caudal endplate was fully restricted and 8 Nm pure moment was applied to the cranial endplate in flexion, extension, lateral flexion and axial rotation. The mechanical constants were determined randomly based on a normal distribution and average values reported. RESULTS: Results of the 576 models show that the ROM was more sensitive to the initial stiffness of the fibers rather than to the stiffening coefficient represented in the exponential function. The ROM was more sensitive to the input variables in extension, flexion, axial rotation and lateral bending. The analysis showed an increased probability for the L5-S1 ROM to be higher in flexion, extension and axial rotation, and smaller in lateral flexion, with respect to the L4-L5 ROM. CONCLUSIONS: An equation was proposed to obtain the ROM as a function of the elastic constants of the fibers and it may be used to facilitate the calibration process of the human spine segments and to understand the influence of each elastic constant on the ROM. PMID- 29507434 TI - Thermographic evaluation of muscle activity after front crawl swimming in young men. AB - PURPOSE: The information about the workload on individual muscles in the course of a specific physical activity is essential for targeted prevention, early diagnosis and suitable therapy concerning their overloading and injury. The aim of this study is to evaluate temperature changes in particular skin areas in the course of front crawl swimming, caused by muscle work. METHODS: Thermograms were taken of 13 students of Defense University immediately and 15 minutes after swimming 1,000 m focused on 20 regions of the skin over the selected agonists and synergists in upper extremities and body. FLUKE TiR infrared hand camera was used. RESULTS: The results indicated the significant increase in the relative temperatures in the areas of agonists of swimmers' movement - triceps brachii: from 0.952 to 0.997 of normalized units (nu) on the right and from 0.955 to 0.986 nu on the left. At the same time, the temperature of the muscles participating in lifting the arms above the water surface and stretching them forward - deltoids - increased as well (rear part: from 1.002 to 1.015 nu on the right and from 1.002 to 1.014 nu on the left, sides: from 1.008 to 1.023 nu on the right and from 1.011 to 1.023 nu on the left). CONCLUSIONS: In conclusion, the order of the other agonists is as follows: biceps brachii, pectoralis major muscle, and latissimus dorsi. This study provides the options for objective assessment of workload on specific muscles or muscle groups during front crawl swimming. PMID- 29507435 TI - Synthesizing and characterization of nano-Graphene Oxide-reinforced Hydroxyapatite Coatings on laser treated Ti6Al4V surfaces. AB - Laser-treated Ti6Al4V surfaces were coated by the single-layer hydroxyapatite (HA) and double-layer hydroxyapatite reinforced by the reduced nano-graphene oxide (rGO) using the sol-gel method. The effects of rGO reinforcement at different ratios and sintering temperatures on surface morphology and adhesion strength of the single and double layer coatings (rGO/HA) were analysed. As the initial treatment process, a laser texturing was patterned on the alloy and then, prepared samples were coated. The coated laser-modified HA and HA/rGO-coated Ti6Al4V surfaces were characterized by Raman spectroscopy, X-ray diffraction (XRD), Field Emission Scanning Electron Microscope (FESEM) and the adhesion strength between the coat and substrates were determined by the standard adhesion tests. The conducted analyses indicated that the substitution of rGO into HA matrix revealed a homogeneous morphology and relatively crack-free coatings on the laser-treated Ti substrate surfaces. Adhesion tests showed that, the HA + rGO (1.0 wt. %) biocomposites exhibited a significant increase in adhesion strength compared to untreated surfaces and to the single HA-coated Ti6Al4V substrates. PMID- 29507436 TI - Microdamage distribution in fatigue fractures of bone allografts following gamma ray exposure. AB - PURPOSE: Although significant differences in bone properties have been extensively studied, results vary when bones are exported to gamma radiation of a range usually used for sterilization purposes (25-35 kGy). Hence, the aim of this work was the study of the mechanical properties and microdamage development of human bones used as allografts following gamma-ray exposure, followed by an extensive statistical analysis of microdamage effects in fatigue behaviour. METHODS: Specimens of the cortical region of human femurs were exposed to 15-25 kGy and 26-30 kGy radiation levels, then they were subjected to compression fatigue tests until fracture. The fatigue life was determined in relation to the radiation level, and the evolution of microdamage was assessed using fluorescence microscopy in order to calculate characteristic lengths of microcracks. RESULTS: Significant differences in fatigue life were detected (p < 0.05) between non radiated (control) and radiated specimens, resulting in a drastic 89.2% fatigue life reduction of the 15-25 kGy group, and 95.3% in the 26-30 kGy group, compared to the reference. Microdamage analysis showed a considerable increase in microcrack lengths when bone was exposed to gamma radiation, which may indicate that bones used as allografts could fracture at some point when subjected to loading conditions in vivo. CONCLUSIONS: The results of our research indicate that even if a range of 15-25 kGy is suggested to sterilize bone allografts, such practice needs to be reconsidered. In addition, using Weibull distribution, this work describes the conditions in which microcracks grow towards the fracture of bones in relation to the decrease in their mechanical properties. PMID- 29507437 TI - Integration of reliability analysis into mini-plate fixation strategy used in human mandible fractures: Convalescence and healing periods. AB - PURPOSE: The objective was to assess the reliability level of mini-plate fixation used in fracture mandibles in order to evaluate the structure stability in both convalescence and healing periods. METHODS: In the convalescence period, the failure scenario is measured by the relative displacement between two fracture surfaces which should not exceed an acceptable value in order to obtain a good stability for rapid bone healing and to limit any trauma. However, in the healing period, it is the objective to obtain an acceptable rigidity. Hereby, the failure scenario is measured by the von Mises stresses being as indicator of mandible fractures. RESULTS: During the surgery operation, some muscles can be cut or harmed and cannot operate at its maximum capability. Thus, there is a strong motivation to introduce the loading uncertainties in order to obtain reliable designs. A 3-dimensional finite element model was developed in order to study the negative effect caused by stabilization of the fracture. The different results were obtained when considering a clinical case of a 35-year-old male patient. The results show the importance of fixation of symphysis fracture by two I-plates with four holes. The structural reliability level was estimated when considering a single failure mode and multiple failure modes. CONCLUSIONS: The integration of reliability concepts into mini-plate fixation strategy is considered a novel aspect. The reliability evaluation seams to be a reasonable asset in both convalescence and healing periods. PMID- 29507438 TI - Assessment of postural stability in stable and unstable conditions. AB - PURPOSE: The aim of the study was to determine whether it is possible to assess static balance on an unstable surface using center of pressure velocities obtained with a force platform when standing on a wobble board. METHODS: The center of pressure velocities were recorded with a force platform within three days (four trials per day) in thirty young adults in three conditions: standing on a rigid surface, compliant surface, and on a wobble board. Reliability of mean velocities of the center of pressure was examined using intraclass correlation coefficients. Relationships between the three conditions were assessed with Pearson correlation coefficients. RESULTS: Intra-session reliability was excellent for standing on a rigid surface and on a compliant surface and good for standing on a wobble board. Inter-session reliability was good for all parameters in all conditions, except for poor reliability in the anterior-posterior direction in standing on a wobble board. All correlations between the same parameter in different conditions were statistically significant (P < 0.05), except for velocity of the center of pressure in the anterior-posterior direction between stance on a rigid surface and stance on a wobble board. CONCLUSIONS: Centre of pressure velocity parameters obtained with a force plate when standing on a wobble board can provide valuable information about postural stability in unstable conditions. PMID- 29507439 TI - Pregnancy-related changes in center of pressure during gait. AB - PURPOSE: Physical and hormonal modifications occuring during the pregnancy, can lead to an increase in postural instability and to a higher risk of falls during gait. The first objective was to describe the center of pressure (COP) during late pregnancy at different gait velocity. Comparison of nulliparous women with postpartum women were conducted in order to investigate the effects of pregnancy. The second objective was to analyse COP variability between pregnant and non pregnant women in order to investigate the effects of pregnancy on gait variability. METHODS: Fifty-eight pregnant women in the last four months of pregnancy, nine postpartum women and twenty-three healthy non-pregnant women performed gait trials at three different speeds: preferred, slow and fast. RESULTS: In the last four months of pregnancy gait velocity decreased. During the pregnancy, gait velocity decreased by 22%, stopover time increased by 6-12%, COP excursion XY decreased by 5% and COP velocity decreased by 16% and 20% along the anteroposterior and transverse axes, respectively. After delivery, gait velocity increased by 3% but remained a lower compared to non-pregnant women (-12%). Intra individual variability was greater for non-pregnant than pregnant women. CONCLUSIONS: COP parameters were influenced by pregnancy. This suggests that pregnant women establish very specific and individual strategies with the aim of maintaining stability during gait. PMID- 29507440 TI - Properties of Ti-6Al-7Nb titanium alloy nitrocarburized under glow discharge conditions. AB - PURPOSE: The paper presents the results of physicochemical and mechanical properties of the Ti-6Al-7Nb alloy with surface modified by formation of a diffusive nitrocarburized layer deposited in a low-temperature plasma process. The main aim of the study was to evaluate the influence of steam sterilization and exposure to Ringer's solution on the utility properties of the alloy. METHODS: Based on the study of the microstructure, roughness, wettability, resistance to pitting corrosion, ion infiltration and mechanical properties, the usefulness of the proposed method of surface treatment for clinical application was proven. RESULTS: Deposition of the nitrocarburized layer increased the surface roughness and surface hardness, but also reduced the contact angle, and corrosion resistance with respect to the polished surfaces. The nitrocarburized layer is a barrier against the infiltration of ions to the solution and sterilization and exposure to Ringer solution have greater effect on the physicochemical properties rather than on the mechanical ones. CONCLUSION: It was found that sterilization, and exposure to Ringer's solution greatly affect the change of physicochemical properties rather than mechanical properties for both nitrocarburized layers and the Ti-6Al-7Nb alloy of mechanically polished surface. PMID- 29507441 TI - The role of hippotherapeutic exercises with larger support surface in development of balance in boys aged 15 to 17 years with mild intellectual disability. AB - PURPOSE: Maintaining balance in humans involves continuous changes in parameters. The aim of this study was to assess the effect of hippotherapeutic exercises on development of the sense of balance in boys aged 15 to 17 years with mild intellectual disability. METHODS: The study examined 50 randomly chosen boys aged 15 to 17 years with mild intellectual disability from the special education centre in Lezajsk, Poland. The study participants were divided into two groups: experimental group, who participated for 3 months in hippotherapeutic classes and the control group, with boys attending outdoor or indoor physical education classes. Before and after completion of the study, both experimental and control groups were diagnosed by means of Accu SwayPlus force plate. The force plate was used to determine alterations in the position of the centre of pressure (COP) on the platform in the frontal and sagittal planes in relaxed standing position with feet spread to the shoulder width and with eye control with respect to the base of support (BOS). The description was based on mean displacement of the centre of gravity (COG), mean velocity of displacements of the COG, mean radial displacement and total length of the COP pathway. RESULTS: In the experimental group, equestrian exercises induced a series of significant changes that pointed to the improved balance reactions. The character of these changes in the positions analysed was similar: values of body sway in the sagittal plane and their range and mean displacements decreased statistically significantly after training. The same tendency was observed for mean radial displacements in the free open position and with closed support surface. Furthermore, the velocity of displacement and the length of the COP's projection pathway on the support surface in the free open position was also reduced. All significant changes and trends found for the experimental group, which occurred after 3 month of hippotherapeutic classes, suggest improved parameters of balance. CONCLUSIONS: The lack of changes in balance parameters in the control group shows that the hippotherapeutic classes significantly develop balance abilities in boys aged 15 to 17 years with mild intellectual disability. PMID- 29507442 TI - Motor functions assessment method based on energy changes in gait cycle. AB - PURPOSE: The aim of the research was to determine the energy changes during the gait cycle for a group of healthy children and a group of patients with cerebral palsy, and to compare the value of energy expenditure (EE) with the determined values of the Gillette Gait Index (GGI) and the Gait Deviation Index (GDI). METHODS: The study group consisted of 56 children with regular gait and 56 patients with diagnosed cerebral palsy (CP). The gait kinematics was determined by BTS Smart System. Based on the identified position of the body mass, the following parameters were determined: the potential energy, kinetic energy, and total energy. The values were standardized to 100% of the gait cycle. The values of the Gillette Gait Index (GGI) and the Gait Deviation Index (GDI) were calculated using the authors' own software. RESULTS: Values of potential, kinematic and mechanical energy changes and mean values of total energy (energy expenditure - EE) were calculated for a reference group and for patients with CP. The obtained results were standardized in relation to the body mass and stride length. Furthermore, the values of the Gillette Gait Index (GGI) and the Gait Deviation Index (GDI) were calculated. Statistical analysis of the obtained results was performed. The Spearman rank correlation coefficient was defined between the calculated GGI and GDI values and energy expenditure EE. CONCLUSIONS: Values of energy expenditure changes can be used as an objective comparative tool for gait results concerning children with various neurological and orthopaedic dysfunctions. PMID- 29507443 TI - Elastic modulus for long-term evaluation of the tensile properties of polypropylene meshes in an in vivo rat model. AB - PURPOSE: Mid-urethral slings have become the gold standard treatment of stress urinary incontinence in women. Their tensile properties should be evaluated in order to measure how they wear off with time. Our objective was a long-term assessment of the tensile properties of 2 synthetic tapes (TVT-O and I-STOP) after in vivo implantation in rats in terms of elastic modulus. METHODS: Strips from both meshes were implanted in the abdominal wall of 30 rats, which were sacrificed at 5 time intervals. Their fibers were untangled to single components. Ultimate tensile strength (UTS), strain at UTS and the elastic modulus of each fiber type were measured. RESULTS: I-STOP maintained UTS and strain over time, while TVT-O UTS and strain were significantly reduced. However, the elastic modulus of both tapes remained constant. CONCLUSIONS: Both meshes maintained their stiffness and elasticity with time. Elastic modulus could be an appropriate factor to predict long-term implantation outcomes. The clinical significance of such findings remains to be demonstrated by long-term analysis. PMID- 29507444 TI - Effect of elliptical deformation of the acetabulum on the stress distribution in the components of hip resurfacing surgery. AB - Hip resurfacing surgery is a matter of controversy. Some authors present very good late results of 99% survival outcomes. However, national records of implants point to the series of complications connected with biomechanical flaws of the implant. These results implicate the experimental research on biomechanical properties of HRS. The aim of the research was to define the nature of cooperation between the components of hip resurfacing surgery (HRS) and the influence of the deformation of acetabulum, the size of the implant and the nature of the bone surface on the stress distribution in the acetabulum and the femoral component. The calculations were run with the use of the finite element method (FEM), using the ANSYS bundle for this purpose. Four decrete models of the studied system were made: a model with the elements of the system connected with glue, a perfect spherical model with cooperating surfaces, a model reflecting an elliptical deformation of the acetabulum, and a model with different sizes of the implant. The results indicate that the stress values obtained for models with the ideally spherical acetabulum cannot cause significant deformation of cooperating implants. In the case of loads of the elliptically deformed acetabulum significant point stress concentrations can be observed in the spots of joint. The size of the acetabular and femoral components of HRS has influence on the stress concentration on the internal surface of the acetabulum as well as in the bone tissue surrounding the madrel of the femoral component. Moreover, physical properties of the base surface surrounding the HRS components have influence on the size of stress in the acetabulum and the femoral component. PMID- 29507445 TI - The Standard Deviation of Differential Index as an innovation diagnostic tool based on kinematic parameters for objective assessment of a upper limb motion pathology. AB - PURPOSE: Indexing methods are very popular in terms of determining the degree of disability associated with motor dysfunctions. Currently, indexing methods dedicated to the upper limbs are not very popular, probably due to difficulties in their interpretation. This work presents the calculation algorithm of new SDDI index and the attempt is made to determine the level of physical dysfunction along with description of its kind, based on the interpretation of the calculation results of SDDI and PULMI indices. METHODS: 23 healthy people (10 women and 13 men), which constituted a reference group, and a group of 3 people with mobility impairments participated in the tests. In order to examine possibilities of the utilization of the SDDI index the participants had to repetitively perform two selected rehabilitation movements of upper extremities. During the tests the kinematic value was registered using inertial motion analysis system MVN BIOMECH. RESULTS: The results of the test were collected in waveforms of 9 anatomical angles in 4 joints of upper extremities. Then, SDDI and PULMI indices were calculated for each person with mobility impairments. Next, the analysis was performed to check which abnormalities in upper extremity motion can influence the value of both indexes and interpretation of those indexes was shown. CONCLUSION: Joint analysis of the both indices provides information on whether the patient has correctly performed the set sequence of movement and enables the determination of possible irregularities in the performance of movement given. PMID- 29507446 TI - The wettability, mechanical and antimicrobial properties of polylactide/montmorillonite nanocomposite films. AB - The aim of this study was to evaluate the effect of the not activated (unmodified) montmorillonite (MMT) filler on the antibacterial properties of polymer nanocomposites with a biodegradable polylactide (PLA) matrix. The subject of research was selected to verify the reports on the lack of antibacterial properties of unmodified montmorillonite in nanocomposites and to investigate the potential conditions of their manufacturing which are decisive for the resulting properties. Evaluation of antibacterial and mechanical properties of both the starting materials and the obtained nanocomposites filled with layered silicates as well as the wettability of the materials, measured by a sitting drop method was made on samples in the form of a film. The results show that the surface wettability of the polymer nanocomposites did not exhibit significant change compared to the film of neat PLA. However, a significant improvement in the mechanical and antimicrobial properties of the nanocomposite films obtained in a specific solvent casting process of the nanocomposite preceded by exfoliation of the film in an ultrasonic homogenizer was demonstrated. The antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis was also observed, and, moreover, the montmorillonite-containing films revealed a zone of inhibition of bacterial growth when tested against the lactosepositive bacteria of the Enterobacteriaceae family, which are present in the waste water. The advantageous properties of the obtained PLA/MMT nanocomposites suggest that the unmodified montmorillonite may be potentially used as filler for polymer films in the packaging industry. PMID- 29507447 TI - Parametric Instability, Inverse Cascade, and the 1/f Range of Solar-Wind Turbulence. AB - In this paper, weak turbulence theory is used to investigate the nonlinear evolution of the parametric instability in 3D low-beta plasmas at wavelengths much greater than the ion inertial length under the assumption that slow magnetosonic waves are strongly damped. It is shown analytically that the parametric instability leads to an inverse cascade of Alfven wave quanta, and several exact solutions to the wave kinetic equations are presented. The main results of the paper concern the parametric decay of Alfven waves that initially satisfy e+ ? e-, where e+ and e- are the frequency (f) spectra of Alfven waves propagating in opposite directions along the magnetic field lines. If e+ initially has a peak frequency f0 (at which fe+ is maximized) and an "infrared" scaling fp at smaller f with -1 < p < 1, then e+ acquires an f-1 scaling throughout a range of frequencies that spreads out in both directions from f0. At the same time, e- acquires an f-2 scaling within this same frequency range. If the plasma parameters and infrared e+ spectrum are chosen to match conditions in the fast solar wind at a heliocentric distance of 0.3 astronomical units (AU), then the nonlinear evolution of the parametric instability leads to an e+ spectrum that matches fast-wind measurements from the Helios spacecraft at 0.3 AU, including the observed f-1 scaling at f ? 3 * 10-4 Hz. The results of this paper suggest that the f-1 spectrum seen by Helios in the fast solar wind at f ? 3 * 10-4 Hz is produced in situ by parametric decay and that the f-1 range of e+ extends over an increasingly narrow range of frequencies as r decreases below 0.3 AU. This prediction will be tested by measurements from the Parker Solar Probe. PMID- 29507449 TI - 1,3,4-Oxadiazole and Heteroaromatic-Fused 1,2,4-Triazole Synthesis using Diverted Umpolung Amide Synthesis. AB - Umpolung Amide Synthesis (UmAS) has emerged as a superior alternative to conventional amide synthesis methods based on carbonyl electrophiles in a range of situations, particularly when epimerization-prone couplings are prescribed. In an unanticipated development during our most recent studies, it was discovered that diacyl hydrazide products from UmAS were not formed as intermediates when using an acyl hydrazide as the amine acceptor. This resulted in a new preparation of 1,3,4-oxadiazoles from alpha-bromonitroalkane donors. We hypothesized that a key tetrahedral intermediate in UmAS was diverted toward a more direct pathway to the heterocycle product rather than through formation of the diacyl hydrazide, a typical oxadiazole progenitor. In studies reported here, diversion to 1,2,4 triazole products is described, a behavior hypothesized to also result from an analogous tetrahedral intermediate, but one formed from heteroaromatic hydrazine acceptors. PMID- 29507450 TI - Changes for codeine. PMID- 29507451 TI - Observations on the launch of new drugs for hepatitis C. PMID- 29507452 TI - Pharmacogenomics and drug therapy. PMID- 29507453 TI - Drugs affecting milk supply during lactation. PMID- 29507454 TI - Adverse effects of sports supplements in men. PMID- 29507455 TI - Prescribing for polymyalgia rheumatica. PMID- 29507457 TI - Alectinib hydrochloride for non-small cell lung cancer. PMID- 29507456 TI - An update on the treatment of rosacea. PMID- 29507458 TI - Ixekizumab for psoriasis. PMID- 29507459 TI - In split-dose prepared patients, water exchange could significantly improve overall and segmental bowel preparation scores and increase adenoma detection rate. PMID- 29507461 TI - Practical management of toxicities associated with targeted therapies for advanced gastroenteropancreatic neuroendocrine tumors. AB - Neuroendocrine tumors are heterogeneous, rare malignancies that arise most frequently in the gastroenteropancreatic tract (GEPNET). The therapeutic armamentarium for the treatment of GEPNETs has expanded significantly over the last two decades, however the ideal sequencing strategy remains controversial. As this disease may be relatively slow-growing, patients are expected to be treated for longer periods, so that even mild toxicities can influence quality of life, compliance and outcome in the long run. Prospective data on optimal adverse event management are lacking and recommendations are largely based on expert opinion and drug prescribing information. This review summarizes practical recommendations for toxicity management associated with the most commonly used GEPNET treatment options and stresses important focus points for future clinical trials. PMID- 29507460 TI - Medical and surgical management of perianal Crohn's disease. AB - Crohn's disease is increasingly thought to encompass multiple possible phenotypes. Perianal manifestations account for one such phenotype and represent an independent disease modifier. In its more severe form, perianal Crohn's disease confers a higher risk of a severe and disabling disease course, relapses, hospital admissions and operations. This, in turn, imposes a considerable burden and disability on patients. Identification of the precise manifestation is important, as management is nuanced, with both medical and surgical components, and is best undertaken in a multidisciplinary setting for both diagnosis and ongoing treatment. The introduction of biologic medication has heralded a significant addition to the management of fistulizing perianal Crohn's disease in particular, albeit with modest results. It remains a very challenging condition to treat and further work is required to optimize management in this group of patients. PMID- 29507462 TI - The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies. AB - Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE). It affects the performance of psychometric tests focused on attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients. By being related to falls, an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life and their socioeconomic status. MHE is detected in clinically asymptomatic patients using appropriate psychometric tests and neurophysiological methods that highlight neuropsychological alterations, such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency-evoked cognitive potentials, and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics such as rifaximin, probiotics and branched-chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, the treatment of MHE is not currently recommended as routine, but only on a case-by case basis. PMID- 29507463 TI - Evaluation and management of esophageal manifestations in systemic sclerosis. AB - Systemic sclerosis (SSc) is a multisystemic autoimmune connective tissue disorder; in the gastrointestinal tract, the esophagus is the most commonly affected organ. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Since the development of high resolution manometry (HRM), this method has been preferred for the study of SSc patients with esophageal involvement. Using HRM, classic scleroderma esophagus, defined as absent or ineffective peristalsis of the distal esophagus in combination with a hypotensive lower esophageal sphincter, was found in as many as 55% of SSc patients. Endoscopy is the appropriate test for evaluating dysphagia and identifying evidence and possible complications of GERD. In the therapeutic area, treatment ranges from general supportive measures to the administration of drugs such as proton pump inhibitors and/or prokinetics. However, as many SSc patients do not respond to existing therapies, there is an urgent need for new therapeutic modalities. Buspirone, a 5-hydroxytryptamine 1A receptor agonist, could be a putative therapeutic option, as it was found to exert a significant beneficial effect in SSc patients with esophageal involvement. This review summarizes our knowledge concerning the evaluation and management of esophageal manifestations in SSc patients, including emerging therapeutic modalities. PMID- 29507464 TI - Current insights into the innate immune system dysfunction in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients' quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results. PMID- 29507466 TI - Seven-day genotypic resistance-guided triple Helicobacter pylori eradication therapy can be highly effective. AB - Background: The efficacy and applicability of molecular testing to guide the selection of antibiotics in triple Helicobacter pylori (H. pylori) eradication regimens have not been reported. We tested a 7-day, genotypic resistance-guided triple H. pylori eradication therapy in a high-resistance setting. Methods: Consecutive dyspeptic patients with H. pylori infection were prospectively enrolled. Genotypic resistances to clarithromycin (23SrRNA mutations) and fluoroquinolones (gyrA mutations) were determined from gastric biopsy specimens using a commercially available molecular assay (GenoTypea HelicoDR). A tailored genotypic resistance-guided 7-day triple therapy comprised esomeprazole, amoxicillin, and either clarithromycin (wild-type 23SrRNA), levofloxacin (23SrRNA mutated/wild-type gyrA) or rifabutin (both 23SrRNA/gyrA mutated). H. pylori eradication was confirmed by 13C-urea breath test. Results: Of 148 subjects screened, 51 patients were enrolled (male/female: 27/24, mean age: 50.7+/-11.4 years, treatment-naive/-experienced: 32/19). The molecular kit was easily implemented, allowing for rapid (within 24 h) and relatively inexpensive determination of H. pylori resistance (clarithromycin: 47.1%, fluoroquinolones: 15.7%, dual clarithromycin/fluoroquinolones: 7.8%). For patients who received clarithromycin-, levofloxacin- and rifabutin-containing triple therapy, the respective eradication rates were 24/27, 20/20, and 2/4 by intention-to-treat (ITT); and 24/24, 19/19 and 2/3 by per-protocol (PP) analysis. Overall eradication rates were 90.2% (95% confidence interval [CI] 77.8-96.3%) by ITT and 97.8% (95%CI 87-99.8%) by PP analysis, showing no significant difference between treatment-naive and -experienced patients (ITT: 87.5% vs. 94.7%, P=0.64; PP: 96.4% vs. 100%, respectively, P=1.00). Conclusions: Regardless of prior treatment history, a genotypic resistance-guided 7-day triple therapy, based on a simple molecular assay, achieved a high H. pylori eradication rate. PMID- 29507467 TI - Hybrid therapy as first-line regimen for Helicobacter pylori eradication in a high clarithromycin resistance area: a prospective open-label trial. AB - Background: Hybrid therapy is a promising first-line regimen for Helicobacter pylori (H. pylori) eradication. We evaluated a hybrid therapy, assessing the impact of antibiotic resistance on eradication outcome. Methods: This was a prospective study that included 155 treatment-naive patients diagnosed with H. pylori infection by positive CLO-test, confirmed with histology and/or culture. The hybrid therapy consisted of 40 mg esomeprazole and 1 g amoxicillin for 14 days, with the addition of 500 mg clarithromycin and 500 mg metronidazole for the final 7 days (all b.i.d.). Eradication was defined by negative 13C-urea breath test or histology. Results: The eradication rates were 85.8% (133/155; 95% confidence interval [CI] 79.4-90.5%) by intention-to-treat and 90.2% (129/143; 95%CI 84.1-94.2%) by per-protocol analysis in a setting of high antibiotic resistance (clarithromycin 25.9%, metronidazole 31.1%, dual resistance 8.9%). Adverse events occurred in 29.7% and 1.3% discontinued treatment because of adverse events. Adherence >90% was achieved in 96.6%. The eradication rate in patients with dual clarithromycin/metronidazole resistance (50%) was markedly lower compared to those with single clarithromycin resistance (91.4%), single metronidazole resistance (90.5%) or dual susceptibility (97.8%). Dual resistance was the only factor to correlate with the failure of hybrid therapy (odds ratio 14.4, 95%CI 3.8-54.9, P=0.0003). Conclusions: Hybrid therapy is an effective and safe first-line regimen in populations with relatively high rates of antibiotic resistance. However, dual clarithromycin/metronidazole resistance may significantly compromise its efficacy. PMID- 29507465 TI - Surgical options for full-thickness rectal prolapse: current status and institutional choice. AB - Full-thickness rectal prolapse (FTRP) is generally believed to result from a sliding hernia through a pelvic fascial defect, or from rectal intussusception. The currently accepted cause is a pelvic floor disorder. Surgery is the only definitive treatment, although the ideal therapeutic option for FTRP has not been determined. Auffret reported the first FTRP surgery using a perineal approach in 1882, and rectopexy using conventional laparotomy was first described by Sudeck in 1922. Laparoscopy was first used by Bermann in 1992, and laparoscopic surgery is now used worldwide; robotic surgery was first described by Munz in 2004. Postoperative morbidity, mortality, and recurrence rates with FTRP surgery are an active research area and in this article we review previously documented surgeries and discuss the best approach for FTRP. We also introduce our institution's laparoscopic surgical technique for FTRP (laparoscopic rectopexy with posterior wrap and peritoneal closure). Therapeutic decisions must be individualized to each patient, while the surgeon's experience must also be considered. PMID- 29507468 TI - Association of sleep quality and mucosal healing in patients with inflammatory bowel disease in clinical remission. AB - Background: The interaction between sleep and the immune system has been increasingly studied over the last decades. The aim of this study was to investigate the association between sleep quality and mucosal healing in patients with inflammatory bowel disease (IBD) currently in clinical remission. Methods: Ninety patients with IBD in clinical remission were studied: 54 (60%) with Crohn's disease and 36 (40%) with ulcerative colitis. All completed the Pittsburgh Sleep Quality Index, and mucosal healing was estimated with ileocolonoscopy. A subgroup analysis was also performed in order to investigate these associations in Crohn's disease and ulcerative colitis separately. Results: Of the 90 patients, 45.56% had poor sleep quality. Patients without mucosal healing expressed higher absolute values of the Pittsburgh Sleep Quality Index (P<0.001), while absence of mucosal healing and poor sleep quality were statistically associated (P<0.05). Subgroup analysis showed that the same pattern was present in patients with Crohn's disease: patients without mucosal healing expressed higher absolute values of the Pittsburgh Sleep Quality Index (P<0.001) and the absence of mucosal healing was statistically associated with poor sleep quality (P<0.05). However, these associations were not observed in the subgroup of patients with ulcerative colitis (P>0.05). Conclusion: In patients with IBD in clinical remission, absence of mucosal healing seems to be associated with poor sleep quality, especially in patients with Crohn's disease. PMID- 29507469 TI - Is the level of cleanliness using segmental Boston bowel preparation scale associated with a higher adenoma detection rate? AB - Background: The impact of Boston bowel preparation scale (BBPS) scores on the adenoma detection rate (ADR) in each segment has not been adequately addressed. The aim of this study was to determine the association between segmental or overall ADR and serrated polyp detection rate (SDR) with segmental and total BBPS scores. Methods: All outpatient screening colonoscopies with documented BBPS scores were retrospectively reviewed at a tertiary institution from January to December 2013. Chi-square tests and logistic regression were used to analyze the detection rates of adenomas and serrated polyps with bowel prep scores. Odds ratios were calculated using logistic regression that controlled for withdrawal time, age, body mass index, diabetes status and sex. Results: We analyzed 1991 colonoscopies. The overall ADR was 37.5% (95% confidence interval [CI], 35.3 39.6). There was a significant difference in the overall ADR, and in SDR across all bowel category groups, with total BBPS scores of 8 and 9 having lower detection rates than scores of 5, 6 and 7. As the quality of bowel preparation increased, there was a statistical decrease in the ADR (odds ratio [OR] 0.79 [CI 0.66-0.94], P=0.04) of the right colon, while in the left colon, there was a statistical decrease in SDR (OR 0.78, [CI 0.65-0.92] P=0.019). Conclusion: Segmental ADR and SDR both decreased as prep scores increased, decreasing notably in patients with excellent prep scores of 8 and 9. A possible explanation for this unexpected discrepancy may be related to longer and better visualization of the mucosa when cleansing and suctioning is necessary. PMID- 29507470 TI - Propranolol reduces systemic oxidative stress and endotoxemia in cirrhotic patients with esophageal varices. AB - Background: The aim of the study was to investigate the effect of propranolol on systemic oxidative stress and endotoxemia in patients with liver cirrhosis and clinically significant portal hypertension evidenced by the presence of esophageal varices. Methods: Fourteen patients with liver cirrhosis and esophageal varices, not previously been treated with non-selective beta-blockers (NSBB), were prospectively started on propranolol and followed up for three months. Serum early and late lipid peroxidation products (lipid hydroperoxides [LOOH] and malondialdehyde [MDA], respectively), and endotoxin concentrations in peripheral blood were measured. Fourteen age- and sex-matched healthy individuals were used as controls. Results: Patients with liver cirrhosis presented significantly higher systemic oxidative stress and endotoxin concentrations compared to healthy controls (P<0.001). Propranolol treatment for one month significantly reduced serum MDA (P<0.05), LOOH (P<0.01), and endotoxin levels (P<0.01) compared to pre-treatment values, whilst LOOH reached control levels. At three months of propranolol treatment, serum LOOH did not differ significantly from the one-month values, whilst serum endotoxin and MDA levels were further reduced between 3- and 1-month period (P<0.05 and P<0.01, respectively), with the latter reaching control levels. Amelioration of systemic endotoxemia at the one- and three-month follow-up intervals (compared to pre-treatment values) was not correlated with the respective reductions in serum MDA and LOOH. Conclusions: This is the first study to show that NSBB treatment in liver cirrhosis exerts a significant systemic antioxidant action. This effect seems to be, at least partly, independent of their beneficial effects on intestinal barrier function and endotoxemia. PMID- 29507471 TI - Demographics, tumor characteristics, treatment, and survival of patients with Klatskin tumors. AB - Background: The objective of this study was to investigate the incidence, demographics, tumor characteristics, treatment, and survival of patients with hilar cholangiocarcinoma. Methods: Data on Klatskin tumors between 2004 and 2013 was extracted from the Surveillance, Epidemiology and End Results Registry. The epidemiology of these tumors was then analyzed. Results: A total of 254 patients with Klatskin tumors were identified. The overall age-adjusted incidence of Klatskin tumors between 2004 and 2013 was 0.38 per 1,000,000 per year. A gradual decline in the incidence was noted, with the highest (0.44) in 2005 and lowest (0.24) in 2010. Males had a higher incidence of Klatskin tumors compared to females (0.47 vs. 0.25 per 1,000,000 per year). These tumors were more common among Asian and Pacific islanders, who had an age-adjusted incidence rate of 0.48 per 1,000,000. Incidence increased with age, with the peak incidence between the ages of 80 and 84 years. The majority of the tumors were extrahepatic (67.3%). Approximately one-fourth (22.4%) of these patients had metastatic disease at presentation. Only 26.8% of patients had surgically resectable disease at presentation. One- and 5-year cause-specific survival for Klatskin tumors was 41% and 10.4%, respectively, with a median survival of 7 months. On Cox proportional hazard regression analysis, extrahepatic tumors (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.37-0.80, P=0.02) and those treated surgically (HR 0.47, 95%CI 0.29-0.77, P=0.003) had significantly better outcomes. Conclusions: Klatskin tumors are rare and have a very poor prognosis with low survival rate. Among these tumors, extrahepatic and surgically treated tumors tend to have better outcomes. PMID- 29507472 TI - Patients' perceptions of gastroenterologists' attire in the clinic and endoscopy suite. AB - Background: Studying the role of gastroenterologists' attire can provide insight into patients' perceptions and help us optimize the physician-patient relationship. In this study we assessed patients' preference concerning gastroenterologists' attire, and its influence on patients' trust, empathy and perceptions of the quality of care in the clinic and endoscopic suite. Methods: A cross-sectional survey was conducted from August 2016 to February 2017. A total of 240 consecutive patients who presented to the Gastroenterology Department at the University of Florida in Jacksonville both in the clinic and endoscopic suite were included in this study. The questionnaire applied included 8 questions concerning patients' preferences regarding gastroenterologists' attire and the impact the attire had on patients' trust, empathy and perceptions of quality of care. Results: Overall, 85% of patients preferred scrubs to formal dress clothes. The preference for scrubs was higher in the endoscopic suites (89% and 93%) compared to the outpatient office (66%, P<0.01). In addition, 82% of patients said they felt more comfortable speaking with gastroenterology doctors wearing scrubs and 85% of patients felt more confident about the skills of those gastroenterologists. Conclusions: Gastroenterologists' attire does influence patients' perception of the care they are receiving. There is an overall preference for the use of scrubs in the different settings of gastroenterology, both office and lab. PMID- 29507473 TI - Publication dynamics in gastroenterology and hepatology over the last decade in Greece: a SCImago-based study. AB - Background: There is evidence that the financial crisis has deleteriously affected scientific output. We aimed to assess the dynamics of Greek publications in gastroenterology and hepatology over the last ten years. Methods: Data were collected from SCImago. The average annual growth rate (AAGR) of total and citable documents published in Greece in the field of gastroenterology and hepatology was compared with that of cardiology, surgery, and radiology. In addition, it was compared with the corresponding rates in Belgium, Ireland and Portugal. Results: The annual number of Greek publications (total and citable documents) remained relatively unchanged in the field of gastroenterology and hepatology from 2006-2011. During the following years, we detected a negative AAGR, with values of -12%, -3.3%, -9.5% and -5.4% for gastroenterology hepatology, cardiology, surgery and radiology, respectively. During the same period, the AAGR of the citable documents of the respective specialties was 8.6%, -3.7%, -9.8%, and -5.1%. Comparison of the 4 European countries in the field of gastroenterology and hepatology revealed that publications from Portugal rose massively (AAGR +24.6% and +20.6% for total and citable documents, respectively), almost reaching the number of Greek publications in 2015. The number of publications from Belgium and Ireland remained essentially unchanged after 2011, with AAGR values of -0.7%, and -2.1% for total and -1.1% and -1.4% for citable documents, respectively. Conclusion: The publication output in the field of gastroenterology and hepatology decreased significantly after the outbreak of the financial crisis in Greece, not only in relation to other medical specialties, but also compared to the output of other European countries with or without fiscal austerity measures. PMID- 29507474 TI - Endoscopic closure of gastric perforation from eroded Jackson-Pratt drain using over-the-scope clips. PMID- 29507475 TI - Asymptomatic Anisakis and erosive lesions in the colon. PMID- 29507476 TI - A novel gel immersion technique using a bipolar needle-knife in endoscopic submucosal dissection for superficial gastrointestinal neoplasms. PMID- 29507477 TI - Post-transplantation lymphoproliferative disorder with gastrointestinal involvement. AB - Post-transplantation lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that are the second most common tumors in adult transplant recipients. Most cases of PTLD are attributed to Epstein-Barr virus, which induces B-cell proliferation and occurs in the setting of severe immunosuppression after solid organ or bone marrow transplantation. The disorder is seen in 1-3% of liver transplant recipients and has a variable presentation chronology. Herein, we chronicle a case of aggressive B-cell lymphoma (PTLD WHO class-3) presenting with isolated gastrointestinal involvement in an Epstein-Barr virus-negative patient with living-donor liver transplantation, 4 years after receiving the transplant. While typical symptoms may be elusive in the immunocompromised setting, clinicians should be vigilant for underlying PTLD with isolated gastrointestinal involvement. Prompt detection and characterization by endoscopic evaluation with biopsy should be particularly stressed in such patients. PMID- 29507478 TI - Closure of a mucosal entry using the clip-with-line method. PMID- 29507479 TI - HPV self-sampling: A promising approach to reduce cervical cancer screening disparities in Canada. PMID- 29507481 TI - Cost-effectiveness of everolimus for the treatment of advanced neuroendocrine tumours of gastrointestinal or lung origin in Canada. AB - Background: In 2016, everolimus was approved by Health Canada for the treatment of unresectable, locally advanced or metastatic, well-differentiated, non functional, neuroendocrine tumours (NET) of gastrointestinal (GI) or lung origin in adult patients with progressive disease. This analysis evaluated the cost effectiveness of everolimus in this setting from a Canadian societal perspective. Methods: A partitioned survival model was developed to compare the cost per life year (LY) gained and cost per quality-adjusted life-year (QALY) gained of everolimus plus best supportive care (BSC) versus BSC alone in patients with advanced or metastatic NET of GI or lung origin. Model health states included stable disease, disease progression, and death. Efficacy inputs were based on the RADIANT-4 trial and utilities were mapped from quality-of-life data retrieved from RADIANT-4. Resource utilization inputs were derived from a Canadian physician survey, while cost inputs were obtained from official reimbursement lists from Ontario and other published sources. Costs and efficacy outcomes were discounted 5% annually over a 10-year time horizon, and sensitivity analyses were conducted to test the robustness of the base case results. Results: Everolimus had an incremental gain of 0.616 QALYs (0.823 LYs) and CA$89,795 resulting in an incremental cost-effectiveness ratio of CA$145,670 per QALY gained (CA$109,166 per LY gained). The probability of cost-effectiveness was 52.1% at a willingness to pay (WTP) threshold of CA$150,000 per QALY. Conclusions: Results of the probabilistic sensitivity analysis indicate that everolimus has a 52.1% probability of being cost-effective at a WTP threshold of CA$150,000 per QALY gained in Canada. PMID- 29507480 TI - Phase I study of concurrent and consolidation cisplatin and docetaxel chemotherapy with thoracic radiotherapy in non-small cell lung cancer. AB - Background: We designed a phase i study of concurrent chemoradiotherapy (ccrt) with docetaxel (D) and cisplatin (C), followed by consolidation dc, for unresectable stage iii non-small cell lung cancer (nsclc). Methods: Patients with histologically proven and unresectable stage iii nsclc were eligible. During ccrt, C was given every 3 weeks (75 mg/m2) and D given weekly. The starting dose of D was 20 mg/m2, escalated in cohorts of 3 to define the maximum tolerated dose (mtd). Radiotherapy was prescribed to a dose of 60 Gy in 30 fractions. This was followed by 2 cycles of consolidation dc, which were dose escalated if ccrt was tolerated. Results: Twenty-six patients were enrolled, with 1 excluded following evidence of metastatic disease. Nineteen patients completed both phases of treatment. There were 7 grade 3 events during ccrt (5 esophagitis, 2 nausea), and 8 grade 3 events during consolidation (2 neutropenia, 2 leukopenia, 1 esophagitis, 2 nausea, and 1 pneumonitis). Three patients had grade 4 neutropenia. No patients died due to toxicities. The mtd of concurrent weekly D was 20 mg/m2. Consolidation D and C were each dose escalated to 75 mg/m2 in 8 patients. The median overall survival (os) and progression-free survival (pfs) of all patients were 33.6 months and 17.2 months, respectively, with median follow up of 26.6 months (range 0.43-110.8). Conclusions: The use of docetaxel 20 mg/m2 weekly and cisplatin 75 mg/m2 every 3 weeks concurrent with thoracic radiotherapy, followed by consolidation docetaxel and cisplatin, both given at 75 mg/m2 every 3 weeks, appears to be safe in this phase i trial. PMID- 29507482 TI - Quality of life in pediatric cancer survivors: contributions of parental distress and psychosocial family risk. AB - Background: Pediatric survivors of childhood cancer are at increased risk of poor quality of life and social-emotional outcomes following treatment. The relationship between parent psychological distress and child adjustment in pediatric cancer survivors has been well established. However, limited research has examined the factors that may buffer this association. The current study examined the associations between psychosocial family risk factors, parental psychological distress, and health-related quality of life (hrql) in pediatric cancer survivors. Methods: Fifty-two pediatric cancer survivors (34 males, 18 females, mean age = 11.92) and their parents were recruited from a long-term cancer survivor clinic. Children and their parents who consented to participate completed the Pediatric Quality of Life Inventory 4.0. Parents completed a demographic information form, the Psychosocial Assessment Tool (pat 2.0) and the Brief Symptom Inventory (bsi). The Intensity of Treatment Rating (itr-3) was evaluated by the research team. Results: Multiple regression analyses revealed that parental psychological distress negatively predicted parent-reported hrql, while treatment intensity, gender, and psychosocial risk negatively predicted parent and child-reported hrql. Psychosocial risk moderated the association between parent psychological distress and parent-reported child hrql (p = 0.03), whereby parents with high psychological distress but low levels of psychosocial risk reported their children to have higher hrql. Conclusion: Low levels of family psychosocial risk buffer the impact of parent psychological distress on child hrql in pediatric cancer survivors. The findings highlight the importance of identifying parents and families with at-risk psychological distress and psychosocial risk in order to provide targeted support interventions to mitigate the impact on hrql. PMID- 29507483 TI - Assessing post-radiotherapy handover notes from a family physician perspective. AB - Background: Across our province, post-radiotherapy (rt) handover notes are sent to family physicians (fps) after rt. Based on previous fp feedback, we created a revised post-radiotherapy handover note with more information requested by fps. The purpose of this study was to determine whether the revised handover note improved the note as a communication aid. Methods: Potential common and rare treatment side effects, oncologist contact information, and treatment intent were added to the revised handover note. Both versions were sent alongside a questionnaire to fps. Paired t-tests were carried out to compare satisfaction differences. Results: There was a response rate of 37% for the questionnaires. Significantly greater clarity in the following categories was observed: responsibility for patient follow-up (mean score improvement of 1.2 on a 7-point Likert scale, p < 0.001), follow-up schedule (1.1, p < 0.001) as well as how and when to contact the oncologist (1.4, p = 0.001). Family physicians were also more content with how the institute transitioned care back to them (1.5, p = 0.012). Overall, fps were generally satisfied with the content of the revised post-rt handover note and noted improvement over the previous version. The frequency of investigations and institute supports initiated such as counselling services were suggested further additions. Conclusions: The inclusion of potential treatment side effects, oncologist contact information, treatment intent and a well-laid out follow-up schedule were essential information needed by fps for an effective post-rt completion note. With these additions, the revised post-rt handover note showed significant improvement. PMID- 29507484 TI - Impact of the Spinal Instability Neoplastic Score on Surgical Referral Patterns and Outcomes. AB - Background: The Spinal Instability Neoplastic Score (sins) was developed to identify patients with spinal metastases who may benefit from surgical consultation. We aimed to assess the distribution of sins in a population-based cohort of patients undergoing palliative spine radiotherapy (rt) and referral rates to spinal surgery pre-rt. Secondary outcomes included referral to a spine surgeon post-rt, overall survival, maintenance of ambulation, need for re intervention, and presence of spinal adverse events. Methods: We retrospectively reviewed ct simulation scans and charts of consecutive patients receiving palliative spine rt between 2012 and 2013. Data were analyzed using Student's t test, Chi-squared, Fisher's exact, and Kaplan-Meier log-rank tests. Patients were stratified into low (<7) and high (>=7) sins groups. Results: We included 195 patients with a follow-up of 6.1 months. The median sins was 7. The score was 0 to 6 (low, no referral recommended), 7 to 12 (intermediate, consider referral), and 13 to 18 (high, referral suggested) in 34%, 59%, and 7% of patients, respectively. Eleven patients had pre-rt referral to spine surgery, with a surgery performed in 0 of 1 patient with sins 0 to 6, 1 of 7 with sins 7 to 12, and 1 of 3 with sins 13 to 18. Seven patients were referred to a surgeon post-rt with salvage surgery performed in two of those patients. Primary and secondary outcomes did not differ between low and high sins groups. Conclusion: Higher sins was associated with pre-rt referral to a spine surgeon, but most patients with high sins were not referred. Higher sins was not associated with shorter survival or worse outcome following rt. PMID- 29507485 TI - Regional process redesign of lung cancer care: a learning health system pilot project. AB - Background: The Ottawa Hospital (toh) defined delay to timely lung cancer care as a system design problem. Recognizing the patient need for an integrated journey and the need for dynamic alignment of providers, toh used a learning health system (lhs) vision to redesign regional diagnostic processes. A lhs is driven by feedback utilizing operational and clinical information to drive system optimization and innovation. An essential component of a lhs is a collaborative platform that provides connectivity across silos, organizations, and professions. Methods: To operationalize a lhs, we developed the Ottawa Health Transformation Model (ohtm) as a consensus approach that addresses process barriers, resistance to change, and conflicting priorities. A regional Community of Practice (cop) was established to engage stakeholders, and a dedicated transformation team supported process improvements and implementation. Results: The project operationalized the lung cancer diagnostic pathway and optimized patient flow from referral to initiation of treatment. Twelve major processes in referral, review, diagnostics, assessment, triage, and consult were redesigned. The Ottawa Hospital now provides a diagnosis to 80% of referrals within the provincial target of 28 days. The median patient journey from referral to initial treatment decreased by 48% from 92 to 47 days. Conclusions: The initiative optimized regional integration from referral to initial treatment. Use of a lhs lens enabled the creation of a system that is standardized to best practice and open to ongoing innovation. Continued transformation initiatives across the continuum of care are needed to incorporate best practice and optimize delivery systems for regional populations. PMID- 29507486 TI - The impact of seasonal operating room closures on wait times for oral cancer surgery. AB - Background: Operating room slowdowns occur at specific intervals in the year as a cost-saving measure. We aim to investigate the impact of these slowdowns on the care of oral cavity cancer patients at a Canadian tertiary care centre. Methods: A total of 585 oral cavity cancer patients seen between 1999 and 2015 at the London Health Science Centre (lhsc) Head and Neck Multidisciplinary Clinic were included in this study. Operating room hours and patient load from 2006 to 2014 were calculated. Our primary endpoint was the wait time from consultation to definitive surgery. Exposure variables were defined according to wait time intervals occurring during time periods with reduced operating room hours. Results: Overall case volume rose significantly from 2006 to 2014 (p < 0.001), while operating room hours remained stable (p = 0.555). Patient wait times for surgery increased from 16.3 days prior to 2003 to 25.5 days in 2015 (p = 0.008). Significant variability in operating room hours was observed by month, with lowest reported for July and August (p = 0.002). The greater the exposure to these months, the more likely patients were to wait longer than 28 days for surgery (odds ratio per day [or]: 1.07, 95% confidence interval [ci]: 1.05 to 1.10, p < 0.001). Individuals seen in consultation preceding a month with below average operating room hours had a higher risk of disease recurrence and/or death (hazard ratio [hr]: 1.59, 95% ci: 1.10 to 2.30, p = 0.014). Conclusions: Scheduled reductions in available operating room hours contribute to prolonged wait times and higher disease recurrence. Further work is needed to identify strategies maximizing efficient use of health care resources without negatively affecting patient outcomes. PMID- 29507488 TI - Self-sampling for cervical cancer screening: Empowering women to lead a paradigm change in cancer control. PMID- 29507487 TI - Standardizing biomarker testing for Canadian patients with advanced lung cancer. AB - Background: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor (EGFR) inhibitors, is the standard of care in Canada and many parts of the world. Methods: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF V600 and programmed death-ligand (PD L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression. As well, additional exploratory molecules and targets are likely to impact future patient care, including MET exon 14 skipping mutations and whole gene amplification, RET translocations, HER2 (ERBB2) mutations, NTRK, RAS (KRAS and NRAS), as well as TP53. Results: The standard of care must include the incorporation of testing for novel biomarkers as they become available, as it will be difficult for national guidelines to keep pace with technological advances in this area. Conclusions: Canadian patients with nsclc should be treated equally; the minimum standard of care is defined in this paper. PMID- 29507489 TI - Implementation considerations using HPV self-collection to reach women under screened for cervical cancer in high-income settings. PMID- 29507490 TI - Strategies to reach marginalized women for cervical cancer screening: A qualitative study of stakeholder perspectives. AB - Background: Self-sampling for human papillomavirus (hpv) has the potential to reach marginalized populations that are underserved for cervical cancer screening. However, before implementing an alternative screening strategy such as self-sampling for under- and never-screened women, the key processes, facilitators, and barriers to reform need to be understood. Methods: A descriptive qualitative study was conducted that involved semi-structured interviews with Canadian and international cancer screening health care providers and policy-makers. Respondents were purposively selected from a list of thirty stakeholders generated through an environmental scan. The interviews were transcribed verbatim and analyzed using directed content analysis. Results: Nineteen stakeholders participated in the interviews. Most respondents thought that self-sampling was an appropriate cervical screening alternative for hard-to reach populations, as it addressed barriers to cervical screening related to various social determinants of health. All respondents emphasized that transitioning to hpv primary screening would catalyze a policy shift towards self sampling. Clinician respondents were less enthusiastic about self-sampling strategies since that discouraged women's appointments with primary care providers, because cervical screening offered an opportunity to discuss other preventive health topics. There also was little consensus between respondents on whether the state of evidence was satisfactory to integrate a self-sampling option into policy, or whether more Canadian research was needed. Conclusion: Canadian cervical cancer screening stakeholders should collaborate to identify the knowledge gaps that researchers should address and leverage the existing literature to implement tailored, patient-centred alternative cervical screening strategies. The transition to hpv primary screening would be a key first step in the broad implementation of hpv self-sampling in Canada. PMID- 29507491 TI - Completing the cervical screening pathway: Factors that facilitate the increase of self-collection uptake among under-screened and never-screened women, an Australian pilot study. AB - Objectives: To examine factors that enhance under-screened and never-screened women's completion of the self-collection alternative pathway of the Renewed National Cervical Screening Program (ncsp) in Victoria, Australia. Background: With the Australian ncsp changing, starting on 1 December 2017, the Medical Services Advisory Committee (msac) recommended implementing human papillomavirus (hpv) testing using a self-collected sample for under-screened and never-screened populations. In response, a multi-agency group implemented an hpv self-collection pilot project to trial self-collection screening pathways for eligible women. Methods: Quantitative data were collected on participation rates and compliance rates with follow-up procedures across three primary health care settings. Forty women who self-collected were interviewed in a semi-structured format, and seven agency staff completed in-depth interviews. Qualitative data were used to identify and understand clinical and personal enablers that assisted women to complete self-collection cervical screening pathways successfully. Results: Eighty-five per cent (10 women) of participants who tested positive for hpv successfully received their results and completed follow-up procedures as required. Two remaining participants also received hpv-positive results. However, agencies were unable to engage them in follow-up services and procedures. The overall participation rate in screening (self-collection or Pap test) was 85.7% (84 women), with 79 women self-collecting. Qualitative data indicated that clear explanations on self-collection, development of trusting, empathetic relationships with health professionals, and recognition of participants' past experiences were critical to the successful completion of the self-collection pathway. When asked about possible inhibitors to screening and to following up on results and appointments, women cited poor physical and mental health, as well as financial and other structural barriers. Conclusion: A well-implemented process, led by trusted, knowledgeable, and engaged health care professionals who can provide appropriate support and information, can assist under-screened and never screened women to complete the hpv self-collection pathway successfully. PMID- 29507492 TI - Self-collection for under-screened women in a National Cervical Screening Program: pilot study. AB - Background: Commencing 1 December 2017, Australia introduced human papillomavirus (hpv)-based cervical screening. As part of this Australian renewed National Cervical Screening Program (ncsp) women who are either never- or under-screened and who refuse a practitioner collected sample will be able to collect their own sample for cervical screening. The aim of this study is to examine the quantitative results of a pilot study into the acceptability of the self collection alternative pathway. Methods: Eligible participants were offered the opportunity to collect their own sample. Those who agreed were given a flocked swab and an instruction sheet and took their own sample in an area of the health care clinic that afforded them adequate privacy. These samples were then given to clinic staff who returned them to Victorian Cytology Service (vcs) Pathology for hpv nucleic acid testing. Results: Of 98 eligible women, seventy-nine undertook self-collection for hpv-based cervical screening. Seventy-seven produced valid results, 14 were positive for oncogenic hpv, with 10 undertaking follow-up. Three women were found to have cervical squamous abnormalities with two of those being high-grade intraepithelial squamous lesions. Conclusion: The pilot study for self collection for cervical screening produced quantitative data that were similar to that already reported in the literature, but had a much higher rate of acceptance compared with self-collection programs based in the home. PMID- 29507493 TI - Procarbazine, lomustine and vincristine toxicity in low-grade gliomas. AB - Background: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. Methods: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Universite de Montreal between 1 January 2005 and 27 July 2016. Results: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). Conclusion: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity. PMID- 29507494 TI - Real-world outcomes in patients with ALK-positive non-small cell lung cancer treated with crizotinib. AB - Background: Crizotinib has shown greater efficacy in clinical trials than chemotherapy in patients with anaplastic lymphoma kinase-positive (alk+) non small cell lung cancer (nsclc), but little information is available on its use and outcomes in real-world settings. We therefore assessed treatment patterns and outcomes in alk+ nsclc patients treated with crizotinib in regular clinical practice. Methods: A retrospective medical record review was conducted in North America for adults with alk+ nsclc treated with crizotinib as first- or later line therapy for metastatic disease between 1 August 2011 and 31 March 2013 (for the United States) or 1 May 2012 and 31 March 2013 (for Canada). Crizotinib related trial enrollees were excluded. Descriptive analyses were conducted to assess treatment patterns and objective response rate (orr). Progression-free survival (pfs) and overall survival (os) were descriptively analyzed using Kaplan Meier methods. Results: Data were extracted for 212 patients in the United States (n = 147) and Canada (n = 65). Mean (standard deviation [sd]) age was 58.9 (9.5) years, and 69% were male. Seventy-nine patients (37%) were deceased at record abstraction. Sixty-five percent (n = 137) initiated crizotinib as first-line therapy. Mean (sd) duration of crizotinib treatment was 8.7 (4.9) months. Objective response rate was 66% (69% for first-line recipients, 60% for second /later-line). Median (95% ci) pfs and os from crizotinib initiation were 9.5 (8.7, 10.1) and 23.4 (19.5, -) months, respectively. One- and two-year survival probabilities were 82% and 49%, respectively. Conclusions: Outcomes for crizotinib recipients in this study align with previous trials, with orr appearing more favourable in first-line recipients. Our findings indicate that crizotinib outcomes in clinical studies may translate to regular clinical practice. PMID- 29507495 TI - Primary angiosarcoma of the breast-series of 11 consecutive cases-a single-centre experience. AB - Angiosarcomas of the breast are rare parenchymal malignancies of the chest wall. Surgery is the main treatment modality with chemotherapy and radiotherapy used in case of recurrence. With generally unfavourable prognosis and lack of clear treatment guidelines due to its rarity and scarcity of available data, angiosarcoma of the breast is a challenging clinical situation for both oncologist and patient. We present here the results of a series of 11 consecutive primary angiosarcoma cases treated at our institute between 2000 and 2015. PMID- 29507496 TI - Effect of early palliative care on quality of life in patients with non-small cell lung cancer. AB - Background: Patients with metastatic non-small-cell lung cancer (nsclc) experience great pain and stress. Our study aimed to explore the effect of early palliative care on quality of life in patients with nsclc. Methods: A total of 150 patients were randomly divided into two groups: control group with conventional care and study group with early palliative care. The quality of life (qol) rating scale and self-rating scale of life quality (sslq) were used to analyze the patients' quality of life. The Hospital Anxiety and Depression Scale D/A (hads-d/a) and Patient Health Questionnaire 9 (phq-9) were used to analyze the patients' mood. Pulmonary function indexes of peak expiratory flow (pef), functional residual capacity (frc), and trachea-esophageal fistula 25% (tef 25%) were analyzed using the lung function detector. Results: The qol and sslq scales scores of patients receiving early palliative care were significantly higher than those in the control group (p < 0.05). Moreover, the questionnaire results of the hads-d/a and phq-9 were better in patients receiving palliative care than in the control group (p < 0.05 or p < 0.01). In addition, analytical results of pulmonary function showed that the levels of pef, frc, and tef 25% in patients assigned to early palliative care were remarkably higher than those in the control group (p < 0.01 or p < 0.001). Conclusions: These data demonstrate that early palliative care improves life quality, mood, and pulmonary function of nsclc patients, indicating that early palliative care could be used as a clinically meaningful and feasible care model for patients with metastatic nsclc. PMID- 29507497 TI - Alberta CancerBridges development of a care plan evaluation measure. AB - Background: No standardized measures specifically assess cancer survivors' and healthcare providers' experience of Survivor Care Plans (scps). We sought to develop two care plan evaluation (cpe) measures, one for survivors (cpe-s) and one for healthcare providers (cpe-p), examine initial psychometric qualities in Alberta, and assess generalizability in Manitoba, Canada. Methods: We developed the initial measures using convenience samples of breast (n = 35) and head and neck (n = 18) survivors who received scps at the end of active cancer-centre treatment. After assessing Alberta's scp concordance with Institute of Medicine (iom) recommendations using a published coding scheme, we examined psychometric qualities for the cpe-s and cpe-p. We examined generalizability in Manitoba, Canada, with colorectal survivors discharged to primary care providers for follow up (n = 75). Results: We demonstrated acceptable internal consistency for the cpe s and cpe-p subscales and total score after eliminating one item per subscale for cpe-s, two for cpe-p, resulting in revised scales with four 7-item and 6-item subscales, respectively. Subscale scores correlated highly indicating that for each measure the total score may be the most reliable and valid. We provide initial cpe-s discriminant, convergent, and predictive validity using the total score. Using the Manitoba sample, initial psychometrics similarly indicated good generalizability across differences in tumour groups, scp, and location. Conclusions: We recommend the revised cpe-s and cpe-p for further use and development. Studies documenting the creation and standardization of scp evaluations are few, and we recommend further development of patient experience measures to improve both clinical practice and the specificity of research questions. PMID- 29507498 TI - Knowledge of HPV/cervical cancer and acceptability of HPV self-sampling among women living with HIV: A scoping review. AB - Cervical cancer rates are disproportionately high among women living with the human immunodeficiency virus (wlhiv). Cervical cancer is preventable through hpv screening, regular Pap tests, and early cancer detection. Evidence indicates that hpv and cervical cancer screening are suboptimal among wlhiv, who face a myriad of access barriers. Considering that screening is an effective first-line defense to cervical cancer, we conducted a scoping review with the aim of gaining a better understanding about: (1) the knowledge and perceptions of hpv and cervical cancer screening among wlhiv; and (2) the acceptability of self-sampling for hpv among wlhiv. We searched five electronic databases for peer-reviewed articles that were published in English within the last ten years, reported on studies with hiv-positive women who were aged 16 or older, and satisfied the topics of the review. A total of 621 articles were found. After accounting for duplicates and unmet criteria, 17 articles and 1 abstract, reporting on studies in the United States and Africa, were included in this review. The review highlighted that most wlhiv had inadequate knowledge of hpv transmission and cervical cancer prevention, which influenced their perceptions of risk and susceptibility. Screening barriers included misconceptions about Pap tests, fear of diagnosis of serious illness, perceived pain, embarrassment, bodily modesty, and limited access to female health care providers. This review also affirms that self sampling is an acceptable and promising screening option for wlhiv. Implications for policy, research, and practice are discussed. PMID- 29507499 TI - HIV-positive MSM's knowledge of HPV and anal cancer self-sampling: A scoping review. AB - Human papillomavirus (hpv) infection is the cause of anal squamous cell cancer (ascc) in 80% of cases. Available research has also shown high prevalence of anal hpv infection among men who have sex with men (msm). However, hpv vaccination is low among msm in Canada. In light of this information, we conducted a scoping review with the aim of exploring (1) the knowledge of hpv and anal cancer among hiv-positive msm and (2) the acceptability of hpv and anal cancer self-sampling in this population. In conducting the review, we searched five electronic databases for peer-reviewed articles and abstracts published in English, between 2007 and 2017. A total of 803 articles were retrieved; after accounting for duplicates (n=40) and unmet criteria (n=754), a total of 794 articles were excluded. A final total of nine articles were used in this review. Results of this review show that hiv-positive msm have limited knowledge regarding the risks of anal cancer associated with hiv and hpv coinfection. Furthermore, there is limited research on hpv and anal cancer self-sampling in this population. However, the review of available studies suggested that hiv-positive msm were open to anal cancer self-sampling. It also identified potential barriers to self sampling. In conclusion, we provide suggestions and future directions for policy makers and educators to develop inclusive and accessible strategies to reach hiv positive msm regarding anal cancer education and self-screening. PMID- 29507500 TI - Towards an optimal treatment algorithm for metastatic pancreatic ductal adenocarcinoma (PDA). AB - Chemotherapy remains the mainstay of treatment for advanced pancreatic ductal adenocarcinoma (pda). Two randomized trials have demonstrated superiority of the combination regimens folfirinox (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) and gemcitabine plus nab-paclitaxel over gemcitabine monotherapy as a first-line treatment in adequately fit subjects. Selected pda patients progressing to first-line therapy can receive secondline treatment with moderate clinical benefit. Nevertheless, the optimal algorithm and the role of combination therapy in second-line are still unclear. Published second-line pda clinical trials enrolled patients progressing to gemcitabine-based therapies in use before the approval of nab-paclitaxel and folfirinox. The evolving scenario in second line may affect the choice of the first-line treatment. For example, nanoliposomal irinotecan plus 5-fluouracil and leucovorin is a novel second-line option which will be suitable only for patients progressing to gemcitabine-based therapy. Therefore, clinical judgement and appropriate patient selection remain key elements in treatment decision. In this review, we aim to illustrate currently available options and define a possible algorithm to guide treatment choice. Future clinical trials taking into account sequential treatment as a new paradigm in pda will help define a standard algorithm. PMID- 29507501 TI - Improving pneumococcal vaccine uptake in veterans with chronic lymphocytic leukemia through a virtual clinic. AB - Through a "virtual clinic," we used the electronic medical record to identify and intervene upon patients with chronic lymphocytic leukemia (cll) who were not current for pneumococcal vaccines. Within 180 days, 100/160 patients (62%) received the recommended pneumococcal vaccine. A virtual clinic may improve vaccination rates among high-risk patient populations. PMID- 29507502 TI - Progressive multifocal leukoencephalopathy during ixazomib-based chemotherapy. AB - Progressive multifocal leukoencephalopathy (pml) is a rare demyelinating disease of the central nervous system that most often affects immunocompromised individuals. It is caused by the reactivation of the John Cunningham virus (jcv), which is found in latent form in the majority of adults. We describe a 59-year old man with multiple myeloma who developed severe neurological deficits during treatment with ixazomib-based chemotherapy. A diagnosis of pml was established with gadolinium-enhanced magnetic resonance imaging (mri) and by detection of jcv in the cerebrospinal fluid. Despite cessation of chemotherapy and treatment with mirtazapine, he had an inexorable neurological decline and died two months after presenting to hospital. Multiple myeloma and its treatments can predispose patients to opportunistic infections including pml. Although there have been case reports of pml in patients with multiple myeloma treated with bortezomib (a different proteosome inhibitor), this is, to our knowledge, the first documented case of pml in a patient treated with a regimen that includes ixazomib. PMID- 29507503 TI - Azacitidine-induced pyoderma gangrenosum at injection sites in a patient with myelodysplastic syndrome. AB - Pyoderma gangrenosum (pg) is a rare neutrophilic dermatosis characterized by painful necrotic ulceration affecting preferentially the lower extremities. Diagnosis is challenging, and a thorough workup (including biopsy) is required. In this case report, we describe a 67-year-old patient with a diagnosis of myelodysplastic syndrome (mds) who developed fever and pg two days after the first cycle of subcutaneous azacitidine (Vidaza; Celgene Corporation, Summit, NJ, USA). On physical examination, the patient had four erythematous plaques at sites of subcutaneous injections of azacitidine on the arms, as well as three other plaques in proximity. A skin biopsy demonstrated a dense neutrophilic interstitial infiltrate in the dermis. After the diagnosis of pg, prednisone 1 mg/kg was started and the fever subsided rapidly. This was followed by the resolution of the cutaneous lesions. Changing the route of administration of azacitidine from subcutaneous to intravenous and adding a daily dose of prednisone during the treatment allowed the patient to receive a total of 10 cycles of azacitidine. This is the second case reported in the literature. Because azacitidine is frequently used in mds and acute myeloid leukemia, clinicians should be aware of this rare cutaneous adverse event. Our approach can be used to avoid the recurrence of pg when continuing azacitidine treatment. PMID- 29507504 TI - Merkel cell carcinoma masquerading as cellulitis: a case report and review of the literature. AB - Merkel cell carcinoma (mcc) is an uncommon malignancy of the skin arising from cells located in the deeper layers of the epidermis called Merkel cells. This malignancy rarely presents as a metastatic disease, and the field is therefore deficient in regards to management. We report the case of a 49-year-old woman who presented with a presumptive diagnosis of osteomyelitis of the left fifth digit that was resistant to treatment with antibiotics; she underwent debridement of the digit that revealed mcc and was later to have metastatic disease to her lungs, liver, and musculoskeletal system. The management of mcc, although simple in the early stage of the disease, can become challenging when it is more advanced. Multiple new modalities for its treatment have emerged over the last few years, and more recently, clinical trials are being conducted for the use of immunotherapy agents in the treatment of this malignancy. PMID- 29507505 TI - Canada's eight-component vaccine safety system: A primer for health care workers. AB - Concerns about vaccine safety make some parents hesitant about immunization. Health care providers are pivotal in helping parents understand that Canada is a leader in vaccine safety. The present practice point provides an update on the eight components of Canada's vaccine safety system: (1) an evidence-based pre license review and approval process; (2) strong regulations for manufacturers; (3) independent evidence-based vaccine use recommendations; (4) immunization competency training and standards for health care providers; (5) pharmacovigilance programs to detect and (6) determine causality of adverse events following immunization (AEFIs); (7) a program for vaccine safety and efficacy signal detection; and (8) the Canadian Immunization Research Network's special immunization clinics for children who have experienced serious AEFIs. PMID- 29507507 TI - A time-domain method for prediction of noise radiated from supersonic rotating sources in a moving medium. AB - This paper presents a time-domain method for noise prediction of supersonic rotating sources in a moving medium. The proposed approach can be interpreted as an extensive time-domain solution for the convected permeable Ffowcs Williams and Hawkings equation, which is capable of avoiding the Doppler singularity. The solution requires special treatment for construction of the emission surface. The derived formula can explicitly and efficiently account for subsonic uniform constant flow effects on radiated noise. Implementation of the methodology is realized through the Isom thickness noise case and high-speed impulsive noise prediction from helicopter rotors. PMID- 29507506 TI - Violence against women and mental disorder: a qualitative study in Bangladesh. AB - Background: Violence affects 15-75% of women across the globe and has a significant impact on their health, well-being, and rights. While quantitative research links it to poor mental health, there is a lack of qualitative enquiry in how women experience it, and how it is related to the mental disorders in Bangladesh. This information is important in understanding the situation and structuring a locally appropriate and culturally sensitive program. Methods: We adopted a phenomenological approach and conducted 16 in-depth interviews, three informal interviews, one focus group discussion, and one key informant interview. We also reviewed published reports and documents. We followed criterion sampling in selecting women with mental disorders who experienced violence. We explored their experiences and understanding of the issues and described the phenomenon. Results: We found that Bangladesh society was largely controlled by men, and marriage was often forced on women. Women often were blamed for any mishap in the family and married women were under social and emotional pressure to keep the marital relationship going even when painful. We found all forms of violence (physical, emotional, sexual etc.) and most of the time found more than one type in women with mental disorders. Sexual violence is a reality for some women but rarely discussed. We found the society very tolerant with mental disorder patients and those who resorted to violence against them.We identified four theoretical understandings about the role of violence in mental disorders. Sometimes the violence predisposed the mental illness, sometimes it precipitated it, while other times it maintained and was a consequence of it. Sometimes the violence may be unrelated to the mental illness. The relationships were complex and depended on both the type of mental disorder and the nature and intensity of the violence. We found most of the time that more than one type of violence was involved and played more than one role, which varied across different types of mental disorders. Interestingly, not all violence that mentally disordered women faced was because they were women, but because of mental disorders, which brought violence to them as a consequence. Conclusions: The findings of this first ever qualitative study into the experiences of violence by women with mental disorder in Bangladesh can be used in developing a culturally specific intervention to reduce both violence and mental disorders in women. PMID- 29507508 TI - Analysis and control of the dynamical response of a higher order drifting oscillator. AB - This paper studies a position feedback control strategy for controlling a higher order drifting oscillator which could be used in modelling vibro-impact drilling. Special attention is given to two control issues, eliminating bistability and suppressing chaos, which may cause inefficient and unstable drilling. Numerical continuation methods implemented via the continuation platform COCO are adopted to investigate the dynamical response of the system. Our analyses show that the proposed controller is capable of eliminating coexisting attractors and mitigating chaotic behaviour of the system, providing that its feedback control gain is chosen properly. Our investigations also reveal that, when the slider's property modelling the drilled formation changes, the rate of penetration for the controlled drilling can be significantly improved. PMID- 29507509 TI - Nematic director fields and topographies of solid shells of revolution. AB - We solve the forward and inverse problems associated with the transformation of flat sheets with circularly symmetric director fields to surfaces of revolution with non-trivial topography, including Gaussian curvature, without a stretch elastic cost. We deal with systems slender enough to have a small bend energy cost. Shape change is induced by light or heat causing contraction along a non uniform director field in the plane of an initially flat nematic sheet. The forward problem is, given a director distribution, what shape is induced? Along the way, we determine the Gaussian curvature and the evolution with induced mechanical deformation of the director field and of material curves in the surface (proto-radii) that will become radii in the final surface. The inverse problem is, given a target shape, what director field does one need to specify? Analytic examples of director fields are fully calculated that will, for specific deformations, yield catenoids and paraboloids of revolution. The general prescription is given in terms of an integral equation and yields a method that is generally applicable to surfaces of revolution. PMID- 29507510 TI - Texture evolution and mechanical behaviour of irradiated face-centred cubic metals. AB - A physically based theoretical model is proposed to investigate the mechanical behaviour and crystallographic texture evolution of irradiated face-centred cubic metals. This model is capable of capturing the main features of irradiated polycrystalline materials including irradiation hardening, post-yield softening and plasticity localization. Numerical results show a good agreement with experimental data for both unirradiated and irradiated stress-strain relationships. The study of crystallographic texture reveals that the initial randomly distributed texture of unirradiated metals under tensile loading can evolve into a mixture of [111] and [100] textures. Regarding the irradiated case, crystallographic texture develops in a different way, and an extra part of [110] texture evolves into [100] and [111] textures. Thus, [100] and [111] textures become dominant more quickly compared with those of the unirradiated case for the reason that [100] and [111]-oriented crystals have higher strength, and their plastic deformation behaviours are more active than other oriented crystals. It can be concluded that irradiation-induced defects can affect both the mechanical behaviour and texture evolution of metals, both of which are closely related to irradiation hardening. PMID- 29507511 TI - Globular cluster formation and evolution in the context of cosmological galaxy assembly: open questions. AB - We discuss some of the key open questions regarding the formation and evolution of globular clusters (GCs) during galaxy formation and assembly within a cosmological framework. The current state of the art for both observations and simulations is described, and we briefly mention directions for future research. The oldest GCs have ages greater than or equal to 12.5 Gyr and formed around the time of reionization. Resolved colour-magnitude diagrams of Milky Way GCs and direct imaging of lensed proto-GCs at z~6 with the James Webb Space Telescope (JWST) promise further insight. GCs are known to host multiple populations of stars with variations in their chemical abundances. Recently, such multiple populations have been detected in ~2 Gyr old compact, massive star clusters. This suggests a common, single pathway for the formation of GCs at high and low redshift. The shape of the initial mass function for GCs remains unknown; however, for massive galaxies a power-law mass function is favoured. Significant progress has been made recently modelling GC formation in the context of galaxy formation, with success in reproducing many of the observed GC-galaxy scaling relations. PMID- 29507512 TI - Mobile assemblies of Bennett linkages from four-crease origami patterns. AB - This paper deals with constructing mobile assemblies of Bennett linkages inspired by four-crease origami patterns. A transition technique has been proposed by taking the thick-panel form of an origami pattern as an intermediate bridge. A zero-thickness rigid origami pattern and its thick-panel form share the same sector angles and folding behaviours, while the thick-panel origami and the mobile assembly of linkages are kinematically equivalent with differences only in link profiles. Applying this transition technique to typical four-crease origami patterns, we have found that the Miura-ori and graded Miura-ori patterns lead to assemblies of Bennett linkages with identical link lengths. The supplementary type origami patterns with different mountain-valley crease assignments correspond to different types of Bennett linkage assemblies with negative link lengths. And the identical linkage-type origami pattern generates a new mobile assembly. Hence, the transition technique offers a novel approach to constructing mobile assemblies of spatial linkages from origami patterns. PMID- 29507513 TI - Shear flow dynamics in the Beris-Edwards model of nematic liquid crystals. AB - We consider the Beris-Edwards model describing nematic liquid crystal dynamics and restrict it to a shear flow and spatially homogeneous situation. We analyse the dynamics focusing on the effect of the flow. We show that in the co rotational case one has gradient dynamics, up to a periodic eigenframe rotation, while in the non-co-rotational case we identify the short- and long-time regimes of the dynamics. We express these in terms of the physical variables and compare with the predictions of other models of liquid crystal dynamics. PMID- 29507514 TI - Pairwise approximation for SIR-type network epidemics with non-Markovian recovery. AB - We present the generalized mean-field and pairwise models for non-Markovian epidemics on networks with arbitrary recovery time distributions. First we consider a hyperbolic partial differential equation (PDE) system, where the population of infective nodes and links are structured by age since infection. We show that the PDE system can be reduced to a system of integro-differential equations, which is analysed analytically and numerically. We investigate the asymptotic behaviour of the generalized model and provide an implicit analytical expression involving the final epidemic size and pairwise reproduction number. As an illustration of the applicability of the general model, we recover known results for the exponentially distributed and fixed recovery time cases. For gamma- and uniformly distributed infectious periods, new pairwise models are derived. Theoretical findings are confirmed by comparing results from the new pairwise model and explicit stochastic network simulation. A major benefit of the generalized pairwise model lies in approximating the time evolution of the epidemic. PMID- 29507515 TI - On the homogenization of the acoustic wave propagation in perforated ducts of finite length for an inviscid and a viscous model. AB - The direct numerical simulation of the acoustic wave propagation in multiperforated absorbers with hundreds or thousands of tiny openings would result in a huge number of basis functions to resolve the microstructure. One is, however, primarily interested in effective and so homogenized transmission and absorption properties and how they are influenced by microstructure and its endpoints. For this, we introduce the surface homogenization that asymptotically decomposes the solution in a macroscopic part, a boundary layer corrector close to the interface and a near-field part close to its ends. The effective transmission and absorption properties are expressed by transmission conditions for the macroscopic solution on an infinitely thin interface and corner conditions at its endpoints to ensure the correct singular behaviour, which are intrinsic to the microstructure. We study and give details on the computation of the effective parameters for an inviscid and a viscous model and show their dependence on geometrical properties of the microstructure for the example of Helmholtz equation. Numerical experiments indicate that with the obtained macroscopic solution representation one can achieve an high accuracy for low and high porosities as well as for viscous boundary conditions while using only a small number of basis functions. PMID- 29507516 TI - A dislocation-based model for twin growth within and across grains. AB - A computational method is presented for representing twins via two-dimensional dislocation statics in an isotropic elastic solid. The method is compared with analytical approximations of twin shape and is used to study how twins evolve within grains subjected to an arbitrary external shear stress. Twin transfer across grains is then studied using the same computational method. The dislocation-based model for twin growth gives the following dependencies: twin thickness increases linearly with grain size and external stress, and increases substantially as the grain is able to traverse multiple grain boundaries with low misorientation angles; the model also predicts that twin transfer becomes less prominent across grain boundaries with high misorientation angles. These predictions are consistent with experimentally measured extension twin growth in magnesium polycrystals. This study suggests that representing twins via discrete dislocations provides a physically reasonable approximation of twinning that can be naturally incorporated into existing dislocation statics and dynamics codes. PMID- 29507517 TI - Equal-area criterion in power systems revisited. AB - The classic equal-area criterion (EAC) is of key importance in power system analysis, and provides a powerful, pictorial and quantitative means of analysing transient stability (i.e. the system's ability to maintain stable operation when subjected to a large disturbance). Based on the traditional EAC, it is common sense in engineering that there is a critical cleaning time (CCT); namely, a power system is stable (unstable) if a fault is cleared before (after) this CCT. We regard this form of CCT as bipartite. In this paper, we revisit the EAC theory and, surprisingly, find different kinds of transient stability behaviour. Based on these analyses, we discover that the bipartite CCT is only one type among four major types, and, actually, the forms of CCT can be diversified. In particular, under some circumstances, a system may have no CCT or show a periodic CCT. Our theoretical analysis is verified by numerical simulations in a single-machine infinite-bus system and also in multi-machine systems. Thus, our study provides a panoramic framework for diverse transient stability behaviour in power systems and also may have a significant impact on applications of multi-stability in various other systems, such as neuroscience, climatology or photonics. PMID- 29507518 TI - Analytic analysis of auxetic metamaterials through analogy with rigid link systems. AB - In recent years, many structural motifs have been designed with the aim of creating auxetic metamaterials. One area of particular interest in this subject is the creation of auxetic material properties through elastic instability. Such metamaterials switch from conventional behaviour to an auxetic response for loads greater than some threshold value. This paper develops a novel methodology in the analysis of auxetic metamaterials which exhibit elastic instability through analogy with rigid link lattice systems. The results of our analytic approach are confirmed by finite-element simulations for both the onset of elastic instability and post-buckling behaviour including Poisson's ratio. The method gives insight into the relationships between mechanisms within lattices and their mechanical behaviour; as such, it has the potential to allow existing knowledge of rigid link lattices with auxetic paths to be used in the design of future buckling induced auxetic metamaterials. PMID- 29507519 TI - A family of wave equations with some remarkable properties. AB - We consider a family of homogeneous nonlinear dispersive equations with two arbitrary parameters. Conservation laws are established from the point symmetries and imply that the whole family admits square integrable solutions. Recursion operators are found for two members of the family investigated. For one of them, a Lax pair is also obtained, proving its complete integrability. From the Lax pair, we construct a Miura-type transformation relating the original equation to the Korteweg-de Vries (KdV) equation. This transformation, on the other hand, enables us to obtain solutions of the equation from the kernel of a Schrodinger operator with potential parametrized by the solutions of the KdV equation. In particular, this allows us to exhibit a kink solution to the completely integrable equation from the 1-soliton solution of the KdV equation. Finally, peakon-type solutions are also found for a certain choice of the parameters, although for this particular case the equation is reduced to a homogeneous second order nonlinear evolution equation. PMID- 29507521 TI - Rogue periodic waves of the focusing nonlinear Schrodinger equation. AB - Rogue periodic waves stand for rogue waves on a periodic background. The nonlinear Schrodinger equation in the focusing case admits two families of periodic wave solutions expressed by the Jacobian elliptic functions dn and cn. Both periodic waves are modulationally unstable with respect to long-wave perturbations. Exact solutions for the rogue periodic waves are constructed by using the explicit expressions for the periodic eigenfunctions of the Zakharov Shabat spectral problem and the Darboux transformations. These exact solutions generalize the classical rogue wave (the so-called Peregrine's breather). The magnification factor of the rogue periodic waves is computed as a function of the elliptic modulus. Rogue periodic waves constructed here are compared with the rogue wave patterns obtained numerically in recent publications. PMID- 29507522 TI - Computational logic: its origins and applications. AB - Computational logic is the use of computers to establish facts in a logical formalism. Originating in nineteenth century attempts to understand the nature of mathematical reasoning, the subject now comprises a wide variety of formalisms, techniques and technologies. One strand of work follows the 'logic for computable functions (LCF) approach' pioneered by Robin Milner, where proofs can be constructed interactively or with the help of users' code (which does not compromise correctness). A refinement of LCF, called Isabelle, retains these advantages while providing flexibility in the choice of logical formalism and much stronger automation. The main application of these techniques has been to prove the correctness of hardware and software systems, but increasingly researchers have been applying them to mathematics itself. PMID- 29507520 TI - How the formation of amyloid plaques and neurofibrillary tangles may be related: a mathematical modelling study. AB - We develop a mathematical model that enables us to investigate possible mechanisms by which two primary markers of Alzheimer's disease (AD), extracellular amyloid plaques and intracellular tangles, may be related. Our model investigates the possibility that the decay of anterograde axonal transport of amyloid precursor protein (APP), caused by toxic tau aggregates, leads to decreased APP transport towards the synapse and APP accumulation in the soma. The developed model thus couples three processes: (i) slow axonal transport of tau, (ii) tau misfolding and agglomeration, which we simulated by using the Finke Watzky model and (iii) fast axonal transport of APP. Because the timescale for tau agglomeration is much larger than that for tau transport, we suggest using the quasi-steady-state approximation for formulating and solving the governing equations for these three processes. Our results suggest that misfolded tau most likely accumulates in the beginning of the axon. The analysis of APP transport suggests that APP will also likely accumulate in the beginning of the axon, causing an increased APP concentration in this region, which could be interpreted as a 'traffic jam'. The APP flux towards the synapse is significantly reduced by tau misfolding, but not due to the APP traffic jam, which can be viewed as a symptom, but rather due to the reduced affinity of kinesin-1 motors to APP transporting vesicles. PMID- 29507523 TI - Energy approach to brittle fracture in strain-gradient modelling. AB - In this paper, we exploit some results in the theory of irreversible phenomena to address the study of quasi-static brittle fracture propagation in a two dimensional isotropic continuum. The elastic strain energy density of the body has been assumed to be geometrically nonlinear and to depend on the strain gradient. Such generalized continua often arise in the description of microstructured media. These materials possess an intrinsic length scale, which determines the size of internal boundary layers. In particular, the non-locality conferred by this internal length scale avoids the concentration of deformations, which is usually observed when dealing with local models and which leads to mesh dependency. A scalar Lagrangian damage field, ranging from zero to one, is introduced to describe the internal state of structural degradation of the material. Standard Lame and second-gradient elastic coefficients are all assumed to decrease as damage increases and to be locally zero if the value attained by damage is one. This last situation is associated with crack formation and/or propagation. Numerical solutions of the model are provided in the case of an obliquely notched rectangular specimen subjected to monotonous tensile and shear loading tests, and brittle fracture propagation is discussed. PMID- 29507524 TI - Stability of barotropic vortex strip on a rotating sphere. AB - We study the stability of a barotropic vortex strip on a rotating sphere, as a simple model of jet streams. The flow is approximated by a piecewise-continuous vorticity distribution by zonal bands of uniform vorticity. The linear stability analysis shows that the vortex strip becomes stable as the strip widens or the rotation speed increases. When the vorticity constants in the upper and the lower regions of the vortex strip have the same positive value, the inner flow region of the vortex strip becomes the most unstable. However, when the upper and the lower vorticity constants in the polar regions have different signs, a complex pattern of instability is found, depending on the wavenumber of perturbations, and interestingly, a boundary far away from the vortex strip can be unstable. We also compute the nonlinear evolution of the vortex strip on the rotating sphere and compare with the linear stability analysis. When the width of the vortex strip is small, we observe a good agreement in the growth rate of perturbation at an early time, and the eigenvector corresponding to the unstable eigenvalue coincides with the most unstable part of the flow. We demonstrate that a large structure of rolling-up vortex cores appears in the vortex strip after a long time evolution. Furthermore, the geophysical relevance of the model to jet streams of Jupiter, Saturn and Earth is examined. PMID- 29507525 TI - Modelling resonant arrays of the Helmholtz type in the time domain. AB - We present a model based on a two-scale asymptotic analysis for resonant arrays of the Helmholtz type, with resonators open at a single extremity (standard resonators) or open at both extremities (double-sided resonators). The effective behaviour of such arrays is that of a homogeneous anisotropic slab replacing the cavity region, associated with transmission, or jump, conditions for the acoustic pressure and for the normal velocity across the region of the necks. The coefficients entering in the effective wave equation are simply related to the fraction of air in the periodic cell of the array. Those entering in the jump conditions are related to near field effects in the vicinity of the necks and they encapsulate the effects of their geometry. The effective problem, which accounts for the coupling of the resonators with the surrounding air, is written in the time domain which allows us to question the equation of energy conservation. This is of practical importance if the numerical implementations of the effective problem in the time domain is sought. PMID- 29507526 TI - Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway. AB - Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-alpha in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL 1beta) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation. PMID- 29507528 TI - Primary hepatic neuroendocrine carcinoma: report of two cases and literature review. AB - Background: Primary hepatic neuroendocrine carcinoma (PHNEC) is extremely rare. The diagnosis of PHNEC remains challenging-partly due to its rarity, and partly due to its lack of unique clinical features. Available treatment options for PHNEC include surgical resection of the liver tumor(s), radiotherapy, liver transplant, transcatheter arterial chemoembolization (TACE), and administration of somatostatin analogues. Case presentation: We report two male PHNEC cases and discuss the diagnosis and treatment options. Both cases presented with abdominal pain; case two also presented with symptoms of jaundice. The initial diagnosis for both cases was poorly differentiated grade 3 small-cell neuroendocrine carcinoma, based on imaging characteristics and the pathology of liver biopsies. Final diagnoses of PHNEC were arrived at by ruling out non-hepatic origins. Case one presented with a large tumor in the right liver lobe, and the patient was treated with TACE. Case two presented with tumors in both liver lobes, invasions into the left branch of hepatic portal vein, and metastasis in the hepatic hilar lymph node. This patient was ineligible for TACE and was allergic to the somatostatin analogue octreotide. This limited treatment options to supportive therapies such as albumin supplementation for liver protection. Patient one and two died at 61 and 109 days, respectively, following initial hospital admission. Conclusions: We diagnosed both cases with poorly differentiated grade 3 small cell PHNEC through imaging characteristics, immunohistochemical staining of liver biopsies, and examinations to eliminate non-hepatic origins. Neither TACE nor liver protection appeared to significantly extend survival time of the two patients, suggesting these treatments may be inadequate to improve survival of patients with poorly differentiated grade 3 small-cell PHNEC. The prognosis of poorly differentiated grade 3 small-cell PHNEC is poor due to limited and ineffective treatment options. PMID- 29507529 TI - From apprehension to advocacy: a qualitative study of undergraduate nursing student experience in clinical placement in residential aged care. AB - Background: Undergraduate nursing placement in aged care is forecast to grow in importance with the increasing aging population, and to help to reverse trends in student lack of interest in gerontology careers. However, there is a need to better understand undergraduate nursing students' experiences on placement with older adults, as well as key features of quality learning within residential aged care. The aim of this study was to explore how nursing students understand learning within residential aged care. Methods: This qualitative study used a participatory action research approach, and this paper reports on the thematic analysis of data from one cycle of undergraduate nursing placement in a Canadian residential aged care setting, with two groups of 7-8 students and two university instructors. Staff and residents at the research site were also included. Researchers interviewed both groups of students prior to and after placement. Instructors, staff and residents were interviewed post placement. Results: Students commenced placement full of apprehension, and progressed in their learning by taking initiative and through self-directed learning pathways. Engagement with residents was key to student learning on person-centred care and increased understanding of older adults. Students faced challenges to their learning through limited exposure to professional nursing roles and healthcare aide/student relationship issues. By placement end, students had gained unique insights on resident care and began to step into advocacy roles. Conclusions: In learning on placement within residential aged care, students moved from feelings of apprehension to taking on advocacy roles for residents. Better formalizing routes for students to feedback their unique understandings on resident care could ensure their contributions are better integrated and not lost when placements end. PMID- 29507527 TI - Critical Roles of IL-33/ST2 Pathway in Neurological Disorders. AB - Interleukin-33 (IL-33) is an IL-1 family member, which exhibits both pro- and anti-inflammatory properties solely based on the type of the disease itself. Generally, IL-33 is expressed by both endothelial and epithelial cells and mediates its function based on the interaction with various receptors, mainly with ST2 variants. IL-33 is a potent inducer for the Th2 immune response which includes defence mechanism in brain diseases. Thus, in this paper, we review the biological features of IL-33 and the critical roles of IL-33/ST2 pathway in selected neurological disorders including Alzheimer's disease, multiple sclerosis, and malaria infection to discuss the involvement of IL-33/ST2 pathway during these brain diseases and its potential as future immunotherapeutic agents or for intervention purposes. PMID- 29507530 TI - The tyrosine kinase inhibitor nilotinib is more efficient than mitotane in decreasing cell viability in spheroids prepared from adrenocortical carcinoma cells. AB - Background: New drugs for adrenocortical carcinoma (ACC) are needed because most patients undergo rapid disease progression despite surgery and adjuvant therapy with mitotane. In this study, we aimed to investigate the in vitro effects of different chemotherapy drugs, alone or combined with mitotane, on the viability of adrenocortical carcinoma cells. Methods: Everolimus, sunitinib, zoledronic acid, imatinib and nilotinib cytotoxicity, alone or combined with mitotane were tested on ACC H295R cells in monolayer or spheroid cultures using MTS assays and confocal microscopy. Moreover, the nilotinib effects were investigated in spheroids cultured from patient tumor-derived ACC-T36 cells. Results: Morphological characterization of H295R cell spheroids using histochemistry was performed and showed that dense, homogenously sized, multicellular spheroids were obtained. We observed that sunitinib and nilotinib alone were equally effective in a monolayer preparation, whereas mitotane was the most effective even at a low dose. A combination of sunitinib and mitotane was the most effective treatment, with only 23.8% of cells in the monolayer remaining viable. Spheroid preparations showed resistance to different drugs, although the poor effect produced by mitotane alone was surprising, with a cell viability of 84.6% in comparison with 13.1% in monolayer cells. The most ineffective drugs in spheroid preparations were everolimus, zoledronic acid and imatinib. In both cell types, nilotinib, either alone or in combination with mitotane induced more significant cell viability inhibition in monolayer and spheroid preparations. In addition, the mechanism of nilotinib activity involves the ERK1/2 pathway. Conclusion: Taken together, our data identified nilotinib as a cytotoxic drug that combined with ERK inhibitors deserves to be tested as a novel therapy for adrenocortical carcinoma. PMID- 29507531 TI - Arachidonic acid-induced Ca2+ entry and migration in a neuroendocrine cancer cell line. AB - Background: Store-operated Ca2+ entry (SOCE) has been implicated in the migration of some cancer cell lines. The canonical SOCE is defined as the Ca2+ entry that occurs in response to near-maximal depletion of Ca2+ within the endoplasmic reticulum. Alternatively, arachidonic acid (AA) has been shown to induce Ca2+ entry in a store-independent manner through Orai1/Orai3 hetero-multimeric channels. However, the role of this AA-induced Ca2+ entry pathway in cancer cell migration has not been adequately assessed. Methods: The present study investigated the involvement of AA-induced Ca2+ entry in migration in BON cells, a model gastro-enteropancreatic neuroendocrine tumor (GEPNET) cell line using pharmacological and gene knockdown methods in combination with live cell fluorescence imaging and standard migration assays. Results: We showed that both the store-dependent and AA-induced Ca2+ entry modes could be selectively activated and that exogenous administration of AA resulted in Ca2+ entry that was pharmacologically distinct from SOCE. Also, whereas homomeric Orai1-containing channels appeared to largely underlie SOCE, the AA-induced Ca2+ entry channel required the expression of Orai3 as well as Orai1. Moreover, we showed that AA treatment enhanced the migration of BON cells and that this migration could be abrogated by selective inhibition of the AA-induced Ca2+ entry. Conclusions: Taken together, these data revealed that an alternative Orai3-dependent Ca2+ entry pathway is an important signal for GEPNET cell migration. PMID- 29507532 TI - Thromboembolic events in cancer patients on active treatment with cisplatin-based chemotherapy: another look! AB - Background: The risk of thromboembolic events is higher among cancer patients, especially in patients undergoing chemotherapy. Cisplatin-based regimens claim to be associated with a very high thromboembolic rate. In this study, we report on our own experience with thrombosis among patients on active cisplatin-based chemotherapy. Methods: Medical records and hospital databases were searched for all the patients treated with any cisplatin-based regimen for any kind of cancer. Thrombosis was considered cisplatin-related if diagnosed any time after the first dose and up to 4 weeks after the last. The Khorana risk assessment model was performed in all cases. Results: A total of 1677 patients (65.5% males, median age: 50 years) treated with cisplatin-based regimens were identified. Head and neck (22.9%), lung (22.2%), lymphoma and gastric (11.4% each) were the most common primary tumors. Thromboembolic events were reported in 110 (6.6%); the highest was in patients with gastric cancer (20.9%) and the lowest in patients with head and neck cancers (2.3%) and lymphoma (1.6%). Thrombosis included deep vein thrombosis (DVT) in 69 (62.7%), pulmonary embolism (PE) in 18 (16.9%) and arterial thrombosis in 17 (15.6%). A majority (51.1%) of the patients had stage IV disease and only 16% had stage I or II.In a multivariate analysis, significantly higher rates of thrombosis were associated with gastric as the primary tumor, advanced-stage disease, female sex but not age, and the Khorana risk score or type of cisplatin regimen. While the presence of CVC was significantly associated with the risk of thrombosis (p < 0.0001) in the univariate analysis, and such significance was lost in the multivariate analysis (odds ratio, 1.098; 95%CI, 0.603-1.999, p = 0.7599). Conclusions: Thromboembolic events in cancer patients on active cisplatin-based chemotherapy were commonly encountered. Gastric cancer, regardless of other clinical variables, was associated with the highest risk. PMID- 29507533 TI - Higher pharmaceutical public expenditure after direct price control: improved access or induced demand? The Colombian case. AB - Background: High pharmaceutical expenditure is one of the main concerns for policymakers worldwide. In Colombia, a middle-income country, outpatient prescription represents over 10% of total health expenditure in the mandatory benefits package (POS), and close to 90% in the complementary government fund (No POS). In order to control expenditure, since 2011, the Ministry of Health introduced price caps on inpatient drugs reimbursements by active ingredient. By 2013, more than 400 different products, covering 80% of public pharmaceutical expenditure were controlled. This paper investigates the effects of the Colombian policy efforts to control expenditure by controlling prices. Methods: Using SISMED data, the official database for prices and quantities sold in the domestic market, we estimate a Laspeyres price index for 90 relevant markets in the period 2011-2015, and, then, we estimate real pharmaceutical expenditure. Results: Results show that, after direct price controls were enacted, price inflation decreased almost - 43%, but real pharmaceutical expenditure almost doubled due mainly to an increase in units sold. Such disproportionate increase in units sold maybe attributable to better access to drugs due to lower prices, and/or to an increase in marketing efforts by the pharmaceutical industry to maintain profits. Conclusions: We conclude that pricing interventions should be implemented along with a strong market monitoring to prevent market distortions such as inappropriate and unnecessary drug use. PMID- 29507534 TI - Silhouette Scores for Arbitrary Defined Groups in Gene Expression Data and Insights into Differential Expression Results. AB - Background: Hierarchical Sample clustering (HSC) is widely performed to examine associations within expression data obtained from microarrays and RNA sequencing (RNA-seq). Researchers have investigated the HSC results with several possible criteria for grouping (e.g., sex, age, and disease types). However, the evaluation of arbitrary defined groups still counts in subjective visual inspection. Results: To objectively evaluate the degree of separation between groups of interest in the HSC dendrogram, we propose to use Silhouette scores. Silhouettes was originally developed as a graphical aid for the validation of data clusters. It provides a measure of how well a sample is classified when it was assigned to a cluster by according to both the tightness of the clusters and the separation between them. It ranges from 1.0 to - 1.0, and a larger value for the average silhouette (AS) over all samples to be analyzed indicates a higher degree of cluster separation. The basic idea to use an AS is to replace the term cluster by group when calculating the scores. We investigated the validity of this score using simulated and real data designed for differential expression (DE) analysis. We found that larger (or smaller) AS values agreed well with both higher (or lower) degrees of separation between different groups and higher percentages of differentially expressed genes (PDEG). We also found that the AS values were generally independent on the number of replicates (Nrep). Although the PDEG values depended on Nrep, we confirmed that both AS and PDEG values were close to zero when samples in the data showed an intermingled nature between the groups in the HSC dendrogram. Conclusion: Silhouettes is useful for exploring data with predefined group labels. It would help provide both an objective evaluation of HSC dendrograms and insights into the DE results with regard to the compared groups. PMID- 29507536 TI - FAST AND EFFICIENT REJECTION OF BACKGROUND WAVEFORMS IN INTERICTAL EEG. AB - Automated annotation of electroencephalograms (EEG) of epileptic patients is important in diagnosis and management of epilepsy. Epilepsy is often associated with the presence of epileptiform transients (ET) in the EEG. To develop an efficient ET detector, a vast amount of data is required to train and evaluate the performance of the detector. Interictal EEG data contains mostly background waveforms, since ETs only occur occasionally in most patients. In order to detect ETs in an automated fashion, it is meaningful to first try to eliminate most background waveforms by means of simple, fast classifiers. The remaining waveforms can in a following step be processed by more sophisticated and computationally demanding classification algorithms, such as deep learning systems. In this study, we design a cascade of simple thresholding steps to reject most background waveforms in interictal EEG, while maintaining most ETs. Several simple and quick-to-compute EEG features are chosen. By thresholding these features in consecutive steps, background waveforms are rejected sequentially. In our numerical experiments, a cascade of 10 steps is able to reject 98.65% of all background segments in the dataset, while preserving 90.6% of the ETs. PMID- 29507535 TI - High-Sensitivity and High-Resolution In Situ Hybridization of Coding and Long Non coding RNAs in Vertebrate Ovaries and Testes. AB - Background: Subcellular localization of coding and non-coding RNAs has emerged as major regulatory mechanisms of gene expression in various cell types and many organisms. However, techniques that enable detection of the subcellular distribution of these RNAs with high sensitivity and high resolution remain limited, particularly in vertebrate adult tissues and organs. In this study, we examined the expression and localization of mRNAs encoding Pou5f1/Oct4, Mos, Cyclin B1 and Deleted in Azoospermia-like (Dazl) in zebrafish and mouse ovaries by combining tyramide signal amplification (TSA)-based in situ hybridization with paraffin sections which can preserve cell morphology of tissues and organs at subcellular levels. In addition, the distribution of a long non-coding RNA (lncRNA), lncRNA-HSVIII, in mouse testes was examined by the same method. Results: The mRNAs encoding Mos, Cyclin B1 and Dazl were found to assemble into distinct granules that were distributed in different subcellular regions of zebrafish and mouse oocytes, suggesting conserved and specific regulations of these mRNAs. The lncRNA-HSVIII was first detected in the nucleus of spermatocytes at prophase I of the meiotic cell cycle and was then found in the cytoplasm of round spermatids, revealing expression patterns of lncRNA during germ cell development. Collectively, the in situ hybridization method demonstrated in this study achieved the detection and comparison of precise distribution patterns of coding and non-coding RNAs at subcellular levels in single cells of adult tissues and organs. Conclusions: This high-sensitivity and high-resolution in situ hybridization is applicable to many vertebrate species and to various tissues and organs and will be useful for studies on the subcellular regulation of gene expression at the level of RNA localization. PMID- 29507537 TI - Sedentary Behavior and Blood Pressure in Patients with Multiple Sclerosis. AB - Background: Sedentary behavior is a pervasive public health concern in the general population. To date, little is known regarding the possible health risks associated with sedentary behavior in patients with multiple sclerosis (MS), although this population has increased risks of comorbidities such as hypertension. Methods: This cross-sectional study examined the association between sedentary behavior and blood pressure (BP) in 31 patients with MS and 31 matched controls. Self-reported sitting time, one form of sedentary behavior, was measured using the International Physical Activity Questionnaire. Using an automated oscillometric monitor, systolic BP, diastolic BP, and mean arterial pressure were measured in the supine position after 10 minutes of rest lying down in a quiet room. Results: There were significant correlations between International Physical Activity Questionnaire-measured sitting time and systolic BP (r = 0.365, P = .044, 95% CI, 0.013-0.636), diastolic BP (r = 0.382, P = .034, 95% CI, 0.032-0.648), and mean arterial pressure (r = 0.425, P = .017, 95% CI, 0.084-0.677) in patients with MS but not in controls (P > .05). The associations in patients with MS were unchanged even after adjusting for body mass index in linear regression analyses. Conclusions: This study identified a significant association between sitting time and BP outcomes in patients with MS, supporting the need for additional examinations of sitting time and its possible health consequences in patients with MS. PMID- 29507538 TI - Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database. AB - Background: Appropriate counseling and treatment for women with multiple sclerosis (MS) who may become pregnant requires an understanding of the effects of exposure to disease-modifying therapies (DMTs) during pregnancy. Current reports and studies are limited in their usefulness, mostly by small sample size. Branded glatiramer acetate (GA) is a DMT approved for the treatment of relapsing forms of MS. For more than 2 decades, it has been shown to be efficacious and to have a favorable safety profile. The Teva Pharmaceutical Industries Ltd global pharmacovigilance database comprises data from more than 7000 pregnancies, during which women with MS were exposed to treatment with branded GA. Methods: We analyzed data from Teva's global pharmacovigilance database. Pregnancy outcomes for patients treated with branded GA were compared with reference rates of abnormal pregnancy outcomes reported in two large registries representing the general population. Results: Pregnancies exposed to branded GA were not at higher risk for congenital anomalies than what is expected in the general population. Conclusions: These data provide evidence that branded GA exposure during pregnancy seems safe, without teratogenic effect. PMID- 29507539 TI - Feasibility of an International Multiple Sclerosis Rehabilitation Data Repository: Perceived Challenges and Motivators for Sharing Data. AB - Background: Multiple sclerosis (MS) rehabilitation evidence is limited due to methodological factors, which may be addressed by a data repository. We describe the perceived challenges of, motivators for, interest in participating in, and key features of an international MS rehabilitation data repository. Methods: A multimethod sequential investigation was performed with the results of two focus groups, using nominal group technique, and study aims informing the development of an online questionnaire. Percentage agreement and key quotations illustrated questionnaire findings. Subgroup comparisons were made between clinicians and researchers and between participants in North America and Europe. Results: Rehabilitation professionals from 25 countries participated (focus groups: n = 21; questionnaire: n = 166). The top ten challenges (C) and motivators (M) identified by the focus groups were database control/management (C); ethical/legal concerns (C); data quality (C); time, effort, and cost (C); best practice (M); uniformity (C); sustainability (C); deeper analysis (M); collaboration (M); and identifying research needs (M). Percentage agreement with questionnaire statements regarding challenges to, motivators for, interest in, and key features of a successful repository was at least 80%, 85%, 72%, and 83%, respectively, across each group of statements. Questionnaire subgroup analysis revealed a few differences (P < .05), including that clinicians more strongly identified with improving best practice as a motivator. Conclusions: Findings support clinician and researcher interest in and potential for success of an international MS rehabilitation data repository if prioritized challenges and motivators are addressed and key features are included. PMID- 29507540 TI - Association Between Pain and Mindfulness in Multiple Sclerosis: A Cross-sectional Survey. AB - Background: Chronic pain is a common symptom in people with multiple sclerosis (MS) and often requires a multimodal approach to care. The practice of mindfulness has been shown to decrease the experience of pain in other conditions, yet little is known about the relationship between mindfulness and pain in people with MS. The objective of this study was to evaluate the association between pain interference and trait mindfulness in people with MS. Methods: In this cross-sectional survey, 132 people with any type of MS completed the Patient-Reported Outcomes Measurement Information System Pain Interference scale and the Five Facet Mindfulness Questionnaire. Linear regression was used to test the association between pain and mindfulness while adjusting for demographic and MS-related characteristics. Results: The relationship between pain and mindfulness was clinically meaningful and highly significant (t = -5.52, P < .0001). For every 18-point increase in mindfulness scores, pain interference scores are expected to decrease by 3.96 (95% CI, -2.52 to -5.40) points (beta = 0.22, P < .0001). The adjusted model, including age, type of MS, the interaction between mindfulness and age, and the interaction between mindfulness and MS type, explains 26% of the variability in pain interference scores (R2 = 0.26). Conclusions: These results suggest a clinically significant association between mindfulness and pain interference in MS and support further exploration of mindfulness-based interventions in the management of MS-related pain. PMID- 29507541 TI - Projecting the Adequacy of the Multiple Sclerosis Neurologist Workforce. AB - Background: Anecdotal reports suggest shortages among neurologists who provide multiple sclerosis (MS) patient care. However, little information is available regarding the current and future supply of and demand for this neurologist workforce. Methods: We used information from neurologist and neurology resident surveys, professional organizations, and previously reported studies to develop a model assessing the projected supply and demand (ie, expected physician visits) of neurologists providing MS patient care. Model projections extended through 2035. Results: The capacity for MS patient visits among the overall neurologist workforce is projected to increase by approximately 1% by 2025 and by 12% by 2035. However, the number of individuals with MS may increase at a greater rate, potentially resulting in decreased access to timely and high-quality care for this patient population. Shortages in the MS neurologist workforce may be particularly acute in small cities and rural areas. Based on model sensitivity analyses, potential strategies to substantially increase the capacity for MS physicians include increasing the number of patients with MS seen per neurologist, offering incentives to decrease neurologist retirement rates, and increasing the number of MS fellowship program positions. Conclusions: The neurologist workforce may be adequate for providing MS care currently, but shortages are projected over the next 2 decades. To help ensure access to needed care and support optimal outcomes among individuals with MS, policies and strategies to enhance the MS neurologist workforce must be explored now. PMID- 29507542 TI - Short Report: Evaluation of Acceptance and Commitment Therapy Training for Psychologists Working with People with Multiple Sclerosis. AB - Background: Acceptance and commitment therapy (ACT) is the most widely used and researched recent variant of cognitive behavioral therapy and has been shown to increase quality of life in people with chronic illnesses, including multiple sclerosis (MS). However, few MS health practitioners are trained in ACT. This study evaluated a 2-day ACT training workshop for Italian psychologists working with people with MS. Methods: Data were collected via online questionnaires from 34 psychologists before the workshop, after the workshop, and at 6-month follow up. Two sets of variables were measured at each assessment: primary outcomes (well-being, negative affect, positive affect, and job satisfaction) and ACT processes (values, mindfulness, psychological flexibility, and cognitive defusion). A separate online workshop evaluation questionnaire and an ACT knowledge examination were administered after the workshop. Results: Most participants (94%) acknowledged the potential beneficial effects of the workshop on their work. Almost all participants reported their intention to apply ACT clinically. More than 90% of participants indicated that the workshop was efficacious. All participants scored higher than 75% on the examination. Mindfulness increased from after the workshop to follow-up; however, there were no statistically significant changes in other variables. Correlations suggested beneficial associations between the ACT processes and the primary outcomes. Conclusions: Results suggest that ACT training is personally and professionally helpful for psychologists in the MS field. PMID- 29507543 TI - Reliability and Validity of a Danish Version of the Multiple Sclerosis Neuropsychological Screening Questionnaire. AB - Background: More than half of all patients with multiple sclerosis (MS) acquire cognitive impairment as part of their disease progression. Because cognitive dysfunction adds substantially to disability and coping strategies, a cost effective screening tool is needed for cognitive impairment. The Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) has previously shown good validity in American, Argentinean, and Dutch MS cohorts. We sought to test reliability and validity of a Danish translation of the MSNQ compared with formal neuropsychological testing, and measures of depression and disability, and to compare self-reported cognition with Symbol Digit Modalities Test (SDMT) results. Methods: Of 126 patients with MS and their informants tested with the MSNQ, 77 also underwent formal neuropsychological testing. All patients were tested with the SDMT and assessed clinically using the Expanded Disability Status Scale and MS Impairment Scale. Results: The test-retest reliability of the MSNQ-P was significant (R2 = 0.79, P < .0001). R2 of informants (MSNQ-I) and patients (MSNQ P) was much lower (R2 = 0.22, P < .0001). Compared with formal neuropsychological testing, the MSNQ-P and MSNQ-I performed poorly, with no correlation to individual neuropsychological tests, combined neuropsychological tests, or disability scores (Expanded Disability Status Scale and MS Impairment Scale). Depression/anxiety (Beck Depression Inventory) showed a weak linear relationship (R2 = 0.25, P < .0001), suggesting that the MSNQ-P measures these items more than the cognitive abilities of the patients. Conclusions: This study does not support use of the MSNQ as a sensitive or valid screening tool for cognitive impairment in Danish patients with MS. PMID- 29507544 TI - Editorial. PMID- 29507545 TI - Current applications of antibody microarrays. AB - The concept of antibody microarrays is one of the most versatile approaches within multiplexed immunoassay technologies. These types of arrays have increasingly become an attractive tool for the exploratory detection and study of protein abundance, function, pathways, and potential drug targets. Due to the properties of the antibody microarrays and their potential use in basic research and clinical analytics, various types of antibody microarrays have already been developed. In spite of the growing number of studies utilizing this technique, few reviews about antibody microarray technology have been presented to reflect the quality and future uses of the generated data. In this review, we provide a summary of the recent applications of antibody microarray techniques in basic biology and clinical studies, providing insights into the current trends and future of protein analysis. PMID- 29507546 TI - Glycan analysis of colorectal cancer samples reveals stage-dependent changes in CEA glycosylation patterns. AB - Background: Carcinoembryonic antigen (CEA) is a glycoprotein associated with colorectal cancer (CRC). While the functions of its gene and protein have been fully characterized, its post-translational modifications in the context of CRC development remain undefined. Methods: To show the correlation between the different stages of CRC development and changes in the glycosylation patterns of CEA, we analyzed CEA in tumor tissues (CEA-T) and paired tumor-adjacent normal tissues (CEA-A) from 53 colorectal cancer patients using a high-density lectin microarray containing 56 plant lectins. Results: We detected higher expression levels of fucose, mannose and Thomsen-Friedenreich antigen, and lower expression levels of N-acetylgalactosamine, N-acetylglucosamine, galactose, branched and bisecting N-glycans on CEA in the tumor tissues relative to the tumor-adjacent normal tissues. Furthermore, a combinatorial assessment of 9 lectins is sufficient to distinguish CRC tumor tissues from tumor-adjacent normal tissues with 83% sensitivity and ~ 90% specificity. Moreover, the levels of N acetylgalactosamine, mannose, galactose, N-acetylglucosamine on CEA showed a downward trend after first experiencing an increase at Stage II with the stages of CRC. Conclusions: Our insights into the changing CEA glycosylation patterns and their role in the development of CRC highlight the importance of glycan variants on CEA for early clinical detection and staging of CRC. PMID- 29507548 TI - Interpretation of solution scattering data from lipid nanodiscs. AB - The structural information contained in solution scattering data from empty lipid nanodiscs is examined in the context of a multi-component geometric model. X-ray scattering data were collected on nanodiscs of different compositions at scattering vector magnitudes up to 2.0 A-1. Through the calculation of the partial form factor for each of the nanodisc components before the isotropic average, structural parameters in the model were correlated to the features observed in the X-ray scattering data and to the corresponding distance distribution function. It is shown that, in general, the features at ~0.3-0.6 A-1 in the scattering data correlate to the bilayer structure. The data also support the argument that the elliptical shape of nanodiscs found in model fitting is physical, rather than an artefact due to the nanodisc size distribution. The lipid chain packing peak at ~1.5 A-1 is visible in the data and reflects the lipid bilayer phase transition. The shape change in the distance distribution function across the phase transition suggests that the nanodiscs are more circular in the fluid phase. The implication of these findings for model fitting of empty and protein-loaded nanodiscs is discussed. PMID- 29507547 TI - Femtosecond X-ray diffraction from an aerosolized beam of protein nanocrystals. AB - High-resolution Bragg diffraction from aerosolized single granulovirus nanocrystals using an X-ray free-electron laser is demonstrated. The outer dimensions of the in-vacuum aerosol injector components are identical to conventional liquid-microjet nozzles used in serial diffraction experiments, which allows the injector to be utilized with standard mountings. As compared with liquid-jet injection, the X-ray scattering background is reduced by several orders of magnitude by the use of helium carrier gas rather than liquid. Such reduction is required for diffraction measurements of small macromolecular nanocrystals and single particles. High particle speeds are achieved, making the approach suitable for use at upcoming high-repetition-rate facilities. PMID- 29507549 TI - Dynamic diffraction artefacts in Bragg coherent diffractive imaging. AB - This article reports a theoretical study on the reconstruction artefacts in Bragg coherent diffractive imaging caused by dynamical diffraction effects. It is shown that, unlike the absorption and refraction effects that can be corrected after reconstruction, dynamical diffraction effects have profound impacts on both the amplitude and the phase of the reconstructed complex object, causing strong artefacts. At the dynamical diffraction limit, the reconstructed shape is no longer correct, as a result of the strong extinction effect. Simulations for hemispherical particles of different sizes show the type, magnitude and extent of the dynamical diffraction artefacts, as well as the conditions under which they are negligible. PMID- 29507551 TI - CAPOW: a standalone program for the calculation of optimal weighting parameters for least-squares crystallographic refinements. AB - The rigorous analysis of crystallographic models, refined through the use of least-squares minimization, is founded on the expectation that the data provided have a normal distribution of residuals. Processed single-crystal diffraction data rarely exhibit this feature without a weighting scheme being applied. These schemes are designed to reflect the precision and accuracy of the measurement of observed reflection intensities. While many programs have the ability to calculate optimal parameters for applied weighting schemes, there are still programs that do not contain this functionality, particularly when moving beyond the spherical atom model. For this purpose, CAPOW (calculation and plotting of optimal weights), a new program for the calculation of optimal weighting parameters for a SHELXL weighting scheme, is presented and an example of its application in a multipole refinement is given. PMID- 29507550 TI - DiSCaMB: a software library for aspherical atom model X-ray scattering factor calculations with CPUs and GPUs. AB - It has been recently established that the accuracy of structural parameters from X-ray refinement of crystal structures can be improved by using a bank of aspherical pseudoatoms instead of the classical spherical model of atomic form factors. This comes, however, at the cost of increased complexity of the underlying calculations. In order to facilitate the adoption of this more advanced electron density model by the broader community of crystallographers, a new software implementation called DiSCaMB, 'densities in structural chemistry and molecular biology', has been developed. It addresses the challenge of providing for high performance on modern computing architectures. With parallelization options for both multi-core processors and graphics processing units (using CUDA), the library features calculation of X-ray scattering factors and their derivatives with respect to structural parameters, gives access to intermediate steps of the scattering factor calculations (thus allowing for experimentation with modifications of the underlying electron density model), and provides tools for basic structural crystallographic operations. Permissively (MIT) licensed, DiSCaMB is an open-source C++ library that can be embedded in both academic and commercial tools for X-ray structure refinement. PMID- 29507552 TI - Erratum: Reconstructing three-dimensional protein crystal intensities from sparse unoriented two-axis X-ray diffraction patterns. Corrigendum. AB - [This corrects the article DOI: 10.1107/S1600576717006537.]. PMID- 29507553 TI - The diagnosis and management of food allergies. Position paper of the Food Allergy Section the Polish Society of Allergology. AB - The paper concerns the current position of the Polish Society of Allergology Food Allergy Section on the diagnosis and management of food allergies. The aim of this position is to provide evidence-based recommendations on the diagnosis and management of patients with allergic hypersensitivity to foods. This position statement includes a systematic review of studies in three areas, namely, the epidemiology, diagnosis and management of food allergies. While taking into account the specific Polish setting, in this publication we also used the current European Academy of Allergy and Clinical Immunology (EAACI) position paper and other current position statements, including those of the United States National Institute of Allergy and Infectious Diseases (NIAID). PMID- 29507555 TI - The incidence and management of cutaneous adverse events of the epidermal growth factor receptor inhibitors. AB - Overexpression of the epidermal growth factor receptor (EGFR) is found in many cancers, including those of the head and neck area, non-small-cell lung cancer, and colorectal, cervical, prostate, breast, ovary, stomach, and pancreatic cancer. The EGFR inhibitors are used at present in the treatment of such cancers. Skin lesions that develop during and after cancer treatment may be due to specific cytostatics, molecular-targeted drugs, radiation therapy, complementary therapy, or the cancer itself, and hence knowledge is essential to distinguish between them. The mechanism through which skin toxicity arises during treatment with EGFR inhibitors is not well known, but seems to be due to the modification of the RAS/RAF/MEK/ERK signal path associated with its activation, which results in the similarity between the adverse effects of EGFR inhibitors and the treatment of melanoma with BRAF and MEK inhibitors. The most common side effects are pruritus, xerosis, papulopustular rash, hand-foot skin reaction, alopecia and dystrophy of the hair, and paronychia. This work presents options for prevention and suggestions for managing these adverse events, which are of importance in the care of patients undergoing oncological treatment. PMID- 29507554 TI - The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part II: The Treg role in skin diseases pathogenesis. AB - Regulatory FOXP3+ T cells (Tregs) constitute 5% to 10% of T cells in the normal human skin. They play an important role in the induction and maintenance of immunological tolerance. The suppressive effects of these cells are exerted by various mechanisms including the direct cytotoxic effect, anti-inflammatory cytokines, metabolic disruption, and modulation of the dendritic cells function. The deficiency of Treg cells number or function are one of the basic elements of the pathogenesis of many skin diseases, such as psoriasis, atopic dermatitis, bacterial and viral infections. They also play a role in the pathogenesis of T cell lymphomas of the skin (cutaneous T cell lymphomas - CTCL), skin tumors and mastocytosis. Here, in the second part of the cycle, we describe dysfunctions of Tregs in selected skin diseases. PMID- 29507556 TI - Risks of on-pump coronary artery bypass grafting surgery in patients with chronic obstructive pulmonary disease due to sulfur mustard. AB - Sulfur mustard (SM) is a toxic chemical agent that belongs to a class of vesicant compounds. In the 1980s it was used by the Iraqi army against Iranian forces. Sulfur mustard severely irritates the skin, eyes and lungs. The highest side effects seen in patients affected by this gas are pulmonary complications including different types of lung diseases such as bronchiolitis. It has also led to a certain type of chronic obstructive pulmonary disease called mustard lung. Similar extra-pulmonary, molecular and hormonal effects can be observed in these patients and patients with chronic obstructive pulmonary disease. Here cardiovascular complications may be one of the most dangerous visible effects. And atherosclerosis is probable following the direct effects or consequential long-term effects of SM. The development of atherosclerosis in these patients is associated with an increased risk of cardiovascular and coronary artery disease. Coronary artery bypass grafting surgery is the treatment of coronary artery disease. Doing this surgery by bypass pump has its own morbidity and due to local and systemic inflammation changes in patients with SM pulmonary disorders it may have more side effects. Therefore, detailed knowledge of inflammatory diseases as well as the serum level or even the local lung fluid of the inflammatory factors in these patients before surgery are needed so that it would be possible to reduce the rate of morbidity and mortality by normalizing the inflammatory conditions of the patients before cardiac surgery. PMID- 29507557 TI - Pregnancy: a therapeutic dilemma. AB - Treatment during pregnancy is problematic. The Food and Drug Administration established drug categories to help in the treatment process. First-generation antihistamines are considered safe but they have sedative properties. Second generation antihistamines cause less adverse reactions but besides cetirizine and loratadine they belong to category C. All retinoids should be avoided during pregnancy due to the risk of fetal malformations. Antimalarial drugs should be considered based on the clinical data. Sulfones can be considered as safe for use during pregnancy only with proper monitoring. Prednisone is administered in pregnancy. Other glucocorticosteroids have a different safety profile. Cyclosporine A treatment should be reserved as rescue therapy in severe stages of the disease. Treatment during pregnancy should be precise when it comes to pregnant woman and safe for the fetus. PMID- 29507558 TI - Quality of life in asthmatic children and their caregivers after two-year treatment with omalizumab, a real-life study. AB - Introduction: Omalizumab, a monoclonal anti-immunoglobulin E antibody, has been successfully used as a supplementary therapy to improve asthma control in children aged >= 6 years with severe persistent allergic asthma. Aim: To demonstrate the quality of life in children with severe asthma and their caregivers, and changes from baseline in forced expiratory volume in 1 s (FEV1) and daily inhaled corticosteroids (ICS) dose after 2-year treatment with omalizumab. Material and methods: Participants were seen in the clinic at enrollment (visit 1), after 16 weeks (visit 2), after 52 weeks (visit 3) and after 104 weeks (visit 4) of treatment with omalizumab. We evaluated lung function, ICS use and the quality of life with the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ). Results: Nineteen children and caregivers were enrolled. Significant improvement was observed in PAQLQ and PACQLQ scores, both in all domains and in total scores. Significant differences were found between the first and the other visits. A positive correlation between PAQLQ and PACQLQ at the first and at the second visit was found, 63.3% of patients achieved reduction in ICS doses. We did not notice any significant improvement in FEV1. Conclusions: The improvement in quality of life in asthmatic children and adolescents observed after omalizumab correlates with the improvement of quality of life in caregivers, reduction in ICS use but not with FEV1. PMID- 29507559 TI - Involvement of new oxidative stress markers in chronic spontaneous urticaria. AB - Introduction: Oxidative stress is a result of an imbalance between endogenous production of free reactive oxygen species and reduced effectiveness of antioxidant defence mechanisms. Advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) are compounds formed by transformation of macromolecules, including proteins which can serve as markers of oxidative stress and inflammation in several diseases. Aim: To investigate the role of AGEs and AOPPs as new markers of oxidative stress and inflammation in patients with chronic spontaneous urticaria (CSU). Material and methods: Advanced glycation end products and AOPP levels were determined in the sera of 85 patients with CSU and 64 healthy controls, using spectrofluorimetry and spectrophotometry, respectively. Results: Advanced oxidation protein products levels in patients were statistically higher than those in controls. These levels were not affected by the presence of positive autologous serum test results or autologous plasma test results. No statistically significant differences were found between AGE levels in patients and controls. Conclusions: Formation of AGEs and AOPPs may be accelerated in immunological and allergic disorders. Depending on the sites evaluated, the presence or absence of oxidative stress in chronic urticaria is controversial. To our knowledge, this is the first study showing the possible involvement of AOPPs in CSU. The different behaviour observed for these two biomarkers is very likely due to the activation of specific related biochemical pathways associated with the condition under study. PMID- 29507560 TI - Evaluation of abdominal fat index by ultrasonography and its relationship with psoriasis and metabolic syndrome. AB - Introduction: Accumulating evidence indicates that psoriasis is associated with obesity and metabolic syndrome. Psoriasis and obesity share similar inflammatory mediators, and obesity may potentiate some inflammatory cytokines seen in psoriasis. Body fat distribution, particularly visceral adipose tissue (VAT), is an important factor in metabolic syndrome and atherosclerotic diseases. An association has been demonstrated between psoriasis and abdominal VAT measured by computed tomography (CT). Aim: To measure abdominal VAT noninvasively by ultrasonography (USG) in patients with psoriasis and investigated its relation to psoriasis and metabolic syndrome. Material and methods: The study population consisted of 41 psoriasis patients and 41 control subjects matched for age, sex, and body mass index. The maximal preperitoneal fat thickness (Pmax) at the anterior surface of the liver and the minimal subcutaneous fat thickness (Smin) of the abdomen were measured by USG. The abdominal fat index (AFI = Pmax/Smin ratio) was calculated and the results were compared between groups. Results: The rate of metabolic syndrome was significantly higher in psoriasis patients (p = 0.0018). The mean AFI was similar in both groups. AFI was not associated with psoriasis in subjects with metabolic syndrome (p = 0.495) or with Psoriasis Area and Severity Index (r = 0.123, p = 0.443). Conclusions: This is the first study to evaluate abdominal VAT by USG. Computed tomography may be more reliable than USG, but its high cost and radiation exposure are major disadvantages. Further studies are required to determine the relationships between psoriasis and VAT. PMID- 29507561 TI - Antihistamines in the treatment of pruritus in psoriasis. AB - Aim: To evaluate the efficacy of antihistamines in reducing pruritus in psoriasis, 61 patients were randomized to be treated for 1 week with clemastine (n = 20), levocetirizine (n = 21) or placebo (n = 20). Material and methods: All patients received the same routine antipsoriatic treatment. Itch intensity was assessed with VAS and the Itch Questionnaire, and hand movements during sleep were counted with an accelerometer. Results: There was a statistically significant decrease in mean VAS scoring in clemastine and levocetirizine groups (p < 0.001), but not in the placebo group. Questionnaire scoring decreased significantly during the study in all study groups, with the greatest improvement noted in the clemastine group. The number of wrist movements during sleep did not differ significantly between groups. Conclusions: Antihistamines of the first and second generations seem to be effective in reducing itch in patients with psoriasis, albeit the antipruritic effect is rather moderate. These observations need to be confirmed on larger patient groups. PMID- 29507562 TI - An evaluation of thiol/disulphide homeostasis in patients with psoriasis. AB - Introduction: The role of oxidative stress in the pathogenesis of psoriasis has been investigated in previous studies with conflicting results. On the other hand, well-established treatments currently used in psoriasis exert their effects via a boost of oxidative stress. Recently, a strong positive association between psoriasis, metabolic syndrome and dyslipidemia has also been described showing the complex nature of the disease. Aim: To examine thiol/disulphide homeostasis, a newly developed homeostasis assay in psoriasis and evaluate the possible association between thiol/disulphide homeostasis and dyslipidemia in psoriasis. Material and methods: The study population included 92 psoriasis patients and 71 healthy subjects. Serum native thiol, total thiol and disulphide levels were investigated in patients with psoriasis and in healthy subjects. In addition, lipid profile (serum total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) levels were investigated in both groups. The association between thiol-disulphide parameters and dyslipidemia was also evaluated. Results: Serum total cholesterol and triglyceride levels were found to be higher in patients with psoriasis than in the healthy group. Lower plasma disulphide and higher native thiol levels were found in patients with psoriasis indicating an antioxidant status. Conclusions: To our knowledge, this is the first study showing the shift of dynamic thiol/disulphide homeostasis towards the thiol form in psoriasis which indicate higher antioxidant status. PMID- 29507563 TI - Influence of ulceration etiology on the global quality of life and its specific dimensions, including the control of pain, in patients with lower limb vascular insufficiency. AB - Introduction: The results of previous studies suggest that the quality of life in patients with lower limb ulcerations is markedly poorer than in the general population - with regard to physical, mental and social spheres. This complex character of that parameter necessitates comprehensive analyses of its specific aspects, including the level of the acceptance of illness and associated pain symptoms. Aim: To compare the quality of life and its specific dimensions in patients with lower limb ulcerations of various etiology. Material and methods: Patients with the ulcerations resulting from venous (n = 101) or arterial pathologies (n = 98), or having mixed etiology (n = 99) were examined with the: 1) Skindex-29 instrument, 2) Acceptance of Illness Scale, 3) Beliefs about Pain Control Questionnaire, and 4) Coping Strategy Questionnaire. Results: The average quality of life related to physical symptoms was significantly higher in patients with venous ulcerations. Patients with ulcerations of arterial etiology more frequently used catastrophizing, and less often ignored pain sensations, used coping self-statements, and increased their activity levels; they were characterized by lower levels of control and poorer ability to decrease the pain. The internal locus of pain control increased proportionally to the global quality of life scores and levels of illness acceptance. Control over pain and ability to decrease the pain were more effective in individuals who used ignoring pain sensations, increasing the activity level, coping self-statements, and reinterpreting pain than in those using catastrophizing or praying and hoping strategies. Conclusions: Physical complaints seem to be the basic determinant of the quality of life in patients with the lower limb ulceration, irrespective of its etiology. PMID- 29507564 TI - The usefulness of Duplex Doppler ultrasound in the angiological and dermatological diagnosis of patients with blue toe syndrome. AB - Introduction: Peripheral microembolism is one of the most frequent causes of acute limb ischemia. In order to effectively prevent relapses it is essential to localize and eliminate the source of embolism. Aim: To evaluate the role of Duplex Doppler ultrasound examination in identifying the causes of blue toe syndrome (BTS). Material and methods: The group of 165 patients with clinical symptoms of BTS on their upper limbs (n = 16) and lower limbs (n = 149) was investigated. They all underwent Duplex Doppler ultrasound of the major arteries of the extremities, where ischemic changes occurred. Results: Morphological and functional changes which might be potential sources of microembolism were identified in 146 patients. These changes included significant short-length stenoses or unstable atherosclerotic plaque (n = 73), true aneurysms (n = 42) and pseudoaneurysms (n = 17). In 11 cases, pathology of vascular prostheses in the form of anastomotic aneurysms, infection and residual thrombi after fibrinolysis was detected. In all cases, Duplex diagnosis was confirmed by other imaging and intraoperative tests. Conclusions: Duplex Doppler ultrasound of the arteries in the affected limb with a full length view should be the first-line examination in diagnosing patients with BTS. In the absence of hemodynamic blood flow disturbances in the major arteries in patients with symptoms of BTS, it is advisable to start haematological tests to identify/exclude congenital or acquired thrombophilia. PMID- 29507565 TI - High-frequency ultrasonography (HFUS) as a useful tool in differentiating between plaque morphea and extragenital lichen sclerosus lesions. AB - Introduction: Morphea and lichen sclerosus (LS) are chronic inflammatory diseases that may pose a diagnostic challenge for a physician. High-frequency ultrasonography (HFUS) is a versatile diagnostic method utilized in dermatologic practice, allowing monitoring the course of the disease, treatment response and differentiation between certain skin disorders. Aim: To prove the usefulness of HFUS in differentiating between plaque morphea and extragenital LS lesions. Material and methods: We examined 16 patients with plaque morphea and 4 patients with extragenital LS using 20 MHz taberna pro medicumTM (Germany) device. Results: Investigations revealed hyperechogenic entrance echo in both morphea and LS lesions, whereas a distinct polycyclic surface of the entrance echo was detected exclusively in LS. Conclusions: High-frequency ultrasonography is a current diagnostic modality that may prove useful in differentiating between morphea and LS lesions. PMID- 29507567 TI - Influence of lifestyle factors and stress on the radioallergosorbent test scores: two case reports. PMID- 29507566 TI - Oncogenic BRAF mutations and p16 expression in melanocytic nevi and melanoma in the Polish population. AB - Introduction: Twenty-five - fifty percent of skin melanomas arise from nevi. Melanocyte proliferation is activated by BRAFV600E, then is arrested, but single nevi transform to melanomas. p16 controls arrest, and p16 loss may promote transformation. Aim: To analyze BRAFV600E, p16 expression and melanocyte proliferation in dermal, compound and dysplastic nevi, cells of primary and metastatic melanoma in the Polish population. Material and methods: One hundred and thirty-two nevi (dermal, compound, dysplastic) and 41 melanomas (in situ, primary, metastatic) were studied. BRAF was assessed by cobas(r) 4800 BRAFV600 Mutation Test, High Resolution Melting Assay validated with: pyrosequencing and immunohistochemistry. p16 and Ki67 expression was analyzed by IHC. Results: Eighty-two percent of nevi and 57% of melanomas display BRAFV600E expression. Most dermal and compound nevi had > 50% of p16(+) cells. BRAFV600E dysplastic nevi had a low number of p16(+) cells. Nevi without BRAFV600E (WT), had 90% of cells p16(+). In 60% of in situ and primary melanomas, there was a low number of cells of p16(+). Fifty percent of WT metastatic melanoma and 33% of BRAFV600E showed a high level of p16. The number of Ki67(+) cells in dysplastic nevi was very low. In 25% of BRAFV600E melanomas in situ and 55% of WT, > 10% cells were Ki67(+). All BRAFV600E primary melanomas and 66% of WT had > 10% Ki67(+) cells. Twenty percent of BRAFV600E and WT metastases had > 10% of Ki67(+), however, 62% of BRAFV600E and 32% of WT samples had > 50% of Ki67(+) cells. Conclusions: BRAFV600E and p16 are more frequent in nevi than in melanoma in vivo. A significantly higher p16 expression was observed in mutated nevi than in WT, while in melanoma it was just the opposite. The proliferation rate of melanoma cells negatively correlated with p16 expression. PMID- 29507568 TI - Pyoderma gangrenosum mimicking inflammatory breast cancer. PMID- 29507569 TI - Blastic plasmacytoid dendritic cell neoplasm: a rare lymphoma of extremely aggressive course. PMID- 29507570 TI - Unmasking of severe hypertriglyceridaemia associated with antipsychotic therapy by atypical eruptive xanthomas. PMID- 29507571 TI - Horton's disease: still an important medical problem in elderly patients: a review and case report. PMID- 29507572 TI - Denosumab - a new medication in the treatment of postmenopausal osteoporosis. AB - Osteoporosis is a chronic, systemic skeletal disorder characterised by decreased bone density. It leads to an increased risk of bone fractures - one of the major causes of disability in modern societies. Bisphosphonates are the most commonly used medications in the treatment of postmenopausal osteoporosis. Denosumab, a new approach to fracture prevention, is a fully human monoclonal antibody that targets nuclear factor-kappaB ligand (RANKL), an important cytokine regulating formation and function of osteoclasts. Generally, denosumab is not used as initial therapy; however, in some cases it should be considered. It concerns patients at high risk of fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates or who have markedly impaired renal function. Denosumab can be also considered in patients who present intolerance or unresponsiveness to other therapies. Clinical studies have shown that denosumab is highly effective in increasing bone mineral density (BMD) in postmenopausal women regardless of the site analysed, as well as reducing the risk of bone fractures. The risk of developing antiresorptive, agent-induced osteonecrosis of the jaw related to denosumab therapy is low. PMID- 29507573 TI - Perceived quality of life and acceptance of illness in people with type 2 diabetes mellitus. AB - Objectives: Type 2 diabetes exerts a significant impact on the patient's quality of life. Its chronic nature, incurability and complications weaken the motivation of patients to fight the disease and its acceptance. The aim of research was to determine whether and to what extent diabetes modulates the quality of life of patients and in particular which domain of the patient's life is most limited. In addition, we looked at whether the quality of life perceived by patients is determined by gender and whether and to what extent they accept their illness. Material and methods: A study on 100 patients with type 2 diabetes from the Wielkopolska region in Poland was carried out at the end of 2013/beginning of 2014 using a diagnostic survey, and the research techniques were a standardized questionnaire - ADDQoL19 (Audit of Diabetes-Dependent Quality of Life 19) and the AIS questionnaire (Acceptance of Illness Scale) developed by Felton and modified by Juczynski. Results: The results suggest that the quality of life of the patients was "neither good nor bad", whereby women perceive it as being lower than men. While analysing the impact of diabetes on the different domains of the lives of men and women, it should be stressed that most affected were diet, satisfying appetite, independence, financial position, feelings about the future, sex life, and freedom in the consumption of drinks. More than half of men and women did not accept their illness; however, younger persons unlike older accepted diabetes to a much greater degree. Conclusions: Type 2 diabetes negatively affects the quality of life of patients and its impact is felt more by women. In both sexes, the most affected domain of quality of life is the lack of nutritional freedom. The acceptance of illness is dependent upon age. PMID- 29507574 TI - General self-efficacy level and health behaviours in women over the age of 45 years who have undergone osteoporosis treatment. AB - Introduction: Contemporary people do not follow the civilisation development in every life domain, their lifestyle is not always healthy. Self-efficacy is the factor that plays an important role in undertaking actions towards struggling with the disease. The aim of the study: The aim of the study was to determine the relationship between the general self-efficacy level and health behaviours as well as chosen sociodemographic features in women over the age of 45 years who have undergone osteoporosis treatment. Material and methods: The study comprised 151 women over the age of 45 years. The research was conducted in 2016 in health care centres in Lublin, a city in south-eastern Poland. The Generalised Self Efficacy Scale (GSES) by R. Schwarzer, M. Jerusalem and Z. Juczynski and an original questionnaire were used as research tools. The obtained material was subjected to descriptive and statistical analysis. chi2 test, Kruskal-Wallis test, Mann-Whitney Test and Spearman's rank correlation coefficient were all applied. Results: The analysis of obtained results showed that as much as 73.5% of the respondents showed very low and low generalised self-efficacy level. On the other hand, only 22.5% of the examined were characterised by high and very high generalised self-efficacy level. The longer the duration of osteoporosis treatment (rho = 0.251; p = 0.002) and the better the self-estimation of health status (rho = 0.473; p = 0.000), the higher the respondents' generalised self efficacy level. The women's self-efficacy level declined with increasing ailments (rho = -0.190; p = 0.019). Conclusions: The generalized self-efficacy level and the health behaviours are not satisfactory. PMID- 29507575 TI - Changes in microscopic analysis of the urinary sediment in postmenopausal women who receive vaginal conjugated oestrogens. AB - Introduction: Microscopic haematuria is common in adults and it has been reported in 13% of postmenopausal women. Objective: To evaluate the changes in urinary sediment after the use of vaginal conjugated oestrogens. Material and methods: Postmenopausal women with vaginal dryness were studied. In all them a urinalysis was done, looking for density, pH, and the presence of leukocytes and erythrocytes. In order to be included in the study, all of the women had to have microscopic haematuria, considered as the presence of 3 or more erythrocytes in the urinary sediment. All received vaginally 1 g of conjugated equine oestrogens cream 3 times per week for one month, moment in which a new urinalysis was carried out and the same parameters were evaluated. Results: Twenty-four women were studied. The median age was 62 years (40-83), and the time since menopause was 144 months (24-336). When comparing the values between baseline and end of treatment urinalyses, no significant differences in pH and urinary density were found. The number of leukocytes significantly decreased after treatment (3.0 [1 6] vs. 1.0 [1-6], p < 0.026), and the erythrocytes number decreased (4.5 [3-12] vs. 0.0 [0-2], p < 0.001). Conclusion: In postmenopausal women with microscopic haematuria and vaginal dryness, it is worth considering administration of local oestrogen for one month, and after repeat the urine exam, before deciding to begin the microscopic haematuria study protocol. PMID- 29507576 TI - Effect of counseling on sexual function and behavior in postmenopausal women and their spouses: a randomized, controlled trial (RCT) study. AB - Sexual dysfunction is present the most important problem among menopausal women and thus counseling may have a major role for improving menopausal sexual state in this population. We aimed to assess effects of counseling on sexual function of menopause women and their spouses. An interventional trial study was performed on 120 consecutive Iranian couples (menopause women and their spouses) who were resident in Hamadan, Iran in 2015. The subjects were randomly assigned to receive counseling service (n = 60) or did not receive this service (n = 60). Couples were asked to complete a standardized validated questionnaire assessing sexual function and behaviors. The frequency of sexual intercourse was considerably increased following first and second counseling sessions compared with the time before counseling in former group, while sexually state was remained unchanged in those who not received these counseling. Furthermore, dyspareunia in interventional women with counseling was significantly reduced after the first and second counseling, whereas this complaint was not significantly removed in the control group within the study period. Also, unsuccessful intercourse was significantly decreased in men who received counseling sessions, while this parameter was remained unchanged in other men. In addition, talking with the partner about sexually and Satisfaction degree of wife's love was significantly improved in both men and women in interventional groups compared with the control groups. Active and structured counseling effectively improve sexual functions and behaviors in menopausal women and their spouses. PMID- 29507577 TI - Differences in the What's My M3? test between pre- and postmenopausal women. AB - Aim of the study: To evaluate the differences in the What's My M3 test between pre and postmenopausal women. Material and methods: Pre- and postmenopausal women who attended an endocrine gynaecology consultation were studied. In all them, the What's My M3? test was applied. Descriptive statistics, central tendency and dispersion measures were used. Differences between groups were assessed with Mann Whitney U test, and Spearman correlation analysis was carried out for age and time since menopause with the What's My M3? score. Results: A total of 404 patients, aged 45 to 55 years, were surveyed. Women with previous diagnosis of depressive disorder, antidepressant use, history of hysterectomy with or without bilateral salpingo-oophorectomy were excluded. Finally 202 premenopausal and 164 postmenopausal were studied. A score in the What's My M3? test >= 33 was considered as abnormal. Postmenopausal women had a higher score in the test than premenopausal women, 15 (0-69) and 6 (0-42) respectively (p < 0.001). In the sub analysis of the What's My M3? test, also the postmenopausal women had statistically significant greater score in depression, anxiety, bipolar disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. It was found that when older, the women had a higher score (p < 0.001), (Spearman's Rho, p < 0.005). Conclusions: Postmenopausal women had higher score in the What's My M3? test than premenopausal women. PMID- 29507578 TI - New classification system of endometrial hyperplasia WHO 2014 and its clinical implications. AB - Endometrial hyperplasia (EH) is a pathological condition characterised by hyperplastic changes in endometrial glandular and stromal structures lining the uterine cavity. Endometrial hyperplasia, particularly with atypia, is a significant clinical concern because it can be a precursor of endometrial cancer. Accurate diagnosis of precancerous lesions of the endometrium and exclusion of coexisting endometrial carcinomas are absolutely required for the optimal management of patients. The classification of endometrial hyperplasia has had numerous terminology. According to the classification of WHO94, based on glandular complexity and nuclear atypia, EH is divided into four groups: non atypical endometrial hyperplasia (simple, complex) and atypical endometrial hyperplasia (simple, complex). Estimated risk of progression of atypical hyperplasia to endometrial cancer is 8-29%. The American College of Obstetricians and Gynaecologists and the Society of Gynaecological Oncology states that endometrial intraepithelial neoplasia (EIN) classification is superior to the World Health Organisation (WHO 94) classification for histology of endometrial hyperplasia. However, the WHO classification system remains the most commonly used and reported in existing literature. The new classification, WHO 2014, accepted by the International Society of Gynaecological Pathologists, divided hyperplasia into two groups: benign hyperplasia and atypical hyperplasia/endometrial intraepithelial neoplasia (EIN). The WHO 2014 schema is more likely to successfully identify precancerous lesions than the WHO94 classification. PMID- 29507579 TI - Corrigendum: Dynamic Changes in DNA Methylation Occur during the First Year of Life in Preterm Infants. AB - [This corrects the article on p. 158 in vol. 7, PMID: 28018293.]. PMID- 29507580 TI - Antivenom therapy: efficacy of premedication for the prevention of adverse reactions. AB - Antivenoms or antitoxins have been effectively used for more than a century. During this time, these products have always proven to be highly effective in the treatment of infections and envenomations. However, antivenoms did not exhibit good safety results in their initial applications. After many improvements, antivenoms have substantially better safety profiles but still have some side effects. Due to the occurrence of adverse reactions, the practice of using premedication with the intent to decrease side effects has become accepted or mandatory in many countries. The drugs used for premedication belong to the histamine H1 antagonist, glucocorticoid and catecholamine groups. Currently, this practice is being questioned due to low or controversial efficacies in clinical assays. In this article, we discuss the causes of adverse reactions, the mechanisms of drugs that block the undesired effects and the results obtained in clinical trials. Although these three families of drugs could have positive effects on reducing adverse reactions, only adrenaline has demonstrated positive results in clinical assays. PMID- 29507581 TI - Scorpionism by Hemiscorpius spp. in Iran: a review. AB - Scorpions are distributed throughout Iran and the genus Hemiscorpius is particularly important in this region. Hemiscorpius lepturus is the most significant species within the genus in the country. Since scorpionism provoked by Hemiscorpius comprises a medical emergency, the present study is focused on this important issue. In order to perform the present work, a review of the medical and health-related literature was carried out in several databases. The current findings indicate that six species of Hemiscorpius are found in 15 states of Iran, mainly in the south and southwest. Deaths caused by stings were reported only for two species. The morphological characteristics and geographical distribution of H. lepturus in Iran, its venom and the toxic compounds, epidemiologic data and clinical manifestations of envenomation as well as treatment for affected people are herein reviewed and described. H. lepturus venom toxicity differs from other Iranian scorpions regarding duration and severity. Scorpionism is an important public health problem in Iran, especially in southwest and south regions and in urban areas. It is more prevalent in children and young people. H. lepturus venom is primarily a cytotoxic agent and has hemolytic, nephrotoxic and to some extent hepatotoxic activity. The use of polyvalent antivenom to prevent scorpion sting symptoms is recommended. A well planned health education program might be useful in preventing scorpionism. PMID- 29507582 TI - Differential Effects of Three Techniques for Hepatic Vascular Exclusion during Resection for Liver Cirrhosis on Hepatic Ischemia-Reperfusion Injury in Rats. AB - Background/Aims: Hepatic ischemia-reperfusion (I/R) injury is a serious concern during hepatic vascular occlusion. The objectives of this study were to assess effects of three techniques for hepatic vascular occlusion on I/R injury and to explore the underlying mechanisms. Methods: Liver cirrhotic rats had undertaken Pringle maneuver (PR), hemihepatic vascular occlusion (HH), or hepatic blood inflow occlusion without hemihepatic artery control (WH). Levels of tumor necrosis factor alpha (TNF-alpha), nuclear factor kappa B (NF-kappaB), toll-like receptor 4 (TLR4), TIR-domain-containing adapter-inducing interferon-beta (TRIF), and hemeoxygenase 1 (HMOX1) were assayed. Results: The histopathologic analysis displayed that liver harm was more prominent in the PR group, but similar in the HH and WH groups. The HH and WH groups responded to hepatic I/R inflammation similarly but better than the PR group. Mechanical studies suggested that TNF alpha/NF-kappaB signaling and TLR4/TRIF transduction pathways were associated with the differential effects. In addition, the HH and WH groups had significantly higher levels of hepatic HMOX1 (P < 0.05) than the PR group. Conclusions: HH and WH confer better preservation of liver function and protection than the Pringle maneuver in combating I/R injury. Upregulation of HMOX1 may lead to better protection and clinical outcomes after liver resection. PMID- 29507583 TI - A novel, homozygous mutation in desert hedgehog (DHH) in a 46, XY patient with dysgenetic testes presenting with primary amenorrhoea: a case report. AB - Background: Desert hedgehog (DHH) mutations have been described in only a limited number of individuals with 46, XY disorders of sex development (DSD) presenting as either partial or complete gonadal dysgenesis. Gonadal tumours and peripheral neuropathy have been associated with DHH mutations. Herein we report a novel, homozygous mutation of DHH identified through a targeted, massively parallel sequencing (MPS) DSD panel, in a patient presenting with partial gonadal dysgenesis. This novel mutation is two amino acids away from a previously described mutation in a patient who presented with complete gonadal dysgenesis. Adding to the complexity of work-up, our patient also expressed gender identity concern. Case presentation: A 14-year-old, phenotypic female presented with primary amenorrhoea and absent secondary sex characteristics. Investigations revealed elevated gonadotrophins with low oestradiol, testosterone of 0.6 nmol/L and a 46, XY karyotype. Mullerian structures were not seen on pelvic ultrasound or laparoscopically and gonadal biopsies demonstrated dysgenetic testes without neoplasia (partial gonadal dysgenesis). The patient expressed gender identity confusion upon initial notification of investigation findings. Formal psychiatric evaluation excluded gender dysphoria. Genetic analysis was performed using a targeted, MPS DSD panel of 64 diagnostic and 927 research candidate genes. This identified a novel, homozygous mutation in exon 2 of DHH (DHH:NM_021044:exon2:c.G491C:p.R164P). With this finding our patient was screened for the possibility of peripheral neuropathy which was not evident clinically nor on investigation. She was commenced on oestrogen for pubertal induction. Conclusion: The evaluation of patients with DSD is associated with considerable psychological distress. Targeted MPS enables an affordable and efficient method for diagnosis of 46, XY DSD cases. Identifying a genetic diagnosis may inform clinical management and in this case directed screening for peripheral neuropathy. In addition to the structural location of the mutation other interacting factors may influence phenotypic expression in homozygous DHH mutations. PMID- 29507584 TI - Clinical implications of CD4+ T cell subsets in adult atopic asthma patients. AB - Background: T cells play a central role in chronic inflammation in asthma. However, the roles of individual subsets of T cells in the pathology of asthma in patients remain to be better understood. Methods: We investigated the potential signatures of T cell subset phenotypes in asthma using fresh whole blood from adult atopic asthma patients (n = 43) and non-asthmatic control subjects (n = 22). We further assessed their potential clinical implications by correlating asthma severity. Results: We report four major features of CD4+ T cells in the blood of atopic asthma patients. First, patients had a profound increase of CCR7+ memory CD4+ T cells, but not CCR7- memory CD4+ T cells. Second, an increase in CCR4+ CD4+ T cells in patients was mainly attributed to the increase of CCR7+ memory CD4+ T cells. Accordingly, the frequency of CCR4+CCR7+ memory CD4+ T cells correlated with asthma severity. Current common asthma therapeutics (including corticosteroids) were not able to affect the frequency of CCR4+CCR7+ memory CD4+ T cell subsets. Third, patients had an increase of Tregs, as assessed by measuring CD25, Foxp3, IL-10 and CTLA-4 expression. However, asthma severity was inversely correlated only with the frequency of CTLA-4+ CD4+ T cells. Lastly, patients and control subjects have similar frequencies of CD4+ T cells that express CCR5, CCR6, CXCR3, CXCR5, CD11a, or alpha4 integrin. However, the frequency of alpha4+ CD4+ T cells in patients correlated with asthma severity. Conclusions: CCR4+CCR7+ memory, but not CCR4+CCR7- memory, alpha4+, and CTLA4+ CD4+ T cells in patients show significant clinical implications in atopic asthma. Current common therapeutics cannot alter the frequency of such CD4+ T cell subsets in adult atopic asthma patients. PMID- 29507585 TI - The Anti-Inflammatory Effect of Fructus Kochiae on Allergic Contact Dermatitis Rats via pERK1/2/TLR4/NF-kappaB Pathway Activation. AB - Allergic contact dermatitis (ACD) is a common irritability skin disease, which can be cured by using the Chinese patent medicine. To explore the pharmacological effect of total flavonoids of Fructus Kochiae (FK) on ACD, we used dinitrochlorobenzene- (DNCB-) induced ACD rats. Five groups were used in our experiments. The normal group and the DNCB group were treated with 0.5% CMC-Na; the DNCB + hFK group was treated with a high dose of total flavonoids of FK (200 mg/kg); the DNCB + lFK group was treated with a low dose of FK (100 mg/kg); the DNCB + Pre group was treated with prednisolone acetate (2.5 mg/kg). The results showed that FK treatment had significantly attenuated the inflammation induced by DNCB. The increased concentration of cytokines including IL-6, IL-18, and IFN gamma in ACD rats could be reversed by the FK administration, while IL-10 expressed the opposite result; the expression level of TLR4, pERK1/2, and NF kappaB could be downregulated by the treatment with FK in the ACD rat. In a word, the total flavonoids of the FK had an anti-inflammatory effect on the DNCB induced ACD rat; this regulatory mechanism was highly possible based on the pERK1/2/TLR4-NF-kappaB pathway activation. PMID- 29507587 TI - Isolation and Identification of Compounds from Bioactive Extracts of Taraxacum officinale Weber ex F. H. Wigg. (Dandelion) as a Potential Source of Antibacterial Agents. AB - Currently, the most effective treatment for recurrent urinary tract infections in women is antibiotics. However, the limitation for this treatment is the duration and dosage of antibiotics and the resistance that bacteria develop after a long period of administration. With the aim of identifying mainly novel natural agents with antibacterial activity, the present study was undertaken to investigate the biological and phytochemical properties of extracts from the leaves Taraxacum officinale. The structural identification of compounds present in hexane (Hex) and ethyl acetate (AcOEt) extracts was performed by mass spectrometry (GC-MS) spectroscopic techniques and nuclear magnetic resonance (NMR) with the major compounds corresponding to different sesquiterpene lactones (alpha-santonin, glabellin, arborescin, and estafiatin), monoterpene (9,10-dimethyltricycle [4.2.1.1 (2,5)]decane-9,10-diol), phytosterol (Stigmasta-5,22-dien-3beta-ol acetate), terpenes (lupeol acetate, pregn-5-en-20-one-3beta-acetyloxy-17-hydroxy, 2-hydroxy-4-methoxy benzaldehyde), and coumarin (benzofuranone 5,6,7,7-a tetraaldehyde-4,4,7a-trimethyl). The results obtained show that the Hex extract was highly active against Staphylococcus aureus showing a MIC of 200 MUg/mL and moderately active against Escherichia coli and Klebsiella pneumoniae with MIC values of 400 MUg/mL and 800 MUg/mL for the other Gram-negative strains tested with Proteus mirabilis as uropathogens in vitro. Therefore, the effective dandelion extracts could be used in the development of future products with industrial application. PMID- 29507586 TI - Change of Safe Needling Depth at Acupoint GB21 according to Posture and Breathing. AB - Acupoint GB21 (Jianjing) is used for treating back and shoulder pain but is associated with a risk of pneumothorax. We aimed to determine the SND (safe needling depth) at GB21 according to posture and breathing in real time. Ultrasonographic images of GB21 during normal breathing, inspiration, and expiration in a SP (sitting position) were acquired for 52 healthy volunteers. Images were also acquired during normal respiration in the PP (prone position) with arms raised and lowered. The average SND was greater for men than for women (p < 0.05). Analysis of variance revealed that the SND was greater for the PP than for the SP (p = 0.01 and p < 0.05, resp.). Although the SND tended to change according to posture, the average depth tended to deviate widely in some subjects. During breathing, the differences between inspiration and expiration were less than 1 mm in most subjects, but some showed differences more than 4.5 mm. The SND at GB21 was greater in overweight subjects and significantly greater in the PP and during maximal expiration. However, intragroup differences were greater than the intergroup differences. Therefore, it is dangerous to simply apply needling depth on a gender or BMI basis. The practitioner would adjust the SND by examining the individual anatomical structures. PMID- 29507588 TI - Yuk-Mi-Jihwang-Tang, a Traditional Korean Multiple Herbal Formulae, Improves Hippocampal Memory on Scopolamine Injection-Induced Amnesia Model of C57BL/6 Mice. AB - We evaluated neuropharmacological properties of Yuk-Mi-Jihwang-Tang (YJT) against scopolamine injection-induced memory impairment mice model. Mice were orally administered with YJT (50, 100, or 200 mg/kg) or tacrine (TAC, 12.5 mg/kg) for 10 days. At the first day of Morris water maze task, scopolamine (2 mg/kg) was intraperitoneally injected before 30 min of it. The hippocampal memory function was determined by the Morris water maze task for 5 days consecutively. Scopolamine drastically increased escape latency and decreased time spent in target quadrant. Pretreatment YJT properly improved them. Regarding the redox status, YJT significantly reduced the oxidative stress and it also exerted much effort to improve both superoxide dismutase and catalase activities in hippocampal gene expression and protein levels. These effects were well coincided with immunohistochemical analysis of 4-hydroxyneal-positive signals in hippocampal areas. Additionally, acetylcholine esterase activities and brain derived neurotrophic factor abnormalities in the hippocampal protein levels were significantly normalized by YJT, and their related molecules were also improved. The neuronal proliferation in hippocampal regions was markedly inhibited by scopolamine, whereas YJT notably recovered them. Collectively, YJT exerts much effort to enhance memorial functions through improving redox status homeostasis and partially regulates acetylcholine esterase activities as well as neuronal cell proliferation. PMID- 29507589 TI - Gastroprotective Mechanism and Ulcer Resolution Effect of Cyrtocarpa procera Methanolic Extract on Ethanol-Induced Gastric Injury. AB - Gastric ulcers are a worldwide health problem and their poor healing is one of the most important causes for their recurrence. We have previously reported the remarkable gastroprotective and anti-Helicobacter pylori activities of the methanolic extract (CpMet) of Cyrtocarpa procera bark. This work investigates, in a murine model, the CpMet gastroprotective mechanism and establishes its preclinical efficacy in the resolution of ethanol-induced gastric ulcers. The results showed that the gastroprotective activity of CpMet is mainly associated with endogenous NO and prostaglandins, followed by sulfhydryl groups and KATP channels. Furthermore, CpMet (300 mg/kg, twice a day) orally administered during 20 consecutive days promoted an ulcer area reduction of 62.65% at the 20th day of the treatment. The effect was confirmed macroscopically by the alleviation of gastric mucosal erosions and microscopically by an increase in mucin content and a reduction in the inflammatory infiltration at the site of the ulcer. No clinical symptoms or signs of toxicity were observed in the treated animals. The results indicate the safety and efficacy of CpMet in promoting high quality of ulcer healing by different mechanisms, but mostly through cytoprotective and anti inflammatory effects, making it a promising phytodrug for ulcer treatment. PMID- 29507590 TI - Electroacupuncture Improved the Function of Myocardial Ischemia Involved in the Hippocampus-Paraventricular Nucleus-Sympathetic Nerve Pathway. AB - We investigated the hippocampus-paraventricular nucleus- (PVN-) sympathetic nerve pathway in electroacupuncture (EA) at the heart meridian for the treatment of myocardial ischemia by observing PVN neuronal discharge, sympathetic nerve discharge, and hemodynamics parameters. Sprague Dawley (SD) rats were equally divided into four groups: Sham, Model, Model + EA, and Model + EA + Lesion. The model rat was established by ligating the left anterior descending branch of the coronary artery. Changes in the sympathetic nerve discharge and hemodynamic parameters were observed. The Model + EA exhibited a significantly lower discharge frequency of PVN neurons compared with the Model. The Model + EA + Lesion had a significantly higher discharge frequency compared with the Model + EA. The total discharge frequency of PVN neurons and interneurons were positively correlated with the sympathetic nerve discharge. The total discharge frequency of PVN neurons was positively correlated with heart rate (HR) and negatively correlated with mean arterial pressure (MAP) and rate pressure product (RPP). The discharge frequency of interneurons was positively correlated with HR and negatively correlated with MAP and RPP. The hippocampus-PVN-sympathetic nerve pathway is involved in electroacupuncture at the heart meridian and interneurons are the key neurons in PVNs. PMID- 29507591 TI - Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells. AB - Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS) and TNF-alpha, suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells. PMID- 29507592 TI - Therapeutic Effectiveness and Safety of Mesotherapy in Patients with Osteoarthritis of the Knee. AB - Objective: To evaluate the therapeutic effectiveness and safety of mesotherapy by comparing it with the classic systematic therapy in patients with osteoarthritis (OA). Methods: Sixty patients were included and classified into two groups based on the existence of contraindications for nonsteroidal anti-inflammatory drugs (NSAIDs). These patients were treated with oral NSAIDs (Group A) or mesotherapy (Group B). After completing the treatment, the patients were followed up for 6 months. Their clinical features, laboratory results, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were evaluated. Results: A total of 50 patients completed treatment and follow-up. The patients in Group B had significantly fewer gastric acid-related complaints and requested less supplementary treatment for recurrent pain (p < 0.05). The patients in both groups exhibited decreased blood viscosity after treatment (p < 0.05). WOMAC scores, specifically those for pain and stiffness, were found to be significantly improved after either type of treatment (p < 0.05). Mesotherapy also ameliorated physical function (p < 0.05). Furthermore, Group B presented with better outcomes than Group A (p < 0.05 or p < 0.01). Conclusion: Our results suggest that mesotherapy is an effective and safe treatment for patients with OA. Clinicians should consider mesotherapy as an alternative therapy for patients with contraindications for NSAID use. PMID- 29507593 TI - The Effects of Qigong on Type 2 Diabetes Mellitus: A Systematic Review and Meta Analysis. AB - Objective: The purpose of this study was to investigate the effects of Qigong on type 2 diabetes mellitus (DM) using the systematic review and meta-analysis. Methods: All prospective, randomized, controlled clinical trials published in English or Chinese and involving the use of Qigong by patients with DM were searched in 7 electronic databases from their respective inception to June 2016. The meta-analysis was conducted using the Revman 5.2. The quality of the included trials was assessed using the Jadad rating scale. Two researchers independently completed the inclusion, data extraction, and quality assessment. Results: Twenty one trials with 1326 patients met the inclusion criteria and were reviewed. The meta-analysis demonstrated that, compared with no exercise, the Qigong had significant effects on fasting blood glucose (MD = -0.99, 95% CI (-1.23, 0.75), P < 0.0001), HbA1c (MD = -0.84, 95% CI (-1.02, -0.65), P < 0.0001), and postprandial blood glucose (MD = -1.55, 95% CI (-2.19, -0.91), P < 0.00001). Conclusion: The Qigong training can improve the blood glucose status of the type 2 DM patients and has positive effects on the management of type 2 DM. However, future research with better quality still needs to be conducted to address the effects of Qigong on type 2 DM. PMID- 29507594 TI - Traditional Chinese Medicine for Refractory Nephrotic Syndrome: Strategies and Promising Treatments. AB - Refractory nephrotic syndrome (RNS) is an immune-related kidney disease with poor clinical outcomes. Standard treatments include corticosteroids as the initial therapy and other immunosuppressants as second-line options. A substantial proportion of patients with RNS are resistant to or dependent on immunosuppressive drugs and often experience unremitting edema and proteinuria, cycles of remission and relapse, and/or serious adverse events due to long-term immunosuppression. Traditional Chinese medicine has a long history of treating complicated kidney diseases and holds great potential for providing effective treatments for RNS. This review describes the Chinese medical theories relating to the pathogenesis of RNS and discusses the strategies and treatment options using Chinese herbal medicine. Available preclinical and clinical evidence strongly supports the integration of traditional Chinese medicine and Western medicine for improving the outcome of RNS. Herbal medicine such as Astragalus membranaceus, Stephania tetrandra S. Moore, and Tripterygium wilfordii Hook F can serve as the alternative therapy when patients fail to respond to immunosuppression or as the complementary therapy to improve therapeutic efficacy and reduce side effects of immunosuppressive agents. Wuzhi capsules (Schisandra sphenanthera extract) with tacrolimus and tetrandrine with corticosteroids are two herb-drug combinations that have shown great promise and warrant further studies. PMID- 29507595 TI - Immune-inflammatory responses in the elderly: an update. PMID- 29507596 TI - Modelling fertility in rural South Africa with combined nonlinear parametric and semi-parametric methods. AB - Background: Central to the study of populations, and therefore to the analysis of the development of countries undergoing major transitions, is the calculation of fertility patterns and their dependence on different variables such as age, education, and socio-economic status. Most epidemiological research on these matters rely on the often unjustified assumption of (generalised) linearity, or alternatively makes a parametric assumption (e.g. for age-patterns). Methods: We consider nonlinearity of fertility in the covariates by combining an established nonlinear parametric model for fertility over age with nonlinear modelling of fertility over other covariates. For the latter, we use the semi-parametric method of Gaussian process regression which is a popular methodology in many fields including machine learning, computer science, and systems biology. We applied the method to data from the Agincourt Health and Socio-Demographic Surveillance System, annual census rounds performed on a poor rural region of South Africa since 1992, to analyse fertility patterns over age and socio economic status. Results: We capture a previously established age-pattern of fertility, whilst being able to more robustly model the relationship between fertility and socio-economic status without unjustified a priori assumptions of linearity. Peak fertility over age is shown to be increasing over time, as well as for adolescents but not for those later in life for whom fertility is generally decreasing over time. Conclusions: Combining Gaussian process regression with nonlinear parametric modelling of fertility over age allowed for the incorporation of further covariates into the analysis without needing to assume a linear relationship. This enabled us to provide further insights into the fertility patterns of the Agincourt study area, in particular the interaction between age and socio-economic status. PMID- 29507597 TI - A low-protein diet exerts a beneficial effect on diabetic status and prevents diabetic nephropathy in Wistar fatty rats, an animal model of type 2 diabetes and obesity. AB - Background: The objective of this study is to investigate the effects of a low protein diet (LPD) starting from a young age on diabetic status and renal injury in a rat model of type 2 diabetes and obesity. Methods: Diabetic male Wistar fatty (fa/fa) rats (WFRs) were fed a standard diet (23.84% protein) or an LPD (5.77% protein) for 24 weeks beginning at 6 weeks of age. We investigated the effects of the LPD on total body weight (BW); fat weight (FW); lower-limb muscle weight (MW); several measures of diabetic status, including fasting/random glucose levels, HOMA-IR and the IPITT; and renal injuries, including renal hypertrophy, albuminuria and histological changes. Additionally, autophagy and activation of mTORC1 were evaluated in the diabetic renal cortex. Furthermore, plasma FGF21 and high-molecular-weight (HMW) adiponectin levels, as well as UCP1 expression levels in brown adipose tissue (BAT), were evaluated. Results: Increases in BW and FW in WFRs were significantly reduced by the LPD, and the LPD resulted in a significant reduction of lower-limb MW in WFRs. The LPD suppressed the elevation of glucose levels in WFRs through improvement of insulin resistance. The LPD also elevated the plasma FGF21 and HMW adiponectin of WFRs, as well as UCP1 expression in the BAT of the animals. Renal hypertrophy, albuminuria, renal histological changes, and increased expression of p62 and phospho-S6 ribosomal protein (p-S6RP) were observed in WFRs compared with the values from WLRs. The LPD clearly prevented the diabetic kidneys from sustaining any damage. Conclusions: The LPD prevented the progression of diabetic status; this effect may have been associated with the reduction of FW and the elevation of plasma FGF21 and HMW adiponectin, as well as UCP1 expression in BAT, resulting in suppression of diabetic nephropathy. However, MW was decreased in rats by the consumption of an LPD from a young age; therefore, further research is needed to resolve the nutritional issue of LPD on decreasing in MW. PMID- 29507598 TI - Undetected psychiatric morbidity among HIV/AIDS patients attending Comprehensive Care Clinic (CCC) in Nairobi Kenya: towards an integrated mental health care. AB - Background: Psychiatric morbidity is commonly associated with HIV disease and may have adverse effects. This aspect may be overlooked at comprehensive HIV care centers in Low and Middle-Income Countries. Objectives: The aim of this study was to determine the prevalence of undetected psychiatric morbidity among HIV/AIDS adult patients attending Comprehensive Care Centre in a semi-urban clinic, in Nairobi, Kenya. Design: Descriptive cross-sectional study of adult HIV patients not receiving any psychiatric treatment was conducted. Participants/methods: The participants consisted of consecutive sample of adults (n = 245) attending HIV Comprehensive Care Clinic at Kangemi Health Centre, Nairobi. The Mini International Neuropsychiatric Interview (MINI) was administered to screen for undetected psychiatric morbidity. Socio-demographic characteristics were recorded in a questionnaire. Sample descriptive analysis was performed and prevalence of undetected psychiatric morbidity calculated. Chi-square test for independence was used to examine the associations between patient characteristics and undetected morbidity. Multivariable logistic regression analysis was performed to determine independent predictors of undetected psychiatric morbidity. Results: The mean age of our participants was 37.3 years (SD 9.2) Three-quarters (75.9%) of participants were females and median duration of HIV illness was 5 years. The prevalence of (previously undetected) psychiatric morbidity was 71.4% (95% CI 65.3-77). The leading psychiatric disorders were MDD (32.2%), PTSD (18.4%), Dysthymia (17.6%), and OCD (17.6%). Overall psychiatric morbidity was associated with low income ( 0.1 ppm.From the mixed-model analyses we see that exposure level, expressed as H2S index IN, varied between places, work type, season and degree of flushing. For the work in a plant in the capital, the exposure index varied from 0.02 for working in spring doing some flushing, to 0.7 for working at the same plant in winter doing flushing more than three times or more than 10 min. Collecting sewage from cesspools in city 2 in winter doing a lot of flushing gave a hydrogen sulphide index of 230. Conclusions: The use of a H2S index, taking into consideration peak height, duration and number of peaks, could be a tool for exposure assessment for H2S. PMID- 29507600 TI - Predictors of exclusive breastfeeding knowledge and intention to or practice of exclusive breastfeeding among antenatal and postnatal women receiving routine care: a cross-sectional study. AB - Background: Despite consistent evidence showing the importance of exclusive breastfeeding (EBF) for six months, it remains a sub-optimal practice in The Gambia. This study aimed at investigating the determinants of EBF knowledge and intention to or practice of EBF. Methods: A cross-sectional study was conducted among 334 women receiving care at the Edward Francis Small Teaching Hospital (EFSTH) from December 2015 to February 2016. Using a structured interviewer administered questionnaire, knowledge on EBF was determined and scored. Participants scoring above or equal to the median were determined to have sufficient EBF knowledge. Multivariate logistic regression analyses were used to identify predictors of EBF knowledge and intention to or practice of exclusive breastfeeding. Results: The proportion of women with sufficient exclusive breastfeeding knowledge and intended to or practice EBF were 60.2% and 38.6% respectively, while only 34.4% received EBF counseling. Earning >=1500 GMD monthly (Adjusted Odds Ratio [aOR] 1.98; 95% Confidence Interval [Cl] 1.24, 3.16), having positive attitude (aOR 2.40; 95% Cl 1.40, 4.10) and partner supporting EBF (aOR 2.18; 95% Cl 1.23, 3.87) predicted sufficient EBF knowledge. Mothers aged 26-34 years (aOR 0.50; 9 5% Cl 0.31, 0.82) and EBF counseling (aOR 2.68; 95% Cl 1.68, 4.29) significantly associated with intention to or practice of exclusive breastfeeding. Conclusion: In conclusion, improving EBF rates will, therefore, require improved access to information on EBF targeting low socio economically disadvantaged and older mothers. In addition, emphasis on strengthening the ongoing EBF counseling already within the health system is required. PMID- 29507601 TI - The annual cost of not breastfeeding in Indonesia: the economic burden of treating diarrhea and respiratory disease among children (< 24mo) due to not breastfeeding according to recommendation. AB - Background: In Indonesia, 96% of children (< 24mo) are breastfed. However, only 42% of children (< 6mo) are exclusively breastfed, as per World Health Organization recommendations. Breastfeeding provides protective benefits such as reducing the risk of morbidity and mortality associated with diarrhea and pneumonia/respiratory disease (PRD). This study estimates the potential economic impact of not breastfeeding according to recommendation in Indonesia based on infants suffering from attributable diarrhea and PRD. Methods: A cost analysis examined both the healthcare system costs and non-medical costs for children (< 24mo) with diarrhea and PRD. Data collection took place between 2015 and 2016 and healthcare expenditures were assessed in 13 facilities, in five sites including Bandung and Tomohon City. Costs from a provider perspective were estimated using healthcare records and 26 interviews with healthcare workers. A discount rate of 3% was used. A cross-sectional survey with caregiver-child pairs (n = 615) collected data related to out of pocket costs such transportation and opportunity costs such as wage loss. These figures were combined with the national disease prevalence rates from Indonesia Demographic and Health Survey 2012, and the relative risk of disease of not breastfeeding according to recommendation from literatures to extrapolate the financial burden of treatment. Results: The healthcare system cost due to not breastfeeding according to recommendation was estimated at US$118 million annually. The mean healthcare system cost and out of pocket costs was US$11.37 and US$3.85 respectively. This cost consists of US$88.64 million of provider costs and US$29.98 million of non-medical patient costs. Conclusions: The cost of not breastfeeding according to recommendation is potentially high, therefore the Indonesian government needs to invest in breastfeeding protection, promotion and support as the potential healthcare system cost savings are significant. As suggested by other studies, the long term cost due to cognitive losses of providing not breastfeeding according to recommendation should also be taken into account to provide a complete understanding of the economic impact of not breastfeeding according to recommendation. PMID- 29507602 TI - Comparison of knowledge, attitudes and practices on exclusive breastfeeding between primiparous and multiparous mothers attending Wajir District hospital, Wajir County, Kenya: a cross-sectional analytical study. AB - Background: Exclusive breastfeeding (EBF) is recommended for 6 months of age, with continued breastfeeding for 2 years of age or beyond. There is paucity of information on the disparity in Knowledge, Attitudes and Practices (KAP) on EBF between primiparous and multiparous mothers. This study compared the KAP on EBF between primiparous and multiparous mothers attending Wajir County Hospital, Wajir County, Kenya and investigated the association between maternal knowledge and attitudes and EBF. Methods: Information on maternal KAP on EBF was collected through structured researcher administered questionnaires for a total of 281 mothers, recruited from a maternal and child health centre in 2014; primiparous (n = 137) and multiparous (n = 144) with infants 0-5 months of age. Maternal knowledge and attitudes on various aspects of breastfeeding were determined. The knowledge and attitude scores were also calculated. The practice of EBF was determined based on a 24-h recall. Results: The prevalence of EBF among infants 0 5 months old was 45.5%. The rate of EBF among primiparous mothers was 39.4% and multiparous mothers 49.3%. The knowledge score on breastfeeding (out of a total of 10) for the primiparous mothers was 7.93 +/- 2.10 and 7.49 +/- 2.20 for the multiparous mothers. The mean attitude score (out of a total score of 40) for the primiparous mothers was 29.46 +/- 5.65 and 28.65 +/- 6.40 for the multiparous mothers. The prevalence of EBF and maternal knowledge and attitudes towards breastfeeding was similar among the two groups of mothers. Those mothers with positive attitudes towards breastfeeding were more likely to EBF (Fisher's exact test; p = 0.00) compared with those with lower scores. Conclusions: Interventions to promote exclusive breastfeeding should be tailored to the needs of each population by identifying the factors that influence the practice in a given context. The findings of this study will be useful particularly for behavior change communication interventions by those organizations working in similar circumstances to the study area. PMID- 29507603 TI - Nonoperative management of appendiceal phlegmon or abscess in children less than 3 years of age. AB - Background: In children less than 3 years of age, there is little experience in the nonoperative management of appendiceal phlegmon or abscess (APA), especially in APA with an appendicolith. The purposes of this study were to evaluate the effects of an appendicolith and the success rate of nonoperative management for APA in these young children. Methods: Children younger than 3 years of age with APA who underwent attempted initial nonoperative treatment between January 2008 and December 2016 were reviewed. Based on the presence or absence of an appendicolith on admission ultrasonography examination or computed tomography scan, children were divided into two groups: appendicolith group and no appendicolith group. Results: There were 50 children who met the study criteria. Among 50 children, three children failed to respond to nonoperative treatment because of aggravated intestinal obstruction or recurrent appendicitis within 30 days of admission. The overall success rate for nonoperative management of APA was 94% (47/50) in children younger than 3 years old. The rate of diarrhea and CRP levels were higher in the appendicolith group than that of the no appendicolith group (P < 0.05). However, the success rate and the hospital length of stay for nonoperative treatment in the appendicolith group and the no appendicolith group were similar without statistical significance. Conclusion: APA with or without an appendicolith can have nonoperative management without immediate appendectomy in children less than 3 years old. PMID- 29507604 TI - Analysis of the Health Insurance Review and Assessment Service data from 2011 to 2015. AB - Background: Schizophrenia is a recurrent, debilitating disease that is rarely curable. Rapid intervention after the first episode of schizophrenia has been shown to positively affect the prognosis. Unfortunately, basic data is scarce on first-episode schizophrenia in Korean patients making it difficult to create a comprehensive list of risk factors for relapse. This study aims to investigate the demographic characteristics and institutional factors of patients with first episode schizophrenia in order to identify risk factors for relapse. Methods: Data from the Health Insurance Review & Assessment Service (HIRA) was used for this study to represent the Korean patient population. To identify factors affecting relapse, we explored gender, age, geographic location, medical benefits, type of medical institution, type of medication used, medication adherence, and the severity of symptoms. Data analysis was performed using the Cox proportional hazard model. Results: The number of patients diagnosed with first-episode schizophrenia in Korea over a 2-year period was 4567 of which 1265 (27.7%) patients experienced a relapse during the observational period. Factors affecting relapse included age, type of medical institution, type of medication used, medication adherence, and type of treatment (inpatient or outpatient) after the initial diagnosis, which varied depending upon the severity of symptoms. Conclusions: It was found that environmental and institutional factors as well as the type of medical treatment were crucial in determining whether patients with first-episode schizophrenia subsequently relapsed. The results of this study can be utilized as source material for directing therapeutic interventions and improving mental health policies in the future. PMID- 29507605 TI - High-level accumulation of oleyl oleate in plant seed oil by abundant supply of oleic acid substrates to efficient wax ester synthesis enzymes. AB - Background: Biotechnology enables the production of high-valued industrial feedstocks from plant seed oil. The plant-derived wax esters with long-chain monounsaturated acyl moieties, like oleyl oleate, have favorite properties for lubrication. For biosynthesis of wax esters using acyl-CoA substrates, expressions of a fatty acyl reductase (FAR) and a wax synthase (WS) in seeds are sufficient. Results: For optimization of the enzymatic activity and subcellular localization of wax ester synthesis enzymes, two fusion proteins were created, which showed wax ester-forming activities in Saccharomyces cerevisiae. To promote the formation of oleyl oleate in seed oil, WSs from Acinetobactor baylyi (AbWSD1) and Marinobacter aquaeolei (MaWS2), as well as the two created fusion proteins were tested in Arabidopsis to evaluate their abilities and substrate preference for wax ester production. The tested seven enzyme combinations resulted in different yields and compositions of wax esters. Expression of a FAR of Marinobacter aquaeolei (MaFAR) with AbWSD1 or MaWS2 led to a high incorporation of C18 substrates in wax esters. The MaFAR/TMMmAWAT2-AbWSD1 combination resulted in the incorporation of more C18:1 alcohol and C18:0 acyl moieties into wax esters compared with MaFAR/AbWSD1. The fusion protein of a WS from Simmondsia chinensis (ScWS) with MaFAR exhibited higher specificity toward C20:1 substrates in preference to C18:1 substrates. Expression of MaFAR/AbWSD1 in the Arabidopsis fad2 fae1 double mutant resulted in the accumulation of oleyl oleate (18:1/18:1) in up to 62 mol% of total wax esters in seed oil, which was much higher than the 15 mol% reached by MaFAR/AbWSD1 in Arabidopsis Col-0 background. In order to increase the level of oleyl oleate in seed oil of Camelina, lines expressing MaFAR/ScWS were crossed with a transgenic high oleate line. The resulting plants accumulated up to >40 mg g seed-1 of wax esters, containing 27-34 mol% oleyl oleate. Conclusions: The overall yields and the compositions of wax esters can be strongly affected by the availability of acyl-CoA substrates and to a lesser extent, by the characteristics of wax ester synthesis enzymes. For synthesis of oleyl oleate in plant seed oil, appropriate wax ester synthesis enzymes with high catalytic efficiency and desired substrate specificity should be expressed in plant cells; meanwhile, high levels of oleic acid-derived substrates need to be supplied to these enzymes by modifying the fatty acid profile of developing seeds. PMID- 29507606 TI - Mn2+ modulates the expression of cellulase genes in Trichoderma reesei Rut-C30 via calcium signaling. AB - Background: The filamentous fungus Trichoderma reesei Rut-C30 is one of the most vital fungi for the production of cellulases, which can be used for biofuel production from lignocellulose. Nevertheless, the mechanism of transmission of external stimuli and signals in modulating cellulase production in T. reesei Rut C30 remains unclear. Calcium is a known second messenger regulating cellulase gene expression in T. reesei. Results: In this study, we found that a biologically relevant extracellular Mn2+ concentration markedly stimulates cellulase production, total protein secretion, and the intracellular Mn2+ concentration of Rut-C30, a cellulase hyper-producing strain of T. reesei. Furthermore, we identified two Mn2+ transport proteins, designated as TPHO84-1 and TPHO84-2, indicating that they are upstream in the signaling pathway that leads to cellulase upregulation. We also found that Mn2+ induced a significant increase in cytosolic Ca2+ concentration, and that this increased cytosolic Ca2+ might be a key step in the Mn2+-mediated regulation of cellulase gene transcription and production. The utilization of LaCl3 to block plasma membrane Ca2+ channels, and deletion of crz1 (calcineurin-responsive zinc finger transcription factor 1) to interrupt calcium signaling, showed that Mn2+ exerts the induction of cellulase genes via calcium channels and calcium signaling. To substantiate this, we identified a Ca2+/Mn2+ P-type ATPase, TPMR1, which could play a pivotal role in Ca2+/Mn2+ homeostasis and Mn2+ induction of cellulase genes in T. reesei Rut-C30. Conclusions: Taken together, our results revealed for the first time that Mn2+ stimulates cellulase production, and demonstrates that Mn2+ upregulates cellulase genes via calcium channels and calcium signaling. Our research also provides a direction to facilitate enhanced cellulase production by T. reesei. PMID- 29507608 TI - Creating a more robust 5-hydroxymethylfurfural oxidase by combining computational predictions with a novel effective library design. AB - Background: HMF oxidase (HMFO) from Methylovorus sp. is a recently characterized flavoprotein oxidase. HMFO is a remarkable enzyme as it is able to oxidize 5 hydroxymethylfurfural (HMF) into 2,5-furandicarboxylic acid (FDCA): a catalytic cascade of three oxidation steps. Because HMF can be formed from fructose or other sugars and FDCA is a polymer building block, this enzyme has gained interest as an industrially relevant biocatalyst. Results: To increase the robustness of HMFO, a requirement for biotechnological applications, we decided to enhance its thermostability using the recently developed FRESCO method: a computational approach to identify thermostabilizing mutations in a protein structure. To make this approach even more effective, we now developed a new and facile gene shuffling approach to rapidly combine stabilizing mutations in a one pot reaction. This allowed the identification of the optimal combination of seven beneficial mutations. The created thermostable HMFO mutant was further studied as a biocatalyst for the production of FDCA from HMF and was shown to perform significantly better than the original HMFO. Conclusions: The described new gene shuffling approach quickly discriminates stable and active multi-site variants. This makes it a very useful addition to FRESCO. The resulting thermostable HMFO variant tolerates the presence of cosolvents and also remained thermotolerant after introduction of additional mutations aimed at improving the catalytic activity. Due to its stability and catalytic efficiency, the final HMFO variant appears to be a promising candidate for industrial scale production of FDCA from HMF. PMID- 29507607 TI - H2 drives metabolic rearrangements in gas-fermenting Clostridium autoethanogenum. AB - Background: The global demand for affordable carbon has never been stronger, and there is an imperative in many industrial processes to use waste streams to make products. Gas-fermenting acetogens offer a potential solution and several commercial gas fermentation plants are currently under construction. As energy limits acetogen metabolism, supply of H2 should diminish substrate loss to CO2 and facilitate production of reduced and energy-intensive products. However, the effects of H2 supply on CO-grown acetogens have yet to be experimentally quantified under controlled growth conditions. Results: Here, we quantify the effects of H2 supplementation by comparing growth on CO, syngas, and a high-H2 CO gas mix using chemostat cultures of Clostridium autoethanogenum. Cultures were characterised at the molecular level using metabolomics, proteomics, gas analysis, and a genome-scale metabolic model. CO-limited chemostats operated at two steady-state biomass concentrations facilitated co-utilisation of CO and H2. We show that H2 supply strongly impacts carbon distribution with a fourfold reduction in substrate loss as CO2 (61% vs. 17%) and a proportional increase of flux to ethanol (15% vs. 61%). Notably, H2 supplementation lowers the molar acetate/ethanol ratio by fivefold. At the molecular level, quantitative proteome analysis showed no obvious changes leading to these metabolic rearrangements suggesting the involvement of post-translational regulation. Metabolic modelling showed that H2 availability provided reducing power via H2 oxidation and saved redox as cells reduced all the CO2 to formate directly using H2 in the Wood Ljungdahl pathway. Modelling further indicated that the methylene-THF reductase reaction was ferredoxin reducing under all conditions. In combination with proteomics, modelling also showed that ethanol was synthesised through the acetaldehyde:ferredoxin oxidoreductase (AOR) activity. Conclusions: Our quantitative molecular analysis revealed that H2 drives rearrangements at several layers of metabolism and provides novel links between carbon, energy, and redox metabolism advancing our understanding of energy conservation in acetogens. We conclude that H2 supply can substantially increase the efficiency of gas fermentation and thus the feed gas composition can be considered an important factor in developing gas fermentation-based bioprocesses. PMID- 29507609 TI - Rheology of transgenic switchgrass reveals practical aspects of biomass processing. AB - Background: Mechanical properties of transgenic switchgrass have practical implications for biorefinery technologies. Presented are fundamentals for simple (thermo)mechanical measurements of genetically transformed switchgrass. Experimental basics are provided for the novice, where the intention is to promote collaboration between plant biologists and materials scientists. Results: Stem sections were subjected to two stress modes: (1) torsional oscillation in the linear response region, and (2) unidirectional torsion to failure. Specimens were analyzed while submerged/saturated in ethylene glycol, simulating natural hydration and allowing experimental temperatures above 100 degrees C for an improved view of the lignin glass transition. Down-regulation of the 4 Coumarate:coenzyme A ligase gene (reduced lignin content and altered monomer composition) generally resulted in less stiff and weaker stems. These observations were associated with a reduction in the temperature and activation energy of the lignin glass transition, but surprisingly with no difference in the breadth and intensity of the tan delta signal. The results showed promise in further investigations of how rheological methods relate to stem lignin content, composition, and functional properties in the field and in bioprocessing. Conclusions: Measurements such as these are complicated by small specimen size; however, torsional rheometers (relatively common in polymer laboratories) are well suited for this task. As opposed to the expense and complication of relative humidity control, solvent-submersion rheological methods effectively reveal fundamental structure/property relationships in plant tissues. Demonstrated are low-strain linear methods, and also nonlinear yield and failure analysis; the latter is very uncommon for typical rheological equipment. PMID- 29507610 TI - Deciphering lignocellulose deconstruction by the white rot fungus Irpex lacteus based on genomic and transcriptomic analyses. AB - Background: Irpex lacteus is one of the most potent white rot fungi for biological pretreatment of lignocellulose for second biofuel production. To elucidate the underlying molecular mechanism involved in lignocellulose deconstruction, genomic and transcriptomic analyses were carried out for I. lacteus CD2 grown in submerged fermentation using ball-milled corn stover as the carbon source. Results: Irpex lacteus CD2 efficiently decomposed 74.9% lignin, 86.3% cellulose, and 83.5% hemicellulose in corn stover within 9 days. Manganese peroxidases were rapidly induced, followed by accumulation of cellulase and hemicellulase. Genomic analysis revealed that I. lacteus CD2 possessed a complete set of lignocellulose-degrading enzyme system composed mainly of class II peroxidases, dye-decolorizing peroxidases, auxiliary enzymes, and 182 glycoside hydrolases. Comparative transcriptomic analysis substantiated the notion of a selection mode of degradation. These analyses also suggested that free radicals, derived either from MnP-organic acid interplay or from Fenton reaction involving Fe2+ and H2O2, could play an important role in lignocellulose degradation. Conclusions: The selective strategy employed by I. lacteus CD2, in combination with low extracellular glycosidases cleaving plant cell wall polysaccharides into fermentable sugars, may account for high pretreatment efficiency of I. lacteus. Our study also hints the importance of free radicals for future designing of novel, robust lignocellulose-degrading enzyme cocktails. PMID- 29507612 TI - Predicting type 2 diabetes mellitus: a comparison between the FINDRISC score and the metabolic syndrome. AB - Background: The aim of this study to compare the diagnostic accuracy of the metabolic syndrome (MetS) with the FINDRISC score to screen for type 2 diabetes mellitus T2DM in an overweight/obese population. Methods: Subjects 18 years or older visiting the obesity clinic of the Antwerp University Hospital were consecutively recruited between 2012 and 2014. Every patient underwent a standard metabolic work-up including a clinical examination with anthropometry. Glucose status was tested using OGTT and Hba1c. FINDRISC questionnaire and MetS were examined. Results: Of 651 subjects, 50.4% were diagnosed with prediabetes, whereas 11.1% was diagnosed with T2DM. FINDRISC score increased with worsening of glucose status 11 +/- 3, 13 +/- 4 and 15 +/- 5 in respectively, subjects without T2DM, prediabetes and T2DM. 312 subjects had the MetS. The aROC of the FINDRISC to identify subjects with T2DM was 0.76 (95% CI 0.72-0.82), sensitivity was 64% and specificity was 63% with 13 as cutoff point. Adding FPG or HbA1c to FINDRISC, the aROC increased significantly to 0.91(95% CI 0.88-0.95) and 0.93(95% CI 0.90 0.97), respectively (p < 0.001). The aROC of the MetS to identify subjects with diabetes was 0.72 (95% CI 0.65-0.78), sensitivity was 75% and specificity was 55%. The aROC of the FINDRISC + HbA1c was significantly higher than the MetS for predicting T2DM (p < 0.001). Conclusion: Prediction of type 2 diabetes is important for timely intervention and to avoid chronic complications associated with the disease. Our findings suggest, that it may be of good clinical practice to use the FINDRISC score + HbA1c in a two-step screening model for diabetes rather than using the metabolic syndrome. PMID- 29507611 TI - Dapagliflozin improves treatment satisfaction in overweight patients with type 2 diabetes mellitus: a patient reported outcome study (PRO study). AB - Background: The benefits of sodium glucose cotransporters 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus include plasma glucose control, reduction in body weight and blood pressure, and low risk of hypoglycemia, although they may also cause genitourinary infections, polyuria, or volume depletion. It is not clear whether dapagliflozin, an SGLT2 inhibitor, improves treatment satisfaction among patients in a comprehensive way despite the negative side effects. This study assessed the effect of dapagliflozin on glycosylated hemoglobin (HbA1c), body weight, and treatment satisfaction in overweight patients with type 2 diabetes mellitus treated with oral hypoglycemic agents. Methods: This multicenter, open-label, single-arm observational study included patients with type 2 diabetes mellitus administering dapagliflozin 5 or 10 mg per day for 14 weeks. Changes in treatment satisfaction were evaluated using a new version of the Oral Hypoglycemic Agent-Questionnaire (OHA-Q ver. 2) consisting of 23 items. Correlation between treatment satisfaction and HbA1c levels and body weight were analyzed using the Spearman's rank-correlation coefficient. Results: Of the 221 patients enrolled, 188 completed the study. Mean HbA1c decreased from 7.8 +/- 0.7% (62.1 +/- 7.5 mmol/mol) to 7.3 +/- 0.8% (55.9 +/- 8.7 mmol/mol) (change - 0.6 +/- 0.7%, P < 0.001) and body weight decreased from 82.5 +/- 14.6 to 80.7 +/- 14.8 kg (change - 2.3 +/- 2.8 kg, P < 0.001). OHA-Q ver. 2 was validated as well, the mean OHA-Q ver. 2 total score increased from 44.3 +/- 9.4 to 46.6 +/- 9.8 (best score 69, worst score 0; change 2.3 +/- 6.6, P < 0.001). The change in body weight significantly correlated with the OHA-Q ver. 2 total score (Spearman's rho = - 0.17, P = 0.035). The change in HbA1c levels significantly correlated with the satisfaction subscale score (Spearman's rho = - 0.19, P = 0.011). Conclusions: Dapagliflozin significantly improved treatment satisfaction among patients with type 2 diabetes mellitus for 14 weeks. Body weight loss significantly correlated with treatment satisfaction.Trial registration UMIN-CTR: UMIN000016304. PMID- 29507613 TI - Up-regulated autophagy: as a protective factor in adipose tissue of WOKW rats with metabolic syndrome. AB - Background: Wistar Ottawa Karlsburg W (RT1u) rats (WOKW) are a model of the metabolic syndrome (MetS). Adipose tissue (AT) and peripheral nerves of WOKW rats exhibit up-regulated autophagy and inflammation corresponding with decreased apoptosis rate. The aim of this study was to characterize AT in WOKW rats in relation to autophagic activity. Methods: mRNA and protein expression of adiponectin, pro-inflammatory and pro-apoptotic markers including MCP1, TNFalpha, cleaved caspase-3 and RNF157, a new candidate gene regulated through autophagy, were analyzed in adipocytes isolated from visceral and subcutaneous AT of 5-month old WOKW rats with MetS and LEW.1W controls in response to pharmacological inhibition of autophagy. Immunohistochemistry was performed to detect adiponectin and RNF157 protein in cultured adipocytes. Results: Inhibition of autophagy by LY294002 was associated with a fourfold up-regulation of adiponectin expression and a decrease of RNF157 protein and pro-inflammatory markers-MCP-1 and TNFalpha predominantly in visceral adipocytes of obese WOKW rats compared to LEW.1W rats. Moreover, inhibition of autophagic activity correlates with an activation of cleaved caspase-3 apoptotic signaling pathway. Conclusions: Up-regulated autophagy in obese WOKW rats contributes to the regulation of visceral AT function and involves an altered balance between pro-inflammatory and protective adipokine expression. Our data suggest that activation of AT autophagy protects against adipocyte apoptosis at least under conditions of obesity related MetS in WOKW rats. PMID- 29507615 TI - Systematic Assessment of Strategies for Lung-targeted Delivery of MicroRNA Mimics. AB - There is considerable interest in the use of synthetic miRNA mimics (or inhibitors) as potential therapeutic agents in pulmonary vascular disease; however, the optimal delivery method to achieve high efficiency, selective lung targeting has not been determined. Here, we sought to investigate the relative merits of different lung-targeted strategies for delivering miRNA mimics in rats. Methods: Tissue levels of a synthetic miRNA mimic, cel-miR-39-3p (0.5 nmol in 50 uL invivofectamine/PBS vehicle) were compared in male rats (n=3 rats/method) after delivery by commonly used lung-targeting strategies including intratracheal liquid instillation (IT-L), intratracheal aerosolization with (IT-AV) or without ventilator assistance (IT-A), intranasal liquid instillation (IN-L) and intranasal aerosolization (IN-A). Intravenous (IV; via jugular vein), intraperitoneal (IP) and subcutaneous (SC) delivery served as controls. Relative levels of cel-miR-39 were quantified by RT-qPCR. Results: At 2 h post delivery, IT-L showed the highest lung mimic level, which was significantly higher than levels achieved by all other methods (from ~10- to 10,000-fold, p<0.05). Mimic levels remained detectable in the lung 24 h after delivery, but were 10- to 100 fold lower. The intrapulmonary distribution of cel-miR-39 was comparable when delivered as either a liquid or aerosol, with evidence of mimic distribution to both the left and right lung lobes and penetration to distal regions. All lung targeted strategies showed lung-selective mimic uptake, with mimic levels 10- to 100-fold lower in heart and 100- to 10,000-fold lower in liver, kidney and spleen. In contrast, IV, SC and IP routes showed comparable or higher mimic levels in non-pulmonary tissues. Conclusions: miRNA uptake in the lungs differed markedly by up to 4 orders of magnitude, demonstrating that the choice of delivery strategy could have a significant impact on potential therapeutic outcomes in preclinical investigations of miRNA-based drug candidates. PMID- 29507614 TI - Molecular Magnetic Resonance Imaging of Endothelial Activation in the Central Nervous System. AB - Endothelial cells of the central nervous system over-express surface proteins during neurological disorders, either as a cause, or a consequence, of the disease. Since the cerebral vasculature is easily accessible by large contrast carrying particles, it constitutes a target of choice for molecular magnetic resonance imaging (MRI). In this review, we highlight the most recent advances in molecular MRI of brain endothelial activation and focus on the development of micro-sized particles of iron oxide (MPIO) targeting adhesion molecules including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), P-Selectin and E-Selectin. We also discuss the perspectives and challenges for the clinical application of this technology in neurovascular disorders (ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, diabetes mellitus), neuroinflammatory disorders (multiple sclerosis, brain infectious diseases, sepsis), neurodegenerative disorders (Alzheimer's disease, vascular dementia, aging) and brain cancers (primitive neoplasms, metastasis). PMID- 29507616 TI - Indocyanine green-incorporating nanoparticles for cancer theranostics. AB - Indocyanine green (ICG) is a near-infrared dye that has been used in the clinic for retinal angiography, and defining cardiovascular and liver function for over 50 years. Recently, there has been an increasing interest in the incorporation of ICG into nanoparticles (NPs) for cancer theranostic applications. Various types of ICG-incorporated NPs have been developed and strategically functionalised to embrace multiple imaging and therapeutic techniques for cancer diagnosis and treatment. This review systematically summaries the biodistribution of various types of ICG-incorporated NPs for the first time, and discusses the principles, opportunities, limitations, and application of ICG-incorporated NPs for cancer theranostics. We believe that ICG-incorporated NPs would be a promising multifunctional theranostic platform in oncology and facilitate significant advancements in this research-active area. PMID- 29507617 TI - Serum exosomes can restore cellular function in vitro and be used for diagnosis in dysferlinopathy. AB - Purpose: It is challenging to deliver the full-length dysferlin gene or protein to restore cellular functions of dysferlin-deficient (DYSF-/-) myofibres in dysferlinopathy, a disease caused by the absence of dysferlin, which is currently without effective treatment. Exosomes, efficient membranous nanoscale carriers of biological cargoes, could be useful. Experimental design: Myotube- and human serum-derived exosomes were investigated for their capabilities of restoring dysferlin protein and cellular functions in murine and human DYSF-/- cells. Moreover, dysferlinopathic patient serum- and urine-derived exosomes were assessed for their abilities as diagnostic tools for dysferlinopathy. Results: Here we show that exosomes from dysferlin-expressing myotubes carry abundant dysferlin and enable transfer of full-length dysferlin protein to DYSF-/- myotubes. Exogenous dysferlin correctly localizes on DYSF-/- myotube membranes, enabling membrane resealing in response to injury. Human serum exosomes also carry dysferlin protein and improve membrane repair capabilities of human DYSF-/- myotubes irrespective of mutations. Lack of dysferlin in dysferlinopathic patient serum and urine exosomes enables differentiation between healthy controls and dysferlinopathic patients. Conclusions: Our findings provide evidence that exosomes are efficient carriers of dysferlin and can be employed for the treatment and non-invasive diagnosis of dysferlinopathy. PMID- 29507618 TI - A low microRNA-630 expression confers resistance to tyrosine kinase inhibitors in EGFR-mutated lung adenocarcinomas via miR-630/YAP1/ERK feedback loop. AB - Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated. Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop. A retrospective study was conducted to examine whether the expression of miR-630 and YAP1 could be associated with TKI therapeutic response in patients with lung adenocarcinoma. Results: Low miR 630 expression may confer TKI resistance via increased SP1 binding to the miR-630 promoter due to ERK activation by YAP1 de-targeting. Persistent activation of ERK signaling via the miR-630/YAP1/ERK feedback loop may be responsible for TKI resistance in EGFR-mutated cells. Moreover, a decrease in Bad expression by its phosphorylation at Serine 75 through ERK activation conferred low miR-630 mediated TKI resistance by modulating the apoptotic pathway. Xenographic tumors induced by miR-630-knockdown PC9 and PC9GR cells in nude mice were nearly suppressed by the combination of gefitinib with the YAP1 inhibitor verteporfin or an MEK/ERK inhibitor AZD6244. Patients with low miR-630 and high YAP1 expressing tumors had a higher prevalence of unfavorable responses to TKI therapy and poorer outcomes when compared with their counterparts. Conclusion: MiR-630 may be a potential biomarker for the prediction of TKI therapeutic response and outcome in patients with lung adenocarcinoma. PMID- 29507619 TI - GRO-alpha and IL-8 enhance ovarian cancer metastatic potential via the CXCR2 mediated TAK1/NFkappaB signaling cascade. AB - Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-alpha and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness. Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-alpha, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models. Results: Both GRO-alpha and IL-8 can activate TAK1/NFkappaB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFkappaB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-alpha and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFkappaB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-alpha and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity. Conclusion: This study highlights the significance of GRO-alpha and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer. PMID- 29507620 TI - S6K1 phosphorylation-dependent degradation of Mxi1 by beta-Trcp ubiquitin ligase promotes Myc activation and radioresistance in lung cancer. AB - Rationale: Mxi1 is regarded as a potential tumor suppressor protein that antagonizes the transcriptional activity of proto-oncogene Myc. However, the clinical significances and underlying mechanisms by which Mxi1 is regulated in lung cancer remain poorly understood. Methods: Mass spectrometry analysis and immunoprecipitation assay were utilized to detect the protein-protein interaction. The phosphorylation of Mxi1 was evaluated by in vitro kinase assays. Poly-ubiquitination of Mxi1 was examined by in vivo ubiquitination assay. Lung cancer cells stably expressing wild-type Mxi1 or Mxi1-S160A were used for functional analyses. The expression levels of Mxi1 and S6K1 were determined by immunohistochemistry in lung cancer tissues and adjacent normal lung tissues. Results: We found that Mxi1 is downregulated and correlated with poor prognosis in lung cancer. Using tandem affinity purification technology, we provided evidence that beta-Trcp E3 ubiquitin ligase interacts with and promotes the ubiquitination and degradation of Mxi1. Furthermore, we demonstrated that Mxi1 is phosphorylated at S160 site by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase beta-Trcp. Moreover, a phosphorylation mutant form of Mxi1 (Mxi1-S160A), which cannot be degraded by S6K1 and beta-Trcp, is much more stable and efficient in suppressing the transcriptional activity of Myc and radioresistance in lung cancer cells. More importantly, a strong inverse correlation between S6K1 and Mxi1 expression was observed in human lung cancer tissues. Conclusion: Our findings not only establish a crosstalk between the mTOR/S6K1 signaling pathway and Myc activation, but also suggest that targeting S6K1/Mxi1 pathway is a promising therapeutic strategy for the treatment of lung cancer. PMID- 29507621 TI - Non-invasive Prenatal Diagnosis of Chromosomal Aneuploidies and Microdeletion Syndrome Using Fetal Nucleated Red Blood Cells Isolated by Nanostructure Microchips. AB - Detection of detached fetal nucleated red blood cells (fNRBCs) in the maternal peripheral blood may serve as a prospective testing method competing with the cell-free DNA, in non-invasive prenatal testing (NIPT). Methods: Herein, we introduce a facile and effective lab-on-a-chip method of fNRBCs detection using a capture-releasing material that is composed of biotin-doped polypyrrole nanoparticles. To enhance local topographic interactions between the nano components and fNRBC, a specific antibody, CD147, coated on the nanostructured substrate led to the isolation of fNRBCs from maternal peripheral blood. Subsequently, an electrical system was employed to release the captured cells using 0.8 V for 15 s. The diagnostic application of fNRBCs for fetal chromosomal disorders (Trisomy 13/21/18/X syndrome, microdeletion syndrome) was demonstrated. Results: Cells captured by nanostructured microchips were identified as fNRBCs. Twelve cases of chromosomal aneuploidies and one case of 18q21 microdeletion syndrome were diagnosed using the fNRBCs released from the microchips. Conclusion: Our method offers effective and accurate analysis of fNRBCs for comprehensive NIPT to monitor fetal cell development. PMID- 29507622 TI - Pharmacological Ascorbate Suppresses Growth of Gastric Cancer Cells with GLUT1 Overexpression and Enhances the Efficacy of Oxaliplatin Through Redox Modulation. AB - Rationale: The antitumor activity of high-dose ascorbate has been re-evaluated recently, but the mechanism underlying cell-specific sensitivity to ascorbate has not yet been clarified. Methods: The effects of high-dose ascorbate on gastric cancer were assessed using cancer cell lines with high and low expression of GLUT1 via flow cytometry and colony formation assays in vitro and patient-derived xenografts in vivo. Results: In this study, we demonstrated that gastric cancer cells with high GLUT1 expression were more sensitive to ascorbate treatment than cells with low GLUT1 expression. GLUT1 knockdown significantly reversed the therapeutic effects of pharmacological ascorbate, while enforced expression of GLUT1 enhanced the sensitivity to ascorbate treatment. The efficacy of pharmacological ascorbate administration in mice bearing cell line-based and patient-derived xenografts was influenced by GLUT1 protein levels. Mechanistically, ascorbate depleted intracellular glutathione, generated oxidative stress and induced DNA damage. The combination of pharmacological ascorbate with genotoxic agents, including oxaliplatin and irinotecan, synergistically inhibited gastric tumor growth in mouse models. Conclusions: The current study showed that GLUT1 expression was inversely correlated with sensitivity of gastric cancer cells to pharmacological ascorbate and suggested that GLUT1 expression in gastric cancer may serve as a marker for sensitivity to pharmacological ascorbate. PMID- 29507623 TI - Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound. AB - Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release. PMID- 29507624 TI - Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc GlcNAc-PEI for liver fibrosis imaging with SPECT. AB - Extracellular matrix (ECM) accumulation in liver fibrosis is caused by the activation of hepatic stellate cells (HSCs). The goal of this study was to develop a 99mTc-labeled N-acetylglucosamine (GlcNAc) that specifically interacts with desmin and vimentin expressed on activated HSCs to monitor the progression and prognosis of liver fibrosis using single-photon emission computed tomography (SPECT) imaging. Methods: GlcNAc-conjugated polyethylenimine (PEI) was first prepared and radiolabeled with 99mTc. Noninvasive SPECT imaging with 99mTc-GlcNAc PEI was used to assess liver fibrosis in a carbon tetrachloride (CCl4) mouse model. The liver uptake value (LUV) of 99mTc-GlcNAc-PEI was measured by drawing the region of interest (ROI) of the whole liver as previously suggested. The LUV of the CCl4 groups was compared with that of the olive oil group. Next, we estimated the correlation between the results of SPECT imaging and physiological indexes. After treatment with clodronate liposome, the LUV of 99mTc-GlcNAc-PEI in fibrotic mice was compared with that in control mice. Results:99mTc-GlcNAc-PEI is a hydrophilic compound with high radiochemical purity (>98%) and good stability. It could specifically target desmin and vimentin on the surface of activated HSCs with high affinity (the Kd values were 53.75 +/- 9.50 nM and 20.98 +/- 3.56 nM, respectively). The LUV of 99mTc-GlcNAc-PEI was significantly different between the CCl4 and control groups as early as 4 weeks of CCl4 administration (3.30 +/- 0.160 vs 2.34 +/- 0.114%/cc; P ? 0.05). There was a strong correlation between the LUV and Sirius Red quantification (R = 0.92, P ? 0.001). Compared with control, clodronate liposome treatment reduced the LUV of 99mTc-GlcNAc-PEI (4.62 +/- 0.352 vs 2.133 +/- 0.414%/cc; P ? 0.05). Conclusion:99mTc-GlcNAc-PEI SPECT/CT was useful in assessing liver fibrosis and monitoring the treatment response. PMID- 29507626 TI - Sarcoma-Targeting Peptide-Decorated Polypeptide Nanogel Intracellularly Delivers Shikonin for Upregulated Osteosarcoma Necroptosis and Diminished Pulmonary Metastasis. AB - PURPOSE: Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed. DESIGN: In this study, a sarcoma-targeting peptide-decorated disulfide crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity. RESULTS: The targeted, loaded nanogel, STP-NG/SHK, killed osteosarcoma cells by inducing RIP1- and RIP3 dependent necroptosis in vitro. Necroptosis is a novel cell death form that could be well adapted as an efficient antitumor strategy, the main obstacle of which is its high toxicity. After intravenous injection, STP-NG/SHK efficiently suppressed tumor growth and reduced pulmonary metastasis, offering greater tumor necrosis and higher RIP1 and RIP3 upregulation compared to free SHK or untargeted NG/SHK in vivo. Additionally, the treatment with NG/SHK or STP-NG/SHK showed minimal toxicity to normal organs, suggesting low systemic toxicity compared to free SHK. CONCLUSION: The STP-guided intracellular drug delivery system using the necroptosis mechanism showed profound anti-osteosarcoma activity, especially eliminated lung metastasis in vivo. This drug formulation may have great potential for treatment of osteosarcoma. PMID- 29507625 TI - Targeting Tumor Hypoxia Using Nanoparticle-engineered CXCR4-overexpressing Adipose-derived Stem Cells. AB - Hypoxia, a hallmark of malignant tumors, often correlates with increasing tumor aggressiveness and poor treatment outcomes. Due to a lack of vasculature, effective drug delivery to hypoxic tumor regions remains challenging. Signaling through the chemokine SDF-1alpha and its receptor CXCR4 plays a critical role in the homing of stem cells to ischemia for potential use as drug-delivery vehicles. To harness this mechanism for targeting tumor hypoxia, we developed polymeric nanoparticle-induced CXCR4-overexpressing human adipose-derived stem cells (hADSCs). Using glioblastoma multiforme (GBM) as a model tumor, we evaluated the ability of CXCR4-overexpressing hADSCs to target tumor hypoxia in vitro using a 2D migration assay and a 3D collagen hydrogel model. Compared to untransfected hADSCs, CXCR4-overexpressing hADSCs showed enhanced migration in response to hypoxia and penetrated the hypoxic core within tumor spheres. When injected in the contralateral brain in a mouse intracranial GBM xenograft, CXCR4 overexpressing hADSCs exhibited long-range migration toward GBM and preferentially penetrated the hypoxic tumor core. Intravenous injection also led to effective targeting of tumor hypoxia in a subcutaneous tumor model. Together, these results validate polymeric nanoparticle-induced CXCR4-overexpressing hADSCs as a potent cellular vehicle for targeting tumor hypoxia, which may be broadly useful for enhancing drug delivery to various cancer types. PMID- 29507627 TI - Cancer-associated fibroblasts enhance tumor 18F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT. AB - Purpose: Elevated glucose uptake is a hallmark of cancer. Fluorodeoxyglucose (FDG) uptake was believed to indicate the aggressiveness of tumors and the standardized uptake value (SUV) is a well-known measurement for FDG uptake in positron emission tomography-computed tomography (PET/CT). However, the SUV is variable due to the heterogeneity of tumors. Methods: 126 patients with colorectal cancer underwent 18F-FDG PET/CT scanning before surgery between Jan 2011 and April 2016. Cancer-associated fibroblast (CAF) densities were calculated with the inForm Advanced image analysis software and were comparatively analyzed between patients with high and low maximum SUV (SUVmax-high and SUVmax-low). Glucose uptake was evaluated in induced and isolated CAFs and CAF-cocultured colon cancer HCT116 cells. Moreover, micro-PET/CT was performed on xenografted tumors and autoradiography was performed in the AOM/DSS induced colon cancer model. Results: CAFs were glycolytic, evidenced by glucose uptake and upregulated HK2 expression. Compared to non-activated fibroblasts (NAFs), CAFs were more dependent on glucose and sensitive to a glycolysis inhibitor. CAFs increased the SUVmax in xenograft tumors and spontaneous colon cancers. Moreover, multivariate analysis revealed that the SUVmax was only associated with tumor size among conventional parameters in colon cancer patients (126 cases, p = 0.009). Besides tumor size, the CAF density was the critical factor associated with SUVmax and outcome, which was 2.27 +/- 0.74 and 1.68 +/- 0.45 in the SUVmax-high and the SUVmax-low groups, respectively (p = 0.014). Conclusion: CAFs promote tumor progression and increase SUVmax of 18F-FDG, suggesting CAFs lead to the intratumor heterogeneity of the SUV and the SUVmax is a prognostic marker for cancer patients. PMID- 29507628 TI - Longitudinal Multiplexed Measurement of Quantitative Proteomic Signatures in Mouse Lymphoma Models Using Magneto-Nanosensors. AB - Cancer proteomics is the manifestation of relevant biological processes in cancer development. Thus, it reflects the activities of tumor cells, host-tumor interactions, and systemic responses to cancer therapy. To understand the causal effects of tumorigenesis or therapeutic intervention, longitudinal studies are greatly needed. However, most of the conventional mouse experiments are unlikely to accommodate frequent collection of serum samples with a large enough volume for multiple protein assays towards single-object analysis. Here, we present a technique based on magneto-nanosensors to longitudinally monitor the protein profiles in individual mice of lymphoma models using a small volume of a sample for multiplex assays. Methods: Drug-sensitive and -resistant cancer cell lines were used to develop the mouse models that render different outcomes upon the drug treatment. Two groups of mice were inoculated with each cell line, and treated with either cyclophosphamide or vehicle solution. Serum samples taken longitudinally from each mouse in the groups were measured with 6-plex magneto nanosensor cytokine assays. To find the origin of IL-6, experiments were performed using IL-6 knock-out mice. Results: The differences in serum IL-6 and GCSF levels between the drug-treated and untreated groups were revealed by the magneto-nanosensor measurement on individual mice. Using the multiplex assays and mouse models, we found that IL-6 is secreted by the host in the presence of tumor cells upon the drug treatment. Conclusion: The multiplex magneto-nanosensor assays enable longitudinal proteomic studies on mouse tumor models to understand tumor development and therapy mechanisms more precisely within a single biological object. PMID- 29507629 TI - Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. AB - Objectives: Mesenchymal stem cells (MSCs) release extracellular vesicles (EVs) that display a therapeutic effect in inflammatory disease models. Although MSCs can prevent arthritis, the role of MSCs-derived EVs has never been reported in rheumatoid arthritis. This prompted us to compare the function of exosomes (Exos) and microparticles (MPs) isolated from MSCs and investigate their immunomodulatory function in arthritis. Methods: MSCs-derived Exos and MPs were isolated by differential ultracentrifugation. Immunosuppressive effects of MPs or Exos were investigated on T and B lymphocytes in vitro and in the Delayed-Type Hypersensitivity (DTH) and Collagen-Induced Arthritis (CIA) models. Results: Exos and MPs from MSCs inhibited T lymphocyte proliferation in a dose-dependent manner and decreased the percentage of CD4+ and CD8+ T cell subsets. Interestingly, Exos increased Treg cell populations while parental MSCs did not. Conversely, plasmablast differentiation was reduced to a similar extent by MSCs, Exos or MPs. IFN-gamma priming of MSCs before vesicles isolation did not influence the immunomodulatory function of isolated Exos or MPs. In DTH, we observed a dose dependent anti-inflammatory effect of MPs and Exos, while in the CIA model, Exos efficiently decreased clinical signs of inflammation. The beneficial effect of Exos was associated with fewer plasmablasts and more Breg-like cells in lymph nodes. Conclusions: Both MSCs-derived MPs and Exos exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming. However, Exos were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived EVs in inflammatory arthritis. PMID- 29507630 TI - Naphthalene-based fluorescent probes for glutathione and their applications in living cells and patients with sepsis. AB - Rationale: Among the biothiols-related diseases, sepsis is defined as life threatening organ dysfunction caused by a dysregulated host response to infection and can result in severe oxidative stress and damage to multiple organs. In this study, we aimed to develop a fluorescence chemosensor that can both detect GSH and further predict sepsis. Methods: In this study, two new naphthalene dialdehyde compounds containing different functional groups were synthesized, and the sensing abilities of these compounds towards biothiols and its applications for prediction of sepsis were investigated. Results: Our study revealed that the newly developed probe 6-methoxynaphthalene-2, 3-dicarbaldehyde (MNDA) has two photon is capable of detecting GSH in live cells with two-photon microscopy (TPM) under the excitation at a wavelength of 900 nm. Furthermore, two GSH detection probes naphthalene-2,3-dicarboxaldehyde (NDA) and 6-fluoronaphthalene-2,3 dicarbaldehyde (FNDA) not only can detect GSH in living cells, but also showed clinical significance for the diagnosis and prediction of mortality in patients with sepsis. Conclusions: These results open up a promising direction for further medical diagnostic techniques. PMID- 29507631 TI - Selection of Tissue Factor-Deficient Cell Transplants as a Novel Strategy for Improving Hemocompatibility of Human Bone Marrow Stromal Cells. AB - Intravascular transplantation of tissue factor (TF)-bearing cells elicits an instant blood-mediated inflammatory reaction (IBMIR) resulting in thrombotic complications and reduced engraftment. Here we studied the hemocompatibility of commonly used human white adipose tissue (WAT), umbilical cord (UC) and bone marrow stromal cells (BMSC) and devised a possible strategy for safe and efficient stromal cell transplantation. Methods: Stromal cell identity, purity, and TF expression was tested by RTQ-PCR, flow cytometry and immunohistochemistry. Pro-coagulant activity and fibrin clot formation/stabilization was measured In Vitro by viscoelastic rotational plasma-thromboelastometry and in vivo by injecting sorted human stromal cells intravenously into rats. The impact of TF was verified in factor VII-deficient plasma and by sort-depleting TF/CD142+ BMSC. Results: We found significantly less TF expression by a subpopulation of BMSC corresponding to reduced pro-coagulant activity. UC and WAT stroma showed broad TF expression and durable clotting. Higher cell numbers significantly increased clot formation partially dependent on coagulation factor VII. Depleting the TF/CD142+ subpopulation significantly ameliorated BMSC's hemocompatibility without affecting immunomodulation. TF-deficient BMSC did not produce thromboembolism in vivo, comparing favorably to massive intravascular thrombosis induction by TF-expressing stromal cells. Conclusion: We demonstrate that plasma based thromboelastometry provides a reliable tool to detect pro-coagulant activity of therapeutic cells. Selecting TF-deficient BMSC is a novel strategy for improving cell therapy applicability by reducing cell dose-dependent IBMIR risk. The particularly strong pro-coagulant activity of UC and WAT preparations sounds an additional note of caution regarding uncritical systemic application of stromal cells, particularly from non-hematopoietic extravascular sources. PMID- 29507632 TI - Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma. AB - Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM. PMID- 29507633 TI - D-alanyl-D-alanine-Modified Gold Nanoparticles Form a Broad-Spectrum Sensor for Bacteria. AB - Rationale: Rapid and facile detection of pathogenic bacteria is challenging due to the requirement of large-scale instruments and equipment in conventional methods. We utilize D-amino acid as molecules to selectively target bacteria because bacteria can incorporate DADA in its cell wall while mammalian cells or fungi cannot. Methods: We show a broad-spectrum bacterial detection system based on D-amino acid-capped gold nanoparticles (AuNPs). AuNPs serve as the signal output that we can monitor without relying on any complex instruments. Results: In the presence of bacteria, the AuNPs aggregate and the color of AuNPs changes from red to blue. This convenient color change can distinguish between Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA). This system can be applied for detection of ascites samples from patients. Conclusion: These D-amino acid-modified AuNPs serve as a promising platform for rapid visual identification of pathogens in the clinic. PMID- 29507635 TI - Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs). AB - The design of highly emissive and stable blue emitters for organic light emitting diodes (OLEDs) is still a challenge, justifying the intense research activity of the scientific community in this field. Recently, a great deal of interest has been devoted to the elaboration of emitters exhibiting a thermally activated delayed fluorescence (TADF). By a specific molecular design consisting into a minimal overlap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) due to a spatial separation of the electron-donating and the electron-releasing parts, luminescent materials exhibiting small S1-T1 energy splitting could be obtained, enabling to thermally upconvert the electrons from the triplet to the singlet excited states by reverse intersystem crossing (RISC). By harvesting both singlet and triplet excitons for light emission, OLEDs competing and sometimes overcoming the performance of phosphorescence-based OLEDs could be fabricated, justifying the interest for this new family of materials massively popularized by Chihaya Adachi since 2012. In this review, we proposed to focus on the recent advances in the molecular design of blue TADF emitters for OLEDs during the last few years. PMID- 29507636 TI - Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides. AB - A family of novel chloramphenicol base-amide organocatalysts possessing a NH functionality at C-1 position as monodentate hydrogen bond donor were developed and evaluated for enantioselective organocatalytic alcoholysis of meso-cyclic anhydrides. These structural diversified organocatalysts were found to induce high enantioselectivity in alcoholysis of anhydrides and was successfully applied to the asymmetric synthesis of (S)-GABOB. PMID- 29507637 TI - Continuous-flow retro-Diels-Alder reaction: an efficient method for the preparation of pyrimidinone derivatives. AB - The syntheses of various pyrimidinones as potentially bioactive products by means of the highly controlled continuous-flow retro-Diels-Alder reaction of condensed pyrimidinone derivatives are presented. Noteworthy, the use of this approach allowed us to rapidly screen a selection of conditions and quickly confirm the viability of preparing the desired pyrimidinones in short reaction times. Yields typically higher than those published earlier using conventional batch or microwave processes were achieved. PMID- 29507634 TI - Fluorogenic PNA probes. AB - Fluorogenic oligonucleotide probes that can produce a change in fluorescence signal upon binding to specific biomolecular targets, including nucleic acids as well as non-nucleic acid targets, such as proteins and small molecules, have applications in various important areas. These include diagnostics, drug development and as tools for studying biomolecular interactions in situ and in real time. The probes usually consist of a labeled oligonucleotide strand as a recognition element together with a mechanism for signal transduction that can translate the binding event into a measurable signal. While a number of strategies have been developed for the signal transduction, relatively little attention has been paid to the recognition element. Peptide nucleic acids (PNA) are DNA mimics with several favorable properties making them a potential alternative to natural nucleic acids for the development of fluorogenic probes, including their very strong and specific recognition and excellent chemical and biological stabilities in addition to their ability to bind to structured nucleic acid targets. In addition, the uncharged backbone of PNA allows for other unique designs that cannot be performed with oligonucleotides or analogues with negatively-charged backbones. This review aims to introduce the principle, showcase state-of-the-art technologies and update recent developments in the areas of fluorogenic PNA probes during the past 20 years. PMID- 29507638 TI - Recent developments in the asymmetric Reformatsky-type reaction. AB - This review collects the most important developments in asymmetric Reformatsky type reactions published since the beginning of 2013, including both diastereoselective methodologies based on the use of chiral substrates and enantioselective catalytic procedures. PMID- 29507639 TI - One-pot preparation of 4-aryl-3-bromocoumarins from 4-aryl-2-propynoic acids with diaryliodonium salts, TBAB, and Na2S2O8. AB - Various 4-aryl-3-bromocoumarins were smoothly obtained in moderate yields in one pot by treating 3-aryl-2-propynoic acids with diaryliodonium triflates and K2CO3 in the presence of CuCl, followed by the reaction with tetrabutylammonium bromide (TBAB) and Na2S2O8. The obtained 3-bromo-4-phenylcoumarin was transformed into 4 phenylcoumarin derivatives bearing C-H, C-S, C-N, and C-C bonds at 3-position. PMID- 29507640 TI - Diels-Alder cycloadditions of N-arylpyrroles via aryne intermediates using diaryliodonium salts. AB - With a strategy of the formation of benzynes by using diaryliodonium salts, a cycloaddition reaction of N-arylpyrroles with benzynes was reported. A wide range of bridge-ring amines with various substituents have been synthesized in moderate to excellent yields (35-96%). Furthermore, with a catalytic amount of TsOH.H2O, these amines can be converted into the corresponding N-phenylamine derivatives easily, which are potentially useful in photosensitive dyes. PMID- 29507641 TI - Synthesis of fluoro-functionalized diaryl-lambda3-iodonium salts and their cytotoxicity against human lymphoma U937 cells. AB - Conscious of the potential bioactivity of fluorine, an investigation was conducted using various fluorine-containing diaryliodonium salts in order to study and compare their biological activity against human lymphoma U937 cells. Most of the compounds tested are well-known reagents for fluoro-functionalized arylation reactions in synthetic organic chemistry, but their biological properties are not fully understood. Herein, after initially investigating 18 fluoro-functionalized reagents, we discovered that the ortho-fluoro functionalized diaryliodonium salt reagents showed remarkable cytotoxicity in vitro. These results led us to synthesize more compounds, previously unknown sterically demanding diaryliodonium salts having a pentafluorosulfanyl (SF5) functional group at the ortho-position, that is, unsymmetrical ortho-SF5 phenylaryl-lambda3-iodonium salts. Newly synthesized mesityl(2-(pentafluoro lambda6-sulfanyl)phenyl)iodonium exhibited the greatest potency in vitro against U937 cells. Evaluation of the cytotoxicity of selected phenylaryl-lambda3 iodonium salts against AGLCL (a normal human B cell line) was also examined. PMID- 29507642 TI - Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-lambda6 sulfanyl)acetic acid esters with aldehydes. AB - Aldol reactions belong to the most frequently used C-C bond forming transformations utilized particularly for the construction of complex structures. The selectivity of these reactions depends on the geometry of the intermediate enolates. Here, we have reacted octyl pentafluoro-lambda6-sulfanylacetate with substituted benzaldehydes and acetaldehyde under the conditions of the silicon mediated Mukaiyama aldol reaction. The transformations proceeded with high diastereoselectivity. In case of benzaldehydes with electron-withdrawing substituents in the para-position, syn-alpha-SF5-beta-hydroxyalkanoic acid esters were produced. The reaction was also successful with meta-substituted benzaldehydes and o-fluorobenzaldehyde. In contrast, p-methyl-, p-methoxy-, and p ethoxybenzaldehydes led selectively to aldol condensation products with (E) configured double bonds in 30-40% yields. In preliminary experiments with an SF5 substituted acetic acid morpholide and p-nitrobenzaldehyde, a low amount of an aldol product was formed under similar conditions. PMID- 29507643 TI - Terahertz spectroscopy of 2,4,6-trinitrotoluene molecular solids from first principles. AB - We present a computational analysis of the terahertz spectra of the monoclinic and the orthorhombic polymorphs of 2,4,6-trinitrotoluene. Very good agreement with experimental data is found when using density functional theory that includes Tkatchenko-Scheffler pair-wise dispersion interactions. Furthermore, we show that for these polymorphs the theoretical results are only weakly affected by many-body dispersion contributions. The absence of dispersion interactions, however, causes sizable shifts in vibrational frequencies and directly affects the spatial character of the vibrational modes. Mode assignment allows for a distinction between the contributions of the monoclinic and orthorhombic polymorphs and shows that modes in the range from 0 to ca. 3.3 THz comprise both inter- and intramolecular vibrations, with the former dominating below ca. 1.5 THz. We also find that intramolecular contributions primarily involve the nitro and methyl groups. Finally, we present a prediction for the terahertz spectrum of 1,3,5-trinitrobenzene, showing that a modest chemical change leads to a markedly different terahertz spectrum. PMID- 29507644 TI - Bioavailability of transgenic microRNAs in genetically modified plants. AB - Background: Transgenic expression of small RNAs is a prevalent approach in agrobiotechnology for the global enhancement of plant foods. Meanwhile, emerging studies have, on the one hand, emphasized the potential of transgenic microRNAs (miRNAs) as novel dietary therapeutics and, on the other, suggested potential food safety issues if harmful miRNAs are absorbed and bioactive. For these reasons, it is necessary to evaluate the bioavailability of transgenic miRNAs in genetically modified crops. Results: As a pilot study, two transgenic Arabidopsis lines ectopically expressing unique miRNAs were compared and contrasted with the plant bioavailable small RNA MIR2911 for digestive stability and serum bioavailability. The expression levels of these transgenic miRNAs in Arabidopsis were found to be comparable to that of MIR2911 in fresh tissues. Assays of digestive stability in vitro and in vivo suggested the transgenic miRNAs and MIR2911 had comparable resistance to degradation. Healthy mice consuming diets rich in Arabidopsis lines expressing these miRNAs displayed MIR2911 in the bloodstream but no detectable levels of the transgenic miRNAs. Conclusions: These preliminary results imply digestive stability and high expression levels of miRNAs in plants do not readily equate to bioavailability. This initial work suggests novel engineering strategies be employed to enhance miRNA bioavailability when attempting to use transgenic foods as a delivery platform. PMID- 29507645 TI - Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma. AB - Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature. Conclusion: These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients. PMID- 29507646 TI - Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia. AB - Background: Preeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. We hypothesized that this heterogeneity is due to the existence of multiple subtypes of PE and, in support of this hypothesis, we recently identified five clusters of placentas within a large gene expression microarray dataset (N = 330), of which four (clusters 1, 2, 3, and 5) contained a substantial number of PE samples. However, while transcriptional analysis of placentas can subtype patients, we propose that the addition of epigenetic information could discern gene regulatory mechanisms behind the distinct PE pathologies, as well as identify clinically useful potential biomarkers. Results: We subjected 48 of our samples from transcriptional clusters 1, 2, 3, and 5 to Infinium HumanMethylation450 arrays. Samples belonging to transcriptional clusters 1-3 still showed visible relationships to each other by methylation, but cluster 5, with known chromosomal abnormalities, no longer formed a cohesive group. Within transcriptional clusters 2 and 3, controlling for fetal sex and gestational age in the identification of differentially methylated sites, compared to the healthier cluster 1, dramatically reduced the number of significant sites, but increased the percentage that demonstrated a strong linear correlation with gene expression (from 5% and 2% to 9% and 8%, respectively). Locations exhibiting a positive relationship between methylation and gene expression were most frequently found in CpG open sea enhancer regions within the gene body, while those with a significant negative correlation were often annotated to the promoter in a CpG shore region. Integrated transcriptome and epigenome analysis revealed modifications in TGF-beta signaling, cell adhesion, oxidative phosphorylation, and metabolism pathways in cluster 2 placentas, and aberrations in antigen presentation, allograft rejection, and cytokine-cytokine receptor interaction in cluster 3 samples. Conclusions: Overall, we have established DNA methylation alterations underlying a portion of the transcriptional development of "canonical" PE in cluster 2 and "immunological" PE in cluster 3. However, a significant number of the observed methylation changes were not associated with corresponding changes in gene expression, and vice versa, indicating that alternate methods of gene regulation will need to be explored to fully comprehend these PE subtypes. PMID- 29507647 TI - SMYD2 promoter DNA methylation is associated with abdominal aortic aneurysm (AAA) and SMYD2 expression in vascular smooth muscle cells. AB - Background: Abdominal aortic aneurysm (AAA) is a deadly cardiovascular disease characterised by the gradual, irreversible dilation of the abdominal aorta. AAA is a complex genetic disease but little is known about the role of epigenetics. Our objective was to determine if global DNA methylation and CpG-specific methylation at known AAA risk loci is associated with AAA, and the functional effects of methylation changes. Results: We assessed global methylation in peripheral blood mononuclear cell DNA from 92 individuals with AAA and 93 controls using enzyme-linked immunosorbent assays, identifying hyper-methylation in those with large AAA and a positive linear association with AAA diameter (P < 0.0001, R2 = 0.3175).We then determined CpG methylation status of regulatory regions in genes located at AAA risk loci identified in genome-wide association studies, using bisulphite next-generation sequencing (NGS) in vascular smooth muscle cells (VSMCs) taken from aortic tissues of 44 individuals (24 AAAs and 20 controls). In IL6R, 2 CpGs were hyper-methylated (P = 0.0145); in ERG, 13 CpGs were hyper-methylated (P = 0.0005); in SERPINB9, 6 CpGs were hypo-methylated (P = 0.0037) and 1 CpG was hyper-methylated (P = 0.0098); and in SMYD2, 4 CpGs were hypo-methylated (P = 0.0012).RT-qPCR was performed for each differentially methylated gene on mRNA from the same VSMCs and compared with methylation. This analysis revealed downregulation of SMYD2 and SERPINB9 in AAA, and a direct linear relationship between SMYD2 promoter methylation and SMYD2 expression (P = 0.038). Furthermore, downregulation of SMYD2 at the site of aneurysm in the aortic wall was further corroborated in 6 of the same samples used for methylation and gene expression analysis with immunohistochemistry. Conclusions: This study is the first to assess DNA methylation in VSMCs from individuals with AAA using NGS, and provides further evidence there is an epigenetic basis to AAA. Our study shows that methylation status of the SMYD2 promoter may be linked with decreased SMYD2 expression in disease pathobiology. In support of our work, downregulated SMYD2 has previously been associated with adverse cardiovascular physiology and inflammation, which are both hallmarks of AAA. The identification of such adverse epigenetic modifications could potentially contribute towards the development of epigenetic treatment strategies in the future. PMID- 29507649 TI - Magnetization Analysis by Spin-Polarized Scanning Electron Microscopy. AB - Spin-polarized scanning electron microscopy (spin SEM) is a method for observing magnetic-domain structures by detecting the spin polarization of secondary electrons. It has several unique abilities such as detection of full magnetization orientation and high-spatial-resolution measurement. Several spin SEM experiments have demonstrated that it is a promising method for studying various types of magnetic materials and devices. This review paper presents several spin-SEM observations to demonstrate the capability and potential of spin SEM. PMID- 29507648 TI - Integrated analyses of multi-omics reveal global patterns of methylation and hydroxymethylation and screen the tumor suppressive roles of HADHB in colorectal cancer. AB - Background: DNA methylation is an important epigenetic modification, associated with gene expression. 5-Methylcytosine and 5-hydroxymethylcytosine are two epigenetic hallmarks that maintain the equilibrium of epigenetic reprogramming. Disequilibrium in genomic methylation leads to carcinogenesis. The purpose of this study was to elucidate the epigenetic mechanisms of DNA methylation and hydroxymethylation in the carcinogenesis of colorectal cancer. Methods: Genome wide patterns of DNA methylation and hydroxymethylation in six paired colorectal tumor tissues and corresponding normal tissues were determined using immunoprecipitation and sequencing. Transcriptional expression was determined by RNA sequencing (RNA-Seq). Groupwise differential methylation regions (DMR), differential hydroxymethylation regions (DhMR), and differentially expressed gene (DEG) regions were identified. Epigenetic biomarkers were screened by integrating DMR, DhMR, and DEGs and confirmed using functional analysis. Results: We identified a genome-wide distinct hydroxymethylation pattern that could be used as an epigenetic biomarker for clearly differentiating colorectal tumor tissues from normal tissues. We identified 59,249 DMRs, 187,172 DhMRs, and 948 DEGs by comparing between tumors and normal tissues. After cross-matching genes containing DMRs or DhMRs with DEGs, we screened seven genes that were aberrantly regulated by DNA methylation in tumors. Furthermore, hypermethylation of the HADHB gene was persistently found to be correlated with downregulation of its transcription in colorectal cancer (CRC). These findings were confirmed in other patients of colorectal cancer. Tumor functional analysis indicated that HADHB reduced cancer cell migration and invasiveness. These findings suggested its possible role as a tumor suppressor gene (TSG). Conclusion: This study reveals the global patterns of methylation and hydroxymethylation in CRC. Several CRC associated genes were screened with multi-omic analysis. Aberrant methylation and hydroxymethylation were found to be in the carcinogenesis of CRC. PMID- 29507651 TI - Honey and Diabetes: The Importance of Natural Simple Sugars in Diet for Preventing and Treating Different Type of Diabetes. AB - Diabetes is a metabolic disorder with multifactorial and heterogeneous etiologies. Two types of diabetes are common among humans: type 1 diabetes that occurs when the immune system attacks and destroys insulin and type 2 diabetes, the most common form, that may be caused by several factors, the most important being lifestyle, but also may be determined by different genes. Honey was used in folk medicine for a long time, but the health benefits were explained in the last decades, when the scientific world was concerned in testing and thus explaining the benefits of honey. Different studies demonstrate the hypoglycemic effect of honey, but the mechanism of this effect remains unclear. This review presents the experimental studies completed in the recent years, which support honey as a novel antidiabetic agent that might be of potential significance for the management of diabetes and its complications and also highlights the potential impacts and future perspectives on the use of honey as an antidiabetic agent. PMID- 29507650 TI - Antioxidant and Cell-Signaling Functions of Hydrogen Sulfide in the Central Nervous System. AB - Hydrogen sulfide (H2S), a toxic gaseous molecule, plays a physiological role in regulating homeostasis and cell signaling. H2S is produced from cysteine by enzymes, such as cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfurtransferase (3MST). These enzymes regulate the overall production of H2S in the body. H2S has a cell-signaling function in the CNS and plays important roles in combating oxidative species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body. H2S is crucial for maintaining balanced amounts of antioxidants to protect the body from oxidative stress, and appropriate amounts of H2S are required to protect the CNS in particular. The body regulates CBS, 3MST, and CSE levels in the CNS, and higher or lower levels of these enzymes cause various neurodegenerative diseases. This review discusses how H2S protects the CNS by acting as an antioxidant that reduces excessive amounts of ROS and RNS. Additionally, H2S regulates cell signaling to combat neuroinflammation and protect against central neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). PMID- 29507652 TI - 36H: A Novel Potent Inhibitor for Antimelanogenesis. AB - N-Hydroxycinnamoylphenalkylamides (36H) exhibited both antioxidation and antityrosinase abilities. The compound was studied for its antioxidative properties, using a 1,1-diphenyl-2-picrylhydrazul- (DPPH-) scavenging test, a ferric ion-reducing antioxidant power assay (FRAP) assessment, and a metal chelating power assay. The results showed that 36H had antioxidative capabilities in the DPPH-scavenging and ferric-reducing power examinations but the chelating power assay did not demonstrate antioxidative capability. 36H was also measured for tyrosinase inhibitory activity applying various species platforms, including in vitro mushroom, B16F10 mouse melanoma, and human melanocyte cells. In terms of in vitro mushroom tyrosinase suppression, 36H restrained the melanogenesis processes. It is assumed that 36H blocked the tyrosinase active site as a competitive inhibitor for mushroom tyrosinase, hence not decreasing the human normal melanocyte cellular viability. A quantitative real-time polymerase chain reaction (qRT-PCR) and western blot discovered that 36H downregulated melanogenesis-related RNA and proteins, including pigment production (MITF, tyrosinase, TRP-1, and TRP-2), melanosome maturation (Rab27a), and melanosome transportation (Myo5a, MLPH and Mreg). Overall, 36H displayed the biofunctions of antioxidation and melanin suppression, so there was a possibility for its application as a food additive or a skin-whitening agent. PMID- 29507655 TI - Immune checkpoint inhibitors in neuroendocrine tumors: A single institution experience with review of literature. AB - : This unique case series and review of literature suggests that immune checkpoint inhibitors may have clinical activity in neuroendocrine tumors. Objective: Summarize advances of immuno-oncology in neuroendocrine tumors with the help of a case series. Design: Case series and review of literature. Intervention or Exposure: The patients were treated with immune checkpoint inhibitors (pembrolizumab or nivolumab). Main Outcomes and Measuress: Life expectancy, quality of life, disease progression. Results: Maximum durable response of 16 months in one of the patients so far. All patients showed improvement in quality of life before disease progression. Two out of four are still on therapy. None of the patients experienced immune checkpoint inhibitor associated side-effects. All patients had failed standard of care therapy prior to the initiation of immune checkpoint inhibitors and were on the verge of hospice. Conclusions: Immune checkpoint inhibitors have revolutionized cancer management and the last 5 years have seen a rapid expansion in the indications for this class of drug. Neuroendocrine tumors, unfortunately, have been slow to catch on to the immuno-oncology, partly due to difficulties in establishing relevant preclinical neuroendocrine tumors models for immune-oncology studies. In this manuscript, we review the current status of immunotherapy in neuroendocrine tumors. PMID- 29507654 TI - Nocturnal Hypoxia Improves Glucose Disposal, Decreases Mitochondrial Efficiency, and Increases Reactive Oxygen Species in the Muscle and Liver of C57BL/6J Mice Independent of Weight Change. AB - Although acute exposure to hypoxia can disrupt metabolism, longer-term exposure may normalize glucose homeostasis or even improve glucose disposal in the presence of obesity. We examined the effects of two-week exposure to room air (Air), continuous 10% oxygen (C10%), and 12 hr nocturnal periods of 10% oxygen (N10%) on glucose disposal, insulin responsiveness, and mitochondrial function in lean and obese C57BL/6J mice. Both C10% and N10% improved glucose disposal relative to Air in lean and obese mice without evidence of an increase in insulin responsiveness; however, only the metabolic improvements with N10% exposure occurred in the absence of confounding effects of weight loss. In lean mice, N10% exposure caused a decreased respiratory control ratio (RCR) and increased reactive oxygen species (ROS) production in the mitochondria of the muscle and liver compared to Air-exposed mice. In the absence of hypoxia, obese mice exhibited a decreased RCR in the muscle and increased ROS production in the liver compared to lean mice; however, any additional effects of hypoxia in the presence of obesity were minimal. Our data suggest that the development of mitochondrial inefficiency may contribute to metabolic adaptions to hypoxia, independent of weight, and metabolic adaptations to adiposity, independent of hypoxia. PMID- 29507656 TI - Estrogen receptor alpha drives mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer. AB - The mTORC1 inhibitor RAD001 (everolimus) is approved for treatment of recurrent/metastatic estrogen receptor (ER)-positive breast cancer in combination with the aromatase inhibitor (AI) exemestane. The benefits of A) continued anti estrogen therapy for anti-estrogen-resistant disease in the context of mTORC1 inhibition, and B) adjuvant everolimus in combination with anti-estrogen therapy for early-stage disease are being tested clinically, but molecular rationale remains unclear. We hypothesized that mTORC1 inhibition activates the IGF 1R/InsR/IRS-1/2 axis in an ER-dependent manner to drive PI3K/AKT and promote cancer cell survival, implicating ER in survival signaling induced by mTORC1 inhibition. Anti-estrogen treatment synergized with RAD001 to inhibit ER+ breast cancer cell growth. Inhibition of ER, IGF-1R/InsR, or IRS-1/2 suppressed AKT activation induced by mTORC1 inhibition. RAD001 primed IGF-1R/InsR for activation, which was enhanced by ER signaling. Post-menopausal patients with early-stage ER+ breast cancer were treated presurgically +/- the AI letrozole. Viable tumor fragments from surgical specimens were treated with RAD001 and/or OSI-906 ex vivo; RAD001 increased AKT activation, which was abrogated by presurgical letrozole. Letrozole decreased IGF-1R and IRS-1/2 tumor levels. These data suggest that ER drives PI3K/AKT activation in response to mTORC1 inhibition, providing molecular rationale for therapeutic combinations of anti-estrogens and mTORC1 inhibitors in endocrine-sensitive disease. PMID- 29507653 TI - The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases. AB - Liver disease, involving a wide range of liver pathologies from fatty liver, hepatitis, and fibrosis to cirrhosis and hepatocellular carcinoma, is a serious health problem worldwide. In recent years, many natural foods and herbs with abundant phytochemicals have been proposed as health supplementation for patients with hepatic disorders. As an important category of phytochemicals, natural polyphenols have attracted increasing attention as potential agents for the prevention and treatment of liver diseases. The striking capacities in remitting oxidative stress, lipid metabolism, insulin resistance, and inflammation put polyphenols in the spotlight for the therapies of liver diseases. It has been reported that many polyphenols from a wide range of foods and herbs exert therapeutic effects on liver injuries via complicated mechanisms. Therefore, it is necessary to have a systematical review to sort out current researches to help better understand the potentials of polyphenols in liver diseases. In this review, we aim to summarize and update the existing evidence of natural polyphenols in the treatment of various liver diseases by in vitro, in vivo, and clinical studies, while special attention is paid to the action mechanisms. PMID- 29507657 TI - ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. AB - A subset of lung cancers is dependent on the anaplastic lymphoma kinase (ALK) oncogene for survival, a mechanism that is exploited by the use of the ALK inhibitor crizotinib. Despite exceptional initial tumor responses to ALK inhibition by crizotinib, durable clinical response is limited and the emergence of drug resistance occurs. Furthermore, intrinsic resistance is frequently observed, where patients fail to respond initially to ALK-inhibitor therapy. These events demonstrate the underlying complexity of a molecularly-defined oncogene-driven cancer and highlights the need to identify compensating survival pathways. Using a loss-of-function whole genome short-hairpin (shRNA) screen, we identified MYCBP as a determinant of response to crizotinib, implicating the MYC signaling axis in resistance to crizotinib-treated ALK+ NSCLC. Further analysis reveals that ALK regulates transcriptional expression of MYC and activates c-MYC transactivation of c-MYC target genes. Inhibition of MYC by RNAi or small molecules sensitizes ALK+ cells to crizotinib. Taken together, our findings demonstrate a dual oncogene mechanism, where ALK positively regulates the MYC signaling axis, providing an additional oncogene target whose inhibition may prevent or overcome resistance. PMID- 29507658 TI - Elevation of autoantibody level against PDCD11 in patients with transient ischemic attack. AB - Background: Disease specific autoantibodies have been detected in the sera of patients with atherosclerosis-related diseases, such as cerebral infarction, cardiovascular disease. In the present study, we aimed to identify novel autoantibodies responsible for transient ischemic attack (TIA), a prodromal condition for cerebral infarction. Methods: To identify candidate antigens, we screened a human aortic endothelial cell cDNA library using sera from 20 patients with TIA. Serum antibody levels were measured using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 2 independent patient/healthy donor (HD) cohorts (n = 192 and n = 906 in the second screening and validation cohort, respectively). Results: First screening identified 3 candidate antigens. Of these, programmed cell death 11 (PDCD11) was determined to be associated with stroke (p < 0.0001), as evidenced from the second screening using AlphaLISA. The validation cohort revealed significantly higher antibody levels against PDCD11 (PDCD11-Ab levels) in patients with TIA than in HDs. Multivariate logistic regression analysis indicated that the predictive value of PDCD11-Ab levels for TIA [Odds ratio (OR): 2.44, 95% confidence interval (CI): 1.33-4.57, p = 0.0039] was not inferior to other known risk factors for ischemic stroke, including age (OR: 4.97, 95% CI: 2.67-9.48, p < 0.0001); hypertension (OR: 3.21, 95% CI: 1.76-5.86, p = 0.0001); and diabetes (OR: 4.31, 95% CI: 1.74-11.2, p = 0.0015). Conclusion: Serum PDCD11-Ab level may serve as a potential biomarker for TIA. PMID- 29507660 TI - FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway. AB - FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells. These cooperative effects were enhanced or inhibited by knock down of mTOR or expression of its activated mutant, respectively. Overexpression of Mcl-1 conferred the resistance on 32D/ITD cells to combined inhibition of the PI3K/Akt pathway and Pim kinases, while the Mcl-1 specific BH3 mimetic A-1210477 conquered the resistance of MV4-11 cells to GDC 0941. Furthermore, overexpression of Pim-1 in 32D/TKD enhanced the mTORC1/Mcl-1 pathway and partially protected it from the PI3K/Akt inhibitors or the FLT3 inhibitor gilteritinib to confer the resistance to PI3K/Akt inhibitors. Finally, AZD1208 and GDC-0941 cooperatively inhibited the mTORC1/Mcl-1 pathway and reduced viable cell numbers of primary AML cells from some FLT3-ITD positive cases. Thus, Pim kinases may protect the mTORC1/4EBP1/Mcl-1 pathway to confer the resistance to the PI3K/Akt inhibitors on FLT3-ITD cells and represent promising therapeutic targets. PMID- 29507659 TI - LRP1 expression in colon cancer predicts clinical outcome. AB - : LRP1 (low-density lipoprotein receptor-related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub within a biomarker network for multi-cancer clinical outcome prediction. As its role in colon cancer has not yet been characterized, we here investigate the relationship between LRP1 and outcome. Materials and Methods: LRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection. Clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series (n = 307). LRP1 methylation, mutation and miR-205 expression were evaluated and compared with LRP1 expression levels. Results: LRP1 mRNA levels were significantly lower in colon adenocarcinoma cells compared with colon mucosa and stromal cells obtained after laser capture microdissection. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and BRAFV600E mutation. Low LRP1 expression correlated with poor clinical outcome, especially in stage IV patients. While LRP1 expression was downregulated by LRP1 mutation, LRP1 promoter was never methylated. Conclusions: Loss of LRP1 expression is associated with worse colon cancer outcomes. Mechanistically, LRP1 mutation modulates LRP1 expression. PMID- 29507661 TI - Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells. AB - Background: Resistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer. Materials and methods: In this study, we developed a novel miR-129 mimic with potent efficacy in eliminating resistant colon cancer stem cells both in vitro and in vivo. We integrated 5-FU into miR-129 by replacing Uracil (U) to generate 5-FU-miR-129 mimics (Mimic-1). Results: Mimic-1 is a strong therapeutic candidate with a number of unique features. Mimic-1 can be delivered to cancer cells without any transfection reagents (e.g. lipids, viral vector, nanoparticles). Mimic-1 is more potent at inhibiting cell proliferation and inducing cell cycle arrest at G1 phase than native miR-129 and the other mimics tested, while retaining target specificity. Mimic-1 prevents colon cancer metastasis in vivo without toxicity. Conclusion: This represents a significant advancement in the development of a nontoxic and highly potent miRNA based cancer therapeutics and establishes a foundation for further developing Mimic-1 as a novel anti-cancer therapeutic for treating colorectal cancer. PMID- 29507662 TI - Teneligliptin enhances the beneficial effects of GLP-1 in endothelial cells exposed to hyperglycemic conditions. AB - High-glucose-induced oxidative stress contributes to cardiovascular endothelial damage in diabetes. Glucagon-like peptide 1 (GLP-1) is beneficial to endothelial cells, but its effects are diminished when cells are continuously exposed to high glucose. Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that prevents oxidative stress, apoptosis and the metabolic memory effect. We explored the potential additive effects of Teneligliptin and GLP-1 in hyperglycemia damaged endothelial cells. Human umbilical vein endothelial cells (HUVECs) were exposed to normal-glucose (5 mmol/L) or high-glucose (HG, 25 mmol/L) for 21 days, or to HG for 14 days followed by normal-glucose for 7 days (HM). These cells were continually treated with Teneligliptin 3.0 MUmol/L, alone or in combination with an acute dose of GLP-1 50 nmol/L. DPP-4 was upregulated under hyperglycemic conditions, but Teneligliptin reduced DPP-4 expression and activity. Simultaneous Teneligliptin and GLP-1 synergistically increased the antioxidant response and reduced ROS levels in HG- and HM-exposed HUVECs. Concurrent treatment also enhanced cell proliferation, reduced apoptotic gene expression and ameliorated endoplasmic reticulum stress in HG- and HM-exposed HUVECs. Thus, long-term Teneligliptin treatment reduced DPP-4 levels and activity in HUVECs exposed to chronic hyperglycemia. Moreover, Teneligliptin enhanced the beneficial effects of GLP-1 on oxidative stress, proliferation, apoptosis and endoplasmic reticulum homeostasis. PMID- 29507663 TI - A comprehensive function analysis of LMO2 in different breast cancer subtypes. AB - Breast cancer is the most common invasive cancer in women worldwide, and can be subdivided into Luminal A, Luminal B, Her2, and Basal subtype (the PAM50 subtyping system). The lmo2 gene was traditionally recognized as a proto-oncogene in hematopoietic system but its functions in breast cancers remained largely unclear. Based on the Cancer Genome Atlas (TCGA) breast cancer dataset, herein we found that the significantly LMO2-correlated genes in normal or malignant samples were enriched in rather divergent cellular pathways, suggesting the function complexity of LMO2 in breast tissues. Moreover, high LMO2 expression level was found to predict a shorter patient survival in Luminal A type whereas a better outcome in Her2 type. Correspondingly, LMO2 also revealed function diversities in different PAM50 subtypes. In Luminal A type, the LMO2 related genes were primarily enriched in cancer-promoting pathways, including VEGF production, stemness, PPAR signal pathways, MAPK cascade and cell cycle regulation. In Her2 type however, the LMO2 related genes lacked the enrichment on most of the generally cancer-related pathways and were particularly enriched in negative regulation of ErbB pathway as well as MAPK cascade, suggesting a potentially anti oncogenic role of LMO2 on this subtype. Taken together, this study drew a comprehensive overview of divergent functions of LMO2 on breast cancers, provided additional evidence for the function complexity of LMO2 in solid tumors and suggested the potential usage of LMO2 as a PAM50 subtype dependent biomarker for breast cancer clinic in the precision medicine era. PMID- 29507664 TI - Let-7c inhibits migration and epithelial-mesenchymal transition in head and neck squamous cell carcinoma by targeting IGF1R and HMGA2. AB - To elucidate the molecular mechanisms underlying the progression of head and neck squamous cell carcinoma (HNSCC), we investigated the function of let-7c as a tumor suppressor. Let-7c expression was significantly down-regulated in HNSCC tumor tissues and cell lines. In vitro and in vivo studies revealed that let-7c negatively regulated HNSCC proliferation, migration and epithelial-mesenchymal transition (EMT). To explore the underlying mechanisms that affect these molecular events achieved by let-7c, we predicted its target genes. We performed luciferase assay and confirmed that insulin-like growth factor 1 receptor (IGF1R) and high mobility group AT-hook 2 (HMGA2) were the direct targets of let-7c. Knocking down of IGF1R and HMGA2 inhibited HNSCC progression, including proliferation, migration and EMT in HNSCC cells. Re-expression of these genes overcame let-7c-mediated inhibition. Taken together, our finding suggests that let-7c inhibits HNSCC progression by targeting IGF1R and HMGA2 and might be a novel target for HNSCC treatment. PMID- 29507665 TI - TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. AB - Matrix metalloproteinases and their natural inhibitors (TIMPs) are important elements in a wide range of oncology settings. Elevated levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) have often been associated with increased tumorigenesis. This has been demonstrated in a number of clinical and experimental models which include breast, gastric, colorectal and non-small cell lung carcinoma (NSCLC). Our earlier studies have identified increased angiogenic activity and aggressive tumor kinetics in TIMP-1 overexpressing H2009 lung adenocarcinoma cells. TIMP-1 overexpression has also been implicated in antiapoptotic responses, inducing a significant upregulation of Bcl-2. These TIMP 1 functions have been shown to be MMP-independent and provide insight into its pleiotropic activities. The current study examines microRNA (miRNA) interactions with this molecule. We have sought to define the relationship between TIMP-1 and miRNA by knocking down TIMP-1 in high TIMP-1 expressing lung adenocarcinoma cell lines. TIMP-1 knockdown resulted in increased expression of miR-125a-5p with a concomitant increase in apoptosis and attenuation of the tumorigenic features of these cells. We have identified TIMP-1 as a bona fide target of miR-125a-5p, and their interaction resulted in an increase in p53 expression. We further corroborated our in vitro data with patient samples, which exhibited an inverse correlation between TIMP-1 and miR-125a-5p expression. Our study lends support to the notion that elevated TIMP-1 levels, which are frequently associated with poor prognosis, cause aberrant modulation of miRNAs. PMID- 29507666 TI - High GSTP1 inhibits cell proliferation by reducing Akt phosphorylation and is associated with a better prognosis in hepatocellular carcinoma. AB - Glutathione S-transferase (GST) family members promote carcinogenesis and cancer progression. We assessed GST pi 1 (GSTP1) mRNA and protein levels in hepatocellular carcinoma (HCC) using genome databases and tissue microarray (TMA) technology. We found that in cancerous tissues, GSTP1 mRNA was down-regulated in genome databases, and immunohistochemical staining of GSTP1 in 237 HCC cases varied from negative to strongly positive. GSTP1 levels correlated negatively with tumor size and serum alpha-fetoprotein (AFP) in HCC patients, and higher GSTP1 levels associated with longer overall survival (OS) and disease-free survival (DFS). We also found that GSTP1 overexpression restrained HepG2 and Huh7 liver cancer cell proliferation in vivo and in vitro. GSTP1 arrested the cell cycle at G1/S by up-regulating p21 and p27 and down-regulating p-Akt. Interrupting GSTP1 gene expression promoted liver cancer cell proliferation and increased the percentage of cells in S phase by decreasing levels of p21 and p27 and increasing p-Akt. These results suggest high GSTP1 levels provide a better prognosis through suppression of tumorigenesis in HCC. PMID- 29507667 TI - Evaluation of SAS1B as a target for antibody-drug conjugate therapy in the treatment of pancreatic cancer. AB - Successful therapeutic options remain elusive for pancreatic cancer. The exquisite sensitivity and specificity of humoral and cellular immunity may provide therapeutic approaches if antigens specific for pancreatic cancer cells can be identified. Here we characterize SAS1B (ovastacin, ASTL, astacin-like), a cancer-oocyte antigen, as an attractive immunotoxin target expressed at the surface of human pancreatic cancer cells, with limited expression among normal tissues. Immunohistochemistry shows that most pancreatic cancers are SAS1Bpos (68%), while normal pancreatic ductal epithelium is SAS1Bneg. Pancreatic cancer cell lines developed from patient-derived xenograft models display SAS1B cell surface localization, in addition to cytoplasmic expression, suggesting utility for SAS1B in multiple immunotherapeutic approaches. When pancreatic cancer cells were treated with an anti-SAS1B antibody-drug conjugate, significant cell death was observed at 0.01-0.1 MUg/mL, while SAS1Bneg human keratinocytes were resistant. Cytotoxicity was correlated with SAS1B cell surface expression; substantial killing was observed for tumors with low steady state SAS1B expression, suggesting a substantial proportion of SAS1Bpos tumors can be targeted in this manner. These results demonstrate SAS1B is a surface target in pancreatic cancer cells capable of binding monoclonal antibodies, internalization, and delivering cytotoxic drug payloads, supporting further development of SAS1B as a novel target for pancreatic cancer. PMID- 29507669 TI - Tension-induced cytokinetic abscission in human fibroblasts. AB - Previous studies have shown that cytokinetic abscission at the end of mitosis is executed by the ESCRT machinery in mammalian cells, and that the process is dependent on adhesion-induced integrin signalling via a FAK-PLK1-CEP55 TSG101/Alix-CHMP4B pathway. The present study identified an alternative abscission mechanism driven by mechanical force. In the absence of integrin signals (non-adherent conditions), cytokinesis in non-transformed human fibroblasts proceeds to CEP55 accumulation at the midbody, but after prolonged time (>3 hours) the major midbody components Aurora B, MKLP1 and CEP55 were no longer detected in the area. Upon adhesion to fibronectin, such cells were able to complete abscission without re-appearance of midbody proteins. Live-cell imaging revealed that re-plating on stiff fibronectin matrix (64 KPa) allowed >95% of the cells to complete abscission within 9 hours while the corresponding number was 40% on soft fibronectin matrix (0.5 KPa). The cells re-plated on poly L-lysine were not able to generate tension and did not divide. Thus, mechanical tension can cause cytokinetic abscission by stretching of the intercellular bridge between the two daughter cells until it eventually ruptures without the involvement of ESCRT complexes. Importantly, regression of the cleavage furrow and formation of bi-nucleated cells did not occur in most of the suspension treated mitotic cells after re-plating on fibronectin. Septin, which stabilizes the membrane associated with the midbody, was found to remain along the ingressed membrane, suggesting that this filament system maintains the membrane bridge although the midbody had dissolved, thereby preventing regression and allowing tension to act on the narrow intercellular bridge. PMID- 29507668 TI - Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer. AB - Upregulation of the H3K4me3 demethylase JARID1B is linked to acquisition of aggressive, stem cell-like features by many cancer types. However, the utility of emerging JARID1 family inhibitors remains uncertain, in part because JARID1B's functions in normal development and malignancy are diverse and highly context specific. In this study, responses of oral squamous cell carcinomas (OSCCs) to catalytic inhibition of JARID1B were assessed using CPI-455, the first tool compound with true JARID1 family selectivity. CPI-455 attenuated clonal sphere and tumor formation by stem-like cells that highly express JARID1B while also depleting the CD44-positive and Aldefluor-high fractions conventionally used to designate OSCC stem cells. Silencing JARID1B abrogated CPI-455's effects on sphere formation, supporting that the drug acted through this isoform. To further delineate CPI-455's capacity to block JARID1B's functions, its biologic effects were compared against those indicated by pathway analysis of the transcriptional profile produced by JARID1B knockdown. Downregulation of multiple gene sets related to stem cell function was consistent with the drug's observed actions. However, strong E-Cadherin upregulation seen upon silencing JARID1B surprisingly could not be reproduced using CPI-455. Expressing a demethylase-inactive mutant of JARID1B demonstrated suppression of this transcript to be demethylase independent, and the capacity of mutant JARID1B but not CPI-455 to modulate invasion provided a functional correlate of this finding. These results show that JARID1B catalytic inhibition effectively targets some stem cell-like features of malignancy but also reveal demethylase-independent actions refractory to inhibition. Future application of JARID1 inhibitors in combinatorial use for cancer therapy may be guided by these findings. PMID- 29507670 TI - The prognostic significance of protein arginine methyltransferase 6 expression in colon cancer. AB - Protein arginine methylation is involved in cellular differentiation and proliferation. Recently, aberrant expression of protein arginine methyltransferases, which are responsible for the methylation reaction, has been reported in various types of cancer. However, there is no clear evidence regarding the prognostic value of abnormal PRMT6 expression in colorectal cancer or the effect of PRMT6 regulation on CRC cells. We investigated the expression patterns of PRMT6 in patients with stage II and III CRC. We detected nuclear expression of PRMT6 in 23.7% of carcinoma samples by immunohistochemistry. Among the clinicopathological parameters, the ratio of poorly differentiated cancer cells was approximately two-fold higher in patients with PRMT6-positive disease than in those with PRMT6-negative disease (p = 0.002). Patients with PRMT6 positive CRC had a shorter disease-free survival than those with PRMT6-negative CRC in both univariate and multivariate analyses (p = 0.018 and p = 0.035, respectively). siRNA-mediated inhibition of PRMT6 expression in CRC cells induced p21WAF1/CIP1 overexpression and suppressed cell growth and colony-forming ability. Concomitantly, apoptosis was induced in PRMT6-suppressed CRC cells. These data suggest that PRMT6 can serve as a biomarker for unfavorable prognosis and as a therapeutic target in CRC. PMID- 29507671 TI - VEGFR2-specific FnCAR effectively redirects the cytotoxic activity of T cells and YT NK cells. AB - T and NK cells armed with chimeric antigen receptors (CAR) are promising tools for the specific elimination of cancer cells. In most CAR designs implemented to date, the recognition of target cells is mediated by single-chain variable fragments (scFvs) derived from murine monoclonal antibodies. This format, however, has a number of limitations, including its relatively large size and potential immunogenicity in humans. In this study, we explored the feasibility of using human fibronectin type III domains (Fn3) as the antigen recognition domain in CARs. Human Fn3 domains have lower predicted immunogenicity compared to mouse derived sequences, and a reduced molecular weight compared to scFvs. We created a functional CAR using a VEGFR2-specific Fn3 module replacing the conventional scFv. The resulting FnCAR specifically potentiates the cytotoxic activity of human T cells and YT NK cells in the presence of VEGFR2-positive targets. These findings demonstrate that Fn3 domains can be used in CARs for antigen recognition. PMID- 29507672 TI - Association of miR-548c-5p, miR-7-5p, miR-210-3p, miR-128-3p with recurrence in systemically untreated breast cancer. AB - Current prognostic markers allocate the majority of lymph node (LN) negative and estrogen receptor (ER) positive breast cancer patients into the high-risk group. Accordingly, most patients receive systemic treatments although approximately 40% of these patients may have been cured by surgery and radiotherapy alone. Two studies identified seven prognostic microRNAs in systemically untreated, LN negative and ER positive breast cancer patients which may allow more precise patient classification. However, six of the seven microRNAs were analyzed in both studies but only found to be prognostic in one study. To validate their prognostic potential, we analyzed microRNA expression in an independent cohort (n = 110) using a pair-matched study design minimizing dependence of classical markers. The expression of hsa-miR-548c-5p was significantly associated with abridged disease-free survival (hazard ratio [HR]:1.96, p = 0.027). Contradicting published results, high hsa-miR-516-3p expression was associated with favorable outcome (HR:0.29, p = 0.0068). The association is probably time-dependent indicating later relapse. Additionally, re-analysis of previously published expression data of two matching cohorts (n = 100, n = 255) supports an association of hsa-miR-128-3p with shortened disease-free survival (HR:2.48, p = 0.0033) and an upregulation of miR-7-5p (p = 0.0038; p = 0.039) and miR-210-3p (p = 0.031) in primary tumors of patients who experienced metastases. Further analysis may verify the prognostic potential of these microRNAs. PMID- 29507673 TI - Analysis of a gene panel for targeted sequencing of colorectal cancer samples. AB - Colorectal cancer (CRC) is a leading cause of death worldwide. Surgical intervention is a successful treatment for stage I patients, whereas other more advanced cases may require adjuvant chemotherapy. The selection of effective adjuvant treatments remains, however, challenging. Accurate patient stratification is necessary for the identification of the subset of patients likely responding to treatment, while sparing others from pernicious treatment. Targeted sequencing approaches may help in this regard, enabling rapid genetic investigation, and at the same time easily applicable in routine diagnosis. We propose a set of guidelines for the identification, including variant calling and filtering, of somatic mutations driving tumorigenesis in the absence of matched healthy tissue. We also discuss the inclusion criteria for the generation of our gene panel. Furthermore, we evaluate the prognostic impact of individual genes, using Cox regression models in the context of overall survival and disease-free survival. These analyses confirmed the role of commonly used biomarkers, and shed light on controversial genes such as CYP2C8. Applying those guidelines, we created a novel gene panel to investigate the onset and progression of CRC in 273 patients. Our comprehensive biomarker set includes 266 genes that may play a role in the progression through the different stages of the disease. Tracing the developmental state of the tumour, and its resistances, is instrumental in patient stratification and reliable decision making in precision clinical practice. PMID- 29507674 TI - Comparison of Immuno-PET of CD138 and PET imaging with 64CuCl2 and 18F-FDG in a preclinical syngeneic model of multiple myeloma. AB - Purpose: Although recent data from the literature suggest that PET imaging with [18]-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker in many laboratories for the identification and purification of myeloma cells, and could be used in phenotype tumor imaging. In this study, we evaluated a 64Cu-labeled anti-CD138 murine antibody (64Cu-TE2A 9E7.4) and a metabolic tracer (64CuCl2) for PET imaging in a MM syngeneic mouse model. Experimental Design and Results: 64Cu-TE2A-9E7.4 antibody and 64CuCl2 were evaluated via PET imaging and biodistribution studies in C57BL / KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions. These results were compared to 18F-FDG-PET imaging. Autoradiography and histology of representative tumors were secondly conducted. In biodistribution and PET studies, 64Cu-TE2A 9E7.4 displayed good tumor uptake of subcutaneous and intra-medullary lesions, greater than that demonstrated with 18F-FDG-PET. In control experiments, only low level, non-specific uptake of 64Cu-labeled isotype IgG was observed in tumors. Similarly, low activity concentrations of 64CuCl2 were accumulated in MM lesions. Histopathologic analysis of the immuno-PET-positive lesions revealed the presence of plasma cell infiltrates within the bone marrow. Conclusions: 64Cu-labeled anti CD138 antibody can detect subcutaneous MM tumors and bone marrow lesions with high sensitivity, outperforming 18F-FDG-PET and 64CuCl2 in this preclinical model. These data support 64Cu-anti-CD138 antibody as a specific and promising new imaging radiopharmaceutical agent in MM. PMID- 29507675 TI - The effects of taxanes, vorinostat and doxorubicin on growth and proliferation of Echinococcus multilocularis metacestodes assessed with magnetic resonance imaging and simultaneous positron emission tomography. AB - Cytostatic drugs used in cancer therapy were evaluated for their capacity to inhibit Echinococcus multilocularis metacestode growth and proliferation. Metacestode tissues were exposed in vitro to docetaxel, doxorubicin, navelbine, paclitaxel, and vorinostat for 1 week, then incubated in drug-free culture, and thereafter metacestodes were injected into the peritoneum of Meriones unguiculatus. Magnetic resonance imaging (MRI) and simultaneous positron emission tomography (PET) were applied to monitor in vivo growth of drug-exposed E. multilocularis in Meriones. At 3 month p.i., docetaxel (at 10 MUM, 5 MUM and 2 MUM) inhibited in vivo growth and proliferation of E. multilocularis, and at 5 months p.i., only in the 2 MUM docetaxel exposure group 0.3 cm 3 of parasite tissue was found. With paclitaxel and navelbine the in vivo growth of metacestodes was suppressed until 3 months p.i., thereafter, parasite tissues enlarged up to 3 cm 3 in both groups. E. multilocularis tissues of more than 10 g developed in Meriones injected with metacestodes which were previously exposed in vitro to doxorubicin, navelbine, paclitaxel or vorinostat. In Meriones infected with metacestodes previously exposed to docetaxel, the in vivo grown parasite tissues weighted 0.2 g. In vitro cultured E. multilocularis metacestodes exposed to docetaxel did not produce vesicles until 7 weeks post drug exposure, while metacestodes exposed to doxorubicin, navelbine and vorinostat proliferated continuously. In summary, docetaxel, and less efficaciously paclitaxel, inhibited in vivo and in vitro parasite growth and proliferation, and these observations suggest further experimental studies with selected drug combinations which may translate into new treatment options against alveolar echinococcosis. PMID- 29507676 TI - Dimethyl fumarate is highly cytotoxic in KRAS mutated cancer cells but spares non tumorigenic cells. AB - KRAS mutation, one of the most common molecular alterations observed in adult carcinomas, was reported to activate the anti-oxidant program driven by the transcription factor NRF2 (Nuclear factor-erythroid 2-related factor 2). We previously observed that the antitumoral effect of Dimethyl fumarate (DMF) is dependent of NRF2 pathway inhibition. We used in vitro methods to examine the effect of DMF on cell death and the activation of the NRF2/DJ-1 antioxidant pathway. We report here that DMF is preferentially cytotoxic against KRAS mutated cancer cells. This effect was observed in patient-derived cancer cell lines harbouring a G12V KRAS mutation, compared with cell lines without such a mutation. In addition, KRAS*G12V over-expression in the human Caco-2 colon cancer cell line significantly promoted DMF-induced cell death, as well as DMF-induced- reactive oxygen species (ROS) formation and -glutathione (GSH) depletion. Moreover, in contrast to malignant cells, our data confirms that the same concentration of DMF has no significant cytotoxic effects on non-tumorigenic human ARPE-19 retinal epithelial, murine 3T3 fibroblasts and primary mice bone marrow cells; but is rather associated with NRF2 activation, decreased ROS and increased GSH levels. Furthermore, DJ-1 down-regulation experiments showed that this protein does not play a protective role against NRF2 in non-tumorigenic cells, as it does in malignant ones. This, interestingly, could be at the root of the differential effect of DMF observed between malignant and non-tumorigenic cells. Our results suggest for the first time that the dependence on NRF2 observed in mutated KRAS malignant cells makes them more sensitive to the cytotoxic effect of DMF, which thus opens up new prospects for the therapeutic applications of DMF. PMID- 29507677 TI - New localization and function of calpain-2 in nucleoli of colorectal cancer cells in ribosomal biogenesis: effect of KRAS status. AB - Calpain-2 belongs to a family of pleiotropic Cys-proteases with modulatory rather than degradative functions. Calpain (CAPN) overexpression has been controversially correlated with poor prognosis in several cancer types, including colorectal carcinoma (CRC). However, the mechanisms of substrate-recognition, calpain-2 regulation/deregulation and specific functions in CRC remain elusive. Herein, calpain subcellular distribution was studied as a key event for substrate recognition and consequently, for calpain-mediated function. We describe a new localization for calpain-2 in the nucleoli of CRC cells. Calpain-2 nucleolar distribution resulted dependent on its enzymatic activity and on the mutational status of KRAS. In KRASWT/- cells serum-starvation induced CAPN2 expression, nucleolar accumulation and increased binding to the rDNA-core promoter and intergenic spacer (IGS), concomitant with a reduction in pre-rRNA levels. Depletion of calpain-2 by specific siRNA prevented pre-rRNA down-regulation after serum removal. Conversely, ribosomal biogenesis proceeded in the absence of serum in unresponsive KRASG13D/- cells whose CAPN2 expression, nucleolar localization and rDNA-occupancy remained unchanged during the time-course of serum starvation. We propose here that nucleolar calpain-2 might be a KRAS-dependent sensor to repress ribosomal biogenesis in growth limiting conditions. Under constitutive activation of the pathway commonly found in CRC, calpain-2 is deregulated and tumor cells become insensitive to the extracellular microenvironment. PMID- 29507678 TI - Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients. AB - The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1). The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life. PMID- 29507680 TI - Endoscopic prediction model for differentiating upper submucosal invasion (< 200 MUm) and beyond in superficial esophageal squamous cell carcinoma. AB - Esophageal endoscopic submucosal dissection (ESD) can be attempted in superficial esophageal squamous cell carcinoma (SESCC) invading the upper submucosal layer (SM1: invasion < 200 MUm). This study aimed to determine endoscopic predictive features associated with beyond SM1 invasion in SESCC and establish a predictive model using the identified features. This study retrospectively analyzed 203 esophageal ESD for SESCC. Endoscopic images were reviewed by two endoscopists. Tumors were evaluated for main shape, sizes, and surface characteristics. The association between each endoscopic feature and beyond SM1 invasion was evaluated. Using the significant endoscopic features in multivariate analysis, a predictive model for beyond SM1 invasion in SESCC was established. Among 203 SESCCs, 40 (19.7%) invaded beyond SM1. Multivariate analysis revealed that surface nodularity [odds ratio (OR) 41.340, 95% confidence interval (CI) 8.492 201.252, p < 0.001], surface granularity (OR 18.682, 95% CI 4.818-72.440, p < 0.001), surface unevenness, (OR 4.107, 95% CI 1.160-14.543, p = 0.029), deep depression (OR 27.490, 95% CI 2.897-260.853, p = 0.004), and thick notch (OR 41.701, 95% CI 6.646-261.672, p < 0.001) were independently associated with beyond SM1 invasion. An established model showed an area under the curve of 0.921 with 95% CI 0.881-0.960. The best cut-off value showed the following: sensitivity, 0.85; specificity, 0.83; positive predictive value, 0.55; and negative predictive value, 0.96. In conclusion, endoscopic features can predict beyond SM1 invasion in SESCC. Our prediction model is potentially useful for screening ESD candidates in SESCC. PMID- 29507679 TI - Differentially expressed microRNAs in lung adenocarcinoma invert effects of copy number aberrations of prognostic genes. AB - In many cancers, significantly down- or upregulated genes are found within chromosomal regions with DNA copy number alteration opposite to the expression changes. Generally, this paradox has been overlooked as noise, but can potentially be a consequence of interference of epigenetic regulatory mechanisms, including microRNA-mediated control of mRNA levels. To explore potential associations between microRNAs and paradoxes in non-small-cell lung cancer (NSCLC) we curated and analyzed lung adenocarcinoma (LUAD) data, comprising gene expressions, copy number aberrations (CNAs) and microRNA expressions. We integrated data from 1,062 tumor samples and 241 normal lung samples, including newly-generated array comparative genomic hybridization (aCGH) data from 63 LUAD samples. We identified 85 "paradoxical" genes whose differential expression consistently contrasted with aberrations of their copy numbers. Paradoxical status of 70 out of 85 genes was validated on sample-wise basis using The Cancer Genome Atlas (TCGA) LUAD data. Of these, 41 genes are prognostic and form a clinically relevant signature, which we validated on three independent datasets. By meta-analysis of results from 9 LUAD microRNA expression studies we identified 24 consistently-deregulated microRNAs. Using TCGA-LUAD data we showed that deregulation of 19 of these microRNAs explains differential expression of the paradoxical genes. Our results show that deregulation of paradoxical genes is crucial in LUAD and their expression pattern is maintained epigenetically, defying gene copy number status. PMID- 29507681 TI - Diagnostic value of the 2011 International Federation for Cervical Pathology and Colposcopy Terminology in predicting cervical lesions. AB - Objective: To evaluate the diagnostic accuracy of the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) colposcopic terminology. Methods: The clinicopathological data of 2262 patients who underwent colposcopy from September 2012 to September 2016 were reviewed. The colposcopic findings, colposcopic impression, and cervical histopathology of the patients were analyzed. Correlations between variables were evaluated using cervical histopathology as the gold standard. Results: Colposcopic diagnosis matched biopsy histopathology in 1482 patients (65.5%), and the weighted kappa strength of agreement was 0.480 (P<0.01). Colposcopic diagnoses more often underestimated (22.1%) than overestimated (12.3%) cervical pathology. There was no significant difference between the colposcopic diagnosis and cervical pathology agreement among the various grades of lesions (P=0.282). The sensitivity, specificity for detecting high-grade lesions/carcinoma was 71.6% and 98.0%, respectively. Multivariate analysis showed that major changes were independent factors in predicting high-grade lesion/carcinoma, whereas transformation zone, lesion size, and non-stained were not statistically related to high-grade lesion/carcinoma. Conclusions: The 2011 IFCPC terminology can improve the diagnostic accuracy for all lesion severities. The categorization of major changes and minor changes is appropriate. However, colposcopic diagnosis remains unsatisfactory. Poor reproducibility of type 2 transformation zone and the significance of leukoplakia require further study. PMID- 29507683 TI - Association of TERT polymorphisms with chronic hepatitis B in a Chinese Han population. AB - In this study, we investigated the association between the polymorphisms of telomerase reverse transcriptase (TERT) gene and the risk of chronic hepatitis B (CHB) in a Chinese Han population. Four single nucleotide polymorphisms (SNPs) in TERT (rs10069690, rs2242652, rs2853677 and rs2853676) were genotyped from 224 CHB patients and 300 healthy controls using the Sequenom Mass-ARRAY platform. We used genetic model, haplotype analyses, chi-square test, logistic regression analysis to evaluate the association between SNPs and CHB risk. The relative risk was estimated by odd ratios (ORs) and 95% confidence intervals (CIs). We found that rs10069690 was significantly associated with an increased CHB risk in the dominant model (adjusted OR = 1.70, 95% CI: 1.06-2.71, P = 0.031) and additive model (adjusted OR = 1.62, 95% CI: 1.09-2.41, P = 0.018). The haplotype "TA" (rs10069690 and rs2242652) was found to be associated with an increased risk of CHB (adjusted OR = 1.58, 95% CI: 1.05-2.38, P = 0.027). Our results suggested potential genetic contributes for TERT in CHB development in a Chinese Han population. Future functional and association studies with larger sample sizes are required to confirm these findings. PMID- 29507682 TI - Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland. AB - Despite the well-recognized role of loss-of-function mutations of the aryl hydrocarbon receptor interacting protein gene (AIP) predisposing to pituitary adenomas, the pituitary-specific function of this tumor suppressor remains an enigma. To determine the repertoire of interacting partners for the AIP protein in somatotroph cells, wild-type and variant AIP proteins were used for pull down/quantitative mass spectrometry experiments against lysates of rat somatotropinoma-derived cells; relevant findings were validated by co immunoprecipitation and co-localization. Global gene expression was studied in AIP mutation positive and negative pituitary adenomas via RNA microarrays. Direct interaction with AIP was confirmed for three known and six novel partner proteins. Novel interactions with HSPA5 and HSPA9, together with known interactions with HSP90AA1, HSP90AB1 and HSPA8, indicate that the function/stability of multiple chaperone client proteins could be perturbed by a deficient AIP co-chaperone function. Interactions with TUBB, TUBB2A, NME1 and SOD1 were also identified. The AIP variants p.R304* and p.R304Q showed impaired interactions with HSPA8, HSP90AB1, NME1 and SOD1; p.R304* also displayed reduced binding to TUBB and TUBB2A, and AIP-mutated tumors showed reduced TUBB2A expression. Our findings suggest that cytoskeletal organization, cell motility/adhesion, as well as oxidative stress responses, are functions that are likely to be involved in the tumor suppressor activity of AIP. PMID- 29507684 TI - Tumor microenvironment promotes prostate cancer cell dissemination via the Akt/mTOR pathway. AB - Metastasis causes high mortality in various malignancies, including prostate cancer (PCa). Accumulating data has suggested that cancer cells spread from the primary tumor to distant sites at early stage, which is characterized by disseminated tumor cells (DTCs). However, lack of direct evidence of partial localized PCa cells occurring epithelial-to-mesenchymal transition (EMT) and disseminating to distant sites (e.g bone marrow). In this study, we used luciferase labeled PCa cells to establish an EMT mouse model and to detect whether DTCs spread into the bone marrow. We observed tumor cells existing in mouse bone marrow when tumor grew subcutaneously at palpable stage. Studies also showed that ex vivo tumor cells exhibited increased proliferative, migratory, invasive and angiogenesis abilities. When compared ex vivo tumor cells with parental cells, hallmarks of EMT including E-cadherin, Vimentin, Snail, and ZO-1 were altered significantly. Specifically, the ex vivo tumor cells showed more mesenchymal properties. Angiogenesis markers, including VEGFR2, VEGFR3, MCP-3, I TAC, I309, uPAR and GROalpha, were also increased in the ex vivo tumor cells. Intriguingly, MCP-1 expression was dramatically increased in those cells. Mechanistic analyses indicated that AP1 mediates PCa EMT and the appearance of DTCs via the Akt/mTOR pathway. This study may provide potential therapeutic targets and diagnostic biomarkers of PCa progression and metastasis. PMID- 29507685 TI - NUMB and NUMBL differences in gene regulation. AB - NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network. We have also found differences in gene expression due to NUMB or NUMBL downregulation. These differences in gene regulation extend to pathways, such as WNT or Hedgehog. In addition to these differences, the downregulation of either gene triggers a cancer stem cell-like related phenotype. These results show the importance of both genes as an intersection with different effects over cancer stem cell signaling pathways. PMID- 29507686 TI - Mitochondrial oxidative stress activates COX-2/mPGES-1/PGE2 cascade induced by albumin in renal proximal tubular cells. AB - COX-2/mPGES-1/PGE2 cascade is of importance in the pathogenesis of kidney injury. Meanwhile, recent studies documented a detrimental role of mitochondrial oxidative stress in kidney diseases. The present study was undertaken to investigate the role of mitochondrial oxidative stress in albumin-induced activation of COX-2/mPGES-1/PGE2 cascade in renal proximal tubular cells. Following albumin overload in mice, we observed a significant increase of oxidative stress and mitochondrial abnormality determined by transmission electron microscope, which was attenuated by the administration of MnTBAP, a mitochondrial SOD2 mimic. More interestingly, albumin overload-induced upregulation of COX-2 and mPGES-1 at mRNA and protein levels was largely abolished by MnTBAP treatment in mice. Meanwhile, urinary PGE2 excretion was also blocked by MnTBAP treatment. Furthermore, mouse proximal tubule epithelial cells (mPTCs) were treated with albumin. Similarly, COX-2/mPGES-1/PGE2 cascade was significantly activated by albumin in dose- and time-dependent manners, which was abolished by MnTBAP treatment in parallel with a blockade of oxidative stress. Collectively, the findings from current study demonstrated that mitochondrial oxidative stress could activate COX-2/mPGES-1/PGE2 cascade in proximal tubular cells under the proteinuria condition. Mitochondrial oxidative stress/COX-2/mPGES 1/PGE2 could serve as the important targets for the treatment of proteinuria associated kidney injury. PMID- 29507687 TI - An integrative transcriptomic approach to identify depot differences in genes and microRNAs in adipose tissues from high fat fed mice. AB - Obesity contributes to metabolic disorders such as diabetes and cardiovascular disease. Characterization of differences between the main adipose tissue depots, white (WAT) [including subcutaneous (SAT) and visceral adipose tissue (VAT)] and brown adipose tissue (BAT) helps to identify their roles in obesity. Thus, we studied depot-specific differences in whole transcriptome and miRNA profiles of SAT, VAT and BAT from high fat diet (HFD/45% of calories from fat) fed mice using RNA sequencing and small RNA-Seq. Using quantitative real-time polymerase chain reaction, we validated depot-specific differences in endoplasmic reticulum (ER) stress related genes and miRNAs using mice fed a HFD vs. low fat diet (LFD/10% of calories from fat). According to the transcriptomic analysis, lipogenesis, adipogenesis, inflammation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were higher in VAT compared to BAT, whereas energy expenditure, fatty acid oxidation and oxidative phosphorylation were higher in BAT than in VAT of the HFD fed mice. In contrast to BAT, ER stress marker genes were significantly upregulated in VAT of HFD fed mice than the LFD fed mice. For the first time, we report depot specific differences in ER stress related miRNAs including; downregulation of miR-125b-5p, upregulation miR-143-3p, and miR-222-3p in VAT following HFD and upregulation of miR-30c-2-3p only in BAT following a HFD in mice than the LFD mice. In conclusion, HFD differentially regulates miRNAs and genes in different adipose depots with significant induction of genes related to lipogenesis, adipogenesis, inflammation, ER stress, and UPR in WAT compared to BAT. PMID- 29507688 TI - Prognostic implications of HER2 heterogeneity in gastric cancer. AB - The prognostic implications of human epidermal growth receptor 2 (HER2) heterogeneity in gastric cancer (GC) are not well established. Therefore, the aim of the present study was to determine to the effect of HER2 status on the prognosis of GC patients. We retrieved data on 248 pathologically-confirmed, consecutive patients with primary adenocarcinoma of the stomach or gastro esophageal junction who underwent surgical resection at Kurume University Medical Center between July 2000 and December 2012. HER2 status was classified as HER2 positive or negative and HER2 heterogeneity or homogeneity. The endpoint was overall survival (OS), which was compared using the generalized Wilcoxon test. HER2 status was positive in 36 patients (14.5%) and negative in 212 patients (85.5%). Among the 36 HER2 positive patients, 25 patients (69.4%) had HER2 heterogeneity and the remaining 11 patients (30.6%) had HER2 homogeneity. Among the 141 patients with stage III or IV disease, the prognosis of the HER2 homogeneity group was significantly worse than that of the HER2 heterogeneity group (p = 0.019; median OS 193 and 831 days, respectively). The prognosis was not significantly different between the HER2 positive group and the HER2 negative group (p = 0.84; median OS 552 and 556 days, respectively). The present study was conducted with small samples, however, the results of the study suggest that HER2 homogeneity but not HER2 positivity may represent a prognostic indicator in GC. PMID- 29507689 TI - Single cell profiling of phospho-protein levels in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) has a high incidence and a steeply growing prevalence in the Western world. The heterogeneity of the disease necessitates individual mapping of biology and predicted drug response in each patient as basis for administration of tailored treatments. Cell signaling aberrations may serve as biological indicators for suitable therapy. By applying phospho-specific flow cytometry, we mapped basal and induced phosphorylation levels of 20 phospho epitopes on proteins relevant to B-cell signaling in B cells from 22 CLL patients and 25 normal controls. The signaling response of the cytostatic drugs fludarabine, doxorubicin and vincristine was also investigated. CLL cells exerted similar or lower basal phosphorylation levels compared to normal B cells, with the exception of STAT3 (pY705) which was increased. Interestingly, STAT3 inhibitors normalized the STAT3 (pY705) level and reduced cell viability. Vincristine treatment significantly modulated phosphorylation levels in CLL cells, while no effect was observed in controls or after fludarabine or doxorubicin treatment. After BCR stimulation, CLL cells showed a tendency towards impaired phosphorylation levels, significant for several of the analyzed proteins. However, the level of Akt (pS473) was more potently induced in IgHV unmutated CLL (UM-CLL) patient samples and was significantly higher than in M-CLL samples. Importantly, the PI3Kdelta inhibitor idelalisib potently reversed the effect of anti-IgM on Akt (pS473). Thus, signaling aberrations could be identified by phosphoflow cytometry and aberrant signaling could be normalized by small molecule drugs. This approach can identify relevant drug targets as well as drug effects in the individual patient. PMID- 29507691 TI - Locally advanced cervical cancer with bladder invasion: clinical outcomes and predictive factors for vesicovaginal fistulae. AB - Objective: We report outcomes of cervical cancer patients with bladder invasion (CCBI) at diagnosis, with focus on the incidence and predictive factors of vesicovaginal fistula (VVF). Results: Seventy-one patients were identified. Twenty-one (30%) had para-aortic nodal involvement. Eight had VVF at diagnosis. With a mean follow-up time of 34.2 months (range: 1.9 months-14.8 years), among 63 patients without VVF at diagnosis, 15 (24%) developed VVF. A VVF occurred in 19% of patients without local relapses (9/48) and 40% of patients with local relapse (6/15). Two-year overall survival (OS), disease-free survival (DFS) and local control rates were 56.4% (95% CI: 44.1-67.9%), 39.1% (95% CI: 28.1-51.4%) and 63.8% (95% CI: 50.4-75.4%), respectively. Para-aortic nodes were associated with poorer OS (adjusted HR = 3.78, P-value = 0.001). In multivariate analysis, anterior tumor necrosis on baseline MRI was associated with VVF formation (63% vs 0% at 1 year, adjusted-HR = 34.13, 95% CI: 4.07-286, P-value = 0.001), as well as the height of the bladder wall involvement of >26 mm (adjusted-HR = 5.08, 95% CI: 1.38-18.64, P-value = 0.014). Conclusions: A curative intent strategy including brachytherapy is feasible in patients with CCBI, with VVF occurrence in 24% of the patients. MRI patterns help predicting VVF occurrence. Methods: Patients with locally advanced CCBI treated with (chemo)radiation +/- brachytherapy in our institute from 1989 to 2015 were analyzed. Reviews of baseline magnetic resonance imaging (MRI) scans were carried out blind to clinical data, retrieving potential parameters correlated to VVF formation (including necrosis and tumor volume). PMID- 29507690 TI - Chronic hyperuricemia impairs blood flow recovery in the ischemic hindlimb through suppression of endothelial progenitor cells. AB - Objective: Chronic hyperuricemia is associated with cardiovascular disease, but its impact on endothelial progenitor cells (EPC) and ischemia-induced neovascularization remains unclear. Herein we investigated whether chronic hyperuricemia could impede blood flow recovery in response to tissue ischemia by suppression of EPC. Methods: Human EPC were isolated and cultured in a high-level uric acid medium for functional testing. Cell proliferation, nitric oxide (NO) production and apoptosis assay were examined. A chronic hyperuricemia mouse model was established by potassium oxonate treatment and/or a high-level uric acid diet to evaluate the actions of chronic hyperuricemia on ischemia-induced blood flow recovery. After 4 weeks of drug treatment, hindlimb ischemia surgery was performed in the control and hyperuricemia mice. Blood flow recovery was followed up every week before and after ischemic surgery using a laser Doppler Perfusion Imager System. The circulating EPC number in the peripheral blood was determined by flow cytometry (Sca-1+/Flk-1+). Results: Incubation with a high-level uric acid medium (10 mg/dL) significantly suppressed EPC proliferation, reduced NO production, and lessened phosphorylation of Akt and eNOS. Moreover, EPC treated with high-level uric acid increased reactive oxygen species production, promoted cellular apoptosis and senescence, and also inhibited EPC tube formation. Four weeks after hindlimb ischemia surgery, the chronic hyperuricemia mice had significantly reduced tissue reperfusion, EPC mobilization, and impaired neovascularization in the ischemic hindlimbs compared with the control mice. Conclusions: Chronic hyperuricemia impaired blood flow recovery and EPC mobilization in response to tissue ischemia, and these effects could have occurred through suppression of EPC. PMID- 29507692 TI - Pazopanib radio-sensitization of human sarcoma tumors. AB - Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation. Angiogenic factors repressed this activity while a monoclonal antibody targeting VEGF, de-repressed ASMase activity and radiosensitized tumor endothelium when delivered immediately prior to SDRT. In this study, we tested the effect of SDRT in combination with the short-acting anti-angiogenic agent, Pazopanib (anti-VEGFR-1/2/3, PDGF alpha/beta and c-kit), in two xenograft models of human sarcoma. Pre-treatment with a single dose of Pazopanib increased SDRT-induced ASMase activity and endothelial dysfunction in vitro and in vivo, enhancing SDRT tumor cure, and exhibiting critical dependence on timing relative to SDRT exposure, suggesting a mechanism of action identical to that demonstrated for anti-VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to shift the response towards tumor cure and could therefore have a significant impact on clinical trial development in combination with SDRT for sarcoma cancer patients. PMID- 29507693 TI - Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma. AB - Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies. PMID- 29507694 TI - Notoginsenoside R1 ameliorates diabetic encephalopathy by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation. AB - Numerous researches supported that oxidative stress and inflammation play important roles in the development of diabetic encephalopathy (DEP). Notoginsenoside R1 (NGR1), one major component of Panax notoginseng, is believed to have anti-oxidative, anti-inflammatory and neuroprotective properties. However, its neuroprotective effects against DEP and underlying mechanisms are still unknown. In this study, db/db mice as well as high-glucose (HG)-treated HT22 hippocampal neurons were used as in vivo and in vitro models to estimate NGR1 neuroprotection. NGR1 administration for 10 weeks could ameliorate cognitive dysfunction, depression-like behaviors, insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation in db/db mice. NGR1 markedly decreased the oxidative stress induced by hyperglycemia in hippocampal neurons. NGR1 significantly activated the protein kinase B (Akt)/nuclear factor-erythroid 2 related factor2 (Nrf2) pathway, and inhibited NLRP3 inflammasome activation in hippocampal neurons, which might be essential for the neuroprotective effects of NGR1. Further supporting these results, we observed that pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 abolished NGR1-mediated neuroprotective effects against oxidative stress and NLRP3 inflammasome activation in HG-treated HT22 hippocampal neurons. In conclusion, the present study demonstrates the neuroprotective effects of NGR1 on DEP by activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome activation. This study also provides a novel strategy for the application of NGR1 as a therapeutic agent for patients with DEP. PMID- 29507695 TI - Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model. AB - DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone resorbing osteoclasts by downregulating NFATc1. In the mouse model, Chk1 inhibitor reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Analysis of RNA-seq expression data indicated that the observed effects were mediated through the regulation of eukaryotic translation initiation factor 2 alpha, stress to the endoplasmic reticulum, S100 proteins, and bone remodeling-linked genes. Our findings suggest that targeting Chk1 signaling without adding DNA damaging agents may protect bone from degradation while suppressing tumor growth and migration. PMID- 29507696 TI - miR-758-3p: a blood-based biomarker that's influence on the expression of CERP/ABCA1 may contribute to the progression of obesity to metabolic syndrome. AB - Due to increasing prevalence of obesity, a simple method or methods for the diagnosis of metabolic syndrome are urgently required to reduce the risk of associated cardiovascular disease, diabetes and cancer. This study aimed to identify a miRNA biomarker that may distinguish metabolic syndrome from obesity and to investigate if such a miRNA may have functional relevance for metabolic syndrome. 52 adults with clinical obesity (n=26) or metabolic syndrome (n=26) were recruited. Plasma specimens were procured from all and were randomly designated to discovery and validation cohorts. miRNA discovery profiling was performed, using array technology, on plasma RNA. Validation was performed by quantitative polymerase chain reaction. The functional effect of miR-758-3p on its predicted target, cholesterol efflux regulatory protein/ATP-binding cassette transporter, was investigated using HepG2 liver cells. Custom miRNA profiling of 25 miRNAs in the discovery cohort found miR-758-3p to be detected in the obese cohort but undetected in the metabolic syndrome cohort. miR-758-3p was subsequently validated as a potential biomarker for metabolic syndrome by quantitative polymerase chain reaction. Bioinformatics analysis identified cholesterol efflux regulatory protein/ATP-binding cassette transporter as miR-758 3p's predicted target. Specifically, mimicking miR-758-3p in HepG2 cells suppressed cholesterol efflux regulatory protein/ATP-binding cassette transporter protein expression; conversely, inhibiting miR-758-3p increased cholesterol efflux regulatory protein/ATP-binding cassette transporter protein expression. miR-758-3p holds potential as a blood-based biomarker for distinguishing progression from obesity to metabolic syndrome and as a driver in controlling cholesterol efflux regulatory protein/ATP-binding cassette transporter expression, indicating it potential role in cholesterol control in metabolic syndrome. PMID- 29507697 TI - Differential scanning calorimetry of plasma in glioblastoma: toward a new prognostic / monitoring tool. AB - Glioblastoma is the most frequent and aggressive primary brain tumor in adults. Recently, a growing number of studies have shown that denaturation profile of plasma samples obtained by differential scanning calorimetry (DSC) can represent a signature of a disease. In this study, we analyzed for the first time the DSC denaturation profiles of the plasma from patients with recurrent glioblastoma (n=17). Comparison to the one of healthy individuals (n=10) and to already described profiles in others cancer showed clear differences suggesting that this DSC profile may constitute a signature of glioblastoma. Parameters extracted from these profiles were used for cluster analysis which revealed the existence of glioblastoma profile subgroups which correlated with prognostic factors. Moreover, we showed that the presence of circulating bevacizumab and carmustine did not alter this calorimetric signature of the disease, indicating that an evolution of the profile could be followed without being masked by ongoing systemic treatment. Thus, our results constitute a very promising proof of principle that a specific calorimetric profile could be detected in the plasma of glioblastoma patients. Moreover, we believe that our findings point to a potential easy-to-use non-invasive monitoring tool for glioblastoma patients. PMID- 29507698 TI - SuperQuant-assisted comparative proteome analysis of glioblastoma subpopulations allows for identification of potential novel therapeutic targets and cell markers. AB - Glioblastoma (GBM) is a highly aggressive brain cancer with poor prognosis and low survival rate. Invasive cancer stem-like cells (CSCs) are responsible for tumor recurrence because they escape current treatments. Our main goal was to study the proteome of three GBM subpopulations to identify key molecules behind GBM cell phenotypes and potential cell markers for migrating cells. We used SuperQuant-an enhanced quantitative proteome approach-to increase proteome coverage. We found 148 proteins differentially regulated in migrating CSCs and 199 proteins differentially regulated in differentiated cells. We used Ingenuity Pathway Analysis (IPA) to predict upstream regulators, downstream effects and canonical pathways associated with regulated proteins. IPA analysis predicted activation of integrin-linked kinase (ILK) signaling, actin cytoskeleton signaling, and lysine demethylase 5B (KDM5B) in CSC migration. Moreover, our data suggested that microRNA-122 (miR-122) is a potential upstream regulator of GBM phenotypes as miR-122 activation was predicted for differentiated cells while its inhibition was predicted for migrating CSCs. Finally, we validated transferrin (TF) and procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) as potential markers for migrating cells. PMID- 29507699 TI - Grade progression in urothelial carcinoma can occur with high or low mutational homology: a first-step toward tumor-specific care in initial low-grade bladder cancer. AB - Purpose: Low-grade (LG) urothelial carcinomas of the bladder (UCB) are common malignancies that are costly to surveil and rarely progress to life threatening, high-grade (HG) malignancies. It is unknown if the progression of LG to HG is a result of second primary tumors or transformation of existing LG tumors. We examined tumor genetics in patients with grade progression in urothelial carcinoma and compared to patients with no progression. Results: Five patients were identified with progression. Median time from initial LG diagnosis to HG diagnosis in those experiencing progression was 19 months. Progression with both high and low mutational homology was identified. Gene alterations associated with tumor grade progression in initial low grade tumors include FBN3, CIT and HECTD4. Materials and Methods: An institutional cancer database at a tertiary referral center in the United States identified patients who progressed from LG to HG UCB. Histologic re-review was performed by a genitourinary pathologist. Whole exome sequencing with correction for germline mutations by buffy coat subtraction was performed. Mutations were assessed between LG tumors and subsequent same-patient HG tumors and for LG patients who did not progress. Individual genes were assessed as potential predictors of risk for progression. Conclusions: Tumor grade progression occurred with both high mutational homology and low mutational homology, which may represent both true tumor progression and de-novo growth. Validation of the identified tumor genes that appeared associated with progression may provide a clinically valuable tool to providers managing patients with LG urothelial carcinomas. PMID- 29507700 TI - Glucose-regulated protein 94 mediates progression and metastasis of esophageal squamous cell carcinoma via mitochondrial function and the NF-kB/COX-2/VEGF axis. AB - Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucose-regulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94-KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells. PMID- 29507701 TI - PTPRG and PTPRC modulate nilotinib response in chronic myeloid leukemia cells. AB - The introduction of second-generation tyrosine kinase inhibitors (TKIs) targeting the protein-tyrosine kinase (PTK) BCR-ABL1 has improved treatment response in chronic myeloid leukemia (CML). However, in some patients response still remains suboptimal. Protein-tyrosine phosphatases (PTPs) are natural counter-actors of PTK activity and can affect TKI sensitivity, but the impact of PTPs on treatment response to second-generation TKIs is unknown. We assessed the mRNA expression level of 38 PTPs in 66 newly diagnosed CML patients and analyzed the potential relation with treatment outcome after 9 months of nilotinib medication. A significantly positive association with response was observed for higher PTPN13, PTPRA, PTPRC (also known as CD45), PTPRG, and PTPRM expression. Selected PTPs were then subjected to a functional analysis in CML cell line models using PTP gene knockout by CRISPR/Cas9 technology or PTP overexpression. These analyses revealed PTPRG positively and PTPRC negatively modulating nilotinib response. Consistently, PTPRG negatively and PTPRC positively affected BCR-ABL1 dependent transformation. We identified BCR-ABL1 signaling events, which were affected by modulating PTP levels or nilotinib treatment in the same direction. In conclusion, the PTP status of CML cells is important for the response to second generation TKIs and may help in optimizing therapeutic strategies. PMID- 29507702 TI - Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients? AB - We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers. Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations. The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001). PMID- 29507703 TI - Association between matrix metalloproteinase 9 C-1562T polymorphism and the risk of coronary artery disease: an update systematic review and meta-analysis. AB - Polymorphism (rs3918242) in the MMP9 gene has been reported to be associated with coronary artery disease (CAD). This study aims to investigate a more accurate estimation of the relationship between CAD and rs3918242 polymorphism by a meta analysis method. We systematically searched studies on the association of rs3918242 polymorphism and CAD in PubMed, Web of Science, the Cochrane Library, Wanfang Data and CNKI. We used Stata 12.0 and RevMan 5.3 software to perform the meta-analyses. A total of 37 case-control studies involving 13,035 CAD patients and 11,372 non-CAD controls were included. A statistically significant association between rs3918242 polymorphism and CAD was observed in allelic model (Odds ratio (OR) 1.34; 95% confidence interval (CI) 1.20-1.50; p < 0.00001), recessive model (OR 1.43; 95% CI 1.17-1.75; p = 0.0004), and in dominant model ( OR 1.36; 95% CI 1.20-1.53; p < 0.00001). Moreover, we also found that there is a statistically significant association between rs3918242 polymorphism and myocardial infarction (MI) in Asians with allelic model (OR 1.66; 95% CI 1.29 2.14; p < 0.0001), recessive model (OR 2.29; 95% CI 1.44-3.63; p = 0.004), and dominant (OR 1.74; 95% CI 1.29-2.35; p = 0.0003) model. A similar result in Caucasians with allelic model (OR 1.14; 95% CI 1.02-1.27; p = 0.02), and in dominant (OR 1.17; 95% CI 1.04-1.32; p = 0.01) model. Our meta-analysis suggested that the MMP9 T allele is a risk factor for CAD and MI. PMID- 29507704 TI - Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis. AB - Background: Two anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors ( TKIs) have been approved for the treatment of patients with ALK-rearranged (ALK positive) advanced non-small cell lung cancer (NSCLC). Severe hepatotoxicity has been observed in several clinical studies. We aim to assess the incidence and risk of liver toxicity with these drugs by a systematic review and meta-analysis of clinical trials. Materials and Methods: The databases of PubMed, Web of Science and abstracts presented at oncology conferences' proceedings were searched for relevant studies from January 2000 to January 2017. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models. Results: A total of 1,908 patients from 10 clinical trials were included. The incidences of all-grade aspartate aminotransferase (AST) and alanine transaminase (ALT) elevation were 25.2% (95% CI 17.7-34.7%), and 26.0% (95% CI 17.8-36.3%), respectively. The incidences of high-grade (grade 3 and 4) AST and ALT elevation were 7.0% (95% CI: 5.4-9.0%), and 9.9% (95%CI: 5.6-16.7%), respectively. Sub group analysis according to ALK-TKIs showed that the incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK-TKIs significantly increased the risk of developing all-grade and high-grade AST elevation (RR, 2.30, 95%CI: 1.87 2.83, p < 0.001; RR 10.14, 95% CI: 3.9-26.39, p < 0.001) and ALT elevation (RR 2.37, 95%CI: 1.97-2.86, p < 0.001; RR 7.34, 95% CI: 3.95-13.63, p < 0.001), respectively. Conclusions: The use of ALK-TKIs significantly increases the risk of developing all-grade and high-grade liver toxicities in lung cancer patients. PMID- 29507705 TI - Efficacy and safety of Zhibitai in combination with atorvastatin for lipid lowering in patients with coronary heart disease. AB - Background: Zhibitai, a natural lipid-lowering Chinese medicine, is well tolerated in patients and has low incidence of adverse events. In this study, we evaluated the efficacy, safety, and side effects of Zhibitai in combination with low dose Atorvastatin compared to high dose Atorvastatin in patients with coronary heart disease or at high risk of coronary heart disease. Methods: This was a randomized, double-blind, multi-center clinical trial on 720 patients with coronary heart disease or at high risk of coronary heart disease. The patients were randomly assigned to a Zhibitai-Atorvastatin group (480 mg Zhibitai twice daily plus 10 mg atorvastatin once daily) or Monotherapy group (40 mg Atorvastatin once daily). Blood samples were obtained at baseline, week 4, and week 8 after a minimum 8-hour fast. Efficacy was evaluated in terms of the changes in the following parameters: lipoprotein profiles [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C)]. Safety was assessed throughout the study by clinical laboratory tests including liver function [alanine transaminase, aspartate transaminase] and renal function [blood urea nitrogen], and creatine kinase; physical examination; and adverse events monitoring. Results: TC, TG, LDL-C levels were significantly decreased andHDL-C levels were significantly increased at week 4 and week 8 (all P < 0.05) in both groups but had no significant differences between the two groups (P > 0.05). In subgroup analyses, Zhibitai-Atorvastatin Group produced significantly greater reduction in TG compared with Monotherapy Group at week 8 in patients with TG > 203.72mg/dL (P < 0.01). Among patients with LDL-C levels > 131.48 mg/dL, Zhibitai-Atorvastatin Group produced a greater reduction of LDL-C levels compared with the Monotherapy Group at week 4 (P < 0.05). The incidence of liver dysfunction, headache, or gastrointestinal intolerance was significantly lower in the Zhibitai-Atorvastatin Group compared with Monotherapy Group during the 8-week study peroid (P < 0.001). There were no significant differences in renal function, myopathy, and other adverse events between the groups. Conclusion: Overall the two groups have similar lipid regulation efficacy. Zhibitai plus low dose Atorvastatin is more efficacious in lowering TG in patients with TG > 203.72 mg/dL at week 8. There are fewer side effects in Zhibitai plus low dose Atorvastatin group. Long term follow up is required to evaluate cardiovascular outcomes. PMID- 29507706 TI - Randomized clinical trial studying effects of a personalized supervised lifestyle intervention program on cardiovascular status in physically inactive healthy volunteers. AB - Background: The impact of personalized exercise training and a healthy dietary lifestyle in healthy volunteers on coronary flow reserve and cardiovascular function remains to be investigated in a controlled study setting. Purpose: To examine the effects of a Mediterranean-inspired diet combined with regular physical exercise (standard) and a personalized supervised exercise program (DAPS) on coronary flow reserve and cardiovascular function. Results: The number of males were 10 (59%) and 9 (47%) and mean age was 54 +/- 12 and 55 +/- 5 years in standard versus DAPS group, respectively. Primary outcomes were in addition to improved body composition and aerobic capacity, increased TDE-CFR (5.0%, CI:1.62,8.64, p = 0.005) and left ventricle ejection fraction (LVEF) during hyperemia (10.2%, CI:1.62,19.4, p = 0.022) in DAPS adjusted for the control period. Also, plasma fibrinogen decreased (-12.1%, CI:-22.0,-0.92, p = 0.035) in the DAPS group. Secondary outcomes, after adjusting DAPS intervention effects for the standard-training period, TDE-CFR and hyperemic LVEF remained significantly improved. Materials and Methods: This randomized, controlled clinical trial (URL: http://www.clinicaltrials.gov NCT02713724) included 36 healthy volunteers who underwent exercise ECG before randomization to standard or DAPS groups. Standard group was given gym-membership with limited instructions and general dietary advice. DAPS-group received personalized supervised exercise programs and more detailed dietary advice with regular contact with a personal trainer. Effects were evaluated after 3 months. All participants underwent coronary flow reserve by transthoracic ultrasound (TDE-CFR), blood marker analysis and examinations of vascular function. Standard-group was evaluated pre-control, post-control (=pre intervention) and post-intervention. DAPS-group was examined at pre-intervention and post-intervention. Conclusions: A personalized supervised training- and diet program improves cardiovascular status in healthy subjects with a physically inactive lifestyle and may be a promising approach for cardiovascular prevention in the general population. PMID- 29507707 TI - Survival based radiographic-grouping for esophageal squamous cell carcinoma may impact clinical T stage. AB - Most patients diagnosed with thoracic esophageal squamous cell carcinoma (ESCC) have progressed beyond surgical resection as a therapeutic option. Difficulties in the proper assessment of tumor invasion depth before treatment complicate determination of the type and extent of therapy. Therefore, accurate tumor clinical staging is a necessity for identifying treatment options and aiding in patient prognosis. We investigated radiographic factors as prognostic indicators for survival in ESCC. Between July 2006 - July 2010, 324 thoracic ESCC patients who underwent surgery were selected. All patients received contrast enhanced preoperative chest CT scans and esophageal barium swallow examinations. Measurement of maximal lesion cross-sectional area, the largest long diameter, largest short diameter, CT-indicated lesion length, barium-indicated lesion length and the length of pericardial fat reduction were performed. Relationships between these indicators and post-surgical survival time and the cutoff values of related factors were analyzed. Maximum long diameter, maximum lesion area and lesion length, as measured by CT imaging, were correlated with survival. Survival effects were clearly associated with group intervals, calculated by a genetic algorithm, and tumor stages. Risk-stratification intervals of esophageal lesions from radiographic imaging included: maximum long diameter < 28.7, 28.7-34.6mm, 34.6-41.4mm and >41.4mm; maximum lesion area < 355.8mm2, 355.8-568.0mm2, 568.0 907.3mm2 and >907.3mm2; and CT-indicated lesion length <30.9mm, 30.9-57.3mm, 57.3 70.6mm and > 70.6mm. The reasonable stratification of maximum esophageal lesion area, largest long diameter and lesion length measured in CT is valuable for clinical T staging of ESCC. Radiographic parameters may have prognostic clinical value in the staging of esophageal carcinoma. PMID- 29507708 TI - Survival rates are higher in married patients with biliary tract cancer: a population-based study. AB - Marital status has been identified as a prognostic factor in multiple malignancies. In this study, we assessed the prognostic value of marital status in 24,035 patients from the Surveillance, Epidemiology, and End Results database diagnosed with biliary tract cancer (BTC) between 2004 and 2014. Widowed patients were more likely to be women, elderly (> 60 years), have gallbladder cancer, and have localized SEER Stage disease than all other patients. Marital status was identified as an independent prognostic factor in both univariate and multivariate analyses, and cause-specific survival (CSS) rates were higher in married patients than unmarried patients. In addition, CSS rates were higher in ampulla of Vater cancer patients than in gallbladder cancer or cholangiocarcinoma patients. Further analysis revealed that CSS rates were lowest in widowed patients at each TNM stage and for all tumor sites. These results suggest marital status is a prognostic factor for clinical outcomes in patients with BTC, and widowed patients are at greater risk of cancer-specific mortality. PMID- 29507709 TI - Glioblastoma: new therapeutic strategies to address cellular and genomic complexity. AB - Glioblastoma (GBM) is the most invasive and devastating primary brain tumor with a median overall survival rate about 18 months with aggressive multimodality therapy. Its unique characteristics of heterogeneity, invasion, clonal populations maintaining stem cell-like cells and recurrence, have limited responses to a variety of therapeutic approaches, and have made GBM the most difficult brain cancer to treat. A great effort and progress has been made to reveal promising molecular mechanisms to target therapeutically. Especially with the emerging of new technologies, the mechanisms underlying the pathology of GBM are becoming more clear. The purpose of this review is to summarize the current knowledge of molecular mechanisms of GBM and highlight the novel strategies and concepts for the treatment of GBM. PMID- 29507710 TI - Magnetic resonance imaging ancillary features used in Liver Imaging Reporting and Data System: An illustrative review. AB - Hepatocellular carcinoma (HCC) usually develops in the setting of chronic liver disease. In the adequate clinical context, both multiphasic contrast-enhanced CT and magnetic resonance imaging are non-invasive modalities that allow accurate diagnosis and staging of HCC, although the latter demonstrates greater sensitivity and specificity. Imaging criteria for HCC diagnosis rely on hemodynamic features such as hyperenhancement in the arterial phase and washout in the portal or equilibrium phase. However, imaging performance drops considerably for small (< 20 mm) nodules because their tendency to exhibit atypical enhancement patterns. In order to improve accuracy in the diagnosis and staging of HCC, particularly in cases of atypical nodules, ancillary features, i.e., imaging characteristics that modify the likelihood of HCC, have been described and incorporated into clinical reports, especially in Liver Imaging Reporting and Data System. In this paper, ancillary imaging features will be reviewed and illustrated. PMID- 29507711 TI - 17-beta estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms. AB - Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV-/-, PV+/-), as well as Shank1-/-, Shank3-/-, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels. Methods: Based on the hypothesis that PV expression might be increased by 17-beta estradiol (E2), PV+/- mice were treated with E2 from postnatal days 5-15 and ASD-related behavior was tested between postnatal days 25 and 31. Results: PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/- mice in the direct reciprocal social interaction and the 3 chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV-/- mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle treated PV-/- mice. Conclusion: Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/- mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD relevant behavioral impairments. PMID- 29507712 TI - Different quality of treatment in retroperitoneal sarcomas (RPS) according to hospital-case volume and surgeon-case volume: a retrospective regional analysis in Italy. AB - Background: Retroperitoneal sarcomas (RPS) should be surgically managed in specialized sarcoma centers. However, it is not clearly demonstrated if clinical outcome is more influenced by Center Case Volume (CCV) or by Surgeon Case Volume (SCV). The aim of this study is to retrospectively explore the relationship between CCV and SCV and the quality of surgery in a wide region of Northern Italy. Methods: We retrospectively collected data about patients M0 surgically treated for RPSs in 22 different hospitals from 2006 to 2011, dividing them in two hospital groups according to sarcoma clinical activity volume (HCV, high case volume or LCV, low case volume hospitals). The HCV group (> 100 sarcomas observed per year) included a Comprehensive Cancer Center (HVCCC) with a high sarcoma SCV (> 20 cases/year), and a Tertiary Academic Hospital (HVTCA) with multiple surgeon teams and a low sarcoma SCV (<= 5 cases/year for each involved surgeon). All other hospitals were included in the LCV group (< 100 sarcomas observed per year). Results: Data regarding 138 patients were collected. Patients coming from LCV hospitals (66) were excluded from the analysis as prognostic data were frequently not available. Among the 72 remaining cases of HCV hospitals 60% of cases had R0/R1 margins, with a more favorable distribution of R0/R1 versus R2 in HVCCC compared to HVTCA. Conclusions: In HCV hospitals, sarcoma SCV may significantly influence RPS treatment quality. In low-volume centers surgical reports can often miss important prognostic issues and surgical quality is generally poor. PMID- 29507714 TI - A Mokken scale analysis of the peer physical examination questionnaire. AB - Background: Peer physical examination (PPE) is a teaching and learning strategy utilised in most health profession education programs. Perceptions of participating in PPE have been described in the literature, focusing on areas of the body students are willing, or unwilling, to examine. A small number of questionnaires exist to evaluate these perceptions, however none have described the measurement properties that may allow them to be used longitudinally. The present study undertook a Mokken scale analysis of the Peer Physical Examination Questionnaire (PPEQ) to evaluate its dimensionality and structure when used with Australian osteopathy students. Methods: Students enrolled in Year 1 of the osteopathy programs at Victoria University (Melbourne, Australia) and Southern Cross University (Lismore, Australia) were invited to complete the PPEQ prior to their first practical skills examination class. R, an open-source statistics program, was used to generate the descriptive statistics and perform a Mokken scale analysis. Mokken scale analysis is a non-parametric item response theory approach that is used to cluster items measuring a latent construct. Results: Initial analysis suggested the PPEQ did not form a single scale. Further analysis identified three subscales: 'comfort', 'concern', and 'professionalism and education'. The properties of each subscale suggested they were unidimensional with variable internal structures. The 'comfort' subscale was the strongest of the three identified. All subscales demonstrated acceptable reliability estimation statistics (McDonald's omega > 0.75) supporting the calculation of a sum score for each subscale. Conclusion: The subscales identified are consistent with the literature. The 'comfort' subscale may be useful to longitudinally evaluate student perceptions of PPE. Further research is required to evaluate changes with PPE and the utility of the questionnaire with other health profession education programs. PMID- 29507713 TI - The suppressing role of miR-622 in renal cell carcinoma progression by down regulation of CCL18/MAPK signal pathway. AB - Background: MicroRNAs have emerged as critical modulators of carcinogenesis and tumor progression including renal cell carcinoma (RCC). MiR-622 plays as a tumor inhibitor in some types of cancer, however, its role in kidney cancer is unknown. The purpose of the present work is to investigate the functional behaviors and regulatory mechanism of miR-622 in RCC. Results: We examined the expression of miR-622 in RCC and adjacent normal tissues and then explored the roles of miR 622. The results of this analysis indicated that miR-622 activity was significantly downregulated in RCC tissues compared with the corresponding normal tissues, so did in RCC cell lines. MiR-622 was associated with RCC aggressiveness. MiR-622 in RCC cells decreased CCL18 expression and suppressed CCL18 activated MAPK signal pathway. Using Western blot and luciferase reporter assays, it was verified that CCL18 was a direct target of miR-622. A specific and inverse correlation between miR-622 and CCL18 expression was found in human RCC samples. Conclusions: The results demonstrated that miR-622 acted as a tumor promoting miRNA by targeting CCL18 in RCC. PMID- 29507716 TI - Identifying physiological measures of lifetime welfare status in pigs: exploring the usefulness of haptoglobin, C- reactive protein and hair cortisol sampled at the time of slaughter. AB - Background: Physiological measures indicative of the welfare status of animals during rearing could form part of an abattoir-based animal health and welfare assessment tool. A total of 66 pigs were used in this study, the aim of which was to assess how serum concentrations of haptoglobin (Hp) and C-reactive protein (CRP) (assessed in 51 pigs), and hair concentrations of cortisol (assessed in 65 pigs), measured at or close to slaughter, reflected welfare-related indicators recorded from the animal during its lifetime. These indicators were recorded at intervals between 7 and 21 weeks of age and included assigning scores for levels of tail and skin lesions, recording the presence or absence of certain health issues, and conducting qualitative behavioural assessments (QBA). Results: Pigs recorded as having tail lesions during their lifetime had higher hair cortisol levels than those with no tail lesions (tail lesions: 47.87 +/- 3.34 pg/mg, no tail lesions: 42.20 +/- 3.29 pg/mg, P = 0.023), and pigs recorded as having moderate or severe tail lesions had higher Hp levels than those with no or mild tail lesions (moderate/severe: 1.711 mg/ml +/- 0.74, none/mild: 0.731 mg/ml +/ 0.10, P = 0.010). Pigs recorded as being lame during their lifetime tended to have higher hair cortisol levels than non-lame pigs (lame: 52.72 pg/mg +/- 3.83, not lame: 43.07 pg/mg +/- 2.69, P = 0.062). QBA scores were not associated with any of the physiological measures (P > 0.05). Receiver Operator Curve (ROC) analysis was also carried out to get a better understanding of the usefulness of the physiological measures in discriminating animals that had had welfare-related issues recorded during their lifetime from those that had not. Hair cortisol was determined as having 'moderate' accuracy in discriminating pigs that were tail bitten on-farm from unbitten pigs (AUC: 0.748) while Hp and CRP were determined to have no meaningful discriminatory ability (AUC < 0.600). Conclusion: This research should be repeated on a larger scale, but the results suggest that hair cortisol measured at slaughter could provide insight into the welfare status of pigs during their lifetime. Hp may be a useful indicator of tail lesions in pigs. However, further research utilising a greater proportion of severely bitten pigs is required before conclusions can be drawn. PMID- 29263780 TI - GAC: Gene Associations with Clinical, a web based application. AB - We present GAC, a shiny R based tool for interactive visualization of clinical associations based on high-dimensional data. The tool provides a web-based suite to perform supervised principal component analysis (SuperPC), an approach that uses both high-dimensional data, such as gene expression, combined with clinical data to infer clinical associations. We extended the approach to address binary outcomes, in addition to continuous and time-to-event data in our package, thereby increasing the use and flexibility of SuperPC. Additionally, the tool provides an interactive visualization for summarizing results based on a forest plot for both binary and time-to-event data. In summary, the GAC suite of tools provide a one stop shop for conducting statistical analysis to identify and visualize the association between a clinical outcome of interest and high dimensional data types, such as genomic data. Our GAC package has been implemented in R and is available via http://shinygispa.winship.emory.edu/GAC/. The developmental repository is available at https://github.com/manalirupji/GAC. PMID- 29507715 TI - A comparison of a novel time-based summary measure of dairy cow health against cumulative disease frequency. AB - Background: There is an increasing push for dairy production to be scientifically grounded and ethically responsible in the oversight of animal health and well being. Addressing underlying challenges affecting the quality and length of productive life necessitates novel assessment and accountability metrics. Human medical epidemiologists developed the Disability-Adjusted Life Year metric as a summary measure of health addressing the complementary nature of disease and death. The goal of this project was to develop and implement a dairy Disease Adjusted Lactation (DALact) summary measure of health, as a comparison against cumulative disease frequency. Methods: A total of 5694 cows were enrolled at freshening from January 1st, 2014 through May 26th, 2015 on 3 similarly managed U.S. Midwestern Plains' region dairies. Eleven health categories of interest were tracked from enrollment until culling, death, or the study's completion date. The DALact accounted for the days of life lost due to illness, forced removal, and death relative to the average lactation length across the participating farms. Results: The DALact consistently identified mastitis as the primary disease of concern on all 3 dairies (19,007-23,955 days lost). Secondary issues included musculoskeletal injuries (19,559 days), pneumonia (11,034 days), or lameness (8858 days). By comparison, cumulative frequency measures pointed to mastitis (31 50%) and lameness (25-54%) as the 2 most frequent diseases. Notably, the DALact provided a robust accounting of health events such as musculoskeletal injuries (5010-19,559 days) and calving trauma (2952-5868 days) otherwise overlooked by frequency measures (0-3%). Conclusions: The DALact provides a time-based method for assessing the overall burden of disease on dairies. It is important to emphasize that a summary measure of dairy health goes beyond simply linking morbidity to culling and mortality in a standardized fashion. A summary measure speaks to the burden of disease on both the well-being and productivity of individuals and populations. When framed as lost days, years, or lactations the various health issues on a farm are more comprehensible than they may be by frequency measures alone. Such an alternative accounting of disease highlights the lost opportunity costs of production as well as the burden of disease on life as a whole. PMID- 29507718 TI - The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. AB - Nearly 30% of adults 40 years and older in the United States are on a statin. Their widespread use heightens the importance of careful consideration of their varied effects on the body. Although randomized controlled trials have not confirmed cognitive impairing effects with statins, continuing evidence suggests statins have the ability to cause reversible cognitive impairment in some patients. Paradoxically, statins have also been shown to decrease the risk of dementia, Alzheimer's disease, and improve cognitive impairment in some cases. However, randomized controlled trials have similarly failed to find the beneficial effect. Supporting evidence for both claims is compelling whereas known limitations of the clinical trials may explain the lack of findings. This narrative review aims to explain why there is still controversy and how both effects can, and may, be possible. The mechanisms that have been hypothesized for each effect are seemingly independent from one another and may explain the contradicting results. Being mindful of the complex effects of statins, health care providers need to be able to identify patients who are at risk for or already experiencing cognitive impairment from statin use while also identifying those who could potentially decrease their risk of dementia with statins. PMID- 29507720 TI - Hyperactivity in anorexia nervosa: to warm or not to warm. That is the question (a translational research one). AB - In the Editorial 'Is the neglect of exercise in anorexia nervosa research a case of "running out" of ideas or do we need to take a "LEAP" of faith into the future?' these authors express their doubts concerning the suitability of keeping patients warm as a beneficial treatment option in managing excessive activity in anorexia nervosa (AN) patients. The case for warming as an adjunctive treatment for AN patients is based on strong experimental evidence gathered from research on animals with Activity-Based Anorexia (ABA). We posit that the beneficial effect of heat results, at least in part, from heat blocking the vicious cycle that hyperactivity plays on AN. Hyperactivity decreases caloric intake by interfering with feeding and increases energy expenditure through excess motor activity which in turn increases emaciation that further strengthens anorexic thinking. PMID- 29507721 TI - Mahaim Accessory Pathways. PMID- 29507722 TI - Mechanical insufflation-exsufflation for airway clearance in adults with cystic fibrosis. AB - In cystic fibrosis (CF), acute exacerbations can decrease the effectiveness of patients' usual airway clearance techniques (ACT). In order to maintain effective airway clearance and preserve lung function, these ACT must be adapted to prevent further dyspnoea and fatigue and improve ease of expectoration. Mechanical insufflation-exsufflation (MI-E) is widely used in neuromuscular disorders to facilitate airway clearance and augment cough but has rarely been used in CF despite potential indications. The NIPPY Clearway, an airway clearance device with multiple modes including MI-E, can be set to deliver multiple insufflations prior to a single exsufflation. We present two cases where this modified version of MI-E was used as an adjunct to traditional ACT in adults during an acute exacerbation of CF. PMID- 29507719 TI - The patient needing prolonged mechanical ventilation: a narrative review. AB - Background: Progress in management has improved hospital mortality of patients admitted to the intensive care units, but also the prevalence of those patients needing weaning from prolonged mechanical ventilation, and of ventilator assisted individuals. The result is a number of difficult clinical and organizational problems for patients, caregivers and health services, as well as high human and financial resources consumption, despite poor long-term outcomes. An effort should be made to improve the management of these patients. This narrative review summarizes the main concepts in this field. Main body: There is great variability in terminology and definitions of prolonged mechanical ventilation.There have been several recent developments in the field of prolonged weaning: ventilatory strategies, use of protocols, early mobilisation and physiotherapy, specialised weaning units.There are few published data on discharge home rates, need of home mechanical ventilation, or long-term survival of these patients.Whether artificial nutritional support improves the outcome for these chronic critically ill patients, is unclear and controversial how these data are reported on the optimal time of initiation of parenteral vs enteral nutrition.There is no consensus on time of tracheostomy or decannulation. Despite several individualized, non-comparative and non-validated decannulation protocols exist, universally accepted protocols are lacking as well as randomised controlled trials on this critical issue. End of life decisions should result from appropriate communication among professionals, patients and surrogates and national legislations should give clear indications. Conclusion: Present medical training of clinicians and locations like traditional intensive care units do not appear enough to face the dramatic problems posed by these patients. The solutions cannot be reserved to professionals but must involve also families and all other stakeholders. Large multicentric, multinational studies on several aspects of management are needed. PMID- 29507723 TI - Extrapleural pneumonectomy of recurrent thymoma with pleural dissemination. AB - Complete surgical resection has been considered the only curable treatment for thymoma. The efficacy of extrapleural pneumonectomy (EPP) for stage IV thymomas remains controversial. In this case report, we utilize EPP for recurrent thymoma with pleural dissemination and describe the resulting outcome. A 39-year-old female with a history of thoracoscopic thymectomy for type B2 thymoma was referred to our hospital for a recurrence of thymoma with pleural dissemination. She underwent EPP as a radical surgery. Histopathological investigation revealed complete resection. The postoperative course was uneventful. She returned to her full-time job and showed no sign of recurrence at 31 months after surgery. EPP for recurrent thymoma with pleural dissemination may be considered to achieve macroscopically complete resection when the patient is young and has a sufficient pulmonary function reservoir without preoperative complications. PMID- 29507724 TI - Respiratory failure patient with lung cancer diagnosed by transesophageal bronchoscopic ultrasound-guided aspirates. AB - A 71-year-old man, who had received long-term oxygen therapy for respiratory failure caused by chronic obstructive pulmonary disease, had an enlarged mediastinal lymph node for one year. As his lung function was poor, we tried performing endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure ventilation for diagnosis but could not obtain sufficient specimens. Later, we performed an endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) using a transesophageal approach. Rapid on-site cytology revealed that adequate specimens were obtained, and we could terminate the procedure in 12 min without any complications. The histological findings revealed lung adenocarcinoma. EUS-B-FNA, which can be performed by a pulmonologist, is a useful alternative for diagnosing mediastinal lesions in patients with respiratory failure. PMID- 29507725 TI - Desmoid fibromatosis of the chest wall. AB - We report a case of desmoid fibromatosis of the chest wall. A 70-year-old woman was referred to our hospital with right shoulder blade pain and paresthesia over the right upper breast. Chest X-ray and computed tomography demonstrated a 5 cm right apical mass in the chest. Biopsy of the mass demonstrated features of desmoid fibromatosis. The patient subsequently underwent surgical resection of the mass and received adjuvant radiation therapy for microscopic positive margins. In conclusion, although desmoid tumour of the chest is rare, it is worth considering in the differential diagnoses of chest wall tumours. PMID- 29507726 TI - Report on the breakage of the tip of a radial endobronchial ultrasonic probe sheath during bronchoscopy. AB - A lesion in a 73-year-old woman that was suspected to be right lung cancer was biopsied under ultrasound-guided bronchoscopy with a guide sheath. The procedure was completed without a noticeable problem, but after 3 days, it was found that the tip of the ultrasonic probe sheath was broken and that the broken fragment was missing. Based on the concern that the fragment had been left in the lung, the patient was examined by computed tomography scan 4 days after the biopsy, and bronchoscopy was repeated 38 days after the biopsy, but no fragment was detected. These procedures and an investigation by the Olympus Corporation led to the conclusion that the fragment was not in the lung, and it was not found in a subsequent surgical specimen. Breakage of devices may occur at any time regardless of progression of fatigue (wear) with increased use, and thorough device management before, during, and after use is important. PMID- 29507727 TI - Rapid diffuse pleural thickening due to metastatic meningioma. AB - A 64-year-old man was referred to our hospital because of persistent dyspnoea for the past 1 month. He had recurrent brain anaplastic meningioma after two operations and irradiation. He suffered from right pleural effusion in the previous few months and was diagnosed with malignant mesothelioma via pleural biopsy 1 month prior to coming to our hospital. At his first visit to our hospital, thoracic computed tomography demonstrated rapidly developed large inhomogeneously enhancing pleural thickening up to 3 cm, which surrounded the right hemithorax, together with left-sided pleural effusion. After re-evaluation of the pathological specimens retrieved from the local hospital, he was finally diagnosed with pleural metastasis secondary to anaplastic meningioma (WHO classification, grade 3). Generally, brain meningiomas are believed to be benign and seldom metastasize to other organs. However, the present case clearly demonstrated the unique clinical presentation of anaplastic meningioma, also known as malignant meningioma, which mimicked the pathological and radiological findings of a malignant mesothelioma. PMID- 29507728 TI - Predictors associated with unplanned hospital readmission of medical and surgical intensive care unit survivors within 30 days of discharge. AB - Background: Reducing the 30-day unplanned hospital readmission rate is a goal for physicians and policymakers in order to improve quality of care. However, data on the readmission rate of critically ill patients in Japan and knowledge of the predictors associated with readmission are lacking. We investigated predictors associated with 30-day rehospitalization for medical and surgical adult patients separately. Methods: Patient data from 502 acute care hospitals with intensive care unit (ICU) facilities in Japan were retrospectively extracted from the Japanese Diagnosis Procedure Combination (DPC) database between April 2012 and February 2014. Factors associated with unplanned hospital readmission within 30 days of hospital discharge among medical and surgical ICU survivors were identified using multivariable logistic regression analysis. Results: Of 486,651 ICU survivors, we identified 5583 unplanned hospital readmissions within 30 days of discharge following 147,423 medical hospitalizations (3.8% readmitted) and 11,142 unplanned readmissions after 339,228 surgical hospitalizations (3.3% readmitted). The majority of unplanned hospital readmissions, 60.9% of medical and 63.1% of surgical case readmissions, occurred within 15 days of discharge. For both medical and surgical patients, the Charlson comorbidity index score; category of primary diagnosis during the index admission (respiratory, gastrointestinal, and metabolic and renal); hospital length of stay; discharge to skilled nursing facilities; and having received a packed red blood cell transfusion, low-dose steroids, or renal replacement therapy were significantly associated with higher unplanned hospital readmission rates. Conclusions: From patient data extracted from a large Japanese national database, the 30-day unplanned hospital readmission rate after ICU stay was 3.4%. Further studies are required to improve readmission prediction models and to develop targeted interventions for high-risk patients. PMID- 29507729 TI - Management of acute aortic dissection and thoracic aortic rupture. AB - Background: Both acute aortic dissection and ruptured aortic aneurysm are leading causes of death in cardiovascular disease. These life-threatening conditions have recently been categorized as acute aortic syndrome. This review describes the etiology, clinical presentation, and therapeutic options for acute aortic syndrome including acute aortic dissection and ruptured aortic aneurysm. Main body: Several diagnostic tools for detecting these critical conditions have been developed including computed tomography, ultrasonography, magnetic resonance imaging, and laboratory tests. Early and accurate diagnosis is most important to determine appropriate treatment. Initial treatment for these conditions should be aimed at controlling pain and the hemodynamic state with further treatment based on the imaging diagnosis and hematological assessment. Surgical outcomes after acute aortic syndrome are improving gradually; however, mortality remains high. Recently, thoracic endovascular aortic repair has become an alternative technique to treat complicated type B aortic dissection. Rapid treatment after early diagnosis is essential to save patients' lives. Conclusions: Continuous advances in imaging and treatment technologies are improving short- and long-term outcomes in patients with acute aortic syndrome. Knowledge and interest in intensive care medicine in this area are contributing to improved outcomes, and further research into this life-threatening disease will lead to improvements in diagnosis and management. PMID- 29507730 TI - Association between exposure to ambient air pollution and renal function in Korean adults. AB - Background: Ambient air pollution has a negative effect on many diseases, such as cardiovascular and respiratory diseases. Recent studies have reported a relationship between air pollution and renal function, but the results were limited to exposure to particulate matter (PM). This study was to identify associations between various air pollutants and renal function among Korean adults. Methods: Nationwide survey data for a total of 24,407 adults were analyzed. We calculated the estimated glomerular filtration rate (eGFR) for each individual to assess their renal function and used this to categorize those with chronic kidney disease (CKD). To evaluate exposure to ambient air pollution, we used the annual mean concentrations of four ambient air pollutants: PM with an aerodynamic diameter <= 10 MUm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO). Results: We identified significant inverse relationships between the air pollutants PM10 and NO2 and eGFR in all statistical adjustment models (all p < 0.05). In the full covariate model, interquartile range increases in the annual mean concentrations of PM10 and NO2 were associated with decreases in eGFR levels of 0.46 (95% CI = - 0.87, - 0.04) and 0.85 (95% CI = - 1.40, - 0.30), respectively. Three of the ambient air pollutants were significantly related to an increased risk of CKD in the unadjusted model (p < 0.0001), but all significant associations disappeared after adjusting for covariates (all p > 0.05). Conclusions: Exposures to PM10 and NO2 were significantly associated with decreases in eGFR levels, but not CKD, in Korean adults. PMID- 29507731 TI - The perceived effects and comfort of various body armour systems on police officers while performing occupational tasks. AB - Background: The nature of police work often necessitates use of Individual Light Armour Vests (ILAVs) for officer protection. Previous research has demonstrated various biomechanical and physical performance impacts of ILAVs, however, little knowledge exists on the individual officer's perceptions of ILAV. The aim of this study was to investigate officers' perceptions of the impacts of three different ILAVs and normal station wear whilst performing police occupational tasks. Methods: A prospective, within subjects, repeated measures design was employed in which 11 serving police officers wore each of three different types of body armour (ILAV A, ILAV B or ILAV C) and normal station wear for a full day while performing tasks including a simulated victim drag, a patrol vehicle exit and a marksmanship shoot. Ratings of Perceived Exertion (RPE) and a Visual Analogue Scale (VAS; - 10 to + 10) were used to examine officer perceptions of each ILAV. Finally, officers were asked to indicate areas of both discomfort and comfort of each ILAV on a mannequin chart. Results: Officers perceived less effort was required for the victim drag whilst wearing ILAV B (RPE = 3.6/10) when compared to ILAV A, ILAV C and even station wear (RPE = 4.7/10, 4.0/10, 3.8/10, respectively). A positive impact on performance was perceived for ILAV B (VAS = + 0.26) when performing a patrol vehicle exit and sprint task but not for the other two ILAVs (VAS = - 3.58, - 0.55, - 0.85, respectively). Officers perceived a positive impact of ILAV B (VAS = + 2.7) and station wear (VAS = + 1.4) and a negative impact of ILAVs A and C (VAS = - 2.1, - 1.7 respectively) on marksmanship. Despite all armour types being criticized for discomfort, ILAV B received lower ratings of discomfort overall, and some positive comments regarding both comfort and performance. Conclusions: Officers perceived ILAV B to have positive effects on task performance. It was also rated more comfortable than the other two, possibly due to a longer torso design which shifted load from the shoulders to the hips and pelvis. Officer perceptions of comfort and effects on occupational performance should be considered when designing and procuring armour systems. Although ILAVs may be similar, perceived impacts may vary between officers. PMID- 29507732 TI - Improved cardiorespiratory fitness after occupational rehabilitation in merged diagnostic groups. AB - Background: Various occupational inpatient rehabilitation programs are established in Norway. This study aimed to assess change in cardiorespiratory fitness, pain, anxiety, depression, and quality of life in persons on long-term sick leave due to musculoskeletal-, mental or unspecific disorders after participation in multicomponent inpatient occupational rehabilitation. Methods: Twenty-five women and five men (mean age 45.2 years, SD 6.7, range 30-57) volunteered to participate in the study. The participants attended either 8 or 17 full days of occupational multicomponent rehabilitation including physical exercise, cognitive behavioral therapy in the form of acceptance and commitment therapy (ACT), and development of a tailored plan for return to work. Cardiorespiratory fitness was assessed by the Astrand/Ryhming cycle test at the start and end of rehabilitation program, and at one-year follow-up. Changes in somatic and mental health were measured by questionnaires up to 4 months after start of the program. Results: Linear mixed models showed that the maximal oxygen uptake increased by 1.1 mL degrees kg-1 degrees min- 1 during the rehabilitation program and by 3.7 mL degrees kg-1 degrees min- 1 at one-year follow-up. There were minor improvements in somatic and mental health, and quality of life. Conclusions: This study indicates that occupational inpatient multicomponent rehabilitation including physical exercise and ACT may promote a long-term increase in physical exercise that is sufficient to induce a significant increase in cardiorespiratory fitness. Trial registration: The current study is not registered, but is part of a larger trial registered at clinicaltrials.gov (No.: NCT01926574, registered 21. Aug 2013). PMID- 29507733 TI - Function identification of miR482b, a negative regulator during tomato resistance to Phytophthora infestans. AB - Tomato is an important horticultural and economic crop cultivated worldwide. As Phytophthora infestans becomes a huge threat to tomato production, it is necessary to study the resistance mechanisms of tomato against P. infestans. Our previous research has found that miR482 might be involved in tomato-P. infestans interaction. In this study, miR482b precursor was cloned from Solanum pimpinellifolium "L3708" and miR482b was shown to decrease in abundance in tomato following P. infestans infection. Compared to wild-type tomato plants, tomato plants that overexpressed miR482b displayed more serious disease symptoms after P. infestans infection, with more necrotic cells, longer lesion diameters, and increased P. infestans abundance. Meanwhile, silencing of miR482b was performed by short tandem target mimic (STTM), resulting in enhancement of tomato resistance to P. infestans. Using miRNA and degradome data sets, NBS-LRR disease resistance genes targeted by miR482b were validated. Negative correlation between the expression of miR482b and its target genes was found in all miR482b overexpressing and -silencing tomato plants. Our results provide insight into tomato miR482b involved in the response to P. infestans infection, and demonstrate that miR482b-NBS-LRR is an important component in the network of tomato-P. infestans interaction. PMID- 29507734 TI - Divergence in the transcriptional landscape between low temperature and freeze shock in cultivated grapevine (Vitis vinifera). AB - Low-temperature stresses limit the sustainability and productivity of grapevines when early spring frosts damage young grapevine leaves. Spring conditions often expose grapevines to low, but not damaging, chilling temperatures and these temperatures have been shown to increase freeze resistance in other model systems. In this study, we examined whole-transcriptome gene expression patterns of young leaf tissue from cuttings of five different grapevine cultivars, exposed to chill and freeze shock, in order to understand the underlying transcriptional landscape associated with cold stress response. No visible damage was observed when grapevine leaves were exposed to chilling temperatures while freeze temperatures resulted in variable damage in all cultivars. Significant differences in gene expression were observed between warm control conditions and all types of cold stress. Exposure to chill stress (4 degrees C) versus freezing stress (-3 degrees C) resulted in very different patterns of gene expression and enriched pathway responses. Genes from the ethylene signaling, ABA signaling, the AP2/ERF, WRKY, and NAC transcription factor families, and starch/sucrose/galactose pathways were among the most commonly observed to be differentially regulated. Preconditioning leaves to chill temperatures prior to freezing temperatures resulted in slight buffering of gene expression responses, suggesting that differences between chill and freeze shock perception complicates identification of candidate genes for cold resistance in grapevine. Overall, the transcriptional landscape contrasts observed between low temperature and freezing stresses demonstrate very different activation of candidate pathways impacting grapevine cold response. PMID- 29507735 TI - An integrated approach for increasing breeding efficiency in apple and peach in Europe. AB - Despite the availability of whole genome sequences of apple and peach, there has been a considerable gap between genomics and breeding. To bridge the gap, the European Union funded the FruitBreedomics project (March 2011 to August 2015) involving 28 research institutes and private companies. Three complementary approaches were pursued: (i) tool and software development, (ii) deciphering genetic control of main horticultural traits taking into account allelic diversity and (iii) developing plant materials, tools and methodologies for breeders. Decisive breakthroughs were made including the making available of ready-to-go DNA diagnostic tests for Marker Assisted Breeding, development of new, dense SNP arrays in apple and peach, new phenotypic methods for some complex traits, software for gene/QTL discovery on breeding germplasm via Pedigree Based Analysis (PBA). This resulted in the discovery of highly predictive molecular markers for traits of horticultural interest via PBA and via Genome Wide Association Studies (GWAS) on several European genebank collections. FruitBreedomics also developed pre-breeding plant materials in which multiple sources of resistance were pyramided and software that can support breeders in their selection activities. Through FruitBreedomics, significant progresses were made in the field of apple and peach breeding, genetics, genomics and bioinformatics of which advantage will be made by breeders, germplasm curators and scientists. A major part of the data collected during the project has been stored in the FruitBreedomics database and has been made available to the public. This review covers the scientific discoveries made in this major endeavour, and perspective in the apple and peach breeding and genomics in Europe and beyond. PMID- 29507736 TI - Cytological, physiological, and transcriptomic analyses of golden leaf coloration in Ginkgo biloba L. AB - Ginkgo biloba is grown worldwide as an ornamental plant for its golden leaf color. However, the regulatory mechanism of leaf coloration in G. biloba remains unclear. Here, we compared G. biloba gold-colored mutant leaves and normal green leaves in cytological, physiological and transcriptomic terms. We found that chloroplasts of the mutant were fewer and smaller, and exhibited ruptured thylakoid membranes, indistinct stromal lamellae and irregularly arranged vesicles. Physiological experiments also showed that the mutant had a lower chlorophyll, lower flavonoid and higher carotenoid contents (especially lutein). We further used transcriptomic sequencing to identify 116 differentially expressed genes (DEGs) and 46 transcription factors (TFs) involved in chloroplast development, chlorophyll metabolism, pigment biosynthesis and photosynthesis. Among these, the chlorophyll biosynthesis-related PPO showed down-regulation, while chlorophyll degradation-related NYC/NOL had up-regulated expression in mutant leaves. Z-ISO, ZDS, and LCYE, which are involved in carotenoid biosynthesis were up-regulated. Quantitative real-time PCR (RT-qPCR) further confirmed the altered expression levels of these genes at three stages. The alteration of PPO and NYC/NOL gene expression might affect chlorophyll biosynthesis and promote degradation of chlorophyll b to chlorophyll a, while the up-regulated genes Z-ISO, ZDS and LCYE enhanced carotenoid accumulation. Consequently, changes in the ratio of carotenoids to chlorophylls were the main factors driving the golden leaf coloration in the mutant G. biloba. PMID- 29507737 TI - Willingness to participate in weight-related research as reported by patients in PCORnet clinical data research networks. AB - Background: Since 2014 the Patient Centered Outcomes Research Institute (PCORI) has funded 13 Clinical Data Research Networks (CDRNs) around the country to support large-scale comparative effectiveness research and pragmatic clinical trials. To provide guidance for future recruitment efforts among CDRNs this study described differential willingness to participate in weight-related research by body mass index (BMI) and sociodemographic characteristics. Methods: During 2014 2016 we surveyed participants from three CDRNs including the Mid-South CDRN, REACHnet, and the PaTH Network, representing 14 medical centers. Participants were eligible if they were >=18 years, had >=2 weights and >=1 height in the electronic health record. Respondents were recruited face-to-face in primary care and specialty clinics, and via email from doctors' offices, patient registries and health systems' patient portals. Data was collected on willingness to participate in weight-related research (four items combined into a single scale; range 4-12), BMI, and sociodemographics (age, sex, number of people in household, marital status, education level, race, and ethnicity). Adjusted ordinal regression models tested associations between participant characteristics and willingness to participate in weight-related research. Results: Among 11,624 respondents, mean BMI was 29.6 (SD 7.6) kg/m2. Mean willingness to participate in weight-related research was 7.1 (SD 2.5). More respondents were willing to participate in studies with lower burden: healthy lifestyles (82.2%), genetics (71.3%), medication (52.2%), and surgery (22.6%). In adjusted models, higher BMI was associated with greater willingness to participate in weight-related research (OR = 1.13) as were younger age (OR = 0.98), being a woman (OR 1.59), and college education (OR = 1.72) (all p < 0.001). Conclusions: Associations among BMI, age, sex, and education level with willingness to participate in weight-related research highlight the need for future research to reduce barriers for populations less willing to engage in weight-related research. PMID- 29507738 TI - Fournier Gangrene in a patient receiving chemo-radiation for rectal cancer. AB - We herein present a case of a 24-year-old patient with a cT4N+ rectal cancer who developed Fournier's gangrene (FG) 1 week after the completion of preoperative chemoradiotherapy. The patient was promptly referred to the surgical department where she was treated with antibiotics and repeated surgical debridement. FG is a rare and life-threatening situation that needs to be managed aggressively with no delay. The clinical image above is unique and characteristic of this clinical entity. PMID- 29507739 TI - Normal function of a 43-year-old Braunwald Cutter heart valve. AB - We present the case of a 72-year-old woman diagnosed with rheumatic fever at the age of 6. In 1972, she was diagnosed with mitral valve insufficiency and mitral valve stenosis, then in 1974, a decision was made to perform mitral valve replacement surgery with a 32-mm Braunwald-Cutter ball cage prosthesis. An echocardiogram performed in 2014 revealed normal biventricular systolic function, mechanical prosthesis in mitral position with maximum speed of 1.9 m/s, maximum gradient of 15 mmHg, mean gradient of 6 mmHg, severe tricuspid valve insufficiency, inferior vena cava measuring 15 mm with more than 50% collapse and pulmonary artery systolic pressure of 40 mmHg. We report the use of the 32-mm Braunwald-Cutter ball cage prosthesis with the longest longevity that remains functional after more than 43 years of implantation. PMID- 29507741 TI - Special issue: e-health innovations for global mental health. PMID- 29507740 TI - Aspergillus niger is a superior expression host for the production of bioactive fungal cyclodepsipeptides. AB - Background: Fungal cyclodepsipeptides (CDPs) are non-ribosomally synthesized peptides produced by a variety of filamentous fungi and are of interest to the pharmaceutical industry due to their anticancer, antimicrobial and anthelmintic bioactivities. However, both chemical synthesis and isolation of CDPs from their natural producers are limited due to high costs and comparatively low yields. These challenges might be overcome by heterologous expression of the respective CDP-synthesizing genes in a suitable fungal host. The well-established industrial fungus Aspergillus niger was recently genetically reprogrammed to overproduce the cyclodepsipeptide enniatin B in g/L scale, suggesting that it can generally serve as a high production strain for natural products such as CDPs. In this study, we thus aimed to determine whether other CDPs such as beauvericin and bassianolide can be produced with high titres in A. niger, and whether the generated expression strains can be used to synthesize new-to-nature CDP derivatives. Results: The beauvericin and bassianolide synthetases were expressed under control of the tuneable Tet-on promoter, and titres of about 350-600 mg/L for bassianolide and beauvericin were achieved when using optimized feeding conditions, respectively. These are the highest concentrations ever reported for both compounds, whether isolated from natural or heterologous expression systems. We also show that the newly established Tet-on based expression strains can be used to produce new-to-nature beauvericin derivatives by precursor directed biosynthesis, including the compounds 12-hydroxyvalerate-beauvericin and bromo beauvericin. By feeding deuterated variants of one of the necessary precursors (d hydroxyisovalerate), we were able to purify deuterated analogues of beauvericin and bassianolide from the respective A. niger expression strains. These deuterated compounds could potentially be used as internal standards in stable isotope dilution analyses to evaluate and quantify fungal spoilage of food and feed products. Conclusion: In this study, we show that the product portfolio of A. niger can be expanded from enniatin to other CDPs such as beauvericin and bassianolide, as well as derivatives thereof. This illustrates the capability of A. niger to produce a range of different peptide natural products in titres high enough to become industrially relevant. PMID- 29507742 TI - A qualitative evaluation of a brief multicomponent intervention provided by lay health workers for women affected by adversity in urban Kenya. AB - Background: Problem Management Plus (PM+) is a brief multicomponent intervention incorporating behavioral strategies delivered by lay health workers. The effectiveness of PM+ has been evaluated in randomized controlled trials in Kenya and Pakistan. When developing interventions for large-scale implementation it is considered essential to evaluate their feasibility and acceptability in addition to their efficacy. This paper discusses a qualitative evaluation of PM+ for women affected by adversity in Kenya. Methods: Qualitative interviews were conducted with 27 key informants from peri-urban Nairobi, Kenya, where PM+ was tested. Interview participants included six women who completed PM+, six community health volunteers (CHVs) who delivered the intervention, seven people with local decision making power, and eight project staff involved in the PM+ trial. Results: Key informants generally noted positive experiences with PM+. Participants and CHVs reported the positive impact PM+ had made on their lives. Nonetheless, potential structural and psychological barriers to scale up were identified. The sustainability of CHVs as unsalaried, volunteer providers was mentioned by most interviewees as the main barrier to scaling up the intervention. Conclusions: The findings across diverse stakeholders show that PM+ is largely acceptable in this Kenyan setting. The results indicated that when further implemented, PM+ could be of great value to people in communities exposed to adversities such as interpersonal violence and chronic poverty. Barriers to large-scale implementation were identified, of which the sustainability of the non-specialist health workforce was the most important one. PMID- 29507743 TI - Effect of transporting an evidence-based, violence prevention intervention to Jamaican preschools on teacher and class-wide child behaviour: a cluster randomised trial. AB - Introduction: Based on extensive piloting work, we adapted the Incredible Years (IY) teacher-training programme to the Jamaican preschool setting and evaluated this adapted version through a cluster-randomised trial. Methods: Twenty-four community preschools in Kingston, Jamaica were randomly assigned to intervention (12 schools, 37 teachers) or control (12 schools, 36 teachers). The intervention involved training teachers in classroom management through eight full-day training workshops and four individual 1-h in-class support sessions. Outcome measurements included direct observation of teachers' positive and negative behaviours to the whole class and to high-risk children and four observer ratings: two measures of class-wide child behaviour and two measures of classroom atmosphere. Measures were repeated at a six-month follow-up. Results: Significant benefits of intervention were found for teachers' positive [effect size (ES) = 3.35] and negative (ES = 1.29) behaviours to the whole class and to high-risk children (positive: ES = 0.83; negative: ES = 0.50) and for observer ratings of class-wide child behaviour (ES = 0.73), child interest and enthusiasm (ES = 0.98), teacher warmth (ES = 2.03) and opportunities provided to share and help (ES = 5.72). At 6-month follow-up, significant benefits of intervention were sustained: positive behaviours (ES = 2.70), negative behaviours (ES = 0.98), child behaviour (ES = 0.50), child interest and enthusiasm (ES = 0.78), teacher warmth (ES = 0.91), opportunities to share and help (ES = 1.42). Conclusions: The adapted IY teacher-training programme produced large benefits to teacher's behaviour and to class-wide measures of children's behaviour, which were sustained at 6-month follow-up. Benefits were of a similar magnitude to those found in a pilot study of the minimally adapted version that required significantly more in-class support for teachers. PMID- 29507744 TI - Mental health interventions in Myanmar: a review of the academic and gray literature. AB - Background: Recent political changes in Myanmar provide opportunities to expand mental health (MH) services. Given Myanmar's unique situation, we felt a need to assemble and interpret available local information on MH in Myanmar to inform service design, rather than simply drawing lessons from other countries. We reviewed academic and gray literature on the experience of MH problems in Myanmar and the suitability, availability, and effectiveness of MH and psychosocial programming. Methods: We searched: (1) Google Scholar; (2) PubMed; (3) PsychInfo; (4) English-language Myanmar journals and databases; (5) the Mental Health and Psychosocial Support (MHPSS) Network resources website; (6) websites and (7) local contacts of organizations identified during 2010 and 2013 mapping exercise of MHPSS providers; (8) the Myanmar Information Management Unit (MIMU) website; (9) University libraries in Yangon and Mandalay; and (10) identified local MH professionals. Results: Qualitative data suggest that MH conditions resulting from stress are similar to those experienced elsewhere. Fourteen intervention evaluations were identified: three on community-level interventions, three on adult religion-based practice (meditation), four adult psychotherapeutic interventions, and four child-focused interventions. Support for the acceptability and effectiveness of interventions is mostly anecdotal. With the exception of two rigorous, randomized control trials, most evaluations had serious methodologic limitations. Conclusions: Few evaluations of psychotherapeutic or psychosocial programs for people from Myanmar have been published in the black or gray literature. Incorporating rigorous evaluations into existing and future programs is imperative for expanding the evidence base for psychotherapeutic and psychosocial programs in this context. PMID- 29507745 TI - Interpersonal violence and suicidality among former child soldiers and war exposed civilian children in Nepal. AB - Background: Suicide risk reduction is crucial for 15-29-year-old youth, who account for 46% of suicide deaths in low- and middle-income countries. Suicide predictors in high-resource settings, specifically depression, do not adequately predict suicidality in these settings. We explored if interpersonal violence (IPV) was associated with suicidality, independent of depression, in Nepal. Methods: A longitudinal cohort of child soldiers and matched civilian children, enrolled in 2007 after the People's War in Nepal, were re-interviewed in 2012. The Depression Self-Rating Scale and Composite International Diagnostic Interview assessed depression and suicidality, respectively. Non-verbal response cards were used to capture experiences of sexual and physical IPV. Results: One of five participants (19%) reported any lifetime suicidal ideation, which was associated with sexual IPV, female gender, former child soldier status and lack of support from teachers. Among young men, the relationship between sexual IPV and suicidality was explained by depression, and teacher support reduced suicidality. Among young women, sexual IPV was associated with suicidality, independent of depression; child soldier status increased suicidality, and teacher support decreased suicidality. Suicide plans were associated with sexual IPV but not with depression. One of 11 female former child soldiers (9%) had attempted suicide. Conclusion: Sexual IPV is associated with suicidal ideation and plans among conflict-affected young women, independent of depression. Reducing suicide risk among women should include screening, care, and prevention programs for sexual IPV. Programs involving teachers may be particularly impactful for reducing suicidality among IPV survivors. PMID- 29507746 TI - Anti-oxidant mediated normalisation of raised intracellular cytokines in patients with reproductive failure. AB - Background: Raised intracellular cytokine ratios (CKR) are proposed as a significant risk factor for adverse reproductive outcome. An elevated cytokine ratio, such as between TNFa and/or IFNg to IL-10 is associated with recurrent miscarriage (RM). The use of pharmacological immunomodulators such as TNFalpha inhibitors in these patients is controversial and not generally recommended due to a lack of conclusive data supporting their use. We evaluated whether the use of anti-oxidants/dietary supplements as an alternative could positively influence CKR's in ART patients. Methods: A prospective non-placebo control trial of antioxidant treatment for abnormal peripheral inflammatory cytokine ratios was performed. CKRs were assessed using flow cytometry in stimulated versus unstimulated whole blood samples in 337 IVF patients presenting with a previous history of poor outcome (RM or implantation failure). CKR's were found to be elevated in 150/337. 70/150 patients in this elevated group agreed to a 10 week regime of Omega 3, vitamin D3, and B complex, followed by retesting to evaluate effect. Results: Mean cytokine ratios significantly improved between tests. Pre treatment TNFa:IL-10 ratio improved from 71.6 to 21.0 (p < 0.0001) and IFNg:IL-10 ratio dropped from 24.5 to 12.5 (p < 0.0001). The improved ratios were achieved primarily by an increase in IL-10 expression (P = 0.0007), but also by a moderate decrease in stimulated TNFa expression (p = 0.008). Mean IFNg expression was unchanged (p = 0.42). On an individual basis CKR levels were normalised in 43 patients, improved in 12 and remained unchanged in 15. No significant differences in improvement were found between RM and IF subgroups. Conclusions: Intracellular cytokine expression levels and ratios were modifiable by the supplement regime employed. Elevated cytokine ratios have been linked with adverse reproductive outcomes, and proposed treatments have included biological immunomodulators which antagonise TNFa, but come with significant associated cost implications and more importantly, cytotoxic side-effects. A dietary regime is more patient friendly and lower risk, while still achieving a similar effect in many patients. PMID- 29507747 TI - New low-dose liquid pilocarpine formulation for treating dry mouth in Sjogren's syndrome: clinical efficacy, symptom relief, and improvement in quality of life. AB - Background: Patients with Sjogren's syndrome (SS) typically present clinically with xerostomia (dry mouth) because of progressive damage to the exocrine glands. We developed a new, low-dose pilocarpine/sodium alginate (LPA) solution with pilocarpine hydrochloride to inhibit systemic adverse effects by administering via the oral mucosa. The purpose of this study was to assess its stability, safety, and efficacy. Methods: The pilocarpine concentration in an LPA liquid formulation was measured 3, 7, 14, and 28 days after preparation to assess its stability. A prospective clinical trial was undertaken to assess the efficacy and safety of the LPA solution as a symptomatic treatment for dry mouth in SS. Patients (n = 24) with clinically significant xerostomia were enrolled after providing written informed consent. Whole-mouth salivary flow rate was measured twice; immediately before and 60 min after LPA application. Symptoms were assessed by questionnaire with visual analog scales or checkboxes before the first application (baseline), and then once daily for 7 days. Results: The pilocarpine content 3, 7, 14, and 28 days after preparation showed no marked change, confirming its stability. Salivary flow was significantly increased from 0.076 +/- 0.092 g/30 s to 0.122 +/- 0.140 g/30 s 60 min after LPA administration (P < 0.001). Dry mouth and thirstiness showed significant improvement compared with that of baseline (P <= 0.01). The only adverse effect was sweating, and no serious drug-related adverse events were reported. Conclusions: This new, low dose pilocarpine formulation was well-tolerated and resulted in significant improvements in symptoms of dry mouth and other xerostomic conditions in patients with SS. Trial registration: The study approval number in the institution; 08-068 2. Registered January 19, 2009. UMIN000029307. Registered 27 September 2017 (retrospectively registered). PMID- 29507748 TI - Evaluation of safety tool for ambulatory leprosy patients at risk of adverse outcome. AB - Background: Leprosy is a potentially debilitating disease of the skin and nerves that requires a complex management approach consisting of laboratory monitoring, screening for factors that will adversely affect outcome with corticosteroids, engagement of allied health services, and prolonged follow-up. Given the complexities of leprosy management, a safety tool was developed and implemented in the Tropical Disease Unit at Toronto General Hospital. Our objective was to evaluate the utility of the tool using a retrospective chart review. Methods: We reviewed the charts of patients with leprosy treated over a 3.5-year period: up to 3 years prior to tool implementation, and 6-months following implementation. Pre-determined outcomes of interest included: loss to follow-up; monitoring of laboratory parameters; allied health services engagement; baseline ophthalmologic assessment; and risk mitigation interventions. Results: Of 17 patients enrolled, 8 were treated pre-implementation, and 9 post-implementation. Five (29.4%) pre implementation patients were lost to follow-up compared to none post implementation (p = 0.009). One (12.5%) pre-implementation patient was sent for baseline ophthalmologic assessment versus 8 (88.9%) post-implementation (p = 0.0034). Only post-implementation patients received referrals for occupational therapy and social work, with 77.8% (n = 7) receiving occupational therapy (p = 0.0023) and 33.3% (n = 3) social work (p = 0.2059). Laboratory parameters such as hemoglobin, hepatic transaminases, and methemoglobin were routinely monitored for patients on dapsone irrespective of tool implementation. Conclusions: Implementation of a leprosy-specific safety tool has established a user-friendly method for systemizing all elements of care, and ensuring the involvement of allied health services necessary for optimizing health outcomes. PMID- 29507749 TI - Precision antimicrobial therapeutics: the path of least resistance? AB - The emergence of drug-resistant pathogens has led to a decline in the efficacy of traditional antimicrobial therapy. The rise in resistance has been driven by widespread use, and in some cases misuse, of antibacterial agents in treating a variety of infections. A growing body of research has begun to elucidate the harmful effects of broad-spectrum antibiotic therapy on the beneficial host microbiota. To combat these threats, increasing effort is being directed toward the development of precision antimicrobial therapeutics that target key virulence determinants of specific pathogens while leaving the remainder of the host microbiota undisturbed. This includes the recent development of small molecules termed "mannosides" that specifically target uropathogenic E. coli (UPEC). Mannosides are glycomimetics of the natural mannosylated host receptor for type 1 pili, extracellular appendages that promotes UPEC colonization in the intestine. Type 1 pili are also critical for colonization and infection in the bladder. In both cases, mannosides act as molecular decoys which potently prevent bacteria from binding to host tissues. In mice, oral treatment with mannosides simultaneously clears active bladder infection and removes intestinal UPEC while leaving the gut microbiota structure relatively unchanged. Similar treatment strategies successfully target other pathogens, like adherent-invasive E. coli (AIEC), an organism associated with Crohn's disease (CD), in mouse models. While not without its challenges, antibiotic-sparing therapeutic approaches hold great promise in a variety of disease systems, including UTI, CD, otitis media (OM), and others. In this perspective we highlight the benefits, progress, and roadblocks to the development of precision antimicrobial therapeutics. PMID- 29507750 TI - Development and feasibility of a wearable infant wrist band for the objective measurement of physical activity using accelerometery. AB - Background: It is important to be able to reliably and feasibly measure infant and toddler physical activity in order to determine adherence to current physical activity guidelines and effects on early life development, growth and health. This study aimed to describe the development of an infant wearable wrist-worn band for the measurement of physical activity; to determine the feasibility of the device data for observational measurement of physical activity and to determine the caregiver reported acceptability of the infant wearable wrist band. Methods: After various iterations of prototypes and piloting thereof, a final wearable band was designed to fit an Axivity AX3 monitor. Mother and infant/toddler (aged 3-24 months) pairs (n = 152) were recruited, and mothers were asked for their child to wear the band with enclosed monitor at all times for 1 week (minimum 3 days). Feasibility was assessed by determining technical reliability of the data, as well as wear time and compliance according to requirements for observational measurement. Acceptability was assessed via questionnaire. Results: Technical reliability of the Axivity AX3 monitors in this age group was good. After excluding days that did not have at least 15 h of wear time, only 2% of participants had less than three valid days of data remaining, and 4% of participants had no data (due to device loss or data loss). Therefore, 94% of participants were compliant, having three or more days of wear with at least 15 h of wear per day, thus providing enough valid data for observational measurement. The majority (60%) of mothers reported being "very happy" with the safety of the device, while only 8% were "a little worried". A large majority (86%) of mothers stated that the band attracted attention from others, although this was mostly attributed to curiosity about the function of the band. Most (80%) of participants rated the comfort of the band as "comfortable", and 10% rated it as "very comfortable". Conclusions: The infant wearable band proved to be feasible and acceptable according to the criteria tested, and compliance wearing the band was good. We have therefore provided a replicable, comfortable and acceptable wearable band for the measurement of infant and toddler physical activity. PMID- 29507752 TI - Chlorthalidone, not hydrochlorothiazide, is the right diuretic for comparison. AB - We have read the study design "Comparison of effects between calcium channel blocker and diuretics in combination with angiotensin II receptor blocker on 24-h central blood pressure and vascular hemodynamic parameters in hypertensive patients: study design for a multicenter, double-blinded, active controlled, phase 4, randomized trial" by Oh GC, et al. with interest. The authors aim to compare the efficacy of amlodipine or hydrochlorothiazide (HCTZ) with an ARB. However, we wish to highlight that chlorthalidone (CTD) is the evidence-based and recommended anti-hypertensive diuretic, and should replace HCTZ in the trial to effectively compare efficacy against the CCB amlodipine. PMID- 29507751 TI - Graves' hyperthyroidism in pregnancy: a clinical review. AB - Background: Graves' hyperthyroidism affects 0.2% of pregnant women. Establishing the correct diagnosis and effectively managing Graves' hyperthyroidism in pregnancy remains a challenge for physicians. Main: The goal of this paper is to review the diagnosis and management of Graves' hyperthyroidism in pregnancy. The paper will discuss preconception counseling, etiologies of hyperthyroidism, thyroid function testing, pregnancy-related complications, maternal management, including thyroid storm, anti-thyroid drugs and the complications for mother and fetus, fetal and neonatal thyroid function, neonatal management, and maternal post-partum management. Conclusion: Establishing the diagnosis of Graves' hyperthyroidism early, maintaining euthyroidism, and achieving a serum total T4 in the upper limit of normal throughout pregnancy is key to reducing the risk of maternal, fetal, and newborn complications. The key to a successful pregnancy begins with preconception counseling. PMID- 29507753 TI - Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress. AB - Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity in hepatocytes. There are various gene variants and pseudogenes for MTs; however, there is little understanding on the functions of those non-coding MT members that are known to be expressed as long non-coding RNAs (lncRNAs) nowadays. Different from most protein-coding MT members, MT1DP was here found that remarkably induced to provoke cytotoxicity in hepatocytes in response to Cd treatment. MT1DP exerted such a pro-apoptotic function in Cd-treated hepatocytes through interacting with two partners: RhoC and MT1H. On one hand, MT1DP interacted with RhoC protein to increase the latter's stability by preventing lysosome-dependent protein degradation. Therefore, upon Cd stress, MT1DP/RhoC complex was quickly reinforced to activate RhoC-CCN1/2-AKT signaling and potentiate Ca2+ influx, leading to enhanced Cd uptake and elevated Cd toxicity. On the other hand, MT1H, a protein coding member of the MT family with little known function, was found to quickly respond to Cd exposure along with MT1DP. Mechanistically, MT1H and MT1DP were uncovered to mutually protect each other through a reciprocal ceRNA mechanism, building up a positive feedback loop to enforce MT1DP-conducted signaling upon Cd exposure. Moreover, MT1DP was found to contribute much more to the activation of RhoC-CCN1/2-AKT signaling than MT1H. Considered together, we here unveiled a mystery whether a pseudogene within the MT family, MT1DP, has actual biological functions in regulating Cd-induced cellular defense. Our findings unearthed an important role of pseudogene MT1DP in calibrating the cellular machinery to switch the cellular defense to cytotoxicity through crosslinking an interplay between its two partners, namely MT1H and RhoC, under cadmium stress. PMID- 29507754 TI - Dual extra-retinal origins of microglia in the model of retinal microglia repopulation. AB - Elucidating the origin of microglia is crucial for understanding their functions and homeostasis. Previous study has indicated that Nestin-positive progenitor cells differentiate into microglia and replenish the brain after depleting most brain microglia. Microglia have also shown the capacity to repopulate the retina after eliminating all retinal microglia. However, the origin(s) of repopulated retinal microglia is/are unknown. In this study, we aim to investigate the origins of repopulated microglia in the retina. Interestingly, we find that repopulated retinal microglia are not derived from Nestin-positive progenitor cells. Instead, they have two origins: the center-emerging microglia are derived from residual microglia in the optic nerve and the periphery-emerging microglia are derived from macrophages in the ciliary body/iris. Therefore, we have for the first time identified the extra-retinal origins of microglia in the adult mammalian retina by using a model of microglial repopulation, which may shed light on the target exploration of therapeutic interventions for retinal degenerative disorders. PMID- 29507756 TI - Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation. AB - Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis, which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future. PMID- 29507755 TI - VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. AB - N6-methyladenosine (m6A) is enriched in 3'untranslated region (3'UTR) and near stop codon of mature polyadenylated mRNAs in mammalian systems and has regulatory roles in eukaryotic mRNA transcriptome switch. Significantly, the mechanism for this modification preference remains unknown, however. Herein we report a characterization of the full m6A methyltransferase complex in HeLa cells identifying METTL3/METTL14/WTAP/VIRMA/HAKAI/ZC3H13 as the key components, and we show that VIRMA mediates preferential mRNA methylation in 3'UTR and near stop codon. Biochemical studies reveal that VIRMA recruits the catalytic core components METTL3/METTL14/WTAP to guide region-selective methylations. Around 60% of VIRMA mRNA immunoprecipitation targets manifest strong m6A enrichment in 3'UTR. Depletions of VIRMA and METTL3 induce 3'UTR lengthening of several hundred mRNAs with over 50% targets in common. VIRMA associates with polyadenylation cleavage factors CPSF5 and CPSF6 in an RNA-dependent manner. Depletion of CPSF5 leads to significant shortening of 3'UTR of over 2800 mRNAs, 84% of which are modified with m6A and have increased m6A peak density in 3'UTR and near stop codon after CPSF5 knockdown. Together, our studies provide insights into m6A deposition specificity in 3'UTR and its correlation with alternative polyadenylation. PMID- 29507757 TI - Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types. AB - Quantitative mismatches between human physiology and experimental models can be problematic for the development of effective therapeutics. When the effects of drugs on human adult cardiac electrophysiology are of interest, phenotypic differences with animal cells, and more recently stem cell-derived models, can present serious limitations. We addressed this issue through a combination of mechanistic mathematical modeling and statistical analyses. Physiological metrics were simulated in heterogeneous populations of models describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC CMs). These simulated measures were used to construct a cross-cell type regression model that predicts adult myocyte drug responses from iPSC-CM behaviors. We found that (1) quantitatively accurate predictions of responses to selective or non-selective ion channel blocking drugs could be generated based on iPSC-CM responses under multiple experimental conditions; (2) altering extracellular ion concentrations is an effective experimental perturbation for improving the model's predictive strength; (3) the method can be extended to predict and contrast drug responses in diseased as well as healthy cells, indicating a broader application of the concept. This cross-cell type model can be of great value in drug development, and the approach, which can be applied to other fields, represents an important strategy for overcoming experimental model limitations. PMID- 29507759 TI - The Ottawa Citizen Engagement and Action Model (OCEAM): A Citizen engagement Strategy Operationalized Through The Participatory Research in Ottawa, Management and Point-of-care of Tobacco (PROMPT) Study: A Community Based Participatory Action Research Project in Inner City Ottawa. AB - Plain language summary: The PROMPT study is a community-based research project designed to understand the factors which affect smoking as well as ways to manage, reduce and quit smoking among people who use drugs in Ottawa. There is strong medical evidence that smoking tobacco is related to more than two dozen diseases and conditions. Smoking tobacco remains the leading cause of preventable death and has negative health impacts on people of all ages. Although Ottawa has one of the lowest smoking rates in Ontario (12 %), major differences exist, with approximately a 96 % smoking rate among those who use drugs in the city of Ottawa. To address this inequity, we recruited and trained four community research peers who were representative of the study target population (ex- or currently homeless, insecurely housed or multi-drug users). We designed the ten step Ottawa Citizen Engagement and Action Model (OCEAM) for the PROMPT study. In this paper we have described this process in a step-by-step fashion, as used in the PROMPT study. The eighty PROMPT participants are being followed for six months and are being provided with free and off-label Nicotine Replacement Therapy (NRT). Abstract: Objectives The PROMPT study, Participatory Research in Ottawa, Management and Point-of-care of Tobacco, is a prospective cohort study which utilizes community-based participation and social network-based approaches to address tobacco dependence in inner city Ottawa. The project was designed to: facilitate retention of participants; to understand the barriers and facilitators of smoking; optimize ways to manage, reduce, and quit tobacco use among people who use drugs in Ottawa, Canada. The purpose of this paper is to describe the processes utilized in citizen or patient engagement in academic research, through our tobacco dependence management project in the inner city population in Ottawa, Canada.Background Tobacco smoking is inequitably distributed in Canada with rates at 12 % in Ottawa, as compared to 18 % in rest of Canada. However, the PROUD Study (Participatory Research in Ottawa: Understanding Drugs) demonstrated that 96 % of the inner city population, of Ottawa currently smoke tobacco. This distinct inequity in tobacco use translates into inequitable distribution of health outcomes, such morbidity and mortality in this population. Consequently, a community-based participatory, peer-led research project was conducted in the inner city population of Ottawa.Methods We recruited and trained four community research peers who were representative of the study target population. We conceived, designed and operationalized the ten-step Ottawa Citizen Engagement and Action Model (OCEAM) for the PROMPT study. The peers have co-led all aspects of the project from conceptualizing the study question to participating in knowledge translation. Each step of the project had defined objectives and outcome measures.Discussion The involvement of peers in recruitment ensured representation of tobacco and drug users-individuals truly representative of the intended target population. Peer, participant engagement and trust was established from the conception of the project. For historical and self-evident reasons, trust and engagement is rarely found in this population. Peers successfully participated in all ten steps of the Citizen Engagement and Action model. The PROMPT study utilized the CBPR (Community Based Participatory research) approach to encourage engagement and build trust in a difficult to reach and hard to treat, inner city population. The ten-step OCEAM model was conceived, designed and operationalized and the PROMPT study will continue to follow the eighty PROMPT participants for six months to understand the optimal ways to manage, reduce, and quit smoking within an inner city population. PMID- 29507760 TI - What's in a "research passport"? A collaborative autoethnography of institutional approvals in public involvement in research. AB - Plain English summary: The article analyses the process of securing permissions for members of the public (we refer to them as "research partners") and academics involved in a qualitative study of public involvement in research (PIR) across eight health sciences projects in England and Wales. All researchers, including research partners, need to obtain a "research passport" from UK NHS trusts where they intend to carry out research. The article presents the experiences and observations of the authors, who all went through the process.Research partners encountered many challenges, as the overall bureaucratic procedures proved burdensome. The effects were felt by the academics too who had to manage the whole process. This influenced the way research partners and academics built social and personal relationships required for the successful conduct of the project. We also discuss the tensions that emerged around the issue of whether research partners should be treated as a professional category on their own, and other issues that influenced the PIR processes.In the concluding section, we make a number of practical recommendations. Project teams should allow enough time to go through all the hurdles and steps required for institutional permissions, and should plan in advance for the right amount of time and capacity needed from project leaders and administrators. Bureaucratic and organisational processes involved in PIR can sometimes produce unanticipated and unwanted negative effects on research partners. Our final recommendation to policy makers is to focus their efforts on making PIR bureaucracy more inclusive and ultimately more democratic. Abstract: Background In the growing literature on public involvement in research (PIR), very few works analyse PIR organizational and institutional dimensions in depth. We explore the complex interactions of PIR with institutions and bureaucratic procedures, with a focus on the process of securing institutional permissions for members of the public (we refer to them as "research partners") and academics involved in health research. Methods We employ a collaborative autoethnographic approach to describe the process of validating "research passports" required by UK NHS trusts, and the individual experiences of the authors who went through this journey - research partners and academics involved in a qualitative study of PIR across eight health sciences projects in England and Wales. Results Our findings show that research partners encountered many challenges, as the overall bureaucratic procedures and the emotional work required to deal with them proved burdensome. The effects were felt by the academics too who had to manage the whole process at an early stage of team building in the project. Our thematic discussion focuses on two additional themes: the emerging tensions around professionalisation of research partners, and the reflexive effects on PIR processes. Conclusions In the concluding section, we make a number of practical recommendations. Project teams should allow enough time to go through all the hurdles and steps required for institutional permissions, and should plan in advance for the right amount of time and capacity needed from project leaders and administrators. Our findings are a reminder that the bureaucratic and organisational structures involved in PIR can sometimes produce unanticipated and unwanted negative effects on research partners, hence affecting the overall quality and effectiveness of PIR. Our final recommendation to policy makers is to focus their efforts on making PIR bureaucracy more inclusive and ultimately more democratic. PMID- 29507758 TI - A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure. AB - A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those "fold-change" genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies. PMID- 29507761 TI - Including patients in core outcome set development: issues to consider based on three workshops with around 100 international delegates. AB - Plain English summary: This commentary article describes three interactive workshops that explored how patients can contribute to decisions about what outcomes are measured in clinical trials across the world. Outcomes like quality of life, side-effects and pain are used in trials to measure whether a treatment is effective. Here, we outline how research groups are increasingly coming together to develop 'core outcomes sets' for particular conditions. Core outcome sets are lists of agreed outcomes. Their use will help in identifying which treatments are effective by enabling people to compare the findings of different clinical trials in the same condition. Currently, it is often very difficult to make these comparisons because different studies often measure different outcomes. Delegates attending the workshops included patients, clinicians and researchers. They discussed ways of making core outcome set development more meaningful and accessible for patients, and ensuring that they have a genuine say in the development process. This article summarises these discussions and concludes by identifying three distinctive challenges in securing patient input to core outcome set development: the process and objectives can seem far removed from the immediate concerns of patients, difficulties can arise in securing patient input on an international scale, and difficulties can also arise in bringing multiple stakeholder groups together to achieve consensus. While patient participation, involvement and engagement in core outcome set development can draw on lessons from other research areas, these distinctive challenges point to the need for distinctive solutions to enable meaningful patient input to core outcome set development. Abstract: Background This article describes three workshops that explored how patients can contribute to decisions about what outcomes are measured in clinical trials. People need evidence about what treatments are best for particular health conditions. The strongest evidence comes from systematic reviews comparing outcomes across different studies of treatments for a particular condition. However, it is often difficult to do these comparisons because the different studies-even though they have all investigated the same condition-often measure different outcomes. To tackle this problem, research teams are increasingly coming together to develop core outcome sets (COS) for particular conditions or treatments. The goal is that across the world, all the research teams working on the same condition or treatment will then use the COS in their research.Main body We report on three interactive workshops that explored how patients and the public can contribute to decision making about what outcomes should be included in a COS. About 100 international delegates, including researchers, clinicians and patients, attended the workshops. The workshops were held in the United Kingdom, Italy and Canada as part of the COMET (Core Outcome Measures in Effectiveness Trials) Initiative annual meetings. Patients who had some experience as research advisors, collaborators, partners or co-ordinators facilitated the workshops together with a researcher. Notes made during each workshop informed the preparation of this article. Workshop discussion focussed on ways of making core outcome set development more meaningful and accessible for patients. Delegates wanted patients to have a genuine say, alongside other stakeholders, in what outcomes are included in COS. Delegates felt that key to ensuring this is recognising that patient participation in COS development alone is not enough, and that patients will also need to be involved in the design of COS development studies.Conclusion We conclude by pointing to some distinctive challenges in including patients in COS development. While the COS development community can draw on the lessons learnt from other research areas about patient participation, involvement and engagement, the distinctive challenges that arise in COS development point to the need for some distinctive solutions too. PMID- 29507762 TI - "Exploring knowledge-user experiences in integrated knowledge translation: a biomedical investigation of the causes and consequences of food allergy". AB - Plain English summary: Food allergy is a serious public health problem in Canada and other high-income countries, as it is potentially life threatening and severely impacts the quality of life for individuals and their families. Yet, many questions still remain as to its origins and determinants, and the best practices for treatment. Formed to tackle these very questions, the GET-FACTS research study centers on a novel concept in biomedical research: in order to make this science useful, knowledge creation must include meaningful interactions with knowledge-users. With this, knowledge-users are present at every stage of the research and are crucial, central and equal contributors. This study reflects on the early part of that journey from the perspective of the knowledge-users. We conducted interviews with all non-scientist members of the GET-FACTS steering committee, representing Canadian organizations that deal with patient advocacy and policy with regards to food allergy. Steering committee members had a clear sense that scientists and knowledge-users are equally responsible for putting knowledge into action and the importance of consulting and integrating knowledge users throughout research. They also have high expectations for the GET-FACTS integrated process; that this model of doing science will create better scientists (e.g. improve communication skills) and make the scientific output more useful and relevant. Our work highlights both the unique contributions that knowledge-users can offer to knowledge creation as well as the challenges of trying to unify members from such different communities (policy/advocacy and biomedical science). There remains a real need to develop more touch points and opportunities for collaboration if true integration is to be achieved. Despite the obstacles, this model can help change the way knowledge is created in the biomedical world. Abstract: ?. Background: Despite the burden of food allergic disease many questions remain as to its origins, determinants and best practices for treatment. Formed to tackle these very questions, the GET-FACTS (Genetics, Environment and Therapies: Food Allergy Clinical Tolerance Studies) research study centers around a novel concept in biomedical research: in order to make this science useful, knowledge creation must include meaningful interactions with knowledge-users, known as Integrated Knowledge Translation (IKT). In IKT, knowledge-users are present at every stage of the research and are crucial, central and equal contributors. This paper contributes to this exciting form of research by reflecting on the beginning of that journey from the perspective of the knowledge-users. Methods: Semi structured in-depth interviews were conducted in year 2 of the 5 year GET-FACTS project with all (n = 9) non-scientist members of the GET-FACTS steering committee, representing Canadian organizations that deal with patient advocacy and policy with regards to food allergy. Transcripts were coded and organized by themes developed both deductively and inductively. Results: Steering committee members indicated a clear sense that scientists and knowledge-users are equally responsible for the translation of knowledge into action and the importance of consulting and integrating knowledge-users throughout research. Overall, these knowledge-users have very high expectations for the GET-FACTS IKT process; they feel that this model of doing science will create better scientists (e.g. improve communication skills) and make the resulting science more useful and relevant; indeed, they reported that this model of knowledge creation can be paradigm shifting. Conclusions: This study highlights both the unique contributions that knowledge-users can offer to knowledge creation as well as the challenges of trying to unify members from such different communities (policy/advocacy and biomedical science). While our steering committee has a strong conceptual grasp on IKT and vision for their contributions, execution is not without challenges. There remains a real need to develop more touch points and opportunities for collaboration if true integration is to be achieved. Despite the obstacles, the GET-FACTS IKT model represents a new approach to knowledge creation in Canadian biomedical research and can help foster a culture of openness to participant involvement. PMID- 29507763 TI - Power to the people: To what extent has public involvement in applied health research achieved this? AB - Plain English summary: Public involvement is required for applied health research funded in the UK. One of the largest funders, the National Institute of Health Research (NIHR), makes it clear that it values the knowledge of patients and the public. As a result, there are now many resources to make sure that the public voice is included in decision-making about research. However, there is concern that the public voice still has limited impact on research decision-making. This article asks to what extent has power shifted from the scientific research community to the public? It looks at how much power and impact patients and members of the public have about research by asking: How do the public contribute to deciding which research areas and which research projects should be funded? How do they influence how the research is carried out? The article argues that there is evidence that the public voice is present in research decision-making. However, there is less evidence of a change in the power dynamic between the scientific research community and the public. The public involved in research are not always equal partners. The scientific research community still has the loudest voice and patients and the public do not always feel sufficiently empowered to challenge it. Abstract: Public involvement in applied health research is a pre-requisite for funding from many funding bodies. In particular the National Institute of Health Research (NIHR) in the UK, clearly states that it values lay knowledge and there is an expectation that members of the public will participate as research partners in research. As a result a large public involvement infrastructure has emerged to facilitate this. However, there is concern that despite the flurry of activity in promoting public involvement, lay knowledge is marginalised and has limited impact on research decision-making. This article asks to what extent has power shifted from the scientific research community to the public? It discusses the meaning of power and models of public involvement and examines the development of public involvement in applied health research. It identifies public involvement in a range of decision-making: identifying priority areas for commissioning research; making decisions about which projects are funded; decisions about details of research design. Whilst there is evidence that the public voice is present in the composition of research proposals submitted to NIHR and in the decision-making about which projects are funded and how they are carried out, there is less evidence of a change in the power dynamic manifest in social relations between the scientific research community and the public. As a result the biomedical model remains dominant and largely unchallenged in research decision-making. PMID- 29507764 TI - Lay involvement in the analysis of qualitative data in health services research: a descriptive study. AB - Plain English summary: There is a consensus that patients and the public should be involved in research in a meaningful way. However, to date, lay people have been mostly involved in developing research ideas and commenting on patient information.We previously published a paper describing our experience with lay partners conducting observations in a study of how patients in hospital are involved with their medicines. In a later part of the same study, lay partners were also involved in analysing interviews that a researcher had conducted with patients, carers and healthcare professionals about patient and carer involvement with medicines in hospital. We therefore wanted to build on our previous paper and report on our experiences with lay partners helping to conduct data analysis. We therefore interviewed the lay members and researchers involved in the analysis to find out their views.Both lay members and researchers reported that lay partners added value to the study by bringing their own perspectives and identifying further areas for the researcher to look for in the interviews. In this way researchers and lay partners were able to work together to produce a richer analysis than would have been possible from either alone. Abstract: Background It is recognised that involving lay people in research in a meaningful rather than tokenistic way is both important and challenging. In this paper, we contribute to this debate by describing our experiences of lay involvement in data analysis.Methods We conducted semi-structured interviews with the lay partners and researchers involved in qualitative data analysis in a wider study of inpatient involvement in medication safety. The interviews were transcribed verbatim and coded using open thematic analysis.Results We interviewed three lay partners and the three researchers involved. These interviews demonstrated that the lay members added value to the analysis by bringing their own perspectives; these were systematically integrated into the analysis by the lead researcher to create a synergistic output. Some challenges arose, including difficulties in recruiting a diverse range of members of the public to carry out the role; however there were generally fewer challenges in data analysis than there had been with our previous experience of lay partners' involvement in data collection.Conclusions Lay members can add value to health services research by being involved in qualitative data analysis. PMID- 29507765 TI - Determining priorities for research to improve fundamental care on hospital wards. AB - Plain English summary: The aim of this project was to find out the priorities for research that could improve fundamental care. 'Fundamental care' covers all aspects of basic care in hospital wards, such as helping with core physical needs, building positive relationships and keeping patients safe.By setting the priorities with patients, carers, the public and health care professionals, research can look at the issues that really matter to people who are receiving or delivering care in hospital wards.Previously, prioritisation exercises have started with a menu of options and asked people to choose from that list. They have also been focused on specific health conditions. Traditionally, there has been little opportunity for patients, carers and the public to contribute to identifying the issues to be prioritised.To develop the priorities for research, we started by exploring what is meant by 'fundamental care', looking at patient and carer accounts and academic and policy reports. Patients, carers, staff, and members of the public were consulted via surveys, interviews and group discussions to share experiences and issues.A list of 15 topics was identified based on what was most commonly mentioned by patients, carers and healthcare professionals as well as what was practical for the CLAHRC Wessex team to research. A workshop with patients, carers and healthcare professionals was held, to decide the top 5 areas.The five priority areas identified were:Nurse staffingIndividualised patient careStaff communicationStaff attitudes and relationships with patientsInformation about care/communication. Abstract: Background The provision of high quality fundamental care in hospitals is a top priority for the NHS. Recent reports and investigations highlight that at times care has fallen below standard. It is unclear what research should be prioritised to improve care. The aim of this work is to involve patients/carers/public, clinicians and other stakeholders to identify issues that are priorities for research which could improve fundamental care in hospital. Methods Patient and public involvement was integral to this project, with a patient leader/service user being a member of the core team who designed and executed this research. After consideration of existing priority setting approaches, we developed an inclusive approach which consisted of six main phases: 1) Development of a conceptual framework of fundamental care, based on reports and literature 2) Consultation with a wide range of stakeholders through a survey, focus groups and interviews 3) Identifying themes from the responses to the consultation phase (76 themes identified) 4) Analysis to identify the 15 topics most frequently cited 5) Prioritisation of the top 15 themes through a half day workshop, which led to a shortlist of five themes 6) Development of the top 5 themes into research areas. Results Three hundred forty stakeholders (29 % of whom were patients/carers/public) completed the consultation survey. Analysis of the survey responses and of focus groups and interviews led us to identify 15 high scoring themes. We presented these at the prioritisation workshop, attended by 39 participants (23 of whom patients/carers/public). After a voting exercise, the 5 top research priorities which emerged were: nurse staffing; individualised patient care; staff communication; staff attitudes and relationships with patients; and information about care. Conclusions We involved a range of stakeholders in identifying topics for research to improve fundamental care and asked them to prioritise these. The process provided a means of reaching consensus as to the important issues for future research to focus on to improve fundamental care on hospital wards. PMID- 29507766 TI - Patient and public involvement in Paediatric Intensive Care research: considerations, challenges and facilitating factors. AB - Plain English summary: Paediatric Intensive Care (PIC) provides care to extremely ill children. Research in this area can be difficult because children are often too sick to discuss being involved in a study and parents are too upset about their child to think about taking part. This makes it even more important that research is well designed. We conducted a review of the literature about involving patients and the public (PPI) in PIC research. We wanted to know what PPI has taken place, who had been consulted and how this was undertaken. We reviewed the titles and abstracts of 4717 papers but found only 4 relevant papers. Three of the papers had consulted with parents of children who had been on PIC but only one study had spoken directly to a child themselves. The studies had used a number of different methods to invite people to take part but there did not appear to be one solution. All of the studies thought PPI was good for the development of their research but none of them had tried to measure what had changed as a result. There are difficulties associated with carrying out PPI in the PIC setting. Researchers need to share more of their experiences, positive and negative, so we can try to identify the best ways of carrying out PPI in PIC studies. This will help ensure that research studies are designed which address the needs and concerns of children and their parents. Abstract: Introduction Involving the public in health care research is reported to enhance the quality, appropriateness, acceptability and relevance to patients and the public (INVOLVE, Briefing notes for researchers, 2012; Staniszewska et al., Int J Technol Assess Health Care 274:391-9, 2011). Conducting research with children and young people is regarded as challenging and this makes it even more important that the research is well designed and understands the perspective of the child and family. We conducted a narrative literature review of the Patient and Public Involvement (PPI) literature, in the context of Paediatric Intensive Care (PIC). Our aims were to identify what PPI activity has taken place, with whom researchers engaged and what outcomes they reported. Method Electronic databases Medline, CINAHL and Embase (January 2000- June 2016) were searched using the search terms patient and public involvement and consultation. Participants were defined as child, parent, paediatric or pediatric and the context as intensive or critical care. Papers were excluded where activity reflected 'participants' as research subjects. Included papers were reviewed using the GRIPP checklist to appraise the quality of reporting. Results The search strategy identified 4717 abstracts. Seventeen papers were reviewed in full and four papers were included, all of which are case studies, describing a consultation approach. None of the papers described PPI as a multi-stage process. Only one study engaged with a former PIC patient and the majority of those consulted did not have any PIC experience. Activity was reported as being of benefit but there was no measurement of the impact of PPI. Conclusion There are numerous challenges associated with the conduct of research in PIC. It is therefore essential that the perspective of children, young people and their parents have been considered in the design of trials. However, there are few published accounts of PPI within the PIC context and the accounts that exist highlight issues about who to approach and when, and a lack of clarity about the best ways to engage with them. Research Ethics Committees and funding bodies expect to see evidence of PPI in research applications and we need to develop our understanding of what contributes towards successful PPI in this context. PMID- 29507767 TI - Patients' motivations and interest in research: characteristics of volunteers for patient-led projects on PatientsLikeMe. AB - Plain English summary: PLM is an online platform that provides tools for individuals to track their health and connect with other patients and while PLM has invited patients to participate in various research projects throughout the years, an examination into what motivates patients to want to get involved in clinical research has not been done. During our analysis of applications submitted by members of the PLM community, we looked for reasons patients want to participate in research and their overall beliefs about clinical research, in general. In addition, we analyzed obstacles and barriers toward patients' research participation. We observed the following:Patients are typically motivated by their individual needs and are most interested in research specific to their own condition.To get the most from patients' involvement and to enhance patients' contribution towards research goals, researchers should explain the research goal and requirements of each goal in clear and transparent terms, making it easy for patients to understand, thus avoiding any potential miscommunication.Future studies are needed to determine the best methods for involving patients in clinical research. Background: Historically, throughout the clinical and medical research arenas, patients have been perceived as passive "subjects" rather than as individuals who may have thoughts regarding research development, research plans, implementation of research studies, and data analysis. However, it is becoming more clear that patients increasingly want to have a more active role in clinical research studies and in the management of their own medical conditions as evidenced by a "no decision about us without us" stance, meaning patients want to make informed decisions about their health while working alongside their healthcare professionals. The central aim of this research study was to determine patients' motivations for being involved in research design and understand their perceptions of current research practices. Methods: Two independent qualitative studies were conducted. In Study 1, we analyzed applications submitted by self-identified patients from within the PatientsLikeMe (PLM) community, for acceptance onto our advisory panel. The advisory panel was tasked with developing a best practice guide for how to involve patients in research. During the qualitative analysis, we identified major reasons for and topics of interest associated with PLM members' motivation to apply to the advisory panel. In Study 2, we analyzed applications from PLM community members and from patients outside the PLM community for a patient-led patient-reported-outcome (PRO) development project. Similar to Study 1, we identified themes associated with patients' motivations to participate in developing a new PRO. Results: PLM members are interested in being involved in medical research for various reasons, including facilitating provider-patient communication, improving comprehension of medical information, understanding their disease, and bringing a more individualized approach to health care in general. Conclusion: Challenges in the process of appropriate involvement of patients in research are discussed. In both studies, the applicants shared their interests in being involved in research. However, in Study 2, many of the patients shared ideas that were not appropriate for the development of a PRO, which indicated limitations in how the invitation and application explained the project to patients. Future studies should contribute to determining the most appropriate method for involving patients in various settings. PMID- 29507768 TI - Exploring the motivations of patients with type 2 diabetes to participate in clinical trials: a qualitative analysis. AB - Plain English Summary: Certain patient groups are reluctant to engage with clinical research and consequently findings are not always truly representative of the wider population. With the emphasis on evidence-based clinical practice, clinical research as a core activity for the National Health Service (NHS) and the rising prevalence of diabetes within the United Kingdom (UK) it is important to understand what motivates people to volunteer for research in diabetes and identify the barriers to this involvement. This research interviewed 12 people with type 2 diabetes who had previously taken part in diabetes clinical trials. The transcripts of these interviews were analysed to identify themes that informed the study findings.There were wide ranging reasons for participating in clinical trials. Both altruistic and self-interest motivation were universally expressed. The thought of helping others was a powerful experience but for some there was a sense of duty to volunteer especially if they had benefited from NHS care. Participating was empowering, with extra access to healthcare professionals, practical information and support for their condition. Coping with the logistics of being in a trial relied upon a strong network of family and friends. Some felt anxious at the end of the trial having been supported during the research and appreciating the camaraderie of belonging to a group or team.This study provides insights into the motivations and barriers to involvement in clinical research in type 2 diabetes helping researchers to encourage and support more volunteers in clinical trials. Abstract: Background Certain patient groups are reluctant to engage with clinical research and consequently findings of the research are not always truly representative of the wider population. This, together with a growing prominence of evidence-based clinical practice, an increasing emphasis of clinical research as a core activity for the NHS and the rising prevalence of diabetes within the UK population, requires an understanding of motivations and barriers for patients consenting to participate in diabetes clinical trials.Methods To understand patients' motivations for participating in clinical trials in type 2 diabetes. We conducted a qualitative study involving 12 participants with type 2 diabetes with previous involvement in clinical trials. Individual, tape-recorded, semi structured interviews were conducted to explore motivations and experiences of the participants. We carried out thematic content analysis to identify themes, from which theoretical interpretations were formed.Results There were wide ranging reasons for participating in clinical trials. We identified 3 key themes: (1) Motivations ranged from altruism to self-interest; (2) participation in clinical trials was an empowering experience; and (3) key to participation was a strong network of support.Conclusion Patients are motivated to participate in clinical trials by a sense of altruism coupled with self-interest. This self-interest centres on the belief that participation would be an informative and empowering experience with increased access to healthcare professionals. However the ability to cope with the logistics of being in clinical trials relies upon an extensive and reliable network of support from family, friends, work colleagues and employers, together with a collaborative approach to their care from the researchers and their usual healthcare providers. PMID- 29507769 TI - Involvement of persons with lived experience of a prenatal diagnosis of congenital heart defect: an explorative study to gain insights into perspectives on future research. AB - Plain English summary: Ultrasound examinations during pregnancy have led to an increased number of detected heart defects in fetuses. Pregnant women and their partners are often unprepared for these news, and experience several difficulties following the diagnosis. We asked persons with personal experience to participate in group discussions about relevant future research topics. The discussions revealed that future research should investigate supplemental written information or follow-up appointments with health professionals. Researchers were also encouraged to focus their efforts on structures that offer emotional support. The emotional support could be from those that share similar experiences, or additional support from a health professional. The results of this study illustrate the need for researchers to continue their work to test ways to support persons faced with these diagnoses. Abstract: Background A prenatal diagnosis of a congenital heart defect in the fetus is a traumatic life event for pregnant women and their partners. Previous research indicates a need for research that takes steps to support these individuals following the diagnosis. Patient and public involvement is a proposed method of identifying relevant research topics, leading to patient-focused research protocols and relevant support interventions.The overarching aim of this study was to gain insights into relevant future research topics among persons faced with a pre na tal diagnosis of congenita l heart defect in the fetus. Methods One group of parents to prenatally diagnosed children with a congenital heart defect (n = 5) and one group of individuals with experience of termination of a pregnancy following a prenatal diagnosis of a congenital heart defect (n = 5) were purposefully recruited. Each group of representatives was involved in a face-to-face focus group discussion, analyzed through qualitative content analysis. Results The representatives suggested a need for future research that addresses informational support in the forms as supplemental written information or follow-up consultations. Moreover, interventions that offer emotional support were suggested, in the forms of peer support or additional professional psychosocial support. Conclusion Several interventions were suggested by patient representatives, indicating a need for multiple intervention studies to be conducted in the context of a prenatal diagnosis of a congenital heart defect in the fetus. We recommend that future studies test supplemental written information, follow-up consultations, peer support, and additional professionals psychosocial support following the diagnosis. PMID- 29507770 TI - A systematic scoping review of the evidence for consumer involvement in organisations undertaking systematic reviews: focus on Cochrane. AB - Plain English summary: Cochrane is the largest international producer of systematic reviews of clinical trial evidence. We looked for published evidence that reports where consumers (patients and the public) have been involved in Cochrane systematic reviews, and also in reviews published by other organisations.We found 36 studies that reported about consumer involvement either in individual systematic reviews, or in other organisations. The studies showed that consumers were involved in reviews in a range of different ways: coordinating and producing reviews, making reviews more accessible, and spreading the results of reviews ("knowledge transfer"). The most common role was commenting on reviews ("peer reviewing"). Consumers also had other general roles, for example in educating people about evidence or helping other consumers. There were some interesting examples of new ways of involving consumers. The studies showed that most consumers came from rich and English speaking countries. There was little evidence about how consumer involvement had changed the reviews ("impact"). The studies found that consumer involvement needed to be properly supported.In future we believe that more research should be done to understand what kind of consumer involvement has the best impact; that more review authors should report how consumers have been involved; and that consumers who help with reviews should come from more varied backgrounds. Abstract: Background Cochrane is the largest international producer of systematic reviews, and is committed to consumer involvement in the production and dissemination of its reviews. The review aims to systematically scope the evidence base for consumer involvement in organisations which commission, undertake or support systematic reviews; with an emphasis on Cochrane. Methods In June 2015 we searched six databases and other sources for studies of consumer involvement in organisations which commission, undertake or support systematic reviews, or in individual systematic review processes. All types of reports and evaluations were eligible. Included studies were combined in a narrative synthesis structured by the level of evaluation and the type of involvement. Results We identified 36 relevant studies. Eleven of these were evaluations at the level of a whole organisation; seven of these studied consumer involvement in Cochrane. Ten studies examined individual Cochrane review groups. Twelve studies reported on individual reviews; only two of these were Cochrane reviews. Finally, three studies were themselves syntheses of other studies. The included studies reported varying levels of consumer involvement across a wide range of activities related to review design and conduct. These included activities such as priority setting and outcome definition as well as review-specific roles such as acting as peer referees and producing plain language summaries. The level of satisfaction and awareness of impact was generally higher in studies focused on individual Cochrane review groups than in the organisation-wide studies. Conclusions There was evidence of highly variable levels and types of consumer involvement within and beyond Cochrane, but limited evidence for what makes the most effective methods and levels of involving consumers in review production. Where evidence of impact was found at the level of individual reviews and review groups it underlined the need for properly resourced and supported processes in order to derive the greatest benefit from the lived experiences of consumers who are willing to be involved. Where reviews do involve consumers, their contribution to the final result could be more clearly identified. More rigorous evaluations are needed to determine the best approach to achieving this. Trial registration Not applicable. PMID- 29507771 TI - Tailoring and field-testing the use of a knowledge translation peer support shared decision making strategy with First Nations, Inuit and Metis people making decisions about their cancer care: a study protocol. AB - Plain English summary: Tailoring and testing a peer support decision making strategy with First Nations, Inuit and Metis people making decisions about their cancer care: A study protocol.First Nations, Inuit and Metis (FNIM) people face higher risks for cancer compared to non-FNIM populations. They also face cultural barriers to health service use. Within non-FNIM populations an approach to health decision making, called shared decision making (SDM), has been found to improve the participation of people in their healthcare. Peer support with SDM further improves these benefits. The purpose of this study is to tailor and test a peer support SDM strategy with community support workers to increase FNIM people's participation in their cancer care.This project has two phases that will be designed and conducted with a Steering Committee that includes members of the FNIM and cancer care communities. First, a peer support SDM strategy will be tailored to meet the needs of cancer system users who are receiving care in urban settings, and training in the SDM strategy developed for community support workers. Three communities will be supported for participation in the study and community support workers who are peers from each community will be trained to use the SDM strategy.Next, each community support worker will work with a community member who has a diagnosis of cancer or who has supported a family member with cancer. Each community support worker and community member pair will use the SDM strategy. The participation and experience of the community support worker and community member will be evaluated.The research will be used to develop strategies to support people who are making decisions about their health. Abstract: Tailoring and field-testing the use of a knowledge translation peer support shared decision making strategy with First Nations, Inuit and Metis people making decisions about their cancer care: A study protocol Background First Nations, Inuit and Metis ("FNIM") people face increased cancer risks in relation to general populations and experience barriers to health service use. Shared decision making (SDM) has been found to improve peoples' participation and outcomes in healthcare and peer support with SDM further improves these benefits. The purpose of this study is to tailor and then field test, by and with FNIM communities, a peer support SDM strategy for use in cancer care. Methods This project has 2 theory-driven phases and 5 stages (a-e). A core research team that includes members of the Aboriginal Cancer Control Unit of Cancer Care Ontario communities and academic researchers, will work with a Steering Committee. In phase 1, (stage a) a peer support SDM strategy will be tailored to meet the needs of cancer system users who are receiving care in urban settings and (stage b), training developed that will i) introduce participant communities to SDM, and ii) train community support workers (CSWs) within these communities. Next (stage c), three communities will be approached for voluntary participation in the study. These communities will be introduced to SDM in community meetings, and if in agreement then CSWs from each community will be recruited to participate in the study. One volunteer CSW from each community will be trained to use the peer support SDM strategy to enable phase 2 (field test of the peer support SDM strategy).During phase 2 (stage d), each CSW will be matched to a volunteer community member who has had a diagnosis of cancer or has supported a family member with cancer and is familiar with Ontario cancer systems. Each CSW community member pair (3 to 4 pairs/community) will use the tailored peer support SDM strategy; their interaction will be audio-recorded and their participation and experience evaluated (total of 9 to 12 interviews). As well (stage e), data will be collected on health systems' factors related to the use of the peer support SDM strategy. Discussion Findings will develop peer support SDM strategies to enhance participation of FNIM people in cancer care decisions, advance knowledge translation science, and support a proposal to conduct a multi site implementation trial. PMID- 29507772 TI - Defining and evaluating novel procedures for involving patients in Core Outcome Set research: creating a meaningful long list of candidate outcome domains. AB - Plain English summary: Outcome domains are aspects of a condition that matter to patients and clinicians and can be measured to assess treatment effects. For tinnitus, examples include 'tinnitus loudness' and 'ability to concentrate'. This study focuses on the first stage of agreeing which outcome domains should be measured in all clinical trials of tinnitus. Crucially, it involves identifying outcome domains, prior to a voting process. This article describes how we effectively involved patients in that study design process, and reflects on the impact of their input.The study first compiled a long list of all possible outcome domains before asking interested parties, including patients, to vote which ones to include. Ensuring patients fully participate in this process holds unique challenges as it can be long, repetitive and its purpose far removed from their needs. These challenges may be addressed by involving patients in designing the research. There is evidence that other research teams are doing this, but its reporting is not detailed enough to guide others. Our paper seeks to address this.We describe how we involved patients (people living with tinnitus) in creating a long list of outcome domains that we included in our study. We also reflect on the benefits this brought. Two patients partnered with us in designing the survey. We also consulted an independent patient review panel. Involving patients reduced the list of domains included in the survey and made domain names and associated descriptions clearer. Our resulting survey performed well in recruiting and retaining patients as participants. Abstract: Background Tinnitus is a complex audiological condition affecting many different domains of everyday life. Clinical trials of tinnitus interventions measure and report those outcome domains inconsistently and this hinders direct comparison between study findings. To address this problem, an ongoing project is developing a Core Outcome Set; an agreed list of outcome domains to be measured and reported in all future trials. Part of this project uses a consensus methodology ('Delphi' survey), whereby all relevant stakeholders identify important and critical outcome domains from a long list of candidates. This article addresses a gap in the patient involvement literature by describing and reflecting on our involvement of patients to create a meaningful long list of candidate outcome domains.Methods Two Public Research Partners with lived experience of tinnitus reviewed an initial list of 124 outcome domains over two face-to-face workshops. With the Study Management Team, they interpreted each candidate outcome domain and generated a plain language description. Following this, the domain names and descriptions underwent an additional lay review by 14 patients and 5 clinical experts, via an online survey platform.Results Insights gained from the workshops and survey feedback prompted substantial, unforeseen modifications to the long list. These included the reduction of the number of outcome domains (from 124 to 66) via the exclusion of broad concepts and consolidation of equivalent domains or domains outside the scope of the study. Reviewers also applied their lived experience of tinnitus to bring clarity and relevance to domain names and plain language descriptions. Four impacts on the Delphi survey were observed: recruitment exceeded the target by 171%, there were equivalent numbers of patient and professional participants (n = 358 and n = 312, respectively), feedback was mostly positive, and retention was high (87%).Conclusions Patient involvement was an integral and transformative step of the study design process. Patient involvement was impactful because the online Delphi survey was successful in recruiting and retaining participants, and there were many comments about a positive participatory experience. Seven general methodological features are highlighted which fit with general principles of good patient involvement. These can benefit other Core Outcome Set developers. PMID- 29507773 TI - Exploring cued and non-cued motor imagery interventions in people with multiple sclerosis: a randomised feasibility trial and reliability study. AB - Background: Motor imagery (MI) is increasingly used in neurorehabilitation to facilitate motor performance. Our previous study results demonstrated significantly improved walking after rhythmic-cued MI in people with multiple sclerosis (pwMS). The present feasibility study was aimed to obtain preliminary information of changes in walking, fatigue, quality of life (QoL) and MI ability following cued and non-cued MI in pwMS. The study further investigated the feasibility of a larger study and examined the reliability of a two-dimensional gait analysis system. Methods: At the MS-Clinic, Department of Neurology, Medical University of Innsbruck, Austria, 15 adult pwMS (1.5-4.5 on the Expanded Disability Status Scale, 13 females) were randomised to one of three groups: 24 sessions of 17 min of MI with music and verbal cueing (MVMI), with music alone (MMI), or non-cued (MI). Descriptive statistics were reported for all outcomes. Primary outcomes were walking speed (Timed 25-Foot Walk) and walking distance (6 Minute Walk Test). Secondary outcomes were recruitment rate, retention, adherence, acceptability, adverse events, MI ability (Kinaesthetic and Visual Imagery Questionnaire, Time-Dependent MI test), fatigue (Modified Fatigue Impact Scale) and QoL (Multiple Sclerosis Impact Scale-29). The reliability of a gait analysis system used to assess gait synchronisation with music beat was tested. Results: Participants showed adequate MI abilities. Post-intervention, improvements in walking speed, walking distance, fatigue, QoL and MI ability were observed in all groups. Success of the feasibility criteria was demonstrated by recruitment and retention rates of 8.6% (95% confidence interval, CI 5.2, 13.8%) and 100% (95% CI 76.4, 100%), which exceeded the target rates of 5.7% and 80%. Additionally, the 83% (95% CI 0.42, 0.99) adherence rate surpassed the 67% target rate. Intra-rater reliability analysis of the gait measurement instruments demonstrated excellent Intra-Class Correlation coefficients for step length of 0.978 (95% CI 0.973, 0.982) and step time of 0.880 (95% CI 0.855, 0.902). Conclusion: Results from our study suggest that cued and non-cued MI are valuable interventions in pwMS who were able to imagine movements. A larger study appears feasible, however, substantial improvements to the methods are required such as stratified randomisation using a computer-generated sequence and blinding of the assessors. Trial registration: ISRCTN ISRCTN92351899. Registered 10 December 2015. PMID- 29507775 TI - A geriatric patient with spinal cord injury without radiographic abnormality: outcomes and causes. AB - Introduction: Although the prognosis of spinal cord injury without radiographic evidence of abnormality (SCIWORA) depends on the severity of the initial neurological damage, most patients with American Spinal Injury Association impairment scale grade D are expected to recover fully. Case presentation: An 85 year-old patient with SCIWORA and urinary incontinence, who did not produce the expected response to rehabilitation, displayed the central, peripheral, and autonomic nervous system findings together. Conventional radiography, computed tomography, and even magnetic resonance imaging were unable to explain this complicated neurological condition thoroughly. More in-depth research into the patient's history revealed some sequelae left by urinary surgery and chemotherapy. Discussion: Comorbidities in geriatric SCIWORA have severe effects on both etiology and prognosis. Furthermore, incontinence in SCIWORA is an essential condition that has not been addressed until now and may play a role in prognosis. PMID- 29507777 TI - Risk factors associated with 90-day recurrent stroke in patients on dual antiplatelet therapy for minor stroke or high-risk TIA: a subgroup analysis of the CHANCE trial. AB - Objective: Many patients receiving dual antiplatelet therapy still had recurrent strokes. We aimed to identify factors associated with recurrent stroke at 90 days in patients receiving dual antiplatelet therapy in Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events trial. Methods: Patients with transient ischaemic attack or minor stroke receiving clopidogrel and aspirin in the trial were analysed in the study. The primary outcome was recurrent stroke within 90 days after the index event. Cox proportional hazard model with backward selection was used to identify factors associated with stroke. Results: Among 2584 patients, 212 (8.2%) had a recurrent stroke, 216 (8.4%) had a composite of stroke, myocardial infarction, or vascular death and 204 (7.9%) had ischaemic stroke within 90 days. Multivariate analysis identified the following factors associated with stroke: history of hypertension with poor blood pressure control (HR, 1.92; 95% CI 1.22 to 3.03), the high baseline National Institute of Health Stroke Scale (NIHSS) score of 2 and 3 (2.12 (1.07 to 4.21) and 4.11 (2.05 to 8.22), respectively), time from onset to randomisation of <12 hours (1.47 (1.12 to 1.94)), the lipid-lowering therapy (0.61 (0.47 to 0.83)), the open-label aspirin dose at day 1 of >=300 mg (1.98 (1.45 to 2.69)). Intracranial arterial stenosis (ICAS) was significantly associated with stroke in the sensitivity analysis (2.17 (1.16 to 4.04)). Conclusions: The high baseline NIHSS score, hypertension with poor blood pressure control, ICAS, time from onset to randomisation of less than 12 hours and no lipid-lowering therapy were associated with stroke, suggesting that patients with identified predictors still remain to be at high risk of recurrent stroke although being under the dual antiplatelet therapy. Trial registration number: http://clinicaltrials.gov/show/NCT00979589. ClinicalTrials.gov number: NCT00979589. PMID- 29507776 TI - Prospects for strain-specific immunotherapy in Alzheimer's disease and tauopathies. AB - With increasing age, as the incidence of Alzheimer's disease is increasing, finding a therapeutic intervention is becoming critically important to either prevent or slow down the progression of the disease. Passive immunotherapy has been demonstrated as a successful way of reducing large aggregates and improving cognition in animal models of both tauopathies and Alzheimer's disease. However, with all the continuous attempts and significant success of immunotherapy in preclinical studies, finding a successful clinical therapy has been a great challenge, possibly indicating a lack of accuracy in targeting the toxic species. Both active and passive immunotherapy approaches in transgenic animals have been demonstrated to have pros and cons. Passive immunotherapy has been favored and many mechanisms have been shown to clear toxic amyloid and tau aggregates and improve memory. These mechanisms may differ depending on the antibodie's' target and administration route. In this regard, deciding on affinity vs. specificity of the antibodies plays a significant role in terms of avoiding the clearance of the physiological forms of the targeted proteins and reducing adverse side effects. In addition, knowing that a single protein can exist in different conformational states, termed as strains, with varying degrees of neurotoxicity and seeding properties, presents an additional level of complexity. Therefore, immunotherapy targeting specifically the toxic strains will aid in developing potential strategies for intervention. Moreover, an approach of combinatorial immunotherapies against different amyloidogenic proteins, at distinct levels of the disease progression, might offer an effective therapy in many neurodegenerative diseases. PMID- 29507778 TI - Clinical features of seizures after cerebral venous sinus thrombosis and its effect on outcome among Chinese Han population. AB - Background and purpose: Clinical features of epileptic seizures after cerebral venous sinus thrombosis (CVST) among Chinese patients are not known, and it is still controversial whether seizures would affect the outcome of CVST. Methods: In a Chinese hospital-based study of consecutive patients with CVST between 2003 and 2015, we described the clinical features of seizures and determined the predictors of seizure onset using multivariable logistic regression analysis. We also compared the in-hospital case-fatality and short-term functional outcome (modified Rankin Scale (mRS) at discharge) in patients with versus without seizures using ordinal regression analysis. Results: Among 151 patients with CVST, 52 (34.4%) presented seizures, of which 42 (80.8%) were generalised seizures. Male gender (OR 6.32, 95% CI 2.06 to 19.35, p=0.001), motor deficits (OR 4.89, 95% CI 1.52 to 15.68, p=0.008), intracerebral haemorrhage (OR 3.93, 95% CI 1.16 to 13.26, p=0.027), cerebral infarction (OR 3.78, 95% CI 1.15 to 12.36, p=0.029) and superior sagittal sinus thrombosis (OR 3.38, 95% CI 91.16 to 9.86, p=0.026) were independent predictors for seizures. The overall in-hospital case fatality rate was 2.0% (3/151), and 21 (13.9%) had mRS >2 at discharge. Compared with patients without seizures, patients with seizures were more likely to have a worse outcome (p=0.02) at discharge, independent of age, gender, clinical presentation, clot burden and presence of parenchymal lesions. Conclusions: In Chinese Han patients, compared with patients without seizures, patients with seizures after CVST had a worse outcome. Risk factors such as male gender, paresis, parenchymal lesion and superior sagittal sinus thrombosis were independently associated with seizure onset after CVST. Generalised seizure was the main form of seizures after CVST, which was obviously different to seizures after strokes of arterial origin. PMID- 29507774 TI - Comparative regenerative mechanisms across different mammalian tissues. AB - Stimulating regeneration of complex tissues and organs after injury to effect complete structural and functional repair, is an attractive therapeutic option that would revolutionize clinical medicine. Compared to many metazoan phyla that show extraordinary regenerative capacity, which in some instances persists throughout life, regeneration in mammalians, particularly humans, is limited or absent. Here we consider recent insights in the elucidation of molecular mechanisms of regeneration that have come from studies of tissue homeostasis and injury repair in mammalian tissues that span the spectrum from little or no self renewal, to those showing active cell turnover throughout life. These studies highlight the diversity of factors that constrain regeneration, including immune responses, extracellular matrix composition, age, injury type, physiological adaptation, and angiogenic and neurogenic capacity. Despite these constraints, much progress has been made in elucidating key molecular mechanisms that may provide therapeutic targets for the development of future regenerative therapies, as well as previously unidentified developmental paradigms and windows-of opportunity for improved regenerative repair. PMID- 29507779 TI - Ginkgo biloba extract improved cognitive and neurological functions of acute ischaemic stroke: a randomised controlled trial. AB - Purpose: To evaluate the efficacy and safety of Ginkgo biloba extract (GBE) in acute ischaemic stroke and its impact on the recurrence of vascular events. Methods: We conducted a multicentre, prospective, randomised, open label, blinded, controlled clinical trial enrollingpatients with an onset of acute stroke within 7 days from five hospitals in China Jiangsu Province. Participants were assigned to the GBE group (450 mg GBE with 100 mg aspirin daily) or the control group (100 mg aspirin daily) for 6 months. The primary outcome was the decline in the Montreal Cognitive Assessment score at 6 months. Secondary outcomes were other neuropsychological tests of cognitive and neurological function, the the incidence of adverse events and vascular events. Results: 348 patients were enrolled: 179 in the GBE group and 169 in the control group. With 18 patients lost to follow-up, the dropout rate was 5.17%. Admission data between two groups were similar, but in the GBE group there was a marked slow down in the decline in the Montreal Cognitive Assessment scores (-2.77+/-0.21 vs -1.99+/ 0.23, P=0.0116 (30 days); -3.34+/-0.24 vs -2.48+/-0.26, P=0.0165 (90 days); 4.00+/-0.26 vs -2.71+/-0.26, P=0.0004 (180 days)) compared with controls. The National Institutes of Health Stroke Scale scores at 12 and 30 days, the modified Rankin Scale scores for independent rate at 30, 90 and 180 days, and the Barthel Index scores at 30, 90 and 180 days in the GBE group were significantly improved compared with controls. Improvements were also observedin GBE groups for Mini Metal State Examination scores of 30, 90 and 180 days, Webster's digit symbol test scores at 30 days and Executive Dysfunction Index scores at 30 and 180 days. No significant differences were seen in the incidence of adverse events or vascular events. Conclusions: We conclude that GBE in combination with aspirin treatment alleviated cognitive and neurological deficits after acute ischaemic stroke without increasing the incidence of vascular events. Trial registration number: ChiCTR-TRC-12002688. PMID- 29507780 TI - Association of homocysteine and smoking with cerebral microemboli in patients with mechanical heart valves: a transcranial Doppler study. AB - Objectives: Microembolic signals (MES) on transcranial Doppler (TCD) predict stroke and cognitive decline. Plasma levels of total homocysteine (tHcy), a prothrombotic factor, are higher in patients with microemboli in carotid stenosis and in patients with paradoxical embolism. In this study we assessed the association between the level of tHcy and the number of MES in patients with mechanical heart valves (MHVs). Methods: TCD monitoring was performed to detect MES before and after breathing 100% oxygen and repeated every 2-4 weeks up to six times. Results: Twenty-five patients with MHVs (mean age: 63.60+/-10.15 years) participated in this study; 15 were men (66.47+/-7.25 years) and 10 were women (59.30+/-12.60 years). In total, there were 126 study visits. In multiple regression, higher tHcy was associated with more MES in both preoxygenation (OR 1.34 (95% CI 1.07 to 1.68, P=0.009)) and postoxygenation (OR 1.40 (95% CI 1.07 to 1.83, P=0.01)) phases. Current smoking and the length of time between the operation and monitoring also correlated with a higher number of MES before and after breathing oxygen, particularly in women. Conclusions: Higher tHcy and smoking were associated with a higher MES count in both preoxygenation and postoxygenation phases. Because smoking can be stopped and hyperhomocysteinaemia is treatable, these are clinically important findings. PMID- 29507781 TI - Adenosine to facilitate the clipping of cerebral aneurysms: literature review. AB - Cerebral aneurysms have a high mortality rate when ruptured. Endovascular techniques have improved substantially in treating this pathology. However, surgical clip ligation remains the preferred option for some aneurysms. Various techniques are used intraoperatively to assist the surgeon in dissecting the aneurysmal dome free of surrounding tissue and placing a clip around the neck safely and effectively so that no nearby perforating vessels are affected and no residual remains. These techniques include temporary clip ligation, endovascular balloon occlusion and cardiac standstill. Adenosine use is one viable option for induced cardiac arrest leading to a short period of controlled hypotension. Its predictable course of action, rapid onset and offset and rare incidence of adverse side effects make it an attractive agent in this regard. Below, we provide an introduction to adenosine use, describing its pharmacokinetic properties, indications, contraindications, complications and future directions. PMID- 29507782 TI - Eyes and stroke: the visual aspects of cerebrovascular disease. AB - A large portion of the central nervous system is dedicated to vision and therefore strokes have a high likelihood of involving vision in some way. Vision loss can be the most disabling residual effect after a cerebral infarction. Transient vision problems can likewise be a harbinger of stroke and prompt evaluation after recognition of visual symptoms can prevent future vascular injury. In this review, we discuss the visual aspects of stroke. First, anatomy and the vascular supply of the visual system are considered. Then, the different stroke syndromes which involve vision are discussed. Finally, topics involving the assessment, prognosis, treatment and therapeutic intervention of vision specific stroke topics are reviewed. PMID- 29507783 TI - Stroke recovery and rehabilitation in 2016: a year in review of basic science and clinical science. PMID- 29507784 TI - Artificial intelligence in healthcare: past, present and future. AB - Artificial intelligence (AI) aims to mimic human cognitive functions. It is bringing a paradigm shift to healthcare, powered by increasing availability of healthcare data and rapid progress of analytics techniques. We survey the current status of AI applications in healthcare and discuss its future. AI can be applied to various types of healthcare data (structured and unstructured). Popular AI techniques include machine learning methods for structured data, such as the classical support vector machine and neural network, and the modern deep learning, as well as natural language processing for unstructured data. Major disease areas that use AI tools include cancer, neurology and cardiology. We then review in more details the AI applications in stroke, in the three major areas of early detection and diagnosis, treatment, as well as outcome prediction and prognosis evaluation. We conclude with discussion about pioneer AI systems, such as IBM Watson, and hurdles for real-life deployment of AI. PMID- 29507786 TI - The everlasting story of malignant pleural mesothelioma: where do we stand? PMID- 29507785 TI - Recanalisation therapy in patients with acute ischaemic stroke caused by large artery occlusion: choice of therapeutic strategy according to underlying aetiological mechanism? AB - Various mechanisms underlie causative large artery occlusion (LAO) in patients with acute ischaemic stroke. Cardioembolic and atherosclerotic occlusions are the two most common types. The pathophysiological changes and responses to mechanical thrombectomy (MT) and antithrombotic treatments including thrombolysis, antiplatelet and anticoagulation therapy may vary among patients with different aetiological mechanisms of occlusion. Atherosclerotic occlusion is inclined to have relatively abundant collaterals and larger area of penumbra, hence a relatively wider time window for reperfusion therapy, while poor response to medical thrombolysis and MT. Severe residual stenosis and reocclusion occurred frequently after MT in atherosclerotic LAO. Angioplasty and stenting as rescue or the first-line therapy and more intensified antiplatelet therapy beyond related recommendations in the current guidelines are sometimes used in managing acute causative LAO because of poor recanalisation after recommended standard thrombolysis or MT therapy, which are usually based on individual experience. Standard protocol to establish emergent aetiological diagnosis of causative LAO and individualised aetiology-specific treatment strategy is needed. PMID- 29507787 TI - Physicochemical and pharmacokinetic properties of polymeric films loaded with cisplatin for the treatment of malignant pleural mesothelioma. AB - Background: Malignant mesothelioma is an invasive neoplasm arising from mesothelial surfaces of the pleural and peritoneal cavities. Mesothelioma treatment is unsatisfactory and recurrence is common. Here an innovative locoregional treatment for malignant pleural mesothelioma is presented. Methods: Chitosan- and hyaluronate-based films were loaded with 0.5% and 4% w/w cisplatin and were studied for their physicochemical, mechanical and drug release characteristics. The performance of the drug delivery systems was assessed in vitro on A549 cells and on an orthotopic model of MPM recurrence in rats. Results: Polysaccharide films produced were thin, flexible and resistant. Cisplatin was completely released from hyaluronic acid films within 96 hours, while drug release was found to be much more prolonged with chitosan films. The drug released from hyaluronate films was effective against A549 cell line, while for chitosan films the release was too slow to produce cytotoxicity. Similarly, cisplatin-loaded chitosan films in vivo released minimal quantities of cisplatin and induced inflammation and foreign body reaction. Cisplatin-loaded hyaluronate acid films on the contrary were able to prevent tumor recurrence. The cisplatin loaded hyaluronate films provided higher Cmax and AUC compared to a solution of cisplatin administered intrapleurally, but did not show any sign of treatment related toxicity. Conclusions: Hyaluronate-based films appear as an optimal platform for the development of drug delivery systems suitable for the loco regional post-surgical treatment of lung malignancies. PMID- 29507789 TI - Epidemiology of malignant mesothelioma in Italy: surveillance systems, territorial clusters and occupations involved. AB - Background: As a legacy of the large asbestos consumption until the definitive ban in 1992, Italy is currently suffering a severe epidemic of asbestos related diseases. The aim of this paper is to describe the surveillance system for mesothelioma incidence and to provide evidences regarding the occurrence of the disease in Italy and the circumstances of asbestos exposure. Methods: Italian National Register of Malignant Mesotheliomas (ReNaM) is a permanent surveillance system of mesothelioma incidence, with Regional Operating Centres (CORs) active in each Italian region, identifying incident malignant mesothelioma (MM) cases from health care structures. Occupational history, lifestyle habits and residential history are obtained using a standardised questionnaire, administered by a trained interviewer, to the subject or to the next of kin. Descriptive epidemiological figures, occupations involved in exposures and territorial maps of MM cases have been produced. Results: At December 2016, ReNaM has collected 27,356 MM cases for the incidence period between 1993 and 2015. The modalities of exposure to asbestos have been investigated for 21,387 (78%) and an occupational exposure has been defined for around 70% of interviewed cases (14,818). Non occupational exposure is still relevant with 4.9% and 4.4% of cases for which respectively a familial exposure (due to the cohabitation with an occupational exposed subject) and an environmental exposure (due to the residence near a contaminated site) has been detected. Discussion: The epidemiological surveillance of MM incident cases, by the means of a national register for estimating the occurrence of the disease and identifying the circumstances of asbestos exposure, is a relevant tool for preventing asbestos exposure, for supporting the effectiveness of insurance system and for estimating reliable epidemiological figures. PMID- 29507788 TI - Polymeric films loaded with cisplatin for malignant pleural mesothelioma: a pharmacokinetic study in an ovine model. AB - Background: Malignant pleural mesothelioma (MPM) continues to be a distressing tumor due to its aggressive biologic behavior and scanty prognosis. Several therapeutic approaches have been tested both in clinical and preclinical settings, being intrapleural chemotherapy one of the most promising. Some years ago, our interest focused on polymeric films loaded with cisplatin for the adjuvant intrapleural treatment of surgical patients. After in vitro and in vivo studies in a rat recurrence model of MPM, the aim of this study was to evaluate the pharmacokinetics of the polymeric films in a sheep model in view of further studies in a clinical setting. Methods: An ovine model was used. Animals were divided into four groups according to pharmacologic treatment: control group (three animals undergoing left pneumonectomy and saline-NaCl solution); intrapleural hyaluronate cisplatin films (HYALCIS) group (six animals undergoing left pneumonectomy and intrapleural application of polymeric films loaded with cisplatin); intrapleural cisplatin solution (six animals undergoing left pneumonectomy and intrapleural application of cisplatin solution); intravenous cisplatin (five animals undergoing left pneumonectomy and intravenous administration of cisplatin solution). The primary objective was the plasmatic and pleural concentration of cisplatin in the treatment groups. The secondary objective was the treatment-related toxicity evaluated by plasmatic analysis performed at prearranged time intervals and histological examinations of tissue samples collected during animal autopsy. Analysis of variance (ANOVA) was used for statistical analysis. Bonferroni correction was applied for comparison between all groups. Results: Twenty female Sardinian sheep with a mean weight of 45.1 kg were studied. All animals survived the surgical procedures. The whole surgical procedure had a mean duration of 113 minutes. Cisplatin blood levels obtained from polymeric films application were low during the first 24 hours after the application; then, the cisplatin blood level increased gradually and progressively until it reached significantly higher plasmatic concentrations after 120 hours compared to intrapleural cisplatin solution (P=0.004) and intravenous administration (P=0.001), respectively. Considering cisplatin concentration at 168 hours after the application, animals treated with polymeric films had higher plasmatic values than animals treated with intrapleural cisplatin solution and intravenous cisplatin (P=0.001). Despite the high cisplatin plasmatic concentrations, treatment related-toxicity towards kidneys and liver was comparatively lower compared to the intravenous and intrapleural cisplatin administration and closer to the control levels. Conclusions: Polymeric films loaded with cisplatin allowed to reach significantly higher intrapleural and plasmatic cisplatin concentrations compared to intrapleural and intravenous cisplatin solution, providing at the same time, a significant reduction of treatment related toxicity. PMID- 29507790 TI - Hyperthermic intrathoracic chemotherapy after extended pleurectomy and decortication for malignant pleura mesothelioma: an observational study on outcome and microcirculatory changes. AB - Background: In the treatment of malignant pleural mesothelioma the Hyperthermic Intra THOracic Chemotherapy (HITHOC) can improve the efficacy of pleurectomy and decortication with a local cytotoxic effect. However its biological impact in patient's hemodynamic and microcirculatory changes were rarely investigated. Aim of this study is to describe our experience with HITHOC after pleurectomy and decortication evaluating the role of sublingual video-microscopy in assessing the microcirculatory changes in the perioperative period. Methods: This is a prospective and observational study concerning 10 consecutive patients undergoing extended P/D followed by HITHOC. These patients underwent sublingual microcirculatory monitoring, which was adopted as a routine procedure since 2012. Haemodynamic parameters were collected at eight consecutive times: the day before surgery (T1), induction of anaesthesia (T2), surgical phase before HITHOC beginning (T3), 5 and 30 minutes after HITHOC start (T4 and T5, respectively), 5 minutes from HITHOC end (T6), after the admission in ICU (T7), at discharge from the ICU (T8). Cardiac output (CO) was calculated with MostCare. Systemic vascular resistance (SVR), oxygen delivery (DO2), and oxygen extraction rate (O2ER) were calculated using standard formulas. Arterial blood pressure and central venous pressure (CVP) were obtained with standard arterial and venous catheters. At the same times we assessed the sublingual microcirculation with Sidestream Dark Field technique. Results: Hemodynamic and microcirculatory data were collected in 10 patients, 8 male and 2 females (mean age 68.6+/-9.0, and body surface area of 1.9+/-0.1 m2). All patients had arterial hypertension, and one patient had diabetes. The mean arterial pressure significantly decreased at T2, with respect to T1 (P=0.05). CO, CVP, DO2, O2ER, and ScvO2, did not change significantly over the time. All patients needed infusion of noradrenalin from T4 to T6. TVD significantly decreased from T1 to T3, T5, and T8. Similarly, PVD significantly decreased from T1 to T3 and T8, and MFI from T1 to T6 and T8. PPV and HI did not change over the study period. No correlation was found between hemodynamic parameters (MAP, CO, CVP, DO2, O2ER, ScvO2) and microcirculatory data (TVD, PVD, PPV, MFI, HI), at any time of the study. Conclusions: In patients who receive HITHOC the fluid load can reduce the microvascular impairment restoring the normal tissue perfusion. This process takes days but is most evident in the first 72 h. The use of colloid and blood transfusion is much more effective in restoring microcirculation and reducing tissue damaging. PMID- 29507791 TI - Exposure to asbestos: past, present and future. AB - This paper summarises the past, present and future of asbestos exposure. The future scenarios as to the mesothelioma incidence in countries, where asbestos has been banned, are discussed. PMID- 29507792 TI - The genetic susceptibility in the development of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity whose main risk factor is exposure to asbestos. However, it has been shown that only a minority of exposed people develops MPM. In fact, the incidence among professionally exposed workers was shown to vary between 0.5% and 18.0%. Various hints suggested that other important cofactors could play a role, in particular the genetic susceptibility. Impressive is the case of Cappadocians families exposed to erionite and affected by an "epidemic" of MPM with about half of the inhabitants dying for the disease. However, no results for a "Cappadocia" gene of susceptibility to MPM have been obtained yet and more studies are needed. Among asbestos-exposed workers, several studies reported familial cases of MPM, suggesting that heredity could be important in the tumor development. However, large studies on familial clusters showed only weak increased risks that could be attributable also to indirect exposures in a contaminated household. Moreover, the risk of developing MPM is increased of a limited extent among people exposed to asbestos with a positive history of familial cancers. A particular is represented by carriers of germline mutations within BAP1 gene. In families and in animal models, mutations within BAP1 are strongly predisposing to develop MPM. However, also other types of cancer (such as uveal melanoma) are present, thus BAP1 mutations are considered as responsible for a hereditary form of a multi cancer syndrome. In any case, among sporadic MPM, the prevalence of germline BAP1 mutations is negligible. Finally, genetic studies highlighted the presence of low risk susceptibility alleles, such as those within XRCC3, NAT2 or GSTM1. Two different genome-wide association studies could not find positive associations reaching the genome-wide statistical significance threshold, however, both were concordant in showing a weak signal within the SDK1 gene region. Overall, it could be concluded that, as for other types of sporadic cancers, the susceptibility to develop MPM following asbestos exposure is modulated moderately by the individual genetic background. Further studies on larger series could help in a better characterization of more genes predisposing to MPM, being this tumor a rare disease. PMID- 29507793 TI - Clinical diagnosis of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a tumour which, despite progress in diagnostic procedures and biomolecular research, has poor prognosis. Symptoms reflect extension of disease and include shortness of breath and chest pain. Unexplained pleural effusion and pleural pain in patients exposed to asbestos should raise the suspicion of MPM. MPM diagnosis requires imaging procedures X ray and computed tomography (CT) scans; magnetic resonance imaging (MRI) better defines the extension of the tumor while PET scanning provides additional information on metabolic activity, metastases, and response to treatment. Thoracoscopic biopsy remains the most appropriate procedure for definitive diagnosis of mesothelioma. Multimodality treatment including surgery, chemotherapy and radiotherapy has been associated with a better survival in selected patients. Clinical translational research including new approaches targeting immune-checkpoints is opening new horizons which may lead to personalised treatments. PMID- 29507794 TI - Imaging of malignant pleural mesothelioma: it is possible a screening or early diagnosis program?-a systematic review about the use of screening programs in a population of asbestos exposed workers. AB - Malignant pleural mesothelioma (MPM) in an uncommon neoplasia with high mortality rate, mostly related to professional asbestos exposure. Clinical manifestations are not specific so that diagnosis is performed at advanced stage and screening protocols are not feasible now. On the other hand, asbestos-exposed workers have a high incidence of developing lung cancer. Low-dose computed tomography (LDCT) is a volumetric acquisition technique with high spatial resolution and a low dose exposure; it is used in many trials to detect lung tumours at an early stage in screening protocols, reducing mortality rate in smoker subjects. In recent papers, the possibly role of lung cancer screening was evaluated and recommended also in subjects exposed to asbestos. This article summarizes previous and present clinical trials validated for lung cancer screening, to discuss the possibility of early diagnosis or screening programs in a population of asbestos exposed workers by LDCT. PMID- 29507795 TI - Endoscopic diagnosis and management of pleural effusion in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive tumor, that requires proper diagnosis and management. Symptoms are nonspecific and chest computed tomography (CT) and chest ultrasound (US) are important radiological tools in the initial workup to identify early pathological signs. Performing a medical thoracoscopy (MT) is essential for a definitive diagnosis of MPM. The procedure, integrated with a prior US, allows a global evaluation of the pleural cavity and the execution of multiple targeted biopsies, with low risk of complications. Some different endoscopic patterns are recognized. Thoracoscopic biopsies provide enough material to allow a thorough pathological and immunohistochemical characterization. The presence of extensive pleural adhesions and critical patient conditions are the only absolute contraindications. The clinical course of MPM is characterized by chronic symptoms such as chest pain and progressive dyspnea, the latter caused mainly by recurrent pleural effusion. Palliative interventions are required in order to relieve symptoms and improve the quality of life (QoL). These include thoracentesis, pleurodesis and the placement of an indwelling pleural catheter. PMID- 29507796 TI - The pathological and molecular diagnosis of malignant pleural mesothelioma: a literature review. AB - Malignant pleural mesothelioma (MPM), an asbestos-induced tumor, represents significant diagnostic challenges for pathologists. Its histological diagnosis is stepwise and should be based on morphological assessment, supported by clinical and radiological findings, and supplemented with immunohistochemistry (IHC) and, more recently, molecular tests. The main diagnostic dilemmas are the differential diagnoses with benign mesothelial proliferations and other pleural malignant tumors. The present review is an update regarding the morphological, immunohistochemical, and molecular features with respect to MPM diagnosis. Data sources include a survey of the biomedical literature from PubMed (http://www.ncbi.nlm.nih.gov/pubmed) and textbooks focusing on the pathological diagnosis of MPM and associated immunohistochemical and molecular markers. The histological findings of MPM could facilitate its diagnosis and provide important prognostic information. The immunohistochemical approach should rest on the application of a panel including positive (mesothelial-related) and negative markers with greater than 80% sensitivity and specificity, which need to be selected based on morphology and clinical information. Moreover, in challenging cases, fluorescent in situ hybridization (FISH) testing for the p16 deletion and IHC to evaluate the loss of BRCA1-associated protein 1 (BAP1) expression could be useful in distinguishing benign from malignant pleural proliferations. PMID- 29507797 TI - Surgery for malignant pleural mesothelioma: an international guidelines review. AB - Currently there is no universally accepted surgical therapy for malignant pleural mesothelioma (MPM). The goal of surgery in this dismal disease is a macroscopic complete resection (MCR) and there are two types of intervention with a curative intent. At one side, there is the extrapleural pneumonectomy (EPP) which consists in an en-bloc resection of the lung, pleura, pericardium and diaphragm and at the other side, there is pleurectomy/decortication (P/D) a lung-sparing surgery. Initially, EPP was considered the only surgical option with a curative aim, but during the decades P/D have acquired a role of increasing importance in MPM therapy. Several randomized prospective trials are required to establish the best strategy in the treatment of pleural mesothelioma. Although which is the best surgical option remains unclear, the International Mesothelioma Interest Group (IMIG), recently have stated that the type of surgery depends on clinical factors and on individual surgical judgment and expertise. Moreover, according to the current evidence, the surgery should be performed in high-volume centres within multimodality protocols. The aim of this study is to examine the currently available international guidelines in the surgical diagnosis and treatment of MPM. PMID- 29507798 TI - The role of intracavitary therapies in the treatment of malignant pleural mesothelioma. AB - Surgery is one of the steps of multimodality approach for the treatment of MPM. Due to anatomical features, microscopically radical (R0) resection is never possible and a Macroscopic Complete Resection (R1) is considered the target for mesothelioma surgeons. Recently, intracavitary therapies have been described with the aim of extending the loco-regional effect of surgery. Different agents might be administered intrapleurally: chemotherapy drugs are the most widely used, but also photodynamic therapy (PDT) showed to lead to satisfactory long-term outcomes; furthermore, immunotherapies and gene therapies have been also reported. Despite promising results, no high-quality evidences are currently available and controlled randomized trials are required to establish the exact role of intracavitary therapies and to standardize the technique. PMID- 29507799 TI - Diaphragmatic and pericardial reconstruction after surgery for malignant pleural mesothelioma. AB - Extrapleural pneumonectomy (EPP) and pleurectomy-decortication (P/D) are both recognised surgical procedures for selected cases affected by malignant pleural mesothelioma (MPM). Surgical techniques have ameliorated over the last years, remaining the complete macroscopic resection of the disease the main surgical principle. EPP is defined as an en-bloc resection of the visceral pleura, parietal pleura, pericardium and diaphragm alongside the pneumonectomy. The thoracic domain of the International Association for Study of Lung Cancer (IASLC) recently clarified the, previously confused, surgical terminology. "Extended P/D" is considered as parietal and visceral pleurectomy, diaphragmatic and pericardial resection with the purpose to remove all macroscopic disease. The term "radical" was replaced by "extended" to underline that this procedure does not have oncologic radicality aims. Both operations above are technically challenging and associated with a significant rate of peri-operative morbidity and non-negligible mortality. The diaphragmatic and pericardial reconstruction technique is mandatory to avoid respiratory impairment and to reduce post-operative complications like gastric and cardiac herniation. The technical aspects of resection and reconstruction are described and the choice of different prosthetic materials, considering the most recent innovations in the field, are discussed. PMID- 29507800 TI - Chemotherapy treatment in malignant pleural mesothelioma: a difficult history. AB - Malignant pleural mesothelioma (MPM) is a rare neoplasm that typically arises from mesothelial surfaces of the pleural cavity. Despite treatment improvements, it carries a dismal prognosis. The majority of patients either have unresectable disease or are not candidates for surgery due to medical comorbidities or old age. For such patients, chemotherapy (CT) represents the gold-standard treatment. To date, combination CT with cisplatin plus pemetrexed represents the most widely used regimen in first-line setting for patients with unresectable MPM. Other first-line options are currently available, including the use of raltitrexed instead of pemetrexed combined with platinum. In this review, we discuss the role of CT in MPM mainly focusing on the results of the trials conducted in first-line setting. PMID- 29507801 TI - Target therapy: new drugs or new combinations of drugs in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a disease with a poor prognosis due to its aggressive nature. The management of patients with MPM is controversial. Considering that the contribution of surgery and radiation therapy in the management of this disease is not yet established, systemic treatments are predominantly considered during the course of MPM. Unfortunately, the currently therapeutic armamentarium is scarce and its outcomes still appear modest. New treatment strategies are needed. In preclinical setting, cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis pathways involved in the development of MPM have been identified. However, in clinical setting, several drugs targeting these pathways resulted without a significant activity. A deeper knowledge of the biology and pathogenesis of this disease is required to develop more effective tools for diagnosis, therapy and prevention. This paper reviews therapeutic advances in MPM, with a particular focus on new drugs and new association of drugs of target therapy. PMID- 29507802 TI - New horizons from immunotherapy in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive disease with a severe prognosis. Medical treatment for MPM unresectable patients is still unsatisfactory; therefore novel therapeutic approaches are urgently needed. Immunotherapy represents a promising treatment for MPM patients. Here, we'll discuss the most promising immunotherapeutic treatments currently under active investigation for this still dreadful disease. PMID- 29507803 TI - Medical treatment of malignant pleural mesothelioma relapses. AB - There are not established treatments for patients with advanced malignant pleural mesothelioma that progressed after first-line chemotherapy with cisplatin and pemetrexed. Retrospective analyses suggest a possible role for rechallenge with pemetrexed for selected patients. Phase II trials demonstrate a modest efficacy of vinorelbine monotherapy with a response rate ranging between 0% and 18% and a tolerable toxicity profile. Combination schedules, despite an increased toxicity, fail to demonstrate an improved efficacy. To date, genome wide analyses did not show molecular targets suitable for therapy and biological drugs did not exert a significant efficacy in clinical trials. Immunotherapy has given a hint of efficacy in early clinical trials but definitive evaluations are still ongoing. PMID- 29507804 TI - Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure. Histopathological analysis of pleural tissues is the gold standard for diagnosis; however, it can be difficult to differentiate malignant from benign pleural lesions. The purpose of this review is to describe the most important biomarkers and new diagnostic tools suggested for this differential diagnosis. There are many studies concerning the separation between MPM and benign pleural proliferations from both pleural tissues or effusions; most of them are based on the evaluation of one or few biomarkers by immunohistochemistry (IHC) or enzyme-linked immunosorbent assays (ELISAs), whereas others focused on the identification of MPM signatures given by microRNA (miRNA) or gene expression profiles as well as on the combination of molecular data and classification algorithms. None of the reported biomarkers showed adequate diagnostic accuracy, except for p16 [evaluated by fluorescent in situ hybridization (FISH)] and BAP1 (evaluated by IHC), both biomarkers are recommended by the International Mesothelioma Interest Group guidelines for histological and cytological diagnosis. BAP1 and p16 showed a specificity of 100% in discerning malignant from benign lesions because they are exclusively unexpressed or deleted in MPM. However, their sensitivity, even when used together, is not completely sufficient, and absence of their alterations cannot confirm the benign nature of the lesion. Recently, the availability of new techniques and increasing knowledge regarding MPM genetics led to the definition of some molecular panels, including genes or miRNAs specifically deregulated in MPM, that are extremely valuable for differential diagnosis. Moreover, the development of classification algorithms is facilitating the application of molecular data for clinical practice. Data regarding new diagnostic tools and MPM signatures are absolutely promising; however, before their application in clinical practice, a prospective validation is necessary, as these approaches could surely improve the differential diagnosis between malignant and benign pleural lesions. PMID- 29507805 TI - Serum mesothelin and other biomarkers: what have we learned in the last decade? AB - In the last decade there is been much interest in noninvasive, economic and well accepted diagnostic tests for screening of subjects exposed to asbestos, and in patients with malignant pleuric mesothelioma (MPM) for diagnosis or monitoring response to treatment. Several biomarkers have been suggested as tools for screening and early diagnosis of MPM. Currently, in patients with MPM, have been reported high levels of soluble mesothelin-related peptides (SMRP), plasmatic osteopontin (pOPN), vimentin, fibulin-3 and many others as promising marker for diagnosis, even their use in prevention monitoring is still discussed. In this type of disease, a key role could be played by miRNAs, which expression has been investigated in a large series of MPM to examine new pathways useful in diagnosis, prognosis and therapy. An altered expression of some proteins has been reported, useful as biomarkers, in comparative proteomic analysis of malignant pleural mesothelioma. New promising markers are nowadays under study and alone or better in combination, they'll be very helpful in diagnosing, monitoring mesothelioma patients or for screening of risk groups. PMID- 29507806 TI - Biomarkers in the prevention and follow-up of workers exposed to asbestos. AB - Although in most developed countries the use of asbestos is banned, there is still a consistent portion of the world where asbestos extraction, trading and manufacturing of asbestos-made products is largely diffuse. Worldwide, hundreds of millions of people are at risk of developing an asbestos caused disease because of occupational, environmental or domestic exposure. The WHO estimates that asbestos is responsible for more than 100,000 deaths yearly. This scenario has prompted the research on biomarkers potentially useful for early diagnosis, prognosis and preventive programs on exposed population as well. Here we reviewed the up-to-date literature on this field of research highlighting that along with mesothelin and osteopontin (OPN), some more recently investigated molecules, such as high mobility group box 1 (HMGB1) protein, fibulin-3 and some miRNAs showed very promising. Most of the carried-out studies showed an interesting diagnostic and prognostic performance of some biomarkers, but since they usually lack adequate either specificity or sensitivity, their use in screening or in preventive programs is still not recommended on a routine basis. However, this review suggests the need for more reliable experimental design involving larger population and preferring longitudinal screening of asbestos exposed individuals rather than a single baseline assessment investigation. In addition, given their better diagnostic accuracy, the use of panels including several biomarkers is highly recommended. PMID- 29507808 TI - Health surveillance for former asbestos exposed worker: a specific programme developed in an Italian region. AB - Asbestos-related diseases usually have a long latency since first exposure and this legitimates a health surveillance programme addressed to asbestos workers after the cessation of their occupational exposure. After a brief history of health surveillance initiatives performed in Italy as well as in other countries, we describe a regional programme for former asbestos-exposed workers, focusing on organizational features. A regional group of experts defined its operational and economical aspects. The Regional Council supported the whole programme, making it free of charge for all subjects who fulfil the predefined enrolment criteria (being resident in the region, being younger than 80 years old with cessation of occupational asbestos exposure within the last 30 years). The programme activities are classified in two levels: a first level for a basic health evaluation and a second level for in-depth analyses. In order to guarantee an homogeneous delivery in the whole region, the programme has to be performed by public health services with a quality control of activities. The involvement of specific public health services and the cooperation of social stakeholders are expected to play a major role in overcoming still open critical issues, such as the lack of programme existence awareness and adhesion, the correct stratification of subjects for the follow-up, and the real homogeneous delivery of the health surveillance in whole region. PMID- 29507807 TI - Overexpressed genes in malignant pleural mesothelioma: implications in clinical management. AB - Malignant pleural mesothelioma (MPM) is a very aggressive cancer poorly responsive to current therapies. MPM patients have a very poor prognosis with a median survival of less than one year from the onset of symptoms. The biomarkers proposed so far do not lead to a sufficiently early diagnosis for a radical treatment of the disease. Thus, the finding of novel diagnostic and prognostic biomarkers and therapeutic targets is needed. Gene overexpression has been frequently associated with a malignant phenotype in several cancer types; therefore the identification of overexpressed genes may lead to the detection of novel prognostic or diagnostic marker and to the development of novel therapeutic approaches, based on their inhibition. In the last years, several overexpressed genes have been identified in MPM through gene expression profiling techniques: among them it has been found a group of 51 genes that resulted overexpressed in more than one independent study, revealing their consistency among studies. This article reviews the clinical implications of confirmed overexpressed genes in MPM described so far in literature. PMID- 29507809 TI - Pleurectomy/decortication versus extrapleural pneumonectomy: a critical choice. PMID- 29507810 TI - Optical Coherence Tomography Angiography to Distinguish Changes of Choroidal Neovascularization after Anti-VEGF Therapy: Monthly Loading Dose versus Pro Re Nata Regimen. AB - Purpose: To compare the qualitative and quantitative choroidal neovascularization (CNV) changes after antivascular endothelial growth factor (anti-VEGF) therapy in treatment-naive and treated eyes with age-related macular degeneration (AMD) using optical coherence tomography angiography (OCTA). Methods: Consecutive patients with neovascular AMD underwent multimodal imaging, including OCTA (AngioPlex, CIRRUS HD-OCT model 5000; Carl Zeiss Meditec, Inc., Dublin, OH) at baseline and at three monthly follow-up visits. Treatment-naive AMD patients undergoing anti-VEGF loading phase were included in group A, while treated patients were included in group B. Qualitative and quantitative OCTA analyses were performed on outer retina to choriocapillaris (ORCC) slab. CNV size was measured using a free image analysis software (ImageJ, open-source imaging processing software, 2.0.0). Results: Twenty-five eyes of 25 patients were enrolled in our study (mean age 78.32 +/- 6.8 years): 13 treatment-naive eyes in group A and 12 treated eyes in group B. While qualitative analysis revealed no significant differences from baseline to follow-up in the two groups, quantitative analysis showed in group A a significant decrease in lesion area (P = 0.023); in group B, no significant change in the lesion area was observed during anti-VEGF therapy (P = 0.93). Conclusion: Treatment-naive and treated eyes with CNV secondary to neovascular AMD respond differently to anti-VEGF therapy. This should be taken into account when using OCTA for CNV follow-up or planning therapeutic strategies. PMID- 29507812 TI - Automated Diagnosis of Coronary Artery Disease: A Review and Workflow. AB - Coronary artery disease (CAD) is the most dangerous heart disease which may lead to sudden cardiac death. However, CAD diagnoses are quite expensive and time consuming procedures which a patient need to go through. The aim of our paper is to present a unique review of state-of-the-art methods up to 2017 for automatic CAD classification. The protocol of review methods is identifying best methods and classifier for CAD identification. The study proposes two workflows based on two parameter sets for instances A and B. It is necessary to follow the proper procedure, for future evaluation process of automatic diagnosis of CAD. The initial two stages of the parameter set A workflow are preprocessing and feature extraction. Subsequently, stages (feature selection and classification) are same for both workflows. In literature, the SVM classifier represents a promising approach for CAD classification. Moreover, the limitation leads to extract proper features from noninvasive signals. PMID- 29507813 TI - Corrigendum to "Current Status of Sodium Bicarbonate in Coronary Angiography: An Updated Comprehensive Meta-Analysis and Systematic Review". AB - [This corrects the article DOI: 10.1155/2015/690308.]. PMID- 29507811 TI - Prevalence and Related Factors for Myopia in School-Aged Children in Qingdao. AB - Purpose: To investigate the prevalence and related factors for myopia in school aged children in the Economic and Technological Development Zone of Qingdao, Eastern China. Methods: A total of 4890 (aged 10 to 15 years) students were initially enrolled in this study. 3753 (76.75%) students with completed refractive error and questionnaire data were analyzed. The children underwent a comprehensive eye examination. Multiple logistic regression models were applied to assess possible factors associated with myopia. Results: The prevalence of myopia increased as the children's grade increased (chi2 = 560.584, P < 0.001). Low myopia was the main form of myopia in adolescent students (30.22%). With the growth of age, students spent significantly more time on near work (P = 0.03) and less time on outdoor activity (P < 0.001). In multivariate models, only the following variables were significantly associated with myopia: age, two myopic parents, outdoor activity time, and continuous near work without 5 min rest. Conclusions: The prevalence of myopia increased as the grade increased. Age, two myopic parents, and continuous near work time without 5 min rest were risk factors for myopia. Outdoor activities had protective effect for myopia. PMID- 29507814 TI - HIV-TB Coinfection among 57 Million Pregnant Women, Obstetric Complications, Alcohol Use, Drug Abuse, and Depression. AB - Objective: HIV and tuberculosis represent diseases of major public health importance worldwide. Very little is known about HIV-TB coinfection among pregnant women, especially from industrialized settings. In this study, we examined the association between TB, HIV, and HIV-TB coinfection among pregnant mothers and obstetric complications, alcohol use, drug abuse, and depression. Method: We examined inpatient hospital discharges in the United States from January 1, 2002, through December 31, 2014. We employed multivariable survey logistic regression to generate adjusted estimates for the association between infection status and study outcomes. Results: We analyzed approximately 57 million records of pregnant women and their delivery information. HIV-TB coinfection was associated with the highest risks for several obstetric complications, alcohol use, and drug abuse. The risk for alcohol abuse was more than twice as high among HIV-monoinfected as compared to TB-monoinfected mothers. That risk gap more than doubled with HIV-TB coinfection. Both HIV-monoinfected and HIV-TB coinfected mothers experienced similarly increased risks for depression. Conclusions: Mothers with HIV-TB coinfection experienced relatively heightened risks for obstetric complications, alcohol use, and drug abuse. The findings of this study underscore the importance of augmenting and enhancing social and structural support systems for HIV-TB coinfected pregnant women. PMID- 29507815 TI - The Use of Sentinel Lymph Node Biopsy in BRCA1/2 Mutation Carriers Undergoing Prophylactic Mastectomy: A Retrospective Consecutive Case-Series Study. AB - Introduction: Sentinel lymph node biopsy in prophylactic mastectomy is controversial. It avoids lymphadenectomy in occult carcinoma but is associated with increased morbidity. Women with BRCA mutations have a higher incidence of occult carcinoma and our objective was to assess the clinical utility of sentinel lymph node biopsy when these women undergo prophylactic mastectomy. Materials and Methods: Seven-year retrospective consecutive case-series study of women, with a BRCA deleterious mutation, admitted to prophylactic mastectomy, at our center. Breast MRI < 6 months before surgery was routine, unless contraindicated. Results: Fifty-seven patients (43% BRCA1; 57% BRCA2) underwent 80 prophylactic mastectomies. 72% of patients had had breast cancer treated before prophylactic mastectomy or synchronously to it. The occult carcinoma incidence was 5%, and half of the cases were invasive. SLNB was performed in 19% of the prophylactic mastectomies; none of these had tumor invasion. Women with invasive carcinoma who had not undergone sentinel lymph node biopsy were followed closely with axillary ultrasound. The median follow-up was 37 months, with no local recurrence; 1 patient died of primary tumor systemic relapse. Conclusions: Our data do not support this procedure for routine (in agreement with previous literature), in this high risk for occult carcinoma population. PMID- 29507816 TI - Phenolic Acid Content and Antioxidant Properties of Extruded Corn Snacks Enriched with Kale. AB - Prohealth food contains specific components which have positive influence on the health and well-being of the consumer. An important position among bioactive compounds occurs for polyphenols. Many results have indicated that an increased intake of phenolic compounds may reduce the risk of cardiovascular diseases and type 2 diabetes. The objective of the study was production of extruded corn snacks with addition (0, 2, 4, 6, and 8%) of kale (Brassica oleracea L. var. sabellica)-a polyphenol-rich plant. Afterwards, high-performance liquid chromatography-mass spectrometry (LC-ESI-MS/MS) and antioxidant activity analyses of snack extracts were performed. In the corn snacks enriched with kale, fifteen phenolic acids were indicated. These were protocatechuic, 4-OH-benzoic, vanillic, trans-caffeic, cis-caffeic, trans-p-coumaric, cis-p-coumaric, trans-ferulic, cis ferulic, salicylic, gentisic, syringic, 3-OH-cinnamic, trans-sinapic, and cis sinapic acids. Both the qualitative and quantitative content of polyphenols increased with the addition of B. oleracea. Data from spectrophotometric analyses of the samples showed high DPPH radical scavenging potential of snacks enriched with 4, 6, and 8% of kale. Snacks enriched with kale contain high level of phenolic acids and, therefore, have great potential to make a valuable source of natural antioxidants. High-temperature short-time extrusion-cooking process had no negative impact on polyphenol's activity. PMID- 29507817 TI - Engineering 3D approaches to model the dynamic microenvironments of cancer bone metastasis. AB - Cancer metastasis to bone is a three-dimensional (3D), multistep, dynamic process that requires the sequential involvement of three microenvironments, namely, the primary tumour microenvironment, the circulation microenvironment and the bone microenvironment. Engineered 3D approaches allow for a vivid recapitulation of in vivo cancerous microenvironments in vitro, in which the biological behaviours of cancer cells can be assessed under different metastatic conditions. Therefore, modelling bone metastasis microenvironments with 3D cultures is imperative for advancing cancer research and anti-cancer treatment strategies. In this review, multicellular tumour spheroids and bioreactors, tissue engineering constructs and scaffolds, microfluidic systems and 3D bioprinting technology are discussed to explore the progression of the 3D engineering approaches used to model the three microenvironments of bone metastasis. We aim to provide new insights into cancer biology and advance the translation of new therapies for bone metastasis. PMID- 29507818 TI - Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling. AB - Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1 (Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass. Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-kappaB ligand (RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor (PDGF BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRbeta-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF-RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans. PMID- 29507820 TI - Cancer screening recommendations: an international comparison of high income countries. AB - Background: Recommendations regarding cancer screening vary from country to country, and may also vary within countries depending on the organization making the recommendations. The goal of this study was to summarize the cancer screening recommendations from the 21 countries with the highest per capita spending on healthcare. Main body: Cancer screening guidelines were identified for each country based on a review of the medical literature, internet searches, and contact with key informants in most countries. The highest level recommendation was identified for each country, in the order of national recommendation, cancer society recommendation, or medical specialty society recommendation. Breast cancer screening recommendations were generally consistent across countries, most commonly recommending mammography biennially from ages 50 to 69 or 70 years. In the USA, specialty societies generally offered more intensive screening recommendations. All countries also recommend cervical cancer screening, although there is some heterogeneity regarding the test (cytology or HPV or both) and the age of initiation and screening interval. Most countries recommend colorectal cancer screening using fecal immunochemical (FIT) testing, while only seven countries recommend general or selective screening for prostate cancer, and a similar number explicitly recommend against screening for prostate cancer. Screening for lung and skin cancer is only recommended by a few countries. Greater per capita healthcare expenditures are not associated with greater screening intensity, with the possible exception of prostate cancer. Conclusions: Guidelines for cancer screening differ between countries, with areas of commonality but also clear differences. Recommendations have important commonalities for well-established cancer screening programs such as breast and cervical cancer, with greater variation between countries regarding prostate, colorectal, lung, and skin cancer screening. Ideally, recommendations should be made by a professionally diverse, independent panel of experts that make evidence based recommendations regarding screening based on the benefits, harms, and available resources in that country's context. PMID- 29507819 TI - IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. AB - Parathyroid hormone (PTH) regulates bone remodeling by activating PTH type 1 receptor (PTH1R) in osteoblasts/osteocytes. Insulin-like growth factor type 1 (IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor (IGF1R) in vitro. Phosphorylated PTH1R localized to the barbed ends of actin filaments and increased actin polymerization during morphological change of osteoblasts into osteocytes. Disruption of the phosphorylation site reduced actin polymerization and dendrite length. Mouse models with conditional ablation of PTH1R in osteoblasts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with complete overlap of PTH1R with phosphorylated-PTH1R positioning in osteocyte dendrites in wild-type mice. Thus, our findings reveal a novel signaling mechanism that enhances osteoblast-to-osteocyte transition by direct phosphorylation of PTH1R by IGF1R. PMID- 29507822 TI - Seasonal variation in the abundance and distribution of Anomalocardia flexuosa (Mollusca, Bivalvia, Veneridae) in an estuarine intertidal plain. AB - Spatial and temporal density and biomass of the infaunal mollusk Anomalocardia flexuosa (Linnaeus, 1767) evaluated a tidal plain at Goiana estuary (Northeast Brazil). Three hundred and sixty core samples were taken during an annual cycle from three intertidal habitats (A, B and C). Shell ranged from 2.20 to 28.48 mm (15.08 +/- 4.08 mm). Recruitment occurred more intensely from January to March. Total (0-1,129 g m-2) differed seasons (rainy and dry), with highest values in the early rainy season (221.0 +/- 231.44 g m-2); and lowest values in the late dry season (57.34 +/- 97 g m-2). The lowest occurred during the late rainy (319 +/- 259 ind m-2) and early dry (496 +/- 607 ind m-2) seasons. Extreme environmental situations (e.g., river flow, salinity and water temperature) at the end of each season also affected density ranges (late dry: 0-5,798 ind m-2; late rainy: 0-1,170 ind m-2). A. flexuosa in the Goiana estuary presented a dominance of juvenile individuals (shell length < 20 mm), with high biomass main the recruitment period. Average shell length, density and biomass values suggest overfishing of the stock unit. A. flexuosa is an important food and income resource along its whole distribution range. The species was previously also known as Anomalocardia brasiliana (Gmelin, 1791). PMID- 29507821 TI - Gender-associated factors for frailty and their impact on hospitalization and mortality among community-dwelling older adults: a cross-sectional population based study. AB - Background: Frailty associated with aging increases the risk of falls, disability, and death. We investigated gender-associated factors for frailty. Methods: Data of 3,079 geriatric subjects were retrieved from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 database. After excluding 1,126 subjects with missing data on frailty, medical history and survival, data of 1,953 patients were analyzed. Main endpoints were frailty prevalence, mortality rates and causes of death. Results: Frailty prevalence was 5.4% in males, 8.8% in females. Significant risk factors for geriatric frailty in males were being widowed/divorced/separated, low daily total calorie intake, physical inactivity, sleeping >9 h, smoking and hospitalization history; and in females were obesity, physical inactivity, sleeping <6 h, family history of diabetes and heart attack, and hospitalization history. Frail subjects had higher mortality rates (22.5% male; 8.5% female) than pre-frail (8.7% male; 6.4% female) and non frail (5.4% male; 2.5% female). Main causes of death were heart diseases (41%) and chronic lower respiratory diseases (23.0%) in males and nephritis/nephrosis (32.3%) and chronic lower respiratory diseases (17.6%) in females. Discussion: Factors associated with frailty differ by gender, with higher frailty prevalence in females and higher mortality in males. Gender-associated factors for frailty identified in this study may be useful in evaluating frailty and guiding development of public health measures for prevention. Key Message: Common predictive factors for frailty among older adults of both genders, including more frequent previous hospitalizations, physical inactivity, and certain gender associated factors for frailty, are consistent with results of other NHANES studies in which self-reported higher levels of illness and sedentary behavior were directly associated with frailty. PMID- 29507823 TI - Precopulatory behavior and sexual conflict in the desert locust. AB - Studies of mating and reproductive behavior have contributed much to our understanding of various animals' ecological success. The desert locust, Schistocerca gregaria, is an important agricultural pest. However, knowledge of locust courtship and precopulatory behavior is surprisingly limited. Here we provide a comprehensive study of the precopulatory behavior of both sexes of the desert locust in the gregarious phase, with particular emphasis on the conflict between the sexes. Detailed HD-video monitoring of courtship and mating of 20 locust pairs, in a controlled environment, enabled both qualitative and quantitative descriptions of the behavior. A comprehensive list of behavioral elements was used to generate an eight-step ethogram, from first encounter between the sexes to actual copulation. Further analyses included the probability of each element occurring, and a kinematic diagram based on a transitional matrix. Eleven novel behavioral elements are described in this study, and two potential points of conflict between the sexes are identified. Locust sexual interaction was characterized by the dominance of the males during the pre mounting stage, and an overall stereotypic male courtship behavior. In contrast, females displayed no clear courtship-related behavior and an overall less organized behavioral sequence. Central elements in the sexual behavior of the females were low-amplitude hind-leg vibration, as well as rejecting males by jumping and kicking. Intricate reciprocal interactions between the sexes were evident mostly at the mounting stage. The reported findings contribute important insights to our knowledge of locust mating and reproductive behavior, and may assist in confronting this devastating agricultural pest. PMID- 29507825 TI - Marine exotic isopods from the Iberian Peninsula and nearby waters. AB - Effective management of marine bioinvasions starts with prevention, communication among the scientific community and comprehensive updated data on the distribution ranges of exotic species. Despite being a hotspot for introduction due to numerous shipping routes converging at the Strait of Gibraltar, knowledge of marine exotics in the Iberian Peninsula is scarce, especially of abundant but small-sized and taxonomically challenging taxa such as the Order Isopoda. To fill this gap, we conducted several sampling surveys in 44 marinas and provide the first comprehensive study of marine exotic isopods from the Iberian Peninsula, the southern side of the Strait of Gibraltar (northern Africa) and the Balearic Islands. Exotic species included Ianiropsis serricaudis (first record for the Iberian Peninsula and Lusitanian marine province), Paracerceis sculpta (first record for the Alboran Sea ecoregion), Paradella dianae, Paranthura japonica (earliest record for the Iberian Peninsula) and Sphaeroma walkeri. Photographs with morphological details for identification for non-taxonomic experts are provided, their worldwide distribution is updated and patterns of invasion are discussed. We report an expansion in the distribution range of all species, especially at the Strait of Gibraltar and nearby areas. Ianiropsis serricaudis and Paranthura japonica are polyvectic, with shellfish trade and recreational boating being most probable vectors for their introduction and secondary spread. The subsequent finding of the studied species in additional marinas over the years points at recreational boating as a vector and indicates a future spread. We call for attention to reduce lags in the detection and reporting of small-size exotics, which usually remain overlooked or underestimated until the invasion process is at an advanced stage. PMID- 29507824 TI - Similar acute physiological responses from effort and duration matched leg press and recumbent cycling tasks. AB - The present study examined the effects of exercise utilising traditional resistance training (leg press) or 'cardio' exercise (recumbent cycle ergometry) modalities upon acute physiological responses. Nine healthy males underwent a within session randomised crossover design where they completed both the leg press and recumbent cycle ergometer conditions. Conditions were approximately matched for effort and duration (leg press: 4 * 12RM using a 2 s concentric and 3 s eccentric repetition duration controlled with a metronome, thus each set lasted 60 s; recumbent cycle ergometer: 4 * 60 s bouts using a resistance level permitting 80-100 rpm but culminating with being unable to sustain the minimum cadence for the final 5-10 s). Measurements included VO2, respiratory exchange ratio (RER), blood lactate, energy expenditure, muscle swelling, and electromyography. Perceived effort was similar between conditions and thus both were well matched with respect to effort. There were no significant effects by 'condition' in any of the physiological responses examined (all p > 0.05). The present study shows that, when both effort and duration are matched, resistance training (leg press) and 'cardio' exercise (recumbent cycle ergometry) may produce largely similar responses in VO2, RER, blood lactate, energy expenditure, muscle swelling, and electromyography. It therefore seems reasonable to suggest that both may offer a similar stimulus to produce chronic physiological adaptations in outcomes such as cardiorespiratory fitness, strength, and hypertrophy. Future work should look to both replicate the study conducted here with respect to the same, and additional physiological measures, and rigorously test the comparative efficacy of effort and duration matched exercise of differing modalities with respect to chronic improvements in physiological fitness. PMID- 29507826 TI - Intraspecific functional and genetic diversity of Petriella setifera. AB - The aim of the study was an analysis of the intraspecific genetic and functional diversity of the new isolated fungal strains of P. setifera. This is the first report concerning the genetic and metabolic diversity of Petriella setifera strains isolated from industrial compost and the first description of a protocol for AFLP fingerprinting analysis optimised for these fungal species. The results showed a significant degree of variability among the isolates, which was demonstrated by the clearly subdivision of all the isolates into two clusters with 51% and 62% similarity, respectively. For the metabolic diversity, the BIOLOG system was used and this analysis revealed clearly different patterns of carbon substrates utilization between the isolates resulting in a clear separation of the five isolates into three clusters with 0%, 42% and 54% of similarity, respectively. These results suggest that genetic diversity does not always match the level of functional diversity, which may be useful in discovering the importance of this fungus to ecosystem functioning. The results indicated that P. setifera strains were able to degrade substrates produced in the degradation of hemicellulose (D-Arabinose, L-Arabinose, D-Glucuronic Acid, Xylitol, gamma-Amino-Butyric Acid, D-Mannose, D-Xylose and L-Rhamnose), cellulose (alpha-D-Glucose and D-Cellobiose) and the synthesis of lignin (Quinic Acid) at a high level, showing their importance in ecosystem services as a decomposer of carbon compounds and as organisms, which make a significant contribution to carbon cycling in the ecosystem.The results showed for the first time that the use of molecular biology techniques (such as AFLP and BIOLOG analyses) may allow for the identification of intraspecific diversity of as yet poorly investigated fungal species with favourable consequences for our understanding their ecosystem function. PMID- 29507827 TI - Landscape connectivity among remnant populations of guanaco (Lama guanicoe Muller, 1776) in an arid region of Chile impacted by global change. AB - Connectivity between populations plays a key role in the long-term persistence of species in fragmented habitats. This is of particular concern for biodiversity preservation in drylands, since water limited landscapes are typically characterized by little suitable habitat cover, high habitat fragmentation, harsh matrices, and are being rapidly degraded at a global scale. In this study, we modelled landscape connectivity between 11 guanaco Lama guanicoe populations in Chile's arid Norte Chico, a region that supports the last remnant coastal populations of this emblematic herbivore indigenous to South America. We produced a habitat suitability model to derive a regional surface resistance map, and used circuit theory to map functional connectivity, investigate the relative isolation between populations, and identify those that contribute most to the patch connectivity network. Predicted suitable habitat for L. guanicoe represented about 25% of the study region (i.e., 29,173 km2) and was heterogeneously distributed along a continuous stretch along the Andes, and discontinuous patches along the coast. As a result, we found that high connectivity current flows in the mid and high Andes formed a wide, continuous connectivity corridor, enabling connectivity between all high Andean populations. Coastal populations, in contrast, were more isolated. These groups demonstrate no inter-population connectivity between themselves, only with higher altitude populations, and for two of them, animal movement was linked to the effectiveness of wildlife crossings along the Pan-American highway. Our results indicate that functional connectivity is an issue of concern for L. guanicoe in Chile's Norte Chico, implying that future conservation and management plans should emphasize strategies aimed at conserving functional connectivity between coastal and Andean populations, as well as the protection of habitat patches likely to act as stepping stones within the connectivity network. PMID- 29507828 TI - Human anti-HIV IgM detection by the OraQuick ADVANCE(r) Rapid HIV 1/2 Antibody Test. AB - The Centers for Disease Control and Prevention (CDC) and many public health jurisdictions continue to advocate for the most sensitive rapid HIV test that is available. Currently, the recommendation is to utilize tests that can detect HIV infection biomarkers within 30 days of infection, when initial immune responses are mounted. The infected patient's IgM response is often used to detect acute infection within a 20-25 days window after infection. This requirement applies to lab-based testing with automated analyzers and rapid, point of care (POC) testing used for screening in a non-clinical setting. A recent study has demonstrated that POC tests using a Protein A-based detection system can detect samples with predominantly HIV-1 IgM reactivity (Moshgabadi et al., 2015). The OraQuick ADVANCE(r) Rapid HIV-1/2 Antibody Test (OraQuick ADVANCE(r)) also uses Protein A as the detection protein in the antibody-binding colloidal gold conjugate, so it is expected that the OraQuick ADVANCE(r) Test will also detect samples with predominantly IgM reactivity. This report definitively demonstrates that the OraQuick ADVANCE(r) Test can detect IgM antibodies during an acute infection window period of approximately 20-25 days after infection, and is therefore suitable for use in testing environments requiring adherence to current CDC recommendations. PMID- 29507829 TI - Outplanting technique, host genotype, and site affect the initial success of outplanted Acropora cervicornis. AB - Acropora cervicornis is the most widely used coral species for reef restoration in the greater Caribbean. However, outplanting methodologies (e.g., colony density, size, host genotype, and attachment technique) vary greatly, and to date have not been evaluated for optimality across multiple sites. Two experiments were completed during this study, the first evaluated the effects of attachment technique, colony size, and genotype by outplanting 405 A. cervicornis colonies, from ten genotypes, four size classes, and three attachment techniques (epoxy, nail and cable tie, or puck) across three sites. Colony survival, health condition, tissue productivity, and growth were assessed across one year for this experiment. The second experiment assessed the effect of colony density by outplanting colonies in plots of one, four, or 25 corals per 4 m2 across four separate sites. Plot survival and condition were evaluated across two years for this experiment in order to better capture the effect of increasing cover. Colonies attached with a nail and cable tie resulted in the highest survival regardless of colony size. Small corals had the lowest survival, but the greatest productivity. The majority of colony loss was attributed to missing colonies and was highest for pucks and small epoxied colonies. Disease and predation were observed at all sites, but did not affect all genotypes, however due to the overall low prevalence of either condition there were no significant differences found in any comparison. Low density plots had significantly higher survival and significantly lower prevalence of disease, predation, and missing colonies than high density plots. These results indicate that to increase initial outplant success, colonies of many genotypes should be outplanted to multiple sites using a nail and cable tie, in low densities, and with colonies over 15 cm total linear extension. PMID- 29507830 TI - Factors affecting sustainable adoption of e-health technology in developing countries: an exploratory survey of Nigerian hospitals from the perspective of healthcare professionals. AB - Background: E-health technology applications are essential tools of modern information technology that improve quality of healthcare delivery in hospitals of both developed and developing countries. However, despite its positive benefits, studies indicate that the rate of the e-health adoption in some developing countries is either low or underutilized. This is due in part, to barriers such as resistance from healthcare professionals, poor infrastructure, and low technical expertise among others. Objective: The aim of this study is to investigate, identify and analyze the underlying factors that affect healthcare professionals decision to adopt and use e-health technology applications in developing countries, with particular reference to hospitals in Nigeria. Methods: The study used a cross sectional approach in the form of a close-ended questionnaire to collect quantitative data from a sample of 465 healthcare professionals randomly selected from 15 hospitals in Nigeria. We used the modified Technology Acceptance Model (TAM) as the dependent variable and external factors as independent variables. The collected data was then analyzed using SPSS statistical analysis such as frequency test, reliability analysis, and correlation coefficient analysis. Results: The results obtained, which correspond with findings from other researches published, indicate that perceived usefulness, belief, willingness, as well as attitude of healthcare professionals have significant influence on their intention to adopt and use the e-health technology applications. Other strategic factors identified include low literacy level and experience in using the e-health technology applications, lack of motivation, poor organizational and management policies. Conclusion: The study contributes to the literature by pinpointing significant areas where findings can positively affect, or be found useful by, healthcare policy decision makers in Nigeria and other developing countries. This can help them understand their areas of priorities and weaknesses when planning for e-health technology adoption and implementation. PMID- 29507831 TI - Bilateral asymmetry of skin temperature is not related to bilateral asymmetry of crank torque during an incremental cycling exercise to exhaustion. AB - Although moderate relationships (|r| ~ 0.5) were reported between skin temperature and performance-related variables (e.g., kinetic), it remains unclear whether skin temperature asymmetry reflects muscle force imbalance in cycling. Therefore, the aim of this study was to assess whether a relationship exists between kinetic and thermal asymmetry during a fatiguing exercise. Ten elite cyclists were enrolled and tested on a maximal incremental cycling test. Peak crank torques of both legs were obtained at the initial and final workload. Likewise, bilateral skin temperatures were recorded before and after exercise. Asymmetric indexes were also calculated for kinetic (AIK) and skin temperature (AIT) outcomes. The bilateral peak crank torques showed a larger difference at the final compared to the initial workload (p < 0.05) of the incremental exercise. Conversely, the bilateral skin temperature did not show any differences at both initial and final workload (p > 0.05). Additionally, trivial relationships were reported between AIK and AIT (-0.3 < r < 0.2) at the initial and final workload. The obtained results showed that changes in bilateral kinetic values did not reflect concurrent changes in bilateral skin temperatures. This finding emphasizes the difficulty of associating the asymmetry of skin temperature with those of muscle effort in elite cyclists. Lastly, our study also provided further insights on thermal skin responses during exhaustive cycling exercise in very highly-trained athletes. PMID- 29507832 TI - Depressive symptoms and web user experience. AB - Background: Depression, as one of the most prevalent mental disorders, is expected to become a leading cause of disability. While evidence-based treatments are not always easily accessible, Internet-based information and self-help appears as a promising approach to improve the strained supply situation by avoiding barriers of traditional offline treatment. User experience in the domain of mental problems therefore emerges as an important research topic. The aim of our study is to investigate the impact of depressive symptoms on subjective and objective measures of web user experience. Method: In this two-part online study (Ntotal = 721) we investigate the relationship between depressive symptoms of web users and basic website characteristics (i.e., content, subjective and objective usability, aesthetics). Participants completed search and memory tasks on different fully-functional websites. In addition, they were asked to evaluate the given websites with standardized measures and were screened for symptoms of depression using the PHQ-9. We used structural equation modeling (SEM) to determine whether depression severity affects users' perception of and performance in using information websites. Results: We found significant associations between depressive symptoms and subjective user experience, specifically of website content, usability, and aesthetics, as well as an effect of content perception on the overall appraisal of a website in terms of the intention to visit it again. Small yet significant negative effects of depression severity on all named subjective website evaluations were revealed, leading to an indirect negative effect on the intention to revisit a website via impaired content perceptions. However, objective task performance was not influenced by depressiveness of users. Discussion: Depression emerges as capable of altering the subjective perception of a website to some extend with respect to the main features content, usability, and aesthetics. The user experience of a website is crucial, especially as it facilitates revisiting a website and thus might be relevant in avoiding drop-out in online interventions. Thus, the biased impression of persons affected by symptoms of depression and resulting needs of those users should be considered when designing and evaluating E-(Mental)-Health platforms. The high prevalence of some mental disorders such as depression in the general population stresses the need for further investigations of the found effects. PMID- 29507833 TI - Benthic macrofaunal structure and secondary production in tropical estuaries on the Eastern Marine Ecoregion of Brazil. AB - Tropical estuaries are highly productive and support diverse benthic assemblages within mangroves and tidal flats habitats. Determining differences and similarities of benthic assemblages within estuarine habitats and between regional ecosystems may provide scientific support for management of those ecosystems. Here we studied three tropical estuaries in the Eastern Marine Ecoregion of Brazil to assess the spatial variability of benthic assemblages from vegetated (mangroves) and unvegetated (tidal flats) habitats. A nested sampling design was used to determine spatial scales of variability in benthic macrofaunal density, biomass and secondary production. Habitat differences in benthic assemblage composition were evident, with mangrove forests being dominated by annelids (Oligochaeta and Capitellidae) whereas peracarid crustaceans were also abundant on tidal flats. Macrofaunal biomass, density and secondary production also differed between habitats and among estuaries. Those differences were related both to the composition of benthic assemblages and to random spatial variability, underscoring the importance of hierarchical sampling in estuarine ecological studies. Given variable levels of human impacts and predicted climate change effects on tropical estuarine assemblages in Eastern Brazil, our data support the use of benthic secondary production to address long-term changes and improved management of estuaries in Eastern Brazil. PMID- 29507834 TI - An extended research of crossmodal correspondence between color and sound in psychology and cognitive ergonomics. AB - Based on the existing research on sound symbolism and crossmodal correspondence, this study proposed an extended research on cross-modal correspondence between various sound attributes and color properties in a group of non-synesthetes. In Experiment 1, we assessed the associations between each property of sounds and colors. Twenty sounds with five auditory properties (pitch, roughness, sharpness, tempo and discontinuity), each varied in four levels, were used as the sound stimuli. Forty-nine colors with different hues, saturation and brightness were used to match to those sounds. Result revealed that besides pitch and tempo, roughness and sharpness also played roles in sound-color correspondence. Reaction times of sound-hue were a little longer than the reaction times of sound lightness. In Experiment 2, a speeded target discrimination task was used to assess whether the associations between sound attributes and color properties could invoke natural cross-modal correspondence and improve participants' cognitive efficiency in cognitive tasks. Several typical sound-color pairings were selected according to the results of Experiment 1. Participants were divided into two groups (congruent and incongruent). In each trial participants had to judge whether the presented color could appropriately be associated with the sound stimuli. Result revealed that participants responded more quickly and accurately in the congruent group than in the incongruent group. It was also found that there was no significant difference in reaction times and error rates between sound-hue and sound-lightness. The results of Experiment 1 and 2 indicate the existence of a robust crossmodal correspondence between multiple attributes of sound and color, which also has strong influence on cognitive tasks. The inconsistency of the reaction times between sound-hue and sound-lightness in Experiment 1 and 2 is probably owing to the difference in experimental protocol, which indicates that the complexity of experiment design may be an important factor in crossmodal correspondence phenomena. PMID- 29507835 TI - Psychrophrynella glauca sp. n., a new species of terrestrial-breeding frogs (Amphibia, Anura, Strabomantidae) from the montane forests of the Amazonian Andes of Puno, Peru. AB - We describe a new species of small strabomantid frog (genus Psychrophrynella) from a humid montane forest in the Peruvian Department of Puno. Specimens were collected at 2,225 m a.s.l. in the leaf litter of primary montane forest near Thiuni, along the Macusani-San Gaban road, in the province of Carabaya. The new species is assigned to Psychrophrynella on the basis of morphological similarity, including presence of a tubercle on the inner edge of the tarsus, and call composed of multiple notes. We also include genetic distances for 16S rRNA partial sequences between the new species and other strabomantid frogs. The species with lowest genetic distances are Psychrophrynella chirihampatu and Psychrophrynella usurpator. Psychrophrynella glauca sp. n. is readily distinguished from the three other species of Psychrophrynella (Psychrophrynella bagrecito, P. chirihampatu, and P. usurpator) by its small size, and by having belly and ventral surfaces of legs reddish-brown or red, and chest and throat brown to dark brown with a profusion of bluish-gray flecks. The new species is only known from its type locality. With the discovery of P. glauca, the geographic distribution of Psychrophrynella is extended to the Department of Puno, where it was no longer represented after the description of the genus Microkayla. Furthermore, the Cordillera de Carabaya is the only mountain range known to be home to four of the seven genera of Holoadeninae (Bryophryne, Microkayla, Noblella, and Psychrophrynella), suggesting an intriguing evolutionary history for this group in southern Peru. PMID- 29507836 TI - Expression pattern of Wif1 and beta-catenin during development of anorectum in fetal rats with anorectal malformations. AB - Purpose: This study was performed to investigate the expression pattern of Wnt inhibitory factor 1 (Wif1) and beta-catenin during anorectal development in normal and anorectal malformation (ARM) embryos and the possible role of Wif1 and beta-catenin in the pathogenesis of ARM. Methods: ARM was induced with ethylenethiourea on the 10th gestational day in rat embryos. Cesarean deliveries were performed to harvest the embryos. The expression pattern of Wif1 and beta catenin protein and mRNA was evaluated in normal rat embryos (n = 288) and ARM rat embryos (n = 306) from GD13 to GD16 using immunohistochemical staining, Western blot, and real time RT-PCR. Results: Immunohistochemical staining revealed that in normal embryos Wif1 was constantly expressed in the cloaca from GD13 to GD16. On GD13 and GD14, Wif1-immunopositive cells were extensively expressed in the cloaca. On GD15, the expression of Wif1 were mainly detected on the very thin anal membrane. In ARM embryos, the epithelium of the hindgut and urorectal septum demonstrated faint immunostaining for Wif1 from GD14 to GD16. Western blot and real time RT-PCR revealed that Wif1 and beta-catenin protein and mRNA expression level was significantly decreased in the ARM groups compared with the normal group on GD14 and GD15 (p < 0.05). Conclusions: This study demonstrated that the expression pattern of Wif1 and beta-catenin was disrupted in ARM embryos during anorectal morphogenesis, which demonstrated that downregulation of Wif1 and beta-catenin at the time of cloacal separation into the primitive rectum and urogenital septum might related to the development of ARM. PMID- 29507838 TI - Grazing influences Stipa breviflora seed germination in desert grasslands of the Inner Mongolia Plateau. AB - Seed germination plays an important role in determining the composition and regeneration of plant populations (Stipa breviflora). However, the influencing factors and strategies employed for seed germination in desert grasslands under grazing remain unknown. Therefore, in this study, the reproductive allocation, seed density, seed properties, and corresponding seed germination rates of S. breviflora were examined. Possible situations encountered during dispersal were also simulated to determine their effects on seed germination. The results showed that reproductive individual density not subjected to grazing were significantly higher than those subjected to moderate and heavy grazing. For seed density and seed bank in soil, the highest values were observed for the no grazing treatment, followed by the moderate and heavy grazing treatments. The seed density for germination of soil seed banks was nearly one-fourth of seed density during the growing season. In addition, grazing treatments affected the phenotypic characteristics of seeds and reduced the lower limit of the weight of germinable seeds. Awn removal significantly increased germination. The longest germination time was observed for seeds that entered the soil at an angle of 0 degrees . Our research demonstrated that grazing negatively affected the desert grassland edificator. Individual plants adopted different adaptation strategies under different grazing intensities; for example, a fixed proportion of the seed number and seed germination number of S. breviflora in the soil seed bank was maintained by exceeding the minimum weight of a seed for seed germination. During seed dispersion, the awn effectively prevented germination under unfavourable conditions and helped seeds enter the soil at an optimal angle for promoting germination. PMID- 29507837 TI - Inulin-type fructan improves diabetic phenotype and gut microbiota profiles in rats. AB - Background & Aims: Accumulating research has addressed the linkage between the changes to gut microbiota structure and type 2 diabetes (T2D). Inulin is one type of soluble dietary fiber that can alleviate T2D. As a prebiotic, inulin cannot be digested by humans, but rather is digested by probiotics. However, whether inulin treatment can benefit the entire gut bacteria community remains unknown. In this study, we evaluated the differences in gut microbiota composition among diabetic, inulin-treated diabetic, normal control, and inulin-treated normal control rats. Methods: A diabetic rat model was generated by a high-fat diet and streptozotocin injections (HF/STZ). Inulin was orally administered to normal and diabetic rats. To determine the composition of the gut microbiota, fecal DNA extraction and 16S rRNA gene 454 pyrosequencing were performed. Results: We found that inulin treatment reduced fasting blood glucose levels and alleviated glucose intolerance and blood lipid panels in diabetic rats. Additionally, inulin treatment increased the serum glucagon-like peptide-1 (GLP-1) level, reduced serum IL-6 level, Il6 expression in epididymal adipose tissue, and Pepck, G6pc expression in liver of diabetic rats. Pyrophosphate sequencing of the 16s V3-V4 region demonstrated an elevated proportion of Firmicutes and a reduced abundance of Bacteroidetes at the phylogenetic level in diabetic rats compared to normal control rats. The characteristics of the gut microbiota in control and inulin-treated rats were similar. Inulin treatment can normalize the composition of the gut microbiota in diabetic rats. At the family and genus levels, probiotic bacteria Lactobacillus and short-chain fatty acid (SCFA)-producing bacteria Lachnospiraceae, Phascolarctobacterium, and Bacteroides were found to be significantly more abundant in the inulin-treated diabetic group than in the non-treated diabetic group. In addition, inulin-treated rats had a lower abundance of Desulfovibrio, which produce lipopolysaccharide (LPS). The abundance of Lachnospiraceae was negatively correlated with the blood glucose response after a glucose load. Conclusion: In summary, diabetic rats have different gut microbiota from control rats. Inulin treatment can alleviate gut microbiota dysbiosis in T2D model rats. Moreover, inulin treatment enhanced serum GLP-1 level to suppress IL-6 secretion and production and hepatic gluconeogenesis, resulted in moderation of insulin tolerance. PMID- 29507839 TI - Investigating the molecular basis for heterophylly in the aquatic plant Potamogeton octandrus (Potamogetonaceae) with comparative transcriptomics. AB - Many plant species exhibit different leaf morphologies within a single plant, or heterophylly. The molecular mechanisms regulating this phenomenon, however, have remained elusive. In this study, the transcriptomes of submerged and floating leaves of an aquatic heterophyllous plant, Potamogeton octandrus Poir, at different stages of development, were sequenced using high-throughput sequencing (RNA-Seq), in order to aid gene discovery and functional studies of genes involved in heterophylly. A total of 81,103 unigenes were identified in submerged and floating leaves and 6,822 differentially expressed genes (DEGs) were identified by comparing samples at differing time points of development. KEGG pathway enrichment analysis categorized these unigenes into 128 pathways. A total of 24,025 differentially expressed genes were involved in carbon metabolic pathways, biosynthesis of amino acids, ribosomal processes, and plant-pathogen interactions. In particular, KEGG pathway enrichment analysis categorized a total of 70 DEGs into plant hormone signal transduction pathways. The high-throughput transcriptomic results presented here highlight the potential for understanding the molecular mechanisms underlying heterophylly, which is still poorly understood. Further, these data provide a framework to better understand heterophyllous leaf development in P. octandrus via targeted studies utilizing gene cloning and functional analyses. PMID- 29507840 TI - First insight into the viral community of the cnidarian model metaorganism Aiptasia using RNA-Seq data. AB - Current research posits that all multicellular organisms live in symbioses with associated microorganisms and form so-called metaorganisms or holobionts. Cnidarian metaorganisms are of specific interest given that stony corals provide the foundation of the globally threatened coral reef ecosystems. To gain first insight into viruses associated with the coral model system Aiptasia (sensu Exaiptasia pallida), we analyzed an existing RNA-Seq dataset of aposymbiotic, partially populated, and fully symbiotic Aiptasia CC7 anemones with Symbiodinium. Our approach included the selective removal of anemone host and algal endosymbiont sequences and subsequent microbial sequence annotation. Of a total of 297 million raw sequence reads, 8.6 million (~3%) remained after host and endosymbiont sequence removal. Of these, 3,293 sequences could be assigned as of viral origin. Taxonomic annotation of these sequences suggests that Aiptasia is associated with a diverse viral community, comprising 116 viral taxa covering 40 families. The viral assemblage was dominated by viruses from the families Herpesviridae (12.00%), Partitiviridae (9.93%), and Picornaviridae (9.87%). Despite an overall stable viral assemblage, we found that some viral taxa exhibited significant changes in their relative abundance when Aiptasia engaged in a symbiotic relationship with Symbiodinium. Elucidation of viral taxa consistently present across all conditions revealed a core virome of 15 viral taxa from 11 viral families, encompassing many viruses previously reported as members of coral viromes. Despite the non-random selection of viral genetic material due to the nature of the sequencing data analyzed, our study provides a first insight into the viral community associated with Aiptasia. Similarities of the Aiptasia viral community with those of corals corroborate the application of Aiptasia as a model system to study coral holobionts. Further, the change in abundance of certain viral taxa across different symbiotic states suggests a role of viruses in the algal endosymbiosis, but the functional significance of this remains to be determined. PMID- 29507841 TI - Reproduction and community structure of fish from winter catch sites from industrial shrimp bycatch from the northeast and southeast Mexican Pacific. AB - The shrimp fishery is one of the most important fisheries in the world, although the low selectivity from trawling nets has led to the capture of a large number of non-target species. Shrimp-bycatch species include a large number of fish and invertebrate species, of which fish species are the most abundant. The present study aims to determine the community structure as well as the average sizes at first maturity of the fish species from shrimp-bycatch caught from industrial fisheries in the Mexican Pacific from Sinaloa to Guerrero, from January to March 2015. The shrimp-bycatch fish diversity value was found to be 2.22. A total of 37 species of finfish were found, of which five were considered rare. The fish species with the highest Importance Value Index (IVI) levels were Pseudupeneus grandisquamis, Paralichthys woolmani, Lutjanus peru and Diapterus peruvianus. The average size at first maturity was calculated for all species. Of the analysed organisms, 90% were in the juvenile stage, including species with riverine and artisanal fisheries. The present study demonstrates the risk within marine populations to different non-target species due to the poor selectivity of shrimp trawls. PMID- 29507842 TI - High variability of dung beetle diversity patterns at four mountains of the Trans Mexican Volcanic Belt. AB - Insect diversity patterns of high mountain ecosystems remain poorly studied in the tropics. Sampling dung beetles of the subfamilies Aphodiinae, Scarabaeinae, and Geotrupinae was carried out at four volcanoes in the Trans-Mexican Volcanic Belt (TMVB) in the Mexican transition zone at 2,700 and 3,400 MASL, and on the windward and leeward sides. Sampling units represented a forest-shrubland-pasture (FSP) mosaic typical of this mountain region. A total of 3,430 individuals of 29 dung beetle species were collected. Diversity, abundance and compositional similarity (CS) displayed a high variability at all scales; elevation, cardinal direction, or FSP mosaics did not show any patterns of higher or lower values of those measures. The four mountains were different regarding dispersion patterns and taxonomic groups, both for species and individuals. Onthophagus chevrolati dominated all four mountains with an overall relative abundance of 63%. CS was not related to distance among mountains, but when O. chevrolati was excluded from the analysis, CS values based on species abundance decreased with increasing distance. Speciation, dispersion, and environmental instability are suggested as the main drivers of high mountain diversity patterns, acting together at different spatial and temporal scales. Three species new to science were collected (>10% of all species sampled). These discoveries may indicate that speciation rate is high among these volcanoes-a hypothesis that is also supported by the elevated number of collected species with a restricted montane distribution. Dispersion is an important factor in driving species composition, although naturally limited between high mountains; horizontal colonization events at different time scales may best explain the observed species composition in the TMVB, complemented by vertical colonization events to a lesser extent. Environmental instability may be the main factor causing the high variability of diversity and abundance patterns found during sampling. Together, we interpret these results as indicating that species richness and composition in the high mountains of the TMVB may be driven by biogeographical history while variability in diversity is determined by ecological factors. We argue that current conservation strategies do not focus sufficiently on protecting high mountain fauna, and that there is a need for developing and applying new conservation concepts that take into account the high spatial and temporal variability of this system. PMID- 29507843 TI - Obstructive Sleep Apnea in a Patient with Cornelia de Lange Syndrome. AB - Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is characterized by specific facial, skeletal, and behavioral features associated with variable degrees of intellectual disabilities. Sleep disturbances have been reported in patients with CdLS including insomnia, sleep-disordered breathing, intrinsic sleep disorders, and circadian rhythm disorders. The prevalence of sleep-related breathing disorders, in particular, obstructive sleep apnea (OSA), was conducted using validated questionnaires. We report the first case of CdLS that confirmed a moderate to severe degree of OSA using overnight polysomnography, which is the gold standard diagnostic test for OSA. PMID- 29507844 TI - Acquired Elastotic Hemangioma: Case Series and Comprehensive Literature Review. AB - Background Acquired elastotic hemangioma is a benign vascular proliferation that typically presents as an asymptomatic red plaque on a sun-exposed site of an adult. Material and Methods The PubMed database was used to search the following words: acquired, angioma, arm, basal, carcinoma, cell, elastosis, elastotic, exposed, forearm, hemangioma, solar, sun, and vascular. The relevant papers and reference cited generated by the search were reviewed. The features from a case series of 11 patients with acquired elastotic hemangioma are presented. In addition, a comprehensive review of the characteristics of this unique hemangioma not only in our 11 patients but also in the previously reported 34 individuals with this lesion-is provided. Results Acquired elastotic hemangioma, reported in 45 patients (24 women and 21 men), typically appeared as an asymptomatic solitary red plaque in sun-exposed areas-most commonly the forearm--of adults aged 50 years or older. The pathology shows a proliferation of vascular channels surrounded and intertwined by intense solar elastosis--in the upper dermis, located parallel to the overlying epidermis, and separated from it by a zone of normal-appearing superficial papillary dermis. There was extensive solar elastosis surrounding and between the new blood vessels; some of the endothelial cells protrude (in a hob-nail pattern) into the vessel lumen. The clinical differential diagnosis includes basal cell carcinoma and the pathologic differential diagnosis includes other benign, malignant, and reactive vascular lesions. Ultraviolet radiation may contribute to the pathogenesis of this hemangioma since it occurs on sun-exposed sites. There was no recurrence of the lesion following either excision or observation. Conclusions The possibility of acquired elastotic hemangioma should be considered by clinicians when they encounter an older individual with a new red plaque on a sun-exposed site that clinically appears to be a superficial basal cell carcinoma. PMID- 29507845 TI - Stereotactic Radiosurgery for Multiple Brain Metastases: Two Cases of Preserved Quality of Life. AB - Brain metastases are the most common intracranial tumors in the adult population and have been historically treated with whole brain radiation therapy (WBRT). However, as medical advances improve life expectancy, stereotactic radiosurgery (SRS) has replaced WBRT as the standard of care for limited (one to three) brain metastases due to the relative sparing of neurocognitive function (NCF) and therefore quality of life (QoL). The use of SRS has been less documented in the case of multiple (four or more) brain metastases, with literature limited to non randomized studies showing comparable survival and local control. In this series, we detail the case of two individuals who received SRS at our institution for multiple brain metastases and demonstrated remarkable response. The first patient is a 78-year-old woman who received Gamma Knife (GK) treatment to 17 lesions at our institution. This patient responded very well to treatment and maintains an excellent quality of life, with no deficits on serial neurological examination as she continues to travel and drive for ridesharing businesses. The second patient is an active 44-year-old woman who received SRS to 24 lesions at our institution. The patient has now been free of intracranial failures for two years and continues fulfilling her love for travel and long-distance biking. SRS is emerging as an acceptable alternative to WBRT in treating multiple brain metastases due to its preservation of NCF. Because omission of WBRT may lead to increased probability of distant brain metastasis failure, it is critical to follow these patients closely with frequent neuroimaging. In the event of a failure, it is also possible to use SRS salvage therapy with good response. Some patients who receive SRS alone demonstrate exceptional outcomes with excellent QoL, and it is possible that certain prognostication factors such as performance status, tumor histology, and tumor volume may play a role in identifying these patients. The decision to treat a patient with SRS alone for multiple brain metastases should be made carefully with consideration of systemic therapeutic options, overall prognosis, and the patient's goals of care, with adherence to a careful follow-up plan by the physician and patient. PMID- 29507846 TI - Giant Cell Tumour of Knee Popliteus Muscle Synovial Sheath. AB - The giant cell tumour of the tendon sheath (GCTTS) is the second most common soft tissue benign tumour and rarely presents in the knee. We report a rare presentation of a GCTTS in the knee with corresponding magnetic resonance imaging (MRI), an arthroscopic picture, and histological presentation. It is a rare occurrence but should be considered as a differential in atraumatic knee pain presentation. This case report gives a classic picture of its presentation, diagnosis, and histopathology. PMID- 29507847 TI - Does a Spontaneous Intracerebral Hemorrhage Predispose to a Secondary, Distant Intracerebral Hemorrhage? A Case Report and Review of the Literature. AB - Cerebrovascular autoregulation may be dysfunctional after acute intracerebral hemorrhage (ICH). This disruption in autoregulation can potentially result in secondary neurological damage that may present as an intracranial hemorrhage at locations distant from the primary site of hemorrhage. We discuss a case of 68 year-old female who presented with acute left hemiparesis from a spontaneous right frontal ICH. Magnetic resonance imaging (MRI) was negative for any other blooming artifact. Her weakness was improving, but after 72 hours from admission, she had an acute change in her mental status and was found to have a new left frontal ICH distant from the primary hemorrhage. Cerebral dysregulation following spontaneous ICH may predispose patients with risk factors, such as chronic hypertension, to a secondary spontaneous ICH distant from initial ICH. Recognizing this phenomenon can guide the management of acute ICH. PMID- 29507848 TI - "Beer Potomania" - A Syndrome of Severe Hyponatremia with Unique Pathophysiology: Case Studies and Literature Review. AB - Beer potomania, a unique syndrome of hyponatremia, was first reported in 1972. It is described as the excessive intake of alcohol, particularly beer, together with poor dietary solute intake that leads to fatigue, dizziness, and muscular weakness. The low solute content of beer, and suppressive effect of alcohol on proteolysis result in reduced solute delivery to the kidney. The presence of inadequate solute in the kidney eventually causes dilutional hyponatremia secondary to reduced clearance of excess fluid from the body. Early detection of hyponatremia due to beer potomania in the hospital is necessary to carefully manage the patient in order to avoid neurological consequences as this syndrome has unique pathophysiology. We are reporting two cases, presenting to the emergency department with severe hyponatremia. After a detailed initial evaluation of the patients and labs for hyponatremia, a diagnosis of beer potomania was established in both cases. Considering the unique pathophysiology of beer potomania syndrome, the patients were closely monitored and treated appropriately to prevent any neurological sequelae. PMID- 29507849 TI - Exceptional Eight-year Response to Stereotactic Radiosurgery Monotherapy for Multiple Brain Metastases. AB - Breast cancer represents the second leading cause of brain metastases in women. Once diagnosed, brain metastases have been associated with a rapidly progressive and universally poor prognosis. Breast cancer patients, particularly those with advantageous disease characteristics, may achieve extended survival. This extended life expectancy highlights the importance of effective intracranial treatments that minimize treatment-related late toxicity. Whole brain radiation therapy (WBRT) remains a standard of care palliative option; however, concerns remain regarding the late neurocognitive effects. Stereotactic radiosurgery (SRS) provides dose-escalated radiation therapy over a shortened course, maintaining equivalent survival and minimizing normal brain tissue exposure. Herein, we present a breast cancer patient who demonstrated an exceptional response and remained functionally independent following 12 SRS courses targeting 14 unique brain metastases over eight years. The case illustrates the efficacy of SRS alone, as well as the comparable utility of multiple SRS treatment techniques (Gamma Knife (AB Elekta, Stockholm, Sweden), CyberKnife (Accuray, Sunnyvale, California), and TrueBeam (Varian Medical Systems, Palo Alto, California)). PMID- 29507850 TI - CyberKnife Stereotactic Radiosurgery for Primary and Metastatic Cancer in the Cervix. AB - Standard radiation therapy for cervical cancer consists of external beam radiation therapy followed by an intracavitary brachytherapy boost. When brachytherapy cannot be performed due to unfavorable anatomy or coexisting medical conditions, stereotactic body radiotherapy with the CyberKnife is another treatment option which is less invasive and can be performed in a shorter treatment time. We performed non-invasive therapy using the CyberKnife for five cases of urogenital cancer located in the cervix. The local tumor control was excellent with minimal toxicity. Non-invasive treatment was demonstrated as feasible with the CyberKnife for contraindication of surgery or brachytherapy. PMID- 29507851 TI - Non-small Cell Lung Cancer with Multiple Brain Metastases Treated with Radiosurgery and Erlotinib: A Case Report. AB - Brain metastases are commonly seen complications in non-small cell lung cancer (NSCLC) patients. The incidence of brain metastases is increasing as a result of more effective systemic targeted therapies with prolonged survival. The prognosis is usually poor, and up to six months of median survivals were reported with different therapeutic options. Here, we present an NSCLC case with multiple brain metastases treated with radiosurgery and systemic erlotinib therapy with prolonged survival. The use of tyrosine kinase inhibitors (TKI) in conjunction with either stereotactic radiosurgery or whole brain radiotherapy is not well established in terms of efficiency and toxicity. This reported case had an excellent response with a tolerable toxicity profile from the combination of either therapies. PMID- 29507852 TI - Pitfall in Pupillometry: Exaggerated Ciliospinal Reflex in a Patient in Barbiturate Coma Mimicking a Nonreactive Pupil. AB - Although a neurological examination is fundamental to the evaluation of comatose patients, it is less reliable in a medically induced coma. A commonly misinterpreted finding in patients in a pentobarbital coma is altered pupillary reactivity secondary to an exaggerated ciliospinal reflex. Recognizing an exaggerated ciliospinal reflex in patients in a pentobarbital coma is important and may prevent unnecessary intervention. We present a patient induced in a pentobarbital coma for the treatment of status epilepticus who exhibited a nonreactive pupil secondary to an exaggerated ciliospinal reflex confirmed by pupillometry. We also discuss the anatomy of the ciliospinal reflex and literature regarding its clinical relevance. PMID- 29507853 TI - Repeated Stereotactic Radiosurgery in Brain Metastases: A Case Report. AB - The aims of radiation therapy of brain metastases include maintaining neurocognitive function and control of disease and, hopefully, improvement of survival. We present a case report with a very long survival in which the role of repeated stereotactic radiosurgery (SRS) was investigated for a patient with a recurrent brain metastasis from non-small cell lung cancer in the same area. Stereotactic re-irradiation was successful and well-tolerated with no neurological toxicity after 16 months. PMID- 29507854 TI - Primary Intramedullary Malignant Lymphoma in the Cervical Cord with a Presyrinx State. AB - A 79-year-old man presented with primary intramedullary malignant lymphoma with a presyrinx state in the cervical cord manifesting as left hemiparesis and hemidysesthesia. The magnetic resonance imaging (MRI) scan showed an intramedullary mass in the cervical spinal cord at the level of C1 and T2 weighted image prolongation from the medulla to the level of C5. According to the progression of hemiparesis, he underwent an emergency removal of the tumor under general anesthesia. The tumor was totally removed, and the peritumoral signal abnormality was not present in the postoperative MRI. Histological examination revealed diffuse large B cell lymphoma. While brain MRI, bone marrow puncture, and 18F-fluorodeoxy-glucose positron emission tomography (18FDG-PET) of the whole body were performed to find out a primary lesion, there were no abnormalities. He underwent a high-dose methotrexate-based chemotherapy and a local irradiation therapy (40Gy). He has been alive for more than two years since the symptom onset, and without any evidence of recurrence. This case suggests that malignant lymphoma, as an infiltrating and rapidly progressive tumor, may be accompanied by syrinx. PMID- 29507855 TI - Pure Ocular Weakness as the Initial Manifestation of Lambert-Eaton Myasthenic Syndrome. AB - Pure ocular presentation of Lambert-Eaton syndrome is not a common phenomenon. Such presentation poses significant diagnostic challenges and requires conscientious evaluation. In this review, we have described a case of a patient with pure ocular weakness, initially diagnosed as seronegative ocular myasthenia which on further evaluation was found to have ocular Lambert-Eaton myasthenic syndrome (LEMS). PMID- 29507856 TI - Factors Associated with Consuming Junk Food among Saudi Adults in Jeddah City. AB - Introduction Junk food (JF) consumption trend is increasing in all parts of the world. The transition in lifestyle and dietary habits is leading to many non communicable diseases. The objectives of this study are twofold: (1) To examine the prevalence of junk food consumption and factors associated with consuming junk food among Saudi adults in Jeddah; and (2) to compare the trends of junk food consumption among males and females in Jeddah. Methodology This cross sectional study was conducted in five different Primary Health Care centers (PHCCs) of Jeddah working under Ministry of Health. The subjects were men (n = 146) and women (n = 254) aged 18-67 years visiting these centers. Structured validated close ended questionnaire was filled by all the participants. Data analysis was done using SPSS. Chi-square was applied to analyze the difference between male and female JF consumption and multivariate logistic regression analysis was done to examine the risk factors. Results Overall the JF consumption in subjects with mean age 33.69 +/- 12.29 years was highly prevalent in both genders (86.5%); (men = 85.6% and women = 87.4%). Controlling for some demographic and socioeconomic variables, increased junk food consumption was independently associated with education (OR = 2.47, 95% CI: 1.088-5.605, p = 0.031), individuals who had limited time (OR = 3.82, 95% CI: 1.690-8.642, p < 0.001), for the change of routine and taste (OR = 7.64, 95% CI: 3.145-18.563, p < 0.001 and OR = 11.031, 95% CI: 4.219-28.843, p < 0.001, respectively). Conclusion The study findings provide evidence on the high prevalence of junk food consumption among Saudi adults. Junk food has influence in the dietary patterns of Saudi adults and this trend is likely to rise. This growing widespread use of junk food is of concern which may cause obesity-related non-communicable diseases. PMID- 29507857 TI - Importance of physical capacity and the effects of exercise in heart transplant recipients. AB - One of the most important prognostic factors in heart failure patients is physical capacity. Patients with very poor physical performance and otherwise eligible, may be listed as candidates for heart transplantation (HTx). After such surgery, life-long immunosuppression therapy is needed to prevent rejection of the new heart. The dark side of immunosuppression is the increased risk of infections, kidney failure, cancer and advanced atherosclerosis (cardiac allograft vasculopathy), with the two latter conditions as the main causes of later mortality. In a worldwide perspective, 50% of the HTx patients survive past 10 years. Poor aerobic capacity prior to graft deterioration is not only limited to the failing heart, but also caused by peripheral factors, such as limited function in the skeletal muscles and in the blood vessels walls. Exercise rehabilitation after HTx is of major importance in order to improve physical capacity and prognosis. Effects of high-intensity interval training (HIT) in HTx recipients is a growing field of research attracting worldwide focus and interest. Accumulating evidence has shown that HIT is safe and efficient in maintenance HTx recipients; with superior effects on physical capacity compared to conventional moderate exercise. This article generates further evidence to the field by summarizing results from a decade of research performed at our center supported by a broad, but not strict formal, literature review. In short, this article demonstrates a strong association between physical capacity measured after HTx and long-term survival. It describes the possible "HIT-effect" with increased levels of inflammatory mediators of angiogenesis. It also describes long-term effects of HIT; showing a positive effect in development of anxiety symptoms despite that the improved physical capacity was not sustained, due to downregulation of exercise and intensity. Finally, our results are linked to the ongoing HITTS study, which investigates safety and efficiency of HIT in de novo HTx recipients. Together with previous results, this study may have the potential to change existing guidelines and contribute to a better prognosis for the HTx population as a whole. PMID- 29507858 TI - Renal function and physical fitness after 12-mo supervised training in kidney transplant recipients. AB - AIM: To evaluate the effect of a 12-mo supervised aerobic and resistance training, on renal function and exercise capacity compared to usual care recommendations. METHODS: Ninety-nine kidney transplant recipients (KTRs) were assigned to interventional exercise (Group A; n = 52) and a usual care cohort (Group B; n = 47). Blood and urine chemistry, exercise capacity, muscular strength, anthropometric measures and health-related quality of life (HRQoL) were assessed at baseline, and after 6 and 12 mo. Group A underwent a supervised training three times per week for 12 mo. Group B received only general recommendations about home-based physical activities. RESULTS: Eighty-five KTRs completed the study (Group A, n = 44; Group B, n = 41). After 12 mo, renal function remained stable in both groups. Group A significantly increased maximum workload (+13 W, P = 0.0003), V'O2 peak (+3.1 mL/kg per minute, P = 0.0099), muscular strength in plantar flexor (+12 kg, P = 0.0368), height in the countermovement jump (+1.9 cm, P = 0.0293) and decreased in Body Mass Index (-0.5 kg/m2, P = 0.0013). HRQoL significantly improved in physical function (P = 0.0019), physical-role limitations (P = 0.0321) and social functioning scales (P = 0.0346). No improvements were found in Group B. CONCLUSION: Twelve-month of supervised aerobic and resistance training improves the physiological variables related to physical fitness and cardiovascular risks without consequences on renal function. Recommendations alone are not sufficient to induce changes in exercise capacity of KTRs. Our study is an example of collaborative working between transplant centres, sports medicine and exercise facilities. PMID- 29507859 TI - In vitro intracellular IFNgamma, IL-17 and IL-10 producing T cells correlates with the occurrence of post-transplant opportunistic infection in liver and kidney recipients. AB - AIM: To validate intracellular cytokine production functional assay as means of cell-mediated immunity monitoring of post-transplant patients with opportunistic infection (OI). METHODS: Intracellular cytokine-producing CD4+ and CD8+ T-cell monitoring was carried out in 30 liver transplant (LTr) and 31 kidney transplant (KTr) recipients from 2010 to 2012. Patients were assessed in our Department of Immunology at the Clinical University 'Hospital Virgen de la Arrixaca-IMIB' in Murcia, Spain for one year following transplantation. FACS Canto II flow cytometer was employed to quantify the intracellular production of IL-17, IFNgamma and IL-10 cytokines on stimulated CD4+CD69+ and CD8+CD69+ T cells and BD FACS DIVA v.6 software was used to analysed the data. Statistical analysis was carried out using SPSS 22.0. RESULTS: LTr with OI had significantly lower % of CD8+CD69+IFNgamma+ T cells at 60 (7.95 +/- 0.77 vs 26.25 +/- 2.09, P < 0.001), 90 (7.47 +/- 1.05 vs 30.34 +/- 3.52, P < 0.001) and 180 (15.31 +/- 3.24 vs 24.59 +/- 3.28, P = 0.01) d post-transplantation. Higher % of CD4+CD69+IL-10+ as well as CD4+CD69+IL-17+ T cells were yet reported at 30 (14.06 +/- 1.65 vs 6.09 +/- 0.53, P = 0.0007 and 4.23 +/- 0.56 vs 0.81 +/- 0.14, P = 0.005; respectively), 60 (11.46 +/- 1.42 vs 4.54 +/- 0.91, P = 0.001 and 4.21 +/- 0.59 vs 1.43 +/- 0.42, P = 0.03; respectively) and 90 d (16.85 +/- 1.60 vs 4.07 +/- 0.63, P < 0.001 and 3.97 +/- 0.43 vs 0.96 +/- 0.17, P = 0.001). Yet, KTr with OI had significantly lower percentage of CD4+CD69+IFNgamma+ at 30 (11.80 +/- 1.59 vs 20.64 +/- 3.26, P = 0.035), 60 (11.19 +/- 1.35 vs 15.85 +/- 1.58, P = 0.02), 90 (11.37 +/- 1.42 vs 22.99 +/- 4.12, P = 0.028) and 180 (13.63 +/- 2.21 vs 21.93 +/- 3.88, P = 0.008) d post-transplantation as opposed to CD4+CD69+IL-10+ and CD8+CD69+IL-10+ T cells which percentages were higher at 30 (25.21 +/- 2.74 vs 8.54 +/- 1.64, P < 0.001 and 22.37 +/- 1.35 vs 17.18 +/- 3.54, P = 0.032; respectively), 90 (16.85 +/- 1.60 vs 4.07 +/- 0.63, P < 0.001 and 23.06 +/- 2.89 vs 10.19 +/- 1.98, P = 0.002) and 180 (21.81 +/- 1.72 vs 6.07 +/- 0.98, P < 0.001 and 19.68 +/- 2.27 vs 10.59 +/- 3.17, P = 0.016) d post-transplantation. The auROC curve model determined the most accurate cut-off values to stratify LTr and KTr at high risk of OI and Cox Regression model confirmed these biomarkers as the most significant risk factors to opportunistic infection. CONCLUSION: Post-transplant percentages of T-cell subsets differed significantly amongst infected- and non-infected-LTr and -KTr and yet this imbalance was found to contribute towards a worst clinical outcome. PMID- 29507861 TI - Fibrin Clot Strength in Patients with Diabetes Mellitus Measured by Thrombelastography. AB - Background: Patients with diabetes mellitus (DM) exhibit increased risk of recurrent myocardial infarction. Maximal clot strength measured by thrombelastography (TEG) is a risk factor for recurrent ischemic events. We hypothesized that diabetic subjects exhibit increased fibrin clot strength in platelet-poor plasma and that glycemic control correlates with maximal fibrin clot strength. Methods: We collected plasma samples from subjects with known or suspected coronary artery disease undergoing cardiac catheterization (n = 354). We measured kaolin-activated TEG in platelet-poor citrate plasma. Time to fibrin formation (R), clot formation time (K), and maximal fibrin clot strength (MA) were recorded. Results: Plasma fibrin MA was increased among subjects with DM (n = 152) as compared to non-DM (n = 202) (37.0 +/- 8 versus 34.1 +/- 8 mm; p < 0.001). Hemoglobin A1c (HbA1c) (rho = 0.22; p = 0.001) and fibrinogen (rho = 0.29; p < 0.001) correlated with fibrin MA. In multivariable regression analysis, DM remained significantly associated with plasma MA after adjustment for fibrinogen level (p = 0.003). Conclusions: Subjects with diabetes mellitus exhibit increased maximal fibrin clot strength measured by TEG in platelet-poor plasma. PMID- 29507862 TI - DPP-4 Inhibitors as Treatments for Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - Objective: Several clinical studies have reported the application of dipeptidyl peptidase-4 (DPP-4) inhibitors as treatments for type 1 diabetes mellitus (T1DM). This study aims to review the outcomes of these existing studies and to discuss the therapeutic effects of DPP-4 inhibitors on T1DM. Methods: We thoroughly searched the Medline, Embase, PubMed, and Cochrane Library databases and ClinicalTrials.gov for studies concerning the use of DPP-4 inhibitors in patients with T1DM. Results: In preclinical trials, DPP-4 inhibitors improved the pathogenesis of T1DM. However, only a portion of the studies showed potential efficacy regarding clinical glycemic control and other clinical parameters. From this meta-analysis, pooled data from 5 randomized controlled trials revealed that the additional use of DPP-4 inhibitors resulted in a greater decrease in glycated hemoglobin A1c (HbA1c) levels (0.07%, 95% CI (-0.37%-0.23%)) than insulin monotherapy, although the decrease was not significant. A small decrease in postprandial glucose or insulin consumption was confirmed. Conclusion: Although DPP-4 inhibitors may be beneficial for T1DM, existing studies do not strongly support these positive effects in clinical practice. Further optimized clinical trials are needed. PMID- 29507860 TI - Inhibitor of Differentiation-3 and Estrogenic Endocrine Disruptors: Implications for Susceptibility to Obesity and Metabolic Disorders. AB - The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3) promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17beta-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs) in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling. PMID- 29507863 TI - Effect of Tofogliflozin on Body Composition and Glycemic Control in Japanese Subjects with Type 2 Diabetes Mellitus. AB - Sodium-glucose cotransporter 2 inhibitor tofogliflozin is a new type of antidiabetic drug for individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to examine in which type of individuals and/or under which conditions tofogliflozin could exert more beneficial effects on body composition and/or glycemic control in Japanese individuals with T2DM. We retrospectively evaluated the effects of tofogliflozin on body composition and/or glycemic control in individuals with T2DM who newly started taking tofogliflozin. After tofogliflozin treatment, body weight was significantly reduced and HbA1c levels were significantly decreased. Body fat mass, skeletal muscle mass, and skeletal muscle index, a marker for sarcopenia, were also reduced after the treatment. In univariate analyses, there was a statistically significant association between the decrease of HbA1c level after tofogliflozin treatment (Delta HbA1c) and the following parameters such as HbA1c levels at baseline, visceral fat area (VFA) at baseline, and reduction of VFA after the treatment (Delta VFA). Furthermore, in multivariate analyses, HbA1c levels at baseline and duration of diabetes were independently associated with Delta HbA1c. These results suggest that tofogliflozin would be more suitable for relatively obese individuals whose duration of diabetes is relatively short. PMID- 29507864 TI - Distinct Profiles of CD163-Positive Macrophages in Idiopathic Interstitial Pneumonias. AB - Background: The types of cells most significantly linked to individual subtypes of idiopathic interstitial pneumonias (IIPs) remain unclear. Few studies have examined CD163+ macrophages in IIPs. Objective: We retrospectively aimed to immunohistochemically characterize the CD163+ macrophages in IIPs. Methods: Paraffin-embedded lung tissue samples were obtained from 47 patients with IIPs, including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (NSIP), and cryptogenic organizing pneumonia (COP), and 12 normal controls were immunohistochemically analyzed, using primary antibodies against CD68 and CD163 as indicators of pan and M2 macrophages, respectively. Results: CD68+ macrophage density was significantly increased in the 3 subtypes of IIPs relative to that in the control group, although no difference was detected within the different IIPs. CD163+ macrophage density was significantly increased in NSIP and COP samples relative to that in IPF samples. The density ratio of CD163+ macrophages to CD68+ macrophages was significantly decreased in IPF/UIP samples relative to that in the others, while the densities in NSIP and COP were significantly higher than those in control cases. Conclusion: CD163+ macrophages show distinct profiles among IIPs, and the standardized numerical density is decreased in IPF cases that have poor prognoses. PMID- 29507866 TI - Adalimumab for Corticosteroid and Infliximab-Resistant Immune Reconstitution Inflammatory Syndrome in the Setting of TB/HIV Coinfection. AB - Corticosteroids are the mainstay of therapy for immune reconstitution inflammatory syndrome (IRIS). However, little is known about how to treat IRIS unresponsive to steroids. We report a patient with HIV-TB coinfection who was unresponsive to first prednisolone and then infliximab but whose IRIS resolved with adalimumab. PMID- 29507867 TI - Factors Associated With Persistence of Plasma HIV-1 RNA During Long-term Continuously Suppressive Firstline Antiretroviral Therapy. AB - Background: Persistence of plasma HIV-1 RNA during seemingly effective antiretroviral thereapy (ART) is incompletely understood. Using an ultrasensitive assay, this cross-sectional study investigated residual plasma HIV-1 RNA in subjects maintained on firstline ART with continuous viral load suppression <50 copies/mL for <=15 years without recognized viral load blips or treatment interruptions and explored its relationship with the duration of suppressive ART, efavirenz concentrations in plasma, 2-LTR circular HIV-1 DNA (2-LTRc DNA) in peripheral blood mononuclear cells, and cellular (CD4 plus CD26/CD38/CD69; CD8 plus CD38/HLA-DR/DP/DQ) and soluble (sCD14, sCD27, sCD30, IL-6) markers of immune activation in peripheral blood. Methods: Residual plasma HIV-1 RNA, total HIV-1 DNA and 2-LTRc DNA were quantified by real-time and digital droplet PCR. Cellular (CD4 plus CD26/CD38/CD69; CD8 plus CD38/HLA-DR/DP/DQ) and soluble (sCD14, sCD27, sCD30, IL-6) markers of immune activation were measured by flow cytometry and ELISA. Results: Residual plasma HIV-1 RNA and 2-LTRc DNA were detected in 52/104 (50%) and 24/104 (23%) subjects, respectively. Among subjects with detectable HIV 1 RNA, 50/52 showed levels <=11 copies/mL. In adjusted analyses, HIV-1 RNA levels were 0.37 log10 copies/mL higher with each log10 U/mL increase in sCD27 (95% confidence interval, 0.01-0.73; P = .02). No significant association was found between residual plasma HIV-1 RNA and other explored parameters. Conclusions: These findings point to an ongoing relationship between plasma HIV-1 RNA and selected markers of immune activation during continuously suppressive ART. The novel direct association with levels of sCD27 warrants further investigation. PMID- 29507868 TI - Effective and less invasive diagnostic strategy for gastrointestinal GVHD. AB - Background and study aims: Rectosigmoidoscopy with biopsy has been regarded to be a useful procedure to diagnose gastrointestinal graft-versus-host disease (GVHD). However, little is known about the specific colonoscopic features of gastrointestinal GVHD. In this study, we focused on the 4 unique colonoscopic findings - orange peel appearance, spotty redness, small mucosal sloughing, and diffuse mucosal defect - which are possible specific findings of gastrointestinal GVHD. We aimed to estimate the usefulness of these four unique colonoscopic findings in the rectosigmoid portion to diagnose gastrointestinal GVHD. Patients and methods: Seventy patients who were histologically diagnosed with gastrointestinal GVHD at our institute were retrospectively enrolled. Colonoscopic findings were reviewed, focusing on the four characteristic findings. The percentage of the positive cases for the characteristic findings was calculated. The final scoping portion and the number of cases showing any of the four characteristic findings in the rectosigmoid portion were also evaluated. The relationships between biopsy sites and the histological findings were also evaluated. Results: Orange peel appearance was observed in 66 cases (94.3 %). Spotty redness was observed in 45 cases (64.3 %). Small mucosal sloughing was observed in 49 cases (70.0 %). Diffuse mucosal defect was observed in six cases (8.6 %). The number of cases that were concurrently positive for one, two, and three findings were 16 (20.8 %), 20 (26.0 %), and 34 (48.6 %), respectively. Fifty-eight cases (82.9 %) were investigated up to the rectosigmoid portion, and 12 (17.1 %) were investigated beyond the sigmoid colon. All of the cases showed at least 1 of the 4 characteristics in the rectosigmoid portion. The percentage of crypt apoptosis in the biopsy specimen from orange peel appearance, spotty redness, small mucosal sloughing, and diffuse mucosal defect were 87.5 %, 83.3 %, 87.2 %, and 88.9 %, respectively. Conclusion: Orange peel appearance, spotty redness, small mucosal sloughing, and diffuse mucosal defect are the characteristic colonoscopic findings useful for diagnosis of gastrointestinal GVHD. These findings are frequently observed in the rectosigmoid portion. The histological detection rates for crypt cell apoptosis from these findings are high. Identifying the four characteristic findings on rectosigmoidoscopy and taking biopsies from these areas could be essential for the diagnostic strategy for gastrointestinal GVHD. PMID- 29507869 TI - Endoscopic ultrasound assessment of gastrointestinal polypoid lesions of indeterminate morphology in patients with portal hypertension. AB - Background and study aims: Polypoid lesions found during upper gastrointestinal endoscopy (UGIE) are occasionally found in patients with portal hypertension (PH). This study aimed to assess the true nature of such polypoid lesions using endoscopic ultrasound (EUS) and determine the accuracy of UGIE in differentiating between vascular and non-vascular lesions in PH. Patients and methods: We retrospectively assessed all patients with PH referred for EUS due to polypoid lesions of unknown nature at UGIE over a 7-year period. Cases of known varices were excluded. UGIE findings were compared to EUS findings. Results: 66 patients were included (26 male). Commonest UGIE findings were: possible varices (19.4 %), polypoid/neoplastic lesion (52.8 %) and submucosal lesion (16.7 %). After EUS, the final diagnoses were: varices in 25 %, polypoid lesion with underlying vessel/varix in 27.8 % and non-vascular lesion or submucosal lesion in 47.2 %. The diagnostic accuracy of UGIE was suboptimal, since 28.6 % of possible varices were eventually found to be non-vascular, while 15.8 % of polyp/neoplastic looking lesions proved to be varices and 42.1 % were lesions with underlying vessel/varix. 50 % of submucosal lesions were eventually found to be varices. Conclusion: Endoscopists should have a high index of suspicion of varices or polyps related to varices when assessing atypical looking polypoid lesions in patients with PH. In such cases EUS should be considered before obtaining biopsies. PMID- 29507870 TI - Adherence to quality indicators and surveillance guidelines in the management of Barrett's esophagus: a retrospective analysis. AB - Background: Adherence to quality indicators and surveillance guidelines in the management of Barrett's esophagus (BE) promotes high-quality, cost-effective care. The aims of this study were (1) to evaluate adherence to standardized classification (Prague Criteria) and systematic (four-quadrant) biopsy protocol, (2) to identify predictors of practice patterns, and (3) to assess adherence to surveillance guidelines for non-dysplastic BE (NDBE). Methods: This was a single center retrospective study of esophagogastroduodenoscopy (EGD) performed for BE (June 2008 to December 2015). Patient demographics, procedure characteristics, and histology results were obtained from the procedure report-generating database and chart review. Adherence to Prague Criteria and systematic biopsies was based on operative report documentation. Multiple logistic regression analysis was performed to identify predictors of practice patterns. Guideline adherent surveillance EGD was defined as those performed within 6 months of the recommended 3- to 5-year interval. Results: In total, 397 patients (66.5 % male; mean age 60.1 +/- 12.5 years) had an index EGD during the study period. Adherence to Prague Criteria and systematic biopsies was 27.4 % and 24.1 %, respectively. Endoscopists who performed therapeutic interventions for BE were more likely to use the Prague Criteria (OR: 3.16; 95 %CI: 1.47 - 6.82; P < 0.01) than those who did not. Longer time in practice was positively associated with adherence to Prague Criteria (OR 1.07; 95 %CI: 1.02 - 1.12; P < 0.01) but with a lower likelihood of performing systematic biopsies (OR 0.91; 95 %CI: 0.85 - 0.97; P < 0.01). More than half (55.6 %) of patients with NDBE underwent surveillance EGD sooner (range 1 - 29 months) than the recommended interval. Conclusion: Adherence to quality indicators and surveillance guidelines in BE is low. Operator characteristics, including experience with endoscopic therapy for BE and time in practice predicted practice pattern. Future efforts are needed to reduce variability in practice and promote high-value care. PMID- 29507871 TI - How familiar are we with decision-making concerning the treatment of perforation after endoscopic mucosal resection (EMR) in the colon? A case report. AB - Background and study aims We describe a case of perforation after colonic endoscopic mucosal resection (EMR) that was treated conservatively. We would like to highlight the importance of decision-making mainly based on the endoscopist's point of view in combination with the surgical consultation. Although the radiological imaging is always needed, it cannot solely lead to a decision for operation. Intraperitoneal gas in computed tomography is not always associated with a hole in the endoscopic field and could be possibly explained from a "balloon" phenomenon. The amount of extraluminal air after an EMR does not correlate reciprocally with patient's pain after the procedure. Even though perforation is a radiological diagnosis and endoscopists should be aware of the common post-EMR radiological findings, the surgical examination is mandatory and should be coupled with the endoscopic opinion in order to guide appropriately the treatment in patients with acute pain. PMID- 29507865 TI - Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders? AB - Macrophages are key cellular components of the innate immunity, acting as the main player in the first-line defence against the pathogens and modulating homeostatic and inflammatory responses. Plasticity is a major feature of macrophages resulting in extreme heterogeneity both in normal and in pathological conditions. Macrophages are not homogenous, and they are generally categorized into two broad but distinct subsets as either classically activated (M1) or alternatively activated (M2). However, macrophages represent a continuum of highly plastic effector cells, resembling a spectrum of diverse phenotype states. Induction of specific macrophage functions is closely related to the surrounding environment that acts as a relevant orchestrator of macrophage functions. This phenomenon, termed polarization, results from cell/cell, cell/molecule interaction, governing macrophage functionality within the hosting tissues. Here, we summarized relevant cellular and molecular mechanisms driving macrophage polarization in "distant" pathological conditions, such as cancer, type 2 diabetes, atherosclerosis, and periodontitis that share macrophage-driven inflammation as a key feature, playing their dual role as killers (M1-like) and/or builders (M2-like). We also dissect the physio/pathological consequences related to macrophage polarization within selected chronic inflammatory diseases, placing polarized macrophages as a relevant hallmark, putative biomarkers, and possible target for prevention/therapy. PMID- 29507874 TI - Submesoscale-selective compensation of fronts in a salinity-stratified ocean. AB - Salinity, rather than temperature, is the leading influence on density in some regions of the world's upper oceans. In the Bay of Bengal, heavy monsoonal rains and runoff generate strong salinity gradients that define density fronts and stratification in the upper ~50 m. Ship-based observations made in winter reveal that fronts exist over a wide range of length scales, but at O(1)-km scales, horizontal salinity gradients are compensated by temperature to alleviate about half the cross-front density gradient. Using a process study ocean model, we show that scale-selective compensation occurs because of surface cooling. Submesoscale instabilities cause density fronts to slump, enhancing stratification along front. Specifically for salinity fronts, the surface mixed layer (SML) shoals on the less saline side, correlating sea surface salinity (SSS) with SML depth at O(1)-km scales. When losing heat to the atmosphere, the shallower and less saline SML experiences a larger drop in temperature compared to the adjacent deeper SML on the salty side of the front, thus correlating sea surface temperature (SST) with SSS at the submesoscale. This compensation of submesoscale fronts can diminish their strength and thwart the forward cascade of energy to smaller scales. During winter, salinity fronts that are dynamically submesoscale experience larger temperature drops, appearing in satellite-derived SST as cold filaments. In freshwater-influenced regions, cold filaments can mark surface trapped layers insulated from deeper nutrient-rich waters, unlike in other regions, where they indicate upwelling of nutrient-rich water and enhanced surface biological productivity. PMID- 29507872 TI - Optimizing Parkinson's disease diagnosis: the role of a dual nuclear imaging algorithm. AB - The diagnosis of Parkinson's disease (PD) currently relies almost exclusively on the clinical judgment of an experienced neurologist, ideally a specialist in movement disorders. However, such clinical diagnosis is often incorrect in a large percentage of patients, particularly in the early stages of the disease. A commercially available, objective and quantitative marker of nigrostriatal neurodegeneration was recently provided by 123-iodine 123I-ioflupane SPECT imaging, which is however unable to differentiate PD from a variety of other parkinsonian syndromes associated with striatal dopamine deficiency. There is evidence to support an algorithm utilizing a dual neuroimaging strategy combining 123I-ioflupane SPECT and the noradrenergic receptor ligand 123I metaiodobenzylguanidine (MIBG), which assesses the post-ganglion peripheral autonomic nervous system. Evolving concepts regarding the synucleinopathy affecting the central and peripheral autonomic nervous systems as part of a multisystem disease are reviewed to sustain such strategy. Data are presented to show how MIBG deficits are a common feature of multisystem Lewy body disease and can be used as a unique feature to distinguish PD from atypical parkinsonisms. We propose that the combination of cardiac (MIBG) and cerebral 123I-ioflupane SPECT could satisfy one of the most significant unmet needs of current PD diagnosis and management, namely the early and accurate diagnosis of patients with typical Lewy body PD. Exemplary case scenarios will be described, highlighting how dual neuroimaging strategy can maximize diagnostic accuracy for patient care, clinical trials, pre-symptomatic PD screening, and special cases provided by specific genetic mutations associated with PD. PMID- 29507873 TI - Anaesthesia in austere environments: literature review and considerations for future space exploration missions. AB - Future space exploration missions will take humans far beyond low Earth orbit and require complete crew autonomy. The ability to provide anaesthesia will be important given the expected risk of severe medical events requiring surgery. Knowledge and experience of such procedures during space missions is currently extremely limited. Austere and isolated environments (such as polar bases or submarines) have been used extensively as test beds for spaceflight to probe hazards, train crews, develop clinical protocols and countermeasures for prospective space missions. We have conducted a literature review on anaesthesia in austere environments relevant to distant space missions. In each setting, we assessed how the problems related to the provision of anaesthesia (e.g., medical kit and skills) are dealt with or prepared for. We analysed how these factors could be applied to the unique environment of a space exploration mission. The delivery of anaesthesia will be complicated by many factors including space induced physiological changes and limitations in skills and equipment. The basic principles of a safe anaesthesia in an austere environment (appropriate training, presence of minimal safety and monitoring equipment, etc.) can be extended to the context of a space exploration mission. Skills redundancy is an important safety factor, and basic competency in anaesthesia should be part of the skillset of several crewmembers. The literature suggests that safe and effective anaesthesia could be achieved by a physician during future space exploration missions. In a life-or-limb situation, non-physicians may be able to conduct anaesthetic procedures, including simplified general anaesthesia. PMID- 29507875 TI - Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1. AB - We integrated data obtained from HIV-1 genome-wide association studies with T cell-derived epigenome data and found that the noncoding intergenic variant rs4349147, which is statistically associated with HIV-1 acquisition, is located in a CD4+ T cell-specific deoxyribonuclease I hypersensitive region, suggesting regulatory potential for this variant. Deletion of the rs4349147 element in Jurkat cells strongly reduced expression of interleukin-32 (IL-32), approximately 10-kb upstream, and chromosome conformation capture assays identified a chromatin loop between rs4349147 and the IL-32 promoter validating its function as a long distance enhancer. We generated single rs4349147-A or rs4349147-G allele clones and demonstrated that IL-32 enhancer activity and interaction with the IL-32 promoter are strongly allele dependent; rs4349147 -/A cells display reduced IL-32 expression and altered chromatin conformation as compared to rs4349147 G/- cells. Moreover, RNA sequencing demonstrated that rs4349147 G/- cells express a lower relative ratio of IL-32alpha to non-alpha isoforms than rs4349147 -/A cells and display increased expression of lymphocyte activation factors rendering them more prone to infection with HIV-1. In agreement, in primary CD4+ T cells, both treatment with recombinant IL-32gamma (rIL-32gamma) but not rIL-32alpha, and exogenous lentiviral overexpression of IL-32gamma or IL-32beta but not IL-32alpha resulted in a proinflammatory T cell cytokine environment concomitant with increased susceptibility to HIV infection. Our data demonstrate that rs4349147-G promotes transcription of non-IL-32alpha isoforms, generating a proinflammatory environment more conducive to HIV infection. This study provides a mechanistic link between a HIV-associated noncoding DNA variant and the expression of different IL-32 isoforms that display discrete anti-HIV properties. PMID- 29507876 TI - U.S. Pacific coastal wetland resilience and vulnerability to sea-level rise. AB - We used a first-of-its-kind comprehensive scenario approach to evaluate both the vertical and horizontal response of tidal wetlands to projected changes in the rate of sea-level rise (SLR) across 14 estuaries along the Pacific coast of the continental United States. Throughout the U.S. Pacific region, we found that tidal wetlands are highly vulnerable to end-of-century submergence, with resulting extensive loss of habitat. Using higher-range SLR scenarios, all high and middle marsh habitats were lost, with 83% of current tidal wetlands transitioning to unvegetated habitats by 2110. The wetland area lost was greater in California and Oregon (100%) but still severe in Washington, with 68% submerged by the end of the century. The only wetland habitat remaining at the end of the century was low marsh under higher-range SLR rates. Tidal wetland loss was also likely under more conservative SLR scenarios, including loss of 95% of high marsh and 60% of middle marsh habitats by the end of the century. Horizontal migration of most wetlands was constrained by coastal development or steep topography, with just two wetland sites having sufficient upland space for migration and the possibility for nearly 1:1 replacement, making SLR threats particularly high in this region and generally undocumented. With low vertical accretion rates and little upland migration space, Pacific coast tidal wetlands are at imminent risk of submergence with projected rates of rapid SLR. PMID- 29507877 TI - Trends and fluctuations in the severity of interstate wars. AB - Since 1945, there have been relatively few large interstate wars, especially compared to the preceding 30 years, which included both World Wars. This pattern, sometimes called the long peace, is highly controversial. Does it represent an enduring trend caused by a genuine change in the underlying conflict-generating processes? Or is it consistent with a highly variable but otherwise stable system of conflict? Using the empirical distributions of interstate war sizes and onset times from 1823 to 2003, we parameterize stationary models of conflict generation that can distinguish trends from statistical fluctuations in the statistics of war. These models indicate that both the long peace and the period of great violence that preceded it are not statistically uncommon patterns in realistic but stationary conflict time series. This fact does not detract from the importance of the long peace or the proposed mechanisms that explain it. However, the models indicate that the postwar pattern of peace would need to endure at least another 100 to 140 years to become a statistically significant trend. This fact places an implicit upper bound on the magnitude of any change in the true likelihood of a large war after the end of the Second World War. The historical patterns of war thus seem to imply that the long peace may be substantially more fragile than proponents believe, despite recent efforts to identify mechanisms that reduce the likelihood of interstate wars. PMID- 29507878 TI - A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. AB - We report the discovery that strains of Staphylococcus epidermidis produce 6-N hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control strain that did not produce 6-HAP. S. epidermidis strains producing 6 HAP were found in the metagenome from multiple healthy human subjects, suggesting that the microbiome of some individuals may confer protection against skin cancer. These findings show a new role for skin commensal bacteria in host defense. PMID- 29507879 TI - Landscape variation influences trophic cascades in dengue vector food webs. AB - The epidemiology of vector-borne diseases is governed by a structured array of correlative and causative factors, including landscape (for example, rural versus urban), abiotic (for example, weather), and biotic (for example, food web) factors. Studies of mosquito-borne diseases rarely address these multiple factors at large spatial scales, which limits insights into how human alterations of landscapes and food webs alter mosquito abundance. We used structural equation modeling to identify the relative magnitude and direction of landscape, abiotic, and food web factors on Aedes larvae and adults across 70 sites in northern Thailand. Food web factors were modeled as mosquito-predator trophic cascades. Landscape context affected mosquito-predator communities in aquatic and terrestrial environments via cascading food web interactions. Several mosquito predators within these food webs showed potential as biocontrol agents in mosquito population control, but their potentials for control were landscape dependent. In terrestrial food webs, the habitat-sensitive tokay gecko structured mosquito-predator communities, indicating that a conservation approach to vector control could be a useful addition to existing control efforts. PMID- 29507880 TI - Adaptive metalenses with simultaneous electrical control of focal length, astigmatism, and shift. AB - Focal adjustment and zooming are universal features of cameras and advanced optical systems. Such tuning is usually performed longitudinally along the optical axis by mechanical or electrical control of focal length. However, the recent advent of ultrathin planar lenses based on metasurfaces (metalenses), which opens the door to future drastic miniaturization of mobile devices such as cell phones and wearable displays, mandates fundamentally different forms of tuning based on lateral motion rather than longitudinal motion. Theory shows that the strain field of a metalens substrate can be directly mapped into the outgoing optical wavefront to achieve large diffraction-limited focal length tuning and control of aberrations. We demonstrate electrically tunable large-area metalenses controlled by artificial muscles capable of simultaneously performing focal length tuning (>100%) as well as on-the-fly astigmatism and image shift corrections, which until now were only possible in electron optics. The device thickness is only 30 MUm. Our results demonstrate the possibility of future optical microscopes that fully operate electronically, as well as compact optical systems that use the principles of adaptive optics to correct many orders of aberrations simultaneously. PMID- 29507881 TI - Nasalization by Nasalis larvatus: Larger noses audiovisually advertise conspecifics in proboscis monkeys. AB - Male proboscis monkeys have uniquely enlarged noses that are prominent adornments, which may have evolved through their sexually competitive harem group social system. Nevertheless, the ecological roles of the signals encoded by enlarged noses remain unclear. We found significant correlations among nose, body, and testis sizes and a clear link between nose size and number of harem females. Therefore, there is evidence supporting both male-male competition and female choice as causal factors in the evolution of enlarged male noses. We also observed that nasal enlargement systematically modifies the resonance properties of male vocalizations, which probably encode male quality. Our results indicate that the audiovisual contributions of enlarged male noses serve as advertisements to females in their mate selection. This is the first primate research to evaluate the evolutionary processes involved in linking morphology, acoustics, and socioecology with unique masculine characteristics. PMID- 29507882 TI - Cardiorespiratory interactions previously identified as mammalian are present in the primitive lungfish. AB - The present study has revealed that the lungfish has both structural and functional features of its system for physiological control of heart rate, previously considered solely mammalian, that together generate variability (HRV). Ultrastructural and electrophysiological investigation revealed that the nerves connecting the brain to the heart are myelinated, conferring rapid conduction velocities, comparable to mammalian fibers that generate instantaneous changes in heart rate at the onset of each air breath. These respiration-related changes in beat-to-beat cardiac intervals were detected by complex analysis of HRV and shown to maximize oxygen uptake per breath, a causal relationship never conclusively demonstrated in mammals. Cardiac vagal preganglionic neurons, responsible for controlling heart rate via the parasympathetic vagus nerve, were shown to have multiple locations, chiefly within the dorsal vagal motor nucleus that may enable interactive control of the circulatory and respiratory systems, similar to that described for tetrapods. The present illustration of an apparently highly evolved control system for HRV in a fish with a proven ancient lineage, based on paleontological, morphological, and recent genetic evidence, questions much of the anthropocentric thinking implied by some mammalian physiologists and encouraged by many psychobiologists. It is possible that some characteristics of mammalian respiratory sinus arrhythmia, for which functional roles have been sought, are evolutionary relics that had their physiological role defined in ancient representatives of the vertebrates with undivided circulatory systems. PMID- 29507883 TI - Autoregulation of von Willebrand factor function by a disulfide bond switch. AB - Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ~75% of VWF subunits in healthy human donor plasma but in just ~25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF. PMID- 29507884 TI - Climate warming drives local extinction: Evidence from observation and experimentation. AB - Despite increasing concern about elevated extinction risk as global temperatures rise, it is difficult to confirm causal links between climate change and extinction. By coupling 25 years of in situ climate manipulation with experimental seed introductions and both historical and current plant surveys, we identify causal, mechanistic links between climate change and the local extinction of a widespread mountain plant (Androsace septentrionalis). Climate warming causes precipitous declines in population size by reducing fecundity and survival across multiple life stages. Climate warming also purges belowground seed banks, limiting the potential for the future recovery of at-risk populations under ameliorated conditions. Bolstered by previous reports of plant community shifts in this experiment and in other habitats, our findings not only support the hypothesis that climate change can drive local extinction but also foreshadow potentially widespread species losses in subalpine meadows as climate warming continues. PMID- 29507885 TI - Dynamics of correlation-frozen antinodal quasiparticles in superconducting cuprates. AB - Many puzzling properties of high-critical temperature (Tc) superconducting (HTSC) copper oxides have deep roots in the nature of the antinodal quasiparticles, the elementary excitations with wave vector parallel to the Cu-O bonds. These electronic states are most affected by the onset of antiferromagnetic correlations and charge instabilities, and they host the maximum of the anisotropic superconducting gap and pseudogap. We use time-resolved extreme ultraviolet photoemission with proper photon energy (18 eV) and time resolution (50 fs) to disclose the ultrafast dynamics of the antinodal states in a prototypical HTSC cuprate. After photoinducing a nonthermal charge redistribution within the Cu and O orbitals, we reveal a dramatic momentum-space differentiation of the transient electron dynamics. Whereas the nodal quasiparticle distribution is heated up as in a conventional metal, new quasiparticle states transiently emerge at the antinodes, similarly to what is expected for a photoexcited Mott insulator, where the frozen charges can be released by an impulsive excitation. This transient antinodal metallicity is mapped into the dynamics of the O-2p bands, thus directly demonstrating the intertwining between the low- and high energy scales that is typical of correlated materials. Our results suggest that the correlation-driven freezing of the electrons moving along the Cu-O bonds, analogous to the Mott localization mechanism, constitutes the starting point for any model of high-Tc superconductivity and other exotic phases of HTSC cuprates. PMID- 29507886 TI - Archean kerogen as a new tracer of atmospheric evolution: Implications for dating the widespread nature of early life. AB - Understanding the composition of the Archean atmosphere is vital for unraveling the origin of volatiles and the environmental conditions that led to the development of life. The isotopic composition of xenon in the Archean atmosphere has evolved through time by mass-dependent fractionation from a precursor comprising cometary and solar/chondritic contributions (referred to as U-Xe). Evaluating the composition of the Archean atmosphere is challenging because limited amounts of atmospheric gas are trapped within minerals during their formation. We show that organic matter, known to be efficient at preserving large quantities of noble gases, can be used as a new archive of atmospheric noble gases. Xe isotopes in a kerogen isolated from the 3.0-billion-year-old Farrel Quartzite (Pilbara Craton, Western Australia) are mass fractionated by 9.8 +/- 2.1 per mil (0/00) (2sigma) per atomic mass unit, in line with a progressive evolution toward modern atmospheric values. Archean atmospheric Xe signatures in kerogens open a new avenue for following the evolution of atmospheric composition through time. The degree of mass fractionation of Xe isotopes relative to the modern atmosphere can provide a time stamp for dating Archean kerogens and therefore narrowing the time window for the diversification of early life during the Archean eon. PMID- 29507887 TI - Current-induced magnetization switching using an electrically insulating spin torque generator. AB - Current-induced magnetization switching through spin-orbit torques is the fundamental building block of spin-orbitronics, which promises high-performance, low-power memory and logic devices. The spin-orbit torques generally arise from spin-orbit coupling of heavy metals. However, even in a heterostructure where a metallic magnet is sandwiched by two different insulators, a nonzero spin-orbit torque is expected because of the broken inversion symmetry; an electrical insulator can be a source of the spin-orbit torques. We demonstrate current induced magnetization switching using an insulator. We show that oxygen incorporation into the most widely used spintronic material, Pt, turns the heavy metal into an electrically insulating generator of the spin-orbit torques, which enables the electrical switching of perpendicular magnetization in a ferrimagnet sandwiched by insulating oxides. We also show that the spin-orbit torques generated from the Pt oxide can be controlled electrically through voltage-driven oxygen migration. These findings open a route toward energy-efficient, voltage programmable spin-orbit devices based on insulating metal oxides. PMID- 29507888 TI - A "cation-anion regulation" synergistic anode host for dendrite-free lithium metal batteries. AB - Dendritic Li deposition has been "a Gordian knot" for almost half a century, which significantly hinders the practical use of high-energy lithium metal batteries (LMBs). The underlying mechanisms of this dendrite formation are related to the preferential lithium deposition on the tips of the protuberances of the anode surface and also associated with the concentration gradient or even depletion of anions during cycling. Therefore, a synergistic regulation of cations and anions at the interface is vital to promoting dendrite-free Li anodes. An ingenious molecular structure is designed to realize the "cation-anion regulation" with strong interactions between adsorption sites and ions at the molecular level. A quaternized polyethylene terephthalate interlayer with a "lithiophilic" ester building block and an "anionphilic" quaternary ammonium functional block can guide ions to form dendrite-free Li metal deposits at an ultrahigh current density of 10 mA cm-2, enabling stable LMBs. PMID- 29507889 TI - Symbolic use of marine shells and mineral pigments by Iberian Neandertals 115,000 years ago. AB - Cueva de los Aviones (southeast Spain) is a site of the Neandertal-associated Middle Paleolithic of Europe. It has yielded ochred and perforated marine shells, red and yellow colorants, and shell containers that feature residues of complex pigmentatious mixtures. Similar finds from the Middle Stone Age of South Africa have been widely accepted as archaeological proxies for symbolic behavior. U series dating of the flowstone capping the Cueva de los Aviones deposit shows that the symbolic finds made therein are 115,000 to 120,000 years old and predate the earliest known comparable evidence associated with modern humans by 20,000 to 40,000 years. Given our findings, it is possible that the roots of symbolic material culture may be found among the common ancestor of Neandertals and modern humans, more than half-a-million years ago. PMID- 29507890 TI - Antibiotic Stimulation of a Bacillus subtilis Migratory Response. AB - Competitive interactions between bacteria reveal physiological adaptations that benefit fitness. Bacillus subtilis is a Gram-positive species with several adaptive mechanisms for competition and environmental stress. Biofilm formation, sporulation, and motility are the outcomes of widespread changes in a population of B. subtilis. These changes emerge from complex, regulated pathways for adapting to external stresses, including competition from other species. To identify competition-specific functions, we cultured B. subtilis with multiple species of Streptomyces and observed altered patterns of growth for each organism. In particular, when plated on agar medium near Streptomyces venezuelae, B. subtilis initiates a robust and reproducible mobile response. To investigate the mechanistic basis for the interaction, we determined the type of motility used by B. subtilis and isolated inducing metabolites produced by S. venezuelae. Bacillus subtilis has three defined forms of motility: swimming, swarming, and sliding. Streptomyces venezuelae induced sliding motility specifically in our experiments. The inducing agents produced by S. venezuelae were identified as chloramphenicol and a brominated derivative at subinhibitory concentrations. Upon further characterization of the mobile response, our results demonstrated that subinhibitory concentrations of chloramphenicol, erythromycin, tetracycline, and spectinomycin all activate a sliding motility response by B. subtilis. Our data are consistent with sliding motility initiating under conditions of protein translation stress. This report underscores the importance of hormesis as an early warning system for potential bacterial competitors and antibiotic exposure. IMPORTANCE Antibiotic resistance is a major challenge for the effective treatment of infectious diseases. Identifying adaptive mechanisms that bacteria use to survive low levels of antibiotic stress is important for understanding pathways to antibiotic resistance. Furthermore, little is known about the effects of individual bacterial interactions on multispecies communities. This work demonstrates that subinhibitory amounts of some antibiotics produced by streptomycetes induce active motility in B. subtilis, which may alter species interaction dynamics among species-diverse bacterial communities in natural environments. The use of antibiotics at subinhibitory concentrations results in many changes in bacteria, including changes in biofilm formation, small-colony variants, formation of persisters, and motility. Identifying the mechanistic bases of these adaptations is crucial for understanding how bacterial communities are impacted by antibiotics. PMID- 29507891 TI - Jjj1 Is a Negative Regulator of Pdr1-Mediated Fluconazole Resistance in Candida glabrata. AB - The high prevalence of fluconazole resistance among clinical isolates of Candida glabrata has greatly hampered the utility of fluconazole for the treatment of invasive candidiasis. Fluconazole resistance in this yeast is almost exclusively due to activating mutations in the transcription factor Pdr1, which result in upregulation of the ABC transporter genes CDR1, PDH1, and SNQ2 and therefore increased fluconazole efflux. However, the regulation of Pdr1 is poorly understood. In order to identify genes that interact with the Pdr1 transcriptional pathway and influence the susceptibility of C. glabrata to fluconazole, we screened a collection of deletion mutants for those exhibiting increased resistance to fluconazole. Deletion of the gene coding for a protein homologous to the Saccharomyces cerevisiae J protein Jjj1 resulted in decreased fluconazole susceptibility. We used the SAT1 flipper method to generate independent deletion mutants for JJJ1 in an SDD clinical isolate. Expression of both CDR1 and PDR1 was increased in the absence of JJJ1. In the absence of CDR1 or PDR1, deletion of JJJ1 has only a modest effect on fluconazole susceptibility. Transcriptional profiling using transcriptome sequencing (RNA-seq) revealed upregulation of genes of the Pdr1 regulon in the absence of JJJ1. Jjj1 appears to be a negative regulator of fluconazole resistance in C. glabrata and acts primarily through upregulation of the ABC transporter gene CDR1 via activation of the Pdr1 transcriptional pathway. IMPORTANCECandida glabrata is the second most common species of Candida recovered from patients with invasive candidiasis. The increasing number of infections due to C. glabrata, combined with its high rates of resistance to the commonly used, well-tolerated azole class of antifungal agents, has limited the use of this antifungal class. This has led to the preferential use of echinocandins as empirical treatment for serious Candida infections. The primary mechanism of resistance found in clinical isolates is the presence of an activating mutation in the gene encoding the transcription factor Pdr1 that results in upregulation of one or more of the efflux pumps Cdr1, Pdh1, and Snq2. By developing a better understanding of this mechanism of resistance to the azoles, it will be possible to develop strategies for reclaiming the utility of the azole antifungals against this important fungal pathogen. PMID- 29507892 TI - Conversion of RpoS- Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS+ Improves Their Resistance to Host Defense Barriers. AB - The vast majority of live attenuated typhoid vaccines are constructed from the Salmonella enterica serovar Typhi strain Ty2, which is devoid of a functioning alternative sigma factor, RpoS, due to the presence of a frameshift mutation. RpoS is a specialized sigma factor that plays an important role in the general stress response of a number of Gram-negative organisms, including Salmonella. Previous studies have demonstrated that this sigma factor is necessary for survival following exposure to acid, hydrogen peroxide, nutrient-limiting conditions, and starvation. In addition, studies with Salmonella enterica serovar Typhimurium and the mouse model of typhoid fever have shown that RpoS is important in colonization and survival within the infected murine host. We converted 4 clinically studied candidate typhoid vaccine strains derived from Ty2 [CVD908-htrA, Ty800, and chi9639(pYA3493)] and the licensed live typhoid vaccine Ty21a (also derived from Ty2) to RpoS+ and compared their abilities to withstand environmental stresses that may be encountered within the host to those of the RpoS- parent strains. The results of our study indicate that strains that contain a functional RpoS were better able to survive following stress and that they would be ideal for further development as safe, effective vaccines to prevent S. Typhi infections or as vectors in recombinant attenuated Salmonella vaccines (RASVs) designed to protect against other infectious disease agents in humans. The S. Typhi strains constructed and described here will be made freely available upon request, as will the suicide vector used to convert rpoS mutants to RpoS+. IMPORTANCE Recombinant attenuated Salmonella vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of Salmonella to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS+ derivative of Ty2 was better at inducing immune responses than its RpoS- counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against S. Typhi or in using S. Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens. PMID- 29507893 TI - Toxoplasma gondii LCAT Primarily Contributes to Tachyzoite Egress. AB - Egress is a crucial phase of the Toxoplasma gondii intracellular lytic cycle. This is a process that drives inflammation and is strongly associated with the pathogenesis observed during toxoplasmosis. Despite the link between this process and virulence, little is known about egress on a mechanistic or descriptive level. Previously published work has suggested that a phospholipase, lecithin cholesterol acyltransferase (LCAT), secreted from the parasite's dense granules contributes to parasite growth, virulence, and egress. Here we present evidence from several independent mutant parasite lines confirming a role for LCAT in efficient egress, although no defects in growth or virulence were apparent. We also show via genetic complementation that the catalytic activity of LCAT is required for its role in parasite egress. This work solidifies the contribution of LCAT to egress of T. gondii tachyzoites. IMPORTANCEToxoplasma gondii is one of the most successful human pathogens, infecting an estimated 2.5 billion people across the globe. Pathogenesis seen during acute or reactivated toxoplasmosis has been closely tied to the parasite's intracellular lytic life cycle, which culminates in an event called egress that results in the release of freshly replicated parasites from the infected host cell. Despite the highly destructive, cytolytic nature of this event and its downstream consequences, very little is known about how the parasite accomplishes this step. Previous work has suggested a role for a secreted phospholipase, LCAT, in Toxoplasma egress and roles in cell traversal and egress in the Plasmodium species orthologue. We confirm here that LCAT-deficient tachyzoites are unable to efficiently egress from infected monolayers, and we provide evidence that LCAT catalytic activity is required for its role in egress. PMID- 29507894 TI - A Novel aadA Aminoglycoside Resistance Gene in Bovine and Porcine Pathogens. AB - A novel variant of the AAD(3") class of aminoglycoside-modifying enzymes was discovered in fatal bovine respiratory disease-associated pathogens Pasteurella multocida and Histophilus somni. The aadA31 gene encodes a spectinomycin/streptomycin adenylyltransferase and was located in a variant of the integrative and conjugative element ICEMh1, a mobile genetic element transmissible among members of the family Pasteurellaceae. The gene was also detected in Mannheimia haemolytica from a case of porcine pneumonia and in Moraxella bovoculi from a case of keratoconjunctivitis. IMPORTANCE Aminoglycosides are important antimicrobials used worldwide for prophylaxis and/or therapy in multiple production animal species. The emergence of new resistance genes jeopardizes current pathogen detection and treatment methods. The risk of resistance gene transfer to other animal and human pathogens is elevated when resistance genes are carried by mobile genetic elements. This study identified a new variant of a spectinomycin/streptomycin resistance gene harbored in a self-transmissible mobile element. The gene was also present in four different bovine pathogen species. PMID- 29507895 TI - Inhibition of Cyanobacterial Growth on a Municipal Wastewater Sidestream Is Impacted by Temperature. AB - Sidestreams in wastewater treatment plants can serve as concentrated sources of nutrients (i.e., nitrogen and phosphorus) to support the growth of photosynthetic organisms that ultimately serve as feedstock for production of fuels and chemicals. However, other chemical characteristics of these streams may inhibit growth in unanticipated ways. Here, we evaluated the use of liquid recovered from municipal anaerobic digesters via gravity belt filtration as a nutrient source for growing the cyanobacterium Synechococcus sp. strain PCC 7002. The gravity belt filtrate (GBF) contained high levels of complex dissolved organic matter (DOM), which seemed to negatively influence cells. We investigated the impact of GBF on physiological parameters such as growth rate, membrane integrity, membrane composition, photosystem composition, and oxygen evolution from photosystem II. At 37 degrees C, we observed an inverse correlation between GBF concentration and membrane integrity. Radical production was also detected upon exposure to GBF at 37 degrees C. However, the dose-dependent relationship between the GBF concentration and the lack of membrane integrity was abolished at 27 degrees C. Immediate resuspension of strains in high levels of GBF showed markedly reduced oxygen evolution rates relative to those seen with the control. Taken together, the data indicate that one mechanism responsible for GBF toxicity to Synechococcus is the interruption of photosynthetic electron flow and subsequent phenomena. We hypothesize that this is likely due to the presence of phenolic compounds within the DOM. IMPORTANCE Cyanobacteria are viewed as promising platforms to produce fuels and/or high-value chemicals as part of so-called "biorefineries." Their integration into wastewater treatment systems is particularly interesting because removal of the nitrogen and phosphorus in many wastewater streams is an expensive but necessary part of wastewater treatment. In this study, we evaluated strategies for cultivating Synechococcus sp. strain PCC 7002 on media comprised of two wastewater streams, i.e., treated secondary effluent supplemented with the liquid fraction extracted from sludge following anaerobic digestion. This strain is commonly used for metabolic engineering to produce a variety of valuable chemical products and product precursors (e.g., lactate). However, initial attempts to grow PCC 7002 under otherwise-standard conditions of light and temperature failed. We thus systematically evaluated alternative cultivation conditions and then used multiple methods to dissect the apparent toxicity of the media under standard cultivation conditions. PMID- 29507896 TI - Market Integration Predicts Human Gut Microbiome Attributes across a Gradient of Economic Development. AB - Economic development is marked by dramatic increases in the incidence of microbiome-associated diseases, such as autoimmune diseases and metabolic syndromes, but the lifestyle changes that drive alterations in the human microbiome are not known. We measured market integration as a proxy for economically related lifestyle attributes, such as ownership of specific market goods that index degree of market integration and components of traditional and nontraditional (more modern) house structure and infrastructure, and profiled the fecal microbiomes of 213 participants from a contiguous, indigenous Ecuadorian population. Despite relatively modest differences in lifestyle across the population, greater economic development correlated with significantly lower within-host diversity, higher between-host dissimilarity, and a decrease in the relative abundance of the bacterium Prevotella. These microbiome shifts were most strongly associated with more modern housing, followed by reduced ownership of traditional subsistence lifestyle-associated items. IMPORTANCE Previous research has reported differences in the gut microbiome between populations residing in wealthy versus poorer countries, leading to the assertion that lifestyle changes associated with economic development promote changes in the gut microbiome that promote the proliferation of microbiome-associated diseases. However, a direct relationship between economic development and the gut microbiome has not previously been shown. We surveyed the gut microbiomes of a single indigenous population undergoing economic development and found significant associations between features of the gut microbiome and lifestyle changes associated with economic development. These findings suggest that even the earliest stages of economic development can drive changes in the gut microbiome, which may provide a warning sign for the development of microbiome-associated diseases. PMID- 29507897 TI - Exposure to sub-parts per million levels of vinyl chloride can increase the risk of developing liver injury. PMID- 29507898 TI - Role of monocyte chemoattractant protein-1 in liver fibrosis with transient myeloproliferative disorder in down syndrome. AB - Liver fibrosis is a common complication associated with transient myeloproliferative disorder (TMD) in Down syndrome (DS). The exact molecular pathogenesis that regulates disease progression is largely unknown. We recently found serum and/or urinary monocyte chemoattractant protein-1 (MCP-1) as a novel biomarker of liver fibrosis. This study was an in vitro analysis to investigate the fibrogenic activity of MCP-1 using the collagen-producing LX-2 human hepatic stellate cell line. We also examined the fibrogenic activity of serum from a male neonate with DS in whom late-onset liver fibrosis developed even after the resolution of TMD. MCP-1 stimulated both cell growth and collagen synthesis of LX 2 in a dose-dependent manner. Patient serum obtained during the active disease phase significantly up-regulated fibrogenic activity, which was suppressed in the presence of MCP-1-blocking antibody. Transient transforming growth factor beta 1 stimulation primed LX-2 to induce prolonged hypersecretion of MCP-1 in the culture supernatant and in collagen synthesis, which was suppressed with MCP-1 blocking antibody as well. Conclusion: MCP-1 accounts for the prolonged activation of collagen-producing hepatic stellate cells in both a paracrine and autocrine manner, thereby promoting liver fibrosis. Anti-cytokine therapy targeting the fibrogenic cytokines of MCP-1, for example, herbal medicine, could provide a new therapeutic intervention for liver fibrosis associated with TMD in DS. (Hepatology Communications 2018;2:230-236). PMID- 29507899 TI - Exploring opportunities to prevent cirrhosis admissions in the emergency department: A multicenter multidisciplinary survey. AB - Patients with cirrhosis have high admission and readmission rates, and it is estimated that a quarter are potentially preventable. Little data are available regarding nonmedical factors impacting triage decisions in this patient population. This study sought to explore such factors as well as to determine provider perspectives on low-acuity clinical presentations to the emergency department, including ascites and hepatic encephalopathy. A survey was distributed in four liver transplant centers to both emergency medicine and hepatology providers, who included attending physicians, house staff, and advanced practitioners; 196 surveys were returned (estimated response rate 50.6%). Emergency medicine providers identified several influential nonmedical factors impacting inpatient triage decisions, including input from a hepatologist (77.7%), inadequate patient access to outpatient specialty care (68.6%), and patient need for diagnostic testing for a procedure (65.6%). When given patient based scenarios of low-acuity cases, such as ascites requiring paracentesis, only 7.0% believed patients should be hospitalized while 48.9% said these patients would be hospitalized at their institution (P < 0.0001). For mild hepatic encephalopathy, the comparable numbers were 19.5% and 55.2%, respectively (P < 0.001). Several perceived barriers were cited for this discrepancy, including limited resources both in the outpatient setting and emergency department. Most providers believed that an emergency department observation unit protocol would influence triage toward an emergency department observation unit visit instead of inpatient admission for both ascites requiring large volume paracentesis (83.2%) and mild hepatic encephalopathy (79.4%). Conclusion: Many nonmedical factors that influence inpatient triage for patients with cirrhosis could be targeted for quality improvement initiatives. In some scenarios, providers are limited by resource availability, which results in triage to an inpatient admission even when they believe this is not the most appropriate disposition. (Hepatology Communications 2018;2:237-244). PMID- 29507900 TI - New scoring classification for primary biliary cholangitis-autoimmune hepatitis overlap syndrome. AB - Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are two major immune-mediated chronic liver diseases. Overlap syndrome (OS) is diagnosed if patients have features of both AIH and PBC; however, there is no consensus on the definition or diagnostic criteria for OS. Here, we report a new scoring classification for OS and evaluate its usefulness. This new scoring classification was developed by modifying the International Autoimmune Hepatitis Group classification by selecting histologic features of AIH and PBC along with modifications of biochemical and immunologic characteristics. We evaluated 272 patients with chronic liver disease, including 105 with AIH, 102 with PBC, and 65 with OS. The best performance for the diagnosis of OS was noted among patients with an overlap score of >=21 who had a sensitivity of 98.5%, a specificity of 92.8%, a positive predictive value of 81.0%, and a negative predictive value of 99.5%. By using a cut-off score of 21, 64 (98.5%) patients were diagnosed with OS as opposed to 9 (8.8%) and 6 (5.7%) with PBC and AIH, respectively. All patients with OS had an aggregate score of >19, whereas most patients with PBC or AIH scored <19, making this a safe discriminatory cut-off point against OS. Conclusion: The new scoring system for the diagnosis of OS has a high sensitivity and specificity for scores >=21, while a score <19 suggests a diagnosis other than OS. This classification can identify patients and diagnose OS with a reasonable amount of accuracy and may be superior to current OS scoring systems in detecting mild forms of OS. (Hepatology Communications 2018;2:245-253). PMID- 29507901 TI - A novel transforming growth factor beta-induced long noncoding RNA promotes an inflammatory microenvironment in human intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (iCCA) is a deadly liver primary cancer associated with poor prognosis and limited therapeutic opportunities. Active transforming growth factor beta (TGFbeta) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGFbeta on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGFbeta signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGFbeta targets were identified, including a TGFbeta-induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGFbeta in hepatic and nonhepatic cell types. In iCCA cell lines, the expression of a long and short TLINC isoform was associated with an epithelial or mesenchymal phenotype, respectively. Both isoforms were detected in the nucleus and cytoplasm. The long isoform of TLINC was associated with a migratory phenotype in iCCA cell lines and with the induction of proinflammatory cytokines, including interleukin 8, both in vitro and in resected human iCCA. TLINC was also identified as a tumor marker expressed in both epithelial and stroma cells. In nontumor livers, TLINC was only expressed in specific portal areas with signs of ductular reaction and inflammation. Finally, we provide experimental evidence of circular isoforms of TLINC, both in iCCA cells treated with TGFbeta and in resected human iCCA. Conclusion: We identify a novel TGFbeta-induced long noncoding RNA up-regulated in human iCCA and associated with an inflammatory microenvironment. (Hepatology Communications 2018;2:254-269). PMID- 29507902 TI - Vinyl chloride dysregulates metabolic homeostasis and enhances diet-induced liver injury in mice. AB - Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g., nonalcoholic fatty liver disease [NAFLD]) is unclear. Given the high prevalence of NAFLD in the United States (and worldwide) population, this is an important concern. Recent studies by our group with VC metabolites suggest a potential interaction between VC exposure and underlying liver disease to cause enhanced damage. Here, a novel mouse model determined the effects of VC inhalation at levels below the current Occupational Safety and Health Administration limit (<1 ppm) in the context of NAFLD to better mimic human exposure and identify potential mechanisms of VC-induced liver injury. VC exposure caused no overt liver injury in mice fed a low-fat diet. However, in mice fed a high-fat diet (HFD), VC significantly increased liver damage, steatosis, and increased neutrophil infiltration. Moreover, VC further enhanced HFD-induced oxidative and endoplasmic reticulum stress. Importantly, VC exposure dysregulated energy homeostasis and impaired mitochondrial function, even in mice fed a low-fat diet. In toto, the results indicate that VC exposure causes metabolic stress that sensitizes the liver to steatohepatitis caused by HFD. Conclusion: The hypothesis that low-level (below the Occupational Safety and Health Administration limit) chronic exposure to VC by inhalation enhances liver injury caused by an HFD is supported. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co-exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. (Hepatology Communications 2018;2:270-284). PMID- 29507903 TI - Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease. AB - Insulin resistance is a key risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) and may lead to liver fibrosis. Natural killer (NK) cells are thought to exert an antifibrotic effect through their killing of activated hepatic stellate cells (HSCs). Here, we investigated how the interplay between NK cells and HSCs are modified by insulin resistance in NAFLD. Fresh peripheral blood NK cells (clusters of differentiation [CD]56dim, CD16+) were collected from 22 healthy adults and 72 patients with NAFLD not currently taking any medications and without signs of metabolic syndrome. NK cells were assessed for insulin receptor expressions and cytotoxic activity when cultured in medium with HSCs. Fibrosis severities in patients with NAFLD were correlated linearly with elevated serum proinflammatory cytokine expression and insulin resistance severity. At the same time, fibrosis severities inversely correlated with insulin receptor expressions on NK cells as well as with their cytotoxic activities determined by CD107a by flow cytometry. NK cells from donors exhibiting severe fibrosis and insulin resistance exhibited significant mammalian target of rapamycin and extracellular signal-regulated kinase depletion (through NK cell western blot quantitation), increased apoptosis, and failure to attenuate HSC activation in vitro. While exposure to insulin stimulated the cytotoxic activity of healthy NK cells, rapamycin prevented this effect and reduced NK insulin receptor expressions. Conclusion: Elevated insulin levels in F1 and F2 fibrosis enhances NK cell cytotoxic activity toward HSCs and prevents fibrosis progression by insulin receptors and downstream mammalian target of rapamycin and extracellular signal-regulated kinase pathways. At more advanced stages of insulin resistance (F3 and F4 fibrosis), impaired NK cell activity rooted in low insulin receptor expression and or low serum insulin levels could further deteriorate fibrosis and may likely lead to cirrhosis development. (Hepatology Communications 2018;2:285 298). PMID- 29507904 TI - Improved oxygenation dramatically alters metabolism and gene expression in cultured primary mouse hepatocytes. AB - Primary hepatocyte culture is an important in vitro system for the study of liver functions. In vivo, hepatocytes have high oxidative metabolism. However, oxygen supply by means of diffusion in in vitro static cultures is much less than that by blood circulation in vivo. Therefore, we investigated whether hypoxia contributes to dedifferentiation and deregulated metabolism in cultured hepatocytes. To this end, murine hepatocytes were cultured under static or shaken (60 revolutions per minute) conditions in a collagen sandwich. The effect of hypoxia on hepatocyte cultures was examined by metabolites in media and cells, hypoxia-inducible factors (HIF)-1/2alpha western blotting, and real-time quantitative polymerase chain reaction for HIF target genes and key genes of glucose and lipid metabolism. Hepatocytes in shaken cultures showed lower glycolytic activity and triglyceride accumulation than static cultures, compatible with improved oxygen delivery and mitochondrial energy metabolism. Consistently, static cultures displayed significant HIF-2alpha expression, which was undetectable in freshly isolated hepatocytes and shaken cultures. Transcript levels of HIF target genes (glyceraldehyde 3-phosphate dehydrogenase [Gapdh], glucose transporter 1 [Glut1], pyruvate dehydrogenase kinase 1 [Pdk1], and lactate dehydrogenase A [Ldha]) and key genes of lipid metabolism, such as carnitine palmitoyltransferase 1 (Cpt1), apolipoprotein B (Apob), and acetyl coenzyme A carboxylase 1 (Acc1), were significantly lower in shaken compared to static cultures. Moreover, expression of hepatocyte nuclear factor 4alpha (Hnf4alpha) and farnesoid X receptor (Fxr) were better preserved in shaken cultures as a result of improved oxygen delivery. We further revealed that HIF-2 signaling was involved in hypoxia-induced down-regulation of Fxr. Conclusion: Primary murine hepatocytes in static culture suffer from hypoxia. Improving oxygenation by simple shaking prevents major changes in expression of metabolic enzymes and aberrant triglyceride accumulation; in addition, it better maintains the differentiation state of the cells. The shaken culture is, therefore, an advisable strategy for the use of primary hepatocytes as an in vitro model. (Hepatology Communications 2018;2:299-312). PMID- 29507905 TI - Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice. AB - Increasingly, evidence suggests that exposure to maternal obesity creates an inflammatory environment in utero, exerting long-lasting postnatal signatures on the juvenile innate immune system and microbiome that may predispose offspring to development of fatty liver disease. We found that exposure to a maternal Western style diet (WD) accelerated fibrogenesis in the liver of offspring and was associated with early recruitment of proinflammatory macrophages at 8-12 weeks and microbial dysbiosis as early as 3 weeks of age. We further demonstrated that bone marrow-derived macrophages (BMDMs) were polarized toward an inflammatory state at 8 weeks of age and that a potent antioxidant, pyrroloquinoline quinone (PQQ), reversed BMDM metabolic reprogramming from glycolytic toward oxidative metabolism by restoring trichloroacetic acid cycle function at isocitrate dehydrogenase. This resulted in reduced inflammation and inhibited collagen fibril formation in the liver at 20 weeks of age, even when PQQ was withdrawn at 3 weeks of age. Beginning at 3 weeks of age, WD-fed mice developed a decreased abundance of Parabacteroides and Lactobacillus, together with increased Ruminococcus and decreased tight junction gene expression by 20 weeks, whereas microbiota of mice exposed to PQQ retained compositional stability with age, which was associated with improved liver health. Conclusion: Exposure to a maternal WD induces early gut dysbiosis and disrupts intestinal tight junctions, resulting in BMDM polarization and induction of proinflammatory and profibrotic programs in the offspring that persist into adulthood. Disrupted macrophage and microbiota function can be attenuated by short-term maternal treatment with PQQ prior to weaning, suggesting that reshaping the early gut microbiota in combination with reprogramming macrophages during early weaning may alleviate the sustained proinflammatory environment, preventing the rapid progression of nonalcoholic fatty liver disease to nonalcoholic steatohepatitis in offspring of obese mothers. (Hepatology Communications 2018;2:313-328). PMID- 29507906 TI - Interleukins-17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation. AB - Liver progenitor cells (LPCs)/ductular reactions (DRs) are associated with inflammation and implicated in the pathogenesis of chronic liver diseases. However, how inflammation regulates LPCs/DRs remains largely unknown. Identification of inflammatory processes that involve LPC activation and expansion represent a key step in understanding the pathogenesis of liver diseases. In the current study, we found that diverse types of chronic liver diseases are associated with elevation of infiltrated interleukin (IL)-17 positive (+) cells and cytokeratin 19 (CK19)+ LPCs, and both cell types colocalized and their numbers positively correlated with each other. The role of IL-17 in the induction of LPCs was examined in a mouse model fed a choline deficient and ethionine-supplemented (CDE) diet. Feeding of wild-type mice with the CDE diet markedly elevated CK19+Ki67+ proliferating LPCs and hepatic inflammation. Disruption of the IL-17 gene or IL-27 receptor, alpha subunit (WSX 1) gene abolished CDE diet-induced LPC expansion and inflammation. In vitro treatment with IL-17 promoted proliferation of bipotential murine oval liver cells (a liver progenitor cell line) and markedly up-regulated IL-27 expression in macrophages. Treatment with IL-27 favored the differentiation of bipotential murine oval liver cells and freshly isolated LPCs into hepatocytes. Conclusion: The current data provide evidence for a collaborative role between IL-17 and IL 27 in promoting LPC expansion and differentiation, respectively, thereby contributing to liver regeneration. (Hepatology Communications 2018;2:329-343). PMID- 29507907 TI - Editorial. PMID- 29507908 TI - Understanding of Burning Mouth Syndrome Based on Psychological Aspects. AB - Burning mouth syndrome (BMS) is a chronic pain condition characterised by a persistent burning sensation in clinically normal oral mucosa. BMS most commonly occurs in middleaged and elderly women. Various local and systemic factors can cause oral burning symptoms. When all possible local and systemic factors are excluded, burning mouth symptoms can be diagnosed as BMS. Psychophysical tests and histopathological data suggest the involvement of peripheral and central neuropathic mechanisms in BMS etiopathogenesis. Psychological problems are frequently observed in BMS patients. Several mechanisms, including increased parafunctional habits, steroid dysregulation, central disinhibition due to taste dysfunction, and low dopamine levels in the brain, have been proposed as an explanation for the role of psychological factors in BMS pathophysiology. However, the causal relationship between BMS and psychological problems remains controversial. Given the neuropathic nature of BMS, treatment for it is similar to other neuropathic pain conditions. Although various treatment modalities, including pharmacological intervention, behavioural therapy and psychotherapy, have been proposed, there is no definitive treatment always effective for the majority of BMS patients. In conclusion, for better understanding of the relationship between BMS and psychological factors, well-designed prospective studies are needed. In addition, the evaluation and treatment of psychological problems are essential for successful management of BMS patients. PMID- 29507909 TI - Utilisation of a Bioreactor for Culture and Expansion of Epithelial Cells without the use of Trypsin or Enzymes. AB - OBJECTIVE: To develop a bioreactor for automated culture, maintenance, and collection of normal human keratinocytes using an enzyme-free propagation method. METHODS: The culture of normal human epithelial keratinocytes was compared in two culture methods - a study team-developed automated bioreactor utilising an enzyme free passage method, and a manual culture method. Cell size, glucose utilisation, and the proliferative capacity of the two cultures were evaluated. RESULTS: An automated bioreactor, not using enzymes for passage, but instead using the novel Epithelial Pop Up Keratinocytes (ePUK)1 culture technique, resulted in an extended culture longevity and proliferative capacity in normal primary human keratinocytes. Daughter cells were collected up to three times per day utilising the bioreactor. The daughter cells produced by the bioreactor were smaller than daughter cells produced by the manual culture method. The proliferative capacity and health of the parent monolayer within both the bioreactor and the manual culture flask was dependent upon sufficient glucose availability. Due to the contact inhibition nature of epithelial keratinocytes, the bioreactor enabled the study of an adherent cell type soon after cytokinesis and before the cell has integrated as part of an adherent matrix. CONCLUSION: The study demonstrates that increasing the number of media changes per day as necessary, based on glucose utilisation, is necessary for prolonged longevity and functional productivity of ePUK cultures. PMID- 29507912 TI - Optimal Matrix Preparation Methods for Matrix-assisted Laser Desorption/ionisation Time-of-flight Mass Spectrometry Profiling of Low Molecular Weight Peptides in Human Saliva and Serum Samples. AB - OBJECTIVE: To develop standard experimental methods to minimise technical variance in matrix preparation for MALDI-TOF MS (matrix-assisted laser desorption/ionisation time-offlight) profiling. METHODS: Matrix factors in saliva and serum samples of 20 healthy volunteers were examined, assuring their peptide components using seven different matrix type/preparation methods, HCCA(a-cyano-4 hydroxycinnamic acid)/SM(sample/matrix), SA(sinapinic acid)/DD(dried droplet), SA/SM, DHB(2.5-dihydroxyhenz-zoic acid)/DD, DHB/SM, DHAP(2.5 dihydroxyacetophenone)/ DD, DHAP/SM. Number of peaks, S/N(signal to noise) ratio and approximate range of target peaks were set as main selection criteria to find if these spell out any common regularity in results. RESULTS: Different methods perform differently. DHB/DD performed worst in both samples, with no effective peak detected. For saliva sample, the S/N ratios of other six methods were lower. M/z range distributed differently. DHB/SM and DHAP/DD performed best in number of peaks, m/z distributing in 1000 to 2000 account for the vast majority. For serum sample, S/N ratios and m/z range distribution were different in different methods. S/N ratio of SA/DD and SA/SM were higher, number of peaks and m/z distribution were not irreplaceable. S/N ratios of the other four methods were lower. CONCLUSION: DHAP/DD and HCCA/SM performed best in number of peaks, m/z in 5000 - 7000 account for the vast majority in HCCA/SM and 1000 - 2000 in DHAP/DD. Further studies should focus on other characteristics of peptide components detected in different matrix methods to increase evidence when selecting matrix type/preparation methods. PMID- 29507910 TI - Sonic Hedgehog Signalling Activation Contributes to ALCAM Over-Expression and Poor Clinical Outcome in Patients with Oral Squamous Cell Carcinoma. AB - OBJECTIVE: To investigate the Sonic Hedgehog (SHH) signalling molecules and activated leukocyte cell adhesion molecule (ALCAM) expression in the mechanisms regulating invasion and metastasis in oral squamous cell carcinoma (OSCC). METHODS: The expressions of SHH signalling molecules Gli family zinc finger 1/2 (Gli1/Gli2), as well as ALCAM expression, was analysed in 101 OSCC patients by immunohistochemistry. The potential relationship between Gli1/Gli2 and ALCAM in regard to invasion and metastasis were studied by western blot, invasion and wound-healing assays. RESULTS: Gli1, Gli2 and ALCAM were expressed in 54.5%, 49.5% and 47.5% of the 101 OSCC specimens, respectively. High expression of ALCAM was associated with shorter survival in the patient population (P = 0.018), which was independent of other clinical parameters. Notably, when both ALCAM expression and positive nodal status were considered, an enhanced prediction of clinical outcomes was achieved (P = 0.001). In OSCC cell lines, down-regulation of ALCAM resulted in reduced cell invasion and metastasis. Importantly, SHH activation increased the half-life of ALCAM leading to ALCAM accumulation and increased cell invasion and migration. CONCLUSION: ALCAM over-expression in OSCC is an independent prognostic factor for OSCC patients. Its over-expression may be the result of the activation of the SHH signalling pathway and contributes to OSCC progression. PMID- 29507911 TI - Magnetic Bead-based Salivary Peptidome Profiling for Accelerated Osteogenic Orthodontic Treatments. AB - OBJECTIVE: To identify a panel of differentially expressed candidate biomarkers for patients undergoing accelerated osteogenic orthodontics (AOO). METHODS: This study included 36 saliva samples taken from six Class III surgical patients at six time points: the date before the corticotomy procedure (T1) and at 1 week, 2 weeks, 1 month, 2 months and 6 months after the procedure (T2, T3, T4, T5 and T6, respectively). After the maxillary dental arch was aligned and levelled, AOO procedures were performed in the maxillary alveolar bone. Saliva samples were used to create peptide mass fingerprints using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) combined with magnetic beads. RESULTS: When the six groups were compared, 182 peaks were significantly different (P < 0.01), and the biomarker profiles changed over time. After corticotomy, the mass peaks predicted to be the Apolipoprotein A-I precursor (APOA1) increased sharply in T2 then decreased. The peptides predicted to be complement component 3 decreased in T2, then gradually increased and declined in T6. The peptides predicted to be the vitamin D-binding protein precursor increased in T2, then fell to the preoperative level. The mass peaks of the peptides predicted to be Isoform 1 of the fibrinogen alpha chain precursor (FGA) first decreased, then increased with time. CONCLUSION: The salivary protein profiles changed with accelerated tooth movement induced by AOO. This method provides a tool for investigating corticotomy-induced accelerated tooth movement in humans, and explored the critical factors responsible for the regional acceleratory phenomenon. PMID- 29507913 TI - Magnetic Resonance Sialography and Salivary Gland Scintigraphy of Parotid Glands in Sjogren's Syndrome. AB - OBJECTIVE: To assess the correlation between conventional magnetic resonance (MR) imaging and MR sialography of parotid glands with salivary gland scintigraphy in patients with Sjogren's syndrome. METHODS: A retrospective study was conducted on eight patients with Sjogren's syndrome who underwent MR imaging and salivary gland scintigraphy. Conventional MR imaging techniques, such as T1-weighted images (T1WI), T2-weighted images (T2WI), and short TI inversion recovery images (STIR) were used for changes of fat signal in the parotid gland, while the MR sialography were used for ducts dilation of the parotid gland. Regarding scintigraphy, time-activity curves of each parotid gland were analysed. The salivary gland excretion fraction was defined as A (before stimulation test (counts/20 s)) and B (after stimulation test (counts/20 s)). RESULTS: Regarding characteristic appearances of fat signal, the A/B of parotid gland with homogeneous intensity distribution (3.51 +/- 0.75) was higher than that with heterogeneous intensity distribution (1.56 +/- 0.66, P = 0.001). Regarding MR sialographic stages, the A/B of parotid gland with stage 0 (3.51 +/- 0.75) was higher than that with stage 1 (2.03 +/- 0.86, P = 0.009) and with stage 2 (1.26 +/- 0.25, P = 0.000). CONCLUSION: The results suggest that MR sialography of the parotid glands is a useful noninvasive tool for evaluating the decrease of salivary gland excretion in patients with Sjogren's syndrome. PMID- 29507915 TI - Editorial: Hunting for evidence - a plea for clinical research. PMID- 29507914 TI - Comparison of the Psychological Condition of Chinese Patients with or without Halitosis Complaints. AB - OBJECTIVE: To investigate the psychological condition of Chinese patients with or without a primary complaint of halitosis. METHODS: The psychological condition of 196 Chinese patients who visited the Department of Periodontics was evaluated using the Cornell Medical Index (CMI) health questionnaire. The breath malodour of all patients was scored using the organoleptic test (OLT). RESULTS: More than half of patients (53.1%) complaining of halitosis actually demonstrated pseudo halitosis. The overall scores and scores for emotional symptoms of CMI were significantly higher in patients with a chief complaint of halitosis than in those without such a complaint (P < 0.05). Females with a chief complaint of halitosis exhibited significantly higher scores for all parameters relative to females without a complaint (P < 0.05), while males with a chief complaint of halitosis exhibited enhanced emotional symptoms, particularly inadequacy, anxiety, and tension (P < 0.05) when compared with males without a halitosis complaint. Among patients complaining of halitosis, CMI scores for all parameters showed no difference between genuine halitosis female patients and pseudo halitosis female patients, while male patients with pseudo-halitosis showed higher scores in the CMI overall score, scores for emotional symptoms and sensitivity, than males with genuine halitosis. CONCLUSION: There was a marked inconsistency between the complaints of patients and their actual odour status. Patients with a chief complaint of halitosis exhibited a greater level of inadequacy, depression, anxiety, sensitivity, anger, and stress. The psychological status of the patients varied with gender. PMID- 29507916 TI - Postendodontic Restoration: Endodontic Post-and-Core or No Post At All? AB - PURPOSE: The objective of this systematic review was to assess the impact of endodontic post insertion on the clinical performance of endodontically treated teeth (ETT). MATERIALS AND METHODS: A specific PICO question was developed and a Medline search was performed in January 2017 using relevant terms in order to identify studies comparing the success/survival of dental restorations using endodontic posts or no posts. Additionally, the electronic databases "Opengrey", "BBO", "LILAC" and "IBECS" were assessed and a hand search of cross references from original articles and reviews was performed. The methodological quality of the included studies was assessed independently by three referees using (1) the critical appraisal skills program (CASP) and (2) Cochrane checklist (version 5.1.0). RESULTS: A total of 14 studies were included, among them 11 randomized controlled trials (RCT), two prospective clinical trials, and one retrospective clinical trial. The overall quality of the studies was good according to the CASP. However, the Cochrane rating showed that in seven studies, the risk of bias was high in > 40% of the items, indicating a relevant level of methodological flaws. Three studies showed a low risk of bias in > 80% of the items. The majority (10 out of 14) of the clinical studies included failed to show a positive effect of post placement. A post effect is possible when no cavity wall is present. CONCLUSION: There is no unequivocal clinical evidence to support or reject the use of posts even for no-wall cavities, either for direct or indirect restorations. PMID- 29507917 TI - Are Clinically Successful Amalgam and ART Restorations in Primary Molars Microgap Free? AB - PURPOSE: To determine whether the frequency of microleakage at the margin of the tooth-restoration interface in primary molars restored with high-viscosity glass ionomer cement (HVGIC) differs from that of primary molars restored with amalgam. MATERIALS AND METHODS: The HVGIC restorations were performed according to the ART method. A total of 19 naturally exfoliated primary molars (10 amalgam and 9 ART/HVGIC) with clinically assessed intact restorations fulfilled the inclusion criteria. SEM analyses using replicas were performed to assess the microgap presence and size of the tooth-restoration interface The depth of a microgap was measured from histological sections after infiltration of 50% (w/v) AgNO3 solution. Independent variables were restorative material, age of restoration, and number of tooth surfaces. Data analyses included Fisher's Exact version of the chi-squared test, independent t-test and one-way ANOVA. RESULTS: More ART/HVGIC than amalgam-restored teeth were gap free (p = 0.14). The mean gap size for teeth with a gap between amalgam (322.0 um) and ART/HVGIC (201.0 um) restorations did not differ statistically significantly. AgNO3 infiltration was not influenced by restorative material or age of restoration. Infiltration in multiple-surface was higher than in single-surface restorations (p = 0.02). CONCLUSION: The occurrence of marginal microleakage in primary molars restored by ART/HVGIC is no different from that observed in primary molars restored with amalgam. Microleakage was deeper in multiple-surface than in single-surface restorations. Despite the presence of microleakage, restoration functionality up to exfoliation is secured, reinforcing the importance of biofilm removal and behavioral education of patients. PMID- 29507918 TI - Ultrastructural Analysis and Long-term Evaluation of Composite-Zirconia Bond Strength. AB - PURPOSE: To evaluate the influence of different aging techniques on zirconia composite microtensile bond strength using different surface treatments over a 5 year follow-up period. MATERIALS AND METHODS: Zirconia disks received three surface treatments: airborne-particle abrasion with 50-MUm aluminum oxide particles, selective infiltration etching (SIE), or fusion sputtering (FS). The specimens were bonded to pre-aged composite disks using a composite cement containing phosphate monomers (Panavia F2.0). Bonded specimens were sectioned into microbars (1 x 1 x 6 mm) using a precision cutting machine, and all microbars received thermocycling (15,000 cycles between 5 degrees C and 55 degrees C). Initial microtensile bond strength was evaluated, and the test was repeated after storage in the following media for five years (artificial saliva, 20% ethanol, 5% NaOH, 4% acetic acid, and 5% phosphoric acid). The test was repeated every 12 months for 5 years. Scanning electron microscopic images were used to analyze the zirconia-composite interface. A repeated measures ANOVA and Bonferroni post-hoc tests were used to analyze the data (n = 20, alpha = 0.05). RESULTS: Significantly higher microtensile bond strength was observed for SIE compared to fusion sputtering and airborne particle abrasion. Five years of artificial aging resulted in significant reduction of zirconia-composite bond strength for all tested specimens. Zirconia-composite bond strength was more sensitive to storage in sodium hydroxide and phosphoric acid, while it was least affected when stored under saliva. These changes were related to the mechanism of ultra-structural interaction between surface treatment and adhesive, as deterioration of the hybrid layer (composite-infiltrated ceramic) was responsible for bond degeneration. CONCLUSION: Zirconia-composite bond strength was influenced by 5 years of artificial aging. PMID- 29507919 TI - Influence of Application Time and Etching Mode of Universal Adhesives on Enamel Adhesion. AB - PURPOSE: To investigate the influence of application time and etching mode of universal adhesives on enamel adhesion. MATERIALS AND METHODS: Five universal adhesives, Adhese Universal, Bondmer Lightless, Clearfil Universal Bond Quick, G Premio Bond, and Scotchbond Universal, were used. Bovine incisors were prepared and divided into four groups of ten teeth each. SBS, Ra, and SFE were determined after the following procedures: 1. self-etch mode with immediate air blowing after application (IA); 2. self-etch mode with prolonged application time (PA); 3. etch-and-rinse mode with IA; 4. etch-and-rinse mode with PA. After 24-h water storage, the bonded assemblies were subjected to shear bond strength (SBS) tests. For surface roughness (Ra) and surface free energy (SFE) measurements, the adhesives were simply applied to the enamel and rinsed with acetone and water before the measurements were carried out. RESULTS: Significantly higher SBS and Ra values were obtained with etch-and-rinse mode than with self-etch mode regardless of the application time or type of adhesive. Although most adhesives showed decreased SFE values with increased application time in self-etch mode, SFE values in etch-and-rinse mode were dependent on the adhesive type and application time. CONCLUSIONS: Etching mode, application time, and type of adhesive significantly influenced the SBS, Ra, and SFE values. PMID- 29507921 TI - Focusing manipulation of microalgae in a microfluidic device using self-produced macromolecules. AB - Extracellular polymeric substances (EPSs) are self-produced biosynthetic macromolecules that have a three-dimensional architecture in bacterial biofilms and are mainly composed of a mixture of polysaccharides, proteins and nucleic acids. Compared with synthetic polymers, EPSs can have a long relaxation time due to their structural complexity. We exploited the non-Newtonian rheological behavior of EPSs extracted from Chlorella vulgaris with the help of cell focusing and particle focusing in confined microchannels. The microalgae showed a 'self ordering' behavior in the 'self-secreted' substances. The EPSs were characterized and analyzed chemically and rheologically. In a microfluidic device, they enable outstanding particle focusing over a wide range of flow rates. This study can open an effective, unique pathway for applications of biomass related resources such as EPSs. PMID- 29507922 TI - Hand-twistable plastically deformable crystals of a rigid small organic molecule. AB - 4-Bromobenzonitrile was crystallised by sublimation under vacuum. The crystals show highly flexible plastic bending along two perpendicular faces when a mechanical force is applied. The rare occurrence of bending along two perpendicular faces results in twisting or helix formation. PMID- 29507920 TI - Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease. AB - Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases. Here we combine metal imaging and optical imaging techniques at a variety of spatial resolutions to identify tissues and structures with altered copper levels in the Calamitygw71 zebrafish model of Menkes disease. Rapid profiling of tissue slices with LA-ICP-MS identified reduced copper levels in the brain, neuroretina, and liver of Menkes fish compared to control specimens. High resolution nanoSIMS imaging of the neuroretina, combined with electron and confocal microscopies, identified the megamitochondria of photoreceptors as loci of copper accumulation in wildtype fish, with lower levels of megamitochondrial copper observed in Calamitygw71 zebrafish. Interestingly, this localized copper decrease does not result in impaired photoreceptor development or altered megamitochondrial morphology, suggesting the prioritization of copper at sufficient levels for maintaining essential mitochondrial functions. Together, these data establish the Calamitygw71 zebrafish as an optically transparent in vivo model for the study of neural copper misregulation, illuminate a role for the ATP7A copper exporter in trafficking copper to the neuroretina, and highlight the utility of combining multiple imaging techniques for studying metals in whole organism settings with spatial resolution. PMID- 29507924 TI - A new metal-organic framework constructed from cationic nodes and cationic linkers for highly efficient anion exchange. AB - A novel cationic metal-organic framework, FJI-Y6, was designed and constructed by combining [In3O(COO)6(H2O)3]+ with cationic linkers. FJI-Y6 exhibits highly efficient anion exchangeability. For example, Acid orange 7, with a single negative charge and which cannot be adsorbed effectively by previously reported MOFs, is captured and released rapidly by FJI-Y6. PMID- 29507930 TI - Local Movement to Ban Menthol Tobacco Products as a Result of Federal Inaction. PMID- 29507932 TI - Determining If Rest Is Best After Concussion. PMID- 29507931 TI - Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model. AB - Importance: Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby a promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation and promote the activation of neuroprotective microglia in mouse models of ALS. To our knowledge, the therapeutic association of host Treg expansion with ALS progression has not been studied in vivo. Objective: To assess the role of Tregs in regulating the pathophysiology of ALS in humans and the therapeutic outcome of increasing Treg activity in a mouse model of the disease. Design, Setting, and Participants: This prospective multicenter human and animal study was performed in hospitals, outpatient clinics, and research institutes. Clinical and function assessment, as well as immunological studies, were undertaken in 33 patients with sporadic ALS, and results were compared with 38 healthy control participants who were consecutively recruited from the multidisciplinary ALS clinic at Westmead Hospital between February 1, 2013, and December 31, 2014. All data analysis on patients with ALS was undertaken between January 2015 and December 2016. Subsequently, we implemented a novel approach to amplify the endogenous Treg population using peripheral injections of interleukin 2/interleukin 2 monoclonal antibody complexes (IL-2c) in transgenic mice that expressed mutant superoxide dismutase 1 (SOD1), a gene associated with motor neuron degeneration. Main Outcomes and Measures: In patients with ALS, Treg levels were determined and then correlated with disease progression. Circulating T-cell populations, motor neuron size, glial cell activation, and T-cell and microglial gene expression in spinal cords were determined in SOD1G93A mice, as well as the association of Treg amplification with disease onset and survival time in mice. Results: The cohort of patients with ALS included 24 male patients and 9 female patients (mean [SD] age at assessment, 58.9 [10.9] years). There was an inverse correlation between total Treg levels (including the effector CD45RO+ subset) and rate of disease progression (R = -0.40, P = .002). Expansion of the effector Treg population in the SOD1G93A mice was associated with a significant slowing of disease progression, which was accompanied by an increase in survival time (IL-2c-treated mice: mean [SD], 160.6 [10.8] days; control mice: mean [SD], 144.9 [10.6] days; P = .003). Importantly, Treg expansion was associated with preserved motor neuron soma size and marked suppression of astrocytic and microglial immunoreactivity in the spinal cords of SOD1G93A mice, as well as elevated neurotrophic factor gene expression in spinal cord and peripheral nerves. Conclusions and Relevance: These findings establish a neuroprotective effect of Tregs, possibly mediated by suppression of toxic neuroinflammation in the central nervous system. Strategies aimed at enhancing the Treg population and neuroprotective activity from the periphery may prove therapeutically useful for patients with ALS. PMID- 29507933 TI - Chest Reconstruction and Chest Dysphoria in Transmasculine Minors and Young Adults: Comparisons of Nonsurgical and Postsurgical Cohorts. AB - Importance: Transmasculine youth, who are assigned female at birth but have a gender identity along the masculine spectrum, often report considerable distress after breast development (chest dysphoria). Professional guidelines lack clarity regarding referring minors (defined as people younger than 18 years) for chest surgery because there are no data documenting the effect of chest surgery on minors. Objective: To examine the amount of chest dysphoria in transmasculine youth who had had chest reconstruction surgery compared with those who had not undergone this surgery. Design, Setting, and Participants: Using a novel measure of chest dysphoria, this cohort study at a large, urban, hospital-affiliated ambulatory clinic specializing in transgender youth care collected survey data about testosterone use and chest distress among transmasculine youth and young adults. Additional information about regret and adverse effects was collected from those who had undergone surgery. Eligible youth were 13 to 25 years old, had been assigned female at birth, and had an identified gender as something other than female. Recruitment occurred during clinical visits and via telephone between June 2016 and December 2016. Surveys were collected from participants who had undergone chest surgery at the time of survey collection and an equal number of youth who had not undergone surgery. Main Outcomes and Measures: Outcomes were chest dysphoria composite score (range 0-51, with higher scores indicating greater distress) in all participants; desire for chest surgery in patients who had not had surgery; and regret about surgery and complications of surgery in patients who were postsurgical. Results: Of 136 completed surveys, 68 (50.0%) were from postsurgical participants, and 68 (50.0%) were from nonsurgical participants. At the time of the survey, the mean (SD) age was 19 (2.5) years for postsurgical participants and 17 (2.5) years for nonsurgical participants. Chest dysphoria composite score mean (SD) was 29.6 (10.0) for participants who had not undergone chest reconstruction, which was significantly higher than mean (SD) scores in those who had undergone this procedure (3.3 [3.8]; P < .001). Among the nonsurgical cohort, 64 (94%) perceived chest surgery as very important, and chest dysphoria increased by 0.33 points each month that passed between a youth initiating testosterone therapy and undergoing surgery. Among the postsurgical cohort, the most common complication of surgery was loss of nipple sensation, whether temporary (59%) or permanent (41%). Serious complications were rare and included postoperative hematoma (10%) and complications of anesthesia (7%). Self reported regret was near 0. Conclusions and Relevance: Chest dysphoria was high among presurgical transmasculine youth, and surgical intervention positively affected both minors and young adults. Given these findings, professional guidelines and clinical practice should consider patients for chest surgery based on individual need rather than chronologic age. PMID- 29507934 TI - Association of Ontario's Ban on Menthol Cigarettes With Smoking Behavior 1 Month After Implementation. PMID- 29507935 TI - The Cost of Vancomycin and Piperacillin/Tazobactam Treatment-Reply. PMID- 29507936 TI - The Role of Regulatory T Lymphocytes in Amyotrophic Lateral Sclerosis. PMID- 29507937 TI - An Adolescent With Desquamation of Both Feet. PMID- 29507939 TI - Prolonged Persistence of Adalimumab Transferred From Mother to Infant During Pregnancy. PMID- 29507940 TI - The Cost of Vancomycin and Piperacillin/Tazobactam Treatment. PMID- 29507941 TI - Technology and Transparency: Empowering Patients and Clinicians to Improve Health Care Value. PMID- 29507938 TI - Daily vs Intermittent Antituberculosis Therapy for Pulmonary Tuberculosis in Patients With HIV: A Randomized Clinical Trial. AB - Importance: The benefit of daily over thrice-weekly antituberculosis therapy among HIV-positive patients with pulmonary tuberculosis (TB) who are receiving antiretroviral therapy remains unproven. Objective: To compare the efficacy and safety of daily, part-daily, and intermittent antituberculosis therapy regimens in the treatment of HIV-associated pulmonary TB. Design, Setting, and Participants: This open-label, randomized clinical trial was conducted by the National Institute for Research in Tuberculosis, south India. Adults infected with HIV with newly diagnosed, culture-positive, pulmonary TB were enrolled between September 14, 2009, and January 18, 2016. Interventions: Patients were randomized to daily, part-daily, and intermittent antituberculosis therapy regimens, stratified by baseline CD4 lymphocyte count and sputum smear grade. Antiretroviral therapy was initiated as per national guidelines. Clinical and sputum microbiological examinations of patients were performed monthly until 18 months after randomization. Adverse events were recorded using standard criteria. Main Outcomes and Measures: The primary outcome was favorable response, defined as treatment completion with all available sputum cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment. Unfavorable responses included treatment failures, dropouts, deaths, and toxic effects among regimens. Results: Of 331 patients (251 [76%] male; mean [SD] age, 39 [9] years; mean [SD] HIV viral load, 4.9 [1.2] log10 copies/mL; and median [interquartile range] CD4 lymphocyte count, 138 [69-248] cells/MUL), favorable responses were experienced by 91% (89 of 98), 80% (77 of 96), and 77% (75 of 98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O'Brien-Fleming group sequential boundaries and acquired rifampicin resistance emergence (n = 4) confined to the intermittent group, the data safety monitoring committee halted the study. A total of 18 patients died and 18 patients dropped out during the treatment period in the 3 regimens. Six, 4, and 6 patients in the daily, part daily, and intermittent regimens, respectively, had TB recurrence. Conclusions and Relevance: Among HIV-positive patients with pulmonary TB receiving antiretroviral therapy, a daily anti-TB regimen proved superior to a thrice weekly regimen in terms of efficacy and emergence of rifampicin resistance. Trial Registration: clinicaltrials.gov Identifier: NCT00933790. PMID- 29507943 TI - Interstate Association of State Firearm Laws With Suicide and Homicide. PMID- 29507942 TI - Effect of Treating Acute Optic Neuritis With Bioequivalent Oral vs Intravenous Corticosteroids: A Randomized Clinical Trial. AB - Importance: Intravenous (IV) administration of corticosteroids is the standard of care in the treatment of acute optic neuritis. However, it is uncertain whether a bioequivalent dose of corticosteroid administered orally, which may be more cost efficient and convenient for patients, is as effective as IV administration in the treatment of acute optic neuritis. Objective: To determine whether recovery of vision following treatment of acute optic neuritis with a high-dose IV corticosteroid is superior to that with a bioequivalent dose of an oral corticosteroid. Design, Setting, and Participants: This single-blind (participants unblinded) randomized clinical trial with 6-month follow-up was conducted at a single tertiary care center in London, Ontario, Canada. Participants were enrolled from March 2012 to May 2015, with the last participant's final visit occurring November 2015. Patients 18 to 64 years of age presenting within 14 days of acute optic neuritis onset, without any recovery at time of randomization and without history of optic neuritis in the same eye, were screened. Inclusion criteria included best-corrected visual acuity (BCVA) of 20/40 or worse and corticosteroids deemed required by treating physician. In total, 89 participants were screened; 64 were eligible, but 9 declined to participate. Thus, 55 participants were enrolled and randomized. Primary analysis was unadjusted and according to the intention-to-treat principle. Interventions: Participants were randomized 1:1 to the IV methylprednisolone sodium succinate (1000-mg) or oral prednisone (1250-mg) group. Main Outcomes and Measures: Primary outcome was recovery of the latency of the P100 component of the visual evoked potential at 6 months. Secondary outcomes were the P100 latency at 1 month and BCVA as assessed with Early Treatment Diabetic Retinopathy Study letter scores on the alphabet chart and scores on low-contrast letters at 1 and 6 months. Results: Of 55 randomized participants, the final analyzed cohort comprised 23 participants in the IV and 22 in the oral treatment groups. The mean (SD) age of the cohort was 34.6 (9.5) years, and there were 28 women (62.2%). At 6 months' recovery, P100 latency in the IV group improved by 62.9 milliseconds (from a mean [SD] of 181.9 [53.6] to 119.0 [16.5] milliseconds), and the oral group improved by 66.7 milliseconds (from a mean [SD] of 200.5 [67.2] to 133.8 [31.5] milliseconds), with no significant difference between groups (P = .07). Similarly, no significant group difference was found in the mean P100 latency recovery at 1 month. For BCVA, recovery between the groups did not reach statistical significance at 1 month or 6 months. In addition, improvements in low contrast (1.25% and 2.5%) BCVA were not significantly different between treatment groups at 1 or 6 months' recovery. Conclusions and Relevance: This study finds that bioequivalent doses of oral corticosteroids may be used as an alternative to IV corticosteroids to treat acute optic neuritis. Trial Registration: clinicaltrials.gov Identifier: NCT01524250. PMID- 29507944 TI - Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease: The PRESERVE Randomized Clinical Trial. AB - Importance: Blood pressure (BP) lowering is considered neuroprotective in patients with cerebral small vessel disease; however, more intensive regimens may increase cerebral hypoperfusion. This study examined the effect of standard vs intensive BP treatment on cerebral perfusion in patients with severe small vessel disease. Objective: To investigate whether standard vs intensive BP lowering over 3 months causes decreased cerebral perfusion in small vessel disease. Design, Setting, and Participants: This randomized clinical trial took place at 2 English university medical centers. Patients were randomized via a central online system (in a 1:1 ratio). Seventy patients with hypertension and with magnetic resonance imaging-confirmed symptomatic lacunar infarct and confluent white matter hyperintensities were recruited between February 29, 2012, and October 21, 2015, and randomized (36 in the standard group and 34 in the intensive group). Analyzable data were available in 62 patients, 33 in the standard group and 29 in the intensive group, for intent-to-treat analysis. This experiment examines the 3 month follow-up period. Interventions: Patients were randomized to standard (systolic, 130-140 mm Hg) or intensive (systolic, <125 mm Hg) BP targets, to be achieved through medication changes. Main Outcomes and Measures: Cerebral perfusion was measured using arterial spin labeling; the primary end point was change in global perfusion between baseline and 3 months, compared between treatment groups by analysis of variance. Linear regression compared change in perfusion against change in BP. Magnetic resonance imaging scan analysis was masked to treatment group. Results: Among 62 analyzable patients, the mean age was 69.3 years, and 60% (n = 37) were male. The mean (SD) systolic BP decreased by 8 (12) mm Hg in the standard group and by 27 (17) mm Hg in the intensive group (P < .001), with mean (SD) achieved pressures of 141 (13) and 126 (10) mm Hg, respectively. Change in global perfusion did not differ between treatment groups: the mean (SD) change was -0.5 (9.4) mL/min/100 g in the standard group vs 0.7 (8.6) mL/min/100 g in the intensive group (partial eta2, 0.004; 95% CI, -3.551 to 5.818; P = .63). No differences were observed when the analysis examined gray or white matter only or was confined to those achieving target BP. The number of adverse events did not differ between treatment groups, with a mean (SD) of 0.21 (0.65) for the standard group and 0.32 (0.75) for the intensive group (P = .44). Conclusions and Relevance: Intensive BP lowering did not reduce cerebral perfusion in severe small vessel disease. Trial Registration: isrctn.org Identifier: ISRCTN37694103. PMID- 29507945 TI - Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians. AB - Description: The American College of Physicians developed this guidance statement to guide clinicians in selecting targets for pharmacologic treatment of type 2 diabetes. Methods: The National Guideline Clearinghouse and the Guidelines International Network library were searched (May 2017) for national guidelines, published in English, that addressed hemoglobin A1c (HbA1c) targets for treating type 2 diabetes in nonpregnant outpatient adults. The authors identified guidelines from the National Institute for Health and Care Excellence and the Institute for Clinical Systems Improvement. In addition, 4 commonly used guidelines were reviewed, from the American Association of Clinical Endocrinologists and American College of Endocrinology, the American Diabetes Association, the Scottish Intercollegiate Guidelines Network, and the U.S. Department of Veterans Affairs and Department of Defense. The AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument was used to evaluate the guidelines. Guidance Statement 1: Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care. Guidance Statement 2: Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes. Guidance Statement 3: Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%. Guidance Statement 4: Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population. PMID- 29507947 TI - Hemoglobin A1c Targets for Nonpregnant Adults With Type 2 Diabetes Mellitus. PMID- 29507946 TI - Cognitive and Mind-Body Therapies for Chronic Low Back Pain and Neck Pain: Effectiveness and Value. PMID- 29507948 TI - What Pediatricians Should Know About Lassa Virus. PMID- 29507949 TI - Masked Speech Recognition and Reading Ability in School-Age Children: Is There a Relationship? AB - Purpose: The relationship between reading (decoding) skills, phonological processing abilities, and masked speech recognition in typically developing children was explored. This experiment was designed to evaluate the relationship between phonological processing and decoding abilities and 2 aspects of masked speech recognition in typically developing children: (a) the ability to benefit from temporal and spectral modulations within a noise masker and (b) the masking exerted by a speech masker. Method: Forty-two typically developing 3rd- and 4th grade children with normal hearing, ranging in age from 8;10 to 10;6 years (mean age = 9;2 years, SD = 0.5 months), completed sentence recognition testing in 4 different maskers: steady-state noise, temporally modulated noise, spectrally modulated noise, and two-talker speech. Children also underwent assessment of phonological processing abilities and assessments of single-word decoding. As a comparison group, 15 adults with normal hearing also completed speech-in-noise testing. Results: Speech recognition thresholds varied between approximately 3 and 7 dB across children, depending on the masker condition. Compared to adults, performance in the 2-talker masker was relatively consistent across children. Furthermore, decreasing the signal-to-noise ratio had a more precipitously deleterious effect on children's speech recognition in the 2-talker masker than was observed for adults. For children, individual differences in speech recognition threshold were not predicted by phonological awareness or decoding ability in any masker condition. Conclusions: No relationship was found between phonological awareness and/or decoding ability and a child's ability to benefit from spectral or temporal modulations. In addition, phonological awareness and/or decoding ability was not related to speech recognition in a 2-talker masker. Last, these data suggest that the between-listeners variability often observed in 2-talker maskers for adults may be smaller for children. The reasons for this child-adult difference need to be further explored. Supplemental Material: https://doi.org/10.23641/asha.5913547. PMID- 29507951 TI - Restoration of Full Shoulder Range of Motion After Application of the Fascial Distortion Model. AB - Decreased active and passive range of motion (ROM) accompanied by pain in the shoulder is a common presentation for patients with frozen shoulder, and it can be difficult to restore normal function. Through the fascial distortion model, physicians can apply a manual technique to rapidly and effectively increase ROM and decrease pain. A 28-year-old man presented 18 months after sustaining a shoulder hyperextension injury. On active and passive ROM examination, he had approximately 90 degrees of shoulder abduction and moderately reduced internal rotation associated with 8/10 pain. After 2 applications of the fascial distortion model, his shoulder restored to full abduction and internal rotation with no pain. PMID- 29507950 TI - Preventing the Malignant Transformation of Bipolar Disorder. PMID- 29507952 TI - Effect of a Health Care Professional Communication Training Intervention on Adolescent Human Papillomavirus Vaccination: A Cluster Randomized Clinical Trial. AB - Importance: The incidence of human papillomavirus (HPV)-related cancers is more than 35 000 cases in the United States each year. Effective HPV vaccines have been available in the United States for several years but are underused among adolescents, the target population for vaccination. Interventions to increase uptake are needed. Objective: To evaluate the effect of a 5-component health care professional HPV vaccine communication intervention on adolescent HPV vaccination. Design, Setting, and Participants: A cluster randomized clinical trial using covariate-constrained randomization to assign study arms and an intent-to-treat protocol was conducted in 16 primary care practices in the Denver, Colorado, metropolitan area. Participants included 188 medical professionals and 43 132 adolescents. Interventions: The 5 components of the intervention were an HPV fact sheet library to create customized information sheets relevant to each practice's patient population, a tailored parent education website, a set of HPV-related disease images, an HPV vaccine decision aid, and 21/2 hours of communication training on using a presumptive vaccine recommendation, followed by motivational interviewing if parents were resistant to vaccination. Each practice participated in a series of 2 intervention development meetings over a 6-month period (August 1, 2014, to January 31, 2015) before the intervention. Main Outcomes and Measures: Differences between control and intervention changes over time (ie, difference in differences between the baseline and intervention period cohorts of patients) in HPV vaccine series initiation (>=1 dose) and completion (>=3 doses) among patients aged 11 to 17 years seen at the practices between February 1, 2015, and January 31, 2016. Vaccination data were obtained from the practices' records and augmented with state immunization information system data. Results: Sixteen practices and 43 132 patients (50.3% female; median age, 12.6 years [interquartile range, 10.8-14.7 years] at the beginning of the study period) participated in this trial. Adolescents in the intervention practices had significantly higher odds of HPV vaccine series initiation (adjusted odds ratio [aOR], 1.46; 95% CI, 1.31-1.62) and completion (aOR, 1.56; 95% CI, 1.27-1.92) than those in the control practices (a 9.5-absolute percentage point increase in HPV vaccine series initiation and a 4.4-absolute percentage point increase in HPV vaccine series completion in intervention practices). The intervention had a greater effect in pediatric practices compared with family medicine practices and in private practices compared with public ones. Health care professionals reported that communication training and the fact sheets were the most used and useful intervention components. Conclusions and Relevance: A health care professional communication intervention significantly improved HPV vaccine series initiation and completion among adolescent patients. Trial Registration: clinicaltrials.gov Identifier: NCT02456077. PMID- 29507954 TI - Patient Acceptance of Invasive Treatments for Tinnitus. AB - Purpose: The field of neuromodulation is currently seeking to treat a wide range of disorders with various types of invasive devices. In recent years, several preclinical trials and case reports in humans have been published on their potential for chronic tinnitus. However, studies to obtain insight into patients' willingness to undergo these treatments are scarce. The aim of this survey study was to find out whether tinnitus patients are willing to undergo invasive neuromodulation when taking its risks, costs, and potential benefits into account. Method: A Visual Analog Scale (VAS, 0-10) was used to measure the outcome. Spearman's rank-order correlation coefficients were computed to determine the correlation between patient characteristics and acceptance rates. Results: Around one fifth of the patients were reasonably willing to undergo invasive treatment (VAS 5-7), and around one fifth were fully willing to do so (VAS 8-10). Hearing aids, used as a control, were accepted most, followed by cochlear implantation, deep brain stimulation, and cortical stimulation. Acceptance rates were slightly higher when the chance of cure was higher. Patients with a history of attempted treatments were more eager than others to find a new treatment for tinnitus. Conclusions: A considerable proportion of patients with tinnitus would accept a variety of invasive treatments despite the associated risks or costs. When clinical neuromodulatory studies for tinnitus are to be performed, particular attention should be given to obtaining informed consent, including explaining the potential risks and providing a realistic outcome expectation. PMID- 29507953 TI - State Firearm Laws and Interstate Firearm Deaths From Homicide and Suicide in the United States: A Cross-sectional Analysis of Data by County. AB - Importance: Firearm laws in one state may be associated with increased firearm death rates from homicide and suicide in neighboring states. Objective: To determine whether counties located closer to states with lenient firearm policies have higher firearm death rates. Design, Setting, and Participants: This cross sectional study of firearm death rates by county for January 2010 to December 2014 examined data from the US Centers for Disease Control and Prevention for firearm suicide and homicide decedents for 3108 counties in the 48 contiguous states of the United States. Exposures: Each county was assigned 2 scores, a state policy score (range, 0-12) based on the strength of its state firearm laws, and an interstate policy score (range, -1.33 to 8.31) based on the sum of population-weighted and distance-decayed policy scores for all other states. Counties were divided into those with low, medium, and high home state and interstate policy scores. Main Outcomes and Measures: County-level rates of firearm, nonfirearm, and total homicide and suicide. With multilevel Bayesian spatial Poisson models, we generated incidence rate ratios (IRR) comparing incidence rates between each group of counties and the reference group, counties with high home state and high interstate policy scores. Results: Stronger firearm laws in a state were associated with lower firearm suicide rates and lower overall suicide rates regardless of the strength of the other states' laws. Counties with low state scores had the highest rates of firearm suicide. Rates were similar across levels of interstate policy score (low: IRR, 1.34; 95% credible interval [CI], 1.11-1.65; medium: IRR, 1.36, (95% CI, 1.15-1.65; and high: IRR, 1.43; 95% CI, 1.20-1.73). Counties with low state and low or medium interstate policy scores had the highest rates of firearm homicide. Counties with low home state and interstate scores had higher firearm homicide rates (IRR, 1.38; 95% CI, 1.02-1.88) and overall homicide rates (IRR, 1.32; 95% CI, 1.03 1.67). Counties in states with low firearm policy scores had lower rates of firearm homicide only if the interstate firearm policy score was high. Conclusions and Relevance: Strong state firearm policies were associated with lower suicide rates regardless of other states' laws. Strong policies were associated with lower homicide rates, and strong interstate policies were also associated with lower homicide rates, where home state policies were permissive. Strengthening state firearm policies may prevent firearm suicide and homicide, with benefits that may extend beyond state lines. PMID- 29507956 TI - Annals for Educators - 6 March 2018. PMID- 29507957 TI - Web Exclusives. Annals Graphic Medicine - Is This What Depression Looks Like? PMID- 29507958 TI - Statin Denial: An Internet-Driven Cult With Deadly Consequences. PMID- 29507960 TI - Statin Denial: An Internet-Driven Cult With Deadly Consequences. PMID- 29507959 TI - Statin Denial: An Internet-Driven Cult With Deadly Consequences. PMID- 29507961 TI - Coffee Drinking and Mortality in 10 European Countries. PMID- 29507962 TI - Coffee Drinking and Mortality in 10 European Countries. PMID- 29507955 TI - Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events. AB - Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective: To clarify the association of the z score with time dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, >=5 to <10; actual internal diameter, <8 mm), and large (z score, >=10 or >=8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA. PMID- 29507963 TI - Coffee Drinking and Mortality in 10 European Countries. PMID- 29507964 TI - Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults. PMID- 29507965 TI - Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults. PMID- 29507966 TI - Correction: Presence of Human Hepegivirus-1 in a Cohort of People Who Inject Drugs. PMID- 29507967 TI - Note to an Oncology Fellow. PMID- 29507968 TI - Death Is a Small Thing. PMID- 29507969 TI - Lie to me: Tell me bald is beautiful. PMID- 29507970 TI - Palliative Care. AB - Palliative care prioritizes symptom management and quality of life throughout the course of serious illness. Regardless of whether care is inpatient or outpatient, primary or subspecialty, a solid understanding of the basics of effective communication, symptom management, and end-of-life care is crucial. This article reviews these essentials and provides an overview of current evidence to support patient-centered palliative care. PMID- 29507975 TI - New York City Skyline View From Staten Island Ferry. PMID- 29507976 TI - Necessary Clarifications Concerning Results of the SUMMIT Trial. PMID- 29507971 TI - Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial. AB - Background: Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. Objective: To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation). Design: Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649). Setting: Single center. Participants: 10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors. Intervention: Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy. Measurements: The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Results: Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitation: Nonrandomized study design and a small number of patients. Conclusion: Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Primary Funding Source: Merck Sharp & Dohme. PMID- 29507977 TI - Expanding the Scope of High-Value Practice Beyond Guideline-Based Care. PMID- 29507978 TI - Evidence-Based Guidelines to Eliminate Repetitive Laboratory Testing? PMID- 29507979 TI - Medical Overuse of Prostate-Specific Antigen Testing and Overprescription of Antibiotics. PMID- 29507980 TI - Drivers of Low-Value Care. PMID- 29507981 TI - Nil Per Os Before Procedures-Time to Reevaluate the Practice. PMID- 29507982 TI - Beware of Limb Lead Reversal. PMID- 29507983 TI - Coronary Computed Tomographic Angiography and Potential for Overtreatment. PMID- 29507984 TI - Disagreement With the NICE Decision. PMID- 29507985 TI - Life Expectancy of Patients With Low-Normal Thyroid Function. PMID- 29507986 TI - Necessary Clarifications Concerning Results of the SUMMIT Trial-Reply. PMID- 29507987 TI - Expanding the Scope of High-Value Practice Beyond Guideline-Based Care-Reply. PMID- 29507988 TI - Evidence-Based Guidelines to Eliminate Repetitive Laboratory Testing?-Reply. PMID- 29507989 TI - Medical Overuse of Prostate-Specific Antigen Testing and Overprescription of Antibiotics-Reply. PMID- 29507990 TI - Drivers of Low-Value Care-Reply. PMID- 29507991 TI - Beware of Limb Lead Reversal-Reply. PMID- 29507992 TI - Coronary Computed Tomographic Angiography and Potential for Overtreatment-Reply. PMID- 29507993 TI - Life Expectancy of Patients With Low-Normal Thyroid Function-Reply. PMID- 29507995 TI - Classical Hand, Foot and Mouth Disease Replaced by Atypical Hand, Foot and Mouth Disease. PMID- 29507997 TI - Extensive Nasal Plaque: An Unusual Presentation of IgG4-related Disease. PMID- 29507996 TI - Prognosis of Preschool Eczema and Factors of Importance for Remission. AB - Information on factors of importance for remission of eczema is scarce. This study explored factors related to the remission and course of preschool eczema (PSE) (eczema at 1, 2 and/or 4 years of age) to 16 years of age (n = 889) in a Swedish cohort. Half of the children were in complete remission by school age (at age 8, 12, and 16 years). In multivariate prognostic models, persistent PSE (eczema at 1, 2 and 4 years of age) (odds ratio 0.27 (95% confidence interval 0.18-0.41)), PSE with sleep disturbance (due to itch at least once a week at 1, 2 and/or 4 years of age) (0.59 (0.43-0.81)), parental allergy (0.73 (0.55-0.96)), parental smoking at child's birth (0.70 (0.50-0.99)) and filaggrin mutation (R501X, R2447X, 2282del4) (0.47 (0.26-0.85)) were inversely associated with complete remission by school age. Male sex (1.37 (1.03-1.82)) and exclusive breastfeeding >=4 months (1.44 (1.01-2.05)) were positively associated with complete remission by school age. In conclusion, half of the children with PSE were in complete remission by school age. The most important prognostic factors were persistent PSE and PSE with sleep disturbance due to itch. PMID- 29507998 TI - Localized Scleroderma of the Head and Face Area: A Retrospective Cross-sectional Study of 96 Patients from 5 German Tertiary Referral Centres. PMID- 29507999 TI - The Role of Therapy in Impairing Quality of Life in Dermatological Patients: A Multinational Study. AB - Skin disease and its therapy affect health-related quality of life (HRQoL). The aim of this study was to measure the burden caused by dermatological therapy in 3,846 patients from 13 European countries. Adult outpatients completed questionnaires, including the Dermatology Life Quality Index (DLQI), which has a therapy impact question. Therapy issues were reported by a majority of patients with atopic dermatitis (63.4%), psoriasis (60.7%), prurigo (54.4%), hidradenitis suppurativa (54.3%) and blistering conditions (53%). The largest reduction in HRQoL attributable to therapy, as a percentage of total DLQI, adjusted for confounders, was seen in blistering conditions (10.7%), allergic/drug reactions (10.2%), psoriasis (9.9%), vasculitis/immunological ulcers (8.8%), atopic dermatitis (8.7%), and venous leg ulcers (8.5%). In skin cancer, although it had less impact on HRQoL, the reduction due to therapy was 6.8%. Treatment for skin disease contributes considerably to reducing HRQoL: the burden of dermatological treatment should be considered when planning therapy and designing new dermatological therapies. PMID- 29508000 TI - Spontaneous Regression of Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type. PMID- 29508001 TI - Matrix-Assisted Laser Desorption/Ionisation Time-Of-Flight (MALDI-TOF) Mass Spectrometry in Dermatology. PMID- 29508002 TI - [Local metastasis treatment in oligometastatic disease : Also relevant for prostate cancer]. PMID- 29508003 TI - [Pharmacological treatment of rheumatoid arthritis and its comorbidities]. AB - Due to therapeutic advances, rheumatoid arthritis (RA) today has developed into a satisfactorily treatable disease in most cases, with remission being the target of treatment. Early diagnosis with immediate treatment initiation following treat to-target strategy is the key to a favorable long-term outcome. A guideline directed treatment algorithm determines the use of conventional synthetic disease modifying anti-rheumatic drugs (DMARD; e.g., methotrexate), biological DMARD, and targeted oral DMARD (Janus kinase inhibitors). Comorbidities-in particular cardiovascular and interstitial lung disease-affect 80% of RA patients and represent the leading causes for mortality. The choice of drug treatment is influenced by the presence of comorbidities. PMID- 29508005 TI - Role of Coulombic Repulsion in Collisional Lipid Transfer Among SMA(2:1)-Bounded Nanodiscs. AB - Styrene/maleic acid (SMA) and related copolymers are attracting great interest because they solubilise membrane proteins and lipids to form polymer-encapsulated nanodiscs. These nanodiscs retain a lipid-bilayer core surrounded by a polymer rim and can harbour a membrane protein or a membrane-protein complex. SMA exists in different styrene/maleic acid molar ratios, which results in differences in hydrophobicity and solubilisation properties. We have recently demonstrated fast collisional lipid transfer among nanodiscs encapsulated by the relatively hydrophobic copolymer SMA(3:1). Here, we used time-resolved Forster resonance energy transfer to quantify the lipid-transfer kinetics among nanodiscs bounded by SMA(2:1), a less hydrophobic copolymer that is superior in terms of lipid and membrane-protein solubilisation. Moreover, we assessed the effects of ionic strength and, thereby, the role of Coulombic repulsion in the exchange of lipid molecules among these polyanionic nanodiscs. Collisional lipid transfer was slower among SMA(2:1) nanodiscs (kcol = 5.9 M-1 s-1) than among SMA(3:1) nanodiscs (kcol = 222 M-1 s-1) but still two to three orders of magnitude faster than diffusional lipid exchange among protein-encapsulated nanodiscs or vesicles. Increasing ionic strength accelerated lipid transfer in a manner predicted by the Davies equation, an empirical extension of the Debye-Huckel limiting law, or an extended equation taking into account the finite size of the nanodiscs. Using the latter approach, quantitative agreement between experiment and theory was achieved for an effective nanodisc charge number of z ~ -33, which is an order of magnitude less than their nominal overall charge. PMID- 29508007 TI - [Complications of the lumbosacral junction in adult deformity surgery : Indications and technique for posterior and anterior revision surgery]. AB - BACKGROUND: Surgical correction of ASD can be challenging. The indication for surgery is individual and after specification of the therapeutic goals, detailed planning of the surgery is essential to achieve a good postoperative result. COMPLICATIONS AND INDICATION: The reasons for the comparatively high complication rate are well investigated and are often located at the lumbosacral junction. In addition to negative general factors like osteoporosis, especially undercorrection of the sagittal profile and insufficient lumbo-pelvic stabilization are causative. The main indications for revision surgery are a loss of lordosis due to progressive degeneration of the unfused segment L5/S1 or implant loosening and pseudarthrosis of a failed lumbosacral fusion. TREATMENT: The goals of revision surgery are restoration of the spinal balance as well as stable fixation and fusion in consideration of the general condition of the patient. Besides osteotomies in a previously fused region, especially reinstrumentation of the lumbosacral region can be challenging, although ala ilium and ilium screws give the greatest stability. Additional anterior intersomatic cages allow for a better fusion rate, and, moreover they provide better lordozation. Each PLIF, TLIF, and ALIF cage has its own specific advantages. This article summarizes the reasons for complications of the lumbosacral junction after ASD correction and describes surgical principles for revision surgery. PMID- 29508009 TI - The inlet patch. PMID- 29508006 TI - Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines. AB - Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient's immune system against tumor derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies. PMID- 29508008 TI - [Options in joint-preserving surgical treatment of osteoarthritis]. AB - BACKGROUND: The treatment of glenohumeral arthritis represents a major challenge in highly active younger patients. In these patients, an endoprosthetic treatment often achieves only unsatisfactory results with a limited lifetime of the implant. OBJECTIVES: The aim of the study was to identify joint-preserving therapies for glenohumeral arthritis. MATERIALS AND METHODS: For this study, an extensive and selective literature search was performed. RESULTS: There are several options available for joint-preserving treatment of glenohumeral arthritis. In addition to arthroscopic debridement with treatment of concomitant pathologies, CAM procedures (CAM: comprehensive arthroscopic management) according to Millett, as well as the interposition of allografts are other options. For all therapy options, an improved range of motion and pain reduction is described. A joint gap of <2 mm, bipolar cartilage lesions and age are described as risk factors for failure of the therapies. DISCUSSION: Short and mid term results have been described for arthroscopic debridement, but there are no long-term and high-quality studies to enable us to make clear recommendations. The CAM procedure and the interposition of an allograft are demanding procedures that should be reserved for experienced arthroscopists. The therapies are an option for younger patients in accordance with individual decisions and realistic expectations. PMID- 29508004 TI - The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders. AB - The hypocretin/orexin (ORX) system has been repeatedly demonstrated to regulate motivation for drugs of abuse, including alcohol. In particular, ORX seems to be critically involved in highly motivated behaviors, as is observed in high-seeking individuals in a population, in the seeking of highly palatable substances, and in models of dependence. It seems logical that this system could be considered as a potential target for treatment for addiction, particularly alcohol addiction, as ORX pharmacological manipulations significantly reduce drinking. However, the ORX system also plays a role in a wide range of other behaviors, emotions, and physiological functions and is disrupted in a number of non-dependence-associated disorders. It is therefore important to consider how the ORX system might be optimally targeted for potential treatment for alcohol use disorders either in combination with or separate from its role in other functions or diseases. This review will focus on the role of ORX in alcohol-associated behaviors and whether and how this system could be targeted to treat alcohol use disorders while avoiding impacts on other ORX-relevant functions. A brief overview of the ORX system will be followed by a discussion of some of the factors that makes it particularly intriguing as a target for alcohol addiction treatment, a consideration of some potential challenges associated with targeting this system and, finally, some future directions to optimize new treatments. PMID- 29508010 TI - The "double target sign" in liver abscess. PMID- 29508011 TI - Imaging with ultrasound contrast agents: current status and future. AB - Microbubble ultrasound contrast agents (UCAs) were recently approved by the Food and Drug administration for non-cardiac imaging. The physical principles of UCAs, methods of administration, dosage, adverse effects, and imaging techniques both current and future are described. UCAs consist of microbubbles in suspension which strongly interact with the ultrasound beam and are readily detectable by ultrasound imaging systems. They are confined to the blood pool when administered intravenously, unlike iodinated and gadolinium contrast agents. UCAs have a proven safety record based on over two decades of use, during which they have been used in echocardiography in the U.S. and for non-cardiac imaging in the rest of the world. Adverse effects are less common with UCAs than CT/MR contrast agents. Compared to CT and MR, contrast-enhanced ultrasound has the advantages of real-time imaging, portability, and reduced susceptibility to metal and motion artifact. UCAs are not nephrotoxic and can be used in renal failure. High acoustic amplitudes can cause microbubbles to fragment in a manner that can result in short-term increases in capillary permeability or capillary rupture. These bioeffects can be beneficial and have been used to enhance drug delivery under appropriate conditions. Imaging with a mechanical index of < 0.4 preserves the microbubbles and is not typically associated with substantial bioeffects. Molecularly targeted ultrasound contrast agents are created by conjugating the microbubble shell with a peptide, antibody, or other ligand designed to target an endothelial biomarker associated with tumor angiogenesis or inflammation. These microbubbles then accumulate in the microvasculature at target sites where they can be imaged. Ultrasound contrast agents are a valuable addition to the diagnostic imaging toolkit. They will facilitate cross-sectional abdominal imaging in situations where contrast-enhanced CT and MR are contraindicated or impractical. PMID- 29508012 TI - CT evaluation of the renal donor and recipient. AB - Proper pre- and post-transplant diagnostic imaging work-up is fundamental in ensuring a successful outcome for renal transplantation. Despite exposure to ionizing radiation, CT has high spatial resolution and is a widely available and fast imaging technique. CT is performed routinely to delineate the anatomy of the kidney, relevant vasculature, and urinary collecting system in the living donor, to assess the iliac vessels in potential recipients prior to surgery, and to assess early and late-term post-transplant complications. The purpose of this article is to outline the optimal CT protocol and the main reportable findings for both the donor and the recipient diagnostic imaging work-up as well as to point out the main issues regarding ionizing radiation exposure and contrast medium injection in these subjects. PMID- 29508013 TI - An ecological study of the link between the risk of most frequent types of cancer in Poland and socioeconomic variables. AB - OBJECTIVES: To assess the link between the risks of most frequent cancer sites in Poland and selected socioeconomic variables that potentially affect health outcomes throughout the life course. METHODS: This is a cross-sectional ecological study. Incidence of lung, breast, and colon cancer by voivodeships in 2014 was calculated based on Polish National Cancer Registry. Socioeconomic variables in individual voivodeships were assessed based on Polish Social Cohesion Survey for 2015. Spearman's rank correlation coefficient was used to test the association of incidence rates and socioeconomic variables. The significance level was set at p < 0.05 (two-tailed tests). RESULTS: Statistically significant negative correlation exists between: (1) friend-/neighbour-based social capital and colon and breast cancer, (2) association-based social capital and lung cancer, (3) high religiousness and lung and breast cancer, and (4) income poverty and breast cancer. Statistically significant positive correlation exists between: (1) social isolation, living conditions poverty, poverty resulting from the lack of budget balance, and lung cancer; (2) low/no involvement in religious activity and lung and breast cancer. CONCLUSIONS: Our findings support public health concerns over the implication of socioeconomic environment for cancer. PMID- 29508014 TI - [Certain and controversial components of "rapid sequence induction"]. AB - Rapid sequence induction (RSI) is a specific technique for anesthesia induction, which is performed in patients with an increased risk for pulmonary aspiration (e.g. intestinal obstruction, severe injuries and cesarean section). The incidence of acute respiratory distress syndrome (ARDS) is very low but 10-30% of anesthesia-related deaths are caused by the consequences of ARDS. The classical RSI with its main components (i.e. head-up position, avoidance of positive pressure ventilation and administration of succinylcholine) was published nearly 50 years ago and has remained almost unchanged. The modified RSI consists of mask ventilation before endotracheal intubation is performed or the use of non depolarizing muscle relaxants. Succinylcholine 1.0 mg/kg or rocuronium 1.0-1.2 mg/kg should be administered to achieve excellent intubation conditions. The use of cricoid pressure was a cornerstone of RSI after its introduction in 1961; however, after controversial discussions in recent years, cricoid pressure has lost its importance. Before surgery gastric emptying with a nasogastric tube is mandatory in patients with ileus and passage or defecation disorders. PMID- 29508015 TI - [Resuscitative endovascular balloon occlusion of the aorta : Option for incompressible trunk bleeding?] AB - Hemorrhage is the single largest cause of avoidable death in trauma patients, whereby in civil emergency medicine in Europe most life-threatening hemorrhages occur in the abdomen and the pelvis. This is one reason why endovascular balloon occlusion of the aorta (EBOA), a procedure especially established in vascular surgery, is increasingly propagated for rapid bleeding control in these patients. This review article provides a comprehensive overview of the technique, indications, contraindications and complications of resuscitative endovascular balloon occlusion of the aorta (REBOA). Additionally, outcomes reported in in the currently available literature are summarized and discussed. From this practical and user-oriented consequences for future successful introduction of REBOA in the field of emergency medicine are deduced. PMID- 29508016 TI - Dual immuno-renal targeting of 7-benzylidenenaltrexone alleviates lupus nephritis via FcgammaRIIB and HO-1. AB - : Known as a selective delta1 opioid receptor (DOR1) antagonist, the 7 benzylidenenaltrexone (BNTX) is also a DOR1-independent immunosuppressant with unknown mechanisms. Here we investigated if BNTX could be beneficial for diseased MRL/lpr lupus mice. We treated mice with 0.5, 2, 5 or 10 mg/kg/day of BNTX for 2 weeks. At as low as 2 mg/kg/day, BNTX significantly improved splenomegaly and lymphadenopathy. Notably, B cell numbers, particularly autoreactive plasma cells, were preferentially reduced; moreover, BNTX enhanced surface expression of FcgammaRIIB, an immune complex (IC)-dependent apoptotic trigger of B cells. Consequently, serum autoantibody concentrations were significantly decreased, leading to diminished glomerular IC deposition and renal fibrosis, thereby improving proteinuria. Microarray and pathway analyses revealed heme oxygenase-1 (HO-1) and p38 MAPK as key mediators of BNTX-induced upregulation of FcgammaRIIB. Moreover, HO-1 expression was also induced by BNTX via p38 MAPK at renal proximal tubules to further cytoprotection. Taken together, we demonstrate that BNTX can alleviate lupus nephritis by reducing autoreactive B cells via FcgammaRIIB and by augmenting renal protection via HO-1. Accordingly, we propose a new strategy to treat lupus nephritis via such a dual immuno-renal targeting using either a single agent or combined agents to simultaneously deplete B cells and enhance renal protection. KEY MESSAGES: 7-Benzylidenenaltrexone (BNTX) alleviates lupus nephritis in diseased MRL/lpr mice. BNTX reduces autoreactive plasma cell numbers and serum autoantibody titers. BNTX upregulates FcgammaRIIB levels via p38 MAPK and HO-1 to reduce B cell numbers. Reduction of immune complex deposition and fibrosis by BNTX improves proteinuria. BNTX induces HO-1 via p38 MAPK to enhance protection of renal proximal tubules. PMID- 29508018 TI - ESSKA partners and the IOC join forces to improve children ACL treatment. PMID- 29508017 TI - Environmental Exposure of Children to Toxic Trace Elements (Hg, Cr, As) in an Urban Area of Yucatan, Mexico: Water, Blood, and Urine Levels. AB - Merida is the largest urban center in the Mexican State of Yucatan. Here domestic sewage is deposited in poorly built septic tanks and is not adequately treated. Because of contamination from such waste, water from the top 20 m of the aquifer is unsuitable for human consumption. Given this situation and because children are highly vulnerable to environmental pollution, including exposure to toxic trace elements, this study focused on evaluating the exposure of children to arsenic (As), chromium (Cr), and mercury (Hg) in water. It also evaluated the relationship between the levels of these elements in water and their concentrations in urine and blood. Among the 33 children monitored in the study, arsenic surpassed WHO limits for blood in 37% of the cases, which could result from the ingestion of poultry contaminated with organoarsenic compounds. In the case of WHO limits for Mercury, 65% of the water samples analyzed, 28% of urine samples, and 12% of blood samples exceeded them. Mercury exposure was correlated with biological sex, some lifestyle factors, and the zone in Merida in which children live. These data suggest that the levels of some toxic metals in children may be affected by water source, socioeconomic factors, and individual behavior. PMID- 29508019 TI - Let us rethink research for ACL injuries: a call for a more complex scientific approach. PMID- 29508020 TI - Venoplant Effect in the Management of the Post-operative Oedema in Plastic Surgery: Results of a Randomized and Controlled Clinical Trial. AB - BACKGROUND: Post-operative oedema and ecchymosis represent early post-operative complications, impacting negatively on the final aesthetic outcome of each surgical procedure. In particular, such complications are very frustrating for patients and-sometimes-are difficult to be managed by surgeons. Several strategies are available for managing oedema, although some side effects have been reported. A new promising compound for the management of oedema is Venoplant, and this study aims to assess its effectiveness in decreasing post operative oedema. METHODS: Patients were randomly allocated for receiving three different treatments: (1) Venoplant tablets and Venoplant gel; (2) only Venoplant tablets; and (3) not treated with Venoplant. The aesthetical outcome has been evaluated using the Global Aesthetic Improvement Scale (GAIS), compiled by both patient and clinician. The GAIS scale was administered several times: the day following the surgical procedure (T0) after 3 days (T1), after 7 days (T2), after 15 days (T3) and after 1 month (T4). RESULTS: Forty-three patients participated in the study. According to patient's evaluations, at T0 in Group 1 and in Group 2 a significant statistical difference was found compared to the control group (p < 0.001 and p < 0.05, respectively). Over time, a significant reduction in swelling and ecchymosis was reported by patients treated with Venoplant (tablets alone or in combination with gel) compared to the control group. According to the physician's assessment, during the different time points of evaluation, a significant reduction in post-operative oedema in Group 1 and in Group 2 compared to the control group was found. CONCLUSION: Venoplant represents a valid therapeutic strategy for the management of post-operative oedema, guaranteeing a good level of patient satisfaction, in the absence of common side effects which are often associated with other therapies. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29508022 TI - Attitudinal Factors and Personal Characteristics Influence Support for Shellfish Aquaculture in Rhode Island (US) Coastal Waters. AB - This study explores public interests associated with shellfish aquaculture development in coastal waters of Rhode Island (US). Specifically, we examine (1) the levels of public support for (or opposition to) shellfish aquaculture development and (2) factors driving the levels of support, using survey data and ordinal logistic regressions. Results of the analysis identify several key attitudinal factors affecting individual's support for shellfish aquaculture in Rhode Island (RI). The level of support is positively associated with attitudes related to shellfish aquaculture's benefits to the local economy and its role as a nutritional food option, and negatively influenced by attitudes related to aquaculture farms' effects on aesthetic quality and their interference with other uses. Findings highlight that support for (or opposition to) aquaculture in RI is driven more by attitudes associated with social impacts than by those associated with environmental impacts. The level of support is also affected by personal characteristics related to an individual's participation in recreational activities. For instance, bicycle riders tend to be supportive of shellfish aquaculture while respondents who participate in sailing and birding are less supportive. By identifying the broader public's interests in shellfish aquaculture, findings from this study and others like it can be used to address public concerns, incorporate public perceptions and attitudes into permitting decisions, and develop outreach targeted at specific stakeholder groups. PMID- 29508021 TI - Temporal Variability of Faecal Contamination from On-Site Sanitation Systems in the Groundwater of Northern Thailand. AB - We investigated the impacts of on-site sanitation systems to local groundwater. In this year-long study, we monitored the response of faecal contamination levels to hydroclimatological factors including rainfall and groundwater table. Concentration of faecal indicators-E. coli (ESC), Enterococcus (ENT), nitrate-in thirteen pairs of shallow and deep wells were determined every 7-14 days. All samples from shallow wells were tested positive for faecal contamination (ESC and ENT > 1 MPN/100 mL) but concentration varies. A maximum of 24,000 MPN/100 mL were recorded in some shallow wells. Water from deep wells showed lower susceptibility to contamination with only 4 and 23% of samples tested positive for ESC and ENT, respectively. Concentrations of ESC and ENT were lower too, with a maximum of 5 MPN/100 mL and 28 MPN/100 mL, respectively. Fluctuation in contamination among the wells was described by four archetypal responses to hydroclimatological forcing: (i) flushing during the onset of wet season, (ii) dilution over the course of the wet season, (iii) concentration during the dry season, and (iv) synoptic response to storms. Previous studies attempting to link the prevalence of faecal/waterborne diseases and temporal factors (e.g., dry vs wet season) have produced differing outcomes. Our study may help explain the relevant hydrological mechanisms leading to these varying observations. Presently, most communities in Thailand have access to 'improved' sanitation systems. However, due to the unsustainable implementation of these systems, the otherwise viable drinking water resources in the form of the abundant local groundwater has become a genuine health hazard. PMID- 29508023 TI - Anoplasty for Post-hemorrhoidectomy Low Anal Stenosis: A New Technique. AB - BACKGROUND: Post-hemorrhoidectomy anal stenosis though rare is very disturbing and devastating complication. Many surgical procedures have been described, but despite good results, many complications can ensue like flap necrosis, mucosal ectropion, and restenosis. OBJECTIVE: We report a new simple technique for repair of severe/moderate anal stenosis which requires no extensive flap mobilization or many sutures. PATIENTS AND INTERVENTIONS: This is a personal series of 65 patients treated over a period of 20 years. The data were prospectively recorded by the author. The essence of this simple procedure is mobilizing the anal mucosa to the dentate line via a vertical incision and mobilizing the adjacent perianal skin and subcutaneous fat to allow a completely tension-free approximation of the perianal skin and the anal mucosa which are sutured together transversely. A tension-releasing incision is made in the perianal region which is left to heal by secondary intention. RESULTS: Fifty-nine patients (90.8%) continued the 5-year follow-up, and 6 patients left the country after 2 years of follow-up. There was only one case of recurrence after 2 years, which was treated by a second anoplasty. Four patients (59-66 years old) developed transient urine retention after surgery. One patient developed partial dehiscence of the suture line which was treated conservatively. No mucosal ectropion or perianal skin necrosis was observed. Complete healing of the perianal tension-releasing wound was within 2-3 months. By the third week after surgery, all the patients discontinued use of stool softeners or laxatives and were able to defecate comfortably. CONCLUSIONS: This procedure is simple and requires little dissection and only a few sutures with minimal complications. It is suitable for low severe and moderate anal stenosis. PMID- 29508024 TI - T-cell receptor-beta V and J usage, in combination with particular HLA class I and class II alleles, correlates with cancer survival patterns. AB - Class I and class II HLA proteins, respectively, have been associated with subsets of V(D)J usage resulting from recombination of the T-cell receptor (TCR) genes. Additionally, particular HLA alleles, in combination with dominant TCR V(D)J recombinations, have been associated with several autoimmune diseases. The recovery of TCR recombination reads from tumor specimen exome files has allowed rapid and extensive assessments of V(D)J usage, likely for cancer resident T cells, across relatively large cancer datasets. The results from this approach, in this report, have permitted an extensive alignment of TCR-beta VDJ usage and HLA class I and II alleles. Results indicate the correlation of both better and worse cancer survival rates with particular TCR-beta, V and J usage-HLA allele combinations, with differences in median survival times ranging from 7 to 130 months, depending on the cancer and the specific TCR-beta V and J usage/HLA class allele combination. PMID- 29508025 TI - CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype. AB - Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8+ T-cell responses against Epstein-Barr virus (EBV) and Hepatitis B virus (HBV), and that T cells primed by CD137L-DCs more effectively lyse EBV+ and HBV+ target cells. The chemokine profile of CD137L-DCs identifies them as inflammatory DCs, and they polarize CD8+ T cells to a Tc1 phenotype. Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L DCs possessing a stronger T cell activation ability. CD137L-DCs are effective in crosspresentation. PGE2 as a maturation factor is required for enhancing migration of CD137L-DCs but does not significantly reduce their potency. This study shows that CD137L-DCs have a superior ability to activate T cells and to induce potent Tc1 responses against the cancer-causing viruses EBV and HBV which suggest CD137L-DCs as promising candidates for DC-based tumor immunotherapy. PMID- 29508026 TI - A phase II trial to evaluate the efficacy of panitumumab combined with fluorouracil-based chemotherapy for metastatic colorectal cancer: the PF trial. AB - PURPOSE: Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted. METHODS: This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data. RESULTS: Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect >= grade 3. The response rate was 10.0% (95% confidence interval 2.8 23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression. CONCLUSIONS: Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses. PMID- 29508028 TI - [Controlled cyclophotocoagulation (COCO) : What needs to be considered?] AB - The major disadvantage of modern laser cyclocoagulation is the low predictability of therapeutic success in individual cases. Unwanted damage and complications of controlled cyclophotocoagulation (COCO) are very unlikely, particularly because of the high selectivity of photoabsorption. Therefore, these interventions can and must be repeated if the intraocular pressure reduction is insufficient after the initial treatment or if the pressure increases again later. The indications and protocol for repeat interventions are the same as for the initial intervention. PMID- 29508029 TI - [Oncological emergencies in chemotherapy : Febrile neutropenia, tumor lysis syndrome, and extravasation]. AB - BACKGROUND: Uro-oncological emergencies can be caused by the tumor, treatment complications, or non-oncological diseases. This review focuses on chemotherapy associated emergencies, especially febrile neutropenia (FN), tumor lysis syndrome (TLS), and extravasations. AIM: The goal is to provide an overview on the most relevant chemotherapy-associated emergencies and treatment methods. MATERIALS AND METHODS: The ESMO (European Society of Medical Oncology), EORTC (European Organization for Research and Treatment of Cancer), and S3 guidelines were used for the preparation of this review and a PubMed search was performed for "febrile neutropenia", "extravasation", and "tumor lysis syndrome". A selection of the most relevant articles was included. RESULTS: A comprehensive medical history and examination are prerequisite for optimal treatment of chemotherapy-associated emergencies. The following aspects are of special interest: the malignant disease (tumor proliferation rate and burden); the applied medication (e. g., risk of FN, tissue damaging potential); the physical condition of the patient; age and relevant concomitant diseases (e. g., cardiovascular disease). Based on the diagnosis and the individual risk profile, therapeutic procedures are initiated. Distinct complications require an interdisciplinary treatment strategy. CONCLUSION: New treatment options such as checkpoint inhibitors complicate diagnosis and treatment of uro-oncological emergencies. Thus, improved diagnostic tools are required to draw the right conclusions in an emergency. PMID- 29508030 TI - Biotin-mediated growth and gene expression in Staphylococcus aureus is highly responsive to environmental biotin. AB - Biotin (Vitamin B7) is a critical enzyme co-factor in metabolic pathways important for bacterial survival. Biotin is obtained either from the environment or by de novo synthesis, with some bacteria capable of both. In certain species, the bifunctional protein BirA plays a key role in biotin homeostasis as it regulates expression of biotin biosynthetic enzymes in response to biotin demand and supply. Here, we compare the effect of biotin on the growth of two bacteria that possess a bifunctional BirA, namely Escherichia coli and Staphylococcus aureus. Unlike E. coli that could fulfill its biotin requirements through de novo synthesis, S. aureus showed improved growth rates in media supplemented with 10 nM biotin. S. aureus also accumulated more radiolabeled biotin from the media highlighting its ability to efficiently scavenge exogenous material. These data are consistent with S. aureus colonizing low biotin microhabitats. We also demonstrate that the S. aureus BirA protein is a transcriptional repressor of BioY, a subunit of the biotin transporter, and an operon containing yhfT and yhfS, the products of which have a putative role in fatty acid homeostasis. Increased expression of bioY is proposed to help cue S. aureus for efficient scavenging in low biotin environments. PMID- 29508031 TI - Neisseria zalophi sp. nov., isolated from oral cavity of California sea lions (Zalophus californianus). AB - Three independent strains of Neisseria sp. were isolated from the oral cavity of California sea lions (Zalophus californianus) that were admitted to The Marine Mammal Center facilities in California, USA. The strains were isolated from oral swabs by cultivation on Trypticase Soy agar with 5% sheep blood under aerobic conditions. The 16S rRNA gene sequence of these three strains shared 99% similarity, but demonstrated only 97-98% nucleotide similarity to the phylogenetically closest relatives such as N. canis, N. zoodegmatis, N. animaloris, and N. dumasiana. These three strains also shared 99% sequence similarity of their rplF, rpoB, and gyrB gene sequences. Based on the biochemical tests alone (i.e., without genetic analysis of housekeeping genes), it is difficult to discriminate this novel species from N. canis; however, it can be easily discriminated from all phylogenetically closely related species using the sequencing analysis of its housekeeping genes (e.g., rplF, rpoB, or gyrB genes). Thus, genetic testing is indispensable for accurate identification of this species in a routine laboratory practice. The species is an obligate aerobe and able to grow in Mueller-Hinton broth supplemented with 6% NaCl, but the phylogenetically closely related species (N. canis, N. zoodegmatis, N. animaloris, and N. dumasiana) were not. Based on these phenotypic and genotypic characteristics and phylogenetic data, we conclude that these new strains represent a novel species of the genus Neisseria, for which the name Neisseria zalophi sp. nov. is proposed. The type strain is CSL 7565T (= ATCC BAA2455T = DSM 102031T). PMID- 29508032 TI - Fractionation, Mobility, and Contamination Assessment of Potentially Toxic Metals in Urban Soils in Four Industrial Serbian Cities. AB - The main soil properties, concentrations of selected elements (As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn), and the chemical speciation of each element were determined in urban soil samples taken from urban parks in four Serbian cities (Belgrade, Pancevo, Obrenovac, and Smederevo) exposed to different sources of pollution. Pollution indices (PI, PIN) and factors (MF, ICF, GCF) also were evaluated. The study revealed As and Cd concentrations below the detection limit, whereas the content of Cr, Cu, Fe, Mn, Ni, Pb, and Zn at some sites exceeded the limits established by local regulations, as well as the background values, which may represent an environmental threat. Sequential extraction results show that Fe, Cr, Cu, and Ni were predominantly in the residual fraction at most sites; however, Ni from Pancevo and Smederevo also was bound to the reducible fraction. The presence of Pb at all sites and Zn in Smederevo and Belgrade was mainly associated with the reducible and residual fractions. The highest Mn content was found in the reducible fraction, followed by the acid soluble/exchangeable and residual fractions. Based on the obtained indices and factors, the overall soil status at the selected sampling sites was found to range from the warning limit to slightly polluted, whereby Smederevo had the highest risk, and Pancevo and the control site the lowest risk of contamination by toxic metals. PMID- 29508033 TI - Development of an analytical method to assess the occupational health risk of therapeutic monoclonal antibodies using LC-HRMS. AB - Monoclonal antibodies are a group of commonly used therapeutics, whose occupational health risk is still discussed controversially. The long-term low dose exposure side effects are insufficiently evaluated; hence, discussions are often based on a theoretical level or extrapolating side effects from therapeutic dosages. While some research groups recommend applying the precautionary principle for monoclonal antibodies, others consider the exposure risk too low for measures taken towards occupational health and safety. However, both groups agree that airborne monoclonal antibodies have the biggest risk potential. Therefore, we developed a peptide-based analytical method for occupational exposure monitoring of airborne monoclonal antibodies. The method will allow collecting data about the occupational exposure to monoclonal antibodies. Thus, the mean daily intake for personnel in pharmacies and the pharmaceutical industry can be determined for the first time and will help to substantiate the risk assessment by relevant data. The introduced monitoring method includes air sampling, sample preparation and detection by liquid chromatography coupled with high-resolution mass spectrometry of individual monoclonal antibodies as well as sum parameter. For method development and validation, a chimeric (rituximab), humanised (trastuzumab) and a fully humanised (daratumumab) monoclonal antibody are used. A limit of detection between 1 MUg per sample for daratumumab and 25 MUg per sample for the collective peptide is achieved. Graphical abstract Demonstration of the analytical workflow, from the release of monoclonal antibodies to the detection as single substances as well as sum parameter. PMID- 29508034 TI - Evaluation of on-line concentration coupled to liquid chromatography tandem mass spectrometry for the quantification of neonicotinoids and fipronil in surface water and tap water. AB - A study was initiated to investigate a fast and reliable method for the determination of selected systemic insecticides in water matrixes and to evaluate potential sources of bias in their analysis. Acetamiprid, clothianidin, desnitro imidacloprid, dinotefuran, fipronil, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam were amenable to analysis via on-line sample enrichment hyphenated to ultra-high-performance liquid chromatography tandem mass spectrometry. The selection of on-line solid-phase extraction parameters was dictated by a multicriterion desirability approach. A 2-mL on-line injection volume with a 1500 MUL min-1 loading flow rate met the objectives sought in terms of chromatographic requirements, extraction efficiency, sensitivity, and precision. A total analysis time of 8 min per sample was obtained with method limits of detection in the range of 0.1-5 ng L-1 for the scope of targeted analytes. Automation at the sample concentration step yielded intraday and interday precisions in the range of 1-23 and 2-26%, respectively. Factors that could affect the whole method accuracy were further evaluated in matrix-specific experiments. The impact of the initial filtration step on analyte recovery was evaluated in ultra-pure water, tap water, and surface water. Out of the nine membranes tested, glass fiber filters and polyester filters appeared as the most appropriate materials. Sample storage stability was also investigated across the three matrix types; the targeted analytes displayed suitable stability during 28 days at either 4 degrees C or - 20 degrees C, with little deviations (+/- 10%) with respect to the initial T0 concentration. Method applicability was demonstrated in a range of tap water and surface water samples from the province of Quebec, Canada. Results from the present survey indicated a predominance of thiamethoxam (< 0.5-10 and 3 61 ng L-1 in tap water and river water, respectively), clothianidin (< 0.5-6 and 2-88 ng L-1 in tap water and river water, respectively), and imidacloprid (< 0.1 1 and 0.8-38 ng L-1 in tap water and river water, respectively) among the targeted analytes. Graphical abstract ? Development of solid-phase extraction coupled on-line to UHPLC-MS/MS for the rapid screening of systemic insecticides in water. PMID- 29508035 TI - Specific and robust ion chromatographic determination of hypothiocyanite in saliva samples. AB - The enzymatic system in saliva, consisting of salivary peroxidase (SPO), hydrogen peroxide (H2O2), and thiocyanate (SCN-), produces hypothiocyanite (OSCN-) as a high effective antibacterial compound. OSCN- is of great importance for the natural non-specific antibacterial resistance in the oral cavity. However, no analytical method currently exists to selectively quantify OSCN- in saliva samples. A robust and specific analytical method for the determination of OSCN- was developed based on ion chromatography with combined UV and electrochemical detection. Calibration was achieved by calculating a derived calibration factor based on the known ratio of molar extinction coefficients of SCN- and OSCN-. Thus, the specific quantification of OSCN- in saliva samples is possible, as demonstrated here. The median value of 200 saliva samples was determined to be 0.56 mg L-1 (median), with a maximum of 3.9 mg L-1; the minimum value was below the detection limit (< 0.09 mg L-1). The recovery rate in individual saliva samples was 95 +/- 8%. PMID- 29508036 TI - The expression profile of the ubiquitin-like modifier FAT10 in immune cells suggests cell type-specific functions. AB - The TNF and IFN-gamma-inducible ubiquitin-like modifier HLA-F adjacent transcript 10 (FAT10) is most prominently expressed in immunological tissues but information regarding basal expression and inducibility of FAT10 in the different types of immune cells is still lacking. Hence, we investigated FAT10 mRNA expression in the major human and murine immune cell subsets, and FAT10 protein expression in human leukocytes. We isolated the different human leukocytes from peripheral blood and the murine immune cell subsets from spleen. The purified leukocytes were left untreated or stimulated with TNF and INF-gamma or LPS to induce FAT10 followed by quantitative real-time PCR or western blot analysis. Basal expression of FAT10 mRNA and protein was generally low but strongly up-regulated by IFN gamma and TNF in all immune cell subsets. LPS treatment induced FAT10 expression marginally in human CD8+ T cells and murine granulocytes, but it increased Fat10 expression significantly in murine regulatory T cells. Yet, in human CD8+ T cells, natural killer cells, natural killer T cells, and dendritic cells, the FAT10 mRNA was expressed without induction. Similarly, murine macrophages, monocytes, and regulatory T cells expressed Fat10 in the absence of stimulation. In summary, our findings suggest particular functions of FAT10 in these cell types. Furthermore, we observed not only a cell type-specific but also a species specific basal FAT10 expression profile. Our data will serve as a guideline for future investigations to further elucidate FAT10's role in the immune system. PMID- 29508037 TI - Correction to: Remarkable improvement in serum 25-hydroxyvitamin levels among hip fracture patients over a 12-year period: a prospective study in South-eastern Finland. AB - The presentation of Table 4 was unclear in the original publication. The article has now been corrected in this respect. PMID- 29508038 TI - Mediterranean diet, diet quality, and bone mineral content in adolescents: the HELENA study. AB - : Dietary scores, rather than individual nutrients, allow exploring associations between overall diet and bone health. The aim of the present study was to assess the associations between the Mediterranean Diet Score for Adolescents (MDS-A) and the Diet Quality Index for Adolescents (DQI-A) and bone mineral content (BMC) among Spanish adolescents. Our results do not support an association between dietary scores or indices and BMC in adolescents. INTRODUCTION: To assess the associations between the MDS-A and a DQI-A with the BMC measured with dual-energy X-ray absorptiometry. METHODS: The MDS-A and the DQI-A were calculated in 179 Spanish adolescents, based on two 24-h dietary recalls from the HELENA cross sectional study. The associations between the diet scores and the BMC outcomes [total body less head (TBLH), femoral neck (FN), lumbar spine (LS), and hip] were analyzed using logistic regression models adjusting for several confounders. RESULTS: Four hundred ninety-two models were included and only fruits and nuts and cereal and roots were found to provide significant ORs with regard to BMC. The risk of having low BMC reduced by 32% (OR 0.684; CI 0.473-0.988) for FN when following the ideal MDS-A, but this association lost significance when adjusting for lean mass and physical activity. For every 1-point increase in the cereal and root and the fruit and nut components, the risk of having low FN diminished by 56% (OR 0.442; CI 0.216-0.901) and by 67% (OR 0.332; CI 0.146-0.755), respectively. CONCLUSION: An overall dietary score or index is not associated with BMC in our adolescent Spanish sample. PMID- 29508039 TI - Bone mineral density averaged over a region of interest on femur is affected by age-related change of bone geometry. AB - : Femur expansion occurs during normal aging in both men and women. Average bone mineral density (BMD) over a region of interest (ROI) on the femur may considerably decrease with age even in healthy people, and therefore, it is inaccurate if used to monitor treatment-induced bone change. INTRODUCTION: Areal bone mineral density (BMD), averaged over a region of interest (ROI) on the femur, is widely used in the diagnosis of osteoporosis, assessment of fracture risk, and monitoring of treatment effectiveness. We studied the effect of age related change in femur geometry on average BMD. METHODS: The effect of age related bone geometric change on averaged BMD was investigated by a cross sectional study. Total 83 healthy subjects were selected for this study. For each subject, QCT of left femur was scanned using clinical scanner. For each standard volume of interest (VOI), integral/cortical/trabecular bone volume, volumetric BMD (vBMD), and bone mass were measured using QCT Pro; the corresponding areal BMD (aBMD) was projected using CTXA-Hip. Both QCT Pro and CTXA-Hip are commercial software. Correlations between bone volume/density/mass and age were studied. RESULTS: In the studied population, there was no association between body weight/BMI (body mass index) and age, correlation between normalized femoral neck width and age was 0.24 (p < 0.05). Both aBMD and integral vBMD decreased with age (after adjusted by BMI, for aBMD, r = - 0.21 to - 0.24, p <= 0.05 except at trochanter; for vBMD, r = - 0.20 to - 0.31, p < 0.05); cortical vBMD had no significant change; trabecular vBMD decreased at all VOIs except at trochanter (after adjusted by BMI, r = - 0.22 to 0.32, p <= 0.05). Integral volume showed slight increase but only significant at the trochanter after adjusted by body size, cortical volume showed insignificant decrease, and trabecular volume considerably increased with age in all VOIs (after adjusted by body size, r = 0.27-0.40, p < 0.05). Integral, cortical, and trabecular mass had no significant change in all VOIs, except that at the trochanter trabecular mass slightly increased with age (r = 0.31, p < 0.05). CONCLUSIONS: Even though there is no change in bone mass, average BMD may considerably decrease with age due to bone expansion. Comparatively, aBMD is less affected than vBMD. PMID- 29508040 TI - Learning dynamic control of body yaw orientation. AB - To investigate the role of gravitational cues in the learning of a dynamic balancing task, we placed blindfolded subjects in a device programmed with inverted pendulum dynamics about the yaw axis. Subjects used a joystick to try and maintain a stable orientation at the direction of balance during 20 100 s long trials. They pressed a trigger button on the joystick to indicate whenever they felt at the direction of balance. Three groups of ten subjects each participated. One group balanced with their body and the yaw axis vertical, and thus did not have gravitational cues to help them to determine their angular position. They showed minimal learning, inaccurate indications of the direction of balance, and a characteristic pattern of positional drifting away from the balance point. A second group balanced with the yaw axis pitched 45 degrees from the gravitational vertical and had gravity relevant position cues. The third group balanced with their yaw axis horizontal where they had gravity-dependent cues about body position in yaw. Groups 2 and 3 showed better initial balancing performance and more learning across trials than Group 1. These results indicate that in the absence of vision, the integration of transient semicircular canal and somatosensory signals about angular acceleration is insufficient for determining angular position during dynamic balancing; direct position-dependent gravity cues are necessary. PMID- 29508041 TI - Pituitary height at magnetic resonance imaging in pediatric isolated growth hormone deficiency. AB - BACKGROUND: Magnetic resonance imaging (MRI) is used for neuroradiologic evaluation of patients with idiopathic growth hormone deficiency (IGHD). OBJECTIVES: To compare pituitary height and morphology at MRI between patients with IGHD and controls. MATERIALS AND METHODS: This retrospective study was conducted in pediatric patients, 3 years-15 years old, who had had brain MRI with non-contrast-enhanced midsagittal T1-weighted images. These images were measured for pituitary height and morphology of the pituitary gland including shape, stalk and posterior pituitary bright spot was evaluated. RESULTS: One hundred and nineteen patients were included, with 49 and 70 patients assigned to the study and control groups, respectively. Mean pituitary height was significantly less in the IGHD group than in the control group (3.81 mm+/-1.38 vs. 4.92 mm+/-1.13, retrospectively; P<0.001). Subgroup analysis revealed a significant difference in the pituitary height between groups in the prepubertal (8-10 years) and pubertal (11-13 years) periods (P=0.039 and P=0.006, respectively) and a trend toward significance in the postpubertal period (P=0.053). There was a significant difference in pituitary shape between IGHD and controls when combining grades III, IV and V (P=0.007). Other abnormal MRI findings of the pituitary stalk and posterior bright spot were significantly more often observed in the IGHD group (P<0.05). CONCLUSION: Pituitary height was significantly smaller in patients with IGHD than in controls during prepuberty and puberty. Abnormal concave superior contour, hypoplastic stalk and absent/ectopic posterior bright spot were observed significantly more often among patients with IGHD. PMID- 29508042 TI - Treatment of stress urinary incontinence with a mobile app. PMID- 29508043 TI - A generic health-related quality of life instrument for assessing pelvic organ prolapse surgery: correlation with condition-specific outcome measures. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate the use of a generic and globally accessible instrument for assessing health-related quality of life (HR-QoL) in pelvic organ prolapse (POP) surgery. METHODS: In a prospective multicenter setting, 207 women underwent surgery for apical prolapse [stage >=2, Pelvic Organ Prolapse Quantificcation (POP-Q) system] with or without anterior wall defect. Demographic and surgical characteristics were collected before surgery. Results of the 15-dimensional (15D) instrument and condition specific pelvic floor symptoms as assessed using the Pelvic Floor Distress Inventory questionnaire (PFDI-20), including its subscales Pelvic Organ Prolapse Distress Inventory-6 (POPDI-6), Colorectal-Anal Distress Inventory-8 (CRADI-8), and Urinary Distress Inventory-6 (UDI-6), were assessed preoperatively and 2 months and 1 year after surgery. RESULTS: HR-QoL as estimated by 15D was improved 1 year after surgery (p < 0.001). Prolapse-related 15D profile-index measures (excretion, discomfort, sexual activity, distress, and mobility) were significantly improved after surgery (p < 0.05-0.001). Significant inverse associations were detected between increased 15D scores and a decrease in PFDI-20 and subscale scores (p < 0.001), indicating improvements on both instruments. CONCLUSIONS: Generic HR-QoL as estimated by 15D improved significantly after apical POP surgery and correlated with improvements of condition-specific outcome measures. These results suggest that a comprehensive evaluation of global HR-QoL is valid in assessing pelvic reconstructive surgery and may provide novel and important insights into previously understudied areas, such as cost-utility and cost-effectiveness analysis after urogynecological surgery. PMID- 29508044 TI - Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation, overactivity, and nociception in a chemically induced interstitial cystitis-like rat model. AB - INTRODUCTION AND HYPOTHESIS: We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model. METHODS: Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl + MSCs) or phosphate-buffered saline (HCl + PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS). RESULTS: The number of mast cells and expression of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2 4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-alpha, TGF-beta, and collagen fibers were observed in HCl + PBS compared with sham + PBS, whereas these changes were significantly decreased in HCl + MSCs compared with HCl + PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl + PBS but not in HCl + MSCs compared with sham + PBS. CONCLUSIONS: The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis. PMID- 29508045 TI - Relationship of degree of uterine prolapse between pelvic examination in lithotomy position with cervical traction and pelvic examination in standing position. AB - INTRODUCTION AND HYPOTHESIS: The Pelvic Organ Prolapse Quantification (POP-Q) assessment is a standardized tool for evaluating pelvic organ prolapse (POP). However, intraoperative evaluation reveals greater apical prolapse than do POP-Q scores. There is a need to implement a method for performing POP-Q at the outpatient clinic that reveals maximal prolapse and causes the least pain. This study was performed to compare the degree of uterine prolapse between POP-Q with cervical traction and POP-Q in the standing position. Secondary objectives were to compare pain and acceptability scores between the two examinations. METHODS: Women with uterine prolapse stage I or II by routine examination were invited to participate. Comparison of degree of uterine prolapse, POP-Q stages, acceptability score, and pain score between the two types of examinations were undertaken. RESULTS: Seventy-eight participants were recruited. The median point C in routine POP-Q examination was -5 (-9 to +1), -0.5 (-3 to +4) with cervical traction, and -4 (-7 to +2) in the standing position. When examined with cervical traction, 61.5% women were upstaged by one and 9.0% by two compared with examination in the standing position; 39.7% reported visual analog scale (VAS) pain scores of >=5 under examination with traction, but only 2.6% reported that level of pain in the standing position. There was no significant difference in acceptability scores between groups. CONCLUSION: In an outpatient clinic setting, POP-Q examination with cervical traction revealed maximal prolapse at an acceptable level of pain. Accordingly, this method is recommended for POP-Q examination. PMID- 29508046 TI - Effects of two nonpharmacological treatments on the sleep quality of women with nocturia: a randomized controlled clinical trial. AB - INTRODUCTION AND HYPOTHESIS: The objective was to check the effects of two nonpharmacological treatments on the sleep quality of women with nocturia. METHODS: A randomized controlled clinical trial in which 40 women with nocturia were randomized into two groups; one was subjected to tibial nerve stimulation (GTNS) and the other received pelvic floor muscle training associated with behavioral therapy (GPFMT). Both groups were followed for 12 weeks, with one session/week; evaluated by the Pittsburgh Sleep Quality Index (PSQI), King's Heath Questionnaire (KHQ), and Epworth Sleepiness Scale (ESS). The Wilcoxon test was used to compare intra-group data and the Mann-Whitney test for intergroup results. Effect size and confidence interval were calculated, and the level of significance was set at 5%. RESULTS: Both groups showed improvements in quality of sleep, observed by the PSQI total score (GTNS from 9 +/- 0.88 to 7 +/- 0.94, p = 0.002; GPFMT from 8 +/- 0.80 to 5 +/- 0.94, p < 0.001) and the sleep/energy domain of the KHQ (GTNS from 66.66 +/- 9.03 to 16.66 +/- 7.20, p = 0.002; GPFMT from 66.66 +/- 9.30 to 0.00 +/- 7.26, p = 0.001). CONCLUSIONS: Both nonpharmacological treatments proposed (TNS or PFMT) were equally able to improve quality of sleep of women with nocturia. PMID- 29508047 TI - Clinical and ultrasonographic evaluation of the pelvic floor in primiparous women: a cross-sectional study. AB - INTRODUCTION AND HYPOTHESIS: We used clinical examination and transperineal 3D/4D ultrasound (US) to evaluate pelvic floor muscles (PFM) after different delivery modes. METHODS: Women were surveyed using validated questionnaires. PFM were evaluated and classified according to the Modified Oxford Scale following 3D/4D transperineal US. For statistical analysis, Kruskal-Wallis, Mann-Whitney, chi square, and Fisher exact tests were used. RESULTS: Fifty-three women were evaluated: 32 with previous vaginal delivery (VD) and 21 with cesarean section (CS) (8 nonelective and 13 elective). No significant difference among groups was observed regarding urinary incontinence (UI) after delivery (p = 0.39), loss of muscle strength referred by the patient (p = 0.48), or evaluated through digital examination (p = 0.87). No patient with elective CS had avulsion, with difference between VD and elective CS (p = 0.008). US evaluation identified no differences in bladder-neck elevation (p = 0.69) or descent (p = 0.65) , and no difference in genital hiatus size (p = 0.35), levator ani thickness (p = 0.35 -0.44), or presence of major or minor levator ani avulsion (p = 0.10). CONCLUSIONS: We evaluated primiparous women within 12 to 24 months of delivery and found that VD was associated with PFM avulsion. There was no difference among VD and nonelective or elective CS in symptomatology or other anatomic alterations evaluated through 3D/4D transperineal US. PMID- 29508049 TI - Quantitation of hypoechoic lesions for the prediction and Gleason grading of prostate cancer: a prospective study. AB - PURPOSE: Hypoechoic lesions are not included as indicators for prostate biopsy. To discriminate the features of hypoechoic lesions, we investigated the ultrasonographic characteristics of hypoechoic lesions using numerical analysis in image. In addition, we evaluated previously suggested subjective parameters on hypoechoic lesion. METHODS: We performed one-core targeted biopsy (TBx) for each hypoechoic lesion in up to two lesions in each patient before the 12-core systemic biopsy was obtained between July 2015 and May 2016. Image analysis data were analyzed using grayscale values and Hounsfield units (HU) to measure heterogeneity. Subjective evaluation of hypoechoic lesions including hypoechoicity, irregularity, vascularity, and microcalcification was also validated. RESULTS: Of 157 patients (median age = 67.1 years, median prostate specific antigen = 6.21 ng/mL) included in the study, 77 (49.0%) were diagnosed with prostate cancer (PCa), and 39 (17.0%) diagnoses were confirmed by the results of targeted cores. The existence of hypoechoic lesions was not a final predictor for PCa detection. In multivariate analysis using a combination of clinical and quantitative image analyses, the grayscale value was identified as a significant predictive factor for the presence of PCa and high-grade disease (Gleason score >= 7) on target lesions. The combination of clinical and image variables had the highest area under the curve (0.890) for detecting PCa in TBx. CONCLUSIONS: The proposed method for the quantitation of hypoechoic lesions using grayscale images and HU is simple. Combined with the current clinical approaches, quantitative scoring of lesions can be useful for detecting PCa and making more precise diagnoses. PMID- 29508048 TI - Poor reproducibility of PIRADS score in two multiparametric MRIs before biopsy in men with elevated PSA. AB - PURPOSE: Since January 2015, all men referred to urologists in Norway due to elevated PSA or other suspicion of prostate cancer underwent multiparametric MRI (mpMRI) before prostate biopsy. At our hospital, patients and the initial MRI were assessed by an urologist and if deemed necessary, patients were referred to another institution for MR/US fusion biopsies. Before MR/US biopsy, patients underwent a second mpMRI. Since we noticed disagreement of these two mpMRIs before biopsy, we retrospectively assessed the level of agreement between the two mpMRIs from the two institutions. METHODS: During the first 6 months of 2015, 292 patients were referred to our outpatient clinic. We referred 126 patients of these to the other institution for MR/US fusion biopsy. The 2 mpMRIs were performed within 4 weeks. We analyzed MR reports and schematics for number of lesions and highest PIRADS score per side of the prostate and histological result of the biopsies. Bland-Altman's plot was used to compare the level of agreement between the two mpMRIs of the same patient before biopsy. RESULTS: There was a poor level of agreement between the two mpMRIs and a statistically significant difference in PIRADS scores. Regression analysis showed that there was no proportional or systematic bias. CONCLUSION: In unselected patients with elevated PSA, there seems to be a significant variation of mpMRI results across institutions. The PIRADS scoring system needs to be validated with regards to MR equipment, mpMRI protocols and inter-reader variability of radiologists. PMID- 29508050 TI - Loop-ileostomy reversal-patient-related characteristics influencing time to closure. AB - PURPOSE: To identify factors associated with timing of stoma reversal after rectal cancer surgery in a large Swedish register-based cohort. METHODS: Three thousand five hundred sixty-four patients with rectal cancer who received a protective stoma during surgery in 2007-2013 were identified in the Swedish colorectal cancer register. Time to stoma reversal was evaluated over a follow-up period of one and a half years. Factors associated with timing of stoma reversal were analysed using Cox regression analysis. Reversal within 9 months (12 months if adjuvant chemotherapy) was considered latest expected time to closure. RESULTS: Stoma reversal was performed in 2954 (82.9%) patients during follow-up. Patients with post-secondary education had an increased chance for early stoma reversal (HR 1.13; 95% CI 1.02-1.25). Postoperative complications (0.67; 0.62 0.73), adjuvant chemotherapy (0.63; 0.57-0.69), more advanced cancer stage (stage III 0.74; 0.66-0.83 and stage IV 0.38; 0.32-0.46) and higher ASA score (0.80; 0.71-0.90 for ASA 3-4) were associated with longer time to reversal. Two thousand four hundred thirty-seven (68.4%) patients had stoma reversal within latest expected time to closure. Factors associated to decreased chance of timely reversal were more advanced cancer stage (stage III 0.64; 0.50-0.81 and stage IV 0.19; 0.13-0.27), postoperative complications (0.50; 0.42-0.59) and higher ASA score (0.77; 0.61-0.96 for ASA 3-4). CONCLUSIONS: Patients with a high level of education had a higher chance of timely reversal but medical factors had a stronger association to time to reversal. Patients with advanced rectal cancer are at high risk for non-reversal and should be considered for permanent stoma. PMID- 29508051 TI - Effect of culture condition on the growth, biochemical composition and EPA production of alkaliphilic Nitzschia plea isolated in the Southeast of China. AB - To overcome the contamination in open pond, microalgal strain selection should focus on species with tolerability to extreme environments. In this study, a native alkaliphilic algae, diatom Nitzschia plea was obtained in Southeast of China, which could tolerate high concentration of NaHCO3 (0.15 mol/L) and high pH (> 10). The effects of initial pH, light intensity and temperature on cell growth, biochemical composition and fatty acid profile of N. plea were investigated. Results indicated its specific growth rate could reach 1.2 day-1, lipid content was in the range 14.6-30.2% of dry weight, eicosapntemacnioc acid (EPA, C20:5) accounted for around 15% of total fatty acids. Alkalic condition benefited for both cell growth and EPA synthesis. Appropriately increasing light intensity and temperature could improve cell growth rate and lipid synthesis, although the proportion of EPA in total fatty acids decreased slightly. The optimal culture condition (pH 9.00, temperature 35.0 degrees C, light intensity 158.6 umol/m2s) was suggested for maximum yield of EPA based on the response surface model. The overall biomass productivity and EPA productivity were 0.301 g/L/day and 7.43 mg/L/day, respectively. In conclusion, alkalic environment was helpful for the steady operation of open pond cultivation of N. plea with the characteristics of fast growth rate and high EPA content, which exhibited its commercial value. PMID- 29508052 TI - Bioclimatic conditions of the winter months in Western Kazakhstan and their dynamics in relation to climate change. AB - The territory of West Kazakhstan is an intensively developing region. The main oil and gas fields are concentrated there. In addition, this region is well-known as a region of nomad cattle breeding. Both of industry and agriculture demand a lot of employees, working in the open air in wintertime. Severe winter conditions, primary very low temperatures, and strong winds characterize the region. In this work, we calculated and analyzed the spatial and temporal distributions of effective temperatures in the region and their dynamics due to the global warming in the last decades. To calculate the equivalent temperature (WCET) was used the method of OFCM 2003. Nowadays, it is known as a common method for similar studies. It was shown that in the observed region, WCET is significantly lower than the ambient temperature. Repeatability of WCET, corresponding to "increasing risk", "high risk" is high in the main part of the region. Global warming in the region results in returning extremely high temperatures of the air, decreasing repeatability of the average gradation of WCET approximately on 4%, but there is no any visible changing repeatability of extreme WCET. Obtained results can be used for planning any construction work in the open air and agriculture branches. PMID- 29508053 TI - [Arthur Vick Prize 2017 of the German Society of Orthopaedic Rheumatology]. AB - The German Society of Orthopaedic Rheumatology (DGORh) honored Prof. Dr. med. Veit Krenn (MVZ-ZHZMD-Trier) with the Arthur Vick Prize 2017. With this award, scientific results with high impact on the diagnosis, therapy and pathogenetic understanding of rheumatic diseases are honored. In cooperation with pathologists and colleagues from various clinical disciplines Prof. Dr. med. Veit Krenn developed several histopathologic scoring systems which contribute to the diagnosis and pathogenetic understanding of degenerative and rheumatic diseases. These scores include the synovitis score, the meniscal degeneration score, the classification of periprosthetic tissues (SLIM classification), the arthrofibrosis score, the particle score and the CD15 focus score. Of highest relevance for orthopedic rheumatology is the synovitis score which is a semiquantitative score for evaluating immunological and inflammatory changes of synovitis in a graded manner. Based on this score, it is possible to divide results into low-grade synovitis and high-grade synovitis: a synovitis score of 1 4 is called low-grade synovitis and occurs for example in association with osteoarthritis (OA), post-trauma, with meniscal lesions and hemochromatosis. A synovitis score of 5-9 is called high-grade synovitis, e.g. rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection and reactive arthritis as well as peripheral arthritis with Bechterew's disease (sensitivity 61.7%, specificity 96.1%). The first publication (2002) and an associated subsequent publication (2006) of the synovitis score has led to national and international acceptance of this score as the standard for histopathological assessment of synovitis. The synovitis score provides a diagnostic, standardized and reproducible histopathological evaluation method for joint diseases, particularly when this score is applied in the context with the joint pathology algorithm. PMID- 29508054 TI - Sleep quality moderates the association between physical activity frequency and feelings of energy and fatigue in adolescents. AB - Physical activity (PA) can improve sleep quality, low energy, and fatigue. Though poor sleep quality may induce feelings of low energy and fatigue, the potential moderating effect of sleep quality on associations between PA and feelings of energy and fatigue among adolescents is unknown. Thus, this study examined the moderating effect of sleep quality on associations between PA frequency and feelings of energy and fatigue among adolescents in Ireland. Adolescents (N = 481; 281 males, 200 females) aged 15.1 +/- 1.7 years self-reported PA frequency, feelings of energy and fatigue, and sleep quality (September to December 2015). Two-way ANCOVAs examined variation in feelings of energy and fatigue according to the interaction of PA and sleep quality. Standardized mean difference (d) quantified the magnitude of differences. Poor sleepers with low PA reported greater feelings of fatigue compared to normal sleepers with low PA (d = 1.02; 95% CI 0.60, 1.44), and poor sleepers with moderate PA reported greater feelings of fatigue compared to normal sleepers with moderate PA (d = 0.50; 0.17, 0.82). Poor sleepers with low PA reported greater feelings of fatigue compared to both poor sleepers with moderate PA (d = 0.44; 0.05, 0.83) and poor sleepers with high PA (d = 0.87; 0.46, 1.28). Poor sleepers with moderate PA reported greater feelings of fatigue compared to poor sleepers with high PA (d = 0.52; 0.14, 0.91). Poor sleep did not moderate the association between PA and feelings of energy. Sleep quality moderates the association between PA frequency and feelings of fatigue. Fatigue symptoms improve as PA frequency increases among adolescents with poor sleep quality. PMID- 29508055 TI - Endoscopic visualization to the anterior surface of the malleus and tensor tympani tendon in congenital cholesteatoma. AB - PURPOSE: This study evaluated the feasibility of endoscopy in exposing the anterior surface of the malleus and tensor tympani tendon (ASMT) in children with congenital cholesteatoma (CC), and investigated the outcomes of hearing, postoperative complications, and residual or recurrent disease in endoscopic surgical approach cases. METHODS: A retrospective case review was performed in one tertiary referral center. Twelve children with CC involving the ASMT were recruited, and their medical records were reviewed. All patients underwent either total endoscopic surgery (n = 3) or endoscope-assisted surgery (n = 9), and Potsic staging was adopted to classify CC according to its severity: stage I (n = 8), stage II (n = 2), and stage III (n = 2). The mean follow-up period was 15.5 +/- 2.8 months. The visibility of the ASMT by endoscope assistance, audiological results, surgical and postoperative complications, and recidivism of CC were analyzed. RESULTS: The ASMT was well visualized by endoscope assistance in all cases. No patient showed hearing deterioration at 3 months after surgery, and none experienced residual or recurrent disease during the follow-up period. Postoperative complications were not observed. CONCLUSIONS: Total endoscopic or endoscope-assisted surgery could help surgeons directly visualize the ASMT in children, with negligible risks of hearing deterioration, postoperative complications, and recurrent disease. Our study might suggest that endoscopic ear surgery should be considered in patients with CC in the ASMT. PMID- 29508056 TI - Inspiratory muscle weakness, diaphragm immobility and diaphragm atrophy after neck dissection. AB - BACKGROUND: Inspiratory strength after a neck dissection has not been evaluated, and diaphragm function has not been adequately evaluated. OBJECTIVE: Evaluate diaphragm mobility and inspiratory strength after neck dissection. METHODS: Prospective data collection of a consecutive series of adult patients submitted to neck dissection for head and neck cancer treatment, in a tertiary referral cancer center, from January to September 2014, with 30 days of follow-up. A total of 43 were studied (recruited 56; excluded 13). MAIN OUTCOME MEASURES: Determine diaphragm mobility and inspiratory muscle strength after neck dissection, using diaphragm ultrasound and by measuring maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (SNIP). RESULTS: Thirty patients underwent unilateral neck dissection, and thirteen patients underwent bilateral neck dissection. Diaphragm immobility occurred in 8.9% of diaphragms at risk. For the entire cohort, inspiratory strength decreased immediately after the dissection but returned to preoperative values after 1 month. Except for those with diaphragm immobility, diaphragm mobility remained unchanged after the dissection. One month after the dissection, the diaphragm thickness decreased, indicating diaphragm atrophy. CONCLUSIONS: Immediately after a neck dissection, just a few patients showed diaphragmatic immobility, and there was a transient decrease in inspiratory strength in all individuals. Such findings can increase the risk of postoperative complications in patients with previous lung disease. PMID- 29508057 TI - Late-onset hydrocephalus in a child with Joubert syndrome: a case report. AB - INTRODUCTION: The ciliopathy "Joubert syndrome" was first described in 1969 by Dr. Marie Joubert and most subtypes follow an autosomal recessive inheritance. The complex disorder shows typical clinical features, such as hyperventilation, abnormal eye movements, and retardation. A pathognomonic midbrain-hindbrain malformation, the molar tooth sign, can be found on magnetic resonance imaging of the brainstem. There are a little more than 200 reports of Joubert syndrome in the literature. CASE PRESENTATION: We report a case of a 9-year-old boy who developed a progressive hydrocephalus starting from the age of 4. He underwent VP shunt placement at 8 years, which relieved hydrocephalus-related clinical symptoms and put development of the macrocephalus to a halt. CONCLUSION: Neonatal hydrocephalus due to the altered anatomy of the posterior fossa has been reported earlier, but to our knowledge, this is the first case of a delayed onset of hydrocephalus in a patient with Joubert syndrome. PMID- 29508058 TI - Fatal Abeta cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years. PMID- 29508059 TI - Can groundwater sampling techniques used in monitoring wells influence methane concentrations and isotopes? AB - Methane concentrations and isotopic composition in groundwater are the focus of a growing number of studies. However, concerns are often expressed regarding the integrity of samples, as methane is very volatile and may partially exsolve during sample lifting in the well and transfer to sampling containers. While issues concerning bottle-filling techniques have already been documented, this paper documents a comparison of methane concentration and isotopic composition obtained with three devices commonly used to retrieve water samples from dedicated observation wells. This work lies within the framework of a larger project carried out in the Saint-Edouard area (southern Quebec, Canada), whose objective was to assess the risk to shallow groundwater quality related to potential shale gas exploitation. The selected sampling devices, which were tested on ten wells during three sampling campaigns, consist of an impeller pump, a bladder pump, and disposable sampling bags (HydraSleeve). The sampling bags were used both before and after pumping, to verify the appropriateness of a no purge approach, compared to the low-flow approach involving pumping until stabilization of field physicochemical parameters. Results show that methane concentrations obtained with the selected sampling techniques are usually similar and that there is no systematic bias related to a specific technique. Nonetheless, concentrations can sometimes vary quite significantly (up to 3.5 times) for a given well and sampling event. Methane isotopic composition obtained with all sampling techniques is very similar, except in some cases where sampling bags were used before pumping (no-purge approach), in wells where multiple groundwater sources enter the borehole. PMID- 29508060 TI - Taurine protects noradrenergic locus coeruleus neurons in a mouse Parkinson's disease model by inhibiting microglial M1 polarization. AB - Beyond nigrostriatal dopaminergic system, the noradrenergic locus coeruleus (LC/NE) neurons are also degenerated in patients with Parkinson's disease (PD), the second most common neurodegenerative disorder. We previously reported that microglia-mediated neuroinflammation contributes to LC/NE neurodegeneration. The purpose of this study is aimed to test whether taurine, an endogenous amino acid, could be able to protect LC/NE neurons through inhibition of microglial activation using paraquat and maneb-induced mouse PD model. Taurine (150 mg/kg) was administrated (i.p) to mice 30 min prior to paraquat (10 mg/kg) and maneb (30 mg/kg) intoxication for consecutive 6 weeks (twice per week). The results clearly demonstrated that paraquat and maneb co-exposure resulted in loss of tyrosine hydroxylase-positive neurons in the LC in mice, which was significantly ameliorated by taurine. Mechanistically, inhibition of microglia-mediated neuroinflammation contributed to taurine-afforded neuroprotection. Taurine attenuated paraquat and maneb-induced microglial activation and M1 polarization as well as release of proinflammatory cytokines in brainstem of mice. Taurine also abrogated microglial NADPH oxidase activation and oxidative damage in paraquat and maneb-treated mice. Furthermore, inhibition of nuclear factor-kappaB (NF-kappaB) but not signal transducers and activators of transcription 1/3 (STAT1/3) signaling pathway participated in taurine-inhibited microglial activation. Collectively, taurine exerted LC/NE neuroprotection against microglia mediated neurotoxicity. The robust neuroprotective effects of taurine suggest that taurine may be a promising candidate for potential therapy for patients suffering from PD. PMID- 29508062 TI - Analysis of fumarate-sensitive proteins and sites by exploiting residue interaction networks. AB - Fumarate adduction to cysteines has been implicated in the pathogenesis of several disorders. Its role, however, still remains elusive, and the need of predictive methods has not yet been met. The reactivity of cysteines found in fumarate-sensitive proteins was predicted when the collected data for eight network-type features were analyzed using classification models. Therefore, methods for evaluating the likelihood of a cysteine site to be modified by fumarate could be developed by combining concepts of network theory and machine learning. PMID- 29508061 TI - New aspects of antiproliferative activity of 4-hydroxybenzyl isothiocyanate, a natural H2S-donor. AB - The effect of 4-hydroxybenzyl isothiocyanate (HBITC), a natural H2S-donor from white mustard seeds (Sinapis alba), on the proliferation of human neuroblastoma (SH-SY5Y) and glioblastoma (U87MG) cells was studied and some aspects of the mechanism of its activity were suggested. The inhibition of both SH-SY5Y and U87MG cell proliferation was associated with an increase in the thiosulfate level, the number of cells with the inactive form of Bcl-2 protein, and with a decrease of mitochondrial membrane potential. Interestingly, HBITC results in downregulation of p53 protein and upregulation of p21 protein levels in SH-SY5Y cells. In the presence of elevated levels of H2S and thiosulfate, the sulfhydryl groups of p53 protein as well as Bcl-2 protein could be modified via HBITC induced S-sulfuration or by oxidative stress. It seems that the induction of p21 protein level is mediated in SH-SY5Y cells by p53-independent mechanisms. In addition, HBITC-treatment caused downregulation of the level of mitochondrial rhodanese and 3-mercaptopyruvate sulfurtransferase, and consequently increased the level of the reactive oxygen species in SH-SY5Y cells. PMID- 29508063 TI - Labor estimation by informational objective assessment (LEIOA) for preterm delivery prediction. AB - PURPOSE: To introduce LEIOA, a new screening method to forecast which patients admitted to the hospital because of suspected threatened premature delivery will give birth in < 7 days, so that it can be used to assist in the prognosis and treatment jointly with other clinical tools. METHODS: From 2010 to 2013, 286 tocographies from women with gestational ages comprehended between 24 and 37 weeks were collected and studied. Then, we developed a new predictive model based on uterine contractions which combine the Generalized Hurst Exponent and the Approximate Entropy by logistic regression (LEIOA model). We compared it with a model using exclusively obstetric variables, and afterwards, we joined both to evaluate the gain. Finally, a cross validation was performed. RESULTS: The combination of LEIOA with the medical model resulted in an increase (in average) of predictive values of 12% with respect to the medical model alone, giving a sensitivity of 0.937, a specificity of 0.747, a positive predictive value of 0.907 and a negative predictive value of 0.819. Besides, adding LEIOA reduced the percentage of incorrectly classified cases by the medical model by almost 50%. CONCLUSIONS: Due to the significant increase in predictive parameters and the reduction of incorrectly classified cases when LEIOA was combined with the medical variables, we conclude that it could be a very useful tool to improve the estimation of the immediacy of preterm delivery. PMID- 29508064 TI - Single nucleotide polymorphisms within Adducin 3 and Adducin 3 antisense RNA1 genes are associated with biliary atresia in Thai infants. AB - BACKGROUND: A genome-wide association study in East Asians suggested a genetic association between biliary atresia (BA) and a cluster of variants within the Adducin 3 (ADD3) and ADD3 antisense RNA1 (ADD3-AS1) genes. Another study in Thai neonates reported an association between BA and rs17095355. To validate those findings, this study aimed to analyze the BA association with single nucleotide polymorphisms (SNPs) and the additive influence of ADD3 and ADD3-AS1 in Thai neonates. METHODS: DNAs from 56 BA cases and 166 controls were genotyped for rs2501577, rs11194981, rs12268910 (ADD3) and rs17095355 (ADD3-AS1), using TaqMan PCR. Genotype distributions were compared between the groups, and SNP-SNP interactions were analyzed by combination of allelotypes. RESULTS: The risk allele frequencies of rs2501577, rs11194981, and rs17095355 in the BA group were significantly higher than in the controls. Univariate analysis showed that recessive variants in the three SNPs were associated with BA risk at ORs of 1.81 (95% CI 1.32-2.50), 1.58 (95% CI 1.14-2.20) and 1.92 (95% CI 1.39-2.66), respectively. SNP-SNP interaction analysis showed that the SNP combination of the two genes rs17095355 and rs2501577 provided an additive increase in BA risk. CONCLUSION: ADD3 and ADD3-AS1 variants increased susceptibility to BA, suggesting that these genes may play an additive role in the pathogenesis of the disease. In addition, these interactions may give a clue to the overexpression of the ADD3 protein in the liver of BA patients. PMID- 29508065 TI - Nicorandil increased the cerebral blood flow via nitric oxide pathway and ATP sensitive potassium channel opening in mice. AB - PURPOSE: Nicorandil has dual properties and acts as a nitric oxide donor and an ATP-sensitive potassium (KATP) channel opener. Considering its pharmacological profile, nicorandil might exert protective effects on the brain as well as on the heart. The purpose of this study was to directly evaluate the effect of nicorandil on cerebral blood flow (CBF) in mice using a transcranial Doppler method. METHODS: Under general anesthesia, the nicorandil groups received a single-bolus intraperitoneal injection of the respective doses of nicorandil (1, 5, or 10 mg/kg), while the control group received vehicle only. CBF was measured using a transcranial Doppler flowmeter. NG-nitro-L-arginine methyl ester and glibenclamide were used to elucidate the underlying mechanisms. RESULTS: A single bolus injection of 1 mg/kg of nicorandil increased the CBF (11.6 +/- 3.6 vs. 0.5 +/- 0.7%, p < 0.001) without affecting the heart rate and blood pressure. On the contrary, 5 and 10 mg/kg of nicorandil significantly decreased the cerebral blood flow by decreasing the mean blood pressure below the cerebral autoregulation range. The positive effect of 1 mg/kg of nicorandil on the cerebral blood flow was inhibited by co-administration of either NG-nitro-L-arginine methyl ester or glibenclamide. CONCLUSIONS: A clinical dose of nicorandil increases CBF without affecting systemic hemodynamics. The positive effect of nicorandil on CBF is most likely caused via both the nitric oxide pathway and KATP channel opening. PMID- 29508066 TI - Local infiltration analgesia combined with a standardized multimodal approach including an adductor canal block in total knee arthroplasty: a prospective randomized, placebo-controlled, double-blinded clinical trial. AB - PURPOSE: Total knee arthroplasty (TKA) is associated with moderate to severe postoperative pain. This study evaluates the technique of local infiltration analgesia (LIA), by comparing it to saline injections in addition to a standardized multimodal regimen including an adductor canal block. METHODS: Between September 2015 and March 2016, forty patients aged 18 years and older, ASA I-III, undergoing primary unilateral cemented TKA under spinal anesthesia were randomized to receive either LIA (LIA group) or normal saline (sham LIA group). Morphine consumption during the first 24 postoperative hours, time to first IV morphine dose request, pain intensity at rest and passive knee flexion, complication rates, patient satisfaction and duration of hospitalization were documented (Clinicaltrials.gov, identifier: NCT03206554). RESULTS: Compared with the sham LIA group, the LIA group showed statistically significant lower morphine consumption at all times (6, 12, 18, 24 h-P value: 0.035, 0.008, 0.015 and 0.003, respectively). Time to first IV morphine dose request did not differ significantly between groups (P = 0.902). The intergroup difference in NRS pain scores was statistically significant, with the LIA group showing lower resting and dynamic pain scores in all instances and additionally higher patient satisfaction. The groups did not differ in terms of complication rates and duration of hospitalization. CONCLUSIONS: Performing LIA in addition to a standardized multimodal analgesia regimen results in superior pain control, demonstrated as reduced opioid needs and lower resting and dynamic pain intensity scores on the first postoperative day after TKA. Further studies are needed to establish an LIA protocol that could maximize postoperative pain control. PMID- 29508067 TI - Three-dimensional reconstruction of the intercalated disc including the intercellular junctions by applying volume scanning electron microscopy. AB - The intercalated disc (ID) contains different kinds of intercellular junctions: gap junctions (GJs), desmosomes and areae compositae, essential for adhesion and communication between adjacent cardiomyocytes. The junctions can be identified based on their morphology when imaged using transmission electron microscopy (TEM), however, only with very limited information in the z-dimension. The application of volume EM techniques can give insight into the three-dimensional (3-D) organization of complex biological structures. In this study, we generated 3-D datasets using serial block-face scanning electron microscopy (SBF-SEM) and focused ion beam SEM (FIB-SEM), the latter resulting in datasets with 5 nm isotropic voxels. We visualized cardiomyocytes in murine ventricular heart tissue and, for the first time, we could three-dimensionally reconstruct the ID including desmosomes and GJs with 5 nm precision in a large volume. Results show in three dimensions a highly folded structure of the ID, with the presence of GJs and desmosomes in both plicae and interplicae regions. We observed close contact of GJs with mitochondria and a variable spatial distribution of the junctions. Based on measurements of the shape of the intercellular junctions in 3-D, it is seen that GJs and desmosomes vary in size, depending on the region within the ID. This demonstrates that volume EM is essential to visualize morphological changes and its potential to quantitatively determine structural changes between normal and pathological conditions, e.g., cardiomyopathies. PMID- 29508068 TI - In focus in HCB: Hard Tissue Biology. PMID- 29508070 TI - Transdiaphragmatic Migration of a Spinal Fixation Rod into the Lung. AB - Adolescent idiopathic scoliosis may require surgical treatment for extreme curvature of the spine or loss of pulmonary function. We present a report of a 31 year-old woman with a history of scoliosis and anterolateral spinal fusion who developed chest pain and hemoptysis. Imaging revealed that a fixation rod had migrated cephalad, penetrating the diaphragm into the left lower lobe of the lung. The hardware was removed and lung repaired with good results. This is the first reported case of cranial spinal rod migration over a decade after initial implantation. PMID- 29508071 TI - Fibrin scaffold could promote survival of the human adipose-derived stem cells during differentiation into cardiomyocyte-like cells. AB - Human adipose-derived stem cells (hADSCs) are capable of differentiation into many cells including cardiac cells. Different types of scaffolds are used for cell differentiation but the best is yet to be determined. In this study, fibrin scaffold (3D) was fabricated using human plasma fibrinogen and compared with culture plates (2D) for the growth and differentiation of hADSCs into cardiomyocyte-like cells. For this purpose, after obtaining the properties of the isolated hADSCs and fibrin scaffold, four biochemical tests were employed to determine the relative growth rate of hADSCs in 2D and 3D cultures. To examine the effects of two different culture systems on cardiomyogenic differentiation, hADSCs were treated with 10 or 50 MUM 5-azacytidine (5-Aza) for 24 h and followed until 10 weeks. The results indicated that the growth of hADSCs in 3D significantly increased after the seventh day (P < 0.05). Western blot, qRT-PCR and immunochemistry assays were used to evaluate the rate of cardiac differentiation, which showed significantly higher expression of special cardiac genes such as NKX2.5, Cx43, MLC2v, betaMHC, HAND1, HAND2 and cTnI (P < 0.05) in the treated hADSCs with 50 MUM 5-Aza in the 3D group. However, the expression level of the specific cardiac proteins in 3D was not significant using western blot and immunofluorescence staining. In conclusion, this study suggests that the fibrin scaffold with a compressive stress of 107.74 kPa can keep the cells alive for 10 weeks and also allows a higher and sooner differentiation of hADSCs into cardiomyocyte-like cells treated with 50 MUM 5-Aza. PMID- 29508069 TI - Overexpression of tryptophan decarboxylase and strictosidine synthase enhanced terpenoid indole alkaloid pathway activity and antineoplastic vinblastine biosynthesis in Catharanthus roseus. AB - Terpenoid indole alkaloid (TIA) biosynthetic pathway of Catharanthus roseus possesses the major attention in current metabolic engineering efforts being the sole source of highly expensive antineoplastic molecules vinblastine and vincristine. The entire TIA pathway is fairly known at biochemical and genetic levels except the pathway steps leading to biosynthesis of catharanthine and tabersonine. To increase the in-planta yield of these antineoplastic metabolites for the pharmaceutical and drug industry, extensive plant tissue culture-based studies were performed to provide alternative production systems. However, the strict spatiotemporal developmental regulation of TIA biosynthesis has restricted the utility of these cultures for large-scale production. Therefore, the present study was performed to enhance the metabolic flux of TIA pathway towards the biosynthesis of vinblastine by overexpressing two upstream TIA pathway genes, tryptophan decarboxylase (CrTDC) and strictosidine synthase (CrSTR), at whole plant levels in C. roseus. Whole plant transgenic of C. roseus was developed using Agrobacterium tumefaciens LBA1119 strain having CrTDC and CrSTR gene cassette. Developed transgenic lines demonstrated up to twofold enhanced total alkaloid production with maximum ninefold increase in vindoline and catharanthine, and fivefold increased vinblastine production. These lines recorded a maximum of 38-fold and 65-fold enhanced transcript levels of CrTDC and CrSTR genes, respectively. PMID- 29508072 TI - Induction of PIR-A/B+ DCs in the in vitro inflammatory condition and their immunoregulatory function. AB - BACKGROUND: Dendritic cells (DCs), primary antigen-presenting cells, are now well known as an immunoregulator of many aspects of immune responses including inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis. We have reported that PIR-A/Bhigh cDCs (conventional DCs) appeared in dextran sodium sulfate (DSS)-induced colitis and serve as a negative immunoregulator in an animal model of IBD. The immunoregulatory role of PIR-A/B+ cDCs was confirmed in both an in vitro culture system and an in vivo transfer experiment. Here, we have investigated the differentiation process of PIR-A/B+ cDCs in an in vitro inflammatory environment and examined their functions. METHODS: cDCs were isolated from the large intestinal lamina propria from C57BL/6 mice and cultured in an inflammatory environment (IL-1, IL-6, TNFalpha, and LPS). The appearance of PIR-A/B+ cDCs was determined after 24 h, and the in vitro induced PIR-A/B+ cDCs were functionally and genetically examined. RESULTS: PIR A/B+ cDCs were detected after a 24-h culture only in the inflammatory environment, and the cells acted as a negative immunoregulator when examined in an allogenic mixed leukocyte reaction (MLR). The message level of IL-27 was highly upregulated in PIR-A/B+ cDCs, while that of high mobility group box 1 protein (HMGB1) was downregulated in these cells. This was well in accordance with the fact that PIR-A/B+ cDCs showed a suppressive function against activated T cells. We found that PIR-A/B+ cDCs produced IL-27, as verified by an ELISA assay, and that the inhibitory effect by PIR-A/B+ cDCs was, at least partially, due to IL-27. Furthermore, CD85d+ cells, a human counterpart of mouse PIR-A/B+ cDCs, were found in the lamina propria of the colon of the patients with ulcerative colitis, but not in the similar part of the non-inflammatory area of colon specimens from patients with colon cancer. CONCLUSIONS: PIR-A/B+ cDCs induced in an in vitro inflammatory environment model showed a suppressive function against activated T cells by producing an inhibitory cytokine. PMID- 29508073 TI - Are reindeer a significant carrier of disease-causing ticks? PMID- 29508074 TI - Proximal junctional kyphosis in adult spinal deformity: a novel predictive index. AB - PURPOSE: Proximal junctional kyphosis (PJK) is a devastating complication for adult spinal deformity (ASD) after correction surgery. However, there is no consensus on the risk factors of PJK, and whether it can be predicted remains unknown. The aim of this study is to detect the primary risk factors for PJK in ASD, and introduce a novel index for prediction of PJK. METHODS: Medical records of 62 ASD patients receiving correction surgery from January 2010 to January 2015 were analyzed. Spino-pelvic parameters were evaluated on lateral films before surgery, at 2 weeks' and at follow-up. Primary factors for PJK were evaluated. PJK index was proposed and verified. RESULTS: Cervical lordosis at follow-up, postoperative C2-C7 SVA, C2-C7 SVA at follow-up, postoperative T1 slope, T1 slope at follow-up, preoperative TLK, LL at follow-up, preoperative PT, postoperative PT, PT at follow-up, preoperative SS, postoperative SS, SS at follow-up, preoperative PT/SS, postoperative PT/SS and PT/SS at follow-up were significantly different between ASD with and without PJK. Adjusted logistic regression analysis showed that preoperative TLK, LL at follow-up, preoperative PT/SS and PT/SS at follow-up were primary factors for PJK. PJK index was defined as 0.160*LL at follow-up-0.121*preoperative TLK-4.625*preoperative PT/SS-3.315*PT/SS at follow up. On the basis of ROC curve, if PJK index was smaller and larger than - 2, the occurrence rate of PJK and non-PJK was 82 and 95%, respectively. CONCLUSIONS: Preoperative TLK, LL at follow-up, preoperative PT/SS and PT/SS at follow-up were primary factors for PJK. PJK index could be used to predict occurrence of PJK effectively. These slides can be retrieved under Electronic Supplementary Material. PMID- 29508075 TI - Correlation between the Oswestry Disability Index and objective measurements of walking capacity and performance in patients with lumbar spinal stenosis: a systematic literature review. AB - PURPOSE: The Oswestry Disability Index (ODI) plays a significant role in lumbar spinal stenosis research and is used to assess patient's walking limitations. The World Health Organisation describes the constructs of walking capacity and performance and recommend measuring both to fully describe patient's walking ability. Objective methods to assess walking capacity and performance is being investigated and used alongside the traditional use of PROs. This review of the literature was made to provide an overview of relations between the ODI and outcome measures of walking capacity and performance in spinal stenosis research, and to provide a strategy for improving such measures in future research. METHODS: The review was conducted according to the Prisma Statement. In February 2017, a search was performed in Pubmed, Embase and Cochrane database. Authors independently screened articles by title, abstract, and full text, and studies were included if both authors agreed. Articles with correlation analysis between the ODI, walking capacity and performance measures by accelerometer or GPS were included. RESULTS: The results support a correlation between the ODI and walking capacity measures. The available studies using ODI and accelerometers were too few to reach a conclusion regarding correlation between ODI and walking performance. No articles with GPS measure were identified. CONCLUSIONS: The ODI should not stand alone when evaluating walking limitations in patients with lumbar spinal stenosis. To enable a comprehensive assessment of walking ability, a walking test should be used to assess walking capacity and accelerometers should be investigated and standardized in measuring walking performance. These slides can be retrieved under Electronic Supplementary Material. PMID- 29508077 TI - Acute kidney injury is associated with subsequent infection in neonates after the Norwood procedure: a retrospective chart review. AB - BACKGROUND: Acute kidney injury (AKI) and infection are common complications after pediatric cardiac surgery. No pediatric study has evaluated for an association between postoperative AKI and infection. The objective of this study was to determine if AKI in neonates after cardiopulmonary bypass was associated with the development of a postoperative infection. METHODS: We performed a single center retrospective chart review from January 2009 to December 2015 of neonates (age <= 30 days) undergoing the Norwood procedure. AKI was defined by the modified neonatal Kidney Disease Improving Global outcomes serum creatinine criteria using (1) measured serum creatinine and (2) creatinine corrected for fluid balance on postoperative days 1-4. Infection, (culture positive or presumed), must have occurred after a diagnosis of AKI and within 60 days of surgery. RESULTS: Ninety-five patients were included, of which postoperative infection occurred in 42 (44%). AKI occurred in 38 (40%) and 42 (44%) patients by measured serum creatinine and fluid overload corrected creatinine, respectively, and was most commonly diagnosed on postoperative day 2. The median time to infection from the time of surgery and AKI was 7 days (IQR 5-14 days) and 6 days (IQR 3-13 days), respectively. After adjusting for confounders, the odds of a postoperative infection were 3.64 times greater in patients with fluid corrected AKI (95% CI, 1.36-9.75; p = 0.01). CONCLUSIONS: Fluid corrected AKI was independently associated with the development of a postoperative infection. These findings support the notion that AKI is an immunosuppressed state that increases the risk of infection. PMID- 29508076 TI - The role of receptor-like kinases in regulating plant male reproduction. AB - KEY MESSAGE: RLKs in anther development. The cell-to-cell communication is essential for specifying different cell types during plant growth, development and adaption to the ever-changing environment. Plant male reproduction, in particular, requires the exquisitely synchronized development of different cell layers within the male tissue, the anther. Receptor-like kinases (RLKs) belong to a large group of kinases localized on the cell surfaces, perceiving extracellular signals and thereafter regulating intracellular processes. Here we update the role of RLKs in early anther development by defining the cell fate and anther patterning, responding to the changing environment and controlling anther carbohydrate metabolism. We provide speculation of the poorly characterized ligands and substrates of these RLKs. The conserved and diversified aspects underlying the function of RLKs in anther development are discussed. PMID- 29508078 TI - Ionophore and Biometal Modulation of P-glycoprotein Expression and Function in Human Brain Microvascular Endothelial Cells. AB - PURPOSE: Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown. METHODS: Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper. The fluorescent P-gp substrate rhodamine-123 was employed to observe functional modulation, and inductively coupled plasma mass spectrometry (ICP-MS) provided information on biometal trafficking. RESULTS: A 24-h treatment with clioquinol, zinc and copper (0.5, 0.5 and 0.1 MUM) induced a significant upregulation of P-gp (1.7-fold) assessed by in-cell western and this was confirmed with western blotting (1.8-fold increase). This same treatment resulted in a 23% decrease in rhodamine-123 accumulation over a 1 h incubation. ICP-MS demonstrated that while t8his combination treatment had no effect on intracellular zinc concentrations, the treatment significantly enhanced bioavailable copper (4.6-fold). CONCLUSIONS: Enhanced delivery of copper to human brain microvascular endothelial cells is associated with enhanced expression and function of the important efflux pump P-gp, which may provide therapeutic opportunities for P-gp modulation. PMID- 29508079 TI - Erodibility of calcareous soils as influenced by land use and intrinsic soil properties in a semiarid region of central Iran. AB - The most important properties affecting the soil loss and runoff were investigated, and the effects of land use on the soil properties, together with the erodibility indices in a semiarid zone, central Iran, were evaluated. The locations of 100 positions were acquired by cLHS and 0-5-cm surface soil layer samples were used for laboratory analyses from the Borujen Region, Chaharmahal-Va Bakhtiari Province, central Iran. To measure in situ runoff and soil erodibility of three different land uses comprising dryland, irrigated farming, and rangeland, a portable rainfall simulator was used. The results showed that the high variations (coefficient of variation, CV) were obtained for electrical conductivity (EC), mean weight diameter (MWD), soil organic carbon (SOC), and soil erodibility indices including runoff volume, soil loss, and sediment concentration (CV ~ 43.6-77.4%). Soil erodibility indices showed positive and significant correlations with bulk density and negative correlations with SOC, MWD, clay content, and soil shear strength in the area under investigation. The values of runoff in the dryland, irrigated farming, and rangeland were found 1.5, 28.9, and 58.7 cm3; soil loss in the dryland, irrigated farming, and rangeland were observed 0.25, 2.96, and 76.8 g; and the amount of sediment concentration in the dryland, irrigated farming, and rangeland were found 0.01, 0.11, and 0.15 g cm-3. It is suggested that further investigations should be carried out on soil erodibility and the potential of sediment yield in various land uses with varying topography and soil properties in semiarid regions of Iran facing the high risk of soil loss. PMID- 29508080 TI - Knowledge-Based Cancer Control. PMID- 29508081 TI - Validated Methods of Assessing Quality of Life in Stone Disease. AB - PURPOSE OF REVIEW: With the emphasis on quality standards when determining reimbursements rates, patient reported outcomes are now of particular interest to clinicians. This review addresses health-related quality of life (HRQOL) detriments that have been studied in patients with stone disease. RECENT FINDINGS: Several instruments been validated for use in stone formers. Previously, generic instruments revealed decreased HRQOL in urolithiasis patients. Recently, a disease-specific tool has been developed and has provided more insight into the specific symptoms that negatively affect the patient experience. Evidence now reveals lower HRQOL in both symptomatic and asymptomatic patients with calculi, as well as varying determinants after certain interventions. Disease-specific tools have been shown to be more sensitive to urologic-related complaints. These findings should be considered in management decisions to allow for patient-centered care. Further application and standardization of these assessment tools into prospective studies may have value in refining current treatment guidelines. PMID- 29508082 TI - High Throughput Differential Scanning Fluorimetry (DSF) Formulation Screening with Complementary Dyes to Assess Protein Unfolding and Aggregation in Presence of Surfactants. AB - PURPOSE: The purpose was to evaluate DSF for high throughput screening of protein thermal stability (unfolding/ aggregation) across a wide range of formulations. Particular focus was exploring PROTEOSTAT(r) - a commercially available fluorescent rotor dye - for detection of aggregation in surfactant containing formulations. Commonly used hydrophobic dyes (e.g. SYPROTM Orange) interact with surfactants, complicating DSF measurements. METHODS: CRM197 formulations were prepared and analyzed in standard 96-well plate rT-PCR system, using SYPROTM Orange and PROTEOSTAT(r) dyes. Orthogonal techniques (DLS and IPF) are employed to confirm unfolding/aggregation in selected formulations. Selected formulations are subjected to non-thermal stresses (stirring and shaking) in plate based format to characterize aggregation with PROTEOSTAT(r). RESULTS: Agreement is observed between SYPROTM Orange (unfolding) and PROTEOSTAT(r) (aggregation) DSF melt temperatures across wide range of non-surfactant formulations. PROTEOSTAT(r) can clearly detect temperature induced aggregation in low concentration (0.2 mg/mL) CRM197 formulations containing surfactant. PROTEOSTAT(r) can be used to explore aggregation due to non-thermal stresses in plate based format amenable to high throughput screening. CONCLUSIONS: DSF measurements with complementary extrinsic dyes (PROTEOSTAT(r), SYPROTM Orange) are suitable for high throughput screening of antigen thermal stability, across a wide range of relevant formulation conditions - including surfactants -with standard, plate based rT-PCR instrumentation. PMID- 29508083 TI - Ablation Approaches for Ventricular Fibrillation. AB - Invasive electrophysiology (EP) mapping and catheter ablation has increasingly become the standard of care for many cardiac arrhythmias like supraventricular tachycardias, atrial fibrillation, premature ventricular complexes (PVC), and monomorphic ventricular tachycardia. In this review, we discuss the recent progress made in the mapping and ablation of ventricular fibrillation (VF). Ventricular activation during VF is apparently disorganized, making mapping and interpretation difficult. Prolonged mapping during VF would require mechanical circulatory support as VF causes complete hemodynamic collapse. These limitations have been addressed by the realization that there is often a reliable trigger arrhythmia that initiates the clinical VF episodes, and an approach to map and ablate this trigger can be successful. Such triggers can be PVCs localizing to the Purkinje/fascicular system, and in other cases can be ectopy from outflow tracts or intracavitary structures like papillary muscles, false tendons or moderator band, or can be monomorphic VT or preexcited atrial fibrillation that degenerate into VF. More recently, approaches beyond trigger elimination directly targeting the VF substrate have been devised. This includes elimination of the arrhythmogenic substrate localizing to the epicardial right ventricular outflow tract in patients with Brugada syndrome, akin to elimination of the arrhythmogenic substrate harbored by regions within scar in ischemic and non ischemic cardiomyopathies. Further, recent attempts have been made to try to identify and ablate rotors during VF that may be important in perpetuating the VF episode. Such exciting advances in "curing" VF are proving to be life saving for resuscitated survivors of arrhythmic death. PMID- 29508085 TI - Perception of Lung Cancer Risk: Impact of Smoking Status and Nicotine Dependence. AB - BACKGROUND: The general population is nowadays well aware that tobacco smoking dramatically increases the risk of developing lung cancer. We hypothesized that a personal history of smoking and the level of nicotine dependence in current smokers may affect the perception of this risk among healthy individuals. METHODS: The fourth French nationwide observational survey, EDIFICE 4, was conducted by telephone among a representative sample of individuals (N = 1602) aged between 40 and 75 years. Interviewees were asked about their smoking habits, perception of the risk of lung cancer, and nicotine dependence (Fagerstrom test). RESULTS: Regardless of their smoking status or level of nicotine dependence, the majority (96%) of our study population (N = 1463) acknowledged that tobacco smoking is a major risk factor for lung cancer. For 34% of all respondents, smoking <= 10 cigarettes per day does not carry any risk of lung cancer. Only half the current smokers considered themselves to be at higher risk of lung cancer than the average-risk population. The majority of current cigarette smokers with a nicotine dependence considered themselves to be at higher risk for lung cancer while only 37% of non-nicotine-dependent individuals had the same perception (P < 0.01). Current smokers were more likely to consider a screening examination than former smokers and never-smokers. However, the intention to undergo screening was not significantly affected by the level of nicotine dependence. CONCLUSIONS: Awareness campaigns may first have to overcome misconceptions about light smoking and, secondly, to target specific populations (heavy smokers, those with a long history, highly dependent smokers). PMID- 29508084 TI - Decline in Cancer Screening in Vulnerable Populations? Results of the EDIFICE Surveys. AB - BACKGROUND: We studied cancer screening over time and social vulnerability via surveys of representative populations. METHODS: Individuals aged 50-75 years with no personal history of cancer were questioned about lifetime participation in screening tests, compliance (adherence to recommended intervals [colorectal, breast and cervical cancer]) and opportunistic screening (prostate and lung cancer). RESULTS: The proportion of vulnerable/non-vulnerable individuals remained stable between 2011 and 2016. In 2011, social vulnerability had no impact on screening participation, nor on compliance. In 2014, however, vulnerability was correlated with less frequent uptake of colorectal screening (despite an organised programme) and prostate cancer screening (opportunistic), and also with reduced compliance with recommended intervals (breast and cervical cancer screening). In 2016, the trends observed in 2014 were substantiated and even extended to breast, colorectal and cervical cancer screening uptakes. Social vulnerability has an increasingly negative impact on cancer screening attendance. The phenomenon was identified in 2014 and had expanded by 2016. CONCLUSION: Although organised programmes have been shown to ensure equitable access to cancer screening, this remains a precarious achievement requiring regular monitoring. Further studies should focus on attitudes of vulnerable populations and on ways to improve cancer awareness campaigns. PMID- 29508086 TI - Sleep apnea and femoral neck BMD among Singaporean mid-life women. AB - : The relationship between sleep apnea and bone health remains controversial. This study explored the relationship between sleep apnea and femoral neck BMD in midlife Asian women. Partner-witnessed apnea predicted higher femoral neck BMD, an effect validated by the STOP index. Our findings suggest that sleep apnea may protect bone health. PURPOSE: The menopause transition is associated with decline in bone mineral density (BMD) and sleep quality. However, any relationship between these two factors remains controversial. This study explored the association between sleep apnea and femoral neck BMD in middle-aged women. METHODS: Participants (n = 1201) aged 45-69 years attending well-women visits at the National University Hospital, Singapore were recruited. Self-reported breathing discomfort and snoring, partner-witnessed apnea and snoring were assessed from the Pittsburgh Sleep Quality Index. Femoral neck BMD was assessed with dual-energy X-ray absorptiometry scan and classified into tertiles based on T-scores. Factors reported to affect sleep apnea and bone health in medical literature were potential covariates, p < 0.10. Multivariable ordinal regression analyses assessed associations between sleep measures and BMD. To further validate our findings, we analyzed four sleep apnea characteristics from the STOP questionnaire, a screening tool for sleep apnea. All analyses were performed using SPSS version 20.0. RESULTS: Mean (SD) age of participants was 56.3 (6.2) years. Partner-witnessed apnea predicted higher BMD tertiles (OR per unit increase in severity 1.39, 95% CI [1.02, 1.89]), independent of age, ethnicity, diabetes, BMI, and handgrip strength. This was further corroborated by the STOP index (OR 1.45, 95% CI [1.07, 1.96]). CONCLUSIONS: This study adds to the literature on sleep apnea and bone health in a non-Caucasian and younger population. Our findings support OSA-associated intermittent hypoxia protecting bone health. PMID- 29508087 TI - Cardiovascular Complications of Multiple Myeloma Treatment: Evaluation, Management, and Prevention. AB - PURPOSE OF REVIEW: Multiple myeloma treatment regimens consist of proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and steroids. In this paper, we will review the pathophysiology and associated cardiotoxicities of the different multiple myeloma therapeutic modalities and present methods to mitigate the development of cardiovascular complications. RECENT FINDINGS: Although proteasome inhibitors and immunomodulatory drugs have led to significant improvements in oncologic outcomes, there is increasing evidence of serious cardiovascular side effects which may be exacerbated in the setting of underlying cardiovascular risk factors or disease. Cardiotoxicities include cardiomyopathy and heart failure, accelerated hypertension, arrhythmias, and both arterial and venous thromboembolism. Given the frequency of cardiovascular risk factors in multiple myeloma patients as well as the cardiotoxicities associated with the different treatment regimens, it is essential to closely monitor these patients. Collaboration between cardiologists and oncologists is necessary to ensure patients receive optimal cancer treatment while minimizing cardiovascular risk. PMID- 29508088 TI - Fluctuating Behavior of the French Population in Cancer Screening: 5th Edition of the EDIFICE Survey. AB - BACKGROUND: The EDIFICE surveys have assessed cancer screening behavior in the French population since 2005. METHODS: The 2016 edition was conducted among a representative sample of 1501 individuals (age, 50-75 years). The current analysis focuses on breast, colorectal, prostate, lung, and cervical cancer screening. RESULTS: The rate of women (50 to 74 years) declaring having had at least one breast cancer screening test in their lifetime remained stable and high between 2005 and 2016. Compliance with recommended screening intervals improved between 2005 and 2011 from 75 to 83%, respectively, then decreased significantly to 75% in 2016 (P = 0.02). Uptake of at least one lifetime colorectal cancer screening test procedure declared (individuals aged 50-74 years) increase from 25% in 2005 to 59% in 2011, stabilized at 60% in 2014, then reached 64% in 2016. Opportunistic prostate cancer screening (men aged 50-75 years) rose between 2005 and 2008 from 36 to 49%, plateaued until 2014 then dropped to 42% in 2016. The proportion of women aged 50-65 declaring having undergone one cervical cancer screening test dropped significantly between 2014 and 2016 from 99 to 94% (P < 0.01). Lastly, 11% of our survey population in 2014 and 2016 (55-74 years) declared having already undergone lung cancer screening. CONCLUSION: Cancer screening behavior fluctuates in France, regardless of the context, i.e., organized programs or opportunistic screening. This observation highlights the need for constant analysis of population attitudes to optimize public awareness campaigns. PMID- 29508089 TI - A Novel and Freely Available Interactive 3d Model of the Internal Carotid Artery. AB - We describe a new and freely available 3D interactive model of the intracranial internal carotid artery (ICA) and the skull base that also allows to display and compare its main segment classifications. High-resolution 3D human angiography (isometric voxel's size 0.36 mm) and Computed Tomography angiography images were exported to Virtual Reality Modeling Language (VRML) format for processing in a 3D software platform and embedding in a 3D Portable Document Format (PDF) document that can be freely downloaded at http://diposit.ub.edu/dspace/handle/2445/112442 and runs under Acrobat Reader on Mac and Windows computers and Windows 10 tablets. The 3D-PDF allows for visualisation and interaction through JavaScript-based functions (including zoom, rotation, selective visualization and transparentation of structures or a predefined sequence view of the main segment classifications if desired). The ICA and its main branches and loops, the Gasserian ganglion, the petrolingual ligament and the proximal and distal dural rings within the skull base environment (anterior and posterior clinoid processes, silla turcica, ethmoid and sphenoid bones, orbital fossae) may be visualized from different perspectives. This interactive 3D-PDF provides virtual views of the ICA and becomes an innovative tool to improve the understanding of the neuroanatomy of the ICA and surrounding structures. PMID- 29508090 TI - PACAP in hypothalamic regulation of sleep and circadian rhythm: importance for headache. AB - The interaction between sleep and primary headaches has gained considerable interest due to their strong, bidirectional, clinical relationship. Several primary headaches demonstrate either a circadian/circannual rhythmicity in attack onset or are directly associated with sleep itself. Migraine and cluster headache both show distinct attack patterns and while the underlying mechanisms of this circadian variation in attack onset remain to be fully explored, recent evidence points to clear physiological, anatomical and genetic points of convergence. The hypothalamus has emerged as a key brain area in several headache disorders including migraine and cluster headache. It is involved in homeostatic regulation, including pain processing and sleep regulation, enabling appropriate physiological responses to diverse stimuli. It is also a key integrator of circadian entrainment to light, in part regulated by pituitary adenylate cyclase activating peptide (PACAP). With its established role in experimental headache research the peptide has been extensively studied in relation to headache in both humans and animals, however, there are only few studies investigating its effect on sleep in humans. Given its prominent role in circadian entrainment, established in preclinical research, and the ability of exogenous PACAP to trigger attacks experimentally, further research is very much warranted. The current review will focus on the role of the hypothalamus in the regulation of sleep-wake and circadian rhythms and provide suggestions for the future direction of such research, with a particular focus on PACAP. PMID- 29508092 TI - Double or Simple Emulsion Process to Encapsulate Hydrophilic Oxytocin Peptide in PLA-PEG Nanoparticles. AB - PURPOSE: Oral drug delivery using NPs is a current strategy for poorly absorbed molecules. It offers significant improvement in terms of bioavailability. However, the encapsulation of proteins and peptides in polymeric NPs is a challenge. Firstly, the present study focused on the double emulsion process in order to encapsulate the OXY peptide. Then the technique was challenged by a one step simplified process, the simple emulsion. METHODS: In order to study the influence of formulation and process parameters, factorial experimental designs were carried on. The responses observed were the NP size (<200 nm in order to penetrate the intestinal mucus layer), the suspension stability (ZP < |30| mV) and the OXY loading. RESULTS: It was thus found that the amount and the nature of surfactant, the ratio between the phases, the amount of PLA-PEG polymer and OXY, the presence of a viscosifying agent, and the duration of the sonication could significantly influence the responses. Finally, OXY-loaded NPs from both processes were obtained with NP size of 195 and 226 nm and OXY loading of 4 and 3.3% for double and simple emulsions, respectively. CONCLUSION: The two processes appeared to be suitable for OXY encapsulation and comparable in term of NP size, peptide drug load and release obtained. PMID- 29508091 TI - Current Treatment Options: Headache Related to Menopause-Diagnosis and Management. AB - PURPOSE OF REVIEW: Menopause is a life-changing event in numerous ways. Many women with migraine hold hope that the transition to the climacteric state will coincide with a cessation or improvement of migraine. This assumption is based mainly on common lay perceptions as well as assertions from many in the healthcare community. Unfortunately, evidence suggests this is far from the rule. Many women turn to a general practitioner or a headache specialist for prognosis and management. A natural instinct is to manipulate the offending agent, but in some cases, this approach backfires, or the concern for adverse events outweighs the desire for a therapeutic trial, and other strategies must be pursued. Our aim was to review the frequency and type of headache syndromes associated with menopause, to review the evidence for specific treatments for headache associated with menopause, and to provide management recommendations and prognostic guidance. RECENT FINDINGS: We reviewed both clinic- and population-based studies assessing headache associated with menopause. Headache in menopause is less common than headache at earlier ages but can present a unique challenge. Migraine phenotype predominates, but presentations can vary or be due to secondary causes. Other headache types, such as tension-type headache (TTH) and cluster headache (CH) may also be linked to or altered by hormonal changes. There is a lack of well-defined diagnostic criteria for headache syndromes associated with menopause. Women with surgical menopause often experience a worse course of disease status than those with natural menopause. Hormonal replacement therapy (HRT) often results in worsening of migraine and carries potential for increased cardiovascular and ischemic stroke risk. Estrogen replacement therapy (ERT) in patients with migraine with aura (MA) may increase the risk of ischemic stroke; however, the effect is likely dose-dependent. Some medications used in the prophylaxis of migraine may be useful in ameliorating the vasomotor and mood effects of menopause, including venlafaxine, escitalopram, paroxetine, and gabapentin. Other non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga may also be helpful in reducing headache and/or vasomotor symptoms associated with menopause. The frequency and type of headache associated with menopause is variable, though migraine and TTH are most common. Women may experience a worsening, an improvement, or no change in headache during the menopausal transition. Treatment may be limited by vascular risks or other medical and psychiatric factors. We recommend using medications with dual benefit for migraine and vasomotor symptoms including venlafaxine, escitalopram, paroxetine, and gabapentin, as well as non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga. If HRT is pursued, continuous (rather than cyclical) physiological doses should be used, transdermal route of administration is recommended, and the patient should be counseled on the potential for increased risk of adverse events (AEs). Concomitant use of a progestogen decreases the risk of endometrial hyperplasia with ERT. Biological mechanisms are incompletely understood, and there is a lack of consensus on how to define and classify headache in menopause. Further research to focus on pathophysiology and nuanced management is desired. PMID- 29508093 TI - The Optimization of Spacer Engineering for Capacitor-Less DRAM Based on the Dual Gate Tunneling Transistor. AB - The DRAM based on the dual-gate tunneling FET (DGTFET) has the advantages of capacitor-less structure and high retention time. In this paper, the optimization of spacer engineering for DGTFET DRAM is systematically investigated by Silvaco Atlas tool to further improve its performance, including the reduction of reading "0" current and extension of retention time. The simulation results show that spacers at the source and drain sides should apply the low-k and high-k dielectrics, respectively, which can enhance the reading "1" current and reduce reading "0" current. Applying this optimized spacer engineering, the DGTFET DRAM obtains the optimum performance-extremely low reading "0" current (10-14A/MUm) and large retention time (10s), which decreases its static power consumption and dynamic refresh rate. And the low reading "0" current also enhances its current ratio (107) of reading "1" to reading "0". Furthermore, the analysis about scalability reveals its inherent shortcoming, which offers the further investigation direction for DGTFET DRAM. PMID- 29508094 TI - The effect of post-progression survival on overall survival among patients with sensitive relapse of small cell lung cancer. AB - Recent studies have suggested that, among patients with advanced lung cancer, subsequent treatment after failure of first-line or second-line chemotherapy has a greater effect on overall survival (OS) than tumor shrinkage or progression free survival (PFS). However, no studies have examined this issue among patients with sensitive relapse of small cell lung cancer (SCLC). We retrospectively evaluate 77 patients with sensitive relapse of SCLC who received second-line chemotherapy after first-line platinum doublet chemotherapy between January 1999 and November 2013. The analyses included patient characteristics, treatment parameters, tumor shrinkage, PFS, post-progression survival (PPS), and OS. Spearman rank correlation analysis and linear regression analysis revealed that PPS was strongly correlated with OS (r = 0.91, p < 0.01, R2 = 0.96), PFS was moderately correlated with OS (r = 0.58, p < 0.01, R2 = 0.28), and tumor shrinkage was weakly correlated with OS (r = 0.34, p < 0.01, R2 = 0.12). A multivariate Cox proportional hazards model with a stepwise regression procedure revealed that PPS was significantly associated with age at the start of second line chemotherapy, best response to second-line and third-line chemotherapy, and the number of regimens after progression beyond second-line chemotherapy (p < 0.05). These findings suggest that PPS has a stronger effect than PFS on OS among patients with sensitive relapse of SCLC. Thus, response to second-line chemotherapy and subsequent treatment for disease progression after second-line chemotherapy may be important factors that influence OS. PMID- 29508095 TI - Ramucirumab for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression on first-line platinum- or fluoropyrimidine-containing combination therapy in Japanese patients: a phase 2, open-label study. AB - BACKGROUND: Ramucirumab, a monoclonal antibody vascular endothelial growth factor receptor-2 antagonist, given as monotherapy improved survival in a global phase 3 study (REGARD) of patients with gastric cancer. However, REGARD did not include Japanese patients. This study evaluated the efficacy and safety of ramucirumab monotherapy in Japanese patients with advanced gastric cancer. METHODS: This multicenter, open-label, nonrandomized phase 2 study (Clinicaltrials.gov: NCT01983878) was performed at 16 Japanese sites. Patients with advanced gastric or gastroesophageal junction cancer after disease progression following first line chemotherapy received intravenous ramucirumab 8 mg/kg every 2 weeks. Primary efficacy outcome: 12-week progression-free survival rate (PFS). RESULTS: Thirty six patients were enrolled. The 12-week PFS rate was 23.8% [90% confidence interval (CI) 12.4-37.2); the primary outcome was not met as the lower limit of the CI was outside the threshold of 16%. Median PFS was 6.6 weeks (90% CI 6.1 7.1). No patients achieved an objective response, and 11 (31%) patients achieved disease control. Median overall survival was 8.6 months (90% CI 5.7-10.7). The most frequent treatment-emergent adverse events (TEAEs) were diarrhea (9/36; 25%) and decreased appetite (8/36; 22%). Three patients reported Grade >= 3 ileus; all other Grade >= 3 TEAEs were reported by <= 2 patients. The most frequent adverse events of special interest (AESIs) were hypertension (10/36; 28%), bleeding/hemorrhage (7/36; 19%), and proteinuria (7/36; 19%). All Grade >= 3 AESIs were reported by <= 2 patients. CONCLUSIONS: These findings suggest that ramucirumab monotherapy has clinical activity and a manageable safety profile in Japanese patients with gastric cancer after disease progression following first line chemotherapy. PMID- 29508096 TI - Low-dose methotrexate in rheumatoid arthritis: a potential risk factor for bisphosphonate-induced osteonecrosis of the jaw. AB - Bisphosphonate-induced osteonecrosis of the jaw [BIONJ] is a relatively new pathological condition which was first described in the year 2003. The prevalence of BIONJ in patients on oral formulations is around 0.05% within the first 3 years and increases up to 0.2% after 4 years of consumption. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases [e.g., high doses of methotrexate up to 30 mg daily] significantly increase the chances of acquiring BIONJ. We present three patients with osteoporosis and rheumatoid arthritis [RA] who consumed oral bisphosphonates [alendronate] for less than 1 year and developed BIONJ within 2 to 5 months of undergoing a traumatic dental procedure. The patients also gave a history of consuming low doses of methotrexate [disease-modifying anti-rheumatic drugs] up to 20 mg weekly for 4 to 10 years. No history of steroid consumption was given by any of the patients. This case series highlights the possibility of rheumatoid arthritis and low-dose methotrexate being potential risk factors for BIONJ. This may be on account of the synergistic effect of methotrexate and bisphosphonates and the pro-inflammatory state created by RA which increased the risk of acquiring BIONJ. PMID- 29508097 TI - Exploring D-xylose oxidation in Saccharomyces cerevisiae through the Weimberg pathway. AB - Engineering of the yeast Saccharomyces cerevisiae towards efficient D-xylose assimilation has been a major focus over the last decades since D-xylose is the second most abundant sugar in nature, and its conversion into products could significantly improve process economy in biomass-based processes. Up to now, two different metabolic routes have been introduced via genetic engineering, consisting of either the isomerization or the oxido-reduction of D-xylose to D xylulose that is further connected to the pentose phosphate pathway and glycolysis. In the present study, cytosolic D-xylose oxidation was investigated instead, through the introduction of the Weimberg pathway from Caulobacter crescentus in S. cerevisiae. This pathway consists of five reaction steps that connect D-xylose to the TCA cycle intermediate alpha-ketoglutarate. The corresponding genes could be expressed in S. cerevisiae, but no growth was observed on D-xylose indicating that not all the enzymes were functionally active. The accumulation of the Weimberg intermediate D-xylonate suggested that the dehydration step(s) might be limiting, blocking further conversion into alpha ketoglutarate. Although four alternative dehydratases both of bacterial and archaeon origins were evaluated, D-xylonate accumulation still occurred. A better understanding of the mechanisms associated with the activity of dehydratases, both at a bacterial and yeast level, appears essential to obtain a fully functional Weimberg pathway in S. cerevisiae. PMID- 29508098 TI - Assessment of the mental health of carers according to the stage of patients with diagnosis of Alzheimer-type dementia. AB - In this study, the aims were to assess the mental health state of carers for patients with Alzheimer-type dementia (AD) according to stage of disease and to collect data with the aim of determining precautions to reduce the load of the patient and disease on the carer. The study included 120 patients with stages determined, according to the clinical dementia rating scale (CDR), and 120 patient relatives above the age of 18 who cared for these patients every day, for the whole day or part of the day, and who accepted participation in the research. This prospective and cross-sectional study performed a detailed neurological examination of patients, and after completing the "personal information form" with the interviewer, each patient had CDR and mini-mental test (MMSE) applied to determine stage of dementia and physical state. Carers first completed the "personal information form" and then had the short symptom inventory (SSI) applied. According to the stage of patients, there were significant differences determined in the points for all sub-scales belonging to the SSI of carers. As the disease stage increased, all sub-scale points for the SSI increased. With the transition of disease stages from 0.5-1 to stage 2, from stage 2 to 3, and with the inverse reduction in MMT scores, the points obtained by carers on the SSI sub scales increased. This data shows that with progressing disease stage, the load on the carer increases and mental health begins to dysfunction. PMID- 29508099 TI - Characteristic deterioration of ADAS-Jcog subscale scores and correlations with regional cerebral blood flow reductions in Alzheimer's disease. AB - The Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale (ADAS-Jcog) is composed of a number of subscale tasks. However, it is not clear which subscale tasks are most susceptible to impairment in Alzheimer's disease (AD) or what is the relationship between reduction in regional cerebral blood flow (rCBF) and decreased ADAS-Jcog scores. Subjects were 32 AD patients, aged 52 86 years. We examined the relationship between subscale tasks that showed marked score changes and brain regions that showed reduced rCBF over a 2-year period. rCBF was measured by single-photon emission computed tomography (SPECT) with technetium-99m ethyl cysteinate dimer (99mTc-ECD), and the SPECT imaging data were analyzed with the easy Z-score imaging system (eZIS) and voxel-based stereotactic extraction estimation (vbSEE) methods. Total score of ADAS-Jcog deteriorated from 19.5 +/- 7.0 to 35.7 +/- 15.2 after 2 years. Subscale scores were significantly worse in all fields, particularly in orientation, word recall, remembering test instructions, commands, constructional praxis, and ideational praxis, in that order. Significant correlations were found between (1) word recall and commands and rCBF in the left middle temporal lobe, (2) naming objects/fingers and rCBF in the left temporal (middle, inferior) lobe, and (3) constructional and ideational praxis and rCBF in the right parietal (superior, inferior) lobe, temporal (superior, middle) lobe, angular gyrus, and cingulate gyrus. We identified the brain regions associated with specifically impaired subscales of ADAS-Jcog during progressive deterioration of AD over 2 years. PMID- 29508101 TI - The metabolic effects of mercury during the biological cycle of vines (Vitis vinifera). AB - Mercury (Hg) is a major environmental pollutant that can be disposed to the environment by human activities, reaching crops like vineyards during irrigation with contaminated waters. A 2-year study was performed to monitor Hg variations during reproductive and vegetative stages of vines after Hg supplementation. Variations were focused on total Hg concentration, the molecular weight of Hg fractions and Hg-proteins associations in roots, stems and leaves. Total Hg concentrations increased during reproductive stages and decreased during vegetative stages. Variations in length of these stages were observed, according to an extension of the vegetative period. Six months post Hg administration, in roots, stems and leaves, initial Hg proteic fractions of 200 kDa were catabolized to 66 kDa fractions according to a transition from reproductive to vegetative stages. However, 24 months after Hg supplementation, the 66 kDa Hg proteic fraction was continuously determined in a prolonged senescence. Accordingly, the identified proteins associated to Hg show catabolic functions such as endopeptidases, hydrolases, glucosidases and nucleosidases. Stress associated proteins, like peroxidase and chitinase were also found associated to Hg. During the reproductive periods of vines, Hg was associated to membrane proteins, such as ATPases and lipid transfer proteins, especially in roots where Hg is absorbed. PMID- 29508100 TI - Temporal Effects on Monaural Amplitude-Modulation Sensitivity in Ipsilateral, Contralateral and Bilateral Noise. AB - The amplitude modulations (AMs) in speech signals are useful cues for speech recognition. Several adaptation mechanisms may make the detection of AM in noisy backgrounds easier when the AM carrier is presented later rather than earlier in the noise. The aim of the present study was to characterize temporal adaptation to noise in AM detection. AM detection thresholds were measured for monaural (50 ms, 1.5 kHz) pure-tone carriers presented at the onset ('early' condition) and 300 ms after the onset ('late' condition) of ipsilateral, contralateral, and bilateral (diotic) broadband noise, as well as in quiet. Thresholds were 2-4 dB better in the late than in the early condition for the three noise lateralities. The temporal effect held for carriers at equal sensation levels, confirming that it was not due to overshoot on carrier audibility. The temporal effect was larger for broadband than for low-band contralateral noises. Many aspects in the results were consistent with the noise activating the medial olivocochlear reflex (MOCR) and enhancing AM depth in the peripheral auditory response. Other aspects, however, indicate that central masking and adaptation unrelated to the MOCR also affect both carrier-tone and AM detection and are involved in the temporal effects. PMID- 29508102 TI - The impact of complications after elective colorectal resection within an enhanced recovery pathway. AB - BACKGROUND: Despite the implementation of enhanced recovery pathways (ERP), morbidity following colorectal surgery remains high. The aim of the present study was to estimate the impact of postoperative complications on excess hospital length of stay (LOS) in patients undergoing elective colorectal resection. METHODS: A retrospective study of patients undergoing elective colorectal surgery at a single institution from 2003 to 2010 was performed. Patients managed by an ERP were compared to conventional care (CC), matched by propensity score radius matching. Complications were defined a priori. Excess (independent effect on LOS from multivariate analysis) and attributable (absolute number of additional bed days) LOS of common postoperative complications determined the impact of complications on bed utilization. Multivariate analysis was performed using multiple linear regression. RESULTS: A total of 810 propensity-score-matched patients were included (ERP = 472, CC = 338). Complications were significantly lower in the ERP group compared to the CC group (20 vs. 31%, p < 0.001). Median LOS decreased from 7 days in the CC group to 5 days in the ERP group [adjusted decrease in mean LOS of 2.8 days (95% CI 0.8, 4.8)]. Anastomotic leak, myocardial infarction and C. difficile infection had the highest excess LOS for both the ERP and CC groups. However, impaired gastrointestinal function had a higher impact on the absolute number of hospital bed days in the ERP group, as high as anastomotic leak (72.7 vs. 73.5 days respectively), while in the CC group the impact of gastrointestinal dysfunction was less of that of anastomotic leak (50.6 vs. 78.9 days respectively). CONCLUSIONS: In the setting of an ERP, postoperative complications have significant impact on total bed utilization. Impaired gastrointestinal function, given its high incidence, accounted for almost the same number of additional hospital bed days as anastomotic leak in the ERP group and is a target for quality improvement. PMID- 29508103 TI - Utility of Using the Montreal Cognitive Assessment (MoCA) as a Screening Tool for HIV-Associated Neurocognitive Disorders (HAND) In Multi-Ethnic Malaysia. AB - This study determines the optimal cut-off scores for the Montreal Cognitive Assessment (MoCA) to detect HIV-associated neurocognitive disorders (HAND) in a multi-ethnic Malaysian HIV-positive cohort by developing demographically corrected normative standards among 283 HIV-negative community-based controls with overlapping demographic characteristics. The norms (corrected for age, sex, education, ethnicity) were applied to 342 HIV-positive virally suppressed individuals on cART. Impairment rates were classified using the Global Deficit Score (GDS >= .5) method. The MoCA was also scored according to the recommended cut-off of <= 26, and functional decline was applied to both impairment definitions to classify HAND per the Frascati criteria. The <= 26 cut-off considerably overestimated cognitive impairment in both samples (59.4% HIV negative; 69.3% HIV-positive). In contrast, corrected scores yielded impairment rates consistent with what has been reported internationally in virally suppressed cohorts (23.4% with 83.3% mild impairment, 16.7% moderate impairment). A supplemental file allowing the computation of corrected MoCA scores and impairment status is included. PMID- 29508104 TI - Seven-month prostate-specific antigen (PSA) is prognostic in patients with prostate cancer initially diagnosed with distant metastases. AB - Recent research suggests that prostate-specific antigen (PSA) <= 0.2 ng/dl at 7 months is prognostic for better survival with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer regardless of chemotherapy with docetaxel. These results were derived from a group of clinical trial participants. Therefore, we performed a confirmatory analysis in patients treated outside of trials. Furthermore, we limited inclusion to those who presented with metastases at the initial diagnosis of prostate cancer (synchronous metastases). A retrospective analysis of a comprehensive regional database was performed. The oncology care in this region (Nordland County, Northern Norway) was provided by one center. Patients who were diagnosed between January 01, 2004 and December 31, 2016 were included. Of 101 patients, 90 were alive at 7 months and had their PSA value measured. Their median age was 68.5 years. Only six patients (7%) achieved PSA <= 0.2 ng/dl at 7 months. The median value was 4.05 ng/dl. Median overall survival was shortest in patients with PSA > 4.0 ng/dl (22 months). For patients with PSA between 0.3 and 4.0 ng/dl, median survival was 54 months (p = 0.0001). No further increase was seen in the small group with lower PSA. Statistical significance was also found for a cutoff of <= 1.0 ng/dl (55 vs. 32 months). PSA at 7 months predicts overall survival. Given that only 7% of patients achieved PSA <= 0.2 ng/dl, confirmation of this particular cutoff requires additional studies in other populations. PMID- 29508105 TI - Decellularized amnion scaffold with activated PRP: a new paradigm dressing material for burn wound healing. AB - Direct application of amnion has greater risk of immunological rejection and infection. Decellularization is an effective method to lower the risk of immune complications and infections. The bioreactor assembly with multiple cassettes was designed for decellurization of multiple amnions with different cell types simultaneously in single run. A detergent-based protocol was modified to remove all cellular components from amnion and diminish the DNA content to render it non immunogenic. Amnion (n = 10) were treated with 2% sodium dodecyl sulphate (SDS), 5% dimethyl sulfoxide (DMSO) and 2% sodium deoxycholeate (SD). Decellularized amnion samples were analyzed by haematoxylin-eosin staining (HE), Alcian blue pH 1 (AB-pH-1), 4,6-diamnionidino-2-phenylindol (DAPI), Massion's trichrome stain, DNA quantification, mechanical testing and scanning electron microscopy (SEM). Histological analysis showed complete removal of cellular components and the histoarchitecture of scaffold remained intact. Amnion scaffold activated with platelet rich plasma (PRP) and calcium chloride composition supported better adherence to the wound than amnion alone. Only single application showed good healing. In vivo assessment of activated amnion revealed stable dressing. It has good promising outcome. At day 7, histologically the wounds treated with activated amnion were almost closed without scarring and showed well differentiated epidermis, proliferation of keratinocytes, hair follicles and basement membrane as compared to controls and silver nitrate gel dressings in a mouse (Mus musculus). Cryopreservation had no adverse effect on the mechanical properties of the amnion scaffold. Cryopreservation of decellularized amnion by Dulbecco's modified eagle medium (DMEM) was expected to prepare off-the-shelf skin substitutes and preserve them to be immediately available upon request of patients' needs. PMID- 29508106 TI - Results after arthroscopic treatment of central traumatic lesions of the triangular fibrocartilage complex. AB - INTRODUCTION: Injuries of the triangular fibrocartilage complex (TFCC) are of high clinical relevance; however, the clinical evidence for treatment is poor and long-term results are rarely published. The purpose of this study was to evaluate the clinical outcome of symptomatic central traumatic lesions of the TFCC (Palmer 1A) following arthroscopic debridement. MATERIALS AND METHODS: Between 2007 and 2013, 87 patients were arthroscopically diagnosed with Palmer 1A lesion and accordingly treated with debridement. Follow-up was available for 43 patients. Activities of daily living (ADLs) were measured with the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Pain perception was evaluated with visual analogue scale (VAS 0-10). Grip strength and wrist motion were assessed with conventional techniques using a Jamar dynamometer and a goniometer. Patient satisfaction was assessed using a questionnaire at follow-up. RESULTS: Mean follow-up was 42.5 months (range 5-70). The mean age of the patients (22 male and 21 female) at time of surgery was 41 +/- 15.9 years. No major complication occurred during surgery and follow-up. The DASH score (preoperatively 49.8 +/- 19.3 vs. postoperatively 14.1 +/- 17.9, p < 0.05) and pain perception (VAS: preoperatively 7.2 +/- 2.0 vs. postoperatively 1.4 +/- 1.6, p < 0.05) improved significantly. Grip strength was satisfactory after surgery (19.6 +/- 13.1). Ulnar deviation improved significantly from 29.3 +/- 10.4 degrees to 35.6 +/- 8.3 degrees (p < 0.05) and wrist flexion improved from 53.8 +/- 18.9 degrees to 67.4 +/- 12.9 degrees (p < 0.05). Wrist extension, radial deviation, pronation and supination did not change significantly after surgery. Improved symptoms were reported by 41/43 (95.3%) patients and 40/43 (93%) patients would have had the same procedure again knowing the final outcome. Six of 43 patients (15%) had an ulnar plus variance. None of these needed ulnar shortening. CONCLUSIONS: Central traumatic TFCC lesions can safely be treated by arthroscopic debridement. We showed a sustained pain relief with significantly improved quality of life (DASH score) and wrist motion at follow-up. This resulted in a high patient satisfaction and acceptance of the procedure. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 29508107 TI - I-124 codrituzumab imaging and biodistribution in patients with hepatocellular carcinoma. AB - BACKGROUND: I-124 codrituzumab (aka GC33), an antibody directed at Glypican 3, was evaluated in patients with hepatocellular carcinoma (HCC). Fourteen patients with HCC underwent baseline imaging with I-124 codrituzumab (~ 185 MBq, 10 mg). Seven of these patients undergoing sorafenib/immunotherapy with 2.5 or 5 mg/kg of cold codrituzumab had repeat imaging, with co-infusion of I-124 codrituzumab, as part of their immunotherapy treatment. Three patients who progressed while on sorafenib/immunotherapy were re-imaged after a 4-week washout period to assess for the presence of antigen. Serial positron emission tomography (PET) imaging and pharmacokinetics were performed following I-124 codrituzumab. An ELISA assay was used to determine "cold" codrituzumab serum pharmacokinetics and compare it to that of I-124 codrituzumab. Correlation of imaging results was performed with IHC. Short-term safety assessment was also evaluated. RESULTS: Thirteen patients had tumor localization on baseline I-124 codrituzumab; heterogeneity in tumor uptake was noted. In three patients undergoing repeat imaging while on immunotherapy/sorafenib, evidence of decreased I-124 codrituzumab uptake was noted. All three patients who underwent imaging after progression while on immunotherapy continued to have I-124 codrituzumab tumor uptake. Pharmacokinetics of I-124 codrituzumab was similar to that of other intact IgG. No significant adverse events were observed related to the I-124 codrituzumab. CONCLUSIONS: I 124 codrituzumab detected tumor localization in most patients with HCC. Pharmacokinetics was similar to that of other intact iodinated humanized IgG. No visible cross-reactivity with normal organs was observed. PMID- 29508108 TI - Feminization of Male Brown Treesnake Methyl Ketone Expression via Steroid Hormone Manipulation. AB - Pheromones are useful tools for the management of invasive invertebrates, but have proven less successful in field applications for invasive vertebrates. The brown treesnake, Boiga irregularis, is an invasive predator that has fundamentally altered the ecology of Guam. The development of control tools to manage Boiga remains ongoing. Skin-based, lipophilic pheromone components facilitate mating in brown treesnakes, with females producing the same long chain, saturated and monounsaturated (ketomonoene) methyl ketones known to function as pheromones in garter snakes, Thamnophis sirtalis. Boiga also express novel, diunsaturated methyl ketones (ketodienes) with a purported function as a sex pheromone. In our study, we implanted 17 beta-estradiol in adult male brown treesnakes in order to manipulate methyl ketone expression as sex attractants, an effect that would mirror findings with garter snakes. Specifically, estrogen promoted production of two ketomonoenes, pentatriaconten-2-one and hexatriaconten 2-one, and suppressed production of one ketodiene, heptatriacontadien-2-one. In bioassays, estrogen-implanted males elicited tongue-flicking and chin rubbing behavior from unmanipulated males, though the responses were weaker than those elicited by females. On Guam, wild males exhibited greatest responses to whole female skin lipid extracts and only weak responses to the methyl ketone fractions from females and implanted males. Our results suggest that sex identity in brown treesnakes may be conferred by the ratio of ketomonoenes (female) to ketodienes (male) from skin lipids and may be augmented by a sex-specific endocrine signal (estradiol). However, a blend of long-chain methyl ketones alone is not sufficient to elicit maximal reproductive behaviors in male Boiga. PMID- 29508110 TI - Regulatory roles of OASL in lung cancer cell sensitivity to Actinidia chinensis Planch root extract (acRoots). AB - Lung cancer is one of the most common malignancies worldwide. Actinidia chinensis Planch root extract (acRoots) was found to have the capacity of the anti-tumor, although the molecular mechanisms remain unclear. The present study aims to investigate the molecular mechanisms by which lung cancer cells sense to inhibitory effects of acRoots with a special focus on immune-associated gene profiles. We firstly provide a preclinical evidence that acRoots can significantly inhibit lung cancer cell proliferation and apoptosis via the PI3K OASL signal pathway. The heterogeneous alterations of immune-associated gene profiles of lung cancer cell types were measured after treatment with various doses of acRoots. The OASL gene was identified as the key regulator in molecular networks of acRoots-treated lung cancer cells and validated. The OASL gene plays an important role in the regulation of lung cancer cell sensitivity to acRoots, which modulated by the PI3K signal pathway. Thus, our data indicate that OASL can be one of the decisive regulators to maintain lung cancer cell susceptibility to acRoots and may be associated with the development of drug resistance. The regulation of OASL can be an alternative strategy to improve drug efficacy during cancer therapies. PMID- 29508109 TI - IL-6 signalling pathways and the development of type 2 diabetes. AB - Interleukin 6 (IL-6), a multifunctional cytokine, has been implicated in the pathophysiology of type 2 diabetes (T2D). The elevated circulating level of IL-6 is an independent predictor of T2D and is considered to be involved in the development of inflammation, insulin resistance and beta-cell dysfunction. On the other hand, an increasing number of evidence suggests that IL-6 has an anti inflammatory role and improves glucose metabolism. The complex signal transduction mechanism of IL-6 may help explain the pleiotropic nature of the cytokine. IL-6 acts via two distinct signalling pathways called classic signalling and trans-signalling. While both signalling modes lead to activation of the same receptor subunit, their final biological effects are completely different. The aim of this review is to summarize our current knowledge about the role of IL-6 in the development of T2D. We will also discuss the importance of specific blockade of IL-6 trans-signalling rather than inhibiting both signalling pathways as a therapeutic strategy for the treatment of T2D and its associated macrovascular complications. PMID- 29508111 TI - Precision of automated QRS duration measurement in patients treated with cardiac resynchronization therapy. AB - PURPOSE: Shortening of the QRS duration (QRSd) is often used to guide device optimization and reprogramming in patients with cardiac resynchronization therapy (CRT). Detecting the small changes expected during reprogramming requires that the QRSd can be measured with high precision, but this has never been studied in patients with CRT. In this study, we wanted to assess the precision of automated QRSd measurement in patients treated with CRT using two commonly available electrocardiographs. METHODS: Patients treated with CRT were recruited during routine follow-up in our pacemaker clinic. In all participants, a number of immediate successive ECGs were recorded with the GE MAC 5500 (Mac55) and the GE MAC 1600 (Mac16). Data were analyzed with a linear mixed model. RESULTS: A total of 785 12-lead ECGs were recorded in 36 patients with an average of 11.2 and 10.6 ECGs per patient with the Mac55 and Mac16, respectively. The Mac55 measured the QRSd longer by 10.3 milliseconds (ms) (95% CI 7.1-13.5 ms, p < 0.001) and with significantly smaller standard deviation for repeated measurements (6.3 vs. 10.4 ms, p < 0.001). Limits of agreement were +/- 17.5 and +/- 28.8 ms for the Mac55 and Mac16, respectively. CONCLUSIONS: Automated measurement of QRSd in patients with CRT shows low precision with limits of agreement of +/- 17.5 and +/- 28.8 ms for repeated measurements in two commercially available electrocardiographs. Device programming solely by QRSd changes should be done with caution, and clinical effects should be demonstrated in future trials. Device programming based on QRSd changes should be done with caution until the ability of this measure to predict clinical outcome can be demonstrated in prospective study. PMID- 29508112 TI - Youth with Chronic Pain and Postural Orthostatic Tachycardia Syndrome (POTS): Treatment Mediators of Improvement in Functional Disability. AB - Intensive pain rehabilitation programs are effective in increasing functioning for youth with chronic pain (CP). However, the utility of such programs for youth with CP and co-morbid postural orthostatic tachycardia syndrome (POTS) is rarely examined. In addition, studies examining mediators of treatment for CP are sparse. This paper compares treatment outcomes for youth with CP (n = 117) and youth with CP + POTS (n = 118). Additionally, depression and pain catastrophizing were tested as potential mediators of treatment effects. Significant treatment improvements were found for functional disability, depression, pain catastrophizing, and perceived pain intensity but with no differences between groups. Improvements in depressed mood, pain catastrophizing (helplessness subscale), and pain severity partially mediated functioning improvement. Pain severity was not a significant mediator in the CP + POTS group. We concluded that depression and pain catastrophizing, especially the helplessness domain, can impact functioning improvement in adolescents with CP and POTS and are particularly important to target in treatment. PMID- 29508113 TI - Legislative and Policy Developments and Imperatives for Advancing the Primary Care Behavioral Health (PCBH) Model. AB - The Primary Care Behavioral Health (PCBH) practice model continues to gain converts among primary care and behavioral health professionals as the evidence supporting its effectiveness continues to accumulate. Despite a growing number of practices and organizations using the model effectively, widespread implementation has been hampered by outmoded policies and regulatory barriers. As policymakers and legislators begin to recognize the contributions that PCBH model services make to the care of complex patients and the expansion of access to those in need of behavioral health interventions, some encouraging policy initiatives are emerging and the policy environment is becoming more favorable to implementation of the PCBH model. This article outlines the necessity for policy change, exposing the policy issues and barriers that serve to limit the practice of the PCBH model; highlights innovative approaches some states are taking to foster integrated practice; and discusses the compatibility of the PCBH model with the nation's health care reform agenda. Psychologists have emerged as leaders in the design and implementation of PCBH model integration and are encouraged to continue to advance the model through the demonstration of efficient and effective clinical practice, participation in the expansion of an appropriately trained workforce, and advocacy for the inclusion of this practice model in emerging healthcare systems and value-based payment methodologies. PMID- 29508114 TI - Socioeconomic Status and Psychopathic Traits in a Community Sample of Youth. AB - The current study aims to address socioeconomic status (SES) as a moderating variable between psychopathic traits and conduct problems in a sample of 2432 Dutch adolescents (Mage = 14.50 years, SD = 1.67, 56% male). Both family and neighborhood SES were measured, with income as a proxy for the level of SES. There were small but significant positive correlations between the behavioral and interpersonal dimensions of psychopathy and family SES, a small but significant negative correlation between the affective dimension and neighborhood SES, and a small and significant positive correlation between neighborhood SES and the behavioral dimension of psychopathy. Results further showed that the relations between youth psychopathic traits were moderated by neither family SES nor neighborhood SES. The results suggest that the relations between psychopathic traits and conduct problems are equally strong for lower and higher SES youth. Taken together, these findings warrant the conclusions that SES does not play a role as a moderator in the relation between psychopathy and conduct problems. PMID- 29508115 TI - Identity, Bipolar Disorder, and the Problem of Self-Narration in Kay Redfield Jamison's An Unquiet Mind and Ellen Forney's Marbles. AB - The field of narrative medicine holds that personal narratives about illness have the potential to give illness meaning and to create order out of disparate facets of experience, thereby aiding a patient's treatment and resisting universalizing medical discourse. Two narratives of bipolar disorder, Kay Redfield Jamison's prose memoir An Unquiet Mind (1995) and Ellen Forney's graphic memoir Marbles (2012) challenge these ideas. These writers demonstrate that one result of bipolar disorder is a rupture to their sense of identity, making straightforward and verbal forms of narrative impossible. During periods of relative mood stability, reliable memories of mania or depression are equally impossible. As a result, these memoirists seek to develop sources of self-knowledge other than memory and introspection, long the foundations of personal narrative. Finally, An Unquiet Mind and Marbles return attention to questions of selfhood at a time when scholarship on memoir rejects interpretations of life stories as clear and reliable expressions of identity. PMID- 29508116 TI - Locales of Trust: How Two Forms of Community Trust are Associated with Mothers' Self-Rated Health in Indonesia. AB - Objectives Social trust and access to social capital serve as important mechanisms to offset gender disparities in health in low-middle-income countries (LMICs) such as Indonesia. Indonesian women may have fewer opportunities to create strong social ties outside her social sphere and thus may benefit particularly from individual-level thin trust because generalized trust lowers barriers to gaining social support. We examined the role of thin trust and thick trust, two unique forms of social trust, to better understand the links between individual- and community-level trust and maternal health. Thin trust represents generalized trust in community members while thick trust represents strong and longstanding trusting relationships. Methods We employed nationally representative data from Wave 5 of the Indonesian Family Life Survey collected in 2014-2015 (n = 7276) to identify relationships between social trust and the self rated health (SRH) of women in Indonesia, net of both individual- and community level controls. Results We found evidence that both thick and thin trust benefit women's health but operate at different levels. While thick trust decreased likelihoods of poor SRH at the community level, thin trust was associated with lower likelihoods of poor SRH at the individual level. Conclusions for Practice We argue that for women in LMICs, trust provides an important mechanism through which women potentially access both tangible and immaterial resources that positively influence health outcomes. PMID- 29508117 TI - Transitions in Smoking Across a Pregnancy: New Information from the Growing Up in New Zealand Longitudinal Study. AB - Introduction Maternal smoking remains a modifiable cause of adverse maternal and child health outcomes. This study investigated smoking transitions across pregnancy. Methods Data from the contemporary child cohort study Growing Up in New Zealand (n = 6822) were used to analyse smoking status across three points across a pregnancy: pre-pregnancy, during pregnancy and after pregnancy. Odds ratios (OR) were calculated for maternal, socio-economic and pregnancy-related factors associated with each transition using multivariate logistic regression. Results The prevalence of smoking pre-pregnancy was 20.3%. The cessation rate during pregnancy was 48.5%, while the postpartum relapse rate was 36.0%. Heavy smokers were less likely to quit during pregnancy (OR 0.13, 95% CI 0.08-0.20), and more likely to relapse at 9 months (OR 2.63, CI 1.60-4.32), relative to light smokers. Women in households with another smoker were less likely to quit during pregnancy (OR 0.35, CI 0.25-0.48), and more likely to relapse postpartum (OR 2.00, CI 1.14-3.51), relative to women in a smoke-free household. Women without high school qualifications were less likely to quit during pregnancy than women with bachelor degrees (OR 0.21, CI 0.11-0.41) but no more likely to relapse. Maori women were less likely to quit during pregnancy than European women (OR 0.35, CI 0.25-0.49) but no more likely to relapse. Conclusion Heavy smokers and those with another smoker in the household are at high risk of smoking during pregnancy or relapsing after pregnancy. Decreasing smoking across a pregnancy therefore requires a focus on cessation in all households with heavy smokers of child-bearing age. The association between smoking and ethnicity may be confounded as it not consistent across the pregnancy. PMID- 29508118 TI - Green and Cost Effective Synthesis of Fluorescent Carbon Quantum Dots for Dopamine Detection. AB - Carbon quantum dots (CQDs) due to its high fluorescent output is evolving as novel sensing material and is considered as future building blocks for nano sensing devices. Hence, in this investigation we report microwave assisted preparation and multi sensing application of CQDs. The microwave derived CQDs are characterized by Dynamic Light Scattering (DLS) experiment and Fourier Infrared spectra (FTIR) to investigate the size distribution and chemical purity respectively. Fluorescent emission spectra recorded at varying pH shows varying fluorescence emission intensities. Further, emission spectra recorded at different temperatures shows that fluorescence emission of CQDs greatly depends on temperature. Therefore, we demonstrate the pH and temperature sensing characteristics of CQDs by fluorescence quenching behaviour. In addition, the interaction and sensing behaviour of CQDs for dopamine is also presented in this work with a detection limit of 0.2 mM. The steady state and time-resolved methods have been employed in fluorescence quenching methods for sensing dopamine through CQDs at room temperature. The bimolecular quenching rate constants for different concentration have been measured. The interaction between CQDs and dopamine indicates fluorescence quenching method is an elegant process for detecting dopamine through CQDs. PMID- 29508119 TI - Temperature effects on the blood oxygen affinity in sharks. AB - In fish, regional endothermy (i.e., the capacity to significantly elevate tissue temperatures above ambient via vascular heat exchangers) in the red swimming muscles (RM) has evolved only in a few marine groups (e.g., sharks: Lamnidae, Alopiidae, and teleosts Scombridae). Within these taxa, several species have also been shown to share similar physiological adaptations to enhance oxygen delivery to the working tissues. Although the hemoglobin (Hb) of most fish has a decreased affinity for oxygen with an increase in temperature, some regionally endothermic teleosts (e.g., tunas) have evolved Hbs that have a very low or even an increased affinity for oxygen with an increase in temperature. For sharks, however, blood oxygen affinities remain largely unknown. We examined the effects of temperature on the blood oxygen affinity in two pelagic species (the regionally endothermic shortfin mako shark and the ectothermic blue shark) at 15, 20, and 25 degrees C, and two coastal ectothermic species (the leopard shark and brown smooth-hound shark) at 10, 15, and 20 degrees C. Relative to the effects of temperature on the blood oxygen affinity of ectothermic sharks (e.g., blue shark), shortfin mako shark blood was less affected by an increase in temperature, a scenario similar to that documented in some of the tunas. In the shortfin mako shark, this may act to prevent premature oxygen dissociation from Hb as the blood is warmed during its passage through vascular heat exchangers. Even though the shortfin mako shark and blue shark occupy a similar niche, the effects of temperature on blood oxygen affinity in the latter more closely resembled that of the blood in the two coastal shark species examined in this study. The only exception was a small, reverse temperature effect (an increase in blood oxygen affinity with temperature) observed during the warming of the leopard shark blood under simulated arterial conditions, a finding that is likely related to the estuarine ecology of this species. Taken together, we found species-specific differences in how temperature affects blood oxygen affinity in sharks, with some similarities between the regionally endothermic sharks and several regionally endothermic teleost fishes. PMID- 29508120 TI - Changes in Emotional and Behavioral Problems Between 2000 and 2011 Among 16-Year Old Polish Children: A Cross-Sectional Study. AB - Since after the second world war there has been an increasing number of studies investigating secular changes in adolescent mental health. Although no general trends could be outlined, the majority of studies show at least partial deterioration of psychological wellbeing from year 2000 on. Our study adds to this knowledge by exploring changes in self-declared emotional and behavioral problems in Poland, which is a part of post-communist Europe. In this paper, we compared responses on the Youth Self-Report by Polish 16-year-olds from 2000 and those from 2011. Two independent samples consisted of 259 (year 2000) and 185 (year 2011) 16-year-olds of both genders, drawn from randomized, normative, school-based groups. We analyzed linear, ordinal and binary logistic regression models. The results revealed that teenagers from 2011 reported more self-rated internalizing and total problems. Social and thought problems also rose significantly. Gender related time trends hint at a male increase in externalizing, aggressive behaviors and anxiety/depression. Caseness rose significantly in most scales with female gender being an additional risk factor for internalizing and total problems. No reduction in self-reported emotional and behavioral problems was detected. PMID- 29508121 TI - Assessment of atherosclerotic plaque activity in patients with sleep apnea using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI): a feasibility study. AB - PURPOSE: Evidence suggests that the inflammatory state of an atherosclerotic plaque is important in predicting future risk of plaque rupture. This study aims to investigate the feasibility of measuring plaque inflammation in patients with obstructive sleep apnea (OSA) utilizing advanced vascular imaging - hybrid positron-emission tomography/magnetic resonance imaging (PET/MRI) with fluorodeoxyglucose (FDG) tracer-before and after continuous positive airway pressure (CPAP). METHODS: Patients with newly diagnosed moderate to severe OSA underwent baseline PET/MRI for assessment of vascular inflammation of the carotid arteries and thoracic aorta prior to initiation of CPAP. Those adherent to CPAP returned for repeat imaging after 3-6 months of CPAP use. Atherosclerotic plaque activity, as measured by arterial wall FDG uptake, was calculated using target-to background ratios (TBR) before and after CPAP. RESULTS: Five patients were recruited as part of a focused project. Mean age was 52 years (80% male), and mean apnea-hypopnea index (AHI) was 33. Three patients were objectively adherent with CPAP. In the pre-CPAP phase, all patients had focal FDG uptake in the carotid arteries and aorta. After CPAP, there was an average reduction in TBR of 5.5% (TBRmean) and 6.2% (TBRmax) in carotid and aortic plaque inflammation, similar in magnitude to the reduction observed with statin therapy alone in non OSA patients (previously reported by others). CONCLUSIONS: We demonstrate the feasibility of using hybrid PET/MRI to assess atherosclerotic plaque inflammation in patients with OSA before and after CPAP. Use of the vascular PET/MRI platform in patients with OSA may provide better insight into the role of OSA and its treatment in reducing atherosclerotic inflammation. PMID- 29508122 TI - Embryonal mitochondrial DNA: relationship to embryo quality and transfer outcomes. AB - PURPOSE: The aim was to study the association between embryonal mitochondrial DNA (mtDNA) content and embryo quality and implantation outcomes. METHODS: A retrospective chart review was performed with data collected from a private IVF center database. The study population included female infertility patients with ages ranging from 31 to 38 years old, and the main outcome measures were embryo quality and transfer outcomes. RESULTS: From a total of 1510 blastocyst biopsies, the majority of embryos consisted of grade 1 (High), followed by grade 2 (mid), and grade 3 (poor). Embryos with higher mtDNA content were found to be of poorer quality (grade 3) relative to grades 1 and 2 (P = 0.003). Using a logistic model, mtDNA best predicted lowest and highest grades, but not mid-grade embryos. There was no correlation between mtDNA content and the subjects' age (R2 = 0.0018). In an analysis of only euploid embryos (N = 717), there was no longer an association between mtDNA content and embryo quality (P = 0.834). There was no difference in mtDNA content between groups of embryos that did and did not implant (P = 0.53). There was also no association noted between mtDNA content and ongoing pregnancy. Compared to day 6, day 5 blastocysts contain significantly higher amounts of mtDNA (P = 0.0005), lower rates of aneuploidy (P < 0.001), and were more likely to be high-quality blastocysts (grade 1) (P < 0.001). CONCLUSION: Although the mtDNA content shows some association to the morphologic grade of an embryo, this association does not persist in an analysis of only euploid embryos. Mitochondrial DNA content also does not appear to be associated with implantation or ongoing pregnancy. Day 5 blastocysts have significantly higher mtDNA content compared to day 6 blastocysts. PMID- 29508123 TI - A Bit-Encoding Based New Data Structure for Time and Memory Efficient Handling of Spike Times in an Electrophysiological Setup. AB - Recent neuroscientific and technical developments of brain machine interfaces have put increasing demands on neuroinformatic databases and data handling software, especially when managing data in real time from large numbers of neurons. Extrapolating these developments we here set out to construct a scalable software architecture that would enable near-future massive parallel recording, organization and analysis of neurophysiological data on a standard computer. To this end we combined, for the first time in the present context, bit-encoding of spike data with a specific communication format for real time transfer and storage of neuronal data, synchronized by a common time base across all unit sources. We demonstrate that our architecture can simultaneously handle data from more than one million neurons and provide, in real time (< 25 ms), feedback based on analysis of previously recorded data. In addition to managing recordings from very large numbers of neurons in real time, it also has the capacity to handle the extensive periods of recording time necessary in certain scientific and clinical applications. Furthermore, the bit-encoding proposed has the additional advantage of allowing an extremely fast analysis of spatiotemporal spike patterns in a large number of neurons. Thus, we conclude that this architecture is well suited to support current and near-future Brain Machine Interface requirements. PMID- 29508124 TI - Timing and Outcomes of PCI in the TAVR Era. AB - PURPOSE OF REVIEW: Transcatheter aortic valve replacement (TAVR) has become an established therapy for patients with symptomatic severe aortic stenosis (AS). As the number of patients referred for TAVR increases, so does the prevalence of untreated obstructive coronary artery disease (CAD) in the population under evaluation. Despite the high prevalence of CAD in patients treated with TAVR, the management strategy of concomitant CAD in these patients remains an area of considerable uncertainty. RECENT FINDINGS: Percutaneous coronary intervention (PCI) in patients with CAD and severe AS has been shown to be feasible and safe. Whether revascularization before, during, or after TAVR is optimal remains a subject of debate. All three approaches represent valid strategies with advantages and disadvantages that need to be carefully weighed on an individual basis. Current expert opinions recommend that PCI should be performed before or at the time of TAVR as long as the risk of the procedure does not outweigh the potential benefits. The results of large clinical trials evaluating the optimal revascularization time are closely awaited. PMID- 29508125 TI - Investigation of clinicopathological parameters and expression of COX-2, bcl-2, PCNA, and p53 in primary and recurrent sporadic odontogenic keratocysts. AB - OBJECTIVES: Odontogenic keratocyst (OKC) presents considerable variation in aggressiveness and propensity for recurrence, yet hitherto, no explicit clinicopathological features have been determined to clearly demonstrate the potential for relapse. This retrospective study aims to investigate the prognostic relevance of various clinicopathological features as well as immunoexpression of COX-2, bcl-2, PCNA, and p53 in sporadic OKC. MATERIALS AND METHODS: Among 41 patients with OKC treated by enucleation, the frequency of recurrence for various clinicopathological features as well as immunoexpression for COX-2, bcl-2, PCNA, and p53 was evaluated. RESULTS: The mean follow-up was 8.49 years, and recurrences were ascertained in 29.27% of cases. We found significant differences between recurrent and non-recurrent cysts in terms of multilocularity (P = 0.029), cortical perforation (P = 0.001), and lesion size (P < 0.001). Hazard risk for the recurrence was 3.362 (95% CI 1.066-10.598) for multilocular cysts, 7.801 (95% CI 2.1-28.985) for evidence of cortical perforation, and 1.004 (1.002-1.006) for 1 mm2 of lesion size on panoramic radiographs. We also found that immunoexpression of PCNA significantly correlates with the radiographic evidence of cortical perforation (P = 0.048) and that there is significant positive correlation between expression of COX-2 and bcl-2 (P = 0.001) as well as significant negative correlation between immunoexpression of COX-2 and age (P = 0.002). None of the other analyzed factors were associated with the recurrence. CONCLUSIONS: Larger size, multilocularity, and cortical perforation in sporadic OKC may be correlated with the relapse. CLINICAL RELEVANCE: Immunohistochemical analyses of COX-2, bcl-2, PCNA, and p53 lack prognostic utility in sporadic OKC. PMID- 29508127 TI - Toward a Responsibility-Catering Prioritarian Ethical Theory of Risk. AB - Standard tools used in societal risk management such as probabilistic risk analysis or cost-benefit analysis typically define risks in terms of only probabilities and consequences and assume a utilitarian approach to ethics that aims to maximize expected utility. The philosopher Carl F. Cranor has argued against this view by devising a list of plausible aspects of the acceptability of risks that points towards a non-consequentialist ethical theory of societal risk management. This paper revisits Cranor's list to argue that the alternative ethical theory responsibility-catering prioritarianism can accommodate the aspects identified by Cranor and that the elements in the list can be used to inform the details of how to view risks within this theory. An approach towards operationalizing the theory is proposed based on a prioritarian social welfare function that operates on responsibility-adjusted utilities. A responsibility catering prioritarian ethical approach towards managing risks is a promising alternative to standard tools such as cost-benefit analysis. PMID- 29508126 TI - miR-152 regulates the proliferation and differentiation of C2C12 myoblasts by targeting E2F3. AB - The development of skeletal muscle is a complex process involving the proliferation, differentiation, apoptosis, and changing of muscle fiber types in myoblasts. Many reports have described the involvement of microRNAs in the myogenesis of myoblasts. In this study, we found that the expression of miR-152 was gradually down-regulated during myoblast proliferation, but gradually up regulated during the differentiation of myoblasts. Transfection with miR-152 mimics restrained cell proliferation and decreased the expression levels of cyclin E, CDK4, and cyclin D1, but promoted myotube formation and significantly increased the mRNA expression levels of MyHC, MyoD, MRF4, and MyoG in C2C12 myoblasts. However, treatment with miR-152 inhibitors promoted cell proliferation and restrained differentiation. Moreover, over-expression of miR-152 significantly decreased E2F3 production in C2C12 myoblasts. A luciferase assay confirmed that miR-152 could bind to the 3' UTR of E2F3. In conclusion, this study showed that miR-152 inhibited proliferation and promoted myoblast differentiation by targeting E2F3. PMID- 29508129 TI - Large Paediatric Central Osteoma with Osteoblastoma-Like Features in the Mandible. AB - The diagnosis of osteomas in the paediatric population can pose a challenge to pathologists in excluding malignant bony tumours. We present the case of a 10 year old male presenting with a large left mandibular radiopaque lesion. This paper discusses the case of a central osteoma with osteoblastoma-like features, literature review, differential diagnosis of radiopaque lesions of the maxilla and mandible as well as a detailed discussion of the pathology of the lesion. Although similar lesions have been described in the sino-orbital region, this is believed to be the first report of this pathological entity in the mandible. PMID- 29508128 TI - Investigation of the interactions between 1-butyl-3-methylimidazolium-based ionic liquids and isobutylene using density functional theory. AB - To identify ionic liquids (ILs) that could be used as solvents in isobutylene (IB) polymerization, the interactions between IB and eight different ILs based on the 1-butyl-3-methylimidazolium cation ([Bmim]+) were investigated using density functional theory (DFT). The anions in the ILs were chloride, hexafluorophosphate, tetrafluoroborate, bis[(trifluoromethyl)sulfonyl]imide, tetrachloroaluminate ([AlCl4]-), tetrachloroferrate, acetate, and trifluoroacetate. The interaction geometries were explained by changes in the total energy, intermolecular distances, Hirshfeld charges, and the electrostatic potential surface. The IL solvents were screened by comparing their interaction intensities with IB to the interaction intensities of reference ILs ([AlCl4]- based ILs) with IB. The microscopic mechanism for IB dissolution was rationalized by invoking a previously reported microscopic mechanism for the dissolution of gases in ILs. Computation results revealed that hydrogen (H) bonding between C2-H on the imidazolium ring and the anions plays a key role in ion pair (IP) formation. The addition of IB leads to slight changes in the dominant interactions of the IP. IB molecules occupied cavities created by small angular rearrangements of the anions, just as CO2 does when it is dissolved in an IL. The limited total free space in the ILs and the much larger size of IB than CO2 were found to be responsible for the poor solubility of IB compared with that of CO2 in the ILs. PMID- 29508130 TI - Head and Neck Kaposi Sarcoma: Clinicopathological Analysis of 11 Cases. AB - Kaposi sarcoma (KS) of the head and neck area is uncommon with limited published case series. Our routine and consultation files were reviewed for histologically and immunohistochemically proven KS affecting any cutaneous or mucosal head and neck site. Ten males and one female aged 42-78 years (median, 51 years; mean, 52 years) were retrieved. Eight patients were HIV-positive and three were HIV negative. The affected sites were skin (n = 5), oral/oropharyngeal mucosa (n = 5), and lymph nodes (n = 3) in variable combination. The ear (pinna and external auditory canal) was affected in two cases; both were HIV-negative. Multifocal non head and neck KS was reported in 50% of patients. At last follow-up (12-94 months; median, 46 months), most of patients were either KS-free (n = 8) or had ongoing remission under systemic maintenance therapy (n = 2). One patient was alive with KS (poor compliance). Histopathological evaluation showed classical features of KS. One case was predominantly sarcomatoid with prominent inflammation mimicking undifferentiated sarcoma. Immunohistochemistry showed consistent expression of CD31, CD34, ERG, D2-40 and HHV8 in all cases. This is one of the few series devoted to head and neck KS showing high prevalence of HIV positivity, but also unusual presentations in HIV-negative patients with primary origin in the skin of the ear and the auditory canal. KS should be included in the differential diagnosis of difficult-to-classify spindle cell lesions at this uncommon location. PMID- 29508131 TI - Acute vestibular syndrome: clinical head impulse test versus video head impulse test. AB - HINTS battery involving head impulse test (HIT), nystagmus, and test of skew is the critical bedside examination to differentiate acute unilateral peripheral vestibulopathy from posterior circulation stroke (PCS) in acute vestibular syndrome (AVS). The highest sensitivity component of the battery has been reported to be the horizontal HIT, whereas skew deviation is defined as the most specific but non-sensitive sign for PCS. Video-oculography-based HIT (vHIT) may have an additional power in making the differentiation. If vHIT is undertaken, then both gain and gain asymmetry should be taken into account as anterior inferior cerebellar artery (AICA) strokes are at risk of being misclassified based on VOR gain alone. Further refinement in video technology, increased operator proficiency and incorporation with saccade analysis will increase the sensitivity of vHIT for PCS diagnosis. For the time being, clinical examination seems adequate in frontline diagnostic evaluation of AVS. PMID- 29508132 TI - Vestibular perception thresholds tested by galvanic vestibular stimulation. PMID- 29508135 TI - Community Services for Mental Illnesses and Substance Use Disorders: the Moral Test of Our Time. PMID- 29508133 TI - Autoimmune comorbidities in multiple sclerosis: what is the influence on brain volumes? A case-control MRI study. AB - BACKGROUND: Several studies indicated that multiple sclerosis (MS) is frequently associated with other autoimmune diseases. However, it is little known if the coexistence of these conditions may influence the radiologic features of MS, and in particular the brain volumes. OBJECTIVES: To evaluate the effect of autoimmune comorbidities on brain atrophy in a large case-control MS population. METHODS: A group of MS patients affected by a second autoimmune disorder, and a control MS group without any comorbidity, were recruited. Patients underwent a brain MRI and volumes of whole brain (WB), white matter (WM), and gray matter (GM) with cortical GM were estimated by SIENAX. RESULTS: The sample included 286 MS patients, of which 30 (10.5%) subjects with type 1 diabetes (T1D), 53 (18.5%) with autoimmune thyroiditis (AT) and 4 (0.1%) with celiac disease. Multiple regression analysis found an association between T1D and lower GM (p = 0.038) and cortical GM (p = 0.036) volumes, independent from MS clinical features and related to T1D duration (p < 0.01), while no association was observed with AT and celiac disease. CONCLUSIONS: Our data support the importance of considering T1D as possible factors influencing the brain atrophy in MS. Further studies are needed to confirm our data and to clarify the underlying mechanisms. PMID- 29508134 TI - Noisy vestibular stimulation improves vestibulospinal function in patients with bilateral vestibulopathy. AB - OBJECTIVES: To examine the mechanism underlying previously reported ameliorating effects of noisy galvanic vestibular stimulation (GVS) on balance performance in patients with bilateral vestibulopathy (BVP) and determine those patients (incomplete versus complete vestibular loss) that might benefit from this intervention. METHODS: Vestibulospinal reflex thresholds were determined in 12 patients with BVP [2 with complete loss (cBVP) and 10 with residual function (rBVP)]. Patients were stimulated with 1 Hz sinusoidal GVS of increasing amplitudes (0-1.9 mA). Coherence between GVS input and stimulation-induced body motion was determined and psychometric function fits were subsequently used to determine individual vestibulospinal reflex thresholds. The procedure was repeated with an additional application of imperceptible white noise GVS (nGVS). RESULTS: All patients with rBVP but none with cBVP exhibited stimulation-induced vestibulospinal reflex responses with a mean threshold level of 1.26 +/- 0.08 mA. Additional nGVS resulted in improved processing of weak subthreshold vestibular stimuli (p = 0.015) and thereby effectively decreased the vestibulospinal threshold in 90% of patients with rBVP (mean reduction 17.3 +/- 3.9%; p < 0.001). CONCLUSION: The present findings allow to identify the mechanism by which nGVS appears to stabilize stance and gait performance in patients with BVP. Accordingly, nGVS effectively lowers the vestibular threshold to elicit balance related reflexes that are required to adequately regulate postural equilibrium. This intervention is only effective in the presence of a residual vestibular functionality, which, however, applies for the majority of patients with BVP. Low intensity noise stimulation thereby provides a non-invasive treatment option to optimize residual vestibular resources in BVP. PMID- 29508136 TI - A heterometallic ruthenium-gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer. AB - Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2(p cymene)Ru(MU-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru based compounds. Following recent studies of the anticancer efficacies of these Ru-Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(MU-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion, and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer. PMID- 29508137 TI - Consumption of fruit and vegetables in relation with psychological disorders in Iranian adults. AB - OBJECTIVE: Findings from observational studies on the relationship between fruit and vegetables consumption and risk of mental disorders are contradictory. We aimed to examine the association between fruit and vegetables intake and prevalence of depression, anxiety, and psychological distress in a large group of Iranian adults. METHODS: This cross-sectional study was conducted on 3362 people of Iranian adults working in 50 health centers. Dietary data were collected using a validated dish-based 106-item semi-quantitative food frequency questionnaire (FFQ). The Iranian-validated version of Hospital Anxiety and Depression Scale (HADS) was used to screen for anxiety and depression. The General Health Questionnaire (GHQ) was used to assess psychological distress. RESULTS: The prevalence of depression, anxiety, and high psychological distress among the study population was 30.0, 15.2, and 25.0%, respectively. Women in the top quintile of fruit intake, compared with those in the bottom quintile, had 57, 50, and 60% lower odds of depression, anxiety, and psychological distress. Consumption of vegetables was significantly associated with lower odds of depression (OR 0.65; 95% CI 0.46, 0.93) in women and lower odds of anxiety (OR 0.43; 95% CI 0.22, 0.87) in men. In addition, after adjustment for potential confounders, women in the highest quintile of fruit and vegetables intake, compared with those in the bottom quintile, had significantly lower odds of depression (OR 0.55; 95% CI 0.37, 0.80) and psychological distress (OR 0.60; 95% CI 0.40, 0.90). Furthermore, high intake of total fruit and vegetables was associated with lower odds of psychological distress (OR 0.42; 95% CI 0.21, 0.81) in men. CONCLUSION: We found significant inverse associations between high intake of fruit with depression, anxiety, and psychological distress in Iranian women. High consumption of vegetables was also associated with lower risk of depression and anxiety, respectively, in women and men. In addition, high intake of total fruit and vegetable was associated with lower odds of depression and psychological distress in women and men. PMID- 29508138 TI - Perception of need for nutritional support in advanced cancer patients with cachexia: a survey in palliative care settings. AB - PURPOSE: Few studies have investigated the need for nutritional support in advanced cancer patients in palliative care settings. Therefore, we conducted a questionnaire to examine the relationship between the perception of need for nutritional support and cancer cachexia and the prevalence of specific needs, perceptions, and beliefs in nutritional support. METHODS: We conducted a questionnaire in palliative care settings. Patients were classified into two groups: (1) non-cachexia/pre-cachexia and (2) cachexia/refractory cachexia. RESULTS: A total of 117 out of 121 patients responded (96.7%). A significant difference was observed in the need for nutritional support between the groups: non-cachexia/pre-cachexia (32.7%) and cachexia/refractory cachexia (53.6%) (p = 0.031). The specific needs of patients requiring nutritional support were nutritional counseling (93.8%), ideas to improve food intake (87.5%), oral nutritional supplements (83.0%), parenteral nutrition and hydration (77.1%), and tube feeding (22.9%). The top perceptions regarding the best time to receive nutritional support and the best medical staff to provide nutritional support were "when anorexia, weight loss, and muscle weakness become apparent" (48.6%) and "nutritional support team" (67.3%), respectively. The top three beliefs of nutritional treatments were "I do not wish to receive tube feeding" (78.6%), "parenteral nutrition and hydration are essential" (60.7%), and "parenteral hydration is essential" (59.6%). CONCLUSIONS: Patients with cancer cachexia expressed a greater need for nutritional support. They wished to receive nutritional support from medical staff when they become unable to take sufficient nourishment orally and the negative impact of cachexia becomes apparent. Most patients wished to receive parenteral nutrition and hydration. PMID- 29508139 TI - Axillary web syndrome assessment using a self-assessment questionnaire: a prospective cohort study. AB - BACKGROUND: Surgical procedure for breast cancer is not without its side effects and one such side effect is axillary web syndrome (AWS), characterized by palpable fibrotic-like cords in the operated arm. As physical evaluation is the only gold standard method used, our study aims to assess the incidence and early detection of AWS with a self-assessment questionnaire. METHODS: From July 2013 to July 2014, 370 breast cancer patients were enrolled. AWS incidence was 51.1%, with 94.1% onset in the first 4 weeks after surgery; 43.5% of the patients did not recover in the first 8 weeks. Univariate analysis showed that BMI (P < 0.001), age (P < 0.001), educational level (P = 0.01), and exercise frequency in the eighth week of follow-up (P < 0.001) were significantly associated with the AWS detection, and multivariate analyses confirmed that younger patients (age < 50) have significantly higher AWS detection (OR = 2.38 (95%CI 1.53, 3.71) and that BMI is associated with AWS, with normal weight patients (BMI <= 25) having a significantly greater AWS detection with an odds ratio of 2.11 (95%CI 1.33, 3.36). CONCLUSION: Our findings indicated that the incidence of AWS is high in breast cancer patients, particularly in the first month after surgery. Not all patients achieved recovery during our 8 week follow-up, suggesting that evaluation and treatment should be longer. Double AWS detection was found for patients who were younger (age < 50) and with normal weight. PMID- 29508140 TI - Prolonged versus short infusion rates for intravenous magnesium sulfate administration in hematopoietic cell transplant patients. AB - PURPOSE: Hematopoietic cell transplant (HCT) recipients often require intravenous (IV) magnesium repletion due to poor dietary intake, gastrointestinal loss, and use of concomitant magnesium wasting medications. Prolonging the IV magnesium infusion rate has been postulated to reduce renal clearance and improve retention; however, limited evidence supports this hypothesis. METHODS: We reviewed autologous and allogeneic HCT recipients (n = 82) who received IV magnesium at our institution between 2014 and 2016: 41 patients received IV magnesium at a prolonged rate of 0.5 g/h and 41 patients at > 0.5 g/h (mean 2.07 g/h). Primary outcome was percent of days in which magnesium levels were in desired therapeutic range (2-2.7 mg/dL) during hospitalization. RESULTS: Baseline characteristics were similar between cohorts: no difference existed between groups in incidence of gastrointestinal graft-versus-host disease or the percentage of patients who received magnesium replacement in maintenance fluids, received concomitant oral magnesium supplementation, or received parenteral nutrition. Percent of days in desired therapeutic range was not different between groups (p = 0.3). No difference existed between groups with respect to total amount of IV magnesium repletion (22.5 vs. 21.4 g, p = 0.81) or number of days of IV replacement (7.2 vs. 6.2 days, p = 0.41). In terms of safety, there was no difference between groups with respect to incidence of hypomagnesemia or hypermagnesemia (p = 0.43 each). CONCLUSIONS: Overall, prolonging the infusion rate did not correlate with improved magnesium retention based on amount and frequency of magnesium repletion or attainment of goal levels in HCT patients. PMID- 29508141 TI - Scientific Session of the 16th World Congress of Endoscopic Surgery, jointly hosted by Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) & Canadian Association of General Surgeons (CAGS), Seattle, Washington, USA, 11-14 April 2018: Video Loop Videos. PMID- 29508142 TI - Computer-assisted 3D bowel length measurement for quantitative laparoscopy. AB - BACKGROUND: This study aimed at developing and evaluating a tool for computer assisted 3D bowel length measurement (BMS) to improve objective measurement in minimally invasive surgery. Standardization and quality of surgery as well as its documentation are currently limited by lack of objective intraoperative measurements. To solve this problem, we developed BMS as a clinical application of Quantitative Laparoscopy (QL). METHODS: BMS processes images from a conventional 3D laparoscope. Computer vision algorithms are used to measure the distance between laparoscopic instruments along a 3D reconstruction of the bowel surface. Preclinical evaluation was performed in phantom, ex vivo porcine, and in vivo porcine models. A bowel length of 70 cm was measured with BMS and compared to a manually obtained ground truth. Afterwards 70 cm of bowel (ground truth) was measured and compared to BMS. RESULTS: Ground truth was 66.1 +/- 2.7 cm (relative error + 5.8%) in phantom, 65.8 +/- 2.5 cm (relative error + 6.4%) in ex vivo, and 67.5 +/- 6.6 cm (relative error + 3.7%) in in vivo porcine evaluation when 70 cm was measured with BMS. Using 70 cm of bowel, BMS measured 75.0 +/- 2.9 cm (relative error + 7.2%) in phantom and 74.4 +/- 2.8 cm (relative error + 6.3%) in ex vivo porcine evaluation. After thorough preclinical evaluation, BMS was successfully used in a patient undergoing laparoscopic Roux-en-Y gastric bypass for morbid obesity. CONCLUSIONS: QL using BMS was shown to be feasible and was successfully translated from studies on phantom, ex vivo, and in vivo porcine bowel to a clinical feasibility study. PMID- 29508143 TI - The Role of the Immune Cells in Fracture Healing. AB - PURPOSE OF REVIEW: Bone fracture healing is a complex physiological process relying on numerous cell types and signals. Inflammatory factors secreted by immune cells help to control recruitment, proliferation, differentiation, and activation of hematopoietic and mesenchymal cells. Within this review we will discuss the functional role of immune cells as it pertains to bone fracture healing. In doing so, we will outline the cytokines secreted and their effects within the healing fracture callus. RECENT FINDINGS: Macrophages have been found to play an important role in fracture healing. These immune cells signal to other cells of the fracture callus, modulating bone healing. Cytokines and cellular signals within fracture healing continue to be studied. The findings from this work have helped to reinforce the importance of osteoimmunity in bone fracture healing. Owing to these efforts, immunomodulation is emerging as a potential therapeutic target to improve bone fracture healing. PMID- 29508145 TI - An International Interobserver Variability Reporting of the Nuclear Scoring Criteria to Diagnose Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: a Validation Study. AB - The aim of the study was to assess interobserver variation in reporting nuclear features of encapsulated follicular variant of papillary thyroid carcinoma, newly reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), based on a proposed standardized scoring system. An education module was individually reviewed as a pre-evaluation teaching guide of the specific features of classical papillary carcinoma, the specific inclusion and exclusion features for the diagnosis of NIFTP, and a catalog of the standardized scoring system of the nuclear features of papillary carcinoma used to reach this diagnosis. Participants subsequently reviewed 30 cases of thyroid lesions previously scored by members of the Endocrine Pathology Society Working Group for the Re-evaluation of the Encapsulated Follicular Variant of Papillary Thyroid Carcinoma. There was one uninvolved reference image to demonstrate fixation, processing, and cell size and one image from each case for scoring, with results recorded for each participant. The location of training (country and program), years as a practicing pathologist, and approximate number of thyroid gland surgical cases diagnosed per year were recorded. The degree of agreement between participants was assessed by kappa statistics, using the individual criteria and the average composite scores of the Working Group as a point of comparison. Using the Nuclear Standardized Scoring System, the interobserver agreement for final diagnosis score was generally excellent: unweighted and weighted kappa values between individual observers ranging from 0.242 to 0.930 (average 0.626). There was significant agreement between observers in reaching an interpretation of the presence or absence of nuclear features to diagnose NIFTP (score 0-1 versus score of 2-3), with California pathologists, 0.63 (median 0.66, SD 0.15); Japanese pathologists, 0.64 (median 0.66, SD 0.16); and UK pathologists, 0.60 (median 0.57, SD 014) compared to the expert panel, 0.70 (median 0.73, SD 0.19). The use of the nuclear scoring system to evaluate the nuclear features of papillary thyroid carcinoma as applied to reach the diagnosis of NIFTP shows a good to substantial interobserver agreement, suggesting that consensus can be reached in diagnosing the nuclear features required for this newly reclassified neoplasm. PMID- 29508144 TI - Screening Gene Knockout Mice for Variation in Bone Mass: Analysis by MUCT and Histomorphometry. AB - PURPOSE OF REVIEW: The international mouse phenotyping consortium (IMPC) is producing defined gene knockout mouse lines. Here, a phenotyping program is presented that is based on micro-computed tomography (MUCT) assessment of distal femur and vertebra. Lines with significant variation undergo a computer-based bone histomorphometric analysis. RECENT FINDINGS: Of the 220 lines examined to date, approximately 15% have a significant variation (high or low) by MUCT, most of which are not identified by the IMPC screen. Significant dimorphism between the sexes and bone compartments adds to the complexity of the skeletal findings. The MUCT information that is posted at www.bonebase.org can group KOMP lines with similar morphological features. The histological data is presented in a graphic form that associates the cellular features with a specific anatomic group. The web portal presents a bone-centric view appropriate for the skeletal biologist/clinician to organize and understand the large number of genes that can influence skeletal health. Cataloging the relative severity of each variant is the first step towards compiling the dataset necessary to appreciate the full polygenic basis of degenerative bone disease. PMID- 29508146 TI - Correction to: Emergency Medicine in the Kingdom of Bahrain. AB - Following the publication of the original article [1], it was brought to our attention that author Leena Alqasem was erroneously included as Leena Alqusem. PMID- 29508147 TI - Glutamate and Its Receptors as Therapeutic Targets for Migraine. AB - There is substantial evidence indicating a role for glutamate in migraine. Levels of glutamate are higher in the brain and possibly also in the peripheral circulation in migraine patients, particularly during attacks. Altered blood levels of kynurenines, endogenous modulators of glutamate receptors, have been reported in migraine patients. Population genetic studies implicate genes that are involved with glutamate signaling in migraine, and gene mutations responsible for familial hemiplegic migraine and other familial migraine syndromes may influence glutamate signaling. Animal studies indicate that glutamate plays a key role in pain transmission, central sensitization, and cortical spreading depression. Multiple therapies that target glutamate receptors including magnesium, topiramate, memantine, and ketamine have been reported to have efficacy in the treatment of migraine, although with the exception of topiramate, the evidence for the efficacy of these therapies is not strong. Also, because all of these therapies have other mechanisms of action, it is not possible to conclude that the efficacy of these drugs is entirely due to their effects on glutamate receptors. Further studies are needed to more clearly delineate the possible roles of glutamate and its specific receptor subtypes in migraine and to identify new ways of targeting glutamate for migraine therapy. PMID- 29508148 TI - Awareness and Misconceptions of Breast Cancer Risk Factors Among Laypersons and Physicians. AB - BACKGROUND: Primary prevention of cancer relies on awareness of and consequent identification of risk factors. We investigated knowledge of breast cancer risk factors not only among laywomen but also among female physicians. METHODS: The EDIFICE 4 nationwide observational survey was conducted by phone interviews of a representative female population (737 laywomen and 105 female physicians) aged 40 75 years, using the quota method. This analysis focuses on spontaneous replies to the question "In your opinion, what are the five main risk factors that increase the risk of breast cancer?". RESULTS: Heredity/Family history of breast cancer was the most widely recognized risk factor in both study populations (98.1% physicians vs. 54.2% laywomen; P <= 0.01). Smoking (19.0 and 17.5%) and alcohol consumption (3.8 and 5.5%) were among the lifestyle risk factors that were cited by similar proportions of physicians and laywomen, respectively. Other established risk factors were however very rarely cited by either physicians or laywomen, e.g., Exposure to medical radiation (4.8 vs. 0.4%, respectively; P <= 0.05) or not cited at all, i.e., Benign mastopathy and Personal history of breast cancer. CONCLUSION: This survey highlights a number of misconceptions relating to behavioral risk factors for breast cancer, including the relative impact of alcohol and tobacco consumption and the importance of menopausal status. The limited awareness of the risk related to Exposure to medical radiation, Benign mastopathy, or Personal history raises concern regarding compliance with national screening recommendations. PMID- 29508150 TI - Analgesia-related differences among the erector spinae, multifidus cervicis, and inter-semispinal plane blocks. PMID- 29508151 TI - Bromage motor blockade score - a score that has lasted more than a lifetime. PMID- 29508149 TI - Permanent His Bundle Pacing for Cardiac Resynchronization. AB - His bundle pacing (HBP) has been shown to be a feasible, beneficial, and safe way to achieve cardiac resynchronization therapy (CRT) with recruitment of the heart's physiological conduction system. HBP should be considered for those with unfavorable coronary sinus (CS) anatomy, and nonresponders to biventricular (BiV) pacing. HBP CRT may also help patients with the nonleft bundle branch block form of conduction delay and heart failure (HF). HBP CRT should be considered strongly in preventing right ventricular (RV) pacing-induced cardiomyopathy, especially after atrioventricular nodal ablation given the discrete nature of the block and the low likelihood of distal block. With increased operator experience and improved lead delivery systems, HBP success rates and safety have improved and are comparable to traditional RV pacing. Battery longevity is also likely comparable to traditional BiV CRT devices. We anticipate the use of HBP CRT growing significantly. PMID- 29508152 TI - A Systematic Literature Review of Technologies for Suicidal Behavior Prevention. AB - Suicide is the second cause of death in young people. The use of technologies as tools facilitates the detection of individuals at risk of suicide thus allowing early intervention and efficacy. Suicide can be prevented in many cases. Technology can help people at risk of suicide and their families. It could prevent situations of risk of suicide with the technological evolution that is increasing. This work is a systematic review of research papers published in the last ten years on technology for suicide prevention. In September 2017, the consultation was carried out in the scientific databases PubMed, ScienceDirect, PsycINFO, The Cochrane Library and Google Scholar. A general search was conducted with the terms "prevention" AND "suicide" AND "technology. More specific searches included technologies such as "Web", "mobile", "social networks", and others terms related to technologies. The number of articles found following the methodology proposed was 90, but only 30 are focused on the objective of this work. Most of them were Web technologies (51.61%), mobile solutions (22.58%), social networks (12.90%), machine learning (3.23%) and other technologies (9.68%). According to the results obtained, although there are technological solutions that help the prevention of suicide, much remains to be done in this field. Collaboration among technologists, psychiatrists, patients, and family members is key to advancing the development of new technology-based solutions that can help save lives. PMID- 29508154 TI - Complementary and Alternative Medicine Treatments for Generalized Anxiety Disorder: Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - INTRODUCTION: The objective was to evaluate efficacy/safety of complementary and alternative medicine (CAM) methods for generalized anxiety disorder (GAD) based on randomized controlled trials in adults. METHODS: Data sources. Six electronic databases ("generalized anxiety (disorder)" and "randomized trial") and reference lists of identified publications were searched to March 2017. STUDY SELECTION: Eligibility: full-text publications (English, German language); CAM versus conventional treatment, placebo/sham or no treatment; GAD diagnosed according to standard criteria; and a validated scale for disease severity. Of the 6693 screened records, 32 were included (18 on biologically-based therapies, exclusively herbal preparations; eight on manipulative and body-based therapies; and three on alternative medical systems and three on mind-body therapies). DATA EXTRACTION: Cochrane Collaboration methodology was used for quality assessment and data extraction. RESULTS: Direct comparisons of Kava Kava (Piper methysticum) extracts to placebo (4 quality trials, n = 233) were highly heterogeneous. Network meta-regression reduced heterogeneity and suggested a modest Kava effect [end-of-treatment Hamilton Anxiety scale score difference adjusted for baseline scores and trial duration: - 3.24 (95% CI - 6.65, 0.17; P = 0.059), Kava Kava 4 arms, n = 139; placebo 5 arms, n = 359]. Lavender (Lavandula angustifolia) extract (1 quality trial, 10 weeks, n = 523) and a combination of extracts of C. oxycantha, E. californica and magnesium (1 quality trial, 12 weeks, n = 264) were superior to placebo and balneotherapy was superior to paroxetine (1 quality trial, 8 weeks, n = 237) indicating efficacy. All other trials were small and/or of modest/low quality and/or lacked assay sensitivity. Safety reporting was poor. CONCLUSION: Evidence about efficacy/safety of most CAM methods in GAD is limited. Apparent efficacy of certain herbal preparations and body-based therapies requires further confirmation. PMID- 29508153 TI - Efficacy of Ivabradine in Combination with Beta-Blockers Versus Uptitration of Beta-Blockers in Patients with Stable Angina (CONTROL-2 Study). AB - INTRODUCTION: Heart rate (HR) reduction is an integral part of antianginal therapy, but many patients do not reach the guideline-recommended target of less than 60 bpm despite high use of beta-blockers (BB). Failure to uptitrate BB doses may be partly to blame. To explore other options for lowering HR and improving angina control, CONTROL-2 was initiated to compare the efficacy and tolerability of the combination of BBs with ivabradine versus uptitration of BBs to maximal tolerated dose, in patients with stable angina. METHODS: This multicenter, open, randomized study included 1104 patients with Canadian Cardiovascular Society (CCS) class II or III stable angina, in sinus rhythm, and on background stable treatment with non-maximal recommended doses of BBs. Consecutive patients were allocated to ivabradine + BB or BB uptitration in a 4:1 ratio. RESULTS: At the end of the study (week 16), addition of ivabradine to BB treatment and BB uptitration resulted in reduction in HR (61 +/- 6 vs. 63 +/- 8 bpm; p = 0.001). At week 16, significantly more patients on ivabradine + BB were in CCS class I than with BB uptitration (37.1% vs. 28%; p = 0.017) and significantly more patients were angina-free (50.6% vs. 34.2%; p < 0.001). Patient health status based on the visual analogue scale (VAS) was also better in the ivabradine + BB group. Adverse events (AEs) were significantly more common with BB uptitration than with the ivabradine + BB combination (18.4% vs. 9.4%, p < 0.001). CONCLUSION: In patients with stable angina, combination therapy with ivabradine + BB demonstrated good tolerability, safety, and more pronounced clinical improvement, compared to BB uptitration. TRIAL REGISTRATION: ISRCTN30654443. FUNDING: Servier. PMID- 29508155 TI - Distance and direction, but not light cues, support response reversal learning. AB - Across three experiments, we examined the cuing properties of metric (distance and direction) and nonmetric (lighting) cues in different tasks. In Experiment 1, rats were trained on a response problem in a T-maze, followed by four reversals. Rats that experienced a change in maze orientation (Direction group) or a change in the length of the start arm (Distance group) across reversals showed facilitation of reversal learning relative to a group that experienced changes in room lighting across reversals. In Experiment 2, rats learned a discrimination task more readily when distance or direction cues were used than when light cues were used as the discriminative stimuli. In Experiment 3, performance on a go/no go task was equivalent using both direction and lighting cues. The successful use of both metric and nonmetric cues in the go/no-go task indicates that rats are sensitive to both types of cues and that the usefulness of different cues is dependent on the nature of the task. PMID- 29508157 TI - Colon Cancer Screening Programs: Impact of an Organized Screening Strategy Assessed by the EDIFICE Surveys. AB - BACKGROUND: The aim of EDIFICE surveys is to improve insight into the behavior of the French population with regard to cancer prevention and participation in screening programs. Via the colorectal cancer screening program, all average-risk individuals in the 50-74-year age group are invited every 2 years to do a guaiac based or, since April 2015, an immunochemical fecal occult blood test. METHODS: The fifth edition of the nationwide observational survey was conducted by phone interviews using the quota method. A representative sample of 1299 individuals with no history of cancer (age, 50-74 years) was interviewed between 22 November and 7 December 2016. The present analysis focuses on minimum lifetime uptake of screening tests, compliance to recommended repeat-screening intervals, and reasons for non-participation. RESULTS: In 2016, 64% survey participants had been screened at least once and 38% had been screened in the previous 2 years, suggesting a trend towards increasing participation rates, particularly in the younger age categories and among men. The 2016 data also suggest that the newly implemented FIT-based screening program has been well perceived by the population. Up to one in four individuals cited "no risk factors" as the reason for not undergoing screening. This reveals ignorance of the fact that the colorectal cancer screening program actually targets all average-risk individuals in a given age group, without individual risk factors. CONCLUSION: We suggest the next step should be dedicated to educational approaches to explain exactly what screening involves and to persuasive messages targeting those who to date have remained unreceptive to information campaigns. PMID- 29508156 TI - Cardiac Resynchronization Therapy-Emerging Therapeutic Approaches. AB - Cardiac resynchronization therapy (CRT) is an important therapeutic tool in the management of patients with heart failure and electrical dyssynchrony. In appropriately selected patients, landmark randomized controlled trials have demonstrated morbidity and mortality benefit beyond standard goal-directed medical therapy. Current guidelines emphasize the greatest clinical efficacy of CRT in patients with symptomatic heart failure, left bundle branch block, and wide QRS duration (> 150 ms). Other relevant considerations include the presence of atrial fibrillation, the presence of AV block, the etiology of cardiomyopathy, the presence of masked left-sided conduction delay, and the impact of comorbidities that might predict poor clinical response. At the time of CRT implantation, key considerations include targeting of the left ventricular (LV) lead to sites of greatest electrical and/or mechanical delay, the use of quadripolar versus bipolar LV pacing leads, evaluation of multiple pacing vectors to maximize electrical resynchronization, and in select instances pre-procedure imaging of the coronary venous anatomy to help guide decision-making at the time implant. Post-implant care includes the selective use of atrio-ventricular and inter-ventricular optimization algorithms, mitigation of right ventricular pacing, recognition, and treatment of suboptimal biventricular pacing, as well as management by a multi-disciplinary team of cardiovascular specialists. Emerging therapeutic strategies for patients eligible for CRT include the use of endocardial LV pacing, novel LV pacing options including multi-point pacing, His bundle pacing, and the integration of remote monitoring platforms that may identify patients at risk for clinical worsening. PMID- 29508158 TI - What Is the Role of Left Atrial Appendage Closure in the Rhythm Control of Atrial Fibrillation? AB - Interventional catheter ablation approaches to the rhythm control of atrial fibrillation (AF) have advanced significantly in the past decade. The foundation of the catheter ablation in AF is electrical isolation of the pulmonary veins (PVI). However, PVI only in more advanced stages of AF (persistent AF) has only modest to poor success rates prompting a search for alternative and adjunctive procedures to improve the outcomes of ablation in persistent AF. The left atrial appendage (LAA) is well understood to be a primary source of emboli in AF but less well known be a trigger or driver for AF. Therefore, LAA exclusion is an attractive target to potentially improve AF ablation outcomes in more advanced stages of AF and possibly as an alternative to chronic oral anticoagulation in the prevention of stroke and systemic embolism in AF. However, the precise role of LAA closure in the interventional approach to AF is still to be elucidated with ongoing clinical investigations. PMID- 29508159 TI - A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery. AB - Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%. There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye. The hydrogel is formulated as a composite of hyaluronic acid (HA) and methylcellulose (MC). The amphiphilic nanoparticles are composed of poly(ethylene oxide) (PEO) and poly(lactic acid) (PLA). Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation, and the formulation reliably switched between thixotropy and temperature-dependent rheopexy when it was tested in a rheometer under conditions that simulate the ocular surface, including blinking. These properties should ensure that the formulation coats the cornea through blinking of the eyelid and facilitate application of the medication as an eye drop immediately prior to the patient's bedtime. We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations. This work paves the way for the introduction of novel products targeting ocular diseases to the market. PMID- 29508160 TI - Microstructural properties of trabecular bone autografts: comparison of men and women with and without osteoporosis. AB - : The microstructure of autologous bone grafts from men over 50 years old and postmenopausal women undergoing spinal fusion were evaluated using micro-CT. We demonstrated postmenopausal women, especially those with osteoporosis (OP) presented more serious microarchitectural deterioration of bone grafts. PURPOSE: This study was undertaken to determine microstructural properties of cancellous bone used as autologous bone grafts from osteoporosis patients undergoing lumbar fusion by comparing microstructural indices to controls. METHODS: Cancellous bone specimens from spinous processes were obtained from 41 postmenopausal women (osteoporosis women, n = 19; controls, n = 22) and 26 men over 50 years old (osteoporosis men, n = 8; controls, n = 18) during lumbar fusion surgery. The microstructural parameters were measured using micro-CT. RESULTS: Significant difference in bone volume fraction (BV/TV), specific bone surface (BS/BV), trabecular thickness (Tb.Th), and structure model index (SMI) value existed between postmenopausal women with OP and controls. Significant difference in trabecular number (Tb.N) existed between men over 50 years old with OP and controls. Postmenopausal women exhibited lower BV/TV, Tb.Th, and higher SMI value than men over 50 years old. Postmenopausal women with OP exhibited lower BV/TV, Tb.Th, and higher BS/BV than men over 50 years old with OP. CONCLUSIONS: Post menopausal women and older men with OP have worse bone quality in autografts than non-osteoporotic men and women. Postmenopausal women with OP presented serious microarchitectural deterioration in older population. PMID- 29508161 TI - ACMT 2018 Annual Scientific Meeting Abstracts-Washington, DC. PMID- 29508162 TI - Elevation of the serum liver enzyme levels during tolvaptan treatment in patients with autosomal dominant polycystic kidney disease (ADPKD). AB - BACKGROUND: In 2014, tolvaptan, a vasopressin receptor antagonist, was approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD) in Japan. Clinical trials of tolvaptan revealed frequent occurrence of the liver function abnormality. According to the package insert in Japan, liver function tests should be performed once a month in patients receiving tolvaptan. Furthermore, immediate discontinuation of tolvaptan is recommended in the appearance of liver function abnormalities. METHODS: Seven patients of ADPKD who was discontinued tolvaptan because of elevation of the serum liver enzyme levels were described in detail and analyzed. RESULTS: None of them fulfilled the criteria for applicability of Hy's law, which predicts a high risk of severe, potentially fatal, drug-induced liver injury (DILI). In our patients, the rate of increase of total kidney volume (TKV) significantly decreased during tolvaptan administration, but increased after discontinuation; in Cases 1-5, mean annual growth rate of TKV during administration was - 10.15%/year, and during discontinuation was + 23.72%/year. After the serum liver enzyme levels returned to normal range, tolvaptan was resumed in six patients with informed consent. Except one patient, tolvaptan has been continued without increase of the serum liver enzyme levels. CONCLUSION: In patients with mild elevation of the serum liver enzyme, as is less than three times the upper limit of normal (ULN), resumption of tolvaptan may be considered after the serum liver enzyme levels return to normal range. PMID- 29508163 TI - Flocculation and pentadecane production of a novel filamentous cyanobacterium Limnothrix sp. strain SK1-2-1. AB - OBJECTIVE: A novel filamentous cyanobacterium, a photosynthesizing microorganism, was isolated from a river, and its unique features of flocculation and pentadecane production were characterized. RESULTS: Microscopic observations and a phylogenetic analysis with 16S rDNA revealed that this strain was a Limnothrix species denoted as the SK1-2-1 strain. Auto cell-flocculation was observed when this strain was exposed to a two-step incubation involving a standing cultivation following a shaking preincubation. Flocculation was enhanced by blue light at a wavelength at 470 nm and irradiation for several hours to 1 day. Moreover, the strain exhibiting exponential cell growth may preferentially accumulate alkanes as pentadecane C15H32 alkane, which may be used as jet fuel, at a range of approximately 1% in the dry cell weight of flocculated cells. CONCLUSION: This is the first study on biofuel production using flocculated cells in which the specific manner of production may be regulated by cultivation conditions. PMID- 29508164 TI - Dependence and power in healthcare equipment supply chains. AB - Most healthcare organizations (HCOs) engage Group Purchasing Organizations (GPOs) as an outsourcing strategy to secure their supplies and materials. When an HCO outsources the procurement function to a GPO, this GPO will directly interact with the HCO's supplier on the HCO's behalf. This study investigates how an HCO's dependence on a GPO affects supply chain relationships and power in the healthcare medical equipment supply chain. Hypotheses are tested through factor analysis and structural equation modeling, using primary survey data from HCO procurement managers. An HCO's dependence on a GPO is found to be positively associated with a GPO's reliance on mediated power, but, surprisingly, negatively associated with a GPO's mediated power. Furthermore, analysis indicates that an HCO's dependence on a GPO is positively associated with an HCO's dependence on a GPO-contracted Original Equipment Manufacturer (OEM). HCO reliance on GPOs may lead to a buyer's dependence trap, where HCOs are increasingly dependent on GPOs and OEMs. Implications for HCO procurement managers and recommended steps for mitigation are offered. Power-dependence relationships in the medical equipment supply chain are not consistent with relationships in other, more traditional, supply chains. While dependence in a supply chain relationship typically leads to an increase in reliance on mediated power, GPO-dependent HCOs instead perceive a decrease in GPO mediated power. Furthermore, HCOs that rely on procurement service from GPOs are increasingly dependent on the OEMs. PMID- 29508165 TI - Determinants and Outcomes of Hospice Utilization Among Patients with Advance Staged Hepatocellular Carcinoma in a Veteran Affairs Population. AB - BACKGROUND: Hospice provides integrative palliative care for advance-staged hepatocellular carcinoma (HCC) patients, but hospice utilization in HCC patients in the USA is not clearly understood. AIMS: We examined hospice use and subsequent clinical course in advance-staged HCC patients. METHODS: We conducted a retrospective study on a national, Veterans Affairs cohort with stage C or D HCC. We evaluated demographics, clinical factors, treatment, and clinical course in relation to hospice use. RESULTS: We identified 814 patients with advanced HCC, of whom 597 (73.3%) used hospice. Oncologist management consistently predicted hospice use, irrespective of HCC treatment [no treatment: OR 2.25 (1.18 4.3), treatment: OR 1.80 (1.10-2.95)]. Among patients who received HCC treatment, hospice users were less likely to have insurance beyond VA benefits (47.2 vs. 60.0%, p = 0.01). Among patients without HCC treatment, hospice users were older (62.2 [17.2] vs. 60.2 [14.0] years, p = 0.05), white (62.1 vs. 52.9%, p = 0.01), resided in the Southern USA (39.5 vs. 31.8%, p = 0.05), and had a performance score >= 3 (41.9 vs. 31.8%, p = 0.01). The median time from hospice entry to death or end of study was 1.05 [2.96] months for stage C and 0.53 [1.18] months for stage D patients. CONCLUSIONS: 26.7% advance-staged HCC patients never entered hospice, representing potential missed opportunities for improving end-of life care. Age, race, location, performance, insurance, and managing specialty can predict hospice use. Differences in managing specialty and short-term hospice use suggest that interventions to optimize early palliative care are necessary. PMID- 29508166 TI - Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis in Mice via a Toll Like Receptor 4/p21-Activated Kinase 1 Cascade. AB - BACKGROUND: The underlying pathogenic mechanism of Fusobacterium nucleatum in the carcinogenesis of colorectal cancer has been poorly understood. METHODS: Using C57BL/6-ApcMin/+ mice, we investigated gut microbial structures with F. nucleatum, antibiotics, and Toll-like receptor 4 (TLR4) antagonist TAK-242 treatment. In addition, we measured intestinal tumor formation and the expression of TLR4, p21-activated kinase 1 (PAK1), phosphorylated-PAK1 (p-PAK1), phosphorylated-beta-catenin S675 (p-beta-catenin S675), and cyclin D1 in mice with different treatments. RESULTS: Fusobacterium nucleatum and antibiotics treatment altered gut microbial structures in mice. In addition, F. nucleatum invaded into the intestinal mucosa in large amounts but were less abundant in the feces of F. nucleatum-fed mice. The average number and size of intestinal tumors in F. nucleatum groups was significantly increased compared to control groups in ApcMin/+ mice (P < 0.05). The expression of TLR4, PAK1, p-PAK1, p-beta-catenin S675, and cyclin D1 was significantly increased in F. nucleatum groups compared to the control groups (P < 0.05). Moreover, TAK-242 significantly decreased the average number and size of intestinal tumors compared to F. nucleatum groups (P < 0.05). The expression of p-PAK1, p-beta-catenin S675, and cyclin D1 was also significantly decreased in the TAK-242-treated group compared to F. nucleatum groups (P < 0.05). CONCLUSIONS: Fusobacterium nucleatum potentiates intestinal tumorigenesis in ApcMin/+ mice via a TLR4/p-PAK1/p-beta-catenin S675 cascade. Fusobacterium nucleatum-induced intestinal tumorigenesis can be inhibited by TAK 242, implicating TLR4 as a potential target for the prevention and therapy of F. nucleatum-related colorectal cancer. PMID- 29508167 TI - Inhalative sedation with small tidal volumes under venovenous ECMO. AB - BACKGROUND: Inhalative sedation is an emerging method for long-term sedation in intensive care therapy. There is evidence that it is easy to control and may be beneficial compared to intravenous sedation. Yet little is known about the use in patients with compromised lung function. In this retrospective analysis, we searched files of patients receiving inhalative sedation under venovenous extracorporeal membrane oxygenator (vv-ECMO) support due to lung failure. METHODS: After ethical approval, we performed a retrospective analysis of patients receiving vv-ECMO support and inhalative sedation in the surgical ICU in 2015. Isoflurane was administered via the AnaConDa(r)-system. Sedation was tested using Richmond Agitation and Sedation scale (RASS). RESULTS: 7 patients were identified. Median age was 50 years (26/70 years). All were male. Median ECMO runtime was 129 h (37/1008 h) and the survival rate was 57.9%. Dose of isoflurane was 1.7 ml/h (0.8 / 4.0 ml/h) resulting in expiratory concentrations of 0.8 Vol% (0.3/1.8 Vol%), inspiratory of 0.6 Vol% (0.1/1.4 Vol%). Higher concentrations of isoflurane were associated with increased depth of sedation (expiratory p = 0.016; inspiratory p = 0.027; averaged p = 0.015). With tidal volume below 350 ml, association was still present for expiratory and averaged concentrations of isoflurane (expiratory p = 0.031; inspiratory p = 0.082; average p = 0.039). CONCLUSIONS: This is the first study that shows that inhalative concentrations of isoflurane are associated with depth of sedation in patients with lung failure. We were able to show that even with major impacts in lung mechanics and function targeted sedation with volatile anaesthetics is feasible and dose-response relationship appears to exist. PMID- 29508168 TI - Frequency Modulation and Absorption Improvement of THz Micro-bolometer with Micro bridge Structure by Spiral-Type Antennas. AB - Antenna-coupled micro-bridge structure is proven to be a good solution to extend infrared micro-bolometer technology for THz application. Spiral-type antennas are proposed in 25 MUm * 25 MUm micro-bridge structure with a single separate linear antenna, two separate linear antennas, or two connected linear antennas on the bridge legs, in addition to traditional spiral-type antenna on the support layer. The effects of structural parameters of each antenna on THz absorption of micro bridge structure are discussed for optimized absorption of 2.52 THz wave radiated by far infrared CO2 lasers. The design of spiral-type antenna with two separate linear antennas for wide absorption peak and spiral-type antenna with two connected linear antennas for relatively stable absorption are good candidates for high absorption at low absorption frequency with a rotation angle of 360*n (n = 1.6). Spiral-type antenna with extended legs also provides a highly integrated micro-bridge structure with fast response and a highly compatible, process simplified way to realize the structure. This research demonstrates the design of several spiral-type antenna-coupled micro-bridge structures and provides preferred schemes for potential device applications in room temperature sensing and real-time imaging. PMID- 29508169 TI - Combined SGLT2 and DPP4 Inhibition Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Nephropathy in Mice with Type 2 Diabetes. AB - BACGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). METHODS AND RESULTS: Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 +/- 0.8 mg/dl. It increased to 55.7 +/- 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 +/- 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 +/- 0.8 mg/dl). Serum creatinine was 0.16 +/- 0.02 and 1.01 +/- 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 +/- 0.02 and 0.40 +/- 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 +/- 0.1 vs. 0.6 +/- 0.2 ng/ml) as compared to WT mice. Dapa (2.4 +/- 0.1) and Dapa+Saxa (1.4 +/- 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1beta, IL-6, caspase-1, TNF-alpha, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio. CONCLUSIONS: Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM. PMID- 29508170 TI - Is Male Facial Width-to-Height Ratio the Target of Sexual Selection? PMID- 29508171 TI - Differences in HIV Risk Behaviors Between Self-Identified Gay and Bisexual Young Men Who are HIV-Negative. AB - Young men who have sex with men (MSM) are disproportionately affected by HIV, but it remains unclear whether there are differences in HIV risk behaviors between self-identified gay and bisexual young men. To address this, the current study examined differences in condomless sex and substance use before sex with male partners between self-identified gay and bisexual young men who are HIV-negative. Additionally, we examined differences in HIV risk behaviors with male versus female partners among the bisexual men. We used four waves of data spanning 24 months from a cohort of young MSM ages 16-29. At each wave, participants reported on up to four partners, allowing us to examine within-person associations. Compared to gay men, bisexual men reported more insertive condomless anal sex (CAS) with casual partners, they were more likely to report marijuana use before sex, and they were less likely to report lifetime HIV testing and PrEP use. Alcohol and marijuana use before sex were associated with CAS for both gay and bisexual men, but the association between marijuana use and insertive CAS was stronger for bisexual men. Bisexual men reported more condomless sex with female partners compared to male partners, but this was not significant after accounting for alcohol and marijuana use. Bisexual men were more likely to report alcohol and marijuana use with female partners compared to male partners, but both alcohol and marijuana use were associated with condomless sex regardless of partner gender. Findings support the need for tailored HIV prevention for self identified bisexual men to address their lack of preventive behaviors, their increased engagement in certain risk behaviors with male partners, and their engagement in risk behaviors with female partners. PMID- 29508172 TI - Epidermal growth factor receptor function in the human urothelium. AB - PURPOSE: Epidermal growth factor receptor (EGFr)-targeted therapy may be used in subgroups of patients with urinary bladder cancer. Here we assessed the role of EGFr in urothelial proliferation and migration in a two- and three-dimensional cell culture system. METHODS: UROtsa cells derived from normal urothelium and malignant T24 cells were cultured in a Type I collagen gel. Proliferation and migration of urothelial cells, in the absence and presence of the EGFr inhibitor cetuximab, were assessed with a proliferation test (ATCC) and with the Axioplan 2 imaging microscope with a motorized stage (Carl Zeiss), respectively. The expressions of cytokeratin (CK) 17, CK20, EGFr, pEGFr, laminin, occludin and zonula occludens 1 (ZO-1) were assessed with immunohistochemistry and/or western blot. RESULTS: UROtsa spheroids were formed after 7 days in culture, while T24 cells did not form spheroids. UROtsa expressed CK20 but not laminin or CK17 and consequently resembled umbrella cells. In UROtsa and T24, cetuximab inhibited urothelial proliferation, induced cleavage of EGFr and/or pEGFR but did not affect urothelial migration. The tight junction protein occludin was cleaved, and the formation of cellular spheroids was inhibited in UROtsa by the presence of cetuximab. CONCLUSIONS: EGFr modulates urothelial proliferation and the formation of the three-dimensional structure of the urothelium possibly by interfering with occludin. The present data also show a cell culture technique enabling phenotypically normal urothelial cells to form epithelial structures in contrast to malignant urothelial cells. PMID- 29508173 TI - Benefit of an operating vehicle preventing peritonitis in peritoneal dialysis patients: a retrospective, case-controlled study. AB - BACKGROUND: Peritonitis, which is one of the leading complications of peritoneal dialysis (PD) worldwide, severely affected morbidity and mortality of the PD patients. Although many efforts have been made to prevent PD-related peritonitis, it seems impossible to prevent it completely. Many causes have been reported to lead to peritonitis, and contamination during bag exchange is one of the important risk factors for peritonitis. METHODS: Here, we introduce an operating vehicle, which we invented to provide a sterile and safe space for bag exchange. A single-center, retrospective, case-control study was undertaken to determine whether this operating vehicle has a protective role in preventing peritonitis. In total, 462 continuous ambulatory peritoneal dialysis patients were included in this study from October 2014 to March 2017. According to their personal will, these patients chose to use operating vehicle or traditional method during their bag exchange. The demographic, clinical and laboratory data of these patients in the two groups were collected, analyzed and compared. RESULTS: Of 462 patients with home dialysis, operating vehicle group consisted of 61 patients, and control group consisted of 401 patients. In the control group, over 677 patient-years, peritonitis occurred in 69 of 401 patients (17.2%), while in the operating vehicle group, over 60 patient-years, only 4 of 61 patients (6.6%) had episodes of peritonitis. The number of patients suffered from peritonitis was significantly decreased in the operating vehicle group (P = 0.034). Besides, there were a total of 99 episodes of peritonitis, and the rate was 1 episode every 7.2 patient-years in control group and 1 episode every 12 patient-years in the operating vehicle group. There was significant difference between the two groups (0.013). Positive dialysate cultures were obtained in majority of the peritonitis episodes (60.6%). CONCLUSION: Operating vehicle might help to reduce PD-related peritonitis by preventing contamination during bag exchange. Further studies are still needed to demonstrate the protective role of the operating vehicle in preventing peritonitis. PMID- 29508174 TI - Silencing of CXCL12 performs a protective effect on C5b-9-induced injury in podocytes. AB - PURPOSE: Podocytes, terminal differentiation cell in glomerulu, are crucial to kidney-related diseases such as membranous nephropathy (MN). MN is characterized by podocyte injury and glomerular basement membrane thickening. This paper focused to investigate the expression of chemokine (C-X-C motif) ligand 12 (CXCL12) in MN patients and its possible role in podocyte injury. METHODS: Through the enzyme-linked immunosorbent assay, CXCL12 level in the serum and urine of MN patients was examined. Further, several assays of cell viability, apoptosis, quantitative real-time PCR and western blot were applied to explore the effects of CXCL12 in the model of podocyte injury. RESULTS: We found a significant increase of CXCL12 in serum and urine of MN patients, which indicated that CXCL12 may be involved in the progression of MN. And in vitro C5b-9-induced podocyte injury model, the proliferation of podocytes was inhibited whereas CXCL12/CXCR4 and phosphorylated STAT3 (p-STAT3) were increased. Silencing of CXCL12 remarkably promoted cell proliferation, inhibited cell apoptosis and suppressed CXCL12/CXCR4, p-STAT3 and caspase 3. Consistently, STAT3 inhibitor and berberine (a CXCL12 antagonist) also reduced CXCL12 treatment-induced apoptosis. CONCLUSIONS: All data suggested that silencing of CXCL12 had a protective effect on podocyte injury, which may be through inhibiting CXCL12/STAT3 signaling pathway. PMID- 29508175 TI - A Novel Role of Id1 in Regulating Oscillatory Shear Stress-Mediated Lipid Uptake in Endothelial Cells. AB - Inhibitor of DNA binding 1 (Id1) has been shown to be involved in adipogenesis and metabolism, which may contribute to atherosclerotic progression. However, it remains unclear how Id1 regulates endothelial cell functions and atherosclerosis in response to oscillatory shear stress. The current study aims to evaluate the effects of oscillatory shear stress on LDL uptake by endothelial cells and to delineate the roles of Id1 in this process. Using an in vivo ligation model of ApoE-/- mice and applying low and oscillatory shear stress (OSS) in vitro, we found that OSS can effectively promote lipid uptake. In vivo en face staining results showed that OSS down-regulated Id1 expression. In vitro, OSS activated Id1 transiently but eventually inhibited its expression with time. Overexpression of Id1 can abolish OSS-mediated lipid uptake in ECs. In addition, Id1 overexpression and knockdown experiments demonstrated that Id1 can regulate LDLR expression to influence lipid uptake. Immunoprecipitation and subcellular localization results further suggested that Id1 can combine with sterol regulatory element-binding protein1 (SREBP1), which may be related to the Id1 mediated LDLR down-expression. Our study shows a biomechanical role of Id1 in endothelial cells' uptake of lipid by down-regulating LDLR, which could help understand how oscillatory flow affects atherosclerotic development. PMID- 29508176 TI - Factor VIIa administration in orthotopic heart transplant recipients and its impact on thromboembolic events and post-transplant outcomes. AB - Recombinant, activated factor VIIa (rFVIIa) is used during cardiac surgeries to mitigate refractory coagulopathic bleeding. The purpose of this study was to examine whether rFVIIa use in orthotopic heart transplant (OHT) recipients was associated with a higher incidence of thromboembolic (TE) events compared to patients who did not. A single-center, retrospective, cohort study was performed on OHT recipients who received rFVIIa for refractory coagulopathic bleeding from January 2013 to December 2015. Patients were evaluated for up to 6 months after transplantation and assessed for TE events, rejection, readmissions, graft survival, and patient survival. Categorical variables were analyzed using the Chi square test while student's t or ANOVA testing was utilized for continuous variables. Of the 62 patients who met inclusion criteria, 27 patients received rFVIIa, and 35 patients were selected for the control group. The overall incidence of TE events was not significantly different between patients who received rFVIIa compared to patients in the control group (14.8% vs 11.4%) (p = 0.69). Within 14 days, 14.81% of rFVIIa patients suffered a TE event compared to 5.7% of the control group (p = 0.23). Rejection, readmissions, graft survival, and patient survival were not significantly different at any time points. Use of rFVIIa in heart transplantation showed no difference in the overall rate of TE events, however, there was a nonsignificant trend toward higher risk of early TE development in the rFVIIa group compared to the control group. PMID- 29508178 TI - Prevalence of Childhood Mental Disorders Among School Children of Kashmir Valley. AB - Prevalence of mental disorders among children is affected by armed conflict and same is true in protracted conflict of Kashmir, where the ongoing conflict has affected mental health of children badly. In order to understand mental health condition of school going children, the present study was designed to study the nature and prevalence of mental disorders among school children in Kashmir valley. The present study employed multi-stage sampling and multi-informant reporting of mental health problems in children. A sample of 1000 school children was taken from 12 schools of Shopian district through systematic random sampling method. Data was collected at different levels of screening by using Strength and Difficulties Questionnaire (SDQ) (Teacher form) and Mini International Neuropsychiatric Inventory (MINI-Kid). Socio-demographic data sheet was included to gather relevant information. The prevalence rates of mental disorders among school children were presented at different levels of screening. It was found to be 27.1% based on SDQ and 22.2% when assessed by MINI-Kid at second level of screening. The most commonly found mental disorders were of anxiety (8.5%), followed by mood disorders (6.3%) and then behavioural disorders (4.3%). Percentage of schoolgoing children with mental disorders in Kashmir is much more than in other states of India. The political conflict in the state and lack of mental health facilities give rise to high prevalence rates of mental disorders and warrant our urgent attention. PMID- 29508177 TI - Anti-adalimumab antibodies in a cohort of patients with juvenile idiopathic arthritis: incidence and clinical correlations. AB - Adalimumab is a TNF-alpha blocker antibody similar in structure and function to natural human IgG1. Even if adalimumab is fully humanized, the development of anti-drug antibodies has been reported in several inflammatory conditions. The objective of our study was to assess the presence of anti-adalimumab antibodies (AAA) and their clinical relevance in a cohort of juvenile idiopathic arthritis (JIA) patients on adalimumab. This is a prospective observational cohort study recruiting JIA children. Experiments were performed using a validated surface plasmon resonance (SPR)-based optical assay (Biacore(r) T100). Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score with 10 joint count (JADAS-10). The Mann-Whitney U test, Wilcoxon signed-rank test for paired samples, chi-square, and Fisher exact test were used to compare data. Pearson's and Spearman's correlation tests were used to determine correlation coefficients for entered variables: demographic, clinical, and serological data. Ten (37%) out of 27 patients included in the study had at least one AAA-positive sample. Patients developed AAA between 3 and 38 months after starting adalimumab. Seven (70%) out of 10 children with AAA positivity experienced at least a relapse compared to 4 (23.5%) out of 17 AAA-negative children (rs 0.45, p < 0.017). In conclusion, using an innovative and accurate assay method, we found a high incidence of anti-drug antibodies in a cohort of adalimumab-treated JIA patients observed over a mean period of 40 weeks; the presence of anti-adalimumab antibodies seemed to be related to the number of relapses. PMID- 29508180 TI - Predictors of Adoption and Reach Following Dialectical Behavior Therapy Intensive TrainingTM. AB - Dialectical behavior therapy (DBT) is an evidence-based treatment for borderline personality disorder. The DBT Intensive TrainingTM is widely used to train community clinicians to deliver DBT, but little is known about its effectiveness. This study prospectively evaluated predictors of adoption and reach of DBT among 52 community teams (212 clinicians) after DBT Intensive TrainingTM. Pre-post training questionnaires were completed by trainees and a follow-up survey by team leaders approximately 8 months later. Overall, 75% of teams adopted all DBT modes and delivered DBT to an average of 118 clients. Lower training and program needs, fewer bachelor's-level clinicians, and greater prior DBT experience predicted adoption of more DBT modes. More prior DBT experience, smaller team size, more negative team functioning, and staff with lower job satisfaction, growth, efficacy, and influence predicted greater DBT reach. DBT Intensive TrainingTM appears effective in promoting DBT adoption and reach in routine clinical practice settings. PMID- 29508179 TI - Stakeholder Perceptions of the Barriers to Receiving and Delivering Exposure Based Cognitive Behavioral Therapy for Anxiety Disorders in Adult Community Mental Health Settings. AB - CBT is considered the first-line treatment for anxiety disorders, particularly when it involves gradual confrontation with feared stimuli (i.e., exposure); however, delivery of CBT for anxiety disorders in real-world community clinics is lacking. This study utilized surveys we developed with key stakeholder feedback (patient, provider, and administrator) to assess patient and provider/administrator perceptions of the barriers to delivering (or receiving) CBT for anxiety disorders. Providers/administrators from two counties in California (N = 106) indicated lack of training/competency as primary barriers. Patients in one large county (N = 42) reported their own symptoms most often impacted treatment receipt. Both groups endorsed acceptability of exposure but indicated that its use in treatment provided/received had been limited. Implications and recommendations are discussed. PMID- 29508181 TI - Movement of Genetic Counselors from Clinical to Non-clinical Positions: Identifying Driving Forces. AB - A previous study of genetic counselors (GCs) in the state of Indiana identified movement out of clinical positions within the past 2 years. The aims of this study were to determine if this trend is nationwide and identify reasons why GCs are leaving their positions and factors that might help employers attract and retain GCs. An email was sent to members of the American Board of Genetic Counseling with a link to an online confidential survey. There were 939 responses (23.5% response rate). Overall, 52% of GCs report being highly satisfied in their current position, although almost two thirds think about leaving and one third had changed jobs within the past 2 years. Of those who had changed jobs (n = 295), 74.9% had been working in a hospital/clinic setting but only 46.3% currently do, demonstrating a major shift out of the clinic (p < 0.001). The top three reasons cited for leaving a position were work environment/institutional climate, salary/benefits, and a lack of feeling valued/recognized as a professional. These results confirm that GCs are moving out of clinical positions and document elements of job satisfaction. We suggest points for employers to consider when trying to recruit or retain GCs. PMID- 29508182 TI - Development and Validation of a Prediction Model for Postoperative Peritoneal Metastasis After Curative Resection of Colon Cancer. AB - BACKGROUND: Detection of peritoneal metastasis remains challenging due to the limited sensitivity of current examination methods. This study aimed to establish a prediction model for estimating the individual risk of postoperative peritoneal metastasis from colon cancer to facilitate early interventions for high-risk patients. METHODS: This study investigated 1720 patients with stages 1-3 colon cancer who underwent curative resection at the University of Tokyo Hospital between 1997 and 2015. The data for the patients were retrospectively retrieved from their medical records. The risk score was developed using the elastic net techniques in a derivation cohort (973 patients treated in 1997-2009) and validated in a validation cohort (747 patients treated in 2010-2015). RESULTS: The factors selected using the elastic net approaches included the T stage, N stage, number of examined lymph nodes, preoperative carcinoembryonic antigen level, large bowel obstruction, and anastomotic leakage. The model had good discrimination (c-index, 0.85) and was well-calibrated after application of the bootstrap resampling method. Discrimination and calibration were favorable in external validation (c-index, 0.83). The model presented a clear stratification of patients' risk for postoperative peritoneal recurrence, and decision curve analysis showed its net benefit across a wide range of threshold probabilities. CONCLUSIONS: This study established and validated a prediction model that can aid clinicians in optimizing postoperative surveillance and therapeutic strategies according to the individual patient risk of peritoneal recurrence. PMID- 29508183 TI - Possible Modulatory Effect of Tamarind Seed Coat Extract on Fluoride-Induced Pulmonary Inflammation and Fibrosis in Rats. AB - Fluorosis (fluoride toxicity) seems to be reduced by plant secondary metabolites. Tamarind seed coat extract (TSCE), a mixture of procyanidins and polyphenols, possesses numerous pharmacological activities. Regardless of its beneficial properties, the underlying molecular mechanism against chronic fluorosis in vivo is not known. Hence, the present study is aimed to investigate the efficacy of TSCE against fluoride (F-)-induced pulmonary toxicity in rats. Female Wistar rats were randomly divided into four groups and treated with NaF (300 ppm in drinking water) and TSCE (100 mg/kg/bw by oral intubation) alone and in combination daily for 30 days. The results showed that F- exposure-induced modifications in lung injury markers in both serum and BALF were restored by TSCE supplementation. Additionally, F--induced changes in oxidative stress (NOX4 and p38alpha MAPK), inflammation (NF-kappaB, COX-2, and HO-1), apoptosis (Hsp27, Hsp60, caspase3p20, and PARP1), and fibrosis (TGF-beta1, psmad3, Col1alphal, and hydroxyproline level) markers in the lungs were modulated by TSCE. Thus, TSCE offers protection against F--induced pulmonary inflammation and fibrosis in rats. PMID- 29508184 TI - IL-33 Treatment Attenuates the Systemic Inflammation Reaction in Acinetobacter baumannii Pneumonia by Suppressing TLR4/NF-kappaB Signaling. AB - Interleukin (IL)-33 treatment has been reported to reduce mortality in a rat model of sepsis, and the present study aimed to determine whether this effect of IL-33 is achieved through a reduction in the systemic inflammatory response in Acinetobacter baumannii pneumonia. After induction of pneumonia, rats were treated with normal saline or IL-33, and mortality over 5 days was recorded. Inflammation within lung tissues was evaluated by hematoxylin and eosin staining as well as measurement of the concentrations of IL-8 and tumor necrosis factor alpha (TNF-alpha) in the bronchoalveolar lavage fluid (BALF) and plasma by enzyme linked immunosorbent assay. In addition, the expression of Toll-like receptor 4 (TLR4), ST2, and nuclear factor kappa B (NF-kappaB) in rat lung tissues was assessed by western blotting. The result showed that the mortality rate and systemic inflammation were significantly increased in rats upon infection with A. baumannii, as evidenced by significant increases in the IL-8 and TNF-alpha levels in BALF and plasma as well as increased NF-kappaB activity and TLR4 expression in rat lung tissues. Importantly, IL-33 (1 MUg/kg) treatment significantly decreased mortality and pulmonary inflammation in A. baumannii-infected rats. Moreover, IL 33 treatment suppressed the elevation of IL-8 and TNF-alpha levels and inhibited TLR4 expression and NF-kappaB activation. Overall, these results suggest that IL 33 may decrease the mortality and inhibit the systematic inflammatory response associated with A. baumannii pneumonia by suppressing TLR4/NF-kappaB signaling. PMID- 29508185 TI - Anti-Inflammatory Effects of Gingerol on Lipopolysaccharide-Stimulated RAW 264.7 Cells by Inhibiting NF-kappaB Signaling Pathway. AB - Gingerol was the main functional substance of Zingiberaceous plant which has been known as traditional medicine for thousands of years. The purpose of this experiment was to explore anti-inflammatory effects of gingerol and study the possible mechanism in lipopolysaccharide (LPS)-stimulated RAW246.7 cells. The cells were treated with 10 MUg/mL LPS and 300, 200, 100, and 50 MUg/mL gingerol for 24 h. The cytotoxicity of gingerol was determined by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetra-zoliumbromide (MTT) method. Nitric oxide (NO) production was observed using Griess assays. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL 6 have been analyzed by ELISA. Real-time PCR was used to detect the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-6, and IL-1beta in LPS-induced RAW246.7 cells. Nuclear transcription factor kappa-B (NF-kappaB) signaling pathway-related proteins have been assessed by western blot assays. The determination of MTT showed that cell viability was not significantly affected by up to 300 MUg/mL gingerol. Compared with LPS group, 50, 100, 200, and 300 MUg/mL gingerol can inhibit the production of NO and the inhibitory rate was 10.4, 29.1, 58.9, and 62.4%, respectively. The results indicated gingerol existed anti-inflammatory effect. In addition, gingerol also observably inhibited LPS-induced TNF-alpha, IL-1beta, IL-6, and PGE2 (p < 0.01) expression and secretion in a dose-dependent manner. At the genetic level, after the intervention of gingerol, mRNA transcriptions of iNOS, COX-2, IL-6, and IL 1beta were all decreased. The protein expressions of iNOS, NF-kappaB, p-p65, and p-IkappaB were significantly increased in LPS-induced cells, while these changes were reversed by the treatment with gingerol. This study suggested that gingerol exerts its anti-inflammatory activities in LPS-induced macrophages which can inhibit the production of inflammatory cytokines by targeting the NF-kappaB signaling pathway. PMID- 29508187 TI - Editorial: 2017 in Review. PMID- 29508188 TI - Detection and Characterization of a Novel Norovirus in Bats, China. PMID- 29508186 TI - Mesenchymal stem cell cultivation in electrospun scaffolds: mechanistic modeling for tissue engineering. AB - Tissue engineering is a multidisciplinary field of research in which the cells, biomaterials, and processes can be optimized to develop a tissue substitute. Three-dimensional (3D) architectural features from electrospun scaffolds, such as porosity, tortuosity, fiber diameter, pore size, and interconnectivity have a great impact on cell behavior. Regarding tissue development in vitro, culture conditions such as pH, osmolality, temperature, nutrient, and metabolite concentrations dictate cell viability inside the constructs. The effect of different electrospun scaffold properties, bioreactor designs, mesenchymal stem cell culture parameters, and seeding techniques on cell behavior can be studied individually or combined with phenomenological modeling techniques. This work reviews the main culture and scaffold factors that affect tissue development in vitro regarding the culture of cells inside 3D matrices. The mathematical modeling of the relationship between these factors and cell behavior inside 3D constructs has also been critically reviewed, focusing on mesenchymal stem cell culture in electrospun scaffolds. PMID- 29508189 TI - Avian Influenza A (H7N9) Virus in a Wild Land Bird in Central China, Late 2015. PMID- 29508190 TI - Long-term evaluation of ocular hypertension with primary angle closure and primary open angles. AB - PURPOSE: To evaluate the long-term course of primary angle-closure ocular hypertension and primary open-angle ocular hypertension and possible risk factors for progression to glaucoma. METHODS: A total of 109 eyes of 109 ocular hypertension (OHT) patients with a minimum follow-up period of 5 years having complete ocular/medical records were evaluated. They were classified into primary angle closure or primary open angle based on gonioscopy at baseline. Baseline and review data of Humphrey field analyser, HFA, and Heidelberg retinal tomography, HRT, were recorded. Guided progression analysis (GPA) and univariate Cox regression were used for time to event analysis in identifying progression to glaucoma. RESULTS: Over a mean follow-up of 12.18 +/- 4.8 years, progression to glaucoma was 17.43% (19 eyes), out of whom 5.5% (6 eyes) showed >= 3 loci on GPA. Sub-classifying them, progression to primary angle-closure glaucoma was 19.72%, and that of primary open-angle glaucoma was 13.16%. The mean time to progression was 9.34 +/- 3.6 years. Significant risk factors included small disc area (<= 1.99 sq.mm on HRT), requirement of >= 2 drugs to maintain target IOP and those engaged in activities yielding a Valsalva effect in daily life. Coronary artery disease (CAD) and systemic use of steroids were associated with increased severity. CONCLUSION: Overall progression of OHT to glaucoma was 17.43% over a mean of 9 years, with target IOP of <= 18 mm Hg. Patients with smaller discs, CAD, exercising Valsalva type activities and using >= 2 glaucoma medications or systemic steroids should be closely monitored. PMID- 29508192 TI - Correction to: Risk exposure assessment of per- and polyfluoroalkyl substances (PFASs) in drinking water and atmosphere in central eastern China. AB - The original publication of this paper contains a mistake. PMID- 29508191 TI - Relative Abundance of Proteins in Blood Plasma Samples from Patients with Chronic Cerebral Ischemia. AB - A comparative protein profile analysis of 17 blood plasma samples from patients with ischemia and 20 samples from healthy volunteers was carried out using ultra high resolution mass spectrometry. The analysis of measurements was performed using the proteomics search engine OMSSA. Normalized spectrum abundance factor (NSAF) in the biological samples was assessed using SearchGUI. The findings of mass spectrometry analysis of the protein composition of blood plasma samples demonstrate that the depleted samples are quite similar in protein composition and relative abundance of proteins. By comparing them with the control samples, we have found a small group of 44 proteins characteristic of the blood plasma samples from patients with chronic cerebral ischemia. These proteins contribute to the processes of homeostasis maintenance, including innate immune response unfolding, the response of a body to stress, and contribution to the blood clotting cascade. PMID- 29508193 TI - Phytotoxicity and cytogenotoxicity of hydroalcoholic extracts from Solanum muricatum Ait. and Solanum betaceum Cav. (Solanaceae) in the plant model Lactuca sativa. AB - Plants are rich in biologically active compounds. They can be explored for the production of bioherbicides. In this context, the present work aimed to evaluate the allelopathic effect of hydroalcoholic extracts from two Solanaceae species: Solanum muricatum Ait. and Solanum betaceum Cav. For this end, we conducted phytochemical screening and biological assays, determining the effects of the extracts on germination, early development, cell cycle, and DNA fragmentation in plantlets and meristematic cells of the plant model Lactuca sativa L. (lettuce). The percentage of seeds germinated under effect of S. muricatum extract did not differ from the control, but plantlet growth was reduced at the highest concentrations. For S. betaceum extract, dose dependence was observed for both germination and plantlet development, with the highest concentrations inhibiting germination. The growth curves revealed the concentrations of 2.06 and 1.93 g/L for S. muricatum and S. betaceum extracts, respectively, as those reducing 50% of root growth (RG). At these concentrations, both extracts presented mitodepressive effect, besides inducing significant increase in the frequency of condensed nuclei, associated to DNA fragmentation and cytoplasmic shrinkage. The frequency of chromosome alterations was not significant. We further discuss the mechanisms of action related to the chemical composition of the extracts, which presented organic acids, reducing sugars, proteins, amino acids, and tannins, besides catechins and flavonoids, only found in the extract of S. betaceum. PMID- 29508194 TI - Potential impacts of climate change and adaptation strategies for sunflower in Pakistan. AB - Growth, development, and economic yield of agricultural crops rely on moisture, temperature, light, and carbon dioxide concentration. However, the amount of these parameters is varying with time due to climate change. Climate change is factual and ongoing so, first principle of agronomy should be to identify climate change potential impacts and adaptation measures to manage the susceptibilities of agricultural sector. Crop models have ability to predict the crop's yield under changing climatic conditions. We used OILCROP-SUN model to simulate the influence of elevated temperature and CO2 on crop growth duration, maximum leaf area index (LAI), total dry matter (TDM), and achene yield of sunflower under semi-arid conditions of Pakistan (Faisalabad, Punjab). The model was calibrated and validated with the experimental data of 2012 and 2013, respectively. The simulation results showed that phenological events of sunflower were not changed at higher concentration of CO2 (430 and 550 ppm). However LAI, achene yield, and TDM increased by 0.24, 2.41, and 4.67% at 430 ppm and by 0.48, 3.09, and 9.87% at 550 ppm, respectively. Increased temperature (1 and 2 degrees C) reduced the sunflower duration to remain green that finally led to less LAI, achene yield, and TDM as compared to present conditions. However, the drastic effects of increased temperature on sunflower were reduced to some extent at 550 ppm CO2 concentration. Evaluation of different adaptation options revealed that 21 days earlier (as compared to current sowing date) planting of sunflower crop with increased plant population (83,333 plants ha-1) could reduce the yield losses due to climate change. Flowering is the most critical stage of sunflower to water scarcity. We recommended skipping second irrigation or 10% (337.5 mm) less irrigation water application to conserve moisture under possible water scarce conditions of 2025 and 2050. PMID- 29508195 TI - Assessment of n-pentanol/Calophyllum inophyllum/diesel blends on the performance, emission, and combustion characteristics of a constant-speed variable compression ratio direct injection diesel engine. AB - Alcohol is used as an additive for a long time with the petroleum-based fuels. In this study, the higher alcohol, n-pentanol, was used as an additive to Calophyllum inophyllum (CI) biodiesel/diesel blends at 10, 15, and 20% by volume. In all blends, the ratio of CI was maintained at 20% by volume. The engine characteristics of the pentanol fuel blends were compared with the diesel and CI20 (Calophyllum inophyllum 20% and diesel 80%) biodiesel blend. The nitrogen oxide (NO) emission of the pentanol fuel blends showed an increased value than CI20 and neat diesel fuel. The carbon dioxide (CO2) also increased with increase in pentanol addition with the fuel blends than CI20 fuel blend and diesel. The carbon monoxide (CO) and hydrocarbon (HC) emissions were decreased with increase in pentanol proportion in the blend than the CI20 fuel and diesel. The smoke emission was reduced and the combustion characteristics of the engine were also improved by using pentanol blended fuels. From this investigation, it is suggested that 20% pentanol addition with the biodiesel/diesel fuel is suitable for improved performance and combustion characteristics of a diesel engine without any engine modifications, whereas CO2 and NO emissions increased with addition of pentanol due to effective combustion. PMID- 29508196 TI - Spatial econometric analysis of factors influencing regional energy efficiency in China. AB - Increased environmental pollution and energy consumption caused by the country's rapid development has raised considerable public concern, and has become the focus of the government and public. This study employs the super-efficiency slack based model-data envelopment analysis (SBM-DEA) to measure the total factor energy efficiency of 30 provinces in China. The estimation model for the spatial interaction intensity of regional total factor energy efficiency is based on Wilson's maximum entropy model. The model is used to analyze the factors that affect the potential value of total factor energy efficiency using spatial dynamic panel data for 30 provinces during 2000-2014. The study found that there are differences and spatial correlations of energy efficiency among provinces and regions in China. The energy efficiency in the eastern, central, and western regions fluctuated significantly, and was mainly because of significant energy efficiency impacts on influences of industrial structure, energy intensity, and technological progress. This research is of great significance to China's energy efficiency and regional coordinated development. PMID- 29508197 TI - Sulfur removal from model fuel by Zn impregnated retorted shale and with assistance of design of experiments. AB - There is global concern about acid rain and other pollution which is caused by the consumption of oil. By decreasing sulfur content in the oil, we can reduce unwanted emissions and acid rain. Shale was used which is a solid waste generated in the pyrolysis of shale, impregnated with Zn as an adsorbent which removes sulfur present in fuels from the hexane/toluene model solution. An influence of the agitation time (60-180 min), temperature (25-35 degrees C), adsorbent mass (0.1-0.25 g), and initial sulfur concentration (100-250 ppm) factorial 24 with three central points totaling 19 experiments was applied to investigate the effect of the variables on the efficiency of sulfur removal in fuels. The values of the parameters tested for maximum sulfur removal were obtained as follows: contact time = 180 min, temperature = 35 degrees C, adsorbent mass = 0.25 g, and initial sulfur concentration = 100 ppm. The mathematical model proposed with R2 99.97% satisfied the experimental data. This may provide a theoretical basis for new research and alternative uses for tailings of schist industrialization in order to evaluate its potential. PMID- 29508198 TI - Investigation on the origin of sperm morphological defects: oxidative attacks, chromatin immaturity, and DNA fragmentation. AB - DNA fragmentation can be deleterious on spermatozoon morphology but the pathogenesis of teratozoospermia associated with DNA breaks is not fully understood, even if oxidative attacks and defects in chromatin maturation are hypothesized. Therefore, this study is one of the first to clarify on the underlying hypothesizes behind such observations. The objectives of our study were to assess the role of oxidative attacks in DNA damage pathogenesis in ejaculated spermatozoa from patients with isolated teratozoospermia. We aimed to assess the correlation of DNA breaks with morphologically abnormal spermatozoa, as well as ROS level and impairment chromatin condensation. A total of 90 patients were divided into two groups, men with isolated teratozoospermia (n = 60) and men with normal semen parameters (n = 30) as controls. DNA fragmentation was evaluated by TUNEL assay; chromatin immaturity was studied using acridine orange and toluidine blue staining. We evaluated the ability of spermatozoa to produce reactive oxygen species with nitro blue tetrazolium staining. Patient with teratozoospermia when compared to fertile men showed significantly higher rates of semen ROS production, sperm hypocondensated chromatin, denaturated DNA, and fragmented DNA. All these parameters were positively correlated with abnormal sperm morphology. The studied DNA integrity markers were also correlated with ROS production. Fragmented DNA is the main pathway leading to morphology defects in the sperm. In fact, impaired chromatin compaction may induce DNA breaks and free radicals, which can break the DNA backbone indirectly, by reducing protamination and disulphide bond formation, as oxidative attack appears to be the major cause of poor semen morphology. PMID- 29508199 TI - Spatiotemporal distribution and risk assessment of organophosphate esters in sediment from Taihu Lake, China. AB - The occurrence and spatiotemporal distribution of 12 organophosphate esters (OPEs) were investigated in the sediments collected from Taihu Lake. Compared to the same lake in 2012 (3.4-14 ng/g dw), the concentrations of ?12 OPEs in sediments ranged from 10.76 to 335.37 ng/g dw and from 8.06 to 425.39 ng/g dw in 2015 and in 2016, respectively, indicating that the OPEs levels in Taihu Lake have aggravated, recently. TEHP was the most abundant compound of the OPEs, which suggested that TEHP was the most widely used around Taihu Lake recently. The positive correlations between some of individual OPEs and the principal components analysis suggested the same potential sources for them. The strong positive correlation between ?BPs and TOC content indicated that TOC content was one of the factors affected the distribution of ?OPEs in the sediment. Risk quotient (RQ) for OPEs showed no high eco-toxicity risk in sediment for aquatic organisms. PMID- 29508200 TI - Contamination and Ecological Hazard Assessment of Heavy Metals in Freshwater Sediments and Oreochromis niloticus (Linnaeus, 1758) Fish Muscles in a Nile River Canal in Egypt. AB - Heavy metal residues in sediment and Oreochromis niloticus fish muscles, collected from a Nile River Canal (Bahr Shebeen Canal), Egypt, were investigated from September 2014 to December 2015. The spatial and seasonal distributions of Cd, Cu, Fe, Pb, and Zn are described and discussed. Relative abundance of these metals in sediment was found as follows: Fe > Zn > Cu > Pb > Cd. Indices of pollution were used to detect the degree of sediment contamination and indicated elevated concentrations likely to adversely affect benthic and benthic-associated organisms. Anthropogenic activities strongly influenced metal occurrence in sediments. Accumulation of heavy metals in fish muscular tissue was found to be nearly comparable to the sediment. Relative abundance of metals in fish tissue followed the trend of Fe > Zn > Pb > Cu > Cd. Fish can be used as a surrogate for heavy metals pollution. The bioaccumulation factor (BAF) in fish muscle showed the following trend: Pb > Zn > Cu > Fe > Cd. Levels of most selected heavy metals detected in muscular tissue of fish were below admissible limits set by different organizations. However, HI (hazard index) showed that the cumulative risk effects are of considerable concern, especially where fish consumption is high. Consequently, it is recommended that discharged water containing pollutants should be prioritized to include continuous monitoring, and adequate public awareness. PMID- 29508201 TI - Rapid and high-capacity adsorption of PFOS and PFOA by regenerable ammoniated magnetic particle. AB - Adsorption is well accepted as an effective method for perfluorinated compounds' (PFCs) removal from water among various conventional methods. However, development of adsorbents that combine good performance of PFC removal and regenerability has not yet been realized. This work demonstrated the fabrication and application of an ammoniated magnetic adsorbent for efficient and economical PFOS and PFOA removal. Functional ammonium groups and gamma-Fe2O3 were effectively incorporated in the particle with the proposed method. These fabricated magnetic particles presented superior adsorption performance for PFOS and PFOA with short equilibrium time of 120 min and high adsorption capacity. The isotherms revealed that the adsorption process belonged to multilayer sorption with their intricate interactions including anion exchange and hydrophobic interaction. The magnetic particle maintained its removal efficacy over a wide pH range of 3-9 or with coexisting substances. Moreover, the regeneration and reuse of the magnetic particle were successfully carried out with PFOS and PFOA removal efficiency sustained higher than 80% in 15 consecutive treatment cycles. Along with the efficient adsorption and easy separation of adsorbents, we expect that this ammoniated magnetic particle can serve as an excellent alternative for PFOS and PFOA removal from water. PMID- 29508202 TI - Characterizing the environmental impact of metals in construction and demolition waste. AB - Large quantities of construction and demolition (C&D) waste are generated in China every year, but their potential environmental impacts on the surrounding areas are rarely assessed. This study focuses on metals contained in C&D waste, characterizing the metal concentrations and their related environmental risks. C&D waste samples were collected in Shenzhen City, China, from building demolition sites, renovation areas undergoing refurbishment, landfill sites, and recycling companies (all located in Shenzhen city) that produce recycled aggregate, in order to identify pollution levels of the metals As, Cd, Cr, Cu, Pb, Ni, and Zn. The results showed that (1) the metal concentrations in most demolition and renovation waste samples were below the soil environmental quality standard for agricultural purposes (SQ-Agr.) in China; (2) Cd, Cu, and Zn led to relatively higher environmental risks than other metals, especially for Zn (DM5 tile sample, 360 mg/kg; R4 tile sample, 281 mg/kg); (3) non-inert C&D waste such as wall insulation and foamed plastic had high concentrations of As and Cd, so that these materials required special attention for sound waste management; and (4) C&D waste collected from landfill sites had higher concentrations of Cd and Cu than did waste collected from demolition and refurbishment sites. PMID- 29508203 TI - "The Rowdy Ones:" Configurations of Difference in a Private Psychiatric Hospital. AB - Drawing on participant-observation and semi-structured interviews, this paper examines the local forms of clinical practice in a 26-bed acute psychiatric inpatient unit located within a private psychiatric hospital in the Northeastern United States. It focuses on how clinicians, staff, and management understand and utilize the concepts of culture, race, and ethnicity in their daily work, finding that a humanistic approach to care that that treats patients as "individuals" was dominant. Clinicians and staff categorized patients using descriptive, behavior based categories including language, propensity for violence, and whether patients are "from the streets." They also used additional forms of difference such as the patient's pathway to care, their illness category or severity, and whether they use drugs. These forms of difference were shaped by the urgent needs of daily work. These local practices of categorization directly affected the quality of care when staff members assigned cultural characteristics to group members and treated them differently as a result. These findings suggest that anthropologists and clinicians should focus on the way new forms of cultural difference are constructed in small social settings in order to provide equitable treatment to all patients. PMID- 29508204 TI - Medical Student Attitudes Towards People with Mental Illness in China: A Qualitative Study. AB - Stigma towards people with mental illness is a worldwide concern. A five-nation survey of medical student attitudes towards people with mental illness recently reported far lower levels of social acceptance among Chinese medical students compared to those from the US, Brazil, Ghana, and Nigeria. This qualitative study presented recent Chinese medical school graduates with probes based on questions used in the aforementioned cross-national study to elicit their views of factors underlying the negative attitudes towards social acceptance of people with mental illness. One-hour interviews were conducted with twenty psychiatry residents in June, 2016. Of 241 coded responses concerning negative attitudes, 51.5% were coded as reflecting fear of violent behavior, 22.8% as loss of face (i.e. shame from interpersonal associations), 17.0% lowered social status, 4.98% nonconforming social behavior, and 3.73% the heritability of mental illness. Low levels of social acceptance of individuals with mental illness among medical students in China are largely related to fears of violence of and loss of face. Understanding the attitudes of medical students may inform efforts to reduce stigma through educational initiatives targeted at both medical students and the general public. PMID- 29508205 TI - Phagocytosis and oxycytosis: two arms of human innate immunity. AB - Human innate immunity operates in two compartments: extravascular (the tissues) and intravascular (the bloodstream). Physical conditions (fluid dynamics) in the compartments are different and, as a result, bactericidal mechanisms and involved cells are different as well. In relatively static media (the tissues, lymph nodes), bacteria are killed by phagocytes; in dynamic media (the bloodstream), bacteria are killed by erythrocytes. In the tissues and lymph nodes, resident macrophages and transmigrated from blood leukocytes (neutrophils and monocytes) recognize, engulf, kill, and digest bacteria; the clearance of the bloodstream from bacteria is performed by oxycytosis: erythrocytes catch bacteria by electric charge attraction and kill them by the oxygen released from oxyhemoglobin. Killed by erythrocytes, bacteria are decomposed and digested in the liver and the spleen. Phagocytosis by leukocytes in the tissues and oxycytosis by erythrocytes in the bloodstream are the main bactericidal mechanisms of human innate immunity. PMID- 29508207 TI - Short form development for oral health patient-reported outcome evaluation in children and adolescents. AB - PURPOSE: Children and adolescents are vulnerable to dental problems and oral diseases. This paper presents the development of two multi-item self-report scales for use in assessing oral health status of children and adolescents. METHODS: Following the Patient-Reported Outcome Measurement Information System framework, survey questions were designed using a newly developed conceptual model. These items were administered to 334 children and adolescents (8-17 years) along with concurrent dental exams. Exploratory and confirmatory factor analyses were conducted and the item response theory graded response model was used to estimate item parameters and oral health status scores and to identify short-form items. The items were selected by high level of information and wide coverage of different domains to assess Child Oral Health Status Index (COHSI) and treatment referral recommendations (RR). RESULTS: The long form consists of 28 items. The short-form includes 12 items (8 for COHSI and 7 for RR with 3 common items).The intra-class correlations between long form and short-form were 0.90 for COHSI and 0.87 for RR. CONCLUSION: The short-forms provide a possible solution for the longstanding challenge of oral health evaluation for large populations of children and adolescents. The calibrated long form provides the foundation for computer adaptive test administration. These oral health assessment toolkits can be used for oral health screening, surveillance program, policy planning, and research. PMID- 29508208 TI - Longitudinal and dynamic measurement invariance of the FACIT-Fatigue scale: an application of the measurement model of derivatives to ECOG-ACRIN study E2805. AB - PURPOSE: While quality of life measures may be used to assess meaningful change and group differences, their scaling and validation often rely on a single occasion of measurement. Using the 13-item FACIT-Fatigue questionnaire at three timepoints, this study tests whether individual items change together in ways consistent with a general fatigue factor. METHODS: The measurement model of derivatives (MMOD) is a novel method for measurement evaluation that directly assesses whether a given factor structure accurately describes how individual test items change over time. MMOD transforms item-level longitudinal data into a set of orthogonal change scores, each one representing either a within-person longitudinal mean or a different type of longitudinal change. These change scores are then factor analyzed and tested for invariance. This approach is applied to the FACIT-Fatigue scale in a sample of patients with renal cell carcinoma treated on 'ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) study 2805. RESULTS: Analyses revealed strong evidence of unidimensionality, and apparent factorial invariance using traditional techniques. MMOD revealed a small but statistically significant difference in factor structure ([Formula: see text], [Formula: see text]), where factor loadings were weaker and more variable for measuring longitudinal change. CONCLUSIONS: The differences in factor structure were not large enough to substantially affect scale usage in this application, but they do reveal some variability across items in the FACIT-Fatigue in their ability to detect change. Future applications should consider differential sensitivity of individual items in multi-item scales, and perhaps even capitalize upon these differences by selecting items that are more sensitive to change. PMID- 29508209 TI - Expression, Purification and Characterization of Hiv-1 Capsid Precursor Protein p41. AB - Human immunodeficiency virus type 1 (HIV-1) has been a global epidemic since 1983; yet, the virology and immunology related to HIV-1 remain elusive. Furthermore, as there is still no effective chemoprophylaxis or vaccine to treat patients with HIV-1, most research focuses on strategies to prevent HIV-1 infection, such as with antiviral drugs, novel therapeutics, or improved diagnostic kits. The HIV-1 Gag precursor protein (p55)-comprising the matrix (MA/p17), capsid (CA/p24), and nucleocapsid (NC/p7) protein domains-is the main structural HIV-1 protein, and is uniquely responsible for virion assembly within the virus life cycle. Recently, the immature and mature capsid structures were solved; however, the precursor protein structure is still unknown. Here, we expressed two subtypes of HIV-1 MA-CA stretch of the Gag protein, referred to as p41, in a bacterial expression system. We characterized the purified p41 protein, and showed its superior antigenicity over that of p24, highlighting the potential influence of the p17 domain on p24 structure. We further showed that p41 has good immunogenicity to induce an antibody response in mice. These results will aid future investigations into the HIV-1 capsid precursor structure, and potentially contribute to improving the design of diagnostic kits. PMID- 29508211 TI - Ligand-Based Pharmacophore Screening Strategy: a Pragmatic Approach for Targeting HER Proteins. AB - Targeting ErbB family of receptors is an important therapeutic option, because of its essential role in the broad spectrum of human cancers, including non-small cell lung cancer (NSCLC). Therefore, in the present work, considerable effort has been made to develop an inhibitor against HER family proteins, by combining the use of pharmacophore modelling, docking scoring functions, and ADME property analysis. Initially, a five-point pharmacophore model was developed using known HER family inhibitors. The generated model was then used as a query to screen a total of 468,880 compounds of three databases namely ZINC, ASINEX, and DrugBank. Subsequently, docking analysis was carried out to obtain hit molecules that could inhibit the HER receptors. Further, analysis of GLIDE scores and ADME properties resulted in one hit namely BAS01025917 with higher glide scores, increased CNS involvement, and good pharmaceutically relevant properties than reference ligand, afatinib. Furthermore, the inhibitory activity of the lead compounds was validated by performing molecular dynamic simulations. Of note, BAS01025917 was found to possess scaffolds with a broad spectrum of antitumor activity. We believe that this novel hit molecule can be further exploited for the development of a pan-HER inhibitor with low toxicity and greater potential. PMID- 29508210 TI - Biochemical Characterization of the Cytochrome P450 CYP107CB2 from Bacillus lehensis G1. AB - The bioconversion of vitamin D3 catalyzed by cytochrome P450 (CYP) requires 25 hydroxylation and subsequent 1alpha-hydroxylation to produce the hormonal activated 1alpha,25-dihydroxyvitamin D3. Vitamin D3 25-hydroxylase catalyses the first step in the vitamin D3 biosynthetic pathway, essential in the de novo activation of vitamin D3. A CYP known as CYP107CB2 has been identified as a novel vitamin D hydroxylase in Bacillus lehensis G1. In order to deepen the understanding of this bacterial origin CYP107CB2, its detailed biological functions as well as biochemical characteristics were defined. CYP107CB2 was characterized through the absorption spectral analysis and accordingly, the enzyme was assayed for vitamin D3 hydroxylation activity. CYP-ligand characterization and catalysis optimization were conducted to increase the turnover of hydroxylated products in an NADPH-regenerating system. Results revealed that the over-expressed CYP107CB2 protein was dominantly cytosolic and the purified fraction showed a protein band at approximately 62 kDa on SDS-PAGE, indicative of CYP107CB2. Spectral analysis indicated that CYP107CB2 protein was properly folded and it was in the active form to catalyze vitamin D3 reaction at C25. HPLC and MS analysis from a reconstituted enzymatic reaction confirmed the hydroxylated products were 25-hydroxyitamin D3 and 1alpha,25-dihydroxyvitamin D3 when the substrates vitamin D3 and 1alpha-hydroxyvitamin D3 were used. Biochemical characterization shows that CYP107CB2 performed hydroxylation activity at 25 degrees C in pH 8 and successfully increased the production of 1alpha,25-dihydroxyvitamin D3 up to four fold. These findings show that CYP107CB2 has a biologically relevant vitamin D3 25-hydroxylase activity and further suggest the contribution of CYP family to the metabolism of vitamin D3. PMID- 29508212 TI - Bamboo (Phyllostachys pubescens) as a Natural Support for Neutral Protease Immobilization. AB - Lignin polymers in bamboo (Phyllostachys pubescens) were decomposed into polyphenols at high temperatures and oxidized for the introduction of quinone groups from peroxidase extracted from bamboo shoots and catalysis of UV. According to the results of FT-IR spectra analysis, neutral proteases (NPs) can be immobilized on the oxidized lignin by covalent bonding formed by amine group and quinone group. The optimum condition for the immobilization of NPs on the bamboo bar was obtained at pH 7.0, 40 degrees C, and duration of 4 h; the amount of immobilized enzyme was up to 5 mg g-1 bamboo bar. The optimal pH for both free NP (FNP) and INP was approximately 7.0, and the maximum activity of INP was determined at 60 degrees C, whereas FNP presented maximum activity at 50 degrees C. The Km values of INP and FNP were determined as 0.773 and 0.843 mg ml 1, respectively; INP showed a lower Km value and Vmax, than FNP, which demonstrated that INP presented higher affinity to substrate. Compared to FNP, INP showed broader thermal and storage stability under the same trial condition. With respect to cost, INP presented considerable recycling efficiency for up to six consecutive cycles. PMID- 29508213 TI - Sexual function in adolescent and young adult cancer survivors-a population-based study. AB - PURPOSE: Previous research has established that treatments for cancer can result in short- and long-term effects on sexual function in adult cancer patients. The purpose was to investigate patient-reported physical and psychosexual complications in adolescents and young adults after they have undergone treatment for cancer. METHODS: In this population-based study, a study-specific questionnaire was developed by a method used in several previous investigations carried out by our research group, Clinical Cancer Epidemiology. The questionnaire was developed in collaboration with adolescent and young adult cancer survivors (15-29 years) and validated by professionals from oncology units, midwives, epidemiologists, and statisticians. The topics covered in the questionnaire were psychosocial health, body image, sexuality, fertility, education, work, and leisure. The web-based questionnaire was sent to adolescent and young adult cancer survivors and matched controls in Sweden. RESULTS: In this study, adolescent and young adult cancer survivors (15-29 years) showed low satisfaction regarding sexual function compared to controls (P < 0.01). Female adolescent and young adult cancer survivors had a statistically significant lower frequency of orgasm during sexual activity than the controls (P < 0.01). Male adolescent and young adult cancer survivors had statistically significant lower sexual desire than the controls (P = 0.04). CONCLUSIONS: We found that adolescent and young adult cancer survivors perceived themselves as being less satisfied with their sexual function than matched population-based controls. IMPLICATIONS FOR CANCER SURVIVORS: Adolescent and young adult cancer survivors need psychological rehabilitation support from the health care profession during and after cancer treatment to help them to reduce their reported poor sexual function to enhance a good sexual quality of life. PMID- 29508215 TI - Effect of Everolimus on Heterogenous Renal Cancer Cells Populations Including Renal Cancer Stem Cells. AB - The aim of this study was to compare effect of everolimus on growth of different renal cell carcinoma (RCC) populations and develop experimental design to measure the early response of everolimus in clear cell RCC (ccRCC) cell lines including renal cancer stem cells. Effect of everolimus on RCC cell lines which include primary (786-0) and metastatic (ACHN) RCC cell lines as well as heterogenous populations of tumor cells of different histological RCC subtypes (clear cell RCC and papillary RCC) was measured when treated with everolimus in the range of 1-9 uM. Gene expression profiling using microarray was performed to determine the early response to everolimus in ccRCC cell lines after optimizing concentration of drug. Gene Set Enrichment Analysis (GSEA) was done which mainly focused on basic genes related to mTOR, hormonal and metabolic pathways. Everolimus acts on RCC cells in a dose-dependent manner. In all examined cell lines IC50 dose was possible to calculate after the third day of treatment. In ccRCC lines (parental and stem cell) everolimus changes expression of mTOR complexes elements and elements of related pathways when treated with optimized doses of drug. Characteristic expression profile for ccRCC cells at an early exposure time to everolimus is to elucidate. Wevarie include some basic observations derived from data analysis in the context of mechanism of action of drug with a view to better understand biology of renal cancer cells. PMID- 29508214 TI - Wharton's Jelly Derived Mesenchymal Stem Cells: Comparing Human and Horse. AB - Wharton's jelly (WJ) is an important source of mesenchymal stem cells (MSCs) both in human and other animals. The aim of this study was to compare human and equine WJMSCs. Human and equine WJMSCs were isolated and cultured using the same protocols and culture media. Cells were characterized by analysing morphology, growth rate, migration and adhesion capability, immunophenotype, differentiation potential and ultrastructure. Results showed that human and equine WJMSCs have similar ultrastructural details connected with intense synthetic and metabolic activity, but differ in growth, migration, adhesion capability and differentiation potential. In fact, at the scratch assay and transwell migration assay, the migration ability of human WJMSCs was higher (P < 0.05) than that of equine cells, while the volume of spheroids obtained after 48 h of culture in hanging drop was larger than the volume of equine ones (P < 0.05), demonstrating a lower cell adhesion ability. This can also revealed in the lower doubling time of equine cells (3.5 +/- 2.4 days) as compared to human (6.5 +/- 4.3 days) (P < 0.05), and subsequently in the higher number of cell doubling after 44 days of culture observed for the equine (20.3 +/- 1.7) as compared to human cells (8.7 +/ 2.4) (P < 0.05), and to the higher (P < 0.05) ability to form fibroblast colonies at P3. Even if in both species tri-lineage differentiation was achieved, equine cells showed an higher chondrogenic and osteogenic differentiation ability (P < 0.05). Our findings indicate that, although the ultrastructure demonstrated a staminal phenotype in human and equine WJMSCs, they showed different properties reflecting the different sources of MSCs. PMID- 29508216 TI - Usefulness of Infra-hepatic Inferior Vena Cava Clamping During Liver Resection: a Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Infra-hepatic vena cava clamping (IIVCC) may reduce blood losses during liver resection. However, available literature is limited to reports from single institutions with a small sample size. To overcome those limitations, we performed a meta-analysis to examine the association between IIVCC and surgical outcomes. METHODS: A systematic literature review was conducted to identify RCTs reporting on quantitative data on IIVCC. Random effects logistic regression calculated the pooled odds ratio (OR) for each surgical outcome. RESULTS: Six studies were identified that included 714 patients, of whom 359 received IIVCC and 355 did not. Patients receiving IIVCC had significantly less total blood loss (MD - 353.08, 95% CI - 393.36 to 312.81, P < 0.00001), blood loss during parenchymal transection (MD - 243.28, 95% CI - 311.67 to - 174.88, P < 0.0001), blood loss volume per transection area (MD - 1.63, 95% CI - 2.14 to - 1.13, P < 0.00001), and intraoperative blood transfusion (OR 0.45, 95% CI 0.23 to 0.89, P = 0.02). Operative time was similar in the two groups (MD - 2.89, 95% CI - 18.45 to 12.68, P = 0.72). No differences between groups were observed in central venous pressure, heart rate, and mean arterial pressure before, after, and during parenchymal transection. Rates of overall morbidity (OR 0.79, 95% CI 0.56-1.13, P = 0.20), major complications (OR 0.89, 95% CI 0.47-1.80, P = 0.73), and perioperative mortality (OR 1.32, 95% CI 0.29-6.09, P = 0.72) were similar in the two groups. CONCLUSIONS: IIVCC was associated to decreased blood loss (overall, during parenchymal transection, and per transection area) and decreased intraoperative transfusions, in the absence of increased operative times. PMID- 29508217 TI - Quality of Endoscopy Reports for Esophageal Cancer Patients: Where Do We Stand? AB - BACKGROUNDS AND AIMS: As treatment for esophageal cancer often involves a multidisciplinary approach, the initial endoscopic report is essential for communication between providers. Several guidelines have been established to standardize endoscopic reporting. This study evaluates the compliance of esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS) reporting with the current national guidelines. METHODS: Combining the National Comprehensive Cancer Network and Society of Thoracic Surgeons guidelines, 11 quality indicators (QIs) for EGD and 8 for EUS were identified. We evaluated initial EGD and EUS reports from our institution (Memorial Sloan Kettering [MSK]) and outside hospitals (OSHs) and calculated individual and overall quality measure scores. Scores between locations were compared using the Wilcoxon signed-rank test and McNemar's test for paired data. RESULTS: In total, 115 initial EGD reports and 105 EUS reports were reviewed for patients who underwent surgery for esophageal cancer between 2014 and 2016. The median number of QIs reported for the initial EGD was 4 (IQR, 3-6)-only 34% of reports qualified as "good quality" (those with >= 6 QIs). None of the reports included all QIs. For patients who underwent EGD at both MSK and an OSH, 32% of reports from OSHs were good quality, compared with 68% from MSK (p < 0.001). Compliance with QIs was better for EUS reports: 71% of OSH reports and 72% of MSK reports were good quality. CONCLUSIONS: Detailed information on the initial endoscopic assessment is essential in today's age of multidisciplinary care. Identification and adoption of QIs for endoscopic reporting is warranted to ensure the provision of appropriate treatment. PMID- 29508218 TI - Comparative Quality of Life in Patients Following Transanal Minimally Invasive Surgery and Healthy Control Subjects. AB - BACKGROUND: Transanal minimally invasive surgery (TAMIS) is considered the successor of transanal endoscopic microsurgery (TEMS). It makes use of more readily available laparoscopic instruments and single-port access platforms with similar perioperative, clinical and oncological outcomes. Little is known about quality of life (QoL) outcomes after the use of TAMIS. The aim of this study was to assess QoL after TAMIS in our patients and compare this with QoL in the healthy Dutch population. METHODS: All patients undergoing TAMIS for selected rectal neoplasms between October 2011 and March 2014 were included in this analysis. Patients were studied for a minimal period of 24 months. QoL outcomes were measured using the Short-Form 36 Health Survey (SF-36) questionnaire; faecal continence was measured using the Faecal Incontinence Severity Index questionnaire. Patient reported outcomes were compared to case-matched healthy Dutch control subjects. We hypothesise that undergoing TAMIS will subsequently result in a decreased quality of life in patients compared to healthy individuals. RESULTS: Thirty-seven patients (m:f = 17:20, median 67 years) were included in the current analysis. In four patients (10.8%), postoperative complications occurred. The median follow-up was 36 (range 21-47) months. Postoperative QoL scores are similar comparable to those reported by Dutch healthy controls. Patients reported a statistically significant better QoL score in the 'bodily pain' domain when compared to the controls (81.8 vs. 74.1 points) (p = 0.01). Significant worse QoL scores for the 'social functioning' domain were reported by patients after TAMIS (84.4 vs. 100 points) (p = 0.03). CONCLUSION: TAMIS seems to be a safe technique with postoperative QoL scores similar to that of healthy case matched controls in 3-year follow-up. There seems to be no association between faecal incontinence and reported QoL. Negative effects of TAMIS on social functioning of patients should not be underestimated and should be discussed during preoperative counselling. PMID- 29508219 TI - Colo-Urethral Fistula: an Uncommon Complication of Sigmoid Diverticulitis. PMID- 29508221 TI - The effect of antiepileptic drugs on thyroid hormonal function: valproic acid and phenobarbital. AB - The aim of this study was to evaluate the thyroid function alterations in a group of epileptic children taking antiepileptic drugs. The study included a total of 183 pediatric epilepsy patients, aged 15 months-16 years, comprising 114 patients treated with valproic acid, 69 patients treated with phenobarbital, and 151 age matched healthy volunteers as the control group. Serum levels of thyroid hormones were measured before the beginning of the antiepileptic therapy and after 12 months of treatment. Thyroid-stimulating hormone levels were significantly higher in the 12th month of phenobarbital and valproic acid treatment. The level of free triiodothyronine before treatment was higher in epileptic patients than in the control group. Subclinical hypothyroidism at month 12 was determined in 15.2% of the valproic acid group and in 2.9% of the phenobarbital group. When compared with the pre-treatment values, there was a statistically significant difference in the incidence of subclinical hypothyroid in the valproic acid group and no significant difference in the phenobarbital group. Symptomatic hypothyroidism was not detected. It was concluded that the thyroid functions of patients using valproic acid and phenobarbital for a long time should be regularly monitored. PMID- 29508222 TI - Correction to: The sTOF, a Favorable Geometry for a Time-of-Flight Analyzer. AB - In the article "The sTOF, a Favorable Geometry for a Time-of-Flight Analyzer", the electric sectors in the prototype analyzer used to generate the data in Figure 4 were mistakenly listed as having a radius of 165 mm. The correct size is a diameter of 165 mm. PMID- 29508223 TI - Isomer Information from Ion Mobility Separation of High-Mannose Glycan Fragments. AB - Extracted arrival time distributions of negative ion CID-derived fragments produced prior to traveling-wave ion mobility separation were evaluated for their ability to provide structural information on N-linked glycans. Fragmentation of high-mannose glycans released from several glycoproteins, including those from viral sources, provided over 50 fragments, many of which gave unique collisional cross-sections and provided additional information used to assign structural isomers. For example, cross-ring fragments arising from cleavage of the reducing terminal GlcNAc residue on Man8GlcNAc2 isomers have unique collision cross sections enabling isomers to be differentiated in mixtures. Specific fragment collision cross-sections enabled identification of glycans, the antennae of which terminated in the antigenic alpha-galactose residue, and ions defining the composition of the 6-antenna of several of the glycans were also found to have different cross-sections from isomeric ions produced in the same spectra. Potential mechanisms for the formation of the various ions are discussed and the estimated collisional cross-sections are tabulated. Graphical Abstract ?. PMID- 29508224 TI - Prognostic role of neutrophils to lymphocytes ratio in patients with acute pulmonary embolism: a systematic review and meta-analysis of the literature. AB - The prognostic assessment of patients with acute pulmonary embolism (PE) is essential to drive its management. The search for new prognostic factors is a central issue for a more accurate estimate of short-term adverse events. Circulating neutrophils/lymphocytes ratio (NLR) has been suggested as prognostic biomarker for different cardiovascular diseases. Given the central role of inflammation, and in particular of neutrophils in the pathogenesis of VTE and its clinical history, NLR might represent a prognostic tool also in this setting. We performed a systematic review and meta-analysis of the literature to assess the prognostic role of NLR in patients with acute PE. MEDLINE and EMBASE were searched up to 2017, week 21. A bivariate random-effects regression approach was used to obtain summary estimate of accuracy of the high NLR adjusting for inter study variability. Six studies for a total of 1424 patient are included. High NLR has a weighted mean sensitivity of 77% (95% CI 68-83) and a weighted mean specificity of 74% (95% CI 68-79). High NLR positive and negative predictive values are 24.4% (95% CI 20.4-28.3) and 96.7% (95% CI 95.6-97.8), respectively. The relevant impact of NLR on short-term mortality after an acute PE makes it a promising biomarker to better stratify patient prognosis. PMID- 29508225 TI - A simplified diagnostic algorithm for the management of suspected pulmonary embolism: the YEARS study. PMID- 29508226 TI - Hip fracture unit: beyond orthogeriatrics. PMID- 29508227 TI - Prognostic influence of prior chronic obstructive pulmonary disease in patients admitted for their first episode of acute heart failure. AB - Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in heart failure (HF) patients. Whether a prior COPD diagnosis influences patients' prognosis in early stages of HF is unknown. We reviewed patients > 50 years old admitted because of a first episode of acute HF. We divided the sample into two groups according to the existence of a prior diagnosis of COPD. We used regression analysis to identify the baseline patients' characteristics associated with the presence of COPD, and Cox mortality analysis to identify baseline and discharge data related to higher risk of a combined outcome of 1-year all-cause readmission or mortality. Finally, 985 patients were included in the analysis; 212 (21.5%) with a prior diagnosis of COPD. Baseline characteristics were similar between both groups except for a much higher prevalence of male gender, higher number of chronic therapies, and lower prevalence of atrial fibrillation among COPD patients. The combined primary outcome is significantly more prevalent in COPD patients (68.4 vs. 59.8%, p = 0.022). Cox analysis identified this prior diagnosis of COPD (HR 1.282, 95% CI 1.063-1.547; p = 0.001) as an independent risk factor for 1-year readmission and mortality, together with older age, higher admission creatinine and potassium values, and a higher number of chronic therapies. Our study confirms that in a "real-life" cohort of elderly patients experiencing a first episode of acute HF, the presence of a prior diagnosis of COPD is common, and confers a higher risk of adverse outcomes (death or readmission) during the year following discharge. PMID- 29508229 TI - Development of a Measurement Tool to Assess Students' Knowledge and Perceptions About Cancer (SKPaC). AB - Cancer literacy is currently one of the most important dimensions of cancer continuum. Objective assessment of cancer knowledge in populations remains a challenging field to public health entities. Different evaluation tools are currently available; still, some groups remain disregarded due to the absence of validated instruments. Cancer literacy in adolescents and young adults has been clearly overlooked being a subject that requires new tools to be properly studied. To address this topic, we developed a new instrument and field tested it in a classroom environment for internal reliability, construct, and face validity. "Students Knowledge and Perceptions about Cancer questionnaire" was designed in Portuguese language and adapted to the Portuguese context by a multidisciplinary team. The final version of the questionnaire includes 35 items organized in three sections, encompassing knowledge and perceptions about cancer and socio-biographic data. Cancer experts ensured content validity, while tailoring of contents was refined with high school teachers. Test and retest of the instrument showed a good reliability of the scale and construct validity. Also, the clarity of the questionnaire and suitability to proper evaluate cancer knowledge was consistent between test and retest. The Students' Knowledge and Perceptions About Cancer Questionnaire (SKPaC) showed to be a valid tool to assess adolescents' knowledge and perceptions about cancer that can be used in the educational context. PMID- 29508230 TI - Cancer Awareness and Behavioral Determinants Associated with Cancer Prevention-a Quantitative Study Among Young Adults in Rural Settings. AB - Although college is a crucial time to establish healthy behaviors for cancer prevention, little is known about cancer awareness and behaviors among US college students in less economically developed, rural areas. The purpose of this study was to examine college students' cancer-preventative knowledge and health behaviors. This cross-sectional study was conducted at a large southeastern university in the USA, on a convenience sample of students attending a campus wide health education class. Data were collected during April and May 2017. Pearson's chi-square tests, independent samples t test, and one-way ANOVA were used. Participants (n = 1511) were female (59.1%), non-Hispanic White (69.7%), first-year college students (76.7%), and either 18 (35.9%) or 19 (44.6%) years old. Participants recognized an average of 6.69 (SD = 3.08) out of 11 risk factors on the Cancer Awareness Measure (Cronbach's alpha = 0.874), with a statistically significant difference observed by gender (t(1471) = - 3.348, p = 0.001), but not by race ((F(2,1474) = 1.742, p = 0.176). Chi-square analyses revealed significant associations by gender for exercise (p < 0.001), tobacco use (p < 0.001), and alcohol use (p < 0.001). Significant associations were also found by race/ethnicity for exercise (p < 0.001), tobacco use (p < 0.001), alcohol use (p < 0.001), and fruit and vegetable consumption (p = 0.035). Findings indicate a need to educate college students to recognize and modify cancer-related behavioral risk factors, particularly dietary habits. Specifically, health campaigns to reduce gender and racial gaps in cancer preventative knowledge and behavior among first-year students are recommended. PMID- 29508228 TI - T-cell-replete haploidentical stem cell transplantation using low-dose antithymocyte globulin in children with relapsed or refractory acute leukemia. AB - We evaluated the efficacy and toxicity of T-cell-replete haploidentical stem cell transplantation (TCR-haploSCT) using low-dose antithymocyte globulin (ATG) in children with refractory/relapsed (R/R) acute leukemia. From October 2009 to April 2016, 39 consecutive patients with R/R acute leukemia who underwent TCR haploSCT were included. At the time of TCR-haploSCT, 17 patients were in complete remission (CR), but 22 had active disease. Thirty-three patients received a myeloablative regimen and six received a reduced-intensity conditioning regimen. Graft-versus-host disease (GvHD) prophylaxis comprised tacrolimus, methotrexate, prednisolone, and low-dose ATG (thymoglobulin 2.5 mg/kg). Neutrophil engraftment (> 0.5 * 109/L) was 95% after a median of 13 days. The median follow-up period was 527 days, with mean 3-year overall and disease-free survival rates of 45.1% [standard deviation (SD), +/- 8.5%) and 33.8% (SD, +/- 7.9%), respectively. The cumulative incidence of acute GvHD was 73.0%, but that of grade III-IV acute GvHD was 34.1%. The 3-year cumulative incidences of relapse and transplant-related mortality were 50.3 and 15.9%, respectively. Age < 10 years at transplantation was associated with a better overall survival in the multivariate analysis. These data suggest that TCR-haploSCT using a low-dose ATG combined with the GvHD prophylaxis described here has a significant anti-leukemic activity, particularly in younger patients. PMID- 29508231 TI - More than a Conversation: the Power of Bringing Scientists and the Community Together to Change Perceptions About Cancer. AB - According to the Centers for Disease Control and Prevention, up to 40% of annual deaths are due to preventable, modifiable risk factors (Centers for Disease Control and Prevention 2014). Evidence in the literature suggests that increased knowledge and engagement is a critical step in preventing disease and improving health behaviors (Health Promotion International 15(3):259-267, 2000; Risk Manag Healthc Policy 3:61-72, 2010; Urology 61(2):308-313, 2003). Educational seminars, titled Conversations with Scientists, are offered twice per year by the Advancing a Healthier Wisconsin Endowment with the goal of helping community members, patients, and families inform themselves and others about science and health. In the first series, Cancer: Past, Present, and Future, the goals of increasing (1) knowledge, (2) intent to improve health behaviors, and (3) intent to disseminate information to friends and family were evaluated. Additionally, focus groups and interviews were conducted with speakers and audience members to explore strengths of the existing program format and opportunities to improve. The World Health Organization estimates that between 30 and 50% of all cancer cases are preventable, and has called for efforts to raise public awareness of cancer risks (World Health Organization 2017). Findings indicate that the existing seminar format achieved its intended goals, and provided additional value that can be leveraged to improve health outcomes for participants and their families. PMID- 29508232 TI - Rare case of osteomyelitis of tibial shaft caused by Nocardia cyriacigeorgica. AB - Nocardiosis is a rare infection caused by the aerobic actinomycete of the Nocardia genus. In most cases, nocardiosis manifests as a lung infection or a bone lesion. Due to the nonspecific and mild clinical manifestations of nocardiosis, the establishment of definite diagnosis can be difficult. When antibiotic therapy is incorrectly targeted, only the symptoms of the disease are suppressed. The mainstay in the treatment of Nocardia osteomyelitis has so far been the combined surgical debridement with long-term, initially intravenous, antibiotic administration. We present the successful conservative treatment of a nocardiosis osteomyelitis of the tibia caused by the Nocardia cyriacigeorgica species in an 81-year-old female patient that manifested itself as a secondary affection on top of a primary nocardiosis infection of the lung. From microbiological examination, N. cyriacigeorgica was discovered; the identification was made using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) with an identification score of 1.9. The sensitivity was evaluated using E test. Sensitivity to trimethoprim/sulfamethoxazole, amikacin, imipenem, and linezolid was demonstrated. The bacteria were shown to be resistant to ciprofloxacin. For treatment, trimethoprim/sulfamethoxazole was used due to the value of minimum inhibitory concentration, which was 0.25 mg/L. The initial dose of 960 mg of trimethoprim/sulfamethoxazole every 8 h was reduced to 960 mg every 12 h after 3 months. The total duration of treatment was 7.5 months. Under the established treatment, the bone and lung lesions healed. Nocardiosis of the long bone is considered a rare disease and its precise diagnosis has not yet been standardized. We used the MALDI-TOF MS method for the identification of the causal organism which is a fast and reliable method according to current world literature even when compared with the rRNA genetic sequencing reference method. Our case study presents a rare case of osteomyelitis of tibial shaft caused by N. cyriacigeorgica and its successful conservative treatment. PMID- 29508234 TI - A commentary on Chen and Campbell (2017): Is there a clear case for addition fact recall? AB - In their review of Uittenhove, Thevenot and Barrouillet (Cognition, 146, 289-303, 2016), Chen and Campbell (Psychonomic Bulletin & Review, 2017 https://doi.org/10.3758/s13423-017-1328-2 ) concluded that existing evidence supports the conventional wisdom that basic non-zero addition combinations are stored and retrieved as discrete facts and that compacted reconstructive strategies play no role in expert mental addition. One aim of the present commentary is to detail why their evidence supporting these conclusions is not unequivocal. A second aim is to delineate key issues that still need to be addressed to build an accurate model of how basic sums are represented and retrieved. PMID- 29508233 TI - Factors that Can Help Select the Timing for Decompressive Hemicraniectomy for Malignant MCA Stroke. AB - In patients with malignant middle cerebral artery (MMCA) stroke, a vital clinically relevant question is determination of the speed with which infarction evolves to select the time for decompressive hemicraniectomy [DHC]. A retrospective, multicenter cross-sectional study of patients referred for DHC, based on the criteria of randomized controlled trials, was undertaken to identify factors for selecting the timing of DHC in MMCA stroke, stratified by time [< 48, 48-72, > 72 h]. Infarction volume and infarct growth rate [IGR] were measured on all CT scans. One hundred eighty-two patients [135 underwent DHC and 47 survived without DHC] were included in the analysis. After multivariate adjustment, factors showing the strongest independent association with DHC were patients < 55 years of age, septum pellucidum deviation, temporal lobe involvement, MCA with additional infarcts, and IGR on second CT. Of the five factors identified, different combinations of determining factors were observed in each subgroup. Both first and second IGRs were highest in the < 48, 48-< 72, and > 72 h [p < 0.001]. Patients who survived without surgery had the slowest IGRs. There was no association between time to DHC and infarct volume, although infarct volume was lower in patients who survived without DHC compared to the DHC subgroups. We identify the major risk factors associated with DHC in time-stratified subgroups of patients with MMCA. Evaluation of IGRs between the first and second scan and when possible second and third scan can help in selecting the timing of hemicraniectomy. PMID- 29508235 TI - Feedback increases benefits but not costs of retrieval practice: Retrieval induced forgetting is strength independent. AB - We examined how the provision of feedback affected two separate effects of retrieval practice: strengthening of practiced information and forgetting of related, unpracticed information. Feedback substantially increased recall of retrieval-practiced items. This unsurprising result shows once again that restudy opportunities boost the benefits of testing. In contrast, retrieval-induced forgetting was unaffected by the manipulation and occurred in equal size with or without feedback. These findings demonstrate strength independence of retrieval induced forgetting and thus support a theoretical account assuming that an inhibitory mechanism causes retrieval-induced forgetting. According to this theory, inhibition resolves competition that arises during retrieval attempts but is unrelated to the consequences of retrieval practice concerning practiced items. The present results match these assumptions and contradict the theoretical alternative that blocking by strengthened information might explain retrieval induced forgetting. We discuss our findings against the background of previous studies. PMID- 29508237 TI - Development and validation of a high-speed stereoscopic eyetracker. AB - Traditional video-based eyetrackers require participants to perform an individual calibration procedure, which involves the fixation of multiple points on a screen. However, certain participants (e.g., people with oculomotor and/or visual problems or infants) are unable to perform this task reliably. Previous work has shown that with two cameras one can estimate the orientation of the eyes' optical axis directly. Consequently, only one calibration point is needed to determine the deviation between an eye's optical and visual axes. We developed a stereo eyetracker with two USB 3.0 cameras and two infrared light sources that can track both eyes at ~ 350 Hz for eccentricities of up to 20 degrees . A user interface allows for online monitoring and threshold adjustments of the pupil and corneal reflections. We validated this tracker by collecting eye movement data from nine healthy participants and compared these data to eye movement records obtained simultaneously with an established eyetracking system (EyeLink 1000 Plus). The results demonstrated that the two-dimensional accuracy of our portable system is better than 1 degrees , allowing for at least +/- 5-cm head motion. Its resolution is better than 0.2 degrees (SD), and its sample-to-sample noise is less than 0.05 degrees (RMS). We concluded that our stereo eyetracker is a valid instrument, especially in settings in which individual calibration is challenging. PMID- 29508236 TI - Mortality impact of post-discharge myocardial infarction size after percutaneous coronary intervention: a patient-level pooled analysis from the 4 large-scale Japanese studies. AB - It is unknown whether there is a threshold of creatine kinase (CK) or CK-MB affecting the subsequent mortality for post-discharge myocardial infarction (PDMI) after percutaneous coronary intervention. Current study sought to evaluate the impact of PDMI. The study population included 30,051 patients with successful coronary stenting and discharged alive in the pooled patient-level database of 4 Japanese studies (j-Cypher registry, CREDO-Kyoto PCI/CABG registry cohort-2, RESET, and NEXT). During 4.4 +/- 1.4 year follow-up, 915 patients experienced PDMI (cumulative 5-year incidence of 3.6%). Among 466 patients with available peak CK ratio (peak CK/upper limit of normal), peak CK ratio (< 3) was present in 21% of patients, while peak CK ratios (>= 3 and < 5), (>= 5 and < 10), (>= 10 and < 30), and (>= 30) were present in 17, 25, 30, and 7.3% of patients, respectively. The excess mortality risk of patients with relative to those without PDMI for subsequent mortality was significant (adjusted HR 5.12, 95% CI 4.52-5.80, P < 0.001) by the Cox model with PDMI incorporated as the time-updated covariate. However, the mortality risk of patients in the smallest peak CK ratio category (< 3) was insignificant (HR 0.85, 95% CI 0.43-1.71, P = 0.65). In conclusion, despite significant overall mortality risk of PDMI, the mortality risk of small PDMI was similar to that of no PDMI, suggesting the presence of some threshold about infarct size influencing mortality.Trial registrations The Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial (RESET); NCT01035450 and NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus Eluting Stent Trial (NEXT); NCT01303640. J-Cypher and CREDO-Kyoto PCI/CABG registry cohort 2 were not registered into clinical trial database. PMID- 29508238 TI - Predicting group-level outcome variables: An empirical comparison of analysis strategies. AB - This study provides a review of two methods for analyzing multilevel data with group-level outcome variables and compares them in a simulation study. The analytical methods included an unadjusted ordinary least squares (OLS) analysis of group means and a two-step adjustment of the group means suggested by Croon and van Veldhoven (2007). The Type I error control, power, bias, standard errors, and RMSE in parameter estimates were compared across design conditions that included manipulations of number of predictor variables, level of correlation between predictors, level of intraclass correlation, predictor reliability, effect size, and sample size. The results suggested that an OLS analysis of the group means, with White's heteroscedasticity adjustment, provided more power for tests of group-level predictors, but less power for tests of individual-level predictors. Furthermore, this simple analysis avoided the extreme bias in parameter estimates and inadmissible solutions that were encountered with other strategies. These results were interpreted in terms of recommended analytical methods for applied researchers. PMID- 29508239 TI - Proteome analysis of differential protein expression in porcine alveolar macrophages regulated by porcine reproductive and respiratory syndrome virus nsp1beta protein. AB - Porcine reproductive and respiratory syndrome virus (PRRSV), an acute infectious disease agent in swine, causes enormous economic losses to the global swine industry. PRRSV nonstructural protein 1beta (nsp1beta) plays a critical role in viral subgenomic mRNA synthesis and host immune regulation. However, the global changes of cellular gene expression in natural target cells regulated by the nsp1beta have not yet been identified. Here, isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with liquid chromatography tandem mass spectrometry were used to quantitatively identify cellular proteins in porcine alveolar macrophage (PAM) 3D4/21 cells transduced with recombinant lentivirus expressing PRRSV nsp1beta that are differentially expressed compared with PAM 3D4/21 cells transduced with recombinant lentivirus expressing GFP. Of the 425 cellular proteins detected as differentially expressed, 186 were upregulated and 239 were downregulated. Based on the identities of the differentially expressed cellular proteins and the essential role of nsp1beta in interferon (IFN) activation and inflammatory factor antagonism during PRRSV infection, we propose a potential mechanism in which nsp1beta inhibits IFN induction and nuclear factor kappaB (NF-kappaB) signaling pathways. Our results suggest that mitochondrial antiviral signaling (MAVS) protein and translocases of outer membrane complex 70 (TOM70), involved in type I IFN induction, were downregulated, while protein phosphatase 1A (PPM1A), related to the inhibition of NF-kappaB pathway activation, was upregulated in nsp1beta-overexpressed PAM 3D4/21 cells. These data provide valuable information for better understanding the potential biological function of nsp1beta during PRRSV infection and the mechanism of virus escape from host immune surveillance of viral replication. PMID- 29508240 TI - Eigenfactor score and alternative bibliometrics surpass the impact factor in a 2 years ahead annual-citation calculation: a linear mixed design model analysis of Radiology, Nuclear Medicine and Medical Imaging journals. AB - INTRODUCTION: Because we believe the journal selection before a manuscript submission deserves further investigation in each medical specialty, we aimed to evaluate the predictive ability of seven bibliometrics in the Radiology, Nuclear Medicine and Medical Imaging category of the Web of Knowledge to calculate total citations over a 7-year period. METHODS: A linear mixed effects design using random slopes and intercepts were performed on bibliometrics corresponding to 124 journals from 2007 to 2011, with their corresponding citations from 2009 to 2013, which appeared in the Journal Citations Report Science Edition. RESULTS: The Eigenfactor Score, Article Influence Score, Cited Half-life, 5-years impact factor and Number of Articles are significant predictors of 2-year-ahead total citations (p <= 0.010 for all variables). The impact factor and Immediacy Index are not significant predictors. There was a significant global effect size (R2 = 0.934; p < 0.001), which yielded a total variance of 93.4%. CONCLUSIONS: Our findings support researchers' decision to stop the misuse of IF alone to evaluate journals. Radiologists and other researchers should review journal's bibliometrics for their decision-making during the manuscript submission phase. A re-ranking of journals using Eigenfactor Score, Article Influence Score, and Cited Half-life provides a better assessment of their significance and importance in particular disciplines. PMID- 29508241 TI - Multiparametric MR imaging detects therapy efficacy of radioactive seeds brachytherapy in pancreatic ductal adenocarcinoma xenografts. AB - OBJECTIVE: To investigate the therapeutic efficacy of Iodine-125 (125I) seeds brachytherapy to pancreatic ductal adenocarcinoma (PDAC) xenografts via multiparametric magnetic resonance imaging (MRI) analysis. MATERIALS AND METHODS: Twenty mice were implanted subcutaneously with SW-1990 PDAC xenografts. The tumor bearing mice were randomly divided into 125I seeds group (n = 10) and blank control group (n = 10). Treatment response was monitored by diffusion-weighted magnetic resonance imaging (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) obtained 1 day before, 14 and 60 days after treatment. Imaging results were correlated with histopathology. RESULTS: 125I seeds brachytherapy resulted in a significant increase in mean tumor apparent diffusion coefficient (ADC) values compared to the control at 14 and 60 days after treatment (p < 0.05). DCE-MRI showed a significant decrease in the perfusion parameters including Ktrans and Kep (p < 0.05). The mean ADCs within the peripheral region of the tumors were linearly proportional to the mean apoptotic cell density (p = 0.015; Spearman's coefficient = 0.945). The Ktrans and Kep were linearly proportional to microvessel density (MVD) (p = 0.043, 0.047; Spearman's coefficient = 0.891, 0.884). CONCLUSION: 125I seeds brachytherapy leads to effective inhibition of PDAC cell proliferation, higher degree of necrosis and necroptosis, and lower MVD. Both DW-MRI and DCE-MRI are feasible to monitor a response to 125I seeds brachytherapy in the PDAC xenografts. This paper shows an original project concerning about a possible palliative treatment not only in a murine model (preclinical setting) but also in humans. PMID- 29508242 TI - Dynamic susceptibility contrast (DSC) perfusion MRI in differential diagnosis between radionecrosis and neoangiogenesis in cerebral metastases using rCBV, rCBF and K2. AB - INTRODUCTION: Distinction between treatment-related changes and tumour recurrence in patients who have received radiation treatment for brain metastases can be difficult on conventional MRI. In this study, we investigated the ability of dynamic susceptibility contrast (DSC) perfusion in differentiating necrotic changes from pathological angiogenesis and compared measurements of relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and K2, using a dedicated software. METHODS: Twenty-nine patients with secondary brain tumors were included in this retrospective study and underwent DSC perfusion MRI with a 3-month follow-up imaging after chemo- or radiation-therapy. Region-of-interests were drawn around the contrast enhancing lesions and measurements of rCBV, rCBF and K2 were performed in all patients. Based on subsequent histological examination or clinico-radiological follow-up, the cohort was divided in two groups: recurrent disease and stable disease. Differences between the two groups were analyzed using the Student's t test. Sensitivity, specificity and diagnostic accuracy of rCBV measurements were analyzed considering three different cut-off values. RESULTS: Between patients with and without disease, only rCBV and rCBF values were significant (p < 0.05). The only cut-off value giving the best diagnostic accuracy of 100% was rCBV = 2.1 (sensitivity = 100%; specificity = 100%). Patients with tumor recurrence showed a higher mean value of rCBV (mean = 4.28, standard deviation = 2.09) than patients with necrotic-related changes (mean = 0.77, standard deviation = 0.44). CONCLUSION: DSC-MRI appears a clinically useful method to differentiate between tumor recurrence, tumor necrosis and pseudoprogression in patients treated for cerebral metastases. Relative CBV using a cut-off value of 2.1 proved to be the most accurate and reliable parameter. PMID- 29508243 TI - Adjunctive Eslicarbazepine Acetate in Pediatric Patients with Focal Epilepsy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: In the treatment of pediatric epilepsy, there is a critical demand for effective and safe therapeutic options to address patients' unmet clinical needs. Eslicarbazepine acetate is a novel once-daily antiepileptic drug and a third-generation single enantiomer member of the dibenzazepine family. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of eslicarbazepine acetate as add-on treatment for focal-onset seizures in pediatric patients using meta-analytical techniques. METHODS: Randomized, placebo controlled, single- or double-blinded add-on trials of eslicarbazepine acetate in patients < 18 years of age with focal-onset seizures uncontrolled by concomitant stable antiepileptic drug regimens were identified through a systematic literature search. The assessed outcomes included the mean relative change and >= 50% reduction in the baseline seizure frequency, the incidence of treatment withdrawal, serious adverse events, and treatment-emergent adverse events. Risk ratio and weighted mean difference with 95% confidence intervals were estimated for dichotomous/continuous outcomes. RESULTS: Two trials were included involving 386 participants (age range 2-18 years), 217 for eslicarbazepine acetate and 169 for placebo groups, respectively. At the dosage of 30 mg/kg/day, eslicarbazepine acetate-treated patients had a significantly greater reduction in baseline seizure frequency (weighted mean difference - 21.67, 95% confidence interval - 40.87 to - 2.46; p = 0.027) and 58 patients (44.6%) were seizure responders compared with 27 controls (29.7%) [risk ratio 1.48, 95% confidence interval 0.99 2.20; p = 0.055]. There were no differences in treatment withdrawal (risk ratio 1.24, 95% confidence interval 0.65-2.37; p = 0.513), serious adverse events (risk ratio 1.40, 95% confidence interval 0.69-2.86; p = 0.350), and treatment-emergent adverse events (risk ratio 1.07, 95% confidence interval 0.94-1.22; p = 0.313). CONCLUSIONS: Adjunctive eslicarbazepine acetate could be an effective well tolerated option in children and adolescents with focal-onset seizures uncontrolled by one or more concomitant anti-epileptic drugs. PMID- 29508244 TI - An Update on the Use of Disease-Modifying Therapy in Pregnant Patients with Multiple Sclerosis. AB - The active management of multiple sclerosis (MS) has been made possible during the last two decades with the advent of disease-modifying therapies (DMTs), leading to improved clinical outcomes for many patients. Furthermore, with the realization that MS does not adversely affect pregnancy outcome and that pregnancy does not have an overall negative impact on the long-term disease course of MS, the importance of appropriate counseling and discussion of future pregnancy plans with women of childbearing age is greater than ever. Although several DMTs are licensed for the treatment of MS, none are specifically approved for use during pregnancy or breastfeeding and the use of DMTs during these periods frequently gives rise to concerns regarding potential risks to the fetus. The outcomes of studies in patients with MS treated with DMTs during pregnancy and immediately postpartum have been the focus of several recently published papers. Given the high level of interest surrounding the prescribing of DMTs for MS patients of childbearing age, and the lack of clear guidance in this respect, the current review presents an up-to-date overview of new data, including observational data on real-world outcomes, that have been published during the last 2 years, and could inform future prescribing decisions. PMID- 29508245 TI - Gadolinium-Based Contrast Agent-Related Toxicities. AB - In recent years, gadolinium-based contrast agents have been associated with different types of toxicity. In particular, nephrogenic systemic fibrosis, a progressive sclerotic-myxedematous systemic disease of unknown etiology, is related to gadolinium-based contrast agent administration in patients with kidney dysfunction. More recently, evidence of magnetic resonance signal intensity changes on pre-contrast T1-weighted images after multiple gadolinium-based contrast agent administrations resulted in the hypothesis of gadolinium brain accumulation in patients with normal renal function, subsequently confirmed in pathological samples. However, there is limited current data and further investigations are necessary before drawing definite conclusions on the clinical consequences of gadolinium-based contrast agent accumulation in human tissues and particularly in the brain. Gadolinium-based contrast agent-related toxicity appears connected to molecular stability, which varies together with the pharmacokinetic properties of the compound and depends on the individual characteristics of the subject. During a lifetime, the physiological changes occurring in the human body may influence its interaction with gadolinium-based contrast agents: the integrity and developmental stage of the organs has an effect on the dynamics of gadolinium-based contrast agent distribution and excretion, thus leading to different possible mechanisms of deposition and toxicity. Therefore, the aim of this work is to discuss the pharmacokinetics and pharmacodynamics of gadolinium-based contrast agents, with a special focus on the brain, and to explore potential predominant gadolinium-based contrast agent related toxicity in two cornerstone periods of the human life cycle: fetal/neonatal and adulthood/aged. PMID- 29508246 TI - A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer. AB - Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily. Primary endpoint was progression-free survival at 6 months. Results Nine patients were enrolled and median time on treatment was 11 weeks (range: 3-30). Best response was stable disease. All patients had a rise in PSA on treatment, with a median 159% increase from baseline (range: 12-620%). Median baseline circulating tumor cell count was 1 cell/mL (range: 0-40); none had a decrease in cell count posttreatment. Grade <= 2 adverse events included fatigue, anorexia, and rash. The most common serious adverse events were grade 3 dyspnea and maculopapular rash. Eight patients discontinued treatment early because of radiographic progression (n = 1), grade 3 toxicity (n = 5), or investigator discretion (n = 2). Four patients had immediate PSA decline following drug discontinuation, suggesting MLN0128 could cause compensatory increase of androgen receptor (AR) activity. Correlative studies of pretreatment and posttreatment biopsy specimens revealed limited inhibition of AKT phosphorylation, 4EBP1 phosphorylation, and eIF4E activity. Conclusions Clinical efficacy of MLN0128 in mCRPC was limited likely due to dose reductions secondary to toxicity, PSA kinetics suggesting AR activation resulting from mTOR inhibition, and poor inhibition of mTOR signaling targets. PMID- 29508247 TI - Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. AB - Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m2/day (Days 1-14) or placebo plus capecitabine. The primary endpoint was OS. Results Both studies were terminated following a planned interim futility/efficacy analysis of JANUS 1. Overall, 321 and 86 patients were randomized in JANUS 1 (ruxolitinib: n = 161; placebo: n = 160) and JANUS 2 (ruxolitinib: n = 43; placebo: n = 43). There was no significant difference in OS or progression-free survival (PFS) between treatments in JANUS 1 (OS: hazard ratio [HR], 0.969, 95% confidence interval [CI], 0.747-1.256; PFS: HR, 1.056; 95% CI, 0.827-1.348) or JANUS 2 (OS: HR, 1.584; 95% CI, 0.886-2.830; PFS: HR, 1.166; 95% CI, 0.687-1.978). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib or capecitabine were identified. Conclusions Ruxolitinib plus capecitabine was well tolerated in refractory pancreatic cancer patients; this combination did not improve survival. PMID- 29508248 TI - Inhibition of Rb and mTOR signaling associates with synergistic anticancer effect of palbociclib and erlotinib in glioblastoma cells. AB - Genomic studies have established a set of three core-signaling pathways, receptor tyrosine kinase (RTK), p53 and retinoblastoma (Rb) signaling pathways, contributing glioblastoma (GBM) and revealed that dysregulation of at least two pathways is required for GBM progression. In the present study, we investigate efficacy of combination of palbociclib, cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and erlotinib, epidermal growth factor receptor (EGFR) inhibitor in GBM cell systems with different p53 status. Cell proliferation and colony formation assays showed that the combination treatment synergistically suppressed GBM cell proliferation. LN229 cells with mutant p53 and wild-type PTEN were more sensitive to the combination treatment. Further studies indicated that the synergetic anti-GBM effects were due to cell apoptosis induction and cell cycle arrest at G1 phase. Signaling examination indicated that levels of p-Rb and p-4E BP1 significantly decreased by the combination treatment; however, Akt and MAPK signaling were differentially suppressed among the three GBM cell lines. Hence, our data demonstrate that palbociclib and erlotinib exert synergistic anti-GBM activity, providing pre-clinical evidence and a proof-ofconcept that usage of the combination of EGFR and CDK4/6 inhibitors for GBM treatment. PMID- 29508250 TI - The Mechanism of Cortico-Striato-Thalamo-Cortical Neurocircuitry in Response Inhibition and Emotional Responding in Attention Deficit Hyperactivity Disorder with Comorbid Disruptive Behavior Disorder. AB - The neurocircuitries that constitute the cortico-striato-thalamo-cortical (CSTC) circuit provide a framework for bridging gaps between neuroscience and executive function in attention deficit hyperactivity disorder (ADHD), but it has been difficult to identify the mechanisms for regulating emotional problems from the understanding of ADHD comorbidity with disruptive behavior disorders (DBD). Research based on "cool" and "hot" executive functional theory and the dual pathway models, which are thought of as applied response inhibition and delay aversion, respectively, within the neuropsychological view of ADHD, has shed light on emotional responding before and after decontextualized stimuli, while CSTC circuit-related domains have been suggested to explain the different emotional symptoms of ADHD with or without comorbid DBD. This review discusses the role of abnormal connections in each CSTC circuit, especially in the emotion circuit, which may be responsible for targeted executive dysfunction at the neuroscience level. Thus, the two major domains - abstract thinking (cool) and emotional trait (hot) - trigger the mechanism of onset of ADHD. PMID- 29508249 TI - Atlas of the Striatum and Globus Pallidus in the Tree Shrew: Comparison with Rat and Mouse. AB - The striatum and globus pallidus are principal nuclei of the basal ganglia. Nissl and acetylcholinesterase-stained sections of the tree shrew brain showed the neuroanatomical features of the caudate nucleus (Cd), internal capsule (ic), putamen (Pu), accumbens, internal globus pallidus, and external globus pallidus. The ic separated the dorsal striatum into the Cd and Pu in the tree shrew, but not in rats and mice. In addition, computer-based 3D images allowed a better understanding of the position and orientation of these structures. These data provided a large-scale atlas of the striatum and globus pallidus in the coronal, sagittal, and horizontal planes, the first detailed distribution of parvalbumin immunoreactive cells in the tree shrew, and the differences in morphological characteristics and density of parvalbumin-immunoreactive neurons between tree shrew and rat. Our findings support the tree shrew as a potential model for human striatal disorders. PMID- 29508252 TI - Biophotonic Activity and Transmission Mediated by Mutual Actions of Neurotransmitters are Involved in the Origin and Altered States of Consciousness. PMID- 29508251 TI - Electroacupuncture Alleviates Motor Symptoms and Up-Regulates Vesicular Glutamatergic Transporter 1 Expression in the Subthalamic Nucleus in a Unilateral 6-Hydroxydopamine-Lesioned Hemi-Parkinsonian Rat Model. AB - Previous studies have shown that electroacupuncture (EA) promotes recovery of motor function in Parkinson's disease (PD). However the mechanisms are not completely understood. Clinically, the subthalamic nucleus (STN) is a critical target for deep brain stimulation treatment of PD, and vesicular glutamate transporter 1 (VGluT1) plays an important role in the modulation of glutamate in the STN derived from the cortex. In this study, a 6-hydroxydopamine (6-OHDA) lesioned rat model of PD was treated with 100 Hz EA for 4 weeks. Immunohistochemical analysis of tyrosine hydroxylase (TH) showed that EA treatment had no effect on TH expression in the ipsilateral striatum or substantia nigra pars compacta, though it alleviated several of the parkinsonian motor symptoms. Compared with the hemi-parkinsonian rats without EA treatment, the 100 Hz EA treatment significantly decreased apomorphine-induced rotation and increased the latency in the Rotarod test. Notably, the EA treatment reversed the 6-OHDA-induced down-regulation of VGluT1 in the STN. The results demonstrated that EA alleviated motor symptoms and up-regulated VGluT1 in the ipsilateral STN of hemi-parkinsonian rats, suggesting that up-regulation of VGluT1 in the STN may be related to the effects of EA on parkinsonian motor symptoms via restoration of function in the cortico-STN pathway. PMID- 29508253 TI - Total syntheses of schizandriside, saracoside and (+/-)-isolariciresinol with antioxidant activities. AB - Lignans are widely distributed in plants and exhibit significant pharmacological effects, including anti-tumor and antioxidative activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca asoca by monitoring antioxidative activity using the 1,1-diphenyl-2 picrylhydrazyl radical scavenging assay. Starting from a tandem Michael-aldol reaction, the lignan skeleton was synthesized in 6 steps, including a cyclization step. To determine the stereochemistry of 1, we synthesized the natural product (+/-)-isolariciresinol (18) from alcohol 17. Comparison of the spectral data showed good agreement. Glycosylation was investigated using four different glycosyl donors. Only the Koenigs-Knorr condition using silver trifluoromethanesulfonate with 1,1,3,3-tetramethylurea provided the glycosylated product. Deprotection and purification using reverse-phase high-performance liquid chromatography gave schizandriside (1) and its diastereomer saracoside (2). Synthesized 1, 2 and 18 showed antioxidant activity with IC50 = 34.4, 28.8, 53.0 MUM, respectively. PMID- 29508254 TI - Four new resin glycosides, murasakimasarins I-IV, from the tuber of Ipomoea batatas. AB - Four new resin glycosides having macrolactone structures (jalapins), murasakimasarins I-IV, were isolated from the tubers of Ipomoea batatas (L.) Lam. ('Murasakimasari', Convolvulaceae), along with three known glycosides. Their structures were determined on the basis of spectroscopic data as well as chemical evidence. Murasakimasarin III is the first representative of a resin glycoside with 10-methylundecanoic acid as the component organic acid. PMID- 29508255 TI - Anti-amyloidgenic and neurotrophic effects of tetrahydroxystilbene glucoside on a chronic mitochondrial dysfunction rat model induced by sodium azide. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. Emerging evidence indicates that there is a tight relationship between mitochondrial dysfunction and beta-amyloid (Abeta) formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on Abeta production and neurotrophins in the brains of rats by using a mitochondrial dysfunction rat model induced by sodium azide (NaN3), an inhibitor of mitochondrial cytochrome c oxidase (COX). NaN3 was administered to rats by continuous subcutaneous infusion for 28 days via implanted osmotic minipumps to establish the animal model. TSG was intragastrically administered starting 24 h after the operation. The activity of mitochondrial COX was measured by a biochemical method. The content of Abeta 1 42 was detected by ELISA. The expression of neurotrophic factors was determined by Western blot and immunohistochemistry. The results showed that NaN3 infusion for 28 days induced a decrease in mitochondrial COX activity, an increase in Abeta 1-42 content and the expression of amyloidogenic beta-amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1) and presenilin 1 (PS1), and a decline in the expression of neurotrophins in the hippocampus of rats. Intragastrical administration of TSG elevated mitochondrial COX activity, decreased Abeta 1-42 content and the expression of APP, BACE1 and PS1, and enhanced the expression of nerve growth factor, brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of NaN3-infused rats. These findings suggest that TSG may be beneficial in blocking or slowing the progression of AD by enhancing mitochondrial function, decreasing Abeta production and increasing neurotrophic factors at some extent. PMID- 29508256 TI - Cladosporamide A, a new protein tyrosine phosphatase 1B inhibitor, produced by an Indonesian marine sponge-derived Cladosporium sp. AB - Cladosporamide A (1), a new protein tyrosine phosphatase (PTP) 1B inhibitor, was isolated together with a known prenylated flavanone derivative (2) from the culture broth of an Indonesian marine sponge-derived Cladosporium sp. TPU1507 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was elucidated based on 1D and 2D NMR data. Compound 1 modestly inhibited PTP1B and T-cell PTP (TCPTP) activities with IC50 values of 48 and 54 MUM, respectively. The inhibitory activity of 2 against PTP1B (IC50 = 11 MUM) was approximately 2-fold stronger than that against TCPTP (IC50 = 27 MUM). PMID- 29508257 TI - Resident Preferences for Program Director Role in Wellness Management. AB - BACKGROUND: Burnout and depression are prevalent among resident physicians, though the supportive role of the program director (PD) is not well defined. OBJECTIVE: To understand the residents' view of the residency program director's role in assessing and promoting resident wellness. METHODS: A single institution survey of all house staff was conducted in 2017. Rates of burnout and depression were identified via the 2-item Maslach Burnout Inventory (MBI) and the Patient Health Questionaire-2 (PHQ-2), respectively. Residents then qualified their preferences for various assistance services and for the role of their program directors in assisting them. RESULTS: One-hundred sixty-one of 202 (79.7%) residents completed the survey. The rate of depression was 28%. Rates of emotional exhaustion and depersonalization (2-item MBI) were 44 and 62%, respectively. Only 4% of respondents had used the Employee Assistance Program (EAP) in the prior 12 months. Eighty-two percent of residents were in favor of PDs inquiring about wellness regardless of their job performance and only 1% of residents stated the PD should not inquire about wellness at all. Thirty-three percent of residents reported that they would be likely to contact EAP on their own if they felt unwell. Significantly more residents (62%) reported being more likely to contact EAP if recommended by their PD (33 vs 62%, p < 0.001%). Important perceived barriers to seeking assistance were lack of time (65%), lack of knowledge of how to contact EAP (41%), and concerns about appearing weak (35%). CONCLUSIONS: Despite a high prevalence of burnout and depression, residents are unlikely to seek help on their own. Program directors have an important role in assessing and promoting the wellness of their residents. The majority of residents wants their PD to inquire about wellness and may be more likely to seek and receive help if recommended and facilitated by their PD. PMID- 29508258 TI - Valued Components of a Consultant Letter from Referring Physicians' Perspective: a Systematic Literature Synthesis. AB - BACKGROUND: Effective communication between the consultants and physicians form an integral foundation of effective and expert patient care. A broad review of the literature has not been undertaken to determine the components of a consultant's letter of most value to the referring physician. We aimed to identify the components of a consultant's letter preferred by referring physicians. METHODS: We searched Embase and MEDLINE (OVID) Medicine (EBM) Reviews and Cochrane Database of Systematic Reviews for English articles with no restriction on initial date to January 6, 2017. Articles containing letters from specialists to referring physicians regarding outpatient assessments with either an observational or experimental design were included. Studies were excluded if they pertained to communications from referring physicians to consultant specialists, or pertained to allied health professionals, inpatient documents, or opinion articles. We enumerated the frequencies with which three common themes were addressed, and the positive or negative nature of the comments. The three themes were the structure of consultant letters, their contents, and whether referring physicians and consultants shared a common opinion about the items. RESULTS: Eighteen articles were included in our synthesis. In 11 reports, 91% of respondents preferred structured formats. Other preferred structural features were problem lists and brevity (four reports each). The most preferred contents were oriented to insight: diagnosis, prognosis, and management plan (16/21 mentions in the top tertile). Data items such as history, physical examination, and medication lists were less important (1/23 mentions in the top tertile). Reports varied as to whether referring physicians and consultants shared common opinions about letter features. CONCLUSIONS: Referring physicians prefer brief, structured letters from consultants that feature diagnostic and prognostic opinions and management plans over unstructured letters that emphasize data elements such as detailed histories and medication lists. Whether these features improve outcomes is unknown. PMID- 29508259 TI - Underdiagnosis of Dementia: an Observational Study of Patterns in Diagnosis and Awareness in US Older Adults. AB - BACKGROUND: Many older adults living with dementia have not been formally diagnosed. Even when clinicians document the diagnosis, patients and families may be unaware of the diagnosis. Knowledge of how individual characteristics affect detection and awareness of dementia is limited. OBJECTIVE: To identify characteristics associated with dementia diagnosis and awareness of diagnosis. DESIGN: Cross-sectional observational study. PARTICIPANTS: Five hundred eighty five adults aged >= 65 in the National Health and Aging Trends Study who met assessment-based study criteria for probable dementia in 2011 and had 3 years of continuous, fee-for-service Medicare claims prior to 2011. MAIN MEASURES: Using multivariable logistic regression, we compared participants with undiagnosed versus diagnosed dementia (based on Medicare claims) on demographic, social/behavioral, functional, medical, and healthcare utilization characteristics. Among those diagnosed, we compared characteristics of participants unaware versus aware of the diagnosis (based on self or proxy report). KEY RESULTS: Among older adults with probable dementia, 58.7% were either undiagnosed (39.5%) or unaware of the diagnosis (19.2%). In adjusted analyses, individuals who were Hispanic (OR 2.48, 95% CI 1.19, 5.14), had less than high school education (OR 0.54 for at least high school education, 95% CI 0.32, 0.91), attended medical visits alone (OR 1.98, 95% CI 1.11, 3.51), or had fewer functional impairments (OR 0.79 for each impairment, 95% CI 0.69, 0.90) were more likely to be undiagnosed. Similarly, among those diagnosed, having less education (OR 0.42), attending medical visits alone (OR 1.97), and fewer functional impairments (OR 0.72) were associated with unawareness of diagnosis (all ps < 0.05). CONCLUSIONS: The majority of older adults with dementia are either undiagnosed or unaware of the diagnosis, suggesting shortcomings in detection and communication of dementia. Individuals who may benefit from targeted screening include racial/ethnic minorities and persons who have lower educational attainment, any functional impairment, or attend medical visits alone. PMID- 29508260 TI - The Psychology of Esports: A Systematic Literature Review. AB - Recently, the skill involved in playing and mastering video games has led to the professionalization of the activity in the form of 'esports' (electronic sports). The aim of the present paper was to review the main topics of psychological interest about esports and then to examine the similarities of esports to professional and problem gambling. As a result of a systematic literature search, eight studies were identified that had investigated three topics: (1) the process of becoming an esport player, (2) the characteristics of esport players such as mental skills and motivations, and (3) the motivations of esport spectators. These findings draw attention to the new research field of professional video game playing and provides some preliminary insight into the psychology of esports players. The paper also examines the similarities between esport players and professional gamblers (and more specifically poker players). It is suggested that future research should focus on esport players' psychological vulnerability because some studies have begun to investigate the difference between problematic and professional gambling and this might provide insights into whether the playing of esports could also be potentially problematic for some players. PMID- 29508262 TI - Glucose Metabolism as a Pre-clinical Biomarker for the Golden Retriever Model of Duchenne Muscular Dystrophy. AB - PURPOSE: Metabolic dysfunction in Duchenne muscular dystrophy (DMD) is characterized by reduced glycolytic and oxidative enzymes, decreased and abnormal mitochondria, decreased ATP, and increased oxidative stress. We analyzed glucose metabolism as a potential disease biomarker in the genetically homologous golden retriever muscular dystrophy (GRMD) dog with molecular, biochemical, and in vivo imaging. PROCEDURES: Pelvic limb skeletal muscle and left ventricle tissue from the heart were analyzed by mRNA profiling, qPCR, western blotting, and immunofluorescence microscopy for the primary glucose transporter (GLUT4). Physiologic glucose handling was measured by fasting glucose tolerance test (GTT), insulin levels, and skeletal and cardiac positron emission tomography/X ray computed tomography (PET/CT) using the glucose analog 2-deoxy-2-[18F]fluoro-D glucose ([18F]FDG). RESULTS: MRNA profiles showed decreased GLUT4 in the cranial sartorius (CS), vastus lateralis (VL), and long digital extensor (LDE) of GRMD vs. normal dogs. QPCR confirmed GLUT4 downregulation but increased hexokinase-1. GLUT4 protein levels were not different in the CS, VL, or left ventricle but increased in the LDE of GRMD vs. normal. Microscopy revealed diffuse membrane expression of GLUT4 in GRMD skeletal but not cardiac muscle. GTT showed higher basal glucose and insulin in GRMD but rapid tissue glucose uptake at 5 min post dextrose injection in GRMD vs. normal/carrier dogs. PET/ CT with [18F]FDG and simultaneous insulin stimulation showed a significant increase (p = 0.03) in mean standard uptake values (SUV) in GRMD skeletal muscle but not pelvic fat at 5 min post-[18F]FDG /insulin injection. Conversely, mean cardiac SUV was lower in GRMD than carrier/normal (p < 0.01). CONCLUSIONS: Altered glucose metabolism in skeletal and cardiac muscle of GRMD dogs can be monitored with molecular, biochemical, and in vivo imaging studies and potentially utilized as a biomarker for disease progression and therapeutic response. PMID- 29508261 TI - Pathology and images of radiation-induced hepatitis: a review article. AB - Recent advances in highly conformal radiotherapies greatly extend the indications for radiotherapy of liver tumors. However, because of poor tolerance to hepatic radiation, estimation of the intensity of irradiation of the liver is important, particularly for a cirrhotic liver. Knowledge of radiation-induced hepatitis is important for understanding how to optimize hepatic radiation therapy. Pathological changes of the irradiated liver, which include perivenular fibrosis, sinusoidal obstruction, and damage to Kupffer cells and hepatocytes, can be visualized using clinical imaging techniques. This review article discusses and illustrates the pathological and radiological changes of hepatic tumors and the surrounding parenchyma of the irradiated liver. PMID- 29508263 TI - Tumor-Specific Zr-89 Immuno-PET Imaging in a Human Bladder Cancer Model. AB - PURPOSE: Tumor-specific molecular imaging is an important tool for assessing disease burden and treatment response. CA19.9 is an important tumor-specific marker in several malignancies, including urothelial carcinoma. [89Zr]DFO-HuMab 5B1 (MVT-2163) is a CA19.9-specific antibody-based construct that has been validated in preclinical animal models of lung, colorectal, and pancreatic malignancies for positron emission tomography (PET) imaging and is currently in a phase I trial for pancreatic cancer (NCT02687230). Here, we examine whether [89Zr]DFO-HuMab-5B1 may be useful in defining urothelial malignancies. PROCEDURES: Surface expression of CA19.9 was confirmed in the human bladder cancer line HT 1197. The radioimmunoconjugate [89Zr]DFO-HuMab-5B1 was injected into mice bearing HT 1197 xenografts, and followed by PET imaging, ex vivo experiments including biodistribution, histology and autoradiography, and analysis of blood samples for shed antigen levels were performed. RESULTS: [89Zr]DFO-HuMab-5B1 specifically accumulates in HT 1197 engrafted tumors when imaged with PET. Ex vivo biodistribution of organs and autoradiography of engrafted tumors confirm our construct's specific tumor binding. The target antigen CA19.9 was not found to be shed in vitro or in vivo. CONCLUSIONS: [89Zr]DFO-HuMab-5B1 can be used to delineate urothelial carcinomas by PET imaging and may provide tumor-specific information prior to, during, and after systemic therapies. PMID- 29508265 TI - Cerebral Metabolic Changes Related to Oxidative Metabolism in a Model of Bacterial Meningitis Induced by Lipopolysaccharide. AB - BACKGROUND: Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis. METHODS: Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral microdialysis technique and included interstitial glucose, lactate, pyruvate, glutamate, and glycerol. The intracranial pressure (ICP) and brain tissue oxygen tension (PbtO2) were also monitored along with physiological variables including mean arterial pressure, blood glucose, lactate, and partial pressure of O2 and CO2. Pigs were monitored for 60 min at baseline and 240 min after LPS/NaCl injection. RESULTS: After LPS injection, a significant increase in cerebral lactate/pyruvate ratio (LPR) compared to control group was registered (p = 0.01). This increase was due to a significant increased lactate with stable and normal values of pyruvate. No significant change in PbtO2 or ICP was registered. No changes in physiological variables were observed. CONCLUSIONS: The metabolic changes after intracisternal LPS injection is compatible with disturbance in the oxidative metabolism and partly due to mitochondrial dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO2, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed by conventional intensive care monitoring. PMID- 29508264 TI - [18F]Fluorocholine Uptake of Parathyroid Adenoma Is Correlated with Parathyroid Hormone Level. AB - PURPOSE: The aim of the study was to investigate the relationship between [18F]fluoromethyl-dimethyl-2-hydroxyethylammonium ([18F]FCh) positron emission tomography (PET) parameters, laboratory parameters, and postoperative histopathological results in patients with primary hyperparathyroidism (pHPT) due to parathyroid adenomas. PROCEDURES: This retrospective study was conducted in 52 patients with biochemically proven pHPT. [18F]FCh-PET parameters (maximum standardized uptake value: SUVmax) in early phase (after 2 min) and late phase (after 50 min), metabolic volume, and adenoma-to-background ratio (ABR), preoperative laboratory results (PTH and serum calcium concentration), and postoperative histopathology (location, size, volume, and weight of adenoma) were assessed. Relationship of PET parameters, laboratory parameters, and histopathological parameters was assessed using the Mann-Whitney U test and Spearman correlation coefficient. MRI characteristics of parathyroid adenomas were also analyzed. RESULTS: The majority of patients underwent a PET/MR scan, 42 patients (80.7 %); 10 patients (19.3 %) underwent PET/CT. We found a strong positive correlation between late-phase SUVmax and preoperative PTH level (r = 0.768, p < 0.001) and between late-phase ABR and preoperative PTH level (r = 0.680, p < 0.001). The surgical specimen volume was positively correlated with the PET/MR lesion volume (r = 0.659, p < 0.001). No significant association was observed between other [18F]FCh-PET parameters, laboratory parameters, and histopathological findings. Cystic adenomas were larger than non-cystic adenomas (p = 0.048). CONCLUSIONS: [18F]FCh uptake of parathyroid adenomas is strongly correlated with preoperative PTH serum concentration. Therefore, the preoperative PTH level might potentially be able to predict success of [18F]FCh-PET imaging in hyperparathyroidism, with higher lesion-to-background ratios being expected in patients with high PTH. PET/MR is accurate in estimating the volume of parathyroid adenomas. PMID- 29508266 TI - Comments on the Cerebral Edema After CPR: A Therapeutic Target Following Cardiac Arrest? PMID- 29508267 TI - Dephytinizing and Probiotic Potentials of Saccharomyces cerevisiae (NCIM 3662) Strain for Amelioration of Nutritional Quality of Functional Foods. AB - Increase of undigested complexes of phytic acid in food is gaining serious attention to overcome nutritional challenges due to chelation effects. We investigated soil-borne yeast phytase from Saccharomyces cerevisiae (NCIM 3662) for dephytinization of foods, probiotic properties, and process development. The strain produced 45 IU/DCG by cell-bound phytase in an unoptimized medium was increased fourfold (164 IU/DCG) in 12 h using statistical media optimization. The process was scaled-up up to 10-L fermenter scale with increased phytase productivity of 6.4 IU/DCG/h as compared to the lab scale. The strain displayed probiotic characteristics like tolerance to artificial gastric acid conditions, hydrophobicity, autoaggregation, coaggregation, and bile salt hydrolase (BSH) activity. Further, it could dephytinize (removal of phytic acid; an anti nutritional factor) functional foods like ragi (finger millet) flour, soya flour, chickpea flour, and poultry animal feed. A combination of cell-bound dephytinizing phytase and nutrition-ameliorating probiotic traits of S. cerevisiae (NCIM 3662) presents profound applications in food technology sector. PMID- 29508268 TI - Effect of a Preparation of Four Probiotics on Symptoms of Patients with Irritable Bowel Syndrome: Association with Intestinal Bacterial Overgrowth. AB - : The effect of probiotics on small intestinal bacterial overgrowth (SIBO) in irritable bowel syndrome (IBS) has never been studied so far. In this prospective trial, five patients with IBS and SIBO and 21 patients with IBS without SIBO were administered an oral capsule containing Saccharomyces boulardii, Bifidobacterium lactis, Lactobacillus acidophilus, and Lactobacillus plantarum (Lactolevure(r)) every 12 h for 30 days. SIBO was defined by quantitative culture of the third part of the duodenum; IBS was defined by the Rome III criteria. Severity of symptoms was graded by the IBS severity scoring system (SSS). The primary study endpoint was the efficacy of probiotics in improvement of symptoms of IBS in patients with SIBO. Thirty days after the end of treatment, a 71.3% decrease of the total IBS score was detected in patients with IBS and SIBO compared to 10.6% in those without SIBO (p 0.017). A similar decrease was achieved among patients with constipation-predominant IBS without SIBO. Post-treatment satisfaction from bowel function was greater in patients with SIBO. Similar satisfaction improvement was found among patients with diarrhea-predominant IBS irrespective from SIBO; pain intensity score decreased in patients with constipation predominant IBS irrespective from SIBO. The benefit of probiotics was greater among patients with a pro-inflammatory cytokine pattern in the duodenal fluid. This is the first study that prospectively demonstrated superior clinical efficacy of probiotics in patients with IBS with SIBO. Analysis also showed considerable benefit from probiotic intake regarding certain symptoms of patients with diarrhea-predominant and constipation-predominant IBS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02204891. PMID- 29508269 TI - Specialty Article: so You Think You Got a Bypass? A Case Series of Adventures in Bariatric Surgery. AB - To raise awareness for surgeons encountering bariatric patients with anatomy that deviates from the standard Roux-en-Y gastric bypass (RYGB). This is a single institution retrospective case series over 12 years (2003-2014) involving patients who believed they received RYGBs, but actually did not. Data was obtained reviewing physician encounters, imaging, and operative reports. There were six cases with confusing clinical pictures, found to have aberrant RYGB anatomy: (1) gastric bypass with jejuno-jejunostomy only without gastrojejunostomy, (2) distal partial vertical gastrectomy without expected prosthetic band, (3) inverse vertical banded gastroplasty, (4) non-divided gastric bypass with no gastrojejunostomy, (5) 20-cm Roux limb, with gastro gastric fistula, and (6) 200-cm bilio-pancreatic limb similar to the traditional Scopinaro procedure. There are cases of "Roux-en-Y gastric bypasses" that have no resemblance to the named procedure at all. Adjunctive upper gastrointestinal studies and upper endoscopies help surgeons make diagnoses that are incongruent with the surgical history. It is important to keep in mind that there could be anatomic or surgical variations which were born out of necessity or based on other surgeons' creativities. PMID- 29508271 TI - Miguel-Angel Carbajo, MD, PhD. PMID- 29508270 TI - Sleeve Gastrectomy Reversed Obesity-Induced Hypogonadism in a Rat Model by Regulating Inflammatory Responses in the Hypothalamus and Testis. AB - BACKGROUND: Obesity is a metabolic disease with a serious health burden in children and adults, and it induces a variety of conditions including subfecundity. Sleeve gastrectomy showed encouraging results in terms of weight loss and improve quality of life, and this study aimed to determine whether sleeve gastrectomy could reverse obesity-induced impaired fertility in male Sprague-Dawley rats. METHODS: After 16 weeks of a chow diet (CD) or a high-fat diet (HFD) challenge, rats on the HFD were given a sleeve gastrectomy or sham operation and then fed an HFD for another 8 weeks. Serum glucose, insulin, lipids, sex hormone, sperm quality, inflammatory profile of the testis, and hypothalamic Kiss1 expression in the three study groups were compared. RESULTS: Sleeve gastrectomy significantly decreased HFD-induced obesity and serum glucose and insulin levels. It also reversed the HFD-induced increase in teratozoospermia and decreases in sperm motility and progressive motility. Testicular morphological abnormalities were also improved after sleeve gastrectomy. Enzyme linked immunosorbent assay showed that the expression of sex hormones increased after sleeve gastrectomy and that expression of inflammatory factors decreased. The HFD induced a hypothalamic inflammatory response that inhibited Kiss1 expression, which in turn mediated sex hormone expression. Sleeve gastrectomy treatment improved the hypothalamic response. CONCLUSIONS: The results consistently showed that sleeve gastrectomy reversed obesity-induced male fertility impairment by decreasing the inflammatory responses of the testis and hypothalamus. PMID- 29508272 TI - Laparoscopic Treatment of Gastro-Gastric Fistula After RYGB: Technical Points. AB - PURPOSE: Postoperative abdominal pain after Roux en Y gastric bypass associated with gastro esophageal reflux is difficult to manage. A gastro-gastric fistula can be the etiology and besides pain and weight regain, it can also be revealed by a dilatation of the excluded stomach and duodenum. METHODS: We present the case of a 45-year-old woman who had a medical history of revisional RYGB after failure of gastric band. She recently complained of recurrent epigastric abdominal pain and biliary GERD. Upper gastro intestinal endoscopy found biliary reflux gastritis. The CT scan with gas expansion and opacification revealed a dilated excluded stomach and duodenum leading to the diagnosis of gastro-gastric fistula. Because of pain and GERD correlated to this radiological finding, we decided to perform an exploratory laparoscopy. The patient was placed in a half sitting position, surgeon between the legs. A 12-mmHg pneumoperitoneum was made. A 4-port technique was used. The first step consisted of a complete adhesiolysis. The second step consisted in the dissection of the excluded stomach, stuck to the gastric pouch, and revealed two gastro-gastric fistulas treated by stapling. An epiploplasty was performed on the excluded stomach and the staple line of the gastric pouch was invaginated. RESULTS: Postoperative course was uneventful. One year later, she had no more reflux and no more pain. CONCLUSION: Causes of abdominal pain and GERD after RYGB are difficult to identify. Gastro-gastric fistula is one of them and should be evoked when biliary reflux and abdominal pain appear. PMID- 29508273 TI - Comparison Between Stable Line Reinforcement by Barbed Suture and Non reinforcement in Sleeve Gastrectomy: a Randomized Prospective Controlled Study. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is now a popular bariatric procedure worldwide with rising prevalence over the last decade. Staple line leak and bleeding are the most dangerous complications of LSG. Staple line reinforcement (SLR) by oversewing the staple line was suggested to reduce the incidence of leak and bleeding. We designed a randomized controlled prospective study to investigate the value of SLR by invaginating the whole staple line using unidirectional absorbable 3/0 V-Loc 180 sutures (Covidien, Mansfield, MA, USA) to no SLR in LSG. PATIENTS AND METHODS: Nine hundred and twenty patients undergoing LSG between March 2016 and March 2017 were included in the study; they were prospectively randomized into two groups: A and B, each of 460 patients. In group A, the entire staple line was invaginated with continuous seromuscular suturing using 3/0 V-Loc 180 suture (Covidien, Mansfield, MA, USA), and in group B, no reinforcement was done. The patients were selected according to National Institute of Health (NIH) guidelines. All procedures were performed by the same team of experienced bariatric surgeons. Patients were followed up for 6 weeks after surgery for occurrence of complications. RESULTS: The two groups were matched considering the demographic data. Operative time was significantly longer in group A (P = 0.001), with mean operative time in group A was 69 min, while that in Group B was 50.8 min. Leak occurred in eight cases (1.7%) in group B and none (0%) in group A; leak was significantly lower in group A (P = 0.008). Bleeding occurred in two patients (0.4%) in group A and in seven (1.5%) in group B (P = 0.178), with no statistically significant difference between both groups as regards bleeding. CONCLUSION: Comparing SLR by invaginating the whole staple line using unidirectional absorbable 3/0 V-Loc 180 sutures (Covidien, Mansfield, MA, USA) to no SLR in a relatively large cohort of patients undergoing LSG, in a randomized controlled prospective study, has proved statistically significant value for SLR by invaginating sutures. PMID- 29508274 TI - Author Correction: Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. AB - The original version of this article unfortunately contained a mistake. PMID- 29508276 TI - Identification of natural compounds targeting Annexin A2 with an anti-cancer effect. AB - Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor kappa B (NF-kappaB) activation by interacting with NF-kappaB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 (G-Rg5) and Rk1 (G-Rk1), with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rk1 inhibited the interaction between Annexin A2 and NF-kappaB p50 subunit, their translocation to nuclear and NF-kappaB activation. Inhibition of NF-kappaB by these two ginsenosides decreased the expression of inhibitor of apoptosis proteins (IAPs), leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G Rg5 and G-Rk1, effectively reduced the NF-kappaB inhibitory effect and apoptosis induced by G-Rg5 and G-Rk1. In addition, the knockdown of Annexin A2 largely enhanced NF-kappaB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rk1 on NF-kappaB were mainly mediated by Annexin A2. Taken together, this study for the first time demonstrated that G Rg5 and G-Rk1 inhibit tumor cell growth by targeting Annexin A2 and NF-kappaB pathway, and G-Rg5 and G-Rk1 might be promising natural compounds for targeted cancer therapy. PMID- 29508277 TI - BMAL1 functions as a cAMP-responsive coactivator of HDAC5 to regulate hepatic gluconeogenesis. PMID- 29508278 TI - IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis. AB - Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-gamma. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-gamma T (RORgammaT) pathway. T-bet mediates the IFN-gamma production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines related pathogenesis. PMID- 29508275 TI - EADSG Guidelines: Insulin Therapy in Diabetes. AB - A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A). Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A). Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin. Two or three premixed insulin injections per day may be used (A). The target glycated hemoglobin A1c (HbA1c) for all children with T1DM, including preschool children, is recommended to be < 7.5% (< 58 mmol/mol). The target is chosen aiming at minimizing hyperglycemia, severe hypoglycemia, hypoglycemic unawareness, and reducing the likelihood of development of long-term complications (B). For patients prone to glycemic variability, glycemic control is best evaluated by a combination of results with self-monitoring of blood glucose (SMBG) (B). Indications for exogenous insulin therapy in patients with type 2 diabetes mellitus (T2DM) include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy (B). In T2DM patients, with regards to achieving glycemic goals, insulin is considered alone or in combination with oral agents when HbA1c is >= 7.5% (>= 58 mmol/mol); and is essential for treatment in those with HbA1c >= 10% (>= 86 mmol/mol), when diet, physical activity, and other antihyperglycemic agents have been optimally used (B). The preferred method of insulin initiation in T2DM is to begin by adding a long-acting (basal) insulin or once-daily premixed/co-formulation insulin or twice-daily premixed insulin, alone or in combination with glucagon like peptide-1 receptor agonist (GLP-1 RA) or in combination with other oral antidiabetic drugs (OADs) (B). If the desired glucose targets are not met, rapid acting or short-acting (bolus or prandial) insulin can be added at mealtime to control the expected postprandial raise in glucose. An insulin regimen should be adopted and individualized but should, to the extent possible, closely resemble a natural physiologic state and avoid, to the extent possible, wide fluctuating glucose levels (C). Blood glucose monitoring is an integral part of effective insulin therapy and should not be omitted in the patient's care plan. Fasting plasma glucose (FPG) values should be used to titrate basal insulin, whereas both FPG and postprandial glucose (PPG) values should be used to titrate mealtime insulin (B). Metformin combined with insulin is associated with decreased weight gain, lower insulin dose, and less hypoglycemia when compared with insulin alone (C). Oral medications should not be abruptly discontinued when starting insulin therapy because of the risk of rebound hyperglycemia (D). Analogue insulin is as effective as human insulin but is associated with less postprandial hyperglycemia and delayed hypoglycemia (B). The shortest needles (currently the 4-mm pen and 6 mm syringe needles) are safe, effective, and less painful and should be the first line choice in all patient categories; intramuscular (IM) injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them (A). Many patients in East Africa reuse syringes for various reasons, including financial. This is not recommended by the manufacturer and there is an association between needle reuse and lipohypertrophy. However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice (A). Health care authorities and planners should be alerted to the risks associated with syringe or pen needles 6 mm or longer in children (A). PMID- 29508279 TI - Zing-Yang Kuo and behavior epigenesis based on animal experiments. PMID- 29508280 TI - The Dynamics of Impaired Blood-Brain Barrier Restoration in a Rat Model of Co morbid Injury. AB - Defect in brain microperfusion is increasingly recognized as an antecedent event to Alzheimer's disease (AD) and ischemia. Nevertheless, studies on the role of impaired microperfusion as a pathological trigger to neuroinflammation, Abeta deposition as well as blood-brain barrier (BBB) disruption, and the etiological link between AD and ischemia are lacking. In this study, we employ in vivo sequential magnetic resonance imaging (MRI) and computed tomography (CT) imaging in a co-morbid rat model of beta-amyloid toxicity (Abeta) and ischemia (ET1) with subsequent histopathology of striatal lesion core and penumbra at 1, 7, and 28 days post injury. Within 24 h, cerebral injury resulted in increased BBB permeability due to the dissolution of beta-dystroglycan (beta-DG) and basement membrane laminin by active matrix metalloproteinase9 (MMP9). As a result, net flow of circulating IgG down a hydrostatic gradient into the parenchyma led to vasogenic edema and impaired perfusion, thus increasing the apparent hyperintensity in true fast imaging with steady-state free precession (true FISP) imaging and acute hypoperfusion in CT. This was followed by a slow recruitment of reactive astroglia to the affected brain and depolarization of aquaporin4 (AQP4) expression resulting in cytotoxic edema-in an attempt to resolve vasogenic edema. On d28, functional BBB was restored in ET1 rats as observed by astrocytic MMP9 release, beta-DG stabilization, and new vessel formation. This was confirmed by reduced hyperintensity on true FISP imaging and normalized cerebral blood flow in CT. While, Abeta toxicity alone was not detrimental enough, Abeta+ET1 rats showed delayed differential expression of MMP9, late recruitment of astroglial cells, protracted loss of AQP4 depolarization, and thus delayed BBB restoration and cerebral perfusion. PMID- 29508281 TI - Altered Intracellular Calcium Homeostasis Underlying Enhanced Glutamatergic Transmission in Striatal-Enriched Tyrosine Phosphatase (STEP) Knockout Mice. AB - The striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase involved in synaptic transmission. The current hypothesis on STEP function holds that it opposes synaptic strengthening by dephosphorylating and inactivating key neuronal proteins involved in synaptic plasticity and intracellular signaling, such as the MAP kinases ERK1/2 and p38, as well as the tyrosine kinase Fyn. Although STEP has a predominant role at the post-synaptic level, it is also expressed in nerve terminals. To better investigate its physiological role at the presynaptic level, we functionally investigated brain synaptosomes and autaptic hippocampal neurons from STEP knockout (KO) mice. Synaptosomes purified from mutant mice were characterized by an increased basal and evoked glutamate release compared with wild-type animals. Under resting conditions, STEP KO synaptosomes displayed increased cytosolic Ca2+ levels accompanied by an enhanced basal activity of Ca2+/calmodulin-dependent protein kinase type II (CaMKII) and hyperphosphorylation of synapsin I at CaMKII sites. Moreover, STEP KO hippocampal neurons exhibit an increase of excitatory synaptic strength attributable to an increased size of the readily releasable pool of synaptic vesicles. These results provide new evidence that STEP plays an important role at nerve terminals in the regulation of Ca2+ homeostasis and neurotransmitter release. PMID- 29508282 TI - Activation of Nrf2 Pathway Contributes to Neuroprotection by the Dietary Flavonoid Tiliroside. AB - Hyperactivated microglia plays a key role in regulating neuroinflammatory responses which cause damage to neurons. In recent years, substantial attention has been paid in identifying new strategies to abrogate neuroinflammation. Tiliroside, a natural dietary glycosidic flavonoid, is known to inhibit neuroinflammation. This study was aimed at investigating the molecular mechanisms involved in the inhibition of neuroinflammation and neurotoxicity by tiliroside. The effects of tiliroside on Nrf2 and SIRT1 activities in BV2 microglia and HT22 hippocampal neurons were investigated using immunoblotting and DNA binding assays. The roles of Nrf2 and SIRT1 in the anti-inflammatory activity of tiliroside were further investigated using RNA interference experiments. HT22 neuronal viability was determined by XTT, calcium influx, DNA fragmentation assays. The effect of tiliroside on MAP2 protein expression in HT22 neurons was investigated using western blotting and immunofluorescence. We also studied the impact of tiliroside on DNA fragmentation and ROS generation in APPSwe transfected 3D neuronal stem cells. Results show that tiliroside increased protein levels of Nrf2, HO-1 and NQO1, indicating an activation of the Nrf2 protective mechanisms in the microglia. Furthermore, transfection of BV2 cells with Nrf2 siRNA resulted in the loss of anti-inflammatory activity by tiliroside. Tiliroside reduced protein levels of acetylated-NF-kappaB-p65, and increased SIRT1 in LPS/IFNgamma-activated BV2 microglia. RNAi experiments revealed that inhibition of neuroinflammation by tiliroside was not affected by silencing SIRT1 gene. Results of neurotoxicity experiments revealed that neuroinflammation induced toxicity, DNA fragmentation, ROS generation and calcium accumulation in HT22 neurons were significantly reduced by tiliroside treatment. In addition, the compound also protected differentiated human neural progenitor cells by blocking ROS generation and DNA fragmentation. Overall, this study has established that tiliroside protected BV2 microglia from LPS/IFNgamma-induced neuroinflammation and HT22 neuronal toxicity by targeting Nrf2 antioxidant mechanisms. The compound also produced inhibition of NF-kappaB acetylation through activation of SIRT1, as well as increasing SIRT1 activity in mouse hippocampal neurons. Results from this study have further established the mechanisms involved in the anti neuroinflammatory and neuroprotective activities of tiliroside. PMID- 29508285 TI - A new flexible piezoelectric pressure sensor array for the noninvasive detection of laryngeal movement during swallowing. AB - We tried to develop a new device to detect laryngeal movement noninvasively. We made small piezo pressure sensors (length, 1.5 mm, width, 7.0 mm), and five of these were lined up with 3.0-mm intervals and embedded in the middle of a palm sized urethane resin sheet. This sheet was lightly attached to the ventral surface of the neck near the laryngeal prominence. The first and second peaks obtained from each sensor should correspond to the period when the larynx moves to the upper and lower positions during swallowing. The mean maximum rising velocities for men and women were about 0.08 and 0.11 m/s, respectively. Similarly, the mean maximum lowering velocities for men and women were about 0.09 and 0.11 m/s, respectively. The swallowing latencies for men and women were about 0.49 and 0.53 s, respectively. In conclusion, we succeeded in developing a new device, which will be useful in evaluating the swallowing function. PMID- 29508286 TI - Comparison of Gene Expression Profiles in Nonmodel Eukaryotic Organisms with RNA Seq. AB - With recent advances of next-generation sequencing technology, RNA-Sequencing (RNA-Seq) has emerged as a powerful approach for the transcriptomic profiling. RNA-Seq has been used in almost every field of biological studies, and has greatly extended our view of transcriptomic complexity in different species. In particular, for nonmodel organisms which are usually without high-quality reference genomes, the de novo transcriptome assembly from RNA-Seq data provides a solution for their comparative transcriptomic study. In this chapter, we focus on the comparative transcriptomic analysis of nonmodel organisms. Two analysis strategies (without or with reference genome) are described step-by-step, with the differentially expressed genes explored. PMID- 29508287 TI - Microarray Data Analysis for Transcriptome Profiling. AB - Microarray data have vastly accumulated in the past two decades. Due to the high throughput characteristic of microarray techniques, it has transformed biological studies from specific genes to transcriptome level, and deeply boosted many fields of biological studies. While microarray offers great advantages for expression profiling, on the other hand it faces a lot challenges for computational analysis. In this chapter, we demonstrate how to perform standard analysis including data preprocessing, quality assessment, differential expression analysis, and general downstream analyses. PMID- 29508288 TI - Pathway and Network Analysis of Differentially Expressed Genes in Transcriptomes. AB - In recent years, transcriptome sequencing has become very popular, encompassing a wide variety of applications from simple mRNA profiling to discovery and analysis of the entire transcriptome. One of the most common aims of transcriptome sequencing is to identify genes that are differentially expressed (DE) between two or more biological conditions, and to infer associated pathways and gene networks from expression profiles. It can provide avenues for further systematic investigation into potential biologic mechanisms. Gene Set (GS) enrichment analysis is a popular approach to identify pathways or sets of genes that are significantly enriched in the context of differentially expressed genes. However, the approach considers a pathway as a simple gene collection disregarding knowledge of gene or protein interactions. In contrast, topology-based methods integrate the topological structure of a pathway and gene network into the analysis. To provide a panoramic view of such approaches, this chapter demonstrates several recent computational workflows, including gene set enrichment and topology-based methods, for analysis of the DE pathways and gene networks from transcriptome-wide sequencing data. PMID- 29508290 TI - Tracking Alternatively Spliced Isoforms from Long Reads by SpliceHunter. AB - Alternative splicing increases the functional complexity of a genome by generating multiple isoforms and potentially proteins from the same gene. Vast amounts of alternative splicing events are routinely detected by short read deep sequencing technologies but their functional interpretation is hampered by an uncertain transcript context. Emerging long-read sequencing technologies provide a more complete picture of full-length transcript sequences. We introduce SpliceHunter, a tool for the computational interpretation of long reads generated by for example Pacific Biosciences instruments. SpliceHunter defines and tracks isoforms and novel transcription units across time points, compares their splicing pattern to a reference annotation, and translates them into potential protein sequences. PMID- 29508289 TI - QuickRNASeq: Guide for Pipeline Implementation and for Interactive Results Visualization. AB - Sequencing of transcribed RNA molecules (RNA-Seq) has been used wildly for studying cell transcriptomes in bulk or at the single-cell level (Wang et al., Nat Rev Genet, 10:57-63, 2009; Ozsolak and Milos, Nat Rev Genet, 12:87-98, 2011; Sandberg, Nat Methods, 11:22-24, 2014) and is becoming the de facto technology for investigating gene expression level changes in various biological conditions, on the time course, and under drug treatments. Furthermore, RNA-Seq data helped identify fusion genes that are related to certain cancers (Maher et al., Nature, 458:97-101, 2009). Differential gene expression before and after drug treatments provides insights to mechanism of action, pharmacodynamics of the drugs, and safety concerns (Dixit et al., Genomics, 107:178-188, 2016). Because each RNA-Seq run generates tens to hundreds of millions of short reads with size ranging from 50 to 200 bp, a tool that deciphers these short reads to an integrated and digestible analysis report is in high demand. QuickRNASeq (Zhao et al., BMC Genomics, 17:39-53, 2016) is an application for large-scale RNA-Seq data analysis and real-time interactive visualization of complex data sets. This application automates the use of several of the best open-source tools to efficiently generate user friendly, easy to share, and ready to publish report. Figures in this protocol illustrate some of the interactive plots produced by QuickRNASeq. The visualization features of the application have been further improved since its first publication in early 2016. The original QuickRNASeq publication (Zhao et al., BMC Genomics, 17:39-53, 2016) provided details of background, software selection, and implementation. Here, we outline the steps required to implement QuickRNASeq in user's own environment, as well as demonstrate some basic yet powerful utilities of the advanced interactive visualization modules in the report. PMID- 29508283 TI - AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy. AB - The NH2tau 26-44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20-22-kDa NH2-truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies. PMID- 29508291 TI - RNA-Seq-Based Transcript Structure Analysis with TrBorderExt. AB - RNA-Seq has become a routine strategy for genome-wide gene expression comparisons in bacteria. Despite lower resolution in transcript border parsing compared with dRNA-Seq, TSS-EMOTE, Cappable-seq, Term-seq, and others, directional RNA-Seq still illustrates its advantages: low cost, quantification and transcript border analysis with a medium resolution (+/-10-20 nt). To facilitate mining of directional RNA-Seq datasets especially with respect to transcript structure analysis, we developed a tool, TrBorderExt, which can parse transcript start sites and termination sites accurately in bacteria. A detailed protocol is described in this chapter for how to use the software package step by step to identify bacterial transcript borders from raw RNA-Seq data. The package was developed with Perl and R programming languages, and is accessible freely through the website: http://www.szu-bioinf.org/TrBorderExt . PMID- 29508292 TI - Analysis of RNA Editing Sites from RNA-Seq Data Using GIREMI. AB - RNA editing is a posttranscriptional modification process that alters the sequence of RNA molecules. RNA editing is related to many human diseases. However, the identification of RNA editing sites typically requires matched genomic sequence or multiple related expression data sets. Here we describe the GIREMI tool (genome-independent identification of RNA editing by mutual information; https://github.com/zhqingit/giremi ) that is designed to accurately and sensitively predict adenosine-to-inosine editing from a single RNA-Seq data set. PMID- 29508284 TI - NLRs as Helpline in the Brain: Mechanisms and Therapeutic Implications. AB - Nucleotide binding domain, leucine-rich repeat containing proteins (NLRs) are a family of pattern recognition receptors involved in major innate immune defense mechanisms. NLRs play a key role in several cancers, autoimmune, and inflammation associated diseases. Association of NLRP3 has been widely investigated in neurodegenerative diseases, chronic alcoholism, depression, traumatic brain injury, and pathogenic infections. Several research studies have shown possible involvement of various other inflammasome-forming and non-inflammasome-forming NLRs in the brain; however, their mechanisms of action are yet to be defined clearly. Our review provides a comprehensive overview of the expression of NLRs in human brain and their critical association with inflammation and neurodegenerative diseases. The review also summarizes promising NLR-targeted therapeutics and their prospects for brain pathologies. PMID- 29508293 TI - Bioinformatic Analysis of MicroRNA Sequencing Data. AB - The vital role of microRNAs (miRNAs) involved in gene expression regulation has been confirmed in many biological processes. With the growing power and reducing cost of next-generation sequencing, more and more researchers turn to apply this high-throughput method to solve their biological problems. For miRNAs with known sequences, their expression profiles can be generated from the sequencing data. It also allows us to identify some novel miRNAs and explore the sequence variations under different conditions. Currently, there are a handful of tools available to analyze the miRNA sequencing data with separated or combined features, such as reads preprocessing, mapping and differential expression analysis. However, to our knowledge, a hands-on guideline for miRNA sequencing data analysis covering all steps is not available. Here we will utilize a set of published tools to perform the miRNA analysis with detailed explanation. Particularly, the miRNA target prediction and annotation may provide useful information for further experimental verification. PMID- 29508294 TI - Microarray-Based MicroRNA Expression Data Analysis with Bioconductor. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that are able to regulate the expression of targeted mRNAs. Thousands of miRNAs have been identified; however, only a few of them have been functionally annotated. Microarray-based expression analysis represents a cost-effective way to identify candidate miRNAs that correlate with specific biological pathways, and to detect disease-associated molecular signatures. Generally, microarray-based miRNA data analysis contains four major steps: (1) quality control and normalization, (2) differential expression analysis, (3) target gene prediction, and (4) functional annotation. For each step, a large couple of software tools or packages have been developed. In this chapter, we present a standard analysis pipeline for miRNA microarray data, assembled by packages mainly developed with R and hosted in Bioconductor project. PMID- 29508295 TI - Identification and Expression Analysis of Long Intergenic Noncoding RNAs. AB - Long intergenic noncoding RNAs (lincRNAs) have caught increasing attention in recent years. The advance of RNA-Seq has greatly facilitated the discovery of novel lincRNAs. However, the computational analysis of lincRNAs is still challenging. In this protocol, we presented a step-by-step protocol for computational analyses of lincRNAs, including read processing and alignment, transcript assembly, lincRNA identification and annotation, and differential expression analysis. PMID- 29508296 TI - Analysis of RNA-Seq Data Using TEtranscripts. AB - Transposable elements (TE) are mobile genetic elements that can readily change their genomic position. When not properly silenced, TEs can contribute a substantial portion to the cell's transcriptome, but are typically ignored in most RNA-seq data analyses. One reason for leaving TE-derived reads out of RNA seq analyses is the complexities involved in properly aligning short sequencing reads to these highly repetitive regions. Here we describe a method for including TE-derived reads in RNA-seq differential expression analysis using an open source software package called TEtranscripts. TEtranscripts is designed to assign both uniquely and ambiguously mapped reads to all possible gene and TE-derived transcripts in order to statistically infer the correct gene/TE abundances. Here, we provide a detailed tutorial of TEtranscripts using a published qPCR validated dataset.Barbara McClintock laid the foundation for TE research with her discoveries in maize of mobile genetic elements capable of inserting into novel locations in the genome, altering the expression of nearby genes [1]. Since then, our appreciation of the contribution of repetitive TE-derived sequences to eukaryotic genomes has vastly increased. With the publication of the first human genome draft by the Human Genome Project, it was determined that nearly half of the human genome is derived from TE sequences [2, 3], with varying levels of repetitive DNA present in most plant and animal species. More recent studies looking at distantly related TE-like sequences have estimated that up to two thirds of the human genome might be repeat-derived [4], with the vast majority of these sequences attributed to retrotransposons that require transcription as part of the mobilization process, as discussed below. PMID- 29508297 TI - Computational Analysis of RNA-Protein Interactions via Deep Sequencing. AB - RNA-binding proteins (RBPs) function in all aspects of RNA processes including stability, structure, export, localization and translation, and control gene expression at the posttranscriptional level. To investigate the roles of RBPs and their direct RNA ligands in vivo, recent global approaches combining RNA immunoprecipitation and deep sequencing (RIP-seq) as well as UV-cross-linking (CLIP-seq) have become instrumental in dissecting RNA-protein interactions. However, the computational analysis of these high-throughput sequencing data is still challenging. Here, we provide a computational pipeline to analyze CLIP-seq and RIP-seq datasets. This generic analytic procedure may help accelerate the identification of direct RNA-protein interactions from high-throughput RBP profiling experiments in a variety of bacterial species. PMID- 29508298 TI - Predicting Gene Expression Noise from Gene Expression Variations. AB - The level of gene expression is known to vary from cell to cell and even in the same cell over time. This variability provides cells with the ability to mitigate environmental stresses and genetic perturbations, and facilitates gene expression evolution. Recently, many valuable gene expression noise data measured at the single-cell level and gene expression variation measured for cell populations have become available. In this chapter, we show how to perform integrative analysis using these data. Specifically, we introduce how to apply a machine learning technique (support vector regression) to explore the relationship between gene expression variations and stochastic noise. PMID- 29508299 TI - A Protocol for Epigenetic Imprinting Analysis with RNA-Seq Data. AB - Genomic imprinting is an epigenetic regulatory mechanism that operates through expression of certain genes from maternal or paternal in a parent-of-origin specific manner. Imprinted genes have been identified in diverse biological systems that are implicated in some human diseases and in embryonic and seed developmental programs in plants. The molecular underpinning programs and mechanisms involved in imprinting are yet to be explored in depth in plants. The recent advances in RNA-Seq-based methods and technologies offer an opportunity to systematically analyze epigenetic imprinting that operates at the whole genome level in the model and crop plants. We are interested using Arabidopsis model system, to investigate gene expression patterns associated with parent of origin and their implications to imprinting during embryo and seed development. Toward this, we have generated early embryo development RNA-Seq-based transcriptome datasets in F1s from a genetic cross between two diverse Arabidopsis thaliana ecotypes Col-0 and Tsu-1. With the data, we developed a protocol for evaluating the maternal and paternal contributions of genes during the early stages of embryo development after fertilization. This protocol is also designed to consider the contamination from other potential seed tissues, sequencing quality, proper processing of sequenced reads and variant calling, and appropriate inference of the parental contributions based on the parent-of-origin-specific single-nucleotide polymorphisms within the expressed genes. The approach, methods and the protocol developed in this study can be used for evaluating the effects of epigenetic imprinting in plants. PMID- 29508300 TI - Single-Cell Transcriptome Analysis Using SINCERA Pipeline. AB - Genome-scale single-cell biology has recently emerged as a powerful technology with important implications for both basic and medical research. There are urgent needs for the development of computational methods or analytic pipelines to facilitate large amounts of single-cell RNA-Seq data analysis. Here, we present a detailed protocol for SINCERA (SINgle CEll RNA-Seq profiling Analysis), a generally applicable analytic pipeline for processing single-cell data from a whole organ or sorted cells. The pipeline supports the analysis for the identification of major cell types, cell type-specific gene signatures, and driving forces of given cell types. In this chapter, we provide step-by-step instructions for the functions and features of SINCERA together with application examples to provide a practical guide for the research community. SINCERA is implemented in R, licensed under the GNU General Public License v3, and freely available from CCHMC PBGE website, https://research.cchmc.org/pbge/sincera.html . PMID- 29508301 TI - Mathematical Modeling and Deconvolution of Molecular Heterogeneity Identifies Novel Subpopulations in Complex Tissues. AB - Tissue heterogeneity is both a major confounding factor and an underexploited information source. While a handful of reports have demonstrated the potential of supervised methods to deconvolve tissue heterogeneity, these approaches require a priori information on the marker genes or composition of known subpopulations. To address the critical problem of the absence of validated marker genes for many (including novel) subpopulations, we develop a novel unsupervised deconvolution method, Convex Analysis of Mixtures (CAM), within a well-grounded mathematical framework, to dissect mixed gene expressions in heterogeneous tissue samples. To facilitate the utility of this method, we implement an R-Java CAM package that provides comprehensive analytic functions and graphic user interface (GUI). PMID- 29508302 TI - Erratum to: Probing Protein Kinase-ATP Interactions Using a Fluorescent ATP Analog. PMID- 29508303 TI - Sarcocystis myopathy in a patient with HIV-AIDS. AB - Sarcocystosis is a zoonotic infection that causes intestinal and muscular illnesses in humans. Sarcocystosis was until recently considered rare in humans. To complete their life cycle, Sarcocystis species require both a definitive and an intermediate host. Humans are the definitive host when infected by one of two species: Sarcocystis hominis (from eating undercooked beef) or Sarcocystis suihominis (from eating uncooked pork). Infection with either of these species results in intestinal sarcocystosis, causing a self-limited disease characterized by nausea, abdominal pain, and diarrhea. Humans act as the intermediate host when infected by Sarcocystis nesbitti, resulting in the markedly different clinical picture of muscular sarcocystosis. Most documented cases of muscular sarcocystosis were assumed to be acquired in Malaysia, in addition to other regions of Southeast Asia and India. Published cases of muscular sarcocystosis from the Middle East, Central and South America, and Africa are all rare. Although the clinical presentation of muscular sarcocystosis remains to be fully characterized, fever, myalgia, and headache are among the most common symptoms. Here, we report a patient from sub-Saharan Africa with chronic Sarcocystis myopathy and well-controlled HIV-AIDS. PMID- 29508304 TI - Hemorrhagic fever with renal syndrome accompanied by panhypopituitarism and central diabetes insipidus: a case report. AB - Central diabetes insipidus (DI) was detected in a patient with hemorrhagic fever with renal syndrome (HFRS) who had been molecularly and serologically diagnosed with Hantaan virus infection. We recommend that clinicians differentiate central DI in HFRS patients with a persistent diuretic phase even when pituitary MRI findings are normal. PMID- 29508305 TI - Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event. AB - This report assesses the observed risk of PML in patients treated with the anti CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ~ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000-50,000 patients). In all cases, patients had >= 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time. PMID- 29508306 TI - Correction to: Postoperative recurrence from tract seeding after use of EUS-FNA for preoperative diagnosis of cancer in pancreatic tail. AB - The correct name of the corresponding author should be ''Nobuhiko Fukuba'', and not ''Nobuhiko Fukuban'' as given in the original publication of the article. PMID- 29508307 TI - Usefulness of four-dimensional flow-sensitive magnetic resonance imaging to evaluate hemodynamics in the pancreaticoduodenal artery. AB - Pancreaticoduodenal artery (PDA) aneurysm associated with celiac axis compression by the median arcuate ligament (MAL) is a rare disorder, but may be lethal if ruptured. Therefore, prophylactic surgical treatments need to be considered when MAL compresses the celiac axis. We herein report the usefulness of an arterial flow analysis for objectively evaluating this pathophysiology under four dimensional flow-sensitive magnetic resonance imaging (4D-flow MRI). Celiac artery stenosis was incidentally found under contrast-enhanced CT in a 50-year old woman with symptomatic solitary pancreatic insulinoma. Under 4D-flow MRI, retrograde blood flow and aberrant wall shear stress were detected in the pancreaticoduodenal artery arcade. After obtaining informed consent, enucleation for insulinoma concomitant with MAL dissection was performed. Hypoglycemic attack completely resolved immediately after surgery. One month after surgery, 4D-flow MRI revealed normalized vectorial flow and wall shear stress in the PDA arcade without hypoglycemic attack. 4D-flow MRI is a very useful and non-invasive modality for objectively evaluating visceral artery hemodynamics. PMID- 29508308 TI - EUS-guided colo-enterostomy as a salvage drainage procedure in a high surgical risk patient with small bowel obstruction due to severe ileocolonic anastomotic stricture: a new application of lumen-apposing metal stent (LAMS). AB - We submit the first case report of a successful EUS-guided transmural LAMS placement to drain the small bowel directly into the transverse colon in a high surgical risk patient with obstruction due to severe anastomotic stricture. We describe our technique for endoscopic colo-enterostomy and are hopeful that this will become a viable option to manage non-operable high-grade distal small bowel obstruction. PMID- 29508309 TI - Author's reply for letter to editor: Acute pancreatitis-onset carcinoma in situ of the pancreas with focal fat replacement diagnosed using serial pancreatic juice aspiration cytologic examination (SPACE). PMID- 29508310 TI - Diagnostic significance of SPACE for PCIS. PMID- 29508311 TI - The Impact of Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass on Intestinal Microbiota Differs from that of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Obesity. AB - BACKGROUND AND OBJECTIVES: Bariatric surgery improves metabolic diseases and alters the intestinal microbiota in animals and humans, but different procedures reportedly have different impacts on the intestinal microbiota. We developed laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB) as an alternative to laparoscopic Roux-en-Y gastric bypass (LRYGB) in addition to laparoscopic sleeve gastrectomy (LSG) for Japanese patients with obesity. We investigated the precise change in the intestinal microbiota induced by these procedures in the present study. METHODS: A prospective observational study of 44 Japanese patients with obesity was conducted [22 patients underwent LSG, 18 underwent LSG-DJB, and 4 underwent laparoscopic adjustable gastric banding (LAGB)]. The patients' clinical parameters and intestinal microbiota were investigated before and for 6 months after surgery. The microbiota was analyzed by a 16S rDNA method. RESULTS: LSG and LSG-DJB significantly improved the metabolic disorders in the patients with obesity. The proportion of the phylum Bacteroidetes and order Lactobacillales increased significantly in the LSG group, and that of the order Enterobacteriales increased significantly in the LSG-DJB group. CONCLUSIONS: LSG and LSG-DJB improved obesity and type 2 diabetes in Japanese patients with obesity, but the impact of LSG-DJB on the intestinal microbiota differed from that of LSG. This difference in the impact on the intestinal environment could explain the different efficacies of LSG and LSG-DJB in terms of their ability to resolve metabolic disorders in the clinical setting. PMID- 29508312 TI - Climate Change: From Science to Practice. AB - PURPOSE OF REVIEW: Climate change poses a significant threat to human health. Understanding how climate science can be translated into public health practice is an essential first step in enabling robust adaptation and improving resiliency to climate change. RECENT FINDINGS: Recent research highlights the importance of iterative approaches to public health adaptation to climate change, enabling uncertainties of health impacts and barriers to adaptation to be accounted for. There are still significant barriers to adaptation, which are context-specific and thus present unique challenges to public health practice. The implementation of flexible adaptation approaches, using frameworks targeted for public health, is key to ensuring robust adaptation to climate change in public health practice. The BRACE framework provides an excellent approach for health adaptation to climate change. Combining this with the insights provided and by the adaptation pathways approach allows for more deliberate accounting of long-term uncertainties. The mainstreaming of climate change adaptation into public health practice and planning is important in facilitating this approach and overcoming the significant barriers to effective adaptation. Yet, the immediate and future limits to adaptation provide clear justification for urgent and accelerated efforts to mitigate climate change. PMID- 29508313 TI - [The post-mortem examination]. PMID- 29508314 TI - ? PMID- 29508315 TI - ? PMID- 29508316 TI - ? PMID- 29508317 TI - ? PMID- 29508318 TI - ? PMID- 29508319 TI - ? PMID- 29508320 TI - ? PMID- 29508321 TI - [Disease management program diabetes in Germany - update to reduce foot amputations]. PMID- 29508322 TI - [Priapism]. PMID- 29508323 TI - [Do you know your risk of getting a heart attack?] PMID- 29508325 TI - ? PMID- 29508324 TI - [Heart failure in the general medical practice - A guide to diagnosis and therapy]. PMID- 29508326 TI - ? PMID- 29508327 TI - ? PMID- 29508328 TI - ? PMID- 29508329 TI - ? PMID- 29508330 TI - ? PMID- 29508331 TI - ? PMID- 29508332 TI - ? PMID- 29508333 TI - ? PMID- 29508334 TI - ? PMID- 29508336 TI - ? PMID- 29508335 TI - ? PMID- 29508337 TI - ? PMID- 29508338 TI - ? PMID- 29508339 TI - ? PMID- 29508340 TI - ? PMID- 29508341 TI - ? PMID- 29508342 TI - ? PMID- 29508343 TI - ? PMID- 29508344 TI - ? PMID- 29508345 TI - ? PMID- 29508346 TI - ? PMID- 29508347 TI - ? PMID- 29508348 TI - ? PMID- 29508349 TI - ? PMID- 29508350 TI - ? PMID- 29508352 TI - ? PMID- 29508353 TI - ? PMID- 29508354 TI - ? PMID- 29508355 TI - ? PMID- 29508356 TI - Building a Bridge Between Genetics and Outcomes Research: Application in Autism (The AutGO Study). AB - BACKGROUND: Concerns over the need to improve translational aspects of genetics research studies and engaging community members in the research process have been noted in the literature and raised by patient advocates. In addition to the work done by patient advocacy groups, organizations such as the Patient-Centered Outcomes Research Institute advocate for a change in the culture of research from being researcher-driven to becoming more patient-driven. OBJECTIVE: Our project, Autism Genetics and Outcomes (AutGO), consists of two phases. The goal for phase I was to initiate a general discussion around the main topic (i.e., linking genetics and outcomes research). We used the Patient-Centered Outcomes Research Institute engagement approach to: (aim 1) develop a partnership with a wide range of stakeholders to assess their perspective on developing projects that use both genetics and outcomes research data/principles; (aim 2) identify barriers, facilitators, and needs to promote engagement in patient-centered genetics research; and (aim 3) distill and describe actions that may facilitate utilization of patient/parent perspectives in designing genetics research studies. METHODS: In phase I, we formed a community advisory board composed of 33 participants, including outcomes and genetics researchers, clinicians, healthcare providers, patients/family members, and community/industry representatives, and convened six sessions over the 12-month period. We structured the sessions as a combination of online PowerPoint presentations, surveys, and in-person group discussions. During the sessions, we discussed topics pertaining to linking genetics and outcomes research and reviewed relevant materials, including patient stories, research projects, and existing resources. RESULTS: Two sets of surveys, project evaluations (k = 2) and session evaluations (k = 6), were distributed among participants. Feedback was analyzed using content analysis strategies to identify the themes and subthemes. Herein, we describe: the established partnership (aim 1), the identified barriers, facilitators, and needs (aim 2), as well as the lessons learned and suggested recommendations for the research community (aim 3). Following phase I participants' recommendation, in phase II, we will focus on a specific disease (i.e., autism); this projected plan is briefly outlined to highlight the overarching goal of the project and its potential significance. We also discuss the study limitations, challenges for conducting this type of multidisciplinary work, as well as potential ways to address them. CONCLUSIONS: The AutGO project has created a unique collaborative forum to facilitate the much needed dialogue between genetics and outcomes researchers, which may contribute to finding ways to improve the translational aspects of genetics research studies. PMID- 29508357 TI - CD117 is not always positive in infantile gastrointestinal stromal tumor. PMID- 29508358 TI - The role of melatonin and cortisol circadian rhythms in the pathogenesis of infantile colic. AB - BACKGROUND: Despite the high prevalence of infantile colic, the pathogenesis remains incompletely understood. Cortisol and melatonin hormones affect gastrointestinal system development in several ways, and interestingly, both cortisol and melatonin's circadian rhythms begin around the 3rd month in which infantile colic symptoms start to decrease. We hypothesized that infantile colic might associate with desynchronization of normal circadian rhythms of these hormones. In this study, we aimed to investigate the role of melatonin and cortisol in the pathogenesis of infantile colic. METHODS: Patients who were diagnosed as infantile colic according to Wessel's "rule of three" were enrolled in the colic group. We measured the saliva melatonin and cortisol levels of colic group and control group infants. In both groups, the saliva samples were taken in mornings and at evenings, at the time of diagnosis and 6th month. RESULTS: Fifty five infants finished the study. Melatonin circadian rhythm developed earlier in the control group than the infantile colic group in our study. We found no significant difference between the daily mean cortisol levels. However, infants with colic had flatter daily cortisol slope than controls which pointed out the probability that they had a less clearly defined cortisol rhythm than infants without colic. CONCLUSIONS: We found an association between melatonin levels and infantile colic. However, more research is needed to fully understand the role of hypothalamic-pituitary-adrenal axis and hormone's role on infantile colic physiopathology. PMID- 29508359 TI - Eight novel mutations of CBS gene in nine Chinese patients with classical homocystinuria. AB - BACKGROUND: Classical homocystinuria (homocysteinemia type 1, MIM# 236200) is a rare inherited disorder in Mainland China. This study aimed to identify mutations in the cystathionine beta-synthase (CBS) gene which are associated with classical homocystinuria in nine Chinese patients. METHODS: Nine Chinese patients were diagnosed at the age of 5 years 4 months to 18 years by plasma total homocysteine and blood methionine determination. CBS gene analysis was performed for the patients and their families. RESULTS: All nine patients had significantly increased plasma total homocysteine (142-500 MUmol/L vs. the normal range of 0-15 MUmol/L) and blood methionine (144.3-500 MUmol/L vs. the normal range of 0-50 MUmol/L). None of the patients was pyridoxine responsive. Eleven mutations in CBS gene were identified in the nine patients. Eight mutations (IVS3+1G>A, p.Thr493fsX46, p.Thr236Asn, p.Leu230Gln, p.Lys72Ile, p.Ser201ProfsX36, p.Met337IlefsX115, and IVS14-1G>C) were novel. Three mutations (p.Arg125Gln, p.Thr257Met and p.Gly116Arg) had been previously reported. CONCLUSIONS: In this study, eight novel mutations in CBS were identified in nine Chinese patients with classical homocystinuria. None of the hotspot mutations reported in other regions previously was found. These data indicated that Chinese maybe had different CBS mutation spectrum from other population. The identification of mutations not only confirms the diagnosis but also enables accurate genetic counselling and prenatal diagnosis for the fetuses of the families. PMID- 29508360 TI - Ex utero intrapartum treatment for giant congenital omphalocele. AB - BACKGROUND: To determine whether ex utero intrapartum treatment (EXIT) is an appropriate approach for managing fetuses antenatally diagnosed with giant congenital omphaloceles. METHODS: We retrospectively reviewed patients with omphaloceles who underwent either an EXIT procedure or a traditional repair surgery. Basic and clinical parameters including gender, gestational age, birth weight, maternal blood loss, operative times and operative complications were analyzed. During the 6-12-month follow-ups, postoperative complications including bowel obstruction, abdominal infections, postoperative abdominal distension were monitored, and survival rate was analyzed. RESULTS: A total of seven patients underwent the EXIT procedure and 11 patients underwent the traditional postnatal surgery. We found no differences in maternal age, gestational age at diagnosis, gestational age at delivery and birth weight between the two groups. In the EXIT group, the average operation time for mother was 68.3 +/- 17.5 minutes and the average maternal blood loss was 233.0 +/- 57.7 mL. The operation time in the EXIT group (22.0 +/- 4.5 minutes) was shorter than that in the traditional group (35 +/- 8.7 minutes), but the length of hospital stay in the EXIT group (20.5 +/- 3.1 days) was longer than that in the traditional group (15.7 +/- 2.5 days, P < 0.05). During the follow-up, one patient in the EXIT group had an intestinal obstruction, one developed abdominal compartment syndrome and one died in the traditional group. CONCLUSIONS: In our experience, EXIT is a safe and effective procedure for the treatment of giant congenital omphaloceles. However, more experience is needed before this procedure can be widely recommended. PMID- 29508361 TI - Surgical chylothorax in neonates: management and outcomes. AB - BACKGROUND: Postoperative chylothorax occurs due to trauma to lymphatic vessels and can occur after any thoracic procedure. This study reviewed recent literature to evaluate the management and outcomes of surgical chylothorax in neonates. METHODS: PubMed database was searched for articles in English, Portuguese and Spanish from 2000 to 2016. Data were collected for surgery, chylothorax management, complications, mortality and length of hospital stay (LOS). RESULTS: Twenty studies offered 107 neonates: congenital diaphragmatic hernia (CDH) (n = 76, 71%), cardiac malformations (n = 25, 23.4%), esophageal atresia (n = 5, 4.7%) and CDH + extralobar sequestration (n = 1, 0.9%). Medium-chain triglycerides (MCT) was the initial treatment in 52 neonates (48.6%), prednisolone + MCT in one (0.9%), total parenteral nutrition in 51 patients (47.7%), and three patients (2.8%) did not require any treatment. Octreotide and somatostatin were used as second or third line treatment in 25 neonates (23.4%), and 15 neonates (14%) underwent 17 surgeries, including thoracic duct ligation (TDL) (n = 9); pleurodesis (n = 3) (2 patients required TDL); TDL + pleurodesis (n = 2), and TDL + placement of hemostat (n = 1). Complications due to the chylothorax were reported in 27 neonates (25.2%): hypoalbuminemia + hyponatremia (n = 18), hypoalbuminemia (n = 4), hypoalbuminemia with cutaneous flushing as colateral effect of somatostatin (n = 1), loose stool after somatostatin use (n = 1), pneumonia (n = 1), congestive heart failure + hypernatremia (n = 1), and hyponatremia (n = 1). There were 21 deaths (19.6%) and median LOS was 53.4 days (30-93.1 days). CONCLUSIONS: Conservative management is appropriate as initial treatment for neonatal postsurgical chylothorax. Octreotide and somatostatin are safe in neonates and surgical approach should be considered in prolonged leaks. PMID- 29508362 TI - Staphylococcal-scalded skin syndrome: evaluation, diagnosis, and management. AB - BACKGROUND: Staphylococcal-scalded skin syndrome (SSSS), also known as Ritter disease, is a potentially life-threatening disorder and a pediatric emergency. Early diagnosis and treatment is imperative to reduce the morbidity and mortality of this condition. The purpose of this article is to familiarize physicians with the evaluation, diagnosis, and treatment of SSSS. DATA SOURCES: A PubMed search was completed in Clinical Queries using the key terms "Staphylococcal scalded skin syndrome" and "Ritter disease". RESULTS: SSSS is caused by toxigenic strains of Staphylococcus aureus. Hydrolysis of the amino-terminal extracellular domain of desmoglein 1 by staphylococcal exfoliative toxins results in disruption of keratinocytes adhesion and cleavage within the stratum granulosum which leads to bulla formation. The diagnosis is mainly clinical, based on the findings of tender erythroderma, bullae, and desquamation with a scalded appearance especially in friction zones, periorificial scabs/crusting, positive Nikolsky sign, and absence of mucosal involvement. Prompt empiric treatment with intravenous anti-staphylococcal antibiotic such as nafcillin, oxacillin, or flucloxacillin is essential until cultures are available to guide therapy. Clarithromycin or cefuroxime may be used should the patient have penicillin allergy. If the patient is not improving, critically ill, or in communities where the prevalence of methicillin-resistant S. aureus is high, vancomycin should be used. CONCLUSION: A high index of suspicion is essential for an accurate diagnosis to be made and treatment promptly initiated. PMID- 29508363 TI - Pediatric appendicitis with appendicolith often presents with prolonged abdominal pain and a high risk of perforation. AB - BACKGROUND: Appendicolith can cause appendiceal obstruction and acute appendicitis. Its high prevalence may be related to the high perforation rate in pediatric appendicitis. This study assessed the characteristics of appendicolith and its clinical significance in pediatric appendicitis. METHODS: A retrospective study was performed among children and adolescents younger than 17 years who were preoperatively diagnosed with appendicitis in the pediatric emergency department (ED). A total of 269 patients with a mean age of 9.98 +/- 3.37 years were enrolled. Clinical features and contrast-enhanced computed tomography findings were analyzed. RESULTS: Among the 269 patients, 147 (54.6%) had appendicoliths, with a mean maximal diameter of 5.21 +/- 2.34 mm. Compared to the no appendicolith group, the appendicolith group demonstrated more prolonged abdominal pain (>= 48 hours) before the ED visit (23.1% vs. 11.5%; P = 0.013), clinical features of severe appendicitis (presence of fever, vomiting, positive urine ketone, and increased C-reactive protein), and higher rate of perforation (43.5% vs. 9.8%; P < 0.001). Multivariate risk factor analysis for perforated appendicitis in the appendicolith group revealed that maximal diameter of 5 mm or more in the appendicolith (adjusted odds ratio [aOR] 2.919; 95% CI 1.325-6.428, P = 0.008) and proximal collapse adjacent to the appendicolith (aOR 2.943; 95% CI 1.344-6.443, P = 0.007) were significant. CONCLUSIONS: Pediatric appendicitis with appendicolith often presents with prolonged abdominal pain and severe clinical conditions with a high risk of perforation. PMID- 29508364 TI - Impact of hospital volume on outcomes of percutaneous ASD/PFO closure in pediatric patients. AB - BACKGROUND: We investigated the effect of hospital volume on percutaneous closure of atrial septal defect/patent foramen ovale (ASD) among pediatric patients. METHODS: We identified patients undergoing percutaneous closure of ASD with device using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure code 35.52 from the National Inpatient Sample, years 2002-2011. Patients with age <= 18 years and primary diagnosis code 745.5 for ASD were included. Hospital volume was calculated using unique identification numbers and divided into tertiles for analysis. Multivariate regression analysis was performed to determine independent predictors of procedure-related complications which were coded using specific codes released by Healthcare Cost and Utilization Project. RESULTS: 6162 percutaneous ASD closure procedures were analyzed. There was no mortality associated with percutaneous ASD closure. Cardiac complications (9.5%) were most common. On multivariate analysis, age increment of 3 years decreased the odds of developing complications (OR 0.83, 95% CI 0.79-0.87, P < 0.001). Odds of developing complications in the 2nd (OR 0.74, 95% CI 0.62-0.89, P = 0.007) and 3rd tertiles (OR 0.34, 95% CI 0.27-0.42, P < 0.001) were lower as compared to the 1st tertile of hospital volume. CONCLUSION: Increasing annual hospital volume is an independent predictor of lower complication rates in percutaneous ASD closure cases with no associated mortality in pediatric patients. PMID- 29508365 TI - Introducing an antibiotic stewardship program in a pediatric center in China. AB - BACKGROUND: This study aimed to investigate the effect of antibiotic stewardship programs (ASP) on reducing antimicrobial resistance rate, antibiotics consumption and multi-drug resistance bacterial infections in the pediatric patients. METHODS: This study was carried out in the Pediatric Center of a tertiary hospital of Shandong Province, China. The study duration was separated into two periods according to introduction of ASP (began from April 2011). Before intervention: from April 2009 to March 2011; after intervention: from April 2012 to March 2014. The consumption of antibiotics, defined daily dose (DDD), isolation of multidrug-resistant organisms (MDRO) and resistance rate of antibiotics were analyzed and compared between the two study periods. RESULTS: Total antibiotics consumption (DDDs) reduced from 56,725 in 2011 to 31,380 in 2014; antibiotic use density (AUD) reduced from 93.8 to 43.5; mean (+/- SD) antibiotic costs per patient (per quarter) decreased from 637 (+/- 29) RMB to 462 (+/- 49) RMB; and the mean total drug consumption (g)/DDD (DDDs) for inpatients decreased from 90.4 (+/- 3.3) to 56.4 (+/- 9.5). Multidrug-resistant microorganisms isolation reduced significantly from 463 (20.0) to 216 (6.9%). Resistance rate of general spectrum antibiotics reduced remarkably after intervention. The proportion of patients colonized or infected with Carbapenems resistant Acinetobacter baumannii was correlated with DDDs of carbapenem. CONCLUSIONS: Implementation of ASP leads to reduced medical expense, decrease of improper and abuse of antibiotics, and reduced antibiotics resistance rate and MDRO isolation. Continuous efforts to improve antibiotic use are required. PMID- 29508367 TI - Evaluating and improving the implementation of a community-based hereditary cancer screening program. AB - Healthcare disparities exist in the provision of cancer genetic services including genetic counseling and testing related to BRCA1/2 mutations. To address this in a community health setting a screening tool was created to identify high risk women. This study evaluates the implementation of the tool and identifies opportunities for improved cancer genetic screening, including regular clinician education. A mixed-method approach was used to evaluate clinician utilization of the screening tool at Planned Parenthood affiliates. Novel surveys that evaluated acceptance and implementation were administered to clinicians (n = 14) and semi structured interviews (n = 6) were used to explore clinicians' perspectives and identify gaps in its utilization. Educational modules that addressed gaps were developed, implemented, and evaluated using a post-education survey (n = 8). Clinicians reported confidence in administering and interpreting the screening tool, but reported less confidence in their knowledge of cancer genetics and ability to connect clients with genetic counseling and testing (p = .003). Educational modules resulted in significant gains in clinician knowledge on genetic topics (p < .05) and increased self-reported confidence in connecting clients with genetic services. The modules reinforced the belief that genetic testing is beneficial for patients at increased risk (p = .001) and is important to inform subsequent medical management (p = .027). While building community clinicians' capacity to connect clients with genetic services is crucial, it is challenged by knowledge and confidence gaps in discussions of genetic services with clients. Consistent genetic-focused education with non-genetic clinicians can improve confidence and knowledge, enabling a more effective screening program in community health settings. PMID- 29508366 TI - Prevalence of obesity in Italian adolescents: does the use of different growth charts make the difference? AB - BACKGROUND: Since populations are becoming increasingly multi-ethnic, the use of local or international charts is a matter of debate. This study aimed to evaluate how the choice of cut-off thresholds affected prevalence of underweight (UW), overweight (OW), obesity (OB) in 1200 11-12-year Italian adolescents, and how their somatic growth depended on parental origin. METHODS: The height, weight and body mass index were expressed as standard deviation score (SDS) using Italian (ISPED-2006) and UK (UK-1990) charts. The classification of UW/OW/OB was computed with the IOTF international cut-offs, and thresholds were identified as centiles corresponding to BMI values of 18.5/25.0/30.0 kg/m2 at 18-year in ISPED-2006 or UK-1990 references. RESULTS: About 30% participants had non-Italian parents, above all from North-Africa and Romania. Referring to the UK-1990 charts, all groups showed negative mean SDS for height, and positive SDS for weight and BMI. Referring to the ISPED-2006 charts, all mean SDS were negative. Percentage of UW individuals was higher in accordance with ISPED-2006 than with UK-1990 charts, whereas percentages of OW/OB were higher with UK-1990 than ISPED-2006 charts. The results obtained using IOFT cut-offs were similar to UK-1990 cut-offs. These results were due to the different shape of age-dependent cut-off centiles. Independently by the parental origin, the percentages of adolescents classified as OW/OB were closer to the expected values using the ISPED-2006 then the UK-1990 cut-offs. The results suggested the use of the Italian references for adolescents with immigrant parents. CONCLUSION: The use of local charts seems more appropriate at least in Italian adolescents in the age range studied. PMID- 29508368 TI - Clinicians' use of breast cancer risk assessment tools according to their perceived importance of breast cancer risk factors: an international survey. AB - The BOADICEA breast cancer (BC) risk assessment model and its associated Web Application v3 (BWA) tool are being extended to incorporate additional genetic and non-genetic BC risk factors. From an online survey through the BOADICEA website and UK, Dutch, French and Swedish national genetic societies, we explored the relationships between the usage frequencies of the BWA and six other common BC risk assessment tools and respondents' perceived importance of BC risk factors. Respondents (N = 443) varied in age, country and clinical seniority but comprised mainly genetics health professionals (82%) and BWA users (93%). Oncology professionals perceived reproductive, hormonal (exogenous) and lifestyle BC risk factors as more important in BC risk assessment compared to genetics professionals (p values < 0.05 to 0.0001). BWA was used more frequently by respondents who gave high weight to breast tumour pathology and low weight to personal BC history as BC risk factors. BWA use was positively related to the weight given to hormonal BC risk factors. The importance attributed to lifestyle and BMI BC risk factors was not associated with the use of BWA or any of the other tools. Next version of the BWA encompassing additional BC risk factors will facilitate more comprehensive BC risk assessment in genetics and oncology practice. PMID- 29508369 TI - Development and Application of the GheOP3S-Tool Addendum on Potentially Inappropriate Prescribing (PIP) of Renally Excreted Active Drugs (READs) in Older Adults with Polypharmacy. AB - BACKGROUND: Renal function progressively worsens with age. Potentially inappropriate prescribing (PIP) of renally excreted active drugs (READs) is common in older adults, leading to an increased rate of iatrogenic illness. The Ghent Older People's Prescription community Pharmacy Screening (GheOP3S-) tool is an effective, explicit instrument that was developed for community pharmacists (CPs) to detect PIP. So far, this tool does not assess PIP of the frequently used READs in older patients with renal impairment. OBJECTIVES: This study aimed to expand the GheOP3S-tool with the first addendum to screen for PIP of frequently used READs, and to perform a cross-sectional analysis using the addendum and the medication history of a group of older adults with polypharmacy. METHODS: The addendum was developed in three steps: (1) collection of individual and combined READs, (2) collection of dose-adjustment recommendations, and (3) expert panel evaluation. Consequently, the addendum was applied retrospectively on the medication list of 60 older adults with polypharmacy and with four renal function estimating equations. RESULTS: The addendum includes 61 READs recommendations for dose/drug-adjustment alternatives, laboratory test follow-ups, and patients' referral to specialists' care. In the cross-sectional analysis, 35-78% of patients were diagnosed with renal impairment, depending on the equations used for renal function estimation. Among patients with renal impairment, 21-46% of the prescribed READs were deemed potentially inappropriate by the GheOP3S-tool addendum. CONCLUSION: The GheOP3S-tool was expanded with an addendum on PIP of READs in renal impairment for older patients. The cross-sectional analysis using the addendum suggests that PIP of READs is common in older patients with polypharmacy and renal impairment. Using this addendum, CPs might contribute to diminishing PIP of READs. PMID- 29508371 TI - Correction to: LY2963016 Insulin Glargine: A Review in Type 1 and 2 Diabetes. AB - Page 91, abstract, lines 1-6: The following sentence, which previously read. PMID- 29508370 TI - Aflibercept in Diabetic Macular Oedema Previously Refractory to Standard Intravitreal Therapy: An Irish Retrospective Study. AB - INTRODUCTION: To determine visual and anatomical outcomes of diabetic macular oedema (DMO) patients in a tertiary centre following conversion to aflibercept having been refractory to previous treatment with bevacizumab/ranibizumab. METHODS: A retrospective case series of patients with a diagnosis of DMO undergoing aflibercept intravitreal therapy for at least 6 months who had previous treatment with three consecutive bevacizumab/ranibizumab injections pre switch. Exclusion criteria included other procedures affecting visual outcome performed within the treatment period. Outcomes measured included visual acuity (VA), central macular thickness (CMT) and injection frequency. RESULTS: Eighteen eyes of 13 patients were included. Mean VA pre-switch was 61.5 +/- 13.8 letters and CMT was 433.2 +/- 101.4. Mean number of prior bevacizumab/ranibizumab treatments was 11.3 +/- 7.2. Mean follow-up post-switch was 22.5 months (SD 7.9). Mean VA improved from baseline by 4.8 letters at 6 months (p = 0.005), by 6.1 letters at 12 months (p = 0.006), by 7.9 letters (p = 0.004) at 18 months and by 6.4 letters (p = 0.1) at 24 months. Mean CMT decreased from baseline by 108.6 MUm at 6 months (p = 0.01), 117.7 MUm at 12 months (p = 0.0003), 158.0 MUm at 18 months (p = 0.005) and by 123.3 MUm at 24 months (p = 0.02). CONCLUSION: Switching to aflibercept in treatment-resistant DMO produces significant improvements in visual and anatomical outcomes, with eventual maintenance of VA levels. PMID- 29508372 TI - The "Pectoral-Gap Phenomenon": A Hypothesis on Origin and Mechanism. PMID- 29508373 TI - Validity of Measures Assessing Oral Health Beliefs of American Indian Parents. AB - OBJECTIVES: This aimed to validate measures of constructs included in an extended Health Belief Model (EHBM) addressing oral health beliefs among American Indian (AI) parents. METHODS: Questionnaire data were collected as part of a randomized controlled trial (n = 1016) aimed at reducing childhood caries. Participants were AI parents with a preschool-age child enrolled in the Navajo Nation Head Start program. Questionnaire items addressed five EHBM constructs: perceived susceptibility, severity, barriers, benefits, and parental self-efficacy. Subscales representing each construct underwent reliability and validity testing. Internal consistency reliability of each subscale was evaluated using Cronbach's alpha. Convergent validity was assessed using linear regression to evaluate the association of each EHBM subscale with oral health-related measures. RESULTS: Internal consistency reliability was high for self-efficacy (alpha = 0.83) and perceived benefits (alpha = 0.83) compared to remaining EHBM subscales (alpha < 0.50). Parents with more education (p < 0.0001) and income (p = 0.0002) perceived dental caries as more severe younger parents (ps = 0.02) and those with more education (ps < 0.0001) perceived greater benefits and fewer barriers to following recommended oral health behavior. Female parents (p < 0.0001) and those with more education (p = 0.02) had higher levels of self-efficacy. Parental knowledge was associated with all EHBM measures (ps < 0.0001) excluding perceived susceptibility (p > 0.05). Parents with increased self-efficacy had greater behavioral adherence (p < 0.0001), whereas lower behavioral adherence was associated with parents who reported higher perceived barriers (p < 0.0001). Better pediatric oral health outcomes were associated with higher levels of self efficacy (p < 0.0001) and lower levels of perceived severity (p = 0.02) and barriers (p = 0.05). CONCLUSIONS: Results support the value of questionnaire items addressing the EHBM subscales, which functioned in a manner consistent with the EHBM theoretical framework in AI participants. PMID- 29508375 TI - Effect of Interstitial Fluid Flow on Drug-Coated Balloon Delivery in a Patient Specific Arterial Vessel with Heterogeneous Tissue Composition: A Simulation Study. AB - Angioplasty with drug-coated balloons (DCBs) using excipients as drug carriers is emerging as a potentially viable strategy demonstrating clinical efficacy and proposing additional compliance for the treatment of obstructive vascular diseases. An attempt is made to develop an improved computational model where attention has been paid to the effect of interstitial flow, that is, plasma convection and internalization of bound drug. The present model is capable of capturing the phenomena of the transport of free drug and its retention, and also the internalization of drug in the process of endocytosis to atherosclerotic vessel of heterogeneous tissue composition comprising of healthy tissue, as well as regions of fibrous cap, fibro-fatty, calcified and necrotic core lesions. Image processing based on an unsupervised clustering technique is used for color based segmentation of a patient-specific longitudinal image of atherosclerotic vessel obtained from intravascular ultrasound derived virtual histology. As the residence time of drug in a stent-based delivery within the arterial tissue is strongly influenced by convective forces, effect of interstitial fluid flow in case of DCB delivery can not be ruled out, and has been investigated by modeling it through unsteady Navier-Stokes equations. Transport of free drug is modeled by considering unsteady advection-reaction-diffusion process, while the bound drug, assuming completely immobilized in the tissue, by unsteady reaction process. The model also takes into account the internalization of drug through the process of endocytosis which gets degraded by the lysosomes and finally recycled into the extracellular fluid. All the governing equations representing the flow of interstitial fluid, the transport of free drug, the metabolization of free drug into bound phase and the process of internalization along with the physiologically realistic boundary and initial conditions are solved numerically using marker and cell method satisfying necessary stability criteria. Simulated results obtained predict that faster drug transfer promotes rapid saturation of binding sites despite perivascular wash out and the concentrations of all drug forms are modulated by the presence of interstitial flow. Such premier attempt of its kind would certainly be of great help in the optimization of therapeutic efficacy of drug. PMID- 29508374 TI - Factors Related to Physician Clinical Decision-Making for African-American and Hispanic Patients: a Qualitative Meta-Synthesis. AB - Clinical decision-making may have a role in racial and ethnic disparities in healthcare but has not been evaluated systematically. The purpose of this study was to synthesize qualitative studies that explore various aspects of how a patient's African-American race or Hispanic ethnicity may factor into physician clinical decision-making. Using Ovid MEDLINE, Embase, and Cochrane Library, we identified 13 manuscripts that met inclusion criteria of usage of qualitative methods; addressed US physician clinical decision-making factors when caring for African-American, Hispanic, or Caucasian patients; and published between 2000 and 2017. We derived six fundamental themes that detail the role of patient race and ethnicity on physician decision-making, including importance of race, patient level issues, system-level issues, bias and racism, patient values, and communication. In conclusion, a non-hierarchical system of intertwining themes influenced clinical decision-making among racial and ethnic minority patients. Future study should systematically intervene upon each theme in order to promote equitable clinical decision-making among diverse racial/ethnic patients. PMID- 29508376 TI - Blocking the ART2.2/P2X7-system is essential to avoid a detrimental bias in functional CD4 T cell studies. AB - Murine T cell subsets differ in their expression level of P2X7. Depending on several parameters like extracellular NAD+ , P2X7 can be ADP-ribosylated rapidly by adjacent ARTC2.2 resulting in susceptibilities to apoptosis to a varying extent. This detrimental effect can be prevented when drugs like KN-62 are present during cell preparations. PMID- 29508377 TI - Fluvastatin for lowering lipids. AB - BACKGROUND: Fluvastatin is thought to be the least potent statin on the market, however, the dose-related magnitude of effect of fluvastatin on blood lipids is not known. OBJECTIVES: Primary objectiveTo quantify the effects of various doses of fluvastatin on blood total cholesterol, low-density lipoprotein (LDL cholesterol), high-density lipoprotein (HDL cholesterol), and triglycerides in participants with and without evidence of cardiovascular disease.Secondary objectivesTo quantify the variability of the effect of various doses of fluvastatin.To quantify withdrawals due to adverse effects (WDAEs) in randomised placebo-controlled trials. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to February 2017: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to February Week 2 2017), MEDLINE In-Process, MEDLINE Epub Ahead of Print, Embase (1974 to February Week 2 2017), the World Health Organization International Clinical Trials Registry Platform, CDSR, DARE, Epistemonikos and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. No language restrictions were applied. SELECTION CRITERIA: Randomised placebo-controlled and uncontrolled before and after trials evaluating the dose response of different fixed doses of fluvastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without evidence of cardiovascular disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility criteria for studies to be included, and extracted data. We entered data from placebo controlled and uncontrolled before and after trials into Review Manager 5 as continuous and generic inverse variance data, respectively. WDAEs information was collected from the placebo-controlled trials. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. MAIN RESULTS: One-hundred and forty-five trials (36 placebo controlled and 109 before and after) evaluated the dose-related efficacy of fluvastatin in 18,846 participants. The participants were of any age with and without evidence of cardiovascular disease, and fluvastatin effects were studied within a treatment period of three to 12 weeks. Log dose-response data over doses of 2.5 mg to 80 mg revealed strong linear dose-related effects on blood total cholesterol and LDL cholesterol and a weak linear dose-related effect on blood triglycerides. There was no dose-related effect of fluvastatin on blood HDL cholesterol. Fluvastatin 10 mg/day to 80 mg/day reduced LDL cholesterol by 15% to 33%, total cholesterol by 11% to 25% and triglycerides by 3% to 17.5%. For every two-fold dose increase there was a 6.0% (95% CI 5.4 to 6.6) decrease in blood LDL cholesterol, a 4.2% (95% CI 3.7 to 4.8) decrease in blood total cholesterol and a 4.2% (95% CI 2.0 to 6.3) decrease in blood triglycerides. The quality of evidence for these effects was judged to be high. When compared to atorvastatin and rosuvastatin, fluvastatin was about 12-fold less potent than atorvastatin and 46 fold less potent than rosuvastatin at reducing LDL cholesterol. Very low quality of evidence showed no difference in WDAEs between fluvastatin and placebo in 16 of 36 of these short-term trials (risk ratio 1.52 (95% CI 0.94 to 2.45). AUTHORS' CONCLUSIONS: Fluvastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose-dependent linear fashion. Based on the effect on LDL cholesterol, fluvastatin is 12-fold less potent than atorvastatin and 46-fold less potent than rosuvastatin. This review did not provide a good estimate of the incidence of harms associated with fluvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 56% of the placebo controlled trials. PMID- 29508378 TI - Closed Analytic Elements with Flexible Geometry. AB - A simple and fast treatment of hydrogeologic features with irregularly shaped boundaries in two-dimensional analytic element groundwater flow models is presented. The star domain shapes of the features are restricted to closed shapes represented as smooth and continuous single-valued functions of distance from a focus point, r^theta . The element can be used to treat a variety of boundary and continuity conditions, including those of irregularly shaped lakes or heterogeneities in hydraulic conductivity. The new element is demonstrated via some simple illustrative test cases and shown to be efficient, accurate, and much simpler to implement than existing solutions for irregular shapes. PMID- 29508379 TI - Heterogeneity of functional outcomes in patients with bipolar disorder: a cluster analytic approach. AB - OBJECTIVE: The aim was to examine the heterogeneity of psychosocial outcomes in euthymic bipolar disorder (BD) patients and analyse the potential influence of distinct variables on functioning. METHOD: Using a hierarchical cluster exploratory analysis, 143 euthymic patients with diagnosis of BD were grouped according to their functional performance based on domains scores of the Functioning Assessment Short Test (FAST). The resulting groups were compared on sociodemographic, clinical and neurocognitive variables to find factors associated with each functional cluster. RESULTS: Patients were grouped in three functional profiles: patients with good functioning in all the FAST areas, patients with an intermediate profile showing great difficulties in the occupational domain and milder difficulties in most of the rest domains, and a third group with serious difficulties in almost all functional areas. Both functionally impaired groups were characterized by higher subthreshold symptoms (depressive and manic) and higher unemployment rates. The most functionally impaired group also showed lower scores on some measures of processing speed. CONCLUSION: Two of three functional profiles showed some kind of impairment which was associated with subsyndromal symptoms and cognitive performance. These patterns should be taken into consideration to develop more individualized interventions to restore, or improve, psychosocial outcomes. PMID- 29508380 TI - Evaluating Micrometeorological Estimates of Groundwater Discharge from Great Basin Desert Playas. AB - Groundwater availability studies in the arid southwestern United States traditionally have assumed that groundwater discharge by evapotranspiration (ETg ) from desert playas is a significant component of the groundwater budget. However, desert playa ETg rates are poorly constrained by Bowen ratio energy budget (BREB) and eddy-covariance (EC) micrometeorological measurement approaches. Best attempts by previous studies to constrain ETg from desert playas have resulted in ETg rates that are within the measurement error of micrometeorological approaches. This study uses numerical models to further constrain desert playa ETg rates that are within the measurement error of BREB and EC approaches, and to evaluate the effect of hydraulic properties and salinity-based groundwater density contrasts on desert playa ETg rates. Numerical models simulated ETg rates from desert playas in Death Valley, California and Dixie Valley, Nevada. Results indicate that actual ETg rates from desert playas are significantly below the uncertainty thresholds of BREB- and EC-based micrometeorological measurements. Discharge from desert playas likely contributes less than 2% of total groundwater discharge from Dixie and Death Valleys, which suggests discharge from desert playas also is negligible in other basins. Simulation results also show that ETg from desert playas primarily is limited by differences in hydraulic properties between alluvial fan and playa sediments and, to a lesser extent, by salinity-based groundwater density contrasts. PMID- 29508381 TI - Guilt in bereavement: Its relationship with complicated grief and depression. AB - This study investigated the relationship between guilt and well-being of bereaved persons, and explored potential differences in the associations between guilt complicated grief (CG) and guilt-depression. In total, 1358 Chinese bereaved adults were recruited to fill out questionnaires. Participants (N = 194) who had been bereaved within 2 years of the first survey, filled out the same questionnaires 1 year later. Higher guilt was associated with higher degrees of both CG and depression. The level of guilt predicted CG and depression symptoms 1 year later. Bereavement-related guilt has a closer association with CG than depression. Responsibility guilt, indebtedness guilt and degree of guilt feeling are more prominent aspects of guilt in CG than in depression. These findings demonstrate the significant role of guilt (perhaps a core symptom) in mental health of the bereaved, having implications for identifying persons with grief complications and depression. PMID- 29508382 TI - International Fragility Fracture Network Delphi consensus statement on the principles of anaesthesia for patients with hip fracture. PMID- 29508383 TI - Information matrix estimation procedures for cognitive diagnostic models. AB - Two new methods to estimate the asymptotic covariance matrix for marginal maximum likelihood estimation of cognitive diagnosis models (CDMs), the inverse of the observed information matrix and the sandwich-type estimator, are introduced. Unlike several previous covariance matrix estimators, the new methods take into account both the item and structural parameters. The relationships between the observed information matrix, the empirical cross-product information matrix, the sandwich-type covariance matrix and the two approaches proposed by de la Torre (2009, J. Educ. Behav. Stat., 34, 115) are discussed. Simulation results show that, for a correctly specified CDM and Q-matrix or with a slightly misspecified probability model, the observed information matrix and the sandwich-type covariance matrix exhibit good performance with respect to providing consistent standard errors of item parameter estimates. However, with substantial model misspecification only the sandwich-type covariance matrix exhibits robust performance. PMID- 29508384 TI - Childhood height and risk of testicular germ cell tumors in adulthood. AB - Increased adult stature has been associated with risk of testicular germ cell tumors (TGCT) in a number of studies. Whether childhood stature is also associated with TGCT is unclear as no studies of measured childhood height and TGCT have been reported. Thus, associations between TGCT in adulthood and childhood height and growth between ages 7 and 13 years were examined in a cohort from the Copenhagen School Health Records Register. Analyses included 162,607 boys born during the years 1930-1989. Development of TGCT was determined via linkage to the Danish Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression. Between 1968 and 2014, 782 TGCT were diagnosed. Childhood height, per one unit increase in z-score, was associated with risk of TGCT, with HRs ranging from 1.11 (95%CI 1.03-1.20) at age 7 to 1.09 (95%CI = 1.01-1.18) at age 13. In a categorical analysis, the shortest boys were at the lowest risk of developing TGCT. Results varied little by TGCT histology (seminoma and nonseminoma). Growth between ages 7 and 13 years was not associated with risk. These findings suggest that risk of TGCT in adulthood was already determined by age 7 years. Although the mechanism requires further investigation, these results provide additional evidence that risk of TGCT is determined at a young age, thus suggesting that additional investigation of early life factors is warranted. PMID- 29508385 TI - Walking Speed, Cognitive Function, and Dementia Risk in the English Longitudinal Study of Ageing. AB - OBJECTIVES: To determine the relationships between walking speed, cognitive function, and the interaction between changes in these measures and dementia risk. DESIGN: Longitudinal observational study. SETTING: English Longitudinal Study of Ageing. PARTICIPANTS: Individuals aged 60 and older (N=3,932). MEASUREMENTS: Walking speed and cognition were assessed at Waves 1 (2002-03) and 2 (2004-05) of the English Longitudinal Study of Ageing. New dementia cases were assessed from Wave 3 (2006-07) to Wave 7 (2014-15). The associations were modelled using Cox proportional hazards regression. RESULTS: Participants with faster baseline walking speeds were at lower risk of developing dementia (hazard ratio (HR)=0.36, 95% confidence interval (CI)=0.22-0.60). Those with a greater decline in walking speed from Wave 1 to 2 were at greater risk of developing dementia (HR=1.23, 95% CI=1.03-1.47). Participants with better baseline cognition (HR=0.42, 95% CI=0.34-0.54) were at lower risk of developing dementia. Those with a greater decline in cognition from Wave 1 to 2 were at greater risk of developing dementia (HR=1.78, 95% CI=1.53-2.06). Change in walking speed and change in cognition did not have an interactive effect on dementia risk (HR=1.01, 95% CI=0.88-1.17). CONCLUSION: In this community-dwelling sample of English adults, those with slower walking speeds and a greater decline in speed over time were at greater risk of developing dementia independent of changes in cognition. Further research is required to understand the mechanisms that may drive these associations. PMID- 29508387 TI - MoisturEC: A New R Program for Moisture Content Estimation from Electrical Conductivity Data. AB - Noninvasive geophysical estimation of soil moisture has potential to improve understanding of flow in the unsaturated zone for problems involving agricultural management, aquifer recharge, and optimization of landfill design and operations. In principle, several geophysical techniques (e.g., electrical resistivity, electromagnetic induction, and nuclear magnetic resonance) offer insight into soil moisture, but data-analysis tools are needed to "translate" geophysical results into estimates of soil moisture, consistent with (1) the uncertainty of this translation and (2) direct measurements of moisture. Although geostatistical frameworks exist for this purpose, straightforward and user-friendly tools are required to fully capitalize on the potential of geophysical information for soil moisture estimation. Here, we present MoisturEC, a simple R program with a graphical user interface to convert measurements or images of electrical conductivity (EC) to soil moisture. Input includes EC values, point moisture estimates, and definition of either Archie parameters (based on experimental or literature values) or empirical data of moisture vs. EC. The program produces two and three-dimensional images of moisture based on available EC and direct measurements of moisture, interpolating between measurement locations using a Tikhonov regularization approach. PMID- 29508386 TI - Bepridil exhibits anti-leukemic activity associated with NOTCH1 pathway inhibition in chronic lymphocytic leukemia. AB - Dysregulated NOTCH1 signaling, by either gene mutations or microenvironment interactions, has been increasingly linked to chronic lymphocytic leukemia (CLL). Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression-based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of NOTCH1 mutation and other prognostic markers. The antitumor efficacy of bepridil was associated with inhibition of NOTCH1 activity through a decrement in trans membrane and activated NOTCH1 protein levels with unchanged NOTCH2 protein levels. In a CLL xenotransplant model, bepridil significantly reduced the percentage of leukemic cells infiltrating the spleen via enhanced apoptosis and decreased NOTCH1 activation. In conclusion, we report in vitro and in vivo anti leukemic activity of bepridil associated with inhibition of the NOTCH1 pathway in CLL. These data provide a rationale for the clinical development of bepridil as anti-NOTCH1 targeted therapy for CLL patients. PMID- 29508388 TI - Streamlining screening of emotional function in Veterans with traumatic brain injury. AB - OBJECTIVES: This study examined how depression, anxiety, and sleep items from the Neurobehavioral Symptom Inventory (NSI) predict results from longer inventories. METHOD: This was a retrospective review from 484, predominantly male (96.1%) Veterans, mean age 29.7 years, who underwent brief neuropsychological screening during a comprehensive, multidisciplinary evaluation for mild traumatic brain injury (TBI). Participants completed the NSI, insomnia severity index (ISI), and hospital anxiety and depression scale (HADS). RESULTS: OVERALL,: 97.1% who endorsed "severe"/"very severe" anxiety on the NSI had significant anxiety on the HADS; 85% reporting "severe"/"very severe" depression on the NSI, had significant depression on the HADS; and 97.7% reporting "severe"/"very severe" sleep problems on the NSI, had significant sleep difficulties on the ISI. CONCLUSION: Close correspondence between "severe"/"very severe" symptoms on the NSI and lengthier checklists suggests additional checklists may be eliminated and individuals can be referred for mental health treatment. NSI reports of "mild"/"moderate" require further screening. PMID- 29508390 TI - Scaffolding for motivation by parents, and child homework motivations and emotions: Effects of a training programme. AB - BACKGROUND AND AIMS: Based on the principles of scaffolding for motivation and on the assumptions of self-determination theory, two studies aimed to assess the role played by perceived parental autonomy-supportive scaffolding on child homework autonomous motivation, self-efficacy, affect, and engagement. SAMPLES AND RESULTS: The results of Study 1, which involved 122 parents and their children, showed that the higher the parental autonomous motivation, the more their children perceived them as autonomy-supportive while scaffolding for motivation, and hence developed autonomous motivation, self-efficacy, and engagement in homework. In Study 2, 37 parents were involved in a four-session training programme that focused on sustaining autonomy-supportive scaffolding modalities. The training decreased parental negative affect, prevented child negative affect increase, and maintained child homework motivation. CONCLUSIONS: The discussion focuses on the strength that parents have with regard to helping their children develop less negative, and potentially also more positive attitude towards homework, through autonomy support as a scaffold for motivation. PMID- 29508389 TI - Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. AB - The gastrointestinal mucosae provide a critical barrier between the external and internal milieu. Thus, damage to the mucosa requires an immediate response to provide appropriate wound closure and healing. Metaplastic lineages with phenotypes similar to the mucous glands of the distal stomach or Brunner's glands have been associated with various injurious scenarios in the stomach, small bowel, and colon. These lineages have been assigned various names including pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage (UACL), and spasmolytic polypeptide-expressing metaplasia (SPEM). A re examination of the literature on these various forms of mucous cell metaplasia suggests that pyloric-type mucosal gland lineages may provide a ubiquitous response to mucosal injury throughout the gastrointestinal tract as well as in the pancreas, esophagus, and other mucosal surfaces. While the cellular origin of these putative reparative lineages likely varies in different regions of the gut, their final phenotypes may converge on a pyloric-type gland dedicated to mucous secretion. In addition to their healing properties in the setting of acute injury, these pyloric-type lineages may also represent precursors to neoplastic transitions in the face of chronic inflammatory influences. Further investigations are needed to determine how discrete molecular profiles relate to the origin and function of pyloric-type metaplasias previously described by histological characteristics in multiple epithelial mucosal systems in the setting of acute and chronic damage. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29508391 TI - Should We Bury "The Good Death"? PMID- 29508392 TI - EFNB2 haploinsufficiency causes a syndromic neurodevelopmental disorder. AB - Ephrin B2, one of the ligand of the EphB receptors, is involved in a complex signaling pathway regulating the development of the nervous system, neuronal migration, erythropoiesis and vasculogenesis. We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay. One of the affected sibs further had myoclonic epilepsy and bilateral sensorineural hearing loss. The carrier mother was apparently asymptomatic. Because EFNB2 is located in the subtelomeric region of 13q chromosome, we reviewed the previous reports of terminal 13q deletion. We suggest that haploinsufficiency of the EFNB2 could be at the origin of several clinical features reported in 13qter deletions, including intellectual disability, seizures, congenital heart defects, anorectal malformation and hearing loss. PMID- 29508393 TI - Optimization of ultrasound-assisted extraction of phenolic compounds from grapefruit (Citrus paradisi Macf.) leaves via D-optimal design and artificial neural network design with categorical and quantitative variables. AB - BACKGROUND: The extraction of phenolic compounds from grapefruit leaves assisted by ultrasound-assisted extraction (UAE) was optimized using response surface methodology (RSM) by means of D-optimal experimental design and artificial neural network (ANN). For this purpose, five numerical factors were selected: ethanol concentration (0-50%), extraction time (15-60 min), extraction temperature (25-50 degrees C), solid:liquid ratio (50-100 g L-1 ) and calorimetric energy density of ultrasound (0.25-0.50 kW L-1 ), whereas ultrasound probe horn diameter (13 or 19 mm) was chosen as categorical factor. RESULTS: The optimized experimental conditions yielded by RSM were: 10.80% for ethanol concentration; 58.52 min for extraction time; 30.37 degrees C for extraction temperature; 52.33 g L-1 for solid:liquid ratio; 0.457 kW L-1 for ultrasonic power density, with thick probe type. Under these conditions total phenolics content was found to be 19.04 mg gallic acid equivalents g-1 dried leaf. CONCLUSION: The same dataset was used to train multilayer feed-forward networks using different approaches via MATLAB, with ANN exhibiting superior performance to RSM (differences included categorical factor in one model and higher regression coefficients), while close values were obtained for the extraction variables under study, except for ethanol concentration and extraction time. (c) 2018 Society of Chemical Industry. PMID- 29508395 TI - Not just there to fill space: profound observations on interstitial cells of Cajal in the gastric fundus. PMID- 29508394 TI - Loss of GABAB -mediated interhemispheric synaptic inhibition in stroke periphery. AB - KEY POINTS: Recovery from the potentially devastating consequences of stroke depends largely upon plastic changes occurring in the lesion periphery and its inputs. In a focal model of stroke in mouse somatosensory cortex, we found that the recovery of sensory responsiveness occurs at the level of synaptic inputs, without gross changes of the intrinsic electrical excitability of neurons, and also that recovered responses had longer than normal latencies. Under normal conditions, one somatosensory cortex inhibits the responsiveness of the other located in the opposite hemisphere (interhemispheric inhibition) via activation of GABAB receptors. In stroke-recovered animals, the powerful interhemispheric inhibition normally present in controls is lost in the lesion periphery. By contrast, contralateral hemisphere activation selective contributes to the recovery of sensory responsiveness after stroke. ABSTRACT: Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known about the microcircuit changes underlying recovery, the extent to which perilesional plasticity occurs at synaptic input vs. spike output level, and the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extracellular and intracellular recordings and pharmacological inactivation in a focal stroke in mouse somatosensory cortex (S1). In vivo whole-cell recordings in hindlimb S1 (hS1) showed synaptic responses also to forelimb stimulation in controls, and such responses were abolished by stroke in the neighbouring forelimb area (fS1), suggesting that, under normal conditions, they originate via horizontal connections from the neighbouring fS1. Synaptic and spike responses to forelimb stimulation in hS1 recovered to quasi-normal levels 2 weeks after stroke, without changes in intrinsic excitability and hindlimb-evoked spike responses. Recovered synaptic responses had longer latencies, suggesting a long-range origin of the recovery, prompting us to investigate the role of callosal inputs in the recovery process. Contralesional S1 silencing unmasked significantly larger responses to both limbs in controls, a phenomenon that was not observed when GABAB receptors were antagonized in the recorded area. Conversely, such GABAB -mediated interhemispheric inhibition was not detectable after stroke: callosal input silencing failed to change hindlimb responses, whereas it robustly reduced recovered forelimb responses. Thus, recovery of subthreshold responsiveness in the stroke periphery is accompanied by a loss of interhemispheric inhibition and this is a result of pathway-specific facilitatory action on the affected sensory response from the contralateral cortex. PMID- 29508396 TI - Influence of cultivar and of conventional and organic agricultural practices on phenolic and sensory profile of blackberries (Rubus fruticosus). AB - BACKGROUND: Consumer demand for organic products is increasing because of their claimed health benefits. Blackberries are a rich source of polyphenols, with high antioxidant activity; nevertheless, the impact of organic versus conventional agricultural practices on its phytochemical composition is unknown. 'Loch Ness' and 'Chester Thornless' were selected as blackberry cultivars for this study because of their desired sensory and technological properties, which make them more suitable for export. RESULTS: 'Loch Ness' variety presented a higher amounts of polyphenols and higher antioxidant activity when compared to the 'Chester Thornless' variety. The impact of agricultural practices on the phytochemical composition of the two varieties was contradictory. Under organic agricultural practices, levels of polyphenols increased for 'Loch Ness' and decreased for 'Chester Thornless', whereas the soluble solids content increased in both varieties. These changes in composition were correlated with changes observed in the blackberries' sensory profile. CONCLUSION: The effect of agricultural practices on the blackberries' chemical and sensory profile was dependent on the variety and cannot be generalized. (c) 2018 Society of Chemical Industry. PMID- 29508397 TI - 1-Methylcyclopropene (1-MCP) effects on natural disease resistance in stored sweet potato. AB - BACKGROUND: The potential of 1-methylcyclopropene (1-MCP) to maintain postharvest storage of sweet potato was studied. In two separate experiments, the orange fleshed sweet potato cv. Covington was treated with 1-MCP (1.0 uL L-1 , 24 h) and roots stored at 15 degrees C. During storage, samples were evaluated for the respiration rate, sprout growth, weight loss, incidence of decay and changes in dry matter. The roots were further assayed for the temporal changes in individual non-structural carbohydrates and phenolic compounds in the skin and flesh tissues of the proximal (stem end), middle and distal (root end) regions. RESULTS: 1-MCP treatment reduced root weight loss and decay but respiration rate and non structural carbohydrates were not affected. No sprouting was recorded irrespective of the treatment. 1-MCP transiently suppressed the accumulation of individual phenolic compounds, especially in the middle and distal segments. This accentuated the proximal dominance of phenolic compounds. Isochlorogenic acid A and chlorogenic acid were the dominant phenolics in the skin and flesh tissues, respectively. CONCLUSION: 1-MCP treatment may have an anti-decay effect and reduce weight loss. Therefore, storage trials that involve the use of continuous ethylene supplementation to inhibit sprout growth may be combined with 1-MCP to alleviate ethylene-induced weight loss and decay in sweet potato. (c) 2018 Society of Chemical Industry. PMID- 29508398 TI - Effect of organic agronomic techniques and packaging on the quality of lamb's lettuce. AB - BACKGROUND: This research focused on the effect of organic production systems on initial quality and postharvest performance of lamb's lettuce leaves stored in air or under modified atmosphere at refrigerated temperature. Different strategies of organic soil fertility management were compared under the same environmental conditions: (i) a simplified organic production system based on organic commercial fertilizers to recover crop uptake (SB); (ii) an organic production system based on organic matter amendment mainly supplied by animal manure (AM); and (iii) an organic production system based on organic matter amendment supplied by green waste compost (AC). Fully developed lamb's lettuce leaves were harvested and then packed into perforated bags (control in AIR) or in modified atmosphere packaging (MAP) and stored at 4 degrees C. RESULTS: At harvest, the yield of lamb's lettuce in the AM and AC systems was higher than that in SB. Phenol and dehydroascorbic acid accumulation was observed in the system with the lowest initial supply of organic amendment (SB). Regarding the effect of packaging, AIR conditions maintained the initial quality attributes for a longer period than MAP, which developed off-odours above the threshold of acceptability at 11 days, irrespective of the production system used. CONCLUSION: In general, the initial differences among the production systems were minimal during the postharvest storage. As for the tested packaging systems, AIR successfully maintained the initial quality attributes for a longer period than the MAP. (c) 2018 Society of Chemical Industry. PMID- 29508399 TI - Music training and child development: a review of recent findings from a longitudinal study. AB - Evidence suggests that learning to play music enhances musical processing skills and benefits other cognitive abilities. Furthermore, studies of children and adults indicate that the brains of musicians and nonmusicians are different. It has not been determined, however, whether such differences result from pre existing traits, musical training, or an interaction between the two. As part of an ongoing longitudinal study, we investigated the effects of music training on children's brain and cognitive development. The target group of children was compared with two groups of children, one involved in sports and another not enrolled in any systematic afterschool training. Two years after training, we observed that children in the music group had better performance than comparison groups in musically relevant auditory skills and showed related brain changes. For nonmusical skills, children with music training, compared with children without music or with sports training, showed stronger neural activation during a cognitive inhibition task in regions involved in response inhibition despite no differences in performance on behavioral measures of executive function. No such differences were found between music and sports groups. We conclude that music training induces brain and behavioral changes in children, and those changes are not attributable to pre-existing biological traits. PMID- 29508400 TI - Ultrasound view of vein collapse during therapeutic apheresis performed with peripheral access. PMID- 29508401 TI - Hand eczema and wet work: dose-response relationship and effect of leaving the profession. AB - BACKGROUND: Wet work is an important risk factor for occupational hand eczema. OBJECTIVES: To examine the effect of job change in workers with occupational hand eczema caused by wet work, and to evaluate the dose-response relationship between intensity of wet work and eczema. METHOD: The study is based on a subgroup (n = 954) from a descriptive, registry-based study including all participants with occupational hand eczema caused by wet work recognized by the Danish Labour Market Insurance Authority in 2010 and 2011. A follow-up questionnaire was sent out 4-5 years later (response 58%). RESULTS: Change of profession and being outside the labour market had a positive effect on healing and improvement of hand eczema. Inverse dose-response relationships were found between the amount of time spent with wet hands at work and healing (p = 0.001) and improvement (p < 0.001), and between the frequency of hand washing at work and healing (p = 0.013) and improvement (p < 0.001). CONCLUSIONS: Leaving the profession has a positive effect on eczema; however, even minor changes in exposure to wet work were associated with healing and improvement. This information has implications with respect to advice given to patients with occupational hand eczema caused by wet work. PMID- 29508402 TI - Factors associated with a second deferral among donors eligible for re-entry after a false-positive screening test for syphilis, HCV, HBV and HIV. AB - BACKGROUND AND OBJECTIVES: Since 25 May 2010, all donors at our blood centre who tested false-positive for HIV, HBV, HCV or syphilis are eligible for re-entry after further testing. Donors who have a second false-positive screening test, either during qualification for or after re-entry, are deferred for life. This study reports on factors associated with the occurrence of such deferrals. MATERIALS AND METHODS: Rates of second false-positive results were compared by year of deferral, transmissible disease marker, gender, age, donor status (new or repeat) and testing platform (same or different) both at qualification for re entry and afterwards. Chi-square tests were used to compare proportions. Cox regression was used for multivariate analyses. RESULTS: Participation rates in the re-entry programme were 42.1%: 25.6% failed to qualify for re-entry [different platform: 2.7%; same platform: 42.9% (P < 0.0001)]. After re-entry, rates of deferral for second false-positive results were 8.4% after 3 years [different platform: 1.8%; same platform: 21.4% (P < 0.0001)]. Deferral rates were higher for HIV and HCV than for HBV at qualification when tested on the same platform. The risk, when analysed by multivariate analyses, of a second deferral for a false-positive result, both at qualification and 3 years after re-entry, was lower for donors deferred on a different platform; this risk was higher for HIV, HCV and syphilis than for HBV and for new donors if tested on the same platform. CONCLUSION: Re-entry is more often successful when donors are tested on a testing platform different from the one on which they obtained their first false-positive result. PMID- 29508403 TI - From intuition to intervention: developing an intonation-based treatment for autism. AB - Autism affects ~1.5% of children under age 8; its core symptoms include impairment in social-communicative functioning and repetitive behaviors/restricted interests. Music-based interventions have been considered one modality through which to treat autism. This report discusses considerations to take into account when developing a music-based intervention for a core symptom of autism. Treatment modality must be matched to symptom both clinically and theoretically, the behavior to be treated must be carefully defined and assessed, and outcome measures must be capable of showing improvement in that behavior over the course of the study. Fidelity assessment and rater blinding reduce experimenter bias. High inter-rater reliability for perceptually determined outcome measures helps obtain accurate estimates of treatment response. Later stages of testing compare the experimental intervention to matched control treatments or other validated therapies, isolating the intervention's "active ingredients." Such systematic investigation of a new music based intervention can provide information of different types, ranging from an assessment of whether the intervention has any effect at all to an assessment of its outcomes and risks in uncontrolled community settings. Findings ultimately compose the evidence base that clinicians and families can use to decide the most effective way of addressing symptoms of autism for particular children. PMID- 29508405 TI - Evolving building blocks of rhythm: how human cognition creates music via cultural transmission. AB - Why does musical rhythm have the structure it does? Musical rhythm, in all its cross-cultural diversity, exhibits commonalities across world cultures. Traditionally, music research has been split into two fields. Some scientists focused on musicality, namely the human biocognitive predispositions for music, with an emphasis on cross-cultural similarities. Other scholars investigated music, seen as a cultural product, focusing on the variation in world musical cultures. Recent experiments found deep connections between music and musicality, reconciling these opposing views. Here, we address the question of how individual cognitive biases affect the process of cultural evolution of music. Data from two experiments are analyzed using two complementary techniques. In the experiments, participants hear drumming patterns and imitate them. These patterns are then given to the same or another participant to imitate. The structure of these initially random patterns is tracked along experimental "generations." Frequentist statistics show how participants' biases are amplified by cultural transmission, making drumming patterns more structured. Structure is achieved faster in transmission within rather than between participants. A Bayesian model approximates the motif structures participants learned and created. Our data and models suggest that individual biases for musicality may shape the cultural transmission of musical rhythm. PMID- 29508404 TI - Effect of substituting fresh-cut perennial ryegrass with fresh-cut white clover on bovine milk fatty acid profile. AB - BACKGROUND: Including forage legumes in dairy systems can help address increasing environmental/economic concerns about perennial ryegrass monoculture pastures. This work investigated the effect of substituting fresh-cut grass with increasing quantities of fresh-cut white clover (WC) on milk fatty acid (FA) profile and transfer efficiency of dietary linoleic (LA) and alpha-linolenic (ALNA) acids to milk fat. Three groups of three crossbred dairy cows were used in a 3 * 3 crossover design. Dietary treatments were 0 g kg-1 WC + 600 g kg-1 grass, 200 g kg-1 WC + 400 g kg-1 grass, and 400 g kg-1 WC + 200 g kg-1 grass. All treatments were supplemented with 400 g kg-1 concentrates on a dry matter basis. Cows had a 19-day adaptation period to the experimental diet before a 6-day measurement period in individual tie stalls. RESULTS: Increasing dietary WC did not affect dry matter intake, milk yield or milk concentrations of fat, protein or lactose. Milk polyunsaturated FA concentrations (total n-3, total n-6, LA and ALNA) and transfer efficiency of LA and ALNA were increased with increasing dietary WC supply. CONCLUSION: Inclusion of WC in pastures may increase concentrations of nutritionally beneficial FA, without influencing milk yield and basic composition, but any implications on human health cannot be drawn. (c) 2018 The Authors. Journal of the Science of Food and Agriculture published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29508406 TI - Utility of shear-wave elastography to differentiate low from advanced degrees of liver fibrosis in patients with hepatitis C virus infection of native and transplant livers. AB - OBJECTIVE: To determine the accuracy of shear-wave elastography (SWE) to differentiate low from advanced degrees of liver fibrosis in hepatitis C patients. MATERIAL & METHOD: Consented native/transplant hepatitis C patients underwent SWE using a C1-6 MHz transducer before ultrasound (US)-guided liver biopsy. Five interpretable SWE samples were obtained from the right lobe of the liver immediately before US-guided random biopsy of the right lobe. Average kilopascal (kPa) values were compared to the meta-analysis of histological data in viral hepatitis (METAVIR) fibrosis grading. SWE values were correlated with the degree of inflammation and fatty infiltration. RESULTS: Study population consisted of 115 patients (63 with transplant, and 52 with native liver) including 29 women and 86 men, with a mean +/- SD age of 56 +/- 8.7 years. Mean +/- SD SWE values were 7.9 +/- 3 kPa in 83 patients with METAVIR scores of 0-2 and 13.2 +/- 5.9 kPa in 32 patients with METAVIR scores of 3 or 4 (P < .001). Area under curve (AUC) of a Receiver Operating Characteristics curve for advanced degrees of fibrosis was 0.81 (95% CI: 0.71, 0.90) (P < .001). AUCs of transplant versus native livers (0.78 [CI:0.62, 0.94] versus 0.85 [CI: 0.73, 0.96]), degree of inflammation (0.81 [CI: 0.65, 0.97] versus 0.72 [0.56, 0.88]), or degree of fat deposition (0.81 [CI:0.70, 0.92] versus 0.80 [CI:0.61, 1]) were not statistically different (P > .05). for kPa threshold of SWE value of 10.67 kPa to differentiate advanced from low degree of fibrosis had a sensitivity of 59% (CI: 41%-76%) and specificity of 90% (CI: 82%-96%). CONCLUSION: Liver stiffness evaluated by SWE can differentiate low from advanced liver fibrosis. PMID- 29508408 TI - Laryngeal cancer: Global socioeconomic trends in disease burden and smoking habits. AB - OBJECTIVES/HYPOTHESIS: To characterize health burden and determine the associated level of equality of laryngeal carcinoma (LC) burden at a global level. METHODS: One hundred eighty-four countries were organized by socioeconomic status using Human Development Index (HDI) categorizations provided by the United Nations Development Program. Disability-adjusted life years (DALYs), obtained from The Global Health Data Exchange, were calculated and compared between each HDI category for the period from 1990 to 2015. Equality of LC burden was then evaluated with concentration indices. RESULTS: Global LC burden, as measured by age-standardized DALYs, has improved significantly over the 25-year period studied. This burden has declined for very high, high, and medium HDI countries, whereas it has remained unchanged for low HDI countries. The majority of LC global burden was found in high socioeconomic countries before 2010 and has shifted toward low socioeconomic countries, as indicated by concentration indices. Over the last 25 years, Central and Eastern Europe continue to have the largest disease burden in the world. CONCLUSION: This is the first analysis that we are aware of investigating health disparities of LC at a global level. The global burden of the disease has declined, which is a trend corresponding with significantly reduced smoking behaviors in developed countries. Although the global inequality gap decreased between 2010 and 2015, there remain reasons for concern. Smoking continues to trend upward in low socioeconomic countries, which could increase LC burden in low socioeconomic countries in the near future. A new global initiative directed toward low socioeconomic countries may yield dividends in preventing subsequent disparities in the LC burden. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2039-2053, 2018. PMID- 29508407 TI - Moderate preterm birth affects right ventricular structure and function and pulmonary artery blood flow in adult sheep. AB - KEY POINTS: Preterm birth occurs when the heart muscle is immature and ill prepared for the changes in heart and lung function at birth. MRI imaging studies show differences in the growth and function of the heart of young adults born preterm, with the effects more pronounced in the right ventricle. The findings of this study, conducted in sheep, showed that following moderate preterm birth the right ventricular wall was thinner in adulthood, with a reduction in the number and size of the heart muscle cells; in addition, there was impaired blood flow in the main artery leading from the right ventricle to the lungs. The findings indicate that being born only a few weeks early adversely affects the cellular structure of the right ventricle and blood flow to the lungs in adulthood. The reduced number of heart muscle cells has the potential to deleteriously affect right ventricular growth potential and function. ABSTRACT: Preterm birth prematurely exposes the immature heart to the haemodynamic transition at birth, which has the potential to induce abnormal cardiac remodelling. Magnetic resonance imaging studies in young adults born preterm have shown abnormalities in the gross structure of the ventricles (particularly the right ventricle; RV), but the cellular basis of these alterations is unknown. The aim of this study, conducted in sheep, was to determine the effect of moderate preterm birth on RV cellular structure and function in early adulthood. Male singleton lambs were delivered moderately preterm (132 +/- 1 days; n = 7) or at term (147 +/- 1 days; n = 7). At 14.5 months of age, intra-arterial blood pressure and heart rate were measured. Pulmonary artery diameter and peak systolic blood flow were determined using ultrasound imaging, and RV stroke volume and output calculated. Cardiomyocyte number, size, nuclearity and levels of cardiac fibrosis were subsequently assessed in perfusion-fixed hearts using image analysis and stereological methods. Blood pressure (systolic, diastolic and mean), heart rate, levels of myocardial fibrosis and RV stroke volume and output were not different between groups. There was, however, a significant reduction in RV wall thickness in preterm sheep, and this was accompanied by a significant reduction in peak systolic blood flow in the pulmonary artery and in RV cardiomyocyte number. Cellular changes in the RV wall and reduced pulmonary artery blood flow following preterm birth have the potential to adversely affect cardiac and respiratory haemodynamics, especially when the cardiovascular system is physiologically or pathologically challenged. PMID- 29508409 TI - Meta-Analysis of Time in Therapeutic Range in Continuous-Flow Left Ventricular Assist Device Patients Receiving Warfarin. AB - Continuous-flow left ventricular assist devices (CF-LVADs) prolong survival in advanced heart failure patients. Anticoagulation control is critical in CF-LVAD patients due to increased thromboembolic and bleeding risk. We assessed the quality of INR control in CF-LVAD patients measured by time in therapeutic range (TTR). We performed a systematic literature search of MEDLINE and SCOPUS through July 2017 to identify studies evaluating TTR in anticoagulated adult CF-LVAD patients. Data on key characteristics and the TTR end point were then extracted from each study by two investigators using a standardized tool. Using a Hartung Knapp random effects model, a weighted mean TTR estimate with accompanying 95% confidence interval (CI) was calculated. Statistical heterogeneity was estimated using the I2 statistic. Five published studies were included. All studies were single-center, retrospective investigations that calculated TTR using the Rosendaal method. Sample sizes ranged from 11 to 115 patients (total of 270 patients) with durations of follow-up ranging from 9 to 76 person-years. On meta analysis, CF-LVAD patients had a weighted mean TTR of 46.6% (95% CI: 36.0-57.3%, I2 = 94%). This suggests that warfarin is difficult to manage in CF-LVAD patients, which may contribute to high rates of bleeding and thromboembolic complications. PMID- 29508410 TI - Selective Cerebro-Myocardial Perfusion in Complex Neonatal Aortic Arch Pathology: Midterm Results. AB - Aortic arch repair in newborns and infants has traditionally been accomplished using a period of deep hypothermic circulatory arrest. To reduce neurologic and cardiac dysfunction related to circulatory arrest and myocardial ischemia during complex aortic arch surgery, an alternative and novel strategy for cerebro myocardial protection was recently developed, where regional low-flow perfusion is combined with controlled and independent coronary perfusion. The aim of the present retrospective study was to assess short-term and mid-term results of selective and independent cerebro-myocardial perfusion in neonatal aortic arch surgery. From April 2008 to August 2015, 28 consecutive neonates underwent aortic arch surgery under cerebro-myocardial perfusion. There were 17 male and 11 female, with median age of 15 days (3-30 days) and median body weight of 3 kg (1.6-4.2 kg), 9 (32%) of whom with low body weight (<2.5 kg). The spectrum of pathologies treated was heterogeneous and included 13 neonates having single stage biventricular repair (46%), 7 staged biventricular repair (25%), and 8 single-ventricle repair (29%). All operations were performed under moderate hypothermia and with a "beating heart and brain." Average cardiopulmonary bypass time was 131 +/- 64 min (42-310 min). A period of cardiac arrest to complete intra-cardiac repair was required in nine patients (32%), and circulatory arrest in 1 to repair total anomalous pulmonary venous connection. Average time of splanchnic ischemia during cerebro-myocardial perfusion was 30 +/- 11 min (15-69 min). Renal dysfunction, requiring a period of peritoneal dialysis was observed in 10 (36%) patients, while liver dysfunction was noted only in 3 (11%). There were three (11%) early and two late deaths during a median follow-up of 2.9 years (range 6 months-7.7 years), with an actuarial survival of 82% at 7 years. At latest follow-up, no patient showed signs of cardiac or neurologic dysfunction. The present experience shows that a strategy of selective and independent cerebro myocardial perfusion is safe, versatile, and feasible in high-risk neonates with complex congenital arch pathology. Encouraging outcomes were noted in terms of cardiac and neurological function, with limited end-organ morbidity. PMID- 29508411 TI - Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease-a nested case-control study. AB - BACKGROUND: Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory. AIM: To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community dwelling persons with Alzheimer's disease. METHODS: In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N = 4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N = 19 235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30 days before the index date), and cumulative duration of use during 10 years before was investigated with conditional logistic regression. RESULTS: Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (<1 year) (adjusted OR 1.23, 95% CI 1.10-1.37). CONCLUSIONS: The increased risk of hip fracture was evident only in short-term proton pump inhibitor use, but no association was found for long-term or cumulative use. Thus, our findings do not support previous assumptions that long term proton pump inhibitor use would be associated with an increased risk of hip fractures. PMID- 29508412 TI - An enlarging nodule on the shin. PMID- 29508413 TI - Capillary electrophoresis method for the discrimination between natural and artificial vanilla flavor for controlling food frauds. AB - A capillary electrophoresis method was developed for the determination of coumarin (COUM), ethyl vanillin (EVA), p-hydroxybenzaldehyde (PHB), p hydroxybenzoic acid (PHBA), vanillin (VAN), vanillic acid (VANA) and vanillic alcohol (VOH) in vanilla products. The measured concentrations are compared to values obtained by liquid chromatography (LC) method. Analytical results, method precision, and accuracy data are presented and limits of detection for the method ranged from 2 to 5 MUg/mL. The results obtained are used in monitoring the composition of vanilla flavorings, as well as for confirmation of natural or non natural origin of vanilla in samples using four selected food samples containing this flavor. PMID- 29508414 TI - Reduced vitamin D receptor (VDR) expression and plasma vitamin D levels are associated with aging-related prostate lesions. AB - BACKGROUND: Protective roles have been proposed for vitamin D in prostate cancer, which has the advanced age as the major risk factor. However, little is known about the expression of the vitamin D receptor (VDR) in the aging prostate and its association with the development of epithelial lesions that affect tissue homeostasis and may precede prostate tumors. METHODS: VDR expression in the prostatic complex of young adults to senile Wistar rats, a natural model to study age-related prostatic disorders, was evaluated by immunohistochemical, Western blotting, and image-assisted analyzes. Results were correlated with the plasma levels of vitamin D and testosterone, the occurrence of punctual histopathological changes in the aging prostate, and the expression of retinoid X receptors (RXR). RESULTS: VDR was widely distributed in the prostatic complex at all ages analyzed, with the highest immunoexpression found in basal epithelial cells. As the animals aged, VDR levels increased, except in punctual areas with intraepithelial proliferation, metaplasia, or proliferative inflammatory atrophy, which had reduced expression of this receptor concomitantly with increased cell proliferation. Interestingly, RXR expression in the aging prostate was similar to that found for its partner VDR, indicating that components of the VDR/RXR complex required for vitamin D signaling are affected in aging-related prostatic lesions. Moreover, plasma vitamin D levels declined at the same ages when prostatic alterations appeared. Although circulating levels of testosterone also decreased with aging, the changes observed in the components of the vitamin D system were not correlated with androgens. CONCLUSIONS: Our data indicate that the aging prostate suffers from an imbalance on the intricate mechanism of tissue regulation by the vitamin D responsive system. We argue that the status of VDR expression might be determinant for the development of histopathological alterations in the aging prostate, which include premalignant lesions. PMID- 29508415 TI - Preclinical In Vitro Safety Investigations of Submicron Sized Hemoglobin Based Oxygen Carrier HbMP-700. AB - Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury and nitric oxide (NO) scavenging combined with vasoconstriction has raised safety concerns. Therefore, we focused on these aspects during preclinical studies performed with the recently introduced hemoglobin microparticles (HbMP 700). Besides oxidative stress, we investigated possible vasoconstrictory influence of HBOCs as well as genetic toxicity. The novel developed HbMP-700 presented here provides a high oxygen affinity which prevents premature oxygen oversupply and avoids vasoconstriction of small blood vessels in vitro. The size of these particles is 700 nm (larger than 100 nm and smaller than 1000 nm) in order to prevent penetration through the blood vessel's endothelial gaps, NO scavenging, and to avoid phagocytosis of large particles. We expect that the HbMP 700 meets the sophisticated requirements as a universal blood substitute. PMID- 29508416 TI - The Progress in the Novel Pediatric Rotary Blood Pump Sputnik Development. AB - In this work, the study results of an implantable pediatric rotary blood pump (PRBP) are presented. They show the results of the numerical simulation of fluid flow rates in the pump. The determination method of the backflows and stagnation regions is represented. The operating points corresponding to fluid flow rates of 1, 3, and 5 L/min for 75-80 mm Hg pressure head are investigated. The study results have shown that use of the pump in the 1 L/min operating point can potentially lead to the appearance of backflows and stagnation regions. In the case of using pumps in fluid flow rates ranging from 3 to 5 L/min, the number of stagnation regions decreases and the fluid flow rate changes marginally. Using the pump in this flow rate range is considered judicious. The study shows an increase in shear stress with an increase in fluid flow rates, while there is no increase in shear stress above the critical condition of 150 Pa (which does not allow us to reliably speak about the increased risk of blood cell damage). The aim of this work was to design, prototype, and study interaction of the Sputnik PRBP with the cardiovascular system. A three-dimensional model of Sputnik PRBP was designed with the following geometrical specifications: flow unit length of 51.5 mm, flow unit diameter of 10 mm, and spacing between the rotor and housing of 0.1 mm. Computational fluid dynamics studies were used to calculate head pressure-flow rate (H-Q) curves at rotor speeds ranging from 10 000 to 14 000 rpm (R2 = 0.866 between numerical simulation and experiment) and comparing flow patterns at various points of the flow rate operating range (1, 3, and 5 L/min) for operating pressures ranging from 75 to 80 mm Hg. It is noted that when fluid flow rate changes from 1 L/min to 3 L/min, significant changes are observed in the distribution of zero flow zones. At the inlet and outlet of the pump, when going to the operating point of 3 L/min, zones of stagnation become minuscule. The shear stress distribution was calculated along the pump volume. The volume in which shear stress exceed 150 Pa is less than 0.38% of the total pump volume at flow rates of 1, 3, and 5 L/min. In this study, a mock circulatory system (MCS) allowing simulation of physiological cardiovascular characteristics was used to investigate the interaction of the Sputnik PRBP with the cardiovascular system. MCS allows reproducing the Frank-Starling autoregulation mechanism of the heart. PRBP behavior was tested in the speed range of 6 000 to 15 000 rpm. Decreased contractility can be expressed in a stroke volume decrease approximately from 18 to 4 mL and ventricle systolic pressure decrease approximately from 92 to 20 mm Hg. The left ventricle becomes fully supported at a pump speed of 10 000 rpm. At a pump speed of 14 000 rpm, the left ventricle goes into a suction state in which fluid almost does not accumulate in the ventricle and only passes through it to the pump. The proposed PRBP showed potential for improved clinical outcomes in pediatric patients with a body surface area greater than 0.6 m2 and weight greater than 12 kg. PMID- 29508417 TI - Some methods for heterogeneous treatment effect estimation in high dimensions. AB - When devising a course of treatment for a patient, doctors often have little quantitative evidence on which to base their decisions, beyond their medical education and published clinical trials. Stanford Health Care alone has millions of electronic medical records that are only just recently being leveraged to inform better treatment recommendations. These data present a unique challenge because they are high dimensional and observational. Our goal is to make personalized treatment recommendations based on the outcomes for past patients similar to a new patient. We propose and analyze 3 methods for estimating heterogeneous treatment effects using observational data. Our methods perform well in simulations using a wide variety of treatment effect functions, and we present results of applying the 2 most promising methods to data from The SPRINT Data Analysis Challenge, from a large randomized trial of a treatment for high blood pressure. PMID- 29508418 TI - Synchronized Pulsatile Flow With Low Systolic Output From Veno-Arterial Extracorporeal Membrane Oxygenation Improves Myocardial Recovery After Experimental Cardiac Arrest in Pigs. AB - Circulatory failure following cardiac arrest (CA) requires catecholamine support and occasionally veno-arterial extracorporeal membrane oxygenation (vaECMO). VaECMO-generated blood flow is continuous and retrograde, increasing ventricular stroke work. Our aim was to assess the benefit of a device generating a pulsatile vaECMO flow synchronized with the heart rhythm lowering systolic vaECMO output on the left ventricular ejection fraction (LVEF) and pulmonary capillary pressure (Pcap) after CA. This experimental randomized study in pigs compared standard nonpulsatile vaECMO (control) with pulsatile synchronized vaECMO (study) group using a pulsatility-generating device. After sedation and intubation, ventricular fibrillation was induced by pacing. After 10-min ventricular fibrillation, cardiopulmonary resuscitation was performed for 20 min then vaECMO, defibrillation and 0.15 ug/kg/min intravenous epinephrine infusion were initiated. Hemodynamics, Pcap, LVEF by echocardiography and angiography were measured at baseline and every 30 min after the vaECMO start until vaECMO and epinephrine were stopped (at 120 min), and 30 min later. Baseline hemodynamics did not differ between groups; 120 min after vaECMO initiation, LVEF by echocardiography and angiography was significantly higher in the study than control group 55 +/- 19% versus 34 +/- 13% (P = 0.042), 50 +/- 16% versus 33 +/- 12% (P = 0.043), respectively. Pcap decreased from baseline by 4.2 +/- 8.6 mm Hg in the study group but increased by 5.6 +/- 5.9 mm Hg in the control group (P = 0.043). Thirty minutes later, LVEF remained higher in the study group 44 +/- 7% versus 26 +/- 11% (P = 0.008) while Pcap did not differ. A synchronized pulsatile device decreasing systolic output from vaECMO improved LVEF and Pcap in a pig model of CA and resuscitation. PMID- 29508419 TI - Plagiarised letters of recommendation submitted for the National Resident Matching Program. AB - OBJECTIVES: Residency is a critical step in the professional development of physicians. Given the high stakes of the process, it is not surprising, although nonetheless troubling, that professional misconduct may occur: multiple studies have, rightfully, condemned applicants for plagiarising personal statements or misrepresenting publications. To date, however, no studies have examined whether faculty members may engage in similar behaviours. METHODS: Software was used to evaluate 3864 unique applications containing 13 617 letters of recommendation submitted through the Electronic Residency Application Service (ERAS) to the Yale University Department of Psychiatry Residency Program in recruitment cycles from 2013-2014 to 2016-2017. The software identified pairs of letters written by different authors with at least 75 words of shared language, counting only words present in contiguous phrases of at least eight words (Shared Wording Across People, SWAP). Independent reviewers determined whether the shared language reflected acceptable forms of common usage (e.g. describing a setting of care) or was intended to convey unique attributes of an applicant, thereby representing plagiarism. RESULTS: We found that 5.1% of letters contained SWAP and 4.1% of letters contained plagiarism. In total, 11.8% of all applications included at least one plagiarised letter. By comparison, 2.6% of applicants' personal statements contained plagiarism. CONCLUSIONS: The present data demonstrate a surprising prevalence of plagiarism in letters of recommendation written for residency applicants. These data call into question both the relative weight that should be accorded to letters of recommendation and, more broadly, beg further discussion of how we conceptualise professionalism in medicine. PMID- 29508420 TI - Control of abusive water addition to Octopus vulgaris with non-destructive methods. PMID- 29508421 TI - Discrimination surfaces with application to region-specific brain asymmetry analysis. AB - Discrimination surfaces are here introduced as a diagnostic tool for localizing brain regions where discrimination between diseased and nondiseased participants is higher. To estimate discrimination surfaces, we introduce a Mann-Whitney type of statistic for random fields and present large-sample results characterizing its asymptotic behavior. Simulation results demonstrate that our estimator accurately recovers the true surface and corresponding interval of maximal discrimination. The empirical analysis suggests that in the anterior region of the brain, schizophrenic patients tend to present lower local asymmetry scores in comparison with participants in the control group. PMID- 29508422 TI - Why women go to medical college but fail to practise medicine: perspectives from the Islamic Republic of Pakistan. AB - CONTEXT: Female medical students outnumber men in countries such as Saudi Arabia, India and Pakistan, yet many fail to practise medicine following graduation. In Pakistan, 70% of medical students are women, yet it is estimated that half of them will not pursue medicine following graduation. This is considered a major reason for physician shortages in the country. METHODS: We conducted a qualitative study drawing upon the 'role strain' theory to explore the views of final-year medical students from four medical colleges in Karachi, Pakistan, on female graduates not entering the medical field. Data were obtained through 20 individual in-depth interviews and two focus group discussions. Themes were developed inductively from the data using the constant comparison method. RESULTS: Pakistani parents actively channel daughters into medical education, considering medicine to be the most 'respectable' field. However, in a patrilocal society with norms of early, arranged marriages for daughters, there is a significant influence of in-laws and a husband on a woman's professional future. Parents perceive the medical degree as a 'safety net' should something go wrong with the marriage, rather than a step toward a medical career. Female respondents experience significant role conflict between their socially rooted gender roles as homemakers and mothers and their careers in medicine. Postgraduate training systems that are unfriendly to women provide further deterrents for women wishing to work. Contrary to popular belief, women not practising medicine is not the sole contributor to physician shortages. A significant factor appears to be male graduates migrating abroad for better training and financial prospects. CONCLUSIONS: Acceptance of traditional cultural values, including entrenched gender roles in society, deters women from practising medicine. To enable greater participation of women in the medical field, steps are required that will allow women to better manage family and work conflicts. PMID- 29508423 TI - Faecal calprotectin effectively excludes inflammatory bowel disease in 789 symptomatic young adults with/without alarm symptoms: a prospective UK primary care cohort study. AB - BACKGROUND: Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms. AIMS: We sought to evaluate the diagnostic accuracy of calprotectin to distinguish IBD from functional gut disorder in young adults in whom general practitioners (GPs) suspected IBD; including patients reporting gastrointestinal alarm symptoms. We hypothesised that calprotectin would reduce secondary care referrals and healthcare costs. METHODS: We undertook a prospective cohort study of 789 young adults (18-46 years old) presenting with gastrointestinal symptoms to 49 local general practices that had undergone calprotectin testing (1053 tests: between Jan 2014 and May 2016) because of suspected IBD. We considered calprotectin levels of >=100 MUg/g positive. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard. RESULTS: Overall, 39% (308/789) patients reported gastrointestinal alarm symptoms and 6% (50/789) tested patients were diagnosed with IBD. The positive and negative predictive values of calprotectin testing for distinguishing IBD from functional gut disorder in patients with gastrointestinal alarm symptoms were 50% (95% CI 36%-64%) and 98% (96%-100%): and in patients without gastrointestinal alarm symptoms were 27% (16%-41%) and 99% (98%-100%), respectively. We estimate savings of 279 referrals and L160 per patient. CONCLUSIONS: Calprotectin testing of young adults with suspected IBD in primary care accurately distinguishes IBD from functional gut disorder, even in patients with gastrointestinal alarm symptoms and reduces secondary care referrals and diagnostic healthcare costs. PMID- 29508424 TI - Assessing the performance of the generalized propensity score for estimating the effect of quantitative or continuous exposures on binary outcomes. AB - Propensity score methods are increasingly being used to estimate the effects of treatments and exposures when using observational data. The propensity score was initially developed for use with binary exposures. The generalized propensity score (GPS) is an extension of the propensity score for use with quantitative or continuous exposures (eg, dose or quantity of medication, income, or years of education). We used Monte Carlo simulations to examine the performance of different methods of using the GPS to estimate the effect of continuous exposures on binary outcomes. We examined covariate adjustment using the GPS and weighting using weights based on the inverse of the GPS. We examined both the use of ordinary least squares to estimate the propensity function and the use of the covariate balancing propensity score algorithm. The use of methods based on the GPS was compared with the use of G-computation. All methods resulted in essentially unbiased estimation of the population dose-response function. However, GPS-based weighting tended to result in estimates that displayed greater variability and had higher mean squared error when the magnitude of confounding was strong. Of the methods based on the GPS, covariate adjustment using the GPS tended to result in estimates with lower variability and mean squared error when the magnitude of confounding was strong. We illustrate the application of these methods by estimating the effect of average neighborhood income on the probability of death within 1 year of hospitalization for an acute myocardial infarction. PMID- 29508425 TI - AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients. AB - OBJECTIVE: We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. METHODS: We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined <=50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. RESULTS: All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD >=3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P < 0.001), and visceral metastases (P < 0.001). On multivariable analysis, pretherapy CTC cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. CONCLUSION: The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. PMID- 29508426 TI - Standardized morbidity ratios of four chronic health conditions among World Trade Center responders: Comparison to the National Health Interview Survey. AB - PURPOSE: We conducted external comparisons for the prevalence of asthma, hypertension, diabetes, and cancer among World Trade Center (WTC) general responders using the National Health Interview Survey (NHIS) as the reference, along with internal comparisons for the incidence of asthma. METHODS: Standardized Morbidity Ratios (SMRs) were calculated for the prevalence of the health conditions, and risk ratios (RRs) for asthma incidence. RESULTS: Relative to the NHIS, asthma prevalence was in excess in responders over the study years (age-adjusted SMRs = 1.3-2.8). Hypertension prevalence began to exceed expected from 2006 while diabetes was lower than expected. An upward trend towards excess cancer prevalence was observed. Internal comparisons showed elevated asthma incidence among protective service and utility workers compared to construction workers; while those who arrived at the WTC site in the morning of 9/11 had a lower asthma risk than those who arrived in the afternoon. CONCLUSIONS: The use of NHIS data as a reference population demonstrates and reconfirms several important patterns of excess risk in WTC responders. External comparisons are an alternative for disaster cohorts without an established comparison group. PMID- 29508427 TI - When I say... threshold concepts. PMID- 29508428 TI - Chlorogenic acid improves the quality of boar semen subjected to cooled storage at 15 degrees C. AB - The aim of this study was to investigate the effect of chlorogenic acid (ChA) in boar semen stored at 15 degrees C. Twelve ejaculates were processed into insemination doses at different concentrations of ChA (0.0, 1.5, 3.0, 4.0 and 6.0 mg/ml) or vitamin E (200 MUl/ml) as positive control. Semen was analysed after 0, 24 and 72 hr of storage. ChA improved (p < .05) sperm motility, acrosome integrity and mitochondrial activity in all periods of storage. Furthermore, after 24 hr of storage, ChA above 1.5 mg/ml supported the sperm viability until 120 min after reheating (p < .05). Both ChA and vitamin E were similarly efficient in increasing the antioxidant capacity of semen, reducing the malondialdehyde levels before and after 72 hr of storage (p < .05). However, with 72 hr of storage, ChA at 3.0 mg/ml improved the mitochondrial activity over vitamin E (p < .05). In conclusion, results suggest that the concentration of 3.2 mg/ml of ChA is the best for semen stored for up to 24 hr. However, for semen stored for a longer period, 6.0 mg/ml or more should be used. PMID- 29508429 TI - Mechanical and Chemical Predifferentiation of Mesenchymal Stem Cells Into Cardiomyocytes and Their Effectiveness on Acute Myocardial Infarction. AB - Myocardial infarction is one of the leading causes of death all over the world. Mesenchymal stem cells (MSCs) transplantation has shown a promising potential to recovery of ischemic heart disease due to their capability in differentiating into cardiac cells. However, various investigations have been performed to optimize the efficacy of cardiac cell therapy in recent years. Here, we sought to interrogate the effect of autologous transplantation of undifferentiated and predifferentiated adipose and bone marrow-derived MSCs in a rabbit model of myocardial infarction and also to investigate whether cardiac function could be improved by mechanically induced MSCs via equiaxial cyclic strain. The two sources of MSCs were induced toward cardiomyocyte phenotype using mechanical loading and chemical factors and thereafter injected into the infarcted myocardium of 35 rabbits. Echocardiography and histopathology studies were used to evaluate cardiac function after 2 months. The results demonstrated significant scar size reduction and greater recovery of left ventricle ejection fraction after transplantation of predifferentiated cells, though the differences were not significant when comparing mechanically with chemically predifferentiated MSCs. Thus, although there was no significant improvement in infarcted myocardium between chemically and mechanically predifferentiated MSCs, mechanically induced cells are more preferred due to lack of any chemical intervention and cost reasonableness in their preparation method. Outcomes of this study may be useful for developing future therapeutic strategies, however long-term assessments are still required to further examine their effectiveness. PMID- 29508430 TI - Capillary electrophoresis in association with chemometrics approach for bitterness hop (Humulus lupulus L.) classification. AB - The precursor compounds related to the bitterness of beer are called alpha-acids. These compounds are extracted from the hop, which is an important ingredient in the brewing process. These compounds were analyzed by capillary electrophoresis. The electrophoretic method used 160 mmol/L of ammonium carbonate (pH 9) as BGE (background electrolyte), a voltage of +20 kV in a capillary with 50 MUm of internal diameter and with a 62.5 cm of total length (54 cm effective). The samples were injected in hydrodynamic mode applying a pressure of 25 mbar for 5 s and the analytes were detected at 230 nm. A hydromethanolic extraction during 3 h was considered as the optimum condition for the sample preparation using MeOH/H2 O 80:20 v/v as the extract solution. From the optimized conditions the electropherograms were evaluated for their use as input for chemometric modeling. Preprocessing investigation for electrophoretic data taking into account the alignment, denoising and baseline correction, and variable selection were considered before the chemometric modeling using principal component analysis (PCA). The electrophoretic data were systematically evaluated to find the optimum conditions to modeling. A PCA analysis for all tests was carried out using different preprocessing methods and, an explained variance higher than 90% was achieved in all of them. The optimized chemometric method worked with aligned and meancentered data. From this approach, a simple and efficient method to classify hop samples with high and low alpha-acids content without the use of analytical standards was established from a simple electrophoretic analysis. PMID- 29508431 TI - A comprehensive approach of the gender bias in occupational cancer epidemiology: A systematic review of lung cancer studies (2003-2014). AB - BACKGROUND: In occupational epidemiology, a male-centered perspective often predominates. We aimed to describe current research practices in terms of gender consideration at different stages of epidemiological studies. METHODS: A systematic review of occupational lung cancer publications indexed in PubMed was conducted over the period 2003-2014. Articles were described according to the sex composition of their study sample. RESULTS: In 243 studies, 7 (3%) were women only, 101 (41%) were mixed, with a disproportionate men-to-women ratio (P50 = 3.5; P75 = 12.4). A shift was observed from mixed and unspecified source populations to men-only final samples. Our results also suggest implicit generalization of results from men-only studies, a lack of tests of interaction and often unjustified sex-adjustment for mixed studies. CONCLUSIONS: The lower proportion of women in studies cannot be fully explained by their under representation in the target populations, since there were large numbers of women among both potentially exposed workers and patients diagnosed with lung cancer. PMID- 29508433 TI - Promoting leadership and teamwork development through Escape Rooms. PMID- 29508432 TI - Systematic review: adrenal insufficiency secondary to swallowed topical corticosteroids in eosinophilic oesophagitis. AB - BACKGROUND: Swallowed topical corticosteroids are prescribed for eosinophilic oesophagitis (EoE), but there is a theoretical risk of adrenal insufficiency from their use. AIMS: To determine if the use of topical corticosteroids to treat EoE is associated with the development of adrenal insufficiency. METHOD: We conducted a systematic review of the published literature from January 1, 1950 to April 1, 2017 using Pubmed, Embase, Web of Science and Cochrane Central. Studies and meeting abstracts were included that described patients with EoE who received swallowed topical corticosteroids and any investigation for adrenal insufficiency. RESULTS: The search revealed 1610 unique publications, and 17 met inclusion criteria. There were 7 randomised controlled trials (RCTs), 6 prospective observational studies, 3 retrospective observational studies, and 1 case report. Cortisol measurements were performed on 596 individuals with EoE who received topical corticosteroids. Adrenal testing was abnormal, as defined by each study, in 94/596 patients (crude rate of 15.8%). Only 2 studies were considered to have a low risk of bias, being randomised controlled trials that estimated adrenal insufficiency in the active treatment and placebo groups, before and after treatment. None of the seven randomised controlled trials demonstrated statistically significantly different rates of adrenal insufficiency between topical corticosteroid and placebo over treatment intervals of 2-12 weeks. CONCLUSION: Topical corticosteroids were associated with adrenal insufficiency in a minority of patients. Most cases came from uncontrolled observational studies, with widely varying definitions of adrenal insufficiency. Longer follow-up and larger controlled studies are needed to quantify the risk of adrenal insufficiency with maintenance topical corticosteroid therapy in EoE. PMID- 29508434 TI - An autopsy case of globular glial tauopathy presenting with clinical features of motor neuron disease with dementia and iron deposition in the motor cortex. AB - Globular glial tauopathy (GGT) is a 4-repeat (4R) tauopathy in which 4R tau accumulates to form globular glial inclusions (GGIs), predominantly in oligodendroglia. To date, little has been reported on iron deposits in patients with GGT. We report a case of GGT with iron deposits in a 78-year-old woman presenting with an 8-year history of slowly progressing limb weakness and cognitive decline. Susceptibility-weighted imaging revealed a low signal intensity in the right precentral gyrus, suggesting iron deposition. A clinical diagnosis of motor neuron disease with dementia was made 4 years after onset. At autopsy, gross pathological findings showed atrophy of the frontal and temporal lobes. A localized area of the precentral gyrus corresponding to the most severely affected limb showed the strongest atrophy, macroscopically, and displayed 4R tau-immunoreactive GGIs and microscopically many ferritin immunoreactive neurons. We diagnosed this patient as having GGT. This is the first GGT case with iron deposition confirmed both radiologically and pathologically. PMID- 29508435 TI - Macrophage-derived inflammatory cytokines regulate growth factors and pain related molecules in mice with intervertebral disc injury. AB - Upregulation of inflammatory cytokines and various growth factors is a significant contributor to discogenic low back pain. The aim of this study was to investigate possible regulation of pain-related molecules by macrophages and the role of macrophage-derived molecules in injured intervertebral disc (IVD)s. C57BL/6J mice were used in this study. We characterized the expression profiles of genes for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in both intact and injured IVDs. We examined whether macrophage depletion, induced by systemic injection of clodronate-laden liposomes, affected the expression of these molecules in injured IVDs. The effect of TNF-alpha on cultured F4/80-CD11b-cells in injured IVDs was investigated. Expression of TNF-alpha and IL-1beta was significantly increased in injured IVDs, but decreased by macrophage depletion. Expression of NGF and VEGF was also significantly increased, but by contrast was not decreased by macrophage depletion. TNF-alpha treatment of F4/80-cells from injured IVDs upregulated NGF, VEGF, cyclooxygenase (COX)-2, and microsomal prostaglandin E synthase-1 (mPGES1). IVD injury upregulated inflammatory cytokines and various growth factors. Macrophages in the injured IVDs produced inflammatory cytokines, but not growth factors. Macrophage-derived inflammatory cytokines regulate growth factors and pain-related molecules. These findings demonstrate further complexity in the pathogenesis of discogenic pain. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29508436 TI - CD117- and vimentin-positive telocytes in the bovine teat sphincter. AB - Mastitis is a common economically relevant problem in dairy farming. As the major entry for pathogens is the papillary duct, one of the first defence mechanisms is the teat sphincter. This sphincter shows a rhythmic contractility of yet unknown origin. Searching for possible modulatory pacemaker cells, teat sphincters of eight cows were stained immunohistochemically with antibodies against CD117 and vimentin and evaluated microscopically for the presence of telocytes. CD117- and vimentin-positive telocytes with telopodes were found in close contact with smooth muscle cells. Our findings present a first evidence of telocytes in the teat of bovines. PMID- 29508437 TI - Inhibitory effects of silodosin on the bladder mechanosensitive afferent activities and their relation with bladder myogenic contractions in male rats with bladder outlet obstruction. AB - AIMS: We investigated the effects of silodosin, an alpha1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model. METHODS: BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Adelta- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary." RESULTS: The silodosin treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Adelta- and C-fibers than the vehicle-treated group during bladder filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group. CONCLUSION: The present results suggest that silodosin inhibits the SAAs of mechanosensitive Adelta- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats. PMID- 29508438 TI - The role of bacteria in the inflammatory bowel disease development: a narrative review. AB - Inflammatory bowel disease (IBD) is a general term used for the ulcerative colitis (UC) and Crohn's disease (CD); in addition, IBD principally refers to a chronic disease of the gastrointestinal tract in which mediated by immune system. Consequently, IBD could progress in individuals who are genetically prone. Infections role in the development of inflammatory disease of the gastrointestinal tract has been studied by quite many clinical studies; furthermore, the possible role of some pathogens in the development and exacerbation of the inflammatory disease of the gastrointestinal tract have been described. Evidently, the most indispensable pathogens that could be associated with the IBD disease, Mycobacterium avium subspecies paratuberculosis, Clostridium difficile, Escherichia coli, Listeria monocytogenes, Campylobacter concisus; as well as viruses, such as, cytomegalovirus, Epstein-Barr Virus, and measles virus are notable. A number of pathogenic parasites may also be involved in the development and progression of the disease. As a matter of fact, overexposure of immune system in the presence of excessive bacterial substances could also lead to the loss of immunological tolerance to the bacteria, which are commonly considered as the normal flora in the intestine; furthermore, it may subsequently elicit bowel inflammation and IBD development. In the current study, we discussed the most common bacterial pathogens that may be involved in the development of IBD; as well as, a comprehensive narrative review related to the evidences which support or ignore the possible role of bacteria in progression of IBD, indeed. PMID- 29508439 TI - Dopamine D1 receptor-mediated upregulation of BKCa currents modifies Muller cell gliosis in a rat chronic ocular hypertension model. AB - Muller cell gliosis is a common response in many retinal pathological conditions. We previously demonstrated that downregulation of Kir channels contributes to Muller cell gliosis in a rat chronic ocular hypertension (COH) model. Here, the possible involvement of outward K+ currents in Muller cell gliosis was investigated. Outward K+ current densities in Muller cells isolated from COH rats, as compared with those in normal rats, showed a significant increase, which was mainly contributed by large-conductance Ca2+ -activated K+ (BKCa ) channels. The involvement of BKCa channels in Muller cell gliosis is suggested by the fact that glial fibrillary acidic protein (GFAP) levels were augmented in COH retinas when these channels were suppressed by intravitreal injections of iberiotoxin. In COH retinas an increase in dopamine (DA) D1 receptor (D1R) expression in Muller cells was revealed by both immunohistochemistry and Western blotting. Moreover, protein levels of tyrosine hydroxylase were also increased, and consistent to this, retinal DA contents were elevated. SKF81297, a selective D1R agonist, enhanced BKCa currents of normal Muller cells through intracellular cAMP-PKA signaling pathway. Furthermore, GFAP levels were increased by the D1R antagonist SCH23390 injected intravitreally through eliminating the BKCa current upregulation in COH retinas, but partially reduced by SKF81297. All these results strongly suggest that the DA-D1R system may be activated to a stronger extent in COH rat retinas, thus increasing BKCa currents of Muller cells. The upregulation of BKCa channels may antagonize the Kir channel inhibition-induced depolarization of Muller cells, thereby attenuating the gliosis of these cells. PMID- 29508440 TI - Bandgap Engineering of Stable Lead-Free Oxide Double Perovskites for Photovoltaics. AB - Despite the rapid progress in solar power conversion efficiency of archetype organic-inorganic hybrid perovskite CH3 NH3 PbI3 -based solar cells, the long term stability and toxicity of Pb remain the main challenges for the industrial deployment, leading to more uncertainties for global commercialization. The poor stabilities of CH3 NH3 PbI3 -based solar cells may not only be attributed to the organic molecules but also the halides themself, most of which exhibit intrinsic instability under moisture and light. As an alternative, the possibility of oxide perovskites for photovoltaic applications is explored here. The class of lead free stable oxide double perovskites A2 M(III)M(V)O6 (A = Ca, Sr, Ba; M(III) = Sb3+ or Bi3+ ; M(V) = V5+ , Nb5+ , or Ta5+ ) is comprehensively explored with regard to their stability and their electronic and optical properties. Apart from the strong stability, this class of double perovskites exhibits direct bandgaps ranging from 0.3 to 3.8 eV. With proper B site alloying, the bandgap can be tuned within the range of 1.0-1.6 eV with optical absorptions as strong as CH3 NH3 PbI3 , making them suitable for efficient single-junction thin-film solar cell application. PMID- 29508441 TI - Pre-anthracycline echocardiogram rarely changes treatment strategy in acute myeloid leukemia. PMID- 29508442 TI - Beneficial impact of zinc supplementation on the collagen in the bone tissue of cadmium-exposed rats. AB - Cadmium (Cd) is a toxic metal that damages bone tissue by affecting its mineral and organic components. The organic matrix is mainly (90%) composed of collagen, which determines the biomechanical strength of bone. The aim of this study was to evaluate the effect of zinc (Zn) supplementation (30 or 60 mg l-1 ) under moderate and relatively high exposure to Cd (5 and 50 mg l-1 ) on collagen in the rat tibia proximal epiphysis and diaphysis (regions abundant in trabecular and cortical bone, respectively). Significant decrease in collagen type I biosynthesis was found in both regions of the tibia in Cd-treated rats, whereas the supplementation with Zn provided significant protection against this effect. Western blot confirmed the presence of the major type I collagen in the tibia epiphysis and diaphysis, but collagen type II was revealed only in the epiphysis. Acetic acid- and pepsin-soluble collagen concentration in the tibia epiphysis and diaphysis was significantly increased due to the exposure to Cd, whereas the supplementation with Zn protected, partially or totally, from these effects, depending on the used concentration. The supplementation with Zn also provided protection from unfavorable Cd impact on the maturation of the bone collagen, as the ratio of cross-links to monomers was higher compared to the Cd-treated group. This report confirms our previous findings on the preventive action of Zn against harmful effects of Cd on bone, but additionally, and to the best of our knowledge for the first time, explains the possible mechanism of the beneficial influence of this bioelement. PMID- 29508443 TI - Measurement of blood-brain barrier permeability using dynamic contrast-enhanced magnetic resonance imaging with reduced scan time. AB - PURPOSE: To investigate the feasibility of measuring the subtle disruption of blood-brain barrier (BBB) using DCE-MRI with a scan duration shorter than 10 min. METHODS: The extended Patlak-model (EPM) was introduced to include the effect of plasma flow (Fp ) in the estimation of vascular permeability-surface area product (PS). Numerical simulation studies were carried out to investigate how the reduction in scan time affects the accuracy in estimating contrast kinetic parameters. DCE-MRI studies of the rat brain were conducted with Fisher rats to confirm the results from the simulation. Intracranial F98 glioblastoma models were used to assess areas with different levels of permeability. In the normal brain tissues, the Patlak model (PM) and EPM were compared, whereas the 2 compartment-exchange-model (TCM) and EPM were assessed in the peri-tumor and the tumor regions. RESULTS: The simulation study results demonstrated that scan time reduction could lead to larger bias in PS estimated by PM (>2000%) than by EPM (<47%), especially when Fp is low. When Fp was high as in the gray matter, the bias in PM-PS (>900%) were larger than that in EPM-PS (<42%). The animal study also showed similar results, where the PM parameters were more sensitive to the scan duration than the EPM parameters. It was also demonstrated that, in the peri tumor region, the EPM parameters showed less change by scan duration than the TCM parameters. CONCLUSION: The results of this study suggest that EPM can be used to measure PS with a scan duration of 10 min or less. PMID- 29508444 TI - Evaluation of the Virclia(r) automated chemiluminescent immunoassay system for diagnosing pneumonia caused by Mycoplasma pneumoniae. AB - BACKGROUND: Mycoplasma pneumoniae is considered an important etiologic agent of community-acquired pneumonia (CAP) in outpatients. We aimed to evaluate the diagnostic accuracy of a quick automated chemiluminescent immunoassay (CLIA) for M. pneumoniae in a population-based prospective study of CAP. METHODS: A total of 137 outpatients diagnosed with CAP were included in the study. Acute- and convalescent phase sera were analyzed for IgG and IgM to M. pneumoniae with both CLIA (VirClia(r) ) and ELISA immunoassays. Conventional serological criteria by quantitative ELISA were considered as reference standard. Sensitivity and specificity of the assay were assessed with the construction of receiver operating characteristic (ROC) curves, and the kappa index was used to evaluate the accuracy of the IgG and IgM determinations in the acute phase. RESULTS: Thirty-eight patients were diagnosed with pneumonia by M. pneumoniae. ROC curves for IgG and IgM of convalescent and acute phase (C/A) quotients by the CLIA and ELISA assays were comparable. Specifically, for the CLIA, the best C/A quotient for IgG was 2.617 (sensitivity, 94.9%; specificity, 99.9%), and for IgM 1.400 (sensitivity, 65.8%; specificity, 100%). Regarding the acute phase, the best diagnostic accuracy for the CLIA was obtained with an IgG index of 1.120 (sensitivity, 89.5%; specificity, 73.7%). The CLIA was very simple to execute and required a minimum sample handling. CONCLUSION: The accuracy of the Virclia(r) assay for the diagnosis of M. pneumoniae infection in outpatients with CAP was equivalent to the quantitative ELISA. The CLIA was quicker to perform and displayed better analytic workability than conventional ELISA. PMID- 29508445 TI - Esthetics in periodontics and implantology. AB - Periodontal plastic surgery comprises an increasing part of clinical periodontology. Clinical trials have traditionally used professionals to judge esthetic outcome, and few studies have addressed patient needs and requests (true end points). Development of universally accepted and validated methods for professional esthetic assessment, together with standardized questionnaires for patient-perceived outcome, may help to provide better insights into the true needs and benefits of periodontal and implant-associated plastic surgery. In this volume of Periodontology 2000, experienced researchers and clinicians from different subdisciplines of periodontology evaluate: treatment of gingival recession with or without papilla elevation; clinical crown lengthening in the natural dentition and in prosthodontic preparative treatment; periodontal regeneration around natural teeth; and soft-tissue augmentation in edentulous areas. Similarly, experts in different areas of implant science address esthetic outcomes with single and multiple implant rehabilitation, alveolar ridge preservation, implant positioning and immediate implant placement in the esthetic zone. PMID- 29508446 TI - Predicting a successful outcome in sacral neuromodulation testing: Are urodynamic parameters prognostic? AB - AIMS: To assess whether the urodynamic parameters of mean voided volume, peak detrusor overactivity (DO) pressure, bladder compliance, capacity, and volume at first detrusor overactivity during filling cystometry can predict a successful outcome at first stage tined lead placement (FSTLP). METHODS: Ninty-nine consecutive patients with urodynamically proven idiopathic detrusor overactivity (IDO) refractory to medical treatment and opting for Sacral Nerve Stimulation (SNS), were assessed pre and post FSTLP. Data from 3-day frequency-volume charts, and patient reported (subjective) outcomes were used to assess success or failure after FSTLP. Success was defined as improvement in symptoms >50%. Binary logistic regression analysis was used to ascertain whether key parameters at filling cystometrogram were predictors for success prior to FSTLP. RESULTS: Binary logistic regression analysis did not demonstrate any significant relationship between the five parameters at urodynamics and outcome at FSTLP (B < 0.01, P > 0.16) for all parameters. CONCLUSIONS: The results from this prospective analysis on patients with IDO refractive to medical therapy referred for SNS would suggest that aside from proving DO at urodynamics as a pre-requisite for intervention as per NICE and EAU guidelines, no parameter is predictive for a successful outcome at FSTLP. PMID- 29508447 TI - The structure of the perceived professional identity of Japanese public health nurses. AB - OBJECTIVE: As health problems become more diverse and complicated, the way public health nurses (PHNs) work is changing. Research at the conceptual level of professional identity of PHNs is lacking. This study aimed to explore the structure of the perceived professional identity of Japanese PHNs. DESIGN AND SAMPLE: Grounded theory method was used. Twenty-five PHNs in Japanese municipalities were participated in the study. MEASUREMENTS: Data were collected through semistructured interviews and analyzed using open, axial, and selective coding. RESULTS: Three categories emerged: (1) providing support to the consulter directly, (2) working as a member of the administrative organization, and (3) working for all residents to improve community development. The modality of perceived professional identity showed interindividual and intraindividual differences and was either stable or unstable. The perceived professional identities coexisted, but there was a conflict between (1) and (2). CONCLUSION: PHNs should be made aware of the three identities revealed in our study and the possibility of a conflict between identities. Moreover, to ensure working for all residents to improve community development, a population-based approach to education is needed with cooperation of universities and clinical practice. PMID- 29508448 TI - SPIN2: Predicting sequence profiles from protein structures using deep neural networks. AB - Designing protein sequences that can fold into a given structure is a well-known inverse protein-folding problem. One important characteristic to attain for a protein design program is the ability to recover wild-type sequences given their native backbone structures. The highest average sequence identity accuracy achieved by current protein-design programs in this problem is around 30%, achieved by our previous system, SPIN. SPIN is a program that predicts sequences compatible with a provided structure using a neural network with fragment-based local and energy-based nonlocal profiles. Our new model, SPIN2, uses a deep neural network and additional structural features to improve on SPIN. SPIN2 achieves over 34% in sequence recovery in 10-fold cross-validation and independent tests, a 4% improvement over the previous version. The sequence profiles generated from SPIN2 are expected to be useful for improving existing fold recognition and protein design techniques. SPIN2 is available at http://sparks-lab.org. PMID- 29508449 TI - Accelerated 4D phase contrast MRI in skeletal muscle contraction. AB - PURPOSE: 3D time-resolved (4D) phase contrast MRI can be used to study muscle contraction. However, 3D coverage with sufficient spatiotemporal resolution can only be achieved by interleaved acquisitions during many repetitions of the motion task, resulting in long scan times. The aim of this study was to develop a compressed sensing accelerated 4D phase contrast MRI technique for quantification of velocities and strain rate of the muscles in the lower leg during active plantarflexion/dorsiflexion. METHODS: Nine healthy volunteers were scanned during active dorsiflexion/plantarflexion task. For each volunteer, we acquired a reference scan, as well as 4 different accelerated scans (k-space undersampling factors: 3.14X, 4.09X, 4.89X, and 6.41X) obtained using Cartesian Poisson disk undersampling schemes. The data was reconstructed using a compressed sensing pipeline. For each scan, velocity and strain rate values were quantified in the gastrocnemius lateralis, gastrocnemius medialis, tibialis anterior, and soleus. RESULTS: No significant differences in velocity values were observed as a function acceleration factor in the investigated muscles. The strain rate calculation resulted in one positive (s+ ) and one negative (s- ) eigenvalue, whereas the third eigenvalue (s3 ) was consistently 0 for all the acquisitions. No significant differences were observed for the strain rate eigenvalues as a function of acceleration factor. CONCLUSIONS: Data undersampling combined with compressed sensing reconstruction allowed obtainment of time-resolved phase contrast acquisitions with 3D coverage and quantitative information comparable to the reference scan. The 3D sensitivity of the method can help in understanding the connection between muscle architecture and muscle function in future studies. PMID- 29508451 TI - A Polymer Encapsulation Strategy to Synthesize Porous Nitrogen-Doped Carbon Nanosphere-Supported Metal Isolated-Single-Atomic-Site Catalysts. AB - A novel polymer encapsulation strategy to synthesize metal isolated-single-atomic site (ISAS) catalysts supported by porous nitrogen-doped carbon nanospheres is reported. First, metal precursors are encapsulated in situ by polymers through polymerization; then, metal ISASs are created within the polymer-derived p-CN nanospheres by controlled pyrolysis at high temperature (200-900 degrees C). Transmission electron microscopy and N2 sorption results reveal this material to exhibit a nanospheric morphology, a high surface area (~380 m2 g-1 ), and a porous structure (with micropores and mesopores). Characterization by aberration corrected high-angle annular dark-field scanning transmission electron microscopy and X-ray absorption fine structure confirms the metal to be present as metal ISASs. This methodology is applicable to both noble and nonprecious metals (M ISAS/p-CN, M = Co, Ni, Cu, Mn, Pd, etc.). In particular, the Co-ISAS/p-CN nanospheres obtained using this method show comparable (E1/2 = 0.838 V) electrochemical oxygen reduction activity to commercial Pt/C with 20 wt% Pt loading (E1/2 = 0.834 V) in alkaline media, superior methanol tolerance, and outstanding stability, even after 5000 cycles. PMID- 29508450 TI - Salicylic Acid-Based Polymeric Contrast Agents for Molecular Magnetic Resonance Imaging of Prostate Cancer. AB - Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is an innovative molecular imaging technique in which contrast agents are labeled by saturating their exchangeable proton spins by radio-frequency irradiation. Salicylic acid and its analogues are a promising class of highly sensitive, diamagnetic CEST agents. Herein, polymeric agents grafted with salicylic acid moieties and a known high-affinity ligand targeting prostate-specific membrane antigen in approximately 10:1 molar ratio were synthesized to provide sufficient MRI sensitivity and receptor specificity. The proton-exchange properties of the contrast agent in solution and in an experimental murine model are reported to demonstrate the feasibility of receptor-targeted CEST MRI of prostate cancer. Furthermore, the CEST imaging data were validated with an 111 In-labeled analogue of the agent by in vivo single photon emission computed tomographic imaging and tissue biodistribution studies. PMID- 29508452 TI - Oncologists' identification of mental health distress in cancer patients: Strategies and barriers. AB - The purpose of this research was to examine oncologists' perspectives on indicators of mental health distress in patients: what strategies they use to identify these indicators, and what barriers they face in this task. Twenty-three oncologists were interviewed, and the grounded theory method of data collection and analysis was used. Oncologists perceived distress to be a normative part of having cancer and looked for affective, physical, verbal and behavioural indicators using a number of strategies. Barriers to identification of mental health distress included difficulty in differentiating between mental health distress and symptoms of the disease, and lack of training. A systematic, time efficient assessment of symptoms of emotional distress is critical for identification of psychiatric disorders among patients and differentiating normative emotional responses from psychopathology. Clinical bias and misdiagnosis can be a consequence of an ad hoc, intuitive approach to assessment, which can have consequences for patients and their families. Once elevated risk is identified for mental health distress, the patient can be referred to specialised care that can offer evidence-based treatments. PMID- 29508453 TI - ATP3 and MTP3: Easily Prepared Stable Perruthenate Salts for Oxidation Applications in Synthesis. AB - The Ley-Griffith tetra-n-propylammonium perruthenate (TPAP) catalyst has been widely deployed by the synthesis community, mainly for the oxidation of alcohols to aldehydes and ketones, but also for a variety of other synthetic transformations (e.g. diol cleavage, isomerizations, imine formation and heterocyclic synthesis). Such popularity has been forged on broad reaction scope, functional group tolerance, mild conditions, and commercial catalyst supply. However, the mild instability of TPAP creates preparation, storage, and reaction reproducibility issues, due to unpreventable slow decomposition. In search of attributes conducive to catalyst longevity an extensive range of novel perruthenate salts were prepared. Subsequent evaluation unearthed a set of readily synthesized, bench stable, phosphonium perruthenates (ATP3 and MTP3) that mirror the reactivity of TPAP, but avoid storage decomposition issues. PMID- 29508454 TI - On the Electron-Transfer Mechanism in the Contact-Electrification Effect. AB - A long debate on the charge identity and the associated mechanisms occurring in contact-electrification (CE) (or triboelectrification) has persisted for many decades, while a conclusive model has not yet been reached for explaining this phenomenon known for more than 2600 years! Here, a new method is reported to quantitatively investigate real-time charge transfer in CE via triboelectric nanogenerator as a function of temperature, which reveals that electron transfer is the dominant process for CE between two inorganic solids. A study on the surface charge density evolution with time at various high temperatures is consistent with the electron thermionic emission theory for triboelectric pairs composed of Ti-SiO2 and Ti-Al2 O3 . Moreover, it is found that a potential barrier exists at the surface that prevents the charges generated by CE from flowing back to the solid where they are escaping from the surface after the contacting. This pinpoints the main reason why the charges generated in CE are readily retained by the material as electrostatic charges for hours at room temperature. Furthermore, an electron-cloud-potential-well model is proposed based on the electron-emission-dominatedcharge-transfer mechanism, which can be generally applied to explain all types of CE in conventional materials. PMID- 29508456 TI - Autonomic dysfunction in genetic forms of synucleinopathies. AB - The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29508457 TI - The link between maternal sleep and permissive parenting during late adolescence. AB - Utilizing a multi-method design, the present study examined the association between maternal sleep, assessed via actigraphy and self-reports, and permissive parenting (e.g. lax, inconsistent discipline) during adolescence, as well as the extent to which this association differed by mothers' race/ethnicity and socioeconomic status. The sample was comprised of 234 mothers (M age = 41.76 years, SD = 6.25; 67% European-American, 31% African-American, 2% other race/ethnicities) and 237 adolescents (113 boys, 124 girls; M age = 15.80 years, SD = 0.80; 66% European-American, 34% African-American). Mothers' sleep duration (actual sleep minutes) and quality (sleep efficiency, latency, long wake episodes) were assessed using actigraphy. Mothers also reported on their sleep problems and adolescents reported on mothers' permissive parenting behaviours. Results revealed that actigraphy-based longer sleep duration and shorter sleep latency were associated with lower levels of permissive parenting. Further, mothers' race/ethnicity and socioeconomic status moderated the association between actigraphy-based sleep quality (i.e. sleep efficiency, long wake episodes) and permissive parenting. Specifically, a negative association between sleep efficiency and permissive parenting was evident only for African-American mothers. In addition, a positive association between more frequent night wakings and permissive parenting was evident only for mothers from lower socioeconomic status households. The findings highlight the benefits of longer and higher quality sleep for reducing the risk of permissive parenting, especially among ethnic minority mothers and mothers from lower socioeconomic status households. PMID- 29508459 TI - Corrigendum. PMID- 29508458 TI - Assessment of velopharyngeal function with dual-planar high-resolution real-time spiral dynamic MRI. AB - PURPOSE: To develop a real-time dynamic MRI method for comprehensive evaluation of velum movement during speech. METHODS: Dynamic MRI has been used to study velopharyngeal insufficiency (VPI) by imaging the movement of the velum during speech, because it can provide good anatomic details with no exposed radiation. To be able to comprehensively evaluate dynamic velum movement, a real-time spiral non-balanced SSFP sequence was developed with simultaneous dual-planar coverage and improved spatial and temporal resolution using a combination of parallel imaging and spatial and temporal compressed sensing to achieve 6 * acceleration. New off-resonance correction and post-processing methods were also developed to reduce blurring and slice crosstalk. RESULTS: The method demonstrated good image quality for visualizing dynamic velum movement with reduced blurring and improved image homogeneity. Spatial resolution of 1.2*1.2 mm2 with 150 mm FOV and temporal resolution of 20 frames-per-second with simultaneous dual-planar coverage was achieved. CONCLUSIONS: This work describes a new technique for studying speech disorders using dual-planar accelerated spiral dynamic MRI. PMID- 29508455 TI - Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. AB - Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29508460 TI - Associations between quantitative sleep EEG and subsequent cognitive decline in older women. AB - The pathophysiological processes of Alzheimer's dementia predate its clinical manifestation. Sleep disturbances can accelerate the aging process and are common features of dementia. This study examined whether quantitative sleep electroencephalogram changes predate the clinical development of mild cognitive impairment and/or incident dementia. We collected data from a nested case-control sample of women (mean age 83 years) from the Sleep and Cognition Study, an ancillary study to the longitudinal Study of Osteoporotic Fractures, who were characterized as cognitively normal at the time of a baseline polysomnography study (Study of Osteoporotic Fractures visit 8) based on a Mini-Mental Status Exam (MMSE) score >24. Cases (n = 85) were women who developed new mild cognitive impairment or dementia by objective cognitive testing 5 years after polysomnography. Controls were women with no mild cognitive impairment/dementia (n = 85) at baseline or at follow-up. Differences in electroencephalogram absolute and relative power density were observed between the two groups. Specifically, higher electroencephalogram power values were found in the dementia/mild cognitive impairment group, for the alpha (p = .01) and theta bands (p = .04) in non-rapid eye movement sleep, as well as alpha (p = .04) and sigma (p = .04) bands in rapid eye movement sleep. In contrast, there were no group differences in traditional polysomnography measures of sleep architecture and sleep stage distribution, as well as sleep apnea and periodic limb movement indices. Our results provide evidence for quantitative electroencephalogram changes, which precede the clinical onset of cognitive decline and the diagnosis of dementia in elderly women, and support the application of quantitative sleep electroencephalogram analysis as a promising biomarker for imminent cognitive decline. PMID- 29508462 TI - Corrigenda. PMID- 29508461 TI - Editorial comments on this issue of the Journal. PMID- 29508464 TI - Cytomorphology of proximal epithelioid sarcoma in the paratesticular location. PMID- 29508463 TI - Exploration of Strategies for Mechanism-Based Inhibitor Design for Family GH99 endo-alpha-1,2-Mannanases. AB - endo-alpha-1,2-Mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave alpha-Glc/Man-1,3-alpha-Man-OR structures within mammalian N-linked glycans and fungal alpha-mannan, respectively. They are proposed to act through a two-step mechanism involving a 1,2-anhydrosugar "epoxide" intermediate incorporating two conserved catalytic carboxylates. In the first step, one carboxylate acts as a general base to deprotonate the 2-hydroxy group adjacent to the fissile glycosidic bond, and the other provides general acid assistance to the departure of the aglycon. We report herein the synthesis of two inhibitors designed to interact with either the general base (alpha mannosyl-1,3-(2-aminodeoxymannojirimycin), Man2NH2 DMJ) or the general acid (alpha-mannosyl-1,3-mannoimidazole, ManManIm). Modest affinities were observed for an endo-alpha-1,2-mannanase from Bacteroides thetaiotaomicron. Structural studies revealed that Man2NH2 DMJ binds like other iminosugar inhibitors, which suggests that the poor inhibition shown by this compound is not a result of a failure to achieve the expected interaction with the general base, but rather the reduction in basicity of the endocyclic nitrogen caused by introduction of a vicinal, protonated amine at C2. ManManIm binds with the imidazole headgroup distorted downwards, a result of an unfavourable interaction with a conserved active site tyrosine. This study has identified important limitations associated with mechanism-inspired inhibitor design for GH99 enzymes. PMID- 29508466 TI - A General Catalytic Method for Highly Cost- and Atom-Efficient Nucleophilic Substitutions. AB - A general formamide-catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT-mediated dihydroxychlorination of an OH-containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E-factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional-group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one-pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN 2 inversion, which demonstrates the high practical value of the presented method. PMID- 29508465 TI - Casticin alleviates lipopolysaccharide-induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF-kappaB pathways. AB - Asthma is one of the most common chronic inflammatory diseases of childhood, characterized by airway inflammation, mucus hypersecretion, and accumulation of extracellular matrix proteins. Casticin is an active compound that possesses broad biological activities including anti-inflammatory effect. However, the effect of casticin on asthma remains unknown. The aim of the present study was to evaluate the effect and mechanism of casticin on inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells. The results showed that lipopolysaccharide induced the mRNA and protein levels of IL-6, IL-8, MUC5AC, collagen type I, and fibronectin in 16-HBE cells, whereas casticin treatment significantly inhibited the induction of lipopolysaccharide. Casticin induced Nrf2/Keap1 and inhibited nuclear factor kappaB pathways in 16 HBE cells. Knockdown of Nrf2 attenuated the effect of casticin on production of IL-6 and IL-8, expression of MUC5AC, collagen type I, and fibronectin in 16-HBE cells. In conclusion, the results indicated that casticin might be a novel therapeutic strategy for the treatment of asthma. PMID- 29508467 TI - Towards a systematic approach for (de)implementation of patient blood management strategies. AB - Despite the increasing availability of evidence in transfusion medicine literature, this evidence does not automatically find its way into practice. This is also applicable to patient blood management (PBM). It may concern the lack of implementation of effective new techniques or treatments, or it may apply to the (over)use of techniques and treatments (e.g. inappropriate transfusions) that have proven to be of limited benefit for patients (low-value care) and could be abandoned (de-implementation). In PBM literature, the implementation of restrictive transfusion thresholds and the de-implementation of inappropriate transfusions are described. However, most implementation strategies were not preceded by the identification of relevant barriers, and the used strategies were not often supported by literature on behavioural changes. In this article, we describe implementation vs de-implementation, highlight the current situation of (de)implementation in PBM and describe a systematic approach for (de)implementation illustrated by an example of a PBM de-implementation study regarding '(cost-) effective patient blood management in total hip and knee arthroplasty'. The systematic approach used for (de)implementation is based on the implementation model of Grol, which consists of the following five steps: the detection of improvement goals, a problem analysis, the selection of (de)implementation strategies, the execution of the (de)implementation strategy and an evaluation. Based on the description of the current situation and the experiences in our de-implementation study, we can conclude that de implementation may be more difficult than expected as other factors may play a role in effective de-implementation compared to implementation. PMID- 29508468 TI - The Nobel Legacy: A Journey through Chemistry Inspired by the Achievements of Nobel Laureates. AB - The Prize is right! Chemistry-A European Journal will start an exciting journey exploring the significance of Nobel Prize awards in Chemistry in the corresponding contemporary chemistry fields. In this new journal feature called "The Nobel Legacy", a recurring series of invited Review-type articles each one connected to a particular Nobel Prize in Chemistry will be published. PMID- 29508469 TI - The Development of Nonanatomic Denture Occlusion: Part III. AB - Part III of this four-part series about nonanatomic denture tooth development traces the evolution of this movement from the mid-1930s through the World War II era up to the early 1950s. By this time, the general preference for posterior denture occlusion had shifted from anatomic to nonanatomic teeth, and all the major denture tooth manufacturing companies listed at least one nonanatomic design in their inventories. PMID- 29508471 TI - Psychometric testing of the Fear of Cancer Recurrence Inventory-caregiver Chinese version in cancer family caregivers in Taiwan. AB - OBJECTIVE: The purposes of this study were to develop a Chinese version of the Fear of Cancer Recurrence Inventory-caregiver (FCRI-c Chinese) and assess the psychometrics of this test in the family caregivers (FCs) of Taiwanese patients with head and neck cancer. METHODS: An instrument testing study was conducted at a major medical center in Taiwan. Head and neck cancer patients and their major FCs were recruited as dyads from the radiation outpatient department. The FCRI-c Chinese was tested for internal consistency reliability, test-retest reliability, and construct validity (including theoretically supported correlation, discriminant validity, and factor structure). RESULTS: We recruited 300 patient caregiver dyads. The test had good internal consistency (Cronbach alpha = .94) and a 2-week test-retest reliability of .88. Confirmatory factor analysis indicated an acceptable fit of the model to the data. The construct validity was also satisfactory, as indicated by the significant positive correlations of the test with depression and anxiety in FCs, and the significant negative correlation of the test with patients' quality of life. A significantly higher test score was present in FCs caring for patients with metastasis and patients who completed treatment a long time ago. CONCLUSIONS: The FCRI-c Chinese is a valid instrument for examination of the fear of cancer recurrence in the FCs of patients with head and neck cancer. Clinicians can use this multidimensional instrument to assess important clinical care issues and improve the quality of care provided by FCs. PMID- 29508472 TI - Physical Properties, Film Thickness, and Bond Strengths of Resin-Modified Glass Ionomer Cements According to Their Delivery Method. AB - PURPOSE: To determine the effect of changing the dispensing or mixing method of resin-modified glass ionomer (RMGI) cements on their water sorption, solubility, film thickness, and shear bond strength. MATERIALS AND METHODS: Disc-shaped specimens of RMGI cements (RelyX: Luting [handmix], Luting Plus [clicker handmix], Luting Plus [automix], GC: Fuji PLUS [capsule-automix], FujiCEM 2 [automix], [n = 10]) were prepared according to ISO standard 4049 for water sorption and solubility tests. Furthermore, the percentage of mass change, percentage of solubility, and percentage of water absorbed was also determined. Film thickness was measured according to ISO standard 9917-2; the mean of 5 measurements for each cement was calculated. Shear bond strength for each cement was determined according to ISO standard 29022 before and after thermocycling at 20,000 cycles, temperatures 5 to 55 degrees C with a 15-second dwell time (n = 10/subgroup). Two- and one-way ANOVA were used to analyze data for statistical significance (p < 0.05). RESULTS: Water sorptions of the RMGI cements were in close range (214-250 MUg/mm3 ) with no statistical differences between counterparts (p > 0.05). RelyX Luting Plus (clicker-handmix) displayed lower solubility than its handmix and automix counterparts (p < 0.05). Film thickness of RelyX cements was significantly different (p < 0.05). RelyX Luting Plus (automix) had the lowest film thickness (19 MUm) compared to its handmix (48 MUm) and clicker-handmix (117 MUm) counterparts (p < 0.05). GC Fuji PLUS (capsule automix, 22 MUm) was significantly lower than the automix version (GC FujiCEM 2, 127 MUm) (p < 0.05). Shear bond strength of RelyX Luting Plus (automix) was significantly lower than its handmix and clicker-handmix versions (p < 0.05). GC Fuji PLUS (capsule-automix) was significantly higher than GC FujiCEM 2 (automix) (p < 0.05). The binary interaction of the two independent variables (dispensing/mixing method and thermocycling) was significant for the shear bond strengths of the GC cements only (p < 0.05). CONCLUSIONS: Change in the dispensing/mixing method of RMGI cement from the same brand may have an effect on its physical properties, in addition to its film thickness and shear bond strength. Newer, easier, and faster cement delivery systems are not necessarily better. Clinical outcomes of these differences are yet to be confirmed. PMID- 29508470 TI - Factors associated with the efficacy of smoking cessation treatments and predictors of smoking abstinence in EAGLES. AB - AIMS: To assess (1) how far the efficacies of front-line smoking cessation pharmacotherapies vary as a function of smoker characteristics and (2) associations between these characteristics and success of smoking cessation attempts. DESIGN: Prospective correlational study in the context of a double blind randomized trial. The outcome was regressed individually onto each covariate after adjusting for treatment, and then a forward stepwise model constructed. Treatment moderator effects of covariates were tested by treatment * covariate interactions. SETTING: Health service facilities in multiple countries. PARTICIPANTS: Data came from 8120 smokers willing to make a quit attempt, randomized to varenicline, bupropion, nicotine replacement therapy (NRT) or placebo in Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) between 30 November 2011 and 13 January 2015. MEASUREMENTS: Smoker characteristics measured at baseline were country, psychiatric history, sex, age, body mass index (BMI), ethnic group, life-time suicidal ideation/behaviour, anxiety, depression, aggression, psychotropic medication, history of alcohol/substance use disorder, age of starting smoking, cigarette dependence [Fagerstrom Test for Cigarette Dependence (FTCD)] and prior use of study medicines. Outcome was biochemically confirmed continuous abstinence at weeks 9 24 from start of treatment. FINDINGS: No statistically significant treatment * covariate interactions were found. Odds of success were associated independently positively with age [odds ratio (OR) = 1.01; 95% confidence interval (CI) = 1.00, 1.01], BMI (1.01; 95% CI = 1.00, 1.02) and age of starting smoking (1.03; 95% CI = 1.02, 1.04). Odds were associated independently negatively with US (versus non US) study site (0.53; 95% CI = 0.46, 0.61), black (versus white) ethnic group (0.57; 95% CI = 0.45, 0.72), mood disorder (0.85; 95% CI = 0.73, 0.99), anxiety disorder (0.71; 95% CI = 0.55, 0.90) and psychotic disorder (0.73; 95% CI = 0.50, 1.07), taking psychotropic medication (0.81; 95% CI = 0.68, 0.95), FTCD (0.89; 95% CI = 0.87, 0.92) and previous use of NRT (0.78; 95% CI = 0.67, 0.91). CONCLUSIONS: While a range of smoker characteristics-including psychiatric history, cigarette dependence and prior use of nicotine replacement therapy (NRT) are associated with lower cessation rates, they do not substantially influence the efficacy of varenicline, bupropion or NRT. PMID- 29508473 TI - Attractiveness of people-centred and integrated Dutch Home Care: A nationwide survey among nurses. AB - The World Health Organization is calling for a fundamental change in healthcare services delivery, towards people-centred and integrated health services. This includes providing integrated care around people's needs that is effectively co ordinated across providers and co-produced by professionals, the patient, the family and the community. At the same time, healthcare policies aim to scale back hospital and residential care in favour of home care. This is one reason for the home-care nursing staff shortages in Europe. Therefore, this study aimed to examine whether people-centred, integrated home care appeals to nurses with different levels of education in home care and hospitals. A questionnaire survey was held among registered nurses in Dutch home-care organisations and hospitals in 2015. The questionnaire addressed the perceived attractiveness of different aspects of people-centred, integrated home care. In total 328 nurses filled in the questionnaire (54% response rate). The findings showed that most home-care nurses (70% to 97%) and 36% to 76% of the hospital nurses regard the different aspects of people-centred, integrated home care as attractive. Specific aspects that home-care nurses find attractive are promoting the patient's self-reliance and having a network in the community. Hospital nurses are mainly attracted to health-related prevention and taking control in complex situations. No clear differences between the educational levels were found. It is concluded that most home-care nurses and a minority of hospital nurses feel attracted to people centred, integrated home care, irrespective of their educational level. The findings are relevant to policy makers and home-care organisations who aim to expand the home-care nursing workforce. PMID- 29508474 TI - In Vitro Fracture Resistance of Adhesively Restored Molar Teeth with Different MOD Cavity Dimensions. AB - PURPOSE: Molar MOD (mesial-occlusal-distal) cavity preparation weakens relative cuspal stiffness by up to 63%, often resulting in cuspal fracture. This investigation inspects fracture resistance of MOD cavities restored using direct composite restoration. MATERIALS AND METHODS: 120 extracted, intact mandibular molars were selected. MOD cavities with different depth/wall thickness were prepared in 9 groups (n = 12): A: 3 mm/3.5 mm, B: 3 mm/2.5 mm, C: 3 mm/1.5 mm, D: 5 mm/3.5 mm, E: 5 mm/2.5 mm, F: 5 mm/1.5 mm, G: 7 mm/3.5 mm, H: 7 mm/2.5 mm, I: 7 mm/1.5 mm. Specimens with 7 mm deep cavities received root canal treatment. The teeth were restored with dental composite. Maximal fracture strength test was conducted. Intact natural teeth were used as control. For statistical analysis Kruskal-Wallis ANOVA with post-hoc pairwise comparisons was used (alpha = 0.05). RESULTS: Significant difference was indicated between the control and groups D, E, F, G, H, and I. No significant differences were found between the A, B, C groups and the control. Comparing the 5 and 7 mm cavity depth groups, there was no statistical difference between any of them. CONCLUSIONS: Within the limitations of this investigation, the following conclusions can be drawn regarding molar teeth with a MOD cavity: 3 mm or shallower cavities can be restored to the physiological fracture strength with direct composite restorations; 5 mm or deeper cavities cannot be restored to the physiological fracture strength with direct composite restorations. Cusp thickness does not significantly influence fracture strength in molar MOD cavities with a direct composite restoration. PMID- 29508475 TI - Effect of aripiprazole monotherapy in a patient presenting with delayed sleep phase syndrome associated with depressive symptoms. PMID- 29508476 TI - "Strangers in the ER": Quality indicators and third party interference in Dutch emergency care. AB - RATIONALE, AIMS, AND OBJECTIVES: This paper examines a remarkable dispute between Dutch insurers, hospitals, doctors, and patients about a set of quality indicators. In 2013, private insurers planned to drastically reform Dutch emergency care using quality indicators they had formulated drawing from clinical guidelines, RCTs, and systematic reviews. Insurers' plans caused much debate in the field of emergency care. As quality indicators have come to play a more central role in health care governance, the questions what constitutes good evidence for them, how they ought to be used, and who controls them have become politically and morally charged. This paper is a case study of how a Dutch public knowledge institution, the National Health Care Institute, intervened in this dispute and how they addressed these questions. METHOD: We conducted ethnographic research into the knowledge work of the National Health Care Institute. Research entailed document analysis, participant observation, in-depth conversations, and formal interviews with 5 key-informants. RESULTS: The National Health Care Institute problematized not only the evidence supporting insurers' indicators, but also-and especially-the scope, purpose, and use of the indicators. Our analysis shows the institute's struggle to reconcile the technical rationality of quality indicators with their social and political implications in practice. The institute deconstructed quality indicators as national standards and, instead, promoted the use of indicators in dialogue with stakeholders and their local and contextual knowledge. CONCLUSIONS: Even if quality indicators are based on scientific evidence, they are not axiomatically good or useful. Both proponents and critics of Evidence-based Medicine always feared uncritical use of evidence by third parties. For non-medical parties who have no access to primary care processes, the type of standardized knowledge professed by Evidence-based Medicine provides the easiest way to gain insights into "what works" in clinical practice. This case study reminds us that using standardized knowledge for the management of health care quality requires the involvement of stakeholders for the development and implementation of indicators, and for the interpretation of their results. PMID- 29508477 TI - Understanding cardiac shunts. AB - Most patients with congenital heart disease have a cardiac shunt whose direction and magnitude can have a major impact on cardiorespiratory physiology and function. The dynamics of the shunt can be significantly altered by anesthetic management and must be understood in order to provide optimal anesthetic care. Given that there are now more adults than children with congenital heart disease and that the majority of nonpediatric patients are cared for in centers without special expertise in congenital heart disease, it is imperative that all anesthesia providers have a general understanding of the subject. This educational review describes a technique to explain this complex subject using simple pictorial diagrams. PMID- 29508478 TI - Being we and being me: Exploring the needs of Austrian families with caring children. AB - Children and adolescents with caring responsibilities are an uncontested reality in our society. Most are hidden from public view, and they perform a broad range of caring activities for chronically ill or disabled family members. The research literature has accumulated a comprehensive body of knowledge about young carers' personal needs. However, knowledge and understanding are limited regarding the needs of young carers' families. This knowledge can contribute to preventing children and adolescents from assuming inappropriate caring roles. A qualitative research approach was used to investigate the needs of young carers' families in terms of managing daily caring demands. Nine family interviews were conducted with 34 individuals including 15 young carers during spring/summer 2015 in eastern Austria. Open and axial coding procedures and constant comparison method were used to analyse the data. The findings revealed that young carers' families need to live in accordance with their inherent family logic. Family logic is generated and maintained via (i) family reciprocity that involves the natural help within the family, (ii) individual developmental space that allows family members to be perceived and act as individuals and (iii) network cooperation that offers formal and informal support and recognition from society in general. The findings contribute to understanding how families with caring children manage the caring demands of their everyday lives. The findings also indicate that formal support for families with young carers should consider the individuality of caring arrangements with respect to the holistic and personal needs and avoid stigmatising families that integrate children into caring. PMID- 29508479 TI - Racism & Health: A public health perspective on racial discrimination. AB - Racial discrimination has been increasingly reported to have a causal link with morbidity and mortality of Black Americans, yet this issue is rarely addressed in a public health perspective. Racism affects health at different levels: institutional racism is a structural and legalized system that results in differential access to health services; cultural racism refers to the negative racial stereotypes, often reinforced by media, that results in poorer psychological and physiological wellbeing of the minorities. Lastly, interpersonal racism refers to the persistence of racial prejudice that seriously undermines the doctor-patient relationship. After analysing these concepts with examples and relevant studies, this paper explores current literature. Racism as a Determinant of Health: A Systematic Review and Meta-Analyses (Paradies et al, 2015) is the most recent and comprehensive research on the issue, yet it cannot be used to base public health interventions as it contains several limitations. Forward Through Ferguson: A Path Toward Racial Equity (Ferguson Commission, 2015) is a report that identifies 4 priority areas for framing public health interventions: Racial Equity, Justice for All, Youth at the Centre and Opportunity to Thrive. This study represents an important milestone in the application of public health on racial injustices, yet racism must be tackled with a sustained, multilevel, and interdisciplinary approach. In conclusion, this paper addresses how public health interventions can empower Black minorities and bring forward long-term policies. Racism is a structural and long-standing system that can be eliminated only with the collective effort. PMID- 29508480 TI - Identification of metastatic papillary thyroid carcinoma in FNA specimens using thyroid peroxidase immunohistochemistry. AB - INTRODUCTION: We evaluated immunohistochemical staining for thyroid peroxidase (TPO), a glycoprotein found in the apical plasma membrane of thyroid follicular cells, as a marker for metastatic PTC in FNA samples and compared results with thyroglobulin (Tg) and thyroid transcription factor 1 (TTF1) staining. METHODS: Cell block sections prepared from 100 FNA specimens were stained with a rabbit monoclonal antibody to TPO (EP159). The FNAs included 64 metastatic malignancies from non-thyroid primary sites, including 18 lung, and 36 cases of thyroid tumours (29 PTC, six cases of medullary thyroid carcinoma and one thyroid anaplastic carcinoma). Thyroid tumours were stained with TTF1 and Tg in addition to TPO. All cases of metastatic lung carcinoma also had TTF-1 staining results. RESULTS: TPO staining was negative in all non-thyroid malignancies. Ninety percent (26/29) of PTC were positive. All positive cases showed strong cytoplasmic staining, although 54% (14/26) showed positivity in less than half of the cells. By comparison, Tg staining of TPC cases was present in 62% and TTF-1 in 100%. In addition to showing higher sensitivity, interpretation of staining results with TPO was generally easier with than Tg. All metastatic lung adenocarcinomas were positive for TTF-1 and TPO negative. The six medullary cancers showed positivity in 17%, 0% and 83% with TPO, Tg and TTF-1, respectively. CONCLUSIONS: TPO (mAb EP159) may be a useful addition to immunohistochemical panels for FNA specimens where metastatic PTC is a consideration, particularly in cases where metastatic lung carcinoma features in the differential diagnosis. PMID- 29508481 TI - Longitudinal Improvement in Periodontal Parameters between RPD Abutment Teeth with Direct and Indirect Retainers, after Periodontal Therapy. AB - PURPOSE: To evaluate the effect of basic periodontal treatment on clinical periodontal parameters associated with abutment teeth of patients with mandibular Kennedy class I removable partial dentures (RPD) 18 months after treatment. MATERIALS AND METHODS: Thirty patients with periodontal disease were treated and evaluated according to the following periodontal parameters: visible plaque index (VPI), bleeding on probing (BOP), probing depth (PD), gingival recession (GR), clinical attachment loss (CAL), and keratinized mucosa (KM). These parameters were compared between abutment teeth with direct and indirect retainers at baseline, and after 6 and 18 months. Data were analyzed by Friedman Test and Wilcoxon Test for all variables. RESULTS: Most patients (n = 26; 86.7%) included in the study were female and had a mean age of 61 years (+/-7.54). Results showed that VPI and BOP decreased over time, and that VPI values were higher in abutment teeth with direct retainers (p = 0.001). There was a reduction in PD after 6 months, which was maintained up to 18 months. In general, abutment teeth with direct retainers had significantly higher values for PD, GR, and CAL (p = 0.029). Data also indicated that the parameters for VPI, BOP, and PD improved; however, abutment teeth with direct retainers presented smaller improvements, compared with abutment teeth with indirect retainers, which presented significant improvements for almost all variables. CONCLUSION: Periodontal treatment and oral hygiene care of patients were adequate for maintenance of adequate periodontal conditions, regardless of the use of prostheses. PMID- 29508482 TI - Use of pediatric Tracheal Stoma Retainer(r) in a 24-year-old spinal muscular atrophy patient. PMID- 29508483 TI - Barth syndrome associated with triple mutation. PMID- 29508484 TI - A psychometric evaluation of the Pediatric Anesthesia Emergence Delirium scale. AB - BACKGROUND: Emergence delirium and emergence agitation have been a subject of interest since the early 1960s. This behavior has been associated with increased risk of injury in children and dissatisfaction with anesthesia care in their parents. The Pediatric Anesthesia Emergence Delirium Scale is a commonly used instrument for codifying and recording this behavior. AIMS: The aim of this study was to psychometrically evaluate the Pediatric Anesthesia Emergence Delirium scale, focusing on the factor structure, in a sample of children recovering from anesthesia after surgery or diagnostic procedures. The reliability of the Pediatric Anesthesia Emergence Delirium scale was also tested. METHODS: One hundred and twenty-two children younger than seven years were observed at postoperative care units during recovery from anesthesia. Two or 3 observers independently assessed the children using the Pediatric Anesthesia Emergence Delirium scale. RESULTS: The factor analysis clearly revealed a one-factor solution, which accounted for 82% of the variation in the data. Internal consistency, calculated with Cronbach's alpha, was good (0.96). The Intraclass Correlation Coefficient, which was used to assess interrater reliability for the Pediatric Anesthesia Emergence Delirium scale sum score, was 0.97 (P < .001). The weighted kappa statistics were almost perfect in 4 of 5 items, with substantial agreement in the fifth (P < .001). CONCLUSION: The one-factor solution and the satisfactory reliability in terms of internal consistency and stability support the use of the Pediatric Anesthesia Emergence Delirium scale for assessing emergence delirium in children recovering from anesthesia after surgery or diagnostic procedures. The kappa statistics for the Pediatric Anesthesia Emergence Delirium scale items essentially indicated good agreement between independent raters, supporting interrater reliability. PMID- 29508485 TI - Erratum. PMID- 29508486 TI - Auricular Retentive Prosthetic Conformer Post Brent's Stage III Surgery in Microtia Repair: A Clinical Report. AB - Auricular reconstruction is an interdisciplinary approach where multiple specialties play a vital role in the treatment provided to the patient. This article provides a comprehensive interpretation of the process carried out for the fabrication of a custom-made prosthetic conformer for the management of postoperative contraction of a skin graft after ear reconstruction surgery-Brent stage III. The prosthesis is used as a precautionary measure and is simple, effective, and economical. PMID- 29508487 TI - Wear Characteristics and Volume Loss of CAD/CAM Ceramic Materials. AB - PURPOSE: In the field of prosthodontics, patients often require complex and extensive restorative care. This can involve the use of dental restorations to restore teeth on both the maxillary and mandibular arch. Current literature has evaluated the wear properties of different dental ceramics against enamel, but studies regarding dental ceramics opposing one another are limited. The purpose of this study was to assess the wear potential and wear behavior of CAD/CAM zirconia (ZR) and lithium disilicate (LD) materials against a similar ceramic material, and how the surface finish of these dental ceramics might affect patterns of wear. MATERIALS AND METHODS: Using a sphere-on-plate tribometer system, different surface finishes (glazed-G and glazed then polished-GP) of ZR and LD were evaluated following wear simulation. Artificial saliva of physiologic pH was used as a lubricant during wear simulation at 37 degrees C. The coefficient of friction (COF) was calculated during the wear simulation. After wear simulation was complete, volume loss, surface roughness, and surface characterization of the specimens were analyzed using white-light interferometry and scanning electron microscopy (SEM). Statistical significance between materials and surface finish was established with two-way ANOVA and Bonferroni post hoc test (alpha = 0.05). RESULTS: Based on the 2-way ANOVA, material (p = 0.002) significantly affected the COF. LD showed a higher COF (p = 0.002) than ZR. Material (p < 0.001) and surface finish (p = 0.004) significantly affected the surface roughness inside the scar. ZR had significantly lower surface roughness compared to LD (p < 0.001). For outside scar, surface finish (p < 0.001) significantly affected the surface roughness. Polished specimens showed significantly higher roughness compared to glazed specimens for both inside (p = 0.004) and outside scar (p < 0.001). For volume loss, material (p < 0.001) and the interaction between material and surface finish (p < 0.001) were statistically significant. LD had higher volume loss than ZR (p < 0.001). For both glazed and polished finished, LD-G and LD-GP had significantly higher volume loss than ZR-G (p = 0.028), and ZR-GP (p < 0.001), respectively. SEM analysis indicated particle build-up and a grooving mechanism of wear for the LD-GP specimens. This suggested a three-body wear phenomenon occurring for LD-GP specimens, which was not visible in SEM imaging for other specimen types. CONCLUSIONS: This study demonstrated the resistance to wear and low abrasiveness of ZR when compared to LD in a simulated masticatory environment. This can be best explained by the increased strength of ZR, and the introduction of three body wear to LD specimens from the accumulation of embedded wear debris onto its surface. Wear data and comparison of SEM images following wear simulation confirmed this interpretation. PMID- 29508488 TI - Three-Dimensional Digital Evaluation of the Fit of Endocrowns Fabricated from Different CAD/CAM Materials. AB - PURPOSE: A wide variety of CAD/CAM materials are available for single-tooth restorations. CAD/CAM material characteristics are different and may influence CAM fabrication accuracy. There is no study investigating the influence of different CAD/CAM materials on the final fit of the restoration. The aim of this study was to evaluate the fit of endocrowns fabricated from different CAD/CAM materials using a new 3D evaluation method with an intraoral scanning system. The null hypothesis was that there are no significant differences for the fitting accuracy of different CAD/CAM materials. MATERIALS AND METHODS: Preparation for an endocrown was performed on a maxillary right first molar on a typodont, and restorations were fabricated with a chairside CAD/CAM system (CEREC Omnicam, MCXL). Three groups using three different CAD/CAM materials were established (each n = 10): zirconia-reinforced lithium silicate ceramic (Celtra Duo; CD), leucite-reinforced silicate ceramic (Empress CAD; EM), resin nanoceramic (Lava Ultimate; LU). A 3D digital measurement technique (OraCheck, Cyfex AG) using an intraoral scanner (CEREC Omnicam) was used to measure the difference in fit between the three materials for a master endocrown preparation. The preparation scan and the endocrown fit scan were matched with special difference analysis software OraCheck. Three areas were selected for fitting accuracy measurements: margin (MA), axial (AX), occlusal (OC). Statistical analysis was performed using 80% percentile, one-way ANOVA, and post-hoc Scheffe test. Significance level was set to p = 0.05. RESULTS: Results varied from best 88.9 +/- 7.7 MUm for marginal fit of resin nanoceramic restorations (LU_MA) to worst 182.3 +/- 24.0 MUm for occlusal fit of zirconia-reinforced lithium silicate restorations (CD_OC). Statistically significant differences were found both within and among the test groups. Group CD performed statistically significantly different from group LU for marginal fit (MA) and axial fit (AX) (p < 0.05). For occlusal fit (OC), no statistically significant differences were found within all three test groups (p > 0.05). Deviation pattern for differences was visually analyzed with a color coded scheme for each restoration. CONCLUSIONS: Statistically significant differences were found for different CAD/CAM materials if the CAM procedure was identical. Within the limitations of this study, the choice of CAD/CAM material may influence the fitting accuracy of CAD/CAM-fabricated restorations. PMID- 29508489 TI - Portman Group response to Petticrew et al.: 'How alcohol industry organisations mislead the public about alcohol and cancer'. PMID- 29508491 TI - Egyptian Grave Goods of Kha and Merit Studied by Neutron and Gamma Techniques. AB - Artifacts from the Egyptian grave goods of Kha and Merit preserved at the Museo Egizio in Turin were studied through a combination of non-destructive and non invasive neutron and gamma techniques (namely neutron imaging, neutron diffraction and prompt gamma activation analysis). The results provide unprecedented morphological reconstructions of the inner parts of the two alabaster and metallic vases and their isotopic and phase composition, thereby extending our knowledge of the hitherto unknown content of the vases and their functions. PMID- 29508492 TI - Impact of educational outreach intervention on enhancing health care providers' knowledge about statin therapy prescribing in Malaysian patients with type 2 diabetes mellitus. AB - RATIONALE: Previous research reported underutilization of statin therapy among patients with type 2 diabetes mellitus. Improving health care providers' awareness and understanding of the benefits and risks of statin treatment could be of assistance in optimizing the statin prescribing process. AIMS AND OBJECTIVES: This study aimed to assess health care providers' knowledge related to statin therapy and the impact of educational outreach intervention based on the perceived knowledge. METHODS: This was a cross-sectional study based on educational outreach intervention targeting physicians and pharmacists in 1 major tertiary hospital in the state of Pahang, Malaysia. Participants responded to a 12-item, validated questionnaire both prior to and after the outreach educational program. Two sessions were conducted separately for 2 cohorts of pharmacists and physicians. The knowledge scores prior to and after the educational intervention were calculated and compared using a paired-samples t-test. RESULTS: The response rate to both pre-and post-educational outreach questionnaires was 91% (40/44). Prior to the intervention, around 84% (n37) of the participants decided to initiate statin therapy for both pre-assessment clinical case scenarios; however, only 27% (n12) could state the clinical benefits of statin therapy. Forty-five percent (n20) could state the drug to drug interactions, and 52.3% (n23) could identify the statin therapy that can be given at any time day/evening. The educational outreach program increased participants' knowledge scores of 1.450 (95% CI, 0.918 to 1.982) point, P < .0005, which is statistically significant. Forty respondents (91%) were of the opinion that statin side effects are the most common cause of treatment discontinuation. CONCLUSION: This work demonstrated the impact of an educational outreach intervention on improving health care providers' knowledge and beliefs about statin therapy. This type of intervention is considered effective for short-term knowledge enhancement. Further research is needed to test the long-term efficacy of such intervention. PMID- 29508493 TI - Survival analysis of dogs with advanced primary lung carcinoma treated by metronomic cyclophosphamide, piroxicam and thalidomide. AB - Unresectable or metastatic (advanced) primary pulmonary carcinoma (PPC) represents a therapeutic challenge where surgery may be contraindicated and the therapeutic role of maximum-tolerated dose (MTD) chemotherapy remains uncertain. This study was undertaken to explore the impact of metronomic chemotherapy (MC) in dogs with advanced PPC. Previously untreated dogs with advanced (T3 or N1 or M1) PPC, with complete staging work-up and follow-up data, receiving MC (comprising low-dose cyclophosphamide, piroxicam and thalidomide), surgery, MTD chemotherapy or no oncologic treatment were eligible for inclusion. For all patients, time to progression (TTP) and survival time (ST) were evaluated. Quality-of-life (QoL) was only evaluated in patients receiving MC. To assess QoL, owners of dogs receiving MC were asked to complete a questionnaire before and during treatment. Ninety-one dogs were included: 25 received MC, 36 were treated with surgery, 11 with MTD chemotherapy and 19 received no treatment. QoL was improved in dogs receiving MC. Median TTP was significantly longer in patients receiving MC (172 days) than patients undergoing surgery (87 days), receiving MTD chemotherapy (22 days), or no oncologic treatment (20 days). Median ST was similarly longer in patients receiving MC (139 days) than those undergoing surgery (92 days), MTD chemotherapy (61 days) and no oncologic treatment (60 days). In dogs with advanced PPC, MC achieved a measurable clinical benefit without significant risk or toxicity. This makes MC a potential alternative to other recognized management approaches. PMID- 29508494 TI - Phosphorylation of N-terminal regions of REV-ERBs regulates their intracellular localization. AB - Circadian rhythms are generated by the cyclic expression of several clock genes in mammals. The rhythmic expression of these genes is maintained by multiple transcriptional-translational feedback loops in addition to the posttranslational regulation of the clock proteins. Transcription of one of the key clock genes, Bmal1, which exhibits a nocturnal transcriptional rhythm in the suprachiasmatic nucleus of the mouse brain, is induced and repressed by RORs and REV-ERBs, respectively. Thus, the dynamics of the RORs and REV-ERBs expression, modification, subcellular localization and degradation of these transcriptional factors are critical for the transcriptional regulation of Bmal1. In this study, we found that the highly homologous N-terminal regions of REV-ERBalpha and REV ERBbeta determined both their own CK1-catalyzed phosphorylation and the cytoplasmic accumulation of each hyperphosphorylated form. Of the homologous N terminal regions, three serine-rich clusters in REV-ERBbeta are required for the phosphorylation and cytoplasmic localization. Our results indicate that the REV ERBs phosphorylation by CK1 plays a key role in their subcellular localization, thereby controlling the timings of the transcriptional activation and inhibition of Bmal1. PMID- 29508495 TI - A Supramolecular Polymer Network of Graphene Quantum Dots. AB - Graphene quantum dot (GQD)-organic hybrid compounds (GQD-2 b-e) were prepared by introducing 3,4,5-tri(hexadecyloxy)benzyl groups (C16) and linear chains terminated with a 2-ureido-4-[1H]-pyrimidinone (UPy) moiety onto the periphery of GQD-1. GQD-2 b-e formed supramolecular assemblies through hydrogen bonding between the UPy units. GPC analysis showed that GQDs with high loadings of the UPy group formed larger assemblies, and this trend was confirmed by DOSY and viscosity measurements. AFM images showed the polymeric network structures of GQD 2 e on mica with flat structures (ca. 1.1 nm in height), but no such structures were observed in GQD-2 a, which only carries the C16 group. GQD-2 c and GQD-2 d formed organogels in n-decanol, and the gelation properties can be altered by replacing the alkyl chains in the UPy group with ethylene glycol chains (GQD-3). GQD can thus be used as a platform for supramolecular polymers and organogelators by suitable chemical functionalization. PMID- 29508496 TI - Ultrashort Broadband Cooperative Pulses for Multidimensional Biomolecular NMR Experiments. AB - NMR spectroscopy at ultra-high magnetic fields requires improved radiofrequency (rf) pulses to cover the increased spectral bandwidth. Optimized 90 degrees pulse pairs were introduced as Ramsey-type cooperative (Ram-COOP) pulses for biomolecular NMR applications. The Ram-COOP element provides broadband excitation with enhanced sensitivity and reduced artifacts even at magnetic fields >1.0 GHz 1 H Larmor frequency (23 T). A pair of 30 MUs Ram-COOP pulses achieves an excitation bandwidth of 100 kHz with a maximum rf field of 20 kHz, more than three-fold improved compared to excitation by rectangular pulses. Ram-COOP pulses exhibit little offset-dependent phase errors and are robust to rf inhomogeneity. The performance of the Ram-COOP element is experimentally confirmed with heteronuclear multidimensional NMR experiments, applied to proteins and nucleic acids. Ram-COOP provides broadband excitation at low rf field strength suitable for application at current magnetic fields and beyond 23 T. PMID- 29508497 TI - Does genomic variation in a foundation species predict arthropod community structure in a riparian forest? AB - Understanding how genetic variation within a foundation species determines the structure of associated communities and ecosystem processes has been an emerging frontier in ecology. Previous studies in common gardens identified close links between intraspecific variation and multispecies community structure, and these findings are now being evaluated directly in the complex natural ecosystem. In this study, we examined to what extent genomic variation in a foundation tree species explains the structure of associated arthropod communities in the field, comparing with spatial, temporal and environmental factors. In a continuous mixed forest, arthropods were surveyed on 85 mature alders (Alnus hirsuta) in 2 years. Moreover, we estimated Nei's genetic distance among the alders based on 1,077 single nucleotide polymorphisms obtained from restricted-site-associated DNA sequencing of the alders' genome. In both years, we detected significant correlations between genetic distance and dissimilarity of arthropod communities. A generalized dissimilarity modelling indicated that the genetic distance of alder populations was the most important predictor to explain the variance of arthropod communities. Among arthropod functional groups, carnivores were consistently correlated with genetic distance of the foundation species in both years. Furthermore, the extent of year-to-year changes in arthropod communities was more similar between more genetically closed alder populations. This study demonstrates that the genetic similarity rule would be primarily prominent in community assembly of plant-associated arthropods under temporally and spatially variable environments in the field. PMID- 29508498 TI - Effect of Implant Position on Clinical and Radiographic Outcomes of Locator Retained Mandibular Overdentures: A 1-Year Prospective Study. AB - PURPOSE: To evaluate the influence of implant position on clinical and radiographic outcomes of Locator-retained mandibular overdentures MATERIALS AND METHODS: Fifteen edentulous participants with compromised bone at canine regions of the mandible were given 2 implants in the premolar areas (study group, PM). The control group (CA) consisted of 15 participants who received 2 implants in the canine regions, matched to PM and assigned as historical control. For study and control groups, mandibular dentures were constructed and attached to the fixtures with Locator attachments using the delayed loading protocol. Clinical (plaque scores, gingival scores, pocket depth, and implant stability) and radiographic (marginal bone loss) outcomes were assessed after denture delivery (T0), 6 months (T6), and 12 months (T12) later. RESULTS: The survival rate was 100% in both groups. All clinical and radiographic parameters increased significantly with time. No significant difference in plaque scores, gingival scores, or implant stability between groups was observed. PM group recorded significantly higher pocket depth and marginal bone loss than CA group at T6 and T12. CONCLUSIONS: Within the limits of this short-term clinical study, canine position for implants retaining mandibular overdentures with Locator attachments is preferred over the first premolar position, as it was associated with reduced peri-implant pocket depth and marginal bone loss after 1 year. PMID- 29508499 TI - Current use of antihypertensive drugs in Japanese patients with hypertension: Analysis by age group. AB - AIM: To analyze the current use of antihypertensive drug classes in Japanese hypertensive patients stratified by age, highlighting differences between older and younger patients. METHODS: A nationwide medical database was used to evaluate antihypertensive use in patients (aged >=20 years) who had received a prescription for one or more antihypertensive drug as an outpatient from April 2014 to March 2015. Patients (n = 59 867) were age-stratified into three groups: <65 years (28.7%), 65-74 years (33.1%) and >=75 years (38.2%). RESULTS: The mean number of antihypertensive drugs prescribed for patients in the overall population was 1.9 +/- 1.0, with no appreciable differences between age groups. The most commonly prescribed drug classes for all ages were calcium channel blockers (CCB) and angiotensin II receptor blockers (ARB). CCB were prescribed more often than ARB in the 65-74 years (66.9% vs 60.5%) and >=75 years (70.4% vs 56.8%) years age groups, and ARB were prescribed more often than CCB in patients aged <65 years (63.1% vs 61.9%). There were minimal differences by age in prescription rates for beta-blockers, angiotensin-converting enzyme inhibitors and thiazide diuretics. ARB prescription rates were lower in patients aged >=75 years with diabetes mellitus or renal disease than in younger age groups. Prescription rates for loop diuretics were higher in patients aged >=75 years than in younger age groups, especially among those with renal disease. CONCLUSIONS: Antihypertensive drugs selected for patients aged >=75 years differed from those selected for younger patients, in particular CCB and loop diuretics (prescribed more often), and ARB (prescribed less often). Geriatr Gerontol Int 2018; 18: 899-906. PMID- 29508500 TI - Stigma and its influencing factors among Chinese patients with stoma. AB - BACKGROUND: Although stomas are necessary for disease treatment, they unavoidably affect patients' lives from physical, psychological, social, spiritual, and familial perspectives and contribute to feelings of embarrassment and shame. This study explored the current status and factors influencing stigma among Chinese patients with stoma. METHODS: A total of 209 patients with stoma at the stoma clinic of a tertiary cancer centre in Guangzhou, China, were recruited and investigated by using the Social Impact Scale, the Coping Self-Efficacy Scale, the State Self-Esteem Scale, and a demographic questionnaire. Multivariate linear regression was used to identify the factors influencing stigma. RESULTS: The mean Social Impact Scale score was 69.65 +/- 13.18, which represents a moderate effect; specifically, 44% of the patients experienced high levels of stigma. Stoma patients with the following characteristics had high levels of stigma: young, low coping self-efficacy, low stoma acceptance by one's spouse or other family members, poor perceived body image, stool leakage, and no experience of participating in activities with other stoma patients. CONCLUSIONS: Medical staff members should pay more attention to stigma in stoma patients. Coping self efficacy, family members' acceptance of the stoma, and participation in activities with other stoma patients are influencing factors that protect these patients against stigma, whereas body image loss and stool leakage place them at higher risk for stigma. Interventions aimed at improving protective factors and decreasing risk factors should be considered to reduce the level of stigma in patients with stoma. PMID- 29508501 TI - Pore-Environment Engineering with Multiple Metal Sites in Rare-Earth Porphyrinic Metal-Organic Frameworks. AB - Multi-component metal-organic frameworks (MOFs) with precisely controlled pore environments are highly desired owing to their potential applications in gas adsorption, separation, cooperative catalysis, and biomimetics. A series of multi component MOFs, namely PCN-900(RE), were constructed from a combination of tetratopic porphyrinic linkers, linear linkers, and rare-earth hexanuclear clusters (RE6 ) under the guidance of thermodynamics. These MOFs exhibit high surface areas (up to 2523 cm2 g-1 ) and unlimited tunability by modification of metal nodes and/or linker components. Post-synthetic exchange of linear linkers and metalation of two organic linkers were realized, allowing the incorporation of a wide range of functional moieties. Two different metal sites were sequentially placed on the linear linker and the tetratopic porphyrinic linker, respectively, giving rise to an ideal platform for heterogeneous catalysis. PMID- 29508502 TI - Risk of Dental Implant Failure Associated With Medication Use. AB - PURPOSE: The probability of achieving important clinical outcomes is an increasingly important factor for patients considering various treatment options for tooth loss. For oral reconstruction involving dental implants, the patient specific risks of implant failure may be influenced by the patient's medication profile. The purpose of this study was to identify associations between dental implant failure and medication use in a consecutive series of patients seen from October 1983 through December 2014 at the Department of Dental Specialties, Mayo Clinic (Rochester, Minnesota). MATERIALS AND METHODS: In this patient-level analysis, demographic, implant-specific, and medical profile data were abstracted from a prospective clinical database and individual medical records and used to determine the time to first implant failure. Implant failure-free survival at the patient level was estimated using the Kaplan-Meier method. Associations of demographic characteristics and medication use with implant failure were evaluated by using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals. RESULTS: In the 31-year study period, 6358 patients received their first dental implant (median age, 53 years). The median follow-up duration of the 5645 patients whose implants did not fail was 5.8 years, and 713 patients had implant failure (median, 0.6 years). All associations were adjusted for age, sex, and era of implantation because these features strongly influence medication use and implant failure. After adjustment, no medication increased the risk of implant failure in the cohort; specifically, medication use at the time of implant placement or starting a medication after implant placement did not increase the risk of implant failure. Among the medications used at the time of implant placement, corticosteroids were associated with a reduced risk of implant failure (hazard ratio, 0.82; 95% CI, 0.67-0.99; p = 0.04). This association was not seen when corticosteroids were started after implant placement. CONCLUSION: In the population studied, medication use was not associated with an increased risk of dental implant failure. PMID- 29508503 TI - Beyond using composite measures to analyze the effect of unmet supportive care needs on caregivers' anxiety and depression. AB - OBJECTIVE: Caregiver research has relied on composite measures (eg, count) of unmet supportive care needs to determine relationships with anxiety and depression. Such composite measures assume that all unmet needs have a similar impact on outcomes. The purpose of this study is to identify individual unmet needs most associated with caregivers' anxiety and depression. METHODS: Two hundred nineteen caregivers completed the 44-item Supportive Care Needs Survey and the Hospital Anxiety and Depression Scale (minimal clinically important difference = 1.5) at 6 to 8 months and 1, 2, 3.5, and 5 years following the patients' cancer diagnosis. The list of needs was reduced using partial least square regression, and those with a variance importance in projection >1 were analyzed using Bayesian model averaging. RESULTS: Across time, 8 items remained in the top 10 based on prevalence and were labelled "core." Three additional ones were labelled "frequent," as they remained in the top 10 from 1 year onwards. Bayesian model averaging identified a maximum of 3 significant unmet needs per time point-all leading to a difference greater than the minimal clinically important difference. For depression, none of the core unmet needs were significant, rather significance was noted for frequent needs and needs that were not prevalent. For anxiety, 3/8 core and 3/3 frequent unmet needs were significant. CONCLUSIONS: Those unmet needs that are most prevalent are not necessarily the most significant ones, and findings provide an evidence-based framework to guide the development of caregiver interventions. A broader contribution is proposing a different approach to identify significant unmet needs. PMID- 29508504 TI - A RHAG point mutation selectively disrupts Rh antigen expression. AB - OBJECTIVES: The aim of this study was to characterise a novel mutation in the gene encoding RhAG in order to elucidate a molecular mechanism for Rh antigen expression and spherocytosis. BACKGROUND: Rhesus-associated glycoprotein (RhAG) is critical for maintaining the structure and stability of erythrocytes. Single missense mutations in the gene encoding RhAG are sufficient to induce spherocytosis and deficiencies in Rh complex formation. We report a novel missense mutation that incompletely disrupts Rh antigen expression and selectively knocks out RhD antigen expression. METHODS: Blood samples were taken from a 38-year-old male, his brother, his wife and his daughter in Xi'an, China. To detect the proband's RhAG and D antigen expression, the RBC were stained with anti-D and anti-RhAG and analysed by flow cytometry. Red blood cell morphology was detected with atomic force microscopy (AFM). Genomic DNA was isolated from whole blood samples, and the RHD, RHCE and RHAG alleles were sequenced and analysed. The mutation was mapped onto a predicted crystal structure of RhAG by the I-TASSER server and visualised using PyMOL. RESULTS: Morphological testing by AFM found clear evidence of spherocytosis in the proband's erythrocytes. RHAG gene sequencing identified the mutation at sequence 236G > A, resulting in a serine to asparagine substitution at residue 79 (S79N). Family survey indicated that inheriting this allele is necessary and sufficient to cause the condition. Mapping the mutation onto a predicted crystal structure of RhAG revealed the proximity of the mutation to the critical structural elements of the protein. CONCLUSIONS: A novel RHAG mutation significantly lowers RhAG antigen expression and antigen-mediated agglutination intensity. PMID- 29508505 TI - How an ordeal becomes the norm: A qualitative exploration of experiences of self cannulation in male home haemodialysis patients. AB - OBJECTIVES: Despite home haemodialysis (HHD) being associated with significant health and psychosocial benefits, it remains an under-utilized dialysis modality for people with chronic kidney disease. Self-cannulation, where patients insert their own needles for dialysis, is a key component of HHD. Recent research suggests that the prospect of self-cannulation is a barrier for patients, but there is little research which examines why this is the case. The aim of this study was to explore male HHD patients' experiences and attitudes towards self cannulation. DESIGN: Qualitative methods were adopted to gather in-depth views from experienced HHD patients from a UK renal centre. METHODS: Semi-structured interviews were conducted with eight male HHD patients (HHD duration: 12-55 months). During the interview, the researcher elicited participants' lived experience of self-cannulation. Topics included the decision to self-cannulate and the impact of self-cannulation on the patient. The data collected were analysed using interpretative phenomenological analysis. RESULTS: The findings from this study elucidate the process of how self-cannulation changed from an ordeal to the norm in these participants' lives. The central theme from these interviews is that 'becoming a person who self-cannulates is a process'. Three super-ordinate themes were discussed that relate to this central theme: 'gaining control', 'building confidence', and 'becoming the norm'. CONCLUSIONS: The findings from this study suggest that some patients' initial fears of self cannulation can be overcome. These findings offer health care professionals and patients alike a greater understanding of how patients who self-cannulate conceptualize it and its role in their mental and physical health. Statement of contribution What is already known on this subject? Home haemodialysis is a cost effective form of renal replacement therapy which is under-utilized in the United Kingdom. Home haemodialysis is associated with positive health outcomes. Self cannulation is noted as a barrier to home haemodialysis. What does this study add? Describes the process by which male dialysis patients became proficient in self-cannulation. Highlights psychological mechanisms which may facilitate and maintain self-cannulation. Suggests practical techniques which can be incorporated into renal clinics and care plans. PMID- 29508507 TI - Genetic evaluation of reproductive potential in the Zatorska goose under a conservation program. AB - The aim of this study was to estimate the genetic parameters and inbreeding effect on the fertility, embryo mortality and hatchability traits in the Zatorska goose covered by the animal genetic resources conservation program. The material for this study contains information about results of hatching of 18 863 eggs from 721 dams and 168 sires, laid between 1998-2015. Genetic parameters were estimated based on the threshold animal model by the use of Restricted Maximum Likelihood and Gibbs sampling. The percentage of fertilized eggs ranged yearly between 37 80%. The percentage of embryo mortality was very low, ranging between 4.63 23.73%. The percentage of the hatched goslings from the total number of analyzed eggs was on average 33.18%, and 53.72% from fertilized eggs. On average based on both methods, the heritability estimates of the fertility, embryo mortality and hatchability reached 0.36, 0.07, 0.24 for males and 0.44, 0.11, 0.32 for females. The genetic trend had increasing tendency for fertility and hatchability and was stable for embryo mortality for both sexes. The obtained result shows that the Zatorska goose can be still maintained in the reserves of the local gene pool according to current rules and use in the local market as a breed with good reproductive potential. PMID- 29508506 TI - Beating-heart registration for organ-mounted robots. AB - BACKGROUND: Organ-mounted robots address the problem of beating-heart surgery by adhering to the heart, passively providing a platform that approaches zero relative motion. Because of the quasi-periodic deformation of the heart due to heartbeat and respiration, registration must address not only spatial registration but also temporal registration. METHODS: Motion data were collected in the porcine model in vivo (N = 6). Fourier series models of heart motion were developed. By comparing registrations generated using an iterative closest-point approach at different phases of respiration, the phase corresponding to minimum registration distance is identified. RESULTS: The spatiotemporal registration technique presented here reduces registration error by an average of 4.2 mm over the 6 trials, in comparison with a more simplistic static registration that merely averages out the physiological motion. CONCLUSIONS: An empirical metric for spatiotemporal registration of organ-mounted robots is defined and demonstrated using data from animal models in vivo. PMID- 29508508 TI - Elevated CO2 and water addition enhance nitrogen turnover in grassland plants with implications for temporal stability. AB - Temporal variation in soil nitrogen (N) availability affects growth of grassland communities that differ in their use and reuse of N. In a 7-year-long climate change experiment in a semi-arid grassland, the temporal stability of plant biomass production varied with plant N turnover (reliance on externally acquired N relative to internally recycled N). Species with high N turnover were less stable in time compared to species with low N turnover. In contrast, N turnover at the community level was positively associated with asynchrony in biomass production, which in turn increased community temporal stability. Elevated CO2 and summer irrigation, but not warming, enhanced community N turnover and stability, possibly because treatments promoted greater abundance of species with high N turnover. Our study highlights the importance of plant N turnover for determining the temporal stability of individual species and plant communities affected by climate change. PMID- 29508510 TI - Simple Synthesis of Functionalized 2-Phosphanaphthalenes. AB - A simple synthesis of sodium 2-phosphanaphthalene-3-olate (1) based on the extrusion of N2 from phthalazine using Na[OCP] is reported. This heterocycle can be readily functionalized at the negatively charged oxygen center using a variety of electrophilic substrates. The coordination chemistry of both 1 and its neutral derivatives was explored, revealing their facile use as P-donor ligands for late transition-metal complexes. PMID- 29508509 TI - Safety of intranasal human insulin: A review. AB - AIMS: To conduct a review in order to assess the safety of intranasal human insulin in clinical studies as well as the temporal stability of nasal insulin sprays. MATERIAL AND METHODS: An electronic search was performed using MEDLINE. We selected original research on intranasal human insulin without further additives in humans. The studies included could be of any design as long as they used human intranasal insulin as their study product. All outcomes and adverse side effects were extracted. RESULTS: A total of 38 studies in 1092 individuals receiving acute human intranasal insulin treatment and 18 studies in 832 individuals receiving human intranasal insulin treatment lasting between 21 days and 9.7 years were identified. No cases of symptomatic hypoglycaemia or severe adverse events (AEs) were reported. Transient local side effects in the nasal area were frequently experienced after intranasal insulin and placebo spray, while other AEs were less commonly reported. There were no reports of participants being excluded as a result of AEs. No instances of temporal stability of nasal insulin were reported in the literature. Tests on insulin that had been repacked into spray flasks showed that it had a chemical stability of up to 57 days. CONCLUSIONS: Our retrospective review of published studies on intranasal insulin did not reveal any safety concerns; however, there were insufficient data to ensure the long-term safety of this method of chronic insulin administration. Improved insulin preparations that cause less nasal irritation would be desirable for future treatment. PMID- 29508511 TI - A Regularly Channeled Lamellar Membrane for Unparalleled Water and Organics Permeation. AB - Lamellar membranes show exceptional molecular permeation properties of key importance for many applications. However, their design and development need the construction of regular and straight interlayer channels and the establishment of corresponding transport rate equation. The fabrication of a uniformly lamellar membrane is reported using double-layered Ti3 C2 Tx MXenes as rigid building blocks. This membrane possesses ordered and straight 2 nm channels formed via a direct self-stacking, in contrast to the conventional irregular ones from flexible sheets. Such channels permit precise molecular rejection and unparalleled molecular permeation. The permeance of water and organics by this membrane reached 2300 and 5000 L m-2 h-1 bar-1 , respectively. The molecular transfer mechanism in confined nanochannels, and the corresponding model equation are established, paving a way to nanoscale design of highly efficient channeled membranes for transport and separation applications. PMID- 29508512 TI - Electro-Controlled Living Cationic Polymerization. AB - Cationic polymerizations have long been industrialized; however, stimulus regulated cationic polymerization remains to be developed. An electrochemically controlled living cationic polymerization is presented for the first time. In the presence of external potential and organic-based electrocatalyst, a series of monomers can be polymerized under a cationic chain-transfer mechanism. The resulting polymers exhibit well-defined molecular mass, narrow dispersity, and good chain-end fidelity. By controlling the external potential to switch the electrocatalyst between its oxidized and reduced states, ON/OFF polymerization can be achieved. This method is a versatile way to a large range of monomers, including vinyl ether-type and p-substituted styrene-type monomers. Given the sustainability feature and broad interest of electrochemical synthetic techniques, we envisaged that this method would lead a new direction of external regulated living ionic polymerization. PMID- 29508514 TI - Erratum. PMID- 29508515 TI - Unexpected delayed complete atrioventricular block after Cardioband implantation. AB - The Cardioband system is a transcatheter direct annuloplasty device that is implanted in patients with severe symptomatic functional mitral regurgitation (MR) due to annulus dilatation and high surgical risk. This device covers the posterior two-thirds of the annulus, from the anterolateral to the posteromedial commissure, implanted in close proximity of the left circumflex artery, atrioventricular (AV) conduction system, and coronary sinus. We present the case of an 80-year-old-gentleman with prohibitive surgical risk, treated with Cardioband implantation for functional MR with an evident P1-P2 cleft and P2-P3 indentation, a relative contraindication to MitraClip implantation. We achieved procedural success with significative mitral annulus reduction (30% anteroposterior reduction from 37 to 26 mm) and MR reduction (from grade 4 to grade 1-2). A late onset Mobitz 2 AV block developed after 26 hr and evolved to complete AV block in the following day, requiring definitive biventricular pacemaker (PM). Less than 200 Cardioband implantations have been performed but, to our knowledge, this is the first reported AV block, possibly facilitated by the pre-existing bifascicular block, suggesting the opportunity of prolonged ECG monitoring after Cardioband like any other mechanical transcatheter structural intervention possibly affecting the AV conduction system. PMID- 29508513 TI - NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting. AB - Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator-activated receptor alpha (PPARalpha), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monooxygenase. These NHR-49 dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, with two of them making critical contributions to the oxidative stress resistance of wild-type and long-lived glp-1 mutants worms. Similar to its role in lipid metabolism, NHR-49 requires the mediator subunit mdt-15 to promote stress-induced gene expression. However, NHR-49 acts independently from the transcription factor hlh-30/TFEB that also promotes fmo-2 expression. We show that activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is also important for peroxide-induced expression of a subset of NHR-49-dependent genes that includes fmo-2. However, organic peroxide increases NHR-49 protein levels, by a posttranscriptional mechanism that does not require PMK-1 activation. Together, these findings establish a new role for the HNF4/PPARalpha-related NHR-49 as a stress-activated regulator of cytoprotective gene expression. PMID- 29508516 TI - Electron microscopy examination of platelet whole mount preparations to quantitate platelet dense granule numbers: Implications for diagnosing suspected platelet function disorders due to dense granule deficiency. AB - INTRODUCTION: Dense granule (DG) deficiency (DGD) is a feature of some platelet function disorders (PFD) with a prevalence similar to von Willebrand disease. Most laboratories assess for DGD using whole mount platelet preparations and electron microscopy (EM). We evaluated our experiences with this test and associations between DGD and bleeding. METHODS: Dense granule EM records for 2006 2017 were examined for patients and simultaneously tested controls, and for an overlapping PFD study cohort to evaluate findings and their relationship to bleeding. RESULTS: More patient than control samples had reduced DG counts (6.5% vs 0.3%, P < .01). DG counts showed no relationship to age or mean platelet volume and had acceptable within-subject variability that was higher for DGD than control participants (28% vs 12%). Repeat tests confirmed DGD in all persons with initial DG counts <4.0/platelet, but not in those with less severe reductions (4.0-4.8 DG/platelet) or normal DG counts (>=4.9 DG/platelet). Aggregometry and adenosine triphosphate release tests, respectively, had only ~52% and 70% sensitivity for DGD. Confirmed DGD by EM was associated with higher bleeding scores and a bleeding disorder. CONCLUSION: Whole mount EM is useful for the evaluation of suspected PFD due to DGD and detects abnormalities associated with bleeding. PMID- 29508517 TI - Generation and characterization of a mouse line carrying Reck-CreERT2 knock-in allele. AB - Reck encodes a membrane-anchored glycoprotein implicated in the regulation of extracellular metalloproteinases, Notch-signaling, and Wnt7-signaling and shown to play critical roles in embryogenesis and tumor suppression. Precise mechanisms of its actions in vivo, however, remain largely unknown. By homologous recombination, we generated a new Reck allele, ReckCreERT2 (MGI symbol: Reck). This allele is defective in terms of Reck function but expected to induce loxP-mediated recombination in the cells committed to express Reck. Similarity in the expression patterns of the ReckCreERT2 transgene and the endogenous Reck gene was confirmed in five tissues. In the adult hippocampus, induction of Reck expression after transient cerebral ischemia could be demonstrated using this allele. These results indicate the utility of this Cre driver allele in further studies. PMID- 29508518 TI - A multicenter post-marketing evaluation of the Elixir DESolve(r) Novolimus eluting bioresorbable coronary scaffold system: First results from the DESolve PMCF study. AB - OBJECTIVES: To date, experience with bioresorbable scaffolds (BRS) that elute agents other than everolimus is limited. Thus, a post-marketing clinical follow up study was conducted to evaluate the continued safety and effectiveness of the DESolve(r) NOVOLIMUSTM Eluting BRS as treatment for patients with stable coronary artery disease. BACKGROUND: The DESolve BRS combines a poly-l-lactide-based backbone with a biodegradable polylactide-based polymer and Novolimus, a macrocyclic lactone mTOR inhibitor. METHODS: One hundred and two patients (mean age 62 years, 77.5% male) were enrolled at 10 European sites. Comparison of baseline and post-procedural angiographic assessment was performed, and a device oriented composite endpoint (comprising cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) and rate of scaffold thrombosis at 12 months were examined. RESULTS: The device was successfully delivered and deployed in 98.2% (107/109) of the lesions, with two failures to cross the lesion. A total of 100 patients (109 lesions) were treated with a DESolve BRS. Post-procedural angiographic assessment indicated an in scaffold acute gain of 1.54 +/- 0.44 mm, with a reduction in % diameter stenosis from 61.00 +/- 11.29 to 12.69 +/- 0.44. At 12 months, the device-oriented composite endpoint had occurred in 3.0% (3/100) of patients, with 1.0% (1/100) experiencing scaffold thrombosis and myocardial infarction and 3.0% (3/100) undergoing target lesion revascularization. There were no cardiac deaths. CONCLUSIONS: Results through 12 months indicate that the DESolve BRS is a safe and effective treatment for coronary lesions, though larger, long-term prospective studies are needed. PMID- 29508519 TI - Caffeic Acid Phenethyl Ester Improves Metabolic Syndrome by Activating PPAR-gamma and Inducing Adipose Tissue Remodeling in Diet-Induced Obese Mice. AB - SCOPE: This study investigated the effects of caffeic acid phenethyl ester (CAPE), a bioactive component of honeybee hives, on the prevention and treatment of metabolic syndrome (MetS) by comparing the efficacy of CAPE intake at the beginning of obesity and after obesity. The functional mechanism of CAPE was also investigated. METHODS AND RESULTS: C57BL/6 mice were fed a high-fat diet (HFD) containing 0.05% CAPE (HFD+C) for 12 weeks (HFD+C(Pre) group) or received HFD+C for 6 weeks after consuming the HFD for 6 weeks (HFD+C(Post) group). Both CAPE fed groups showed significant improvements in body weight, fatty liver, inflammation, and insulin resistance, but not serum lipid levels. Hyperlipidemia was only ameliorated in the HFD+C(Pre). Adipose tissue (AT) remodeling occurred in the CAPE-fed groups. Specifically, CAPE induced PPAR-gamma activation, resulting in adipogenesis, a smaller and more uniform distribution of adipocytes, and decreased immune cell penetration and inflammation; CAPE also improved the disturbed pattern of adipokine secretion. Hypoxia was improved by promoting angiogenesis in AT. CONCLUSION: CAPE ameliorates metabolic disease by inducing PPAR-gamma activation and AT remodeling. Additionally, this study reveals that the intake of CAPE after obesity, as well as in the early stage of obesity, helps in the prevention and treatment of MetS. PMID- 29508520 TI - Sugary Kefir Strain Lactobacillus mali APS1 Ameliorated Hepatic Steatosis by Regulation of SIRT-1/Nrf-2 and Gut Microbiota in Rats. AB - SCOPE: Non-alcoholic fatty liver disease (NAFLD) is a common disease that is concomitant with obesity, resulting in increased mortality. To date, the efficiency of NAFLD treatment still needs to be improved. Therefore, we aimed to evaluate the effect of Lactobacillus mali APS1, which was isolated from sugary kefir, on hepatic steatosis in rats fed a high-fat diet (HFD). METHODS AND RESULTS: Sprague Dawley rats were fed a control diet, a HFD with saline, and a HFD with APS1 intervention by gavage daily for 12 weeks. The results showed that APS1 significantly reduced body weight and body weight gain in HFD-fed rats. APS1 reduced hepatic lipid accumulation by regulating SIRT-1/PGC-1alpha/SREBP-1 expression. Moreover, APS1 increased hepatic antioxidant activity by modulating Nrf-2/HO-1 expression. Notably, APS1 manipulated the gut microbiota, resulting in increasing proportions of the phylum Bacteroidetes/Firmicutes and reducing the abundance of specific NAFLD-associated bacteria. CONCLUSION: These results suggested that APS1 ameliorated hepatic steatosis by modulating lipid metabolism and antioxidant activity via manipulating specific NAFLD-associated gut microbiota in vivo. PMID- 29508521 TI - Oxa[7]superhelicene: A pi-Extended Helical Chromophore Based on Hexa-peri hexabenzocoronenes. AB - A novel pi-extended "superhelicene" based on hexa-peri-hexabenzocoronenes (HBCs) has been synthesized by an efficient four-step synthetic procedure starting from diphenyl ether. Comprehensive structural analysis of the helicene was performed by NMR spectroscopy and mass spectrometry measurements together with X-ray analysis. Physicochemical analysis of the superhelicene and suitable HBC references revealed it had outstanding fluorescent features with quantum yields of over 80 %. PMID- 29508522 TI - Medication recommendation by physiotherapists: A survey of Quebec physiotherapists' opinions regarding a new interprofessional model of care with pharmacists. AB - BACKGROUND: To improve the efficiency of the health care system, new interprofessional models of care are emerging. In 2015, two provincial professional colleges, regulating the practice of physiotherapists and that of pharmacists in the province of Quebec, Canada, developed a new interprofessional model of care. This model is designed to guide non-prescription medication recommendations by physiotherapists treating patients in primary care with neuromusculoskeletal disorders (NMSKD) with the collaboration of pharmacists. PURPOSE: To assess Quebec physiotherapists' interests to use this model and explore their opinions concerning their ability to recommend non-prescription medications to patients in primary care with NMSKD. METHODS: An email invitation to complete an electronic survey was sent in February 2016 to all the Ordre professionnel de la physiotherapie du Quebec's registered physiotherapists. The survey included a questionnaire with 31 questions divided into 5 sections. Descriptive analyses and Chi-square tests (chi2 ) were performed to compare proportions (%) across demographic and clinical characteristics. RESULTS: Two hundred twenty-five physiotherapists completed the full survey. Of these, 70% of respondents knew of the model of care, but only 15% had previously used it. Perceived workload increase was one major reason reported for this lack of use (51%). Most of the respondents had a positive perception of this model and interactions with pharmacists and were confident regarding their ability to safely recommend medication (63%). However, 63% believed that further training was necessary to enable physiotherapists to provide efficient and safe non prescription medication recommendations to patients with NMSKD. CONCLUSIONS: Overall, physiotherapists have a positive perception of this model, but there remain opportunities for increased integration into practice. Most respondents believe that additional training is required regarding non-prescription medication recommendations. PMID- 29508523 TI - Impact of resilience and job involvement on turnover intention of new graduate nurses using structural equation modeling. AB - AIMS: Nurses' turnover intention is not just a result of their maladjustment to the field; it is an organizational issue. This study aimed to construct a structural model to verify the effects of new graduate nurses' work environment satisfaction, emotional labor, and burnout on their turnover intention, with consideration of resilience and job involvement, and to test the adequacy of the developed model. METHODS: A cross-sectional study and a structural equation modelling approach were used. A nationwide survey was conducted of 371 new nurses who were working in hospitals for <=18 months between July and October, 2014. RESULTS: The final model accounted for 40% of the variance in turnover intention. Emotional labor and burnout had a significant positive direct effect and an indirect effect on nurses' turnover intention. Resilience had a positive direct effect on job involvement. Job involvement had a negative direct effect on turnover intention. Resilience and job involvement mediated the effect of work environment satisfaction, emotional labor, and burnout on turnover intention. CONCLUSION: It is important to strengthen new graduate nurses' resilience in order to increase their job involvement and to reduce their turnover intention. PMID- 29508524 TI - Weight management programmes: Re-analysis of a systematic review to identify pathways to effectiveness. AB - BACKGROUND: Previous systematic reviews of weight management programmes (WMPs) have not been able to account for heterogeneity of effectiveness within programmes using top-down behavioural change taxonomies. This could be due to overlapping causal pathways to effectiveness (or lack of effectiveness) in these complex interventions. Qualitative comparative analysis (QCA) can help identify these overlapping pathways. METHODS: Using trials of adult WMPs with dietary and physical activity components identified from a previous systematic review, we selected the 10 most and 10 least effective interventions by amount of weight loss at 12 months compared to minimal treatment. Using intervention components suggested by synthesis of studies of programme user views, we labelled interventions as to the presence of these components and, using qualitative comparative analysis, developed pathways of component combinations that created the conditions sufficient for interventions to be most effective and least effective. RESULTS: Informed by the synthesis of views studies, we constructed 3 truth tables relating to quality of the user-provider relationship; perceived high need for guidance from providers; and quality of the relationship between peers in weight management programmes. We found effective interventions were characterized by opportunities to develop supportive relationships with providers or peers, directive provider-led goal setting and components perceived to foster self-regulation. CONCLUSIONS: Although QCA is an inductive method, this innovative approach has enabled the identification of potentially critical aspects of WMPs, such as the nature of relationships within them, which were previously not considered to be as important as more concrete content such as dietary focus. PMID- 29508525 TI - Secretome Analysis Identifies Potential Pathogenicity/Virulence Factors of Tilletia indica, a Quarantined Fungal Pathogen Inciting Karnal Bunt Disease in Wheat. AB - Tilletia indica is a smut fungus that incites Karnal bunt in wheat. It has been considered as quarantine pest in more than 70 countries. Despite its quarantine significance, there is meager knowledge regarding the molecular mechanisms of disease pathogenesis. Moreover, various disease management strategies have proven futile. Development of effective disease management strategy requires identification of pathogenicity/virulence factors. With this aim, the present study was conducted to compare the secretomes of T. indica isolates, that is, highly (TiK) and low (TiP) virulent isolates. About 120 and 95 protein spots were detected reproducibly in TiK and TiP secretome gel images. Nineteen protein spots, which were consistently observed as upregulated/differential in the secretome of TiK isolate, were selected for their identification by MALDI TOF/TOF. Identified proteins exhibited homology with fungal proteins playing important role in fungal adhesion, penetration, invasion, protection against host derived reactive oxygen species, production of virulence factors, cellular signaling, and degradation of host cell wall proteins and antifungal proteins. These results were complemented with T. indica genome sequence leading to identification of candidate pathogenicity/virulence factors homologs that were further subjected to sequence- and structure-based functional annotation. Thus, present study reports the first comparative secretome analysis of T. indica for identification of pathogenicity/virulence factors. This would provide insights into pathogenic mechanisms of T. indica and aid in devising effective disease management strategies. PMID- 29508526 TI - Standardized training for AVT pacing in paediatric patients with postoperative junctional ectopic tachycardia. AB - BACKGROUND: Junctional ectopic tachycardia is a serious complication of surgery for paediatric congenital heart disease. R-wave synchronized atrial (AVT) pacing, an innovative temporary pacing technique, restores atrioventricular synchrony in these patients. The method is highly effective but technically complex. A standardized training model exists for doctors but not for paediatric intensive care nurses. AIMS: This study seeks to evaluate whether a standardized programme involving simulation and vignettes increases knowledge of AVT pacing and accuracy of its documentation, as well as recognition and management of specific complications. STUDY DESIGN: This study was an experimental simulation test with before and after descriptive evaluation. METHODS: A custom-made simulation model was used in combination with standardized training. Before and after training, 10 paediatric nurse specialists were asked to document pacing, to identify complications and to intervene as necessary. Four clinical scenarios were presented: effective AVT pacing, ineffective AVT pacing, pacing with narrow interval between atrial pacing and ventricular sensing and pacemaker-induced tachycardia. Identification and management of complications were evaluated using a 3-point scale. RESULTS: Training improved the quality of documentation and complication management. At outset, documentation by 1 of 10 participants was completely correct, and after training, documentation by 8 of 10 participants was completely correct. Before training, 30% of interpretations of the four presented clinical scenarios were correct (12/40) versus 83% (33/40) after training. The decision to notify a doctor of a complication was correct in 83% (33/40) before versus 95% (38/40) after the training. CONCLUSION: Standardized simulation training improves quality and safety in AVT pacing, with more accurate documentation of the pacing mode and better recognition and management of specific complications during pacing. RELEVANCE TO CLINICAL PRACTICE: AVT pacing should be performed in conjunction with standardized simulation training in paediatric cardiac intensive care units. PMID- 29508527 TI - Trabecular bone microstructure and mineral density in human residual ridge at various intervals over a long period after tooth extraction. AB - BACKGROUND: Long-term changes of trabecular microstructure in human tooth extraction socket have not been investigated. PURPOSE: To examine the trabecular microstructure of human residual ridges at various intervals following tooth extraction, and to determine whether bone remodeling activity can attain points of relative stability and when such points are reached. MATERIALS AND METHODS: Forty-four bone biopsy specimens were obtained from lower molar or premolar regions of residual ridges. Postextraction times ranged from 1.6 to 360 months. Samples were analyzed using micro-computed tomography and three-dimensional bone morphometry with histological analyses. Trabecular bone parameters were plotted against postextraction times, and a stepwise piecewise linear regression analysis was performed to determine at which points of time these parameters either increased or decreased. RESULTS: Using piecewise linear regression, "inflection points" were found in most trabecular bone parameters between 7 and 12 months postextraction. Among the residual ridge samples, woven trabecular structure became mature, consisting of thick lamellar trabeculae with sufficient bone density, under dynamic bone remodeling until the 7th to 12th month post-tooth extraction. After this period, the mature network structure remained stable with low remodeling activity. CONCLUSION: Bone remodeling of trabecular structure in human residual ridge after tooth extraction had a stabilization period. PMID- 29508528 TI - Epidemiology and clinical presentation of feline cataracts in france: A retrospective study of 268 cases. AB - OBJECTIVE: To describe the epidemiology and the clinical presentation of cataracts in a population of cats in France. PROCEDURES: A review of medical records of cats presented to the Ophthalmology Unit of the National Veterinary School of Alfort between January 2010 and June 2017 was carried out to identify cats affected by cataracts. The signalment of affected cats, medical history, etiology of cataract, age of onset, stage of development, location of opacities, and concurrent ocular lesions were evaluated. RESULTS: Of 2054 cats which were presented to the Ophthalmology Unit of the National Veterinary School of Alfort during the study period, 268 (383 eyes) were diagnosed with a cataract (13%; CI [11.3-14.7]). The median age of all cats affected by cataract was 9.5 years (range: 0.1-18.6 years). Eighteen breeds were represented. The recorded causes of cataract were uveitis (35.8%), congenital (15.7%), aging (10.8%), presumed hereditary (8.2%), trauma (7.8%), lens luxation (3.3%), glaucoma (1.5%) and diabetes mellitus (0.4%). In 16.4% of the cases, the etiology could not be determined. The domestic short-hair was significantly overrepresented in cats with uveitis-related cataract (P < .001). The most common ocular lesions associated with cataracts were lens subluxation or luxation (17.8%), glaucoma (14.9%), and retinal detachment (4.4%). Lens subluxation/luxation and glaucoma were also significantly associated with uveitis-related cataract (P < .001). CONCLUSIONS: In a French population of referred cats, 13% were affected by cataract. The main causes identified were anterior uveitis, congenital, and aging. Lens subluxation/luxation and glaucoma were associated with uveitis related cataract. PMID- 29508529 TI - Sensitivity study of an automated system for daily patient QA using EPID exit dose images. AB - The dosimetric consequences of errors in patient setup or beam delivery and anatomical changes are not readily known. A new product, PerFRACTION (Sun Nuclear Corporation), is designed to identify these errors by comparing the exit dose image measured on an electronic portal imaging device (EPID) from each field of each fraction to those from baseline fraction images. This work investigates the sensitivity of PerFRACTION to detect the deviation caused by these errors in a variety of realistic scenarios. Integrated EPID images were acquired in clinical mode and saved in ARIA. PerFRACTION automatically pulled the images into its database and performed the user-defined comparison. We induced errors of 1 mm and greater in jaw, multileaf collimator (MLC), and couch position, 1 degrees and greater in collimation rotation (patient yaw), 0.5-1.5% in machine output, rail position, and setup errors of 1-2 mm shifts and 0.5-1 degrees roll rotation. The planning techniques included static, intensity modulated radiation therapy (IMRT) and VMAT fields. Rectangular solid water phantom or anthropomorphic head phantom were used in the beam path in the delivery of some fields. PerFRACTION detected position errors of the jaws, MLC, and couch with an accuracy of better than 0.4 mm, and 0.5 degrees for collimator rotation error and detected the machine output error within 0.2%. The rail position error resulted in PerFRACTION detected dose deviations up to 8% and 3% in open field and VMAT field delivery, respectively. PerFRACTION detected induced errors in IMRT fields within 2.2% of the gamma passing rate using an independent conventional analysis. Using an anthropomorphic phantom, setup errors as small as 1 mm and 0.5 degrees were detected. Our work demonstrates that PerFRACTION, using integrated EPID image, is sensitive enough to identify positional, angular, and dosimetric errors. PMID- 29508530 TI - Interactive value-based curriculum: a pilot study. AB - BACKGROUND: Current health care costs are unsustainable, with a large percentage of waste attributed to doctor practices. Medical educators are developing curricula to address value-based care (VBC) in education. There is, however, a paucity of curricula and assessments addressing levels higher than 'knows' at the base of Miller's pyramid of assessment. Our objective was to: (1) teach residents the principles of VBC using active learning strategies; and (2) develop and pilot a tool to assess residents' ability to apply principles of VBC at the higher level of 'knows how' on Miller's pyramid. METHODS: Residents in medicine, medicine-paediatrics and medicine-dermatology participated in a 5-week VBC morning report curriculum using active learning techniques. Early sessions targeted knowledge and later sessions emphasised the application of VBC principles. Medical educators are developing curricula to address value-based care in education RESULTS: Thirty residents attended at least one session and completed both pre- and post-intervention tests, using a newly developed case based assessment tool featuring a 'waste score' balanced with 'standard of care'. Residents, on average, reduced their waste score from pre-intervention to post intervention [mean 8.8 (SD 6.3) versus mean 4.7 (SD 4.6), p = 0.001]. For those who reduced their waste score, most maintained or improved their standard of care. DISCUSSION: Our results suggest that residents may be able to decrease health care waste, with the majority maintaining or improving their management of care in a case-based assessment after participation in the curriculum. We are working to further incorporate VBC principles into more morning reports, and to develop further interventions and assessments to evaluate our residents at higher levels on Miller's pyramid of assessment. PMID- 29508531 TI - Electronic tool helps anaesthesia trainee handovers. AB - BACKGROUND: Handovers in patient care are increasingly common occurrences in medicine and are highly susceptible to communication failures. Intraoperative anaesthesiology handovers are especially challenging because of concurrent management of the patient. Our goal was to develop and use an electronic handover checklist as an educational tool to teach anaesthesiology trainees a standardised method of handing over a case intraoperatively. We hypothesised that the use of the checklist would systematically enhance the transfer of accurate and complete information. METHODS: Thirty-four anaesthesia trainees were observed giving an intraoperative handover without the checklist, and then again with the checklist at a later time. An observational handover assessment tool was used by investigators to mark each item as either spontaneously relayed by the giver, elicited by the receiver, not discussed or not applicable to the case. After the use of the checklist, each handover giver filled out a survey related to his or her perceptions of the checklist. RESULTS: The proportion of items spontaneously relayed increased from 54% without the checklist to 98% when using the checklist (p < 0.0001). More than 90% of participants felt that the checklist increased handover efficiency and communication skills. All participants stated that the handovers were more thorough with the checklist and that they would incorporate it into their daily practice. Intraoperative anaesthesiology handovers are especially challenging because of concurrent management of the patient DISCUSSION: With the intervention of the checklist, our results show that the use of a standardised intraoperative checklist improved the transfer of important patient information among anaesthesia trainees. PMID- 29508532 TI - Cardiovascular self-management support program for preventing cardiovascular complication behaviors and clinical outcomes in the elderly with poorly controlled type 2 diabetes mellitus in Indonesia: A pilot study. AB - AIM: The aim of the study was to determine the feasibility, and to evaluate the effect of, a cardiovascular self-management support program by applying the 5A's self-management support program on preventing cardiovascular complication behaviors and to assess the clinical outcomes in the elderly with poorly controlled type 2 diabetes mellitus (DM). METHODS: This pilot study used a quasi experimental study design. Twelve elderly persons with poorly controlled type 2 DM were assigned into either a control or experimental group, with six participants in each group. The Preventing Cardiovascular Complication Behaviors (PCCB) was measured by the Preventing Cardiovascular Complication Behaviors Questionnaire, while the clinical outcomes were measured by clinical devices that were provided. These measurements were conducted and compared at baseline and 6 weeks after the completion of the program. The self-management support program was a 6 week program with several implementation methods, based on the 5A's self management support program. RESULTS: The participants who received the cardiovascular self-management support program reported a significant improvement in their PCCB and clinical outcomes, compared to those receiving the usual care. CONCLUSION: This study revealed that a cardiovascular self-management support program that applies the 5A's self-management support program is feasible for implementation. PMID- 29508533 TI - Comparison of the MHC I Immunopeptidome Repertoire of B-Cell Lymphoblasts Using Two Isolation Methods. AB - Significant technological advances in both affinity chromatography and mass spectrometry have facilitated the identification of peptides associated with the major histocompatibility complex class I (MHC I) molecules, and enabled a greater understanding of the dynamic nature of the immunopeptidome of normal and neoplastic cells. While the isolation of MHC I-associated peptides (MIPs) typically used mild acid elution (MAE) or immunoprecipitation (IP), limited information currently exists regarding their respective analytical merits. Here, a comparison of these approaches for the isolation of two different B-cell lymphoblast cell models is presented, and it is reported on the recovery, reproducibility, scalability, and complementarity of identification from each method. Both approaches yielded reproducible datasets for peptide extracts obtained from 2 to 100 million cells, with 2016 to 5093 MIPs, respectively. The IP typically provides up to 6.4-fold increase in MIPs compared to the MAE. The comprehensiveness of these immunopeptidome analyses is extended using personalized genomic database of B-cell lymphoblasts, and it is discovered that 0.4% of their respective MIP repertoire harbored nonsynonymous single nucleotide variations (also known as minor histocompatibility antigens, MiHAs). PMID- 29508534 TI - Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues. AB - The total synthesis of siladenoserinol A, an inhibitor of the p53-Hdm2 interaction, has been achieved. AuCl3 -catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner-Wadsworth-Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid-labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53 Hdm2 interaction. PMID- 29508535 TI - Design and development of a phantom for tomosynthesis with potential for automated analysis via the cloud. AB - This paper describes Development of a Phantom for Tomosynthesis with Potential for Automated Analysis via the Cloud. Several studies are underway to investigate the effectiveness of Tomosynthesis Mammographic Image Screening, including the large TMIST project as funded by the National Cancer Institute https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci supported/tmist. The development of the phantom described in this paper follows initiatives from the FDA, the AAPM TG245 task group, and European Reference Organization (EUREF) for Quality Assured Breast Screening and Diagnostic Services Committee report noting, that no formal endorsement nor recommendation for use has been sought, or granted by any of these groups. This paper reports on the possibility of using this newly developed Tomosynthesis Phantom for Quality Assurance, field testing of image performance, including remote monitoring of DBT system performance, e.g., via transmission over the cloud. The phantom includes tests for: phantom positioning and alignment (important for remote analysis), scan geometry (x and y), chest wall offset, scan slice width and Slice Sensitivity Profile (SSP(z)) slice geometry (slice width), scan slice incrementation (z), z axis geometry bead, low contrast detectability using low contrast spheres, spatial resolution via Point Spread Function (PSF), Image uniformity, Signal to Noise Ratio (SNR), and Contrast to Noise Ratio (CNR) via readings over an Aluminum square. The phantom is designed for use with automated analysis via transmission of images over the cloud and the analysis package includes test of positioning accuracy (roll, pitch, and yaw). Data are shown from several commercial Tomosynthesis Scanners including Fuji, GE, Hologic, IMS Giotti, and Siemens; however, the focus of this paper is on phantom design, and not in general aimed at direct commercial comparisons, and wherever possible the identity of the data is anonymized. Results of automated analysis of the phantom are shown, and it is demonstrated that reliable analysis of such a phantom can be achieved remotely, including transmission of data through the cloud. PMID- 29508536 TI - Chronic myeloid leukemia, BCR-ABL1-positive with CALR and MPL mutations. PMID- 29508537 TI - Multiband modulation spectroscopy for the determination of sex and species of mosquitoes in flight. AB - We present a dual-wavelength polarimetric measurement method to distinguish species and sexes of disease transmitting mosquitoes in flight. By measuring co- and de-polarized backscattered light at 808 and 1550 nm, the degree of linear polarization, wingbeat frequency, reflectance, spectral ratio and glossiness of mosquitoes can be retrieved. Body and wing contributions to these signals can be separated. Whereas the optical cross section is sensitive to the aspect of observation, thus the heading direction of the insect in flight, we demonstrate that polarimetric- and spectral-band ratios are largely invariant to the aspect of observation. We show that wing glossiness, as well as wing- and body-spectral ratios are particularly efficient in distinguishing Anopheles coluzzii and Anopheles arabiensis, 2 closely related species of malaria vectors. Spectral and polarimetric ratios relate to microstructural and melanization features of the wing and body of these species. We conclude that multiband modulation spectroscopy is a useful expansion of the parameter space that can be used to improve the specificity of entomological lidars. PMID- 29508538 TI - Does the tumour microenvironment alter tumorigenesis and clinical response in transmissible venereal tumour in dogs? AB - The canine transmissible venereal tumour (CTVT) is a transmissible cancer that is spread naturally between dogs, with the ability to develop and evade the immune system, despite strict immune surveillance of the host. Furthermore, molecular signalling between cells of the immune system and the tumour microenvironment appear to influence the behaviour and development of the tumour. Thus, this study aimed to quantify the expression of genes related to the immune system such as IL 6, IFN-gamma, and TGF-beta, as well as angiogenic factors (VEGF, CXCR4), in CTVT cells in vivo and in vitro (primary culture), correlating with the clinical response of the animals treated with vincristine. As expected, the most prevalent subtype was plasmacytoid cells, although lymphocytic cells were also found, indicating the possibility of polyclonality. When we compared the gene expressions of IFN-gamma and IL-6, we mostly found low expression, concluding that MHC expression was probably not occurring in tumour cells, and no activation of immune cells to eliminate the tumour. The TGF-beta gene was normal in the majority of animals but demonstrated decreased expression in vincristine resistant animals, leading to the hypothesis that the concentration of tumour derived TGF-beta was affecting and even suppressing the real TGF-beta expression, favouring tumour proliferation and progression in these cases. VEGF expression was extremely high, demonstrating its angiogenic role in tumour growth, while CXCR4 was decreased, possibly because of CTVT's low metastatic potential. Thus, we concluded that the tumour microenvironment, together with the immune system of the host, influences CTVT, presumably altering its tumorigenesis and the animal's clinical response to treatment. PMID- 29508540 TI - Tailoring Fluorescence Emission of Diketopyrrolopyrrole Dyes by an Aggregation induced Emission Coupled Excited-state Intramolecular Proton Transfer Process. AB - Two diketopyrrolopyrrole derivatives (DPP1 and DPP2) are used for generating multiple luminescent colors (yellow-orange-red-deep red) in solution, nanoparticle, aggregate and solid states through an aggregation-induced emission (AIE) coupled excited-state intramolecular proton transfer (ESIPT) process. They are potentially useful for bioimaging due to their good biocompatibility and large Stoke shifts. PMID- 29508539 TI - Desperately seeking a cure: Treatment seeking and appraisal in irritable bowel syndrome. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is common and adversely affects patients' quality of life. Multiple potential treatment options exist for patients (and clinicians) to choose from, with limited evidence to inform treatment selection. The aim was to explore how patients with IBS go about seeking and appraising different treatment modalities, with a view to elucidating the psychological processes involved and identifying opportunities to improve clinical practice. DESIGN: Qualitative study nested within a randomized controlled trial of therapist-delivered and web-based cognitive behavioural therapy versus treatment-as-usual for IBS. METHODS: A total of 52 people participated in semi-structured interviews about their prior experiences of treatments for IBS. Transcripts were analysed using inductive thematic analysis. RESULTS: Key themes (desperation for a cure, disappointment at lack of cure, appraising the effects of diverse treatments, and hope for positive effects) clustered around an overarching theme of being trapped within a vicious cycle of hope and despair on treatment seeking. A desperation and willingness drove interviewees to try any treatment modality available that might potentially offer relief. Coming to accept there is no cure for IBS helped interviewees escape the vicious cycle. Treatments were appraised for their effects on symptoms and quality of life while also considering, but rarely prioritizing, other aspects including convenience of the regimen itself, whether it addressed the perceived root causes of IBS, perceived side-effects, and cost. CONCLUSION: Treatment seeking in IBS can be challenging for patients. Supportive discussions with health care professionals about illness perceptions, treatment beliefs, and goals could improve patients' experiences. Statement of contribution What is already known on this subject? Irritable bowel syndrome (IBS) is a highly prevalent chronic relapsing functional gastrointestinal disorder. Studies show few treatment modalities provide complete symptom relief. IBS is associated with emotional and physical distress, and negatively impacts personal, social, and professional aspects of quality of life. What does this study add? Patients appraise IBS treatments for impact on quality of life and treatment characteristics. Developing acceptance and coping strategies helps escape treatment-seeking vicious cycles of hope and despair. Clinicians could better support patients by discussing their illness perceptions, treatment goals, and values. PMID- 29508541 TI - Early experience with totally robotic esophagectomy for malignancy. Surgical and oncological outcomes. AB - BACKGROUND: Over recent decades, minimally invasive esophagectomy has gained popularity and is increasingly performed worldwide. The aim of this work was to investigate the perioperative, clinicopathologic, and oncological outcomes of robot-assisted esophagectomy on a consecutive series of totally robotic procedures. METHODS: All patients received either an Ivor Lewis or a McKeown procedure according to tumor location. Perioperative, clinicopathologic and oncological outcomes were examined. RESULTS: A total of 38 patients underwent robot-assisted esophagectomy procedures. All underwent surgery for primary esophageal neoplasms. Neoadjuvant therapy was given to 22 patients. R0 resections were achieved in all patients and no conversion to open surgery occurred. Overall morbidity and mortality were 42% and 10%, respectively. The 1 year disease free survival was 78.9%, whereas the 1 year overall survival was 84.2%. CONCLUSIONS: Robotic surgery can be employed to treat esophageal malignancy competently. Robotic esophagectomy satisfies all features of pathologic appropriateness and offers the expected oncological results. PMID- 29508542 TI - One-Step Hydrothermal Synthesis of Nitrogen-Doped Conjugated Carbonized Polymer Dots with 31% Efficient Red Emission for In Vivo Imaging. AB - Carbon dots with long-wavelength emissions, high quantum yield (QY) and good biocompatibility are highly desirable for biomedical applications. Herein, a green, facile hydrothermal synthesis of highly efficient red emissive nitrogen doped carbonized polymer dots (CPDs) with optimal emission at around 630 nm are reported. The red emissive CPDs possess a variety of superior properties including excellent water dispersibility, good biocompatibility, narrow bandwidth emission, an excitation-independent emission, and high QY (10.83% (in water) and 31.54% (in ethanol)). Further studies prove that such strong red fluorescence is ascribed to the efficient conjugated aromatic pi systems and hydrogen bonds of CPDs. And the fluorescence properties of CPDs can be regulated by adjusting the dosage of HNO3 before the reaction. Additionally, the as-prepared CPDs are successfully used as a fluorescent probe for bioimaging, both in vitro and in vivo. More importantly, biodistribution results demonstrate that most CPDs and their metabolites are not only excreted in urine but also excreted by hepatobiliary system in a rapid manner. Besides, the CPDs could easily cross the blood brain barrier, which may provide a valuable strategy for the theranostics of some brain diseases through real-time tracking. PMID- 29508543 TI - Photothermally Controlled MHC Class I Restricted CD8+ T-Cell Responses Elicited by Hyaluronic Acid Decorated Gold Nanoparticles as a Vaccine for Cancer Immunotherapy. AB - Cancer vaccines aim to induce a strong major histocompatibility complex class I (MHC-I)-restricted CD8+ cytotoxic T-cell response, which is an important prerequisite for successful cancer immunotherapy. Herein, a hyaluronic acid (HA) and antigen (ovalbumin, OVA)-decorated gold nanoparticle (AuNPs)-based (HA-OVA AuNPs) vaccine is developed for photothermally controlled cytosolic antigen delivery using near-infrared (NIR) irradiation and is found to induce antigen specific CD8+ T-cell responses. Chemical binding of thiolated HA and OVA to AuNPs facilitates antigen uptake of dendritic cells via receptor-mediated endocytosis. HA-OVA-AuNPs exhibit enhanced NIR absorption and thermal energy translation. Cytosolic antigen delivery is then permitted through the photothermally controlled process of local heat-mediated endo/lysosome disruption by laser irradiation along with reactive oxygen species generation, which helps to augment proteasome activity and downstream MHC I antigen presentation. Consequently, the HA-OVA-AuNPs nanovaccine can effectively evoke a potent anticancer immune response in mice under laser irradiation. This NIR-responsive nanovaccine is promising as a potent vaccination method for improving cancer vaccine efficacy. PMID- 29508545 TI - Quality of life assessment of patients utilizing orbital implant-supported prostheses. AB - STATEMENT OF PROBLEM: Evaluate the effect of orbital prosthesis retained by implants through a specific quality of life (QOL) questionnaire provides important information on patients QOL, great incentive for the multidisciplinary team and public health support to continue work in this area. PURPOSE: The objective of the study was to evaluate patient satisfaction with orbital implant supported prostheses using an adapted quality of life questionnaire. MATERIALS AND METHODS: Forty five patients using orbital implant-supported prostheses for a period ranging from six to 120 months. The subjects answered a questionnaire that consisted of 10 questions covering appearance, retention, conspicuousness, self confidence, difficulty of placement, difficulty of removal, cleaning, limitation of activities, discomfort of tissues, and recommendation of the method to other patients. Answers were expressed using a visual 100-mm scale. The arithmetic mean of the responses was converted into a percentage to represent the satisfaction index. RESULTS: Patients demonstrated a high level of satisfaction on all items, with the lowest rate being for aesthetics and the highest being for recommending the method to other patients. High satisfaction rates regarding the placement and removal of the prosthesis, discomfort to the tissues, and cleaning suggest the ease of handling of the prosthesis. High satisfaction with retention, self confidence, conspicuousness of the prosthesis, and limitation of activities indicated an association with a better social life. CONCLUSIONS: The results showed that use of bone anchorage technique of extraoral prostheses provided a high level of satisfaction among patients, confirming that osseointegrated implants are a very important resource for the rehabilitation of orbital deformities. PMID- 29508544 TI - Generation and characterization of Lhx3GFP reporter knockin and Lhx3loxP conditional knockout mice. AB - LHX3, a LIM-homeodomain transcription factor, is broadly expressed in the developing pituitary, spinal cord, medulla, retina and inner ear, and plays essential roles during embryonic development. Mice with homozygous Lhx3 null mutation exhibit failure in the formation of pituitary gland and die perinatally. To facilitate the functional study of Lhx3 in mice, we engineered and characterized two novel Lhx3 mouse strains: Lhx3GFP reporter knock-in and Lhx3loxP conditional knockout mice. Coimmunolabeling of LHX3 and GFP shows that the expression pattern of the knock-in GFP reporter recapitulates that of endogenous LHX3 in cochlea, vestibule, retina, and spinal cord. By crossing Lhx3loxP mice with the ubiquitous CMV-Cre mice, we have demonstrated a high efficiency of Cre recombinase-mediated removal of exons 3 to 5 of Lhx3, which encode the second LIM-domain and the HD domain of LHX3, resulting global knockout of Lhx3. Thus, Lhx3GFP and Lhx3loxP mice serve as valuable genetic tools to dissect the tissue-specific roles of Lhx3 at late-gestation and postnatal stages in mice. PMID- 29508546 TI - COMP report: CPQR technical quality control guidelines for accelerator-integrated cone-beam systems for verification imaging. AB - The Canadian Organization of Medical Physicists, in close partnership with the Canadian Partnership for Quality Radiotherapy has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology. This article presents the quality control guideline accelerator-integrated cone-beam systems for verification imaging that has resulted from this process. PMID- 29508547 TI - Advances and Opportunities in Nanoparticle- and Nanomaterial-Based Vaccines against Bacterial Infections. AB - As the dawn of the postantibiotic era we approach, antibacterial vaccines are becoming increasingly important for managing bacterial infection and reducing the need for antibiotics. Despite the success of vaccination, vaccines remain unavailable for many pressing microbial diseases, including tuberculosis, chlamydia, and staphylococcus infections. Amid continuing research efforts in antibacterial vaccine development, the advancement of nanomaterial engineering has brought forth new opportunities in vaccine designs. With increasing knowledge in antibacterial immunity and immunologic adjuvants, innovative nanoparticles are designed to elicit the appropriate immune responses for effective antimicrobial defense. Rationally designed nanoparticles are demonstrated to overcome delivery barriers to shape the adaptive immunity. This article reviews the advances in nanoparticle- and nanomaterial-based antibacterial vaccines and summarizes the development of nanoparticulate adjuvants for immune potentiation against microbial pathogens. In addition, challenges and progress in ongoing antibacterial vaccine development are discussed to highlight the opportunities for future vaccine designs. PMID- 29508548 TI - Effectiveness of various isometric exercises at improving bone strength in cortical regions prone to distal tibial stress fractures. AB - A computational model was used to compare the local bone strengthening effectiveness of various isometric exercises that may reduce the likelihood of distal tibial stress fractures. The developed model predicts local endosteal and periosteal cortical accretion and resorption based on relative local and global measures of the tibial stress state and its surface variation. Using a multisegment 3-dimensional leg model, tibia shape adaptations due to 33 combinations of hip, knee, and ankle joint angles and the direction of a single or sequential series of generated isometric resultant forces were predicted. The maximum stress at a common fracture-prone region in each optimized geometry was compared under likely stress fracture-inducing midstance jogging conditions. No direct correlations were found between stress reductions over an initially uniform circular hollow cylindrical geometry under these critical design conditions and the exercise-based sets of active muscles, joint angles, or individual muscle force and local stress magnitudes. Additionally, typically favorable increases in cross-sectional geometric measures did not guarantee stress decreases at these locations. Instead, tibial stress distributions under the exercise conditions best predicted strengthening ability. Exercises producing larger anterior distal stresses created optimized tibia shapes that better resisted the high midstance jogging bending stresses. Bent leg configurations generating anteriorly directed or inferiorly directed resultant forces created favorable adaptations. None of the studied loads produced by a straight leg was significantly advantageous. These predictions and the insight gained can provide preliminary guidance in the screening and development of targeted bone strengthening techniques for those susceptible to distal tibial stress fractures. PMID- 29508549 TI - Biowaste-Derived Hierarchical Porous Carbon Nanosheets for Ultrahigh Power Density Supercapacitors. AB - Low-cost activated carbons with high capacitive properties remain desirable for supercapacitor applications. Herein, a three-dimensional scaffolding framework of porous carbon nanosheets (PCNSs) has been produced from a typical biowaste, namely, ground cherry calyces, the specific composition and natural structures of which have contributed to the PCNSs having a very large specific surface area of 1612 m2 g-1 , a hierarchical pore size distribution, a turbostratic carbon structure with a high degree graphitization, and about 10 % oxygen and nitrogen heteroatoms. A high specific capacitance of 350 F g-1 at 0.1 A g-1 has been achieved in a two-electrode system with 6 m KOH; this value is among the highest specific capacitance of biomass-derived carbon materials. More inspiringly, a high energy density of 22.8 Wh kg-1 at a power density of 198.8 W kg-1 can be obtained with 1 m aqueous solution of Li2 SO4 , and an ultrahigh energy density of 81.4 Wh kg-1 at a power density of 446.3 W kg-1 is realized with 1-ethyl-3 methylimidazolium tetrafluoroborate electrolyte. PMID- 29508550 TI - Detection of bovine coronavirus in nasal swab of non-captive wild water deer, Korea. AB - Bovine coronavirus (BCoV) is a causative agent of respiratory and enteric diseases in cattle and calves. BCoV infection was also evident in captive wild ruminants. Recently, water deer are recognized as the most common wildlife to approach farmhouses and livestock barns in Korea. Therefore, we investigated 77 nasal swab samples from non-captive wild water deer (Hydropotes inermis) between November 2016 and September 2017 and identified three samples positive for coronavirus, indicating potential for respiratory shedding. The full genomic sequences of the water deer coronavirus were closely related to BCoV (>98%). Therefore, effective biosecurity system in bovine farms would be necessary to prevent contact between farm ruminants and free-ranging wild water deer. PMID- 29508551 TI - Fluorocarbon Separation in a Thermally Robust Zirconium Carboxylate Metal-Organic Framework. AB - Fluorocarbons have important applications in industry, but are environmentally unfriendly, and can cause ozone depletion and contribute to the global warming with long atmospheric lifetimes and high global warming potential. In this work, the metal-organic framework UiO-66(Zr) is demonstrated to have excellent performance characteristics to separate fluorocarbon mixtures at room temperature. Adsorption isotherm measurements of UiO-66(Zr) display high fluorocarbon sorption uptakes of 5.0 mmol g-1 for R22 (CHClF2 ), 4.6 mmol g-1 for R125 (CHF2 CF3 ), and 2.9 mmol g-1 for R32 (CH2 F2 ) at 298 K and 1 bar. Breakthrough data obtained for binary (R22/R32 and R32/R125) and ternary (R32/R125/R134a) mixtures reveal high selectivities and capacities of UiO-66(Zr) for the separation and recycling of these fluorocarbon mixtures. Furthermore, the UiO-66(Zr) saturated with R22 and R125 can be regenerated at temperatures as low as 120 degrees C with excellent desorption-adsorption cycling stabilities. PMID- 29508552 TI - Coexistence of JAK2 or CALR mutation is a rare but clinically important event in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. AB - INTRODUCTION: There are 7 designated conditions under the category of myeloproliferative neoplasms (MPN), including chronic myelogenous leukemia (CML) and classical MPN, that is, polycythemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF). Recently, reports about Philadelphia and JAK2 V617F-positive MPN cases have been described in literature. The coexistence of different molecular defects may change the clinical and laboratory manifestation of MPN and may result in an inappropriate interpretation of the response to treatment with tyrosine kinase inhibitors in CML patients. METHODS: The morphological, cytogenetic, and molecular genetic data from a retrospective analysis of 592 adult patients aged 18-86 years diagnosed with CML were analyzed. RESULTS: In 5 CML patients, the presence of JAK2 V617F or CALR mutation was confirmed. Three of 4 TKI-treated patients did not reach complete hematologic response due to the persistence of thrombocytosis and/or splenomegaly. In all of them (in 3 with JAK2 V617F mutation and 1 with CALR mutation), thrombocytosis was present at the time when complete cytogenetic response was documented. In 3 out of 4 reported CML patients, thrombocytosis and/or splenomegaly were still present even at the time when deep molecular response was reached. CONCLUSION: In our opinion, a detailed evaluation and appropriate interpretation of clinical and laboratory data in such a category of patients seem to be extremely important, especially when a decision about the TKI change due to therapy failure is considered. PMID- 29508553 TI - Biocompatibility and osteoconductivity of PLCL coated and noncoated xenografts: An in vitro and preclinical trial. AB - BACKGROUND: Cells, scaffolds, and growth factors are the key components in bone tissue engineering. Scaffold composition, topography, and architecture influence the amount of regenerated bone in the implantation site. The aims of the study were to compare viability and proliferation of mesenchymal stem cells (MSCs) seeded onto two commercial xenografts: Bio-Oss (BO) and bioactive bone bovine (BB). Next, these materials were compared for histomorphometric bone formation in a socket preservation model in rats. MATERIALS AND METHODS: MSCs were seeded onto monolayers of BO or BB granules. Cell viability and proliferation were evaluated after incubation of 0, 2, 20, and 48 h. A total of 24 Sprague Dawley rats underwent unilateral extraction of maxillary molars. Rats were randomly divided into three groups: natural healing (nongrafted socket) or socket preservation with either BO or BB. Rats were sacrificed after 8 weeks, and histomorphometric analysis was done to evaluate bone formation and residual scaffold at the extraction site. RESULTS: Differences in the metabolic activity of MSCs that were seeded onto BO or BB was observed at 2 h after seeding: the metabolic activity was elevated compared to baseline in the BB (P = .046) and not changed in the BO wells (P = .84). After 20 h, the metabolic activity of MSCs seeded onto BO was decreasing (P = .005), while cell viability was not changed in the BB group (P = .356). Intergroup comparison revealed higher metabolic activity of MSCs seeded on BB after 48 h compared with BO (P = .016). The in vivo results demonstrated differences in socket healing between the groups: percentage of new bone was higher in the BB compared to BO group (39.1 +/- 14.3 vs. 23.7 +/- 10.8%, respectively, P = .096). Connective tissue portion was higher in the BO group compared with BB (73.7 +/- 11.1 vs. 49.6 +/- 13.7%, respectively, P = .018). Residual grafting martial was higher in the BB (11.34 +/- 4.18 vs. 2.62 +/- 1.23%, P = .011). CONCLUSIONS: The results of this study demonstrating higher vitality and proliferation of MSCs seeded onto BB. Furthermore, following ridge preservation, higher percentage of new bone and lower residual scaffold were found in the BB compared with BO. This enhanced regenerative response might be the result of an enhancement of metabolic activity in cells attached to it. Further research will be needed to understand the precise mechanism. PMID- 29508554 TI - Conceptually Novel Black Phosphorus/Cellulose Hydrogels as Promising Photothermal Agents for Effective Cancer Therapy. AB - Black phosphorus (BP) has recently emerged as an intriguing photothermal agent in photothermal therapy (PTT) against cancer by virtue of its high photothermal efficiency, biocompatibility, and biodegradability. However, naked BP is intrinsically characterized by easy oxidation (or natural degradation) and sedimentation inside the tumor microenvironment, leading to a short-term therapeutic and inhomogeneous photothermal effect. Development of BP-based nanocomposites for PTT against cancer therefore remains challenging. The present work demonstrates that green and injectable composite hydrogels based on cellulose and BP nanosheets (BPNSs) are of great efficiency for PTT against cancer. The resultant cellulose/BPNS-based hydrogel possesses 3D networks with irregular micrometer-sized pores and thin, strong cellulose-formed walls and exhibits an excellent photothermal response, enhanced stability, and good flexibility. Importantly, this hydrogel nanoplatform is totally harmless and biocompatible both in vivo and in vitro. This work may facilitate the development of BP-polymer-based photothermal agents in the form of hydrogels for biomedical related clinic applications. PMID- 29508555 TI - Internal Polarization Modulation in Bi2 MoO6 for Photocatalytic Performance Enhancement under Visible-Light Illumination. AB - A built-in electric field from polarization inside polar photocatalysts could provide the driving force for photogenerated electrons and holes to move in opposite directions for better separation to improve their photocatalytic performance. The photocatalytic performance of a polar photocatalyst of Bi2 MoO6 has been enhanced through the precise control of its structure to increase internal polarization. DFT calculations predicted that a shortened crystal lattice parameter b in Bi2 MoO6 could induce larger internal polarization, which was achieved by the modulation of the pH of the reaction solution during a solvothermal synthetic process. A series of Bi2 MoO6 samples were created with reaction solutions of pH~1, 4, and 8; the crystal lattice parameter b was found to decrease gradually with increasing solution pH. Accordingly, these Bi2 MoO6 samples demonstrated a gradually enhanced photocatalytic performance with decreasing crystal lattice parameter b, as demonstrated by the photocatalytic degradation of sulfamethoxazole/phenol and disinfection of Staphylococcus aureus bacteria under visible-light illumination due to improved photogenerated charge carrier separation. This study demonstrates an innovative design strategy for materials to further enhance the photocatalytic performance of polar photocatalysts for a broad range of technical applications. PMID- 29508556 TI - Short-term results of changes in existing and de novo lower urinary tract symptoms after robot-assisted laparoscopic uterosacral ligament suspension and sacrocolpopexy. AB - OBJECTIVE: This study presents short-term outcomes related to changes in existing and de novo lower urinary tract symptoms (LUTS), pelvic pain, and bowel function following robot-assisted laparoscopic uterosacral ligament suspension (RALUSLS) and sacrocolpopexy (RALSC). METHODS: Observational data for RALUSLS (n = 23) and RALSC (n = 25) collected between August 2014 and March 2016 from a single institute (The University of Texas Medical Branch) were evaluated retrospectively. Patient characteristics, concomitant procedures, and the occurrence of lower urinary tract, pelvic pain, and bowel symptoms were compared between patients undergoing RALUSLS and RALSC. RESULTS: There was no significant difference in background characteristics between the 2 groups, except for parity, which was high in the RALUSLS group. In the RALUSLS group, patients experienced significant resolution of urinary urgency (P < .001) and frequency, urge and mixed incontinence, and pelvic pain (P < .05). In the RALSC group, there was significant resolution of nocturia, mixed incontinence, pelvic pain, and dyspareunia (P < .05). There was no significant difference in the occurrence of de novo symptoms in the RALUSLS and RALSC groups (P > .05), although newly appearing urinary urgency or frequency and stress or urge incontinence were more common after RALSC. CONCLUSION: Mixed incontinence and pelvic pain improved significantly in patients after RALUSLS or RALSC. In RALUSLS patients, urgency, frequency, and urge incontinence also improved, whereas additional improvement in nocturia and dyspareunia was evident only in RALSC patients. De novo LUTS developing after these procedures, especially after RALSC, necessitate careful patient consultation prior to surgery. PMID- 29508557 TI - Nanoscaled Metal-Organic Frameworks for Biosensing, Imaging, and Cancer Therapy. AB - Owing to the progressive development of metal-organic frameworks (MOFs) synthetic processes and their unique characters associated with the excellent performance selectable composition, tunable pore scale, large surface area, and good thermal stability, MOFs have captured the interest and the imagination of an increasing number of scientists working in different fields. In the area of biomedical applications, MOFs are especially involved in sensing, molecular imaging, and drug delivery, with strong contributions to the whole nanomedicine area. Recently, these materials have been scaled down to nanometer sizes with the advancement of chemical synthesis gradually reaching an adjustable level. This review mainly discusses and summarizes the general synthesis, properties, and biomedical applications of nanoscaled MOFs and their composites in biosensing, imaging, and cancer therapy within the latest three years. The remaining challenges and future opportunities in this field, in terms of processing techniques, maximizing composite properties, and prospects for clinical applications, are also indicated. PMID- 29508558 TI - Platelet parameters in children with chromosome 22q11 deletion and conotruncal heart defects. AB - BACKGROUND AND OBJECTIVES: The 22q11 deletion syndrome is associated with a wide spectrum of phenotypic features, hence clinical diagnosis is difficult. Individuals with this syndrome are found to have a risk of developing transfusion associated graft-versus-host reaction, if they are given nonirradiated blood. Our aim was to elucidate whether chromosome 22q11 deletion in children with syndromic conotruncal heart defects is associated with platelet abnormality. MATERIALS AND METHODS: The genetic analysis was performed by standard cytogenetic and Fluorescence in situ hybridization technique. The platelet parameters in 39 patients with chromosome 22q11 deletion were compared with 154 cases without deletion. RESULTS: In deletion versus no deletion group, the mean of mean platelet volume (MPV) was 10.5 +/- 2.5 vs 7.6 +/- 1.5 fL, platelet count was 225 +/- 80.7 and 339 +/- 127.3 * 10 9 /L and frequency of high MPV was 49% vs 7% (P < .0001). The MPV was associated with a sensitivity of 90.9% and a specificity of 79.6% at a cutoff value of 8.32 fL, (area under the ROC curve 91%). A nonsignificant negative correlation was found between MPV and platelet count (r = -0.152; P = .361) in children with deletion. CONCLUSION: A cutoff value of 8.32 fL for MPV can be an indicator of high risk of chromosome 22q11 deletion in individuals with syndromic conotruncal defects. Individuals with chromosome 22q11 deletion should be given irradiated blood especially during cardiac surgery. Further investigation should clarify the etiology behind variation in frequency of high MPV in different conotruncal lesions. PMID- 29508559 TI - Spatio-temporal patterns of foot-and-mouth disease transmission in cattle between 2007 and 2015 and quantitative assessment of the economic impact of the disease in Niger. AB - Foot-and-mouth disease (FMD) is endemic in Niger, with outbreaks occurring every year. Recently, there was an increasing interest from veterinary authorities to implement preventive and control measures against FMD. However, for an efficient control, improving the current knowledge on the disease dynamics and factors related to FMD occurrence is a prerequisite. The objective of this study was therefore to obtain insights into the incidence and the spatio-temporal patterns of transmission of FMD outbreaks in Niger based on the retrospective analysis of 9-year outbreak data. A regression tree analysis model was used to identify statistically significant predictors associated with FMD incidence, including the period (year and month), the location (region), the animal-contact density and the animal-contact frequency. This study provided also a first report on economic losses associated with FMD. From 2007 to 2015, 791 clinical FMD outbreaks were reported from the eight regions of Niger, with the number of outbreaks per region ranging from 5 to 309. The statistical analysis revealed that three regions (Dosso, Tillabery and Zinder), the months (September, corresponding to the end of rainy season, to December and January, i.e., during the dry and cold season), the years (2007 and 2015) and the density of contact were the main predictors of FMD occurrence. The quantitative assessment of the economic impacts showed that the average total cost of FMD at outbreak level was 499 euros, while the average price for FMD vaccination of one outbreak was estimated to be more than 314 euros. Despite some limitations of the clinical data used, this study will guide further research into the epidemiology of FMD in Niger and will promote a better understanding of the disease as well as an efficient control and prevention of FMD. PMID- 29508560 TI - Brain structure alterations in depression: Psychoradiological evidence. AB - Depression is the leading cause of disability around the world, but little is known about its pathology. Currently, the diagnosis of depression is made based on clinical manifestations, with little objective evidence. Magnetic resonance imaging (MRI) has been used to investigate the pathological changes in brain anatomy associated with this disorder. MRI can identify structural alterations in depressive patients in vivo, which could make considerable contributions to clinical diagnosis and treatment. Numerous studies that focused on gray and white matter have found significant brain region alterations in major depressive disorder patients, such as in the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. The results are inconsistent and controversial because of the different demographic and clinical characteristics. However, some regions overlapped; thus, we think that there may be a "hub" in MDD and that an impairment in these regions contributes to disease severity. Brain connections contain both structural connections and functional connections, which reflect disease from a different view and support that MDD may be caused by the interaction of multiple brain regions. According to previous reports, significant circuits include the frontal-subcortical circuit, the suicide circuit, and the reward circuit. As has been recognized, the pathophysiology of major depressive disorder is complex and changeable. The current review focuses on the significant alterations in the gray and white matter of patients with the depressive disorder to generate a better understanding of the circuits. Moreover, identifying the nuances of depressive disorder and finding a biomarker will make a significant contribution to the guidance of clinical diagnosis and treatment. PMID- 29508561 TI - Phenylboronic Acid Functionalized Polycarbonate Hydrogels for Controlled Release of Polymyxin B in Pseudomonas Aeruginosa Infected Burn Wounds. AB - While physically crosslinked polycarbonate hydrogels are effective drug delivery platforms, their hydrophobic nature and lack of side chain functionality or affinity ligands for controlled release of hydrophilic drugs underscore the importance of their chemical compositions. This study evaluates an array of anionic hydrogel systems of phenylboronic acid functionalized triblock copolymers prepared via reversible physical interactions. Variation of key chemical functionalities while maintaining similar core structural features demonstrates the influence of the substitution position and protection of the boronic acid functionality on gel viscoelasticity and mechanical strength at physiological pH. The optimum gel systems obtained from the meta-substituted copolymers (m-PAP) are stable at physiological pH and nontoxic to mammalian dermal cells. The polymyxin B loaded m-PAP hydrogels demonstrate controlled in vitro drug release kinetics and in vitro antimicrobial activity against Pseudomonas aeruginosa over 48 h. In vivo antimicrobial efficacy of the drug loaded hydrogels further corroborates the in vitro results, demonstrating sustained antimicrobial activity against P. aeruginosa burn wound infections. The current strategy described in this study demonstrates a straightforward approach in designing physiologically relevant boronic acid hydrogel systems for controlled release of cationic antimicrobials for future clinical applications. PMID- 29508562 TI - Nocturnal oximetry in pediatric respiratory disease: Urgent need for developing standardized interpretation rules. PMID- 29508563 TI - Correction of saturation effects in endoscopic swept-source optical coherence tomography based on dual-channel detection. AB - Saturation artifacts that are commonly observed in endoscopic swept-source optical coherence tomography (SSOCT) images cause image degradation and loss of image information. We present work on the correction of saturation effects in endoscopic SSOCT imaging. This method utilizes a broadband power divider with excellent pick-off flatness to divide the detected interference signal into the two channels of an analog-to-digital converter. Based on the precise calibration of the splitting ratio between the two channels, the maximum measurable signal power of the system was drastically increased by using the low level signal in one channel to correct the saturated signal in the other channel. The experimental results demonstrated that this technique can efficiently correct the saturation artifacts in endoscopic two- and three-dimensional SSOCT images in an accurate and cost-effective manner. PMID- 29508564 TI - Volumetric imaging of rod and cone photoreceptor structure with a combined adaptive optics-optical coherence tomography-scanning laser ophthalmoscope. AB - We have designed and implemented a dual-mode adaptive optics (AO) imaging system that combines spectral domain optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) for in vivo imaging of the human retina. The system simultaneously acquires SLO frames and OCT B-scans at 60 Hz with an OCT volume acquisition time of 4.2 s. Transverse eye motion measured from the SLO is used to register the OCT B-scans to generate three-dimensional (3-D) volumes. Key optical design considerations include: minimizing system aberrations through the use of off-axis relay telescopes, conjugate pupil plane requirements, and the use of dichroic beam splitters to separate and recombine the OCT and SLO beams around the nonshared horizontal scanning mirrors. To demonstrate system performance, AO OCT-SLO images and measurements are taken from three normal human subjects ranging in retinal eccentricity from the fovea out to 15-deg temporal and 20-deg superior. Also presented are en face OCT projections generated from the registered 3-D volumes. The ability to acquire high-resolution 3-D images of the human retina in the midperiphery and beyond has clinical importance in diseases, such as retinitis pigmentosa and cone-rod dystrophy. PMID- 29508565 TI - Age-related morphological changes of the dermal matrix in human skin documented in vivo by multiphoton microscopy. AB - Two-photon fluorescence (TPF) and second harmonic generation (SHG) microscopy provide direct visualization of the skin dermal fibers in vivo. A typical method for analyzing TPF/SHG images involves averaging the image intensity and therefore disregarding the spatial distribution information. The goal of this study is to develop an algorithm to document age-related effects of the dermal matrix. TPF and SHG images were acquired from the upper inner arm, volar forearm, and cheek of female volunteers of two age groups: 20 to 30 and 60 to 80 years of age. The acquired images were analyzed for parameters relating to collagen and elastin fiber features, such as orientation and density. Both collagen and elastin fibers showed higher anisotropy in fiber orientation for the older group. The greatest difference in elastin fiber anisotropy between the two groups was found for the upper inner arm site. Elastin fiber density increased with age, whereas collagen fiber density decreased with age. The proposed analysis considers the spatial information inherent to the TPF and SHG images and provides additional insights into how the dermal fiber structure is affected by the aging process. PMID- 29508566 TI - Influence of material and haptic design on the mechanical stability of intraocular lenses by means of finite-element modeling. AB - Intraocular lenses (IOLs) are used in the cataract treatment for surgical replacement of the opacified crystalline lens. Before being implanted they have to pass the strict quality control to guarantee a good biomechanical stability inside the capsular bag, avoiding the rotation, and to provide a good optical quality. The goal of this study was to investigate the influence of the material and haptic design on the behavior of the IOLs under dynamic compression condition. For this purpose, the strain-stress characteristics of the hydrophobic and hydrophilic materials were estimated experimentally. Next, these data were used as the input for a finite-element model (FEM) to analyze the stability of different IOL haptic designs, according to the procedure described by the ISO standards. Finally, the simulations of the effect of IOL tilt and decentration on the optical performance were performed in an eye model using a ray-tracing software. The results suggest the major importance of the haptic design rather than the material on the postoperative behavior of an IOL. FEM appears to be a powerful tool for numerical studies of the biomechanical properties of IOLs and it allows one to help in the design phase to the manufacturers. PMID- 29508567 TI - [Establishment of response system to emergency parasitic disease affairs in China]. AB - China's prevention and control of parasitic diseases has made remarkable achievements. However, the prevalence and transmission of parasitic diseases is impacted by the complicated natural and social factors of environment, natural disasters, population movements, and so on. Therefore, there are still the risks of the outbreak of emergency parasitic diseases affairs, which may affect the control effectiveness of parasitic diseases and endanger the social stability seriously. In this article, we aim at the analysis of typical cases of emergency parasitic disease affairs and their impacts on public health security in China in recently years, and we also elaborate the disposal characteristics of emergency parasitic disease affairs, and propose the establishment of response system to emergency parasitic disease affairs in China, including the organizational structure and response flow path, and in addition, point out that, in the future, we should strengthen the system construction and measures of the response system to emergency parasitic disease affairs, so as to control the risk and harm of parasitic disease spread as much as possible and to realize the early intervention and proper disposal of emergency parasitic disease affairs. PMID- 29508568 TI - [Effect of comprehensive schistosomiasis control strategy with focus on cattle and sheep removal in Junshan District, Yueyang City]. AB - Objective To evaluate the effect of comprehensive schistosomiasis control measures with focus on total removal of cattle and sheep in Junshan District, Yueyang City. Methods The retrospective review and field survey were implemented in the pilot villages in Junshan District. The data of Schistosoma japonicum infection status of human, cattle, sheep and Oncomelania hupensis snails, and density of snails were gathered and modeled in the period of 2006 to 2016. Results The prevalence of schistosome infection in residents in the pilot villages decreased from 3.44% in 2006 to 0.59% in 2012 (F = 14.501, P = 0.013). After removal of all the cattle and sheep in 2013, the prevalence of schistosome infection in the residents decreased to zero in 2016 (F = 14.148, P = 0.033). The density of living snails decreased from 0.883 3/0.1 m2 in 2006 to 0.308 8/0.1 m2 in 2012 (F = 76.250, P = 0.005). Conclusion The comprehensive schistosomiasis control strategy with focus on cattle and sheep removal is remarkably effective. PMID- 29508569 TI - [Study on spatial - temporal characteristics of Schistosoma japonicum infections among human in Hunan Province, 2004-2011]. AB - Objective To explore the spatial-temporal characteristics and changing regularities of Schistosoma japonicum infections among human from 2004 to 2011. Methods The township level spatial databases of schistosomiasis in Hunan Province from 2004 to 2011 were established, and the related spatial analysis was performed by SPSS 17.0, ArcGIS 10.1 and SaTScan 7.03. Results The schistosome infection rate among human in Hunan Province sharply decreased from 3.0% in 2004 to 0.8% in 2011. However, the rate among residents in parts of some townships in 2011 was still hovering at a higher level (P90 = 2.12%), and the higher rate was distributed along the Oncomelania hupensis snail ridden areas outside embankment. The autocorrelation analysis showed that the global Moran's I for schistosome infection rate among human was 0.34 to 0.53 from 2004 to 2011, and was higher than the expected value (Z > 8.71, P < 0.05). The local G statistics indicated that the positive hotspot high-high clustering areas were mainly near the coast of Dongting Lake from 2004 to 2011, and the number of townships with schistosomiasis endemic in the clustering areas reached 30 to 70. The spatial scan analysis showed that the number of townships in the clustering areas ran up to 145 to 183 from 2004 to 2011. Conclusions The schistosome infection rate among human decreased significantly in Hunan Province from 2004 to 2011. However, the rate in parts of some townships still remains at a comparatively high level, and there are positive spatial correlation and spatial agglomerations in the schistosome infection rate among human, suggesting that the prevention and control work on schistosomiasis in these areas should be strengthened in the future. PMID- 29508570 TI - [Surveillance results and risk analysis of Schistosoma japonicum-infected sentinel mice in key water regions in Hubei Province in 2016]. AB - Objective To investigate the water infectivity in key water regions, and analyze the transmission risk of schistosomiasis in suspicious and high-risk environments in Hubei Province in 2016. Methods Schistosome-endemic areas of the Yangtze River, the Hanbei River and the Fu River were chosen as the surveillance and forecast sites. The water infectivity was detected by using the sentinel mice during the flood season. The infection status of residents in the villages around the surveillance sites and the activities of human beings and domestic animals were surveyed. The emergency response system was initiated when the water infectivity areas were detected. Results From May to June, among the ten surveillance sites of the first batch, two positive spots with infected mice were found, accounting for 20%. All the recovered mice (totally 200) were dissected: five mice were infected, with a total infection rate of 2.5%. Totally five schistosome adult worms were collected, with mean worm burden of 1 worm per infected mouse. The site with cercariae-infected water body started the emergency response and no epidemic occurred. From August to September, among the eight surveillance sites of the second batch, the recovered mice (totally 160) were dissected, and no infected sentinel mice were found. Conclusion The sentinel mice method plays an important role in analyzing the schistosomiasis transmission risk in Hubei Province. PMID- 29508571 TI - [Molluscicidal effect of suspension concentrate of niclosamide ethanolamine salt]. AB - Objective To evaluate the molluscicidal effect of suspension concentrate of niclosamide ethanolamine salt (SCNE) against Oncomelania hupensis snails in laboratory and field. Methods The experiment of SCNE against the snails by using the immersing and spraying methods was performed in laboratory and field, with control groups of wettable powder of niclosamide ethanolamine salt (WPN). Results In the laboratory, LC50(s) of SCNE for 24, 48 h and 72 h by using the immersion method were 0.092 6, 0.062 9 mg/L and 0.054 9 mg/L, respectively. The mortality rates of snails for 24, 48 h and 72 h by using the immersion method were all 100% with the concentrations of 0.25 mg/L. The mortality rates of snails were all 100% while spraying SCNE for 3 d in the laboratory with the concentrations of 0.25 g/m2. In Jiangling County, except 0.5 g/m3 SCNE immersing the snails for 24 h, the mortality rates of snails by using SCNE with the immersing method were all 100%. While the concentration of SCNE was 0.5 g/m3 or above, the mortality rates were all 100% after the use of it with the immersion method for 2 d in Gong'an County. In Jiangling County, the mortality rates of snails by using SCNE 0.5 g/m3 for 1 d, 3 d, and 7 d with the spraying method were 87.5%, 92.82% and 97.40% respectively. While the concentration of SCNE was 0.5 g/m3, the mortality rates were 85.94%, 86.78% and 94.21% respectively after the use of it with the spraying method for 1 d, 3 d, 7 d in Gong'an County, and the molluscicidal effect of SCNE (1.0 g/m2) was higher than that of WPN. Conclusion SCNE has a high molluscicidal effect in the laboratory and field, and it is a novel and simple formulation of niclosamide. PMID- 29508572 TI - [Study of spatial stratified sampling strategy of Oncomelania hupensis snail survey based on plant abundance]. AB - Objective To optimize and simplify the survey method of Oncomelania hupensis snails in marshland endemic regions of schistosomiasis, so as to improve the precision, efficiency and economy of the snail survey. Methods A snail sampling strategy (Spatial Sampling Scenario of Oncomelania based on Plant Abundance, SOPA) which took the plant abundance as auxiliary variable was explored and an experimental study in a 50 m*50 m plot in a marshland in the Poyang Lake region was performed. Firstly, the push broom surveyed data was stratified into 5 layers by the plant abundance data; then, the required numbers of optimal sampling points of each layer through Hammond McCullagh equation were calculated; thirdly, every sample point in the line with the Multiple Directional Interpolation (MDI) placement scheme was pinpointed; and finally, the comparison study among the outcomes of the spatial random sampling strategy, the traditional systematic sampling method, the spatial stratified sampling method, Sandwich spatial sampling and inference and SOPA was performed. Results The method (SOPA) proposed in this study had the minimal absolute error of 0.213 8; and the traditional systematic sampling method had the largest estimate, and the absolute error was 0.924 4. Conclusion The snail sampling strategy (SOPA) proposed in this study obtains the higher estimation accuracy than the other four methods. PMID- 29508573 TI - [Dynamic change of population structure of Oncomelania hupensis]. AB - Objective To understand the successive dynamic change of population structure of Oncomelania hupensis during a one-year period, so as to provide the evidence for snail control. Methods A river beach and a ditch infested with O. hupensis snails were selected and longitudinally investigated in the midmonth during one year. The snail survey indices included the survival status, gender, number of whorls, length and width of shell, and gonad development status (measured by the color depth of gonad and the length ratio of gonad to liver), and the monthly snail eggs in the soil were collected and counted simultaneously. In addition, the temperature and humidity of the soil and the daily data of air temperature and precipitation were measured or collected during the study period (every month). Results Both survival rate of snails and live snail density at the two environments were positively correlated with the temperatures of air and soil. With a slight bimodal distribution, the snail survival rate peaked from May to June, and in September. The living snail densities got the highest level in July and September in the river beach, and from April to May in the ditch. The regression equations of snail length (L) and width (W) were Lbeach = 2.355 + 1.678W (F = 2 989.43, P < 0.01) and Lditch = 0.478 + 2.091W (F = 2.989.43, P < 0.01), respectively. The snails were the ones with 4.07-11.81 mm in the length (8.98 +/- 0.92) mm in the river beach, and the snails were the ones with 3.63 9.92 mm in the length (7.03 +/- 0.82) mm in the ditch. The main snails were the ones with five to eight whorls of shell in the river beach and four to seven whorls of shell in the ditch. The proportions of snails with less than or equal to five whorls (in the river beach) and four (in the ditch) were the highest in May and September, about 20%. The ratios of male and female snails were 1.66 in the river beach and 1.22 in the ditch, respectively. The gonad development status of male and female snails was basically synchronous and had a bimodal abundance period - from April to May and September to October. The numbers of snail eggs in the soil among months were significantly different, reaching the highest in June in the river beach (100.8/0.1 m2), and May in the ditch (82.5/ 0.1 m2). Conclusion The principal periods of breeding and alternation of generations of snails are April-May and SeptemberOctober every year, which should also be the optimal time for mollusciciding in schistosomiasis susceptible zones. PMID- 29508574 TI - [Pharmacokinetics of praziquantel injection in healthy buffaloes]. AB - Objective To investigate the pharmacokinetics and relative bioavailability of praziquantel injection in buffaloes in contrast to praziquantel tablet. Methods A single oral administration of praziquantel tablet at a dose of 20 mg/kg or intramuscular administration of praziquantel injection at a dose of 10 mg/kg was performed in six healthy adult buffalos according to a twoperiod crossover design. The praziquantel concentration in plasma was determined by a high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters were calculated by non-compartmental analysis. Results The main pharmacokinetic parameters of praziquantel tablet were as follows: Tmax = (0.60+/-0.29)h, Cmax = (0.57+/-0.37)MUg/ml, T1/2beta = (0.70+/-0.42)h, AUC = (0.80+/-0.70) (MUg/ml).h. The main pharmacokinetic parameters of praziquantel injection were as follows: Tmax = (0.65+/- 0.49)h, Cmax = (3.82+/-1.17)MUg/ml, T1/2beta = (1.00+/-0.73)h, AUC = (1.61+/-0.89) (MUg/ml).h. The relative bioavailability of praziquantel injection was 402.5% in contrast to praziquantel tablet. Conclusion The praziquantel injection has pharmacokinetic characteristics of rapid absorption, high bioavailability and extensive distribution, and the clinical recommended dosage of praziquantel injection is 10 mg/kg. PMID- 29508575 TI - [Application of ARIMA model to predict number of malaria cases in China]. AB - Objective To study the application of autoregressive integrated moving average (ARIMA) model to predict the monthly reported malaria cases in China, so as to provide a reference for prevention and control of malaria. Methods SPSS 24.0 software was used to construct the ARIMA models based on the monthly reported malaria cases of the time series of 20062015 and 2011-2015, respectively. The data of malaria cases from January to December, 2016 were used as validation data to compare the accuracy of the two ARIMA models. Results The models of the monthly reported cases of malaria in China were ARIMA (2, 1, 1) (1, 1, 0)12 and ARIMA (1, 0, 0) (1, 1, 0)12 respectively. The comparison between the predictions of the two models and actual situation of malaria cases showed that the ARIMA model based on the data of 2011-2015 had a higher accuracy of forecasting than the model based on the data of 2006-2015 had. Conclusion The establishment and prediction of ARIMA model is a dynamic process, which needs to be adjusted unceasingly according to the accumulated data, and in addition, the major changes of epidemic characteristics of infectious diseases must be considered. PMID- 29508576 TI - [Epidemiological analysis of malaria prevalence in Jiangsu Province in 2015]. AB - Objective To understand the malaria epidemic situation and characteristics in Jiangsu Province in 2015, so as to provide the evidence for malaria elimination. Methods The data of malaria cases in Jiangsu Province in 2015 were collected from China's routine diseases surveillance information system. Results Totally 405 imported cases were reported in Jiangsu Province in 2015, and the cases increased by 14.08% compared with those in 2014. All the malaria cases were imported, and 5 cases (1.23%) were from Southeast Asia and 400 (98.77%) were from 25 African countries or regions. The imported malaria cases were reported in 13 cities across Jiangsu Province, where Taizhou, Lianyungang, Nantong, Huaian and Yangzhou cities accounted for 68.64% of all the cases in the province. Jiangsu Institute of Parasitic Diseases (JIPD) reference lab checked all the cases and classified 299 falciparum malaria cases, 13 vivax malaria cases, 18 quartan malaria cases, 71 ovale malaria cases, and 4 mixed Plasmodium infection cases. Conclusions In Jiangsu Province, there are no local malaria cases for 4 consecutive years, but the imported cases are on the rise. Compared to 2014, the imported vivax cases increased significantly in 2015. It should be the key points to strengthen the surveillance of imported malaria cases, improve malaria diagnosis and treatment abilities for all levels of medical institutions, and promote the abilities of Plasmodium check, and focus survey and disposal of all Center for Disease Control (CDC) staffs across Jiangsu Province. PMID- 29508577 TI - [Time characteristics of imported malaria cases in Yunnan Province]. AB - Objective To investigate the time distribution characteristics and the epidemic trends of imported malaria cases in Yunnan Province. Methods The malaria case records and epidemiological history data of Yunnan Province were collected, and the local infection cases were excluded. The data were statistical analyzed. Results The imported malaria cases had a significantly seasonal periodicity (Q = 26.574, P < 0.05) and epidemic trends (Q = 35.487, P < 0.05). The imported peak was in May, while February was the lowest month of imported cases, and the difference was significant (Z = -2.619, P < 0.05). The simple seasonal prediction model was the best model (R2 = 0.677, BIC = 4.867) for forecast while the residual sequence was white noise (Q = 14.226, P > 0.05). By using the model to predict the cases in January, February and March of 2016, the number (95% CI) were 29 (7-50), 22 (0-44) and 31 (8-54), and the actual number of imported malaria cases were 29, 24 and 38 cases respectively and all cases were included in the 95% CI. Conclusion The imported malaria cases in Yunnan Province had a significantly seasonal periodicity and epidemic trends, and the established model has good prediction on the recent cases. PMID- 29508578 TI - [Optimized application of nested PCR method for detection of malaria]. AB - Objective To optimize the application of the nested PCR method for the detection of malaria according to the working practice, so as to improve the efficiency of malaria detection. Methods Premixing solution of PCR, internal primers for further amplification and new designed primers that aimed at two Plasmodium ovale subspecies were employed to optimize the reaction system, reaction condition and specific primers of P. ovale on basis of routine nested PCR. Then the specificity and the sensitivity of the optimized method were analyzed. The positive blood samples and examination samples of malaria were detected by the routine nested PCR and the optimized method simultaneously, and the detection results were compared and analyzed. Results The optimized method showed good specificity, and its sensitivity could reach the pg to fg level. The two methods were used to detect the same positive malarial blood samples simultaneously, the results indicated that the PCR products of the two methods had no significant difference, but the non-specific amplification reduced obviously and the detection rates of P. ovale subspecies improved, as well as the total specificity also increased through the use of the optimized method. The actual detection results of 111 cases of malarial blood samples showed that the sensitivity and specificity of the routine nested PCR were 94.57% and 86.96%, respectively, and those of the optimized method were both 93.48%, and there was no statistically significant difference between the two methods in the sensitivity (P > 0.05), but there was a statistically significant difference between the two methods in the specificity (P < 0.05). Conclusion The optimized PCR can improve the specificity without reducing the sensitivity on the basis of the routine nested PCR, it also can save the cost and increase the efficiency of malaria detection as less experiment links. PMID- 29508579 TI - [Investigation on contamination of Giardia and Cryptosporidium in drinking water in Jiangsu Province]. AB - Objective To know the contamination status of Giardia lamblia and Cryptosporidium in drinking water of Jiangsu Province, so as to provide the evidence for producing hygiene and safety drinking water. Methods A total of 28 water plants of 13 cities in Jiangsu Province were selected, and the source water (10 L), chlorinated water (100 L) and tap water (100 L) were collected separately in each site. The water samples were then treated by filtration, washing, centrifuging concentration, immune magnetic separation, and immunofluorescent assay, to detect the numbers of Giardia cysts and Cryptosporidium oocysts. Results Totally 84 samples from 13 cities were collected, including 28 source water, 28 chlorinated water and 28 tap water samples. Among the chlorinated water and tap water samples, no Giardia cysts and Cryptosporidium oocysts were found. However, Giardia cysts were detected in 3 (10.71%, 3/28) source water samples (Yancheng, Lianyungang, Changzhou cities), with the density of 1 cyst/10 L of all. Cryptosporidium oocysts were also detected in 3 (10.71%, 3/28) source water samples (Nanjing, Zhenjiang, Yangzhou cities), with the density of 1 oocyst/10 L of all. Conclusions The source water in partial areas of Jiangsu Province has been contaminated by Giardia and Cryptosporidium. To ensure the safety of drinking, the regulation of source water and surveillance of drinking water should be strengthened. PMID- 29508580 TI - [Investigation on epidemic status of clonorchiasis sinensis based on inpatients in Zhongshan City, China]. AB - Objective To understand the prevalence and epidemiological features of clonorchiasis sinensis based on inpatients in Zhongshan City. Methods All of the 23 town hospitals in Zhongshan City were selected as the surveillance hospitals in 2016. Among the inpatients from those hospitals, those lived in the city longer than 6 months were selected as the surveillance subjects. The stool specimens of the subjects were collected and examined by the modified Kato-Katz thick smear method for the eggs of Clonorchis sinensis. The crude infection rates of C. sinensis of the subjects were standardized according to the age and sex compositions of the population in Zhongshan City, 2016. Meanwhile, the infection rates of the subjects from different towns and those combined with related clinical diseases were analyzed. Results A total of 2 667 people were included in the surveillance, among which 219 were tested as positives, with a crude infection rate of 8.21%. For the positives, the male accounted for 81.74% (179/219), and their age ranged from 4 to 89 years with the mean value of (62.20+/-13.80) years. After standardization by age and sex composition, the infection rate was 3.62% for the whole population, the rates of the male and the female were 5.46% and 1.53%, respectively, and the former was 3.57 times as high as the latter. Both the infection rates of the male and the female rose as the age increasing (chi2male = 99.91, chi2female = 16.51, both P < 0.01). The standardized infection rates among the subjects in different towns ranged from 0 to 10.40%, and the rates in the north towns were higher than those in the south towns. The standardized rate was 9.22% for the subjects combined with gallstone, 3.40% for those not combined with gallstone, and the former was 2.71 times as high as that of the latter. Conclusion The people aged 30 years and above, with gallstone or living in towns with high C. sinensis infection rates are the key population for prevention and control of clonorchiasis in Zhongshan City. PMID- 29508581 TI - [Primary culture of cat intestinal epithelial cell and construction of its cDNA library]. AB - Objective To establish the primary cat intestinal epithelial cells (IECs) culture methods and construct the cDNA library for the following yeast two-hybrid experiment, so as to screen the virulence interaction factors among the final host. Methods The primary cat IECs were cultured by the tissue cultivation and combined digestion with collagenase XI and dispase I separately. Then the cat IECs cultured was identified with the morphological observation and cyto-keratin detection, by using goat anti-cyto-keratin monoclonal antibodies. The mRNA of cat IECs was isolated and used as the template to synthesize the first strand cDNA by SMARTTM technology, and then the double-strand cDNAs were acquired by LD-PCR, which were subsequently cloned into the plasmid PGADT7-Rec to construct yeast two hybrid cDNA library in the yeast strain Y187 by homologous recombination. MatchmakerTM Insert Check PCR was used to detect the size distribution of cDNA fragments after the capacity calculation of the cDNA library. Results The comparison of the two cultivation methods indicated that the combined digestion of collagenase XI and dispase I was more effective than the tissue cultivation. The cat IECs system of continuous culture was established and the cat IECs with high purity were harvested for constructing the yeast two-hybrid cDNA library. The library contained 1.1*106 independent clones. The titer was 2.8*109 cfu/ml. The size of inserted fragments was among 0.5-2.0 kb. Conclusion The yeast two hybrid cDNA library of cat IECs meets the requirements of further screen research, and this study lays the foundation of screening the Toxoplasma gondii virulence interaction factors among the cDNA libraries of its final hosts. PMID- 29508582 TI - [Observation on destroyed architecture of splenic lymphoid follicles in mice infected with Schistosoma japonicum by immunohistochemistry]. AB - Objective To observe the destroyed architecture of splenic lymphoid follicles in mice infected with Schistosoma japonicum by immunohistochemistry. Methods The mice infected with S. japonicum (20 cercariae/mouse) for 8 weeks were sacrificed, and the splenic samples were paraffin embedded and sliced. The sections were first stained by hematoxylin and eosin to observe the massive structure of splenic lymphoid follicles, and then B cells, follicular dendritic cells (FDC) and germinal center cells were labeled with anti-B220, anti-CD21 or anti-Ki67 antibodies respectively by immunohistochemistry to observe the distribution of the specific cells of lymphoid follicles. Results The results of HE staining showed that the structure of lymphoid follicles in spleens of infected mice was blurred, the number and area of follicles were significantly reduced compared to those of the normal mice. The immunohistochemical staining showed that the splenic T/B lymphocyte segregation, FDC network and germinal centers of the infected mice all disappeared. Conclusion The structure of splenic lymphoid follicles in the mice infected with S. japonicum is obviously damaged. PMID- 29508583 TI - [Study of schistosomiasis transmission interruption based on intensive agriculture]. AB - Objective To study the effect of schistosomiasis transmission interruption model based on intensive agriculture in hilly endemic areas, so as to provide the reference for the similar endemic areas. Methods Based on the development of intensive agriculture in Guanghan City, a comprehensive demonstration area of schistosomiasis control with measures such as new rural construction, hardening ditches, the adjustment of industrial structure and water remediation measures was constructed. Jinhua, Shiguan and Hongyan villages were chosen as the evaluation sites to comparatively analyze the indexes of intensive agriculture and schistosomiasis control effects. Results Compared with the demonstration area before construction, in 2014, the harden rates of ditches and village roads were increased by 49.57% and 39.33% respectively; and the proportion of agricultural machinery increased by 25%. The positive rate of serological tests of schistosomiasis was decreased by 81.74%. The Oncomelania hupensis snail area was decreased from 2.44 hm2 (2007) to 0 (2014). The awareness rate of schistosomiasis control knowledge and correct behavior rate of the residents were increased from 51.28% and 90.85% to 91.29% and 97.69% respectively. The experience of the demonstration area ensured the entire Guanghan District achieved the schistosomiasis transmission interruption criterion at the end of 2014. Conclusions The schistosomiasis control model of intensive agriculture combined with other comprehensive measures has a good effect on interrupting the endemic of schistosomiasis, and it can realize the sustainable development of the agricultural economy and schistosomiasis control. PMID- 29508584 TI - [Effectiveness of clinical pathway for treatment of advanced schistosomiasis hepatic fibrosis]. AB - Objective To assess the effectiveness of the clinical pathway for the treatment of advanced schistosomiasis hepatic fibrosis. Methods The duration of hospital stay, gross hospitalization expense, individual-paid expense, interior diameter of portal vein, levels of four serum hepatic fibrosis-related parameters (PIIIP, CIV, HA, and LN), and activities of ALT, AST and gamma-GT were assessed and compared between the advanced schistosomiasis patients receiving the clinical pathway and ones receiving non-clinical pathway. Results There were 142 advanced schistosomiasis patients with hepatic fibrosis receiving the clinical pathway of anti-hepatic fibrosis. Compared with the patients receiving non-clinical pathway, the gross hospitalization expenses reduced by 11.2% (t = 6.310, P < 0.05), and the individual-paid expenses reduced by 16.1% (t = 4.326, P < 0.05). The mean HA level was twice higher than the normal range, with a positive rising from 70.4% to 83.1%, and the abnormal rates of CIV and gamma-GT were 64.1% and 28.9% respectively. Conclusions The clinical pathway can drastically reduce the treatment expenses in advanced schistosomiasis patients with hepatic fibrosis. However, the patients have a trend towards the persistent disease progression. Therefore, the researches of more effective therapeutic methods for advanced schistosomiasis hepatic fibrosis are urgently needed. PMID- 29508585 TI - [Epidemiological analysis of imported malaria in Suining City, Sichuan Province from 2011 to 2016]. AB - Objective To investigate the epidemiological characteristics of imported malaria in Suining City from 2011 to 2016, so as to provide the evidence for improving the surveillance, risk assessment and control measures of imported malaria. Methods The malaria epidemic data in Suining City from 2011 to 2016 were collected from the reporting system, and statistical analyzed. Results Totally 71 malaria cases were reported in Suining City from 2011 to 2016, and they were all imported cases. Sixty cases (84.51%) were imported from Africa. There were cases reported throughout the year, and no obvious seasonal distribution characteristics. The median time from onset to seeing a doctor was 2 days; the median time from seeing a doctor to confirmed diagnosis of malaria was 4 days. Totally 63.38% of the cases were diagnosed of malaria in initially seeing a doctor. Forty-three cases were diagnosed by county and municipal medical institutions, accounting for 60.56%. All cases were laboratory confirmed cases, and they all received the standardized treatment. Conclusion The imported malaria epidemic situation in Suining City is still severe, and it is necessary to strengthen the management of floating population and professional training of medical staff so as to prevent the second malaria cases and deaths. PMID- 29508586 TI - [Analysis of assessment results of malaria elimination in counties (districts) of Huai'an City]. AB - Objective To analyze the results of the assessment of malaria elimination in 8 counties (districts) in Huai'an City, Jiangsu Province, so as to provide evidences for consolidating the achievement of malaria elimination. Methods The data from the network reports of malaria epidemic situation, blood examinations of febrile patients, epidemiological questionnaires of malaria cases, investigation and disposal of epidemic focuses were collected and analyzed in Huai'an City from 2010 to 2016. The results of the assessment on the clinicians'ability of malaria diagnosis and treatment as well as the inspectors'skill of Plasmodium microscopic examinations were analyzed. In the natural village where the last local case of malaria was reported, no less than 200 blood filter papers were made for gene detection of Plasmodium. Results From 2010 to 2016, 308 malaria cases were reported in Huai'an City. Totally 323 002 patients received blood detection of malaria, among which 272 ones were positive and the positive rate was 0.08%. The majority of the malaria cases were imported, except 19 and 3 local infection cases in 2010 and 2011, respectively. Except Qinghe District, a total of 1 420 blood filter papers from the other 7 counties (districts) were detected genetically, and the results were all negative. Six of the eight counties (districts) gained an average score of 20 points on the Plasmodium microscopic examination, and Jinhu County and Huai'an District got a minimum average score of 19.6 points. In capacity assessment of malaria diagnosis and treatment, Hongze District gained the highest average score of 20 points, and Huai'an District got the lowest average score of 18.8 points. The malaria elimination assessment scores of the eight counties (districts) were all above 97 points. All the 8 counties (districts) in Huai'an City passed the malaria elimination assessment at county (district) level until 2016. Conclusions All the 8 counties (districts) in Huai'an City have passed the malaria elimination assessment with high scores. After the malaria elimination, the monitoring still should continue to consolidate the achievement. PMID- 29508587 TI - [Analysis of overseas imported malaria and implication for prevention and control strategy in Shijiazhuang City from 2012 to 2015]. AB - Objective To analyze the overseas imported malaria situation of Shijiazhuang City from 2012 to 2015, so as to provide the evidence for exploring the prevention and control strategy. Methods The data of overseas imported malaria were collected and analyzed with the descriptive method including Plasmodium species, population characteristics, epidemic focus distribution, onset time, diagnosis and treatment in Shijiazhuang City from 2012 to 2015, and the time from the onset to first medical visit, time from first medical visit to being diagnosed, and time from onset to being diagnosed of different Plasmodium species were analyzed respectively with the statistical analysis method. Results A total of 92 overseas imported malaria cases were reported in Shijiazhuang City from 2012 to 2015, including 88 cases from African countries (falciparum malaria taking 53.41%), and 4 cases from Southeast Asian and other countries (vivax malaria taking 50%). Eighty-nine cases were distributed in 28 counties (districts) of 6 cities in Hebei Province, except 2 persons with foreign nationalities and 1 with Anhui Province census register. The male and young adults were dominant. The median time from the onset to seeing a doctor was one day and the median time from seeing a doctor to being diagnosed was five days. Most cases were reported by the Fifth Hospital of Shijiazhuang which was the sentinel hospital. Totally 42.39% of the cases were misdiagnosed when the first visit to a doctor. All of the cases were laboratory confirmed and 100% of them received the standard treatment after diagnosis. Conclusions The overseas imported malaria cases are increasing rapidly with years and the malignant malaria cases were more than other malaria cases in Shijiazhuang City. It is necessary to further strengthen the long-term cooperation mechanism between the medical institutions and the entry-exit inspection and quarantine department. The technician training should be strengthened to avoid the severe cases and death cases. PMID- 29508588 TI - [Investigation of health knowledge and behaviors on clonorchiasis sinensis of urban residents in Yanqing District, Beijing City]. AB - Objective To understand the status of health knowledge and behaviors on clonorchiasis sinensis of urban residents in Yanqing District of Beijing City, China, so as to provide the targeted suggestions for further health education. Methods The communities/streets were selected as the investigation sites by using the stratified randomly sampling method. A total of 283 residents were randomly selected and investigated with the structural questionnaire designed by Beijing Center for Disease Control and Prevention. The fecal samples were collected and the eggs of Clonorchis sinensis were detected with Kato-Katz technique. Results All of the questionnaires were valid. The awareness rate about clonorchiasis was 25.09%. The rates of knowing clonorchiasis infection route, harm and prevention measures were 10.60%, 9.89% and 10.60% respectively. Totally 7.07% of the residents had the habits of eating raw or undercooked fresh water fish, and 2.47% of the residents had the behavior of eating sashimi. C. sinensis eggs were not found among the research objects. Conclusions The awareness rate about clonorchiasis is low among urban residents in Yanqing District. The focus of the future work is to extensively carry out the health education about clonorchiasis prevention and control and take relevant interventions. PMID- 29508589 TI - [Gohieria fuscus breeding heavily in grand dust flour of a flourmill]. AB - Objective To investigate the breeding quantity and average breeding density of Gohieria fuscus in the grand dust flour of a flourmill and explore the prevention and control measures. Methods A certain amount of grand dust flour was collected from a flourmill, and it was sieved. The powder was placed into the glass pan, and the mites were sought out under an optical microscope and made of specimens. The mites were identified on the basis of literature. Results In this survey, 400 g samples were collected from 4 habitats. The average breeding density of mites was 3 516/g. The mite was identified as Gohieria fuscus. ConclusionsGohieria fuscus is one of the widely distributed stored mites. It impacts the stored food and reduces the quality of food. In addition, the mite affects human health. Therefore, the preventive measures should be taken. PMID- 29508590 TI - [Blomia tropicalis is found in a flour warehouse of a food factory in a civil aviation airport]. AB - Objective To investigate whether there is Blomia tropicalis breeding in the flour warehouse of food factory in a civil aviation airport, and, if there is, to observe the morphological structure of the mite. Methods The flour samples were collected from the flour warehouse of food factory in a civil aviation airport. The breeding mites were isolated from the samples by direct microscopy and made into specimens to observe with a light microscope. Results Female Blomia tropicalis was found in the collected flour samples. Under the microscope, the mite was nearly spherical, and it had no tergum and claw. Its apodemeI was developed and connected in the midline. The reproductive hole was located between the foot III and IV level and was covered with a pair of oblique genital folds. The foot III and IV had no solenoids. The copulatory pouch was a long, slightly curved tube, extending from the end of the mite. ConclusionsBlomia tropicalis has been found in the flour warehouse of a food factory in the civil aviation airport. The main distinguishing feature of this mite is that it has no tergum, its feet have no pectinate inferior tarsus scales or claw, the feetIgenu has only one solenidia, and feet III and IV have no solenidias. PMID- 29508591 TI - [Infection status of Toxoplasma gondii and its related knowledge and behavior among special population in Changzhou City]. AB - Objective To investigate the prevalence of Toxoplasma gondii infection and related knowledge and behavior among special population in Changzhou City, so as to provide the evidence for formulating effective measures of toxoplasmosis prevention. Methods The pregnant women and patients with neoplasia in Changzhou hospitals, and livestock and poultry breeding or processing workers were selected as the subjects of the study. Venous blood samples were collected from each participant for detecting IgG and IgM antibodies against T. gondii by ELISA. A questionnaire investigation on knowledge and behavior about T. gondii infection was conducted. Results Among the total 300 respondents investigated from March to May, 2015, the prevalence of T. gondii infection was 16.3% (49/300). Totally 52 respondents knew the knowledge about the prevention and control of T. gondii infection with an awareness rate of 17.3% (52/300). The proportion of participants who frequently contacted with cats/dogs (25.0%, 13/52) in the group who knew the knowledge about the prevention and control of T. gondii infection was lower than that of participants (50.8%, 126/248) in the group who did not know the knowledge about the prevention and control of T. gondii infection, and the difference was statistically significant (chi2 = 11.51, P < 0.05). The proportion of participants separating chopping boards for raw and cooked food (61.5%, 32/52) in the group who knew the knowledge about the prevention and control of T. gondii infection was statistically higher than that of the participants (9.3%, 23/248) in the group who did not know the knowledge about the prevention and control of T. gondii infection, and the difference was statistically significant (chi2 = 78.43, P < 0.001). There was a negative correlation between the awareness rate of the knowledge about the prevention and control of T. gondii infection and the infection rate of T. gondii. The infection rate of T. gondii (5.8%, 3/52) in the group who knew the knowledge about the prevention and control of T. gondii infection was lower than that (18.5%, 46/248) of the group who did not know the knowledge about the prevention and control of T. gondii infection, and the difference was statistically significant (chi2 = 5.14, P < 0.05). Conclusions The awareness rate of the knowledge about the prevention and control of T. gondii infection among special population in Changzhou City is low. The health education on the knowledge of the prevention and control of toxoplasmosis should be strengthened, in order to improve the awareness of personal hygiene and change the unhealthy lifestyles and dietary habits. PMID- 29508592 TI - [Epidemic situation of imported malaria in Chengdu City from 2012 to 2016]. AB - Objective To understand the malaria epidemic situation in Chengdu City, so as to provide the evidence for effectively carrying out the malaria elimination work. Methods The data of imported malaria in Chengdu City from 2012 to 2016 were collected from the Disease Surveillance Information Reporting System of Chinese Center for Disease Control and Prevention and analyzed respectively. Results A total of 240 imported malaria cases were reported in Chengdu City from 2012 to 2016. In detail, 68.75% of the cases were falciparum malaria cases, 20.41% were vivax malaria cases, 2.50% were quartan malaria cases, 6.25% were ovale malaria cases, and 2.08% were mixed Plasmodium infections. Among them three patients died, with a mortality of 1.25%. All of the cases were infected overseas, among which 224 patients returned from Africa and 16 patients from Southeast Asia. The annual average morbidity was 0.28/100 000, and there was a significantly difference among annual average morbidities (chi2 = 23.87, P < 0.001). There were malaria cases reported in every month, and no significantly difference among seasons (chi2 = 0.833, P > 0.05). Conclusion The number of overseas imported malaria in Chengdu City increases year by year. The effective measures to control the overseas imported malaria should be strengthened to consolidate the achievements of malaria elimination. PMID- 29508593 TI - [Morphological observation on hypopus of Lepidoglyphus destructor by optical microscope]. AB - Objective To observe the external morphology of Lepidoglyphus destructor hypopus under an optical microscope. Methods The samples were collected in a store of Chinese medicinal herbs in Huainan City in September, 2016, the L. destructor and the hypopus were isolated, and then made of slide specimens. The slide samples were prepared and observed under an optical microscope. Results The L. destructor hypopus and protonymph were found. The inactive hypopus was oval in shape, the feet were not welldeveloped, there was a distinct transverse seam on its back, and there were 2 pairs of genital sensory organs. Conclusion The optical microscopy shows the morphological characteristics of L. destructor hypopus, which can provide the basis for the biological classification and the prevention. PMID- 29508594 TI - [Diagnostic knowledge and skills of parasitic diseases based on competition of professional personnel in Jiangsu Province, China]. AB - Objective To understand the integrated ability of parasitic disease prevention and control of professional personnel of Jiangsu Province through the contest. Methods Totally 56 players from the whole province were selected, and all the players participated in the contest. The theory knowledge and skill scores were collected and the statistical analyses were conducted. Results The average theoretical score of the participants was 88.86+/-15.56 and the passing rate was 91.1%. The average skill operating score was 69.16+/-16.01 and the passing rate was 67.9%. The average Plasmodium microscopy score was 16.54+/-8.09 and the passing rate was 50%. The average helminth egg microscopy score was 34.27+/-10.66 and the passing rate was 67.9%. There were statistical differences among the age groups and different levels of schistosomiasis endemic situation (F = 5.10, 6.39, both P < 0.01). The theoretical knowledge including schistosomiasis, malaria, hydatid disease and others and the score rates were 91.07%, 90.94%, 85.83% and 90.93%, respectively. The hydatid disease score rate was lower (chi2 = 19.17, P < 0.01). The radar chart displayed that the score rates of tabletting and microscopy test in Kato-Katz film production, malaria blood film production and microscopy test were all low. Conclusion In Jiangsu Province, the participants have higher score in the theory test. However, they have lower skill test score, especially in the parasite species identification. The operational skills still need to be strengthened for center for disease control (CDC) participants. PMID- 29508595 TI - [Analysis of inspection certification results on malaria elimination in Baise City]. AB - Objective To analyze the results of inspection certification on malaria elimination in Baise City, and summarize the experiences of malaria elimination at a prefecture level. Methods According to Evaluation Schemes of Malaria Elimination (2014 edition) and Municipal Evaluation Schemes of Malaria Elimination in Guangxi (2016 edition), the malaria elimination work in Baise City was evaluated. In addition, 2 counties (cities, districts) in the administrative region of Baise City were randomly selected for review assessment. Then the assessment and certification results were analyzed. Results The score of evaluation on malaria elimination in Baise City was 95.80, and the scores of review in Tiandong County and Jingxi City were 94.70 and 90.60, respectively. According to the weight of the three scores, namely 0.4, 0.3, 0.3, the final score of malaria elimination in Baise City was 93.91, which reached the national standards of malaria elimination score (more than 85). Conclusions Baise City has passed the inspection certification of malaria elimination by the authority of Guangxi Zhuang Autonomous Region. However, the malaria monitoring post elimination still should continue to consolidate the elimination achievements. PMID- 29508596 TI - [Analysis of epidemic situation of schistosomiasis in Wuhu County from 2012 to 2016]. AB - Objective To analyze the epidemic situation of schistosomiasis in Wuhu County from 2012 to 2016, so as to provide the reference for adjusting the control strategy. Methods The data of schistosomiasis prevention and control in Wuhu County from 2012 to 2016 were collected and longitudinally analyzed. Results Since 2013, the average infection rate of schistosomiasis in the population decreased year by year, and the infection rate decreased to 0 in 2016. Since 2012, the infection rate of livestock was 0. The area with Oncomelania hupensis snails decreased year by year, but it drastically rebounded in 2016. No schistosome-infected snails were found since 2012. Conclusions Schistosomiasis epidemic is effectively controlled in Wuhu County, but there is a possibility of recovery. In the next stage, we should focus on strengthening the control of snails and imported infectious sources in order to consolidate the achievements of prevention and control. PMID- 29508597 TI - [Epidemiological analysis and countermeasures discussion on imported malaria in Zhangjiagang City]. AB - Objective To analyze the epidemiological characteristics of imported malaria in Zhangjiagang City. Methods The epidemiological data were collected and retrospectively analyzed for the distribution, cost, and exit-entry mode and port of imported malaria cases in Zhangjiagang City from 2005 to 2015. Results There were 25 imported malaria cases in Zhangjiagang City from 2005 to 2015, and among them, there were 16 cases of falciparum malaria (64%), 6 cases of vivax malaria (24%), and 3 cases of ovale malaria (12%); there was 1 cases of critically ill (4%), there were 8 cases of serious ill (32%) and 16 cases of mild ill (64%). The time of onset was in accordance with the circular distribution. The peak of the incidence of the imported malaria was one month earlier than that of the domestic infection. The seasonal peak was gentle, and there was also the occurrence in the non-epidemic season in the city. The imported malaria patients were mainly from Africa, followed by Southeast Asia and Oceania. Conclusion The information technology should be applied to improve the key population coverage on the basis of improving the ability of malaria diagnosis and treatment of medical staff and the multi-sector's cooperation for the imported malaria prevention and control in Zhangjiagang City. PMID- 29508598 TI - [Oncomelania hupensis status monitoring in Changzhou City, Jiangsu Province from 2013 to 2016]. AB - Objective To analyze the Oncomelania hupensis snail distribution and the changes of snail situation in Changzhou City from 2013 to 2016, so as to provide the evidence for formulating the schistosomiasis prevention and control interventions. Methods The data of snail monitoring in Changzhou City from 2013 to 2016 were collected and statistically analyzed. Results The total area with snails was 40.17 hm2 and the newly discovered area was 30.63 hm2 in Changzhou City from 2013 to 2016. In the four years, 3 454 snails were dissected, and no schistosome infected snails were found. There were totally 51 spots with snails, and the areas with snails of different types of marshland, inland and mountain were 12.13 (30.19%), 25.54 hm2 (63.57%) and 2.51 hm2 (6.24%), respectively. In the newly discovered snail environment, the areas of types of marshland and inland were 8.00 hm2 (26.12%) and 22.63 hm2 (73.88%), respectively. The main causes for snail existence were external input and adjacent diffusion. In the past four years, the total snail control area with molluscicides was 71.74 hm2, the consolidated snail control area with molluscicides was 155.15 hm2, and the total environmental modification areas in the current snail spots and historic snail spots were 15.90 hm2 and 11.30 hm2 respectively. Conclusion The diffusion of snails in inland rivers is the key of the newly discovered snail areas in Changzhou City in recent years, and the snail monitoring and control measures should be strengthened in the future. PMID- 29508599 TI - [Investigation on current situation of Plasmodium microscopic examination capabilities of professional staff in medical situations in Wuxi City]. AB - Objective To investigate the capabilities of Plasmodium microscopic examinations of professional staff in medical institutions in Wuxi City, so as to provide evidences for improving malaria control and elimination work in the future. Methods The data of questionnaires for laboratorial staff in charge of Plasmodium microscopic examinations were collected and analyzed in the medical institutions in Wuxi City in 2016, and the influencing factors related to the capabilities of Plasmodium microscopic examinations were analyzed by the method of logistic regression. Results Totally 54 laboratorial workers in 54 medical institutions in Wuxi City were investigated, 16 of them were male, and 38 were female, and the ratio of male to female was 0.42:1. Among the 54 laboratorial workers, 12 persons (22.22%) had the experience of detecting Plasmodium in the work. The multivariable analysis showed the ability to detect Plasmodium was associated with male laboratorial workers (adjusted OR = 0.11, 95%CI:0.02-0.53), laboratorial workers with intermediate or higher professional titles (adjusted OR = 5.31, 95%CI: 1.04-27.19) and laboratorial workers from county and township medical institutions (adjusted OR = 0.04, 95%CI:0.01-0.98). Conclusions All of the medical institutions in Wuxi City have the capability of microscopic examinations of Plasmodium. However, the ability of laboratorial staff in primary hospitals still should be improved. PMID- 29508600 TI - [ATP-P2X7R signalling pathway and its effects in parasitic diseases]. AB - ATP (Adenosine triphosphate) is an important endogenous damage - associated molecular pattern (DAMP). P2X7R is an ATP-gated cation channel. ATP-P2X7R plays a vital role in the pathophysiology of many diseases because P2X7R is distributed on various immune cells. ATP-P2X7R signal transduction pathway has been implicated to participate in the body's immune defense against pathogens. This paper reviews the recent progress regarding ATP-P2X7R and its effects on parasitic diseases. PMID- 29508601 TI - [Progress in researches of benzimidazole in treatment of echinococcosis]. AB - Echinococcosis is a severe zoonosis parasitic disease and mainly caused by the larvae of Echinococcus granulosus and E. multilocularis. Because of the limitation of operation level, such as recurrence and death, the drug treatment is still the most important method in our country. Meanwhile, the annual number of drug treatments is far greater than surgical treatments. Drugs play a significant role in the preoperative reduction of lesions, reducing pain, extending the life of patients .This article reviews the status of animals treatment and clinical treatment of echinococcosis treated by the benzimidazole drugs and their new formulations, provides the basis for exploring the development direction of anti-echinococcosis drug treatment research. PMID- 29508602 TI - [Pulmonary ectopic lesion of acute schistosomiasis: a report of two cases]. AB - This paper reports the diagnosis and treatment of 2 cases of acute schistosomiasis with ectopic lesion in the lung. It suggests that in schistosomiasis endemic areas, if the patients with the contact history of infested water have the symptom of fever, while the effects of anti-infection and the corresponding treatments are not good, the clinician should consider acute schistosomiasis. PMID- 29508603 TI - Simple Unbiased Hot-Electron Polarization-Sensitive Near-Infrared Photodetector. AB - Plasmonic nanostructures can generate energetic "hot" electrons from light in a broad band fashion depending on their shape, size, and arrangement. Such structures have a promising use in photodetectors, allowing high speed, broad band, and multicolor photodetection. Because they function without a band gap absorption, photon detection at any energy would be possible through engineering of the plasmonic nanostructure. Herein, a compact hot-electron-based photodetector that combines polarization sensitivity and circularly polarized light detection in the near-infrared region was fabricated using an indium tin oxide (ITO)-Au hybrid layer. Furthermore, the sensitivity of the device was significantly increased by adding a poled Azo molecular glass film in a capacitor configuration. The resulting device is capable of detecting light below the ITO band gap at ambient temperature without any bias voltage. This photodetector, which is amenable to large-area fabrication, can be integrated with other nanophotonic and nanoplasmonic structures for operation at telecom wavelengths. PMID- 29508604 TI - Controlling Molecular Conformation for Highly Efficient and Stable Deep-Blue Copolymer Light-Emitting Diodes. AB - We report a novel approach to achieve deep-blue, high-efficiency, and long-lived solution-processed polymer light-emitting diodes (PLEDs) via a simple molecular level conformation change of an emissive conjugated polymer. We introduce rigid beta-phase segments into a 95% fluorene-5% arylamine copolymer emissive layer. The arylamine moieties at low density act as efficient exciton formation sites in PLEDs, whereas the conformational change alters the nature of the dominant luminescence from a broad, charge transfer like emission to a significantly blue shifted and highly vibronically structured excitonic emission. As a consequence, we observe a significant improvement in the Commission International de L'Eclairage ( x, y) coordinates from (0.149, 0.175) to (0.145, 0.123) while maintaining high efficiency and improved stability. We achieve a peak luminous efficiency, eta = 3.60 cd/A, and a luminous power efficiency, etaw = 2.44 lm/W, values that represent state-of-the-art performance for single copolymer deep-blue PLEDs. These values are 5-fold better than for otherwise-equivalent, beta-phase poly(9,9-dioctylfluorene) PLEDs (0.70 cd/A and 0.38 lm/W). This report represents the first demonstration of the use of molecular conformation as a simple but effective method to control the optoelectronic properties of a fluorene copolymer; previous examples have been confined to homopolymers. PMID- 29508605 TI - Expansion of the Graphdiyne Family: A Triphenylene-Cored Analogue. AB - Graphdiyne (GDY) comprises an important class in functional covalent organic nanosheets based on carbon-carbon bond formation, and recent focus has collected in the expansion of its variations. Here we report on the synthesis of a GDY analogue, TP-GDY, which has triphenylene as the aromatic core. Our liquid/liquid interfacial synthesis for GDY ( J. Am. Chem. Soc. 2017, 139, 3145) was modified for hexaethynyltriphenylene monomer to afford a TP-GDY film with a free-standing morphology, a smooth texture, a domain size of >1 mm, and a thickness of 220 nm. Resultant TP-GDY is characterized by series of microscopies, spectroscopies, and thermogravimetric and gas adsorption analyses. PMID- 29508606 TI - Self-Templated, Green-Synthetic, Size-Controlled Protein Nanoassembly as a Robust Nanoplatform for Biomedical Application. AB - Despite inherent advantages over their synthetic polymer-based counterparts, protein nanoparticles remain unsatisfactory in fabrication owing to their low size control, usage of toxic cross-linkers, or organic solvents. This partially contributes to the marginal benefits of Abraxane in clinics. Herein, a green synthetic, size-controlled approach was developed to generate stable albumin nanoparticles. Physically packed ovalbumin nanoclusters were temporally formed in heat, which was then used as the template to form protein nanoparticles chemically stabilized by the intermolecular disulfide network. Exposure of embedded free thiols within a hydrophobic albumin structure and oxidation of them into disulfides (2-3 fold reduction of thiols groups in this process) were identified as key factors during the process. The fact that the structure was stable in sodium dodecyl sulfate treatment (hydrophobic destroyer) while disassembling fast in reduction condition (to cleave disulfide) validated the disulfide cross-linked mechanism. The developed approach is facile and reproducible with precision size control (from tens to hundreds of nanometers). The approach can be extended to other proteins such as bovine serum albumin, underscoring the potential universal applicability. Further study demonstrated that the resultant protein nanoparticles can be a robust nanoplatform for extensive biomedical applications including drug delivery (doxorubicin encapsulation of 5.7%), target bioconjugation, or robust immune adjuvant effect. PMID- 29508607 TI - Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis. AB - A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members. PMID- 29508608 TI - Carrier Charge Polarity in Mixed-Stack Charge-Transfer Crystals Containing Dithienobenzodithiophene. AB - Dithieno[2,3- d;2'3'- d']benzo[1,2- b;4,5- b']dithiophene forms mixed-stack charge-transfer complexes with fluorinated tetracyanoquinodimethanes (F nTCNQs, n = 0, 2, and 4) and dimethyldicyanoquinonediimine (DMDCNQI). The single-crystal transistors of the F nTCNQ complexes exhibit electron transport, whereas the DMDCNQI complex shows hole transport as well. The dominance of electron transport is explained by the superexchange mechanism, where transfers corresponding to the acceptor-to-acceptor hopping ( teeff) are more than 10 times larger than the donor-to-donor hopping ( theff). This is because the donor orbital next to the highest occupied molecular orbital makes a large contribution to the electron transport owing to the symmetry matching. Like this, inherently asymmetrical electron and hole transport in alternating stacks is understood by analyzing bridge orbitals other than the transport orbitals. PMID- 29508609 TI - Simplified Real-Time Multiplex Detection of Loop-Mediated Isothermal Amplification Using Novel Mediator Displacement Probes with Universal Reporters. AB - A variety of real-time detection techniques for loop-mediated isothermal amplification (LAMP) based on the change in fluorescence intensity during DNA amplification enable simultaneous detection of multiple targets. However, these techniques depend on fluorogenic probes containing target-specific sequences. That complicates the adaption to different targets leading to time-consuming assay optimization. Here, we present the first universal real-time detection technique for multiplex LAMP. The novel approach allows simple assay design and is easy to implement for various targets. The innovation features a mediator displacement probe and a universal reporter. During amplification of target DNA the mediator is displaced from the mediator displacement probe. Then it hybridizes to the reporter generating a fluorescence signal. The novel mediator displacement (MD) detection was validated against state-of-the-art molecular beacon (MB) detection by means of a HIV-1 RT-LAMP: MD surpassed MB detection by accelerated probe design (MD: 10 min, MB: 3-4 h), shorter times to positive (MD 4.1 +/- 0.1 min shorter than MB, n = 36), improved signal-to-noise fluorescence ratio (MD: 5.9 +/- 0.4, MB: 2.7 +/- 0.4; n = 15), and showed equally good or better analytical performance parameters. The usability of one universal mediator reporter set in different multiplex assays was successfully demonstrated for a biplex RT-LAMP of HIV-1 and HTLV-1 and a biplex LAMP of Haemophilus ducreyi and Treponema pallidum, both showing good correlation between target concentration and time to positive. Due to its simple implementation it is suggested to extend the use of the universal mediator-reporter sets to the detection of various other diagnostic panels. PMID- 29508610 TI - Asymmetric Total Synthesis of Lancifodilactone G Acetate. 1. Diastereoselective Synthesis of CDEFGH Ring System. AB - The stereoselective construction of the CDEFGH ring system of lancifodilactone G is described. The key steps in this synthesis are (i) ring-closing metathesis for formation of the oxa-bridged eight-membered ring; (ii) an intramolecular Pauson Khand reaction for construction of the sterically congested F ring; and (iii) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G. PMID- 29508611 TI - Highly Enhanced Photoresponsivity of a Monolayer WSe2 Photodetector with Nitrogen Doped Graphene Quantum Dots. AB - Hybrid structures of two-dimensional (2D) materials and quantum dots (QDs) are particularly interesting in the field of nanoscale optoelectronic devices because QDs are efficient light absorbers and can inject photocarriers into thin layers of 2D transition-metal dichalcogenides, which have high carrier mobility. In this study, we present a heterostructure that consists of a monolayer of tungsten diselenide (ML WSe2) covered by nitrogen-doped graphene QDs (N-GQDs). The improved photoluminescence of ML WSe2 is attributed to the dominant neutral exciton emission caused by the n-doping effect. Owing to strong light absorption and charge transfer from N-GQDs to ML WSe2, N-GQD-covered ML WSe2 showed up to 480% higher photoresponsivity than that of a pristine ML WSe2 photodetector. The hybrid photodetector exhibits good environmental stability, with 46% performance retention after 30 days under ambient conditions. The photogating effect also plays a key role in the improvement of hybrid photodetector performance. On applying the back-gate voltage modulation, the hybrid photodetector shows a responsivity of 2578 A W-1, which is much higher than that of the ML WSe2-based device. PMID- 29508612 TI - Fluorescent Carbon Quantum Dots with Intrinsic Nucleolus-Targeting Capability for Nucleolus Imaging and Enhanced Cytosolic and Nuclear Drug Delivery. AB - Nucleolus tracking and nucleus-targeted photodynamic therapy are attracting increasing attention due to the importance of nucleolus and the sensitivity of nucleus to various therapeutic stimuli. Herein, a new class of multifunctional fluorescent carbon quantum dots (or carbon dots, CDs) synthesized via the one-pot hydrothermal reaction of m-phenylenediamine and l-cysteine was reported to effectively target nucleolus. The as-prepared CDs possess superior properties, such as low-cost and facile synthesis, good water dispersibility, various surface groups for further modifications, prominent photostability, excellent compatibility, and rapid/convenient/wash-free staining procedures. Besides, as compared with SYTO RNASelect (a commonly used commercial dye for nucleolus imaging) that can only image nucleolus in fixed cells, the CDs can realize high quality nucleolus imaging in not only fixed cells but also living cells, allowing the real-time tracking of nucleolus-related biological behaviors. Furthermore, after conjugating with protoporphyrin IX (PpIX), a commonly used photosensitizer, the resultant CD-PpIX nanomissiles showed remarkably increased cellular uptake and nucleus-targeting properties and achieved greatly enhanced phototherapeutic efficiency because the nuclei show poor tolerance to reactive oxygen species produced during the photodynamic therapy. The in vivo experiments revealed that the negatively charged CD-PpIX nanomissiles could rapidly and specifically target a tumor site after intravenous injection and cause efficient tumor ablation with no toxic side effects after laser irradiation. It is believed that the present CD based nanosystem will hold great potential in nucleolus imaging and nucleus targeted drug delivery and cancer therapy. PMID- 29508613 TI - Quantitative Proteomics and Cytology of Rice Pollen Sterol-Rich Membrane Domains Reveals Pre-established Cell Polarity Cues in Mature Pollen. AB - Cell polarity is essential for generating diverse cell functions. The underlying mechanisms of how a cell establishes, maintains, and changes its polarity are poorly understood. Recently, sterol-rich membrane microdomains are found to be associated with these processes. However, both its exact characteristics and importance are still unclear. Here we show microdomains change dynamically in developing and germinating rice pollen with selective enrichment in the aperture and the tip of newly born pollen tubes by use of the sterol-specific probe filipin. Using the sterol extraction sensitivities of microdomain proteins and quantitative proteomics, we identified 237 microdomain-associated proteins from 934 identified pollen detergent resistant membrane proteins. This proteome includes almost all of the known key regulators comprising the polar growth network, and it shows more similarity to front-back polarized HeLa cells than nonpolarized Arabidopsis suspension cells. We immunolocalize flotilin-like protein, a representative of these sterol-dependent proteins and directly visualize microdomains in pollen. These results indicate the presence of microdomains in pollen and pre-established cell polarity around the aperture during pollen maturation. Our findings reveal an atlas of the microdomain associated proteome in pollen. This work provides useful resources and knowledge needed to further dissect the mechanisms for the establishment and maintenance of cell polarity. PMID- 29508614 TI - Mitochondria-Accessing Ratiometric Fluorescent Probe for Imaging Endogenous Superoxide Anion in Live Cells and Daphnia magna. AB - Superoxide anion (O2*-), as the precursor of other reactive oxygen species (ROS), is significantly important in the maintenance of redox homeostasis and various cellular signaling pathways. Here we present a ratiometric mitochondria-accessing fluorescent probe (NA-T) based on nucleophilic substitution mechanism for real time measuring O2*-. By regulating the intramolecular charge of 1,8 naphthalimide, a ratiometric response model was obtained, which evinced 18-fold enhancement of fluorescence ratio ( I540 nm/ I475 nm) in the presence of O2*- over other ROS with rapid response (132 s), high sensitivity (DL = 0.370 MUM) and selectivity. Confocal fluorescence images demonstrated that the probe could well permeate through plasma membrane for visualizing endogenous O2*- changes in mitochondria of living cells and in inflammatory Daphnia magna, indicating NA-T a potential tool for the diagnosis and research of corresponding diseases. PMID- 29508615 TI - Hydrogen-Bonded Duplexes with Lengthened Linkers. AB - Connecting basic hydrogen-bonding units with lengthened flexible or rigid linkers generates oligoamide strands that carry new H-bonding sequences and association specificity, leading to H-bonded homo- and heteroduplexes with association constants in the 104 M-1 range in chloroform. Computational and experimental studies indicate that in duplexes with rigid aromatic linkers the oligoamide strands adopt bent conformations that allow the formation of interstrand H-bonds and accommodate the introduced aromatic liners, offering a new series of association units. PMID- 29508617 TI - Iron-Catalyzed C(sp3)-H Acyloxylation of Aryl-2 H Azirines with Hypervalent Iodine(III) Reagents. AB - This letter describes an iron-catalyzed C(sp3)-H acyloxylation of aryl-2 H azirines with hypervalent iodine(III) reagents (HIRs) serving as both an oxidant and a reagent. This methodology provides a rapid access to a wide range of monoacyloxylated 3-aryl-2 H-azirines in moderate to good yields. PMID- 29508616 TI - Proteomic Identification of Interferon-Induced Proteins with Tetratricopeptide Repeats as Markers of M1 Macrophage Polarization. AB - Macrophages, which accumulate in tissues during inflammation, may be polarized toward pro-inflammatory (M1) or tissue reparative (M2) phenotypes. The balance between these phenotypes can have a substantial influence on the outcome of inflammatory diseases such as atherosclerosis. Improved biomarkers of M1 and M2 macrophages would be beneficial for research, diagnosis, and monitoring the effects of trial therapeutics in such diseases. To identify novel biomarkers, we have characterized the global proteomes of THP-1 macrophages polarized to M1 and M2 states in comparison with unpolarized (M0) macrophages. M1 polarization resulted in increased expression of numerous pro-inflammatory proteins including the products of 31 genes under the transcriptional control of interferon regulatory factor 1 (IRF-1). In contrast, M2 polarization identified proteins regulated by components of the transcription factor AP-1. Among the most highly upregulated proteins under M1 conditions were the three interferon-induced proteins with tetratricopeptide repeats (IFITs: IFIT1, IFIT2, and IFIT3), which function in antiviral defense. Moreover, IFIT1, IFIT2, and IFIT3 mRNA were strongly upregulated in M1 polarized human primary macrophages and IFIT1 was also expressed in a subset of macrophages in aortic sinus and brachiocephalic artery sections from atherosclerotic ApoE-/- mice. On the basis of these results, we propose that IFITs may serve as useful markers of atherosclerosis and potentially other inflammatory diseases. PMID- 29508618 TI - Hydrolysis-Kinetic Study of AEBSF, a Protease Inhibitor Used during Cell-Culture Processing of the HIV-1 Broadly Neutralizing Antibody CAP256-VRC25.26. AB - One approach to mitigate product clipping during HIV mAb CAP256-VRC26.25 cell culture development is the addition of the protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) to the cell-culture media. AEBSF can undergo hydrolysis to form an inactive compound, 4-(2-aminoethyl) benzenesulfonic acid. Using mass-spectrometry detection, a kinetic profile of AEBSF hydrolysis was generated for conditions simulating those of cell culture at pH 7.0 and 37 degrees C. It was found that increasing the pH or the temperature could accelerate AEBSF hydrolysis. The kinetic-study results in this report provide an analytical characterization and guidance when optimizing an AEBSF-addition strategy for product-clipping control during cell-culture development and offer an alternative approach for AEBSF-related clearance studies post protein production. PMID- 29508619 TI - Electrostatic Selectivity of Volatile Organic Compounds Using Electrostatically Formed Nanowire Sensor. AB - For the past several decades, there is growing demand for the development of low power gas sensing technology for the selective detection of volatile organic compounds (VOCs), important for monitoring safety, pollution, and healthcare. Here we report the selective detection of homologous alcohols and different functional groups containing VOCs using the electrostatically formed nanowire (EFN) sensor without any surface modification of the device. Selectivity toward specific VOC is achieved by training machine-learning based classifiers using the calculated changes in the threshold voltage and the drain-source on current, obtained from systematically controlled biasing of the surrounding gates (junction and back gates) of the field-effect transistors (FET). This work paves the way for a Si complementary metal-oxide-semiconductor (CMOS)-based FET device as an electrostatically selective sensor suitable for mass production and low power sensing technology. PMID- 29508620 TI - Asymmetric Total Synthesis of Lancifodilactone G Acetate. 2. Final Phase and Completion of the Total Synthesis. AB - The asymmetric total synthesis of lancifodilactone G acetate was accomplished in 28 steps. The key steps in this synthesis include (i) an asymmetric Diels-Alder reaction for formation of the scaffold of the BC ring; (ii) an intramolecular ring-closing metathesis reaction for the formation of the trisubstituted cyclooctene using a Hoveyda-Grubbs II catalyst; (iii) an intramolecular Pauson Khand reaction for construction of the sterically congested F ring; (iv) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G; and (v) a Dieckmann-type condensation reaction for installation of the A ring. The strategy and chemistry developed for the total synthesis will be useful in the synthesis of other natural products and complex molecules. PMID- 29508621 TI - Anti-Inflammatory Isoquinoline with Bis- seco-aporphine Skeleton from Dactylicapnos scandens. AB - Dactyllactone A (1), which was isolated from Dactylicapnos scandens, is an isoquinoline alkaloid with a rearranged and reconstructed D ring, making it the first of a new subtype of aporphines. Compound 1 might be derived from a common aporphine skeleton, which may have undergone biogenetic rearrangement and cleavage of the aromatic ring. Its structure was determined by extensive spectroscopic analysis and single-crystal X-ray diffraction. Compound 1 exhibited anti-inflammatory activity in vitro significantly by inhibiting the expression of IL-1beta and PGE2 in a dose-dependent manner. PMID- 29508622 TI - Solution to the Problem of Calibration of Low-Cost Air Quality Measurement Sensors in Networks. AB - We provide a simple, remote, continuous calibration technique suitable for application in a hierarchical network featuring a few well-maintained, high quality instruments ("proxies") and a larger number of low-cost devices. The ideas are grounded in a clear definition of the purpose of a low-cost network, defined here as providing reliable information on air quality at small spatiotemporal scales. The technique assumes linearity of the sensor signal. It derives running slope and offset estimates by matching mean and standard deviations of the sensor data to values derived from proxies over the same time. The idea is extremely simple: choose an appropriate proxy and an averaging-time that is sufficiently long to remove the influence of short-term fluctuations but sufficiently short that it preserves the regular diurnal variations. The use of running statistical measures rather than cross-correlation of sites means that the method is robust against periods of missing data. Ideas are first developed using simulated data and then demonstrated using field data, at hourly and 1 min time-scales, from a real network of low-cost semiconductor-based sensors. Despite the almost naive simplicity of the method, it was robust for both drift detection and calibration correction applications. We discuss the use of generally available geographic and environmental data as well as microscale land-use regression as means to enhance the proxy estimates and to generalize the ideas to other pollutants with high spatial variability, such as nitrogen dioxide and particulates. These improvements can also be used to minimize the required number of proxy sites. PMID- 29508623 TI - Does the uptake of wagering inducements predict impulse betting on sport? AB - Background and aims Marketing inducements for addictive products, such as wagering, can prompt impulse purchasing by triggering consumption reminders, urges, and cravings. Wagering inducements incentivize betting by providing bonus bets, money-back guarantees, deposits into betting accounts, and discounts. Their promotion during sporting events, push marketing efforts directed at consumers, and ease of uptake at the point-of-sale, may trigger betting on impulse. This study examined whether the uptake of wagering inducements predicted impulse betting on sport. Methods Australian sports bettors (N = 1,813) completed an online survey measuring their proportion of planned bets, impulse bets before match commencement, and impulse bets during play; frequency of using wagering inducements; and several psychological, behavioral, and demographic variables. Results More frequent users of wagering inducements had a greater tendency to place impulse in-play bets, which were also predicted by problem gambling, higher buying impulsiveness, higher frequency of watching sports, younger age, and higher educational status. Sports bettors with a greater tendency to place impulse bets before match commencement also tended to have higher buying impulsiveness and to be younger, but they used inducements less frequently, and tended to be female, less-educated and non-problem, moderate risk, or problem gamblers. Discussion and conclusions Uptake of wagering inducements appeared to be particularly effective in stimulating impulse in-play betting among problem gamblers and frequent sports viewers. These results suggest that a more cautious approach to the regulation of both in-play bets and wagering inducements may be required to better protect young adults from gambling problems and harm. PMID- 29508624 TI - Optimization and simplification of transcatheter aortic valve implantation therapy. AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is now a widely adopted therapy for the treatment of elderly patients with severe aortic stenosis. Improved pre-procedural screening, increased operators' experience and technology advancement have made this technique highly reliable and standardized. Areas covered: The purpose of this review article is to provide an overview of the strategies that can be adopted to optimize the TAVI procedure (pre interventional work-up and procedural simplification and early discharge). Expert commentary: Optimization of TAVI therapy is already a reality and has shown to be safe in most patients, but its penetration has to face with real-world practice. The adoption of a minimalistic and optimized approach requires integration of multidisciplinary competences and an extended, dynamic conception of heart team, which also includes patients' families, referring cardiologist and general practitioners. PMID- 29508625 TI - Reactive nitrogen species control apoptosis and autophagy in K562 cells: implication of TAp73alpha induction in controlling autophagy. AB - The biological outcome of nitric oxide (NO) and reactive nitrogen species (RNS) in regulating pro survival and pro death autophagic pathways still demand further investigation. In the present study, we investigated the effect of nitrosative stress in K562 cells using NO donor compound DETA-NONOate, peroxynitrite, and SIN 1. Exposure to NO, peroxynitrite, and SIN-1 caused decrease in K562 cell survival. NO induced autophagy but not apoptosis or necrosis in K562 cells. In contrast, peroxynitrite and SIN-1 treatment induced apoptosis in K562 cells. Surprisingly, inhibition of autophagic response using 3-methyladenine led to the induction of apoptosis in K562 cells. Increase in 5'adenosine monophosphate activated protein kinase (AMPK) phosphorylation was only observed in the presence of NO donor indicated that AMPK was crucial to induce autophagy in K562 cells. We for the first time discovered a novel role of p73 in autophagy induction under nitrosative stress in K562 cells. TAp73alpha was only induced upon exposure to NO but not in the presence of peroxynitrite. Reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio remained unaltered upon NO exposure. Our data suggest a complex network of interaction and cross regulations between NO and p73. These data open a new path for therapies based on the abilities of RNS to induce autophagy-mediated cell death. PMID- 29508626 TI - Individual risk assessment in the diagnosis of immediate type drug hypersensitivity reactions to betalactam and non-betalactam antibiotics using basophil activation test: a single center experience. AB - BACKGROUND: Drug hypersensitivity reactions of immediate type pose a challenging problem, especially, if standard diagnostic procedures do not lead to conclusive results. The aim of this investigation is to identify, whether basophil activation test (BAT) is able to provide additional benefit in the diagnostic evaluation of immediate type drug hypersensitivity reactions to antibiotics in comparison with the routine allergological diagnostic methods. MATERIALS AND METHODS: We investigated patients, who presented to the Department of Dermatology and Allergology of the University Hospital of RWTH Aachen in Germany for diagnostic workup of type I allergic reactions to antibiotics during the period from 2009 to 2012. The analysis was performed retrospectively based on patient records. The inclusion criteria were performed standard allergological in vivo diagnostic and a BAT as a part of diagnostic workup. RESULTS: Eighty-two diagnostic investigations were performed in 52 patients. BAT was positive in 9 of 12 cases with a positive clinical history but negative skin test results. Furthermore, all patients who reported severe drug hypersensitivity reactions (anaphylactic reaction grade 2 and above) showed positive BAT (5/5), while only three of these five cases demonstrated a positive skin testing that led to the conclusion of possible immediate type drug hypersensitivity. CONCLUSIONS: Although skin tests remain the most important part of the primary diagnostic investigation, BAT is an additional valuable and sensitive in vitro test in the diagnostic procedure of immediate type allergic reactions to antibiotics. However, further standardized investigations are needed in order to calculate exact sensitivity and specificity of this diagnostic tool in both, adult and pediatric populations. PMID- 29508627 TI - The invisible injured. Psychological trauma in the Canadian military from the First World War to Afghanistan. PMID- 29508628 TI - Drug-associated pulmonary arterial hypertension. AB - INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension. METHODS: A systematic search was conducted using PubMed covering the period September 1970- 2017. The search term utilized was "drug induced pulmonary hypertension". This resulted in the identification of 853 peer-reviewed articles including case reports. Each paper was then reviewed by the authors for its relevance. The majority of these papers (599) were excluded as they related to systemic hypertension, chronic obstructive pulmonary disease, human immunodeficiency virus, pulmonary fibrosis, alternate differential diagnosis, treatment, basic science, adverse effects of treatment, and pulmonary hypertension secondary to pulmonary embolism. Agents affecting serotonin metabolism (and related anorexigens): Anorexigens, such as aminorex, fenfluramine, benfluorex, phenylpropanolamine, and dexfenfluramine were the first class of medications recognized to cause pulmonary arterial hypertension. Although most of these medications have now been withdrawn worldwide, they remain important not only from a historical perspective, but because their impact on serotonin metabolism remains relevant. Selective serotonin reuptake inhibitors, tryptophan, and lithium, which affect serotonin metabolism, have also been implicated in the development of pulmonary arterial hypertension. Interferon and related medications: Interferon alfa and sofosbuvir have been linked to the development of pulmonary arterial hypertension in patients with other risk factors, such as human immunodeficiency virus co-infection. Antiviral therapies: Sofosbuvir has been associated with two cases of pulmonary artery hypertension in patients with multiple risk factors for its development. Its role in pathogenesis remains unclear. Small molecule tyrosine kinase inhibitors: Small molecule tyrosine kinase inhibitors represent a relatively new class of medications. Of these dasatinib has the strongest evidence in drug-induced pulmonary arterial hypertension, considered a recognized cause. Nilotinib, ponatinib, carfilzomib, and ruxolitinib are newer agents, which paradoxically have been linked to both cause and treatment for pulmonary arterial hypertension. Monoclonal antibodies and immune regulating medications: Several case reports have linked some monoclonal antibodies and immune modulating therapies to pulmonary arterial hypertension. There are no large series documenting an increased prevalence of pulmonary arterial hypertension complicating these agents; nonetheless, trastuzumab emtansine, rituximab, bevacizumab, cyclosporine, and leflunomide have all been implicated in case reports. Opioids and substances of abuse: Buprenorphine and cocaine have been identified as potential causes of pulmonary arterial hypertension. The mechanism by which this occurs is unclear. Tramadol has been demonstrated to cause severe, transient, and reversible pulmonary hypertension. Chemotherapeutic agents: Alkylating and alkylating-like agents, such as bleomycin, cyclophosphamide, and mitomycin have increased the risk of pulmonary veno-occlusive disease, which may be clinically indistinct from pulmonary arterial hypertension. Thalidomide and paclitaxel have also been implicated as potential causes. Miscellaneous medications: Protamine appears to be able to cause acute, reversible pulmonary hypertension when bound to heparin. Amiodarone is also capable of causing pulmonary hypertension by way of recognized side effects. CONCLUSIONS: Pulmonary arterial hypertension remains a rare diagnosis, with drug-induced causes even more uncommon, accounting for only 10.5% of cases in large registry series. Despite several agents being implicated in the development of PAH, the supportive evidence is typically limited, based on case series and observational data. Furthermore, even in the drugs with relatively strong associations, factors that predispose an individual to PAH have yet to be elucidated. PMID- 29508629 TI - Thymosin beta 4 regulation of actin in sepsis. AB - INTRODUCTION: Sepsis is the dysregulated host response to an infection resulting in life-threatening organ damage. Thymosin Beta 4 is an actin binding protein that inhibits the polymerization of G-actin into F-actin and improves mortality when administered intravenously to septic rats. Thymosin Beta 4 decreases inflammatory mediators, lowers reactive oxygen species, up-regulates anti oxidative enzymes, anti-inflammatory genes, and anti-apoptotic enzymes making it an interesting protein to study in sepsis. Areas covered: The authors summarize the current knowledge of actin and Thymosin Beta 4 as it relates to sepsis via a comprehensive literature search. Expert opinion: Sepsis results in measurable levels of F-actin in the circulation as well as a decreased concentration of Thymosin Beta 4. It is speculated that F-actinemia contributes to microcirculatory perturbations present in patients with sepsis by disturbing laminar flow. Given that Thymosin Beta 4 inhibits the polymerization of F-actin, it is possible that Thymosin Beta 4 decreases mortality in sepsis via the regulation of actin as well as its other anti-inflammatory properties and should be further pursued as a clinical trial in humans with sepsis. PMID- 29508630 TI - The importance of microfluidics for the preparation of nanoparticles as advanced drug delivery systems. AB - INTRODUCTION: Nanoparticles are anticipated to overcome persistent challenges in efficient drug delivery, but the limitations associated with conventional methods of preparation are resulting in slow translation from research to clinical applications. Due to their enormous potential, microfluidic technologies have emerged as an advanced approach for the development of drug delivery systems with well-defined physicochemical characteristics and in a reproducible manner. Areas covered: This review provides an overview of microfluidic devices and materials used for their manufacturing, together with the flow patterns and regimes commonly used for nanoparticle preparation. Additionally, the different geometries used in droplet microfluidics are reviewed, with particular attention to the co-flow geometry used for the production of nanoparticles. Finally, this review summarizes the main and most recent nanoparticulate systems prepared using microfluidics, including drug nanosuspensions, polymeric, lipid, structured, and theranostic nanoparticles. Expert opinion: The production of nanoparticles at industrial scale is still a challenge, but the microfluidic technologies bring exciting opportunities to develop drug delivery systems that can be engineered in an easy, cost-effective and reproducible manner. As a highly interdisciplinary research field, more efforts and general acceptance are needed to allow for the translation of nanoparticulate drug delivery systems from academic research to the clinical practice. PMID- 29508631 TI - Clinico-epidemiology of arthropod stings and bites in primary hospitals of North Western province of Sri Lanka. AB - OBJECTIVE: Arthropod stinging and bites are common environmental hazards in Sri Lanka. However, their medical importance has not been fully evaluated yet. This study aims to study the burden, epidemiology, and outcome of stings and bites in primary hospitals in the Kurunegala district in North Western Province (NWP) of Sri Lanka. METHODOLOGY: The study was conducted one year from 25th May 2013 to 25th May 2014. Details of all stings and bites admissions and their outcomes were retrospectively extracted from hospital records in all 44 primary hospitals in the district. RESULTS: There were 623 stings and bites with population incidence of 38/100,000 (95% CI 27-52). There were no deaths. Median age was 38 years (IQR: 19-53 years), and 351 (56%) were males. Most of stings and bites (75%) occurred in the daytime. Median time to hospital arrival was 55 minutes (IQR: 30 min to 2 h). The offending arthropods had been identified in 557 (89%) cases, of them, 357 (57%) were Hymenoptera (hornet and bees), 99 centipedes, 61 spiders and 40 scorpions. Local pain occurred in 346 (56%) cases - centipede 69 (70%), Scorpion 24 (60%), spider 36 (59%), Hymenoptera 187 (52%) and unidentified 30 (45%). Hymenoptera stings and spider bites occurred between 06 am to 12 noon, and scorpion stings and centipede bites mostly occurred between 06 pm to 12 midnight. Mild, moderate to severe anaphylaxis reactions occurred in 173 (28%) patients including 110 Hymenoptera stings - mild 39, moderate 62 and severe 9. From primary hospitals, 53(9%) cases had been transferred to tertiary care units for further management. Of them, 41 cases were Hymenoptera stings and 24 (58%) of them had mild, moderate to severe anaphylaxis. In the entire group, 27% severe cases received adrenaline. CONCLUSIONS: The primary hospitals in NW province of Sri Lanka manage large numbers of arthropod stings and bites. These include Hymenoptera (hornet and bee), centipedes, spiders, and scorpions. Pain, swellings and anaphylactic reactions were the most common adverse effects. PMID- 29508632 TI - PAK4 pathway as a potential therapeutic target in pancreatic cancer. PMID- 29508633 TI - Rabbit relinquishment through online classified advertisements in the United Kingdom: when, why, and how many? AB - To identify implicit causes of companion rabbit relinquishment, this study investigated whether there was annual and seasonal variation in the number of advertisements and ages of rabbits posted as free or for sale on classified websites in the United Kingdom. The number of advertisements posted decreased from 2014 to 2016. There was an increase in the number of advertisements for free rabbits in winter compared with other seasons, which could be a result of caregivers' reduced willingness to interact with their rabbits and carry out husbandry during periods of inclement weather. Rabbits advertised as free were older than rabbits advertised for sale, and rabbits relinquished due to human related reasons were older than those relinquished because of rabbit-related factors. It is recommended that further research is undertaken to elucidate whether providing education to prospective rabbit caregivers regarding the life span of rabbits and their substantial husbandry requirements, especially in winter, would deter the purchase of rabbits by caregivers unable or unwilling to care for them in the long term. PMID- 29508635 TI - Sexual function and depressive symptoms in young women with hypothyroidism receiving levothyroxine/liothyronine combination therapy: a pilot study. AB - Objective Even mild hypothyroidism in pre-menopausal women is accompanied by impaired sexual functioning. The study was aimed at comparing the effect of levothyroxine, administered alone or in combination with liothyronine, on sexual function and depressive symptoms in pre-menopausal women treated because of hypothyroidism. Methods This quasi-randomized, single-blind study included 39 young women receiving levothyroxine treatment who, despite thyrotropin and thyroid hormone levels within normal limits, still experienced clinical symptoms of hypothyroidism. These patients were divided into two groups: group A (n = 20) continued levothyroxine treatment, while group B (n = 19) received levothyroxine/liothyronine combination therapy. At the beginning of the study, and 6 months later, all participants of the study filled in questionnaires evaluating female sexual functioning (Female Sexual Function Index; FSFI) and the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition; BDI-II). Results The study was completed by 37 women. Baseline sexual functioning and depressive symptoms did not differ between the study groups. Neither the total FSFI score nor the domain scores changed throughout the study in women who continued levothyroxine treatment. Compared to levothyroxine administered alone, levothyroxine/liothyronine combination therapy increased scores for two domains: sexual desire and arousal, tended to increase the total FSFI score, as well as tended to decrease the overall BDI-II score. The effect of the combination therapy on sexual function correlated with a treatment-induced increase in serum levels of free triiodothyronine and testosterone. Conclusions The obtained results suggest that levothyroxine administered together with liothyronine is superior to levothyroxine administered alone in affecting female sexual functioning. PMID- 29508634 TI - On-target and direct modulation of alloreactive T cells by a nanoparticle carrying MHC alloantigen, regulatory molecules and CD47 in a murine model of alloskin transplantation. AB - Biomimetic nanoparticles have been reported as immune modulators in autoimmune diseases and allograft rejections by numerous researchers. However, most of the therapeutics carrying antigens, toxins or cytokines underlay the mechanism of antigen presentation by cellular uptake of NPs through pinocytosis and phagocytosis. Few researches focus on the direct and antigen-specific modulation on T cells by NPs and combined use of multiple regulatory molecules. Here, polylactic-co-glycolic acid nanoparticles (PLGA-NPs) were fabricated as scaffold to cocoupling H-2Kb-Ig dimer, anti-Fas mAb, PD-L1-Fc, TGF-beta and CD47-Fc for the generation of alloantigen-presenting and tolerance-inducing NPs, termed killer NPs and followed by i.v. injection into a single MHC-mismatched murine model of alloskin transplantation. Three infusions prolonged alloskin graft survival for 45 days; depleted most of H-2Kb alloreactive CD8+ T cells in peripheral blood, spleen and local graft, in an antigen-specific manner. The killer NPs circulated throughout vasculature into various organs and local allograft, with a retention time up to 30 h. They made contacts with CD8+ T cells to facilitate vigorous apoptosis, inhibit the activation and proliferation of alloreactive CD8+ T cells and induce regulatory T cells in secondary lymphoid organs, with the greatly minimized uptake by phagocytes. More importantly, the impairment of host overall immune function and visible organ toxicity were not found. Our results provide the first experimental evidence for the direct and on target modulation on alloreactive T cells by the biodegradable 200-nm killer NPs via co-presentation of alloantigen and multiple regulatory molecules, thus suggest a novel antigen-specific immune modulator for allograft rejections. PMID- 29508636 TI - Emerging pharmacotherapies for the treatment of atrial fibrillation. AB - INTRODUCTION: The main aim of current research on the field of atrial fibrillation (AF) treatment is to find new antiarrhythmic drugs with less side effects. Areas covered: Dronedarone and vernakalant showed promising result in term of efficacy and safety in selected patients. Ranolazine and colchicine are obtaining a role as a potential antiarrhythmic drug. Ivabradine is used in experimental studies for the rate control of AF. Moreover, new compounds (vanoxerine, moxonidine, budiodarone) are still under investigation. Monoclonal antibodies or selective antagonist of potassium channel are under investigation for long term maintenance of sinus rhythm. Clinical evidence and new pharmacological investigation on new drugs will be accurately reviewed in this article. Expert opinion: Dronedarone use is not recommended in patients with symptomatic heart failure (HF), NYHA class III-IV, depressed ventricular function and permanent AF, especially in patients assuming a concomitant therapy with digoxin. Vernakalant had superior efficacy than amiodarone, flecainide and propafenone in single studies and similar efficacy to direct current cardioversion. Several of the developing drugs examined in this paper show an interesting potential, in particular the research on selective ionic channel inhibition and on compounds which reduce the inflammation state, especially after ablation or surgery. PMID- 29508637 TI - Hierarchical competition models with the Allee effect III: multispecies. AB - A general notion of the Allee effect for higher dimensional triangular maps is proposed. A global dynamics theory is established. The theory is applied to multi species hierarchical models. Then we provide a detailed study of the global dynamics of three-species Ricker competition models with the Allee effect. Regions of extinction, exclusion and coexistence are identified. PMID- 29508638 TI - What influences a woman's decision to access contraception in Timor-Leste? Perceptions from Timorese women and men. AB - Timor-Leste's Maternal Mortality Ratio remains one of the highest in Asia. There is ample evidence that maternal deaths may be reduced substantially through the provision of good-quality modern methods of contraception. Many Timorese women wish to stop or delay having children. However, even when health services make contraception available, it does not mean that people will use it. Collaborating with Marie Stopes Timor-Leste, this qualitative research project used decolonising methodology to explore perceived influences contributing to contraceptive choices, and gain insight into how women's decisions to access contraception in Timor-Leste occur. Over two fieldwork periods (2013 and 2015), we used focus group discussions and structured interviews to speak with 68 women and 80 men, aged 18-49 years, across four districts of Timor-Leste. Findings demonstrate that the decision to access contraception is often contentious and complicated. These tensions echo concerns and ambiguities contained within global and national reproductive health policy. Overwhelmingly, participants emphasised that despite her wishes, a woman can only rarely exercise her right to access contraception freely and independently. She is most often constrained by family, cultural, traditional and educational influences. PMID- 29508640 TI - The use of selective estrogen receptor modulators on bone health in men. AB - Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review. PMID- 29508639 TI - A transcultural study of hoarding disorder: Insights from the United Kingdom, Spain, Japan, and Brazil. AB - Though problematic hoarding is believed to be a universal human behavior, investigations of clinically-defined hoarding disorder (HD) have been confined almost exclusively to Western countries. The current investigation sought to describe and directly compare the features of individuals meeting diagnostic criteria for HD across four distinct cultural settings. Participants were 82 individuals meeting DSM-5 diagnostic criteria for HD, recruited and assessed by trained clinicians at one of four project sites: London, Barcelona, Fukuoka, and Rio de Janeiro. A series of semi-structured interviews and self-report scales were administered, including assessments of socio-demographic characteristics, psychiatric comorbidity, and severity of hoarding and related features. Results indicate that the severity and core features of HD, as well as the cognitions and behaviors commonly associated with this condition, are largely stable across cultures. However, some differences in patient demographics-in particular age, marital status, and clinical expression-as well as comorbid psychiatric features also emerged. These findings confirm that HD, as defined in DSM-5, exists and presents with similar phenomenology across the studied cultures. Future, more fine-grained, research will be needed to study the features of the disorder in additional cultures (e.g., non-industrialized nations) and to evaluate the impact of these cultural aspects on the design of interventions for the disorder. PMID- 29508641 TI - Accounting for youth audiences' resistances to HIV and AIDS messages in the television drama Tsha Tsha in South Africa. AB - Theoretical debates and literature on E-E efforts in Africa have largely focussed on understanding how and why interventions on HIV and AIDS are effective in influencing behaviour change among target communities. Very few studies have sought to investigate and understand why a substantial number of targeted audiences resist the preferred readings that are encoded into E-E interventions on HIV and AIDS. Using cultural studies as its conceptual framework and reception analysis as its methodology, this study investigated and accounted for the oppositional readings that subaltern black South African youths negotiate from Tsha Tsha, an E-E television drama on HIV and AIDS in South Africa. Results from the study show that HIV and AIDS messages in Tsha Tsha face substantial resistances from situated youth viewers whose social contexts of consumption, shared identities, quotidian experiences and subjectivities, provide critical lines along which the E-E text is often resisted and inflected. These findings do not only hold several implications for E-E practice and research, they further reflect the utility of articulating cultural studies and reception analysis into a more nuanced theoretical and methodological framework for evaluating the 'impact' of E-E interventions on HIV and AIDS. PMID- 29508642 TI - Minding the gap: health and social care provider perceptions of parental communication and Black-Canadian youths' sexual health. AB - Health and social care providers' perceptions of Black-Canadian parent-youth sexual health communication has important implications for addressing knowledge gaps in the provision of services to young people and their parents. Providers' perceptions are crucial as they often act as advisers in tailoring programmes or services to the perceived needs of parents and youth. To understand these perceptions, 17 semi-structured in-depth interviews were conducted with providers who worked with African, Caribbean or Black (ACB) parents and youth in Toronto, Ontario, Canada. Critical Race Theory was used to help guide the interpretation of findings. The findings revealed providers believed that many parents were unlikely to explicitly discuss sexual health or HIV prevention with young people. Additionally, providers perceived that the content of and approach to parent youth sexual health communication differed between African and Caribbean clients. Moreover, providers believed that both parents' and young people's sex and gender impacted the quality, content and style of sexual health communication and had important implications for programme development. Overall, findings suggest a need for understanding the development of providers' perceptions of this communication, ways to address these perceptions and further parent-provider collaboration to promote Black youths' sexual health. PMID- 29508643 TI - Does surgeon experience affect patient-reported outcomes 1 year after primary total hip arthroplasty? AB - Background and purpose - Several studies have reported on the influence of various factors on patient-reported outcomes (PROs) after total hip arthroplasty (THA), but very few have focused on the experience of the surgeon. We investigated any association between surgeons' experience and PROs 1 year after primary THA. Patients and methods - Patient characteristics and surgical data at 10 hospitals in western Sweden were linked with PROs (EQ-5D-3L, Satisfaction Visual Analogue Scale (VAS), Pain VAS). These data were retrieved from the Swedish Hip Arthroplasty Register (SHAR). The surgeon's level of experience was divided into 4 subgroups related to experience: < 8 years, 8-15 years, and >15 years of clinical practice after specialist certificate. If no specialist certificate was obtained the surgery was classified as a trainee surgery. Surgeons with >15 years' experience as an orthopedic specialist were used as reference group in the analyses. Results - 8,158 primary THAs due to osteoarthritis were identified. We identified the surgeons' level of experience in 8,116 THAs. Data from SHAR on pre- and postoperative PROs and satisfaction at 1 year were available for 6,713 THAs. We observed a statistically significant difference among the 4 groups of surgeons regarding mean patient age, ASA classification, Charnley classification, diagnosis, and fixation technique. At 1 year follow-up, there were no statistically significant differences in Pain VAS, EQ-5D index, or EQ VAS among the subgroups of orthopedic specialists. Patients operated on by orthopedic trainees reported less satisfaction with the result of the surgery compared with the reference group. Interpretation - These findings indicate that patients can expect similar health improvements, pain reduction, and satisfaction 1 year after a primary THA operation irrespective of years in practice after specialty certification as an orthopedic surgeon. PMID- 29508644 TI - Quantitative Identification of the Annealing Degree of Apatite Fission Tracks Using Terahertz Time Domain Spectroscopy (THz-TDS). AB - Apatite fission-track (AFT) analysis, a widely used low-temperature thermochronology method, can provide details of the hydrocarbon generation history of source rocks for use in hydrocarbon exploration. The AFT method is based on the annealing behavior of fission tracks generated by 238U fission in apatite particles during geological history. Due to the cumbersome experimental steps and high expense, it is imperative to find an efficient and inexpensive technique to determinate the annealing degree of AFT. In this study, on the basis of the ellipsoid configuration of tracks, the track volume fraction model (TVFM) is established and the fission-track volume index is proposed. Furthermore, terahertz time domain spectroscopy (THz-TDS) is used for the first time to identify the variation of the AFT annealing degree of Durango apatite particles heated at 20, 275, 300, 325, 450, and 500 C for 10 h. The THz absorbance of the sample increases with the degree of annealing. In addition, the THz absorption index is exponentially related to annealing temperature and can be used to characterize the fission-track volume index. Terahertz time domain spectroscopy can be an ancillary technique for AFT thermochronological research. More work is urgently needed to extrapolate experimental data to geological conditions. PMID- 29508645 TI - Identifying the role of sociodemographic factors in major depressive disorder and suicidality among Spanish-speaking Latino patients in a federally qualified health center. AB - Rates of suicide and major depressive disorder (MDD) are currently at the highest point in the history of the United States (US). However, these rates are not distributed evenly among the population and Latinos show disproportionately high rates of both suicide and MDD. Yet, past research has infrequently explored factors related to suicide and MDD in primary care settings that serve as the major community portal for mental health among the Latino population. Thus, the current study investigated sociodemographic variables (marital status, nativity, education, employment, primary language, age, and gender) in terms of their relations with suicidal ideation, suicide risk, MDD, and MDD symptom severity among Latino primary care patients in a Federally Qualified Health Center (N = 634, M age = 39.46, SD = 11.46, 87.1% female). Results indicated that gender and Nativity were associated with suicidal ideation, older age was associated with suicide risk, and higher education and having a partner were negatively associated with MDD and depressive symptom severity. These results provide novel insight into the role of sociodemographic factors predicting suicide and MDD among Latinos in primary care, and suggest greater scientific and clinical attention can be focused on certain sociodemographic factors to offset mental health disparities among this group. PMID- 29508646 TI - Pattern of cerebral hypoperfusion according to the clinical staging in dementia with Lewy bodies. AB - This study aimed to detect different patterns of cerebral hypoperfusion in DLB according to clinical staging. Thirty-three patients with DLB were recruited by clinical dementia rating (CDR) stage. Compared with control, cerebral hypoperfusion was mainly observed in the lingual gyrus, the cuneus, the occipital gyrus in CDR 0.5 group; the fusiform gyrus, the middle temporal gyrus, and the posterior cingulate in CDR 1; and the lingual gyrus, the cuneus, the hippocampus, the fusiform gyrus, and the inferior frontal gyrus in CDR 2. Our findings suggest that cerebral hypoperfusion spreads to the frontal cortex and temporal lobes as disease progresses. PMID- 29508647 TI - Queering abortion rights: notes from Argentina. AB - In recent years, there have been calls in activist spaces to 'queer' abortion rights advocacy and to incorporate non-normative notions of gender identity and sexuality into abortion struggles and services. Argentina provides an interesting site in which to examine these developments, since there is a longstanding movement for abortion rights in a context of illegal abortion and a recent ground breaking Gender Identity Law that recognises key trans rights. In this paper, we analyse public documents from the abortion rights movement's main coalition - the National Campaign for the Right to Legal, Safe and Free Abortion - alongside interviews with 19 Campaign activists to examine shifts and tensions in contemporary abortion rights activism. We trace the incorporation of trans inclusive language into the newly proposed abortion rights bill and conclude by pointing to contextual factors that may limit or enhance the further queering of abortion rights. PMID- 29508648 TI - Who talks to whom about what? How interdisciplinary communication and knowledge of expertise distribution improve in integrated R&D labs. AB - Although several studies have examined the impact of open workspaces, there is still an on-going debate about its advantages and disadvantages. Our paper contributes to this debate by shedding light on three issues: the effect of open workspaces on (1) the flow of communication along and across hierarchical lines; (2) the content of communication; and (3) the specificities of open integrated laboratories. Our findings derive from a longitudinal case in a large pharmaceutical company that has relocated some R&D teams from enclosed to multi space offices and labs. The relocation has resulted in (a) increased interdisciplinary communication, particularly at lower hierarchical levels, (b) a shift of the location of discussions and the content of conversations and (c) an improved knowledge about expertise distribution. Practitioner Summary: Communication is essential in knowledge-driven organisations. This article examines the impact of a relocation of R&D employees from enclosed to multi-space offices and labs on communication patterns. We explain how the new environment fosters interdisciplinary communication, shifts the location of discussions and increases the knowledge of expertise distribution. PMID- 29508649 TI - New data about preeclampsia: some possibilities of prevention. AB - This concise report deals with the known effects of progestogen lack in early pregnancy with failure of implantation and blood supply to the placenta depending on proper trophoblast invasion, spiral artery remodeling, and vessel dilatation. The pathophysiology of preeclampsia will be outlined and the most recent data on the effect of dydrogesterone presented. Dydrogesterone appears to be able to reduce significantly the development of preeclampsia. The effect is related to begin with such prevention and this should be continued until 37th weeks of gestation which would also mean prevention of premature labor. PMID- 29508650 TI - Sex difference in long-distance open-water swimming races - does nationality play a role? AB - In open-water swimming events with non-elite swimmers held in the USA, but not in Europe, women were faster than men. We examined the sex difference in elite long distance open-water swimming races and the role of nationality by investigating 7,468 swimmers competing in 5 km, 10 km and 25 km FINA races held between 2000 and 2016. More men participated in 10 km and 25 km than in 5km races. Men were faster than women and the sex difference was similar in all race distances. Swimming speed was faster for 5km than for 10km, which in turn was faster than 25km. There was a major effect of nationality on swimming speed at 5 km and 10 km, but not at 25km. No dominance of a particular nationality was observed for all race distances. In summary, men were faster than women in all FINA race distances from 5km to 25km but nationality played no role in the sex difference. PMID- 29508651 TI - Why We Lie About Aid; development and the messy politics of change. PMID- 29508652 TI - A realistic in vitro exposure revealed seasonal differences in (pro-)inflammatory effects from ambient air in Fribourg, Switzerland. AB - Ambient air pollutant levels vary widely in space and time, therefore thorough local evaluation of possible effects is needed. In vitro approaches using lung cell cultures grown at the air-liquid interface and directly exposed to ambient air can offer a reliable addition to animal experimentations and epidemiological studies. To evaluate the adverse effects of ambient air in summer and winter a multi-cellular lung model (16HBE14o-, macrophages, and dendritic cells) was exposed in a mobile cell exposure system. Cells were exposed on up to three consecutive days each 12 h to ambient air from Fribourg, Switzerland, during summer and winter seasons. Higher particle number, particulate matter mass, and nitrogen oxide levels were observed in winter ambient air compared to summer. Good cell viability was seen in cells exposed to summer air and short-term winter air, but cells exposed three days to winter air were compromised. Exposure of summer ambient air revealed no significant upregulation of oxidative stress or pro-inflammatory genes. On the opposite, the winter ambient air exposure led to an increased oxidative stress after two exposure days, and an increase in three assessed pro-inflammatory genes already after 12 h of exposure. We found that even with a short exposure time of 12 h adverse effects in vitro were observed only during exposure to winter but not summer ambient air. With this work we have demonstrated that our simple, fast, and cost-effective approach can be used to assess (adverse) effects of ambient air. PMID- 29508653 TI - Reply to letter to the editor on: "is there a relationship between excessive sugar consumption and sleep quality in children?" PMID- 29508654 TI - Primary to comprehensive stroke center transfers: Appropriateness, not futility. AB - Background and purpose Ischemic stroke patients must be transferred to comprehensive stroke centers for endovascular treatment, but this transfer can be interpreted post hoc as "futile" if patients do not ultimately undergo the procedure or have a poor outcome. We posit that transfer decisions must instead be evaluated in terms of appropriateness at the time of decision-making. Methods We propose a classification schema for Appropriateness of Transfer for Endovascular Thrombectomy based on patient, logistic, and center characteristics. Results The classification outline characteristics of patients that are 1. Appropriate for transfer for endovascular treatment; 2. Inappropriate for transfer; and 3. Appropriate for transfer for higher level of care. Conclusions Appropriate transfer decisions for endovascular treatment are significant for patient outcomes. A more nuanced understanding of transfer decision-making and a classification for such transfers can help minimize inappropriate transfers in acute stroke. PMID- 29508656 TI - Is there a relationship between excessive sugar consumption and sleep quality in children? PMID- 29508655 TI - Graft failure and recurrence of symptoms after coronary artery bypass grafting. AB - OBJECTIVES: Saphenous vein grafts (SVGs) most often used in coronary artery bypass grafting (CABG) are subject to graft disease and have poor long-term patency, however the clinical implication of this is not completely known. We aim to assess the influence of graft failure on the postoperative recurrence of coronary artery disease (CAD) symptoms in relation to the contribution from progression of atherosclerosis in the native coronary vessels. DESIGN: Within the SWEDEHEART registry we identified 46,663 CABG cases between 2001 and 2015 with patient age 40-80 years where single internal mammary artery (IMA) anastomosis (IMA), single IMA with one (1SVG) or multiple SVG anastomoses (2+ SVG) had been performed. Clinical characteristics as well as mortality and postoperative incidence of coronary angiography were recorded and multivariable adjusted hazard ratios were calculated. Indications for the angiographies and occurrence of graft failure were also registered. RESULTS: The adjusted hazard ratio for death was similar for the three groups. The adjusted hazard ratio for being submitted to angiography as compared to 2+ SVG was (95% CI) 1.24 (1.06-1.46) for IMA and 1.21 (1.15-1.28) for 1SVG. Failed grafts were found at the first postoperative angiography with preceding CAD symptoms in 21.4% of patients in the IMA group, 41.6% in the 1SVG group and 61.1% in the 2+ SVG group. CONCLUSIONS: A substantial amount of angiographies occur in patients without any graft failure and a large part of postoperative recurrence of CAD symptoms and are likely attributed to IMA failure or progression of atherosclerosis in the native coronary arteries. PMID- 29508658 TI - Special focus: metals in medicine. PMID- 29508657 TI - Analysis of LncRNA expression in cell differentiation. AB - Lineage-specific cell differentiation is a precise and coordinated biological process. To explore the roles of long noncoding RNA (lncRNA) in this process, the expression of polyA-minus RNAs was comparatively studied during the course of myocyte and adipocyte differentiation. In addition to identifying thousands of novel lncRNAs, distinct lncRNA profiles were revealed during lineage-specific differentiation, showing their active involvement in this process. This study further found that lncRNAs were organized in clusters and are co-regulated, constituting transcription open domains (TODs). In myocyte differentiation of C2C12 cells, loss-of-function screening identified three myogenic lncRNAs. Knockdown of their expression compromised not only the differentiation process, but also the essential signaling pathway. In addition to showing that lncRNAs are actively involved in cell differentiation, our results start to reveal a comprehensive signaling pathway, involving both protein and lncRNA factors. PMID- 29508659 TI - Blood culture useful only in selected patients with urinary tract infections - a literature review. AB - PURPOSE: The practice of obtaining blood culture in febrile urinary tract infections is controversial, considering that blood cultures rarely provide additional useful information compared to urine cultures alone. Furthermore, whether a longer treatment duration is necessary in bacteremic patients is also controversial. Here, we aim to review to relevant studies. MATERIALS AND METHODS: We searched PubMed and Scopus for studies providing information regarding the discordance between urine and blood cultures. We also searched for clinical trials regarding the treatment duration in bacteremic patients with urinary tract infections. RESULTS: It seems that a higher likelihood of a negative urine culture (e.g. in patients with antibiotic pre-treatment) combined with a higher likelihood of a positive blood culture (e.g. patients with high fever, or patients with complicated urinary tract infections) increases the chance that a blood culture might provide additional useful information. Furthermore, when polymicrobial infection or contamination of the urine specimen is likely (e.g. in patients with indwelling urinary tract catheters or bedridden patients with frequent hospitalizations and catheterizations), blood cultures may help identify the clinically significant pathogen and guide the choice of the antimicrobial regimen. Finally, because bacteremia has been associated with more severe disease and worse outcomes, some authors suggest a longer treatment duration for bacteremic patients. However, whether the presence of bacteremia should alter the duration of treatment remains unclear. CONCLUSIONS: Obtaining blood cultures may be useful in selected patients. Randomized controlled trials are needed to clarify the value of bacteremia in guiding the duration of antimicrobial therapy. PMID- 29508660 TI - A case of semantic variant primary progressive aphasia with Pick's pathology. AB - Neurodegenerative diseases are caused by aggregation of specific proteins that catalyze a cascade of changes that ultimately lead to neurodegeneration. This concept guides current diagnostic approaches, as well as clinical trials, that focus on detecting or removing amyloid or tau from the brain. The semantic variant of primary progressive aphasia (svPPA), a clinical syndrome associated with frontotemporal lobar degeneration (FTLD) pathology, is usually associated with the molecular pathology TDP-C, but there are cases with TDP-B and Pick's disease. The existing literature on the clinical differentiation of these pathologies is limited. Here, we present a case study, in conjunction with a cross-sectional voxel-based morphometry (VBM), to elucidate the clinical and imaging features of a patient with svPPA due to Pick's disease. PMID- 29508661 TI - RSA migration of total knee replacements. AB - Purpose - We performed a systematic review and meta-analyses to evaluate the early and long-term migration patterns of tibial components of TKR of all known RSA studies. Methods - Migration pattern was defined as at least 2 postoperative RSA follow-up moments. Maximal total point motion (MTPM) at 6 weeks, 3 months, 6 months, 1 year, 2 years, 5 years, and 10 years were considered. Results - The literature search yielded 1,167 hits of which 53 studies were included, comprising 111 study groups and 2,470 knees. The majority of the early migration occurred in the first 6 months postoperatively followed by a period of stability, i.e., no or very little migration. Cemented and uncemented tibial components had different migration patterns. For cemented tibial components there was no difference in migration between all-poly and metal-backed components, between mobile bearing and fixed bearing, between cruciate retaining and posterior stabilized. Furthermore, no difference existed between TKR measured with model based RSA or marker-based RSA methods. For uncemented TKR there was some variation in migration with the highest migration for uncoated TKR. Interpretation - The results from this meta-analysis on RSA migration of TKR are in line with both the survival analyses results from joint registries of these TKRs as well as revision rates results from meta-analyses, thus providing further proof for the association between early migration and late revision for loosening. The pooled migration patterns can be used both as benchmarks and for defining migration thresholds for future evaluation of new TKR. PMID- 29508662 TI - A potential neurophysiological correlate of electric-acoustic pitch matching in adult cochlear implant users: Pilot data. AB - The overall goal of this study was to identify an objective physiological correlate of electric-acoustic pitch matching in unilaterally implanted cochlear implant (CI) participants with residual hearing in the non-implanted ear. Electrical and acoustic stimuli were presented in a continuously alternating fashion across ears. The acoustic stimulus and the electrical stimulus were either matched or mismatched in pitch. Auditory evoked potentials were obtained from nine CI users. Results indicated that N1 latency was stimulus-dependent, decreasing when the acoustic frequency of the tone presented to the non-implanted ear was increased. More importantly, there was an additional decrease in N1 latency in the pitch-matched condition. These results indicate the potential utility of N1 latency as an index of pitch matching in CI users. PMID- 29508663 TI - Daptomycin and combination daptomycin-ceftaroline as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia. PMID- 29508664 TI - Low sensitivity of a-defensin (Synovasure) test for intra-operative exclusion of prosthetic joint infection. AB - Background and purpose - The Synovasure lateral flow test was developed as a rapid test for the detection or exclusion of periprosthetic joint infection (PJI). 3 studies have reported promising results on its diagnostic value in total joint revision surgery. We aimed to assess the sensitivity and specificity of the Synovasure test to exclude infection in patients undergoing revision surgery for suspected early aseptic loosening of a total hip or knee arthroplasty. Patients and methods - In a prospective study design, 37 patients who underwent revision surgery for suspected early aseptic loosening (< 3 years after primary arthroplasty) were included. The Synovasure test was used intraoperatively to confirm the aseptic nature of the loosening and 6 tissue cultures were obtained in all cases. Exclusion criteria were patients with a preoperatively confirmed PJI, acute revisions (< 90 days after primary arthroplasty) and cases with malpositioning, wear, or instability of the prosthesis. Results - 5 of the 37 patients were diagnosed with a PJI based on the intraoperative tissue cultures. In only 1 out of these 5 cases this was confirmed by the intraoperative Synovasure test. No tests were falsely positive. Interpretation - In this case series the Synovasure lateral flow test had a low sensitivity to exclude PJI in patients with suspected aseptic loosening. The role of the Synovasure lateral flow test in the intraoperative exclusion of PJI during revision surgery for suspected early aseptic loosening appears to be more limited than previously indicated. PMID- 29508665 TI - Collaboration and patient safety at an emergency department - a qualitative case study. AB - Purpose The purpose of this paper is to examine how conflicts about collaboration between staff at different departments arose during the establishment of a new emergency department and how these conflicts affected the daily work and ultimately patient safety at the emergency department. Design/methodology/approach This qualitative single case study draws on qualitative semi-structured interviews and participant observation. The theoretical concepts "availability" and "receptiveness" as antecedents for collaboration will be applied in the analysis. Findings Close collaboration between departments was an essential precondition for the functioning of the new emergency department. The study shows how a lack of antecedents for collaboration affected the working relation and communication between employees and departments, which spurred negative feelings and reproduced conflicts. This situation was seen as a potential threat for the safety of the emergency patients. Research limitations/implications This study presents a single case study, at a specific point in time, and should be used as an illustrative example of how contextual and situational factors affect the working environment and through that patient safety. Originality/value Few studies provide an in-depth investigation of what actually takes place when collaboration between professional groups goes wrong and escalates, and how problems in collaboration may affect patient safety. PMID- 29508666 TI - How to improve healthcare? Identify, nurture and embed individuals and teams with "deep smarts". AB - Purpose Unlocking and transferring skills and capabilities in individuals to the teams they work within, and across, is the key to positive organisational development and improved patient care. Using the "deep smarts" model, the purpose of this paper is to examine these issues. Design/methodology/approach The "deep smarts" model is described, reviewed and proposed as a way of transferring knowledge and capabilities within healthcare organisations. Findings Effective healthcare delivery is achieved through, and continues to require, integrative care involving numerous, dispersed service providers. In the space of overlapping organisational boundaries, there is a need for "deep smarts" people who act as "boundary spanners". These are critical integrative, networking roles employing clinical, organisational and people skills across multiple settings. Research limitations/implications Studies evaluating the barriers and enablers to the application of the deep smarts model and 13 knowledge development strategies proposed are required. Such future research will empirically and contemporary ground our understanding of organisational development in modern complex healthcare settings. Practical implications An organisation with "deep smarts" people - in managerial, auxiliary and clinical positions - has a greater capacity for integration and achieving improved patient-centred care. Originality/value In total, 13 developmental strategies, to transfer individual capabilities into organisational capability, are proposed. These strategies are applicable to different contexts and challenges faced by individuals and teams in complex healthcare organisations. PMID- 29508667 TI - Physicians' accounts of frontline tensions when implementing pilot projects to improve primary care. AB - Purpose Canada's primary care system has been described as "a culture of pilot projects" with little evidence of converting successful initiatives into funded, permanent programs or sharing project outcomes and insights across jurisdictions. Health services pilot projects are advocated as an effective strategy for identifying promising models of care and building integrated care partnerships in local settings. In the qualitative study reported here, the purpose of this paper is to investigate the strengths and challenges of this approach. Design/methodology/approach Semi-structured interviews were conducted with 34 primary care physicians who discussed their experiences as pilot project leads. Following thematic analysis methods, broad system issues were captured as well as individual project information. Findings While participants often portrayed themselves as advocates for vulnerable patients, mobilizing healthcare organizations and providers to support new models of care was discussed as challenging. Competition between local healthcare providers and initiatives could impact pilot project success. Participants also reported tensions between their clinical, project management and research roles with additional time demands and skill requirements interfering with the work of implementing and evaluating service innovations. Originality/value Study findings highlight the complexity of pilot project implementation, which encompasses physician commitment to addressing care for vulnerable populations through to the need for additional skill set requirements and the impact of local project environments. The current pilot project approach could be strengthened by including more multidisciplinary collaboration and providing infrastructure supports to enhance the design, implementation and evaluation of health services improvement initiatives. PMID- 29508668 TI - Next level of board accountability in health care quality. AB - Purpose The purpose of this paper is to offer six principles that health system leaders can apply to establish a governance and management system for the quality of care and patient safety. Design/methodology/approach Leaders of a large academic health system set a goal of high reliability and formed a quality board committee in 2011 to oversee quality and patient safety everywhere care was delivered. Leaders of the health system and every entity, including inpatient hospitals, home care companies, and ambulatory services staff the committee. The committee works with the management for each entity to set and achieve quality goals. Through this work, the six principles emerged to address management structures and processes. Findings The principles are: ensure there is oversight for quality everywhere care is delivered under the health system; create a framework to organize and report the work; identify care areas where quality is ambiguous or underdeveloped (i.e. islands of quality) and work to ensure there is reporting and accountability for quality measures; create a consolidated quality statement similar to a financial statement; ensure the integrity of the data used to measure and report quality and safety performance; and transparently report performance and create an explicit accountability model. Originality/value This governance and management system for quality and safety functions similar to a finance system, with quality performance documented and reported, data integrity monitored, and accountability for performance from board to bedside. To the authors' knowledge, this is the first description of how a board has taken this type of systematic approach to oversee the quality of care. PMID- 29508669 TI - Networks as systems. AB - Purpose The purpose of this paper is to present a case study of the World Health Organization's Global Healthcare Workforce Alliance (GHWA). Based on a commissioned evaluation of GHWA, it applies network theory and key concepts from systems thinking to explore network emergence, effectiveness, and evolution to over a ten-year period. The research was designed to provide high-level strategic guidance for further evolution of global governance in human resources for health (HRH). Design/methodology/approach Methods included a review of published literature on HRH governance and current practice in the field and an in-depth case study whose main data sources were relevant GHWA background documents and key informant interviews with GHWA leaders, staff, and stakeholders. Sampling was purposive and at a senior level, focusing on board members, executive directors, funders, and academics. Data were analyzed thematically with reference to systems theory and Shiffman's theory of network development. Findings Five key lessons emerged: effective management and leadership are critical; networks need to balance "tight" and "loose" approaches to their structure and processes; an active communication strategy is key to create and maintain support; the goals, priorities, and membership must be carefully focused; and the network needs to support shared measurement of progress on agreed-upon goals. Shiffman's middle range network theory is a useful tool when guided by the principles of complex systems that illuminate dynamic situations and shifting interests as global alliances evolve. Research limitations/implications This study was implemented at the end of the ten-year funding cycle. A more continuous evaluation throughout the term would have provided richer understanding of issues. Experience and perspectives at the country level were not assessed. Practical implications Design and management of large, complex networks requires ongoing attention to key issues like leadership, and flexible structures and processes to accommodate the dynamic reality of these networks. Originality/value This case study builds on growing interest in the role of networks to foster large-scale change. The particular value rests on the longitudinal perspective on the evolution of a large, complex global network, and the use of theory to guide understanding. PMID- 29508670 TI - Paired learning - improving collaboration between clinicians and managers. AB - Purpose Close collaboration between NHS clinicians and managers is essential in providing effective healthcare, but relationships between the two groups are often poor. Paired learning is a peer-peer buddying tool that can break down barriers, increase knowledge and change attitudes. Paired learning has been used with doctors and managers but not for multi-professional clinicians. The purpose of this paper is to assess whether a paired learning programme (PLP) can improve knowledge and attitudes between multi-professional NHS clinicians and managers. Design/methodology/approach A PLP pairing clinicians and managers over a four month period to participate in four buddy meetings and three group meetings was delivered. A mixed methods study was completed which collected quantitative and qualitative data in the form of pre- and post-course questionnaires and focus group discussions. Findings Participants reported increased understanding, changed attitudes and better communication between clinicians and managers following the PLP. Self-rated knowledge increased across all domains but was only statistically significant for ability to engage, ability to establish shared goals and knowledge of decision-making processes. Research limitations/implications This paper highlights the value of paired learning in encouraging collaboration between clinicians and managers but is of a small size. The PLP did not provide enough data to examine relationships and interaction between clinicians and managers, this should be considered in any future work. Originality/value To the authors' knowledge, this is the only published paper showing data from a PLP involving multi-disciplinary health professionals. PMID- 29508671 TI - A long-term follow-up of a physician leadership program. AB - Purpose Physician leadership programs serve to develop individual capabilities and to affect organizational outcomes. Evaluations of such programs often focus solely on short-term increases in individual capabilities. The purpose of this paper is to assess long-term individual and organizational outcomes of the Stanford Leadership Development Program. Design/methodology/approach There are three data sources for this mixed-methods study: a follow-up survey in 2013-2014 of program participants ( n=131) and matched (control) non-participants ( n=82) from the 2006 to 2011 program years; promotion and retention data; and qualitative in-person interview data. The authors analyzed survey data across leadership knowledge, skills, and attitudes as well as leadership titles held, following program participation using Pearson's chi2 test of independence. Using logistic regression, the authors analyzed promotion and retention among participants and non-participants. Finally, the authors applied both a grounded theory approach and qualitative content analysis to analyze interview data. Findings Program participants rated higher than non-participants across 25 of 30 items measuring leadership knowledge, skills, and attitudes, and were more likely to hold regional/national leadership titles and to have gained in leadership since program participation. Asian program participants were significantly more likely than Asian non-participants to have been promoted, and women participants were less likely to have left the institution than non-participants. Finally, qualitative interviews revealed the long-term impact of leadership learning and networking, as well as the enduring, sustained impact on the organization of projects undertaken during the program. Originality/value This study is unique in its long-term and comprehensive mixed-methods nature of evaluation to assess individual and organizational impact of a physician leadership program. PMID- 29508672 TI - Integrated care. AB - Purpose The purpose of this paper is to try and understand how several organisations in one area in England are working together to develop an integrated care programme. Weick's (1995) concept of sensemaking is used as a lens to examine how the organisations are working collaboratively and maintaining the programme. Design/methodology/approach Qualitative methods included: non participant observations of meetings, interviews with key stakeholders and the collection of documents relating to the programme. These provided wider contextual information about the programme. Comprehensive field notes were taken during observations and analysed alongside interview transcriptions using NVIVO software. Findings This paper illustrates the importance of the construction of a shared identity across all organisations involved in the programme. Furthermore, the wider policy discourse impacted on how the programme developed and influenced how organisations worked together. Originality/value The role of leaders from all organisations involved in the programme was of significance to the overall development of the programme and the sustained momentum behind the programme. Leaders were able to generate a "narrative of success" to drive the programme forward. This is of particular relevance to evaluators, highlighting the importance of using multiple methods to allow researchers to probe beneath the surface of programmes to ensure that evidence moves beyond this public narrative. PMID- 29508673 TI - Driving for successful change processes in healthcare by putting staff at the wheel. AB - Purpose The purpose of this paper is to describe five salient factors that emerge in two successful change processes in healthcare. Organizational changes in healthcare are often characterized by problems and solutions that have been formulated by higher levels of management. This top-down management approach has not been well received by the professional community. As a result, improvement processes are frequently abandoned, resulting in disrupted and dysfunctional organizations. This paper presents two successful change processes where managerial leadership was used to coach the change processes by distributing mandates and resources. After being managerially initiated, both processes were driven by local agency, decisions, planning and engagement. Design/methodology/approach The data in the paper derive from two qualitative case studies. Data were collected through in-depth interviews, observations and document studies. The cases are presented as process descriptions covering the different phases of the change processes. The focus in the studies is on the roles and interactions of the actors involved, the type of leadership and the distribution of agency. Findings Five factors emerged as paramount to the successful change processes in the two cases: local ownership of problems; a coached process where management initiates the change process and the problem recognition, and then lets the staff define the problems, formulate solutions and drive necessary changes; distributed leadership directed at enabling and supporting the staff's intentions and long-term self-leadership; mutually formulated norms and values that serve as a unifying force for the staff; and generous time allocation and planning, which allows the process to take time, and creates room for reevaluation. The authors also noted that in both cases, reorganization into multi-professional teams lent stability and endurance to the completed changes. Originality/value The research shows how management can initiate and support successful change processes that are staff driven and characterized by local agency, decisions, planning and engagement. Empirical descriptions of successful change processes are rare, which is why the description of such processes in this research increases the value of the paper. PMID- 29508674 TI - Validation of a management competency assessment tool for health service managers. AB - Purpose The purpose of this paper is to report on the validation of a management competency assessment tool for health services managers (HSM), which resulted from the development and validation of the framework, addressed by a previous paper. Design/methodology/approach The management competency assessment tool (MCAP Tool) was validated using assessment data from a sample of 117 senior and middle managers working in two public hospitals and five community services in Victoria, Australia. The assessments were conducted between January 2013 and September 2014. Findings Both validity and reliability of the MCAP Tool were demonstrated. Practical implications The MCAP Tool has the potential to assist in the measurement of the competencies of HSM. Further research is required to determine if the framework and tool are applicable to HSM in other settings. Originality/value This is the first published study outlining the validity and reliability of an assessment tool to measure the management competencies of Australian health service managers. PMID- 29508675 TI - Bioassays and In Silico Methods in the Identification of Human DNA Topoisomerase IIalpha Inhibitors. AB - BACKGROUND: The family of DNA topoisomerases comprises a group of enzymes that catalyse the induction of topological changes to DNA. These enzymes play a role in the cell replication machinery and are, therefore, important targets for anticancer drugs - with human DNA topoisomerase IIalpha being one of the most prominent. Active compounds targeting this enzyme are classified into two groups with diverse mechanisms of action: DNA poisons act by stabilizing a covalent cleavage complex between DNA and the topoisomerase enzyme, transforming it into a cellular toxin, while the second diverse group of catalytic inhibitors, provides novel inhibition avenues for tackling this enzyme due to frequent occurrence of side effects observed during the DNA poison therapy. METHODS: Based on a comprehensive literature search we present an overview of available bioassays and in silico methods in the identification of human DNA topoisomerase IIalpha inhibitors. RESULTS AND CONCLUSION: A comprehensive outline of the available methods and approaches that explore in detail the in vitro mechanistic and functional aspects of the topoisomerase IIalpha inhibition of both topo IIalpha inhibitor groups is presented. The utilized in vitro cell-based assays and in vivo studies to further explore the validated topo IIalpha inhibitors in subsequent preclinical stages of the drug discovery are discussed. The potential of in silico methods in topoisomerase IIalpha inhibitor discovery is outlined. A list of practical guidelines was compiled to aid new as well experienced researchers in how to optimally approach the design of targeted inhibitors and validation in the preclinical drug development stages. PMID- 29508676 TI - Novel Optical Techniques for Imaging Microcirculation in the Diabetic Foot. AB - BACKGROUND: The most severe diabetic foot ulcers are those related with critical ischemia, which is primarily diagnosed with non-invasive diagnostics. However, these diagnostics have several disadvantages. For example, they only provide global indications of the (macro)level of ischemia. A potential solution can be found in novel optical imaging techniques for local assessment of the microcirculation in diabetic foot ulcers. This review provides an overview of these imaging techniques (Laser Doppler Perfusion Imaging, Laser Speckle Contrast Imaging, Photoacoustic Imaging and Hyperspectral Imaging) and their applicability for the diagnostic assessment of microcirculation in diabetic foot ulcers. METHOD: For each technique, the following parts are described: a) their technical background; b) general clinical applications; and, c) its application for microcirculation assessment in diabetic foot ulcers. Parts a-b are based on a narrative review of the literature, part c on a systematic review that was performed in the database Scopus, covering the period from January 1, 2000 to November 31, 2017. RESULTS: Each of these techniques has specific advantages and disadvantages for imaging microcirculation. Potential clinical use depends on measurement aims, and clinical relevance. However, none of the techniques has a strongly established clinical relevance yet: we found a limited number of publications describing clinical outcomes. Future research is needed to determine which technique is the most clinically relevant for the assessment of microcirculation in diabetic foot ulcers. CONCLUSION: Although promising, the currently available novel optical techniques need to be further improved technically and prospective trials are necessary to evaluate their clinical value. PMID- 29508677 TI - An Overview on Diabetic Foot Infections, including Issues Related to Associated Pain, Hyperglycemia and Limb Ischemia. AB - Factors strongly related to the risk of developing diabetic foot infections include vascular, neuropathic and hyperglycemic complications of long-standing diabetes mellitus. These infections are common and serious, posing a worldwide burden on administrative providers of healthcare, patients and physicians. The most appropriate approach to these infections is with a multidisciplinary team. This subchapter summarizes the current state-of the-art concerning therapy, and scientific knowledge, for peripheral arterial insufficiency, hyperglycemia, and peripheral neuropathy of the diabetic foot, with an emphasis on the infectious complications. PMID- 29508678 TI - Editorial: Current Vision of Systemic Autoimmune Diseases - From Diagnosis to Management. PMID- 29508679 TI - Newborn electroencephalographic correlates of maternal prenatal depressive symptoms. AB - Maternal perinatal depression exerts pervasive effects on the developing brain, as evidenced by electroencephalographic (EEG) patterns that differ between children of women who do and do not meet DSM or ICD diagnostic criteria. However, little research has examined if the same EEG pattern of right-frontal alpha asymmetry exists in newborns and thus originates in utero independent of postnatal influences, and if depressive symptoms are associated with this neural signature. Utilizing 125-lead EEG (n=18), this study considered clinician-rated maternal prenatal depressive symptoms in relation to newborn EEG. Maternal depressive symptomatology was associated with greater relative right-frontal alpha asymmetry during quiet sleep. These results suggest that even subclinical levels of maternal depression may influence infant brain development, and further support the role of the prenatal environment in shaping children's future neurobehavioral trajectories. PMID- 29508680 TI - Medium-chain TAG improve intestinal integrity by suppressing toll-like receptor 4, nucleotide-binding oligomerisation domain proteins and necroptosis signalling in weanling piglets challenged with lipopolysaccharide. AB - This study was conducted to evaluate whether medium-chain TAG (MCT) could alleviate Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury by regulating intestinal epithelial inflammatory response, as well as necroptosis. A total of twenty-four weanling piglets were randomly allotted to one of four treatments in a 2*2 factorial arrangement including diet type (5 % maize oil v. 4 % MCT+1 % maize oil) and immune stress (saline v. E. coli LPS). The piglets were fed diets containing maize oil or MCT for 21 d. On 21 d, piglets were injected intraperitoneally with saline or LPS. The blood and intestinal samples were collected at 4 h post injection. Supplementation with MCT improved intestinal morphology, digestive and barrier function, indicated by increased jejunal villus height, increased jejunal and ileal disaccharidases (sucrase and maltase) activities, as well as enhanced protein expression of claudin-1. Furthermore, the protein expression of heat-shock protein 70 in jejunum and the concentration of TNF-alpha in plasma were reduced in the piglets fed diets supplemented with MCT. In addition, MCT down-regulated the mRNA expression of toll-like receptor 4 (TLR4) and nucleotide-binding oligomerisation domain proteins (NOD) signalling related genes in jejunum and ileum. Finally, MCT inhibited jejunal and ileal enterocyte necroptosis indicated by suppressed mRNA expression of the receptor interacting protein 3 and mixed-lineage kinase domain-like protein. These results indicate that MCT supplementation may be closely related to inhibition of TLR4, NOD and necroptosis signalling pathways and concomitant improvement of intestinal integrity under an inflammatory condition. PMID- 29508681 TI - The effects of xylanase on grower pig performance, concentrations of volatile fatty acids and peptide YY in portal and peripheral blood. AB - Non-starch polysaccharides (NSP) present in wheat and barley can act as anti nutrients leading to an increase in digesta viscosity and a reduction in nutrient digestibility. Xylanase, an NSP-degrading enzyme, has been shown to increase nutrient digestibility in pigs. The objectives of this study were: (1) to identify the optimum inclusion level of xylanase in grower pig diets by measuring the effect of increasing enzyme levels on growth performance, the concentration of volatile fatty acids (VFA) and peptide YY concentration in portal and peripheral blood of grower pigs and (2) to increase our understanding of the interrelationships between xylanase inclusion, VFA production and peptide YY secretion. A total of 512 grower pigs ((Large White*Landrace)*MAXGRO) were allocated to pens creating 32 replicates of four pigs per pen per treatment. Pigs were allocated to trial weighing 14.2+/-0.31 kg and remained on trial until ~41.5+/-3.31 kg. The experiment was a dose response design with four inclusion levels (0, 8000, 16 000 or 32 000 BXU/kg) of xylanase (Econase XT). Diets were cereal-based wheat, barley mix formulated to meet or exceed the nutrient requirements of grower pigs. Body weight and feed intake were recorded to calculate growth performance. Pen faecal samples were collected to estimate DM, organic matter (OM) and crude fibre (CF) apparent total-tract digestibility. At the end of the trial 16 pigs per treatment were euthanised by schedule 1 procedures. Peripheral and portal blood samples were collected for peptide YY and VFA analysis. The addition of xylanase to the diet had no effect on growth performance, DM, OM or CF total-tract digestibility; however, xylanase tended to have a quadratic effect on ileum pH with higher pH values recorded for pigs fed a diet supplemented with 8000 and 16 000 BXU/kg xylanase (P<0.1). Xylanase had no effect on peptide YY levels or VFA concentration. Total VFA concentration was higher in portal compared with peripheral blood (P<0.05). In conclusion, the addition of xylanase had no effect on grower pig performance, nutrient digestibility, VFA concentration or peptide YY concentration when fed up to 32 000 BXU/kg over a 35-day period. Pig performance was good for all treatments throughout the trial suggesting that diet quality was sufficient thus there were no beneficial effects of adding xylanase. PMID- 29508682 TI - INDIVIDUAL- AND COMMUNITY-LEVEL DETERMINANTS OF ANTENATAL HIV TESTING IN ZIMBABWE. AB - This study contributes to the dialogue on the prevention of mother-to-child HIV transmission (PMTCT) through the use of HIV and antenatal care (ANC) integrated services. The determinants of antenatal HIV testing in Zimbabwe were explored. Multilevel logistic regression models were applied to data for 8471 women from 406 clusters who gave birth in the 5 years preceding Zimbabwe Demographic and Health Surveys conducted in 2005/6 and 2010/11. The uptake of antenatal HIV testing was found to be determined by a wide range of individual-level factors relating to women's economic and demographic status, as well as HIV-related factors, including HIV awareness and stigma within the community. Important individual-level enabling and perceived need factors included high socioeconomic status, not having observed HIV-related stigma and knowledge of HIV status (based on a previous HIV test), such that these groups of individuals had a significantly higher likelihood of being tested for HIV during pregnancy than their counterparts of lower socioeconomic status, and who had observed HIV related stigma or did not know their HIV status. The results further revealed that community HIV awareness is important for improving antenatal HIV testing, while stigma is associated with reduced testing uptake. Most contextual community level factors were not found to have much effect on the uptake of antenatal HIV testing. Therefore, policies should focus on individual-level predisposing and enabling factors to improve the uptake of antenatal HIV testing in Zimbabwe. PMID- 29508683 TI - High temperature and oxygen supplementation can mitigate the effects of hypoxia on developmental stability of bilateral traits during incubation of broiler breeder eggs. AB - Hypoxia strongly affects embryonic development during the pre-hatch period. This study was conducted to investigate the effects of oxygen supplementation (O) and a 38.5 degrees C high temperature (HT) at high altitude (HA, 1720 m) on morphological traits during a pre-hatch period and on relative fluctuating asymmetry (relative FA) and allometric growth during an early post-hatch period in broilers. A total of 720 eggs were obtained from a 45-week-old Ross 308 broiler breeder flock raised at sea level (2 m). The eggs were divided into six incubation condition (IC) groups and were incubated at HA. O groups were exposed to 23.5% O2 for 1 h daily from either days 0 to 11 (O0-11), days 12 to 21 (O12 21) or days 18 to 21 (O18-21) of incubation. HT groups were exposed to 38.5 degrees C daily from either days 12 to 21 (HT12-21) or days 18 to 21 (HT18-21) of incubation. A control was maintained at 37.8 degrees C and 21% O2. The hatched chicks were raised for 6 days at HA. Embryo/chick and beak lengths and head diameter were measured during pre- and post-hatch periods. The face, middle toe and shank lengths were measured for each chick. The relative asymmetry (RA), mean RA (MRA) and allometric growth of the lengths were computed and the existence of FA was demonstrated. The IC significantly affected the embryo length, with embryos of the O0-11 group shorter than embryos of the other O groups. Chicks were longer in the O and HT groups than those in the control, except for the O0 11. We found significant interactions between the IC and each development period for beak length. During the post-hatch period, the head diameter of the O0-11 was significantly smaller than that of the other groups, but not in O12-21. The interactions among IC, age and sex were significant for the RA of the face and middle toe lengths and for MRA. All the examined bilateral traits were evaluated as allometric growth. The FA for bilateral traits was determined in both sexes. The right (R) - left (L) and IR-Ll were the lowest in females for face length and in males for shank length from the O18-21 and in males for middle toe length from the O0-11 and HT18-21 groups. Therefore, the effects of factors such as HT and O2 could mitigate the adverse effects of HA-induced hypoxia on optimal developmental stability of bilateral traits of broiler. PMID- 29508684 TI - PATIENT AND PUBLIC INVOLVEMENT IN EARLY AWARENESS AND ALERT ACTIVITIES: AN EXAMPLE FROM THE UNITED KINGDOM. AB - OBJECTIVES: The aim of this study is to report on the experiences, benefits, and challenges of patient and public involvement and engagement (PPIE) from a publicly funded early awareness and alert (EAA) system in the United Kingdom. METHODS: Using email, telephone, a Web site portal, Twitter and focus groups, patients and the public were involved and engaged in the recognized stages of an EAA system: identification, filtration, prioritization, early assessment, and dissemination. RESULTS: Approaches for PPIE were successfully integrated into all aspects of the National Institute for Health Research Horizon Scanning Research and Intelligence Centre's EAA system. Input into identification activities was not as beneficial as involvement in prioritization and early assessment. Patients gave useful insight into the Centre's Web site and engaging patients using Twitter has enabled the Centre to disseminate outputs to a wider audience. CONCLUSIONS: EAA systems should consider involving and engaging with patients and the public in identification, prioritization, and assessment of emerging health technologies where practicable. Further research is required to examine the value and impact of PPIE in EAA activities and in the early development of health technologies. PMID- 29508685 TI - NATIONAL FRAMEWORK FOR THE SUSTAINABILITY OF HEALTH KNOWLEDGE TRANSLATION INITIATIVES IN UGANDA. AB - OBJECTIVES: The aim of this study was to provide evidence about the design and implementation of policies for advancing the sustainability of knowledge translation (KT) initiatives and policies in Uganda's health system. METHODS: We searched for and reviewed evidence about KT sustainability issues in Uganda, the impacts of options, barriers to implementing these options, and implementation strategies to address such barriers. In instances where the systematic reviews provided limited evidence, these were supplemented with relevant primary studies. Documents such as the government reports and unpublished literature were also included in the search. Key informant interviews and a policy dialogue were conducted, and an expert working group guided the study. RESULTS: The KT sustainability issues identified were: the absence of a specific unit within the health sector to coordinate and synthesize research; health worker not familiar with KT activities and not often used. Furthermore, Uganda lacks a mechanism to sustain its current national health frameworks or platforms, and does not have a system to ensure the sustained coordination of existing national health KT platforms. The policy options proposed include: (i) the identification of a KT champion; (ii) the establishment of an operational KT framework; (iii) KT capacity building for researchers and research users, as well as policy and decision makers. CONCLUSIONS: The sustainability of KT will be influenced by the prevailing context and concerns within healthcare both in Uganda and internationally. Furthermore, the availability of resources for KT advocacy, communication, and program design will impact on the sustainability of Uganda's KT activities. PMID- 29508686 TI - Right ventricular pressure response to exercise in adults with isolated ventricular septal defect closed in early childhood. AB - We previously demonstrated an abnormally high right ventricular systolic pressure response to exercise in 50% of adolescents operated on for isolated ventricular septal defect. The present study investigated the prevalence of abnormal right ventricular systolic pressure response in 20 adult (age 30-45 years) patients who underwent surgery for early ventricular septal defect closure and its association with impaired ventricular function, pulmonary function, or exercise capacity. The patients underwent cardiopulmonary tests, including exercise stress echocardiography. Five of 19 patients (26%) presented an abnormal right ventricular systolic pressure response to exercise ? 52 mmHg. Right ventricular systolic function was mixed, with normal tricuspid annular plane systolic excursion and fractional area change, but abnormal tricuspid annular systolic motion velocity (median 6.7 cm/second) and isovolumetric acceleration (median 0.8 m/second2). Left ventricular systolic and diastolic function was normal at rest as measured by the peak systolic velocity of the lateral wall and isovolumic acceleration, early diastolic velocity, and ratio of early diastolic flow to tissue velocity, except for ejection fraction (median 53%). The myocardial performance index was abnormal for both the left and right ventricle. Peak oxygen uptake was normal (mean z score -0.4, 95% CI -2.8-0.3). There was no association between an abnormal right ventricular systolic pressure response during exercise and right or left ventricular function, pulmonary function, or exercise capacity. Abnormal right ventricular pressure response is not more frequent in adult patients compared with adolescents. This does not support the theory of progressive pulmonary vascular disease following closure of left-to-right shunts. PMID- 29508687 TI - The main determinants of iodine in cows' milk in Switzerland are farm type, season and teat dipping. AB - Milk and dairy products are important iodine sources and contribute about 30-40 % of total iodine in the Swiss diet. Information about variation in milk iodine concentration (MIC) in Switzerland is limited. We examined MIC and its potential determinants in milk from organic and conventional farms. We collected bulk milk samples at 3-month intervals over 1 year from thirty-two farms throughout Switzerland and Aosta valley, North-West Italy. We sampled all feed components including tap water, collected information on farm characteristics, feeding and teat disinfection practices by questionnaire and estimated the cows' winter and summer iodine intake. Iodine in milk and feed components was measured using inductively coupled plasma MS. The overall median MIC was 87 (range 5-371) ug/l. In multivariate analysis, predictors of MIC were as follows: (1) farm type: median MIC from organic and conventional farms was 55 and 93 ug/l (P=0.022); (2) season: 53, 97 and 101 ug/l in September, December and March (P<0.002); and (3) teat dipping: 97 ug/l with v. 56 ug/l without (P=0.028). In conclusion, MIC varied widely between farms because of diverse farming practices that result in large differences in dairy cow exposure to iodine via ingestion or skin application. Standardisation of MIC is potentially achievable by controlling these iodine exposures. In order for milk to be a stable iodine source all year round, dietary iodine could be added at a set level to one feed component whose intake is regular and controllable, such as the mineral supplement, and by limiting the use of iodine-containing teat disinfectants. PMID- 29508689 TI - A randomised, double-blind, cross-over trial to evaluate bread, in which gluten has been pre-digested by prolyl endoprotease treatment, in subjects self reporting benefits of adopting a gluten-free or low-gluten diet. AB - The aim of the present study was to determine if the enzyme Aspergillus niger prolyl endoprotease (ANPEP), which degrades the immunogenic proline-rich residues in gluten peptides, can be used in the development of new wheat products, suitable for gluten-sensitive (GS) individuals. We have carried out a double blind, randomised, cross-over trial with two groups of adults; subjects, self reporting benefits of adopting a gluten-free or low-gluten diet (GS, n 16) and a control non-GS group (n 12). For the trial, volunteers consumed four wheat breads: normal bread, bread treated with 0.8 or 1 % ANPEP and low-protein bread made from biscuit flour. Compared with controls, GS subjects had a favourable cardiovascular lipid profile - lower LDL (4.0 (sem 0.3) v. 2.8 (sem 0.2) mmol/l; P=0.008) and LDL:HDL ratio (3.2 (sem 0.4) v. 1.8 (sem 0.2); P=0.005) and modified haematological profile. The majority of the GS subjects followed a low-gluten lifestyle, which helps to reduce the gastrointestinal (GI) symptoms severity. The low-gluten lifestyle does not have any effect on the quality of life, fatigue or mental state of this population. Consumption of normal wheat bread increased GI symptoms in GS subjects compared with their habitual diet. ANPEP lowered the immunogenic gluten in the treated bread by approximately 40 %. However, when compared with the control bread for inducing GI symptoms, no treatment effects were apparent. ANPEP can be applied in the production of bread with taste, texture and appearance comparable with standard bread. PMID- 29508688 TI - Adherence to a Dietary Approaches to Stop Hypertension (DASH)-type diet over the life course and associated vascular function: a study based on the MRC 1946 British birth cohort. AB - Little is known about long-term associations between the Dietary Approaches to Stop Hypertension (DASH) diet and conventional cardiovascular (CV)-risk factors as well as novel measures of vascular function. This study aimed to examine whether long-term adherence to a DASH-type diet in a British birth cohort is associated with conventional CV-risk factors and two vascular function markers, carotid intima-media thickness (cIMT) and pulse wave velocity (PWV). Data came from 1409 participants of the Medical Research Council (MRC) National Survey of Health and Development. Dietary intake was assessed at 36, 43, 53 and 60-64 years using 5-d estimated food diaries. The DASH-type diet score was calculated using the Fung index. Conventional CV-risk factors (blood pressure (BP) and lipids), cIMT in the right and/or left common carotid artery and PWV was measured when participants were 60-64 years. Associations between the DASH-type diet score and outcomes were assessed using multiple regression models adjusted for socioeconomic position, BMI, smoking and physical activity. Participants in higher sex-specific quintiles (Q) of the long-term DASH-type diet had lower BP (P<=0.08), higher HDL-cholesterol (P<0.001) and lower TAG (P<0.001) compared with people in Q1. Participants in Q5 of the long-term DASH-type diet had lower PWV ( 0.28 sd; 95 % CI -0.50, -0.07, P trend=0.01) and cIMT (-0.24 sd; 95 % CI -0.44, 0.04, P trend=0.02) compared with participants in the Q1. This association was independent of the conventional CV-risk factors. Greater adherence to a DASH diet over the life course is associated with conventional CV-risk factors and independently associated with cIMT and PWV. PMID- 29508690 TI - Leptin and adiponectin supplementation modifies mesenteric lymph node lymphocyte composition and functionality in suckling rats. AB - At birth, when immune responses are insufficient, there begins the development of the defence capability against pathogens. Leptin and adiponectin, adipokines that are present in breast milk, have been shown to play a role in the regulation of immune responses. We report here, for the first time, the influence of in vivo adipokine supplementation on the intestinal immune system in early life. Suckling Wistar rats were daily supplemented with leptin (0.7 MUg/kg per d, n 36) or adiponectin (35 MUg/kg per d, n 36) during the suckling period. The lymphocyte composition, proliferation and cytokine secretion from mesenteric lymph node lymphocytes (on days 14 and 21), as well as intestinal IgA and IgM concentration (day 21), were evaluated. At day 14, leptin supplementation significantly increased the TCRalphabeta + cell proportion in mesenteric lymph nodes, in particular owing to an increase in the TCRalphabeta + CD8+ cell population. Moreover, the leptin or adiponectin supplementation promoted the early development CD8+ cells, with adiponectin being the only adipokine capable of enhancing the lymphoproliferative ability at the end of the suckling period. Although leptin decreased intestinal IgA concentration, it had a trophic effect on the intestine in early life. Supplementation of both adipokines modulated the cytokine profile during (day 14) and at the end (day 21) of the suckling period. These results suggest that leptin and adiponectin during suckling play a role in the development of mucosal immunity in early life. PMID- 29508691 TI - Systematic review and meta-analysis of the effect of protein and amino acid supplements in older adults with acute or chronic conditions. AB - The loss of lean body mass, muscle strength and physical function causes significant problems in older adults. Protein and amino acid supplements can preserve muscle strength but the effect on function is variable. We conducted a systematic literature review and meta-analysis to investigate the effect of protein and amino acid supplementation on fat-free mass, muscle strength and physical function in malnourished, frail, sarcopenic, dependent or elderly with acute or chronic conditions, with or without rehabilitation exercise. Databases searched included Medline, BIOSIS, CINAHL, Cochrane Library, EBM Reviews, Embase, Pre-Medline, ProQuest, PubMed and Scopus. Retrieved articles were assessed by two reviewers using the Cochrane Risk of Bias (ROB) Tool. In all, thirty nine randomised controlled trails (n 4274) were included. The studies used a range of protein or essential amino acid (EAA) supplements in a variety of settings, including hospital, community and long-term care. Only seven studies had low ROB and no effect of supplementation was found on any outcomes. Analysis of all thirty-nine studies suggest protein and EAA supplements may improve fat-free mass, muscle strength and physical function (standardised mean difference 0.21 0.27, all P<0.005), but significant heterogeneity and ROB was evident. Predetermined subgroup analysis found undernourished elderly benefitted most; EAA were the most effective supplements and small beneficial effects were seen without rehabilitation exercise. The high heterogeneity and few studies with low ROB limits the conclusions and more high quality studies are needed to determine the best nutritional strategies for the maintenance of strength and function with increasing age. PMID- 29508692 TI - Cross-sectional association between sugar-sweetened beverage intake and cardiometabolic biomarkers in US women. AB - Few studies have evaluated the relationships between intake of sugar-sweetened beverages (SSB) and intermediate biomarkers of cardiometabolic risk. Associations between artificially sweetened beverages (ASB) and fruit juice with cardiometabolic biomarkers are also unclear. We investigated habitual SSB, ASB and fruit juice intake in relation to biomarkers of hepatic function, lipid metabolism, inflammation and glucose metabolism. We analysed cross-sectional data from 8492 participants in the Nurses' Health Study who were free of diabetes and CVD. Multivariate linear regression was used to assess the associations of SSB, ASB and fruit juice intake with concentrations of fetuin-A, alanine transaminase, gamma-glutamyl transferase, TAG, HDL-cholesterol, LDL-cholesterol, total cholesterol, C-reactive protein (CRP), intracellular adhesion molecule 1 (ICAM 1), vascular cell adhesion protein 1, adiponectin, insulin and HbA1c as well as total cholesterol:HDL-cholesterol ratio. More frequent intake of SSB was significantly associated with higher concentrations of fetuin-A, TAG, CRP, ICAM 1, adiponectin and insulin, a higher total cholesterol:HDL-cholesterol ratio, and a lower concentration of HDL-cholesterol (P trend ranges from <0.0001 to 0.04) after adjusting for demographic, medical, dietary and lifestyle variables. ASB intake was marginally associated with increased concentrations of CRP (P trend=0.04) and adiponectin (P trend=0.01). Fruit juice intake was associated with increased concentrations of TAG and HbA1c and a lower concentration of adiponectin (P trend ranges from <0.0001 to 0.01). In conclusion, habitual intake of SSB was associated with adverse levels of multiple cardiometabolic biomarkers. Associations between ASB and fruit juice with cardiometabolic risk markers warrant further exploration. PMID- 29508693 TI - Intermittent v. continuous energy restriction: differential effects on postprandial glucose and lipid metabolism following matched weight loss in overweight/obese participants. AB - The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30.1 (sem 1.0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0.3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0.8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41-80) and 73 d (IQR 48-128), respectively, P=0.246), or in body composition (P>=0.437). For postprandial measures, neither diet significantly altered glycaemia (P=0.266), whereas insulinaemia was reduced comparatively (P=0.903). The reduction in C-peptide tended (P=0.057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol*360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol*360 min/l). The relative reduction in TAG responses was greater (P=0.045) following IER (106 (sem30) to 68 (sem 15) mmol*360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol*360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts. PMID- 29508694 TI - Association of energy and protein intakes with length of stay, readmission and mortality in hospitalised patients with chronic obstructive pulmonary disease. AB - Low energy and protein intakes have been associated with an increased risk of malnutrition in outpatients with chronic obstructive pulmonary disease (COPD). We aimed to assess the energy and protein intakes of hospitalised COPD patients according to nutritional risk status and requirements, and the relative contribution from meals, snacks, drinks and oral nutritional supplements (ONS), and to examine whether either energy or protein intake predicts outcomes. Subjects were COPD patients (n 99) admitted to Landspitali University Hospital in 1 year (March 2015-March 2016). Patients were screened for nutritional risk using a validated screening tool, and energy and protein intake for 3 d, 1-5 d after admission to the hospital, was estimated using a validated plate diagram sheet. The percentage of patients reaching energy and protein intake >=75 % of requirements was on average 59 and 37 %, respectively. Malnourished patients consumed less at mealtimes and more from ONS than lower-risk patients, resulting in no difference in total energy and protein intakes between groups. No clear associations between energy or protein intake and outcomes were found, although the association between energy intake, as percentage of requirement, and mortality at 12 months of follow-up was of borderline significance (OR 0.12; 95 % CI 0.01, 1.15; P=0.066). Energy and protein intakes during hospitalisation in the study population failed to meet requirements. Further studies are needed on how to increase energy and protein intakes during hospitalisation and after discharge and to assess whether higher intake in relation to requirement of hospitalised COPD patients results in better outcomes. PMID- 29508695 TI - beta-Hydroxy beta-methylbutyrate free acid alters cortisol responses, but not myofibrillar proteolysis, during a 24-h fast. AB - This study was a randomised, double-blind, placebo-controlled cross-over trial examining the effects of beta-hydroxy beta-methylbutyrate free acid (HMB-FA) supplementation on muscle protein breakdown, cortisol, testosterone and resting energy expenditure (REE) during acute fasting. Conditions consisted of supplementation with 3 g/d HMB-FA or placebo during a 3-d meat-free diet followed by a 24-h fast. Urine was collected before and during the 24-h fast for analysis of 3-methylhistidine:creatinine ratio (3MH:CR). Salivary cortisol, testosterone, their ratio (T:C), and the cortisol awakening response were assessed. ANOVA was used to analyse all dependent variables, and linear mixed models were used to confirm the absence of carryover effects. Eleven participants (six females, five males) completed the study. Urinary HMB concentrations confirmed compliance with supplementation. 3MH:CR was unaffected by fasting and supplementation, but the cortisol awakening response differed between conditions. In both conditions, cortisol increased from awakening to 30 min post-awakening (P=0.01). Cortisol was reduced from 30 to 45 min post-awakening with HMB-FA (-32 %, d=-1.0, P=0.04), but not placebo (PL) (-6 %, d=-0.2, P=0.14). In males, T:C increased from 0 to 24 h of fasting with HMB-FA (+162 %, d=3.0, P=0.001), but not placebo (+13 %, d=0.4, P=0.60), due to reductions in cortisol. REE was higher at 24 h of fasting than 16 h of fasting independent of supplementation (+4.0 %, d=0.3, P=0.04). In conclusion, HMB-FA may affect cortisol responses, but not myofibrillar proteolysis, during acute 24-h fasting. PMID- 29508696 TI - Higher dietary and serum carotenoid levels are associated with lower carotid intima-media thickness in middle-aged and elderly people. AB - Several studies have suggested that higher carotenoid levels may be beneficial for atherosclerosis patients, but few studies have examined this relationship in the Chinese population. This cross-sectional study examined the association between the levels of carotenoids in diet and serum and carotid intima-media thickness (IMT) in Chinese adults aged 50-75 years in Guangzhou, China. Dietary intake was assessed using a FFQ. HPLC was used to assay the serum concentrations of alpha-carotene, beta-carotene, lutein+zeaxanthin, beta-cryptoxanthin and lycopene. The IMT at the common carotid artery (CCA) and bifurcation of the carotid artery was measured by B-mode ultrasound. A total of 3707 and 2947 participants were included in the analyses of dietary and serum carotenoids. After adjustment for demographic, socio-economic and lifestyle factors, all the serum carotenoids levels except lycopene were found to be inversely associated with the IMT at the CCA and bifurcation (P trend<0.001 to 0.013) in both men and women. The absolute mean differences in the IMT between the subjects in the extreme quartiles of serum carotenoid levels were 0.034 mm (alpha-carotene), 0.037 mm (beta-carotene), 0.032 mm (lutein+zeaxanthin), 0.030 mm (beta cryptoxanthin), 0.015 mm (lycopene) and 0.035 mm (total carotenoids) at the CCA; the corresponding values were 0.025, 0.053 0.043, 0.050, 0.011 and 0.042 mm at the bifurcation. The favourable associations were also observed between dietary carotenoids (except lycopene) and the CCA IMT. In conclusion, elevated carotenoid levels in diet and serum are associated with lower carotid IMT values (particular at the CCA) in Chinese adults. PMID- 29508697 TI - Corrigendum: Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation. PMID- 29508698 TI - Consciousness reflected in the eyes. AB - People with higher autistic traits display stronger fluctuations in pupil size when presented with an optical illusion. PMID- 29508700 TI - Crying wolf: the growing fatigue around sepsis alerts. PMID- 29508699 TI - Antibiotic-induced population fluctuations and stochastic clearance of bacteria. AB - Effective antibiotic use that minimizes treatment failures remains a challenge. A better understanding of how bacterial populations respond to antibiotics is necessary. Previous studies of large bacterial populations established the deterministic framework of pharmacodynamics. Here, characterizing the dynamics of population extinction, we demonstrated the stochastic nature of eradicating bacteria with antibiotics. Antibiotics known to kill bacteria (bactericidal) induced population fluctuations. Thus, at high antibiotic concentrations, the dynamics of bacterial clearance were heterogeneous. At low concentrations, clearance still occurred with a non-zero probability. These striking outcomes of population fluctuations were well captured by our probabilistic model. Our model further suggested a strategy to facilitate eradication by increasing extinction probability. We experimentally tested this prediction for antibiotic-susceptible and clinically-isolated resistant bacteria. This new knowledge exposes fundamental limits in our ability to predict bacterial eradication. Additionally, it demonstrates the potential of using antibiotic concentrations that were previously deemed inefficacious to eradicate bacteria. PMID- 29508701 TI - Does sedation related delirium matter? PMID- 29508702 TI - Increased pollution and problems in respiratory health menace Pakistan's soaring population. PMID- 29508703 TI - Regressing or progressing: what next for the doctor-patient relationship? PMID- 29508704 TI - The long road to recovery after the ICU. PMID- 29508705 TI - Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study. AB - BACKGROUND: Delirium during critical illness results from numerous insults, which might be interconnected and yet individually contribute to long-term cognitive impairment. We sought to describe the prevalence and duration of clinical phenotypes of delirium (ie, phenotypes defined by clinical risk factors) and to understand associations between these clinical phenotypes and severity of subsequent long-term cognitive impairment. METHODS: In this multicentre, prospective cohort study, we included adult (>=18 years) medical or surgical ICU patients with respiratory failure, shock, or both as part of two parallel studies: the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study, and the Delirium and Dementia in Veterans Surviving ICU Care (MIND-ICU) study. We assessed patients at least once a day for delirium using the Confusion Assessment Method-ICU and identified a priori-defined, non-mutually exclusive phenotypes of delirium per the presence of hypoxia, sepsis, sedative exposure, or metabolic (eg, renal or hepatic) dysfunction. We considered delirium in the absence of hypoxia, sepsis, sedation, and metabolic dysfunction to be unclassified. 3 and 12 months after discharge, we assessed cognition with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We used multiple linear regression to separately analyse associations between the duration of each phenotype of delirium and RBANS global cognition scores at 3-month and 12-month follow-up, adjusting for potential confounders. FINDINGS: Between March 14, 2007, and May 27, 2010, 1048 participants were enrolled, eight of whom could not be analysed. Of 1040 participants, 708 survived to 3 months of follow-up and 628 to 12 months. Delirium was common, affecting 740 (71%) of 1040 participants at some point during the study and occurring on 4187 (31%) of all 13 434 participant days. A single delirium phenotype was present on only 1355 (32%) of all 4187 participant-delirium days, whereas two or more phenotypes were present during 2832 (68%) delirium days. Sedative-associated delirium was most common (present during 2634 [63%] delirium days), and a longer duration of sedative-associated delirium predicted a worse RBANS global cognition score 12 months later, after adjusting for covariates (difference in score comparing 3 days vs 0 days: -4.03, 95% CI -7.80 to -0.26). Similarly, longer durations of hypoxic delirium (-3.76, 95% CI -7.16 to -0.37), septic delirium (-3.67, -7.13 to -0.22), and unclassified delirium (-4.70, -7.16 to -2.25) also predicted worse cognitive function at 12 months, whereas duration of metabolic delirium did not (1.14, -0.12 to 3.01). INTERPRETATION: Our findings suggest that clinicians should consider sedative associated, hypoxic, and septic delirium, which often co-occur, as distinct indicators of acute brain injury and seek to identify all potential risk factors that may impact on long-term cognitive impairment, especially those that are iatrogenic and potentially modifiable such as sedation. FUNDING: National Institutes of Health and the Department of Veterans Affairs. PMID- 29508706 TI - The global burden of paediatric and neonatal sepsis: a systematic review. AB - The incidence of sepsis is highest in neonates and children, yet the global burden of sepsis in these age groups has not been assessed. We reviewed available evidence from observational epidemiological studies to estimate the global burden and mortality of sepsis in neonates and children. We did a systematic review and meta-analysis of studies reporting population-based sepsis incidence in neonates and children, published between 1979 and 2016. Our search yielded 1270 studies, 23 of which met the inclusion criteria; 16 were from high-income countries and seven from middle-income countries. 15 studies from 12 countries reported complete data and were included in the meta-analysis. We found an aggregate estimate of 48 (95% CI 27-86) sepsis cases and 22 (14-33) severe sepsis cases in children per 100 000 person-years. Mortality ranged from 1% to 5% for sepsis and 9% to 20% for severe sepsis. The population-level estimate for neonatal sepsis was 2202 (95% CI 1099-4360) per 100 000 livebirths, with mortality between 11% and 19%. Extrapolating these figures on a global scale, we estimate an incidence of 3.0 million cases of sepsis in neonates and 1.2 million cases in children. Although these results confirm that sepsis is a common and frequently fatal condition affecting neonates and children globally, few population-based data are available from low-income settings and the lack of standardisation of diagnostic criteria and definition of sepsis in the reviewed studies are obstacles to the accurate estimation of global burden. Robust epidemiological monitoring to define global sepsis incidence and mortality in children is urgently needed. PMID- 29508707 TI - Corrections. PMID- 29508708 TI - Prehospital antibiotics for sepsis: beyond mortality? PMID- 29508709 TI - Simvastatin for the prevention and treatment of delirium in critically ill, mechanically ventilated patients (MoDUS): a cost-effectiveness analysis. PMID- 29508710 TI - Allergists' use of epinephrine for food-induced anaphylaxis: Time to practice what we preach. PMID- 29508711 TI - The role of environmental exposure to peanut and the development of peanut allergy. PMID- 29508713 TI - Common questions in food allergy avoidance. PMID- 29508712 TI - New treatment directions in food allergy. PMID- 29508714 TI - Infant rhinitis and watery eyes predict school-age exercise-induced wheeze, emergency department visits and respiratory-related hospitalizations. AB - BACKGROUND: Rhinitis and conjunctivitis are often linked to asthma development through an allergic pathway. However, runny nose and watery eyes can result from nonallergic mechanisms. These mechanisms can also underlie exercise-induced wheeze (EIW), which has been associated with urgent medical visits for asthma, independent of other indicators of asthma severity or control. OBJECTIVE: To test the hypothesis that rhinitis or watery eyes without cold symptoms (RWWC) in infancy predict development of EIW and urgent respiratory-related medical visits at school age, independent of seroatopy. METHODS: Within a prospective birth cohort of low-income, urban children (n = 332), RWWC was queried during the first year of life. Relative risks (RRs) for EIW, emergency department (ED) visits, and hospitalizations for asthma and other breathing difficulties at 5 to 7 years of age were estimated with multivariable models. Seroatopy was determined at 7 years of age. RESULTS: Infant RWWC was common (49% of children) and predicted school age EIW (RR, 2.8; P < .001), ED visits (RR, 1.8; P = .001), and hospitalizations (RR, 9.8; P = .002). These associations were independent of infant wheeze. They were also independent of birth order, an indicator of increased risk of exposure to viruses in infancy, and infant ear infections, an indicator of sequelae of upper airway infections. The association between infant RWWC and ED visits at 5 to 7 years of age was attenuated (RR, 1.2; P = .23) when EIW at 5 to 7 years of age was included in the model, suggesting EIW mediates the association. Adjustment for seroatopy did not diminish the magnitudes of any of these associations. CONCLUSION: These findings suggest a nonallergic connection between infant nonwheeze symptoms and important consequences of urban respiratory health by school age through EIW. PMID- 29508715 TI - Phenotyping patients with chronic cough: Evaluating the ability to predict the response to anti-inflammatory therapy. AB - BACKGROUND: Whether the fraction of exhaled nitric oxide (FeNO) measurement can predict the response to anti-inflammatory treatment in chronic cough is unknown. OBJECTIVE: To explore whether the effectiveness of treatment with 10 mg of montelukast or 20 mg of prednisolone in patients with chronic cough is predicted by FeNO level. METHODS: In this randomized, open-label, controlled pilot study conducted in the Clinical Trial Unit in Castle Hospital in the United Kingdom, 50 nonsmoking patients with a cough that lasted more than 8 weeks were sequentially enrolled in the study. Thirty patients with high FeNO levels (>=30 ppb) were randomized in a 1:1 ratio to receive 10 mg of montelukast or 20 mg of prednisolone for 2 weeks followed by 10 mg of montelukast for 2 weeks. Twenty patients with a low FeNO level (<=20 ppb) received 10 mg of montelukast. The primary objective was to determine the effectiveness of treatment on 24-hour cough counts. RESULTS: The 24-hour cough counts decreased in both groups by approximately 50% (P < .005), indicating that FeNO did not predict treatment response. However, it was a good marker for eosinophilic inflammation with a high degree of correlation with blood and sputum eosinophilia (P < .001). CONCLUSION: These results suggest that prior investigation may not predict response to anti inflammatory treatment, which may be consequent on localized leukotriene-mediated inflammation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02479074. PMID- 29508716 TI - Perinatal factors and the development of childhood asthma. AB - BACKGROUND: Perinatal factors are suspected to have a significant impact on the development of asthma; however, sufficiently powered studies have not been performed to investigate this issue. OBJECTIVE: To evaluate whether perinatal factors and other risk factors have an independent or combined effect on the development of asthma. METHODS: This study involved 3,770 children (mean age 9.1 years, range 5.68-12.16 years; 51.9% boys) who were enrolled in the Elementary School Student Cohort (2009-2014) in Ulsan University Hospital (Ulsan, Korea). Subjects were divided into an asthma group (n = 514) and a non-asthma group (n = 3,256). RESULTS: Multivariate analyses showed that early life (within first week) oxygen therapy (adjusted odds ratio [aOR] 1.864, 95% confidence interval [CI] 1.156-3.004) and breastfeeding (aOR 0.763, 95% CI 0.606-0.960) were 2 significant perinatal factors influencing the development of asthma. Environmental tobacco smoke (aOR 1.634, 95% CI 1.298-2.058) and parental allergic disease (aOR 1.882, 95% CI 1.521-2.328) also were identified as risk factors. Using subgroup analyses, combined effects on asthma development were observed between perinatal factors (early life oxygen therapy and breastfeeding) and other risk factors (vicinity to major roadway [traffic-related air pollution], environmental tobacco smoke, parental allergic disease, and atopy). CONCLUSION: Early life oxygen therapy and breastfeeding were identified as 2 important perinatal factors influencing the development of asthma. Furthermore, these factors showed combined effects with other risk factors (environmental tobacco smoke, traffic-related air pollution, parental allergic disease, and atopy) on the development of asthma. PMID- 29508717 TI - School nurse perspectives on school policies for food allergy and anaphylaxis. AB - BACKGROUND: Although school health care professionals are integral to the management of students with food allergy, their views on school food allergy policies have not yet been reported. OBJECTIVE: To characterize food allergy policies currently being used in schools and their utility and potential barriers to implementation from the perspective of school health care professionals. METHODS: An electronic survey was disseminated to school nurses at the 2016 National Association of School Nurses meeting and through the Allergy and Asthma Network listserv. Frequencies were calculated to describe participant characteristics and responses. Unadjusted associations were examined using chi2 tests; adjusted associations were examined using multiple logistic regression models. RESULTS: A total of 242 completed surveys were included in the analysis. Thirty-two percent of nurses reported an allergic reaction in their school in the past year. Most schools used a variety of policies, including anaphylaxis training for staff (96.7%), stock epinephrine availability (81.7%), designated lunch areas (62.2%), and food guidelines for classrooms (61.8%). Barriers to implementation included financial, time, and attitudinal considerations. Schools with pre-K or kindergarten students had higher odds of having designated lunch areas (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0-4.1; P < .05). The odds of having emergency epinephrine available were higher in schools with a full-time nurse (OR, 2.6; 95% CI, 1.1-6.3; P < .05) and in schools reporting at least 1 severe reaction in the past year (OR, 3.2; 95% CI, 1.2-8.5; P < .05). CONCLUSION: With one-third of school nurses reporting an allergic reaction in the past year, schools use many strategies to minimize allergen exposures and increase anaphylaxis preparedness. Most school nurses favor these policies and acknowledge barriers to implementation. PMID- 29508718 TI - Allergic disorders and risk of depression: A systematic review and meta-analysis of 51 large-scale studies. AB - BACKGROUND: Previous studies have suggested that allergic disorders are associated with an increased risk of depression. However, the results are conflicting. OBJECTIVE: To determine the association between allergic disorders and depression based on large-scale studies. METHODS: We reviewed relevant articles obtained from PubMed and Embase. Studies were eligible if they reported an association between allergic disorders and depression and provided available data. Study selection, data extraction, and analyses were undertaken. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated. RESULTS: Of 1,827 studies identified, 51 including more than 2.5 million participants met our inclusion criteria. Overall, the results showed that allergic disorders were associated with a significant increased risk of depression (pooled RR 1.59, 95% CI 1.48-1.71). A higher risk of depression also was observed in patients with asthma (RR 1.59, 95% CI 1.46-1.74) and those with allergic rhinitis (RR 1.57, 95% CI 1.27-1.93). Subgroup analyses were conducted based on sex and age. Children (RR 1.66, 95% CI 1.41-1.96) and adults (RR 1.58, 95% CI 1.44-1.74) with allergic disorders had a higher risk of depression than controls. However, no significant association was found between allergic disorders and risk of depression in male subjects (RR 1.37, 95% CI 0.98-1.91), but a positive association was detected in female subjects (RR 1.65, 95% CI 1.44 1.89). CONCLUSION: The results from our study showed that allergic disorders significantly increased the risk of depression. PMID- 29508720 TI - X-linked chronic granulomatous disease in a female carrier with novel pathogenic mutation and skewed X-inactivation. PMID- 29508721 TI - Anaphylaxis due to roasted sunflower seeds with tolerance to raw sunflower seeds. PMID- 29508722 TI - Parental and parent-perceived child interest in clinical trials for food allergen immunotherapy. PMID- 29508719 TI - Omalizumab in elderly patients with chronic spontaneous urticaria: An Italian real-life experience. AB - BACKGROUND: Omalizumab therapy is effective and safe in patients with chronic spontaneous urticaria (CSU) resistant to nonsedating histamine1 (H1) antihistamines (nsAHs). OBJECTIVE: To evaluate the efficacy and safety of omalizumab in elderly (aged >=65 years) patients with nonsedating H1 antihistamine-refractory CSU in a real-life setting. METHODS: Patients with nonsedating H1-antihistamine-refractory CSU (n = 322) treated with omalizumab administered every 4 weeks in doses of 300 mg for 24 weeks were divided into 2 groups according to age at omalizumab treatment onset: 15 to 64 years and 65 years or older. Treatment response was assessed using a 7-day urticaria activity score (UAS7). Adverse effects of omalizumab therapy were recorded. RESULTS: Among patients, 32 (9.9%) were 65 years or older. At baseline, CSU characteristics were generally similar among the groups, although the presence of angioedema was statistically significantly lower in patients younger than 65 years. Any differences in weekly itch severity score, hive score, and UAS7 between the 2 age groups were not significant at weeks 4, 12, and 24, with the exception of the hive score at 24 weeks and the UAS7 at week 24. No significant between-group differences were seen in the proportion of patients with a UAS7 of 6 or lower and with a UAS7 score of 0 at weeks 4, 12, 24, and 40. The proportion of patients with at least one adverse event reported as suspected to be caused by study drug was 10% in the younger group vs 6.3% in the older group (P = .53). CONCLUSION: Our study found that omalizumab is a well-tolerated and effective therapy for elderly patients with nonsedating H1-antihistamine-refractory CSU. PMID- 29508723 TI - Challenge-confirmed peanut allergy in older patients: Performance of skin tests, specific immunoglobulin E, and ara h 2. PMID- 29508724 TI - Cross-reaction of recombinant termite (Coptotermes formosanus) tropomyosin with IgE from cockroach and shrimp allergic individuals. PMID- 29508725 TI - Ethanol-induced urticaria caused by sensitization to acetic acid. PMID- 29508726 TI - Venom anaphylaxis can mimic other serious conditions and disclose important underlying disease. PMID- 29508727 TI - Fractional exhaled nitric oxide: Signaling lung function changes in obstructive lung diseases. PMID- 29508728 TI - Treatment with omalizumab or cyclosporine for resistant chronic spontaneous urticaria? PMID- 29508729 TI - Authors' response. PMID- 29508730 TI - The burden of traumatic brain injury in children. PMID- 29508731 TI - Wellcome seeks Brexit carve-out for UK research. PMID- 29508732 TI - Stem cells, regenerative medicine, and Prometheus. PMID- 29508733 TI - Offline: Canada and global health-iconic or ironic? PMID- 29508734 TI - Libya: war and migration strain a broken health system. PMID- 29508735 TI - Negotiations lagging for science and technology in the UK. PMID- 29508736 TI - Edna Adan Ismail: midwife and champion of women's health. PMID- 29508737 TI - A day in the life of a surgical intern: women in surgery. PMID- 29508738 TI - Putting Ireland's health spending into perspective. PMID- 29508739 TI - Tackling hepatitis C-Pakistan's road to success. PMID- 29508740 TI - Issues with measuring hepatitis prevalence in resource-limited settings. PMID- 29508741 TI - Ensuring value in health-related research. PMID- 29508742 TI - Foley catheterisation versus oral misoprostol to induce labour. PMID- 29508743 TI - Foley catheterisation versus oral misoprostol to induce labour - Author's reply. PMID- 29508744 TI - UK National Health Service-beyond repair? PMID- 29508745 TI - 10-year report on the European Paediatric Regulation and its impact on new drugs for children's cancers. PMID- 29508746 TI - Cancer groundshot: going global before going to the moon. PMID- 29508747 TI - Cancer control in war-torn Iraq. PMID- 29508748 TI - The evolution of anticancer drug discovery from plants. PMID- 29508749 TI - Adjuvant therapy for resected EGFR-mutant non-small-cell lung cancer. PMID- 29508750 TI - Adjuvant therapy for resected EGFR-mutant non-small-cell lung cancer. PMID- 29508751 TI - Adjuvant therapy for resected EGFR-mutant non-small-cell lung cancer. PMID- 29508752 TI - Adjuvant therapy for resected EGFR-mutant non-small-cell lung cancer - Authors' reply. PMID- 29508753 TI - Neoadjuvant chemotherapy for early breast cancer. PMID- 29508754 TI - Neoadjuvant chemotherapy for early breast cancer. PMID- 29508755 TI - Neoadjuvant chemotherapy for early breast cancer - Author's reply. PMID- 29508756 TI - Low-dose CT for lung cancer screening. PMID- 29508757 TI - Low-dose CT for lung cancer screening. PMID- 29508758 TI - Low-dose CT for lung cancer screening - Authors' reply. PMID- 29508759 TI - Correction to Lancet Oncol 2017; 18: e354-63. PMID- 29508760 TI - Correction to Lancet Oncol 2018; 19: 87-100. PMID- 29508761 TI - Correction to Lancet Oncol 2018; 19: 257-66. PMID- 29508763 TI - Novel therapies for malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is a rare cancer that is typically associated with exposure to asbestos. Patients with malignant pleural mesothelioma have poor outcomes with suboptimal therapeutic options and currently no treatment is curative. The standard frontline treatment, cisplatin plus pemetrexed chemotherapy, has only short and insufficient efficacy, and no validated treatment beyond first-line therapy is available. New therapeutic strategies are therefore needed. The addition of bevacizumab (an anti-VEGF antibody) combined with cisplatin plus pemetrexed has shown some promise. However, immunotherapy, especially immune checkpoint inhibitors, has generated a lot of excitement because of data suggesting the potential value of immune checkpoint inhibitors for patients who have failed chemotherapy. In this Review, we describe immune checkpoint inhibitors, other immunotherapies, targeted therapies, or combinations of novel drugs being investigated in malignant pleural mesothelioma, as well as the issues surrounding the selection of the best candidates for these treatments. PMID- 29508762 TI - Consensus statement on mandatory measurements in pancreatic cancer trials (COMM PACT) for systemic treatment of unresectable disease. AB - Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies. PMID- 29508764 TI - Working plan for the use of patient-reported outcome measures in adults with brain tumours: a Response Assessment in Neuro-Oncology (RANO) initiative. AB - The Response Assessment in Neuro-Oncology-Patient-Reported Outcome (RANO-PRO) working group is an international multidisciplinary collaboration that provides guidance on the use of patient-reported outcome (PRO) measures in clinical trials and practice for adult patients with brain tumours. Findings from both PROs and traditional outcome measures, such as survival, and clinical or radiological response, are essential to inform the research community, policy makers, physicians, and patients in the treatment decision-making process. Previous initiatives in oncology have focused on guidelines concerning the collection, analysis, interpretation, and reporting of PRO data. However, we recommend the application of appropriate PRO instruments, with respect to its content and measurement properties (ie, research question, content validity, and other measurement properties), in brain tumour research. PROs should be well defined and reliable to generate high-quality evidence, and our recommendations on the use of specific PRO measures could help to improve the quality of PRO evidence derived from neuro-oncological studies, and might add a new dimension in how the value of therapeutics is assessed in patients with brain tumours. In this Policy Review, we present the RANO-PRO working plan for the use of PROs in adults with brain tumours. PMID- 29508765 TI - Large parapharyngeal mass: a challenging differential diagnosis. PMID- 29508766 TI - Impact of left atrial appendage morphology on indication and procedural outcome after interventional occlusion: results from the prospective multicentre German LAARGE registry. AB - AIMS: Interventional left atrial appendage closure (LAAC) is an emerging alternative to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation (AF) in concomitance with a contraindication for standard OAC. This sub-analysis of the LAARGE registry aimed to investigate differences between different LAA morphologies in a real-world setting. METHODS AND RESULTS: This prospective, multicentre, observational registry included 562 patients from 37 centres with ineligibility for long-term OAC between April 2014 and January 2016. Baseline characteristics, indications, procedural data and complications were registered according to each LAA morphology (i.e., chicken wing, cauliflower, windsock, cactus and atypical morphologies). Implantation success was high across the four typical anatomies (>=97.5%, p=n.s.); only atypical anatomies exhibited a lower success rate (94%). The cactus-shaped LAA was linked to a trend indicating a shorter fluoroscopy time, while the atypical LAA was linked to a significantly prolonged fluoroscopy time (p=0.089 and p=0.025 versus the overall mean, respectively). Periprocedural and intra-hospital complications were generally rare, with no differences among the different morphologies (p=n.s.). CONCLUSIONS: Procedural success as well as the complication rates of LAAC were not different among the four typical LAA morphologies. A lower implantation success rate was only obvious in patients with atypical LAA morphologies. PMID- 29508767 TI - Hydrogels with reversible chemical environments for in vitro cell culture. AB - Methods to reversibly control the chemical environment of hydrogels have application in three-dimensional cell culture to study cell proliferation, migration and differentiation in environments more representative of in vivo environments. Herein, we have developed a method to temporally control the chemical environment of agarose hydrogels through non-covalent attachment of peptide motifs. Streptavidin-GRGDS conjugates were immobilized in desthiobiotin modified agarose hydrogels through the desthiobiotin-streptavidin interaction (KD 10-11 M). Streptavidin-GRGDS was then displaced from the gel by the addition of biotin, which has a higher affinity for streptavidin (KD 10-15 M). This process was repeated to sequentially and simultaneously immobilize different biomolecules and model compounds in hydrogels over the course of several hours to weeks. The influence of dynamic chemical environments on cellular activity was demonstrated by monitoring HUVEC tube formation for 30 h. PMID- 29508768 TI - BIANCA, a biophysical model of cell survival and chromosome damage by protons, C ions and He-ions at energies and doses used in hadrontherapy. AB - An upgraded version of the BIANCA II biophysical model, which describes more realistically interphase chromosome organization and the link between chromosome aberrations and cell death, was applied to V79 and AG01522 cells exposed to protons, C-ions and He-ions over a wide LET interval (0.6-502 keV um-1), as well as proton-irradiated U87 cells. The model assumes that (i) ionizing radiation induces DNA 'cluster lesions' (CLs), where by definition each CL produces two independent chromosome fragments; (ii) fragment (distance-dependent) mis rejoining, or un-rejoining, produces chromosome aberrations; (iii) some aberrations lead to cell death. The CL yield, which mainly depends on radiation quality but is also modulated by the target cell, is an adjustable parameter. The fragment un-rejoining probability, f, is the second, and last, parameter. The value of f, which is assumed to depend on the cell type but not on radiation quality, was taken from previous studies, and only the CL yield was adjusted in the present work. Good agreement between simulations and experimental data was obtained, suggesting that BIANCA II is suitable for calculating the biological effectiveness of hadrontherapy beams. For both V79 and AG01522 cells, the mean number of CLs per micrometer was found to increase with LET in a linear-quadratic fashion before the over-killing region, where a less rapid increase, with a tendency to saturation, was observed. Although the over-killing region deserves further investigation, the possibility of fitting the CL yields is an important feature for hadrontherapy, because it allows performing predictions also at LET values where experimental data are not available. Finally, an approach was proposed to predict the ion-response of the cell line(s) of interest from the ion response of a reference cell line and the photon response of both. A pilot study on proton-irradiated AG01522 and U87 cells, taking V79 cells as a reference, showed encouraging results. PMID- 29508769 TI - Phase boundaries, nucleation rates and speed of crystal growth of the water-to ice transition under an electric field: a simulation study. AB - We investigate with computer simulations the effect of applying an electric field on the water-to-ice transition. We use a combination of state-of-the-art simulation techniques to obtain phase boundaries and crystal growth rates (direct coexistence), nucleation rates (seeding) and interfacial free energies (seeding and mold integration). First, we consider ice Ih, the most stable polymorph in the absence of a field. Its normal melting temperature, speed of crystal growth and nucleation rate (for a given supercooling) diminish as the intensity of the field goes up. Then, we study polarised cubic ice, or ice Icf, the most stable solid phase under a strong electric field. Its normal melting point goes up with the field and, for a given supercooling, under the studied field (0.3 V nm-1) ice Icf nucleates and grows at a similar rate as Ih with no field. The net effect of the field would then be that ice nucleates at warmer temperatures, but in the form of ice Icf. The main conclusion of this work is that reasonable electric fields (not strong enough to break water molecules apart) are not relevant in the context of homogeneous ice nucleation at 1 bar. PMID- 29508770 TI - Multiline 3D beamforming using micro-beamformed datasets for pediatric transesophageal echocardiography. AB - Until now, no matrix transducer has been realized for 3D transesophageal echocardiography (TEE) in pediatric patients. In 3D TEE with a matrix transducer, the biggest challenges are to connect a large number of elements to a standard ultrasound system, and to achieve a high volume rate (>200 Hz). To address these issues, we have recently developed a prototype miniaturized matrix transducer for pediatric patients with micro-beamforming and a small central transmitter. In this paper we propose two multiline parallel 3D beamforming techniques (uBF25 and uBF169) using the micro-beamformed datasets from 25 and 169 transmit events to achieve volume rates of 300 Hz and 44 Hz, respectively. Both the realizations use angle-weighted combination of the neighboring overlapping sub-volumes to avoid artifacts due to sharp intensity changes introduced by parallel beamforming. In simulation, the image quality in terms of the width of the point spread function (PSF), lateral shift invariance and mean clutter level for volumes produced by uBF25 and uBF169 are similar to the idealized beamforming using a conventional single-line acquisition with a fully-sampled matrix transducer (FS4k, 4225 transmit events). For completeness, we also investigated a 9 transmit-scheme (3 * 3) that allows even higher frame rates but found worse B-mode image quality with our probe. The simulations were experimentally verified by acquiring the uBF datasets from the prototype using a Verasonics V1 research ultrasound system. For both uBF169 and uBF25, the experimental PSFs were similar to the simulated PSFs, but in the experimental PSFs, the clutter level was ~10 dB higher. Results indicate that the proposed multiline 3D beamforming techniques with the prototype matrix transducer are promising candidates for real-time pediatric 3D TEE. PMID- 29508771 TI - Structural, electrical properties and dielectric relaxations in Na+-ion conducting solid polymer electrolyte. AB - In this paper, we have studied the structural, microstructural, electrical, dielectric properties and ion dynamics of a sodium-ion-conducting solid polymer electrolyte film comprising PEO8-NaPF6+ x wt. % succinonitrile. The structural and surface morphology properties have been investigated, respectively using x ray diffraction and field emission scanning electron microscopy. The complex formation was examined using Fourier transform infrared spectroscopy, and the fraction of free anions/ion pairs obtained via deconvolution. The complex dielectric permittivity and loss tangent has been analyzed across the whole frequency window, and enables us to estimate the DC conductivity, dielectric strength, double layer capacitance and relaxation time. The presence of relaxing dipoles was determined by the addition of succinonitrile (wt./wt.) and the peak shift towards high frequency indicates the decrease of relaxation time. Further, relations among various relaxation times ([Formula: see text]) have been elucidated. The complex conductivity has been examined across the whole frequency window; it obeys the Universal Power Law, and displays strong dependency on succinonitrile content. The sigma representation ([Formula: see text]) was introduced in order to explore the ion dynamics by highlighting the dispersion region in the Cole-Cole plot ([Formula: see text]) in the lower frequency window; increase in the semicircle radius indicates a decrease of relaxation time. This observation is accompanied by enhancement in ionic conductivity and faster ion transport. A convincing, logical scheme to justify the experimental data has been proposed. PMID- 29508772 TI - Leading temperature dependence of the conductance in Kondo-correlated quantum dots. AB - Using renormalized perturbation theory in the Coulomb repulsion, we derive an analytical expression for the leading term in the temperature dependence of the conductance through a quantum dot described by the impurity Anderson model, in terms of the renormalized parameters of the model. Taking these parameters from the literature, we compare the results with published ones calculated using the numerical renormalization group obtaining a very good agreement. The approach is superior to alternative perturbative treatments. We compare in particular to the results of a simple interpolative perturbation approach. PMID- 29508773 TI - Locomotion of arthropods in aquatic environment and their applications in robotics. AB - Many bio-inspired robots have been developed so far after careful investigation of animals' locomotion. To successfully apply the locomotion of natural counterparts to robots for efficient and improved mobility, it is essential to understand their principles. Although a lot of research has studied either animals' locomotion or bio-inspired robots, there have only been a few attempts to broadly review both of them in a single article. Among the millions of animal species, this article reviewed various forms of aquatic locomotion in arthropods including relevant bio-inspired robots. Despite some previous robotics research inspired by aquatic arthropods, we found that many less-investigated or even unexplored areas are still present. Therefore, this article has been prepared to identify what types of new robotics research can be carried out after drawing inspiration from the aquatic locomotion of arthropods and to provide fruitful insights that may lead us to develop an agile and efficient aquatic robot. PMID- 29508774 TI - Diagnosis of muscular dystrophies : the changing concepts. AB - Detailed analysis of muscle biopsy using histological and enzyme histochemical staining techniques forms the basis of diagnosis of muscular dystrophies, while clinical features and family history are important adjuncts in categorising the type of dystrophy. However, in a significant proportion of cases having overlapping clinical and histological features, it is not possible to provide accurate diagnosis. These conditions can be grouped as Limb girdle muscular dystrophy (LGMD), Decker muscular dystrophy (BMD), early onset Duchenne muscular dystrophy (DMD), Congenital muscular dystrophy (CMD), Severe childhood autosomal recessive muscular dystrophy (SCARMD), and SCARMD in girls/manifesting DMD carriers. Immunohistochemical staining procedures demonstrating the presence/absence of dystrophin, adhalin and merosin are found to be of immense value in arriving at a conclusive opinion specifying the type of muscular dystrophy. It is also evident that muscular dystrophy in young girls resembling DMD is not uncommon and that these are mostly cases of SCARMD in girls having adhalinopathy. In addition, a significant proportion of patients (9 in the present series) with clinical and histopathological diagnosis of DMD are likely to be cases of SCARMD in boys after immunohistochemical study of muscle biopsies. PMID- 29508775 TI - Neurocysticercosis : surgical considerations. AB - Neurocysticercosis is the most frequently encountered parasitic infestation in nervous system. Epilepsy is the most common clinical manifestation. Cysticidal drugs are helpful in upto 96 of parenchymal cysts and 80 of intraventricular cysts. Surgery is considered when diagnosis is uncertain, cysts exhibit tumour like behaviour, oedema (pseudotumour) is refrectory to medical treatment, or when hydrocephalus develops. PMID- 29508776 TI - Coagulation disorders and neo-membrane formation in the pathogenesis of chronic subdural haematoma. AB - Haematological investigations in the haematoma fluid and venous blood along with histological changes in the haematoma membrane were studied in twenty five patients of chronic subdural haematoma. Their median age was 60 years with a marked male predominance. Haemoglobin level in the haematoma fluid was unrelated to its age. Prolongation of prothrombin time and activated partial thromboplastin time was observed in all the haematoma fluid samples. Fibrinogen and antithrombin III levels were significantly decreased in haematoma fluid and fibrin degradation products were positive in 44 of these specimens. The neo-membrane showed 'giant' capillaries and abundant eosinophils with an inverse relationship between the presence of inflammatory cells andfibroblasts. These findings suggest a localized consumption coagulopathy and hyperfibrinolysis with reactive formation of a leaky neo-membrane resulting in recurrent haemorrhages and progressive enlargement of chronic subdural haematoma. PMID- 29508777 TI - Molecular diagnosis of myotonic dystrophy and Huntington's disease from Calcutta, India. AB - It has been identified that the expansion of normally polymorphic CTG repeats in myotonin protein kinase (DM-PK) gene in myotonic dystrophy (DM) and CAG repeats in huntingtin gene in Huntington's disease (HD) acts as the causative mutation. This hasimproved the ability of molecular diagnosis of these diseases. On molecular genetic screening of 40 normal chromosomes from people living in and around Calcutta, we have obtained 10 distinct alleles at the DM locus, with an estimated heterozygosity of 0.83. We have also observed 10 alleles at the HD locus on 32 chromosomes, with an estimated heterozygosity of 0.79. We further report here that at the DM locus, in two clinically diagnosed heterozygous individuals, the expanded alleles were of sizes 330 repeats and 1400 repeats respectively; the allele on the homologous chromosome was within the normal repeat range for both these individuals. Of two HD patients, one carried an expanded allele of size of 57 repeats, the other allele being in the normal range; while the second patient had both the alleles in the normal range. PMID- 29508778 TI - POEMS syndrome : a clinico pathological study. AB - Clinical features of five patients with POEMS syndrome and one with Castleman's disease, who presented with chronic, progressive motor sensory peripheral neuropathy are described. Papilloedema was seen in all patients with POEMS syndrome. Four of them also had bone lesions, biopsy of which established the diagnosis. Lymph node biopsy revealed angiofollicular lymphoid hyperplasia in the patient with Castleman's disease. Response to therapy was not satisfactory. The clinical features are compared with other reported series. A high index of suspicion, meticulous clinical examination and investigations are essential for establishing the diagnosis. PMID- 29508779 TI - Cranioplasty using silastic implants. AB - Twenty five cases of post operative cranial vault defects were repaired using tailor made silastic implants in the last three years. Twenty four patients are tolerating the implant without any problems. All of them had symptomatic, relief and achieved an excellent cosmetic skull contour. Ten patients had subgaleal serous collection postoperatively, probably due to reaction to the implanted material, which usually subsided within three weeks. Only in one patient, the implant had to be removed due to infection. In conclusion, silastic is a good implant material for cranioplasty. PMID- 29508780 TI - Is infantile spinal muscular atrophy a disease of maturation arrest or a dynamic neurogenic atrophy of the skeletal muscle? AB - Spinal muscular atrophy constitutes one of the major disease entities amongst infantile neuro-muscular disorders. On the basis of morphological evidence, it had been suggested that the infantile spinal muscular atrophy (ISMA) is due to maturation arrest of the myofibres at 20 weeks gestation. Therefore, in the present study morphological features of skeletal muscles from patients with ISMA was compared with foetal muscle obtained at different gestational ages (9-36 weeks, n=18). Of the 35 cases ofISMA, 22 were diagnosed as having SMA-I and 13 cases an SMA-II, characterised histologically by fascicles composed of groups of small, normal, intermediate sized and hypertrophic fibres. The former ones belonged to both histochemical fibre types, while the hypertrophic fibres in 21/35 cases were type I in nature. Redundant basal lamina was a predominant finding at ultrastructural level. Mature myotubes, a feature seen during foetal muscle development was not noticed in any of the cases of ISMA. Our observations suggest denervation atrophy to be the basic pathogenic mechanism rather than arrest in maturation. This was further supported by the changes seen in the spinal cord specimen of a 20 day old infant from a case of SMA I which revealed marked fallout of motor neurons in the anterior horn, chromatolysis and gliosis. Thus ISMA is a dynamic and progressive neurogenic atrophy secondary to degeneration and loss of spinal motor neurons possibly resulting in lack of trophic factors. PMID- 29508781 TI - Role of dexamethasone as adjunctive therapy in acute bacterial meningitis in adults. AB - Thirty patients of bacterial meningitis (age> 12 years) were randomised into two treatment groups. Group I (n=14) received intravenous dexamethasone with antibiotics and group II (n=16)received only antibiotics. Baseline demographic, clinical and laboratory features of the two groups were similar. Four patients died, three in control group and one in dexamethasone group (p=0.60). Focal neurological deficits at discharge were found in three patients receiving dexamethasone and two in control group (p=0.64). Audiological sequelae were found in seven (23) patients, four in group I and three in group II (p = 1.00) but there were no statistically significant differences between the two groups. No steroid side effects were noted. In the present study, dexamethasone treatment was not found to significantly improve survival but sample size was too small to reliably exclude clinically important benefit of dexamethasone. Larger randomised controlled studies in adult population are needed to reliably estimate the effects of dexamethasone as adjunctive therapy in acute bacterial meningitis in adults. PMID- 29508782 TI - Influence of kinnow juice on the bioavailability of carbamazepine in healthy male volunteers. AB - Kinnow juice produces a marked and variable increase in carbamazepine bioavailability. The pharmacokinetics of carbamazepine was studied after drug administration with 300 ml water or kinnow juice in a randomized cross over trial on nine healthy male volunteers. With kinnow juice peak serum concentration (Cmax) and area under the serum concentration time curve (AUC) was significantly (P < 0.05) increased and time to reach peak serum concentration (tmax) was significantly decreased (p < 0.05) as compared with water. No change was observed in the elimination half life (t1/2) of drug. The mechanism by which kinnow juice enhances carbamazepine bioavailability could be due to inhibition of cytochrome P 450 enzyme, since kinnow juice contains naringin which is considered to be inhibitor of liver microsomal dihydropyridine oxidation. PMID- 29508783 TI - Myasthenia gravis, motor neuron syndrome and thymoma. AB - An adult male with thymomatous myasthenia gravis (MG) and a motor neuron syndrome simulating amyotrophic lateral sclerosis is reported. After thymectomy and corticosteroid therapy, the MG remitted. During 4 years of follow-up, the lower motor neuronsigns in the upper limbs and upper motor neuron signs in the lower limbs remained unchanged. Literature concerning paraneoplastic neurological syndromes associated with thymoma has been reviewed. PMID- 29508784 TI - Neurological manifestations in hypoparathyroidism. AB - Neurological manifestations in three cases of hypoparathyroidism, two of the idiopathic variety and one consequent to thyroidectomy are reported. The rare manifestations included the presentation as paroxysmal kinesogenic choreoathetosis in a twelveyear old boy who had history of seizures in childhood. He responded to carbamazepine. The second case, a known epileptic well controlled on sodium valproate, presented with mental dullness, bone pain and showed features of neuromuscular irritability. Thethird patient presented with raised intracranial tension. He had history of thyroidectomy in the past. The diagnosis was confirmed by the classical blood changes of hypoparathyroidism and the presence of basal ganglia calcification in the two idiopathic cases. All the cases finally responded to combination of calcium and D3. PMID- 29508785 TI - Herpes simplex myelitis in a patient with acquired immune deficiency syndrome. AB - Herpes simplex virus type-I is the commonest cause of focal encephalitis in immunocompetent adults. We report a 35 year old man, who presented with acute ascending myelitis which progressed to encephalitis within one week. The patient's MRI revealed nonhaemorrhagic lesions in frontotemporal areas and midbrain without any evidence of herniation. The CSF was positive for IgM and IgG antibodies against herpes simplex virus 1 (HSV1) and serum was positive for HIV by ELISA and Western blot techniques. The patient died on 18th day of illness due to resistant pseudomonas septicaemia.The presence of disseminated involvement of the central nervous system in HSV infection should raise the suspicion of the HIV coinfection. PMID- 29508786 TI - Sclerosing aspergilloma mimiking sphenoid ridge meningioma in an immunologically competent patient. AB - A 30 year old man presented with history suggestive of a parasellar tumour. Computerised tomography of brain revealed a hyperdense lesion on either side of sphenoid ridge having extension to floor of middle cranial fossa on the left side, enhancing homogenously with contrast and suggestive of a meningioma. Paranasal sinuses and orbit were free of tumour. He did not have any predisposing factor to harbour oppurtunistic infection. Craniotomy and total excision of the lesion was done. Histopathology was reported as aspergilloma. PMID- 29508787 TI - Bilateral trigonal lateral ventricular mirror image meningiomas : a case report. AB - A seventeen year old male patient presented with clinical features suggestive of raised intracranial pressure. CT Scan and MRI of brain revealed two mass lesions, one in trigone of each lateral ventricle. They were imageologically alike, appearing as mirror image masses. Both ware totally excised through occipitoparietal transventricular approach on the respective side of the lesion. Postoperative period was uneventful. Repeat CT Scan showed no residue of the lesions. Histopathological examination showed meningioma. To the best of our knowledge this is the first published report on bilateral trigonal meningiomas. PMID- 29508788 TI - Syringomyelia presenting soon after cranial and possible spinal trauma : a case report. AB - A 30 year old man, who had a fall from the top of a vehicle, was operated for frontal extradural haematoma. In the post-operative period he was noted to have features of central cord syndrome. MRI of the cervical spine revealed a multiseptate cervicothoracic syringomyelia, suggesting a long standing but asymptomatic syrinx. A syrinx-subarachnoid shunt was placed through a C6 and C7 hemilaminectomy. Patient improved in neurological status postoperatively. The possible mechanism of conversion of an asymptomatic syrinx to symptomatic syrinx following cranial and possible spinal trauma shall be discussed. PMID- 29508789 TI - Chronic extradural haematoma : a case report. PMID- 29508790 TI - Pituitary tuberculoma. PMID- 29508791 TI - Chloroquine induced psychosis in a child. PMID- 29508792 TI - Ganglion cyst of the common peroneal nerve : an unusual cause of foot drop. PMID- 29508793 TI - Neurological complications of HIV infection. AB - More than half of HIV - infected persons develop symptomatic neurological disease. The nervous system is extensively involved with no part of the neuraxis being immune from the virus. Beisdes the brain and spinal cord, the peripheral nerves and muscles may be affected. Neurological complications typically occur with advanced disease and profound immunosuppression, hence a knowledge of the CD4 lymphocyte count is of paramount importance. Since many of the conditions are amenable to treatment, a proper diagnosis and therapy may decrease morbidity in the already curtailed life span of the patient. Some opportunistic neurological infection is a result of latent/persistent infection requiring lifelong secondary prophylaxis e.g. toxoplasma encephalitis and cryptococcal meningitis. Neuroaids does not follow the law of parsimony i.e. a single entity may not be responsible for the entire constellation of signs and symptoms. HIV infection is the commonest cause of dementia in people under the age 50 in thedeveloped world. Cryptococcosis is the commonest infection affecting the nervous system in HIV positive patients. Tuberculosis has seen a resurgence following the out break of AIDS. CNS lymphoma is the commonest cause of raised ICP followed by tuberculoma, toxoplasmosis and brain abscess. Most patients with paraparesis have a typical HIV associated vacuolar myelopathy. A distal predominantly sensory neuropathy is the initial feature of insult to peripheral nerves. Muscle involvement may be due to polymyositis and HIV associated wasting syndrome but may also be aggravated by drugs (e.g. zidoudine). PMID- 29508794 TI - Impact of arterial displacements on strategy for cavernous sinus surgery. AB - Selection of the operative route for cavernous sinus related lesions, the extent of the exposure necessary, the need for intra-operative control of the carotid artery and feasibility of radical resection depend on the nature of the tumour. The importance of the arterial relationship in preoperative evaluation of the histology of the lesion and the impact on decision regarding the surgical strategy is discussed in the present report. An anatomical, radiological and clinical analysis of some of the more common lesions involving the cavernous sinus is presented. PMID- 29508795 TI - Gabapentin in refractory partial seizures. AB - We report our preliminary observations on the role of Gabapentin as an add - on therapy in 16 patients with partial or secondary generalised seizures who were resistant to conventional antiepileptic drugs. There was a reduction in the seizure frequency by more than 50 in 11 (69), less than 50 in 3 (18.75), and increase in 1 (6.25). Adverse effects were noted in 9 (56.25 ) of them. The giddiness and sleepiness was seen in 5 (31.25 ); in one it was so severe that he withdrew from the study. Ataxic gait was observed in 1 (6.25). Reduction in the haemoglobin by 2 gms. occurred in 2 (12.5) and asymptomatic eosinophilia in 1 (6.25). As an add - on drug, the efficacy of Gabapentin was good. Regular haematological monitoring is necessary while the patients are on the drug. Further studies involving large number of patients in our country is necessary. PMID- 29508796 TI - Efficacy and tolerability of oral sumatriptan in Indian patients with acute migraine : a multicentre study. AB - This multicentre, randomized, double-blind, cross over, placebo controlled study evaluated the efficacy and tolerability of oral Sumatriptan (100 mg) in 100 migraineurs. 59 patients completed the study. The results indicate that by 4 hours post-dose62 of patients treated with Sumatriptan achieved relief of headache, compared with 10 of patients treated with placebo. The results show that oral Sumatriptan is an effective drug for treatment of acute migraine in Indian patients, though smaller dosage may be more beneficial. PMID- 29508797 TI - Role of intracranial pressure monitoring in head injury : a prospective study. AB - Intra-cranial pressure (ICP) monitoring was carried out in 51 patients with head injury, admitted to the intensive care unit of All India Institute of Medical Sciences for a minimum of 24 hours. 74 patients with mass lesion and 33 patients without mass lesion had raised ICP (<15 mm of Hg). CT scan was not always reflective of ICP status. ICP monitoring helped in avoiding unnecessary mannitol therapy in 8 out of 12 patients without mass lesion. In this group presence or absence of raised ICP did not affect the outcome. Among 21 patients with mass lesions initially managed conservatively, 3 were operated upon on the basis of raised ICP alone. Four patients with good Glasgow Coma Sclae (GCS) (11-14), who had raised ICP were operated after clinical deterioration. However, in these patients raised ICP preceded clinical deterioration by 8-12 hours. In electively ventilated patients, raised ICP guided early repeat scan and early detection of postoperative haematomas. Patients with mass lesionand increasing ICP had poor outcome, overall mortality being 41. Among them 48 died due to raised ICP. Damped tracings or blockage of device were the most common complication of ICP monitoring. This complication was recorded in 25 of cases in whom Richmond screw was used and 12 of cases in whom intra-cavitary catheter was used. Six percent cases developed meningitis. PMID- 29508798 TI - Smear diagnosis of central nervous system lesions : a critical appraisal. AB - Smears, imprints and frozen sections have been recognised as useful adjuncts to diagnosis by the traditional paraffin section in neurosurgical biopsies. In this study, 251 intracranial space occupying lesions were studied by smears and paraffin sections to determine the causes of error and the possible means to avoid them. There were 63 computed tomography guided stereotactic microbiopsies and 188 open biopsies. The overall diagnostic accuracy was 88. In 6.8 of cases the tumour type was diagnosedcorrectly, but the grade was altered subsequent to examining the paraffin sections owing probably to sampling errors. Only 5.2 of cases had an entirely incorrect diagnosis. PMID- 29508799 TI - A Study of H reflex in amyotrophic lateral sclerosis. AB - In amyotrophic lateral sclerosis (ALS), both anterior horn cell and corticospinal tracts are affected. H reflex studies were performed in 15 patients to study motor neuron excitability and to correlate the changes with the clinical signs. Soleus H reflex was unrecordable in two patients. In the remaining patients, there was lack of vibratory inhibition and reciprocal inhibition which was consistent with pronounced presynaptic and supraspinal influences respectively. High HM ratio was consistent with increased motor neuron excitability. Significant reduction of maximum M response in our patients was consistent with fall out of anterior horn cells. HM ratio, vibratory inhibition and reciprocal inhibition were not related with power, spasticity, clonus or extensor plantar response, which could be due to asymmetric focal neuronopathy. PMID- 29508800 TI - Dermatomal somato sensory evoked potentials in cervical spondylosis. AB - Dermatomal somatosensory evoked potentials (DSSEP) from C5-T1 dermatomes were recorded in 20 normal healthy adult volunteers as controls and 61 patients with neck pain. The patients were divided into three groups. Group I : symptomatic patients withclinical signs of C5-T1 radiculopathy and radiological evidence of cervical spondylosis (21 patients). Group II : symptomatic patients without clinical signs of radiculopathy but with radiological evidence of cervical spondylosis (20 patients). Group III: patients with persistent neck pain without any clinical radiculopathy or radiological evidence of cervical spondylosis (20 patients). A complete neurological examination and nerve conduction study of median and ulnar nerves were done to rule out peripheral neuropathy. Normative data was established for DSSEP from C5-T1 dermatomes using the control group and the values obtained were comparable with western normative data. In the group I, DSSEP was abnormal in all the cases. It was possible to preciselylocate the involvement of C5 root in 75 , C6 root in 88.88, C7 root in 92.30 , C8 root in 76.92, and T1 root in 100. The DSSEP was abnormal in 11 patients in Group II, but was normal in all the patients of Gruoup III. DSSEP of C5-T1 dermatomes correlated well with the clinical findings in Group I patients. It was possible to detect subclinical radioculopathy in a significant number of patients in Group II. DSSEP is a simple non invasive method for evaluation of cervical radiculopathy. PMID- 29508801 TI - Rhinocerebral zygomycosis : a clinicopathological study. AB - Clinicopathologial features of six cases of rhinocerebral zygomycosis are described. The diagnosis was based on the demonstration of broad, non-septate hyphae in tissue sections. Four patients had rhinocerebral/rhinoorbitocerebral zygomycosis and one had isolated cerebral zygomycosis. Intense polymorphonuclear response was the pathological feature in 4 patients. Three cases had angioinvasion resulting in haemorrhage, infarction and necrosis. PMID- 29508802 TI - Lamotrigene and vigabatrin in intractable seizures in children. AB - Twenty seven children with intractable seizures in the age group of 5 months - 14 years were treated with vigabatrin (VGB) and Lamotrigene (LTG) as an add-on therapy. Fourteen children (6M:8F) were given VGB and thirteen children (9M:4F) received LTG. The drug selection was made according to the type of seizures and associated neurological abnormalities. Attempt was made to exclude children with progressive neurologic disorders or severe systemic disease. EEG, CT scan head and relevant metabolic work up was done in all. VGB was found to be most effective in seizures associated with tuberous sclerosis. It was always useful in infantile spasm (IS) and tonic clonic (TC) seizures. LTG was effective in complex partial seizure (CPS) and TC seizures withmyoclonus. PMID- 29508803 TI - Intramedullary spinal cord metastasis : an under-diagnosed entity. AB - Intramedullary spinal cord metastatic tumours, generally considered to be rare, are increasingly being diagnosed due to aggressive management of the primary malignancy, better imaging facilities and attempts at total excision of these lesions. Sincethese lesions were diagnosed late in the course of the disease patients were earlier given only palliative treatment. Presently, with more intensive treatment protocols the immediate outcome appears to be better.The present report is about two patients in whom the spinal cord lesion was the primary manifestation of an underlying malignancy. Total excision of the lesion was done in both the patients. Post operatively, one patient had marked improvement in the neurological status. He underwent radiation and chemotherapy and survived for seven months. He later succumbed to multiple secondaries involving the brain. The other patient did not improve in her neurological function in the immediate post-operative period and was lost to follow up. PMID- 29508804 TI - Davidenkow's syndrome : a clinical, electrophysiological and histomorphometric evaluation. AB - Davidenkow's syndrome is being reported in three members of a family. The affected subjects had weakness and wasting of the deltoids and the distal muscles of the lower limbs. The onset of the disorder was in the middle of the second decade and the affected subjects retained the capability of independent mobility till the fifth decade. Neuroelectromyographic studies revealed the presence of a demyelinating neuropathy. Sural nerve histology was characterised by loss of myelinated fibres and segmental demyelination. PMID- 29508805 TI - Intracranial plasma cell granuloma : a report of four cases. AB - Intracranial plasma cell granulomas are a rare group of idiopathic inflammatory pseudotumours often mistaken for lymphoreticular malignancies and myeloproliferative disorders. The clinial and pathological findings in respect of four cases of intracranial plasma cell granuloma clinically diagnosed as meningioma and glioma are presented in this report. The range of microscopic features seen included a mixed cell population with predominance of plasma cells, absence of cellular atypia and mitosis, multinucleate giant cells, perivascular cuffing by inflammatory cells and emperipolesis. The major considerations in differential diagnosis of this lesion are discussed. PMID- 29508806 TI - Insulinoma presenting with dementia and hemiplegia. AB - A 23 year non-diabetic female presented with history of episodic alteration of sensorium, cognitive decline and right hemiparesis. Fasting blood glucose was found to be low on multiple occasions along with raised insulin levels. Abdominal CT scan and coeliac axis angiogram were normal. The diagnosis of insulinoma was confirmed on removal of the tumour on exploratory laprotomy. The patient was left with residual mild dementia and hemiparesis. PMID- 29508807 TI - Spinal cord tuberculoma and misleading MR imaging : a case report. AB - A case of multiple spinal cord tuberculomas has been presented because of its rarity and misleading picture on MR imaging. The MRI suggested intradural extramedullary spinal tumours, possibly neurofibromata, because of associated cafe-au-lait spot. Various tubercular processes involving the spinal cord and meninges are discussed in the light of the present case. PMID- 29508808 TI - Spinal epidural tuberculoma simulating prolapsed intervertebral lumber disc. AB - 50 year old man presented with right sciatica syndrome of 10 months duration. Clinically and radiologically he seemed to have prolapse of intervertebral disc at L5 - S1. At surgery a well demarcated greyish yellow mas sticking to S1 root and adjacemt dura was found. Histology confirmed it to be tuberculoma. Patient was put on anti-tubercular chemotherapy and made good recovery. PMID- 29508809 TI - Acute disseminated encephalomyelitis presenting as ataxic hemiparesis. AB - A patient of acute disseminated encephalomyelitis (ADEM) with a rare clinical presentation is described. The temporal profile of the disease suggested parainfectious central demyelination. The magnetic resonance imaging (MRI) also showed large demyelinating lesions scattered bilaterally in the cerebral white matter, thalami and brain stem. However, clinically he had only right ataxic hemiparesis and dysphasia without any impairment of cognition or consciousness. PMID- 29508811 TI - Therapeutic efficacy of thrombolytic therapy in acute ischaemic insults to the brain. PMID- 29508810 TI - Primary Ewing's sarcoma of the skull. PMID- 29508812 TI - Dumb-bell schwannoma of the cervical spine. PMID- 29508813 TI - Risk factors for stroke : relative risk in young and elderly. AB - Stroke is a leading cause of morbidity and mortality. A significant proportion of stroke victims in India are below the age of 40 years and may have specific risk factors. 101 patients (42 less than 40 years of age) of ischaemic stroke were studiedat NIMHANS to estimate the relative risk of various contributing factors. Hypercholesterolaemia, hyperglycaemia and hypertension were more common in elderly group, while smoking, alcohol and tobacco abuse were more prevalent in younger age group (relative risk 1.2, 1.9 and 1.5 respectively). A better understanding of these risk factors may play a key role in the prevention of stroke in young. PMID- 29508814 TI - Long-term effect of controlled-release carbidopa/levodopa in levodopa-na. AB - This study reports long-term (over 6 years) effect of controlled-release carbidopa/levodopa (CRCL, Sinemet-CR) in levodopa-naive Parkinson's disease patients. Parkinsonian features were evaluated utilizing the Northwestern University Disability Scale (NUDS) and modified New York University Parkinson's Disease Rating Scale (NYUPDRS). The NUDS scores showed significant variation over time by 2-way ANOVA (P < 0.0001). Following treatment, compared to baseline scores, the NYUPDRS scores showed significant improvement in rigidity, tremor, bradykinesia, while the postural stability scores worsened and gait scores, after initial improvement, returned to baseline level. At the end of the study period 5 patients were alive, 1 became disabled due to myocardial infarction and 3 were holding on to full time occupations. Three patients developed medication related dyskinesia, 1 developed myoclonus and 1 developed a combination of dyskinesia, motor fluctuations and early morning dystonia. Due to small number of patients, while a definite conclusion cannot be drawn, it appears that the incidence of motor fluctuation may be much less prevalent than dyskinesia in patients with Parkinson's disease treated with CRCL. PMID- 29508815 TI - A Prospective study of corpus callosotomy for medically intractable epilepsy. AB - Results of corpus callosotomy on ten patients with medically intractable epilepsy, done between 1991 and 1996 are reported. Mean age of the patients was 20.5 years and mean duration of seizures 9.5 years. They underwent neurological assessment, detailed EEG studies and neuropsychological evaluation to rule out a resectable seizure focus. Seven patients underwent anterior callosotomy and three, a two staged total callosotomy. Acute disconnection syndrome was observed in about 50 cases which resolved completely in 1-3 weeks. The outcome was excellent in three, good in three, moderate in three and poor in one after a mean follow up of 21 months. Best response was seen in generalized tonic clonic, absence, atonic and tonic seizures. Most patientshad definite improvement in the quality of life after surgery. Age of patient, age at onset of seizures, duration of seizures and degree of mental retardation had no correlation with the outcome. Total callosotomy was found to have much better outcome compared to partial section. We conclude that callosotomy has a definite place in the management of medically intractable epilepsy especially for some seizure types. PMID- 29508816 TI - Molecular diagnosis of DMD/BMD. AB - Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X- linked recessive disorders with the former following a severe and fatal course and the latter a milder clinical profile. Accurate diagnosis of these disorders, therefore, becomes crucial for patient counselling and management. A number of molecular diagnostic criteria for DMD/BMD have evolved with the growth of molecular biology. These include multiplex PCR, southern blot analysis, denaturing gradient-gel electrophoresis, western blot analysis, immunocytochemistry, CA repeat analysis, entangled solution capillary electrophoresis, heteroduplex analysis, single strand conformation electrophoresis and direct sequencing. RNA finger-printing has the potential to lead the present day molecular diagnostics of muscular dystrophies to a new dimension hitherto unexplored. PMID- 29508817 TI - Digoxin : a model for hypothalamic regulation of neuronal transmission, endocrine function, immunity and cytodifferentiation. AB - The case report of a family with coexistence of schizophrenia, systemic malignancy, Parkinson's disease, rheumatoid arthritis and syndrome X is described. The coexistence of malignant transformation, neuronal degeneration, immune dysfunction and psychiatric manifestation have been extensively documented in literature. It is possible that a central dysfunction in neuroendocrine and immune integration may play a role in the pathophysiology of these diseases. Elevated levels of an endogenous sodium-potassium ATPase inhibitor, digoxin, a steroidal glycoside, has been reported in syndrome X. The human hypothalamus is the principal source of digoxin. Serum digoxin level and RBC sodium-potassium ATPase were measured in the members of the index family and8 groups of patients with CNS gliomas, Parkinson's disease, motor neuron disease, CNS vasculitis, multiple sclerosis, primary generalised epilepsy, schizophrenia and the acquired immunodeficiency syndrome. Digoxin, being a isoprenoidal compound, its synthesis was assessed by HMG CoA reductase activity. The levels of serum digoxin and HMG CoA reductase activity were found to be increased in the members of the index family and all the 8 groups studied with a corresponding reduction in RBC sodium potassium ATPase activity. The role of hypothalamic digoxin in the pathogenesis of these diseases is discussed. A digoxin model for hypothalamic regulation of neuronal transmission, endocrine function, immunity and cytodifferentiation is proposed. PMID- 29508818 TI - Stereotactic catheter placement in the management of cystic intrcranial lesions : indications and results. AB - Stereotactic techniques were used to place a catheter into cystic intracranial lesions in 11 patients. These patients had 4 types of cystic lesions : suprasellar craniopharyngiomas (4), benign epithelial cysts (2), suprasellar arachnoid cysts (3) and tumour cysts (2). Seven patients had subgaleal reservoir placement and four had cystoperitoneal shunt. There was no procedure related morbidity. In all the patients, a post procedure CT scan revealed accurate placement of the catheter. The mean follow-up period was 23 months. During this period, 3 of the 7 patients with reservoir placement had become symptomatic and had to undergo a percutaneous aspiration of the cyst through the subgaleal reservoir. One patient required repositioning of a displaced catheter, and one patient received bleomycin through the reservoir after aspiration of the craniopharyngioma cyst. Eight patients improved and are leading independent lives. Stereotactic catheter placement is a minimally invasive, safe, accurate and simple procedure which can be used in the management of selected cystic masses in the brain. Connection of the catheter to a reservoir or a shunt ensures access to the cyst in case of reaccumulation of its contents and provides continuous drainage of its contents. PMID- 29508819 TI - Evaluation of muscle changes in patients with chronic renal failure. AB - Forty patients of chronic renal failure (CRF) and five patients of acute on chronic renal failure (ACRF) were evaluated clinically and electrophysiologically for involvement of muscles. EMG studies showed features suggestive of denervation myopathy in 10 of patients of CRF only. Histopathological study of muscle biopsies, done in 25 patients with CRF, showed constellation of histopathological features suggestive of denervation myopathy in 48 and toxic myopathy in 24. In five patients with ACRF,denervation myopathy was observed in 60 and toxic myopathy in 20 cases on histopathological examination. PMID- 29508820 TI - Profile of status epilepticus : a prospective study. AB - Forty adult patients (age> 14 years) of generalised convulsive status epilepticus were studied prospectively. All the patients were subjected to detailed history, neurological examination and baseline investigations including haemogram and metabolicprofile. CT scan was carried out in 26 patients. All the patients were treated with intravenous diazepam and phenytoin. The age range of the patients was 14-71 years with a mean of 32.75 ? 15.78. There were 24 males and 16 females. Twenty six patients had generalised tonic clonic seizures while 14 had partial seizures with secondary generalisation. Symptomatic epilepsy was the commonest type of epilepsy and was seen in 25 patients. The diagnosis of cryptogenic and idiopathic epilepsies was made in 11 and 4 patients respectively. Drug withdrawl precipitated status epilepticus in 5 patients and systemic infection in one. The mean frequency of seizures was 4.70??1.83/hour, mean duration was 1.78???l.0l/minutes and cumulative convulsive time 25.27??21.50 minutes. Twelve patients had focal neurologic deficits. Papilloedema was seen in four cases only. CT scan was abnormal in 18 of 26 patients. All patients except one showed immediate response to therapy. Seven patients had recurrence of seizures after initial response to diazepam and phenytoin. Low serum level of the drug at 12 hours had a significant correlation with recurrence of seizures. Ataxia was the most common side effect of phenytoin therapy. Serious side effects e.g. hypotension and respiratory depression were seen in 4 and 2 patients respectively. Two patients expired during 48 hours follow up. PMID- 29508821 TI - Shunt malfunction : unusual cause [Letter]. PMID- 29508822 TI - Long-term use of clobazam in the management of intractable epilepsy : a prospective study. AB - Clobazam, a 1-5 benzodiazepine, was used as add-on in the management of intractable epilepsy prospectively from 1993-1996. Forty patients who satisfied the defined inclusion and exclusion criteria with minimum one year follow-up were included. Therewere 25 male and 15 female patients, which included 15 children (37.5 ) and 25 adults (62.5 ). They had epilepsy for a mean period of 145.3 ? 106.9 months. Majority had uncontrolled complex partial seizures with or without secondary generalization. 55had single type of epilepsy and 45 had multiple type of seizures. Clobazam (Frisium) was added as an adjuvant in the dose of 5-30 mg. Patients were followed regularly to evaluate its efficacy and toxic effects. Follow up ranged from 12-66 months with amean of 27.2 ? 13 months. Twelve patients (30) were totally free from seizure, 16 (40) had more than 75 reduction in frequency and 6 (15) had no effect. Tolerance was seen in 7 ( 17.5) patients. This could be managed by increasing the dosage in a step-wise manner. Three female patients complained of increase in weight which has not been reported in the literature so far. We could reduce the dose of other antiepileptics in all and stopped one AED in 8 patients. Clobazam is recently introduced in the Indian market and relatively very economical compared to other newer antiepileptic drugs and effective as first line add-on drug in the management of refractory epilepsy in both adults and children. PMID- 29508823 TI - Brain stem dysfunction in spasmodic torticollis : an electrophysiological study. AB - Continuous or intermittent deviation of head seen in spasmodic torticollis (ST) may result in abnormalities of blink reflex or brain stem auditory evoked potentials (BAEP). The present study was undertaken on 10 patients of ST and an equal number ofage and sex matched healthy controls. BAEP showed no difference in the two groups. R1 and contralateral R2 of blink reflex were similar in the patients and the controls. R2 contralateral to torticollis was also similar to controls but R2 ipsilateral to torticollis was prolonged in ST patients (32.28??1.91 msec) as compared to controls (30.96??1.53 msec) (p<0.05). Our findings suggest brainstem dysfunction in some patients with spasmodic torticollis. PMID- 29508824 TI - Symptomatic spinal haemangioma : radiological aspects. AB - Five cases (three male and two female) of dorsal spinal haemangioma in the age group of 16-43 years, presenting as compressive myelopathy, are reported. Three of them had vertebral haemangioma with extradural extension. One patient had isolated extradural haemangioma and one had extramedullary intradural haemangioma. One female patient presented during the seventh month of gestation and one case had associated cyanotic congenital heart disease. All except one had slowly progressive evolution of complaints. The duration of symptoms ranged from two weeks to six months. PMID- 29508825 TI - Extensive cranial vault and skull base osteomyelitis complicating chronic mastoiditis : a case report. AB - The authors report an unusual case of extensive osteomyelitis of cranial vault and skull base as a complication of chronic mastoiditis in a 19 year old girl. The diagnosis was confirmed by bone biopsy which revealed osteomyelitic changes and large bacterial colonies. The unusual features of this case is discussed along with review of relevant literature. PMID- 29508826 TI - Dorsal spinal enterogenous cyst : a case report and review of literature. AB - A case of a histologically proven dorsally situated spinal enterogenous cyst of the cervical region is reported with a brief review of literature on the subject. PMID- 29508827 TI - Peripheral nerve damage following lightening injury. AB - A 20 year old male after being struck by lightening remained quadriplegic for several months and finally almost fully recovered. His weakness was due to extensive peripheral nerve injury (involvement of plexuses, radicles and peripheral nerve trunks) as evident by clinical and neurophysiological studies. He also showed many well known medical complications of lightening injury viz. acute renal failure, hypercalcaemia, autonomic dysfunction and cataract. PMID- 29508828 TI - Wegener's granulomatosis : a case with multiple symmetric cranial neuropathy. AB - We report a 47 year-old woman with Wegener's granulomatosis presenting with an atypical onset of multiple symmetric cranial neuropathies. The diagnosis was established by clinical and laboratory data. To our knowledge, this is the first case of Wegener's granulomatosis presenting with bilateral multiple symmetric cranial neuropathy. PMID- 29508829 TI - Neurofibromatosis 2 : unusual presentation with review of literature. AB - A case of central neurofibromatosis with various associated neurological abnormalities is reported. Apart from symptoms of eighth nerve involvement the patient had a hypotonic, hyporeflexic quadriparesis. Radiology revealed scoliosis, an intramedullary spinal tumour, bilateral acoustic neurinoma, tectal glioma and hydrocephalus. In view of the rapid progression of the disease process a palliative shunt procedure was carried out without any definitive surgery. The various ravages of nervous system in NF2 are discussed along with a brief review of literature. PMID- 29508830 TI - Haemorrhage during cranial CT : spontaneous or contrast related? AB - Two cases of haemorrhage during cranial computed tomography (CT) occurring during the enhancement phase of CT examination immediately after the administration of intravenous contrast medium are reported. In both cases, the preceding unenhanced scansshowed evidence of haemorrhage. The risk of aneurysmal rupture as a result of retching and vomiting induced by intravenous contrast is stressed. Judicious use of contrast enhanced CT is suggested in patients with suspected aneurysmal subarachnoid haemorrhage. PMID- 29508831 TI - Adult diastematomyelia : a case report and review of literature. AB - Adult presentation in diastematomyelia is very rare. The common location is from first to third lumbar vertebrae. Lumbosacral adult diastematomyelia is even rarer. A 42 years male with lumbosacral diastematomyelia is described. Combined myelographic-CT scan study demonstrated lumbar canal stenosis and bony spur attached to vertebral bodies of the fifth lumbar and first sacral vertebra. Surgery with decompression of neural elements and removal of bony spur resulted in complete relief of symptoms. Detailed case representation and a review of 74 cases of adult diastematomyelia is reported. PMID- 29508832 TI - Diastematomyelia in adults : pathogenesis, MR imaging and management principles. AB - Diastematomyelia is an uncommon developmental anomaly, usually presenting in childhood. Adult presentation is rare. We report three patients of diastematomyelia, becoming symptomatic in adulthood. These constituted 17 of all adult patients with tethered cord syndrome. One patient had a nonprogressive childhood deficit and two had a cutaneous stigmata in the lower back. In one patient, the symptoms were precipitated following trauma. All patients were investigated by MRI which demonstrated the diastematomyelic lesion. One had an associated intraspinal enterogenous cyst. We recommend prophylactic surgery in patients with diastematomyelia, once the diagnosis is established. The pathogenesis of adult diastematomyelia is discussed. PMID- 29508833 TI - Third ventricle choroid plexus papilloma with head tremors. AB - A rare case of third ventricular choroid plexus papilloma is reported. A two year male child presented with clinical features of raised intracranial pressure, meningismus, gait ataxia and abnormal head tremors. Abnormal head tremor is an extremely uncommon presenting feature of a choroid plexus papilloma of third ventricle. PMID- 29508834 TI - Lumbar intradural disc herniation. AB - A 60 year old man presented with chronic backache of six months duration, sciatica of three months duration, weakness of both lower limbs of two months duration, urinary retention and bowel incontinence of one month duration. Neurologically, he hadparaplegia with motor and sensory level at L1 dermatome. X ray lumbar spine showed spondylotic changes with reduction of L1/L2 disc space.Myelography revealed an intradural mass. A diagnosis of intradural disc herniation was made and confirmed by surgery.However, neurological status remained unchanged at the time of discharge. PMID- 29508835 TI - Superficial siderosis of the nervous system. AB - A male patient had been operated in 1990 at a different hospital for a suprasellar mass lesion causing progressive blindness. At exploration, the mass was felt to be inflammatory in nature with arachnoiditis and hydrocephalus. Deep yellow staining of tissues round the mass was recorded at the time of first surgery. The patient was readmitted in 1996 for progressive visual failure, ataxia, mental changes and deafness. MRI confirmed persistence of suprasellar mass and showed the characteristic findings of superficial siderosis of CNS. On reexploration, the mass had multiple vessels over the walls and contained xanthochromic fluid. It was excised and histologically examined to be an epidermoid with a cyst. The patient developed chest infection, became drowsy and died. The MRI picture, the CSF finding and the yellow staining of tissue confirmed the diagnosis of superficial siderosis of the CNS, which was first thought of after seeing the diagnostic MRI. The cause of the superficial siderosis was recurrent bleeding from the tumour. PMID- 29508837 TI - Double aneurysm on the anterior communicating artery. PMID- 29508836 TI - Epidermoid cyst of the brain stem : a case report. AB - Intracranial epidermoids account for 0.2 to 1.8 of all brain tumours. We report an epidermoid cyst in an unusual location - the brain stem. At this site safe and adequate resection implies decompression of the cyst contents and removal of the non-adherent cyst capsule. PMID- 29508838 TI - Dolichoectasia of basilar artery : a cause of trigeminal neuralgia and haemorrhage. PMID- 29508839 TI - Spinal intramedullary tuberculoma : a report of two cases. PMID- 29508840 TI - Idiopathic pituitary granuloma of possible cysticercus aetiology. PMID- 29508842 TI - Vasculitic neuropathy. PMID- 29508841 TI - Primary osteosarcoma of the spine. PMID- 29508844 TI - Bladder cancer: Mechanisms of anti-PDL1 resistance. PMID- 29508843 TI - Application of an Infection Control Protocol (ICP) Reduced Cardiac Device Infection (CDI) in Low-Volume Centers. AB - BACKGROUND Cardiac device infection (CDI) is a serious complication of cardiovascular implantable electronic device (CIED) implantations. Many risk factors have been identified, but several are still uncertain. This study aimed to identify and evaluate the risk factors. Moreover, an infection control protocol (ICP) was carried out, and its efficacy in reducing CDIs was investigated. MATERIAL AND METHODS A total of 1259 patients who received permanent pacemaker (PPM) implantations were enrolled in this study in a 3-year period in a high-volume center and low-volume centers in the central area of Shaanxi Province, China. Follow-up data of all enrolled patients were collected. The risk factors for CDIs were identified and analyzed. The ICP was adopted in the low-volume centers. Data, including CDI rates, medical costs, and microbiology, were collected and compared. RESULTS Male gender, diabetes, CKD, operation duration, PPM replacement, and low center volume were identified as the risk factors for CDIs. Furthermore, CDI rates in low-volume centers were significantly higher than in high-volume centers. The adoption of an ICP dramatically reduced CDI rates in low-volume centers without significant increases in medical costs. CONCLUSIONS ICPs were easily carried out, effective, and economical in controlling CDIs in low-volume centers, which was identified as a risk factor of CDIs. PMID- 29508845 TI - Prostate cancer: Molecular lymph node analysis for prognostication. PMID- 29508846 TI - Prostate cancer: Circulating tumour cells in prostate cancer. PMID- 29508847 TI - Urinary incontinence: Electrical stimulation for OAB. PMID- 29508848 TI - Testicular cancer: Serum miRNA predicts viable postchemotherapy lesions. PMID- 29508849 TI - Prostate cancer: Mouse model for testing treatments. PMID- 29508850 TI - Testicular cancer: No major predisposition gene in TGCT. PMID- 29508851 TI - Kidney cancer: ccrcc1-4 classification for prediction of relapse. PMID- 29508852 TI - Andrology: Ibuprofen and hypogonadism - bench to bedside to misinterpreted hype? PMID- 29508853 TI - Chemically synthesized histone H2A Lys13 di-ubiquitination promotes binding of 53BP1 to nucleosomes. AB - This corrects the article DOI: 10.1038/cr.2017.157. PMID- 29508854 TI - Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation. AB - This corrects the article DOI: 10.1038/cr.2012.160. PMID- 29508856 TI - Sarcoma: Local hyperthermia improves survival. PMID- 29508858 TI - Breast cancer: Fibroblast subtypes alter the microenvironment. PMID- 29508855 TI - Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. AB - Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research. PMID- 29508859 TI - Immunotherapy: Inhibition of TGFbeta enhances immune-checkpoint blockade. PMID- 29508857 TI - Targeting the PI3K pathway in cancer: are we making headway? AB - The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit alpha isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K AKT-mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K-AKT-mTOR pathway. PMID- 29508861 TI - Corrigendum: Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination. AB - [This corrects the article on p. 1883 in vol. 8, PMID: 29326728.]. PMID- 29508862 TI - Correction: Predictive value of post-procedural early (within 24 h) increase in cystatin C for contrast-induced acute kidney injury and mortality following coronary angiography or intervention. AB - [This corrects the article DOI: 10.18632/oncotarget.19034.]. PMID- 29508863 TI - Differences in the behavior of dicationic and monocationic ionic liquids as revealed by time resolved-fluorescence, NMR and fluorescence correlation spectroscopy. AB - With an aim to understand the behavior in terms of the intermolecular interactions, structure and dynamics of dicationic and monocationic ionic liquids (ILs), two imidazolium-based dicationic ionic liquids (DILs), 1,8-bis-(3 methylimidazolium-1-yl)octane bis-(trifluoromethylsulfonyl)amide ([C8(mim)2][NTf2]2), 1,9-bis-(3-methylimidazolium-1-yl)nonane bis (trifluoromethylsulfonyl)amide ([C9(mim)2][NTf2]2), and one monocationic ionic liquid (MIL), 1-butyl-3-methyl imidazolium bis(trifluoromethylsulfonyl)amide ([C4(mim)][NTf2]), have been investigated through combined fluorescence, electron paramagnetic resonance (EPR), NMR and fluorescence correlation spectroscopy (FCS). The DILs were synthesized by following a standard synthetic protocol and subsequently characterized by different analytical techniques. Steady state absorption, emission and EPR spectroscopic data reveal that DILs are less polar compared to MIL. The polarities of the DILs and MIL were found to be close to those of acetonitrile and short chain alcohols, respectively. The excitation wavelength dependent emission data reveals that DILs are more micro-heterogeneous in nature than MIL. The rotational diffusion of two organic solutes, perylene and 8-methoxypyrene-1,3,6-sulfonate (MPTS), were examined in the DILs and MIL. The rotational diffusion data for perylene and MPTS were analyzed in light of the Stokes-Einstein-Debye (SED) hydrodynamic theory. The rotation of perylene in the DILs was observed to be relatively faster to that in the MIL, and it goes beyond the limit predicted by the SED theory. In order to explain the rotational motion of perylene in DILs, the data was analyzed further by invoking quasi-hydrodynamic theory. The observed rotational behavior of perylene has been explained by considering the fact that perylene is located in the nonpolar region of ILs, and larger solvent molecules (DILs) induce a lower friction to the rotating solute. Interestingly, unlike perylene, rotations of MPTS in both of the ILs were observed to be much hindered indicating a relatively stronger MPTS-IL interaction than perylene-IL interaction. More interestingly, rotation of MPTS was observed to be faster in the DILs than that in the MIL despite the fact that DILs are more viscous than MILs. Relatively faster rotation of MPTS in DILs has been explained by resorting to NMR and FCS studies. The outcomes of the NMR and FCS studies revealed that DILs in the experimental condition exist in their folded form and because of this structural restriction of DILs it becomes difficult for the bulky MPTS to make stronger hydrogen bonding interactions with DILs, which eventually makes the rotation of MPTS in DILs faster. Essentially, the outcomes of all of these studies have demonstrated that the behavior of DILs is quite different to that of the usual MILs. PMID- 29508864 TI - Synergistic interactions between lecithin and fruit wax in oleogel formation. AB - In this study, the effect of lecithin (LEC) on the crystallization and gelation of fruit wax (FW) with sunflower oil was researched. A synergistic effect on the gel strength was observed at FW : LEC ratios of 75 : 25 and 50 : 50, compared to the corresponding single component formulations (100 : 0 and 0 : 100). Even below the critical gelling concentration (Cg) of FW, the addition of lecithin enabled gel formation. Lecithin affected the thermal behavior of the structure by delaying both crystallization and gel formation. The phospholipid acted as a crystal habit modifier changing the microstructure of the oleogel, as was observed by polarized light microscopy. Cryo-scanning electron microscopy revealed a similar platelet-like arrangement for both FW as a single oleogelator and FW in combination with LEC. However, a denser structure could be observed in the FW : LEC oleogelator mixture. Both the oil-binding capacity and the thixotropic recovery were enhanced upon lecithin addition. These improvements were attributed to the hydrogen bonding between FW and LEC, as suggested by Raman spectroscopy. We hypothesized that lecithin alters the molecular assembly properties of the FW due to the interactions between the polar moieties of the oleogelators, which consequently impacts the hydrophobic tail (re)arrangement in gelator-gelator and solvent-gelator interactions. The lipid crystal engineering approach followed here offered prospects of obtaining harder self-standing structures at a lower oleogelator concentration. These synergistic interactions provide an opportunity to reduce the wax concentration and, as such, the waxy mouthfeel without compromising the oleogel properties. PMID- 29508865 TI - Genetic incorporation of l-dihydroxyphenylalanine (DOPA) biosynthesized by a tyrosine phenol-lyase. AB - l-Dihydroxyphenylalanine (DOPA) was biosynthesized by a tyrosine-phenol lyase from catechol, pyruvate, and ammonia in Escherichia coli, and the biosynthesized amino acid was directly incorporated into proteins. Three biochemical experiments with mutant proteins containing DOPA confirmed the genetic incorporation of biosynthesized DOPA, and revealed its potential for various biochemical applications. PMID- 29508866 TI - Improved fill factor in inverted planar perovskite solar cells with zirconium acetate as the hole-and-ion-blocking layer. AB - Planar perovskite solar cells (PSCs) have gained great interest due to their low temperature solution preparation and simple process. In inverted planar PSCs, an additional buffer layer is usually needed on the top of the PCBM electron transport layer (ETL) to enhance the device performance. In this work, we used a new buffer layer, zirconium acetate (Zr(Ac)4). The inclusion of the Zr(Ac)4 buffer layer leads to the increase of FF from ~68% to ~79% and PCE from ~14% to ~17% in the planar PSCs. The UPS measurement indicates that the Zr(Ac)4 layer has a low HOMO level of -8.2 eV, indicating that the buffer layer can act as a hole blocking layer. Surface morphology and surface chemistry investigations reveal that the elements I, MA and Pb can diffuse across the PCBM ETL, damaging the device performance. The covering Zr(Ac)4 molecules fill in the pinholes of the PCBM layer and effectively block the ions/molecules of the perovskite from diffusion across the ETL. The resulting more robust PCBM/Zr(Ac)4 ETL leads to weaker ionic charge accumulation and lower diode leakage current. The double role of hole-and-ion blocking of the Zr(Ac)4 layer explains the improved FF and PCE in the PSCs. PMID- 29508867 TI - An anionic single-walled metal-organic nanotube with an armchair (3,3) topology as an extremely smart adsorbent for the effective and selective adsorption of cationic carcinogenic dyes. AB - A novel discrete single-walled metal-organic nanotube (JLU-MONT1) with a rare armchair (3,3) carbon nanotube topology is successfully synthesized, which is further linked by hydrogen-bonds forming a 3D supramolecular architecture. Benefiting from its anionic skeletal features and open mesoporous channels (21 A), JLU-MONT1 exhibits extremely high efficiency and capability to adsorb carcinogens basic red 9 and basic violet 14. PMID- 29508869 TI - Synthesis of zwitterionic hydrophilic magnetic mesoporous silica materials for endogenous glycopeptide analysis in human saliva. AB - A novel zwitterionic hydrophilic magnetic mesoporous silica was prepared for endogenous glycopeptide enrichment prior to MS analysis. For the first time, the material was successfully applied in capturing endogenous glycopeptides from human saliva, indicating great potential of this strategy for glycopeptidome analysis. PMID- 29508870 TI - Effects of different thickening agents on infant gut microbiota. AB - Infant microbiota has to progress from an almost sterile to a complex and varied community, so the main objective of this work was to evaluate the effect of three thickening ingredients on infant microbiota, as well as their in vitro gut fermentability. Experiments were performed using fresh faecal samples from healthy donors of 2-3 months of age. Stabilised stool samples were injected into Wheaton serum bottles containing pre-reduced MBM and 1% (w/v) fermentation substrates (locust bean gum, LBG; maize hydroxypropylated distarch phosphate, Mhdp; and pre-gelatinized rice starch, gRS). Samples were taken during fermentation, and pH, gas pressure, SCFA and bacterial population were analysed. The addition of thickeners resulted in a significant negative correlation (p < 0.05) between time and pH, showing significantly lower (p < 0.01) pH values for Mhdp and gRS than for LBG. Modified starches showed significantly higher values (p < 0.05) of total gas production than did LBG. Total SCFA molar concentrations for LBG, as well as propionate production, were significantly higher (p < 0.05) than for Mhdp and gRS. Regarding bacterial population, LBG promoted a more varied microbiota enhancing the growth of Atopobium and Bacteroidetes, whereas Mhdp and gRS induced higher Lactobacillus and Bifidobacteria at the beginning of fermentation. LBG induced moderate gas production and a slow drop of pH, and caused a decreasing acetate : propionate ratio, enhancing the development of a varied faecal microbiota. In contrast, Mhdp and gRS induced high gas production, a sudden drop of pH and a greater production of acetate, which promoted a less varied faecal microbiota. PMID- 29508875 TI - Pressure-induced abnormal ionic-polaronic-ionic transition sequences in AgBr. AB - The electrical transport behavior of the superionic conductor AgBr was systematically studied under high pressure up to 30.0 GPa with electrochemical impedance spectra measurements and first-principles calculations. From impedance spectra measurements, a pressure-induced abnormal ionic-polaronic-ionic transition was found. Herein, the ionic to polaronic transition at 5.0 GPa occurs with the absence of a structural phase transition. At 8.6 GPa, the ionic state of AgBr can be reactivated after a structural phase transition. Previous structural studies based on X-ray diffraction data cannot provide strong evidence to support the ionic-polaronic transition in AgBr at 5.0 GPa. In this paper, based on first principles calculations, a localized-electron-soup model was proposed to explain the physical origin of the ionic-polaronic transition. In this model, more localized electrons around the Br atoms are pressed into interstitial spaces and, simultaneously, polarons are formed between Ag+ ions and the localized electron background at 5.0 GPa. Therefore, the diffusion of Ag+ ions is effectively screened by the movement of the localized electron background from its equilibrium position, much like beans completely trapped in a cup of thick soup. PMID- 29508876 TI - The synthesis of benzimidazoles via a recycled palladium catalysed hydrogen transfer under mild conditions. AB - An efficient synthesis of benzimidazoles was developed by virtue of a recycled palladium catalyzed hydrogen transfer. The reaction can be carried out smoothly under mild conditions to give rise to a variety of benzimidazoles with good to excellent yields. The palladium catalyst could be recovered easily and reused six times with great catalytic activity. PMID- 29508877 TI - Singlet-assisted diffusion-NMR (SAD-NMR): redefining the limits when measuring tortuosity in porous media. AB - Long-lived singlet order is exploited in diffusion NMR experiments to successfully measure the tortuosity of randomly packed spheres with diameters ranging from 500 to 1000 MUm. The pore spaces in such packings have characteristic length scales well beyond the length scale limit set by spin relaxation in conventional NMR-diffusion experiments. Diffusion times of up to 240 s were used to obtain the restricted diffusion coefficient as a function of diffusion time in the long-time diffusion regime. Experimental results were validated with numerical simulations and data from X-ray micro-computed tomography. PMID- 29508878 TI - Magnetic steering of liquid metal mobiles. AB - Gallium-based liquid metal has captivated exceptionally keen interest in recent years since it remains in the liquid phase at room temperature and thus conforms to the surrounding medium. Meanwhile, such morphing capability can be tuned via altering the oxide layer on the surface of the liquid metal, which further triggers enthusiasm for investigating its locomotion. In this study, we proposed a magnetic actuation scenario for steering liquid metal locomotion in an easily accessible and highly directed manner. The soft mobile composed of liquid metal performed satisfyingly in locomotion and assembly tasks in various circumstances (on a solid surface and in a water environment). Furthermore, promising applications as switches for logic circuits and carriers for cargo transfer, as well as motors for vessel cleaning were also demonstrated, revealing the versatility of such liquid metal mobiles. PMID- 29508879 TI - Computer simulations of the catalytic mechanism of wild-type and mutant beta phosphoglucomutase. AB - beta-Phosphoglucomutase (beta-PGM) has served as an important model system for understanding biological phosphoryl transfer. This enzyme catalyzes the isomerization of beta-glucose-1-phosphate to beta-glucose-6-phosphate in a two step process proceeding via a bisphosphate intermediate. The conventionally accepted mechanism is that both steps are concerted processes involving acid-base catalysis from a nearby aspartate (D10) side chain. This argument is supported by the observation that mutation of D10 leaves the enzyme with no detectable activity. However, computational studies have suggested that a substrate-assisted mechanism is viable for many phosphotransferases. Therefore, we carried out empirical valence bond (EVB) simulations to address the plausibility of this mechanistic alternative, including its role in the abolished catalytic activity of the D10S, D10C and D10N point mutants of beta-PGM. In addition, we considered both of these mechanisms when performing EVB calculations of the catalysis of the wild type (WT), H20A, H20Q, T16P, K76A, D170A and E169A/D170A protein variants. Our calculated activation free energies confirm that D10 is likely to serve as the general base/acid for the reaction catalyzed by the WT enzyme and all its variants, in which D10 is not chemically altered. Our calculations also suggest that D10 plays a dual role in structural organization and maintaining electrostatic balance in the active site. The correct positioning of this residue in a catalytically competent conformation is provided by a functionally important conformational change in this enzyme and by the extensive network of H-bonding interactions that appear to be exquisitely preorganized for the transition state stabilization. PMID- 29508884 TI - Full imitation of synaptic metaplasticity based on memristor devices. AB - Neuromorphic engineering is a promising technology for developing new computing systems owing to the low-power operation and the massive parallelism similarity to the human brain. Optimal function of neuronal networks requires interplay between rapid forms of Hebbian plasticity and homeostatic mechanisms that adjust the threshold for plasticity, termed metaplasticity. Metaplasticity has important implications in synapses and is barely addressed in neuromorphic devices. An understanding of metaplasticity might yield new insights into how the modification of synapses is regulated and how information is stored by synapses in the brain. Here, we propose a method to imitate the metaplasticity inhibition of long-term potentiation (MILTP) for the first time based on memristors. In addition, the metaplasticity facilitation of long-term potentiation (MFLTP) and the metaplasticity facilitation of long-term depression (MFLTD) are also achieved. Moreover, the mechanisms of metaplasticity in memristors are discussed. Additionally, the proposed method to mimic the metaplasticity is verified by three different memristor devices including oxide-based resistive memory (OxRAM), interface switching random access memory, and conductive bridging random access memory (CBRAM). This is a further step toward developing fully bio-realistic artificial synapses using memristors. The findings in this study will deepen our understanding of metaplasticity, as well as provide new insight into bio realistic neuromorphic engineering. PMID- 29508881 TI - Feruloylated oligosaccharides from maize bran alleviate the symptoms of diabetes in streptozotocin-induced type 2 diabetic rats. AB - This study investigated the therapeutic effect of feruloylated oligosaccharides (FOs) extracted from maize bran on type 2 diabetic rats and its potential mechanism. Streptozotocin (STZ) induced type 2 diabetic male rats were orally administered with different levels of FOs for 8 weeks, and ferulic acid (FA) treatment was conducted as the positive control. Among all the treatments, the oral administration of 600 mg per kg bw per d FOs showed the best therapeutic effects on the diabetic rats by significantly lowering the levels of fasting plasma glucose (FPG), fasting insulin, TG, LDL-c, aspartate transaminase, creatine kinase and lactate dehydrogenase in plasma, while increasing the level of plasma HDL-c. In addition, the intake of FOs at 600 mg per kg bw per d exhibited the best antioxidant effects in the plasma, liver, kidney and heart of the diabetic rats, and the highest inhibitory effects on the formation of AGEs and CML in the organs, which might explain the alleviating effects of FOs on abdominal aorta injury observed in the current study. FOs presented better regulation effects on FPG, plasma lipid and the protection of abdominal aorta than FA under the same administered dosage. Based on these outcomes, FOs from maize bran could be beneficial for prevention or early treatment of diabetes mellitus. PMID- 29508887 TI - A Pd-catalyzed optional approach for the synthesis of dibenzothiophenes. AB - A direct and practical approach for the construction of DBTs was developed via a Pd-catalyzed tandem reaction, in which commercially available o-bromo iodobenzenes combined with benzene thiols or iodobenzenes combined with o-bromo benzene thiols were applied. These two approaches will provide an alternative for the synthesis of DBT derivatives. PMID- 29508888 TI - A fast response fluorescence probe specific for hypochlorous acid detection and its applications in bioimaging. AB - Quantitative detection and visualization of hypochlorous acid (HOCl) in biological samples has emerged as a hot topic in biochemical research because of the important role of this biomolecule in live organisms. In this contribution, a novel 1,8-naphthalimide-based fluorescence probe, DNPH-NA, was designed and synthesized for HOCl detection in aqueous solutions and in biological systems. In the presence of HOCl, significant changes in absorption and fluorescence spectra were observed, which allow for the quantitative detection of HOCl in PBS buffer. The detection limit for HOCl was determined to be 50 nM. In the presence of HOCl, the fluorescence response of DNPH-NA was found to be completed within 2 seconds. The desirable features of DNPH-NA for the detection of HOCl in aqueous solutions, such as its high sensitivity and selectivity, reliability at physiological pH, rapid fluorescence response, and biocompatibility enabled its application in the detection of HOCl in biological samples. Imaging of exogenous HOCl in live HeLa cells and endogenous HOCl generation in live J774A.1 macrophage cells and zebrafish was then successfully performed using DNPH-NA as a fluorescence probe. PMID- 29508889 TI - The expression of CD markers in solid tumors: Significance in metastasis and prognostic value. AB - OBJECTIVE: The clusters of differentiations (CDs) are among the surface markers expressed on different cells in the body, which are involved in the communication of cells with each other and the induction of signaling. Moreover, the evaluation of the ectopic expression of these markers in solid tumors has led to the detection of disease in early stages. In this paper, we have examined the effect of CD markers expression on the function of cancer cells, as well as their importance as the diagnostic and prognostic factors for monitoring the progression of solid tumors. MATERIALS AND METHODS: Relevant literature was identified by a PubMed search (1988-2017) of English language papers using the terms "CD markers", "diagnostic", "prognostic", "predictive marker" and "solid tumors." DISCUSSION: Finally, it can be stated that the evaluation of CDs is not only of diagnostic value at disease onset, but these markers can be used as prognostic and predictive markers to contribute to the treatment of disease and predict its relapse. CONCLUSION: Monitoring of tumors progression through CDs expressed on circulating tumor cells could be a new diagnostic and prognostic factor in the future. PMID- 29508890 TI - Letter to the Editor: Substance use disorder?Substance-induced disorder clinics for pain-medication addictions and addicted patients' pains: futuristic need for pain physicians sub-specializing in addiction-medicine. PMID- 29508891 TI - A Rasch analysis of the Current Opioid Misuse Measure for patients with chronic pain. AB - OBJECTIVE: Pilot study to assess psychometric indices of the Current Opioid Misuse Measure (COMM). DESIGN: Correlational. SETTING: Patients with varied chronic pain from a family healthcare center. PATIENTS: Inclusion criteria were over 21 years of age and prescribed opioids for any-origin noncancer pain; 46 patients were enrolled. OUTCOME MEASURE(S): The COMM, the Pain Self-Efficacy Questionnaire (PSE-Q), and the Patient Health Questionnaire-9 (PHQ-9) and a demographic -questionnaire. RESULTS: Preliminary analysis indicated issues with dimensionality and scale use. Analysis after remedial procedures yielded unidimensionality and appropriate scale use, with the measure showing invariance across sex and low significant correlation with the PHQ-9 but not the PSE-Q. CONCLUSIONS: The COMM had adequate reliability, measured a distinct construct, and no significant differential item function was found. However, scale use for this sample was questionable, and three items misfit the Rasch model. Replication with a larger sample is needed to ensure the measure's psychometric quality for diagnostic use. PMID- 29508892 TI - The role of transdermal compounding in opioid safety. AB - Since the number of prescriptions for opioid medications have continued to rise, there have been questions about the safety of using opioids in pain management. Traditionally, opioid analgesics were reserved for a few select conditions, such as terminal illness and surgery, but currently opioids have been readily prescribed for multiple conditions. The objective of this manuscript is to clarify the current state of opioid use and to discuss alternative transdermal analgesic therapies in pain management. Transdermal compounded medications are patient-specific and customizable to include different types of drugs, in various dosage strengths, that are to be delivered simultaneously in one application. Due to the different origins and types of pain, treatments may be most beneficial with multiple classes of drugs with various mechanisms of action. In addition, combination drug therapy may include nontraditional pain management options, and has the ability to maximize therapeutic effects of medications through additive or synergistic properties, without increasing the dosage strengths of the drugs. Many of the challenges faced when using oral opioid therapy may be overcome by using transdermal drug delivery since this route of administration reduces adverse effects, increases patient compliance, and limits exposure to potentially abusive drugs. Although prescribing practices surrounding opioids remains to be a controversial topic, the use of compounded pain medications may help healthcare providers effectively treat their patients while avoiding the use of addictive drugs. PMID- 29508893 TI - Correlates of opiate misuse based on aberrant urine drug tests for patients on chronic opiate therapy in a safety-net, academic primary care clinic. AB - OBJECTIVE: Determine correlates of opiate misuse based on urine drug test (UDT) among patients on chronic opiate therapy (COT) for chronic noncancer pain. DESIGN: A cross-sectional study. SETTING: Urban, academic clinic. PARTICIPANTS: UDT performed in 206 patients on COT for at least 3 months duration within a one year period. Patients were classified based on UDT results: (1) Appearance of Opiate Adherence: Positive UDT for prescribed opiate and negative for illicit drugs and nonprescribed control substances; (2) Opiate Misuse; Overt nonadherence: (a) Positive UDT for illicit drugs and/or nonprescribed controlled substances AND positive or negative for prescribed opiates (b) Overdose; (3) Possible opiate nonadherence: Negative for prescribed opiates and negative for illicit and nonprescribed controlled substances. INTERVENTIONS: None. MAIN OUTCOME MEASURES: UDT results, patient demographics, medical history, healthcare adherence, and utilization measures. RESULTS: Of the 206 records analyzed, 80 (38 percent) had appearance of opiate adherence, 91 (44 percent) had misuse, and 35 (17 percent) had possible opiate nonadherence. Analysis was performed comparing misuse and appearance of opiate adherence groups. In bivariate analyses, history of smoking (OR 3.90, 95% CI 1.69-9.03), substance use (OR 7.02, 95% CI 2.56 19.20), missed medical appointments (OR 2.85, 95% CI 1.44-5.63), and nonadherence to other medications correlated with misuse group (OR 18.86, 95% CI 8.73-40.74). In logistic regression, only substance use history (OR 4.32, 95% CI 1.27-14.64) and nonadherence with nonopiate medications (OR 13.22, 95% CI 5.81-30.10) correlated with misuse. CONCLUSIONS: Medication nonadherence and missed appointments for other chronic conditions were significant correlates of opiate misuse. PMID- 29508894 TI - Discharge prescribing of enteral opioids after initiation as a weaning strategy from continuous opioid infusions in the Intensive Care Unit. AB - OBJECTIVE: To evaluate the proportion of patients receiving a hospital discharge prescription for a scheduled enteral opioid following initiation as a weaning strategy from a continuous opioid infusion in the Intensive Care Unit (ICU). DESIGN: Retrospective, observational study. SETTING: Five adult ICUs at a large, quaternary care academic medical center. PATIENTS: Endotracheally intubated, opioid-naive adults receiving a continuous opioid infusion with a concomitant scheduled enteral opioid initiated. Exclusion criteria were receipt of fewer than two enteral opioid doses, documentation of a long-acting opioid as a home medication, the indication for the enteral opioid was not a weaning strategy, death during hospital admission or discharge to hospice. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The proportion of ICU and hospital survivors who received a discharge prescription for a scheduled enteral opioid, total duration of continuous opioid infusion, duration of continuous opioid infusion after initiation of an enteral opioid therapy, total duration of enteral therapy, ICU and hospital length of stay. RESULTS: Of 62 included patients, 19 patients (30.6 percent) received a new prescription for a scheduled enteral opioid at hospital discharge. The median duration of enteral opioid therapy was longer for patients who received a discharge prescription compared to those who did not (20.09 vs 8.89 days, p = 0.02), though the remaining endpoints were not different. CONCLUSIONS: Utilizing scheduled enteral opioids as a weaning strategy from continuous opioid infusions may place patients at risk of ICU-acquired physical dependence on opioids. PMID- 29508895 TI - A snap shot of patients' recall, attitudes, and perceptions of their pain contracts from a family medicine resident outpatient clinic. AB - OBJECTIVE: Determine patient recall, attitudes, and perceptions of their pain contract in a family medicine resident out-patient clinic. DESIGN: A cross sectional study design using a telephone survey to all eligible subjects who signed a hardcopy pain contract from August 29, 2014 to May 19, 2016 at a resident outpatient clinic. SETTING: Penn State Hershey Family and Community Medicine Residency clinic. PARTICIPANTS: All patients who signed a hardcopy pain contract at the practice site who met specific inclusion criteria. MAIN OUTCOME MEASURES: What proportions of items are remembered from the standardized Penn State Hershey pain contract and does recall vary with time of contract signing. SECONDARY OUTCOME MEASURES: Patient attitudes and perceptions of their pain contract. RESULTS: Ninety-five percent of patients recalled agreeing to random urine drug screens (UDS) and 60 percent recalled they were not to receive prescriptions from another provider unless approved by their practice site. The recall rate for the remaining 33 items in the contract ranged from 0 percent to 20 percent. The highest recall rate was for contracts signed between 0-3 months. Patient feedback regarding the pain contract was recorded and while five were positive or neutral, 15 patients recorded negative attitudes toward the process, the physician, and/or the UDS. CONCLUSIONS: This study highlights limited recall and negative patient attitudes toward the pain contract. Considering the public health concerns with regard to the current opioid epidemic in the United States, additional training of providers, redesign of pain contracts and new models for informing patients about safe chronic pain management may be warranted. PMID- 29508896 TI - Oxycodone/naloxone in postoperative pain management of surgical patients. AB - BACKGROUND: The role of analgesia is crucial in the management of postoperative pain. Different combinations of oral analgesics have been proposed in the past. The oxycodone/naloxone (OXN) combination is a recent addition and is being used by different surgical specialties. The aim of our study was to clarify the possible role, advantages, and disadvantages of OXN in the pain management of surgical patients. METHOD: The authors retrieved the included studies after performing a systematic search in PubMed and Scopus. RESULTS: Ten studies (six randomized controlled trials, three retrospective studies, and a prospective study) were eligible for inclusion in this review. In total, 1,996 patients were included. Six studies reported on orthopedic procedures while four studies referred to colorectal, gynecologic, cardiac, and thoracic surgery procedures, respectively. The analgesic effect of OXN was evaluated in nine out of 10 studies, where OXN showed superiority only in two out of nine studies. Postoperative bowel function was evaluated in seven out of 10 studies. Patients treated with OXN did not show any significant differences in bowel function when compared to control groups. No superiority was found regarding the possible adverse events. CONCLUSION: Analgesia is crucial to postoperative recovery. Pain control can be achieved a combination of different analgesics, including OXN. This oral analgesic combination can have the potential to minimize side effects, such as opioid-induced constipation and optimize the recovery period. PMID- 29508897 TI - Hydromorphone use for acute pain: Misconceptions, controversies, and risks. AB - Hydromorphone (HM) is a potent opioid analgesic that is commonly administered in the emergency department (ED) and other acute care settings, such as medical surgical wards. In recent years, there has been a significant increase in the ED administration of HM relative to other opioids. Although HM is an effective analgesic, its use has been commonly implicated in adverse drug events and medication errors. In addition, intravenous HM has potent euphoric effects that may contribute to its abuse liability. There are limited data regarding how acute parenteral administration of opioid analgesics in the setting of high rates of preexisting chronic opioid use (medical or nonmedical) may contribute to or reinforce addictive behavior, making the potential contribution of rising HM administration to subsequent prescription opioid abuse and overdose uncertain. This review addresses the pharmacology of HM, recommended dosing, its efficacy for acute pain, as well as its tolerability, safety, and abuse profiles. Controversies and strategies for appropriate use of this medication are also described. PMID- 29508898 TI - On Using Lumped Parameter Models and Temperature Cycles in Heterogeneous Aquifers. AB - The use of the annual cycles of stable isotopes to estimate the parameters of transit time distribution (TTD) functions has been recently criticized by Kirchner who showed that if the catchment is heterogeneous the mean residence time calculated from the damping of the amplitude of the input signal is often underestimated by large factors. We modify Kirchner's initial analysis and show that the estimation bias is a function of the degree of heterogeneity. In low heterogeneity cases corresponding to permeable aquifers, the TTD of a simple exponential model developed assuming a homogeneous medium deviates only slightly from the true TTD, and thus estimated and true mean transit times are close. We also develop and test for a sandstone aquifer a model predicting the temperature amplitude of water at the outlet of a groundwater system from the annual air temperature cycle, and show that even though temperature is not a conservative tracer, it can be used to calibrate a lumped parameter model describing the TTD of the aquifer. PMID- 29508899 TI - Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. AB - BACKGROUND: Inotuzumab ozogamicin (InO), an anti-CD22 antibody-calicheamicin conjugate, demonstrated superior clinical activity versus standard-of-care (SOC) chemotherapies for relapsed/refractory B-cell acute lymphoblastic leukemia in the phase 3 randomized controlled INO-VATE trial. The authors assessed patient reported outcomes (PROs) from that study. METHODS: Patients were randomized to receive either InO (1.8 mg/m2 per cycle for <=6 cycles) or SOC (fludarabine/cytarabine [ara-C]/granulocyte colony-stimulating factor, or ara-C plus mitoxantrone, or high-dose ara-C for <=4 cycles) and completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the EuroQoL 5 Dimensions Questionnaires at baseline, on day 1 of each cycle, and at the end of treatment. Treatment differences in PROs were assessed using longitudinal mixed-effects models with random intercepts and slopes. RESULTS: Questionnaire completion rates in the InO (n = 164) and SOC (n = 162) arms were 85% and 65%, respectively. Baseline scores were similar between arms. Patients who received InO reported better quality of life (QoL), functioning, and symptom scores (except for constipation and emotional functioning). Least-squares mean (95% confidence interval [CI]) differences in physical, role, and social functioning and in appetite loss were significant (6.9 [95% CI, 1.4-12.3], 11.4 [95% CI, 3.2-19.5], 8.4 [95% CI, 0.7-16.1], and -8.7 [95% CI, -16.0 to -1.4], respectively; all P < .05) and had exceeded the minimally important difference of 5. Mean treatment differences in favor of InO on the EuroQoL visual analog scale and the global health status/QoL, dyspnea, and fatigue scales reached or approached the minimally important difference of 5, although without statistical significance. No dimensions were significantly worse with InO versus SOC. CONCLUSIONS: The current PRO data support the favorable benefit/risk ratio of InO for the treatment of relapsed/refractory acute lymphoblastic leukemia, with superior clinical efficacy and better QoL. Cancer 2018;124:2151-60. (c) 2018 American Cancer Society. PMID- 29508900 TI - Comparative assessment of serum 25-hydroxyvitamin D patterns in dermatological diseases: a Moroccan retrospective study. PMID- 29508901 TI - Extrahippocampal high-frequency oscillations during epileptogenesis. AB - The current study aimed to investigate the spatial and temporal patterns of high frequency oscillations (HFOs) in the intra-/extrahippocampal areas during epileptogenesis. Local field potentials were bilaterally recorded from hippocampus (CA1), thalamus, motor cortex, and prefrontal cortex in 13 rats before and after intrahippocampal kainic acid (KA) lesions. HFOs in the ripple (100-200 Hz) and fast ripple (250-500 Hz) ranges were detected and their rates were computed during different time periods (1-5 weeks) after KA-induced status epilepticus (SE). Recurrent spontaneous seizures were observed in 7 rats after SE, and the other 6 rats did not develop epilepsy. During the latent period, the rate of hippocampal HFOs increased at the ipsilateral site of the KA lesion in both groups, and the HFO rate was significantly higher in the animals that later developed epilepsy. Animals that later developed epilepsy also demonstrated widespread appearance of HFOs, in both the ripple and the fast ripple range, whereas animals that did not develop epilepsy only exhibited changes in the ipsilateral intrahippocampal HFO rate. This study demonstrates an association between an increased rate of widespread HFOs and the later development of epilepsy, suggesting the formation of large-scale distributed pathological networks during epileptogenesis. PMID- 29508902 TI - Toxicity of various road-deicing salts to Asian clams (Corbicula fluminea). AB - Humans are altering environments by destroying habitats, introducing species, and releasing pollution. One emergent pollutant is the salinization of freshwater habitats from road-deicing salts. Government agencies have set thresholds to protect freshwater ecosystems, yet these values are exceeded in many systems. The present study investigated the tolerance of Asian clams (Corbicula fluminea), a common invasive bivalve, to the common road salt (sodium chloride [NaCl]) and 2 alternatives (magnesium chloride [MgCl2 ] and calcium chloride [CaCl2 ]). Experiments conducted at 4 and 8 d revealed that Asian clams are very salt tolerant. The median lethal concentration after 4 d of exposure (LC504-d ) estimate was 2162 mg Cl- /L for MgCl2 , 3554 mg Cl- /L for CaCl2 , and more than 22 581 mg Cl- /L for NaCl, which were all significantly different from each other (p <= 0.05). The LC508-d values were significantly different (p <= 0.05) from each other and from the LC504-d values, and were estimated to be 1769 mg Cl- /L for MgCl2 , 2235 Cl- /L for CaCl2 , and 10 069 mg Cl- /L for NaCl. Mortality was determined using 2 methods: either no response after exposure or no response after being in freshwater following exposure. For the majority of the LC50s, these methods were not significantly different (p > 0.05). The high salt tolerance of Asian clams is a concern because of their transportation in ballast water between aquatic ecosystems. Furthermore, salt-tolerant organisms may outcompete sensitive organisms in salinized ecosystems, which may alter ecosystem services. Environ Toxicol Chem 2018;37:1839-1845. (c) 2018 SETAC. PMID- 29508903 TI - Presence of rare hepatitis C virus subtypes, 2j, 2k, and 2r in Mexico City as identified by sequencing. AB - The HCV 5'UTR, Core/E1, and NS5B regions of samples from fifty patients infected with the hepatitis C virus (HCV) were analyzed. Seventeen patients were identified with genotype (GT) 1b, eleven with GT-1a, nine with GT-2b and four with GT-3a. Two rare subtypes were detected: GT-2j in two patients and GT-2r in one patient. Three patients had mixed infections: one with GT-2k + 2j and two with GT-1b + 2b. This work identifies HCV GTs, 2j, 2k, and 2r for the first time in Mexico. PMID- 29508904 TI - Vitamin B12 and Homocysteine Levels Predict Different Outcomes in Early Parkinson's Disease. AB - BACKGROUND: In moderately advanced Parkinson's disease (PD), low serum vitamin B12 levels are common and are associated with neuropathy and cognitive impairment. However, little is known about B12 in early PD. OBJECTIVE: To determine the prevalence of low vitamin B12 status in early PD and whether it is associated with clinical progression. METHODS: We measured vitamin B12 and other B12 status determinants (methylmalonic acid, homocysteine, and holotranscobalamin) in 680 baseline and 456 follow-up serum samples collected from DATATOP participants with early, untreated PD. Borderline low B12 status was defined as serum B12 <184 pmol/L (250 pg/mL), and elevated homocysteine was defined as >15 umol/L. Outcomes included the UPDRS, ambulatory capacity score (sum of UPDRS items 13-15, 29&30), and MMSE, calculated as annualized rates of change. RESULTS: At baseline, 13% had borderline low B12 levels, 7% had elevated homocysteine, whereas 2% had both. Elevated homocysteine at baseline was associated with worse scores on the baseline MMSE. Analysis of study outcomes showed that compared with the other tertiles, participants in the low B12 tertile (<234 pmol/L; 317 pg/mL) developed greater morbidity as assessed by greater annualized worsening of the ambulatory capacity score. Elevated homocysteine was associated with greater annualized decline in MMSE (-1.96 vs. 0.06; P = 0001). Blood count indices were not associated with B12 or homocysteine status. CONCLUSIONS: In this study of early PD, low B12 status was common. Low B12 at baseline predicted greater worsening of mobility whereas elevated homocysteine predicted greater cognitive decline. Given that low B12 and elevated homocysteine can improve with vitamin supplementation, future studies should test whether prevention or early correction of these nutritionally modifiable conditions slows development of disability. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29508905 TI - Effect of different CT scanners and settings on femoral failure loads calculated by finite element models. AB - In a multi-center patient study, using different CT scanners, CT-based finite element (FE) models are utilized to calculate failure loads of femora with metastases. Previous studies showed that using different CT scanners can result in different outcomes. This study aims to quantify the effects of (i) different CT scanners; (ii) different CT protocols with variations in slice thickness, field of view (FOV), and reconstruction kernel; and (iii) air between calibration phantom and patient, on Hounsfield Units (HU), bone mineral density (BMD), and FE failure load. Six cadaveric femora were scanned on four CT scanners. Scans were made with multiple CT protocols and with or without an air gap between the body model and calibration phantom. HU and calibrated BMD were determined in cortical and trabecular regions of interest. Non-linear isotropic FE models were constructed to calculate failure load. Mean differences between CT scanners varied up to 7% in cortical HU, 6% in trabecular HU, 6% in cortical BMD, 12% in trabecular BMD, and 17% in failure load. Changes in slice thickness and FOV had little effect (<=4%), while reconstruction kernels had a larger effect on HU (16%), BMD (17%), and failure load (9%). Air between the body model and calibration phantom slightly decreased the HU, BMD, and failure loads (<=8%). In conclusion, this study showed that quantitative analysis of CT images acquired with different CT scanners, and particularly reconstruction kernels, can induce relatively large differences in HU, BMD, and failure loads. Additionally, if possible, air artifacts should be avoided. (c) 2018 Orthopaedic Research Society. (c) 2018 The Authors. Journal of Orthopaedic Research(r) Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res. PMID- 29508906 TI - Pedunculopontine Nucleus Cholinergic Deficiency in Cervical Dystonia. AB - BACKGROUND: The etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus. OBJECTIVES: The objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors. METHODS: Formalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus. RESULTS: Decreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls. CONCLUSIONS: Our findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29508908 TI - Metabolic engineering of Escherichia coli to produce succinate from soybean hydrolysate under anaerobic conditions. AB - It is of great economic interest to produce succinate from low-grade carbon sources, which can enhance the competitiveness of the biological route. In this study, succinate producer Escherichia coli CT550/pHL413KF1 was further engineered to efficiently use the mixed sugars from non-food based soybean hydrolysate to produce succinate under anaerobic conditions. Since many common E. coli strains fail to use galactose anaerobically even if they can use it aerobically, the glucose, and galactose related sugar transporters were deactivated individually and evaluated. The PTS system was found to be important for utilization of mixed sugars, and galactose uptake was activated by deactivating ptsG. In the ptsG- strain, glucose, and galactose were used simultaneously. Glucose was assimilated mainly through the mannose PTS system while galactose was transferred mainly through GalP in a ptsG- strain. A new succinate producing strain, FZ591C which can efficiently produce succinate from the mixed sugars present in soybean hydrolysate was constructed by integration of the high succinate yield producing module and the galactose utilization module into the chromosome of the CT550 ptsG strain. The succinate yield reached 1.64 mol/mol hexose consumed (95% of maximum theoretical yield) when a mixed sugars feedstock was used as a carbon source. Based on the three monitored sugars, a nominal succinate yield of 1.95 mol/mol was observed as the strain can apparently also use some other minor sugars in the hydrolysate. In this study, we demonstrate that FZ591C can use soybean hydrolysate as an inexpensive carbon source for high yield succinate production under anaerobic conditions, giving it the potential for industrial application. PMID- 29508907 TI - Weight Gain for Gestational-Age Charts in Dichorionic Twins: Tool for Establishing Optimal Weight Gain in Twin Pregnancies. PMID- 29508909 TI - An analysis of white-handed gibbon male song reveals speech-like phrases. AB - OBJECTIVES: Our goal was to document song phrases of the white-handed gibbon (Hylobates lar), an Asian ape that produces elaborate songs, often in well coordinated male/female duets. We focused on the male coda, which is produced during vocal turn-taking with one's mate, and particularly its phrases containing rapid spectral and temporal variation, to investigate if modulation rates resemble those of lip-smacking in other nonhuman primates and human speech rhythm. MATERIALS AND METHODS: We produced recordings from a large population of wild gibbons. Using terminology consistent with that used to describe vocalizations in other singing species, we analyzed coda phrases, overall coda properties, coda distinctiveness across individuals, and flexibility of phrase production within song bouts. RESULTS: Our song phrase-level analysis showed that male codas differed between individuals and increase in complexity within song bouts by the addition of the only two male-specific phrases of the species' repertoire. These phrases differ from all others of the species and from vocalizations typical of the larger, nonhuman great apes, in that they contain rapid within-phrase modulation. Their modulation rates (6.82 and 7.34 Hz) are similar to that of lip-smacking in other nonhuman primates and speech in humans and, like human speech, are produced exclusively during exhalation. One phrase type (trills) contains multiple notes per exhalation, another characteristic similar to speech but not most primate vocalizations. DISCUSSION: Our data highlight the complexity and flexibility of gibbon song, and show that particular phrase features likely arose from sexual selection pressures and possess similarities to human speech rhythm. PMID- 29508910 TI - The Rise of the Cartwheel: Seeding the Centriole Organelle. AB - The cartwheel is a striking structure critical for building the centriole, a microtubule-based organelle fundamental for organizing centrosomes, cilia, and flagella. Over the last 50 years, the cartwheel has been described in many systems using electron microscopy, but the molecular nature of its constituent building blocks and their assembly mechanisms have long remained mysterious. Here, we review discoveries that led to the current understanding of cartwheel structure, assembly, and function. We focus on the key role of SAS-6 protein self organization, both for building the signature ring-like structure with hub and spokes, as well as for their vertical stacking. The resemblance of assembly intermediates in vitro and in vivo leads us to propose a novel registration step in cartwheel biogenesis, whereby stacked SAS-6-containing rings are put in register through interactions with peripheral elements anchored to microtubules. We conclude by evoking some avenues for further uncovering cartwheel and centriole assembly mechanisms. PMID- 29508911 TI - Analysis of crestal bone loss around single piece ball attachment implant placed bilaterally in canine region and wear of O-ring in implant supported overdenture: Three year follow-up. AB - BACKGROUND: Single piece implant in fixed prosthesis is widely been evaluated, however, long term evaluation of crestal bone loss and the wear of O-ring in single piece ball attachment implant supported overdenture is yet to be evaluated PURPOSE: The present article evaluates the crestal bone loss around single piece ball attachment implants placed bilaterally in the canine region and the wear of O-ring in implant supported overdenture over a period of three years. MATERIALS AND METHODS: Twelve completely edentulous patients between the age group of 55-65 years were selected. Two 3.3 mm * 13 mm myriad snap fit implants were placed in the mandibular interforaminal region. All the implants were conventionally loaded at three months after surgical placement. Intra-oral periapical radiographs were made and crestal bone loss was measured at the end of one year and three years. The elasticity and wear of O-Ring was assessed after three years of usage. RESULTS: The crestal bone loss showed no significant difference between the first and third year after implant placement. The mean bone loss at the end of third year was 1.5 mm. Analysis of O-ring for change in the elasticity showed reduction in displacement and a significant increase in maximum displacement and elongation. The area of O-ring and yield stress did not show any changes from the standard value. Compression set damage was observed in the O-ring at the end of three years. CONCLUSIONS: The present study shows that the bilateral single piece implant supported overdenture has a success rate equivalent to the two piece implant supported overdenture and is a viable treatment option. PMID- 29508912 TI - Photocatalyzed ortho-Alkylation of Pyridine N-Oxides through Alkene Cleavage. AB - A photocatalyzed reaction of pyridine N-oxides with alkenes gives ortho-alkylated pyridines with cleavage of the carbon-carbon double bond. Benzyl and secondary alkyl groups are incorporated at the ortho position of pyridines in one pot. PMID- 29508914 TI - Association between induced abortion history and later in vitro fertilization outcomes. AB - OBJECTIVE: To establish an effective and safe clinical fertility strategy by investigating the relationship between abortion history and pregnancy outcomes of in vitro fertilization (IVF) treatment. METHODS: In the present retrospective cohort study, data from IVF treatment cycles performed at a reproductive center in China between October 1, 2014, and October 31, 2015, were assessed. Outcomes were compared between women with a history of induced abortion and those without. RESULTS: There were 1532 IVF treatment cycles included; 454 patients had a history of induced abortion and 1078 did not. The spontaneous abortion rate was significantly higher (30/170 [17.6%] vs 41/420 [9.8%]; P=0.002) and the endometrium was significantly thinner (8.8 +/- 1.8 vs 9.7 +/- 1.8 cm; P=0.001) among patients with a history of induced abortion compared with those without. In a subgroup analysis of patients with a history of induced abortion, women who had undergone surgical abortions had a lower live delivery rate compared with medical abortions (29/76 [38%] vs 101/378 [27%]; P=0.039). Further, women who had a history of more than two surgical abortions had lower live delivery and clinical pregnancy rates (both P<0.05). CONCLUSION: A history of induced abortion was associated with worse IVF outcomes, especially a history of more than two surgical abortions. PMID- 29508913 TI - Active Sleep Promotes Functional Connectivity in Developing Sensorimotor Networks. AB - A ubiquitous feature of active (REM) sleep in mammals and birds is its relative abundance in early development. In rat pups across the first two postnatal weeks, active sleep promotes the expression of synchronized oscillatory activity within and between cortical and subcortical sensorimotor structures. Sensory feedback from self-generated myoclonic twitches - which are produced exclusively during active sleep - also triggers neural oscillations in those structures. We have proposed that one of the functions of active sleep in early infancy is to provide a context for synchronizing developing structures. Specifically, neural oscillations contribute to a variety of neurodevelopmental processes, including synapse formation, neuronal differentiation and migration, apoptosis, and the refinement of topographic maps. In addition, synchronized oscillations promote functional connectivity between distant brain areas. Consequently, any condition or manipulation that restricts active sleep can, in turn, deprive the infant animal of substantial sensory experience, resulting in atypical developmental trajectories. PMID- 29508915 TI - An Iron Complex with a Bent, O-Coordinated CO2 Ligand Discovered by Femtosecond Mid-Infrared Spectroscopy. AB - The activation of carbon dioxide by transition metals is widely recognized as a key step for utilizing this greenhouse gas as a renewable feedstock for the sustainable production of fine chemicals. However, the dynamics of CO2 binding and unbinding to and from the ligand sphere of a metal have never been observed in the time domain. The ferrioxalate anion is used in aqueous solution as a unique model system for these dynamics and femtosecond UV-pump mid-infrared-probe spectroscopy is applied to explore its photoinduced primary processes in a time resolved fashion. Following optical excitation, a neutral CO2 molecule is expelled from the complex within about 500 fs to generate a highly intriguing pentacoordinate ferrous dioxalate that carries a bent carbon dioxide radical anion ligand, that is, a reductively activated form of CO2 , which is end-on coordinated to the metal center by one of its two oxygen atoms. PMID- 29508916 TI - Transcriptomic reprogramming in soybean seedlings under salt stress. AB - To obtain a comprehensive understanding of transcriptomic reprogramming under salt stress, we performed whole-transcriptome sequencing on the leaf and root of soybean seedlings subjected to salt treatment in a time-course experiment (0, 1, 2, 4, 24, and 48 hr). This time series dataset enabled us to identify important hubs and connections of gene expressions. We highlighted the analysis on phytohormone signaling pathways and their possible crosstalks. Differential expressions were also found among those genes involved in carbon and nitrogen metabolism. In general, the salt-treated seedlings slowed down their photosynthetic functions and ramped up sugar catabolism to provide extra energy for survival. Primary nitrogen assimilation was shut down whereas nitrogen resources were redistributed. Overall, the results from the transcriptomic analyses indicate that the plant uses a multipronged approach to overcome salt stress, with both fast-acting, immediate physiological responses, and longer term reactions that may involve metabolic adjustment. PMID- 29508917 TI - Voluntary inhibitory motor control over involuntary tic movements. AB - Inhibitory control is crucial for normal adaptive motor behavior. In hyperkinesias, such as tics, disinhibition within the cortico-striato-thalamo cortical loops is thought to underlie the presence of involuntary movements. Paradoxically, tics are also subject to voluntary inhibitory control. This puzzling clinical observation questions the traditional definition of tics as purely involuntary motor behaviors. Importantly, it suggests novel insights into tic pathophysiology. In this review, we first define voluntary inhibitory tic control and compare it with other notions of tic control from the literature. We then examine the association between voluntary inhibitory tic control with premonitory urges and review evidence linking voluntary tic inhibition to other forms of executive control of action. We discuss the somatotopic selectivity and the neural correlates of voluntary inhibitory tic control. Finally, we provide a scientific framework with regard to the clinical relevance of the study of voluntary inhibitory tic control within the context of the neurodevelopmental disorder of Tourette syndrome. We identify current knowledge gaps that deserve attention in future research. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29508918 TI - A comparative review of the isotretinoin pregnancy risk management programs across four continents. AB - Isotretinoin has revolutionized the treatment of severe acne vulgaris, a condition which if left untreated may result in significant socio-psychological implications for those affected. Timely access to isotretinoin therapy is important to avoid the risks of potential physical and emotional scarring. However, due to its high risks of teratogenicity, isotretinoin must be used with care in females of childbearing potential. Since isotretinoin's introduction, numerous risk management programs have been implemented across the world in an attempt to prevent isotretinoin use in pregnancy. This paper aims to provide an evidence-based review of the risk management programs for isotretinoin in Australia, Europe, Singapore, New Zealand, and the United States of America. The effectiveness of these programs and the factors leading to isotretinoin exposure in pregnancy are critically analyzed in an effort to inform the future direction with respect to designing the ideal regulatory program. Stringent risk management programs, such as the iPLEDGE in the US and Pregnancy Prevention Program (PPP) in Europe, may not be effective in reducing the risks of fetal exposure to isotretinoin when used alone. There is evidence that such strenuous regulation results in increased fear of teratogenic risks but does not translate into a reduced rate of pregnancies exposed to isotretinoin. A successful program must prioritize education about effective contraception, while minimizing any extraneous requirements, to ensure that women are not inadvertently undertreated for acne. PMID- 29508920 TI - RECENT ABSTRACTS OF INTEREST. PMID- 29508919 TI - Photocatalytic Hydrogen Production Coupled with Selective Benzylamine Oxidation over MOF Composites. AB - Photocatalytic water splitting requires separation of the mixed H2 and O2 products and is often hampered by the sluggish O2 -producing half reaction. An approach is now reported to address these issues by coupling the H2 -producing half reaction with value-added benzylamine oxidation reaction using metal-organic framework (MOF) composites. Upon MOF photoexcitation, the electrons rapidly reduce the protons to generate H2 and the holes promote considerable benzylamine oxidation to N-benzylbenzaldimine with high selectivity. Further experimental characterizations and theoretical calculation reveal that the highly conjugated s triazine strut in the MOF structure is crucial to the efficient charge separation and excellent photocatalytic activity. PMID- 29508921 TI - ATLANTIC CITY TO ATLANTIC CITY IN EIGHT SHORT YEARS. PMID- 29508922 TI - Trichomes form an important first line of defence against adverse environment-New evidence for ozone stress mitigation. PMID- 29508923 TI - When significance becomes insignificant: Effect sizes and their uncertainties in Bayesian and frequentist frameworks as an alternative approach when analyzing ecotoxicological data. AB - Bayesian methods and frequentist confidence intervals are proposed as an alternative approach in ecotoxicology, emphasizing effect sizes and associated (un)certainties to judge the biological relevance of effects instead of basing decisions on p values. These approaches show advantages over null hypothesis significance testing. In particular, Bayesian methods revealed more potential than frequentist counterparts, as the posterior distribution and its credible intervals can be directly interpreted as the probability of effect sizes. Environ Toxicol Chem 2018;37:1949-1955. (c) 2018 SETAC. PMID- 29508925 TI - Vitamin B12 and Parkinson's Disease: What is the Relationship? PMID- 29508924 TI - A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys. AB - BACKGROUND: Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia. OBJECTIVES: The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials. METHODS: Five MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined. RESULTS: MR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically. CONCLUSIONS: Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29508926 TI - When leaves go over the thermal edge. PMID- 29508927 TI - Roles for scientific societies to engage with conservation policy. PMID- 29508928 TI - Genomic signatures reveal selection of characteristics within and between Meishan pig populations. AB - The Chinese Meishan pig breed is well known for its high prolificacy. Moreover, this breed can be divided into three types based on their body size: big Meishan, middle Meishan (MMS) and small Meishan (SMS) pigs. Few studies have reported on the genetic signatures of Meishan pigs, particularly on a genome-wide scale. Exploring for genetic signatures could be quite valuable for revealing the genetic architecture of phenotypic variation. Thus, we performed research in two parts based on the genome reducing and sequencing data of 143 Meishan pigs (74 MMS pigs, 69 SMS pigs). First, we detected the selection signatures among all Meishan pigs studied using the relative extended haplotype homozygosity test. Second, we detected the selection signatures between MMS and SMS pigs using the cross-population extended haplotype homozygosity and FST methods. A total of 111 398 SNPs were identified from the sequenced genomes. In the population analysis, the most significant genes were associated with the mental development (RGMA), reproduction (HDAC4, FOXL2) and lipid metabolism (ACACB). From the cross population analysis, we detected genes related to body weight (SPDEF, PACSIN1) in both methods. We suggest that rs341373351, located within the PACSIN1 gene, might be the causal variant. This study may have achieved consistency between selection signatures and characteristics within and between Meishan pig populations. These findings can provide insight into investigating the molecular background of high prolificacy and body size in pig. PMID- 29508929 TI - Inducing Axial Chirality in a Supramolecular Catalyst. AB - A new type of ligand, which is able to form axially chiral, supramolecular complexes was designed using DFT calculations. Two chiral monomers, each featuring a covalently bound chiral auxiliary, form a bidentate phosphine ligand with a twisted, hydrogen-bonded backbone upon coordination to a transition metal center which results in two diastereomeric, tropos complexes. The ratio of the diastereomers in solution is very temperature- and solvent-dependent. Rhodium and platinum complexes were analyzed through a combination of NMR studies, ESI-MS measurements, as well as UV-VIS and circular dichroism spectroscopy. The chiral self-organized ligands were evaluated in the rhodium-catalyzed asymmetric hydrogenation of alpha-dehydrogenated amino acids and resulted in good conversion and high enantioselectivity. This research opens the way for new ligand designs based on stereocontrol of supramolecular assemblies through stereodirecting chiral centers. PMID- 29508930 TI - Formation and Properties of Poly(Ionic Liquid)-Carbene Nanogels Containing Individually Stabilized Silver Species. AB - Imidazolium-based ionic liquids have the ability to undergo a variety of chemical reactions through an N-heterocyclic carbene (NHC) intermediate, which has expanded the chemical toolbox for new applications. Despite their uses and exploration, the carbene-forming properties and applications of their polymeric congeners, poly(ionic liquid)s (PILs), is still underdeveloped. Herein, we explore the NHC-forming properties of a theophylline-derived PIL for nanogel synthesis. Using silver oxide as both the carbene-forming reagent and cross linker, nanogels containing individually stabilized ions can be created with different sizes and morphology, including large "galaxy-like" superstructures. Using high-resolution TEM techniques, we directly observed the sub-nanometer structure of these constructs. These features combined exemplify the unique chemistry of poly-NHCs for single-metal-ion-stabilization nanogel design. PMID- 29508931 TI - A Biomimetic Synthetic Receptor Selectively Recognising Fucose in Water. AB - Carbohydrate recognition in water by biomimetic receptors is an attractive, but very challenging goal. Despite advances achieved in glucose recognition, little or no success has been obtained in the recognition of other saccharidic epitopes of paramount importance in biological processes. Herein, the unprecedented recognition of fucose in water by an artificial receptor that shows affinities closely comparable to those of several lectins is reported. The receptor has been constructed by assembling a hydrogen-bonding element (carbazole), a hydrophobic aromatic moiety (anthracene), and a water-solubilising function (phosphonate) into a macrocyclic structure to provide the appropriate binding geometry. The described receptor binds fucose with sub-millimolar affinity in water at physiological pH; this shows that enthalpic binding can be ascribed to hydrogen bonding to saccharidic hydroxy groups and to CH-pi interactions between the sugar backbone and aromatic moieties. Experimental NOE contacts coupled to conformational search calculations return a picture of a binding site in which fucose assumes a staggered orientation reminiscent of that shown by fucose when bound to the Ralstonia solanacearum lectin (RSL). PMID- 29508932 TI - Genome-wide expression profiling analysis to identify key genes in the anti-HIV mechanism of CD4+ and CD8+ T cells. AB - Comprehensive bioinformatics analyses were performed to explore the key biomarkers in response to HIV infection of CD4+ and CD8+ T cells. The numbers of CD4+ and CD8+ T cells of HIV infected individuals were analyzed and the GEO database (GSE6740) was screened for differentially expressed genes (DEGs) in HIV infected CD4+ and CD8+ T cells. Gene Ontology enrichment, KEGG pathway analyses, and protein-protein interaction (PPI) network were performed to identify the key pathway and core proteins in anti-HIV virus process of CD4+ and CD8+ T cells. Finally, we analyzed the expressions of key proteins in HIV-infected T cells (GSE6740 dataset) and peripheral blood mononuclear cells(PBMCs) (GSE511 dataset). 1) CD4+ T cells counts and ratio of CD4+ /CD8+ T cells decreased while CD8+ T cells counts increased in HIV positive individuals; 2) 517 DEGs were found in HIV infected CD4+ and CD8+ T cells at acute and chronic stage with the criterial of P value <0.05 and fold change (FC) >=2; 3) In acute HIV infection, type 1 interferon (IFN-1) pathway might played a critical role in response to HIV infection of T cells. The main biological processes of the DEGs were response to virus and defense response to virus. At chronic stage, ISG15 protein, in conjunction with IFN-1 pathway might play key roles in anti-HIV responses of CD4+ T cells; and 4) The expression of ISG15 increased in both T cells and PBMCs after HIV infection. Gene expression profile of CD4+ and CD8+ T cells changed significantly in HIV infection, in which ISG15 gene may play a central role in activating the natural antiviral process of immune cells. PMID- 29508933 TI - Breast MRI and BI-RADS category 3: Is it appropriate? PMID- 29508934 TI - Ordered Mesoporous Titania/Carbon Hybrid Monoliths for Lithium-ion Battery Anodes with High Areal and Volumetric Capacity. AB - Free-standing, binder-free, and conductive additive-free mesoporous titanium dioxide/carbon hybrid electrodes were prepared from co-assembly of a poly(isoprene)-block-poly(styrene)-block-poly(ethylene oxide) block copolymer and a titanium alkoxide. By tailoring an optimized morphology, we prepared macroscopic mechanically stable 300 MUm thick monoliths that were directly employed as lithium-ion battery electrodes. High areal mass loading of up to 26.4 mg cm-2 and a high bulk density of 0.88 g cm-3 were obtained. This resulted in a highly increased volumetric capacity of 155 mAh cm-3 , compared to cast thin film electrodes. Further, the areal capacity of 4.5 mAh cm-2 represented a 9-fold increase compared to conventionally cast electrodes. These attractive performance metrics are related to the superior electrolyte transport and shortened diffusion lengths provided by the interconnected mesoporous nature of the monolith material, assuring superior rate handling, even at high cycling rates. PMID- 29508935 TI - Natural Product Diversification Mediated by Alternative Transcriptional Starting. AB - Photorhabdus luminescens dedicates a significant proportion of its genome to the production of natural products. These products and the structural variation in their derivatives may occur by a number of well-described mechanisms, such as module skipping or precursor promiscuity. Cappable-seq was used to identify transcriptional start sites of many of the gene clusters present in P. luminescens TTO1. We discovered that variations associated with the non-ribosomal peptide synthetase Kol, which is responsible for kolossin A production, possessed a number of internal transcripts that lead to synthesis of the smaller kolossin derivatives kolossin B and C. The data here support a new mechanism of natural product biosynthetic variation whereby mRNA may code for shorter NRPS enzymes in addition to full-length proteins, resulting in the production of smaller peptide derivatives. PMID- 29508936 TI - Electron ionization mass spectrometry fragmentation and multiple reaction monitoring quantification of bacterial metabolites of the sea ice biomarker proxy IP25 in Arctic sediments. AB - RATIONALE: 3,9,13-Trimethyl-6-(1,5-dimethylhexyl)tetradecan-1,2-diol and 2,8,12 trimethyl-5-(1,5-dimethylhexyl)tridecanoic acid appear to be produced during the bacterial metabolism of IP25 , a highly branched isoprenoid lipid often employed for past Arctic sea ice reconstruction. Characterization and quantification of these metabolites in sediments are essential to determine if bacterial degradation may exert a significant influence on IP25 -based palaeo sea ice reconstructions. METHODS: Electron ionization mass spectrometry (EIMS) fragmentation pathways of 3,9,13-trimethyl-6-(1,5-dimethylhexyl)tetradecan-1,2 diol and 2,8,12-trimethyl-5-(1,5-dimethylhexyl)tridecanoic acid trimethylsilyl (TMS) derivatives were investigated. These pathways were deduced by: (i) low energy collision-induced dissociation (CID) gas chromatography/tandem mass spectrometry (GC/MS/MS), (ii) accurate mass measurement, and (iii) deuterium labelling. RESULTS: CID-MS/MS analyses, accurate mass measurement and deuterium labelling experiments enabled us to elucidate the EIMS fragmentations of 3,9,13 trimethyl-6-(1,5-dimethylhexyl)tetradecan-1,2-diol and 2,8,12-trimethyl-5-(1,5 dimethylhexyl)tridecanoic acid TMS derivatives. Some specific fragment ions useful in addition to chromatographic retention times for further characterization could be identified. As an application of some of the described fragmentations, the TMS derivatives of these metabolites were characterized and quantified in MRM mode in different Arctic sediments. CONCLUSIONS: EIMS fragmentations of 3,9,13-trimethyl-6-(1,5-dimethylhexyl)tetradecan-1,2-diol and 2,8,12-trimethyl-5-(1,5-dimethylhexyl)tridecanoic acid TMS derivatives exhibit specific fragment ions, which appear to be very useful for the quantification of these bacterial metabolites of the palaeo tracer IP25 in sediments. PMID- 29508937 TI - Association between type 2 diabetes mellitus and disability: What is the contribution of diabetes risk factors and diabetes complications? AB - BACKGROUND: The aim of this study was to evaluate the association between type 2 diabetes and disability in Mauritius and to assess the extent to which the effect of diabetes is explained by diabetes risk factors and concomitant complications. METHODS: Data from a national survey in the multiethnic nation of Mauritius, which comprises South Asians and African Creoles, were analyzed. Disability was measured using the Katz activities of daily living questionnaire in participants aged >50 years. RESULTS: Among 3692 participants, 487 (13.2%) had some level of disability. Diabetes was associated with significantly higher risk of disability (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.34-2.08). After adjusting for demographic, behavioral, and metabolic factors, as well as comorbidities, disability was significantly associated with diabetes among African Creoles (OR 2.03; 95% CI 1.16-3.56), but not South Asians (OR 1.27; 95% CI 0.98-1.66). Obesity explained much of the association between diabetes and disability (excess percentage of risk: 26.3% in South Asians and 12.1% in African Creoles). Obesity, history of cardiovascular disease (CVD), asthma-like symptoms, and depression together explained 46.5% and 29.0% of the excess risk in South Asians and African Creoles, respectively. CONCLUSIONS: Diabetes is associated with a 67% increased risk of disability. Diabetes risk factors and comorbidities explain more of the association between diabetes and disability among South Asians than Africans. Obesity and history of CVD explained the largest percentage of the relationship between diabetes and disability, indicating that weight and CVD management may be helpful in controlling disability related to diabetes. PMID- 29508938 TI - Cultural adaptation and validation of the Chinese version of the expanded prostate cancer index composite. AB - AIM: The expanded prostate cancer index composite (EPIC) is a widely adopted instrument for the quality of life of patients with prostate cancer. We aimed to create a Chinese version of EPIC to further research in the Chinese-speaking population. METHODS: A prototype was created by forward-backward translations and revisions. During cultural adaptation, 15 participants were interviewed after they had completed the prototype. A few issues highlighted included confusion related to the question format, subject non-familiarity with the Chinese term for "hot flashes," and the use of the Chinese term for "breast" as a strictly female body part. A pilot version was created based on the cultural adaptation findings. Validation of the pilot version was performed by having 50 participants complete the Chinese EPIC and EORTC QLQ-c30 twice within a 4-week period. Test-retest reliability (Pearson's correlations and difference distribution) and internal consistency (Cronbach's alpha) were measured using SAS version 9.4. RESULTS: Test retest reliability values for the urinary, bowel, sexual and hormone domains were 0.71, 0.51, 0.51 and 0.66, respectively; subscale test-retest reliability ranged between 0.29 and 0.82. Internal consistency for domains was good with Cronbach's alpha ranging from 0.76 to 0.78 for the initial test and 0.67 to 0.85 for the retest. The performance of this version of EPIC was comparable to the validated EORTC QLQ-C30. CONCLUSION: The EPIC questionnaire was successfully translated into Chinese and was culturally adapted. The resultant Chinese version has high reliability and validity and will be an important tool for research on quality of life in the Chinese population. PMID- 29508939 TI - Case sharing of a patient re-challenged with afatinib for EGFR-mutated advanced non-small cell lung cancer. AB - A 65-year-old female with diabetes mellitus but otherwise good health in the past suffered from cough with occasional blood-stained sputum during initial presentation. The patient was diagnosed with pulmonary poorly differentiated adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 19 deletion and hence received afatinib therapy for 25 months without obvious adverse events except for a grade 1-2 acneiform rash. The disease was stabilized after subsequent cycles of chemotherapy with pemetrexed and carboplatin followed by maintenance pemetrexed. The patient was rechallenged with afatinib treatment as a named-patient drug in July 2014 (after approval) and later received afatinib in combination with palliative radiation. A blood test confirmed the presence of the T790M mutation and the patient was on osimertinib as part of a compassionate use program. The patient experienced good drug tolerance and eventually had a significant drop in tumor marker levels. This case provides insight into the use of afatinib in first-line setting of EGFR-mutated lung cancer. PMID- 29508940 TI - Afatinib for an EGFR exon 20 insertion mutation: A case report of progressive stage IV metastatic lung adenocarcinoma with 54 months' survival. AB - Non-small cell lung cancers (NSCLC) harboring the uncommon epidermal growth factor receptor (EGFR) exon 20 insertion mutations are generally thought to be unresponsive to EGFR-tyrosine kinase inhibitor (TKI) therapy. Presented here is a case of stage IV NSCLC harboring an uncommon EGFR exon 20 insertion mutation that was maintained at minimal progressive disease for 54 months, with 36 months on the second-generation TKI afatinib. Contrary to the existing literature, the patient in this case demonstrated a long, durable response to the EGFR-TKI, which was exhibited by a long survival endpoint. This suggests that stability in clinical symptoms might be sufficient to warrant continuation of therapy. PMID- 29508941 TI - Editorial. PMID- 29508943 TI - Are malignant self-regard and vulnerable narcissism different constructs? AB - In the clinical and empirical literature, vulnerable narcissism and malignant self-regard (MSR) have been found to be highly interrelated and associated with theoretically related personality constructs, suggesting that the two constructs may be much more similar than different. The present study set out to test this hypothesis by examining the relationship of vulnerable narcissism and MSR to experiences and expressions of anger, the factor structure of grandiose and vulnerable narcissism with MSR, the associations of MSR and vulnerable narcissism to the five factor model of personality, and to global self-esteem in self-report measures within 1168 undergraduate students. A separate study of 158 undergraduates also assessed how MSR and vulnerable narcissism predicted state and trait anxiety and anger after receiving positive or negative feedback, and the extent to which negative feedback interacted with MSR and vulnerable narcissism. Overall, compared with grandiose narcissism, both MSR and vulnerable narcissism were more associated with experiencing anger internally, self-reports of state and trait anger, high levels of neuroticism and openness, and lower levels of extraversion and global self-esteem. Both vulnerable narcissism and MSR uniquely predicted trait levels of anger and anxiety and state levels of anger after receiving negative feedback. It is concluded that MSR and vulnerable narcissism are likely identical constructs. PMID- 29508944 TI - Understanding Kombucha Tea Fermentation: A Review. AB - : Kombucha is a beverage of probable Manchurian origins obtained from fermented tea by a microbial consortium composed of several bacteria and yeasts. This mixed consortium forms a powerful symbiosis capable of inhibiting the growth of potentially contaminating bacteria. The fermentation process also leads to the formation of a polymeric cellulose pellicle due to the activity of certain strains of Acetobacter sp. The tea fermentation process by the microbial consortium was able to show an increase in certain biological activities which have been already studied; however, little information is available on the characterization of its active components and their evolution during fermentation. Studies have also reported that the use of infusions from other plants may be a promising alternative. PRACTICAL APPLICATION: Kombucha is a traditional fermented tea whose consumption has increased in the recent years due to its multiple functional properties such as anti-inflammatory potential and antioxidant activity. The microbiological composition of this beverage is quite complex and still more research is needed in order to fully understand its behavior. This study comprises the chemical and microbiological composition of the tea and the main factors that may affect its production. PMID- 29508942 TI - Intron retention in viruses and cellular genes: Detention, border controls and passports. AB - Intron retention (IR), where one or more introns remain in the RNA after splicing, was long thought to be rare in mammalian cells, albeit common in plants and some viruses. Largely due to the development of better methods for RNA analysis, it has now been recognized that IR is much more common than previously thought and that this mechanism is likely to play an important role in mammalian gene regulation. To date, most publications and reviews about IR have described the resulting mRNAs as "dead end" products, with no direct consequence for the proteome. However, there are also many reports of mRNAs with retained introns giving rise to alternative protein isoforms. Although this was originally revealed in viral systems, there are now numerous examples of bona fide cellular proteins that are translated from mRNAs with retained introns. These new isoforms have sometimes been shown to have important regulatory functions. In this review, we highlight recent developments in this area and the research on viruses that led the way to the realization of the many ways in which mRNAs with retained introns can be regulated. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA Export and Localization > Nuclear Export/Import RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes. PMID- 29508945 TI - A tale of two countries: progress towards UNAIDS 90-90-90 targets in Botswana and Australia. AB - UNAIDS 90-90-90 targets and Fast-Track commitments are presented as precursors to ending the AIDS epidemic by 2030, through effecting a 90% reduction in new HIV infections and AIDS-related deaths from 2010 levels (HIV epidemic control). Botswana, a low to middle-income country with the third-highest HIV prevalence, and Australia, a low-prevalence high-income country with an epidemic concentrated among men who have sex with men (MSM), have made significant strides towards achieving the UNAIDS 90-90-90 targets. These two countries provide lessons for different epidemic settings. This paper discusses the lessons that can be drawn from Botswana and Australia with respect to their success in HIV testing, treatment, viral suppression and other HIV prevention strategies for HIV epidemic control. Botswana and Australia are on target to achieving the 90-90-90 targets for HIV epidemic control, made possible by comprehensive HIV testing and treatment programmes in the two countries. As of 2015, 70% of all people assumed to be living with HIV had viral suppression in Botswana and Australia. However, HIV incidence remains above one per cent in the general population in Botswana and in MSM in Australia. The two countries have demonstrated that rapid HIV testing that is accessible and targeted at key and vulnerable populations is required in order to continue identifying new HIV infections. All citizens living with HIV in both countries are eligible for antiretroviral therapy (ART) and viral load monitoring through government-funded programmes. Notwithstanding their success in reducing HIV transmission to date, programmes in both countries must continue to be supported at current levels to maintain epidemic suppression. Scaled HIV testing, linkage to care, universal ART, monitoring patients on treatment over and above strengthened HIV prevention strategies (e.g. male circumcision and pre-exposure prophylaxis) will all continue to require funding. The progress that Botswana and Australia have made towards meeting the 90-90-90 targets is commendable. However, in order to reduce HIV incidence significantly towards 2030, there is a need for sustained HIV testing, linkage to care and high treatment coverage. Botswana and Australia provide useful lessons for developing countries with generalized epidemics and high-income countries with concentrated epidemics. PMID- 29508946 TI - Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe. AB - Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week. PMID- 29508947 TI - Unexpected donor-derived infectious transmissions by kidney transplantation: A systematic review. AB - BACKGROUND: Unexpected donor-derived transmission of infections is rare, but is associated with significant morbidity and mortality. We aimed to provide an overview of published cases on unexpected infectious transmissions. METHODS: We systematically reviewed all published evidence describing any unexpected donor derived viral, bacterial, fungal, and parasitic infections in kidney transplant recipients. RESULTS: In all, 119 studies (case reports [n = 36], case series [n = 78], cohort studies [n = 2], and case-control studies [n = 3]) involving 139 donors and 207 kidney recipients were included. Donor-derived viral (n = 116, 56.0%) infections were most prevalent, followed by bacterial (32, 15.5%), fungal (32, 15.5%), and parasitic (27, 13.0%) infections. The most commonly reported viral infections were human immunodeficiency virus (HIV) (n = 20, 9.7%), human T cell lymphotrophic virus (HTLV) (n = 20, 9.7%), and West Nile virus (WNV) (n = 13, 6.3%). The most frequent bacterial infections were caused by Mycobacterium tuberculosis (10, 4.8%) and Pseudomonas aeruginosa (9, 4.3%). Candida species were the most frequent causes of fungal donor-derived infections (8, 3.9%). Toxoplasma gondii accounted for seven (3.4%) cases of transmitted parasitic infections. Patients with rabies experienced the highest probability of recipient death from virus-related complications at 90.0%, within a median time of 2.8 months after transplantation. CONCLUSION: The frequency of donor-derived infectious transmission appears low in kidney transplantation, with viral transmissions being most commonly reported overall. PMID- 29508948 TI - Medical Abortion Provision by Pharmacies and Drug Sellers in Low- and Middle Income Countries: A Systematic Review. AB - We undertook a systematic review to assess 1) the level and quality of pharmacy and drug shop provision of medical abortion (MA) in low- and middle-income countries (LMICs) and 2) interventions to improve quality of provision. We used standardized terms to search six databases for peer-reviewed and grey literature. We double-extracted data using a standardized template, and double-graded studies for methodological quality. We identified 22 studies from 16 countries reporting on level and quality of MA provision through pharmacies and drug sellers, and three intervention studies. Despite widespread awareness and provision of MA drugs, even in legally restricted contexts, most studies found that pharmacy workers and drug sellers had poor knowledge of effective regimens. Evidence on interventions to improve pharmacy and drug shop provision of MA was limited and generally low quality, but indicated that training could be effective in improving knowledge. Programmatic attention should focus on the development and rigorous evaluation of innovative interventions to improve women's access to information about MA self-management in low-and middle-income countries. PMID- 29508949 TI - Heterogeneous Effects of Birth Spacing on Neonatal Mortality Risks in Bangladesh. AB - The negative relationship between birth interval length and neonatal mortality risks is well documented, but heterogeneity in this relationship has been largely ignored. Using the Bangladesh Maternal Mortality and Health Care Survey 2010, this study investigates how the effect of birth interval length on neonatal mortality risks varies by maternal age at birth and maternal education. There is significant variation in the effect of interval length on neonatal mortality along these dimensions. Young mothers and those with little education, both of which make up a large share of the Bangladeshi population, can disproportionately benefit from longer intervals. Because these results were obtained from within family models, they are not due to unobservable heterogeneity between mothers. Targeting women with these characteristics may lead to significant improvements in neonatal mortality rates, but there are significant challenges in reaching them. PMID- 29508950 TI - Core-Shell NiO@Ni-P Hybrid Nanosheet Array for Synergistically Enhanced Oxygen Evolution Electrocatalysis: Experimental and Theoretical Insights. AB - Cost-effective and highly-efficient electrocatalysts for the oxygen evolution reaction are crucial for electrolytic hydrogen production. Here, we report core shell NiO@Ni-P nanosheet arrays as a high-performance 3D catalyst for water oxidation electrocatalysis. Such nanoarrays demand overpotentials of 292 and 350 mV to drive geometrical catalytic current densities of 10 and 100 mA cm-2 , respectively, with an activity superior to its NiO and Ni-P counterparts. Notably, this catalyst also shows a high long-term electrochemical durability with a Faradaic efficiency of 98.1 %. Density functional theory calculation reveals that the superior activity benefits from the synergistic effect between NiO and Ni-P. PMID- 29508951 TI - Canine and Premolar Root Dimensions in Chinese. A Reference for Osteoodontokeratoprosthesis Surgery. AB - PURPOSE: Osteoodontokeratoprosthesis (OOKP) surgery is used to restore vision in end-stage corneal disorders, where an autogenous tooth supporting an optical cylinder is implanted through the cornea under a buccal mucosal graft. The ideal tooth for OOKP is a healthy single-rooted permanent tooth with sufficient buccolingual/palatal root diameter to accommodate an optical cylinder. The aim of this study was to determine the buccolingual/palatal diameters of canine and premolar roots in Chinese, for selection of teeth for OOKP surgery. DESIGN: This was an anatomical study on root dimensions of extracted intact teeth. METHODS: Extracted canine and premolar teeth (excluding maxillary first premolars) were collected and the buccolingual/palatal and mesiodistal diameters of the root at the cervical line and at 2-mm intervals below the cervical line were measured with Vernier calipers. Other measurements included total tooth length, crown buccolingual/palatal diameter, and root length. Mean and minimum buccolingual/palatal root diameters were compiled for each 2-mm interval. RESULTS: A total of 415 extracted teeth (198 male, 217 female) were collected and measured. Recorded dimensions of keratoprostheses in 55 previous OOKP surgeries were used to establish acceptable lamina dimensions to ascertain root size adequacy. Premolars in Chinese female patients were undersized in a small minority. Minimal dimensions of teeth were insufficient if at 6 mm root level, the buccolingual/palatal width was less than 5 mm, or the mesiodistal width was less than 3 mm. This was noted in female mandibular first premolars (5.6%), maxillary second premolars (4.5%), and mandibular second premolars (1.5%). CONCLUSIONS: Canines have adequate dimensions for OOKP surgery. However, premolars in Chinese females may be undersized in a small minority. PMID- 29508952 TI - The Synthetic Experiment: E. B. Titchener's Cornell Psychological Laboratory and the Test of Introspective Analysis. AB - Beginning in 1 9a0, a major thread of research was added to E. B. Titchener's Cornell laboratory: the synthetic experiment. Titchener and his graduate students used introspective analysis to reduce a perception, a complex experience, into its simple sensory constituents. To test the validity of that analysis, stimulus patterns were selected to reprodiuce the patterns of sensations found in the introspective analyses. If the original perception can be reconstructed in this way, then the analysis was considered validated. This article reviews development of the synthetic method in E. B. Titchener's laboratory at Cornell University and examines its impact on psychological research. PMID- 29508954 TI - Perception of Scenes in Different Sensory Modalities: A Result of Modal Completion. AB - Dynamic perception includes amodal and modal completion, along with apparent movement. It fills temporal gaps for single objects. In 2 experiments, using 6 stimulus presentation conditions involving 3 sensory modalities, participants experienced 8-10 sequential stimuli (200 ms each) with interstimulus intervals (ISIs) of 0.25-7.0 s. Experiments focused on spatiotemporal completion (walking), featural completion (object changing), auditory, completion (falling bomb), and haptic changes (insect crawling). After each trial, participants judged whether they experienced the process of "happening " or whether they simply knew that the process must have occurred. The phenomenon was frequency independent, being reported at short ISIs but not at long ISIs. The phenomenon involves dynamic modal completion and possibly also conceptual processes. PMID- 29508953 TI - The Method of Negative Instruction: Herbert S. Langfeld's and Ludwig R. Geissler's 1910-1913 Insightful Studies. AB - Herbert S. Langfeld and Ludwig R. Geissler published insightful articles during the period of 1910-1913 using what they called the Method of Negative Instruction, which anticipated much current research on action control and the role of instructions. We review their studies and relate the findings to contemporary research and views concerning task-irrelevant congruency effects and deception, concluding that their work has not received the credit it warrants. We also call for contemporary researchers to revisit prior studies, especially ones conducted before the cognitive revolution in psychology, to enrich their knowledge of the field and improve the quality of their research. PMID- 29508955 TI - Feature-to-Feature Inference Under Conditions of Cue Restriction and Dimensional Correlation. AB - The present study explored feature-to-feature and label-to-feature inference in a category task for different category structures. In the correlated condition, each of the 4 dimensions comprising the category was positively correlated to each other and to the category label. In the uncorrelated condition, no correlation existed between the 4 dimensions comprising the category, although the dimension to category label correlation matched that of the correlated condition. After learning, participants made inference judgments of a missing feature, given 1, 2, or 3 feature cues; on half the trials, the category label was also included as a cue. The results showed superior inference of features following training on the correlated structure, with accurate inference when only a single feature was presented. In contrast, a single-feature cue resulted in chance levels of inference for the uncorrelated structure. Feature inference systematically improved with number of cues after training on the correlated structure. Surprisingly, a similar outcome was obtained for the uncorrelated structure, an outcome that must have reflected mediation via the category label. A descriptive model is briefly introduced to explain the results, with a suggestion that this paradigm might be profitably extended to hierarchical structures where the levels of feature-to-feature inference might vary with the depth of the hierarchy. PMID- 29508956 TI - Realistic Stimuli Reveal Selective Effects of Motor Expertise During a Mental Body Rotation Task. AB - To investigate the effects of stimulus features on the implementation of motor expertise in body rotations during a mental body rotation task, 2 experiments were conducted. In Experiment 1, we investigated the mental rotation abilities in 27 male participants: 14 experts in real body rotations (national level gymnasts) and 13 nonexperts (national handball players). The mental rotation task used left right judgments and involved 3 types of stimuli: images of a stick figure person, images of line drawings of the human body, and photographs of real male persons. In Experiment 2, 10 experts and 11 nonexperts performed a mental body rotation task on the same stimuli as in Experiment 1 using this time a same-different judgment. Results showed that stimulus features had a significant effect on the mental rotation of the participants because the more realistic stimuli resulted in shorter response times. Furthermore, experts outperformed nonexperts when the stimuli were presented in unfamiliar orientations (180* rotation). However, this pattern was significant only during the mental rotation task of photographs with left- right judgments, suggesting that stick figure person and line drawings of the human body did not differentiate experts and nonexperts. In conclusion, results suggest the existence of optimal stimulus features to elicit optimal embodiment and allow revealing selective effects of motor expertise in body rotations. PMID- 29508957 TI - Reading Aloud to Children: Benefits and Implications for Acquiring Literacy Before Schooling Begins. AB - Extensive experience in written language might provide children the opportunity to learn to read in the same manner they learn spoken language. One potential type of written language immersion is reading aloud to children, which is additionally valuable because the vocabulary in picture books is richer and more extensive than that found in child-directed speech. This study continues a comparison between these 2 communication media by evaluating their relative linguistic and cognitive complexity. Although reading grade level has been used only to assess the complexity of written language, it was also applied to both child-directed and adult-directed speech. Five measures of reading grade level gave an average grade level of 4.2 for picture books, 1.9 for child-directed speech, and 3.0 for adult-directed speech. The language in picture books is more challenging than that found in both child-directed and adult-directed speech. It is proposed that this difference between written and spoken language is the formal versus informal genre of their occurrence rather than their text or oral medium. The value of reading books aloud therefore exposes children to a linguistic and cognitive complexity not typically found in speech to children. PMID- 29508958 TI - Visual Search Load Effects on Age-Related Cognitive Decline: Evidence From the Yakumo Longitudinal Study. AB - The validity of Bucur and Madden's (2010) proposal that an age-related decline is particularly pronounced in executive function measures rather than in elementary perceptual speed measures was examined via the Yakumo Study longitudinal database. Their proposal suggests that cognitive load differentially affects cognitive abilities in older adults. To address their proposal, linear regression coefficients of 104 participants were calculated individually for the digit cancellation task 1 (D-CAT1), where participants search for a given single digit, and the D-CAT3, where they search for 3 digits simultaneously. Therefore, it can be conjectured that the D-CAT1 represents primarily elementary perceptual speed and low-visual search load task. whereas the D-CAT3 represents primarily executive function and high-visual search load task. Regression coefficients from age 65 to 75 for the D-CAT3 showed a significantly steeper decline than that for the D-CAT1, and a large number of participants showed this tendency. These results support the proposal by Brcur and Madden (2010) and suggest that the degree of cognitive load affects age-related cognitive decline. PMID- 29508959 TI - Alexithymia and Mood: Recognition of Emotion in Self and Others. AB - The present study explored relationships between alexithymia-a trait characterized by difficulties identifying and describing feelings and an external thinking style-and negative moods, negative mood regulation expectancies, facial recognition of emotions, emotional empathy, and alcohol consumption. The sample consisted of 102 university (primarily psychology) students (13 men, 89 women) aged 18 to 50 years (M = 22.18 years). Participants completed the Toronto Alexithymia Scale (TAS-20), Negative Mood Regulation Scale (NMRS), Depression Anxiety Stress Scales (DASS-21), Reading the Mind in the Eyes Test (RMET), Interpersonal Reactivity Index (IRI), and Alcohol Use Disorders Identification Test (AUDIT). Results were consistent with previous findings of positive relationships of TAS-20 alexithymia scores with both alcohol use (AUDIT) and negative moods (DASS-21) and a negative relationship with emotional self regulation as indexed by NMRS. Predicted negative associations of both overall TAS-20 alexithymia scores and the externally oriented thinking (EOT) subscale of the TAS-20 with both RMET facial recognition of emotions and the empathic concern (EC) subscale of the IRI were supported. The mood self-regulation index NMRS fully mediated the relationship between alexithymia and negative moods. Hierarchical linear regressions revealed that, after other relevant variables were controlled for, the EOT subscale of the TAS-20 predicted RMET and EC. The concrete thinking or EDT facet of alexithymia thus appears to be associated with diminished facial recognition of emotions and reduced emotional empathy. The negative moods associated with alexithymia appear to be linked to subjective difficulties in self-regulation of emotions. PMID- 29508960 TI - The Effect of Sleep Loss on Dual Time-Based Prospective Memory Tasks. AB - The aim of the present study was to deepen knowledge about the effect of a lowered vigilance state on time-based prospective memory (TBPM) performance. For this purpose 2 TBPM tasks (primary and interpolated), which shared a portion of the retention interval, and 3 reasoning tasks, as ongoing activities, were administered after total sleep deprivation and in a regular sleep condition. The results showed a detrimental effect of sleep deprivation on prospective memory performance and a partial dissociation between clock-checking behavior and time estimation for prospective compliance. This study clearly indicates that total sleep deprivation im- pairs the ability to complete multiple prospective task assignments in a timely fashion. Results are discussed suggesting the existence of different mechanisms involved in time monitoring and other cognitive functions underlying TBPM performance. PMID- 29508961 TI - History of Psychology Publish and Perish: Psychology's Most Prolific Authors Are Not Always the Ones We Remember. AB - What is the relationship between being highly prolific in the realm of publication and being remembered as a great psychologist of the past? In this study, the PsycINFO database was used to identify the historical figures who wrote the most journal articles during the half-century from 1890 to 1939. Although a number of the 10 most prolific authors are widely remembered for their influence on the discipline today-E. L. Thorndike, Karl Pearson, E. B. Titchener, Henri Pi6ron-the majority are mostly forgotten. The data were also separated into the 5 distinct decades. Once again, a mixture of eminent and obscure individuals made appearances. Most striking, perhaps, was the great increase in articles published over the course of the half-century-approximately doubling each decade and the enormous turnover in who was most prolific, decade over decade. In total, 100 distinct individuals appeared across just 5 lists of about 25 names each. PMID- 29508962 TI - Obituary: BRUCE BRIDGEMAN (1944-2016). PMID- 29508963 TI - Another Look at the Impacts of Health Reform in Massachusetts: Evidence Using New Data and a Stronger Model. AB - In April 2006, Massachusetts enacted a comprehensive health care reform bill that seeks to move the state to near universal insurance coverage. The bill included expanded eligibility for public coverage, subsidized insurance,market reforms, requirements for employers, and, most controversial, an individual mandate. A study of the early impacts of the state's initiative found evidence of a substantial drop in uninsurance--from 13 to 7 percent for nonelderly adults (Long 2008). Because that study relied on a simple pre-post comparison, it is possible that the estimates of the impact of health reform reflect both the changes under health reform and factors beyond health reform that changed over the same period, leading to biased estimates of the impacts of reform (Lawrence B. Mohr 1995). This paper expands on the earlierwork to estimate the impacts of health reform in Massachusetts using new data and a stronger research design. Specifically, we rely on data over time for Massachusetts and other states from the Current Population Survey (CPS) toestimate difference-in-differences (DD) models (Jeffrey M. Wooldridge 2002). PMID- 29508964 TI - Disability Screening and Labor Supply: Evidence from South Africa. PMID- 29508965 TI - Public Policy and the Dynamics of Children's Health Insurance, 1986-1999. AB - The past 20 years have seen important changes in public policy with the potential for significant impacts on health insurance for children. These changes included both those explicitly intended to expand access to public insurancefor children, including expansions in eligibility for Medicaid and the introduction of the State Children's Health Insurance Program (SCHIP), and other changes in antipoverty policy. Since health insurance coverage among children is entwined with parental welfare participation and employment, shifts in policy designed to encourage work in place of welfare participation--such as welfare reform and the expansion of the Earned Income Tax Credit (EITC)--may have secondary impacts on children's health insurance coverage. As parents leave welfare, with its guaranteed health insurance throughMedicaid, for jobs that may or may not have health insurance coverage offered as a benefit, children may experience a change in the source of their health insurance coverage or may become uninsured. Similarly, changes in healthcare markets and economic conditions such as rising health care prices and cyclicality in the availability of employment may also affect children's coverage. Despite the potential importance of these factors for coverage, the fraction of children who are uninsured has remained largely constant, particularly through the 1990s. However, this relativelyconstant level of uninsurance may mask changes in the underlying dynamics of health insurance among children. In this paper, we use monthly data from the 1986-1996 panels of the Survey of Income and Program Participation (SIPP) to examine patterns of health insurance coverage among children during the period 1986-1999, focusing on transitions between public coverage, private coverage, and no coverage. Using these data, we find that over the 1990s the rate of transitions among all three insurance states--public insurance, private insurance, and no insurance- increased, with a particular increase in transitions involving public coverage. We investigate whether there is evidence of a relationship between insurance transitions and various policy and economic variables, focusing on the impacts of expansions in public coverage availability, the effects of other policies directed at the poor that affect employment and insurancecoverage, and economic conditions. We find that several of the policy changes that took place over the 1990s had important effects on health insurance transitions for children. PMID- 29508967 TI - Will Public Sector Retiree Health Benefit Plans Survive? Economic and Policy Implications of Unfunded Liabilities. AB - Recent articles have reported a large and growing financial crisis associated with retiree health plans offered by state and local governments, and have expressed alarm over their impact on the financial status of these governmentalunits (Goldman Sachs 2007; David Zion and Amit Varshney 2007). The concern about the unfunded liabilities of retiree health plans follows from a change in the public accounting rules issued by the Governmental Accounting Standards Board (GASB). GASB Statement No. 45 requires state and local governments to report unfunded accrued liabilities and annual required contributions needed to fully fund the retiree health promises. The GASB 45 statements produced by state governments indicate that unfunded liabilities for state employees and retirees total approximately $500 billion. Thisdoes not include additional liabilities associated with retiree health plans for local governments and public school teachers with plans that are not managed at the state level. The explicit acknowledgement of these liabilities and theirabsolute and relative size has created considerable concern and debate among economists, policymakers, and voters. This article presents data from state actuarial reports on the size of retiree health liabilities, examines the key assumptions used to determine the unfunded liabilities, and then assesses the potential future of retiree health plans in the public sector. PMID- 29508968 TI - [Nodulation competitiveness of nodule bacteria: Genetic control and adaptive significance]. AB - The most recent data on the system of cmp (competitiveness) genes that determine the nodulation competitiveness of rhizobial strains, i.e., the ability to compete for nodule formation in leguminous plants, is analyzed. Three genetic approaches for the construction of economically valuable strains of rhizobia are proposed: the amplification of positive regulators of competitiveness, the inactivation of the negative regulators of this trait, and the introduction of efficient competitiveness factors into strains capable of active nitrogen fixation. PMID- 29508969 TI - Under the Weather: Health, Schooling, and Economic Consequences of Early-Life Rainfall. PMID- 29508970 TI - [Immunity of a leguminous plant infected by nodular bacteria Rhizobium spp. F.] AB - Recent studies of the immune system of leguminous plants infected with nodular bacteria (rhizobia) are summarized. The possibility of blocking the invasion of rhizobia into plant organs not affected by the primary infection is discussed. The concept of local and systemic resistance of the leguminous plant to rhizobial infection is introduced. The Nod factors of rhizobia are considered, as well as the plant receptors that interact with these factors upon the formation of symbiosis of the plant and bacteria. The role of bacterial surface exopolysaccharides in the suppression of the protective system of the plants is discussed. The innate immunity of leguminous plant cells is assumed to affect the formation and functioning of the symbiosis of the plant and the bacteria. PMID- 29508972 TI - One Chance in a Million: Altruism and the Bone Marrow Registry. AB - Stem cell transplants save lives of many patients with blood diseases. Donation is painful, but rarely has lasting adverse effects. Patients can accept transplants only from donors with compatible immune systems. Those lacking a siblingmatch must seek donations from the general population. The probability that two unrelated persons are compatible is less than 1/10,000. Health authorities maintain a registry of several million genetically tested potential donors whoagree to donate if asked. We find that the benefits of adding registrants of every race exceed costs. We also explore the peculiar structure of voluntary public good provision that faces potential donors. PMID- 29508971 TI - [Flavonoid oxidation kinetics in aqueous and aqueous organic media in the presence of peroxidase, tyrosynase, and hemoglobin]. AB - The kinetics of oxidation reactions of flavonoids, quercetin, dihydroquercetin, and epicatechin has been studied in the presence of biocatalysts of different natures: horseradish peroxidase, mushroom tyrosinase, and hemoglobin from bull blood. Comparison of the kinetic parameters of the oxidation reaction showed that peroxidase appeared to be the most effective biocatalyst in these processes. The specificity of the enzyme for quercetin increased with increasing the polarity of the solvent in a series of ethanol-acetonitrile-dimethyl sulfoxide. PMID- 29508973 TI - [Peroxidase activity of octaheme nitrite reductases from bacteria of the Thioalkalivibrio genus]. AB - Closely related penta- and octaheme nitrite reductases catalyze the reduction of nitrite, nitric oxide, and hydroxylamine to ammonium and of sulfite to sulfide. NrfA pentaheme nitrite reductase plays the key role in anaerobic nitrate respiration and the protection of bacterial cells from stresses caused by nitrogen oxides and hydrogen peroxide. Octaheme nitrite reductases from bacteria of the Thioalkalivibrio genus are less studied, and their function in the cell is unknown. In order to estimate the possible role of octaheme nitrite reductases in the cell resistance to oxidative stress, the peroxidase activity of the enzyme from T. nitratireducens (TvNiR) has been studied in detail. Comparative analysis of the active site structure of TvNiR and cytochrome c peroxidases has shown some common features, such as a five-coordinated catalytic heme and identical catalytic residues in active sites. A model of the possible productive binding of peroxide at the active site of TvNiR has been proposed. The peroxidase activity has been measured for TvNiR hexamers and trimers under different conditions (pH, buffers, the addition of CaCl2 and EDTA). The maximum peroxidase activity of TvNiR with ABTS as a substrate (k cat = 17 s-1; k cat/K m = 855 mM-1 s-1) has been 100-300 times lower than the activity of natural peroxidases. The different activities of TvNiR trimers and hexamers indicate that the rate-limiting stage of the reaction is not the catalytic event at the active site but the electron transfer along the heme c electron-transport chain. PMID- 29508975 TI - The Effect of Medicare Part D on Pharmaceutical Prices and Utilization. PMID- 29508974 TI - "Momma's Got the Pill": How Anthony Comstock and Griswold v. Connecticut Shaped US Childbearing. AB - The 1960s ushered in a new era in US demographic history characterized by significantly lower fertility rates and smaller family sizes. What catalyzed these changes remains a matter of considerable debate. This paper exploits idiosyncraticvariation in the language of "Comstock" statutes, enacted in the late 1800s, to quantify the role of the birth control pill in this transition. Almost 50 years after the contraceptive pill appeared on the US market, this analysis provides new evidence that it accelerated the post-1960 decline in marital fertility. PMID- 29508976 TI - The Health Returns of Education Policies from Preschool to High School and Beyond. PMID- 29508977 TI - [PEGylated recombinant L-asparaginase from Erwinia carotovora: Production, properties, and potential applications]. AB - N-hydroxysuccinimide ester of monomethoxy polyethylene glycol hemisuccinate was synthesized. It acylated amino groups in a molecule of recombinant L-asparaginase from Erwinia carotovora. A method of L-asparaginase modification by the obtained activated polyethylene glycol derivative was developed. The best results were produced by modification of the enzyme with a 25-fold excess of reagent relative to the enzyme tetramer. The modified L-asparaginase was isolated from the reaction mixture by gel filtration on Sepharose CL-6B. The purified bioconjugate did not contain PEG unbound to the protein, demonstrated high catalytic activity, and exhibited antiproliferative action on cell cultures. PMID- 29508978 TI - [Proteomic analysis of contaminants in recombinant membrane hemeproteins expressed in E. coli and isolated by metal affinity chromatography]. AB - Contaminating proteins have been identified by "shotgun" proteomic analysis in 14 recombinant preparations of human membrane heme- and flavoproteins expressed in Escherichia coli and purified by immobilized metal ion affinity chromatography. Immobilized metal ion affinity chromatography of ten proteins was performed on Ni2+-NTA-sepharose 6B, and the remaining four proteins were purified by ligand affinity chromatography on 2',5'-ADP-sepharose 4B. Proteomic analysis allowed to detect 50 protein impurities from E. coli. The most common contaminant was Elongation factor Tu2. It is characterized by a large dipole moment and a cluster arrangement of acidic amino acid residues that mediate the specific interaction with the sorbent. Peptidyl prolyl-cis-trans isomerase SlyD, glutamine-fructose-6 phosphate aminotransferase, and catalase HPII that contained repeating HxH, QxQ, and RxR fragments capable of specific interaction with the sorbent were identified among the protein contaminants as well. GroL/GroS chaperonins were probably copurified due to the formation of complexes with the target proteins. The Ni2+ cations leakage from the sorbent during lead to formation of free carboxyl groups that is the reason of cation exchanger properties of the sorbent. This was the putative reason for the copurification of basic proteins, such as the ribosomal proteins of E. coli and the widely occurring uncharacterized protein YqjD. The results of the analysis revealed variation in the contaminant composition related to the type of protein expressed. This is probably related to the reaction of E. coli cell proteome to the expression of a foreign protein. We concluded that the nature of the protein contaminants in a preparation of a recombinant protein purified by immobilized metal ion affinity chromatography on a certain sorbent could be predicted if information on the host cell proteome were available. PMID- 29508979 TI - [Novel biocatalyst for productions of S-(-)-2-[6-benzyloxy -2,5,7,8 tetramethylchroman -2-yl] ethanol-precursor of natural alpha-tocols]. AB - A novel promising strain of actinobacteria Rhodococcus sp. 77-32 was identified. Its acetonetreated biomass the could be used as a biocatalyst for production of S (-)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (S-BCE), a precursor of natural alpha-tocols. It was established that a reaction of enantioselective hydrolysis of racemic (+/-)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8 tetramethylchroman (BCEA) occurred in the phosphate buffer-acetone system, resulting in enrichment of the residual substrate by S-enantiomer (S-(+)-2-(2 acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman, S-BCEA). It was shown that the hydrolysis was accompanied by stereoinversion of the formed product, R-(+)-2 [6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (R-BCE), into the S-BCE. The transformation conditions (acetone content, acidity, temperature, reaction duration) were optimized, providing simultaneous production of optically pure S BCE and S-BCEA with an almost quantitative yield. PMID- 29508980 TI - Family Health, Children's Own Health, and Test Score Gaps. PMID- 29508981 TI - [Functionality of Metdi5511gene in Methylobacterium dichloromethanicum DM4]. AB - A knockout mutant of Methylobacterium dichloromethanicum DM4 with an inactivated gene of a putative transcription regulator METDI5511 (DeltaMETDI5511) has been obtained. The expression of this gene increases many times when the strain is grown on dichloromethane compared to methanol. The mutant had a low growth rate on dichloromethane as compared with the original strain and was found to be more sensitive to influences of various types of stress (oxidative, osmotic stress, heat, and drying). The cells were stained with Fluorescent Brightener 28 (Calcofluor white), and the intensity of their fluorescence showed that the DeltaMETDI5511 mutant had significantly increased numbers of surface polysaccharides with beta-1,3 and beta-1,4-glycoside bonds. The results indicate that the METDI5511 gene is involved in the regulation of surface polysaccharides that play an important role in adaptation of cells to growth on dichloromethane. PMID- 29508982 TI - How Sensitive are Low Income Families to Health Plan Prices? PMID- 29508983 TI - Disentangling the Effects of Health Reform in Massachusetts: How Important Are the Special Provisions for Young Adults? PMID- 29508984 TI - Human factors study of ZENEO(r) (needle-free autoinjector) and comparison of different user instruction formats. AB - BACKGROUND: ZENEO(r) (Crossject, Dijon France) is a novel prefilled, disposable needle-free auto-injector (AI) device under development for drug deliverer in a variety of routine-use or emergency situations. At present, reported user experience and patient preferences are limited. To determine what impact different forms of user instructions may have on successful use of the ZENEO(r) device. METHODS: We conducted a human factors study on 134 healthy volunteers. On enrolment, subjects were provided with different instructive training material; a device quick guide plus either use of a dummy training device, an illustrated leaflet, or a demonstration video. After 6 weeks, subjects returned and performed an unaided simulated injection, and compliance with specific steps necessary for successful use, and avoidance of actions that interfere with appropriate use was recorded by an investigator. RESULTS: Most subjects (93.3%) successfully performed a simulated injection without major errors (regardless of type of educational instructions), and the great majority (97.5%) reported no difficulty in a range of objective measures of important necessary steps. Compliance with necessary steps and avoidance of detrimental actions was greater in those subjects with prior access to a demonstration video or provided with an illustrated patient leaflet. Prior experience with a dummy training device provided little if any benefit. User satisfaction with the device was high. CONCLUSIONS: The results show that the ZENEO(r) device can be effectively used with a conventional suite of printed user instructions. Use of a demonstration video provides additional value, whereas use of a dummy training device had limited value. PMID- 29508985 TI - Spectroscopic Diagnosis of Excited-State Aromaticity: Capturing Electronic Structures and Conformations upon Aromaticity Reversal. AB - Aromaticity, the special energetic stability derived from cyclic [4 n + 2]pi conjugated electronic structures, has been the topic of intense interest in chemistry because it plays a critical role in rationalizing molecular stability, reactivity, and physical/chemical properties. Recently, the pioneering work by Colin Baird on aromaticity reversal, postulating that aromatic (antiaromatic) character in the ground state reverses to antiaromatic (aromatic) character in the lowest excited triplet state, has attracted much scientific attention. The completely reversed aromaticity in the excited state provides direct insight into understanding the photophysical/chemical properties of photoactive materials. In turn, the application of aromatic molecules to photoactive materials has led to numerous studies revealing this aromaticity reversal. However, most studies of excited-state aromaticity have been based on the theoretical point of view. The experimental evaluation of aromaticity in the excited state is still challenging and strenuous because the assessment of (anti)aromaticity with conventional magnetic, energetic, and geometric indices is difficult in the excited state, which practically restricts the extension and application of the concept of excited-state aromaticity. Time-resolved optical spectroscopies can provide a new and alternative avenue to evaluate excited-state aromaticity experimentally while observing changes in the molecular features in the excited states. Time-resolved optical spectroscopies take advantage of ultrafast laser pulses to achieve high time resolution, making them suitable for monitoring ultrafast changes in the excited states of molecular systems. This can provide valuable information for understanding the aromaticity reversal. This Account presents recent breakthroughs in the experimental assessment of excited-state aromaticity and the verification of aromaticity reversal with time-resolved optical spectroscopic measurements. To scrutinize this intriguing and challenging scientific issue, expanded porphyrins have been utilized as the ideal testing platform for investigating aromaticity because they show distinct aromatic and antiaromatic characters with aromaticity-specific spectroscopic features. Expanded porphyrins exhibit perfect aromatic and antiaromatic congener pairs having the same molecular framework but different numbers of pi electrons, which facilitates the study of the pure effect of aromaticity by comparative analyses. On the basis of the characteristics of expanded porphyrins, time-resolved electronic and vibrational absorption spectroscopies capture the changes in electronic structure and molecular conformations driven by the change in aromaticity and provide clear evidence for aromaticity reversal in the excited states. The approaches described in this Account pave the way for the development of new and alternative experimental indices for the evaluation of excited-state aromaticity, which will enable overarching and fundamental comprehension of the role of (anti)aromaticity in the stability, dynamics, and reactivity in the excited states with possible implications for practical applications. PMID- 29508986 TI - Solution-Processed Interfacial PEDOT:PSS Assembly into Porous Tungsten Molybdenum Oxide Nanocomposite Films for Electrochromic Applications. AB - Electrochromic devices (ECDs) have received increased attention for applications including optoelectronics, smart windows, and low-emission displays. However, it has been recognized that the ECDs with transition-metal oxide (TMO) electrodes possess a high charge transport barrier because of their poor electrical conductivity, which limits their electrochromic performance. In this work, we addressed this limitation by utilizing a conjugated polymer to fabricate an organic-inorganic nanocomposite film that decreases the charge transport barrier of typical TMO electrodes. Using a conventional spray-layer-by-layer (spray-LbL) deposition technique, we demonstrate an electrochromic film composed of porous layers of tungsten molybdenum oxide (W0.71Mo0.29O3) nanorods permeated with an interconnected conductive layer of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS). The introduction of PEDOT:PSS is shown to significantly reduce the charge transport barrier, allowing the nanocomposite W0.71Mo0.29O3/PEDOT:PSS electrode to exhibit significantly improved electrochromic switching kinetics compared with the deposited W0.71Mo0.29O3 films. Furthermore, the optical contrast of the nanocomposite electrode was observed to be superior to both pure PEDOT:PSS and W0.71Mo0.29O3 electrodes, with a performance that exceeded the linearly predicted contrast of combining the pure films by 23%. The enhanced performance of the PEDOT:PSS-intercalated porous W0.71Mo0.29O3 nanocomposite electrodes and the facile synthesis through a spray LbL method demonstrate a viable strategy for preparing fast assembling high performance nanocomposite electrodes for a wide variety of electrochemical devices. PMID- 29508987 TI - Elucidating the Structures of Amyloid Oligomers with Macrocyclic beta-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases. AB - In the more than a century since its identification, Alzheimer's disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer's disease began with the identification of "amyloid" plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with "cross-beta" structure in 1968. Further efforts led to the discovery of the beta-amyloid peptide, Abeta, as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade-long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer's disease. Along the way, an alternative model began to emerge in which small aggregates of Abeta, called "oligomers", rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer's disease. This Account describes what is known about the structures of the fibrils and details our research group's efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. beta-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel beta-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel beta-sheets comprising beta-hairpins. beta-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic beta-sheets that are designed to mimic beta-hairpins formed by amyloidogenic peptides and proteins. The beta-hairpin mimics contain two beta strand peptide fragments linked together at their N- and C-termini by two delta linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the beta-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the beta-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by beta-hairpin mimics derived from Abeta, alpha-synuclein, and beta2-microglobulin. Out of these three amyloidogenic peptides and proteins, the Abeta beta-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three Abeta beta-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the beta-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer's disease, Parkinson's disease, and other amyloid diseases. PMID- 29508988 TI - Quorum Sensing Signals Form Complexes with Ag+ and Cu2+ Cations. AB - Quorum sensing (QS) regulates important bacterial behaviors such as virulent protein production and biofilm formation. QS requires that molecular signals are exchanged between cells, extracellularly, where environmental conditions influence signal stability. In this work, we present a novel complexation between metal cations (Ag+ and Cu2+) and a QS autoinducer signal, N-hexanoyl- L homoserine lactone (HHL). The molecular interactions were investigated using mass spectrometery, attenuated total reflectance-Fourier transform infrared spectroscopy, and computational simulations. Results show that HHL forms predominantly 1:1 complexes with Ag+ ( Kd = 3.41 * 10-4 M) or Cu2+ ( Kd = 1.40 * 10-5 M), with the coordination chemistry occurring on the oxygen moieties. In vivo experiments with Chromobacterium violaceum CV026 show that sublethal concentrations of Ag+ and Cu2+ decreased HHL-regulated QS activity. Furthermore, when Ag+ was preincubated with HHL, Ag+ toxicity to CV026 decreased by an order of magnitude, suggesting HHL:metal complexes alter the bioavailability of the individual constituents. PMID- 29508989 TI - Poly-gamma-glutamate Binder To Enhance Electrode Performances of P2 Na2/3Ni1/3Mn2/3O2 for Na-Ion Batteries. AB - P2-Na2/3Ni1/3Mn2/3O2 (P2-NiMn) is one of the promising positive electrode materials for high-energy Na-ion batteries because of large reversible capacity and high working voltage by charging up to 4.5 V versus Na+/Na. However, the capacity rapidly decays during charge/discharge cycles, which is caused by the large volume shrinkage of ca. 23% by sodium deintercalation and following electric isolation of P2-NiMn particles in the composite electrode. Serious electrolyte decomposition at the higher voltage region than 4.1 V also brings deterioration of the particle surface and capacity decay during cycles. To solve these drawbacks, we apply water-soluble sodium poly-gamma-glutamate (PGluNa) as an efficient binder to P2-NiMn instead of conventional poly(vinylidene difluoride) (PVdF) and examined the electrode performances of P2-NiMn composite electrode with PGluNa binder for the first time. The PGluNa electrode shows Coulombic efficiency of 95% at the first cycle and capacity retention of 89% after 50 cycles, whereas the PVdF electrode exhibits only 80 and 71%, respectively. The alternating current impedance measurements reveal that the PGluNa electrode shows a much lower resistance during the cycles compared with the PVdF one. From the surface analysis and peeling test of the electrodes, the PGluNa binder was found to cover the surface of the P2-NiMn particles and suppresses the electrolyte decomposition and surface degradation. The PGluNa binder further enhance the mechanical strength of the electrodes and suppresses the electrical isolation of the P2-NiMn particles during sodium extraction/insertion. The efficient binder with noticeable adhesion strength and surface coverage of active materials and carbon has paved a new way to enhance the electrochemical performances of high-voltage positive electrode materials for Na-ion batteries. PMID- 29508990 TI - Dynamical Magnetic Response of Iron Oxide Nanoparticles Inside Live Cells. AB - Magnetic nanoparticles exposed to alternating magnetic fields have shown a great potential acting as magnetic hyperthermia mediators for cancer treatment. However, a dramatic and unexplained reduction of the nanoparticle magnetic heating efficiency has been evidenced when nanoparticles are located inside cells or tissues. Recent studies suggest the enhancement of nanoparticle clustering and/or immobilization after interaction with cells as possible causes, although a quantitative description of the influence of biological matrices on the magnetic response of magnetic nanoparticles under AC magnetic fields is still lacking. Here, we studied the effect of cell internalization on the dynamical magnetic response of iron oxide nanoparticles (IONPs). AC magnetometry and magnetic susceptibility measurements of two magnetic core sizes (11 and 21 nm) underscored differences in the dynamical magnetic response following cell uptake with effects more pronounced for larger sizes. Two methodologies have been employed for experimentally determining the magnetic heat losses of magnetic nanoparticles inside live cells without risking their viability as well as the suitability of magnetic nanostructures for in vitro hyperthermia studies. Our experimental results-supported by theoretical calculations-reveal that the enhancement of intracellular IONP clustering mainly drives the cell internalization effects rather than intracellular IONP immobilization. Understanding the effects related to the nanoparticle transit into live cells on their magnetic response will allow the design of nanostructures containing magnetic nanoparticles whose dynamical magnetic response will remain invariable in any biological environments, allowing sustained and predictable in vivo heating efficiency. PMID- 29508991 TI - Mass Spectrometry Imaging Shows Cocaine and Methylphenidate Have Opposite Effects on Major Lipids in Drosophila Brain. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to study the effects of cocaine versus methylphenidate administration on both the localization and abundance of lipids in Drosophila melanogaster brain. A J105 ToF-SIMS with a 40 keV gas cluster primary ion source enabled us to probe molecular ions of biomolecules on the fly with a spatial resolution of ~3 MUm, giving us unique insights into the effect of these drugs on molecular lipids in the nervous system. Significant changes in phospholipid composition were observed in the central brain for both. Principal components image analysis revealed that changes occurred mainly for phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositols. When the lipid changes caused by cocaine were compared with those induced by methylphenidate, it was shown that these drugs exert opposite effects on the brain lipid structure. We speculate that this might relate to the molecular mechanism of cognition and memory. PMID- 29508992 TI - Bactericidal and Hemocompatible Coating via the Mixed-Charged Copolymer. AB - Cationic antibacterial coating based on quaternary ammonium compounds, with an efficient and broad spectrum bactericidal property, has been widely used in various fields. However, the high density of positive charges tends to induce weak hemocompatibility, which hinders the application of the cationic antibacterial coating in blood-contacting devices and implants. It has been reported that a negatively charged surface can reduce blood coagulation, showing improved hemocompatibility. Here, we describe a strategy to combine the cationic and anionic groups by using mixed-charged copolymers. The copolymers of poly (quaternized vinyl pyridine- co- n-butyl methacrylate- co-methacrylate acid) [P(QVP- co- nBMA- co-MAA)] were synthesized through free radical copolymerization. The cationic group of QVP, the anionic group of MAA, and the hydrophobic group of nBMA were designed to provide bactericidal capability, hemocompatibility, and coating stability, respectively. Our findings show that the hydrophilicity of the copolymer coating increased, and its zeta potential decreased from positive charge to negative charge with the increase of the anionic/cationic ratio. Meanwhile, the bactericidal property of the copolymer coating was kept around a similar level compared with the pure quaternary ammonium copolymer coating. Furthermore, the coagulation time, platelet adhesion, and hemolysis tests revealed that the hemocompatibility of the copolymer coating improved with the addition of the anionic group. The mixed-charged copolymer combined both bactericidal property and hemocompatibility and has a promising potential in blood-contacting antibacterial devices and implants. PMID- 29508993 TI - Highly Compressible Carbon Sponge Supercapacitor Electrode with Enhanced Performance by Growing Nickel-Cobalt Sulfide Nanosheets. AB - The development of compressible supercapacitor highly relies on the innovative design of electrode materials with both superior compression property and high capacitive performance. This work reports a highly compressible supercapacitor electrode which is prepared by growing electroactive NiCo2S4 (NCS) nanosheets on the compressible carbon sponge (CS). The strong adhesion of the metallic conductive NCS nanosheets to the highly porous carbon scaffolds enable the CS-NCS composite electrode to exhibit an enhanced conductivity and ideal structural integrity during repeated compression-release cycles. Accordingly, the CS-NCS composite electrode delivers a specific capacitance of 1093 F g-1 at 0.5 A g-1 and remarkable rate performance with 91% capacitance retention in the range of 0.5-20 A g-1. Capacitance performance under the strain of 60% shows that the incorporation of NCS nanosheets in CS scaffolds leads to over five times enhancement in gravimetric capacitance and 17 times enhancement in volumetric capacitance. These performances enable the CS-NCS composite to be one of the promising candidates for potential applications in compressible electrochemical energy storage devices. PMID- 29508994 TI - Low-Voltage Organic Single-Crystal Field-Effect Transistor with Steep Subthreshold Slope. AB - Anodization is a promising technique to form high- k dielectrics for low-power organic field-effect transistor (OFET) applications. However, the surface quality of the dielectric, which is mainly inherited from the metal electrode, can be improved further than other fabrication techniques, such as sol-gel. In this study, we applied the template stripping method to fabricate a low-power single crystalline OFET based on the anodized AlO x dielectric. We found that the template stripping method largely improves the surface roughness of the deposited Al and allows for the formation of a high-quality AlO x high- k dielectric by anodization. The ultraflat AlO x/SAM dielectric combined with a single-crystal 2,6-diphenylanthracene (DPA) semiconductor produced a nearly defect-free interface with a steep subthreshold swing (SS) of 66 mV/decade. The current device is a promising candidate for future ultralow-power applications. Other than metal deposition, template stripping could provide a general approach to improve thin-film quality for many other types of materials and processes. PMID- 29508995 TI - Characterization of a 5-HT3-ELIC Chimera Revealing the Sites of Action of Modulators. AB - Cys-loop receptors are major sites of action for many important therapeutically active compounds, but the sites of action of those that do not act at the orthosteric binding site or at the pore are mostly poorly understood. To help understand these, we here describe a chimeric receptor consisting of the extracellular domain of the 5-HT3A receptor and the transmembrane domain of a prokaryotic homologue, ELIC. Alterations of some residues at the coupling interface are required for function, but the resulting receptor expresses well and responds to 5-HT with a lower EC50 (0.34 MUM) than that of the 5-HT3A receptor. Partial agonists and competitive antagonists of the 5-HT3A receptor activate and inhibit the chimera as expected. Examination of a range of receptor modulators, including ethanol, thymol, 5-hydroxyindole, and 5-chloroindole, which can affect the 5-HT3A receptor and ELIC, suggest that these compounds act via the transmembrane domain, except for 5-hydroxyindole, which can compete with 5-HT at the orthosteric binding site. The data throw further light on the importance of coupling interface in Cys-loop receptors and provide a platform for examining the mechanism of action of compounds that act in the extracellular domain of the 5 HT3A receptor and the transmembrane domain of ELIC. PMID- 29508996 TI - Enhancement of the Power-Conversion Efficiency of Organic Solar Cells via Unveiling an Appropriate Rational Design Strategy in Indacenodithiophene- alt quinoxaline pi-Conjugated Polymers. AB - We report on the photovoltaic parameters, photophysical properties, optoelectronic properties, self-assembly, and morphology variations in a series of high-performance donor-acceptor (D-A) pi-conjugated polymers based on indacenodithiophene and quinoxaline moieties as a function of the number-average molecular weight ([Formula: see text]), the nature of aryl substituents, and the enlargement of the polymer backbone. One of the most important outcome is that from the three optimization approaches followed to tune the chemical structure toward enhanced photovoltaic performance in bulk heterojunction solar cell devices with the fullerene derivative [6,6]-phenyl-C71-butyric acid methyl ester as the electron acceptor, the choice of the aryl substituent is the most efficient rational design strategy. Incorporation of thienyl rings as substituents versus phenyl rings accelerates the electron-hole extraction process to the respective electrode, despite the slightly lower recombination lifetime and, thus, improves the electrical performance of the device. Single-junction solar cells based on ThIDT-TQxT feature a maximum power-conversion efficiency of 7.26%. This study provides significant insights toward understanding of the structure-properties-performance relationship for D-A pi-conjugated polymers in solid state, which provide helpful inputs for the design of next-generation polymeric semiconductors for organic solar cells with enhanced performance. PMID- 29508997 TI - Highly Stretchable and Conductive Superhydrophobic Coating for Flexible Electronics. AB - Superhydrophobic materials integrating stretchability with conductivity have huge potential in the emerging application horizons such as wearable electronic sensors, flexible power storage apparatus, and corrosion-resistant circuits. Herein, a facile spraying method is reported to fabricate a durable superhydrophobic coating with excellent stretchable and electrical performance by combing 1-octadecanethiol-modified silver nanoparticles (M-AgNPs) with polystyrene- b-poly(ethylene- co-butylene)- b-polystyrene (SEBS) on a prestretched natural rubber (NR) substrate. The embedding of M-AgNPs in elastic SEBS matrix and relaxation of prestretched NR substrate construct hierarchical rough architecture and endow the coating with dense charge-transport pathways. The fabricated coating exhibits superhydrophobicity with water contact angle larger than 160 degrees and a high conductivity with resistance of about 10 Omega. The coating not only maintains superhydrophobicity at low/high stretch ratio for the newly generated small/large protuberances but also responds to stretching and bending with good sensitivity, broad sensing range, and stable response cycles. Moreover, the coating exhibits excellent durability to heat and strong acid/alkali and mechanical forces including droplet impact, kneading, torsion, and repetitive stretching-relaxation. The findings conceivably stand out as a new tool to fabricate multifunctional superhydrophobic materials with excellent stretchability and conductivity for flexible electronics under wet or corrosive environments. PMID- 29508998 TI - Pt/TiSi x-NCNT Novel Janus Nanostructure: A New Type of High-Performance Electrocatalyst. AB - Novel Janus nanostructured electrocatalyst (Pt/TiSi x-NCNT) was prepared by first sputtering TiSi x on one side of N-doped carbon nanotubes (NCNTs), followed by wet chemical deposition of Pt nanoparticles (NPs) on the other side. Transmission electron microscopy (TEM) studies showed that the Pt NPs are mainly deposited on the NCNT surface where no TiSi x (i.e., between the gaps of TiSi x film). This feature could benefit the increase in the stability of the Pt NP catalyst. Indeed, compared to the state-of-the-art commercial Pt/C catalyst, this novel Pt/TiSi x-NCNT Janus structure showed ~3 times increase in stability as well as significantly improved CO tolerance. The obvious performance enhancement could be attributed to the better corrosion resistance of TiSi x and NCNTs than the carbon black that is used in the commercial Pt/C catalyst. Pt/TiSi x-NCNT Janus nanostructures open the door for designing new type of high-performance electrocatalyst for fuel cells and other oxygen reduction reaction-related energy devices. PMID- 29508999 TI - Iron Phthalocyanine Decorated Nitrogen-Doped Graphene Biosensing Platform for Real-Time Detection of Nitric Oxide Released from Living Cells. AB - Nitric oxide (NO) is a transcellular messenger involved in many physiological and pathological processes, but the real-time detection of NO in biological systems is still challenging due to its rapid diffusion, low concentration, and short half-life. A novel electrochemical sensing platform based on iron phthalocyanine (FePc) functionalized nitrogen-doped graphene (N-G) nanocomposites was constructed to achieve in situ monitoring of NO released from living cells on the sensing layer. By taking advantage of the synergetic effect of N-G and FePc nanocomposites, the N-G/FePc sensor displays excellent electrocatalytic activity toward NO with a high sensitivity of 0.21 MUA MUM-1 cm-2 and a low detection limit of 180 nmol L-1. The following layer-by-layer assembly of poly-l-lysine (PLL) and Nafion further improved the capacity of resisting disturbance as well as the biocompatibility of the sensing interface. The flexible design of the ITO substrate based electrode provides a more controlled cellular biosensing system which could capture molecular signals immediately after NO released from human umbilical vein endothelial cells (HUVECs). The exhibited additional features of high sensitivity, rapid response, and ease of operation implies that the proposed N-G/FePc/Nafion/PLL ITO biosensor is a promising powerful platform in various complex biological systems. PMID- 29509000 TI - CsMn4As3: A Layered Tetragonal Transition-Metal Pnictide Compound with an Antiferromagnetic Ground State. AB - We report the synthesis and properties of a new layered tetragonal ternary compound CsMn4As3 (structure type, KCu4S3; space group, P4/ mmm, no. 123; and Z = 2). The material is a small band gap semiconductor and exhibits an antiferromagnetic ground state associated with Mn spins. The compound exhibits a signature of a distinct magnetic moment canting event at 150(5) K with a canting angle ~ 0.3 degrees . Although some features of the magnetic characteristics of this new compound are qualitatively similar to those of the related BaMn2As2, the underlying Mn sublattices of the two materials are quite different. While the Mn square-lattice layers in BaMn2As2 are equally spaced along the c-direction with the interlayer distance dL Ba = 6.7341(4) A, the Mn sublattice forms bilayers in CsMn4As3 with the interlayer distance within a bilayer being dL Cs = 3.1661(6) A; the distance between the two adjacent bilayers is dB = 7.290(6) A. This difference in the Mn sublattice is bound to significantly alter the energy balance among the J1, J2, and J c exchange interactions within the J1- J2- J c model compared to those in BaMn2As2 and the other related 122 compounds, including the well-known iron-arsenide superconductor parent compound BaFe2As2. Owing to the novelty of its transition-metal sublattice, this new addition to the family of tetragonal materials related to the iron-based superconductors brings prospects for doping and pressure studies in the search of new superconducting phases as well as other exciting correlated electron properties. PMID- 29509001 TI - Determination of Pesticides by Gas Chromatography Combined with Mass Spectrometry Using Femtosecond Lasers Emitting at 267, 400, and 800 nm as the Ionization Source. AB - A standard sample mixture containing 51 pesticides was separated by gas chromatography (GC), and the constituents were identified by mass spectrometry (MS) using femtosecond lasers emitting at 267, 400, and 800 nm as the ionization source. A two-dimensional display of the GC/MS was successfully used for the determination of these compounds. A molecular ion was observed for 38 of the compounds at 267 nm and for 30 of the compounds at 800 nm, in contrast to 27 among 50 compounds when electron ionization was used. These results suggest that the ultraviolet laser is superior to the near-infrared laser for molecular weight determinations and for a more reliable analysis of these compounds. In order to study the conditions for optimal ionization, the experimental data were examined using the spectral properties (i.e., the excitation and ionization energies and absorption spectra for the neutral and ionized species) obtained by quantum chemical calculations. A few molecules remained unexplained by the currently reported rules, requiring additional rules for developing a full understanding of the femtosecond ionization process. The pesticides in the homogenized matrix obtained from kabosu ( citrus sphaerocarpa) were measured using lasers emitting at 267 and 800 nm. The pesticides were clearly separated and measured on the two dimensional display, especially for the data measured at 267 nm, suggesting that this technique would have potential for use in the practical trace analysis of the pesticides in the environment. PMID- 29509002 TI - Photophysics and Photoredox Catalysis of a Homoleptic Rhenium(I) Tris(diisocyanide) Complex. AB - Herein a homoleptic rhenium(I) complex bearing three chelating diisocyanide ligands and its photophysical properties are communicated. The complex emits weakly from a high-energy triplet metal-to-ligand charge-transfer excited state with an 8 ns lifetime in deaerated CH3CN at 22 degrees C and is shown to act as an efficient photoredox catalyst comparable to [Ir(ppy)3] (ppy = 2 phenylpyridine) in representative test reactions. PMID- 29509004 TI - "Click and Screen" Technology for the Detection of Explosives on Human Hands by a Portable MicroNIR-Chemometrics Platform. AB - Portable near-infrared spectroscopy (MicroNIR) coupled with chemometrics was investigated for the first time as a new tool for the on-site analysis of explosives on human hands. A novel, entirely on-site approach based on the use of a particular miniaturized NIR spectrometer was developed and validated in cooperation with the Scientific Investigation Department (Carabinieri RIS) of Rome. Spectra from 25 volunteers were acquired in the NIR region in reflectance mode, and a prediction model was optimized on the basis of chemometric tools. The results demonstrated the capability of the MicroNIR-Chemometrics approach to correctly identify explosives from hands and not be affected by the complexity and variability of the matrix. This study has shown that the MicroNIR Chemometrics approach can be considered a useful, fast, nondestructive tool identifying the manipulation of explosives in real forensic cases. PMID- 29509003 TI - Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes. AB - A sulfenium-ion-initiated, catalytic, enantioselective polyene cyclization is described. Homogeranylarenes and ortho-geranylphenols undergo polycyclization in good yield, diastereoselectivity, and enantioselectivity. The stereodetermining step is the generation of an enantiomerically enriched thiiranium ion from a terminal alkene and a sulfenylating agent in the presence of a chiral Lewis basic catalyst. The use of hexafluoroisopropyl alcohol as the solvent is crucial to obtain good yields. The thioether moiety resulting from the reaction can be subsequently transformed into diverse oxygen and carbon functionality postcyclization. The utility of this method is demonstrated by the enantioselective syntheses of (+)-ferruginol and (+)-hinokiol. PMID- 29509005 TI - Exploration of Uncharted 3PES Territory for [Ru(bpy)3]2+: A New 3MC Minimum Prone to Ligand Loss Photochemistry. AB - We have identified a new 3MC state bearing two elongated Ru-N bonds to the same ligand in [Ru(bpy)3]2+. This DFT-optimized structure is a local minimum on the 3PES. This distal MC state (3MCcis) is destabilized by less than 2 kcal/mol with respect to the classical MC state (3MCtrans), and energy barriers to populate 3MCcis and 3MCtrans from the 3MLCT state are similar according to nudged elastic band minimum energy path calculations. Distortions in the classical 3MCtrans, that is, elongation of two Ru-N bonds toward two different bpy ligands, are not expected to favor the formation of ligand-loss photoproducts. On the contrary, the new 3MCcis could be particularly relevant in the photodegradation of Ru(II) polypyridine complexes. PMID- 29509006 TI - Quantitative Characterization of the Membrane Dynamics of Newly Delivered TGF beta Receptors by Single-Molecule Imaging. AB - The dynamics and stoichiometry of receptors newly delivered on the plasma membrane play a vital role in cell signal transduction, yet knowledge of this process is limited because of the lack of suitable analytical methods. Here we developed a new strategy that combines single-molecule imaging (SMI) and fluorescence recovery after photobleaching (FRAP), named FRAP-SMI, to monitor and quantify individual newly delivered and inserted transmembrane receptors on plasma membranes of living cells. Transforming-growth-factor-beta type II receptor (TbetaRII), a typical serine/threoninekinase receptor, was studied with this method. We first eliminated the fluorescence signals from the pre-existing EGFP-labeled TbetaRII molecules on the plasma membrane, and then we recorded the individual newly appeared TbetaRII-GFP by total-internal-reflection fluorescence imaging. The fluorescence-intensity distributions, photobleaching steps, and diffusion rates of the single TbetaRII-GFP molecules were analyzed. We reported, for the first time, that TbetaRII was transported to the plasma membrane mainly in the monomeric form in both resting and TGF-beta1stimulated cells. This strongly supported our former discovery that TbetaRII could exist as a monomer on the cell membrane. We also found that ligand stimulation resulted in enhanced delivery rates and prolonged membrane-association times for the TbetaRII molecules. On the basis of these observations, we proposed a mechanism of TGF beta1-induced TbetaRII dimerization for receptor activation. Our method provides a useful tool for the real-time quantification of the spatial arrangement, mobility, and oligomerization of cell-surface proteins in living cells, thus providing a better understanding of cell signaling. PMID- 29509007 TI - Lycopene Supplementation Attenuates Oxidative Stress, Neuroinflammation, and Cognitive Impairment in Aged CD-1 Mice. AB - The carotenoid pigment lycopene (LYC) possesses several properties, including antioxidative, anti-inflammatory, and neuroprotective properties. This study examined the effects of dietary supplementation with LYC on age-induced cognitive impairment, and the potential underlying mechanisms. Behavioral tests revealed that chronic LYC supplementation alleviated age-associated memory loss and cognitive defects. Histological and immunofluorescence-staining results indicated that LYC treatment reversed age-associated neuronal damage and synaptic dysfunctions in the brain. Additionally, LYC supplementation decreased age associated oxidative stress via suppression of malondialdehyde levels, which increased glutathione, catalase, and superoxide dismutase activities and the levels of antioxidant-enzyme mRNAs, including those of heme oxygenase 1 and NAD (P)-H-quinone oxidoreductase-1. Furthermore, LYC supplementation significantly reduced age-associated neuroinflammation by inhibiting microgliosis (Iba-1) and downregulating related inflammatory mediators. Moreover, LYC lowered the accumulation of Abeta1-42 in the brains of aged CD-1 mice. Therefore, LYC has the potential for use in the treatment of several age-associated chronic diseases. PMID- 29509008 TI - [(CH3)2NH2]7Pb4X15 (X = Cl- and Br-), 2D-Perovskite Related Hybrids with Dielectric Transitions and Broadband Photoluminiscent Emission. AB - We have prepared two new lead halides with the novel general formula of DMA7Pb4X15 (DMA = [(CH3)2NH2]+ and X = Cl- or Br-) by using an easy route under mild conditions at room temperature. These compounds exhibit an unprecedented crystal structure, are formed by layers of distorted [PbX6] octahedra, which share corners and faces, and contain intercalated DMA cations. Very interestingly, they display dielectric transitions, which are related to a partial order-disorder process of the DMA cations between 160 and 260 K. Additionally, these new layered hybrids exhibit a broadband photoluminiscent emission, which is related to the structural distortions of the [PbX6] octahedra. These findings not only open up large possibilities for future optoelectronic applications of these materials, but they also offer a novel playground for an easy modulation of electrical and optical properties of hybrid organic-inorganic materials. We anticipate that this novel A7Pb4X15 formula can be adequate to tune the family of the hybrid lead halides using other alkylammonium cations, such as methylammonium, formamidinium, or ethylammonium, to improve their photoelectronic properties. PMID- 29509010 TI - Insight into the Electrochemical Reduction Mechanism of Pt(IV) Anticancer Complexes. AB - We carried out a theoretical study on the mechanism of electrochemical reduction of the prototypical platinum(IV) anticancer complex [Pt(NH3)2(CH3COO)2Cl2] to the corresponding platinum(II) [Pt(NH3)2Cl2] derivative. Energies and geometric structures of the original Pt(IV) complex and all possible Pt(III) and Pt(II) intermediates and transition states involved in the reduction process have been calculated using density functional theory and Moller-Plesset perturbation theory. This study allowed us to formulate a detailed mechanism for the two electron reduction of the [PtIV(NH3)2(CH3COO)2Cl2] complex. The results show that, in agreement with the experimental evidence from cyclic voltammetry, the initial one-electron reduction of the [PtIV(NH3)2(CH3COO)2Cl2] complex occurs through a stepwise mechanism via a metastable hexacoordinated platinum(III) [PtIII(NH3)2(CH3COO)2Cl2]- intermediate and a subsequent acetate ligand detachment with an activation free energy of 5.1 kcal mol-1. On the other hand, the second electron reduction of the resulting pentacoordinated [PtIII(NH3)2(CH3COO)Cl2] species occurs through a barrierless concerted process to the final [PtII(NH3)2Cl2] derivative. PMID- 29509009 TI - Balanced Regulation of Redox Status of Intracellular Thioredoxin Revealed by in Cell NMR. AB - To understand how intracellular proteins respond to oxidative stresses, the redox status of the target protein, as well as the intracellular redox potential ( EGSH), which is defined by the concentrations of reduced and oxidized glutathione, should be observed simultaneously within living cells. In this study, we developed a method that can monitor the redox status of thioredoxin (Trx) and EGSH by direct NMR observation of Trx and glutathione within living cells. Unlike the midpoint potential of Trx measured in vitro (~ -300 mV), the intracellular Trx exhibited the redox transition at EGSH between -250 and -200 mV, the range known to trigger the oxidative stress-mediated signalings. Furthermore, we quantified the contribution of Trx reductase to the redox status of Trx, demonstrating that the redox profile of Trx is determined by the interplay between the elevation of EGSH and the reduction by Trx reductase and other endogenous molecules. PMID- 29509012 TI - Organocatalytic Diversity-Oriented Asymmetric Synthesis of Structurally and Stereochemically Complex Heterocycles. AB - An asymmetric organocatalytic direct arylation approach to construct arylated quaternary stereogenic centers with a catalyst loading of 1 mol % is reported. The formation of the hemiketal moiety in stabilizing the hydroquinone intermediate proves to be important in leading to hydroquinone products instead of oxidation quinone products obtained in previously reported methods. A series of structurally and stereochemically complex heterocyclic frameworks are obtained, including spiro-, dispiro-, fused, and bridged heterocycles. PMID- 29509011 TI - Five-Coordinate Platinum(II) Compounds Containing Sugar Ligands: Synthesis, Characterization, Cytotoxic Activity, and Interaction with Biological Macromolecules. AB - This article describes the synthesis and characterization of novel cationic five coordinate Pt(II) complexes containing nitrogen sugar-based ligands. The cytotoxicity of the complexes was evaluated on different cell lines with the expectation that both the coordinative saturation and the sugar moiety cooperate to enhance their biological activity. In fact, the complexes resulted to be more active than cisplatin but still with little selectivity. They activate the apoptosis pathway. Binding of representative compounds with DNA was studied by ethidium bromide displacement assay and circular dichroism. Binding to model proteins was also investigated; the X-ray structure of the adduct formed in the reaction between a representative compound and the model protein bovine pancreatic ribonuclease was obtained. The structure discloses an unprecedented interaction between a five-coordinate Pt(II) moiety and a His side chain. PMID- 29509013 TI - Silver-Catalyzed Stereoselective Cyclization to Polysubstituted ( Z)-1,2 Dihydrobenzo[ cd]indoles. AB - Silver-catalyzed stereoselective synthesis of polysubstituted ( Z)-1,2 dihydrobenzo[ cd]indoles from 8-ethynylnaphthalen-1-amines is reported. In this protocol, a series of nitrogen-containing heterocyclic compounds were synthesized by silver-catalyzed alpha-addition of an alkyne bond with high selectivity and high yields. The synthesized polysubstituted 1,2-dihydrobenzo[ cd]indoles could be easily converted to benzo[ cd]indol-2(1 H)-ones, and both 1,2-dihydrobenzo[ cd]indoles and benzo[ cd]indol- 2(1 H)-ones are biological and pharmaceutical cores. PMID- 29509014 TI - Palladium-Catalyzed Domino Cyclization/Alkylation of Terminal Alkynes: Synthesis of Alkynyl-Functionalized Azaindoline Derivatives. AB - A novel palladium-catalyzed domino cyclization/alkylation of terminal alkynes was achieved for the synthesis of alkynyl-functionalized 3,3-disubstituted azaindoline derivatives under air atmosphere conditions. Various types of terminal alkynes, including aromatic alkynes, aliphatic alkynes, and ferrocene acetylene, can undergo the process successfully. The protocol provides a range of alkynyl-functionalized azaindoline scaffolds bearing a quarternary carbon center. PMID- 29509015 TI - C-H Amination of Purine Derivatives via Radical Oxidative Coupling. AB - An oxidative coupling reaction between purines and alkyl ethers/benzyl compounds was developed to synthesize a series of N9 alkylated purine derivatives using n Bu4NI as a catalyst and t-BuOOH as an oxidant. This protocol uses commercially available, inexpensive catalysts and oxidants and has a wide range of substrates with a simple operation. PMID- 29509016 TI - Photocatalytic Supramolecular Enantiodifferentiating Dimerization of 2 Anthracenecarboxylic Acid through Triplet-Triplet Annihilation. AB - Visible-light-driven enantiodifferentiating photodimerization of 2 anthracenecarboxylic acid (AC) sensitized by Schiff base Pt(II) complex-grafted gamma-cyclodextrins leads the first triplet-triplet annihilation-based catalytic photochirogenesis. The syn-head-to-tail (HT) photodimer 2 was achieved in up to 31.4% ee at 61.0% conversion in the presence of 0.5% equiv of the photocatalyst. PMID- 29509017 TI - Interfacial Charge Contributions to Chemical Sensing by Electrolyte-Gated Transistors with Floating Gates. AB - The floating gate, electrolyte-gated transistor (FGT) is a chemical sensing device utilizing a floating gate electrode to physically separate and electronically couple the active sensing area with the transistor. The FGT platform has yielded promising results for the detection of DNA and proteins, but questions remain regarding its fundamental operating mechanism. Using carboxylic acid-terminated self-assembled monolayers (SAMs) exposed to solutions of different pH, we create a charged surface and hence characterize the role that interfacial charge concentration plays relative to capacitance changes. The results agree with theoretical predictions from conventional double-layer theory, rationalizing nonlinear responses obtained at high analyte concentrations in previous work using the FGT architecture. Our study elucidates an important effect in the sensing mechanism of FGTs, expanding opportunities for the rational optimization of these devices for chemical and biochemical detection. PMID- 29509018 TI - Mechanism of Iridium-Mediated Selective Arene Cleavage: Insights from Density Functional Theory (DFT) Calculations. AB - The mechanism and regioselectivity of iridium-mediated cleavage of aromatic C-C bonds in a series of monomethylated, dimethylated, and trimethylated benzenes without the activation of weaker C-H and C-C bonds are clarified using density functional theory (DFT) calculations. The calculations explained why the reactivity of the coordinated arene in the observed C-C bond cleavage reaction decreases as the degree of substitution decreases. PMID- 29509019 TI - Studies on the Bridge Dependence of Bis(triarylamine) Diradical Dications: Long Range pi-Conjugation and pi-pi Coupling Systems. AB - Three bis(triarylamine) dications bridged with 2,2'-bithienyl group (12+), biphenyl group (22+) and [2,2]paracyclophane (32+) have been successfully isolated. The electronic structures of 12+ - 32+ show bridge dependence. Magnetic studies and DFT calculations show that dications 12+ - 32+ possess an open-shell singlet ground state with a thermally excited triplet state. Dication 32+ has rather small singlet-triplet energy gap and could basically be regarded as a nearly pure diradical. Diradical dications 12+ - 32+ represent rare examples of diradicaloids with intramolecular long-range pi-conjugation or pi-pi coupling interaction. PMID- 29509020 TI - Post-B3LYP Functionals Do Not Improve the Description of Magnetic Coupling in Cu(II) Dinuclear Complexes. AB - The accuracy of post-B3LYP functionals is analyzed using an open-shell database of Cu(II) dinuclear complexes with well-defined experimental values of the magnetic coupling constants. This database provides a sound open-shell training set to be used to improve the fitting schemes in defining new functionals or when reparametrizing the existing ones. For a large set of representative hybrid exchange-correlation functionals, it is shown that the overall description of moderate-to-strong antiferromagnetic interactions is significantly more accurate than the description of ferromagnetic or weakly antiferromagnetic interactions. In the case of global hybrids, the most reliable ones have 25-40% Fock exchange with SOGGA and PBE0 being the most reliable and M06 the exception. For range corrected hybrids, the long-range corrected CAM-B3LYP and omegaB97XD provide acceptable results, and M11 is comparable but more erratic. It is concluded that the reliability of the calculated values is system- and range-dependent, and this fact introduces a serious warning on the blind use of a single functional to predict magnetic coupling constants. Hence, to extract acceptable magnetostructural correlations, a "standardization" of the method to be used is advised to choose the optimal functional. PMID- 29509021 TI - Ambient Pressure Hard X-ray Photoelectron Spectroscopy for Functional Material Systems as Fuel Cells under Working Conditions. AB - Heterogeneous interfaces play important roles in a variety of functional material systems and technologies, such as catalysis, batteries, and devices. A fundamental understanding of efficient functions at interfaces under realistic conditions is crucial for sophisticated designs of useful material systems and novel devices. X-ray photoelectron spectroscopy is one of the most promising and common methods to investigate such material systems. Although X-ray photoelectron spectroscopy is usually conducted under high vacuum because of the requirement of electron detection with the precise measurement of kinetic energies, extensive efforts have been devoted to the measurements in gaseous environments. Very recently, we have succeeded in measuring X-ray photoelectron spectra under real ambient atmosphere (105 Pa), using synchrotron radiation hard X-rays with the photon energy of 8 keV and the windowless electron spectrometer system. In this Account, the novel useful technique of real ambient pressure hard X-ray photoelectron spectroscopy is reviewed. As examples of (near) ambient pressure hard X-ray photoelectron spectroscopy, hydrogen storage of Pd nanoparticles is at first investigated by recording Pd 3d and valence band spectra under hydrogen atmosphere. The Pd 3d and valence band spectra are found to change rather abruptly depending on the hydrogen pressure, demonstrating a behavior like phase transformation. Subsequently, as a main topic in this Account, we describe investigations of the electronic states of platinum nanoparticles on the cathode electrocatalyst in a polymer electrolyte fuel cell (PEFC) under the voltage operating conditions using the near ambient pressure hard X-ray photoelectron spectroscopic system. The Pt 4f and 3d X-ray photoelectron spectra of the cathode Pt/C catalysts clearly show that the oxidized Pt species is at most divalent and the tetravalent Pt species does not exist on the Pt nanoparticles even at the positive cathode-anode voltage of ~1.4 V. Although the water oxidation reaction may take place at the potential, such a reaction does not lead to a buildup of detectable tetravalent Pt in the PEFC. The voltage-dependent Pt 3d X-ray photoelectron spectra show a clear hysteresis between the voltage increase and decrease processes. The fraction of oxidized Pt species matched the ratio of surface to total Pt atoms in the nanoparticles, which suggests that Pt oxidation occurs as a reaction event at only the first Pt layer of the Pt nanoparticles and the inner Pt atoms do not participate in the reaction practically. The developed technique is a valuable in situ tool for the investigation of the electronic states of PEFCs and other interesting functional material systems and devices under realistic working conditions. PMID- 29509022 TI - Self-Assembly of Janus Nanoparticles into Transformable Suprastructures. AB - One of the greatest challenges in colloidal self-assembly is to obtain multiple distinct but transformable suprastructures from the same particles in monophasic solvent. Here, we combined deformable and rigid lobes in snowman-shaped amphiphilic Janus nanoparticles (JNPs). These JNPs exhibited excellent ability to self-assemble into micelles, worms, mini-capsules, giant- and elongated-vesicles. This rich suprastructural diversity was obtained by kinetic manipulation of the self-assembly conditions. The suprastructures consist of four to thousands of highly oriented JNPs with dimensions ranging from 500-nanometer to 30-MUm. Moreover, the suprastructures can be transformed into one another or dissembled into individual particles. These features make colloidal assembly highly comparable to that of amphiphilic molecules, however, key differences were discovered. PMID- 29509023 TI - Accuracy of three-dimensional dental resin models created by fused deposition modeling, stereolithography, and Polyjet prototype technologies: A comparative study. AB - OBJECTIVES: The aim of this study was to assess the dimensional accuracy of fused deposition modeling (FDM)-, Polyjet-, and stereolithography (SLA)-produced models by comparing them to traditional plaster casts. MATERIALS AND METHODS: A total of 12 maxillary and mandibular posttreatment orthodontic plaster casts were selected from the archives of the Orthodontic Department at the Indiana University School of Dentistry. Plaster models were scanned, saved as stereolithography files, and printed as physical models using three different three-dimensional (3D) printers: Makerbot Replicator (FDM), 3D Systems SLA 6000 (SLA), and Objet Eden500V (Polyjet). A digital caliper was used to obtain measurements on the original plaster models as well as on the printed resin models. RESULTS: Comparison between the 3D printed models and the plaster casts showed no statistically significant differences in most of the parameters. However, FDM was significantly higher on average than were plaster casts in maxillary left mixed plane (MxL-MP) and mandibular intermolar width (Md-IMW). Polyjet was significantly higher on average than were plaster casts in maxillary intercanine width (Mx-ICW), mandibular intercanine width (Md-ICW), and mandibular left mixed plane (MdL-MP). Polyjet was significantly lower on average than were plaster casts in maxillary right vertical plane (MxR-vertical), maxillary left vertical plane (MxL vertical), mandibular right anteroposterior plane (MdR-AP), mandibular right vertical plane (MdR-vertical), and mandibular left vertical plane (MdL-vertical). SLA was significantly higher on average than were plaster casts in MxL-MP, Md ICW, and overbite. SLA was significantly lower on average than were plaster casts in MdR-vertical and MdL-vertical. CONCLUSIONS: Dental models reconstructed by FDM technology had the fewest dimensional measurement differences compared to plaster models. PMID- 29509024 TI - Long-term effects of seven cleaning methods on light transmittance, surface roughness, and flexural modulus of polyurethane retainer material. AB - OBJECTIVES: To evaluate the long-term effects of seven different cleaning methods on light transmittance, surface roughness, and flexural modulus of a polyurethane retainer material. MATERIALS AND METHODS: Polyurethane retainer specimens (Vivera(r), Align Technology Inc) (70 specimens, n = 10 per method, 50.8 mm * 12.7 mm * 1.0 mm) were exposed to seven cleaning methods twice a week for 6 months. Before treatment and after 6 months, light transmittance, surface roughness, and flexural modulus of the specimens were quantified. Qualitative assessment of randomly selected specimens from each solution was performed at baseline and after 6 months using a scanning electron microscope. Statistical analyses were performed at the .05 significance level. RESULTS: Of the three test variables, light transmittance through the specimens was the only one that changed significantly from baseline to 6 months for all cleaning solutions, with all of them causing a decrease. However, except for 0.6% sodium hypochlorite showing a change in surface roughness values and 2.5% vinegar and toothbrushing showing an increase in flexural modulus, none of the other four cleaning methods resulted in significant changes in surface roughness or flexural modulus values for the polyurethane specimens between baseline and after 6 months. CONCLUSIONS: Of the seven cleaning methods, Invisalign(r) cleaning crystals, Polident(r), and Listerine(r) showed the least amount of change in light transmittance values for the polyurethane specimens over 6 months, and they had no effect on surface roughness and flexural modulus values. PMID- 29509025 TI - Galvanic coupling of steel and gold alloy lingual brackets with orthodontic wires: Is corrosion a concern? AB - OBJECTIVES: The aim of this research was to assess galvanic behavior of lingual orthodontic brackets coupled with representative types of orthodontic wires. MATERIALS AND METHODS: Three types of lingual brackets: Incognito (INC), In Ovation L (IOV), and STb (STB) were combined with a stainless steel (SS) and a nickel-titanium (NiTi) orthodontic archwire. All materials were initially investigated by scanning electron microscopy / x-ray energy dispersive spectroscopy (SEM/EDX) while wires were also tested by x-ray diffraction spectroscopy (XRD). All bracket-wire combinations were immersed in acidic 0.1M NaCl 0.1M lactic acid and neutral NaF 0.3% (wt) electrolyte, and the potential differences were continuously recorded for 48 hours. RESULTS: The SEM/EDX analysis revealed that INC is a single-unit bracket made of a high gold (Au) alloy while IOV and STB are two-piece appliances in which the base and wing are made of SS alloys. The SS wire demonstrated austenite and martensite iron phase, while NiTi wire illustrated an intense austenite crystallographic structure with limited martensite. All bracket wire combinations showed potential differences below the threshold of galvanic corrosion (200 mV) except for INC and STB coupled with NiTi wire in NaF media. CONCLUSIONS: The electrochemical results indicate that all brackets tested demonstrated galvanic compatibility with SS wire, but fluoride treatment should be used cautiously with NiTi wires coupled with Au and SS brackets. PMID- 29509026 TI - Pain experience in adults undergoing treatment: A longitudinal evaluation. AB - OBJECTIVES: To quantify the intensity and duration of pain experience in adults over the initial three visits of fixed appliance-based orthodontic treatment. A secondary objective was to assess the relationship between pain experience and analgesic use, dental irregularity, gender, and age. MATERIALS AND METHODS: A prospective longitudinal study design was adopted. Fifty-eight adults undergoing fixed appliance treatment in five orthodontic practices recorded pain experience at four time points (4 hours, 24 hours, 3 days, and 7 days) following the initial bond-up appointment (T0) and first (T1) and second (T2) routine follow-up adjustment appointments using a visual analogue scale. In addition, subjects recorded the dosage and frequency of analgesic use. RESULTS: A slightly greater proportion of women (57%) were recruited, with a mean sample age of 34.69 (SD 12.11) years. Peak pain was experienced between 24 hours and 3 days following appliance placement (T0) and subsequent adjustments (T1 and T2). The highest mean pain score arose at T0 followed by T2 and T1 adjustments, with the difference between pain levels at these appointment intervals being statistically significant ( P < .001). The use of analgesics following each appointment mirrored pain experience, with pain score, appointment, and time point all being significant predictors of analgesic consumption. The level of dental irregularity, gender, or age did not predict pain levels reported. CONCLUSIONS: Adults undergoing fixed orthodontic therapy should be advised that they are most likely to experience increased levels of pain for 1 to 3 days following placement of their appliance and subsequent adjustment visits. PMID- 29509027 TI - Test-retest reliability of smile tasks using three-dimensional facial topography. AB - OBJECTIVES: To evaluate the test-retest reliability of three types of facial expression tasks using three-dimensional (3D) facial topography. MATERIALS AND METHODS: Twelve adult volunteers were enrolled in this study. They were instructed to perform three different facial expression tasks: rest posture, posed smile, and maximum effort smile. Each task was recorded using a 3D image capturing device on two separate occasions with an interval of 1 week between sessions. The images of two sessions were superimposed based on the forehead. For each participant and for each facial expression, a wire mesh fitting was conducted. This method generated 6,017 points on the wire mesh. Intraindividual reliability between sessions for each task was statistically tested by intraclass correlation coefficients (ICCs) and the 95% confidence interval minimal detectable change (MDC95). RESULTS: The MDC95 for the repeated measures of the rest posture, posed smile, and maximum effort smile exhibited means of 0.8, 1.5, and 1.3 mm, respectively, on the z-axis. The ICCs ranged from substantial to almost perfect agreement for repeated measures for the rest posture and maximum effort smile (0.60 < ICC <= 1.00). The right corner of the mouth in the posed smile showed moderate agreement (0.40 < ICC <= 0.60). CONCLUSIONS: The overall test-retest reliability of the maximum effort smile and rest posture showed substantial to almost perfect agreement, and this was clinically acceptable. PMID- 29509028 TI - Developing a comprehensive framework of community integration for people with acquired brain injury: a conceptual analysis. AB - PURPOSE: Despite increasing emphasis on the importance of community integration as an outcome for acquired brain injury (ABI), there is still no consensus on the definition of community integration. The aim of this study was to complete a concept analysis of community integration in people with ABI. MATERIALS AND METHODS: The method of concept clarification was used to guide concept analysis of community integration based on a literature review. Articles were included if they explored community integration in people with ABI. Data extraction was performed by the initial coding of (1) the definition of community integration used in the articles, (2) attributes of community integration recognized in the articles' findings, and (3) the process of community integration. This information was synthesized to develop a model of community integration. RESULTS: Thirty-three articles were identified that met the inclusion criteria. The construct of community integration was found to be a non-linear process reflecting recovery over time, sequential goals, and transitions. Community integration was found to encompass six components including: independence, sense of belonging, adjustment, having a place to live, involved in a meaningful occupational activity, and being socially connected into the community. Antecedents to community integration included individual, injury-related, environmental, and societal factors. CONCLUSION: The findings of this concept analysis suggest that the concept of community integration is more diverse than previously recognized. New measures and rehabilitation plans capturing all attributes of community integration are needed in clinical practice. Implications for rehabilitation Understanding of perceptions and lived experiences of people with acquired brain injury through this analysis provides basis to ensure rehabilitation meets patients' needs. This model highlights the need for clinicians to be aware and assess the role of antecedents as well as the attributes of community integration itself to ensure all aspects are addressed in in a manner that will enhance the recovery and improve the level of integration into the community. The finding that community integration is a non-linear process also highlights the need for rehabilitation professionals to review and revise plans over time in response to a person's changing circumstances and recovery journey. This analysis provides the groundwork for an operational model of community integration for the development of a measure of community integration that assesses all six attributes revealed in this review not recognized in previous frameworks. PMID- 29509029 TI - Aluminum Toxicity: Evaluation of 16-Year Trend Among 14 919 Patients and 45 480 Results. AB - CONTEXT: - Annual monitoring with serum aluminum measurements is recommended for dialysis patients who are susceptible to toxic accumulation from contaminated dialysis fluid or from ingestion of aluminum-containing medications. OBJECTIVE: - To evaluate long-term trends in serum aluminum concentrations and frequency of chronic toxicity. DESIGN: - A retrospective observational study was conducted by analyzing serum aluminum results obtained from the Veterans Affairs corporate data warehouse. Serum aluminum concentrations of 60 MUg/L or greater were considered false positives and not indicative of chronic toxicity if another specimen retested within 45 days had a concentration below 20 MUg/L. RESULTS: - A total of 45 480 serum aluminum results involving 14 919 patients and 119 Veteran Affairs facilities during a 16-year period ending in October 2016 were evaluated. The percentage of elevated (>=20 MUg/L) serum aluminum results declined from 31.5% in 2000 to 2.0% in 2015. Average testing intervals changed from every 159 days in 2000 to every 238 days in 2015. Of 529 patients with serum aluminum concentrations of 60 MUg/L or greater, 216 (40.8%) were retested within 45 days (average = 21 days); of these, 83 (38.4%) had concentrations below 20 MUg/L after repeated measurements. Retesting rates increased with higher initial serum aluminum concentrations. CONCLUSIONS: - Aluminum toxicity, as assessed by serum levels, has substantially declined over time and is now rare. Many serum aluminum concentrations in the toxic range were not confirmed after retesting. Patients with toxic serum aluminum concentrations should be retested with another specimen before undergoing treatment or investigating sources of exposure to verify abnormal results. PMID- 29509030 TI - Reproducibility of Malignant Pleural Mesothelioma Histopathologic Subtyping. AB - CONTEXT: - Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis. Several studies have analyzed potential prognostic markers, but histologic type remains the single most important prognostic factor. Histologic subtypes of epithelioid MPM seem to have prognostic and therapeutic implications. Interobserver agreement in histologic pattern classification should be high. OBJECTIVE: - To assess interobserver and intraobserver reproducibility in histologic differentiation between the main types of MPMs, and in further subtyping of epithelioid-type mesothelioma. DESIGN: - One representative hematoxylin-eosin-stained slide was selected from the archive for each of 200 patients with MPM. They were reviewed independently by 3 pathologists and classified according to the current World Health Organization classification of pleural tumors. After the first round of evaluations, a consensus meeting was organized where problems were addressed and representative images for each histologic category were selected. Two months later, cases were reevaluated by all 3 pathologists. RESULTS: - After the first round, overall interobserver agreement for histologic subtyping of mesothelioma was fair (kappa, 0.36). The agreement was increased to substantial (kappa, 0.63) in the second round. Improvement was found in interobserver agreement for all types of MPM and for most epithelioid subtypes. CONCLUSIONS: - Moderate to substantial agreement in histologic typing and subtyping of MPM can be achieved. However, training with additional clarification of diagnostic criteria, their strict application, and help from consensus-based illustrative images is needed. PMID- 29509031 TI - Microbial diversity associated with the anaerobic sediments of a soda lake (Mono Lake, California, USA). AB - Soda lakes are inhabited by important haloalkaliphilic microbial communities that are well adapted to these extreme characteristics. The surface waters of the haloalkaline Mono Lake (California, USA) are alkaline but, in contrast to its bottom waters, do not present high salinity. We have studied the microbiota present in the shoreline sediments of Mono Lake using next-generation sequencing techniques. The statistical indexes showed that Bacteria had a higher richness, diversity, and evenness than Archaea. Seventeen phyla and 8 "candidate divisions" were identified among the Bacteria, with a predominance of the phyla Firmicutes, Proteobacteria, and Bacteroidetes. Among the Proteobacteria, there was a notable presence of Rhodoplanes and a high diversity of sulfate-reducing Deltaproteobacteria, in accordance with the high sulfate-reducing activity detected in soda lakes. Numerous families of bacterial fermenters were identified among the Firmicutes. The Bacteroides were represented by several environmental groups that have not yet been isolated. Since final organic matter in anaerobic environments with high sulfate contents is mineralized mainly by sulfate-reducing bacteria, very little methanogenic archaeal biodiversity was detected. Only 2 genera, Methanocalculus and Methanosarcina, were retrieved. The species similarities described indicate that a significant number of the operational taxonomic units identified may represent new species. PMID- 29509032 TI - Using a cultural-ecological framework to explore dietary beliefs and practices during pregnancy and lactation among women in Adivasi communities in the Nilgiris Biosphere Reserve, India. AB - This article explores maternal dietary beliefs and practices gathered through interviews with mothers of infants and young children in Adivasi communities in the Nilgiris Biosphere Reserve, India. Guided by focused ethnographic study methods, interviews were conducted with 33 key informants. We used a cultural ecological framework to analyze and interpret the texts that were elicited from women about dietary beliefs and eating patterns during pregnancy and lactation. We identify differences between what women were advised to eat, felt they should eat, and reported consuming. The findings offer guidance for interventions to improve maternal diets in this vulnerable population. PMID- 29509034 TI - Myocardial healing using cardiac fat. AB - INTRODUCTION: Chronic diseases, including myocardial scar healing and heart failure remission, impose huge social and economic burdens, and novel approaches are needed. Several therapeutic modalities are currently being evaluated, including cell therapy, stem cell conditioning, and cardiac tissue engineering. Areas covered: This review discusses the restoration of cardiac function after myocardial infarction using a vascularized flap of autologous cardiac adipose tissue over an akinetic scar. It addresses the risks and benefits of using cardiac adipose progenitors and the adipose graft transposition procedure (AGTP) to ameliorate cardiac dysfunction in preclinical and clinical trials. Expert commentary: The focus is shifting from first-generation studies that used ex vivo expanded and manipulated progenitors to newer second-generation approaches, including AGTP, which are inexpensive and do not raise ethical issues. AGTP safety has been validated, and the ongoing AGTP-2 trial to determine AGTP efficacy and outcome is currently recruiting patients (NCT02798276). This reparative strategy is safe, avoids the risks associated with ex vivo manipulation, and the preclinical and clinical trials performed to date show cardiac function recovery and reduced necrosis. Confirmation of these data in the AGTP-2 trial could pave the way for the clinical use of this novel modality. PMID- 29509035 TI - Parent-child agreement on the Behavior Rating Inventory of Executive Functioning (BRIEF) in a community sample of adolescents. AB - Despite its widespread use, a minimal amount is known regarding the agreement between parent and youth ratings of youth's executive functioning on the Behavior Rating Inventory of Executive Functioning (BRIEF) in typically developing youth. The present study examined parent-child agreement on the BRIEF with a community sample of adolescents and their parents. Ninety-seven parent-child dyads (Mage = 13.91 years; SD = .52) completed the BRIEF self- and parent-report forms and a demographic questionnaire. Intraclass Correlation Coefficients (ICCs) and paired sample t-tests were used to evaluate agreement between self- and parent-reports on the BRIEF. Total sample ICCs indicated moderate to good parent-child agreement (0.46-0.68). Parents from the total sample reported significantly higher mean T scores for their adolescents on Inhibit, Working Memory, Planning/Organization, Behavioral Regulation Index (BRI), Metacognition Index, and Global Executive Composite. Differences were found in regard to gender and race/ethnicity: ICCs were higher between parent-girl dyads on the scales that comprise the BRI than between parent-boy dyads. Parent-adolescent ICCs were also higher for adolescents who self-identified as White in comparison to those who identified as Non White/Mixed Race on Emotional Control. These findings suggest gender and racial/ethnic differences should be considered when examining parent-child agreement on the BRIEF in typically developing adolescents. PMID- 29509036 TI - A Possible Technique for the Complex Reconstruction of Exposed Breast Implant: Applicability and Microcirculation of the Capsule Flap. AB - AIM OF THE STUDY: Immediate breast reconstruction is often applied after mastectomy. However, inappropriate surgical technique, postoperative radiotherapy and infection may lead to tissue necrosis and implant protrusion. Traditional therapies frequently fail. However, previous data suggested that capsule flaps may be appropriate for the salvage of implants. Our goal was to investigate the usefulness of capsuloplasty in patients with exposed breast implant and to monitor the blood supply of capsule flaps during the operation. MATERIALS AND METHODS: Capsuloplasty was performed in 19 patients with exposed implant. After removal of necrotic tissue, capsulotomy was performed, the planned flap was dissected free, the implant was covered with the flap and the wound was then closed. During operation, the blood flow of the flap was determined by means of laser Doppler flowmetry. Moreover, tissue samples were taken for histology and immunostaining for CD34. RESULTS: The postoperative follow-up showed that capsule flaps survived in each case: no complications were found. The blood flow of the flaps did not change significantly during the intervention as compared with the baseline values. The histology and the immunohistochemistry revealed considerable vascularization and angiogenesis in the flap. CONCLUSIONS: Capsule flaps seem to be appropriate for the salvage of exposed implants and for enhancement of implant cover in the case of thin and injured tissue. PMID- 29509037 TI - Psychometric properties of field-based anaerobic capacity tests in children with Developmental Coordination Disorder. AB - BACKGROUND: Assessment of anaerobic capacity in children with Developmental Coordination Disorder (DCD) is essential for treatment planning. However, available field-based measures have no established validity and reliability in this population. PURPOSE: To examine the psychometric properties of selected field-based anaerobic capacity tests in children with and without DCD. METHODS: School-aged children (6-16 years) with and without DCD participated in the study. The children completed the shuttle run sub-item of the Bruninks-Oseretsky test of motor proficiency-second edition, the 10 * 5 m sprint tests (straight and slalom) and the muscle power sprint test (MPST). RESULTS: The shuttle run test item of the Bruninks-Oseretsky test of motor proficiency-second edition and 10 * 5 m sprint tests possess good construct validity and test-retest reliability in children with DCD. The 10 * 5 m sprint test-slalom was found to be the most responsive test among children with DCD. However, the MPST was less reliable in children with DCD compared to their typically developing peers, leading to a very large Smallest Detectable Difference. CONCLUSIONS: The findings suggest that the selected anaerobic capacity measures have sound psychometric properties among children with DCD with the exception of the MPST. Clinicians working on children with DCD could use these tests in their practice, especially in situations where logistical resources are limited. Implications for Rehabilitation Field-based anaerobic capacity tests are suitable measures for assessing anaerobic capacity in children with Developmental Coordination Disorder, particularly in situations where laboratory assessments are not feasible. The shuttle run test item of the Bruninks-Oseretsky test of motor proficiency-second edition and the 10 * 5 sprint tests (straight and slalom) have good construct validity in this population. The 10 * 5 sprint test (slalom) is the most sensitive anaerobic capacity test among children with Developmental Coordination Disorder. PMID- 29509038 TI - Understanding Clerkship Student Roles in the Context of 21st-Century Healthcare Systems and Curricular Reform. AB - : Phenomenon: Preclerkship medical education has undergone extensive reform, and the clerkship years are growing targets for curricular innovation. As institutions implement new preclerkship curricula to better prepare medical students to practice medicine in the context of modern healthcare systems, the perspective of clerkship leaders regarding clerkship student roles and potential for change will facilitate redefining these roles so that preclerkship educational innovations can continue into clerkships. APPROACH: In this qualitative exploratory study, authors conducted semistructured interviews with clerkship and site directors for eight core clerkships from April to May 2016. Questions addressed how clerkship leaders perceive current student roles and the potential for change. Through iterative consensus building, authors identified themes describing current ideal clerkship student roles applicable to future roles. FINDINGS: Twenty-three of 24 (96%) directors participated. Findings fell into four themes: factors influencing the clerkship role, clerkship student role archetypes, workplace authenticity and value, and potential for change. Student, supervisor, and context factors determine the clerkship student role. Three role archetypes emerged: the apprentice (an assistant completing concrete patient care tasks), the academic (a researcher bringing literature back to the team), and the communicator (an interdisciplinary and patient liaison). Each archetype was considered authentic and valuable. Positive attitudes toward preclerkship curricular changes were associated with openness to evolution of the clerkship students' role. These emerging roles mapped to the archetypes. Insights: Clerkship leaders perceive that student, supervisor, and context factors result in varying emphasis on role archetypes, which in turn lead to different types of learning. Medical educators can use the archetypes to articulate how expanded student roles align learning with clinical needs, particularly as they relate to health systems science and inquiry. PMID- 29509041 TI - An update on the pathogenesis of hidradenitis suppurativa: implications for therapy. AB - INTRODUCTION: Hidradenitis suppurativa is a chronic, inflammatory disease characterized by painful nodules, abscesses, and sinuses in the intertriginous areas, with significant associated comorbidities. The pathogenesis remains unclear, although advances have been made in understanding the disease process. Management of the disease is challenging, with a wide range of treatment options available with variable clinical response. Areas covered: This review discusses the most updated studies on the complex pathogenic mechanisms of hidradenitis suppurativa and the relevant literature on the current treatment options for this condition. Expert commentary: There is increasing evidence supporting the role of Th17 cells and enhanced expression of IL-17 and IL-1beta, which represent potential targets for therapy. Bacteria and biofilms are likely contributory but secondary drivers of inflammation. There is also evolving evidence to suggest the presence of systemic comorbidities associated with HS, which underlie the importance of better understanding the pathogenesis and treatment of this disease. PMID- 29509042 TI - Lactated Ringer' Solution may be Superior to Saline-Based 6% Hydroxyethyl Starch 130/0.4 for Early Resuscitation within 12 hours from Hemorrhagic Shock. AB - PURPOSE: To compare the effects of fluid resuscitation with lactated Ringer's solution (LR) and saline-based 6% hydroxyethyl starch 130/0.4 (HES) on the inflammatory response and oxidative stress in the small intestine as well as on bacterial translocation to the liver. METHODS: Sprague-Dawley rats were subjected to blood pressure-controlled hemorrhagic shock and then resuscitated with LR or HES. At 1, 3, 6, 12, and 24 hr after resuscitation, liver tissues were collected to count the bacterial colonies, and small intestines were harvested to analyze the levels of inflammatory (TNF-alpha and HO-1) and oxidative stress (MPO) mediators as well as the intestinal injury by immunohistochemistry, colorimetry and hematoxylin & eosin staining, respectively. RESULTS: The expression level of TNF-alpha in the LR group was stable from 1 to 6 hr but decreased at 12 hr and then abruptly increased at 24 hr. The expression level of TNF-alpha in the LR group was significantly lower than that in the HES group, especially during the first 12 hr post-fluid infusion. MPO activity decreased to its lowest level at 3 hr but increased from 6 to 12 hr, with no difference at 24 hr between the two groups. Although a decreasing tendency was observed from 6 hr, HO-1 expression levels remained higher in the LR group than in the HES group at 12 and 24 hr, particularly at 12 hr. During the initial 12 hr, the LR group exhibited significantly lower colony-forming units in the liver tissues than the HES group. Chiu's score in the intestine decreased regardless of which resuscitative fluids were used. CONCLUSIONS: During early resuscitation (within 12 hr), LR may be superior to HES in reducing intestinal injuries by suppressing inflammatory and oxidative mediators. PMID- 29509043 TI - Locoregional hyperthermia of deep-seated tumours applied with capacitive and radiative systems: a simulation study. AB - BACKGROUND: Locoregional hyperthermia is applied to deep-seated tumours in the pelvic region. Two very different heating techniques are often applied: capacitive and radiative heating. In this paper, numerical simulations are applied to compare the performance of both techniques in heating of deep-seated tumours. METHODS: Phantom simulations were performed for small (30 * 20 * 50 cm3) and large (45 * 30 * 50 cm3), homogeneous fatless and inhomogeneous fat-muscle, tissue-equivalent phantoms with a central or eccentric target region. Radiative heating was simulated with the 70 MHz AMC-4 system and capacitive heating was simulated at 13.56 MHz. Simulations were performed for small fatless, small (i.e. fat layer typically <2 cm) and large (i.e. fat layer typically >3 cm) patients with cervix, prostate, bladder and rectum cancer. Temperature distributions were simulated using constant hyperthermic-level perfusion values with tissue constraints of 44 degrees C and compared for both heating techniques. RESULTS: For the small homogeneous phantom, similar target heating was predicted with radiative and capacitive heating. For the large homogeneous phantom, most effective target heating was predicted with capacitive heating. For inhomogeneous phantoms, hot spots in the fat layer limit adequate capacitive heating, and simulated target temperatures with radiative heating were 2-4 degrees C higher. Patient simulations predicted therapeutic target temperatures with capacitive heating for fatless patients, but radiative heating was more robust for all tumour sites and patient sizes, yielding target temperatures 1-3 degrees C higher than those predicted for capacitive heating. CONCLUSION: Generally, radiative locoregional heating yields more favourable simulated temperature distributions for deep-seated pelvic tumours, compared with capacitive heating. Therapeutic temperatures are predicted for capacitive heating in patients with (almost) no fat. PMID- 29509044 TI - Representing and organizing information to describe the lived experience of health from a personal factors perspective in the light of the International Classification of Functioning, Disability and Health (ICF): a discussion paper. AB - PURPOSE: To discuss the representation and organization of information describing persons' lived experience of health from a personal factors perspective in the light of the International Classification of Functioning, Disability and Health, using spinal cord injury as a case in point for disability. METHODS: The scientific literature was reviewed, discussion rounds conducted, and qualitative secondary analyses of data carried out using an iterative inductive-deductive approach. RESULTS: Conceptual considerations are explicated that distinguish the personal factors perspective from other components of the International Classification of Functioning, Disability and Health. A representation structure is developed that organizes health-related concepts describing the internal context of functioning. Concepts are organized as individual facts, subjective experiences, and recurrent patterns of experience and behavior specifying 7 areas and 211 concept groups. CONCLUSIONS: The article calls for further scientific debate on the perspective of personal factors in the light of the International Classification of Functioning, Disability and Health. A structure that organizes concepts in relation to a personal factors perspective can enhance the comprehensiveness, transparency and standardization of health information, and contribute to the empowerment of persons with disabilities. Implications for rehabilitation The present study collected data from scientific literature reviews, discussion rounds and qualitative secondary analyses in order to develop a representation and organization of information describing persons' lived experience of health from a personal factors perspective in the light of the International Classification of Functioning, Disability and Health. The following representation structure for health-related information from a personal factors perspective was developed: (i) Individuals facts (i.e., socio-demographical factors, position in the immediate social and physical context, personal history and biography), (ii) subjective experience (i.e., feelings, thoughts and beliefs, motives), and (iii) recurrent patterns of experience (i.e., feelings, thoughts and beliefs) and behavior. With this study, we aim to stimulate further scientific discussion about the personal factors component in the International Classification of Functioning, Disability and Health, including its application and subsequent validation for potential implementation into clinical practice. PMID- 29509045 TI - Abdominopelvic injuries due to road traffic accidents: Characteristics in a registry of 162,695 victims. AB - OBJECTIVE: Road traffic accidents (RTAs) are the first cause of abdominopelvic injuries (APIs). The objective of this study was to describe the characteristics and severity of APIs due to traffic accidents in a large French trauma registry and to identify risk factors for API. METHODS: All victims from the French Rhone registry of victims of RTAs were analyzed from 1996 to 2013. This registry contained data that were issued over a 20-year period from 245 medical departments, from prehospital care until re-adaptation, and forensic medicine departments. All APIs, defined as an injury between the diaphragm and the pelvic bone, were extracted and studied. RESULTS: Among 162,695 victims, 10,165 had an API (6.7%). Accidents frequently involved young men and 2 cars. Mean Injury Severity Score (ISS) was 8.7. Mortality rate was 5.6%. Soft tissue injuries largely predominated (n = 6,388; 54.4% of patients). Overall, 2,322 victims had a pelvic bone injury. Internal abdominal organs were involved in 2,425 patients; the most frequent were the spleen, liver, and kidney. Wearing of the seat belt appeared to be a significant protective factor in API, including serious injuries. A partial analysis over the past 2 years among the most severe patients hospitalized in the intensive care unit indicated that nonoperative management was carried out in two thirds of the wounded. In uni- or multivariate analysis, sex, age, type of user, antagonist, time of occurrence, associated severe lesions, or wearing of the seat belt were statistically associated with the occurrence of API, highlighting a more dangerous user profile. CONCLUSIONS: Abdominopelvic injuries concern a minority of road traffic injuries, but they are responsible for significant mortality. Large solid organs are the most frequently affected. Women drivers wearing a seat belt and driving in town during the day appear to be more protected against API. PMID- 29509046 TI - A 3-Year Study of Predictive Factors for Positive and Negative Appendicectomies. AB - BACKGROUND: Early and accurate identification or exclusion of acute appendicitis is the key to avoid the morbidity of delayed treatment for true appendicitis or unnecessary appendicectomy, respectively. We aim (i) to identify potential predictive factors for positive and negative appendicectomies; and (ii) to analyse the use of ultrasound scans (US) and computed tomography (CT) scans for acute appendicitis. MATERIALS AND METHODS: All appendicectomies that took place at our hospital from the 1st of January 2013 to the 31st of December 2015 were retrospectively recorded. Test results of potential predictive factors of acute appendicitis were recorded. Statistical analysis was performed using Fisher exact test, logistic regression analysis, sensitivity, specificity, and positive and negative predictive values calculation. RESULTS: 208 patients were included in this study. 184 patients had histologically proven acute appendicitis. The other 24 patients had either nonappendicitis pathology or normal appendix. Logistic regression analysis showed statistically significant associations between appendicitis and white cell count, neutrophil count, C-reactive protein, and bilirubin. Neutrophil count was the test with the highest sensitivity and negative predictive values, whereas bilirubin was the test with the highest specificity and positive predictive values (PPV). US and CT scans had high sensitivity and PPV for diagnosing appendicitis. CONCLUSIONS: No single test was sufficient to diagnose or exclude acute appendicitis by itself. Combining tests with high sensitivity (abnormal neutrophil count, and US and CT scans) and high specificity (raised bilirubin) may predict acute appendicitis more accurately. PMID- 29509048 TI - zHSF1 modulates zper2 expression in zebrafish embryos. AB - HSF1 is a transcription factor that plays a key role in circadian resetting by temperature. We have used zebrafish embryos to decipher the roles of zHsf1, heat and light on zper2 transcription in vivo. Our results show that heat shock (HS) stimulated zper2 expression in the dark but has no cumulative effect combined with light. After light exposition, zper2 expression was 2.7 fold increased threefold in the hsf1-morphants in comparison to control embryos. Our results show that zHsf1 plays a positive role in HS-driven expression of zper2 in the dark but seems to act as an attenuator in the presence light. PMID- 29509047 TI - Adipocyte CD1d determines adipose inflammation and insulin resistance in obesity. AB - Obesity-induced adipose tissue inflammation is regulated by various immune cells for innate and adaptive immunity. Among adipose tissue immune cells, it has been proposed that invariant Natural Killer T (iNKT) cells play crucial roles in anti inflammatory responses in obesity. iNKT cells recognize 'lipid' antigens loaded on CD1d of antigen presenting cells and modulate immune responses by secreting Th1 or Th2 type cytokines depending on species of lipid antigens, antigen presenting cell types, and environmental cytokine milieu. However, the regulatory mechanisms of antigen presenting cells for adipose iNKT cell stimulation have not been clearly elucidated. Recently, we have reported that CD1d expressing adipocytes could act as an antigen presenting cell for adipose iNKT cells by characterization of adipocyte-specific CD1d knockout (CD1dADKO) mice. Upon high fat diet (HFD) feeding, CD1dADKO mice aggravated adipose tissue inflammation and insulin resistance compared with CD1df/f mice. In this commentary, we provide the additional data of adipocyte CD1d-dependent regulation of adipose iNKT cell responses as well as systemic insulin sensitivity. In addition, we discuss how the interaction between adipocytes and iNKT cells would be regulated with the progression of obesity. PMID- 29509049 TI - Atorvastatin might resist tobacco smoking-induced endothelial inflammation through the inhibition of NF-kappaB signal pathway. AB - Endothelial inflammation caused by tobacco smoking is widely considered as a pathogenic factor in many vascular diseases. Drugs such as atorvastatin were found to be an effective treatment in smoking-dependent vascular diseases, but the underlying mechanism is still unclear. Here, we investigated the mechanism of atorvastatin resisting endothelial inflammation caused by tobacco smoking. Firstly, isolated human umbilical vein endothelial cells (HUVECs) were divided into normal control group, cigarette smoking extract (CSE) group, and atorvastatin (AS)+CSE group. Then the expressions of inflammatory factors (vascular cell adhesion molecule-1 (VCAM-1) and E-selectin) and nuclear transcription factor kappa (NF-kappaB) in HUVECs were detected by western blot after separate treatments. The results showed that the expressions of VCAM-1, E selectin, and NF-kappaB in CSE group were significantly higher than the other two groups (P< 0.05). We also found that the expressions of VCAM-1, E-selectin, and NF-kappaB in CSE + atorvastatin group were a little higher than the normal control group (P< 0.05). Our results showed that atorvastatin might partly resist tobacco smoking-induced endothelial inflammation through the inhibition of NF kappaB signal pathway. PMID- 29509050 TI - A low-speed centrifugation concept leads to cell accumulation and vascularization of solid platelet-rich fibrin: an experimental study in vivo. AB - Platelet-rich fibrin (PRF) is generated from the patients' own venous blood by a single centrifugation step without the additional use of anticoagulants. Based on the previously described LSCC (low-speed centrifugation concept), our group showed that modification of the centrifugation setting, that is, reducing the relative centrifugal force (RCF) and mildly increasing the centrifugation time, resulted in modified solid and liquid PRF-matrices with increased number of platelets, leukocytes, and growth factors' concentrations. The aim of this study was to determine whether RCF reduction might also result in different tissue reactions toward the two PRF-based matrices, especially vascularization and cell distribution in vivo. Two centrifugation protocols (PRF-high [719 g] and PRF medium [222 g]) were compared in a subcutaneous implantation model of SCID mice at 5 and 10 days. Histological and histomorphometrical analyses were performed to quantify lymphocyte, neutrophil, human macrophage, and monocyte populations. CD31 was used to detect newly formed vessels, while all human cells were detected by using human vimentin as a pan-cellular marker. The results demonstrated that PRF high elicited a dense and stable fibrin structure and prevented cellular penetration of the host tissue. By contrast, PRF-medium was more porous, had a significantly higher in vivo vascularization rate, and included significantly more human cells, especially at day 10, compared to PRF-high. These findings highlight the possibility of modifying the structure and composition of PRF matrices and thus selectively altering their regenerative potential in vivo. Clinical studies now must evaluate the different PRF matrices for bone and soft tissue regeneration to validate possible benefits using personalized preparation protocols. PMID- 29509051 TI - Bright Light Therapy to Treat Depression in Individuals with Mild/Moderate or Severe Dementia. AB - This secondary analysis examined whether the benefits of bright light therapy on depression are greater in persons with mild/moderate or severe dementia. Exploratory analyses were also conducted to determine if bright light treatment targets different depressive symptom clusters based on dementia severity. Analyses using total scores from the instruments, Depressive Symptom Assessment for Older Adults and the Cornell Scale for Depression in Dementia, showed that bright light exposure is an equally effective intervention for depression in persons with both mild/moderate and severe dementia. Analyses of individual depressive subscales revealed that for disagreeable behavior and sleep impairment, bright light therapy appears to have greater benefits in persons with severe dementia than for those with mild/moderate dementia. Overall, this investigation supports the use of bright light therapy to treat depression regardless of dementia severity. PMID- 29509052 TI - Comparison of Central Corneal Thickness with Ultrasound Pachymetry, Noncontact Specular Microscopy and Spectral Domain Optical Coherence Tomography. AB - BACKGROUND: To determine the agreement of central corneal thickness (CCT) measurements taken with ultrasonic pachymetry (USP), spectral domain optical coherence tomography (SD-OCT) and noncontact specular microscopy (NSM). METHODS: A prospective, observational, cross-sectional study was performed in the outpatient ophthalmology clinic. CCT was measured in a total of 147 eyes of 147 consecutive healthy patients with USP, NSM, and SD-OCT. Same examiner performed all examinations. Bland-Altman plots were used to evaluate the agreement between instruments. RESULTS: The average CCT values obtained by USP, NSM, and SD-OCT were 555 +/- 37 um, 554 +/- 34 um, and 546 +/- 34 um, respectively. There was a strong correlation between instruments: USP with SD-OCT (r = 0.937, p < 0.01), USP with NSM (r = 0.943, p < 0.01) SD-OCT with NSM (r = 0.975, p < 0.01) for CCT. The mean differences (lower/upper limit of agreement) for CCT measurements were 10 +/- 12.9 um (15.28/-35.28) between SD-OCT and USP, -8.1 +/- 7.7 um (7/-23.2) between SD-OCT and NSM, and 1.8 +/- 12.3 um (25.9/-22.3) between USP and NSM. CONCLUSIONS: USP and NSM were found to have comparable CCT measurements and these two methods can be used correspondingly. However, CCT measurements by SD-OCT were lower when compared to other methods. PMID- 29509053 TI - Equine-Assisted Therapeutic Interventions Among Individuals Diagnosed with Schizophrenia. A Systematic Review. AB - Persons diagnosed with schizophrenia are not sufficiently offered health promotion interventions, notwithstanding their increased risk of bodily ill health. Physical activity is found to improve health and decrease psychiatric symptoms although, there is a challenge to motivate and increase physical activity in people with schizophrenia and innovative evidence-based treatment interventions are needed. The aim was to systematically review studies concerning equine assisted interventions among individuals diagnosed with schizophrenia. The findings of the six included articles indicate that therapeutic equine assisted interventions could be beneficial for individuals with severe mental illness such as schizophrenia or schizophrenia like disorders. PMID- 29509054 TI - Electronic patient agenda forms: comparing agreement between the reason for specialty consultation reported by referring providers and patients. AB - OBJECTIVE: Little is known about the agreement between referring providers' reason for specialty evaluation and patients' understanding of why they are referred for consultation. Here, we compared the reason for consult (RFC) documented by referring providers during usual care vs. the perceived RFC independently reported by patients through an e-portal just prior to the specialist visit. METHODS: We performed an observational study among patients referred for gastrointestinal (GI) evaluation. Patients referred to the specialty clinic submitted their self-reported RFC using an online patient agenda form prior to their visit. Therefore, each participant had a referring provider- and patient-documented RFC. Blinded physicians reviewed the RFCs in random order using a priori coding criteria. We then compared whether the provider and patient RFC pairs were concordant (i.e., >=1 clinical topic[s] in the RFCs matched). RESULTS: Sixty patients completed the e-portal prior to their visit, leading to 60 provider-patient RFC pairs. The RFC pairs were concordant in only 52% of cases. CONCLUSIONS: There is poor agreement between referring providers' reason for GI referral and patients' understanding of why they are visiting the clinic. Future research examining whether electronic patient agenda forms impact diagnostic and management precision, patient satisfaction, and healthcare utilization is warranted. PMID- 29509055 TI - MiR-422a weakened breast cancer stem cells properties by targeting PLP2. AB - OBJECTIVE: This study investigated miR-422a and PLP2 expressions in breast cancer cells and breast cancer stem cells (BCSCs). Besides, their influences on polymorphism changes were observed. METHODS: Flow cytometry and fluorescence activated cell sorting was performed and CD24-/CD44+ cells were sorted from breast cancer cells and recognized as BCSCs. Microarray was applied to search for the differentially expressed miRNAs and mRNAs between MCF7 and BCSCs. The aberrant expression of miR-422a and PLP2 was further confirmed by RT-qPCR and the direct targeted relationship was verified by dual-luciferase reporter assay. After in vitro transfection, the expression of miR-422a and PLP2 were manipulated and biological functions of BMSCs were compared with CCK-8, colony formation and sphere formation assay. The tumorigenesis ability of transfected BMSCs was also investigated in NOD/SCID tumor mice models. RESULTS: BMSCs were successfully established from MCF7 cells and miR-422a expression was downregulated while PLP2 level decreased in BMSCs. MiR-422a directly targets the 3'UTR of PLP2 and suppressed its expression. Besides, the up-regulation of miR-422a contributed to weakened ability of proliferation and microsphere formation of BMSCs, while PLP2 overexpression facilitated those biological abilities. Tumorigenesis of BMSCs in mice models was impaired by either overexpression of miR-442a or silencing of PLP2. CONCLUSION: Up-regulation of miR-422a attenuated microsphere formation, proliferation and tumor formation of breast cancer stem cells via suppressing the PLP2 expression. PMID- 29509057 TI - Gut microbiota in toxicological risk assessment of drugs and chemicals: The need of hour. AB - The advent of industrial revolution caused a large inflow of synthetic chemicals for medical, agricultural, industrial and other purposes in the world. In general, these chemicals were subjected to toxicological risk assessment for human health and ecology before release for public use. But today we are witnessing a negative impact of some of these chemicals on human health and environment indicating an underestimation of toxic effects by current risk assessment protocol. Recent studies established gut microbiota as one of the key player in intercession of toxicity of drugs and synthetic chemicals. Hence, the need of the hour is to include the assessment for microbiota specifically gut microbiota in human toxicological risk assessment protocol. Herewith we are proposing a framework for assessment of gut microbiota upon exposure to drugs or chemicals. PMID- 29509056 TI - Revisiting the Crabtree/Warburg effect in a dynamic perspective: a fitness advantage against sugar-induced cell death. AB - The mechanisms behind the Warburg effect in mammalian cells, as well as for the similar Crabtree effect in the yeast Saccharomyces cerevisiae, are still a matter of debate: why do cells shift from the energy-efficient respiration to the energy inefficient fermentation at high sugar concentration? This review reports on the strong similarities of these phenomena in both cell types, discusses the current ideas, and provides a novel interpretation of their common functional mechanism in a dynamic perspective. This is achieved by analysing another phenomenon, the sugar-induced-cell-death (SICD) occurring in yeast at high sugar concentration, to highlight the link between ATP depletion and cell death. The integration between SICD and the dynamic functioning of the glycolytic process, suggests that the Crabtree/Warburg effect may be interpreted as the avoidance of ATP depletion in those conditions where glucose uptake is higher than the downstream processing capability of the second phase of glycolysis. It follows that the down-regulation of respiration is strategic for cell survival allowing the allocation of more resources to the fermentation pathway, thus maintaining the cell energetic homeostasis. PMID- 29509058 TI - Gene Expression Analysis in Human Peripheral Blood Cells after 900 MHz RF-EMF Short-Term Exposure. AB - Radiofrequency electromagnetic fields (RF-EMF) are a basic requirement of modern wireless communication technology. Statutory thresholds of RF-EMF are established to limit relevant additional heat supply in human tissue. Nevertheless, to date, questions concerning nonthermal biological effects have yet to be fully addressed. New versions of microarrays (8 * 60K v2) provide a higher resolution of whole genome gene expression to display adaptive processes in cells after irradiation. In this ex vivo/ in vitro study, we irradiated peripheral blood cells from five donors with a continuous wave of 900 MHz RF-EMF for 0, 30, 60 and 90 min. Gene expression changes ( P <= 0.05 and >=twofold differences above or below the room temperature control exposed samples) were evaluated with microarray analysis. The results were compared with data from room temperature + 2 degrees C samples. Verification of microarray results was performed using bioinformatic analyses and qRT-PCR. We registered a lack of an EMF-specific gene expression response after applying the false discovery rate adjustment (FDR), using a high-stringency approach. Low-stringency analysis revealed 483 statistically significant deregulated transcripts in all RF-EMF groups relative to the room temperature exposed samples without an association with their corresponding room temperature + 2 degrees C controls. Nevertheless, these transcripts must be regarded as statistical artefacts due to the absence of a targeted biological response, including enrichment and network analyses administered to microarray expressed gene subset profiles. Correspondingly, 14 most promising candidate transcripts examined by qRT-PCR displayed an absence of correlation with respect to the microarray results. In conclusion, these findings indicate that 900 MHz EMF exposure establishing an average specific absorption rate of 9.3 W/kg to whole blood cells is insufficient to induce nonthermal effects in gene expression during short-time exposure up to 90 min. PMID- 29509059 TI - MiR-122-5p inhibits cell migration and invasion in gastric cancer by down regulating DUSP4. AB - OBJECTIVE: To explore the relationship between miR-122-5p and DUSP4 and their effects on gastric cancer (GC) cell mobility and invasiveness. METHODS: Abnormally expressed miRNAs and mRNAs were analyzed using microarrays. The miR 122-5p and DUSP4 mRNA expression levels in GC tissues and cells were determined by RT-qPCR. The target relationship between miR-122-5p and DUSP4 was validated by dual luciferase reporter assay. GC cell mobility and invasiveness were respectively observed by wound healing assay and transwell invasion assay. Western blot and immunohistochemistry were used for detection of the expressions of DUSP4 protein and MMP2 and MMP9 proteins related to cell invasion and migration. The migration and invasion abilities of gastric cancer cells in vivo were evaluated according to the number of lung metastatic nodules in mice. RESULTS: The expression of miR-122-5p in GC tissues and cells was significantly down-regulated, whereas DUSP4 expression was up-regulated. Bioinformatics prediction strategies and dual luciferase reporter assay verified the binding sites of miR-122-5p on 3'UTR of DUSP4 and the target relationship between miR-122 5p and DUSP4. Overexpression of miR-122-5p and knockdown of DUSP4 in BGC-823 cells observantly suppressed GC cell mobility and invasiveness, whereas downregulation of miR-122-5p expression promoted cell metastasis. MiR-122-5p inhibited GC cell mobility and invasiveness and pulmonary tumor metastasis via downregulation of DUSP4. CONCLUSION: MiR-122-5p restrained migration and invasion abilities of GC cells by repressing DUSP4. PMID- 29509060 TI - Cream of the Crop: Clinical Representativeness of Eligible and Ineligible Cannabis Users in Research. AB - BACKGROUND: Experts have recommended criteria (Gonzalez et al., 2002) for recruiting pure chronic cannabis users (i.e., those without polysubstance use or psychiatric illness) when evaluating cannabis' non-acute effects on cognition. OBJECTIVES: We sought to demonstrate the implications of using such criteria by examining characteristics of respondents who completed an eligibility screening for a parent study evaluating the cognitive effects of chronic cannabis use. METHODS: Over a 3-year, 8-month period, 612 respondents from the community completed an eligibility screening based on recommendations in the cannabis literature. Using independent samples t-tests and chi-square tests, we examined whether qualified/eligible respondents (n = 219) differed from non qualified/ineligible respondents (n = 393). RESULTS: Compared to ineligible cannabis users, eligible cannabis-using respondents were significantly younger, used cannabis more frequently, used alcohol less frequently, and were less likely to have a history of other drug use, a psychiatric diagnosis, or to have used psychiatric medication. Conclusions/Importance: Our findings indicate that eligible/pure cannabis users are not representative of typical cannabis users in the general community (i.e., ineligible users with polysubstance use and/or psychiatric diagnoses) who ultimately comprised the majority of our cannabis using sample (65.2%). Thus, typical cannabis users may be more accurately characterized as polysubstance users, posing a number of challenges related to the generalizability of findings from studies utilizing pure samples of cannabis users. Recruiting samples of typical cannabis users will improve external validity in research. Furthermore, reporting comprehensive characteristics of such samples will enable consumers to gauge the applicability of study findings to populations of interest. PMID- 29509061 TI - The Observed Longitudinal Relationship between Future Orientation and Substance Use Among a Cohort of Youth with Serious Criminal Offenses. AB - BACKGROUND: Future orientation (FO), an essential construct in youth development, encompassing goals, expectations for life, and ability to plan for the future. This study uses a multidimensional measure of future orientation to assess the relationship between change in future orientation and change in substance use over time. METHODS: Data were from the Pathways to Desistence study. Justice involved youth (n = 1,354), ages 14 to 18 at time of recruitment, completed interviews every six months for three years. Multiple measures were chosen a priori as elements of future orientation. After evaluating the psychometrics of a new measure for future orientation, we ran mixed effects cross-lagged panel models to assess the relationship between changes in future orientation and substance use (tobacco, marijuana, hard drugs, and alcohol). RESULTS: There was a significant bidirectional relationship between future orientation and all substance use outcomes. Adjusted models accounted for different sites, sex, age, ethnicity, parental education, and proportion of time spent in a facility. In adjusted models, higher levels of future orientation resulted in smaller increases in substance use at future time points. CONCLUSIONS: Future orientation and substance use influence each other in this sample of adolescent offenders. Treating substance use disorders is also likely to increase future orientation, promoting positive youth development more generally. This study expands our understanding of the longitudinal relationship between changes in future orientation and changes in levels of substance use in a sample of justice involved youth with high levels of substance use, a group of considerable clinical and policy interest. PMID- 29509063 TI - Arabidopsis thaliana homeodomain-leucine zipper type I transcription factors contribute to control leaf venation patterning. AB - Venation patterning is a taxonomic attribute for classification of plants and it also plays a role in the interaction of plants with the environment. Despite its importance, the molecular physiology controlling this aspect of plant development is still poorly understood. Auxin plays a central role modulating the final vein network and patterning. This addendum discusses recent findings on the role of homeodomain-leucine zipper (HD-Zip) transcription factors on the regulation of leaf venation patterning. Moreno-Piovano et al. reported that ectopic expression of a sunflower HD-Zip I gene, HaHB4, increased the asymmetry of leaf venation. Even more, this work showed that auxin transport in the leaf through LAX carriers controls venation patterning. Here, we provide evidence indicating that some Arabidopsis thaliana HD-Zip I genes play a role in the determination of the final leaf venation patterning. We propose that these genes contribute to regulate vein patterning, likely controlling auxin homeostasis. PMID- 29509062 TI - Chitosan/cellulose-based beads for the affinity purification of histidine-tagged proteins. AB - Chitosan/cellulose-based beads (CCBs) for the affinity purification of histidine tagged proteins were prepared from chitosan/cellulose dissolved in ionic liquid as a solvent, and their structures were characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, and thermogravimetric analysis. The affinity purification was used to separate hexahistidine-tagged (his-tagged) enhanced green fluorescent protein (EGFP) from Escherichia coli. The results showed that Zn2+-CCB exhibited more specific adsorption capacity toward the target protein compared with Ni2+-CCB and Cu2+-CCB. The maximum adsorption of EGFP was 1.84 mg/g of Zn2+-CCB, with 90% purity under the optimized conditions (ionic strength (1.0 M NaCl), pH (7.2) and imidazole concentration (500 mM)). In addition, a regeneration method for the sorbent was further developed by washing with ethylenediaminetetraacetic acid disodium and then reimmobilizing with metal ions. This technique is an alternative method for the purification of his-tagged proteins, making the process more economical, fast, stable, and large batch. PMID- 29509064 TI - A Chinese patient of P102L Gerstmann-Straussler-Scheinker disease contains three other disease-associated mutations in SYNE1. AB - Gerstmann-Straussler-Scheinker disease (GSS) with the P102L mutation in PRNP gene is characterized with progressive cerebellar dysfunction clinically and PrPSc plaques neurologically. Due to the cerebellar ataxia in the early stage, GSS P102L is often misdiagnosed as other neurodegenerative disorders. We presented here a 49-year-old female patient with proven P102L PRNP mutation, and three heterologous mutations in hereditary ataxias associated gene SYNE1, including p.V3643L, p.M3376V and p.T2860A. The patient appeared progressive unsteady gait in early stage and developed the Creutzfeldt-Jacob disease (CJD) - associated clinical manifestations, including progressive dementia, myoclonus, pyramidal and extrapyramidal signs. She is still alive but with akinetic mutism 21 months after onset. Observation of intense signal changes in cortical regions (cortical ribboning) in diffusion weighted imaging (DWI) MRI scanning and positive protein 14-3-3 in cerebrospinal fluid (CSF) proposed the diagnosis of sporadic CJD. The final diagnosis of P102L GSS was made after PRNP sequencing. PMID- 29509065 TI - Cell therapy-processing economics: small-scale microfactories as a stepping stone toward large-scale macrofactories. AB - AIM: Manufacturing methods for cell-based therapies differ markedly from those established for noncellular pharmaceuticals and biologics. Attempts to 'shoehorn' these into existing frameworks have yielded poor outcomes. Some excellent clinical results have been realized, yet emergence of a 'blockbuster' cell-based therapy has so far proved elusive. MATERIALS & METHODS: The pressure to provide these innovative therapies, even at a smaller scale, remains. In this process, economics research paper, we utilize cell expansion research data combined with operational cost modeling in a case study to demonstrate the alternative ways in which a novel mesenchymal stem cell-based therapy could be provided at small scale. RESULTS & CONCLUSIONS: This research outlines the feasibility of cell microfactories but highlighted that there is a strong pressure to automate processes and split the quality control cost-burden over larger production batches. The study explores one potential paradigm of cell-based therapy provisioning as a potential exemplar on which to base manufacturing strategy. PMID- 29509066 TI - Sorbic, benzoic and propionic acids in fishery products: a survey of the South Korean market. AB - This study was conducted to provide basic data as part of a project to distinguish naturally occurring organic acids from added preservatives. Accordingly, we investigated naturally occurring levels of sorbic, benzoic and propionic acids in fish and their processed commodities. The levels of sorbic, benzoic and propionic acids in 265 fish and their processed commodities were determined by high-performance liquid chromatography-photodiode detection array (HPLC-PDA) of sorbic and benzoic acids and gas chromatography-mass spectrometry (GC/MS) of propionic acid. For propionic acid, GC-MS was used because of its high sensitivity and selectivity in complicated matrix samples. Propionic acid was detected in 36.6% of fish samples and 50.4% of processed fish commodities. In contrast, benzoic acid was detected in 5.6% of fish samples, and sorbic acid was not detected in any sample. According to the Korean Food and Drug Administration (KFDA), fishery products and salted fish may only contain sorbic acid in amounts up to 2.0 g kg-1 and 1.0 g kg-1, respectively. The results of the monitoring in this study can be considered violations of KFDA regulations (total 124; benzoic acid 8, propionic acid 116). However, it is difficult to distinguish naturally generated organic acids and artificially added preservatives in fishery products. Therefore, further studies are needed to extend the database for distinction of naturally generated organic acids and added preservatives. PMID- 29509067 TI - Assessing posttraumatic growth, complicated grief, and psychological distress in bereaved atheists and believers. AB - The present study examines how meaning and belief in God or god(s) is related to bereavement outcomes. Data from 299 participants residing in the United States indicated that the variables of search for meaning, presence of meaning, and belief in God or god(s) were significantly related to posttraumatic growth, complicated grief, and psychological distress. Results from this study can be used to identify appropriate clinical strategies for mental health practitioners working with bereaved clients and will expand the breadth of literature on bereavement with atheist populations in the United States. PMID- 29509068 TI - An Experimental Test of the Two-Dimensional Theory of Cultural Sensitivity in Health Communication. AB - Based on a theoretical framework describing culturally sensitive (CS) health communication, this experiment tested the relative contributions of surface structure and deep structure in the recall of oral health information from pamphlets varied in written message and images. Using a 2 * 2 factorial design, Spanish-speaking Mexican heritage mothers of children under six (n = 160) were randomly assigned to read one of four 12-page pamphlets containing the same oral health information in Spanish: (1) standard written message/standard images; (2) standard written message/CS images; (3) CS written message/standard images; and (4) CS written message/CS images. Participants completed a 22-item oral health knowledge questionnaire before and after reading the pamphlet. Controlling for the effects of pretest scores, acculturation, and educational level on information recall, findings showed significant positive main effects for CS images (F(1, 152) = 5.03, p = .026, partial n2 = .032) and CS written message (F(1, 152) = 5.21, p = .024, partial n2 = .033). There was no interaction. These results support the two dimensions of CS and their independent effects. They should be applicable to a variety of health communication channels. Further research is needed to investigate the causal mechanism behind the observed effects. PMID- 29509069 TI - Can Hovering Hinder Helping? Examining the Joint Effects of Helicopter Parenting and Attachment on Prosocial Behaviors and Empathy in Emerging Adults. AB - While previous research has established links among multiple aspects of parenting, empathy, and prosocial behaviors in youth, little is known regarding the relations between helicopter parenting, a particular type of parental over control, and empathy and prosocial behaviors (Padilla-Walker, 2014). Because helicopter parenting could undermine empathic and prosocial outcomes by negatively impacting self-regulatory behaviors and promoting narcissistic tendencies (Padilla-Walker, 2014; Segrin, Woszidlo, Givertz, Bauer, & Murphy, 2012; Segrin, Woszidlo, Givertz, & Montgomery, 2013), the author sought to examine potential relationships among these constructs. A battery of self-report measures was administered to an emerging adult sample (N = 187 college students; 49% women; M age = 18.81 years; 71% White). Hierarchical multiple regression model results indicated that both maternal and paternal helicopter parenting predicted fewer positive prosocial and empathic outcomes, and these relations depended on parental attachment, gender, and specific outcome assessed. Helicopter parenting appears to be a distinct type of parental overcontrol that especially contributes to moral development. PMID- 29509070 TI - Direct bioconversion of rice residue from canteen waste into lipids by new amylolytic oleaginous yeast Sporidiobolus pararoseus KX709872. AB - The new amylolytic oleaginous red yeast, Sporidiobolus pararoseus KX709872, produced both alpha-amylase (540 +/- 0.09 mU/mL) and amyloglucosidase (23 +/- 0.00 mU/mL) and showed good ability to directly convert rice residue from canteen waste to biomass and lipids. Effects of medium composition and cultivation conditions on growth and lipid accumulation for strain KX709872 were investigated under shaking flask and upscaling levels. At C : N ratio of 25 : 1, pH 5.45, 22.36 degrees C, and 199.40 rpm for 7 days, volumetric production of biomass and lipids, lipid content, and lipid productivity reached 17.69 +/- 0.44, 8.35 +/- 0.19 g/L, 49.48 +/- 0.41% (w/w), and 1.67 +/- 0.11 g/L/day, respectively. Production of lipids was also implemented in 5.0-L stirred tank bioreactor with 2.5 L of optimized medium at 300 rpm and 3.0 vvm for 5 days. Volumetric production of biomass and lipids, lipid content, and lipid productivity were 16.33 +/- 0.49, 8.75 +/- 0.13 g/L, 56.61 +/- 0.04% (w/w), and 2.19 +/- 0.03 g/L/day, respectively. Meanwhile, the fatty acids of lipids from strain KX709872 had high oleic acid content (60-62%) which was similar to those of vegetable oils, indicating that these lipids are promising as an alternative biodiesel feedstock. Moreover, the biodiesel derived from lipids of strain KX709872 had properties satisfying the criteria of ASTM D6751 and EN 14214 standards. PMID- 29509071 TI - FAL Clowes, 1921-2016: a Memoir. AB - With the death of Frederick Albert Lionel Clowes on 21 September 2016, plant sciences lost a member of that lineage of experimental morphologists which reaches back to Johann Wolfgang von Goethe. In 1949, he discovered a group of cells at the tip of the beech root apex which were metabolically inert. In 1954, he confirmed generality of this root apex feature and coined the term 'quiescent center'. He continued to study these unique cells throughout next decades up to his last papers published in 1980s. Concept of the quiescent centre of plant roots is one of the milestones in plant cell biology and plant physiology. PMID- 29509072 TI - Biosafety and bioefficacy assessment of human mesenchymal stem cells: what do we know so far? AB - An outstanding amount of resources has been used in research on manipulation of human stem cells, especially mesenchymal stem cells (MSCs), for various clinical applications. However, human MSCs have not been fully utilized in clinical applications due to restrictions with regard to their certain biosafety and bioefficacy concerns, for example, genetic abnormality, tumor formation, induction of host immune response and failure of homing and engraftment. This review summarizes the biosafety and bioefficacy assessment of human MSCs in terms of genetic stability, tumorigenicity, immunogenicity, homing and engraftment. The strategies used to reduce the biosafety concerns and improve the bioefficacy of human MSCs are highlighted. In addition, the approaches that can be implemented to improve their biosafety and bioefficacy assessment are briefly discussed. PMID- 29509073 TI - Race walking gait and its influence on race walking economy in world-class race walkers. AB - AIM: The aim of this study was to determine the relationships between biomechanical parameters of the gait cycle and race walking economy in world class Olympic race walkers. METHODS: Twenty-One world-class race walkers possessing the Olympic qualifying standard participated in this study. Participants completed an incremental race walking test starting at 10 km.h-1, where race walking economy (ml.kg-1.km-1) and spatiotemporal gait variables were analysed at different speeds. RESULTS: 20-km race walking performance was related to race walking economy, being the fastest race walkers those displaying reduced oxygen cost at a given speed (R = 0.760, p < 0.001). Longer ground contact times, shorter flight times, longer midstance sub-phase and shorter propulsive sub-phase during stance were related to a better race walking economy (moderate effect, p < 0.05). CONCLUSION: According to the results of this study, the fastest race walkers were more economi cal than the lesser performers. Similarly, shorter flight times are associated with a more efficient race walking economy. Coaches and race walkers should avoid modifying their race walking style by increasing flight times, as it may not only impair economy, but also lead to disqualification. PMID- 29509074 TI - Mathematical modeling of ethanol production in solid-state fermentation based on solid medium' dry weight variation. AB - In this work, mathematical modeling of ethanol production in solid-state fermentation (SSF) has been done based on the variation in the dry weight of solid medium. This method was previously used for mathematical modeling of enzyme production; however, the model should be modified to predict the production of a volatile compound like ethanol. The experimental results of bioethanol production from the mixture of carob pods and wheat bran by Zymomonas mobilis in SSF were used for the model validation. Exponential and logistic kinetic models were used for modeling the growth of microorganism. In both cases, the model predictions matched well with the experimental results during the exponential growth phase, indicating the good ability of solid medium weight variation method for modeling a volatile product formation in solid-state fermentation. In addition, using logistic model, better predictions were obtained. PMID- 29509075 TI - Imbalance between cognitive systems in alcohol-dependence and Korsakoff syndrome: An exploration using the Alcohol Flanker Task. AB - BACKGROUND: Alcohol-dependent individuals (ALC) simultaneously present decreased inhibitory control and increased attention towards alcohol-related cues. The dual process models have proposed that these symptoms reflect an imbalance between prefrontal/reflective and limbic/automatic systems, respectively leading to cognitive dysfunctions in executive processes and to alcohol-related bias. However, most previous research has focused on a separate exploration of these systems among ALC, and the direct measure of their interactions remains to be conducted. Moreover, no study has explored the evolution of this imbalance across the successive stages of alcohol-related disorders, and particularly in Korsakoff syndrome (KS), the most frequent neurological complication of alcohol-dependence. METHOD: Ten KS, 14 ALC, and 14 matched control participants performed a modified Flanker task, the "Alcohol Flanker Task," based on congruent, incongruent, and neutral conditions with alcohol-related stimuli. This task required inhibitory processing on alcohol-related stimuli and evaluated, through a behavioral approach, the interaction between reflective and automatic systems, as well as its evolution between ALC and KS. RESULTS: ALC and KS both presented high reactivity towards alcohol-related stimuli, confirming the presence of alcohol related bias. KS showed increased omission rates (related to distractor interference) while ALC showed higher false-alarm rates (related to prepotent response inhibition). These results suggest that different inhibitory subcomponents might be altered at the successive stages of the pathology, and experimentally confirms the crucial role of the interaction between reflective and automatic processes in alcohol-use disorders. CONCLUSION: The present results reinforce the proposal that alcohol-related cues significantly impact inhibitory control in alcohol-related disorders. However, ALC and KS present different patterns of deficits depending on task complexity (i.e., executive load), thus suggesting a dissociation in inhibitory functions when processing alcohol-related cues. PMID- 29509076 TI - Sexual Dysfunction Among Patients With Schizophrenia in Southwest Nigeria. AB - Sexual functioning has received little attention as an important aspect of patient care for those suffering from schizophrenia. In Nigeria, cultural and religious factors often prevent patients from talking with their clinician about their sexual life. The aim of our study was to assess the frequency and nature of sexual dysfunction in patients with schizophrenia and assess the determinants of sexual dysfunction in such patients. Sexual dysfunction was assessed with the Arizona Sexual Experience Scale in 90 patients with schizophrenia. Demographic and clinical characteristics including quality of life, the severity of schizophrenia, and perceived stigma were recorded using a standardized protocol and data collection. The prevalence of sexual dysfunction was 36.7%. Higher scores on the negative subscale of the Positive and Negative Syndrome Scale (PANSS), the general subscale of the PANSS, the total scores on the PANSS, and a family history of mental illness were significantly associated with sexual dysfunction. The only significant predictor of sexual dysfunction was the severity of the negative subscale of the PANSS. This study highlights the high prevalence of sexual dysfunction among patients with schizophrenia. Efforts should be made to identify and address this problem. PMID- 29509077 TI - Connecting older grandmothers raising grandchildren with community resources improves family resiliency, social support, and caregiver self-efficacy. AB - Custodial grandparenting can be especially challenging for older grandmothers facing age specific issues. Kinship navigator programs are social service delivery programs intended to inform grandparents and other relatives raising children about available resources and services, provide information specific to their individual needs, and help families navigate service systems. Our study utilizes self-report data from one kinship navigator federal demonstration project, which used a randomized control trial, to examine demographic characteristics for grandmothers under and over 55 years of age, whether grandmother caregivers (>=55 years) improve family resilience, social support, and caregiver self-efficacy, and which interventions improved outcomes for grandmothers (>=55 years). Each participant was randomly assigned to one of four groups: Usual Care (traditional child welfare services), Standard Care (family support and case management), Peer-to-Peer Care Only, and Full Kin Tech Care (peer navigators with computer access and interdisciplinary team). Thirty-nine percent of grandmothers (55-75 years) were mostly living in poverty, predominantly Caucasian, with 36% identifying as African American/Black, with at least one to two children at home. Repeated-measures ANOVAs for each subscale showed statistically significant within- and between-group differences for Family Functioning, Social Supports, Concrete Supports, Child Development, and Nurturing and Attachment, with the exception of Usual Care, which showed a decline in protective factors consistently across subscales. Future research with kinship families could qualitatively examine the experiences for older women in navigator programs and replication of kinship navigator programs could build capacity in data collection and maintenance systems to gain better perspective about how systems of care impact families. PMID- 29509078 TI - Prevalence of Childhood Sexual Abuse in China: A Meta-Analysis. AB - The objective of the current study was to explore the estimated prevalence of childhood sexual abuse in China. We conducted a meta-analysis that used the data from 36 articles. A total of 125 independent samples and 131,734 participants were included. The results revealed no significant difference in the prevalence of childhood sexual abuse between Chinese men (9.1%) and women (8.9%). The prevalence of childhood sexual abuse in studies from mainland areas was significantly higher than that from Hong Kong/Taiwan. The estimated prevalence of childhood sexual abuse in China also differed according to the definition of child sexual abuse, data collection method, year of data collection, and the mean age of participants at the time of assessment. PMID- 29509079 TI - Love and loss in wartime: An unpublished narrative by Pamela Frankau (1908-67). AB - This article discusses an unpublished book by the popular and prolific novelist Pamela Frankau (1908-67), which was rejected by her publishers in 1946 as "almost too personal for publication," and which for many years was believed lost. The work is addressed to Frankau's dead lover, Marjorie Vernon Whitefoord (1907-44), a fellow officer in the women's Auxiliary Territorial Service, and takes the form of a letter to Vernon. The article examines what Frankau's unpublished narrative of love and loss in wartime reveals about her life and later novels, and its implications for the official record of her life and writing. PMID- 29509082 TI - Circadian expression of DNA methylation and demethylation genes in zebrafish gonads. AB - This research aimed at investigating the light synchronization and endogenous origin of daily expression rhythms of eight key genes involved in epigenetic mechanisms (DNA methylation and demethylation) in zebrafish gonads. To this end, 84 zebrafish were distributed into six tanks, each one containing 14 fish (7 males and 7 females). Animals were subjected to 12 h light:12 h dark cycles (LD, lights on at ZT0 h) and fed randomly three times a day during the light phase. Locomotor activity rhythms were recorded in each tank for 20 days to test their synchronization to light. Then, zebrafish were fasted for one day and gonad samples were collected every 4 h during a 24 h cycle (ZT2, 6, 10, 14, 18, and 22 h). The results revealed that most of the epigenetic genes investigated exhibited a significant daily rhythm. DNA methylation genes (dnmt4, dnmt5, dnmt7) exhibited a daily rhythm of expression with a nocturnal acrophase (ZT14:01~ZT22:17 h), except for dnmt7 in males (ZT2:25 h). Similarly, all DNA demethylation genes (tet2, tdg, mb4, gadd45aa, and apobec2b) revealed the existence of statistically significant daily rhythms, except for gadd45aa in females. In females, tdg, mb4, and apobec2b presented a nocturnal peak (ZT14:20 ~ ZT22:04 h), whereas the tet2 acrophase was diurnal (ZT4:02 h). In males, tet2, tdg, and gadd45aa had nocturnal acrophases (ZT18:26~ZT21:31 h), whereas mb4 and apobec2b displayed diurnal acrophases (ZT5:28 and ZT4:02 h, respectively). To determine the endogenous nature of gene expression rhythms, another experiment was performed: 12 groups of 14 fish (7 males and 7 females) were kept in complete darkness (DD) and sampled every 4 h during a 48 h cycle (CT2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46 h). Under DD, most of the genes (7 out of 8) presented circadian rhythmicity with different endogenous periodicities (tau), suggesting that the epigenetic mechanisms of DNA methylation and demethylation in the gonads follow an internal control, functioning as part of the translation network linking the environment into somatic signals in fish reproduction. PMID- 29509084 TI - An Ethnographic Study of Mental Healthcare Services for People with Mental Illness in Rural Thailand. AB - Little is known about access to healthcare services among people with mental illness in rural Thailand. This study describes a contextual understanding of access to mental healthcare services for people with mental illness in three selected villages located in a rural district in Northeastern Thailand. An ethnographic approach was adopted wherein in-depth interviews and site observation were conducted. In all, 14 participants were interviewed, 9 persons with mental illness and 5 caregivers, between January and July in 2017. The study described how people with a mental illness and their primary caregivers experience access to mental health services. Three major cultural theme patterns emerged during the analysis: Theme 1- family stress: avoiding repercussion from the bad experience, Theme 2 - waking before dawn: the most important rule to abide by, and Theme 3- going quickly only to remain silent and still: the duty of a good patient. This study has provided an insight into the experiences of people with mental illness accessing mental health services, which is of importance for improving the queuing system at the outpatient mental health clinic and guidelines for healthcare providers interacting with patients and their families. PMID- 29509083 TI - Association of SNP rs1867277 in FOXE1 Gene and Cleft Lip with or without Cleft Palate in a Han Chinese Population. AB - BACKGROUND: The genetic factors causing cleft lip with or without cleft palate (CL +/- P) are still unclear. The SNPs in FOXE1 gene were associated with CL +/- P. However, the results have been inconsistent. OBJECTIVE: We explored the associations of four SNPs in FOXE1 gene and CL +/- P by a family based study. MATERIALS AND METHODS: 128 children with CL +/- P and their parents were recruited. rs3758249 and rs1867277 were genotyped by high-resolution melting curve (HRM) method, whereas rs1443434 and rs907577 were genotyped by Sequenom MassARRAY(r) method. The software PLINK, FBAT and FAMHAP were used for analyzing data. RESULTS: rs1867277 was associated with CL +/- P (Pm = 0.0395). The patients were divided into two subgroups, individuals with cleft lip only and persons with cleft lip and palate. There were no associations in subgroup analyses. CONCLUSION: We confirmed the association of FOXE1 gene and CL +/- P by a family based study. For the first time, rs1867277 was significantly associated with CL +/- P. PMID- 29509085 TI - Testing the Social Interaction Learning Model's Applicability to Adolescent Substance Misuse in an Australian Context. AB - BACKGROUND: Parents and peers both influence the development of adolescent substance misuse, and the Social Interaction Learning (SIL) model provides a theoretical explanation of the paths through which this occurs. OBJECTIVE: The SIL model has primarily been tested with conduct outcomes and in US samples. This study adds to the literature by testing the SIL model with four substance use outcomes in a sample of Australian youth. METHOD: We used structural equation modeling to test the fit of the SIL model to a longitudinal sample (n = 907) of students recruited in grade 5 in Victoria, Australia participating in the International Youth Development Study, who were resurveyed in grades 6 and 10. RESULTS: The model fit was good (chi2(95) = 248.52, p < .001; RMSEA = .04 [90% CI: .036 - .049]; CFI = .94; SRMR = .04). Path estimates from parenting to antisocial behavior and from antisocial behavior to antisocial peers were significant. In turn, having antisocial peers was significantly related to alcohol use, binge drinking, tobacco use, and marijuana use. From parenting, only the direct path to marijuana use was significant, but indirect effects were significant. CONCLUSIONS: The SIL model illustrates that parenting plays an early role in the formation of adolescent peer relations that influence substance misuse and identifies etiological pathways that can guide the targets of prevention. The SIL pathways appear robust to the Australian social and policy context. PMID- 29509087 TI - Avelle NPWT system: frequently asked questions. PMID- 29509088 TI - Proposed treatment pathway for the management of incisions. AB - Assessment of patients and their surgical risk is at the discretion of the clinician. There may be patients who present with two or less risk factors, such as a lower BMI, but are still suitable for NPWT incision management. PMID- 29509086 TI - A novel enhanced diffusion sampler for collecting gaseous pollutants without air agitation. AB - A novel enhanced diffusion sampler for collecting gaseous phase polycyclic aromatic hydrocarbons (PAHs) without air agitation is proposed. The diffusion of target compounds into a sampling chamber is facilitated by continuously purging through a closed-loop flow to create a large concentration difference between the ambient air and the air in the sampling chamber. A glass-fiber filter-based prototype was developed. It was demonstrated that the device could collect gaseous PAHs at a much higher rate (1.6 +/- 1.4 L/min) than regular passive samplers, while the ambient air is not agitated. The prototype was also tested in both the laboratory and field for characterizing the concentration gradients over a short distance from the soil surface. The sampler has potential to be applied in other similar situations to characterize the concentration profiles of other chemicals. PMID- 29509089 TI - The Avelle NPWT system. PMID- 29509090 TI - Case study 3: breast reconstruction. PMID- 29509091 TI - Foreword. PMID- 29509092 TI - Case study 1: dehisced abdominal wound. PMID- 29509093 TI - Case study 2: assorted surgical dehiscences. PMID- 29509094 TI - Using negative pressure wound therapy to prevent surgical site infection. AB - It is estimated that, at the very least, 5% of patients who undergo surgery develop a surgical site infection (SSI). There has been much interest in the use of negative pressure wound therapy (NPWT) as a prophylactic treatment to reduce the risk of SSI. Evidence suggests it can accelerate healing times, reduce both the length of hospital stay and the frequency of dressing changes, and improve patients' quality of life. The efficacy of traditional and portable NPWT systems is similar. However, the latter has an advantage in that it increases patient mobility and does not hinder individuals from carrying out activities of daily living. There are also economic data suggesting that portable NPWT devices are associated with long-term cost savings. PMID- 29509095 TI - Delayed Metastasis of Clear Cell Sarcoma of Kidney to Bladder After 7 Disease Free Years. AB - INTRODUCTION: Clear cell sarcoma of the kidney (CCSK) is childhood neoplasm with its own distinctive pattern of metastasis and may appear after a disease free interval of 5 years or more. MATERIALS AND METHODS: Histopathology and immunohistochemistry were available from the radical nephrectomy and the later partial cystectomy, which was performed after a seven disease-free interval. RESULTS: The pathologic features of the primary tumor were those of a classic CCSK with a monotypic pattern of uniform rounded to ovoid tumor cells with a background network of delicate blood vessels. By contrast, the bladder recurrence had a myxoid hypocellular appearance (one of the known variant patterns of CCSK). Both tumors displayed immunopositivity for Cyclin-D1 and CD117 with a less intense reaction in the bladder metastasis. CONCLUSIONS: This case demonstrates that CCSK has the potential to metastasize after a prolonged disease-free interval and may have deceptively bland histopathologic features. PMID- 29509096 TI - Impact of interdisciplinary rounds in the spinal cord injury unit on relational coordination for patients with pressure injury: A pilot study. AB - CONTEXT/OBJECTIVE: Multiple medical specialties are often involved in the management of patients with both spinal cord injuries (SCI) and pressure injuries (PIs), sometimes leading to inadequate communication. Our Veterans Affairs (VA) hospital has an interdisciplinary team for PI patients in the SCI unit. This team conducts monthly bedside rounds and journal clubs; there is no similar team for patients with PIs outside the SCI unit. This pilot study aims to determine whether such an interdisciplinary team improves care coordination among practitioners. DESIGN: Survey-based study. SETTING: VA hospital. PARTICIPANTS: Healthcare providers who participate in interdisciplinary SCI rounds and who also care for patients with PIs outside the SCI unit. INTERVENTIONS: Interdisciplinary rounds, including monthly bedside rounds and journal clubs with variety of specialists take place within the SCI unit. There are no similar interdisciplinary rounds for patients with PIs outside of the SCI unit. OUTCOME MEASURES: The Relational Coordination (RC) survey is a validated tool for gauging team performance. Survey results quantified relational dynamics inside and outside the SCI unit across four communication domains (frequent communication, timely communication, accurate communication, and problem-solving communication) and three relationship domains (shared knowledge, mutual respect, and shared goals). RESULTS: Interdisciplinary rounds in the SCI unit was associated with significantly better RC with hospitalists, surgical specialists, infectious diseases, nursing, and pharmacy. This effect was primarily due to improvements in communication domains, without significant difference in relationship domains. CONCLUSIONS: Interdisciplinary rounds in the SCI unit significantly improves RC in the care of PI patients. PMID- 29509097 TI - Cognitive Bias for the Distribution of Ball Landing Positions in Amateur Tennis Players (Cognitive Bias for the Motor Variance in Tennis). AB - This study aimed to investigate whether the isotropy bias (estimating one's own motor variance as an approximately circular distribution rather than a vertically elongated distribution) arises in tennis players for the estimation of the two dimensional variance for forehand strokes in tennis (Experiment 1), as well as the process underlying the isotropy bias (Experiment 2). In Experiment 1, 31 tennis players were asked to estimate prospectively their distribution of ball landing positions. They were then instructed to hit 50 forehand strokes. We compared the eccentricity of the ellipse calculated from estimated and observed landing positions. Eccentricity was significantly smaller in the estimated ellipse than in the observed ellipse. We assumed that the isotropy bias for the estimated ellipse comes from the process of variance estimation. In Experiment 2, nine participants estimated the 95% confidence interval of 300 dots. Eccentricity was significantly smaller in their estimated ellipses than it was in the ellipses for the dots, though the magnitude of bias decreased for the estimation of dots. These results suggest that the isotropy bias in tennis ball landing position includes the bias of recognizing landing position and the bias of estimating the ellipse confidence interval from the recognized landing position. PMID- 29509098 TI - Statistical trends of episiotomy around the world: Comparative systematic review of changing practices. AB - The authors' purpose for this article is to identify, review and interpret all publications about the episiotomy rates worldwide. Based on the criteria from the PRISMA guidelines, twenty databases were scrutinized. All studies which include national statistics related to episiotomy were selected, as well as studies presenting estimated data. Sixty-one papers were selected with publication dates between 1995 and 2016. A static and dynamic analysis of all the results was carried out. The assumption for the decline in the number of episiotomies is discussed and confirmed, recalling that nowadays high rates of episiotomy remain in less industrialized countries and East Asia. Finally, our analysis aims to investigate the potential determinants which influence apparent statistical disparities. PMID- 29509099 TI - Abstracts presented at the Association for Medical Education and Research in Substance Abuse (AMERSA) 41st Annual Conference, Washington, DC, USA, November 2017. AB - The 41st annual meeting of the Association for Medical Education and Research in Substance Abuse (AMERSA) was held in Washington, DC, USA, in November 2017. Contained in this paper are the abstracts of scientific work presented at the conference. PMID- 29509100 TI - Abstracts presented at the International Society of Addiction Medicine (ISAM) 19th Annual Meeting, Abu Dhabi, United Arab Emirates, October 2017. AB - The 19th Annual Meeting of the International Society of Addiction Medicine (ISAM) was held in Abu Dhabi, United Arab Emirates, in October 2017. Contained in this paper are the abstracts of scientific work presented at the conference. PMID- 29509101 TI - Integrated continuous biomanufacturing platform with ATF perfusion and one column chromatography operation for optimum resin utilization and productivity. AB - A new integrated continuous biomanufacturing platform for continuous production of antibodies at fixed cell volumes and cell concentrations for extended periods with immediate capture is presented. Upstream antibody production has reached technological maturity, however, the bottleneck for continuous biomanufacturing remains the efficient and cost-effective capture of therapeutic antibodies in an initial chromatography step. In this study, the first successful attempt at using one-column continuous chromatography (OCC) for the continuous capture of therapeutic antibodies produced through alternating tangential flow perfusion is presented. By performing upstream media optimizations, the upstream perfusion rate was reduced to one vessel volume per day (vv/d), increasing antibody titer and reducing the volume of perfusate. In addition, process improvements were performed to increase productivity by 80% over previously reported values. In addition, a real-time method for evaluating column performance to make column switching decisions was developed. This improved productivity coupled with the use of a single-column improved process monitoring and control in OCC compared to multi-column systems. This approach is the first report on using a single column for the implementation of an integrated continuous biomanufacturing platform and offers a cost-effective and flexible platform process for the manufacture of therapeutic proteins. PMID- 29509102 TI - Development and validation of HPLC methods for analysis of chlorantraniliprole insecticide in technical and commercial formulations. AB - Effective, selective, precise and accurate liquid chromatographic analytical methods for the analysis of a novel chlorantraniliprole insecticide in technical and formulation (coragen, 20% SC) have been optimized and validated. Eight methods were designed based on different mobile phases, temperature and two HPLC columns. The mobile phase consists of two mixtures (acetonitrile:water, 70:30 and methanol:water, 70:30) with 25 or 40oC. HPLC analysis of chlorantraniliprole was carried out at a wavelength of 260 nm, with a flow rate of 0.8 mL/min. The calibration curves showed a good linear relationship (R2 ? 0.99) in the injected quantities ranged from 0.0125 to 1.00 MUg. Limit of detection (LOD) was found to be 3.94 to 14.56 ng and from 5.95 to 12.93 ng using the analytical methods I to IV by MicroPack CN-10 and V-VIII by ZORBAX Eclips Plus C18 columns, respectively, based on SDslope values. ZORBAX Eclips Plus C18 column with method VI was the best one (R2 = 1.00 and RSD = 0.30), short retention time (4.936 min), high theoretical plates per column (65457.15) compared to others and LOD = 6.49 ng. The accuracy of the best method was demonstrated by recovery rates of 83.04% to 98.50% for grape samples supplemented with 5, 10 and 50 mg chlorantraniliprole/kg. PMID- 29509103 TI - Betrayal of the Body: Group Approaches to Hypo-Sexuality for Adult Female Sufferers of Childhood Sexual Abuse. AB - Hypo-sexuality, self-reported hypoactive sexual desire and/or sexual aversion, is a common symptom experienced by women who were victims of childhood sexual abuse. This symptom may be distressing to the patient herself, and may place strain on her romantic relationships in adulthood. Unfortunately, this problem often remains undiscussed between patient and provider, in part due to the provider's lack of comfort or knowledge regarding how best to address this issue. In this article, we explore several strategies that providers may employ in a group setting in order to help women realize their sexuality while minimizing untoward side effects such as feelings of guilt or shame, or flashbacks. We highlight the merits of each technique, and provide insights from clinical experience to guide practitioners to help their patients facing this difficult issue. PMID- 29509104 TI - Improved stability and catalytic activity of graphene oxide/chitosan hybrid beads loaded with porcine liver esterase. AB - Graphene oxide/chitosan and reduced graphene oxide/chitosan (GO/CS and RGO/CS) beads were prepared by precipitation with NaOH. Porcine liver esterase was immobilized on these beads to give GO/CS/E and RGO/CS/E beads. The optimum conditions for the maximum activity of RGO/CS/E beads were pH 8 and 50 degrees C. The stability of the enzyme immobilized on GO/CS/E and RGO/CS/E was high in the pH range of 5-8. The GO/CS/E beads showed superior stability compared to that of the free enzyme and CS/E beads between 20 and 50 degrees C. Kinetic analysis showed that GO/CS/E was a better catalyst than the RGO/CS/E beads with a lower Km value of 0.9 mM. The hybrid beads also retained more than 95% activity after 10 consecutive cycles. The GO/CS/E and RGO/CS/E beads retained 84% and 87% activity after 40 days at 4 degrees C. The GO/CS/E beads were used for the successful hydrolysis of methyl 4-hydroxy benzoate. PMID- 29509105 TI - Resistant and undertreated hypertension in patients with chronic kidney disease: data from the PATRIOTIC survey. AB - BACKGROUND: Hypertension is prevalent in chronic kidney disease (CKD), but the control of hypertension is suboptimal. We reported the prevalence and characteristics of resistant and undertreated hypertension based on a nationwide survey aiming to improve blood pressure (BP) control. METHODS: Resistant hypertension (RH) was defined as BP above the target (<140/90 mm Hg) despite the use of 3 antihypertensive drugs or achieving the target BP by using >=4 antihypertensive drugs. Undertreated hypertension was defined as uncontrolled hypertension (unCH) using <=2 drugs. We compared the characteristics and antihypertensive treatment among different groups (including RH and unCH using <=2 drugs). Multivariable logistic regression was used to detect factors associated with unCH using <=2 drugs and RH. RESULTS: 4,435 nondialysis CKD patients with hypertension were analyzed, and 36.9% of participants achieved controlled hypertension (CH) using <=3 drugs, 11.1% met the criteria for RH, and 52% had unCH despite the use of <= 2 antihypertensive drugs. Participants with unCH using <= 2 drugs had low usage of renin-angiotensin system blockers (36.8%) and diuretics (5.5%), which was much lower than participants with CH using <=3 drugs and RH (P< 0.05). After multivariable adjustment, obesity, advanced CKD stages, urinary protein level of >=1.5 g/24 h, diabetes, and cardiovascular disease were associated with RH in CKD patients (P< 0.05). CONCLUSION: Compared with RH, undertreated hypertension contributes more to the unCH in Chinese CKD patients. It is important to ensure adequate antihypertensive treatment, including choosing antihypertensive drugs, that guidelines recommended. PMID- 29509106 TI - Novel method for restoration of anorectal function following spinal cord injury via nerve transfer in rats. AB - OBJECTIVES: Nerve transfer has been developed to restore partial function after serious nerve injuries, for example, restoring bladder control after spinal cord injury (SCI). Our aim here was to establish a preclinical proof-of-concept model using nerve transfer for restoring anorectal function after SCI. SETTING: We used laminectomy to model SCI, and bilateral spinal ventral and dorsal nerve root anastomosis to re-establish connectivity to the anorectal musculature. METHODS: Multidisciplinary methods were used to assess the anatomical and functional integrity of the alternative spinal-to-anorectal nerve circuit. Adult rats were used to establish the model. Bilateral anterior and posterior L5 nerve roots were surgically matched with anterior and posterior of S1 nerve roots by microscopic anastomosis to establish an artificial rectal reflex arc with complete sensory and motor pathways. Twelve weeks later, we used retrograde nerve tracing and neurohistomorphological analysis to assess anatomical integrity of the new artificial rectal reflex arc. Anorectal manometry was used to assess the function of the new nerve circuit. RESULTS: Retrograde tracing with recombinant attenuated pseudo rabies virus indicated that the new neural pathway was successfully established to the anorectal musculature after experimental SCI. Toluidine blue stained sections of the anastomosis site revealed normal-appearing nerve fiber morphology and regeneration, and transmission electron microscopy revealed myelinated axons. Anorectal manometry revealed significant anorectal functional recovery. CONCLUSION: These results suggest that our model is a feasible first step in developing an alternative reflex pathway after laminectomy at L4 to S2 and shows promise for effective restoration of anorectal function. PMID- 29509107 TI - Surgical wound dehiscence: a conceptual framework for patient assessment. AB - This paper presents a conceptual framework which outlines the risk factors associated with surgical wound dehiscence (SWD) as identified in the literature. The purpose for the development of the conceptual framework was to derive an evidence-based, informed understanding of factors associated with SWD, in order to inform a programme of research on the aetiology and potential risk factors of SWD. Incorporated within the patient-centric conceptual framework are patient related comorbidities, intraoperative and postoperative risk factors related to SWD. These are categorised as either 'mechanical' or 'physiological mechanisms' posited to influence these relationships. The use of the conceptual model for assessment of patients has particular clinical relevance for identification of risk and the management of patients in the pre-, intra- and postoperative period. PMID- 29509109 TI - Remote monitoring-the rise of the wound selfie. PMID- 29509108 TI - Use of photograph-based telemedicine in postoperative wound assessment to diagnose or exclude surgical site infection. AB - OBJECTIVE: This study aims to assess whether a clinician reviewing photographs of a wound was an acceptable substitute for clinical review in order to identify or exclude surgical site infection (SSI). METHOD: We undertook a mixed methods study consisting of a qualitative public involvement exercise and a prospective, non randomised, single-centre study of patients undergoing clean or clean contaminated vascular surgery. For the qualitative study, two semi-structured focus group interviews were conducted. For the prospective study, patients were invited to attend a wound review at 5-7 days and 30 days postoperatively. At review, wounds were scored by a study nurse or doctor, according to the ASEPSIS scale. Anonymised wound photographs were taken and independently reviewed, and ASEPSIS scored by two independent investigators blinded to the original 'clinical review' ASEPSIS score. RESULTS: In the qualitative study, three female patients were interviewed across two dates. Emerging themes included the burden of SSI, hospital follow-up and telemedical follow-up. A total of 37 patients with a mean age of 61.14 years were included in the quantitative analysis. There was a total of 53 wound reviews. There was >85% agreement between photograph and clinical reviewers in all categories except erythema. The specificity of photograph review for diagnosis of SSI was 90%. The intraclass correlation coefficient for total ASEPSIS score was R=0.806 (95% CI 0.694, 0.881), indicating strong reliability between reviewers. CONCLUSION: Our data shows that, in the assessment of SSI, there is good correlation between face-to-face clinical and remote photographic review. Incorporating this method of wound assessment into a postoperative follow up care pathway may save patients and clinicians from unnecessary hospital visits, particularly when conducting health research. PMID- 29509110 TI - Potential cost-effectiveness of using a collagen-containing dressing in managing diabetic foot ulcers in the UK. AB - OBJECTIVE: To estimate whether a collagen-containing dressing could potentially afford the UK's National Health Service (NHS) a cost-effective intervention for the management of diabetic foot ulcers (DFUs). METHOD: A decision model depicting the management of a DFU was constructed and populated with a combination of published clinical outcomes, resource use estimates and utilities for DFUs. The model estimated the incremental cost-effectiveness of a collagen-containing dressing plus standard care compared with standard care alone over a period of four months in terms of the incremental cost per quality-adjusted life year (QALY) gained. RESULTS: Treatment of DFUs of >6 months duration with a collagen containing dressing plus standard care instead of standard care alone is expected to increase the probability of healing from 0.08 to 0.53 by four months and increase health-related quality of life at four months from 0.156 to 0.163 QALYs per patient. Additionally, treatment with a collagen-containing dressing has the potential to reduce management costs by 22% over four months when compared with standard care alone (from L2897 to L2255 per patient). Treatment of new DFUs with a collagen-containing dressing plus standard care instead of standard care alone was also found to improve outcomes for less cost. CONCLUSION: Within the study's limitations, use of a collagen-containing dressing plus standard care instead of standard care alone potentially affords the NHS a cost-effective (dominant) treatment for both non-healing and new DFUs, since it improves outcomes for less cost. Hence, protocols should be established which enable clinicians to effectively introduce collagen-containing dressings into care pathways and monitor response to treatment. PMID- 29509112 TI - Effectiveness of a non-medicated wound dressing on attached and biofilm encased bacteria: laboratory and clinical evidence. AB - OBJECTIVE: The objective of this study was to evaluate the ability of a non medicated, hydro-responsive wound dressing (HRWD) to effectively aid in the removal of bacteria known to reside (and cause infections) within the wound environment. METHOD: A series of in vitro studies were undertaken using Staphylococcus aureus and Pseudomonas aeruginosa biofilms to evaluate the capabilities of the HRWD to disrupt and disperse biofilms. RESULTS: Biofilms can be broken up and dispersed by HRWD and both Staphylococcus aureus and Pseudomonas aeruginosa numbers can be reduced by a greater than log2 reduction in the presence of HRWD. However, no 'active' agents are released into the wound environment that have an antimicrobial effect. CONCLUSION: Overall, these studies have shown that this dressing acts as an effective debridement tool, and there are other 'physical' antimicrobial mechanisms impacting bacterial residence. These mechanisms include 1) breaking up and dispersal of biofilms so that the resultant planktonic bacteria are absorbed by the dressing and then 2) sequestered and retained (trapped) within its matrix. Additionally, when PHMB (polyhexamethylene biguanide) is bound within the dressing core but is not released into the wound environment there is the added antimicrobial effect resulting from 3) physical contact with this antiseptic component. Reducing the pathogenicity of the bacteria still further is the dressings ability to 4) absorb and sequester the damaging proteases released by pathogenic bacteria. PMID- 29509111 TI - Using a modified Delphi methodology to gain consensus on the use of dressings in chronic wounds management. AB - OBJECTIVE: Managing chronic wounds is associated with a burden to patients, caregivers, health services and society and there is a lack of clarity regarding the role of dressings in improving outcomes. This study aimed to provide understanding on a range of topics, including: the definition of chronicity in wounds, the burden of illness, clinical outcomes of reducing healing time and the impact of early interventions on clinical and economic outcomes and the role of matrix metalloproteinases (MMPs) in wound healing. METHOD: A systematic review of the literature was carried out on the role of dressings in diabetic foot ulcer (DFU), and venous leg ulcer (VLU) management strategies, their effectiveness, associated resource use/cost, and quality of life (QoL) impact on patients. From this evidence-base statements were written regarding chronicity in wounds, burden of illness, healing time, and the role of MMPs, early interventions and dressings. A modified Delphi methodology involving two iterations of email questionnaires followed by a face-to-face meeting was used to validate the statements, in order to arrive at a consensus for each. Clinical experts were selected, representing nurses, surgeons, podiatrists, academics, and policy experts. RESULTS: In the first round, 38/47 statements reached or exceeded the consensus threshold of 80% and none were rejected. According to the protocol, any statement not confirmed or rejected had to be modified using the comments from participants and resubmitted. In the second round, 5/9 remaining statements were confirmed and none rejected, leaving 4 to discuss at the meeting. All final statements were confirmed with at least 80% consensus. CONCLUSION: This modified Delphi panel sought to gain clarity from clinical experts surrounding the use of dressings in the management of chronic wounds. A full consensus statement was developed to help clinicians and policy makers improve the management of patients with these conditions. PMID- 29509113 TI - A cost-effectiveness analysis of a hydration response technology dressing in the treatment of venous leg ulcers in the UK. AB - OBJECTIVE: Venous leg ulcers (VLUs) cause significant pain and suffering for patients. Additionally, they place considerable financial and service burden on the National Health Service (NHS). A large proportion of VLUs do not heal within the standard time frame of 16-24 weeks, resulting in static wounds which commonly have issues with increasing exudate production. As the NHS continues to face times of austerity, services need to find solutions to be able to reduce costs and release nursing time while maintaining standards of care. Cutimed Sorbion Sachet S, a hydration response technology dressing (HRTD), is a treatment option for the management of patients with a VLU. The objective of this study was to provide an update of the health economic analysis of HRTD in comparison with relevant comparators in the UK with current cost data. METHOD: HRTD was compared against four different dressings, Zetuvit Plus (a super absorbent polymer dressing SAP), DryMax extra (a superabsorbent dressing, SADM), KerraMax Care (superabsorbent dressing, SAKM) and Eclypse (superabsorbent dressing, SAE) from a cost-effectiveness perspective. Clinical data were derived from literature and expert opinion. Cost input was utilised based on publicly available data and literature. The average patient in the model is assumed to be 65 years with a diagnosed VLU. It is assumed that patients in the different treatment arms have the same background mortality, hence the endpoint mortality is not included in the model. The analysis is based on a deterministic Markov model derived from Harding et al. with weekly cycles. The following assumptions are made: first, all patients start in a static health state with a non-healed but non-progressing VLU. It is assumed in the model that patients wounds can transition to a deteriorating state or one where a wound is improving or could progress. Additionally, VLUs could be healed from a progressed wound (i.e. improved wound), or they could develop into a severe wound with complications (infections) to be treated in hospitals. The time frame for the analysis was fixed for one year and no re-occurence after healing was assumed to happen. RESULTS: The cost effectiveness analysis demonstrates health economic dominance of HRDT being more effective and cost-saving against all analysed comparators. When using literature based input values, the incrementally higher healing rates for HRDT are 11.04 months (versus SAP), 29.04 months (versus SADM), 1.68 months (versus SAKM) and 11.04 months (versus SAE). Cost savings per patient were L37.60 versus SAP, L171.68 versus SADM, L3.13 versus SAKM and L43.63 versus SAE. CONCLUSION: Clinical benefits and cost savings increase when real-life practice assumptions, based on expert opinion, are included. Based on the underlying health economic model, HRDT is more effective and less costly than other comparative products in VLUs in the UK. PMID- 29509114 TI - The Japanese registry for surgery of ischial pressure ulcers: STANDARDS-I. AB - OBJECTIVE: To clarify the surgical indications and the appropriate perioperative management of ischial pressure ulcers (PUs). METHOD: A two-year prospective, nationwide registry study was carried out across 26 medical institutions in Japan. All participating institutions managed ischial PUs according to the standardisation of total management and surgical application for the refractory decubitus (STANDARDS-I) perioperative protocol. Analysis was conducted on a range of clinically or statistically important variables for the achievement of primary or secondary endpoints: complete wound healing and hospital discharge at three months, and complete wound healing at one month after surgery, respectively. RESULTS: A total of 59 patients took part in the study. All patients underwent surgery for ischial PUs during the study period. Patients who had achieved the primary endpoint had a higer preoperative functional independence measurement (FIM score), a higher 'G' score in the DESIGN-R scale and were more likely to have healed by primary intention. Patients who had achieved the secondary endpoint were more likely to have spastic paralysis, preoperative physiotherapy and localised infection of the wound, among other variables. CONCLUSION: This survey suggests that preoperative physiotherapy increases the speed of wound healing, and good granulation of the wound bed preoperatively increases the likelihood of woundless discharge from hospital, whereas the existence of comorbidities negatively influences the likelihood of woundless discharge from hospital. The study also suggests that the existence of spastic paralysis, preoperative infection of the wound, or surgical reduction of the ischial tubercle speeds up the healing of the wound. However, the wound failed to heal significantly more often in patients with increasing white blood cell count after surgery. PMID- 29509116 TI - Medicine and Contextual Justice. AB - This article provides a critique of the monolithic accounts that define justice in terms of a single and often inappropriate goal. By providing an array of real examples, I argue that there is no simple definition of justice, because allocations that express justice are governed by a variety of reasons that reasonable people endorse for their saliency. In making difficult choices about ranking priorities, different considerations have different importance in different kinds of situations. In this sense, justice is a conclusion about whether an allocation reflects the human interests and priorities that are at stake. The article describes how several principles of justice have a legitimate place in medical allocations. To achieve justice within medical practice, professionals should focus on the human interests and compelling reasons for prioritizing specific principles within their specific medical domain. PMID- 29509115 TI - Delayed referral of patients with diabetic foot ulcers across Europe: patterns between primary care and specialised units. AB - OBJECTIVE: Diabetic foot ulceration (DFU) has the potential to deteriorate rapidly without prompt assessment and treatment. The aim of this study was to assess the referral patterns for DFU, from primary care to specialised diabetes foot care units. METHOD: A two-part, quantitative, online questionnaire was administered to GPs across four countries in Europe: France, the UK, Germany and Spain. The first part entailed a survey of GPs' perceptions of referrals for DFU. The second part of the questionnaire collected data on recently managed DFU cases. RESULTS: There were 600 questionnaires collected in the first part of the study (150 per country), and 1188 patient cases of DFU management were included in the second part. Up to 95% of patients had type 2 diabetes. Patients' complaints led to diagnosis, on average, 60% of the time, and the diagnosis was an incidental finding during a consultation 13-28% of the time. On average, only 40% of GPs completely agreed that they have clearly identified DFU clinical practitioners working in a hospital facility. In 55-66% of cases, the duration of DFU was unknown or DFU diagnosis was delayed more than three weeks from the onset of the wound. On average, 48% of patients were referred after an unknown duration or more than one month from the onset of DFU. CONCLUSION: Despite differences in health-care structures across Europe, delays in referral to specialist foot care teams seems to be a common theme. There is an ongoing need to educate GPs, nurses and patients to be more aware of the risk of DFU, and the need for prompt referral to specialist diabetic foot teams. PMID- 29509117 TI - Genetics and Justice: Must One Theory Fit All Contexts? AB - Appeals to social justice that argue medicine and healthcare should have certain priorities and not others are common. It is an obvious question to ask: What does social justice demand of the new genetic technologies? However, it is important to note that there are many theories and sub-theories of justice. There are utilitarian theories, libertarian theories, and egalitarian theories. There are so-called luck egalitarians, equality-as-fairness thinkers, and capability theorists, with each having his or her own distinctive approach to the distribution of medical goods and technologies, and to healthcare priorities. This article argues that the discussion surrounding this question is potentially hampered by an implicit assumption that if one theory of justice is applicable in one context, then it must also be applicable in others. Instead, it is proposed that one adopt the stance, influenced by Michael Waltzer, that different theories with their opposing principles may be applicable to different questions regarding justice and genetics. The specific view advanced is that to answer questions about what justice requires regarding the therapeutic and enhancement use of genetic techniques, a method of reflective equilibrium can show how intuitions, in context, may support different theories of justice. When particular pre theoretic ethical judgments are balanced against the theories that might explain or justify them, and are in accord with what seems emotionally acceptable, then it can be seen how different general theories may be applicable in the different contexts in which questions of justice and genetics arise. PMID- 29509118 TI - Editorial: Moving from Theory to Practice. PMID- 29509119 TI - Doctrines and Dimensions of Justice: Their Historical Backgrounds and Ideological Underpinnings. AB - Justice can be approached from many angles in ethical and political debates, including those involving healthcare, biomedical research, and well-being. The main doctrines of justice are liberal egalitarianism, libertarianism, luck egalitarianism, socialism, utilitarianism, capability approach, communitarianism, and care ethics. These can be further elaborated in the light of traditional moral and social theories, values, ideals, and interests, and there are distinct dimensions of justice that are captured better by some tactics than by others. In this article, questions surrounding these matters are approached with the hermeneutic idea of a distinction between "American" and "European" ways of thinking. PMID- 29509120 TI - Anarchism and Health. AB - This article looks at what anarchism has to offer in debates concerning health and healthcare. I present the case that anarchism's interest in supporting the poor, sick, and marginalized, and rejection of state and corporate power, places it in a good position to offer creative ways to address health problems. I maintain that anarchistic values of autonomy, responsibility, solidarity, and community are central to this endeavor. Rather than presenting a case that follows one particular anarchist theory, my main goal is to raise issues and initiate debate in this underresearched field in mainstream bioethics. PMID- 29509121 TI - Perchance to Dream: Pathology, Pharmacology, and Politics in a 24-Hour Economy. AB - The lack of sleep is a significant problem in the modern world. The structure of the economy means that 24 hour working is required from some of us, sometimes because we are expected to be able to respond to share-price fluctuations on the other side of the planet, sometimes because we are expected to serve kebabs to people leaving nightclubs, and sometimes because lives depend on it. The immediate effect is that we feel groggy; but there may be much more sinister long term effects of persistent sleep deprivation and disruption, the evidence for which is significant, and worth taking seriously. If sleeplessness has a serious impact on health, it represents a notable public health problem. In this article, I sketch that problem, and look at how exploiting the pharmacopoeia (or a possible future pharmacopoeia) might allow us to tackle it. I also suggest that using drugs to mitigate or militate against sleeplessness is potentially morally and politically fraught, with implications for social justice. Hence, whatever reasons we have to use drugs to deal with the problems of sleeplessness, we ought to be careful. PMID- 29509122 TI - Charting Regulatory Stewardship in Health Research: Making the Invisible Visible. AB - This section focuses on the ethical, legal, social, and policy questions arising from research involving human and animal subjects. PMID- 29509123 TI - Beyond the Waiver: An Ethical Approach to Discharge Against Medical Advice. PMID- 29509124 TI - Can Theories of Global Justice Be Useful in Humanitarian Response? AB - Why is it that humanitarianism and theories of global justice seem to have relatively little engagement with each other? This article discusses some of the reasons for this being the case, and argues that instead of seeing these two fields as separate or adversarial they should be viewed as complementary. The article begins with a brief overview of humanitarianism, in order to argue for the relevance of justice in humanitarianism. The second section focuses on analyzing selected theories of justice- those of Peter Singer, John Kekes, and Thomas Pogge-through a particular lens, that of the question of responsibility for global well-being. The article concludes by arguing that theories of global justice can be beneficial for humanitarian causes, not in a comprehensive and consistent "all-or-nothing" manner, but rather on a case-by-case basis and through selective application of particular arguments. PMID- 29509125 TI - Controlling Healthcare Costs: Just Cost Effectiveness or "Just" Cost Effectiveness? AB - Meeting healthcare needs is a matter of social justice. Healthcare needs are virtually limitless; however, resources, such as money, for meeting those needs, are limited. How then should we (just and caring citizens and policymakers in such a society) decide which needs must be met as a matter of justice with those limited resources? One reasonable response would be that we should use cost effectiveness as our primary criterion for making those choices. This article argues instead that cost-effectiveness considerations must be constrained by considerations of healthcare justice. The goal of this article will be to provide a preliminary account of how we might distinguish just from unjust or insufficiently just applications of cost-effectiveness analysis to some healthcare rationing problems; specifically, problems related to extraordinarily expensive targeted cancer therapies. Unconstrained compassionate appeals for resources for the medically least well-off cancer patients will be neither just nor cost effective. PMID- 29509126 TI - The Quality Adjusted Life Year: A Total-Utility Perspective. AB - Given that a properly formed utilitarian response to healthcare distribution issues should evaluate cost effectiveness against the total utility increase, it follows that any utilitarian cost-effectiveness metric should be sensitive to increases in both individual and social utility afforded by a given intervention. Quality adjusted life year (QALY) based decisionmaking in healthcare cannot track increases in social utility, and as a result, the QALY cannot be considered a strict utilitarian response to issues of healthcare distribution. This article considers arguments against, and a possible defence of, the QALY as a utilitarian concept; in response, the article offers a similar - but properly formed - utilitarian metric called the (IALY). This article also advances a tool called the 'glee factor' (GF) on which the IALY may lean in a similar way to which the QALY leans on the Rosser Index. PMID- 29509127 TI - Justice at the Workplace: A Review. AB - Modern work life is characterized by constant change, reorganizations, and requirements of efficiency, which make the distribution of resources and obligations, as well as justice in decisionmaking, highly important. In the work life context, it is a question not only of distributing resources and obligations, but also of the procedures and rules that guide the decisionmaking in the organization. Studies of these rules and procedures have provided the basis for a new line of research that evaluates leadership and social relationships in working communities; that is, distributive, procedural, and relational justice. This review follows the development of research on organizational justice from its origins in early social and motivational psychological theories to its establishment as a major line of research in modern work and organizational psychology. The adverse consequences of injustice include poor team climate, reduced productivity and well-being, and work-related illnesses. PMID- 29509129 TI - Ethics of Virtual Reality in Medical Education and Licensure. AB - The aim of this section is to expand and accelerate advances in curriculum developments and in methods of teaching bioethics. PMID- 29509128 TI - The Effects of Closed-Loop Brain Implants on Autonomy and Deliberation: What are the Risks of Being Kept in the Loop? AB - Neuroethics Now welcomes articles addressing the ethical application of neuroscience in research and patient care, as well as its impact on society. PMID- 29509130 TI - A drag force interpolation model for capsule-shaped cells in fluid flows near a surface. AB - We report an interpolation model to calculate the hydrodynamic force on tethered capsule-shaped cells in micro-fluidic flows near a surface. Our model is based on numerical solutions of the full Navier-Stokes equations for capsule-shaped objects considering their geometry, aspect ratio and orientation with respect to fluid flow. The model reproduced the results from computational fluid dynamic simulations, with an average error of <0.15 % for objects with an aspect ratio up to 5, and the model exactly reproduced the Goldman approximation of spherical objects close to a surface. We estimated the hydrodynamic force imposed on tethered Escherichia coli cells using the interpolation model and approximate models found in the literature, for example, one that assumes that E. coli is ellipsoid shaped. We fitted the 2D-projected area of a capsule and ellipsoid to segmented E. coli cells. We found that even though an ellipsoidal shape is a reasonable approximation of the cell shape, the capsule gives 4.4 % better agreement, a small difference that corresponds to 15 % difference in hydrodynamic force. In addition, we showed that the new interpolation model provides a significantly better agreement compared to estimates from commonly used models and that it can be used as a fast and accurate substitute for complex and computationally heavy fluid dynamic simulations. This is useful when performing bacterial adhesion experiments in parallel-plate flow channels. We include a MATLAB script that can track cells in a video time-series and estimate the hydrodynamic force using our interpolation formula. PMID- 29509131 TI - Methanolobus psychrotolerans sp. nov., a psychrotolerant methanoarchaeon isolated from a saline meromictic lake in Siberia. AB - A psychrotolerant, methylotrophic methanogen, strain YSF-03T, was isolated from the saline meromictic Lake Shira in Siberia. Cells of strain YSF-03T were non motile, irregular cocci and 0.8-1.2 um in diameter. The methanogenic substrates utilized by strain YSF-03T were methanol and trimethylamine. The temperature range of growth for strain YSF-03T was from 0 to 37 degrees C. The optimum growth conditions were 30-37 degrees C, pH 7.0-7.4 and 0.17 M NaCl. The G+C content of the genome of strain YSF-03T was 41.3 mol%. Phylogenetic analysis revealed that strain YSF-03T was most closely related to Methanolobus profundi MobMT (98.15 % similarity in 16S rRNA gene sequence). Genome relatedness between strain YSF-03T and MobMT was computed using the Genome-to-Genome Distance Calculator and average nucleotide identity, which gave values of 23.5 and 79.3 %, respectively. Based on the morphological, phenotypic, phylogenetic and genomic relatedness data presented here, it is evident that strain YSF-03T represents a novel species of the genus Methanolobus, for which the name Methanolobus psychrotolerans sp. nov. is proposed. The type strain is YSF-03T (=BCRC AR10049T=DSM 104044T=NBRC 112514T). PMID- 29509132 TI - The protective effect and diagnostic performance of NOX-5 in Crimean-Congo haemorrhagic fever patients. AB - INTRODUCTION: Crimean-Congo haemorrhagic fever (CCHF) is an acute viral haemorrhagic disease. Reactive oxygen species that are mainly generated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme family have a pivotal role in the pathophysiology of many diseases. The serum levels of NOX isoforms in patients with CCHF have yet to be assessed. METHODS: This prospective study was conducted at Cumhuriyet University, Turkey. Only patients with CCHF confirmed by the National Reference Virology Laboratory were enrolled in the study. The study subjects comprised 67 CCHF patients and 70 healthy control subjects. The quantitative sandwich ELISA technique was used for the determination of serum NOX 1, 2, 4 and 5. RESULTS: Higher median median NOX-1 (P=0.001) and NOX-5 (P<0.001) levels were found in patients compared to the control group. Higher median serum NOX-5 levels were found in the low-grade disease group compared to the intermediate-high disease group according to two different severity scores (P=0.003). Negative correlations were also found between the serum NOX-5 levels and the severity scores [(P<0.05, r=-0.259), (P<0.01, r=-0.417)]. The area under the curve (AUC) values for the NOX-1 and NOX 5 were 0.67 (confidence interval: 0.58-0.75) and 0.99 (confidence interval: 0.95 1.00), respectively. Lower NOX-5 levels were found in patients receiving thrombocyte suspension (P=0.004)Conclusions. NOX-5 may have a protective effect on CCHF patients and the measurement of serum NOX-5 levels may be used as a novel biochemical test in the diagnosis of CCHF. PMID- 29509133 TI - Proteus alimentorum sp. nov., isolated from pork and lobster in Ma'anshan city, China. AB - Two strains of Gram-stain-negative, facultatively anaerobic short-rod bacteria were recovered from two different food samples in Ma'anshan city, Anhui province, China in 2008. The bacteria were characterized in a polyphasic taxonomic study that included phenotypic, phylogenetic and genotypic methodologies. Phylogenetic analysis of the 16S rRNA gene demonstrated that the two strains belonged to the genus Proteus and were most similar to Proteus vulgaris ATCC 29905T with a score of 99.7 %. Phylogenetic analysis of the rpoB gene placed the two strains into a cluster with a distinctly interspecies phylogenetic branch that was clearly separated from six type strains of the genus Proteus, with the most closely related species being Proteus mirabilis ATCC 29906T. In silico genomic comparisons, including in silico DNA-DNA hybridization (isDDH) and average nucleotide identity (ANI) analysis showed that the representative strain, 08MAS0041T, and all six Proteus species share less than 70 % isDDH and have a 95 % ANI cutoff level, supporting the designation of the two strains as a novel species of the genus Proteus. The predominant cellular fatty acids of strain 08MAS0041T were C16 : 0 (24.8 %), C16 : 1omega7c/16 : 1omega6c (16.5 %), C18 : 1omega6c/C18 : 1omega7c (14.5 %), C17 : 0 cyclo (12.6 %) and C16 : 1iso I/C14 : 0 3-OH (10.6 %). The analysis of biochemical, phylogenetic and genomic data confirmed that the two strains were clearly different from all recognized species of the genus Proteus and represent a novel Proteus species, for which the name Proteus alimentorum sp. nov. is proposed. The type strain is 08MAS0041T (=DSM 104685T=CGMCC 1.15939T). PMID- 29509134 TI - Human respiratory syncytial virus: prevalence, viral co-infections and risk factors for lower respiratory tract infections in children under 5 years of age at a general hospital in the Democratic Republic of Congo. AB - PURPOSE: This study aimed to determine the prevalence of human respiratory syncytial virus (HRSV) acute respiratory infection (ARI) in children under the age of 5 years at the Provincial General Hospital of Bukavu (PGHB), and to analyse factors associated with the risk of ARI being diagnosed as lower respiratory tract infection (LRTI). METHODOLOGY: A total of 146 children under 5 years visiting the PGHB for ARI between August and December 2016 were recruited, and socio-demographic information, clinical data and nasopharyngeal swabs were collected. The samples were analysed by a multiplex reverse transcriptase polymerase chain reaction targeting 15 different viruses. RESULTS: Of 146 samples collected, 84 (57.5 %) displayed a positive result of at least one of the 15 viruses. The overall prevalence of HRSV was 21.2 %. HRSV A (30, 20.5 %) was the virus the most detected, followed by HRV (24, 16.4 %), PIV3 (20, 16.6) and ADV (7, 4.79 %). The other viruses were detected in three or fewer cases. There were only 11 (7.5 %) cases of co-infection. HRSV infection, malnutrition, younger age, rural settings, low income and mother illiteracy were associated with the risk of ARI being diagnosed as LRTI in bivariate analyses but, after adjusting for the confounding factors, only HRSV infection and younger age were independently associated with LRTI. CONCLUSION: The prevalence of HRSV is high among children visiting the PGHB for ARI. HRSV infection and lower age are independently associated with the risk of ARI being diagnosed as LRTI. PMID- 29509135 TI - Rubritalea profundi sp. nov., isolated from deep-seawater and emended description of the genus Rubritalea in the phylum Verrucomicrobia. AB - A Gram-stain-negative, short-rod, facultatively anaerobic, non-motile and red pigmented bacterium, designated SAORIC-165T, was isolated from a deep-seawater sample collected from the Pacific Ocean. The 16S rRNA gene sequence analysis showed that strain SAORIC-165T was most closely related to Rubritalea marina Pol012T (95.7 % sequence similarity) and formed a robust phylogenetic clade with other species of the genus Rubritalea in the phylum Verrucomicrobia. Optimal growth of strain SAORIC-165T was observed at 10 degrees C, pH 7.0 and in the presence of 2.0-3.5 % (w/v) NaCl. The DNA G+C content of strain SAORIC-165T was 50.7 mol% and MK-9 was the predominant isoprenoid quinone. The major cellular fatty acids were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C14 : 0, anteiso-C15 : 0, C16 : 0 and C14 : 0. The major polar lipids constituted phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and unidentified phospholipids and aminolipids. On the basis of the taxonomic data obtained in this study, it was concluded that strain SAORIC-165T represented a novel species of the genus Rubritalea, for which the name Rubritalea profundi sp. nov. is proposed. The type strain of Rubritalea profundi is SAORIC-165T (=NBRC 110691T=KCTC 52460T). PMID- 29509136 TI - Hypervirulence and biofilm production in KPC-2-producing Klebsiella pneumoniae CG258 isolated in Brazil. AB - In this study, we describe the frequency of virulence genes in Klebsiella pneumoniae carbapenemase-2-producing Klebsiella pneumoniae (KPC-KP), including hypervirulent (hv) and hypermucoviscous (hm) strains by whole-genome sequencing. We also evaluate the capacity for biofilm formation by using phenotypic techniques. The occurrence of several virulence genes (fimABCDEFGHIK, mrkABCDFHJ, ecpA, wabG, entB, ugE, irp1, irp2, traT, iutA and ureADE) and a high frequency of hvhmKPC-KP isolates was found. Most hospital-associated lineages of KPC-KP belong to the international clonal group 258 (CG258). Biofilm formation was a constant feature among 90.9 % of KPC-KP strains. This report suggests a close relationship between ST437 and weak biofilm production, given that all weakly biofilm producing strains belonged to this sequence type. This also supports the dissemination of KPC-KP containing numerous virulence determinants belonging to the biofilm-producing CG258 type in Brazil, including hv and hm strains. These factors allow this pathogen to cause infections, leading to its rapid expansion and persistence in hospital settings. PMID- 29509138 TI - 2018 Trauma Association of Canada Annual Scientific Meeting Abstracts. PMID- 29509137 TI - A novel prophage identified in strains from Salmonella enterica serovar Enteritidis is a phylogenetic signature of the lineage ST-1974. AB - Salmonella enterica serovar Enteritidis is a major agent of foodborne diseases worldwide. In Uruguay, this serovar was almost negligible until the mid 1990s but since then it has become the most prevalent. Previously, we characterized a collection of strains isolated from 1988 to 2005 and found that the two oldest strains were the most genetically divergent. In order to further characterize these strains, we sequenced and annotated eight genomes including those of the two oldest isolates. We report on the identification and characterization of a novel 44 kbp Salmonella prophage found exclusively in these two genomes. Sequence analysis reveals that the prophage is a mosaic, with homologous regions in different Salmonella prophages. It contains 60 coding sequences, including two genes, gogB and sseK3, involved in virulence and modulation of host immune response. Analysis of serovar Enteritidis genomes available in public databases confirmed that this prophage is absent in most of them, with the exception of a group of 154 genomes. All 154 strains carrying this prophage belong to the same sequence type (ST-1974), suggesting that its acquisition occurred in a common ancestor. We tested this by phylogenetic analysis of 203 genomes representative of the intraserovar diversity. The ST-1974 forms a distinctive monophyletic lineage, and the newly described prophage is a phylogenetic signature of this lineage that could be used as a molecular marker. The phylogenetic analysis also shows that the major ST (ST-11) is polyphyletic and might have given rise to almost all other STs, including ST-1974. PMID- 29509139 TI - Determination of reference intervals and comparison of venous blood gas parameters using a standard and nonstandard collection method in 51 dogs. AB - INTRODUCTION: The aim of this study was to determine reference intervals (RI) for venous blood parameters determined with the RAPIDPoint 500 (RP500) blood gas analyzer using blood gas syringes (BGS) and to determine whether immediate analysis of venous blood collected into lithium heparin (LH) tubes can replace anaerobic blood sampling into BGS. The null hypothesis was that canine venous blood samples collected in BGS and in LH tubes are comparable. Jugular blood was collected from 51 healthy dogs into a BGS and a LH tube. The BGS was immediately analyzed followed by the LH tube. The RI were calculated from BGS results. The BGS and LH tubes results were compared using paired t-test or Wilcoxon matched pairs signed-rank test and Bland-Altman analysis. To assess clinical relevance, the bias between BGS and LH tubes was compared with the allowable total error (TEa). Values derived from LH tubes showed no significant difference for standard bicarbonate (HCO3std), whole blood base excess (BE B), Na, K, Cl, glucose and hemoglobin (tHb). The pH, partial pressure of carbon dioxide and oxygen, actual bicarbonate, extracellular base excess, ionized Ca, anion gap and lactate were significantly (p. PMID- 29509140 TI - [Efficacy of the combination of glucocorticoids, mycophenolate-mofetil and human immunoglobulin for the therapy of immune mediated haemolytic anaemia in dogs]. AB - INTRODUCTION: Idiopathic immune-mediated haemolytic anaemia (IMHA) is one of the most common immune-mediated diseases in dogs with a high mortality rate. In this retrospective study, we examined the effect of mycophenolate- mofetil (MMF) and human intravenous immunoglobulin (hIVIG) in combination with glucocorticoids on canine IMHA patients. Six dogs were treated with prednisolone and MMF (hIVIG-) and in 15 patients hIVIG was added (hIVIG+). There was no significant difference between the groups regarding age, weight, number of blood transfusions or hematocrit on the day of diagnosis. The hIVIG+ group showed a significantly faster recovery of the hematocrit, but this difference was only short-lived. The survival in the first year was similar in both groups and was with 71.5% somewhat higher than in other published studies. The addition of MMF to prednisolone for the treatment of dogs with acute IMHA was well tolerated and seemed to positively affect the course of the disease. Randomized studies are necessary to confirm this observation. Human immunoglobulin had only minimal clinical advantages and no effect on mortality. PMID- 29509141 TI - [Fanconi-Bickel-Syndrom: a novel genetic disease in Original Braunvieh]. AB - INTRODUCTION: This case report describes a new genetic disease of the Braunvieh breed in Switzerland. The bovine disorder also occurs in German Fleckvieh, and corresponds to human Fanconi-Bickel syndrome which is an inherited glycogen storage disease caused by mutations of the SLC2A2 gene encoding the glucose transporter GLUT2. This case report describes a single affected Original Braunvieh calf genotyped as homozygous for the FH2-associated SLC2A2 frame shift mutation. The clinical examination showed stunted growth, polyuria and polydipsia, as well as poor claw horn and coat quality. Necropsy revealed a pale cortex of the kidneys and a unilateral renal hypoplasia. Histology showed tubulonephrosis of the proximal tubules with protein- and glucose-rich contents. Glycogen accumulation was not evident in any organ. This finding is different from the reported lesions in two previously described GLUT2-deficient Fleckvieh heifers. In the presented case, growth retardation mainly seems to be associated with renal dysfunction. A direct gene test is available to eliminate the mutant allele from the population. PMID- 29509142 TI - [Tularemia in a jogger woman after the attack by a common buzzard (Buteo buteo): A "One Health" case report]. AB - INTRODUCTION: A female jogger was attacked by a common buzzard (Buteo buteo) and was scratched lightly at the back of the head. One week later she was taken ill with high fever and headache which was later diagnosed as ulcero-glandular tularemia in regional lymph nodes, caused by Francisella tularensis. Recovery was only achieved after several weeks of systemic antibiotic treatment (Gentamicin/ Ciprofloxacine). Tularemia is a well known zoonotic disease, called "rabbit fever", mainly affecting rabbits and hares, but also small rodents. Human infection occurs often following tick bites or bloodsucking insects, or in hunters or slaughterers handling infected animals. Bites by mice have also been reported as a cause of tularemia. For the first time we report this case of tularemia as a result of an attack by a bird of prey. We assume that the bird acted as a vector just carrying the F. tularensis on its claws or beak, but we cannot exclude an infection of the bird itself. Several other joggers had also been attacked by a common buzzard in the same area shortly after the above described event and one of these also became infected with F. tularensis. PMID- 29509143 TI - Acoustic radiation force induced resonance elastography of coagulating blood: theoretical viscoelasticity modeling and ex-vivo experimentation. AB - Deep vein thrombosis is a common vascular disease that can lead to pulmonary embolism and death. The early diagnosis and clot age staging are important parameters for reliable therapy planning. This article presents an acoustic radiation force induced resonance elastography method for the viscoelastic characterization of clotting blood. The physical concept of this method relies on the mechanical resonance of the blood clot occurring at specific frequencies. Resonances are induced by focusing ultrasound beams inside the sample under investigation. Coupled to an analytical model of wave scattering, the ability of the proposed method to characterize the viscoelasticity of a mimicked venous thrombosis in the acute phase is demonstrated. Experiments with a gelatin-agar inclusion sample of known viscoelasticity are performed for validation and establishment of the proof of concept. In addition, an inversion method is applied in-vitro for the kinetic monitoring of the blood coagulation process of six human blood samples obtained from two volunteers. The computed elasticity and viscosity values of blood samples at the end of the 90 min kinetics were estimated at 411 +/- 71 Pa and 0.25 +/- 0.03 Pa.s for volunteer #1, and 387 +/- 35 Pa and 0.23 +/- 0.02 Pa.s for volunteer #2, respectively. The proposed method allowed reproducible time-varying thrombus viscoelastic measurements from samples having physiological dimensions. PMID- 29509144 TI - Principles and technicalities: The Bernard Wheatley Award for 2017. PMID- 29509145 TI - Low-field magnetotransport in graphene cavity devices. AB - Confinement and edge structures are known to play significant roles in the electronic and transport properties of two-dimensional materials. Here, we report on low-temperature magnetotransport measurements of lithographically patterned graphene cavity nanodevices. It is found that the evolution of the low-field magnetoconductance characteristics with varying carrier density exhibits different behaviors in graphene cavity and bulk graphene devices. In the graphene cavity devices, we observed that intravalley scattering becomes dominant as the Fermi level gets close to the Dirac point. We associate this enhanced intravalley scattering to the effect of charge inhomogeneities and edge disorder in the confined graphene nanostructures. We also observed that the dephasing rate of carriers in the cavity devices follows a parabolic temperature dependence, indicating that the direct Coulomb interaction scattering mechanism governs the dephasing at low temperatures. Our results demonstrate the importance of confinement in carrier transport in graphene nanostructure devices. PMID- 29509146 TI - Tuning the morphology of self-assisted GaP nanowires. AB - Patterned arrays of self-assisted GaP nanowires (NWs) were grown on a Si substrate by gas source molecular beam epitaxy using various V/III flux ratios from 1-6, and various pitches from 360-1000 nm. As the V/III flux ratio was increased from 1-6, the NWs showed a change in morphology from outward tapering to straight, and eventually to inward tapering. The morphologies of the self assisted GaP NWs are well described by a simple kinetic equation for the NW radius versus the position along the NW axis. The most important growth parameter that governs the NW morphology is the V/III flux ratio. Sharpened NWs with a stable radius equal to only 12 nm at a V/III flux of 6 were achieved, demonstrating their suitability for the insertion of quantum dots. PMID- 29509147 TI - Catalyst-substrate interaction and growth delay in vapor-liquid-solid nanowire growth. AB - Understanding of the initial stage of nanowire growth on a bulk substrate is crucial for the rational design of nanowire building blocks in future electronic and optoelectronic devices. Here, we provide in situ scanning electron microscopy and Auger microscopy analysis of the initial stage of Au-catalyzed Ge nanowire growth on different substrates. Real-time microscopy imaging and elementally resolved spectroscopy clearly show that the catalyst dissolves the underlying substrate if held above a certain temperature. If the substrate dissolution is blocked (or in the case of heteroepitaxy) the catalyst needs to be filled with nanowire material from the external supply, which significantly increases the initial growth delay. The experiments presented here reveal the important role of the substrate in metal-catalyzed nanowire growth and pave the way for different growth delay mitigation strategies. PMID- 29509148 TI - Dose distribution of secondary radiation in a water phantom for a proton pencil beam-EURADOS WG9 intercomparison exercise. AB - Systematic 3D mapping of out-of-field doses induced by a therapeutic proton pencil scanning beam in a 300 * 300 * 600 mm3 water phantom was performed using a set of thermoluminescence detectors (TLDs): MTS-7 (7LiF:Mg,Ti), MTS-6 (6LiF:Mg,Ti), MTS-N (natLiF:Mg,Ti) and TLD-700 (7LiF:Mg,Ti), radiophotoluminescent (RPL) detectors GD-352M and GD-302M, and polyallyldiglycol carbonate (PADC)-based (C12H18O7) track-etched detectors. Neutron and gamma-ray doses, as well as linear energy transfer distributions, were experimentally determined at 200 points within the phantom. In parallel, the Geant4 Monte Carlo code was applied to calculate neutron and gamma radiation spectra at the position of each detector. For the cubic proton target volume of 100 * 100 * 100 mm3 (spread out Bragg peak with a modulation of 100 mm) the scattered photon doses along the main axis of the phantom perpendicular to the primary beam were approximately 0.5 mGy Gy-1 at a distance of 100 mm and 0.02 mGy Gy-1 at 300 mm from the center of the target. For the neutrons, the corresponding values of dose equivalent were found to be ~0.7 and ~0.06 mSv Gy-1, respectively. The measured neutron doses were comparable with the out-of-field neutron doses from a similar experiment with 20 MV x-rays, whereas photon doses for the scanning proton beam were up to three orders of magnitude lower. PMID- 29509149 TI - Interior tomography in microscopic CT with image reconstruction constrained by full field of view scan at low spatial resolution. AB - In high resolution (microscopic) CT applications, the scan field of view should cover the entire specimen or sample to allow complete data acquisition and image reconstruction. However, truncation may occur in projection data and results in artifacts in reconstructed images. In this study, we propose a low resolution image constrained reconstruction algorithm (LRICR) for interior tomography in microscopic CT at high resolution. In general, the multi-resolution acquisition based methods can be employed to solve the data truncation problem if the project data acquired at low resolution are utilized to fill up the truncated projection data acquired at high resolution. However, most existing methods place quite strict restrictions on the data acquisition geometry, which greatly limits their utility in practice. In the proposed LRICR algorithm, full and partial data acquisition (scan) at low and high resolutions, respectively, are carried out. Using the image reconstructed from sparse projection data acquired at low resolution as the prior, a microscopic image at high resolution is reconstructed from the truncated projection data acquired at high resolution. Two synthesized digital phantoms, a raw bamboo culm and a specimen of mouse femur, were utilized to evaluate and verify performance of the proposed LRICR algorithm. Compared with the conventional TV minimization based algorithm and the multi-resolution scout reconstruction algorithm, the proposed LRICR algorithm shows significant improvement in reduction of the artifacts caused by data truncation, providing a practical solution for high quality and reliable interior tomography in microscopic CT applications. The proposed LRICR algorithm outperforms the multi resolution scout-reconstruction method and the TV minimization based reconstruction for interior tomography in microscopic CT. PMID- 29509150 TI - Medically intractable partial epilepsy. PMID- 29509151 TI - The New millennium : unfinished agenda and tasks ahead. PMID- 29509152 TI - Early onset cerebellar ataxia with retained tendon reflexes comparison with Friedreich's ataxia and olivopontocerebellar atrophy : an evoked potential study. AB - 14 patients with the clinical diagnosis of early onset cerebellar ataxia with retained tendon reflexes (EOCA) were evaluated by multimodal evoked potential (EP) studies. The results were compared with observations made on 10 patients with Friedreich's ataxia (FA) and 16 patients with olivopontocerebellar atrophy (OPCA). Ten patients (71.4) with EOCA had abnormality of at least one of the EP parameters. Brainstem auditory evoked response (BAER) studies were abnormal in 50, followed by abnormalities in posterior tibial somatosensory evoked potential (SSEP) (46.1), visual evoked potential (VEP) and median SSEP (30.8 each). Only the abnormality of posterior tibial SSEP had a positive correlation with the duration of disease. The abnormalities in SSEP were more frequent in EOCA than in OPCA and were comparable to that of FA patients. On the contrary, abnormalities of VEP and BAER in EOCA patients were significantly less common (especially VEP) than in FA patients and were almost comparable to OPCA. Thus, on the basis of conventional evoked potential studies, EOCA patients seem to share some common features of FA and OPCA patients. There was no single EP feature to characterize EOCA as a distinct entity. PMID- 29509153 TI - Surgery of perirolandic mass lesions with central sulcus mapping. AB - In a series of forty eight consecutive patients with parenchymatous mass lesions in the perirolandic area the central sulcus was identified intraoperatively in forty six. In patients in whom the mass lesion was seen on the surface, the relationship of the lesion to the somatosensory cortex and its underlying white matter was precisely determined. When the lesion was subcortical, the relationship of the mass lesion to the central sulcus on the MR image together with the central sulcus identified peroperatively, again, helped to determine the exact site of the tumour. Knowledge of the exact location of the tumour in relation to the central sulcus helped in the radical excision of seventy seven percent of these tumours. The morbidity following the operation was minimal. PMID- 29509154 TI - Intraparenchymal cerebellar schwannoma. AB - A case of left cerebellar intraparenchymal schwannoma in an adult is being presented along with ten available reports in the literature, differential diagnosis and management of the condition. PMID- 29509155 TI - Changes in the glycosaminoglycans, glycoproteins and lipid components of erythrocyte membrane in neuroacanthocytosis. AB - Changes in the glycosaminoglycans (GAG), glycoproteins (GP) and lipid components of erythrocyte membrane were studied in two patients of neuroacanthocytosis, as compared to normal, control subjects. Concentration of GAG, decreased in the erythrocytemembrane in patients of neuroacanthocytosis while the carbohydrate components of the glycoproteins showed alterations both quantitatively and qualitatively. The ratio of W6 to W3 fatty acids showed increase in the erythrocyte membrane in neuroacanthocytosis patients while the ratio of cholesterol to phospholipids was decreased. PMID- 29509156 TI - Marinesco Sjogren syndrome : a case report. AB - Three members of one family suffering from Marinesco Sjogren syndrome are being reported. All the three cases had mental retardation, congenital bilateral cataracts and cerebellar ataxia. It is a rare autosomal recessive disorder. PMID- 29509157 TI - Primary melanoma of the pineal gland. AB - Primary leptomeningeal melanoma presenting as a lesion in the region of the pineal gland is rare. The MRI characteristic of this interesting condition is described and its value in studying spread or other foci is emphasized. PMID- 29509159 TI - Spinal extradural cavernous haemangioma. AB - A case of spinal extradural cavernous haemangioma without a vertebral lesion is reported. Clinical and radiological features of the lesion are discussed. Relevant literature is reviewed. PMID- 29509158 TI - Oral facial digital syndrome. AB - We report a female infant with features suggestive of Oral Facial Digital Syndrome (OFDS) Type I and associated cerebellar anomalies with Dandy-Walker malformation which suggest OFDS Type VI. The phenotypic overlap in this child OFDS type I and TypeVI raises the question as to whether they represent separate genetic entities. This pattern of abnormalities appears to be unique. PMID- 29509160 TI - Wegener's granulomatosis : a case with multiple symmetric cranial neuropathies. AB - A 47 year-old woman with Wegener's granulomatosis presented with an atypical onset of multiple symmetric cranial nerve involvement. The diagnosis was established by clinical examination and laboratory data. To our knowledge, this is the first case of Wegener's granulomatosis presenting with bilateral multiple symmetric cranial neuropathies. PMID- 29509161 TI - Miliary tuberculosis presenting with brain tuberculomas. PMID- 29509162 TI - Trapped temporal horn. PMID- 29509163 TI - Post traumatic CSF blepherocele. PMID- 29509164 TI - Paraldehyde in the management of simple partial status epilepticus. PMID- 29509165 TI - Acute transverse myelitis following electrical injury. PMID- 29509166 TI - Aplasia cutis congenita in two infants exposed to carbamazepine in utero. PMID- 29509168 TI - Ceftriaxone-Associated Leukocytoclastic Vasculitis. PMID- 29509167 TI - Impact of CYP2C19 Polymorphisms on Clinical Outcomes and Antiplatelet Potency of Clopidogrel in Caucasian Poststroke Survivors. AB - BACKGROUND: Variable response after clopidogrel is well documented and may affect major adverse clinical events after stroke. Impact of CYP2C19 genetic polymorphisms is an established marker linked to variable response after clopidogrel. However, the association of certain genetic polymorphisms with prediction of major adverse clinical events following stroke still remains controversial, especially in Caucasians. STUDY QUESTION: The primary aim was to evaluate the impact of CYP2C19 allele *2 in heterozygote form on major adverse clinical events in Caucasian poststroke survivors treated with clopidogrel. The secondary aim was to analyze the potential link between CYP2C19 genetic polymorphism and variable response after clopidogrel. STUDY DESIGN: One hundred thirty patients of Caucasian origin following documented ischemic stroke were included. Platelet reactivity was assessed by light transmittance aggregometry (LTA) and matched with various CYP2C19 loss-of-function genetic polymorphisms and major adverse clinical events (composite of vascular deaths, stroke/transient ischemic attack, and myocardial infarction). RESULTS: Over the mean follow-up of 14.9 months, 19 patients experienced major adverse clinical events. The risk of major adverse clinical events was nearly 3-fold in loss-of-function allele carriers (hazard ratio = 2.904; 95% confidence interval, 1.083-7.786; P = 0.013), whereas the risk of ischemic stroke or transient ischemic attack alone was also higher (hazard ratio = 3.170; 95% confidence interval, 1.281-7.849; P = 0.034). Platelet activity was strongly associated with allele *2 status (rs = 0.21, P = 0.016) but not with other genetic polymorphisms. Carriers of allele*2 exhibited lower platelet response to adenosine diphosphate-mean LTA (30.1% vs. 42.0%; P = 0.017). There were no significant differences in LTA results with other agonists. Strong association of increase in adenosine diphosphate-induced aggregation with diabetes mellitus (rs = 0.20, P = 0.023), increasing age (rs = 0.23, P = 0.008), and conversely diminishing over increased weight (rs = 0.23, P = 0.009) was also detected. The carriers of other gene allele variants lack uniformed impact on variable response after clopidogrel. CONCLUSIONS: Even heterozygous CYP2C19*2 allele carriers among Caucasian patients after ischemic stroke had a higher risk of major adverse clinical events. The LTA, however, did not predict major adverse clinical events. The exact clinical utility of these findings is still uncertain and requires large outcome-driven randomized trial in Caucasians for proof of concept. PMID- 29509169 TI - Testing a Model of Consultation-based Reassurance and Back Pain Outcomes With Psychological Risk as Moderator: A Prospective Cohort Study. AB - OBJECTIVES: Reassurance is an essential part of treatment for low back pain (LBP), but evidence on effective methods to deliver reassurance remains scarce. The interaction between consultation-based reassurance and patients' psychological risk is unknown. Our objective was to investigate the relationship between consultation-based reassurance and clinical outcomes at follow-up, in people with and without psychological risk. METHODS: We tested the associations between specific reassurance components (data gathering, relationship building, generic reassurance, and cognitive reassurance), patients' psychological risk (the presence of depression, anxiety, catastrophizing, or fear-avoidance), and postconsultation outcomes including, satisfaction and enablement, disability, pain, and mood at 3-month follow-up. RESULTS: Adjusted linear regression models using data from patients who had recently consulted for LBP in primary care (n=142 in 43 practices) indicated that all reassurance components were strongly associated with increased satisfaction, whereas generic reassurance was significantly associated with postconsultation enablement. Generic reassurance was also associated with lower pain at 3 months, whereas cognitive reassurance was associated with increased pain. A significant interaction was observed between generic reassurance and psychological risk for depression at 3 months: high rates of generic reassurance were associated with lower depression in low risk patients, but with higher rates of depression for high-risk groups. DISCUSSION: The findings support the hypothesis that different components of reassurance are associated with specific outcomes, and that psychological risk moderates this relationship for depression. Clinicians reassuring behaviors might therefore have the potential to improve outcomes in people with LBP, especially for patients with higher psychological risk profiles. PMID- 29509170 TI - Temporomandibular Joint Ankylosis: Algorithm of Treatment. AB - : : Temporomandibular joint ankylosis, according to age of onset, causes severe functional and morphological disorders, as well as stunted craniofacial growth and development.The primary goal of treatment is to resolve the functional and morphological disorders. METHOD: Pre- and posttreatment clinical and cephalometric registries were conducted in 15 patients with temporomandibular joint ankylosis over a 10-year period (2002-2012). All the patients underwent complete removal of the ankylotic block, gap arthroplasty, and ipsilateral coronoidectomy. Distraction osteogenesis was performed on 12 patients. RESULTS: Fifteen patients, 8 female and 7 male, ranging from 3 to 30 years of age, were included in this study. The posttreatment follow-up period ranged from 3 to 13 years.The mean preoperative maximum mouth opening was 3 +/- 1.7 mm, and the mean postoperative maximum mouth opening was 36 +/- 6.5 mm. The labial inclination with respect to the true horizontal decreased considerably (6.2 degrees +/- 2.3 degrees preoperative to 1 degrees +/- 1.6 degrees postoperative). A correction of the mandibular deviation was measured at the symphysis with respect to the facial midline (8 degrees +/- 2 degrees preoperative to 2 degrees postoperative). Finally, the height ratio of both mandibular rami (the healthy side and the affected side) decreased considerably (1.27 +/- 0.05 preoperative to 1.07 +/- 0.06 postoperative).Reankylosis only occurred in 2 patients, who were then successfully treated by means of gap arthroplasty. CONCLUSIONS: The therapeutic algorithm proposed in the present work provides favorable functional and morphological results. Early and aggressive functional physiotherapy is essential to minimize the risk of reankylosis. PMID- 29509171 TI - Effect Evaluation of Modified Uvulopalatopharyngoplasty With Low-Temperature Plasma and Selective Nasal Cavity Vasodilatation With Tongue Volume Reduction in Patients With Obstructive Sleep Apnea Hypopnea Syndrome. AB - OBJECTIVE: To compare the clinical effects of modified uvulopalatopharyngoplasty (UPPP) with low-temperature plasma with selective nasal cavity vasodilatation with tongue volume reduction for obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: A retrospective analysis based on 156 patients with serious OSAHS was used for the evaluation. These patients were divided into 2 groups according to surgery methods according to 1:1.s. The patients in observation group accepted modified UPPP with low-temperature plasma and selective nasal cavity vasodilatation with tongue root volume reduction on the basis of fully preparation for surgery, while the patients in the control group accepted normal treatment. The clinic effects, operative complications, postoperative relapse, and other indexes were compared. RESULT: After 6 months of follow-up visit, the general effective rates of the observation group and control groups were 80.77% and 61.54%, the difference was statistically significant (P < 0.05). Besides, the rate complication occurrence in the observation group was also lower than that in the control group. CONCLUSION: The effect of modified UPPP with low-temperature plasma and selective nasal cavity vasodilatation with tongue volume reduction is satisfactory for patients with moderate and severe OSAHS after enough preparation. PMID- 29509172 TI - Effect of Septoplasty on the Heart Rate Variability in Patients With Nasal Septum Deviation. AB - BACKGROUND: Nasal septum deformities (NSD) are one of the most common causes of upper airway obstruction. Heart rate variability (HRV) is a physiologic parameter that is affected by the balance between the sympathetic and parasympathetic tonus. OBJECTIVE: The aim of this study was to evaluate the effects of a septoplasty operation on HRV parameters as assessed by 24 hours ambulatory Holter recordings in patients with NSD. METHODS: The prospective study involved 54 consecutive patients (16 women and 38 men) who underwent septoplasty due to a marked C- or S-shaped NSD. Twenty-four-hour Holter monitoring was performed to all patients pre- and 2 months postseptoplasty operation. For the HRV analyses, the definitions of evaluated parameters were made according to the Task Force of European Society of Cardiology and the North American Society of Pacing and Electrophysiology on HRV. RESULTS: Low-frequency norm () (73 [68-86] versus 78 [70-81], P = 0.039) values were significantly increased after septoplasty whereas changes in other parameters were not statistically significant. CONCLUSION: The authors' study showed that low-frequency norm values were significantly increased after septoplasty operation in patients with NSD which may be interpreted as a decreased sympathetic tone. PMID- 29509173 TI - Management of Rare Craniofacial Anomalies With Soft Tissue Reconstruction on Humanitarian Missions. AB - In poor communities, patients may suffer from health problems requiring special management that cannot be provided locally because of lack of equipment and/or expertise. Children with craniofacial anomalies represent one of these challenging problems. Visiting medical missionary teams have attempted to address these issues for a long time. This article highlights healthcare difficulties in one of the third-world countries with personally based trials for providing free surgeries in tough situation and with hardly available diagnostic and therapeutic facilities. During 15 years, >5000 surgeries were performed in repeated missionary visits. The majority of operations were to correct post-burn complications or to repair cleft lip and/or palate. Of 33 cases of rare craniofacial anomalies, 14 patients were treated with simple soft tissue reconstruction without interference in the underlying bone deformities. This may not be optimal; however, it can give good results even with the limited resources. PMID- 29509174 TI - Sensory Innervation of the Upper Eyelid. AB - The aim of this study was to elucidate the sensory territory of the trigeminal nerve on the upper eyelid.Eight hemifaces from Korean cadavers were dissected. The frontal nerve (FN), supraorbital nerve (SON), supratrochlear nerve (STN), infratrochlear nerve (ITN), and lacrimal nerve (LN) were traced.The terminal branches to the eyelid margin of FN were distributed between 1/6 and 2/5 of the palpebral fissure width lateral to the medial canthus and 1/6 of the eyebrow height from eyelid margin. The SON was distributed between 2/5 and 9/10 of the eye width lateral to the medial canthus, at 1/3 of the eyebrow height. The STN was distributed between -1/4 and -1/5 of the eye width medial to the medial canthus, at 1/5 of the eyebrow height. The ITN was distributed at -1/4 and 1/10 of the eye width medial to the medial canthus, and at 1/5 of the eyebrow height. The LN was distributed between approximately 3/5 and 13/10 of the eye width lateral to the medial canthus, and at 1/4 of the eyebrow height. The main branches of FN and SON ran deep to the orbicularis from the supraorbital notch to the upper border of the tarsal plate. In the pretarsal area, they were between the orbicularis and tarsal plate. The STN and ITN were between the orbicularis and the skin. The LN was observed between the orbicularis and the tarsal plate.Upper eyelid was mainly supplied by SON and FN. The medial extremity was supplied by STN and ITN, and the lateral extremity by LN. PMID- 29509175 TI - Human Trafficking. PMID- 29509176 TI - Relationship Between Antipsychotic Medications and Cerebrovascular Disease in Patients With Serious Mental Illness. AB - INTRODUCTION AND OBJECTIVES: Cerebrovascular disease (CVD), especially in its asymptomatic forms, is relatively common in patients with serious mental illness (SMI). Nevertheless, the literature on this topic is scarce and sometimes contradictory. Antipsychotic medications, especially atypical agents, play an important role in the overall cardiovascular health of these patients. The goal of this study was to analyze the frequency of CVD in patients with and without SMI. PATIENTS AND METHODS: This retrospective cohort study compared the frequency of CVD, including silent forms, in a group of patients without mental illness and without a history of taking antipsychotic medication, with another group of patients diagnosed with SMI who had received antipsychotic treatment. The 2 groups were matched for age and sex, and the mean age of the subjects in the 2 groups was 63 years. RESULTS: The frequency of CVD was the same in both groups and it was not modified by the use of antipsychotic medications. A nonsignificant trend toward an association between CVD and prolonged use of antipsychotic polypharmacy was found. CONCLUSIONS: In this study, in contrast to previous reports, use of antipsychotic medications and the presence of SMI were not associated with an increased risk of CVD. PMID- 29509177 TI - Psychiatry's Role in the Management of Human Trafficking Victims: An Integrated Care Approach. AB - Human trafficking is an outrageous human rights violation with potentially devastating consequences to individuals and the public health. Victims are often underrecognized and there are few guidelines for how best to identify, care for, and safely reintegrate victims back into the community. The purpose of this paper is to propose a multifaceted, interdisciplinary, and interprofessional guideline for providing care and services to human trafficking victims. Databases such as PubMed and PsycINFO were searched for papers outlining human trafficking programs with a primary psychiatric focus. No integrated care models that provide decisional guidelines at different points of intervention for human trafficking patients and that highlight the important role of psychiatric consultation were found. Psychiatrists and psychologists are pivotal to an integrated care approach in health care settings. The provision of such a comprehensive and integrated model of care should facilitate the identification of victims, promote their recovery, and reduce the possibility of retraumatization. PMID- 29509178 TI - What Therapies are Favored in the Treatment of the Psychological Sequelae of Trauma in Human Trafficking Victims? AB - Human trafficking is a major public health concern that brings about deleterious psychological consequences and sequelae. Although a number of risk and protective factors for the health consequences of human trafficking victims have been identified, there is a dearth of information in the area of treatment. Specifically, we found no articles comparing the different components of prevailing trauma treatment strategies, and the potential usefulness of these strategies in the treatment of human trafficking victims. To this end, we compared and contrasted the different therapeutic treatments typically implemented with victims of trauma (including domestic violence victims and torture victims), and discussed how the different components of these treatments may or may not be helpful for human trafficking victims. We assessed the impact of these treatments on the psychological consequences of trauma and, in particular on posttraumatic stress disorder. We also assessed the potential usefulness of these treatments with co-occurring problems such as substance use, psychosis, dissociation, and other mood and anxiety disorders. On the basis of the prevailing research, we highlighted cognitive therapies as being preferred in addressing the needs of human trafficking victims. Mental health providers who work with human trafficking victims should become aware of and practiced in the use of cognitive therapeutic approaches in treating this population. Efficacy and effectiveness studies are needed to validate our recommendations. PMID- 29509179 TI - Does Late-onset Anorexia Nervosa Exist? Findings From a Comparative Study in Singapore. AB - OBJECTIVE: The incidence of cases of older onset anorexia nervosa (AN) has increased in recent years. However, the literature on late-onset AN has been inconclusive. The goal of this study was to compare late-onset with early-onset cases of AN. METHODS: Cases of AN presenting to an eating disorders treatment service were identified and the associated medical records were studied retrospectively. RESULTS: Of the 577 cases of AN that were studied, 7.1% were late-onset. Unlike the early-onset cases of AN, the late-onset cases reported less teasing and more relationship problems as a trigger for the illness. They were also less likely to join the eating disorders treatment program. Otherwise, the late-onset AN cases were largely similar to the early-onset cases. CONCLUSIONS: Although differences exist between early-onset and late-onset cases of AN, these are few. Until stronger evidence emerges over time, there currently seems to be minimal justification to accord late-onset AN a unique position in psychiatric nosology. PMID- 29509180 TI - CNS Drug Development, Lessons Learned, Part 5: How Preclinical and Human Safety Studies Inform the Approval and Subsequent Use of a New Drug-Suvorexant as an Example. AB - This column is the fifth in a series examining the advances being made in central nervous system drug development because of advances in molecular pharmacology and an improved understanding of the neurobiology underlying disturbances in brain function including psychiatric illnesses. This column covers the special animal and human studies conducted as part of the development of suvorexant, which is the first in the class of dual orexin 1 and 2 receptor antagonists to be approved; it has an indication for the treatment of disturbances in sleep onset and maintenance. The animal studies included determination of the therapeutic index of the drug (ie, lethal dose 50 which is the dose at which 50% of animals die following administration of the drug), adverse effects on fertility, teratogenicity, carcinogenicity, and ability to cause narcolepsy. The human studies included investigation of the effects of the drug on balance, memory, driving performance, and propensity to cause respiratory depression in normal volunteers and individuals with mild to moderate chronic obstructive pulmonary disorder or mild to moderate obstructive sleep apnea. This column illustrates how targeting the drug to one mechanism out of hundreds yields increased safety and highlights the importance of the package insert which summarizes the results of all of the studies from the drug's development program. PMID- 29509181 TI - Clinical and Insurance Perspectives on Intermediate Levels of Care in Psychiatry. AB - This column compares a clinical perspective on the continuum of care for mental health and substance use disorders with a different perspective derived from publicly available insurance company documents and experience dealing with managed care utilization reviewers. The latter perspective tends to determine the need for access to levels of care based on the need for crisis stabilization, whereas the generally accepted clinical standard is more nuanced than the need for crisis stabilization alone. The column proposes that this discrepancy in perspectives makes a substantial contribution to disagreements between treating clinicians, such as therapists, and insurance utilization reviewers concerning the medical necessity of various requested levels of care. PMID- 29509182 TI - Seizure Induced by a Therapeutic Dose of Venlafaxine ER: A Case Report. AB - Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor commonly used for the treatment of depression. Although listed as an adverse reaction, seizure activity associated with a therapeutic dose of venlafaxine has rarely been documented. A review of the literature reveals only 2 cases of venlafaxine-induced seizures, both of which were generalized tonic-clonic seizures in patients on doses at the higher end of the therapeutic range. We report the case of a 44-year-old woman undergoing antituberculosis therapy who suffered complex partial seizures after ingestion of a low therapeutic dose of venlafaxine extended release (ER). Her first seizure was observed soon after venlafaxine ER was titrated from 37.5 to 75 mg daily, with a total of 9 witnessed complex partial seizures. After titrating the dose of the venlafaxine ER back down to 37.5 mg daily and beginning lamotrigine anticonvulsant therapy, the patient exhibited no further seizures. The development of seizure activity under therapeutic dosing of venlafaxine should be brought to the attention of the health care prescriber. The potential for drug-drug interactions involving venlafazine, particularly in combination with multiple drugs, such as isoniazid and levofloxacin, needs to be recognized. PMID- 29509183 TI - Olanzapine-induced and Risperidone-induced Leukopenia: A Case of Synergistic Adverse Reaction? AB - Leukopenia is a known hematological side effect of atypical antipsychotics. We report a case of an antipsychotic-naive patient with schizophrenia who developed leukopenia after a single dose of olanzapine, which worsened during subsequent treatment with risperidone. Normalization of the white blood cell counts occurred within 24 hours of risperidone discontinuation. Possible synergistic mechanisms underlying olanzapine-induced and risperidone-induced leukopenia are discussed. This case highlights the challenges in identifying and managing nonclozapine antipsychotic-induced leukopenia in a susceptible patient. PMID- 29509184 TI - Commentary on 2 Cases of Rare but Serious Side Effects of Commonly Used Medications: Dilemmas in Clinical Decision-making. AB - In this issue of the journal, 2 case reports are presented that describe rare but serious side effects of commonly used medications. These cases illustrate dilemmas in clinical decision-making. The first describes the induction of seizures by low-dose venlafaxine in a predisposed individual, and the second describes the development of mild but significant leukopenia with sequential trials of olanzapine and risperidone. The association between a drug and a rare but potentially serious side effect in an individual patient can be difficult to determine with precision, and the decision to press ahead and try to work around the reaction, versus stopping the likely offender and finding a substitute, is a matter for seasoned clinical judgment. PMID- 29509185 TI - Beyond Social Media: A Cross-Sectional Survey of Other Internet and Mobile Phone Applications in a Community Psychiatry Population. AB - OBJECTIVE: Popular media applications have been shown to benefit people with severe mental illness by facilitating communication and social support, helping patients cope with or manage symptoms, and providing a way to monitor or predict mental health states. Although many studies of technology use by individuals with severe mental illness have focused primarily on use of social media, this study provides additional information about use of Internet applications such as blogs, wikis (websites that allow collaborative editing of content and structure by users), video games, and Skype by a community psychiatry population. METHODS: All English-speaking patients attending an outpatient program during a 4-week period in 2011 (N=274) were surveyed about their technology use and demographic information; 189 patients provided demographic data and comprised the sample. RESULTS: Among Internet users (n=112), rates of use of message boards, wikis, Skype, role-playing games, and blogs ranged from 26.8% to 34.8%. Among mobile phone users (n=162), 41.4% used their phones to access the Internet and 25.3% used Twitter on their phones. In multivariate analysis, patients who had attended or completed college had much greater odds of accessing the Internet on mobile phones. Older patients were much less likely to access the Internet or use Twitter. CONCLUSIONS: Our findings indicate that use of several popular forms of media is not uncommon in a community psychiatry population, but that rates of use differ on the basis of age and education. As the digital divide between people with severe mental illness and the general population is lessening, further research is needed to determine how to best leverage various types of media to support mental health recovery and complement clinical care. PMID- 29509186 TI - Small RNA-seq analysis of circulating miRNAs to identify phenotypic variability in Friedreich's ataxia patients. AB - Friedreich's ataxia (FRDA; OMIM 229300), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia. In addition, FRDA patients have shown additional non-neurological features such as scoliosis, diabetes, and cardiac complications. Hypertrophic cardiomyopathy, which is found in two thirds of patients at the time of diagnosis, is the primary cause of death in these patients. Here, we used small RNA-seq of microRNAs (miRNAs) purified from plasma samples of FRDA patients and controls. Furthermore, we present the rationale, experimental methodology, and analytical procedures for dataset analysis. This dataset will facilitate the identification of miRNA signatures and provide new molecular explanation for pathological mechanisms occurring during the natural history of FRDA. Since miRNA levels change with disease progression and pharmacological interventions, miRNAs will contribute to the design of new therapeutic strategies and will improve clinical decisions. PMID- 29509188 TI - Corrigendum: Long-read sequencing of the human cytomegalovirus transcriptome with the pacific biosciences RSII platform. AB - This corrects the article DOI: 10.1038/sdata.2017.194. PMID- 29509187 TI - Survival, gene and metabolite responses of Litoria verreauxii alpina frogs to fungal disease chytridiomycosis. AB - The fungal skin disease chytridiomycosis has caused the devastating decline and extinction of hundreds of amphibian species globally, yet the potential for evolving resistance, and the underlying pathophysiological mechanisms remain poorly understood. We exposed 406 naive, captive-raised alpine tree frogs (Litoria verreauxii alpina) from multiple populations (one evolutionarily naive to chytridiomycosis) to the aetiological agent Batrachochytrium dendrobatidis in two concurrent and controlled infection experiments. We investigated (A) survival outcomes and clinical pathogen burdens between populations and clutches, and (B) individual host tissue responses to chytridiomycosis. Here we present multiple interrelated datasets associated with these exposure experiments, including animal signalment, survival and pathogen burden of 355 animals from Experiment A, and the following datasets related to 61 animals from Experiment B: animal signalment and pathogen burden; raw RNA-Seq reads from skin, liver and spleen tissues; de novo assembled transcriptomes for each tissue type; raw gene expression data; annotation data for each gene; and raw metabolite expression data from skin and liver tissues. These data provide an extensive baseline for future analyses. PMID- 29509189 TI - Demographic aspects of first names. AB - We introduce a list that offers information on the relation between first names and race or ethnicity. Drawing information from mortgage applications, the list includes 4,250 first names and information on their respective count and proportions across six mutually exclusive racial and Hispanic origin groups. These six categories are consistent with the categories used in the Census Bureau's list on surnames' demographic information. Also, just like the Census Bureau's list of surnames, the list of first names is highly aggregated, so as to not identify any specific individuals. PMID- 29509190 TI - Quantitative mapping of RNA-mediated nuclear estrogen receptor beta interactome in human breast cancer cells. AB - The nuclear receptor estrogen receptor 2 (ESR2, ERbeta) modulates cancer cell proliferation and tumor growth, exerting an oncosuppressive role in breast cancer (BC). Interaction proteomics by tandem affinity purification coupled to mass spectrometry was previously applied in BC cells to identify proteins acting in concert with ERbeta to control key cellular functions, including gene transcription, RNA splicing and post-transcriptional mRNA regulation. These studies revealed an involvement of RNA in ERbeta interactome assembly and functions. By applying native protein complex purification followed by nano LC MS/MS before and after in vitro RNA removal, we generated a large dataset of newly identified nuclear ERbeta interactors, including a subset associating with the receptor via RNA bridging. These datasets will be useful to investigate further the role of ERbeta, nuclear RNAs and the other proteins identified here in BC and other cell types. PMID- 29509191 TI - ChIP-seq and ChIP-exo profiling of Pol II, H2A.Z, and H3K4me3 in human K562 cells. AB - The human K562 chronic myeloid leukemia cell line has long served as an experimental paradigm for functional genomic studies. To systematically and functionally annotate the human genome, the ENCODE consortium generated hundreds of functional genomic data sets, such as chromatin immunoprecipitation coupled to sequencing (ChIP-seq). While ChIP-seq analyses have provided tremendous insights into gene regulation, spatiotemporal insights were limited by a resolution of several hundred base pairs. ChIP-exonuclease (ChIP-exo) is a refined version of ChIP-seq that overcomes this limitation by providing higher precision mapping of protein-DNA interactions. To study the interplay of transcription initiation and chromatin, we profiled the genome-wide locations for RNA polymerase II (Pol II), the histone variant H2A.Z, and the histone modification H3K4me3 using ChIP-seq and ChIP-exo. In this Data Descriptor, we present detailed information on parallel experimental design, data generation, quality control analysis, and data validation. We discuss how these data lay the foundation for future analysis to understand the relationship between the occupancy of Pol II and nucleosome positions at near base pair resolution. PMID- 29509192 TI - Synthesis and some coordination chemistry of the PSnP pincer-type stannylene Sn(NCH2PtBu2)2C6H4, attempts to prepare the PSiP analogue, and the effect of the E atom on the molecular structures of E(NCH2PtBu2)2C6H4 (E = C, Si, Ge, Sn). AB - The non-donor-stabilized PSnP pincer-type stannylene Sn(NCH2PtBu2)2C6H4 (1) has been prepared by treating SnCl2 with Li2(NCH2PtBu2)2C6H4. All attempts to synthesize the analogous PSiP silylene by reduction of the (previously unknown) silanes SiCl2(NCH2PtBu2)2C6H4 (2), SiHCl(NCH2PtBu2)2C6H4 (3) and SiH(HMDS)(NCH2PtBu2)2C6H4 (4; HMDS = N(SiMe3)2) have been unsuccessful. The almost planar (excluding the tert-butyl groups) molecular structure of stannylene 1 (determined by X-ray crystallography) has been rationalized with the help of DFT calculations, which have shown that, in the series of diphosphanetetrylenes E(NCH2PtBu2)2C6H4 (E = C, Si, Ge, Sn), the most stable conformation of the compounds with E = Ge and Sn has both P atoms very close to the EN2C6H4 plane, near (interacting with) the E atom, whereas for the compounds with E = C and Si, both phosphane groups are located at one side of the EN2C6H4 plane and far away from the E atom. The size of the E atom and the strength of stabilizing donor acceptor PE interactions (both increase on going down in group 14) are key factors in determining the molecular structures of these diphosphanetetrylenes. The syntheses of the chloridostannyl complexes [Rh{kappa2Sn,P SnCl(NCH2PtBu2)2C6H4}(eta4-cod)] (5), [RuCl{kappa2Sn,P-SnCl(NCH2PtBu2)2C6H4}(eta6 cym)] (6) and [IrCl{kappa2Sn,P-SnCl(NCH2PtBu2)2C6H4}(eta5-C5Me5)] (7) have demonstrated the tendency of stannylene 1 to insert its Sn atom into M-Cl bonds of transition metal complexes and the preference of the resulting PSnP chloridostannyl group to act as a kappa2Sn,P-chelating ligand, maintaining an uncoordinated phosphane fragment. X-ray diffraction data (of 6), 31P{1H} NMR data (of 5-7) and DFT calculations (on 6) are consistent with the existence of a weak PSn interaction involving the non-coordinated P atom of complexes 5-7, similar to that found in stannylene 1. PMID- 29509193 TI - Label-free fluorescence imaging of cytochrome c in living systems and anti-cancer drug screening with nitrogen doped carbon quantum dots. AB - As an important biomarker for the early stage of apoptosis, cytochrome c (Cyt c) has been recognized as a key component of the intrinsic apoptotic pathway. Fluorescence imaging tools enabling detection of Cyt c in apoptotic signaling have been rarely explored, though they are critical for cell biology and clinical theranostics. Here, we designed a novel label-free N-doped carbon dot (N-doped CD)-based nanosensor that enables fluorescence activation imaging of Cyt c release in cell apoptosis. The inner filter effect of Cyt c towards N-doped CDs enabled quantitative Cyt c measurement. The nanosensor exhibited high sensitivity and selectivity, rapid response, good cell-membrane permeability and low cytotoxicity. All these features are favorable for in situ visualization of Cyt c for apoptosis research. Notably, the developed nanosensor was successfully applied to monitor intracellular release of Cyt c, and to visualize Cyt c in living zebrafish for the first time. Moreover, it also provided a viable platform for cell-based screening of apoptosis-inducing compounds. In virtue of these advantages and potential, the developed assay not only holds great significance for the better understanding of certain diseases at the cellular level, but also provides an invaluable platform for apoptotic studies and screening of anti cancer drugs toward drug development. PMID- 29509194 TI - A novel reduced graphene oxide/molybdenum disulfide/polyaniline nanocomposite based electrochemical aptasensor for detection of aflatoxin B1. AB - In this study, we developed a novel reduced graphene oxide/molybdenum disulfide/polyaniline@gold nanoparticles-based electrochemical aptasensor (termed as RGO/MoS2/PANI@AuNPs/Apt) for detection of aflatoxin B1 (AFB1). The RGO/MoS2/PANI nanocomposites were synthesized and characterized by multiple techniques, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), infrared spectroscopy (FTIR), UV-visible spectroscopy, and X ray photoelectron spectroscopy (XPS). A glassy carbon electrode (GCE) was then modified by the RGO/MoS2/PANI nanocomposites, coated with a chitosan (Cs) film, and followed by AuNPs attachment for immobilizing the AFB1 aptamers. In the presence of AFB1, the AFB1 binding-induced conformation change of the immobilized aptamer on the electrode surface results in the reduction of the electron transfer from a [Fe(CN)6]3-/4- redox couple in the solution to the GCE surface. Therefore, the aptamer-AFB1 binding event can be easily monitored by the peak current change of the RGO/MoS2/PANI@AuNPs/Apt through differential pulse voltammetry (DPV) measurement. Under the optimized conditions, the as-developed RGO/MoS2/PANI@AuNPs/Apt exhibits a wide linear range from 0.01 fg mL-1 to 1.0 fg mL-1 and a remarkably low detection limit (3sigma) of 0.002 fg mL-1. The aptasensor also has good reproducibility as well as shows high selectivity against other fungal toxins, such as OTA and FB1. Moreover, the practicability of the RGO/MoS2/PANI@AuNPs/Apt was demonstrated by the analysis of AFB1 in the spiked wine samples. PMID- 29509195 TI - Electron induced surface reactions of (eta5-C5H5)Fe(CO)2Mn(CO)5, a potential heterobimetallic precursor for focused electron beam induced deposition (FEBID). AB - Electron-induced surface reactions of (eta5-C5H5)Fe(CO)2Mn(CO)5 were explored in situ under ultra-high vacuum conditions using X-ray photoelectron spectroscopy and mass spectrometry. The initial step involves electron-stimulated decomposition of adsorbed (eta5-C5H5)Fe(CO)2Mn(CO)5 molecules, accompanied by the desorption of an average of five CO ligands. A comparison with recent gas phase studies suggests that this precursor decomposition step occurs by a dissociative ionization (DI) process. Further electron irradiation decomposes the residual CO groups and (eta5-C5H5, Cp) ligand, in the absence of any ligand desorption. The decomposition of CO ligands leads to Mn oxidation, while electron stimulated Cp decomposition causes all of the associated carbon atoms to be retained in the deposit. The lack of any Fe oxidation is ascribed to either the presence of a protective carbonaceous matrix around the Fe atoms created by the decomposition of the Cp ligand, or to desorption of both CO ligands bound to Fe in the initial decomposition step. The selective oxidation of Mn in the absence of any Fe oxidation suggests that the fate of metal atoms in mixed-metal precursors for focused electron beam induced deposition (FEBID) will be sensitive to the nature and number of ligands in the immediate coordination sphere. In related studies, the composition of deposits created from (eta5-C5H5)Fe(CO)2Mn(CO)5 under steady state deposition conditions, representative of those used to create nanostructures in electron microscopes, were measured and found to be qualitatively consistent with predictions from the UHV surface science studies. PMID- 29509196 TI - Free charges versus excitons: photoluminescence investigation of InGaN/GaN multiple quantum well nanorods and their planar counterparts. AB - InGaN/GaN multiple quantum well (MQW) nanorods have demonstrated significantly improved optical and electronic properties compared to their planar counterparts. However, the exact nature of the processes whereby nanorod structures impact the optical properties of quantum wells is not well understood, even though a variety of mechanisms have been proposed. We performed nanoscale spatially resolved, steady-state, and time-resolved photoluminescence (PL) experiments confirming that photoexcited electrons and holes are strongly bound by Coulomb interactions (i.e., excitons) in planar MQWs due to the large exciton binding energy in InGaN quantum wells. In contrast, free electron-hole recombination becomes the dominant mechanism in nanorods, which is ascribed to efficient exciton dissociation. The nanorod sidewall provides an effective pathway for exciton dissociation that significantly improves the optical performance of InGaN/GaN MQWs. We also confirm that surface treatment of nanorod sidewalls has an impact on exciton dissociation. Our results provide new insights into excitonic and charge carrier dynamics of quantum confined materials as well as the influence of surface states. PMID- 29509197 TI - Monocrystalline platinum-nickel branched nanocages with enhanced catalytic performance towards the hydrogen evolution reaction. AB - Single crystalline noble metal nanocages are the most promising candidates for heterogeneous catalysis due to their large specific surface area, well-defined structure and enhanced structural stability. Herein, based on the observation of an unexpected phenomenon that the alloying of Pt and transition metals by co reduction is more preferential than the formation of pure Pt NCs, we propose a feasible one-pot strategy to synthesize a uniformly epitaxial core-shell Pt-Ni structure with a Ni-rich alloy as the core and a Pt-rich alloy as the shell. The as-prepared Pt-Ni core-shell structures are subsequently etched into monocrystalline Pt-Ni branched nanocages with the wall thickness being 2.8 nm. This unique structure exhibits excellent catalytic performance and stability for the hydrogen evolution reaction (HER) in alkaline solution which is of great significance for the energy-intensive water-alkali and chlor-alkali industry. PMID- 29509198 TI - Ultrasensitive chemiluminescence biosensors using nucleic acid-functionalized silver-cysteine nanowires as signal amplifying labels. AB - Ultrasensitive chemiluminescence (CL) sensors for biomolecules (DNA and proteins) have been developed by adopting DNA-functionalized silver-cysteine hybrid nanowires (p-SCNWs) as signal amplifying labels. The sensing is established from a sandwich-type DNA hybridization, where the target DNA strands are initially hybridized with the capture DNA located at paramagnetic microspheres (PMs) and subsequently hybridized with p-SCNWs functionalized with the signal DNA probe. After magnetic separation, p-SCNWs on the hybrids were completely decomposed with HNO3 to release numerous silver ions. The powerful catalysis of silver ions toward the redox reaction of K2S2O8-Mn2+-H3PO4 causes the generation of KMnO4 that is capable of oxidizing luminol at high pH, triggering an amplified chemiluminescent signal emission. The sensing combines the extraordinary sensitivity of the catalytic chemiluminescence technology and the amplifying strategy via releasing large quantities of silver ions as the catalyst from each hybrid, enabling the assay of target DNA strands at a concentration as low as 0.34 fM. The CL signals associated with single-base pair mismatched DNA strands and non-complementary DNA strands are able to be discriminated well from the CL signal related to the complementary DNA hybridization. Likewise, the combination of p-SCNWs functionalized with an aptamer and PMs/aptamer/thrombin complex allowed the chemiluminescence sensing of thrombin with a low limit of detection corresponding to 0.17 pM. PMID- 29509199 TI - Structural investigations of amorphous metal-organic frameworks formed via different routes. AB - The structures of chemically identical amorphous zeolitic amorphous frameworks (ZIFs), which were prepared from crystalline ZIF-4 via three different routes, are compared by refining atomistic models against their neutron and X-ray total scattering data. The diffraction data are very similar at all but the lowest values of momentum transfer and this is reflected in the ability of models with the same continuous random network topology to fit the data from each of the three amorphous ZIFs. Despite this there are differences in the detail; the relative positions of the lowest-Q peak in the Zn-Zn partial structure factors are consistent with differences in the densities of the different amorphous samples, and peaks in the ZIF-4 glass total scattering structure factors are in general broader, suggesting shorter-ranged correlations. PMID- 29509200 TI - Ultrafast photophysics of the environment-sensitive 4'-methoxy-3-hydroxyflavone fluorescent dye. AB - The excited state intramolecular proton transfer (ESIPT) of 3-hydroxyflavone derivatives results in a fluorescence spectrum composed of two emission bands, the relative intensity of which is strongly influenced by the interaction with the local environment. We use time-resolved fluorescence and ultrafast transient absorption spectroscopies to investigate the photophysics of 4'-methoxy-3 hydroxyflavone in different solvents characterized by various polarities and hydrogen (H) bonding capabilities. We evidence that in this compound, the ESIPT reaction rate varies by more than 3 orders of magnitude, depending on the H bonding capability of its local environment. This remarkable property is attributed to the moderate electron-donating strength of the 4'-methoxy substituent, and turns this fluorescent dye into a very promising fluorescent probe of biomolecular structures and interactions, where local structural heterogeneity may possibly be revealed by resolving a distribution of ESIPT reaction rates. PMID- 29509201 TI - Graphene-coated polymer foams as tuneable impact sensors. AB - The use of graphene-based nanocomposites as electromechanical sensors has been broadly explored in recent times with a number of papers describing porous, foam like composites. However, there are no reported foam-based materials that are capable of large dynamic compressive load measurements and very few studies on composite impact sensing. In this work, we describe a simple method of infusing commercially-available foams with pristine graphene to form conductive composites, which we refer to as G-foam. Displaying a strain-dependent electrical response, G-foam was found to be a reasonably effective pressure sensing material. More interestingly, G-foam is a sensitive impact-sensing material. Through the addition of various amounts of polymer filler, the mechanical properties of the composites can be tuned leading to the controllable variation of the impact sensing range. We have developed a simple model which quantitatively explains all our impact sensing data. PMID- 29509202 TI - Fabrication of sub-nanometer pores on graphene membrane for ion selective transport. AB - The ability to sieve ions through nanopores with high throughput has significant importance in seawater desalination and other separation applications. In this study, a plasma etching process has been demonstrated to be an efficient way to produce high-density nanopores on graphene membranes with tunable size in the sub nanometer range. Besides the pore size, the nanopore density is also controllable through adjusting the exposure time of the sample to argon or oxygen plasma. The plasma-treated graphene membranes can selectively transport protons, Na+ and Cl- ions. Density function theory calculations uncover that the sp3 and vacancy-type defects construct different energy barriers for different ions, which allow the defected graphene membrane to selectively transport ions. Our study indicates that oxygen plasma etching can be used as a very convenient and efficient method for fabricating a monolayer filtration graphene membrane with tunable sub nanometer pores. PMID- 29509203 TI - The peculiarities of complex formation and energy transfer processes in lanthanide complexes with 2-(tosylamino)-benzylidene-N-benzoylhydrazone. AB - Depending on the local excess of lanthanide ions (Ln = Lu, Yb, Er, Dy, Tb, Gd, Eu, Nd) or 2-(tosylamino)-benzylidene-N-benzoylhydrazone (H2L), lanthanide complexes, containing either a mono-deprotonated ligand (Ln(HL)2X, X = Cl, NO3) or both mono- and dideprotonated ligands (Ln(L)(HL)), were preparatively obtained. The crystal structures of Lu(HL)2Cl, Yb(L)(HL)(H2O)2, Yb(L)(HL)(EtOH)2(H2O) and Er(L)(HL), determined by single crystal diffraction data or from powder diffraction data using Rietveld refinement, have shown the surprising resemblance. The study of luminescence temperature dependence of Eu(HL)2Cl and Eu(L)(HL) showed that europium luminescence is quenched by thermally-activated 5D0 -> T1 energy transfer. Luminescent thermometers based on these complexes demonstrated the sensitivity of up to 7.7% at 85 K which is the highest value above liquid-nitrogen temperatures obtained to date. PMID- 29509204 TI - The role and fate of capping ligands in colloidally prepared metal nanoparticle catalysts. AB - Metal nanoparticles have received intense scientific attention in the field of catalysis. Precise engineering of nanomaterials' size, shape and surface composition, including adsorbed capping ligands, is of utmost importance to control activity and selectivity, and distinguish colloidally prepared metal nanoparticle catalysts from traditional heterogeneous catalysts. The interface between the material and the reaction medium is where the key interactions occur; therefore, catalysis occurs under the influence of capping ligands. In this Perspective review, we focus on the choice of capping ligands (or stabilizing agents), and their role and fate in different steps from preparation to catalysis. Evaluating the influence of the ligands on the catalytic response is not trivial, but the literature provides examples where the ligands adsorbed on the nanoparticle surface dramatically change the activity and selectivity for a particular reaction, while acting either as a dynamic shell or a passivation coating. Steric and electronic effects resulting from the presence of adsorbed ligands have been proposed to influence the catalytic properties. Attempts to remove the capping ligands are discussed, even though they are not always successful or even necessary. Finally, we outline our personal understanding and perspectives on the use of ligands or functionalized supports to tune the activity and selectivity of supported metal nanoparticles. PMID- 29509205 TI - Interfacial anti-fatigue effect in graphene-copper nanolayered composites under cyclic shear loading. AB - Low-cycle fatigue behaviors of graphene-copper nanolayered (GCuNL) composites are explored at different interface configurations and repeat layer spacings. The graphene interfaces can trap dislocations through impeding the propagation of dislocations in copper layers, giving rise to the absence of softening, and an increase in the fatigue strength of GCuNL composites (up to 400% that of pure copper). This anti-fatigue effect is independent of the crystal orientation of copper or the chirality of graphene due to interfacial constraints and can be controlled by tailoring the repeat layer spacing. Low repeat layer spacing increases the instability and nonlinearity of the composites, while high repeat layer spacing decreases the anti-fatigue effect. The optimum value of the repeat layer spacing for the GCuNL composites is 3-7 nm, in order to achieve a balanced anti-fatigue capability and interface stability. PMID- 29509206 TI - Two-dimensional transition metal dichalcogenides: interface and defect engineering. AB - Two-dimensional (2D) transition metal dichalcogenides (TMDCs) have been considered as promising candidates for next generation nanoelectronics. Because of their atomically-thin structure and high surface to volume ratio, the interfaces involved in TMDC-based devices play a predominant role in determining the device performance, such as charge injection/collection at the metal/TMDC interface, and charge carrier trapping at the dielectric/TMDC interface. On the other hand, the crystalline structures of TMDCs are enriched by a variety of intrinsic defects, including vacancies, adatoms, grain boundaries, and substitutional impurities. Customized design and engineering of the interfaces and defects provides an effective way to modulate the properties of TMDCs and finally enhance the device performance. Herein, we summarize and highlight recent advances and state-of-the-art investigations on the interface and defect engineering of TMDCs and their corresponding applications in electronic and optoelectronic devices. Various interface engineering approaches for TMDCs are overviewed, including surface charge transfer doping, TMDC/metal contact engineering, and TMDC/dielectric interface engineering. Subsequently, different types of structural defects in TMDCs are introduced. Defect engineering strategies utilized to modulate the optical and electronic properties of TMDCs, as well as the developed high-performance and functional devices are summarized. Finally, we highlight the challenges and opportunities for interface and defect engineering in TMDC materials for electronics and optoelectronics. PMID- 29509207 TI - A multifunctional MOF as a recyclable catalyst for the fixation of CO2 with aziridines or epoxides and as a luminescent probe of Cr(vi). AB - A multifunctional metal-organic framework (1) containing 24-nuclear zinc nanocages shows high solvent- and pH-stability. Compound 1 can be employed as a catalyst for the conversion of CO2 with aziridines or epoxides, which can be reused at least ten times just by a simple and rapid method. The PXRD of compound 1 after ten recyclings remains well consistent with the original one. The inductively coupled plasma measurement of a reaction filtrate revealed that only trace amount leakage of Zn2+ was observed, indicating that the framework did not collapse after recyclings. Compound 1 can effectively catalyze the cycloaddition reaction of CO2 and five aziridines or five epoxides with different substituent groups. To our knowledge, this is the first multifunctional MOF-based catalyst used for the conversion of CO2 with aziridines or epoxides. Furthermore, luminescence investigations reveal that compound 1 can also act as a luminescent probe for chromium(vi) anion species, which is seriously harmful to humans and the environment. After five cycle tests, the PXRD of compound 1 is still in accordance with the original one, indicating that compound 1 can serve as a circulatory luminescent probe for Cr(vi) anions. PMID- 29509208 TI - ? PMID- 29509209 TI - ? PMID- 29509210 TI - Better Diabetes Diagnoses in Sweden AB - The Swedish study Better Diabetes Diagnosis (BDD) has now been ongoing for ten years and detailed information and blood samples have been collected from more than 8000 children and adolescents with newly diagnosed diabetes. We have been able to demonstrate that by means of HLA diabetes antibodies and C-peptide the discrimination between type one and type 2 diabetes is improved. These analyses are therefore included in the clinical check-up for all children and adolescents in Sweden who are diagnosed with diabetes. Type 1 diabetes is by far the most prevalent type of diabetes among Swedish children and adolescents. Type 2 diabetes is still relatively rare in Sweden but it is urgent to obtain a correct diagnosis as the long-term prognosis depends on a prompt pharmacological treatment. Monogenic diabetes (MODY) is also important to identify early. We therefore recommend that sequencing of MODY genes should be performed if an individual with newly-diagnosed diabetes is auto-antibody negative and has an HLA pattern associated with low risk for type 1 diabetes. However, despite these analytical tools it can be difficult to make the correct diabetes diagnosis initially. It is therefore prudent to re-evaluate the diabetes diagnosis after one year. PMID- 29509211 TI - Rights and duties of patients suffering from Human immunodeficiency virus (HIV) in Tunisia. AB - The spread of the disease of HIV has been decreased since the promotion and protection of human rights. In Tunisian law, patient infected by HIV, as every citizen, enjoys of all his rights without any discrimination, including the right to life and dignity, the right to care access, the free choice of doctor, the right to be informed and consent before any health care and specially the right to medical confidentiality. The Code of patients rights and the law no degrees 2007-12 of 12 February 2007 supplementing the law no degrees 92-71 of 27 July 1992 related to transmitted diseases ensure the protection and the respect of these rights. However, law requires a great sense of responsibility from patients and obliges them to avoid any unconscious behavior that can risk transmission of the disease. But, the application of these laws raises always many ethical problems that need reflexions. PMID- 29509212 TI - The script concordance test as a tool to evaluate clinical reasoning in neonatology. AB - BACKGROUND: Script concordance test aims to evaluate knowledge organization, which represents an essential component of the clinical competence. OBJECTIVE: To build a script concordance test and demonstrate its relevance in the evaluation of Neonatology skills. METHODS: A script concordance test including 20 vignettes and 20 items, was provided to 52 fourth year medical students and 11 family medicine interns. RESULTS: Script concordance test scores obtained by experts were higher then those obtained by students and family medicine interns. The scores (out of 100) were 82.52 +/- 7.35 CI95% [77.26-87.78] for the experts, 58.52 +/- 9.72 CI95% [55.82-61.23] for the students, and 63.17+/-11.36 IC95% [55.53-70.81] (p<0.0001) for the interns. CONCLUSION: Our data suggest that script concordance tests could be used to assess the acquisition of clinical reasoning among fourth year medical students in neonatolgy. PMID- 29509213 TI - Blunt scrotal trauma in adults: A multi-institution study evaluating the American Association for the Surgery of Trauma organ injury grading scale About 107 cases. AB - PURPOSE: The authors evaluated the usefulness of the American Association for the Surgery of Trauma (AAST) testis injury scale based on preoperative scrotal ultrasonography (US) and physical examination compared to peroperative findings. METHODS: A retrospective review was performed on 107 patients (mean age=29,2+/ 5.8 years) with a testis blunt trauma treated between January 2005 and August 2015. All patients underwent surgical scrotal exploration. Preoperative US was performed in all cases. Testis trauma was classified according to the AAST organ injury scale, preoperatively based on physical examination and scrotal US and then compared to peroperative definitif grading scale. RESULTS: Of the included patients, 14 were found to have abnormal testis contours on US, 25 had a rupture of the tunica albuginea, with a sensitivity of 70,8% and a specificity of 71,2%. Orchidectomy was performed in 12 cases, partial orchidectomy in 32 and tunica albuginea repair in 35 patients. CONCLUSIONS: Through this series, US was not a specific and sensitive exam to really precise the severity grade of testis trauma. Pre- and preoperative findings were significantly different. Thus, we continue to support history and clinical findings and we encourage surgical exploration when testis lesion is suspected. PMID- 29509214 TI - Missed injuries in pre-hospital trauma patients. AB - BACKGROUND: During primary survey of trauma patients, missed injuries and delayed diagnosis can be a potential source of morbidity and mortality. OBJECTIVE: To assess type and frequency of missed injuries in prehospital care in trauma patients and to analyze their contributing factors and implications. METHODS: It is a descriptive and analytic prospective study. It was performed over six months which had included 200 trauma patients. The initial assessment made by the out-of hospital team of Sousse was compared to the second survey made in the emergency room and intensive care unit after the radiological assessment. RESULTS: Sixty seven (67) missed injuries were discovered in 51 patients, so 25.5% missed injuries incidence. These injuries were avoidable in 35.82% of cases. Twenty (20) injuries (29.85%) had clinically significant outcomes. Injuries are missed in the abdomen in 62.5% of cases, in the pelvis in 61.11% of cases, in the chest in 41.66% of cases, in the spine in 38.06 % of cases and in 20% of cases in the limbs. Multiple contributing factors were assigned, the most important were: the hemodynamic instability (Systolic blood pressure less than 90 mmHg), the tachycardia and the low RTS. Altered level of consciousness (GCS of twelve or lower), multiple and violence of the trauma were observed but not retained as predictive factors of missing injuries. CONCLUSION: Our study showed higher rates of severe missed injuries mainly in abdomen and pelvis. Circulatory instability and low RTS were assigned as significant factors predicting of this obviousness. Various solutions are proposed to prevent missed during the first assessment in prehospital care. PMID- 29509215 TI - Predictors of repeat emergency department visits among patients aged over 65 years. AB - BACKGROUND: The objective of our study was to evaluate the predictors of repeat visits at Emergency Department (ED) in patients aged >= 65 years. METHODS: A prospective observational study was conducted over a month. Inclusion: patients (age> = 65 year) seen in the ED and leaving the same day. The epidemiological and clinical characteristics at the first visit (index visit (IV)) were collected. The Identification of Senior At Risk (ISAR) score was used to assess our patients. The number of visits (n >= 2) to ED within 30 days of the IV was estimated by a phone contact. RESULTS: Inclusion of125 patients. Mean age = 76 +/ 7 years. The sex ratio was 0.85. Twenty five percent of our patients made repeat visits the following period. Univariate analysis identified: age> 75 years, mean ISAR score>2, history of renal failure, ED visit a month prior to the IV, hospitalization in the last 6 months, patients who depend on someone else help at home and those taking more than 3 medications daily. In multivariate analysis, ED visit a month prior to the IV, hospitalization in the last 6 months, and patients who depend on someone else help at home were independent factors of repeat visits to the ED. CONCLUSION: Efforts to identify patients at high risk of repeat visits to the ED should be made. PMID- 29509216 TI - Resected colorectal cancer liver metastases : Prognostic study about 110 patients. AB - INTRODUCTION: The prognosis of hepatic metastases in colorectal cancers is constantly being improved at the cost of multidisciplinary care, allowing each patient to have an adapted strategy. The prognostic factors make it possible to recognize patients needing further treatment after resection and closer monitoring. OBJECTIVE: The aim of our study was to conduct a prognostic study to identify factors influencing survival at 5 years for patients operated of colorectal liver metastases. METHODS: This is a retrospective study conducted over a period of 10 years (2005-2015). All patients operated for liver metastasis of colorectal cancers were included. The primary endpoint was overall survival. Secondary endpoints were recurrence-free survival and operative morbidity and mortality. The proportions were compared by the Chi 2 test. The survival curves were established according to the Kaplan-Meier method and the comparison of the curves according to the Logrank test. A univariate and then multivariate Cox model was used to determine prognostic factors. The significance level was set at 0.05. RESULTS: Overall survival of our patients at 3 and 5 years was 49% and 32% respectively. Recurrence-free survival was 21% at 3 years and 15% at 5 years. In multivariate analysis, the hepatic resection margin <1 mm and the number of hepatic metastases >=3 were independent factors correlated with survival. CONCLUSIONS: colorectal liver metastases surgery improves patient survival. Some factors need to be sought to adapt care strategies. PMID- 29509217 TI - Particularities of cardiac surgery in chronic hemodialysis patients. AB - INTRODUCTION: Cardiovascular disease is the most common cause of death in chronic hemodialysis patients(1). Cardiac surgery in hemodialysis patients exposes to higher risks inherent in the particular status of these patients. The aim of our study is to report the perioperative particularities of hemodialysis patients undergoing cardiac surgery, and to determine the impact of preoperative clinical status on hospital and late morbidity and mortality. METHODS: Between January 1998 and December 2012, 48 patients in chronic hemodialysis (HD) and candidates for cardiac surgery on cardiopulmonary bypass were retrospectively included. RESULTS: The mean age was 56 years. Causes of renal insufficiency were dominated by diabetes (n = 20; 42%) and nephroangiosclerosis (n= 9, 18.8%). The duration of HD was 48.22 +/- 44.5 months (1 month -11 years). Surgical procedures included coronary artery bypass grafting CABG (n = 33, 68.75%), Valvular replacement (n = 13, 27%) and combined surgery (n = 2, 4.25%). Nine patients (18.8%) underwent emergency surgery. The mean Euroscore I was 8.82 +/- 7.76. Hospital mortality was 20.8%. Postoperative complications were observed in 87.5%patients. Age, diabetic nephropathy, Duration of hemodialysis greater than 54 months, preoperative hemoglobin <9 g / dl, combined surgery and emergency surgery were independent predictors of hospital mortality with odds ratio respectively 1.21; 2.7; 2.54; 1.83; 2.54 and 2.85. The survival rates at 1, 4 and 7 years were respectively 75, 65 and 50%. CONCLUSION: Age, diabetic nephropathy, Duration of hemodialysis greater than 54 months, preoperative hemoglobin <9 g / dl, combined surgery and emergency surgery are predictive factors for hospital mortality. Early diagnosis of coronary and valvular damage and preoperative preparation considering these factors could improve the prognosis. PMID- 29509218 TI - Fitness for work of hospital personnel in sickness absence. AB - INTRODUCTION: The evaluation of fitness for work can be conducted upon the employer's request even during the employee's sickness absence. AIM: Determine the contribution of conducting medical examinations to assess the working ability of Charles Nicolle hospital's workers who are on sick leave. METHODS: A descriptive and retrospective study included all the medical records, completed over a two-year period (2013-2014), of Charles Nicolle hospital's personnel who were on sick leave and who consulted the service of occupational medicine and professional pathology to undergo a fitness for work evaluation requested by the employer. RESULTS: Our study was based on a total of 170 cases of sickness absenteeism reported from a population of 133 employees. The average age of the study population was 39 years (+/- 9.5) with a sex ratio of 0.51. The category of nurses was the most represented (44.4 %). The average work seniority was 10.6 years (+/- 8.4). It is worth notifying that in 65.3% of the cases (111/170), medical examinations were conducted on the employees during the time they were off work. However, in the remaining 34.7 % of the cases (59/170), medical examinations were conducted on the employees after they go back to work. Our study showed that among the 111 employees who were subject to a medical examination during their sickness absence, 88 of them, which is the equivalent of 79.3 %, were found to be fit for work. Among those, 8 cases were fit for work but with some restrictions. A temporary unfitness for work was indicated in only 20.7% of the cases (23/111). CONCLUSION: Our study unveiled a discrepancy between sickness absenteeism and fitness for work in Charles Nicolle hospital. Employees on sick leave had the physical and the mental abilities that would allow them to work with some individualized accommodations based on their health-related needs. PMID- 29509219 TI - Observance of the practice of digital rectal examination. Survey of general practitioners in East-central Tunisia. AB - INTRODUCTION: Digital rectal examination (DRE) is a simple gesture, used for diagnosis of several diseases. However, some general practitioners (GPs) are practicing it less and less often. AIM: To estimate the rate of unrealized DRE and to analyze the factors preventing threir achievement. METHODS: This is a prospective observational study conducted among 105 GPs practicing in Sousse. We used a pre-established pre-tested and self-administered questionnaire. RESULTS: We identified 551 DRE that were indicated but unrealized. There was a significant influence between the non-realization of DRE on the one hand, and on the other hand: the lack of experience; the closeness of the specialist; the lack of training and the lack of conviction of the importance of this examination. Embarrassment during the realization of the DRE was felt in 69.3% of cases. Factors associated with this embarrassment were: female practitioner; the young age of the practitioner; the rural practice and the nature of internship placements. CONCLUSION: Although it is a simple and inexpensive gesture, the DRE remains neglected by many physicians. Several factors appear to influence the achievement of the DRE. Ongoing continuing medical education seems necessary, especially as we found a lack of belief in the importance of this examination. PMID- 29509220 TI - Valvular unvolvement in carcinoid disease. a case report. AB - Carcinoid tumors are rare, mainly located in the gastrointestinal tract particularly in the small intestine. Cardiac involvement, fairly frequent and usually affecting right sided heart valves, had a poor prognosis that is improved by an earlier detection and valve surgery. We report the case of a 50-years old woman with neuroendocrine tumor and liver metastases, in whom carcinoid involvement of the right heart was diagnosed following exertional dyspnea. She had dilated right cavities, severe tricuspid regurgitation, mild tricuspid stenosis and a moderate pulmonary stenosis. She underwent a double valve replacement by bioprosthesis with improvement of symptoms and recovery of normal right cavities size. PMID- 29509221 TI - Matricide in schizophrenia : a case report. AB - INTRODUCTION: matricide is the murder of the mother. In this study, we report through a clinical case the circumstances of matricide and we underlined the predictive elements of the acting out. CLINICAL CASE: mister S, 31 years old had low socioeconomic conditions. He was a single man, unemployed and consumed alcohol. He was followed for a paranoid schizophrenia, but his therapeutic observance was bad, and he was aggressive with his mother. This aggressiveness was fostered by persecution and filiations' delusions. At the moment of the crime, his mother had appeared to him as so terrifying form that he had to kill her to defend itself. This clinical case confronts us with the difficulty of matricide prevention. If the short term prediction of the violence act was possible, the medium and long terms were harder. CONCLUSION: the regular evaluation of psychotic patients' dangerousness is needed to reduce the acting out risque. PMID- 29509222 TI - Agressive infection following a dental extraction in a diabetic patient :Rhinocerebral mucormycosis. AB - Mucormycosis is a rare and acute fungal infection which is frequently lethal, usually observed in non-controlled diabetic patients. The infection usually begins in the nose but it can invade the lung, the digestive tract, and the skin. Rhinocerebral mucormycosis accounts for 40 to 49% of mucormycosis cases. We report the case of a 44-year-old diabetic man, presenting with rhinocerebral mucormycosis. Our patient was treated by an association of amphotericin B and surgical debridement. PMID- 29509223 TI - The neuropathic osteoarthropathy of the hip: About two cases. AB - The neuropathic osteoarthropathy are ectopic ossifications, developed near the joints, secondary to a process of neo-osteogenesis in the case of central neurological lesions and rarely peripheral lesions. We report the case of two patients aged of 7 years and 35 years, for whom the CT scan allowed us to make the positive diagnosis, and an accurate preoperative assessment, by studying the seat, the vessels and nerves, allowing an adapted and precocious management. We propose an update of neuropathic osteoarthropathy based on data from the literature. PMID- 29509224 TI - A rare coexistence of Riedel's and Hashimoto's thyroiditis. PMID- 29509225 TI - Secondary chondrosarcoma arising in solitary sacro-iliac osteochondroma: a case report. PMID- 29509226 TI - The osteo-inductive activity of bone-marrow-derived mononuclear cells resides within the CD14+ population and is independent of the CD34+ population. AB - Bone marrow mononuclear cells (BMC) seeded on a scaffold of beta-tricalcium phosphate (beta-TCP) promote bone healing in a critical-size femur defect model. Being BMC a mixed population of predominantly mature haematopoietic cells, which cell type(s) is(are) instrumental for healing remains elusive. Although clinical therapies using BMC are often dubbed as stem cell therapies, whether stem cells are relevant for the therapeutic effects is unclear and, at least in the context of bone repair, seems dubious. Instead, in light of the critical contribution of monocytes and macrophages to tissue development, homeostasis and injury repair, in the current study it was hypothesised that BMC-mediated bone healing derived from the stem cell population. To test this hypothesis, bone remodelling studies were performed in an established athymic rats critical-size femoral defect model, with beta-TCP scaffolds augmented with complete BMC or BMC immunomagnetically depleted of stem cells (CD34+) or monocytes/macrophages (CD14+). Bone healing was assessed 8 weeks after transplantation. Compared to BMC-augmented controls, when CD14- BMC, but not CD34- BMC were transplanted into the bone defect, femora possessed dramatically decreased biomechanical stability and new bone formation was markedly reduced, as measured by histology. The degree of vascularisation did not differ between the two groups. It was concluded that the monocyte fraction within the BMC provided critical osteo-inductive cues during fracture healing. Which factors were responsible at the molecular levels remained elusive. However, this study marked a significant progress towards elucidating the mechanisms by which BMC elicit their therapeutic effects, at least in bone regeneration. PMID- 29509227 TI - Experimental study on the prevention of liver cancer angiogenesis via miR-126. Promising results for targeted therapy. PMID- 29509228 TI - Up-regulation of LINC00346 inhibits proliferation of NSCLC cells through mediating JAK-STAT3 signaling pathway. PMID- 29509229 TI - Laparoscopic pancreaticoduodenectomy for tumors of the head of the pancreas; 10 cases for a single center experience. PMID- 29509230 TI - Hepatitis C-related hepatocellular carcinoma: diagnostic and therapeutic management in HIV-patients. PMID- 29509231 TI - The challenge of clinical application of FM2 cannabis oil produced in Italy for the treatment of neuropathic pain. PMID- 29509232 TI - Peri-implant diseases and metabolic syndrome components: a systematic review. AB - OBJECTIVE: Metabolic syndrome (MetS) is defined as a spectrum of conditions associated with an increased risk of developing CVD and type 2 diabetes. MetS include: hyperglycemia, hypertension, visceral obesity, dyslipidemia with elevated values of triglycerides (TG) and low levels of HDL. The aim of this review is to provide current knowledge of the relationship between MetS, its components and peri-implant diseases. MATERIALS AND METHODS: An electronic literature search was conducted in the English language in several databases. The Newcastle-Ottawa Scale was used for quality assessment of cohort and cross sectional studies; while systematic reviews were evaluated through AMSTAR; results were reported according to the PRISMA Statement. RESULTS: A total of 272 records were identified through database searching, six studies were included for qualitative analysis. No study directly related to MetS was found, there was inconsistent and controversial evidence regarding association with cardiovascular disease. A higher risk of peri-implantitis was detected in people with hyperglycemia. CONCLUSIONS: Future research should be orientated in assessing the risk of peri-implant diseases, evaluating patient's therapeutic response, analyzing directionality of the relationship between MetS, its components and biologic implant complications. PMID- 29509233 TI - Oral management of adult patients undergoing hematopoietic stem cell transplantation. AB - Chemotherapy and hematopoietic stem cell transplantation (HSCT) are the current treatments for patients with hematological diseases; they result in myelosuppression, and increase the susceptibility of patients to severe infections. The oral cavity is a potential site of complications in HSCT patients, because it is the entrance for agents that can cause systemic infections; it is one of the most frequent locations for side effects deriving from conditioning therapy. The importance of dental pre-chemotherapy and transplant prescription is often stressed, since both therapies depress the immune system and platelets, making each intervention at this stage a high risk. The aim of this article is to review the potential complications of HSCT, and to extrapolate from the scientific literature the treatments and timeframes in which dental therapies can be performed, avoiding important risks for patients. PMID- 29509234 TI - The mechanisms of beta-catenin on keloid fibroblast cells proliferation and apoptosis. AB - OBJECTIVE: To investigate the role of beta-catenin siRNA on proliferation and apoptosis of keloid fibroblast cell. PATIENTS AND METHODS: Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to monitor the mRNA and protein expression levels of beta-catenin in pathological scar tissue and adjacent normal tissue. Human keloid fibroblast cells (KFB) were isolated from the keloid's tissue by enzyme digestion assay and identified by immunocytochemistry assay. Keloid fibroblast cell lines in vitro were transfected with 3 pairs of specific beta-catenin small interfering RNA (siRNA); RT-PCR and Western blot were performed to identify the best siRNA. The proliferation and apoptosis of KFB transfected with beta-catenin were estimated by MTT 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometry (FCM). In addition, the expression levels of Bcl-2, p53, and active-caspase-3 were detected by Western blot. RESULTS: The RT-PCR and Western blot assay results showed that the expression levels of beta-catenin mRNA and protein in pathological scar tissue were significantly higher than those in adjacent normal tissue (p<0.05). KFB were successfully separated from human pathological scar tissue, and immunofluorescence staining results showed that cells were spindle and positively stained with vimentin. The beta-catenin siRNA2 remarkably inhibited the expression of beta-catenin at mRNA and proteins levels in the human keloid fibroblasts. Compared with the control group, cell proliferation was decreased, and apoptotic rate was increased in beta-catenin siRNA2 group. CONCLUSIONS: Knockdown of beta-catenin significantly decreased the proliferation and increased apoptosis of KFB, which could inhibit the formation of pathological scar. PMID- 29509235 TI - Long non-coding RNA GAS5 contributed to the development of glaucoma via regulating the TGF-beta signaling pathway. AB - OBJECTIVE: We aimed at discussing the biological function of lncRNA GAS5 (Growth Arrest Specific 5) on the proliferative, apoptotic and differentiative abilities of retinal ganglion cells. MATERIALS AND METHODS: GAS5 expression was knocked down by transfection with siRNA targeting GAS5 (siGAS5) in retinal ganglion cells. After transfection, qRT-PCR was utilized to evaluate the mRNA level of GAS5 expression. The protein levels of smad2 and smad3 were detected by Western blot. Proliferative ability was accessed by Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle changes were tested by flow cytometry. Also, the differentiative ability of RGC-5 cells was evaluated. TGF-beta was exogenously administered to test its function on regulation of GAS5. RESULTS: Knockdown of GAS5 promoted the cell proliferation and differentiation, but negatively regulated cell apoptosis, and had no effect on cell cycle. Exogenous administration of TGF-beta could decrease the expression level of GAS5 in a dose dependent manner. Meanwhile, lowly expressed GAS5 could improve the phosphorylation of smad2 and smad3. CONCLUSIONS: In our study, we found that down regulation of lncRNA GAS5 may maintain retinal ganglion cell survival in glaucoma through the activation of TGF-beta pathway to promote cell proliferation and differentiation. PMID- 29509236 TI - The application of PRP combined with TCP in repairing avascular necrosis of the femoral head after femoral neck fracture in rabbit. AB - OBJECTIVE: In view of the high occurrence of avascular necrosis of the femoral head (ANFH) after femoral neck fracture and the difficulties in the treatment, our work aimed to explore the effects of platelet-rich plasma (PRP) combined with tri-calcium phosphate (TCP) on the repair of ANFH after femoral neck fracture and to provide reference for clinical treatment. MATERIALS AND METHODS: Thirty New Zealand white rabbits were randomly divided into control group, TCP group, and PRP+TCP group. The rabbit ANFH model was established and femoral head tissues were collected. HE staining was used for histological observation. Image analysis and statistical analysis were used to calculate the New Bone Area fraction (NBA %). The levels of bone morphogenetic protein (BMP)-7, transforming growth factor (TGF)-beta1, basic fibroblast growth factor (bFGF), interleukin (IL)-6 and tumor necrosis factor (TNF)-a in serum were detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: The new bone area of TCP group was significantly lower than that of PRP+TCP group (p<0.05). Compared with the control group, the levels of BMP-7, TGF-beta1 and bFGF were significantly increased in both TCP and PRP+TCP groups (p<0.05), and the increase in PRP+TCP group was higher than that in TCP group. TCP and PRP+TCP can both significantly reduce the content of IL-6 and TNF a (p<0.05); however, higher decrease was found in PRP+TCP group compared with the TCP group at 8 weeks after injection. CONCLUSIONS: PRP combined with TCP, which can promote new bone formation and inhibit inflammatory response, showed higher efficiency in repairing ANFH than internal fixation alone. PMID- 29509237 TI - Do the trace elements play a role in the etiopathogenesis of developmental dysplasia of hip? AB - OBJECTIVE: Alterations in the connective tissue of the hip joint capsule and ligaments might account for the increased laxity seen in patients with developmental dysplasia of the hip. The tensile features of the connective tissue depend on collagen. A number of prior studies have noted the association between the trace elements and collagen biosynthesis. The aim of this research is to determine whether there exists an association between the trace elements and developmental dysplasia of the hip. PATIENTS AND METHODS: This investigation included 27 patients with developmental dysplasia of the hip (18 females and nine males; mean age 24.3 +/- 6.3 months, range 18-36 months) and 26 healthy controls (15 females and 11 males; mean age 23.8 +/- 5.4 months, range 18-36 months). The levels of the serum trace elements in the groups were statistically compared. RESULTS: The Cu levels of the patients with developmental dysplasia of hip were statistically higher than those of the control group (p<0.05). The Zn, Fe, Mg, and Mn levels of the patients with developmental dysplasia of hip were statistically lower than those of the control group (p<0.05). CONCLUSIONS: We found an association between developmental dysplasia of the hip and the serum trace element levels. We, therefore, believe that the trace element levels may shed light on the etiopathogenesis of developmental dysplasia of the hip. This work should be supported by future studies concerning the causes of the alterations in the serum trace element levels seen in patients with developmental dysplasia of the hip. PMID- 29509238 TI - UCA1 impacts progress of rheumatoid arthritis by inducing the apoptosis of fibroblast-like synoviocyte. AB - OBJECTIVE: Rheumatoid arthritis is a chronic autoimmune joint disease, which is characterized by the proliferation of fibroblast-like synoviocyte. Long non coding RNA (lncRNA) has been reported to play an important role in the progression of many different diseases. The main objective of this research was to find out whether the lncRNAs influence the activity of fibroblast-like synoviocyte and the progression of this disease. PATIENTS AND METHODS: qRT-PCR was used to detect the expression of UCA1 in fibroblast-like synoviocyte from normal people and rheumatoid arthritis patients. MTT assay was used to detect the viability of cells. Apoptosis was detected by Caspase-3 Colorimetric Activity Assay Kit (Millipore, Billerica, MA, USA). Western blot was used to analyze the relationship of UCA1 and apoptosis. RESULTS: We found that the UCA1 was highly expressed in the normal fibroblast-like synoviocyte (NFLS), compared with the fibroblast-like synoviocyte of rheumatoid arthritis (RAFLS). We also found that the decrease in UCA1 expression increased the viability in NFLS and overexpressed UCA1 level in RAFLS decreased the viability. Caspase-3 was highly expressed in cells with higher viability. What's more, UCA1 could affect the viability of FLS by changing the expression of Wnt6. CONCLUSIONS: According to the results, we found that UCA1 was closely related to rheumatoid arthritis, which could be a potential target for treating it. PMID- 29509239 TI - Prognostic value of long non-coding RNA HOST2 expression and its tumor-promotive function in human osteosarcoma. AB - OBJECTIVE: Aberrant expression of long noncoding RNA (lncRNA) is associated with carcinogenesis of various tumors. The aim of current study was to explore the clinical significance and biological function of long non-coding RNA HOST2 (lnc HOST2) in patients with osteosarcoma. PATIENTS AND METHODS: The expression of lnc HOST2 was detected by quantitative Real-time PCR (qRT-PCR) in 163 osteosarcoma specimens and matched the normal tissues. The significance of lnc-HOST2 as a prognostic factor as well as its relationship with survival was determined. The effects of lnc-HOST2 expression on the biological behavior of osteosarcoma cells were investigated by MTT and flow cytometry. qRT-PCR and Western blot were used to evaluate the mRNA and protein expression of apoptosis-related factors. RESULTS: The expression levels of lnc-HOST2 in osteosarcoma tissues were significantly higher than those in corresponding noncancerous bone tissues (p < 0.01). Statistical assay indicated that the expression level of lnc-HOST2 was positively correlated with tumor stage (p = 0.003) and distant metastasis (p = 0.000). Furthermore, Kaplan-Meier analysis suggested that patients with high lnc HOST2 showed poorer overall survival than those with low lnc-HOST2 (p = 0.000). The univariate and multivariate analysis further revealed that lnc-HOST2 expression was an independent prognostic factor for overall survival. Then, functionally, down-regulation of lnc-HOST2 suppressed proliferation and induced cell apoptosis in osteosarcoma cells. Notably, we confirmed that up-regulation of lnc-HOST2 led to Bcl-2 downregulation and Bax upregulation in osteosarcoma cells. CONCLUSIONS: We provided the first evidence that lnc-HOST2 may serve as a novel prognostic marker in osteosarcoma. Further, targeting lnc-HOST2 may represent an attractive target therapy for osteosarcoma. PMID- 29509240 TI - Cisplatin suppresses tumor proliferation by inhibiting autophagy in ovarian cancer via long non-coding RNA RP11-135L22.1. AB - OBJECTIVE: To observe the effect of cisplatin-induced autophagy in human ovarian cancer cell lines and explore the correlation between RP11-135L22.1 with cisplatin-induced autophagy. MATERIALS AND METHODS: Genome-wide expression profile and chemotherapy sensitivity data of ovarian cancer were downloaded from TCGA database. It was found that the expression level of lncRNA RP11-135L22.1 differed between chemotherapy-sensitive group and insensitive group. Besides, RP11-135L22.1 expression levels were detected in 64 ovarian cancer tissues and 30 normal tissues by qRT-PCR. Relationship between RP11-135L22.1 expression levels in 64 ovarian cancer tissues and their clinicopathological characteristics were analyzed by x2-test. Cell viability was detected by CCK8 assay. Cell apoptosis and cell cycle were accessed by flow cytometry. HO8910 cells were selected for transfection of pcDNA-RP11-135L22.1, and qRT-PCR was used to evaluate RP11 135L22.1 expression in cisplatin-treated HO8910 cells. Western blot was performed to analyze the expression changes of autophagy-related proteins. RESULTS: Genome wide expression profile of chemotherapy-sensitive and -insensitive patients with ovarian cancer from TCGA database was analyzed by edger package. It was found that RP11-135L22.1 level in chemotherapy-sensitive group was significantly lower than that of insensitive group. QRT-PCR results confirmed that RP11-135L22.1 was lowly expressed in ovarian cancer. The overall survival of patients was positively correlated with the expression of RP11-135L22.1. Furthermore, RP11 135L22.1 was associated with FIGO stage and tumor size. Flow cytometry showed that cisplatin could induce apoptosis and arrest cell cycle in ovarian cancer cells lines. CCK8 assay showed that cisplatin decreased viability of ovarian cancer cells. For in vitro study, HO8910 cells were cultured with medium containing different concentrations of cisplatin or treated with cisplatin for different times. The results revealed that RP11-135L22.1 expression was negatively correlated with the treating time and dose of cisplatin. Western blot showed that cisplatin induced autophagy in ovarian cancer cells in a time- and dose-dependent manner. Cisplatin combined with RP11-135L22.1 can reduce autophagy, increase the apoptosis and inhibit its activity of ovarian cancer cells to a certain extent. CONCLUSIONS: Cisplatin can induce autophagy in HO8910 ovarian cancer cells. After overexpression of RP11-135L22.1, it inhibited cisplatin-induced autophagy, thus enhancing the effect of cisplatin on ovarian cancer cells. PMID- 29509241 TI - MicroRNA-409 inhibits the proliferative ability of cervical carcinoma cells by regulating AKT. AB - OBJECTIVE: To observe the microRNA-409-3p expression in cervical carcinoma and its effect on the growth and proliferative ability of cervical carcinoma cells. PATIENTS AND METHODS: The microRNA-409-3p level in 62 cases of cervical carcinoma and 38 cases of normal cervical tissue was detected by qRT-PCR. The association between the microRNA-409-3p level and clinicopathological features of cervical carcinoma was investigated. Knockdown and overexpressed microRNA-409-3p in cervical carcinoma cells, HeLa and SiHa, were used to detect the cell cycle and the activity of cervical carcinoma cells. Subsequently, potentially target genes of microRNA-409-3p were predicted by bioinformatics website. Western Blot and luciferase assay were used to confirm their correlation. RESULTS: We observed a significant lower microRNA-409-3p level in cervical carcinoma tissues than that in normal cervical tissues. Significant correlation was found between the microRNA-409-3p level in patients with cervical carcinoma and the overall survival rate, tumor size and TNM stage (p<0.05), but correlations with age, pathological type and lymph node metastasis were not found (p>0.05). After silencing the expression of microRNA-409-3p in cervical carcinoma cells, the proliferative ability of cervical carcinoma cells was greatly promoted. In addition, microRNA-409-3p was targeting on protein kinase B (AKT) and had a negative correlation with AKT expression. CONCLUSIONS: The microRNA-409-3p level was lower in cervical carcinoma tissues, and was significantly affected the overall survival, tumor size and TNM staging in clinical patients. Low expression of microRNA-409-3p could promote the proliferative ability of cervical carcinoma cells through the target gene AKT. PMID- 29509242 TI - Correlation between long strand non-coding RNA GASS expression and prognosis of cervical cancer patients. AB - OBJECTIVE: Cervical cancer is the second popular female specific malignant tumors. Long-strand non-coding RNA (lncRNA) GAS5 (Growth Arrest Specific 5) participates in pathological processes of various malignant tumors. This study aimed at investigating the correlation between lncRNA GAS5 expression and prognosis of cervical cancer patients. PATIENTS AND METHODS: Cancer tissues were collected from 48 cervical cancer patients. GAS5 expression in cervical cancer cells was determined by qRT-PCR and in situ hybridization (ISH). The correlation between GAS5 expression and pathological parameters of patients was analyzed. Cervical cancer cell line HeLa was used as the in vitro model, RNA interference approach was adopted to suppress lnc-RNA GAS5 expression. MTT assay was employed to analyze cell proliferation potency. Transwell assay was conducted to analyze the cell migration potency, and tumor cell invasion was measured. RESULTS: qRT PCR and ISH results showed that GAS5 expression in cervical cancer tissues was significantly inhibited compared to that in adjacent tissues (p<0.05). GAS5 expression was correlated with FIGO stage and metastatic tumor parameters of cervical cancer patients (p<0.01). RNA interference data showed that the down regulation of GAS5 significantly enhanced cell proliferation and invasion potency (p<0.05). CONCLUSIONS: GAS5 is down-regulated in cervical cancer cells, and this is probably related to patient clinical stage and tumor invasion or metastasis. The regulatory role of GAS5 on cell proliferation provides the academic basis for the future therapy of cervical cancer. PMID- 29509243 TI - Targeting histone deacetylases in endometrial cancer: a paradigm-shifting therapeutic strategy? AB - OBJECTIVE: Endometrial cancer is increasingly prevalent in western societies and affects mainly postmenopausal women; notably incidence rates have been rising by 1.9% per year on average since 2005. Although the early-stage endometrial cancer can be effectively managed with surgery, more advanced stages of the disease require multimodality treatment with varying results. In recent years, endometrial cancer has been extensively studied at the molecular level in an attempt to develop effective therapies. Recently, a family of compounds that alter epigenetic expression, namely histone deacetylase inhibitors, have shown promise as possible therapeutic agents in endometrial cancer. The present review aims to discuss the therapeutic potential of these agents. MATERIALS AND METHODS: This literature review was performed using the MEDLINE database; the search terms histone, deacetylase, inhibitors, endometrial, targeted therapies for endometrial cancer were employed to identify relevant studies. We only reviewed English language publications and also considered studies that were not entirely focused on endometrial cancer. Ultimately, sixty-four articles published until January 2018 were incorporated into our review. RESULTS: Studies in cell cultures have demonstrated that histone deacetylase inhibitors exert their antineoplastic activity by promoting expression of p21WAF1 and p27KIP1, cyclin-dependent kinase inhibitors, that have important roles in cell cycle regulation; importantly, the transcription of specific genes (e.g., E-cadherin, PTEN) that are commonly silenced in endometrial cancer is also enhanced. In addition to these abstracts effects, novel compounds with histone deacetylase inhibitor activity (e.g., scriptaid, trichostatin, entinostat) have also demonstrated significant antineoplastic activity both in vitro and in vivo, by liming tumor growth, inducing apoptosis, inhibiting angiogenesis and potentiating the effects of chemotherapy. CONCLUSIONS: The applications of histone deacetylase inhibitors in endometrial cancer appear promising; nonetheless, additional trials are necessary to establish the therapeutic role, clinical utility, and safety of these promising compounds. PMID- 29509244 TI - HMGN5 expression in bladder cancer tissue and its role on prognosis. AB - OBJECTIVE: High mobility group protein N5 subtype (HMGN5) is overexpressed in bladder cancer tissue, while its specific mechanism in bladder cancer oncogenesis has not been fully elucidated. This study intends to investigate the impact of HMGN5 on clinical staging and prognosis of bladder cancer. PATIENTS AND METHODS: A total of 26 cases of patients with bladder transitional cell carcinoma (BTCC) received transurethral resection (TUR-BT) in our hospital between March 2015 and February 2016. Para-carcinoma tissue at 5 cm away from cancer tissue was selected as normal control. The expressions of HMGN5 mRNA and protein in different clinical stages were tested by Real-time PCR and Western blot. The relationship between HMGN5 expression and clinical stage along with prognosis was analyzed. RESULTS: HMGN5 mRNA was significantly elevated in BTCC tissue compared with that in para-carcinoma tissue (p < 0.05). HMGN5 mRNA level was gradually upregulated following BTCC upstage according to UICC-TNM stage and WHO stage. The level of HMGN5 protein showed similar changes with mRNA. Follow-up results demonstrated that patients with high HMGN5 level have more tendency of occurrence. CONCLUSIONS: HMGN5 protein level has an important influence on BTCC clinicopathological staging and prognosis. This investigation provides theoretical basis the future therapy of bladder cancer. PMID- 29509245 TI - Long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) promote cell proliferation in colorectal cancer by affecting P53. AB - OBJECTIVE: Colorectal cancer (CRC) is one of the most frequent malignant tumors worldwide. The connection between lncRNAs expression and CRC development has not been well identified in the recent literature. This study focuses on the role of lncRNA-SNHG1 on CRC progression and development. The quantitative Real-time PCR (qRT-PCR) assay was conducted to identify the expression level of small nucleolar RNA host gene 1 (SNHG1). PATIENTS AND METHODS: Cell proliferation and viability were examined by 3-(4,5)-dimethylthiazol(-z-y1)-3,5-diphenyl tetrazoliumbromide (MTT assay) and colony formation assay. Cell apoptosis and cell cycle distribution were detected by flow cytometry. RESULTS: Expressions of p53, p21, BAX were assessed by Western blotting. CRC cells transfected with lncRNA-shRNA were injected into nude mice to identify the role of SNHG1 on tumorigenesis in vivo. SNHG1 expression level was elevated in CRC tissues when compared to adjacent tissues (n=86). SNHG1 knockdown significantly suppressed cell proliferation and viability, while SNHG1 overexpression had the opposite effect. Decreased SNHG1 expression enhanced cell apoptosis and triggered cell cycle arrest in G0/G1 phase, while elevated SNHG1 expression done the opposite. Besides, downregulation of SNHG1 impeded tumorigenesis in vivo. Protein levels of p53 and p53 target genes were affected by SNHG1 in vitro. CONCLUSIONS: Our research demonstrated that SNHG1 may participate in controlling CRC proliferation, viability, and apoptosis via modulating p53 partially, which provides potential therapeutic targets for CRC. PMID- 29509246 TI - Downregulation of COPB2 by RNAi inhibits growth of human cholangiocellular carcinoma cells. AB - OBJECTIVE: The present study aimed to explore the contribution of COPB2 (coatomer subunit beta) towards the tumorigenesis of cholangiocellular carcinomas and to elucidate the underlying mechanism(s). MATERIALS AND METHODS: Expression of COPB2 mRNA by RBE and QBC939 cholangiocellular carcinoma cell lines was determined by qRT-PCR. We, then, silenced COPB2 expression in RBE cells by infection with a COPB2-siRNA lentivirus and measured the proliferation, cell-cycle distribution, and apoptosis of transduced cells. RESULTS: COPB2 was highly expressed in RBE and QBC939 cholangiocellular carcinoma cell lines. Infection with COPB2-siRNA lentivirus in RBE cells significantly decreased COPB2 expression. More so, silencing of COPB2 by COPB2-siRNA significantly suppressed the proliferation and promoted the apoptosis of RBE cells by arresting transduced cells in the G1 phase. CONCLUSIONS: Our results demonstrate that the COPB2 gene is highly expressed in cholangiocellular carcinoma cell lines, wherein knockdown inhibited the proliferation and promoted the arrest of cell-cycle progression and the apoptosis of cholangiocellular carcinomas. COPB2 may constitute an attractive target for therapeutic strategies against cholangiocellular cancers. PMID- 29509247 TI - Long non-coding RNA CACNA1G-AS1 promotes cell migration, invasion and epithelial mesenchymal transition by HNRNPA2B1 in non-small cell lung cancer. AB - OBJECTIVE: In recent years, long non-coding RNAs (lncRNAs) have been identified to participate in tumor progression. The purpose of this study was to investigate the role of CACNA1G-AS1 in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect the CACNA1G-AS1 expression level in 122 pairs of NSCLC and para-carcinoma normal tissue samples as well as in NSCLC cell lines. Moreover, the relationship of clinical pathological features with CACNA1G-AS1 was analyzed. Functional experiment cell lines were established using lentivirus and siRNA to study the effects of CACNA1G-AS1 on cell invasion and migration abilities. Several epithelial-mesenchymal transition (EMT) markers were measured using Western blotting. The expression level of HNRNPA2B1 was analyzed to further investigate the mechanism. RESULTS: The expression level of CACNA1G-AS1 in NSCLC tissues was significantly higher than that in para-carcinoma normal tissues, and the expression of CACNA1G-AS1 was higher in NSCLC cell lines than that in normal BEAS-2B cells. The higher CACNA1G-AS1 level was relative to more lymph node metastasis and distant metastasis. Function experiments revealed that CACNA1G-AS1 promoted cell invasion and migration. Also, CACNA1G-AS1 over-expression increased EMT in NSCLC cells. Besides, HNRNPA2B1 was regulated by CACNA1G-AS1 in NSCLC cells. CONCLUSIONS: CACNA1G-AS1 was identified as an oncogene in NSCLC for the first time, and could promote cell invasion, migration and EMT via increasing HNRNPA2B1 expression, providing a novel target for the biological therapy and prevention. PMID- 29509248 TI - Effects of Linc00460 on cell migration and invasion through regulating epithelial mesenchymal transition (EMT) in non-small cell lung cancer. AB - OBJECTIVE: To detect the relative expression of long intergenic non-protein coding RNA 460 (linc00460) in non-small cell lung cancer (NSCLC) tissues and cells, to investigate the effects of linc00460 on proliferation, migration and invasion of NSCLC and to preliminarily explore its potential molecular action mechanisms. PATIENTS AND METHODS: The relative expression of cancer tissues from 52 patients with NSCLC compared with that of para-carcinoma normal tissues was detected through Real-time quantitative polymerase chain reaction (qRT-PCR). qRT PCR was also used to test the relative expressions of linc00460 in 4 strains of NSCLC cells. Effects of knockdown of linc00460 expression on the cell proliferation ability were detected by cell counting kit-8 (CCK-8) assay through transfection of small interfering linc00460 (si-linc00460) interference sequence in A549 cells and PC-9 cells. Transwell assay was used to detect the effects of lic00460 on the migration and invasion abilities of NSCLC cells. Western blot was applied to observe the changes of epithelial-mesenchymal transition (EMT)-related proteins. The expression changes of EMT-related proteins were detected by immunofluorescence assay. RESULTS: qRT-PCR results showed that there were 40 cases (76.9%) with up-regulated linc00460 expressions in tissues from 52 patients with NSCLC. The linc00460 expressions in 5 strains of NSCLC cells were higher than those of human bronchial epithelial (16HBE) cells. Interference in linc00460 expression could inhibit the proliferation, invasion and migration of NSCLC cells. Results of Western blot and immunofluorescence found that interfering with the linc00460 expression could affect the expression changes of EMT-related proteins. CONCLUSIONS: The relative expression of linc00460 is upregulated in NSCLC tissues. Cells and linc00460 can promote the tumor invasion and migration through affecting EMT. PMID- 29509249 TI - MiR-378 promotes the cell proliferation of non-small cell lung cancer by inhibiting FOXG1. AB - OBJECTIVE: To identify the functioning mode of miR-378 on non-small cell lung cancer (NSCLC) and provide therapeutic targets for NSCLC. PATIENTS AND METHODS: Expression levels of miR-378 in human NSCLC tissue samples and NSCLC-derived cell lines were measured by using quantitative Real-time polymerase chain reaction (PCR). Cell proliferation capacity was assessed by methyl thiazolyl tetrazolium (MTT) assay and colony formation assay. Cell apoptosis and cell cycle distribution were identified by flow cytometry. Downstream target gene was confirmed by using luciferase and Western blotting assays. RESULTS: MiR-378 was significantly elevated in NSCLC tissues when compared with para-carcinoma tissues (n=42). Decreased-miR-378 could attenuate cell proliferation capacity, as well as promoted cell apoptosis and induced cell cycle arrest at G0/G1 phase. FOXG1 was chosen as the target gene of miR-378 by bioinformatics analysis and luciferase reporter assay. Moreover, restoration of miR-378 could impair the tumor suppression role of downregulated-miR-378 on NSCLC growth. CONCLUSIONS: Decreased miR-378 exerted tumor-suppressive effects on NSCLC growth via targeting FOXG1 in vitro, which provided an innovative and candidate target for diagnosis and treatment of NSCLC. PMID- 29509250 TI - LncRNA MEG3 promotes the sensitivity of vincristine by inhibiting autophagy in lung cancer chemotherapy. AB - OBJECTIVE: Lung cancer is one of the most common malignancies worldwide, the morbidity and mortality of which have been on rising in recent years. Moreover, lncRNAs have been implicated in the development of various cancers, as well as cancer treatment and prognosis. In this study, long non-coding RNA (lncRNA) MEG3, an identified tumor suppressor, was explored for its role in the chemotherapy of lung cancer. MATERIALS AND METHODS: All cases were divided into (I+II) group and (III+IV) group according to different stages of tumor node metastasis (TNM), and were divided into sensitive group and insensitive group according to chemotherapy sensitivity. A549 and H292 cells were selected as the resistant cell and non resistant lung cancer cells. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed to detect the expression of MEG3. After transfection with overexpression plasmid pcDNA-MEG3 or/and different concentrations of vincristine, cell viability and proliferation were measured by cell counting kit-8 (CCK-8) assay and plate cloning assay, respectively. Western blotting was used to analyze the expressions of autophagy-related proteins. RESULTS: In vivo, lncRNA MEG3 was significantly lower in III+IV group and insensitive group than that in I+II group and sensitive group. In vitro, MEG3 expression in resistant cells was significantly lower than that in non-resistant cells. Overexpression of MEG3 significant inhibited the viability and proliferation of both resistant and non-resistant lung cancer cells. Western blot results showed that autophagy level was higher in resistant cells than that in non-resistant cells, while overexpression of MEG3 significantly reduced the expression of autophagy-related proteins. CCK-8 results also indicated that the cell viability was negatively correlated with the dose of vincristine, while the viability of drug-resistant cells was higher than that of non-drug resistant cells after the treatment of vincristine. The vitality of both cells decreased in a concentration-dependent manner after combined treatment with vincristine and MEG3. CONCLUSIONS: Our data indicated that lncRNA MEG3 showed a low expression in chemotherapy-sensitive lung cancer tissues, and overexpression of lncRNA MEG3 attenuated autophagy level, thus increasing the sensitivity of vincristine in chemotherapy of lung cancer. PMID- 29509251 TI - Enhanced expression of non coding miR 92a expression is implicated in the development of lung cancer. AB - OBJECTIVE: MicroRNAs (miRNAs/miRs) are small noncoding RNAs that primarily function in RNA silencing and gene regulation at the posttranscriptional level in animals, plants and certain viruses. They have been reported to play a vital role in development and progression of diseases such as cancer. The present study was undertaken to establish a correlation between a specific miRNA in this cluster, termed miR92a, and its association with nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Total RNA was isolated from the plasma using an RNeasy mini kit and cDNA was synthesized by TaqMan MicroRNA Reverse Transcription kit. The expression of miR-92a was quantified by quantitative Real-time PCR (RT-PCR). All transfections were performed using Lipofectamine 2000. Digoxigenin (DIG)labeled locked nucleic acid (LNA)modified probes for miR92a and negative control oligonucleotides were used for in vitro hybridization following manufacturers protocol. Digoxigenin (DIG)labeled locked nucleic acid (LNA)modified probes for miR92a and negative control oligonucleotides (miRCURY LNA MicroRNA Detection Probes; Exiqon, Vedbaek, Denmark) were used. Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) MTT assay. RESULTS: It was observed that miR92a is highly expressed in NSCLC compared with adjacent tissue samples and plasma from healthy donors. Additionally, the proliferation of three NSCLCderived cell lines, SPCA1, A549 and H2170, was enhanced by miR92a and inhibited by a complementary antimiR92a oligonucleotide sequence. Although the underlying mechanisms of reduced cellular proliferation in the presence of miR92a antagomirs cannot be explained from the current results. CONCLUSIONS: The upregulation of miR92a expression, in cells and plasma, is manifested during the development of NSCLC. PMID- 29509252 TI - Semaphorin-7A contributes to growth, migration and invasion of oral tongue squamous cell carcinoma through TGF-beta-mediated EMT signaling pathway. AB - OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) is the most frequently encountered malignant epithelial tumors. Semaphorin-7A is a membrane associated/secreted protein that plays an essential role in the migration and progression of human malignancies. We aimed to investigate the mechanisms of Semaphorin-7A in the growth and migration of OTSCC. MATERIALS AND METHODS: The expressions of Semaphorin-7A in cells were tested by RT-PCR, Western blot, and Immunofluorescence, separately. The activities of OTSCC cells (HSC-3 and Tca8113) were analyzed by MTT, following treatment with Semaphorin-7A or PBS. The migration, invasion, and apoptosis of cells were also determined. The protein expressions of epithelial mesenchymal transition (EMT) pathway were analyzed by Western blot, after treated with Semaphorin-7A in vitro and in vivo. Finally, the mouse model of OTSCC was treated with antibody target for Semaphorin-7A (AntiSema 7A), Semaphorin-7A or PBS, then the tumor size was determined, and histopathological examination and western blot was applied for further confirmation. RESULTS: In OTSCC cells, Semaphorin-7A was highly expressed, and Semaphorin-7A promoted growth in multiple metastatic OTSCC cell lines. Further study indicated that Semaphorin-7A resulted in up-regulation of Snail, N-cadherin and Vimentin expression, and downregulating of E-cadherin. In addition, The Ets2 repressor factor (ERF) expression was down-regulated, and transforming growth factor (TGF-beta)-induced EMT was promoted in OTSCC cells. Then, the proteins of collagen types I (CT-I) and fibronectin (FIB) were also up-regulated after Semaphorin-7A treatment. Furthermore, our results indicated that inhibition of Semaphorin-7A by antibody target for Semaphorin-7A (AntiSema-7A) suppressed OTSCC growth and increased survival in a mouse model of OTSCC. Histopathological examination confirmed the inhibitory effects in vivo. CONCLUSIONS: Semaphorin-7A promoted growth and migration of OTSCC by regulating TGF-beta-induced EMT signaling pathway in OTSCC cells, which provided a new interconnection between the Semaphorin-7A and TGF-beta-induced EMT signaling pathway. PMID- 29509253 TI - MicroRNA-129-3p suppresses tumor growth by targeting E2F5 in glioblastoma. AB - OBJECTIVE: Neuroma is the most common intracranial tumor. The mechanism of miRNA in glioma has gradually been understood. The purpose of this study was to investigate the role of MicroRNA-129-3p (miR-129-3p) in the pathogenesis of glioblastoma (GBM). PATIENTS AND METHODS: Differential expression of miR-129-3p in samples was analyzed by bioinformatics. PCR was used to detect the expression of miR-129-3p in samples. CCK8 assay was used to detect the cell viability. Transfection of mimic and inhibitor altered the expression of miR-129-3p, and the biological function of miRNA was explored. Luciferase reporter gene was used to detect target genes of miRNA. E2F5 expression was inhibited by transfection of small interfering RNAs. Western blotting was used to detect protein expressions of cells. RESULTS: miR-129-3p was low-expressed in the tissue samples. By transfecting mimic and the inhibitor, we found that increasing the expression of miR-129-3p can inhibit the cell viability. In contrast, inhibition of miR-129-3p promoted cell growth. Luciferase reporter gene and Western blot results suggested that E2F5 can be used as the target gene of miR-129-3p. Knockdown the target gene of the miR-129-3p, E2F5, also inhibited proliferation of glioblastoma. CONCLUSIONS: miR-129-3p can inhibit the growth of glioblastoma by down-regulating the expression of E2F5. miR-129-3p can be a new target for the treatment of glioblastoma. Our research provides new ideas for the target therapy of glioma. PMID- 29509254 TI - Oxidative stress induces B lymphocyte DNA damage and apoptosis by upregulating p66shc. AB - OBJECTIVE: B lymphoma is a type of malignant tumor originating from the lymphatic hematopoietic system. The pathogenesis and treatment methods are not clear. The change of oxidative stress is closely related to the cell DNA damage and cell apoptosis, which may be served as a target for cancer treatment. This study aims to illustrate the role of oxidative stress in the regulation of B lymphocytoma. PATIENTS AND METHODS: The tumor tissue was collected from patients with B lymphocytoma. The p66shc level was detected by Western blot. Hydrogen peroxide (H2O2) was assessed by the kit. The oxidative stress model of B lymphoma cell was established by H2O2 treatment. ROS inhibitor or RNAi was used to regulate ROS level. ROS level was determined by flow cytometry. 8-OHdG level (DNA damage product) was tested by the kit. Cell apoptosis was evaluated by annexin V-PI. RESULTS: P66shc expression was significantly reduced, while H2O2 production was significantly decreased in the tumor tissue of B lymphoma compared with adjacent normal control. H2O2 stimulation markedly elevated ROS level and p66shc expression (p < 0.05), accompanied by the aggravation of DNA damage and increase of apoptosis. ROS inhibitor or p66shc RNAi treatment significantly attenuated DNA damage and declined cell apoptosis (p < 0.05). CONCLUSIONS: ROS production promoted p66shc expression, induced DNA damage, and facilitated cell apoptosis. Upregulation of p66shc by oxidative stress could be treated as a new therapeutic target for B lymphoma. PMID- 29509255 TI - Study on the relationship between changes of immune cells and TNF-alpha in peripheral blood of patients with multidrug-resistant and extensively drug resistant tuberculosis. AB - OBJECTIVE: To investigate the relationship between changes in CD4- and CD8 positive immune cells and TNF-alpha in the peripheral blood of patients affected by multidrug-resistant and extensively drug-resistant tuberculosis. PATIENTS AND METHODS: 179 patients suffering from tuberculosis treated in the Chest Hospital of Hebei from April 2010 to December 2015 were selected for the study. There were 47 cases affected by drug-resistant tuberculosis and 132 cases affected by non drug-resistant tuberculosis. The control group included 183 healthy subjects examined during the same period. ELISA was used to compare and analyze serum levels of TNF-alpha, CD4- and CD8-positive cell levels, and CD4/CD8 ratio in the two groups. RESULTS: CD4- and CD8-positive cell count, CD4/CD8 ratio, and serum TNF-a were significantly higher in patients with drug-resistant tuberculosis compared with healthy controls and the non-drug-resistant tuberculosis patients (p < 0.05). There was a positive correlation between TNF-alpha level and CD4/CD8 ratio (r=0.892, p < 0.05). Before treatment, the differences in the levels of TNF a in the different groups of drug-resistant patients were insignificant (p >0.05). After treatment, the levels of TNF-a in the different groups of drug resistant patients were decreased, except for patients with extensively drug resistant tuberculosis, whose levels were significantly decreased compared with before treatment (t = 0.648, p>0.05). The differences in the levels of TNF-alpha in the other groups of patients before and after treatment were statistically significant (t = 8.497, 6.258, 5.346, p < 0.05, fully sensitive tuberculosis single drug-resistant tuberculosis, multidrug-resistant tuberculosis, respectively). CONCLUSIONS: The level of TNF-alpha plays a critical role in the evaluation of the severity of patients with drug-resistant tuberculosis and it has a clinical value. PMID- 29509256 TI - Up-regulation of miR-190b promoted growth, invasion, migration and inhibited apoptosis of Wilms' tumor cells by repressing the PTEN expression. AB - OBJECTIVE: Wilms' tumor (WT) is the most common malignant tumor in the children's urogenital system. MiR-190b was found to participate in the development and progression of several cancers. However, the molecular mechanism of miR-190b in WT is still unclear. PATIENTS AND METHODS: We detected the miR-190b in WT tissue samples compared to adjacent normal samples as well as in WT patients' blood sample compared to normal volunteers using qRT-PCR. With over-expression and knockdown of miR-190b in WT-derived cell line SK-NEP-1, we next studied cell proliferation, cell circle, apoptosis, invasion and migration abilities change caused by miR-190b ectopic expression. Dual-luciferase assay and Western-blot analysis were used to explain the mechanism of miR-190b in WT. RESULTS: MiR-190b was over-expressed in WT tissue and blood samples compared to normal group, relatively. Up-regulation of miR-190b in SK-NEP-1 cells significantly increased the growth and decreased the apoptosis of cells, while its down-regulation reduced cell proliferation and promoted cell apoptosis of SK-NEP-1. Also, cell invasion and migration abilities were significantly improved after miR-190b over expression. Moreover, PTEN was proved to be a direct target of miR-190b and its protein level was remarkably decreased after miR-190b up-regulation. CONCLUSIONS: miR-190b over-expressed in WT and promoted cell proliferation, invasion and migration while reduced cell apoptosis of WT cells by repressing PTEN repression, which might provide a potential target for WT diagnosis and therapy. PMID- 29509257 TI - The gambling disorder: family styles and cognitive dimensions. AB - OBJECTIVE: In this study we present data from a research carried out on a population of people with gambling disorder (GD). SUBJECTS AND METHODS: This research investigated the representation of family styles for subjects with gambling disorder, using the Family Adaptability and Cohesion Evaluation Scale (FACES-IV), their cognitive distortions through Gambling Related Cognitions Scale (GRCS-I), and the relation between these two dimensions. RESULTS: People with GD represent families with emotional detachment, while in the area of management of relational rules and roles, they reveal a perception of disorganization. Concerning their cognitive bias, GD people show the illusion of being able to control and predict the winnings and the perception of being unable to quit playing. CONCLUSIONS: Overall, these data provide specific directions for both the prevention and the therapeutic treatment of GD, highlighting the importance of a family therapeutic approach for the prevention of cognitive distortions. PMID- 29509258 TI - The role of AMPK/mTOR signal pathway in brain injury following chronic intermittent hypoxia in growing rats. AB - OBJECTIVE: To investigate the role of AMPK-mTOR signal pathway in brain injury induced by chronic intermittent hypoxia (CIH) in young rats. MATERIALS AND METHODS: Forty healthy male Sprague-Dawley rats (3-4 weeks old, weighing 80-100 g) were randomly assigned to four groups: 2-week-CIH group (2IH), 4-week-CIH group (4IH), 2-week-simulated air control group (2AC) and 4-week-simulated air control group (4AC). TUNEL staining was used to detect the cell apoptosis in the hippocampus and pre-frontal cortexes, respectively. The Western blot was conducted to analysis the P-AMPK (Phospho-AMP-activated protein kinase) and P mTOR (phosphorylated mammalian target of rapamycin) protein expression. RESULTS: The neurons apoptosis in the hippocampus and pre-frontal cortex in 2IH and 4IH groups increased significantly, compared with that of in 2AC and 4AC groups, (p<0.05, respectively). Moreover, 4IH group exhibited significantly increased apoptosis rates than 2IH group (p<0.05). 2IH and 4IH groups exhibited increased protein expression levels of P-AMPK in the hippocampus and prefrontal cortexes compared with 2AC and 4AC groups (p<0.05, respectively), whereas the protein expression of P-mTOR decreased after CIH treatment (p<0.05, respectively). Higher expression levels of P-AMPK and lower levels of P-mTOR were observed in 4IH group compared to 2IH group. No difference of apoptotic cells and protein expression of P-AMPK and P-mTOR was exhibited between 2AC and 4AC groups. CONCLUSIONS: CIH induces neural apoptosis in a time-dependent manner by activating AMPK and inhibiting mTOR phosphorylation in young rats. PMID- 29509259 TI - Endothelial progenitor cell miR-126 promotes homing of endothelial progenitor cells within arterial thrombus in patients with cerebral infarction and its molecular mechanism. AB - OBJECTIVE: The present study was designed to investigate the effect of microRNA 126 (miR-126) on the migration and homing of endothelial progenitor cells (EPCs) within arterial thrombus of cerebral infarction patients. MATERIALS AND METHODS: EPCs from rat bone marrow were isolated, and miR-126 overexpressed EPCs were constructed by lentiviral transfection. Then, the middle cerebral artery occlusion (MCAO) model was established by the method of thread ligation. Successfully established model rats were randomly divided into miR-126 overexpression EPC group, miR-126 wild type EPC group, and normal saline group. One day after the infarction, the miR-126 overexpression EPCs, miR-126 wild type EPCs, and normal saline, were injected into the lateral ventricle of the corresponding groups. Also, the transplanted cells were tracked by cell dye SPDiIC18. The expression of tight junction proteins ZO-1 and Claudin-5 in brain tissue was detected by Western blotting. RESULTS: Transplanted cells were detected in the cerebral infarction area 3 days after transplantation by cell dye SP-DiIC18. The number of homing EPCs in miR-126 overexpression group was significantly higher than that of miR-126 wild type EPC group (p < 0.05). Also, the protein expression of ZO-1 and Claudin-5 in the miR- 126 overexpression EPC group was significantly higher compared with that of the miR-126 wild type EPC group and the normal saline group. CONCLUSIONS: miR-126 overexpression EPCs, which were transplanted in the lateral ventricle, can home to the cerebral infarction areas via increasing increase. PMID- 29509260 TI - Che-1 attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by upregulation of Nrf2 signaling. AB - OBJECTIVE: Hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis plays a critical role in the development of myocardial infarction. Che-1 has been reported as an anti-apoptotic gene in response to various cellular stresses. However, whether Che-1 regulates cardiomyocyte apoptosis in myocardial infarction remains unclear. In this study, we aimed to investigate the role of Che-1 in regulating H/R-induced cardiomyocyte apoptosis and the underlying molecular mechanism. MATERIALS AND METHODS: The expression of mRNA and protein was detected by Real-time quantitative polymerase chain reaction and Western blot. Cell viability was detected by cell counting kit-8 assay. Cell cytotoxicity was measured by lactate dehydrogenase assay. Cell apoptosis was assessed by caspase-3 activity assay. Intracellular ROS generation was determined using a Reactive Oxygen Species Assay Kit. The activity of antioxidant response elements was detected by luciferase reporter assay. RESULTS: We found that Che-1 expression was significantly upregulated in cardiomyocytes in response to H/R treatment. Functional experiments showed that silencing of Che-1 promoted H/R-induced cell apoptosis and oxidative stress. By contrast, overexpression of Che-1 significantly alleviated H/R-induced cell apoptosis and oxidative stress. Interestingly, we found that Che-1 promoted the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the activity of antioxidant response elements. Moreover, Che-1 significantly upregulated the expression of Nrf2 downstream target genes, including heme oxygenase-1 and NADPH-quinone oxidoreductase 1. CONCLUSIONS: Our results showed that Che-1 alleviates H/R induced cardiomyocyte apoptosis by upregulation of Nrf2 signaling. Our study suggests that Che-1 may serve as a potential and promising therapeutic target for the treatment of myocardial infarction. PMID- 29509261 TI - A volumetric intracoronary ultrasonographic study of coronary bifurcation lesions. AB - OBJECTIVE: To evaluate the plaque distribution and composition pattern in the left main coronary artery (LMCA) disease using intracoronary ultrasound. PATIENTS AND METHODS: Intravascular ultrasound data of 50 patients from the January 2010 to December 2015 with significant LMCA bifurcation lesions, with angiographic diameter stenosis >50%, and requiring revascularization, were evaluated. Plaque burden and percentage of necrotic core (% NC) at the minimal lumen area site and maximal % NC site were measured in different segments. The segments that were included in the study are as follows: segment 1: proximal LMCA, segment 2: left anterior descending (LAD) ostium, segment 3: left circumflex branch (LCX) ostium, segment 4: proximal LAD, segment 5: proximal LCX. According to its relationship with the bifurcation ridge, the blood vessel wall was divided into the contralateral bifurcation ridge blood vessel wall and bifurcation ridge blood vessel wall. RESULTS: Plaque burden results showed that the plaque eccentricity index of segment 2 and segment 3 was significantly higher than that of the other segments at sites of the minimal lumen area and maximal % NC with a statistically significant difference (p<0.05). Plaque eccentricity index of contralateral bifurcation ridge was significantly higher than that of the bifurcation ridge, and the difference was statistically significant (p<0.05). Analysis of plaque composition showed the fibrous tissue percentage of segment 2 and segment 3 was significantly higher than the other segments that at the sites of minimal lumen area and the maximal % NC site. The fibrous percentage of the contralateral bifurcation ridge was significantly lower than that of the bifurcation ridge. CONCLUSIONS: Intravascular ultrasound is an effective way for detecting the distribution and composition of the atherosclerotic plaque at the left main coronary artery bifurcation and is of great significance to adjuvant interventional therapy. PMID- 29509262 TI - Heart rate variability in children with myocarditis presenting with ventricular arrhythmias. AB - OBJECTIVE: We aimed to investigate the heart rate variability in children with myocarditis presenting with ventricular arrhythmias. PATIENTS AND METHODS: The study compared the characteristics of heart rate variability (HRV) among 67 children with viral myocarditis (VMC), presenting with (n=35) and without (n=32) ventricular arrhythmias and a control group of 30 healthy children. RESULTS: Compared with the control group, the HRV time-domain indicators of children with VMC were significantly lower (p<0.05); also, the indicators of children with ventricular arrhythmias were significantly lower than those of children without ventricular arrhythmias (p<0.05). Equally, during both the lucid and sleep periods, the time-domain indicators of HRV were significantly lower in patients with VMC and arrhythmias than in either the control group (p<0.05) or the group with VMC but no ventricular arrhythmias (p<0.05). CONCLUSIONS: We conclude that the HRV of children with VMC probably decreased because of impaired vagal nerve function, with ventricular arrhythmias developing only when the decrease was most significant. Thus, HRV can be a useful predictive indicator for ventricular arrhythmias in children with VMC. PMID- 29509263 TI - The role of adiponectin gene mediated by NF-kappaB signaling pathway in the pathogenesis of type 2 diabetes. AB - OBJECTIVE: To investigate the role of adiponectin (ADPN) gene mediated by NF kappaB signaling pathway in the pathogenesis of type 2 diabetes (T2DM). PATIENTS AND METHODS: The levels of expression of ADPN were measured by fluorescence quantitative PCR technology, enzyme-linked immunosorbent assay, Western-blotting and immunohistochemistry in 78 patients with type 2 diabetes. RESULTS: Compared with the normal population, the levels of expression of ADPN and NF-kappaB mRNA in the blood of patients with type 2 diabetes were significantly reduced (p < 0.05). The detection of ADPN gene protein expression in normal population and patients with type 2 diabetes by enzyme-linked immunosorbent assay showed that ADPN gene protein expression in type 2 diabetic patients (1.26 +/- 0.73) ug/l was significantly lower (p < 0.05) than ADPN gene protein expression of the normal population (3.26 +/- 1.25) ug/l. At the same time, the detection of the expression of NF-kappaB gene showed that the protein expression in type 2 diabetic patients (0.58 +/- 0.15) ug/l was significantly lower (p < 0.05) than that in the normal population (1.67 +/- 1.04) ug/l. The results of Western blotting were consistent with the results of enzyme-linked immunosorbent assay. Immunohistochemical results also showed that the percentage of ADPN positive cells in patients with type 2 diabetes (25.47%) was significantly lower (p < 0.05) than that in the normal population (79.47%). CONCLUSIONS: ADPN gene in the human body can be involved in the pathogenesis of T2DM through the NF-kappaB signaling pathway. PMID- 29509264 TI - Efficacy of inhalational sevoflurane anesthesia induction on inhibiting the stress response to endotracheal intubation in children with congenital heart disease. AB - OBJECTIVE: To investigate the efficacy of inhalational sevoflurane anesthesia induction on inhibiting the stress response to endotracheal intubation in pediatric patients with congenital heart disease (CHD). PATIENTS AND METHODS: Forty ASA physical status I/II pediatric patients scheduled for interventricular septal defect repair or interatrial septal defect repair, were randomly divided into two groups (20 each): intravenous induction group (Group C) and inhalational sevoflurane anesthesia induction group (Group D). In group C, anesthesia was induced with midazolam, pipecuronium bromide and fentanyl, and the children were examined by radial artery monitoring after the consciousness extinction. Also, they were endotracheally intubated after muscle relaxation. In group D, anesthesia was induced with inhalation of 8% sevoflurane and 6 L/min oxygen, and the children were examined by radial artery monitoring after the consciousness extinction and were endotracheally intubated 4 min later. Before anesthesia induction (T0), consciousness extinction (T1), endotracheal intubation (T2), endotracheal intubation (T3), and after endotracheal intubation (T4), 1 and 3 min after intratracheal intubation (T5,6), HR and bispectral index (BIS) were monitored. The MAP of T2-T6 points was recorded. Ulnar vein blood samples were taken for determination of Endothelin (ET) and Thromboxane A2(TXA2) in the points of consciousness extinction, and 5 and 10 min after endotracheal. RESULTS: All the children were well examined by endotracheal intubation. Compared with the baseline value at T0, there was no significant difference of HR in group D, but the HR of group C was decreased at T2, T3, T4 and T6. The BIS of the two groups were decreased at T1-T6 (p<0.05). Compared with the values at T2, they were increased at T5 and T6 in group C, and increased at T6 in group D (p<0.05). Compared with group C, the MAP of group D was decreased at T5, and the BIS of the two groups was decreased at T2-T6 (p<0.05). There were no significant differences of ET and TXA2 between groups. CONCLUSIONS: It is well inhibited the endotracheal intubation stress response in children with congenital heart diseases using sevoflurane inhalational anesthesia induction. PMID- 29509265 TI - Plasma exchange combining with plasma bilirubin adsorption effectively removes toxic substances and improves liver functions of hepatic failure patients. AB - OBJECTIVE: Hepatic failure (HF) is a kind of complex disease characterizing with liver dysfunction and a few clinical complications. Artificial liver support system (ALSS) has been applied to HF patients to improve dysfunctional liver in recent years. This study aims to evaluate therapeutic effects of ALSS approaches, including plasma exchange (PE), plasma diafiltration (PDF) and plasma bilirubin adsorption (PBA), on liver function of HF patients. PATIENTS AND METHODS: This study is a retrospective analysis involving 516 patients diagnosed as HF between February 2014 and February 2015. Patients were randomly divided into PE, PDF, PE plus PBA, and PDF plus PBA group. Meanwhile, single-drug group and combined-drug group were also divided. The liver functions, capability of removing toxic substances and coagulation functions were evaluated both pre-treatment and post treatment. The side effects and hospital improvement rate were also observed post treatment. RESULTS: Hospital improvement rate achieves to 69.6%. TBIL levels and MELD scores were significantly decreased post-treatment compared to pre-treatment (p<0.05). PTA values were significantly increased post-treatment compared to pre treatment (p<0.05). Reduction value in PE+PBA group was significantly higher compared to PE and PDF group (p=0.002, 0.002, respectively). MELD scores were significantly decreased post-treatment compared to pre-treatment in each group (p<0.05). Combined-drug treatment is superior to single-drug treatment for removing toxic substances and improving liver functions. PE treatment, PDF treatment and PE+PBA treatment induced more side effects compared to PDF+PBA treatment. CONCLUSIONS: PE combining with PBA plays a better role in removing toxic substances, improving liver functions of HF patients. PMID- 29509266 TI - Effects of ulinastatin on inflammatory response and cognitive function after hip arthroplasty for the elderly patients with femoral neck fracture. AB - OBJECTIVE: To investigate the effects of ulinastatin on inflammatory response and cognitive function after hip arthroplasty for the elderly patients with femoral neck fracture. PATIENTS AND METHODS: A total of 80 patients with femoral neck fracture receiving hip arthroplasty in our hospital from August 2016 to February 2017 were selected and divided into observation group (n=40) and control group (n=40) using a random number table. The control group was treated with hip arthroplasty and symptomatic and supportive treatment after operation, while the observation group was treated with ulinastatin based on the treatment means of control group. The changes in antioxidant capacities, plasma noradrenaline (NA) and adrenaline (A) levels between the two groups before and after intervention were compared. The changes in neuron-specific enolase (NSE) and plasma S-100B protein levels before intervention and at 48 h after intervention were also compared. Moreover, the changes in mini-mental state examination (MMSE) scores during intervention and the Harris hip scores before intervention and at discharge between the two groups were compared. Finally, the off-bed walking time and postoperative discharge time of the two groups were recorded. RESULTS: After intervention, the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) and the total antioxidant capacity in observation group were significantly superior to those in observation group before intervention and control group after intervention (p<0.05). After intervention, the levels of NA and A in observation group were lower than those in control group (p<0.05), and the levels of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha) and high sensitivity C-reactive protein (hs-CRP) in observation group were also lower than those in control group (p<0.05). At 48 h after intervention, the levels of NSE and plasma S-100B protein in observation group were significantly lower than those in observation group before intervention and control group at 48 h after intervention (p<0.05). At 12 h, 24 h and 48 h after intervention, the MMSE scores of observation group were superior to those of control group in the same period (p<0.05). After intervention, the Harris hip score of observation group was superior to that of control group before and after intervention (p<0.05). The postoperative discharge time of observation group was earlier than that of control group (p<0.05), and the off-bed walking time was also earlier than that of control group (p<0.05). CONCLUSIONS: The combined application of ulinastatin could effectively reduce the oxidative stress and inflammatory response, improve the neurological functions, and promote the postoperative recovery in the elderly patients with femoral neck fracture after hip arthroplasty. PMID- 29509267 TI - Protective effect of tauroursodeoxycholic acid on the autophagy of nerve cells in rats with acute spinal cord injury. AB - OBJECTIVE: To investigate the impact and protective effect of tauroursodeoxycholic acid (TUDCA) on the autophagy of nerve cells in rats with acute spinal cord injury. MATERIALS AND METHODS: Seventy-two 6-8-week-old male Sprague-Dawley (SD) rats were selected and were randomly divided into a sham operation group, a saline control group and a TUDCA treatment group (high and low dose groups). The experimental animals were sacrificed at 24 hours, 5 days and 10 days after spinal cord injury. The Basso, Beattie, Bresnahan locomotor scale was used to assess the hind limb locomotor function after the rats were injured but before sudden death. Electron microscopy, hematoxylin and eosin (HE) staining, TUNEL assays and immunohistochemistry techniques were used to observe the autophagy of the cells. Western blotting was used to analyze the expression of the autophagy-related factor Beclin-1 and the apoptosis-related factor caspase-3, and reverse transcription polymerase chain reaction (RT-PCR) was used to analyze the mRNA expression levels of the above proteins. RESULTS: The locomotor scores of the rats in the saline group were significantly reduced, their Beclin-1 expression levels in neurons were decreased, and caspase-3 expression was increased. The hind limb locomotor scores of rats in the TUDCA groups were decreased, with no difference between the high- and low-dose groups. Beclin-1 expression in their neurons was increased, and caspase-3 expression was decreased; there was a significant difference when compared with the control group, while there was no significant difference between the high- and low-dose groups. CONCLUSIONS: TUDCA significantly activates the neuronal autophagic expression in rats with acute spinal cord injury to inhibit the apoptosis of nerve cells; therefore, it has a protective effect on neurons. PMID- 29509268 TI - Atorvastatin improves plaque stability in diabetic atherosclerosis through the RAGE pathway. AB - OBJECTIVE: To study the improving effect of atorvastatin on plaque stability in diabetes mellitus (DM) mice complicated with atherosclerosis. MATERIALS AND METHODS: Apolipoprotein E (ApoE)-/- mice were used to establish the DM mouse model. Half of the mice received atorvastatin after successful modeling. ApoE-/- and C57BL/6J mice were used as controls. Oil red O staining and Masson staining were performed to detect the lipid and collagen components in mice. Immunohistochemical assay was used to observe the expressions of smooth muscle cell (SMC) and Ly-6c. The expressions of receptor for advanced glycation end products (RAGE), monocyte chemoattractant protein-1 (MCP-1) and nuclear factor kappaB (NF-kappaB) in tissues were detected by Western blotting. Finally, the levels of serum soluble RAGE (sRAGE), advanced glycation end products (AGEs), malondialdehyde (MDA) and reduced glutathione (GSH) in mice were also detected. RESULTS: Atorvastatin reduced the area of atherosclerotic plaque and improved the stability of arterial plaque through reducing lipid deposition, the number of macrophages and SMC, increasing collagen fibers. In mice in atorvastatin group, the levels of serum AGEs and sRAGE were decreased. Moreover, atorvastatin inhibited the downstream pathway of RAGE as well as DM, thus inducing the oxidative stress. CONCLUSIONS: Atorvastatin improves plaque stability in diabetic atherosclerosis through the RAGE pathway. PMID- 29509269 TI - Curcumin attenuates IR-induced myocardial injury by activating SIRT3. AB - OBJECTIVE: Ischemia-reperfusion (IR) injury remains an unresolved and complicated situation in clinical practice. In this study, H9c2 cardiomyocytes were subjected to curcumin (Cur) treatment in the absence or presence of the silent information regulator 3 (SIRT3) inhibitor 3-TYP and were then subjected to IR. MATERIALS AND METHODS: H9c2 cells and male Sprague-Dawley (SD) rats were cultured. MTT assay was performed to assess H9c2 cell viability. Cellular apoptosis was analyzed by TUNEL assay. The expressions of Bcl-2, Bax, SIRT3, and AcSOD2 were measured by Western-blotting. The activities of SOD, GSH-Px, and MDA were determined using commercially available kits. The myocardial infarct size was evaluated using TTC staining. RESULTS: Cur significantly increased H9c2 cell viability, decreased the cell apoptotic index, and altered several biochemical parameters, including upregulation of the anti-apoptotic protein Bcl-2, downregulation of the proapoptotic protein Bax and AcSOD2, activation of SIRT3, increase in SOD and GSH Px activity, and decrease in MDA content. In isolated rat hearts, Cur significantly improved cardiac function, decreased infarct size, and lowered lactate dehydrogenase levels. These protective effects induced by Cur were reversed by treatment with the SIRT3 inhibitor 3-TYP. CONCLUSIONS: These results demonstrate that Cur protects cardiomyocytes and that rat hearts were exposed to IRI by activating SIRT3. PMID- 29509270 TI - Medical use of cannabis: Italian and European legislation. AB - This review illustrates some brief considerations of the medical use of cannabis recently issued in Italy. History and uses of cannabis throughout centuries and different countries are illustrated together with a description of botany and active phytocannabinoids. Then, medical use of cannabis anti-pain treatment for patients resistant to conventional therapies is described in case of chronic neuropathic pain, spasticity, for anticinetosic and antiemetic effect in nausea and vomiting caused by chemotherapy, for appetite stimulating effect in cachexia, anorexia, loss of appetite in cancer patients or patients with AIDS and in anorexia nervosa, hypotensive effect in glaucoma resistant to conventional therapies and for reduction of involuntary body and facial movements in Gilles de la Tourette syndrome. Italian most recent legislation on medical cannabis is detailed with some law proposals, also showing the inconsistent legislation within European Union. Some final considerations of future studies are also reported. PMID- 29509271 TI - Formation of new stimulus equivalence classes by exclusion. AB - This study presents three experiments that aimed to show the formation of stimulus equivalence relations among stimuli that had been previously related only by exclusion. In Experiment 1, participants were trained on baseline conditional discriminations to establish two 3-member equivalence classes. Then, they were exposed to exclusion trials, without feedback, in which undefined stimuli had to be matched by rejecting the defined baseline stimuli. Finally, participants responded to test trials evaluating the emergence of symmetry and transitivity among the undefined stimuli from the exclusion trials. For half of the participants, the stimuli related by exclusion were introduced as S- stimuli in the baseline trials, whereas for the other half they were not. Further, half of the participants were assessed for emergent relations with stimuli from all the classes, whereas the other half was assessed for emergent relations with only the stimuli related by exclusion. In Experiment 2, the S- comparisons in the emergent relations test trials with stimuli only related by exclusion were stimuli from a null class. In Experiment 3, the number of exclusion trials was doubled. Across experiments, most participants showed emergence of equivalence relations among the stimuli related by exclusion. Some conditions of stimulus control associated with exclusion learning and the emergence of equivalence relations are discussed. PMID- 29509272 TI - Equivalence-based instruction of academic skills: Application to adolescents with autism. AB - This study evaluated the efficacy of three equivalence-based instruction procedures on the acquisition of novel academic skills by 3 adolescents diagnosed with autism in a school setting. The skills targeted for instruction were related to topics in history, science, and mathematics, and were taught using different training structures from the PEAK-E curriculum. All participants demonstrated mastery of the trained relations and the tested derived relations following all variants of equivalence-based instruction. PMID- 29509273 TI - Dispersal: a matter of scale. AB - Population density around the natal site is often invoked as an explanation for variation in dispersal distance, with the expectation that competition for limiting resources, coupled with increased intra-specific aggression at high densities, should drive changes in dispersal distances. However, tests of the density-dependent dispersal hypothesis in long-lived vertebrates have yielded mixed results. Furthermore, conclusions from dispersal studies may depend on the spatial and temporal scales at which density and dispersal patterns are examined, yet multi-scale studies of dispersal are rare. Here, we present the findings of a long-term study examining factors influencing natal dispersal distances for the non-migratory population of Peregrine Falcons (Falco peregrinus) in the British Isles across distinct spatial and temporal scales. Our smallest scale study included Peregrines ringed as nestlings and subsequently recaptured alive in south Scotland-north England, an area that was intensively studied during the time periods 1974-1982 and 2002-2016. Second, we examined dispersal patterns of birds ringed as nestlings in south Scotland-north England, but subsequently recaptured alive or recovered dead anywhere in the British Isles. Finally, we examined the natal dispersal patterns for Peregrines ringed and recaptured or recovered anywhere in the British Isles from 1964 to 2016. Consistent with prior findings, females dispersed farther than males across all scales. However, the patterns of dispersal were strongly scale dependent. Specifically, we found a lack of a discernible relationship between index of density and dispersal distance in the limited study area, but when region-wide recaptures and recoveries were included in the analyses, a negative relationship was revealed. Our results suggest that conclusions of dispersal studies may be scale dependent, highlighting the importance of spatial and temporal scales in examining and interpreting the relationship between population density and dispersal patterns. PMID- 29509274 TI - Early estimates of cancer incidence for 2015: Expanding to include estimates for white and black races. AB - BACKGROUND: The National Cancer Institute's cancer incidence estimates through 2015 from the Surveillance, Epidemiology, and End Results (SEER) registries' November 2017 submission are released in April 2018. METHODS: Early estimates (February 2017) of cancer incidence rates and trends from the SEER 18 registries for diagnoses in 2000 through 2015 were evaluated with a revised delay-adjustment model, which was used to adjust for the undercount of cases in the early release. For the first time, early estimates were produced for race (whites and blacks) along with estimates for new sites: the oral cavity and pharynx, leukemia, and myeloma. RESULTS: Model validation comparing delay-adjusted rates and trends through 2014 and using 2016 submissions showed good agreement. Differences in trends through 2015 in comparison with those through 2014 were evident. The rate of female breast cancer rose significantly from 2004 to 2015 by 0.3% per year (annual percent change [APC] = 0.3%); the prior trend through 2014 (the same magnitude) was not yet significant. The female colon and rectum cancer trend for whites became flat after previously declining. Lung and bronchus cancer for whites showed a significant decline (APC for males = -2.3%, 2012-2015; APC for females = -0.7%, 2011-2015). Thyroid cancer for black females changed from a continuous rise to a flat final segment (APC = 1.6%, not significant, 2011-2015). Both kidney and renal pelvis cancer (APC = 1.5%, 2011-2015) and childhood cancers (APC = 0.5%, 2000-2015) for white males showed a significant rise in the final segments from previously flat trends. Kidney and renal pelvis cancer for black males showed a change from a significant rise to a flat trend. CONCLUSIONS: The early release of SEER data continues to be useful as a preliminary estimate of the most current cancer incidence trends. Cancer 2018;124:2192-204. (c) 2018 American Cancer Society. PMID- 29509275 TI - Is hypoxia-induced skeletal muscle dysfunction lost in space or just a matter of a time? PMID- 29509276 TI - Effect of sorafenib on the outcomes of patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: The objective of this study was to evaluate the effect of sorafenib on the outcomes of patients with acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 144 patients with FLT3-ITD AML undergoing allo-HSCT between January 2012 and December 2015 were enrolled in this study. Depending on whether they were receiving sorafenib before transplantation or sorafenib maintenance after transplantation, patients were divided into 4 groups: patients receiving sorafenib before transplantation (group A; n = 36), patients receiving sorafenib after transplantation (group B; n = 32), patients receiving sorafenib both before and after transplantation (group C; n = 26), and patients receiving sorafenib neither before nor after transplantation (group D; n = 50). Outcomes were compared among these groups. RESULTS: The 3-year relapse rates were 22.2%, 18.8%, 15.8%, and 46.1% for groups A, B, C, and D, respectively (P = .006). The 3-year overall survival (OS) rates were 74.9%, 78.1%, 84.6%, and 50.9%, respectively (P = .023), and the 3-year leukemia-free survival (LFS) rates were 69.4%, 78.1%, 80.4%, and 34.8%, respectively (P < .001). The relapse rate was higher and the LFS was shorter in group D versus groups A, B, and C. The OS in group D was shorter than the OS in group C but was similar to the OS in groups A and B. A multivariate analysis revealed that sorafenib before transplantation, sorafenib maintenance after transplantation, and their combined application were protective factors for a lower relapse rate (hazard ratios [HRs], 0.436 [P = .048], 0.431 [P = .046], and 0.173 [P = .002], respectively) and longer LFS (HRs, 0.322 [P = .010], 0.343 [P = .014], and 0.187 [P = .001], respectively). CONCLUSIONS: Sorafenib before transplantation, sorafenib maintenance after transplantation, and their combined application all could improve the outcomes for patients with FLT3-ITD AML. Further study is needed to determine whether the use of sorafenib both before and after transplantation might be ideal. Cancer 2018;124:1954-63. (c) 2018 American Cancer Society. PMID- 29509277 TI - Periodontal disease severity is associated with micronutrient intake. AB - BACKGROUND: This study aimed to examine if specific micronutrients were associated with periodontal disease using data from the US National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. METHODS: Participants who were aged 30 years or more and received complete periodontal examinations were included. Regression analyses were performed to determine associations of variables of interest with periodontal disease. RESULTS: Data of 6415 NHANES participants were included in the analysis. Multivariable analysis revealed that less intake of vitamin A (adjusted odds ratio (aOR) = 1.784), vitamin B1 (aOR = 1.334), vitamin C (aOR = 1.401), vitamin E (aOR = 1.576), iron (aOR = 1.234), folate (aOR = 1.254) and phosphorus (aOR = 1.280) was associated with increased severity of periodontal disease. Compared with the highest level of vitamin D intake, the second highest level of vitamin D intake was associated with lower severity of periodontal disease (aOR = 0.727). CONCLUSIONS: Insufficient intake of vitamin A, B1, C and E, iron, folate and phosphorus was significantly associated with severity of periodontal disease. Results of the present study suggest that the above micronutrients may be increased in the diet or taken as dietary supplements in order to reduce severity of periodontal disease. PMID- 29509278 TI - The effectiveness of the peak relational training system and corresponding changes on the VB-MAPP for young adults with autism. AB - The current investigation sought to extend prior research evaluating the use of the PEAK Relational Training System as a comprehensive treatment model in improving language skills demonstrated by individuals with autism. Baseline PEAK Direct Training and Verbal Behavior Milestone Assessment and Placement Program (VB-MAPP) assessments were conducted across 3 adult male participants, and scores on the PEAK-Direct Training assessment were used to select targets for intervention. Language instruction guided by the PEAK-Direct Training module was implemented for 45 to 69 days across participants. Results suggest that participants mastered target skills throughout the training phase, and VB-MAPP test probes showed an increasing trend. Follow-up probes suggested that scores on the VB-MAPP maintained when training was discontinued. In addition, participants demonstrated an increase in assessment scores on the PEAK-Direct Training assessment in the follow-up phase, including the mastery of untargeted verbal skills. PMID- 29509279 TI - Abnormal development of the inferior temporal region in fetuses with Down syndrome. AB - Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17-21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR-positive vs. CR-negative cells was greater than in euploid fetuses, both in the FG (+77%) and ITG (+61%). An increased ratio of CR-positive vs. CR-negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS. PMID- 29509280 TI - Prognostic importance of solid variant papillary thyroid carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: Solid variant papillary thyroid carcinoma (SVPTC) is a rare variant of papillary thyroid cancer (PTC) and its prognostic value is still unclear. The purpose of this systematic clinical review and meta-analysis is to investigate the prognostic value of SVPTC in comparison with classical PTC (cPTC). METHODS: Four electronic databases, including PubMed, Scopus, Web of Science, and Virtual Health Library, were searched in June 2017. Extracted data were pooled into odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence interval (CI) using the random-effect model. RESULTS: From 1439 articles, we finally included 11 studies with 205 SVPTCs for meta-analysis. Overall, SVPTC manifested a significantly higher risk for vascular invasion, tumor recurrence, and cancer mortality as compared to cPTC. The genetic profile of SVPTC was also distinct from that of cPTC. CONCLUSION: A case of SVPTC should be regarded as an aggressive variant of PTC because of a higher risk for tumor recurrence and mortality. PMID- 29509281 TI - Rapid detection of superficial head and neck squamous cell carcinoma by topically spraying fluorescent probe targeting dipeptidyl peptidase-IV. AB - BACKGROUND: A fluorescent probe glutamylprolyl hydroxymethyl rhodamine green (EP HMRG), which becomes fluorescent after cleavage by dipeptidyl peptidase-IV (DPP IV), has been reported to be useful for the detection of esophageal cancer. Thus, we investigated whether head and neck squamous cell carcinoma (HNSCC) can be detected by spraying EP-HMRG. METHODS: Fluorescence imaging of 17 cases of HNSCCs resected using endoscopic or surgical resection was performed ex vivo after spraying EP-HMRG, and then the fluorescence intensity of the tumors and normal mucosa were measured. RESULTS: Iodine-voiding lesions became fluorescent within a few minutes after the application of EP-HMRG in 12 resected tumors without a history of radiotherapy but this was not observed in the normal mucosa. Fluorescence intensity in tumor lesions was significantly higher than normal lesions. However, 5 other tumors that developed after radiotherapy did not have sufficient contrast against normal mucosa. CONCLUSION: Fluorescence imaging with EP-HMRG would be useful for rapid detection of superficial HNSCC without a history of radiotherapy. PMID- 29509282 TI - Medicare Part D Use of Older Medicare Beneficiaries Admitted to Hospice. AB - OBJECTIVES: To describe medications that older hospice beneficiaries receive through Medicare Part D and assess patterns in Part D use for individuals admitted to hospice for cancer and noncancer causes. DESIGN: Descriptive cohort analysis using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. SETTING: U.S. hospice programs PARTICIPANTS: Part D-enrolled Medicare beneficiaries aged 66 and older who were admitted to hospice and died while under hospice care between January 1, 2008, and December 31, 2013 (N = 88,957). MEASUREMENTS: We determined the 25 most commonly dispensed medications and the prevalence of at least 1 dispensing through Part D after hospice admission. The prevalence and temporal trends in receipt of opioid analgesics and several preventative medication classes are described. RESULTS: More than half of individuals admitted to hospice for cancer (53.5%) and noncancer causes (52.9%) received at least 1 medication through Part D after hospice admission. The prevalence of receiving at least 1 Part D medication after admission was greatest in individuals admitted for debility or failure to thrive (63.5%) and dementia (61.5%) and lowest in those admitted for ischemic stroke (35.4%) and renal disease (36.0%). Beta-blockers, angiotensin-converting enzyme inhibitors, proton pump inhibitors, and statins were among the most common preventative drug classes received overall, although prevalence differed according to admission diagnosis. Nearly 1 in 6 individuals received opioids through Part D after admission, with prevalence steadily decreasing over the study period. CONCLUSION: Receipt of medications through Medicare Part D after hospice admission is common, particularly for preventative medications, and varies according to admission diagnosis. Further research aimed at better understanding individual-, provider-, and healthcare system-level contributors to nonpalliative medication use in the hospice population is warranted. PMID- 29509283 TI - Current and historical land use influence soil-based ecosystem services in an urban landscape. AB - Urban landscapes are increasingly recognized as providing important ecosystem services (ES) to their occupants. Yet, urban ES assessments often ignore the complex spatial heterogeneity and land-use history of cities. Soil-based services may be particularly susceptible to land-use legacy effects. We studied indicators of three soil-based ES, carbon storage, water quality regulation, and runoff regulation, in a historically agricultural urban landscape and asked (1) How do ES indicators vary with contemporary land cover and time since development? (2) Do ES indicators vary primarily among land-cover classes, within land-cover classes, or within sites? (3) What is the relative contribution of urban land cover classes to potential citywide ES provision? We measured biophysical indicators (soil carbon [C], available phosphorus [P], and saturated hydraulic conductivity [Ks ]) in 100 sites across five land-cover classes, spanning an ~125 year gradient of time since development within each land-cover class. Potential for ES provision was substantial in urban green spaces, including developed land. Runoff regulation services (high Ks ) were highest in forests; water quality regulation (low P) was highest in open spaces and grasslands; and open spaces and developed land (e.g., residential yards) had the highest C storage. In developed land covers, both C and P increased with time since development, indicating effects of historical land-use on contemporary ES and trade-offs between two important ES. Among-site differences accounted for a high proportion of variance in soil properties in forests, grasslands, and open space, while residential areas had high within-site variability, underscoring the leverage city residents have to improve urban ES provision. Developed land covers contributed most ES supply at the citywide scale, even after accounting for potential impacts of impervious surfaces. Considering the full mosaic of urban green space and its history is needed to estimate the kinds and magnitude of ES provided in cities, and to augment regional ES assessments that often ignore or underestimate urban ES supply. PMID- 29509284 TI - SUMO-wrestling the pre-eclamptic placenta. PMID- 29509286 TI - Toward a contemporary quantitative model of punishment. AB - A direct-suppression, or subtractive, model of punishment has been supported as the qualitatively and quantitatively superior matching law-based punishment model (Critchfield, Paletz, MacAleese, & Newland, 2003; de Villiers, 1980; Farley, 1980). However, this conclusion was made without testing the model against its predecessors, including the original (Herrnstein, 1961) and generalized (Baum, 1974) matching laws, which have different numbers of parameters. To rectify this issue, we reanalyzed a set of data collected by Critchfield et al. (2003) using information theoretic model selection criteria. We found that the most advanced version of the direct-suppression model (Critchfield et al., 2003) does not convincingly outperform the generalized matching law, an account that does not include punishment rates in its prediction of behavior allocation. We hypothesize that this failure to outperform the generalized matching law is due to significant theoretical shortcomings in model development. To address these shortcomings, we present a list of requirements that all punishment models should satisfy. The requirements include formal statements of flexibility, efficiency, and adherence to theory. We compare all past punishment models to the items on this list through algebraic arguments and model selection criteria. None of the models presented in the literature thus far meets all of the requirements. PMID- 29509285 TI - Impact of the new kidney allocation system A2/A2B -> B policy on access to transplantation among minority candidates. AB - Blood group B candidates, many of whom represent ethnic minorities, have historically had diminished access to deceased donor kidney transplantation (DDKT). The new national kidney allocation system (KAS) preferentially allocates blood group A2/A2B deceased donor kidneys to B recipients to address this ethnic and blood group disparity. No study has yet examined the impact of KAS on A2 incompatible (A2i) DDKT for blood group B recipients overall or among minorities. A case-control study of adult blood group B DDKT recipients from 2013 to 2017 was performed, as reported to the Scientific Registry of Transplant Recipients. Cases were defined as recipients of A2/A2B kidneys, whereas controls were all remaining recipients of non-A2/A2B kidneys. A2i DDKT trends were compared from the pre-KAS (1/1/2013-12/3/2014) to the post-KAS period (12/4/2014-2/28/2017) using multivariable logistic regression. Post-KAS, there was a 4.9-fold increase in the likelihood of A2i DDKT, compared to the pre-KAS period (odds ratio [OR] 4.92, 95% confidence interval [CI] 3.67-6.60). However, compared to whites, there was no difference in the likelihood of A2i DDKT among minorities post-KAS. Although KAS resulted in increasing A2/A2B->B DDKT, the likelihood of A2i DDKT among minorities, relative to whites, was not improved. Further discussion regarding A2/A2B->B policy revisions aiming to improve DDKT access for minorities is warranted. PMID- 29509287 TI - Association between symptoms of depression and oral health conditions. AB - AIMS: To investigate the symptoms of depression and oral health status in Brazilian public healthcare system users. MATERIALS AND METHODS: Analysis of a cross-sectional study conducted with a sample of 776 individuals aged 15 years or older, in the urban areas of Recife (Brazil), obtained by multistage sampling. Committee on Ethics in Research with Human Beings (CAAE) 0538.0.172.172-11. Depression symptoms were verified by means of Axis II of the Research Diagnostic Criteria in Temporomandibular Disorder. For the socioeconomic level, the economic classification criteria of the Brazilian Association of Research Companies and clinical exam record charts were used to establish variables related to oral health conditions. RESULTS: The variables discomfort on occlusion (OR = 1.882 CI = 1.384-2.560), gingival bleeding (OR = 1.384 CI = 1.002-1.912), and self perception of oral health (OR = 1.549 CI = 1.054-2.277), remained in the regression model. CONCLUSION: Discomfort on occlusion, self-perception of oral health, gingival bleeding, sex, and skin color were shown to be associated with the presence of depressive symptoms. PMID- 29509289 TI - Abracadabra. PMID- 29509288 TI - Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients. AB - Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid-derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33+ CD11b+ lineage(CD3/CD56/CD19)- HLA DR-/low cells with 3 subsets, CD14- CD15- (e-MDSCs), CD14+ CD15- (M-MDSCs), and CD14- CD15+ (PMN-MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa. Total MDSC numbers increased in PBMCs after ITx; among MDSC subsets, M-MDSC numbers were maintained at a high level after 2 months post ITx. The MDSC numbers decreased in ITx recipients with ACR. MDSC numbers were positively correlated with serum interleukin (IL)-6 levels and the glucocorticoid administration index. IL-6 and methylprednisolone enhanced the differentiation of bone marrow cells to MDSCs in vitro. M-MDSCs and e-MDSCs expressed CCR1, -2, and -3; e-MDSCs and PMN-MDSCs expressed CXCR2; and intestinal grafts expressed the corresponding chemokine ligands after ITx. Of note, the percentage of MDSCs among intestinal mucosal CD45+ cells increased after ITx. A novel in vitro assay demonstrated that MDSCs suppressed donor-reactive T cell mediated destruction of donor intestinal epithelial organoids. Taken together, our results suggest that MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa in ITx, and may regulate ACR. PMID- 29509290 TI - Self-reference, emotion inhibition and somatosensory disturbance: preliminary investigation of network perturbations in conversion disorder. AB - BACKGROUND AND PURPOSE: Conversion disorder (CD), or functional neurological disorder, is manifested as a neurological disturbance that is not macroscopically visible on clinical structural neuroimaging and is instead ascribed to underlying psychological stress. Known for many years in neuropsychiatry, a comprehensive explanation of the way in which psychological stress leads to a neurological deficit of a structural-like origin is still lacking. METHODS: We applied whole brain network-based data-driven analyses on resting-state functional magnetic resonance imaging, recorded in seven patients with acute-onset, stroke-like CD with unilateral paresis and hypoesthesia as compared with 15 age-matched healthy controls. We used a clustering analysis to measure functional connectivity (FC) strength within 10 different brain networks, as well as between these networks. Finally, we tested FC of specific brain regions that are known to be involved in CD. RESULTS: We found a significant increase in FC strength only within the default-mode network (DMN), which manages self-referential processing. Examination of inter-connectivity between networks showed a structure of disturbed connectivity, which included decreased connectivity between the DMN and limbic/salience network, increased connectivity between the limbic/salience network and body-related temporo-parieto-occipital junction network, decreased connectivity between the temporo-parieto-occipital junction and memory-related medial temporal lobe, and decreased connectivity between the medial temporal lobe and sensorimotor network. Region-specific FC analysis showed increased connectivity between the hippocampus and DMN. DISCUSSION: These preliminary results of disturbances in brain networks related to memory, emotions and self referential processing, and networks involved in motor planning and execution, suggest a role of these cognitive functions in the psychopathology of CD. PMID- 29509291 TI - Short bowel syndrome: influence of nutritional therapy and incretin GLP1 on bone marrow adipose tissue. AB - Energy deprivation leads to a decrease in white adipose tissue and bone mineral density (BMD), while simultaneously inducing the expansion of marrow adipose tissue (MAT). In short bowel syndrome (SBS), parenteral nutrition mitigates the deterioration of nutritional status, including decreases in MAT. Osteoporosis is, however, a frequent complication of SBS. The objective of our study here was to evaluate the association of fat deposit sites (subcutaneous and visceral adipose tissues: intrahepatic lipid (IHL) and MAT) and the incretin glucagon-like peptide 1 (GLP1) with BMD in individuals with SBS. MAT was negatively correlated with lumbar spine BMD in normal individuals, but not in those in the SBS group, who otherwise showed a positive correlation between MAT and GLP1. In addition, in individuals with SBS, IHL was negatively associated with lumbar spine BMD and positively associated with C-terminal telopeptide of type 1 collagen (a serum biomarker of bone turnover). Caloric maintenance in individuals with SBS, therefore, seems to positively affect the relationship between MAT and BMD, which may be modulated, at least in part, by GLP1. PMID- 29509292 TI - Development and initial psychometric properties of the 'ICIQ-Cog': a new assessment tool to measure the disease-related impact and care effort associated with incontinence in cognitively impaired adults. AB - OBJECTIVES: To develop a new assessment tool, the ICIQ-Cog, to measure the disease-related impact of incontinence in cognitively impaired adults and the effort associated with the care of this population, and to present the initial psychometric properties of this tool and outline the possible clinical implications. PARTICIPANTS AND METHODS: The ICIQ-Cog consists of two scales: a 12 item scale measuring disease-specific bother (ICIQ-Cog-P) and a four-item scale assessing efforts associated with care of people with incontinence and cognitive impairment (ICIQ-Cog-C). Data on 60 nursing home residents with incontinence and cognitive impairment were obtained in a test-retest research design. The psychometric properties of the ICIQ-Cog were examined using a combination of classic and item response theory methods. RESULTS: Factor analyses resulted in a three-factor solution for the ICIQ-Cog-P, with interrelated factors. Rasch analysis showed a good model fit when collapsing response categories. The ICIQ Cog-C fitted to one dimension. The ICIQ-Cog tool provided reliable measures in terms of internal consistency (0.69-0.82) and retest reliability (0.71-0.83). The preliminary results on external validity showed that the ICIQ-Cog assessed disease-specific aspects linked to the group of cognitively impaired people with incontinence. CONCLUSION: The ICIQ-Cog tool has appropriate psychometric and clinometric properties and is therefore useful for making decisions about treatment in cognitively impaired adults with incontinence. PMID- 29509293 TI - Response of periodontium to mineral trioxide aggregate and Biodentine: a pilot histological study on humans. AB - BACKGROUND: The aim of this study was to investigate for the first time the histological response of human periodontium to mineral trioxide aggregate (MTA) and Biodentine. METHODS: Six patients scheduled for implant full-arch rehabilitation were randomly assigned to one of the two test groups: MTA or Biodentine treatment. For each patient, two teeth scheduled for strategic extraction were randomly assigned either to the test or to the control treatment. A lateral perforation was drilled on the root and either repaired with MTA/Biodentine or filled with gutta-percha(control). Three months later, the teeth were extracted along with the coronal third of the alveolar bone and a portion of gingival tissue, while performing implant placement, and processed for histological analysis. RESULTS: Biodentine resulted in less extrusion into the periodontal environment. All the materials showed good biocompatibility. A new mineralized cementum-like tissue incorporating periodontal fibres was visible in all cases treated with MTA. A small amount of new mineralized tissue was found in two Biodentine cases but not in control cases. Biodentine resulted in less damage to the periodontal ligament. CONCLUSIONS: Bioactivity and biocompatibility of MTA were confirmed in human models. Biodentine proved to be biocompatible, but it seems not to induce cementum regeneration. PMID- 29509294 TI - Essential Oil Composition and Volatile Profile of Seven Helichrysum Species Grown in Italy. AB - Helichrysum genus consists of about 600 species widespread throughout the world, especially in South Africa and in the Mediterranean area. In this study the aroma profile (HS-SPME) and the EO compositions of seven Helichrysum species (H. cymosum, H. odoratissimum, H. petiolare, H. fontanesii, H. saxatile, H. sanguineum, and H. tenax) were evaluated. All the plants were grown in Italy under the same growth conditions. The volatile constituents, particularly monoterpenes, depended by the plant's genotype and ecological adaptation. This study represents the first headspace evaluation on the selected plants and the results evidenced that monoterpenes represented the main class of constituents in five of the seven species analysed (from 59.2% to 95.0%). The higher content in sesquiterpene hydrocarbons was observed in the Mediterranean species of H. sanguineum (68.0%). Only H. saxatile showed relative similar abundance of monoterpenes and sesquiterpene hydrocarbons. The essential oil composition of the majority of examined species are characterised by high percentage of sesquiterpenes (especially beta-caryophyllene and delta-cadinene) ranging from 51.3% to 92.0%, except for H. cymosum, H. tenax, and H. sanguineum leaves where monoterpenes predominated (from 51.7% to 74.7%). PMID- 29509295 TI - De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies. AB - Donor-specific antibodies (DSAs) are associated with an increased risk of antibody-mediated rejection and graft failure. In BENEFIT and BENEFIT-EXT, kidney transplant recipients were randomized to receive belatacept more intense (MI) based, belatacept less intense (LI)-based, or cyclosporine-based immunosuppression for up to 7 years (84 months). The presence/absence of HLA specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid-phase flow-cytometry screening. Samples from anti-HLA-positive patients were further tested with a single-antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI-treated, belatacept LI-treated, and cyclosporine-treated patients, respectively. The corresponding values in BENEFIT-EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan-Meier analysis, de novo DSA incidence was significantly lower in belatacept-treated vs cyclosporine-treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept-based immunosuppression was associated with numerically lower MFI vs cyclosporine-based immunosuppression. Although derived post hoc, these data suggest that belatacept based immunosuppression suppresses de novo DSA development more effectively than cyclosporine-based immunosuppression. PMID- 29509296 TI - Vitamin B complex mitigates cardiac dysfunction in high-methionine diet-induced hyperhomocysteinemia. AB - This research is designed to test the hypothesis that elevated homocysteine (Hcy) levels in vivo, caused by a deficit in vitamin B complex, promote changes in cardiac function and redox status that lead to heart failure. In order to conduct the study, we used adult male Wistar albino rats (n = 30; 4 weeks old; 100 +/- 15 g body weight). Hyperhomocysteinaemia (HHcy) in these animals was achieved by dietary manipulation. For 4 weeks, the animals were fed with a standard rodent chow (control, CF), a diet enriched in methionine with no deficiency in B vitamins (i.e., folic acid, B6 and B12) (HMNV) or a diet enriched in methionine and deficient in B vitamins (HMLV). After 28 days of dietary manipulation, all animals were killed. The rat hearts were isolated and retrogradely perfused according to the Langendorff technique at a gradually increasing perfusion pressure. We found a negative correlation between elevated serum Hcy and total body and heart weight. The maximum rate of left ventricular pressure development was significantly increased in the HMNV group compared with in the other groups. Systolic left ventricular pressure was significantly changed in all groups. HHcy induces remodelling of the cardiac tissues, as moderate HHcy is associated with more prominent interstitial and perivascular fibrosis. Our results suggest that a high methionine diet without vitamin B complex causes profound negative effects associated with HHcy. PMID- 29509297 TI - Possible association between Helicobacter pylori infection and vocal fold leukoplakia. AB - BACKGROUND: Several studies have indicated the larynx as possible Helicobacter pylori (H. pylori) reservoirs. This study explored the association between H. pylori and vocal fold leukoplakia. METHODS: The case-control study involved 51 patients with vocal fold leukoplakia and 35 control patients with vocal polyps. Helicobacter pylori was detected in tissues by the rapid urease test, nested polymerase chain reaction (PCR), and single-step PCR. The H. pylori-specific immunoglobulin antibodies were detected in plasma by enzyme-linked immunosorbent assay (ELISA). RESULTS: Helicobacter pylori-positive rate of vocal fold leukoplakia and vocal polyps was 23.5% versus 11.4% (P = .157), 37.2% versus 14.3% (P = .020), 27.5% versus 8.6% (P = .031), and 70.6% versus 68.6% (P = .841) detected by rapid urease test, nested PCR, single-step PCR, and ELISA, respectively. Regression analysis indicated that H. pylori infection (P = .044) was the independent risk factor for vocal fold leukoplakia. CONCLUSION: Helicobacter pylori infection exists in the larynx and may be associated with vocal fold leukoplakia. PMID- 29509298 TI - Applying a dryland degradation framework for rangelands: the case of Mongolia. AB - Livestock-caused rangeland degradation remains a major policy concern globally and the subject of widespread scientific study. This concern persists in part because it is difficult to isolate the effects of livestock from climate and other factors that influence ecosystem conditions. Further, degradation studies seldom use multiple plant and soil indicators linked to a clear definition of and ecologically grounded framework for degradation assessment that distinguishes different levels of degradation. Here, we integrate two globally applicable rangeland degradation frameworks and apply them to a broad-scale empirical data set for the country of Mongolia. We compare our assessment results with two other recent national rangeland degradation assessments in Mongolia to gauge consistency of findings across assessments and evaluate the utility of our framework. We measured livestock-use impacts across Mongolia's major ecological zones: mountain and forest steppe, eastern steppe, steppe, and desert steppe. At 143 sites in 36 counties, we measured livestock-use and degradation indicators at increasing distances from livestock corrals in winter-grazed pastures. At each site, we measured multiple indicators linked to our degradation framework, including plant cover, standing biomass, palatability, species richness, forage quality, vegetation gaps, and soil surface characteristics. Livestock use had no effect on soils, plant species richness, or standing crop biomass in any ecological zone, but subtly affected plant cover and palatable plant abundance. Livestock effects were strongest in the steppe zone, moderate in the desert steppe, and limited in the mountain/forest and eastern steppes. Our results aligned closely with those of two other recent country-wide assessments, suggesting that our framework may have widespread application. All three assessments found that very severe and irreversible degradation is rare in Mongolia (1-18% of land area), with most rangelands slightly (33-53%) or moderately (25-40%) degraded. We conclude that very severe livestock-induced rangeland degradation is overstated in Mongolia. However, targeted rangeland restoration coupled with monitoring, adaptive management and stronger rangeland governance are needed to prevent further degradation where heavy grazing could cause irreversible change. Given the broad applicability of our degradation framework for Mongolia, we suggest it be tested for application in other temperate grasslands throughout Central Asia and North America. PMID- 29509299 TI - Supplementing non-target taxa: bird feeding alters the local distribution of mammals. AB - Although the effects of bird feeding on avian species have been extensively examined, few studies evaluate the indirect effects of bird feeding on non-target taxa. Bird seed could provide direct nourishment to several mammalian species (e.g., Lagomorpha, Rodentia, and Cetartiodactyla), potentially altering their distribution and behavior with possible unintended consequences for some avian populations, particularly those not directly benefiting from the resource. To examine how bird feeders may influence the presence and behavior of mammals, we used camera traps to quantify differences in the distribution and richness of mammal species frequenting sites with bird feeders and control sites (lacking feeders) in Ithaca, New York, USA. We recorded 15,684 images capturing 12 mammal species with gray squirrel (Sciurus carolinensis) and raccoon (Procyon lotor) detected significantly more often at feeder sites than at control sites. Detections of white-tailed deer (Odocoileus virginianus) marginally increased near feeders whereas detections of several carnivorous species were unrelated to the presence of bird feeders. We recorded larger gray squirrel and raccoon group sizes and greater mammal richness at feeder sites than at nearby control sites. We detected squirrels and raccoons less when snow covered the ground than on snow free days. Ambient temperature was not a strong predictor of mammal detections. Camera trapping revealed strong, species-specific patterns in the timing of daily visitation to areas with feeders. Because many mammals depredate bird nests, the local increases in mammal richness and activity near bird feeders may create an ecological trap for avian species nesting in close proximity to supplemental feeding stations. PMID- 29509300 TI - Psychological distress in student nurses undertaking an educational programme with professional registration as a nurse: Their perceived barriers and facilitators in seeking psychological support. AB - : WHAT IS KNOWN ON THE SUBJECT?: Psychological distress is a major health concern, and university student populations are at a risk due to high academic, economic and interpersonal demands at this time. While a number of studies have been conducted looking at distress and service uptake amongst university students, there is a lack of comparative information in the student nurse population. Therefore, this study focuses on level of psychological distress and service uptake in student nurses during their training. Student nurses in training are acknowledged as particularly vulnerable to anxiety and depression. Anxiety and depression can interfere with educational achievement and interfere with working relationships, which are an important aspect of clinical practice. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study investigates psychological distress and service uptake in student nurses, in a single study, by measuring the level of distress and comparing this with adult nonpatient norms. The key findings suggest high levels of anxiety and depression and poor uptake of support in student nurses. The main barrier to seeking support was the fear of disclosure about their anxiety and/or depression, and feared impact on their suitability to train as a nurse. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Due to the fear of disclosure and low levels of support seeking, mental health nurses and academics have a key role to play in mental health literacy. It seems reasonable, given the key findings, to suggest that interventions be directed at decreasing anxiety and depression such as mindfulness training and other evidence based strategies. It is recommended that psychological distress needs due attention from higher education sector and those health professionals involved in mental health service provision to support evidence-based strategies that target these issues. ABSTRACT: Introduction This study adds to the existing international evidence on psychological distress in the student population by focusing on student nurses. It quantitatively assesses psychological distress with comparative norms and investigates service uptake in a single study. Aim The aim of this study was to investigate the level of psychological distress in students and compare this with population norms and highlight potential facilitators and barriers to help seeking. Methods This study recruited N = 121 student nurses from one university in a cross-sectional design. Data were analysed using descriptive statistics, independent t tests and one-way ANOVAs. Findings The key findings show high levels of psychological distress, which is above levels seen in the general population. The main barriers to seeking support were fear of disclosure and the perceived impact on their suitability as a student nurse. Discussion The study highlights that high levels of distress identified in the literature are seen in student nurses and that fear of disclosure may account for some not seeking support. Relevance The fear of disclosure and low levels of seeking support suggest there is a need for mental health nurses and academics to play a key role in mental health literacy and evidence-based interventions such as mindfulness to combat these issues. PMID- 29509301 TI - Declining trend in valproate use in Finland among females of childbearing age in 2012-2016 - a nationwide registry-based outpatient study. AB - BACKGROUND AND PURPOSE: Documented teratogenic effects of valproate (VPA) prompted restrictions of its use in females of childbearing age in 2014. We investigated possible annual changes in the outpatient use of VPA in Finland during 2008-2016 with a special focus on women. METHODS: We identified all outpatients with VPA purchases between 2008 and 2016 categorizing users due to epilepsy, bipolar disorder or miscellaneous indications. Temporal trends in the annual prevalence rates of VPA use were estimated using Poisson regression analyses. RESULTS: Between 2012 and 2016, the prevalence of VPA use among women aged 15-44 years decreased by 19%, from 50/10 000 to 40/10 000 (prevalence rate ratio, 0.81; 95% confidence intervals, 0.77-0.91; P < 0.001). The use of VPA due to epilepsy decreased significantly in females aged 15-24 and 25-34 years and that due to bipolar disorders decreased significantly in females aged 25-34 and 35-44 years. The use of VPA in the miscellaneous indication group decreased by 32% after 2014 in females aged 15-44 years and, most strikingly, by 56% among those aged 15-25 years. In women with epilepsy, the use of VPA increased among those over the age of 44 years. CONCLUSIONS: The rates of female VPA users with childbearing potential have decreased in all three major indication groups in Finland during recent years, especially after the European Medicines Agency restrictions were published in 2014. However, it still remains open to question as to whether the practice of VPA use follows current guidelines. A special concern is the relatively high prevalence of off-label use of VPA in fertile-aged females. PMID- 29509302 TI - Effective and Selective Catalysts for Cinnamaldehyde Hydrogenation: Hydrophobic Hybrids of Metal-Organic Frameworks, Metal Nanoparticles, and Micro- and Mesoporous Polymers. AB - Metal-organic frameworks (MOFs) as selectivity regulators for catalytic reactions have attracted much attention, especially MOFs and metal nanoparticle (NP) shelled structures, e.g., MOFs@NPs@MOFs. Nevertheless, making hydrophilic MOF shells for gathering hydrophobic reactants is challenging. Described here is a new and viable approach employing conjugated micro- and mesoporous polymers with iron(III) porphyrin (FeP-CMPs) as a new shell to fabricate MIL-101@Pt@FeP-CMP. It is not only hydrophobic and porous for enriching reactants, but also possesses iron sites to activate C=O bonds, thereby regulating the selectivity for cinnamyl alcohol in the hydrogenation of cinnamaldehyde. Interestingly, MIL-101@Pt@FeP CMPsponge can achieve a high turnover frequency ( 1516.1 h-1 ), with 97.3 % selectivity for cinnamyl alcohol at 97.6 % conversion. PMID- 29509303 TI - Three-dimensional printing in robot-assisted radical prostatectomy - an Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) Phase 2a study. PMID- 29509306 TI - In vitro 3D regeneration-like growth of human patient brain tissue. AB - In vitro culture of primary neurons is widely adapted with embryonic but not mature brain tissue. Here, we extended a previously developed bioengineered three dimensional (3D) embryonic brain tissue model to resected normal patient brain tissue in an attempt to regenerate human neurons in vitro. Single cells and small sized (diameter < 100 MUm) spheroids from dissociated brain tissue were seeded into 3D silk fibroin-based scaffolds, with or without collagen or Matrigel, and compared with two-dimensional cultures and scaffold-free suspension cultures. Changes of cell phenotypes (neuronal, astroglial, neural progenitor, and neuroepithelial) were quantified with flow cytometry and analyzed with a new method of statistical analysis specifically designed for percentage comparison. Compared with a complete lack of viable cells in conventional neuronal cell culture condition, supplements of vascular endothelial growth factor-containing pro-endothelial cell condition led to regenerative growth of neurons and astroglial cells from "normal" human brain tissue of epilepsy surgical patients. This process involved delayed expansion of Nestin+ neural progenitor cells, emergence of TUJ1+ immature neurons, and Vimentin+ neuroepithelium-like cell sheet formation in prolonged cultures (14 weeks). Micro-tissue spheroids, but not single cells, supported the brain tissue growth, suggesting importance of preserving native cell-cell interactions. The presence of 3D scaffold, but not hydrogel, allowed for Vimentin+ cell expansion, indicating a different growth mechanism than pluripotent cell-based brain organoid formation. The slow and delayed process implied an origin of quiescent neural precursors in the neocortex tissue. Further optimization of the 3D tissue model with primary human brain cells could provide personalized brain disease models. PMID- 29509307 TI - Retinoic acid receptor-alpha regulates synthetic events in human platelets: reply. PMID- 29509308 TI - A new measure of child vocal reciprocity in children with autism spectrum disorder. AB - : Children's vocal development occurs in the context of reciprocal exchanges with a communication partner who models "speechlike" productions. We propose a new measure of child vocal reciprocity, which we define as the degree to which an adult vocal response increases the probability of an immediately following child vocal response. Vocal reciprocity is likely to be associated with the speechlikeness of vocal communication in young children with autism spectrum disorder (ASD). Two studies were conducted to test the utility of the new measure. The first used simulated vocal samples with randomly sequenced child and adult vocalizations to test the accuracy of the proposed index of child vocal reciprocity. The second was an empirical study of 21 children with ASD who were preverbal or in the early stages of language development. Daylong vocal samples collected in the natural environment were computer analyzed to derive the proposed index of child vocal reciprocity, which was highly stable when derived from two daylong vocal samples and was associated with speechlikeness of vocal communication. This association was significant even when controlling for chance probability of child vocalizations to adult vocal responses, probability of adult vocalizations, or probability of child vocalizations. A valid measure of children's vocal reciprocity might eventually improve our ability to predict which children are on track to develop useful speech and/or are most likely to respond to language intervention. A link to a free, publicly-available software program to derive the new measure of child vocal reciprocity is provided. Autism Res 2018, 11: 903-915. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Children and adults often engage in back-and-forth vocal exchanges. The extent to which they do so is believed to support children's early speech and language development. Two studies tested a new measure of child vocal reciprocity using computer-generated and real-life vocal samples of young children with autism collected in natural settings. The results provide initial evidence of accuracy, test-retest reliability, and validity of the new measure of child vocal reciprocity. A sound measure of children's vocal reciprocity might improve our ability to predict which children are on track to develop useful speech and/or are most likely to respond to language intervention. A free, publicly-available software program and manuals are provided. PMID- 29509309 TI - Can Variations of 1 H NMR Chemical Shifts in Benzene Substituted with an Electron Accepting (NO2 )/Donating (NH2 ) Group be Explained in Terms of Resonance Effects of Substituents? AB - The classical textbook explanation of variations of 1 H NMR chemical shifts in benzenes bearing an electron-donating (NH2 ) or an electron-withdrawing (NO2 ) group in terms of substituent resonance effects was examined by analyzing molecular orbital contributions to the total shielding. It was found that the pi electronic system showed a more pronounced shielding effect on all ring hydrogen atoms, relative to benzene, irrespective of substituent +R/-R effects. For the latter, this was in contrast to the traditional explanations of downfield shift of nitrobenzene proton resonances, which were found to be determined by the sigma electronic system and oxygen in-plane lone pairs. In aniline, the +R effect of NH2 group can be used to fully explain the upfield position of meta-H signals and partly the upfield position of para-H signals, the latter also being influenced by the sigma-system. The position of the lowest frequency signal of ortho-Hs was fully determined by sigma-electrons. PMID- 29509311 TI - Equine cheek teeth occlusal fissures: Prevalence, association with dental wear abnormalities and occlusal angles. AB - BACKGROUND: Fissures of the occlusal surface of equine cheek teeth are commonly encountered during oral examination but their aetiology is unknown. OBJECTIVES: To examine the prevalence and characteristics of occlusal fissures in cadaver teeth. It is hypothesised that their prevalence is influenced by masticatory forces. Consequently, their possible association with wear disorders and occlusal angles were examined. STUDY DESIGN: Cross-sectional survey. METHODS: The dental abnormalities and occlusal fissure findings in the cheek teeth of 143 cadaver heads were recorded. The cheek teeth occlusal angles were measured using the stiff-hinge technique. Multiple regression analyses were performed to establish possible relationships between age, sex, dental wear, occlusal angle and fissure prevalence. RESULTS: Occlusal fissures were found in 103/143 (72%) heads. Sex and age were determining factors in the prevalence of fissures. A similar prevalence was found in mandibular (54.1%) and maxillary teeth (45.9%, OR = 1.10; 95% CI = 0.95-1.29, P = 0.2). Mandibular fissures were more commonly located on the buccal aspect (OR = 1.42; 95% CI = 1.16-1.65, P < 0.001), whereas for maxillary fissures there was no difference in prevalence between palatal and buccal aspects (OR = 1.19; 95% CI = 0.97-1.46, P = 0.1). Two main fissure types were identified. Type 1a fissures were the most prevalent type (39.5%). No significant correlation was found between the presence of wear abnormalities or the occlusal angle of cheek teeth, and the prevalence of fissures. MAIN LIMITATIONS: No dental histories were available. CONCLUSION: Equine cheek teeth show a high prevalence of occlusal fissures. Despite some evidence of predilection sites on the tooth surface that might indicate a mechanical aetiology for these lesions, no associations were found with wear abnormalities or occlusal angles of affected cheek teeth. Further histological and ultrastructural studies are warranted to elucidate their aetiology and possible role in other dental diseases. PMID- 29509310 TI - Satellite sensor requirements for monitoring essential biodiversity variables of coastal ecosystems. AB - The biodiversity and high productivity of coastal terrestrial and aquatic habitats are the foundation for important benefits to human societies around the world. These globally distributed habitats need frequent and broad systematic assessments, but field surveys only cover a small fraction of these areas. Satellite-based sensors can repeatedly record the visible and near-infrared reflectance spectra that contain the absorption, scattering, and fluorescence signatures of functional phytoplankton groups, colored dissolved matter, and particulate matter near the surface ocean, and of biologically structured habitats (floating and emergent vegetation, benthic habitats like coral, seagrass, and algae). These measures can be incorporated into Essential Biodiversity Variables (EBVs), including the distribution, abundance, and traits of groups of species populations, and used to evaluate habitat fragmentation. However, current and planned satellites are not designed to observe the EBVs that change rapidly with extreme tides, salinity, temperatures, storms, pollution, or physical habitat destruction over scales relevant to human activity. Making these observations requires a new generation of satellite sensors able to sample with these combined characteristics: (1) spatial resolution on the order of 30 to 100 m pixels or smaller; (2) spectral resolution on the order of 5 nm in the visible and 10 nm in the short-wave infrared spectrum (or at least two or more bands at 1,030, 1,240, 1,630, 2,125, and/or 2,260 nm) for atmospheric correction and aquatic and vegetation assessments; (3) radiometric quality with signal to noise ratios (SNR) above 800 (relative to signal levels typical of the open ocean), 14 bit digitization, absolute radiometric calibration <2%, relative calibration of 0.2%, polarization sensitivity <1%, high radiometric stability and linearity, and operations designed to minimize sunglint; and (4) temporal resolution of hours to days. We refer to these combined specifications as H4 imaging. Enabling H4 imaging is vital for the conservation and management of global biodiversity and ecosystem services, including food provisioning and water security. An agile satellite in a 3-d repeat low-Earth orbit could sample 30-km swath images of several hundred coastal habitats daily. Nine H4 satellites would provide weekly coverage of global coastal zones. Such satellite constellations are now feasible and are used in various applications. PMID- 29509312 TI - Using the Hendrich II Inpatient Fall Risk Screen to Predict Outpatient Falls After Emergency Department Visits. AB - OBJECTIVES: To evaluate the utility of routinely collected Hendrich II fall scores in predicting returns to the emergency department (ED) for falls within 6 months. DESIGN: Retrospective electronic record review. SETTING: Academic medical center ED. PARTICIPANTS: Individuals aged 65 and older seen in the ED from January 1, 2013, through September 30, 2015. MEASUREMENTS: We evaluated the utility of routinely collected Hendrich II fall risk scores in predicting ED visits for a fall within 6 months of an all-cause index ED visit. RESULTS: For in network patient visits resulting in discharge with a completed Hendrich II score (N = 4,366), the return rate for a fall within 6 months was 8.3%. When applying the score alone to predict revisit for falls among the study population the resultant receiver operating characteristic (ROC) plot had an area under the curve (AUC) of 0.64. In a univariate model, the odds of returning to the ED for a fall in 6 months were 1.23 times as high for every 1-point increase in Hendrich II score (odds ratio (OR)=1.23 (95% confidence interval (CI)=1.19-1.28). When included in a model with other potential confounders or predictors of falls, the Hendrich II score is a significant predictor of a return ED visit for fall (adjusted OR=1.15, 95% CI=1.10-1.20, AUC=0.75). CONCLUSION: Routinely collected Hendrich II scores were correlated with outpatient falls, but it is likely that they would have little utility as a stand-alone fall risk screen. When combined with easily extractable covariates, the screen performs much better. These results highlight the potential for secondary use of electronic health record data for risk stratification of individuals in the ED. Using data already routinely collected, individuals at high risk of falls after discharge could be identified for referral without requiring additional screening resources. PMID- 29509313 TI - Creutzfeldt astrocytes may be seen in IDH-wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins. AB - Astrocytes with multiple micronuclei ("Creutzfeldt cells") in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high-grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico-radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell-rich GBMs were IDH wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich-GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH-wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells. PMID- 29509314 TI - The use of antimicrobial photodynamic therapy in oral injuries of a pediatric patient with myelodysplastic syndrome: case report. AB - AIM: To report a case of a pediatric patient carrier of myelodysplastic syndrome (MDS) with severe oral infectious disease, in which antimicrobial photodynamic therapy (aPDT) was used as a therapeutic choice to support systemic treatment. METHODS AND RESULTS: This case report refers to a 1-year-old male patient with MDS and hospitalized for investigation and treatment of complications at a Pediatric Oncology and Hematology Center in Recife/PE, Brazil. The intraoral examination revealed a violaceous lesion surrounding the lower incisor teeth, which progressed with alteration of color to milky yellowish white, compromising the entire lower gingival border, leading to tooth mobility and consequent loss of teeth 71 and 81. The patient was treated under systemic antimicrobial therapy and aPDT was also performed, using a photosensitizing agent (methylene blue, 0.01%) and a low-intensity laser in the visible red spectrum. Oral clinical improvement was observed, but the patient died after 45 days of hospitalization in the Pediatric ICU due to other systemic complications. CONCLUSION: MDS may present limiting oral repercussions interfering in patients' quality of life. The aPDT is presented as an adjuvant therapeutic modality in oral infections with satisfactory results. PMID- 29509315 TI - The Effect of Lean-Seafood and Non-Seafood Diets on Fecal Metabolites and Gut Microbiome: Results from a Randomized Crossover Intervention Study. AB - SCOPE: The impact of dietary protein types on the gut microbiome is scarcely studied. The aim of the present study is therefore to examine the effects of lean seafood and non-seafood proteins on the gut microbiome composition and activity and elucidate potential associations to cardiovascular disease (CVD) risk factors. METHODS: A crossover intervention study in which 20 healthy subjects consumed two diets that varied in protein source was conducted. 1 H NMR spectroscopy and 16S rDNA sequencing analyses were applied to characterize fecal metabolites and gut microbiota composition, respectively. RESULTS: A twofold increase in fecal trimethylamine excretion was observed after the lean-seafood diet period. Circulating TAG and the total to high-density lipoprotein (HDL) cholesterol ratio as well as circulating TMAO levels were each associated with specific gut bacteria. Following the non-seafood diet period, a decreased relative abundance of Clostridium cluster IV and a tendency toward an increased Firmicutes/Bacteroidetes ratio were found. CONCLUSIONS: Lean-seafood and non seafood diets differentially modulate the gut microbiome composition and activity. Furthermore, the gut microbiota composition seems to affect circulating TMAO levels and CVD risk factors. PMID- 29509316 TI - Palladium/Norbornene-Catalyzed C-H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine-Containing Pentacyclic Frameworks. AB - Reported is a highly chemoselective intermolecular annulation of indole-based biaryls with bromoalkyl alkynes by using palladium/norbornene (Pd/NBE) cooperative catalysis. This reaction is realized through a sequence of Catellani type C-H alkylation, alkyne insertion, and indole dearomatization, by forming two C(sp2 )-C(sp3 ) and one C(sp2 )-C(sp2 ) bonds in a single chemical operation, thus providing a diverse range of pentacyclic molecules, containing a spiroindolenine fragment, in good yields with excellent functional-group tolerance. Preliminary mechanistic studies reveal that C-H bond cleavage is likely involved in the rate-determining step, and the indole dearomatization might take place through an olefin coordination/insertion and beta-hydride elimination Heck-type pathway. PMID- 29509317 TI - Superoxide Stabilization and a Universal KO2 Growth Mechanism in Potassium-Oxygen Batteries. AB - Rechargeable potassium-oxygen (K-O2 ) batteries promise to provide higher round trip efficiency and cycle life than other alkali-oxygen batteries with satisfactory gravimetric energy density (935 Wh kg-1 ). Exploiting a strong electron-donating solvent, for example, dimethyl sulfoxide (DMSO) strongly stabilizes the discharge product (KO2 ), resulting in significant improvement in electrode kinetics and chemical/electrochemical reversibility. The first DMSO based K-O2 battery demonstrates a much higher energy efficiency and stability than the glyme-based electrolyte. A universal KO2 growth model is developed and it is demonstrated that the ideal solvent for K-O2 batteries should strongly stabilize superoxide (strong donor ability) to obtain high electrode kinetics and reversibility while providing fast oxygen diffusion to achieve high discharge capacity. This work elucidates key electrolyte properties that control the efficiency and reversibility of K-O2 batteries. PMID- 29509318 TI - A Multivariable Prediction Model for Mortality in Individuals Admitted for Heart Failure. AB - OBJECTIVES: To derive and validate a 30-day mortality clinical prediction rule for heart failure based on admission data and prior healthcare usage. A secondary objective was to determine the discriminatory function for mortality at 1 and 2 years. DESIGN: Observational cohort. SETTING: Veterans Affairs inpatient medical centers (n=124). PARTICIPANTS: The derivation (2010-12; n=36,021) and validation (2013-15; n=30,364) cohorts included randomly selected veterans admitted for HF exacerbation (mean age 71+/-11; 98% male). MEASUREMENTS: The primary outcome was 30-day mortality. Secondary outcomes were 1- and 2-year mortality. Candidate variables were drawn from electronic medical records. Discriminatory function was measured as the area under the receiver operating characteristic curve. RESULTS: Thirteen risk factors were identified: age, ejection fraction, mean arterial pressure, pulse, brain natriuretic peptide, blood urea nitrogen, sodium, potassium, more than 7 inpatient days in the past year, metastatic disease, and prior palliative care. The model stratified participants into low- (1%), intermediate- (2%), high- (5%), and very high- (15%) mortality risk groups (C statistic=0.72, 95% confidence interval (CI)=0.71-0.74). These findings were confirmed in the validation cohort (C-statistic=0.70, 95% CI=0.68-0.71). Subgroup analysis of age strata confirmed model discrimination. CONCLUSION: This simple prediction rule allows clinicians to risk-stratify individuals on admission for HF using characteristics captured in electronic medical record systems. The identification of high-risk groups allows individuals to be targeted for discussion of goals and treatment. PMID- 29509319 TI - Partial loss of function of colony-stimulating factor 1 receptor in a patient with white matter abnormalities. AB - BACKGROUND AND PURPOSE: Mutations in colony-stimulating factor 1 receptor (CSF1R) cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Patients with ALSP can be misdiagnosed as having acute ischemic stroke due to hyperintensity lesions on diffusion-weighted magnetic resonance imaging. Mutant CSF1R proteins identified in ALSP show a complete loss of autophosphorylation of CSF1R. METHODS: We conducted mutation screening of CSF1R in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke. The pathogenicity of identified variants was evaluated using functional analyses. The levels of autophosphorylation of CSF1R in response to treatment with ligands of CSF1R were examined in cells transfected with wild-type and mutant CSF1R. RESULTS: We identified eight CSF1R variants, six were known non-pathogenic polymorphisms, whereas the other two were missense variants inducing substitution of amino acid residues (p.Glu573Lys and p.Gly747Arg). Functional assay showed that the levels of autophosphorylation of p.Gly747Arg were similar to those of wild-type when treated with ligands. The autophosphorylation of p.Glu573Lys was detectable, but significantly decreased compared with those of wild-type CSF1R (P < 0.001, two-way anova with Bonferroni). The clinical presentation of the patient with p.Glu573Lys was consistent with cerebral embolism. The patient did not have typical clinical findings of ALSP. However, periventricular white matter abnormalities, unrelated to the recent infarct, were evident on brain magnetic resonance imaging. CONCLUSIONS: In contrast to ALSP-associated missense mutations, CSF1R p.Glu573Lys variant in a patient with acute ischemic cerebrovascular syndrome showed a partial loss of autophosphorylation of CSF1R; its clinical significance warrants further investigation. PMID- 29509321 TI - The controversy of social media at conferences. PMID- 29509320 TI - Is there an established hemoglobin target range for patients undergoing chronic dialysis? AB - Anemia is a common complication of advanced chronic kidney disease (CKD). Treatment with erythropoiesis-stimulating agents (ESAs) remains a common approach in managing anemia of CKD. The 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Anemia in CKD suggests avoiding ESA therapy use to maintain Hb level above 11.5 g/dL. However, optimal Hb target range in adult patients undergoing chronic dialysis remains unknown. Clinical studies suggest risks associated with normalization of Hb levels in adult patients with CKD. In this article, we briefly review some of these studies and the concerns associated with higher Hb targets in this patient population. We also suggest a target Hb range for adult chronic dialysis patients receiving ESAs. It is currently undetermined if this target Hb range would apply to newer agents that are being studied for anemia management in this population. PMID- 29509322 TI - Epidemiology, clinical management, and outcomes of dogs involved in road traffic accidents in the United Kingdom (2009-2014). AB - OBJECTIVE: To estimate the prevalence and risk factors for road traffic accidents (RTA) in dogs and describe the management and outcome of these dogs attending primary-care veterinary practices in the United Kingdom. DESIGN: Retrospective cross-sectional study. SETTING: Primary-care veterinary practices in the United Kingdom. ANIMALS: The study population included 199,464 dogs attending 115 primary-care clinics across the United Kingdom. MEASUREMENTS AND MAIN RESULTS: Electronic patient records of dogs attending practices participating in the VetCompass Programme were assessed against selection criteria used to define RTA cases. Cases identified as RTAs were identified and manually verified to calculate prevalence. Univariable and multivariable logistic regression methods were used to evaluate associations between risk factors and RTA. The prevalence of RTA was 0.41%. Of the RTA cases, 615 (74.9%) were purebred, 322 (39.2%) were female, and 285 (54.8%) were insured. The median age at RTA was 2.5 years. After accounting for the effects of other factors, younger dogs had increased odds of an RTA event: dogs aged under 3 years showed 2.9 times the odds and dogs aged between 6-9 years showed 1.8 times the odds of an RTA event compared with dogs aged over 14 years. Males had 1.4 times the odds of an RTA event compared with females. Overall, 22.9% of cases died from a cause associated with RTA. Of dogs with information available, 34.0% underwent diagnostic imaging, 29.4% received intravenous fluid-therapy, 71.1% received pain relief, 46.0% were hospitalized, and 15.6% had surgery performed under general anesthetic. CONCLUSIONS: This study identified important demographic factors associated with RTA in dogs, notably being young and male. PMID- 29509323 TI - Recombinant thrombomodulin ameliorates experimental autoimmune encephalomyelitis by suppressing high mobility group box 1 and inflammatory cytokines. AB - Recombinant thrombomodulin (rTM) has pleiotrophic properties, including anti coagulation and anti-inflammation; however, its effectiveness as a treatment for multiple sclerosis (MS) has not been evaluated fully. High mobility group box 1 (HMGB1) and proinflammatory cytokines, working as inflammatory mediators, are reportedly involved in the inflammatory pathogenesis of MS. The aim of this study was to determine whether rTM can be a potential therapeutic agent for experimental autoimmune encephalomyelitis (EAE). EAE mice received rTM treatment (1 mg or 0.1 mg/kg/day) from days 11 to 15 after immunization. The clinical variables, plasma levels of inflammatory cytokines and HMGB1 and pathological findings in EAE were evaluated. rTM administration ameliorated the clinical and pathological severity of EAE. An immunohistochemical study of the spinal cord showed weaker cytoplasmic HMGB1 staining in the rTM-treated EAE mice than in the untreated EAE mice. Plasma levels of inflammatory cytokines and HMGB1 were suppressed by rTM treatment. In conclusion, rTM down-regulated inflammatory mediators in the peripheral circulation and prevented HMGB1 release from nuclei in the central nervous system, suppressing EAE-related inflammation. rTM could have a novel therapeutic potential for patients with MS. PMID- 29509325 TI - Survivors of childhood cancer are more likely to develop high blood pressure as adults. PMID- 29509324 TI - Erratum: Pashankar F, Hale JP, Dang H, et al. Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative. Cancer. 2016;122:230-237. PMID- 29509326 TI - Overweight women may require more frequent mammograms. PMID- 29509327 TI - First person: Antoni Ribas, MD, PhD: The physician-scientist from the University of California at Los Angeles researches how new therapies for patients with advanced malignant melanoma can help to overcome resistance to treatment. PMID- 29509328 TI - An Introduction to dialysis education: Issues, innovations and impact. PMID- 29509330 TI - Comment on: Botulinum toxin injection vs topical nitrates for chronic anal fissure: an updated systematic review and meta-analysis of randomized controlled trials. PMID- 29509331 TI - Tandem tyrosine phosphosites in the Enteropathogenic Escherichia coli chaperone CesT are required for differential type III effector translocation and virulence. AB - Enteropathogenic Escherichia coli (EPEC) use a type 3 secretion system (T3SS) for injection of effectors into host cells and intestinal colonization. Here, we demonstrate that the multicargo chaperone CesT has two strictly conserved tyrosine phosphosites, Y152 and Y153 that regulate differential effector secretion in EPEC. Conservative substitution of both tyrosine residues to phenylalanine strongly attenuated EPEC type 3 effector injection into host cells, and limited Tir effector mediated intimate adherence during infection. EPEC expressing a CesT Y152F variant were deficient for NleA effector expression and exhibited significantly reduced translocation of NleA into host cells during infection. Other effectors were observed to be dependent on CesT Y152 for maximal translocation efficiency. Unexpectedly, EPEC expressing a CesT Y153F variant exhibited significantly enhanced effector translocation of many CesT-interacting effectors, further implicating phosphosites Y152 and Y153 in CesT functionality. A mouse infection model of intestinal disease using Citrobacter rodentium revealed that CesT tyrosine substitution variants displayed delayed colonization and were more rapidly cleared from the intestine. These data demonstrate genetically separable functions for tandem tyrosine phosphosites within CesT. Therefore, CesT via its C-terminal tyrosine phosphosites, has relevant roles beyond typical type III secretion chaperones that interact and stabilize effector proteins. PMID- 29509332 TI - Extract of Euryale ferox Salisb exerts antidepressant effects and regulates autophagy through the adenosine monophosphate-activated protein kinase-UNC-51 like kinase 1 pathway. AB - Positive regulation of autophagy by Euryale ferox Salisb (ES) leads to antidepressant effects. This study focused on the potential antidepressant mechanisms induced by the petroleum ether fraction of ES (ES-PE) in the chronically unpredictable mild stress (CUMS) mouse model. Deficits in the sucrose preference test, open field test, tail suspension test, and forced swim test were observed following CUMS, and were reversed following ES-PE administration. Contrary to the expression of mammalian target of rapamycin, autophagy was decreased after establishment of the CUMS model. We also observed trends for downregulation of adenosine mononphosphate-activated protein kinase (AMPK) and mammalian autophagy-initiating kinase (ULK1), which were differentially affected by ES-PE. HT22 cells and Compound C, an inhibitor of AMPK, were used to verify the results in mice. Gas chromatography-mass spectrometry analysis revealed high level of vitamin E acetate in ES-PE. Taken together, our data indicate that ES-PE activated autophagy by regulating the AMPK pathway. (c) 2018 IUBMB Life, 70(4):300-309, 2018. PMID- 29509333 TI - Erratum Re: Relationship Between Neonatal Vitamin D at Birth and Risk of Autism Spectrum Disorders: the NBSIB Study. PMID- 29509305 TI - Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study. AB - INTRODUCTION: There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV-positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study. METHODS: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid-lowering drugs (LLDs), angiotensin converting enzyme inhibitors (ACEIs), anti-hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders. RESULTS: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti-hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow-up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti-hypertensives (1.17 [1.10, 1.25]). CONCLUSION: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV-positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions. PMID- 29509335 TI - Issue Information-Declaration of Helsinki. PMID- 29509334 TI - Osteoporosis-Related Health Services Utilization Following First Hip Fracture Among a Cohort of Privately-Insured Women in the United States, 2008-2014: An Observational Study. PMID- 29509336 TI - Electrochemical C-H Amination by Cobalt Catalysis in a Renewable Solvent. AB - Syntheses of substituted anilines primarily rely on palladium-catalyzed coupling chemistry with prefunctionalized aryl electrophiles. While oxidative aminations have emerged as powerful alternatives, they largely produce undesired metal containing by-products in stoichiometric quantities. In contrast, described herein is the unprecedented electrochemical C-H amination by cobalt-catalyzed C-H activation. The environmentally benign electrocatalysis avoids stoichiometric metal oxidants, can be conducted under ambient air, and employs a biomass derived, renewable solvent for sustainable aminations in an atom- and step economical manner with H2 as the sole byproduct. PMID- 29509337 TI - The Herbst appliance and the Activator: influence of the vertical facial pattern. AB - AIM: To compare the effects of the Herbst appliance and the Activator at the completion of two-phase treatment, with respect to the vertical facial pattern (VFP) and to identify possible predictors of treatment effect. MATERIALS AND METHODS: Pretreatment, post-treatment and overall cephalometric change data were used to assess the dental and skeletal effects. Results for the change in mandibular length were also compared with changes reported for an untreated external control group. RESULTS: Clinically significant dental and skeletal changes (including mandibular incisor proclination and overjet reduction) were characteristics of both treatment methods. Any increases in mandibular length and chin prominence were not greater than those expected following natural growth. The pretreatment VFP remained essentially unaltered, while mean changes as a result of treatment were similar for brachyfacial, mesofacial, and dolichofacial subjects. No predictive factors were identified. CONCLUSIONS: Clinicians are advised to expect significant overlet reduction and mandibular incisor proclination with either treatment method. Significant skeletal change may be observed in growing subjects; however, any increase in mandibular length or chin projection is not likely to be beyond the limit set by nature. While there will be some individual variation, no significant long-term alteration in the pretreatment vertical facial pattern should be expected with either treatment. Long faces will remain long and short faces will remain short. PMID- 29509338 TI - Effects of strontium ranelate on sutural bone formation: a histological and immunohistochemical study. AB - AIM: Rapid maxillary expansion is performed to correct a skeletal transverse deficiency of the maxilla, which is a frequently- encountered orthodontic anomaly. Strontium ranelate (SrR) is a novel agent that has a dual action, involving anti-resorptive and bone-forming effects. The aim of this study was to evaluate the effects of systemically applied SrR on osteoblastic bone formation after maxillary expansion on the mid-palatal suture of rats using histological and immunohistochemical tests. MATERIALS AND METHODS: A total of 24 Wistar rats were randomly divided into two equal groups. In all animals, five-day inter premaxillary expansion was applied and maintained for a seven-day retention period, during which 625mg/kg/day SrR diluted with saline solution was administered orally to the experimental group. The rats were sacrificed and the tissues prepared for histological and immunohistochemical examinations after the retention period. RESULTS: Osteoblastic activity and the width of the blood vessels in the suture area were significantly increased in the SrR group compared with the control group (p < 0.051. Ossification was also observed to be active under light microscopy by staining with hematoxylin and eosin in the experimental group. Immunohistochemical labelling performed using osteonectin, osteocalcin, TGF-P and VEGF antibodies revealed significant immunoreactivity in the experimental group (p < 0.05). CONCLUSION: It may be concluded that SrR contributed to stimulatory osteogenesis in the expansion region. Therefore, a retention period may be shortened and relapse possibly reduced, following the application of SrR after the expansion. PMID- 29509339 TI - Correction of the transverse discrepancy-induced spontaneous mandibular protrusion in Class II Division 1 adolescent patients. AB - BACKGROUND: A Class Il malocclusion is the most frequent sagittal skeletal disharmony presenting for orthodontic treatment. A transverse interarch discrepancy ITID) may be considered as a possible functional cause of a Class 11 relationship. OBJECTIVE: The purpose of the present study was to determine transverse interarch width dimensions before and after orthodontic therapy and their possible relationship with increased mandibular projection following treatment. METHODS: The sample included 40 adolescent patients who were divided into two groups, one possessing and one without a transverse discrepancy. Interarch width differences (including ICWD, IPWD, IMWD, IAWD) were measured before and after treatment, and Pogonion (Pog) to Nasion (NJ perpendicular was similarly measured in each group. RESULTS: The differences in arch and alveolar width dimensions between the two groups (including ICWD, IPWDI, IPWDII, IMWD, IAWD) before treatment were statistically significant (p < 0.05). A comparison of Pog to N perpendicular between the two groups showed that mandibular protrusion after treatment in the transverse discrepancy group was 2.6 +/- 1.3 mm, while mandibular protrusion after treatment in the group without a transverse discrepancy was 0.6 +/-0.3 mm. The statistical comparison showed that the differences were significant (p < 0.01). CONCLUSION: A transverse interarch discrepancy may have a functional relationship with mandible retrusion. If a transverse discrepancy is corrected via orthodontic treatment, the mandible may spontaneously protrude. PMID- 29509340 TI - A qualitative study of orthodontic screening and referral practices among dental therapists in New Zealand. AB - BACKGROUND: Appropriate screening and referral is important in delivering effective and timely orthodontic treatment. In New Zealand, dental therapists are usually the initial contact for oral health care (including the assessment of malocclusion) in child and adolescent patients. OBJECTIVE: To investigate the orthodontic screening and referral practices of dental therapists in New Zealand. METHODS: Ten registered dental therapists from Auckland and Dunedin were interviewed using a semi-structured approach. Participants were selected based on years of work experience, where they practised, their educational background, and their sector of work (private/public). Resu/ts: Three main themes were identified: (I) the orthodontic screening and referral process; (2) the factors affecting orthodontic referral; and (3) their attitudes towards orthodontic treatment. Orthodontic screening and referrals were uniform among public dental therapists but varied for private dental therapists with regard to the type of malocclusions referred, the frequency of the referrals and to whom they referred. Factors that affected orthodontic referrals included participants' orthodontic educational background, work experience, Continuing Professional Development courses attended, and the opinions of orthodontists and/ or dentists. Dental therapists found that most patients were receptive to the idea of orthodontic treatment, but that cost was a major concern. Dental therapists were enthusiastic about the development and use of resources that could aid in the orthodontic screening and referral process. Conc/usions: This study has provided valuable insights into the current orthodontic referral process of New Zealand dental therapists. Variations among public and private therapists were identified. The implementation of an orthodontic referral guideline was viewed favourably by dental therapists. PMID- 29509341 TI - A comparative evaluation of ion release from different commercially-available orthodontic mini-implants - an in-vitro study. AB - BACKGROUND: Titanium alloy mini-implants have become popular in recent times and have been extensively used and studied. Although corrosion resistance of orthodontic materials has always been of concern, this property has been the least explored. The present study aimed to assess the composition, surface characterisation and corrosion resistance of five commercially available mini implants by assaying ion release in artificial saliva. METHODS: Ten mini-implants each from five companies were obtained: Group 1 - AbsoAnchor (Dentos Inc, South Korea); Group 2 - Microimplant Anchorage System (MIA, Biomaterials Korea); Group 3 - The Orthodontic Mini Anchorage System (TOMAS, Dentaurum, Germany); Group 4 - mini-implants (Denticon, Maharashtra, India); Group 5 - orthodontic mini-implants (lJ.Orthodontics, Kerala, India). One mini-implant from each group was subjected to characterisation and surface microstructure analysis using Energy Dispersive Atomic Spectrometry (EDAX) and Scanning Electron Microscope (SEM), respectively. Ten mini- implants were immersed for 30 days in Fusayama-Meyer artificial saliva solution and the release of titanium, aluminium and vanadium ions was detected with Inductively Coupled Plasma - Optical Emission Spectrometry (ICP-OES). The Kruskal-Wallis test was used for multi-variate analysis. In order to determine the significant differences between the groups on independent samples, the Mann Whitney U test (bi-variate analysis) was applied. RESULTS AND CONCLUSION: All groups showed machining defects but surface pitting after immersion was mostly evident in Group 4. Although the composition of all the implants was comparable, there was a statistically significant difference in the Ti, Al and V release between Group 4 - the group with maximum release - and Group 2, the group with least release. PMID- 29509342 TI - Expression of neural crest markers by human embryonic stem cells: an introductory project. AB - INTRODUCTION: Neural crest cells make up a transient migratory population of cells found in all vertebrate embryos. Great advances have been made over the past 20 years in clarifying the molecular basis of neural crest induction and, although much still remains unclear, it appears that it is a process involving several factors acting at different stages of embryogenesis. In the future, an understanding of the precise mechanisms involved in orofacial development, even at the earliest stages, may well be of use to all clinicians interested in the management of these tissues. AIM: The present study was designed to determine if the early addition of noggin (a bone morphogenetic protein lBMP) antagonist) and/or the late addition of BMP4 would increase the expression of the transcription factors: Msx-1, Snail, Slug and Pax-7. METHOD: This involved an assessment of the effects of early addition ( Days 0 to 3) of noggin and/or the late addition ( Days 4 to 7) of BMP4 on2the expression of the neural crest markers by human embryonic stem cells, co-cultured for eight days on a feeder layer of mouse PA6 cells. RESULTS AND CONCLUSIONS: The expression of the neural crest markers Pax-7, Msx-1, Slug, and Snail by human embryonic stem cells is likely to be affected by the addition of noggin and BMP4. Not all of these effects will necessarily be significant. The late addition of BMP4 is likely to significantly increase the expression of Pax-7 by human embryonic stem cells (hESCs), when compared with the effects of co-culturing with stromal cell-derived inducing activity, alone. The early addition of noggin and the late addition of BMP4 are likely to significantly increase the expression of Msx-1 by hESCs, when compared with the late addition of BMP4, alone. The hESC results support those from animal ESC studies that the late addition of BMP4, especially, may result in the differentiation of neural crest precursors. PMID- 29509343 TI - Comparison of validity, repeatability and reproducibility of the Peer Assessment Rating (PAR) between digital and conventional study models. AB - INTRODUCTION: The validity, reliability and inter-method agreement of Peer Assessment Scores (PAR) from acrylic models and their digital analogues were assessed. METHOD: Ten models of different occlusions were digitised, using a 3 Shape R700 laser scanner (Copenhagen, Denmark). Each set of models was conventionally and digitally PAR-scored twice in random order by 10 examiners. The minimum time between repeat measurements was two weeks. The repeatability was assessed by applying Carstensen's analysis. Inter-method agreement (IEMA) was assessed by Carstensen's limit of agreement (LOA). RESULTS: Intra-examiner repeatability (IER) for the unweighted and weighted data was slightly better for the conventional rather than the digital models. There was a slightly higher negative bias of -1 .62 for the weighted PAR data for the digital models. IEMA for the overall weighted data ranged from -8.70 - 5.45 (95% Confidence Interval, CI). Intra-class Correlation Coefficients lICC) for the weighted data for conventional, individual and average scenarios were 0.955 0.906 - 0.986 CI), 0.998 (0.995 - 0.999 CII. ICC for the weighted digital data, individual and average scenarios were 0.99 (0.97 - 1.00) and 1.00. The percentage reduction required to achieve an optimal occlusion increased by 0.4% for the digital scoring of the weighted data. CONCLUSION: Digital PAR scores obtained from scanned plastic models were valid and reliable and, in this context, the digital semi-automated method can be used interchangeably with the conventional method of PAR scoring. PMID- 29509344 TI - Orthodontists and the thyroid gland. AB - This paper questions the adequacy of orthodontists' full appreciation of the issues associated with the routine prescription of extra- oral radiography, particularly that related to a high risk of thyroid gland exposure to ionising radiation. There does not appear to be adequate application of the ALARA principle in the consileration of justifiable options to minimise the cumulative effects of radiation exposure in young patients. PMID- 29509345 TI - A computed tomographic, mixed dentition, space analysis comparison. AB - INTRODUCTION: A considered space analysis aims to predict the combined mesiodistal widths of unerupted permanent canine and premolars. A miscalculation can lead to the application of inadequate and irreversible treatments. OBJECTIVE: To assess the level of agreement between predictions generated by three methods (Moyers' predictive tables at the 50th and 75th percentiles and Tanaka-Johnston's equations) on the sum of unerupted teeth compared with measurements derived from cone beam computed tomography, considered in the present study as a 'gold standard'. MATERIALS AND METHODS: The study sample was comprised of children (N = 26) aged 8-13 who visited the Department of Dentistry. Moyers' predictive tables and the Tanaka-Johnston equation were applied to ascertain the space requirements. Cone beam computed tomography was performed on each patient and the volumetric data analysed. A concordance correlation coefficient between each method's predictions was applied. RESULTS: The three methods tended to overestimate the cone beam computed tomography readings and were not able to entirely capture the variability of the sum of the unerupted teeth. Moyers' 50th percentile estimate revealed a more balanced distribution between over- and underestimation. CONCLUSION: The present study suggested that Moyers' 50th percentile is the predictive method with the lowest absolute error and is preferred for clinical use. PMID- 29509346 TI - The effects of blocking N/OFQ receptors on orofacial pain following experimental tooth movement in rats. AB - OBJECTIVE: The aim of this study was to determine the effects of nociceptin/orphanin FQ peptide receptor (N/OFQ receptor) antagonist on orofacial pain induced by experimental tooth movement in rats. METHODS: A total of 36 male Sprague-Dawley rats weighing 200-300 g were divided into six groups: a control group, force group, force+saline intraperitoneal group, force+saline periodontal group, force+UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ-NH 2 antagonist for N/OFQ receptor) intraperitoneal group, and force+UFP-1 01 periodontal group. Closed coil springs were ligated between the upper incisors and first molar to exert an orthodontic force (40 g) between the teeth. Injectable administration dosages were 30 MUl saline or 30 MUl saline containing 0.03 mg/kg UFP-1 01. Following the injections, orofacial pain levels were assessed through directed face grooming (mouth wiping). Statistical analyses were performed in SPSS 17.0 (Statistical Package for the Social Sciences) and p values less than 0.05 were considered as statistically significant. RESULTS: Orofacial pain levels were significantly higher in the force group than in the control group. Orofacial pain levels differed significantly between the force)group, force+saline periodontal group and force+UFP-101 periodontal group, but were similar between the control group, force+UFP-101 intraperitoneal group and force+saline intraperitoneal group. Moreover, orofacial pain levels did not differ between the force group, force+saline intraperitoneal group and force+UFP-1 01 intraperitoneal group. CONCLUSIONS: Periodontal, but not intraperitoneal, administration of UFP-101 could alleviate orofacial pain induced by experimental tooth movement in rats, suggesting that periodontal N/OFQ receptors participate in orofacial pain induced by experimental tooth movement. PMID- 29509347 TI - Short-term treatment effects of the quad-helix appliance on dentofacial morphology of hyperdivergent patients. AB - OBJECTIVES: The purpose of this study was to evaluate the effects of shor-term expansion treatment using the quad-helix appliance on dentofacial morphology in orthodontic patients presenting with a hyperdivergent facial pattern. METHODS: The treatment group consisted of 40 patients with a hyperdivergent facial pattern, who were treated for maxillary incisor crowding with a quad-helix appliance during the mixed dentition period. Lateral cephalograms taken at the start (TO) and end (TI) of the treatment were obtained as a course of care. A similar number of patients, who possessed the same type of facial pattern and who remained untreated, were assigned to a control group. Two consecutive lateral cephalograms of each untreated patient were taken at the same time points as TO and T1. All cephalograms were traced, analysed and compared between the two groups. RESULTS: The treatment changes as a result of the quad-helix appliance were expressed in an upward rotation of the mandible [2.340] and distal tipping and impeded mesial movement of the maxillary first molars. Significant differences were evident between the treatment and control groups. CONCLUSION: Quad-helix appliance treatment can be appropriate for significantly decreasing the mandibular plane angle in hyperdivergent patients presenting with moderate maxillary incisor crowding and a positive overjet and overbite. PMID- 29509348 TI - Effectiveness of photographs of study models for IOTN scoring. AB - AIM: The aim'of the present study was to investigate whether the same orthodontic information can be obtained from study models or photographs of study models in order to assess the Index of Orthodontic Treatment Need (IOTN). The study also aimed to assess inter- and intra-examiner reliability in the assessment of orthodontic treatment need. SAMPLE: Thirty sets of start and finish study models, demonstrating a range of malocclusions, were non-randomly obtained from patients treated at the University of Manchester Dental Hospital. The start models demonstrated a range of malocclusions (according to The British Standard Institute Incisor Classification 1983) of varying complexity. METHOD: Six photographic views of each set of study models were taken against a dark background. Millimetric distances were determined by using dividers to measure photographic distances and actual distances in millimeters from a ruler embedded in the image. Four examiners assessed the study models and photographs of the models in a random order and the Aesthetic and Dental Health components of the IOTN were recorded. RESULTS: There were no statistically significant differences in the IOTN scores from photographs of study models compared with IOTN scoresrom study models of the same patient. CONCLUSION: The IOTN scores derived from photographs of study models are valid and reliable measures of malocclusion. PMID- 29509349 TI - The Hawlix: a simple and aesthetic prosthetic- orthodontic retainer. AB - This report introduces the Hawlix, a hybrid thermoformed and cold-cured retainer. It was developed to overcome the limitations that modified Hawley retainers possess when used in patients with bounded saddles, attributable to dental trauma or hypodontia. The Hawlix can be used as an intermediate retainer while a patient is waiting to receive restorative treatment. Some of the advantages of the Hawlix over the modified Hawley retainer include: superior aesthetics, cost effectiveness, ease of manufacture, adequate resistance to fracture, preservation of a residual ridge, and precise space maintenance. PMID- 29509350 TI - True intrusion of maxillary first molars with zygomatic and palatal miniscrew anchorage: a case report. AB - The intrusion of the maxillary first molar is indicated when occlusal clearance is needed for prosthetic rehabilitation. Maxillary molar intrusion may be undertaken using skeletal anchorage systems to avoid complicated mechanics delivered by conventional intra-oral fixed appliances. In the present case report, the efficient use of orthodontic miniscrew anchorage by applying simple mechanics for true maxillary first molar intrusion is described. This was followed by the rehabilitation of the mandibular first molar spaces with implant prostheses. A 16-year-old female patient had masticatory difficulty due to the bilateral overeruption of the maxillary first molars and carious mandibular first molars. True intrusion of each maxillary first molar was achieved using zygomatic and palatal paramedian miniscrews placed in line with the central axis of the teeth. Simultaneously, alignment of the upper arch was achieved via fixed appliance therapy. Using two orthodontic miniscrews to intrude each maxillary molar, orthodontic treatment was simplified by eliminating the need for miniplate placement by extensive surgery and the creation of intra-oral multiunit anchorage. Masticatory efficiency was improved by increasing the occlusal table with prosthetic rehabilitation of the mandibular first molar spaces with dental implant prostheses. PMID- 29509351 TI - Leadership Challenge No. 2. PMID- 29509352 TI - What makes your boss a good leader?. PMID- 29509353 TI - Getting assistance. PMID- 29509354 TI - Lead by example; leave a legacy. PMID- 29509356 TI - Confronting difficult choices. PMID- 29509355 TI - Sahar Alrayyes goes a long distance to bring care to special needs children. PMID- 29509357 TI - Influence of Binocular Visual Anomalies on Reading in First Grade School Children with High Visual Acuity. AB - The aim of this study was to describe the binocular visual status of first grade children with high binocular visual acuity. The results have shown that only 5.1% of children had normal binocular vision, 25.7% had only moderate and 67.9% had severe and moderate binocular anomalies. Significant differences were revealed between students with poor reading and with normal reading with respect to reduced convergence (P < 0.001), and mean scores of behavior symptom numbers, indicating the presence of binocular visual anomalies (P < 0.002). PMID- 29509358 TI - Evaluation of the Functional State of Operators with Allowance for Individual Psychological Characteristics. AB - The article deals with the features of the evaluation of changes in functional state during the professional activity of operators. We estimated the dynamics of the functional state and efficiency of operatorsunder the effect of aircraft noise and individual psychophysiological characteristics. We also investigated changes in the functional state of operators depending on their psychological characteristics. It was found that changes in the functional state of the organism in operators with high level of anxiety, low degree of extroversion and high emotional lability were more pronounced in the modeling of operator activity with exposure to aircraft noise, as evidenced by significant changes in psychophysiological parameters. After 60 minutes of noise stress, the latent period of a simple and a complex sensorimotor reaction in introverts increased by 9.1% (p < 0.05) and 8.1% (p < 0.05), respectively. In the group of subjects with high level of anxiety, there were a decrease in the general state, activity and mood by 18.9% (p < 0.01), 20.9 and 14.9% (p < 0.05), respectively, and a decrease in the accuracy of reaction to a.moving object by 3 times (p < 0.05). The latent period of simple sensorimotor reaction in emotionally labile subjects after the exercise was increased by 15% (p < 0.05), and the reaction time on a moving object was increased by 8:9% (p < 0.05) as compared with the group of emotionally stable sub- jects. Thus, the data suggest that changes in the functional state of operators depend on the level of extroversion, personal anxiety and emotional lability and do not depend on'the level of behavioral regulation, which must be taken into considerationduring the assessment of functional state. PMID- 29509359 TI - Memorization of Sequences of Movements of the Right or the Left Hand by Right- and Left-Handers: Vector Coding. AB - In order to test the hypothesis of hemisphere specialization for different types of information coding (the right hemisphere, for positional coding; the left one, for vector coding), we analyzed the errors of right and left-handers during a task involving the memorization of sequences of movements by the left or the right hand, which activates vector coding by changing the order of movements in memorized sequences. The task was first performed by the right or the left hand, then by the opposite hand. It was found that both'right- and left-handers use the information about the previous movements of the dominant hand, but not of the non dom" inant one. After changing the hand, right-handers use the information about previous movements of the second hand, while left-handers do not. We compared our results with the data of previous experiments, in which positional coding was activated, and concluded that both right- and left-handers use vector coding for memorizing the sequences of their dominant hands and positional coding for memorizing the sequences of non-dominant hand. No similar patterns of errors were found between right- and left-handers after changing the hand, which suggests that in right- and left-handersthe skills are transferred in different ways depending on the type of coding. PMID- 29509360 TI - Comparative Analysis of the Clinical Significance of Oscillatory Components in the Rhythmic Structure of Pulse Signal in the Diagnostics of Psychosomatic Disorders in School Age Children. AB - We performed a comparative analysis of the types of spectral density typical of various parameters of pulse signal. The experimental material was obtained during the examination of school age children with various psychosomatic disorders. We also performed a typological analysis of the spectral density functions corresponding to the time series of different parameters of a single oscillation of pulse signals; the results of their comparative analysis are presented. We determined the most significant spectral components for two disordersin children: arterial hypertension and mitral valve prolapse. PMID- 29509361 TI - Age-Related Parameters of the Spinal Inhibition of Skeletal Muscles in the Regulation of Voluntary Movements in Males. AB - We studied the age-related features of spinal inhibition in the regulation of voluntary movements in males. It was found that presynaptic, nonreciprocal and reciprocal inhibition of the flexor of toes during voluntary movements was less intense as compared with relative muscle rest in all studied age groups. This results from the age-related features of supraspinalactivatory and inhibitory effects on la and Ib spinal interneurons, which change the mechanism of spinal inhibition of voluntary movements during the development of the organism. In boys aged 9-12 years, the presynaptic inhibition of Iaafferents is lowest, while the nonreciprocal and reciprocal inhibition of (alphamotoneurons of the flexor of toes is highest among all studied age groups. In boys aged 14-15 years, the presynaptic inhibition of Ialphaafferents is higher, while the nonreciprocal and reciprocal inhibition of cxmotoneurons of the flexor of toes is lowest among the age groups. By the age of 17-18 years, the mechanism of nonreciprocal inhibition of alphamotoneurons of the flexor of toes during voluntary movements is similar to that at the age of 14-15 years. The final level of presynaptic inhibition of Ialphaafferents and reciprocal inhibition of alphamotoneurons. is reached at the age of 17-18 years. PMID- 29509362 TI - Integrated Assessment of Neurodynamic and Vegetative Indicators in Adolescents: Age- and Gender-Related Differences and Typological Features. AB - We examined schoolchildren aged 11-16 years (n = 930) and determined the features of neurodynamic and vegetative parameters associated with age and sex and the factors affectingthe psycho-physiological statusof adolescents. An analysis of the relationship of studied parameters in adolescents with different types of autonomic regulation showed thatthe evaluation of functional constitution has prognostic significance since it is indicative of the adaptation potential. PMID- 29509363 TI - Postural Performance at Different Breathing Strategies in Patients with Limitation of Mobility. AB - We investigated the effect of different breathing strategies on postural performance in the patients with joint mobility limitations. The amplitude and velocity of thecenter-of-pressure movements in the frontal.and sagittal planes were measured by the force platform in48 healthy volunteers. The stability of vertical posture was estimated during normal breathing, inspiratory and expiratory breath holding and hyperventilation with immobilization of the neck, trunk, hip and knee joints, and without immobilization. In general, the restriction of mobility caused a reduction in the postural stability in the sagittal plane, while the frontalbody swayamplitude decreased. These results suggest that body immobilization reduces the ability to compensate the effect of respiration on the stability of vertical posture in the sagittal plane and, on the contrary, facilitatesthe balance in the frontal plane. PMID- 29509364 TI - Differences in the Force-Interval. Relationship of Isolated Human Myocardium with Chronic Coronary Artery Diseasein Patients with and without Type 2 Diabetes Mellitus and the Role of Ca2+-ATPase of Sarcoplasmic Reticulum. AB - We studied the force--interval relationship of human myocardium in coronary artery d isease (CAD) and CAD with concomitant diabetes mellitus and evaluated its dependence on the level of expression of Ca2+-AT Pase of the sarcoplasmic reticulum (SR). We used the myocardial biopsies obtained during coronary artery bypass grafting with the use of cardiopulmonary bypass techniques. The study included patients with chronic CAD and patients with CAD and concomitant type II diabetes mellitus. It was found that patients with CAD with and without diabetes with similar clinical signs had both negative and positive dynamics of the force interval relationship. The positive. force-interval relationship was associated with the ''high level" of Ca2+-ATPase, while the negative force-interval relationship was associated with the "low level" of this protein. In cases of small CAD and diabetes duration, the positive "force-interval" relationship is more pronounced and corresponds to a higher level of expression Ca2+- ATPase in the SR than in case of CAD without diabetes mellitus. PMID- 29509365 TI - Model of Human Cardiovascular System Containing a Loop for the Autonomic Control of Mean Arterial Pressure. AB - We proposed a model of human cardiovascular system that describes the cardiac cycle, the autonomic regulation of heart and vessels, the baroreflex, and the formation of arterial pressure. The model also makes allowance for the influence of respiration on these processes. It was found that an allowance for nonlinearity and insertion of a loop for the autonomic control of mean arterial pressure (having the form of self oscillating time-delay system) enables to obtain model signals with statistical and spectral characteristics that are qualitatively and quantitatively similar to.those for experimental signals. The model reproduces the phenomenon of synchronization of the loop for mean arterial pressure regulation with a basic frequency of approximately 10 s by the signal of respiration. PMID- 29509366 TI - Importance of RR-Interval Variability in Stress Test. AB - The variability of cardiac rhythmogram (CRG) at the early stage of loading and recovery periods has a number of parametersassociated with the functional state of subjects.These parameters can be estimatedby measuring the probability of pairs of RR-intervals with certain length differences (pNNx). At the same time,each of these parameters has its own diagnostic role, such as a binary marker of adaptation reserves (pNN 15), loading tolerance level (pNN5, 10) and a criterion. for the training level (pNN 10, 15). The association of pNNx with the endured load power and the dynamics of heart rate is to a great extent determined by the mixed endurance level. Higher values ofpNNxcorrespond with the predominant load and lower heart rate, regardless of the period. Physiological relevance of pNNxis determinedby their behavior, diagnostic role, the sensitivity of each argument ("x"), and the level of aerobic/anaerobic endurance of a subject. PMID- 29509367 TI - Effect of Different Levels of Salt Consumption on Urine Protein Composition during 105-Day Isolation Analyzed with the Use of opoSOM Software. AB - We investigated changes in the urine protein composition of healthy volunteers in controlled conditions during 105-day isolation (Mars-500 program) at different levels of salt consumption. We used newest proteomic techniques based on chromatography-mass spectrometry and various methods of bioinformatics including opoSOM. The period of observation can be divided into three intervals with different dynamics of protein excretion: early (week 1-6), intermediate (week 7 11) and late interval (week 12-15). We identified about 10 different groups of co detected proteins, which are directly affected by periods with different-levels of salt consumption. We also determined the biological functions of these proteins, tissue specificity and signaling pathways that involve them. PMID- 29509368 TI - Human Chorionic Gonadotropin: Unknown about Known. AB - The last two decade discoveries shift the accent from consideration of human chorionic gonadotripin (hCG) as a hormone, that controls progesterone production by corpus luteum cells, to a powerful paracrine regulator which'in the tandem with its hyperglycozilated analog (hCG-H) induces successful implantation and coordinated dialog between blastocyst and uterus tissues. Ability of hCG to interact with TSH receptor and hCG-H with TGF-beta-RII extend significantly the spectrum of processes controlled by these molecules. Differences between intracellular pathways of signal transduction between hCG and LH mediated by the same receptor (LH/hCG-R) impugn unity of their effector mechanisms previously considered as obvious. Paracine properties-of hCG comprise control of fusing of trophoblasts into syncytiotrophoblasts, angiogenesis, immunity regulation and endometrium predisposition to implantation. Angiogenesis is associated with LH/hCG-R expressed on mural cells of uterine spiral arteries as well as induced secretion of soluble VEGF type by endometrial cells. hCG.regulates ratio between different forms of T-helper cells in maternal organism on the initial gestation stage determining high level of Th2 cells. hCG supports local immunotolerance acting as chemoattractant for T-suppressors (T-Treg) and apoptotic factor for T lymphocytes. Endometrial susceptibility arises from activation of osteopantin secretion and decline of mucin secretion by epithelial cells. hCG-H acts on the same tissues as hCG as a paracrine agent regulating multiple cascades of cytokines. hCG-H plays the key role in trophoblast invasion into,uterine decidua as a result of gelatinase secretion by these cells.The degree of angiogenic effect of hCG-H is compatiblewith hCG but its signal transduction is mediated by TGF-beta signal transduction pathway that stimulates mural cell proliferation. hCG-H acts as mitogen on NK-cells and is able to activate them and direct to angiogenesis maintenance. In this article the attempt was made to elucidate the most important discoveries about the role of hCG and its hyperglycosylated analog yet accomplished and still upcoming. PMID- 29509369 TI - Ophthalmic Changes Associated with Long-Term Exposure to Microgravity. AB - This review discusses recent publications on the problem of ophthalmic changes associated with long-term effects of microgravity during space flights. Described changes include hyperopic shift of refraction, change in intraocular pressure, increased intracranial pressure, changes in the choroid and retina tissues, and swelling of the optic nerve. These effects are caused by redistribution of blood and fluid to the upper half of the body, increased intracranial pressure and congestion of venous blood and lymph in the upper half of the body and head. The reviewed also discusses other factors that may triggervision impairment caused by microgravity. Photographic illustrations of changes are also provided. PMID- 29509370 TI - Some Immunophysiological Features of Sport Activity in the Climatic and Geographical Conditions of the Middle Ob Region. AB - We analyzed the cellular and humoral.components of immune system in athletes who were born, lived and trained in the conditions of the Middle Ob Region (Khanty Mansi Autonomous Okrug - Ugra). The main group included young males and females engaged in cross country skiing (12 males, 10 females) and volleyball (11 males, 10 females). The control group (normal inhabitants of the region) consisted of 10 males and 10 females who were born and currently live in. KMAO-Ugra and do not do any sports on a regular basis. The age of subjects ranged from 19 to 22 years. It was found that the indices of cell and humoral components of immune system differed slightly between young women in the control and main groups. As for men, a significant decrease in total leukocyte, neutrophil and lymphocyte counts were observed; a decrease in the parameters of humoral immunity (b-lymphocytes and IgA) was also observed in male skiers. It was found that the total leukocyte count, the level of B-lymphocytes and the concentration of IgG in men who live in the Middle Ob region and do not do any sports is higher than in women of the same group. PMID- 29509371 TI - Reference Values of the Hemostasis System Indices in Cosmonauts. AB - The values of 11 diagnostically significant hemostasis system indices in venous blood were determined during the preflight (30-45 days before start) clinical and physiological examination of 39 cosmonauts aged 35 to 54 who were the members of the main and backup crews of missions to the International Space Station in the period from 2007 to 2014. Since most of the cosmonauts performed several flights during this period, and they were repeatedly included in backup crews, each of the cosmonauts underwent preflight examinations one to five times. The reference values were calculated for each of the studied indices. It was'found that the reference ranges for parameters indicative of integral pro-, anticoagulant and fibrinolytic potential were narrowed and close to the boundaries of ranges for the general population,- which indicates that the cosmonauts had relatively decreased procoagulant potential and increased hemostasis regulative.potential. This was probably due to the criteria of selection, physical training status, and emotional status of crew members during the preflight professional activity, when the adaptive changes against the stress-inducing effects occur in the organism. The cosmonauts who underwent strict medical examination may also have some genetic features which provide higher body resistance and more rapid adaptation processes. PMID- 29509372 TI - Lipid derivatives of arachidonic acid used as markers of atherosclerotic plaque instability: a pilot study. AB - BACKGROUND: To compare the results of computer estimation of atherosclerotic plaque with biochemical data and ascertain any relationship with the occurrence of stroke. METHODS: The study involved 20 atherosclerotic plaques causing 70-99% stenosis of internal carotid arteries (ICA). Ultrasonographic examination (USG) images of plaques were analyzed using a computer program. A histogram was obtained for each plaque and a gray scale median (GSM) was determined for each histogram in order to measure the echogenicity of an examined plaque. Then the plaques, collected during endarterectomy, were examined with regard to the concentration of prostaglandins E2 (PGE2), thromboxane A2 (TXA2), and 8 - epi prostaglandin F2alpha. This data was compared with GSM and the occurrence of stroke. RESULTS: The statistical analysis showed significant correlations between low GSM and the occurrence of strokes. Out of 10 plaques with GSM<35, 6 (60.0%) were associated with a stroke. In contrast, out of 10 plaques with GSM>35, only 1 (10.0%) had a stroke. In addition, there were significant differences in the plaque content of PGE 2, (P<0.05) and (TXA2, P<0.011) between groups. CONCLUSIONS: High levels of PGE2 and TXA2, correlated with the low GSM values, may be the features of unstable plaques and that may be associated with a risk for stroke. PMID- 29509373 TI - Combined use of MR-PET and 5-ALA for neurosurgical management of recurrent multiple malignant hemangiopericytomas. PMID- 29509374 TI - [The new bacterial strain Paenibacillus sp. IB-1: A producer of exopolysaccharide and biologically active substances with phytohormonal and antifungal activities]. AB - The bacterial strain IB-1, which exhibits antagonism towards phytopathogens and stimulates the growth of agricultural plants, was isolated from the soil. Analysis of the cultural, morphological, physiological, and biochemical features and nucleotide sequences of the genes 16S rRNA and gyrB, as well as the fatty acid composition, made it possible to attribute the strain IB-1 to the genus Paenibacillus; however, the results did not provide an unambiguous conclusion on its species. The strain Paenibacillus sp. IB-1 possesses nitrogenase activity, the ability to synthesize indoleacetic acid and cytokinin-like compounds, and antagonistic activity towards phytopathogenic fungi, which indicates prospects for its use as a biological product for agricultural purposes. A high-viscous exopolysaccharide was isolated from the cultural fluid of Paenibacillus sp. IB-1. Based on the data from IR and NMR spectroscopy, it was shown to be a heteropolymer comprised of one to four linked alpha-L-guluronic acid and beta-D mannuronic acid residues. The exopolysaccharide was successfully tested as an adhesive for presowing treatment of barley and wheat seeds with biofungicides. PMID- 29509375 TI - [Synthesis of L-lactate oxidaze in yeast Yarrowia lipolytica during submerged cultivation]. AB - The biosynthesis of L-lactate oxidase in the Yarrowia lipolytica yeast during submerged cultivation in laboratory bioreactors ANKUM-2M has been studied. It has been shown under optimal conditions of yeast cultivation with L-lactate that 24.5 U/L enzyme accumulated in the medium and the yield was 2.0 U/(L h). An increase in the biosynthesis of L-lactate oxidase to 75 U/L and the yield to 3.2 U/(L h) was achieved in the medium with L-lactate (1%) and glucose (2%). The enzyme was purified 251 times to homogeneity by hydrophobic and ion exchange chromatography state with a yield of 45% and a specific activity of 55.3 U/mg. Techniques of gel filtration and denaturing electrophoresis showed that L-lactate oxidase from Y. lipolytica is a tetramer with a molecular mass of 200-230 kDa. The enzyme showed a strict specificity to L-lactate and did not oxidize fumarate, pyruvate, succinate, ascorbate, dihydroxyacetone, glycolate, D-lactate, D, L-2 hydroxybutyrate and D, L-alanine or D-serine. PMID- 29509376 TI - [Content of salicylic and jasmonic acids in pea roots (Pisum sativum L.) at the initial stage of symbiotic or pathogenic interaction with bacteria of the family Rhizobiaceae]. AB - A change in the contents of endogenous salicylic and jasmonic acids in the roots of the host plant at the preinfectious stage of interaction with symbiotic (Rhizobium leguminosarum) and pathogenic (Agrobacterium rizogenes) bacteria belonging for to the family Rhizobiaceae was studied. It was found that the jasmonic acid content increased 1.5-2 times 5 min after inoculation with these bacterial species. It was shown that dynamics of the change in the JA and SA contents depends on the type of infection. Thus, the JA content decreased in the case of pathogenesis, while the SA content increased. At the same time, an increased JA content was observed during symbiosis. The observed regularities could indicate the presence of different strategies of hormonal regulation for interaction with symbiotic and pathogenic bacteria belonging to the family Rhizobiaceae in peas plants. PMID- 29509377 TI - [Production of Methane in Anaerobic Digestion of Organic Waste of Vegetable Processing Facilities]. AB - The article concerns converting waste from vegetable processing facilities into methane in anaerobic reactors with a small amount of inoculum (8.4%). Anaerobic digestion of vegetable waste with a high content of organic acids and carbohydrates makes it possible to achieve a methanogenesis productivity of 273 436 L CH4/kg of volatile solidis, which is comparable to or higher than the productivity of such reactors in the world (according to the literature). The contents of ammonia nitrogen and soluble phosphorus in the form of on undiluted substrate basis in the digested vegetable wastes ranged from 3.39 to 5.06 and from 0.78 to 1.03 g/L respectively. Thus, mineralized vegetable waste can be used as an organic fertilizer with a high nutrient content. The results show the feasibility of the technology of conversion of organic waste from vegetable processing facilities into methane and organic fertilizer in anaerobic fermenters (digesters). PMID- 29509378 TI - [Effect of lipopolysaccharide O-side chains on the adhesiveness of Yersinia pseudotuberculosis to J774 macrophages as revealed by optical trap]. AB - A method has been developed for the quantitative estimation of the binding force of a model microsphere with a eukaryocyte based on the optical trap in order to study the molecular mechanism of adhesion between an individual bacterium and a host cell. The substantial role of LPS O-side chains in the adhesiveness of Yersinia pseudotuberculosis 1b to J774 macrophages has been revealed with the use of a set of microspheres functionalized with lipopolysaccharide (LPS) preparations and antibodies with different specificities. The results indicate the significance of the O-antigen as a pathogenicity factor of Y. pseudotuberculosis in colonization of a macroorganism. The developed methodical approaches can be applied to the study of molecular mechanisms of the pathogenesis of pseudotuberculosis and other infectious diseases to improve antiepidemic service. PMID- 29509379 TI - [Competition between redox mediator and oxygen in the microbial fuel cell]. AB - The maximal rates and effective constants of 2,6-dichlorphenolindophenol and oxygen reduction by bacterim Gluconobacter oxydans in bacterial fuel cells under different conditions were evaluated. In an open-circuit mode, the rate of 2,6 dichlorphenolindophenol reduction coupled with ethanol oxidation under oxygen and nirogen atmospheres were 1.0 and 1.1 MUM s-1 g-1, respectively. In closed-circuit mode, these values were 0.4 and 0.44 MUM s-1 g-1, respectively. The initial rate of mediator reduction with the use of membrane fractions of bacteria in oxygen and nitrogen atmospheres in open-circuit mode were 6.3 and 6.9 MUM s-1 g-1, whereas these values in closed-circuit mode comprised 2.2 and 2.4 MUM s-1 g-1, respectively. The oxygen reduction rates in the presence and absence of 2,6 dichlorphenolindophenol were 0.31 and 0.32 MUM s-1 g-1, respectively. The data obtained in this work demonstrated independent electron transfer from bacterial redox centers to the mediator and the absence of competition between the redox mediator and oxygen. The results can make it possible to reduce costs of microbial fuel cells based on activity of acetic acid bacteria G. oxydans. PMID- 29509380 TI - [Enzymatic biocatalysis in chemical synthesis of pharmaceuticals]. AB - In this review we summarize the available research on enzymatic biocatalysis in the chemical synthesis of drugs. We focus on oxydoreductsases, particularly ketoreductases, that are widely used in biotechnological processes: alpha- and omega-transaminases, lipases, nitrile hydrolases, and aldolases. The potential for the extended use of novel enzymes produced via bioengineering is discussed. PMID- 29509381 TI - [Catalytic properties of aminoacylase of strain Rhodococcus armeniensis AM6.1]. AB - Studies of substrate specificity revealed that the D-aminoacylase of Rhodococcus armeniensis AM6.1 strain exhibits absolute stereospecificity to the D stereoisomers of N-acetyl-amino acids. The enzyme is the most active reacted with N-acetyl-D-methionine, as well as with aromatic and hydrophobic N-acetylamino acids and interacts weakly with the basic substrates. It is practically not reacted with acidic and hydrophilic N-acetyl-amino acids. Michaelis constants (K m) and maximum reaction velocities (V max) were calculated, using linear regression analysis, for the following substrates: N-acetyl-D-methionine, N acetyl-D-alanine, N-acetyl-D-phenylalanine, N-acetyl-D-tyrosine, N-acetyl-D valine, N-acetyl-D-oxyvaline, N-acetyl- D-leucine. Substrate inhibition of D aminoacylase was displayed with N-acetyl-D-leucine (K s = 35.5 +/- 28.3 mM) and N-acetyl-DL-tyrosine (K s = 15.8 +/- 4.5 mM). Competitive inhibition of the enzyme with product-acetic acid (K i = 104.7 +/- 21.7 mM, K m = 2.5 +/- 0.5 mM, V max = 25.1 +/- 1.5 U/mg) was observed. PMID- 29509382 TI - Erratum: Correction of author name and credentials and errors in text: Effectiveness of the CANRISK tool in the identification of dysglycemia in First Nations and Metis in Canada. PMID- 29509383 TI - [Homo- and heterologous reporter proteins for evaluation of promoter activity in Methylomicrobium alcaliphilum 20Z]. AB - A number of vectors were constructed based on the plasmid from the broad range of pMHA200 hosts. Also, the expression of some key genes of the haloalkalitolerant methanotroph Methylomicrobium alcaliphilum 20Z was studied. The activities of the promoter regions of genes for hexulose phosphate synthase, glutamine synthetase, and glucokinase, as well as the promoter of the ectABC-ask operon, which encodes enzymes for osmoprotectant ectoine biosynthesis, were evaluated with the use of the gfp gene; the evaluation was proven to be ineffective. Conversely, glucokinase and a heterologous enzyme of chloramphenicol acetyltransferase were useful for the evaluation of promoter activity. In M. alcaliphilum 20Z cells, the expression level of chloramphenicol acetyltransferase transcribed from the methanol dehydrogenase promoter was higher as compared with that of glucokinase. This seems to be due to a regulatory mechanism for homologous protein expression. The introduction of a synthetic nucleotide sequence forming the secondary structure in the 5' untranslated region of the glucokinase mRNA resulted in an increase of this enzyme level. This is the first attempt to use M. alcaliphilum 20Z for homo- and heterologous protein expression. PMID- 29509384 TI - [Reactive oxygen and nitrogen species' effect on lux-biosensors based on Escherichia coli and Salmonella typhimurium]. AB - The effect of reactive oxygen and nitrogen species on lux-biosensors based on the Escherichia coli K12 MG1655 and Salmonella typhimurium LT2 host strains was investigated. The bioactivity of exogenous free radicals to the constitutively luminescent E. coli strain with plasmid pXen7 decreased in the order H2O2 > OCl- > NO* > ROO* > ONOO-> O 2 *- while the bioluminescence of S. typhimurium strain transformed with this plasmid decreased in the order NO* > H2O2 > ONOO- > ROO* > OCl- > O 2 *- The cross-reactivity of induced lux-biosensors to reactive oxygen and nitrogen species, the threshold sensitivity and the luminescence amplitude dependences from the plasmid specificity and the host strain were indicated. The biosensors with plasmid pSoxS'::lux possessed a wider range of sensitivity, including H2O2 and OCl-, along with O 2 *- and NO*. Among the used reactive oxygen and nitrogen species, H2O2 showed the highest induction activity concerning to the plasmids pKatG'::lux, pSoxS'::lux and pRecA'::lux. The inducible lux-biosensors based on S. typhimurium host strain possessed a higher sensitivity to the reactive oxygen and nitrogen species in comparison than the biosensors based on E. coli. . PMID- 29509385 TI - Cloning, purification and characterization of a cellulase-free xylanase from Geobacillus thermodenitrificans AK53. AB - Geobacillus thermodenitrificans AK53 xyl gene encoding xylanase was isolated, cloned and expressed in Escherichia coli. After purifying recombinant xylanase from G. thermodenitrificans AK53 (GthAK53Xyl) to homogeneity by ammonium sulfate precipitation and ion exchange chromatography, biochemical properties of the enzyme were determined. The kinetic studies for GthAK53Xyl showed K M value to be 4.34 mg/mL (for D-xylose) and V max value to be 2028.9 MUmoles mg-1 min-1. The optimal temperature and pH for enzyme activity were found out to be 70 degrees C and 5.0, respectively. The expressed protein showed the highest sequence similarity with the xylanases of G. thermodenitrificans JK1 (JN209933) and G. thermodenitrificans T-2 (EU599644). Metal cations Mg2+ and Mn2+ were found to be required for the enzyme activity, however, Co2+, Hg2+, Fe2+ and Cu2+ ions caused inhibitor effect on it. GthAK53Xyl had no cellulolytic activity and degraded xylan in an endo-fashion. The action of the enzyme on xylan from oat spelt produced xylobiose and xylopentose. The reported results are suggestive of a xylanase exhibiting desirable kinetics, stability parameters and metal resistance required for the efficient production of xylobiose at industrial scale. PMID- 29509386 TI - [Effect of N-phenyl-2-naphthylamine on activity of adenylate cyclase signal system components and virulence of bacterial phytopathogens and mutualists]. AB - The effect of N-phenyl-2-naphthylamine, negative allelochemical isolated from the exudates of roots of pea (Pisum sativum L.), on the growth and activity of the adenylate cyclase signal system and virulence factors of the bacteria Rhizobium leguminosarum bv. viciae and Pseudomonas siringae pv. pisi was studied. It was demonstrated that N-phenyl-2-naphthylamine at a physiological concentration nonspecifically inhibited the growth of these bacteria in both planktonic cultures and biofilms. One of the reasons for this phenomenon is the reduction of intra- and extracellular concentrations of cAMP due to greater activation of phosphodiesterase, which disrupts cAMP, in comparison to soluble adenylyl cyclase, which synthesizes it. At the same time, N-phenyl-2-naphthylamine did not affect activity of either membrane-bound adenylyl cyclase or bacterial virulence factors. PMID- 29509387 TI - [Effects of bacteriophages on biofilm formation by strains of Pseudomonas aeruginosa]. AB - The effects of two Pseudomonas aeruginosa bacteriophages, vB-Pa 4 and vB-Pa 5, on the formation and development of biofilms of six polyresistant hospital strains of P. aeruginosa have been investigated. Pretreatment of bacteriophages prevented the formation or almost completely prevented the growth of adequate biofilms. The biofilms that had already formed were partially or completely destroyed after phage treatment. The results demonstrate the prospects of using isolated bacteriophages of P. aeruginosa to destroy biofilms and prevent their formation. PMID- 29509388 TI - [Preparation of protoplasts of the fungus Trametes hirsuta 072 and study of the effect of antioxidants on their formation and regeneration]. AB - The consistent application of homogenization and enzymatic treatment is required to obtain protoplasts from the basidiomycete fungus Trametes hirsuta. The maximum yield of protoplasts (~2.5 * 107/mL) was achieved when mycelium in the exponential growth phase (60 h) was used. The maximum stability was observed in MES+ buffer during 4 h of incubation; in this case the titer reduction was 5-7%. Studies of the effect of antioxidants with different antioxidant capacities expressed in mmol equivalents of Trolox (ascorbate, 0.99; alpha-tocopherol, 1.0; beta-carotene, 2.14; quercetin, 3.98) indicated that the yield of protoplasts was increased in the presence of beta-carotene and quercetin by 18-24%. The studied antioxidants did not affect the protoplasts stability. The degree of regeneration of protoplasts correlated with the antioxidant capacity of the studied antioxidants and was maximal (0.4%) in the presence of beta-carotene and quercetin; it was 0.1% in the presence of MES+. The rate of protoplast growth was two times higher in the presence of beta-carotene and quercetin. PMID- 29509389 TI - [A search for microscopic fungi with directed hydroxylase activity for the synthesis of steroid drugs]. AB - The hydroxylase activities of new strains such as Curvularia lunata, C. geniculata, C. eragrostidis, C. prasadii, Ulocladium botrytis, Alternaria tenuis, and Fusarium oxysporum toward three steroid substrates, namely, androstenedione (AD), cortexolone (S), and dehydroepiandrosterone acetate (DAA), were characterized. The 9alpha-hydroxylase activity of C. lunata 1011 cells against S to form 9alpha-hydroxy-S was shown for the first time. It was found that C. geniculata 837 and F. oxysporum 11dn1 strains can hydroxylate substrates to form pharmacologically promising 7alpha-hydroxysteroids. C. geniculata 837 cells selectively hydroxylate AD, resulting in 7alpha-hydroxytestosterone, whereas F. oxysporum 11dn1 leads to the transformation of DAA to 7alpha hydroxydehydroepiandrosterone. PMID- 29509390 TI - [Production characteristics of Phaeodactylum tricornutum Bohlin grown on medium with artificial sea water]. AB - The growth of marine diatoms Phaeodactylum tricornutum was investigated on a medium with artificial sea water under artificial and natural light. The maximum specific growth rate was 0.7 day-1, the productivity was 0.8 g/L day, and the maximum biomass was 3.86 g/L under artificial light in laboratory conditions. In the conditions of Crimea, the maximum productivity of P. tricornutum amounted to 6 g/m2 day under natural light in an outdoor photobioreactor (pool). The results of cultivation of P. tricornutum in a pool with artificial seawater under natural light may serve as a basis for developing technologies for the industrial cultivation of algae. PMID- 29509391 TI - [Inhibition of oxidation of unsaturated fatty acid methyl esters by essential oils]. AB - The essential oils from 16 various spice plants were studied as natural antioxidants for the inhibition of autooxidation of polyunsaturated fatty acids methyl esters isolated from linseed oil. The content of methyl oleate, methyl linoleate, and methyl linolenoate after 1, 2, and 4 months of autooxidation were used as criteria to estimate the antioxidant efficiencies of essential oils. In 4 months, 92% of the methyl linolenoate and 79% of the methyl linoleate were oxidized in a control sample of a model system. It was found that the most effective antioxidants were essential oils from clove bud, cinnamon leaves, and oregano. They inhibited autooxidation of methyl linolenoate by 76-85%. The antioxidant properties of these essential oils were due to phenols- eugenol, carvacrol, and thymol. Essential oil from coriander did not contain phenols, but it inhibited methyl linolenoate oxidation by 38%. Essential oils from thyme, savory, mace, lemon, and tea tree inhibited methyl linolenoate oxidation by 17 24%. The other essential oils had no antioxidant properties. PMID- 29509392 TI - [Bioregulator from rat liver tissue]. AB - It has been shown that the membranotropic homeostatic tissue-specific bioregulator isolated from rat liver tissue contains a nanosized peptide-protein complex consisting of low-molecular peptides (1-6.5 kDa) and a protein from the serum albumin family. This bioregulator modulated the peptide biological activity and determined the tissue specificity. PMID- 29509393 TI - Thiol-Reactive Bifunctional Chelators for the Creation of Site-Selectively Modified Radioimmunoconjugates with Improved Stability. AB - Maleimide-bearing bifunctional chelators have been used extensively for the site selective bioconjugation and radiolabeling of peptides and proteins. However, bioconjugates obtained using these constructs inevitably suffer from limited stability in vivo, a trait that translates into suboptimal activity concentrations in target tissues and higher uptake levels in healthy, nontarget tissues. To circumvent this issue, phenyloxadiazolyl methylsulfones have previously been reported as alternatives to maleimides for thiol-based ligations, but these constructs have scarcely been used in the field of radiochemistry. In this report, we describe the synthesis of two thiol-reactive bifunctional chelators for 89Zr and 177Lu based on a new, easy-to-make phenyloxadiazolyl methylsulfone reagent, PODS. Radioimmunoconjugates created using these novel bifunctional chelators displayed in vitro stability that was higher than that of their maleimide-derived cousins. More importantly, positron emission tomography imaging in murine models of cancer revealed that a 89Zr-labeled radioimmunoconjugate created using a PODS-bearing bifunctional chelator produced a rate of uptake in nontarget tissues that is significantly lower than that of its analogous maleimide-based counterpart. PMID- 29509394 TI - Graphdiyne Nanoparticles with High Free Radical Scavenging Activity for Radiation Protection. AB - Numerous carbon networks materials comprised of benzene moieties, such as graphene and fullerene, have held great fascination for radioprotection because of their acknowledged good biocompatibility and strong free radical scavenging activity derived from their delocalized pi-conjugated structure. Recently, graphdiyne, a new emerging carbon network material consisting of a unique chemical structure of benzene and acetylenic moieties, has gradually attracted attention in many research fields. Encouraged by its unique structure with strong conjugated pi-system and highly reactive diacetylenic linkages, graphdiyne might have free radical activity and can thus be used as a radioprotector, which has not been investigated so far. Herein, for the first time, we synthesized bovine serum albumin (BSA)-modified graphdiyne nanoparticles (graphdiyne-BSA NPs) to evaluate their free radical scavenging ability and investigate their application for radioprotection both in cell and animal models. In vitro studies indicated that the graphdiyne-BSA NPs could effectively eliminate the free-radicals, decrease radiation-induced DNA damage in cells, and improve the viability of cells under ionizing radiation. In vivo experiments showed that the graphdiyne BSA NPs could protect the bone marrow DNA of mice from radiation-induced damage and make the superoxide dismutase (SOD) and malondialdehyde (MDA) (two kinds of vital indicators of radiation-induced injury) recover back to normal levels. Furthermore, the good biocompatibility and negligible systemically toxicity responses of the graphdiyne-BSA NPs to mice were verified. All these results manifest the good biosafety and radioprotection activity of graphdiyne-BSA NPs to normal tissues. Therefore, our studies not only provide a new radiation protection platform based on graphdiyne for protecting normal tissues from radiation-caused injury but also provide a promising direction for the application of graphdiyne in the biomedicine field. PMID- 29509395 TI - Recent Advances of Solution-Processed Metal Oxide Thin-Film Transistors. AB - Solution-processed metal oxide thin-film transistors (TFTs) are considered as one of the most promising transistor technologies for future large-area flexible electronics. This work surveys the recent advances in solution-processed metal oxide TFTs, including n-type oxide semiconductors, oxide dielectrics, and p-type oxide semiconductors. We first deliver a review on the history and present status of metal oxide TFTs. Then, we present the recent progress in solution-processed n type oxide semiconductors, with a special focus on low-temperature and large-area solution-based approaches as well as emerging nondisplay applications. Next, we give a detailed analysis of the state-of-the-art solution-processed oxide dielectrics for low-power electronics. We further discuss the recent advances in solution-based p-type oxide semiconductors, which will enable the highly desirable future low-cost large-area complementary circuits. Finally, we draw conclusions and outline the perspectives over the research field. PMID- 29509396 TI - Characterization of Hepatitis C Virus Core Protein Dimerization by Atomic Force Microscopy. AB - Dimerization of core protein is a crucial step in the formation of the hepatitis C virus (HCV) nucleocapsid, and inhibition of dimer formation is regarded as an attractive approach to design anti-HCV drugs. In this work, we developed the atomic force microscopy based single molecular force spectroscopy (AFM-SMFS) method for the characterization of core protein dimerization with the advantages of small amount of sample consumption and no need of labeling. Interaction force of the core protein with its antibody or aptamer was analyzed to investigate its stoichiometry and binding property. The two specific binding forces were detected due to the probing of dimeric and monomeric core protein, respectively. Moreover, the binding property of protein dimer was different from the monomer. Our work offers a new approach to study the dimerization of core protein, as well as other proteins, and to screen the HCV candidate inhibitors. PMID- 29509397 TI - Improving the Safety of Lithium-Ion Battery via a Redox Shuttle Additive 2,5-Di- tert-butyl-1,4-bis(2-methoxyethoxy)benzene (DBBB). AB - 2,5-Di- tert-butyl-1,4-bis(2-methoxyethoxy)benzene (DBBB) is studied as a redox shuttle additive for overcharge protection for a 1.5 Ah graphite/C-LFP lithium ion pouch cell for the first time. The electrochemical performance demonstrated that the protecting additive remains inert during the extended standard cycling for 4000 cycles. When a 100% overcharge is introduced in the charging protocol, the baseline cell fails rapidly during the first abusive event, whereas the cell containing DBBB additive withstands 700 overcharge cycles with 87% capacity retention and no gas evolution or cell swelling was observed. It is the first time the effectiveness of the DBBB as overcharge protection additive in a large pouch cell format is demonstrated. PMID- 29509398 TI - Hypothesis Test of the Photon Count Distribution for Dust Discrimination in Dynamic Light Scattering. AB - Users of dynamic light scattering (DLS) are challenged when a sample of nanoparticles (NPs) contains dust. This is a frequently inevitable scenario and a major problem that critically affects the reproducibility and accuracy of DLS measurements. Current methods approach this problem via photon correlation spectroscopy, but remedy exists only for a few special cases. We introduce here a general criterion and a clearly defined measure to discriminate between NPs and dust particles. The experimental results show that, in contrast to photon correlation spectroscopy, hypothesis testing and the statistical moment analysis of the photon count distribution provides an accurate and precise way to characterize NPs and Brownian dynamics in the presence of dust. To demonstrate, analyses of silica, iron oxide, and gold NPs of low polydispersity are presented. PMID- 29509399 TI - Designing Binary Ru-Sn Oxides with Optimized Performances for the Air Electrode of Rechargeable Zinc-Air Batteries. AB - Because of the sluggish kinetics of the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR), binary ruthenium-tin oxides synthesized by a hydrothermal method with postannealing at 450 degrees C for 2 h are first proposed as bifunctional catalysts for these two reactions on the air electrode of rechargeable zinc-air batteries. The binary Ru-Sn oxides in various compositions show the typical oxide solid solution in the rutile phase. Among all binary Ru-Sn oxides, RuSn73 (70 atom % RuO2 and 30 atom % SnO2) and RuSn37 (30 atom % RuO2 and 70 atom % SnO2) show the highest catalytic activities toward the OER and ORR, respectively. Consequently, a novel design of the air electrode consisting of a RuSn37 coating on the carbon paper and a Ti mesh coated with RuSn73 (denoted RuSn(37-C|73-Ti)) is proposed to possess the optimal charge discharge performances. A unique cell employing such an air electrode has been demonstrated to exhibit a very low charge-discharge cell voltage gap of 0.75 V at 10 mA cm-2. This cell with a peak power density of 120 mW cm-2 at the current density of 235 mA cm-2 also shows an outstanding charge-discharge stability over 80 h. This cell also exhibits an exceptionally high charge rate capability at 150 mA cm-2 with a low charging voltage of 2.0 V. PMID- 29509400 TI - Reconfigurable Microfluidic Droplets Stabilized by Nanoparticle Surfactants. AB - Interfacial assemblies of nanoparticles can stabilize liquid-liquid interfaces. Due to the interactions between functional groups on nanoparticles dispersed in one liquid and polymers having complementary end-functionality dissolved in a second immiscible fluid, the anchoring of a well-defined number of polymer chains onto the nanoparticles leads to the formation of NP-surfactants that assemble at the interface and reduce the interfacial energy. We have developed droplet interfaces covered with elastic, responsive monolayers of NP-surfactants. Due to the presence of an elastic layer at the interface, the droplets offer a greater resistance to coalescence and can prevent the exchange of materials across interfaces. Our results show the successful encapsulation of nanoparticles, dyes, and proteins with diameters in the 2.4-30 nm range. Further, we show that stable water-in-oil droplets can be generated for various combinations of polymer ligands and nanoparticles bearing complementary functionalities. These NP surfactant-stabilized microfluidic emulsions would enable applications requiring liquid-liquid interfaces that can adapt and respond to external stimuli and whose mechanical properties can be easily tailored. PMID- 29509401 TI - Crystalline Bilayer Graphene with Preferential Stacking from Ni-Cu Gradient Alloy. AB - We developed a high-yield synthesis of highly crystalline bilayer graphene (BLG) with two preferential stacking modes using a Ni-Cu gradient alloy growth substrate. Previously reported approaches for BLG growth include flat growth substrates of Cu or Ni-Cu uniform alloys and "copper pocket" structures. Use of flat substrates has the advantage of being scalable, but the growth mechanism is either "surface limited" (for Cu) or carbon precipitation (for uniform Ni-Cu), which results in multicrystalline BLG grains. For copper pockets, growth proceeds through a carbon back-diffusion mechanism, which leads to the formation of highly crystalline BLG, but scaling of the copper pocket structure is expected to be difficult. Here we demonstrate a Ni-Cu gradient alloy that combines the advantages of these earlier methods: the substrate is flat, so easy to scale, while growth proceeds by a carbon back-diffusion mechanism leading to high-yield growth of BLG with high crystallinity. The BLG layer stacking was almost exclusively Bernal or twisted with an angle of 30 degrees , consistent with first principles calculations we conducted. Furthermore, we demonstrated scalable production of transistor arrays based crystalline Bernal-stacked BLG with a band gap that was tunable at room temperature. PMID- 29509402 TI - Activity-Based Phosphatidylinositol Kinase Probes Detect Changes to Protein Protein Interactions During Hepatitis C Virus Replication. AB - Protein-protein interactions are integral to host-virus interactions and can contribute significantly to enzyme regulation by changing the localization of both host and viral enzymes within the cell, inducing conformational change relevant to enzyme activity or recruiting other additional proteins to form functional complexes. Identifying the interactors of active enzymes using an activity-based protein profiling probe has allowed us to characterize both normal enzyme activation mechanisms and the manner by which these mechanisms are hijacked and altered by the hepatitis C virus (HCV). Here, we report use of a novel activity-based probe, PIKBPyne, which labels phosphatidylinositol kinases (PIKs) in an activity-based manner, to investigate HCV-dependent changes in protein-protein interactions for PI4KB. Herein, we report the synthesis of new variations on PIKBPyne, compare their ability to label the interacting partners of PI4KB, and demonstrate the utility of our approach in characterizing virus mediated changes to host function. PMID- 29509403 TI - Recent Advances of Membrane-Cloaked Nanoplatforms for Biomedical Applications. AB - In terms of the extremely small size and large specific surface area, nanomaterials often exhibit unusual physical and chemical properties, which have recently attracted considerable attention in bionanotechnology and nanomedicine. Currently, the extensive usage of nanotechnology in medicine holds great potential for precise diagnosis and effective therapeutics of various human diseases in clinical practice. However, a detailed understanding regarding how nanomedicine interacts with the intricate environment in complex living systems remains a pressing and challenging goal. Inspired by the diversified membrane structures and functions of natural prototypes, research activities on biomimetic and bioinspired membranes, especially for those cloaking nanosized platforms, have increased exponentially. By taking advantage of the flexible synthesis and multiple functionality of nanomaterials, a variety of unique nanostructures including inorganic nanocrystals and organic polymers have been widely devised to substantially integrate with intrinsic biomoieties such as lipids, glycans, and even cell and bacteria membrane components, which endow these abiotic nanomaterials with specific biological functionalities for the purpose of detailed investigation of the complicated interactions and activities of nanomedicine in living bodies, including their immune response activation, phagocytosis escape, and subsequent clearance from vascular system. In this review, we summarize the strategies established recently for the development of biomimetic membrane-cloaked nanoplatforms derived from inherent host cells (e.g., erythrocytes, leukocytes, platelets, and exosomes) and invasive pathogens (e.g., bacteria and viruses), mainly attributed to their versatile membrane properties in biological fluids. Meanwhile, the promising biomedical applications based on nanoplatforms inspired by diverse moieties, such as selective drug delivery in targeted sites and effective vaccine development for disease prevention, have also been outlined. Finally, the potential challenges and future prospects of the biomimetic membrane-cloaked nanoplatforms are also discussed. PMID- 29509404 TI - Real-Time Gas Mixture Analysis Using Mid-Infrared Membrane Microcavities. AB - Real-time gas analysis on-a-chip was demonstrated using a mid-infrared (mid-IR) microcavity. Optical apertures for the microcavity were made of ultrathin silicate membranes embedded in a silicon chip using the complementary metal-oxide semiconductor (CMOS) process. Fourier transform infrared spectroscopy (FTIR) shows that the silicate membrane is transparent in the range of 2.5-6.0 MUm, a region that overlaps with multiple characteristic gas absorption lines and therefore enables gas detection applications. A test station integrating a mid-IR tunable laser, a microgas delivery system, and a mid-IR camera was assembled to evaluate the gas detection performance. CH4, CO2, and N2O were selected as analytes due to their strong absorption bands at lambda = 3.25-3.50, 4.20-4.35, and 4.40-4.65 MUm, which correspond to C-H, C-O, and O-N stretching, respectively. A short subsecond response time and high gas identification accuracy were achieved. Therefore, our chip-scale mid-IR sensor provides a new platform for an in situ, remote, and embedded gas monitoring system. PMID- 29509406 TI - Nanoporous Anodic Alumina Surface Modification by Electrostatic, Covalent, and Immune Complexation Binding Investigated by Capillary Filling. AB - The fluid imbibition-coupled laser interferometry (FICLI) technique has been applied to detect and quantify surface changes and pore dimension variations in nanoporous anodic alumina (NAA) structures. FICLI is a noninvasive optical technique that permits the determination of the NAA average pore radius with high accuracy. In this work, the technique is applied after each step of different surface modification paths of the NAA pores: (i) electrostatic immobilization of bovine serum albumin (BSA), (ii) covalent attachment of streptavidin via (3 aminipropyl)-triethoxysilane and glutaraldehyde grafting, and (iii) immune complexation. Results show that BSA attachment can be detected as a reduction in estimated radius from FICLI with high accuracy and reproducibility. In the case of the covalent attachment of streptavidin, FICLI is able to recognize a multilayer formation of the silane and the protein. For immune complexation, the technique is able to detect different antibody-antigen bindings and distinguish different dynamics among different immune species. PMID- 29509405 TI - Insulated Interlayer for Efficient and Photostable Electron-Transport-Layer-Free Perovskite Solar Cells. AB - Currently, the most efficient perovskite solar cells (PSCs) mainly use planar and mesoporous titanium dioxide (TiO2) as an electron-transport layer (ETL). However, because of its intrinsic photocatalytic properties, TiO2 can decompose perovskite absorber and lead to poor stability under solar illumination (ultraviolet light). Herein, a simplified architectural ETL-free PSC with enhanced efficiency and outstanding photostability is produced by the facile deposition of a bathocuproine (BCP) interlayer. Power conversion efficiency of the ETL-free PSC improves from 15.56 to 19.07% after inserting the BCP layer, which is the highest efficiency reported for PSCs involving an ETL-free architecture, versus 19.03% for the n-i-p full device using TiO2 as an ETL. The BCP interlayer has been demonstrated to have several positive effects on the photovoltaic performances of devices, such as "modulation doping" of the perovskite layer, modification of FTO surface work function, and enhancing the charge-transfer efficiency between FTO and perovskite. Moreover, the BCP-based ETL-free devices exhibit outstanding photostability: the unencapsulated BCP-based ETL-free PSCs retain over 90% of their initial efficiencies after 1000 h of storage in air and maintain 92.2% after 450 h of exposure to full solar irradiation (without a UV filter), compared to only 14.1% in the n-i-p full cells under the same condition. PMID- 29509407 TI - Structure-Based Engineering of Steroidogenic CYP260A1 for Stereo- and Regioselective Hydroxylation of Progesterone. AB - The production of regio- and stereoselectively hydroxylated steroids is of high pharmaceutical interest and can be achieved by cytochrome P450-based biocatalysts. CYP260A1 from Sorangium cellulosum strain So ce56 catalyzes hydroxylation of C19 or C21 steroids at the very unique 1alpha-position. However, the conversion of progesterone (PROG) by CYP260A1 is very unselective. In order to improve its selectivity we applied a semirational protein engineering approach, resulting in two different, highly regio- and stereoselective mutants by replacing a single serine residue (S276) of the substrate recognition site 5 with an asparagine or isoleucine. The S276N mutant converted PROG predominantly into 1alpha-hydroxy-PROG, while the S276I mutant led to 17alpha-hydroxy-PROG. We solved the high-resolution crystal structures of the PROG-bound S276N and S276I mutants, which revealed two different binding modes of PROG in the active site. The orientations were consistent with the exclusive 1alpha- (pro-1alpha binding mode) and 17alpha-hydroxylation (pro-17alpha-binding mode) of S276N and S276I, respectively. We observed that water-mediated hydrogen bonds contribute to the stabilization of the polar C3 and C17 substituents of PROG. Both binding modes of PROG may be stabilized in the wild-type enzyme. The change in regioselectivity is mainly driven by destabilizing the alternative binding mode due to steric hindrance and hydrogen bond disruption, caused by the mutations of Ser276. Thus, for the first time, the change in the selectivity of cytochrome P450-mediated steroid hydroxylation created by rational mutagenesis can be explained by the obtained 3D structures of the substrate-bound mutants, providing the basis for further experiments to engineer the biocatalyst toward novel steroid hydroxylation positions. PMID- 29509408 TI - DNA Polymerase theta Increases Mutational Rates in Mitochondrial DNA. AB - Replication and maintenance of mitochondrial DNA (mtDNA) is essential for cellular function, yet few DNA polymerases are known to function in mitochondria. Here, we conclusively demonstrate that DNA polymerase theta (Poltheta) localizes to mitochondria and explore whether this protein is overexpressed in patient derived cells and tumors. Poltheta appears to play an important role in facilitating mtDNA replication under conditions of oxidative stress, and this error-prone polymerase was found to introduce mutations into mtDNA. In patient derived cells bearing a pathogenic mtDNA mutation, Poltheta expression levels were increased, indicating that the oxidative conditions in these cells promote higher expression levels for Poltheta. Heightened Poltheta expression levels were also associated with elevated mtDNA mutation rates in a selected panel of human tumor tissues, suggesting that this protein can influence mutational frequencies in tumors. The results reported indicate that the mitochondrial function of Poltheta may have relevance to human disease. PMID- 29509409 TI - ALD-Developed Plasmonic Two-Dimensional Au-WO3-TiO2 Heterojunction Architectonics for Design of Photovoltaic Devices. AB - Electrically responsive plasmonic devices, which benefit from the privilege of surface plasmon excited hot carries, have supported fascinating applications in the visible-light-assisted technologies. The properties of plasmonic devices can be tuned by controlling charge transfer. It can be attained by intentional architecturing of the metal-semiconductor (MS) interfaces. In this study, the wafer-scaled fabrication of two-dimensional (2D) TiO2 semiconductors on the granular Au metal substrate is achieved using the atomic layer deposition (ALD) technique. The ALD-developed 2D MS heterojunctions exhibited substantial enhancement of the photoresponsivity and demonstrated the improvement of response time for 2D Au-TiO2-based plasmonic devices under visible light illumination. To circumvent the undesired dark current in the plasmonic devices, a 2D WO3 nanofilm (~0.7 nm) was employed as the intermediate layer on the MS interface to develop the metal-insulator-semiconductor (MIS) 2D heterostructure. As a result, 13.4% improvement of the external quantum efficiency was obtained for fabricated 2D Au WO3-TiO2 heterojunctions. The impedancometry measurements confirmed the modulation of charge transfer at the 2D MS interface using MIS architectonics. Broadband photoresponsivity from the UV to the visible light region was observed for Au-TiO2 and Au-WO3-TiO2 heterostructures, whereas near-infrared responsivity was not observed. Consequently, considering the versatile nature of the ALD technique, this approach can facilitate the architecturing and design of novel 2D MS and MIS heterojunctions for efficient plasmonic devices. PMID- 29509410 TI - Iterative Polyketide Synthesis via a Consecutive Carbonyl-Protecting Strategy. AB - To address the difficulty in protecting a beta-polycarbonyl compound, a method for the sequential protection of elongating carbonyl groups was demonstrated. The iterative chain elongation of a carboxylic acid with malonic acid half thioester followed by the protection of the resulting beta-ketothioester was performed via the stepwise formation of an isoxazole ring using an O-protected oxime functionality. Yangonin and isosakuranetin were synthesized according to this procedure. PMID- 29509411 TI - UNC-51-like Kinase 1: From an Autophagic Initiator to Multifunctional Drug Target. AB - UNC-51-like kinase 1 (ULK1), known as an ortholog of the yeast Atg1, is the serine-threonine kinase and the autophagic initiator in mammals. Accumulating evidence has recently revealed the kinase domain structure of ULK1 and its post translational modifications, as well as further elucidated its regulatory autophagic pathways and associations with diverse human diseases. Interestingly, a series of small molecules have been recently reported to target ULK1 or ULK1 modulating autophagy, which may provide a clue on exploiting them as novel candidate drugs. Taken together, this review discusses how ULK1 acts as an autophagic initiator for modulation of its intricate mechanisms, as well as how ULK1 becomes a multifunctional target for potential therapeutic applications. PMID- 29509412 TI - Effect of Element Substitution on Structural Transformation and Optical Performances in I2BaMIVQ4 ( I = Li, Na, Cu, and Ag; MIV = Si, Ge, and Sn; Q = S and Se). AB - In the exploration of new infrared nonlinear optical (IR NLO) materials, element substitution has been developed as an effective way to adjust the structural features and material performances. A series of new IR NLO materials have been discovered in the I-Ba-MIV-Q system ( I = Li, Na, Cu, and Ag; MIV = Si, Ge, and Sn; Q = S and Se), and they undergo interesting structural transformation with different element substitution except Li analogues. Herein, we have successfully synthesized three selenides with different space groups (Ag2BaSiSe4: I42 m; Ag2BaGeSe4 and Ag2BaSnSe4: I222) in the above system and studied their properties through experimental and theoretical methods. Remarkably, the detailed analysis on the structural changes and properties comparison was also systematically investigated in the I-Ba-MIV-Q system and the results indicate that the distortion degrees of different IQ4 tetrahedra play the critical role to cause the structural transformation with the M or Q elements substitution. More importantly, we have also found that the structural changes have the close relationship with the distance d( I- I) between adjacent I cations in the I2BaSnSe4 system, which makes the four-membered rings formed by edge-sharing BaSe8 units change from the square to rhombus with the increase of d( I- I). The properties comparisons (band gap and NLO effect) in this system have been also systematically studied. PMID- 29509413 TI - Synthesis and Biological Evaluation of Selenium-Containing 4-Anilinoquinazoline Derivatives as Novel Antimitotic Agents. AB - Twenty-eight novel selenium-containing 4-anilinoquinazoline derivatives were designed, synthesized, and evaluated as antiproliferative agents. Most of them had significant in vitro activities, particularly for compounds 23a, 25a, and 25d, which also exhibited the most potent antitumor activities against cisplatin resistant cell lines and the doxorubicin-resistant cell lines, good selectivity toward normal cells, and obvious inhibitory effect on migration of A549 cell lines. Further mechanistic studies revealed that 23a, 25a, and 25d induce G2/M phase arrest and apoptosis in A549 cells, which was associated with a collapse of the mitochondrial membrane potential, alterations in the expression of some cell cycle-related and apoptosis-related proteins, and increasing the intracellular ROS level. Finally, compounds 23a, 25a, and 25d also effectively inhibited the tumor growth in the A549 xenograft model without obvious hints of toxicity. Taken together, these in vitro and in vivo results suggest that 23a, 25a, and 25d may be promising microtubule-stabilizing agents and can be used as a promising lead for the development of new antitumor agents. PMID- 29509414 TI - Role of Brassinosteroids in Persimmon ( Diospyros kaki L.) Fruit Ripening. AB - Brassinosteroids (BRs) are phytohormones that regulate numerous processes including fruit ripening. In this study, persimmon ( Diospyros kaki L.) fruits were treated with 24-epibrassinolide (EBR) or brassinazole (Brz, a BR biosynthesis inhibitor) and then stored at ambient temperature. The results show that endogenous BR contents gradually increased during persimmon fruit ripening. EBR treatment significantly increased both the content of water-soluble pectin and the activities of polygalacturonase, pectate lyase, and endo-1,4-beta glucanase but significantly reduced the content of acid-soluble pectin and cellulose, resulting in rapid fruit softening. The EBR treatment also promoted ethylene production and respiration rate. In contrast, Brz treatment delayed persimmon fruit ripening. qRT-PCR analysis showed that DkPG1, DkPL1, DkPE2, DkEGase1, DkACO2, DkACS1, and DkACS2 were up-regulated (especially a 38-fold increase in DkEGase1) in the fruit of the EBR-treated group. These results suggest that BRs are involved in persimmon fruit ripening by influencing cell wall-degrading enzymes and ethylene biosynthesis. PMID- 29509415 TI - Alternative Flame Retardant, 2,4,6-Tris(2,4,6-tribromophenoxy)-1,3,5-triazine, in an E-waste Recycling Facility and House Dust in North America. AB - A high molecular weight compound, 2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5 triazine (TTBP-TAZ), was detected during the analysis of brominated flame retardants in dust samples collected from an electrical and electronic waste (e waste) recycling facility in Ontario, Canada. Gas chromatography coupled with both high-resolution and low-resolution mass spectrometry (MS) was used to determine TTBP-TAZ's chemical structure and concentrations. To date, TTBP-TAZ has only been detected in plastic casings of electrical and electronic equipment and house dust from The Netherlands. Here we report on the concentrations of TTBP-TAZ in selected samples from North America: e-waste dust ( n = 7) and air ( n = 4), residential dust ( n = 30), and selected outdoor air ( n = 146), precipitation ( n = 19), sediment ( n = 11) and water ( n = 2) samples from the Great Lakes environment. TTBP-TAZ was detected in all the e-waste dust and air samples, and in 70% of residential dust samples. The median concentrations of TTBP-TAZ in these three types of samples were 5540 ng/g, 5.75 ng/m3 and 6.76 ng/g, respectively. The flame retardants 2,4,6-tribromophenol, tris(2,3-dibromopropyl) isocyanurate, and 3,3',5,5'-tetrabromobisphenol A bis(2,3-dibromopropyl) ether, BDE-47 and BDE-209 were also measured for comparison. None of these other flame retardants concentrations was significantly correlated with those of TTBP-TAZ in any of the sample types suggesting different sources. TTBP-TAZ was not detected in any of the outdoor environmental samples, which may relate to its application history and physicochemical properties. This is the first report of TTBP-TAZ in North America. PMID- 29509416 TI - Preparation, Characterization, and In Vitro Testing of Nanoclay Antimicrobial Activities and Elicitor Capacity. AB - Clay-based nanocomposites (nanoclays) are interesting systems to hold a wide type of active substances with a wide field of industrial applications. Bentonite chitosan nanoclay was obtained via cationic exchange of natural bentonite (Bent) with an aqueous solution of chitosan (CS). Their physicochemical and morphological properties were discussed under the light of Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopy. Bent-CS characterization indicated that CS was intercalated in 10% (w/w). This polycationic polymer was oriented mostly in a monolayer arrangement, interacting by electrostatic forces between Bent sheets. The antimicrobial action of Bent-CS nanoclay was assayed onto phytopathogens, the bacterium model Pseudomonas syringe pv. tomato DC3000 ( Psy) and the necrotrophic fungus Fusarium solani f. sp. eumartii ( F. eumartii). In addition to demonstrating cell death on both microorganisms, Bent-CS exerted elicitor property on tomato plantlets. The biological actions of this natural nanomaterial might make it proper to be used in crops. PMID- 29509417 TI - Versatile Coordination Modes of Triphospha-1,4-pentadiene-2,4-diamine. AB - 1,3,5-Triphospha-1,4-pentadiene-2,4-diamine reacts with [M(CO)4L] (M = Mo, L = nbd (norbornadiene); M = W, L = 2 CH3CN) to give the chelate complexes [M(CO)4(PMes{C(NHCy)PMes}2-kappa P1 ,P3)]. In contrast, an unusual intramolecular rearrangement occurred with [Cu(CH3CN)4]PF6 leading to the dimeric copper(I) complex [Cu(CNCy){PHMesPMesC(NHCy)PMes-kappa P1 ,P3}]2(PF6)2. The mechanism of the rearrangement was supported by quantum-mechanical calculations. The transition-metal complexes were characterized by multinuclear NMR spectroscopy, mass spectrometry, infrared spectroscopy, and X-ray crystallography. PMID- 29509418 TI - Correction to The Theory of Ultra-Coarse-Graining. 3. Coarse-Grained Sites with Rapid Local Equilibrium of Internal States. PMID- 29509419 TI - Simulation and Analysis of the Spectroscopic Properties of Oxyluciferin and Its Analogues in Water. AB - Firefly bioluminescence is a quite efficient process largely used for numerous applications. However, some fundamental photochemical properties of the light emitter are still to be analyzed. Indeed, the light emitter, oxyluciferin, can be in six different forms due to interexchange reactions. In this work, we present the simulation of the absorption and emission spectra of the possible natural oxyluciferin forms in water and some of their analogues considering both the solvent/oxyluciferin interactions and the dynamical effects by using MD simulations and QM/MM methods. On the one hand, the absorption band shapes have been rationalized by analyzing the electronic nature of the transitions involved. On the other hand, the simulated and experimental emission spectra have been compared. In this case, an ultrafast excited state proton transfer (ESPT) occurs in oxyluciferin and its analogues, which impairs the detection of the emission from the protonated state by steady-state fluorescence spectroscopy. Transient absorption spectroscopy was used to evidence this ultrafast ESPT and rationalize the comparison between simulated and experimental steady-state emission spectra. Finally, this work shows the suitability of the studied oxyluciferin analogues to mimic the corresponding natural forms in water solution, as an elegant way to block the desired interexchange reactions allowing the study of each oxyluciferin form separately. PMID- 29509420 TI - Precursor-Directed Biosynthesis of Phenylbenzoisoquinolindione Alkaloids and the Discovery of a Phenylphenalenone-Based Plant Defense Mechanism. AB - Phenylbenzoisochromenone glucosides (oxa-phenylphenalenone glucosides) occurring in some phenylphenalenone-producing plants of the Haemodoraceae undergo conversion to phenylbenzoisoquinolindiones (aza-phenylphenalenones) in extracts of Xiphidium caeruleum. Precursor-directed biosynthetic experiments were used to generate a series of new phenylbenzoisoquinolindiones from native phenylbenzoisochromenone glucosides and external amines, amino acids, and peptides. Intermediates of the conversion were isolated, incubated with cell-free extracts, and exposed to reactions under oxidative or inert conditions, respectively, to elucidate the entire pathway from phenylbenzoisochromenones to phenylbenzoisoquinolindiones. An intermediate in this pathway, a reactive hydroxylactone/aldehyde, readily binds not only to amines in vitro but may also bind to the N-terminus of biogenic peptides and proteins of herbivores and pathogens in vivo. The deactivation of biogenic amino compounds by N-terminal modification is discussed as the key reaction of a novel phenylphenalenone-based plant defense mechanism. According to these data, the ecological function of phenylphenalenone-type compounds in the Haemodoraceae, subfamily Haemodoroideae, has been substantiated. PMID- 29509421 TI - Mechanism of Gas-Phase Ozonolysis of beta-Myrcene in the Atmosphere. AB - beta-Myrcene is one of the major monoterpenes in the atmosphere. Ozonolysis is one of the oxidation removal processes for myrcene in the atmosphere during the daytime. In this study, the mechanism of myrcene ozonolysis is studied using high level quantum chemistry calculations and kinetic calculations. The reaction starts with the formation of primary ozonides (POZs), which decompose to three primary product channels as 4-vinyl-4-pentenal (4V4P) + (CH3)2OO and two Criegee intermediates ( anti- and syn-My-CIs) + acetone with branching ratios of 0.73, 0.23, and 0.04, respectively. The Criegee intermediates (CIs) are formed with high excitation, and they could either isomerize promptly or be thermalized to stabilized CIs (sCIs) at fractions of 0.39, 0.23, and 0.25 for (CH3)2COO*, anti My-CI*, and syn-My-CI*. For stabilized My-CIs, syn-My-CI would undergo unimolecular H-migration to a vinyl hydroperoxide (VHP), which decomposes readily to OH radical and a vinoxy-type radical, while anti-My-CI would most likely react with water vapor or cyclize to a bicyclic compound when relative humidity is low. Reaction of My-CIs with SO2 is important only for conditions of low temperatures (<273 K) and low relative humidity. The predicted yields of 0.73 and 0.27 for 4V4P and acetone agree reasonably with previous experimental measurements. PMID- 29509423 TI - Group 10 Bis(iminosemiquinone) Complexes: Measurement of Singlet-Triplet Gaps and Analysis of the Effects of Metal and Geometry on Electronic Structure. AB - Bis(iminosemiquinone) complexes of divalent group 10 metals have been described as having open-shell singlet ground states characteristic of very strong coupling between the two ligand radicals. By using the nonlinear temperature dependence of the chemical shifts of the 1H NMR spectra, the singlet-triplet gaps in seven of these compounds have been measured, with the nickel compounds having gaps of about 2400 cm-1 and the palladium compounds about 1800 cm-1. Bis(iminosemiquinone)platinum complexes have singlet-triplet gaps too large to measure by this technique (over 2800 cm-1, estimated to be about 3000 cm-1), though bis(3,5-di- tert-butylbenzosemiquinonato)platinum(II) has a measurable singlet-triplet gap of 1850 cm-1. In combination with near-IR absorption data of the neutral, cationic, and anionic bis(iminosemiquinone) complexes, a simplified two-electron, two-orbital bonding model describing these compounds can be fully parametrized based on experimental data. The identity of the central metal principally affects the difference in energy between metal-ligand pi nonbonding and metal-ligand pi antibonding orbitals, with the strength of the bonding interactions increasing in the order Pd < Ni < Pt. Twisting the ligands out of planarity (by using a 2,2'-biphenylenediyl linker) has a marked effect on the optical spectra of the compounds but not on their singlet-triplet gaps; this indicates that the effect is not due to changes in bonding interactions but rather due to a decrease in the magnitude of the quantum mechanical exchange interactions in the twisted compared to the flat compounds. PMID- 29509422 TI - Theories for Sequence-Dependent Phase Behaviors of Biomolecular Condensates. AB - Liquid-liquid phase separation and related condensation processes of intrinsically disordered proteins (IDPs), proteins with intrinsically disordered regions, and nucleic acids underpin various condensed-liquid droplets or gel-like assemblies in the cellular environment. Collectively referred to as condensates, these bodies provide spatial/temporal compartmentalization, often serving as hubs for regulated biomolecular interactions. Examples include certain extracellular materials, transcription complexes, and membraneless organelles such as germ and stress granules and the nucleolus. They are critically important to cellular function; thus misregulation of their assembly is implicated in many diseases. Biomolecular condensates are complex entities. Our understanding of their inner workings is only in its infancy. Nonetheless, insights into basic biophysical principles of their assembly can be gained by applying analytical theories to elucidate how IDP phase behaviors are governed by the properties of the multivalent, solvent-mediated interactions entailed by the proteins' amino acid sequences. Here we briefly review the background of the pertinent polymer theories and outline the approximations that enable a tractable theoretical account of the dependence of IDP phase behaviors on the charge pattern of the IDP sequence. Of relevance to the homeostatic assembly of compositionally and functionally distinct condensates in the cellular context, theory indicates that the propensity for populations of different IDP sequences to mix or demix upon phase separation is affected by the similarity or dissimilarity of the sequence charge patterns. We also explore prospects of extending analytical theories to account for dynamic aspects of biomolecular condensates and to incorporate effects of cation-pi, pi-pi, and temperature-dependent hydrophobic interactions on IDP phase properties. PMID- 29509424 TI - A Lanthanide Luminescent Cation Exchange Material Derived from a Flexible Tricarboxylic Acid 2,6-Bis(1,2,3-triazol-4-yl)pyridine (btp) Tecton. AB - The synthesis of the three-dimensional metal-organic framework material, [Zn7L6].(H2NMe2)4.(H2O)45 (1), derived from a flexible tricarboxylic acid 2,6 bis(1,2,3-triazol-4-yl)pyridine (btp) ligand, is presented. The btp ligand, H3L, adopts a three-dimensional hydrogen bonding network in the crystalline state through a combination of carboxylic acid dimer and syn-anti-btp/carboxylic acid hydrogen bonding synthons. The Zn(II) species 1 exhibits a three-dimensional framework structure with the rare crs topology and contains linear and undulated solvent channels extending in three dimensions. The guest exchange and gas adsorption properties of 1 were investigated; herein we demonstrate the exchange of dimethylammonium cations from the as-synthesized material with cationic guest molecules in the form of dyes and luminescent Ln(III) ions. Sensitization of Eu(III) and Tb(III) inside the porous network of 1 was achieved upon cation exchange, with a view toward developing functional luminescent materials. PMID- 29509426 TI - Functional Replacement of Histidine in Proteins To Generate Noncanonical Amino Acid Dependent Organisms. AB - Simple strategies to produce organisms whose growth is strictly dependent on the presence of a noncanonical amino acid are useful for the generation of live vaccines and the biological containment of recombinant organisms. To this end, we report an approach based on genetically replacing key histidine (His) residues in essential proteins with functional His analogs. We demonstrate that 3-methyl-l histidine (MeH) functionally substitutes for a key metal binding ligand, H264, in the zinc-containing metalloenzyme mannose-6-phosphate isomerase (ManA). An evolved variant, Opt5, harboring both N262S and H264MeH substitutions exhibited comparable activities to wild type ManA. An engineered Escherichia coli strain containing the ManA variant Opt5 was strictly dependent on MeH for growth with an extremely low reversion rate. This straightforward strategy should be applicable to other metallo- or nonmetalloproteins that contain essential His residues. PMID- 29509427 TI - Bacterial Attachment, Aggregation, and Alignment on Subcellular Nanogratings. AB - Recent investigations on the interactions of bacteria with micro/nanostructures have revealed a wide range of prokaryotic responses that were previously unknown. Despite these advances, however, it remains unclear how collective bacterial behavior on a surface would be influenced by the presence of anisotropic nanostructures with subcellular dimensions. To clarify this, the attachment, aggregation, and alignment of Pseudomonas aeruginosa on orderly subcellular nanogratings with systematically varied geometries were investigated. Compared with a flat surface, attachment and aggregation of bacteria on the nanogratings were reduced by up to 83 and 84% respectively, whereas alignment increased by a maximum of 850%. Using a semiempirical quantitative model, these results were shown to be caused by a lowering of physicochemical attraction between the substrate and bacteria, possible disruption to cell communication, and physical isolation of bacteria that were entrenched in the nanogratings by capillary action. Furthermore, the bacterial attachment level was generally found to be exponentially related to the contact area between the substrate and bacterial cells, except when there were significant deficits in the available contact area, which prompted the bacterial cells to employ their appendages to maintain a minimum attachment rate. Because the contact area for adhesion is strongly dependent on the geometry of the surface features and orientation of the bacterial cells, these results indicate that the conventional practice of using roughness parameters to draw quantitative relationships between surface topographies and bacterial attachment could suffer from inaccuracies due to the lack of shape and orientation information provided by these parameters. On the basis of these insights, design principles for generating maximal and minimal bacterial attachment on a surface were also proposed and verified with results reported in the literature. PMID- 29509425 TI - It Pays To Be in Phase. AB - To survive, organisms must orchestrate competing biochemical and regulatory processes in time and space. Recent work has suggested that the underlying chemical properties of some biomolecules allow them to self-organize and that life may have exploited this property to organize biochemistry in space and time. Such phase separation is ubiquitous, particularly among the many regulatory proteins that harbor prion-like intrinsically disordered domains. And yet, despite evident regulation by post-translational modification and myriad other stimuli, the biological significance of many phase-separated compartments remains uncertain. Many potential functions have been proposed, but far fewer have been demonstrated. A burgeoning subfield at the intersection of cell biology and polymer physics has defined the biophysical underpinnings that govern the genesis and stability of these particles. The picture is complex: many assemblies are composed of multiple proteins that each have the capacity to phase separate. Here, we briefly discuss this foundational work and survey recent efforts combining targeted biochemical perturbations and quantitative modeling to specifically address the diverse roles that phase separation processes may play in biology. PMID- 29509428 TI - Probing the Internal Heterogeneity of Responsive Microgels Adsorbed to an Interface by a Sharp SFM Tip: Comparing Core-Shell and Hollow Microgels. AB - Microgels composed of thermoresponsive polymer poly( N-isopropylacrylamide) (PNIPAM) are interfacial active. Their adsorption leads to deformation, causing conformational changes that have profound effects on the macroscopic properties of these films. Yet, methods to quantitatively probe the local density are lacking. We introduced scanning force microscopy (SFM) to quantitatively probe the internal structure of microgels physically adsorbed on a solid (SiO2)/water interface. Using a sharp SFM tip, we investigated the two types of microgels: (i) core-shell microgels featuring a hard silica core and a PNIPAM shell and (ii) hollow microgels obtained by dissolution of the silica core. Thus, both systems have the same polymer network as the peripheral structure but a distinctly different internal structure, that is, a rigid core versus a void. By evaluating the force-distance curves, the force profile during insertion of the tip into the polymer network enables to determine a depth-dependent contact resistance, which closely correlates with the density profiles determined in solution by small angle neutron scattering. We found that the cavity of the swollen hollow microgels is still present when adsorbed to the solid substrate. Remarkably, while currently used techniques such as colloidal probe or reflectometry only provide an average of the z-profile, the methodology introduced herein actually probes the real three-dimensional density profile, which is ultimately important to understand the macroscopic behavior of microgel films. This will bridge the gap between the colloidal probe experiments that deform the microgel globally and the insertion in which the disturbance is located near the tip. PMID- 29509429 TI - Poly(sodium 4-styrenesulfonate) Stabilized Janus Nanosheets in Brine with Retained Amphiphilicity. AB - Maintaining colloidal stability in unfriendly environments while retaining surface chemical properties is challenging for fundamental science and crucial for many applications. Here, we report for the first time that by using a low concentration of poly(sodium 4-styrenesulfonate) (PSS), graphene-based amphiphilic Janus nanosheets (AJNs) can be stabilized in high salt brine (3 wt % NaCl and 0.5 wt % CaCl2), whereas the interfacial behavior of the nanosheets is not affected. The adsorption of PSS on the hydrophilic and hydrophobic surfaces of AJNs in brine was investigated experimentally and by molecular dynamics simulations. Simulations further showed that the spatial configuration of absorbed PSS molecules with sulfonate functional groups facing outward favored the generation of electrosteric repulsive interactions. Calculations of the interaction energy between PSS molecules and the nanosheet revealed surface charge as a key parameter to stabilize AJNs in the salt environment, as demonstrated by the case of graphene oxide with higher surface charge. Simulations were also used to examine the interfacial behavior of graphene-based AJNs in biphasic systems. The AJNs, which exhibited asymmetry in surface wettability, remained at the oil/brine interface because of PSS detachment from the hydrophobic surface. The results were subsequently experimentally confirmed, consistent with our previously reported graphene-based AJN fluid prepared in fresh water. The process was thermodynamically supported by the demonstrated negative change of Gibbs free energy. We believe that such a strategy could benefit for the stabilization of other AJNs with surface chemical accessibility under harsh conditions. PMID- 29509430 TI - Transpulmonary Pressure-based Mechanical Ventilation in Acute Respiratory Distress Syndrome. From Theory to Practice? PMID- 29509431 TI - The WHO 2018 Hand Hygiene Campaign: Make a Difference-Prevent Sepsis in Health Care. PMID- 29509432 TI - Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice. AB - Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKbeta and the p65 subunit of NF-kappaB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice. PMID- 29509433 TI - Reduced skeletal muscle phosphocreatine concentration in type 2 diabetic patients: a quantitative image-based phosphorus-31 MR spectroscopy study. AB - Mitochondrial function has been examined in insulin-resistant (IR) states including type 2 diabetes mellitus (T2DM). Previous studies using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in T2DM reported results as relative concentrations of metabolite ratios, which could obscure differences in phosphocreatine ([PCr]) and adenosine triphosphate concentrations ([ATP]) between T2DM and normal glucose tolerance (NGT) individuals. We used an image-guided 31P MRS method to quantitate [PCr], inorganic phosphate [Pi], phosphodiester [PDE], and [ATP] in vastus lateralis (VL) muscle in 11 T2DM and 14 NGT subjects. Subjects also received oral glucose tolerance test, euglycemic insulin clamp, 1H MRS to measure intramyocellular lipids [IMCL], and VL muscle biopsy to evaluate mitochondrial density. T2DM subjects had lower absolute [PCr] and [ATP] than NGT subjects (PCr 28.6 +/- 3.2 vs. 24.6 +/- 2.4, P < 0.002, and ATP 7.18 +/- 0.6 vs. 6.37 +/- 1.1, P < 0.02) while [PDE] was higher, but not significantly. [PCr], obtained using the traditional ratio method, showed no significant difference between groups. [PCr] was negatively correlated with HbA1c ( r = -0.63, P < 0.01) and fasting plasma glucose ( r = -0.51, P = 0.01). [PDE] was negatively correlated with Matsuda index ( r = -0.43, P = 0.03) and M/I ( r = -0.46, P = 0.04), but was positively correlated with [IMCL] ( r = 0.64, P < 0.005), HbA1c, and FPG ( r = 0.60, P = 0.001). To summarize, using a modified, in vivo quantitative 31P-MRS method, skeletal muscle [PCr] and [ATP] are reduced in T2DM, while this difference was not observed with the traditional ratio method. The strong inverse correlation between [PCr] vs. HbA1c, FPG, and insulin sensitivity supports the concept that lower baseline skeletal muscle [PCr] is related to key determinants of glucose homeostasis. PMID- 29509435 TI - Insulin uptake and action in microvascular endothelial cells of lymphatic and blood origin. AB - Whereas the blood microvasculature constitutes a biological barrier to the action of blood-borne insulin on target tissues, the lymphatic microvasculature might act as a barrier to subcutaneously administrated insulin reaching the circulation. Here, we evaluate the interaction of insulin with primary microvascular endothelial cells of lymphatic [human dermal lymphatic endothelial cells (HDLEC)] and blood [human adipose microvascular endothelial cells (HAMEC)] origin, derived from human dermal and adipose tissues, respectively. HDLEC express higher levels of insulin receptor and signal in response to insulin as low as 2.5 nM, while HAMEC only activate signaling at 100 nM (a dose that blood vessels do not normally encounter). Low insulin acts specifically through the insulin receptor, while supraphysiological insulin acts through both the IR and insulin growth factor-1 receptor. At supraphysiological or injection site compatible doses pertinent to lymphatic microvessels, insulin enters HAMEC and HDLEC via fluid-phase endocytosis. Conversely, at physiologically circulating doses (0.2 nM) pertinent to blood microvessels, insulin enters HAMEC through a receptor-mediated process requiring IR autophosphorylation but not downstream insulin signaling. At physiological doses, internalized insulin is barely degraded and is instead released intact to the extracellular medium. In conclusion, we document for the first time the mechanism of interaction of insulin with lymphatic endothelial cells, which may be relevant to insulin absorption during therapeutic injections. Furthermore, we describe distinct action and uptake routes for insulin at physiological and supraphysiological doses in blood microvascular endothelial cells, providing a potential explanation for previously conflicting studies on endothelial insulin uptake. PMID- 29509436 TI - Developmental origins of non-alcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. AB - Intrauterine growth restriction (IUGR) is linked to increased risk for chronic disease. Placental ischemia and insufficiency in the mother are implicated in predisposing IUGR offspring to metabolic dysfunction, including hypertension, insulin resistance, abnormalities in glucose homeostasis, and non-alcoholic fatty liver disease (NAFLD). Whether these metabolic disturbances contribute to the developmental origins of exaggerated cardiovascular-renal disease (CVRD) risk accompanying IUGR is unclear. IUGR impacts the pancreas, adipose tissue, and liver, which are hypothesized to program for hepatic insulin resistance and subsequent NAFLD. NAFLD is projected to become the major cause of chronic liver disease and contributor to uncontrolled Type 2 Diabetes Mellitus (T2DM), which is a leading cause of chronic kidney disease. While NAFLD is increased in experimental models of IUGR, lacking is a full comprehension of the mechanisms responsible for programming of NAFLD and whether this potentiates susceptibility to liver injury. The use of well-established and clinically relevant rodent models, which mimic the clinical characteristics of IUGR, metabolic disturbances, and increased blood pressure in the offspring, will permit investigation into mechanisms linking adverse influences during early life and later chronic health. The purpose of this review is to propose mechanisms, including those pro inflammatory in nature, whereby IUGR exacerbates the pathogenesis of NAFLD and how these adverse programmed outcomes contribute to exaggerated CVRD risk. Understanding the etiology of the developmental origins of chronic disease will allow investigators to uncover treatment strategies to intervene in the mother and her offspring to halt the increasing prevalence of metabolic dysfunction and CVRD. PMID- 29509437 TI - Impact of estrogens and estrogen receptor-alpha in brain lipid metabolism. AB - Estrogens and their receptors play key roles in regulating body weight, energy expenditure, and metabolic homeostasis. It is known that lack of estrogens promotes increased food intake and induces the expansion of adipose tissues, for which much is known. An area of estrogenic research that has received less attention is the role of estrogens and their receptors in influencing intermediary lipid metabolism in organs such as the brain. In this review, we highlight the actions of estrogens and their receptors in regulating their impact on modulating fatty acid content, utilization, and oxidation through their direct impact on intracellular signaling cascades within the central nervous system. PMID- 29509434 TI - Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement. AB - Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min 1) and FPE (%). In contrast, we observed a poor association between MCR (ml.min 1.kg-1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE. PMID- 29509438 TI - Quantifying ceramide kinetics in vivo using stable isotope tracers and LC-MS/MS. AB - Numerous studies have implicated dyslipidemia as a key factor in mediating insulin resistance. Ceramides have received special attention since their levels are inversely associated with normal insulin signaling and positively associated with factors that are involved in cardiometabolic disease. Despite the growing literature surrounding ceramide biology, there are limited data regarding the activity of ceramide synthesis and turnover in vivo. Herein, we demonstrate the ability to measure ceramide kinetics by coupling the administration of [2H]water with LC-MS/MS analyses. As a "proof-of-concept" we determined the effect of a diet-induced alteration on ceramide flux; studies also examined the effect of myriocin (a known inhibitor of serine palmitoyltransferase, the first step in sphingosine biosynthesis). Our data suggest that one can estimate ceramide synthesis and draw conclusions regarding the source of fatty acids; we discuss caveats in regards to method development in this area. PMID- 29509440 TI - The Values of the Nursing Discipline: Where Are They in Practice? PMID- 29509439 TI - Initial Inflammatory Profile in Community-acquired Pneumonia Depends on Time since Onset of Symptoms. AB - RATIONALE: Assessment of the inflammatory response can help the decision-making process when diagnosing community-acquired pneumonia (CAP), but there is a lack of information about the influence of time since onset of symptoms. OBJECTIVES: We studied the impact of the number of days since onset of symptoms on inflammatory cytokines and biomarker concentrations at CAP diagnosis in hospitalized patients. METHODS: We performed a secondary analysis in two prospective cohorts including 541 patients in the derivation cohort and 422 in the validation cohort. The time since onset of symptoms was self-reported, and patients were classified as early presenters (<3 d) and nonearly presenters. Biomarkers (C-reactive protein [CRP] and procalcitonin [PCT] in both cohorts) and cytokines in the derivation cohort (IL-1, - 6, -8, -10, and tumor necrosis factor alpha) were measured within 24 hours of hospital admission. MEASUREMENTS AND MAIN RESULTS: In early presenters, CRP was significantly lower, whereas PCT, IL-6, and IL-8 were higher. Nonearly presenters showed significantly lower PCT, IL-6, and IL-8 levels. In the validation cohort, CRP and PCT exhibited identical patterns: CRP levels were 36.4% greater in patients with 3 or more days since onset of symptoms than in those with less than 3 days since symptom onset in the derivation cohort and 38.2% in the validation cohort. PCT levels were 40% lower in patients with 3 or more days since onset of symptoms in the derivation cohort and 56% in the validation cohort. CONCLUSIONS: Time since symptom onset modifies the systemic inflammatory profile at CAP diagnosis. This information has relevant clinical implications for management, and it should be taken into account in the design of future clinical trials. PMID- 29509441 TI - Needless Suffering. PMID- 29509442 TI - Promoting Cultural Awareness: A Faculty Development Workshop on Cultural Competency. AB - An interdisciplinary faculty development workshop on cultural competency (CC) was implemented and evaluated for the Faculty of Medicine at McGill University. It consisted of a 4-hour workshop and 2 follow-up sessions. A reflective practice framework was used. The project was evaluated using the Multicultural Assessment Questionnaire (MAQ), evaluation forms completed by participants, and detailed field notes taken during the sessions. The workshop was attended by 49 faculty members with diverse professional backgrounds. Statistically significant improvements were measured using the MAQ. On a scale of 1 to 5 (5 = very useful) on the evaluation form, the majority of participants (76.1%) gave the workshop a score of 4 or 5 for overall usefulness. A thematic analysis of field-note data highlighted participant responses to specific activities in the workshop. Participants expressed a need for faculty development initiatives on CC such as this one. PMID- 29509443 TI - Reality Check: Are We Truly Preparing Our Students for Interprofessional Collaborative Practice? AB - Many academic settings offer interprofessional education (IPE) experiences that are of short duration and situated in safe, controlled environments such as classrooms or simulation labs. The purpose of this study was to examine the effects of a 10-week IPE strategy that was incorporated into the final clinical practicum of a BScN program. A mixed methods design was chosen, in the belief that qualitative data would help explain quantitative data from pre-test/post test design (n = 268). Quantitative results revealed that participants disagreed more with statements on interprofessional collaboration (IPC) after completion of the strategy (p = 0.00). Qualitative findings reinforced these results, revealing a theme of common sense is not so common when it comes to IPC in the health-care setting. When student nurses are being prepared for IPC, IPE strategies should be as "real" as possible, with exposure to some of the realities of interprofessional team functioning. PMID- 29509444 TI - The Contribution of Treatment Allocation Method to Outcomes in Intervention Research. AB - The purpose of this methodological study was to examine the contribution of treatment allocation method (random vs. preference) on the immediate, intermediate, and ultimate outcomes of a behavioural intervention (MCI) for insomnia. Participants were allocated to the MCI randomly or by preference. Outcomes were assessed before, during, and after completion of the MCI using validated self-report measures. Analysis of covariance was used to compare the post-test outcomes for the 2 groups, controlling for baseline differences. Compared to those randomized, participants in the preference group showed improvement in most immediate outcomes (sleep onset latency, wake after sleep onset, sleep efficiency), both intermediate outcomes (insomnia severity and daytime fatigue), and one ultimate outcome (resolution of insomnia). Using a systematic method for eliciting participants' preferences and involving participants in treatment selection had a beneficial impact on immediate and intermediate outcomes. Additional research should validate the mechanism through which treatment preferences contribute to outcomes. PMID- 29509446 TI - Together We Move Forward. PMID- 29509445 TI - Immunization Rejection in Southern Alberta: A Comparison of the Perspectives of Mothers and Health Professionals. AB - Qualitative grounded theory was used to compare and contrast the understanding and decision-making process of non-immunizing mothers and health professionals' perceptions of these mothers' understanding and decision-making process. The sample comprised 8 mothers with purposefully unimmunized children under the age of 6 years and 12 health professionals. Semi-structured interviews were conducted and the data generated were analyzed using data immersion, memo-writing, and 3 stages of coding. The mothers and health professionals identified similar, interrelated factors influencing the mothers' decision, categorized into 4 groups: emotions, beliefs, facts, and information. Three primary themes were evident: the health professionals emphasized the influence of religion in decision-making to a greater extent than did the mothers, the meaning of evidence appeared to differ for mothers and health professionals, and mothers revealed a mistrust of health professionals. Immunization is a public health issue; collaboration and understanding are necessary to promote positive health outcomes in children. PMID- 29509447 TI - Pain Assessment and Management in Canada: We've Come a Long Way but there are Challenges on the Road Ahead. PMID- 29509449 TI - Method of Treatment Allocation: Does It Affect Adherence to Behavioural Therapy for Insomnia? AB - Adherence to treatment is critical in determining the effects of behavioural therapy and may be affected by participants' preference for treatment. The purpose of this study was to determine the extent to which method of allocation to treatment (random vs. preference-based) influences adherence (exposure and enactment) to behavioural therapy. Participants received behavioural therapy for the management of insomnia randomly or by preference. Exposure was assessed as attendance at the treatment sessions, enactment as self-reported application of treatment recommendations. Participants (N = 262) attended a mean of 5.6 treatment sessions, applied the treatment recommendations frequently, and reported high levels of overall compliance. There was no difference between the random and preference groups in terms of exposure to and enactment of treatment. Randomization to the preferred treatment, dissatisfaction with the allocated treatment, and self-report bias could play a role in the findings and should be explored in future research. PMID- 29509448 TI - Attrition in Randomized and Preference Trials of Behavioural Treatments for Insomnia. AB - Preferences for treatment contribute to attrition. Providing participants with their preferred treatment, as done in a partially randomized clinical or preference trial (PRCT), is a means to mitigate the influence of treatment preferences on attrition. This study examined attrition in an RCT and a PRCT. Persons with insomnia were randomly assigned (n = 150) or allocated (n = 198) to the preferred treatment. The number of dropouts at different time points in the study arms was documented and the influence of participant characteristics and treatment-related factors on attrition was examined. The overall attrition rate was higher in the RCT arm (46%) than in the PRCT arm (33%). In both arms, differences in sociodemographic and clinical characteristics were found between dropouts and completers. The type of treatment significantly predicted attrition (all p <= .05). The results provide some evidence of a lower attrition rate in the PRCT arm, supporting the benefit of accounting for preferences as a method of treatment allocation. PMID- 29509450 TI - Pilot Testing of a Psycho-educational Telephone Intervention for Women Receiving Uninformative BRCA1/2 Genetic Test Results. AB - Evidence suggests that women who receive uninformative results for breast and ovarian cancer (BRCA1/2) gene mutations may experience as much distress as women whose results indicate the presence of a gene mutation. No intervention to reduce distress after receipt of uninformative results has yet been tested. The purpose of this study was to test the feasibility and preliminary effects of a psycho educational telephone (PET) intervention to reduce distress in women who receive uninformative BRCA1/2 results. A single group with repeated measures was used to assess the impact of the intervention on 72 such women. After receiving the results, most of the women continued to feel uncertain about their carrier genetic status. However, their distress significantly decreased between receipt of uninformative results and 3 months post-intervention (p = 0.01). The preliminary findings suggest that a PET uncertainty intervention is clinically feasible and may reduce the distress of receiving uninformative results. PMID- 29509451 TI - Honouring Stories: Mi'kmaq Women's Experiences with Pap Screening in Eastern Canada. AB - Mi'kmaq women are reported to have lower rates of Papanicolaou (Pap) screening and higher rates of cervical cancer than non-Aboriginal women. This qualitative participatory study used postcolonial feminist perspectives and Indigenous principles to explore Mi'kmaq women's experiences with Pap screening within the contexts that shaped their experiences. Community facilitators assisted with the research process. Talking circles and individual in-depth interviews were conducted with 16 Mi'kmaq women. Also, health-care providers were interviewed in 2 Mi'kmaq communities. The findings indicate that historical and social contexts are shaping Mi'kmaq women's screening experiences and that these experiences are diverse, as are their understandings about screening. Some women were accessing regular screening despite challenging personal circumstances. The results highlight the need for nurses and other health-care providers to understand the uniqueness of each woman's experiences with Pap screening. Improvements in screening rates depend on multifaceted nursing approaches developed in partnership with Mi'kmaq women. PMID- 29509452 TI - Rethinking Case Study Methodology in Poststructural Research. AB - Little consideration has been given to how case study might be used in poststructural research to explore power relations that constitute a phenomenon. Many case study scholars, most notably Robert Yin, adopt a postpositivist perspective that assumes the "truth" can be accessed through applying prescriptive and rigid research techniques. Using a discussion of Michel Foucault's key theoretical ideas and the insights gained through a Foucauldian case study of people with advanced cancer who continue to receive curative treatment, the authors argue for the expansion of case study in poststructural inquiry. They propose that the use of poststructuralist case study is valuable because of the flexibility and comprehensiveness of the methodology, which allows for the exploration of a deeper understanding of the broader discourses that shape a phenomenon, as well as how power/knowledge relations shape the behaviours and perceptions of people. They also introduce the reflexive implications of poststructural case study research. PMID- 29509453 TI - Coming to Terms with the Nursing Discipline: A Call for More Bicultural Troublemakers. PMID- 29509454 TI - Reflections on the "Caring Disconnect" in Nursing. PMID- 29509456 TI - Knowledge of Risk Factors for Type 2 Diabetes Mellitus in Adolescents: Psychometric Analysis of Instrument. AB - The study evaluates the psychometric properties of the instrument Knowledge of Risk Factors for Type 2 Diabetes Mellitus in Adolescents. T2DM is on the increase among adolescents and there are no instruments to assess knowledge of risk factors in this population. The author revised parts of an adult instrument and reviewed the items for content validity. The final instrument, comprising 11 items, was administered to 225 high-school students 13 to 19 years of age in the New York City area. An exploratory factor analysis was conducted using maximum likelihood estimation and geomin rotation. Two factors were extracted. The overall reliability of the scale was found to be acceptable at .76. The instrument appears to be a promising tool for the evaluation of knowledge of risk factors for T2DM in adolescents. PMID- 29509455 TI - Canadian Nurse Practitioners' Therapeutic Commitment to Persons with Mental Illness. AB - The purpose of this study was to determine how Canadian nurse practitioners (NPs) rate their levels of therapeutic commitment, role competency, and role support when working with persons with mental health problems. A cross-sectional descriptive, co-relational design was used. The Therapeutic Commitment Model was the theoretical framework for the study. A sample of 680 Canadian NPs accessed through 2 territorial and 9 provincial nursing jurisdictions completed a postal survey. NPs scored highest on the therapeutic commitment subscale and lowest on the role support subscale. The 3 subscales were correlated: role competency and therapeutic commitment were the most strongly associated (r = .754, p < .001). To have a positive impact on the care of persons with mental health problems, educators, policy-makers, and NPs need to assess and support therapeutic commitment, role support, and role competency development. PMID- 29509457 TI - Comparative Analysis of External Validity Reporting in Non-randomized Intervention Studies. AB - This article describes a comparative analysis of external validity reporting in non-randomized behavioural and public health intervention studies that used and did not use the TREND (Transparent Reporting of Evaluations with Non-randomized Designs) statement. The search resulted in 14 non-randomized intervention studies that were rated based on Green and Glasgow's criteria for external validity reporting. Studies that used the TREND statement demonstrated improved external validity reporting when compared with studies that did not use the TREND statement. The implication is that the TREND statement and Green and Glasgow's criteria can improve external validity reporting of non-randomized behavioural and public health interventions. PMID- 29509458 TI - Workforce Integration of Philippine-Educated Nurses who Migrate to Canada through the Live-in Caregiver Program. AB - Nurses who migrate through the Canadian Live-in Caregiver Program face significant barriers to their subsequent workforce integration as registered nurses in Canada. This study applies the concept of global care chains and uses single case study methodology to explore the experiences of 15 Philippine educated nurses who migrated to Ontario, Canada, through the Live-in Caregiver Program. The focus is the various challenges they encountered with nursing workforce integration and how they negotiated their contradictory class status. Due to their initial legal status in Canada and working conditions as migrant workers, they were challenged by credential assessment, the registration examination, access to bridging programs, high financial costs, and ambivalent employer support. The results of the study are pertinent for nursing policymakers and educators aiming to facilitate the integration of internationally educated nurses in Canada. PMID- 29509459 TI - A Critical Perspective on Relations between Staff Nurses and their Nurse Manager: Advancing Nurse Empowerment Theory. AB - This study considers empowerment in nurse-manager relations by examining how conflict is handled on both sides and how the critical social perspective has influenced these relations. The authors use inductive analysis of empirical data to explain how (1) nursing work is organized, structured, and circumscribed by centrally determined policies and practices that downplay nurses' professional judgement about patient care; (2) power is held over nurses in their relationship with their manager; and (3) nurses' response to power is to engage in strategies of resistance. The authors illustrate how power influences relations between staff nurses and managers and provide a critical analysis of the strategies of resistance that result in personal, relational, and critical empowerment among staff nurses. Through resistance, staff nurses engage in alternative discourses to counteract the prevailing neoliberal organizational and managerial discourses of efficiency and cost-effectiveness. PMID- 29509461 TI - Limitations of Nursing Education in Promoting Client-Centred Care and Self Management. PMID- 29509460 TI - uLearning for Nursing Professional Development: Paving the Road Ahead. PMID- 29509462 TI - Development and Validation of a Self-Care Ability Measure. AB - Self-care is an outcome of nursing care that is instrumental for promoting recovery and preventing complications following hospitalization. The Therapeutic Self-Care (TSC) measure was developed to assess self-care ability in acute-care settings. Its content was derived from a conceptualization of selfcare generated from an extensive literature review. Clinical experts considered the 13 items of the TSC measure as relevant, supporting its content validity. Findings of 1 study indicate that the items are internally consistent and loaded on 1 factor. The TSC scores correlate with relevant concepts. The TSC measure quantifies patients' perceived ability for self-care, operationalized in behaviours related to taking medications, recognizing and managing symptoms, carrying out activities of daily living, and managing changes in condition. It can be used to guide and evaluate nursing care. PMID- 29509463 TI - Computer Intervention: Illness Self-Management/Quality of Life of Rural Women. AB - The Women To Women project, a computer-based support and educational research intervention, was designed to help rural women better understand and manage their chronic illnesses. Its impact on psychosocial adaptation has been reported elsewhere. This article reports on the effect of a computer intervention on chronic illness self-management skills and quality of life. Using a parallel 2 group study design, the researchers randomized 309 middle-aged rural women with chronic conditions to either a computer-based intervention or a control group. They collected data on self-management of chronic illness and quality of life indicators at baseline and at the end of the intervention. Women in the intervention group reported significantly more self-efficacy in managing their chronic disease than those in the control group and the observed effect was of moderate size. Women in the intervention group also reported statistically significant gains in quality of life; effect sizes were small but consistent. Select chronic illness self-management skills and quality of life can be positively influenced by a well-designed computer intervention. PMID- 29509464 TI - Electronic Record Adoption and Use among Nurse Practitioners in British Columbia. AB - There has been a research focus on physician adoption of electronic medical records (EMRs). However, there has been less research into nurse practitioner (NP) use of EMRs. The authors present findings on the adoption and use of EMRs by NPs arising from a survey of the patterns of NP practices in the Canadian province of British Columbia. The research reveals a high rate of NP adoption of EMRs, with 82% of respondents indicating that they were using the technology. However, only 19% of NPs were using fully electronic records while 63% were using hybrid records, with only components of the electronic record being available. Respondents were found to be using several EMR features and functions, namely patient demographics, clinical notes, medication lists, laboratory results, and patient problems. NPs' high rate of EMR adoption suggests that there is much to be learned regarding the effect of eHealth strategies on EMR adoption. PMID- 29509465 TI - Designing Tailored Messages about Smoking and Breast Cancer: A Focus Group Study with Youth. AB - The purpose of this study was to design an approach to supporting the development of gender- and Aboriginal-specific messages regarding the link between tobacco exposure and breast cancer, drawing on youth perspectives. Focus groups were held with 18 girls (8 First Nations and Metis) and 25 boys (12 First Nations and Metis) to solicit advice in the design of messages. Transcribed data were analyzed for themes. Girls preferred messages that included the use of novel images, a personal story of breast cancer, and ways to avoid secondhand smoke. Boys endorsed messages that were "catchy" but not "cheesy" and had masculine themes. First Nations and Metis participants confirmed the use of Aboriginal symbols in messages as signalling their relevance to youth in their communities. The results can be used as a guide in developing tailored health promotion messages. Challenges in developing gender-appropriate messages for youth are described. PMID- 29509466 TI - Reflections of a Novice Institutional Ethnographer. AB - Institutional ethnography (IE) was developed by Dorothy E. Smith, a Canadian sociologist, in the 1980s. This method of inquiry helps to uncover how the everyday experiences of people in local settings are organized by and linked to the work of others. The purpose of this article is to provide newcomers to IE with insights gained from the first author's learning as a novice institutional ethnographer. These insights stem from her doctoral thesis, which examined how the promotion of physical activity is socially organized in long-term-care homes. The benefits of using IE are considered and the challenges encountered in trying to understand and use this method of inquiry are examined. Strategies used to overcome the challenges are discussed. PMID- 29509467 TI - Promoting Health Equity Research: Insights from a Canadian Initiative. AB - In 2002 the Canadian Institutes of Health Research launched a national initiative to promote health equity research reflecting the World Health Organization imperative of investment in health equity research. Funded researchers and teams have investigated health disparities faced by vulnerable populations, analyzed interactions of health determinants, and tested innovative interventions. Strategies for building research capacity have supported students, postdoctoral fellows, new investigators, and interdisciplinary research teams. Partnerships have been created with 10 national and 7 international organizations. Strategies used to secure and sustain this research initiative could be adapted to other contexts. Nurse scholars led the launch and have sustained the legacy of this national research initiative. Moreover, nurse researchers and research trainees, supported by the initiative, have contributed to the expansion and translation of the health equity knowledge base. PMID- 29509470 TI - The Mental Health of those who Serve Canada. PMID- 29509468 TI - Clinical Management of Multidrug-Resistant Tuberculosis in 16 European Countries. AB - RATIONALE: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower. OBJECTIVES: To document the management and treatment outcome in patients with MDR-TB in Europe. METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET). MEASUREMENTS AND MAIN RESULTS: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high incidence countries (24.1% vs. 14.6%). CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions. PMID- 29509469 TI - Do as we say or do as we Do? Examining the Hidden Curriculum in Nursing Education. PMID- 29509471 TI - University Students' Sexual Health Knowledge: A Scoping Literature Review. AB - Sexual health plays an important role in the well-being of university students. The literature shows that the majority of university undergraduates are sexually active and at high risk of contracting sexually transmitted infections (STIs); however, the breadth and degree of the literature on their sexual health knowledge is unclear. The purpose of this scoping review was to gain a deeper understanding of the state of research on the sexual health knowledge of university/college students globally. A 5-stage framework was used to guide the review and to characterize the literature on sexual health knowledge. Articles published in English between 2000 and 2014 were reviewed if they included university students as a population of interest and described the methods used to measure sexual health knowledge. Of the 2,386 articles retrieved, 91 met the criteria. The majority of the articles (n = 79) used a cross-sectional design to investigate students' knowledge about HIV/AIDS (n = 45), STIs (n = 23), HPV (n = 9), and contraception (n = 24). The review highlights gaps in the literature and in findings relating to the research dominance of various geographic locations, common research designs, the wide range of measurement tools used, and the variety of sexual health knowledge outcomes of interest. The review provides a useful description of the literature on sexual health knowledge among university/college students and some recommendations for moving the field forward. PMID- 29509472 TI - Evaluating the Effectiveness of a Nurse Practitioner-Led Outreach Program for Long-Term-Care Homes. AB - An observational prospective cohort study was conducted on 1,353 observations from a convenience sample of 311 long-term-care (LTC) residents to evaluate the effectiveness of a nurse practitioner-led outreach program on the health outcomes, emergency department (ED) transfers, and hospital admissions of LTC residents. The results show that ED transfers by the NPs were 27% less likely to be non-urgent than transfers made by MDs (OR = .73; 95% CI .54-.97) and that ED transfers by the NPs were 3.23 times more likely to be admitted to hospital than transfers by MDs (OR = 3.23; 95% CI 1.17-8.90). These findings highlight the potential benefits of the NP-led outreach program for LTC residents and for the health-care system. PMID- 29509473 TI - Social Exclusion and Health: The Development of Nursing Knowledge. AB - The concept of social exclusion has been proposed as an important social determinant of health. However, use of the concept in health and health promotion research is in its infancy. In nursing discourse, in particular, exploration and application of the concept of social exclusion is minimal. The purpose of this article is to explore the relevance of the concept of social exclusion in the development of nursing knowledge. Current knowledge regarding social exclusion is examined and its use in health-related research is explored. To conclude, a conceptualization of social exclusion for the development of nursing knowledge is proposed. PMID- 29509474 TI - Reflections on a Canadian Online Telehealth Course: Going Forward with Telehealth Nursing. PMID- 29509475 TI - Developing a Web Site: A Strategy for Employment Integration of Internationally Educated Nurses. AB - In Canada and elsewhere, the case for hiring internationally educated nurses (IENs) has not been adequately made and guidance for employers is lacking. The Web site Internationally Educated Nurses: An Employer's Guide, launched in 2012, is intended to provide healthcare employers in Ontario with comprehensive information on the hiring and integration of IENs. An evaluation framework and mixed methods design were used to determine the usability of the site in relation to its goal. Convenience sampling was employed to select participants representing specified users (i.e., healthcare employers). Overall evaluation of usability was positive. Participants indicated that it raised their awareness of the advantages of hiring and integrating IENs to address shortages, increase workforce diversity, and provide culturally competent care. Future projects should focus on collaboration with employers to increase the uptake of IENs. PMID- 29509476 TI - Attrition in Smoking Cessation Intervention Studies: A Systematic Review. AB - Withdrawal of participants from intervention studies has dire methodological and clinical consequences. Attrition rates in smoking cessation studies have been found to be particularly high. Identifying factors that contribute to attrition may inform strategies to address the problem and prevent its consequences. This systematic review had 2 objectives: to report attrition rates, and to identify factors that influence attrition of adult smokers participating in smoking cessation intervention studies. Inclusion criteria were (1) published between 1980 and 2015; (2) experimental or quasi-experimental design; (3) pharmacological, educational, or behavioural intervention; (4) target population of adult smokers; (5) examination of attrition rate; and (6) exploration of factors associated with attrition and/or of reasons given by participants for withdrawing. These criteria were met by 10 studies. Attrition rates ranged from 10.8% to 77%. A small number of demographic, clinical, behavioural, health, health-related beliefs, and logistical factors were related to attrition. The report of high attrition rates underlines the importance of incorporating strategies to minimize attrition in smoking cessation studies. Strategies to reduce attrition are proposed. PMID- 29509477 TI - Better Care and Better Value for Canadians: A Review of RCT Studies of Nurse Interventions. AB - This review is focused on the effectiveness of nursing interventions for patient outcomes and healthcare costs. It was guided by ecological and economic evaluation frameworks. Restricting the first-tier search of over 4,000 articles to randomized controlled trials (RCTs) yielded 203 studies and 9 additional trials that used identical methods of cost evaluation. Of 212 RCTs, 37 met the eligibility criteria. Of the 37 articles, 29 came from the literature search and 8 came from the first author's research unit, which used identical methods of economic evaluation. Of the first 29 studies, 26 found that nurse interventions were more or equally effective and less or equally costly compared to usual care, as was true of 7 of the 9 RCTs with comprehensive economic evaluations. It is effective and efficient to deploy specialty-trained nurses to lead teams of professionals, including physicians, assembled to address complex patient needs. A nurse-led model of proactive and supplemental care for the chronically ill, versus the on-demand, physician-led model now in place, would be more or equally effective and less or equally costly. PMID- 29509478 TI - Navigating Relationships: Nursing Teamwork in the Care of Older Adults. AB - As people age there is increasing incidence of chronic illness and atypical presentations of acute illness. Although research suggests that the care of older adults is improved when there is collaboration between nursing staff and other health professionals, there is no clear understanding of how this might occur. This qualitative study describes how how nursing staff work in teams to provide and manage the care of hospitalized older adults. Navigating relationships offers valuable insights into the perspectives of nursing staff working in teams with one another, with their operational leaders, and with other professionals. The language they used contributed to their perceptions of being undervalued within interprofessional teams, which in turn undermined their efforts to navigate relationships. Care for hospitalized older adults would be advanced through the provision of opportunities for interprofessional teams to learn the perspectives of nursing staff. PMID- 29509479 TI - Canadian Nurse Graduates considering Migrating Abroad for Work: Are Their Expectations Being Met in Canada? AB - An RN credential has been called "a ticket to the world." Canadian RNs have been active participants in migration, especially to the United States. In an increasingly globally oriented world, Canadian nurse graduates have many employment options. The purpose of this study was to explore the job values and expectations of baccalaureate nursing students who indicated they were considering migrating for work abroad for their first job and to explore their confidence in having these values met in Canada compared to another country. This was a quantitative study guided by the Value-Expectancy Framework. Data were collected through a Web-based self-report survey and analyzed using descriptive statistics for sample characteristics and t tests for comparison. Nonprobability convenience sampling of graduating baccalaureate nursing students from a Canadian border region was used. Of 130 respondents, 92 (70.8%) indicated that they were considering migrating from Canada for work. Respondents believed that working abroad would provide more adventure, full-time work, professional development, appropriate staffing, flexible scheduling, and freedom to choose their preferred job sector/specialty. The authors conclude that there is a need to study nursing graduates' labour mobility both within and outside of Canada and the factors that influence their decision-making and to address the factors that encourage them to leave Canada. Human resource planning will become increasingly important given the predicted nursing shortage and changes to nurse licensure in Canada with the potential to influence migration. PMID- 29509480 TI - A Precarious Journey: Nurses from the Philippines Seeking RN Licensure and Employment in Canada. AB - Increasingly, internationally educated nurses (IENs) from developing countries are seeking RN licensure and employment in Canada. Despite efforts to support their integration into the nursing workforce, a significant number never achieve integration. To explore this phenomenon, the authors use ethnographic methods informed by postcolonial feminism and relational ethical theory to examine the experiences of nurses educated in the Philippines as they seek Canadian RN licensure and employment. The study's focus on a journey that begins in the Philippines and continues in Canada adds an important temporal dimension located in tensions within and between the contexts of regulatory and immigration policies. The findings illuminate the dual challenge of being a new arrival in the country and being an IEN pursuing the Canadian RN credential. Additionally, the findings deepen our understanding of the dominant political, ideological, and social values, both in the Philippines and in Canada, that shape this experience. PMID- 29509482 TI - Patient- and Family-Centred Care: Some Solutions. PMID- 29509483 TI - Shadows and Sunshine: What Metaphors Reveal about Aging with HIV. AB - Using narrative inquiry, the researchers interviewed 5 older adults on 5 occasions over a period of 3.5 years about their experiences of aging with HIV. The participants' stories were analyzed for metaphors. Individual metaphors reveal a complex, unique struggle: living between tensions of uncertainty and hope, facing death and living in the moment, and suffering hurt amidst the joys of evolving identity. The tensions are fluid, although time and life experience facilitate a shift towards reconciliation. An overarching metaphor across this group of survivors is shadows and sunshine: to survive and live in a fragile state, balancing multiple shadows such as stigma and side effects with joyful experiences of support and belonging. The findings suggest that when nurses invite stories of life experience and listen for language used, they build compassion and gain understanding of what support is most needed to honour the personhood of older adults who are HIV-positive. PMID- 29509481 TI - Impacts of a Support Intervention for Zimbabwean and Sudanese Refugee Parents: "I Am Not Alone". AB - Knowledge about the beneficial effects of social support has not been used to systematically develop and evaluate interventions to help refugee new parents cope. The purpose of this study was to design and evaluate a social support intervention for refugee new parents. A multi-method research design was used and participatory research strategies were employed. Qualitative and quantitative measures were used to understand experiences of participants and to assess the perceived psychosocial and health-related outcomes of the intervention. Mentored support groups, matched by gender and ethnicity, met biweekly over 7 months. The participants were 48 Sudanese and 37 Zimbabwean refugee parents in 2 Canadian provinces. Increases were found in informational support, spousal support, community engagement, coping, and support-seeking. Decreases were found in parenting stress, loneliness, and isolation. The authors conclude that there is a need for culturally appropriate nursing practices and programs for refugee new parents from diverse cultures. PMID- 29509484 TI - A Scoping Review of the Literature on Internationally Educated Nurses in Canada: Mapping a Research Agenda. AB - The purpose of this scoping review was to map key themes in the Canadian literature on the professional integration of internationally educated nurses (IENs), identify the types and sources of and gaps in evidence, and offer recommendations for research. The work was guided by a 6-step methodological framework for scoping reviews. The search and selection of academic and grey literature for the period 2000-13 resulted in a sample of 157 papers for full text screening. Themes derived from the literature reflect stages of IENs' professional integration: pre-immigration and early arrival, professional recertification, workforce integration, and workplace integration. Data were extracted, coded, and collated using electronic charts. Numerical and qualitative thematic summaries were used to analyze the data. Recommendations for research are as follows: create data systems to track IEN immigration and integration; determine the effectiveness of programs and policies for IENs; and examine the influence of language proficiency on professional recertification, workplace integration, and patient safety. PMID- 29509485 TI - Fitting Square Pegs into round Holes: Doing Qualitative Nursing Research in a Quantitative World. AB - The authors, as doctoral candidates and registered nurses, took on a qualitative research project investigating nursing practice in a research-intensive organization. Their aims were to explore and describe how nurses in the ambulatory care setting assist patients and families, including how nursing practice was carried out, constraints to practice, and the influence of the interprofessional milieu. Their first finding, in part because of the qualitative research design used, concerned the potential impact of the organizational ethics review process on the project. The authors discuss how the language, definition of risk, and notion of informed consent articulated in the organizational review process influenced both the research timeline and (potentially) the study itself. While not dismissing the value of ethics review, they explore the tension of overlaying generic criteria for quantitative research, specifically randomized controlled trials, on nursing research from other traditions. PMID- 29509486 TI - An Integrative Review of the Literature on Pain Management Barriers: Implications for the Canadian Clinical Context. AB - Despite decades of pain research, substandard pain management continues to be distressingly prevalent across health-care settings. This integrative literature review analyzes and synthesizes barriers to effective pain management and identifies areas for future investigation in a Canadian context. Three sets of key barriers were identified through thematic analysis of 24 original research studies published in the period 2003-13: patient, professional, and organizational. These barriers rarely occurred in isolation, with many studies reporting examples in all three categories. This suggests that interventions need to reflect the multifactorial nature of pain management. Reframing pain education as a public health initiative could lead to sustainable improvement, as could the strengthening of partnerships between patients and health-care providers. There are tremendous opportunities for the advanced practice nurse to take a lead in pain management. The delivery of high-quality care that encompasses effective pain management strategies must be a priority for nursing. Research approaches, such as pragmatic mixed methods, that offer contextual understanding of how pain is managed are suggested. PMID- 29509487 TI - Male RNs: Work Factors Influencing Job Satisfaction and Intention to Stay in the Profession. AB - Males represent approximately 6.8% of registered nurses in Canada and consequently constitute an untapped health workforce resource. The authors investigated environmental work factors in the acute-care setting and their influence on male RNs' job satisfaction and intention to stay in the profession. They conducted a cross-sectional study of male RNs employed in acute-care settings in the province of Ontario. Correlations and multiple regression analyses were used to examine career satisfaction and intentions. Nurses who were most satisfied with their career valued extrinsic rewards (pay, vacation, and benefits), control and responsibility, and opportunities for professional development; those who were least satisfied and voiced their intention to leave the profession tended to work part time, experience gender mistreatment, and be dissatisfied with extrinsic awards, scheduling, and organizational support. A unique finding of this study relates to the significant predictive relationship between gender mistreatment and males' intention to leave. PMID- 29509488 TI - Seeking Connectivity in Nurses' Work Environments: Advancing Nurse Empowerment Theory. AB - The purpose of this study was to investigate how staff nurses and their managers exercise power in a hospital setting in order to better understand what fosters or constrains staff nurses' empowerment and to extend nurse empowerment theory. Power is integral to empowerment, and attention to the challenges in nurses' work environment and nurse outcomes by administrators, researchers, and policy-makers has created an imperative to advance a theoretical understanding of power in the nurse-manager relationship. A sample of 26 staff nurses on 3 units of a tertiary hospital in western Canada were observed and interviewed about how the manager affected their ability to do their work. Grounded theory methodology was used. The process of seeking connectivity was the basic social process, indicating that the manager plays a critical role in the work environment and nurses need the manager to share power with them in the provision of safe, quality patient care. PMID- 29509489 TI - Correlations between intravoxel incoherent motion diffusion-weighted MR imaging parameters and 18F-FDG PET/CT metabolic parameters in patients with vertebral bone metastases: initial experience. AB - OBJECTIVE: To investigate the relationship between intravoxel incoherent motion (IVIM) diffusion-weighted MRI (DW MRI) parameters and 18F-fluodeoxyglucose (FDG) (PET/CT) metabolic parameters in patients with vertebral bone metastases. METHODS: 19 patients with vertebral bone metastases were retrospectively included in this institutional review board-approved study. All patients underwent IVIM DW MRI and 18F-FDG PET/CT before treatment. The IVIM parameters [molecular diffusion coefficient (D), perfusion fraction (f), and perfusion-related D (D*)] and apparent diffusion coefficient were acquired using 11 b-values (0, 10, 15, 20, 25, 50, 80, 120, 200, 300, and 800 s mm-2). Maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume, and total lesion glycolysis derived from 18F-FDG PET/CT were calculated using thresholds of 3.0 SUV. The associations among parameters were evaluated by Spearman's correlation analysis. RESULTS: A total of 19 patients and 41 regions of interest were included in this study. The IVIM parameter f was positively correlated with the metabolic parameters SUVmean and SUVmax [rho = 0.499 (p < 0.01) and rho = 0.413 (p < 0.01), respectively]. There was a weak positive correlation between D* and SUVmean (rho = 0.321, p = 0.041). CONCLUSION: IVIM perfusion-related parameters, especially f, were correlated with 18F-FDG PET/CT metabolic parameters in patients with vertebral bone metastases. IVIM DW-MRI, used to evaluate metabolic activity, appears to have diagnostic potential for bone metastasis and may also have utility in monitoring the post-treatment response. Advances in knowledge: The use of IVIM for vertebral bone metastasis is demonstrated. f may be more suitable to reflect the metabolic activity and may facilitate another diagnostic potential for monitoring the posttreatment response. PMID- 29509490 TI - Safety of Prasugrel loading in ruptured blister like aneurysm treated with a Pipeline device. AB - OBJECTIVE: Blister like aneurysm (BLA) is extremely challenging to treat; endoluminal reconstruction has emerged as the most promising treatment method. When to treat after the ictus, the timing of administration of antiplatelet and causal relationship between platelet function testing results and thrombo embolism is unclear. We theorized that Prasugrel with a lower incidence of resistance may be a safe suitable alternative to clopidogrel in patients treated with a flow diverter (FD). METHODS: Prospectively collected data from consecutive patients treated for a ruptured blister with an FD was reviewed. Device deployment was timed to be at 2 h following Prasugrel loading. Thrombo-embolic and hemorrhagic complications, and occlusion rates were documented. RESULTS: Nine patients were included. Most were females (55%); the median age was 55 (43, 65). The median Fischer grade was 3 (2, 4). A single pipeline device was deployed in all within 24 h of admission; the median time from ictus to device deployment was 4 days (2, 30). There were no thrombo-embolic or hemorrhagic complication. Complete occlusion was noted in 89% (n = 9). CONCLUSION: Prasugrel loading timed 2 h prior to stent delivery did not increase thrombo-embolic or hemorrhagic complications. Single stent that is well apposed against the wall appears to be an effective treatment strategy to treat BLA. Advances in knowledge: Treatment of acutely ruptured BLA with a single pipeline device deployed at 2 h after Prasugrel loading appears to be safe. PMID- 29509495 TI - Inflammatory and apoptotic signalling pathways and concussion severity: a genetic association study. AB - The objective was to investigate the relationship between IL-1B rs16944, IL-6 rs1800795, and CASP8 rs3834129 genetic polymorphisms and concussion severity. Rugby players from high school, senior amateur, and professional teams completed a concussion severity questionnaire and donated a DNA sample. Participants (n = 163) were split into symptom severity groups around the median number and duration of symptoms. The frequency of participants with high symptom counts (more than five symptoms) increased across the IL-1B (C/C: 35%; C/T: 51%; T/T: 56%; P = 0.047) and the IL-6 (C/C: 31%; C/G: 44%; G/G: 58%; P = 0.027) genotypes. The C-C inferred interleukin allele construct frequency, created from combining the IL-1B and IL-6 genotype data, was lower in participants reporting a high symptom count (18%), compared to those with a low symptom count (fewer than six symptoms, 36%, P = 0.002). Similarly, the C-C inferred interleukin allele construct frequency was lower in those reporting prolonged symptom duration (more than one week, 16%), as opposed to short symptom duration (less than one week, 34%, P = 0.015). This study provides evidence of novel inflammatory pathway genetic associations with concussion severity, which supports the hypothesis implicating neuroinflammation in the development of concussion symptoms. PMID- 29509496 TI - Rogue Publishing, Journal Business Models, and the Future of the Middle Tier. PMID- 29509497 TI - The Enduring Challenge of Cultural Safety in Nursing. PMID- 29509498 TI - Knowledge Transfer and Dissemination of Advanced Practice Nursing Information and Research to Acute-Care Administrators. AB - The objective of this study was to ascertain the information needs and knowledge dissemination preferences of acute-care administrators with respect to advanced practice nursing (APN). Supportive leadership is imperative for the success of APN roles and administrators need up-to-date research evidence and information, but it is unclear what the information needs of administrators are and how they prefer to receive the information. A survey tool was developed from the literature and from the findings of a qualitative study with acute-care leaders. Of 107 surveys distributed to nursing administrators in 2 teaching hospitals, 79 (73.8%) were returned. Just over half of respondents reported wanting APN information related to model of care and patient and systems outcomes of APN care; the majority expressed a preference for electronic transmission of the information. Researchers need multiple strategies for distributing context specific APN evidence and information to nursing administrators. PMID- 29509491 TI - Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. AB - RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 * 10-7) and suggestive (P < 7.06 * 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and beta-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations. PMID- 29509499 TI - Cognitive Load Theory: Implications for Nursing Education and Research. AB - This article provides an overview of cognitive load theory (CLT) and explores applications of CLT to health profession and nursing education research, particularly for multimedia and simulation-based applications. The article first reviews the 3 components of cognitive load: intrinsic, extraneous, and germane. It then discusses strategies for manipulating cognitive load variables to enhance instruction. Examples of how CLT variables can be modulated during instruction are provided. Lastly, the article discusses current applications of CLT to health profession and nursing education research and presents future research directions, focusing on the areas of multimedia and simulation-based learning. PMID- 29509500 TI - Exploring the Impact of Prostate Cancer Radiation Treatment on Functions, Bother, and Well-Being. AB - Though many studies have explored the effects of radiation therapy on urinary, sexual, and bowel function and/or bother, few have focused on symptom experiences from diagnosis through the first year following completion of radiation therapy. The purpose of this study was to compare the effect of 3 types of radiation treatment on functions, bother, and well-being in men with prostate cancer at 1, 6, and 12 months after completion of treatment. A repeated measures survey (N = 73) found that none of the function, bother, emotional, social, or functional well-being scores were significantly different among the 3 groups. However, within-subjects-only repeated measures ANCOVA suggested that emotional well-being and social well-being are different over time. The findings show that clinical treatment of prostate cancer has an impact on functions, bother, and well-being of patients. Thus, it is important that nurses and other healthcare providers listen to what patients are saying before, during, and after treatment. PMID- 29509501 TI - Social Marginalization and Internal Exclusion: Gay Men's Understandings and Experiences of Community. AB - A total of 27 gay and bisexual men were interviewed about how they perceived the criminal prosecution of persons living with HIV who do not disclose their HIV status. The stories that emerged from the interviews raise questions about the nature of the gay community. The findings centre on the participants' descriptions of (1) the heterosexual meta-culture, (2) the locales of gay life, and (3) unsupportive elements in the gay community. Analysis of the interview data situates the gay community as a place of both inclusion and exclusion and as a heterogeneous environment. PMID- 29509502 TI - Acute Coronary Syndrome Pain and Anxiety in a Rural Emergency Department: Patient and Nurse Perspectives. AB - Rural patients can wait up to 32 hours for transfer to cardiac catheterization (CATH) for events related to acute coronary syndrome (ACS). Pain arising from myocardial ischemia can be severe and anxiety-provoking. Pain management during this time should be optimized in order to preserve vulnerable myocardial muscle. This qualitative focus group study solicited the perspectives of ACS patients and emergency staff nurses on the rural patient experience of cardiac pain and anxiety and priorities and barriers to optimal assessment and management of ACS pain. Patients described ACS pain as moderate to severe, with pain in the chest, arms, back, shoulders, and jaw. Pain was well assessed and managed upon arrival in the emergency department but anxiety was not routinely assessed or treated. Barriers identified were poor management of patients with different acuity levels, high patient volumes, and assumptions regarding patients' communication about pain. Research related to ACS pain and anxiety management in the rural context is recommended. PMID- 29509503 TI - Platelets and Tuberculosis: Small Cells, Not So Innocent Bystanders. PMID- 29509504 TI - A cost-minimization analysis of dalbavancin compared to conventional therapy for the outpatient treatment of acute bacterial skin and skin-structure infections. AB - INTRODUCTION: Acute bacterial skin and skin-structure infections (ABSSSI) are common infectious diseases (ID) that often require intravenous (IV) antibiotics. Dalbavancin is a novel lipoglycopeptide antibiotic administered once that is FDA approved for the treatment of ABSSSI. No literature is available for real-world cost-comparability relative to conventional therapy. METHODS: This retrospective chart review examined adults diagnosed with ABSSSI and treated with IV antibiotics at an outpatient ID clinic after hospital discharge from January 2015 to August 2016. Patients received either dalbavancin or conventional therapy. In hospital baseline demographics as well as outpatient clinical variables and outcomes were assessed. The primary outcome was the total ID-related cost of care per patient. A Monte Carlo probalistic sensitivity analysis was conducted. RESULTS: One hundred and fifty-eight patients were included: 64 received dalbavancin and 94 received conventional therapy. The total ID-related cost of care per patient was greater with dalbavancin (mean $4,561) vs conventional (mean $1,668), p < 0.01. In the subset of patients treated with daptomycin, the total ID-related cost (mean $5,218) was comparable to dalbavancin (mean $4,561). CONCLUSIONS: Dalbavancin was more costly than conventional therapy for the outpatient treatment of ABSSSI. This greater overall cost was likely driven by the higher acquisition cost of dalbavancin. Dalbavancin may be comparable to the daily use of daptomycin for ABSSSI. PMID- 29509506 TI - The identity, role, setting, and future of chiropractic practice: a survey of Australian and New Zealand chiropractic students. AB - OBJECTIVE:: To evaluate Australian and New Zealand chiropractic students' opinions regarding the identity, role setting, and future of chiropractic practice. METHODS:: An online, cross-sectional survey was administered to chiropractic students in all chiropractic programs in Australia and New Zealand. The survey explored student viewpoints about the identity, role/scope, setting, and future of chiropractic practice as it relates to chiropractic education and health promotion. Associations between the number of years in the program, highest degree preceding chiropractic education, institution, and opinion summary scores were evaluated by multivariate analysis of variance tests. RESULTS:: A total of 347 chiropractic students participated in the study. For identity, most students (51.3%) hold strongly to the traditional chiropractic theory but also agree (94.5%) it is important that chiropractors are educated in evidence-based practice. The main predictor of student viewpoints was a student's chiropractic institution (Pillai's trace =.638, F[16, 1368] = 16.237, p < .001). Chiropractic institution explained over 50% of the variance around student opinions about role/scope of practice and approximately 25% for identity and future practice. CONCLUSIONS:: Chiropractic students in Australia and New Zealand seem to hold both traditional and mainstream viewpoints toward chiropractic practice. However, students from different chiropractic institutions have divergent opinions about the identity, role, setting, and future of chiropractic practice, which is most strongly predicted by the institution. Chiropractic education may be a potential determinant of chiropractic professional identity, raising concerns about heterogeneity between chiropractic schools. PMID- 29509507 TI - Reply to Vincent and De Backer: We Do Not Appreciate SALT. PMID- 29509509 TI - International Practice Variation in Weaning Critically Ill Adults from Invasive Mechanical Ventilation. AB - RATIONALE: Randomized trials and meta-analyses have informed several aspects of weaning. Results are rarely replicated in practice, as evidence is applied in intensive care units that differ from the settings in which it was generated. OBJECTIVES: We aimed to: 1) describe weaning practice variation (identifying weaning candidates, conducting spontaneous breathing trials, using ventilator modes, and other aspects of care during weaning); 2) characterize regional differences in weaning practices; and 3) identify factors associated with practice variation. METHODS: We conducted a cross-sectional, self-administered, international postal survey of adult intensivist members of regional critical care societies from six geographic regions, including Canada, India, the United Kingdom, Europe, Australia/New Zealand, and the United States. We worked with societies to randomly select potential respondents from membership lists and administer questionnaires with the goal of obtaining 200 responses per region. RESULTS: We analyzed 1,144 questionnaires (Canada, 156; India, 136; United Kingdom, 219; Europe, 260; Australia/New Zealand, 196; United States, 177). Across regions, most respondents screened patients once daily to identify spontaneous breathing trials candidates (regional range, 70.0%-95.6%) and less often screened twice daily (range, 12.2%-33.1%) or more than twice daily (range, 1.6%-18.2%). To wean patients, most respondents used pressure support alone (range, 31.0%-71.7%) or with spontaneous breathing trials (range, 35.7%-68.1%). To conduct spontaneous breathing trials, respondents predominantly used pressure support with positive end-expiratory pressure (range, 56.5%-72.3%) and T-piece (8.9%-59.5%). Across regions, we found important variation in screening frequency, spontaneous breathing trials techniques; ventilator modes, written directives to guide care, noninvasive ventilation; and the roles played by available personnel in various aspects of weaning. CONCLUSIONS: Our findings document the presence and extent of practice variation in ventilator weaning on an international scale, and highlight the multidisciplinary and collaborative nature of weaning. PMID- 29509505 TI - Trauma in the elderly patient. AB - Major Trauma Centres and Emergency Departments are treating an increasing number of elderly trauma patients in the UK. Elderly patients, defined as those over the age of 65 years, are more susceptible to injury from lesser mechanisms of trauma than younger adults. The number of elderly trauma cases is rising yearly, accounting for >25% of all major trauma nationally. The elderly have different physiological reserves and a different response to trauma due to premorbid frailty, co-existing conditions and prescribed medication. These factors need to be appreciated in trauma triaging, radiological assessment and clinical management. A lower threshold for trauma-call activation is recommended, including a lower threshold for advanced imaging. We will review general principles of trauma in the elderly, outline injury patterns in this age group and illustrate the radiological features per anatomical site, from head to pelvis and the extremities. We advocate using contrast-enhanced computed tomography as the primary diagnostic imaging modality as concern about intravenous contrast agent-induced nephropathy is relatively minor. Prompt investigation and diagnosis leads to timely appropriate treatment, therefore the radiologist can discerningly improve morbidity and mortality in this vulnerable group. PMID- 29509511 TI - Deletion of diacylglycerol kinase epsilon confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes. AB - Lipid metabolism is closely involved with signal transduction and energy homeostasis. Excess calorie intake causes abnormal lipid metabolism, promoting obesity and insulin resistance. Diacylglycerol (DG) represents not only a lipidic second messenger but also an intermediate metabolite for triglyceride metabolism in the endoplasmic reticulum (ER). However, it remains undetermined how the roles of DG in signaling and energy homeostasis is regulated within the cell. Of DG kinases (DGKs), which are enzymes that phosphorylate DG, DGKepsilon resides in the ER. This study examined how DGKepsilon is implicated in signal transduction and lipid homeostasis. DGKepsilon-deficient mice were fed a high-fat diet (HFD) for 40 d. We observed that DGKepsilon deficiency promotes fat accumulation in adipocytes and subsequently promotes insulin resistance in mice fed an HFD. This abnormal fat metabolism is mediated by down-regulation of lipolytic activities, such as adipose triglyceride lipase and hormone-sensitive lipase. In addition, activation of DG-sensitive PKC leads to insulin resistance in adipose tissue, which may be caused by delayed metabolism of DG. Our data suggest that DGKepsilon links the second messenger signaling system to energy homeostasis in adipocytes and that its deficiency results in abnormal lipid metabolism such as obesity and insulin resistance.-Nakano, T., Seino, K., Wakabayashi, I., Stafforini, D. M., Topham, M. K., Goto, K. Deletion of diacylglycerol kinase epsilon confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes. PMID- 29509510 TI - Epicutaneous administration of the pattern recognition receptor agonist polyinosinic-polycytidylic acid activates the MDA5/MAVS pathway in Langerhans cells. AB - Together with keratinocytes (KCs) and the dense network of Langerhans cells (LCs), the epidermis is an ideal portal for vaccine delivery. Pattern recognition receptor agonists, in particular polyinosinic-polycytidylic acid [p(I:C)], are promising adjuvant candidates for therapeutic vaccination to generate protective T-cell immunity. Here we established an ex vivo skin explant model to study the expression and activation of double-stranded RNA (dsRNA)-sensing pattern recognition receptors in LCs and KCs in human skin. Whereas KCs expressed all known dsRNA sensing receptors at a constitutive and inducible level, LCs exclusively expressed melanoma differentiation-associated protein 5 (MDA5) in untreated skin and freshly isolated cells. Comparative assessments of downstream signaling pathways induced by p(I:C) revealed distinct mitochondrial antiviral signaling protein, IFN-regulatory factor 3, and NF-kappaB activation in LCs and KCs. Consequently, p(I:C) treatment of LCs significantly induced IFN-alpha and IFN-beta mRNA expression, while in KCs an up-regulation of IFN-beta and TNF-alpha mRNA was detectable. Stimulation of LCs with specific ligands revealed that not the TLR3- but only the MDA5-specific ligand induced IFN-alpha2, IFN-beta, and TNF alpha cytokines, but no IL-6 and -8. In KCs, both ligands induced production of high IL-6 and IL-8 levels, and low IFN-alpha2 and IFN-beta levels, indicating that different dsRNA-sensing receptors and/or downstream signaling pathways are activated in both cell types. Our data suggest that MDA5 may be an attractive adjuvant target for epicutaneous delivery of therapeutic vaccines with the goal to target LCs.-Tajpara, P., Schuster, C., Schon, E., Kienzl, P., Vierhapper, M., Mildner, M., Elbe-Burger, A. Epicutaneous administration of the pattern recognition receptor agonist polyinosinic-polycytidylic acid activates the MDA5/MAVS pathway in Langerhans cells. PMID- 29509512 TI - M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluA1 subunit. AB - M1 muscarinic acetylcholine receptors (M1 mAChRs) are the most abundant muscarinic receptors in the hippocampus and have been shown to have procognitive effects. AMPA receptors (AMPARs), an important subtype of ionotropic glutamate receptors, are key components in neurocognitive networks. However, the role of AMPARs in procognitive effects of M1 mAChRs and how M1 mAChRs affect the function of AMPARs remain poorly understood. Here, we found that basal expression of GluA1, a subunit of AMPARs, and its phosphorylation at Ser845 were maintained by M1 mAChR activity. Activation of M1 mAChRs promoted membrane insertion of GluA1, especially to postsynaptic densities. Impairment of hippocampus-dependent learning and memory by antagonism of M1 mAChRs paralleled the reduction of GluA1 expression, and improvement of learning and memory by activation of M1 mAChRs was accompanied by the synaptic insertion of GluA1 and its increased phosphorylation at Ser845. Furthermore, abrogation of phosphorylation of Ser845 residue of GluA1 ablated M1 mAChR-mediated improvement of learning and memory. Taken together, these results show a functional correlation of M1 mAChRs and GluA1 and the essential role of GluA1 in M1 mAChR-mediated cognitive improvement.-Zhao, L.-X., Ge, Y.-H., Xiong, C.-H., Tang, L., Yan, Y.-H., Law, P.-Y., Qiu, Y., Chen, H.-Z. M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluA1 subunit. PMID- 29509513 TI - CRISPR/Cas9-mediated 2-sgRNA cleavage facilitates pseudorabies virus editing. AB - Several groups have used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) for DNA virus editing. In most cases, one single-guide RNA (sgRNA) is used, which produces inconsistencies in gene editing. In this study, we used a swine herpesvirus, pseudorabies virus, as a model to systematically explore the application of CRISPR/Cas9 in DNA virus editing. In our current report, we demonstrated that cotransfection of 2 sgRNAs and a viral genome resulted in significantly better knockout efficiency than the transfection-infection-based approach. This method could result in 100% knockout of <=3500 bp of viral nonessential large fragments. Furthermore, knockin efficiency was significantly improved by using 2 sgRNAs and was also correlated with the number of background viruses. We also demonstrated that the background viruses were all 2-sgRNA-mediated knockout mutants. Finally, this study demonstrated that the efficacy of gene knockin is determined by the replicative kinetics of background viruses. We propose that CRISPR/Cas9 coupled with 2 sgRNAs creates a powerful tool for DNA virus editing and offers great potential for future applications.-Tang, Y.-D., Guo, J.-C., Wang, T.-Y., Zhao, K., Liu, J.-T., Gao, J.-C., Tian, Z.-J., An, T.-Q., Cai, X.-H. CRISPR/Cas9-mediated 2-sgRNA cleavage facilitates pseudorabies virus editing. PMID- 29509515 TI - Literature Review for Office-Based Anesthesia. PMID- 29509514 TI - Anesthetic Considerations for Patients on Antidepressant Therapy - Part II. AB - Millions of patients take antidepressant medications in the United States for the treatment of depression or anxiety disorders. Some antidepressants are prescribed off-label to treat problems such as chronic pain, low energy, and menstrual symptoms. Antidepressants are a broad and expansive group of medications, but the more common drug classes include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. A miscellaneous or "atypical" category covers other agents. Some herbal supplements that claim to have antidepressant activity will also be discussed. Part I of this series reviewed antidepressant pharmacology, adverse effects, and drug interactions with adrenergic agonists. In part II, drug-drug interactions with sedation and general anesthetics, bleeding effects, and serotonin syndrome will be discussed. PMID- 29509516 TI - A Comparative Study of Oral Analgesics for Postoperative Pain After Minor Oral Surgery. AB - We compared the effects of preoperative administration of diclofenac sodium, celecoxib, and acetaminophen on postoperative pain in patients undergoing minor oral surgery under general anesthesia. One hundred twenty-eight patients were randomly divided into 4 groups preoperatively treated with diclofenac sodium 50 mg, celecoxib 400 mg, acetaminophen 1000 mg, or placebo. Postoperative pain was managed using intravenous patient-controlled infusion of fentanyl. Assessments included levels of postoperative pain by using visual analog scale (VAS) scores at 4, 5, and 6 hours after administration of the test drug; consumption of fentanyl up to each time point; and time to first requirement for fentanyl. Our study demonstrated that, for diclofenac sodium and celecoxib in comparison with placebo, there were significantly lower VAS scores at 4, 5, and 6 hours after oral administration of the study drug; a longer period of time to first requirement for fentanyl after surgery; and less consumption of postoperative fentanyl. A similar analgesic effect versus placebo was noted for acetaminophen but only at the 5- and 6-hour time points. In contrast, no significant differences in VAS scores at 4 hours after administration or time to first requirement for fentanyl were observed between acetaminophen and placebo. Furthermore, no significant differences in measurements were observed between the study drugs at any time point. These findings suggest that oral administration of celecoxib 400 mg is suitable for controlling postoperative pain, and as effective as diclofenac sodium 50 mg. Acetaminophen 1000 mg also exerts analgesic effect with slower onset for postoperative pain. PMID- 29509517 TI - Airway Management for a Pediatric Patient With a Tracheal Bronchus. AB - Tracheal bronchus is an ectopic bronchus almost arising from the right side of the tracheal wall above the carina. The incidence of a tracheal bronchus is reported as 0.1 to 3%. We experienced a patient with tracheal bronchus that was incidentally found at induction of anesthesia. Endotracheal intubation in a patient with tracheal bronchus might cause obstruction of the tracheal bronchus, although in this case, ventilation was not impaired. PMID- 29509518 TI - Volume of Anesthetic Agents and IANB Success: A Systematic Review. AB - The aim of this study was to provide an evidence-based answer to the question: "Is 3.6-mL volume of an anesthetic agent more effective than 1.8-mL volume in providing anesthesia for mandibular molars?" Following formulation of research question and keyword selection, a comprehensive search of the following databases was conducted: Cochrane library, PubMed, Scopus, Google Scholar, ProQuest, and Clinicaltrials.gov. Three-phase eligibility appraisal and quality assessment of the studies were carried out by 2 independent reviewers. To reduce clinical heterogeneity, the included studies were divided into 2 groups: studies on healthy teeth and studies on teeth with pulpitis. The data of included studies were statistically combined through meta-analysis using a fixed-effects model. A total of 20,778 records were initially retrieved from the search. Following screening and eligibility assessment, 8 studies met the eligibility criteria and were included for qualitative synthesis. Of those, 5 studies were qualified for meta-analysis. In the irreversible pulpitis group, increasing the volume of anesthetic agent from 1.8 to 3.6 mL significantly increased the success rate of inferior alveolar nerve block (risk ratio = 2.45, 95% CI: 1.67-3.59, p < .001). However, there was insufficient evidence to draw a conclusion regarding healthy teeth. PMID- 29509519 TI - Challenges of Airway Management. PMID- 29509520 TI - The Effects of Different Levels of Ambient Oxygen in an Oxygen-Enriched Surgical Environment and Production of Surgical Fires. AB - Surgical fires require an oxygen-enriched environment, a flammable substrate, and an ignition source. We hypothesized ambient oxygen concentration is proportional to the latency time to combustion and the incidence of surgical fires that are detected. We examined latency time and number of events, utilizing the VanCleave et al model of intraoral fire ignition under 60, 80, and 100% oxygen concentration and flow rates of 4 and 10 L/min. Results demonstrated that ambient oxygen concentration and flow rate correlated positively to the initiation of combustion. The number of combustion events with 60% oxygen was significantly lower than with both 80% ( p = .0168) and 100% ( p = .002). Likewise, the number of events with 80% oxygen was significantly lower than with 100% oxygen ( p = .0019). Flow rate has a significant effect on the time to the first event ( p = .0002), time to first audible pop ( p = .0039), and time to first flash or fire ( p < .0001). No combustion occurred at oxygen concentrations less than 60% or flows less than 4 L/min. We conclude that latency time to combustion is directly proportional to ambient oxygen concentration and flow rate. Minimum oxygen concentration and flow rate were identified in our model. Further research is indicated to determine the minimal clinical oxygen concentration and flow rate needed to support combustion of an intraoral fire in a patient. PMID- 29509521 TI - Practice Patterns of Dentist Anesthesiologists in North America. AB - This study provides trends in the discipline of dental anesthesiology. A questionnaire-based survey was sent to 338 members of the American Society of Dentist Anesthesiologists to evaluate practice patterns. One focus of the study was modality of sedation/anesthesia used for dentistry in North America. Age, gender, years in practice, and geographic region of practice were also obtained. Data gathered from the returned questionnaires were entered into an Excel spreadsheet and then imported into JMP Statistical Discovery Software (v12.2 Pro) for descriptive analysis. A total of 112 surveys were completed electronically and 102 surveys were returned via post, for a total response rate of 63.3% ( N = 214). Data from this survey suggested a wide variation of therapeutic practices among dentist anesthesiologists in North America. Of the surveyed dentist anesthesiologists, 58.7% (SE = 4.2%) practice as mobile providers, 32.2% (SE = 3.1%) provide care in an academic environment, and 27.7% (SE = 2.8%) function as operator/anesthetists. The majority of anesthesia is provided for pediatric dentistry (47.0%, SE = 4.2%), oral and maxillofacial surgery (18.5%, SE = 3.9%), and special needs (16.7%, SE = 3.6%). Open-airway (58.7%, SE = 5.5%) sedation/anesthesia was the preferred modality of delivery, compared with the use of advanced airway (41.3%, SE = 4.6%). The demographics show diverse practice patterns of dentist anesthesiologists in multiple regions of the continent. Despite concerns regarding specialty recognition, reimbursement difficulties, and competition from alternative anesthesia providers, the overall perceptions of dentist anesthesiologists and the future of the field seem largely favorable. PMID- 29509522 TI - Dexmedetomidine Enhances the Pulpal Anesthetic Effect of Lidocaine: A Pilot Study. AB - Dexmedetomidine hydrochloride (DEX) demonstrates analgesic, sedative, and hypotensive effects. DEX may also enhance the effect of local anesthetics used in the oral cavity, although this has not been well established in combination with lidocaine. We conducted a single-blind crossover study in 8 healthy volunteers to investigate whether DEX enhances the anesthetic effect of lidocaine in the oral cavity. DEX or DEX + lidocaine was injected into the labial gingiva corresponding to the root apex of the maxillary left central incisor and into the buccal gingiva corresponding to the root apex of the mandibular right first molar. Pain threshold, blood pressure, pulse rate, oxygen saturation, and bispectral index were measured 5 minutes after treatment and at 10-minute intervals for 60 minutes. DEX + lidocaine caused pulpal anesthesia in more subjects than lidocaine alone; this difference was significant for both central incisors and first molars up to 40 minutes after treatment. Following DEX + lidocaine treatment, blood pressure and bispectral index were significantly reduced at several time points, and pulse rate significantly reduced at all time points. Neither treatment caused changes in oxygen saturation. In conclusion, administering DEX with lidocaine for dental local anesthesia caused sedation and enhanced local anesthesia compared to lidocaine alone. PMID- 29509523 TI - Electrophysiology of Muscle Fatigue in Cardiopulmonary Resuscitation on Manikin Model. AB - Cardiopulmonary resuscitation requires the provider to adopt positions that could be dangerous for his or her spine, specifically affecting the muscles and ligaments in the lumbar zone and the scapular spinal muscles. Increased fatigue caused by muscular activity during the resuscitation could produce a loss of quality and efficacy, resulting in compromising resuscitation. The aim of this study was to evaluate the maximum time a rescuer can perform uninterrupted chest compressions correctly without muscle fatigue. This pilot study was performed at Universidad Complutense de Madrid (Spain) with the population recruited following CONSORT 2010 guidelines. From the 25 volunteers, a total of 14 students were excluded because of kyphoscoliosis (4), lumbar muscle pain (1), anti-inflammatory treatment (3), or not reaching 80% of effective chest compressions during the test (6). Muscle activity at the high spinal and lumbar (L5) muscles was assessed using electromyography while students performed continuous chest compressions on a ResusciAnne manikin. The data from force exerted were analyzed according to side and muscle groups using Student's t test for paired samples. The influence of time, muscle group, and side was analyzed by multivariate analyses ( p <= .05). At 2 minutes, high spinal muscle activity (right: 50.82 +/- 9.95; left: 57.27 +/- 20.85 MUV/ms) reached the highest values. Activity decreased at 5 and 15 minutes. At 2 minutes, L5 activity (right: 45.82 +/- 9.09; left: 48.91 +/- 10.02 MUV/ms) reached the highest values. After 5 minutes and at 15 minutes, activity decreased. Fatigue occurred bilaterally and time was the most important factor. Fatigue began at 2 minutes. Rescuers exert muscular countervailing forces in order to maintain effective compressions. This imbalance of forces could determine the onset of poor posture, musculoskeletal pain, and long-term injuries in the rescuer. PMID- 29509525 TI - A Case of Rocuronium-Induced Anaphylactic Shock in an Asthmatic Child. AB - We experienced a case of anaphylactic shock in a young asthmatic child immediately after administering rocuronium during the induction of anesthesia. Because urticaria did not develop immediately after ventilation difficulty, we diagnosed and responded to asthma, rather than to anaphylactic shock. Correct and rapid response to anaphylactic is extremely important. PMID- 29509524 TI - Facial Artery Pseudoaneurysm: Challenges of Airway Management. AB - A patient with recent jaw reconstruction presented for treatment of postoperative oropharyngeal hemorrhage. Asleep nasal fiberoptic intubation was attempted, but a rare and unanticipated complication ensued: rupture of right facial artery pseudoaneurysm. The difficult airway algorithm was followed up to the point of surgical airway. While nasal or oral fiberoptic intubation is often perceived as the safest approach for management of a difficult airway, we discuss alternative treatment strategies for patients with a facial pseudoaneurysm. Such alternatives include preoperative angiographic endovascular embolization of the vessel(s) feeding the pseudoaneurysm, and/or elective tracheostomy. PMID- 29509527 TI - One More Checklist? PMID- 29509526 TI - Recurrent Coronary Artery Spasm Induced by Vasopressors During Two Operations in the Same Patient Under General Anesthesia. AB - Variant angina is caused by coronary artery spasm (CAS) with ST-segment elevation. We herein report a case of recurrent CAS during 2 operations in the same patient. An 80-year-old woman was scheduled to undergo tracheostomy, submandibular dissection, left partial maxillectomy, and coronoidectomy. We administered ephedrine and phenylephrine to manage hypotension during general anesthesia. Immediately after the administration of these drugs, the ST segment elevated. We decided to cease the operation and transport the patient to the department of cardiology. Computed tomography angiography revealed pneumomediastinum. The cardiologists considered that the electrocardiography findings had changed secondary to pneumomediastinum. About 6 weeks later, a second operation was scheduled. We administered ephedrine and phenylephrine to manage hypotension during general anesthesia. Immediately after the administration of these drugs, ST-segment elevation occurred. We discontinued use of these drugs, and the ST-segment elevation did not recur. We considered that the cause of the ST-segment elevation was vasopressor-induced CAS because the vasopressors were administered immediately before the occurrence of CAS. Vasopressors such as ephedrine or phenylephrine are frequently used to manage hypotension during general anesthesia. Therefore, anesthesiologists should consider the occurrence of CAS before using vasopressors and know how to manage CAS well. PMID- 29509529 TI - Recent Advances in Minimally Invasive Esophagectomy. AB - The treatment of esophageal cancer has become more effective due to advances in surgical techniques, multidisciplinary approach, appropriate use of neoadjuvant therapy and perioperative care at centers of excellence in esophageal surgery. Esophagectomy is one of the most complicated and demanding procedures among all gastrointestinal surgeries with a very long learning curve in which excellence can only be achieved through improvement during all the surgical career. The results of esophagectomy are related not only to the volume of cases operated but also to the experience of surgeons in the management of postoperative complications. Initially, minimally invasive esophagectomy has encountered obstacles to implementation in several centers due to the cost and complexity of esophageal cancer treatment. Several meta-analyses and clinical trials published so far support the feasibility of the minimally invasive approach, the advantages of the post-operative period and the equivalence of oncological outcomes with the open technique, which is an important step in imposing minimally invasive techniques as a standard in the treatment of esophageal cancer. In this paper, we aim to analyze recent advances in minimally invasive esophagectomy, the evolution of endoscopic surgical techniques through our personal experience and the results of studies published in the medical literature in the last years. PMID- 29509528 TI - Pre-screening method for somatic cell contamination in human sperm epigenetic studies. AB - Sperm epigenetic profiles are frequently studied and are of great interest in many fields. One major technical concern when assessing these marks is the potential for somatic cell contamination. Because somatic cells have dramatically different epigenetic signatures, even small levels of contamination can result in significant problems in analysis and interpretation of data. In this study we evaluate an assay, which we designed to offer a reliable 'pre-screen' for somatic cell contamination that directly assesses the DNA being used in the study to determine tissue purity. In brief, we designed an inexpensive and simple assay that utilizes the strong differential methylation between sperm and somatic cells at four genomic loci to assess the general purity of samples prior to performing expensive and time intensive assays. The assay is able to reliably detect contamination qualitatively by running the sample on an agarose gel, or quantitatively with the use of a bioanalyzer. With this technique we have found that we can detect potentially contaminating signals in samples of many different types, including those from patients with poor sperm phenotypes (oligozoospermia, asthenozoospermia, and teratozoospermia). We also have found that the use of multiple sites to determine potential contamination is key, as some conditions (asthenozoospermia specifically) appear at one site to reflect a somatic-like profile, while at all other sites it appears to have very typical sperm DNA methylation signatures. Taken together, the use of the assay described herein was effective at identifying contamination and could be implemented in many labs to quickly and inexpensively pre-screen samples prior to performing far more expensive and labor intensive procedures. Additionally, the principles applied to the development of this assay could be easily adapted for the development of other assays to pre-screen different tissue/cell types or model organisms. PMID- 29509530 TI - Current Management of Locally Advanced Junction Esophagogastric Adenocarcinoma. AB - Adenocarcinoma of the gastroesophageal junction is more common in the West. Preoperative chemotherapy or chemoradiotherapy is performed for locally advanced disease. Recent studies are suggesting higher rates of curative resection and reduced rates of local recurrence in patients with neoadjuvant combination of chemotherapy and radiation therapy. The role of targeted agents in neoadjuvant therapy is under investigation. PMID- 29509531 TI - Barrett's Esophagus - State of the Art. AB - Barrett's Esophagus (BE) is defined as a premalignant condition, where the esophageal squamous epithelium is replaced by intestinal epithelium. Specialized intestinal columnar metaplasia, typical for Barrett's esophagus, does not generate any symptoms. Most of the patients are initially seen for symptoms associated with the gastroesophageal reflux disease (GERD), such as heartburn, regurgitation and dysphagia. The histological progression from intestinal metaplasia to dysplasia and then to BE-associated adenocarcinoma forms the argument for screening and endoscopic monitoring. The examination of Barrett's esophagus is controversial. Certain groups suggest a screening of the patients who exhibit more risk factors for the development of esophageal adenocarcinoma (for instance, gastroesophageal reflux disease, age 50, male, high body mass index with abdominal fat distribution). The main reason behind the treatment of acid reflux is that it may lead to chronic esophageal inflammation, which in its turn may predispose to the development of cancer. PMID- 29509533 TI - New Minimally Invasive Endoscopic and Surgical Therapies for Gastroesophageal Reflux Disease (GERD). AB - GERD has become one of the most frequent pathology of the upper GI tract. It is a spectrum disease and is a progressive disease as well. Serious and severe complications are possible. The mainstream therapy in most of the patients is the medical therapy with PPI's. The most severe cases with an impaired LES (Lower Esophageal Sphincter) function as well as important anatomical disruptions are of surgical indication, the gold standard being laparoscopic fundoplication, an elective therapy with long term follow up outcomes at the expense of de novo symptoms associated with fundoplications in general. 30% to 40% of the patients are PPI refractory with partial symptom control, but they are not willing to go for the laparoscopic fundoplication because of the invasive character and because of potential postfundoplications syndromes. There is a "treatment gap" for these patients with GERD. For a well selected patient population with GERD, with mild forms of the disease, without complications and without major anatomical disruptions (patients with small hiatal hernias), patients who are refractory on PPI medication, there are today new alternative therapies, minimally invasive. These therapies are less aggressive and basically with no side effects or new onset symptoms that Laparoscopic Fundoplications will give. These are endoscopic therapies which improve the LES function: Stretta utilizes radiofrequence therapy, a novel technique describes mucosal resection at the level of the cardia, while a partial fundoplication from within the stomach can be realized with EsophyX, Muse or Gerd-X. Form all these procedures, EsophyX is the most advanced with more than 20,000 patients treated worldwide, with good clinical outcomes and with no de novo symptoms. The laparoscopic techniques treat hiatal hernias larger than 2 cm. Linx utilizes a magnetic ring at the LES level. EndoStim utilizes electrodes in order to stimulate the LES muscle. These procedures are effective on short term and there are few patients treated with Linx or EndoStim. More research for Linx and EndoStim is necessary with randomized clinical trials, with improvement of the devices and with long term follow up. PMID- 29509532 TI - High Resolution Manometry - A Mandatory Examination in the Pre and Postoperative Assessment of Patients with Achalasia. AB - High resolution manometry (HRM) is currently the gold standard for the diagnosis of achalasia and other functional esophageal disorders. All patients accusing dysphagia should be endoscopically evaluated prior to manometric investigations in order to rule out pseudoachalasia. The Chicago HRM classification has led to a subclassification of three manometric types of achalasia that seem to have different results to treatment. None of the actual achalasia treatment options are curative. Type II achalasia patients respond best to all treatment options compared to those with types I and III. Pneumatic dilation (PD) or Heller miotomy (LHM) can be both chosen as initial therapy in type I and II as they have good outcome , while type III achalasia patients respond better to LHM as a first therapeutic option. Peroral endoscopic myotomy (POEM) is a promising new technique but long-term follow-up studies for its safety and efficacy must be performed. This article reviews the current therapeutic options in achalasia and other functional esophageal disorders, based on the differences in safety and efficacy between approaches, highlighting the impact of HRM to predict the outcome but also the role of the techinque in guiding antireflux surgery. PMID- 29509534 TI - Esophageal Reconstruction with the Stomach, a Functional Dilemma? AB - Background: A few decades ago, esophageal substitution was mainly dedicated particularly in postcaustic esophageal stenosis; currently, the reconstruction has expanded its palette of indications to other areas of benign esophageal pathology (severe motor disorders, esophageal achalasia with multiple relapses, peptic stenosis, etc.) but has also become a quasi-obligatory final time in the esophagectomy for cancer whenever it is possible. The techniques of esophageal reconstruction using the stomach, regardless of the indication and the chosen technical option, remain a valuable and effective method. A number of striking arguments advocate for one or another type of gastric graft: anatomic factors more than convenient (vascularization, sufficient length, a wall structure favorable for suture, etc.) and a sustainable surgical intervention (length, approach, complexity of the surgical steps digestive disorders after surgery, post-therapeutic functionality, etc.). Choosing a technique or another, beyond pathological arguments, should take into account remote functionality, with a clear impact on metabolic status and quality of life. So, according to this criterion, can we functionally justify a type or another of gastric restoration? Finally, the proof of an adequate solution is relatively easy to appreciate: has swallowing been restored and if so, the result has been maintained over time? For oncological cases, the assessment should also take into account the chronological criterion of the postoperative survival rate. Methods: The statistically rated lot ranged from 1981 to 2016 and included 268 patients with surgical interventions for esophageal stenosis, distributed according to etiopathogenesis and indication in 201 reconstructions for post-caustic stenosis, and 67 for post esophagectomy replacement for neoplasm. The techniques used for remote functional evaluation included: barium swallow, endoscopy + biopsy, and in cases with obvious changes pH measurement/24 h and manometry and, only in exceptional cases, scintigraphy with marked foods. Results: two types of problems have been identified: a particular type of neuro-motor dysfunction of the esophageal substitute in 6 patients (1 patient with Gavriliu reconstruction and 5 with Nakayama reconstruction, using the whole stomach), with difficulty, delayed gastric graft evacuation, with major stasis and abdominal discomfort vomiting, inability to eat, aspiration phenomena) respectively a reflux pathology - 8 patients, being proved by a specific simptomatology, barium lunch, endoscopic examination and pH-metric examination. Reflux was alkaline in 7 patients, all with pyloroplasty, 5 with whole stomach and 2 with Akiyama procedure; in 1 case with Gavriliu procedure the reflux was acid. Conclusions: Stomach is a good option in esophageal substitution. Concerning the remote results, a good functionality is found with a reasonable metabolic status. The two phenomena on which the function of the graft depends - secretory activity and motor activity - seem to be restored in time but these does not occur concurrently, the recovery of the secretory function being much faster. PMID- 29509536 TI - Gastroesophageal Reflux Before Metabolic Surgery. AB - : Background: Obesity has significantly increased in the last decades and metabolic (bariatric) surgery has been extended accordingly. Clinical manifestations of Gastroesophageal reflux disease (GERD) are frequent in the obese population but the presence of GERD premises (i.e. Hiatala hernia) or complications in asymptomatic patients undergoing metabolic surgery is unclear. AIM: (1) to identify gastroesophageal reflux condition or complications in patients undergoing metabolic surgery. (2) Study the correlations of the clinical symptoms of GERD with the preoperative radiological and endoscopic findings. Methods: All the consecutive patients (GERD symptomatic or not) undergoing metabolic surgery in a Bariatric Center of Excellence between December, 2015 and May 2016 were included in a prospective study. A multidisciplinary team evaluated all the patients within the bariatric surgery program. Clinical evaluation, radiological and endoscopic investigations were performed to all the included patients. The patients who previously had anti-reflux or bariatric surgery were excluded. Results: Four-hundred-forty-eight consecutive patients were enrolled into the study. The mean age of patients was 41.04 (+-11.15) years, and 29% of them were men. The mean BMI was 39.96 (+-8.17) kg/m2. Symptoms of GERD were recorded only in 93 of the patients (20.76%) while endoscopic examination revealed esophagitis in 139 (31,03%) patients (107 Grade A, 28 Grade B, 3 Grade C, 1 Grade D. Barrett esophagus was suspected in 5 patients but histologic confirmation (gastric metaplasia) was recorded only in 2 patients (0.44%). Hiatal hernia was revealed by endoscopy and radiology in 119 (26,56%) and 112 patients (25%). 62% of the patients presenting esophagitis (86/139) had no pre-operative symptom of GERD, meaning that a significant number of the asymptomatic patients undergoing metabolic surgery may present consequences of gastro-esophageal reflux. Conclusions: The study demonstrates that GERD is more frequent then expected in asymptomatic obese patients undergoing metabolic surgery. The clinical impact of these findings is important for the proper procedure selection and for a correct evaluation of the postoperative evolution. PMID- 29509535 TI - Comparative Study of Early Postoperative Complications: Thoracic Anastomosis vs Cervical Anastomosis - in Esophageal Replacement with Gastric Graft. AB - Gastric pull-up is the most commonly used procedure for esophageal replacement in both malignant and benign conditions. In our article we compare the differences in mortality and morbidity between thoracic anastomosis and cervical anastomosis during gastric pull-up. The study group comprised of 126 patients - 58 patients (56%) with cervical anastomosis and 68 patients (64%) with thoracic anastomosis. The overall mortality in the study group was 5.55% (7 patients), while the overall morbidity was higher at 28%. There were no significant differences between the two subgroups regarding mortality and morbidity, although the rate of anastomotic leakage was higher in the cervical subgroup (13.8% vs 1.5%). We recommend performing thoracic anastomosis during gastric pull-up whenever the location of the lesion allows it, since the procedure is safe, relatively easy to master and it shortens operating time by excluding the cervical approach. PMID- 29509537 TI - Endoscopic Treatment of Benign Esophageal Fistulas Using Fully-covered Metallic Esophageal Stents. AB - : Non-malignant esophageal fistulas have a wide spectrum of clinical and pathological features and it's important to learn to detect and treat them, due to significant morbidity, mortality and costs. The need for minimally invasive, efficient and also quick procedures is imperative. Esophageal stenting using fully-covered expandable stents has become an increasingly preferred option and addresses to fistulas which arise from 2-3 cm beyond Killian's mouth and up to the gastroesophageal junction. The long-term purpose of the procedure is closure of the fistula and thus healing. A second goal would be avoiding the complications generated by long-term wearing of the stent, such as gastrointestinal perforation and stenosis. OBJECTIVES: This review focuses on the efficacy of fully-covered metallic stents in treating benign esophageal fistulas. To this effect, we performed a retrospective study on 21 patients admitted in our clinic between January 2014 and April 2017 for non-malignant esophageal fistulas. The selection criteria were the following: post-operative fistulas (gastric sleeve, fundoplication for transhiatal gastric hernia, even malignancies for which surgical tumor removal was performed), foreign body acquired fistulas, post traumatic fistulas. Esophago-jejunal anastomotic fistulas were also included in the study (following complete gastrectomy). Results: The efficacy of esophageal stenting was proven in 76% of the cases, resulting in fistula closure. The rest of the patients either didn't achieve fistula closure or couldn't tolerate the stent, calling for early removal of the prosthesis. Reintervention procedures such as stent repositioning or stent replacement (with higher diameter) were carried out in 42% of the cases. A percentage of 19% of the patients who achieved fistula closure developed esophageal stricture on stent-induced ulcers and needed recalibration stenting or esophageal Savary dilation. 22% of the cases needed surgical drainage for infected collections developed simultaneously. We recorded 2 deaths, unrelated to the stenting procedure. Patients who didn't acquire fistula closure were referred to thoracic surgery in good physical condition. Conclusions: Fully-covered metallic esophageal stents can be successfully used to treat benign esophageal fistulas. Follow-up of the patient in order to see if stent repositioning or replacement is needed is crucial. Special design esophageal stents are highly recommended and must not lack. Close cooperation with thoracic surgery is indispensable. PMID- 29509538 TI - Distant Oncologic Outcome of Patients with Locally Advanced Unresectable and Metastatic Esophageal Cancer after Multimodality Treatment. AB - Background: Combined modality therapy has been employed for the treatment of choice for locally advanced esophageal and eso-gastric junction cancers all around the globe but a unanimous consensus is missing. Methods: Medical files of 132 patients with confirmed locally advanced un-resectable, and metastatic esophageal cancer who presented to our center between 2010-2015 were retrospectively reviewed. Multimodality treatment consisting of chemo radiotherapy or chemotherapy or radiotherapy alone and surgery in patients who convert to operability was planned according to tumor extend and performance status of the patient. Results: Seventy seven percent of the patient presented with squamous carcinoma and 23 % were adenocarcinoma. At the diagnosis 22 patients (16.6%) were stage IV. Concurrent chemoradiotherapy was administered in 26 patients (19.7%), chemotherapy in 91 patients (68.9%), radiotherapy in 83 patients (62.9%). After combined treatment, surgery with radical intent was possible in 21 patients (15.9%). After a follow up of 17.3 months, overall survival (OS) was 12 months, with one and two-year survival rate of 49.2% and 17.4%. In metastatic patients OS was 10 months. Patients who were converted to operability had a OS of 20 months vs. 10 months in patients who doesn't undergo surgery (p=0.002). Chemo-radiotherapy was superior in terms of OS compare with chemotherapy or radiotherapy administered sequential (17 vs. 10 months, p=0.013). Conclusions: Multimodality treatment in locally advanced esophageal cancers (concurrent radiochemotherapy followed by surgery) can be considered superior to each method as single therapy and radiotherapy and chemotherapy can make certain locally advanced esophageal tumors resectable. PMID- 29509539 TI - Cervical Exenteration - Guidelines and Surgical Technique Principles. AB - : Introduction: Neoplastic invasion of the structures of the cervical region originating from a malignant tumour developed in one of the viscera of the throat may benefit from cervical exenteration. Defined as resection of the hypopharynx, cervical oesophagus, larynx and cervical trachea, exenteration has limited indications and is mandatorily accompanied by digestive tube reconstruction. The aim of this article is to highlight the indication, surgical strategy and important surgical stages illustrated by images from personal professional experience. MATERIALS AND METHOD: Pharyngo-laryngo-oesophageal en bloc resection and radical cervical lymphadenectomy were followed by reconstruction via free jejunal transfer or colic pedicle grafting. Between 2000 and 2018 we have performed cervical exenteration in 25 patients with tumours originating in the pharynx, larynx or cervical oesophagus. In the cases of 5 patients in whom we did not obtain the oncological safety margin for oesophageal cancer we performed transhiatal pharyngo-laryngo-oesophagectomy. In these patients, we performed reconstruction of the oesophagus with colonic graft. In 20 cases we performed jejunal autotransplant. Results: We recorded 4 perioperative deaths, due to major arterial vessel haemorrhage (1 case), after jejunal necrosis (2 cases), and mediastinitis after oesophageal striping and colonic graft necrosis (1 case). One patient presented tumour recurrence at the level of the tracheal stump. Survival rate varied between 6 months and 4 years for the group of patients who presented for postoperative follow-ups. Conclusions: Cervical exenteration remains an option for tumour recurrence after radiochemotherapy or for obstructive airway or digestive tract tumours. It can be burdened by complications difficult to treat. The surgical team has to adapt its initial surgical strategy to the reality of the surgical field, both in terms of exeresis and in terms of types of pharyngo oesophageal reconstruction. PMID- 29509540 TI - Laparogastroscopy and Esophageal Stenosis. AB - PURPOSE: An original technique using laparoscopic instruments in a gastric endocavitary work chamber with potential for esophagus, stomach and D1 vizualisation. The main purpose of laparagastroscopy is to improve the quality of life of the patient disabling by the esophageal tumor. This method has several advantages: providing physiological feeding, harvesting materials for histopathological examination, solving eso-tracheal fistulas concurrently with the proposed operation and hemostatic role through compression, low energy and plastic consumption, rapid socio-economic reintegration, mental psychological care of the patient. Patients and Methods: The paper deals with 162 cases with different tumors of the esophagus, patients with different grades of esophageal stenosis, different stages of esophageal neoplasm. Both the patients with eso tracheal fistulas and those with gastro- or jejunostoma were included. Results: From 162 cases, 33 cases (20%) with cervical esophageal neoplasm, 66 (41%) cases with thoracic esophageal neoplasm and 63 (39%) cases with abdominal esophageal neoplasm. The histopathological type is 37% adenocarcinomas and 63% squamous carcinomas. From total number of cases, 87 (54%) had no metastasis, and 75 (46%) had secondary determinations. The most frequent localization of metastasis was pulmonary, followed by liver (Fig. 1) and bone. The analysis of this intervention has shown that complications have been much lower both in terms of their numerical value and their severity, a longer survival time with a much higher satisfaction index is ensured. CONCLUSION: Esophageal endoprosthesis (EPE) through laparagastroscopic approach should be a a reserve procedure instead of a disabling gastrostomy or jejunostomy. EPE is an extremely effective procedure specially by keeping the physiology of food bowl. The approach is minimally invasive with minimal attack on the body with significant plastic and aesthetic reductions. This procedure allows the prosthesis to be viewed both during and after stenting to check its correct position. This method increases the survival time by keeping a relatively normal regimen. PMID- 29509542 TI - The Surgical Management of Acute Esophageal Perforation by Accidentally Ingested Fish Bone. AB - Esophageal foreign bodies are a relatively frequent pathology which does not need any kind of treatment in up to 80% of cases. Ten to 20% of patients are treated endoscopically, while less than 1% need surgery either due to perforation or to treat complications. We address the case of a 50 year old male who presented with an impacted esophageal foreign body which had perforated the esophageal wall. Flexible endoscopy confirmed the diagnosis and identified a large fish bone that was stuck transversally in the distal cervical esophagus and could not be mobilized. Surgery was mandatory in this case, with the extraction of the bone and double-layer suture, which did not prevent the appearence of an esophageal leakage more than two weeks postoperatively, which was treated conservatively. Even if it is rarely employed in the treatment of gastrointestinal foreign bodies, surgical treatment is unavoidable in cases of irretrievable esophageal foreign bodies or esophageal perforation. PMID- 29509541 TI - Early Postoperative Complications of Thoracic Esophageal Diverticula: A Review of 10 Cases from "Saint Mary" Hospital, Bucharest, Romania. AB - : Introduction: Thoracic esophageal diverticulum is a rare pathology frequently associated with esophageal motility disorders. Surgery is the only option in patients with severe symptoms. METHOD: This is a retrospective case series study of 10 patients who underwent diverticulectomy for thoracic (epiphrenic or mid esophageal) diverticula. It was recorded: main preoperative symptoms, usual blood tests, barium swallow, upper endoscopy and esophageal manometry. We analyzed the postoperative complications, length of stay in hospital and intensive care unit. Results: Most patients presented with regurgitation and/or dysphagia. The surgical approach was through left thoracotomy or abdominal for epiphrenic diverticula and through right thoracotomy or thoracoscopy for mid-esophageal diverticula. 4 patients had severe complications: 3 had major leaks (one death) and one had chylothorax. DISCUSSIONS: Surgery for thoracic diverticula is associated with high mortality and morbidity rates. Leak from the suture line is the most common complication, unlike chylothorax which is a rare complication. Conclusions: Thoracic diverticula represent a benign pathology which can have "?malignant" postoperative complications. A thorough preoperative work-up is mandatory for choosing the appropriate surgical technique. Use of multiple cartridges for stapling suture increase the risk of leakage, but oversewing the suture may diminish it. PMID- 29509543 TI - Management of Pylorus During Esophagectomy. To Drain or Not to Drain? AB - Dear Editor, delayed gastric emptying due to bilateral vagotomy after esophagectomy, has been associated with increased aspiration rates, prolonged hospital stay and impaired quality of life. A pyloric drainage procedure in an effort to reduce its incidence, most commonly a pyloroplasty, represented for years a standard part of distal esophagectomy. This trend has been reevaluated nowadays and the question that still remains open is whether we should further keep on draining pylorus during esophagectomy or not. Surgical pyloric drainage (pyloroplasty/pyloromyotomy), although effective, is directly related to respectable complication rates, such as leakage, bile reflux, dumping sydrome or even postoperative stenosis, with potential fatal outcome. There are several proposed techniques for performing a pyloroplasty nowadays. Heineke- Mikulicz variant is the most widely practiced pyloroplasty (in contrary to Finney or Jaboulay alternatives) and is ideally performed via a 5-cm-long fullthickness antroduodenal longitudinal incision. Pyloroplasty can also be safely performed with a circular or linear stapler, while laparoscopic assisted trans-oral stapled pyloroplasty is also feasible (1). PMID- 29509544 TI - Secretion of full-length Tau or Tau fragments in cell culture models. Propagation of Tau in vivo and in vitro. AB - The microtubule-associated protein Tau plays a crucial role in stabilizing neuronal microtubules. In Tauopathies, Tau loses its ability to bind microtubules, detach from them and forms intracellular aggregates. Increasing evidence in recent years supports the notion that Tau pathology spreading throughout the brain in AD and other Tauopathies is the consequence of the propagation of specific Tau species along neuroanatomically connected brain regions in a so-called "prion-like" manner. A number of steps are assumed to be involved in this process, including secretion, cellular uptake, transcellular transfer and/or seeding, although the precise mechanisms underlying propagation of Tau pathology are not fully understood yet. This review summarizes recent evidence on the nature of the specific Tau species that are propagated and the different mechanisms of Tau pathology spreading. PMID- 29509545 TI - Neurological and psychiatric disorders in psoriasis. AB - Psoriasis used to be known as a skin disorder; however, it can now be considered as a systemic disease with the involvement of multiple organs. Neurological and psychiatric disorders are some of the associated problems that can be observed in patients with psoriasis. Stroke, multiple sclerosis, seizure, migraine, restless leg syndrome, Parkinson's disease, Guillain-Barre syndrome, and myasthenia gravis are the reported neurological diseases, while depression, bipolar mood disorder, anxiety, psychosis, cognitive impairment, personality disorders, sexual disorders, sleep disturbance, and eating disorders are the recognized psychiatric presentations in patients with psoriasis. Herein, the neurological and psychiatric disorders of psoriasis are described. PMID- 29509547 TI - The National Network of Perinatal Quality Collaboratives: Opportunity to Enhance the Care and Outcomes for Mothers and Babies. PMID- 29509546 TI - A PET imaging agent for evaluating PARP-1 expression in ovarian cancer. AB - BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent. METHODS: We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient-derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology. RESULTS: We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2-12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r2 = 0.60). CONCLUSION: This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02637934. FUNDING: Research reported in this publication was supported by the Department of Defense OC160269, a Basser Center team science grant, NIH National Cancer Institute R01CA174904, a Department of Energy training grant DE-SC0012476, Abramson Cancer Center Radiation Oncology pilot grants, the Marsha Rivkin Foundation, Kaleidoscope of Hope Foundation, and Paul Calabresi K12 Career Development Award 5K12CA076931. PMID- 29509548 TI - Association Between Spasticity and Functional Impairments During the First Year After Stroke in Korea: The KOSCO Study. AB - OBJECTIVE: The aim of the study was to investigate the correlation between spasticity severity and functional outcomes during the first year after stroke. DESIGN: The Korean Stroke Cohort for Functioning and Rehabilitation is a large, multicenter, prospective cohort study of all patients with acute first-ever stroke admitted to participating hospitals in nine Korean areas. To investigate the correlation between spasticity severity and functional status measured by using the Institutes of Health Stroke Scale (NIHSS), Modified Barthel Index (MBI), Functional Independence Measurement (FIM), Fugl-Meyer Assessment (FMA), Functional Ambulatory Category (FAC), modified Rankin scale (mRS), and American Speech-Language Hearing Association National Outcome Measurement System Swallowing Scale (ASHA-NOMS), data were analyzed at 3, 6, and 12 mos after the occurrence of stroke. RESULTS: A total of 7359 stroke patients, 3056 were finally included. Prevalence rates of spasticity in patients after stroke were 6.8% at 3 mos, 6.9% at 6 mos, and 7.6% at 12 mos. The scores of mRS and NIHSS were higher and those of K-MBI, FIM, FMA, and ASHA-NOMS were lower in more severe spastic patients, indicating poorer functional outcomes (P < 0.05). CONCLUSIONS: This study demonstrated the coexistence of spasticity and poor functional outcome during the first year after first-ever stroke patients. PMID- 29509549 TI - An Uncommon Cause of Upper Limb Pain: Cervical Perineural (Tarlov) Cyst Chain. PMID- 29509550 TI - Poststroke Depression: A Long-Term Problem for Stroke Survivors. AB - OBJECTIVE: The aim of the study was to ascertain the prevalence of depressive mood and its determinants in the chronic phase after stroke. DESIGN: Five hundred seventy-six consecutive patients were invited to participate 2 to 5 yrs after hospitalization for a first-ever stroke. Stroke characteristics at hospitalization were collected retrospectively from medical records. Patients and their caregivers completed questionnaires on depression (Hospital Anxiety and Depression Scale [HADS]), sociodemographic characteristics, healthcare usage, daily activities, quality of life, and caregiver strain. Patients with HADS depression scores of less than 8 were compared with patients with HADS depression scores of 8 or higher by means of univariate logistic regression analyses, adjusted for age, sex, and Barthel Index at discharge. RESULTS: Two hundred seven patients (36%) returned the questionnaires. After a mean follow-up of 36.3 mos, 67 patients (34%) had a HADS depression score of 8 or higher. Male sex and being born abroad were statistically significantly associated with a high HADS depression score, adjusted for age, sex, and stroke severity. Depressed patients had higher anxiety levels, a more avoidant coping style, less daily activities, and a lower quality of life; their caregivers experienced a higher burden. CONCLUSIONS: In the chronic phase after stroke, a considerable proportion of patients has depressive symptoms. This seems to be related to sex, country of origin, anxiety, coping style, daily activities, quality of life, and caregivers' strain. Future research should focus on causal relationships and opportunities for treatment. PMID- 29509552 TI - Effects of "Essential AD2" Supplement on Blood Acetaldehyde Levels in Individuals Who Have Aldehyde Dehydrogenase (ALDH2) Deficiency. AB - BACKGROUND: It is estimated that 1 billion people in the world have a point mutation in the gene encoding the aldehyde dehydrogenase 2 (ALDH2) enzyme, the primary enzyme responsible for the metabolism of acetaldehyde. The presence of this mutation is called ALDH2 deficiency. Because of limited ability to metabolize acetaldehyde, individuals with ALDH2 deficiency experience elevated levels of blood acetaldehyde after exposure to various common sources such as recreational alcohol. Because of higher levels of acetaldehyde, individuals with ALDH2 deficiency are at higher risk for numerous diseases, including liver cirrhosis, esophageal and gastric cancer, osteoporosis, and Alzheimer disease. STUDY QUESTION: The present trial was designed to study the effectiveness, safety, and tolerability of a nutritional supplement (Essential AD2). MEASURES AND OUTCOMES: The primary outcome was change in acetaldehyde levels in the blood after exposure to alcohol in individuals with ALDH2 deficiency before and after the use of study nutritional supplement. STUDY DESIGN: This was a 28-day open label trial, comparing initial acetaldehyde levels after alcohol ingestion to levels after 28 days of a nutritional supplement (Essential AD2). The study consisted of 12 subjects genotyped to be heterozygous for the ALDH2 gene mutation. RESULTS AND CONCLUSIONS: ALDH2 deficient subjects showed a significant decrease in average blood acetaldehyde level 20 minutes after alcohol consumption (from 0.91 mg/dL to 0.71 mg/dL, P value = 0.02) after receiving 28 days of the nutritional supplement. Acetaldehyde levels taken at 10 minutes and 40 minutes also showed a decrease, although they were not statistically significant. In addition, safety tests looking at liver function tests showed a decrease in aspartate transaminase and alanine transaminase liver proteins from 27.3 to 15.2 and 20.9 to 13.2, respectively, over the 28 days. The treatment was well tolerated and no significant side effects were noted. PMID- 29509551 TI - Fish Oil for Rheumatoid Arthritis: A Home Medicine Review Initiative. PMID- 29509553 TI - Efficacy and Safety of Pegylated Liposomal Doxorubicin-Based Chemotherapy of AIDS Related Kaposi's Sarcoma: A Meta-Analysis. PMID- 29509554 TI - Methylnaltrexone for Neostigmine-Resistant Ogilvie Syndrome. PMID- 29509555 TI - Team Approach: Complex Dermal Wound-Healing Utilizing Negative-Pressure Wound Therapy (NPWT) in Orthopaedic Trauma. PMID- 29509556 TI - Orthopaedic Primer of Nutritional Requirements for Patients with Musculoskeletal Problems. PMID- 29509557 TI - Effect of Methamphetamine Hydrochloride on Pregnancy Outcome: A Systematic Review and Meta-analysis. AB - BACKGROUND: Methamphetamine hydrochloride is 1 of the most widespread psycho stimulants in the world. Nevertheless, its effect on pregnant women and their neonates has not been investigated extensively. OBJECTIVE: To systematically review the literature for the effect of methamphetamine exposure during pregnancy to neonatal and pregnancy outcomes. MATERIALS AND METHODS: A meta-analysis of retrospective, case-control studies was conducted. Inclusion criteria were women who have used methamphetamine during pregnancy, determined by self-report, maternal or neonatal urine test, and/or meconium toxicology, compared with control women not taking methamphetamine. Main study outcomes were gestational age at birth, neonatal characteristics (birth weight, head circumference, body length), and prevalence of gestational hypertensive disorders. RESULTS: Eight studies involving 626 women taking methamphetamine during pregnancy and 2626 controls were included in the meta-analysis. Pregnancies complicated by the use of methamphetamine resulted in younger gestational age at birth (mean difference [MD] -0.90 weeks, 95% confidence interval [CI] -0.11, -1.69), lower birth weight (MD -245 g, 95% CI -137, -353), head circumference (MD -0.88 cm, 95% CI -0.48, 1.28), body length (MD -0.94 cm, 95% CI -0.55, -1.32), and Apgar score (MD -0.94, 95% CI -0.33, -1.54) compared with control pregnancies. On the contrary, there was no statistical difference on the incidence of pre-eclampsia (risk ratio [RR] 1.77, 95% CI 0.75, 4.14) and hypertensive complications (RR 1.62, 95% CI 0.37, 7.06). CONCLUSIONS: Use of methamphetamine during pregnancy results in a deterioration of neonatal somatometric characteristics (birth weight, head circumference, body length), but not in excessive pregnancy complications (hypertension). PMID- 29509558 TI - Transferring Patients From Methadone to Buprenorphine: The Feasibility and Evaluation of Practice Guidelines. AB - INTRODUCTION AND AIMS: Transfer from methadone to buprenorphine is problematic for many opioid-dependent patients, with limited documented evidence or practical clinical guidance, particularly for the range of methadone doses routinely prescribed for most patients (>50 mg). This study aimed to implement and evaluate recent national Australian guidelines for transferring patients from methadone to buprenorphine. DESIGN AND METHODS: A multisite prospective cohort study. Participants were patients who transferred from methadone to buprenorphine naloxone at 1 of 4 specialist addiction centers in Australia and New Zealand. Clinicians were trained in the guidelines, and medical records were reviewed to examine process (eg, transfer setting, doses, and guideline adherence) and safety (precipitated withdrawal) measures. Participants completed research interviews before and after transfer-assessing changes in substance use, health outcomes, and side effects. RESULTS: In all, 33 participants underwent transfer, 9 from low methadone doses (<30 mg), 9 from medium doses (30-50 mg), and 15 from high doses (>50 mg). The majority of high-dose transfers occurred in inpatient settings. There was reasonable guideline adherence, and no complications identified in the low and medium-dose transfers. Three high-dose transfers (20%) experienced precipitated withdrawal, and 7/33 participants (21%) returned to methadone within 1 week of attempted transfer. DISCUSSIONS AND CONCLUSIONS: Transfer is feasible in outpatient settings for those transferring from methadone doses below 50 mg; however, inpatient settings and specialist supervision is recommended for higher dose transfers. The Australian clinical guidelines appear safe and feasible, although further research is required to optimize high-dose transfer procedures. PMID- 29509559 TI - Can Routine Use of Patient-Reported Outcomes Help Guide Systemic Sclerosis Chronic Disease Care? PMID- 29509560 TI - Minimal Disease Activity and Patient-Acceptable Symptom State in Psoriatic Arthritis: A Real-World Evidence Study With Ustekinumab. AB - BACKGROUND/AIMS: Ustekinumab (UST) is a fully human immunoglobulin G1 monoclonal antibody approved for treating moderate to severe psoriasis and, more recently, psoriatic arthritis (PsA) as well. However, information regarding its clinical usefulness in a real-world setting is scarce. We aimed to evaluate the effectiveness and safety of UST in a real-world clinical setting. METHODS: This single-center observational study included PsA outpatients (n = 50) treated with UST from March 2015 to March 2017. Only patients who used at least 3 doses of UST were analyzed. The percentage of patients who achieved a minimal disease activity (MDA) response was collected. The impact of the disease was also evaluated according to the recently developed Psoriatic Arthritis Impact of Disease (PsAID) questionnaire. A binary logistic regression multivariate model was performed to look for variables predicting MDA. RESULTS: Twenty-seven patients (54%) reached an MDA state. Mean PsAID in MDA group was 3.5 +/- 2.9 versus 6.8 +/- 5.1 in non MDA patients (p < 0.001). Among the patients who achieved MDA, 19 (70.4%) had a patient-acceptable symptom state according to the PsAID, whereas only 5 (21.7%) of the 23 patients who did not reach an MDA achieved a patient-acceptable symptom state (p < 0.001). Higher basal Psoriasis Area and Severity Index decreased the odds of achieving MDA (odds ratio [OR], 0.80; 95% CI, 0.65-0.99; p = 0.038), whereas a longer use of UST (OR, 1.52; 95% CI, 1.13-2.06; p = 0.015) and a previous failure to 1 anti-tumor necrosis factor alpha (OR, 18; 95% CI, 2.52 128.63; p = 0.004) increased this odds. We found no major safety problems. CONCLUSIONS: Ustekinumab was effective and safe in this PsA population. Minimal disease activity and PsAID may be useful tools in the evaluation of PsA therapeutic interventions in routine clinical practice. PMID- 29509562 TI - Erythema Elevatum Diutinum Treated With Mycophenolate Mofetil. PMID- 29509561 TI - Eyelid Swelling in a Woman With Immunoglobulin G4-Related Disease. PMID- 29509563 TI - Relationship Between Health-Related Quality of Life and Patient Acceptable Symptom State With Disease Activity and Functional Status in Patients With Ankylosing Spondylitis in Thailand: A Cross-sectional Study. AB - OBJECTIVE: This study aimed to identify factors associated with EuroQoL-5 Dimensions, 5 Levels and Patient Acceptable Symptom State (PASS) and also to estimate health utility (HU) in Thai patients with ankylosing spondylitis (AS). METHODS: This was a cross-sectional study of consecutive AS patients visiting Siriraj Hospital between May 31, 2012, and March 31, 2016. Demographic data and outcomes related to HU (Thai version of EuroQoL-5 Dimensions, 5 Levels), disease activity (Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity Score-erythrocyte sedimentation rate or Ankylosing Spondylitis Disease Activity Score-C-reactive protein, number of tender and swollen joints, and enthesitis), and functional status (Bath Ankylosing Spondylitis Functional Index and Health Assessment Questionnaire) were collected. Regression analysis was used to explore factors associated with each EuroQOL-5 Dimensions (EQ-5D) domain, HU, and PASS. RESULTS: Among 119 AS patients, the mean age was 40.4 years; 61.3% were male. The mean EQ-5D was 0.75. In univariate analysis, lower disease activity and less impaired function were significantly associated with higher HU and no to mild problem in each EQ-5D domain. In multivariate regression analysis, Bath Ankylosing Spondylitis Disease Activity Index, C-reactive protein, and Health Assessment Questionnaire adjusting for age explained 77.4% of the HU variance. Patients answering yes to PASS had significantly higher age, higher HU, and lower disease activity compared with those answering no to PASS. Usual activity and pain problems were the most important relations to PASS after adjusting for other domains and age. CONCLUSIONS: Disease activity and functional status in AS patients were significant factors related to HU and PASS. To improve quality of life, the goal of treatment should be achieving remission, improving function, and controlling pain. PMID- 29509564 TI - Development of a Diagnostic Prediction Model for Conductive Conditions in Neonates Using Wideband Acoustic Immittance. AB - OBJECTIVES: Wideband acoustic immittance (WAI) is an emerging test of middle-ear function with potential applications for neonates in screening and diagnostic settings. Previous large-scale diagnostic accuracy studies have assessed the performance of WAI against evoked otoacoustic emissions, but further research is needed using a more stringent reference standard. Research into suitable quantitative techniques to analyze the large volume of data produced by WAI is still in its infancy. Prediction models are an attractive method for analysis of multivariate data because they provide individualized probabilities that a subject has the condition. A clinically useful prediction model must accurately discriminate between normal and abnormal cases and be well calibrated (i.e., give accurate predictions). The present study aimed to develop a diagnostic prediction model for detecting conductive conditions in neonates using WAI. A stringent reference standard was created by combining results of high-frequency tympanometry and distortion product otoacoustic emissions. DESIGN: High-frequency tympanometry and distortion product otoacoustic emissions were performed on both ears of 629 healthy neonates to assess outer- and middle-ear function. Wideband absorbance and complex admittance (magnitude and phase) were measured at frequencies ranging from 226 to 8000 Hz in each neonate at ambient pressure using a click stimulus. Results from one ear of each neonate were used to develop the prediction model. WAI results were used as logistic regression predictors to model the probability that an ear had outer/middle-ear dysfunction. WAI variables were modeled both linearly and nonlinearly, to test whether allowing nonlinearity improved model fit and thus calibration. The best-fitting model was validated using the opposite ears and with bootstrap resampling. RESULTS: The best-fitting model used absorbance at 1000 and 2000 Hz, admittance magnitude at 1000 and 2000 Hz, and admittance phase at 1000 and 4000 Hz modeled as nonlinear variables. The model accurately discriminated between normal and abnormal ears, with an area under the receiver-operating characteristic curve (AUC) of 0.88. It effectively generalized to the opposite ears (AUC = 0.90) and with bootstrap resampling (AUC = 0.85). The model was well calibrated, with predicted probabilities aligning closely to observed results. CONCLUSIONS: The developed prediction model accurately discriminated between normal and dysfunctional ears and was well calibrated. The model has potential applications in screening or diagnostic contexts. In a screening context, probabilities could be used to set a referral threshold that is intuitive, easy to apply, and sensitive to the costs associated with true- and false-positive referrals. In a clinical setting, using predicted probabilities in conjunction with graphical displays of WAI could be used for individualized diagnoses. Future research investigating the use of the model in diagnostic or screening settings is warranted. PMID- 29509565 TI - Clinical Outcomes of Endoscopic Metal Stent Placement for Esophagojejunostomy Leakage After Total Gastrectomy for Gastric Adenocarcinoma. AB - OBJECTIVE: Management of esophagojejunostomy leakage (EJL) has a high mortality rate and increases length of hospital stay. The aim of this study was to evaluate the feasibility of early postoperative gastroduodenoscopy and stent insertion to control EJL after total gastrectomy for gastric adenocarcinoma. PATIENTS AND METHODS: Among 421 patients, 13 exhibited EJL. Of the 13 patients, 8 were treated with a covered self-expandable metal stent (SEMS) inserted by endoscopy and 5 patients were treated with surgery or conservative treatment. RESULTS: The mortality rate was 0% in the SEMS-treated group. The median duration from primary surgery to discovery of leakage was 3.00 days overall [interquartile range (IQR), 2.00 to 5.50 d]. The time to enteral feeding after operation was 24.00 days (IQR, 18.00 to 31.00 d). Median postoperative hospital days was 35.0 days (IQR, 21.00 to 65.00 d). Median duration from leakage to gastroduodenoscopy was 7.00 days (IQR, 1.25 to 14.50 d). On endoscopic findings, most sizes of leakage site were 25% or smaller (8/9, 88.9%) within whole anastomosis size. Eight patients were treated by SEMS. No endoscopic procedure-related or leakage-related deaths occurred. CONCLUSIONS: The promising results for endoscopic treatment in this study showed that early endoscopic treatment using a covered SEMS for EJL might be a feasible, safe, and effective method in selected patients. PMID- 29509566 TI - Prevalence of Mycoplasma genitalium and Azithromycin-resistant Infections Among Remnant Clinical Specimens, Los Angeles. AB - BACKGROUND: Mycoplasma genitalium is an important cause of bacterial sexually transmitted diseases. Diagnosis and susceptibility testing of M. genitalium are limited by the fastidious nature of the organism. Therefore, the prevalence of infection and azithromycin resistance are poorly studied. METHODS: We conducted an exploratory study on remnant clinical specimens. We collected remnant DNA from consecutive urine samples and clinical swabs (cervical/vaginal, rectal, and pharyngeal) previously tested for Neisseria gonorrhoeae and Chlamydia trachomatis using the Cobas 4800 CT/NG assay (Roche Molecular Systems, Pleasanton, CA) between March-April 2017 from across the University of California, Los Angeles Health System. We then retrospectively tested all specimens with the ResistancePlus MG (550) kit, a molecular assay for the detection of M. genitalium and genetic mutations associated with azithromycin resistance. RESULTS: Among 500 specimens, the prevalence of M. genitalium was 1.1% (95% confidence interval [CI], 0.04%-3.0%) in urine samples (n = 362), 17.4% (95% CI, 5.7%-39.6%) in rectal swabs (n = 23), and 1.9% (95% CI, 0.3%-7.3%) in cervical/vaginal swabs (n = 106). The prevalence of N. gonorrhoeae was 0.6% in urine samples and 4.3% in rectal swabs, whereas the prevalence of C. trachomatis was 2.2% in urine samples, 4.3% in rectal swabs and 3.8% in cervical/vaginal swabs. Of the 10 M. genitalium positive specimens, 8 (80.0%) had a mutation associated with azithromycin resistance. CONCLUSIONS: The prevalence of M. genitalium infection in our population varied by anatomic site of infection. Most M. genitalium infections had at least 1 mutation associated with azithromycin resistance. PMID- 29509567 TI - Immunomodulatory Effects of Fentanyl or Dexmedetomidine Hydrochloride Infusion After Allogeneic Heart Transplantation in Mice. AB - BACKGROUND AND OBJECTIVES: Postoperatively, transplant recipients receive immunosuppressants, as well as sedatives and analgesics. The immunomodulatory effects of these other agents during the induction period following transplantation remain unclear. We aimed to determine whether the agents dexmedetomidine hydrochloride (Dex) and fentanyl (Fen) have immunomodulatory effects during the induction period following heart transplantation (HTx). METHODS: Fifty mice were used for antinociception tests after administration of Dex and Fen, and T cells from 3 naive animals were used for in vitro lymphocyte transformation test (study 1). Fifty-four B6 mice received HTx from BALB/c mice and were treated with Dex, Fen, or neither (study 2). Thirty-six recipients were used for graft survival data and were humanely killed at the time of cessation of heart graft contraction. The remaining 18 were humanely killed at either postoperative day (POD) 4 or 6 for histologic examination of graft survival, as well as in vitro analysis. RESULTS: Based on the results of study 1, daily intraperitoneal administration of Dex at 30 MUg/kg or Fen at 0.25 mg/kg was determined to be the optimal dose to induce analgesia without oversedation following HTx. Graft survivals in both Dex- or Fen-treated animals were statistically prolonged compared with control (P < 0.01). Graft survival of Fen treated recipients was increased up to 15 days, and graft survival of Dex-treated animals was also increased up to 10 days, whereas control mice rejected heart grafts by POD 7. Mixed lymphocyte reaction responses on POD 4 showed statistically lower responses in Dex-treated recipients and Fen-treated recipients when compared with controls (P < 0.01). Cytokine profiles of splenocytes showed markedly fewer interferon gamma-positive splenocytes in Fen treated recipients on POD 4. CONCLUSIONS: These data suggest that both Dex and Fen have immunomodulatory properties in the induction period following transplantation. PMID- 29509569 TI - Association of Early Myocardial Workload and Mortality Following Severe Traumatic Brain Injury. AB - OBJECTIVES: To examine the impact of early myocardial workload on in-hospital mortality following isolated severe traumatic brain injury. DESIGN: Retrospective cohort study. SETTING: Data from the National Trauma Databank, a multicenter trauma registry operated by the American College of Surgeons, from 2007 to 2014. PATIENTS: Adult patients with isolated severe traumatic brain injury (defined as admission Glasgow Coma Scale < 8 and head Abbreviated Injury Score >= 4). INTERVENTIONS: Admission rate-pressure product, categorized into five levels based on published low, normal, and submaximal human thresholds: less than 5,000; 5,000-9,999; 10,000-14,999; 15,000-19,999; and greater than 20,000. MEASUREMENTS AND MAIN RESULTS: Data from 26,412 patients were analyzed. Most patients had a normal rate-pressure product (43%), 35% had elevated rate-pressure product, and 22% had depressed rate-pressure product at hospital admission. Compared with the normal rate-pressure product group, in-hospital mortality was 22 percentage points higher in the lowest rate-pressure product group (cumulative mortality, 50.2%; 95% CI, 43.6-56.9%) and 11 percentage points higher in the highest rate pressure product group (cumulative mortality, 39.2%; 95% CI, 37.4-40.9%). The lowest rate-pressure product group was associated with a 50% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.50; 95% CI, 1.31-1.76%; p < 0.0001), and the highest rate pressure product group was associated with a 25% increased risk of mortality, compared with the normal rate-pressure product group (adjusted relative risk, 1.25; 95% CI, 1.18-1.92%; p < 0.0001). This relationship was blunted with increasing age. Among patients with normotension, those with depressed and elevated rate-pressure products experienced increased mortality. CONCLUSIONS: Adults with severe traumatic brain injury experience heterogeneous myocardial workload profiles that have a "U-shaped" relationship with mortality, even in the presence of a normal blood pressure. Our findings are novel and suggest that cardiac performance is important following severe traumatic brain injury. PMID- 29509570 TI - Liberal Glucose Control in ICU Patients With Diabetes: A Before-and-After Study. AB - OBJECTIVES: To assess the feasibility, biochemical efficacy, and safety of liberal versus conventional glucose control in ICU patients with diabetes. DESIGN: Prospective, open-label, sequential period study. SETTING: A 22-bed mixed ICU of a tertiary hospital in Australia. PATIENTS: We compared 350 consecutive patients with diabetes admitted over 15 months who received liberal glucose control with a preintervention control population of 350 consecutive patients with diabetes who received conventional glucose control. INTERVENTIONS: Liberal control patients received insulin therapy if glucose was greater than 14 mmol/L (target: 10-14 mmol/L [180-252 mg/dL]). Conventional control patients received insulin therapy if glucose was greater than 10 mmol/L (target: 6-10 mmol/L [108 180 mg/dL]). MEASUREMENTS AND MAIN RESULTS: We assessed separation in blood glucose, insulin requirements, occurrence of hypoglycemia (blood glucose <= 3.9 mmol/L [70 mg/dL]), creatinine and white cell count levels, and clinical outcomes. The median (interquartile range) time-weighted average blood glucose concentration was significantly higher in the liberal control group (11.0 mmol/L [8.7-12.0 mmol/L]; 198 mg/dL [157-216 mg/dL]) than in the conventional control group (9.6 mmol/L [8.5-11.0 mmol/L]; 173 mg/dL [153-198 mg/dL]; p < 0.001). Overall, 132 liberal control patients (37.7%) and 188 conventional control patients (53.7%) received insulin in ICU (p < 0.001). Hypoglycemia occurred in 6.6% and 8.6%, respectively (p = 0.32). Among 314 patients with glycated hemoglobin A1c greater than or equal to 7%, hypoglycemia occurred in 4.1% and 9.6%, respectively (p = 0.053). Trajectories of creatinine and white cell count were similar in the groups. In multivariable analyses, we found no independent association between glucose control and mortality, duration of mechanical ventilation, or ICU-free days to day 30. CONCLUSIONS: In ICU patients with diabetes, during a period of liberal glucose control, insulin administration, and among patients with hemoglobin A1c greater than or equal to 7%, the prevalence of hypoglycemia was reduced, without negatively affecting serum creatinine, the white cell count response, or other clinical outcomes. (Trial Registration: Australian New Zealand Clinical Trials Registry; ACTRN12615000216516). PMID- 29509571 TI - Fulminant Acute Respiratory Distress Syndrome After Calcineurin Inhibitor belatacept Conversion in a Lung Transplant Recipient. PMID- 29509572 TI - Porcine Isolated Liver Perfusion for the Study of Ischemia Reperfusion Injury: A Systematic Review. AB - BACKGROUND: Understanding ischemia reperfusion injury (IRI) is essential to further improve outcomes after liver transplantation (LT). Porcine isolated liver perfusion (ILP) is increasingly used to reproduce LT-associated IRI in a strictly controlled environment. However, whether ILP is a reliable substitute of LT was never validated. METHODS: We systematically reviewed the current experimental setups for ILP and parameters of interest reflecting IRI. RESULTS: Isolated liver perfusion was never compared with transplantation in animals. Considerable variability exists between setups, and comparative data are unavailable. Experience so far suggests that centrifugal pump(s) with continuous flow are preferred to reduce the risk of embolism. Hepatic outflow can be established by cannulation of the inferior vena cava or freely drained in an open bath. Whole blood at approximately 38 degrees C, hematocrit of 20% or greater, and the presence of leukocytes to trigger inflammation is considered the optimal perfusate. A number of parameters related to the 4 liver compartments (hepatocyte, cholangiocyte, endothelium, immune cells) are available; however, their significance and relation to clinical outcomes is not well described. CONCLUSIONS: Porcine ILP provides a reproducible model to study early IRI events. As all models, it has its limitations. A standardization of the setup would allow comparison of data and progress in the field. PMID- 29509573 TI - Specific Immunity to Cytomegalovirus in Pediatric Cardiac Transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) infection is implicated in endothelial dysfunction and graft damage after pediatric heart transplantation. CMV-specific immune responses are thought to be necessary for CMV viral control but there is little data in pediatric heart transplantation. METHODS: We studied 28 consecutive pediatric heart transplant recipients for 1 year posttransplant. CMV T-cell expressing IFN-gamma, TNF-alpha, and IL-2 in response to ex vivo stimulation with CMV lysates or peptides were measured. Circulating cytokines were measured in plasma. Generalized Additive Models were applied to the data to model changes of cell population dynamics over time. RESULTS: CMV-specific T cell mediated responses were impaired in the first 8 weeks posttransplant. During this period, 25% of patients had CMV viremia, of which those with VLs of 10 000 or more CMV deoxyribonucleic acid copies/mL were given ganciclovir. In this group, the frequency of CD4+ and CD8+ T cells producing IFN-gamma and the CD8+CD57+ granzyme B+ T-cell population increased at 12 to 24 weeks and remained elevated for the duration of the study. CONCLUSIONS: We have shown that CMV viremia is associated with CMV-specific immune responses and increased CD8+CD57+ granzyme B+ cells at 1 year posttransplant; however, early responses were not predictive of impending CMV viremia. It remains to be seen if the early CMV immune response detected is associated with endothelial and allograft damage, in light of previous studies demonstrating increased vasculopathy in pediatric patients with CMV viremia. PMID- 29509574 TI - Preemptive Kidney Transplantation: What's the Hold Up? PMID- 29509575 TI - Serous Cystic Neoplasms of the Pancreas: Endoscopic Ultrasonographic Versus Computed Tomography and Magnetic Resonance Imaging Features of Surgically Removed Masses. AB - Our purpose was to assess the endoscopic ultrasonography (EUS) features of serous cystic neoplasms (SCNs) of the pancreas in determining the surgical removal compared with computed tomography (CT) and magnetic resonance imaging (MRI) features. For 33 consecutive patients with 34 surgically confirmed SCNs over the past 11 years, preoperative EUS features were compared with those of CT and MRI (CT&MRI). Besides the lesion size and location, a retrospective analysis of the various imaging features was performed by 2 observers to understand the characteristics that determine the need for surgical intervention in terms of multiplicity of locules, calcification, mural thickening, mural nodules, ductal communication, and main pancreatic duct dilatation in addition to the gross morphologic type: microcystic, macrocystic (>1 cm), mixed, or solid. The most common gross morphologic type was mixed lesions, which consisted of microcystic and macrocystic components (15/34; 44%), followed by microcystic (38%), macrocystic (15%), and solid (3%) lesions. A minority (5/34; 18%) of the lesions showed main pancreatic duct dilatation (upstream, n = 3; downstream, n = 0; diffuse, n = 2). Mural nodules or solid components were more frequently noted in EUS (67%) than in CT&MRI (25%; P = 0.001), whereas other findings showed no remarkable difference between EUS and CT&MRI (P > 0.05). In determining the surgical treatment of multiloculated cystic lesions, interpretation of EUS features for the presence of solid component or mural nodules should be more carefully determined, especially in the patients with suggestive features of SCN on CT or MRI to avoid unnecessary surgery. PMID- 29509576 TI - Supporting Our Team Through Creating Awareness: The Society of Radiologists in Ultrasound Sonographer Relations Committee Response to the 2016 Society of Diagnostic Medical Sonography Consensus Conference on Work Related Musculoskeletal Disorders. AB - Musculoskeletal injuries have been and remain a significant issue for sonographers. Despite its importance, the topic of musculoskeletal injury in sonographers has received little attention in the radiology literature. Our goal is to bring this extremely important issue to the forefront, with the hope of initiating conversations and actions leading to improved workplace practices for sonographers. PMID- 29509577 TI - Optimizing the Time for Developmental Dysplasia of the Hip Screening: Earlier or Later? AB - INTRODUCTION: Developmental dysplasia of the hip (DDH) is still a common and important disorder of childhood, with a prevalence of 0.1 to 2/1000 children. Using ultrasonography (US) in screening of DDH reduces the rates of open reductions and complications. In the current study, we aim to detect the optimal time for US examination for detecting DDH to prevent unnecessary repeating US examinations and treatments. METHODS: Children referred to US examination for a healthy child screening program, according to the health policy of our country, are included in the current prospective study. Both hips of each child were sonographically examined by the same radiologist using Graf's method at 4th, 8th, 12th weeks of life. RESULTS: A total of 2020 hips of 1010 children were examined. Fourth-week US results can predict 12th-week results (right hip: sensitivity 100%, specificity 75.7%; left hip: sensitivity 100%, specificity 78.3%). Eighth week US results can predict 12th-week results (right hip: sensitivity 100%, specificity 87.5%; left hip: sensitivity 100%, specificity 83.9%). In predicting 12th-week US results, 8th-week results are found to be more successful than 4th week results. CONCLUSIONS: Late diagnosis of DDH might cause serious public health problems. On the other hand, early US examinations can result in false positive diagnosis. Unfortunately, there is still confusion about the optimal time for DDH screening with US, especially among radiologists who are not specialized in DDH sonography. A US scan performed at eighth week of life can predict any pathology presence safely and correctly. PMID- 29509578 TI - Penile Metastases From Renal Cell Carcinoma: Pre and Postcontrast Sonographic Findings. AB - The prostate and bladder are the most common primary cancer sites for penile metastases. Here, we describe an unusual case of metastases from renal cell carcinoma to the penis discovered 1 month after nephrectomy in a 60-year-old man. The diagnosis was achieved using B-mode and contrast-enhanced ultrasound. PMID- 29509579 TI - Does Equi-Minimum Alveolar Concentration Value Ensure Equivalent Analgesic or Hypnotic Potency?: A Comparison between Desflurane and Sevoflurane. AB - BACKGROUND: Minimum alveolar concentration (MAC) has traditionally been used to compare the potency of volatile anesthetics. However, as it reflects the spinal mechanism of immobility rather than the cerebral mechanism of analgesia and hypnosis, it is doubtful that equi-MAC connotes equivalent analgesic or hypnotic potency. The level of analgesia and hypnosis can be assessed using surgical pleth index and bispectral index (BIS) values, respectively. This study was designed to compare the surgical pleth index and BIS values produced by equi-MAC of desflurane and sevoflurane in patients undergoing single-agent volatile anesthesia. METHODS: Eighty-nine patients were randomly allocated to two groups receiving either desflurane (n = 44) or sevoflurane (n = 45). Anesthesia was only maintained with assigned volatile anesthetic of age-corrected 1.0 MAC. Surgical pleth index values as an analgesic estimate and BIS values as a hypnotic estimate were obtained under standard tetanic stimulation. RESULTS: Post-stimulation surgical pleth index values (mean +/- SD), the primary outcome, were significantly lower for the desflurane group than those for the sevoflurane group (49 +/- 10 vs. 64 +/- 14, difference, 15 [95% CI, 10 to 20], P < 0.001). The desflurane group showed significantly lower poststimulation BIS values (median [interquartile range]) than the sevoflurane group (36 [31 to 41] vs. 41 [38 to 47], difference, 6 [95% CI, 2 to 9], P = 0.001). CONCLUSIONS: During a steady state of 1.0 MAC, desflurane and sevoflurane did not cause similar surgical pleth index and BIS values under the standardized nociceptive stimulus. These findings suggest that equi-MAC of desflurane and sevoflurane may not ensure equivalent analgesic or hypnotic potency. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B726. PMID- 29509581 TI - Subjective Objective: A Researcher's Narrative on Human Relationships. PMID- 29509580 TI - Application of Focused Assessment Ultrasound in Trauma to Perioperative Medicine: A Tool to Quickly Diagnose Postoperative Hemorrhage. PMID- 29509582 TI - Ketamine Action in the In Vitro Cortical Slice Is Mitigated by Potassium Channel Blockade. AB - BACKGROUND: Ketamine is a general anesthetic thought to act by antagonizing N methyl-D-aspartate receptors. However, ketamine acts on multiple channels, many of which are potential targets-including hyperpolarization-activated cyclic nucleotide-gated and potassium channels. In this study we tested the hypothesis that potassium leak channels contribute to the anesthetic action of ketamine. METHODS: Adult mouse cortical slices (400 um) were exposed to no-magnesium artificial cerebrospinal fluid to generate seizure-like event activity. The reduction in seizure-like event frequency after exposure to ketamine (n = 14) was quantified as a signature of anesthetic effect. Pharmacologic manipulation of hyperpolarization-activated cyclic nucleotide-gated and potassium channels using ZD7288 (n = 11), cesium chloride (n = 10), barium chloride (n = 10), low potassium (1.5 mM) artificial cerebrospinal fluid (n = 10), and urethane (n = 7) were investigated. RESULTS: Ketamine reduced the frequency of seizure-like events (mean [SD], -62 [22]%, P < 0.0001). Selective hyperpolarization-activated cyclic nucleotide-gated channel block with ZD7288 did not significantly alter the potency of ketamine to inhibit seizure-like event activity. The inhibition of seizure-like event frequency by ketamine was fully antagonized by the potassium channel blockers cesium chloride and barium chloride (8 [26]% and 39 [58%] increase, respectively, P < 0.0001, compared to ketamine control) and was facilitated by the potassium leak channel opener urethane (-93 [8]%, P = 0.002 compared to ketamine control) and low potassium artificial cerebrospinal fluid ( 86 [11]%, P = 0.004 compared to ketamine control). CONCLUSIONS: The results of this study show that mechanisms additional to hyperpolarization-activated cyclic nucleotide-gated channel block are likely to explain the anesthetic action of ketamine and suggest facilitatory action at two-pore potassium leak channels. PMID- 29509583 TI - Worlds Apart. PMID- 29509584 TI - Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia In Vivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro. AB - BACKGROUND: Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. METHODS: Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. RESULTS: Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 +/- 7%, n = 14) and kidney (19 +/- 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 +/- 9%, unselective Nav-inhibitor), ICA121431 (53 +/- 10%), and Pterinotoxin-2 (55 +/- 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 +/- 19%), ICA121431 (62 +/- 22%), and Pterinotoxin-2 (59 +/- 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 * 20 cells). Lidocaine reduced neutrophil adhesion to 60 +/- 9% (n = 10) and transmigration to 54 +/- 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. CONCLUSIONS: Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine. PMID- 29509585 TI - Arterial Lactate Concentration at the End of Liver Transplantation is an Early Predictor of Primary Graft Dysfunction. AB - BACKGROUND: Although many prognostic factors of primary graft dysfunction after liver transplantation (LT) are available, it remains difficult to predict failure in a given recipient. OBJECTIVE: We aimed to determine whether the intraoperative assay of arterial lactate concentration at the end of LT (LCEOT) might constitute a reliable biological test to predict early outcomes [primary nonfunction (PNF), early graft dysfunction (EAD)]. METHODS: We reviewed data from a prospective database in a single center concerning patients transplanted between January 2015 and December 2016 (n = 296). RESULTS: There was no statistical imbalance between the training (year 2015) and validation groups (year 2016) for epidemiological and perioperative feature. Ten patients (3.4%) presented with PNF, and EAD occurred in 62 patients (20.9%); 9 patients died before postoperative day (POD) 90. LCEOT >=5 mmol/L was the best cut-off point to predict PNF (Se=83.3%, SP=74.3%, positive likelihood ratio (LR+)=3.65, negative likelihood ratio (LR )=0.25, diagnostic odds ratio (DOR)=14.44) and was predictive of PNF (P = 0.02), EAD (P = 0.05), and death <= POD90 (P = 0.06). Added to the validated BAR-score, LCEOT improved its predictive value regarding POD 90 survival with a better AUC (0.87) than BAR score (0.74). The predictive value of LCEOT was confirmed in the validation cohort. CONCLUSION: As a reflection of both hypoperfusion and tissue damage, the assay of arterial LCEOT >=5 mmol/L appears to be a strong predictor of early graft outcomes and may be used as an endpoint in studies assessing the impact of perioperative management. Its accessibility and low cost could impose it as a reliable parameter to anticipate postoperative management and help clinicians for decision-making in the first PODs. PMID- 29509586 TI - LAP-VEGaS Practice Guidelines for Reporting of Educational Videos in Laparoscopic Surgery: A Joint Trainers and Trainees Consensus Statement. AB - OBJECTIVE: Consensus statement by an international multispecialty trainers and trainees expert committee on guidelines for reporting of educational videos in laparoscopic surgery. SUMMARY OF BACKGROUND DATA: Instructive laparoscopy videos with appropriate exposition could be ideal for initial training in laparoscopic surgery, but there are no guidelines for video annotation or procedural educational and safety evaluation. METHODS: Delphi questionnaire of 45 statements prepared by a steering group and voted on over 2 rounds by committee members using an electronic survey tool. Committee selection design included representative surgical training experts worldwide across different laparoscopic specialties, including general surgery, lower and upper gastrointestinal surgery, gynecology and urology, and a proportion of aligned surgical trainees. RESULTS: All 33 committee members completed both the first and the second round of the Delphi questionnaire related to 7 major domains: Video Introduction/Authors' information; Patient Details; Procedure Description; Procedure Outcome; Associated Educational Content; Peer Review; and Use in Educational Curriculae. The 17 statements that did not reach at least 80% agreement after the first round were revised and returned into the second round. The committee consensus approved 37 statements to at least an 82% agreement. CONCLUSION: Consensus guidelines on how to report laparoscopic surgery videos for educational purposes have been developed. We anticipate that following our guidelines could help to improve video quality.These reporting guidelines may be useful as a standard for reviewing videos submitted for publication or conference presentation. PMID- 29509587 TI - Cango Lyec (Healing the Elephant): Gender Differences in HIV Infection in Post conflict Northern Uganda. AB - BACKGROUND: As previously encamped resettle, potential for rapid HIV transmission in post-conflict Northern Uganda is concerning. Women in particular may be experiencing heightened vulnerability resulting from war-related sexual violence. SETTING: Cango Lyec (Healing the Elephant) Project is a cohort involving conflict affected people in 3 districts in Northern Uganda. METHODS: Eight randomly selected communities were mapped, and a census was conducted. Participants aged 13-49 years completed questionnaires in Luo on war-related experiences, mental health, sexual vulnerabilities, and sociodemographics. Blood samples were tested for HIV and syphilis. Baseline data from all sexually active participants was used to determine gender differences in HIV prevalence. Multivariate modeling determined correlates of HIV by gender. RESULTS: Among 2008 participants, HIV prevalence was higher among women [17.2; 95% confidence interval (CI): 14.7 to 19.7] compared to men (10.6; 95% CI: 8.0 to 13.2, <0.001). Among women, correlates of HIV included: war-related sexual assault [adjusted odds ratio (AOR): 1.95; 95% CI: 1.16 to 3.26]; probable depression (AOR: 2.22; 95% CI: 1.46 to 3.37); probable post-traumatic stress disorder (AOR: 2.03; 95% CI: 1.45 to 2.84); experiencing >=12 traumatic events (AOR: 2.04; 95% CI: 1.31 to 3.18); suicide ideation (AOR: 1.67; 95% CI: 1.22 to 2.28); living in a female-headed household (AOR: 2.76; 95% CI: 1.70 to 4.49); first sexual partner >=10 years older (AOR: 1.69; 95% CI: 1.07 to 2.67); sex for exchange (AOR: 5.51; 95% CI: 1.76 to 17.31); having 2 (AOR: 2.54; 95% CI: 1.23 to 5.23) or 3+ (AOR: 4.65; 95% CI: 2.65 to 8.18) sexual partners; inconsistent condom use (AOR: 0.40; 95% CI: 0.29 to 0.57); genital ulcers (AOR: 3.08; 95% CI: 2.16 to 4.38); active syphilis (AOR: 4.33; 95% CI: 1.22 to 15.40); and ill health without medical care (AOR: 2.02; 95% CI: 1.22 to 3.34). Among men, correlates of HIV included no condom at sexual debut (AOR: 1.92; 95% CI: 1.30 to 2.83) and genital ulcers (AOR: 4.40; 95% CI: 1.35 to 14.40). CONCLUSION: Women are disproportionately impacted by HIV, trauma, and depression in this conflict-affected population. Trauma-informed HIV prevention and culturally safe mental health initiatives are urgently required. PMID- 29509588 TI - A Prospective Evaluation of a Multisite Cryptococcal Screening and Treatment Program in HIV Clinics in Uganda. AB - BACKGROUND: Cryptococcus is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) is detectable in blood before meningitis onset and predicts death. CrAg screening among those with advanced HIV, and treatment of those CrAg+ with fluconazole, has demonstrated survival benefit. However, implementation and widespread uptake have been slow outside clinical trials. METHODS: We designed a CrAg screening program for routine care that incorporated intensive education and training of clinic staff. We evaluated programmatic implementation, including time to initiation of fluconazole, time to initiation of antiretroviral therapy, and 6-month clinical outcomes. RESULTS: Between December 2015 and January 2017, 1440 persons were screened at 11 HIV clinics in Kampala, and CRAG+ prevalence was 6.5% (n = 94/1440) among adults with a CD4 <100 cells/uL. Of those CrAg+, 7 of 94 persons (7%) died or were lost before further clinic evaluation. Fifty-three persons (56%) were asymptomatic and had 6-month survival of 87% (46/53). Of CrAg+ persons, 28% (26/94) were symptomatic at the time of clinic return. Most had confirmed cryptococcal meningitis, and 54% (14/26) of the symptomatic CrAg+ persons were dead or lost at 6 months. Of the 7 symptomatic persons who declined lumbar puncture for further evaluation, all were dead or lost by 6 months. CONCLUSION: All asymptomatic CrAg+ persons identified by our screening program who returned to clinic, initated fluconazole and antiretroviral therapy in a timely manner. Despite this, 27% of CrAg+ (asymptomatic and symptomatic) identified on routine screening were dead or lost to follow-up at 6 months, even with preemptive therapy for those asymptomatic, and standard amphotericin-based treatment for meningitis. PMID- 29509589 TI - Gaps Along the HIV Care Continuum: Findings Among a Population Seeking Sexual Health Care Services in New York City. AB - BACKGROUND: Linkage/relinkage to HIV care for virally unsuppressed people with new sexually transmitted infections is critical for ending the HIV epidemic. We quantified HIV care continuum gaps and viral suppression among HIV-positive patients attending New York City (NYC) sexual health clinics (SHCs). METHODS: One thousand six hundred forty-nine HIV-positive patients and a 10% sample of 11,954 patients with unknown HIV status on clinic visit date (DOV) were matched against the NYC HIV registry. Using registry diagnosis dates, we categorized matched HIV positive patients as "new-positives" (newly diagnosed on DOV), "recent-positives (diagnosed <=90 days before DOV), "prevalent-positives" (diagnosed >90 days before DOV), and "unknown-positives" (previously diagnosed but status unknown to clinic on DOV). We assessed HIV care continuum outcomes before and after DOV for new-positives, prevalent-positives, and unknown-positives using registry laboratory data. RESULTS: In addition to 1626 known HIV-positive patients, 5% of the unknown sample (63/1196) matched to the registry, signifying that approximately 630 additional HIV-positive patients attended SHCs. Of new positives, 65% were linked to care after DOV. Of prevalent-positives, 66% were in care on DOV; 43% of the out-of-care patients were relinked after DOV. Of unknown positives, 40% were in care on DOV; 21% of the out-of-care patients relinked after DOV. Viral suppression was achieved by 88% of in-care unknown-positives, 76% in-care prevalent-positives, 50% new-positives, 42% out-of-care prevalent positives, and 16% out-of-care unknown-positives. CONCLUSIONS: Many HIV-positive people, including those with uncontrolled HIV infection, attend SHCs and potentially contribute to HIV spread. However, HIV status often is not known to staff, resulting in missed linkage/relinkage to care opportunities. Better outcomes could be facilitated by real-time ascertainment of HIV status and HIV care status. PMID- 29509590 TI - Time to First-Line ART Failure and Time to Second-Line ART Switch in the IeDEA Pediatric Cohort. AB - BACKGROUND: Globally, 49% of the estimated 1.8 million children living with HIV are accessing antiretroviral therapy (ART). There are limited data concerning long-term durability of first-line ART regimens and time to transition to second line. METHODS: Children initiating their first ART regimen between 2 and 14 years of age and enrolled in one of 208 sites in 30 Asia-Pacific and African countries participating in the Pediatric International Epidemiology Databases to Evaluate AIDS consortium were included in this analysis. Outcomes of interest were: first line ART failure (clinical, immunologic, or virologic), change to second-line, and attrition (death or loss to program ). Cumulative incidence was computed for first-line failure and second-line initiation, with attrition as a competing event. RESULTS: In 27,031 children, median age at ART initiation was 6.7 years. Median baseline CD4% for children <=5 years of age was 13.2% and CD4 count for those >5 years was 258 cells per microliter. Almost all (94.4%) initiated a nonnucleoside reverse transcriptase inhibitor; 5.3% a protease inhibitor, and 0.3% a triple nucleoside reverse transcriptase inhibitor-based regimen. At 1 year, 7.7% had failed and 14.4% had experienced attrition; by 5 years, the cumulative incidence was 25.9% and 29.4%, respectively. At 1 year after ART failure, 13.7% had transitioned to second-line and 11.2% had experienced attrition; by 5 years, the cumulative incidence was 31.6% and 25.9%, respectively. CONCLUSIONS: High rates of first-line failure and attrition were identified in children within 5 years after ART initiation. Of children meeting failure criteria, only one-third were transitioned to second-line ART within 5 years. PMID- 29509591 TI - Phase I/II Study of Hepatic Arterial Infusion of Nab-paclitaxel in Patients With Metastatic Melanoma to the Liver. AB - OBJECTIVES: Hepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anticancer therapy to liver metastases that derive their blood supply from the hepatic artery. Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination. Nanoparticle albumin-bound paclitaxel (nab paclitaxel) has demonstrated efficacy in MM and first-pass hepatic metabolism. Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end organ of interest, with minimal systemic exposure. PATIENT AND METHODS: We performed a single-institution open-label phase I/II study of HAI of nab-paclitaxel in MM patients with liver metastasis. Patients received treatment every 21 days at 4 different dose levels. The primary objective of the phase I portion of the study was safety and determination of the maximum-tolerated dose. The primary objective of the phase II portion of the study was overall response rate per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0. RESULTS: A total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma. The maximum-tolerated dose was 220 mg/m and 19 patients were treated at this dose. There was 1 patient (5%) with a partial response at this dose, and 8 patients (42%) with stable disease at this dose. CONCLUSIONS: HAI nab-paclitaxel demonstrates rare objective responses in melanoma patients with liver metastases. This treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses but should not be considered effective monotherapy. PMID- 29509592 TI - Impact of Trabectedin Interruption and Subsequent Rechallenge on Progression in Patients With Advanced Soft Tissue Sarcoma: Long-term Follow-up of the T-DIS trial. AB - OBJECTIVE: To assess the impact of trabectedin rechallenge. PATIENTS AND METHODS: In the T-DIS trial (NCT0130309), after the 6 initial cycles of trabectedin, patients who were free from progressive disease (PD) were randomly assigned either to continuous treatment with trabectedin (C arm) or therapy interruption (I arm). Patients randomized in the interruption arm were allowed to restart trabectedin in case of PD. Herein we report an update of the impact of trabectedin discontinuation after subsequent rechallenge. RESULTS: From February 2011 to March 2013, 27 and 26 nonprogressive patients were randomized to C and I arm, respectively. Twenty-two of 26 patients in I arm and 25 of 27 patients in C arm received 7 cycles and more. After randomization, the median number of cycles was similar in both arms (C arm: 5 cycles [range, 1 to 34]; I arm: 6 cycles [range, 1 to 48], P=0.96). After a median follow-up from randomization of 35.3 months, continuous treatment with trabectedin was associated with a significant improvement in progression-free survival compared with the rechallenge arm (5.3 vs. 3.5 mo, P=0.019). The observed difference in median overall survival from the seventh cycle did not meet the level of significance (26.0 vs. 14.9 mo, P=0.14). The safety profile was similar in both arms. Mean time spent without symptoms and toxicity (Q-TWIST) was higher in the C arm, but the difference did not reach the level of significance. CONCLUSIONS: We have demonstrated that trabectedin retains its activity when patients are rechallenged on progression after a treatment break. PMID- 29509593 TI - Targeting Tumor Metabolism With Statins During Treatment for Advanced-stage Pancreatic Cancer. AB - INTRODUCTION: A growing body of preclinical data suggests that statins may exert potent antitumor effects, yet the interactions of these medications with standard therapies and clinical outcomes in this population is less clear. We assessed the impact of statin use on outcomes in patients with advanced-stage pancreatic adenocarcinoma undergoing various treatments. MATERIALS AND METHODS: After institutional review board approval, we conducted a retrospective-cohort study consisting of 303 newly diagnosed advanced-stage pancreatic adenocarcinoma patients to determine the impact of statin use on outcomes. Univariate and multivariable Cox proportional hazard regression models were utilized to estimate hazard ratios (HRs). Time-to-event was estimated using Kaplan-Meier survival analysis for overall survival, distant metastasis, and locoregional failure. Baseline and active statin usage were assessed and to mitigate risk of immortal time bias, subanalysis excluding patients with under 6 months of follow-up was conducted. RESULTS: Both prior (P=0.021) and active (P=0.030) statin usage correlated with improved survival in this cohort. Surgery, chemoradiation, and statin use improved 2-year survival rates (84.1% vs. 55.0%; P<0.001). On multivariable analysis, statin exposure was associated with overall survival (HR, 0.662; P=0.027) and trended to significance for freedom from distant metastasis (HR, 0.577; P=0.060). Comorbid conditions were not significantly associated with outcomes. CONCLUSIONS: Statin use was associated with improved overall survival in advanced-stage pancreatic adenocarcinoma patients. This data supports previous findings in early-stage pancreatic adenocarcinoma and other cancer sites. To our knowledge this is the first report to examine the efficacy of statin use as a supplementary treatment option in advanced-stage pancreatic adenocarcinoma patients. PMID- 29509594 TI - Clinical Significance of Molecular Micrometastasis in the Sentinel Lymph Node of Early-stage Non-Small Cell Lung Cancer Patients. AB - OBJECTIVES: Metastatic affectation of lymph node is the main prognostic factor in localized lung cancer. A pathologic study of the obtained samples, even after adequate lymphadenectomy, showed tumor relapses for 20% of stage I patients after oncological curative surgery. We evaluated the prognostic value of molecular micrometastasis in the sentinel lymph node of patients with early-stage lung cancer. PATIENTS AND METHODS: The sentinel node was marked immediately after performing thoracotomy by peritumorally injecting 0.25 mCi of nanocoloid of albumin (Nanocol1) labeled with Tc-99m in 0.3 mL. Guided by a Navigator1 gammagraphic sensor, we proceeded to its resection. The RNA of the tissue was extracted, and the presence of genes CEACAM5, BPIFA1, and CK7 in mRNA was studied. The significant association between the presence of micrometastasis, clinicopathologic characteristics, and patients' outcome was assessed. RESULTS: Eighty-nine stage I-II non-small cell lung cancer patients were included in the study. Of the 89 analyzed sentinel lymph nodes, 44 (49.4%) were positive for CK7, 24 (26.9%) for CEACAM5, and 17 (19.1%) for BPIFA1, whereas 10 (11.2%) were positive for the 3 analyzed genes. A survival analysis showed no significant relation between the presence of molecular micrometastasis in the sentinel node and patients' progression. CONCLUSIONS: The molecular analysis of the sentinel node in patients with early-stage lung cancer shows node affectation in cases staged as stage I/II by hematoxylin-eosin or an immunohistochemical analysis. However, this nodal affectation was not apparently related to patients' outcome. PMID- 29509595 TI - 25-Hydroxyvitamin D (25(OH)D) and biomarkers of ovarian reserve. AB - OBJECTIVE: The aim of the study was to examine the associations between 25 hydroxyvitamin D (25(OH)D) and biomarkers of ovarian reserve in a large community based sample of women. METHODS: In 2010 to 2016, women aged 30 to 44 years without any known fertility problems were recruited from the Chapel Hill, NC area for a prospective time-to-pregnancy cohort study. At enrollment 561 women provided a blood sample that was used to measure 25(OH)D, anti-Mullerian hormone (AMH), follicle-stimulating hormone, and inhibin-B. Unadjusted associations were estimated with Spearman correlation coefficients. Multivariable linear regression was used to estimate associations of 25(OH)D with ovarian reserve biomarkers, after adjusting for age, race, body mass index, smoking history, and recent use of hormonal birth control. RESULTS: The mean 25(OH)D was 36 ng/mL (SD = 11 ng/mL). 25(OH)D was not correlated with AMH, follicle-stimulating hormone, or inhibin-B (all r < 0.03). Multivariable results with continuous hormonal outcomes were also null. For dichotomous outcomes, there was a tendency for insufficient 25(OH)D (<30 ng/mL) to be associated with low AMH (<0.7 ng/mL) (odds ratio [95% CI]: 1.8 [0.9-4]). CONCLUSIONS: For the most part, 25(OH)D was not associated with ovarian reserve biomarkers in a group of women trying to become pregnant. We found some evidence that low 25(OH)D (<30 ng/mL) was associated with low AMH, but this should be confirmed in studies with a higher prevalence of low 25(OH)D. PMID- 29509568 TI - Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II. AB - OBJECTIVE: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. DESIGN: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. SETTING: ICUs. PATIENTS: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively). INTERVENTIONS: IV angiotensin II or placebo. MEASUREMENTS AND MAIN RESULTS: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of >= 10 mm Hg or increase to >= 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively. CONCLUSIONS: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28 day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II. PMID- 29509597 TI - Estrogen therapy: economic considerations. PMID- 29509598 TI - Vaginal pH: a simple assessment highly correlated with vaginal morphology and symptoms in postmenopausal women. AB - OBJECTIVE: The aim of the study was to determine the utility of vaginal pH as a marker of menopause and vulvar and vaginal atrophy (VVA) before and after local estrogen treatment. METHODS: Vaginal pH was determined using standard pH paper strips in two clinical trials involving postmenopausal women with signs and symptoms of VVA evaluated before and after intervention with vaginal estradiol in softgel capsules. The utility of vaginal pH was evaluated as a screening method for VVA due to menopause and correlations were analyzed between vaginal pH and VVA symptoms, physical changes, and maturation of the vaginal epithelium. RESULTS: Changes in vaginal pH were significantly correlated with changes in superficial and parabasal cell counts; vaginal epithelial changes of color, integrity, thickness, and secretion; and the VVA symptoms of vaginal dryness and dyspareunia (vaginal pain with intercourse). CONCLUSIONS: Vaginal pH consistently correlated with parabasal and superficial cells and the visual vaginal epithelial changes and symptoms of dryness and dyspareunia, and is thus a simple outpatient procedure that reflects the hormonal milieu and its effects on the vaginal epithelium. PMID- 29509596 TI - In people living with HIV (PLWH), menopause (natural or surgical) contributes to the greater symptom burden in women: results from an online US survey. AB - OBJECTIVE: The majority of people living with HIV in the United States are now over the age of 50, but symptom burden research has seldom included older women or the potential role of menopause. The aim of the study was to examine the influence of menopause as part of sex differences in HIV symptom burden. METHODS: A cross-sectional study was conducted that included both a sex-based analysis of previously reported HIV symptom characteristics of 1,342 respondents to an online survey (males, n = 957; female, n = 385) and a follow-up online survey of menstrual bleeding patterns (inferred menopause) in eligible females (n = 242) from the respondent pool. Using linear mixed models, we identified predictors of symptom burden scores in female respondents. RESULTS: For the most troublesome symptoms assessed in the sex-based analysis, depression scores were similar (P > 0.05), but higher (worse) burden scores for fatigue (P = 0.013) and muscle aches/pains (P = 0.004) were exclusively observed in females after adjusting for covariates. Respondents to the female survey (n = 222) were predominantly Black, heterosexual, nonsmokers, and obese, with an HIV diagnosis of approximately 16 years and at least one comorbid condition. Burden scores were higher in women reporting amenorrhea due to natural menopause or hysterectomy (n = 104) versus the menstruating group (n = 118) for muscle aches/pains (P = 0.05), fatigue (P = 0.03), and difficulty falling asleep (P = 0.04), independent of age, HIV duration, and number of HIV-associated non-AIDS conditions. CONCLUSIONS: Two of the most common symptoms in people living with HIV-fatigue and muscle aches/joint pains-invoke additional burden in women. Independent of aging, symptom burden may be exacerbated after menopause, supporting a shifting paradigm for HIV care management. PMID- 29509600 TI - Perspectives on counseling patients about menopausal hormone therapy: strategies in a complex data environment. AB - OBJECTIVE: This narrative review strives to give healthcare providers (HCPs) who care for menopausal women better tools and skills to initiate discussions with women about menopause and hormone therapy (HT), communicate complex concepts and data, and promote shared decision-making. METHODS: We review relevant studies on HT, barriers to treatment of menopausal symptoms, and effective communication strategies. We also provide recommendations for communicating with patients about HT based on the medical literature and our own professional experience. RESULTS: Both patient and HCP-related barriers can prevent women from accessing treatment for bothersome symptoms of menopause. Many women and HCPs have a poor understanding of the complex, nuanced data regarding HT. The benefits and risks vary with patient age and time since menopause, duration of use, inclusion of a progestin, and patient medical history. Women may also have fears about potential side effects of HT and feel unable to make informed choices. Strategies for effective patient communication and shared decision-making include use of open ended questions to elicit patient's concerns and preferences, reflecting back to the patient what the HCP heard, presenting evidence about benefits and risks in language the patient can understand, keeping risks in perspective (eg, provide absolute, and also relative risks) without minimizing them, and making conscious efforts to minimize potential bias. CONCLUSIONS: Necessary components for achieving high-quality, shared decisions about HT involve a combination of medical evidence, communication skills, and recognition of patient goals and concerns. Use of such strategies can enhance women's satisfaction with care. PMID- 29509601 TI - Climacteric-related symptoms in menopause transition and beyond: a prospective 19 year follow-up study on previously hysterectomized women. AB - OBJECTIVE: Only a few extended follow-up studies have investigated the natural progress of climacteric-related symptoms. The results have been conflicting. Thus, our aim was to evaluate, through a 19-year longitudinal study, whether these symptoms decrease or disappear as time elapses after menopause. METHODS: Our study was a prospective follow-up survey of 65 hysterectomized peri or postmenopausal women. The women were interviewed at the baseline, and at 6 and 19 years thereafter. Changes in various climacteric-related symptoms were evaluated by repeated-measures analysis of variance with time as the independent variable. The analyses were adjusted for baseline age, body mass index, employment, and use of hormone therapy. Climacteric-related symptoms were evaluated with the Women's Health Questionnaire, of which we included seven symptom domains (vasomotor, sleep, depressive, anxiety/fears, cognitive, sexual, and somatic). RESULTS: Vasomotor symptoms decreased remarkably during the follow-up period. In addition, a statistically significant decrease was found in sleep problems and cognitive difficulties. However, the decrease was minor, and thus probably clinically insignificant. CONCLUSIONS: The only symptom with notable decrease was vasomotor symptoms. The etiology of other symptoms, commonly connected to menopause transition, is probably multifactorial and not substantially dependent on the climacteric. PMID- 29509599 TI - Association between waist-to-height ratio and anxiety in middle-aged women: a secondary analysis of a cross-sectional multicenter Latin American study. AB - OBJECTIVE: The aim of the study was to evaluate the association between waist-to height ratio (WHtR) and anxiety in middle-aged women. METHODS: We carried out a secondary analysis of data from a multicenter study of women between 40 and 59 years old from 11 Latin America countries. Anxiety was assessed using the Goldberg Anxiety and Depression Scale. WHtR was calculated according to World Health Organization standards and categorized in tertiles: upper, middle, and lower using 0.45 and 0.6 as cutoff values. Prevalence ratios (PRs) and 95% CIs were calculated by generalized linear models of Poisson family with robust standard errors, both crude and adjusted models based on statistical and epidemiological criteria. RESULTS: Data of a total of 5,580 women were analyzed. Mean age was 49.7 +/- 5.5 years, and 57.9% were postmenopausal. The 61.3% of women had anxiety and mean WHtR was 0.54 +/- 0.1. In the crude model, compared with women in lower tertile, those in the middle (PR: 1.07; 95% CI, 1.01-1.13) and upper (PR: 1.23 95% CI, 1.07-1.29) WHtR tertile were significantly more likely to have anxiety. In the adjusted models, only women in upper tertile were, however, more likely of displaying anxiety than those in lower tertile (PR: 1.13; 95% CI, 1.08-1.18). CONCLUSIONS: In this series, WHtR was associated with anxiety in middle-aged women. It is advisable to further study this anthropometric measure in order for it to be incorporated in the routine clinical practice and evaluation of middle-aged women. PMID- 29509602 TI - In Reply. PMID- 29509604 TI - Helicobacter pylori infection among patients with liver cirrhosis. PMID- 29509603 TI - Adherence to Barcelona Clinic Liver Cancer therapeutic algorithm for hepatocellular carcinoma in the daily practice: a multicenter cohort study from Argentina. AB - BACKGROUND AND AIM: Adherence to the Barcelona Clinic Liver Cancer (BCLC) staging algorithm for the treatment of hepatocellular carcinoma is challenging in the daily practice. We aimed to analyze adherence to BCLC along with its effect on patient survival. PATIENTS AND METHODS: A cohort study was conducted in 14 hospitals from Argentina including patients with newly diagnosed hepatocellular carcinoma (2009-2016). Adherence was considered when the first treatment was the one recommended by the BCLC. RESULTS: Overall, 708 patients were included. At diagnosis, BCLC stages were as follows: stage 0 4%, A 43%, B 22%, C 9% and D 22%. Overall, 53% of the patients were treated according to BCLC, 24% were undertreated, and 23% overtreated. Adherence to BCLC increased to 63% in subsequent treatments. Independent factors associated with adherence to BCLC were the presence of portal hypertension [odds ratio: 1.63; 95% confidence interval (CI): 1.11-2.39] and BCLC stage C (odds ratio: 0.32; 95% CI: 0.12-0.72). In a multivariable model adjusting for portal hypertension and BCLC stages, adherence to BCLC showed improved survival (hazard ratio: 0.67; 95% CI: 0.52-0.87). CONCLUSION: Adherence to BCLC represents a challenge in the daily practice, with almost half of the patients being treated accordingly, showing that the decision making process should be tailored to each individual patient. PMID- 29509605 TI - Second-line immunosuppressants for autoimmune hepatitis. PMID- 29509607 TI - Subspecialty Training Among Graduates of Pediatric Orthopaedic Fellowships: An 11 Year Analysis of the Database of American Board of Orthopaedic Surgery. AB - BACKGROUND: The field of pediatric orthopaedic surgery is evolving with a reported increase in the number of pediatric orthopaedic fellows being trained as well as an increase in the number of fellows completing additional fellowship training in another subspecialty. The purpose of this study was to examine the historic trends of trainees seeking multiple fellowships within pediatric orthopaedics over an 11-year period using the database of the American Board of Orthopaedic Surgery (ABOS). METHODS: We queried the ABOS database for fellowship choice of applicants for the ABOS part II oral examination with the self-declared subspecialty of pediatric orthopaedics during the years of 2005 to 2015. Descriptive analysis was performed to determine the percentage of applicants who completed >1 fellowship, and the type of subspecialty fellowship completed. chi analysis was used to compare the proportion of multiple fellowship trainees between years. RESULTS: From 2005 to 2015, 310 applicants for ABOS part II pediatric subspecialty examination had completed a fellowship in pediatric orthopaedic surgery, with that number increasing from 14 to 43/y over that span. Forty-five trainees (15%) completed 48 additional fellowships over that decade, with 2 recent trainees completing multiple additional fellowships. The most common additional fellowships were sports (n=22, 46%), hand (n=8, 17%), and spine (n=7, 15%). The rate of additional fellowship training increased over 5-fold from 5% in the first 3 years of the study to 28% in the last 2 years of the study (P=0.001). CONCLUSIONS: The proportion of trainees completing additional subspecialty fellowships in addition to pediatric orthopaedics has risen over the past decade. The precise cause and effect of such change is uncertain and likely multifactorial. Reexamination of our classic training paradigms may be warranted in light of these trends. LEVEL OF EVIDENCE: Level III. PMID- 29509608 TI - Revision ACL Reconstruction in Children and Adolescents. AB - BACKGROUND: Revision anterior cruciate ligament (ACL) reconstruction in pediatric patients has not been well studied. The purpose of this study was to assess the demographics, technique, and results of ACL revision surgery in children and adolescents. METHODS: This was a retrospective case series with outcomes assessment of patients 18 years old and younger who underwent revision ACL surgery over a 16-year period at a single institution. Medical records were reviewed for demographics, clinical and operative data, and patients were contacted for outcomes at a minimum of 1 year after revision surgery. RESULTS: Ninety revision ACL reconstructions were performed by 7 surgeons in 88 patients (44 male, 44 female). Average patient age at the time of revision was 16.6 years (SD, 1.7), and 28.8% of patients were skeletally immature. Time to failure after primary ACL reconstruction was 1.28 years (SD, 1.1) and revision surgery was performed 1.56 years (SD, 1) after the index procedure. Revision graft type included allograft (61.1%), patellar tendon (21.1%), hamstring (16.7%), and iliotibial band (1.1%). There was a 20% graft reinjury rate. Subsequent surgical procedures after revision were required in 25.5% of knees. Twenty percent of revision reconstructions had contralateral ACL injuries, and this percentage was higher (33%) among those who went on to injure their revision graft. Median outcome scores collected from 44 patients (50%) at a mean of 5.1 years following surgery (SD, 3.4) were: Pedi-IKDC 79.9, Lysholm 84.5, and Tegner 9.0. Sixty-nine percent of patients reported returning to sports, however, only 55.2% of these reported being able to return to the same level of play. CONCLUSIONS: Revision ACL reconstruction in pediatric patients was associated with suboptimal patient reported outcomes, high complication rates, relatively high graft retear rates, high risk of contralateral ACL injury, and compromised return to sports rates. LEVEL OF EVIDENCE: Level IV. PMID- 29509609 TI - Using the Medial and Lateral Humeral Lines as an Adjunct to Intraoperative Elbow Arthrography to Guide Intraoperative Reduction and Fixation of Distal Humerus Physeal Separations Reduces the Incidence of Postoperative Cubitus Varus. AB - BACKGROUND: Distal humerus physeal separations are rare pediatric elbow fractures that are often misdiagnosed and difficult to treat. Adequate reduction is often technically challenging and up to 71% of children develop postoperative cubitus varus. We propose using the medial and lateral humeral lines as an adjunct to elbow arthrography in order to guide intraoperative fixation of distal humerus physeal separations to reduce the incidence of postoperative cubitus varus. METHODS: From 2009 to 2014, all pediatric patients under the age of 3 diagnosed with a distal humerus physeal separation and treated surgically at our institution were included for analysis. Two senior pediatric orthopaedic surgeons separately reviewed the preoperative, intraoperative, and postoperative images of all patients and measured the position of the ulnar axis relative to the medial and lateral humeral lines. The medial and lateral humeral shafts were defined as parallel lines drawn along the medial and lateral humeral diaphysis. Adequate reduction was defined by reduction of the ulnar axis within the boundaries of the medial and lateral humeral lines. Patients were assessed at latest follow-up for cubitus varus and any other surgical complications. RESULTS: Thirteen patients fulfilled the inclusion criteria and were on average 1.70 years old, ranging from 0.62 to 3 years old. Intraoperatively and immediately postoperatively, all 13 patients (100%) were noted to have adequate reduction of the ulnar axis within the boundaries medial and lateral humeral lines. None of the patients required intraoperative arthrography (0%). At the date of latest follow-up, 12 patients (92.3%) had no angular deformities compared with the contralateral limb and 1 patient (7.7%) had developed cubitus varus. No surgical complications were noted (0%). CONCLUSION: Intraoperative reduction of the ulnar axis within the boundaries of the medial and lateral humeral lines is associated with a lower incidence of postoperative cubitus varus in the treatment of distal humerus physeal separations in children. LEVEL OF EVIDENCE: Level IV. PMID- 29509610 TI - Pediatric Quality and Safety Come of Age. PMID- 29509611 TI - JBJS: Data You Can Trust. PMID- 29509613 TI - Red Flags for Low Back Pain Are Not Always Really Red: A Prospective Evaluation of the Clinical Utility of Commonly Used Screening Questions for Low Back Pain. AB - BACKGROUND: Low back pain has a high prevalence and morbidity, and is a source of substantial health-care spending. Numerous published guidelines support the use of so-called red flag questions to screen for serious pathology in patients with low back pain. This paper examines the effectiveness of red flag questions as a screening tool for patients presenting with low back pain to a multidisciplinary academic spine center. METHODS: We conducted a retrospective review of the cases of 9,940 patients with a chief complaint of low back pain. The patients completed a questionnaire that included several red flag questions during their first physician visit. Diagnostic data for the same clinical episode were collected from medical records and were corroborated with imaging reports. Patients who were diagnosed as having a vertebral fracture, malignancy, infection, or cauda equina syndrome were classified as having a red flag diagnosis. RESULTS: Specific individual red flags and combinations of red flags were associated with an increased probability of underlying serious spinal pathology, e.g., recent trauma and an age of >50 years were associated with vertebral fracture. The presence or absence of other red flags, such as night pain, was unrelated to any particular diagnosis. For instance, for patients with no recent history of infection and no fever, chills, or sweating, the presence of night pain was a false-positive finding for infection >96% of the time. In general, the absence of red flag responses did not meaningfully decrease the likelihood of a red flag diagnosis; 64% of patients with spinal malignancy had no associated red flags. CONCLUSIONS: While a positive response to a red flag question may indicate the presence of serious disease, a negative response to 1 or 2 red flag questions does not meaningfully decrease the likelihood of a red flag diagnosis. Clinicians should use caution when utilizing red flag questions as screening tools. PMID- 29509612 TI - Ten-Year Trends in Medical Complications Following 540,623 Primary Total Hip Replacements from a National Database. AB - BACKGROUND: More than 75,000 total hip replacements were performed in England and Wales in 2014, and this figure is predicted to increase. Trends in mortality and complications following total hip replacement from 2005 to 2014 were evaluated to quantify risk and to identify "at-risk" groups to better inform recommendations for patient care. METHODS: Our primary analysis estimated 90-day inpatient mortality following total hip replacement using Hospital Episode Statistics data from 2005 to 2014. Secondary analyses explored 30-day rates of lower respiratory tract infection, renal failure, myocardial infarction, pulmonary embolism, deep vein thrombosis, cerebrovascular accident, and Clostridium difficile. Hierarchical logistic regression was used to estimate population averages, adjusting for time and prognostic covariates. RESULTS: From January 2005 to July 2014, a total of 540,623 total hip replacements were reported. The 90-day mortality rate dropped steadily, from 0.60% in 2005 to 0.15% in 2014. Reported postoperative complications (with the exception of lower respiratory tract infection and renal failure) reduced year-on-year, despite a steady rise in the average Charlson Comorbidity Index score. The 30-day rate of lower respiratory tract infection and renal failure increased from 0.54% to 0.84% and 0.21% to 1.09%, respectively. The risk of mortality was significantly higher for those who developed a lower respiratory tract infection (odds ratio [OR] = 42.3) or renal failure (OR = 36.5) than for those who developed pulmonary embolism (OR = 10.9) or deep-vein thrombosis (OR = 2.6). CONCLUSIONS: Despite a population with increasing levels of comorbidity, indicators of quality of care improved from 2005 to 2014, with the exception of the rates of lower respiratory tract infection and renal failure. Postoperative care should focus on reducing the risk of lower respiratory tract infection and renal failure, both of which increased and were strongly associated with mortality. Moreover, they appeared to occur in identifiable high-risk groups; modifications to routine care should be considered for these patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509614 TI - Teaching Patients How to Reduce a Shoulder Dislocation: A Randomized Clinical Trial Comparing the Boss-Holzach-Matter Self-Assisted Technique and the Spaso Method. AB - BACKGROUND: There are many different techniques for reducing acute anterior dislocations of the shoulder, and their use depends on surgeon preference. The objective of this study was to compare the pain experienced by a patient performing a self-reduction technique with the pain felt during a reduction performed by a trained physician. METHODS: The study was carried out at the emergency department of a tertiary referral center. Patients between 18 and 60 years of age with an acute anterior shoulder dislocation were randomly allocated into 2 groups. In 1 group the emergency doctor actively guided the reduction process with the Spaso technique (Sp group), and in the other group the patient used the Boss-Holzach-Matter (also known as Davos or Aronen) self-reduction technique (BHM group). The pain experienced by the patient during the reduction was recorded by means of a visual analogue scale (VAS) ranging from 0 to 10. Other recorded data included demographic characteristics, reduction time, and success rate. RESULTS: Of 378 patients assessed for eligibility from May 2015 until February 2017, 197 did not meet the inclusion criteria, 58 met exclusion criteria, 22 declined to participate, and 41 withdrew before randomization. Sixty acute anterior shoulder dislocations were randomized into the Sp group (n = 30) or the BHM group (n = 30). The BHM group experienced significantly less pain during reduction than the Sp group (p = 0.047), with mean pain scores of 3.57 (standard deviation [SD] = 2.1]) and 5.26 (SD = 2.9), respectively. No significant difference between groups was found with respect to reduction time (105 seconds [range, 10 to 660 seconds] in the Sp group and 90 seconds [range, 5 to 600 seconds] in the BHM group; p = 0.6) or success rate (67% and 77%, respectively; p = 0.39). CONCLUSIONS: The self-reduction technique results in less pain than, and is as efficient in achieving reduction of anterior shoulder dislocations as, the Spaso technique. These findings favor the use of the self assisted method as an effective first-line treatment for shoulder dislocations seen in the emergency department as well as its use by patients with recurrent dislocation. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509615 TI - The Association Between Rotator Cuff Muscle Fatty Infiltration and Glenoid Morphology in Glenohumeral Osteoarthritis. AB - BACKGROUND: Glenoid morphology and rotator cuff muscle quality are important anatomic factors that can impact longevity of the glenoid component following total shoulder arthroplasty (TSA). We hypothesized that rotator cuff muscle fatty infiltration is associated with increased pathologic glenoid bone loss in glenohumeral osteoarthritis (OA). METHODS: We retrospectively reviewed 190 preoperative computed tomography (CT) scans of 175 patients (mean age, 66 years; range, 44 to 90 years) who underwent TSA for the treatment of primary glenohumeral OA. Two-dimensional orthogonal CT images were reformatted in the plane of the scapula from 3-dimensional images. Pathologic joint-line medialization was defined with use of the glenoid vault model. Pathologic glenoid version was measured directly. Glenoid morphology was graded according to a modified Walch classification (subtypes A1, A2, B1, B2, B3, C1, and C2). Rotator cuff muscle fatty infiltration was assessed and assigned a Goutallier score on the sagittal CT slice just medial to the spinoglenoid notch for each muscle. RESULTS: There was a significant difference in the Goutallier score for the supraspinatus, infraspinatus, and teres minor muscles between Walch subtypes (p <= 0.05). High-grade posterior rotator cuff muscle fatty infiltration was present in 55% (21) of 38 B3 glenoids compared with 8% (3) of 39 A1 glenoids. Increasing joint-line medialization was associated with increasing fatty infiltration of all rotator cuff muscles (p <= 0.05). Higher fatty infiltration of the infraspinatus, teres minor, and combined posterior rotator cuff muscles was associated with increasing glenoid retroversion (p <= 0.05). After controlling for joint-line medialization and retroversion, B3 glenoids were more likely to have fatty infiltration of the supraspinatus and infraspinatus muscles than B2 glenoids were. CONCLUSIONS: High-grade rotator cuff muscle fatty infiltration is associated with B3 glenoids, increased pathologic glenoid retroversion, and increased joint-line medialization. Additional studies are needed to determine the causal relationship between these muscle changes and glenoid wear, whether these muscle changes independently affect clinical and radiographic outcomes in anatomic TSA, and whether fatty infiltration can improve postoperatively with correction of pathologic version and/or joint-line restoration. CLINICAL RELEVANCE: This study investigates the association between different patterns of glenoid bone loss and rotator cuff muscle fatty infiltration. Both factors have been shown to affect clinical outcome following TSA. PMID- 29509616 TI - Unexpected Long Lower Limb in Patients with Unilateral Hip Dislocation. AB - BACKGROUND: Several methods are commonly used to predict lower-limb-length discrepancy (LLD) on pelvic radiographs. It is not clear how the lower-limb length of patients with unilateral developmental dislocation of the hip (DDH) changes and whether a pelvic radiograph is reliable to predict LLD. In this study, we analyzed the characteristics of LLD in patients with unilateral DDH by measuring full-length standing anteroposterior radiographs. METHODS: The radiographic data of all patients with unilateral DDH who met the inclusion criteria from March 2011 to May 2016 were retrospectively reviewed. These data included femoral length, tibial length, skeletal limb length, and distance from the lesser trochanter to the tibial plafond. We also compared LLD between patients with Hartofilakidis type-II DDH and those with type III. RESULTS: Sixty seven patients (12 male and 55 female) were included. The tibial length, skeletal limb length, and lesser trochanter-tibial plafond distance were significantly greater (p < 0.001, p = 0.040, and p < 0.001, respectively) on the ipsilateral (DDH) side, compared with the contralateral side, in 51 patients (76%), 43 patients (64%), and 52 patients (78%), respectively, with the values on the ipsilateral side exceeding those on the contralateral side by an average of 4.6 mm (range, 0.4 to 17.5 mm), 7.0 mm (range, 0.3 to 21.1 mm), and 10.0 mm (range, 1.1 to 28.8 mm), respectively. The femoral length did not differ significantly between the 2 sides (p = 0.562). There was also no significant difference in LLD, femoral length, tibial length, skeletal limb length, or lesser trochanter-tibial plafond distance between patients with Hartofilakidis type II and those with type III (p > 0.05). CONCLUSIONS: Patients with unilateral DDH, regardless of whether the hip dislocation is low or high, may present with LLD derived from both the femur and the tibia. This LLD includes a greater ipsilateral tibial length, skeletal limb length, and lesser trochanter-tibial plafond distance in most patients and an unpredictable femoral length. Using the lesser trochanter on pelvic radiographs to predict LLD is not reliable. The use of full-length standing anteroposterior radiographs for preoperative templating is advisable for this special group of patients. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509617 TI - Clinical and Radiographic Outcomes After Posterior Vertebral Column Resection for Severe Spinal Deformity with Five-Year Follow-up. AB - BACKGROUND: Short-term studies have shown improved outcomes and alignment after posterior vertebral column resection for severe spinal deformity. Our goal was to report long-term changes in radiographic and health-related quality-of-life measures in a consecutive series of pediatric and adult patients undergoing posterior vertebral column resection with a minimum follow-up of 5 years. METHODS: We reviewed all patients undergoing posterior vertebral column resection by a single surgeon prior to January 1, 2010, at a single institution. Standard preoperative and perioperative data were collected, including the Scoliosis Research Society (SRS)-22/24 instrument. Radiographic and health-related quality of-life measures changes were evaluated at a minimum follow-up of 5 years. RESULTS: One hundred and nine patients underwent posterior vertebral column resection prior to January 2010, and 54 patients (49.5%) were available for analysis: 31 (57.4%) were pediatric patients, and 23 (42.6%) were adult patients. The mean age (and standard deviation) was 12.5 +/- 3 years for the pediatric cohort and 39.3 +/- 20 years for the adult cohort. Improvements in the mean major Cobb angle at a minimum follow-up of 5 years were seen: 61.6% correction for the pediatric cohort and 53.9% correction for the adult cohort. The rates of proximal junctional kyphosis, defined as proximal junctional kyphosis of >10 degrees , were 16.1% for the pediatric cohort and 34.8% for the adult cohort, but none underwent a revision surgical procedure for symptomatic proximal junctional kyphosis. Of the 54 patients, 30 (55.6%) sustained complications, 5 (9.3%) experienced postoperative neurological deficits, and 7 (13.0%) required a revision by 5 years postoperatively. Significant improvements were observed in the SRS-Self Image with regard to the pediatric cohort at 0.9 (p = 0.017) and the adult cohort at 1.3 (p = 0.002) and in the SRS-Satisfaction with regard to the pediatric cohort at 1.8 (p = 0.008) and the adult cohort at 1.3 (p = 0.005). CONCLUSIONS: Posterior vertebral column resection offers substantial, sustained improvements in global radiographic alignment and patient outcome scores at 5 years. The major radiographic deformity was reduced by 61.6% in the pediatric cohort and by 53.9% in the adult cohort. Despite the high rate of complications, patients experienced significant improvement in the SRS-Self Image and SRS Satisfaction domains. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509618 TI - Maternal Diets Deficient in Vitamin D Increase the Risk of Kyphosis in Offspring: A Novel Kyphotic Porcine Model. AB - BACKGROUND: The purpose of this study was to explore the role of perinatal vitamin-D intake on the development and characterization of hyperkyphosis in a porcine model. METHODS: The spines of 16 pigs were assessed at 9, 13, and 17 weeks of age with radiography and at 17 weeks with computed tomography (CT), magnetic resonance imaging (MRI), histology, and bone-density testing. An additional 169 pigs exposed to 1 of 3 maternal dietary vitamin-D levels from conception through the entire lactation period were fed 1 of 4 nursery diets supplying different levels of vitamin D, calcium, and phosphorus. When the animals were 13 weeks of age, upright lateral spinal radiography was performed with use of a custom porcine lift and sagittal Cobb angles were measured in triplicate to determine the degree of kyphosis in each pig. RESULTS: The experimental animals had significantly greater kyphotic sagittal Cobb angles at all time points when compared with the control animals. These hyperkyphotic deformities demonstrated no significant differences in Hounsfield units, contained a slightly lower ash content (46.7% +/- 1.1% compared with 50.9% +/- 1.6%; p < 0.001), and demonstrated more physeal irregularities. Linear mixed model analysis of the measured kyphosis demonstrated that maternal diet had a greater effect on sagittal Cobb angle than did nursery diet and that postnatal supplementation did not completely eliminate the risk of hyperkyphosis. CONCLUSIONS: Maternal diets deficient in vitamin D increased the development of hyperkyphosis in offspring in this model. CLINICAL RELEVANCE: This study demonstrates that decreased maternal dietary vitamin-D intake during pregnancy increases the risk of spinal deformity in offspring. In addition, these data show the feasibility of generating a large-animal spinal-deformity model through dietary manipulation alone. PMID- 29509619 TI - Late Reconstruction of the Interosseous Membrane with Bone-Patellar Tendon-Bone Graft for Chronic Essex-Lopresti Injuries: Outcomes with a Mean Follow-up of Over 10 Years. AB - BACKGROUND: The purpose of this study was to report our long-term outcomes following reconstruction of the forearm interosseous membrane (IOM) with bone patellar tendon-bone (BPTB) graft for treatment of chronic Essex-Lopresti injuries. METHODS: We identified 33 patients who underwent IOM reconstruction with BPTB graft for chronic Essex-Lopresti injuries over a 20-year treatment interval. Twenty male and 13 female patients, with a mean age of 42.1 years (range, 19 to 73 years) and a minimum follow-up interval of 5 years, were included. Preinjury clinical examination and radiographic measurements were obtained from records for comparison with prospectively collected data. Additional functional outcome data collected postoperatively included QuickDASH (an abbreviated version of the Disabilities of the Arm, Shoulder and Hand [DASH]), modified Mayo wrist (MMW), and Broberg-Morrey elbow function scores. RESULTS: IOM reconstruction was performed at a mean interval (and standard deviation) of 44.9 +/- 60.0 months (range, 6.4 to 208 months) from the time of the initial injury. At a mean follow-up of 10.9 +/- 4.4 years (range, 5.5 to 24.2 years), significant improvements were observed in mean elbow flexion-extension arc (+13 degrees [95% confidence interval (CI), 4 degrees to 22 degrees ]; p = 0.005), wrist flexion-extension arc (+19 degrees [95% CI, 4 degrees to 34 degrees ]; p = 0.016), forearm pronation-supination (+23 degrees [95% CI, 8 degrees to 39 degrees ]; p = 0.004), and grip strength (+25% of that of the contralateral side [95% CI, 18% to 32% of contralateral side]; p < 0.001). Improvements in ulnar variance were sustained over the long term from +3.9 mm (95% CI, 3.2 to 4.6 mm) preoperatively to -1.6 mm (95% CI, -2.3 to -0.9 mm) immediately postoperatively and -1.1 mm (95% CI, -1.8 to -0.4 mm) at the time of the final follow-up (p < 0.001). The mean QuickDASH, MMW, and Broberg-Morrey scores were 29.8 (range, 5 to 61), 82.7 (range, 60 to 100), and 91.6 (range, 64 to 100), respectively. CONCLUSIONS: IOM reconstruction with a BPTB graft is an effective treatment option for chronic Essex-Lopresti injuries, with satisfactory clinical and functional outcomes over the long term. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509620 TI - Mid-Term Results of Periacetabular Osteotomy for the Treatment of Hip Dysplasia Associated with Down Syndrome: Minimum Follow-up of Five Years. AB - BACKGROUND: The treatment of hip dysplasia in patients with Down syndrome is challenging. We investigated the clinical, functional, and radiographic outcomes of periacetabular osteotomy (PAO) as well as factors associated with its failure at a minimum of 5 years of follow-up. METHODS: Between 1992 and 2011, 19 patients with Down syndrome (26 hips) underwent PAO at a mean age of 16.2 +/- 4.7 years. Hip pain and function were assessed with use of the modified Harris hip score (HHS) and the Gross Motor Function Classification System (GMFCS). The criteria for PAO failure were progression of osteoarthritis with a recommendation for total hip arthroplasty or hip arthrodesis, or an HHS of <60 points. Preoperative and most recent radiographs were assessed for measurement of the lateral and anterior center-edge angles, Tonnis angle, extrusion index, and anterior and posterior wall indices, and for evaluation of the Tonnis grade of osteoarthritis. RESULTS: At an average follow-up of 13.1 +/- 5.2 years (range, 5.4 to 24 years), 13 (62%) of 21 hips with an HHS demonstrated good or excellent HHS results (median, 91 points; interquartile range, 65 to 96 points). Ninety-five percent of the patients were independent in ambulation. All radiographic parameters significantly improved after PAO. Eight (31%) of the 26 hips were considered to have failed the procedure. Tonnis grade-2 osteoarthritis (4 hips compared with 1 hip; p = 0.008; odds ratio [OR] = 17.00) and older patient age at the time of the procedure (19.6 +/- 6.7 compared with 14.7 +/- 2.4 years; p = 0.017; OR = 1.36 per year) were demonstrated to be factors associated with PAO failure in an analysis of hips that failed compared with those without failure at the time of latest follow-up. CONCLUSIONS: PAO improves radiographic deformity and helps to preserve independent ambulation in patients with hip dysplasia and Down syndrome. Although nearly 70% of the hips were preserved at an average of 13 years postoperatively, 1 in 3 hips met the criteria for failure, which was associated with older age at the time of the procedure and a moderate osteoarthritis grade (Tonnis grade 2). LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509621 TI - The Acetabular Fossa May Not Be Located at the True Center of the Acetabulum: A Detailed Analysis Using Preoperative CT Images. AB - BACKGROUND: The acetabular fossa is thought to be located in the center of the acetabulum, and acetabular reaming in total hip arthroplasty is conventionally performed in the center of the fossa. However, the actual location of the fossa and the influence that hypoplasia or deformity may have on the position of the fossa are unknown. We hypothesized that the fossa is located in the center of the acetabulum, regardless of hypoplasia or deformity. METHODS: Fifty patients with normal hips (normal hip group), 50 patients with dysplasia who underwent rotational acetabular osteotomy (dysplastic hip group), and 46 patients with osteoarthritis who underwent total hip arthroplasty (osteoarthritic hip group) were evaluated by computed tomography (CT) imaging. On the horizontal plane that passes through the center of the femoral head, the center line of the acetabulum was defined as the perpendicular bisector of the anterior and posterior rims of the acetabulum. The angle and distance of the center of the acetabular fossa in relation to the center line of the acetabulum were evaluated; furthermore, the center position of the fossa from the anterior margin of the acetabulum was calculated as a ratio relative to acetabular size. A 1-way analysis of variance was performed to compare measurements among the 3 groups. RESULTS: The center of the acetabular fossa was positioned anteriorly to the center line of the acetabulum in all 3 groups. The mean center angle of the acetabular fossa was 14.0 degrees +/- 3.8 degrees , 15.2 degrees +/- 5.6 degrees , and 14.9 degrees +/- 5.5 degrees in the normal, dysplastic, and osteoarthritic hip groups, respectively (p = 0.33). The mean center distance of the acetabular fossa was 5.6 +/- 1.8, 5.8 +/- 2.3, and 6.1 +/- 2.2 mm, respectively (p = 0.55). The mean center position of the acetabular fossa was 38.8% +/- 3.3%, 38.5% +/- 4.2%, and 38.3% +/- 3.9%, respectively (p = 0.71). CONCLUSIONS: The center of the acetabular fossa is positioned anteriorly to the center of the acetabulum, and the positioning is affected by neither dysplasia nor osteoarthritis. The preconception that the center of the acetabulum corresponds to the center of the acetabular fossa may risk eccentric reaming, possibly damaging the anterior wall. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29509623 TI - What's Important: Making a Difference May Include Being Different. PMID- 29509622 TI - Patient-Reported Outcomes in Orthopaedics. PMID- 29509624 TI - I Am What I Am Because of Who We All Are: The 2017 American-British-Canadian Traveling Fellowship. PMID- 29509625 TI - The Impact of Specialty on Cases Performed During Hand Surgery Fellowship Training. AB - BACKGROUND: Hand surgery fellowship programs in the United States are predominately sponsored by departments or divisions of orthopaedic surgery or plastic surgery. This study compares the operative experiences of hand surgery fellows graduating from orthopaedic or plastic surgery hand surgery fellowships. METHODS: Operative case logs of 3 cohorts of hand surgery fellows graduating during the academic years of 2012-2013, 2013-2014, and 2014-2015 were analyzed. The median case volumes were compared by specialty via Mann-Whitney U tests. An arbitrary 1,000% change between the 90th and 10th percentiles of fellows was used as a threshold to highlight case categories with substantial variability. RESULTS: In this study, 413 orthopaedic hand surgery fellows (87%) and 62 plastic surgery hand surgery fellows (13%) were included. Plastic surgery fellows reported more cases in the following categories: wound closure with graft; wound reconstruction with flap; vascular repair, reconstruction, replantation, or microvascular; closed treatment of fracture or dislocation; nerve injury; and congenital (p < 0.05). Orthopaedic surgery fellows reported more cases in the following categories: wound irrigation and debridement fasciotomy or wound preparation; hand reconstruction or releases; wrist reconstruction, releases, or arthrodesis; forearm, elbow, or shoulder reconstruction or releases; hand fractures, dislocation, or ligament injury; wrist fractures or dislocations; forearm and proximal fractures or dislocations; miscellaneous insertion or removal of devices; shoulder arthroscopy, elbow arthroscopy, and wrist arthroscopy; decompression of tendon sheath, synovectomy, or ganglions; nerve decompression; Dupuytren; and tumor or osteomyelitis (p < 0.05). Plastic surgery fellows reported substantial variability for 12 case categories (range, 1,024% to 2,880%). Orthopaedic surgery fellows reported substantial variability for 9 case categories (range, 1,110% to 9,700%). CONCLUSIONS: Orthopaedic and plastic hand surgery fellowships afford disparate operative experiences. Understanding these differences may help to align prospective trainees with future career goals and to guide discussions to better standardize hand surgery training. PMID- 29509626 TI - Ever-Safer Total Hip Replacements: Commentary on an article by Thomas Partridge, MBBS, MRCS, et al.: "Ten-Year Trends in Medical Complications Following 540,623 Primary Total Hip Replacements from a National Database". PMID- 29509627 TI - Should We Still Use Red Flags in the Diagnosis of Low Back Pain?: Commentary on an article by Ajay Premkumar, MD, MPH, et al.: "Red Flags for Low Back Pain Are Not Always Really Red. A Prospective Evaluation of the Clinical Utility of Commonly Used Screening Questions for Low Back Pain". PMID- 29509629 TI - Spinal Deformity in Vitamin D-Deprived Pigs: Why and What Next?: Commentary on an article by Matthew A. Halanski, MD, et al.: "Maternal Diets Deficient in Vitamin D Increase the Risk of Kyphosis in Offspring. A Novel Kyphotic Porcine Model". PMID- 29509628 TI - You Can Do It! Directed Self-Reduction of an Anterior Shoulder Dislocation Works: Commentary on an article by F.A. Marcano-Fernandez, MD, MSc, et al.: "Teaching Patients How to Reduce a Shoulder Dislocation. A Randomized Clinical Trial Comparing the Boss-Holzach-Matter Self-Assisted Technique and the Spaso Method". PMID- 29509630 TI - Barriers and Facilitators to a Good Bowel Preparation for Colonoscopy in Children: A Qualitative Study. AB - BACKGROUND: A well-visualized colon during colonoscopy has a direct impact on interpretation of findings and need for repeat procedure. Studies have been conducted in the adult population to assess factors contributing to improved bowel preparation. The primary aim of this study was to determine barriers and facilitators to good preparation in children. METHODS: A qualitative descriptive approach was utilized. Children age 2 to 18 years old, and their parents were recruited from the McMaster University Gastroenterology clinic from May 2015 to January 2016. Semistructured interviews were conducted assessing the understanding of the preparation protocol, and the compliance and tolerability of the preparation. A thematic analysis was conducted. RESULTS: Eleven families participated (7 children and 14 parents). Fifty percent of the children were under 11 years of age, and 73% were undergoing bowel preparation for the first time. Participants identified 26 subthemes, which were categorized into 4 broad themes. Barriers included confusion regarding mixing of the preparation and allowable diet during the preparation day, as well as lack of clarity on expected stool end goals. Facilitators included ease of access of the gastroenterology team, small volume of liquid mixed with the preparation, few adverse effects, and the provision of an understandable handout. Parental motivation to achieve a good outcome was also a facilitator. CONCLUSIONS: This is the first qualitative study focusing on children undergoing a home bowel preparation for a colonoscopy. Being able to identify barriers and facilitators will allow gastroenterologists to improve the quality of bowel preparation and overall experience for the pediatric population. PMID- 29509631 TI - Cardiovascular involvement at initial presentation of Crohn's Disease. PMID- 29509632 TI - Induced Pluripotent Stem Cell-Derived Hepatocytes and Precision Medicine in Human Liver Disease. AB - Liver-like human cells can be generated from human skin by converting fibroblasts to "induced pluripotent stem cells" (iPSCs), then differentiating the iPSCs into "induced hepatocytes". Although still primarily used as a research tool, emerging applications involving iPSC-derived induced hepatocytes have exciting and provocative clinical and translational potential. This review provides a brief summary of the current status of this field and obstacles that must be overcome before this novel tool will enable precision medicine-based approaches to human liver disease. PMID- 29509633 TI - Pediatric Eosinophilic Esophagitis Is Associated With Increased Lamina Propria Immunoglobulin G4-Positive Plasma Cells. AB - OBJECTIVE: Eosinophilic esophagitis (EoE) is considered a TH2-mediated food allergy disease that leads to submucosal esophageal fibrosis and strictures. Recent studies focused on adults with EoE identified a strong association with elevated esophageal IgG4 immunostaining. Our study aimed to determine the association of IgG4 with EoE in pediatric patients. METHODS: Using our local EoE research registry, we identified 41 adequate biopsies from EoE patients. We used 10 age- and sex-matched patients with no diagnostic abnormalities at endoscopy or on biopsy. Using a monoclonal antibody to Immunoglobulin G4 (IgG4), we determined the maximum density of IgG4-positive plasma cells (IgG4-PC) per high-power field (hpf). Using a semi-quantitative assessment, we also graded the noncellular staining of the lamina propria and epithelium. RESULTS: Our EoE cohort consisted predominantly of boys with an average age of 5.9 years and 63% had a documented IgE-based food allergy. Median peak eosinophilia was 40 eosinophils/hpf and the median IgG4-PC density was 39/hpf in the active esophagitis patients, compared with a median of 0 IgG4-PC/hpf in the non-EoE patients (P = 0.0001). EoE patients with a food allergy showed a significantly higher IgG4-PC density (44.5/hpf) than those without a food allergy (8/hpf; P = 0.0385). There was no significant association between IgG4-PC density and peak eosinophilia (r = 0.0011). CONCLUSIONS: We demonstrate that active esophagitis in pediatric EoE patients is associated with elevated levels of IgG4-positive plasma cells, which was more significant in EoE patients with a documented food allergy. Our study also adds to the growing literature that EoE may involve more than just an exaggerated TH2 immune response. PMID- 29509634 TI - Comparison of Transjugular Liver Biopsy and Percutaneous Liver Biopsy With Tract Embolization in Pediatric Patients. AB - PURPOSE: The aim of the study was to compare safety and efficacy of transjugular liver biopsy (TJLB) and percutaneous liver biopsy (PLB) with tract embolization in pediatric patients with liver disease. MATERIALS AND METHODS: TJLB and PLB between December 2009 and October 2015 were retrospectively reviewed. Primary endpoints were adequate sampling and complication rate. Patient age, weight, coagulation factors, ascites, blood transfusions, adequacy of biopsy sample, number of biopsy samples, and complications were compared. RESULTS: There were 39 TJLB (average age 10.6 years) and 120 PLB (average age 7.1 years) (P value <0.05). Average weight was 40.2 kg for TJLB and 26.8 kg for PLB (P value <0.05). Average platelets were 155 for TJLB and 252 for PLB (P value <0.05). Average international normalized ratio was 1.7 for TJLB and 1.3 for PLB (P value <0.05). Mean postbiopsy hematocrit decrease was 0.8 and 0.9, for TJLB and PLB, respectively. Mean postbiopsy hemoglobin decrease was 0.3 in both groups. Number of core biopsy samples was 4.5 and 4.3, for TJLB and PLB, respectively. There was 1 biopsy yielding insufficient sample in each group. TJLB had 1 (2.6%) complication of supraventricular tachycardia. PLB had 4 (3.3%) complications, with 1 hemoperitoneum, 1 hypotension, 1 patient with decreased hemoglobin, and 1 patient with bilious drainage from the biopsy site. CONCLUSIONS: TJLB and PLB with gelatin sponge pledget tract embolization are both safe and effective for the diagnosis of hepatic disease in pediatric patients. To avoid radiation, PLB may be considered as first-line approach in the pediatric population, even in the setting of coagulopathy. PMID- 29509635 TI - Mental Health Service Needs in Children and Adolescents With Inflammatory Bowel Disease and Other Chronic Gastrointestinal Disorders. PMID- 29509636 TI - Long-term Treatment With Proton Pump Inhibitors Is Effective in Children With Eosinophilic Esophagitis. AB - OBJECTIVES: Proton pump inhibitor (PPI)-responsive eosinophilic esophagitis (EoE) is frequently observed in children, but data on long-term treatment are scarce. The objective of this study is to evaluate the long-term efficacy and safety of PPIs in children with EoE. METHODS: This prospective study enrolled children with EoE and histological remission to an 8-week esomeprazole trial (1 mg/kg/dose, twice daily). Esomeprazole was maintained at 1 mg/kg/day for 1 year. Symptom recurrence and adverse events were monitored and a follow-up endoscopy was performed at 12 months. Complete histological remission was defined as <=5 eosinophils/high-power field (eos/hpf), and partial histological remission as >5 and <15 eos/hpf. Patients had no concomitant dietary restrictions or topical steroid. RESULTS: Fifty-seven children were included. Histological remission on maintenance PPI therapy was present in 40 children (70.1%; 95% CI 56.5-81.5). Long-term remission rate was higher in children with initial complete histological remission than in those with partial remission (81% vs 50%, P = 0.014). Forty-nine children (86%) remained asymptomatic. Pretreatment clinical and histological findings and median PPI dose/kg/day were similar between relapsers and nonrelapsers. Eleven out of 12 children (91.6%) receiving esomeprazole 0.5 mg . kg . day for 12 additional months remained in remission. Mild and transient side effects without requiring PPI avoidance were observed in 5 children. CONCLUSIONS: Up to 70% of children with PPI-responsive EoE remain in histological and clinical remission on a low-dose maintenance treatment at 1-year follow-up, with adequate safety profile. Complete histological remission to an 8 week PPI trial was associated with higher probability of histological remission on maintenance therapy. PMID- 29509637 TI - Practice Patterns and Job Satisfaction of Mohs Surgeons: ERRATUM. PMID- 29509638 TI - The Immediate Effect of Foot Orthoses on Subtalar Joint Mechanics and Energetics. AB - PURPOSE: Foot orthoses maybe used in the management of musculoskeletal disorders related to abnormal subtalar joint (STJ) pronation. However, the precise mechanical benefits of foot orthoses for preventing injuries associated with the STJ are not well understood. The aim of this study was to investigate the immediate effect of foot orthoses on the energy absorption requirements of the STJ and subsequently tibialis posterior (TP) muscle function. METHODS: Eighteen asymptomatic subjects with a pes planus foot posture were prescribed custom-made foot orthoses made from a plaster cast impression. Participants walked at preferred and fast velocities barefoot, with athletic footwear and with athletic footwear plus orthoses, as three-dimensional motion capture, force data, and intramuscular electromyography of the TP muscle were simultaneously collected. Statistical parametric mapping was used to identify time periods across the stride cycle during which footwear with foot orthoses significantly differed to barefoot and footwear only. RESULTS: During early stance, footwear alone and footwear with orthoses significantly reduced TP muscle activation (1%-12%), supination moments (3%-21%), and energy absorption (5%-12%) at the STJ, but had no effect on STJ pronation displacement. CONCLUSIONS: The changes in TP muscle activation and STJ energy absorption were primarily attributed to footwear because the addition of foot orthoses provided little additional effect. We speculate that these results are most likely a result of the compliant material properties of footwear. These results suggest that athletic footwear may be sufficient to absorb energy in the frontal plane and potentially reducing any benefit associated with the addition of foot orthoses. PMID- 29509639 TI - Muscle Fiber Hypertrophy and Myonuclei Addition: A Systematic Review and Meta analysis. AB - INTRODUCTION: The myonuclear domain theory postulates that myonuclei are added to muscle fibers when increases in fiber cross-sectional area (i.e., hypertrophy) are >=26%. However, recent studies have reported increased myonuclear content with lower levels (e.g., 12%) of muscle fiber hypertrophy. PURPOSE: This study aimed to determine whether a muscle fiber hypertrophy "threshold" is required to drive the addition of new myonuclei to existing muscle fibers. METHODS: Studies of resistance training endurance training with or without nutrient (i.e., protein) supplementation and steroid administration with measures of muscle fiber hypertrophy and myonuclei number as primary or secondary outcomes were considered. Twenty-seven studies incorporating 62 treatment groups and 903 subjects fulfilled the inclusion criteria and were included in the analyses. RESULTS: Muscle fiber hypertrophy of <=10% induces increases in myonuclear content, although a significantly higher number of myonuclei are observed when muscle hypertrophy is ~22%. Additional analyses showed that age, sex, and muscle fiber type do not influence muscle fiber hypertrophy or myonuclei addition. CONCLUSIONS: Although a more consistent myonuclei addition occurs when muscle fiber hypertrophy is >22%, our results challenge the concept of a muscle hypertrophy threshold as significant myonuclei addition occurs with lower muscle hypertrophy (i.e., <10%). PMID- 29509640 TI - Plasma Metabolite Profiles in Response to Chronic Exercise. AB - PURPOSE: High-throughput profiling of metabolic status (metabolomics) allows for the assessment of small-molecule metabolites that may participate in exercise induced biochemical pathways and corresponding cardiometabolic risk modification. We sought to describe the changes in a diverse set of plasma metabolite profiles in patients undergoing chronic exercise training and assess the relationship between metabolites and cardiometabolic response to exercise. METHODS: A secondary analysis was performed in 216 middle-age abdominally obese men and women (mean +/- SD, 52.4 +/- 8.0 yr) randomized into one of four groups varying in exercise amount and intensity for 6-month duration: high amount high intensity, high amount low intensity, low amount low intensity, and control. One hundred forty-seven metabolites were profiled by liquid chromatography-tandem mass spectrometry. RESULTS: No significant differences in metabolite changes between specific exercise groups were observed; therefore, subsequent analyses were collapsed across exercise groups. There were no significant differences in metabolite changes between the exercise and control groups after 24 wk at a Bonferroni-adjusted statistical significance (P < 3.0 * 10). Seven metabolites changed in the exercise group compared with the control group at P < 0.05. Changes in several metabolites from distinct metabolic pathways were associated with change in cardiometabolic risk traits, and three baseline metabolite levels predicted changes in cardiometabolic risk traits. CONCLUSIONS: Metabolomic profiling revealed no significant plasma metabolite changes between exercise and control after 24 wk at Bonferroni significance. However, we identified circulating biomarkers that were predictive or reflective of improvements in cardiometabolic traits in the exercise group. PMID- 29509641 TI - Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes. AB - PURPOSE: Many studies have examined the effect of caffeine on exercise performance, but findings have not always been consistent. The objective of this study was to determine whether variation in the CYP1A2 gene, which affects caffeine metabolism, modifies the ergogenic effects of caffeine in a 10-km cycling time trial. METHODS: Competitive male athletes (n = 101; age = 25 +/- 4 yr) completed the time trial under three conditions: 0, 2, or 4 mg of caffeine per kilogram body mass, using a split-plot randomized, double-blinded, placebo controlled design. DNA was isolated from saliva and genotyped for the -163A > C polymorphism in the CYP1A2 gene (rs762551). RESULTS: Overall, 4 mg.kg caffeine decreased cycling time by 3% (mean +/- SEM) versus placebo (17.6 +/- 0.1 vs 18.1 +/- 0.1 min, P = 0.01). However, a significant (P <0.0001) caffeine-gene interaction was observed. Among those with the AA genotype, cycling time decreased by 4.8% at 2 mg.kg (17.0 +/- 0.3 vs 17.8 +/- 0.4 min, P = 0.0005) and by 6.8% at 4 mg.kg (16.6 +/- 0.3 vs 17.8 +/- 0.4 min, P < 0.0001). In those with the CC genotype, 4 mg.kg increased cycling time by 13.7% versus placebo (20.8 +/- 0.8 vs 18.3 +/- 0.5 min, P = 0.04). No effects were observed among those with the AC genotype. CONCLUSION: Our findings show that both 2 and 4 mg.kg caffeine improve 10-km cycling time, but only in those with the AA genotype. Caffeine had no effect in those with the AC genotype and diminished performance at 4 mg.kg in those with the CC genotype. CYP1A2 genotype should be considered when deciding whether an athlete should use caffeine for enhancing endurance performance. PMID- 29509642 TI - Influence of Estradiol Status on Physical Activity in Premenopausal Women. AB - PURPOSE: This study aimed to determine the effects of 5 months of ovarian hormone suppression in premenopausal women on objectively measured physical activity (PA). METHODS: Participants (age, 35 +/- 8 yr; body mass index, 27 +/- 6 kg.m) received monthly intramuscular injections of gonadotropin-releasing hormone agonist (GnRHAG) therapy, which suppresses pituitary gonadotropins and results in suppression of ovarian sex hormones. Women were randomized to receive concurrent transdermal E2 (GnRHAG + E2; n = 30) or placebo (GnRHAG + PL, n = 31). PA was assessed for 1 wk before and during each month of the 5-month intervention using a hip-worn accelerometer (Actical, Mini Mitter Co., Inc., Bend, OR). Estimates of time spent in sedentary, light, and moderate-to-vigorous PA (MVPA) were derived using a previously published equation. Subsets of participants in each group were also randomized to a supervised progressive resistance exercise training program. RESULTS: Total MVPA tended toward being higher (P = 0.08) in the GnRHAG + E2 group at month 4. There were no significant effects of intervention or time in sedentary or light PA. In the subset of women who did not participate in structured exercise training for which Actical data were obtained (n = 16 in each group), total MVPA was higher at month 4 (P = 0.01). CONCLUSIONS: PA levels seem to be maintained at a higher level in women undergoing pharmacological suppression of ovarian function with E2 add-back when compared with women treated with placebo. These data provide proof-of-concept data that E2 contributes to the regulation of PA in humans. However, given the exploratory nature of this study, future confirmatory investigations will be necessary. PMID- 29509643 TI - Dehydration Impairs Cycling Performance, Independently of Thirst: A Blinded Study. AB - PURPOSE: The aim of the present study was to examine the effect of dehydration on exercise performance independently of thirst with subjects blinded of their hydration status. METHODS: Seven male cyclists (weight, 72 +/- 9 kg; body fat, 14% +/- 6%; peak oxygen uptake, 59.4 +/- 6 mL.kg.min) exercised for 2 h on a cycle ergometer at 55% peak oxygen uptake, in a hot-dry environment (35 degrees C, 30% relative humidity), with a nasogastric tube under euhydrated-non-thirst (EUH-NT) and dehydrated-non-thirst (DEH-NT) conditions. In both trials, thirst was matched by drinking 25 mL of water every 5 min (300 mL.h). In the EUH-NT trial, sweat losses were fully replaced by water via the nasogastric tube (calculated from the familiarization trial). After the 2 h of steady state, the subjects completed a 5-km cycling time trial at 4% grade. RESULTS: Body mass loss for the EUH-NT and DEH-NT after the 2 h was -0.2% +/- 0.6% and -2.2% +/- 0.4%, whereas after the 5-km time trial, it was -0.7% +/- 0.5% and 2.9% +/- 0.4%, respectively. Thirst (35 +/- 30 vs 42 +/- 31 mm) and stomach fullness (46 +/- 21 vs 35 +/- 20 mm) did not differ at the end of the 2 h of steady state between EUH NT and DEH-NT trials (P > 0.05). Subjects cycled faster during the 5-km time trial in the EUH-NT trial compared with the DEH-NT trial (23.2 +/- 1.5 vs 22.3 +/ 1.8 km.h, P < 0.05), by producing higher-power output (295 +/- 29 vs 276 +/- 29 W, P < 0.05). During the 5-km time trial, core temperature was higher in the DEH NT trial (39.2 degrees C +/- 0.7 degrees C) compared with the EUH-NT trial (38.8 degrees C +/- 0.2 degrees C; P > 0.05). CONCLUSIONS: These data indicated that hypohydration decreased cycling performance and impaired thermoregulation independently of thirst, while the subjects were unaware of their hydration status. PMID- 29509644 TI - Mesocycles with Different Training Intensity Distribution in Recreational Runners. AB - PURPOSE: The aim was to compare mesocycles with progressively increasing workloads and varied training intensity distribution (TID), that is, high intensity (HIGH, > 4 mmol.L blood lactate), low-intensity (LOW, < 2 mmol.L blood lactate) or a combination of HIGH and LOW (referred to as "polarized" [POL]) on 5000-m running time and key components of endurance performance in recreational runners. METHODS: Forty-two runners (peak oxygen uptake (VO2peak): 45.2 +/- 5.8 mL.min.kg) were systematically parallelized to one of three groups performing a 4 wk mesocycle with equal TID (two to four training sessions) followed by a 3-wk mesocycle with increased weekly training impulse (i.e., 50% increase compared to the first 4-wk mesocycle) of either HIGH, LOW, or POL and 1 wk tapering. VO2peak, velocity at lactate threshold and running economy were assessed at baseline (T0), after 4 wk (T1), 7 wk (T2), and 8 wk (T3). RESULTS: The 5000-m time decreased in all groups from T0 to T2 and T3. VO2peak increased from T0 to T2 and T3 (P < 0.03) with HIGH and from T0 to T2 (P = 0.02) in LOW and from T0 to T3 (P = 0.006) with POL. Running economy improved only from T1 to T3 and from T2 to T3 (P < 0.04) with LOW. An individual mean response analysis indicated a high number of responders (n = 13 of 16) in LOW, with less in HIGH (n = 6/13) and POL (n = 8/16). CONCLUSIONS: On a group level, HIGH, LOW, and POL improve 5000-m time and VO2peak. Changes in running economy occurred only with LOW. Based on the individual response of recreational runners the relative risk of nonresponding is greater with HIGH and POL compared with LOW. PMID- 29509645 TI - A Telephone Call to Decrease Patient Anxiety Before Urodynamic Testing: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to determine if a telephone call before undergoing urodynamic study (UDS) would decrease test-related anxiety compared with standard care. METHODS: We performed a randomized controlled trial at a single practice from April 2016 to June 2017. Patients at least 18 years old with lower urinary tract dysfunction and undergoing UDS for the first time were eligible. All participants received standard counseling; participants randomized to the intervention group also received a telephone call before their UDS appointment to answer any questions regarding their upcoming test. All participants completed surveys before and after testing to assess anxiety, preparedness, and satisfaction. The primary outcome was anxiety level immediately before UDS. Secondary outcomes included self-reported patient preparedness, pain, and satisfaction with counseling. Data were compared using chi, Fisher exact, and Wilcoxon rank sum tests. RESULTS: One hundred two participants were included in this as-treated analysis: 52 in the intervention group and 50 in the standard care group. The 2 groups were similar in age, ethnicity, and the proportion seeking additional information before testing. There were no statistically significant differences between groups with respect to overall anxiety, anxiety regarding specific elements of the test, or anticipated pain (all P >= 0.19). Participant satisfaction with pre-UDS counseling was significantly higher in the intervention group (80.8%) compared with the standard care group (54.0%; P = 0.002). CONCLUSIONS: Our study showed that a telephone call before undergoing UDS did not decrease anxiety compared with standard care; however, the telephone call was associated with higher satisfaction with pre-UDS counseling. PMID- 29509646 TI - Duration of Catheterization After Retropubic Midurethral Sling. AB - OBJECTIVE: The objective of this study was to describe the expected duration of self-catheterization in women discharged home performing intermittent self catheterization (ISC) after retropubic midurethral sling (RMUS). METHODS: We conducted a retrospective cohort analysis of women who underwent an isolated RMUS by 3 providers between 2009 and 2014 at a single institution. A 300 mL retrograde fill voiding trial (VT) was performed before discharge. Those who failed their VT (postvoid residual [PVR] >1/3 total bladder volume [TBV]) and could perform ISC are included in this analysis. Subjects were categorized into mild retention (PVR >1/3 and <2/3 the TBV) or severe retention (PVR >=2/3 the TBV). Patients could discontinue ISC after achieving 2 consecutive PVR volumes of less than 75 mL. Duration of catheterization was determined in days. RESULTS: Two hundred women underwent isolated RMUS. Forty-seven (23.5%) failed their VT of whom 39 (included in this analysis) could perform ISC and had complete data. Subjects had a mean +/ SD age of 49 +/- 11 years. The median (interquartile range) PVR volume postoperatively was 250 (190-325) mL. Median (interquartile range) days of postoperative ISC for the cohort was 2 (1-4); 37.5% were catheterized for 1 day, 32.5% for 2 days, 2.5% for 3 days, and 27.5% for more than 3 days. Seventeen (39.5%) met the criteria for mild retention and 26 (60.5%) met the criteria for severe retention. There was no difference in the postoperative catheterization days between the mild and severe retention groups (P = 0.16). CONCLUSIONS: Urinary retention will resolve within 2 days in the majority (73%) of women discharged performing ISC after RMUS. PMID- 29509647 TI - A Scoping Study of Psychosocial Factors in Women Diagnosed With and/or Treated for Pelvic Organ Prolapse. AB - OBJECTIVE: Pelvic organ prolapse (POP) is prevalent and can impact women's physical and psychosocial health. To develop interventions that support this population, an understanding of the state of research on psychosocial factors related to POP is essential. We conducted a scoping study focused on the psychosocial experience of women with POP. The purpose of this review was to (1) inventory and describe the current state of knowledge of the psychosocial experience of women with POP, (2) identify gaps in knowledge, and (3) identify targets for future research. METHOD: Electronic databases PsycINFO, PubMed, EMBASE, and CINAHL were searched through November 1, 2017. RESULTS: Of 524 titles reviewed, 103 articles met all inclusion criteria. Articles were grouped by the disease period (ie, prediagnosis, diagnosis/preintervention, intervention, follow up, and mixed) and psychosocial factors. Most articles (n = 73) focused on women undergoing intervention. Articles focusing on the preintervention period was the next largest category (n = 14). Follow-up after intervention (n = 8) and samples of mixed disease periods (n = 7) were less common. One article focused on women before diagnosis. Articles focused on quality of life (QOL; n = 79), sexual function (n = 51), satisfaction (n = 16), body image (n = 13), psychological distress (n = 4), and knowledge (n = 3). CONCLUSIONS: Research on the psychosocial experience of POP has largely focused on changes in QOL and sexual function. Future research should target emotional experience of women with POP; relationships among QOL, psychological distress, body image, and sexual function; and psychosocial factors related to treatment outcomes. PMID- 29509648 TI - C-Reactive Protein Concentration Can Help to Identify Bacteremia in Children Visiting the Emergency Department: A Single Medical Center Experience. AB - BACKGROUND: For febrile children who are evaluated in a pediatric emergency department (PED), blood culture can be considered the laboratory criterion standard to detect bacteremia. However, high rates of negative, false-positive, or contaminated blood cultures in children often result in this testing being noncontributory. This study determined the factors associated with true-positive blood cultures in children. METHODS: This retrospective study was conducted at a tertiary medical center's PED. The blood culture use reports were prepared by an infectious disease specialist and were classified as bacteremia, nonbacteremia, and contamination. RESULTS: We registered a total of 239,459 PED visits during the 8-year period, and 21,841 blood culture samples were taken. Of the laboratory test studies, higher C-reactive protein (CRP) levels and lower hemoglobin levels were observed in the bacteremia group compared with other groups (all P < 0.001). The cut-off value calculated for each age group was adjusted for better clinical usage and significantly improved the blood culture clinical utility documented in the following age groups: 0 to 1 years (CRP level = 30 mg/L, odds ratio [OR] = 5.4, P < 0.001), 1 to 3 years (CRP level = 45 mg/L, OR = 3.7, P < 0.001), and 12 to 18 years (CRP level = 50 mg/L, OR = 6.3, P = 0.006). Using the CRP cut-off value established in this study, we could reduce the blood culture samples in the PED by 14,108 (64.6%). CONCLUSIONS: This study provides new evidence that CRP may be a useful indicator for blood culture sampling in certain age groups and may help improve the efficiency of blood culture in the PED.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29509649 TI - Presentation and Investigation of Pediatric Bone and Joint Infections in the Pediatric Emergency Department. AB - OBJECTIVE: The objective of this study was to evaluate the presenting features of bone and joint infections with a view to identify distinguishing trends that will be useful for pediatric emergency departments. METHODS: We performed a retrospective review of patient records over a 12-year period in the pediatric emergency department of a large regional pediatric teaching center serving a diverse population. RESULTS: There were 88 cases of osteoarticular infections during the study period. Pain, fever, and impaired function were commonly reported, but overall, there was inconsistency in the presenting features. Inflammatory makers were sensitive tools, particularly in combination. When C reactive protein, total white cell count, and erythrocyte sedimentation rate were all abnormal, 98% of bone and joint infections were identified.Causative organisms were identified in only 38% of cases, mostly from cultures of synovial fluid and bone. Streptococcal organisms were significantly more likely to be isolated in children under 5 years than in children over 5 years (P = <0.014). Staphylococcal organisms were significantly more likely to be isolated in children over 5 years than in children under 5 years (P = <0.001). Identification of virulent organisms such as Panton-Valentine leukocidin Staphylococcus aureus and methicillin-resistant S. aureus in our study should prompt review of diagnostic techniques and antibiotic choices. CONCLUSIONS: Overall, children under 5 years were significantly more likely to be diagnosed with septic arthritis than osteomyelitis (P = 0. 006). Children over 12 years were significantly more likely to be diagnosed with osteomyelitis than septic arthritis (P = 0. 019). These trends are useful to consider at presentation and in cases of diagnostic uncertainty. PMID- 29509650 TI - Chlamydia Conjunctivitis in 2 Prepubertal Children: An Uncommon Presentation of Child Sexual Abuse. AB - Sexually transmitted infection as the result of child sexual abuse in prepubertal children is uncommon. Chlamydia trachomatis conjunctivitis is an even less common entity in prepubertal children outside the newborn period. This report details the presentation of 2 children with conjunctivitis who were subsequently diagnosed as having C. trachomatis conjunctivitis. One child was also diagnosed as having rectal and pharyngeal C. trachomatis infection, and the other also had genital C. trachomatis infection. Even with multisite C. trachomatis infection as an indication of sexual abuse, neither child gave a detailed disclosure of abuse to account for their infections. The absence of a clear disclosure is not uncommon. Previous literature reports that a disclosure in these circumstances occurs in less than half of cases. In this report, we review the recommendations for diagnosis of C. trachomatis using nucleic acid amplification testing and culture as well as treatment. Specific clinical features should alert the clinician to C. trachomatis conjunctivitis and lead to timely diagnosis and protection of the child from further sexual abuse. PMID- 29509651 TI - Hydronephrosis From Ureteropelvic Junction Obstruction Discovered on Point-of Care Ultrasound in Patients With Trauma. AB - We present 2 cases of patients with abdominal trauma who were found to have hydronephrosis on point-of-care ultrasound secondary to previously undiagnosed ureteropelvic junction obstructions. We review the ultrasound findings, technique, and relevant literature regarding renal point-of-care ultrasound and ureteropelvic junction obstruction. PMID- 29509652 TI - Opioids: A public health emergency. PMID- 29509653 TI - Oral Presentations Have a Significantly Higher Publication Rate, But Not Impact Factors, Than Poster Presentations at the International Society for Study of Lumbar Spine meeting: Review of 1126 Abstracts From 2010 to 2012 Meetings. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to determine the publication rate and impact factors (IFs) among all abstracts presented at the 2010 and 2012 meetings of the International Society for the Study of Lumbar Spine (ISSLS). SUMMARY OF BACKGROUND DATA: The publication rate of abstracts presented at overseas meetings was reported to be around 50%. However, the publication rate and IFs of oral and poster presentations made at ISSLS meetings were unclear. Moreover, whether the publication rates and IFs differed for papers associated with oral or poster presentations at ISSLS meetings was unknown. METHODS: We investigated all 1126 abstracts (oral, special posters, general posters) presented at ISSLS meetings held between 2010 and 2012. PubMed was searched to identify publications and IFs were determined using journal citation reports. We also compared the publication rates and IFs between oral and poster presentations. RESULTS: The overall publication rate was 50.1% for three ISSLS meetings (564 publications/1126 abstracts). The overall publication rate for oral presentations, special posters, and general posters given in the 2010 to 2012 meetings was 62.0%, 48.3, and 46.6%, respectively. Overall, papers related to oral presentations had significantly higher publication rates than those of special and general posters (P = 0.0002). The average IFs of publications associated with abstracts presented at three ISSLS meetings was 2.802 for oral presentations, 2.593 for special posters, and 2.589 for general posters. There were no significant differences in average IFs between oral and poster presentations (P > 0.05). CONCLUSION: The publication rate for abstracts presented at ISSLS meetings was high and similar to publication rates for abstracts presented at other meetings concerning orthopedic and spine research. However, there was no significant difference in IFs between oral and poster presentations, suggesting that abstract evaluations cannot predict IFs of the eventual publication. LEVEL OF EVIDENCE: 4. PMID- 29509654 TI - Flexion-Relaxation Phenomenon in Children and Adolescents With and Without Nonspecific Chronic Low Back Pain: An Electromyographic and Kinematic Cross Sectional Comparative Study. AB - STUDY DESIGN: A cross-sectional comparative study. OBJECTIVE: This study aimed to investigate the flexion-relaxation phenomenon (FRP), in standing trunk flexion and slumped sitting tasks, by comparing children and adolescents suffering from nonspecific chronic low back pain (NSCLBP) with controls (CTRL). SUMMARY OF BACKGROUND DATA: The absence of the FRP can accurately discriminate adults with NSCLBP from those without during standing trunk flexion and slumped sitting tasks. Even if the FRP has been extensively studied in adults with NSCLBP, only one study has evaluated the FRP in adolescents, during a slumped sitting task, and this suggested that the FRP was also present in adolescents with NSCLBP. METHODS: Thirty-seven children and adolescents with NSCLBP and 23 CTRL performed standing trunk flexion and slumped sitting tasks. All participants were equipped with surface electromyography (EMG) electrodes on the erector spinae longissimus (ESL) and multifidus (M) muscles and reflective markers on the spinous processes of C7, L1, and S1. Global (C7-S1), thoracic (C7-L1), and lumbar (L1-S1) trunk flexion absolute angle were measured. The FRP was reported using visual inspection and a flexion-relaxation ratio (FRR). A self-reference threshold was used to identify the time of FRP onset. Repeated-measures analysis of variance (ANOVA) was used to determine the main and interaction effects of task, group and muscle on FRR, and the relative maximal angle at FRP onset of the global trunk (C7-S1). RESULTS: Results showed three main findings: (1) the FRP's low sensitivity in discriminating between NSCLBP and CTRL participants in groups, tasks, or muscles; (2) similar observed maximal flexion angles in both groups during flexion tasks; and (3) similar observed relative maximal global trunk flexion angles at FRP onset in groups, tasks, and muscles. CONCLUSION: These results are not consistent with the literature on adults and could lead to modified therapeutic management of NSCLBP in children and adolescents. LEVEL OF EVIDENCE: 3. PMID- 29509656 TI - Reconnecting with the "Why". PMID- 29509655 TI - Sex Specific Sacroiliac Joint Biomechanics During Standing Upright: A Finite Element Study. AB - STUDY DESIGN: The comparison of sacroiliac joint (SIJ) angular motions, pelvis ligaments strain, load sharing, and stress distribution across the joint for male and female spine-pelvis-femur models using finite element analysis. OBJECTIVE: To quantify biomechanical parameters at SIJ for all motions for both male and female models. SUMMARY OF BACKGROUND DATA: SIJ has been recognized as a main source of pain in 13% to 30% of patients with low back pain. It is shown that the SIJ rotation and translation in different planes are not exceeding 2 degrees to 3 degrees and 2 mm, respectively. Due to limitation of in vivo and in vitro studies, it is difficult to quantify certain biomechanical parameters such as load-sharing and stress distribution across the joint. Finite element analysis is a useful tool which can be utilized to understand the biomechanics of the SIJ. METHODS: The validated finite element models of a male and a female lumbar spine pelvis-femur were developed from computer tomography (CT) scans. The models were used to simulate spine physiological motions. The range of motion, ligament strains, load sharing, and stress distribution across the left and right SIJs were compared between male and female models. RESULTS: Motions data at SIJs demonstrated that female model experienced 86% higher mobility in flexion, 264% in extension, 143% in left bending, and 228% in right bending compared with the male model. The stresses and loads on SIJs were higher on the female model compared with the male model. Female model ligaments underwent larger strains compared with the male model ligaments. CONCLUSION: Female SIJ had higher mobility, stresses, loads, and pelvis ligament strains compared with the male SIJ which led to higher stress across the joint, especially on the sacrum under identical loading conditions. This could be a possible reason for higher incidence of SIJ pain and pelvic stress fracture in females. LEVEL OF EVIDENCE: N/A. PMID- 29509657 TI - Acute migraine headache in children. PMID- 29509658 TI - Preliminary Study of the Potential Extracts from Selected Plants to Improve Surface Cleaning. AB - Environment hygiene is important for preventing infection and promoting a healthier environment in which to live or work. The goal of this study was to examine the antimicrobial effects of Citrus aurantifolia (key lime) juice and aqueous extracts of Cinnamomum iners (cinnamon) bark and Citrus hystrix (kaffir lime) leaves on the kinetic growth of Pseudomonas aeruginosa and methicillin resistance Staphylococcus aureus (MRSA). Antimicrobial activity was quantitatively evaluated using spectrophotometry and viable cell counts versus bacterial growth time. The fomite surface samples that were used in the second experiment were chosen randomly from the laboratories. They were assessed both before and after intervention using a mixture of commercial disinfectant detergent and lime juice. In the kinetic growth study, the lime juice effectively eliminated P. aeruginosa and MRSA. The cinnamon bark extract was more effective at inhibiting P. aeruginosa than MRSA. The kaffir lime leaf extract demonstrated bacteriostatic activity for the first 60 min, which then weakened after 90 min for both bacteria. The lime juice extract and commercial disinfectant mixture effectively disinfected the fomites. Further studies of the use of key lime juice as a disinfectant in the hospital environment should be conducted, as C. aurantifolia exhibits antibacterial activities against endemic microbes. PMID- 29509659 TI - Coupling p+n Field-Effect Transistor Circuits for Low Concentration Methane Gas Detection. AB - Nowadays, the detection of low concentration combustible methane gas has attracted great concern. In this paper, a coupling p+n field effect transistor (FET) amplification circuit is designed to detect methane gas. By optimizing the load resistance (RL), the response to methane of the commercial MP-4 sensor can be magnified ~15 times using this coupling circuit. At the same time, it decreases the limit of detection (LOD) from several hundred ppm to ~10 ppm methane, with the apparent response of 7.0 +/- 0.2 and voltage signal of 1.1 +/- 0.1 V. This is promising for the detection of trace concentrations of methane gas to avoid an accidental explosion because its lower explosion limit (LEL) is ~5%. The mechanism of this coupling circuit is that the n-type FET firstly generates an output voltage (VOUT) amplification process caused by the gate voltage-induced resistance change of the FET. Then, the p-type FET continues to amplify the signal based on the previous VOUT amplification process. PMID- 29509660 TI - Overexpression of MAP2 and NF-H Associated with Dendritic Pathology in the Spinal Cord of Mice Infected with Rabies Virus. AB - Rabies is a viral infection that targets the nervous system, specifically neurons. The clinical manifestations of the disease are dramatic and their outcome fatal; paradoxically, conventional histopathological descriptions reveal only subtle changes in the affected nervous tissue. Some researchers have considered that the pathophysiology of rabies is based more on biochemical changes than on structural alterations, as is the case with some psychiatric diseases. However, we believe that it has been necessary to resort to other methods that allow us to analyze the effect of the infection on neurons. The Golgi technique is the gold standard for studying the morphology of all the components of a neuron and the cytoskeletal proteins are the structural support of dendrites and axons. We have previously shown, in the mouse cerebral cortex and now with this work in spinal cord, that rabies virus generates remarkable alterations in the morphological pattern of the neurons and that this effect is associated with the increase in the expression of two cytoskeletal proteins (MAP2 and NF-H). It is necessary to deepen the investigation of the pathogenesis of rabies in order to find therapeutic alternatives to a disease to which the World Health Organization classifies as a neglected disease. PMID- 29509662 TI - A DNA-Based Assay for Digoxin Detection. AB - The most common method for quantifying small-molecule drugs in blood samples is by liquid chromatography in combination with mass spectrometry. Few immuno-based assays are available for the detection of small-molecule drugs in blood. Here we report on a homogeneous assay that enables detection of the concentration of digoxin spiked into in a plasma sample. The assay is based on a shift in the equilibrium of a DNA strand displacement competition reaction, and can be performed in 30 min for concentrations above 10 nM. The equilibrium shift occurs upon binding of anti-digoxigenin antibody. As a model, the assay provides a potential alternative to current small-molecule detection methods used for therapeutic drug monitoring. PMID- 29509661 TI - Two New Cyathane Diterpenoids from Mycelial Cultures of the Medicinal Mushroom Hericium erinaceus and the Rare Species, Hericium flagellum. AB - Basidiomycetes of the genus Hericium are among the most praised medicinal and edible mushrooms, which are known to produce secondary metabolites with the potential to treat neurodegenerative diseases. This activity has been attributed to the discovery of various terpenoids that can stimulate the production of nerve growth factor (NGF) or (as established more recently) brain-derived neurotrophic factor (BDNF) in cell-based bioassays. The present study reports on the metabolite profiles of a Lion's Mane mushroom (Hericium erinaceus) strain and a strain of the rare species, Hericium flagellum (synonym H. alpestre). While we observed highly similar metabolite profiles between the two strains that were examined, we isolated two previously undescribed metabolites, given the trivial names erinacines Z1 and Z2. Their chemical structures were elucidated by means of nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry. Along with six further, previously identified cyathane diterpenes, the novel erinacines were tested for neurotrophin inducing effects. We found that erinacines act on BDNF, which is a neurotrophic factor that has been reported recently by us to be induced by the corallocins, but as well on NGF expression, which is consistent with the literature. PMID- 29509663 TI - Endostatin Stimulates Proliferation and Migration of Myofibroblasts Isolated from Myocardial Infarction Model Rats. AB - Myofibroblasts contribute to the healing of infarcted areas after myocardial infarction through proliferation, migration, and production of extracellular matrix (ECM). Expression of endostatin, a cleaved fragment of type XVIII collagen, increases in the heart tissue of an experimental myocardial infarction model. In the present study, we examined the effect of endostatin on the function of myofibroblasts derived from an infarcted area. The myocardial infarction model was created by ligating the left anterior descending artery in rats. Two weeks after the operation, alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts were isolated from the infarcted area. Endostatin significantly increased the proliferation and migration of myofibroblasts in vitro. On the other hand, endostatin had no effect on the production of type I collagen, a major ECM protein produced by myofibroblasts. Endostatin activated Akt and extracellular signal-regulated kinase (ERK), and the pharmacological inhibition of these signaling pathways suppressed the endostatin-induced proliferation and migration. A knockdown of the COL18A1 gene in the myocardial infarction model rats using small interference RNA (siRNA) worsened the cardiac function concomitant with wall thinning and decreased the alpha-SMA-positive myofibroblasts and scar formation compared with that of control siRNA-injected rats. In summary, we demonstrated for the first time that endostatin might be an important factor in the healing process after myocardial infarction through the activation of myofibroblasts. PMID- 29509664 TI - Key Odorants from Pig Production Based on Improved Measurements of Odor Threshold Values Combining Olfactometry and Proton-Transfer-Reaction Mass Spectrometry (PTR MS). AB - Analytical measurements of odorants in combination with odor threshold values is an alternative to sensory measurements that can be used to evaluate abatement technologies for pig production facilities. The purpose of the present study was to estimate odor threshold values for key odorants found in pig house air. A new method was applied where an olfactometer was used to dilute the sample air and the concentrations of odorants presented to the panelists at the dilutions steps were measured by proton-transfer-reaction mass spectrometry (PTR-MS). The results demonstrate that the odor threshold values of acetic acid, butanoic acid, and 4 methylphenol are considerably lower than reported previously, whereas the values of hydrogen sulfide, methanethiol and dimethylsulfide were comparable. Consequently, acetic acid, butanoic acid, and 4-methyl-phenol will have a larger influence on odor from pig production facilities than previously assumed. The results highlight the necessity for directly measuring exposure concentrations when determining odor threshold values. PMID- 29509665 TI - Generic Meal Patterns Identified by Latent Class Analysis: Insights from NANS (National Adult Nutrition Survey). AB - Nutritional data reduction methods are widely applied in nutrition epidemiology in order to classify individuals into meaningful groups with similar dietary patterns. To date, none of the existing studies have applied latent class analysis to examine dietary patterns which include meal types consumed throughout a day. We investigated main meal patterns followed on weekend and weekdays, and evaluated their associations with cardio-metabolic biomarkers. The analyses were performed within the NANS (National Adult Nutrition Survey) a cross-sectional national food consumption survey of 1500 nationally representative Irish adults. A total number of seven dietary patterns were identified using latent class analysis. The typical meal pattern followed by the majority of the population was characterized by consumption of cereal or toast for breakfast, skipping or consuming a sandwich for light meal, and meat or fish with potatoes, pasta or vegetables for the main meal. Eating patterns differed on weekends, and those participants who consumed meat and eggs for breakfast instead of breakfast cereal and skipped light meal were more likely to have an unhealthier dietary pattern, a higher diastolic blood pressure, and increased serum ferritin. The application of data reduction techniques to simplify the multifaceted nature of dietary data is a useful approach to derive patterns, which might shed further light on the typical dietary patterns followed by populations. PMID- 29509666 TI - Single Image Super-Resolution Based on Multi-Scale Competitive Convolutional Neural Network. AB - Deep convolutional neural networks (CNNs) are successful in single-image super resolution. Traditional CNNs are limited to exploit multi-scale contextual information for image reconstruction due to the fixed convolutional kernel in their building modules. To restore various scales of image details, we enhance the multi-scale inference capability of CNNs by introducing competition among multi-scale convolutional filters, and build up a shallow network under limited computational resources. The proposed network has the following two advantages: (1) the multi-scale convolutional kernel provides the multi-context for image super-resolution, and (2) the maximum competitive strategy adaptively chooses the optimal scale of information for image reconstruction. Our experimental results on image super-resolution show that the performance of the proposed network outperforms the state-of-the-art methods. PMID- 29509667 TI - Genetic Determinants of Tetracycline Resistance in Clinical Streptococcus pneumoniae Serotype 1 Isolates from Niger. AB - Streptococcus pneumoniae serotype 1 is the first cause of pneumococcal meningitis Niger. To determine the underlying mechanism of resistance to tetracycline in serotype 1 Streptococcus pneumoniae, a collection of 37 isolates recovered from meningitis patients over the period of 2002 to 2009 in Niger were analyzed for drug susceptibility, and whole genome sequencing (WGS) was performed for molecular analyses. MIC level was determined for 31/37 (83.8%) isolates and allowed detection of full resistance (MIC = 8 ug) in 24/31 (77.4%) isolates. No resistance was found to macrolides and quinolones. Sequence-types deduced from WGS were ST217 (54.1%), ST303 (35.1%), ST2206 (5.4%), ST2839 (2.7%) and one undetermined ST (2.7%). All tetracycline resistant isolates carried a Tn5253 like element, which was found to be an association of two smaller transposons of Tn916 and Tn5252 families. No tet(O) and tet(Q) genes were detected. However, a tet(M) like sequence was identified in all Tn5253 positive strains and was found associated to Tn916 composite. Only one isolate was phenotypically resistant to chloramphenicol, wherein a chloramphenicol acetyl transferase (cat) gene sequence homologous to catpC194 from the Staphylococcus aureus plasmid pC194 was detected. In conclusion, clinical Streptococcus pneumoniae type 1 isolated during 2002 to 2009 meningitis surveillance in Niger were fully susceptible to macrolides and quinolones but highly resistant to tetracycline (77.4%) through acquisition of a defective Tn5253 like element composed of Tn5252 and Tn916 transposons. Of the 31 tested isolates, only one was exceptionally resistant to chloramphenicol and carried a Tn5253 transposon that contained cat gene sequence. PMID- 29509669 TI - Effect of Presence and Concentration of Plasticizers, Vegetable Oils, and Surfactants on the Properties of Sodium-Alginate-Based Edible Coatings. AB - Achieving high quality of a coated food product is mostly dependent on the characteristics of the food material to be coated, the properties of the components in the coating solution, and the obtained coating material. In the present study, usability and effectiveness of various components as well as their concentrations were assessed to produce an effective coating material. For this purpose, different concentrations of gelling agent (sodium alginate 0-3.5%, w/w), plasticizers (glycerol and sorbitol (0-20%, w/w), surfactants (tween 40, tween 80, span 60, span 80, lecithin (0-5%, w/w), and vegetable oils (sunflower oil, olive oil, rapeseed oil (0-5%, w/w) were used to prepare edible coating solutions. Formulations were built gradually, and characteristics of coatings were evaluated by analyzing surface tension values and its polar and dispersive components, emulsion droplet size, and optical appearance in microscopic scale. The results obtained showed that 1.25% sodium alginate, 2% glycerol, 0.2% sunflower oil, 1% span 80, and 0.2% tween 40 or tween 80 can be used in formulation to obtain an effective coating for hydrophobic food surfaces. Three formulations were designed, and their stability (emulsion droplet size, optical characteristics, and creaming index) and wettability tests on strawberry showed that they could be successfully used in coating applications. PMID- 29509668 TI - Overview of Oxidative Stress Response Genes in Selected Halophilic Fungi. AB - Exposure of microorganisms to stress, including to high concentrations of salt, can lead to increased production of reactive oxygen species in the cell. To limit the resulting damage, cells have evolved a variety of antioxidant defenses. The role of these defenses in halotolerance has been proposed before. Whole genome sequencing for some of the most halotolerant and halophilic fungal species has enabled us to investigate the possible links between oxidative and salt stress tolerance on the genomic level. We identified genes involved in oxidative stress response in the halophilic basidiomycete Wallemia ichthyophaga, and halotolerant ascomycetous black yeasts Hortaea werneckii and Aureobasidium pullulans, and compared them to genes from 16 other fungi, both asco- and basidiomycetes. According to our results, W. ichthyophaga can survive salinities detrimental to most other organisms with only a moderate number of oxidative stress response genes. In other investigated species, however, the maximum tolerated salinity correlated with the number of genes encoding three major enzymes of the cellular oxidative stress response: superoxide dismutases, catalases, and peroxiredoxins. This observation supports the hypothetical link between the antioxidant capacity of cells and their halotolerance. PMID- 29509670 TI - Anti-Inflammatory Effect of Lupinalbin A Isolated from Apios americana on Lipopolysaccharide-Treated RAW264.7 Cells. AB - Apios americana, a leguminous plant, is used as food in some countries. Although the biological activities of Apios extract have been reported, there have been no reports about the anti-inflammatory mechanism of lupinalbin A on the RAW264.7 cells. In this study, we investigated the anti-inflammatory effect of A. americana lupinalbin A on lipopolysaccharide (LPS)-treated RAW264.7 cells. Lupinalbin A significantly inhibited nitric oxide production and inducible nitric oxide synthase expression in LPS-treated RAW264.7 cells. The expression of cytokines, including interleukin-6, tumor necrosis factor-alpha, and chemokine of monocyte chemoattractant protein, was reduced under lupinalbin A exposure in LPS treated RAW264.7 cells. In addition, lupinalbin A significantly decreased LPS induced interferon (IFN)-beta production and STAT1 protein levels in RAW264.7 cells. Taken together, these results suggest that A. americana lupinalbin A exerts anti-inflammatory effects via the inhibition of pro-inflammatory cytokines and blocking of IFN-beta/STAT1 pathway activation. PMID- 29509671 TI - Main Sources, Socio-Demographic and Anthropometric Correlates of Salt Intake in Austria. AB - Excessive salt intake is known to increase blood pressure and cardiovascular risk. Nevertheless, salt intake exceeds the recommendations in most countries. To face this problem, it is important to identify high consumers as well as the main contributors of salt intake. Overall, data of 2018 adults between 18 and 64 years were analysed to determine the main sources, socio-demographic and anthropometric correlates of salt intake. Dietary intake was assessed from 24-h-recalls, information on socio-demographic characteristics was obtained using a questionnaire and anthropometric data were measured. Salt intake was significantly higher in males than in females. There was a significant positive association between salt intake and body mass index. No significant differences in salt intake were observed for other variables including affluence, educational level, smoking status and physical activity. The main contributor to salt intake were condiments including table salt (32.6%), followed by cereals and cereal products (27.0%), meat and meat products (16.1%) and dairy products (14.0%). These results highlight that specific population groups need to be targeted by public health initiatives and that a reduction in salt intake can only be achieved in tandem with the food producers by the reduction of salt in processed foods. PMID- 29509672 TI - Melatonin Improves Heat Tolerance in Kiwifruit Seedlings through Promoting Antioxidant Enzymatic Activity and Glutathione S-Transferase Transcription. AB - Evidence exists to suggest that melatonin (MT) is important to abiotic stress tolerance in plants. Here, we investigated whether exogenous MT reduces heat damage on biological parameters and gene expression in kiwifruit (Actinidia deliciosa) seedlings. Pretreatment with MT alleviates heat-induced oxidative harm through reducing H2O2 content and increasing proline content. Moreover, MT application raised ascorbic acid (AsA) levels and the activity of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). We also observed elevation in the activity of enzymes related to the AsA GSH cycle, such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), and glutathione reductase (GR). Furthermore, MT application increased the expression of 28/31 glutathione S transferase (GST) genes, reducing oxidative stress. These results clearly indicate that in kiwifruit, MT exerts a protective effect against heat-related damage through regulating antioxidant pathways. PMID- 29509673 TI - Special Issue: Antibacterial Materials and Coatings. PMID- 29509674 TI - Amperometric Self-Referencing Ceramic Based Microelectrode Arrays for D-Serine Detection. AB - D-serine is the major D-amino acid in the mammalian central nervous system. As the dominant co-agonist of the endogenous synaptic NMDA receptor, D-serine plays a role in synaptic plasticity, learning, and memory. Alterations in D-serine are linked to neuropsychiatric disorders including schizophrenia. Thus, it is of increasing interest to monitor the concentration of D-serine in vivo as a relevant player in dynamic neuron-glia network activity. Here we present a procedure for amperometric detection of D-serine with self-referencing ceramic based microelectrode arrays (MEAs) coated with D-amino acid oxidase from the yeast Rhodotorulagracilis (RgDAAO). We demonstrate in vitro D-serine recordings with a mean sensitivity of 8.61 +/- 0.83 pA/uM to D-serine, a limit of detection (LOD) of 0.17 +/- 0.01 uM, and a selectivity ratio of 80:1 or greater for D serine over ascorbic acid (mean +/- SEM; n = 12) that can be used for freely moving studies. PMID- 29509675 TI - Community Readiness for the Promotion of Physical Activity in Older Adults-A Cross-Sectional Comparison of Rural and Urban Communities. AB - Communities can play an important role in delivering public health programs to older adults, but they differ in the provision of local structures and resources. The community readiness (CR) approach applies a stage model of change to the community level and analyzes structures and the degree of willingness to take action on a health issue. This study compared the CR regarding the promotion of physical activity as part of healthy ageing for older adults among urban and rural communities in North-West Germany. A cross-sectional CR assessment with key respondents in 23 municipalities (11 urban and 12 rural communities) was conducted using a semi-structured interview. Interviews were scored across the five CR dimensions and global CR score was calculated (scores between 1 = no awareness and 9 = professionalization). Wilcoxon rank-sum test and hierarchical regression models were used to compare urban and rural communities. In total, 118 interviews were conducted (response rate 69.8%). On average, the communities showed moderate CR scores (4.9 +/- 0.3; Range: 4.3-5.4; preplanning or preparation phase). The global CR score was slightly higher in rural than in urban communities (regression coefficient = 0.29, 95% confidence interval (CI): 0.02-0.59). The rural communities showed significantly higher CR scores in the 'Knowledge of efforts' dimension (0.70, 95% CI: 0.26-1.14) and in the 'Knowledge of the issue' (0.37, 95% CI: 0.04-0.70). Rural communities display a slightly higher CR level than urban communities. In the next step, targeted capacity building activities will be initiated among communities with low CR levels. PMID- 29509676 TI - Green Synthesis of Boron Carbonitride with High Capacitance. AB - Boron carbonitrides (BCN) have attracted great interest in superhard or energy storage materials. In this work, thin BCN sheets were synthesized at 250 degrees C by a facile and green solvothermal method. The structure and morphology were characterized by X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Based on the results of electrochemical experiments, the thin BCN sheet exhibited excellent capacitance performance (343.1 F/g at a current density of 0.5 A/g) and cycling stability (90%), which showed high potential applications in supercapacitors. PMID- 29509677 TI - Hybrid GMR Sensor Detecting 950 pT/sqrt(Hz) at 1 Hz and Room Temperature. AB - Advances in the magnetic sensing technology have been driven by the increasing demand for the capability of measuring ultrasensitive magnetic fields. Among other emerging applications, the detection of magnetic fields in the picotesla range is crucial for biomedical applications. In this work Picosense reports a millimeter-scale, low-power hybrid magnetoresistive-piezoelectric magnetometer with subnanotesla sensitivity at low frequency. Through an innovative noise cancelation mechanism, the 1/f noise in the MR sensors is surpassed by the mechanical modulation of the external magnetic fields in the high frequency regime. A modulation efficiency of 13% was obtained enabling a final device's sensitivity of ~950 pT/Hz1/2 at 1 Hz. This hybrid device proved to be capable of measuring biomagnetic signals generated in the heart in an unshielded environment. This result paves the way for the development of a portable, contactless, low-cost and low-power magnetocardiography device. PMID- 29509679 TI - A New Approach for Inspection of Selected Geometric Parameters of a Railway Track Using Image-Based Point Clouds. AB - The paper presents the results of testing a proposed image-based point clouds measuring method for geometric parameters determination of a railway track. The study was performed based on a configuration of digital images and reference control network. A DSLR (digital Single-Lens-Reflex) Nikon D5100 camera was used to acquire six digital images of the tested section of railway tracks. The dense point clouds and the 3D mesh model were generated with the use of two software systems, RealityCapture and PhotoScan, which have implemented different matching and 3D object reconstruction techniques: Multi-View Stereo and Semi-Global Matching, respectively. The study found that both applications could generate appropriate 3D models. Final meshes of 3D models were filtered with the MeshLab software. The CloudCompare application was used to determine the track gauge and cant for defined cross-sections, and the results obtained from point clouds by dense image matching techniques were compared with results of direct geodetic measurements. The obtained RMS difference in the horizontal (gauge) and vertical (cant) plane was RMS? < 0.45 mm. The achieved accuracy meets the accuracy condition of measurements and inspection of the rail tracks (error m < 1 mm), specified in the Polish branch railway instruction Id-14 (D-75) and the European technical norm EN 13848-4:2011. PMID- 29509678 TI - Characterization of Condensed Tannins from Purple Prairie Clover (Dalea purpurea Vent.) Conserved as either Freeze-Dried Forage, Sun-Cured Hay or Silage. AB - Conservation methods have been shown to affect forage nutrient composition and value, but little information is available about the effect of forage conservation on plant condensed tannins (CT). The objective of this study was to assess the effects of conservation method on the concentration, chemical composition and biological activity of CT. Whole-plant purple prairie clover (PPC, Dalea purpurea Vent.) was harvested at full flower and conserved as freeze dried forage (FD), hay (HAY) or silage (SIL). Concentration of CT in conserved PPC was determined by the butanol-HCl-acetone method. Structural composition, protein-precipitation capacity and anti-bacterial activity of CT isolated from conserved forage were determined by in situ thiolytic degradation followed by HPLC-MS analysis, a protein precipitation assay using bovine serum albumin and ribulose 1,5-disphosphate carboxylase as model proteins and by an Escherichia coli (E. coli) growth test, respectively. Conservation method had no effect on concentration of total CT, but ensiling decreased (p < 0.001) extractable CT and increased (p < 0.001) protein- and fiber-bound CT. In contrast, hay-making only increased (p < 0.01) protein-bound CT. Regardless of conservation method, epigallocatechin (EGC), catechin (C) and epicatechin (EC) were the major flavan-3 ol units, and gallocatechin (GC) was absent from both terminal and extension units of PPC CT. The SIL CT had the lowest (p < 0.001) EGC, but the highest (p < 0.01) EC in the extension units. Similarly, SIL CT exhibited a lower (p < 0.001) mean degree of polymerization (mDP), but higher (p < 0.001) procyanidins (PC) than FD or HAY CT. The protein-precipitating capacity of CT in conserved PPC ranked (p < 0.001) as FD > HAY > SIL. E. coli growth n M9 medium was inhibited by 25-100 ug/mL of CT isolated from FD, HAY and SIL (p < 0.05), but preservation method had no effect on the ability of CT to inhibit bacterial growth. The results demonstrated that ensiling decreased the extractability and protein precipitating capacity of CT by increasing the proportions of PC. Purple prairie clover conserved as hay retained more biologically active CT than if it was conserved as silage. PMID- 29509681 TI - Quality Control Procedure Based on Partitioning of NMR Time Series. AB - The quality of the magnetic resonance spectroscopy (MRS) depends on the stability of magnetic resonance (MR) system performance and optimal hardware functioning, which ensure adequate levels of signal-to-noise ratios (SNR) as well as good spectral resolution and minimal artifacts in the spectral data. MRS quality control (QC) protocols and methodologies are based on phantom measurements that are repeated regularly. In this work, a signal partitioning algorithm based on a dynamic programming (DP) method for QC assessment of the spectral data is described. The proposed algorithm allows detection of the change points-the abrupt variations in the time series data. The proposed QC method was tested using the simulated and real phantom data. Simulated data were randomly generated time series distorted by white noise. The real data were taken from the phantom quality control studies of the MRS scanner collected for four and a half years and analyzed by LCModel software. Along with the proposed algorithm, performance of various literature methods was evaluated for the predefined number of change points based on the error values calculated by subtracting the mean values calculated for the periods between the change-points from the original data points. The time series were checked using external software, a set of external methods and the proposed tool, and the obtained results were comparable. The application of dynamic programming in the analysis of the phantom MRS data is a novel approach to QC. The obtained results confirm that the presented change point-detection tool can be used either for independent analysis of MRS time series (or any other) or as a part of quality control. PMID- 29509680 TI - [18F]fallypride-PET/CT Analysis of the Dopamine D2/D3 Receptor in the Hemiparkinsonian Rat Brain Following Intrastriatal Botulinum Neurotoxin A Injection. AB - Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson's disease. The caudate-putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D2/D3 receptor (D2/D3R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [18F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT A injection. Male Wistar rats were assigned to three different groups: controls, sham-injected hemi-PD rats, and BoNT-A-injected hemi-PD rats. Disease-specific motor impairment was verified by apomorphine and amphetamine rotation testing. Animal-specific magnetic resonance imaging was performed for co-registration and anatomical reference. PET quantification was achieved using PMOD software with the simplified reference tissue model 2. Hemi-PD rats exhibited a constant increase of 23% in D2/D3R availability in the CPu, which was almost normalized by intrastriatal application of BoNT-A. Importantly, the BoNT-A effect on striatal D2/D3R significantly correlated with behavioral results in the apomorphine rotation test. Our results suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing interhemispheric changes of striatal D2/D3R. PMID- 29509682 TI - An Optical Biosensing Strategy Based on Selective Light Absorption and Wavelength Filtering from Chromogenic Reaction. AB - To overcome the time and space constraints in disease diagnosis via the biosensing approach, we developed a new signal-transducing strategy that can be applied to colorimetric optical biosensors. Our study is focused on implementation of a signal transduction technology that can directly translate the color intensity signals-that require complicated optical equipment for the analysis-into signals that can be easily counted with the naked eye. Based on the selective light absorption and wavelength-filtering principles, our new optical signaling transducer was built from a common computer monitor and a smartphone. In this signal transducer, the liquid crystal display (LCD) panel of the computer monitor served as a light source and a signal guide generator. In addition, the smartphone was used as an optical receiver and signal display. As a biorecognition layer, a transparent and soft material-based biosensing channel was employed generating blue output via a target-specific bienzymatic chromogenic reaction. Using graphics editor software, we displayed the optical signal guide patterns containing multiple polygons (a triangle, circle, pentagon, heptagon, and 3/4 circle, each associated with a specified color ratio) on the LCD monitor panel. During observation of signal guide patterns displayed on the LCD monitor panel using a smartphone camera via the target analyte-loaded biosensing channel as a color-filtering layer, the number of observed polygons changed according to the concentration of the target analyte via the spectral correlation between absorbance changes in a solution of the biosensing channel and color emission properties of each type of polygon. By simple counting of the changes in the number of polygons registered by the smartphone camera, we could efficiently measure the concentration of a target analyte in a sample without complicated and expensive optical instruments. In a demonstration test on glucose as a model analyte, we could easily measure the concentration of glucose in the range from 0 to 10 mM. PMID- 29509683 TI - Correction: Cooper, A.; Abbass, A.; Town, J. Implementing a Psychotherapy Service for Medically Unexplained Symptoms in a Primary Care Setting. Journal of Clinical Medicine 2017, 6, 109-141. AB - The authors wish to make the following corrections to this paper [1].[...]. PMID- 29509684 TI - Evolution of Carbon Ion Radiotherapy at the National Institute of Radiological Sciences in Japan. AB - Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated for carbon ion treatments in the world. Since its establishment in 1994, the NIRS has pioneered this therapy with more than 69 clinical trials so far, and hundreds of ancillary projects in physics and radiobiology. In this review, we will discuss the evolution of carbon ion radiotherapy at the NIRS and some of the current and future projects in the field. PMID- 29509685 TI - Assessment of Metalloid and Metal Contamination in Soils from Hainan, China. AB - The characterization of the concentrations and sources of metals and metalloids in soils is necessary to establish quality standards on a regional level and to assess the potential threat of metals to food safety and human health. A total of 8713 soil samples throughout Hainan Island, China were collected at a density of one sample per 4 km2, and concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb, Se, and Zn were analyzed. The geometric mean values of the elements were 2.17, 0.60, 26.5, 9.43, 0.033, 8.74, 22.2, 0.26, and 39.6 mg.. kg-1 for As, Cd, Cr, Cu, Hg, Ni, Pb, Se, and Zn, respectively, significantly lower than the background values of Chinese soils with the exception of Se. Principal component analysis (PCA) suggested that multiple anthropogenic sources regulated the elemental compositions of the Hainan environment. Coal combustion and mining are important anthropogenic sources of metals for Hainan. The geochemical maps of elements in Hainan soils were produced using the Geographic Information System (GIS) method, and several hot-spot areas were identified. The ecological impact of As, Cd, Cu, Cr, Hg, Pb, Ni, and Zn pollution to the soils was extremely "low". PMID- 29509686 TI - The Role of Oral Cavity Biofilm on Metallic Biomaterial Surface Destruction Corrosion and Friction Aspects. AB - Metallic biomaterials in the oral cavity are exposed to many factors such as saliva, bacterial microflora, food, temperature fluctuations, and mechanical forces. Extreme conditions present in the oral cavity affect biomaterial exploitation and significantly reduce its biofunctionality, limiting the time of exploitation stability. We mainly refer to friction, corrosion, and biocorrosion processes. Saliva plays an important role and is responsible for lubrication and biofilm formation as a transporter of nutrients for microorganisms. The presence of metallic elements in the oral cavity may lead to the formation of electro galvanic cells and, as a result, may induce corrosion. Transitional microorganisms such as sulfate-reducing bacteria may also be present among the metabolic microflora in the oral cavity, which can induce biological corrosion. Microorganisms that form a biofilm locally change the conditions on the surface of biomaterials and contribute to the intensification of the biocorrosion processes. These processes may enhance allergy to metals, inflammation, or cancer development. On the other hand, the presence of saliva and biofilm may significantly reduce friction and wear on enamel as well as on biomaterials. This work summarizes data on the influence of saliva and oral biofilms on the destruction of metallic biomaterials. PMID- 29509687 TI - Vesicular Axonal Transport is Modified In Vivo by Tau Deletion or Overexpression in Drosophila. AB - Structural microtubule associated protein Tau is found in high amount in axons and is involved in several neurodegenerative diseases. Although many studies have highlighted the toxicity of an excess of Tau in neurons, the in vivo understanding of the endogenous role of Tau in axon morphology and physiology is poor. Indeed, knock-out mice display no strong cytoskeleton or axonal transport phenotype, probably because of some important functional redundancy with other microtubule-associated proteins (MAPs). Here, we took advantage of the model organism Drosophila, which genome contains only one homologue of the Tau/MAP2/MAP4 family to decipher (endogenous) Tau functions. We found that Tau depletion leads to a decrease in microtubule number and microtubule density within axons, while Tau excess leads to the opposite phenotypes. Analysis of vesicular transport in tau mutants showed altered mobility of vesicles, but no change in the total amount of putatively mobile vesicles, whereas both aspects were affected when Tau was overexpressed. In conclusion, we show that loss of Tau in tau mutants not only leads to a decrease in axonal microtubule density, but also impairs axonal vesicular transport, albeit to a lesser extent compared to the effects of an excess of Tau. PMID- 29509688 TI - Electrospun Fibrous Scaffolds for Tissue Engineering: Viewpoints on Architecture and Fabrication. AB - Electrospinning has been used for the fabrication of extracellular matrix (ECM) mimicking fibrous scaffolds for several decades. Electrospun fibrous scaffolds provide nanoscale/microscale fibrous structures with interconnecting pores, resembling natural ECM in tissues, and showing a high potential to facilitate the formation of artificial functional tissues. In this review, we summarize the fundamental principles of electrospinning processes for generating complex fibrous scaffold geometries that are similar in structural complexity to the ECM of living tissues. Moreover, several approaches for the formation of three dimensional fibrous scaffolds arranged in hierarchical structures for tissue engineering are also presented. PMID- 29509690 TI - EMD-Based Methodology for the Identification of a High-Speed Train Running in a Gear Operating State. AB - An efficient maintenance is a key consideration in systems of railway transport, especially in high-speed trains, in order to avoid accidents with catastrophic consequences. In this sense, having a method that allows for the early detection of defects in critical elements, such as the bogie mechanical components, is a crucial for increasing the availability of rolling stock and reducing maintenance costs. The main contribution of this work is the proposal of a methodology that, based on classical signal processing techniques, provides a set of parameters for the fast identification of the operating state of a critical mechanical system. With this methodology, the vibratory behaviour of a very complex mechanical system is characterised, through variable inputs, which will allow for the detection of possible changes in the mechanical elements. This methodology is applied to a real high-speed train in commercial service, with the aim of studying the vibratory behaviour of the train (specifically, the bogie) before and after a maintenance operation. The results obtained with this methodology demonstrated the usefulness of the new procedure and allowed for the disclosure of reductions between 15% and 45% in the spectral power of selected Intrinsic Mode Functions (IMFs) after the maintenance operation. PMID- 29509691 TI - Accurate Decoding of Short, Phase-Encoded SSVEPs. AB - Four novel EEG signal features for discriminating phase-coded steady-state visual evoked potentials (SSVEPs) are presented, and their performance in view of target selection in an SSVEP-based brain-computer interfacing (BCI) is assessed. The novel features are based on phase estimation and correlations between target responses. The targets are decoded from the feature scores using the least squares support vector machine (LS-SVM) classifier, and it is shown that some of the proposed features compete with state-of-the-art classifiers when using short (0.5 s) EEG recordings in a binary classification setting. PMID- 29509689 TI - Novel Furocoumarin Derivatives Stimulate Melanogenesis in B16 Melanoma Cells by Up-Regulation of MITF and TYR Family via Akt/GSK3beta/beta-Catenin Signaling Pathways. AB - The extracts of Ficuscarica L. and Psoralen corylifolia L. are traditional Uygur medicines for the treatment of vitiligo, and its active ingredients furocoumarins, were are found to be the most effective agents against this skin disorder nowadays. Therefore, a series of novel easter derivatives (8a-8p) of furocoumarin were designed and synthesized based on our previous research to improve this activity in the present study. The synthesized derivatives were biologically evaluated for melanin synthesis in murine B16 cells and the SAR (structure-activity relationship) was summarized. Eight derivatives were more potent than positive control (8-MOP, 8-methoxypsoralan), especially compounds 8n (200%) and 8o (197%), which were nearly 1.5-fold potency when compared with 8-MOP (136%). Furthermore, the signaling pathway by which 8n activates the melanin biosynthesis was defined. Our results showed that it not only elevated the melanin content, but also stimulated the activity of tyrosinasein a concentration dependent manner. Increasing of phosphorylation of Akt (also named PKB, protein kinase B) and non-activated GSK3beta (glycogen synthase kinase 3 beta), which inhibited the degradation of beta-catenin were observed through Western blot analysis. The accumulation of beta-catenin probably led to the activation of transcription of MITF (microphthalmia-associated transcription factor) and TYR (tyrosinase) family, as well as the subsequent induction of melanin synthesis. PMID- 29509692 TI - A Novel Anti-Spoofing Solution for Iris Recognition Toward Cosmetic Contact Lens Attack Using Spectral ICA Analysis. AB - In this study, we maneuvered a dual-band spectral imaging system to capture an iridal image from a cosmetic-contact-lens-wearing subject. By using the independent component analysis to separate individual spectral primitives, we successfully distinguished the natural iris texture from the cosmetic contact lens (CCL) pattern, and restored the genuine iris patterns from the CCL-polluted image. Based on a database containing 200 test image pairs from 20 CCL-wearing subjects as the proof of concept, the recognition accuracy (False Rejection Rate: FRR) was improved from FRR = 10.52% to FRR = 0.57% with the proposed ICA anti spoofing scheme. PMID- 29509693 TI - Multi-User Low Intrusive Occupancy Detection. AB - Smart spaces are those that are aware of their state and can act accordingly. Among the central elements of such a state is the presence of humans and their number. For a smart office building, such information can be used for saving energy and safety purposes. While acquiring presence information is crucial, using sensing techniques that are highly intrusive, such as cameras, is often not acceptable for the building occupants. In this paper, we illustrate a proposal for occupancy detection which is low intrusive; it is based on equipment typically available in modern offices such as room-level power-metering and an app running on workers' mobile phones. For power metering, we collect the aggregated power consumption and disaggregate the load of each device. For the mobile phone, we use the Received Signal Strength (RSS) of BLE (Bluetooth Low Energy) nodes deployed around workspaces to localize the phone in a room. We test the system in our offices. The experiments show that sensor fusion of the two sensing modalities gives 87-90% accuracy, demonstrating the effectiveness of the proposed approach. PMID- 29509695 TI - Progress on the Studies of the Key Enzymes of Ginsenoside Biosynthesis. AB - As the main bioactive constituents of Panax species, ginsenosides possess a wide range of notable medicinal effects such as anti-cancer, anti-oxidative, antiaging, anti-inflammatory, anti-apoptotic and neuroprotective activities. However, the increasing medical demand for ginsenosides cannot be met due to the limited resource of Panax species and the low contents of ginsenosides. In recent years, biotechnological approaches have been utilized to increase the production of ginsenosides by regulating the key enzymes of ginsenoside biosynthesis, while synthetic biology strategies have been adopted to produce ginsenosides by introducing these genes into yeast. This review summarizes the latest research progress on cloning and functional characterization of key genes dedicated to the production of ginsenosides, which not only lays the foundation for their application in plant engineering, but also provides the building blocks for the production of ginsenosides by synthetic biology. PMID- 29509696 TI - Enzyme-Assisted Extraction Optimization, Characterization and Antioxidant Activity of Polysaccharides from Sea Cucumber Phyllophorus proteus. AB - Enzyme-assisted extraction optimization, characterization and in vitro antioxidant activity of polysaccharides from sea cucumber Phyllophorus proteus (PPP) were investigated in the present study. The optimal extraction conditions with a yield of 6.44 +/- 0.06% for PPP were determined as follows: Extraction time of 2.89 h, ratio of extraction solvent to raw material of 16.26 mL/g, extraction pH of 6.83, exraction temperature of 50 degrees C and papain concentration of 0.15%. Three purified fractions, PPP-1a, PPP-1b and PPP-2 with molecular weights of 369.60, 41.73 and 57.76 kDa, respectively, were obtained from PPP by chromatography of FPA98Cl and Sepharose CL-6B columns. Analysis of monosaccharide compositions showed that PPP-1a consisted of N-acetyl galactosamine (GalNAc), galactose (Gal) and fucose (Fuc), PPP-1b of Fuc as the only monosaccharide and PPP-2 of glucuronic acid, GalNAc and Fuc. Sulfate contents of PPP, PPP-1a, PPP-1b and PPP-2 were determined to be 21.9%, 20.6%, 25.2% and 28.0% (w/w), respectively. PPP and PPP-1a had higher molecular weight and intrinsic viscosity than those of the PPP-1b and PPP-2. PPP, PPP-1a, PPP-1b and PPP-2 exhibited obvious activities of scavenging 1,1-diphenyl-2 picrylhydrazyl radical, hydroxyl radical, superoxide radical and ABTS radical in different extent, which suggested that the polysaccharides from Phyllophorus proteus may be novel agents having potential value for antioxidation. PMID- 29509694 TI - New Steroidal Saponins from the Rhizomes of Paris vietnamensis and Their Cytotoxicity. AB - Four new spirostanol saponins, named pavitnosides A-D (1-4), with six known steroidal saponins 5-10 were isolated from the rhizomes of Paris vietnamensis. Their chemical structures were determined based on extensive spectroscopic studies and chemical methods. The aglycones of pavitnoside B and pavitnoside C were not reported in previous work. The cytotoxicity of all saponins was evaluated against human glioblastoma U87MG and U251 cell lines. The new spirostanol saponin 1 displayed weak anti-proliferative activity against U87MG cell line and the known saponins 8 and 9 exhibited significant cytotoxicity against the two tumor cell lines, with IC50 values of 2.16 to 3.14 MUM, but did not affect the growth of primary cultures of human astrocytes. PMID- 29509697 TI - Differential Transcriptional Activation of Genes Encoding Soluble Methane Monooxygenase in a Facultative Versus an Obligate Methanotroph. AB - Methanotrophs are a specialized group of bacteria that can utilize methane (CH4) as a sole energy source. A key enzyme responsible for methane oxidation is methane monooxygenase (MMO), of either a soluble, cytoplasmic type (sMMO), or a particulate, membrane-bound type (pMMO). Methylocellasilvestris BL2 and Methyloferulastellata AR4 are closely related methanotroph species that oxidize methane via sMMO only. However, Methyloferulastellata is an obligate methanotroph, while Methylocellasilvestris is a facultative methanotroph able to grow on several multicarbon substrates in addition to methane. We constructed transcriptional fusions of the mmo promoters of Methyloferulastellata and Methylocellasilvestris to a promoterless gfp in order to compare their transcriptional regulation in response to different growth substrates, in the genetic background of both organisms. The following patterns were observed: (1) The mmo promoter of the facultative methanotroph Methylocella silvestris was either transcriptionally downregulated or repressed by any growth substrate other than methane in the genetic background of Methylocellasilvetris; (2) Growth on methane alone upregulated the mmo promoter of Methylocellasilvetris in its native background but not in the obligate methanotroph Methyloferulastellata; (3) The mmo promoter of Methyloferulastellata was constitutive in both organisms regardless of the growth substrate, but with much lower promoter activity than the mmo promoter of Methylocellasilvetris. These results support a conclusion that a different mode of transcriptional regulation of sMMO contributes to the facultative lifestyle of Methylocellasilvetris compared to the obligate methanotroph Methyloferulastellata. PMID- 29509699 TI - Tunable Electronic and Topological Properties of Germanene by Functional Group Modification. AB - Electronic and topological properties of two-dimensional germanene modified by functional group X (X = H, F, OH, CH3) at full coverage are studied with first principles calculation. Without considering the effect of spin-orbit coupling (SOC), all functionalized configurations become semiconductors, removing the Dirac cone at K point in pristine germanene. We also find that their band gaps can be especially well tuned by an external strain. When the SOC is switched on, GeX (X = H, CH3) is a normal insulator and strain leads to a phase transition to a topological insulator (TI) phase. However, GeX (X = F, OH) becomes a TI with a large gap of 0.19 eV for X = F and 0.24 eV for X = OH, even without external strains. More interestingly, when all these functionalized monolayers form a bilayer structure, semiconductor-metal states are observed. All these results suggest a possible route of modulating the electronic properties of germanene and promote applications in nanoelectronics. PMID- 29509700 TI - Meat Mutagens and Colorectal Adenoma and Cancer: A Problem with a Recently Published Systematic Review and Meta-Analysis. AB - Dear Editors and Authors, I had the pleasure to read the published article entitled [1] "Dietary Intake of Meat Cooking-Related Mutagens (HCAs) and Risk of Colorectal Adenoma and Cancer: A Systematic Review and Meta-Analysis" [...]. PMID- 29509698 TI - Electrospun Fibrous Scaffolds for Small-Diameter Blood Vessels: A Review. AB - Small-diameter blood vessels (SDBVs) are still a challenging task to prepare due to the occurrence of thrombosis formation, intimal hyperplasia, and aneurysmal dilation. Electrospinning technique, as a promising tissue engineering approach, can fabricate polymer fibrous scaffolds that satisfy requirements on the construction of extracellular matrix (ECM) of native blood vessel and promote the adhesion, proliferation, and growth of cells. In this review, we summarize the polymers that are deployed for the fabrication of SDBVs and classify them into three categories, synthetic polymers, natural polymers, and hybrid polymers. Furthermore, the biomechanical properties and the biological activities of the electrospun SBVs including anti-thrombogenic ability and cell response are discussed. Polymer blends seem to be a strategic way to fabricate SDBVs because it combines both suitable biomechanical properties coming from synthetic polymers and favorable sites to cell attachment coming from natural polymers. PMID- 29509702 TI - Exposure to Suicide in High Schools: Impact on Serious Suicidal Ideation/Behavior, Depression, Maladaptive Coping Strategies, and Attitudes toward Help-Seeking. AB - Adolescents' exposure to a peer's suicide has been found to be associated with, as well as to predict, suicidal ideation and behavior. Although postvention efforts tend to be school-based, little is known about the impact of a schoolmate's suicide on the school's student population overall. The present study seeks to determine whether there is excess psychological morbidity among students in a school where a schoolmate has died by suicide, and whether students' attitudes about coping and help-seeking strategies are more or less problematic in such schools. Students in twelve high schools in Suffolk and Westchester counties in New York State-2865 students at six schools where a student had died by suicide within the past six months, and 2419 students at six schools where no suicide had occurred within the current students' tenure completed an assessment of their suicidal ideation and behavior, depressive symptoms, coping and help-seeking attitudes, stressful life events, and friendship with suicide decedent (if applicable). No excess morbidity (i.e., serious suicidal ideation/behavior and depression) was evident among the general student population after a schoolmate's death by suicide; however, the risk of serious suicidal ideation/behavior was elevated among students at exposed schools who had concomitant negative life events. There was a significant relationship between friendship with the decedent and morbidity, in that students who were friends, but not close friends, of the decedents had the greatest odds of serious suicidal ideation/behavior. Overall, students in exposed schools had more adaptive attitudes toward help-seeking; but this was not true of the decedents' friends or students with concomitant negative life events. The implications of the findings for postvention strategies are discussed. PMID- 29509703 TI - The Emerging Workforce of International University Student Workers: Injury Experience in an Australian University. AB - International university students are a growing section of the workforce and are thought to be at greater risk of injury. Qualitative studies have highlighted vulnerabilities, but there is a shortage of quantitative research exploring the injury experience and associated risk factors of this emerging issue. In this study, a total of 466 university student workers across a range of study programs in a single Australian university completed an online survey, with questions relating to their background, working experience, training and injury experience. Risk factors for injury were explored in a multivariate statistical model. More than half had not received any safety training before they started work, and 10% reported having had a work injury. About half of these injuries occurred after training. Statistically significant risk factors for injury included working more than 20 h per week (adjusted odds ratio 2.20 (95% CI 1.03-4.71) and lack of confidence in discussing safety issues (AOR 2.17; 95% CI 1.13-4.16). The findings suggest the need for a more engaging and effective approach to safety education and a limit on working hours. This situation is a moral challenge for universities, in that they are effectively sponsoring young workers in the community. It is recommended that longitudinal studies of international student workers be conducted. PMID- 29509704 TI - Ageing, Health and Equity-Broad Perspectives Are Needed to Understand and Tackle Health Challenges of Ageing Societies. AB - Demographic change and the evolving demands on healthcare systems, especially in the provision of healthcare and long-term care for a growing number of older people, are among the greatest social challenges of the next decades.[...]. PMID- 29509705 TI - Two New Anisic Acid Derivatives from Endophytic Fungus Rhizopycnis vagum Nitaf22 and Their Antibacterial Activity. AB - Rhizopycnis acids A (1) and B (2), two new anisic acid derivatives, were obtained from the ethyl acetate extract of the fermentation cultures of Rhizopycnis vagum, an endophytic fungus isolated from the healthy tissues of Nicotiana tabacum. The structures of the two compounds were determined through a series of 1D and 2D NMR and HRMS spectral analyses. Both compounds were the first anisic acid derivatives containing methylbutanoic/methylbutenoic acid group found in fungi. 1 and 2 displayed antibacterial activity against six tested bacteria with IC50 values in the range 16.1~81.3 MUg/mL. PMID- 29509701 TI - The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy? AB - The mechanistic target of rapamycin (mTOR) is part of the phosphoinositide-3 kinase (PI3K)/protein kinase B (AkT)/mTOR pathway and owes its name to the inhibitory effect of rapamycin. The mTOR has a central converging role for many cell functions, serving as a sensor for extracellular signals from energy status and nutrients availability, growth factors, oxygen and stress. Thus, it also modulates switch to anabolic processes (protein and lipid synthesis) and autophagy, in order to regulate cell growth and proliferation. Given its functions in the cell, its deregulation is implicated in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumors (NETs), in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in the treatment of NETs. PMID- 29509706 TI - Polymeric Nano-Micelles as Novel Cargo-Carriers for LY2157299 Liver Cancer Cells Delivery. AB - LY2157299 (LY), which is very small molecule bringing high cancer diffusion, is a pathway antagonist against TGFbeta. LY dosage can be diluted by blood plasma, can be captured by immune system or it might be dissolved during digestion in gastrointestinal tract. The aim of our study is to optimize a "nano-elastic" carrier to avoid acidic pH of gastrointestinal tract, colon alkaline pH, and anti immune recognition. Polygalacturonic acid (PgA) is not degradable in the gastrointestinal tract due to its insolubility at acidic pH. To avoid PgA solubility in the colon, we have designed its conjugation with Polyacrylic acid (PAA). PgA-PAA conjugation has enhanced their potential use for oral and injected dosage. Following these pre-requisites, novel polymeric nano-micelles derived from PgA-PAA conjugation and loading LY2157299 are developed and characterized. Efficacy, uptake and targeting against a hepatocellular carcinoma cell line (HLF) have also been demonstrated. PMID- 29509707 TI - Polar Constituents of Salvia willeana (Holmboe) Hedge, Growing Wild in Cyprus. AB - Twenty compounds were isolated from the aerial parts of Salvia willeana (Holmboe) Hedge, growing wild in Cyprus. These compounds comprise one new and one known acetophenone, one megastigmane glucoside, five phenolic derivatives, two caffeic acid oligomers, three flavonoids, two lignans, two triterpene acids, one monoterpene glucoside, and two fatty acids. The structures of the isolated compounds were established by means of NMR [(Rotating-frame OverhauserEffect SpectroscopY) (1H-1H-COSY (COrrelation SpectroscopUpsilon), 1H-13C-HSQC (Heteronuclear Single Quantum Correlation), HMBC (Heteronuclear Multiple Bond Correlation), NOESY (Nuclear Overhauser Effect SpectroscopY), ROESY (Rotating frame Overhauser Effect SpectroscopY)] and MS spectral analyses. This is the first report of the natural occurrence of 4-hydroxy-acetophenone 4-O-(3,5 dimethoxy-4-hydroxybenzoyl)-beta-d-glucopyranoside. A chemical review on the non volatile secondary metabolites has been carried out. Based on the literature data, the analysis revealed that the chemical profile of S. willeana is close to that of S. officinalis L. PMID- 29509708 TI - The Relationship between Impulsivity and Internet Gaming Disorder in Young Adults: Mediating Effects of Interpersonal Relationships and Depression. AB - Background: This study aimed to explore relationships between impulsivity, interpersonal relationships, depression, and Internet Gaming Disorder (IGD) symptoms. Methods: A total of 118 young adults participated in this study: 67 IGD patients who met five or more of the DSM-5 diagnostic criteria for IGD and 56 healthy controls. We administered questionnaires to assess IGD symptoms (Young's Internet Addiction Test; Y-IAT), impulsivity (Barratt Impulsiveness Scale; BIS 11), interpersonal relationship (Relationship Change Scale; RCS), and depression (Beck Depression Inventory; BDI). We used PROCESS macro in SPSS to perform mediation analysis. Results: IGD symptom was positively related to depression and impulsivity, and negatively related to the quality of interpersonal relationships. Mediation analysis revealed full mediation effects of interpersonal relationships and depression on the association between impulsivity and IGD symptoms in the IGD group. Specifically, even after adjusting for gender as a covariate, high impulsivity was associated with greater difficulty with interpersonal relationships; which further affected depression and increased the risk of IGD. Conclusions: These results demonstrate the importance of early intervention in IGD patients, particularly in young adults with high impulsivity. When intervening in adults' IGD, we should consider not only individual factors (e.g., depression) but also socioenvironmental factors (e.g., interpersonal relationships). PMID- 29509710 TI - What Can We Learn about Workplace Heat Stress Management from a Safety Regulator Complaints Database? AB - Heat exposure can be a health hazard for many Australian workers in both outdoor and indoor situations. With many heat-related incidents left unreported, it is often difficult to determine the underlying causal factors. This study aims to provide insights into perceptions of potentially unsafe or uncomfortably hot working conditions that can affect occupational health and safety using information provided by the public and workers to the safety regulator in South Australia (SafeWork SA). Details of complaints regarding heat exposure to the regulator's "Help Centre" were assembled in a dataset and the textual data analysed thematically. The findings showed that the majority of calls relate to indoor work environments such as kitchens, factories, and warehouses. The main themes identified were work environment, health effects, and organisational issues. Impacts of hot working conditions ranged from discomfort to serious heat related illnesses. Poor management practices and inflexibility of supervisors featured strongly amongst callers' concerns. With temperatures predicted to increase and energy prices escalating, this timely study, using naturalistic data, highlights accounts of hot working conditions that can compromise workers' health and safety and the need for suitable measures to prevent heat stress. These could include risk assessments to assess the likelihood of heat stress in workplaces where excessively hot conditions prevail. PMID- 29509711 TI - Electrodermal Activity during Blood Pooling for Arterial Blood Gases Analysis in Sedated Adult Intensive Care Unit Patients. AB - Electrodermal activity (EDA) is considered a measure of autonomous nervous system activity. This study performed an exploratory analysis of the EDA changes during blood pooling for arterial blood gas analysis in sedated adult critical care patients and correlated the variations to other monitored parameters. EDA, along with other parameters, were monitored during 4 h routine daytime intensive care nursing and treatment in an adult ICU. 4 h measurements were divided into two groups based upon the sedation level. Selected recordings before and after blood pooling for arterial blood gases analysis (stress event) was performed. Nine stress events from Group A and 17 from Group B were included for further analysis. Patients' demographics, laboratory exams, and severity scores were recorded. For both sedation levels, EDA changes are much greater than any other monitoring parameters used. The changes are noticed in both measurement (15 s and 60 s), even though in the 60 s measurement only selected EDA parameters are significantly changed after the start of the procedure. EDA measurements are more sensitive to a given stress event than cardiovascular or respiratory parameters. However, the present results could only be considered as a pilot study. More studies are needed in order to identify the real stress-load and clinical significance of such stimuli, which are considered otherwise painless in those patients. PMID- 29509709 TI - Cell-Free Approaches in Synthetic Biology Utilizing Microfluidics. AB - Synthetic biology is a rapidly growing multidisciplinary branch of science which aims to mimic complex biological systems by creating similar forms. Constructing an artificial system requires optimization at the gene and protein levels to allow the formation of entire biological pathways. Advances in cell-free synthetic biology have helped in discovering new genes, proteins, and pathways bypassing the complexity of the complex pathway interactions in living cells. Furthermore, this method is cost- and time-effective with access to the cellular protein factory without the membrane boundaries. The freedom of design, full automation, and mimicking of in vivo systems reveal advantages of synthetic biology that can improve the molecular understanding of processes, relevant for life science applications. In parallel, in vitro approaches have enhanced our understanding of the living system. This review highlights the recent evolution of cell-free gene design, proteins, and cells integrated with microfluidic platforms as a promising technology, which has allowed for the transformation of the concept of bioprocesses. Although several challenges remain, the manipulation of biological synthetic machinery in microfluidic devices as suitable 'homes' for in vitro protein synthesis has been proposed as a pioneering approach for the development of new platforms, relevant in biomedical and diagnostic contexts towards even the sensing and monitoring of environmental issues. PMID- 29509712 TI - Cyclization Reaction of Acyl Thiourea Chitosan: Enhanced Antifungal Properties via Structural Optimization. AB - In this study, 3-methyl-1,2,4-triazolyl chitosan (MTACS) and 3-chloromethyl-1,2,4 triazolyl chitosan (CMTACS) were prepared via cyclization of acyl thiourea chitosan (TUCS). Their structures were confirmed by FT-IR, 1H-NMR, elemental analysis, DSC, XRD, and SEM. The conformations were predicted using the Gaussian 09 program. Additionally, the antifungal properties of MTACS and CMTACS against Stemphylium solani weber (S. solani), Alternaria porri (A. porri), and Gloeosporium theae-sinensis (G. theae-sinensis) were assayed in vitro and ranged from 250 MUg/mL to 1000 MUg/mL. The results showed that MTACS and CMTACS exhibited enhanced inhibitory effect on the selected fungi compared to the original chitosan and TUCS. In particular, they displayed better antifungal activities against A. porri and G. theae-sinensis than that of the positive control, Triadimefon. The findings described here may lead to them being used as antifungal agents for crop protection. PMID- 29509713 TI - Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring Closing Metathesis from 4-Allyloxy-1H-pyrazoles. AB - Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 degrees C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min. PMID- 29509714 TI - Forsythoside A Modulates Zymosan-Induced Peritonitis in Mice. AB - Acute inflammation is a protective response of the host to physical injury and invading infection. Timely treatment of acute inflammatory reactions is essential to prevent damage to organisms that can eventually lead to chronic inflammation. Forsythoside A (FTA), an active constituent of Forsythia suspensa, has been reported to have anti-inflammatory, antioxidant, and antibacterial properties. Despite increasing knowledge of its anti-inflammatory effects, the mechanism and the effects on acute inflammation are poorly understood. This study is aimed at exploring the pro-resolving effects of FTA on zymosan-induced acute peritonitis. FTA significantly alleviated peritonitis as evidenced by the decreased number of neutrophils and levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) in the peritoneal cavity, without interfering with interleukin-10 (IL-10). FTA showed marked regulation of inflammatory cytokines and chemokine levels in zymosan-stimulated RAW 264.7 macrophages. Moreover, FTA could suppress the activation of NF-kappaB. In conclusion, FTA alleviated zymosan-induced acute peritonitis through inhibition of NF-kappaB activation. PMID- 29509715 TI - Preliminary Results on the Evaluation of the Occurrence of Tetrodotoxin Associated to Marine Vibrio spp. in Bivalves from the Galician Rias (Northwest of Spain). AB - Tetrodotoxins (TTX) are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands) linked to the presence of high concentrations of Vibrio, in particular Vibrio parahaemolyticus. This study is focused on the evaluation of the presence of Vibrio species and TTX in bivalves (mussels, oysters, cockles, clams, scallops, and razor clams) from Galician Rias (northwest of Spain). The detection and isolation of the major Vibrio spp. and other enterobacterial populations have been carried out with the aim of screening for the presence of the pathways genes, poliketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) possibly involved in the biosynthesis of these toxins. Samples containing Vibrio spp. were analyzed by biochemical (API20E-galery) and genetic tests (PCR-RT). These samples were then screened for TTX toxicity by a neuroblastoma cell-based assay (N2a) and the presence of TTX was further confirmed by LC-MS/MS. TTX was detected in two infaunal samples. This is the first confirmation of the presence of TTX in bivalve molluscs from the Galician Rias. PMID- 29509716 TI - Risk Factors Including Age, Stage and Anatomic Location that Impact the Outcomes of Patients with Synovial Sarcoma. AB - Synovial sarcoma is a high-grade soft tissue sarcoma that inflicts mostly children and young adults with high mortality rate; however, the risk factors that impact the outcomes remain incompletely understood. We have identified the synovial sarcoma cases from the Kaiser Permanente Northern California cancer registry between 1981 and 2014. Kaplan-Meier plots were used to display disease free survival (DFS) and overall survival (OS); log-rank tests and Cox proportional hazard models were used to determine the impact of clinical factors on DFS, OS, and disease-specific survival. Tumor size > 5.0 cm and age > 50 years were associated with higher risk of presenting with stage IV disease. Median OS for patients with stage IV was 1.3 years and 7.8 years for early-stage disease. For patients with early-stage disease, tumor size > 5.0 cm was significantly associated with worse DFS, sarcoma-specific morality, and OS. Compared to extremity primary, patients with head and neck and trunk primary had approximately three-fold higher sarcoma-specific mortality and lower OS. There was no significant difference in DFS or OS among three histologic subtypes. Pre operative and/or post-operative chemotherapy was not associated with improvement in DFS or OS. Twenty-six patients relapsed with predominantly lung metastasis, thirteen of whom received metastatectomy with a median OS of 7.8 years, compared to 2.3 years for patients who did not receive metastatectomy. In conclusion, age older than 50 years and tumor size > 5.0 cm are risk factors for presenting with stage IV disease. For early-stage patients, trunk and head and neck primary as well as tumor size > 5.0 cm are risk factors for decreased OS. PMID- 29509717 TI - Oligo-Porphyran Ameliorates Neurobehavioral Deficits in Parkinsonian Mice by Regulating the PI3K/Akt/Bcl-2 Pathway. AB - Parkinson's disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from Porphyra, produces a neuroprotective effect against 6-OHDA-induced damage. Due to its antioxidant and neuroprotective potential, this study evaluates whether oligo porphyran (OP) could be beneficial in an experimental model of PD in mice. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was intraperitoneally injected (20 mg/kg body weight) for seven days to simulate PD, followed by OP administration. We found that the behavioral deficits in spontaneous motor activity, latency to descend in a pole test, and suspension in a traction test were ameliorated, and excessive dopamine (DA) metabolism was suppressed after OP treatment. Additionally, we found that OP protected dopaminergic neurons by preventing MPTP-induced decreases in dopaminergic transporter and tyrosine hydroxylase protein levels. We speculated whether OP regulates a signaling pathway that affects the behavioral changes seen in PD mice. In this study, the PI3K/Akt/Bcl-2 pathway was detected. Our results demonstrate that OP increased the phosphorylation of PI3K/Akt/GSK-3beta and inhibited the activation of caspase 3 and poly (ADP-ribose) polymerase, with changes in the Bax/Bcl-2 ratio. These results showed that OP might promote DA neuron survival in vivo by regulating the PI3K/Akt/Bcl-2 pathway, thereby ameliorating the neurobehavioral deficits in a PD mouse model and suggesting OP as a neuroprotective treatment for PD. PMID- 29509718 TI - A Nanostructured Sensor Based on Gold Nanoparticles and Nafion for Determination of Uric Acid. AB - The paper discusses the mechanism of uric acid (UA) electrooxidation occurring on the surface of gold nanoparticles. It has been shown that the electrode process is purely electrochemical, uncomplicated with catalytic stages. The nanoeffects observed as the reduction of overvoltage and increased current of UA oxidation have been described. These nanoeffects are determined by the size of particles and do not depend on the method of particle preparation (citrate and "green" synthesis). The findings of these studies have been used to select a modifier for carbon screen-printed electrode (CSPE). It has been stated that CSPE modified with gold nanoparticles (5 nm) and 2.5% Nafion (Nf) may serve as non-enzymatic sensor for UA determination. The combination of the properties of nanoparticles and Nafion as a molecular sieve at the selected pH 5 phosphate buffer solution has significantly improved the resolution of the sensor compared to unmodified CSPE. A nanostructured sensor has demonstrated good selectivity in determining UA in the presence of ascorbic acid. The detection limit of UA is 0.25 MUM. A linear calibration curve has been obtained over a range of 0.5-600 MUM. The 2.5%Nf/Au(5nm)/CSPE has been successfully applied to determining UA in blood serum and milk samples. The accuracy and reliability of the obtained results have been confirmed by a good correlation with the enzymatic spectrophotometric analysis (R2 = 0.9938) and the "added-found" technique (recovery close to 100%). PMID- 29509719 TI - Gene Editing of Microalgae: Scientific Progress and Regulatory Challenges in Europe. AB - It is abundantly clear that the development of gene editing technologies, represents a potentially powerful force for good with regard to human and animal health and addressing the challenges we continue to face in a growing global population. This now includes the development of approaches to modify microalgal strains for potential improvements in productivity, robustness, harvestability, processability, nutritional composition, and application. The rapid emergence and ongoing developments in this area demand a timely review and revision of the current definitions and regulations around genetically modified organisms (GMOs), particularly within Europe. Current practices within the EU provide exemptions from the GMO directives for organisms, including crop plants and micro-organisms that are produced through chemical or UV/radiation mutagenesis. However, organisms generated through gene editing, including microalgae, where only genetic changes in native genes are made, remain currently under the GMO umbrella; they are, as such, excluded from practical and commercial opportunities in the EU. In this review, we will review the advances that are being made in the area of gene editing in microalgae and the impact of regulation on commercial advances in this area with consideration to the current regulatory framework as it relates to GMOs including GM microalgae in Europe. PMID- 29509720 TI - Segmentation of Oil Spills on Side-Looking Airborne Radar Imagery with Autoencoders. AB - In this work, we use deep neural autoencoders to segment oil spills from Side Looking Airborne Radar (SLAR) imagery. Synthetic Aperture Radar (SAR) has been much exploited for ocean surface monitoring, especially for oil pollution detection, but few approaches in the literature use SLAR. Our sensor consists of two SAR antennas mounted on an aircraft, enabling a quicker response than satellite sensors for emergency services when an oil spill occurs. Experiments on TERMA radar were carried out to detect oil spills on Spanish coasts using deep selectional autoencoders and RED-nets (very deep Residual Encoder-Decoder Networks). Different configurations of these networks were evaluated and the best topology significantly outperformed previous approaches, correctly detecting 100% of the spills and obtaining an F 1 score of 93.01% at the pixel level. The proposed autoencoders perform accurately in SLAR imagery that has artifacts and noise caused by the aircraft maneuvers, in different weather conditions and with the presence of look-alikes due to natural phenomena such as shoals of fish and seaweed. PMID- 29509721 TI - Deciphering the Human Virome with Single-Virus Genomics and Metagenomics. AB - Single-cell genomics has unveiled the metabolic potential of dominant microbes inhabiting different environments, including the human body. The lack of genomic information for predominant microbes of the human body, such as bacteriophages, hinders our ability to answer fundamental questions about our viral communities. Here, we applied single-virus genomics (SVGs) to natural human salivary samples in combination with viral metagenomics to gain some insights into the viral community structure of the oral cavity. Saliva samples were processed for viral metagenomics (n = 15) and SVGs (n = 3). A total of 1328 uncultured single viruses were sorted by fluorescence-activated virus sorting followed by whole genome amplification. Sequencing of 24 viral single amplified genomes (vSAGs) showed that half of the vSAGs contained viral hallmark genes. Among those bona fide viruses, the uncultured single virus 92-C13 putatively infecting oral Streptococcus-like species was within the top ~10 most abundant viruses in the oral virome. Viral gene network and viral metagenomics analyses of 439 oral viruses from cultures, metagenomics, and SVGs revealed that salivary viruses were tentatively structured into ~200 major viral clusters, corresponding to approximately genus-level groupings. Data showed that none of the publicly available viral isolates, excepting an Actinomyces phage, were significantly abundant in the oral viromes. In addition, none of the obtained viral contigs and vSAGs from this study were present in all viromes. Overall, the data demonstrates that most viral isolates are not naturally abundant in saliva, and furthermore, the predominant viruses in the oral cavity are yet uncharacterized. Results suggest a variable, complex, and interpersonal viral profile. Finally, we demonstrated the power of SVGs in combination with viral metagenomics to unveil the genetic information of the uncultured viruses of the human virome. PMID- 29509722 TI - UDP-Glucosyltransferases from Rice, Brachypodium, and Barley: Substrate Specificities and Synthesis of Type A and B Trichothecene-3-O-beta-d-glucosides. AB - Trichothecene toxins are confirmed or suspected virulence factors of various plant-pathogenic Fusarium species. Plants can detoxify these to a variable extent by glucosylation, a reaction catalyzed by UDP-glucosyltransferases (UGTs). Due to the unavailability of analytical standards for many trichothecene glucoconjugates, information on such compounds is limited. Here, the previously identified deoxynivalenol-conjugating UGTs HvUGT13248 (barley), OsUGT79 (rice) and Bradi5g03300 (Brachypodium), were expressed in E. coli, affinity purified, and characterized towards their abilities to glucosylate the most relevant type A and B trichothecenes. HvUGT13248, which prefers nivalenol over deoxynivalenol, is also able to conjugate C-4 acetylated trichothecenes (e.g., T-2 toxin) to some degree while OsUGT79 and Bradi5g03300 are completely inactive with C-4 acetylated derivatives. The type A trichothecenes HT-2 toxin and T-2 triol are the kinetically preferred substrates in the case of HvUGT13248 and Bradi5g03300. We glucosylated several trichothecenes with OsUGT79 (HT-2 toxin, T-2 triol) and HvUGT13248 (T-2 toxin, neosolaniol, 4,15-diacetoxyscirpenol, fusarenon X) in the preparative scale. NMR analysis of the purified glucosides showed that exclusively beta-D-glucosides were formed regio-selectively at position C-3-OH of the trichothecenes. These synthesized standards can be used to investigate the occurrence and toxicological properties of these modified mycotoxins. PMID- 29509724 TI - Comparative Analysis of GF-1 and HJ-1 Data to Derive the Optimal Scale for Monitoring Heavy Metal Stress in Rice. AB - Remote sensing can actively monitor heavy metal contamination in crops, but with the increase of satellite sensors, the optimal scale for monitoring heavy metal stress in rice is still unknown. This study focused on identifying the optimal scale by comparing the ability to detect heavy metal stress in rice at various spatial scales. The 2 m, 8 m, and 16 m resolution GF-1 (China) data and the 30 m resolution HJ-1 (China) data were used to invert leaf area index (LAI). The LAI was the input parameter of the World Food Studies (WOFOST) model, and we obtained the dry weight of storage organs (WSO) and dry weight of roots (WRT) through the assimilation method; then, the mass ratio of rice storage organs and roots (SORMR) was calculated. Through the comparative analysis of SORMR at each spatial scale of data, we determined the optimal scale to monitor heavy metal stress in rice. The following conclusions were drawn: (1) SORMR could accurately and effectively monitor heavy metal stress; (2) the 8 m and 16 m images from GF-1 were suitable for monitoring heavy metal stress in rice; (3) 16 m was considered the optimal scale to assess heavy metal stress in rice. PMID- 29509723 TI - Socio-Economic Disparities in Attitude and Preference for Menu Labels among Vietnamese Restaurant Customers. AB - Calories and nutrition labeling on restaurant menus are powerful policy interventions to reduce the burden of obesity epidemic. However, the success of this policy requires an assurance of equal benefits among customers with different characteristics, especially people at a higher risk of poor health outcomes and eating habits. This study examined the sociodemographic disparities in the attitude and preference for calories and nutrition labeling on menus among customers in various food facilities. A cross-sectional study was conducted with 1746 customers of food facilities in Hanoi, Vietnam, who were recruited by using a multistage sampling method. Socio-economic characteristics, attitudes regarding the necessity and preferences for calories, and nutrition labeling on menus were analyzed. Multivariate logistic regression was employed to determine the associated factors with attitudes and preferences. Results show that most of the sample understood the necessity to have calories and nutrition labeling (59.8%), and 71.8% preferred to have calories and nutrition labeling. People who often visited food facilities (Odd Ratio (OR) = 1.36; 95% confident interval (CI) = 1.06-1.74) and had higher education and were more likely to understand the necessity of calories and nutrition labeling. Factors such as being homemakers, often going to dine-in restaurants, and perceiving that labeling was unnecessary were negatively associated with preferences for calories and nutrition labeling. The results of this study encourage policymakers to implement calories and nutrition labeling in the future. Health education interventions to improve knowledge and attitude as regards calories and nutrition labeling on menus are important, particularly for males, less-educated individuals, and high-income people. PMID- 29509726 TI - Migraine drug race turns its final corner, FDA decisions in sight. PMID- 29509725 TI - REGgamma Is Associated with Lymph Node Metastasis and T-Stage in Papillary Thyroid Carcinoma. AB - BACKGROUND This paper aimed to evaluate the expression of REGg and characterize its clinical significance in papillary thyroid carcinoma (PTC). MATERIAL AND METHODS In total, 54 patients with PTC who underwent partial or total thyroidectomy and cervical node dissection for PTC from February 2009 to September 2011 were retrospectively reviewed. Thyroid specimens and metastatic lymph nodes from 54 patients and normal thyroid tissues obtained from 13 volunteers were collected and analyzed. Tumor size, T-stage, and lymph nodes metastasis were recorded based on surgical pathology. Immunohistochemical (IHC) technology was performed to analyze REGg protein expression level. Corrections between the expression of REGgamma and the clinicopathological factors were analyzed. RESULTS All the normal thyroid tissues were REGg-negative. REGgamma was positive in 75.9% (41/54) of PTC tissues, of which 29 cases (29/42, 69.0%) were in T1-T2 stage and 12 cases (12/12,100%) were in T3-T4 stage. Positive REGgamma was found in 21 cases (21/24, 87.5%) in T1-T2 stage with lymph nodes metastasis, while 11 cases were in T3-T4 stage with metastases to lymph nodes (11/11, 100%). High level of REGgamma expression was significantly correlated with T-stage (P<0.05) and lymph node metastases (P<0.05). In addition, there was no statistically significant difference between the expression of REGgamma and age, sex, tumor size, or tumor multiplicity (P>0.05). Using binary logistic regression model, positive REGgamma was identified as a significant independent predictor factor of lymph node metastasis in PTC. CONCLUSIONS High expression of REGg seemed positively correlated with T-stage and lymph node metastasis in PTC tissues. PMID- 29509727 TI - First off-the-shelf mesenchymal stem cell therapy nears European approval. PMID- 29509728 TI - First Rounders podcast: Jeffrey Leiden. PMID- 29509731 TI - Around the world in a month. PMID- 29509730 TI - Jury out on liquid biopsies for cancer. PMID- 29509732 TI - Evidence for a mental health crisis in graduate education. PMID- 29509733 TI - Preprint wipes millions off CRISPR companies' stocks. PMID- 29509736 TI - Amazon's cloud on the healthcare horizon. PMID- 29509734 TI - EPO revokes Broad's CRISPR patent. PMID- 29509737 TI - The evidence gap. PMID- 29509738 TI - Correction. AB - This corrects the article DOI: 10.1038/nbt0218-126. PMID- 29509739 TI - The alphabet soup of agreements. PMID- 29509740 TI - An archive written in DNA. PMID- 29509742 TI - All MiNDS on the brain. PMID- 29509743 TI - FDA makes drug data public. PMID- 29509741 TI - The NIEHS TaRGET II Consortium and environmental epigenomics. PMID- 29509744 TI - Smart cancer therapy with DNA origami. PMID- 29509746 TI - Recent patents in DNA sequencing. PMID- 29509745 TI - Driving T-cell immunotherapy to solid tumors. PMID- 29509749 TI - Stimulus package. PMID- 29509748 TI - PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29509747 TI - Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition. AB - This corrects the article DOI: 10.1038/bjc.2017.429. PMID- 29509750 TI - The intestinal microbiome influences checkpoint blockade. PMID- 29509751 TI - Going live: How microRNAs might bring living vaccines back into the fold. PMID- 29509752 TI - An immunosuppressive pathway for tumor progression. PMID- 29509753 TI - A human cellular model of amyotrophic lateral sclerosis. PMID- 29509754 TI - A previously undetected pathology of Zika virus infection. PMID- 29509755 TI - Gut checkpoint: A rising cancer treatment may get a boost from intestinal bacteria. PMID- 29509756 TI - Correction: An autonomous metabolic role for Spen. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006859.]. PMID- 29509757 TI - Patterns and temporal trends of comorbidity among adult patients with incident cardiovascular disease in the UK between 2000 and 2014: A population-based cohort study. AB - BACKGROUND: Multimorbidity in people with cardiovascular disease (CVD) is common, but large-scale contemporary reports of patterns and trends in patients with incident CVD are limited. We investigated the burden of comorbidities in patients with incident CVD, how it changed between 2000 and 2014, and how it varied by age, sex, and socioeconomic status (SES). METHODS AND FINDINGS: We used the UK Clinical Practice Research Datalink with linkage to Hospital Episode Statistics, a population-based dataset from 674 UK general practices covering approximately 7% of the current UK population. We estimated crude and age/sex-standardised (to the 2013 European Standard Population) prevalence and 95% confidence intervals for 56 major comorbidities in individuals with incident non-fatal CVD. We further assessed temporal trends and patterns by age, sex, and SES groups, between 2000 and 2014. Among a total of 4,198,039 people aged 16 to 113 years, 229,205 incident cases of non-fatal CVD, defined as first diagnosis of ischaemic heart disease, stroke, or transient ischaemic attack, were identified. Although the age/sex-standardised incidence of CVD decreased by 34% between 2000 to 2014, the proportion of CVD patients with higher numbers of comorbidities increased. The prevalence of having 5 or more comorbidities increased 4-fold, rising from 6.3% (95% CI 5.6%-17.0%) in 2000 to 24.3% (22.1%-34.8%) in 2014 in age/sex standardised models. The most common comorbidities in age/sex-standardised models were hypertension (28.9% [95% CI 27.7%-31.4%]), depression (23.0% [21.3%-26.0%]), arthritis (20.9% [19.5%-23.5%]), asthma (17.7% [15.8%-20.8%]), and anxiety (15.0% [13.7%-17.6%]). Cardiometabolic conditions and arthritis were highly prevalent among patients aged over 40 years, and mental illnesses were highly prevalent in patients aged 30-59 years. The age-standardised prevalence of having 5 or more comorbidities was 19.1% (95% CI 17.2%-22.7%) in women and 12.5% (12.0%-13.9%) in men, and women had twice the age-standardised prevalence of depression (31.1% [28.3%-35.5%] versus 15.0% [14.3%-16.5%]) and anxiety (19.6% [17.6%-23.3%] versus 10.4% [9.8%-11.8%]). The prevalence of depression was 46% higher in the most deprived fifth of SES compared with the least deprived fifth (age/sex standardised prevalence of 38.4% [31.2%-62.0%] versus 26.3% [23.1%-34.5%], respectively). This is a descriptive study of routine electronic health records in the UK, which might underestimate the true prevalence of diseases. CONCLUSIONS: The burden of multimorbidity and comorbidity in patients with incident non-fatal CVD increased between 2000 and 2014. On average, older patients, women, and socioeconomically deprived groups had higher numbers of comorbidities, but the type of comorbidities varied by age and sex. Cardiometabolic conditions contributed substantially to the burden, but 4 out of the 10 top comorbidities were non-cardiometabolic. The current single-disease paradigm in CVD management needs to broaden and incorporate the large and increasing burden of comorbidities. PMID- 29509758 TI - Correction: Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress. AB - [This corrects the article DOI: 10.1371/journal.pbio.1002197.]. PMID- 29509759 TI - Sexual risk during pregnancy and postpartum periods among HIV-infected and uninfected South African women: Implications for primary and secondary HIV prevention interventions. AB - BACKGROUND: HIV acquisition in pregnancy and breastfeeding contributes significantly toward pediatric HIV infection. However, little is known about how sexual behavior changes during pregnancy and postpartum periods which will help develop targeted HIV prevention and transmission interventions, including pre exposure prophylaxis (PrEP). METHODS: Cross-sectional study in HIV-infected and uninfected pregnant and postpartum women in Cape Town, South Africa. Interviewers collected survey data on demographic, sexual behaviors, and alcohol use among pregnant and post-partum women. We report descriptive results of sexual behavior by trimester and postpartum period, and results of multivariable logistic regression stratified by pregnancy status. RESULTS: We enrolled 377 pregnant and postpartum women (56% pregnant, 40% HIV-infected). During pregnancy, 98% of women reported vaginal sex (8% anal sex, 44% oral sex) vs. 35% and 88% during the periods 0-6 and 7-12 months postpartum, respectively (p<0.05). More pregnant women reported having >1 partner in the past 12-months compared to postpartum women (18% vs. 13%, respectively, p<0.05). Sex frequency varied by trimester with greatest mean sex acts occurring during first trimester and >6-months postpartum (13 mean sex acts in first trimester; 17 mean sex acts >6-months postpartum). Pregnant women had increased odds of reporting condomless sex at last sex (aOR = 2.96;95%CI = 1.84-4.78) and ever having condomless sex in past 3-months (aOR = 2.65;95%CI = 1.30-5.44) adjusting for age, HIV status, and sex frequency compared to postpartum women. CONCLUSION: We identified that sexual behaviors and risk behaviors were high and changing during pregnancy and postpartum periods, presenting challenges to primary and secondary HIV prevention efforts, including PrEP delivery to pregnant and breastfeeding women. PMID- 29509760 TI - A memetic optimization algorithm for multi-constrained multicast routing in ad hoc networks. AB - A mobile ad hoc network is a conventional self-configuring network where the routing optimization problem-subject to various Quality-of-Service (QoS) constraints-represents a major challenge. Unlike previously proposed solutions, in this paper, we propose a memetic algorithm (MA) employing an adaptive mutation parameter, to solve the multicast routing problem with higher search ability and computational efficiency. The proposed algorithm utilizes an updated scheme, based on statistical analysis, to estimate the best values for all MA parameters and enhance MA performance. The numerical results show that the proposed MA improved the delay and jitter of the network, while reducing computational complexity as compared to existing algorithms. PMID- 29509761 TI - Critical domain interactions for type A RNase P RNA catalysis with and without the specificity domain. AB - The natural trans-acting ribozyme RNase P RNA (RPR) is composed of two domains in which the catalytic (C-) domain mediates cleavage of various substrates. The C domain alone, after removal of the second specificity (S-) domain, catalyzes this reaction as well, albeit with reduced efficiency. Here we provide experimental evidence indicating that efficient cleavage mediated by the Escherichia coli C domain (Eco CP RPR) with and without the C5 protein likely depends on an interaction referred to as the "P6-mimic". Moreover, the P18 helix connects the C and S-domains between its loop and the P8 helix in the S-domain (the P8/ P18 interaction). In contrast to the "P6-mimic", the presence of P18 does not contribute to the catalytic performance by the C-domain lacking the S-domain in cleavage of an all ribo model hairpin loop substrate while deletion or disruption of the P8/ P18-interaction in full-size RPR lowers the catalytic efficiency in cleavage of the same model hairpin loop substrate in keeping with previously reported data using precursor tRNAs. Consistent with that P18 is not required for cleavage mediated by the C-domain we show that the archaeal Pyrococcus furiosus RPR C-domain, which lacks the P18 helix, is catalytically active in trans without the S-domain and any protein. Our data also suggest that the S-domain has a larger impact on catalysis for E. coli RPR compared to P. furiosus RPR. Finally, we provide data indicating that the absence of the S-domain and P18, or the P8/ P18-interaction in full-length RPR influences the charge distribution near the cleavage site in the RPR-substrate complex to a small but reproducible extent. PMID- 29509763 TI - Clinical and cost-effectiveness of non-medical prescribing: A systematic review of randomised controlled trials. AB - OBJECTIVE: To evaluate the clinical and cost-effectiveness of non-medical prescribing (NMP). DESIGN: Systematic review. Two reviewers independently completed searches, eligibility assessment and assessment of risk of bias. DATA SOURCES: Pre-defined search terms/combinations were utilised to search electronic databases. In addition, hand searches of reference lists, key journals and grey literature were employed alongside consultation with authors/experts. ELIGIBILITY CRITERIA FOR INCLUDED STUDIES: Randomised controlled trials (RCTs) evaluating clinical or cost-effectiveness of NMP. Measurements reported on one or more outcome(s) of: pain, function, disability, health, social impact, patient-safety, costs-analysis, quality adjusted life years (QALYs), patient satisfaction, clinician perception of clinical and functional outcomes. RESULTS: Three RCTs from two countries were included (n = 932 participants) across primary and tertiary care settings. One RCT was assessed as low risk of bias, one as high risk of bias and one as unclear risk of bias. All RCTs evaluated clinical effectiveness with one also evaluating cost-effectiveness. Clinical effectiveness was evaluated using a range of safety and patient-reported outcome measures. Participants demonstrated significant improvement in outcomes when receiving NMP compared to treatment as usual (TAU) in all RCTs. An associated cost analysis showed NMP to be more expensive than TAU (regression coefficient p = 0.0000), however experimental groups generated increased QALYs compared to TAU. CONCLUSION: Limited evidence with overall unclear risk of bias exists evaluating clinical and cost-effectiveness of NMP across all professions and clinical settings. GRADE assessment revealed moderate quality evidence. Evidence suggests that NMP is safe and can provide beneficial clinical outcomes. Benefits to the health economy remain unclear, with the cost-effectiveness of NMP assessed by a single pilot RCT of low risk of bias. Adequately powered low risk of bias RCTs evaluating clinical and cost effectiveness are required to evaluate NMP across clinical specialities, professions and settings. REGISTRATION: PROSPERO (CRD42015017212). PMID- 29509762 TI - Perception of body movement when real and simulated displacements are combined. AB - Muscle-tendon vibration has often been used to study the contribution of proprioception to kinesthesia and postural control. This technique is known to simulate the lengthening of the vibrated muscle and, in the presence of balance constraints, evoke compensatory postural responses. The objective of the present study was to clarify the consequences of this stimulation on the dynamic features of whole-body movement perception in upright stance and in the absence of balance constraints. Eleven participants were restrained in a dark room on a motorized backboard that was able to tilt the upright body around the ankle joints. The participants were passively tilted backwards or forwards with a maximum amplitude of four degrees and at very low acceleration (thus preventing the semicircular canals from contributing to movement perception). In half the trials, the body displacement was combined with continuous vibration of the Achilles tendons, which simulates a forward tilt. Participants used a joystick to report when and in which direction they perceived their own whole-body movement. Our results showed that during backward whole-body displacement, the movement detection threshold (i.e. the minimum angular velocity required to accurately perceive passive displacement) was higher in the presence of vibration, whereas the accuracy rate (i.e. the proportion of the overall trial duration during which the movement was correctly indicated) was lower. Conversely, the accuracy rate for forward displacements was higher in the presence of vibration. In the absence of vibration, forward movement was detected earlier than backward movement. The simulated whole-body displacement evoked by Achilles tendon vibration was therefore able to either enhance or disrupt the perception of real, slow, whole body tilt movements, depending on the congruence between the direction of real and simulated displacements. PMID- 29509764 TI - Multimorbidity and survival for patients with acute myocardial infarction in England and Wales: Latent class analysis of a nationwide population-based cohort. AB - BACKGROUND: There is limited knowledge of the scale and impact of multimorbidity for patients who have had an acute myocardial infarction (AMI). Therefore, this study aimed to determine the extent to which multimorbidity is associated with long-term survival following AMI. METHODS AND FINDINGS: This national observational study included 693,388 patients (median age 70.7 years, 452,896 [65.5%] male) from the Myocardial Ischaemia National Audit Project (England and Wales) who were admitted with AMI between 1 January 2003 and 30 June 2013. There were 412,809 (59.5%) patients with multimorbidity at the time of admission with AMI, i.e., having at least 1 of the following long-term health conditions: diabetes, chronic obstructive pulmonary disease or asthma, heart failure, renal failure, cerebrovascular disease, peripheral vascular disease, or hypertension. Those with heart failure, renal failure, or cerebrovascular disease had the worst outcomes (39.5 [95% CI 39.0-40.0], 38.2 [27.7-26.8], and 26.6 [25.2-26.4] deaths per 100 person-years, respectively). Latent class analysis revealed 3 multimorbidity phenotype clusters: (1) a high multimorbidity class, with concomitant heart failure, peripheral vascular disease, and hypertension, (2) a medium multimorbidity class, with peripheral vascular disease and hypertension, and (3) a low multimorbidity class. Patients in class 1 were less likely to receive pharmacological therapies compared with class 2 and 3 patients (including aspirin, 83.8% versus 87.3% and 87.2%, respectively; beta-blockers, 74.0% versus 80.9% and 81.4%; and statins, 80.6% versus 85.9% and 85.2%). Flexible parametric survival modelling indicated that patients in class 1 and class 2 had a 2.4-fold (95% CI 2.3-2.5) and 1.5-fold (95% CI 1.4-1.5) increased risk of death and a loss in life expectancy of 2.89 and 1.52 years, respectively, compared with those in class 3 over the 8.4-year follow-up period. The study was limited to all-cause mortality due to the lack of available cause-specific mortality data. However, we isolated the disease-specific association with mortality by providing the loss in life expectancy following AMI according to multimorbidity phenotype cluster compared with the general age-, sex-, and year-matched population. CONCLUSIONS: Multimorbidity among patients with AMI was common, and conferred an accumulative increased risk of death. Three multimorbidity phenotype clusters that were significantly associated with loss in life expectancy were identified and should be a concomitant treatment target to improve cardiovascular outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03037255. PMID- 29509765 TI - Changing demographics of visceral leishmaniasis in northeast Brazil: Lessons for the future. AB - BACKGROUND: Visceral leishmaniasis (VL) caused by Leishmania infantum became a disease of urban areas in Brazil in the last 30 years and there has been an increase in asymptomatic L. infantum infection with these areas. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study of human VL was performed in the state of Rio Grande do Norte, Brazil, for the period of 1990-2014. The data were divided into five-time periods. For all VL cases, data on sex, age, nutritional status and childhood vaccination were collected. Geographic information system tools and statistical models were used to analyze the dispersion of human VL. The mean annual incidence of VL was 4.6 cases/100,000 inhabitants, with total 3,252 cases reported. The lethality rate was 6.4%. Over time the annual incidence of VL decreased in the 0-4 years (p<0.0001) and 5-9 (p <0.0001) age groups, but increased in ages 20-39 (p<0.001) and >40 years (p<0.0001). VL occurred more often in males (beta2 = 2.5; p<0.0001). The decreased incidence of VL in children was associated with improved nutritional status and childhood immunizations including measles, poliomyelitis, BCG, and hepatitis B. Human VL correlated temporally and geographically with canine L. infantum infection (p = 0.002, R2 = 0.438), with rainfall and with Lutzomyia longipalpis density (r = 0.762). Overall, the incidence of VL decreased, while VL AIDS increased, especially between 2010-2014. VL was more frequently found in areas that lacked urban infrastructure, detected by lack of garbage collection and sewers, whereas HIV infection was associated with higher levels of schooling and evidence of higher socioeconomic status. CONCLUSION/SIGNIFICANCE: The demographics of VL in northeastern Brazil have changed. Disease incidence has decreased in children and increased in adults. They were associated with improvements in nutrition, socioeconomic status and immunization rates. Concurrent VL-AIDS poses a serious challenge for the future. PMID- 29509766 TI - The emergence of the visual word form: Longitudinal evolution of category specific ventral visual areas during reading acquisition. AB - How does education affect cortical organization? All literate adults possess a region specialized for letter strings, the visual word form area (VWFA), within the mosaic of ventral regions involved in processing other visual categories such as objects, places, faces, or body parts. Therefore, the acquisition of literacy may induce a reorientation of cortical maps towards letters at the expense of other categories such as faces. To test this cortical recycling hypothesis, we studied how the visual cortex of individual children changes during the first months of reading acquisition. Ten 6-year-old children were scanned longitudinally 6 or 7 times with functional magnetic resonance imaging (fMRI) before and throughout the first year of school. Subjects were exposed to a variety of pictures (words, numbers, tools, houses, faces, and bodies) while performing an unrelated target-detection task. Behavioral assessment indicated a sharp rise in grapheme-phoneme knowledge and reading speed in the first trimester of school. Concurrently, voxels specific to written words and digits emerged at the VWFA location. The responses to other categories remained largely stable, although right-hemispheric face-related activity increased in proportion to reading scores. Retrospective examination of the VWFA voxels prior to reading acquisition showed that reading encroaches on voxels that are initially weakly specialized for tools and close to but distinct from those responsive to faces. Remarkably, those voxels appear to keep their initial category selectivity while acquiring an additional and stronger responsivity to words. We propose a revised model of the neuronal recycling process in which new visual categories invade weakly specified cortex while leaving previously stabilized cortical responses unchanged. PMID- 29509767 TI - The current and potential health benefits of the National Health Service Health Check cardiovascular disease prevention programme in England: A microsimulation study. AB - BACKGROUND: The National Health Service (NHS) Health Check programme was introduced in 2009 in England to systematically assess all adults in midlife for cardiovascular disease risk factors. However, its current benefit and impact on health inequalities are unknown. It is also unclear whether feasible changes in how it is delivered could result in increased benefits. It is one of the first such programmes in the world. We sought to estimate the health benefits and effect on inequalities of the current NHS Health Check programme and the impact of making feasible changes to its implementation. METHODS AND FINDINGS: We developed a microsimulation model to estimate the health benefits (incident ischaemic heart disease, stroke, dementia, and lung cancer) of the NHS Health Check programme in England. We simulated a population of adults in England aged 40-45 years and followed until age 100 years, using data from the Health Survey of England (2009-2012) and the English Longitudinal Study of Aging (1998-2012), to simulate changes in risk factors for simulated individuals over time. We used recent programme data to describe uptake of NHS Health Checks and of 4 associated interventions (statin medication, antihypertensive medication, smoking cessation, and weight management). Estimates of treatment efficacy and adherence were based on trial data. We estimated the benefits of the current NHS Health Check programme compared to a healthcare system without systematic health checks. This counterfactual scenario models the detection and treatment of risk factors that occur within 'routine' primary care. We also explored the impact of making feasible changes to implementation of the programme concerning eligibility, uptake of NHS Health Checks, and uptake of treatments offered through the programme. We estimate that the NHS Health Check programme prevents 390 (95% credible interval 290 to 500) premature deaths before 80 years of age and results in an additional 1,370 (95% credible interval 1,100 to 1,690) people being free of disease (ischaemic heart disease, stroke, dementia, and lung cancer) at age 80 years per million people aged 40-45 years at baseline. Over the life of the cohort (i.e., followed from 40-45 years to 100 years), the changes result in an additional 10,000 (95% credible interval 8,200 to 13,000) quality-adjusted life years (QALYs) and an additional 9,000 (6,900 to 11,300) years of life. This equates to approximately 300 fewer premature deaths and 1,000 more people living free of these diseases each year in England. We estimate that the current programme is increasing QALYs by 3.8 days (95% credible interval 3.0-4.7) per head of population and increasing survival by 3.3 days (2.5-4.1) per head of population over the 60 years of follow-up. The current programme has a greater absolute impact on health for those living in the most deprived areas compared to those living in the least deprived areas (4.4 [2.7-6.5] days of additional quality-adjusted life per head of population versus 2.8 [1.7-4.0] days; 5.1 [3.4 7.1] additional days lived per head of population versus 3.3 [2.1-4.5] days). Making feasible changes to the delivery of the existing programme could result in a sizable increase in the benefit. For example, a strategy that combines extending eligibility to those with preexisting hypertension, extending the upper age of eligibility to 79 years, increasing uptake of health checks by 30%, and increasing treatment rates 2.5-fold amongst eligible patients (i.e., 'maximum potential' scenario) results in at least a 3-fold increase in benefits compared to the current programme (1,360 premature deaths versus 390; 5,100 people free of 1 of the 4 diseases versus 1,370; 37,000 additional QALYs versus 10,000; 33,000 additional years of life versus 9,000). Ensuring those who are assessed and eligible for statins receive statins is a particularly important strategy to increase benefits. Estimates of overall benefit are based on current incidence and management, and future declines in disease incidence or improvements in treatment could alter the actual benefits observed in the long run. We have focused on the cardiovascular element of the NHS Health Check programme. Some important noncardiovascular health outcomes (e.g., chronic obstructive pulmonary disease [COPD] prevention from smoking cessation and cancer prevention from weight loss) and other parts of the programme (e.g., brief interventions to reduce harmful alcohol consumption) have not been modelled. CONCLUSIONS: Our model indicates that the current NHS Health Check programme is contributing to improvements in health and reducing health inequalities. Feasible changes in the organisation of the programme could result in more than a 3-fold increase in health benefits. PMID- 29509768 TI - Trajectories of functional decline in older adults with neuropsychiatric and cardiovascular multimorbidity: A Swedish cohort study. AB - BACKGROUND: Functional decline is a strong health determinant in older adults, and chronic diseases play a major role in this age-related phenomenon. In this study, we explored possible clinical pathways underlying functional heterogeneity in older adults by quantifying the impact of cardiovascular (CV) and neuropsychiatric (NP) chronic diseases and their co-occurrence on trajectories of functional decline. METHODS AND FINDINGS: We studied 2,385 people >=60 years (range 60-101 years) participating in the Swedish National study of Aging and Care in Kungsholmen (SNAC-K). Participants underwent clinical examination at baseline (2001-2004) and every 3 or 6 years for up to 9 years. We grouped participants on the basis of 7 mutually exclusive clinical patterns of 0, 1, or more CV and NP diseases and their co-occurrence, from a group without any CV and NP disease to a group characterised by the presence of CV or NP multimorbidity, accompanied by at least 1 other CV or NP disorder. The group with no CV and/or NP diseases served as the reference group. Functional decline was estimated over 9 years of follow-up by measuring mobility (walking speed, m/s) and independence (ability to carry out six activities of daily living [ADL]). Mixed-effect linear regression models were used (1) to explore the individual-level prognostic predictivity of the different CV and NP clinical patterns at baseline and (2) to quantify the association between the clinical patterns and functional decline at the group level by entering the clinical patterns as time-varying measures. During the 9-year follow-up, participants with multiple CV and NP diseases had the steepest decline in walking speed (up to 0.7 m/s; p < 0.001) and ADL independence (up to three impairments in ADL, p < 0.001) (reference group: participants without any CV and NP disease). When the clinical patterns were analyzed as time varying, isolated CV multimorbidity impacted only walking speed (beta -0.1; p < 0.001). Conversely, all the clinical patterns that included at least 1 NP disease were significantly associated with decline in both walking speed (beta -0.21--0.08; p < 0.001) and ADL independence (beta -0.27--0.06; p < 0.05). Groups with the most complex clinical patterns had 5%-20% lower functioning at follow-up than the reference group. Key limitations of the study include that we did not take into account the specific weight of single diseases and their severity and that the exclusion of participants with less than 2 assessments may have led to an underestimation of the tested associations. CONCLUSIONS: In older adults, different patterns of CV and NP morbidity lead to different trajectories of functional decline over time, a finding that explains part of the heterogeneity observed in older adults' functionality. NP diseases, alone or in association, are prevalent and major determinants of functional decline, whereas isolated CV multimorbidity is associated only with declines in mobility. PMID- 29509769 TI - Effect and cost-effectiveness of educating mothers about childhood DPT vaccination on immunisation uptake, knowledge, and perceptions in Uttar Pradesh, India: A randomised controlled trial. AB - BACKGROUND: To assess the effect of health information on immunisation uptake in rural India, we conducted an individually randomised controlled trial of health information messages targeting the mothers of unvaccinated or incompletely vaccinated children through home visits in rural Uttar Pradesh, India. METHODS AND FINDINGS: The study tested a brief intervention that provided mothers face-to face with information on the benefits of the tetanus vaccine. Participants were 722 mothers of children aged 0-36 months who had not received 3 doses of diphtheria-pertussis-tetanus (DPT) vaccine (DPT3). Mothers were randomly assigned in a ratio of 1:1:1 to 1 of 3 study arms: mothers in the first treatment group received information framed as a gain (e.g., the child is less likely to get tetanus and more likely to be healthy if vaccinated), mothers in the second treatment group received information framed in terms of a loss (e.g., the child is more likely to get tetanus and suffer ill health if not vaccinated), and the third arm acted as a control group, with no information given to the mother. Surveys were conducted at baseline (September 2015) and after the intervention (April 2016). The primary outcome was the proportion of children who had received DPT3 measured after 7 months of follow-up. The analysis was by intention to treat. A total of 16 (2.2%) participants were lost to follow-up. The coverage of DPT3 was 28% in the control group and 43% in the pooled information groups, giving a risk difference of 15 percentage points (95% CI: 7% to 22%, p < 0.001) and a relative risk of 1.52 (95% CI: 1.2 to 1.9, p < 0.001). The information intervention increased the rate of measles vaccination by 22 percentage points (risk difference: 22%, 95% CI: 14% to 30%, p < 0.001; relative risk: 1.53, 95% CI: 1.29 to 1.80) and the rate of full immunisation by 14 percentage points (risk difference: 14%, 95% CI: 8% to 21%, p < 0.001; relative risk: 1.72, 95% CI: 1.29 to 2.29). It had a large positive effect on knowledge of the causes, symptoms, and prevention of tetanus but no effect on perceptions of vaccine efficacy. There was no difference in the proportion of children with DPT3 between the group that received information framed as a loss and the group that received information framed as a gain (risk difference: 4%, 95% CI: -5% to 13%; p = 0.352; relative risk: 1.11, 95% CI: 0.90 to 1.36). The cost per disability-adjusted life year averted of providing information was US$186, making the intervention highly cost effective with respect to the WHO-recommended threshold of once the gross domestic product per capita (US$793 in the case of Uttar Pradesh). Key study limitations include the modest sample size for this trial, limiting power to detect small differences in the framing of information, and the potential for contamination among households. CONCLUSIONS: Providing mothers of unvaccinated/incompletely vaccinated children with information on tetanus and the benefits of DPT vaccination substantially increased immunisation coverage and was highly cost-effective. The framing of the health information message did not appear to matter. TRIAL REGISTRATION: The trial is registered with ISRCTN, number ISRCTN84560580. PMID- 29509770 TI - Selection of suitable reference genes for normalization of quantitative RT-PCR (RT-qPCR) expression data across twelve tissues of riverine buffaloes (Bubalus bubalis). AB - Selection of reference genes has become an integral step in any real time quantitative PCR (RT-qPCR) based expression studies. The importance of this study stems from the fact that riverine buffaloes are major dairy species of Indian sub continent and the information generated here will be of great interest to the investigators engaged in functional genomic studies of this important livestock species. In this study, an effort was made to evaluate a panel of 10 candidate reference genes (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), beta- actin (ACTB), ubiquitously expressed transcript (UXT), ribosomal protein S15 (RPS15), ribosomal protein L-4 (RPL4), ribosomal protein S9 (RPS9), ribosomal protein S23 (RPS23), hydroxymethylbilane synthase (HMBS), beta2 Microglobulin (beta2M) and eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) across 12 tissues (mammary gland, kidney, spleen, liver, heart, intestine, ovary, lung, muscle, brain, subcutaneous fat and testis) of riverine buffaloes. In addition to overall analysis, tissue wise evaluation of expression stability of individual RG was also performed. Three different algorithms provided in geNorm, NormFinder and BestKeeper softwares were used to evaluate the stability of 10 potential reference genes from different functional classes. The M-value given by geNorm ranged from 0.9797 (RPS9 and UXT) to 1.7362 (RPS15). From the most stable to the least stable, genes were ranked as: UXT/RPS9> RPL4> RPS23> EEF1A1> ACTB> HMBS> GAPDH> B2M> RPS15. While NormFinder analysis ranked the genes as: UXT> RPS23> RPL4> RPS9> EEF1A1> HMBS> ACTB> beta2M> GAPDH> RPS15. Based on the crossing point SD value and range of fold change expression, BestKeeper analysis ranked the genes as: RPS9> RPS23/UXT> RPL4> GAPDH> EEF1A1> ACTB> HMBS> beta2M> RPS15. Overall the study has identified RPS23, RPS9, RPL4 and UXT genes to be the most stable and appropriate RGs that could be utilized for normalization of transcriptional data in various tissues of buffaloes. This manuscript thus provide useful information on panel of reference genes that could be helpful for researchers conducting functional genomic studies in riverine buffaloes. PMID- 29509772 TI - The cysteine protease dipeptidyl aminopeptidase 3 does not contribute to egress of Plasmodium falciparum from host red blood cells. AB - The ability of Plasmodium parasites to egress from their host red blood cell is critical for the amplification of these parasites in the blood. Previous forward chemical genetic approaches have implicated the subtilisin-like protease (SUB1) and the cysteine protease dipeptidyl aminopeptidase 3 (DPAP3) as key players in egress, with the final step of SUB1 maturation thought to be due to the activity of DPAP3. In this study, we have utilized a reverse genetics approach to engineer transgenic Plasmodium falciparum parasites in which dpap3 expression can be conditionally regulated using the glmS ribozyme based RNA-degrading system. We show that DPAP3, which is expressed in schizont stages and merozoites and localizes to organelles distinct from the micronemes, rhoptries and dense granules, is not required for the trafficking of apical proteins or processing of SUB1 substrates, nor for parasite maturation and egress from red blood cells. Thus, our findings argue against a role for DPAP3 in parasite egress and indicate that the phenotypes observed with DPAP3 inhibitors are due to off-target effects. PMID- 29509771 TI - Alcohol use disorder and associated factors among human immunodeficiency virus infected patients attending antiretroviral therapy clinic at Bishoftu General Hospital, Oromiya region, Ethiopia. AB - BACKGROUND: Alcohol consumption among patients with HIV/AIDS increases the burden of the disease. HIV/AIDS is an epidemic among Sub-Saharan African countries. Excessive use of alcohol causes a large degree of health problems, social and economic burden in societies. However, the prevalence and associated factors of alcohol use disorder among this group of people has not been studied very well. Therefore, this study sought to assess the magnitude and associated factors of alcohol use disorder among HIV patients attending the antiretroviral (ART) clinic. METHODS: A hospital based cross sectional study design was conducted at Bishoftu General Hospital from May to June 2015. Systematic random sampling technique was used to select the study participants. Data was collected by face to face interview and chart review. Alcohol Use Disorder Identification Test (AUDIT) was used to assess alcohol use disorder. Bivariate and multivariate logistic regression analysis was carried out to identify associated factors and P value < 0.05 was taken as statistically significant. RESULTS: A total of 527 participants were enrolled in the study with a response rate of 100%. The prevalence of alcohol use disorder (AUD) was 14.2%. Factors associated with alcohol use disorder were educational status AOR = 8.5 (95%CI: 1.70, 42.99), social support AOR = 0.5(95%CI: 0.26, 0.95), cigarette smoking AOR = 3.49(95%CI: 1.01, 12.13), khat chewing AOR = 5.11 (95% CI: 1.60, 16.33), family history of alcohol use AOR = 3.58 (95% CI: 1.52, 8.47), and missing ART drugs AOR 3.05 (95% CI: 1.302, 7.131). CONCLUSION: The prevalence of alcohol use disorder was high as compared to similar epidemiological studies. Educational status, social support, cigarette smoking, khat chewing, and family history of alcohol use were independent predictors. Providing health education about alcohol use and proper screening of alcohol use disorder among patients with HIV/AIDS is crucial. Strengthening the referral linkage with the psychiatric unit will decrease the burdens of the problem. PMID- 29509773 TI - Sperm morphology, sperm motility and paternity success in the bluethroat (Luscinia svecica). AB - Postcopulatory sexual selection may select for male primary sexual characteristics like sperm morphology and sperm motility, through sperm competition or cryptic female choice. However, how such characteristics influence male fertilization success remains poorly understood. In this study, we investigate possible correlations between sperm characteristics and paternity success in the socially monogamous bluethroat (Luscinia svecica svecica), predicting that sperm length and sperm swimming speed is positively correlated with paternity success. In total, 25% (15/61) of broods contained extra-pair offspring and 10% (33/315) of the offspring were sired by extra-pair males. Paternity success did not correlate significantly with sperm morphology or any aspects of sperm motility. Furthermore, sperm morphology and sperm motility did not correlate significantly with male morphological characters that previously have been shown to be associated with paternity success. Thus, the sperm characteristics investigated here do not appear to be strong predictors of paternity success in bluethroats. PMID- 29509774 TI - Economic assessment of traditional surgical intervention versus use of a new innovative radiofrequency based surgical system in device replacements. AB - INTRODUCTION: Intra-operative complications like mechanical damages to the leads, infections and hematomas during generator replacements of implantable pacemakers and defibrillators contribute to additional costs for hospitals. The aim of this study was to evaluate operation room use, costs and budget impact of generator replacements using either a traditional surgical intervention (TSI) with scissors, scalpel and electrocautery vs. a new radiofrequency energy based surgical system, called PEAK PlasmaBladeTM (PPB). MATERIALS AND METHODS: We conducted a retrospective analysis of a population including 508 patients with TSI and 254 patients with PPB who underwent generator replacement at the Kepler University Hospital in Linz or the St. Josef Hospital in Braunau, Austria. The economic analysis included costs of resources used for intra-operative complications (lead damages) and of procedure time for TSI vs. PPB. RESULTS: Proportion of males, mean age and type of generator replaced were similar between the two groups. Lead damages occurred significantly more frequent with TSI than with PPB (5.3% and 0.4%; p< 0.001) and the procedure time was significantly longer with TSI than with PPB (47.9+/-24.9 and 34.1+/-18.1 minutes; p<0.001). Shorter procedure time and a lower rate of lead damages with PPB resulted in per patient cost savings of ?81. Based on estimated 2,700 patients annually undergoing generator replacement in Austria, the use of PPB may translate into cost savings of ?219,600 and 621 saved operating facility hours. CONCLUSION: PPB has the potential to minimize the risk of lead damage with more efficient utilization of the operating room. Along with cost savings and improved quality of care, hospitals may use the saved operating room hours to increase the number of daily surgeries. PMID- 29509775 TI - A search algorithm for identifying likely users and non-users of marijuana from the free text of the electronic medical record. AB - BACKGROUND: The harmful effects of marijuana on health and in particular cardiovascular health are understudied. To develop such knowledge, an efficient method of developing an informative cohort of marijuana users and non-users is needed. METHODS: We identified patients with a diagnosis of coronary artery disease using ICD-9 codes who were seen in the San Francisco VA in 2015. We imported these patients' medical record notes into an informatics platform that facilitated text searches. We categorized patients into those with evidence of marijuana use in the past 12 months and patients with no such evidence, using the following text strings: "marijuana", "mjx", and "cannabis". We randomly selected 51 users and 51 non-users based on this preliminary classification, and sent a recruitment letter to 97 of these patients who had contact information available. Patients were interviewed on marijuana use and domains related to cardiovascular health. Data on marijuana use collected from the medical record was compared to data collected as part of the interview. RESULTS: The interview completion rate was 71%. Among the 35 patients identified by text strings as having used marijuana in the previous year, 15 had used marijuana in the past 30 days (positive predictive value = 42.9%). The probability of use in the past month increased from 8.8% to 42.9% in people who have these keywords in their medical record compared to those who did not have these terms in their medical record. CONCLUSION: Methods that combine text search strategies for participant recruitment with health interviews provide an efficient approach to developing prospective cohorts that can be used to study the health effects of marijuana. PMID- 29509776 TI - Trends in lipid profiles and descriptive characteristics of U.S. adults with and without diabetes and cholesterol-lowering medication use-National Health and Nutrition Examination Survey, 2003-2012, United States. AB - BACKGROUND: With a cholesterol-lowering focus for diabetic adults and in the age of polypharmacy, it is important to understand how lipid profile levels differ among those with and without diabetes. OBJECTIVE: Investigate the means, differences, and trends in lipid profile measures [TC, total cholesterol; LDL-c, low-density lipoprotein; HDL-c, high-density lipoprotein; and TG, triglycerides] among US adults by diabetes status and cholesterol-lowering medication. METHODS: Population number and proportion of adults aged >=21 years with diabetes and taking cholesterol-lowering medication were estimated using data on 10,384 participants from NHANES 2003-2012. Age-standardized means, trends, and differences in lipid profile measures were estimated by diabetes status and cholesterol medication use. For trends and differences, linear regression analysis were used adjusted for age, gender, and race/ethnicity. RESULTS: Among diabetic adults, 52% were taking cholesterol-lowering medication compared to the 14% taking cholesterol-lowering medication without diabetes. Although diabetic adults had significantly lower TC and LDL-c levels than non-diabetic adults [% difference (95% confidence interval): TC = -5.2% (-6.8 --3.5), LDL-c = -8.0% ( 10.4 --5.5)], the percent difference was greater among adults taking cholesterol medication [TC = -8.0% (-10.3 --5.7); LDL-c = -13.7% (-17.1 --10.2)] than adults not taking cholesterol medication [TC = -3.5% (-5.2 --1.6); LDL-c = -4.3% (-7.1 - 1.5)] (interaction p-value: TC = <0.001; LDL-c = <0.001). From 2003-2012, mean TC and HDL-c significantly decreased among diabetic adults taking cholesterol medication [% difference per survey cycle (p-value for linear trend): TC = -2.3% (0.003) and HDL-c = -2.3% (0.033)]. Mean TC, HDL-c, and LDL-c levels did not significantly change from 2003 to 2012 in non-diabetic adults taking cholesterol medication or for adults not taking cholesterol medications. CONCLUSIONS: Diabetic adults were more likely to have lower lipid levels, except for triglyceride levels, than non-diabetic adults with profound differences when considering cholesterol medication use, possibly due to the positive effects from clinical diabetes management. PMID- 29509777 TI - Assessing the impact of the 4CL enzyme complex on the robustness of monolignol biosynthesis using metabolic pathway analysis. AB - Lignin is a polymer present in the secondary cell walls of all vascular plants. It is a known barrier to pulping and the extraction of high-energy sugars from cellulosic biomass. The challenge faced with predicting outcomes of transgenic plants with reduced lignin is due in part to the presence of unique protein protein interactions that influence the regulation and metabolic flux in the pathway. Yet, it is unclear why certain plants have evolved to create these protein complexes. In this study, we use mathematical models to investigate the role that the protein complex, formed specifically between Ptr4CL3 and Ptr4CL5 enzymes, have on the monolignol biosynthesis pathway. The role of this Ptr4CL3 Ptr4CL5 enzyme complex on the steady state flux distribution was quantified by performing Monte Carlo simulations. The effect of this complex on the robustness and the homeostatic properties of the pathway were identified by performing sensitivity and stability analyses, respectively. Results from these robustness and stability analyses suggest that the monolignol biosynthetic pathway is resilient to mild perturbations in the presence of the Ptr4CL3-Ptr4CL5 complex. Specifically, the presence of Ptr4CL3-Ptr4CL5 complex increased the stability of the pathway by 22%. The robustness in the pathway is maintained due to the presence of multiple enzyme isoforms as well as the presence of alternative pathways resulting from the presence of the Ptr4CL3-Ptr4CL5 complex. PMID- 29509778 TI - Immunodominance in T cell responses elicited against different domains of detoxified pneumolysin PlyD1. AB - Detoxified pneumolysin, PlyD1, is a protein vaccine candidate that induces protection against infections with Streptococcus pneumoniae in mouse models. Despite extensive knowledge on antibody responses against PlyD1, limited information is available about PlyD1 induced T cell recognition. Here we interrogated epitope breadth and functional characteristics of the T cell response to PlyD1 in two mouse strains. BALB/c (H-2d) and C57BL/6 (H-2b) mice were vaccinated with Al(OH)3-adjuvanted or non-adjuvanted PlyD1, or placebo, on day 0, 21 and 42 and were sacrificed at day 56 for collection of sera and spleens. Vaccination with adjuvanted and non-adjuvanted PlyD1 induced anti pneumolysin IgG antibodies with neutralizing capacity in both mouse strains. Adjuvantation of PlyD1 enhanced the serological responses in both strains. In vitro restimulation of splenocytes with PlyD1 and 18-mer synthetic peptides derived from pneumolysin revealed specific proliferative and cytokine responses. For both mouse strains, one immunodominant and three subdominant natural epitopes were identified. Overlap between H-2d and H-2b restricted T cell epitopes was limited, yet similarities were found between epitopes processed in mice and predicted to be immunogenic in humans. H-2d restricted T cell epitopes were localized in pneumolysin domains 2 and 3, whereas H-2b epitopes were scattered over the protein. Cytokine responses show mostly a Th2 profile, with low levels of Th1 cytokines, in both mouse strains. In conclusion, PlyD1 evokes T cell responses in mice directed against multiple epitope regions, that is dependent on Major Histocompatibility Complex (MHC) background. These results are important to understand human PlyD1 T cell immunogenicity, to guide cell mediated immunity studies in the context of vaccine development. PMID- 29509779 TI - The biogeochemical vertical structure renders a meromictic volcanic lake a trap for geogenic CO2 (Lake Averno, Italy). AB - Volcanic lakes are characterized by physicochemical favorable conditions for the development of reservoirs of C-bearing greenhouse gases that can be dispersed to air during occasional rollover events. By combining a microbiological and geochemical approach, we showed that the chemistry of the CO2- and CH4-rich gas reservoir hosted within the meromictic Lake Averno (Campi Flegrei, southern Italy) are related to the microbial niche differentiation along the vertical water column. The simultaneous occurrence of diverse functional groups of microbes operating under different conditions suggests that these habitats harbor complex microbial consortia that impact on the production and consumption of greenhouse gases. In the epilimnion, the activity of aerobic methanotrophic bacteria and photosynthetic biota, together with CO2 dissolution at relatively high pH, enhanced CO2- and CH4 consumption, which also occurred in the hypolimnion. Moreover, results from computations carried out to evaluate the dependence of the lake stability on the CO2/CH4 ratios, suggested that the water density vertical gradient was mainly controlled by salinity and temperature, whereas the effect of dissolved gases was minor, excepting if extremely high increases of CH4 are admitted. Therefore, biological processes, controlling the composition of CO2 and CH4, contributed to stabilize the lake stratification of the lake. Overall, Lake Averno, and supposedly the numerous worldwide distributed volcanic lakes having similar features (namely bio-activity lakes), acts as a sink for the CO2 supplied from the hydrothermal/magmatic system, displaying a significant influence on the local carbon budget. PMID- 29509780 TI - Optimized 3D co-registration of ultra-low-field and high-field magnetic resonance images. AB - The prototypes of ultra-low-field (ULF) MRI scanners developed in recent years represent new, innovative, cost-effective and safer systems, which are suitable to be integrated in multi-modal (Magnetoencephalography and MRI) devices. Integrated ULF-MRI and MEG scanners could represent an ideal solution to obtain functional (MEG) and anatomical (ULF MRI) information in the same environment, without errors that may limit source reconstruction accuracy. However, the low resolution and signal-to-noise ratio (SNR) of ULF images, as well as their limited coverage, do not generally allow for the construction of an accurate individual volume conductor model suitable for MEG localization. Thus, for practical usage, a high-field (HF) MRI image is also acquired, and the HF-MRI images are co-registered to the ULF-MRI ones. We address here this issue through an optimized pipeline (SWIM-Sliding WIndow grouping supporting Mutual information). The co-registration is performed by an affine transformation, the parameters of which are estimated using Normalized Mutual Information as the cost function, and Adaptive Simulated Annealing as the minimization algorithm. The sub voxel resolution of the ULF images is handled by a sliding-window approach applying multiple grouping strategies to down-sample HF MRI to the ULF-MRI resolution. The pipeline has been tested on phantom and real data from different ULF-MRI devices, and comparison with well-known toolboxes for fMRI analysis has been performed. Our pipeline always outperformed the fMRI toolboxes (FSL and SPM). The HF-ULF MRI co-registration obtained by means of our pipeline could lead to an effective integration of ULF MRI with MEG, with the aim of improving localization accuracy, but also to help exploit ULF MRI in tumor imaging. PMID- 29509782 TI - A Schelling model with adaptive tolerance. AB - We introduce a Schelling model in which people are modelled as agents following simple behavioural rules which dictate their tolerance to others, their corresponding preference for particular locations, and in turn their movement through a geographic or social space. Our innovation over previous work is to allow agents to adapt their tolerance to others in response to their local environment, in line with contemporary theories from social psychology. We show that adaptive tolerance leads to a polarization in tolerance levels, with distinct modes at either extreme of the distribution. Moreover, agents self organize into communities of like-tolerance, just as they congregate with those of same colour. Our results are robust not only to variations in free parameters, but also experimental treatments in which migrants are dynamically introduced into the native population. We argue that this model provides one possible parsimonious explanation of the political landscape circa 2016. PMID- 29509781 TI - The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure. AB - SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of gamma-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) alpha subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease. PMID- 29509783 TI - Graph configuration model based evaluation of the education-occupation match. AB - To study education-occupation matchings we developed a bipartite network model of education to work transition and a graph configuration model based metric. We studied the career paths of 15 thousand Hungarian students based on the integrated database of the National Tax Administration, the National Health Insurance Fund, and the higher education information system of the Hungarian Government. A brief analysis of gender pay gap and the spatial distribution of over-education is presented to demonstrate the background of the research and the resulted open dataset. We highlighted the hierarchical and clustered structure of the career paths based on the multi-resolution analysis of the graph modularity. The results of the cluster analysis can support policymakers to fine-tune the fragmented program structure of higher education. PMID- 29509784 TI - Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N terminal fragment of amyloid-beta peptide. AB - We report microsecond timescale molecular dynamics simulation of the complex formed between Pt(II)-phenanthroline and the 16 N-terminal residues of the Abeta peptide that is implicated in the onset of Alzheimer's disease, along with equivalent simulations of the metal-free peptide. Simulations from a variety of starting points reach equilibrium within 100 ns, as judged by root mean square deviation and radius of gyration. Platinum-bound peptides deviate rather more from starting points, and adopt structures with larger radius of gyration, than their metal-free counterparts. Residues bound directly to Pt show smaller fluctuation, but others actually move more in the Pt-bound peptide. Hydrogen bonding within the peptide is disrupted by binding of Pt, whereas the presence of salt-bridges are enhanced. PMID- 29509785 TI - Exploration of neural correlates of movement intention based on characterisation of temporal dependencies in electroencephalography. AB - Brain computer interfaces (BCIs) provide a direct communication channel by using brain signals, enabling patients with motor impairments to interact with external devices. Motion intention detection is useful for intuitive movement-based BCI as movement is the fundamental mode of interaction with the environment. The aim of this paper is to investigate the temporal dynamics of brain processes using electroencephalography (EEG) to explore novel neural correlates of motion intention. We investigate the changes in temporal dependencies of the EEG by characterising the decay of autocorrelation during asynchronous voluntary finger tapping movement. The evolution of the autocorrelation function is characterised by its relaxation time, which is used as a robust marker for motion intention. We observed that there was reorganisation of temporal dependencies in EEG during motion intention. The autocorrelation decayed slower during movement intention and faster during the resting state. There was an increase in temporal dependence during movement intention. The relaxation time of the autocorrelation function showed significant (p < 0.05) discrimination between movement and resting state with the mean sensitivity of 78.37 +/- 8.83%. The relaxation time provides movement related information that is complementary to the well-known event related desynchronisation (ERD) by characterising the broad band EEG dynamics which is frequency independent in contrast to ERD. It can also detect motion intention on average 0.51s before the actual movement onset. We have thoroughly compared autocorrelation relaxation time features with ERD in four frequency bands. The relaxation time may therefore, complement the well-known features used in motion-based BCI leading to more robust and intuitive BCI solutions. The results obtained suggest that changes in autocorrelation decay may involve reorganisation of temporal dependencies of brain activity over longer duration during motion intention. This opens the possibilities of investigating further the temporal dynamics of fundamental neural processes underpinning motion intention. PMID- 29509786 TI - Imaging systems and algorithms to analyze biological samples in real-time using mobile phone microscopy. AB - Miniaturized imaging devices have pushed the boundaries of point-of-care imaging, but existing mobile-phone-based imaging systems do not exploit the full potential of smart phones. This work demonstrates the use of simple imaging configurations to deliver superior image quality and the ability to handle a wide range of biological samples. Results presented in this work are from analysis of fluorescent beads under fluorescence imaging, as well as helminth eggs and freshwater mussel larvae under white light imaging. To demonstrate versatility of the systems, real time analysis and post-processing results of the sample count and sample size are presented in both still images and videos of flowing samples. PMID- 29509787 TI - Foveal light and dark adaptation in patients with glaucoma and healthy subjects: A case-control study. AB - INTRODUCTION: To determine whether foveal light and dark adaptation are affected in glaucoma. METHODS: Case-control study with 23 glaucoma patients and 51 controls. Light and dark adaptation were measured twice. After 10 minutes pre adaptation to 0.0032 cd/m2, the background luminance increased stepwise to 320 (5 log unit step) or 10,000 cd/m2 (6.5 log unit step) for 10 minutes, then it decreased back to 0.0032 cd/m2 for 30 minutes. Foveal contrast sensitivity [CS]) as a function of time was determined using a 1.15 degree increment. Time resolution of the experiments was 30 seconds. Multiple linear regression was used to analyse the effect of glaucoma on the CS plateau and adaptation time (time to reach the plateau minus 3 dB); analyses were adjusted for age and gender. RESULTS: After light adaptation to 320 and 10,000 cd/m2, glaucoma patients had a 0.22 (P<0.001) and 0.13 (P = 0.010) log unit lower CS plateau than controls, respectively. After dark adaptation, this difference was 0.21 (P = 0.018) and 0.30 (P<0.001) log unit, respectively. Light adaptation occurred too fast to determine an accurate light adaptation time. Dark adaptation times of glaucoma patients and controls were similar, for both the 5 (7.2 versus 5.5 minutes; P = 0.10) and the 6.5 (18.2 versus 16.6 minutes; P = 0.14) log unit step. CONCLUSION: After a sudden increase or decrease in luminance, the logCS adaptation curves of glaucoma patients are shifted downwards compared to the curves of healthy subjects. Glaucoma patients have a lower CS plateau than healthy subjects, for both light and dark adaptation; dark adaptation times are similar. PMID- 29509788 TI - Next generation sequencing for gut microbiome characterization in rainbow trout (Oncorhynchus mykiss) fed animal by-product meals as an alternative to fishmeal protein sources. AB - Animal by-product meals from the rendering industry could provide a sustainable and commercially viable alternative to fishmeal (FM) in aquaculture, as they are rich in most essential amino acids and contain important amounts of water-soluble proteins that improve feed digestibility and palatability. Among them, poultry by product meal (PBM) have given encouraging results in rainbow trout (Oncorhynchus mykiss). However, the introduction of new ingredients in the diet needs to be carefully evaluated since diet is one of the main factors affecting the gut microbiota, which is a complex community that contributes to host metabolism, nutrition, growth, and disease resistance. Accordingly, we investigated the effects of partial replacement of dietary FM with a mix of animal by-product meals and plant proteins on intestinal microbiota composition of rainbow trout in relation to growth and feeding efficiency parameters. We used 1540 trout with an initial mean body weight of 94.6 +/- 14.2 g. Fish were fed for 12 weeks with 7 different feed formulations. The growth data showed that trout fed on diets rich in animal by-product meals grew as well as fish fed on control diet, which was rich in FM (37.3%) and PBM-free. High-throughput 16S rRNA gene amplicon sequencing (MiSeq platform, Illumina) was utilised to study the gut microbial community profile. After discarding Cyanobacteria (class Chloroplast) and mitochondria reads a total of 2,701,274 of reads taxonomically classified, corresponding to a mean of 96,474 +/- 68,056 reads per sample, were obtained. Five thousand three hundred ninety-nine operational taxonomic units (OTUs) were identified, which predominantly mapped to the phyla of Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria. The ratio between vegetable and animal proteins proved to play a central role in determining microbiome profiles and Firmicutes and Proteobacteria phyla were particularly discriminatory for diet type in trout. Plant ingredients favoured a higher Firmicutes:Proteobacteria ratio than animal proteins. Acceptable abundance of Firmicutes was guaranteed by including at least 25% of vegetable proteins in the diet regardless of animal protein source and percentage. In summary animal by-product meals, as replacements to FM, gave good results in terms of growth performances and did not induce significant changes in gut microbial richness, thus proving to be a suitable protein source for use in rainbow trout aqua feed. PMID- 29509789 TI - Can species distribution models really predict the expansion of invasive species? AB - Predictive studies are of paramount importance for biological invasions, one of the biggest threats for biodiversity. To help and better prioritize management strategies, species distribution models (SDMs) are often used to predict the potential invasive range of introduced species. Yet, SDMs have been regularly criticized, due to several strong limitations, such as violating the equilibrium assumption during the invasion process. Unfortunately, validation studies-with independent data-are too scarce to assess the predictive accuracy of SDMs in invasion biology. Yet, biological invasions allow to test SDMs usefulness, by retrospectively assessing whether they would have accurately predicted the latest ranges of invasion. Here, we assess the predictive accuracy of SDMs in predicting the expansion of invasive species. We used temporal occurrence data for the Asian hornet Vespa velutina nigrithorax, a species native to China that is invading Europe with a very fast rate. Specifically, we compared occurrence data from the last stage of invasion (independent validation points) to the climate suitability distribution predicted from models calibrated with data from the early stage of invasion. Despite the invasive species not being at equilibrium yet, the predicted climate suitability of validation points was high. SDMs can thus adequately predict the spread of V. v. nigrithorax, which appears to be-at least partially-climatically driven. In the case of V. v. nigrithorax, SDMs predictive accuracy was slightly but significantly better when models were calibrated with invasive data only, excluding native data. Although more validation studies for other invasion cases are needed to generalize our results, our findings are an important step towards validating the use of SDMs in invasion biology. PMID- 29509790 TI - Serum anti-flagellin and anti-lipopolysaccharide immunoglobulins as predictors of linear growth faltering in Pakistani infants at risk for environmental enteric dysfunction. AB - BACKGROUND: Environmental Enteric Dysfunction (EED) in children from low-income countries has been linked to linear growth declines. There is a critical need to identify sensitive and early EED biomarkers. OBJECTIVE: Determine whether levels of antibodies against bacterial components flagellin (flic) and lipopolysaccharide (LPS) predict poor growth. DESIGN/METHODS: In a prospective birth cohort of 380 children in rural Pakistan blood and stool samples were obtained at ages 6 and 9 months. Linear mixed effects models were used to examine longitudinal associations between quartiles of anti-flic and anti-LPS antibodies and changes in LAZ, WAZ and WLZ scores. Spearman's correlations were measured between anti-flic and anti-LPS immunoglobulins with measures of systemic/enteric inflammation and intestinal regeneration. RESULTS: Anti-LPS IgA correlated significantly with CRP, AGP and Reg1 serum at 6mo and with MPO at 9mo. In multivariate analysis at 6mo of age, higher anti-LPS IgA levels predicted greater declines in LAZ scores over subsequent 18mo (comparing highest to lowest quartile, beta (SE) change in LAZ score/year = -0.313 (0.125), p-value = 0.013). Anti-flic Ig A in the two highest quartiles measured at 9mo of age had declines in LAZ of -0.269 (0.126), p = 0.033; and -0.306 (0.129), p = 0.018 respectively, during the subsequent 18mo of life, compared to those in the lowest quartile of anti-flic IgA. CONCLUSIONS AND RELEVANCE: Elevated anti-flic IgA and anti-LPS IgA antibodies at 6 and 9mo, predict declines in linear growth. Systemic and enteric inflammation correlated with anti-LPS IgA provides mechanistic considerations for potential future interventions. PMID- 29509792 TI - In vitro efficacy of 21 dual antimicrobial combinations comprising novel and currently recommended combinations for treatment of drug resistant gonorrhoea in future era. AB - BACKGROUND: Recent WHO guidelines recommend dual therapy with ceftriaxone or cefixime plus azithromycin for gonorrhea. Azithromycin in combination with gentamicin or spectinomycin has been recommended in treatment failure cases. Due to emergence of multi-drug resistant (MDR) and extensively-drug resistant (XDR) Neisseria gonorrhoeae strains, it is important to look for efficacy of these combinations and also of others that might be used in future. Therefore, we aimed to evaluate in vitro synergy of 21 dual combinations including current and alternative WHO recommended treatment regimens and other dual combinations. METHODS AND FINDINGS: The potential utility of in-vitro interactions of 21 combinations was investigated against 95 N. gonorrhoeae strains including 79 MDR and one XDR strain collected during March 2013 to July 2017 and fractional inhibitory concentration index (FICI) was calculated. These 21 combinations comprised of two WHO currently recommended (cefixime+azithromycin, ceftriaxone+azithromycin); two WHO recommended in treatment failure cases (azithromycin+gentamicin, spectinomycin+azithromycin) and other 17 combinations. RESULTS: FICI of the four WHO recommended antimicrobial combinations were higher (>1.0) than the five novel combinationbreeds (FICI range 0.603-0.951) in the study i.e. gentamicin+ertapenem, moxifloxacin+ertapenem, spectinomycin+ertapenem, azithromycin+ moxifloxacin, cefixime+gentamicin. No antagonistic effect of the above four WHO recommended combinations except spectinomycin+azithromycin (FICI = 4.25) was observed for the XDR strain. Out of above five novel combinations, four combinations produced high synergistic effects in overall 95 strains and also for the XDR strain with FICI of 0.13 to 0.38. Antagonistic effects varying from 3.2 to 12.6% were observed for 10 out of 21 tested combinations (azithromycin in combination with gentamicin and spectinomycin; ceftriaxone with moxifloxacin, gentamicin, spectinomycin and ertapenem; spectinomycin with moxifloxacin and gentamicin; cefixime and gentamicin combination with moxifloxacin). CONCLUSION: WHO recommended cefixime+azithromycin, ceftriaxone+azithromycin combinations having no antagonism indicates their continuing clinical utility. Highest antagonism without any synergistic effect for the WHO recommended spectinomycin+azithromycin in treatment failure cases suggests that this combination should be evaluated further both in vitro and in vivo. Highest synergistic or additive effect without any antagonistic effect of the above five novel combinations suggests that these may be recommended for treatment in future. PMID- 29509791 TI - Taxonomy-based content analysis of sedentary behavior questionnaires: A systematic review. AB - BACKGROUND: Health effects of sedentary behaviors (SB) may vary depending on their characteristics such as type, purpose, duration, and intensity of the behavior. While a growing number of questionnaires assess sedentary behaviors, it is unclear which characteristics of SB are measured. The aim of this review was to examine the content of self-report SB questionnaires. METHODS: Three databases were searched for sedentary behavior questionnaires published before January 1st, 2016. Based on the inclusion criteria, 82 articles out of 1369 were retrieved for a total of 60 questionnaires. For each questionnaire, the sedentary behavior characteristics identified were reported and analyzed. RESULTS: Most of the questionnaires assessed the time (n = 60), posture (n = 54), purpose (n = 46) and the types (n = 45) of SB performed. Fewer questionnaires assessed the environment (n = 20) social context (n = 11), status (n = 2), and associated behaviors (n = 2) related to sedentary behaviors. All the questionnaires except two assessed time spent in SB with 17 assessing frequency and 6 assessing breaks in SB. The most frequent characteristics identified in the questionnaires were the categories of sitting (90%), a day (95%), watching television (65%) and using a computer (55%). Many characteristics of SB were not measured. CONCLUSIONS: By knowing the breadth of SB included in questionnaires, this review provides support to shape the design of new questionnaires designed to reduce the gaps in measuring sedentary behaviors. PMID- 29509793 TI - "Do-It-Yourself" reliable pH-stat device by using open-source software, inexpensive hardware and available laboratory equipment. AB - In this paper, we present the construction of a reliable and inexpensive pH stat device, by using open-source "OpenPhControl" software, inexpensive hardware (a peristaltic and a syringe pump, Arduino, a step motor...), readily available laboratory devices: a pH meter, a computer, a webcam, and some 3D printed parts. We provide a methodology for the design, development and test results of each part of the device, as well as of the entire system. In addition to dosing reagents by means of a low-cost peristaltic pump, we also present carefully controlled dosing of reagents by an open-source syringe pump. The upgrading of the basic open-source syringe pump is given in terms of pump control and application of a larger syringe. In addition to the basic functions of pH stat, i.e. pH value measurement and maintenance, an improvement allowing the device to be used for potentiometric titration has been made as well. We have demonstrated the device's utility when applied for cellulose fibers oxidation with 2,2,6,6 tetramethylpiperidine-1-oxyl radical, i.e. for TEMPO-mediated oxidation. In support of this, we present the results obtained for the oxidation kinetics, the consumption of added reagent and experimental repeatability. Considering that the open-source scientific tools are available to everyone, and that researchers can construct and adjust the device according to their needs, as well as, that the total cost of the open-source pH stat device, excluding the existing laboratory equipment (pH meter, computer and glossary) was less than 150 EUR, we believe that, at a small fraction of the cost of available commercial offers, our open source pH stat can significantly improve experimental work where the use of pH stat is necessary. PMID- 29509794 TI - Identification of proteins interacting with the mitochondrial small heat shock protein Hsp22 of Drosophila melanogaster: Implication in mitochondrial homeostasis. AB - The small heat shock protein (sHsp) Hsp22 from Drosophila melanogaster (DmHsp22) is part of the family of sHsps in this diptera. This sHsp is characterized by its presence in the mitochondrial matrix as well as by its preferential expression during ageing. Although DmHsp22 has been demonstrated to be an efficient in vitro chaperone, its function within mitochondria in vivo remains largely unknown. Thus, determining its protein-interaction network (interactome) in the mitochondrial matrix would help to shed light on its function(s). In the present study we combined immunoaffinity conjugation (IAC) with mass spectroscopy analysis of mitochondria from HeLa cells transfected with DmHsp22 in non-heat shock condition and after heat shock (HS). 60 common DmHsp22-binding mitochondrial partners were detected in two independent IACs. Immunoblotting was used to validate interaction between DmHsp22 and two members of the mitochondrial chaperone machinery; Hsp60 and Hsp70. Among the partners of DmHsp22, several ATP synthase subunits were found. Moreover, we showed that expression of DmHsp22 in transiently transfected HeLa cells increased maximal mitochondrial oxygen consumption capacity and ATP contents, providing a mechanistic link between DmHsp22 and mitochondrial functions. PMID- 29509796 TI - RNA activating-double stranded RNA targeting flt-1 promoter inhibits endothelial cell proliferation through soluble FLT-1 upregulation. AB - Short-activating RNA (saRNA), which targets gene promoters, has been shown to increase the target gene expression. In this study, we describe the use of an saRNA (Flt a-1) to target the flt-1 promoter, leading to upregulation of the soluble isoform of Flt-1 and inhibition of angiogenesis. We demonstrate that Flt a-1 increased sFlt-1 mRNA and protein levels, while reducing VEGF expression. This was associated with suppression of human umbilical vascular endothelial cell (HUVEC) proliferation and cell cycle arrest at the G0/G1 phase. HUVEC migration and tube formation were also suppressed by Flt a-1. An siRNA targeting Flt-1 blocked the effects of Flt a-1. Flt a-1 effects were not mediated via argonaute proteins. However, trichostatin A and 5'-deoxy-5'-(methylthio) adenosine inhibited Flt a-1 effects, indicating that histone acetylation and methylation are mechanistically involved in RNA activation of Flt-1. In conclusion, RNA activation of sFlt-1 can be used to inhibit angiogenesis. PMID- 29509798 TI - Preparation and purification of organic samples for selenium isotope studies. AB - Selenium (Se) is an important micronutrient but also a strong toxin with a narrow tolerance range for many organisms. As such, a globally heterogeneous Se distribution in soils is responsible for various disease patterns (i.e. Se excess and deficiency) and environmental problems, whereby plants play a key role for the Se entrance into the biosphere. Selenium isotope variations were proved to be a powerful tracer for redox processes and are therefore promising for the exploration of the species dependent Se metabolism in plants and the Se cycling within the Critical Zone. Plant cultivation setups enable systematic controlled investigations, but samples derived from them-plant tissue and phytoagar-are particularly challenging and require specific preparation and purification steps to ensure precise and valid Se isotope analytics performed with HG-MC-ICP-MS. In this study, different methods for the entire process from solid tissue preparation to Se isotope measurements were tested, optimized and validated. A particular microwave digestion procedure for plant tissue and a vacuum filtration method for phytoagar led to full Se recoveries, whereby unfavorable organic residues were reduced to a minimum. Three purification methods predominantly described in the literature were systematically tested with pure Se solution, high concentrated multi-element standard solution as well as plant and phytoagar as target matrices. All these methods efficiently remove critical matrix elements, but differ in Se recovery and organic residues. Validation tests doping Se-free plant material and phytoagar with a reference material of known Se isotope composition revealed the high impact of organic residues on the accuracy of MC-ICP-MS measurements. Only the purification method with no detectable organic residues, hydride generation and trapping, results in valid mass bias correction for plant samples with an average deviation to true delta82/76Se values of 0.2 0/00 and a reproducibility (2 SD) of +/- 0.2 0/00. For phytoagar this test yields a higher deviation of 1.1 0/00 from the true value and a 2 SD of +/- 0.1 0/00. The application of the developed methods to cultivated plants shows sufficient accuracy and precision and is a promising approach to resolve plant internal Se isotope fractionations, for which respective delta82/76Se values of +2.3 to +3.5 0/00 for selenate and +1.2 to +1.9 0/00 for selenite were obtained. PMID- 29509795 TI - Out of the net: An agent-based model to study human movements influence on local scale malaria transmission. AB - Though malaria control initiatives have markedly reduced malaria prevalence in recent decades, global eradication is far from actuality. Recent studies show that environmental and social heterogeneities in low-transmission settings have an increased weight in shaping malaria micro-epidemiology. New integrated and more localized control strategies should be developed and tested. Here we present a set of agent-based models designed to study the influence of local scale human movements on local scale malaria transmission in a typical Amazon environment, where malaria is transmission is low and strongly connected with seasonal riverine flooding. The agent-based simulations show that the overall malaria incidence is essentially not influenced by local scale human movements. In contrast, the locations of malaria high risk spatial hotspots heavily depend on human movements because simulated malaria hotspots are mainly centered on farms, were laborers work during the day. The agent-based models are then used to test the effectiveness of two different malaria control strategies both designed to reduce local scale malaria incidence by targeting hotspots. The first control scenario consists in treat against mosquito bites people that, during the simulation, enter at least once inside hotspots revealed considering the actual sites where human individuals were infected. The second scenario involves the treatment of people entering in hotspots calculated assuming that the infection sites of every infected individual is located in the household where the individual lives. Simulations show that both considered scenarios perform better in controlling malaria than a randomized treatment, although targeting household hotspots shows slightly better performance. PMID- 29509797 TI - Genomic differences between nasal Staphylococcus aureus from hog slaughterhouse workers and their communities. AB - New human pathogens can emerge from the livestock-human interface and spread into human populations through many pathways including livestock products. Occupational contact with livestock is a risk factor for exposure to those pathogens and may cause further spreading of those pathogens in the community. The current study used whole genome sequencing to explore nasal Staphylococcus aureus obtained from hog slaughterhouse workers and their community members, all of whom resided in a livestock-dense region in rural North Carolina. Sequence data were analyzed for lineage distribution, pathogenicity-related genomic features, and mobile genetic elements. We observed evidence of nasal S. aureus differences between hog workers and non-workers. Nasal S. aureus from hog workers showed a greater lineage diversity than nasal S. aureus from community residents. Hog worker isolates were less likely to carry the phiSa3 prophage and human specific immune evasion cluster genes than community resident isolates (phiSa3 prophage: 54.5% vs. 91.7%, Benjamini-Hochberg (BH) corrected p = 0.035; immune evasion cluster genes: 66.7% vs. 100%, BH p = 0.021). Hog worker isolates had a lower prevalence and diversity of enterotoxins than community resident isolates, particularly lacking the enterotoxin gene cluster (39.4% vs. 70.8%, BH p = 0.125). Moreover, hog worker isolates harbored more diverse antibiotic resistance genes, with a higher prevalence of carriage of multiple resistance genes, than community resident isolates (75.8% vs. 29.2%, BH p = 0.021). Phylogenetic analysis of all ST5 isolates, the most abundant lineage in the collection, further supported separation of isolates from hog workers and non-workers. Together, our observations suggest impact of occupational contact with livestock on nasal S. aureus colonization and highlight the need for further research on the complex epidemiology of S. aureus at the livestock-human interface. PMID- 29509799 TI - Application of metabolomics in prediction of lymph node metastasis in papillary thyroid carcinoma. AB - PURPOSE: The aim of this study was to find useful metabolites to predict lymph node (LN) metastasis in patients with papillary thyroid cancer (PTC) through a metabolomics approach and investigate the potential role of metabolites as a novel prognostic marker. MATERIALS AND METHODS: Fifty-two consecutive patients (median age: 41.5 years, range 15-74 years) were enrolled who underwent total thyroidectomy and central LN dissection with or without lateral LN dissection in Severance Hospital between October 2013 and July 2015. The study specimens were provided by the Severance Hospital Gene Bank, and consisted of PTC from each patient. The specimens were prepared for proton nuclear magnetic resonance (1H NMR) spectroscopy. Spectral data by 1H-NMR spectroscopy were acquired, processed, and analyzed. Patients were grouped in three ways, according to the presence of LN metastasis, central LN metastasis and lateral LN metastasis. Chi-square test and the student t-test were used to analyze categorical variables and continuous variables, respectively. The Mann-Whitney U test was used for univariate analysis of metabolites. Orthogonal projections to latent structure discriminant analysis (OPLS-DA) was used for multivariate analysis to discriminate metabolic differences between the two groups. RESULTS: Among 52 patients, 32 had central LN metastasis and 19 had lateral LN metastasis. No clinical or histopathological characteristic was significantly different for all comparisons. On univariate analysis, no metabolite showed significant difference for all comparisons. On multivariate analysis, OPLS-DA did not discriminate the presence and absence of LN metastasis. Lactate was found to be the most promising metabolite. CONCLUSIONS: No metabolite could discriminate the presence of LN metastasis. However, lactate was found to be the most promising metabolite for discrimination. Further studies with larger sample sizes are needed to elucidate significant metabolites which can indicate the presence of LN metastasis in patients with PTC. PMID- 29509800 TI - Distinct activation of the sympathetic adreno-medullar system and hypothalamus pituitary adrenal axis following the caloric vestibular test in healthy subjects. AB - INTRODUCTION: The vestibular acute stress induces reversible alert-like reactions that involve the sympathetic adrenal-medullar system and hypothalamic-pituitary adrenal axis responses. The present study aimed to evaluate salivary alpha amylase and salivary cortisol production in relation with cardiovascular reactivity induced by acute stress in healthy subjects. MATERIAL AND METHODS: Forty-eight young healthy male volunteers were examined under basal conditions and at various times after reaching the maximal nystagmic reaction following air caloric vestibular test. Heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure were recorded at the same time as measurement of the salivary alpha-amylase and salivary cortisol. At the end of the caloric vestibular test session, perceived stress scale questionnaires were administered to measure the self-perceived stress impact induced by the task, and individual scores were compared with those measured on the enrollment day. RESULTS: Following caloric vestibular test-evoked vertigo, salivary alpha-amylase and cortisol showed distinct trends in their production after acute stress: Student's t-test was used to compare the alpha-amylase vs cortisol slopes of the respective interpolated regression lines, and the difference was significant (t = -3.283; p<0.001); an increase in salivary cortisol production corresponded with a decrease in the salivary alpha-amylase concentration. In addition, salivary biomarker modifications were associated with consistent changes in the heart rate, systolic blood pressure and mean arterial pressure. CONCLUSIONS: Using the air caloric vestibular test task as a stressor, the present study demonstrated a connection between the acute hormonal stress response to vestibular stimulation and cardiovascular output. However, further research is needed before we can define the potential importance of the consistent cardiovascular activity changes evoked by vestibular stimulation and the possible functional consequences for cardiovascular regulation and orthostatic tolerance in humans. PMID- 29509801 TI - Selective biosorption of thorium (IV) from aqueous solutions by ginkgo leaf. AB - Low-cost biosorbents (ginkgo leaf, osmanthus leaf, banyan leaf, magnolia leaf, holly leaf, walnut shell, and grapefruit peel) were evaluated in the simultaneous removal of La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+, Yb3+, Lu3+, UO22+, Th4+, Y3+, Co2+, Zn2+, Ni2+, and Sr2+ from aqueous solutions. In single metal systems, all adsorbents exhibited good to excellent adsorption capacities toward lanthanides and actinides. In a simulated multicomponent mixed solution study, higher selectivity and efficiency were observed for Th4+ over other metal cations, with ginkgo leaves providing the highest adsorptivity (81.2%) among the seven biosorbents. Through optimization studies, the selectivity of Th4+ biosorption on ginkgo leaf was found to be highly pH-dependent, with optimum Th4+ removal observed at pH 4. Th4+ adsorption was found to proceed rapidly with an equilibrium time of 120 min and conform to pseudo-second-order kinetics. The Langmuir isotherm model best described Th4+ biosorption, with a maximum monolayer adsorption capacity of 103.8 mg g-1. Thermodynamic calculations indicated that Th4+ biosorption was spontaneous and endothermic. Furthermore, the physical and chemical properties of the adsorbent were determined by scanning electron microscopy, Brunauer-Emmett-Teller, X-ray powder diffraction, and Fourier transform infrared analysis. The biosorption of Th from a real sample (monazite mineral) was studied and an efficiency of 90.4% was achieved from nitric acid at pH 4 using ginkgo leaves. PMID- 29509802 TI - Cost-effectiveness analysis of pharmaceutical care for hypertensive patients from the perspective of the public health system in Brazil. AB - INTRODUCTION: Only 20% of patients with systemic arterial hypertension (SAH) have blood pressure within recommended parameters. SAH has been the main risk factor for morbidity and mortality of cardiovascular diseases, which affects the burden of the Public Health System (PHS). Some studies have shown the effectiveness of Pharmaceutical Care (PC) in the care of hypertensive patients. OBJECTIVE: To perform a cost-effectiveness analysis to compare SAH treatment with PC management and conventional treatment for hypertensive patients offered by the PHS. METHODS: A cost-effectiveness study nested to a quasi-experimental study was conducted, in which 104 hypertensive patients were followed up in a PC program. Blood pressure control was considered as the outcome for the economic analysis and the costs were direct and non-direct medical costs. RESULTS: PC was dominant for two years in the post-PC period compared with the pre-PC year. The mean cost effectiveness ratio (CER) for the CERPre-PC, CERPC, and CERPost-PC periods were: US$ 364.65, US$ 415.39, and US$ 231.14 respectively. The incremental cost effectiveness ratio (ICER) analysis presented ICER of US$ 478.41 in the PC period and US$ 42.95 in the post PC period. Monte Carlo sensitivity analysis presented mean ICERPC and ICERPost-PC equal to US$ 605.09 and US$ 128.03, reaching US$ 1,725.00 and US$ 740.00 respectively. CONCLUSION: Even for the highest ICER, the values were below the cost effectiveness threshold, which means that PC was a cost effective strategy for the care of hypertensive patients in the PHS. PMID- 29509803 TI - Catalysing progressive uptake of newer diagnostics by health care providers through outreach and education in four major cities of India. AB - BACKGROUND: Unlike in adults, diagnosis of TB can be challenging in children, as signs and symptoms of paediatric TB can be very non-specific and similar to other common childhood chest infections, which may lead to under or delayed diagnosis of TB disease. In spite of the increasing availability of rapid high-sensitivity diagnostics in public and private sectors, majority of paediatric TB cases are empirically diagnosed, without laboratory confirmation. To address these diagnostic challenges, World Health Organization (WHO) has recommended upfront Xpert MTB/RIF (Xpert) testing for the diagnosis of TB in paediatric presumptive pulmonary and extra-pulmonary TB (EPTB) cases. However, in spite of the increasing availability of rapid high-sensitivity diagnostics, a significant gap exists in its application with Xpert being rarely used as an upfront diagnostic among patients presumed to have TB. Under an ongoing paediatric project since April 2014, which provided free-of-cost upfront Xpert testing, several low-cost outreach and education interventions were undertaken to increase the diagnostic uptake by different providers catering to the paediatric population, thereby increasing adherence to global guidance. METHODS: Providers catering to paediatric population in the project cities were systematically mapped and contacted using different outreach strategies. The focus of outreach efforts was to increase provider literacy and increase their awareness of the availability of free rapid diagnostic services with the goal of changing their diagnostic approaches. RESULTS: From April 2014 to June 2016, more than 5,700 providers/facilities were mapped and 3,670 of them were approached. The number of providers/facilities engaged under the project increased more than 10-fold (43 in April, 2014 to 466 in June, 2016), with significant increase in project uptake, both from public and private sector. Overall 42,238 paediatric presumptive TB cases were enrolled in the project, across the four cities. Over the project period, quarterly diagnostic uptake and paediatric TB cases detection rates increased more than two-fold. TB detection rates were similar in patients from public and private sectors. CONCLUSIONS: Ongoing efforts in scaling up new rapid diagnostics involves significant investments. These efforts need to be complemented with proactive provider engagement to ensure provider-literacy and awareness, for maximizing impact of this scale-up. The current project demonstrated the usefulness of outreach and education interventions for the effective uptake of newer diagnostics. PMID- 29509804 TI - Novel RNA viruses within plant parasitic cyst nematodes. AB - The study of invertebrate-and particularly nematode-viruses is emerging with the advancement of transcriptome sequencing. Five single-stranded RNA viruses have now been confirmed within the economically important soybean cyst nematode (SCN; Heterodera glycines). From previous research, we know these viruses to be widespread in greenhouse and field populations of SCN. Several of the SCN viruses were also confirmed within clover (H. trifolii) and beet (H. schachtii) cyst nematodes. In the presented study, we sequenced the transcriptomes of several inbred SCN populations and identified two previously undiscovered viral-like genomes. Both of these proposed viruses are negative-sense RNA viruses and have been named SCN nyami-like virus (NLV) and SCN bunya-like virus (BLV). Finally, we analyzed publicly available transcriptome data of two potato cyst nematode (PCN) species, Globodera pallida and G. rostochiensis. From these data, a third potential virus was discovered and called PCN picorna-like virus (PLV). PCN PLV is a positive-sense RNA virus, and to the best of our knowledge, is the first virus described within PCN. The presence of these novel viruses was confirmed via qRT-PCR, endpoint PCR, and Sanger sequencing with the exception of PCN PLV due to quarantine restrictions on the nematode host. While much work needs to be done to understand the biological and evolutionary significance of these viruses, they offer insight into nematode ecology and the possibility of novel nematode management strategies. PMID- 29509806 TI - Obstructive sleep apnea and cortical thickness in females and males. AB - INTRODUCTION: Obstructive sleep apnea (OSA) affects approximately 10% of adults, and alters brain gray and white matter. Psychological and physiological symptoms of the disorder are sex-specific, perhaps related to greater injury occurs in female than male patients in white matter. Our objective was to identify influences of OSA separated by sex on cortical gray matter. METHODS: We assessed cortical thickness in 48 mild-severe OSA patients (mean age+/-std[range] = 46.5+/ 9.0[30.8-62.7] years; apnea-hypopnea index = 32.6+/-21.1[6-102] events/hour; 12 female, 36 male; OSA severity: 5 mild, 18 moderate, 25 severe) and 62 controls (mean age = 47.7+/-8.9[30.9-65.8] years; 22 female, 40 male). All OSA patients were recently-diagnosed via polysomnography, and control subjects screened and a subset assessed with sleep studies. We used high-resolution magnetic resonance imaging to identify OSA-related cortical thinning, based on a model with condition and sex as independent variables. OSA and OSA-by-sex interaction effects were assessed (P<0.05, corrected for multiple comparisons). RESULTS: Multiple regions of reduced cortical thickness appeared bilaterally in the superior frontal lobe in female OSA vs. all other groups. Significant thinning within the pre- and post-central gyri and the superior temporal gyrus, extending into the insula, appeared between the general OSA populations vs. control subjects. No areas showed increased thickness in OSA vs. controls or positive female OSA interaction effects. CONCLUSIONS: Reduced cortical thickness likely represents tissue atrophy from long term injury, including death of neurons and supporting glia from repeated intermittent hypoxic exposure in OSA, although disease comordities may also contribute to thinning. Lack of polysomnography in all control subjects means results may be confounded by undiagnosed OSA. The greater cortical injury in cognitive areas of female OSA patients may underlie enhanced symptoms in that group. The thinning associated with OSA in male and females OSA patients may contribute to autonomic dysregulation and impaired upper airway sensori-motor function. PMID- 29509807 TI - Structural, functional and blood perfusion changes in the rat retina associated with elevated intraocular pressure, measured simultaneously with a combined OCT+ERG system. AB - Acute elevation of intraocular pressure (IOP) to ischemic and non-ischemic levels can cause temporary or permanent changes in the retinal morphology, function and blood flow/blood perfusion. Previously, such changes in the retina were assessed separately with different methods in clinical studies and animal models. In this study, we used a combined OCT+ ERG system in combination with Doppler OCT and OCT angiography (OCTA) imaging protocols, in order to evaluate simultaneously and correlate changes in the retinal morphology, the retinal functional response to visual stimulation, and the retinal blood flow/blood perfusion, associated with IOP elevation to ischemic and non-ischemic levels in rats. Results from this study suggest that the inner retina responds faster to IOP elevation to levels greater than 30 mmHg with significant reduction of the total retinal blood flow (TRBF), decrease of the capillaries' perfusion and reduction of the ON bipolar cells contribution to the ERG traces. Furthermore, this study showed that ischemic levels of IOP elevation cause an additional significant decrease in the ERG photoreceptor response in the posterior retina. Thirty minutes after IOP normalization, retinal morphology, blood flow and blood perfusion recovered to baseline values, while retinal function did not recover completely. PMID- 29509805 TI - CENP-C/H/I/K/M/T/W/N/L and hMis12 but not CENP-S/X participate in complex formation in the nucleoplasm of living human interphase cells outside centromeres. AB - Kinetochore proteins assemble onto centromeric chromatin and regulate DNA segregation during cell division. The inner kinetochore proteins bind centromeres while most outer kinetochore proteins assemble at centromeres during mitosis, connecting the complex to microtubules. Here, we measured the co-migration between protein pairs of the constitutive centromere associated network (CCAN) and hMis12 complexes by fluorescence cross-correlation spectroscopy (FCCS) in the nucleoplasm outside centromeres in living human interphase cells. FCCS is a method that can tell if in living cells two differently fluorescently labelled molecules migrate independently, or co-migrate and thus are part of one and the same soluble complex. We also determined the apparent dissociation constants (Kd) of the hetero-dimers CENP-T/W and CENP-S/X. We measured co-migration between CENP K and CENP-T as well as between CENP-M and CENP-T but not between CENP-T/W and CENP-S/X. Furthermore, CENP-C co-migrated with CENP-H, and CENP-K with CENP-N as well as with CENP-L. Thus, in the nucleoplasm outside centromeres, a large fraction of the CENP-H/I/K/M proteins interact with CENP-C, CENP-N/L and CENP-T/W but not with CENP-S/X. Our FCCS analysis of the Mis12 complex showed that hMis12, Nsl1, Dsn1 and Nnf1 also form a complex outside centromeres of which at least hMis12 associated with the CENP-C/H/I/K/M/T/W/N/L complex. PMID- 29509809 TI - Birds in the playground: Evaluating the effectiveness of an urban environmental education project in enhancing school children's awareness, knowledge and attitudes towards local wildlife. AB - Children nowadays, particularly in urban areas, are more disconnected from nature than ever before, leading to a large-scale "extinction of experience" with the natural world. Yet there are many potential benefits from children interacting with nature first-hand, including via outdoor learning opportunities. Urban environmental education programmes typically aim to increase awareness and knowledge of local biodiversity and to promote positive attitudes and behaviour towards the environment. However, limited research has been conducted evaluating to what extent these interventions achieve their goals. Here, we explore and assess the influence of a six-week bird-feeding and monitoring project conducted within school grounds ("Bird Buddies") on individual awareness, knowledge and attitudes towards birds by primary school children. This initiative was conducted across eight (sub-)urban primary schools within Brighton and Hove (UK), with 220 participating children (aged 7 to 10). Via pre- and post-project questionnaires, we found evidence for enhanced awareness of local biodiversity, alongside significant gains in both bird identification knowledge and attitudes, which were greatest for children with little prior exposure to nature. Many children expressed a keenness to continue improving the environmental value of their school grounds and to apply elements of the project at home. Student project evaluation scores were consistently positive. Mirroring this, participating teachers endorsed the project as a positive learning experience for their students. One year after the project, several schools were continuing to feed and watch birds. Collectively, the findings from this study highlight the multiple benefits that can be derived from engagement with a relatively short outdoor environmental activity. We therefore believe that such interventions, if repeated locally/longer term, could enhance children's experience with nature in urban settings with combined positive environmental impact. PMID- 29509808 TI - Complex genetic interactions of novel Suppressor of Hairless alleles deficient in co-repressor binding. AB - Throughout the animal kingdom, the Notch signalling pathway allows cells to acquire diversified cell fates. Notch signals are translated into activation of Notch target genes by CSL transcription factors. In the absence of Notch signals, CSL together with co-repressors functions as a transcriptional repressor. In Drosophila, repression of Notch target genes involves the CSL homologue Suppressor of Hairless (Su(H)) and the Notch (N) antagonist Hairless (H) that together form a repressor complex. Guided by crystal structure, three mutations Su(H)LL, Su(H)LLF and Su(H)LLL were generated that specifically affect interactions with the repressor H, and were introduced into the endogenous Su(H) locus by gene engineering. In contrast to the wild type isoform, these Su(H) mutants are incapable of repressor complex formation. Accordingly, Notch signalling activity is dramatically elevated in the homozygotes, resembling complete absence of H activity. It was noted, however, that heterozygotes do not display a dominant H loss of function phenotype. In this work we addressed genetic interactions the three H-binding deficient Su(H) mutants display in combination with H and N null alleles. We included a null mutant of Delta (Dl), encoding the ligand of the Notch receptor, as well as of Su(H) itself in our genetic analyses. H, N or Dl mutations cause dominant wing phenotypes that are sensitive to gene dose of the others. Moreover, H heterozygotes lack bristle organs and develop bristle sockets instead of shafts. The latter phenotype is suppressed by Su(H) null alleles but not by H-binding deficient Su(H) alleles which we attribute to the socket cell specific activity of Su(H). Modification of the dominant wing phenotypes of either H, N or Dl, however, suggested some lack of repressor activity in the Su(H) null allele and likewise in the H-binding deficient Su(H) alleles. Overall, Su(H) mutants are recessive perhaps reflecting self-adjusting availability of Su(H) protein. PMID- 29509810 TI - Tonsillectomy increases the risk of retropharyngeal and parapharyngeal abscesses in adults, but not in children: A national cohort study. AB - OBJECTIVES: The purpose of this study is to evaluate the risk of retropharyngeal and parapharyngeal abscesses (deep neck infection) after tonsillectomy in Koreans using national cohort data. METHODS: Using the national cohort study from the Korean Health Insurance Review and Assessment Service, participants who had undergone a tonsillectomy (5,299) and control participants (21,196) were selected and matched 1:4 (for age, sex, income, region of residence, and pre-operative upper respiratory infection visits). The Cox-proportional hazard model was used. A crude model and an adjusted model for age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia were used in this analysis. For the subgroup analyses, the participants were divided into 2 groups: children (<= 14 years old) and adolescents and adults (>= 15 years old). RESULTS: The adjusted hazard ratio of deep neck infection after tonsillectomy was 1.43 (95% confidence interval, CI = 1.18-1.72, P < 0.001). In subgroup analysis, this ratio was 1.12 (95% CI = 0.86-1.47, P = 0.390) in children and 1.87 (95% CI = 1.43-2.45, P < 0.001) in adolescents and adults. The crude hazard ratios were almost the same as the adjusted ratios. CONCLUSION: The risk of deep neck infection was higher in the tonsillectomy group. The subgroup analysis showed a similar finding in the adolescent and adult group but not in the child group. PMID- 29509811 TI - Access to primary care for socio-economically disadvantaged older people in rural areas: A qualitative study. AB - OBJECTIVE: We aim to explore the barriers to accessing primary care for socio economically disadvantaged older people in rural areas. METHODS: Using a community recruitment strategy, fifteen people over 65 years, living in a rural area, and receiving financial support were recruited for semi-structured interviews. Four focus groups were held with rural health professionals. Interviews and focus groups were audio-recorded and transcribed. Thematic analysis was used to identify barriers to primary care access. FINDINGS: Older people's experience can be understood within the context of a patient perceived set of unwritten rules or social contract-an individual is careful not to bother the doctor in return for additional goodwill when they become unwell. However, most found it difficult to access primary care due to engaged telephone lines, availability of appointments, interactions with receptionists; breaching their perceived social contract. This left some feeling unwelcome, worthless or marginalised, especially those with high expectations of the social contract or limited resources, skills and/or desire to adapt to service changes. Health professionals' described how rising demands and expectations coupled with service constraints had necessitated service development, such as fewer home visits, more telephone consultations, triaging calls and modifying the appointment system. CONCLUSION: Multiple barriers to accessing primary care exist for this group. As primary care is re-organised to reduce costs, commissioners and practitioners must not lose sight of the perceived social contract and models of care that form the basis of how many older people interact with the service. PMID- 29509812 TI - Reversible and long-term immobilization in a hydrogel-microbead matrix for high resolution imaging of Caenorhabditis elegans and other small organisms. AB - The nematode Caenorhabditis elegans is an important model organism for biomedical research and genetic studies relevant to human biology and disease. Such studies are often based on high-resolution imaging of dynamic biological processes in the worm body tissues, requiring well-immobilized and physiologically active animals in order to avoid movement-related artifacts and to obtain meaningful biological information. However, existing immobilization methods employ the application of either anesthetics or servere physical constraints, by using glue or specific microfluidic on-chip mechanical structures, which in some cases may strongly affect physiological processes of the animals. Here, we immobilize C. elegans nematodes by taking advantage of a biocompatible and temperature-responsive hydrogel-microbead matrix. Our gel-based immobilization technique does not require a specific chip design and enables fast and reversible immobilization, thereby allowing successive imaging of the same single worm or of small worm populations at all development stages for several days. We successfully demonstrated the applicability of this method in challenging worm imaging contexts, in particular by applying it for high-resolution confocal imaging of the mitochondrial morphology in worm body wall muscle cells and for the long-term quantification of number and size of specific protein aggregates in different C. elegans neurodegenerative disease models. Our approach was also suitable for immobilizing other small organisms, such as the larvae of the fruit fly Drosophila melanogaster and the unicellular parasite Trypanosoma brucei. We anticipate that this versatile technique will significantly simplify biological assay-based longitudinal studies and long-term observation of small model organisms. PMID- 29509815 TI - Reduce unnecessary imaging by refining clinical exam skills. PMID- 29509813 TI - All metrics are equal, but some metrics are more equal than others: A systematic search and review on the use of the term 'metric'. AB - OBJECTIVE: To examine the use of the term 'metric' in health and social sciences' literature, focusing on the interval scale implication of the term in Modern Test Theory (MTT). MATERIALS AND METHODS: A systematic search and review on MTT studies including 'metric' or 'interval scale' was performed in the health and social sciences literature. The search was restricted to 2001-2005 and 2011-2015. A Text Mining algorithm was employed to operationalize the eligibility criteria and to explore the uses of 'metric'. The paradigm of each included article (Rasch Measurement Theory (RMT), Item Response Theory (IRT) or both), as well as its type (Theoretical, Methodological, Teaching, Application, Miscellaneous) were determined. An inductive thematic analysis on the first three types was performed. RESULTS: 70.6% of the 1337 included articles were allocated to RMT, and 68.4% were application papers. Among the number of uses of 'metric', it was predominantly a synonym of 'scale'; as adjective, it referred to measurement or quantification. Three incompatible themes 'only RMT/all MTT/no MTT models can provide interval measures' were identified, but 'interval scale' was considerably more mentioned in RMT than in IRT. CONCLUSION: 'Metric' is used in many different ways, and there is no consensus on which MTT metric has interval scale properties. Nevertheless, when using the term 'metric', the authors should specify the level of the metric being used (ordinal, ordered, interval, ratio), and justify why according to them the metric is at that level. PMID- 29509816 TI - The agitated patient: Steps to take, how to stay safe. AB - Situations involving agitated patients are not uncommon in health care settings. And no matter where on the spectrum an incident involving an agitated patient falls, it can leave those involved with various levels of physical, emotional, and psychological harm. It can also leave everyone asking themselves: "How can I better prepare for such occurrences?" This article offers some answers by providing tips and guidelines for handling agitated and/or violent patients in various settings. PMID- 29509817 TI - ACL injury: How do the physical examination tests compare? AB - Three physical examination tests are most commonly used to evaluate cruciate ligament injury. The best known and most frequently used technique is the anterior drawer test. The other 2 tests, the Lachman test and the pivot shift test, are more difficult to perform and are used less often, especially by physicians untrained in their use. In addition, there is a relatively new diagnostic test: the lever sign test. The aim of our article is to provide a short, clinically relevant overview of the literature and to assess the diagnostic value of physical examination for the primary care physician. PMID- 29509818 TI - Limited evidence guides empiric Tx of female chronic pelvic pain. AB - This article reviews the limited evidence for treating chronic pelvic pain and offers recommendations for the primary care physician on providing symptomatic relief in the absence of diagnosed pathology. PMID- 29509814 TI - Structural basis for recognition of the central conserved region of RSV G by neutralizing human antibodies. AB - Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly, and yet there remains no effective treatment or vaccine. The surface of the virion is decorated with the fusion glycoprotein (RSV F) and the attachment glycoprotein (RSV G), which binds to CX3CR1 on human airway epithelial cells to mediate viral attachment and subsequent infection. RSV G is a major target of the humoral immune response, and antibodies that target the central conserved region of G have been shown to neutralize both subtypes of RSV and to protect against severe RSV disease in animal models. However, the molecular underpinnings for antibody recognition of this region have remained unknown. Therefore, we isolated two human antibodies directed against the central conserved region of RSV G and demonstrated that they neutralize RSV infection of human bronchial epithelial cell cultures in the absence of complement. Moreover, the antibodies protected cotton rats from severe RSV disease. Both antibodies bound with high affinity to a secreted form of RSV G as well as to a peptide corresponding to the unglycosylated central conserved region. High-resolution crystal structures of each antibody in complex with the G peptide revealed two distinct conformational epitopes that require proper folding of the cystine noose located in the C-terminal part of the central conserved region. Comparison of these structures with the structure of fractalkine (CX3CL1) alone or in complex with a viral homolog of CX3CR1 (US28) suggests that RSV G would bind to CX3CR1 in a mode that is distinct from that of fractalkine. Collectively, these results build on recent studies demonstrating the importance of RSV G in antibody-mediated protection from severe RSV disease, and the structural information presented here should guide the development of new vaccines and antibody-based therapies for RSV. PMID- 29509819 TI - Bilateral wrist pain . limited range of motion . tenderness to palpation . Dx? AB - A 12-year-old girl presented to my office (JH) with bilateral wrist pain. She had fallen on both wrists palmar-flexed and then, while trying to get up, landed on both wrists dorsi-flexed. The patient did not hear any "pops," but felt immediate pain when her wrists hyperextended. Hand, wrist, and forearm x-rays were negative bilaterally for fractures. She was placed in bilateral thumb spica splints. PMID- 29509820 TI - PURLs: An easy approach to obtaining clean-catch urine from infants. AB - A fussy 6-month-old infant is brought into the emergency department with a rectal temperature of 101.5 degrees F. She is consolable, breathing normally, and appears well hydrated. You find no clear etiology for her fever and suspect that a urinary tract infection may be the source of her illness. How do you proceed with obtaining a urine sample? PMID- 29509821 TI - Practice Alert: ACIP vaccine update. AB - The Advisory Committee on Immunization Practices made relatively few new vaccine recommendations in 2017. One pertained to prevention of hepatitis B virus infection in infants born to HBV-infected mothers. Another recommended a new vaccine to prevent shingles. A third advised considering an additional dose of mumps vaccine during an outbreak. PMID- 29509822 TI - Depigmented plaques on vulva. AB - A mother brought her 8-year-old daughter to our office for evaluation of vitiligo "down there". The skin eruption first appeared on her vulva a year earlier and was intermittently pruritic. The lesions were initially smaller and red, but had since lightened in color, coalesced, and had begun to spread to the perianal area. The patient's mother had received a call from her daughter's teacher who observed that her daughter was scratching the area and might be masturbating in class. WHAT IS YOUR DIAGNOSIS? HOW WOULD YOU TREAT THIS PATIENT? PMID- 29509823 TI - Clinical Inquiries: Does exercise relieve vasomotor menopausal symptoms? AB - No. Exercise doesn't decrease the frequency or severity of vasomotor menopausal symptoms in perimenopausal and postmenopausal women (strength of recommendation: A, systematic review of randomized controlled trials [RCTs] and consistent RCT). PMID- 29509824 TI - HelpDesk: How accurate are point-of-care urine drug screens in patients taking chronic opioid therapy? AB - In adults treated with opioids for chronic pain, point-of-care urine drug screens (immunoassays) for detecting opioids show a false-negative rate of 1.9%, a sensitivity of 92%, and a specificity of 93% compared with the gold-standard liquid chromatography tandem mass spectrometry. Oxycodone has the highest rate of false-negative results at 25%; methadone has the lowest rate at 4% to 6% (strength of recommendation: A, 2 blinded diagnostic accuracy studies with similar results). PMID- 29509825 TI - Diffuse erythematous rash resistant to treatment. AB - A 39-year-old woman presented to the emergency department for evaluation of diffuse redness, itching, and tenderness of her skin. The patient said the eruption began 4 months earlier as localized plaques on her scalp, elbows, and beneath both breasts. Over the course of a few days, the redness became more diffuse, affecting most of her body. She also noticed swelling and skin desquamation on her lower extremities. WHAT IS YOUR DIAGNOSIS? HOW WOULD YOU TREAT THIS PATIENT? PMID- 29509826 TI - Enriched Chicken Bone Broth as a Dietary Supplement Reduces Nociception and Sensitization Associated with Prolonged Jaw Opening. AB - AIMS: To test a commercially available enriched chicken bone broth (ECBB) product for its potential anti-inflammatory properties and to evaluate its ability to reduce nociception and expression of protein kinase A (PKA) in a clinically relevant model of temporomandibular disorder (TMD) caused by prolonged jaw opening in rats. METHODS: The potential of the ECBB and of a homemade broth was investigated using the Folin-Ciocalteu reagent and percent inhibition of cyclooxygenase-2 (COX-2) activity, which was determined using a commercially available kit. Additionally, the effect of ECBB and homemade broth on nocifensive head withdrawal responses to mechanical stimulation in male Sprague-Dawley rats subjected to prolonged jaw opening was evaluated. Differences were considered significant at P < .025. Changes in PKA expression in the medullary dorsal horn region of the spinal trigeminal nucleus associated with prolonged jaw opening were assessed using immunofluorescence, and these changes were considered significant at P < .05. Behavioral data were analyzed by using multiple nonparametric tests, and immunohistochemistry data were analyzed by using one-way analysis of variance with Games-Howell post hoc tests in SPSS software. RESULTS: ECBB exhibited greater reducing potential and inhibition of COX-2 activity compared to homemade broth. Near maximal jaw opening was sufficient to induce sustained nocifensive responses to mechanical stimuli for 7 days. This increased sensitivity was correlated with elevated levels of the active form of PKA. Importantly, dietary inclusion of ECBB, but not of homemade broth, for 2 weeks prior to jaw opening was sufficient to reduce nocifensive behaviors and PKA expression. CONCLUSION: Findings from this study provide evidence that ECBB attenuates nociception and expression of the pro-inflammatory protein PKA and thus may be beneficial as a nutraceutical supplement to manage inflammatory pain associated with TMD. PMID- 29509827 TI - Shared Genetics of Temporomandibular Disorder Pain and Neck Pain: Results of a Twin Study. AB - AIMS: (1) To examine the heritability of TMD pain and of neck pain; and (2) to estimate the potential overlap in genetic and environmental factors influencing TMD pain and neck pain. METHODS: Data from 2,238 adult female twins who completed a survey on TMD pain and neck pain were analyzed. The total variance of TMD pain and neck pain was decomposed into variance attributable to additive genetic effects and nonshared environmental effects. Bivariate structural equation modeling was applied to estimate trait-specific and genetic effects shared between traits. RESULTS: The prevalence of TMD pain and neck pain was 8.6% and 46.8%, respectively, while 6.7% of the twins reported both TMD pain and neck pain. The phenotypic correlation between TMD pain and neck pain, based on a liability threshold model, was 0.43 (95% confidence interval [CI] 0.34 to 0.51). The heritability for TMD was 0.35 (0.17 to 0.51), and for neck pain was 0.33 (0.23 to 0.43). The genetic correlation between TMD pain and neck pain was 0.64 (0.35 to 1.00), and the environmental correlation was 0.32 (0.14 to 0.48). CONCLUSION: This study shows that variation in TMD pain and neck pain can in part be attributed to genes. The comorbidity between them is partly explained by genes that influence both traits and partly by the same environmental factors. PMID- 29509828 TI - Lower airway flow influences peak nasal inspiratory flow in school-aged children. AB - BACKGROUND: Rhinitis and asthma frequently coexist. Peak nasal inspiratory flow (PNIF) objectively evaluates nasal obstruction. Lower airway flow's impact on PNIF has seldom been analysed in children. We aimed to study the associations between PNIF and: 1)forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) in children with allergic rhinitis and asthma and healthy controls; 2)allergic rhinitis and asthma control subjective evaluation. METHODS: Sequential assessments of PNIF before and after nasal decongestion and spirometry with bronchodilation test were performed in 65 children (6-12 years) with allergic rhinitis and asthma, and 24 gender, age-matched healthy controls. The Control of Allergic Rhinitis and Asthma Test in children (CARATkids) was used for control assessment. Associations were investigated by multiple linear regression models. RESULTS: Baseline and decongested PNIF correlated with baseline and post bronchodilation FEV1 and PEF, observed independently of rhinitis and asthma diagnosis. The best model for PNIF included PEF, age and gender. No association was found between PNIF and CARATkids scores, except for nasal obstruction self report. CONCLUSION: In school-aged children, besides age and gender, PEF values should ideally be known to interpret PNIF values. PNIF can be complementary to subjective control assessment in children with allergic rhinitis and asthma. PMID- 29509830 TI - The accessibility of topical treatment in the paranasal sinuses on operated cystic fibrosis patients assessed by scintigraphy. AB - BACKGROUND: Nasal irrigations with antibiotics are used to eradicate Pseudomonas aeruginosa from the upper airways in patients with cystic fibrosis (CF) and thereby avoid lung colonisations; nevertheless, the efficacy is uncertain. METHODOLOGY: The aim of this study was to investigate the accessibility and durability of solutions in the sinuses before and after sinus surgery. The participants irrigated their noses with radioactively marked saline and were evaluated using a dynamic SPECT/CT scan. The preoperative and postoperative (after 30 days) examinations were compared. RESULTS: Twelve CF patients were included. In 10 out of the 24 scanned maxillary sinuses an improvement was seen postoperatively compared with the preoperative fluid volume. Notably, in 7 out of the 24 sinuses the mucosa was so swollen postoperatively that no fluid was detected. Ten patients had developed their frontal sinuses. We observed no fluid in the frontal or sphenoid sinuses, neither before nor after surgery. At best, a mean of 23% of the maxillary sinuses were filled with fluid; thus, all sinuses had postoperatively areas of the mucosa that did not have contact with the fluid. A mean of 76% of the initial volume was present after 30 min in the maxillary sinuses. CONCLUSION: Fluid-depositing using nasal irrigation will not sufficiently or not at all get in contact with all the sinus mucosa despite of sinus surgery. Thus, the efficacy of topical deposition of antibiotics is presumably reduced. PMID- 29509829 TI - Fluorescein transit test time as a tool to assess lacrimal pump function after diode laser transcanalicular dacryocystorhinostomy and external dacryocysto rhinostomy. AB - BACKGROUND: Dacryocystorhinostomy (DCR) is the gold standard surgical treatment for nasolacrimal duct obstruction. External DCR is the traditional approach (EXT DCR); however, the advent of minimally invasive surgeries and the development of optic fiber and laser technologies have made it possible to perform laser transcanalicular DCR (T-DCR), a minimally invasive procedure. This study measured the fluorescein transit time (FTT) after EXT-DCR or T-DCR to evaluate the lacrimal drainage and lacrimal pump function after these two types of DCR. SUBJECTS AND METHODS: A cross-sectional study of 50 patients who underwent EXT DCR (EXT-DCR Group) or T-DCR (T-DCR Group), who were anatomically patent upon irrigation, with a minimum 6 months of follow up. The patients' FTT was measured; it was defined as the time from the instillation of the dye into conjunctival sac to its free flow from the rhinostomy site. This evaluation was performed through nasal endoscopy performed intranasally with a blue filter that enabled the faster detection of fluorescein from the ostium site. The mean FTTs of the two groups were compared using the two-sided Student's unpaired t-test. Other variables such as sex, age, previous lacrimal sac size, and the site and shape of the rhinostomy were evaluated to determine their possible relationships with FTT. RESULTS: The EXT-DCR group had 80% female patients at a mean age of 58 years. The T-DCR group had the same percentage of female patients (80%) and a mean age of 56 years. The mean FTT group was 47.48 sec in the EXT-DCR and 33.04 sec in the T-DCR group. Functional success was 88% in both groups. CONCLUSION: FTT in the DCR-T Group was significantly lower than in the EXT-DCR Group. No other variables exhibited a statistically significant correlation with FTT. Lacrimal drainage was found to be better after T-DCR than after EXT-DCR, results which show that this procedure could prevent lacrimal pump damage. PMID- 29509831 TI - Eustachian tube symptoms are frequent in chronic rhinosinusitis and respond well to endoscopic sinus surgery. AB - BACKGROUND: Symptoms of Eustachian tube (ET) dysfunction are seldom assessed in patients with chronic rhinosinusitis (CRS). The Sino-Nasal Outcome Test (SNOT-22) quality-of-life tool includes two questions that specifically screen for symptoms of ET dysfunction (Ear Fullness; Ear Pain). OBJECTIVE: The purpose of this study was to determine the extent to which these ET symptoms were present in patients with CRS, and whether these symptoms respond to endoscopic sinus surgery (ESS). METHODOLOGY: SNOT-22 data collected prospectively at time of recruitment into IRB approved clinical trials or case-control studies in CRS was pooled to provide a cross section of the frequency and severity of ET dysfunction. When applicable to the trials, the SNOT-22 was repeated at least 3 months following ESS. RESULTS: Five trials rendering 131 patients were available for assessment. The control group comprised of 251 participants from two case-control studies. Ear Fullness of equal/greather than 1 was reported in 80/131 CRS patients compared to 45/251 control patients. Ear Pain of equal/greather than 1 was reported in 39/131 CRS patients compared to 33/251 control patients. Following ESS, mean Ear Fullness and Ear Pain scores decreased to 1.17 and 0.73, respectively. CONCLUSION: Symptoms suggestive of ET dysfunction are frequent in CRS, and for most patients the symptoms will decrease post-ESS to a level comparable with a non-CRS population. Patients whose ET symptoms do not respond to ESS may represent a target population for emerging therapeutic options for ET dysfunction. PMID- 29509832 TI - Using Heart Rate and Accelerometry to Define Quantity and Intensity of Physical Activity in Older Adults. AB - Background: Physical activity (PA) prevents disease and promotes longevity; yet, few older adults meet the recommended daily guidelines. Wearable PA and heart rate monitors provide the opportunity to define age-related differences in the absolute and relative intensity of daily activities, and provide insight into the underlying factors influencing PA in older adults. Methods : Participants in the Baltimore Longitudinal Study of Aging (n = 440, 52% male, aged 31 to 88 years) completed a clinical assessment and wore an Actiheart monitor in the free-living environment. The association between age and minutes per day in sedentary, light, moderate, and vigorous PA was assessed using relative intensity, as defined by heart rate reserve, and absolute intensity using activity count thresholds. Results: In cross-sectional analyses, time spent in sedentary and light activities as defined by relative intensity did not differ across age (p > 0.05), whereas time spent in moderate and vigorous relative PA was higher for each 1 year increase in age (p < .01). Using absolute intensity PA thresholds, older adults registered fewer activity counts per day with more sedentary time and lesser amounts of light, moderate, and vigorous PA (p < .05). Persons with higher relative and lower absolute PA intensity had poorer functional performance and higher subclinical disease indicators. Conclusions: These findings suggest that time spent in moderate or higher intensity activities may not be lower with age after considering changes in physiology, functional ability, and subclinical disease burden and highlight the need for more age- and ability-specific PA research to inform future interventions and public health guidelines. PMID- 29509833 TI - Serial Clustering of Late-Onset Group B Streptococcal Infections in the Neonatal Unit: A Genomic Re-evaluation of Causality. AB - Background: Invasive Group B streptococcus (GBS) is a major cause of serious neonatal infection. Current strategies to reduce early-onset GBS disease have no impact on late-onset disease (LOD). Although GBS LOD is viewed as a sporadic event in the community, LOD arising within the neonatal intensive care unit (ICU) raises questions about mode of acquisition. Methods: Following a cluster of 4 GBS LOD cases, enhanced surveillance for all GBS LOD was undertaken over 2 years in the neonatal ICU supported by neonatal rectal screening. GBS isolates were serotyped and genome-sequenced. Results: Twelve late -onset invasive GBS episodes were identified (incidence 0.6/1000 live births). Genomic analysis revealed that 11/12 GBS isolates (92%) were linked to at least one other LOD isolate. Isolates from the first cluster were serotype V, resistant to macrolides and lincosamides, and sequencing confirmed isolates were indistinguishable, or distinguishable by only one SNP difference, from each other. Rectal carriage was rare. Prospective surveillance identified three further clusters of LOD due to serotypes Ia (3 cases), Ib (2 cases), and III (2 cases), that would not have been identified without surveillance and genome sequencing, leading to a re-evaluation of interventions required to prevent GBS LOD. Conclusion: Acquisition routes for LOD GBS in the neonatal ICU are poorly understood; cases may not necessarily be sporadic. Within this neonatal ICU, our data suggest that a single case of LOD GBS sepsis should be considered a potential nosocomial transmission event warranting prompt investigation, heightened infection prevention vigilance and action where required. PMID- 29509834 TI - Current Epidemiology and Trends in Invasive Haemophilus influenzae Disease-United States, 2009-2015. AB - Background: Following Haemophilus influenzae serotype b (Hib) conjugate vaccine introduction in the 1980s, Hib disease in young children dramatically decreased, and epidemiology of invasive H. influenzae changed. Methods: Active surveillance for invasive H. influenzae disease was conducted through Active Bacterial Core surveillance sites. Incidence rates were directly standardized to the age and race distribution of the US population. Results: During 2009-2015, the estimated mean annual incidence of invasive H. influenzae disease was 1.70 cases per 100000 population. Incidence was highest among adults aged >=65 years (6.30) and children aged <1 year (8.45); many cases in infants aged <1 year occurred during the first month of life in preterm or low-birth-weight infants. Among children aged <5 years (incidence: 2.84), incidence was substantially higher in American Indian and Alaska Natives AI/AN (15.19) than in all other races (2.62). Overall, 14.5% of cases were fatal; case fatality was highest among adults aged >=65 years (20%). Nontypeable H. influenzae had the highest incidence (1.22) and case fatality (16%), as compared with Hib (0.03; 4%) and non-b encapsulated serotypes (0.45; 11%). Compared with 2002-2008, the estimated incidence of invasive H. influenzae disease increased by 16%, driven by increases in disease caused by serotype a and nontypeable strains. Conclusions: Invasive H. influenzae disease has increased, particularly due to nontypeable strains and serotype a. A considerable burden of invasive H. influenzae disease affects the oldest and youngest age groups, particularly AI/AN children. These data can inform prevention strategies, including vaccine development. PMID- 29509835 TI - Strengthening Acute Flaccid Paralysis Surveillance Through the Village Polio Volunteers Program in Somalia. AB - Background: Surveillance for cases of acute flaccid paralysis (AFP) is a key strategy adopted for the eradication of polio. Detection of poliovirus circulation is often predicated on the ability to identify AFP cases and test their stool specimens for poliovirus infection in a timely manner. The Village Polio Volunteers (VPV) program was established in 2013 in a bid to strengthen polio eradication activities in Somalia, including AFP surveillance, given the country's vulnerability to polio outbreaks. Methods: To assess the impact of the VPV program on AFP surveillance, we determined case counts, case-reporting sources, and nonpolio AFP rates in the years before and after program introduction (ie, 2011-2016). We also compared the stool specimen adequacy rates and timeliness of cases reported by VPVs to those reported by other sources. Results: In the years after program introduction, VPVs accounted for a high proportion of AFP cases reported in Somalia. AFP case counts rose from 148 cases in 2012, the year before program introduction, to 279 cases in 2015, when VPVs accounted for 40% of reported cases. Further, from 2012 to 2015, the nonpolio AFP rate improved from 2.8 to 4.8 cases per 100000 persons aged <15 years. Stool specimen adequacy rates have been consistently high, and AFP cases have been detected in a timelier manner since the program was introduced. Conclusions: Given the impact of the VPV program on improving AFP surveillance indicators in Somalia, similar community-based programs could play a crucial role in enhancing surveillance activities in countries with limited healthcare infrastructure. PMID- 29509837 TI - Genetic profiling using plasma-derived cell-free DNA in therapy-naive hepatocellular carcinoma patients: a pilot study. AB - Background: Hepatocellular carcinomas (HCCs) are not routinely biopsied, resulting in a lack of tumor materials for molecular profiling. Here we sought to determine whether plasma-derived cell-free DNA (cfDNA) captures the genetic alterations of HCC in patients who have not undergone systemic therapy. Patients and methods: Frozen biopsies from the primary tumor and plasma were synchronously collected from 30 prospectively recruited, systemic treatment-naive HCC patients. Deep sequencing of the DNA from the biopsies, plasma-derived cfDNA and matched germline was carried out using a panel targeting 46 coding and non-coding genes frequently altered in HCCs. Results: In 26/30 patients, at least one somatic mutation was detected in biopsy and/or cfDNA. Somatic mutations in HCC-associated genes were present in the cfDNA of 63% (19/30) of the patients and could be detected 'de novo' without prior knowledge of the mutations present in the biopsy in 27% (8/30) of the patients. Mutational load and the variant allele fraction of the mutations detected in the cfDNA positively correlated with tumor size and Edmondson grade. Crucially, among the seven patients in whom the largest tumor was >=5 cm or was associated with metastasis, at least one mutation was detected 'de novo' in the cfDNA of 86% (6/7) of the cases. In these patients, cfDNA and tumor DNA captured 87% (80/92) and 95% (87/92) of the mutations, suggesting that cfDNA and tumor DNA captured similar proportions of somatic mutations. Conclusion: In patients with high disease burden, the use of cfDNA for genetic profiling when biopsy is unavailable may be feasible. Our results support further investigations into the clinical utility of cfDNA in a larger cohort of patients. PMID- 29509836 TI - The Global HIV Epidemic: What Will It Take to Get to the Finish Line? PMID- 29509838 TI - Inhibitory site of alpha-hairpinin peptide from tartary buckwheat has no effect on its antimicrobial activities. AB - Antimicrobial peptides (AMPs) are known to play important roles in the innate host defense mechanisms of most living organisms. Protease inhibitors from plants potently inhibit the growth of a variety of pathogenic bacteria and fungi. Therefore, there are excellent candidates for the development of novel antimicrobial agents. In this study, an antimicrobial peptide derived from tartary buckwheat seeds (FtAMP) was obtained by gene cloning, expression and purification, which exhibited inhibitory activity toward trypsin. Furthermore, the relationship between the antimicrobial and inhibitory activities of FtAMP was investigated. Two mutants (FtAMP-R21A and FtAMP-R21F) were generated through site directed mutagenesis. Inhibitory activity analysis showed that both FtAMP-R21A and FtAMP-R21F lost trypsin-inhibitory activity. However, FtAMP-R21A and FtAMP R21F showed novel inhibitory activities against elastase and alpha-chymotrypsin, respectively, suggesting that Arg-21 in the inhibitory site loop is specific for the inhibitory activity of FtAMP against trypsin. Antimicrobial assays showed that all three peptides exhibited strong antifungal activity against Trichoderma koningii, Rhizopus sp., and Fusarium oxysporum. These results showed that the changes in FtAMP inhibitory site have no effect on their antifungal properties. PMID- 29509840 TI - MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer. AB - Background: MSR1 repeats are a 36-38 bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV). Patients and methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer. Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1 and H3K4me3). MSR1-regulated genes were found to have specific molecular roles, such as serine-protease activity (P = 4.80 * 10-7) and ion channel activity (P = 2.7 * 10-4). The kallikrein locus was found to contain a large number of MSR1 clusters, and at least six of these showed CNV. An MSR1 cluster was identified within KLK14, with 9 and 11 copies being normal variants. A significant association with the 9-copy allele and non familial breast cancer was found in two independent populations (P = 0.004; P = 0.03). In the white British population, the minor allele conferred an increased risk of 1.21-3.51 times for all non-familial disease, or 1.7-5.3 times in early onset disease. The 9-copy allele was also found to be associated with increased risk of prostate cancer in an independent population (odds ratio = 1.27-1.56; P =0.009). Conclusions: MSR1 repeats act as molecular switches that modulate gene expression. It is likely that CNV of MSR1 will affect risk of development of various forms of cancer, including that of breast and prostate. The MSR1 cluster at KLK14 represents the strongest risk factor identified to date in non-familial breast cancer and a significant risk factor for prostate cancer. Analysis of MSR1 genotype will allow development of precise stratification of disease risk and provide a novel target for therapeutic agents. PMID- 29509839 TI - Effect of Offering Same-Day ART vs Usual Health Facility Referral During Home Based HIV Testing on Linkage to Care and Viral Suppression Among Adults With HIV in Lesotho: The CASCADE Randomized Clinical Trial. AB - Importance: Home-based HIV testing is a frequently used strategy to increase awareness of HIV status in sub-Saharan Africa. However, with referral to health facilities, less than half of those who test HIV positive link to care and initiate antiretroviral therapy (ART). Objective: To determine whether offering same-day home-based ART to patients with HIV improves linkage to care and viral suppression in a rural, high-prevalence setting in sub-Saharan Africa. Design, Setting, and Participants: Open-label, 2-group, randomized clinical trial (February 22, 2016-September 17, 2017), involving 6 health care facilities in northern Lesotho. During home-based HIV testing in 6655 households from 60 rural villages and 17 urban areas, 278 individuals aged 18 years or older who tested HIV positive and were ART naive from 268 households consented and enrolled. Individuals from the same household were randomized into the same group. Interventions: Participants were randomly assigned to be offered same-day home based ART initiation (n = 138) and subsequent follow-up intervals of 1.5, 3, 6, 9, and 12 months after treatment initiation at the health facility or to receive usual care (n = 140) with referral to the nearest health facility for preparatory counseling followed by ART initiation and monthly follow-up visits thereafter. Main Outcomes and Measures: Primary end points were rates of linkage to care within 3 months (presenting at the health facility within 90 days after the home visit) and viral suppression at 12 months, defined as a viral load of less than 100 copies/mL from 11 through 14 months after enrollment. Results: Among 278 randomized individuals (median age, 39 years [interquartile range, 28.0-52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P < .001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P = .007). Two deaths (1.5%) were reported in the same-day group, none in usual care group. Conclusions and Relevance: Among adults in rural Lesotho, a setting of high HIV prevalence, offering same-day home-based ART initiation to individuals who tested positive during home-based HIV testing, compared with usual care and standard clinic referral, significantly increased linkage to care at 3 months and HIV viral suppression at 12 months. These findings support the practice of offering same-day ART initiation during home based HIV testing. Trial Registration: clinicaltrials.gov Identifier: NCT02692027. PMID- 29509841 TI - Image-based dynamic quantification and high-accuracy 3D evaluation of canopy structure of plant populations. AB - Background and Aims: Global agriculture is facing the challenge of a phenotyping bottleneck due to large-scale screening/breeding experiments with improved breeds. Phenotypic analysis with high-throughput, high-accuracy and low-cost technologies has therefore become urgent. Recent advances in image-based 3D reconstruction offer the opportunity of high-throughput phenotyping. The main aim of this study was to quantify and evaluate the canopy structure of plant populations in two and three dimensions based on the multi-view stereo (MVS) approach, and to monitor plant growth and development from seedling stage to fruiting stage. Methods: Multi-view images of flat-leaf cucumber, small-leaf pepper and curly-leaf eggplant were obtained by moving a camera around the plant canopy. Three-dimensional point clouds were reconstructed from images based on the MVS approach and were then converted into surfaces with triangular facets. Phenotypic parameters, including leaf length, leaf width, leaf area, plant height and maximum canopy width, were calculated from reconstructed surfaces. Accurate evaluation in 2D and 3D for individual leaves was performed by comparing reconstructed phenotypic parameters with referenced values and by calculating the Hausdorff distance, i.e. the mean distance between two surfaces. Key Results: Our analysis demonstrates that there were good agreements in leaf parameters between referenced and estimated values. A high level of overlap was also found between surfaces of image-based reconstructions and laser scanning. Accuracy of 3D reconstruction of curly-leaf plants was relatively lower than that of flat-leaf plants. Plant height of three plants and maximum canopy width of cucumber and pepper showed an increasing trend during the 70 d after transplanting. Maximum canopy width of eggplants reached its peak at the 40th day after transplanting. The larger leaf phenotypic parameters of cucumber were mostly found at the middle upper leaf position. Conclusions: High-accuracy 3D evaluation of reconstruction quality indicated that dynamic capture of the 3D canopy based on the MVS approach can be potentially used in 3D phenotyping for applications in breeding and field management. PMID- 29509842 TI - Modified Composite-Flap Facelift Combined With Finger-Assisted Malar Elevation (FAME): A Cadaver Study. AB - Background: Inadequate release of retaining ligaments during facelift surgery may lead to an unnatural appearance. However, most facelift surgeons are hesitant in transecting these ligaments to avoid possible injury to facial subbranches. Objectives: In the authors' surgical practice for modified composite flap rhytidectomy, the authors employed the finger-assisted malar elevation (FAME) technique in order to enable safe release of the zygomatic cutaneous ligaments through the prezygomatic space under direct vision. The aim was to evaluate the anatomical basis and safety measures of this technique through a cadaveric dissection study. Methods: Modified composite-flap facelift with the FAME technique was carried out in 22 fresh cadaver hemi-faces. All facial nerve subbranches were dissected thoroughly to assess for any evidence of injury during facelift, and to evaluate the safety of the operation. The relations among the facial nerve, zygomatic cutaneous and masseteric ligaments, orbicularis oculi muscle, and malar fat pad were investigated. Results: Finger dissection of the prezygomatic space allows safe release of the zygomatic cutaneous ligaments as well as adequate entry to a proper surgical plane above the zygomatici muscles under direct vision, while leaving the malar fat pad and overlying structures attached to the skin without the need of a transblepharoplasty approach. Conclusions: This study by the authors shows that a modified composite-flap facelift with FAME technique is a safe procedure that allows adequate and effective repositioning of an en-bloc composite flap that produces balanced and harmonious rejuvenation of the midface and lower face without the need of a separate midface lift. PMID- 29509843 TI - Bio-Dermal Restoration With Rapidly Polymerizing Collagen: A Multicenter Clinical Study. AB - Background: Despite the increasing popularity of facial contouring with hyaluronic acid, innovation has been limited to iterations that feature different particle sizes, concentrations, and degrees of crosslinking. Bio-dermal restoration is a new approach for correcting facial tissue defects by supplementing the natural dermal structure providing a scaffold for fibroblast adherence and proliferation. Objectives: The purpose of the study was to evaluate the safety of RPC Pure-Collagen for the treatment of facial contours. Methods: A prospective, multicenter, open-label study in 30 patients treated with RPC Pure Collagen in the nasolabial fold and followed up to 12 weeks after injection. A subset of patients was further followed up to 9 months after treatment. RPC Pure Collagen is a sterile, nonpyrogenic, viscous, clear solution composed of pure porcine collagen ethylenediamine tetraacetic acid (EDTA) and Mannitol that can be injected through a 30 gauge needle as a liquid and fibrilizes in situ forming a natural, open 3-dimensional collagen matrix for bio-dermal restoration. Results: No treatment related adverse events were noted in addition to transient injection site reactions typical to injection procedures, which were mild or moderate in severity except for one case of severe bruising. There were no reports of hypersensitivity, supporting that RPC Pure Collagen does not require skin testing prior to treatment. Performance results showed a significant improvement from baseline upon treatment, and at the end of the study, on both the Merz Aesthetic Scale and the Global Aesthetic Improvement Scale assessments. Conclusions: This initial study shows that RPC Pure-Collagen is safe for its use in facial contouring and provides good indication for long-term safety. Bio-dermal restoration with RPC Pure-Collagen holds promise as safe, lasting, and natural facial contouring treatment. Level of Evidence 4: PMID- 29509844 TI - GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC. AB - Motivation: The large-scale multidimensional omics data in the Genomic Data Commons (GDC) provides opportunities to investigate the crosstalk among different RNA species and their regulatory mechanisms in cancers. Easy-to-use bioinformatics pipelines are needed to facilitate such studies. Results: We have developed a user-friendly R/Bioconductor package, named GDCRNATools, for downloading, organizing and analyzing RNA data in GDC with an emphasis on deciphering the lncRNA-mRNA related competing endogenous RNAs regulatory network in cancers. Many widely used bioinformatics tools and databases are utilized in our package. Users can easily pack preferred downstream analysis pipelines or integrate their own pipelines into the workflow. Interactive shiny web apps built in GDCRNATools greatly improve visualization of results from the analysis. Availability and implementation: GDCRNATools is an R/Bioconductor package that is freely available at Bioconductor (http://bioconductor.org/packages/devel/bioc/html/GDCRNATools.html). Detailed instructions, manual and example code are also available in Github (https://github.com/Jialab-UCR/GDCRNATools). PMID- 29509846 TI - The Humans in Health Care-A Review of The American Mercy Tour. PMID- 29509845 TI - Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer. AB - Background: Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. Methods: We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses. Results: We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%). Conclusions: Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs. PMID- 29509847 TI - Scientists Separate Opioids' Analgesic Effects From Their Dangerous Respiratory Effects. PMID- 29509848 TI - Screening for Prostate Cancer: Is the Third Trial the Charm? PMID- 29509849 TI - Safety of Multiple Antigen Exposure in the Childhood Immunization Schedule. PMID- 29509851 TI - First Radioactive Drug for Adults With Rare Cancer. PMID- 29509850 TI - Procalcitonin Testing to Guide Antibiotic Therapy in Acute Upper and Lower Respiratory Tract Infections. AB - Clinical Question: Is the use of procalcitonin for guiding antibiotic decisions in patients with acute upper and lower respiratory tract infections associated with improved clinical outcomes compared with usual care? Bottom Line: Among patients with varying types and severity of acute respiratory infection, using procalcitonin to guide decisions about antibiotics is associated with lower rates of antibiotic exposure, antibiotic-related adverse effects, and mortality. PMID- 29509852 TI - Scrutiny on Animal Research. PMID- 29509853 TI - Crackdown on False Claims to Ease Opioid Withdrawal Symptoms. PMID- 29509854 TI - Peanut Allergy Prevention. PMID- 29509856 TI - The Health of Women Wage Earners. PMID- 29509857 TI - Characteristics of Hospitals Earning Savings in the First Year of Mandatory Bundled Payment for Hip and Knee Surgery. PMID- 29509858 TI - Patient Data Ownership. PMID- 29509859 TI - Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome. PMID- 29509860 TI - Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome. PMID- 29509861 TI - Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome. PMID- 29509862 TI - Patient Data Ownership-Reply. PMID- 29509863 TI - Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome-Reply. PMID- 29509864 TI - Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial. AB - Importance: Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. Objective: To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. Design, Setting, and Participants: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. Intervention: An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. Main Outcomes and Measures: Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. Results: Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95% CI, -0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66). Conclusions and Relevance: Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. Trial Registration: ISRCTN Identifier: ISRCTN92187251. PMID- 29509865 TI - Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer. AB - Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9 10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1% 5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5 year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow up, EBRT+BT was associated with significantly lower all-cause mortality (cause specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70 1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer specific mortality, distant metastasis, or all-cause mortality (<=7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP. PMID- 29509866 TI - Association Between Estimated Cumulative Vaccine Antigen Exposure Through the First 23 Months of Life and Non-Vaccine-Targeted Infections From 24 Through 47 Months of Age. AB - Importance: Some parents are concerned that multiple vaccines in early childhood could weaken their child's immune system. Biological data suggest that increased vaccine antigen exposure could increase the risk for infections not targeted by vaccines. Objective: To examine estimated cumulative vaccine antigen exposure through the first 23 months of life in children with and without non-vaccine targeted infections from 24 through 47 months of age. Design, Setting, and Participants: A nested case-control study was conducted in 6 US health care organizations participating in the Vaccine Safety Datalink. Cases were identified by International Classification of Diseases codes for infectious diseases in the emergency department and inpatient medical settings and then validated by medical record review. Cases of non-vaccine-targeted infection were matched to controls by age, sex, health care organization site, and chronic disease status. Participants were children ages 24 through 47 months, born between January 1, 2003, and September 31, 2013, followed up until December 31, 2015. Exposures: Cumulative vaccine antigen exposure, estimated by summing the number of antigens in each vaccine dose received from birth through age 23 months. Main Outcomes and Measures: Non-vaccine-targeted infections, including upper and lower respiratory infections and gastrointestinal infections, from 24 through 47 months of age, and the association between these infections and estimated cumulative vaccine exposure from birth through 23 months. Conditional logistic regression was used to estimate matched odds ratios representing the odds of non-vaccine-targeted infections for every 30-unit increase in estimated cumulative number of antigens received. Results: Among the 944 patients (193 cases and 751 controls), the mean (SD) age was 32.5 (6.3) months, 422 (45%) were female, and 61 (7%) had a complex chronic condition. Through the first 23 months, the estimated mean (SD) cumulative vaccine antigen exposure was 240.6 (48.3) for cases and 242.9 (51.1) for controls. The between-group difference for estimated cumulative antigen exposure was -2.3 (95% CI, -10.1 to 5.4; P = .55). Among children with vs without non-vaccine-targeted infections from 24 through 47 months of age, the matched odds ratio for estimated cumulative antigen exposure through age 23 months was not significant (matched odds ratio, 0.94; 95% CI, 0.84 to 1.07). Conclusions and Relevance: Among children from 24 through 47 months of age with emergency department and inpatient visits for infectious diseases not targeted by vaccines, compared with children without such visits, there was no significant difference in estimated cumulative vaccine antigen exposure through the first 23 months of life. PMID- 29509868 TI - Anaphylaxis in Children. PMID- 29509867 TI - Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. AB - Importance: Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain. Objective: To compare opioid vs nonopioid medications over 12 months on pain-related function, pain intensity, and adverse effects. Design, Setting, and Participants: Pragmatic, 12 month, randomized trial with masked outcome assessment. Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015; follow-up was completed December 2016. Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use. Of 265 patients enrolled, 25 withdrew prior to randomization and 240 were randomized. Interventions: Both interventions (opioid and nonopioid medication therapy) followed a treat-to-target strategy aiming for improved pain and function. Each intervention had its own prescribing strategy that included multiple medication options in 3 steps. In the opioid group, the first step was immediate-release morphine, oxycodone, or hydrocodone/acetaminophen. For the nonopioid group, the first step was acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual patient response. Main Outcomes and Measures: The primary outcome was pain-related function (Brief Pain Inventory [BPI] interference scale) over 12 months and the main secondary outcome was pain intensity (BPI severity scale). For both BPI scales (range, 0-10; higher scores = worse function or pain intensity), a 1-point improvement was clinically important. The primary adverse outcome was medication-related symptoms (patient reported checklist; range, 0-19). Results: Among 240 randomized patients (mean age, 58.3 years; women, 32 [13.0%]), 234 (97.5%) completed the trial. Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, -0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]). Conclusions and Relevance: Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months. Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain. Trial Registration: clinicaltrials.gov Identifier: NCT01583985. PMID- 29509870 TI - A Ruse on Eternity. PMID- 29509873 TI - MatrixEpistasis: ultrafast, exhaustive epistasis scan for quantitative traits with covariate adjustment. AB - Motivation: For many traits, causal loci uncovered by genetic mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this 'missing heritability' have been proposed. Single nucleotide polymorphism (SNP)-SNP interaction (epistasis), as one of the compelling models, has been widely studied. However, the genome-wide scan of epistasis, especially for quantitative traits, poses huge computational challenges. Moreover, covariate adjustment is largely ignored in epistasis analysis due to the massive extra computational undertaking. Results: In the current study, we found striking differences among epistasis models using both simulation data and real biological data, suggesting that not only can covariate adjustment remove confounding bias, it can also improve power. Furthermore, we derived mathematical formulas, which enable the exhaustive epistasis scan together with full covariate adjustment to be expressed in terms of large matrix operation, therefore substantially improving the computational efficiency (~104* faster than existing methods). We call the new method MatrixEpistasis. With MatrixEpistasis, we re-analyze a large real yeast dataset comprising 11 623 SNPs, 1008 segregants and 46 quantitative traits with covariates fully adjusted and detect thousands of novel putative epistasis with P-values < 1.48e-10. Availability and implementation: The method is implemented in R and available at https://github.com/fanglab/MatrixEpistasis. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29509874 TI - CarbonylDB: a curated data-resource of protein carbonylation sites. AB - Motivation: Oxidative stress and protein damage have been associated with over 200 human ailments including cancer, stroke, neuro-degenerative diseases and aging. Protein carbonylation, a chemically diverse oxidative post-translational modification, is widely considered as the biomarker for oxidative stress and protein damage. Despite their importance and extensive studies, no database/resource on carbonylated proteins/sites exists. As such information is very useful to research in biology/medicine, we have manually curated a data resource (CarbonylDB) of experimentally-confirmed carbonylated proteins/sites. Results: The CarbonylDB currently contains 1495 carbonylated proteins and 3781 sites from 21 species, with human, rat and yeast as the top three species. We have made further analyses of these carbonylated proteins/sites and presented their occurrence and occupancy patterns. Carbonylation site data on serum albumin, in particular, provides a fine model system to understand the dynamics of oxidative protein modifications/damage. Availability and implementation: The CarbonylDB is available as a web-resource and for download at http://digbio.missouri.edu/CarbonylDB/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29509871 TI - The Diagnosis and Management of Thyroid Nodules: A Review. AB - Importance: Thyroid nodules are common, being detected in up to 65% of the general population. This is likely due to the increased use of diagnostic imaging for purposes unrelated to the thyroid. Most thyroid nodules are benign, clinically insignificant, and safely managed with a surveillance program. The main goal of initial and long-term follow-up is identification of the small subgroup of nodules that harbor a clinically significant cancer (~10%), cause compressive symptoms (~5%), or progress to functional disease (~5%). Observations: Thyroid function testing and ultrasonographic characteristics guide the initial management of thyroid nodules. Certain ultrasound features, such as a cystic or spongiform appearance, suggest a benign process that does not require additional testing. Suspicious sonographic patterns including solid composition, hypoechogenicity, irregular margins, and microcalcifications should prompt cytological evaluation. Additional diagnostic procedures, such as molecular testing, are indicated only in selected cases, such as indeterminate cytology (~20%-30% of all biopsies). The initial risk estimate, derived from ultrasound and, if performed, cytology report, should determine the need for treatment and the type, frequency, and length of subsequent follow-up. Management includes simple observation, local treatments, and surgery and should be based on the estimated risk of malignancy and the presence and severity of compressive symptoms. Conclusions and Relevance: Most thyroid nodules are benign. A diagnostic approach that uses ultrasound and, when indicated, fine-needle aspiration biopsy and molecular testing, facilitates a personalized, risk-based protocol that promotes high-quality care and minimizes cost and unnecessary testing. PMID- 29509875 TI - Can a Mediterranean Diet Pattern Slow Aging? PMID- 29509876 TI - Journal of Gerontology: Biological Sciences. A Long Tradition in Advancing Aging Biology and Translational Gerontology. PMID- 29509878 TI - Cardiac diffusion-weighted magnetic resonance imaging for assessment of cardiac metastasis. PMID- 29509877 TI - Sex Difference in Meningococcal Disease Mortality, New York City, 2008-2016. AB - Background: The case fatality rate (CFR) from invasive meningococcal disease (IMD) in New York City (NYC) is greater than national figures, with higher rates among females than males across all age groups. Methods: We conducted a retrospective cohort study among 151 persons aged >=15 years diagnosed with IMD in NYC during 2008-2016 identified through communicable disease surveillance. We examined demographic, clinical, and community-level associations with death to confirm the elevated risk of mortality among female IMD patients after adjusting for confounders and to determine factors associated with female IMD mortality. Relative risks of death were estimated using multivariable log-linear Poisson regression with a robust error variance. Results: Females had a higher CFR (n = 23/62; 37%) following IMD than males (n = 17/89; 19%) (adjusted relative risk [aRR], 2.1; 95% confidence interval [CI], 1.2-3.8). Controlling for demographic and clinical factors, there was a significant interaction between sex and fatal outcomes related to meningitis: the relative risk of death for females with meningitis was 13.7 (95% CI, 3.2-58.1) compared with males. In the model restricted to females, altered mental status (aRR, 7.5; 95% CI, 2.9-19.6) was significantly associated with an increased risk of death. Conclusions: Female mortality from IMD was significantly increased compared with males, controlling for other predictors of mortality. Sex-based differences in recognition and treatment need to be evaluated in cases of meningococcal disease. Our study highlights the importance of analyzing routine surveillance data to identify and address disparities in disease incidence and outcomes. PMID- 29509879 TI - Chronic Type I and Type III aortic dissections: a propensity analysis of outcomes after open distal repair. AB - OBJECTIVES: To compare short-term outcomes, long-term survival and reinterventions in patients requiring surgery after chronic Type I and chronic primary Type III aortic dissections. METHODS: Over an 11-year period, 466 patients underwent thoraco-abdominal aortic aneurysm repair for chronic Type III (n = 239) and Type I (n = 227) aortic dissections. Short-term outcomes and reinterventions were evaluated by multivariable regression analysis for the entire group; propensity matching produced 169 pairs. RESULTS: Mortality was 6% (n = 28) in the overall cohort and 6.2% (n = 14) and 5.9% (n = 14) in those with chronic Type I and Type III aortic dissections, respectively. Overall stroke and persistent spinal cord deficit rates were 4.0% and 2.6%, respectively, in the Type I group and 1.3% and 3.8% in the Type III group. In the propensity-matched patients, analysis showed no neurological differences between the 2 groups, but respiratory failure was significantly more frequent in the chronic Type I group (30.2% vs 15.4%; P = 0.001). Multivariable analysis identified chronic Type I dissection as an independent risk factor for postoperative pulmonary complications (odds ratio 1.612; 95% confidence interval 1.060-2.452; P = 0.026) and an association between chronic Type I dissection and stroke (odds ratio 4.013; 95% confidence interval 1.026-15.698; P = 0.046). Six-year survival was 74.4% +/- 4.1% and 74.4% +/- 4.6% in the chronic Type I and Type III groups, respectively (P = 0.87). CONCLUSIONS: Short- and long-term mortality and reintervention rates were comparable after open repair for chronic Type I and primary chronic Type III aortic dissections. Respiratory failure was more frequent in the chronic Type I aortic dissection group. PMID- 29509880 TI - Acetylcholine Modulates the Hormones of the Growth Hormone/Insulinlike Growth Factor-1 Axis During Development in Mice. AB - Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and somatostatin (SRIF), and a gastrointestinal hormone, ghrelin. The neurotransmitter acetylcholine (ACh) is involved in tuning GH secretion, and its GH-stimulatory action has mainly been shown in adults but is not clearly documented during development. ACh, together with these hormones and their receptors, is expressed before birth, and somatotroph cells are already responsive to GHRH, SRIF, and ghrelin. We thus hypothesized that ACh could contribute to the modulation of the main components of the somatotropic axis during development. In this study, we generated a choline acetyltransferase knockout mouse line and showed that heterozygous mice display a transient deficit in ACh from embryonic day 18.5 to postnatal day 10, and they recover normal ACh levels from the second postnatal week. This developmental ACh deficiency had no major impact on weight gain and cardiorespiratory status of newborn mice. Using this mouse model, we found that endogenous ACh levels determined the concentrations of circulating GH and IGF-1 at embryonic and postnatal stages. In particular, serum GH level was correlated with brain ACh content. ACh also modulated the levels of GHRH and SRIF in the hypothalamus and ghrelin in the stomach, and it affected the levels of these hormones in the circulation. This study identifies ACh as a potential regulator of the somatotropic axis during the developmental period. PMID- 29509881 TI - Over-expression of mitochondrial creatine kinase in the murine heart improves functional recovery and protects against injury following ischaemia-reperfusion. AB - Aims: Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of ATP at times of high demand. We hypothesized that elevating MtCK would be beneficial in ischaemia-reperfusion (I/R) injury. Methods and results: Mice were created over-expressing the sarcomeric MtCK gene with alphaMHC promoter at the Rosa26 locus (MtCK-OE) and compared with wild-type (WT) littermates. MtCK activity was 27% higher than WT, with no change in other CK isoenzymes or creatine levels. Electron microscopy confirmed normal mitochondrial cell density and mitochondrial localization of transgenic protein. Respiration in isolated mitochondria was unaltered and metabolomic analysis by 1 H-NMR suggests that cellular metabolism was not grossly affected by transgene expression. There were no significant differences in cardiac structure or function under baseline conditions by cine-MRI or LV haemodynamics. In Langendorff-perfused hearts subjected to 20 min ischaemia and 30 min reperfusion, MtCK-OE exhibited less ischaemic contracture, and improved functional recovery (Rate pressure product 58% above WT; P < 0.001). These hearts had reduced myocardial infarct size, which was confirmed in vivo: 55 +/- 4% in WT vs. 29 +/- 4% in MtCK-OE; P < 0.0001). Isolated cardiomyocytes from MtCK-OE hearts exhibited delayed opening of the mitochondrial permeability transition pore (mPTP) compared to WT, which was confirmed by reduced mitochondrial swelling in response to calcium. There was no detectable change in the structural integrity of the mitochondrial membrane. Conclusions: Modest elevation of MtCK activity in the heart does not adversely affect cellular metabolism, mitochondrial or in vivo cardiac function, but modifies mPTP opening to protect against I/R injury and improve functional recovery. Our findings support MtCK as a prime therapeutic target in myocardial ischaemia. PMID- 29509882 TI - Second N-ECCO Consensus Statements on the European Nursing Roles in Caring for Patients with Crohn's Disease or Ulcerative Colitis. PMID- 29509883 TI - A mystery of the myocardial microcirculation during coronary artery bypass grafting. PMID- 29509884 TI - Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study. AB - Background: Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes. Objectives: In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4alpha) related to sofosbuvir transport. Patients and methods: Allelic discrimination was performed through real-time PCR, whereas plasma concentrations were evaluated through liquid chromatography. One hundred and thirteen patients were enrolled. Results: Sofosbuvir concentrations were below the limit of quantification since the drug was converted into its GS-331007 metabolite. ABCB1 2677 G>T (P = 0.044) and HNF4alpha 975 C>G (P = 0.049) SNPs were associated with GS-331007 metabolite plasma concentrations. In linear multivariate analysis, liver stiffness, insulin resistance, baseline haemoglobin and haematocrit and SNPs in the ABCB1 gene (3435 CT/TT and 1236 TT genotypes) were significant predictors of GS-331007 concentrations. Furthermore, we performed sub-analyses considering the anti-HCV concomitant drug and HCV genotype, identifying specific polymorphisms associated with GS-331007 plasma concentrations: ABCB1 3435 C>T and HNF4alpha975 C>G in patients treated with daclatasvir, ABCB1 2677 G>T with ledipasvir and ABCB1 3435 C>T, ABCB1 2677 G>T, ABCG2 421 C>A and ABCG2 1194 + 928 C>A with ribavirin. Conclusions: In this study we suggested sofosbuvir GS-331007 metabolite plasma levels were affected by variants in the ABCB1 and HNFalpha genes. PMID- 29509885 TI - Is smoking heaviness causally associated with alcohol use? A Mendelian randomization study in four European cohorts. AB - Background: Observational studies have shown that tobacco and alcohol use co occur, but it is not clear whether this relationship is causal. Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we used observational methods to test the hypothesis that smoking heaviness increases alcohol consumption. Mendelian randomization (MR) analyses were then used to test the causal relationship between smoking heaviness and alcohol consumption using 55 967 smokers from four European studies [ALSPAC, The Nord-Trondelag Health Study (HUNT), the Copenhagen General Population Study (CGPS) and UK Biobank]. MR analyses used rs1051730/rs16969968 as a genetic proxy for smoking heaviness. Results: Observational results provided evidence of an association between cigarettes per day and weekly alcohol consumption (increase in units of alcohol per additional cigarette smoked per day = 0.10, 95% confidence interval (CI) 0.05 to 0.15, P <= 0.001 in ALSPAC; and 0.48, 95% CI 0.45 to 0.52, P <= 0.001 in UK Biobank). However, there was little evidence for an association between rs1051730/rs16969968 and units of alcohol consumed per week across ALSPAC, HUNT, CGPS and UK Biobank (standard deviation increase in units of alcohol per additional copy of the risk allele = -0.004, 95% CI -0.023 to 0.016, P=0.708, I2 = 51.9%). We had 99% and 88% power to detect a change of 0.03 and 0.02 standard deviation units of alcohol per additional copy of the risk allele, respectively. Conclusions: Previously reported associations between smoking and alcohol are unlikely to be causal, and may be the result of confounding and/or reverse causation. This has implications for public health research and intervention research. PMID- 29509887 TI - Toxic Elements in Human Saliva of Smokeless Tobacco Users. AB - The occurrence and mobility of different elements in oral smokeless tobacco products (STPs) were determined because the effects on human health must take into account their availability. In this research, the elemental analysis of 15 oral STPs of different brands purchased in local specialty stores in Europe, and the determination of % extraction of the different elements into an artificial salivary juice during the sucking or chewing operations were performed. In all samples analyzed, cobalt (Co) and chromium (Cr) (total) levels were <0.326 mg/kg. As far as non-essential or toxic elements, U was always <1.0 mg/kg, Th and Ti <0.1 mg/kg, Cd was <0.5. Pb was detectable in 60% of the samples, As in 33.3% and Ce in 20% of the samples; La was <1 mg/kg in 13 samples; Sb was <5 mg/kg in all sample with exception of sample 13; Al, Ni, Sr, Rb, Ba, Sn, Te, Ti and Hg were detectable in all samples. Using artificial saliva, the data of extractable levels show that the toxic elements, although poorly extracted, are not totally retained within the STPs, with a consequent potential health hazard associated with oral use of these products. PMID- 29509886 TI - Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. PMID- 29509888 TI - Effect of packaging type during postmortem aging and degree of doneness on pork chop sensory traits of loins selected to vary in color and marbling. AB - The objective was to determine the interactions between packaging type and degree of doneness on sensory traits of pork loins classified based on the newly proposed USDA quality grades. A total of 144 loins were selected from 2 groups of pigs (lean growth or meat quality production focus) to represent as much variation in visual color and marbling as possible. Selection was achieved with a VQG grading camera. The ventral surface of the loins was evaluated for loin quality traits at 1 d postmortem. At 2 d postmortem loins were sliced into 28-mm thick chops. Chop within each loin was randomly assigned to either individual vacuum packages or to individual Styrofoam trays and overwrapped in polyvinyl chloride (PVC) oxygen permeable film. Overwrapped PVC packages were then placed in bulk packages and flushed with a gas mixture that contained approximately 0.4% carbon monoxide, 30% carbon dioxide, and 80% nitrogen. Vacuum-packaged chops were aged until 14 d postmortem. Chops packaged in PVC overwrap were aged until 9 d postmortem in the bulk packages, then placed on simulated retail display until 14 d postmortem. Chops from each packaging type were cooked to an internal temperature of either 63 degrees C or 71 degrees C for the evaluation of slice shear force (SSF) or for evaluation of tenderness, juiciness, and flavor by a trained panel. Data were analyzed as split-split plot design with production focus of the pigs, proposed USDA quality grade, packaging type, and degree of doneness as fixed effects. While there were main effect differences between production focuses, there were no interactions with production focus. There were also no 3-way (P >= 0.19) interactions and only one 2-way interaction among quality grade, packaging type, or degree of doneness. There were no differences in sensory tenderness (P = 0.30), juiciness (P = 0.49), flavor (P = 0.89), SSF (P = 0.13), or cook loss (P = 0.06) among USDA quality grades. There were no differences in sensory tenderness (P = 0.06), juiciness (P = 0.32), flavor (P = 0.74), SSF (P = 0.99), or cook loss (P = 0.12) between chops aged in vacuum packages or PVC packages. Chops cooked to 63 degrees C were 4.6% more tender (P < 0.0001), 10.1% juicier (P < 0.0001), and 2.9% less flavorful (P = 0.01) than chops cooked to 71 degrees C. These data suggest that cooking chops to 63 degrees C rather than 71 degrees C was a more effective way to improve tenderness and juiciness than selecting chops of a certain quality grade or altering packaging postmortem. PMID- 29509889 TI - Effects of Pre-exposure Prophylaxis for the Prevention of Human Immunodeficiency Virus Infection on Sexual Risk Behavior in Men Who Have Sex With Men: A Systematic Review and Meta-analysis. AB - Background: Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is effective in reducing HIV risk in men who have sex with men (MSM). However, concerns remain that risk compensation in PrEP users may lead to decreased condom use and increased incidence of sexually transmitted infections (STIs). We assessed the impact of PrEP on sexual risk outcomes in MSM. Methods: We conducted a systematic review of open-label studies published to August 2017 that reported sexual risk outcomes in the context of daily oral PrEP use in HIV-negative MSM and transgender women. Pooled effect estimates were calculated using random effects meta-analysis, and a qualitative review and risk of bias assessment were performed. Results: Sixteen observational studies and 1 open-label trial met selection criteria. Eight studies with a total of 4388 participants reported STI prevalence, and 13 studies with a total of 5008 participants reported change in condom use. Pre-exposure prophylaxis use was associated with a significant increase in rectal chlamydia (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.13) and an increase in any STI diagnosis (OR, 1.24; 95% CI, .99 1.54). The association of PrEP use with STI diagnoses was stronger in later studies. Most studies showed evidence of an increase in condomless sex among PrEP users. Conclusion: Findings highlight the importance of efforts to minimize STIs among PrEP users and their sexual partners. Monitoring of risk compensation among MSM in the context of PrEP scale-up is needed to assess the impact of PrEP on the sexual health of MSM and to inform preventive strategies. PMID- 29509890 TI - Long-term outcome of a mental health promotion program in Germany. AB - Mental health promotion programs (MHP) seek to reduce sub-syndromal symptoms of mental distress and enhance positive mental health. This study evaluates the long term effects of a mindfulness-based MHP program ('Life Balance') provided by health coaches in a multi-site field setting on mental distress, satisfaction with life and resilience. Using a controlled design, propensity score matching was used to select a control group for participants of the MHP. The total study sample (N = 3624) comprised 83% women, with a mean age of 50 years. Data was collected via mailings 1 year after study entry. Results suggest participants experience reduced emotional distress at 12-month follow-up, with a medium between-group effect size (d = 0.40) for those participants who showed clinically relevant symptoms of mental distress at study entry. The effects of the program were more pronounced in participants with higher initial distress scores. New cases of psychopathological symptoms were prevented in 1 of 16 participants. Satisfaction with life and resilience were enhanced significantly. Our data suggest 'Life Balance' shows long-term effectiveness and indicate it is possible to design MHP programs that serve as both primary and indicated prevention, and that these programs can be applied on a population basis. PMID- 29509891 TI - Key factors for school health policy implementation in Thailand. AB - Thailand formulated a National School Health Policy (NSHP) in 1998, and it has been widely implemented but has not been evaluated. This case study aimed to identify factors that have influenced the implementation of NSHP in Thailand. For this purpose, we conducted a document review and key informant interviews. We selected key interviewees, from NSHP implementers at national, provincial and school levels in four geographical areas. We adopted a content analysis method, using a framework of 12 influential components of successful policy implementation and triangular policy framework. This study showed that NSHP was well-disseminated and implemented at whole country. We identified seven positive factors influencing NSHP implementation, namely matching with ongoing educational strategy, competition and encouragement by an awarding system, sustainable human capacity building at school level, participation of multiple stakeholders, sufficient understanding and acceptance of school health concepts, sharing information and collaboration among schools in the same clusters and functional fund raising activities. In addition, we identified three negative factors, namely lack of institutional sustainability, vague role of provincial officers and diverse health problems among Thai children. The government should clarify the role of provincial level and set up institutionalized capacity-building system as measures to strengthen monitoring and evaluation activities. PMID- 29509892 TI - Surgical treatment versus conventional chest tube drainage in primary spontaneous pneumothorax: a randomized controlled trial. AB - OBJECTIVES: Primary spontaneous pneumothorax frequently recurs after chest tube management. Evidence is lacking whether patients may benefit from surgery following their first episode. METHODS: We performed a multicentre, randomized trial and enrolled young, otherwise healthy patients admitted with their first episode of primary spontaneous pneumothorax and treated using conventional chest tube drainage. Patients underwent high-resolution computed tomography on fully expanded lungs, and using web-based randomization, we assigned patients to continued conservative chest tube treatment or chest tube treatment followed by video-assisted thoracoscopic surgery (VATS) with the resection of bullae/blebs and mechanical pleurodesis. Patients were stratified into 2 groups based on the presence of bullae >=1 cm on high-resolution computed tomography. The primary end point was readmission with ipsilateral recurrence. Secondary end points were complications and length of hospitalization. RESULTS: Between 1 August 2009 and 4 November 2016, we screened 457 patients, of whom 373 were eligible for inclusion and 181 were enrolled: male/female ratio = 5.0. We identified 88 patients with blebs <1 cm: 50 were randomly assigned to chest tube treatment and 38 to VATS. Ninety-three patients had bullae >=1 cm: 43 were randomly assigned to chest tube treatment and 50 to VATS. Forty-three (23.8%) patients experienced recurrence during the follow-up period. Overall, recurrence was significantly lower following VATS when compared with conventional chest tube treatment (P = 0.0012). When stratified by bullae size, VATS proved significantly better for bullae >=1 cm (P = 0.014). We observed a size-response relationship with increased risk of recurrence for larger bullae (P = 0.013). CONCLUSIONS: Surgery was an effective treatment to prevent recurrence in patients with their first presentation of primary spontaneous pneumothorax and should be the standard of care when high resolution computed tomography demonstrates bullae >=2 cm. Clinical trial registration: ClinicalTrial.gov: NCT 02866305. PMID- 29509893 TI - A cohort study of cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy. PMID- 29509894 TI - Incomplete Recovery of CD4 Cell Count, CD4 Percentage, and CD4/CD8 Ratio in Patients With Human Immunodeficiency Virus Infection and Suppressed Viremia During Long-term Antiretroviral Therapy. AB - Background: The extent and duration of long-term recovery of CD4 count, CD4 percentage (CD4%), and CD4/CD8 ratio after initiation of combination antiretroviral therapy (cART) in patients with a suppressed viral load (VL) are largely unknown. Methods: Patients infected with human immunodeficiency virus type 1 who started cART between January 2004 and January 2012 and showed persistent viral suppression (VL, <200 copies/mL) for >=4 years were followed up at the AIDS Clinical Center in Tokyo. Change point analysis was used to determine the time point when CD4 count recovery shows a plateau, and a linear mixed model was applied to estimate the CD4 count at this change point. Results: Data were analyzed from 752 patients (93% male; median age, 38 years; median baseline CD4 cell count, 172/uL [interquartile range CD4%, 13.8%]; CD4/CD8 ratio, 0.23). The median follow-up period was 81.2 months, and 91 patients (12.1%) were followed up for >10 years. Change point analysis showed that CD4 count, CD4%, and CD4/CD8 ratio continued to increase until 78.6, 62.2, and 64.3 months, respectively, with adjusted means of 590/uL (95% confidence interval, 29.5%, and 0.89, respectively, at the change point. Although CD4 counts >=500/MUL were achieved in 73.8% of the study patients, they were not achieved in 48.2% of those with a baseline CD4 count <100/MUL. Neither the CD4% nor the CD4/CD8 ratio were normalized in a majority of patients. Conclusions: The results showed lack of normalization of CD4 count, CD4%, and CD4/CD8 ratio to the levels seen in healthy individuals even after long-term successful cART in patients with a suppressed VL. PMID- 29509895 TI - Corrigendum to: The year in cardiology 2017: heart failure. PMID- 29509896 TI - GAIT: Gene expression Analysis for Interval Time. AB - Motivation: Despite the potential usefulness, the association analysis of gene expression with interval times of two events has been hampered because the occurrence of events can be censored and the conventional survival analysis is not suitable to handle two censored events. However, the recent advances of multivariate survival analysis considering multiple censored events together provide an unprecedented chance for this problem. Based on such advances, we have developed a software tool, GAIT, for the association analysis of gene expression with interval time of two events. Results: The performance of GAIT was demonstrated by simulation studies and the real data analysis. The result indicates the usefulness of GAIT in a wide range of biomedical applications. Availability and implementation: http://cdal.korea.ac.kr/GAIT/index.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29509897 TI - Identifying Ant-Mirid Spatial Interactions to Improve Biological Control in Cacao Based Agroforestry System. AB - The use of ants for biological control of insect pests was the first reported case of conservation biological control. Direct and indirect community interactions between ants and pests lead to differential spatial pattern. We investigated spatial interactions between mirids, the major cocoa pest in West Africa and numerically dominant ant species, using bivariate point pattern analysis to identify potential biological control agents. We assume that potential biological control agents should display negative spatial interactions with mirids considering their niche overlap. The mirid/ant data were collected in complex cacao-based agroforestry systems sampled in three agroecological areas over a forest-savannah gradient in Cameroon. Three species, Crematogaster striatula Emery (Hymenoptera: Formicidae), Crematogaster clariventris Mayr (Hymenoptera: Formicidae), and Oecophylla longinoda Latreille (Hymenoptera: Formicidae) with high predator and aggressive behaviors were identified as dominant and showed negative spatial relationships with mirids. The weaver ant, O. longinoda was identified as the only potential biological control agent, considering its ubiquity in the plots, the similarity in niche requirements, and the spatial segregation with mirids resulting probably from exclusion mechanisms. Combining bivariate point pattern analysis to good knowledge of insect ecology was an effective method to identify a potentially good biological control agent. PMID- 29509898 TI - TSC2 regulates microRNA biogenesis via mTORC1 and GSK3beta. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline inactivating mutations of TSC1 or TSC2. In TSC-associated tumors of the brain, heart, skin, kidney and lung, inactivation of both alleles of TSC1 or TSC2 leads to hyperactivation of the mTORC1 pathway. The TSC/mTORC1 pathway is a key regulator of cellular processes related to growth, proliferation and autophagy. We and others have previously found that mTORC1 regulates microRNA biogenesis, but the mechanisms are not fully understood. Microprocessor, a multi-protein complex including the nuclease Drosha, processes the primary miR transcript. Using a dual-luciferase reporter, we found that inhibition of mTORC1 or downregulation of Raptor decreased Microprocessor activity, while loss of TSC2 led to a striking increase (~5-fold) in Microprocessor activity. To determine the global impact of TSC2 on microRNAs we quantitatively analyzed 752 microRNAs in Tsc2-expressing and Tsc2-deficient cells. Out of 259 microRNAs expressed in both cell lines, 137 were significantly upregulated and 24 were significantly downregulated in Tsc2-deficient cells, consistent with the increased Microprocessor activity. Microprocessor activity is known to be regulated in part by GSK3beta. We found that total GSK3beta levels were higher in Tsc2-deficient cells, and the increase in Microprocessor activity associated with Tsc2 loss was reversed by three different GSK3beta inhibitors. Furthermore, mTOR inhibition increased the levels of phospho-GSK3beta (S9), which negatively affects Microprocessor activity. Taken together these data reveal that TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3beta. PMID- 29509899 TI - Exposure of Honey Bee (Apis mellifera L.) Colonies to Pesticides in Pollen, A Statewide Assessment in Maine. AB - In 2015, we conducted a statewide assessment of honey bee exposure to pesticides with assistance of volunteer beekeepers. Pollen trapping was conducted at 32 sites in the spring, summer, and early fall. Apiary locations ranged from unmanaged natural landscapes to managed agricultural or urban landscapes. Pollen samples at each site were aggregated over the collection dates and chemical residue analysis was conducted on each pollen sample for 190 pesticides and metabolites using HPLC/MS. Twenty-five different residues were detected for an average of 2.9 detections per site. Detections were dominated by fungicides, but risk, calculated as: ppb residue concentration/LD50, was mostly due to insecticides. Beekeeper perceived land-use in the vicinity of each apiary was associated with significant differences in the number of detections and residue concentrations, agricultural landscapes greater than nonagricultural. However, there was no significant difference in oral or contact risk quotients due to land use type. The landscape composition surrounding apiaries, derived with GIS, determined pesticide exposure for honey bees when total detections, log pesticide residue concentration, and log contact risk quotients were used as measures. Partial least squares explained 43.9% of the variance in pesticide exposure due to landscape composition. The best predictors describing pesticide exposure were: area (ha) of blueberry, coniferous forest, and urban/developed land cover types. Maine is the most forested state in the United States (as determined by % land area forested, 93%) and a negative exponential decay was observed between land area in conifer forest and the number of pesticide detections per apiary. PMID- 29509901 TI - Apolipoprotein E DNA methylation and late-life disease. AB - Background: This study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimers disease (AD) or cardiovascular disease (CVD). Methods: DNA methylation across the APOE gene has previously been categorized into three distinct regions: a hypermethylated region in the promoter, a hypomethylated region in the first two introns and exons and a hypermethylated region in the 3'exon that also harbours the APOE epsilon2 and epsilon4 alleles. DNA methylation levels in leukocytes were measured using the Illumina 450K array in 447 Swedish twins (mean age 78.1 years). We used logistic regression to investigate whether methylation levels in those regions affect the odds of disease. Results: We found that methylation levels in the promoter region were associated with dementia and AD after adjusting for sex, age at blood draw, education, smoking and relatedness among twins [odds ratio (OR) 1.32 per standard deviation increase in methylation levels, 95% confidence interval (CI) 1.08-1.62 for dementia; OR 1.38, 95% CI 1.07 1.78 for AD). We did not detect any difference in methylation levels between CVD cases and controls. Results were similar when comparing within discordant twin pairs, and did not differ as a function of APOE genotype. Conclusions: We found that higher DNA methylation levels in the promoter region of APOE increase the odds of dementia and AD, but not CVD. The effect was independent of APOE genotype, indicating that allelic variation and methylation variation in APOE may act independently to increase the risk of dementia. PMID- 29509900 TI - A genetic modifier suggests that endurance exercise exacerbates Huntington's disease. AB - Polyglutamine expansions in the huntingtin gene cause Huntington's disease (HD). Huntingtin is ubiquitously expressed, leading to pathological alterations also in peripheral organs. Variations in the length of the polyglutamine tract explain up to 70% of the age-at-onset variance, with the rest of the variance attributed to genetic and environmental modifiers. To identify novel disease modifiers, we performed an unbiased mutagenesis screen on an HD mouse model, identifying a mutation in the skeletal muscle voltage-gated sodium channel (Scn4a, termed 'draggen' mutation) as a novel disease enhancer. Double mutant mice (HD; Scn4aDgn/+) had decreased survival, weight loss and muscle atrophy. Expression patterns show that the main tissue affected is skeletal muscle. Intriguingly, muscles from HD; Scn4aDgn/+ mice showed adaptive changes similar to those found in endurance exercise, including AMPK activation, fibre type switching and upregulation of mitochondrial biogenesis. Therefore, we evaluated the effects of endurance training on HD mice. Crucially, this training regime also led to detrimental effects on HD mice. Overall, these results reveal a novel role for skeletal muscle in modulating systemic HD pathogenesis, suggesting that some forms of physical exercise could be deleterious in neurodegeneration. PMID- 29509902 TI - Contrasting Patterns of Population History and Seed-mediated Gene Flow in Two Endemic Costa Rican Oak Species. AB - Lower Central America is an important area to study recent population history and diversification of Neotropical species due to its complex and dynamic geology and climate. Phylogeographic studies in this region are few in comparison with other regions and even less for tree species. The aim of the present study was to characterize the phylogeographic structure in 2 partially co-distributed endemic oak species (Quercus costaricensis and Q. bumelioides) of the Costa Rican mountains using chloroplast short sequence repeats (cpSSRs), and to test for the effect of geological and palaeoclimatic processes on their population history. Genetic diversity and structure, haplotype networks, patterns of seed-mediated gene flow and historical demography were estimated for both species. Results suggested contrasting patterns. Quercus costaricensis exhibited high values of genetic diversity, a marked phylogeographic structure, a north-to-south genetic diversity gradient and evidence of a demographic expansion during the Quaternary. Quercus bumelioides did not show significant genetic structure and the haplotype network and historical demography estimates suggested a recent population expansion probably during the Pleistocene-Holocene transition. The phylogeographic structure of Q. costaricensis seems to be related to Pleistocene altitudinal migration due to its higher altitudinal distribution. Meanwhile, historical seed-mediated gene flow through the lower altitudinal distribution of Q. bumelioides may have promoted the homogenization of genetic variation. Population expansion and stable availability of suitable climatic areas in both species probably indicate that palaeoclimatic changes promoted downwards altitudinal migration and formation of continuous forests allowing oak species to expand their distribution into the Panamanian mountains during glacial stages. PMID- 29509903 TI - A cohort study of cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy. AB - Aims: Cardiac resynchronization therapy (CRT) is an established procedure for patients with heart failure. However, trials evaluating its efficacy did not include patients with chronic Chagas cardiomyopathy (CCC). We aimed to assess the role of CRT in a cohort of patients with CCC. Methods and results: This retrospective study compared the outcomes of CCC patients who underwent CRT with those of dilated (DCM) and ischaemic cardiomyopathies (ICM). The primary endpoint was all-cause mortality and the secondary endpoints were the rate of non-advanced New York Heart Association (NYHA) class 12 months after CRT and echocardiographic changes evaluated at least 6 months after CRT. There were 115 patients in the CCC group, 177 with DCM, and 134 with ICM. The annual mortality rates were 25.4%, 10.4%, and 11.3%, respectively (P < 0.001). Multivariate analysis adjusted for potential confounders showed that the CCC group had a two-fold [hazard ratio 2.34 (1.47-3.71), P < 0.001] higher risk of death compared to the DCM group. The rate of non-advanced NYHA class 12 months after CRT was significantly higher in non CCC groups than in the CCC group (DCM 74.0% vs. ICM 73.9% vs. 56.5%, P < 0.001). Chronic Chagas cardiomyopathy and ICM patients had no improvement in the echocardiographic evaluation, but patients in the DCM group had an increase in left ventricular ejection fraction and a decrease in left ventricular end diastolic diameter. Conclusion: This study showed that CCC patients submitted to CRT have worse prognosis compared to patients with DCM and ICM who undergo CRT. Studies comparing CCC patients with and without CRT are warranted. PMID- 29509904 TI - Adventitial cystic disease of the common femoral vein misdiagnosed as deep vein thrombosis. AB - We report a case of venous adventitial cystic disease of the right common femoral vein, misdiagnosed as deep vein thrombosis before surgery in a 47-year-old woman who presented with swelling and heaviness in her right leg. Complete cyst wall resection and common femoral vein reconstruction via patch angioplasty were performed. The patient's postoperative course was uneventful. PMID- 29509905 TI - Dysregulation of TBX1 dosage in the anterior heart field results in congenital heart disease resembling the 22q11.2 duplication syndrome. AB - Non-allelic homologous recombination events on chromosome 22q11.2 during meiosis can result in either the deletion (22q11.2DS) or duplication (22q11.2DupS) syndrome. Although the spectrum and frequency of congenital heart disease (CHD) are known for 22q11.2DS, there is less known for 22q11.2DupS. We now evaluated cardiac phenotypes in 235 subjects with 22q11.2DupS including 102 subjects we collected and 133 subjects that were previously reported as a confirmation and found 25% have CHD, mostly affecting the cardiac outflow tract (OFT). Previous studies have shown that global loss or gain of function (LOF; GOF) of mouse Tbx1, encoding a T-box transcription factor mapping to the region of synteny to 22q11.2, results in similar OFT defects. To further evaluate Tbx1 function in the progenitor cells forming the cardiac OFT, termed the anterior heart field, Tbx1 was overexpressed using the Mef2c-AHF-Cre driver (Tbx1 GOF). Here we found that all resulting conditional GOF embryos had a persistent truncus arteriosus (PTA), similar to what was previously reported for conditional Tbx1 LOF mutant embryos. To understand the basis for the PTA in the conditional GOF embryos, we found that proliferation in the Mef2c-AHF-Cre lineage cells before migrating to the heart, was reduced and critical genes were oppositely changed in this tissue in Tbx1 GOF embryos versus conditional LOF embryos. These results suggest that a major function of TBX1 in the AHF is to maintain the normal balance of expression of key cardiac developmental genes required to form the aorta and pulmonary trunk, which is disrupted in 22q11.2DS and 22q11.2DupS. PMID- 29509906 TI - Reduced Levels of Anti-Ageing Hormone Klotho Predict Renal Function Decline in Type 2 Diabetes. AB - Context and Objective: Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) with relatively preserved renal function is unknown. Design, Setting, Participants, and Measurements: Single-center observational follow-up study of 101 patients with T2DM and eGFR >45 mL/min [91% on renin angiotensin system (RAS) blockade] followed for a median of 9 years (range, 2 to 13 years). Main Outcome: Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, and fibroblast growth factor-23 levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements. Results: Patients with residual microalbuminuria (MA) despite RAS blockade (n = 53) had significantly lower levels of sKlotho [median, 184.7 pg/mL; interquartile range (IQR), 130.5 to 271.8 pg/mL) compared with patients without MA (n = 39; median, 235.2 pg/mL; IQR, 172.0 to 289.4 pg/mL; P = 0.03). Of the cohort, 21% reached the primary outcome. In a competing risk analysis, a 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.52; P < 0.001] independent of traditional risk factors. Patients with sKlotho below the median of 204.4 pg/mL had nearly a fourfold higher cumulative incidence of the primary outcome compared with those above the median (24% vs 6.2%; P = 0.01). Conclusions: In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM. PMID- 29509907 TI - Patterns of Interindividual Variability in the Antibody Repertoire Targeting Proteins Across the Epstein-Barr Virus Proteome. AB - Background: Little is known about variation in antibody responses targeting the full spectrum of Epstein-Barr virus (EBV) proteins and how such patterns inform disease risk. Methods: We used a microarray to measure immunoglobulin G (IgG) and immunoglobulin A (IgA) antibody responses against 199 EBV protein sequences from 5 EBV strains recovered from 289 healthy adults from Taiwan. We described positivity patterns, estimated the correlation between antibodies, and investigated the associations between environmental and genetic risk factors and variations in antibody responses. Results: Healthy adults were more likely to mount IgG antibody responses to EBV proteins (median positivity frequency, 46.5% for IgG and 17.3% for IgA; P = 1.6 * 10-46, by the Wilcoxon rank sum test). Responses against glycoproteins were particularly prevalent. The correlations between antibody responses of the same class were higher than correlations across classes. The mucosal exposure to proteins involved in EBV reactivation (as determined by the IgA response) was associated with smoking (P = .002, by the sequence kernel association test-combined), and approximately one quarter of adults displayed antibody responses associated with EBV-related cancer risk. Conclusions: These data comprehensively define the variability in human IgG and IgA antibody responses to the EBV proteome. Patterns observed can serve as the foundation for elucidating which individuals are at highest risk of EBV associated clinical conditions and for identifying targets for effective immunodiagnostic tests. PMID- 29509909 TI - Tackling TB in under-served populations: a resource for TB control boards and their partners. PMID- 29509908 TI - Screening for Family Psychosocial Risk in Pediatric Cancer: Validation of the Psychosocial Assessment Tool (PAT) Version 3. AB - Objective: Family psychosocial risk screening is an important initial step in delivering evidence-based care. The Psychosocial Assessment Tool (PAT) is a brief parent report screener based on the trilevel Pediatric Psychosocial Preventative Health Model (PPPHM; Universal, Targeted, Clinical). The current article validates a revised PAT (version 3.0) in pediatric oncology that includes new items (for families of younger patients; clinically relevant risk items) and applicable to broad health literacy levels (a 4th grade reading level). Methods: Primary caregivers of 394 children newly diagnosed with cancer participated in this multisite investigation, completing the PAT and validation measures using REDCap. Results: The original structure of the PAT, with seven subscales (Family Structure, Social Support, Child Problems, Sibling Problems, Family Problems, Stress Reactions, and Family Beliefs) was supported using a confirmatory factor analysis. Internal consistency for the total score (Kuder-Richardson 20 coefficient [KR20] = 0.81) and the subscales (KR20 = 0.59-0.85) was moderate to strong. Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. The validation measures varied significantly, as expected, across the three levels of the PPPHM. Receiver operating characteristic (ROC) analyses showed that the PAT total and subscale scores can discriminate families above and below clinical thresholds. Conclusions: Results reinforce the psychometric properties of this approach for screening of family psychosocial risk. The PAT provides an evidence-based screener that identifies families at three levels of risk and can provide the basis for further evaluation and treatment of children with cancer and their families. PMID- 29509910 TI - Recommendations from the Salzburg Global Seminar on Rethinking Care Toward the End of Life. AB - Objective: In December 2016, 66 health leaders from 14 countries convened at the Salzburg Global Seminar (SGS) to engage in cross-cultural and collaborative discussions centered on 'Rethinking Care Toward the End of Life'. Conversations focused on global perspectives on death and dying, challenges experienced by researchers, physicians, patients and family caregivers. This paper summarizes key findings and recommendations from SGS. Design: Featured sessions focused on critical issues of end of life care led by key stakeholders, physicians, researchers, and other global leaders in palliative care. Sessions spanned across several critical themes including: patient/family/caregiver engagement, integrating health and community-based social care, eliciting and honoring patient preferences, building an evidence base for palliative care, learning from system failures, and delivering end of life care in low-resource countries. Sessions were followed by intensive collaborative discussions which helped formulate key recommendations for rethinking and ultimately advancing end of life care. Results: Prominent lessons learned from SGS include learning from low resource countries, development of evidence-based quality measures, implementing changes in training and education, and respecting the personal agency of patients and their families. Conclusion: There is a global need to rethink, and ultimately revolutionize end of life care in all countries. This paper outlines key aspects of end of life care that warrant explicit improvement through specific action from key stakeholders. PMID- 29509912 TI - Two health information systems to characterize poisoning in Brazil-a descriptive study. AB - Background: Poisoning is a worldwide public health problem that involves individuals of all ages and a wide range of chemicals. This study investigated the data from two health information systems to characterize poisoning events in the Federal District (DF), Brazil. Methods: Data related to the period from 2009 to 2013 were obtained from the poison information center (Centro de Informacao Toxicologica, CIT) and the Notifiable Diseases Information System (Sistema Nacional de Agravos de Notificacao, SINAN) of the DF. Results: A total of 3622 cases were reported to CIT-DF and 5702 cases to SINAN-DF. Most of the cases in CIT-DF (53%) occurred with children up to 9 years old, while this corresponded to 33.9% in SINAN-DF. Unintentional poisoning was the main circumstance involved in the cases. Pharmaceuticals were the main agent (44.3-47.1% of the cases), mainly clonazepan and paracetamol, and pesticides the most fatal (2.4% fatality rate). Out of the 47 fatal cases reported to the systems, only four were reported to both; six cases occurred with children up to 6 years. Conclusion: Under-reporting and missing information were identified in both systems, but the data were complementary to describe the epidemiology of poisoning cases in the DF. PMID- 29509911 TI - Live-Attenuated Respiratory Syncytial Virus Vaccine Candidate With Deletion of RNA Synthesis Regulatory Protein M2-2 is Highly Immunogenic in Children. AB - Background: Live respiratory syncytial virus (RSV) candidate vaccine LIDDeltaM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication. Methods: RSV-seronegative children ages 6-24 months received a single intranasal dose of 105 plaque forming units (PFU) of LIDDeltaM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies. Results: Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log10 PFU/mL by quantitative culture and 6.3 log10 copies/mL by PCR); 90% had >=4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild type RSV without significant illness. Conclusion: LIDDeltaM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion. Clinical Trials Registration: NCT02237209, NCT02040831. PMID- 29509913 TI - Co-infection of fowl adenovirus with different immunosuppressive viruses in a chicken flock. AB - In poultry, fowl adenovirus (FAdV) and immunosuppressive virus co-infection is likely to cause decreased egg production, inclusion body hepatitis, and pericardial effusion syndrome. In this study, fowl adenovirus infection was found in parental and descendent generations of chickens. We used quantitative polymerase chain reaction (PCR) and dot blot hybridization to detect the infection of reticuloendotheliosis (REV), avian leukosis virus (ALV), and chicken infectious anemia virus (CIAV) in 480 plasma samples. The test samples were 34.58% FADV-positive, 22.29% REV-positive, 7.5% CAV-positive, and 0.63% ALV positive. Sequence analysis showed that FADV belonged to serotype 7, which can cause inclusion body hepatitis. The ALV strain was ALV-A, in which the homology of gp85 gene and SDAU09C1 was 97.3%. The positive rate was lower because of the purification of avian leukemia, whereas the phylogenetic tree analysis of REV showed that the highest homology was with IBD-C1605, which was derived from a vaccine isolate. Through pathogen detection in poultry we present, to our knowledge, the first discovery of fowl adenovirus type 7 infection in parental chickens and found that there was co-infection of FAdV and several immunosuppressive viruses, such as the purified ALV and CIAV. This indicates that multiple infection of different viruses is ever-present, and more attention should be given in the diagnosis process. PMID- 29509914 TI - Culture and characterization of chicken small intestinal crypts. AB - The integrity and normal function of the small intestinal epithelium depends critically on the rapid renewal of epithelial cells from basal stem cells. The intensive proliferation that fuels this self-renewal process is confined to the intestinal crypts. Establishment of suitable protocols for crypt isolation and culture is pivotal for the studies of intestinal self-renewal mechanisms. In this study, chicken small intestinal crypts were isolated, purified, and further cultured in a Matrigel 3-D culture system. The growth factor concentration assay on the fourth d of culture showed that Group C (50 ng/mL epidermal growth factor (EGF), 100 ng/mL Noggin, and 500 ng/mL R-spondin 1) supplement in culture medium could significantly enlarge the diameter of organoids when compared with Group A (5 ng/mL EGF, 10 ng/mL Noggin, 50 ng/mL, and R-spondin 1) and Group B (10 ng/mL EGF, 20 ng/mL Noggin, and 100 ng/mL R-spondin 1) by 188.4% (P = 0.026) and 176.9% (P = 0.034), respectively. Transmission electron microscopy, neutral red staining, and 5-ethynyl-2?-deoxyuridine incorporation demonstrated the integrated structure, high viability, and proliferative activity in cultured chicken intestinal organoids. In addition, intestinal stem cell marker genes (Olfm4, Znrf3, Hopx, and Lgr5) also could be detected in cultured intestinal organoids. Furthermore, CHIR99021 (a glycogen synthase kinase 3beta inhibitor) could enhance the expression of Olfm4, Znrf3, Hopx, and Lgr5 by 750% (P = 0.001), 467% (P < 0.001), 450% (P < 0.001), and 333% (P = 0.008), respectively, indicating the responsiveness of the cultured chicken intestinal organoids to exogenous stimulus. This study modified a murine culture model and optimized it to provide a chicken intestinal organoid model for use as a physiological or pathological research platform in vitro. PMID- 29509916 TI - Dietary supplementation with DHA-rich microalgae improves performance, serum composition, carcass trait, antioxidant status, and fatty acid profile of broilers. AB - This experiment was conducted with 126 as-hatched male Arbor Acres chicks (1-d old, weighing 45.3 +/- 0.72 g) to determine the effects of microalgae [MA, containing 29% docosahexaenoic acid (DHA)] on performance, serum composition, carcass trait, antioxidant status, and fatty acid deposition of birds. The birds were allocated randomly to 1 of 3 treatments with 7 replicate pens per treatment (6 birds per pen). The dietary treatments included a control diet [corn-soybean basal diet supplemented with 3% soybean oil (SO), CON], 1% MA diet (basal diet supplemented with 1% MA and 2% SO, 1MA), and 2% MA diet (basal diet supplemented with 2% MA and 1% SO, 2MA). All birds were raised in wire-floored cages. The trial consists of a starter phase from d 1 to 21 and a grower phase from d 22 to 42. Compared with CON, birds supplemented with MA (1MA or 2MA) had greater (P < 0.05) average daily gain, liver percentage (liver weight/body weight), and serum glucose, as well as lower (P < 0.05) feed conversation ratio, abdominal fat percentage (abdominal fat weight/body weight), and total serum cholesterol. Moreover, due to the high concentration of DHA in MA, birds fed MA showed increased (P < 0.05) concentration of eicosapentaenoic acid, DHA, superoxide dismutase, and total antioxidant capacity, as well as decreased (P < 0.05) n-6/n 3 polyunsaturated fatty acid ratio, polyunsaturated fatty acid/saturated fatty acid ratio, and malondialdehyde in the breast and thigh muscle compared with CON. In conclusion, dietary supplementation with 1% or 2% DHA-rich microalgae had positive effects on performance, serum composition, carcass trait, antioxidant status, and fatty acid deposition in birds. PMID- 29509915 TI - BIFURCATE FLOWER TRUSS: a novel locus controlling inflorescence branching in tomato contains a defective MAP kinase gene. AB - A mutant line, bifurcate flower truss (bif), was recovered from a tomato genetics programme. Plants from the control line produced a mean of 0.16 branches per truss, whereas the value for bif plants was 4.1. This increase in branching was accompanied by a 3.3-fold increase in flower number and showed a significant interaction with exposure to low temperature during truss development. The control line and bif genomes were resequenced and the bif gene was mapped to a 2.01 Mbp interval on chromosome 12; all coding region polymorphisms in the interval were surveyed, and five candidate genes displaying altered protein sequences were detected. One of these genes, SlMAPK1, encoding a mitogen activated protein (MAP) kinase, contained a leucine to stop codon mutation predicted to disrupt kinase function. SlMAPK1 is an excellent candidate for bif because knock-out mutations of an Arabidopsis orthologue MPK6 were reported to have increased flower number. An introgression browser was used to demonstrate that the origin of the bif genomic DNA at the BIF locus was Solanum galapagense and that the SlMAPK1 null mutant is a naturally occurring allele widespread only on the Galapagos Islands. This work strongly implicates SlMAPK1 as part of the network of genes controlling inflorescence branching in tomato. PMID- 29509917 TI - Multigenerational effects of a reduced balanced protein diet during the rearing and laying period of broiler breeders. 1. Performance of the F1 breeder generation. AB - Studies on mammals and poultry showed that maternal dietary treatments can alter the offspring performance. However, in contrast to rodent studies, little is known about multigenerational dietary manipulations in broiler breeders. The presented research aimed to investigate the effects of a reduction of 25% in the dietary crude protein (CP) level in the F0 generation on the body composition and reproductive performance of F1 broiler breeders. In the F0 generation, breeders were fed either a control (C) or reduced balanced protein (RP) diet, 25% reduction in crude protein and amino acids. Female F0-progeny of each treatment were fed a C or RP diet, resulting in 4 treatments in the F1 breeder generation: C/C, C/RP, RP/C, and RP/RP. The reproductive performance of breeders fed RP diets was negatively influenced by the dietary CP reduction in the F1 generation (P < 0.001). Moreover, breeders descending from hens that received RP diets in the F0 generation showed a significantly reduced reproductive capacity compared to their control fed counterparts (P < 0.001). Breeders fed RP diets in the F1 generation were characterized by higher plasma T3 concentrations (P < 0.001), an increased proportional abdominal fat pad (P < 0.001) and proportional liver weight (P < 0.001). During the rearing phase, the RP fed breeders needed a higher feed allowance, whereas no differences could be observed between the C/C and RP/C or the C/RP and RP/RP breeders. However, breeders originating from birds fed RP diets in the F0 generation needed lower feed allocations in the laying phase to maintain a similar body weight. Egg weight was reduced for the C/RP and RP/RP breeders. At 34 wk of age, eggs from C/RP and RP/RP breeders showed a reduced proportional albumen weight, whereas no effects on egg composition were found at 42 wk of age. It was concluded that prenatal protein undernutrition triggered hens to relocate more energy towards growth and maintenance and less towards reproductive capacity. PMID- 29509918 TI - Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects. AB - Background: The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. Methods: A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. Results: At the end of the study, by intention to treat, mean L-T4 doses were 1.50 +/- 0.07, 1.32 +/- 0.07, and 0.78 +/- 0.08 MUg/kg (P < 0.001), and mean TSH levels were 1.85 +/- 0.25, 3.93 +/- 0.38, and 9.49 +/- 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Conclusions: Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement. PMID- 29509919 TI - Primary glomerular nephropathy among hospitalized patients in a national database in China. AB - Background: Primary glomerular nephropathy (PGN) is a leading cause of end-stage renal disease in developing countries, however, nationwide studies investigating the spectrum of PGN are limited. Methods: To evaluate the composition of various pathological types of PGN in a comprehensive geographic coverage in China, a national inpatient database covering 43.7 million patients was used in this analysis. Diagnoses were extracted from the discharge diagnoses. Results: The percentage of patients with PGN in hospitalized patients decreased from 0.80% in 2010 to 0.67% in 2015. Among hospitalized patients with PGN, a decreasing trend of immunoglobulin A nephropathy (from 19.0% in 2010 to 10.6% in 2015) and an increasing trend of idiopathic membranous nephropathy (from 4.5% in 2010 to 8.8% in 2015) were revealed. A positive association between the percentage of idiopathic membranous nephropathy (iMN) and the exposure of particulate matter with a diameter < 2.5 MUm was observed north of the Yangtze River (P < 0.001, R2 = 0.828). South of the Yangtze River, the proportion of the Zhuang population was positively correlated to the frequency of iMN (P = 0.012, r = 0.697). Conclusions: In conclusion, a changing spectrum of PGN was observed between 2010 and 2015 in China and both environmental and genetic factors might play pivotal roles in the pathogenesis of iMN in the Chinese population. PMID- 29509920 TI - The Cardiac Glucagonlike Peptide-1 Receptor: Whither Art Thou? PMID- 29509921 TI - Microstructural observation of casein micelles in milk by cryo-electron microscopy of vitreous sections (CEMOVIS). AB - Casein micelles are present in bovine milk as colloidal particles with diameters of 20-600 nm, which are complex macromolecular assemblies composed of four distinct types of casein and colloidal calcium phosphate (CCP). Multiple structural models of casein micelles have been proposed based on their biochemical or physical properties and observed using electron microscopy. However, the CCP distribution and crosslinking structure between CCP and casein remain unclear. Therefore, the internal structure of casein micelles in raw milk was observed using cryo-electron microscopy of vitreous sections (CEMOVIS) with high precision at high resolution. The results confirmed that the average casein micelle diameter was about 140 nm, and that the CCP diameter in casein micelles was about 2-3 nm, with an average diameter of 2.3 nm. The distribution of CCP in casein micelles was not uniform, with an average interval between CCPs of about 5.4 nm. Areas containing no black particles (attributed to CCP) were present, with an average size of about 19.1 nm. Considering previous reports, these areas possibly correspond to pores or cavities filled with water. Based on differences in the density of structures in casein micelles, we estimated that some of the casein aggregates were able to connect with CCP in a string. PMID- 29509922 TI - A systematic review of direct oral anticoagulant use in chronic kidney disease and dialysis patients with atrial fibrillation. AB - Background: There is a lack of clear benefit and a potential risk of bleeding with direct oral anticoagulant (DOAC) use in chronic kidney disease (CKD) and dialysis patients with atrial fibrillation. The objective of this study was to evaluate how treatment with DOACs affects stroke and bleeding outcomes compared with warfarin or aspirin. Methods: We conducted a systematic review of randomized controlled trials, cohort studies and case series, and searched electronic databases from 1946 to 2017. Studies evaluating stroke and bleeding outcomes with DOAC use in CKD and dialysis patients were included. Results: From 8008 studies, 10 met the inclusion criteria. For moderate CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2), there was no difference in stroke outcomes between dabigatran 110 mg [hazard ratio (HR) 0.78, 95% confidence interval (95% CI) 0.51-1.21], rivaroxaban (HR 0.82-0.84, 95% CI 0.25-2.69) and edoxaban (HR 0.87, 95% CI 0.65-1.18) versus warfarin. Dabigatran (150 mg twice daily) and apixaban reduced risk of stroke or systemic embolism significantly more than warfarin for moderate CKD patients (HR 0.55, 95% CI 0.34-0.89 and HR 0.61, 95% CI 0.39-0.94, respectively). Edoxaban and apixaban were associated with reduced major bleeding events (HR 0.50-0.76) compared with warfarin. Rivaroxaban and dabigatran 110 mg and 150 mg showed no significant difference in major bleeding versus warfarin. In hemodialysis (HD) patients, there was no difference in stroke outcomes between apixaban, dabigatran [relative risk (RR) 1.71, 95% CI 0.97-2.99] or rivaroxaban (RR 1.8, 95% CI 0.89-3.64) versus warfarin. In HD patients, rivaroxaban and dabigatran were associated with an increased major bleeding risk (RR 1.45-1.76), whereas there was no major bleeding difference with apixaban compared to warfarin. Limitations: The heterogeneity of major bleeding and stroke definitions of the 10 included studies. Conclusions: Clinicians should continue to weigh the risk of stroke versus bleeding before prescribing DOACs in the CKD and dialysis population. PMID- 29509923 TI - Letter in Response to Kim M, Torrie I, Poisson R, Withers N, Bjarnason S, DaLuz LT, Pannell D, Beckett A, Tien HC. The Value of Live Tissue Training for Combat Casualty Care: A Survey of Canadian Combat Medics with Battlefield Experience in Afghanistan. Mil Med. 2017 Sep;182(9):e1834-e1840. PMID- 29509926 TI - Erratum. PMID- 29509925 TI - Cardiorenal prognosis by residual proteinuria level in diabetic chronic kidney disease: pooled analysis of four cohort studies. AB - Background: No study has assessed whether the prognosis of coexisting diabetes mellitus and chronic kidney disease (DM-CKD) is dictated by DM per se or by the extent of proteinuria. Methods: In this pooled analysis of four prospective studies in CKD patients treated with drugs inhibiting the renin-angiotensin system, we compared the risk of all-cause mortality, fatal and non-fatal cardiovascular (CV) events and end-stage renal disease (ESRD) between patients with (n = 693) and without diabetes (n = 1481) stratified by proteinuria level (<0.15, 0.15-0.49, 0.5-1 and >1 g/day). Results: The group with DM-CKD was older (69 +/- 11 versus 65 +/- 15 years), had a higher body mass index (29.6 +/- 5.4 versus 27.5 +/- 4.8 kg/m2) and systolic blood pressure (143 +/- 19 versus 136 +/- 18 mmHg), prevalent CV disease (48% versus 29%) and lower estimated glomerular filtration rate (34.5 +/- 17.9 versus 36.6 +/- 19.0 mL/min/1.73 m2). During 4.07 years of follow-up, there were 466 patients with ESRD, 334 deaths and 401 CV events occurred. In the subgroup with urine protein <0.15 g/day (N = 662), the risks of ESRD, CV events and mortality were similar in diabetic and non-diabetic patients. Conversely, in DM-CKD patients, the mortality risk was higher in proteinuric patients {hazard ratio 1.92 [95% confidence interval (CI) 1.25-2.95); 1.99 (1.26-3.15) and 1.98 (1.28-3.06) for proteinuria 0.15-0.49, 0.5-1 and >1 g/day, respectively}, whereas in non-diabetics the mortality risk increased only for proteinuria 0.5-1 g/day [HR 1.60 (95% CI 1.07-2.40)] and >1 g/day [HR 1.69 (95% CI1.20-2.55)]. In both groups, CV risk had a trend similar to that of mortality. ESRD risk increased progressively across strata >0.5 g/day independent of diabetic status. Conclusions: We provide evidence that patients with non proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, in the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and CV events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes. PMID- 29509924 TI - Nonreactive Human Immunodeficiency Virus Type 1 Rapid Tests After Sustained Viral Suppression Following Antiretroviral Therapy Initiation During Primary Infection. AB - We assessed the impact of early antiretroviral treatment (ART) on human immunodeficiency virus (HIV) antibody detection by rapid tests in 44 individuals after several years of successful ART. HIV self-tests and point-of-care tests were negative in 30% and 7%-9% of cases, respectively. These data reinforce the message that patients should never be retested after entering HIV care. PMID- 29509927 TI - Postoperative Outcomes in Vedolizumab-Treated Patients Undergoing Major Abdominal Operations for Inflammatory Bowel Disease: Retrospective Multicenter Cohort Study. AB - Background: Vedolizumab is now widely available for the treatment of moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). We sought to quantify the rates of postoperative complications with preoperative vedolizumab compared with anti-tumor necrosis factor (anti-TNF) therapy. Methods: A multicenter retrospective review of adult inflammatory bowel disease (IBD) patients who underwent an abdominal operation between May 20, 2014, and December 31, 2015, was performed. The study cohort was comprised of patients who had received vedolizumab within 12 weeks of their abdominal operation, and the control cohort was IBD patients who had received anti-TNF therapy. Results: A total of 146 patients received vedolizumab within 12 weeks before an abdominal operation (64% female; n = 93; median age, 33 years; range, 15-74 years), and 289 patients received anti-TNF therapy (49% female; n = 142; median age, 36 years; range, 17 73 years). Vedolizumab-treated patients were younger (P = 0.015) and were more likely to have taken corticosteroids (P < 0.01) within the 12 weeks before surgery. Vedolizumab-treated patients had a significantly increased risk of any postoperative surgical site infection (SSI; P < 0.01), superficial SSI (P < 0.01), deep space SSI (P = 0.39), and mucocutaneous separation of the diverting stoma (P < 0.00) as compared with patients taking anti-TNF therapy. On multivariate analysis, after adjusting for body mass index, steroids at the time of operation, and institution, exposure to vedolizumab remained a significant predictor of postoperative SSI (P < 0.01). Conclusions: We observed that vedolizumab-treated patients were at significantly increased risk of postoperative SSIs after a major abdominal operation, as compared with anti-TNF treated patients. PMID- 29509928 TI - Crafting Live-Attenuated Vaccines Against Respiratory Syncytial Virus. PMID- 29509930 TI - Quality improvement in neurology: Neuro-Oncology Quality Measurement Set. PMID- 29509931 TI - Effects of feeding reduced crude protein diets on growth performance, nitrogen excretion, and plasma uric acid concentration of broiler chicks during the starter period. AB - An experiment (2 trials) was conducted to determine the effects of feeding reduced crude protein (CP) diets to Ross * Ross 708 male broilers while maintaining adequate essential amino acid (AA) concentrations on growth performance, nitrogen excretion, and plasma uric acid (UA) concentration during the starter period. In trial 1, 11 dietary treatments were fed from 1 to 18 d of age containing 1.20% digestible Lys. Diet 1 (23.2% CP) was formulated with DL Met, L-Lys, and L-Thr to contain 1.70 total Gly + Ser to digestible Lys ratio whereas diets 2 (23.4% CP) to 11 were formulated with additional Gly to contain 1.90 total Gly + Ser to digestible Lys ratio. Free AA were added sequentially in the order of limitation (L-Val, L-Ile, L-Arg, L-Trp, L-His, L-Phe, and L-Leu) from diets 3 to 10 to decrease CP content from 22.6 to 18.8%, respectively. In diet 11, L-Gln was added to increase the CP content to 23.4%. Feed conversion of broilers fed diet 2 was lower (P < 0.05) than those consuming diets 6 to 11 from 1 to 17 d of age. Nitrogen excretion (mg/b/d) decreased (P < 0.001) by 14.1% when broilers were fed diet 4 compared with birds fed diet 2 from 15 to 16 d of age. Broilers fed diet 4 had lower (P = 0.011) plasma UA concentration than birds fed diet 2 at 18 d of age. In trial 2, 8 dietary treatments containing 1.25% digestible Lys and 1.70 total Gly + Ser to digestible Lys ratio were fed from 1 to 21 d of age. Diet 1 (24.0% CP) was supplemented with DL-Met, L-Lys, and L-Thr. Free AA (L-Val, Gly, L-Ile, L-Arg, L-Trp, L-His, and L-Phe) were sequentially supplemented in the order of limitation to decrease CP content in diets 2 to 8 from 23.8 to 20.3%. Broilers fed diet 1 had higher (P < 0.05) body weight gain and lower (P < 0.05) feed conversion when compared with diet 7 or 8. Plasma UA concentration of broiler provided diets 4 to 8 was lower (P < 0.05) compared with diet 1 at 21 d of age. Placing a minimum on dietary CP percentage may not be necessary when proper AA ratios are implemented in diet formulation. PMID- 29509932 TI - Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study. AB - Background: Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined. Methods: We conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ~0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively. Results: Thirty-four episodes of renal flare occurred during follow-up (88.8 +/- 77.3 and 82.8 +/- 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 +/- 0.43 mL/min/1.73 m2/year, compared with -2.11 +/- 0.50 and -1.00 +/- 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups. Conclusion: A preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function. PMID- 29509929 TI - Live Respiratory Syncytial Virus (RSV) Vaccine Candidate Containing Stabilized Temperature-Sensitivity Mutations Is Highly Attenuated in RSV-Seronegative Infants and Children. AB - Background: Respiratory syncytial virus (RSV) is the most important viral cause of severe respiratory illness in young children and lacks a vaccine. RSV cold passage/stabilized 2 (RSVcps2) is a modification of a previously evaluated vaccine candidate in which 2 major attenuating mutations have been stabilized against deattenuation. Methods: RSV-seronegative 6-24-month-old children received an intranasal dose of 105.3 plaque-forming units (PFU) of RSVcps2 (n = 34) or placebo (n = 16) (International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1114 and companion protocol CIR285). RSV serum neutralizing antibody titers before and 56 days after vaccination, vaccine virus infectivity (defined as vaccine virus shedding detectable in nasal wash and/or a >=4-fold rise in serum antibodies), reactogenicity, and genetic stability were assessed. During the following RSV transmission season, participants were monitored for respiratory illness, with serum antibody titers measured before and after the season. Results: A total of 85% of vaccinees were infected with RSVcps2 (median peak titer, 0.5 log10 PFU/mL by culture and 2.9 log10 copies/mL by polymerase chain reaction analysis); 77% shed vaccine virus, and 59% developed a >=4-fold rise in RSV-serum neutralizing antibody titers. Respiratory tract and/or febrile illness occurred at the same rate (50%) in the vaccine and placebo groups. Deattenuation was not detected at either of 2 stabilized mutation sites. Conclusions: RSVcps2 was well tolerated and moderately immunogenic and had increased genetic stability in 6-24-month-old RSV-seronegative children. Clinical Trials Registration: NCT01852266 and NCT01968083. PMID- 29509933 TI - Brown eggshell fading with layer ageing: dynamic change in the content of protoporphyrin IX. AB - The dynamic change in brown eggshell color as hens age has been observed, but much uncertainty still exists. We aimed to analyze the depth of eggshell color and quantity of protoporphyrin IotaChi throughout the laying period to explore the reasons for color variation. In this study, 120 Rhode Island Red hens were used, and two eggs were collected from each individual at 26, 34, 42, 50, 60, and 70 wk of age. The eggshell color (L*, a*, b*), egg weight, eggshell dry weight, and protoporphyrin IotaChi quantity in eggshell were measured for individual eggs. Our results showed that the intensity of brown eggshell color weaken as hens aged from 26 to 60 wk of age (L* gradually increased from 61.43 to 68.07), while eggshell lightness recovered slightly at 70 wk (L* = 64.77). The correlation analysis indicated that the content of protoporphyrin IotaChi deposited in the eggshell was an important factor for lightness fading with the ageing process (the average r was 0.66, P < 0.01), while the egg weight had little impact on the eggshell color (the average r was 0.07, P > 0.05). The shade of the eggshell color (L* and a*) at the early laying period (26 or 34 wk) had a low correlation with the other age points (42, 50, 60, and 70 wk). However, high correlations between the shell color at 42 wk of age and subsequent ages (50, 60, and 70 wk) were found, suggesting that the intensity of eggshell color is more stable after egg-laying peaks (such as 42 wk of age). In conclusion, the intensity of brown eggshell color varies greatly among the whole laying cycle and breeders can choose the proper age for eggshell color measurements to ensure the degree of shell color in the late laying period. PMID- 29509934 TI - Military Service, Childhood Socio-Economic Status, and Late-Life Lung Function: Korean War Era Military Service Associated with Smaller Disparities. AB - Background: Military service is associated with smoking initiation, but U.S. veterans are also eligible for special social, financial, and healthcare benefits, which are associated with smoking cessation. A key public health question is how these offsetting pathways affect health disparities; we assessed the net effects of military service on later life pulmonary function among Korean War era veterans by childhood socio-economic status (cSES). Methods: Data came from U.S.-born male Korean War era veteran (service: 1950-1954) and non-veteran participants in the observational U.S. Health and Retirement Study who were alive in 2010 (average age = 78). Veterans (N = 203) and non-veterans (N = 195) were exactly matched using coarsened exact matching on birth year, race, coarsened height, birthplace, childhood health, and parental and childhood smoking. Results were evaluated by cSES (defined as maternal education <8 yr/unknown or >=8 yr), in predicting lung function, as assessed by peak expiratory flow (PEF), measured in 2008 or 2010. Findings: While there was little overall association between veterans and PEF [beta = 12.8 L/min; 95% confidence interval (CI): (-12.1, 37.7); p = 0.314; average non-veteran PEF = 379 L/min], low-cSES veterans had higher PEF than similar non-veterans [beta = 81.9 L/min; 95% CI: (25.2, 138.5); p = 0.005], resulting in smaller socio-economic disparities among veterans compared to non veterans [difference in disparities: beta = -85.0 L/min; 95% CI: (-147.9, -22.2); p = 0.008]. Discussion: Korean War era military service appears to disproportionately benefit low-cSES veteran lung functioning, resulting in smaller socio-economic disparities among veterans compared with non-veterans. PMID- 29509935 TI - Impact of Iowa's Prescription Monitoring Program on Opioid Pain Reliever Prescribing Patterns: An Interrupted Time Series Study 2003-2014. AB - Objective: To evaluate the impact of Iowa's prescription monitoring program (PMP), implemented in 2009, on opioid pain reliever (OPR) prescribing patterns. Methods: We conducted interrupted time series analyses using 2003-2014 health insurance claims from a private health insurer in Iowa. OPR prescriptions for all beneficiaries were included. Another data set included only OPR prescription for new opioid users required to have six months of insurance coverage. We evaluate four OPR prescribing patterns: 1) average daily dosage in morphine milligrams equivalents (MME), 2) MME per prescription, 3) average days' supply per prescription, and 4) prescription rate per 1,000 insured person-years. We examined confounding and effect measure modification of the relationship between PMP and prescribing patterns by age and sex. Results: During the 12 years of follow-up, 1,512,388 insured Iowans contributed 6,169,634.92 person-years of follow-up. Of these, 505,274 patients filled 2,401,818 OPR prescriptions and 360,688 new OPR users filled as many first OPR prescriptions. The increasing trend of OPR prescription rates from 2003 to 2009 declined post-PMP. Similarly, there was a large decline in MME per day and MME per prescription. The OPR days' supply kept increasing post-PMP implementation, albeit at a slightly slower rate than pre-PMP implementation. There was no confounding by age and sex; however, we observed heterogeneity by age and sex; patients aged >=50 years and females received higher doses and more prescriptions pre-PMP and experienced the greatest declines post-PMP. Conclusions: Our study suggests that Iowa PMP implementation may have resulted in declines in OPR prescribing, and this impact varies by patient age and sex. PMID- 29509937 TI - Regression method-derived energy value of dried egg albumen for broiler chickens. AB - The energy value of dried egg albumen (DEA) for broiler chickens was determined with male Ross 708 broilers. Birds were fed a common broiler starter diet from day 0 to 17 and experimental diets from day 17 to 22 post hatching. A total of 192 birds was allotted to 3 diets in a randomized complete block design with 8 replicate cages per diet and 8 birds per cage. The experiment used a corn-soybean meal reference diet and 2 test diets which the DEA was added at 50 or 100 g/kg to partially replace the energy source in the reference diet. The analyzed DM of DEA was 934 g/kg, and the respective analyzed gross energy and CP were 5,310 kcal and 894 g/kg DM. Addition of DEA to the reference diet linearly increased (P < 0.01) ileal DM digestibility, ileal energy digestibility, and ileal digestible energy (IDE), metabolizable energy (ME), and nitrogen-corrected metabolizable energy (MEn), whereas the effect on N retention was quadratic (P < 0.05). The IDE, ME, MEn of DEA values determined by the regression method were 4,777, 4,966, and 4,750 kcal/kg DM, respectively. In conclusion, the current study demonstrated that between 89 and 94% of the gross energy in dried egg albumen is utilized by broiler chickens. PMID- 29509936 TI - CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. AB - In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease. PMID- 29509938 TI - Performance, egg quality, nutrient digestibility, and excreta microbiota shedding in laying hens fed corn-soybean-meal-wheat-based diets supplemented with xylanase. AB - The aim of this study was to evaluate the effects of dietary levels of xylanase on production performance, egg quality, nutrient digestibility, and excreta microbiota shedding of laying hens in a 12-week trial. Two-hundred-forty Hy-Line brown laying hens (44 wk old) were distributed according to a randomized block experimental design into one of 4 dietary treatments with 10 replicates of 6 birds each. The 4 dietary treatments were corn-soybean-meal-wheat-based diets supplemented with 0, 225, 450, or 900 U/kg xylanase. Daily feed intake, egg production, egg weight, egg mass, feed conversion ratio, and damaged egg rate showed no significant response to increasing xylanase supplementation during any phase (P > 0.05). No significant responses were observed for apparent total tract digestibility of dry matter, nitrogen, or gross energy (P > 0.05). A significant linear increase to increasing xylanase supplementation was seen for lactic acid bacteria numbers, although coliforms and Salmonella counts were not affected. Increasing the dietary xylanase resulted in a significant linear increase in eggshell thickness in wk 3, 6, 9, and 12 (P < 0.05). In addition, a significant linear increase occurred for Haugh unit and albumen height in wk 12 (P < 0.05). In summary, the inclusion of xylanase in corn-soybean-meal-wheat-based diets increased eggshell thickness, Haugh unit, albumen height, and excreta lactic acid bacteria count but had no effect on production performance or nutrient digestibility. PMID- 29509939 TI - Heterosis in poplar involves phenotypic stability: cottonwood hybrids outperform their parental species at suboptimal temperatures. AB - Heterosis or hybrid vigor is common in hybrid poplars, and to investigate its occurrence and physiological basis we compared narrowleaf cottonwoods, Populus angustifolia James, prairie cottonwoods, Populus deltoides Bartr. ex Marsh, and their native intersectional hybrids, P. * acuminata Rydb., from Alberta, Canada. Clonal replicates from 10 separate trees from each taxon were raised in growth chambers at different temperatures (T). Growth was similarly vigorous across the taxa at 20 and 24 degrees C, and morphological and physiological traits of the hybrids were generally intermediate between the parental species, or similar to the larger parent, demonstrating additive inheritance or dominance, respectively. Growth declined at 18 and 15 degrees C particularly in the parental species, and consequently hybrid vigor was displayed for root and especially leaf growth. Stomatal distributions and chlorophyll indices were intermediate in the hybrids and unaffected by T. Foliar nitrogen (N), net assimilation (Asat), stomatal conductance (gs) and transpiration (E) per unit of leaf area were lower in the hybrids, but the hybrids generally had larger leaf areas. Water-use efficiencies (Asat/gs) were similar across the taxa and reduced with warming, while nitrogen use efficiencies (Asat/N) increased. delta13C was correlated with leaf mass per area, which varied across the taxa. Photosynthesis (Asat) was correlated with chlorophyll content index, N and/or gs in P. deltoides and the hybrids, but not in P. angustifolia, indicating different physiological limitations. We conclude that heterosis in P. * acuminata results from the compound benefits from multiple dominant traits, and superior growth particularly at suboptimal conditions. This indicates phenotypic stability or environmental adaptability, whereby heterozygosity provides metabolic diversity that allows hybrids to thrive across a broader environmental range. PMID- 29509940 TI - Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma. AB - Background: Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) subtypes. Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in ACP and PCP. Methods: We mapped and quantified PD-L1 and PD 1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1. Results: All ACP (15 +/- 14% of cells, n = 23, average +/- SD) and PCP (35 +/- 22% of cells, n = 18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst lining. In PCP, PD-L1 was highly expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mammalian target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T cells. Conclusions: ACP exhibit PD-L1 expression in the tumor cyst lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy. PMID- 29509942 TI - In situ embolism induction reveals vessel refilling in a natural aspen stand. AB - Little is known about the ability of trees to recover hydraulic conductance (k) within a growing season by regrowth or refilling of embolized conduits. Recovery of k lost to drought or other causes would prevent chronic reductions in gas exchange and productivity. To test recovery ability we conducted a 2-year experiment (2014-15) on a cohort of aspen ramets (Populus tremuloides, Michx.). Whole-tree k was measured from mid-June through September from sapflow (Q) and pre-dawn and mid-day xylem pressure. We induced embolism in the treatment group with high air pressure delivered by a split pressure chamber sealed around the main trunk. Successful treatments reduced k and Q by 50% or more without causing rapid desiccation. The majority of trees recovered following treatment, rising to control levels of k and Q between 12 and 17 days. Failure to recover was correlated with drier climate conditions. The growing-season recovery of k was attributed to refilling of embolized vessels, based on the absence of diameter growth. Pre-dawn xylem pressures during recovery were similar to the threshold needed to passively collapse emboli. Successful recovery during the 2-year study was consistent with no reduction in cumulative Q or canopy area in treatment vs controls. However, non-recovering trees in 2014 exhibited lower basal area growth at the start of the 2015 growing season, suggesting a linkage between recovery ability and productivity. This study provides evidence for the potential of trees to recover xylem function by refilling during the growing season. PMID- 29509941 TI - Environmental and socio-economic determinants associated with the occurrence of cutaneous leishmaniasis in the northeast of Colombia. AB - Background: Cutaneous leishmaniasis (CL) is a vector-borne disease that is widely distributed in most tropical regions. Colombia has experienced an important increase in its incidence during the last decade. There are CL transmission foci in the Colombian departments of Santander and Norte de Santander. Objectives: To identify environmental and socio-economic variables associated with CL incidence in the municipalities of the northeast of Colombia between 2007 and 2016. Methods: This was an ecological study of CL cases aggregated by municipality. The cases reported during the study period were analyzed with a negative binomial regression to obtain the adjusted incident rate ratio for environmental and socio economic variables. Findings: During the study period, 10 924 cases of CL were reported, and 110 (86.6%) municipalities reported at least one CL case. The coverages of forest (aIRR 1.05, 95% CI 1.03-1.07), heterogeneous agricultural zones (aIRR 1.04, 95% CI 1.02-1.06) and permanent crops (aIRR 1.07, 95% CI 1.02 1.12) were associated with a higher incidence of CL. Conversely, urban functionality (aIRR 0.95, 95% CI 0.92-0.96), minimal-altitude above sea level (aIRR 0.84, 95% CI 0.79-0.90) and shrub coverage (aIRR 0.98, 95% CI 0.95-1.0) were negatively associated with the incidence of CL in the municipality. Main conclusions: Our results confirm the importance of environmental determinants, such as height above sea level, and coverage of forest, permanent crops and heterogeneous agricultural zones, for the occurrence of CL; these findings also suggest the importance of shrub coverage. Furthermore, urban functionality was a socio-economic determinant independently associated with CL incidence. PMID- 29509943 TI - Evaluation of haematological and volume, conductivity and scatter parameters of leucocytes for aetiological diagnosis of undifferentiated fevers. AB - Background: In this follow-up study, we aimed to establish the cut-off values of the volume, conductivity and scatter (VCS) parameters of leucocytes that significantly differ in dengue fever, malaria, scrub typhus and enteric fever, as described in our pilot study. Methods: A prospective observational case-control study was undertaken on patients with an established diagnosis of acute malaria (n=476), dengue fever (n=927), scrub typhus (n=425), bacterial sepsis (n=1598) or enteric fever (n=885) and the haematological and VCS data obtained by the Coulter LH 750 analyser were compared with controls. Results: Malaria significantly altered the platelet count and plateletcrit. The cut-offs for the monocyte volume, lymphocyte volume, neutrophil volume, neutrophil volume distribution width, lymphocyte volume distribution width, monocyte volume distribution width and neutrophil conductivity distribution width had 90% negative predictive values (NPVs) for malaria. Except for the proportion of monocytes, lymphocyte scatter distribution width and platelet distribution width, a >70% positive (PPV) and negative predictive value (NPV) for dengue was noted in all the haematological and VCS parameters analysed. While the cut-offs determined in scrub typhus had a good (>80%) PPV and NPV, a significant difference was seen in neutrophil, monocyte and lymphocyte conductivities, but with low sensitivity, specificity, PPV and NPV in enteric fever. Conclusions: Aetiology-specific changes occur both in numbers as well as in VCS properties in acute fevers. Formulae and/or algorithms need to be utilized to realize the full potential of the VCS technology. PMID- 29509944 TI - Effects of quantitative nutrient allocation on myopathies of the Pectoralis major muscles in broiler chickens at 32, 43, and 50 days of age. AB - An experiment was conducted to determine if myopathies of the Pectoralis major muscles are influenced by differences in growth trajectory achieved through a controlled feeding program. Male Yield Plus * Ross 708 broiler chicks were placed into 28 pens (25 birds/pen) equipped with plastic slats to prevent coprophagy. All birds received identical starter (1 to 10 d), grower (11 to 32 d), finisher (33 to 42 d), and withdrawal (43 to 50 d) diets that were formulated to meet or exceed nutrient recommendations of the primary breeder. Each pen of birds was randomly assigned to one of 4 pair-feeding programs (TRT 1: ad libitum; TRT 2: 95% of TRT 1 intake; TRT 3: 90% of TRT 1 intake; and TRT 4: 85% of TRT 1 intake) with 7 replicate pens per treatment. Feed intake and mortality were recorded daily. Individual BW was recorded at 31, 42, and 49 d of age. Blood samples were collected from 4 birds per pen at 31, 41, and 48 d of age and subsequently analyzed for plasma creatine kinase (CK) and lactate dehydrogenase (LDH). At 32, 43, and 50 d of age, 4 birds per pen were euthanized for necropsy. The right breast fillet of each bird was visually scored for white striping (WS) and wooden breast (WB). Linear decreases (P <= 0.01) in feed intake, BW gain, feed conversion ratio, and mortality were observed with decreasing feed allocation. Linear decreases (P <= 0.01) in severity were observed for WS and WB at 33, 43, and 50 d with decreasing feed allocation. Severity of WB at 33 and 43 d, as well as that of WS at 43 and 50 d, decreased (P <= 0.05) quadratically with decreasing feed allocation. Reduced feed allocation produced quadratic decreases (P <= 0.05) in CK and LDH concentrations at 31, 41, and 48 days. These results indicate that the incidence of breast fillet myopathies in broilers may be reduced through controlled feeding programs. PMID- 29509945 TI - RADIATION EXPOSURE OF THE INVESTIGATOR DURING NAVIGATED FUSION OF 124IODINE PET IMAGING AND ULTRASOUND. AB - To assess the radiation exposure of the investigator during navigated fusion of nuclear medicine images with ultrasound after application of I-124. Dosimetry with two different types of thermoluminescent detectors (TLD) was performed in 25 patients. The dose rate at the patient's neck was measured with a calibrated dose rate meter (DRM) and served as the standard of reference. The average exposure per investigation at the patient's neck measured by LiF:Mg,Cu,P TLDs (cumulative: 212 MUSv), LiF:Mg,Ti TLDs (cumulative: 112 MUSv) and DRM (cumulative: 150.3 MUSv). The radiation exposure of the hand during navigated fusion of nuclear medicine imaging with 124I and ultrasound with a mean duration of 13 min is low and comparable between different methods. Yearly examinations are not expected to add a relevant cumulative risk. PMID- 29509946 TI - Comparative proteomic analysis of ovaries from Huoyan geese between pre-laying and laying periods using an iTRAQ-based approach. AB - To explore the key regulatory genes and their translated products involved in Huoyan goose egg laying, we first applied the iTRAQ technology integrated with LC MS/MS analysis to identify differentially abundant proteins in the ovarian tissue of Huoyan geese between the pre-laying and laying periods. Then, Gene Ontology (GO) enrichment and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analyses of the proteins were conducted. As observed, 403 proteins, which included 255 up-regulated and 148 down-regulated proteins, were identified. Some differentially abundant proteins, such as apolipoprotein B (apoB), retinol binding protein 4 (RBP4), vitellogenin-2 (VTG-2), apolipoprotein II (apoVLDL-II), and fatty-acid binding protein 4 (FABP4), were found to be involved in lipid transportation and metabolic process, follicle development and final egg production, ovarian steroidogenesis, and steroid hormone biosynthesis. Subsequently, the modification of the abundance of 3 proteins, adiponectin, FABP4, and RBP4, was verified using Western blotting. Our findings might provide comprehensive protein expression information that can facilitate the understanding of the reproductive biology and improve the egg-laying performance of Huoyan geese. PMID- 29509947 TI - Medical management of acute radiation syndrome and associated infections in a high-casualty incident. AB - A high-casualty incident may result in a significant human toll due to the inability of a community to meet the health care demands of the population. A successful medical response requires health care facilities to not only communicate and integrate medical services, meet surge capacity, protect health care workers and implement triage and treatment protocols, but also to provide the venue for clinical management of acute radiation injuries and their associated infections. Today, clinical management is primarily guided by the recommendations of a Consultancy that were made at the World Health Organization (WHO). This international consensus was reached on evidence-based, clinical management of each of the four sub-syndromes that compose acute radiation syndrome (ARS), including the hematopoietic subsyndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Major findings in studies meeting inclusion criteria for management strategies for HS were that (i) no randomized controlled studies of medical countermeasures have been (or will likely ever be) performed for ARS cases, (ii) the data for management of HS are restricted by the lack of comparator groups, and (iii) reports of countermeasures for management of injury to non hematopoietic organs are often incompletely described. Here, (i) recommendations made in Geneva are summarized; (ii) the analysis of countermeasures for HS is updated by review of two additional cases and extended to published reports not meeting inclusion criteria; and (iii) guidelines are provided for management of microbial infections based upon patient risk for prolonged immunosuppression. PMID- 29509948 TI - Apoptosis during the development of the hepatic steatosis in force-fed ducks and cooking yield implications. AB - Mule ducks were force-fed for 12 d to determine whether or not signs of apoptosis could occur during the development of the hepatic steatosis induced by the huge quantities of corn ingested twice daily by the birds. Presence of apoptosis in hepatocytes was assessed through the measurements of increased activities of capsase-3 +-7, -8, and -9. From d 0 of the force-feeding period until d 8, activities of the different caspases remained at a low level. On the contrary, at d 10 and d 12, activities of all measured caspases dramatically increased, indicating that apoptosis occurred at this stage, which corresponds to the time of accumulation of large quantities of lipids in the hepatic cells.The melting level of the liver issued from force-feeding ("foie gras") during cooking is a point of interest for processors because it could degrade the quality of this delicate dish. In this study, we used the levels of caspases activities to improve the predictability of foie gras cooking, in addition to other parameters usually used, such as its weight or lipid content. From this improvement, we suggest that part of the variability of melting during cooking of fatty livers could reside in more or less intense activity of hepatic proteases. PMID- 29509949 TI - Comment on: The proposed role of ultrasound in the management of giant cell arteritis in routine clinical practice. PMID- 29509950 TI - E-cigarettes and vaping-the lesser of two evils. PMID- 29509951 TI - Salivary Cortisol: Is it Still the Canary in the Coal Mine? PMID- 29509952 TI - Diagnostic performance of Mini Parasep(r) solvent-free faecal parasite concentrator relative to Kato-Katz and McMaster for the diagnosis of intestinal parasitic infections. AB - Background: In this cross-sectional study, we compared the performance of Mini Parasep(r) solvent-free (SF) faecal parasite concentrator, Kato-Katz thick smear and McMaster techniques for the diagnosis of intestinal parasitic infections among children in Wosha Soyama Primary School, Ethiopia. Methods: Stool samples were collected from 381 children and examined for intestinal parasitic infections using Mini Parasep(r) SF faecal parasite concentrator, Kato-Katz thick smear and McMaster techniques. Results: About 86.1% of children were infected with at least one species of intestinal parasite based on combined results of the three techniques. The sensitivity and negative predictive values of Mini Parasep(r) SF, Kato-Katz and McMaster tests for detecting at least one species of intestinal parasite infections were 90.2% and 62.4%, 80.0% and 44.5%, and 55.2% and 26.5%, respectively. While Mini Parasep(r) SF was more sensitive in detecting Ascaris lumbricoides, Schistosoma mansoni and Hymenolepis nana infections, Kato-Katz was more sensitive in detecting Trichuris trichiura infection, and McMaster had higher sensitivity in diagnosing hookworm infection. Conclusions: The Mini Parasep(r) SF faecal parasite concentrator technique showed better performance than the Kato-Katz and McMaster techniques for the detection of intestinal helminth infections in stool samples, particularly for S. mansoni, A. lumbricoides and H. nana. Hence, Mini Parasep(r) SF could be used as one of the suitable faecal examination methods for surveillance and monitoring of preventive chemotherapy of schistosomiasis. PMID- 29509953 TI - Primary healthcare providers' practices related to non-malarial acute febrile illness in Burkina Faso. AB - Background: In Africa, fever is the main reason for consultation, with malaria playing a prominent role. Studies have reported that the widespread use of rapid diagnostic tests for malaria, implemented since 2010, has revealed an increasing proportion of non-malaria acute febrile illnesses (NMAFI). It is an important public health issue because evidence shows that mortality is higher among patients presenting with non-malarial fever than among those with malaria. Methods: This cross-sectional study assessed the professional practices of healthcare providers in the management of NMAFI in urban and rural sites in Burkina Faso. Data was collected from 286 healthcare providers through a questionnaire based on the clinical situation in 2014. Factors have been associated using a hierarchical linear mixed model with random intercepts to model dependence of outcomes for healthcare providers working on the same site. Results: Survey results showed limited knowledge about management of NMAFI, global survey score on General Practice Indicator being 60% (36.02/60.00). This gap was more evident at the admission and diagnosis level. The study's population from rural areas had better survey score than that of urban areas concerning the respect of adequacy diagnosis, treatment and use of antibiotics in NMAFI, 15.71 vs 13.93 mean score (p=0.01) (75 vs 66% on a 0 to 100% scale, with 100% being the best). Overall, more educated participants performed relatively better. A total of 46% (134/286) of participants felt that they needed training in at least one of the fever-related issues. Conclusions: Increased awareness and knowledge of management for NMAFI are urgently required in Burkina Faso. This must be done through regular supervision and training courses targeted specifically at primary healthcare providers. PMID- 29509954 TI - Liana and tree below-ground water competition-evidence for water resource partitioning during the dry season. AB - To date, reasons for the increase in liana abundance and biomass in the Neotropics are still unclear. One proposed hypothesis suggests that lianas, in comparison with trees, are more adaptable to drought conditions. Moreover, previous studies have assumed that lianas have a deeper root system, which provides access to deeper soil layers, thereby making them less susceptible to drought stress. The dual stable water isotope approach (delta18O and delta2H) enables below-ground vegetation competition for water to be studied. Based on the occurrence of a natural gradient in soil water isotopic signatures, with enriched signatures in shallow soil relative to deep soil, the origin of vegetation water sources can be derived. Our study was performed on canopy trees and lianas reaching canopy level in tropical forests of French Guiana. Our results show liana xylem water isotopic signatures to be enriched in heavy isotopes in comparison with those from trees, indicating differences in water source depths and a more superficial root activity for lianas during the dry season. This enables them to efficiently capture dry season precipitation. Our study does not support the liana deep root water extraction hypothesis. Additionally, we provide new insights into water competition between tropical canopy lianas and trees. Results suggest that this competition is mitigated during the dry season due to water resource partitioning. PMID- 29509955 TI - Effect of BMI on pregnancy rates following ovulation induction and assisted conception among women in Qatar experiencing infertility. PMID- 29509956 TI - Relapse in dermatofibrosarcoma protuberans: A histological and molecular analysis. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare low grade tumor with a locally aggressive behavior and low metastatic potential. OBJECTIVES: To evaluate the factors that are associated with relapse in DFSP. Methods Retrospective analysis of medical records from 61 patients with dermatofibrosarcoma. Fluorescence in situ hybridization was used to detect translocations. RESULTS: Of 61 patients, 6 experienced a relapse. No patient with resection margins greater than 3 cm had a recurrence. One relapse was observed in a patient treated with at least 2 cm margins and 4 relapses occurred in 16 patients whose margins were below 2 cm (P = 0.018). The frequency of translocations was 77.8%. The recurrence rate was lower in patients with translocation, but this difference was not significant. Immunohistochemical markers did not correlate with recurrence rates, but greater FasL expression was associated with recurrence in patients with margins smaller than 3 cm. CONCLUSIONS: Surgical margins smaller than than 2 cm are related to higher recurrences in dermatofibrosarcomas. In this analysis a 2 cm margin was acceptable for treatment. Between all the immunohistochemical markers analyzed, only FasL was associated with a higher recurrence rate in patients with margins smaller than 3 cm. PMID- 29509958 TI - Management of thin melanoma. PMID- 29509957 TI - Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery. AB - BACKGROUND: The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may help prevent postoperative cardiac complications. OBJECTIVES: To determine the efficacy and safety of alpha-2 adrenergic agonists for reducing mortality and cardiac complications in adults undergoing cardiac surgery and non-cardiac surgery. SEARCH METHODS: We searched CENTRAL (2017, Issue 4), MEDLINE (1950 to April Week 4, 2017), Embase (1980 to May 2017), the Science Citation Index, clinical trial registries, and reference lists of included articles. SELECTION CRITERIA: We included randomized controlled trials that compared alpha-2 adrenergic agonists (i.e. clonidine, dexmedetomidine or mivazerol) against placebo or non-alpha-2 adrenergic agonists. Included trials had to evaluate the efficacy and safety of alpha-2 adrenergic agonists for preventing perioperative mortality or cardiac complications (or both), or measure one or more relevant outcomes (i.e. death, myocardial infarction, heart failure, acute stroke, supraventricular tachyarrhythmia and myocardial ischaemia). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality, extracted data and independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. We evaluated included studies using the Cochrane 'Risk of bias' tool, and the quality of the evidence underlying pooled treatment effects using GRADE methodology. Given the clinical heterogeneity between cardiac and non-cardiac surgery, we analysed these subgroups separately. We expressed treatment effects as pooled risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included 47 trials with 17,039 participants. Of these studies, 24 trials only included participants undergoing cardiac surgery, 23 only included participants undergoing non-cardiac surgery and eight only included participants undergoing vascular surgery. The alpha-2 adrenergic agonist studied was clonidine in 21 trials, dexmedetomidine in 24 trials and mivazerol in two trials.In non cardiac surgery, there was high quality evidence that alpha-2 adrenergic agonists led to a similar risk of all-cause mortality compared with control groups (1.3% with alpha-2 adrenergic agonists versus 1.7% with control; RR 0.80, 95% CI 0.61 to 1.04; participants = 14,081; studies = 16). Additionally, the risk of cardiac mortality was similar between treatment groups (0.8% with alpha-2 adrenergic agonists versus 1.0% with control; RR 0.86, 95% CI 0.60 to 1.23; participants = 12,525; studies = 5, high quality evidence). The risk of myocardial infarction was probably similar between treatment groups (RR 0.94, 95% CI 0.69 to 1.27; participants = 13,907; studies = 12, moderate quality evidence). There was no associated effect on the risk of stroke (RR 0.93, 95% CI 0.55 to 1.56; participants = 11,542; studies = 7; high quality evidence). Conversely, alpha-2 adrenergic agonists probably increase the risks of clinically significant bradycardia (RR 1.59, 95% CI 1.18 to 2.13; participants = 14,035; studies = 16) and hypotension (RR 1.24, 95% CI 1.03 to 1.48; participants = 13,738; studies = 15), based on moderate quality evidence.There was insufficient evidence to determine the effect of alpha-2 adrenergic agonists on all-cause mortality in cardiac surgery (RR 0.52, 95% CI 0.26 to 1.04; participants = 1947; studies = 16) and myocardial infarction (RR 1.01, 95% CI 0.43 to 2.40; participants = 782; studies = 8), based on moderate quality evidence. There was one cardiac death in the clonidine arm of a study of 22 participants. Based on very limited data, alpha-2 adrenergic agonists may have reduced the risk of stroke (RR 0.37, 95% CI 0.15 to 0.93; participants = 1175; studies = 7; outcome events = 18; low quality evidence). Conversely, alpha-2 adrenergic agonists increased the risk of bradycardia from 6.4% to 12.0% (RR 1.88, 95% CI 1.35 to 2.62; participants = 1477; studies = 10; moderate quality evidence), but their effect on hypotension was uncertain (RR 1.19, 95% CI 0.87 to 1.64; participants = 1413; studies = 9; low quality evidence).These results were qualitatively unchanged in subgroup analyses and sensitivity analyses. AUTHORS' CONCLUSIONS: Our review concludes that prophylactic alpha-2 adrenergic agonists generally do not prevent perioperative death or major cardiac complications. For non-cardiac surgery, there is moderate-to-high quality evidence that these agents do not prevent death, myocardial infarction or stroke. Conversely, there is moderate quality evidence that these agents have important adverse effects, namely increased risks of hypotension and bradycardia. For cardiac surgery, there is moderate quality evidence that alpha-2 adrenergic agonists have no effect on the risk of mortality or myocardial infarction, and that they increase the risk of bradycardia. The quality of evidence was inadequate to draw conclusions regarding the effects of alpha-2 agonists on stroke or hypotension during cardiac surgery. PMID- 29509959 TI - Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. AB - BACKGROUND: Factor Xa inhibitors and vitamin K antagonists (VKAs) are now recommended in treatment guidelines for preventing stroke and systemic embolic events in people with atrial fibrillation (AF). This is an update of a Cochrane review previously published in 2013. OBJECTIVES: To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for preventing cerebral or systemic embolic events in people with AF. SEARCH METHODS: We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2017), MEDLINE (1950 to April 2017), and Embase (1980 to April 2017). We also contacted pharmaceutical companies, authors and sponsors of relevant published trials. We used outcome data from marketing authorisation applications of apixaban, edoxaban and rivaroxaban that were submitted to regulatory authorities in Europe and the USA. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that directly compared the effects of long-term treatment (lasting more than four weeks) with factor Xa inhibitors versus VKAs for preventing cerebral and systemic embolism in people with AF. DATA COLLECTION AND ANALYSIS: The primary efficacy outcome was the composite endpoint of all strokes and systemic embolic events. Two review authors independently extracted data, and assessed the quality of the trials and the risk of bias. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. In case of moderate or high heterogeneity of treatment effects, we used a random effects model to compare the overall treatment effects. We also performed a pre specified sensitivity analysis excluding any open-label studies. MAIN RESULTS: We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. The majority of the included data (approximately 90%) was from apixaban, edoxaban, and rivaroxaban.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in all of the included studies. Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin in participants with AF (OR 0.89, 95% CI 0.82 to 0.97; 13 studies; 67,477 participants; high-quality evidence).Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.78, 95% CI 0.73 to 0.84; 13 studies; 67,396 participants; moderate-quality evidence). There was, however, statistically significant and high heterogeneity (I2 = 83%). When we repeated this analysis using a random-effects model, it did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). A pre specified sensitivity analysis excluding all open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81), but high heterogeneity was also observed in this analysis (I2 = 72%). The same sensitivity analysis using a random-effects model also showed a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96).Treatment with a factor Xa inhibitor significantly reduced the risk of intracranial haemorrhages (ICHs) compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high quality evidence). We observed moderate, but statistically significant heterogeneity (I2 = 55%). The pre-specified sensitivity analysis excluding open label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non-statistically significant heterogeneity (I2 = 27%).Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS: Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in people with AF. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Factor Xa inhibitors also reduced the number of ICHs, all-cause deaths and major bleedings compared with warfarin, although the evidence for a reduction in the latter is less robust. PMID- 29509960 TI - Dock2 in the development of inflammation and cancer. AB - An atypical guanine exchange factor, Dock2 is specifically expressed in hematopoietic cells and regulates activation and migration of immune cells through activating Ras-related C3 botulinum toxin substrate (Rac). Dock2 was shown to be critical in the development of various inflammatory diseases, including allergic diseases, HIV infection, and graft rejection in organ transplantation. DOCK2 mutation in infants was recently identified to be associated with T and B cell combined immunodeficiency. Furthermore, Dock2 is involved in host protection during enteric bacterial infection and is also associated with the proliferation of cancer cells. It was also shown that patients with digestive tract cancer had high frequency mutation of DOCK2. This review summarizes the latest research progresses on the role of Dock2 for the development of various inflammatory diseases and cancers, and discusses the potential application of Dock2 modulators for patient treatment. PMID- 29509961 TI - The value of endocervical curettage during loop electrosurgical excision procedures in predicting persistent/recurrent preinvasive cervical disease. AB - OBJECTIVE: To evaluate the usefulness of endocervical curettage (ECC) during loop electrosurgical excision procedures (LEEPs) in predicting the risk of persistence/recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and informing clinical decision-making after LEEP. METHODS: The present retrospective study included women undergoing LEEP for CIN2+ at a teaching hospital in Chile between January 1, 2007, and December 31, 2014. Demographic, pathologic, and follow-up data were collected. Associations between predictors and treatment failure (persistent/recurrent disease) were examined; a Cox model was used to assess the effects of different variables on the failure rate. RESULTS: The analysis included 330 women with a mean follow-up of 29.4 months; 188 women underwent ECC at the time of LEEP. On multivariate analysis, a positive ECC was the only variable significantly associated with persistence/recurrence (P=0.001). In the Cox model, positive ECC (P=0.001) and positive margins (P=0.009) were independently associated with higher failure rates. When faced with positive ECC findings, clinicians tended to perform additional treatment instead of advising follow-up. CONCLUSION: Positive findings from ECC performed during LEEP were a better predictor of persistent/recurrent disease than margin status, after adjusting the individual variable effect in the Cox modelling. The performance of ECC is recommended during any LEEP performed for CIN2+; in particular, it should never be omitted if endocervical disease is suspected. PMID- 29509962 TI - Burkholderia gladioli-associated facial pustulosis as a first sign of chronic granulomatous disease in a child - Case report and review. PMID- 29509963 TI - Neutrophil-lymphocyte ratio is associated with prognosis in patients who underwent potentially curative resection for gastric cancer. AB - BACKGROUND AND OBJECTIVES: The role of inflammation in cancer development is a well-known phenomenon that may be represented by the neutrophil-lymphocyte ratio (NLR). The present research intends to determine the impact of NLR on the survival outcome of patients with gastric cancer (GC), and to evaluate its use as a stratification factor for the staging groups. METHODS: Data regarding clinical characteristics, surgery, pathology, and follow-up were retrospectively collected from our single-center prospective database. Blood samples were obtained before surgery. RESULTS: A total of 383 patients (231 males) who underwent gastrectomy with lymphadenectomy were evaluated between 2009 and 2016. NLR established cutoff was 2.44, and patients were divided in NLR >=2.44 (hNLR) and <2.44 (lNLR). hNLR patients (38.4% of the cases) had lower disease-free survival and overall survival (OS) compared to lNLR patients (P = 0.047 and P = 0.045, respectively). Risk stratification according to NLR value was done in same tumor depth (T4 and 4 cm) and preoperative cytology. The maximum diameter of thyroid nodule was gradually increased in both groups with statistical significance (P < .001 and P < .001, respectively). No significant differences in change of maximum diameter of thyroid nodule (P = .132) and tumour volume (P = .208) were found between the FA and FTC groups during the follow-up. The median time to a significant tumour growth from baseline was not different between the FA and FTC groups (1.4 years and 1.7 years, respectively, P = .556). When we divided the patients into four groups (rapid, moderate, slow and no growth) according to the growth velocity of the thyroid tumours, no significant difference in growth velocity was found among the groups. CONCLUSIONS: The tumour size and growth rate of the thyroid nodule itself could not predict malignancy. Diagnostic approaches that use molecular markers would be more important than clinical features for the decision of diagnostic surgery for patients with follicular tumours. PMID- 29509976 TI - Sodium Threshold in Model Reduced and Low Fat Oil-in-Water Emulsion Systems. AB - : Sodium and fat reduction in the diet are key factors in the nutrition management of hypertensive individuals. Several reduced and lower fat foods have higher amounts of sodium than their regular fat counterparts, which contradict sodium and fat reduction goals for hypertensive individuals. The objective of this research was to determine the threshold of sodium in a model reduced and low fat oil-in-water emulsion system analogous to salad dressings, so as to identify a reduction level of sodium that may not compromise consumer acceptability. Thirty panelists used the R-index by rating method to evaluate a model reduced fat emulsion system with 7 sodium concentrations (175, 200, 230, 265, 305, and 350 mg) and a model low fat emulsion system with 6 sodium concentrations (160, 170, 180, 190, and 200 mg). For both emulsion systems, 30 g servings of each concentration were presented to panelists. Panelists received 10 replicates of noise and signal samples for both fat levels. The group sodium threshold for the reduced and low fat emulsions was 241.11 and 183.56 mg, respectively. Results indicate saltiness perception is increased when fat content is decreased, and threshold for sodium in the reduced fat emulsion system is higher than the low fat emulsion system with lower fat content. Study findings show opportunities for sodium reduction in reduced and low fat food emulsion systems, particularly additional reductions of sodium without consumer detection. PRACTICAL APPLICATION: Study results demonstrated sodium difference thresholds for the reduced and low fat emulsions were at levels lower than the mean sodium content found in comparable processed food emulsion systems. Results indicate sodium content can potentially be decreased in reduced and lower fat food emulsion systems without consumer detection. Having insight for where consumers are able to detect a difference in sodium levels within reduced and low fat food systems can contribute to a successful reduction of sodium in reduced and lower fat food systems and benefit individuals requiring reductions of sodium and fat in processed food systems. PMID- 29509978 TI - Professional Recognition for Good Reviewers. PMID- 29509974 TI - Left ventricular structural alterations are accompanied by subclinical systolic dysfunction in type 2 diabetes mellitus patients with concomitant hyperlipidemia: An analysis based on 3D speckle tracking echocardiography. AB - AIMS: The aims of the current study were to analyze and compare the left ventricular (LV) structure and function in type 2 diabetes mellitus (T2DM) patients with or without hyperlipidemia using conventional echocardiography and real-time three-dimensional speckle tracking echocardiography (3DSTE) and to determine the variables that could affect LV strain values in these patients. METHODS: Eighty-one T2DM patients with normal LVEF (>=55%) were included, 41 of whom had hyperlipidemia as comorbidity. Forty age- and gender-matched healthy volunteers were recruited as the control group. Conventional echocardiography and 3DSTE were performed, and LV global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS) were measured. RESULTS: Significant differences in two-dimensional LV geometry were found among three groups (P = .015). Compared with the control group, LV remodeling was more prevalent in the patients with T2DM, and LV hypertrophy was most prevalent in the T2DM patients with hyperlipidemia. GLS and GCS values decreased significantly in the T2DM patients without hyperlipidemia relative to the control group (P < .01 and P < .05). The GLS, GCS, GAS, and GRS values in the T2DM patients with hyperlipidemia were all significantly lower than those in the control group (all P < .001) and were also significantly lower than those in the T2DM patients without hyperlipidemia (P < .01 or P < .05). Both fasting plasma glucose (FPG) and hyperlipidemia were independently associated with all strain values in patients with T2DM. CONCLUSIONS: The combination of conventional echocardiography and 3DSTE could detect subclinical LV abnormalities in T2DM patients with or without hyperlipidemia. PMID- 29509979 TI - Comparative Analysis of the Antioxidant Capacities and Phenolic Compounds of Oat and Buckwheat Vinegars During Production Processes. AB - : This study aimed to explore the dynamic changes in the antioxidant activities and phenolic acid profiles of oat and buckwheat vinegars during different production stages. The results showed that both oat and buckwheat vinegar products comparably attenuated D-galactose-induced oxidative damage in mice serum and liver, indicating no obvious dose dependence within the tested concentrations. However, oat vinegar product revealed more favorable in vitro antioxidant activities than those in buckwheat vinegar product as evaluated by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging abilities. Moreover, the alcoholic fermentation, acetic acid fermentation and fumigating induced successive increase in DPPH radical scavenging abilities and phenolic acid contents of the fermentation substrates of oat and buckwheat vinegars. Importantly, the different fermentation processes of oat and buckwheat vinegars were accompanied by the dynamic migration and transformation of specific phenolic acids across bound, esterified and free fractions. Thus, the antioxidant activities of oat and buckwheat vinegars could be improved through targeted modulation of the generation of specific phenolic acid fractions during production processes. PRACTICAL APPLICATION: We had evaluated the in vitro and in vivo antioxidant activities and phenolic acid contents of oat and buckwheat vinegars, and further explored the dynamic changes of bound, esterified and free phenolic acid fractions during successive fermentation processes of oat and buckwheat vinegars. This study provided the theoretical guidance for obtaining minor grain vinegar with the optimal antioxidant activities through targeted modulation of fermentation processes. PMID- 29509981 TI - Myosin 10 is involved in murine pigmentation. AB - Myosins are molecular motors that are well known for their role in cell movement and contractile functions. Although extensively studied in muscle physiology, little is known about the function of myosins in mammalian skin. As part of the Sanger Institute Mouse Genetics Project, we have identified a role for Myo10 in pigmentation, with a phenotype unlike those of Myo5a or Myo7a. Adult mice homozygous for a disrupted Myo10 allele on a C57BL/6N background displayed a high degree of penetrance for white patches on their abdomen and dorsal surface. Forepaw syndactyly and hind paw syndactyly were also observed in these mice. Tail epidermal wholemounts showed a complete lack of melanocytes in the hair follicles and interfollicular epidermis. Myo10 has previously been implicated in human pigmentation. Our current study reveals involvement of Myo10 in murine skin pigmentation. PMID- 29509980 TI - Bt rice could provide ecological resistance against nontarget planthoppers. AB - Genetically engineered (GE) rice lines expressing Lepidoptera-active insecticidal cry genes from the bacterium Bacillus thuringiensis (Bt) have been developed in China. Field surveys indicated that Bt rice harbours fewer rice planthoppers than non-Bt rice although planthoppers are not sensitive to the produced Bt Cry proteins. The mechanisms underlying this phenomenon remain unknown. Here, we show that the low numbers of planthoppers on Bt rice are associated with reduced caterpillar damage. In laboratory and field-cage experiments, the rice planthopper Nilapavata lugens had no feeding preference for undamaged Bt or non Bt plants but exhibited a strong preference for caterpillar-damaged plants whether Bt or non-Bt. Under open-field conditions, rice planthoppers were more abundant on caterpillar-damaged non-Bt rice than on neighbouring healthy Bt rice. GC-MS analyses showed that caterpillar damage induced the release of rice plant volatiles known to be attractive to planthoppers, and metabolome analyses revealed increased amino acid contents and reduced sterol contents known to benefit planthopper development. That Lepidoptera-resistant Bt rice is less attractive to this important nontarget pest in the field is therefore a first example of ecological resistance of Bt plants to nontarget pests. Our findings suggest that non-Bt rice refuges established for delaying the development of Bt resistance may also act as a trap crop for N. lugens and possibly other planthoppers. PMID- 29509982 TI - Development of an anaesthetized-rat model of exercise hyperpnoea: an integrative model of respiratory control using an equilibrium diagram. AB - NEW FINDINGS: What is the central question of this study? The lack of useful small-animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states. What is the main finding and its importance? We developed an anaesthetized-rat model for studying exercise hyperpnoea, using a respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. ABSTRACT: Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiological basis of various disease models, the lack of an integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anaesthetized-rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anaesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO2 pressure (P ETC O2) and minute ventilation (VE), and the plant by the hyperbolic relationship between VE and P ETC O2. During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen uptake. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points (VE and P ETC O2) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anaesthetized-rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. PMID- 29509984 TI - Spatial population genetic structure of a bacterial parasite in close coevolution with its host. AB - Knowledge of a species' population genetic structure can provide insight into fundamental ecological and evolutionary processes including gene flow, genetic drift and adaptive evolution. Such inference is of particular importance for parasites, as an understanding of their population structure can illuminate epidemiological and coevolutionary dynamics. Here, we describe the population genetic structure of the bacterium Pasteuria ramosa, a parasite that infects planktonic crustaceans of the genus Daphnia. This system has become a model for investigations of host-parasite interactions and represents an example of coevolution via negative frequency-dependent selection (aka "Red Queen" dynamics). To sample P. ramosa, we experimentally infected a panel of Daphnia hosts with natural spore banks from the sediments of 25 ponds throughout much of the species range in Europe and western Asia. Using 12 polymorphic variable number tandem repeat loci (VNTR loci), we identified substantial genetic diversity, both within and among localities, that was structured geographically among ponds. Genetic diversity was also structured among host genotypes within ponds, although this pattern varied by locality, with P. ramosa at some localities partitioned into distinct host-specific lineages, and other localities where recombination had shuffled genetic variation among different infection phenotypes. Across the sample range, there was a pattern of isolation by distance, and principal components analysis coupled with Procrustes rotation identified congruence between patterns of genetic variation and geography. Our findings support the hypothesis that Pasteuria is an endemic parasite coevolving closely with its host. These results provide important context for previous studies of this model system and inform hypotheses for future research. PMID- 29509983 TI - Three unrelated protease inhibitors enhance accumulation of pharmaceutical recombinant proteins in Nicotiana benthamiana. AB - Agroinfiltrated Nicotiana benthamiana is a flexible and scalable platform for recombinant protein (RP) production, but its great potential is hampered by plant proteases that degrade RPs. Here, we tested 29 candidate protease inhibitors (PIs) in agroinfiltrated N. benthamiana leaves for enhancing accumulation of three unrelated RPs: glycoenzyme alpha-Galactosidase; glycohormone erythropoietin (EPO); and IgG antibody VRC01. Of the previously described PIs enhancing RP accumulation, we found only cystatin SlCYS8 to be effective. We identified three additional new, unrelated PIs that enhance RP accumulation: N. benthamiana NbPR4, NbPot1 and human HsTIMP, which have been reported to inhibit cysteine, serine and metalloproteases, respectively. Remarkably, accumulation of all three RPs is enhanced by each PI similarly, suggesting that the mechanism of degradation of unrelated RPs follows a common pathway. Inhibitory functions HsTIMP and SlCYS8 are required to enhance RP accumulation, suggesting that their target proteases may degrade RPs. Different PIs additively enhance RP accumulation, but the effect of each PI is dose-dependent. Activity-based protein profiling (ABPP) revealed that the activities of papain-like Cys proteases (PLCPs), Ser hydrolases (SHs) or vacuolar processing enzymes (VPEs) in leaves are unaffected upon expression of the new PIs, whereas SlCYS8 expression specifically suppresses PLCP activity only. Quantitative proteomics indicates that the three new PIs affect agroinfiltrated tissues similarly and that they all increase immune responses. NbPR4, NbPot1 and HsTIMP can be used to study plant proteases and improve RP accumulation in molecular farming. PMID- 29509986 TI - Phenotypic and transcriptomic responses to salinity stress across genetically and geographically divergent Tigriopus californicus populations. AB - Species inhabiting the North American west coast intertidal must tolerate an extremely variable environment, with large fluctuations in both temperature and salinity. Uncovering the mechanisms for this tolerance is key to understanding species' persistence. We tested for differences in salinity tolerance between populations of Tigriopus californicus copepods from locations in northern (Bodega Reserve) and southern (San Diego) California known to differ in temperature, precipitation and humidity. We also tested for differences between populations in their transcriptomic responses to salinity. Although these two populations have ~20% mtDNA sequence divergence and differ strongly in other phenotypic traits, we observed similarities in their phenotypic and transcriptomic responses to low and high salinity stress. Salinity significantly affected respiration rate (increased under low salinity and reduced under high salinity), but we found no significant effect of population on respiration or a population by salinity interaction. Under high salinity, there was no population difference in knock-down response, but northern copepods had a smaller knock-down under low salinity stress, corroborating previous results for T. californicus. Northern and southern populations had a similar transcriptomic response to salinity based on a principle components analysis, although differential gene expression under high salinity stress was three times lower in the northern population compared to the southern population. Transcripts differentially regulated under salinity stress were enriched for "amino acid transport" and "ion transport" annotation categories, supporting previous work demonstrating that the accumulation of free amino acids is important for osmotic regulation in T. californicus. PMID- 29509988 TI - Capsaicin induces atopic dermatitis-like manifestations through dysregulation of proteolytic system and alteration of filaggrin processing in rats. AB - Atopic dermatitis (AD) is a complex disease featuring pruritic skin inflammation. Many animal models have been developed. In a rat model, subcutaneous capsaicin injection within 48 hours after birth induces AD-like skin manifestations of dermatitis and scratching behaviour 3 weeks after the injection. When 2- to 4 week-old rats were injected with capsaicin, the lag period was shortened, and the severity of skin manifestations was significantly reduced, suggesting influences of postnatal development. Lgr6 is an epidermal stem cell marker that is normally restricted to the isthmus area of hair follicles at postnatal 2 weeks. Lgr6 persisted in the interfollicular epidermis of capsaicin-injected rats beyond 3 weeks after birth, indicating that capsaicin-induced skin manifestations were influenced by postnatal epidermal development. Capsaicin injection induced alteration of proteolytic processing of filaggrin and corneodesmosin, suggesting epidermal barrier dysfunction. Inappropriate degradation of matriptase was observed. Degrees of proteolysis of these proteins were corelated with the severity of manifestations, suggesting that inappropriate proteolysis might be a possible cause of the skin manifestations. These results strongly suggest that capsaicin may dysregulate the protease system, resulting in alteration of profilaggrin and corneodesmosin proteolysis and skin manifestations. These events may be influenced by postnatal epidermal development. PMID- 29509987 TI - The rice terpene synthase gene OsTPS19 functions as an (S)-limonene synthase in planta, and its overexpression leads to enhanced resistance to the blast fungus Magnaporthe oryzae. AB - Rice blast disease, caused by the fungus Magnaporthe oryzae, is the most devastating disease of rice. In our ongoing characterization of the defence mechanisms of rice plants against M. oryzae, a terpene synthase gene OsTPS19 was identified as a candidate defence gene. Here, we report the functional characterization of OsTPS19, which is up-regulated by M. oryzae infection. Overexpression of OsTPS19 in rice plants enhanced resistance against M. oryzae, while OsTPS19 RNAi lines were more susceptible to the pathogen. Metabolic analysis revealed that the production of a monoterpene (S)-limonene was increased and decreased in OsTPS19 overexpression and RNAi lines, respectively, suggesting that OsTPS19 functions as a limonene synthase in planta. This notion was further supported by in vitro enzyme assays with recombinant OsTPS19, in which OsTPS19 had both sesquiterpene activity and monoterpene synthase activity, with limonene as a major product. Furthermore, in a subcellular localization experiment, OsTPS19 was localized in plastids. OsTPS19 has a highly homologous paralog, OsTPS20, which likely resulted from a recent gene duplication event. We found that the variation in OsTPS19 and OsTPS20 enzyme activities was determined by a single amino acid in the active site cavity. The expression of OsTPS20 was not affected by M. oryzae infection. This indicates functional divergence of OsTPS19 and OsTPS20. Lastly, (S)-limonene inhibited the germination of M. oryzae spores in vitro. OsTPS19 was determined to function as an (S)-limonene synthase in rice and plays a role in defence against M. oryzae, at least partly, by inhibiting spore germination. PMID- 29509985 TI - Up-regulation of GhTT2-3A in cotton fibres during secondary wall thickening results in brown fibres with improved quality. AB - Brown cotton fibres are the most widely used naturally coloured raw materials for the eco-friendly textile industry. Previous studies have indicated that brown fibre pigments belong to proanthocyanidins (PAs) or their derivatives, and fibre coloration is negatively associated with cotton productivity and fibre quality. To date, the molecular basis controlling the biosynthesis and accumulation of brown pigments in cotton fibres is largely unknown. In this study, based on expressional and transgenic analyses of cotton homologs of ArabidopsisPA regulator TRANSPARENT TESTA 2 (TT2) and fine-mapping of the cotton dark-brown fibre gene (Lc1), we show that a TT2 homolog, GhTT2-3A, controls PA biosynthesis and brown pigmentation in cotton fibres. We observed that GhTT2-3A activated GhbHLH130D, a homolog of ArabidopsisTT8, which in turn synergistically acted with GhTT2-3A to activate downstream PA structural genes and PA synthesis and accumulation in cotton fibres. Furthermore, the up-regulation of GhTT2-3A in fibres at the secondary wall-thickening stage resulted in brown mature fibres, and fibre quality and lint percentage were comparable to that of the white-fibre control. The findings of this study reveal the regulatory mechanism controlling brown pigmentation in cotton fibres and demonstrate a promising biotechnological strategy to break the negative linkage between coloration and fibre quality and/or productivity. PMID- 29509990 TI - Social media engagement amongst 2017 colorectal surgery Tripartite Meeting attendees: updates on contemporary social media use. AB - AIM: Engagement by medical professionals with social media (SM) is increasing. Variation is noted in engagement between SM platforms and between surgical specialities and geographical regions. We aimed to study SM engagement by colorectal surgeons attending an international conference. METHOD: Surgeons were identified from the delegate list of the 2017 Annual Meeting of the American Society of Colon and Rectal Surgeons (ASCRS) and Tripartite Meeting (Seattle, Washington, USA). Delegates were searched on Twitter and LinkedIn for the presence of a matching profile. SM presence, activity, gender and geographical region were analysed. RESULTS: Two hundred and seventy (13.2%) surgeons had Twitter accounts and 994 (44.3%) had LinkedIn profiles. UK surgeons were more likely to be on Twitter than surgeons from elsewhere (23.4% vs 12.7%, P = 0.0072). Significant variation in SM membership between each geographical region was noted, with usage rates for Twitter of 18.1% in Europe, 14.4% in North America, 12.9% in South America, 4.3% in Oceania, 3.7% in Asia and 0% in Africa. A similar picture for LinkedIn is seen. The #ASCRS17 meeting saw the highest participation of users to date (979 participants, over 7000 individual tweets and nearly 14 million impressions). CONCLUSION: SM engagement by colorectal surgeons continues to increase. Significant geographical variation is noted, suggesting that SM's unique potential for education and networking may not yet be widely appreciated globally. Future work should include further analysis into tweet contents to gain insights and optimize the use of SM as an educational adjunct. PMID- 29509989 TI - Lineage-specific plasmid acquisition and the evolution of specialized pathogens in Bacillus thuringiensis and the Bacillus cereus group. AB - Bacterial plasmids can vary from small selfish genetic elements to large autonomous replicons that constitute a significant proportion of total cellular DNA. By conferring novel function to the cell, plasmids may facilitate evolution but their mobility may be opposed by co-evolutionary relationships with chromosomes or encouraged via the infectious sharing of genes encoding public goods. Here, we explore these hypotheses through large-scale examination of the association between plasmids and chromosomal DNA in the phenotypically diverse Bacillus cereus group. This complex group is rich in plasmids, many of which encode essential virulence factors (Cry toxins) that are known public goods. We characterized population genomic structure, gene content and plasmid distribution to investigate the role of mobile elements in diversification. We analysed coding sequence within the core and accessory genome of 190 B. cereus group isolates, including 23 novel sequences and genes from 410 reference plasmid genomes. While cry genes were widely distributed, those with invertebrate toxicity were predominantly associated with one sequence cluster (clade 2) and phenotypically defined Bacillus thuringiensis. Cry toxin plasmids in clade 2 showed evidence of recent horizontal transfer and variable gene content, a pattern of plasmid segregation consistent with transfer during infectious cooperation. Nevertheless, comparison between clades suggests that co-evolutionary interactions may drive association between plasmids and chromosomes and limit wider transfer of key virulence traits. Proliferation of successful plasmid and chromosome combinations is a feature of specialized pathogens with characteristic niches (Bacillus anthracis, B. thuringiensis) and has occurred multiple times in the B. cereus group. PMID- 29509992 TI - Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus infected patients with hepatic fat >=5% by magnetic resonance spectroscopy. METHODS: Five subjects received eplerenone (25 mg daily * 1 week followed by 50 mg daily * 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24. RESULTS: The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 +/ 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 +/- 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values. CONCLUSIONS: The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations. PMID- 29509991 TI - Use of a draft genome of coffee (Coffea arabica) to identify SNPs associated with caffeine content. AB - Arabica coffee (Coffea arabica) has a small gene pool limiting genetic improvement. Selection for caffeine content within this gene pool would be assisted by identification of the genes controlling this important trait. Sequencing of DNA bulks from 18 genotypes with extreme high- or low-caffeine content from a population of 232 genotypes was used to identify linked polymorphisms. To obtain a reference genome, a whole genome assembly of arabica coffee (variety K7) was achieved by sequencing using short read (Illumina) and long-read (PacBio) technology. Assembly was performed using a range of assembly tools resulting in 76 409 scaffolds with a scaffold N50 of 54 544 bp and a total scaffold length of 1448 Mb. Validation of the genome assembly using different tools showed high completeness of the genome. More than 99% of transcriptome sequences mapped to the C. arabica draft genome, and 89% of BUSCOs were present. The assembled genome annotated using AUGUSTUS yielded 99 829 gene models. Using the draft arabica genome as reference in mapping and variant calling allowed the detection of 1444 nonsynonymous single nucleotide polymorphisms (SNPs) associated with caffeine content. Based on Kyoto Encyclopaedia of Genes and Genomes pathway based analysis, 65 caffeine-associated SNPs were discovered, among which 11 SNPs were associated with genes encoding enzymes involved in the conversion of substrates, which participate in the caffeine biosynthesis pathways. This analysis demonstrated the complex genetic control of this key trait in coffee. PMID- 29509993 TI - The need for an extensive neuropsychological assessment for a reliable diagnosis of mild cognitive impairment in patients with Parkinson's disease. PMID- 29509994 TI - A short-term in vivo model for Merkel Cell Carcinoma. AB - In vivo tumor models are essential for studying the biology of cancer, identifying tumor targets and evaluating antitumor drugs. Considering the request for the minimisation of animal experiments and following the "3R"-rule ("replacement," "refinement," "reduction"), it has become crucial to develop alternative experimental models in cancer biology. Several studies have already described the avian chorioallantoic membrane (CAM) model as an alternative to rodents, suitable to investigate growth, progression and metastasis of various types of cancer. In the present work, we grafted three Merkel cell carcinoma (MCC) cell lines onto the avian CAM and monitored tumor growth and development of solid tumor nodules. Morphology of xenograft was characterised histologically and immunohistochemically. Our results demonstrate CAM assay as a useful tool to study MCC pathophysiology. PMID- 29509996 TI - The relationship between mucosal damage in celiac disease and the risk of neurological and psychiatric conditions is much more complex than previously thought. PMID- 29509995 TI - Comparing three types of dietary samples for prey DNA decay in an insect generalist predator. AB - The rapidly growing field of molecular diet analysis is becoming increasingly popular among ecologists, especially when investigating methodologically challenging groups, such as invertebrate generalist predators. Prey DNA detection success is known to be affected by multiple factors; however, the type of dietary sample has rarely been considered. Here, we address this knowledge gap by comparing prey DNA detection success from three types of dietary samples. In a controlled feeding experiment, using the carabid beetle Pterostichus melanarius as a model predator, we collected regurgitates, faeces and whole consumers (including their gut contents) at different time points postfeeding. All dietary samples were analysed using multiplex PCR, targeting three different length DNA fragments (128, 332 and 612 bp). Our results show that both the type of dietary sample and the size of the DNA fragment contribute to a significant part of the variation found in the detectability of prey DNA. Specifically, we observed that in both regurgitates and whole consumers, prey DNA was detectable significantly longer for all fragment sizes than for faeces. Based on these observations, we conclude that prey DNA detected from regurgitates and whole consumers DNA extracts are comparable, whereas prey DNA detected from faeces, though still sufficiently reliable for ecological studies, will not be directly comparable to the former. Therefore, regurgitates and faeces constitute a useful, nonlethal source for dietary information that could be applied to field studies in situations when invertebrate predators should not be killed. PMID- 29509997 TI - Classification of facial vitiligo: A cluster analysis of 473 patients. AB - Vitiligo has a substantial negative impact on quality of life in affected patients, especially those with the involvement of the face. However, the current system can barely distinguish between specific patterns of facial involvement except for the segmental type when focusing only on facial lesions. We classified facial vitiligo into three distinct subtypes using cluster analysis based on facial topography (n = 473): centrofacial vitiligo (72.9%), panfacial vitiligo (18.0%), and hairline vitiligo (9.1%). Centrofacial vitiligo was the most common type and is thought to comprise the typical facial involvement of generalized vitiligo. Panfacial vitiligo was a distinct subtype with onset in old age and less involvement of other body parts. Hairline vitiligo was another distinct subtype with onset in old age and a poor response to conventional phototherapy. A relevant classification system could help us to explore the causes, anticipate the prognosis, and manage the condition in patients with vitiligo. PMID- 29509998 TI - Characterization of the hypersensitive response-like cell death phenomenon induced by targeting antiviral lectin griffithsin to the secretory pathway. AB - Griffithsin (GRFT) is an antiviral lectin, originally derived from a red alga, which is currently being investigated as a topical microbicide to prevent transmission of human immunodeficiency virus (HIV). Targeting GRFT to the apoplast for production in Nicotiana benthamiana resulted in necrotic symptoms associated with a hypersensitive response (HR)-like cell death, accompanied by H2 O2 generation and increased PR1 expression. Mannose-binding lectins surfactant protein D (SP-D), cyanovirin-N (CV-N) and human mannose-binding lectin (hMBL) also induce salicylic acid (SA)-dependent HR-like cell death in N. benthamiana, and this effect is mediated by the lectin's glycan binding activity. We found that secreted GRFT interacts with an endogenous glycoprotein, alpha-xylosidase (XYL1), which is involved in cell wall organization. The necrotic effect could be mitigated by overexpression of Arabidopsis XYL1, and by co-expression of SA degrading enzyme NahG, providing strategies for enhancing expression of oligomannose-binding lectins in plants. PMID- 29510000 TI - Genetic Variations, Exposure to Persistent Organic Pollutants and Breast Cancer Risk - A Greenlandic Case-Control Study. AB - This study investigated the effects of single nucleotide polymorphisms (SNPs) in xenobiotic and steroid hormone-metabolizing genes in relation to breast cancer risk and explored possible effect modifications on persistent organic pollutants (POPs) and breast cancer associations. The study also assessed effects of Greenlandic BRCA1 founder mutations. Greenlandic Inuit women (77 cases and 84 controls) were included. We determined two founder mutations in BRCA1: Cys39Gly (rs80357164) and 4684delCC, and five SNPs in xenobiotic and oestrogen metabolizing genes: CYP17A1 -34T>C (rs743572), CYP19A1 *19C>T (rs10046), CYP1A1 Ile462Val (rs1048943), CYP1B Leu432Val (rs1056836) and COMT Val158Met (rs4680). We used chi-square test for comparison of categorical variables between groups. Odds ratio (OR) estimates with 95% confidence interval (95%CI) were obtained using logistic regression models. The variant allele of BRCA1 Cys39Gly increased breast cancer risk (Gly/Cys versus Cys/Cys, OR: 12.2, 95%CI: 1.53; 98.1), and carriers of the variant allele of CYP17A1 -34T>C had reduced risk (CT+CC versus TT, OR: 0.44, 95%CI: 0.21; 0.93). CYP17A1 -34T>C was an effect modifier on the association between perfluoroalkyl acids (PFAAs) and breast cancer risk (?PFAA, ratio of OR: 0.18, 95%CI: 0.03; 0.97). Non-significant modifying tendencies were seen for the other SNPs on the effect of polychlorinated biphenyls, organochlorine pesticides and PFAAs. In summary, the BRCA1 Cys39Gly and CYP17A1 34T>C genetic variations were associated with breast cancer risk. Our results indicate that the evaluated genetic variants modify the effects of POP exposure on breast cancer risk; however, further studies are needed to document the data from the relatively small sample size. PMID- 29510002 TI - Frequency-dependent resemblance of male-colored females to males in a damselfly. PMID- 29509999 TI - Seed-specific RNAi in safflower generates a superhigh oleic oil with extended oxidative stability. AB - Vegetable oils extracted from oilseeds are an important component of foods, but are also used in a range of high value oleochemical applications. Despite being biodegradable, nontoxic and renewable current plant oils suffer from the presence of residual polyunsaturated fatty acids that are prone to free radical formation that limit their oxidative stability, and consequently shelf life and functionality. Many decades of plant breeding have been successful in raising the oleic content to ~90%, but have come at the expense of overall field performance, including poor yields. Here, we engineer superhigh oleic (SHO) safflower producing a seed oil with 93% oleic generated from seed produced in multisite field trials spanning five generations. SHO safflower oil is the result of seed specific hairpin-based RNA interference of two safflower lipid biosynthetic genes, FAD2.2 and FATB, producing seed oil containing less than 1.5% polyunsaturates and only 4% saturates but with no impact on lipid profiles of leaves and roots. Transgenic SHO events were compared to non-GM safflower in multisite trial plots with a wide range of growing season conditions, which showed no evidence of impact on seed yield. The oxidative stability of the field grown SHO oil produced from various sites was 50 h at 110 degrees C compared to 13 h for conventional ~80% oleic safflower oils. SHO safflower produces a uniquely stable vegetable oil across different field conditions that can provide the scale of production that is required for meeting the global demands for high stability oils in food and the oleochemical industry. PMID- 29510001 TI - Pharmacokinetics of Tildrakizumab (MK-3222), an Anti-IL-23 Monoclonal Antibody, After Intravenous or Subcutaneous Administration in Healthy Subjects. AB - Tildrakizumab, a high-affinity humanized IgG1k antibody that selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function, is under investigation for treatment of moderate-to-severe chronic plaque psoriasis. The objective of this analysis was to assess the pharmacokinetics, bioavailability and safety/tolerability of single ascending doses of tildrakizumab after intravenous (IV) and subcutaneous (SC) dosing in healthy subjects. P05661 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab IV doses of 0.1, 0.5, 3 and 10 mg/kg, or placebo. P05776 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab SC doses of 50 or 200 mg, or placebo. After either single IV or SC dosing, tildrakizumab exhibited slow systemic clearance (CL), limited volume of distribution and a long t1/2 . Both the Cmax and the area under the curve (AUC) increased proportionally with doses from 0.1 to 10 mg/kg, or 50-200 mg. The bioavailability of SC dosing was ~80% (90% CI: 62-103%) for 50 mg and ~73% (90% CI: 46-115%) for 200 mg, respectively, versus 0.5 and 3 mg/kg IV. Across both studies, six of 43 evaluable subjects were positive for post-dose antidrug antibodies; two of these were positive for neutralizing antibodies. Most adverse events (AEs) were mild; the most frequent AEs included upper respiratory tract infection and headache. Single doses of tildrakizumab 0.1, 0.5, 3 and 10 mg/kg administered IV or single doses of 50 and 200 mg administered SC were safe and well tolerated in healthy adult subjects. PMID- 29510003 TI - A bilayer photoreceptor-retinal tissue model with gradient cell density design: A study of microvalve-based bioprinting. AB - ARPE-19 and Y79 cells were precisely and effectively delivered to form an in vitro retinal tissue model via 3D cell bioprinting technology. The samples were characterized by cell viability assay, haematoxylin and eosin and immunofluorescent staining, scanning electrical microscopy and confocal microscopy, and so forth. The bioprinted ARPE-19 cells formed a high-quality cell monolayer in 14 days. Manually seeded ARPE-19 cells were poorly controlled during and after cell seeding, and they aggregated to form uneven cell layer. The Y79 cells were subsequently bioprinted on the ARPE-19 cell monolayer to form 2 distinctive patterns. The microvalve-based bioprinting is efficient and accurate to build the in vitro tissue models with the potential to provide similar pathological responses and mechanism to human diseases, to mimic the phenotypic endpoints that are comparable with clinical studies, and to provide a realistic prediction of clinical efficacy. PMID- 29510004 TI - Transcriptome reprogramming due to the introduction of a barley telosome into bread wheat affects more barley genes than wheat. AB - Despite a long history, the production of useful alien introgression lines in wheat remains difficult mainly due to linkage drag and incomplete genetic compensation. In addition, little is known about the molecular mechanisms underlying the impact of foreign chromatin on plant phenotype. Here, a comparison of the transcriptomes of barley, wheat and a wheat-barley 7HL addition line allowed the transcriptional impact both on 7HL genes of a non-native genetic background and on the wheat gene complement as a result of the presence of 7HL to be assessed. Some 42% (389/923) of the 7HL genes assayed were differentially transcribed, which was the case for only 3% (960/35 301) of the wheat gene complement. The absence of any transcript in the addition line of a suite of chromosome 7A genes implied the presence of a 36 Mbp deletion at the distal end of the 7AL arm; this deletion was found to be in common across the full set of Chinese Spring/Betzes barley addition lines. The remaining differentially transcribed wheat genes were distributed across the whole genome. The up regulated barley genes were mostly located in the proximal part of the 7HL arm, while the down-regulated ones were concentrated in the distal part; as a result, genes encoding basal cellular functions tended to be transcribed, while those encoding specific functions were suppressed. An insight has been gained into gene transcription in an alien introgression line, thereby providing a basis for understanding the interactions between wheat and exotic genes in introgression materials. PMID- 29510005 TI - [The Medical Social Aspects of Health and Satisfaction of Parents with Medical Care of Children with Oncologic Diseases]. AB - The article presents analysis of social economic health determinants of parents of children with oncologic diseases. The evaluation of their satisfaction with accessibility of qualitative medical care was carried out. The questionnaire covered issues concerning medical social aspects of health and satisfaction with quality of medical care. the sampling included 284 parents of children with oncologic diseases receiving treatment in the profile departments of Krasnodar, Stavropol, Volgograd, Makhachkala, Grozny, Cherkessk, Nalchik and Astrakhan in August-September 2015. The parents answered to questionnaire independently. The filled questionnaires handed over to the responsible physician. The responsible physician was fully instructed how to proceed with survey. The study established that oncologic disease of child effects quality of life of parents in 33.2% of cases. The relationships within family deteriorate in 19.7% of cases. According opinion of parents, they have high level of literacy in health issues. Only every second parent trusts official medicine and certain percentage of respondents resorts to non-traditional care including psychic individuals and priests. The analysis of answers permitted to derive that hospitalization provides no difficulties though dissatisfaction with treatment costs and attitude of medical personnel remains.It is established that parents of children with oncologic diseases suffer from anxiety and depression on clinical and sub-clinical level that requires implementation of complex of measures of psychological support. The direct dependence is established concerning between presence of anxiety and depression and also presence of depression and physical indisposition of respondents. PMID- 29510006 TI - [The Attitude to One's Own Health Among Native Residents of Yakutia]. AB - The study was carried out concerning value reference points and attitudes of native population of the Republic of Sakha (Yakutia) intended for health preservation. The analysis was applied to answers of 292 respondents residing in rural area of Yakutia. The analysis of answers of value motivation section demonstrated that for most respondents their health is a priority value of life. At that, most of respondents misunderstand and underestimate role of health in their life because they are unaware of health as an instrumental value. The health as an instrumental value gives its priority to persistence and diligence and hence ranks lower as compared with terminal value. The respondents assume that health mainly depends on diet, life-style, ecology. The results of analysis of answers to questions of "emotional" and "behavioral" sections testify in most of the respondents absence of comprehension about responsibility for one's own health, inadequate commitment to healthy life-style and passive attitude to health. The more active attitude to health is established in respondents of mature age that is rather related to deterioration of well-being feeling and presence of chronic diseases. In the younger age, most of respondents consider they are healthy and hence ignore prevention of diseases. Thereby, in spite of that health is mentioned by respondents as one of priority values most respondents are missing both attitudes to health preservation and clear-cut strategy of health-preserving behavior. In conditions of cardinal alteration of traditional way of life and life-style of native population of the North, behavioral habits of self-preserving behavior helping to survive in the severe climate conditions became inadequate. Nowadays, it is necessary to develop a new behavior strategy of health preservation. PMID- 29510007 TI - [The Regional Risk Factors of Mortality Of Adult Population Because Of Leading Non-Infectious Diseases]. AB - The analysis of data of 2000--2014 established a significant decreasing of total mortality of population of the Republic of Tatarstan. however, this occurrence concerns in a greater degree individuals of retirement age than able-bodied population. The percentage of mortality in connection with diseases of blood circulation diseases, diseases of respiratory system and neoplasms decreased in total mortality and elder age category but remained stable or even increased in population of able-bodied age. The anthropogenic load on objects of environment significantly effects mortality of population of able-bodied age (with wider spectrum of significant parameters) and elder age in the above listed classes of diseases. The values of generalized dispersion explain 95--98% of dispersion of intial indices of chemical pollution of the territory positively and/or negatively correlating with coefficients of mortality in main non-infectious diseases. PMID- 29510008 TI - [The Analysis of Implementation of Time Budget and Certain Health Indices of Female Students-Artists]. AB - The article presents analysis of application of time budget by contingent of female students-artists of different courses. The purpose of study is to investigate life-style and health indices of female students-artists. The study tasks included to determine time spending for various kinds of activity of female students, to analyze certain health indices of female artists and to substantiate activities related to health promotion of this contingent. The applied methods included analysis of publications, analysis of temporarily disability certificates, questionnaire survey, health indices testing. The study carried out in the Gzhelskii state university and covered female students of I--III courses. The greatest percentage in the time budget structure takes sleep (29.8%), though at I and II courses female students sleep less that standard requires. The study established an insufficient motion activity of female artists resulting in immunity decreasing and cold diseases that made up to 86.3% in the structure of morbidity. Certain health indices (breath holding at breathing in and breathing out, wrist dynamometry) in female students-artists are worse than in female students of other professions. The preparation of female artists to future child bearing and efficient professional activity it is necessary to implement health preserving technologies and mass physical culture and sport activities during out learning period. PMID- 29510009 TI - [The Efficiency of Screening of Glaucoma within the Framework of Dispensarization of Patients with Chronic Non-Infectious Diseases]. AB - The development of program of dispensarization of individuals with main chronic non-infectious diseases causing premature death and disability in population is one of strategies of health care system. According the rules of dispensarization, glaucoma, the most severe disease of eye resulting in blindness in case of absence of treatment, is included into listing of main chronic non-infectious diseases. The questionnaire including 35 questions for ophthalmologists of primary medical care was elaborated with purpose of evaluation efficiency of screening of glaucoma within the framework of dispensarization of individuals with chronic non-infectious diseases. The anonymous questionnaire survey of 62 ophthalmologists of primary medical care was carried out. the study demonstrated that the dispensarization system is considered as efficient by 37% of respondents and as an ineffective one -- by 63% of physicians. Nowadays, 32% of respondents more often diagnose glaucoma stage I, 63% 0 glaucoma stage I--II and 5% -- glaucoma stage II--III. The glaucoma is diagnosed by 68% of physicians during self-dependent visits of patients and by 32% during dispensarization. The implementation of tonometry within the framework of dispensarization of adult population is considered by 18% of respondents as a measure that increased diagnosing of glaucoma at early stage. The glaucoma is diagnosed more often at later stages is considered by 50% of respondents and 32% of respondents diagnose glaucoma more often at implementation of tonometry within the framework of dispensarization. The study permitted to conclude that nowadays glaucoma is more frequently diagnosed at early stage though predominantly at self-dependent visit of patients. This occurrence indicates on either inadequate dispensarization coverage of population or low quality of its i9mplementation. The alteration of basic principle of glaucoma screening is required meaning transition from mass screening model with application of tonometry providing high percentage of errors to target screening with application of broadened complex of diagnostic techniques. PMID- 29510011 TI - [The Medical Rehabilitation: History and Definitions]. AB - The article considers the positioning of medical rehabilitation in the health care system. The position of world Health Organization related to significance of rehabilitation for health is demonstrated. The main concepts and definitions of medical rehabilitation are analyzed in details. PMID- 29510012 TI - [The Integral Evaluation of Level of Qualification of Physicians in the Irkutskaia Oblast]. AB - The originally developed technique of integral evaluation of level of qualification of physicians is applied for establishing the level of the given criterion in municipal physicians of the Irkutskaia oblast. The levels of criterion in 2005-2015 were calculated. The results are ranked on the level of criterion. The integral evaluation was implemented to particular medical specialties and subsequent ranking of obtained results was made. PMID- 29510010 TI - [The Actual Approaches to Reformation of Medical Organizations Providing Out Patient Care to Population]. AB - The article presents analysis of the system of organization of primary medical sanitary care in the Russian Federation, its strong and weak aspects are emphasized. The main indices of out-patient care of population and their dynamics are considered. The necessity of system development is substantiated with the purpose of supporting accessibility and quality of medical care in out-patient conditions. The concept of development of organizational functional model of primary medical sanitary care in actual conditions is presented. The main principles of the proposed model are founded on implementation of structural transformation of polyclinics with organization of departments of general practitioner practice, specialized consultative care, medical prevention, diagnostic, medical rehabilitation, medical social care, day-time hospital. PMID- 29510014 TI - [The Application of Expert Judgments under Work Quota Settings]. AB - The article considers results of study concerning substantiation of standards of medical workers in children sanatoriums. The possibilities are demonstrated relating to possibility of application of expert estimate concerning scope of curative diagnostic measures at development of labor standards for these medical workers. PMID- 29510013 TI - [The Accessibility of Phthisiologic in the Primorskii Kraii]. AB - The article presents results of study of accessibility of tuberculous care according medical statistics data of the health department of the Primorskii kraii from 2004 to 2014. The Big Data technology was applied. The systematization of indices of accessibility was carried out. The coefficient of need in tuberculous care was proposed to be used as a basis for applying substantiated management decisions. To support complex analysis of accessibility several indices were introduced and their effect on indices of quality of medical care was evaluated. PMID- 29510015 TI - [The Population Provision with Physicians in the Russian Empire in XIX--Early XX Centuries]. AB - The article presents data concerning number of physicians and their supply to population of the Russian Empire in 1809-1913. It is reasonable to affirm that health care system of the Russian Empire during this period had no opportunities to efficiently implement function of health care. PMID- 29510016 TI - [About History of Scientific Clinical Schools in Russia: Certain Disputable Issues of Methodology of Studying Problem]. AB - The article considers particular key methodological aspects of problem of scientific clinical school in national medicine. These aspects have to do with notion of school, its profile, issues of pedagogues, teachings and followers, subsidiary schools and issue of ethical component of scientific school. The article is a polemic one hence one will find no definite answers to specified questions. The reader is proposed to ponder over answers independently adducing examples of pro and contra. The conclusion is made about necessity of studying scientific schools in other areas of medicine and further elaboration of problem. PMID- 29510017 TI - [The Functioning of the Departments (Prikaz) of Public Charity in the Area of Medicinal Support of Population]. AB - The organization of curative institutions and their medicinal support was one of the main tasks of the departments (prikaz) of public charity. With this purpose hospital pharmacies were organized as pharmacies with free trading of medicinals to population oriented both to supplying prikaz institutions with medicinals and returning of income from selling medicinals to citizen. The medicinal support of prikaz hospitals was strictly regulated and restricted by strict financial limits. So, the prikaz institutions had no significant success in development of free trade of medicinals. PMID- 29510018 TI - [The History of Organization of the Moscow Scientific Institute "Free Scientific Academy"]. AB - The article presents the history of organization of the Society of Moscow scientific institute. The materials are cited concerning its such first institutes of experimental biology, physiology and physics and also about the first directors of these institutes -- P.P. Lazarev, N.K. Koltsov, M.N. Shaternikov. PMID- 29510019 TI - [Stepan Minaievich Khodjamirov]. AB - The article involves archive documents to restore at its most fullness the biography of Stepan Minaievich Khodjamirov. In 1938--1940 he was a former rector of the first Moscow medical institute. S.M. Khodjamirov was born in 1893. He participated in the First World War (1914--1918), in revolutionary events during becoming of the Soviet power in Caucasus (1918--1921). In 1923, he entered medical faculty of the Moscow first medical university, graduated it in 1926 and proceeded education in odinatura (clinical studies) and aspirantura (post graduate study) under the guidance of prominent scientist and therapist D.D. Pletnev. In 1932 S.M. Khodjamirov is appointed on the position of deputy director on scientific activities and in 1937 he acted as director of the institute of functional diagnostic and therapy. In 1938 S.M. Khodjamirov is appointed on the position of director of the first Moscow medical institute but in 1940 he resigned office because of health condition and proceeded to function as associate professor of therapeutic clinic of institute. With beginning of the Great Patriotic War (1941--1945) he voluntary entered the Red Army. From July 1941 to September 1943 working as therapist of military hospital he headed Soviet underground at temporary occupied by German army territory of the Poltavskaia oblast. After liberation of the Poltavskaia oblast S.M. Khodjamirov proceeded service in various front medical institutions of the Red Army. In 1947 he was transfered to the reserve of military service and reinstated in the position of associate professor of the chair of faculty therapy of the first Moscow medical institute. There S.M. Khodjamirov worked until his decease in 1948. PMID- 29510021 TI - Superflexibility of ITO Electrodes via Submicron Patterning. AB - Indium tin oxide (ITO) is the premier choice for transparent conductive electrodes in optoelectronic devices despite its inherent brittleness. Here we report the fabrication of a grating-like structure that obviates ITO's mechanical limitations while retaining its resistivity and optical qualities. ITO nanopatterned films exhibited a resistivity <1.3 * 10-3 Omega cm, which surpassed all previously reported values for flexible ITO, with a normal transmission >90% across the whole visible spectrum range. We demonstrate the nanopatterned ITO retains extraordinary flexibility and durability on heat-sensitive substrates, accommodating cyclic bending to a curvature diameter of at least 3.2 mm for over 50 cycles of compressive and decompressive flexing without significant deterioration of its resistivity or optical properties. Moreover, 2-dimensional extrapolation shows that multiaxial bending is also feasible while maintaining mechanical flexibility, durability, and optical transparency. PMID- 29510020 TI - Ultrastrong Graphene-Copper Core-Shell Wires for High-Performance Electrical Cables. AB - Recent development in mobile electronic devices and electric vehicles requires electrical wires with reduced weight as well as enhanced stability. In addition, since electric energy is mostly generated from power plants located far from its consuming places, mechanically stronger and higher electric power transmission cables are strongly demanded. However, there has been no alternative materials that can practically replace copper materials. Here, we report a method to prepare ultrastrong graphene fibers (GFs)-Cu core-shell wires with significantly enhanced electrical and mechanical properties. The core GFs are synthesized by chemical vapor deposition, followed by electroplating of Cu shells, where the large surface area of GFs in contact with Cu maximizes the mechanical toughness of the core-shell wires. At the same time, the unique electrical and thermal characteristics of graphene allow a ~10 times higher current density limit, providing more efficient and reliable delivery of electrical energies through the GFs-Cu wires. We believe that our results would be useful to overcome the current limit in electrical wires and cables for lightweight, energy-saving, and high power applications. PMID- 29510022 TI - Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling. AB - Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS2 fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant light absorbing species at their chromatographic retention times. Detected oligomers incorporated methylglyoxal and amines, as expected, but also pyruvic acid, hydroxyacetone, and significant quantities of acetaldehyde. The finding that ~80% (by mass) of detected oligomers contained acetaldehyde, a methylglyoxal photolysis product, suggests that daytime methylglyoxal oligomer formation is dominated by radical addition mechanisms involving CH3CO*. These mechanisms are evidently responsible for enhanced browning observed during photolytic cloud events. PMID- 29510023 TI - Principles and Methods for the Rational Design of Core-Shell Nanoparticle Catalysts with Ultralow Noble Metal Loadings. AB - Conspecuts Commercial and emerging renewable energy technologies are underpinned by precious metal catalysts, which enable the transformation of reactants into useful products. However, the noble metals (NMs) comprise the least abundant elements in the lithosphere, making them prohibitively scarce and expensive for future global-scale technologies. As such, intense research efforts have been devoted to eliminating or substantially reducing the loadings of NMs in various catalytic applications. These efforts have resulted in a plethora of heterogeneous NM catalyst morphologies beyond the traditional supported spherical nanoparticle. In many of these new architectures, such as shaped, high index, and bimetallic particles, less than 20% of the loaded NMs are available to perform catalytic turnovers. The majority of NM atoms are subsurface, providing only a secondary catalytic role through geometric and ligand effects with the active surface NM atoms. A handful of architectures can approach 100% NM utilization, but severe drawbacks limit general applicability. For example, in addition to problems with stability and leaching, single atom and ultrasmall cluster catalysts have extreme metal-support interactions, discretized d-bands, and a lack of adjacent NM surface sites. While monolayer thin films do not possess these features, they exhibit such low surface areas that they are not commercially relevant, serving predominantly as model catalysts. This Account champions core-shell nanoparticles (CS NPs) as a vehicle to design highly active, stable, and low-cost materials with high NM utilization for both thermo- and electrocatalysis. The unique benefits of the many emerging NM architectures could be preserved while their fundamental limitations could be overcome through reformulation via a core-shell morphology. However, the commercial realization of CS NPs remains challenging, requiring concerted advances in theory and manufacturing. We begin by formulating seven constraints governing proper core material design, which naturally point to early transition metal ceramics as suitable core candidates. Two constraints prove extremely challenging. The first relates to the core modifying the shell work function and d-band. To properly investigate materials that could satisfy this constraint, we discuss our development of a new heat, quench, and exfoliation (HQE) density functional theory (DFT) technique to model heterometallic interfaces. This technique is used to predict how transition metal carbides can favorably tune the catalytic properties of various NM monolayer shell configurations. The second challenging constraint relates to the scalable manufacturing of CS NP architectures with independent synthetic control of the thickness and composition of the shell and the size and composition of the core. We discuss our development of a synthetic method that enables high temperature self-assembly of tunable CS NP configurations. Finally, we discuss how these principles and methods were used to design catalysts for a variety of applications. These include the design of a thermally stable sub-monolayer CS catalyst, a highly active methanol electrooxidation catalyst, CO-tolerant Pt catalysts, and a hydrogen evolution catalyst that is less expensive than state-of-the-art NM-free catalysts. Such core-shell architectures offer the promise of ultralow precious metal loadings while ceramic cores hold the promise of thermodynamic stability and access to unique catalytic activity/tunability. PMID- 29510024 TI - Structure, Content, and Bioactivity of Food-Derived Peptides in the Body. AB - Orally administered peptides are assumed to be degraded into amino acids in the body. However, our recent studies revealed some food-derived prolyl and pyroglutamyl peptides with 2-3 amino acid residues in the blood of humans and animals, while most of the peptides in the endoproteinase digest of food protein are degraded by exopeptidase. Some food-derived dipeptides in the body display in vitro and in vivo biological activities. These facts indicate that the biological activities of food-derived peptides in the body rather than those in food are crucial to understanding the mechanism of the beneficial effects of orally administered peptides. PMID- 29510025 TI - Nano-"Squeegee" for the Creation of Clean 2D Material Interfaces. AB - Two-dimensional (2D) materials exhibit many exciting phenomena that make them promising as materials for future electronic, optoelectronic, and mechanical devices. Because of their atomic thinness, interfaces play a dominant role in determining material behavior. In order to observe and exploit the unique properties of these materials, it is therefore vital to obtain clean and repeatable interfaces. However, the conventional mechanical stacking of atomically thin layers typically leads to trapped contaminants and spatially inhomogeneous interfaces, which obscure the true intrinsic behavior. This work presents a simple and generic approach to create clean 2D material interfaces in mechanically stacked structures. The operating principle is to use an AFM tip to controllably squeeze contaminants out from between 2D layers and their substrates, similar to a "squeegee". This approach leads to drastically improved homogeneity and consistency of 2D material interfaces, as demonstrated by AFM topography and significant reduction of photoluminescence line widths. Also, this approach enables emission from interlayer excitons, demonstrating that the technique enhances interlayer coupling in van der Waals heterostructures. The technique enables repeatable observation of intrinsic 2D material properties, which is crucial for the continued development of these promising materials. PMID- 29510026 TI - Orthogonal Regulatory Circuits for Escherichia coli Based on the gamma Butyrolactone System of Streptomyces coelicolor. AB - Chemically inducible transcription factors are widely used to control gene expression of synthetic devices. The bacterial quorum sensing system is a popular tool to achieve such control. However, different quorum sensing systems have been found to cross-talk, both between themselves and with the hosts of these devices, and they are leaky by nature. Here we evaluate the potential use of the gamma butyrolactone system from Streptomyces coelicolor A3(2) M145 as a complementary regulatory circuit. First, two additional genes responsible for the biosynthesis of gamma-butyrolactones were identified in S. coelicolor M145 and then expressed in E. coli BL21 under various experimental conditions. Second, the gamma butyrolactone receptor ScbR was optimized for expression in E. coli BL21. Finally, signal and promoter crosstalk between the gamma-butyrolactone system from S. coelicolor and quorum sensing systems from Vibrio fischeri and Pseudomonas aeruginosa was evaluated. The results show that the gamma butyrolactone system does not crosstalk with the quorum sensing systems and can be used to generate orthogonal synthetic circuits. PMID- 29510027 TI - Characterization of Tensioned PDMS Membranes for Imaging Cytometry on Microraft Arrays. AB - Polydimethylsiloxane (PDMS) membranes can act as sensing elements, barriers, and substrates, yet the low rigidity of the elastomeric membranes can limit their practical use in devices. Microraft arrays rely on a freestanding PDMS membrane as a substrate for cell arrays used in imaging cytometry and cellular isolation. However, the underlying PDMS membrane deforms under the weight of the cell media, making automated analytical microscopy (and thus cytometry and cell isolation) challenging. Here we report the development of microfabrication strategies and physically motivated mathematical modeling of membrane deformation of PDMS microarrays. Microraft arrays were fabricated with mechanical tension stored within the PDMS substrate. These membranes deformed 20* less than that of arrays fabricated using prior methods. Modeling of the deformation of pretensioned arrays using linear membrane theory yielded <=15% error in predicting the array deflection and predicted the impact of cure temperatures up to 120 degrees C. A mathematical approach was developed to fit models of microraft shape to sparse real-world shape measurements. Automated imaging of cells on pretensioned microarrays using the focal planes predicted by the model produced high quality fluorescence images of cells, enabling accurate cell area quantification (<4% error) at increased speed (13*) relative to conventional methods. Our microfabrication method and simplified, linear modeling approach is readily applicable to control the deformation of similar membranes in MEMs devices, sensors, and microfluidics. PMID- 29510030 TI - What is the Best Biological Process for Nitrogen Removal: When and Why? AB - Many different aerobic and anaerobic biological processes and treatment schemes are available for transforming organics and/or removing nitrogen from domestic wastewaters. Significant reductions in oxygen requirements and absence of a need for organics for nitrogen reduction are often indicated as advantageous for using the newer anammox organism approach for nitrogen removal rather than the traditional nitrification/denitrification method, the most common one in use today. However, treatment schemes differ, and there are some in which such suggested advantages may not hold. When nitrification/denitrification is used, an anoxic tank is now commonly used first and the nitrate formed by nitrification later is recycled back to that tank for oxidation of wastewater organics. This greatly reduces oxygen requirements and the need for adding organics. So when are such claims correct and when not? What factors in wastewater composition, regulatory requirements, and treatment flow sheet alter which treatment process is best to use? As an aid in making such judgments under different circumstances, the stoichiometry of the different biological processes involved and the different treatment approaches used were determined and compared. Advantages of each as well as imitations and potential opportunities for research to prevent them are presented. PMID- 29510028 TI - Functional and Structural Analysis of Phenazine O-Methyltransferase LaPhzM from Lysobacter antibioticus OH13 and One-Pot Enzymatic Synthesis of the Antibiotic Myxin. AB - Myxin is a well-known antibiotic that had been used for decades. It belongs to the phenazine natural products that exhibit various biological activities, which are often dictated by the decorating groups on the heteroaromatic three-ring system. The three rings of myxin carry a number of decorations, including an unusual aromatic N5, N10-dioxide. We previously showed that phenazine 1,6 dicarboxylic acid (PDC) is the direct precursor of myxin, and two redox enzymes (LaPhzS and LaPhzNO1) catalyze the decarboxylative hydroxylation and aromatic N oxidations of PDC to produce iodinin (1.6-dihydroxy- N5, N10-dioxide phenazine). In this work, we identified the LaPhzM gene from Lysobacter antibioticus OH13 and demonstrated that LaPhzM encodes a SAM-dependent O-methyltransferase converting iodinin to myxin. The results further showed that LaPhzM is responsible for both monomethoxy and dimethoxy formation in all phenazine compounds isolated from strain OH13. LaPhzM exhibits relaxed substrate selectivity, catalyzing O methylation of phenazines with non-, mono-, or di- N-oxide. In addition, we demonstrated a one-pot biosynthesis of myxin by in vitro reconstitution of the three phenazine-ring decorating enzymes. Finally, we determined the X-ray crystal structure of LaPhzM with a bound cofactor at 1.4 A resolution. The structure provided molecular insights into the activity and selectivity of the first characterized phenazine O-methyltransferase. These results will facilitate future exploitation of the thousands of phenazines as new antibiotics through metabolic engineering and chemoenzymatic syntheses. PMID- 29510029 TI - Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics. AB - Natural products (NPs) are a rich source of medicines, but traditional discovery methods are often unsuccessful due to high rates of rediscovery. Genetic approaches for NP discovery are promising, but progress has been slow due to the difficulty of identifying unique biosynthetic gene clusters (BGCs) and poor gene expression. We previously developed the metabologenomics method, which combines genomic and metabolomic data to discover new NPs and their BGCs. Here, we utilize metabologenomics in combination with molecular networking to discover a novel class of NPs, the tyrobetaines: nonribosomal peptides with an unusual trimethylammonium tyrosine residue. The BGC for this unusual class of compounds was identified using metabologenomics and computational structure prediction data. Heterologous expression confirmed the BGC and suggests an unusual mechanism for trimethylammonium formation. Overall, the discovery of the tyrobetaines shows the great potential of metabologenomics combined with molecular networking and computational structure prediction for identifying interesting biosynthetic reactions and novel NPs. PMID- 29510031 TI - Engineering of a Nanosized Biocatalyst for Combined Tumor Starvation and Low Temperature Photothermal Therapy. AB - Tumor hypoxia is one of the major challenges for the treatment of tumors, as it may negatively affect the efficacy of various anticancer modalities. In this study, a tumor-targeted redox-responsive composite biocatalyst is designed and fabricated, which may combine tumor starvation therapy and low-temperature photothermal therapy for the treatment of oxygen-deprived tumors. The nanosystem was prepared by loading porous hollow Prussian Blue nanoparticles (PHPBNs) with glucose oxidase (GOx) and then coating their surface with hyaluronic acid (HA) via redox-cleavable linkage, therefore allowing the nanocarrier to bind specifically with CD44-overexpressing tumor cells while also exerting control over the cargo release profile. The nanocarriers are designed to enhance the efficacy of the hypoxia-suppressed GOx-mediated starvation therapy by catalyzing the decomposition of intratumoral hydroperoxide into oxygen with PHPBNs, and the enhanced glucose depletion by the two complementary biocatalysts may consequently suppress the expression of heat shock proteins (HSPs) after photothermal treatment to reduce their resistance to the PHPBN-mediated low-temperature photothermal therapies. PMID- 29510032 TI - Role of Ionic Charge Density in Donnan Exclusion of Monovalent Anions by Nanofiltration. AB - The main objective of this study is to examine how the charge densities of four monovalent anions-fluoride (F-), chloride (Cl-), bromide (Br-), and nitrate (NO3 )-influence their Donnan (charge) exclusion by a charged nanofiltration (NF) membrane. We systematically studied the rejection behavior of ternary ion solutions containing sodium cation (Na+) and two of the monovalent anions as a function of the pH with a polyamide NF membrane. In the solutions containing F- and Cl- or F- and Br-, F- rejection was higher than Cl- or Br- rejection only when the solution pH was higher than 5.5, suggesting that F- (which has a higher charge density) was repelled more strongly by the negatively charged membrane. The order of change in the activation energy for the transport of the four anions through the polyamide membrane as a response to the increase of the membrane negative charge was the following: F- > Cl- > NO3- > Br-. This order corroborates our main hypothesis that an anion with a smaller ionic radius, and hence a higher charge density, is more affected by the Donnan (charge)-exclusion mechanism in NF. We conclude with a proposed mechanism for the role of ionic charge density in the rejection of monovalent anions in NF. PMID- 29510033 TI - Correction to "Synthetic, Functional Thymidine-Derived Polydeoxyribonucleotide Analogues from a Six-Membered Cyclic Phosphoester". PMID- 29510035 TI - Probing Single Pt Atoms in Complex Intermetallic Al13Fe4. AB - The atomic structure of a 0.2 atom % Pt-doped complex metallic alloy, monoclinic Al13Fe4, was investigated using a single crystal prepared by the Czochralski method. High-angle annular dark-field scanning transmission electron microscopy showed that the Pt atoms were dispersed as single atoms and substituted at Fe sites in Al13Fe4. Single-crystal X-ray structural analysis revealed that the Pt atoms preferentially substitute at Fe(1). Unlike those that have been reported, Pt single atoms in the surface layers showed lower activity and selectivity than those of Al2Pt and bulk Pt for propyne hydrogenation, indicating that the active state of a given single-atom Pt site is strongly dominated by the bonding to surrounding Al atoms. PMID- 29510034 TI - Vapor Annealing Controlled Crystal Growth and Photovoltaic Performance of Bismuth Triiodide Embedded in Mesostructured Configurations. AB - Low stability of organic-inorganic lead halide perovskite and toxicity of lead (Pb) still remain a concern. Therefore, there is a constant quest for alternative nontoxic and stable light-absorbing materials with promising optoelectronic properties. Herein, we report about nontoxic bismuth triiodide (BiI3) photovoltaic device prepared using TiO2 mesoporous film and spiro-OMeTAD as electron- and hole-transporting materials, respectively. Effect of annealing methods (e.g., thermal annealing (TA), solvent vapor annealing (SVA), and Petri dish covered recycled vapor annealing (PR-VA)) and different annealing temperatures (90, 120, 150, and 180 degrees C for PR-VA) on BiI3 film morphology have been investigated. As found in the study, grain size increased and film uniformity improved as temperature was raised from 90 to 150 degrees C. The photovoltaic devices based on BiI3 films processed at 150 degrees C with PR-VA treatment showed power conversion efficiency (PCE) of 0.5% with high reproducibility, which is, so far, the best PCE reported for BiI3 photovoltaic device employing organic hole-transporting material (HTM), owing to the increase in grain size and uniform morphology of BiI3 film. These devices showed stable performance even after 30 days of exposure to 50% relative humidity, and after 100 degrees C heat stress and 20 min light soaking test. More importantly, the study reveals many challenges and room (discussed in the details) for further development of the BiI3 photovoltaic devices. PMID- 29510036 TI - Anti-Proliferative and Anti-Inflammatory Lanostane Triterpenoids from the Polish Edible Mushroom Macrolepiota procera. AB - This study features the isolation and identification of 12 lanostane-type triterpenoids, namely lepiotaprocerins A-L, 1-12, from the fruiting bodies of the Poland-collected edible mushroom Macrolepiota procera. The structures and the absolute configurations of the new compounds were ambiguously established by extensive spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction analyses. Structurally, lepiotaprocerins A-F, 1-6, are distinguished by the presence of a rare "1-en-1,11-epoxy" moiety which has not been previously described in the lanostane class. Biologically, lepiotaprocerins A-F, 1-6, displayed more significant inhibitions of nitric oxide (NO) production than the positive control L- NG-monomethyl arginine (L-NMMA) (IC50 47.1 MUM), and lepiotaprocerins G-L, 7-12, showed various cytotoxicity potencies against a panel of human cancer cell lines. Compound 9 also displayed antitubercular activity against Mycobacterium tuberculosis H37Ra with a minimal inhibitory concentration (MIC) 50 MUg/mL. PMID- 29510037 TI - Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors. AB - In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance. PMID- 29510038 TI - Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5 yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H) yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor gammat Inverse Agonist. AB - A series of tetrahydronaphthyridine derivatives as novel RORgammat inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2 methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORgammat inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases. PMID- 29510039 TI - Metallic Bond-Enabled Wetting Behavior at the Liquid Ga/CuGa2 Interfaces. AB - Interface interaction can strongly modify contact angle, adsorption energy, interfacial tension, and composition of the contact area. In particular, the interfaces between gallium-based liquid metal (LM) and its intermetallic layer present many mysterious and peculiar wetting phenomena, which have not been fully realized up to now. Here in this study, we found that a gallium-based liquid metal droplet can quickly transform into a puddle on the CuGa2 surface through a spreading-wetting procedure. The mechanism lying behind this phenomenon can be ascribed to the formation of an intermetallic CuGa2 on Cu plate surface, which provides a stable metallic bond to induce the wetting behavior. For a quantitative evaluation of the interface force, a metallic bond-enabled wetting model is established on the basis of the density functional theory. The first principles density functional calculations are then performed to examine the work function, density of states, and adsorption energy. The predicted results show that the work function of CuGa2 (010) is approximately 4.47 eV, which is very comparable with that of pure liquid Ga (4.32 eV). This indicates that the valence electrons between Ga and CuGa2 slab can exchange easily, which consequently leads to the strong valence electron hybridization and metallic bond. In addition, the adsorption energy of a single Ga atom on CuGa2 (010) slab has a larger value than In and Sn. The tested metallic bond wetting force at the interface is proportional to the average adsorption energy of the gallium-based LM adatom, and increases with the rising content of gallium. The simulation results demonstrate excellent consistency with the experimental data in this work. PMID- 29510040 TI - Discovery of Novel KRAS-PDEdelta Inhibitors by Fragment-Based Drug Design. AB - Targeting KRAS-PDEdelta protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEdelta inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle these challenges, herein, novel, highly potent KRAS PDEdelta inhibitors were identified by fragment-based drug design, providing promising lead compounds or chemical probes for investigating the biological functions and druggability of KRAS-PDEdelta interaction. PMID- 29510041 TI - Fixed-Charge Atomistic Force Fields for Molecular Dynamics Simulations in the Condensed Phase: An Overview. AB - In molecular dynamics or Monte Carlo simulations, the interactions between the particles (atoms) in the system are described by a so-called force field. The empirical functional form of classical fixed-charge force fields dates back to 1969 and remains essentially unchanged. In a fixed-charge force field, the polarization is not modeled explicitly, i.e. the effective partial charges do not change depending on conformation and environment. This simplification allows, however, a dramatic reduction in computational cost compared to polarizable force fields and in particular quantum-chemical modeling. The past decades have shown that simulations employing carefully parametrized fixed-charge force fields can provide useful insights into biological and chemical questions. This overview focuses on the four major force-field families, i.e. AMBER, CHARMM, GROMOS, and OPLS, which are based on the same classical functional form and are continuously improved to the present day. The overview is aimed at readers entering the field of (bio)molecular simulations. More experienced users may find the comparison and historical development of the force-field families interesting. PMID- 29510042 TI - Arginine-Rich Cell-Penetrating Peptides Require Nucleolin and Cholesterol-Poor Subdomains for Translocation across Membranes. AB - Proficient transport vectors called cell-penetrating peptides (CPPs) internalize into eukaryotic cells mostly via endocytic pathways and facilitate the uptake of various cargo molecules attached to them. However, some CPPs are able to induce disturbances in the plasma membrane and translocate through it seemingly in an energy-independent manner. For understanding this phenomenon, giant plasma membrane vesicles (GPMVs) derived from the cells are a beneficial model system, since GPMVs have a complex membrane composition comparable to the cells yet lack cellular energy-dependent mechanisms. We investigated the translocation of arginine-rich CPPs into GPMVs with different membrane compositions. Our results demonstrate that lower cholesterol content favors accumulation of nona-arginine and, additionally, sequestration of cholesterol increases the uptake of the CPPs in vesicles with higher cholesterol packing density. Furthermore, the proteins on the surface of vesicles are essential for the uptake of arginine-rich CPPs: downregulation of nucleolin decreases the accumulation and digestion of proteins on the membrane suppresses translocation even more efficiently. PMID- 29510043 TI - Supramolecular Pseudorotaxane Polymers from Biscryptands and Bisparaquats. AB - Five new bis(dibenzo-30-crown-10-based cryptand)s were synthesized, two of which (16 and 17) had long (12-atom), flexible spacers that led to cooperative complexation of dibenzyl paraquat TFSI ( Kave = 4.36 * 105 M-1 for 17*2b). Self assembly of 16 and 17 with bisparaquats with similar spacers (18, 21, and 23) led to high molecular weight supramolecular pseudorotaxane polymers in solution. Continuous, flexible fibers were drawn from concentrated solutions. 17 with C10 linked bisparaquat 23 in dichloromethane (DCM) produced a log-log viscosity vs concentration plot with a limiting slope of 3.55, confirming high molecular weight; at 37 mM, the degree of polymerization was estimated to be 126 and Mn = 407 kDa. These are the first truly polymeric pseudorotaxane-type AA/BB supramolecular polymers. PMID- 29510045 TI - Room-Temperature Ionic Liquids and Biomembranes: Setting the Stage for Applications in Pharmacology, Biomedicine, and Bionanotechnology. AB - Empirical evidence and conceptual elaboration reveal and rationalize the remarkable affinity of organic ionic liquids for biomembranes. Cations of the so called room-temperature ionic liquids (RTILs), in particular, are readily absorbed into the lipid fraction of biomembranes, causing a variety of observable biological effects, including generic cytotoxicity, broad antibacterial potential, and anticancer activity. Chemical physics analysis of model systems made of phospholipid bilayers, RTIL ions, and water confirm and partially explain this evidence, quantifying the mild destabilizing effect of RTILs on the structural, dynamic, and thermodynamic properties of lipids in biomembranes. Our Feature Article presents a brief introduction to these systems and to their roles in biophysics and biotechnology, summarizing recent experimental and computational results on their properties. More importantly, it highlights the many developments in pharmacology, biomedicine, and bionanotechnology expected from the current research effort on this topic. To anticipate future developments, we speculate on (i) potential applications of (magnetic) RTILs to affect and control the rheology of cells and biological tissues, of great relevance for diagnostics and (ii) the use of RTILs to improve the durability, reliability, and output of biomimetic photovoltaic devices. PMID- 29510044 TI - Elucidating the Solution-Phase Structure and Behavior of 8-Hydroxyquinoline Zinc in DMSO. AB - The solution-phase structure and electronic relaxation dynamics of zinc bis-8 hydroxyquinoline [Zn(8HQ)2] in dimethyl sulfoxide (DMSO) were examined using a broad array of spectroscopic techniques, complimented by ab initio calculations of molecular structure. The ground-state structure was determined using extended X-ray absorption fine structure (EXAFS) data collected on the Zn K-edge and diffusion ordered spectroscopy (DOSY) NMR. The complex was found to be monomeric and octahedral, with two bidentate 8-hydroxyquinolate ligands and two DMSO molecules coordinated to the zinc through oxygen atoms. Electronic relaxation dynamics were examined with ultrafast transient absorption spectroscopy and complementary density functional calculations. Electronic relaxation was observed to proceed through both singlet and triplet pathways. This solution-phase data provides a deeper physical understanding of the behavior of this molecule, which has a variety of uses such as sensing, OLEDs, and biological applications. PMID- 29510046 TI - Predicting Nucleation of Isonicotinamide from the Solvent-Solute Interactions of Isonicotinamide in Common Organic Solvents. AB - The interactions of isonicotinamide (INA) with seven common solvents (acetic acid, acetonitrile, acetone, chloroform, ethyl acetate, and methanol) have been studied to examine solute-solvent effects on the nucleation of INA from these solvents. In a simple model of 1:1 solute-solvent interactions, the strongest INA solvent interaction is with acetic acid (binding energy, Delta Ebind = -64.05 kJ mol-1) and the weakest is with chloroform (Delta Ebind = -24.85 kJ mol-1). This arises since acetic acid and INA form a hydrogen-bonding motif containing two moderate strength N-H...O hydrogen bonds, while chloroform and INA have a single weak C-H...O hydrogen bond. Taking acetic acid, chloroform, and methanol, the solvents with the strongest, the weakest, and an intermediate strength INA solvent binding energy, the solvation of INA was studied to compare it with the 1:1 model. Acetic acid has the strongest binding energy (-872.24 kJ mol-1) and solvation energy (-341.20 kJ mol-1) with chloroform binding energy (-517.72 kJ mol-1) and solvation energy (-199.05 kJ mol-1). Methanol has intermediate binding energy (-814.19 kJ mol-1) and solvation energies (-320.81 kJ mol-1). These results further confirm the recent the findings which indicate that the key trends in solvent-solute interactions can be determined from a simple and efficient 1:1 dimer model and can be used to predict ease of nucleation with stronger binding energies correlating to slower, more difficult nucleation. A limit of this model is revealed by considering alcohol and acid solvents with longer alkyl chains. PMID- 29510047 TI - Computational Signaling Protein Dynamics and Geometric Mass Relations in Biomolecular Diffusion. AB - We present an atomistic level computational investigation of the dynamics of a signaling protein, monocyte chemoattractant protein-1 (MCP-1), that explores how simulation geometry and solution ionic strength affect the calculated diffusion coefficient. Using a simple extension of noncubic finite size diffusion correction expressions, it is possible to calculate experimentally comparable diffusion coefficients that are fully consistent with those determined from cubic box simulations. Additionally, increasing the concentration of salt in the solvent environment leads to changes in protein dynamics that are not explainable through changes in solvent viscosity alone. This work in accurate computational determination of protein diffusion coefficients led us to investigate molecular weight-based predictors for biomolecular diffusion. By introducing protein volume and protein surface-area-based extensions of traditional statistical relations connecting particle molecular weight to diffusion, we find that protein solvent excluded surface area rather than volume works as a better geometric property for estimating biomolecule Stokes radii. This work highlights the considerations necessary for accurate computational determination of biomolecule diffusivity and presents insight into molecular weight relations for diffusion that could lead to new routes for estimating protein diffusion beyond the traditional approaches. PMID- 29510048 TI - Porous Liquid: A Stable ZIF-8 Colloid in Ionic Liquid with Permanent Porosity. AB - We reported an example of metal-organic framework (MOF)-based porous liquid by dispersing ZIF-8 ({Zn(mim)2}, mim = 2-methylimidazole) nanocrystallites in ionic liquid (IL) of [Bpy][NTf2] ( N-butyl pyridinium bis(trifluoromethyl sulfonyl)imide). Two essential challenges, stable colloid formation and porosity retention, have been overcome to prepare MOF-based porous liquid. Preventing ZIF 8 nanocrystals from aggregation before dispersing is vital to form a stable ZIF-8 colloid in IL via enhancing the interaction between ZIF-8 and IL. The resultant ZIF-8-[Bpy][NTf2] colloid is able to be stable over months without precipitating. [Bpy][NTf2] with larger ion sizes cannot occupy pores in ZIF-8, leaving the ZIF-8 cage empty for enabling access by guest molecules. The porosity of this porous liquid system was verified by positron (e+) annihilation lifetime spectroscopy and I2 adsorption in ZIF-8 in the colloid. MOF-based porous liquids could provide a new material platform for liquid-bed-based gas separations. PMID- 29510049 TI - Shapes, Dynamics, and Stability of beta-Ionone and Its Two Mutants Evidenced by High-Resolution Spectroscopy in the Gas Phase. AB - The conformational landscapes of beta-ionone and two mutants (alpha-ionone and beta-damascone) have been analyzed by means of state-of-the-art rotational spectroscopy and quantum-chemical calculations. The experiments performed at high resolution and sensitivity have provided a deep insight into their conformational spaces, assigning more than 8000 transitions corresponding to the rotational structures of 54 different species (3 isomers, 14 conformers, and 40 isotopologues). Methyl internal rotation dynamics were also observed and analyzed. The work proved the great flexibility of beta-ionone due to its flatter potential energy surface. This feature confers on beta-ionone a wider ability to interconvert between conformers with rather similar energies with respect to its mutants, allowing the retinal ligand to better adapt inside the binding pocket. PMID- 29510050 TI - Realizing Highly Efficient Solution-Processed Homojunction-Like Sky-Blue OLEDs by Using Thermally Activated Delayed Fluorescent Emitters Featuring an Aggregation Induced Emission Property. AB - Two new blue emitters, i.e., bis-[2-(9,9-dimethyl-9,10-dihydroacridine)-phenyl] sulfone ( o-ACSO2) and bis-[3-(9,9-dimethyl-9,10-dihydroacridine)-phenyl]-sulfone ( m-ACSO2), with reserved fine thermally activated delayed fluorescent (TADF) nature and simply tuned thermal and optoelectronic properties, were synthesized by isomer engineering. The meta-linking compound, i.e., m-ACSO2, obtains the highest photoluminescence quantum yield with a small singlet-triplet energy gap, a moderate delayed fluorescent lifetime, excellent solubility, and neat film homogeneity. Due to its unique aggregation-induced emission (AIE) character, neat film-based heterojunction-like organic light-emitting diodes (OLEDs) are achievable. By inserting an excitonic inert exciton-blocking layer, the PN heterojunction-like emission accompanied by intefacial exciplex was shifted to a homojunction-like channel mainly from the AIE emitter itself, providing a new tactic to generate efficient blue color from neat films. The solution-processed nondoped sky-blue OLED employing m-ACSO2 as emitter with homojunction-like emission achieved a maximum external quantum efficiency of 17.2%. The design strategies presented herein provide practical methods to construct efficient blue TADF dyes and realize high-performance blue TADF devices. PMID- 29510051 TI - Opposite Surface and Bulk Solvatochromic Effects in a Molecular Spin-Crossover Compound Revealed by Ambient Pressure X-ray Absorption Spectroscopy. AB - We investigate the solvatochromic effect of a Fe-based spin-crossover (SCO) compound via ambient pressure soft X-ray absorption spectroscopy (AP-XAS) and atomic force microscopy (AFM). AP-XAS provides the direct evidence of the spin configuration for the Fe(II) 3d states of the SCO material upon in situ exposure to specific gas or vapor mixtures; concurrent changes in nanoscale topography and mechanical characteristics are revealed via AFM imaging and AFM-based force spectroscopy, respectively. We find that exposing the SCO material to gaseous helium promotes an effective decrease of the transition temperature of its surface layers, while the exposure to methanol vapor causes opposite surfacial and bulk solvatochromic effects. Surfacial solvatochromism is accompanied by a dramatic reduction of the surface layers stiffness. We propose a rationalization of the observed effects based on interfacial dehydration and solvation phenomena. PMID- 29510052 TI - Direct Structural and Chemical Characterization of the Photolytic Intermediates of Methylcobalamin Using Time-Resolved X-ray Absorption Spectroscopy. AB - Cobalt-carbon bond cleavage is crucial to most natural and synthetic applications of the cobalamin class of compounds, and here we present the first direct electronic and geometric structural characteristics of intermediates formed following photoexcitation of methylcobalamin (MeCbl) using time-resolved X-ray absorption spectroscopy (XAS). We catch transients corresponding to two intermediates, in the hundreds of picoseconds and a few microseconds. Highlights of the picosecond intermediate, which is reduced in comparison to the ground state, are elongation of the upper axial Co-C bond and relaxation of the corrin ring. This is not so with the recombining photocleaved products captured at a few microseconds, where the Co-C bond almost (yet not entirely) reverts to its ground state configuration and a substantially elongated lower axial Co-NIm bond is observed. The reduced cobalt site here confirms formation of methyl radical as the photoproduct. PMID- 29510054 TI - Pulse Radiolysis and Computational Studies on a Pyrrolidinium Dicyanamide Ionic Liquid: Detection of the Dimer Radical Anion. AB - A pulse radiolysis study on pyrrolidinium cation based ionic liquids is presented herein. Time-resolved absorption spectra for 1-methyl-1-propylpyrrolidinium dicyanamide (DCA) at 500 ns after the electron pulse show broad absorption bands at wavelengths below 440 nm and at 640 nm. In pyrrolidinium bis(trifluoromethylsulfonyl)imide (NTf2) and tris(perfluoroethyl)trifluorophosphate (FAP) ILs, the transient absorption below 440 nm is much weaker. The absorption at 500 ns, which increases with wavelength from 500 nm to beyond 800 nm, was assigned to the tail of the solvated electron NIR absorption spectrum, since it disappears in the presence of N2O. In the DCA IL, the presence of a reducing species was confirmed by the formation of pyrene radical anion. The difference in the transient species in the case of the DCA IL compared to other two ILs should be due to the anion, with cations being similar. In pseudohalide ILs such as DCA, radicals are formed by direct hole trapping by the anion (X- + h+ -> X*), followed by addition to the parent anion. Prediction of the UV/vis absorption spectra of the dimer radical anion by computational calculation supports the experimental results. The oxidizing efficiency of (DCA)2*- and its reduction potential ( E(DCA)2*-/(2DCA-)) have been determined. PMID- 29510053 TI - Revealing Strain-Induced Effects in Ultrathin Heterostructures at the Nanoscale. AB - Two-dimensional materials are being increasingly studied, particularly for flexible and wearable technologies because of their inherent thickness and flexibility. Crucially, one aspect where our understanding is still limited is on the effect of mechanical strain, not on individual sheets of materials, but when stacked together as heterostructures in devices. In this paper, we demonstrate the use of Kelvin probe microscopy in capturing the influence of uniaxial tensile strain on the band-structures of graphene and WS2 (mono- and multilayered) based heterostructures at high resolution. We report a major advance in strain characterization tools through enabling a single-shot capture of strain defined changes in a heterogeneous system at the nanoscale, overcoming the limitations (materials, resolution, and substrate effects) of existing techniques such as optical spectroscopy. Using this technique, we observe that the work-functions of graphene and WS2 increase as a function of strain, which we attribute to the Fermi level lowering from increased p-doping. We also extract the nature of the interfacial heterojunctions and find that they get strongly modulated from strain. We observe that the strain-enhanced charge transfer with the substrate plays a dominant role, causing the heterostructures to behave differently from two-dimensional materials in their isolated forms. PMID- 29510055 TI - Optimum Number of Anchored Clathrate Water and Its Instantaneous Fluctuations Dictate Ice Plane Recognition Specificities of Insect Antifreeze Protein. AB - Ice recognition by antifreeze proteins (AFPs) is a subject of topical interest. Among several classes of AFPs, insect AFPs are hyperactive presumably due to their ability to adsorb on basal plane. However, the origin of the basal plane binding specificity is not clearly known. Present work aims to provide atomistic insight into the origin of basal plane recognition by an insect antifreeze protein. Free energy calculations reveal that the order of binding affinity of the AFP toward different ice planes is basal plane > prism plane > pyramidal plane. Critical insight reveals that the observed plane specificity is strongly correlated with the number and their instantaneous fluctuations of clathrate water forming hydrogen bonds with both ice binding surface (IBS) of AFP and ice surface, thus anchoring AFP to the ice surface. On basal plane, anchored clathrate water array is highly stable due to exact match in the periodicity of oxygen atom repeat distances of the ice surface and the threonine repeat distances at the IBS. The stability of anchored clathrate water array progressively decreases upon prism and pyramidal plane adsorption due to mismatch between the threonine ladder and oxygen atom repeat distance. Further analysis reveals that hydration around the methyl side-chains of threonine residues becomes highly significant at low temperature which stabilizes the anchored clathrate water array and dual hydrogen-bonding is a consequence of this stability. Structural insight gained from this study paves the way for rational designing of highly potent antifreeze-mimetic with potential industrial applications. PMID- 29510056 TI - Why Drops Bounce on Smooth Surfaces. AB - It is shown that introducing gravity in the energy minimization of drops on surfaces results in different expressions when minimized with respect to volume or with respect to contact angle. This phenomenon correlates with the probability of drops to bounce on smooth surfaces on which they otherwise form a very small contact angle or wet them completely. Theoretically, none of the two minima is stable: the drop should oscillate from one minimum to the other as long as no other force or friction will dissipate the energy. Experimentally, smooth surfaces indeed show drops that bounce on them. In some cases, they bounce after touching the solid surface, and in some cases they bounce from a nanometric air, or vacuum film. The bouncing energy can be stored in the interfaces: liquid-air, liquid-solid, and solid-air. The lack of a single energy minimum prevents a simple convergence of the drop's shape on the solid surface, and supports its bouncing back to the air. Therefore, the lack of a simple minimum described here supports drop bouncing on hydrophilic surfaces such as that reported by Kolinski et al. Our calculation shows that the smaller the surface tension, the bigger the difference between the contact angles calculated based on the two minima. This agrees with experimental finding where reducing the surface tension, for example, by adding surfactants, increases the probability for bouncing of the drops on smooth surfaces. PMID- 29510057 TI - Manipulating Single Microdroplets of NaCl Solutions: Solvent Dissolution, Microcrystallization, and Crystal Morphology. AB - A new "three-micropipette manipulation technique" for forming, dehydrating, crystallizing, and resolvating nanograms of salt material has been developed to study supersaturated single microdroplets and microcrystals. This is the first report of studies that have measured in situ both supersaturation (as homogeneous nucleation) and saturation (as microcrystal redissolution) for single microdroplets of NaCl solution using the micropipette technique. This work reports a measure of the critical supersaturation concentration for homogeneous nucleation of NaCl (10.3 +/- 0.3 M) at a supersaturation fraction of S = 1.9, the saturation concentration of NaCl in aqueous solution as measured with nanograms of material (5.5 +/- 0.1 M), the diffusion coefficient for water in octanol, D = (1.96 +/- 0.10) * 10-6 cm2/s, and the effect of the solvent's activity on dissolution kinetics. It is further shown that the same Epstein-Plesset (EP) model, which was originally developed for diffusion-controlled dissolution and uptake of gas, and successfully applied to liquid-in-liquid dissolution, can now also be applied to describe the diffusion-controlled uptake of water from a water saturated environment using the extended activity-based model of Bitterfield et al. This aspect of the EP model has not previously been tested using single microdroplets. Finally, it is also reported how the water dissolution rate, rate of NaCl concentration change, resulting crystal structure, and the time frame of initial crystal growth are affected by changing the bathing medium from octanol to decane. A much slower loss of water-solvent and concomitant slower up concentration of the NaCl solute resulted in a lower tendency to nucleate and slower crystal growth because much less excess material was available at the onset of nucleation in the decane system as compared to the octanol system. Thus, the crystal structure is reported to be dendritic for NaCl solution microdroplets dissolving rapidly and nucleating violently in octanol, while they are formed as single cubic crystals in a gentler way for solution-dissolution in decane. These new techniques and analyses can now also be used for any other system where all relevant parameters are known. An example of this is control of drug/hydrogel/emulsion particle size change due to solvent uptake. PMID- 29510058 TI - Redox Potentials and Electronic States of Iron Porphyrin IX Adsorbed on Single Crystal Gold Electrode Surfaces. AB - Metalloporphyrins are active sites in metalloproteins and synthetic catalysts. They have also been studied extensively by electrochemistry as well as being prominent targets in electrochemical scanning tunneling microscopy (STM). Previous studies of FePPIX adsorbed on graphite and alkylthiol modified Au electrodes showed a pair of reversible Fe(III/II)PPIX peaks at about -0.41 V (vs NHE) at high solution pH. We recently used iron protoporphyrin IX (FePPIX) as an intercalating probe for long-range electrochemical electron transfer through a G quadruplex oligonucleotide (DNAzyme); this study disclosed two, rather than a single pair of voltammetric peaks with a new and dominating peak, shifted 200 mV positive relative to the ~-0.4 V peak. Prompted by this unexpected observation, we report here a study of the voltammetry of FePPIX itself on single-crystal Au(111), (100), and (110) and polycrystalline Au electrode surfaces. In all cases the dominating pair of new Fe(III/II)PPIX redox peaks, shifted positively by more than 200 mV compared to those of previous studies appeared. This observation is supported by density functional theory (DFT) which shows that strong dispersion forces in the FePPIX/Au electronic interaction drive the midpoint potential toward positive values. The FePPIX spin states depend on interaction with the Au(111) interface, converting all the Fe(II)/(III)PPIX species into low-spin states. These results support electrochemical evidence for the nature of the electronic coupling between FePPIX and Au-surfaces, and the electronic states of adsorbate molecules, with a bearing also on recent reports of magnetic FePPIX/Au(111) interactions in ultrahigh vacuum (UHV). PMID- 29510059 TI - Unbinding Kinetics of Syndecans by Single-Molecule Force Spectroscopy. AB - Syndecans are transmembrane proteoglycans that, together with integrins, control cell interactions with extracellular matrix components. Despite structural similarities between all members of the syndecan family, their specific attachment to extracellular matrix proteins is defined by heparan and chondroitin chains. We postulate various unbinding kinetics for each type of single syndecan complex. Force spectroscopy data, recorded by atomic force microscope, were analyzed using two theoretical approaches describing force-induced unbinding, authored by Bell-Evans and Dudko-Hummer-Szabo. Our results reveal distinct unbinding pathways dependent on the syndecan family member. Syndecan-1 unbinds by passing over two energy barriers, inner and outer. Syndecan-4 unbinds by crossing over only one energy barrier. It has already been reported that both syndecans bear heparan chains that are structurally indistinguishable. Our finding reveals that unbinding of single syndecan complexes is family-member-dependent. Distinct unbinding pathways can be attributed to structural differences of heparan and chondroitin chains. PMID- 29510060 TI - Defining the regulatory role of programmed cell death 4 in laryngeal squamous cell carcinoma. AB - Programmed cell death 4 (PDCD4) is decreased in many different kinds of malignant tumors. EMT endows tumor cells invasive and metastatic properties. However, few studies have determined the role of PDCD4 in the regulation of EMT in the context of laryngeal carcinoma. We examined the relationship between PDCD4 and EMT associated proteins E-cadherin and N-cadherin using laryngeal carcinoma tissues. Gene manipulation was used to define the regulatory capacity of PDCD4. We report that PDCD4 and E-cadherin/N-cadherin expression were significantly changed in the carcinoma tissues, and their expression was associated with pathological grade, metastatic state, and clinical stage. The suppression of PDCD4 (and consequently, E-cadherin) was concomitant with increased proliferation and G2-phase arrest, decreased apoptosis, and increased cell invasion. PDCD4 upregulation reversed the above-mentioned results. In nude mice, PDCD4 knockdown increased tumor growth and pathological features, confirming the tumorigenic role of PDCD4. Finally, PDCD4 silencing was associated with dysregulation of the carcinogenic Wnt-beta-catenin and the STAT3-miR-21 signaling pathways. This study revealed a dynamic regulatory relationship between PDCD4 and critical factors for EMT, establishing a broad, functional role for PDCD4 in laryngeal carcinoma, which may be propagated by the STAT3-miR-21 pathway. These findings provide new information on an EMT-associated target that may lead to a novel therapy. PMID- 29510061 TI - PmpI antibody reduces the inhibitory effect of Vp1 on Chlamydia trachomatis infectivity. AB - Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections. The effect of antibiotic treatment is not satisfactory, and there is currently no vaccine to prevent C. trachomatis infection. Our results showed that Chlamydia virus CPG1 capsid protein Vp1 treatment significantly inhibited C. trachomatis growth in cell culture, and the inclusion numbers of different C. trachomatis serotypes were decreased. In addition, we conducted a preliminary investigation of the possible mechanisms behind the Vp1 inhibition effects and the C. trachomatis molecules targeted by Vp1. Using far-western blot and GST pull down assay, we found that purified Vp1 can bind to the C. trachomatis outer membrane protein PmpI. PmpI polyclonal antibody treatment markedly reduced the inhibitory effect of Vp1 on C. trachomatis infectivity. On the basis of these experimental results, we infer that PmpI participates in the inhibitory effect of Vp1 and may be a potential receptor of Vp1 in the outer membrane of C. trachomatis. Our research provides clues regarding the molecular mechanisms underlying the interactions between chlamydia virus and chlamydia. PMID- 29510080 TI - Analyzing gene expression profiles with preliminary validations in cardiac hypertrophy induced by pressure overload. AB - The aim of this study was to identify the key genes involved in the cardiac hypertrophy (CH) induced by pressure overload. mRNA microarray data sets GSE5500 and GSE18801 were downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were screened using the Limma package; then, functional and pathway enrichment analysis were performed for common DEGs using the Database for Annotation, Visualization and Integrated Discovery database. Furthermore, the top DEGs were further validated using quantitative PCR in the hypertrophic heart tissue induced by isoprenaline. A total of 113 common DEGs with absolute fold change > 0.5, including 60 significantly upregulated DEGs and 53 downregulated DEGs, were obtained. Gene ontology term enrichment analysis suggested that common upregulated DEG were mainly enriched in neutrophil chemotaxis, extracellular fibril organization, and cell proliferation; and the common downregulated genes were significantly enriched in ion transport, endoplasmic reticulum, and dendritic spine. Kyoto Encyclopedia of Genes and Genomes pathway analysis found that the common DEGs were mainly enriched in extracellular matrix receptor interaction, phagosome, and focal adhesion. Additionally, the expression of Mfap4, Ltbp2, Aspn, Serpina3n, and Cnksr1 were upregulated in the model of CH, while the expression of Anp32a was downregulated. The current study identified the key deregulated genes and pathways involved in the CH, which could shed new light to understand the mechanism of CH. PMID- 29510081 TI - Vildagliptin/pioglitazone combination improved the overall glycemic control in type I diabetic rats. AB - Type I diabetes (TID) is generally assumed to be caused by an immune associated, if not directly immune-mediated, destruction of pancreatic beta-cells. In patients with long-term diabetes, the pancreas lacks insulin-producing cells and the residual beta-cells are unable to regenerate. Patients with TID are subjected to a lifelong insulin therapy which shows risks of hypoglycemia, suboptimal control and ketosis. In this study, we investigated the potential role of vildagliptin (Vilda) alone or in combination with pioglitazone (Pio), as treatment regimens for TID using streptozotocin (STZ)-induced TID model in rats. Daily oral administration of Vilda (5 mg/kg) alone or in combination with Pio (20 mg/kg) for 7 weeks significantly reduced blood glucose levels and HbA1c. It increased serum insulin levels and decreased serum glucagon. It also showed a strong antioxidant activity. Immunohistochemical analysis showed a marked improvement in beta-cells in treated groups when compared with the diabetic group, which appeared in the normal cellular and architecture restoration of beta cells in the islets of Langerhans. Vilda alone or in combination with Pio has the ability to improve the overall glycemic control in type I diabetic rats and may be considered a hopeful and effective remedy for TID. PMID- 29510082 TI - Validation and application of an LC-MS/MS method for the determination of cyclic oligomers originating from polyamide 6 and polyamide 66 in food simulant. AB - Polyamides (PAs) are used in the production of various food contact materials (FCMs) and articles such as kitchen utensils and packaging material. Cyclic oligomers have been identified as potential migrants from PA. This study describes the development, validation and application of a multi-oligomer analytical method based on LC-ESI-MS/MS for the identification and quantification of eight cyclic oligomers of PA 6 and four PA 66 migrating from FCMs into food simulant B (3% acetic acid) and beverages. It was proved that doubly charged precursor ions of the cyclic PA 6 and PA 66 oligomers above a mass of 500 Da are formed during the ionisation process of the electrospray technique used. Direct injection of a diluted food simulant into the LC-ESI-MS/MS system after migration makes the validated method a valuable tool for investigating migration of cyclic PA oligomers. The validation results demonstrate that the multi-oligomer method is applicable for the analysis of cyclic PA 6 and PA 66 oligomers in food simulant B. For all investigated cyclic PA oligomers, detection limits were in the range of 0.1-1.1 ug/l. Linearity (r2 >= 0.99), trueness values between 91% and 122%, and intra-day (RSDr < 10%) and inter-day precision (RSDR < 19%) were determined and satisfied validation criteria set out by the European Reference Laboratory for FCMs. The method was extended to tap water and tea. Finally, the multi-oligomer method was successfully applied to determine cyclic PA oligomers in migration solutions originating from different PA FCMs. In all migration solutions, concentrations of cyclic PA oligomers were determined above the LOQ. A preliminary risk assessment based on in silico tools was performed. The results demonstrate the urgent need for toxicological data that would facilitate the evaluation of the health risk of cyclic PA oligomers. PMID- 29510083 TI - Investigation of the primary plasticisers present in polyvinyl chloride (PVC) products currently authorised as food contact materials. AB - PVC is a common food contact material that is usually plasticised to increase its flexibility. Phthalates are one class of chemical compounds that are often used as plasticisers in PVC in a wide range of industries. They may be used in packaging materials for foods and can also be found in components of certain food processing equipment such as conveyor belts and tubing. Transfer of plasticisers from packaging to foods can occur. In recent years, there has been increased interest in understanding the health effects of phthalates, as well as the possible human exposure levels. However, there is limited information available about the routes of exposure to phthalates. In July 2014, the Chronic Hazard Advisory Panel (CHAP) produced a report for the U.S. Consumer Product Safety Commission detailing the potential health hazards of phthalates and phthalate alternatives. This report listed diet as one factor contributing greater than or equal to 10% of total phthalate exposure. As a result of this report, the U.S. Food and Drug Administration (FDA) is interested in determining the types of the primary plasticiser present in food packaging and processing materials as well as their concentrations. An investigation was conducted of 56 different samples of PVC food packaging and food processing materials available in the US market using a solvent extraction and GC-MS analysis. Nine different plasticisers including three phthalates, di(2-ethylhexyl) phthalate, diisononyl phthalate and diisodecyl phthalate, were identified in the products tested. The plasticiser concentrations ranged from 1 to 53% depending on the types of food contact materials and the type of plasticiser. Overall, it appears that manufacturers are switching away from phthalates as their primary plasticiser to alternate compounds such as ESBO, ATBC, DEHT, DINCH, DEHA and DINA. PMID- 29510085 TI - Anabolic effects of chrysin on the ventral male prostate and female prostate of adult gerbils (Meriones unguiculatus). AB - Chrysin is a bioflavonoid found in fruits, flowers, tea, honey and wine, which has antioxidant, anti-inflammatory, antiallergic and anticarcinogenic properties. This flavone has also been considered as beneficial for reproduction due its testosterone-boosting potential. Thus, the aim of this study was to evaluate the effects of chrysin on the prostate and gonads of male and female adult gerbils. In addition, a comparative analysis of the effects of testosterone on these same organs was conducted. Ninety-day-old male and female gerbils were treated with chrysin (50mgkg-1day-1) or testosterone cypionate (1mgkg-1week-1) for 21 days. The ventral male prostate and female prostate were dissected out for morphological, morphometric-stereological and ultrastructural assays. Testes and ovaries were submitted to morphological and morphometric---stereological analyses. Chrysin treatment caused epithelial hyperplasia and stromal remodelling of the ventral male and female prostate. Ultrastructurally, male and female prostatic epithelial cells in the chrysin group presented marked development of the organelles involved in the biosynthetic-secretory pathway, whereas cellular toxicity was observed only in female glands. Chrysin preserved normal testicular morphology and increased the number of growing ovarian follicles. Comparatively, testosterone treatment was detrimental to the prostate and gonads, since foci of prostatic intraepithelial neoplasia and gonadal degeneration were observed in both sexes. Thus, under the experimental conditions of this study, chrysin was better tolerated than testosterone in the prostate and gonads. PMID- 29510084 TI - Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll like receptor 4 (TLR4)/nuclear factor (NF)-kappaB signaling pathway. AB - Mechanical ventilation (MV) may lead to ventilator-induced lung injury (VILI). Previous research has shown that dexmedetomidine attenuates pulmonary inflammation caused by MV, but the underlying mechanisms remain unclear. Our study aims to test whether dexmedetomidine has a protective effect against VILI and to explore the possible molecular mechanisms using the rat model. Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to 5 groups (n = 6): control, low tidal volume MV (LMV), high tidal volume (HVT) MV (HMV), HVT MV + dexmedetomidine (DEX), HVT MV + dexmedetomidine + yohimbine (DEX+Y). Rats were euthanized after being ventilated for 4 hours. Pathological changes, lung wet/dry (W/D) weight ratio, lung myeloperoxidase (MPO) activity, levels of inflammatory cytokines (i.e., interleukin [IL]-1beta, tumor necrosis factor alpha [TNF-alpha], and IL-6) in the bronchoalveolar lavage fluid (BALF) and lung tissues, expression of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-kappaB, and activation of NF-kappaB in lung tissues were measured. Compared with HMV, DEX group showed fewer pathological changes, lower W/D ratios and decreased MPO activity of the lung tissues and lower concentrations of the inflammatory cytokines in the BALF and lung tissues. Dexmedetomidine significantly inhibited the expression of TLR4 and NF-kappaB and activation of NF-kappaB. Yohimbine partly alleviated the effects of dexmedetomidine. Dexmedetomidine reduced the inflammatory response to HVT-MV and had a protective effect against VILI, with the inhibition of the TLR4/NF-kappaB signaling pathway, at least partly via alpha2-adrenoceptors. PMID- 29510086 TI - The primary cause of muscle disfunction associated with substitutions E240K and R244G in tropomyosin is aberrant behavior of tropomyosin and response of actin and myosin during ATPase cycle. AB - Using the polarized photometry technique we have studied the effects of two amino acid replacements, E240K and R244G, in tropomyosin (Tpm1.1) on the position of Tpm1.1 on troponin-free actin filaments and the spatial arrangement of actin monomers and myosin heads at various mimicked stages of the ATPase cycle in the ghost muscle fibres. E240 and R244 are located in the C-terminal, seventh actin binding period, in f and b positions of the coiled-coil heptapeptide repeat. Actin, Tpm1.1, and myosin subfragment-1 (S1) were fluorescently labeled: 1.5 IAEDANS was attached to actin and S1, 5-IAF was bound to Tpm1.1. The labeled proteins were incorporated in the ghost muscle fibres and changes in polarized fluorescence during the ATPase cycle have been measured. It was found that during the ATPase cycle both mutant tropomyosins occupied a position close to the inner domain of actin. The relative amount of the myosin heads in the strongly-bound conformations and of the switched on actin monomers increased at mimicking different stages of the ATPase cycle. This might be one of the reasons for muscle dysfunction in congenital fibre type disproportion caused by the substitutions E240K and R244G in tropomyosin. PMID- 29510087 TI - ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition. AB - Atg4 is essential for autophagosome formation and Atg8 recycle with the function of processing the precursor and the lipidated Atg8-family proteins. Abnormal autophagic activity is involved in a variety of pathophysiological diseases and ATG4B is of interest as a potential therapeutic target due to its key roles in autophagy process. So ATG4B inhibitors are highly needed. FMK-9a is the most potent inhibitor reported so far. In this study, we confirmed FMK-9a could suppress ATG4B activity in vitro and in cells, with an IC50 of 260 nM. Besides, FMK-9a could also attenuate the process of cleavage of pro-LC3 and the delipidation of LC3-PE. Importantly, FMK-9a could induce autophagy both in HeLa and MEF cells regardless of its inhibition on ATG4B activity. Moreover, FMK-9a induced autophagy required FIP200 and ATG5. In conclusion, we demonstrated that ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition. Thus, FMK-9a may plays multiple roles in autophagy process and cannot simply take it as an ATG4B inhibitor. PMID- 29510088 TI - Vaginal antimycotics and the risk for spontaneous abortions. AB - BACKGROUND: Spontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-antimycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated. OBJECTIVE: The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal antimycotics. STUDY DESIGN: A historical cohort study was conducted including all clinically apparent pregnancies that began from January 2003 through December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Beer-Sheva, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. Time-varying Cox regression models were constructed adjusting for mother's age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use, and the year of admission. RESULTS: A total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6508 (9.9%) with a spontaneous abortion. Overall, 3246 (5%) pregnancies were exposed to vaginal antimycotic medications until the 20th gestational week: 2712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole. Exposure to vaginal antimycotics was not associated with spontaneous abortions as a group (crude hazard ratio, 1.11; 95% confidence interval, 0.96-1.29; adjusted hazard ratio, 1.11; 95% confidence interval, 0.96-1.29) and specifically for clotrimazole (adjusted hazard ratio, 1.05; 95% confidence interval, 0.89-1.25) and miconazole (adjusted hazard ratio, 1.34; 95% confidence interval, 0.99-1.80). Furthermore, no association was found between categories of dosage of vaginal antimycotics and spontaneous abortions. CONCLUSION: Exposure to vaginal antimycotics was not associated with spontaneous abortions. PMID- 29510089 TI - Editorial Comment. PMID- 29510090 TI - Barriers to Exclusive Breastfeeding Among Women With Gestational Diabetes Mellitus in the United States. AB - OBJECTIVE: To identify differences in breastfeeding-related knowledge, attitudes, beliefs, and experiences between women with gestational diabetes mellitus (GDM) and women without GDM. DESIGN: Cross-sectional and prospective cohort study. SETTING: Secondary analysis of data from the U.S. Infant Feeding Practices Study II. PARTICIPANTS: Pregnant women with GDM (n = 195) and pregnant women without GDM (n = 2,815) were included in cross-sectional analyses. For prospective analyses, complete data were available at the postpartum time point for 107 women with and 1,626 women without GDM. METHODS: We compared women with and without GDM for breastfeeding knowledge, attitudes, and beliefs during pregnancy and hospital experiences and problems with breastfeeding after birth. We used multivariate logistic regression to estimate associations between GDM and dependent variables. RESULTS: Women with GDM were less likely to say that breastfeeding is the best way to feed an infant (adjusted odds ratio [aOR] = 0.62, 95% confidence interval [CI] [0.46, 0.85]), more likely to say that the fathers of their infants prefer formula feeding (aOR = 1.74, 95% CI [1.02, 2.97]) or mixed feeding (aOR = 1.78, 95% CI [1.21, 2.61]), and more likely to say their physicians prefer formula (aOR = 2.82, 95% CI [1.17, 6.79]). Women with GDM were less likely to report feeling comfortable breastfeeding in front of female friends (aOR = 0.70, 95% CI [0.50, 0.98]). Newborns of women with GDM were less likely to stay in their mothers' hospital rooms (aOR = 0.55, 95% CI [0.36, 0.85]). CONCLUSION: We identified differences in breastfeeding-related knowledge, attitudes, beliefs, and experiences between women with GDM and women without GDM that could be targets for further research and intervention. PMID- 29510092 TI - Gait Training in Acute Spinal Cord Injury Rehabilitation-Utilization and Outcomes Among Nonambulatory Individuals: Findings From the SCIRehab Project. AB - OBJECTIVES: To investigate the relation of gait training (GT) during inpatient rehabilitation (IPR) to outcomes of people with traumatic spinal cord injury (SCI). DESIGN: Prospective observational study using the SCIRehab database. SETTING: Six IPR facilities. PARTICIPANTS: Patients with new SCI (N=1376) receiving initial rehabilitation. INTERVENTIONS: Patients were divided into groups consisting of those who did and did not receive GT. Patients were further subdivided based on their primary mode of mobility as measured by the FIM. MAIN OUTCOME MEASURES: Pain rating scales, Patient Health Questionnaire Mood Subscale, Satisfaction With Life Scale, and Craig Handicap Assessment and Reporting Technique (CHART). RESULTS: Nearly 58% of all patients received GT, including 33.3% of patients who were primarily using a wheelchair 1 year after discharge from IPR. Those who used a wheelchair and received GT, received significantly less transfer and wheeled mobility training (P<.001). CHART physical independence (P=.002), mobility (P=.024), and occupation (P=.003) scores were significantly worse in patients who used a wheelchair at 1 year and received GT, compared with those who used a wheelchair and did not receive GT in IPR. Older age was also a significant predictor of worse participation as measured by the CHART. CONCLUSIONS: A significant percentage of individuals who are not likely to become functional ambulators are spending portions of their IPR stays performing GT, which is associated with less time allotted for other functional interventions. GT in IPR was also associated with participation deficits at 1 year for those who used a wheelchair, implying the potential consequences of opportunity costs, pain, and psychological difficulties of receiving unsuccessful GT. Clinicians should consider these data when deciding to implement GT during initial IPR. PMID- 29510091 TI - RanGTPase regulates the interaction between the inner nuclear membrane proteins, Samp1 and Emerin. AB - Samp1, spindle associated membrane protein 1, is a type II integral membrane protein localized in the inner nuclear membrane. Recent studies have shown that the inner nuclear membrane protein, Emerin and the small monomeric GTPase, Ran are direct binding partners of Samp1. Here we addressed the question whether Ran could regulate the interaction between Samp1 and Emerin in the inner nuclear membrane. To investigate the interaction between Samp1 and Emerin in live cells, we performed FRAP experiments in cells overexpressing YFP-Emerin. We compared the mobility of YFP-Emerin in Samp1 knock out cells and cells overexpressing Samp1. The results showed that the mobility of YFP-Emerin was higher in Samp1 knock out cells and lower in cells overexpressing Samp1, suggesting that Samp1 significantly attenuates the mobility of Emerin in the nuclear envelope. FRAP experiments using tsBN2 cells showed that the mobility of Emerin depends on RanGTP. Consistently, in vitro binding experiments showed that the affinity between Samp1 and Emerin is decreased in the presence of Ran, suggesting that Ran attenuates the interaction between Samp1 and Emerin. This is the first demonstration that Ran can regulate the interaction between two proteins in the nuclear envelope. PMID- 29510093 TI - Epidural Analgesia Versus Transversus Abdominis Plane Block for Esophagectomy: Are They Equivalent? PMID- 29510094 TI - Flow Preservation of Umbilical Vein for Autologous Shunt and Cardiovascular Reconstruction. AB - BACKGROUND: Synthetic graft materials are commonly used for shunts and cardiovascular reconstruction in neonates, but are prone to thrombosis and scarring. The umbilical vein is a potential source of autologous, endothelialized tissue for neonatal shunts and tissue reconstruction, but requires preservation before implantation. METHODS: Umbilical cords were collected in UW solution with antibiotics at 4 degrees C until dissection. Umbilical vein segments were tested for burst pressure before and after 2 weeks of preservation. Umbilical veins segments were preserved under static or flow conditions at 4 degrees C in UW solution with 5% human plasma lysate for 7 days. Veins were evaluated with histopathology, scanning electron microscopy, and platelet adhesion testing. RESULTS: Umbilical veins have no difference in burst pressure at harvest (n = 16) compared with 2 weeks of preservation (n = 11; 431 +/- 229 versus 438 +/- 244 mm Hg). After 1 week, static and flow-preserved veins showed viability of the vessel segments with endothelium staining positive for CD31, von Willebrand factor, and endothelial nitric oxide synthase. Scanning electron microscopy demonstrated preservation of normal endothelial morphology and flow alignment in the flow preserved samples compared with cobblestone endothelial appearance and some endothelial cell loss in the static samples. Static samples had significantly more platelet adhesion than flow-preserved samples did. CONCLUSIONS: Umbilical veins have adequate burst strength to function at neonatal systemic pressures. Preservation under flow conditions demonstrated normal endothelial and overall vascular morphology with less platelet adhesion compared with static samples. Preserved autologous umbilical veins are potential source for endothelialized shunts or cardiovascular repair tissue for neonates. PMID- 29510095 TI - Thoracoscopic Tracheal Resection and Reconstruction With Single-Incision Method. AB - Tracheal resection and reconstruction are traditionally approached with a right lateral thoracotomy or a median sternotomy. The thoracoscopic approach is usually applied in lung resection surgery in most hospitals but seldom used in tracheal resection. Three or more incisions are usually created during a thoracoscopic tracheal resection. We prescribed a method of single-incision thoracoscopic tracheal resection and reconstruction in a case of squamous cell carcinoma of the right tracheal wall. PMID- 29510096 TI - Prognostic Value of PD-L1 mRNA Sequencing Expression Profile in Non-Small Cell Lung Cancer. AB - BACKGROUND: Immune checkpoint inhibitors that target the programmed cell death protein ligand 1 (PD-L1) pathway have shown benefit for the treatment of metastatic non-small cell lung cancer (NSCLC). However, the prognostic value of PD-L1 independent of immunotherapy is still unclear, with conflicting results reported between PD-L1 expression and patient survival. Our aim was to correlate PD-L1 mRNA level with clinical and pathologic factors and to investigative the prognostic value of PD-L1 mRNA in all stages of NSCLC. METHODS: Gene expression and clinical data were obtained from public repositories in The Cancer Genome Atlas from the National Cancer Institute. Genotype-Tissue Expression was used to compare with normal tissue expression analysis. RESULTS: A total of 985 patients met inclusion criteria, among whom 79.6% were stage I to II, 16.5% were stage III, and 3.5% were stage IV, representing 495 adenocarcinoma and 490 squamous cell carcinoma (SCC). PD-L1 mRNA gene expression in lung cancers was higher than in most other tumor and normal tissue types and was significantly higher in lung SCC than adenocarcinoma (p < 0.001). PD-L1 mRNA expression was associated with pathologic stage in SCC and with smoking status in adenocarcinoma of the lung. However, none of the cutoff values of PD-L1 mRNA expression were prognostic of overall survival. CONCLUSIONS: Our results suggest that the value of PD-L1 mRNA in prognosticating outcome in lung cancer is limited. Further studies are needed to identify novel prognostic biomarkers other than PD-L1 that are associated with improved patient survival. Identification of further prognostically important biomarkers may prove useful in identifying patients suitable for immunotherapy. PMID- 29510097 TI - Implementing a Thoracic Enhanced Recovery Program: Lessons Learned in the First Year. AB - BACKGROUND: To minimize the stress of operations, improve the patient experience, reduce variability, and optimize resource utilization, we implemented a thoracic enhanced recovery after surgery (ERAS) protocol and evaluated progress after 1 year. METHODS: Two protocols were developed: video-assisted thoracic surgery (ERAS-VATS) and thoracotomy (ERAS-T). Each incorporated preoperative patient education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, and early ambulation. Patient outcomes, length of stay, pain scores, opioid use, fluid administration, and cost for ERAS patients were compared with historic controls from the year before program initiation. RESULTS: Historic VATS (n = 162) were compared with 81 ERAS-VATS patients. Median postoperative morphine equivalents (86 versus 22 mg, p < 0.0001), total fluid balance (1279 versus 227 mL, p < 0.0001), and mean inflation adjusted hospital costs ($20,169 versus $14,870, p = 0.0003) all decreased significantly. Historic thoracotomy patients (n = 62) were compared with 58 ERAS-T patients. Median postoperative morphine equivalents (130 versus 54 mg, p < 0.0001), total fluid balance (788 versus -489 mL, p = 0.012), length of stay (6.0 versus 4.0 days, p = 0.009), and mean inflation adjusted hospital costs ($41,950 versus $26,089, p < 0.00001) all decreased significantly. CONCLUSIONS: Implementation of thoracic ERAS is a dynamic process with potential to improve outcomes in thoracic surgical procedures. In the first year we shortened length of stay, decreased opioid usage, minimized fluid overload, and decreased hospital costs. PMID- 29510098 TI - Management of Right Gastroepiploic Arterial Coronary Grafts in Subsequent Abdominal Surgeries. AB - BACKGROUND: The right gastroepiploic artery (GEA) is utilized as an excellent in situ arterial graft conduit to right coronary artery territory for coronary artery bypass grafting (CABG). However, there remain great concerns regarding the management of patients with a patent in situ GEA during abdominal surgery following CABG. METHODS: From 1995 to 2016, GEA was used for CABG in 278 patients at our institution. Of the patients, 14 abdominal surgeries were performed for subsequent abdominal diseases in 11 patients with a patent in situ GEA for CABG. We investigated the results of the surgeries and how to manage the GEAs in abdominal surgery. RESULTS: Laparotomy was required for gastric cancer in 3 patients, pancreatic cancer in 3, hepatic cancer in 2, cholangiocarcinoma in 1, duodenal papillary head cancer in 1, and cholecystitis in 1; multiple abdominal surgeries were needed in 2 patients for cancer recurrence and ileus. The intraabdominal adhesions around the GEAs were minimal in all patients. No graft injury occurred at the time of opening of the abdomen, and the planned procedures were completed without any circulatory problems. In 3 patients undergoing pancreaticoduodenectomy, intraabdominal off-pump rerouting of the GEA with a short saphenous vein was necessary for en bloc resection of the cancers and lymph nodes. There was neither operative mortality nor graft-related cardiac event except for 1 due to multiple organ failure. CONCLUSIONS: Although intraabdominal rerouting of GEA is necessary for pancreaticoduodenectomy, abdominal surgery can be safely performed in patients with a patent in situ GEA coronary graft. PMID- 29510100 TI - Pyruvate Kinase M2 Regulates Hif-1alpha Activity and IL-1beta Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages. PMID- 29510099 TI - Effects of sex and prenatal androgen manipulations on Onuf's nucleus of rhesus macaques. AB - The role of gonadal steroids in sexual differentiation of the central nervous system (CNS) is well established in rodents, but no study to date has manipulated androgens prenatally and examined their effects on any CNS structure in a primate. Onuf's nucleus is a column of motoneurons in the sacral spinal cord that innervates the striated perineal muscles. This cell group is larger in males than in females of many species, due to androgens acting during a sensitive perinatal period. Here, we examined Onuf's nucleus in 21 adult rhesus monkeys, including control males and females, as well as males whose mothers had been treated with an anti-androgen or testosterone during gestation. We found a robust sex difference, with more motoneurons in control males than in females. The soma size of Onuf's nucleus motoneurons was also marginally larger in males. Treatment with the anti-androgen flutamide for 35-40 days during early gestation partially blocked masculinization of Onuf's nucleus: motoneuron number in flutamide-treated males was decreased relative to control and testosterone-treated males, but remained greater than in females, with no effect on cell size. A control motor nucleus that innervates foot muscles (Pes9) showed no difference in motoneuron number or size between control males and females. Prenatal testosterone treatment of males did not alter Onuf's nucleus motoneuron number, but did increase the size of both Onuf's and Pes9 motoneurons. Thus, prenatal androgen manipulations cause cellular-level changes in the primate CNS, which may underlie previously observed effects of these manipulations on behavior. PMID- 29510101 TI - The Human Fetus Preferentially Engages with Face-like Visual Stimuli. PMID- 29510102 TI - Cryptosporidium. AB - The apicomplexan parasite Cryptosporidium parvum is the second leading cause of death in children due to diarrheal disease worldwide. Gibson and Striepen offer insights into the fascinating biology of this poorly understood parasite, and describe new strategies aimed at defeating it. PMID- 29510103 TI - Proprioception. AB - Although familiar to each of us, the sensation of inhabiting a body is ineffable. Traditional senses like vision and hearing monitor the external environment, allowing humans to have shared sensory experiences. But proprioception, the sensation of body position and movement, is fundamentally personal and typically absent from conscious perception. Nonetheless, this 'sixth sense' remains critical to human experience, a fact that is most apparent when one considers those who have lost it. Take, for example, the case of Ian Waterman who, at the age of 19, suffered a rare autoimmune response to a flu infection that attacked the sensory neurons from his neck down. This infection deprived him of the sense of position, movement and touch in his body. With this loss of feedback came a complete inability to coordinate his movements. While he could compel his muscles to contract, he lost the ability to orchestrate these actions into purposeful behaviors, in essence leaving him immobile, unable to stand, walk, or use his body to interact with the world. Only after years of dedicated training was he able to re-learn to move his body entirely under visual control. PMID- 29510104 TI - Black Jacobin hummingbirds vocalize above the known hearing range of birds. AB - Hummingbirds are a fascinating group of birds, but some aspects of their biology are poorly understood, such as their highly diverse vocal behaviors. We show here that the predominant vocalization of black jacobins (Florisuga fusca), a hummingbird prevalent in the mountains of the Brazilian Atlantic Forest, consists of a triplet of syllables with high fundamental frequency (mean F0 ~11.8 kHz), rapid frequency oscillations and strong ultrasonic harmonics and no detectable elements below ~10 kHz. These are the most common vocalizations of these birds, and their frequency range is above the known hearing range of any bird species recorded to date, including hearing specialists such as owls. These observations suggest that black jacobins either have an atypically high frequency hearing range, or alternatively their primary vocalization has a yet unknown function unrelated to vocal communication. Black jacobin vocalizations challenge current notions about vocal communication in birds. PMID- 29510105 TI - Reengineering the primary body axis by ectopic cWnt signaling. AB - The evolution of gastrulation, the embryonic formation of distinct tissue layers, was a pivotal event in the metazoan radiation, as it paved the way for diversification of animal body plans from a hollow, ciliated, radially symmetrical ancestor [1]. The position of the site of gastrulation (that segregates internal endomesodermal precursors from outer ectodermal tissue) has played a role in our understanding of patterns of body plan evolution and is tightly regulated during development. In bilaterians (a large clade of bilaterally symmetrical animals that represent over 99% of all extant species), the site of gastrulation is determined by a localized molecular asymmetry resulting from a differential distribution of maternal determinants [2] along the so-called animal-vegetal axis (A-V axis) where the animal pole is marked by the site of polar body release during meiosis [1,3]. In most bilaterians, the site of gastrulation occurs at the vegetal pole (the side opposite the animal pole); however, in cnidarians (corals, sea anemones, and jellyfish) [3], the sister group to all bilaterians and ctenophores (comb jellies), likely to be the earliest branching group of extant metazoans [3], gastrulation occurs at the animal pole [3,4]. Here we show that components of the canonical Wnt-beta-catenin (cWnt) signaling pathway mediate endomesoderm formation and patterns the adult primary body axis. PMID- 29510106 TI - Visual Circuits: Division of Labor Revealed. AB - Each mosaic of retinal ganglion cells is thought to extract the same visual feature across mouse retina, but a new study shows that ganglion cells of the same type actually show different light response depending on retinal location. PMID- 29510107 TI - Plant Evolution: Phylogenetic Relationships between the Earliest Land Plants. AB - The key structures and functions of land plants are most often studied in flowering plant models. However, the evolution of these traits (character states) is often difficult to infer, because we lack an accurate phylogenetic frame of reference. The potential branching order of the earliest land plants has now been further condensed, narrowing down potential reference frameworks for comparative studies. PMID- 29510108 TI - Brain Evolution: Intelligence without a Cortex. AB - Birds are capable of high level cognition even though their telencephalon is organized into nuclear groups rather than a six-layered cortex as in the mammalian brain. New data show that, despite their different macroscale organization, the circuitries of avian and mammalian telencephalon are fundamentally similar and may therefore carry out equivalent computations. PMID- 29510109 TI - Plant Physiology: FERONIA Defends the Cell Walls against Corrosion. AB - A new study uncovers the role of wall sensing and remodeling in the plant response to salt stress, identifying the FERONIA receptor kinase as a key player in that process, likely through direct sensing of cell wall pectins. PMID- 29510110 TI - Sleep: Eye-Opener Highlights Sleep's Organization. AB - What can eyes tell us about what happens during sleep? Their movements split sleep into two distinct states - rapid-eye-movement (REM) or non-REM sleep. A new study now reveals that periodic pupil constrictions are linked to non-REM sleep plunging into deeper offline states and back about every minute. PMID- 29510111 TI - Early Life: Embracing the RNA World. AB - Protein complexes with artificial aptamers exhibit a bias towards arginine, tryptophan and tyrosine, providing insights into physicochemical traits of the interactions between amino acids and RNA that may have led to the origin of the genetic code and the ribosome. PMID- 29510112 TI - Systems Neuroscience: The Exciting Journey to Oblivion. AB - The mechanisms of anesthetic-induced unconsciousness remain incompletely understood. A recent study reveals that activation of glutamatergic neurons in the lateral habenula plays a causal role in general anesthesia. We explore the systems neuroscience implications of this finding. PMID- 29510113 TI - Animal Evolution: Convergent Nerve Cords? AB - How the centralized nervous systems of animals evolved remains unclear. Do the nerve cords found at various positions in the worm-shaped bodies of bilaterian animals have a common or an independent evolutionary origin? New comparative data fuel this long-standing debate. PMID- 29510114 TI - Neuroscience: An Olfactory Homunculus in the Insect Brain. AB - Animals can follow olfactory traces to find food, detect a sexual mate, or avoid predators. A new study reveals that pheromone-specific projection neurons in the cockroach have a spatially tuned receptive field, and allow encoding spatial information of an odorant. PMID- 29510115 TI - Visual Attention: Mice Can Use Spatial Cues Too. AB - The use of cues to predict the location of a visual target is an important cognitive strategy for primates. While mice are generally considered to be less dependent on vision than primates, new work shows that they can also use spatial cues to direct their visual attention. PMID- 29510116 TI - A New Perspective on Predictive Motor Signaling. AB - Adaptive behavior relies on complex neural processing in multiple interacting networks of both motor and sensory systems. One such interaction employs intrinsic neuronal signals, so-called 'corollary discharge' or 'efference copy', that may be used to predict the sensory consequences of a specific behavioral action, thereby enabling self-generated (reafferent) sensory information and extrinsic (exafferent) sensory inflow to be dissociated. Here, by using well established examples, we seek to identify the distinguishing features of corollary discharge and efference copy within the framework of predictive motor to-sensory system coordination. We then extend the more general concept of predictive signaling by showing how neural replicas of a particular motor command not only inform sensory pathways in order to gate reafferent stimulation, but can also be used to directly coordinate distinct and otherwise independent behaviors to the original motor task. Moreover, this motor-to-motor pairing may additionally extend to a gating of sensory input to either or both of the coupled systems. The employment of predictive internal signaling in such motor systems coupling and remote sensory input control thus adds to our understanding of how an organism's central nervous system is able to coordinate the activity of multiple and generally disparate motor and sensory circuits in the production of effective behavior. PMID- 29510117 TI - Antigenic cross-reactivity between Schistosoma mansoni and pollen allergens from the birch tree (Betula verrucosa) and Timothy grass (Phleum pratense): involvement of shared glycan epitopes and implications for the hygiene hypothesis. AB - Previous studies have shown that schistosome infection can protect against allergic symptoms, but the underlying mechanisms are still not fully understood. Here we have shown that rabbit IgG antibodies raised against Schistosoma mansoni soluble egg antigens (SmSEA) are cross-reactive with a wide array of molecules in Timothy grass pollen (TGP) and birch tree pollen (BTP). Five of the cross reactive pollen molecules (two from TGP and three from BTP) were selected randomly and identified by tandem mass spectrometric (TMS) analysis to be, respectively, the TGP allergens Phl p 1 and Phl p 5b, and BTP glutathione S transferase (GST), and the BTP allergens Bet v 1 and Bet v 6.0102. Rabbit anti SmSEA IgG antibodies that cross-reacted with each of the five allergens were found to be reactive with three major S. mansoni egg antigens, IPSE/alpha-1, omega-1 and kappa-5. Pairwise alignment of the amino acid sequences of each of the five TMS-identified pollen allergens with each of the three egg antigens revealed a low level of amino acid sequence identity. Further experiments indicated that the schistosome antigen/allergen cross-reactivity was mostly due to similar glycans present in helminths and plants, but not in mammals: so called cross-reactive carbohydrate determinants (CCDs). Previously, CCDs have been implicated in the cross-reactivity between many plants and invertebrates. Furthermore, pollen-induced anti-CCD IgGs have been found in sera of patients undergoing allergen-specific immunotherapy (SIT) and implicated in the treatment of the allergy. Thus, our finding provides not only possible explanations for the allergy-protective effect of helminth/schistosome infections as explained by the hygiene hypothesis, but also a potential starting point for improved SIT. PMID- 29510118 TI - TGF-beta mimic proteins form an extended gene family in the murine parasite Heligmosomoides polygyrus. AB - We recently reported the discovery of a new parasite-derived protein that functionally mimics the immunosuppressive cytokine transforming growth factor (TGF)-beta. The Heligmosomoides polygyrus TGF-beta Mimic (Hp-TGM) shares no homology to any TGF-beta family member, however it binds the mammalian TGF-beta receptor and induces expression of Foxp3, the canonical transcription factor of both mouse and human regulatory T cells. Hp-TGM consists of five atypical Complement Control Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and 12-15 amino acids longer than the 60-70 amino acids consensus domain, but with a recognizable 3-cysteine, tryptophan, cysteine motif. We now report on the identification of a family of nine related Hp-TGM homologues represented in the secreted proteome and transcriptome of H. polygyrus. Recombinant proteins from five of the nine new TGM members were tested for TGF beta activity, but only two were functionally active in an MFB-F11 reporter assay, and by the induction of T cell Foxp3 expression. Sequence comparisons reveal that proteins with functional activity are similar or identical to Hp-TGM across the first three CCP domains, but more variable in domains 4 and 5. Inactive proteins diverged in all domains, or lacked some domains entirely. Testing truncated versions of Hp-TGM confirmed that domains 1-3 are essential for full activity in vitro, while domains 4 and 5 are not required. Further studies will elucidate whether these latter domains fulfill other functions in promoting host immune regulation during infection and if the more divergent family members play other roles in immunomodulation. PMID- 29510120 TI - A fluorescence ratio-based method to determine microalgal viability and its application to rapid optimization of cryopreservation. AB - The utility of microalgal biomass and bioproducts depends on long-term maintenance of certain physiological or biochemical features of the species. While unique characteristics may not be durably maintained with general subculture, cryopreservation methods better prevent alterations from desired characteristics. Post-thaw viability is critical to establishing microalgal cultures, and there is a critical need to effectively and rapidly evaluate microalgal viability after the post-thawing process. In the present study, we developed a rapid assay based on the change of fluorescence ratio to determine microalgal viability post-thaw. It was shown that the assessment of microalgal viability by the fluorescence ratio method correlated well with that of the FDA staining (R2 = 0.978) and regrowth method (R2 = 0.976), demonstrating that the present method could be applied in the high-throughput detection of viability of microalgal strains. Subsequent to establishing this method, we aimed to find out optimal cryopreservation protocol for each strain from a group of 125 microalgal strains. The viability of these strains under different treatments was quickly evaluated by the fluorescence ratio method. Of these strains, 95 attained post thaw viability over 60%. DMSO was a suitable cryoprotectant for most strains at a concentration <=10%. Based on the dataset, the relative contribution of 3 variables-genus, cryoprotectants and concentration to post-viability was analyzed with the Random Forest (RF) classification method. All variables together could explain 97.8% of the viability, and type and concentration of cryoprotectant could explain 59.1% in Chlorophyta. This study provided a new approach for viability assay and demonstrated that this method can facilitate to find out the optimal protocols for cryopreservation of microalgal strains. PMID- 29510121 TI - Local quality assurance of serum or plasma (HIL) indices. PMID- 29510119 TI - Domineering non-autonomy in Vangl1;Vangl2 double mutants demonstrates intercellular PCP signaling in the vertebrate inner ear. AB - The organization of polarized stereociliary bundles is critical for the function of the inner ear sensory receptor hair cells that detect sound and motion, and these cells present a striking example of Planar Cell Polarity (PCP); the coordinated orientation of polarized structures within the plane of an epithelium. PCP is best understood in Drosophila where the essential genes regulating PCP were first discovered, and functions for the core PCP proteins encoded by these genes have been deciphered through phenotypic analysis of core PCP gene mutants. One illuminating phenotype is the domineering non-autonomy that is observed where abrupt disruptions in PCP signaling impacts the orientation of neighboring wild type cells, because this demonstrates local intercellular signaling mediated by the core PCP proteins. Using Emx2-Cre to generate an analogous mutant boundary in the mouse inner ear, we disrupted vertebrate PCP signaling in Vangl1;Vangl2 conditional knockouts. Due to unique aspects of vestibular anatomy, core PCP protein distribution along the mutant boundary generated in the utricle resembles the proximal side of vang mutant clones in the Drosophila wing, while the boundary in the saccule resembles and the distal side. Consistent with these protein distributions, a domineering non-autonomy phenotype occurs along the Emx2-Cre boundary in the mutant utricle that does not occur in the saccule. These results further support the hypothesis that core PCP function is conserved in vertebrates by demonstrating intercellular PCP signaling in the sensory epithelia of the mouse ear. PMID- 29510122 TI - Higher risk of myocardial injury in chest pain patients with elevated red blood cell distribution width. AB - BACKGROUND: High level of red blood cell distribution width (RDW) has been associated with adverse outcomes in coronary artery disease patients. We aimed to investigate the relationship between RDW and the risk of myocardial injury in chest pain patients. METHODS AND RESULTS: We retrospectively reviewed 2078 chest pain patients with suspected acute myocardial infarction. Myocardial injury was defined as high-sensitivity cardiac troponin T (hs-cTnT) >14 ng/L. RDW was associated with hs-cTnT (r = 0.607) and the risk of myocardial injury stepwise increased across increasing RDW quartiles in all subgroups based on age and sex. The receiver operating characteristic curve analysis was calculated to assess the elevated RDW to predict myocardial injury, with the cutoff value of 13.25%. RDW had a high sensitivity (78.10%), specificity (87.44%), as well as positive predictive value (77.48%). The area under the curve (AUC) for all patients was 0.88 (95%CI 0.87, 0.90) and there is no statistical significant in AUCs for all subgroups. CONCLUSIONS: Elevated RDW was significantly associated with a higher risk of myocardial injury in chest pain patients with potential acute myocardial infarction. The RDW may be helpful to identify myocardial injury in such patients. PMID- 29510123 TI - Naringin enhances endothelial progenitor cell (EPC) proliferation and tube formation capacity through the CXCL12/CXCR4/PI3K/Akt signaling pathway. AB - Endothelial progenitor cells (EPCs) have been shown to be involved in the process of physiological neovascularization in vivo. Because increasing evidence has indicated that naringin, a major active ingredient in the Chinese herb Drynaria fortunei, can promote angiogenesis and inhibit endothelial cell apoptosis, our study was designed to determine the role of naringin in EPC proliferation and tube formation capacity and examine the potential mechanism for these effects. EPCs were isolated from bone marrow and treated with naringin. An MTT assay was used to investigate EPC proliferation and the tube formation capacity of these EPCs, which were seeded on Matrigel. The protein levels of CXCL12, its receptor (chemokine receptor 4 (CXCR4)) and a downstream signaling molecule (Akt and phosphorylated Akt (pAkt)) were examined using Western blotting. A CXCR4 antagonist (AMD3100) and a phosphatidylinositol 3-kinase (PI3K) antagonist (LY294002) were used to characterize the underlying mechanisms. The results showed that naringin-induced EPC proliferation reached a maximum at day 3 and that the optimal dose of naringin was 500 ng/ml. Treatment with naringin facilitated the EPC tube formation capacity and increased the levels of CXCL12, CXCR4 and pAkt (P < 0.05) relative to those in the control group. Moreover, the naringin-induced EPC tube formation capacity was significantly attenuated by AMD3100 or LY294002. In conclusion, we showed here that the naringin-enhanced EPC proliferation and tube formation were mediated by the activation of the PI3K/Akt signaling pathway via the CXCL12/CXCR4 axis, which suggests that naringin could serve as a new therapeutic medicine and has the potential to be applied for the treatment of ischemic disease. PMID- 29510125 TI - 6,7,4'-Trihydroxyisoflavone, a major metabolite of daidzein, improves learning and memory via the cholinergic system and the p-CREB/BDNF signaling pathway in mice. AB - Daidzein is one of the major isoflavfones found in soy food and plants. Following ingestion, daidzein is readily converted to hydroxylated metabolites in the human body. 6,7,4'-Trihydroxyisoflavone (THIF), one of the metabolites of daidzein, has several pharmacological activities, including anti-cancer and anti-obesity properties. However, no reports exist on the effects of 6,7,4'-THIF for cognitive function in mice. The present study aimed to investigate the effects of 6,7,4' THIF against scopolamine-induced learning and memory impairments using the Y-maze and passive avoidance test. A single administration of 6,7,4'-THIF significantly improved scopolamine-induced cognitive dysfunction in these in vivo tests. Moreover, treatment with 6,7,4'-THIF alone enhanced learning and memory performance in the same behavioral tests. Molecular studies showed that 6,7,4' THIF significantly inhibited acetylcholinesterase and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus of scopolamine-induced mice. In addition, immunohistochemistry and Western blot results revealed that 6,7,4'-THIF significantly increased brain-derived neurotrophic factor (BDNF) and phosphor cAMP response element binding (CREB) in the hippocampus of mice. Taken together, these findings suggest that 6,7,4'-THIF improves cognitive dysfunction induced by scopolamine and enhances learning and memory by activation of the cholinergic system and the p-CREB/BDNF signaling pathway in mice. PMID- 29510127 TI - Histologic Criteria to Define Irritable Bowel Syndrome: Within the Realms of Possibility? PMID- 29510124 TI - Protective effects of 7,8-dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer's disease. AB - Interest in brain-derived neurotrophic factor (BDNF) was greatly enhanced when it was recognized that its expression is reduced in neurodegenerative disorders, especially in Alzheimer's disease (AD). BDNF signaling through the TrkB receptor has a central role in promoting synaptic transmission, synaptogenesis, and facilitating synaptic plasticity making the BDNF-TrkB signaling pathway an attractive candidate for targeted therapies. Here we investigated the early effect of the small molecule TrkB agonist, 7,8 dihydroxyflavone (7,8-DHF), on AD related pathology, dendritic arborization, synaptic density, and neurochemical changes in the 5xFAD mouse model of AD. We treated 5xFAD mice with 7,8-DHF for 2 months beginning at 1 month of age. We found that, in this model of AD, 7,8-DHF treatment decreased cortical Abeta plaque deposition and protected cortical neurons against reduced dendritic arbor complexity but had no significant impact on the density of dendritic spines. In addition 7,8-DHF treatment protected against hippocampal increase in the level of choline-containing compounds and glutamate loss, but had no significant impact on hippocampal neurogenesis. PMID- 29510128 TI - Getting into a TIF(F) Over Fundoplication. PMID- 29510129 TI - Inhibiting Cytokinesis in the Liver: A New Way to Reduce Tumor Development. PMID- 29510130 TI - New Eosinophilic Esophagitis Concepts Call for Change in Proton Pump Inhibitor Management Before Diagnostic Endoscopy. PMID- 29510131 TI - How to Perform a High-Quality Examination in Patients With Barrett's Esophagus. PMID- 29510132 TI - Meeting Report: AGA Biosimilars Roundtable. PMID- 29510133 TI - YAPping About Glutaminolysis in Hepatic Fibrosis. PMID- 29510134 TI - Primary Endoscopic Therapy Should be Preferred Over Surgery for Patients With Infected Pancreatic Necrosis. PMID- 29510135 TI - Overall Mortality and Pancreatic Cancer Mortality Among Patients With Pancreatic Cystic Neoplasms. PMID- 29510136 TI - Interferon gamma is a strong, STAT1-dependent direct inducer of BCL6 expression in multiple myeloma cells. AB - B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that can repress more than 1200 potential target genes. It exerts oncogenic effects through the inhibition of differentiation, DNA damage sensing and apoptosis in several human hematopoietic malignancies, including multiple myeloma (MM). The multifunctional cytokine interferon gamma (IFNgamma) exerts pro-apoptotic and anti-proliferative effects on MM cells in vitro, at least partially through the inhibition of the effects of interleukin 6 (IL6), one of the most important growth factor of MM and a strong inducer of BCL6 expression. However, IFNgamma was also reported to directly upregulate BCL6 in several cell types. These observations prompted us to analyze the effect of IFNgamma on BCL6 expression in MM cells. We discovered that among several myeloma growth/survival factors tested (including IL6, oncostatin M, insulin-like growth factor 1, tumor necrosis factor alpha and IFNalpha) IFNgamma was the strongest inducer of BCL6 mRNA and protein expression in MM cell lines. IFNgamma induced upregulation of BCL6 was dependent on the classical STAT1 signaling pathway, and affected both major BCL6 variants. Interestingly, although IFNalpha induced stronger STAT1 phosphorylation than IFNgamma, it only slightly upregulated BCL6 in MM lines. We proved that IFNalpha induced BCL6 upregulation was limited by the concomitant activation of STAT5 signaling. We assume that BCL6 upregulation may represent a potentially pro tumorigenic effect of IFNgamma signaling in MM cells. PMID- 29510137 TI - Cyclosporin A inhibits adipogenic differentiation and regulates immunomodulatory functions of murine mesenchymal stem cells. AB - Aplastic anemia (AA) is generally considered as an immune-mediated bone marrow failure syndrome. Several studies show that bone marrow mesenchymal stem cells (BM-MSCs), as key cellular components of the bone marrow microenvironment, are also involved in the pathogenic mechanism of AA. Cyclosporin A (CsA) is a classic immunosuppressive drug for AA, and it specifically inhibits mammalian T cells by preventing activation of transcription factors involved in cytokine gene expression. However, little is known about the effect of CsA on the BM-MSCs. In this study, murine BM-MSCs were stimulated in the presence of CsA. Further, we found that CsA could inhibit murine BM-MSC proliferation and promote BM-MSC apoptosis, what's more CsA could inhibit adipogenic differentiation. Our study also showed that CsA could inhibit interleukin-6 expression in BM-MSCs, while promoting programmed death-ligand 2 expression. In conclusion, our results proposed that CsA may exert an effect on regulating the bone marrow environment by influencing BM-MSCs, which have a beneficial effect on treating AA. PMID- 29510138 TI - AIM2 accelerates the atherosclerotic plaque progressions in ApoE-/- mice. AB - Plaque formation is initiated and triggered by cell death in the vascular wall, which gradually leads to the progression of atherosclerosis. Pyroptosis is a newly discovered form of programmed cell death. Absent in melanoma 2 (AIM2), a member of the HIN-200 protein family, plays an important role in activating inflammasomes. However, the role and mechanism of AIM2 in atherosclerotic plaque progression has not been thoroughly elucidated to date. The effect of pyroptosis and the mechanism for this effect were investigated in apolipoprotein E-deficient (ApoE-/-) mice. AIM2 overexpression and inhibition were studied in ApoE-/- mice that were fed a high-fat diet. The specific role of AIM2 in vascular smooth muscle cells (VSMCs) was explored in vitro. The results showed that high fat diet increases the expression of AIM2, ICMA-1, GSDMD-N, which could be mediated by AIM2 expression. The plaque lesion area is lager with AIM2 overexpression. Moreover, TUNEL-positive cells were increased when AIM2 was overexpressed. With increased AIM2, macrophages were enhanced. In vitro studies showed that AIM2 and GSDMD-N expression correlated with ox-LDL levels in a concentration dependent manner. AIM2 expression is associated with NF-kappaB signaling activity and can be inhibited by NF-kappaB inhibitor. AIM2 mediated GSDMD activity through ASC, caspase1 pathway. EthD-III and TUNEL staining showed that AIM2 mediates pyroptosis in VSMCs. Our study suggests that AIM2 is not only a regular of inflammasome but also an active participant in atherosclerosis. PMID- 29510139 TI - ELK3-GATA3 axis modulates MDA-MB-231 metastasis by regulating cell-cell adhesion related genes. AB - GATA3 is a master regulator that drives mammary epithelial cell differentiation, and the suppression of GATA3 expression is associated with the development of aggressive breast cancer. However, the mechanism through which GATA3 loss drives cancer development is poorly understood. Previously, we reported that ELK3 suppression in MDA-MB-231 (ELK3 KD) resulted in the reprogramming of these cells from a basal to luminal subtype, which was associated with the induction of GATA3 expression, and that the ELK3-GATA3 axis orchestrated the metastatic characteristics of MDA-MB-231. Here, we show that GATA3 suppression in ELK3 knockdown MDA-MB-231 cells (ELK3/GATA3 DKD) restores the metastatic ability comparably to that of control MDA-MB-231 cells, even though the epithelial cell morphology and TGF-beta signaling of ELK3 KD are not recovered in ELK3/GATA3 DKD. The expression of E-cadherin and tight junctional proteins, including occludin, claudin and ZO-1, which is activated in ELK3 KD, is suppressed in ELK3/GATA3 DKD. These results reveal the possibility that the ELK3-GATA3 axis determines the metastatic characteristics of MDA-MB-231 by regulating the expression of cell cell adhesion factors. PMID- 29510140 TI - Pentose phosphate pathway activation via HSP27 phosphorylation by ATM kinase: A putative endogenous antioxidant defense mechanism during cerebral ischemia reperfusion. AB - Molecular mechanism underlying ischemic stroke remains poorly understood. We previously reported glucose 6-phosphate dehydrogenase (G6PD) activity in pentose phosphate pathway (PPP) is activated via heat shock protein 27 (HSP27) phosphorylation at serine 85 (S85) by ataxia telangiectasia mutated (ATM) kinase during cerebral ischemia. This mechanism seems to be endogenous antioxidative system. To determine whether this system also works during reperfusion, we performed comparative metabolic analysis of reperfusion effect on metabolism in rat cortex using middle cerebral artery occlusion (MCAO). Metabolic profiling using gas-chromatography/mass-spectrometry analysis showed changes in metabolic state that depended on reperfusion time. Enrichment analysis showed PPP was significantly upregulated during ischemia-reperfusion. Significant increases in fructose 6-phosphate and ribulose 5-phosphate after reperfusion also suggested enhancement of PPP. In relation to PPP, ischemia-reperfusion induced an increase of up to 69-fold in HSP27 transcripts after 24-h reperfusion. Immunoblotting showed gradual increase in HSP27 protein and marked increase in HSP27 phosphorylation (S85) that were time-dependent (4.5-fold after 24-h reperfusion). G6PD activity was significantly elevated after 1-h MCAO (20%), reduced after 1-h reperfusion, increased gradually thereafter and significantly elevated after 24-h reperfusion. The NADPH/NAD+ ratio displayed similar increasing pattern. Intracerebroventricular injection of ATM kinase inhibitor (KU-55933) significantly reduced HSP27 phosphorylation and G6PD activity, significantly increased protein carbonyl, and resulted in increase in infarct size (100%) 24-h after reperfusion following 90-min MCAO. Consequently, G6PD activation via HSP27 phosphorylation by ATM kinase may be part of endogenous antioxidant defense neuroprotection mechanism that is activated during ischemia-reperfusion. These findings have important implications for treatment of stroke. PMID- 29510141 TI - Daily, circadian and seasonal changes of rhodopsin-like encephalic photoreceptor and its involvement in mediating photoperiodic responses of Gambel's white crowned Sparrow, Zonotrichia leucophrys gambelii. AB - Extra-retinal, non-pineal, encephalic photoreceptors (EP) play important roles in mediating development of the reproductive system by the annual change in day length (photoperiodic gonadal response - PGR) in birds. However, the distribution of rhodopsin-like EPs and their functional daily, circadian and seasonal changes are still unclear in the avian brain. This study identifies two novel groups of rhodopsin-immunoreactive cells in the nucleus paraventricularis magnocellularis (PVN) of the hypothalamus and in the medial basal hypothalamus (MBH) in a seasonally breeding species, Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii). In the PVN, rhodopsin-ir cell number showed both daily and circadian changes with more labeled cells apparent in the night phase in photosensitive birds, while only circadian changes were observed involving fewer labeled cells in the night phase in photorefractory birds. Single long day photo stimulation significantly decreased the rhodopsin-ir cell number only in photosensitive birds, coincident with a rise in plasma levels of luteinizing hormone (LH). In the MBH, rhodopsin-ir cell number did not show daily, circadian or single long day induced changes in either photoperiodic states. But, overall these rhodopsin expressing neurons significantly increased from photosensitive to photorefractory states. In the median eminence (ME), more intense rhodopsin-ir was detected in photorefractory birds compared to photosensitive birds. For expression of GnRH and vasoactive intestinal polypeptide (VIP), seasonal differences were found with opposite relationships, consistent with previous studies. Our results suggest different roles of the two groups of rhodopsin-like EPs in the regulation of PGR in white-crowned sparrows. PMID- 29510143 TI - Instructing neuronal identity during CNS development and astroglial-lineage reprogramming: Roles of NEUROG2 and ASCL1. AB - The adult mammalian brain contains an enormous variety of neuronal types, which are generally categorized in large groups, based on their neurochemical identity, hodological properties and molecular markers. This broad classification has allowed the correlation between individual neural progenitor populations and their neuronal progeny, thus contributing to probe the cellular and molecular mechanisms involved in neuronal identity determination during central nervous system (CNS) development. In this review, we discuss the contribution of the proneural genes Neurogenin2 (Neurog2) and Achaete-scute homolog 1 (Ascl1) for the specification of neuronal phenotypes in the developing neocortex, cerebellum and retina. Then, we revise recent data on astroglia cell lineage reprogramming into induced neurons using the same proneural proteins to compare the neuronal phenotypes obtained from astroglial cells originated in those CNS regions. We conclude that Ascl1 and Neurog2 have different contributions to determine neuronal fates, depending on the neural progenitor or astroglial population expressing those proneural factors. Finally, we discuss some possible explanations for these seemingly conflicting effects of Ascl1 and Neurog2 and propose future approaches to further dissect the molecular mechanisms of neuronal identity specification. PMID- 29510142 TI - The P1 visual-evoked potential, red light, and transdiagnostic psychiatric symptoms. AB - A reduced P1 visual-evoked potential amplitude has been reported across several psychiatric disorders, including schizophrenia-spectrum, bipolar, and depressive disorders. In addition, a difference in P1 amplitude change to a red background compared to its opponent color, green, has been found in schizophrenia-spectrum samples. The current study examined whether specific psychiatric symptoms that related to these P1 abnormalities in earlier studies would be replicated when using a broad transdiagnostic sample. The final sample consisted of 135 participants: 26 with bipolar disorders, 25 with schizophrenia-spectrum disorders, 19 with unipolar depression, 62 with no current psychiatric disorder, and 3 with disorders in other categories. Low (8%) and high (64%) contrast check arrays were presented on gray, green, and red background conditions during electroencephalogram, while an eye tracker monitored visual fixation on the stimuli. Linear regressions across the entire sample (N = 135) found that greater severity of both clinician-rated and self-reported delusions/magical thinking correlated with a reduced P1 amplitude on the low contrast gray (neutral) background condition. In addition, across the entire sample, higher self-reported constricted affect was associated with a larger decrease in P1 amplitude (averaged across contrast conditions) to the red, compared to green, background. All relationships remained statistically significant after covarying for diagnostic class, suggesting that they are relatively transdiagnostic in nature. These findings indicate that early visual processing abnormalities may be more directly related to specific transdiagnostic symptoms such as delusions and constricted affect rather than specific psychiatric diagnoses or broad symptom factor scales. PMID- 29510144 TI - Intra-arterial human urinary kallidinogenase alleviates brain injury in rats with permanent middle cerebral artery occlusion through PI3K/AKT/FoxO1 signaling pathway. AB - An urgent need exists to develop intra-arterial treatment for acute ischemic stroke in animal study. This study aimed to explore the beneficial effects of intra-arterial administration of human urinary kallidinogenase (HUK) on brain injury after permanent middle cerebral artery occlusion (pMCAO) in a rat model, and the potential underlying molecular mechanisms. Brain injury induced by pMCAO was evaluated through measuring neurological deficit scores, neuropathological changes, and inflammatory factors. Neurological deficits were observed 24 h after pMCAO and were alleviated by intra-arterial HUK treatment obviously. Inhibition of PI3K by LY294002 blocked the beneficial effect of HUK on neurological functions. In contrast to the pMCAO group, the intra-arterial HUK treatment group showed relatively more regularly arranged neurons and fewer pyknosis. Neurodegeneration, necrosis, infarct area and markers for brain injury were all ameliorated by intra-arterial HUK treatment. Moreover, a lower expression of inflammatory factors including interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and a higher expression of IL-10 were observed in the intra arterial HUK treatment group than that in the pMCAO group. Additionally, when comparing with pMCAO group, a lower level of caspase-3, bax, and apoptotic rate, and a higher level of bcl-2, p-PI3K, p-AKT and p-FoxO1were observed in the pMCAO + HUK group. These results suggest that intra-arterial administration of HUK is a promising therapeutic strategy against pMCAO induced brain injury, and PI3K/AKT/FoxO1 signaling pathway may be involved in this process. PMID- 29510145 TI - Individualized colorectal cancer screening based on the clinical risk factors: beyond family history of colorectal cancer. AB - BACKGROUND AND AIMS: Individuals without a family history of colorectal cancer (CRC) are screened uniformly despite interpersonal risk. To assess individual risk, we examined the age-specific prevalence of advanced colorectal neoplasia (ACRN) according to clinical risk factors and fecal immunochemical test (FIT) results. METHODS: Participants without a family history of CRC who underwent screening colonoscopies and FITs were included. Clinical risk factors for ACRN were identified by using a logistic regression model. Point scores were assigned to each associated factor based on a regression coefficient. RESULTS: A total of 34,658 participants were included. Age, male sex, smoking, and obesity were identified as risk factors. One-, 2-, and 1-point scores were assigned to male sex, smoking, and obesity, respectively. The prevalence of ACRN in individuals with 0, 1, and >=2 risk score points was 1.4%, 1.6%, and 2.9% among those aged 50 to 51 years and 3.1%, 5.5%, and 7.5% among those aged >=66 years, respectively. Among FIT-positive individuals, the prevalence of ACRN was 11.0% and 21.2% in those aged between 50 and 51 years and those aged >=66 years, respectively. Among FIT-negative individuals with >=2 risk score points, the prevalence of ACRN was 2.5% and 6.0% among those aged 50 to 51 years and those aged >=66 years, respectively. CONCLUSION: If the clinical risk score is >=2 points (persons with smoking history or obese men), early colonoscopy may be recommended, even with no family history of CRC. Additionally, FIT may be an appropriate initial screening modality for average-risk individuals if the clinical risk score is 0 to 1. PMID- 29510146 TI - Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts. AB - BACKGROUND AND AIMS: The tissue acquisition and diagnostic yield of cyst fluid cytology is low-to-moderate and rarely provides a specific diagnosis. The aim of this study was to compare the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology. METHODS: In this multicenter study, data of 42 patients who had cysts both aspirated by EUS-guided FNA (EUS FNA) and biopsy specimens were then obtained with an MFB device, were collected. Cytology analysis of cyst fluid and histologic analysis of biopsy specimens were done. Acquisition yield was defined as percentage of patients with tissue present in the aspirate or biopsy. Diagnostic tissue yield was evaluated at 3 levels: the ability of differentiation between mucinous and/or nonmucinous cysts, detection of high risk for malignancy, and specific cyst type diagnosis. RESULTS: The mean patient age was 69 years. Sixteen pancreatic cysts (38.1%) were located in the head, 17 (40.5%) in the body, and 9 (21.4%) in the tail. The mean cyst size was 28.2 mm (12-60 mm); 25 of 42 (60%) were septated. The EUS-FNA tissue (fluid) acquisition yield was 88.1% (37/42). The MFB tissue acquisition yield was 90.4% (38/42). The diagnostic cytology yield to differentiate between mucinous and/or nonmucinous cysts was 47.6% (20/42), and the MFB histologic yield to differentiate between mucinous and/or nonmucinous cysts was 61.9% (26/42) (P = .188). The percentage of cysts at high risk for malignancy by cytology was 54.7% (23/42), and MFB was 71.5% (30/42) (P = .113). However, the ability of MFB to provide a specific cyst type diagnosis was 35.7% (15/42), and that for cytology was 4.8% (2/42) (P = .001). Surgical histology was concordant with that of MFB in 6 of 7 patients (85%), and with that of cytology in 1 of 7 patients (15%). CONCLUSION: The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis. PMID- 29510147 TI - Visceral obesity as a risk factor for colorectal adenoma occurrence in surveillance colonoscopy. AB - BACKGROUND AND AIMS: The aim of this study was to examine the prospective association between visceral obesity and the incidence and recurrence of colorectal adenoma. METHODS: We conducted a cohort study involving 2244 participants between 2006 and 2007. The study participants were prospectively followed until 2014 according to the initial colonoscopy and histopathology findings. Incident and recurrent colorectal adenoma groups were defined as individuals with a positive follow-up colonoscopy result from the normal results and adenoma groups, respectively, at the baseline colonoscopy. RESULTS: Among the 1163 patients (51.8%) who received a follow-up colonoscopy, 509 (43.8%) and 654 (56.2%) were grouped into the normal and adenoma cohorts. Colorectal adenomas occurred in 592 patients (50.9%) during the median period of 43 months, with an incident adenoma prevalence of 39.1% and a recurrent adenoma prevalence of 60.1%. An increase in the visceral adipose tissue (VAT) area was associated with a higher incidence of adenoma (highest quintile vs lowest quintile of the VAT hazard ratios [HRs], 2.16; 95% confidence interval [CI], 1.26-3.71; HR 1.32 [per 1-standard deviation]; 95% CI, 1.10-1.60) in the multivariable analysis. Increases in body mass index and waist circumference were associated with recurrent adenomas (HR 1.33 [per 1 kg/m2], 95% CI, 1.18-1.46; HR 1.04 [per 1 cm], 95% CI, 1.01-1.07, respectively) in the multivariate analysis. CONCLUSION: A higher VAT area was dose-dependently associated with a higher risk of incident adenoma. Furthermore, increases in body mass index and waist circumference as surrogate markers of abdominal obesity were associated with a higher risk of recurrent adenoma. PMID- 29510148 TI - Responses to peripheral neuropeptide Y in avian adipose tissue are diet, depot, and time specific. AB - The goal of this research was to determine the effect of dietary macronutrient composition on peripheral neuropeptide Y (NPY)-induced changes in adipose tissue dynamics in chicks. Chicks were fed one of three isocaloric diets from the day of hatch: high carbohydrate (HC), high fat (HF), or high protein (HP). On day 4 post hatch, 0 (vehicle), 60, or 120 ug/kg BW of NPY was injected intraperitoneally, and subcutaneous, clavicular and abdominal adipose tissue samples were collected at 1 and 3 h post-injection. The effect of NPY was most pronounced in chicks fed the HF or HP diet. In the subcutaneous fat at 1 h post-injection, 60 ug/kg BW of NPY was associated with an increase in NPY receptor 2 (NPYR2) mRNA in chicks fed the HP diet and a decrease in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) mRNA in chicks fed the HC diet. In response to 120 ug/kg BW of NPY, there was greater AGPAT2 mRNA in the clavicular fat of chicks that consumed the HP diet and less CCAAT/enhancer-binding protein alpha in the abdominal fat of chicks that were provided the HF diet. There were no gene expression changes in the abdominal fat at 3 h post-injection, whereas there were decreases in AGPAT2, adipose triglyceride lipase, fatty acid binding protein 4 and NPY mRNA in the clavicular fat of chicks fed the HP diet. Results demonstrate that diet affects exogenous NPY-dependent physiological effects in a time- and depot-dependent manner in chick adipose tissue. PMID- 29510149 TI - Diversification of the functions of proglucagon and glucagon receptor genes in fish. AB - The teleost fish-specific genome duplication gave rise to a great number of species inhabiting diverse environments with different access to nutrients and life histories. This event produced duplicated gcg genes, gcga and gcgb, for proglucagon-derived peptides, glucagon and GLP-1 and duplicated gcgr receptor genes, gcgra and gcgrb, which play key roles connecting the consumption of nutrients with glucose metabolism. We conducted a systematic survey of the genomes from 28 species of fish (24 bony (Superclass Osteichthyes), 1 lobe-finned (Class Sarcoperygii), 1 cartilaginous (Superclass Chondrichthyes), and 2 jawless (Superclass Agnatha)) and find that almost all surveyed ray-finned fish contain gcga and gcgb genes with different coding potential and duplicated gcgr genes, gcgra and gcgrb that form two separate clades in the phylogenetic tree consistent with the accepted species phylogeny. All gcgb genes encoded only glucagon and GLP 1 and gcga genes encoded glucagon, GLP-1, and GLP-2, indicating that gcga was subfunctionalized to produce GLP-2. We find a single glp2r, but no glp1r suggesting that duplicated gcgrb was neofunctionalized to bind GLP-1, as demonstrated for the zebrafish gcgrb (Oren et al., 2016). In functional experiments with zebrafish gcgrb and GLP-1 from diverse fish we find that anglerfish GLP-1a, encoded by gcga, is less biologically active than the gcgb anglerfish GLP-1b paralog. But some other fish (zebrafish, salmon, and catfish) gcga GLP-1a display similar biological activities, indicating that the regulation of glucose metabolism by GLP-1 in ray-finned fish is species-specific. Searches of genomes in cartilaginous fish identified a proglucagon gene that encodes a novel GLP-3 peptide in addition to glucagon, GLP-1, and GLP-2, as well as a single gcgr, glp2r, and a new glucagon receptor-like receptor whose identity still needs to be confirmed. The sequence of the shark GLP-1 contained an N terminal mammalian-like extension that in mammals undergoes a proteolytic cleavage to release biologically active GLP-1. Our results indicate that early in vertebrate evolution diverse regulatory mechanisms emerged for the control of glucose metabolism by proglucagon-derived peptides and their receptors and that in ray-finned fish they included subfunctionalization and neofunctionalization of these genes. PMID- 29510150 TI - Gonadotropin-inhibitory hormone mediates behavioral stress responses. AB - Gonadotropin-inhibitory hormone (GnIH) is an inhibitor of the hypothalamic pituitary-gonadal (HPG) axis. GnIH is also called RFamide-related peptide (RFRP) as GnIH peptides have a characteristic C-terminal LPXRFiamide (X = L or Q) sequence. GnIH is thought to be the mediator of stress by negatively regulating the HPG axis as various stressors increase GnIH mRNA, GnIH peptide or GnIH neuronal activity. On the other hand, GnIH may also mediate behavioral stress responses as GnIH neuronal fibers and GnIH receptors are widely located in the limbic system of telencephalon, diencephalon and midbrain area. Previous studies have shown that intracerebroventricular (i.c.v.) administration of GnIH (RFRP) blocks morphine-induced analgesia in hot plate and formalin injection tests in rats suggesting that GnIH increases sensitivity to pain. GnIH (RFRP) also increases anxiety-like behavior in rats. RNA interference of GnIH gene (GnIH RNAi) increases locomotor activity of white-crowned sparrow and Japanese quail and i.c.v. administration of GnIH decreases GnIH RNAi induced locomotor activity. It was further shown that i.c.v. administration of GnIH (RFRP) decreases aggressive behavior in male quail and sexual behavior in male rats, female white crowned sparrow and female hamsters. These results suggest that GnIH decreases threat to homeostasis of the organism by increasing pain sensitivity, anxiety and decreasing locomotor activity, aggressive behavior and sexual behavior. GnIH may also mediate the effect of stress on behavior. PMID- 29510151 TI - Comparative transcriptome profiling and characterization of gene expression for ovarian differentiation under RU486 treatment. AB - 17alpha, 20beta-dihydroxypregn-4-en-3-one (17alpha, 20beta-DP, DHP), a teleost specific biologically active progestin, has been proved to play a critical role in oocytes maturation, ovulation and spermiation. RU486 (Mifepristone, an antagonist of progestin receptor) has been applied in contraceptives, abortion and hormone therapy in clinical medicine. To get further insights into the molecular mechanisms of nuclear progestin receptor (Pgr) activated ovarian differentiation and maintenance, we conducted comparative gonadal transcriptome analysis, and investigated histological and transcriptional differences using 4 months after hatching (mah) RU486-treated XX and control XX/XY Nile tilapia (Oreochromis niloticus). DESeq analysis identified 7148 DEGs (differentially expressed genes) between RU486-treated and control XX gonads, while merely 442 DEGs were screened between the gonads of RU486-treated XX and control XY fish highlighting that RU486 treatment set forwards masculinity in XX fish. Comprehensive analysis of gene hierarchical clustering revealed that RU486 treatment in XX fish resulted in robust changes of gene expression profiles. In comparison with XX group, female-dominant genes were significantly repressed in RU486 treated XX fish gonads. Moreover, most parts of down-regulated genes in wild type female were evidently up-regulated genes in RU486-treated XX fish gonads. Comparing with control XY group, the majority of male-dominant genes represent a high level of expression. However, RU486-treatment led to an up regulation of a cluster genes specifically which showed relative lower expression in both control XX and XY group. RU486-treatment mediated global changes of gene expression profiles in steroidogenesis, germ cell differentiation and follicular cell trans-differentiation were verified by quantitative PCR. Both morphological and immunohistochemistry results further proved that RU486 treatment initiates testicular-like gonads development in XX fish via simultaneously enhancing the male responsive genes and suppressing the female-dominant genes. Moreover, RU486 treatment caused significant decline of fshr, lhr and increase of ars. Taken together, our data confirms blocking of DHP physiology by RU486 treatment induces masculinization in XX gonad preferably via repressing of gonadotropin physiology, germ cell differentiation and promoting follicular trans-differentiation in teleosts. PMID- 29510152 TI - Changes in sex steroid hormone levels reflect the reproductive status of captive female zebra sharks (Stegostoma fasciatum). AB - Captive breeding in aquaria is a useful means for ex situ preservation of threatened elasmobranch species. To promote captive breeding, it is important to determine the female reproductive status. However, information regarding reproductive status in female elasmobranchs is limited. Here, we used zebra sharks, Stegostoma fasciatum, as a model for elasmobranch reproduction in captivity. We investigated the relationships among changes in the sex steroid hormone levels, follicle size, and egg-laying period to develop indicators for the female reproductive status. We confirmed that mature female zebra sharks undergo an annual reproductive cycle. Additionally, we showed that the variations in sex steroid hormone levels correlated with reproductive status in mature female zebra sharks. Plasma estradiol-17beta (E2) concentrations increased two months before ovarian follicle development and decreased along with follicle regression. Interestingly, E2 levels were inversely correlated with water temperature (R = -0.901). Moreover, high levels of testosterone (T) correlated well with the laying period. These results strongly suggest that E2 is an indicator for ovarian follicle development, and that T is a useful indicator for both the onset and end of the egg-laying period in captive zebra sharks. PMID- 29510153 TI - The influence of arachidonic acid metabolites on PPAR and RXR expression in bovine uterine cells. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the superfamily of nuclear receptors. Three isoforms have been described: alpha (PPARalpha), delta (PPARdelta), and gamma (PPARgamma). PPARs heterodimerize with retinoid X receptors (RXRs: RXRalpha, RXRbeta and RXRgamma). PPAR activity can be modulated by several ligands, including arachidonic acid (AA) metabolites. The aims of the study were to determine the effect of AA metabolites (prostaglandin [PG]E2, PGF2alpha, leukotriene [LT]B4, and LTC4) on mRNA (real-time PCR) and protein expression (Western blotting) of PPARalpha, PPARdelta, and PPARgamma, and on mRNA expression of RXRalpha, RXRbeta, and RXRgamma, in bovine epithelial, stromal, and myometrial primary uterine cells and in bovine stromal cells with silenced PPAR genes (N = 10). All PPAR and RXR isoforms were expressed. Prostaglandins affected expression of PPARs only in stromal cells, whereas LTs modulated PPARgamma mRNA expression in epithelial and myometrial primary cells. Blockade of signal transduction through PPARs prevented interactions between AA metabolites and PPARs and changed RXR expression comparing with primary stromal cells. In primary stromal uterine cells, mRNA expression of RXRs was higher than that of PPARs. In uterine stromal cells in which intracellular signaling through PPARs was blocked, RXRs seem to take over the role of PPARs and are pivotal for cell functions. This study revealed the reaction of PPARs and RXRs to agonists which naturally occur in the bovine uterus. PMID- 29510154 TI - Extraction and identification of alpha-amylase inhibitor peptides from Nephelium lappacheum and Nephelium mutabile seed protein using gastro-digestive enzymes. AB - The potential of N. lappacheum and N. mutabile seed as a source of alpha-amylase inhibitor peptides was explored based on the local traditional practice of using the seed. Different gastro-digestive enzymes (i.e. pepsin or chymotrypsin) or a sequential digestion were used to extract the peptides. The effects of digestion time and enzyme to substrate (E:S) ratio on the alpha-amylase inhibitory activity were investigated. Results showed that chymotrypsin was effective in producing the inhibitor peptides from rambutan seed protein at E:S ratio 1:20 for 1 h, whereas pepsin was more effective for pulasan seed protein under the same condition. A total of 20 and 31 novel inhibitor peptides were identified, respectively. These peptides could bind with the subsites of alpha-amylase (i.e. Trp58, Trp59, Tyr62, Asp96, Arg195, Asp197, Glu233, His299, Asp300, and His305) and formed a sliding barrier that preventing the formation of enzyme/substrate intermediate leading to lower alpha-amylase activity. PMID- 29510155 TI - Nasal route favors the induction of CD4+ T cell responses in the liver of HBV carrier mice immunized with a recombinant hepatitis B surface- and core-based therapeutic vaccine. AB - Immunization routes and number of doses remain largely unexplored in therapeutic vaccination. The aim of the present work is to evaluate their impact on immune responses in naive and hepatitis B virus (HBV)-carrier mouse models following immunization with a non-adjuvanted recombinant vaccine comprising the hepatitis B surface (HBsAg) and core (HBcAg) antigens. Mice were immunized either by intranasal (i.n.), subcutaneous (s.c.) or simultaneous (i.n. + s.c.) routes. Humoral immunity was detected in all the animal models with the induction of a potent antibody (Ab) response against HBcAg, which was stronger than the anti-HBs response. In the HBV-carrier mouse model, the anti-HBs response was predominantly subtype-specific and preferentially induced by the i.n. route. However, the Ab titers were not sufficient to clear the high concentration of HBsAg present in the sera of these mice. The i.n. route was the most efficacious at inducing cellular immune responses, in particular CD4+ T cells. In naive mice, cellular responses in spleen were strong and mainly due to CD4+ T cells whereas the CD8+ T cell response was low. In HBV-carrier mice, high frequencies of HBs-specific CD4+ T cells secreting interferon (IFN)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha were found in liver only after i.n. immunization. Increased frequencies of CD4+ T cells expressing the integrin CD49a in liver suggest a role of nasal route in the cellular homing process. Multiple dose schedules appear to be a prerequisite for protein-based immunization in order to overcome immunotolerance in HBV-carrier mice. These findings provide new avenues for further preclinical and clinical development. PMID- 29510156 TI - USC-087 protects Syrian hamsters against lethal challenge with human species C adenoviruses. AB - Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections. We report here that USC-087, an N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analog of cidofovir, is highly effective against multiple AdV types in cell culture. USC-087 is also effective against AdV-C6 in our immunosuppressed permissive Syrian hamster model. In this model, hamsters are immunosuppressed by treatment with high dose cyclophosphamide. Injection of AdV C6 (or AdV-C5) intravenously leads to a disseminated infection that resembles the disease seen in humans, including death. We have tested the efficacy of orally administered USC-087 against the median lethal dose of intravenously administered AdV-C6. USC-087 completely prevented or significantly decreased mortality when administered up to 4 days post challenge. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection, and suppressed virus replication even when administered 4 days post challenge. These results imply that USC-087 is a promising candidate for drug development against HAdV infections. PMID- 29510157 TI - Demethoxycurcumin mediated targeting of MnSOD leading to activation of apoptotic pathway and inhibition of Akt/NF-kappaB survival signalling in human glioma U87 MG cells. AB - Earlier, we reported that Demethoxycurcumin (DMC) suppressed the growth of human glioma U87 MG cells by downregulation of Bcl-2 expression. In the present work, we investigated the DMC induced reactive oxygen species (ROS) mediated anti proliferative and apoptotic effects in U87 MG cells. Exposure of U87 MG cells to growth-suppressive concentrations of DMC (0-50 MUg/ml) resulted in ROS generation and concomitant increase in apoptosis. The major oxidative species induced by DMC was superoxide anion radical (O2-). DMC-induced anti-proliferation was mediated by Akt/NF-kappaB signalling inhibition and apoptosis through caspase-8 and 9 activation. In silico molecular docking analysis showed that, the amino acid residues His30, Tyr34, Asn37, Ala63, Asn67, His74, Trp123, and Asp159 in the active site of mitochondrial SOD (MnSOD) interacted with DMC. Furthermore, the complex MnSOD-DMC was found to be more stable as compared to native MnSOD in the MD simulations. In the present study, we have demonstrated for the first time using U87 MG cell line that DMC (a) establishes pi-pi interactions with Tyr 34 and Trp 161 in the putative active site of MnSOD to inhibit its activity, generating (O2-) to regulate survival and apoptotic proteins leading to antiproliferative and apoptotic events (b) induces antiproliferative effect via inhibition of Akt/NF-kappaB signalling pathway (c) contributes to the apoptosis via caspase-8 and caspase-9 activation to release the cytochrome c. In exploring the DMC induced cell death events in U 87 MG cell line, we revealed a novel mechanism of DMC-mediated inhibition of MnSOD leading to accumulation of superoxide anions to trigger the inhibition of survival pathways and induction of apoptosis. PMID- 29510158 TI - Endogenous GLP-1 in lateral septum contributes to stress-induced hypophagia. AB - Glucagon-like peptide 1 (GLP-1) neurons of the caudal brainstem project to many brain areas, including the lateral septum (LS), which has a known role in stress responses. Previously, we showed that endogenous GLP-1 in the LS plays a physiologic role in the control of feeding under non-stressed conditions, however, central GLP-1 is also involved in behavioral and endocrine responses to stress. Here, we asked whether LS GLP-1 receptors (GLP-1R) contribute to stress induced hypophagia. Male rats were implanted with bilateral cannulas targeting the dorsal subregion of the LS (dLS). In a within-subjects design, shortly before the onset of the dark phase, rats received dLS injections of saline or the GLP-1R antagonist Exendin (9-39) (Ex9) prior to 30 min restraint stress. Food intake was measured continuously for the next 20 h. The stress-induced hypophagia observed within the first 30 min of dark was not influenced by Ex9 pretreatment, but Ex9 tended to blunt the effect of stress as early as 1 and 2 h into the dark phase. By 4-6 h, there were significant stress X drug interactions, and Ex9 pretreatment blocked the stress-induced suppression of feeding. These effects were mediated entirely through changes in average meal size; stress suppressed meal size while dLS Ex9 attenuated this effect. Using a similar design, we examined the role of dLS GLP-1R in the neuroendocrine response to acute restraint stress. As expected, stress potently increased serum corticosterone, but blockade of dLS GLP-1Rs did not affect this response. Together, these data show that endogenous GLP-1 action in the dLS plays a role in some but not all of the physiologic responses to acute stress. PMID- 29510159 TI - Consumers' physiological and verbal responses towards product packages: Could these responses anticipate product choices? AB - Today, it is a priority to predict what consumers will choose at the point of sale where there are more and more competing brands. But what kind of consumers' information can be used for that purpose? This paper compares the power of physiological responses (unconscious responses) and self-report/verbal responses (conscious responses) towards product packages, as a means of predicting product choices. To this end, six different packaging designs were created by combining three different colors (blue, red and black) and two different messages (simple and reinforced). Eighty-three young consumers were exposed to each of the six designs. In one phase of our investigation, unconscious electrodermal activity (EDA) for each participant and each packaging type was recorded. In another phase, conscious verbal opinions for each packaging type were collected in a questionnaire. Our results show that the blue packaging with a reinforced message was most often selected. For this packaging consumers' electrodermal values (unconscious responses) were lower, and verbal opinions (conscious responses) were higher. Thus, both data sets could be used to anticipate product choice. However, for the other five packages, only unconscious responses were related to product choices. In contrast, higher opinions in a questionnaire did not correspond to selection of packages. PMID- 29510161 TI - Preclinical assessment of the neutralizing efficacy of snake antivenoms in Latin America and the Caribbean: A review. AB - The preclinical evaluation of the neutralizing efficacy of antivenoms is mandatory before a product is introduced for clinical use. The World Health Organization (WHO) guidelines for antivenoms categorize the tests used in preclinical studies as 'essential assay' (neutralization of lethality) and 'additional recommended assays' (neutralization of other relevant toxic activities). The present review presents an overview of the methodological aspects of snake antivenom preclinical efficacy tests, and summarizes the studies performed in this subject on antivenoms used in Latin America and the Caribbean. General trends emerging from this analysis show that: (a) Bothrops antivenoms have a broad spectrum of neutralizing efficacy against venoms of snakes of the genera Agkistrodon, Atropoides, Bothriechis, Bothrops, Cerrophidion, and Porthidium. (b) Crotalus antivenoms show a dichotomic pattern of efficacy depending on whether the venoms used for immunization are crotoxin-rich or metalloproteinase-rich. (c) A complete neutralization of Lachesis sp venoms is achieved only by antivenoms that include Lachesis sp venoms in the immunizing mixture. (d) Micrurus sp venoms have a high immunological heterogeneity which impacts in the cross-neutralization by available antivenoms. There is a need to further expand the knowledge base of the preclinical efficacy of antivenoms in Latin America and the Caribbean. PMID- 29510160 TI - Tropomyosin 2 heterozygous knockout in mice using CRISPR-Cas9 system displays the inhibition of injury-induced epithelial-mesenchymal transition, and lens opacity. AB - The process of epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) after cataract surgery contributes to tissue fibrosis, wound healing and lens regeneration via a mechanism not yet fully understood. Here, we show that tropomyosin 2 (Tpm2) plays a critical role in wound healing and lens aging. Posterior capsular opacification (PCO) after lens extraction surgery was accompanied by elevated expression of Tpm2. Tpm2 heterozygous knockout mice, generated via the clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) system showed promoted progression of cataract with age. Further, injury-induced EMT of the mouse lens epithelium, as evaluated histologically and by the expression patterns of Tpm1 and Tpm2, was attenuated in the absence of Tpm2. In conclusion, Tpm2 may be important in maintaining lens physiology and morphology. However, Tpm2 is involved in the progression of EMT during the wound healing process of mouse LECs, suggesting that inhibition of Tpm2 may suppress PCO. PMID- 29510162 TI - Speedy milking of fresh venom from aculeate hymenopterans. AB - A straightforward method for extracting aculeate arthropod venoms by centrifugation is described, based on adapting a glass insert containing a piece of metal mesh or glass wool into a centrifuge tube. Venom apparatuses are centrifuged for 30 s intervals at ~2000-6000 g, with samples being dislodged between cycles. Venom from fire ants, honeybees, and a social wasp were extracted within minutes. The method is suited for small-scale bioassays and allows for faithful descriptions of unmodified toxin cocktails. PMID- 29510163 TI - Antibacterial properties of plasma from the prairie rattlesnake (Crotalus viridis). AB - The innate immune system functions to quickly respond to pathogens and is likely the primary line of defense for ectothermic vertebrates. Snake populations appear to be in widespread decline globally, but despite the threats from emerging pathogens, very little work has been conducted to characterize their basic immune function. We used a wide-ranging snake species, the Prairie Rattlesnake (Crotalus viridis), to measure effects of snake plasma on the growth of eight bacterial species. Additionally, we quantified bacterial killing ability and kinetics of the immune response. Our results show that Prairie Rattlesnakes have robust innate immune systems, and concentrations of 10% snake plasma inhibit growth of 6 of 8 bacteria tested. Undiluted snake plasma inhibited nearly all bacterial growth. The immune response was fairly rapid, inhibiting 73% of bacterial growth within 20 min of exposure. These results are encouraging for conservation of wild populations, as snakes appear to exhibit a strong innate immune response. However, further work needs to be directed toward the evaluation of immune system capabilities in individual populations of conservation concern, and against pathogens known to cause mortality in wild snakes. PMID- 29510164 TI - An Ns1abp-like gene promotes white spot syndrome virus infection by interacting with the viral envelope protein VP28 in red claw crayfish Cherax quadricarinatus. AB - Influenza A virus non-structural-1A binding protein (named as Ns1abp) was originally identified as a host protein from human that bound to the viral NS-1 protein. In our previous study, the expression of an Ns1abp-like gene (denoted as CqNs1abp-like gene) was found to be up-regulated in a transcriptome library from the haematopoietic tissue (Hpt) cells of red claw crayfish Cherax quadricarinatus post white spot syndrome virus (WSSV) infection. To elucidate the role of CqNs1abp-like gene involved in WSSV infection, we cloned the CqNs1abp-like gene in which the open reading frame was 2232 bp, encoding 743 amino acids with two typical domains of one BTB (Broad-Complex, Tramtrack and Bric a brac) domain at N terminal and six Kelch domains at C-terminal. The gene expression profile showed that the mRNA transcript of CqNs1abp-like gene was widely expressed in all the tested tissues with highest expression in nerve, relatively high expression in Hpt and lowest expression in eyestalk. Importantly, both the WSSV entry and the viral replication were significantly reduced in Hpt cells after gene silencing of CqNs1abp-like gene. By using protein pull-down assay, we found that the recombinant BTB domain, six Kelch domains and CqNs1abp-like intact protein were all bound to the WSSV envelope protein VP28, respectively, in which the BTB domain showed slightly less binding affinity than that of the six Kelch domains or the recombinant intact protein. Besides, the WSSV entry into Hpt cells was clearly decreased when the virus was pre-incubated with the recombinant BTB domain, six Kelch domains, or the recombinant CqNs1abp-like intact protein, respectively, suggesting that the CqNs1abp-like gene was likely to function as a putative recognition molecular towards WSSV infection in a crustacean C. quadricarinatus. Taken together, these data shed new light on the mechanism of WSSV infection and a putatively novel target on anti-WSSV infection in crustacean farming. PMID- 29510165 TI - Pre and post intervention study of antiblastic drugs contamination surface levels at a Pharmacy Department Compounding Area using a closed system drug transfer device and a decontamination process. AB - Assuring healthcare workers security on Hazardous Drugs (HD) compounding is critical in healthcare settings. Our study aims to demonstrate that the use of a Close System drug Transfer Device (CSTD) PhaSealTM added to a decontamination process reduces antiblastic surface contamination levels in the Compounding Area (CA) of our Pharmacy Department (PD). We selected cyclophosphamide, 5 fluorouracil and iphosphamide to be evaluated. Testing was carried out with a wipe kit and quantified by an independent laboratory. We defined four sampling times: baseline; just after a decontamination procedure, which was repeated weekly during the study; four months after introduction of CSTD PhaSealTM for cyclophosphamide and 5-fluorouracil compounding; and after eight months using CSTD PhaSealTM for cyclophosphamide and 5-fluorouracil and one month for iphosphamide compounding. There was a decrease at the number of positive samples at the beginning/end of the study for all the drugs tested: 28/15 for cyclophosphide, 29/23 for iphosphamide and 7/1 for 5-fluorouracile. Comparing to the baseline, median cyclophosphamide levels significantly decreased (p-value <0.001) at 4 and 8 months sampling time (baseline: 1.01 ng/cm2 to 0.06 ng/cm2 and 0.01 ng/cm2), and median iphosphamide levels significantly decreased (p < 0.001) at 8 months sampling time (baseline: 3.02 ng/cm2 to 0.06 ng/cm2). 5-Fluorouracil did not show significant differences between the sampling times (baseline: 0.09 ng/cm2 to 0.09 ng/cm2). We saw a significant increase at iphosphamide levels at 4 months sampling point, contrary to cyclophosphamide, which levels had decreased. The use of CSTD PhaSealTM for iphosphamide compounding the last month was implemented for ethical reasons after this intermediate results review. Our study suggests that the use of CSTD PhaSealTM, adding to decontaminating procedures, significantly reduces antiblastic drug surface levels at the CA of our PD. PMID- 29510166 TI - Uterine adenocarcinoma in the rat induced by afidopyropen. An analysis of the lesion's induction, progression and its relevance to humans. AB - Afidopyropen is a novel insecticide that acts as a TRPV channel modulator in chordotonal organs of target insects. In two carcinogenicity studies with Fischer rats, an increased incidence of uterine adenocarcinomas was observed at 1000 and 3000 ppm. This finding prompted an investigation of the mechanism of the tumor formation as well as the relevance of this mechanism to humans. The mechanistic work took parallel paths: one path investigated the pharmacokinetic properties of the test substance at the doses where the tumors were found; while the second path examined the key mechanistic events that culminated in uterine adenocarcinomas. The results of the investigation indicated that the tumors only occurred at doses where excretion of test substance was saturated - indicating that homeostatic biological and/or physiological processes were overwhelmed. At the doses where these processes were overwhelmed, the test substance acted through a mechanism of dopamine agonism, triggering a cascade key events that resulted in uterine adenocarcinomas. An analysis of these mechanisms observed in rat showed that they are both quantitatively (pharmacokinetic mechanism) and qualitatively (dopamine agonism mechanism) not relevant to humans. Therefore the uterine adenocarcinomas observed in the rat associated with high doses of Afidopyropen are not expected to pose a carcinogenic risk to humans. PMID- 29510167 TI - Role of dopamine D3 receptor in alleviating behavioural deficits in animal models of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a complicated psychiatric disorder, which occurs after exposure to a traumatic event. The main clinical manifestation of PTSD includes fear and stress dysregulation. In both animals and humans, dysregulation of dopamine function appears to be related to conditioned fear responses. Previous studies show that the dopamine D3 receptor (D3R) is involved in schizophrenia, autism, and substance use disorders and is related to emotional disorders. However, few studies have investigated the role of the D3R in the pathogenesis and aetiology of PTSD. In the current study, we have reported that D3R knockout (D3R-/-) mice displayed decreased freezing time of contextual fearing and anxiolytic effects following training sessions consisting of exposure to inescapable electric foot-shocks. Similarly, highly selective blockade of D3Rs by YQA14, a novel D3R antagonist, significantly ameliorated freezing and anxiogenic-like behaviours in the single-prolonged stress (SPS) model of PTSD in rats. And more, YQA14 selectively alleviated the symptoms of PTSD in WT mice but not in D3R-/- mice. In summary, this study demonstrates the anti-PTSD effects of blockade or knockout of the D3R, suggesting that the D3R might play an important role in the pathogenesis and aetiology of PTSD, and might be a potential target for the clinical management of PTSD. PMID- 29510168 TI - Development and characterization of cross-linked enzyme aggregates of thermotolerant alkaline protease from Bacillus licheniformis. AB - An alkaline protease was produced by B. licheniformis with 132.43+/-3.4U/mL activity in LSF which was further enhanced by optimizing culture conditions. The optimum enzyme activity (148.9+/-4.1U/mL) was harvested at pH7.5; temperature, 40 degrees C and inoculum, 1.5mL after 48h incubation. Alkaline protease was immobilization by forming cross linked enzyme aggregates (CLEAs) and the processes of CLEAs formation was also optimized. The protease CLEAs developed using 80% ammonium sulfate, 65mM glutaraldehyde and 0.11mM BSA showed best activity recovery (39.76%). Free protease and CLEAs were characterized and compared. It was observed that CLEAs of protease exhibited broad pH range with best activity at pH10. The immobilized protease was also thermo-tolerant with optimum activity at 65 degrees C temperature. The Vmax and Km of protease-CLEAs were 125.5U/mL and 18.97MUM, respectively as compared to 104.9U/mL and 29MUM, respectively for free protease. It was concluded that immobilized enzyme in the form of CLEAs is a valuable catalyst for potential industrial applications. PMID- 29510170 TI - What Impacts the All Cause Risk of Reoperation after Pelvic Organ Prolapse Repair? A Comparison of Mesh and Native Tissue Approaches in 110,329 Women. AB - PURPOSE: Several factors are hypothesized to impact the risks of mesh augmented pelvic organ prolapse repair, including 1) the characteristics of the material, 2) surgical experience and 3) patient selection. We present a large, population based approach to explore the impact of these factors on outcomes and describe an ideal mesh use strategy. MATERIALS AND METHODS: Data from the Office of Statewide Health Planning and Development were accessed to identify all women who underwent pelvic organ prolapse repair in California from 2005 to 2011. Multivariate mixed effects logistic regression models were constructed to explore which patient, surgical and facility factors were associated with repeat surgery for a complication due to mesh or recurrent pelvic organ prolapse. RESULTS: A total of 110,329 women underwent pelvic organ prolapse repair during the study period and mesh was used in 16.2% of the repairs. The overall repeat surgery rate was higher in women who underwent mesh repair (5.4% vs 4.3%, p <0.001). However, multivariate modeling revealed that mesh itself was not independently associated with repeat surgery. Rather, repair at a facility where there was a greater propensity to use mesh was independently associated with repeat surgery (highest vs lowest mesh use quartile OR 1.55, p <0.01). Further modeling revealed that the lowest risk occurred when mesh was used in 5% of anterior and 10% of anterior apical repairs. CONCLUSIONS: Our findings demonstrate that mesh is not independently associated with an increase in the rate of complications of pelvic organ prolapse repair on a large scale. We present a model that supports judicious use of the product on the population level which balances the risk of complications against that of recurrent pelvic organ prolapse. PMID- 29510169 TI - Acetaldehyde-induced structural and conformational alterations in human immunoglobulin G: A physicochemical and multi-spectroscopic study. AB - Acetaldehyde is a reactive aldehyde produced as an intermediate of alcohol metabolism and tobacco pyrolysis. It has the potential to interact with different biomolecules in various tissues which results in the formation of stable, unstable and covalent adducts. This causes structural and functional modifications that may lead to severe complications such as cancer. This study has probed the structural modifications in human immunoglobulin G (IgG) as a function of different concentrations of acetaldehyde in the presence of reducing agent, sodium borohydride. Acetaldehyde mediated modifications in IgG have been characterised by various physicochemical techniques. UV-spectrophotometry showed that acetaldehyde modified IgG exhibited marked increase in hyperchromicity. Fluorescence studies revealed a significant quenching of tryptophan fluorescence which resulted in loss of beta-sheet secondary structure that was confirmed by circular dichroic analysis. Gross structural changes in the morphology of IgG were confirmed by increase in mass and hydrodynamic radius of this glycoprotein along with the appearance of fibrillar structures in modified IgG, when compared to the granular structure of the native form of IgG observed by scanning electron microscope. The results indicate that acetaldehyde causes alterations in the secondary and tertiary structure of the protein leading to diminution of normal function of IgG molecule. PMID- 29510171 TI - Improvement of a mixture experiment model relating the component proportions to the size of nanonized itraconazole particles in extemporary suspensions. AB - A paper by Foglio Bonda et al. published previously in this journal (2016, Vol. 83, pp. 175-183) discussed the use of mixture experiment design and modeling methods to study how the proportions of three components in an extemporaneous oral suspension affected the mean diameter of drug particles (Zave). The three components were itraconazole (ITZ), Tween 20 (TW20), and Methocel(r) E5 (E5). This commentary addresses some errors and other issues in the previous paper, and also discusses an improved model relating proportions of ITZ, TW20, and E5 to Zave. The improved model contains six of the 10 terms in the full-cubic mixture model, which were selected using a different cross-validation procedure than used in the previous paper. Compared to the four-term model presented in the previous paper, the improved model fit the data better, had excellent cross-validation performance, and the predicted Zave of a validation point was within model uncertainty of the measured value. PMID- 29510172 TI - The role of lactose carrier on the powder behavior and aerodynamic performance of bosentan microparticles for dry powder inhalation. AB - In this study, we prepared carrier-based formulations for dry powder inhalers by mixing bosentan microparticles with carrier, prepared in three separate types of lactose. Spray-dried, milled and sieved lactose resulted in formulations with various shapes, surface morphology and particle size distributions. In the spray dried lactose, the micronized bosentan particles were trapped and strongly interlocked in the rugged surface of spray-dried lactose, whereas in the milled and sieved lactose they exhibited lower binding affinity onto the smooth surface of carrier. In all of the carrier-based formulations, the flow properties were improved compared with bosentan microparticles alone, in the following order spray-dried, sieved and milled lactose. The aerodynamic characteristics of each were evaluated by particle image velocimetry and Andersen cascade impactorTM. Depending on the lactose carrier type, particle dispersion showed different flow characteristics. In the spray-dried lactose, the formulation was dispersed fast in the only frontal direction, while the milled and sieved lactose formulations formed a relatively slower S-shaped and fountain-shaped flow stream, respectively. In addition, milled and sieved lactose formulations showed that the drug particles were readily liberated from the lactose carrier, and demonstrated significantly higher aerosol performance than spray-dried lactose. PMID- 29510173 TI - Apple hammerhead viroid-like RNA is a bona fide viroid: Autonomous replication and structural features support its inclusion as a new member in the genus Pelamoviroid. AB - Apple hammerhead viroid-like RNA (AHVd RNA) has been reported in different apple cultivars and geographic regions and, considering the presence of hammerhead ribozymes in both polarity strands, suspected to be either a viroid of the family Avsunviroidae or a viroid-like satellite RNA. Here we report that dimeric head-to tail in vitro transcripts of a 433-nt reference variant of AHVd RNA from cultivar "Pacific Gala" are infectious when mechanically inoculated to apple, thus showing that this RNA is a bona fide viroid for which we have kept the name apple hammerhead viroid (AHVd) until its pathogenicity, if any, is better assessed. By combining thermodynamics-based predictions with co-variation analyses of the natural genetic diversity found in AHVd we have inferred the most likely conformations for both AHVd polarity strands in vivo, with that of the (+) polarity strand being stabilized by a kissing loop-interaction similar to those reported in peach latent mosaic viroid and chrysathemum chlorotic mottle viroid, the two known members of the genus Pelamoviroid (family Avsunviroidae). Therefore, AHVd RNA fulfills the biological and molecular criteria to be allocated to this genus, the members of which, intriguingly, display low global sequence identity but high structural conservation. PMID- 29510174 TI - Cys Links Heme: Stereo-orientation of Heme Transfer in Cytochrome c Biogenesis. PMID- 29510175 TI - Scaling laws and size effects for amorphous crystallization kinetics: Constraints imposed by nucleation and growth specificities. AB - In the present paper we review different aspects of the crystallization of amorphous compounds in relation to specificities of the nucleation and growth rates. Its main purpose is: i) to underline the interest of a scaling analysis of recrystallization kinetics to identify similarities or disparities of experimental kinetic regimes. ii) to highlight the intrinsic link between the nucleation rate and growth rate with a temperature dependent characteristic transformation time tau(T), and a characteristic size xi(T). The consequences on the influence of the sample size on kinetics of crystallization is considered. The significance of size effect and confinement for amorphous stabilization in the pharmaceutical sciences is discussed. PMID- 29510176 TI - Association between P2RY12 gene polymorphisms and adverse clinical events in coronary artery disease patients treated with clopidogrel: A systematic review and meta-analysis. AB - OBJECTIVE: Investigate the association between P2Y12 Purinoceptor (P2RY12) polymorphisms and adverse clinical events in coronary artery disease (CAD) patients treated with clopidogrel. METHODS: We performed a comprehensive database search, with a particular focus on P2RY12 polymorphisms and their effects on clopidogrel-treated CAD patients, in the PubMed, EMBASE, Cochrane Library, clinicaltrials.gov, Web of Science, and Chinese databases from their inceptions to April 8, 2017. The primary endpoints were composite ischemic events (including cardiovascular and cerebrovascular ischemic events), the secondary endpoints were independent cardiovascular events (mortality, non-fatal myocardial infarction, stent thrombosis, unstable angina, and target vessel revascularization) and the safety endpoints were bleeding events. RESULTS: Overall 10 studies and 10,810 clopidogrel-treated CAD patients were studied in the present work. Subjects of the common alleles of P2RY12 polymorphisms showed higher risk for composite ischemic events compared to non-carriers (n = 434 of 3268[13.3%] vs. n = 646 of 6133[10.5%]; RR: 1.39, 95%CI: 1.14-1.69; p = 0.001). These allele carriers also showed increased risk for stent thrombosis (RR: 2.67, 95%CI: 1.03-6.91; p = 0.04), myocardial infarction (RR: 1.60, 95%CI: 1.06-2.42; p = 0.03), and unstable angina (RR: 1.72, 95%CI: 1.37-2.16; p < 0.00001) (vs. non-carriers). There was no significant difference between two groups in terms of mortality risk, target vessel revascularization or bleeding (p = 0.29; p = 0.48, respectively). CONCLUSIONS: P2RY12 gene polymorphisms might associate with higher risk of composite ischemic events, stent thrombosis, non-fatal myocardial infarction, unstable angina. While we found no significant effect on mortality, target vessel revascularization or bleeding. PMID- 29510177 TI - Age-dependent behaviors, seizure severity and neuronal damage in response to nerve agents or the organophosphate DFP in immature and adult rats. AB - Exposure to nerve agents (NAs) and other organophosphates (OPs) can initiate seizures that rapidly progress to status epilepticus (SE). While the electrographic and neuropathological sequelae of SE evoked by NAs and OPs have been characterized in adult rodents, they have not been adequately investigated in immature animals. In this study postnatal day (PND) 14, 21 and 28 rat pups, along with PND70 animals as adult controls, were exposed to NAs (sarin, VX) or another OP (diisopropylfluorophosphate, DFP). We then evaluated behavioral and electrographic (EEG) correlates of seizure activity, and performed neuropathology using Fluoro-Jade B. Although all immature rats exhibited behaviors that are often characterized as seizures, the incidence, duration, and severity of the electrographic seizure activity were age-dependent. No (sarin and VX) or brief (DFP) EEG seizure activity was evoked in PND14 rats, while SE progressively increased in severity as a function of age in PND21, 28 and 70 animals. Fluoro Jade B staining was observed in multiple brain regions of animals that exhibited prolonged seizure activity. Neuronal injury in PND14 animals treated with DFP was lower than in older animals and absent in rats exposed to sarin or VX. In conclusion, we found that NAs and an OP provoked robust SE and neuronal injury similar to adults in PND21 and PND28, but not in PND14, rat pups. Convulsive behaviors were often present independent of EEG seizures and were unaccompanied by neuronal damage. These differential responses should be considered when investigating medical countermeasures for NA and OP exposure in pediatric populations. PMID- 29510178 TI - Metformin increases urinary sodium excretion by reducing phosphorylation of the sodium-chloride cotransporter. AB - OBJECTIVE: Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys. METHODS: Urinary sodium excretion and expression of renal sodium transporters were examined in 8 week-old male C57BL/6 mice with acute and chronic treatment of metformin. In addition, we examined metformin effects using ex vivo preparations of mice kidney slices. RESULTS: In this study, we demonstrated that metformin increased urinary sodium excretion by reducing phosphorylation of the thiazide-sensitive Na-Cl cotransporter (NCC) in acute and chronic metformin administration. We also confirmed reduction of phosphorylated NCC in an ex vivo study. The activity of other renal sodium transporters, such as NKCC2, ENaC, and NHE3 did not show significant changes. WNK-OSR1/SPAK kinase signals were not involved in this inactivation effect of metformin on NCC. CONCLUSION: Metformin increased urinary sodium excretion by reducing phosphorylation of NCC, suggesting its role in improving hypertension. PMID- 29510179 TI - Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes. AB - A large body of epidemiologic evidence has linked insufficient sleep duration and quality to the risk of obesity, insulin resistance and type 2 diabetes. To address putative causal mechanisms, this review focuses on laboratory interventions involving several nights of experimental sleep restriction, fragmentation or extension and examining metabolically relevant outcomes. Sleep restriction has been consistently shown to increase hunger, appetite and food intake, with the increase in caloric intake in excess of the energy requirements of extended wakefulness. Findings regarding decreases in hormones promoting satiety or increases in hormones promoting hunger have been less consistent, possibly because of confounding effects of changes in adiposity when energy intake was not controlled and sampling protocols that did not cover the entire 24 h cycle. Imaging studies revealed alterations in neuronal activity of brain regions involved in food reward. An adverse impact of experimental sleep restriction on insulin resistance, leading to reduced glucose tolerance and increased diabetes risk, has been well-documented. There is limited evidence indicating that sleep fragmentation without reduction in sleep duration also results in a reduction in insulin sensitivity. The adverse metabolic outcomes of sleep disturbances appear to involve multiple mechanistic pathways acting in concert. Emerging evidence supports the benefits of behavioral, but not pharmacological, sleep extension on appetite and glucose metabolism. Further research should focus on the feasibility and efficacy of strategies to optimize sleep duration and quality on obesity and diabetes risk in at-risk populations as well as those with established diseases. Further work is needed to identify mechanistic pathways. PMID- 29510180 TI - Metabolic syndrome and uric acid nephrolithiasis: insulin resistance in focus. AB - Uric acid nephrolithiasis (UAN) is an increasingly common disease in ethnically diverse populations and constitutes about 10% of all kidney stones. Metabolic syndrome and diabetes mellitus are accounted among the major risk factors for UAN, together with environmental exposure, individual lifestyle habits and genetic predisposition. The development and overt manifestation of UAN appears to stem on the background of insulin resistance, which acts at the kidney level by reducing urinary pH, thus hampering the ability of the kidney to generate renal ammonium in response to an acid load. Unduly acidic urinary pH and overt UAN are both considered renal manifestations of insulin resistance. The mechanisms underlying increased endogenous acid production and/or defective ammonium excretion are yet to be completely understood. Although the development of UAN and, more in general, of kidney stones largely recognizes modifiable individual determining factors, the rising prevalence of diabetes, obesity and accompanying metabolic disorders calls for the identification of novel therapeutic approaches and intervention targets. This review aims at providing an updated picture of existing evidence on the relationship between insulin resistance and UAN in the context of metabolic syndrome and in light of the most recent advancements in our understanding of its genetic signature. PMID- 29510181 TI - Exploring emotion regulation and emotion recognition in people with presymptomatic Huntington's disease: The role of emotional awareness. AB - Interest in the role of both emotion regulation and recognition in our understanding of mental health has been steadily increasing, especially in people with chronic illness who also have psychological difficulties. One illness which belongs to this category is Huntington's disease. Huntington's disease (HD) is a chronic neurodegenerative disorder that can cause a number of cognitive and psychological difficulties, including emotion recognition deficits, even before the onset of the symptoms required to make a formal diagnosis. Despite the lack of definite evidence, recent studies have suggested that deficits of emotion regulation and recognition may be expected to play a pivotal role in the early cognitive manifestations of HD. In this study, we hypothesised that the ability to regulate emotions can be impaired in people with presymptomatic HD, and that such impairment may be associated with a deficit of emotion recognition. To test this, an online survey was carried out with 117 English and Italian-speaking people with presymptomatic HD, compared to 217 controls matched for age and education. The results suggest that, in presymptomatic participants, emotion regulation and emotion recognition are generally not significantly impaired, and no significant relationships between performances on the two constructs were observed. However, a specific impairment in emotional awareness (a subscale on the Difficulties in Emotion Regulation Scale, DERS) was observed, which appears to be enhanced by the co-occurrence of depressive symptoms, even at a subclinical level. Consequently, it is suggested that difficulties in emotional awareness may represent a precursor of more general emotion recognition impairments, which only become apparent as the disease reaches a more symptomatic level. Clinical implications of the findings are discussed and directions for future research are proposed. PMID- 29510182 TI - Inhibiting self-justification for dishonesty with noninvasive brain stimulation. AB - People derive value from self-justifications by allowing themselves to lie for self-interest while feeling honest. This study explores, with the use of transcranial direct current stimulation (tDCS), whether ventrolateral prefrontal cortex (VLPFC) could modulate genuine (dis)honesty by inhibiting self justification for dishonesty. A total of 149 participants complete a die-in-a-cup task, in which they were asked to roll a six-sided die placed in an opaque cup twice but to report the first roll only. The experimental results show that anodal tDCS over right VLPFC increased 35.04% full honesty and decreased 21% high claims, resulting in the cumulative distributions of reported die rolls in the anodal group deviate from justified dishonesty benchmark and cluster around full honesty benchmark. These results add to the growing literature on neuronal mechanisms of genuine (dis)honesty by demonstrating that increasing honesty after anodal tDCS over right VLPFC is based on the mechanism of inhibiting self justification for dishonesty. PMID- 29510183 TI - Revealing the neural time-course of direct gaze processing via spatial frequency manipulation of faces. AB - Direct gaze is a powerful social cue signalling the attention of another person toward oneself. Here we investigated the relevance of low spatial frequency (LSF) and high spatial frequency (HSF) in facial cues for direct gaze processing. We identified two distinct peaks in the ERP response, the N170 and N240 components. These two components were related to different stimulus conditions and influenced by different spatial frequencies. In particular, larger N170 and N240 amplitudes were observed for direct gaze than for averted gaze, but only in the N240 component was this effect modulated by spatial frequency, where it was reliant in LSF information. By contrast, larger N170 and N240 components were observed for faces than for non-facial stimuli, but this effect was only modulated by spatial frequency in the N170 component, where it relied on HSF information. The present study highlights the existence of two functionally distinct components related to direct gaze processing. PMID- 29510184 TI - Don't judge me: Psychophysiological evidence of gender differences to social evaluative feedback. AB - Human beings have a basic need for esteemed social connections, and receiving negative self-evaluative feedback induces emotional distress. The aim of the current study is to measure eye movements (a physiological marker of attention allocation) and pupillary responses (a physiological marker of cognitive and emotional processing) as online and objective indices of participants' reaction to positive/negative social evaluations from the same or opposite sex. Following the paradigm, subjective mood ratings and heart rate variability (HRV) - as an objective index of regulatory effort- were measured. Results demonstrate clear gender-specific results in all measures. Eye-movements demonstrate that male participants respond more with other-focused attention (and specifically to male participants), whereas women respond more with self-focused attention following negative social evaluative feedback. Pupillary responses show that social evaluative feedback is specifically eliciting cognitive/affective processes in male participants to regulate emotional responses when provided by the opposite gender. Finally, following the paradigm, female (as compared to male) participants were more subjectively reactive to the paradigm (i.e., self reports), and were less able to engage contextual- and goal related regulatory control of emotional responses (reduced HRV). Although the current study focused on psychiatrically healthy young adults, results may contribute to our understanding of sex differences in internalizing mental problems, such as rumination. PMID- 29510185 TI - Targeting the Dvl-1/beta-arrestin2/JNK3 interaction disrupts Wnt5a-JNK3 signaling and protects hippocampal CA1 neurons during cerebral ischemia reperfusion. AB - It is well known that Wnt5a activation plays a pivotal role in brain injury and beta-arrestin2 induces c-Jun N-terminal kinase (JNK3) activation is involved in neuronal cell death. Nonetheless, the relationship between Wnt5a and JNK3 remains unexplored during cerebral ischemia/reperfusion (I/R). In the present study, we tested the hypothesis that Wnt5a-mediated JNK3 activation via the Wnt5a-Dvl-1 beta-arrestin2-JNK3 signaling pathway was correlated with I/R brain injury. We found that cerebral I/R could enhance the assembly of the Dvl-1-beta-arrestin2 JNK3 signaling module, Dvl-1 phosphorylation and JNK3 activation. Activated JNK3 could phosphorylate the transcription factor c-Jun, prompt caspase-3 activation and ultimately lead to neuronal cell death. To further explore specifically Wnt5a mediated JNK3 pathway activation in neuronal injury, we used Foxy-5 (a peptide that mimics the effects of Wnt5a) and Box5 (a Wnt5a antagonist) both in vitro and in vivo. AS-beta-arrestin2 (an antisense oligonucleotide against beta-arrestin2) and RRSLHL (a small peptide that competes with beta-arrestin2 for binding to JNK3) were applied to confirm the positive signal transduction effect of the Dvl 1-beta-arrestin2-JNK3 signaling module during cerebral I/R. Furthermore, Box5 and the RRSLHL peptide were found to play protective roles in neuronal death both in vivo global and focal cerebral I/R rat models and in vitro oxygen glucose deprivation (OGD) neural cells. In summary, our results indicate that Wnt5a mediated JNK3 activation participates in I/R brain injury by targeting the Dvl-1 beta-arrestin2/JNK3 interaction. Our results also point to the possibility that disrupting Wnt5a-JNK3 signaling pathway may provide a new approach for stroke therapy. PMID- 29510186 TI - The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. AB - Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB1, CB2 or 5HT1A receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3beta and the synaptic proteins Synapsin Ia/b, mGluR1 and PSD95). After 14 days, CBD injections (30 mg/kg) induced anxiolytic responses in stressed animals in the elevated plus-maze and novelty suppressed feeding tests, that were blocked by pre-treatment with a CB1 (AM251, 0.3 mg/kg) or CB2 (AM630, 0.3 mg/kg), but not by a 5HT1A (WAY100635, 0.05 mg/kg) receptor antagonist. Golgi staining and immunofluorescence revealed that these effects were associated with an increase in hippocampal neurogenesis and spine density in the dentate gyrus of the hippocampus. AM251 and AM630 abolished the effects of CBD on spines density. However, AM630 was more effective in attenuating the pro neurogenic effects of CBD. CBD decreased FAAH and increased p-GSK3beta expression in stressed animals, which was also attenuated by AM630. These results indicate that CBD prevents the behavioral effects caused by CUS probably due to a facilitation of endocannabinoid neurotransmission and consequent CB1/CB2 receptors activation, which could recruit intracellular/synaptic proteins involved in neurogenesis and dendritic remodeling. PMID- 29510187 TI - Rhynchophylline suppresses soluble Abeta1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B containing NMDA receptors. AB - Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid beta protein (Abeta) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Abeta-induced neurotoxicity. However, whether RIN can prevent soluble Abeta1-42-induced impairments in spatial cognitive function and synaptic plasticity is still unclear. Using the combined methods of behavioral tests, immunofluorescence and electrophysiological recordings, we characterized the key neuroprotective properties of RIN and its possible cellular and molecular mechanisms against soluble Abeta1-42-related impairments in rats. Our findings are as follows: (1) RIN efficiently rescued the soluble Abeta1-42-induced spatial learning and memory deficits in the Morris water maze test and prevented soluble Abeta1-42-induced suppression in long term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) circuit. (2) Excessive activation of extrasynaptic GluN2B-NMDAR and subsequent Ca2+ overload contributed to the soluble Abeta1-42-induced impairments in spatial cognitive function and synaptic plasticity. (3) RIN prevented Abeta1 42-induced excessive activation of extrasynaptic NMDARs by reducing extrasynaptic NMDARs -mediated excitatory postsynaptic currents and down regulating GluN2B NMDAR expression in the DG region, which inhibited Abeta1-42-induced Ca2+ overload mediated by extrasynanptic NMDARs. The results suggest that RIN could be an effective therapeutic candidate for cognitive impairment in AD. PMID- 29510188 TI - In vitro antimycobacterial activity of 2-(((2-hydroxyphenyl)amino)methylene)-5,5 dimethylcyclohexane-1,3-dione: a new chemical entity against Mycobacterium tuberculosis. AB - This study reports on the in vitro antituberculosis potential of 2-(((2 hydroxyphenyl) amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD) against Mycobacterium tuberculosis H37Rv. PAMCHD has been proven to be a tuberculostatic as well as a tuberculocidal agent by agar and broth dilution methods with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values equivalent to some standard antituberculosis drugs (ATDs). The dynamics of M. tuberculosis killing revealed the time- as well as concentration-dependent antituberculosis activity of PAMCHD and it sterilized M. tuberculosis culture at or above 10.0 ug/mL. PAMCHD acts either synergistically or additively with ATDs. Isoniazid (INH) and PAMCHD post-antibiotic effects increased with concentration from 16.18 +/- 13.30 and 31.64 +/- 13.30 to 127.9 +/ 27.60 and 138.71 +/- 16.42 h, respectively, from 1 * MIC to 8 * MIC; no significant difference was observed between INH and PAMCHD post-antibiotic effects. M. tuberculosis mutation frequency against PAMCHD is lower than that of INH. Mutant prevention concentration (MPC) of INH, rifampin (RIF) and PAMCHD were observed to be 40, 160 and 160 ug/mL, respectively, and their MPC/MIC values were 128, 2051 and 64, respectively; this lowest MPC/MIC highlights the advantage of PAMCHD over RIF and INH. PMID- 29510189 TI - In vitro activity of meropenem/vaborbactam and characterisation of carbapenem resistance mechanisms among carbapenem-resistant Enterobacteriaceae from the 2015 meropenem/vaborbactam surveillance programme. AB - The activity of meropenem/vaborbactam was evaluated against 11 559 Enterobacteriaceae isolates, including 330 carbapenem-resistant phenotypes (CRE) and carbapenemase genotypes collected worldwide during 2015. Antimicrobial susceptibility testing for meropenem/vaborbactam (inhibitor at 8 mg/L) and comparators was performed by the reference broth microdilution method. CRE isolates were screened for the presence of genes encoding carbapenemases, and 292 (88.5%) of the CRE isolates carried these resistance genes. A total of 209 isolates (63.3% of the CRE; 1.8% of the overall Enterobacteriaceae population) carried blaKPC, including genes encoding KPC-2 (90 isolates), KPC-3 (117 isolates) and KPC-17 (2 isolates). Overall, meropenem/vaborbactam (vaborbactam at 8 mg/L) inhibited 99.3% of all Enterobacteriaceae isolates at the US-FDA susceptibility breakpoint of <=4/8 mg/L. Meropenem alone inhibited 96.9% of the isolates at the current CLSI susceptibility breakpoint of <=2 mg/L. Susceptibility rates for comparator antimicrobial agents tested against Enterobacteriaceae isolates ranged from 82.1-98.2% applying the CLSI breakpoints. Against CRE isolates, meropenem/vaborbactam displayed MIC50/90 values at 0.5/32 mg/L, whereas meropenem MIC50/90 values were 16/>32 mg/L. Meropenem/vaborbactam was very active against KPC-producers, and 99.5% of these isolates were inhibited by <=4/8 mg/L. The single resistant isolate was shown to harbour an outer membrane porin alteration. Meropenem/vaborbactam had limited activity against MBL producing isolates (including 49 NDM-, 1 IMP-64- and 2 VIM-producers) and/or oxacillinases (47 OXA-48/-232) that were detected mainly in European countries. Meropenem/vaborbactam was active against contemporary CRE and wild-type Enterobacteriaceae collected worldwide and this combination demonstrated enhanced activity compared with meropenem and most comparator agents against CRE and KPC producers. PMID- 29510190 TI - SATB1 Defines a Subtype of Cutaneous CD30+ Lymphoproliferative Disorders Associated with a T-Helper 17 Cytokine Profile. AB - Cutaneous CD30+ lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma, comprise the second most common group of cutaneous T-cell lymphomas. Previously, we reported that special SATB1, a thymocyte-specific chromatin organizer, was overexpressed and promoted malignant T-cell proliferation in a portion of CD30+ LPDs. Here, we investigated the expression pattern of SATB1 in CD30+ LPDs with a large cohort of patient samples, and examined the potential of SATB1 as a molecular marker to classify CD30+ LPDs with differential clinicopathological behaviors. SATB1 expression was identified in the CD30+ anaplastic T cells in 11 of 12 (91.7%) lymphomatoid papulosis and 16 of 42 (38.1%) primary cutaneous anaplastic large-cell lymphoma cases. SATB1+ cases showed T-helper 17 polarization, together with more prominent epidermal hyperplasia and granulocytic infiltration. SATB1+ lesions responded better to combined treatment of methotrexate and interferon. SATB1 activated the expression of T-helper 17 cytokines while repressing T-helper 1-related genes. The heterogeneity in SATB1 expression across CD30+ LPDs was associated with the extent of promoter DNA methylation. Hence, SATB1 expression defines a subtype of CD30+ LPDs with characteristic pathobiology and prognosis. These data provide valuable insights into the heterogeneity of cutaneous T-cell malignancies, which may lead to individualized therapy in the future. PMID- 29510191 TI - Resident T Cells in Resolved Psoriasis Steer Tissue Responses that Stratify Clinical Outcome. AB - Psoriasis is driven by focal disruptions of the immune-homeostasis in human skin. Local relapse following cessation of therapy is common and unpredictable, which complicates clinical management of psoriasis. We have previously shown that pathogenic resident T cells accumulate in active and resolved psoriasis, but whether these cells drive psoriasiform tissue reactions is less clear. Here, we activated T cells within skin explants using the pan-T cell activating antibody OKT-3. To explore if T cells induced different tissue response patterns in healthy and psoriasis afflicted skin, transcriptomic analyses were performed with RNA-sequencing and Nanostring. Core tissue responses dominated by IFN-induced pathways were triggered regardless of the inflammatory status of the skin. In contrast, pathways induced by IL-17A, including Defensin beta 2 and keratinocyte differentiation markers, were activated in psoriasis samples. An integrated analysis of IL-17A and IFN-related responses revealed that IL-17 dominated tissue response correlated with early relapse following UVB treatment. Stratification of tissue responses to T cell activation in resolved lesions could potentially offer individualized prediction of disease relapse during long-term immunomodulatory treatment. PMID- 29510192 TI - CCR4 Is Critically Involved in Skin Allergic Inflammation of BALB/c Mice. AB - Atopic dermatitis is a chronic inflammatory skin disease involving T-helper (Th) 2 cells, eosinophils, and mast cells. Although CCR4 is a major chemokine receptor expressed on Th2 cells and regarded as a potential therapeutic target for allergic diseases, its role in atopic dermatitis remains unclear. Here, by using a hydrogel patch as a transcutaneous delivery device for ovalbumin (an antigen) and Staphylococcus aureus delta-toxin (a mast cell activator), we efficiently induced acute atopic dermatitis-like skin lesions in BALB/c mice, a strain prone to Th2 responses, which were characterized by increased numbers of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions; elevated levels of total and ovalbumin-specific IgE in the sera; and increased expression of IL-4, IL-17A, IL-22, CCL17, CCL22, and CCR4 in the skin lesions. Of note, the same model was less efficient in C57BL/6 mice, a strain prone to Th1 responses. Using this atopic dermatitis model in BALB/c mice, we demonstrated that CCR4-deficiency or a CCR4 antagonist ameliorated the allergic responses. Collectively, these results demonstrate that CCR4 plays a pivotal role in skin allergic inflammation of BALB/c mice by recruiting CCR4-expressing Th2 cells and Th17 cells. PMID- 29510193 TI - CCN1/Cyr61 Stimulates Melanogenesis through Integrin alpha6beta1, p38 MAPK, and ERK1/2 Signaling Pathways in Human Epidermal Melanocytes. AB - Fibroblast-derived melanogenic paracrine mediators are known to play a role in melanogenesis. To investigate the effect of CCN1 (also called CYR61 or cysteine rich 61) on melanogenesis, normal human epidermal melanocytes were treated with recombinant CCN1 protein. Our findings show that CCN1 activates melanogenesis through promoting melanosome maturation and up-regulation of MITF, TRP-1, and tyrosinase via the integrin alpha6beta1, p38 MAPK, and ERK signaling pathways. Furthermore, we found that UVB irradiation stimulates the secretion of CCN1 from normal human dermal fibroblasts, and CCN1 knockdown in fibroblasts attenuates melanogenesis in melanocyte-fibroblast co-culture system. Moreover, using immunohistochemistry and immunofluorescence staining, we discovered that CCN1 is overexpressed in the dermis of both solar lentigines and Riehl's melanosis lesions. These findings suggest that CCN1 is a fibroblast-derived melanogenic paracrine mediator that is secreted under UVB irradiation, and it may play an important role in the development of hyperpigmentation diseases such as Riehl's melanosis. PMID- 29510194 TI - Ten years of cardiac arrest resuscitation in Irish general practice. AB - AIM: The aim of this study is to establish the role and outcome of general practitioner (GP) involvement in out of hospital cardiac arrest (OHCA) resuscitation in the Republic of Ireland. METHODS: A ten year prospective observational study involving a cohort of Irish general practices. SETTING: 521 general practice settings distributed throughout the Republic of Ireland, representing approximately one quarter of all practices and a third of Irish GPs. PARTICIPANTS: 534 patients suffering cardiac arrest in the community for whom resuscitation was attempted. INTERVENTIONS: Cardiac arrest with resuscitation attempted (CARA) in which a GP played a role. RESULTS: Over a ten year period almost half of participating practices reported one or more CARAs. A total of 534 CARAs were reported at a variety of locations; 161 (30%) had ROSC (return of spontaneous circulation) at some point, with outcome data available for 147/161; 90 patients survived to hospital discharge. Most survivors for whom follow up data are available were discharged home and were completely independent. The highest rate of survival was achieved when CARAs occurred at a GP practice premises (47.4%). CONCLUSIONS: Resuscitation following OHCA is a key task in general practice. Over time a significant number of GPs encounter OHCA, attempt resuscitation and achieve higher survival to hospital discharge rates than occur nationally among OHCAs in Ireland. We conclude that a defibrillator should be routinely available at all general practices and staff should have appropriate resuscitation skills. PMID- 29510196 TI - PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation. AB - Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells. PD-L1 overexpression and knockout or knockdown demonstrated that PD-L1 promoted GBM cell proliferation and migration in vitro and in vivo. Mechanistically, PD-L1 prominently activated epithelial mesenchymal transition (EMT) process in a MEK/Erk- but not PI3K/Akt dependent manner. Further, we identified intracellular interactions of PD-L1 and H-Ras, which led to Ras/Erk/EMT activation. Finally, we demonstrated that PD-L1 overexpression promoted while knockdown abolished GBM development and invasion in orthotopic GBM models of rodents. Taken together, we found that intracellular PD L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream Erk-EMT signaling. Thus, these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors. PMID- 29510195 TI - LncRNA UCA1 promotes migration and invasion in pancreatic cancer cells via the Hippo pathway. AB - Although overexpression of the long non-coding RNA (lncRNA) UCA1 has been implicated in several human cancers, its biological function in pancreatic cancer remains to be clarified. In this study, we reported that UCA1 expression was significantly increased in pancreatic cancer tissues and correlated with clinicopathological features, tumor stage, and poorer patient outcome. We further showed that UCA1 promoted cell migration and invasion of pancreatic cancer cells. Importantly, we found that UCA1 overexpression inhibited YAP phosphorylation, and increased YAP expression. Mechanistically, UCA1 interacted with MOB1, Lats1, and YAP, forming shielding composites. Moreover, we demonstrated that UCA1 increased YAP nuclear localization and stabilization, and improved TEAD luciferase activity. In turn, YAP promotes UCA1 expression. Collectively, the present study provides insights into the mechanistic regulation of UCA1 promoting pancreatic cancer progression through the Hippo signaling pathway. UCA1 may serve as a candidate biomarker for poor prognosis and a target for new pancreatic cancer therapies. PMID- 29510197 TI - G protein coupled receptors can transduce signals through carboxy terminal and linker region phosphorylation of Smad transcription factors. AB - Smads (sma/mothers against decapentaplegic) are transcription factors, which can be phosphorylated in the carboxy terminal (pSmad2/3C) or in the structurally central linker region (pSmad2/3 L). Only receptor kinases such as Transforming Growth Factor (TGF)-beta receptor (TGFBR1) can mediate carboxy terminal phosphorylation but multiple receptors, including TGFBR1 itself, can activate cytosolic serine/threonine kinases and mediate serine/threonine (S/T) linker region phosphorylation of Smad2/3. One important class of agents that can mediate Smad phosphorylation are the G protein coupled receptors (GPCRs) and their ligands and these agents can meditate both carboxy terminal and linker region phosphorylation. Linker region phosphorylation arises due to activation of kinases including those downstream of the transactivation of the EGFR and carboxy terminal Smad phosphorylation can occur as a result of the recently described activity of GPCRs, notably protease activated receptors (PAR)-1, to transactivate TGFBR1 leading to direct carboxy terminal Smad phosphorylation. This review will summarize the effects of GPCR-mediated receptor transactivation pathways on the phosphorylation of Smad2 linker region, as a better understanding of these pathways may provide new approaches for the identification of novel therapeutic agents. PMID- 29510198 TI - MicroRNA-485-5p suppresses growth and metastasis in non-small cell lung cancer cells by targeting IGF2BP2. AB - miR-485-5p serves as a tumor suppressor in several types of cancers. However, its prognostic and biological significance in non-small cell lung cancer (NSCLC) have not been determined yet. In the present study, we checked the expression of miR 485-5p in 87 pairs of paraffin-embedded lung cancer and matched non-cancerous specimens. The associations of miR-485-5p expression with aggressive parameters and survival in NSCLC were investigated. In addition, the function of miR-485-5p in controlling tumor growth and metastasis was clarified. We found that miR-485 5p was significantly downregulated in NSCLC, relative to adjacent non-cancerous lung tissues. Low miR-485-5p expression was significantly associated with advanced TNM stage, lymph node metastasis, and reduced patient survival. Overexpression of miR-485-5p significantly suppressed the growth and invasion, while knockdown of miR-485-5p had an opposite effect. Moreover, miR-485-5p overexpression caused a G0/G1 cell-cycle arrest and impaired TGF-beta-induced epithelial-mesenchymal transition. Mechanistically, IGF2BP2 was identified as a novel direct target of miR-485-5p. Depletion of IGF2BP2 significantly inhibited NSCLC cell proliferation and invasion. Enforced expression of IGF2BP2 reversed the tumor suppressive activity of miR-485-5p. In vivo studies further demonstrated that overexpression of miR-485-5p interfered with the growth and metastasis of A549 cells in mice and reduced the expression of IGF2BP2. In conclusion, low miR-485-5p expression predicts poor prognosis in NSCLC patients. The miR-485-5p/IGF2BP2 axis orchestrates the growth and metastasis of NSCLC and represents a potential therapeutic target for this disease. PMID- 29510199 TI - Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways. AB - AIMS: Linalool is a plant-derived monoterpene with anticancer activity, however its mechanisms of action remain poorly understood. The aim of this work was to elucidate the anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells. MAIN METHODS: Cell viability and proliferation were determined by WST-1 assay and BrdU incorporation, respectively. Cell cycle analysis was assessed through flow cytometry (FC) and western blot (WB). Apoptosis was determined by caspase-3 activity, TUNEL assay and WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by FC and fluorescence microscopy. Expression of Ras, MAPKs (ERK, JNK and p38) and Akt/mTOR pathways were evaluated by WB. KEY FINDINGS: Linalool (0-2.5 mM) dose dependently inhibited cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by MMP loss, caspase-3 activation, PARP cleavage and DNA fragmentation. Low concentrations of linalool (1.0 mM) reduced membrane-bound Ras and Akt activity whereas higher amounts (2.0 mM) triggered mTOR inhibition and ROS generation, in correlation with MAPKs activation and Akt phosphorylation. ROS scavenger N-acetyl-L-cysteine partially rescued HepG2 cell growth and prevented MPP depolarization, ERK and JNK activation. Moreover, specific ERK and Akt phosphorylation inhibitors potentiated linalool anti-cancer activity, pointing Akt and ERK activation as pro-survival mechanisms in response to higher concentrations of linalool. SIGNIFICANCE: This report reveals that linalool induces G0/G1 arrest and apoptosis in HepG2 cells involving Ras, MAPKs and Akt/mTOR pathways and suggests that linalool is a promising anticancer agent for HCC therapy. PMID- 29510200 TI - Nitric oxide regulates chlorophyllide biosynthesis and singlet oxygen generation differently between Arabidopsis and barley. AB - Nitric oxide (NO) has a general inhibitory effects on chlorophyll biosynthesis, especially to the step of 5-aminolevulinic acid (ALA) biosynthesis and protochlorophyllide (Pchlide) to chlorophyllide (Chlide) conversion (responsible by the NADPH:Pchlide oxidoreductase POR). Previous study suggested that barley large POR aggregates may be generated by dithiol oxidation of cysteines of two POR monomers, which can be disconnected by some reducing agents. POR aggregate assembly may be correlated with seedling greening in barley, but not in Arabidopsis. Thus, NO may affect POR activity and seedling greening differently between Arabidopsis and barley. We proved this assumption by non-denaturing gel analysis and reactive oxygen species (ROS) monitoring during the greening. NO treatments cause S-nitrosylation to POR cysteine residues and disassembly of POR aggregates. This modification reduces POR activity and induces Pchlide accumulation and singlet oxygen generation upon dark-to-high-light shift (and therefore inducing photobleaching lesions) in barley leaf apex, but not in Arabidopsis seedlings. ROS staining and ROS-related-gene expression detection confirmed that superoxide anion and singlet oxygen accumulated in barley etiolated seedlings after the NO treatments, when exposed to a fluctuating light. The data suggest that POR aggregate assembly may be correlated with barley chlorophyll biosynthesis and redox homeostasis during greening. Cysteine S nitrosylation may be one of the key reasons for the NO-induced inhibition to chlorophyll biosynthetic enzymes. PMID- 29510201 TI - Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. AB - : Rat inferior caval vein (ICV) ligation (up to the right ovarian vein (ROV)) commonly represents a recapitulation of Virchow: with ligation leading to vessel injury, stasis, thrombosis and hemodynamic changes. We revealed that BPC 157's therapy collectively attenuated or counteracted all these events and the full syndrome. METHODS: We applied BPC 157 (10 MUg, 10 ng/kg) as an early regimen or as a delayed therapy. Assessment includes gross assessment by microcamera; microscopy, venography, bleeding, blood pressure, ECG, thermography, MDA and NO level in plasma and ICV, and gene expression. RESULTS: Direct vein injury, thrombosis, thrombocytopenia, prolonged bleeding were all counteracted. Also, rapid presentation of collaterals and redistribution of otherwise trapped blood volume (bypassing through the left ovarian vein (LOV) and other veins), with venous hypertension, arterial hypotension and tachycardia counteraction were shown. BPC 157-rats presented raised plasma NO-values, but normal MDA-values; in ICV tissue reverted low NO-values and counteracted increased MDA-levels. Altered expression of EGR, NOS, SRF, VEGFR and KRAS in ICV, ROV and LOV revealed increased or decreased levels, while some genes continuously remained unchanged. CONCLUSION: As a new insight, BPC 157 application largely attenuated or even completely eliminated all consequences of ICV ligation in rats. PMID- 29510202 TI - The Surgical Personality: Does Surgery Resident Motivation Predict Attrition? AB - BACKGROUND: There is limited understanding of the wide variation in attrition rates among general surgery residencies. We used the validated Behavior Inhibitory System/Behavior Approach System (BIS/BAS) instrument to compare motivational traits among residents who did and not complete surgical training. STUDY DESIGN: All US general surgery categorical interns in the class of 2007 2008 were surveyed with a validated motivational trait assessment tool. American Board of Surgery records from 2008-2016 were used to determine who completed training. Motivation, an aspect of personality, was assessed with the BIS/BAS, which correlates with an individual's tendency to approach pleasant stimuli (BAS) or avoid negative stimuli (BIS). Subscale mean scores were compared with regard to the primary end point, attrition. RESULTS: Eight hundred and one (76.5%) interns completed the survey and had matching records. Six hundred and forty-five (80.5%) completed training. Men had lower scores than women in the BAS Drive subscale (12.0 vs 12.5; p < 0.002), BAS Reward Response subscale (17.2 vs 17.7; p < 0.01), and BIS scale (19.3 vs 20.9; p < 0.01). The BAS Reward Response scores differed based on program type (academic 17.3 vs community 17.6 vs military 16.6; p < 0.0027). There were no differences based on program size (BIS average, small program 19.9 vs large program 19.7; p = 0.43). There were also no differences in BIS/BAS subscale scores based on residency completion status (BIS mean: completed 19.9 vs dropped out 20.1; p = 0.51). CONCLUSIONS: Surgery residents are characterized by a strong drive and persistence toward their goals. However, residents who drop out do not differ from those who complete training in their motivational personality traits. PMID- 29510203 TI - Observation of glassy state relaxation during annealing of frozen sugar solutions by X-ray computed tomography. AB - Glassy phase formation in a frozen product determines various properties of the freeze-dried products. When an aqueous solution is subjected to freezing, a glassy phase forms as a consequence of freeze-concentration. During post-freezing annealing, the relaxation of the glassy phase and the ripening of ice crystals (i.e. Ostwald ripening) spontaneously occur, where the kinetics are controlled by the annealing and glass transition temperatures. This study was motivated to observe the progress of glassy state relaxation separate from ice coarsening during annealing. X-ray computed tomography (CT) was used to observe a frozen and post-freezing annealed solutions by using monochromatized X-ray from the synchrotron radiation. CT images were successfully obtained, and the frozen matrix were analyzed based on the gray level values that were equivalent to the linear X-ray attenuation coefficients of the observed matters. The CT images obtained from rapidly frozen sucrose and dextrin solutions with different concentrations gave clear linear relationships between the linear X-ray attenuation coefficients values and the solute concentrations. It was confirmed that the glassy state relaxation progressed as increasing annealing time, and this trend was larger in the order of the glass transition temperature of the maximally freeze-concentrated phase. The sucrose-water system required nearly 20 h of annealing time at -5 degrees C for the completion of the glassy phase relaxation, whereas dextrin-water systems required much longer periods because of their higher glass transition temperatures. The trends of ice coarsening, however, did not perfectly correspond to the trends of the relaxation, suggesting that the glassy phase relaxation and Ostwald ripening would jointly control the ice crystal growth/ripening kinetics, and the dominant mechanism differed by the annealing stage. PMID- 29510204 TI - Strategic drug analysis in fed-state gastric biorelevant media based on drug physicochemical properties. AB - Milk-based media such as the Fed State Simulated Gastric Fluid (FeSSGF) are commonly used in order to simulate the in vivo properties of the fed state stomach. Due to the lack of a specific guideline for standardised sample clean-up in these media, the aim of the current study was to develop an optimum protocol for the extraction and quantification of drugs from the fed state gastric medium based on the APIs' physicochemical properties (lipophilicity, ionisation, aqueous solubility and protein binding). Two different extraction techniques, protein precipitation (PP) and solid phase extraction (SPE) were assessed. A pilot study in six model drugs was performed, with tests using seven different protein precipitation reagents at four different medium:reagent ratios and two drug concentrations as well as different solid phase extraction cartridges and elution protocols. % recovery was analysed using partial least squares (PLS) regression so as to determine the physicochemical parameters affecting the drug percentage recovered. For protein precipitation protocols, drug concentration, selection of protein precipitation reagent and ratio added to the medium significantly affected drug % recovery from FeSSGF (p < 0.05). The same applied for the selection of elution solvent and cartridge type for solid phase extraction. Optimum protocols using MeOH, AlphaCN and 10% w/v TCA at a 1:2 FeSSGF:reagent ratio were effective to a larger group of drugs of a wide range of lipophilicity and ionisation, with AlphaCN being the most effective in the whole range of log P values (-0.56 to 8.81). Solid phase extraction was proven to be effective for compounds of poor to moderate lipophilicity (log P < 4), with extremely hydrophobic compounds demonstrating lower % recovery values (down to 10% recovery). PLS demonstrated that only for 10% w/v TCA (protein precipitation) and HLB (solid phase extraction) can the effect of key drug physicochemical properties on the final amount of drug recovered be accurately predicted. PMID- 29510205 TI - DNA vaccination for cervical cancer: Strategic optimisation of RALA mediated gene delivery from a biodegradable microneedle system. AB - Dissolvable microneedles can be employed to deliver DNA to antigen presenting cells within the skin. However, this technology faces two main challenges: the poor transfection efficacy of pDNA following release from the microneedle matrix, and the limited loading capacity of the micron-scale devices. Two-tier delivery systems combining microneedle platforms and DNA delivery vectors have increased efficacy but the challenge of increasing the loading capacity remains. This study utilised lyophilisation to increase the loading of RALA/pDNA nanoparticles within dissolvable PVA microneedles. As a result, delivery was significantly enhanced in vivo into an appropriate range for DNA vaccination (~50 MUg per array). Furthermore, modifying the manufacturing process was not detrimental to the microneedle mechanical properties or cargo functionality. It was demonstrated that arrays retained mechanical and functional stability over short term storage, and were able to elicit gene expression in vitro and in vivo. Finally, treatment with this novel formulation significantly retarded the growth of established tumours, and proved superior to standard intramuscular injection in a preclinical model of cervical cancer. PMID- 29510206 TI - Classification and structural insight into vibriolysin-like proteases of Vibrio pathogenicity. AB - Vibriolysin-like proteases (VLPs) are important virulence agents in the arsenal of Vibrio causing instant cytotoxic effects during infection. Most of Vibrio secreted VLPs show serious pathogenicity, while some species of Vibrio with VLPs are non-pathogenic, like Vibrio tasmaniensis and Vibrio pacinii. To investigate the relation between VLPs and Vibrio pathogenicity, one phylogenetic tree of VLPs was constructed and compared consensus sequences at the N-terminus of VLPs. Based on these results, VLPs were defined into nine phylogenetic clades. Pathogenicity analysis of Vibrio showed that Vibrio species with VLPs III, VI, VII or VIII are serious pathogenic bacteria, while species with VLPs I, II, IV or IX are opportunistic pathogens. Multiple sequence alignment showed that the N-terminal 5 16 nucleotides of each clade are highly conservative. Topological analysis of VLPs exhibited the structural differences in N-terminal regions of each VLP clade. These results suggest that structure of N-terminus might play a key role in the pathogenicity of VLPs. Our findings give new insights into the classification of VLPs and the relationship between VLPs and Vibrio pathogenicity. PMID- 29510207 TI - Development and evaluation of vaccine against Staphylococcus aureus recovered from naturally occurring mastitis in she-camels. AB - The predominant Staphylococcus aureus (S. aureus), an etiological agent of camel mastitis is becoming drug resistant that invites prevention and control strategies. Vaccine production would have a valuable impact on public health. Therefore, in present study, inactivated vaccine with different adjuvants was prepared and evaluated against S. aureus. The vaccinal isolate recovered from camel subclinical mastitis was coagulase positive (PCR based), having expressed pseudocapsule, holding alpha-beta hemolysin characteristics, and multiple drug resistant. Inactivated alum precipitated S. aureus vaccine (APSV) and oil adjuvant S. aureus vaccine (OASV) were prepared after confirming its antigenicity in rabbits. Three groups of rabbits were randomly inoculated with APSV, OASV, and placebo (Unvaccinated, UV). Each group was further divided into two groups based on single and booster dose inoculation. Booster dose of vaccines in rabbits at day 15th of primary inoculation was given. Serum samples were taken on 15, 30, 45 and 60 days of primary inoculation from all rabbits. Analysis of variance was applied to compare geometric mean titer (GMT) of three groups, while t-test was applied to estimate the difference between single and booster dose response. The study found 1010 CFU/mL S. aureus as standard bacterial load for vaccines with higher and sustained antigenicity. The vaccines were safe from morbidity and mortality, and proved effective and stable for 7 and 4 months at 25 degrees C and 37 degrees C, respectively. The OASV produced significantly (p < 0.05) higher immune response followed by APSV throughout trial. The highest GMT by APSV and OASV vaccines with single dose inoculation was 37.92 and 69.92 at day 45th post primary inoculation, respectively. Similarly, 59.20 and 142.40 GMTs were noted with booster dose in case of APSV and OASV, respectively. The booster dose presented significantly (p < 0.05) higher GMT than that of single dose inoculation of vaccines. The study concluded APSV and OASV safe, effective, and stable with significant immunogenic results in experimental rabbits. PMID- 29510209 TI - Repeated Prenatal Exposure to Valproic Acid Results in Auditory Brainstem Hypoplasia and Reduced Calcium Binding Protein Immunolabeling. AB - Auditory dysfunction is a common occurrence in individuals with autism spectrum disorder (ASD). While most cases of ASD are of unknown etiology, in utero exposure to the antiepileptic valproic acid (VPA) significantly increases risk. We have previously identified significant dysmorphology and hypoplasia in the auditory brainstem of humans with ASD and rodents exposed to VPA in utero. Further, we have identified abnormal c-Fos immunolabeling patterns after exposure to pure tone stimuli in VPA-exposed animals. Herein, we describe the impact of repeated exposure to VPA on key components of the auditory hindbrain, the ventral cochlear nucleus (VCN) and superior olivary complex (SOC). Specifically, we examined neuronal number, neuronal morphology, immunolabeling for the calcium binding proteins calbindin (CB) and calretinin (CR), dopaminergic innervation and the structure of calyx terminals in the medial nucleus of the trapezoid body (MNTB). VPA-exposed animals had significantly fewer neurons in both the VCN and SOC. VPA had a differential impact on the size of neurons in the VCN and SOC. VPA exposed animals have reduced CB and CR immunolabeling and a lower density of dopaminergic terminals. Finally, we saw no difference in the surface area or volume of calyx terminals in the MNTB, although there was a relative increase in the surface area and volume of calyces in VPA-exposed animals. These results indicate hypotrophy of the auditory brainstem, abnormal calcium regulation and reduced dopaminergic input. Together, such alterations suggest abnormal brainstem circuitry and significant auditory dysfunction in VPA-exposed animals. PMID- 29510210 TI - 3,4-Methylenedioxymethamphetamine (MDMA) Alters Synaptic Dopamine Release in the Dorsal Striatum Through Nicotinic Receptors and DAT Inhibition. AB - An increase of extracellular dopamine (DA) has been implicated in the psychostimulant properties of 3,4-methylenedioxymethamphetamine (MDMA). Although this drug has been reported to affect the DA uptake transporter (DAT), it might activate other mechanisms to regulate the outflow of DA in the brain. Our aim was to examine the overall effects of MDMA on the release of DA in the striatum. We studied the effect of MDMA on stimulus-evoked synaptic DA release in dorsal striatal slices of mice using in vitro amperometric techniques. We also tested the effects of MDMA on the nicotine-induced responses in substantia nigra pars compacta (SNpc) neurons using intracellular electrophysiological recordings. MDMA (1-30 uM) depressed the amplitude and prolonged the decay-time of synaptic DA release in the striatum. Interestingly, in the presence of the broad nicotinic receptor antagonist mecamylamine, and the more selective alpha4beta2 antagonist dihydrobetaerythroidine (DHbetaE), MDMA enhanced both peak and duration of DA release. A similar effect was found on cocaine-insensitive (DAT-CI) mice slices. Concentrations of MDMA higher than 100 uM enhanced striatal DA outflow that was in turn, reduced by cocaine. Electrophysiological recordings of dopaminergic neurons in SNpc showed that MDMA depressed the effects of nicotine. Our data are consistent with a prevalent MDMA-induced inhibition of the synaptic release of DA in the dorsal striatum mediated by an interaction with nicotinic receptors. This drug also blocks DAT acting on a different site from cocaine and, at higher concentrations, has amphetamine-like releasing properties. PMID- 29510208 TI - Risk of gastric cancer in association with Helicobacter pylori different virulence factors: A systematic review and meta-analysis. AB - INTRODUCTION: It has been proposed that specific analysis of Helicobacter pylori virulence factors can be suitable for predicting of post H. pylori infection disorders like gastric cancer (GC). The present study was designed to evaluate the association between different virulence factors of H. pylori and GC. METHODS: Studies investigated the association between virulence factors of H. pylori and GC were collected from the several databases. All analysis was performed by Comprehensive Meta-Analysis V2.2 software (Biostat, Englewood, NJ, USA). RESULTS: Based on a comprehensive literature search, 25 eligible studies were included for meta-analyses. Infection with cagA- and vacA s1m1-positive H. pylori strains were significantly associated with increased risk of GC (OR of [2.82 (95% CI 1.96 4.06), P < 0.001]) and ([1.75 (95% CI 1.04-2.96), P 0.034)], respectively. CONCLUSIONS: Infection by H. pylori strains with positive vacA s1m1 and the cagA genes can significantly increase the risk of GC. The association between the vacA s1m1 and the cagA and GC, suggests that screening of these genes may be helpful for identifying populations at higher risk for GC. PMID- 29510211 TI - The Disease-modifying Drug Candidate, SAK3 Improves Cognitive Impairment and Inhibits Amyloid beta Deposition in App Knock-in Mice. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of elderly dementia in the world. At present, acetylcholine inhibitors, such as donepezil, galantamine and rivastigmine, are used for AD therapy, but the therapeutic efficacy is limited. We recently proposed T-type voltage-gated Ca2+ channels' (T-VGCCs) enhancer as a new therapeutic candidate for AD. In the current study, we confirmed the pharmacokinetics of SAK3 in the plasma and brain of mice using ultra performance liquid chromatography-tandem mass spectrometry. We also investigated the effects of SAK3 on the major symptoms of AD, such as cognitive dysfunction and amyloid beta (Abeta) accumulation, in AppNL-F knock-in (NL-F) mice, which have been established as an AD model. Chronic SAK3 (0.5 mg/kg/day) oral administration for 3 months from 9 months of age improved cognitive function and inhibited Abeta deposition in 12-month-old NL-F mice. Using microarray and real-time PCR analysis, we discovered serum- and glucocorticoid-induced protein kinase 1 (SGK1) as one of possible genes involved in the inhibition of Abeta deposition and improvement of cognitive function by SAK3. These results support the idea that T-VGCC enhancer, SAK3 could be a novel candidate for disease-modifying therapeutics for AD. PMID- 29510213 TI - Naked Fat Sign Is a Characteristic of Colonic Lipoma. PMID- 29510212 TI - Overexpression of bifunctional fructose-1,6-bisphosphatase/sedoheptulose-1,7 bisphosphatase leads to enhanced photosynthesis and global reprogramming of carbon metabolism in Synechococcus sp. PCC 7002. AB - Cyanobacteria fix atmospheric CO2 to biomass and through metabolic engineering can also act as photosynthetic factories for sustainable productions of fuels and chemicals. The Calvin Benson cycle is the primary pathway for CO2 fixation in cyanobacteria, algae and C3 plants. Previous studies have overexpressed the Calvin Benson cycle enzymes, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and bifunctional sedoheptulose-1,7-bisphosphatase/fructose-1,6 bisphosphatase (hereafter BiBPase), in both plants and algae, although their impacts on cyanobacteria have not yet been rigorously studied. Here, we show that overexpression of BiBPase and RuBisCO have distinct impacts on carbon metabolism in the cyanobacterium Synechococcus sp. PCC 7002 through physiological, biochemical, and proteomic analyses. The former enhanced growth, cell size, and photosynthetic O2 evolution, and coordinately upregulated enzymes in the Calvin Benson cycle including RuBisCO and fructose-1,6-bisphosphate aldolase. At the same time it downregulated enzymes in respiratory carbon metabolism (glycolysis and the oxidative pentose phosphate pathway) including glucose-6-phosphate dehydrogenase (G6PDH). The content of glycogen was also significantly reduced while the soluble carbohydrate content increased. These results indicate that overexpression of BiBPase leads to global reprogramming of carbon metabolism in Synechococcus sp. PCC 7002, promoting photosynthetic carbon fixation and carbon partitioning towards non-storage carbohydrates. In contrast, whilst overexpression of RuBisCO had no measurable impact on growth and photosynthetic O2 evolution, it led to coordinated increase in the abundance of proteins involved in pyruvate metabolism and fatty acid biosynthesis. Our results underpin that singular genetic modifications in the Calvin Benson cycle can have far broader cellular impact than previously expected. These features could be exploited to more efficiently direct carbons towards desired bioproducts. PMID- 29510214 TI - Development of Irritable Bowel Syndrome Features Over a 5-year Period. AB - BACKGROUND & AIMS: There are few data from longitudinal studies of the gastrointestinal and psychologic features of irritable bowel syndrome (IBS). We studied within-person correlations among features of IBS, along with progression of gastrointestinal (GI) symptoms and quality of life, and factors associated with changes over time. METHODS: We performed a longitudinal study of 276 patients with IBS in Sweden (70% female; ages, 19-76 years) who completed questionnaires, each year for 5 years, about their GI symptom severity, quality of life, GI-specific anxiety, general anxiety, depression, and coping resources. We performed within-person correlation analyses, latent class growth analysis, and random-intercept cross-lagged panel analysis. RESULTS: Within-person correlations with GI symptom severity were strongest for quality of life (r = 0.56) and GI-specific anxiety (r = 0.47). Progression of GI symptom severity was defined based on 3 classes; the class with the highest mean levels of GI, depression, and (GI-specific) anxiety symptoms at baseline did not improve over the 5-year period, contrary to the other classes. GI-specific anxiety was associated with an increase in GI symptom severity and decrease in quality of life 1 year later (P < .05) but other features of IBS were not. CONCLUSIONS: In a 5-year study of patients with IBS in Sweden, we found 3 classes of GI symptom development. We found levels of GI-specific anxiety to associate with GI symptom severity and quality of life 1 year later. Clinicians should be aware of GI specific anxiety in patients with IBS, to identify patients at risk for lack of long-term symptom improvement with standard medical treatment. PMID- 29510215 TI - Factor Analysis Defines Distinct Upper and Lower Gastrointestinal Symptom Groups Compatible With Rome IV Criteria in a Population-based Study. AB - BACKGROUND & AIMS: The Rome IV criteria define functional gastrointestinal (GI) disorders by specific combinations of symptoms. It is possible to empirically evaluate these symptom combinations by factor analysis (a statistical procedure that groups variables that correlate). However, this analysis has not been performed for the Rome IV criteria, and factor analyses based on the previous versions of the Rome criteria did not use population-based data. We therefore investigated symptom grouping by the Rome IV questionnaire using factor analysis of a population-based sample. METHODS: The Rome IV questionnaire was completed online in English by 5931 respondents from the United Kingdom, United States, and Canada (49% female, age range, 18-92 years). We performed an exploratory factor analysis on the Rome IV questions. Next, we performed a confirmatory factor analysis to compare the exploratory factor result to that of the Rome IV criteria. RESULTS: The exploratory factor analysis identified 8 factors that accounted for 45% of the variance in response: constipation, diarrhea, irritable bowel syndrome, abdominal pain, heartburn, nausea or vomiting, globus, and other upper GI symptoms. Most factors corresponded to distinct functional GI disorders defined by the Rome IV criteria-exceptions included abdominal pain and upper GI symptoms. In confirmatory factor analysis, the exploratory model fitted slightly better than that based on the Rome IV criteria (root mean square error of approximation, 0.063 vs 0.077). CONCLUSIONS: We used factor analysis to identify distinct upper and lower GI symptom groups that are compatible with the Rome IV criteria. Our findings support the use of the Rome IV criteria in research and clinical practice as a basis for development of diagnostics and management of patients. PMID- 29510216 TI - Virtual Histology in Everyday Gastrointestinal Endoscopy. AB - Advances in imaging technologies have demonstrated promise in the early detection of dysplasia and cancer. They have also provided the ability to assess submucosal and vascular structures, helping differentiate neoplastic from non-neoplastic tissue. The aim of this concise case-based review is to discuss how optical imaging can impact patient management decisions during endoscopy, using real- life scenarios. PMID- 29510217 TI - Computational prediction of chemical reactions: current status and outlook. AB - Over the past few decades, various computational methods have become increasingly important for discovering and developing novel drugs. Computational prediction of chemical reactions is a key part of an efficient drug discovery process. In this review, we discuss important parts of this field, with a focus on utilizing reaction data to build predictive models, the existing programs for synthesis prediction, and usage of quantum mechanics and molecular mechanics (QM/MM) to explore chemical reactions. We also outline potential future developments with an emphasis on pre-competitive collaboration opportunities. PMID- 29510219 TI - Trace elements in seafood from the Mediterranean sea: An exposure risk assessment. AB - Fish and shellfish belonging to five different species among pelagic, benthonic and molluscs, were collected from the Gulf of Catania in 2017 to evaluate arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb), manganese (Mn), nickel (Ni), selenium (Se) vanadium (V) and zinc (Zn). Risk of developing chronic systemic effects derived from seafood consumption was evaluated with the Target Hazard Quotient (THQ) and compared with the results obtained from the same area and the species, collected in 2012. Hg, Cd and Pb concentrations were found below the limits set by European Community for human consumption in all the analysed species. The total risk is reduced from 1.1 to 0.49, and this result is strongly associated with the lower bioaccumulations levels found for Hg, Mn, Se and V. Others metals such as As, Pb, Ni and Zn bioaccumulation levels remain approximately the same, conversely, it is revealed a slight increase of Cd and Cr. Overall, the present study show a positive picture of the studied area, the Gulf of Catania, highlighting not only a decreased metal availability of the study area, but, above all, a decreased risk to develop chronic systemic effects derived from consumption of local seafood. PMID- 29510218 TI - Unsynchronized influenza epidemics in two neighboring subtropical cities. AB - OBJECTIVE: The aim of this study was to examine the synchrony of influenza epidemics between Hong Kong and Shenzhen, two neighboring subtropical cities in South China. METHODS: Laboratory-confirmed influenza data for the period January 2006 to December 2016 were obtained from the Shenzhen Center for Disease Control and Prevention and the Department of Health in Hong Kong. The population data were retrieved from the 2011 population censuses. The weekly rates of laboratory confirmed influenza cases were compared between Shenzhen and Hong Kong. RESULTS: Unsynchronized influenza epidemics between Hong Kong and Shenzhen were frequently observed during the study period. Influenza A/H1N1 caused a more severe pandemic in Hong Kong in 2009, but the subsequent seasonal epidemics showed similar magnitudes in both cities. Two influenza A/H3N2 dominant epidemic waves were seen in Hong Kong in 2015, but these epidemics were very minor in Shenzhen. More influenza B epidemics occurred in Shenzhen than in Hong Kong. CONCLUSIONS: Influenza epidemics appeared to be unsynchronized between Hong Kong and Shenzhen most of the time. Given the close geographical locations of these two cities, this could be due to the strikingly different age structures of their populations. PMID- 29510220 TI - Modulation of key lipid raft constituents in primary rat hepatocytes by fumonisin B1 - Implications for cancer promotion in the liver. AB - Fumonisin B1 (FB1), a group 2B natural occurring carcinogenic mycotoxin, modulated lipid and fatty acid (FA) constituents of lipid rafts isolated from primary hepatocytes following exposure to a cytotoxic concentration of FB1 (250 MUM). The major effects observed in rafts, included a significant (p < 0.05) increase in raft cholesterol (CHOL) and glycerophospholipid such as phosphatidylethanolamine (PE), whereas sphingomyelin (SM) decreased (p < 0.05). Changes in lipid constituents resulted in the disruption of important membrane fluidity parameters represented as a decreased (p < 0.05) in the phosphatidylcholine (PC)/PE and PC/(PE+SM) ratios and an increase (p < 0.05) in the CHOL/PL (PL=PC+PE) ratio, suggesting the preservation of lipid raft rigidity and integrity. Observed FA changes in the raft PE fraction included a significant (p < 0.05) increase in C18:2omega-6, C20:3omega-6, C20:4omega-6, C22:4omega-6, C22:5omega-3 and C22:6omega-3, with an increase in total omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). Modulation of the FA content in PE, specifically the C20:4omega-6 PC/PE ratio and PUFA levels, together with changes in CHOL and SM are key determinants regulating the integrity and function of lipid rafts. In primary hepatocytes these changes are associated with the inhibition of cell proliferation and induction of apoptosis. A lipogenic mechanism is proposed whereby FB1 modulates lipid rafts and differentially target cell survival indices of normal and preneoplastic hepatocytes during cancer promotion in the liver. PMID- 29510221 TI - Acute toxicity study in mice of orally administrated TiO2 nanoparticles functionalized with caffeic acid. AB - The acute toxicity of surface-modified TiO2 nanoparticles (NPs) with caffeic acid (CA) was compared with those of its separate constituents (free CA and bare TiO2 NPs) upon their oral administration in laboratory mice. Prior to in vivo experiments, the interfacial charge transfer (ICT) complex between surface Ti atoms and CA is thoroughly characterized. Composition and stability constants of ICT complex were determined using Job's method and Banesi-Hildebrand analysis, respectively. The experimental data were supported with quantum chemical calculations based on density functional theory (DFT). Acute toxicity signs, including biochemical alterations and extensive histopathological changes in the liver tissue of mice were detected 14 days after oral administration of bare TiO2 NPs. However, the clinical signs of toxicity, the fractional contribution of organs, biochemical parameters of liver and kidney function, and histopathological changes in liver upon treatment with surface-modified TiO2 NPs with CA were not observed. Also, the genotoxic potential of the ICT complex and its constituents were evaluated in leukocytes of whole blood cells in vivo by comet assay. Both, bare and surface-modified TiO2 NPs did not display DNA damaging effect in time frame of 24 h upon their oral administration in mice. PMID- 29510222 TI - Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA. AB - Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication and language, and restricted repertoire of activities and interests. The etiology of ASD remains unknown and no clinical markers for diagnosis were identified. Environmental factors, including prenatal exposure to valproic acid (VPA), may contribute to increased risk of developing ASD. MicroRNA (miRNA) are small noncoding RNA that regulate gene expression and are frequently linked to biological processes affected in neurodevelopmental disorders. In this work, we analyzed the effects of resveratrol (an antioxidant and anti inflammatory molecule) on behavioral alterations of the VPA model of autism, as well as the levels of circulating miRNA. We also evaluated the same set of miRNA in autistic patients. Rats of the VPA model of autism showed reduced total reciprocal social interaction, prevented by prenatal treatment with resveratrol (RSV). The levels of miR134-5p and miR138-5p increased in autistic patients. Interestingly, miR134-5p is also upregulated in animals of the VPA model, which is prevented by RSV. In conclusion, our findings revealed important preventive actions of RSV in the VPA model, ranging from behavior to molecular alterations. Further evaluation of preventive mechanisms of RSV can shed light in important biomarkers and etiological triggers of ASD. PMID- 29510224 TI - Investigation of LAMTOR1 gene and protein expressions in germinal vesicle and metaphase II oocytes and embryos from 1-cell to blastocyst stage in a mouse model. AB - Improving the success of in vitro fertilization (IVF) and infertility treatment depend on understanding basic cellular and molecular mechanisms of human preimplantation development. Pre-implantation mouse embryo model is an ideal empiric system to understand these mechanisms. This study was aimed to investigate the gene and protein expressions of LAMTOR1 in mouse oocytes and pre implantation embryos at different developmental stages. The findings demonstrate that LAMTOR1 was detected in the oocytes and in subsequent all stages of embryo development. The expression was increased progressively from MII-stage oocyte to morula stage embryo (p < 0.05), highest expression was identified in morula stage (p < 0.05), and decreased in blastocyst stage (p < 0.05). Immunofluorescence analysis showed outer and inner nuclear membranes and cytoplasmic subcellular localizations of LAMTOR1 in oocytes and pre-implantation embryos. The LAMTOR1 immunoexpression was gradually increased from MII oocyte and the highest level was detected at the morula stage of embryo development (p < 0.05). The lowest LAMTOR1 immunoexpression was detected at GV-stage oocyte (p < 0.05) and no clear difference in M2 oocyte, I-cell, 2-cell, and blastocyst stage embryos. In conclusion, both the mRNA and protein levels of LAMTOR1 increase progressively in cleavage-stage mouse embryos. LAMTOR1 has a significant higher embryonic expression at 2-cell to morula stage. LAMTOR1 may play a role in the oogenesis process and probably required for further developmental stages and it may play a possible role in the process of compaction and cavitation in mice. Therefore, further studies are needed to explore the LAMTOR1 expression especially in the different stages of embryonal development. PMID- 29510223 TI - Using Facebook to address smoking and heavy drinking in young adults: Protocol for a randomized, controlled trial. AB - INTRODUCTION: Tobacco and alcohol often are used simultaneously by young adults, and their co-use is associated with greater health consequences than from single use. Social media platforms offer low cost and highly accessible channels to reach and engage young people in substance use interventions. The current trial seeks to compare the Facebook Tobacco Status Project (TSP) smoking cessation intervention to an intervention targeting both tobacco use and heavy episodic drinking (TSP + ALC) among young adults who use both substances. METHODS: This randomized clinical trial will evaluate the feasibility and initial efficacy of TSP + ALC compared to TSP with 225 US young adult smokers reporting heavy drinking. Participants will be recruited online and randomized to one of two conditions (TSP or TSP + ALC), both with assignment to a Facebook group tailored to readiness to quit smoking. Groups will receive a 90-day intervention including daily Facebook postings and weekly live counseling sessions. The TSP + ALC group will include content related to alcohol use. All participants will be offered a 2 week introductory supply of nicotine patch. Participants will complete baseline, 3-, 6-, and 12-month online assessments of substance use and other health risk behaviors. The primary efficacy outcome is biochemically-verified 7-day point prevalence abstinence. Secondary outcomes include alcohol and tobacco use, combined use, and thoughts about each substance. DISCUSSION: This trial examines an innovative and scalable approach to engaging young adults online in tobacco and alcohol use treatment. Study findings will inform digital health interventions and best practices for treating multiple substance use in young adults. PMID- 29510225 TI - Effects of environment pollution on the ocular surface. AB - The twenty-first century is fraught with dangers like climate change and pollution, which impacts human health and mortality. As levels of pollution increase, respiratory illnesses and cardiovascular ailments become more prevalent. Less understood are the eye-related complaints, which are commonly associated with increasing pollution. Affected people may complain of irritation, redness, foreign body sensation, tearing, and blurring of vision. Sources of pollution are varied, ranging from gases (such as ozone and NO2) and particulate matter produced from traffic, to some other hazards associated with indoor environments. Mechanisms causing ocular surface disease involve toxicity, oxidative stress, and inflammation. Homeostatic mechanisms of the ocular surface may adapt to certain chronic changes in the environment, so affected people may not always be symptomatic. However there are many challenges associated with assessing effects of air pollution on eyes, as pollution is large scale and difficult to control. Persons with chronic allergic or atopic tendencies may have a pre-existing state of heightened mucosal immune response, hence they may have less tolerance for further environmental antigenic stimulation. It is beneficial to identify vulnerable people whose quality of life will be significantly impaired by environmental changes and provide counter measures in the form of protection or treatment. Better technologies in monitoring of pollutants and assessment of the eye will facilitate progress in this field. PMID- 29510226 TI - Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye. AB - PURPOSE: To assess tear film parameters, ocular surface characteristics, and dry eye symptomology in patients receiving topical anti-glaucoma medications. METHODS: Thirty-three patients with a diagnosis of open angle glaucoma or ocular hypertension, receiving unilateral topical anti-glaucoma medication for at least 6 months, were recruited in a cross-sectional, investigator-masked, paired-eye comparison study. Tear film parameters, ocular surface characteristics, and dry eye symptomology of treated and fellow eyes were evaluated and compared. RESULTS: The mean +/- SD age of the participants was 67 +/- 12 years, and the mean +/- SD treatment duration was 5.3 +/- 4.4 years. Treated eyes had poorer non-invasive tear film breakup time (p = 0.03), tear film osmolarity (p = 0.04), bulbar conjunctival hyperaemia (p = 0.04), eyelid margin abnormality grade (p = 0.01), tear meniscus height (p = 0.03), and anaesthetised Schirmer value (p = 0.04) than fellow eyes. There were no significant differences in dry eye symptomology, meibomian gland assessments, and ocular surface staining between treated and fellow eyes (all p > 0.05). CONCLUSIONS: Adverse changes in tear film stability, tear osmolarity, conjunctival hyperaemia, and eyelid margins were observed in treated eyes. This suggests that inflammatory mechanisms may be implicated in the development of dry eye in patients receiving long term topical anti-glaucoma therapy. PMID- 29510227 TI - Long non-coding RNA PVT1 as a novel candidate for targeted therapy in hematologic malignancies. AB - Cancerous cells show resistance to various forms of therapy, so applying up to the minute targeted therapy is crucial. For this purpose, long non-coding RNA PVT1 as shown by recent studies is an important oncogene that interacts with vital cellular signaling pathways and different proteins such as c-Myc, NOP2 and LATS2. Due to the enormous role of long non-coding RNAs in development of leukemias, we aimed to show the role of PVT1 knock-down on fate of different hematologic cell lines. owing to this matter, various experiments such as Real time PCR, cell cycle analysis and apoptosis assay were performed. Meanwhile, proliferation rate by CFSE, protein expression of c-Myc and hTERT by western blot and flow cytometry analysis were investigated. Our results demonstrated that PVT1 knock-down results in c-Myc degradation, proliferation down-regulation, induction of apoptosis and G0/G1 arrest. Simultaneously, for the first time, we posited the relation between this oncogene with hTERT that reduced after PVT1 knock-down. Considering these results, long non-coding RNA PVT1 may be a potential option for targeted therapy in hematologic malignancies. PMID- 29510229 TI - Role of hyaluronan in atherosclerosis: Current knowledge and open questions. AB - Hyaluronan (HA), HA synthases (HAS) and HA receptors are expressed during the progression of atherosclerotic plaques. HA is thought to promote the activated phenotype of local vascular smooth muscle cells characterized by increased migration, proliferation and matrix synthesis. Furthermore, HA may modulate the immune response by increasing macrophage retention and by promoting the polarization of Th1 cells that enhance macrophage driven inflammation as well. The pro-atherosclerotic functions of HA are opposed by the presence of HA in the glycocalyx where it critically contributes to anti-thrombotic and anti inflammatory function of the glycocalyx. Patients with atherosclerosis often are affected by comorbidities among them diabetes mellitus type 2 and inflammatory comorbidities. Diabetes mellitus type 2 likely has close interrelations to HA synthesis in atherosclerosis because the activity and transcription of HA synthases are sensitive to the intracellular glucose metabolism, which determines the substrate availability and the posttranslational modifications of HA synthases. The pro-inflammatory comorbidities aggravate the course of atherosclerosis and will affect the expression of the genes related to HA biosynthesis, -degradation, HA-matrix assembly or signaling. One example being the induction of HAS3 by interleukin-1beta and other cytokines. Furthermore complications of atherosclerosis such as the healing after myocardial infarction also involve HA responses. PMID- 29510230 TI - Cervical hyaluronan biology in pregnancy, parturition and preterm birth. AB - Cervical hyaluronan (HA) synthesis is robustly induced in late pregnancy in numerous species including women and mice. Recent evidence highlights the diverse and dynamic functions of HA in cervical biology that stem from its expression in the cervical stroma, epithelia and immune cells, changes in HA molecular weight and cell specific expression of HA binding partners. Mice deficient in HA in the lower reproductive tract confirm a structural role of HA to increase spacing and disorganization of fibrillar collagen, though this function is not critical for pregnancy and parturition. In addition, cervical HA depletion via targeted deletion of HA synthase genes, disrupts cell signaling required for the differentiation of epithelia and their mucosal and junctional barrier, resulting in increased susceptibility to ascending infection-mediated preterm birth. Finally the generation of HA disaccharides by bacterial hyaluronidases as made by Group B streptococcus can ligate toll like receptors TLR2/4 thus preventing appropriate inflammatory responses as needed to fight ascending infection and preterm birth. This review summarizes our current understanding of HA's novel and unique roles in cervical remodeling in the process of birth. PMID- 29510228 TI - Conservation of DNA and ligand binding properties of retinoid X receptor from the placozoan Trichoplax adhaerens to human. AB - Nuclear receptors are a superfamily of transcription factors restricted to animals. These transcription factors regulate a wide variety of genes with diverse roles in cellular homeostasis, development, and physiology. The origin and specificity of ligand binding within lineages of nuclear receptors (e.g., subfamilies) continues to be a focus of investigation geared toward understanding how the functions of these proteins were shaped over evolutionary history. Among early-diverging animal lineages, the retinoid X receptor (RXR) is first detected in the placozoan, Trichoplax adhaerens. To gain insight into RXR evolution, we characterized ligand- and DNA-binding activity of the RXR from T. adhaerens (TaRXR). Like bilaterian RXRs, TaRXR specifically bound 9-cis-retinoic acid, which is consistent with a recently published result and supports a conclusion that the ancestral RXR bound ligand. DNA binding site specificity of TaRXR was determined through protein binding microarrays (PBMs) and compared with human RXRalpha. The binding sites for these two RXR proteins were broadly conserved (~85% shared high-affinity sequences within a targeted array), suggesting evolutionary constraint for the regulation of downstream genes. We searched for predicted binding motifs of the T. adhaerens genome within 1000 bases of annotated genes to identify potential regulatory targets. We identified 648 unique protein coding regions with predicted TaRXR binding sites that had diverse predicted functions, with enriched processes related to intracellular signal transduction and protein transport. Together, our data support hypotheses that the original RXR protein in animals bound a ligand with structural similarity to 9-cis-retinoic acid; the DNA motif recognized by RXR has changed little in more than 1 billion years of evolution; and the suite of processes regulated by this transcription factor diversified early in animal evolution. PMID- 29510231 TI - A Systematic Review of Associations of Physical Activity and Sedentary Time with Asthma Outcomes. AB - BACKGROUND: Physical inactivity and high sedentary time are associated with adverse health outcomes in several diseases. However, their impact in asthma is less clear. OBJECTIVE: We aimed to synthesize the literature characterizing physical activity and sedentary time in adults with asthma, to estimate activity levels using meta-analysis, and to evaluate associations between physical activity and sedentary time and the clinical and physiological characteristics of asthma. METHODS: Articles written in English and addressing the measurement of physical activity or sedentary time in adults >=18 years old with asthma were identified using 4 electronic databases. Meta-analysis was used to estimate steps/day in applicable studies. RESULTS: There were 42 studies that met the inclusion criteria. Physical activity in asthma was lower compared with controls. The pooled mean (95% confidence interval) steps/day for people with asthma was 8390 (7361, 9419). Physical activity tended to be lower in females compared with males, and in older people with asthma compared with their younger counterparts. Higher levels of physical activity were associated with better measures of lung function, disease control, health status, and health care use. Measures of sedentary time were scarce, and indicated a similar engagement in this behavior between participants with asthma and controls. High sedentary time was associated with higher health care use, and poorer lung function, asthma control, and exercise capacity. CONCLUSIONS: People with asthma engage in lower levels of physical activity compared with controls. Higher levels of physical activity may positively impact on asthma clinical outcomes. Sedentary time should be more widely assessed. PMID- 29510232 TI - Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency. PMID- 29510233 TI - The B antigen protects against the development of red meat allergy. PMID- 29510235 TI - Treatment of antiphospholipid syndrome beyond anticoagulation. AB - Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy. PMID- 29510234 TI - The Effects of Botulinum Toxin Injections on Plantar Flexor Spasticity in Different Phases After Stroke: A Secondary Analysis From a Double-Blind, Randomized Trial. AB - BACKGROUND: There are no guidelines on the ideal time to inject botulinum toxin type A (BT-A) for lower leg spasticity in stroke patients. An early injection may produce unwanted weakness, interfering with gait recovery. OBJECTIVE: To evaluate whether the outcomes after BT-A injection for plantarflexion spasticity can be different according to stroke chronicity. DESIGN: A secondary analysis study from a double-blinded, randomized trial with group reclassification according to stroke chronicity. SETTING: Two rehabilitation centers. PARTICIPANTS: Stroke participants (n = 40) with plantar flexor spasticity, treated with BT-A (200 units) into the gastrocnemius muscle. METHODS: Outcome parameters were reanalyzed serially using 2-way repeated measures of analysis of variance (ANOVA), at baseline and 2, 4, and 8 weeks postinjection. Subjects were reclassified into 3 groups: early, within 6 months (n = 12); middle, between 6 months and 1 year (n = 14); and late, between 1 and 2 years from stroke onset (n = 12). MAIN OUTCOME MEASURES: The Modified Ashworth Scale, clonus scale, 10-m walking test, ABILOCO, and the Functional Ambulation Category. RESULTS: The 2-way repeated measures of ANOVA showed improvement in gait and spasticity after injection in the 3 groups. Significant improvement in the Modified Ashworth Scale (P < .001) was observed, starting from the post-2 week injection period. Improvement of gait as assessed by the functional measurement ABILOCO and the Functional Ambulation Category (P < .001) were observed in all 3 groups, mostly at the post-8 week injection period. CONCLUSIONS: Our serial measurements of the outcome parameters indicated that BT A could be expected to lead to consistent improvement in both the muscle tone and gait quality in those with plantar flexor spasticity regardless of stroke chronicity, including those injected as early as within the first 6 months. LEVEL OF EVIDENCE: I. PMID- 29510236 TI - Gene arrangement and sequence of mitochondrial genomes yield insights into the phylogeny and evolution of bees and sphecid wasps (Hymenoptera: Apoidea). AB - The Apoidea represent a large and common superfamily of the Hymenoptera including the bees and sphecid wasps. A robust phylogenetic tree is essential to understanding the diversity, taxonomy and evolution of the Apoidea. In this study, features of apoid mitochondrial genomes were used to reconstruct phylogenetic relationships. Twelve apoid mitochondrial genomes were newly sequenced, representing six families and nine subfamilies. Gene rearrangement events have occurred in all apoid mitochondrial genomes sequenced to date. Sphecid wasps have both tRNA and protein-coding gene rearrangements in 5 of 8 species. In bees, the only rearranged genes are tRNAs; long-tongued bees (Apidae + Megachilidae) are characterized by movement of trnA to the trnI-trnQ-trnM tRNA cluster. Phylogenetic analyses of mitochondrial gene sequences support the known paraphyly of sphecid wasps, with bees nested within this clade. The Ampulicidae is sister to the remaining Apoidea. Crabronidae is paraphyletic, split into Crabronidae s.s. and Philanthidae, with the latter group a sister clade to bees. The monophyletic bees are either classified into two clades, long-tongued bees (Apidae + Megachilidae) and short-tongued bees (Andrenidae + Halictidae + Colletidae + Melitidae), or three groups with the Melitidae sister to the other bees. Our study showed that both gene sequences and arrangements provide information on the phylogeny of apoid families. PMID- 29510237 TI - Relationship between microbial community, operational factors and ammonia inhibition resilience in anaerobic digesters at low and moderate ammonia background concentrations. AB - The relationship between anaerobic digestion operational conditions and (i) microbial community, (ii) acetoclastic methanogenic activity and (iii) free ammonia (NH3) inhibition resilience was investigated. Thirteen inocula were obtained from full and pilot scale digesters fed with different substrates, digester configurations, operating temperatures and NH3 concentrations (0.1-241 mgN.L-1). Substrate type and temperature were the primary factors influencing microbial community composition. Methanogenic activity ranged from 0.04 to 0.14 gCOD-CH4.g-1VS.day-1, and was significantly correlated with archaeal relative abundance and archaeal community PC2. The variability of NH3 resilience among inocula was moderate, with inhibition threshold values (KI50) ranging between 32 and 175 mgNH3-N.L-1. No microbial or operational factors correlated with NH3 resilience. However, the slopes of inhibition threshold curves were influenced by some environmental factors, namely substrate type, digester temperature and NH3 concentration. Overall, these results indicate that low and moderate background NH3 concentrations is not a key determinant of microbial community nor NH3 resilience. PMID- 29510238 TI - Parental presence in post-anaesthesia care unit in French university paediatric hospitals: An overview of the situation in 2016. PMID- 29510239 TI - Longissimus dorsi muscle label-free quantitative proteomic reveals biological mechanisms associated with intramuscular fat deposition. AB - : The pathways involved in intramuscular fat (IMF) deposition in Longissimus dorsi muscle were investigated using an integrated transcriptome-assisted label free quantitative proteomic approach by High Definition Mass Spectrometry. We quantified 1582 proteins, of which 164 were differentially abundant proteins (DAPs, p < 0.05) between animals with high (H) and low (L) genomic estimated breeding values (GEBV) for IMF content. Ingenuity pathway analysis (IPA) revealed that these DAPs were mainly involved in glycolysis metabolism, actin cytoskeleton signaling, cell-cell adherens junction and pathways for MAPK and insulin. A comparative study between transcriptomic (mRNA) and proteomic data showed 17 differentially expressed genes corresponding to DAPs, of which three genes/proteins did not agree on the direction of the fold change between groups. Moreover, we investigated microRNAs data to explain these differences in fold change direction, being able to unravel two of the three unexpected mRNA/protein relationships. Results demonstrated that changes in protein/mRNA levels of sarcomere organization, intracellular signal transduction and regulation of actin cytoskeleton, are involved in IMF deposition. These findings provide a deeper understanding of the highly complex regulatory mechanisms involved in IMF deposition in cattle and indicate target pathways for future studies. SIGNIFICANCE: Intramuscular fat is the amount of fat deposited inside muscle and plays an important role in human health and meat quality attributes, influencing energy metabolism of skeletal muscle, as well as, tenderness, flavor, and juiciness of beef. We performed for the first time the utilization of integrated transcriptome-assisted label-free quantitative proteomic approach using High Definition Mass Spectrometry for characterization of the changes in the proteomic profile of the Longissimus dorsi muscle associated with intramuscular fat deposition in cattle. Furthermore, we compared the muscle proteome with the muscle transcriptome (mRNA and microRNAs), obtained by RNA-sequencing, to better understand the relationship between expression of mRNAs and proteins and to unravel essential biological mechanisms involved in bovine skeletal muscle IMF deposition. PMID- 29510240 TI - Expanding the phenotypic spectrum associated with OPHN1 mutations: Report of 17 individuals with intellectual disability but no cerebellar hypoplasia. AB - Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase activating protein involved in the regulation of the G-protein cycle. Rho protein members play an important role in dendritic growth and in plasticity of excitatory synapses. Here we report on 17 individuals from four unrelated families affected by mild to severe intellectual disability due to OPHN1 mutations without cerebellar anomaly on brain MRI. We describe clinical, genetic and neuroimaging data of affected patients. Among the identified OPHN1 mutations, we report for the first time a missense mutation occurring in a mosaic state. We discuss the intrafamilial clinical variability of the disease and compare our patients with those previously reported. We emphasize the power of next generation techniques (X-exome sequencing, whole-exome sequencing and targeted multi-gene panel) to expand the phenotypic and mutational spectrum of OPHN1 related ID. PMID- 29510241 TI - A male case with CDKL5-associated encephalopathy manifesting transient methylmalonic acidemia. AB - Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive. We herein report a 16-year-old boy, who suffered from intractable seizures 20 days after birth. Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy. Mass-spectrometric analyses revealed increase in urinary excretion of methylmalonic acid without perturbed concentrations of propionic acid, homocystein and methionine. Whole-exome sequencing identified a de novo, truncating mutation in CDKL5 (NM_003159.2:c.419dupA, p.Asn140Lysfs*8). Targeted sequencing excluded concomitant mutations in methylmalonic academia-associated genes. No methylmalonic acidemia has been reported in children with CDKL5 disorder. Extensive analyses on organic acid metabolism for males with CDKL5 mutations will gain more insight into their biochemical profiles in infancy. PMID- 29510243 TI - The anatomy of the thoracic duct at the level of the diaphragm: A cadaver study. AB - BACKGROUND: Injury and subsequent leakage of unrecognized thoracic duct tributaries during transthoracic esophagectomy may lead to chylothorax. Therefore, we hypothesized that thoracic duct anatomy at the diaphragm is more complex than currently recognized and aimed to provide a detailed description of the anatomy of the thoracic duct at the diaphragm. BASIC PROCEDURES: The thoracic duct and its tributaries were dissected in 7 (2 male and 5 female) embalmed human cadavers. The level of origin of the thoracic duct and the points where tributaries entered the thoracic duct were measured using landmarks easily identified during surgery: the aortic and esophageal hiatus and the arch of the azygos vein. MAIN FINDINGS: The thoracic duct was formed in the thoracic cavity by the union of multiple abdominal tributaries in 6 cadavers. In 3 cadavers partially duplicated systems were present that communicated with interductal branches. The thoracic duct was formed by a median of 3 (IQR: 3-5) abdominal tributaries merging 8.3cm (IQR: 7.3-9.3cm) above the aortic hiatus, 1.8cm (IQR: 0.4 to 2.4cm) above the esophageal hiatus, and 12.3cm (IQR: 14.0 to -11.0cm) below the arch of the azygos vein. CONCLUSION: This study challenges the paradigm that abdominal lymphatics join in the abdomen to pass the diaphragm as a single thoracic duct. In this study, this occurred in 1/7 cadavers. Although small, the results of this series suggest that the formation of the thoracic duct above the diaphragm is more common than previously thought. This knowledge may be vital to prevent and treat post-operative chyle leakage. PMID- 29510242 TI - Electrochemical testing of a novel alloy in natural and artificial body fluids. AB - There is a recent trend in tissue engineering and regenerative medicine to use nanotechnology and bionanomaterials to obtain materials that mimic the surface properties of a natural tissue. From this perspective, nanolevel tissue engineering can be viewed as a novel anatomy of the future. In this paper, a novel titanium-based alloy is studied following this strategy. The alloy nanostructuration is proposed as an improved alternative for restorative prosthodontics or an implantable biomaterial. Tests in (i) standard solution of simulated body fluid (SBF) and (ii) natural saliva were performed to investigate the alloy's electrochemical stability. The results show that nanochannel growth on the alloy surface confers a higher stability than that of the untreated one in both natural and simulated environments. PMID- 29510244 TI - Dissecting the pathophysiology of complete heart block in takotsubo syndrome. PMID- 29510245 TI - Response to the letter to the editor: Complete heart block and Takotsubo syndrome: Dissecting the pathophysiology. PMID- 29510246 TI - Demonstration of dual AV nodal physiology - More than one way to skin a cat? PMID- 29510247 TI - Mass spectrometry-enabled structural biology of membrane proteins. AB - The last ~25 years has seen mass spectrometry (MS) emerge as an integral method in the structural biology toolkit. In particular, MS has enabled the structural characterization of proteins and protein assemblies that have been intractable by other methods, especially those that are large, heterogeneous or transient, providing experimental evidence for their structural organization in support of, and in advance of, high resolution methods. The most recent frontier conquered in the field of MS-based structural biology has been the application of established methods for studying water soluble proteins to the more challenging targets of integral membrane proteins. The power of MS in obtaining structural information has been enabled by advances in instrumentation and the development of hyphenated mass spectrometry-based methods, such as ion mobility spectrometry-MS, chemical crosslinking-MS and other chemical labelling/footprinting-MS methods. In this review we detail the insights garnered into the structural biology of membrane proteins by applying such techniques. Application and refinement of these methods has yielded unprecedented insights in many areas, including membrane protein conformation, dynamics, lipid/ligand binding, and conformational perturbations due to ligand binding, which can be challenging to study using other methods. PMID- 29510248 TI - Studying structure and function of membrane proteins with PELDOR/DEER spectroscopy - The crystallographers' perspective. AB - In 1985, the first X-ray structure of a membrane protein was determined. Today, more than 30 years later, many more structures have been solved. Nevertheless, studying the structure of membrane proteins remains a very challenging task. Due to their inherent conformational flexibility, having a single X-ray structure is usually only the first step towards truly understanding the function of these dynamic molecules. For this reason, additional methods are needed that can provide complementary information, especially about conformational flexibility. Pulsed electron-electron double resonance spectroscopy (PELDOR, also known as DEER) is such a method. It can be used to precisely measure nanometer distance distributions between intrinsic or artificially introduced spin-centers in macromolecules and thereby to probe the conformational state of the macromolecule. PELDOR can be applied in solution, in detergent, in lipid bilayers and even within cells. However, PELDOR is an advanced spectroscopy technique and requires specialised equipment and training. This chapter aims to be a starting point for crystallographers and other structural biologists who want to get a better understanding of PELDOR spectroscopy and its application. It gives an insight into the planning stages of the experiment (i.e., which spin labels are possible and where to place them), how a PELDOR experiment is conducted and how the results are interpreted. For this purpose, the substrate binding protein (SBP) from a Vibrio cholerae TRAP transporter is used as a step-by-step example. Further, the chapter gives examples of how PELDOR spectroscopy has previously been applied to overcome known limitations of X-ray crystallography in modern integrative structural biology approaches. PMID- 29510249 TI - Functional characterisation of G protein-coupled receptors. AB - Characterisation of receptors can involve either assessment of their ability to bind ligands or measure receptor activation as a result of agonist or inverse agonist interactions. This review focuses on G protein-coupled receptors (GPCRs), examining techniques that can be applied to both receptors in membranes and after solubilisation. Radioligand binding remains a widely used technique, although there is increasing use of fluorescent ligands. These can be used in a variety of experimental designs, either directly monitoring ligand itself with techniques such as fluorescence polarisation or indirectly via resonance energy transfer (fluorescence/Forster resonance energy transfer, FRET and bioluminescence resonance energy transfer, BRET). Label free techniques such as isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) are also increasingly being used. For GPCRs, the main measure of receptor activation is to investigate the association of the G protein with the receptor. The chief assay measures the receptor-stimulated binding of GTP or a suitable analogue to the receptor. The direct association of the G protein with the receptor has been investigated via resonance energy techniques. These have also been used to measure ligand-induced conformational changes within the receptor; a variety of experimental techniques are available to incorporate suitable donors and acceptors within the receptor. PMID- 29510250 TI - Characterization of solution-phase drug-protein interactions by ultrafast affinity extraction. AB - A number of tools based on high-performance affinity separations have been developed for studying drug-protein interactions. An example of one recent approach is ultrafast affinity extraction. This method has been employed to examine the free (or non-bound) fractions of drugs and other solutes in simple or complex samples that contain soluble binding agents. These free fractions have also been used to determine the binding constants and rate constants for the interactions of drugs with these soluble agents. This report describes the general principles of ultrafast affinity extraction and the experimental conditions under which it can be used to characterize such interactions. This method will be illustrated by utilizing data that have been obtained when using this approach to measure the binding and dissociation of various drugs with the serum transport proteins human serum albumin and alpha1-acid glycoprotein. A number of practical factors will be discussed that should be considered in the design and optimization of this approach for use with single-column or multi column systems. Techniques will also be described for analyzing the resulting data for the determination of free fractions, rate constants and binding constants. In addition, the extension of this method to complex samples, such as clinical specimens, will be considered. PMID- 29510251 TI - Micropterus salmoides rhabdovirus (MSRV) infection induced apoptosis and activated interferon signaling pathway in largemouth bass skin cells. AB - Largemouth bass (Micropterus salmoides) rhabdovirus (MSRV) was isolated from infected juveniles of largemouth bass, and the infected fish exhibited corkscrew, irregular swimming, and crooked body. To our knowledge, the potential molecular mechanisms underlying the pathogenesis of MSRV infection remain largely unknown. In the current study, we found that MSRV infection in largemouth bass skin (LBS) cells induced typical apoptosis, evidenced by the presence of apoptotic bodies and caspase-3 activation. To further analyze the host factors involved in MSRV infection in LBS cells, the transcriptomic profiles during MSRV infection were uncovered using deep RNA sequencing technique, and several differentially expressed genes (DEGs) were validated by quantitative PCR. Our results showed that a total of 124483 unigenes were assembled. Among them, 34465 and 27273 had significant hits to those in the NR and SwissProt databases. After MSRV infection, a total of 2432 and 2480 genes which involved in multiples pathways including TNF signaling, NF-kappaB signaling, Toll-like receptor signaling and RIG-I signaling pathway were differentially expressed in MSRV infected LBS cells compared to mock-infected cells at 12 h, respectively. Furthermore, quantitative PCR showed that the expression levels of 9 differentially expressed genes (DEGs) related to apoptosis and interferon signaling pathway was consistent with that from transcriptomic profiles. Together, our results not only demonstrated that interferon signaling pathway and apoptosis pathway might exerted crucial roles during MSRV infection, but also provided a useful resource for subsequent investigation of other immune-related genes related to virus infection. PMID- 29510252 TI - Antiviral activity of transiently expressed mitochondrial antiviral signaling adapter, MAVS orthologue from Asian seabass. AB - The innate immune signaling adapter, Mitochondrial antiviral signaling protein (MAVS) coordinates the signals received from two independent RLRs (RIG-1 and MDA5) to induce IFN & interferon stimulatory genes (ISGs). In the present study, we report identification of an orthologue of MAVS from Lates calcarifer (LcMAVS) and its functional role in piscine RLR signaling. The LcMAVS-cDNA was cloned into pcDNA and transfected into SISS cells. LcMAVS was detected to be a 61KDa protein in western blot. Confocal microscopy demonstrated the mitochondrial localization of LcMAVS. In addition, pcDNA-MAVS transfected cells were protected against Nervous Necrosis Virus (NNV) infection as manifested by the delayed appearance of cytopathic effect (CPE) and decreased viral transcript levels. Ectopic expression of LcMAVS resulted in activation of an ISRE-containing promoter (52 folds over control cells) as well as transcriptional expression of IRF-3, IFN-1 and IFN inducible genes including Mx and ISG15 (p<0.05). These results suggest that LcMAVS is involved in the antiviral immunity as one of the adaptors in fish IFN activation pathway. PMID- 29510253 TI - Aluminum adjuvant potentiates gilthead seabream immune responses but induces toxicity in splenic melanomacrophage centers. AB - A key goal of a successful vaccine formulation is the strong induction of persistent protective immune responses without producing side-effects. Adjuvants have been proved to be successful in several species at inducing increased immune responses against poorly immunogenic antigens. Fish are not the exception and promising results of adjuvanted vaccine formulations in many species are needed. In this study, over a period of 300 days, we characterized the apparent damage and immune response in gilthead seabream immunized by intraperitoneal injection with the model antigen keyhole limpet hemocyanin (KLH) alone or formulated with Montanide ISA water-in-oil (761 or 763), or ImjectTM aluminum hydroxide (aluminium), as adjuvants. Throughout the trial, external tissue damage was examined visually, but no change was observed. Internally, severe adhesions, increased fat tissue, and hepatomegaly were recorded, but, without impairing animal health. At 120 days post priming (dpp), histopathological evaluations of head-kidney, spleen and liver revealed the presence of altered melanomacrophage centers (MMC) in HK and spleen, but not in liver. Surprisingly, in all aluminium treated fish, classical stains unmasked a toxic effect on splenic-MMC, unequivocally characterized by a strong cell depletion. Furthermore, at 170 dpp transmission electron microscopy confirmed this data. Paradoxically, at the same time powerful immune responses were recorded in most vaccinated groups, including the aluminium treatment. Whatever the case, despite the observed adhesions and MMC depletion, fish physiology was not affected, and most side-effects were resolved after 300 dpp. Therefore, our data support adjuvant inclusion, but strongly suggest that use of aluminium must be further explored in detail before it might benefit the rational design of new vaccination strategies in aquaculture. PMID- 29510254 TI - The functionality of prebiotics as immunostimulant: Evidences from trials on terrestrial and aquatic animals. AB - The gut immune system is, the main option for maintaining host's health, affected by numerous factors comprising dietary constituents and commensal bacteria. These dietary components that affect the intestinal immunity and considered as an alternative of antibiotics are called immunosaccharides. Fructooligosaccharide (FOS), Galactooligosaccharide (GOS), inulin, dietary carbohydrates, and xylooligosaccharide (XOS) are among the most studied prebiotics in human as well as in aquaculture. Although prebiotics and probiotics have revealed potential as treatment for numerous illnesses in both human and fish, a comprehensive understanding of the molecular mechanism behind direct and indirect effect on the intestinal immune response will help more and perhaps extra effective therapy intended for ailments. This review covers the most newly deep-rooted scientific outcomes about the direct and indirect mechanism through which these dietetic strategies can affect intestinal immunity of terrestrial and aquatic animals. Prebiotics exert an influence on gut immune system via the increase in lysozyme and phagocytic activity, macrophage activation and stimulation of monocyte derived dendritic cells. Furthermore, these functional molecules also enhance epithelial barrier function, beneficial gut microbial population, and production of intermediate metabolites for example short chain fatty acids (SCFAs) that assist in balancing the immune system. Moreover, emphasis will be sited on the relationship among food/feed, the microbiota, and the gut immune system. In conclusion, further studies are nonetheless essential to confirm the direct effect of prebiotics on immune response. PMID- 29510255 TI - Chitosan nanoparticles: A positive immune response modulator as display in zebrafish larvae against Aeromonas hydrophila infection. AB - Chitosan nanoparticles (CNPs) were synthesized by ionic gelation method and its immunomodulatory properties were investigated in zebrafish larvae. Average particle size and zeta potential were 181.2 nm and +37.2 mv, respectively. Initially, toxicity profile was tested in zebrafish embryo at 96 h post fertilization (hpf) stage using medium molecular weight chitosan (MMW-C) and CNPs. At 5 MUg/mL, the hatching rate was almost similar in both treatments, however, the survival rate was lower in MMW-C compared to CNPs exposure, suggesting that toxicity effect of CNPs in hatched larvae was minimal at 5 MUg/mL compared to MMW-C. Quantitative real time PCR results showed that in CNPs exposed larvae at 5 days post fertilization (5 dpf) stage, immune related (il-1beta, tnf alpha, il-6, il-10, cxcl-18b, ccl34a.4, cxcl-8a, lyz-c, defbetal-1, irf-1a, irf 3, MxA) and stress response (hsp-70) genes were induced. In contrast, basal or down regulated expression of antioxidant genes (gstp-1, cat, sod-1, prdx-4, txndr 1) were observed. Moreover, zebrafish larvae (at 5 dpf stage) exposed to CNPs (5 MUg/mL) showed higher survival rate at 72 h post infection stage against pathogenic Aeromonas hydrophila challenge compared to controls. These results suggest that although CNPs can have toxic effects to the larvae at higher doses, CNPs exposure at 5 MUg/mL could enhance the immune responses and develop the disease resistance against A. hydrophila, which could be attributed to its strong immune modulatory properties. PMID- 29510256 TI - Transcriptome profiling analysis of grouper during nervous necrosis virus persistent infection. AB - Nervous necrosis virus (NNV) infection has been considered a serious disease in farmed grouper. Particularly, the persistent infection model conducts the grouper into a carrier state that continues to spread the virus through spawning. This particular model makes disease control more difficult in the aquaculture industry. In the present study, we used RNA-Seq, a high-throughput method based on next-generation sequencing, to profile the expression of genes during the period of NNV persistent infection. We evaluated the transcriptomic changes in the brain tissue of grouper. The inactivated-NNV vaccine was used as a comparison group. Based on the differentially expressed genes, highly immune cell active signaling and surface receptor expression were triggered during persistent infection. The interferon-induced response was also highly expressed in the infected brain tissue. However, critical negative regulatory factors of T-cells, such as PD-L1 and LAG3, were up-regulated. The present transcriptome study revealed a comprehensive view of the state of NNV persistent infection and provided insights into the state of impaired NNV clearance in the grouper. PMID- 29510257 TI - Maturation-associated changes in the non-specific immune response against Flavobacterium psychrophilum in Ayu Plecoglossus altivelis. AB - In this study, we investigated maturation-associated changes in non-specific immune responses of ayu against Flavobacterium psychrophilum. The gonadosomatic index was minimum on 16 June, began to increase on 17 July, and reached the maximum value during August. The highest phagocytic rate (16.3%) was observed on 16 June, which decreased significantly to 5.6% on 26 August. The number of viable bacteria after the serum treatment was highest during August, suggesting that bactericidal activity of the serum decreased along with the sexual maturation. Gene expression levels of interleukin-8, and tumor necrosis factor-alpha in the spleen did not change significantly during this period, whereas the level of suppressor of cytokine signaling (SOCS)3 was significantly higher on 26 August than that on 16 July (p < 0.05). These results suggest that phagocytic activity of trunk kidney leukocytes and serum bactericidal activity against F. psychrophilum decreased with sexual maturation, and that SOCS3 may be related to the decrease in non-specific immune activity in ayu. PMID- 29510258 TI - Recombinant Epinephelus lanceolatus serum amyloid A as a feed additive: Effects on immune gene expression and resistance to Vibrio alginolyticus infection in Epinephelus lanceolatus. AB - Recombinant Epinephelus lanceolatus serum amyloid A (rElSAA) exhibits strong immunostimulant activity and enhances phagocytic clearance of bacteria by macrophages. However, the effects of dietary rElSAA supplementation on growth performance, immunomodulation and disease resistance in giant grouper have not been previously evaluated. To test whether oral administration of rElSAA affects growth, fish were fed with 0, 0.88, 4.4 or 22 mg/kg rElSAA-containing diet for 28 days. No statistically significant differences in body weight were observed between groups. Next, we tested whether oral administration of rElSAA may enhance disease resistance. Fish were fed with 0, 0.88, 4.4 or 22 mg/kg rElSAA-containing diet for 3, 7, 14, 21 or 28 days, followed by challenge with Vibrio alginolyticus. Survival was then monitored for 4 days. Fish that were fed with rElSAA-containing diet for 28 days showed significantly improved survival after infection. In addition, the expression levels of immune defense-associated genes in hepatic tissue were assessed by quantitative real-time polymerase chain reaction before and after V. alginolyticus infection. Oral administration of rElSAA increased the expression level of toll-like receptor 5, whereas the expression levels of CC chemokine 1, SAA and C reactive protein were decreased. Thus, the data suggest that rElSAA may enhance host immunity by attenuating regulatory T cell-mediated suppression of inflammation. Together, our results demonstrate that rElSAA is a promising candidate as a feed additive for giant grouper, which may effectively enhance disease resistance after being administered for several weeks. PMID- 29510259 TI - Comparative transcriptomic analysis provides insights into antibacterial mechanisms of Branchiostoma belcheri under Vibrio parahaemolyticus infection. AB - : Amphioxus, a basal chordate, is widely considered to be an existing proxy of the invertebrate ancestor of vertebrates, and it exhibits susceptibility to various pathogen infections and pathogenic mimic challenges. Here, in order to understand more clearly its antibacterial mechanisms, we analyzed the ribosomal RNA (rRNA)-depleted transcriptome of Chinese amphioxus (Branchiostoma belcheri) infected with Vibrio parahaemolyticus (V. p.) via next-generation deep sequencing technology (RNA-seq). We identified a total of 3214 differentially expressed genes (DEGs) by comparing V. p.-infected and control transcriptome libraries, including 2219 significantly up-regulated and 995 significantly down-regulated DEGs in V. p.-infected amphioxus. The DEGs with the top 10 most dramatic expression fold changes after V. p. infection, as well as 53 immune-related DEGs (IRDs) belonging to four primary categories of innate immunity were analyzed further. Through gene ontology (GO) and pathway enrichment analysis, DEGs were found to be primarily related to immune processes, apoptosis, catabolic and metabolic processes, binding and enzyme activity, while pathways involving bacterial infection, immune signaling, immune response, cancer, and apoptosis were overrepresented. We validated the RNA-seq results by detecting the expression levels of 10 IRDs using qRT-PCR, and we surveyed the dynamic variation in gene expression for these IRDs at 0, 6, 12, 24, and 48 h after V. p. TREATMENT: Subsequently, according to the RNA-seq results, the presence of a primitive Toll-like receptor (TLR)-mediated antibacterial immune signaling pathway was predicted in B. belcheri. This study provides valuable information regarding antibacterial immunity for further research into the evolution of immunity in vertebrates and broadens our understanding of the innate immune response against bacterial invasion in amphioxus. PMID- 29510260 TI - Influence of ALA-mediated photodynamic therapy on secretion of interleukins 6, 8 and 10 by colon cancer cells in vitro. AB - BACKGROUND: Photodynamic therapy has apart from a direct cytotoxic effect also immunomodulatory properties. The aim of our study was to investigate how photodynamic therapy with 5-aminolevulinic acid (ALA-PDT) in sublethal doses influences the secretion of interleukins 6, 8 and 10 from colon cancer cells in vitro. METHODS: We used two human colon cancer cell lines SW480 and SW620 of different malignancies which were treated with a sublethal PDT protocol. Determination of interleukins was carried out using the Bio- Plex Assay ProTM kit on the Bio- Plex Suspension Array System. RESULTS: Sublethal ALA-PDT did not affect IL-6 secretion by SW480 cells, but caused a 40% decrease of IL-6 release by the SW620 cell line. It increased IL-8 secretion in both, the SW480 and SW620 cell lines, by 23% and 46%, respectively, and decreased the production of IL-10 (25% in SW480 and 32% in SW620 cells). CONCLUSIONS: ALA-PDT in sublethal doses might influence colon cancer cell's progression and invasion by reducing the secretion of IL-6, IL-10 and increasing the IL-8 concentration with higher values in the more malignant cell line. PMID- 29510261 TI - Ethanol generation, oxidation and energy production in a cooperative bioelectrochemical system. AB - Integrating in situ biofuel production and energy conversion into a single system ensures the production of more robust networks as well as more renewable technologies. For this purpose, identifying and developing new biocatalysts is crucial. Herein, is reported a bioelectrochemical system consisting of alcohol dehydrogenase (ADH) and Saccharomyces cerevisiae, wherein both function cooperatively for ethanol production and its bioelectrochemical oxidation. Here, it is shown that it is possible to produce ethanol and use it as a biofuel in a tandem manner. The strategy is to employ flexible carbon fibres (FCF) electrode that could adsorb both the enzyme and the yeast cells. Glucose is used as a substrate for the yeast for the production of ethanol, while the enzyme is used to catalyse the oxidation of ethanol to acetaldehyde. Regarding the generation of reliable electricity based on electrochemical systems, the biosystem proposed in this study operates at a low temperature and ethanol production is proportional to the generated current. With further optimisation of electrode design, we envision the use of the cooperative biofuel cell for energy conversion and management of organic compounds. PMID- 29510262 TI - Stability analysis for discrete-time stochastic memristive neural networks with both leakage and probabilistic delays. AB - This paper is concerned with the globally exponential stability problem for a class of discrete-time stochastic memristive neural networks (DSMNNs) with both leakage delays as well as probabilistic time-varying delays. For the probabilistic delays, a sequence of Bernoulli distributed random variables is utilized to determine within which intervals the time-varying delays fall at certain time instant. The sector-bounded activation function is considered in the addressed DSMNN. By taking into account the state-dependent characteristics of the network parameters and choosing an appropriate Lyapunov-Krasovskii functional, some sufficient conditions are established under which the underlying DSMNN is globally exponentially stable in the mean square. The derived conditions are made dependent on both the leakage and the probabilistic delays, and are therefore less conservative than the traditional delay-independent criteria. A simulation example is given to show the effectiveness of the proposed stability criterion. PMID- 29510263 TI - A biologically-based computational model of visual cortex that overcomes the X junction illusion. AB - The end-points of a moving bar (intrinsic terminators) contain unambiguous information that can be used to extract the bar's correct direction of motion, regardless of the orientation of the bar. However, extrinsic terminators, formed at the intersection of two overlapping bars, can result in motion signals with conflicting directions compared to those of the intrinsic terminators. Using a computational model, we propose that interactions between form and motion information may assist neurons in the motion-specific regions of primate cortex to differentiate intrinsic from extrinsic terminators. The motion processing model has two stages. The first stage is a model of V1 complex neurons, including end-stopped neurons. The resulting first stage motion signals are transmitted to the second stage, which is a model of MT neurons. In the proposed model, MT neurons additionally receive form information from neurons in V1 that are not orientation or direction selective but respond strongly to the contrast of the stimulus. These neurons have polarity-dependent center-surround receptive fields, as found in layer 4 of V1 in primates. As the inhibitory surrounds of these neurons are less activated at the intrinsic terminators, the signals generated by the end-points of the objects are stronger than the signals from the extrinsic terminators, which are inhibited by strong suppression from the surround. Therefore, the excitatory inputs received by integration MT neurons from center surround V1 neurons enhance the unambiguous motion signals at the intrinsic terminators, which therefore dominate over the local motion signals generated at X-junctions. The results show that, despite the inability of V1 end-stopped neurons to distinguish between the two different types of terminators, center surround V1 neurons provide the capacity for the second stage of the model to preferentially respond to the intrinsic terminators and, therefore, predict the true directions of the crossing bars. PMID- 29510264 TI - The effect of arousal and eye gaze direction on trust evaluations of stranger's faces: A potential pathway to paranoid thinking. AB - BACKGROUND AND OBJECTIVES: When asked to evaluate faces of strangers, people with paranoia show a tendency to rate others as less trustworthy. The present study investigated the impact of arousal on this interpersonal bias, and whether this bias was specific to evaluations of trust or additionally affected other trait judgements. The study also examined the impact of eye gaze direction, as direct eye gaze has been shown to heighten arousal. METHODS: In two experiments, non clinical participants completed face rating tasks before and after either an arousal manipulation or control manipulation. Experiment one examined the effects of heightened arousal on judgements of trustworthiness. Experiment two examined the specificity of the bias, and the impact of gaze direction. RESULTS: Experiment one indicated that the arousal manipulation led to lower trustworthiness ratings. Experiment two showed that heightened arousal reduced trust evaluations of trustworthy faces, particularly trustworthy faces with averted gaze. The control group rated trustworthy faces with direct gaze as more trustworthy post-manipulation. There was some evidence that attractiveness ratings were affected similarly to the trust judgements, whereas judgements of intelligence were not affected by higher arousal. LIMITATIONS: In both studies, participants reported low levels of arousal even after the manipulation and the use of a non-clinical sample limits the generalisability to clinical samples. CONCLUSIONS: There is a complex interplay between arousal, evaluations of trustworthiness and gaze direction. Heightened arousal influences judgements of trustworthiness, but within the context of face type and gaze direction. PMID- 29510265 TI - Marked effectiveness of low-dose oral methotrexate for steroid-resistant idiopathic hypertrophic pachymeningitis: Case report. AB - Idiopathic hypertrophic pachymeningitis (HP) is a rare clinical entity characterized by thickening of the dura mater without obvious underlying disease. High-dose steroid therapy is considered to be the first line for idiopathic HP, but half of patients show resistance for steroid therapy and suffer progressive clinical course. We describe low-dose methotrexate (MTX) administration for recurrent and steroid-resistant idiopathic HP resulting in noticeable improvement without severe adverse effects. A 51-year-old Japanese woman with dermatomyositis first presented with right retro-orbital pain caused by dural thickening in the sella and upper clivus involving the right trigeminal nerve, which was diagnosed as idiopathic HP by transsphenoidal biopsy. High-dose methylprednisolone therapy led to remission, and she remained healthy with low-dose dexamethasone. Three years after the initial therapy she presented with right facial nerve and lower cranial nerve palsies caused by diffuse and significant dural thickening in the posterior cranial fossa. Second highdose methylprednisolone therapy was introduced, but the effect was transient and she suffered aspiration pneumonia. Low-dose oral MTX therapy was begun, and her symptoms were almost resolved and dural thickening was remarkably improved without severe adverse effects. Lowdose MTX may be a more appropriate choice for idiopathic HP than steroid administration. Randomized controlled clinical trials are now needed. PMID- 29510266 TI - What about sentinel lymph node biopsy for early breast cancer during pregnancy? AB - Pregnancy-associated breast cancer is rare, but this clinical situation arises in 1/10,000-1/3000 pregnancies. In patients presenting an early-stage breast tumor devoid of clinically pathological lymph node, sentinel lymph node (SLN) biopsy has not yet been validated as a routine procedure for pregnant women due to the lack of data in the literature. The blue dye injection is not recommended because of 2% theoretical risk of anaphylactic shock. Several studies have shown that Tc99m injection at conventional dose between 12.1 and 18.5MBq exposed the fetus to an irradiation between 0.011 and 0.0245mSv much below the 50mSv recommended threshold. As evidenced by lymphoscintigraphy scans, the dose of injected Tc99m is localized at the injection site and in the SLN. According to the literature, the SLN technique does not seem to impact the fetal or obstetrical prognosis. Studies involving larger cohorts are required to confirm these data and to indicate this technique in pregnant women. Considering the benefit for the patient and the low risk incurred on both fetal and obstetrical levels, it appears reasonable to discuss the indication of SLN on a case-by-case basis in multidisciplinary oncologic meetings. PMID- 29510267 TI - Use and representations of intrauterine device in Martinique, F.W.I.: A cross sectional survey. AB - INTRODUCTION: Abortion rate is higher in Martinique than in metropolitan France. Difference in pattern of contraception may be involved, particularly regarding IUD use. IUD use is often hampered by misconceptions. The aim of the study was to evaluate IUD use in a non-selected population in Martinique and to explore knowledge and acceptance of the method. MATERIAL AND METHODS: Women were submitted a self-questionnaire about their contraceptive history, appropriate candidates for, effectiveness, side effects and perceived risks of IUD. Acceptance of the method among men and women and reasons for rejecting it were also surveyed. We included 112 men and 136 women. Descriptive statistics and comparison of answers between ever and never IUD-users were realized. RESULTS: Past or current IUD use was found in 26.5% [19.3-34.8] of women and the method was known by 90.4% of women and 85.1% of men. Pain at insertion (important for 22%), infectious risk (increased for 23.6%), and eligible candidates for the method (possible in nulliparous for only 56.9%) were the main misconceptions recorded. Knowledge was better among ever than never IUD-users. Theoretical acceptance of the method was high (87.5% among women of reproductive age, 82.5% among men). Rejection of the method was mainly motivated by doubts on efficacy and fear from pain, whereas religious barriers were seldom set forward. DISCUSSION: IUD use seems comparable in Martinique and France but misconceptions are still common. Information may help diffusion of IUD in a targeted population at higher risk of unintended pregnancy. PMID- 29510268 TI - Implementation of laparoscopy surgery training via simulation in a low-income country. AB - OBJECTIVE: The objective of this study was to evaluate laparoscopy training using pelvitrainers for gynaecological surgeons in a low-income country. METHODS: The study was carried out in Madagascar from April 2016 to January 2017. The participants were gynaecological surgeons who had not previously performed laparoscopy. Each surgeon was timed to evaluate the execution times of four proposed exercises, based on the fundamentals of laparoscopic surgery (FLS) programme's skills manual, as follows: exercise 1, involving a simple object transfer; exercises 2 and 3, comprising complex object transfers; and exercise 4, a precision cutting exercise. The 8-month training and evaluation programme was divided into different stages, and the four following evaluations were compared: a pretest (T0), assessment at the end of the first training (T1) and auto evaluation at 2 months (T2) and 8 months (T3). RESULTS: Eight participants were included. The median time was significantly reduced (P<0.05) at each evaluation for exercises 1, 2 and 4 compared to the pretest. For exercise 3, there was no difference between T0 and T1 (P=0.07). After 8 months of training, all participants progressed in all exercises. CONCLUSION: Our study showed that it is possible and beneficial to develop a programme for teaching laparoscopic surgery in low-income countries before providing the necessary equipment. PMID- 29510269 TI - Hysteroscopic resection on virtual reality simulator: What do we measure? AB - OBJECTIVE: The objective was to compare results of two groups of population (novices and experts) on a virtual reality simulator of hysteroscopy resection for different metrics and for a multimetric score to assess its construct validity. MATERIALS AND METHODS: Nineteen gynecologist who had at least 5 years of experience with hysteroscopy and self-evaluated their expertise at 4/5 or 5/5 were included as expert population. Twenty first-year gynecology residents in Paris were included as novice population. A standardized set of 4 hysteroscopy resection cases (polypectomy, myomectomy, roller ball endometrial ablation and septum resection) was performed on a virtual reality simulator (HystSimTM) by the group of novices and experts. Results obtained on the simulator for overall score and for the parameters were compared by applying the Mann-Whitney test. RESULTS: Overall score of novices and experts were significantly different for three resection cases (polypectomy P<0.001, myomectomy P<0.001, roller ball endometrial ablation <0.001). The overall score was not different in the septum resection (P=0.456). For the four cases, the economy score (included cumulative path length, procedure time and camera alignment) were statistically different between novices and experts (polypectomy P<0.001, myomectomy P=0.001, roller ball endometrial ablation P<0.001, septum resection P<0.001). CONCLUSION: The overall score on HystSimTM was able to discriminate novices between experts on polypectomy, myomectomy and roller ball endometrial ablation cases but not on septum resection. The economy score was the more reliable to reflect the surgeon experience. It could be used to evaluate and to train students on hysteroscopic resection on a virtual reality simulator. PMID- 29510270 TI - Persistence of Zika virus in gradient sperm preparation. PMID- 29510271 TI - Management of breech and twin labor during registrarship: A two-year prospective, observational study. AB - INTRODUCTION: Breech presentation and twin pregnancy are regarded as stressful situations for medical staff. This stress is often associated with an increased likelihood of intervention during labor - especially when the on-shift obstetrician lacks experience. MATERIAL AND METHODS: We performed a 2-year prospective, observational study of cesarean section (CSDs) and assisted vaginal (AVDs) deliveries in a tertiary maternity unit for attempted vaginal deliveries of breech presentations and twin pregnancies. The obstetric management decisions taken by a group of four registrars were compared with those taken by a group of 11 experienced obstetricians. Changes over time in practice were also monitored. RESULTS: Registrars managed 66 and 52 breech presentations and twin pregnancies respectively (30 and 27 in the experienced group). Groups' neonatal outcomes were similar. There were no intergroup differences in proportions of CSDs for either breech presentations (25 [37.5%] vs. 15 [50%] in the registrar and experienced groups, respectively; P=0.26) or twin pregnancies (11 [21.1%] vs. 6 [22.2%], respectively; P=0.91) or in proportion of AVDs for twin pregnancies (41 [78.8%] vs. 21 [77.8%], respectively; P=0.91). Proportions of CSDs for breech presentation and AVDs for twin pregnancies did not change over time in either group. However, proportion of CSDs for twin pregnancies increased over time in the registrar group (P=0.004). DISCUSSION: Well-trained registrars appeared to have acquired the skills required to safely manage an obstetric ward; this pleads to maintain clinical practice during residency to preserve low CSD and AVD rates. PMID- 29510272 TI - The definition of Endometriosis Expert Centres. AB - Endometriosis is a common condition that causes pain and infertility. It can lead to absenteeism and also to multiple surgeries with a consequent risk of impaired fertility, and constitutes a major public health cost. Despite the existence of numerous national and international guidelines, the management of endometriosis remains suboptimal. To address this issue, the French College of Gynaecologists and Obstetricians (CNGOF) and the Society of Gynaecological and Pelvic Surgery (SCGP) convened a committee of experts tasked with defining the criteria for establishing a system of care networks, headed by Expert Centres, covering all of mainland France and its overseas territories. This document sets out the criteria for the designation of Expert Centres. It will serve as a guide for the authorities concerned, to ensure that the means are provided to adequately manage patients with endometriosis. PMID- 29510273 TI - Ovarian suppression failure during GnRH agonist treatment: A report of three breast cancer patients. AB - In premenopausal women treated for breast cancer, endocrine therapy combining an aromatase inhibitor (AI) and a gonadotropin-releasing hormone (GnRH) agonist (GA) for ovarian suppression may be indicated in high-risk or in metastatic cancer. AIs are effective in premenopausal women only when ovarian estrogen production is suppressed, a state achievable through the use of GAs. However, a complete suppression sometimes proves elusive. We report here three cases of ovarian suppression failure in premenopausal breast cancer patients who received adjuvant AI+GA. Frequency of GA administration, BMI, and young age could affect gonadotropin suppression and may be implied in these failures. Clinical monitoring of these patients is advisable, and hormone assays and pelvic ultrasound should be performed in case of symptoms of estrogen activity. PMID- 29510274 TI - An Alternative Endoscopic Anterolateral Route to Meckel's Cave: An Anatomic Feasibility Study Using a Sublabial Transmaxillary Approach. AB - OBJECTIVE: To describe an endoscopic anterolateral surgical route to the lateral portion of Meckel's cave. METHODS: A sublabial transmaxillary transpterygoid approach was performed in 6 cadaveric heads (12 sides). A craniectomy was drilled between the foramen rotundum (FR) and foramen ovale (FO) with defined borders. Extradural dissection was performed up to the V2-V3 junction of the trigeminal ganglion. The working space was analyzed using anatomic measurements. RESULTS: The approach allowed for extradural dissection to the lateral aspect of Meckel's cave and provided excellent exposure of V2, V3, and the V2-V3 junction at the gasserian ganglion. The mean distance between the FR and FO along the pterygoid process of the sphenoid bone was 21.3 +/- 2.8 mm (range, 18-24.4 mm). The mean distance of V2 and V3 segments from their foramina to the gasserian ganglion junction was 12.0 +/- 2.3 mm (range, 9.2-14.6 mm) and 15.2 +/- 2.7 mm (range, 12.3-18.5 mm), respectively (6 sides). A potential working area (mean area, 89 mm2) is described. Its superior edge is from the FR to the V2-V3 junction at the gasserian ganglion, its inferior edge is from the FO to the V2-V3 junction at the gasserian ganglion, and its base is from the FO to the FR. The surgical anatomy of the infratemporal fossa, pterygopalatine fossa, and lateral Meckel's cave is highlighted. CONCLUSIONS: An endoscopic anterolateral sublabial transmaxillary transpterygoid approach between the FR and FO avoids crossing critical neurovascular structures within the cavernous sinus and pterygopalatine fossa and can provide a safe surgical corridor for laterally based lesions in Meckel's cave. PMID- 29510275 TI - Headache Outcomes After Coil Embolization in Patients with Unruptured Intracranial Aneurysms: Do They Get Better or Worse? A Prospective Analysis. AB - BACKGROUND: To investigate the association between headache outcomes and coil embolization and to identify potential factors associated with different headache outcomes in patients with unruptured intracranial aneurysms (UIAs) after treatment with coil embolization. METHODS: A prospective study of patients with planned coil embolization for UIAs was conducted. The changes in headache patterns, headache-related disability, and depression were assessed before coil embolization and at 3 days and 2 and 6 weeks after coil embolization. All variables were analyzed to identify factors associated with different headache outcomes. RESULTS: Fifty-nine (72%) of 82 patients reported headaches before coil embolization. Of these, improvements in the severity of headaches were reported by 42 patients (71%). In addition to a significant reduction in headache severity, significant reductions in headache-related disability and depression scores also were observed. Demographic factors, aneurysmal characteristics, or procedural factors were not found to be significantly associated with improvement in the severity of headaches after coil embolization. In addition, the number of microemboli on diffusion-weighted imaging was not significantly associated with improvement of headaches after coil embolization. Twenty-three patients reported no headaches before coil embolization, and 3 (13%) patients reported new-onset headaches after coil embolization. All new-onset headaches were mild and dull in nature without combined symptoms in the temporal area. CONCLUSIONS: Our study suggested that regardless of headache characteristics, the aneurysm size (even those <5 mm in diameter), technique used (stent-assisted or not stent-assisted), and coil embolization of UIAs resulted in headache improvement in most patients with pretreatment headaches. PMID- 29510276 TI - Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device. AB - BACKGROUND: There is a dearth of literature regarding management and outcomes of patients with a left ventricular assist device (LVAD) for advanced heart failure who develop intracranial hemorrhage (ICH). We conducted a case series from 2 centers highlighting patient outcomes and prognostic factors to help clinicians better understand and care for these high-risk patients. METHODS: A case series from 2 large-volume institutions (defined as large by the Nationwide Inpatient Sample hospital size, i.e., >500 beds both with Departments of Neurosurgery and Advanced Heart Failure-Cardiology) was conducted to clarify the prognosis of patients with an LVAD and ICH. We included patients who were being treated with an LVAD who developed ICH. Patient-specific demographics and data regarding heart failure and intracranial hemorrhage characteristics were collected and analyzed to determine which factors contributed to overall survival. RESULTS: We analyzed 59 unique ICHs in patients being treated with an LVAD for heart failure. Initial Glasgow Coma Scale score, presence of midline shift, and ICH size were factors found to be predictive of mortality. One institution had a sicker patient population including patients with ICH with lower Glasgow Coma Scale score, presence of midline shift, and greater hemorrhage size, which led to overall higher mortality compared with the second institution. CONCLUSIONS: Patients being treated with an LVAD who develop ICH have poor outcomes. Predictive factors for same-admission mortality are lower initial Glasgow Coma Scale score, presence of midline shift, and greater ICH volume. PMID- 29510277 TI - Biomechanical Influences of Transcorporeal Tunnels on C4 Vertebra Under Physical Compressive Load Under Flexion Movement: A Finite Element Analysis. AB - BACKGROUND: Anterior percutaneous endoscopic transcorporeal cervical discectomy is an alternative operation for cervical disc herniation. However, few reports have evaluated the biomechanical influence of tunnels on vertebrae. We compared biomechanical distinctions between intact and tunneled models of vertebrae to analyze the safety of anterior percutaneous endoscopic transcorporeal cervical discectomy based on a C2-T1 finite element (FE) model. METHODS: Groups of C2-T1 FE models were simulated with C4 tunneled by 2 methods (group A: with partial superior endplate excision; group B: without partial superior endplate excision) and various tunnel diameters (6, 8, and 10 mm). All FE models were loaded under a 1-Nm flexion moment. RESULTS: The area and maximum of stress concentrations were correlated with tunnel diameter. The distribution of stress on C4 superior endplates showed no significant difference between B6 and the intact model (P > 0.05), but significant differences with other tunneled models (P < 0.001). Maximum stress on the lateral wall of tunnels was positively correlated with tunnel diameter and induced high risks of cancellous bone fracture for diameters reaching 10 mm in group B and 8 mm in group A. CONCLUSIONS: Transcorporeal tunnel in C4 vertebrae without endplate excision should be limited with diameter of 6 mm, and a tunnel diameter >10 mm, excision of the endplate >8 mm, and excision of the center side of the endplate should also be avoided. PMID- 29510278 TI - Microvascular Decompression for Classical Trigeminal Neuralgia Caused by Venous Compression: Novel Anatomic Classifications and Surgical Strategy. AB - BACKGROUND: Microvascular decompression of the trigeminal nerve is the most effective treatment for trigeminal neuralgia. However, when encountering classical trigeminal neuralgia caused by venous compression, the procedure becomes much more difficult, and failure or recurrence because of incomplete decompression may become frequent. This study aimed to investigate the anatomic variation of the culprit veins and discuss the surgical strategy for different types. METHODS: We performed a retrospective analysis of 64 consecutive cases in whom veins were considered as responsible vessels alone or combined with other adjacent arteries. The study classified culprit veins according to operative anatomy and designed personalized approaches and decompression management according to different forms of compressive veins. Curative effects were assessed by the Barrow Neurological Institute (BNI) pain intensity score and BNI facial numbness score. RESULTS: The most commonly encountered veins were the superior petrosal venous complex (SPVC), which was artificially divided into 4 types according to both venous tributary distribution and empty point site. We synthetically considered these factors and selected an approach to expose the trigeminal root entry zone, including the suprafloccular transhorizontal fissure approach and infratentorial supracerebellar approach. The methods of decompression consist of interposing and transposing by using Teflon, and sometimes with the aid of medical adhesive. Nerve combing (NC) of the trigeminal root was conducted in situations of extremely difficult neurovascular compression, instead of sacrificing veins. Pain completely disappeared in 51 patients, and the excellent outcome rate was 79.7%. There were 13 patients with pain relief treated with reoperation. Postoperative complications included 10 cases of facial numbness, 1 case of intracranial infection, and 1 case of high frequency hearing loss. CONCLUSIONS: The accuracy recognition of anatomic variation of the SPVC is crucial for the management of classical trigeminal neuralgia caused by venous compression. Selecting an appropriate approach and using reasonable decompression methods can bring complete postoperative pain relief for most cases. NC can be an alternative choice for extremely difficult cases, but it could lead to facial numbness more frequently. PMID- 29510279 TI - Short-Term Outcome in Subaxial Spine Injury Patients Operated on in a Resource Limited Setting, Addis Ababa, Ethiopia. AB - BACKGROUND: Subaxial spinal injury surgery is expensive, and its significance is uncertain because of limited rehabilitation and postoperative care. OBJECTIVE: To assess complications and outcome in patients surgically treated for subaxial spinal injuries in 2 hospitals in Addis Ababa, Ethiopia. METHODS: Retrospective study, conducted among 85 patients operated on for subaxial spine injury from January 2013 to August 2016. Data were collected from medical charts. Descriptive statistics and binary logistic regression were used for data analysis. RESULTS: A total of 85 patients were included, and 20 patients were not followed up. The mean age was 33 years (standard deviation +/- 12.03 years), and the mean time from injury to surgery was 10 days. The rates of surgical mortality and reoperation were 7.05% and 3.5%, respectively. Deaths occurred in 13 of 16 patients (81.1%) with American Spine Injury Association (ASIA) scores of A and in 3 of 16 patients (18.9%) with ASIA scores of B. The complication rate in patients with a preoperative ASIA score of A was 17/24 (70.8%). The study showed that 55 of 65 patients who were followed up (84.6%; 95% confidence interval [CI]: 75.4, 92.3) experienced improvement. According to the patients' follow-up ASIA scores, 47 (72.3%; 95% CI: 61.5, 83.1) were functional. Sphincter tone before operation (adjusted odds ratio 142.82; 95% CI: 9.973, 204.090) was significantly associated with follow-up ASIA score. CONCLUSIONS: Patients with complete cervical injuries had high rates of mortality and morbidity, indicating that it might be better not to operate on these patients in resource-limited settings. There is a moderate recovery rate in patients with incomplete SCI despite a lack of adequate rehabilitation facilities. PMID- 29510280 TI - Surgical Management of Lumbosacral Giant Invasive Spinal Schwannoma: A Case Report and Literature Review. AB - BACKGROUND: Giant invasive spinal schwannomas (GISSs) comprise a rare, specific subtype of schwannomas that extend >2 spinal levels, erode vertebral bodies, and invade extraspinal tissues. Optimal surgical management of resulting spinal instability has yet to be determined, and overall there is limited published literature on GISS. We report an innovative method used to treat a rare case of lumbosacral GISS using a triangular frame reconstruction to reconnect the spinal column to the pelvis after tumor debulking. This method of using femur allograft in lieu of metal rods can promote stronger bony fusion of the construct. CASE DESCRIPTION: A 19-year-old woman presented with worsening lower back pain, which was due to a giant invasive spinal schwannoma that invaded the L4-S1 vertebral bodies and extended intrathecally from T10-S2, compromising the stability of her spine. The primary resection of the tumor was completed in 3 stages and was followed by a multilevel fusion involving a triangular construct made of femur allograft to reconnect the unstable spinal column with the pelvis. Maximal resection of the tumor was achieved with early rehabilitation. Pseudoarthrosis occurred, which was successfully fused after revision with the addition of an implanted bone stimulator. Seven years later, she remains in stable neurological condition. CONCLUSIONS: We recommend the use of femur allograft in triangular frame constructs for lumbosacral GISS to foster more stable, physiologic spinopelvic fusion. PMID- 29510281 TI - Surgical Management in Cervical Spondylotic Myelopathy Due to Alkaptonuria. AB - BACKGROUND: Ochronotic arthropathy related to alkaptonuria is a rare condition. Cervical spine involvement with myelopathic features has been even more rarely described, particularly related to atlantoaxial instability. As such, little is known about the optimal surgical management in these patients. CASE DESCRIPTION: We described the first case, to our knowledge, of a patient with alkaptonuria and related cervical spondylotic myelopathy from pannus formation at the atlantoaxial joint. We describe our choices in surgical management of this rare condition in a patient with an excellent outcome. CONCLUSION: Ochronotic cervical spondylotic myelopathy is a rare condition and may require additional considerations in surgical treatment compared to more common causes of cervical spondylotic myelopathy. In our case, we elected for decompression with posterior occipitocervical screw fixation and were able to achieve neurologic recovery with no complications, currently at 2-year follow-up. PMID- 29510282 TI - Multimodal Approach for Radical Excision of Focal Cortical Dysplasia by Combining Advanced Magnetic Resonance Imaging Data to Intraoperative Ultrasound, Electrocorticography, and Cortical Stimulation: A Preliminary Experience. AB - BACKGROUND AND OBJECTIVE: Type II focal cortical dysplasia is the most common malformation of cortical development associated with drug resistant epilepsy and susceptible to surgical resection. Although, at present, advanced imaging modalities are capable of detecting most cortical disorders, it is still a challenge for the surgeon to visualize them intraoperatively. The lack of direct identification between normal brain and subtle dysplastic tissue may explain the poor results in terms of being seizure-free versus other forms of epilepsy. The aim of this study is to compare magnetic resonance imaging (MRI) and intraoperative ultrasound-guided neuronavigation, along with cortical stimulation and acute electrocorticography, as a multimodal surgical approach to cortical dysplasia's tailored resection. METHODS: Six consecutive patients with type II cortical dysplasia underwent epilepsy surgery by means of MRI/intraoperative ultrasound-guided neuronavigation. Intraoperative cortical stimulation of sensory/motor cortex was performed to localize cortical eloquent areas. Acute electrocorticography was used to identify epileptogenic tissue. These findings were correlated to real-time ultrasound imaging to establish the extent of the resection. RESULTS: Intraoperative ultrasound depicted cortical dysplasias at a higher resolution and accuracy than MRI. Therefore it maximized the extent of the resection. Both postoperative MRIs and pathology documented the extent of the resection in all patients. Seizure-freedom was achieved in 5 cases (Engel class IA), and in 1 patient it was classified as Engel class IB. No postoperative neurological deficits were observed. CONCLUSIONS: These results strongly suggest feasibility of ultrasound-guided resection of focal cortical dysplasia. Providing high resolution and accuracy, it allows an easy, real-time discrimination between normal and dysplastic brain. PMID- 29510284 TI - Succinate Dehydrogenase B Subunit-Negative Jugular Foramen Paraganglioma Manifesting Malignant Progression with Pseudohypoxia-Related Atypical Uptake of [18F]-Fluoro-2-Deoxy-d-Glucose: A Case Report. AB - BACKGROUND: Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%-20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro 2-deoxy-d-glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. CASE DESCRIPTION: A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1alpha and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. CONCLUSION: In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis. PMID- 29510283 TI - One or Two Drains for the Treatment of Surgical Site Infections After Lumbar Spine Surgery. AB - BACKGROUND: Optimal drainage after debridement for treating postoperative surgical site infection (SSI) is controversial. We compared single-tube drainage with double-tube drainage. METHODS: We retrospectively analyzed 1125 patients with lumbar degenerative disease who underwent lumbar surgery. Postoperative SSI was diagnosed in 26 patients, and these patients were divided into 2 groups: single-tube drainage group (1 drain) and double-tube drainage group (2 drains). RESULTS: The 26 adult patients (17 women and 9 men) with postoperative SSI after lumbar surgery (26/1125 [2.3%]) were treated with debridement. There were no significant differences in patient age, sex, body mass index, mean number of pedicle screws, operative time, amount of bleeding, and drainage between the 2 groups. There were no significant differences between groups in administration of antibiotics (P > 0.05). Bacterial cultures were routinely performed in all 26 cases of SSI; 80.7% (21/26) of patients had a positive culture. Staphylococcus species, including predominantly S. aureus, methicillin-resistant S. aureus, and S. epidermidis, were the most common pathogens, followed by Escherichia coli, Acinetobacter, Klebsiella pneumoniae, and Enterococcus faecalis. There were no significant differences in drainage efficiency between the 1 drain and 2 drains groups (P > 0.05). CONCLUSIONS: There were no significant differences between the 1 drain and 2 drains groups in surgery-related and patient-related risk factors, pathogenic bacteria and antibiotic therapy, laboratory tests results, or drainage efficiency and time. However, patients in the 1 drain group exhibited better clinical outcome and shorter hospital stay. PMID- 29510285 TI - Symptomatic Tarlov Cysts: Surgical Treatment by Subcutaneous Infusion Port. AB - BACKGROUND: The treatment of Tarlov cysts is challenging and difficult. The objective of our study was to describe the security and efficacy of the subcutaneous infusion port for drainage of symptomatic Tarlov cysts. METHODS: The authors executed a retrospective review of data from 5 symptomatic Tarlov cysts patients who were treated using a subcutaneous infusion port from June 2014 to July 2017. Numerical Rating Scale scores and the Japanese Orthopedic Association scores of back pain were analyzed. Complications and adverse effects on postoperative days 1, 7, 14, and 28 were also analyzed. The mean follow-up was 12.6 months. RESULTS: Five adults (3 females and 2 males) who had been symptomatic received a subcutaneous infusion port. After treatment, all patients experienced pain relief and pain alleviation lasted from 1 day to 3 years without complications and adverse effects. CONCLUSIONS: A subcutaneous infusion port is a useful treatment option for symptomatic Tarlov cysts. When the patients' symptoms returned and the cysts repressurized, we quickly and simply drained the cysts by using the infusion port. PMID- 29510287 TI - Endovascular Treatments in Combination with Extracranial-Intracranial Bypass for Complex Intracranial Aneurysms. AB - BACKGROUND: Although most intracranial aneurysms can be treated with microsurgery or endovascular procedure alone, a subset of aneurysms may require a combined approach. The purpose of this study was to assess the efficacy of endovascular interventions combined with bypass surgery for the treatment of complex intracranial aneurysms. METHODS: We retrospectively reviewed medical records from a prospectively maintained patient database to identify patients who underwent endovascular treatment of an intracranial aneurysm at our institutes between 2007 and 2017. We recruited patients who received a preplanned combination of endovascular treatment and extracranial-intracranial bypass surgery. RESULTS: Forty-four patients (44 aneurysms) were treated with a combined approach. Twenty four patients presented with subarachnoid hemorrhage. Treatment strategies included endovascular parent artery occlusion with the bypass surgery to restore cerebral blood flow (n = 12), endovascular trapping with bypass surgery to isolate incorporated branches (n = 12), and intra-aneurysmal coil embolization with bypass surgery to isolate incorporated branches (n = 20). During a mean period of 35.6 months, follow-up catheter angiography was performed in 35 of 44 patients (79.5%) and demonstrated complete aneurysm obliteration in 29 patients (82.9%) and bypass patency in 33 (94.3%). The postoperative aneurysm-related mortality and morbidity rates were 6.8% and 13.6%, respectively. CONCLUSIONS: Combined endovascular and surgical bypass procedures are useful for the treatment of complex intracranial aneurysms when conventional surgical or endovascular techniques are not feasible and show acceptable rates of morbidity and mortality. PMID- 29510286 TI - Creation of 3-Dimensional Life Size: Patient-Specific C1 Fracture Models for Screw Fixation. AB - BACKGROUND: Transarticular screw fixation has fatal complications such as vertebral artery (VA), carotid artery, and spinal cord injuries. The landmarks for deciding the entry point for C1 lateral mass screws were clarified by using life-size 3-dimensional (3D) patient-specific spine models. METHODS: This study included a total of 10 patients with C1 fractures. Dual-energy computed tomography (CT) scan data from C1 pre- and postscrewing were modified into 3D patient-specific life-size cervical spine models. The detailed information, such as bony and vascular elements, of 13 separate parameters of C1 was used as an intraoperative reference. RESULTS: 3D patient-specific models were created preoperatively with the fracture and postoperatively with the screwed vertebrae. After CT scans of the models were measured, the life-size patient-specific models were proven to be individualized. 3D models assisted in determining the fracture locations, pedicle sizes, and positions of the VA. The range of the measurements for ideal point of entry reveals the need for patient-specific intervention was required. CONCLUSIONS: 3D models were used in surgical planning maximizing the possibility of ideal screw position and providing individualized information concerning cervical spinal anatomy. The individualized 3D printing screw insertion template was user-friendly, of moderate cost, and it enabled a radiation-free cervical screw insertion. PMID- 29510288 TI - Comparison of Outcomes After Mechanical Thrombectomy Alone or Combined with Intravenous Thrombolysis and Mechanical Thrombectomy for Patients with Acute Ischemic Stroke due to Large Vessel Occlusion. AB - BACKGROUND: Whether intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) provides additional benefits remains controversial. We aimed to compare clinical and radiologic outcomes between IVT+MT and MT alone groups. METHODS: We retrospectively reviewed the clinical and radiological features of patients from the prospectively collected database who sustained anterior circulation stroke due to large vessel occlusion (LVO) and were treated with MT within 8 hours of symptom onset. We compared rates of successful reperfusion, functional independence and mortality at 90 days, and symptomatic intracranial hemorrhage (sICH) as clinical endpoints between the 2 groups. RESULTS: The 81 patients included in this study included 38 (46.9%) in the MT alone group (mean age, 72.6 +/- 14.1 years; 17 males [44.7%]) and 43 in the IVT+MT group (mean age, 68.9 +/- 12.8 years; 29 males [67.4%]). There were no significant differences in patient baseline characteristics between the 2 groups except for a male predominance in the IVT+MT group. The mean interval from onset to groin puncture (221.6 +/- 110.5 minutes vs. 204.7 +/- 63.7 minutes; P = 0.472) and the rate of successful reperfusion rate (thrombolysis in cerebral infarction 2b/3, 60.5% vs. 58.1%; P = 0.827) did not differ significantly between the MT and IVT+MT groups. The rate of favorable functional outcome, as determined by a modified Rankin Scale score 0-2 (36.8% vs. 51.2%; P = 0.263) and mortality at 90 days (18.4% vs. 9.3%; P = 0.332), and the rate of sICH (5.3% vs. 4.6%; P = 1.000) were also not significantly different between the 2 groups. CONCLUSIONS: This study suggests that previous IVT might not facilitate successful reperfusion and favorable functional outcomes in patients with anterior circulation stroke treated with MT. MT alone can be a safe and effective treatment modality in patients who are ineligible for IVT for various reasons. PMID- 29510289 TI - Ethmoid Meningoencephalocele in a Patient with Cerebrofacial Arteriovenous Metameric Syndrome. AB - BACKGROUND: Skull base meningoencephaloceles are a rare condition, frequently secondary to traumatic or iatrogenic causes. Cerebrofacial arteriovenous metameric syndrome (CAMS) is characterized by the presence of retinal, facial, and cerebral arteriovenous malformations (AVMs) with metameric distribution. To our knowledge, this is the first reported case associating these 2 conditions. CASE DESCRIPTION: A 45-year-old woman previously diagnosed with CAMS type 2 presented with a long history of cerebrospinal fluid (CSF) rhinorrhea. Magnetic resonance imaging and digital subtraction angiography demonstrated a right-sided facial and orbital AVM extending posteriorly along the optic tract into the suprasellar cistern, and a right-sided meningoencephalocele protruding into the olfactory recess and ethmoid sinus. An extended endoscopic endonasal approach was performed to resect the meningoencephalocele and to repair the CSF leak without complications. CONCLUSIONS: We report the unusual association between the development of a meningoencephalocele and a metameric syndrome, and comment on clinical implications in the management of this patient. PMID- 29510290 TI - Impact of Laterality on Surgical Outcome of Glioblastoma Patients: A Retrospective Single-Center Study. AB - BACKGROUND: Resection of left hemisphere (LH) tumors is often complicated by the risks of causing language dysfunction. Although neurosurgeons' concerns when operating on the presumed dominant hemisphere are well known, literature evaluating laterality as a predictive surgical parameter in glioblastoma (GB) patients is sparse. We evaluated whether tumor laterality correlated with surgical performance, functional outcome, and survival. METHODS: All patients with GB treated at our institution between 2006 and 2016 were reviewed. Analysis comprised clinical characteristics, extent of resection (EOR), neurologic outcome, and survival in relation to tumor lateralization. RESULTS: Two hundred thirty-five patients were included. Right hemisphere (RH) tumors were larger and more frequently extended into the frontal lobe. Preoperatively, limb paresis was more frequent in RH, whereas language deficits were more frequent in LH tumors (P = 0.0009 and P < 0.0001, respectively). At 6 months after resection, LH patients presented lower Karnofsky Performance Status (KPS) score (P = 0.036). More patients with LH tumors experienced dysphasia (P < 0.0001), and no difference was seen for paresis. Average EOR was comparable, but complete resection was achieved less often in LH tumors (37.7 vs. 64.8%; P = 0.0028). Although overall survival did not differ between groups, progression-free survival was shorter in LH tumors (7.4 vs. 10.1 months; P = 0.0225). CONCLUSIONS: Patients with LH tumors had a pronounced KPS score decline and shorter progression-free survival without effects on overall survival. This observation might partially be attributed to a more conservative surgical resection. Further investigation is needed to assess whether systematic use of awake surgery and intraoperative mapping results in increased EOR and improved quality survival of patients with GB. PMID- 29510291 TI - Clinical Effects of Posterior Longitudinal Ligament Removal and Wide Anterior Cervical Corpectomy for Spondylosis. AB - BACKGROUND: Removing the posterior longitudinal ligament in cervical corpectomy is a controversial issue. It is unclear whether the risks are counterbalanced by clinical benefits. Another unexplored topic is whether the width of the corpectomy affects outcome. METHODS: This cross-sectional retrospective study included consecutive patients who underwent cervical corpectomy for spondylosis by 6 different neurosurgeons. We compared 2 groups, where the posterior longitudinal ligament was either removed (N = 15 patients) or preserved (N = 21 patients). The posterior width of the corpectomy was assessed postoperatively with computed tomography and magnetic resonance imaging. Clinical results were evaluated with the visual analog scale (VAS), Modified Japanese Orthopedic Association scale (MJOAS), Cooper scale, and neck disability index (NDI), in the long-term follow-up. RESULTS: Compared to preservation, removal of the posterior longitudinal ligament produced more favorable clinical results (but not statistically significant), based on the VAS (+41%, P = 0.48), MJOAS (+26.5%, P = 0.62), Cooper scale (+19%, P = 0.75), and NDI (+62%, P = 0.22). Magnetic resonance imagings showed that removing the posterior longitudinal ligament produced greater evagination of the dural sac into the space left by the corpectomy. Improvements in clinical outcome were associated with more posterior bone wall removal in the corpectomy (corpectomy width >=15.6 mm; P < 0.05), based on the VAS, NDI, and MJOAS. CONCLUSIONS: Removing the posterior longitudinal ligament in cervical corpectomy may produce a better outcome, particularly when associated with more posterior bone wall removal in the corpectomy. PMID- 29510292 TI - Thymoquinone Induces Apoptosis in B16-F10 Melanoma Cell Through Inhibition of p STAT3 and Inhibits Tumor Growth in a Murine Intracerebral Melanoma Model. AB - BACKGROUND: Prognosis of patients with melanoma brain metastasis is poor despite various chemotherapeutic agents. Researchers focus on finding effective treatment with a low risk of toxicity. Thymoquinone (TQ) has been found to be effective on different types of cancer. However, no data exist regarding the effect of TQ in intracerebral melanoma. The purpose of this study was to assess the effect of TQ in B16-F10 melanoma cell in vitro and intracerebral melanoma in vivo. METHODS: The mechanisms of efficacy were investigated using adenosine triphosphate assay for cytotoxicity, flow cytometry, and acridine orange staining for apoptosis, comet assay for genotoxicity, CM-H2DCF-DA (2,7-dichlorodihydrofluorescein) for intracellular reactive oxygen species (ROS) generation and ELISA methods for inflammatory cytokines. Western blotting was performed to assess the expressions of p-JAK2, p-STAT3, caspase-3, Bax, Bcl-2, and survivin. In addition, the effect of TQ was investigated in a model system of intracerebral melanoma in syngeneic mice. RESULTS: The median survival was improved by TQ in mice with intracerebral melanoma compared with the control group (16 days vs 9 days; P = 0.008). Cytotoxicity was enhanced by TQ in B16-F10 cells in a dose-dependent manner. TQ also induced apoptosis, DNA damage, and increased intracellular ROS. TQ inhibited p-STAT3, resulting in apoptosis through regulation of proapoptotic and antiapoptotic proteins. CONCLUSIONS: Our findings suggest that TQ would be an effective treatment in intracerebral metastatic lesions. This warrants further investigation. PMID- 29510293 TI - Comparison of O-(2-18F-Fluoroethyl)-L-Tyrosine Positron Emission Tomography and Perfusion-Weighted Magnetic Resonance Imaging in the Diagnosis of Patients with Progressive and Recurrent Glioma: A Hybrid Positron Emission Tomography/Magnetic Resonance Study. AB - OBJECTIVE: To compare the diagnostic performance of O-(2-18F-fluoroethyl)-L tyrosine (18F-FET) positron emission tomography (PET) and perfusion-weighted magnetic resonance imaging (PWI) for the diagnosis of progressive or recurrent glioma. METHODS: Thirty-two pretreated gliomas (25 progressive or recurrent tumors, 7 treatment-related changes) were investigated with 18F-FET PET and PWI via a hybrid PET/magnetic resonance scanner. Volumes of interest with a diameter of 16 mm were centered on the maximum of abnormality in the tumor area in PET and PWI maps (relative cerebral blood volume, relative cerebral blood flow, mean transit time) and the contralateral unaffected hemisphere. Mean and maximum tumor to-brain ratios as well as dynamic data for 18F-FET uptake were calculated. Diagnostic accuracies were evaluated by receiver operating characteristic analyses, calculating the area under the curve. RESULTS: 18F-FET PET showed a significant greater sensitivity to detect abnormalities in pretreated gliomas than PWI (76% vs. 52%, P = 0.03). The maximum tumor-to-brain ratio of 18F-FET PET was the only parameter that discriminated treatment-related changes from progressive or recurrent gliomas (area under the curve, 0.78; P = 0.03, best cut off 2.61; sensitivity 80%, specificity 86%, accuracy 81%). Among patients with signal abnormality in both modalities, 75% revealed spatially incongruent local hot spots. CONCLUSIONS: This pilot study suggests that 18F-FET PET is superior to PWI to diagnose progressive or recurrent glioma. PMID- 29510294 TI - Local mechanisms regulating selective cargo entry and long-range trafficking in axons. AB - The polarized long-distance transport of neuronal cargoes depends on the presence of functional and structural axonal subcompartments. Given the heterogeneity of neuronal cargoes, selective sorting and entry occurs in the proximal axon where multiple subcellular specializations such as the axon initial segment, the pre axonal exclusion zone, the MAP2 pre-axonal filtering zone and the Tau diffusion barrier provide different levels of regulation. Cargoes allowed to pass through the proximal axon spread into the more distal parts. Recent findings show that diverse cargo distributions along the axon depend on the compartmentalized organization of the cytoskeleton and the local regulation of multiple motor proteins by microtubule associated proteins. In this review, we focus on the local mechanisms that control cargo motility and discuss how they play a role in the overall circulation of axonal cargoes. PMID- 29510296 TI - Revised manual for the Global Assessment of Functioning scale. AB - Global Assessment of Functioning (GAF) is a single measure of overall psychosocial impairment caused by mental factors, constituting Axis V of the Diagnostic and Statistical manual of Mental disorders, third and fourth versions. Despite its widespread use, several challenges and shortcomings have been discussed the last three decades. The current article describes some of the more serious challenges of the GAF manual, and presents a revised version more in accordance with the nature of this clinical construct. Some crucial aspects of the understanding of GAF and general guidelines for scoring are also discussed. PMID- 29510297 TI - Immediate and brief intervention after suicide attempts on patients without major psychiatric morbidity-A pilot study in northern Israel. AB - BACKGROUND: Suicide Prevention is an ongoing task for mental health services. This article describes a pilot program for suicide prevention that took place in two districts in Israel from 2009 to 2012. The program targeted specific population, patients in high-risk for suicide, without major mental illness or previous association with the mental health system. In that group many suicide attempts were due to stressful life events. METHODS: Patients who performed a suicide attempt or were considered high-risk for suicide were referred to the project. The first contact took place up to 24 h after the referral and included a phone call with suggestion for further intervention. If he was willing, the patient was invited to a serious of 8-12 meetings with a therapist that focused on "crisis intervention" techniques. RESULTS: 212 subjects were referred to the project. Three quarters of the referrals were females. Most of them were of Jewish nationality, however, the percentage of Druze in the program's population was higher than their percentage of general population. Only 137 continued participation after the initial phone call, people of Jewish nationality were more willing to continue the intervention. During the intervention there was a decline in suicide rates in the participating districts. CONCLUSIONS: The pilot program exhibits promising preliminary results, it is interesting to examine the difference in participation between different ethnic groups. Since the sample size is small, there is a need to continue the program on a larger scale. PMID- 29510295 TI - Alcohol use and alcohol/marijuana use during the most recent sexual experience differentially predict characteristics of the sexual experience among sexually active young adult drinkers. AB - INTRODUCTION: Few studies have examined associations between using alcohol only and using both alcohol and marijuana with sexual behavior on specific occasions. The current study examined alcohol and marijuana use during the most recent sexual experience in association with relationship characteristics, psychological issues, and condom use. METHODS: Young adult drinkers aged 18-25 who reported not using a condom during sex in the past month were recruited nationally. An analytic subsample (N = 378) was identified based on substance use during the most recent sexual experience [53% female, 70% Caucasian; mean age = 22.42 years (SD = 1.90)]. Using logistic regression, two dummy codes compared the alcohol use only group (n = 197) and the both alcohol and marijuana group (n = 95) to the group who used neither substance (n = 86). Participant sex, drinking frequency, and number of sexual partners were included as covariates. RESULTS: The alcohol only group and the both alcohol and marijuana group had greater odds of being with a casual acquaintance and loss of respect compared to the group who used neither substance. The alcohol only group had greater odds of being with someone they just met and embarrassment compared to the group who used neither substance. No associations were found for condom use or emotional difficulties. CONCLUSIONS: Preventative interventions may need to address both alcohol and marijuana to more effectively reduce risky behaviors. PMID- 29510298 TI - The reciprocal relationship between physical activity and depression: Does age matter? AB - BACKGROUND: The level of physical activity (PA) and the prevalence of depression both change across the lifespan. We examined whether the association between PA and depression is moderated by age. As sense of mastery and functional limitations have been previously associated with low PA and depression in older adults, we also examined whether these are determinants of the differential effect of age on PA and depression. METHODS: 1079 patients with major depressive disorder (aged 18-88 years) were followed-up after two-years; depression diagnosis and severity as well as PA were re-assessed. Linear and logistic regression analyses were used to test reciprocal prospective associations between PA and depression outcomes. In all models the interaction with age was tested. RESULTS: PA at baseline predicted remission of depressive disorder at follow-up (OR = 1.43 [95% CI: 1.07-1.93], p = .018). This effect was not moderated by age. PA predicted improvement of depression symptom severity in younger (B = -2.03; SE = .88; p = .022), but not in older adults (B = 2.24; SE = 1.48; p = .128) (p = .015 for the interaction PA by age in the whole sample). The level of PA was relatively stable over time. Depression, sense of mastery and functional limitation were for all ages not associated with PA at follow-up. CONCLUSIONS: Age did not moderate the impact of PA on depressive disorder remission. Only in younger adults, sufficient PA independently predicts improvement of depressive symptom severity after two-year follow-up. Level of PA rarely changed over time, and none of the determinants tested predicted change in PA, independent of age. PMID- 29510299 TI - Highly efficient separation of surfactant stabilized water-in-oil emulsion based on surface energy gradient and flame retardancy. AB - HYPOTHESIS: Surface energy gradient would generate an imbalance force to drive tiny water droplets in dry air from the hydrophilic bumps to superhydrophobic domains, which has found on the Stenocara beetle's back. EXPERIMENTS: Inspired by this phenomenon, we introduced a pristine superhydrophilic filter paper on the lower surface energy superhydrophobic filter paper. ZnSn(OH)6 particles and polydimethylsiloxane were mixed to prepare the superhydrophobic coating, and the coating was spray-coated on the poly(dialkyldimethylammonium chloride) covered filter paper to separate the span 80 stabilized water-in-isooctane emulsion. A pristine filter paper was added on the superhydrophobic filter paper to fabricate another membrane for separation. FINDINGS: The results revealed that with a pristine filter paper, the membrane performed higher efficiency and more recyclability, and it could separate the emulsions with higher surfactant concentrations. The stabilized water droplets passed the superamphiphilic surface, and hindered by the superhydrophobic surface, generating a surface energy gradient for better separation. In addition, the superhydrophobic membrane could be protected from fire to some degree due to the introduced ZnSn(OH)6 particles with excellent flame retardancy. This easy and efficient approach via simply bringing in pristine superhydrophilic membrane has great potential applications for water-in-oil emulsion separation or oil purification. PMID- 29510300 TI - Attachment and social networks. AB - The current review covers two lines of research linking attachment and social networks. One focuses on attachment networks (the people who fulfill one's attachment needs), examining composition and age-related differences pertaining to these networks. The other line integrates attachment with social network analysis to investigate how individual differences in adult attachment are associated with the management and characteristics (e.g., density, multiplexity, and centrality) of people's social networks. We show that most people's attachment networks are small and hierarchical, with one figure being the primary attachment figure (often a mother or romantic partner, depending on age). Furthermore, attachment style predicts network characteristics and management, such that insecurity is associated with less closeness, multiplexity, centrality, and poorer management (less maintenance, more dissolution). PMID- 29510301 TI - The development of adult attachment styles: four lessons. AB - Why are some adults secure or insecure in their relationships? The authors review four lessons they have learned from longitudinal research on the developmental antecedents of adult attachment styles. First, although adult attachment appears to have its origins in early caregiving experiences, those associations are weak and inconsistent across measurement domains. Second, attachment styles appear to be more malleable in childhood and adolescence than in adulthood, leading to asymmetries in socialization and selection processes. Third, early experiences do not determine adult outcomes. Fourth, there is still a lot to learn, and future research requires examining relationship-specific attachment patterns, the distinction between distal and proximal factors, and interactions between relational and genetic vulnerabilities. PMID- 29510302 TI - County-level job automation risk and health: Evidence from the United States. AB - RATIONALE: Previous studies have observed a positive association between automation risk and employment loss. Based on the job insecurity-health risk hypothesis, greater exposure to automation risk could also be negatively associated with health outcomes. OBJECTIVE: The main objective of this paper is to investigate the county-level association between prevalence of workers in jobs exposed to automation risk and general, physical, and mental health outcomes. METHODS: As a preliminary assessment of the job insecurity-health risk hypothesis (automation risk -> job insecurity -> poorer health), a structural equation model was used based on individual-level data in the two cross-sectional waves (2012 and 2014) of General Social Survey (GSS). Next, using county-level data from County Health Rankings 2017, American Community Survey (ACS) 2015, and Statistics of US Businesses 2014, Two Stage Least Squares (2SLS) regression models were fitted to predict county-level health outcomes. RESULTS: Using the 2012 and 2014 waves of the GSS, employees in occupational classes at higher risk of automation reported more job insecurity, that, in turn, was associated with poorer health. The 2SLS estimates show that a 10% increase in automation risk at county-level is associated with 2.38, 0.8, and 0.6 percentage point lower general, physical, and mental health, respectively. CONCLUSION: Evidence suggests that exposure to automation risk may be negatively associated with health outcomes, plausibly through perceptions of poorer job security. More research is needed on interventions aimed at mitigating negative influence of automation risk on health. PMID- 29510303 TI - Does the sex ratio at sexual maturity affect men's later-life mortality risks? Evidence from historical China. AB - This study examines the relationship between the male-to-female sex ratio (measured as the proportion male) at sexual maturity and later-life mortality risks in the context of pre-industrial northeast China, using registration data from the Qing Dynasty. We find that a higher male-to-female sex ratio at sexual maturity is associated with a higher later-life mortality risk among men. This association is likely due to the long-term adverse consequences of stress caused by low mate availability at sexual maturity. We further find that a high sex ratio at sexual maturity mitigates the health benefits of marriage and exacerbates the health disadvantages of holding an official position in Qing China. PMID- 29510304 TI - Viral mimic polyinosine-polycytidylic acid potentiates liver injury in trichloroethylene-sensitized mice - Viral-chemical interaction as a novel mechanism. AB - Occupational trichloroethylene (TCE) exposure can induce hypersensitivity dermatitis and severe liver injury. Recently, several clinical investigations indicate that viral infection, such as human herpesvirus-6, is associated with hepatic dysfunction in patients with TCE-related generalized skin disorders. However, whether viral infection potentiates TCE-induced liver injury remains unknown. This study aimed to explore the contribution of viral infection to the development of TCE-sensitization-induced liver injury in BALB/c mice. Female BALB/c mice were randomly assigned into four groups: solvent control group (n = 20), TCE group (n = 80), poly(I:C) group (n = 20) and combination of TCE and poly(I:C) (poly(I:C)+TCE) group (n = 80). Poly(I:C) (50 MUg) was i.p. administrated. TCE and poly(I:C)+TCE groups were further divided into sensitization and non-sensitization subgroup. Complement 3 and C3a protein levels, and complement factors were measured. Combination treatment significantly enhanced TCE-induced liver injury, decreased complement 3, but increased C3a in serum and liver tissues in sensitization group. These changes were not correlated with the hepatic complement 3 transcription. Moreover, combination treatment specifically promoted complement factor B, but not factor D and factor H expressions. These data provide first evidence that poly(I:C) potentiates liver injury in BALB/c mouse model of TCE-sensitization. Upregulated C3a and factor B contributes to the poly(I:C) action in TCE-induced liver injury. This new mode of action may explain increased risk of chemical-sensitization induced tissue damage by viral infection. PMID- 29510305 TI - Effects of living hyperaccumulator plants and their straws on the growth and cadmium accumulation of Cyphomandra betacea seedlings. AB - To determine whether the living hyperaccumulator plants and their straws have the same effects on the growth and heavy metal accumulation of common plants, two pot experiments (intercropping experiment and straw mulch experiment) were conducted to study the effects of living hyperaccumulator plants (Solanum photeinocarpum, Tagetes erecta, Galinsoga parviflora and Bidens pilosa) and their straws on the growth and cadmium (Cd) accumulation of common plant Cyphomandra betacea seedlings. Intercropping with T. erecta or B. pilosa promoted the growth of C. betacea seedlings compared with the monoculture, while intercropping with S. photeinocarpum or G. parviflora inhibited that. Intercropping with S. photeinocarpum decreased the Cd contents in the roots and shoots of C. betacea seedlings compared with the monoculture, but intercropping with the other plants did not. In the straw mulch experiment, the straw of S. photeinocarpum or T. erecta promoted the growth of C. betacea seedlings compared with the control, while the straw of G. parviflora or B. pilosa did not. The straw of S. photeinocarpum or T. erecta decreased the Cd contents in the shoots of C. betacea seedlings, and the straw of G. parviflora or B. pilosa increased the shoot Cd contents. Thus, intercropping with S. photeinocarpum and applying S. photeinocarpum or T. erecta straw can reduce the Cd uptake of C. betacea. PMID- 29510306 TI - Accumulation and effects of copper on aquatic macrophytes Potamogeton pectinatus L.: Potential application to environmental monitoring and phytoremediation. AB - This study investigated the ability of Potamogeton pectinatus L. to accumulate copper and its effects on plants. In accumulation tests, macrophytes were exposed (96 h) to different copper concentrations (0-1000 uM) and the metal was measured in media and plant tissues (roots, stems and leaves) to determine the bioconcentration factor (BCF). Plants accumulated high concentrations of copper in a dose-dependent manner and roots was the main organ for copper accumulation. However, the more copper increased in water, the more BCF values decreased. It may be due to either saturation of copper uptake or down-regulation of metal uptake by plants. In the physiological and morphological analyses, plants were kept (96 h) in Hoagland nutrient solution without copper, in full Hoagland solution (0.5 uM Cu) and in Hoagland medium with copper from 1 to 100 uM. The absence and the presence of copper above to 1 uM inhibited photosynthesis. Chlorophylls and carotenoid levels also decreased with the excess of copper, a fact that may have affected the photosystem II-dependent of chlorophyll and caused photosynthesis suppression. Only macrophytes at 10 uM Cu showed decrease in length and number of leaves on the 10th day of the test, when they died. Chlorosis and necrosis were observed in control groups and groups with extra copper, but not in Hoalgand group. Overall, the macrophyte P. pectinatus can be considered a suitable plant for monitoring environments contaminated by copper, based on results of copper accumulation in the plant, decrease in pigment concentration and presence of chlorosis and necrosis. However, values of BCF based on fresh water tissues was not proper to indicate the use of P. pectinatus for cleaning environments contaminated by copper. PMID- 29510307 TI - Influence of soil gamma-irradiation and spiking on sorption of p,p'-DDE and soil organic matter chemistry. AB - The fate of organic chemicals and their metabolites in soils is often investigated in model matrices having undergone various pre-treatment steps that may qualitatively or quantitatively interfere with the results. Presently, effects associated with soil sterilization by gamma-irradiation and soil spiking using an organic solvent were studied in one freshly spiked soil (sterilization prior to contamination) and its field-contaminated (sterilization after contamination) counterpart for the model organic compound 1,1-Dichloro-2,2-bis(4 chlorophenyl)ethene (p,p'-DDE). Changes in the sorption and potential bioavailability of spiked and native p,p'-DDE were measured by supercritical fluid extraction (SFE), XAD-assisted extraction (XAD), and solid-phase microextraction (SPME) and linked to qualitative changes in soil organic matter (SOM) chemistry measured by diffuse reflectance infrared Fourier-transform (DRIFT) spectroscopy. Reduced sorption of p,p'-DDE detected with XAD and SPME was associated more clearly with spiking than with sterilization, but SFE showed a negligible impact. Spiking resulted in an increase of the DRIFT-derived hydrophobicity index, but irradiation did not. Spectral peak height ratio descriptors indicated increasing hydrophobicity and hydrophilicity in pristine soil following sterilization, and a greater reduction of hydrophobic over hydrophilic groups as a consequence of spiking. In parallel, reduced sorption of p,p'-DDE upon spiking was observed. Based on the present samples, gamma irradiation appears to alter soil sorptive properties to a lesser extent when compared to common laboratory processes such as spiking with organic solvents. PMID- 29510309 TI - Enantioselective degradation of ofloxacin and levofloxacin by the bacterial strains Labrys portucalensis F11 and Rhodococcus sp. FP1. AB - Fluoroquinolones are a class of antibiotics widely prescribed in both human and veterinary medicine of high environmental concern and characterized as environmental micropollutants due to their ecotoxicity and persistence and antibacterial resistance potential. Ofloxacin and levofloxacin are chiral fluoroquinolones commercialized as racemate and in enantiomerically pure form, respectively. Since the pharmacological properties and toxicity of the enantiomers may be very different, understanding the stereochemistry of these compounds should be a priority in environmental monitoring. This work presents the biodegradation of racemic ofloxacin and its (S)-enantiomer levofloxacin by the bacterial strains Labrys portucalensis F11 and Rhodococcus sp. FP1 at a laboratory-scale microcosm following the removal and the behavior of the enantiomers. Strain F11 could degrade both antibiotics almost completely when acetate was supplied regularly to the cultures. Enrichment of the (R)-enantiomer was observed in FP1 and F11 cultures supplied with ofloxacin. Racemization was observed in the biodegradation of the pure (S)-ofloxacin (levofloxacin) by strain F11, which was confirmed by liquid chromatography - exact mass spectrometry. Biodegradation of ofloxacin at 450 ug L-1 by both bacterial strains expressed good linear fits (R2 > 0.98) according to the Rayleigh equation. The enantiomeric enrichment factors were comprised between - 22.5% to - 9.1%, and - 18.7% to - 9.0% in the biodegradation of ofloxacin by strains F11 and FP1, respectively, with no significant differences for the two bacteria under the same conditions. This is the first time that enantioselective biodegradation of ofloxacin and levofloxacin by single bacteria is reported. PMID- 29510308 TI - Characteristics and health effects of BTEX in a hot spot for urban pollution. AB - This study reports a spatiotemporal characterization of toluene, benzene, ethylbenzene, and xylenes concentrations (BTEX) in an urban hot spot in Iran, specifically at an bus terminal region in Shiraz. Sampling was carried out according to NIOSH Compendium Method 1501. The inverse distance weighting (IDW) method was applied for spatial mapping. The Monte Carlo simulation technique was applied to evaluate carcinogenic and non-carcinogenic risk owing to BTEX exposure. The highest average BTEX concentrations were observed for benzene in the morning (at 7:00-9:00 A.M. local time) (26.15 +/- 17.65 ug/m3) and evening (at 6:00-8:00 P.M. local time) (34.44 +/- 15.63 ug/m3). The benzene to toluene ratios in the morning and evening were 2.02 and 3.07, respectively. The main sources of BTEX were gas stations and a municipal solid waste transfer station. The inhalation lifetime cancer risk (LTCR) for benzene in the morning and evening were 1.96 * 10-4 and 2.49 * 10-4, respectively, which exceeds the recommended value by US EPA and WHO. The hazard quotient (HQ) of all these pollutants was less than 1. The results of this work have implications for public health near 'hot spots' such as IKBT where large populations are exposed to carcinogenic emissions. PMID- 29510310 TI - Trace metals and oxidative status in soft tissues of caged mussels (Aulacomya atra) on the North Patagonian coastline. AB - This study investigated metal accumulation and oxidative effects in mantle, gill and digestive gland of the ribbed mussel Aulacomya atra from the Argentinean North Patagonian coastline. Mussels were transplanted over an 18-month period from a site with low anthropogenic impact to a harbor site with higher seawater concentration of aluminum, chromium, copper, manganese, nickel and zinc. Total trace metal concentration in seawater did not change throughout the 18-month transplant in either site. A. atra bioaccumulated metals in digestive gland, gills and mantle at different levels. Digestive gland had the highest concentration of metals, especially towards the end of the transplant experiment in the harbor area. Mussels transplanted to the harbor site experienced an upregulation in their antioxidant system, which likely explains the lack of oxidative damage to lipids despite higher metal accumulation. These results demonstrate that A. atra selectively accumulates metals from the water column and their prooxidant effects depend on the tissue antioxidant defenses and the exposure time. PMID- 29510311 TI - The humic acid-induced changes in the water status, chlorophyll fluorescence and antioxidant defense systems of wheat leaves with cadmium stress. AB - The using of bio-stimulant in plants grown under stress conditions for enhancing nutrition efficiency and crop quality traits is an effective approach. One of the bio-stimulants, humus material, is defined as humic acid (HA). HA application as a promotion of plant growth to plants grown in the heavy metals-contaminated soils has promised hope in terms of effects on plants but the its limiting effect is the application dose. Therefore, the wheat seedlings were grown in hydroponic culture for 21 d and the various concentrations of humic acid (HA; 750 or 1500 mg L-1) were treated alone or in combination with cadmium (Cd) stress (100 or 200 MUM) for 7 d. The results showed that after Cd stress treatment, water content (RWC), osmotic potential (PsiPi) and chlorophyll fluorescence parameters decreased and proline content (Pro) increased for 7 d. In spite of activated peroxidase (POX) and ascorbate peroxidase (APX), stress induced the toxic levels of hydrogen peroxide (H2O2) accumulation. Cd stress triggered lipid peroxidation (TBARS content). HA application successfully eliminated the negative effects of stress on RWC, PsiPi and photosynthetic parameters. In the presence of HA under stress, the increased activation of superoxide dismutase (SOD), catalase (CAT) and NADPH-oxidase (NOX) enzymes and ascorbate, glutathione and GSH/GSSG ratio observed. Only 750 mg L-1 HA under stress conditions induced the activities of monodehydroascorbate reductase (MDHAR) and dehydroascorbate reductase (DHAR), and dehydroascorbate (DHA) content. After the combined application of HA and Cd stress, the low contents of H2O2 and TBARS maintained in wheat leaves. Hence, HA successfully eliminated the toxicity of Cd stress by modulating the water status, photosynthetic apparatus and antioxidant activity in wheat leaves. PMID- 29510312 TI - Genotoxicity effects of silver nanoparticles on wheat (Triticum aestivum L.) root tip cells. AB - The distribution and use of nanoparticles have rapidly increased over recent years, but the available knowledge regarding their mode of action, ecological tolerance and biodegradability remains insufficient. Wheat (Triticum aestivum L.) is the most important crop worldwide. In the current study, the effects of silver nanoparticles (AgNPs) obtained from two different sources, namely, green and chemical syntheses, on chromosomal aberrations and cell division were investigated. Wheat root tips were treated with four different AgNP concentrations (10, 20, 40 and 50 ppm) for three different exposure durations (8, 16 and 24 h), and the different concentrations of the nanoparticles were added to the tested grains until the root lengths reached 1.5-2 cm. For each concentration, the mitotic indexes (%) were obtained from an analysis of ~ 2000 cells. The treated root-tip cells exhibited various types of chromosomal aberrations, such as incorrect orientation at metaphase, chromosomal breakage, metaphasic plate distortion, spindle dysfunction, stickiness, aberrant movement at metaphase, fragmentation, scattering, unequal separation, scattering, chromosomal gaps, multipolar anaphase, erosion, and distributed and lagging chromosomes. These results demonstrate that the root tip cells of wheat can readily internalize the AgNPs and that the internalized AgNPs can interfere with the cells' normal function. PMID- 29510313 TI - Effects of manufactured nano-copper on copper uptake, bioaccumulation and enzyme activities in cowpea grown on soil substrate. AB - Increased use of nanoparticles-based products in agriculture portends important implications for agriculture. Therefore, the impact of nano-copper particles (<25 nm and 60-80 nm) on Cu uptake, bioaccumulation (roots, leaves and seeds), activity of ascorbate peroxidase (APX), catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), and lipid peroxidation in leaves and roots of Vigna unguiculata (cowpea) was studied. Plants were exposed to four levels (0, 125, 500 and 1000 mg/kg) of 25 nm or 60-80 nm nano-Cu for 65 days. Results indicated significant (P<.05) uptake of Cu at all nano-Cu levels compared to control, and bioaccumulation increased in seeds by at least 250%. Response of antioxidant enzymes to both nano-Cu types was concentration-dependent. Activity of APX and GR was enhanced in leaves and roots in response to both nano-Cu treatments in similar patterns compared to control. Both nano-Cu increased CAT activity in roots while SOD activity reduced in both leaves and roots. This shows that response of antioxidant enzymes to nano-Cu toxicity was organ-specific in cowpea. Malondialdehyde, a measure of lipid peroxidation, increased at 500 -1000 mg/kg of 25 nm nano-Cu in leaves by average of 8.4%, and 60-80 nm nano-Cu in root by 52.8%, showing particle-size and organ-dependent toxicity of nano-Cu. In conclusion, exposure of cowpea to nano-Cu treatments increased both the uptake and bioaccumulation of Cu, and also promoted the activity of APX and GR in root and leaf tissues of cowpea. Therefore, APX- and GR-activity level could be a useful predictive biomarker of nano-Cu toxicity in cowpea. PMID- 29510314 TI - Whole body dosimetry and risk assessment of agricultural operator exposure to the fungicide kresoxim-methyl in apple orchards. AB - This study examined dermal and inhalation exposure of agricultural operators to kresoxim-methyl during pesticide mixing/loading and speed sprayer application (10 replicates, each of 3000 L of spray suspension) in an apple orchard and performed risk assessment. For the whole body dosimetry (WBD) exposure protocol, outer clothing, inner clothing, gauze, and nitrile gloves were examined to measure dermal exposure. In contrast, an IOM (institute of occupational medicine) sampler with a glass fiber filter was used to measure inhalation exposure. Analytical method accuracy in the exposure matrices was evaluated by a field recovery study. The dermal and inhalation exposure amounts for mixing/loading were 9.7 mg [0.002% of the total mixed/loaded active ingredient (a.i.)] and 1.2 ug (1.7 * 10-6% of the total mixed/loaded a.i.), respectively. The body parts more exposed were the forearms (35.5%), chest & stomach (30.2%), and hands (17.9%). During application, the dermal and inhalation exposure amounts were 66.5 mg (0.009% of the total applied a.i) and 34.8 ug (4.6 * 10-5% of the total applied a.i.), respectively. The shins (18.5%) and chest & stomach (16.0%) were exposed to higher proportion of pesticide, followed by the thighs (15.8%) and back (14.7%). Comparing the exposure pattern as assessed by the WBD method in the present study with the patch method as in our previous study, the ADE (actual dermal exposure) as measured by the WBD method was 25 times less than that measured by the patch method. The daily exposure amounts of ADE and AIE (actual inhalation exposure) for mixing/loading were 711.8 ug/day and 4.3 ug/day, respectively, whereas the amounts of ADE and AIE for application were 1825.8 ug/day and 116.1 ug/day. In risk assessment of the mixing/loading and application scenarios, the AOEL (acceptable operator exposure level) of kresoxim-methyl was used as the reference dose to show that the RI (risk index) was much lower than 1, indicating that agricultural operators are at low risk of exposure to kresoxim-methyl. PMID- 29510315 TI - The Upper Limb Hypermobility Assessment Tool: A novel validated measure of adult joint mobility. AB - BACKGROUND: Existing measures of generalized joint hypermobility do not include commonly affected upper limb joints. OBJECTIVE: To evaluate the reliability of a novel clinically-applicable measure of upper limb joint mobility, its ability to discriminate between varying extents of hypermobility, identify generalized joint hypermobility, and to establish a cut-point for hypermobility classification. DESIGN: Validation of a diagnostic tool. METHOD: Participants were sought from three groups - healthy controls, likely and known hypermobiles, and assessed using the Upper Limb Hypermobility Assessment Tool (ULHAT), Beighton score and clinical opinion. Pearson's correlation coefficient examined individual group and whole cohort relationships between upper limb hypermobility, age, gender and ethnicity. MANOVA investigated between-group differences in ULHAT scores. Median interquartile ranges and ROC Curve analysis identified the cut-off score for identification of upper limb hypermobility. Percent agreement with clinical opinion assessed the ability of the ULHAT to identify generalized joint hypermobility. RESULTS: 112 adult participants (mean age 24.3 +/- 5.5years) across the three groups were assessed. Inter-rater reliability of the tool was high (ICC2,1 = 0.92). The cut-point was established at >=7/12 (sensitivity 0.84, specificity 0.77, +LR 3.7, -LR 0.2). Upper limb hypermobility did not vary with age or ethnicity (both p > 0.12), but was greater in females (p < 0.001). The ULHAT discriminated between the three groups and identified generalized hypermobility. CONCLUSIONS: The 12-item ULHAT measures mobility of multiple upper limb joints in all movement planes. Using a cut-off of >=7/12 in adults, the ULHAT is a reliable and valid tool for identifying upper limb hypermobility and generalized joint hypermobility. PMID- 29510317 TI - What have we learnt from studying the evolution of the arbuscular mycorrhizal symbiosis? AB - The arbuscular mycorrhizal (AM) symbiosis is a nearly ubiquitous association formed by most land plants. Numerous insights into the molecular mechanisms governing this symbiosis have been obtained in recent years leading to the identification of a core set of plant genes essential for successful formation of the AM symbiosis by angiosperm hosts. Recent phylogenetic analyses indicate that while the origin of some of these symbiotic genes predated the first land plants, the rest appeared through processes including de novo evolution and gene duplication that occurred specifically in the land plants. Purifying selection on this core gene set has been maintained over millions of years of plant evolution to conserve the AM symbiosis. However, several independent losses of this association have been recorded in numerous embryophyte lineages. In these lineages, potential compensatory mechanisms have been identified that could have helped these plants overcome the adversities imposed by the loss of the AM symbiosis. This review will focus on the processes governing the conservation of the AM symbiosis in the land plant lineage. PMID- 29510316 TI - The effectiveness of physical therapies for patients with base of thumb osteoarthritis: Systematic review and meta-analysis. AB - BACKGROUND: Trapeziometacarpal osteoarthritis (known as base of thumb OA) is a common condition causing pain and disability worldwide. OBJECTIVE: The purpose of this review was to evaluate the effectiveness of multimodal and unimodal physical therapies for base of thumb osteoarthritis (OA) compared with usual care, placebo or sham interventions. DESIGN: Systematic review and meta-analysis. METHOD: We searched MEDLINE (PubMed), CINAHL, Embase, AMED, PEDro, Cochrane Database of Systematic Review, Cochrane Register of Controlled Trials (CENTRAL) from inception to May 2017. Randomized controlled trials involving adults comparing physical therapy treatment for base of thumb OA with an inactive control (placebo or sham treatment) and reported pain, strength or functional outcomes were included. Meta-analyses were performed where possible. Methodological risk of bias was assessed with the Cochrane Risk of Bias tool. RESULTS: Five papers with low risk of bias were included. Meta-analyses of mean differences (MD) with 95% confidence intervals (95% CI), were calculated for between-group differences in point estimates at 4 weeks post-intervention. Multimodal and unimodal physical therapies resulted in clinically worthwhile improvements in pain intensity (MD 2.9 [95% CI 2.8 to 3.0]; MD 3.1 [95% CI 2.5 to 3.8] on a 0-10 scale, respectively). Hand function improved following unimodal treatments (MD 6.8 points [95% CI 1.7 to 11.9)] on a 0-100 scale) and after a multimodal treatment (MD 20.5 (95%CI -0.7 to 41.7). CONCLUSIONS: High quality evidence shows unimodal and multimodal physical therapy treatments can result in clinically worthwhile improvements in pain and function for patients with base of thumb OA. PMID- 29510318 TI - Parabens in human urine from several Asian countries, Greece, and the United States. AB - Parabens, esters of para-hydroxybenzoic acid, are commonly used as antimicrobial preservatives in cosmetics and personal care products. Although several studies report exposure of humans to parabens in Western countries, little is known about exposure of humans to parabens in Asian countries. In this study, we determined concentrations of six parabens in spot urine samples collected from nine countries and estimated daily intakes (DI) and potential health risks of parabens. Ethyl-paraben, methyl-paraben, and propyl-paraben were detected frequently at 100, 98.0, and 80.3%, respectively, with representative median concentrations of 0.68, 7.02, and 1.21 ng/mL, respectively, for all nine countries. Urine samples from females (total median concentration: 32.3 ng/mL) contained significantly higher concentrations of parabens than did those from males (5.46 ng/mL). Urine samples from Korea (total median paraben concentration: 227 ng/mL) had the highest concentrations, which were one to two orders of magnitude higher than those found in other countries (3.67-29.1 ng/mL). The estimated DI of parabens (on the basis of concentrations measured in urine) varied widely, and several samples had propyl-paraben exposures above the acceptable DI. Our results suggest that paraben exposure is ubiquitous in Asian countries, and further assessment of potential health risk of these chemicals is needed. PMID- 29510319 TI - Fate of inorganic nitrogen species under homogeneous Fenton combined with electro oxidation/reduction treatments in synthetic solutions and reclaimed municipal wastewater. AB - The fate of inorganic nitrogen species has been studied for the first time in electro-Fenton (EF) conditions in acid media. A redox cycle is first obtained and validated with a kinetic model in synthetic solution and highlights the removal of nitrite that is quickly oxidized into nitrate while the reduction conditions are sufficient to reduce nitrate into ammonium cation. However, NH4+ and gaseous nitrogen accumulate in such solution. The study in reclaimed municipal wastewater emphasize the removal of NH4+ with formation of chloramines in the presence of initial chloride ions, a species widely present in wastewater effluent. Contrastingly, NO3- remain constant all along the electrolysis even after 2.1 Ah L-1. The oxidation conditions were not sufficient to produce perchlorate while chlorate accumulated in solution. Therefore, it limits the use of EF for direct use for drinking water purpose but could be considered as complementary treatment for wastewater reuse applications. PMID- 29510320 TI - Bone fragment segmentation from 3D CT imagery. AB - This paper presents a novel method to segment bone fragments imaged using 3D Computed Tomography (CT). Existing image segmentation solutions often lack accuracy when segmenting internal trabecular and cancellous bone tissues from adjacent soft tissues having similar appearance and often merge regions associated with distinct fragments. These issues create problems in downstream visualization and pre-operative planning applications and impede the development of advanced image-based analysis methods such as virtual fracture reconstruction. The proposed segmentation algorithm uses a probability-based variation of the watershed transform, referred to as the Probabilistic Watershed Transform (PWT). The PWT uses a set of probability distributions, one for each bone fragment, that model the likelihood that a given pixel is a measurement from one of the bone fragments. The likelihood distributions proposed improve upon known shortcomings in competing segmentation methods for bone fragments within CT images. A quantitative evaluation of the bone segmentation results is provided that compare our segmentation results with several leading competing methods as well as human generated segmentations. PMID- 29510321 TI - The use of gamma-rays analysis by HPGe detector to assess the gross alpha and beta activities in waters. AB - This paper describes an alternative method for evaluating gross alpha and beta radioactivity in waters by using gamma-rays analysis performed with hyper-pure germanium detector (HPGe). Several gamma emissions related to alpha and beta- decays were used to provide the activity concentration data due to natural radionuclides commonly present in waters like 40K and those belonging to the 238U and 232Th decay series. The most suitable gamma emissions related to beta- decays were 214Bi (1120.29 keV, 238U series) and 208Tl (583.19 keV, 232Th series) as the equation in activity concentration yielded values compatible to those generated by the formula taking into account the detection efficiency. The absence of isolated and intense gamma-rays peaks associated to alpha decays limited the choice to 226Ra (186.21 keV, 238U series) and 224Ra (240.99 keV, 232Th series). In these cases, it was adopted appropriate correction factors involving the absolute intensities and specific activities for avoiding the interferences of other gamma-rays energies. The critical level of detection across the 186-1461 keV energy region corresponded to 0.010, 0.023, 0.038, 0.086, and 0.042 Bq/L, respectively, for 226Ra, 224Ra, 208Tl, 214Bi and 40K. It is much lower than the WHO guideline reference value for gross alpha (0.5 Bq/L) and beta (1.0 Bq/L) in waters. The method applicability was checked by the analysis of groundwater samples from different aquifer systems occurring in the Brazilian states of Sao Paulo, Minas Gerais and Mato Grosso do Sul. The waters exhibit very different chemical composition and the samples with the highest radioactivity levels were those associated with lithotypes possessing enhanced uranium and thorium levels. The technique allowed directly discard the 40K contribution to the gross beta activity as potassium is an essential element for humans. PMID- 29510322 TI - Paradoxical role of tumor necrosis factor on metabolic dysfunction and adipose tissue expansion in mice. AB - OBJECTIVES: Tumor necrosis factor (TNF) is a well-known cytokine that triggers insulin resistance during obesity development. On the other hand, it is also known that TNF induces a fat mass loss during acute diseases. However, whether TNF has a protective and physiological role to control adipose tissue expansion during obesity still needs to be verified. The aim of this study was to evaluate whether the ablation of TNF receptor 1 (TNFR1) alters fat mass and insulin resistance induced by a highly refined carbohydrate-containing (HC) diet. METHODS: Male C57 BL/6 wild-type (WT) mice and TNFR1 knockout (TNFR1-/-) mice were fed with chow or with the HC diet for 16 wk. RESULTS: TNFR1-/- mice gained more body weight than the WT groups independent of the diet composition. TNFR1-/- mice fed with the chow diet showed higher adiposity, accompanied by higher serum leptin levels. However, these mice showed lower non-esterified fatty acid levels. Furthermore, TNFR1-/- mice had suppressed TNF, interleukin (IL)-6, and IL-10 levels in adipose tissue compared with WT mice. TNFR1-/- mice fed with the HC diet were protected from increased adiposity and glucose intolerance induced by the HC diet and exhibited lower serum resistin levels. CONCLUSIONS: TNF signaling appears to have a paradoxical role on metabolism. Ablation of TNFR1 leads to a reduction of inflammatory cytokines in adipose tissue that is accompanied by higher adiposity in mice fed with chow diet. However, when these mice are given the HC diet, the loss of TNFR1 improves insulin sensitivity and protects mice against additional fat mass. PMID- 29510323 TI - Aging effects on leg joint variability during walking with balance perturbations. AB - BACKGROUND: Older adults are more susceptible to balance perturbations during walking than young adults. However, we lack an individual joint-level understanding of how aging affects the neuromechanical strategies used to accommodate balance perturbations. RESEARCH QUESTION: We investigated gait phase dependence in and aging effects on leg joint kinematic variability during walking with balance perturbations. We hypothesized that leg joint variability would: 1) vary across the gait cycle and 2) increase with balance perturbations. We also hypothesized that perturbation effects on leg joint kinematic variability would be larger and more pervasive in older versus young adults. METHODS: We collected leg joint kinematics in young and older adults walking with and without mediolateral optical flow perturbations of different amplitudes. RESULTS: We first found that leg joint variability during walking is gait phase-dependent, with step-to-step adjustments occurring predominantly during push-off and early swing. Second, young adults accommodated perturbations almost exclusively by increasing coronal plane hip joint variability, likely to adjust step width. Third, perturbations elicited larger and more pervasive increases in all joint kinematic outcome measures in older adults. Finally, we also provide insight into which joints contribute more to foot placement variability in walking, adding that variability in sagittal plane knee and coronal plane hip joint angles contributed most to that in step length and step width, respectively. SIGNIFICANCE: Taken together, our findings may be highly relevant to identifying specific joint-level therapeutic targets to mitigate balance impairment in our aging population. PMID- 29510324 TI - A survey of dietary characteristics in a large population of people with multiple sclerosis. AB - INTRODUCTION: Dietary approaches to management of MS has been proposed for several decades, yet very little is known concerning dietary composition or adherence to specialized diets in people with multiple sclerosis (MS). METHODS: We conducted a survey of participants in the North American Research Committee on MS (NARCOMS) registry assessing diet composition and the prevalence of 19 different diets. We characterized prevalence of different diets and compared diet composition with estimated intakes from the National Health and Nutrition Examination Survey (NHANES) survey respondents and across demographics and MS clinical characteristics. RESULTS: Among the 7639 (68%) responders, 6990 provided sufficient information on diet to be included in the analysis. Compared to NHANES participants, responders tended to have comparable intakes of fruit, vegetables and legumes (mean [SD] 2.5 [1.0] servings/day) and whole grains (0.9 [1.3] servings/day) and consume less added sugar (NARCOMS: 9.7 [6.0] vs. NHANES: 18.5[13.5] tsp/day; P < 0.001) and more red meat (NARCOMS: 0.50 [0.47] vs. NHANES: 0.35 [0.97] servings/day; P < 0.001). Of the 3120 (45%) participants who reported any history of following a specific diet, commonly-followed diets were: low-sugar (n = 642), low-carbohydrate (n = 508) and low-calorie (n = 475). Those with no history of following any specific diet were more likely to have progressive MS, be more obese, have worse overall diet quality, not participate in physical activity and smoke (all P < 0.001). CONCLUSIONS: In this large survey, we found that diet composition in MS patients may vary by demographic and disease characteristics. PMID- 29510325 TI - Could antiretrovirals be treating EBV in MS? A case report. AB - We present the case of an HIV-negative patient clinically diagnosed with relapsing-remitting MS who achieved significant disease improvement on Combivir (zidovudine/lamivudine). Within months of treatment, the patient reported complete resolution of previously unremitting fatigue and paresthesiae, with simultaneous improvements in lesion burden detected by MRI. All improvements have been sustained for more than three years. This response may be related to the action of zidovudine as a known inhibitor of EBV lytic DNA replication, suggesting future directions for clinical investigation. PMID- 29510326 TI - Free radical synthesis of nanosilver/gelatin-poly (acrylic acid) nanocomposite hydrogels employed for antibacterial activity and removal of Cu(II) metal ions. AB - The present work involves the synthesis of porous gelatin/AcA (PGE-AcA) hydrogel and novel porous gelatin-silver/AcA (NPGESNC-AcA) nanocomposite hydrogel, and their ability as effective biosorbents for the removal of Cu2+ ions from contaminated water. The formation of the samples was confirmed by UV-Vis, TEM, SEM, EDX, DLS, AFM, XRD, TGA/DTG and FTIR techniques. The adsorption studies results showed that maximum monolayer adsorption capacity of copper ions for PGE AcA was achieved about 130.50 mg g-1 in pH 6.0 for 50 min, and adsorption capacity for the NPGESNC-AcA was nearly 147.10 mg g-1 in pH 5.5 for 40 min by atomic absorption spectroscopy technique. The Cu2+ ions loaded on the PGE-AcA and NPGESNC-AcA could be recovered by HCl above 65.8% and 78.7% after five consecutive cycles of adsorption/desorption, respectively. The results showed that the both of biosorbents loaded by Cu2+ ions could be easily regenerated and reusable. On the other hand, the results of adsorption kinetics and equilibrium isotherms were indicated high correlation coefficient (closer to a unit) for the pseudo-second-order and excellent fitted the adsorption data with the Langmuir isotherm model. Furthermore, the antimicrobial efficiency of the synthesized samples were tested on the Staphylococcus aureus and the Escherichia coli. PMID- 29510327 TI - Enhancement of surfactant efficacy during the cleanup of engine oil contaminated soil using salt and multi-walled carbon nanotubes. AB - The study aims to enhance the efficacy of surfactants using salt and multi-walled carbon nanotubes (MWCNT) for washing used engine oil (UEO) contaminated soil and compare the geotechnical properties of contaminated soil before and after washing (batch washing and soil washing). From batch washing of the contaminated soil the efficacy of the cleaning process is established. Contamination of soil with hydrocarbons present in UEO significantly affects its' engineering properties manifesting in no plasticity and low specific gravity; the corresponding optimum moisture content value is 6.42% while maximum dry density is 1.770 g/cc, which are considerably lower than those of the uncontaminated soil. The result also showed decrease in the values of cohesion intercept and increase in the friction angle values. The adopted soil washing technique resulted increase in specific gravity from 1.85 to 2.13 and cohesion from 0.443 to 1.04 kg/cm2 and substantial decrease in the friction angle from 31.16 degrees to 17.14 degrees when washed with most efficient combination of SDS surfactant along with sodium meta-silicate (salt) and MWCNT. Effectiveness of the washing of contaminated soil by batch processing and soil washing techniques has been established qualitatively. The efficiency of surfactant treatment has been observed to be increased significantly by the addition of salt and MWCNT. PMID- 29510328 TI - Multiparameter analysis of activated sludge inhibition by nickel, cadmium, and cobalt. AB - Activated sludge processes are often inhibited by nickel, cadmium, and cobalt. The inhibitory effect of these heavy metals on a synthetic wastewater treatment process was tested through pulse microrespirometry; i.e., pulse of substrate injected in a microreactor system. The inhibitory effect was tested under different conditions including the heavy metals, substrate and biomass concentrations, and exposure time. The inhibitory effect was quantified by the percentage of inhibition, half saturation constant (KS), inhibition constant (KI), and maximum oxygen uptake rate (OURmax). The results indicated that, in a range of concentration from 0 to 40 mg L-1, the three heavy metals exerted an uncompetitive and incomplete inhibitory effect, with a maximum inhibition of 67, 57, and 53% for Ni, Co, and Cd, respectively. An increase of the biomass concentration by 620% resulted in a decrease of the inhibition by 47 and 69% for Co and Cd, respectively, while no effect was observed on Ni inhibition. An increase of the substrate concentration by 87% resulted in an increase of the inhibition by 24, 70, and 47% for Ni, Co and Cd, respectively. In the case of nickel and cadmium, an increase in the exposure time to the heavy metals also increased the inhibition. PMID- 29510329 TI - LC-MS/MS method for the determination of the prodrug aripiprazole lauroxil and its three metabolites in plasma and its application to in vitro biotransformation and animal pharmacokinetic studies. AB - A sensitive and selective LC-MS/MS method for determination of the prodrug aripiprazole lauroxil (AL) and the three metabolites (N-hydroxymethyl aripiprazole [NHA], aripiprazole [ARP], and dehydro aripiprazole [DHA]) in plasma was developed using ARP-d8 as an internal standard. The analytes were determined on an AB Sciex Triple QuadTM 4500 system using positive ion electrospray ionization and selected multiple reaction monitoring mode. Solid phase extraction was applied for sample preparation for AL, ARP, and DHA, and protein precipitation for NHA. Chromatographic separation was performed on an Agilent Eclipse XDB-CN column (100 * 2.1 mm i.d., 3.5 MUm) using the mobile phase of water and acetonitrile (25:75, v/v) containing 0.1% formic acid with a flow rate of 0.5 mL/min. The linear ranges for AL, NHA, ARP, and DHA were 0.5-50 ng/mL, 1.0 50 ng/mL, 0.5-50 ng/mL, and 0.05-5.0 ng/mL, respectively. The average recovery in the plasma sample was stable and reproducible. The precision and accuracy of the intra- and inter-run were within assay variability criteria limits. The developed method was suitable for in vitro biotransformation studies in plasma and animal pharmacokinetic studies after intramuscular injection of AL formulations. PMID- 29510330 TI - Morphology and systematics of two freshwater Frontonia species (Ciliophora, Peniculida) from northeastern China, with comparisons among the freshwater Frontonia spp. AB - The morphology and infraciliature of two Frontonia species, F. shii spec. nov. and F. paramagna Chen et al., 2014, isolated from a freshwater pond in northeastern China, were investigated using living observation and silver staining methods Frontonia shii spec. nov. is recognized by the combination of the following characters: freshwater Frontonia, size in vivo about 220-350 * 130 250 MUm, elliptical in outline; 128-142 somatic kineties; three or four vestibular kineties, six or seven postoral kineties; peniculi 1-3 each with four kineties; single contractile vacuole with about 10 collecting canals. The improved diagnosis for F. paramagna is based on the current and previous reports. Comparisons among freshwater Frontonia are also provided. The small subunit ribosomal rRNA gene (SSU rDNA) sequences of the two species are characterized and phylogenetic analyses based on these sequences show that both species fall into the core clade of the genus Frontonia, and this genus is not monophyletic. PMID- 29510331 TI - Systematic review of wound healing biomarkers in peri-implant crevicular fluid during osseointegration. AB - OBJECTIVE: To quantify and characterize the role of biomarkers in peri-implant crevicular fluid (PICF) at each stage of healing during osseointegration. DESIGN: This systematic review was performed in accordance with PRISMA guidelines using several databases: MedLine (PubMed), Embase, ISI Web of Science, Scopus, and Cochrane Library. Medical subject headings and their indexers were used with no other limitations until December 2017. The dataset was extended with relevant papers from the reference lists of selected papers and from the gray literature. Data was summarized for study objectives, patient demographics, methods used to analyze PICF, biomarker concentrations, results and main findings. Methodologic quality of each included study was assessed using the checklist created by Downs and Black. RESULTS: Electronic search resulted in 1698 articles. After excluding the duplicates, reading titles, abstracts and reference list reviews 30 prospective studies with longitudinal follow-up were selected. In total, 52 different biomarkers were identified. The most studied cytokines were interleukin (IL)-1, IL-1beta, tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO). The earliest PICF specimens were collected immediately after implantation, and the latest at 16 weeks prior to occlusal loading. 36 biomarkers were quantified during week 1, 49 between day 10 and week 6, and 49 between weeks 8 and 12. Only 5 articles received good quality ratings. CONCLUSION: The mechanism by which inflammatory and bone biomarkers are released during osseointegration has not yet been identified. However, some hypotheses based on immune-modulated reactions are being explored to investigate early and asymptomatic implant failures. Given the available clinical studies, it was not possible to further explore the performance of all biomarkers already analyzed and to extrapolate their results to propose a consultable data system based on release volume or concentration because of clinical study and data heterogeneity. PMID- 29510332 TI - Emerging platforms for co-utilization of one-carbon substrates by photosynthetic organisms. AB - One-carbon substrates have generated increasing attention as long-term sustainable feedstocks for biobased production of fuels and chemicals. However, their physicochemical properties present significant biological and operational challenges for commercial bioprocesses including kinetically slower substrate activation, high energetic cost of assimilation, low mass transfer, substrate toxicity, and low productivity titers. Several different routes including optimization of native pathways, synthetic pathways, and hybrid methods are being explored to overcome these challenges. Integration of emerging biological solutions with process improvements is enabling faster bioprocess development for cost-effective conversion of one-carbon substrates into fuels and chemicals. PMID- 29510333 TI - Networks of protein-protein interactions among structural proteins of budded virus of Bombyx mori nucleopolyhedrovirus. AB - The structural proteins of baculovirus are well studied, but the interactions between them remain unclear. In order to reveal protein-protein interactions among viral structural proteins and their associated proteins of the budded virus of Bombyx mori nucleopolyhedrovirus (BmNPV), the yeast two hybrid (Y2H) system was used to evaluate the interactions of 27 viral genes products. Fifty-seven interactions were identified with 51 binary interactions and 6 self-associations. Among them, 10 interactions were further confirmed by co-immunoprecipitation assays. Five interaction networks were formed based on the direct-cross Y2H assays. VP39, 38 K, and FP were identified to interact with most of the viral proteins, and may form major structural elements of the viral architecture. In addition, each envelope protein was detected to interact with more than one capsid protein. These results suggest how viral structural and structural associated proteins may assemble to form a complete virus through interacting with each other. PMID- 29510334 TI - A 472-SNP panel for pairwise kinship testing of second-degree relatives. AB - Kinship testing based on genetic markers, as forensic short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs), has valuable practical applications. Paternity and first-degree relationship can be accurately identified by current commonly-used forensic STRs and reported SNP markers. However, second-degree and more distant relationships remain challenging. Although ~105-106 SNPs can be used to estimate relatedness of higher degrees, genome-wide genotyping and analysis may be impractical for forensic use. With rapid growth of human genome data sets, it is worthwhile to explore additional markers, especially SNPs, for kinship analysis. Here, we reported an autosomal SNP panel consisted of 342 SNP selected from >84 million SNPs and 131 SNPs from previous systems. We genotyped these SNPs in 136 Chinese individuals by multiplex amplicon Massively Parallel Sequencing, and performed pairwise gender-independent kinship testing. The specificity and sensitivity of these SNPs to distinguish second-degree relatives and the unrelated was 99.9% and 100%, respectively, compared with 53.7% and 99.9% of 19 commonly-used forensic STRs. Moreover, the specificity increased to 100% by the combined use of these STRs and SNPs. The 472-SNP panel could also greatly facilitate the discrimination among different relationships. We estimated that the power of ~6.45 SNPs were equivalent to one forensic STR in the scenario of 2nd-degree relative pedigree. Altogether, we proposed a panel of 472 SNP markers for kinship analysis, which could be important supplementary of current forensic STRs to solve the problem of second-degree relative testing. PMID- 29510335 TI - Oxidative modification of methionine80 in cytochrome c by reaction with peroxides. AB - The Met80-heme iron bond of cytochrome c (cyt c) is cleaved by the interaction of cyt c with cardiolipin (CL) in membranes. The Met80 dissociation enhances the peroxidase activity of cyt c and triggers cyt c release from mitochondrion to the cytosol at the early stage of apoptosis. This paper demonstrates the selective oxidation of Met80 for the reaction of ferric cyt c with a peroxide, meta chloroperbenzoic acid (mCPBA), in the presence of CL-containing liposomes by formation of a ferryl species (Compound I). After the reaction of cyt c with mCPBA in the presence of 1,2-dioloeyl-sn-glycero-3-phosphocholine (DOPC) liposomes containing CL, the electrospray ionization mass spectrum of the peptide fragments, obtained by digestion of cyt c with lysyl endopeptidase, exhibited a peak at m/z = 795.45; whereas, this peak was not observed for the peptide fragments obtained after the reaction in the presence of DOPC liposomes not containing CL. According to the tandem mass spectrum of the m/z = 795.45 peptide fragment, Met80 was modified with a 16 Da mass increase. The purified Met80 modified cyt c exhibited a peroxidase activity more than 5-fold higher than that of the unmodified protein. Transient absorption bands around 650 nm were generated by the reactions with mCPBA for ferric wild-type cyt c in the presence of CL-containing DOPC liposomes and ferric Y67F cyt c in the absence of liposomes. The formation and decomposition rates of the 650-nm absorption species increased and decreased, respectively, by increasing the mCPBA concentration in the reaction, indicating transient formation of Compound I. PMID- 29510336 TI - Nickel(II) bis(isatin thiosemicarbazone) complexes induced apoptosis through mitochondrial signaling pathway and G0/G1 cell cycle arrest in IM-9 cells. AB - Three novel complexes (1, 3 and 4) ligating N-substituted isatin thiosemicarbazone derivatives have been synthesized and their structural and biological characteristics have been compared with those of the known analogs (2, 5-7 and 8). In addition, the structure of the representative ligands (L1, L3 and L4) and complex (4) was confirmed by single crystal X-ray diffraction method. All the complexes (1-8) were assessed for their cytotoxic property against a panel of four human cancer cells such as HepG-2 (liver), MOLM-14 (acute monocytic leukemia), U937 (histiocytic lymphoma). and IM-9 (myeloma). Complex 4 exhibited prominent cytotoxic property against MOLM-14, U937 and IM-9 cell lines. Moreover, the results were compared with the well-known anticancer drugs like doxorubicin, cisplatin and daunorubicin. Besides, complex 4 enhanced the apoptotic cell death in IM-9 cell line and induced cell cycle arrest at G1 phase. Western blot analysis revealed the down-regulation of Bcl-2 (b-cell lymphoma-2), up-regulation of Bax (bcl-2 associated X protein), release of cytochrome c and activation of caspases-3 in IM-9 cells by complex 4. Importantly, complex 4 was not toxic to the normal Vero cell line (IC50 > 300 MUM). In addition, complex 4 showed the concentration dependent cleavage of supercoiled (SC) DNA to its nicked circular (NC) form. PMID- 29510337 TI - Emotional sound symbolism: Languages rapidly signal valence via phonemes. AB - Rapidly communicating the emotional valence of stimuli (i.e., negativity or positivity) is vital for averting dangers and acquiring rewards. We therefore hypothesized that human languages signal emotions via individual phonemes (emotional sound symbolism), and more specifically that the phonemes at the beginning of the word signal its valence, as this would maximize the receiver's time to respond adaptively. Analyzing approximately 37,000 words across five different languages (English, Spanish, Dutch, German, and Polish), we found emotional sound symbolism in all five languages, and within each language the first phoneme of a word predicted its valence better than subsequent phonemes. Moreover, given that averting danger is more urgent than acquiring rewards, we further hypothesized and demonstrated that phonemes that are uttered most rapidly tend to convey negativity rather than positivity. Thus, emotional sound symbolism is an adaptation providing an early warning system in human languages, analogous to other species' alarm calls. PMID- 29510338 TI - mcrA sequencing reveals the role of basophilic methanogens in a cathodic methanogenic community. AB - Cathodic methanogenesis is a promising method for accelerating and stabilising bioenergy recovery in anaerobic processes. The change in composition of microbial (especially methanogenic) communities in response to an applied potential-and especially the associated pH gradient-is critical for achieving this goal, but is not well understood in cathodic biofilms. We found here that the pH-polarised region in the 2 mm surrounding the cathode ranged from 6.9 to 10.1, as determined using a pH microsensor; this substantially affected methane production rate as well as microbial community structure. Miseq sequencing data of a highly conserved region of the mcrA gene revealed a dramatic variation in alpha diversity of methanogens concentrated in electrode biofilms under the applied potential, and confirmed that the dominant microbes at the cathode were hydrogenotrophic methanogens (mostly basophilic Methanobacterium alcaliphilum). These results indicate that regional pH variation in the microenvironment surrounding the electrode is an ecological niche enriched with Methanobacterium. PMID- 29510339 TI - A comparative meta-genomic analysis of HPV strains: A step towards the design, synthesis and characterization of noval quenazoline derivative for antiviral activity. AB - Epigenetic characterization studies have clearly shown that the association of genital Human Papilloma Virus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. Even though all the strains of Human Papilloma Virus can cause cancer, the high-risk strains can cause severe cancer in a human. The E6 and E7 protein are responsible for the carcinogenic property of HPV. Among these two proteins, the HPV E7 protein plays a major role in the viral life cycle by allowing the virus to replicate in differentiating epithelial cells. All the strains of HPV are variants (High risk and low risk). A computational analysis study is done to find which low-risk strain is showing most similarity with the high risk there by predicting that this low-risk strain can be converted to high-risk if a mutation occurs in future. Through mutation, a normal strain will get converted to low-risk and a low-risk to high-risk. So the mutations are important and it can affect the viruses to a greater extent because of their smaller size. In order to inhibit the expression of Type 11 low-risk strain a noval suppressor molecule is synthesized and characterized using UV, FTIR and NMR spectrometry. The suppressor molecule is a quinazoline derivative, as it can act as an anti-cancer agent to inhibit the expression of the E7 protein in Type 11 strain. The efficiency of binding of type 11 E7 protein with quinazoline derivative is calculated through docking studies using G-Score (Schrodinger). Thus proposing this noval suppressor molecule can be lead against cervical cancer caused by HPV Type 11 strain after further in-vitro and in vivo characterization. PMID- 29510340 TI - Effect of Cu on microstructure, mechanical properties, corrosion resistance and cytotoxicity of CoCrW alloy fabricated by selective laser melting. AB - In the study, CoCrWCu alloys with differing Cu content (2, 3, 4 wt%) were prepared by selective laser melting using mixture powders consisting of CoCrW and Cu, aiming at investigating the effect of Cu on the microstructures, mechanical properties, corrosion behavior and cytotoxicity. The SEM observations indicated that the Cu content up to 3 wt% caused the Si-rich precipitates to segregate along grain boundaries and in the grains, and EBSD analysis suggested that the Cu addition decreased the recrystallization degree and increased the grain diameter and fraction of big grains. The tensile tests found that the increasing Cu content led to a decrease of mechanical properties compared with Cu-free CoCrW alloy. The electrochemical tests revealed that the addition of Cu shifted the corrosion potential toward nobler positive, but increased the corrosion current density. Also, a more protective passive film was formed when 2 wt% Cu content was added, but the higher Cu content up to 3 wt% was detrimental to the corrosion resistance. It was noted that there was no cytotoxicity for Cu-bearing CoCrW alloys to MG-63 cell and the cells could spread well on the surfaces of studied alloys. Meanwhile, the Cu-bearing CoCrW alloy exhibited an excellent antibacterial performance against E.coli when Cu content was up to 3 wt%. It is suggested that the feasible fabrication of Cu-bearing CoCrW alloy by SLM using mixed CoCrW and Cu powders is a promising candidate for use in antibacterial oral repair products. This current study also can aid in the further design of antibacterial Cu-containing CoCrW alloying powders. PMID- 29510341 TI - Genetic architecture of obesity and related metabolic traits-recent insights from isolated populations. AB - In this mini-review, we give an overview of what is known about the genetic architecture of obesity and related metabolic traits with a primary focus on recent insights from studies of historically small and isolated populations. We start by briefly explaining what genetic architecture is and why studies of isolated populations in general are valuable if we want a complete picture of the genetic architecture of diseases and other traits among humans. Then we contrast what is known about the genetic architecture of obesity and related metabolic traits among large outbred populations, like Europeans, with results from recent studies of isolated populations. Finally, we briefly discuss the perspectives of studying isolated populations to gain insight into genetic architecture in humans. PMID- 29510344 TI - A comparative study on cardiovascular disease risk factors in Korean adults according to clinical depression status. AB - This study was conducted to compare the association between depression and cardiovascular disease risk factors among Korean adults. This study was based on the data from the Korea National Health and Nutrition Examination Survey conducted in 2012-2014. Using a multivariable logistic regression model, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). A total of 10,359 subjects aged 19-64 years were selected, and 432 subjects (74 men, 358 women) were included in the physician-diagnosed depression group. Several cardiovascular risk factors were associated with higher odds of clinical depression. For men, high waist circumference (>=91.3 cm) and body mass index (>=25.0 kg/m2) were significantly associated with increased odds of depression, and high physical activity (>=50 MET h/week) was associated with decreased odds of depression. Men with dyslipidemia and metabolic syndrome had 2.43-fold and 2.0 fold higher odds of depression than those without the diseases. For women, current smokers had 2.25-fold higher odds of depression than nonsmokers, and frequent alcohol drinkers (>=4 times/week) also had 2.88-fold higher odds of depression than nondrinkers. Korean adults with clinical depression had a higher prevalence of some risk factors for cardiovascular diseases than those without depression. PMID- 29510342 TI - Uric acid disrupts hypochlorous acid production and the bactericidal activity of HL-60 cells. AB - Uric acid is the end product of purine metabolism in humans and is an alternative physiological substrate for myeloperoxidase. Oxidation of uric acid by this enzyme generates uric acid free radical and urate hydroperoxide, a strong oxidant and potentially bactericide agent. In this study, we investigated whether the oxidation of uric acid and production of urate hydroperoxide would affect the killing activity of HL-60 cells differentiated into neutrophil-like cells (dHL 60) against a highly virulent strain (PA14) of the opportunistic pathogen Pseudomonas aeruginosa. While bacterial cell counts decrease due to dHL-60 killing, incubation with uric acid inhibits this activity, also decreasing the release of the inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF- alpha). In a myeloperoxidase/Cl-/H2O2 cell-free system, uric acid inhibited the production of HOCl and bacterial killing. Fluorescence microscopy showed that uric acid also decreased the levels of HOCl produced by dHL-60 cells, while significantly increased superoxide production. Uric acid did not alter the overall oxidative status of dHL-60 cells as measured by the ratio of reduced (GSH) and oxidized (GSSG) glutathione. Our data show that uric acid impairs the killing activity of dHL-60 cells likely by competing with chloride by myeloperoxidase catalysis, decreasing HOCl production. Despite diminishing HOCl, uric acid probably stimulates the formation of other oxidants, maintaining the overall oxidative status of the cells. Altogether, our results demonstrated that HOCl is, indeed, the main relevant oxidant against bacteria and deviation of myeloperoxidase activity to produce other oxidants hampers dHL-60 killing activity. PMID- 29510343 TI - S-phase Specific Downregulation of Human O6-Methylguanine DNA Methyltransferase (MGMT) and its Serendipitous Interactions with PCNA and p21cip1 Proteins in Glioma Cells. AB - Whether the antimutagenic DNA repair protein MGMT works solo in human cells and if it has other cellular functions is not known. Here, we show that human MGMT associates with PCNA and in turn, with the cell cycle inhibitor, p21cip1 in glioblastoma and other cancer cell lines. MGMT protein was shown to harbor a nearly perfect PCNA-Interacting Protein (PIP box) motif. Isogenic p53-null H1299 cells were engineered to express the p21 protein by two different procedures. Reciprocal immunoprecipitation/western blotting, Far-western blotting, and confocal microscopy confirmed the specific association of MGMT with PCNA and the ability of p21 to strongly disrupt the MGMT-PCNA complexes in tumor cells. Alkylation DNA damage resulted in a greater colocalization of MGMT and PCNA proteins, particularly in HCT116 cells deficient in p21 expression. p21 expression in isogenic cell lines directly correlated with markedly higher levels of MGMT mRNA, protein, activity and greater resistance to alkylating agents. In other experiments, four glioblastoma cell lines synchronized at the G1/S phase using either double thymidine or thymidine-mimosine blocks and subsequent cycling consistently showed a loss of MGMT protein at mid- to late S-phase, irrespective of the cell line, suggesting such a downregulation is fundamental to cell cycle control. MGMT protein was also specifically degraded in extracts from S-phase cells and evidence strongly suggested the involvement of PCNA-dependent CRL4Cdt2 ubiquitin-ligase in the reaction. Overall, these data provide the first evidence for non-repair functions of MGMT in cell cycle and highlight the involvement of PCNA in MGMT downregulation, with p21 attenuating the process. PMID- 29510345 TI - Social anxiety and risk factors in patients with schizophrenia: Relationship with duration of untreated psychosis. AB - Social anxiety is commonly reported as a comorbid condition among people with schizophrenia. The aims of this study were to elucidate the associations between demographic/clinical features and social anxiety. A total of 207 outpatients with schizophrenia underwent assessments for social anxiety, psychiatric symptoms, social cognition, cognitive function, social functioning, and quality of life (QOL). To confirm the prediction model for social anxiety, we conducted multiple linear regressions using the Liebowitz Social Anxiety Scale (LSAS) score as an outcome variable and demographic/clinical variables as predictors. Of the 207 patients, 30 (14.5%) met the criteria for social anxiety disorder and 109 (52.7%) had a mean LSAS score higher than 30, suggesting that their social anxiety symptoms had reached a clinical level. Social anxiety was significantly correlated with psychiatric symptoms, social functioning, and QOL, whereas significant correlations with social cognition and cognitive function were not observed. A multiple regression analysis identified social functioning, gender, age of onset, and duration of untreated psychosis (DUP) as predictors that were most closely associated with the LSAS score. We confirmed that social anxiety symptoms were highly prevalent among outpatients with schizophrenia and were closely associated with social functioning and DUP, rather than social cognitive impairments. PMID- 29510346 TI - Age and other risk factors related to reentry to care from kin guardian homes. AB - Although kinship guardianship is an increasingly important foster care exit pathway for children in the United States, research on the factors leading to kinship guardianship breakdown is lacking. This study examines the factors associated with guardianship breakdown for children who exited foster care to kinship guardianship in California between 2003 and 2010 (N = 18,831). Specifying time-dependent Cox relative risk models, children's age trajectories are directly accounted for in the analysis. This allows differentiation between duration dependence (i.e., time spent in guardianship) and children's development (expressed as age). Overall, 17.3% of children reentered care by 2017. Early adolescents, age 13-15 years (HR = 1.63, p < .001), and late adolescents, age 16 17 years (HR = 1.93, p < .001), had an increased hazard of reentry compared with children under the age of six. Children with a history of mental health concerns had more than twice the hazard of reentering than children without such a history (HR = 2.18, p < .001). Our findings indicate that transition to adolescence was associated with increased risk of reentry into care, highlighting the need for guardianship support services leading up to, and during, this child developmental stage. PMID- 29510347 TI - Predictors of foster parents' stress and associations to sensitivity in the first year after placement. AB - In Germany, almost 70 000 children are living in foster families (Statistisches Bundesamt, 2016). Many foster children show mental health problems as they were exposed to an accumulation of risk factors. Hence, foster parents are often faced with challenging parenting situations. The current study focuses on the predictors of foster parents' stress and examines longitudinally whether parenting stress is associated with foster parents' sensitivity. The sample consisted of 55 children (aged from 1 to 6 years) and their foster caregivers. Foster parents' sensitivity was observed during home visits. Caregiver reports were used to assess parenting stress (Parenting Stress Index) as well as foster children's externalizing behavior problems (Child Behavior Checklist). For main caregivers' stress at the beginning of placement, regression analyses revealed both, foster children's externalizing problems as well as partners' stress as predictive. For main caregivers' stress one year after, only initial parenting stress and partners' stress were predictive. Foster parents' sensitivity was correlated with their parenting stress one year after placement. Regression analyses revealed no longitudinal effects of initial parenting stress on overall sensitivity. However, supportive presence was predicted by initial supportive presence and by the interaction between parenting stress and children's externalizing problems at placement. The findings highlight the role of the partner in experiencing parenting stress when taking care of a foster child. Furthermore, they emphasize that foster parents who care for children with behavior problems need adequate support that can buffer initial parenting stress and thereby promote sensitive caregiving. PMID- 29510348 TI - Multi-objective optimization for an automated and simultaneous phase and baseline correction of NMR spectral data. AB - Spectral data preprocessing is an integral and sometimes inevitable part of chemometric analyses. For Nuclear Magnetic Resonance (NMR) spectra a possible first preprocessing step is a phase correction which is applied to the Fourier transformed free induction decay (FID) signal. This preprocessing step can be followed by a separate baseline correction step. Especially if series of high resolution spectra are considered, then automated and computationally fast preprocessing routines are desirable. A new method is suggested that applies the phase and the baseline corrections simultaneously in an automated form without manual input, which distinguishes this work from other approaches. The underlying multi-objective optimization or Pareto optimization provides improved results compared to consecutively applied correction steps. The optimization process uses an objective function which applies strong penalty constraints and weaker regularization conditions. The new method includes an approach for the detection of zero baseline regions. The baseline correction uses a modified Whittaker smoother. The functionality of the new method is demonstrated for experimental NMR spectra. The results are verified against gravimetric data. The method is compared to alternative preprocessing tools. Additionally, the simultaneous correction method is compared to a consecutive application of the two correction steps. PMID- 29510349 TI - The inclusion of LGBT+ health issues within undergraduate healthcare education and professional training programmes: A systematic review. AB - BACKGROUND: An inclusive health curriculum within undergraduate and continuing professional development programmes (CPD) should include issues related to people whom identify as LGBT+. OBJECTIVES: The aim of this systematic review was to examine the education and training requirements of undergraduate students and health professionals regarding the inclusion of LGBT+ health issues. DESIGN: A systematic review of the available published empirical studies. DATA SOURCES: A systematic literature search was undertaken of the following databases: CINAHL, PubMed, PsycINFO, Embase and Sociological Abstracts. All papers reviewed were from the years 2007 to 2017 and written in English. REVIEW METHODS: Three research questions informing the literature review were: (i) What are the education and training requirements of undergraduate students and health professionals regarding the health needs of LGBT+ people? (ii) What are the approaches utilized in the education and training of undergraduate students and health professionals regarding the health needs of LGBT+ people? (iii) What are the best practice examples of the education and training of undergraduate students and health professionals? Following the application of definitive criteria, 22 papers were included in the review. Quality appraisal and data extraction was undertaken by the two authors. RESULTS: The 22 papers were reviewed in detail in the final data analysis and synthesis where four main themes were identified: (1) Cultural competence and inclusivity. (2) Existing knowledge of LGBT+ health-related issues. (3) Curriculum developments and outcomes. (4) Evidence of best practice in education delivery. CONCLUSION: The review highlights the importance of the inclusion of LGBT+ health-related issues within the health curriculum and continuing professional development programmes and the implications for education and training, clinical practice and research. PMID- 29510350 TI - Are attitudes towards emotions associated with depression? A Conceptual and meta analytic review. AB - OBJECTIVES: We performed a conceptual and meta-analytic review of the relationship between negative cognitive and affective evaluations of negative emotional experiences (negative ATE) and depression. We examined the negative ATE depression relationship in terms of three ATE constructs: fear of emotion, non acceptance of emotion, and distress intolerance. We also explored whether the negative ATE-depression relationship differs as a function of specific emotions. METHODS: Seventy articles with a total sample of 19950 adults were included in the general analysis, and 10 studies with a total sample of 1726 were included in the emotion-specific analysis. RESULTS: In the general analysis, negative ATE was associated with depression with a medium to large effect. Notably, this effect size was stronger than previously observed associations between emotion regulation strategies and depression (Aldao et al., 2010). In the emotion specific analysis, negative attitudes towards depressive affect had a particularly strong association with depression. LIMITATIONS: Limitations include heterogeneity in effect sizes and a small number of samples for the emotion specific analyses. CONCLUSIONS: The present review is the first to establish a systematic relationship between negative ATE and depression. We close with suggestions for future work designed to understand why negative ATE is related to depression, which can lead to understanding of depression's etiology and ways to refine interventions to alter ATE. PMID- 29510351 TI - Association between duration of lithium exposure and hippocampus/amygdala volumes in type I bipolar disorder. AB - BACKGROUND: Prior studies on the effects of lithium on limbic and subcortical gray matter volumes are mixed. It is possible that discrepant findings may be explained by the duration of lithium exposure. We investigated this issue in individuals with type I bipolar disorder (BP-I). METHODS: Limbic and subcortical gray matter volume was measured using FreeSurfer in 60 subjects: 15 with BP-I without prior lithium exposure [no-exposure group (NE)]; 15 with BP-I and lithium exposure < 24 months [short-exposure group (SE)]; 15 with BP-I and lithium exposure > 24 months [long-exposure group (LE)]; and 15 healthy controls (HC). RESULTS: No differences in limbic and subcortical gray matter volumes were found between LE and HC. Hippocampal and amygdalar volumes were larger bilaterally in both LE and HC when compared to NE. Amygdalar volumes were larger bilaterally in SE when compared to NE but did not differ from LE. Hippocampal volumes were smaller bilaterally in SE when compared to LE and HC but did not differ from NE. No between-group differences on subcortical gray matter or other limbic structure volumes were observed. LIMITATIONS: Cross-sectional design and concurrent treatment with other medications limit attribution of between-group differences to lithium exposure alone. CONCLUSIONS: The effect of lithium exposure on limbic and subcortical gray matter volumes appears to be time-dependent and relatively specific to the hippocampus and the amygdala, with short-term effects on the amygdala and long-term effects on both structures. These results support the clinical importance of long-term lithium treatment in BP-I. PMID- 29510352 TI - affron(r), a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms: A randomised, double-blind, placebo-controlled study. AB - BACKGROUND: Saffron has antidepressant and anxiolytic effects in adults with mild to-moderate depression. However, this is the first study examining its mood related effects in teenagers. METHODS: In this 8-week, randomised, double-blind, placebo-controlled study, youth aged 12-16 years, with mild-to-moderate anxiety or depressive symptoms were given tablets containing placebo or a saffron extract (affron(r), 14 mg b.i.d). The youth and parent versions of the Revised Child Anxiety and Depression Scale (RCADS) were used as outcome measures. RESULTS: 80 participants were enrolled and 68 completed the study. Based on youth self reports, affron(r) was associated with greater improvements in overall internalising symptoms (p = 0.049), separation anxiety (p = 0.003), social phobia (p = 0.023), and depression (p = 0.016). Total internalising scores decreased by an average of 33% compared to 17% in the placebo group (p = 0.029). However, parental reports of improvements were inconsistent as mean improvements in RCADS scores were greater in the saffron group (40% vs 26%) (p = 0.026), although no other significant differences were identified. affron(r) was well-tolerated and there was a trend of reduced headaches in participants on the active treatment. LIMITATIONS: The use of a self-report instrument, limited study duration, single treatment dose, and non-clinical sample used in this study limit the generalisability of study findings. CONCLUSION: The administration of a standardised saffron extract (affron(r)) for 8 weeks improved anxiety and depressive symptoms in youth with mild-to-moderate symptoms, at least from the perspective of the adolescent. However, these beneficial effects were inconsistently corroborated by parents. PMID- 29510353 TI - Detecting depression stigma on social media: A linguistic analysis. AB - BACKGROUND: Efficient detection of depression stigma in mass media is important for designing effective stigma reduction strategies. Using linguistic analysis methods, this paper aims to build computational models for detecting stigma expressions in Chinese social media posts (Sina Weibo). METHODS: A total of 15,879 Weibo posts with keywords were collected and analyzed. First, a content analysis was conducted on all 15,879 posts to determine whether each of them reflected depression stigma or not. Second, using four algorithms (Simple Logistic Regression, Multilayer Perceptron Neural Networks, Support Vector Machine, and Random Forest), two groups of classification models were built based on selected linguistic features; one for differentiating between posts with and without depression stigma, and one for differentiating among posts with three specific types of depression stigma. RESULTS: First, 967 of 15,879 posts (6.09%) indicated depression stigma. 39.30%, 15.82%, and 14.99% of them endorsed the stigmatizing view that "People with depression are unpredictable", "Depression is a sign of personal weakness", and "Depression is not a real medical illness", respectively. Second, the highest F-Measure value for differentiating between stigma and non-stigma reached 75.2%. The highest F-Measure value for differentiating among three specific types of stigma reached 86.2%. LIMITATIONS: Due to the limited and imbalanced dataset of Chinese Weibo posts, the findings of this study might have limited generalizability. CONCLUSIONS: This paper confirms that incorporating linguistic analysis methods into online detection of stigma can be beneficial to improve the performance of stigma reduction programs. PMID- 29510354 TI - Suicidality, posttraumatic stress, and depressive reactions after earthquake and maltreatment: A cross-sectional survey of a random sample of 6132 chinese children and adolescents. AB - BACKGROUND: Surviving an earthquake can greatly increase the risk of suicidality among children and adolescents, especially if they experience physical and emotional neglect or abuse within the family after the earthquake. How various types of childhood adversity affect the vulnerability of adolescents to suicidality after exposure to a natural disaster is not well understood. This study examined the relationships among different types of earthquake exposure, childhood trauma, psychopathology and suicidality. METHODS: Suicidality, the level of earthquake exposure, post-traumatic stress disorder (PTSD), depression, and maltreatment, including physical and emotional abuse and neglect, were assessed in 6132 child and adolescent survivors randomly selected from three primary schools, five junior high schools, two senior high schools and one six year high school in Baoxing, Lushan and Tianquan counties, which were the areas most severely affected by the 2013 Ya'an earthquake. RESULTS: The Suicidal Behaviors Questionnaire-Revised (SBQ-R) scores were high, with 27.8% of the participants scoring at or above the cut-off score of 7. Multivariate regression showed that emotional abuse and depression experienced after the earthquake contributed to the suicide risk, whereas emotional neglect and PTSD made somewhat smaller contributions. The mediation analysis suggested that PTSD and depression symptoms partially mediated the association of suicidality with emotional neglect or abuse. The PTSD, depression and suicidality scores were generally higher for females than for males, whereas the depression and suicidality scores were higher for older than younger respondents. CONCLUSIONS: Our results highlight the need for the implementation of school-based, adolescent-centered suicide prevention programs in the long-term aftermath of exposure to traumatic events. Interventions may also need to be tailored to gender and developmental stage. Suicidality is independently associated with emotional abuse, neglect, depression and PTSD symptoms in this disaster-exposed young population. Longitudinal studies should explore whether depression and PTSD symptoms mediate the relationship between past emotional abuse or neglect and the current suicide risk. PMID- 29510355 TI - Depression among patients attending antiretroviral treatment program in public health facilities in Bahir Dar City, Ethiopia. AB - BACKGROUND: The magnitude of depression is not well investigated among people living with HIV/AIDS. Thus, this research aimed to assess the magnitude of depression and its influencing factors among people living with HIV/AIDS attending government institutions in Bahir Dar City, North West, Ethiopia. METHODS: institution based-cross-sectional study was done among randomly selected 415 people living with HIV/AIDS attending antiretroviral therapy program in Bahir Dar city, Ethiopia. Socio-demographic data and medical histories for all respondents were collected using interviewer-administered structured questionnaire. We assessed the odds of association of patient characteristics with depression was assessed using multiple logistic regression. The relative effect estimates of the respective factors were presented with odds ratio accompanied by their 95% uncertainty intervals. RESULTS: From 407 people living with HIV/AIDS interviewed, 198(48.6%) of them had depression. Social support, HIV clinical staging, total daily pill burden, treatment regimen and adherence to highly active antiretroviral therapy were significantly associated with depression. CONCLUSION: The magnitude of depression among people living with HIV/AIDS was found to be high. Early mental health screening should be done for people living with HIV/AIDS. PMID- 29510356 TI - Transdiagnostic assessment of repetitive negative thinking and responses to positive affect: Structure and predictive utility for depression, anxiety, and mania symptoms. AB - BACKGROUND: Repetitive negative thinking (RNT) is a cognitive process that is repetitive, passive, relatively uncontrollable, and focused on negative content, and is elevated in emotional disorders including depression and anxiety disorders. Repetitive positive thinking is associated with bipolar disorder symptoms. The unique contributions of positive versus negative repetitive thinking to emotional symptoms are unknown. The first aim of this study was to use confirmatory factor analyses to evaluate the psychometrics of two transdiagnostic measures of RNT, the Repetitive Thinking Questionnaire (RTQ-10) and Perseverative Thinking Questionnaire (PTQ), and a measure of repetitive positive thinking, the Responses to Positive Affect (RPA) Questionnaire. The second aim was to determine incremental predictive utility of these measures. METHOD: All measures were administered to a sample of 2088 undergraduate students from the Netherlands (n = 992), Australia (n = 698), and America (n = 398). RESULTS: Unidimensional, bifactor, and three-factor models were supported for the RTQ-10, PTQ, and RPA, respectively. A common factor measured by all PTQ items explained most variance in PTQ scores suggesting that this measure is essentially unidimensional. The RNT factor of the RTQ-10 demonstrated the strongest predictive utility, although the PTQ was also uniquely although weakly associated with anxiety, depression, and mania symptoms. The RPA dampening factor uniquely predicted anxiety and depression symptoms, suggesting that this scale is a separable process to RNT as measured by the RTQ-10 and PTQ. LIMITATIONS: Findings were cross-sectional and need to be replicated in clinical samples. CONCLUSIONS: Transdiagnostic measures of RNT are essentially unidimensional, whereas RPA is multidimensional. RNT and RPA have unique predictive utility. PMID- 29510357 TI - Bis(MU-chloro) bridged 1D CuI and CuII coordination polymer complex and mononuclear CuII complex: Synthesis, crystal structure and biological properties. AB - A novel one-dimensional coordination polymer containing Cu(I)Cu(II) core with chloro bridge on Cu(I) and ligand bridge on Cu(II) ions (1) and a mononuclear Cu(II) complex (2) have been synthesized from the reactions of 3- and 4-methoxy-3 quinolin-3-ylimino-methyl-2-phenol with [CuCl2(PPh3)2]. The ligands and the complexes have been characterized by spectral and analytical methods. In addition, the structures of both the ligands and the copper complexes were confirmed by single crystal X-ray diffraction studies. In both complexes, the phenolic oxygen and azomethine nitrogen atom of the ligand coordinate to the copper ions in a monobasic bidentate manner resulting in an approximately square planar geometry around the copper ion. In the polymeric complex, the N atom of the quinoline ring is coordinated to Cu(I) in addition to the phenolic oxygen and azomethine nitrogen atom coordinating to Cu(II) ion, thus bridging Cu(I) and Cu(II) ions in the complex. The interactions of the compounds with calf thymus DNA (CT-DNA) have been followed by absorption and emission titration methods, which revealed that the compounds interact with CT-DNA through intercalation. Further, the interactions of the compounds with bovine serum albumin (BSA) were also investigated using UV-visible, fluorescence spectroscopic methods. The results indicated that complex 1 exhibited a stronger binding to CT-DNA and BSA than the free ligands and complex 2. In addition, the in vitro cytotoxicity experiment showed that complexes 1 and 2 exhibit potent cytotoxic properties against PANC-1and Hela cells. Moreover, while complex 1 showed prominent cytotoxic activity against both PANC-1 and Hela cells with IC50 of 17.91 and 11.67 MUM, complex 2 showed moderate cytotoxic activities with IC50 of 25.13 and 16.41 MUM in PANC-1 and Hela cells. Further, apoptosis was confirmed by fluorescence image using EB/AO reagent. PMID- 29510359 TI - Forensic microanalysis of Manhattan Project legacy radioactive wastes in St. Louis, MO. AB - Radioactive particulate matter (RPM) in St Louis, MO, area surface soils, house dusts and sediments was examined by scanning electron microscopy with energy dispersive X-ray analysis. Analyses found RPM containing 238U and decay products (up to 46 wt%), and a distinct second form of RPM containing 230Th and decay products (up to 15.6 wt%). The SEM-EDS analyses found similar RPM in Manhattan Project-era radioactive wastes and indoor dusts in surrounding homes. PMID- 29510358 TI - Swift fabrication of Ag nanostructures using a colloidal solution of Holostemma ada-kodien (Apocynaceae) - Antibiofilm potential, insecticidal activity against mosquitoes and non-target impact on water bugs. AB - Recent research in entomology and parasitology focused on the efficacy of green fabricated nanomaterials as novel insecticides. In this study, we synthesized poly-dispersed and stable silver nanoparticles (AgNPs) using the leaf extract of Holostemma ada-kodien. The nanostructures were characterized by ultraviolet visible spectroscopy, Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray, and X-ray diffraction analysis. The efficacy of H. ada-kodien leaf extract and AgNPs in vector control was evaluated against the mosquitoes Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus, which act as major vectors of important parasitic and arboviral diseases. AgNPs showed higher toxicity if compared to the H. ada-kodien leaf aqueous extract, LC50 towards larvae of A. stephensi, A. aegypti, and C. quinquefasciatus were 12.18, 13.30, and 14.70 MUg/mL, respectively. When the AgNPs were tested on non-target water bugs, Diplonychus indicus, the LC50 value was 623.48 MUg/mL. Furthermore, 100 MUl/mL of AgNPs achieved significant antimicrobial activity against Bacillus pumilus, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus vulgaris, and Candida albicans. Light and confocal laser scanning microscopy highlighted a major impact of the H. ada-kodien-synthesized AgNPs on the external topography and architecture of microbial biofilms, both on Gram-positive and Gram-negative bacteria. Overall, this study sheds light on the insecticidal and antibiofilm potential of H. ada-kodien-synthesized AgNPs, a potential green resource for the rapid synthesis of polydispersed and highly stable AgNPs. PMID- 29510360 TI - Can Imaging Parameters Provide Information Regarding Histopathology in Head and Neck Squamous Cell Carcinoma? A Meta-Analysis. AB - OBJECT: Our purpose was to provide data regarding relationships between different imaging and histopathological parameters in HNSCC. METHODS: MEDLINE library was screened for associations between different imaging parameters and histopathological features in HNSCC up to December 2017. Only papers containing correlation coefficients between different imaging parameters and histopathological findings were acquired for the analysis. RESULTS: Associations between 18F-FDG positron emission tomography (PET) and KI 67 were reported in 8 studies (236 patients). The pooled correlation coefficient was 0.20 (95% CI = [ 0.04; 0.44]). Furthermore, in 4 studies (64 patients), associations between 18F fluorothymidine PET and KI 67 were analyzed. The pooled correlation coefficient between SUVmax and KI 67 was 0.28 (95% CI = [-0.06; 0.94]). In 2 studies (23 patients), relationships between KI 67 and dynamic contrast-enhanced magnetic resonance imaging were reported. The pooled correlation coefficient between Ktrans and KI 67 was -0.68 (95% CI = [-0.91; -0.44]). Two studies (31 patients) investigated correlation between apparent diffusion coefficient (ADC) and KI 67. The pooled correlation coefficient was -0.61 (95% CI = [-0.84; -0.38]). In 2 studies (117 patients), relationships between 18F-FDG PET and p53 were analyzed. The pooled correlation coefficient was 0.0 (95% CI = [-0.87; 0.88]). There were 3 studies (48 patients) that investigated associations between ADC and tumor cell count in HNSCC. The pooled correlation coefficient was -0.53 (95% CI = [-0.74; 0.32]). Associations between 18F-FDG PET and HIF-1alpha were investigated in 3 studies (72 patients). The pooled correlation coefficient was 0.44 (95% CI = [ 0.20; 1.08]). CONCLUSIONS: ADC may predict cell count and proliferation activity, and SUVmax may predict expression of HIF-1alpha in HNSCC. SUVmax cannot be used as surrogate marker for expression of KI 67 and p53. PMID- 29510361 TI - Development of Musca domestica at constant temperatures and the first case report of its application for estimating the minimum postmortem interval. AB - Musca domestica Linnaeus, 1758 (Diptera: Muscidae) is an important cosmopolitan pest with potential forensic value. Thus, the investigation of the development of M. domestica is of vital significance both for the control of its colony and for the estimation of the minimum postmortem interval (PMImin). This study observed the development of M. domestica at seven constant temperatures in the range of 16 34 degrees C; factors such as developmental duration, accumulated degree hours, and changes in larval body length were examined. Using these results, three developmental models that could be used for PMImin estimation were established: an isomorphen diagram, an isomegalen diagram, and a thermal summation model. The mean (+/-SD) developmental durations of M. domestica from egg to adult at 16, 19, 22, 25, 28, 31, and 34 degrees C were 884.6+/-7.4, 627.2+/-23.0, 437.5+/-11.0, 297.0+/-8.8, 226.4+/-6.3, 190.4+/-4.2, and 155.3+/-5.5h, respectively. The mean (+/-SE) developmental threshold temperature D0 and the thermal summation constant K were determined as 12.42+/-0.64 degrees C and 3658.9+/-301.3 degree hours, respectively. Using regression analysis, we obtained equations that model the change in larval body length with time after hatching and change in time after hatching with larval body length. Based on the developmental data obtained, we successfully utilized the development of M. domestica to estimate PMImin for the first time. PMID- 29510362 TI - Factors leading to the involvement of Forensic Advisors in the Belgian criminal justice system. AB - Forensic Advisors at the National Institute for Criminalistics and Criminology in Brussels act as advising body to the magistrate regarding analytical possibilities and the usefulness of trace analysis in a case. Initially, their function was devised to assist in complex murder cases with unknown offender. However, in a previous study, the increasing diversity of the cases they are requested for has been observed (Bitzer et al., in press). In order to deepen our understanding of the decision steps in the criminal investigation process, the decision to involve a Forensic Advisor and the factors leading to their involvement were evaluated. The study focused on homicide, robbery and burglary cases with and without requests for a Forensic Advisor between January 2014 and June 2016. The factors were categorised into five knowledge dimensions: strategic, immediate, physical, criminal and utility. Decision tree modelling was carried out in order to identify the factors influencing the request for a Forensic Advisor in the case. The decision to request a Forensic Advisor differs between different types of offences. It also depends on the complexity of the case in terms of the number of traces and objects collected at the crime scene, and the availability of witness reports. Indeed, Forensic Advisors take the role of trace analysis coordinator by providing an overview of all available traces, objects, analyses and results. According to the principal implication factors and the performed case study, the contribution of Forensic Advisors consists mainly in summarising all information and advise on potential additional analyses. This might be explained by a loss of overview of the information and the possibilities regarding trace analysis by the magistrate responsible of the case. PMID- 29510363 TI - Reliability of 3D arterial spin labeling MR perfusion measurements: The effects of imaging parameters, scanner model, and field strength. AB - The aim of this study was to investigate the reliability of cerebral blood flow (CBF) measurements obtained by 3D pseudo-continuous arterial spin labeling (pCASL) imaging according to imaging parameters, scanner model, and field strength. We acquired 3D pCASL images in 12 healthy volunteers using four different scanners: two 3.0 T scanners and two 1.5 T scanners. Reliability was evaluated using intraclass correlation coefficient. Our results indicate that the influence of the post-labeling delay and scanner model on CBF measurements should be taken into consideration. If two scanners of the same model are used, scannerdependent differences may be small. PMID- 29510364 TI - Photocatalytic disinfection performance in virus and virus/bacteria system by Cu TiO2 nanofibers under visible light. AB - The presence of pathogenic microorganisms in water is a great threat to human health, and photocatalysis is promising for disinfection. However, the research on virus inactivation with visible-light photocatalysis is still limited, especially the coexistence of virus and its host bacteria. In this study, bacteriophage f2 and its host E. coil 285 were used as the model microorganisms, and the disinfection performance of prepared Cu-TiO2 nanofibers under visible light was investigated. The result showed that the prepared Cu-TiO2 nanofibers showed a brilliant ability in terms of removing bacteriophage f2 and E. coil 285 under visible light. Series experiments indicated that the initial pH didn't affect the photocatalytic disinfection performance significantly. In the certain range, the removal efficiency of bacteriophage f2 increased with the increase of catalyst dosage, light intensity and temperature, but decreased with the increase of initial virus concentration. In virus/bacteria mixed system, bacteriophage f2 exhibited stronger resistance to photocatalytic oxidation than E. coil 285, and the removal of bacteriophage f2 was obviously affected by being mixed with E. coil 285, while the removal of E. coil 285 almost remained unchanged after being mixed with bacteriophage f2. Further research proved that competitive adsorption in mixed system played a certain role in E. coli 285 inactivation, while the free reactive oxygen species (ROSs) in the bulk phase played a crucial role in phage f2 inactivation. PMID- 29510365 TI - Adsorption of antibiotics on microplastics. AB - Microplastics and antibiotics are two classes of emerging contaminants with proposed negative impacts to aqueous ecosystems. Adsorption of antibiotics on microplastics may result in their long-range transport and may cause compound combination effects. In this study, we investigated the adsorption of 5 antibiotics [sulfadiazine (SDZ), amoxicillin (AMX), tetracycline (TC), ciprofloxacin (CIP), and trimethoprim (TMP)] on 5 types of microplastics [polyethylene (PE), polystyrene (PS), polypropylene (PP), polyamide (PA), and polyvinyl chloride (PVC)] in the freshwater and seawater systems. Scanning Electron Microscope (SEM) and X-ray diffractometer (XRD) analysis revealed that microplastics have different surface characterizes and various degrees of crystalline. Adsorption isotherms demonstrated that PA had the strongest adsorption capacity for antibiotics with distribution coefficient (Kd) values ranged from 7.36 +/- 0.257 to 756 +/- 48.0 L kg-1 in the freshwater system, which can be attributed to its porous structure and hydrogen bonding. Relatively low adsorption capacity was observed on other four microplastics. The adsorption amounts of 5 antibiotics on PS, PE, PP, and PVC decreased in the order of CIP > AMX > TMP > SDZ > TC with Kf correlated positively with octanol-water partition coefficients (Log Kow). Comparing to freshwater system, adsorption capacity in seawater decreased significantly and no adsorption was observed for CIP and AMX. Our results indicated that commonly observed polyamide particles can serve as a carrier of antibiotics in the aquatic environment. PMID- 29510366 TI - Long-term interactive effects of N addition with P and K availability on N status of Sphagnum. AB - Little information exists concerning the long-term interactive effect of nitrogen (N) addition with phosphorus (P) and potassium (K) on Sphagnum N status. This study was conducted as part of a long-term N manipulation on Whim bog in south Scotland to evaluate the long-term alleviation effects of phosphorus (P) and potassium (K) on N saturation of Sphagnum (S. capillifolium). On this ombrotrophic peatland, where ambient deposition was 8 kg N ha-1 yr-1, 56 kg N ha 1 yr-1 of either ammonium (NH4+, Nred) or nitrate (NO3-, Nox) with and without P and K, were added over 11 years. Nutrient concentrations of Sphagnum stem and capitulum, and pore water quality of the Sphagnum layer were assessed. The N saturated Sphagnum caused by long-term (11 years) and high doses (56 kg N ha-1 yr 1) of reduced N was not completely ameliorated by P and K addition; N concentrations in Sphagnum capitula for Nred 56 PK were comparable with those for Nred 56, although N concentrations in Sphagnum stems for Nred 56 PK were lower than those for Nred 56. While dissolved inorganic nitrogen (DIN) concentrations in pore water for Nred 56 PK were not different from Nred 56, they were lower for Nox 56 PK than for Nox 56 whose stage of N saturation had not advanced compared to Nred 56. These results indicate that increasing P and K availability has only a limited amelioration effect on the N assimilation of Sphagnum at an advanced stage of N saturation. This study concluded that over the long-term P and K additions will not offset the N saturation of Sphagnum. PMID- 29510367 TI - Defining wet season water quality target concentrations for ecosystem conservation using empirical light attenuation models: A case study in the Great Barrier Reef (Australia). AB - Optically active water quality components (OAC) transported by flood plumes to nearshore marine environments affect light levels. The definition of minimum OAC concentrations that must be maintained to sustain sufficient light levels for conservation of light-dependant coastal ecosystems exposed to flood waters is necessary to guide management actions in adjacent catchments. In this study, a framework for defining OAC target concentrations using empirical light attenuation models is proposed and applied to the Wet Tropics region of the Great Barrier Reef (GBR) (Queensland, Australia). This framework comprises several steps: (i) light attenuation (Kd(PAR)) profiles and OAC measurements, including coloured dissolved organic matter (CDOM), chlorophyll-a (Chl-a) and suspended particulate matter (SPM) concentrations collected in flood waters; (ii) empirical light attenuation models used to define the contribution of CDOM, Chl-a and SPM to the light attenuation, and; (iii) translation of empirical models into manageable OAC target concentrations specific for wet season conditions. Results showed that (i) Kd(PAR) variability in the Wet Tropics flood waters is driven primarily by SPM and CDOM, with a lower contribution from Chl-a (r2 = 0.5, p < 0.01), (ii) the relative contributions of each OAC varies across the different water bodies existing along flood waters and strongest Kd(PAR) predictions were achieved when the in-situ data were clustered into water bodies with similar satellite-derived colour characteristics ('brownish flood waters', r2 = 0.8, p < 0.01, 'greenish flood waters', r2 = 0.5, p < 0.01), and (iii) that Kd(PAR) simulations are sensitive to the angular distribution of the light field in the clearest flood water bodies. Empirical models developed were used to translate regional light guidelines (established for the GBR) into manageable OAC target concentrations. Preliminary results suggested that a 90th percentile SPM concentration of 11.4 mg L-1 should be maintained during the wet season to sustain favourable light levels for Wet Tropics coral reefs and seagrass ecosystems exposed to 'brownish' flood waters. Additional data will be collected to validate the light attenuation models and the wet season target concentration which in future will be incorporated into wider catchment modelling efforts to improve coastal water quality in the Wet Tropics and the GBR. PMID- 29510368 TI - Comparison of uptake, translocation and accumulation of several neonicotinoids in komatsuna (Brassica rapa var. perviridis) from contaminated soils. AB - The accumulation of pesticides in vegetables may have serious effects on human health and ecosystems via food chains; therefore, it is of great importance to investigate the uptake and accumulation behaviours of pesticides in vegetable tissues. In the present study, the uptake, translocation and accumulation of five neonicotinoids, thiamethoxam (THIM), clothianidin (CLO), thiacloprid (THID), acetamiprid (ACE) and dinotefuran (DIN), in komatsuna (Brassica rapa var. perviridis, a vegetable) were investigated. The concentrations of neonicotinoids in vegetable tissues ranged from 0.068 +/- 0.002 to 29.6 +/- 2.5 mg/kg. During the cultivation (except for the first day), the concentration of each neonicotinoid in shoots was the highest, followed by roots and the soil. The concentrating of neonicotinoids from the soil to roots followed the order of THIM > CLO > THID > DIN > ACE, while the order of the ability of translocation neonicotinoids from roots to shoots was the just opposite. The difference in uptake and translocation behaviours of the test neonicotinoids seems to be not correlated with the octanol/water partition coefficient (logKow), water solubility or dissociation constant (pKa), but significantly correlated with molecular weight. In addition, a greater concentration of the THIM-metabolite clothianidin (M-CLO) was detected in vegetable shoots than in roots and the soil. PMID- 29510369 TI - Sodium alginate/graphene oxide hydrogel beads as permeable reactive barrier material for the remediation of ciprofloxacin-contaminated groundwater. AB - The wide occurrence of antibiotics in groundwater has raised serious concerns due to their impacts on humans and the ecosystem. Most of the research in groundwater remediation focuses on the exploitation of nano-materials. However, nano materials have several disadvantages such as high production cost, rapid reduction in permeability, disposal problems, and high sensitivity to environmental conditions. To solve these issues, novel sodium alginate/graphene oxide hydrogel beads (GSA) were synthesised and their effectiveness as permeable reactive barrier (PRB) backfill material in the remediation of ciprofloxacin (CPX)-contaminated groundwater was tested. The adsorption of CPX onto GSA followed the pseudo-second-order kinetic model. The isotherm data followed the Freundlich model. The maximum adsorption capacity was 100 mg g-1 at pH 7.0. The adsorption process was sensitive to contact time, initial CPX concentration and ionic strength. However, it was not pH sensitive. Hydrophobic interaction, electrostatic interaction, ion exchange, H-bonding, and pore filling were proposed to be the main adsorption mechanisms. The effects of flow rate, influent CPX concentration, and ionic strength on the performance of PRB were confirmed through flow-through column experiments and by using a chemical non-equilibrium two-site model. Accordingly, a proper PRB was designed based on hydrogeological conditions. Finally, the lifetime and cost of the PRBs were calculated. The results obtained provided concrete evidence that GSA is a promising adsorbent material for PRBs applications in the remediation of CPX-contaminated groundwater. PMID- 29510370 TI - Review of zero-valent aluminium based water and wastewater treatment methods. AB - Zero-valent metals (ZVM) are widely used to remove heavy metals, contaminants, toxicity, etc. from water and wastewater. Zero-valent aluminium (ZVAl) has large surface area and high surface reactivity. It has enormous flexibility for the in situ application. ZVAl can be applied as either a single or a bimetallic system as well as advanced oxidation processes (AOPs). It is observed that ZVAl is capable of generating hydroxyl and sulfate radicals in water medium, which remove non-biodegradable pollutants from aqueous solution. ZVAl-based processes can remove non-biodegradable organic contaminants from water medium within a short duration. ZVAl is also used as a reducing agent. It is efficient to reduce toxic hexavalent chromium to less toxic trivalent chromium. ZVAl, in various combinations in bimetallic system (Fe/Al, Pd/Al, Cu/Al), is able to remove various contaminants from aqueous medium. Overall, it can be concluded that ZVAl based methods for water and wastewater treatment are promising environmental technologies. PMID- 29510371 TI - Seasonal sensitivity of Gammarus pulex towards the pyrethroid cypermethrin. AB - The aquatic toxicity of insecticides like the pyrethroids have been discussed intensively over the recent years especially in relation to risk assessment and how seasonality may or may not affect the sensitivity of non-target organisms. To address this issue, the crustacean Gammarus pulex was collected once a month for 16 months and acclimated to 10 degrees C for four days before being exposed to a 90 min pulse of cypermethrin. In vitro cytochrome P450 activity, total lipid content, total protein content, and dry weight were measured in male and female gammarids from each sampling date and used along with the water temperature as variables for sensitivity prediction by Partial Least Squares (PLS) regression models. The 24 h EC50-values varied more than 30 fold across the sampling period from 0.21 +/- 0.05 MUg L-1 (April 2015) to 6.60 +/- 3.46 MUg L-1 (October 2015), indicating seasonal variances in the acute sensitivity of G. pulex towards cypermethrin. After 168 h of recovery this difference in EC50-values was reduced to seven-fold. In both male and female gammarids seasonal patterns were observed in the total lipid content and in vitro CYP P450 activity, which peaked in spring and fall, respectively. The current study shows the importance of reporting time of organism collection and experimental execution for risk assessment of pyrethroids as season is important for the acute sensitivity of G. pulex. We suggest prolonged acclimation times of sampled macroinvertebrates to constant laboratory conditions in order to even out possible seasonal differences in sensitivity. PMID- 29510372 TI - Associations between fiber intake and Body Mass Index (BMI) among African American women participating in a randomized weight loss and maintenance trial. AB - INTRODUCTION: African-American women are at increased risk for obesity, and therefore it is important to identify dietary factors that have the potential to prevent weight gain within this population. The purpose of the current study was to examine associations between daily fiber intake and Body Mass Index (BMI) over the course of an 18-month weight loss intervention for African-American women. METHODS: Anthropometric measures and the Block Food Frequency Questionnaire were administered at baseline, 6-month, and 18-month follow-up between 2008 and 2010. A mixed-effects linear regression model with random intercept and time slope was used to model associations between fiber consumption and BMI controlling for time trend. RESULTS: Associations between fiber consumption and BMI were significantly different over time (betaFiber*Time=-0.07,p-value=0.003). There was no association between fiber intake and BMI at baseline; however, there was a significant inverse relation between fiber consumption and BMI at 6 months, and the association was even stronger at 18 months. CONCLUSIONS: Results from this study suggest that dietary fiber consumption may be particularly important within weight loss interventions tailored for African-American women. PMID- 29510373 TI - Hysteroscopy in the Netherlands and Flanders: A survey amongst practicing gynaecologists. AB - OBJECTIVE: To gain insight in the current ideas on, and implementation of hysteroscopy amongst practicing gynaecologists in the Netherlands and Flanders. STUDY DESIGN: In August 2016 an electronic questionnaire was sent to practising gynaecologist members of the Dutch (N = 591) and Flemish (N = 586) Society of Obstetrics and Gynaecology. RESULTS: The response rate for the Netherlands was 15.4% (91/591), and for Flanders 27.0% (158/586). Responding gynaecologists have a preference for hysteroscopy for diagnosing and treating most intrauterine pathology. Flemish respondents are more hesitant in opting for hysteroscopy instead of curettage for treatment of polyps and placental remnants. There appears to be a wide diffusion of diagnostic and basic operative hysteroscopy. In contrast to Flanders, responding hysteroscopists from the Netherlands more often perform office hysteroscopic procedures. Hysteroscopic procedures, and office procedures in particular, are now educated during residency. Therefore, recently graduated gynaecologists have a preference for this technique. CONCLUSION: Our survey confirms that nowadays the focus of treating intrauterine pathology is on less invasive techniques and preserving the uterus. Dutch responding hysteroscopists have more expertise concerning office hysteroscopy than their Flemish colleagues. Future research on the cost-effectiveness of and optimisation of patient comfort during office hysteroscopy is needed to support its further implementation. PMID- 29510374 TI - Genome engineering for microbial natural product discovery. AB - The discovery and development of microbial natural products (MNPs) have played pivotal roles in the fields of human medicine and its related biotechnology sectors over the past several decades. The post-genomic era has witnessed the development of microbial genome mining approaches to isolate previously unsuspected MNP biosynthetic gene clusters (BGCs) hidden in the genome, followed by various BGC awakening techniques to visualize compound production. Additional microbial genome engineering techniques have allowed higher MNP production titers, which could complement a traditional culture-based MNP chasing approach. Here, we describe recent developments in the MNP research paradigm, including microbial genome mining, NP BGC activation, and NP overproducing cell factory design. PMID- 29510375 TI - MicroRNA as Crucial Regulators of Gene Expression in Estradiol-Treated Human Endothelial Cells. AB - BACKGROUND/AIMS: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERalpha, ERbeta and GPER) in the regulation of miRNA expression by estrogen. METHODS: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cells (HUVEC) exposed to a physiological concentration of estradiol (E2; 1 nmol/L) for 24 hours. miRNA-gene interactions were computationally predicted using Ingenuity Pathway Analysis and changes in miRNA levels were validated by qRT-PCR. Role of ER in the E2-induced miRNA was additionally confirmed by using specific ER agonists and antagonists. RESULTS: miRNA array revealed that expression of 114 miRNA were significantly modified after E2 exposition. Further biological pathway analysis revealed cell death and survival, lipid metabolism, reproductive system function, as the top functions regulated by E2. We validated changes in the most significantly increased (miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p) and decreased (miR-378h and miR-1244) miRNA and the role of ER in these E2-induced miRNA was determined. Results showed that both classical, ERalpha and ERbeta, and membrane-bound ER, GPER, differentially regulated specific miRNA. In silico analysis of validated miRNA promoters identified specific ER binding sites. CONCLUSION: Our findings identify differentially expressed miRNA pathways linked to E2 in human endothelial cells through ER, and provide new insights by which estrogen can modulate endothelial function. PMID- 29510376 TI - ETS-1 Induces Endothelial-Like Differentiation and Promotes Metastasis in Non Small Cell Lung Cancer. AB - BACKGROUND/AIMS: Recently, endothelial-like cells originating directly from tumor cells have been revealed. However, the mechanism remains unclear. ETS-1 (E26 transformation specific-1), a key transcription factor in the generation and maturation of ECs (endothelial cells), has been reported to be overexpressed in several cancers. Here, we reveal novel regulation of the endothelial-like differentiation of NSCLC (non-small cell lung cancer) cells by ETS-1. METHODS: We up-regulated the expression of ETS-1 in NSCLC cell lines by H2O2 or lentiviral vector. Endothelial phenotypes, such as vWF (von Willebrand factor) and VE cadherin were examined by Western blot analysis and immunofluorescence assay. Tube formation assay and phagocytotic activity assay were performed to evaluate ECs' specific features on NSCLC cells. The effect of ETS-1 on metastasis was determined by wound healing assays, transwell assays and a xenograft tumor model. To explore the role of ETS-1 in the initiation and progression of NSCLC, we examined ETS-1 levels in NSCLC cancerous tissues and paired adjacent normal tissues by immunohistochemstry and analyzed the relationship between ETS-1 levels and clinicopathological parameters, as well as patient survival. Kaplan Meier plotter database was used to assess the prognostic value of ETS-1 in NSCLC. The association between ETS-1 levels and MVD (microvessel density) was analyzed to determine their role in angiogenesis. RESULTS: With ETS-1 up-regulation, the expression of vWF and VE-cadherin was increased in NSCLC cells. Additionally, cells adopted several ECs' specific features, including enhanced tube formation ability and uptake of Dil-ac-LDL (acetylated low-density lipoprotein) and lectin. ETS-1 up-regulation also promoted cell migration, invasion and adhesion. In addition, xenograft mice arising from ETS-1 over-expressing cells had more liver metastases. In the clinical specimens, ETS-1 expression was significantly higher in NSCLC cancerous tissues than adjacent nontumorous tissues and positively associated with tumor size, T stage, N stage and clinical stage. Patients with high levels of ETS-1 expression had significantly poorer OS (overall survival) and FP (first progression) than those with low expression. Furthermore, there was a positive correlation between ETS-1 level and MVD. CONCLUSION: Collectively, our data reveal that ETS-1 can induce the differentiation of tumor cells into endothelial-like cells and further promote metastatic dissemination in NSCLC. PMID- 29510378 TI - Physiological and Molecular Effects of in vivo and ex vivo Mild Skin Barrier Disruption. AB - The success of topically applied treatments on skin relies on the efficacy of skin penetration. In order to increase particle or product penetration, mild skin barrier disruption methods can be used. We previously described cyanoacrylate skin surface stripping as an efficient method to open hair follicles, enhance particle penetration, and activate Langerhans cells. We conducted ex vivo and in vivo measurements on human skin to characterize the biological effect and quantify barrier disruption-related inflammation on a molecular level. Despite the known immunostimulatory effects, this barrier disruption and hair follicle opening method was well accepted and did not result in lasting changes of skin physiological parameters, cytokine production, or clinical side effects. Only in ex vivo human skin did we find a discrete increase in IP-10, TGF-beta, IL-8, and GM-CSF mRNA. The data underline the safety profile of this method and demonstrate that the procedure per se does not cause substantial inflammation or skin damage, which is also of interest when applied to non-invasive sampling of biomarkers in clinical trials. PMID- 29510377 TI - miR-519d-3p Inhibits Cell Proliferation and Invasion of Gastric Cancer by Downregulating B-Cell Lymphoma 6. AB - miR-519d inhibits cell growth, migration, and invasion, but its role in gastric cancer (GC) cells is obscure. We showed that miR-519d-3p was lowly expressed in GC tissues and was associated with the clinical stage and lymph node metastasis of GC tissues. We found that miR-519d-3p repressed cell proliferation and invasion of MGC803 cells and delayed the G1/S phase transition, resulting in decreased cyclin B1 and MMP2 and increased E-cadherin levels. Furthermore, miR 519d-3p targeted and downregulated B-cell lymphoma 6 (BCL6) expression. BCL6 overexpression partially abrogated the suppressive function of miR-519d in MGC803 cells. In conclusion, our study demonstrated that miR-519d-3p functions as a tumor suppressor by targeting and downregulating the expression of BCL6 in GC cells. PMID- 29510380 TI - The Neuroprotective Effects of Hypothermia on Bilirubin-Induced Neurotoxicity in vitro. AB - BACKGROUND: In high-risk newborns indirect hyperbilirubinemia can lead to acute bilirubin encephalopathy and kernicterus. Despite the current therapeutic modalities, preventing or reversing the neurotoxicity cannot be achieved in all infants. OBJECTIVE: To investigate the neuroprotective effects of hypothermia on bilirubin-induced toxicity in primary mouse neuronal cell cultures. METHODS: Hippocampal cell cultures, isolated from newborn mouse brains, were incubated with unconjugated bilirubin (UCB) at 3 days in vitro (DIV) and immediately exposed to varying degrees of hypothermia. Neuronal viability and mitochondrial health were compared between the normothermia (37 degrees C), mild (34 degrees C), moderate (32 degrees C) and severe (29 degrees C) hypothermia groups. Confocal microscopy and fluorescent dyes (propidium iodide and JC-1) were used for cell evaluation. To determine the late effects of hypothermia, the cultures were also examined at 7 DIV after returning to normothermic conditions. RESULTS: Induction of any degree of hypothermia increased the neuronal survival after 24 h of UCB treatment. Neuronal death rate and mitochondrial membrane potential loss were lowest in the neurons exposed to moderate hypothermia. We also observed that mild to moderate hypothermia had late protective effects on neuronal cell viability, whereas deep hypothermia did not improve neuronal survival. CONCLUSIONS: We conclude that hypothermia reduces the cell death induced by bilirubin toxicity in neuronal cells. Although moderate hypothermia has a better outcome than mild hypothermia, deep hypothermia as low as 29 degrees C has adverse effects on neuronal cell viability. PMID- 29510379 TI - Real-World Treatment Patterns for Lung Neuroendocrine Tumors: A Claims Database Analysis. AB - OBJECTIVE: The aim of this study was to describe real-world lung neuroendocrine tumor (NET) treatment patterns. METHODS: This study examined cytotoxic chemotherapy (CC), somatostatin analogues (SSA), targeted therapy (TT), interferon, and liver-directed therapies in 2 US claims databases. Patients >=18 years with >=1 inpatient or >=2 outpatient claims for lung NET, initiating pharmacologic treatment between July 1, 2009, and June 30, 2014, were identified and followed until the end of enrollment or study end, whichever occurred first. RESULTS: A total of 785 newly pharmacologically treated lung NET patients were identified: mean (SD) age was 58.6 (9.1) years; 54.0% were female; 78.2% started first-line therapy with CC, 18.1% with SSA, and 1.1% with TT. Mean duration of first-line treatment was 397 days for SSA, 142 days for CC, and 135 days for TT. 74.1% of patients received no pharmacological treatment beyond first-line. The most common second-line treatment was SSA. CONCLUSIONS: Most patients received CC as first-line treatment, with SSA being less common. SSA-treated patients remained on therapy for > 1 year, compared to < 5 months for CC. The high proportion of patients using chemotherapy and the low proportion receiving second line treatment seems consistent with treatment guidelines for small cell lung cancer rather than for NET. Future studies are warranted to describe reasons for treatment choice, discontinuation, and switching. PMID- 29510382 TI - Enteral Feeding as an Adjunct to Hypothermia in Neonates with Hypoxic-Ischemic Encephalopathy. AB - BACKGROUND: Withholding enteral feedings during hypothermia lacks supporting evidence. OBJECTIVES: We aimed to determine if minimal enteral nutrition (MEN) during hypothermia in patients with hypoxic-ischemic encephalopathy was associated with a reduced duration of parenteral nutrition, time to full oral feeds, and length of stay, but would not be associated with increased systemic inflammation or feeding complications. METHODS: We performed a pilot, retrospective, matched case-control study within the Florida Neonatal Neurologic Network from December 2012 to May 2016 of patients who received MEN during hypothermia (n = 17) versus those who were not fed (n = 17). Length of stay, feeding-related outcomes, and brain injury identified by MRI were compared. Serum inflammatory mediators were measured at 0-6, 24, and 96 h of life by multiplex assay. MRI were scored using the Barkovich system. RESULTS: MEN subjects had a reduced length of hospital stay (mean 15 +/- 11 vs. 24 +/- 19 days, p < 0.05), days receiving parenteral nutrition (7 +/- 2 vs. 11 +/- 6, p < 0.05), and time to full oral feeds (8 +/- 5 vs. 18 +/- 18, p < 0.05). MEN was associated with a significantly reduced serum IL-12p70 at 24 and 96 h (p < 0.05). Brain MRI scores were not significantly different between groups. CONCLUSION: MEN during hypothermia was associated with a reduced length of stay and time to full feeds, but did not increase feeding complications or systemic inflammation. PMID- 29510381 TI - Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-beta1/Smad3 and NF-kappaB Signaling Pathways in a Rat Model of Myocardial Infarction. AB - BACKGROUND/AIMS: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. METHODS: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor beta1 (TGF-beta1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), nuclear factor kappaB (NF kappaB), and phosphorylated inhibitor of kappa B alpha (p-IkappaBalpha) were measured by western blot analysis. RESULTS: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-beta1, and p-Smad3 expression levels but increased p Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-alpha and IL 6, as well as NF-kappaB and p-IkappaBalpha expression. CONCLUSIONS: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-beta1/Smad3 and NF-kappaB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis. PMID- 29510383 TI - Response to the Letter: The Effects of JJ Stents for Extracorporeal Shock Wave Lithotripsy in Pediatric Urolithiasis (Do JJ Stents Increase the Effectiveness of Extracorporeal Shock Wave Lithotripsy for Pediatric Renal Stones?). PMID- 29510384 TI - Full Complement. PMID- 29510385 TI - Assessment of the Utility of Cytology and Flow Cytometry of Cerebrospinal Fluid Samples in Clinical Practice. AB - OBJECTIVES: We sought to assess the utility and limitations of both flow cytometry (FC) and cytology for the analysis of cerebrospinal fluid (CSF) in a practical clinical setting. METHODS: A total of 393 consecutive CSF samples from 171 patients submitted for both cytomorphologic and FC assessments were analyzed. RESULTS: Both FC and cytology findings were negative for malignancy in 315/393 samples (80%), and either positive (POS) or suspicious/atypical (SUSP/AT) in 7% of samples. This resulted in high agreement between FC and cytology (87%). Minor discrepancies were present in 4% of the cases. In 28 samples, an abnormal population was detected by FC but not by cytology. CONCLUSIONS: FC and cytology are important complementary methods for analyzing CSF samples. In cases where cytology is SUSP/AT and FC is inconclusive or negative, additional specimens should be submitted for immunostaining, cytogenetics, and/or molecular studies. PMID- 29510386 TI - Real-World Treatment Patterns, Survival, and Prediction of CNS Progression in ALK Positive Non-Small-Cell Lung Cancer Patients Treated with First-Line Crizotinib in Latin America Oncology Practices. AB - OBJECTIVE: This study describes the real-world characteristics, treatment sequencing, and outcomes among Hispanic patients with locally advanced/metastatic ALK-positive non-small-cell lung cancer (NSCLC) treated with crizotinib. METHODS: A retrospective patient review was conducted for several centers in Latin America. Clinicians identified ALK-positive NSCLC patients who received crizotinib and reported their clinical characteristics, treatments, and survival. Overall survival and progression-free survival (PFS) were described. A Random Forest Tree (RFT) model was constructed to predict brain progression. RESULTS: A total of 73 patients were included; median age at diagnosis was 58 years, 60.3% were female, and 93.2% had adenocarcinoma. Eighty-nine percent of patients were never smokers/former smokers, 71.1% had >=2 sites of metastasis, and 20.5% had brain metastases at diagnosis. The median PFS on first-line crizotinib was 7.07 months (95% CI 3.77-12.37) and the overall response rate was 52%. Of those who discontinued crizotinib, 55.9% progressed in the central nervous system (CNS). The RFT model reached a sensitivity of 100% and a specificity of 88% for prediction of CNS progression. CONCLUSIONS: The overall response rate and the PFS observed in Hispanic patients with ALK-positive NSCLC treated with first-line crizotinib were similar to those in previous reports. An RFT model is helpful in predicting CNS progression and can help clinicians tailor treatments in a resource-limited practice. PMID- 29510387 TI - Suppression of Non-Small Cell Lung Cancer Growth and Metastasis by a Novel Small Molecular Activator of RECK. AB - BACKGROUND/AIMS: Reversion-inducing cysteine-rich protein with kazal motifs (RECK) is a novel tumor suppressor gene that is critical for regulating tumor cell invasion and metastasis. The expression of RECK is dramatically down regulated in human cancers. Harmine, a tricyclic compound from Peganum harmala, has been shown to have potential anti-cancer activity. METHODS: Cell proliferation assay (CCK-8 cell viability assay), cell cycle analysis (detection by flow cytometry), apoptosis staining assay (TUNEL staining), cell migration assay and invasion assay (transwell assay) were carried out to investigate the Harmine's efficacy on non-small cell lung cancer (NSCLC) cells in vitro. A549 luciferase cell orthotropic transplantation xenograft mouse model was used to determine the effect of Harmine treatment on NSCLC in vivo. Western blotting analysis of cell growth and metastasis related signal pathways was conducted to investigate the molecular mechanism of Harmine's inhibitory effect on NSCLC. RESULTS: Harmine treatment effectively inhibited cell proliferation and induced the G1/S cell cycle arrest of NSCLC cells. Further study proved that Harmine treatment led to apoptosis induction. Furthermore, treatment with NSCLC cells with Hamine resulted in decreased cell migration and cell invasion in vitro. More importantly, Harmine treatment significantly suppressed the NSCLC tumor growth and metastasis in mouse xenograft model in vivo. Mechanistically, in Harmine treated NSCLC cells, RECK expression and its downstream signaling cascade were dramatically activated. As a consequence, the expression level of MMP-9 and E cadherin were significantly decreased. CONCLUSION: These findings identify Harmine as a promising activator of RECK signaling for metastatic NSCLC treatment. PMID- 29510388 TI - Acceptance of Adjuvant and Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer in Germany: A Survey of Current Practice. AB - BACKGROUND: Guidelines support the use of neoadjuvant (NAC) and adjuvant (AC) chemotherapy in muscle-invasive bladder cancer. However, data from North America reported the underutilization of NAC in favor of AC despite the lower level of scientific evidence supporting AC. We aimed to assess current practice patterns of NAC and AC in -Germany. METHODS: A 15-question online survey was developed and sent via email newsletters to members of the -German Association of Urology and of the German Society of Residents in Urology in October 2016 to analyze current practice patterns. RESULTS: The survey yielded 141 individual responses from 61 different German urology departments. Eighty-nine (69.0%) and 119 (93.0%) participants were stated to regularly use NAC and AC respectively. The number of participants who were stated to use NAC and AC regularly was not associated with the type of institution (academic vs. nonacademic), number of hospital beds, and number of cystectomies performed annually. Gemcitabine/cisplatin combination chemotherapy was named as the primarily used NAC regimen by 80 (95%) respondents. The median number of administered cycles was 3 for NAC and 4 for AC. In the case of cisplatin ineligibility, combination chemotherapy with gemcitabine/carboplatin was the most common regimen. Respondents stated that chemotherapy was generally administered by urologists (81% for NAC and 85% for AC). CONCLUSIONS: Our survey of current practice shows a high acceptance rate of NAC in Germany, which was independent of the type of institution. Although the scientific level of evidence for AC is lower, it still seems to be more widely accepted than NAC. NAC and AC were generally administered by urologists. PMID- 29510389 TI - Inhibition of MiRNA-125b Decreases Cerebral Ischemia/Reperfusion Injury by Targeting CK2alpha/NADPH Oxidase Signaling. AB - BACKGROUND/AIMS: Cerebral ischemia-reperfusion (I/R) injury involves multiple independently fatal terminal pathways. CK2alpha/NADPH oxidase is an important signaling pathway associated with ischemia-reperfusion injury, and miR-125b can regulate oxidative stress-related injury. In this study, we investigated whether the effect of miR-125b in rat brain I/R injury occurs through its modulation of the CK2alpha/NADPH oxidase pathway. METHODS: Rats were subjected to 2 h of cerebral ischemia followed by 24 h of reperfusion to establish an I/R injury model. Neurological deficit was evaluated using a five-point score. Infarct volume was evaluated with 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, and RT-PCR was used to detect expressions of miR125b and CK2alpha. We then examined the association between miR-125b expression and the CK2alpha/NADPH oxidative signaling pathway in a PC-12 cell oxygen-glucose deprivation and reoxygenation (OGD/R) injury model. Transfection with miR-125b mimics, an miR 125b inhibitor, and luciferase reporter gene plasmid was accomplished using commercial kits. In these cells, Western blots were used to detect the levels of expression of CK2alpha, cleaved caspase-3, NOX2, and NOX4. RT-PCR was used to detect the expressions of CK2alpha, miR125b, NOX2, and NOX4. We evaluated Lactate Dehydrogenase (LDH) level, NADPH oxidase activity, and caspase-3 activity using commercial kits. Mitochondrial reactive oxygen species (ROS) were measured by fluorescence microscopy. For both PC-12 cells and rat brains, histological analyses were conducted to observe morphological changes, and apoptosis was measured using a commercial kit. RESULTS: I/R rats exhibited an increase in neurological deficit score, infarct volume, and cellular apoptosis, along with miR-125b elevation and CK2alpha downregulation. OGD/R treatment increased PC-12 cells' injuries, cellular apoptosis, and ROS levels. These changes were associated with miR-125b elevation, CK2alpha downregulation and activations of NOX2 and NOX4, mimicking our in vivo findings. All of these effects were reversed by the inhibition of miR-125b, confirming a strong correlation between miR-125b activity and the CK2alpha/NADPH oxidase signaling pathway. CONCLUSIONS: Based on these observations, we conclude that inhibition of miR-125b protects the rat brain from I/R injury by regulating the CK2alpha/NADPH oxidative signaling pathway. PMID- 29510391 TI - Cloning and Characterization of a Novel N-acetylglucosaminidase (AtlD) from Enterococcus faecalis. AB - The atlD gene from an Enterococcus faecalis strain isolated from a Mexican artisanal cheese was cloned, sequenced and expressed in Escherichia coli in order to perform a biochemical characterization. A partial amino acid sequence of the heterologous protein was obtained by LC-MS/MS, and it corresponded to a novel peptidoglycan hydrolase designated AtlD. Its molecular mass was 62-75 kDa, as determined by SDS-PAGE, zymography, Western blot, and exclusion chromatography. Electrofocusing rendered an isoelectric point (pI) of 4.8. It exhibited N acetylglucosaminidase activity, with an optimal pH and temperature between 6-7 and 50 degrees C, respectively. It retained 85% activity with NaCl at 1,000 mM, but it was susceptible to divalent ions, particularly Zn2+. It showed antibacterial activity against Listeria monocytogenes, Staphylococcus aureus, and enterococcal strains of clinical origin. Due to the fact that it showed activity versus pathogenic bacteria, and because of its capabilities under ionic strength, temperature, and pH values present in food matrices, it could be applied as an additive in the food industry. This study will aid in the design of new antibacterial agents of natural origin to combat food-borne diseases, and it could be used as an industrial or hospital hygiene agent as well. PMID- 29510390 TI - International Consensus Statement on Screening, Diagnosis and Treatment of Substance Use Disorder Patients with Comorbid Attention Deficit/Hyperactivity Disorder. AB - Adult attention deficit/hyperactivity disorder (ADHD) often co-occurs with substance use disorders (SUD) and is associated with early onset and more severe development of SUD and with reduced treatment effectiveness. Screening tools allow for a good recognition of possible ADHD in adults with SUD and should be used routinely, followed by an ADHD diagnostic process initiated as soon as possible. Simultaneous and integrated treatment of ADHD and SUD, using a combination of pharmaco- and psychotherapy, is recommended. Long-acting methylphenidate, extended-release amphetamines, and atomoxetine with up-titration to higher dosages may be considered in patients unresponsive to standard doses. This paper includes evidence- and consensus-based recommendations developed to provide guidance in the screening, diagnosis and treatment of patients with ADHD SUD comorbidity. PMID- 29510392 TI - Establishment of a Competitive Binding Assay Identifying the Different Characteristics of Neutralizing Epitopes of Hepatitis E Virus. AB - AIMS: To confirm the different characteristics of genotype-specific and common neutralizing epitopes of hepatitis E virus (HEV). METHODS: A competitive binding assay was established with known genotype-common neutralizing monoclonal antibodies (mAbs) 3G1 and 5G5 as well as genotype-specific neutralizing mAbs 2B1 and 4C5. HEV ORF2 recombinant p166W01 derived from genotype 1 and p166Chn derived from genotype 4 were used as coated antigens, to determine whether the mAbs recognize independent, similar, or overlapping epitopes. mAbs were produced, purified, and conjugated with horseradish peroxidase (HRP). HRP-conjugated 2B1 could react only with p166W01 but not p166Chn, HRP-conjugated 4C5 could react only with p166Chn but not p166W01, while HRP-conjugated 3G1 and 5G5 could react both with p166W01 and p166Chn. Thus, competitive binding assays were performed successively using p166W01 and p166Chn antigen. RESULTS AND CONCLUSION: The results of competitive binding assays revealed that the binding of HRP-conjugated 2B1 to p166W01 could not be inhibited by 5G5 or 3G1. Similarly, the binding of HRP-conjugated 4C5 to p166Chn could not be inhibited by 5G5 or 3G1. However, the mAbs 5G5 and 3G1 blocked each other's binding to p166W01 and p166Chn, suggesting that common and genotype-specific neutralizing mAbs recognize independent epitopes. PMID- 29510393 TI - A STAT6 Inhibitor AS1517499 Reduces Preventive Effects of Apoptotic Cell Instillation on Bleomycin-Induced Lung Fibrosis by Suppressing PPARgamma. AB - BACKGROUND/AIMS: The signal transducer and activator of transcription 6 (STAT6) transcription factor mediates PPARgamma-regulated gene expression in macrophages. However, it remains largely unknown how proximal membrane signaling events initiated by apoptotic cell recognition upregulate PPARgamma expression and activate the lung homeostatic program. METHODS: The STAT6 inhibitor AS1517499 was used to determine the role of STAT6 in mediating PPARgamma activity, anti inflammatory effects, and anti-fibrotic effects induced by apoptotic cell instillation after bleomycin treatment into C57BL/6 mice. Bronchoalveolar lavage fluid, alveolar macrophages and lungs were harvested at days 2, 7, and 14 and then analyzed by real-time PCR, immunoblotting, ELISA, immunocytochemistry and immunohistochemistry assays. RESULTS: Our data demonstrate that apoptotic cell instillation after bleomycin results in prolonged enhancement of STAT6 phosphorylation in alveolar macrophages and lung. Co-administration of the STAT6 inhibitor, AS1517499, reversed the enhanced PPARgamma expression and activity induced by apoptotic cell instillation after bleomycin treatment. By reducing the expression of PPARgamma target genes, including CD36, macrophage mannose receptor, and arginase 1, AS1517499 inhibited efferocytosis and restored pro inflammatory cytokine expression, neutrophil recruitment, protein levels, hydroxyproline content, and expression of fibrosis markers, including type 1 collagen alpha2, fibronectin, and alpha-smooth muscle actin. STAT6 inhibition reversed the expression profile of hepatocyte growth factor and interleukin-10. CONCLUSION: These results indicate that prolonged STAT6 activation following one time apoptotic cell instillation facilitates continuous PPARgamma activation, resulting in the resolution of bleomycin-induced lung inflammation and fibrosis. PMID- 29510394 TI - Cytokine Production by Mononuclear Cells from Patients with Familial Infantile Bilateral Striatal Necrosis. AB - Prompted by findings suggesting immune instability in infantile bilateral striatal necrosis (IBSN), we evaluated levels of proinflammatory (tumor necrosis factor alpha, interleukin [IL]-1beta, IL-6, interferon [IFN]gamma) and anti inflammatory (IL-10 and IL-1ra) cytokines produced by peripheral blood mononuclear cells (PBMC) from 6 children with IBSN and 11 age-matched controls. Compared to controls, non-stimulated PBMC from the IBSN group produced a significantly lower level of IL-1ra (by 38%; p < 0.001) and significantly lower levels of TNFalpha, IL-1beta, and IFNgamma (by 36% [p < 0.001], 25% [p = 0.06], and 32% [p < 0.02]) under PBMC stimulation. The severe cachexia manifesting shortly after IBSN onset may impair the immunological state, placing patients at risk of death from hyperpyrexia and sepsis. PMID- 29510395 TI - A Comparative Chromosome Mapping Study in Japanese Podismini Grasshoppers (Orthoptera: Acrididae: Melanoplinae). AB - In the present paper, karyotypes of 7 Japanese Podismini species, Anapodisma beybienkoi, Fruhstorferiola okinawaensis, Parapodisma caelestis, P. mikado, P. setouchiensis, P. tenryuensis, and Sinopodisma punctata (2n? = 21, all acrocentric), are described and compared on the basis of conventional (C-banding, DAPI/CMA3-staining, Ag-NOR) and molecular (FISH with 18S rDNA and telomeric probes) cytogenetic staining methods. This is the first study to report karyotypes of A. beybienkoi and P. caelestis. Differential staining techniques showed karyotypic diversity in these species. The number of 18S rDNA signals ranged from 2 to 6, and the signals were located on the autosomes or sex chromosomes. In all species, clusters of rDNA coincided with Ag-NORs. Telomeric signals occurred at the chromosome ends at the pachytene stage and seldom at other stages of meiosis. Paracentromeric and some distal and interstitial blocks of constitutive heterochromatin were detected in the chromosomes of Anapodisma, Fruhstorferiola, and Parapodisma species. Staining with DAPI and CMA3 revealed 2 groups of heterochromatin composition. In addition, intraspecific differences in the number of rDNA clusters and C-bands were observed within Parapodisma species. Based on the evidence of cytogenetic characteristics, the monophyly of Tonkinacridina cannot be supported. PMID- 29510396 TI - Multiphoton Microscopy for Caries Detection with ICDAS Classification. AB - Dentin carious lesion is a dynamic process that involves demineralization and collagen denaturation. Collagen type I is the major protein in dentin and it has been investigated based on its optical properties. Multiphoton microscopy (MPM) is a nonlinear imaging technique that reveals the caries process using the collagen two-photon excitation fluorescence (2PEF) and its second-harmonic generation (SHG). Combining the histological and the International Caries Detection and Assessment System (ICDAS) classifications with nonlinear optical spectroscopy (NLOS), 2PEF and SHG intensities of enamel and dentin were highly altered during the caries process. It has been proven that the ratio SHG/2PEF is a relevant indicator of the organic matrix denaturation [Terrer et al.: J Dent Res 2016; 96: 574-579]. In the present study, a series of measurable signals is made to detect early stages of carious lesion according to the ICDAS classification and to explore the relationship between these measures and the ICDAS scale. Comparison of the efficiency of nonlinear optical signals for caries detection with the ICDAS classification is essential to evaluate their potential for clinical application. In our study, the use of the NLOS measured by MPM allowed us to monitor a quantitative parameter (SHG/2PEF ratio) according to the dentin carious lesion state (ICDAS and histological examination). Three coherent new groups were defined (ICDAS 0/1; ICDAS 2/3; ICDAS 4/5/6), where the carious process can be clearly described with a statistically significant decrease of the SHG/2PEF ratio. PMID- 29510397 TI - Oxytocin as a Neurobiological Marker of Ruptures in the Working Alliance. PMID- 29510398 TI - Epigenetic Effects of Intravenous Diacetylmorphine on the Methylation of POMC and NR3C1. AB - The administration of diacetylmorphine (DAM) reduces the activation of the hypothalamic-pituitary-adrenal (HPA) axis in opioid-maintained patients. However, the epigenetic effects of DAM on addiction-related genes have not been investigated yet. In a randomized controlled study, we examined the immediate effects of intravenous DAM versus placebo on the promoter methylation of the POMC (pro- opiomelanocortin) and NR3C1 (glucocorticoid receptor 1) genes. Twenty-eight heroin-dependent patients on DAM-assisted treatment received either DAM or saline in a randomized crossover design and 17 healthy participants received saline only. EDTA blood samples were taken 25 min before and 10 min after the injection of DAM or saline. We found reciprocal regulation effects for DAM versus saline application regarding the methylation of POMC; while DAM injection significantly increased methylation, saline injection led to a significant decrease in methylation for patients as well as controls. NR3C1 data did not show significant changes in methylation. Injection of DAM blunted stress hormone levels and the POMC promoter methylation of heroin-dependent patients. These findings provide first preliminary insights into the epigenetic mechanisms underlying the emotional regulation effects of DAM-assisted treatment in severe heroin-dependent patients. PMID- 29510399 TI - Contralesional Brain Activity in Acute Ischemic Stroke. AB - BACKGROUND: The noninjured, contralateral hemisphere is increasingly acknowledged in the process of recovery from acute ischemic stroke. We estimated the value of conventional electroencephalography (EEG) recordings for identifying contralateral hemisphere involvement in relation to functional recovery. METHODS: We analyzed 2-min epochs from 21 electrode EEG registrations of 18 patients with acute hemispheric ischemic stroke and compared with 18 age-matched controls. Outcome was dichotomized as good (modified Rankin Scale [mRS] 0-2) or poor (mRS 3 5 or death) at 3 months. Effects of the infarct on the ipsi-and contralateral hemispheres were analyzed by the delta/alpha ratio (DAR) and 2 measures of functional connectivity (magnitude squared coherence [MSC] and weighted phase lag index [WPLI]). RESULTS: DAR was higher in patients than in controls, both in the ipsilateral and in the contralateral hemisphere (median 4.5 +/- 6.7 ipsilateral and 2.4 +/- 2.0 contralateral vs. 0.5 +/- 0.5 in the control group, p < 0.001), indicating robust EEG changes in both lesioned and non-lesioned hemisphere. MSC and WPLI in the alpha and beta frequency bands were lower in patients than in controls in both hemispheres, indicating clear disturbances of functional connectivity (p < 0.05). In the poor outcome group, contralateral MSC and WPLI were lower than in the good outcome group, although these differences did not reach statistical significance. CONCLUSIONS: Short conventional EEG measurements show robust changes of brain activity and functional connectivity in both ipsilateral and contralateral hemispheres of patients with acute ischemic stroke. Changes of remote functional connectivity tend to interact with functional recovery. Future studies should estimate predictive values for individual patients and interactions with plasticity enhancing treatments. PMID- 29510400 TI - ADAM17-Mediated Ectodomain Shedding of Toll-Like Receptor 4 as a Negative Feedback Regulation in Lipopolysaccharide-Activated Aortic Endothelial Cells. AB - BACKGROUND/AIMS: Lipopolysaccharide (LPS)-activated monocytes/macrophages develop endotoxin tolerance in part by reducing cell surface toll-like receptor 4 (TLR4) through cluster of differentiation 14 (CD14)-dependent endocytosis. In case of endothelial cells, CD14 is expressed in low copy numbers as compared with monocytes/macrophages. Thus, we explored how endothelial cells regulate TLR4 expression after LPS stimulation. METHODS: Cultured human aortic endothelial cells (HAECs) were treated with LPS. TLR4 expression was analyzed by Western blot analysis and immunofluorescence staining. A disintegrin and metalloprotease 17 (ADAM17) activity was measured using a fluorescent substrate. RESULTS: TLR4 in cell lysate began to decrease within 30 min of LPS treatment with a maximal reduction at 2 h, and it was accompanied by an increase of N-terminal fragment of TLR4 in culture supernatant, indicating ectodomain shedding of the receptor. LPS activated p38 mitogen-activated protein kinase (p38 MAPK) and ADAM17, while LPS induced ADAM17 activation was inhibited by SB203580, a p38 MAPK inhibitor. LPS induced ectodomain shedding of TLR4 was attenuated by siRNA depletion of ADAM17 as well as TAPI-2 (an inhibitor of ADAM family) and SB203580. LPS pretreatment resulted in a blunted response of p38 MAPK activation to further LPS stimulation. In the cells depleted of ADAM17, LPS-induced p38 MAPK activation was prolonged and LPS-induced intercellular adhesion molecule-1 expression was potentiated. CONCLUSION: HAECs respond to LPS by rapid shedding of the ectodomain of TLR4 and thereby reduce the responsiveness to subsequent LPS exposure. ADAM17, downstream of p38 MAPK, is implicated in the ectodomain cleavage of TLR4. PMID- 29510401 TI - Subclinical Macular Edema as a Predictor of Progression to Central-Involved Macular Edema in Type 2 Diabetes. AB - PURPOSE: The aim of this study was to examine the relationship between subclinical diabetic macular edema (SCME) and the development of central-involved macular edema (CIME) in patients with diabetes mellitus type-2 and mild nonproliferative diabetic retinopathy (NPDR), from 2 populations of different ethnicities. METHODS: Two hundred and five patients with diabetes mellitus type-2 and mild NPDR with no prior laser or intravitreal treatment were followed for 2 years or until the development of CIME. Ophthalmological examinations, including BCVA, fundus photography with RetmarkerDR analysis, and optical coherence tomography were performed at baseline and months 6, 12, and 24. RESULTS: One hundred and fifty eight eyes/patients reached either the study endpoint, CIME (n = 24), or performed the 24-month visit without developing CIME (n = 134). Fifty eyes/patients had SCME at baseline (31.6%). Of these 50 eyes, 16 (32.0%) developed CIME, whereas of the 108 eyes with normal retinal thickness (RT) at baseline, only 8 (7.4%) developed CIME (p < 0.001). Patients with increased RT in the central subfield at baseline showed a 12-fold risk of progression to CIME compared with patients without SCME. CONCLUSIONS: In patients with mild NPDR, the presence of SCME is a good predictor of progression to CIME. PMID- 29510402 TI - Oxymatrine Inhibits Homocysteine-Mediated Autophagy via MIF/mTOR Signaling in Human Umbilical Vein Endothelial Cells. AB - BACKGROUND/AIMS: Genetic or nutritional deficiencies in homocysteine (Hcy)metabolism lead to the accumulation of Hcy and its metabolites in the blood. This can lead to hyperhomocysteinemia (HHcy), which is an independent risk factor for cardiovascular disease. Studies have shown that HHcy leads to endothelial dysfunction, a hallmark of atherosclerosis, which may explain this link. The precise mechanism remains unclear, but a strong possibility is excessive HHCy induced autophagy. Autophagy has been better studied in ischemia/reperfusion (I/R) injuries, and previous work showed that Oxymatrine (OMT), a quinolizidine alkaloid, protects cells against myocardial I/R injury by inhibiting autophagy. The aim of this study was to determine whether OMT inhibits autophagy in HHcy. METHODS: Autophagy in HUVEC cells treated with Hcy in the presence and absence of OMT was visualized bytransmission electron microscopy and the degree was determined by western blotting and qRT-PCR. Small interfering RNA (siRNA)was used to determine the efficiency of Macrophage migration inhibitory factor (MIF) inhibition. Cell apoptosis wasdetected by western blotting and flow cytometric analysis. RESULTS: OMT inhibited autophagy, MIF, and mTOR in HUVECs during Hcy exposure, depending on the dose. siRNA-mediated MIF knockdown decreased Hcy induced autophagy, while administration of 3-methyladenosine and rapamycin showed that they also induce autophagy. Furthermore, OMT dose-dependently inhibited the Hcy-induced HUVEC apoptosis/death. CONCLUSIONS: These results suggest that Hcy can evokeautophagy-activated HUVEC apoptosis/death via a MIF/mTOR signaling pathway, which can be reversed by OMT. Our results provide a new insight into a functional role of OMT in the prevention of Hcy-induced HUVEC injury and death. PMID- 29510404 TI - Newborn Plasma Glucose Concentration Nadirs by Gestational-Age Group. AB - BACKGROUND: The glucose concentrations and times to nadir for newborns of all gestational ages when intrapartum glucose-containing solutions are not routinely provided are unknown. OBJECTIVE: To characterize and compare patterns of initial glucose concentration nadirs by gestational-age groups. METHODS: A cross sectional cohort study of 1,366 newborns born in 1998 at the University of Arkansas for Medical Sciences, appropriate for gestational age, nonasphyxiated, nonpolycythemic, and not infants of diabetic mothers, were included. Initial plasma glucose concentrations, before intravenous fluids or feedings, were plotted against time after birth for 4 gestational-age groups (full term [FT], >=37-42 weeks; late preterm [LPT], >=34 and < 37 weeks; preterm [PT], >=28 and < 34 weeks; and extremely low gestational age newborns [ELGAN], 23 and < 28 weeks of gestation). RESULTS: ELGAN had the earliest nadir at 61 +/- 4 min, followed by PT newborns (71 +/- 2 min), and then LPT and FT newborns at 92-93 min. The time to nadir for ELGAN and PT newborns was significantly earlier than for FT newborns. Glucose nadir concentrations for ELGAN, PT, and LPT newborns were significantly lower than for FT newborns. LPT newborns' pattern of glucose paralleled those of FT newborns, with values approximately 5-6 mg/dL lower during the first 3 h. CONCLUSION: Plasma glucose nadirs occurred at different times among gestational-age groups during the early postnatal period as follows: ELGAN < PT < LPT ~ FT. In order to potentially prevent low glucose concentrations at the time of the nadir, exogenous glucose should be provided to all newborns as soon as possible after birth. PMID- 29510405 TI - Implementation of an Integrative Oncological Concept in the Daily Care of a German Certified Breast Cancer Center. AB - BACKGROUND: In recent decades the concept of integrative medicine has attracted growing interest in patients and professionals. At the Gemeinschaftskrankenhaus Havelhohe (GKH), a hospital specialized in anthroposophical medicine, a breast cancer center (BCC) has been successfully certified for more than 5 years. The objective of the present study was to analyze how integrative strategies were implemented in the daily care of primary breast cancer patients. METHODS: Clinical, demographic, and follow-up data as well as information on non pharmacological interventions were analyzed. In addition, BCC quality measures were compared with data of the National Breast Cancer Benchmarking Report 2016. RESULTS: Between 2011 and 2016, 741 primary breast cancer patients (median age 57.4 years) were treated at the GKH BCC. 91.5% of the patients showed Union for International Cancer Control (UICC) stage 0, I, II, or III and 8.2% were in UICC stage IV. 97% of the patients underwent surgery, 53% radiation, 38% had hormone therapy, and 25% received cytostatic drugs. 96% of the patients received non pharmacological interventions and 32% received Viscum album L. THERAPY: Follow-up was performed in up to 93% of the patients 2 years after first diagnosis. Compared to nationwide benchmarking BCCs, the GKH BCC met the requirements in central items. CONCLUSIONS: The results of the present study show that integrative therapies offered by the concept of anthroposophical medicine can be implemented in the daily care and treatment of a certified BCC. However, as national guidelines on integrative concepts in oncology are missing, further studies are needed for a systematic evaluation of integrative treatment and care concepts in this field. PMID- 29510403 TI - Genetic Variability and Sequence Relatedness of Matrix Protein in Viruses of the Families Paramyxoviridae and Pneumoviridae. AB - BACKGROUND: The families Paramyxoviridae and Pneumoviridae comprise a broad spectrum of viral pathogens that affect human health. The matrix (M) protein of these viruses has a central role in their life cycle. In line with this, molecular characteristics of the M proteins from variable viruses that circulated in Croatia were investigated. METHODS: Sequences of the M proteins of human parainfluenza virus (HPIV) 1-3 within the family Paramyxoviridae, human metapneumovirus (HMPV), and human respiratory syncytial virus from the family Pneumoviridae were obtained and analyzed. RESULTS: M proteins were very diverse among HPIVs, but highly conserved within each virus. More variability was seen in nucleotide sequences of M proteins from the Pneumoviridae family. An insertion of 8 nucleotides in the 3' untranslated region in 1 HMPV M gene sequence was discovered (HR347-12). As there are no samples with such an insertion in the database, this insertion is of interest and requires further research. CONCLUSION: While we have confirmed that M proteins were conserved among individual viruses, any changes that are observed should be given attention and further researched. Of special interest is inclusion of HPIV2 M proteins in this analysis, as these proteins have not been studied to the same extent as other paramyxoviruses. PMID- 29510407 TI - Erratum. PMID- 29510406 TI - Polymorphisms of IKZF3 Gene and Autoimmune Thyroid Diseases: Associated with Graves' Disease but Not with Hashimoto's Thyroiditis. AB - BACKGROUND/AIMS: The IKZF3 gene encodes a zinc-finger protein that plays an important role in the proliferation and differentiation of B lymphocytes. Autoimmune thyroid diseases (AITDs), mainly include Graves' disease (GD) and Hashimoto's thyroiditis (HT), are probably caused by the aberrant proliferation of B cells. The objective of this study was to explore the association between IKZF3 polymorphisms and AITDs. METHODS: We examined 915 AITD patients (604 GD and 311 HT) and 814 healthy controls. IKZF3 variants (rs2941522, rs907091, rs1453559, rs12150079 and rs2872507) were tested by PCR-ligase detection reaction. RESULTS: It was manifested that that the minor alleles of the five loci increased susceptibility to GD (p<0.05 for rs2941522, and p<0.01 for rs907091, rs1453559, rs12150079 and rs2872507) but in HT patients, these loci showed no significant difference compared with controls. Similarly, the genotype distributions of GD patients manifested obvious differences in all these loci compared with the control group, whereas no statistical differences were observed between HT patients and controls. Furthermore, bioinformatics tools were used to analyze rs1453559, rs12150079 and rs907091. These variants were believed to be the transcription regulator. CONCLUSION: It is the first time we reported the association between the IKZF3 polymorphisms and GD, indicating that IKZF3 gene tends to bean important risk factor for the development of GD. PMID- 29510408 TI - Effect of Phosphorylated Chitosan on Dentin Erosion: An in vitro Study. AB - The aim of this study was to evaluate the antierosive effect of phosphorylated chitosan in dentin. Bovine dentin specimens were randomly distributed into the following groups: (1) no treatment (NoTx/negative control), (2) phosphate buffered saline solution (PBS), (3) AmF/NaF/SnCl2 (positive control), (4) 0.5% chitosan solution (Chi), (5) 0.5% neutral phosphorylated (NP)-Chi, and (6) 0.5% alkaline phosphorylated (AP)-Chi. The specimens were submitted to de remineralization treatment cycles for 5 days: 0.5% citric acid (2 min), remineralizing solution (30 min), and surface treatment according to assigned groups (2 min, 6*/day). The loss of dentin surface was measured by profilometry. Hardness and modulus of elasticity were measured using a nanoindenter equipped with a Berkovich diamond tip. The dentin surface was analyzed by scanning electron microscopy (SEM). The largest loss of dentin was observed in the No Tx and PBS groups (approx. 25 um). The group treated with AmF/NaF/SnCl2 showed less loss of dentin (67% reduction vs. NoTx and PBS), followed by the groups treated with NP-Chi and AP-Chi (33% reduction), and Chi (18% reduction). Nanohardness and modulus of elasticity were similar in the NoTx and PBS groups, with a small increase in stiffness in all other groups. SEM revealed that the experimental solution of AP-Chi had a favorable effect on maintaining the integrity of collagen fibrils. AmF/NaF/SnCl2 showed a preserved mineralized collagen surface. Further studies are warranted to explore this nontoxic phosphorylated chitosan polymer as an effective agent in the prevention and treatment of dental erosion. PMID- 29510409 TI - Congenital Posterior Urethral Fistulae: Literature Review and Case Report. AB - Congenital posterior urethral-perineal fistula is an abnormal communication extending from the posterior urethra to the perineal skin. We present the case of an 11-year-old boy who had recurrent febrile urinary tract infections and abnormal dribbling of urine from the perineum. Fistulogram showed a paraescrotal fistula tract, which was then surgically excised. During the 10 months of follow up, the patient remained asymptomatic without recurrence of urinary pathology. PMID- 29510411 TI - The Effects of JJ Stents for Extracorporeal Shock Wave Lithotripsy in Pediatric Urolithiasis. PMID- 29510410 TI - Body Mass Index as a Risk Factor for Toxicities in Patients with Advanced Soft Tissue Sarcoma Treated with Trabectedin. AB - OBJECTIVES: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on >=1 anthracycline +/- ifosfamide regimen were retrospectively reviewed. RESULTS: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin. PMID- 29510412 TI - Changes in the Proteomic Profile of Acquired Enamel Pellicles as a Function of Their Time of Formation and Hydrochloric Acid Exposure. AB - OBJECTIVE: Changes in the protein profile of acquired enamel pellicles (AEP) formed in vivo over different time periods were evaluated after the application of hydrochloric acid (HCl). METHODS: Nine subjects were submitted to dental prophylaxis with pumice. After 3 or 120 min, the teeth were isolated with cotton rolls and 50 MUL of 0.1 M HCl (pH 1.0), 0.01 M HCl (pH 2.0), or deionized water were applied on the buccal surface of the teeth for 10 s. The AEP was then collected using an electrode filter paper presoaked in 3% citric acid. After protein extraction, the samples were submitted to reverse-phase liquid chromatography coupled to mass spectrometry (nano LC-ESI-MS/MS). Label-free quantification was performed (Protein Lynx Global Service software). RESULTS: A total of 180 proteins were successfully identified in the AEP samples. The number of identified proteins increased with the time of pellicle formation. Only 4 proteins were present in all the groups (isoforms of IgA, serum albumin, and statherin). The greatest number of proteins identified uniquely in one of the groups was obtained for the groups treated with HCl after 2 h of pellicle formation (approx. 50 proteins). CONCLUSION: Proteins resistant to removal by HCl, such as serum albumin and statherin, were identified even in the short-term AEP. In addition, 120-min pellicles present many proteins that are resistant to removal by HCl. This suggests an increase in protection against intrinsic acids with the time of pellicle formation, which should be evaluated in future studies. PMID- 29510413 TI - The Regulator Gene rnc Is Closely Involved in Biofilm Formation in Streptococcus mutans. AB - Streptococcus mutans is an important factor in the etiology and pathogenesis of dental caries, largely owing to its ability to form a stable biofilm. Previous animal studies have indicated that rnc could decrease the amount of sulcal caries, and that the downregulation of cariogenicity might be due to its capacity to disrupt biofilm formation. However, the biofunctions by which rnc is involved in biofilm formation remain to be elucidated. In this study, we further investigate the role of rnc based on the study of mature biofilm. Scanning electron microscopy and the crystal violet assay were used to detect the biofilm forming ability. The production and distribution of exopolysaccharides within biofilm was analyzed by exopolysaccharide staining. Gel permeation chromatography was used to perform molecular weight assessment. Its adhesion force was measured by atomic force microscopy. The expression of biofilm formation-associated genes was analyzed at the mRNA level by qPCR. Here, we found that rnc could occur and function in biofilm formation by assembling well-structured, exopolysaccharide encased, stable biofilms in S. mutans. The weakened biofilm forming ability of rnc-deficient strains was associated with the reduction of exopolysaccharide production and bacterial adhesion. Over all, these data illustrate an interesting situation in which an unappreciated regulatory gene acquired for virulence, rnc, most likely has been coopted as a potential regulator of biofilm formation in S. mutans. Further characterization of rnc may lead to the identification of a possible pathogenic biofilm-specific treatment for dental caries. PMID- 29510415 TI - Donor-Site Outcomes for the Osteocutaneous Radial Forearm Free Flap. PMID- 29510414 TI - Erratum to: A 35-Year Evolution of Free Flap-Based Breast Reconstruction at a Large Urban Academic Center. PMID- 29510416 TI - An Easy Method to Make a Microscale. PMID- 29510417 TI - Development of a Device-Assisted Nerve-Regeneration Procedure in Disruptive Lesions of the Brachial Plexus. AB - BACKGROUND: We describe the development of a new surgical procedure to be used in the treatment of disruptive brachial plexus (BP) lesions. It is centered on an artificial device designed to assist nerve regeneration by providing a confined and protected environment. Nerve fibers can repair inside the device, while the adverse massive scar-tissue formation is limited to the outside of the device. METHODS: Steps in the development of the procedure were (1) definition of the rationale, (2) design of the device, (3) choice of an in vivo translational model, (4)refinement of the surgical procedure, and (5) performance of an in vivo pilot study as a proof of concept. An interdisciplinary team from several laboratories was involved in this work over a period of 6 years. RESULTS: Results showed the absence of significant scar tissue in the regenerate and the presence of myelinated fibers aligned proximodistally between the stumps. This surgical approach can be seen not only as a definitive treatment but also as an early examination and stabilization before some different surgery will be later performed. It may also be used as additional protection for traditional surgery like end-to-end coaptation. CONCLUSIONS: We conclude that the availability of a suitable device-assisted early treatment, even if not to be considered definitive, could help in addressing the BP lesions at an earlier stage and this may improve the final outcome. Our evidence justifies further experimentation on this approach. PMID- 29510418 TI - Immunohistochemical Detection of Motor Endplates in the Long-Term Denervated Muscle. AB - BACKGROUND: We have demonstrated that the native motor zone (NMZ) within a muscle is an ideal target for performing nerve-muscle-endplate band grafting (NMEG) to restore motor function of a denervated muscle. This study was designed to determine spatiotemporal alterations of the myofibers, motor endplates (MEPs), and axons in the NMZ of long-term denervated muscles for exploring if NMEG-NMZ technique would have the potential for delayed reinnervation. METHODS: Sternomastoid (SM) muscles of adult female Sprague-Dawley rats (n = 21) were experimentally denervated and denervation-induced changes in muscle weight, myofiber size, MEPs, and intramuscular nerve axons were evaluated histomorphometrically and immunohistochemically at the end of 3, 6, and 9 months after denervation. The values obtained from the ipsilateral normal side served as control. RESULTS: The denervated SM muscles exhibited a progressive reduction in muscle weight (38%, 31%, and 19% of the control) and fiber diameter (52%, 40%, and 28% of the control) for 3-, 6-, and 9-month denervation, respectively. The denervated MEPs were still detectable even 9 months after denervation. The mean number of the denervated MEPs was 79%, 65%, and 43% of the control in the 3-, 6-, and 9-month denervated SM, respectively. Degenerated axons in the denervated muscles became fragmented. CONCLUSIONS: Persistence of MEPs in the long-term denervated SM suggests that some surgeries targeting the MEPs such as NMEG-NMZ technique should be effective for delayed reinnervation. However, more work is needed to develop strategies for preservation of muscle mass and MEPs after denervation. PMID- 29510419 TI - Initial Management of Traumatic Digit Amputations: A Retrospective Study of Functional Outcomes. AB - BACKGROUND: Traumatic amputation of one or more digits can have a serious detrimental effect on social and economic standings which can be mitigated by successful replantation. Little has been recorded on preoperative management before replantation and how this affects the outcomes of the replanted digit. METHODS: A retrospective cohort study was conducted and data collected over an 18-month period. Three protocols for preoperative management were examined: minimal (basic wound management), complete Buncke (anticoagulation, dry dressing on amputate placed on indirect ice and absence of a digital block), and incomplete (any two or three criteria from complete Buncke in addition to the minimal) protocols. Data was collected on survival rate, secondary operations, and complication rate. Function was defined by sensation, range of movement, and strength. RESULTS: Seventy four of 177 digits were replanted with an overall survival rate of 86.5%. The rates for minimal, incomplete, and complete protocols were 95%, 87%, and 91%, respectively, and not significantly different. The complication rate was significantly different between the complete (20%) and minimal (60%) protocols (p = 0.0484). Differences in sensation and grip strength were statistically significant between protocols (p = 0.0465 and p = 0.0430, respectively). Anticoagulation, no digital block and dry gauze all showed reduced complication rates in comparison to their counterparts. CONCLUSIONS: The Buncke protocol, which includes anticoagulation, no digital block, and dry gauze, was found to significantly reduce the complication rate which suggests that it prevents compromise of tissue integrity. Significant differences were found between protocols for sensation and grip strength. A higher-powered study is needed to investigate the effects of preoperative management on complication rates and functional outcomes. PMID- 29510420 TI - Impact of Obesity on Outcomes in Breast Reconstruction: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Increased rates of both breast cancer and obesity have resulted in more obese women seeking breast reconstruction. Studies demonstrate that these women are at increased risk for perioperative complications. A systematic review was conducted to assess the outcomes in obese women who underwent breast reconstruction following mastectomy. METHODS: Cochrane, PUBMED, and EMBASE electronic databases were screened and data were extracted from included studies. The clinical outcomes assessed were surgical complications, medical complications, length of postoperative hospital stay, reoperation rate, and patient satisfaction. RESULTS: Out of 33 studies met the inclusion criteria for the review and 29 provided enough data to be included in the meta-analysis (71,368 patients, 20,061 of whom were obese). Obese women (body mass index > 30 kg/m2) were 2.29 times more likely to experience surgical complications (95% confidence interval (CI) 2.19-2.39; p < 0.00001), 2.89 times more likely to have medical complications (95% CI 2.50-3.35; p < 0.00001), and had a 1.91 times higher risk of reoperation (95% CI 1.75-2.07; p < 0.00001). The most common complication, wound dehiscence, was 2.51 times more likely in obese women (95% CI 1.80-3.52; p < 0.00001). Sensitivity analysis confirmed that obese women were more likely to experience surgical complications (risk ratio 2.36, 95% CI 2.22 2.52; p < 0.00001). CONCLUSIONS: This study provides evidence that obesity increases the risk of complications in both implant-based and autologous reconstruction. Additional prospective and observational studies are needed to determine if the weight reduction prior to reconstruction reduces the perioperative risks associated with obesity. PMID- 29510421 TI - Using Paralytic as Part of Premedication for Elective Intubation of Premature Neonates May Result in Transient Impairment of Ventilation. PMID- 29510422 TI - Elective Cesarean Delivery at Term and the Long-Term Risk for Neurological Morbidity of the Offspring. AB - OBJECTIVE: The study's objective was to determine whether mode of delivery has an impact on the long-term risk for neurologic morbidity of the offspring. MATERIALS AND METHODS: This population-based cohort analysis included all term singleton deliveries between 1991 and 2014. The study population was divided into two study group: elective cesarean deliveries (CD) versus vaginal deliveries (VD). Urgent cesarean deliveries, pregnancy, and delivery complications including preeclampsia and gestational diabetes were excluded. The evaluation of cumulative neurological hospitalization rate over time was performed with a Kaplan-Meier survival analysis and Cox proportional hazards models were used to study the independent association between mode of delivery and neurological morbidity while controlling for potential confounders. RESULTS: During the study period 132,054 deliveries met the inclusion criteria, 11,746 CD (8.9%), and 120,308 (91.1%) VD. A total of 3,626 neurological hospitalizations were documented with 2.70% (3,244) in the VD group as compared with 3.25% (382) in the CD group. The survival curves showed higher cumulative hospitalization rates in the CD as compared with the VD group (p <= 0.001). The Cox analysis demonstrated CD to be an independent risk factor for pediatric neurological hospitalizations (p < 0.001). CONCLUSION: Term elective CD is an independent risk factor for neurological morbidity of the offspring. PMID- 29510424 TI - Red Blood Cell Transfusions Affect Intestinal and Cerebral Oxygenation Differently in Preterm Infants with and without Subsequent Necrotizing Enterocolitis. AB - OBJECTIVE: To assess intestinal and cerebral oxygenation during and after red blood cell (RBC) transfusions in preterms with or without subsequent transfusion associated necrotizing enterocolitis (TANEC). STUDY DESIGN: In preterms of < 32 weeks' gestational age, we measured intestinal and cerebral regional tissue oxygen saturation (rintSO2, rcSO2) and their variabilities using near-infrared spectroscopy during and after transfusions. We compared eight infants who developed TANEC 6 to 48 hours after RBC transfusions with 16 controls. RESULTS: In TANEC infants, rcSO2 was lower during and after RBC transfusions than in controls, median (interquartile range) 55% (50-62) versus 72% (65-75), p < 0.01. There were no differences regarding rintSO2. Individual rintSO2 and rcSO2 ranges were smaller after transfusions in TANEC infants, 28% (9-36) versus 49% (40-65), p < 0.01, and 17% (14-33) versus 36% (26-57), p = 0.01, as was short-term rintSO2 variability. For each 10% higher rcSO2, the risk of developing TANEC decreased (odds ratio 0.09; 95% confidence interval 0.01-0.63). The smaller the rintSO2 range after transfusion, the higher the risk of developing TANEC. CONCLUSION: In preterm infants lower rcSO2, but not rintSO2, values during and after RBC transfusions are associated with TANEC. Lower rintSO2 and rcSO2 variabilities after RBC transfusions may represent a diminished capacity for vascular adaptation, possibly leading to TANEC. PMID- 29510423 TI - Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth. AB - OBJECTIVE: To evaluate the association of magnesium sulfate (MgSO4) exposure and candidate gene polymorphisms with adverse neurodevelopmental outcomes following preterm birth. STUDY DESIGN: We performed a nested case-control analysis of a randomized trial of maternal MgSO4 before anticipated preterm birth for the prevention of cerebral palsy (CP). Cases were children who died within 1 year of life or were survivors with abnormal neurodevelopment at age 2 years. Controls were race- and sex-matched survivors with normal neurodevelopment. We analyzed 45 candidate gene polymorphisms in inflammation, coagulation, and vascular regulation pathways and their association with (1) psychomotor delay, (2) mental delay, (3) CP, and (4) combined outcome of death/CP. Logistic regression analyses, conditional on maternal race and child sex, and adjusted for treatment group, gestational age at birth and maternal education, were performed. RESULTS: Four hundred and six subjects, 211 cases and 195 controls, were analyzed. The strongest association was for IL6R (rs 4601580) in which each additional copy of the minor allele was associated with an increased risk of psychomotor delay (adjusted odds ratio 3.3; 95% confidence interval, 1.7-6.5; p < 0.001). CONCLUSION: Candidate gene polymorphisms are associated with death and adverse neurodevelopmental outcomes following preterm birth. MgSO4 may abrogate this genotype association for some loci. PMID- 29510425 TI - Impact of Peanut Ball Device on the Duration of Active Labor: A Randomized Control Trial. AB - OBJECTIVE: To evaluate whether the use of a peanut ball device shortens the duration of active labor in nulliparas. STUDY DESIGN: Single-site, nonblinded randomized trial in nulliparous women admitted for labor or labor induction. English-speaking women > 18 years of age with singleton pregnancies were enrolled. Participants were randomized to the use of peanut ball or usual care upon reaching the active phase of labor (>= 6 cm cervical dilation) with an epidural. Primary outcome was rate of cervical dilation. Secondary outcomes were rates of cesarean delivery and fetal presentation at time of full dilation or delivery. RESULTS: Ninety-six patients enrolled; 63 reached full cervical dilation. There was no statistically significant difference in rates of cervical dilation (0.98cm/h vs. 0.79cm/h, p = 0.27) or length of labor (315 minutes vs. 387 minutes, p = 0.14) between the groups. There was no difference in the rates of cesarean delivery (33% vs. 35%, p = 0.8) or occiput posterior presentation. (28% vs. 9%, p = 0.09). Among the subgroup who had labor arrest, fewer patients using the peanut ball experienced arrest of dilation; this approached but did not reach statistical significance (30% vs. 73% p = 0.05). CONCLUSION: Use of the peanut ball does not significantly increase rates of cervical dilation or decrease time in active labor. PMID- 29510426 TI - Incident Risk Factors and Major Bleeding in Patients with Atrial Fibrillation Treated with Oral Anticoagulants: A Comparison of Baseline, Follow-up and Delta HAS-BLED Scores with an Approach Focused on Modifiable Bleeding Risk Factors. AB - AIM: When assessing bleeding risk in patients with atrial fibrillation (AF), risk stratification is often based on the baseline risks. We aimed to investigate changes in bleeding risk factors and alterations in the HAS-BLED score in AF patients. We hypothesized that a follow-up HAS-BLED score and the 'delta HAS-BLED score' (reflecting the change in score between baseline and follow-up) would be more predictive of major bleeding, when compared with baseline HAS-BLED score. METHODS AND RESULTS: A total of 19,566 AF patients receiving warfarin and baseline HAS-BLED score <=2 were studied. After a follow-up of 93,783 person years, 3,032 major bleeds were observed. The accuracies of baseline, follow-up, and delta HAS-BLED scores as well as cumulative numbers of baseline modifiable bleeding risk factors, in predicting subsequent major bleeding, were analysed and compared. The mean baseline HAS-BLED score was 1.43 which increased to 2.45 with a mean 'delta HAS-BLED score' of 1.03. The HAS-BLED score remained unchanged in 38.2% of patients. Of those patients experiencing major bleeding, 76.6% had a 'delta HAS-BLED' score >=1, compared with only 59.0% in patients without major bleeding (p < 0.001). For prediction of major bleeding, AUC was significantly higher for the follow-up HAS-BLED (0.63) or delta HAS-BLED (0.62) scores, compared with baseline HAS-BLED score (0.54). The number of baseline modifiable risk factors was non-significantly predictive of major bleeding (AUC = 0.49). CONCLUSION: In this 'real-world' nationwide AF cohort, follow-up HAS-BLED or 'delta HAS-BLED score' was more predictive of major bleeding compared with baseline HAS-BLED or the simple determination of 'modifiable bleeding risk factors'. Bleeding risk in AF is a dynamic process and use of the HAS-BLED score should be to 'flag up' patients potentially at risk for more regular review and follow-up, and to address the modifiable bleeding risk factors during follow-up visits. PMID- 29510427 TI - Perioperative Complications of Surgery for Hypertrophic Pyloric Stenosis. AB - Pyloromyotomy is the tried and tested surgical procedure for successful operative treatment of pyloric stenosis. Over time, the operative approach has evolved to take advantage of cosmetically superior incisions and more recently minimally invasive surgery. During and following surgery, complications are uncommon. The specific complications of an inadequate pyloromyotomy requiring repeated procedure and mucosal perforation during an overzealous pyloromyotomy represent the ends of a spectrum within which sits the perfect procedure. Here, we discuss these specific complications together with the other potential complications following surgery for hypertrophic pyloric stenosis, including anesthetic considerations. PMID- 29510428 TI - Perioperative Complications in Neonatal Surgery: Biliary Atresia and Choledochal Malformations. AB - Biliary atresia (BA) and congenital choledochal malformations (CCM) are rare. Both pathologies must (BA) or may (CCM) be operated during the neonatal period or early infancy. We briefly describe the classical operative techniques for both pathologies, followed by the most common and severe perioperative complications encountered during and up to 30 days after surgery in children operated for BA and CCM early in life. For patients with BA, intestinal complications represent the most common and hazardous perioperative surgical complications. Cholangitis is the most frequently encountered medical complication post hepato-porto enterostomy. For CCM, it seems that neonates encounter little perioperative complications; however, reports are scarce; bile leak and/or cholangitis are the most reported. Overall, for patients with CCM, the literature is ambivalent whether more perioperative complications occur in the younger or in the older patient, and whether these occur more frequently in those symptomatic or asymptomatic at operation. It is difficult to give clear advice for when children with asymptomatic CCM should be operated, and benefits and risks must be carefully counterbalanced. Perioperative mortality for both BA and CCM is low and is reported to be around 1 to 2%. PMID- 29510429 TI - Perioperative Complications of Video-Assisted Thoracoscopic Pulmonary Procedures in Neonates and Infants. AB - Video-assisted thoracoscopic surgery (VATS) has gained broad acceptance among pediatric surgeons. Today, VATS can be regarded as a routine approach for various conditions in neonates and infants. However, there is a lack of information concerning the complications of thoracoscopic pulmonary surgery in neonates and infants. We aimed to review the available data. A systematic review of the literature was performed using PubMed. All publications reporting on VATS for pulmonary procedures in neonates and infants up to the age of 1 year were included. Articles were reviewed in detail for occurrence of perioperative complications and their treatment. Nine case series were eligible for analysis. Entities treated included lung sequestration, congenital pulmonary airway malformation, congenital lobar emphysema, and bronchogenic cyst. Case series reported on a total number of 135 patients. Complications occurred in 14 patients (10.4%). The major complication was an accidental transection of the middle lobar bronchus that concluded in a later resection of a prior unaffected lung lobe. Other relevant complications reported were bleeding in four patients (3.0%) and persistent air leak in four cases (3.0%). Infectious complications were reported in four patients (3.0%). Additionally, iatrogenic phrenic nerve paralysis occurred in one patient. There were no deaths related to the VATS technique. In 11 cases (8.1%), conversion to thoracotomy had been necessary. General recommendations on the treatment of complications could not be derived due to small patient numbers and lack of details of the complications reported. Reports on major complications of pulmonary VATS in neonates and infants below 1 year of age are scarce. As severe complications such as accidental bronchus transection have been described, feasibility of neonatal/infant VATS cannot be unequivocally confirmed. No literature-based recommendation can be given on the treatment of complications. PMID- 29510430 TI - Is There Any Difference in Risk Factors between Male and Female Patients in New Onset Atrial Fibrillation after Coronary Artery Bypass Grafting? AB - BACKGROUND: We aimed to investigate the risk factors of post-coronary artery bypass grafting (CABG) atrial fibrillation (AF) in male and female patients without any history of AF, to identify the sex-specific risk factors, and to examine the effect of sex-specific risk factors on the overall population. METHODS: This retrospective study was conducted using the hospital database with 4,758 patients who underwent CABG surgery. Among them, 2,836 patients with complete data participated in this study. The female patients were divided into two groups as patients who developed new-onset AF after CABG and those who did not. The relationship between the patients' variables and risk factors of post CABG AF was examined. RESULTS: The overall incidence of post CABG AF was 12.9% (386/2,836). Sex-specific incidence of AF was similar: 3.2% (91/690) and 12.9% (277/2146) in female and male patients, respectively (p = 0.849). Multiple analysis revealed the independent risk factors for male and female patients, respectively: mean age (odds ratio [OR] = 1.057, OR = 1,076), age over 65 years (OR = 2.156, OR = 2.736), the European System For Cardiac Operative Risk Evaluation Scores (EuroSCORE) (OR = 1.13, OR = 1.218), COPD (OR = 1.589, OR = 1.789), BUN level (OR = 1.026, OR = 1.019), mean cardiopulmonary bypass (CPB) time (OR = 1.007, OR = 1.010), prolonged CPB time (OR = 1.604, OR = 2.309), mean cross-clamp time (OR = 1.009, OR = 1.017), need of inotropic support (OR = 2.249, OR = 2.731), and mean mechanical ventilation time (VT) (OR = 1.026, OR = 1.027).Low left ventricular ejection fraction (LVEF) (OR = 1.419), left ventricular (LV) aneurysm repair (OR = 1.533), carotid artery disease (OR = 1.750), prolonged VT (OR = 1.729), and use of intra-aortic balloon pump (IABP) (OR = 2.436) were found to be the risk factors only for male AF patients.Unstable angina (OR = 1.969), right coronary artery (RCA) disease (OR = 2), prolonged cross-clamp time (OR = 2.152), and the number of grafts per operation (OR = 1.298) were found to be the risk factors only for female AF patients. CONCLUSION: This study suggests that predictors of AF in the overall population may be due to isolated patient groups. Multiple regression analysis and artificial intelligence modelling should be performed on large-scale, isolated groups to make strong AF prediction. PMID- 29510431 TI - Non-Small Cell Lung Cancer with Chest Wall Involvement: Integrated Treatment or Surgery Alone? AB - BACKGROUND: The aim of this study was to identify prognostic factors in patients affected by non-small cell lung cancer (NSCLC) with chest wall (CW) involvement, analyzing different strategies of treatment and surgical approaches. METHODS: Records of 59 patients affected by NSCLC with CW involvement underwent surgery were retrospectively reviewed, from January 2000 to March 2013. RESULTS: Induction therapy was administered to 18 (30.5%) patients while adjuvant treatment to 36 (61.0%). In 36 (61%) patients, lung resection was associated only with a parietal pleural resection while in 23 (39%) with CW en-bloc resection. Overall 5-year survival was 34%. Prognostic factors were evaluated in the 51 (86.4%) completely resected (R0) patients.Five-year survival was 60% in patients undergoing induction therapy followed by surgery and 24% in those who underwent surgery as first treatment (p = 0.11). Five-year survival was better in the neoadjuvant group than that in the surgery group in IIB (T3N0) p-stage (100 vs 28%, p = 0.03), while in the IIIA (T3N1-2,T4N0) p-stage it was of 25 vs 0%, respectively (p = 0.53).No 5-year survival difference was found in case of parietal pleural resection versus CW en-bloc resection (p = 0.27) and in case of only parietal pleural involvement versus soft tissue (p = 0.78).In case of incomplete resection (R1), patients undergoing adjuvant radiotherapy had better 2 year survival than patients untreated: 60% vs 0% (p = 0.025). CONCLUSIONS: Type of surgical resection and the deep of infiltration of disease do not influence survival in this subset of patients. Integrated treatments seem to be suitable: neoadjuvant therapies ensure a better survival rate than surgery alone in IIB and IIIA patients, instead adjuvant radiotherapy proves a fundamental option in incomplete resections. PMID- 29510432 TI - Full Orifice Patching without Annuloplasty for Severe Functional Tricuspid Valve Regurgitation. AB - Surgical treatment of severe functional tricuspid regurgitation associated with dilated right ventricle and increased chordal tethering (>8 mm) is challenging. We designed a technique where the anterior and posterior leaflets are detached from 50% of the annulus and a patch as large as the tricuspid orifice is sewn to augment the leaflets' tissue to force the coaptation with the septal leaflet. Annuloplasty is not performed, as it can only increase the chordal tethering, reducing the benefit of tissue augmentation. Early and midterm results in a subgroup of patients with unfavorable anatomical aspects are encouraging. PMID- 29510434 TI - Fast and Furious (?). PMID- 29510433 TI - [Clinical Characteristics and Course of Infections by Influenza A- and Respiratory Syncytial Virus (RSV) in Hospitalized Adults]. AB - : There is little evidence on the clinical characteristics and the course of complicated infections with respiratory syncytial virus (RSV) compared to influenza A in adults. Therefore, the present monocenter study aims to compare infections with RSV and influenza A with regard to potential predisposing factors, clinical profile, course and outcome in hospitalized patient. MATERIAL AND METHODS: the study was performed between Jan 1th and March 31 this year and included all hospitalized patients with a Polymerase chain-reaction-(PCR) confirmed infection of influenza A and RSV. Patients were characterized by clinical symptoms at the time of diagnosis, laboratory parameters of inflammation and potential predisposing factors like chronical diseases of heart, lung, kidney, metabolism and tumors. Data on the length of hospital stay, origin of infection (nosocomial), rate of pneumonia, antimicrobial use, need of mechanical ventilation and hospital mortality were obtained to evaluate clinical severity and outcome. RESULTS: A total of 190 patients with Influenza A and 98 patients with RSV were included. Both patient groups did not differ with regard to anthropometric data and clinical symptoms: it was surprising to see that only 2/3 oft all patients exert symptoms of a respiratory infection. 15.3 % of influenza A and 13.3 % RSV infections were defined as being nosocomial. Comparing the clinical course and outcome, patients with RSV infections and chronical disease of the lung had an increased rate of mechanical ventilations (odds ratio 10.55 [95 % CI 1.18 - 507.1] p = 0.014). CONCLUSIONS: The present data clearly show that RSV is a frequent pathogen in hospitalized adults with complicated infections in the winter season. RSV infections seems to be more severe compared to influenza A particular in patients with chronic lung disease, but were as frequent as influenza A of nosocomial origin. In this context, an early diagnosis seems to be helpful for a successful infections prevention management under hospital conditions. PMID- 29510437 TI - Late-Stage Diagnosis of Breast Cancer in Brazil: Analysis of Data from Hospital Based Cancer Registries (2000-2012). AB - OBJECTIVE: To analyze the time trend and the factors regarding the diagnosis of late-stage breast cancer in Brazil from 2000 to 2012. METHODS: We conducted a retrospective cohort study using data from hospital-based cancer registries. Joinpoint regression was used to analyze the time trends of stage at diagnosis. The risk of late-stage presentation was estimated using multinomial logistic regression. RESULTS: A total of 170,757 cases were analyzed. The median time from diagnosis to treatment was of 43 days (range: 0-182 days). The percentage of cases with late-stage diagnosis decreased from 2000 to 2002, with an annual percent change (APC) of -6.6% (95% confidence interval [95%CI]: -7.6--5.5%); it increased from 2002 until 2009, with an APC of 1.1% (95% CI: 0.9-1.3%), and remained stable up to 2012. Women with college education (compared with illiterate women) had less chance of having a late-stage diagnosis (odds ratio [OR]: 0.32; 95%CI: 0.29-0.35). The odds were greater among brown women (OR: 1.30; 95%CI: 1.21-1.41) and black women (OR: 1.63; 95%CI: 1.47-1.82), compared with white women. The odds were also higher for women treated in facilities located and in the Northern region of Brazil (OR: 1.23; 95%CI: 1.04-1.45) and in the Midwest (OR: 1.61; 95%CI: 1.34-1.94), compared with those treated in the southern region of the country. Age, histological type, and marital status were some of the other factors that were positively related to staging at the diagnosis. CONCLUSION: Access to diagnosis of breast cancer is uneven in Brazil, and women with lower socioeconomic status present a greater probability of having an advanced stage at diagnosis. PMID- 29510436 TI - In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life. AB - Dibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14 hexahydrodibenzo[d,g]azecin-3-ol (LE404: ) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404: . For a multitude of these substances is still a lack of information, inclusive of stability, physicochemical parameters, pharmacokinetics and metabolism. Therefore, the present study investigated the stability properties of 17 new azecine derivatives, including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH-values and determination of octanol/water-partition coefficients. These findings, in correlation to the properties and efficacy of the already in vivo tested substances, will be useful for safety and efficacy in further in vivo tests. PMID- 29510438 TI - DEGUM Recommendations on Infection Prevention in Ultrasound and Endoscopic Ultrasound. AB - Microbial contamination of ultrasound probes for percutaneous or endoscopic use is common. However, infectious diseases caused by transmission of microorganisms by US procedures have rarely been reported. In Germany, legal regulations address hygiene in ultrasound procedures. Based on these regulations and the available literature, an expert panel of the German Society of Ultrasound in Medicine (DEGUM) has formulated sophisticated recommendations on hygienic measures in percutaneous and endoscopic US, including US-guided interventions. PMID- 29510439 TI - The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Long Version). AB - The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications. PMID- 29510441 TI - Re: On the mechanism of the eye. PMID- 29510440 TI - The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Short Version). AB - The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications. PMID- 29510442 TI - Muscle echogenicity ratio can indicate severity of carpal tunnel syndrome. AB - INTRODUCTION: The purpose of this study was to investigate the usefulness of the echogenicity (EI) ratio of the thenar to hypothenar muscle measured using ultrasonography in assessing the severity of carpal tunnel syndrome (CTS). METHODS: Fifty-nine hands of 30 patients electrodiagnostically confirmed as having CTS were classified into 3 subgroups (mild, moderate, and severe). The EI of the thenar and hypothenar muscles was measured with ultrasonography, and the EI ratio was calculated in the patients and 13 normal participants (26 hands). RESULTS: The average EI ratio was higher in the CTS group than in the control group. We also found a positive correlation between the severity of CTS and a high EI ratio measured with ultrasonography. DISCUSSION: The EI ratio of the thenar to hypothenar muscle is a useful parameter that can indicate the severity of CTS. Muscle Nerve 58: 304-306, 2018. PMID- 29510443 TI - Delayed-onset inflammatory polyneuropathy without graft versus host disease after bone marrow transplantation. PMID- 29510444 TI - Real-world study of acute exacerbations of COPD reveals real gaps in care. PMID- 29510445 TI - Laparoscopic repair of large hiatal hernias: clinical outcomes of 10 years. AB - BACKGROUND: Whilst laparoscopic repair is the most common surgical procedure for the treatment of large hiatal hernias, knowledge of long-term outcomes (>10 years) is scarce. The aim of this study was to evaluate the long-term results following this approach, in particular the hernia recurrence rate and the impact of repair on quality of life (QoL). METHODS: Patients were identified from a prospective database. A standardized questionnaire was used to assess symptoms and a barium swallow radiograph was performed to determine anatomy. A validated QoL measure, Gastrointestinal Quality of Life Index (GIQLI) was also applied to all patients. RESULTS: Of the 69 eligible patients, clinical follow-up was available for 54 patients (78.3%). Follow-up ranged from 72 to 185 (median: 114) months. Post-operative heartburn and dysphagia were significantly improved, with 45 patients (83%) reporting a good or excellent result. Contrast radiology in 35 patients (65%) revealed recurrence in 12 patients (34%). Fifty-four patients answered the GIQLI questionnaire. The mean GIQLI score was 117 (61-136). Patients with objectively documented anatomic recurrence had a QoL index of 92 (61-121) compared to an index of 122 (77-136, P < 0.01) in the non-recurrent hernia group. CONCLUSIONS: At mean 114 months follow-up, laparoscopic repair of large hiatal hernias achieves effective and durable relief of symptoms, and most patients are satisfied with the outcome. PMID- 29510446 TI - Neurological injuries from skateboards in paediatric and adolescent populations: injury types and severity. AB - BACKGROUND: Skateboarding is a popular recreation among children and adolescents. Injuries that result in presentation to emergency departments are varied including head injuries. The study aims to assess the type and severity of neurological damage to the brain and spine in children from injuries incurred while using a skateboard. METHODS: After obtaining Ethics approval, a retrospective case review was performed of all admissions to all Brisbane, Australia public hospital neurosurgery departments of children 18 years and less who experienced injuries to the brain and spine for the years 2010-2014. RESULTS: There were 51 skateboard-related admissions over the study period of which 94% were male. The mean age was 14.3 years. The Injury Severity Score (ISS) ranged from 1 to 38 with a mean of 11.4. A total of 70.5% of the ISS scores fell within the minor or moderate categories and 29.5% fell within the serious and severe categories. There were no ISS scores in the critical category. A total of 16 skull vault fractures and 14 skull base fractures were recorded. There were 13 extradural haematomas of which five were evacuated by craniotomy and one of whom experienced hemiplegia. There was a spinal cord injury with paraplegia. A range of other neurological complications occurred. There were no deaths. CONCLUSION: Uncommon but serious neurological morbidity accompanies skateboard use. Concerns remain about the level of helmet use and choice of unsafe locations for skateboarding. PMID- 29510447 TI - Proteomic Analysis Reveals a Strong Association of beta-Catenin With Cadherin Adherens Junctions in Resting Human Platelets. AB - It was previously demonstrated that the WNT/beta-catenin pathway is present and active in platelets and established that the canonical WNT ligand, WNT-3a, suppresses platelet adhesion and activation. In nucleated cells, beta-catenin, the key downstream effector of this pathway, is a dual function protein, regulating the coordination of gene transcription and cell-cell adhesion. The specific role of beta-catenin in the anucleate platelet however remains elusive. Here, a label-free quantitative proteomic analysis of beta-catenin immunoprecipitates from human platelets is performed and nine co immunoprecipitating proteins are identified. Three of the co-immunoprecipitating proteins (alpha-catenin-1, cadherin-6, and beta-catenin-interacting protein 1) are common to both resting and activated conditions. Bioinformatics analysis of proteomics data reveal a strong association of the dataset with both cadherin adherens junctions and regulators of WNT signaling. It is then verified that platelet beta-catenin and cadherin-6 interact and that this interaction is regulated by the activation state of the platelet. Taken together, this proteomics study suggests a novel role for beta-catenin in human platelets where it interacts with platelet cadherins and associated junctional proteins. PMID- 29510449 TI - Telehealth applications for outpatients with neuromuscular or musculoskeletal disorders. AB - Telehealth describes the provision of medical services remotely through technology, and may enhance patient access to specialty care services. Although teleneurology has expanded widely since the introduction of telestroke in 1999, telehealth services for outpatients with neuromuscular or musculoskeletal disorders are less widespread. In this narrative review, we will describe the current technology, applications, outcomes, and limitations of this dynamically growing field. Evidence for telehealth applications related to neuromuscular diseases, palliative care, specialized multidisciplinary services, and musculoskeletal care are reviewed. With growing demand for specialized services and finite resources, telehealth provides a promising avenue to promote access to high-quality care, decrease the cost and burden of travel for patients, and with the expansion of software to personal computing and mobile devices, offer flexible, low-overhead practice opportunities for clinicians. Providers embarking on careers in telehealth should be aware of current legal restrictions impacting care to minimize risk and avoid liability. Muscle Nerve 58: 475-485, 2018. PMID- 29510448 TI - Sighs matter. PMID- 29510450 TI - Surgical management of the hand manifestations of Harlequin ichthyosis. PMID- 29510452 TI - Triple synchronous colorectal carcinoma. PMID- 29510451 TI - The impact of ischemia-reperfusion injuries on skin resident murine dendritic cells. AB - Pressure ulcers are a chronic problem for patients or the elderly who require extended periods of bed rest. The formation of ulcers is due to repeated cycles of ischemia-reperfusion (IR), which initiates an inflammatory response. Advanced ulcers disrupt the skin barrier, resulting in further complications. To date, the immunological aspect of skin IR has been understudied, partly due to the complexity of the skin immune cells. Through a combination of mass cytometry, confocal imaging and intravital multiphoton imaging, this study establishes a workflow for multidimensionality single cell analysis of skin myeloid cell responses in the context of IR injury with high spatiotemporal resolution. The data generated has provided us with previously uncharacterized insights into the distinct cellular behavior of resident dendritic cells (DCs) and recruited neutrophils post IR. Of interest, we observed a drop in DDC numbers in the IR region, which was subsequently replenished 48h post IR. More importantly, in these cells, we observe an attenuated response to repeated injuries, which may have implications in the subsequent wound healing process. PMID- 29510453 TI - Addressing social influences reduces antibiotic duration in complicated abdominal infection: a mixed methods study. AB - BACKGROUND: Antimicrobial therapy for intra-abdominal infections is often inappropriately prolonged. An intervention addressing factors influencing the duration of intravenous antibiotic use was undertaken. This study reports the antibiotic prescribing patterns before and after the intervention and a qualitative analysis of the experience of the intervention. METHODS: Quantitative: A retrospective audit of patients with complicated intra-abdominal infection before and after a multifaceted persuasive intervention was performed. Qualitative: Semi-structured interviews were performed to evaluate which elements of the intervention were perceived to be effective. RESULTS: An intervention including collaborative inter-specialty and inter-professional educational meetings, and education of all professional streams was undertaken. Quantitative: Twenty-three patients before and 22 patients after the intervention were included. The total duration of antibiotics decreased significantly following the intervention (9.2 versus 6.6 days P = 0.02). The duration of intravenous antibiotics did not change significantly (5.4 versus 4.5 days, P = 0.06). Qualitative: Eighteen health-care professionals participated. Thematic analysis indicated that a collaborative approach between senior surgical and infectious disease specialists in the pre-intervention stage led to perceived ownership and leadership of the intervention by the surgical team, which was thought critical to the success of the intervention. Conversely, the ability of nurses and pharmacists to influence antibiotic practice was considered limited and a poster promoting the intervention was perceived as ineffective. CONCLUSION: Consultant leadership and specialty ownership of the process were perceived to be critical in the success of the intervention. Antibiotic stewardship programs which address social factors may have greater efficacy to optimize antimicrobial prescribing. PMID- 29510454 TI - Needle electromyography practice patterns in patients taking novel oral anticoagulants: A survey-based study. AB - INTRODUCTION: This study sought to evaluate needle electromyography (EMG) practice patterns among electromyographers with patients taking novel oral anticoagulants (NOAC). METHODS: A survey questionnaire was sent to members of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) via email web link. Anonymous survey responses were collected through an online website. RESULTS: Fifty-eight AANEM members responded, 28 (48%) of whom worked at a teaching hospital and 30 (52%) of whom worked in a private setting. Fifty-four (93%) responders perform needle EMG on patients taking NOACs. Twenty-nine (50%) responders examine paraspinal muscles, and 20 (40%) responders examine facial muscles. Among 14 responders who perform single-fiber EMG (SFEMG), 8 examine patients taking NOACs. DISCUSSION: Although most of the electromyographers perform needle EMG on patients taking NOACs, they reported variable practice patterns in examination of the paraspinal and facial muscles and in performing SFEMG. A prospective risk-benefit study is required. Muscle Nerve 58: 307-309, 2018. PMID- 29510455 TI - A 20-year experience of ocular herpes virus detection using immunofluorescence and polymerase chain reaction. AB - BACKGROUND: To detect the presence of herpes virus in corneal scrapings/corneal grafts of suspected herpetic keratitis patients attending the outpatient department/casualty of the Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi for the past 20 years with immunofluorescence assay and to analyse the efficacy of polymerase chain reaction over immunofluorescence for routine laboratory diagnosis in some of the specimens. METHODS: Corneal scrapings and corneal grafts were collected by the ophthalmologists from 1,926 suspected herpetic keratitis patients between 1996 and 2015, among whom 1,863 patients were processed with immunofluorescence assay and 302 patients were processed with polymerase chain reaction assay for the detection of herpes virus. Of the 302 patients, clinical specimens from 239 patients were analysed by both polymerase chain reaction and immunofluorescence assay. RESULTS: Of the 1,863 suspected herpetic keratitis patients diagnosed with immunofluorescence assay, 277 (14.9 per cent) were found positive for herpes simplex virus 1 antigen. Similarly, of the 302 suspected herpetic keratitis patients diagnosed by polymerase chain reaction, 70 (23.2 per cent) were found positive for herpes simplex virus DNA. Of the 239 patients diagnosed by both polymerase chain reaction and immunofluorescence assay, 35 (14.6 per cent) were found positive with immunofluorescence assay, 59 (24.7 per cent) were found positive with polymerase chain reaction, 30 (12.5 per cent) were positive with both immunofluorescence and polymerase chain reaction assay. CONCLUSION: Efficacy and accuracy of the polymerase chain reaction assay was greater compared to the immunofluorescence assay for detection of herpes virus in corneal scrapings/corneal grafts of suspected herpetic keratitis patients. Although the immunofluorescence assay is a rapid test for the detection of herpes virus in suspected herpetic keratitis patients, a combination of polymerase chain reaction with immunofluorescence assay will provide higher reliable and accurate results. PMID- 29510456 TI - Prevention of peritoneal recurrence in high-risk colorectal cancer and evidence of T4 status as a potential risk factor. AB - Peritoneal metastasis (PM) following primary resection of colorectal cancer is common. The combined use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has significantly improved the survival outcome of patients with colorectal PM (CRPM). Diagnosing and treating early PM is essential as its extent is correlated with poorer outcomes. There are two novel therapies - second-look surgery and synchronous hyperthermic intraperitoneal chemotherapy - that are proposed to prophylactically treat or intervene early in the disease process to reduce the incidence and adverse outcomes associated with PM. These strategies are limited to patients at high risk of developing CRPM, including those that had synchronous PM or ovarian metastases resected at primary tumour removal, or a perforated primary tumour. The data on advanced primary tumour (T4) as a prognostic factor for PM after primary resection suggest that T4a tumours are prognostically worse than T4b. This literature review outlines the evidence, feasibility and safety regarding the pre-emptive treatments, as well as the relevance of T4a tumours as a risk factor for metachronous CRPM. PMID- 29510457 TI - An insidious and deadly complication of mechanical chest compressions in a patient on anticoagulation and the subtle echocardiographic findings that enabled timely diagnosis. AB - Good-quality chest compressions improve outcomes in cardiac arrest. While manual chest compressions are suboptimal in this regard, the LUCAS device has been shown to improve the effectiveness of chest compressions during cardiopulmonary resuscitation (CPR). The complication rate associated with mechanical CPR, however, has not been adequately studied. Limited evidence suggests no difference in internal injury between manual and mechanical CPR. We report the case of a patient on anticoagulation who developed a mediastinal hematoma post mechanical CPR and on whom subtle findings on initial echocardiography could have alerted the clinician to this complication early during the clinical course. This case further suggests that there may be special populations of patients in whom we may need to be more vigilant in the use of mechanical CPR. PMID- 29510458 TI - Type 4 Luschka duct: a rare anatomical variant to be wary of. PMID- 29510459 TI - Models of care for severe asthma. PMID- 29510460 TI - The extracellular matrix as a key regulator of intracellular signalling networks. AB - The extracellular matrix (ECM) is a salient feature of all solid tissues within the body. This complex, acellular entity is composed of hundreds of individual molecules whose assembly, architecture and biomechanical properties are critical to controlling the behaviour and phenotype of the different cell types residing within tissues. Cells are the basic unit of life and the core building block of tissues and organs. At their simplest, they follow a set of rules, governed by their genetic code and effected through the complex protein signalling networks that these genes encode. These signalling networks assimilate and process the information received by the cell to control cellular decisions that govern cell fate. The ECM is the biggest provider of external stimuli to cells and as such is responsible for influencing intracellular signalling dynamics. In this review, we discuss the inclusion of ECM as a central regulatory signalling sub-network in computational models of cellular decision making, with a focus on its role in diseases such as cancer. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc. PMID- 29510462 TI - Development of a pelvic exenteration service at a tertiary referral centre. AB - BACKGROUND: Over one-third of primary rectal cancers are locally advanced at diagnosis, and local recurrence of rectal cancer occurs at a rate of 3-10% following primary curative resection. Extended resectional surgery, including pelvic exenteration, is the only proven therapy with curative potential in the treatment of these cancers along with many other pelvic malignancies. A microscopically clear resection margin (R0 resection) is the predominant prognostic factor affecting overall and disease-free survival. The extent and complexity of surgery required to achieve an R0 resection is associated with significant risk of morbidity and mortality. The aim of this paper is to show that pelvic exenterations can be performed with acceptable oncological and safe perioperative results in an appropriately resourced specialist centre. METHODS: Data was collected retrospectively for 61 consecutive patients treated between June 2012 and February 2017. This included patient demographics, tumour characteristics, operative, clinical and histological data, length of hospital stay, morbidity and mortality data. RESULTS: A total of 61 patients underwent surgery. Median age was 57 years (range 27-78 years). Median length of stay was 41 days (range 6-288 days). Median operative time was 624 min (range 239-1035 min); 30-day mortality was 3.3% (n = 2). Resection rates were 91.5% - R0, 6.8% - R1 and 1.7% - R2 resections. Histologically, 86.9% - adenocarcinomas, 3.3% - squamous cell carcinomas and 9.8% - represented by leiomyosarcoma, melanoma, myxoid chondrosarcoma, non-neoplastic processes and undifferentiated carcinoma. CONCLUSION: Our experience confirms that radical resectional pelvic surgery can be safely performed with acceptable results during the establishment phase of a dedicated tertiary service. PMID- 29510461 TI - Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial. AB - INTRODUCTION: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available. METHODS: A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps. RESULTS: Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred. DISCUSSION: Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve, 2018. PMID- 29510463 TI - Gastrografin may reduce time to oral diet in prolonged post-operative ileus: a pooled analysis of two randomized trials. AB - BACKGROUND: Gastrografin has been suggested as a rescue therapy for prolonged post-operative ileus (PPOI) but trial data has been inconclusive. This study aimed to determine the benefit of gastrografin use in patients with PPOI by pooling the results of two recent randomized controlled trials assessing the efficacy of gastrografin compared to placebo given at time of PPOI diagnosis. METHODS: Anonymized, individual patient data from patients undergoing elective bowel resection for any indication were included, stoma closure was excluded. The primary outcome was duration of PPOI. Secondary outcomes were time to tolerate oral diet, passage of flatus/stool, requirement and duration of nasogastric tube, length of post-operative stay and rate of post-operative complications. RESULTS: Individual patient data were pooled for analysis (53 gastrografin, 55 placebo). Gastrografin trended towards a reduction in PPOI duration compared to placebo, respectively, median 96 h (interquartile range, IQR, 78 h) versus median 120 h (IQR, 84 h), however, this result was non-significant (P = 0.11). In addition, no significant difference was detected between the two groups for time to passage of flatus/stool (P = 0.36) and overall length of stay (P = 0.35). Gastrografin conferred a significantly faster time to tolerate an oral diet compared to placebo (median 84 h versus median 107 h, P = 0.04). There was no difference in post-operative complications between the two interventions (P > 0.05). CONCLUSION: Gastrografin did not significantly reduce PPOI duration or length of stay after abdominal surgery, but did reduce time to tolerate a solid diet. Further studies are required to clarify the role of gastrografin in PPOI. PMID- 29510464 TI - Impact of stent deformity induced by the kissing balloon technique for bifurcating lesions on in-stent restenosis after coronary intervention. AB - OBJECTIVES: To investigate the impact of stent deformity induced by final kissing balloon technique (KBT) for coronary bifurcation lesions on in-stent restenosis (ISR). BACKGROUND: In experimental models, the detrimental effects of KBT have been clearly demonstrated, but few data exists regarding the impact of proximal stent deformity induced by KBT on clinical outcomes. METHODS: We examined 370 coronary lesions where intravascular ultrasound (IVUS)-guided second-generation drug-eluting stent (DES) implantation for coronary bifurcation lesions was performed. Based on IVUS analysis, the stent symmetry index (minimum/maximum stent diameter) and stent overstretch index (the mean of stent diameter/the mean of reference diameter) were calculated in the proximal main vessel. RESULTS: The stent symmetry index was significantly lower (0.75 +/- 0.07 vs 0.88 +/- 0.06, P < 0.0001) and the stent overstretch index was significantly higher (1.04 +/- 0.08 vs 1.01 +/- 0.06, P = 0.0007) in lesions with KBT (n = 174) compared to those without KBT (n = 196). The number of two-stent technique in lesions with KBT was 31 (18%). In multivariate analysis, the degree of stent deformity indices was not associated with ISR in lesions with KBT; however, two-stent technique use was the only independent predictor of ISR at 8 months (hazard ratio: 3.96, 95% confidence interval: 1.25-12.5, P = 0.01). CONCLUSIONS: Second-generation DES deformity induced by KBT was not associated with mid-term ISR. PMID- 29510465 TI - Green respiratory health care: Time for us all to act. PMID- 29510466 TI - Snapshot of trauma laparotomy deaths in Queensland. AB - BACKGROUND: Trauma remains the most frequent cause of death for patients under 35 years of age. Head injury and catastrophic haemorrhage account for the majority of early deaths. A trauma laparotomy is often necessary to arrest haemorrhage. METHODS: All patients who died in Queensland hospitals between 2011 and 2016 having had a trauma laparotomy were identified from the Queensland Audit of Surgical Mortality. RESULTS: About 69.0% of the 84 deaths were male with a median age of 47.6 years. About 64.3% of deaths occurred within the first 2 days following trauma. Mechanism of injury was typically road traffic accident (77.4%). Sixteen patients underwent a non-therapeutic laparotomy. Following peer review, different management was recommended for only three patients. CONCLUSION: This group of patients who died in the setting of a trauma laparotomy received high quality trauma care. Ongoing education is needed as some non-therapeutic laparotomies may be avoidable. PMID- 29510468 TI - Using geometric morphometric visualizations of directional selection gradients to investigate morphological differentiation. AB - Researchers studying extant and extinct taxa are often interested in identifying the evolutionary processes that have lead to the morphological differences among the taxa. Ideally, one could distinguish the influences of neutral evolutionary processes (genetic drift, mutation) from natural selection, and in situations for which selection is implicated, identify the targets of selection. The directional selection gradient is an effective tool for investigating evolutionary process, because it can relate form (size and shape) differences between taxa to the variation and covariation found within taxa. However, although most modern morphometric analyses use the tools of geometric morphometrics (GM) to analyze landmark data, to date, selection gradients have mainly been calculated from linear measurements. To address this methodological gap, here we present a GM approach for visualizing and comparing between-taxon selection gradients with each other, associated difference vectors, and "selection" gradients from neutral simulations. To exemplify our approach, we use a dataset of 347 three-dimensional landmarks and semilandmarks recorded on the crania of 260 primate specimens (112 humans, 67 common chimpanzees, 36 bonobos, 45 gorillas). Results on this example dataset show how incorporating geometric information can provide important insights into the evolution of the human braincase, and serve to demonstrate the utility of our approach for understanding morphological evolution. PMID- 29510467 TI - High-throughput multipesticides residue analysis in earthworms by the improvement of purification method: Development and application of magnetic Fe3 O4 -SiO2 nanoparticles based dispersive solid-phase extraction. AB - As a key representative organism, earthworms can directly illustrate the influence of pesticides on environmental organisms in soil ecosystems. The present work aimed to develop a high-throughput multipesticides residue analytical method for earthworms using solid-liquid extraction with acetonitrile as the solvent and magnetic material-based dispersive solid-phase extraction for purification. Magnetic Fe3 O4 nanoparticles were modified with a thin silica layer to form Fe3 O4 -SiO2 nanoparticles, which were fully characterized by field emission scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffractometry, and vibrating sample magnetometry. The Fe3 O4 -SiO2 nanoparticles were used as the separation media in dispersive solid-phase extraction with primary secondary amine and ZrO2 as the cleanup adsorbents to eliminate matrix interferences. The amounts of nanoparticles and adsorbents were optimized for the simultaneous determination of 44 pesticides and six metabolites in earthworms by liquid chromatography with tandem mass spectrometry. The method performance was systematically validated with satisfactory results. The limits of quantification were 20 MUg/kg for all analytes studied, while the recoveries of the target analytes ranged from 65.1 to 127% with relative standard deviation values lower than 15.0%. The developed method was subsequently utilized to explore the bioaccumulation of bitertanol in earthworms exposed to contaminated soil, verifying its feasibility for real sample analysis. PMID- 29510469 TI - Flaxseed Oil Attenuates Intestinal Damage and Inflammation by Regulating Necroptosis and TLR4/NOD Signaling Pathways Following Lipopolysaccharide Challenge in a Piglet Model. AB - SCOPE: Flaxseed oil is a rich source of alpha-linolenic acid (ALA), which is the precursor of the long-chain n-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This study investigates the protective effect of flaxseed oil against intestinal injury induced by lipopolysaccharide (LPS). MATERIALS AND RESULTS: Twenty-four weaned pigs were used in a 2 * 2 factorial experiment with dietary treatment (5% corn oil vs 5% flaxseed oil) and LPS challenge (saline vs LPS). On day 21 of the experiment, pigs were administrated with LPS or saline. At 2 h and 4 h post administration, blood samples were collected. After the blood harvest at 4 h, all piglets were slaughtered and intestinal samples were collected. Flaxseed oil supplementation led to the enrichment of ALA, EPA, and total n-3 PUFAs in intestine. Flaxseed oil improved intestinal morphology, jejunal lactase activity, and claudin-1 protein expression. Flaxseed oil downregulated the mRNA expression of intestinal necroptotic signals. Flaxseed oil also downregulated the mRNA expression of intestinal toll-like receptors 4 (TLR4) and its downstream signals myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-kappaB), and nucleotide-binding oligomerization domain proteins 1, 2 (NOD1, NOD2) and its adapter molecule, receptor-interacting protein kinase 2 (RIPK2). CONCLUSION: These results suggest that dietary addition of flaxseed oil enhances intestinal integrity and barrier function, which is involved in modulating necroptosis and TLR4/NOD signaling pathways. PMID- 29510471 TI - Rare presentation of acute abdomen in a spinal cord injury patient: case and review of literature. PMID- 29510470 TI - Post-operative outcomes in older patients: a single-centre observational study. AB - BACKGROUND: Improved life-expectancies have seen increased rates of older patients undergoing surgery worldwide. These patients are at increased risk of post-operative complications. Australian evidence is limited regarding the association between age and post-operative outcomes, especially rapid response calls (RRCs) as indicators of adverse outcomes. The aim was to compare the post operative outcomes of older patients (>=80 years) to younger patients. Specifically, 30-day in-hospital mortality; unplanned intensive care unit (ICU) admission; and RRC activation within 72 h post-operatively. METHODS: Single centre retrospective observational study conducted over 12 months in a metropolitan Australian hospital. All adult patients (>=16 years) undergoing surgical procedures were included, excluding cardiac and obstetric/gynaecological surgeries. Patient co-morbidities were quantified using Charlson co-morbidity index (CCI) and American Society of Anesthesiologists physical status classification. RESULTS: Seven thousand four hundred and seventy-nine patients met inclusion criteria, 14.5% (n = 1086) aged >=80 years. Most procedures (65%) were elective; and general surgical procedures were most common (24.2%). Compared to younger patients, older patients had significantly higher 30-day mortality (2.3% versus 0.2%; P < 0.001), increased post-operative RRC rates (7.3% versus 1.2%; P < 0.001), and unplanned ICU admissions (3.2% versus 1.6%; P < 0.001). Increasing age was associated with increased risk of post-operative RRC, unplanned ICU admission, and in-hospital mortality (all P < 0.01), with associations remaining significant after controlling for surgery type and CCI. CONCLUSION: Older patients are at increased risk of adverse post-operative outcomes, including post-operative RRC, unplanned ICU admission, and mortality, especially if they underwent emergency procedures. This has implications for preoperative risk stratification and post-operative management. Incidence of post operative RRCs may be an important indicator of post-operative care. PMID- 29510472 TI - An enhanced immunochromatographic strip test using colloidal gold nanoparticle labeled dual-type N proteins for detection of antibodies to PRRS virus. AB - Porcine reproductive and respiratory syndrome (PRRS) is recognized as one of the most important infectious diseases causing serious economic loss in the swine industry worldwide. Due to its increasing genetic diversity, a rapid and accurate diagnosis is critical for PRRS control. The immunochromatographic strip test (ICST) is a rapid and convenient type of immunoassay. In this study, an on-site immunochromatographic assay-based diagnostic method was developed for detection of PRRS virus (PRRSV)-specific antibodies. The method utilized colloidal gold nanoparticle-labeled dual-type nucleocapsid proteins encoded by open reading frame 7. We evaluated 991 field samples from pig farms and 66 serum samples from experimentally PRRSV-inoculated pigs. Based on true PRRSV-specific antibody positive or -negative sera determined by immunofluorescence assay and IgM enzyme linked immunosorbent assay (ELISA), the specificity and sensitivity of the ICST were 97.5% and 91.1%, respectively, similar to those of a commercial ELISA (IDEXX PRRS X3 Ab). More importantly, the ICST was completed within 15 min and could detect the PRRSV-specific antibody at an earlier stage of infection (3-7 days) than that of ELISA (7+ days). The results demonstrate that the developed ICST has great potential as an on-farm diagnostic method, providing excellent diagnostic performance in a quick and convenient manner. PMID- 29510473 TI - Unilateral rostral mandibulectomy for gingival vascular hamartoma in two calves. AB - A 2-month-old female Holstein calf and a 5-month-old female Japanese black calf presented with gingival vascular hamartoma located in the interdental space between the second and third mandibular incisors in the right and left mandibles, respectively. On radiographic or computed tomographic images, osteolytic changes appeared within the mandibular bones adjacent to the masses. The masses were removed along with affected mandibular bone by using unilateral rostral mandibulectomy. After surgery, both cases exhibited a normal appetite and grew normally, with no cosmetic changes or recurrences. Unilateral rostral mandibulectomy can be applied for invasive gingival vascular hamartomas associated with osteolytic changes. PMID- 29510474 TI - Toward the development of a one-dose classical swine fever subunit vaccine: antigen titration, immunity onset, and duration of immunity. AB - Highly contagious classical swine fever (CSF) remains a major trade and health problem in the pig industry, resulting in large economic losses worldwide. In CSF endemic countries, attenuated CSF virus (CSFV) vaccines have been routinely used to control the disease. However, eradication of CSFV in a geographical area would require permanent reduction to zero presence of the virus. It is therefore of paramount importance to develop a safe, potent, and non-infectious CSF vaccine. We have previously reported on a cost-effective CSF E2 subunit vaccine, KNB-E2, which can protect against CSF symptoms in a single dose containing 75 ug of recombinant CSFV glycoprotein E2. In this study, we report on a series of animal studies undertaken to elucidate further the efficacy of KNB-E2. We found that pigs vaccinated with a single KNB-E2 dose containing 25 ug of recombinant CSFV glycoprotein E2 were protected from clinical symptoms of CSF. In addition, KNB-E2 mediated reduction of CSF symptoms was observed at two weeks post-vaccination and the vaccinated pigs continued to exhibit reduced CSF clinical signs when virus challenged at two months and four months post-vaccination. These results suggest that KNB-E2 effectively reduces CSF clinical signs, indicating the potential of this vaccine for safely minimizing CSF-related losses. PMID- 29510475 TI - Erratum to: Synthesis of Curcumin Glycosides with Enhanced Anticancer Properties Using One-Pot Multienzyme Glycosylation Technique. AB - This erratum is being published to correct the author's contribution and name of above manuscript by Gurung et al. that was published in Journal of Microbiology and Biotechnology (2017, 27: 1639-1648). The first author (Rit Bahadur Gurung) and the second author (So Youn Gong) contributed equally to this article. And the seventh author (Tae Jin Oh) should appear as 'Tae-Jin Oh'. PMID- 29510477 TI - Physicochemical Properties of Bovine Serum Albumin-Glucose and Bovine Serum Albumin-Mannose Conjugates Prepared by Pulsed Electric Fields Treatment. AB - The pulsed electric fields (PEF) treatment is a novel method for obtaining glycated proteins by way of a Maillard reaction between proteins and polysaccharides but its effect on the preparation of protein-monosaccharide conjugate has not been explored. This study aimed to prepare bovine serum albumin (BSA)-glucose and BSA-mannose conjugates using PEF in pH 10.0 at an intensity of 10 or 20 kV/cm, frequency of 1 kHz, pulse width of 20 MUs and 73.5 pulses. The conjugates were evaluated for physicochemical properties. The results indicated that PEF not only promoted Maillard reaction between BSA and glucose or mannose but also alleviated the undesirable browning. PEF treatment favored the increased surface hydrophobicity and emulsifying activity in BSA but reduced surface hydrophobicity and foaming stability and improved foaming capacity in BSA-glucose and BSA-mannose conjugates. These findings provided useful considerations in the application of PEF treatment as a potential method to prepare BSA-monosaccharide conjugates by Maillard reaction. PMID- 29510476 TI - Pathogen-Derived Carbohydrate Recognition in Molluscs Immune Defense. AB - Self-nonself discrimination is a common theme for all of the organisms in different evolutionary branches, which is also the most fundamental step for host immune protection. Plenty of pattern recognition receptors (PRRs) with great diversity have been identified from different organisms to recognize various pathogen-associated molecular patterns (PAMPs) in the last two decades, depicting a complicated scene of host-pathogen interaction. However, the detailed mechanism of the complicate PAMPs-PRRs interactions at the contacting interface between pathogens and hosts is still not well understood. All of the cells are coated by glycosylation complex and thick carbohydrates layer. The different polysaccharides in extracellular matrix of pathogen-host are important for nonself recognition of most organisms. Coincidentally, massive expansion of PRRs, majority of which contain recognition domains of Ig, leucine-rich repeat (LRR), C type lectin (CTL), C1q and scavenger receptor (SR), have been annotated and identified in invertebrates by screening the available genomic sequence. The phylum Mollusca is one of the largest groups in the animal kingdom with abundant biodiversity providing plenty of solutions about pathogen recognition and immune protection, which might offer a suitable model to figure out the common rules of immune recognition mechanism. The present review summarizes the diverse PRRs and common elements of various PAMPs, especially focusing on the structural and functional characteristics of canonical carbohydrate recognition proteins and some novel proteins functioning in molluscan immune defense system, with the objective to provide new ideas about the immune recognition mechanisms. PMID- 29510479 TI - Conductometric Sensor for PAH Detection with Molecularly Imprinted Polymer as Recognition Layer. AB - A conductometric sensor based on screen-printed interdigital gold electrodes on glass substrate coated with molecularly imprinted polyurethane layers was fabricated to detect polycyclic aromatic hydrocarbons (PAHs) in water. The results prove that screen-printed interdigital electrodes are very suitable transducers to fabricate low-cost sensor systems for measuring change in resistance of PAH-imprinted layers while exposing to different PAHs. The sensor showed good selectivity to its templated molecules and high sensitivity with a detection limit of 1.3 nmol/L e.g., for anthracene in water which is lower than WHO's permissible limit. PMID- 29510478 TI - In Vitro and In Vivo Anti-Osteoarthritis Effects of 2,3,5,4'-Tetrahydroxystilbene 2-O-beta-d-Glucoside from Polygonum Multiflorum. AB - Polygonum multiflorum Thunb. is a traditional herbal medicine that is rich in polyphenols. The major compound, 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d glucoside (THSG) has many pharmacological activities, such as antioxidative and free radical-scavenging properties, and the abilities to reduce hyperlipidemia, prevent lipid peroxidation, and protect the cardiovascular system. In this study, the anti-osteoarthritis (OA) effects of THSG were explored using in vitro and in vivo models. THSG inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production and inducible NO synthase (iNOS) and cyclooxygenase-2 expressions by lipopolysaccharide-stimulated RAW 264.7 cells. On the other hand, THSG inhibited PGE2 production and iNOS and matrix metalloproteinase-13 expressions by interleukin-1beta-stimulated primary rat chondrocytes. Through a mono-iodoacetate induced rat OA model assay, THSG reduced paw edema and improved the weight bearing distribution. Therefore, THSG has anti-inflammatory activity and could be applied as a lead compound for the development as an OA drug. PMID- 29510480 TI - Modification of Physico-Chemical Properties of Acryl-Coated Polypropylene Foils for Food Packaging by Reactive Particles from Oxygen Plasma. AB - This investigation was focused on the influence of long-living neutral reactive oxygen species on the physico-chemical properties of acryl-coated polypropylene foils for food packaging. Reactive species were formed by passing molecular oxygen through a microwave discharge and leaking it to a processing chamber of a volume of 30 L, which was pumped by a rotary pump. The density of neutral O-atoms in the chamber was tuned by adjustment of both the effective pumping speed and the oxygen leak rate. The O-atom density was measured with a catalytic probe and was between 3 * 1018 and 5 * 1019 m-3. Commercial foils of biaxially oriented polypropylene (BOPP) coated with acrylic/ poly(vinylidene chloride) (AcPVDC) were mounted in the chamber and treated at room temperature by O atoms at various conditions, with the fluence between 1 * 1021 and 3 * 1024 m-2. The evolution of the surface wettability versus the fluence was determined by water contact angle (WCA) measurements, the formation of functional groups by X-ray photoelectron spectroscopy (XPS), and the morphology by atomic force microscopy (AFM). The WCA dropped from the initial 75 degrees to approximately 40 degrees after the fluence of a few 1022 m-2 and remained unchanged thereafter, except for fluences above 1024 m-2, where the WCA dropped to approximately 30 degrees . XPS and AFM results allowed for drawing correlations between the wettability, surface composition, and morphology. PMID- 29510481 TI - Network Formation via Anion Coordination: Crystal Structures Based on the Interplay of Non-Covalent Interactions. AB - We describe the synthesis and the structural characterization of new H2L(CF3CO2)2 (1) and H2L(Ph2PO4)2 (2) compounds containing the diprotonated form (H2L2+) of the tetrazine-based molecule 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine. X-ray diffraction (XRD) analysis of single crystals of these compounds showed that H2L2+ displays similar binding properties toward both anions when salt bridge interactions are taken into account. Nevertheless, the different shapes, sizes and functionalities of trifluoroacetate and diphenyl phosphate anions define quite different organization patterns leading to the peculiar crystal lattices of 1 and 2. These three-dimensional (3D) architectures are self-assembled by a variety of non-covalent forces, among which prominent roles are played by fluorine-pi (in 1) and anion-pi (in 2) interactions. PMID- 29510482 TI - Medium and Short Wave RF Energy Harvester for Powering Wireless Sensor Networks. AB - Internet of Things (IoT) is an emerging platform in which every day physical objects provided with unique identifiers are connected to the Internet without requiring human interaction. The possibilities of such a connected world enables new forms of automation to make our lives easier and safer. Evidently, in order to keep billions of these communicating devices powered long-term, a self sustainable operation is a key point for realization of such a complex network. In this sense, energy-harvesting technologies combined with low power consumption ICs eliminate the need for batteries, removing an obstacle to the success of the IoT. In this work, a Radio Frequency (RF) energy harvester tuned at AM broadcast has been developed for low consumption power devices. The AM signals from ambient are detected via a high-performance antenna-free LC circuit with an efficiency of 3.2%. To maximize energy scavenging, the RF-DC conversion stage is based on a full-wave Cockcroft-Walton voltage multiplier (CWVM) with efficiency up to 90%. System performance is evaluated by rating the maximum power delivered into the load via its output impedance, which is around 62 MUW, although power level seems to be low, it is able to power up low consumption devices such as Leds, portable calculators and weather monitoring stations. PMID- 29510483 TI - Effects of Cholesterol Levels on Mortality in Patients with Long-Term Peritoneal Dialysis Based on Residual Renal Function. AB - The effect of dyslipidemia on peritoneal dialysis (PD) patients based on the presence of residual renal function (RRF; renal creatinine clearance >2 mL/min/1.73 m2) is unknown. Data from the Taiwan Renal Registry Data System between 2005 and 2012 were analyzed to estimate the association between dyslipidemia and mortality in PD patients. Long-term PD patients (n = 8032) were divided into groups with (RRF; n = 2691, 33.5%) and without RRF (non-RRF; n = 5341, 66.5%). The primary outcome was three-year mortality, and multivariate Cox regression was used for survival analysis. After stratifying the total cholesterol (TC) level between the first and third years, the hazard ratio for mortality was estimated. In the non-RRF group, TC < 120 mg/dL was associated with independently increased risk of mortality. In the RRF group, low TC was not independently correlated with increased mortality, but TC > 285 mg/dL was associated with increased risk. PD patients with higher level of TC (>200 mg/dL) in both first and third years of dialysis had significantly lower risk of mortality. In this nationwide cohort study, PD patients without RRF who had low TC level had the highest mortality, in contrast to those with RRF. Malnutrition in long-term PD patients without RRF is an important issue to be monitored. PMID- 29510485 TI - The Influence of Salt Anions on Heavy Metal Ion Adsorption on the Example of Nickel. AB - The biodegradable polysaccharide chitosan possesses protonated and natural amino groups at medium pH values and has therefore been used as an adsorbing material for nickel salts in water treatment. Nickel is a problematic heavy metal ion which can cause various diseases and disorders in living organisms. Here, we show the influence of oxyanions (e.g., nitrate and sulfate) to the adsorption of nickel ions. Hence, simultaneously we are addressing the increasing global problem of nitrate and sulfate ion pollution in groundwater and surface water. A series of adsorption experiments was carried out in order to determine (i) the adsorption equilibrium, (ii) the adsorption capacity in dependence on the initial nickel ion concentration, and (iii) the influence of the anion presented in solution for the adsorption capacity. Surface morphology of chitosan flakes before and after the adsorption process has been studied with SEM-EDX analysis. The chitosan flakes exhibited promising adsorption capacities of 81.9 mg.g-1 and 21.2 mg.g-1 for nickel (sulfate) and nickel (nitrate), respectively. The calculated values of Gibbs free energy change DeltaG0 confirm the higher adsorption of nickel ions in presence of sulfate ions. Hence, higher anion valence leads to a higher adsorption capacity. PMID- 29510484 TI - Trends in Pediatric Complicated Pneumonia in an Ontario Local Health Integration Network. AB - Following the introduction of 7-valent pneumococcal vaccine (PCV7), while overall rates of invasive pneumococcal disease and pneumococcal pneumonia in children declined, rates of empyema increased. We examined changes in the incidence of hospitalization for pediatric complicated pneumonia (PCOMP) in Eastern Ontario, Canada, particularly since the introduction of the 13-valent vaccine (PCV13). A retrospective chart review was carried out evaluating previously healthy children admitted with PCOMP, which included empyema, parapneumonic effusion, necrotizing pneumonia, and lung abscess between 2002 and 2015. Three-hundred seventy-one children were included. Subjects had a median age of four years, and 188/370 (50.8%) required a chest tube. Admission rates changed markedly during this time period. The number of admissions per year rose most sharply between 2009 and 2012, corresponding to the period following introduction of PCV7 and then the occurrence of pandemic influenza A (H1N1). In children who likely received PCV13, the incidence of PCOMP returned to approximately pre-PCV7 levels. In contrast, rates of PCOMP in older children (who would not have received PCV13) remained elevated during the post-PCV13 time period. While rates of PCOMP, particularly in older children, remain elevated following the introduction of PCV13, this might be expected to resolve with more widespread vaccine coverage with PCV13 and herd immunity. PMID- 29510486 TI - Increased Effectiveness of Microbiological Verification by Concentration Dependent Neutralization of Sanitizers Used in Poultry Slaughter and Fabrication Allowing Salmonella enterica Survival. AB - Sanitizer neutralizers can assist foodborne pathogen detection during routine testing by counteracting sanitizer residues carried over into fluids collected and tested from food samples. This study tested sanitizer-matched neutralizers applied at increasing concentrations to facilitate Salmonella enterica survival following exposure to cetylpyridinium chloride (CPC) or peracetic acid (PAA), identifying minimum required concentrations of neutralizers to facilitate pathogen survival. Salmonella isolates were individually inoculated into a non selective medium followed immediately by CPC (0.1 to 0.8% v/v) or PAA (0.0125 to 0.2% v/v) application, followed by neutralizers application. CPC was neutralized by lecithin and polysorbate 80, each supplemented into buffered peptone water (BPW) at 0.125 to 2.0X its respective content in Dey-Engley (D/E) neutralizing buffer. PAA was neutralized in BPW supplemented with disodium phosphate, potassium monophosphate, and sodium thiosulfate, each at 0.25 to 3.0X its respective concentration in BPW (phosphates) or D/E buffer (thiosulfate). Addition of neutralizers at 1X their respective concentrations in D/E buffer was required to allow Salmonella growth at the maximum CPC concentration (0.8%), while 2X neutralizer addition was required for Salmonella growth at the maximum PAA level (0.2%). Sanitizer neutralizers can assist pathogen survival and detection during routine food product testing. PMID- 29510487 TI - Quality Evaluation of Apocyni Veneti Folium from Different Habitats and Commercial Herbs Based on Simultaneous Determination of Multiple Bioactive Constituents Combined with Multivariate Statistical Analysis. AB - Apocyni Veneti Folium (AVF) is a kind of staple traditional Chinese medicine with vast clinical consumption because of its positive effects. However, due to the habitats and adulterants, its quality is uneven. To control the quality of this medicinal herb, in this study, the quality of AVF was evaluated based on simultaneous determination of multiple bioactive constituents combined with multivariate statistical analysis. A reliable method based on ultra-fast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-QTRAP-MS/MS) was developed for the simultaneous determination of a total of 43 constituents, including 15 flavonoids, 6 organic acids, 13 amino acids, and 9 nucleosides in 41 Luobumaye samples from different habitats and commercial herbs. Furthermore, according to the contents of these 43 constituents, principal component analysis (PCA) was employed to classify and distinguish between AVF and its adulterants, leaves of Poacynum hendersonii (PHF), and gray relational analysis (GRA) was performed to evaluate the quality of the samples. The proposed method was successfully applied to the comprehensive quality evaluation of AVF, and all results demonstrated that the quality of AVF was higher than the PHF. This study will provide comprehensive information necessary for the quality control of AVF. PMID- 29510488 TI - Anti-Cancer Activity of Phenyl and Pyrid-2-yl 1,3-Substituted Benzo[1,2,4]triazin 7-ones and Stable Free Radical Precursors. AB - Cell viability studies for benzo[1,2,4]triazin-7-ones and 1,2,4-benzotriazinyl (Blatter-type) radical precursors are described with comparisons made with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). All of the stable free radicals were several orders of magnitude less cytotoxic than the benzo[1,2,4]triazin-7 ones. The synthesis and evaluation of two new pyrid-2-yl benzo[1,2,4]triazin-7 ones are described, where altering the 1,3-substitution from phenyl to pyrid-2-yl increased cytotoxicity against most cancer cell lines, as indicated using National Cancer Institute (NCI) one-dose testing. COMPARE analysis of five-dose testing data from the NCI showed very strong correlations to the naturally occurring anti-cancer compound pleurotin. COMPARE is program, which analyzes similarities in cytotoxicity data of compounds, and enables quantitative expression as Pearson correlation coefficients. Compounds were also evaluated using the independent MTT assay, which was compared with SRB assay data generated at the NCI. PMID- 29510491 TI - Crisis Resource Management in the Delivery Room: Development of Behavioral Markers for Team Performance in Emergency Simulation. AB - Human factors are the most relevant issues contributing to adverse events in obstetrics. Specific training of Crisis Resource Management (CRM) skills (i.e., problem solving and team management, resource allocation, awareness of environment, and dynamic decision-making) is now widespread and is often based on High Fidelity Simulation. In order to be used as a guideline in simulated scenarios, CRM skills need to be mapped to specific and observable behavioral markers. For this purpose, we developed a set of observable behaviors related to the main elements of CRM in the delivery room. The observational tool was then adopted in a two-days seminar on obstetric hemorrhage where teams working in obstetric wards of six Italian hospitals took part in simulations. The tool was used as a guide for the debriefing and as a peer-to-peer feedback. It was then rated for its usefulness in facilitating the reflection upon one's own behavior, its ease of use, and its usefulness for the peer-to-peer feedback. The ratings were positive, with a median of 4 on a 5-point scale. The CRM observational tool has therefore been well-received and presents a promising level of inter-rater agreement. We believe the tool could have value in facilitating debriefing and in the peer-to-peer feedback. PMID- 29510490 TI - Gastrointestinal Tolerance and Glycemic Response of Isomaltooligosaccharides in Healthy Adults. AB - Ingredients delivering functional and nutritional benefits are of interest to food manufacturers. Isomaltooligosaccharides (IMOs) which serve as alternate sweeteners fit into this category. IMOs are a mixture of alpha-(1 -> 6) and alpha (1 -> 4)-linked glucose oligomers, synthesized by an enzymatic reaction from starch (corn, tapioca). The aim of this study was to evaluate the fermentability and glycemic response of IMO in a healthy population. Two randomized, double blind, placebo-controlled, cross-over human studies were conducted. In the first study (n = 26), participants' breath hydrogen over 24 h, gastrointestinal tolerance, and glycemic and insulinemic response to BIOLIGOTM IL5040 isomaltooligosaccharide were measured. In another study (n = 10), participants' two-hour post-prandial glycemic response to BIOLIGOTM IL5040 isomaltooligosaccharide and BIOLIGOTM IL7010 isomaltooligosaccharide was measured compared to dextrose (control). The IMOs differed in the composition of mono and di-saccharide sugars. IMO syrup dose was matched for 50 g of total carbohydrates and was consumed by mixing in water (237 mL/8 oz.). Mean composite gastrointestinal score was not significantly different (p = 0.322) between the control (1.42) and IMO (1.38). Lack of difference in glycemic response (p = 0.662), with no impact on breath hydrogen (24 h; p = 0.319) and intestinal tolerance, demonstrates that IMO is digestible and can be used to replace sugars in product formulations. PMID- 29510492 TI - Mechanical Properties of Optimized Diamond Lattice Structure for Bone Scaffolds Fabricated via Selective Laser Melting. AB - Developments in selective laser melting (SLM) have enabled the fabrication of periodic cellular lattice structures characterized by suitable properties matching the bone tissue well and by fluid permeability from interconnected structures. These multifunctional performances are significantly affected by cell topology and constitutive properties of applied materials. In this respect, a diamond unit cell was designed in particular volume fractions corresponding to the host bone tissue and optimized with a smooth surface at nodes leading to fewer stress concentrations. There were 33 porous titanium samples with different volume fractions, from 1.28 to 18.6%, manufactured using SLM. All of them were performed under compressive load to determine the deformation and failure mechanisms, accompanied by an in-situ approach using digital image correlation (DIC) to reveal stress-strain evolution. The results showed that lattice structures manufactured by SLM exhibited comparable properties to those of trabecular bone, avoiding the effects of stress-shielding and increasing longevity of implants. The curvature of optimized surface can play a role in regulating the relationship between density and mechanical properties. Owing to the release of stress concentration from optimized surface, the failure mechanism of porous titanium has been changed from the pattern of bottom-up collapse by layer (or cell row) to that of the diagonal (45 degrees ) shear band, resulting in the significant enhancement of the structural strength. PMID- 29510489 TI - Divergent Role of Sphingosine 1-Phosphate in Liver Health and Disease. AB - Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases. PMID- 29510493 TI - Collagens of Poriferan Origin. AB - The biosynthesis, structural diversity, and functionality of collagens of sponge origin are still paradigms and causes of scientific controversy. This review has the ambitious goal of providing thorough and comprehensive coverage of poriferan collagens as a multifaceted topic with intriguing hypotheses and numerous challenging open questions. The structural diversity, chemistry, and biochemistry of collagens in sponges are analyzed and discussed here. Special attention is paid to spongins, collagen IV-related proteins, fibrillar collagens from demosponges, and collagens from glass sponge skeletal structures. The review also focuses on prospects and trends in applications of sponge collagens for technology, materials science and biomedicine. PMID- 29510495 TI - Age-Related Changes in the Behavior of Apolipoprotein E Knockout Mice. AB - The knockout mouse model, B6.129P2-Apoetm1Unc is homozygotic for the Apolipoprotein E (ApoE) deletion; thus, it is capable of developing hyperlipidemia and atherosclerosis but ApoE is also a lipid-transport protein abundantly expressed in most neurons in the central nervous system, so these animals could also be models of neurodegenerative diseases. The aim of this study was to determine age-related changes in spontaneous behavior and in learning and memory of Apolipoprotein E knockout mice. Spontaneous behavioral measurements included sleeping pattern, motor coordination and balance by rotarod and open field activity, whereas learning and memory tests included forced alternation in Y-maze, novel object recognition and passive avoidance conditioning. Significant behavioral differences between aged knockout mice and age-matched wild type strain, C57Bl/6 were found in all the behavioral tests, except for the rotarod test. Genetically' modified mice exhibited less huddling contact during sleeping, decreased locomotor activity in novel environments and in learning and memory deficits. These results are consistent with the cognitive impairment and memory loss seen as the earliest clinical symptoms in neurodegenerative disorders such as Alzheimer's disease. The ApoE knockout mice might therefore be an appropriate model for studying the underlying mechanisms involved in behavioral changes caused by neurodegenerative diseases as well as for evaluating new therapies for these pathologies. PMID- 29510494 TI - Effects of the Usage of l-Cysteine (l-Cys) on Human Health. AB - This review summarizes recent knowledge about the use of the amino acid l Cysteine (l-Cys) through diet, nutritional supplements or drugs with the aim to improve human health or treat certain diseases. Three databases (PubMed, Scopus, and Web of Science) and different keywords have been used to create a database of documents published between 1950 and 2017 in scientific journals in English or Spanish. A total of 60,885 primary publications were ultimately selected to compile accurate information about the use of l-Cys in medicine and nutritional therapies and to identify the reported benefits of l-Cys on human health. The number of publications about the use of l-Cys for these purposes has increased significantly during the last two decades. This increase seems to be closely related to the rise of nutraceutical industries and personalized medicine. The main evidence reporting benefits of l-Cys usage is summarized. However, the lack of accurate information and studies based on clinical trials hampers consensus among authors. Thus, the debate about the role and effectiveness of supplements/drugs containing l-Cys is still open. PMID- 29510496 TI - Detection and Characterisation of Anaplasma marginale and A. centrale in South Africa. AB - Bovine anaplasmosis is endemic in South Africa and it has a negative economic impact on cattle farming. An improved understanding of Anaplasma marginale and Anaplasma marginale variety centrale (A. centrale) transmission, together with improved tools for pathogen detection and characterisation, are required to inform best management practices. Direct detection methods currently in use for A. marginale and A. centrale in South Africa are light microscopic examination of tissue and organ smears, conventional, nested, and quantitative real-time polymerase chain reaction (qPCR) assays, and a reverse line blot hybridisation assay. Of these, qPCR is the most sensitive for detection of A. marginale and A. centrale in South Africa. Serological assays also feature in routine diagnostics, but cross-reactions prevent accurate species identification. Recently, genetic characterisation has confirmed that A. marginale and A. centrale are separate species. Diversity studies targeting Msp1a repeats for A. marginale and Msp1aS repeats for A. centrale have revealed high genetic variation and point to correspondingly high levels of variation in A. marginale outer membrane proteins (OMPs), which have been shown to be potential vaccine candidates in North American studies. Information on these OMPs is lacking for South African A. marginale strains and should be considered in future recombinant vaccine development studies, ultimately informing the development of regional or global vaccines. PMID- 29510497 TI - Fabrication Approaches to Interconnect Based Devices for Stretchable Electronics: A Review. AB - Stretchable electronics promise to naturalize the way that we are surrounded by and interact with our devices. Sensors that can stretch and bend furthermore have become increasingly relevant as the technology behind them matures rapidly from lab-based workflows to industrially applicable production principles. Regardless of the specific materials used, creating stretchable conductors involves either the implementation of strain reliefs through insightful geometric patterning, the dispersion of stiff conductive filler in an elastomeric matrix, or the employment of intrinsically stretchable conductive materials. These basic principles however have spawned a myriad of materials systems wherein future application engineers need to find their way. This paper reports a literature study on the spectrum of different approaches towards stretchable electronics, discusses standardization of characteristic tests together with their reports and estimates matureness for industry. Patterned copper foils that are embedded in elastomeric sheets, which are closest to conventional electronic circuits processing, make up one end of the spectrum. Furthest from industry are the more recent circuits based on intrinsically stretchable liquid metals. These show extremely promising results, however, as a technology, liquid metal is not mature enough to be adapted. Printing makes up the transition between both ends, and is also well established on an industrial level, but traditionally not linked to creating electronics. Even though a certain level of maturity was found amongst the approaches that are reviewed herein, industrial adaptation for consumer electronics remains unpredictable without a designated break-through commercial application. PMID- 29510498 TI - A Review on the Rising Prevalence of International Standards: Threats or Opportunities for the Agri-Food Produce Sector in Developing Countries, with a Focus on Examples from the MENA Region. AB - Food safety standards are a necessity to protect consumers' health in today's growing global food trade. A number of studies have suggested safety standards can interrupt trade, bringing financial and technical burdens on small as well as large agri-food producers in developing countries. Other examples have shown that economical extension, key intermediaries, and funded initiatives have substantially enhanced the capacities of growers in some countries of the Middle East and North Africa (MENA) region to meet the food safety and quality requirements, and improve their access to international markets. These endeavors often compensate for the weak regulatory framework, but do not offer a sustainable solution. There is a big gap in the food safety level and control systems between countries in the MENA region and those in the developed nations. This certainly has implications for the safety of fresh produce and agricultural practices, which hinders any progress in their international food trade. To overcome the barriers of legal and private standards, food safety should be a national priority for sustainable agricultural development in the MENA countries. Local governments have a primary role in adopting the vision for developing and facilitating the implementation of their national Good Agricultural Practices (GAP) standards that are consistent with the international requirements and adapted to local policies and environment. Together, the public and private sector's support are instrumental to deliver the skills and infrastructure needed for leveraging the safety and quality level of the agri-food chain. PMID- 29510499 TI - Multi-Pixel Simultaneous Classification of PolSAR Image Using Convolutional Neural Networks. AB - Convolutional neural networks (CNN) have achieved great success in the optical image processing field. Because of the excellent performance of CNN, more and more methods based on CNN are applied to polarimetric synthetic aperture radar (PolSAR) image classification. Most CNN-based PolSAR image classification methods can only classify one pixel each time. Because all the pixels of a PolSAR image are classified independently, the inherent interrelation of different land covers is ignored. We use a fixed-feature-size CNN (FFS-CNN) to classify all pixels in a patch simultaneously. The proposed method has several advantages. First, FFS-CNN can classify all the pixels in a small patch simultaneously. When classifying a whole PolSAR image, it is faster than common CNNs. Second, FFS-CNN is trained to learn the interrelation of different land covers in a patch, so it can use the interrelation of land covers to improve the classification results. The experiments of FFS-CNN are evaluated on a Chinese Gaofen-3 PolSAR image and other two real PolSAR images. Experiment results show that FFS-CNN is comparable with the state-of-the-art PolSAR image classification methods. PMID- 29510501 TI - Forward Behavioral Modeling of a Three-Way Amplitude Modulator-Based Transmitter Using an Augmented Memory Polynomial. AB - Reconfigurable and multi-standard RF front-ends for wireless communication and sensor networks have gained importance as building blocks for the Internet of Things. Simpler and highly-efficient transmitter architectures, which can transmit better quality signals with reduced impairments, are an important step in this direction. In this regard, mixer-less transmitter architecture, namely, the three-way amplitude modulator-based transmitter, avoids the use of imperfect mixers and frequency up-converters, and their resulting distortions, leading to an improved signal quality. In this work, an augmented memory polynomial-based model for the behavioral modeling of such mixer-less transmitter architecture is proposed. Extensive simulations and measurements have been carried out in order to validate the accuracy of the proposed modeling strategy. The performance of the proposed model is evaluated using normalized mean square error (NMSE) for long-term evolution (LTE) signals. NMSE for a LTE signal of 1.4 MHz bandwidth with 100,000 samples for digital combining and analog combining are recorded as 36.41 dB and -36.9 dB, respectively. Similarly, for a 5 MHz signal the proposed models achieves -31.93 dB and -32.08 dB NMSE using digital and analog combining, respectively. For further validation of the proposed model, amplitude-to amplitude (AM-AM), amplitude-to-phase (AM-PM), and the spectral response of the modeled and measured data are plotted, reasonably meeting the desired modeling criteria. PMID- 29510500 TI - Chlorogenic Acid and Its Microbial Metabolites Exert Anti-Proliferative Effects, S-Phase Cell-Cycle Arrest and Apoptosis in Human Colon Cancer Caco-2 Cells. AB - Chlorogenic acid (CGA) decreases colon cancer-cell proliferation but the combined anti-cancer effects of CGA with its major colonic microbial metabolites, caffeic acid (CA), 3-phenylpropionic acid (3-PPA) and benzoic acid (BA), needs elucidation as they occur together in colonic digesta. Caco-2 cancer cells were treated for 24 h with the four compounds individually (50-1000 uM) and as an equimolar ratio (1:1:1:1; MIX). The effective concentration to decrease cell proliferation by 50% (EC50) was lower for MIX (431 +/- 51.84 uM) and CA (460 +/- 21.88) versus CGA (758 +/- 19.09 uM). The EC50 for cytotoxicity measured by lactate dehydrogenase release in MIX (527 +/- 75.34 uM) showed more potency than CA (740 +/- 38.68 uM). Cell proliferation was decreased by 3-PPA and BA at 1000 uM with no cytotoxicity. Cell-cycle arrest was induced at the S-phase by CA (100 uM), MIX (100 uM), CGA (250 uM) and 3-PPA (500 uM) with activation of caspase-3 by CGA, CA, MIX (500 and 1000 uM). Mitochondrial DNA content was reduced by 3-PPA (1000 uM). The anti-cancer effects occurred at markedly lower concentrations of each compound within MIX than when provided singly, indicating that they function together to enhance anti-colon cancer activities. PMID- 29510502 TI - Toxicity of Beauveria bassiana-28 Mycelial Extracts on Larvae of Culex quinquefasciatus Mosquito (Diptera: Culicidae). AB - Microbial-based pest control is an attractive alternative to chemical insecticides. The present study sought to evaluate the toxicity of the entomopathogenic fungus Beauveria bassiana-28 ethyl acetate extracts on different larval stages and pupae of Culex quinquefasciatus mosquitoes. B. bassiana-28 ethyl acetate mycelial extracts produced mosquitocidal activity against larvae and pupae which was comparable to that of the commercial insecticide B. bassiana 22 extract. The LC50 (lethal concentration that kills 50% of the exposed larvae) values of B. bassiana-28 extracts for 1st to 4th instar larvae and pupae were 11.538, 6.953, 5.841, 3.581 and 9.041 mg/L respectively. Our results show that B. bassiana-28 ethyl acetate mycelial extract has strong insecticidal activity against larval and pupal stages of Cx. quinquefasciatus. Fourier transform infrared spectrum study of B. bassiana-28 extract shows peaks at 3226.91; 2927.94; 1593.13; 1404.18; 1224.18; 1247.94; 1078.21; 1018.41; 229.69; and 871.82 cm-1. Major spectral peaks were observed at 3226.91 cm-1, assigned to N-H stretching, 2927.94 cm-1 assigned to C-H bonding and 1595.13 cm-1 assigned to C-O stretching. Gas Chromatography-Mass Spectrometry studies of B. bassiana-28 ethyl acetate crude extract showed presence of six major compounds viz. N-hexadecanoic acids (13.6040%); Z,Z-9,12 octadecadienic acid (33.74%); 9-eicosyne (10.832%); heptacosane (5.148%); tetrateracontane (5.801%); and 7 hexyleicosane (5.723%). Histology of mosquito midgut tissue shows tissue lysis as a result of B.bassiana 28 extract exposure. The study shows that bioactive molecules obtained from B. bassiana-28 mycelial extract has insecticidal properties and can be used as alternative for mosquito control. PMID- 29510503 TI - Design and 4D Printing of Cross-Folded Origami Structures: A Preliminary Investigation. AB - In 4D printing research, different types of complex structure folding and unfolding have been investigated. However, research on cross-folding of origami structures (defined as a folding structure with at least two overlapping folds) has not been reported. This research focuses on the investigation of cross folding structures using multi-material components along different axes and different horizontal hinge thickness with single homogeneous material. Tensile tests were conducted to determine the impact of multi-material components and horizontal hinge thickness. In the case of multi-material structures, the hybrid material composition has a significant impact on the overall maximum strain and Young's modulus properties. In the case of single material structures, the shape recovery speed is inversely proportional to the horizontal hinge thickness, while the flexural or bending strength is proportional to the horizontal hinge thickness. A hinge with a thickness of 0.5 mm could be folded three times prior to fracture whilst a hinge with a thickness of 0.3 mm could be folded only once prior to fracture. A hinge with a thickness of 0.1 mm could not even be folded without cracking. The introduction of a physical hole in the center of the folding/unfolding line provided stress relief and prevented fracture. A complex flower petal shape was used to successfully demonstrate the implementation of overlapping and non-overlapping folding lines using both single material segments and multi-material segments. Design guidelines for establishing cross-folding structures using multi-material components along different axes and different horizontal hinge thicknesses with single or homogeneous material were established. These guidelines can be used to design and implement complex origami structures with overlapping and non-overlapping folding lines. Combined overlapping folding structures could be implemented and allocating specific hole locations in the overall designs could be further explored. In addition, creating a more precise prediction by investigating sets of in between hinge thicknesses and comparing the folding times before fracture, will be the subject of future work. PMID- 29510504 TI - Correlates of Objective Social Isolation from Family and Friends among Older Adults. AB - This study examined the correlates of objective social isolation from extended family members and friends among older adults. The analysis is based on the older adult sub-sample of the National Survey of American Life (n = 1321). Multinomial logistic regression analyses examined race/ethnicity, demographics, functional health and family and friend network factors as correlates of objective isolation from family and friends. Only 4.47% of respondents were objectively isolated from both their extended family and friends, 10.82% were isolated from their friends, and 7.43% were isolated from their family members. Men were more likely to be objectively isolated from both family and friends and older adults who live with others were significantly more likely to be objectively isolated from their friends. When controlling for subjective social isolation, the two measures of functional health were significantly associated with objective social isolation. In particular, higher levels of self-care impairment decreased the risk of being objectively isolated from friends only, whereas higher mobility impairment was associated with an increased likelihood of being objectively isolated from friends only. Subjective evaluations of social isolation from family and friends were consistently associated with being objectively isolated from family and friends. There were no significant differences between African-Americans, Black Caribbeans and non-Hispanic Whites in objective isolation. These and other findings are discussed in detail. PMID- 29510505 TI - A Feasibility Study of Ammonia Recovery from Coking Wastewater by Coupled Operation of a Membrane Contactor and Membrane Distillation. AB - More than 80% of ammonia (NH3) in the steel manufacturing process wastewater is contributed from the coking wastewater, which is usually treated by biological processes. However, the NH3 in the coking wastewater is typically too high for biological treatment due to its inhibitory concentration. Therefore, a two-stage process including a hollow fiber membrane contactor (HFMC) and a modified membrane distillation (MD) system was developed and applied to reduce and recover NH3 from coking wastewater. The objectives of this paper are to evaluate different membrane materials, receiving solutions, and operation parameters for the system, remove NH3 from the coking wastewater to less than 300 mg N/L, which is amenable to the biological process, and recover ammonia solution for reuse. As a result, the polytetrafluoroethylene (PTFE) HFMC using sulfuric acid as a receiving solution can achieve a maximum NH3-N transmembrane flux of 1.67 g N/m2.h at pH of 11.5 and reduce NH3 in the coking wastewater to less than 300 mg N/L. The NH3 in the converted ammonium sulfate ((NH4)2SO4) was then recovered by the modified MD using ice water as the receiving solution to produce >=3% of ammonia solution for reuse. PMID- 29510507 TI - Exploring the Driving Factors of Construction Industrialization Development in China. AB - Construction industrialization (CI) has been adopted worldwide because of its potential benefits. However, current research shows the incentives for adopting CI may differ in different regions. While the promotion of CI in China is still at the initial stage, a systematical analysis of the driving factors would help decision makers get a comprehensive understanding of CI development and select proper strategies to promote CI. This research combines qualitative and quantitative methods to explore the construction industrialization driving factors (CIDFs) in China. The grounded theory method (GTM) was employed to explore CI concepts among 182 CI-related articles published in 10 top-tier journals from 2000 to 2017. A total of 15 CIDFs were identified, including one suggested by professionals during a pre-test questionnaire survey. The analysis showed that the development of CI in China is pushed by macrodevelopment and pulled by the government and is also a self-driven process. The major driving factors for CI adoption in China are the transformation and upgrade of the conventional construction industry and the solution of development dilemmas. Our study also suggests that pilot programs are, currently, the most effective method to promote CI in China and to accumulate experience so to gain recognition by the society. This research is also of value for CI promotion in other developing countries. PMID- 29510506 TI - Resveratrol Inhibits Porcine Intestinal Glucose and Alanine Transport: Potential Roles of Na+/K+-ATPase Activity, Protein Kinase A, AMP-Activated Protein Kinase and the Association of Selected Nutrient Transport Proteins with Detergent Resistant Membranes. AB - BACKGROUND: Beneficial effects of Resveratrol (RSV) have been demonstrated, including effects on transporters and channels. However, little is known about how RSV influences intestinal transport. The aim of this study was to further characterize the effects of RSV on intestinal transport and the respective mechanisms. METHODS: Porcine jejunum and ileum were incubated with RSV (300 uM, 30 min) in Ussing chambers (functional studies) and tissue bathes (detection of protein expression, phosphorylation, association with detergent resistant membranes (DRMs)). RESULTS: RSV reduced alanine and glucose-induced short circuit currents (DeltaIsc) and influenced forskolin-induced DeltaIsc. The phosphorylation of sodium-glucose-linked transporter 1 (SGLT1), AMP-activated protein kinase (AMPK), protein kinase A substrates (PKA-S) and liver kinase B1 (LKB1) increased but a causative relation to the inhibitory effects could not directly be established. The DRM association of SGLT1, peptide transporter 1 (PEPT1) and (phosphorylated) Na+/H+-exchanger 3 (NHE3) did not change. CONCLUSION: RSV influences the intestinal transport of glucose, alanine and chloride and is likely to affect other transport processes. As the effects of protein kinase activation vary between the intestinal localizations, it would appear that increasing cyclic adenosine monophosphate (cAMP) levels are part of the mechanism. Nonetheless, the physiological responses depend on cell type specific structures. PMID- 29510508 TI - Hygiene and Health: Who Do Mothers in Vanuatu Communicate with about Health? AB - Health information-seeking behaviour of mothers with children five years of age and younger in Vanuatu was examined using the structural properties of social networks. Data were collected from a rural village from two islands and an urban settlement in the capital, Port Vila, by face-to-face interviews using a structured questionnaire. Sociometric data on the structure of the network, the characteristics of key informants, and associations with outside sources of health information were analysed as interpersonal predictors of health promotion and behavior change. Rural mothers preferred the health advice of biomedical practitioners for diarrheal disease over traditional custom practitioners. Interpersonal connections were restricted in the urban mother network indicating that mothers were merely acquaintances or do not seek health advice from each other. Our findings suggest that biomedical practitioners are the best option for diffusing health and hygiene information for rural and urban mothers. Traditional healers and paraprofessionals could be strategically used to complete the missing links in network connectedness to optimally spread new information. The novel use of cross-sectional social network data can create a baseline evaluation to purposefully frame a health intervention. Our study provided a unique explanation of how network analysis offers insight into how key players can be identified and the circumstances in which they are likely to be able to influence hygiene practices of their peers. PMID- 29510509 TI - Miniaturization of the Clonogenic Assay Using Confluence Measurement. AB - The clonogenic assay is a widely used method to study the ability of cells to 'infinitely' produce progeny and is, therefore, used as a tool in tumor biology to measure tumor-initiating capacity and stem cell status. However, the standard protocol of using 6-well plates has several disadvantages. By miniaturizing the assay to a 96-well microplate format, as well as by utilizing the confluence detection function of a multimode reader, we here describe a new and modified protocol that allows comprehensive experimental setups and a non-endpoint, label free semi-automatic analysis. Comparison of bright field images with confluence images demonstrated robust and reproducible detection of clones by the confluence detection function. Moreover, time-resolved non-endpoint confluence measurement of the same well showed that semi-automatic analysis was suitable for determining the mean size and colony number. By treating cells with an inhibitor of clonogenic growth (PTC-209), we show that our modified protocol is suitable for comprehensive (broad concentration range, addition of technical replicates) concentration- and time-resolved analysis of the effect of substances or treatments on clonogenic growth. In summary, this protocol represents a time- and cost-effective alternative to the commonly used 6-well protocol (with endpoint staining) and also provides additional information about the kinetics of clonogenic growth. PMID- 29510510 TI - Visualization of Concrete Slump Flow Using the Kinect Sensor. AB - Workability is regarded as one of the important parameters of high-performance concrete and monitoring it is essential in concrete quality management at construction sites. The conventional workability test methods are basically based on length and time measured by a ruler and a stopwatch and, as such, inevitably involves human error. In this paper, we propose a 4D slump test method based on digital measurement and data processing as a novel concrete workability test. After acquiring the dynamically changing 3D surface of fresh concrete using a 3D depth sensor during the slump flow test, the stream images are processed with the proposed 4D slump processing algorithm and the results are compressed into a single 4D slump image. This image basically represents the dynamically spreading cross-section of fresh concrete along the time axis. From the 4D slump image, it is possible to determine the slump flow diameter, slump flow time, and slump height at any location simultaneously. The proposed 4D slump test will be able to activate research related to concrete flow simulation and concrete rheology by providing spatiotemporal measurement data of concrete flow. PMID- 29510511 TI - Organ and Tissue-Specific Localisation of Selected Cell Wall Epitopes in the Zygotic Embryo of Brachypodium distachyon. AB - The plant cell wall shows a great diversity regarding its chemical composition, which may vary significantly even during different developmental stages. In this study, we analysed the distribution of several cell wall epitopes in embryos of Brachypodium distachyon (Brachypodium). We also described the variations in the nucleus shape and the number of nucleoli that occurred in some embryo cells. The use of transmission electron microscopy, and histological and immunolocalisation techniques permitted the distribution of selected arabinogalactan proteins, extensins, pectins, and hemicelluloses on the embryo surface, internal cell compartments, and in the context of the cell wall ultrastructure to be demonstrated. We revealed that the majority of arabinogalactan proteins and extensins were distributed on the cell surface and that pectins were the main component of the seed coat and other parts, such as the mesocotyl cell walls and the radicula. Hemicelluloses were localised in the cell wall and outside of the radicula protodermis, respectively. The specific arrangement of those components may indicate their significance during embryo development and seed germination, thus suggesting the importance of their protective functions. Despite the differences in the cell wall composition, we found that some of the antibodies can be used as markers to identify specific cells and the parts of the developing Brachypodium embryo. PMID- 29510512 TI - Functional Characterization of the Steroid Reductase Genes GmDET2a and GmDET2b form Glycine max. AB - Brassinosteroids are important phytohormones for plant growth and development. In soybean (Glycine max), BR receptors have been identified, but the genes encoding BR biosynthesis-related enzymes remain poorly understood. Here, we found that the soybean genome encodes eight steroid reductases (GmDET2a to GmDET2h). Phylogenetic analysis grouped 105 steroid reductases from moss, fern and higher plants into five subgroups and indicated that the steroid reductase family has experienced purifying selection. GmDET2a and GmDET2b, homologs of the Arabidopsis thaliana steroid 5 alpha -reductase AtDET2, are proteins of 263 amino acids. Ectopic expression of GmDET2a and GmDET2b rescued the defects of the Atdet2-1 mutant in both darkness and light. Compared to the mutant, the hypocotyl length and plant height of the transgenic lines GmDET2a and GmDET2b increased significantly, in both darkness and light, and the transcript levels of the BR biosynthesis-related genes CPD, DWF4, BR6ox-1 and BR6ox-2 were downregulated in GmDET2aOX-23 and GmDET2bOX-16 lines compared to that in Atdet2-1. Quantitative real-time PCR revealed that GmDET2a and GmDET2b are ubiquitously expressed in all tested soybean organs, including roots, leaves and hypocotyls. Moreover, epibrassinosteroid negatively regulated GmDET2a and GmDET2b expression. Sulfate deficiency downregulated GmDET2a in leaves and GmDET2b in leaves and roots; by contrast, phosphate deficiency upregulated GmDET2b in roots and leaves. Taken together, our results revealed that GmDET2a and GmDET2b function as steroid reductases. PMID- 29510513 TI - Molecular Requirements for Self-Interaction of the Respiratory Syncytial Virus Matrix Protein in Living Mammalian Cells. AB - Respiratory syncytial virus (RSV) is an important human pathogen, which infects respiratory tract epithelial cells causing bronchiolitis and pneumonia in children and the elderly. Recent studies have linked RSV matrix (M) ability to self-interaction and viral budding. However, RSV M has been crystalized both as a monomer and a dimer, and no formal proof exists to date that it forms dimers in cells. Here, by using a combination of confocal laser scanning microscopy and bioluminescent resonant energy transfer applied to differently tagged deletion mutants of RSV M, we show that the protein can self-interact in living mammalian cells and that both the N and C-terminus of the protein are strictly required for the process, consistent with the reported dimeric crystal structure. PMID- 29510514 TI - EP4 Agonist L-902,688 Suppresses EndMT and Attenuates Right Ventricular Cardiac Fibrosis in Experimental Pulmonary Arterial Hypertension. AB - Right ventricular (RV) hypertrophy is characterized by cardiac fibrosis due to endothelial-mesenchymal transition (EndMT) and increased collagen production in pulmonary arterial hypertension (PAH) patients, but the mechanisms for restoring RV function are unclear. Prostanoid agonists are effective vasodilators for PAH treatment that bind selective prostanoid receptors to modulate vascular dilation. The importance of prostanoid signaling in the RV is not clear. We investigated the effects of the EP4-specific agonist L-902,688 on cardiac fibrosis and TGF beta-induced EndMT. EP4-specific agonist treatment reduced right ventricle fibrosis in the monocrotaline (MCT)-induced PAH rat model. L-902,688 (1 uM) attenuated TGF-beta-induced Twist and alpha-smooth muscle actin (alpha-SMA) expression, but these effects were reversed by AH23848 (an EP4 antagonist), highlighting the crucial role of EP4 in suppressing TGF-beta-induced EndMT. These data indicate that the selective EP4 agonist L-902,688 attenuates RV fibrosis and suggest a potential approach to reducing RV fibrosis in patients with PAH. PMID- 29510516 TI - Metabolic Profiling of Dendrobium officinale in Response to Precursors and Methyl Jasmonate. AB - Alkaloids are the main active ingredients in the medicinal plant Dendrobium officinale. Based on the published genomic and transcriptomic data, a proposed terpenoid indole alkaloid (TIA) biosynthesis pathway may be present in D. officinale. In this study, protocorm-like bodies (PLBs) with a high-yielding production of alkaloids were obtained by the optimization of tryptophan, secologanin and methyl jasmonate (MeJA) treatment. The results showed that the total alkaloid content was 2.05 times greater than that of the control group when the PLBs were fed with 9 uM tryptophan, 6 uM secologanin and 100 uM MeJA after 36 days. HPLC analysis showed that strictosidine synthase (STR) activity also increased in the treated plants. A total of 78 metabolites were identified using gas chromatography-mass spectrometry (GC-MS) in combination with liquid chromatography-mass spectrometry (LC-MS) methods; 29 differential metabolites were identified according to the multivariate statistical analysis. Among them, carapanaubine, a kind of TIA, exhibited dramatically increased levels. In addition, a possible underlying process of the metabolic flux from related metabolism to the TIA biosynthetic pathway was enhanced. These results provide a comprehensive view of the metabolic changes related to alkaloid biosynthesis, especially TIA biosynthesis, in response to tryptophan, secologanin and MeJA treatment. PMID- 29510517 TI - Inhibition of Late and Early Phases of Cancer Metastasis by the NF-kappaB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review. AB - We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-kappaB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis. PMID- 29510518 TI - Harmful Cyanobacterial Material Production in the North Han River (South Korea): Genetic Potential and Temperature-Dependent Properties. AB - Cyanobacteria synthesize various harmful materials, including off-flavor substances and toxins, that are regarded as potential socio-economic and environmental hazards in freshwater systems, however, their production is still not well understood. In this study, we investigated the potential and properties of harmful materials produced by cyanobacteria, depending on temperature, and undertook a phylogenetic analysis of cyanobacteria present in the North Han River (South Korea). Production potentials were evaluated using gene-specific probes, and the harmful material production properties of strains showing positive potentials were further characterized at different temperatures in the range 15 to 30 degrees C. We identified six cyanobacterial strains based on 16S rDNA analysis: two morphological types (coiled and straight type) of Dolichospermum circinale, Aphanizomenon flos-aquae, Oscillatoria limosa, Planktothricoides raciborskii, Pseudanabaena mucicola, and Microcystis aeruginosa. We confirmed that cyanobacterial strains showing harmful material production potential produced the corresponding harmful material, and their production properties varied with temperature. Total harmful material production was maximal at 20~25 degrees C, a temperature range optimal for cell growth. However, harmful material productivity was highest at 15 degrees C. These results indicate that the expression of genes related to synthesis of harmful materials can vary depending on environmental conditions, resulting in variable harmful material production, even within the same cyanobacterial strains. PMID- 29510519 TI - Efflux Activity Differentially Modulates the Levels of Isoniazid and Rifampicin Resistance among Multidrug Resistant and Monoresistant Mycobacterium tuberculosis Strains. AB - With the growing body of knowledge on the contribution of efflux activity to Mycobacterium tuberculosis drug resistance, increased attention has been given to the use of efflux inhibitors as adjuvants of tuberculosis therapy. Here, we investigated how efflux activity modulates the levels of efflux between monoresistant and multi- and extensively drug resistant (M/XDR) M. tuberculosis clinical isolates. The strains were characterized by antibiotic susceptibility testing in the presence/absence of efflux inhibitors, molecular typing, and genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. The results demonstrated that all the M. tuberculosis clinical strains, susceptible or resistant, presented a faster, rapid, and non-specific efflux-mediated short-term response to drugs. The synergism assays demonstrated that the efflux inhibitors were more effective in reducing the resistance levels in the M/XDR strains than in the monoresistant strains. This indicated that M/XDR strains presented a more prolonged response to drugs mediated by efflux compared to the monoresistant strains, but both maintain it as a long-term stress response. This work shows that efflux activity modulates the levels of drug resistance between monoresistant and M/XDR M. tuberculosis clinical strains, allowing the bacteria to survive in the presence of noxious compounds. PMID- 29510521 TI - A Decision-Making Method with Grey Multi-Source Heterogeneous Data and Its Application in Green Supplier Selection. AB - In view of the multi-attribute decision-making problem that the attribute values are grey multi-source heterogeneous data, a decision-making method based on kernel and greyness degree is proposed. The definitions of kernel and greyness degree of an extended grey number in a grey multi-source heterogeneous data sequence are given. On this basis, we construct the kernel vector and greyness degree vector of the sequence to whiten the multi-source heterogeneous information, then a grey relational bi-directional projection ranking method is presented. Considering the multi-attribute multi-level decision structure and the causalities between attributes in decision-making problem, the HG-DEMATEL method is proposed to determine the hierarchical attribute weights. A green supplier selection example is provided to demonstrate the rationality and validity of the proposed method. PMID- 29510515 TI - Are microRNAs Important Players in HIV-1 Infection? An Update. AB - HIV-1 has already claimed over 35 million human lives globally. No curative treatments are currently available, and the only treatment option for over 36 million people currently living with HIV/AIDS are antiretroviral drugs that disrupt the function of virus-encoded proteins. However, such virus-targeted therapeutic strategies are constrained by the ability of the virus to develop drug-resistance. Despite major advances in HIV/AIDS research over the years, substantial knowledge gaps exist in many aspects of HIV-1 replication, especially its interaction with the host. Hence, understanding the mechanistic details of virus-host interactions may lead to novel therapeutic strategies for the prevention and/or management of HIV/AIDS. Notably, unprecedented progress in deciphering host gene silencing processes mediated by several classes of cellular small non-coding RNAs (sncRNA) presents a promising and timely opportunity for developing non-traditional antiviral therapeutic strategies. Cellular microRNAs (miRNA) belong to one such important class of sncRNAs that regulate protein synthesis. Evidence is mounting that cellular miRNAs play important roles in viral replication, either usurped by the virus to promote its replication or employed by the host to control viral infection by directly targeting the viral genome or by targeting cellular proteins required for productive virus replication. In this review, we summarize the findings to date on the role of miRNAs in HIV-1 biology. PMID- 29510520 TI - Urban Green Space and Its Impact on Human Health. AB - Background: Over half of the world's population now lives in urban areas, and this proportion is expected to increase. While there have been numerous reviews of empirical studies on the link between nature and human health, very few have focused on the urban context, and most have examined almost exclusively cross sectional research. This review is a first step toward assessing the possibility of causal relationships between nature and health in urban settings. Methods: Through systematic review of published literature, we explored the association between urban green space and human health. Results: We found consistent negative association between urban green space exposure and mortality, heart rate, and violence, and positive association with attention, mood, and physical activity. Results were mixed, or no association was found, in studies of urban green space exposure and general health, weight status, depression, and stress (via cortisol concentration). The number of studies was too low to generalize about birth outcomes, blood pressure, heart rate variability, cancer, diabetes, or respiratory symptoms. Conclusions: More studies using rigorous study design are needed to make generalizations, and meta-analyses, of these and other health outcomes possible. These findings may assist urban managers, organizations, and communities in their efforts to increase new or preserve existing green space. PMID- 29510523 TI - Liquid Crystal Elastomers-A Path to Biocompatible and Biodegradable 3D-LCE Scaffolds for Tissue Regeneration. AB - The development of appropriate materials that can make breakthroughs in tissue engineering has long been pursued by the scientific community. Several types of material have been long tested and re-designed for this purpose. At the same time, liquid crystals (LCs) have captivated the scientific community since their discovery in 1888 and soon after were thought to be, in combination with polymers, artificial muscles. Within the past decade liquid crystal elastomers (LCE) have been attracting increasing interest for their use as smart advanced materials for biological applications. Here, we examine how LCEs can potentially be used as dynamic substrates for culturing cells, moving away from the classical two-dimensional cell-culture nature. We also briefly discuss the integration of a few technologies for the preparation of more sophisticated LCE-composite scaffolds for more dynamic biomaterials. The anisotropic properties of LCEs can be used not only to promote cell attachment and the proliferation of cells, but also to promote cell alignment under LCE-stimulated deformation. 3D LCEs are ideal materials for new insights to simulate and study the development of tissues and the complex interplay between cells. PMID- 29510524 TI - Performance Evaluation of LoRa Considering Scenario Conditions. AB - New verticals within the Internet of Things (IoT) paradigm such as smart cities, smart farming, or goods monitoring, among many others, are demanding strong requirements to the Radio Access Network (RAN) in terms of coverage, end-node's power consumption, and scalability. The technologies employed so far to provide IoT scenarios with connectivity, e.g., wireless sensor network and cellular technologies, are not able to simultaneously cope with these three requirements. Thus, a novel solution known as Low Power - Wide Area Network (LP-WAN) has emerged as a promising alternative to provide with low-cost and low-power consumption connectivity to end-nodes spread in a wide area. Concretely, the Long Range Wide Area Network (LoRaWAN) technology is one of the LP-WAN platforms that is receiving greater attention from both the industry and the academia. For that reason, in this work, a comprehensive performance evaluation of LoRaWAN under different environmental conditions is presented. The results are obtained from three real scenarios, namely, urban, suburban, and rural, considering both dynamic and static conditions, hence a discussion about the most proper LoRaWAN physical-layer configuration for each scenario is provided. Besides, a theoretical coverage study is also conducted by the use of a radio planning tool considering topographic maps and a precise propagation model. From the attained results, it can be concluded that it is necessary to evaluate the propagation conditions of the deployment scenario prior to the system implantation in order to reach a compromise between the robustness of the network and the transmission data-rate. PMID- 29510522 TI - The Balance of Th17 versus Treg Cells in Autoimmunity. AB - T helper type 17 (Th17) cells and pTreg cells, which share a common precursor cell (the naive CD4 T cell), require a common tumor growth factor (TGF)-beta signal for initial differentiation. However, terminally differentiated cells fulfill opposite functions: Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these phenomena and maintain immune homeostasis. Thus, unraveling the mechanisms that affect the Th17/Treg cell balance is critical if we are to better understand autoimmunity and tolerance. Recent studies have identified many factors that influence this balance; these factors range from signaling pathways triggered by T cell receptors, costimulatory receptors, and cytokines, to various metabolic pathways and the intestinal microbiota. This review article summarizes recent advances in our understanding of the Th17/Treg balance and its implications with respect to autoimmune disease. PMID- 29510525 TI - Non-Enzymatic Electrochemical Sensing of Malathion Pesticide in Tomato and Apple Samples Based on Gold Nanoparticles-Chitosan-Ionic Liquid Hybrid Nanocomposite. AB - Malathion (MLT) is an organophosphorous type pesticide and having seriously high toxicity and electrochemical platforms for rapid, simple, inexpensive and sensitive determination of pesticides is still a special concern. This paper describes a simple preparation of a composite film consisting of ionic liquid (IL), chitosan (CS) and electrochemically synthesized gold nanoparticles (AuNPs) on single use pencil graphite electrodes (PGEs). The microscopic and electrochemical characterization of AuNP-CS-IL/PGE was studied using scanning electron microscopy, cyclic voltammetry and electrochemical impedance spectroscopy. This fabricated surface was then explored for the first time as a sensing matrix for the non-enzymatic electrochemical sensing of malathion by cyclic voltammetry and square wave voltammetry measurements. The proposed AuNP-CS IL/PGE showed excellent characteristics and possessed remarkable affinity for malathion. The voltammetric current response exhibited two linear dynamic ranges, 0.89-5.94 nM and 5.94-44.6 nM reflecting two binding sites, with a detection limit of 0.68 nM. The method was applied in real sample analysis of apple and tomato. The results demonstrate the feasibility of AuNP-CS-IL-modified electrodes for simple, fast, ultrasensitive and inexpensive detection of MLT. PMID- 29510527 TI - Depression, Suicidal Behaviour, and Mental Disorders in Older Aboriginal Australians. AB - Aboriginal Australians experience higher levels of psychological distress, which may develop from the long-term sequelae of social determinants and adversities in early and mid-life. There is little evidence available on the impact of these on the mental health of older Aboriginal Australians. This study enrolled 336 Aboriginal Australian participants over 60 years from 5 major urban and regional areas in NSW, utilizing a structured interview on social determinants, and life time history of physical and mental conditions; current psychosocial determinants and mental health. Univariate and multivariate analyses were utilized to examine the link between these determinants and current depressive scores and suicidality. There was a high rate of life-time depression (33.3%), current late life depression (18.1%), and suicidal ideation (11.1%). Risk factors strongly associated with late-life depression included sleep disturbances, a history of suicidal behaviour, suicidal ideation in late-life and living in a regional location. This study supports certain historical and psychosocial factors predicting later depression in old age, and highlights areas to target for prevention strategies. PMID- 29510528 TI - Virtual Reality Exercise for Anxiety and Depression: A Preliminary Review of Current Research in an Emerging Field. AB - OBJECTIVE: Although current evidence supports the use of virtual reality (VR) in the treatment of mental disorders, it is unknown whether VR exercise would be beneficial to mental health. This review synthesized literature concerning the effect of VR exercise on anxiety and depression among various populations. METHODS: Ten electronic databases were searched for studies on this topic from January 2000 through October 2017. Studies were eligible if the article: (1) was peer-reviewed; (2) was published in English; and (3) used quantitative measures in assessing anxiety- and depression-related outcomes. RESULTS: A total of five empirical studies met the eligibility criteria. These studies included two randomized clinical trials, one control trial, and two cross-sectional studies. Four studies reported significant improvements in anxiety- and depression-related measures following VR exercise, including reduced tiredness and tension, in addition to increased energy and enjoyment. Nonetheless, one study failed to support the effectiveness of VR exercise over traditional exercise alone on depressive symptoms. CONCLUSIONS: Findings favor VR exercise in alleviating anxiety and depression symptomology. However, existing evidence is insufficient to support the advantages of VR exercise as a standalone treatment over traditional therapy in the alleviation of anxiety and depression given the paucity of studies, small sample sizes, and lack of high-quality research designs. Future studies may build upon these limitations to discern the optimal manner by which to employ VR exercise in clinical settings. PMID- 29510526 TI - Nanotechnology and Glycosaminoglycans: Paving the Way Forward for Ovarian Cancer Intervention. AB - Ovarian cancer (OC) has gained a great deal of attention due to its aggressive proliferative capabilities, high death rates and poor treatment outcomes, rendering the disease the ultimate lethal gynaecological cancer. Nanotechnology provides a promising avenue to combat this malignancy by the niche fabrication of optimally-structured nanomedicines that ensure potent delivery of chemotherapeutics to OC, employing nanocarriers to act as "intelligent" drug delivery vehicles, functionalized with active targeting approaches for precision delivery of chemotherapeutics to overexpressed biomarkers on cancer cells. Recently, much focus has been implemented to optimize these active targeting mechanisms for treatment/diagnostic purposes employing nanocarriers. This two part article aims to review the latest advances in active target-based OC interventions, where the impact of the newest antibody, aptamer and folate functionalization on OC detection and treatment is discussed in contrast to the limitations of this targeting mechanism. Furthermore, we discuss the latest advances in nanocarrier based drug delivery in OC, highlighting their commercial/clinical viability of these systems beyond the realms of research. Lastly, in the second section of this review, we comprehensively discussed a focus shift in OC targeting from the well-studied OC cells to the vastly neglected extracellular matrix and motivate the potential for glycosaminoglycans (GAGs) as a more focused extracellular molecular target. PMID- 29510529 TI - Deep Spatial-Temporal Joint Feature Representation for Video Object Detection. AB - With the development of deep neural networks, many object detection frameworks have shown great success in the fields of smart surveillance, self-driving cars, and facial recognition. However, the data sources are usually videos, and the object detection frameworks are mostly established on still images and only use the spatial information, which means that the feature consistency cannot be ensured because the training procedure loses temporal information. To address these problems, we propose a single, fully-convolutional neural network-based object detection framework that involves temporal information by using Siamese networks. In the training procedure, first, the prediction network combines the multiscale feature map to handle objects of various sizes. Second, we introduce a correlation loss by using the Siamese network, which provides neighboring frame features. This correlation loss represents object co-occurrences across time to aid the consistent feature generation. Since the correlation loss should use the information of the track ID and detection label, our video object detection network has been evaluated on the large-scale ImageNet VID dataset where it achieves a 69.5% mean average precision (mAP). PMID- 29510531 TI - GC-MS Analysis of the Composition of the Essential Oil from Dendranthema indicum Var. Aromaticum Using Three Extraction Methods and Two Columns. AB - Dendranthema indicum var. aromaticum, which is an aromatic plant with a strong and special fragrance throughout the whole plant, is used for the treatment of colds and headaches, and as a mosquito repellant in Shennongjia, Hubei province, China. To analyze the composition of the essential oil from this medicinal herb, we developed a gas chromatography-mass Spectrometry (GC-MS) method including microwave-assisted extraction, hydrodistillation and direct headspace analysis in two different stationary phase columns. In total, 115 volatile compounds were identified, of which 90 compounds were identified using Rxi-5MS and 78 using HP INNOWAX. Our results revealed that the oil was mainly composed of five categories of compound: oxygenated monoterpenes (28.76-78.10%), oxygenated sesquiterpenes (4.27-38.06%), sesquiterpenes (3.22-11.57%), fatty hydrocarbons (1.65-9.81%) and monoterpenes (0-3.32%). The major constituents are alpha-thujone, beta-thujone, cis-sabinol, sabinyl acetate and (-)-neointermedeol.However, the essential oil composition in the published literature differs significantly. Therefore, a cluster analysis was carried out using the top ten compositions in the reported literature as well as this study, using Minitab software. To provide detailed information on plant origin, the ITS1-5.8s-ITS2 region was amplified and sequenced (Accession No. MF668250). Besides, in order to provide a macroscopic view of the chemical composition, the biosynthetic pathway of the main components was summarized according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the published literatures. PMID- 29510530 TI - Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene. AB - Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST. PMID- 29510532 TI - Factors Affecting the Success Rate of Percutaneous Nephrolithotomy in Paediatric Patients. AB - In this study, we aimed to determine factors affecting the success rate of percutaneous nephrolithotomy (PNL) in children. The series consisted of 41 consecutive children operated on by the same surgical team for renal calculi with PNL between June 2002 and May 2015 in our institution. A single calyx or pelvic stone was described as simple, while calculi located in more than one location (calyx and pelvis or more than one calices) or staghorn stones were described as complex. The procedure was deemed successful if the patient was completely stone free (SF) or had residual fragments <4 mm. Thirty-four patients were found to be SF or had residual fragments <4 mm on the postoperative first day, thus the success rate was 82.9%. In complex stones, the success rate was significantly lower (45.5%) than simple stones (96.7%) (p < 0.001). The grade of hydronephrosis (Grade 0-1 vs. Grade 2-3) also had a negative impact on the success, with rates of 92.6% vs. 64.3%, respectively (p = 0.022). Previous urological procedure history on the same side yielded a success rate of 58.3%, whereas the success rate in the primary patients was 93.1% (p < 0.001). The localization of the stone (complex vs. simple), degree of hydronephrosis, and history of previous urological procedures were found to be the factors that affected the success of the paediatric PNL. PMID- 29510534 TI - Design and Implementation of a New System for Large Bridge Monitoring-GeoSHM. AB - Structural Health Monitoring (SHM) is a relatively new branch of civil engineering that focuses on assessing the health status of infrastructure, such as long-span bridges. Using a broad range of in-situ monitoring instruments, the purpose of the SHM is to help engineers understand the behaviour of structures, ensuring their structural integrity and the safety of the public. Under the Integrated Applications Promotion (IAP) scheme of the European Space Agency (ESA), a feasibility study (FS) project that used the Global Navigation Satellite Systems (GNSS) and Earth Observation (EO) for Structural Health Monitoring of Long-span Bridges (GeoSHM) was initiated in 2013. The GeoSHM FS Project was led by University of Nottingham and the Forth Road Bridge (Scotland, UK), which is a 2.5 km long suspension bridge across the Firth of Forth connecting Edinburgh and the Northern part of Scotland, was selected as the test structure for the GeoSHM FS project. Initial results have shown the significant potential of the GNSS and EO technologies. With these successes, the FS project was further extended to the demonstration stage, which is called the GeoSHM Demo project where two other long span bridges in China were included as test structures. Led by UbiPOS UK Ltd. (Nottingham, UK), a Nottingham Hi-tech company, this stage focuses on addressing limitations identified during the feasibility study and developing an innovative data strategy to process, store, and interpret monitoring data. This paper will present an overview of the motivation and challenges of the GeoSHM Demo Project, a description of the software and hardware architecture and a discussion of some primary results that were obtained in the last three years. PMID- 29510533 TI - Insights into the Mechanisms of Chloroplast Division. AB - The endosymbiosis of a free-living cyanobacterium into an ancestral eukaryote led to the evolution of the chloroplast (plastid) more than one billion years ago. Given their independent origins, plastid proliferation is restricted to the binary fission of pre-existing plastids within a cell. In the last 25 years, the structure of the supramolecular machinery regulating plastid division has been discovered, and some of its component proteins identified. More recently, isolated plastid-division machineries have been examined to elucidate their structural and mechanistic details. Furthermore, complex studies have revealed how the plastid-division machinery morphologically transforms during plastid division, and which of its component proteins play a critical role in generating the contractile force. Identifying the three-dimensional structures and putative functional domains of the component proteins has given us hints about the mechanisms driving the machinery. Surprisingly, the mechanisms driving plastid division resemble those of mitochondrial division, indicating that these division machineries likely developed from the same evolutionary origin, providing a key insight into how endosymbiotic organelles were established. These findings have opened new avenues of research into organelle proliferation mechanisms and the evolution of organelles. PMID- 29510536 TI - Infrastructure-Less Communication Platform for Off-The-Shelf Android Smartphones. AB - As smartphones and other small portable devices become more sophisticated and popular, opportunities for communication and information sharing among such device users have increased. In particular, since it is known that infrastructure less device-to-device (D2D) communication platforms consisting only of such devices are excellent in terms of, for example, bandwidth efficiency, efforts are being made to merge their information sharing capabilities with conventional infrastructure. However, efficient multi-hop communication is difficult with the D2D communication protocol, and many conventional D2D communication platforms require modifications of the protocol and terminal operating systems (OSs). In response to these issues, this paper reports on a proposed tree-structured D2D communication platform for Android devices that combines Wi-Fi Direct and Wi-Fi functions. The proposed platform, which is expected to be used with general Android 4.0 (or higher) OS equipped terminals, makes it possible to construct an ad hoc network instantaneously without sharing prior knowledge among participating devices. We will show the feasibility of our proposed platform through its design and demonstrate the implementation of a prototype using real devices. In addition, we will report on our investigation into communication delays and stability based on the number of hops and on terminal performance through experimental confirmation experiments. PMID- 29510535 TI - Miro-Working beyond Mitochondria and Microtubules. AB - The small GTPase Miro is best known for its regulation of mitochondrial movement by engaging with the microtubule-based motor proteins kinesin and dynein. Very recent findings have now showed that Miro also targets peroxisomes and regulates microtubule-dependent peroxisome motility. Moreover, Miro recruits and stabilizes the myosin motor Myo19 at the mitochondria to enable actin-based mitochondria movement, which is important for mitochondrial segregation during mitosis. Miro thus has much broader functions that previously known, and these new findings may have important implications on disease pathology. PMID- 29510537 TI - Enhancement of Inverted Polymer Solar Cells Performances Using Cetyltrimethylammonium-Bromide Modified ZnO. AB - In this study, the performance and stability of inverted bulk heterojunction (BHJ) polymer solar cells (PSCs) is enhanced by doping zinc oxide (ZnO) with 0-6 wt % cetyltrimethylammonium bromide (CTAB) in the sol-gel ZnO precursor solution. The power conversion efficiency (PCE) of the optimized 3 wt % CTAB-doped ZnO PSCs was increased by 9.07%, compared to a PCE of 7.31% for the pristine ZnO device. The 0-6 wt % CTAB-doped ZnO surface roughness was reduced from 2.6 to 1 nm and the number of surface defects decreased. The X-ray photoelectron spectroscopy binding energies of Zn 2p3/2 (1021.92 eV) and 2p1/2 (1044.99 eV) shifted to 1022.83 and 1045.88 eV, respectively, which is related to strong chemical bonding via bromide ions (Br-) that occupy oxygen vacancies in the ZnO lattice, improving the PCE of PSCs. The concentration of CTAB in ZnO significantly affected the work function of PSC devices; however, excessive CTAB increased the work function of the ZnO layer, resulting from the aggregation of CTAB molecules. In addition, after a 120-hour stability test in the atmosphere with 40% relative humidity, the inverted device based on CTAB-doped ZnO retained 92% of its original PCE and that based on pristine ZnO retained 68% of its original PCE. The obtained results demonstrate that the addition of CTAB into ZnO can dramatically influence the optical, electrical, and morphological properties of ZnO, enhancing the performance and stability of BHJ PSCs. PMID- 29510538 TI - Miniaturized Sample Preparation and Rapid Detection of Arsenite in Contaminated Soil Using a Smartphone. AB - Conventional methods for analyzing heavy metal contamination in soil and water generally require laboratory equipped instruments, complex procedures, skilled personnel and a significant amount of time. With the advancement in computing and multitasking performances, smartphone-based sensors potentially allow the transition of the laboratory-based analytical processes to field applicable, simple methods. In the present work, we demonstrate the novel miniaturized setup for simultaneous sample preparation and smartphone-based optical sensing of arsenic As(III) in the contaminated soil. Colorimetric detection protocol utilizing aptamers, gold nanoparticles and NaCl have been optimized and tested on the PDMS-chip to obtain the high sensitivity with the limit of detection of 0.71 ppm (in the sample) and a correlation coefficient of 0.98. The performance of the device is further demonstrated through the comparative analysis of arsenic-spiked soil samples with standard laboratory method, and a good agreement with a correlation coefficient of 0.9917 and the average difference of 0.37 ppm, are experimentally achieved. With the android application on the device to run the experiment, the whole process from sample preparation to detection is completed within 3 hours without the necessity of skilled personnel. The approximate cost of setup is estimated around 1 USD, weight 55 g. Therefore, the presented method offers the simple, rapid, portable and cost-effective means for onsite sensing of arsenic in soil. Combined with the geometric information inside the smartphones, the system will allow the monitoring of the contamination status of soils in a nation-wide manner. PMID- 29510539 TI - Robust Time-Difference-of-Arrival (TDOA) Localization Using Weighted Least Squares with Cone Tangent Plane Constraint. AB - Finding the position of a radiative source based on time-difference-of-arrival (TDOA) measurements from spatially separated receivers has been widely applied in sonar, radar, mobile communications and sensor networks. For the nonlinear model in the process of positioning, Taylor series and other novel methods are proposed. The idea of cone constraint provides a new way of solving this problem. However, these approaches do not always perform well and are away from the Cramer Rao-Lower-Bound (CRLB) in the situations when the source is set at the array edge, the noise in measurement is loud, or the initial position is biased. This paper presents a weighted-least-squares (WLS) algorithm with the cone tangent plane constraint for hyperbolic positioning. The method adds the range between the source and the reference sensor as a dimension. So, the space-range frame is established. Different from other cone theories, this paper sets the reference sensor as the apex and finds the optimal source estimation on the cone. WLS is used for the optimal result from the measurement plane equations, a vertical constraint and a cone constraint. The cone constraint equation is linearized by a tangent plane. This method iterates through loops and updates the tangent plane, which approximates the truth-value on the cone. The proposed algorithm was simulated and verified under various conditions of different source positions and noises. Besides, some state-of-the-art algorithms were compared in these simulations. The results show that this algorithm is accurate and robust under poor external environment. PMID- 29510540 TI - Development of a Novel Guided Wave Generation System Using a Giant Magnetostrictive Actuator for Nondestructive Evaluation. AB - As a common approach to nondestructive testing and evaluation, guided wave-based methods have attracted much attention because of their wide detection range and high detection efficiency. It is highly desirable to develop a portable guided wave testing system with high actuating energy and variable frequency. In this paper, a novel giant magnetostrictive actuator with high actuation power is designed and implemented, based on the giant magnetostrictive (GMS) effect. The novel GMS actuator design involves a conical energy-focusing head that can focus the amplified mechanical energy generated by the GMS actuator. This design enables the generation of stress waves with high energy, and the focusing of the generated stress waves on the test object. The guided wave generation system enables two kinds of output modes: the coded pulse signal and the sweep signal. The functionality and the advantages of the developed system are validated through laboratory testing in the quality assessment of rock bolt-reinforced structures. In addition, the developed GMS actuator and the supporting system are successfully implemented and applied in field tests. The device can also be used in other nondestructive testing and evaluation applications that require high power stress wave generation. PMID- 29510541 TI - A Rapid and Semi-Quantitative Gold Nanoparticles Based Strip Sensor for Polymyxin B Sulfate Residues. AB - Increasing attention is now being directed to the utilization of polymyxin B (PMB) as a last-line treatment for life-threatening infections caused by multidrug resistant Gram-negative bacteria. Unfortunately, polymyxins resistance is also increasingly reported, leaving a serious threat to human health. Therefore, the establishment of rapid detection methods for PMB residues is highly essential to ensure public health. In this study, two monoclonal antibodies (mAb; 2A2 and 3C6) were obtained using PMB-bovine serum albumin as the immunogen and PMB-ovalbumin as the coating antigen, which were prepared with N (gamma-maleimidobutyryloxy) succinimide ester and glutaraldehyde as cross-linking agents, respectively. Through an indirect competitive enzyme-linked immunosorbent assay, resultant two mAbs were compared and the results indicated that 3C6 showed higher sensitivity with a half maximum inhibition concentration of 13.13 ng/mL. Based on 3C6, a gold nanoparticles (AuNPs)-based immunochromatographic test (ICT) strip was then established, the mechanism of which is that free PMB competes with the fixed coating antigen to combine with mAb labeled by AuNPs. Using ICT strip to detect milk and animal feed samples revealed the visible detection limits were 25 ng/mL and 500 MUg/kg, respectively and the cutoff limits were 100 ng/mL and 1000 MUg/kg, respectively. The ICT strip provides results within 15 min, facilitating rapid and semi-quantitative analysis of PMB residues in milk and animal feed. PMID- 29510542 TI - 1H-NMR Profiling and Chemometric Analysis of Selected Honeys from South Africa, Zambia, and Slovakia. AB - Honey is the natural sweet substance produced by honeybee from nectar or honeydew, exhibiting several nutritional and health benefits. It contains a complex mixture of compounds in different proportions, with sugars being the main component. The physicochemical characteristics of ten honeys were evaluated; represented by five, three, and two from South Africa, Slovakia, and Zambia, respectively. The range of values for the pH (3.75-4.38), electrical conductivity (99-659 uS/cm), and moisture content (14.2-17.7%) are within the recommended limits for quality honeys. 1H-NMR (Nuclear Magnetic Resonance) profiling of the honeys in D2O was determined, and the data were analysed by chemometrics. This method is fast, reproducible, and sample pre-treatment is not necessary. The 1H NMR fingerprints of various chemical shift regions showed similarity or dissimilarity across geographical origins that are useful for identification, detection of adulteration, and quality control. The principal component analysis PCA and partial linear square discriminant analysis PLS-DA of the 1H-NMR profiles successively categorises the honeys into two chemically related groups. The R2 values are higher than the corresponding Q2 values for all samples, confirming the reliability of the model. Honeys in the same cluster contain similar metabolites and belong to the same botanic or floral origin. PMID- 29510544 TI - Assessing the Understanding of Pharmaceutical Pictograms among Cultural Minorities: The Example of Hindu Individuals Communicating in European Portuguese. AB - One of the sources of poor health outcomes is the lack of compliance with the prescribed treatment plans, often due to communication barriers between healthcare professionals and patients. Pictograms are a form of communication that conveys meaning through its pictorial resemblance to a physical object or an action. Pharmaceutical pictograms are often associated with a better comprehension of treatment regimens, although their use is still subject to limitations. The main goal of this study was to examine the potential understanding of pharmaceutical pictograms by a cultural minority when providing patient information while comparing the effectiveness of two reference systems (United States Pharmacopeia USP and International Pharmacy Federation FIP) for this purpose. A self-administered questionnaire was developed comprising 30 pictograms, 15 selected from the United States Pharmacopeia Dispensing Information and the equivalent from the International Pharmaceutical Federation. The questionnaire comprised plain instructions, socio-demographic data, self reported language fluency and pictogram labels in Portuguese presented to conveniently selected members of the Hindu community of Lisbon (Portugal) until reaching a quota of 50. Participants showed difficulties in understanding some pictograms, which was related to the self-reported reduced fluency in Portuguese. Overall, the interpretation of USP pictograms was better than FIP ones, as well as for pictograms composed of multiple images, presenting a negative reading, or when conveying information unrelated to medication instructions. Even using internationally validated pictograms, added care should be taken when community pharmacists use such communication resources with cultural minorities. It is important not to disregard other forms of patient communication and information, considering pictograms as a complement to other forms of patient counselling. PMID- 29510543 TI - Steroidal Saponins from Vernonia amygdalina Del. and Their Biological Activity. AB - In the present study, four new steroidal saponins, namely vernoniamyoside A-D (1 4), together with the two known steroidal saponins vernoamyoside D (5) and vernonioside B2 (6) were isolated from the ethanol extract of leaves of the African medicinal plant Vernonia amygdalina Del. (Asteraceae). Their structures were demonstrated by spectral analyses along with 1D and 2D nuclear magnetic resonance (NMR) techniques and mass spectrometry (MS). The cytotoxicity of the compounds was also tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method on the cell lines Hela, MCF-7, BT-549 and MDA-MB-231. Vernoniamyoside A, vernoniamyoside B, and vernonioside B2 showed cytotoxicity towards BT-549 cell lines. Vernoniamyoside C, vernoniamyoside D and vernoamyoside D showed different levels of cytotoxic activities. PMID- 29510545 TI - Body Fat Measurements in Singaporean Adults Using Four Methods. AB - Few studies have been conducted to measure body composition in Asian populations. In this study, we determined the percent body fat (PBF) by using dual-energy X ray absorptiometry (DEXA), air-displacement plethysmography (ADP or BOD POD), bioelectrical impedance analysis (BIA) and skinfold (SKF) in 445 healthy Singaporean adults. We observed that the BOD POD, BIA and SKF estimates of PBF were highly correlated with that from DEXA (as a reference method) among Singaporean adults. However, they all underestimated PBF (differences of 3.9% for BOD POD, 5.6% for BIA and 12.5% for SKF). Our results filled a gap in the literature by testing the relationships between DEXA and BOD POD, BIA and SKF in a large sample with a wide range of body mass index (BMI) from 16.1 to 37.5 kg/m2 and age from 21 to 69.2 years. The differences of PBF measured by different methods were dependent on age, gender and ethnicity. No significant difference was observed between DEXA and BOD POD in men aged > 40 or in BMI tertile 3. However, the mean difference between DEXA and BOD POD was significant in women. Different measuring methods of estimating PBF therefore must be cautiously interpreted. PMID- 29510546 TI - A 40-Day Journey to Better Health: Utilizing the DanielFast to Improve Health Outcomes in Urban Church-Based Settings. AB - Background: As the costs associated with obesity increase, it is vital to evaluate the effectiveness of chronic disease prevention among underserved groups, particularly in urban settings. This research study evaluated Philadelphia area Keystone First members and church participants enrolled in a group health education program to determine the impact of the Daniel Fast on physical health and the adoption of healthy behaviors. Methods: Participants attended six-weekly health education sessions in two participating churches, and were provided with a digital healthy eating platform. Results: There was a statistically significant decrease from baseline to post assessment for weight, waist circumference and cholesterol. Participants reported a significant improvement in their overall well-being, social and physical functioning, vitality and mental health. Conclusion: Results of this study demonstrate that dietary recommendations and comprehensive group health education delivered in churches and reinforced on a digital platform can improve physical health, knowledge and psychosocial outcomes. PMID- 29510547 TI - ISBDD Model for Classification of Hyperspectral Remote Sensing Imagery. AB - The diverse density (DD) algorithm was proposed to handle the problem of low classification accuracy when training samples contain interference such as mixed pixels. The DD algorithm can learn a feature vector from training bags, which comprise instances (pixels). However, the feature vector learned by the DD algorithm cannot always effectively represent one type of ground cover. To handle this problem, an instance space-based diverse density (ISBDD) model that employs a novel training strategy is proposed in this paper. In the ISBDD model, DD values of each pixel are computed instead of learning a feature vector, and as a result, the pixel can be classified according to its DD values. Airborne hyperspectral data collected by the Airborne Visible/Infrared Imaging Spectrometer (AVIRIS) sensor and the Push-broom Hyperspectral Imager (PHI) are applied to evaluate the performance of the proposed model. Results show that the overall classification accuracy of ISBDD model on the AVIRIS and PHI images is up to 97.65% and 89.02%, respectively, while the kappa coefficient is up to 0.97 and 0.88, respectively. PMID- 29510548 TI - Analysis of Outcomes of the Nutritional Status in Patients Qualified for Aortic Valve Replacement in Comparison to Healthy Elderly. AB - Severe aortic stenosis (AS) is associated with the reduction of muscle mass and may be associated with deterioration of nutritional status. Furthermore, malnourished cardiac patients are characterized by a higher risk of postoperative complications and mortality. The aim of this study was the evaluation and comparison of nutritional status, appetite and body composition in older people with severe aortic stenosis before aortic valve replacement and healthy elderly volunteers. One hundred and one patients, aged >65 years old with severe AS were included in the study. Nutritional status was assessed. Body composition was estimated using bioelectrical impedance analysis. Concentrations of albumin, prealbumin, triglycerides, total cholesterol and C-reactive protein were measured, and a complete blood count was done. About 40% of AS patients were at risk of malnutrition. They had decreased hand grip strength and they lost more body mass than the control group. Malnourished AS patients were older, had lower body mass indexes (BMIs) and lower aortic valve areas in comparison to well nourished patients. Older AS patients, like their peers, show excessive body mass and, at the same time, the features of malnutrition. They have additional factors such as unintentional weight lost and decreased muscle strength which may be associated with worse outcomes. PMID- 29510549 TI - The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability. AB - Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies. PMID- 29510551 TI - Improving Mechanical Properties of PVPPA Welded Joints of 7075 Aluminum Alloy by PWHT. AB - In this study, 7075 aluminum alloy with a thickness of 10 mm was successfully welded with no obvious defects by pulsed variable polarity plasma arc (PVPPA) welding. The mechanical properties of PVPPA welded joints have been researched by post weld heat treatment (PWHT). The results indicate that the heat treatment strongly affects the mechanical properties of the welded joints. The tensile strength and the microhardness of the welded joints gradually improved with the increase of the solution temperature. With the increase of the solution time, the tensile strength, and microhardness first dramatically increased and then decreased slightly. The best tensile strength of 537.5 MPa and the microhardness of 143.7 HV were obtained after 490 degrees C * 80 min + 120 degrees C * 24 h, and the strength was nearly 91.2% of that of the parent metal, and increased about 35% compared with as-welded. The improvement of strength and microhardness was mainly due to the precipitation of eta' phase. PMID- 29510550 TI - The Multiplicity of Infection-Dependent Effects of Recombinant Adenovirus Carrying HGF Gene on the Proliferation and Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. AB - Absence of effective therapeutic methods for avascular necrosis of femoral head (ANFH) is still perplexing the world's medical community. Bone marrow mesenchymal stem cells (BMSCs) adoptive cell therapy combined with core decompression is a promising modality, which is highly dependent on the cellular activities of BMSCs. Hepatocyte growth factor (HGF) is a survival factor for BMSCs, yet the underlying mechanism is not fully elucidated. In this study, the effects of multiplicity of infections (MOIs) of recombinant adenovirus carrying HGF gene (rAd-HGF) on human BMSC proliferation and osteogenic differentiation were systemically examined. Infection of rAd-HGF produced secretory HGF and promoted hBMSC proliferation in a MOI-dependent manner, while the osteogenesis was also strengthened as indicated by enhanced calcium nodule formation with the strongest effects achieved at MOI = 250. Blocking the activities of c-MET or its downstream signaling pathways, WNT, ERK1/2, and PI3K/AKT led to differential consequents. Specifically, blockage of the WNT pathway significantly promoted osteogenic differentiation, which also showed additive effects when combined application with rAd-HGF. Our data demonstrated the pro-osteogenic effects of optimized MOIs of rAd-HGF, while inhibition of WNT pathway or activation of PI3K/AKT pathway may act as candidate adjuvant modalities for promoting osteogenic differentiation in rAd-HGF-modified hBMSC treatment on ANFH. PMID- 29510552 TI - Hydrolytic Degradation and Mechanical Stability of Poly(epsilon Caprolactone)/Reduced Graphene Oxide Membranes as Scaffolds for In Vitro Neural Tissue Regeneration. AB - The present work studies the functional behavior of novel poly(epsilon caprolactone) (PCL) membranes functionalized with reduced graphene oxide (rGO) nanoplatelets under simulated in vitro culture conditions (phosphate buffer solution (PBS) at 37 degrees C) during 1 year, in order to elucidate their applicability as scaffolds for in vitro neural regeneration. The morphological, chemical, and DSC results demonstrated that high internal porosity of the membranes facilitated water permeation and procured an accelerated hydrolytic degradation throughout the bulk pathway. Therefore, similar molecular weight reduction, from 80 kDa to 33 kDa for the control PCL, and to 27 kDa for PCL/rGO membranes, at the end of the study, was observed. After 1 year of hydrolytic degradation, though monomers coming from the hydrolytic cleavage of PCL diffused towards the PBS medium, the pH was barely affected, and the rGO nanoplatelets mainly remained in the membranes which envisaged low cytotoxic effect. On the other hand, the presence of rGO nanomaterials accelerated the loss of mechanical stability of the membranes. However, it is envisioned that the gradual degradation of the PCL/rGO membranes could facilitate cells infiltration, interconnectivity, and tissue formation. PMID- 29510553 TI - Multi-Scale Modeling for Predicting the Stiffness and Strength of Hollow Structured Metal Foams with Structural Hierarchy. AB - This work was inspired by previous experiments which managed to establish an optimal template-dealloying route to prepare ultralow density metal foams. In this study, we propose a new analytical-numerical model of hollow-structured metal foams with structural hierarchy to predict its stiffness and strength. The two-level model comprises a main backbone and a secondary nanoporous structure. The main backbone is composed of hollow sphere-packing architecture, while the secondary one is constructed of a bicontinuous nanoporous network proposed to describe the nanoscale interactions in the shell. Firstly, two nanoporous models with different geometries are generated by Voronoi tessellation, then the scaling laws of the mechanical properties are determined as a function of relative density by finite volume simulation. Furthermore, the scaling laws are applied to identify the uniaxial compression behavior of metal foams. It is shown that the thickness and relative density highly influence the Young's modulus and yield strength, and vacancy defect determines the foams being self-supported. The present study provides not only new insights into the mechanical behaviors of both nanoporous metals and metal foams, but also a practical guide for their fabrication and application. PMID- 29510554 TI - Iodine Status among Somali Immigrants in Norway. AB - We lack knowledge about iodine status in the Norwegian population in general, and particularly among immigrants. We aimed to estimate the iodine status and potentially associated factors in a Somali population in Norway. Somali men and women aged 20-73, who were living in one district in Oslo, were recruited between December 2015 and October 2016. Twenty-four-hour urine was collected from 169 participants (91 females and 78 males). Iodine was analysed using the Sandell Kolthoff reaction on microplates and colorimetric measurement. Information about diet was collected using a short food frequency questionnaire. Iodine intake was calculated from the 24-h iodine excretion. The mean urine volume over 24-h was 1.93 liters (min-max: 0.55-4.0) and the urinary iodine concentration (UIC) varied from 13 to 263 ug/L with a median value of 62.5 ug/L indicating a population with mild iodine deficiency. The median daily iodine intake for the study population was estimated to be 124 MUg/day. Mean serum thyroid-stimulating hormone, thyroxine (T4) and triiodothyronine (T3) was 2.1 (SD 1.1) mU/L, 15.0 (SD 2.1) pmol/L, and 5.1 (SD 0.6) pmol/L, respectively. No food groups were associated with iodine intake and neither was gender, age, education level nor length of residence in Norway. In conclusion, this study showed that iodine intake was low, and a considerable proportion of the Somali population studied had sub-optimal iodine status. Monitoring of iodine status should be prioritised and measures to ensure adequate iodine intake, particularly among vulnerable groups initiated. PMID- 29510555 TI - Assessment of Blend PVDF Membranes, and the Effect of Polymer Concentration and Blend Composition. AB - In this work, PVDF homopolymer was blended with PVDF-co-HFP copolymer and studied in terms of morphology, porosity, pore size, hydrophobicity, permeability, and mechanical properties. Different solvents, namely N-Methyl-2 pyrrolidone (NMP), Tetrahydrofuran (THF), and Dimethylformamide (DMF) solvents, were used to fabricate blended PVDF flat sheet membranes without the introduction of any pore forming agent, through a non-solvent induced phase separation (NIPS) technique. Furthermore, the performance of the fabricated membranes was investigated for pressure and thermal driven applications. The porosity of the membranes was slightly increased with the increase in the overall content of PVDF and by the inclusion of PVDF copolymer. Total PVDF content, copolymer content, and mixed solvent have a positive effect on mechanical properties. The addition of copolymer increased the hydrophobicity when the total PVDF content was 20%. At 25% and with the inclusion of mixed-solvent, the hydrophobicity was adversely affected. The permeability of the membranes increased with the increase in the overall content of PVDF. Mixed-solvents significantly improved permeability. PMID- 29510556 TI - Preparation and Characterization of TiO2/g-C3N4/PVDF Composite Membrane with Enhanced Physical Properties. AB - TiO2/g-C3N4/PVDF composite membranes were prepared by a phase inversion method. A comparison of the performance and morphology was carried out among pure PVDF, g C3N4/PVDF, TiO2/PVDF and TiO2/g-C3N4/PVDF composite membranes. The results of permeability and instrumental analysis indicated that TiO2 and g-C3N4 organic inorganic composites obviously changed the performance and structure of the PVDF membranes. The porosity and water content of 0.75TiO2/0.25g-C3N4/PVDF composite membranes were 97.3 and 188.3 L/(m2.h), respectively. The porosity and water content of the 0.75TiO2/0.25g-C3N4 membranes were increased by 20.8% and 27.4%, respectively, compared with that of pure PVDF membranes. This suggested that the combination of organic-inorganic composite with PVDF could remarkably improve UTS, membrane porosity and water content. PMID- 29510557 TI - Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells. AB - Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP). However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell's metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents. PMID- 29510559 TI - Design Parameter Optimization of a Silicon-Based Grating Waveguide for Performance Improvement in Biochemical Sensor Application. AB - We performed numerical analysis and design parameter optimization of a silicon based grating waveguide refractive index (RI) sensor. The performance of the grating waveguide RI sensor was determined by the full-width at half-maximum (FWHM) and the shift in the resonance wavelength in the transmission spectrum. The transmission extinction, a major figure-of-merit of an RI sensor that reflects both FWHM and resonance shift performance, could be significantly improved by the proper determination of three major grating waveguide parameters: duty ratio, grating period, and etching depth. We analyzed the transmission characteristics of the grating waveguide under various design parameter conditions using a finite-difference time domain method. We achieved a transmission extinction improvement of >26 dB under a given bioenvironmental target change by the proper choice of the design procedure and parameters. This design procedure and choice of appropriate parameters would enable the widespread application of silicon-based grating waveguide in high-performance RI biochemical sensor. PMID- 29510558 TI - Helicobacter Pylori Serology in Relation to Hepatitis C Virus Infection and IL28B Single Nucleotide Polymorphism. AB - The aim of the study was to evaluate the serological rate of Helicobacter pylori (H. pylori) infection in patients with chronic hepatitis C virus (HCV) infection and determine any correlations with liver damage and IL28B single-nucleotide polymorphism (SNP). One hundred eighty-nine patients with chronic HCV infection were included in the study, and H. pylori status was defined based on anti-H. pylori-IgG or anti-CagA-IgG antibodies using enzyme-linked immunosorbent assay (ELISA). Liver damage was assessed using histology or transient elastography. IL28B C/T polymorphism (rs12979860) was evaluated in circulating blood cells using a PCR-based restriction fragment length polymorphism assay. Overall H. pylori serology was positive in 38.1% of our HCV-infected subjects. Among those, the anti-CagA-IgG positivity rate was 43.1% and was within the range of previously described populations of the same region. Highest prevalence of H. pylori was found in patients between 31 and 40 years compared to other age subgroups. The seropositivity rate was higher in the non-cirrhotic group than the cirrhotic one (45.4% vs. 20.0%, p < 0.05). No difference was found in IL28B genotype between H. pylori-positive and -negative cohorts. However, we observed a trend for the lower anti-CagA-IgG expression level in relation to the IL28B T allele. Our results do not support an association between HCV and H. pylori infection. Whether IL28B SNP has a functional role in modulation of serological response to H. pylori CagA needs further investigation. PMID- 29510560 TI - Processing Technology Selection for Municipal Sewage Treatment Based on a Multi Objective Decision Model under Uncertainty. AB - This study considers the two factors of environmental protection and economic benefits to address municipal sewage treatment. Based on considerations regarding the sewage treatment plant construction site, processing technology, capital investment, operation costs, water pollutant emissions, water quality and other indicators, we establish a general multi-objective decision model for optimizing municipal sewage treatment plant construction. Using the construction of a sewage treatment plant in a suburb of Chengdu as an example, this paper tests the general model of multi-objective decision-making for the sewage treatment plant construction by implementing a genetic algorithm. The results show the applicability and effectiveness of the multi-objective decision model for the sewage treatment plant. This paper provides decision and technical support for the optimization of municipal sewage treatment. PMID- 29510561 TI - Survival Analysis in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Chemoradiotherapy Followed by Surgery According to the International Consensus on the 2017 Definition of Borderline Resectable Cancer. AB - Background: The aim of this study was to validate a new definition of borderline resectable pancreatic ductal adenocarcinoma (PDAC) provided by the 2017 international consensus on the basis of three dimensions of anatomical (A), biological (B), and conditional (C) factors, using the data of the patients who had been registered for our institutional protocol of chemoradiotherapy followed by surgery (CRTS) for localized patients with PDAC. Methods: Among 307 consecutive patients pathologically diagnosed with localized PDAC who were enrolled in our CRTS protocol from February 2005 to December 2016, we selected 285 patients who could be re-evaluated after CRT. These 285 patients were classified according to international consensus A definitions as follows: R (resectable; n = 62), BR-PV (borderline resectable, superior mesenteric vein (SMV)/portal vein (PV) involvement alone; n = 27), BR-A (borderline resectable, arterial involvement; n = 50), LA (locally advanced; n = 146). Disease-specific survival (DSS) was analyzed according to A, B (serum CA 19-9 levels and lymph node metastasis diagnosed by computed tomography findings before CRT), and C factors (performance status (PS)) factors. Results: The rates of resection and R0 resection were similar between R (83.9 and 98.0%) and BR-PV (85.2 and 95.5%), but much lower in BR-A (70.0 and 84.8%) and LA (46.6 and 62.5%). DSS evaluated by median survival time (months) showed a similar trend to surgical outcomes: 33.7 in R, 27.3 in BR-PV, 18.9 in BR-A and 19.3 in LA, respectively. DSS in R patients with CA 19-9 levels > 500 U/mL was significantly poorer than in patients with CA 19-9 levels <= 500 U/mL, but there were no differences in DSS among BR-PV, BR-A, and LA patients according to CA 19-9 levels. Regarding lymph node metastasis, there was no significant difference in DSS according to each resectability group. DSS in R patients with PS >= 2 was significantly worse than in patients with PS 0 1. Conclusions: The international consensus on the definition of BR-PDAC based on three dimensions of A, B, and C is useful and practicable because prognosis of PDAC patients is influenced by anatomical factors as well as biological and conditional factors, which in turn may help to decide treatment strategy. PMID- 29510562 TI - Modifiable "Predictors" of Zinc Status in Toddlers. AB - Suboptimal zinc status is common in very young children and likely associated with increased risk of infection and detrimental effects on growth. No studies have determined potentially modifiable "predictors" of zinc status in toddlers from high-income countries. This cross-sectional analysis of 115 toddlers from the Baby-Led Introduction to SolidS (BLISS) study used weighed diet records (three non-consecutive days) to assess dietary intake, and a venous blood sample (trace-element free techniques) to assess plasma zinc, at 12 months of age. "Predictors" of plasma zinc were determined by univariate analysis and multiple regression. Mean (SD) plasma zinc was 9.7 (1.5) MUmol/L, 60% were below the IZiNCG reference limit of <9.9 MUmol/L. Median (25th, 75th percentiles) intake of zinc was 4.4 (3.7, 5.4) mg/day. Red meat intake (p = 0.004), consumption of zinc fortified infant formula (3-6 mg zinc/100 g) (p = 0.026), and food fussiness (p = 0.028) were statistically significant "predictors" of plasma zinc at 12 months. Although higher intakes of red meat, and consumption of infant formula, are potentially achievable, it is important to consider possible barriers, particularly impact on breastfeeding, cost, and the challenges of behavior modification. Of interest is the association with food fussiness-further research should investigate the direction of this association. PMID- 29510563 TI - Molecular Characterization of a Novel N-Acetylneuraminate Lyase from a Deep-Sea Symbiotic Mycoplasma. AB - N-acetylneuraminic acid (Neu5Ac) based novel pharmaceutical agents and diagnostic reagents are highly required in medical fields. However, N-acetylneuraminate lyase(NAL)for Neu5Ac synthesis is not applicable for industry due to its low catalytic efficiency. In this study, we biochemically characterized a deep-sea NAL enzyme (abbreviated form: MyNal) from a symbiotic Mycoplasma inhabiting the stomach of a deep-sea isopod, Bathynomus jamesi. Enzyme kinetic studies of MyNal showed that it exhibited a very low Km for both cleavage and synthesis activities compared to previously described NALs. Though it favors the cleavage process, MyNal out-competes the known NALs with respect to the efficiency of Neu5Ac synthesis and exhibits the highest kcat/Km values. High expression levels of recombinant MyNal could be achieved (9.56 mol L-1 culture) with a stable activity in a wide pH (5.0-9.0) and temperature (40-60 degrees C) range. All these features indicated that the deep-sea NAL has potential in the industrial production of Neu5Ac. Furthermore, we found that the amino acid 189 of MyNal (equivalent to Phe190 in Escherichia coli NAL), located in the sugar-binding domain, GX189DE, was also involved in conferring its enzymatic features. Therefore, the results of this study improved our understanding of the NALs from different environments and provided a model for protein engineering of NAL for biosynthesis of Neu5Ac. PMID- 29510566 TI - Recyclable Aggregates of Mesoporous Titania Synthesized by Thermal Treatment of Amorphous or Peptized Precursors. AB - Recyclable aggregates of mesoporous titania with different anatase-rutile ratios have been prepared by thermal treatments of either amorphous or peptized precursors. These last two have been obtained by hydrolysis of either Ti(OC2H5)4 or of Ti(OC2H5)4 in mixture with 5 mol % Zr(OC3H7)4 at room temperature in the presence of NH4OH as a catalyzing agent. The anatase-rutile ratio, the recyclable aggregates of the nano-sized particles, the mesoporosity, the surface area and the crystallinity of the resulting crystallized products of titania can be controlled by the synthesis parameters including: concentration of ammonia catalyst, stirring time and concentration of the peptizing HNO3, drying method of peptized precursors, calcination temperature, and finally the ramp rate up to the titania crystallization temperature. A broad range of synthesis parameters control the crystal sizes of titania particles produced. This allows catalyst preparation with very different crystal size, surface area, anatase to rutile crystal ratio and various mesoporous structures. Drying by lyophilization of precursors reduce the aggregation of the primary particles giving micro /macroporous structures. PMID- 29510565 TI - Impact of the Social and Natural Environment on Preschool-Age Children Weight. AB - Background: The complex impact of environmental and social factors on preschool children being overweight/obese is unclear. We examined the associations between the levels of green space exposure and the risk of being overweight/obese for 4-6 year-old children and assessed the impact of maternal education on these associations. Methods: This cross-sectional study included 1489 mother-child pairs living in Kaunas, Lithuania, in 2012-2013. We assessed children overweight/obesity by standardized questionnaires using international body mass index cut-off points, and the level of greenness exposures by satellite-derived normalized difference vegetation index (NDVI) of each child's home and by the distance to a nearest city park. The maternal education was used as the SES indicator. We used logistic regression models to investigate the strength of the associations. Results: Children from families with poorer maternal education, pathological mother-child relations and smoking mothers, and living in areas with less greenness exposure (NDVI-100 m), had significantly higher odds ratios of being overweight/obese. Lower maternal education and distance to a city park modified the effect of greenness cover level exposure on the risk of children being overweight/obese. Conclusions: Higher greenness exposure in the residential settings has beneficial effects on children's physical development. The green spaces exposures for psychosocial stress management is recommended as a measure to prevent overweight/obesity among children. PMID- 29510564 TI - Higher Dietary Magnesium Intake and Higher Magnesium Status Are Associated with Lower Prevalence of Coronary Heart Disease in Patients with Type 2 Diabetes. AB - In type 2 diabetes mellitus (T2D), the handling of magnesium is disturbed. Magnesium deficiency may be associated with a higher risk of coronary heart disease (CHD). We investigated the associations between (1) dietary magnesium intake; (2) 24 h urinary magnesium excretion; and (3) plasma magnesium concentration with prevalent CHD in T2D patients. This cross-sectional analysis was performed on baseline data from the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 +/- 9 years, 57% men, and diabetes duration of 11 (7 18) years). Prevalence ratios (95% CI) of CHD by sex-specific quartiles of magnesium indicators, as well as by magnesium intake per dietary source, were determined using multivariable Cox proportional hazard models. CHD was present in 100 (22%) subjects. Adjusted CHD prevalence ratios for the highest compared to the lowest quartiles were 0.40 (0.20, 0.79) for magnesium intake, 0.63 (0.32, 1.26) for 24 h urinary magnesium excretion, and 0.62 (0.32, 1.20) for plasma magnesium concentration. For every 10 mg increase of magnesium intake from vegetables, the prevalence of CHD was, statistically non-significantly, lower (0.75 (0.52, 1.08)). In this T2D cohort, higher magnesium intake, higher 24 h urinary magnesium excretion, and higher plasma magnesium concentration are associated with a lower prevalence of CHD. PMID- 29510567 TI - Phenolic Compounds from Belamcanda chinensis Seeds. AB - Two new sucrose derivatives, namely, belamcanosides A (1) and B (2), together with five other known compounds (3-7), were isolated from the seeds of Belamcanda chinensis (L.) DC. Their structures were identified based on spectroscopic data. Especially, the absolute configurations of fructose and glucose residues in 1 and 2 were assigned by acid hydrolysis, followed by derivatization and gas chromatography (GC) analysis. Among the known compounds, (-)-hopeaphenol (3), (+) syringaresinol (4), and quercetin (5), were isolated from B. chinensis for the first time. In addition, biological evaluation of 1 and 2 against cholesterol synthesis and metabolism at the gene level was carried out. The results showed that compounds 1 and 2 could regulate the expression of cholesterol synthesis and metabolism-associated genes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), squalene epoxidase (SQLE), low density lipoprotein receptor (LDLR), and sortilin (SORT1) genes in HepG2 cells. PMID- 29510569 TI - Research of Planetary Gear Fault Diagnosis Based on Permutation Entropy of CEEMDAN and ANFIS. AB - For planetary gear has the characteristics of small volume, light weight and large transmission ratio, it is widely used in high speed and high power mechanical system. Poor working conditions result in frequent failures of planetary gear. A method is proposed for diagnosing faults in planetary gear based on permutation entropy of Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN) Adaptive Neuro-fuzzy Inference System (ANFIS) in this paper. The original signal is decomposed into 6 intrinsic mode functions (IMF) and residual components by CEEMDAN. Since the IMF contains the main characteristic information of planetary gear faults, time complexity of IMFs are reflected by permutation entropies to quantify the fault features. The permutation entropies of each IMF component are defined as the input of ANFIS, and its parameters and membership functions are adaptively adjusted according to training samples. Finally, the fuzzy inference rules are determined, and the optimal ANFIS is obtained. The overall recognition rate of the test sample used for ANFIS is 90%, and the recognition rate of gear with one missing tooth is relatively high. The recognition rates of different fault gears based on the method can also achieve better results. Therefore, the proposed method can be applied to planetary gear fault diagnosis effectively. PMID- 29510570 TI - Organ Transplantation in Iran; Current State and Challenges with a View on Ethical Consideration. AB - Organ transplantation is a new issue in medical science. It is an important achievement and a sign of the progression and ability of medical centers around the world. Governments, populations, the medical community and people involved in culture, art, and media all have a decisive role in the culture of organ donation, which is the only way to guarantee that the healthy organs of a brain dead person can continue to work and save the lives of people in need of organ transplantation. The brain death phenomenon and its possible application in organ transplantation, while offering new hope for the salvation of a number of patients, has led to many ethical, cultural, and legal issues. Ethical issues in organ transplantation are very complicated due to many social factors such as religion, culture, and traditions of the affected communities. The ethical and legal points of removing organs from the body of a living or cadaveric source, the definition of brain death, the moral and legal conditions of the donor and the recipient, and the financial relationship between them and many others, are all critical issues in organ transplantation. While there may be no available explicit solution to these issues, they should be rigorously considered by the experts. Efforts to systematically eliminate barriers and solve problems in organ transplantation, can not only reduce the costs of maintaining brain-dead patients and encourage patients that need organ transplantation but can also prevent immoral and illegal activities. In this paper, we have reviewed the most important and current challenges in organ transplantation with a view to the ethical considerations, and we have suggested some strategies to extend it in Iran. PMID- 29510571 TI - Recent Advances in Discotic Liquid Crystal-Assisted Nanoparticles. AB - This article primarily summarizes recent advancement in the field of discotic liquid crystal (DLC) nanocomposites. Discotic liquid crystals are nanostructured materials, usually 2 to 6 nm size and have been recognized as organic semiconducting materials. Recently, it has been observed that the dispersion of small concentration of various functionalized zero-, one- and two-dimensional nanomaterials in the supramolecular order of mesophases of DLCs imparts negligible impact on liquid crystalline properties but enhances their thermal, supramolecular and electronic properties. Synthesis, characterization and dispersion of various nanoparticles in different discotics are presented. PMID- 29510568 TI - Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators. AB - This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments. PMID- 29510572 TI - Diet Quality and Sarcopenia in Older Adults: A Systematic Review. AB - The increasing recognition of sarcopenia, the age-related loss of skeletal muscle mass and function (muscle strength and physical performance), as a determinant of poor health in older age, has emphasized the importance of understanding more about its aetiology to inform strategies both for preventing and treating this condition. There is growing interest in the effects of modifiable factors such as diet; some nutrients have been studied but less is known about the influence of overall diet quality on sarcopenia. We conducted a systematic review of the literature examining the relationship between diet quality and the individual components of sarcopenia, i.e., muscle mass, muscle strength and physical performance, and the overall risk of sarcopenia, among older adults. We identified 23 studies that met review inclusion criteria. The studies were diverse in terms of the design, setting, measures of diet quality, and outcome measurements. A small body of evidence suggested a relationship between "healthier" diets and better muscle mass outcomes. There was limited and inconsistent evidence for a link between "healthier" diets and lower risk of declines in muscle strength. There was strong and consistent observational evidence for a link between "healthier" diets and lower risk of declines in physical performance. There was a small body of cross-sectional evidence showing an association between "healthier" diets and lower risk of sarcopenia. This review provides observational evidence to support the benefits of diets of higher quality for physical performance among older adults. Findings for the other outcomes considered suggest some benefits, although the evidence is either limited in its extent (sarcopenia) or inconsistent/weak in its nature (muscle mass, muscle strength). Further studies are needed to assess the potential of whole-diet interventions for the prevention and management of sarcopenia. PMID- 29510574 TI - Potential Role of Inorganic Confined Environments in Prebiotic Phosphorylation. AB - A concise outlook on the potential role of confinement in phosphorylation and phosphate condensation pertaining to prebiotic chemistry is presented. Inorganic confinement is a relatively uncharted domain in studies concerning prebiotic chemistry, and even more so in terms of experimentation. However, molecular crowding within confined dimensions is central to the functioning of contemporary biology. There are numerous advantages to confined environments and an attempt to highlight this fact, within this article, has been undertaken, keeping in context the limitations of aqueous phase chemistry in phosphorylation and, to a certain extent, traditional approaches in prebiotic chemistry. PMID- 29510573 TI - Regulation of Ion Transport in the Intestine by Free Fatty Acid Receptor 2 and 3: Possible Involvement of the Diffuse Chemosensory System. AB - The diffuse chemosensory system (DCS) is well developed in the apparatuses of endodermal origin like gastrointestinal (GI) tract. The primary function of the GI tract is the extraction of nutrients from the diet. Therefore, the GI tract must possess an efficient surveillance system that continuously monitors the luminal contents for beneficial or harmful compounds. Recent studies have shown that specialized cells in the intestinal lining can sense changes in the luminal content. The chemosensory cells in the GI tract belong to the DCS which consists of enteroendocrine and related cells. These cells initiate various important local and remote reflexes. Although neural and hormonal involvements in ion transport in the GI tract are well documented, involvement of the DCS in the regulation of intestinal ion transport is much less understood. Since activation of luminal chemosensory receptors is a primary signal that elicits changes in intestinal ion transport and motility and failure of the system causes dysfunctions in host homeostasis, as well as functional GI disorders, study of the regulation of GI function by the DCS has become increasingly important. This review discusses the role of the DCS in epithelial ion transport, with particular emphasis on the involvement of free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3). PMID- 29510575 TI - Quantum Chemical Design Guidelines for Absorption and Emission Color Tuning of fac-Ir(ppy)3 Complexes. AB - The fac-Ir(ppy)3 complex, where ppy denotes 2-phenylpyridine, is one of the well known luminescent metal complexes having a high quantum yield. However, there have been no specific molecular design guidelines for color tuning. For example, it is still unclear how its optical properties are changed when changing substitution groups of ligands. Therefore, in this study, differences in the electronic structures and optical properties among several substituted fac Ir(ppy)3 derivatives are examined in detail by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. On the basis of those results, we present rational design guidelines for absorption and emission color tuning by modifying the species of substituents and their substitution positions. PMID- 29510576 TI - SK-216, a Novel Inhibitor of Plasminogen Activator Inhibitor-1, Suppresses Lung Metastasis of Human Osteosarcoma. AB - Lung metastasis constitutes the leading cause of the death in patients with osteosarcoma. We have previously reported that plasminogen activator inhibitor-1 (PAI-1) regulates the invasion and lung metastasis of osteosarcoma cells in a mouse model and as well as in clinical samples. In the present study, we examined the anti-metastatic effect of SK-216, a small compound PAI-1 inhibitor, in human 143B osteosarcoma cells. An in vitro study showed that SK-216 treatment suppressed invasion activity by inhibiting PAI-1 expression in 143B cells, but had no influence on their proliferation or migration. 143B cells treated with SK 216 exhibited reduced matrix metalloproteinase-13 (MMP-13) secretion in a dose dependent manner. Moreover, intraperitoneal injection of SK-216 into mouse models resulted in downregulation of PAI-1 expression levels in the primary tumors and showed suppression of lung metastases without influencing the proliferative activity of the tumor cells in the primary lesions. These results indicate that SK-216, a PAI-1 inhibitor, may serve as a novel drug to prevent lung metastasis in human osteosarcoma. PMID- 29510577 TI - Loss of Actin-Based Motility Impairs Ectromelia Virus Release In Vitro but Is Not Critical to Spread In Vivo. AB - Ectromelia virus (ECTV) is an orthopoxvirus and the causative agent of mousepox. Like other poxviruses such as variola virus (agent of smallpox), monkeypox virus and vaccinia virus (the live vaccine for smallpox), ECTV promotes actin nucleation at the surface of infected cells during virus release. Homologs of the viral protein A36 mediate this function through phosphorylation of one or two tyrosine residues that ultimately recruit the cellular Arp2/3 actin-nucleating complex. A36 also functions in the intracellular trafficking of virus mediated by kinesin-1. Here, we describe the generation of a recombinant ECTV that is specifically disrupted in actin-based motility allowing us to examine the role of this transport step in vivo for the first time. We show that actin-based motility has a critical role in promoting the release of virus from infected cells in vitro but plays a minor role in virus spread in vivo. It is likely that loss of microtubule-dependent transport is a major factor for the attenuation observed when A36R is deleted. PMID- 29510578 TI - Identification and Functional Analysis of a Novel Cytochrome P450 Gene CYP9A105 Associated with Pyrethroid Detoxification in Spodoptera exigua Hubner. AB - In insects, cytochrome P450 monooxygenases (P450s or CYPs) are known to be involved in the detoxification and metabolism of insecticides, leading to increased resistance in insect populations. Spodoptera exigua is a serious polyphagous insect pest worldwide and has developed resistance to various insecticides. In this study, a novel CYP3 clan P450 gene CYP9A105 was identified and characterized from S. exigua. The cDNAs of CYP9A105 encoded 530 amino acid proteins, respectively. Quantitative real-time PCR analyses showed that CYP9A105 was expressed at all developmental stages, with maximal expression observed in fifth instar stage larvae, and in dissected fifth instar larvae the highest transcript levels were found in midguts and fat bodies. The expression of CYP9A105 in midguts was upregulated by treatments with the insecticides alpha cypermethrin, deltamethrin and fenvalerate at both LC15 concentrations (0.10, 0.20 and 5.0 mg/L, respectively) and LC50 concentrations (0.25, 0.40 and 10.00 mg/L, respectively). RNA interference (RNAi) mediated silencing of CYP9A105 led to increased mortalities of insecticide-treated 4th instar S. exigua larvae. Our results suggest that CYP9A105 might play an important role in alpha-cypermethrin, deltamethrin and fenvalerate detoxification in S. exigua. PMID- 29510579 TI - Amiloride Promotes Oligodendrocyte Survival and Remyelination after Spinal Cord Injury in Rats. AB - After spinal cord injury (SCI), secondary injury results in an expanding area of glial cell apoptosis. Oligodendrocyte precursor cells (OPCs) actively proliferate after SCI, but many of these cells undergo apoptosis. One of the factors that exacerbates secondary injury is endoplasmic reticulum (ER) stress. In this study, we tested the effects of amiloride treatment on the fate of OPCs during secondary injury in rats. Amiloride is an FDA-approved diuretic for treating hypertension, which in rats enhances ER stress response and suppresses the apoptosis of glial cells after SCI. A severe contusive SCI was induced in Sprague-Dawley rats using an infinite horizon (IH)-impactor (200 kdyne). Beginning 24 h after SCI, 10 mg/kg of amiloride or phosphate buffered saline (PBS) was intraperitoneally administered daily for a period of 14 days. At 7, 14, 28, and 56 days after SCI, animals were subsequently euthanized in order to analyze the injured spinal cord. We labeled proliferating OPCs and demonstrated that amiloride treatment led to greater numbers of OPCs and oligodendrocytes in the injured spinal cord. Increased myelin basic protein (MBP) expression levels were observed, suggesting that increased numbers of mature oligodendrocytes led to improved remyelination, significantly improving motor function recovery. PMID- 29510580 TI - Topical Digitoxigenin for Wound Healing: A Feasibility Study. AB - (1) Background: Cardiotonic steroids have been found to stimulate collagen synthesis and might be potential wound healing therapeutics. The objective of this study was to evaluate the feasibility of digitoxigenin and its topical formulation for wound healing; (2) Methods: In the in vitro study, the human dermal fibroblast cells were treated with digitoxigenin and collagen synthesis was assessed. In the in vivo study, digitoxigenin was applied to excisional full thickness wounds in rats immediately after wounding and remained for three days, and wound open was evaluated over 10 days. A digitoxigenin formulation for topical administration was prepared, and the in vitro release and in vivo wound healing effect were investigated; (3) Results: The expression of procollagen in human dermal fibroblast was significantly increased with the exposure to 0.1 nM digitoxigenin. Topical application of digitoxigenin in olive oil or alginate solution for three days significantly decreased the wound open in rats. Similarly, topical administration of the developed digitoxigenin formulation for three days also significantly increased wound healing. No wound healing effects were observed at days 7 and 10 after wounding when digitoxigenin was not applied; and, (4) Conclusions: It was possible to deliver digitoxigenin using the developed formulation. However, the wound healing effect of digitoxigenin and its mechanisms need to be further investigated in future studies. PMID- 29510581 TI - An Individual's Connection to Nature Can Affect Perceived Restorativeness of Natural Environments. Some Observations about Biophilia. AB - This study investigates the relationship between the level to which a person feels connected to Nature and that person's ability to perceive the restorative value of a natural environment. We assume that perceived restorativeness may depend on an individual's connection to Nature and this relationship may also vary with the biophilic quality of the environment, i.e., the functional and aesthetic value of the natural environment which presumably gave an evolutionary advantage to our species. To this end, the level of connection to Nature and the perceived restorativeness of the environment were assessed in individuals visiting three parks characterized by their high level of "naturalness" and high or low biophilic quality. The results show that the perceived level of restorativeness is associated with the sense of connection to Nature, as well as the biophilic quality of the environment: individuals with different degrees of connection to Nature seek settings with different degrees of restorativeness and biophilic quality. This means that perceived restorativeness can also depend on an individual's "inclination" towards Nature. PMID- 29510582 TI - The Non-Coding Regulatory RNA Revolution in Archaea. AB - Small non-coding RNAs (sRNAs) are ubiquitously found in the three domains of life playing large-scale roles in gene regulation, transposable element silencing and defense against foreign elements. While a substantial body of experimental work has been done to uncover function of sRNAs in Bacteria and Eukarya, the functional roles of sRNAs in Archaea are still poorly understood. Recently, high throughput studies using RNA-sequencing revealed that sRNAs are broadly expressed in the Archaea, comprising thousands of transcripts within the transcriptome during non-challenged and stressed conditions. Antisense sRNAs, which overlap a portion of a gene on the opposite strand (cis-acting), are the most abundantly expressed non-coding RNAs and they can be classified based on their binding patterns to mRNAs (3' untranslated region (UTR), 5' UTR, CDS-binding). These antisense sRNAs target many genes and pathways, suggesting extensive roles in gene regulation. Intergenic sRNAs are less abundantly expressed and their targets are difficult to find because of a lack of complete overlap between sRNAs and target mRNAs (trans-acting). While many sRNAs have been validated experimentally, a regulatory role has only been reported for very few of them. Further work is needed to elucidate sRNA-RNA binding mechanisms, the molecular determinants of sRNA-mediated regulation, whether protein components are involved and how sRNAs integrate with complex regulatory networks. PMID- 29510584 TI - A Novel Sidelobe Reduction Algorithm Based on Two-Dimensional Sidelobe Correction Using D-SVA for Squint SAR Images. AB - Sidelobe reduction is a very primary task for synthetic aperture radar (SAR) images. Various methods have been proposed for broadside SAR, which can suppress the sidelobes effectively while maintaining high image resolution at the same time. Alternatively, squint SAR, especially highly squint SAR, has emerged as an important tool that provides more mobility and flexibility and has become a focus of recent research studies. One of the research challenges for squint SAR is how to resolve the severe range-azimuth coupling of echo signals. Unlike broadside SAR images, the range and azimuth sidelobes of the squint SAR images no longer locate on the principal axes with high probability. Thus the spatially variant apodization (SVA) filters could hardly get all the sidelobe information, and hence the sidelobe reduction process is not optimal. In this paper, we present an improved algorithm called double spatially variant apodization (D-SVA) for better sidelobe suppression. Satisfactory sidelobe reduction results are achieved with the proposed algorithm by comparing the squint SAR images to the broadside SAR images. Simulation results also demonstrate the reliability and efficiency of the proposed method. PMID- 29510583 TI - Integration of lncRNA and mRNA Transcriptome Analyses Reveals Genes and Pathways Potentially Involved in Calf Intestinal Growth and Development during the Early Weeks of Life. AB - A better understanding of the factors that regulate growth and immune response of the gastrointestinal tract (GIT) of calves will promote informed management practices in calf rearing. This study aimed to explore genomics (messenger RNA (mRNA)) and epigenomics (long non-coding RNA (lncRNA)) mechanisms regulating the development of the rumen and ileum in calves. Thirty-two calves (~5-days-old) were reared for 96 days following standard procedures. Sixteen calves were humanely euthanized on experiment day 33 (D33) (pre-weaning) and another 16 on D96 (post-weaning) for collection of ileum and rumen tissues. RNA from tissues was subjected to next generation sequencing and 3310 and 4217 mRNAs were differentially expressed (DE) between D33 and D96 in ileum and rumen tissues, respectively. Gene ontology and pathways enrichment of DE genes confirmed their roles in developmental processes, immunity and lipid metabolism. A total of 1568 (63 known and 1505 novel) and 4243 (88 known and 4155 novel) lncRNAs were detected in ileum and rumen tissues, respectively. Cis target gene analysis identified BMPR1A, an important gene for a GIT disease (juvenile polyposis syndrome) in humans, as a candidate cis target gene for lncRNAs in both tissues. LncRNA cis target gene enrichment suggested that lncRNAs might regulate growth and development in both tissues as well as posttranscriptional gene silencing by RNA or microRNA processing in rumen, or disease resistance mechanisms in ileum. This study provides a catalog of bovine lncRNAs and set a baseline for exploring their functions in calf GIT development. PMID- 29510585 TI - A New Method for Immobilization of His-Tagged Proteins with the Application of Low-Frequency AC Electric Field. AB - Continued advancement of protein array, bioelectrode, and biosensor technologies is necessary to develop methods for higher amount and highly oriented immobilization activity of proteins. In pursuit of these goals, we developed a new immobilization method by combining electrostatic transport and subsequent molecular diffusion of protein molecules. Our developed immobilization method is based on a model that transports proteins toward the substrate surface due to steep concentration gradient generated by low-frequency AC electric field. The immobilization of the maximum amounts can be obtained by the application of the AC voltage of 80 Vpp, 20 Hz both for His-tagged Green Fluorescent Protein (GFP) and Discosoma sp. Red Fluorescent Protein (DsRed), used as model proteins. The amounts of the immobilized His-tagged GFP and DsRed were approximately seven-fold higher than that in the absence of the application of low-frequency AC electric field. Furthermore, the positively and negatively charged His-tagged GFP at acidic and alkaline pH were immobilized by applying of low-frequency AC electric field, whereas the non-charged His-tagged GFP at the pH corresponding to its isoelectric point (pI) was not immobilized. Therefore, unless the pH is equal to pI, the immobilization of electrically charged proteins was strongly enhanced through electrostatic transport and subsequent molecular diffusion. PMID- 29510586 TI - Demonstrating Impact: Lessons Learned from the Queensland Aboriginal and Islander Health Council's AOD-Our-Way Program. AB - In this paper, we describe the innovative way in which the Queensland Aboriginal and Islander Health Council uses "clicker technology" to gather data to report on the key performance indicators of its "AOD-our-way" program, and how, with the subsequent combination of those data with other performance measures, it was possible to go beyond the initial evaluation. The paper also illustrates how the application of survey research methods could further enable enhanced reporting of program outcomes and impacts in an Indigenous context where Indigenous community controlled organisations want to build the evidence base for the issues they care about and ultimately drive their own research agendas. PMID- 29510587 TI - The Coordinated Activities of nAChR and Wnt Signaling Regulate Intestinal Stem Cell Function in Mice. AB - Cholinergic signaling, which modulates cell activities via nicotinic and muscarinic acetylcholine receptors (n- and mAChRs) in response to internal or external stimuli, has been demonstrated in mammalian non-neuronal cells that synthesize acetylcholine (ACh). One of the major pathways of excitatory transmission in the enteric nervous system (ENS) is mediated by cholinergic transmission, with the transmitter ACh producing excitatory potentials in postsynaptic effector cells. In addition to ACh-synthesizing and ACh-metabolizing elements in the ENS, the presence of non-neuronal ACh machinery has been reported in epithelial cells of the small and large intestines of rats and humans. However, little is known about how non-neuronal ACh controls physiological function in the intestine. Here, experiments using crypt-villus organoids that lack nerve and immune cells in culture suggest that endogenous ACh is synthesized in the intestinal epithelium to drive organoid growth and differentiation through activation of nAChRs. Treatment of organoids with nicotine enhanced cell growth and the expression of marker genes for stem and epithelial cells. On the other hand, the nAChR antagonist mecamylamine strongly inhibited the growth and differentiation of organoids, suggesting the involvement of nAChRs in the regulation of proliferation and differentiation of Lgr5-positive stem cells. More specifically, RNA sequencing analysis revealed that Wnt5a expression was dramatically upregulated after nicotine treatment, and Wnt5a rescued organoid growth and differentiation in response to mecamylamine. Taken together, our results indicate that coordinated activities of nAChR and Wnt signaling maintain Lgr5-positive stem cell activity and balanced differentiation. Furthermore, we could clearly separate the two groups, neuronal ACh in the ENS and non-neuronal ACh in the intestinal epithelium. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of disease. The data will increase our understanding of the cholinergic properties of non-neuronal cells and lead to optimization of drug therapy. PMID- 29510589 TI - Systems-Level Feedbacks of NRF2 Controlling Autophagy upon Oxidative Stress Response. AB - Although the primary role of autophagy-dependent cellular self-eating is cytoprotective upon various stress events (such as starvation, oxidative stress, and high temperatures), sustained autophagy might lead to cell death. A transcription factor called NRF2 (nuclear factor erythroid-related factor 2) seems to be essential in maintaining cellular homeostasis in the presence of either reactive oxygen or nitrogen species generated by internal metabolism or external exposure. Accumulating experimental evidence reveals that oxidative stress also influences the balance of the 5' AMP-activated protein kinase (AMPK)/rapamycin (mammalian kinase target of rapamycin or mTOR) signaling pathway, thereby inducing autophagy. Based on computational modeling here we propose that the regulatory triangle of AMPK, NRF2 and mTOR guaranties a precise oxidative stress response mechanism comprising of autophagy. We suggest that under conditions of oxidative stress, AMPK is crucial for autophagy induction via mTOR down-regulation, while NRF2 fine-tunes the process of autophagy according to the level of oxidative stress. We claim that the cellular oxidative stress response mechanism achieves an incoherently amplified negative feedback loop involving NRF2, mTOR and AMPK. The mTOR-NRF2 double negative feedback generates bistability, supporting the proper separation of two alternative steady states, called autophagy-dependent survival (at low stress) and cell death (at high stress). In addition, an AMPK-mTOR-NRF2 negative feedback loop suggests an oscillatory characteristic of autophagy upon prolonged intermediate levels of oxidative stress, resulting in new rounds of autophagy stimulation until the stress events cannot be dissolved. Our results indicate that AMPK-, NRF2- and mTOR-controlled autophagy induction provides a dynamic adaptation to altering environmental conditions, assuming their new frontier in biomedicine. PMID- 29510590 TI - A Facile One-Pot Construction of Succinimide-Fused Spiro[Pyrrolidine-2,3' Oxindoles] via 1,3-Dipolar Cycloaddition Involving 3-Amino Oxindoles and Maleimides. AB - Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3'-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from 3-amino oxindoles and aldehydes with maleimides has been described. The protocol provides a facile and efficient access to structurally diverse succinimide-fused spiro[pyrrolidine-2,3'-oxindole] compounds in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of cycloaddition products has been assigned by X-ray diffraction analysis. PMID- 29510591 TI - Assessing the Use of Media Reporting Recommendations by the World Health Organization in Suicide News Published in the Most Influential Media Sources in China, 2003-2015. AB - Public media reports about suicide are likely to influence the population's suicidal attempts and completed suicides. Irresponsible reports might trigger copycat suicidal behaviors, while responsible reports may help reduce suicide rates. The World Health Organization (WHO) released recommendations to encourage responsible suicide reports in 2008. However, little is known about whether these recommendations are reflected in the suicide news for most countries, including China. In this study, we assessed the responsibility of suicide stories published in the most influential newspaper and Internet media sources in China from 2003 to 2015, using the media reporting recommendations by the World Health Organization (WHO). In total, 3965 and 1836 eligible stories from newspaper and Internet-based media, respectively, were included in the study. Newspapers and Internet-based media performed similarly in applying WHO recommendations to report suicide news. Three recommendations were applied in over 88% of suicide stories. However, four recommendations were seldom applied, including offering information about where to seek help and linking the suicide event to mental disorders. Government and the journalism industry should work together to improve media reporting of news about suicide in China. PMID- 29510592 TI - Production of Low Cost Carbon-Fiber through Energy Optimization of Stabilization Process. AB - To produce high quality and low cost carbon fiber-based composites, the optimization of the production process of carbon fiber and its properties is one of the main keys. The stabilization process is the most important step in carbon fiber production that consumes a large amount of energy and its optimization can reduce the cost to a large extent. In this study, two intelligent optimization techniques, namely Support Vector Regression (SVR) and Artificial Neural Network (ANN), were studied and compared, with a limited dataset obtained to predict physical property (density) of oxidative stabilized PAN fiber (OPF) in the second zone of a stabilization oven within a carbon fiber production line. The results were then used to optimize the energy consumption in the process. The case study can be beneficial to chemical industries involving carbon fiber manufacturing, for assessing and optimizing different stabilization process conditions at large. PMID- 29510588 TI - Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas. AB - Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib's approval as a treatment for gastrointestinal stromal tumors (GISTs) has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs) have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-alpha, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor kappaB ligand (RANKL) inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas. PMID- 29510593 TI - Advancements, Challenges and Prospects of Chemical Vapour Pressure at Atmospheric Pressure on Vanadium Dioxide Structures. AB - Vanadium (IV) oxide (VO2) layers have received extensive interest for applications in smart windows to batteries and gas sensors due to the multi phases of the oxide. Among the methods utilized for their growth, chemical vapour deposition is a technology that is proven to be industrially competitive because of its simplicity when performed at atmospheric pressure (APCVD). APCVD's success has shown that it is possible to create tough and stable materials in which their stoichiometry may be precisely controlled. Initially, we give a brief overview of the basic processes taking place during this procedure. Then, we present recent progress on experimental procedures for isolating different polymorphs of VO2. We outline emerging techniques and processes that yield in optimum characteristics for potentially useful layers. Finally, we discuss the possibility to grow 2D VO2 by APCVD. PMID- 29510594 TI - Effect of Growth Temperature on the Structural and Electrical Properties of ZrO2 Films Fabricated by Atomic Layer Deposition Using a CpZr[N(CH3)2]3/C7H8 Cocktail Precursor. AB - The effect of growth temperature on the atomic layer deposition of zirconium oxide (ZrO2) dielectric thin films that were fabricated using a CpZr[N(CH3)2]3/C7H8 cocktail precursor with ozone was investigated. The chemical, structural, and electrical properties of ZrO2 films grown at temperatures from 250 to 350 degrees C were characterized. Stoichiometric ZrO2 films formed at 250 350 degrees C with an atomic ratio of O to Zr of 1.8-1.9 and a low content of carbon impurities. The film formed at 300 degrees C was predominantly the tetragonal crystalline phase, whereas that formed at 350 degrees C was a mixture of tetragonal and monoclinic phases. Electrical properties, such as capacitance, leakage current, and voltage linearity of TiN/ZrO2/TiN capacitors fabricated using the thin ZrO2 films grown at different temperatures were compared capacitor applications. The ZrO2 film grown at 300 degrees C exhibited low impurity content, predominantly tetragonal crystalline structure, a high dielectric permittivity of 38.3, a low leakage current of below 10-7 A/cm2 at 2 V, and low voltage linearity. PMID- 29510595 TI - Sonication-Induced Modification of Carbon Nanotubes: Effect on the Rheological and Thermo-Oxidative Behaviour of Polymer-Based Nanocomposites. AB - The aim of this work is the investigation of the effect of ultrasound treatment on the structural characteristics of carbon nanotubes (CNTs) and the consequent influence that the shortening induced by sonication exerts on the morphology, rheological behaviour and thermo-oxidative resistance of ultra-high molecular weight polyethylene (UHMWPE)-based nanocomposites. First, CNTs have been subjected to sonication for different time intervals and the performed spectroscopic and morphological analyses reveal that a dramatic decrease of the CNT's original length occurs with increased sonication time. The reduction of the initial length of CNTs strongly affects the nanocomposite rheological behaviour, which progressively changes from solid-like to liquid-like as the CNT sonication time increases. The study of the thermo-oxidative behaviour of the investigated nanocomposites reveals that the CNT sonication has a detrimental effect on the thermo-oxidative stability of nanocomposites, especially for long exposure times. The worsening of the thermo-oxidative resistance of sonicated CNT-containing nanocomposites could be attributed to the lower thermal conductivity of low aspect-ratio CNTs, which causes the increase of the local temperature at the polymer/nanofillers interphase, with the consequent acceleration of the degradative phenomena. PMID- 29510596 TI - Virtual Sensors for Advanced Controllers in Rehabilitation Robotics. AB - In order to properly control rehabilitation robotic devices, the measurement of interaction force and motion between patient and robot is an essential part. Usually, however, this is a complex task that requires the use of accurate sensors which increase the cost and the complexity of the robotic device. In this work, we address the development of virtual sensors that can be used as an alternative of actual force and motion sensors for the Universal Haptic Pantograph (UHP) rehabilitation robot for upper limbs training. These virtual sensors estimate the force and motion at the contact point where the patient interacts with the robot using the mathematical model of the robotic device and measurement through low cost position sensors. To demonstrate the performance of the proposed virtual sensors, they have been implemented in an advanced position/force controller of the UHP rehabilitation robot and experimentally evaluated. The experimental results reveal that the controller based on the virtual sensors has similar performance to the one using direct measurement (less than 0.005 m and 1.5 N difference in mean error). Hence, the developed virtual sensors to estimate interaction force and motion can be adopted to replace actual precise but normally high-priced sensors which are fundamental components for advanced control of rehabilitation robotic devices. PMID- 29510599 TI - The Dynamic Photometric Stereo Method Using a Multi-Tap CMOS Image Sensor. AB - The photometric stereo method enables estimation of surface normals from images that have been captured using different but known lighting directions. The classical photometric stereo method requires at least three images to determine the normals in a given scene. However, this method cannot be applied to dynamic scenes because it is assumed that the scene remains static while the required images are captured. In this work, we present a dynamic photometric stereo method for estimation of the surface normals in a dynamic scene. We use a multi-tap complementary metal-oxide-semiconductor (CMOS) image sensor to capture the input images required for the proposed photometric stereo method. This image sensor can divide the electrons from the photodiode from a single pixel into the different taps of the exposures and can thus capture multiple images under different lighting conditions with almost identical timing. We implemented a camera lighting system and created a software application to enable estimation of the normal map in real time. We also evaluated the accuracy of the estimated surface normals and demonstrated that our proposed method can estimate the surface normals of dynamic scenes. PMID- 29510598 TI - Removal and Biodegradation of 17beta-Estradiol and Diethylstilbestrol by the Freshwater Microalgae Raphidocelis subcapitata. AB - Natural steroidal and synthetic non-steroidal estrogens such as 17beta-estradiol (E2) and diethylstilbestrol (DES) have been found in natural water, which can potentially endanger public health and aquatic ecosystems. The removal and biodegradation of E2 and DES by Raphidocelis subcapitata were studied in bacteria free cultures exposed to single and mixture treatments at different concentrations for 96 h. The results showed that R. subcapitata exhibited a rapid and strong ability to remove E2 and DES in both single and mixture treatments by biodegradation. At the end of 96 h, the removal percentage of single E2 and DES achieved 82.0%, 80.4%, 74.6% and 89.9%, 73.4%, 54.1% in 0.1, 0.5, and 1.5 mg.L-1, respectively. With the exception of the 0.1 mg.L-1 treatment at 96 h, the removal capacity of E2 was more efficient than that of DES by R. subcapitata. Furthermore, the removal percentage of mixture E2 and DES achieved 88.5%, 82.9%, 84.3% and 87.2%, 71.8%, 51.1% in 0.1, 0.5, and 1.5 mg.L-1, respectively. The removal percentage of mixed E2 was significantly higher than that of the single E2. The presence of DES could accelerate the removal of E2 from the mixture treatments in equal concentrations. In addition, the removal was mainly attributed to the biodegradation or biotransformation process by the microalgae cells rather than simple sorption and accumulation in the cells. The microalgae R. subcapitata demonstrated a high capability for the removal of the E2 and DES indicating future prospects for its application. PMID- 29510597 TI - Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs), which are commonly found in fish oil supplements, are known to possess anti-inflammatory properties and more recently alter skeletal muscle function. In this review, we discuss novel findings related to how n-3 PUFAs modulate molecular signaling responsible for growth and hypertrophy as well as the activity of muscle stem cells. Muscle stem cells commonly known as satellite cells, are primarily responsible for driving the skeletal muscle repair process to potentially damaging stimuli, such as mechanical stress elicited by exercise contraction. To date, there is a paucity of human investigations related to the effects of n-3 PUFAs on satellite cell content and activity. Based on current in vitro investigations, this review focuses on novel mechanisms linking n-3 PUFA's to satellite cell activity and how they may improve muscle repair. Understanding the role of n-3 PUFAs during muscle growth and regeneration in association with exercise could lead to the development of novel supplementation strategies that increase muscle mass and strength, therefore possibly reducing the burden of muscle wasting with age. PMID- 29510601 TI - Formative feedback from the first-person perspective using Google Glass in a family medicine objective structured clinical examination station in the United States. AB - PURPOSE: This case study explored the use of Google Glass in a clinical examination scenario to capture the first-person perspective of a standardized patient as a way to provide formative feedback on students' communication and empathy skills 'through the patient's eyes.' METHODS: During a 3-year period between 2014 and 2017, third-year students enrolled in a family medicine clerkship participated in a Google Glass station during a summative clinical examination. At this station, standardized patients wore Google Glass to record an encounter focused on communication and empathy skills 'through the patient's eyes.' Students completed an online survey using a 4-point Likert scale about their perspectives on Google Glass as a feedback tool (N= 255). RESULTS: We found that the students' experiences with Google Glass 'through the patient's eyes' were largely positive and that students felt the feedback provided by the Google Glass recording to be helpful. Although a third of the students felt that Google Glass was a distraction, the majority believed that the first-person perspective recordings provided an opportunity for feedback that did not exist before. CONCLUSION: Continuing exploration of first-person perspective recordings using Google Glass to improve education on communication and empathy skills is warranted. PMID- 29510600 TI - Changes in Phenylpropanoid and Trichothecene Production by Fusarium culmorum and F. graminearum Sensu Stricto via Exposure to Flavonoids. AB - Flavonoids are a group of hydroxylated polyphenolic compounds widely distributed in the plant kingdom. Biosynthesis of these compounds involves type III PKSs, whose presence has been recently predicted in some fungal species through genome sequencing efforts. In this study, for the first time it was found that Fusaria produce flavonoids on solid YES medium. Naringenin, as the central precursor of all flavonoids, was produced at highest quantities, followed by quercetin, kaempferol, apigenin and luteolin. In plants, flavonoids are involved in the protection of cereals to a wide range of stresses, including host defense against Fusaria. Under in vitro conditions, strains of Fusarium culmorum and F. graminearum sensu stricto were incubated at levels of flavonoids close to amounts produced by cereals in response to fungal infection. The amounts of exogenous naringenin, apigenin, luteolin, kaempferol and quercetin were reduced and converted by fungi to the other flavonoid derivatives. Treatment of fungi with naringenin derivatives led to the inhibition of naringenin production. Correspondingly, the production of fungal-derived phenolic acids decreased in flavonoid treated samples, although this effect appeared to be dependent on the strain, flavonoid molecule and its concentration. Fusaria showed high variability in trichothecene production in response to flavonoids. With emphasis on quercetin, mycotoxin accumulation in the media was significantly decreased by luteolin, kaempferol, naringenin and apigenin. However, in some cases, apigenin led to the increase of mycotoxin content in the media. Gene expression experiments of Tri genes responsible for trichothecene biosynthesis (Tri4, Tri5 and Tri10) proved that the inhibition of mycotoxin production by flavonoids occurred at the transcriptional level. However, the changes in Tri transcript levels were not significant in most apigenin and all kaempferol-treated cultures. In this study, a link was established between antioxidant and antiradical properties of flavonoids and their effects on fungi. PMID- 29510602 TI - Evaluation of Antimycobacterial and Synergistic Activity of Plants Selected Based on Cheminformatic Parameters AB - Background: Drug resistance is a major public health problem and a threat to progress made in bovine tuberculosis care and control worldwide. This study aimed at evaluating anti-mycobacterial and synergistic activity of some medicinal plants that were selected by cheminformatics studies against Mycobacterium bovis. Methods: Considering the strong synergistic antimycobacterial action of oleanolic acid in combination with tuberculosis drugs, NCBI database was explored to find the compounds with over 80% similarity to oleanolic acid, called S1. Plants containing S1-type compounds were traced to and resulted in five plants, including Datura stramonium, Boswellia serrata Lavandula stoechas, Rosmarinus officinalis, and Thymus vulgaris, as experimental samples. Crude extracts were prepared by percolation using 80% ethanol or as the product of a pharmaceutical company. The extracts were screened against Mycobacterium bovis using broth microdilution method and Alamar Blue Assay. Extracts from these plants were used in combination with isoniazid and ethambutol to investigate the possibility of synergy with respect to antimycobacterial activity. Results: The extracts from D. stramonium, B. serrata a, L. stoechas, R. officinalis, and T. Thymus vulgaris showed antimycobacterial activity of 375, 125, 250, 187.5, 500 ug/ml, respectively. The best synergistic results were for L. stoechas and D. stramonium in combination with ethambutol, the fractional inhibitory concentration index was 0.125 ug/ml for both. Conclusion: The observed antimycobacterial and synergistic activities are completely novel and obtained from targeted screening designed according to cheminformatics strategy. As for the synergistic action of the extracts, they could be used as supplements in bTB treatment. PMID- 29510604 TI - Impact of faculty development programs for positive behavioural changes among teachers: a case study. AB - PURPOSE: Faculty development (FD) is essential to prepare faculty members to become effective teachers to meet the challenges in medical education. Despite the growth of FD programmes, most evaluations were often conducted using short questionnaires to assess participants' satisfaction immediately after they attended a programme. Consequently, there were calls for more rigorous evaluations based on observed changes in participants' behaviours. Hence, this study aims to explore how the FD workshops run by the Centre for Medical Education, Yong Loo Lin School of Medicine, National University of Singapore have impacted behavioural changes in the educators. METHODS: We followed up with the educators at least half a year after they have attended the workshops. With limited literature as reference, we initiated a small-scale case-study research design involving semi-structured interviews with six educators which was triangulated with three focus group discussions with their students. This allowed us to explore behavioural changes among the educators as well as evaluate the feasibility of this research methodology. RESULTS: We identified three emerging categories among the educators: ignorance to awareness, from intuition to confirmation and expansion, and from individualism to community of practice. CONCLUSION: Although FD have placed much emphasis on teaching and learning approaches, we found that the teacher-student interaction or human character components (passionate, willing to sacrifice, are open to feedback) in becoming a good educator are lacking in our FD workshops. PMID- 29510605 TI - Validity and reliability assessment of a peer evaluation method in team-based learning classes. AB - PURPOSE: Team-based learning (TBL) is increasingly employed in medical education because of its potential to promote active group learning. In TBL, learners are usually asked to assess the contributions of peers within their group to ensure accountability. The purpose of this study is to assess the validity and reliability of a peer evaluation instrument that was used in TBL classes in a single medical school. METHODS: A total of 141 students were divided into 18 groups in 11 TBL classes. The students were asked to evaluate their peers in the group based on evaluation criteria that were provided to them. We analyzed the comments that were written for the highest and lowest achievers to assess the validity of the peer evaluation instrument. The reliability of the instrument was assessed by examining the agreement among peer ratings within each group of students via intraclass correlation coefficient (ICC) analysis. RESULTS: Most of the students provided reasonable and understandable comments for the high and low achievers within their group, and most of those comments were compatible with the evaluation criteria. The average ICC of each group ranged from 0.390 to 0.863, and the overall average was 0.659. There was no significant difference in inter rater reliability according to the number of members in the group or the timing of the evaluation within the course. CONCLUSION: The peer evaluation instrument that was used in the TBL classes was valid and reliable. Providing evaluation criteria and rules seemed to improve the validity and reliability of the instrument. PMID- 29510603 TI - A primer on entrustable professional activities. AB - Entrustable professional activities (EPAs) have become a popular topic within competency-based medical education programs in many countries and hundreds of publications within only a few years. This paper was written to introduce the ins and outs of EPAs. After a brief historical overview, the rational of EPAs, as a bridge between a competency framework and daily clinical practice, is explained. Next, entrustment decision-making as a form of assessment is elaborated and framework of levels of supervision is presented. For readers interested to apply the concept in practice a stepwise approach to curriculum development is proposed. The paper concludes with an overview of the state of the art of working with EPAs in across disciplines, professions and countries. PMID- 29510606 TI - Medical students' clinical performance of dealing with patients in the context of domestic violence. AB - PURPOSE: The aim of this study was to inquire about the clinical performance and determine the performance pattern of medical students in standardized patient (SP) based examinations of domestic violence (DV). METHODS: The clinical performance sores in DV station with SP of third-year (n=111, in 2014) and 4th year (n=143, in 2016) medical students of five universities in the Busan Gyeongnam Clinical Skills Examination Consortium were subjected in this study. The scenarios and checklists of DV cases were developed by the case development committee of the consortium. The students' performance was compared with other stations encountered in SP. The items of the checklists were categorized to determine the performance pattern of students investigating DV into six domains: disclosure strategy (D), DV related history taking (H), checking the perpetrator's psychosocial state (P), checking the victim's condition (V), negotiating and persuading the interviewee (N), and providing information about DV (I). RESULTS: Medical students showed poorer performance in DV stations than in the other stations with SP in the same examination. Most students did confirm the perpetrator and commented on confidentiality but ignored the perpetrator's state and patient's physical and psychological condition. The students performed well in the domains of D, H, and I but performed poorly in domains P, V, and N. CONCLUSION: Medical students showed poor clinical performance in the DV station. They performed an 'event oriented interview' rather than 'patient centered' communication. An integrated educational program of DV should be set to improve students' clinical performance. PMID- 29510607 TI - Development of a systematic career coaching program for medical students. AB - PURPOSE: This study aimed to develop a systematic career-coaching program (SCCP) that can be used by medical teaching schools to address a growing need for career coaching. The program objectives were to help students (1) develop a comprehensive self-understanding of their aptitudes, interests, and personality traits; (2) explore possible career choices and decide on a career path; and (3) develop the competencies needed to prepare for their future careers. METHODS: The SCCP was based on the ADDIE (analysis, design, development, implementation, and evaluation) model and decision-making questioning model. Medical professionals, medical education and career counseling experts, and students participated in designing the program. RESULTS: The SCCP describes coaching content, tools, operational methods, and appropriate timing, and identifies the professionals and specialists who can offer their expertise in the different coaching phases. It is designed to allow medical schools to offer the program in segments or in its entirety, depending on the curriculum and environment. CONCLUSION: The SCCP represents a viable career-coaching program for medical students that can be applied in part or in its entirety, depending on a medical school's curriculum and educational environment. PMID- 29510609 TI - An analysis of medical students' reflective essays in problem-based learning. AB - PURPOSE: This study aimed to explore students' learning experience in problem based learning (PBL) particularly in terms of what they learned and how they learned in one Korean medical school by analyzing their reflective essays with qualitative research methods. METHODS: This study included 44 first-year medical students. They took three consecutive PBL courses and wrote reflective essays 3 times anonymously on the last day of each course. Their reflective essays were analyzed using an inductive content analysis method. RESULTS: The coding process yielded 16 sub-categories and these categories were grouped into six categories according to the distinctive characteristics of PBL learning experience: integrated knowledge base, clinical problem solving, collaboration, intrinsic motivation, self-directed learning, and professional attitude. Among these categories, integrated knowledge base (34.68%) and professional attitude (2.31%) were the categories mentioned most and least frequently. CONCLUSION: The findings of this study provide an overall understanding of the learning experience of Korean medical students during PBL in terms of what they learned and how they learned with rich descriptive commentaries from their perspectives as well as several thoughtful insights to help develop instructional strategies to enhance the effectiveness of PBL. PMID- 29510608 TI - Discrepancies in general surgery medical terminology between South and North Korea. AB - PURPOSE: The purpose of this study was to categorize surgery-related medical terminologies used in South and North Korea and to compare and analyze discrepancies observed in the terms. METHODS: This study collected medical terminology used in the North Korean medical book "Surgery" and compared it to medical terminology found in the medical glossary of South Korea. The order of the subtitle was described according to the Instruction to Authors. RESULTS: In total, there were 2,168 individual medical terms, of which only 1,004 words (46.3%) were identical to South Korean medical terms. There were 581 similar terms (26.8%), 265 different terms (12.2%), and 318 terms that are nonexistent in South Korea (14.7%). CONCLUSION: Less than half of the medical terms used in North Korea match those used in South Korea. It is expected that the prolongation of the current division of South and North Korea will only worsen this discrepancy. Further efforts to bridge the gap through academic exchange between South Korea and North Korea are required in preparation for an era of reunification. PMID- 29510610 TI - Development and Validation of Ovarian Symptom Index-18 and Neurotoxicity-4 for Korean Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. AB - Purpose: The purpose of this study was to develop Korean versions of the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy (NCCN-FACT) Ovarian Symptom Index-18 (NFOSI-18) and FACT/Gynecologic Oncology Group (FACT GOG) Neurotoxicity 4-item (NTX-4), evaluating their reliability and reproducibility. Materials and Methods: In converting NFOSI-18 and NTX-4, the following steps were performed: forward translation, backward translation, expert review, pretest of preliminary format, and finalization of Korean versions (K NFOSI-18 and K-NTX-4). Patients were enrolled from six institutions where each had completed chemotherapy for ovarian, tubal, or peritoneal cancer at least 1 month earlier. In addition to demographics obtained by questionnaire, all subjects were assessed via K-NFOSI-18, K-NTX-4, and a Korean version of the EuroQoL-5 Dimension. Internal structural validity and reliability were evaluated using item internal consistency, item discriminant validity, and Cronbach's alpha. To evaluate test-retest reliability, K-NFOSI-18 and K-NTX-4 were readministered after 7-21 days, and intraclass correlation coefficients (ICCs) were calculated. Results: Of the 250 women enrolled during the 3-month recruitment period, 13 withdrew or did not respond, leaving 237 (94.8%) for the analyses. Mean patient age was 54.3+/-10.8 years. Re-testing was performed in 190 patients (80.2%). The total K-NFOSI-18 and K-NTX-4 scores were 49 (range, 20 to 72) and 9 (range, 0 to 16), respectively, with high reliability (Cronbach's alpha=0.84 and 0.89, respectively) and reproducibility (ICC=0.77 and 0.84, respectively) achieved in retesting. Conclusion: Both NFOSI-18 and NTX-4 were successfully developed in Korean with minimal modification. Each Korean version showed high internal consistency and reproducibility. PMID- 29510611 TI - Validation of the eighth American Joint Committee on Cancer Staging System for Distal Bile Duct Carcinoma. AB - Purpose: T category of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for distal bile-duct carcinoma (DBDC) was changed to include tumor invasion depth measurement, while the N-category adopted a 3-tier classification system based on the number of metastatic nodes. Materials and Methods: To validate cancer staging, a total of 200 surgically resected DBDCs were staged and compared according to the seventh and eighth editions. Results: T categories included T1 (n=37, 18.5%), T2 (n=114, 57.0%), and T3 (n=49, 24.5%). N categories included N0 (n=133, 66.5%), N1 (n=50, 25.0%), and N2 (n=17, 8.5%). Stage groupings included I (n=33, 16.5%), II (n=150, 75.0%), and III (n=17, 8.5%). The overall 5-year survival rates (5-YSRs) of T1, T2, and T3 were 59.3%, 42.4%, and 12.2%, respectively. T-category could discriminate patient survival by both pairwise (T1 and T2, p=0.011; T2 and T3, p<0.001) and overall (p<0.001) comparisons. The overall 5-YSRs of N0, N1, and N2 were 47.3%, 17.0%, and 14.7%, respectively. N category could partly discriminate patient survival by both pairwise (N0 and N1, p<0.001; N1 and N2, p=0.579) and overall (p<0.001) comparisons. The overall 5-YSRs of stages I, II, and III were 59.0%, 35.4%, and 14.7%, respectively. Stages could distinguish patient survival by both pairwise (I and II, p=0.002; II and III, p=0.015) and overall (p<0.001) comparisons. On multivariate analyses, T and N-categories (p=0.014 and 0.029) and pancreatic invasion (p=0.006) remained significant prognostic factors. Conclusion: The T and N categories of the eighth edition AJCC staging system for DBDC accurately predict patient prognosis. PMID- 29510612 TI - PTEN Mutation Identified in Patient Diagnosed with Simultaneous Multiple Cancers. AB - PTEN hamartoma tumor syndrome is a spectrum of disorders characterized by unique phenotypic features including multiple hamartomas caused by mutations of the tumor suppressor gene PTEN. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are representative diseases, and both have several common clinical features and differences. Because PTEN mutations are associated with an increased risk of malignancy including breast, thyroid, endometrial, and renal cancers, cancer surveillance is an important element of disease management. We report a germline mutation of the PTEN (c.723dupT, exon 7) identified in a young woman with a simultaneous occurrence of breast cancer, dermatofibrosarcoma protuberans, and follicular neoplasm. This case suggests that it is critical for clinicians to recognize the phenotypic features associated with these syndromes to accurately diagnose them and provide preventive care. PMID- 29510613 TI - A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients Receiving Moderately Emetogenic Chemotherapy: Results of the Korean South West Oncology Group (KSWOG) Study. AB - Purpose: Data on the efficacy of olanzapine in patients receiving moderately emetogenic chemotherapy (MEC) are limited. This study aimed to evaluate and compare the efficacy of olanzapine versus placebo in controlling nausea and vomiting in patients receiving MEC. Materials and Methods: We conducted a randomized, double-blind, placebo-controlled study to determine whether olanzapine can reduce the frequency of chemotherapy-induced nausea and vomiting (CINV) and improve the quality of life (QOL) in patients receiving palonosetron and dexamethasone as prophylaxis for MEC-induced nausea and vomiting. The primary end point was complete response for the acute phase (0-24 hours after chemotherapy). The secondary end points were complete response for the delayed (24-120 hours) and overall phase (0-120 hours), proportion of significant nausea (VAS >=25 mm), use of rescue medications, and effect on QOL. Results: Fifty-six patients were randomized to the olanzapine (n=29) and placebo (n=27) groups. Complete response rates were not significantly different between the olanzapine and placebo groups in the acute (96.5% vs. 88.0%, P=0.326), delayed (69.0% vs. 48.0%, P=0.118), and overall phases (69.0% vs. 48.0%, P=0.118). However, the percentage of patients with significant nausea (17.2% vs. 44.0%, P=0.032) and the use of rescue medications (0.03+/-0.19 vs. 1.88+/-2.88, P=0.002) were lower in the olanzapine group than in the placebo. Furthermore, the olanzapine group demonstrated better QOL (P=0.015). Conclusions: Olanzapine combined with palonosetron and dexamethasone significantly improved QOL and vomiting control among previously untreated patients receiving MEC, although the efficacy was limited to the reduction of the frequency of CINV. PMID- 29510614 TI - Expression of Immunoproteasome Subunit LMP7 in Breast Cancer and Its Association with Immune-Related Markers. AB - Purpose: In the presence of interferon, proteasome subunits are replaced by their inducible counterparts to form an immunoproteasome (IP) plays a key role in generation of antigenic peptides presented by MHC class I molecules, leading to elicitation of a T cell-mediated immune response. Although the roles of IP in other cancers, and inflammatory diseases have been extensively studied, its significance in breast cancer is unclear. Materials and Methods: We investigated the expression of LMP7, an IP subunit, and its relationship with immune system components in two breast cancer cohorts. Results: In 668 consecutive breast cancer cohort, 40% of tumors showed high level of LMP7 expression, and tumors with high expression of LMP7 had more tumor-infiltrating lymphocytes (TILs) in each subtype of breast cancer. In another cohort of 681 triple-negative breast cancer patients cohort, the expression of LMP7 in tumor cells was significantly correlated with the amount of TILs and the expression of interferon-associated molecules (MxA [p < 0.001] and PKR [p < 0.001]), endoplasmic reticulum stress associated molecules (PERK [p=0.012], p-eIF2a [p=0.001], and XBP1 [p < 0.001]), and damage-associated molecular patterns (HMGN1 [p < 0.001] and HMGB1 [p < 0.001]). Patients with higher LMP7 expression had better disease-free survival outcomes than those with no or low expression in the positive lymph node metastasis group (p=0.041). Conclusion: Close association between the TIL levels and LMP7 expression in breast cancer indicates that better antigen presentation through greater LMP7 expression might be associated with more TILs. PMID- 29510615 TI - Paranasal Sinus Invasion in Nasopharyngeal Carcinoma after Intensity-Modulated Radiotherapy. AB - Purpose: The aim of this study is to evaluate the prognostic significance of paranasal sinus invasion for nasopharyngeal carcinoma (NPC) and its suitable position in the T classification. Materials and Methods: The magnetic resonance imaging (MRI) scans of 695 patients with previously untreated, biopsy-proven, non metastatic NPC that was treated with intensity-modulated radiotherapy (IMRT) were reviewed retrospectively. Results: The incidence of paranasal sinus invasion was 39.4% (274 of 695 patients). Multivariate analysis showed that paranasal sinus invasion was an independent negative prognostic factor for local failure-free survival (LFFS) (p < 0.05). According to the eighth American Joint Committee on Cancer (AJCC) staging system, 275 patients were classified as T3 classification. Of these, 78 patients (28.4%) developed paranasal sinus invasion (T3b) and 197 (71.6%) didn't (T3a). The estimated 5-year LFFS and overall survival (OS) rates for the patients with T3b and T3a classification were 88.6% versus 95.0% (p = 0.047), and 84.5% versus 93.3% (p = 0.183), respectively. The estimated 5-year LFFS and OS rates for the patients with T4 classification were 89.5% and 83.2%, which were similar with the outcomes of patients with T3b classification. Conclusion: MRI-determined paranasal sinus invasion is an independent prognostic factor of NPC treated by IMRT. Paranasal sinus invasion is recommended to classify as T4 classification in the 8th AJCC staging system for NPC. PMID- 29510616 TI - Hepatic Resection Provides Survival Benefit for Selected Intermediate-Stage (BCLC B) Hepatocellular Carcinoma Patients. AB - Purpose: The intermediate stage of HCC (BCLC B) comprises a highly heterogeneous population, and the treatment strategy is still controversial. Because of the heterogeneity, a subclassification of intermediate-stage HCCs was put forward by Bolondi et al according to the 'beyond Milan and within up-to-7'criteria and Child-Pugh score. In this study, we aim to analyze the prognosis of BCLC B stage HCC patients who received hepatic resection according to the Bolondi's subclassification. Materials and Methods: 1,103 patients diagnosed with HCC and treated with hepatic resection were enrolled in our hospital between 2006 and 2012. According to Bolondi 's subclassification, the BCLC-B patients were divided into 4 groups. Recurrence-free survival (RFS) and overall survival (OS) were analyzed. Results: According to Bolondi 's subclassification, the BCLC-B patients were divided into 4 groups: B1 (41,18.7%), B2 (160,73.1%), B3 (11,5.0%) and B4 (7,3.2%). Significant difference was observed between B1 and other groups (B1 Vs. B2: P = 0.0224, B1 Vs. B3: P <0.001, B1 Vs. B4: P <0.001), but no difference for B2 Vs. B4 (P = 0.542) and B3 Vs. B4 (P = 0.542). In addition, no significant differences were observed between BCLC-A and BCLC-B1 group for both RFS (P =0.0865) and OS (P =0.643). In multivariate analysis, BCLC-B subclassification was not a risk factor for both OS (P =0.263) and (P =0.892). Conclusions: In our study, HCC patients at B1 stage were benefited from hepatic resection and had similar survival to BCLC A stage patients. Our study provided rationality of hepatic resection for selected BCLC B stage HCC patients instead of routine TACE. PMID- 29510617 TI - Light-Induced Spin Crossover in an Fe(II) Low-Spin Complex Enabled by Surface Adsorption. AB - Understanding and controlling the spin-crossover properties of molecular complexes can be of particular interest for potential applications in molecular spintronics. Using near-edge X-ray absorption fine structure spectroscopy, we investigated these properties for a new vacuum-evaporable Fe(II) complex, namely [Fe(pypyr(CF3)2)2(phen)] (pypyr = 2-(2'-pyridyl)pyrrolide, phen = 1,10 phenanthroline). We find that the spin-transition temperature, well above room temperature for the bulk compound, is drastically lowered for molecules arranged in thin films. Furthermore, while within the experimentally accessible temperature range (2 K < T < 410 K) the bulk material shows indication of neither light-induced excited spin-state trapping nor soft X-ray-induced excited spin state trapping, these effects are observed for molecules within thin films up to temperatures around 100 K. Thus, by arranging the molecules into thin films, a nominal low-spin complex is effectively transformed into a spin-crossover complex. PMID- 29510618 TI - pH Mapping on Tooth Surfaces for Quantitative Caries Diagnosis Using Micro Ir/IrOx pH Sensor. AB - A quantitative diagnostic method for dental caries would improve oral health, which directly affects the quality of life. Here we describe the preparation and application of Ir/IrOx pH sensors, which are used to measure the surface pH of dental caries. The pH level is used as an indicator to distinguish between active and arrested caries. After a dentist visually inspected and defined 18 extracted dentinal caries at various positions as active or arrested caries, the surface pH values of sound and caries areas were directly measured with an Ir/IrOx pH sensor with a diameter of 300 MUm as a dental explorer. The average pH values of the sound root, the arrested caries, and active caries were 6.85, 6.07, and 5.30, respectively. The pH obtained with an Ir/IrOx sensor was highly correlated with the inspection results by the dentist, indicating that the types of caries were successfully categorized. This caries testing technique using a micro Ir/IrOx pH sensor provides an accurate quantitative caries evaluation and has potential in clinical diagnosis. PMID- 29510619 TI - Large Piezoelectric Strain with Superior Thermal Stability and Excellent Fatigue Resistance of Lead-Free Potassium Sodium Niobate-Based Grain Orientation Controlled Ceramics. AB - Environment-friendly lead-free piezoelectric materials with high piezoelectric response and high stability in a wide temperature range are urgently needed for various applications. In this work, grain orientation-controlled (with a 90% ?001?c-oriented texture) (K,Na)NbO3-based ceramics with a large piezoelectric response ( d33*) = 505 pm V-1 and a high Curie temperature ( TC) of 247 degrees C have been developed. Such a high d33* value varies by less than 5% from 30 to 180 degrees C, showing a superior thermal stability. Furthermore, the high piezoelectricity exhibits an excellent fatigue resistance with the d33* value decreasing within only by 6% at a field of 20 kV cm-1 up to 107 cycles. These exceptional properties can be attributed to the vertical morphotropic phase boundary and the highly ?001?c-oriented textured ceramic microstructure. These results open a pathway to promote lead-free piezoelectric ceramics as a viable alternative to lead-based piezoceramics for various practical applications, such as actuators, transducers, sensors, and acoustic devices, in a wide temperature range. PMID- 29510620 TI - Manipulating the Structural and Electronic Properties of Epitaxial SrCoO2.5 Thin Films by Tuning the Epitaxial Strain. AB - Structure determines material's functionality, and strain tunes the structure. Tuning the coherent epitaxial strain by varying the thickness of the films is a precise route to manipulate the functional properties in the low-dimensional oxide materials. Here, to explore the effects of the coherent epitaxial strain on the properties of SrCoO2.5 thin films, thickness-dependent evolutions of the structural properties and electronic structures were investigated by X-ray diffraction, Raman spectra, optical absorption spectra, scanning transmission electron microscopy (STEM), and first-principles calculations. By increasing the thickness of the SrCoO2.5 films, the c-axis lattice constant decreases, indicating the relaxation of the coherent epitaxial strain. The energy band gap increases and the Raman spectra undergo a substantial softening with the relaxation of the coherent epitaxial strain. From the STEM results, it can be concluded that the strain causes the variation of the oxygen content in the BM SCO2.5 films, which results in the variation of band gaps with varying the strain. First-principles calculations show that strain-induced changes in bond lengths and angles of the octahedral CoO6 and tetrahedral CoO4 cannot explain the variation band gap. Our findings offer an alternative strategy to manipulate structural and electronic properties by tuning the coherent epitaxial strain in transition-metal oxide thin films. PMID- 29510621 TI - De Novo Synthesis of Basal Bacterial Cell Division Proteins FtsZ, FtsA, and ZipA Inside Giant Vesicles. AB - Cell division is the most dynamic event in the cell cycle. Recently, efforts have been made to reconstruct it using the individual component proteins to obtain a better understanding of the process of self-reproduction of cells. However, such reconstruction studies are frequently hampered by difficulties in preparing membrane-associated proteins. Here we demonstrate a de novo synthesis approach based on a cell-free translation system. Genes for fundamental cell division proteins, FtsZ, FtsA, and ZipA, were expressed inside the lipid compartment of giant vesicles (GVs). The synthesized proteins showed polymerization, membrane localization, and eventually membrane deformation. Notably, we found that this morphological change of the vesicle is forced by only FtsZ and ZipA, which form clusters on the membrane at the vesicle interior. Our cell-free approach provides a platform for studying protein dynamics associated with lipid membrane and paves the way to create a synthetic cell that undergoes self-reproduction. PMID- 29510622 TI - Sensitive Detection of Single-Cell Secreted H2O2 by Integrating a Microfluidic Droplet Sensor and Au Nanoclusters. AB - As an important signaling molecule, hydrogen peroxide (H2O2) secreted externally by the cells influences cell migration, immunity generation, and cellular communications. Herein, we have developed a microfluidic approach with droplets in combination with Au nanoclusters for the sensitive detection of H2O2 secreted by a single cell. Isolated in the ultrasmall volume (4.2 nL) of a microdroplet, single-cell secreted H2O2 can initiate dramatic fluorescence changes of horseradish peroxidase-Au nanoclusters. We have demonstrated an ultrahigh sensitivity (200-400 attomole H2O2 directly measured from a single cell) with good specificity. It offers a useful research tool to study the cell-to-cell differences of H2O2 secretion at the single-cell level. PMID- 29510623 TI - Electronic Origin and Kinetic Feasibility of the Lattice Oxygen Participation During the Oxygen Evolution Reaction on Perovskites. AB - Density functional theory is employed to investigate the electronic origin and feasibility of surface lattice oxygen (Osurf) participation during the oxygen evolution reaction (OER) on perovskites. Osurf participation occurs via the nonelectrochemical pathway in which adsorbed atomic oxygen (O*) diffuses from the transition-metal site to the oxygen site, and then Osurf shifts out of the surface plane to react with O* to form Osurf-O* and a surface oxygen vacancy. The different thermodynamic driving forces of Osurf participation on LaMO3-delta (M = Ni, Co, and Cu) are explained by the changes in the oxidation state of the transition-metal site throughout the reaction. We show that Osurf participation on LaNiO3 cannot be hindered by Osurf protonation in the OER potential range. By including the coverage effect and utilizing the implicit solvent model, we finally show that lattice oxygen mechanism is more feasible than the conventional mechanism for OER on LaNiO3. PMID- 29510624 TI - Titanium Insertion into CO Bonds in Anionic Ti-CO2 Complexes. AB - We explore the structures of [Ti(CO2) y]- cluster anions using infrared photodissociation spectroscopy and quantum chemistry calculations. The existence of spectral signatures of metal carbonyl CO stretching modes shows that insertion of titanium atoms into C-O bonds represents an important reaction during the formation of these clusters. In addition to carbonyl groups, the infrared spectra show that the titanium center is coordinated to oxalato, carbonato, and oxo ligands, which form along with the metal carbonyls. The presence of a metal oxalato ligand promotes C-O bond insertion in these systems. These results highlight the affinity of titanium for C-O bond insertion processes. PMID- 29510625 TI - Statistical Mechanics of Multilayer Sorption: Surface Concentration Modeling and XPS Measurement. AB - The concentration of solute molecules at the surface of a liquid is a factor in heterogeneous reactions, surface tension, and Marangoni-effect-driven surface flows. Increasingly, X-ray photoelectron spectroscopy (XPS) has enabled surface concentrations to be measured. In prior work, we employed statistical mechanics to derive expressions for surface tension as a function of solute activity in a binary solution. Here we use a Gibbs relation to derive concomitant expressions for surface concentration. Surface tension data from the literature for five alcohols are used to identify parameters in the surface tension equation. These parameters are then used in the surface concentration equation to predict surface concentrations. Comparison of these predictions to those measured with XPS shows a factor of three difference between measured and predicted surface concentrations. Potential reasons for the discrepancy are discussed, including lack of surface-bulk equilibrium in the measurements. PMID- 29510626 TI - Neuropeptidome of the Hypothalamus and Pituitary Gland of Indicine * Taurine Heifers: Evidence of Differential Neuropeptide Processing in the Pituitary Gland before and after Puberty. AB - Puberty in cattle is regulated by an endocrine axis, which includes a complex milieu of neuropeptides in the hypothalamus and pituitary gland. The neuropeptidome of hypothalamic-pituitary gland tissue of pre- (PRE) and postpubertal (POST) Bos indicus-influenced heifers was characterized, followed by quantitative analysis of 51 fertility-related neuropeptides in these tissues. Comparison of peptide abundances with gene expression levels allowed assessment of post-transcriptional peptide processing. On the basis of classical cleavage, 124 mature neuropeptides from 35 precursor proteins were detected in hypothalamus and pituitary gland tissues of three PRE and three POST Brangus heifers. An additional 19 peptides (cerebellins, PEN peptides) previously reported as neuropeptides that did not follow classical cleavage were also identified. In the pre-pubertal hypothalamus, a greater diversity of neuropeptides (25.8%) was identified relative to post-pubertal heifers, while in the pituitary gland, 38.6% more neuropeptides were detected in the post-pubertal heifers. Neuro-tissues of PRE and POST heifers revealed abundance differences ( p < 0.05) in peptides from protein precursors involved in packaging and processing (e.g., the granin family and ProSAAS) or neuron stimulation (PENK, CART, POMC, cerebellins). On their own, the transcriptome data of the precursor genes could not predict the neuropeptide profile in the exact same tissues in several cases. This provides further evidence of the importance of differential processing of the neuropeptide precursors in the pituitary before and after puberty. PMID- 29510627 TI - Wrinkling Instability and Adhesion of a Highly Bendable Gallium Oxide Nanofilm Encapsulating a Liquid-Gallium Droplet. AB - The wrinkling and interfacial adhesion mechanics of a gallium-oxide nanofilm encapsulating a liquid-gallium droplet are presented. The native oxide nanofilm provides mechanical stability by preventing the flow of the liquid metal. We show how a crumpled oxide skin a few nanometers thick behaves akin to a highly bendable elastic nanofilm under ambient conditions. Upon compression, a wrinkling instability emerges at the contact interface to relieve the applied stress. As the load is further increased, radial wrinkles evolve, and, eventually, the oxide nanofilm ruptures. The observed wrinkling closely resembles the instability experienced by nanofilms under axisymmetric loading, thus providing further insights into the behaviors of elastic nanofilms. Moreover, the mechanical attributes of the oxide skin enable high surface conformation by exhibiting liquid-like behavior. We measured an adhesion energy of 0.238 +/- 0.008 J m-2 between a liquid-gallium droplet and smooth flat glass, which is close to the measurements of thin-sheet nanomaterials such as graphene on silicon dioxide. PMID- 29510628 TI - Exciton-Phonon Spectroscopy of Quantum Dots Below the Single-Particle Homogeneous Line Width. AB - We demonstrate that high-dimensionality coherent spectroscopy yields "super resolved" spectra whereby peaks may be localized far below their homogeneous line width by resolving them across multiple, coherently coupled dimensions. We implement this technique using a fifth-order photon-echo spectroscopy called Gradient-Assisted Multidimensional Electronic-Raman Spectroscopy (GAMERS) that combines resonant and nonresonant excitation to disperse the optical response across three spectral dimensions: two involving excitonic transitions and one that encodes phonon energies. In analogy to super-resolution localization microscopies, which separate spatially overlapping signals in time, GAMERS isolates signals spectrally using combined electronic and nuclear resolution. Optical phonon lines in a colloidal solution of CdSe quantum dots at room temperature separated by less than 150 MUeV are resolved despite the homogeneous line width of these transitions being nearly an order of magnitude broader. The frequency difference between these phonon modes is attributed to softening of the longitudinal phonon mode upon excitation to the lowest exciton state. Further, such phonon mode selectivity yields spectra with electronic line widths that approach the single particle limit. Through this enhanced spectral resolution, the GAMERS method yields insights into the nature of coupling between longitudinal optical and acoustic phonons and specific excitonic transitions that were previously hidden. PMID- 29510629 TI - Observation of Nanosecond Hot Carrier Decay in Graphene. AB - An extremely long decay time of hot carriers in graphene at room temperature was observed for the first time by monitoring the photoinduced thermionic emission using a highly sensitive time-of-flight angle-resolved photoemission spectroscopy method. The emission persisted beyond 1 ns, two orders of magnitude longer than previously reported carrier decay. The long lifetime was attributed to the excitation of image potential states at very low laser fluencies. PMID- 29510631 TI - Ten Years of Polydopamine: Current Status and Future Directions. PMID- 29510632 TI - Impact of cesarean section in a private health service in Brazil: indications and neonatal morbidity and mortality rates. AB - OBJECTIVE: To evaluate the incidence of, indications of, and maternal and neonatal morbidity and mortality rates in cesarean sections in a private health service in Brazil. DESIGN: Retrospective and observational study. SETTING: Private health service in Vitoria, Espirito Santo, Brazil. METHODS: The patients were interviewed using a structured questionnaire to determine maternal age, gestational age at the time of delivery, number of previous deliveries, type of delivery performed, duration of labor, indications for cesarean delivery, point at which cesarean section was performed, physician responsible for delivery, and maternal morbidity, fetal morbidity, and fetal mortality rates. A descriptive analysis of the data was conducted. Students t-test was performed to compare quantitative variables, and Fishers exact test was performed for categorical variables. RESULTS: A total of 584 patients were evaluated. Of these, 91.8% (536/584) had cesarean sections, while only 8.2% (48/584) had vaginal deliveries. There were no reports of forceps-assisted vaginal deliveries. In 87.49% of the deliveries, the number of gestational weeks was more than 37. In terms of indications for performing cesarean section, 48.5% were for maternal causes, 30.41% were for fetal causes, and 17.17% were elective. Maternal re hospitalization due to puerperal complications was necessary in 10.42% of the vaginal deliveries and in 0.93% of the cesarean deliveries (p<0.001). Complications were observed in 18.75% of the vaginally delivered newborns and in 17.16% of those delivered by cesarean section. Of the newborns with complications at birth, 40.59% (41/101) had to be admitted to the neonatal intensive care unit. There were no cases of maternal death. There were seven cases of fetal/neonatal death. CONCLUSION: We observed that the vast majority of deliveries in the private sector are performed by cesarean section, without labor, and by the patients obstetrician. We found no serious maternal complications or increased neonatal morbidity rates associated with cesarean section. PMID- 29510633 TI - [Medroxyprogesteron acetate use to block LH surge in oocyte donor stimulation]. AB - OBJECTIVE: To compare the results of ovarian stimulation with LH surge blockade by medroxyprogesterone acetate or GnRH antagonist in oocytes donors. To present current options of exogenous and endogenous progestins instead of GnRH analogues to block LH surge during ovarian stimulation. DESIGN: Retrospective study of oocyte donor cycles and literature review. SETTING: Department of Obstetrics and Gynecology, Faculty of Medicine, Masaryk university and University Hospital Brno. METHODS: Thirteen oocyte donors (26.8 +/- 2.5 years old) were stimulated with recFSH and MPA to block the LH surge during January - October 2017. The results were compared to the previous cycle stimulated with recFSH and GnRH antagonist performed during January -December 2016. Wilcoxon's pair test was used to test the statistics. A literature search of SCOPUS was carried out. RESULTS: In cycles with MPA blockade the average number of oocytes was 14.5 +/- 5.1, in cycles with GnRH anta-gonist blockade 12.0 +/- 4.5 oocytes (statistical significance p = 0.025). FSH total dose (1611 +/- 327 vs. 1565 +/- 322 IU), days of stimulation (9.1 +/- 0.8 vs. 8.5 +/- 0.9) and maximum estradiol levels (5.9 +/- 2.1 vs. 6.0 +/- 3.0 nmol/l) were not statistically different. Progestins are effective in blocking the LH surge during ovarian stimulation and do not affect the number and quality of collected oocytes or obtained embryos. Their adverse effect on the endometrial receptivity obstructs the embryo implantation in the same cycle. Such protocol requires total freezing and delayed transfer. Progestins can be used in a variety of stimulation protocols - progestin primed follicular phase stimulation, luteal phase stimulation with endogenous progesteron, double stimulation in follicular and luteal phase of the same cycle "duostim" in low responders. CONCLUSION: Eggs donor ovarian stimulation with MPA resulted in more oocytes than stimulation protocol with GnRH antagonist, the total dose of FSH and the length of stimulation were similar. According to current experiences progestins effectively block the LH surge and do not affect the number and quality of collected eggs and obtained embryos. Their use opens new possibilities of ovarian stimulation protocols and their flexibility. Its main constraint is that it requires total freezing and delayed transfer. PMID- 29510634 TI - [Development of prenatal diagnostics of congenital heart defects, profit of standardized scanning planes]. AB - OBJECTIVE: To audit the development and success rate of prenatal detection of congenital heart defects (CHDs), and to evaluate the effectiveness of diagnostics performed in standardized scanning planes. SETTING: Department of Pediatrics, University Hospital Ostrava. DESIGN: Retrospective study. METHODS: Ultrasound examination of fetal heart (fetal echocardiography) was performed in the second trimester pregnancy. The observed region was the Moravian-Silesian region; the assessment was performed in the retrospective study performed between 2000- 2016. The knowledge of all significant heart defects in the region, processing of data from genetic reporting, further examination of all prenatal pathologies by a pediatric cardiologist, presence of a pediatric cardiologist at all autopsies, with a precise description of the defect, birth of a pathological new-born at a specialized centre. Analysis of detected CHDs was performed in relation to the ultrasound scans used. RESULTS: During the monitored 17-year period, a total of 748 (3.8 cases per 1,000 foetuses) of prenatally identified and postnatally significant CHDs were observed in the total population of 198,300 foetuses. There were 53% (393/748) CHDs detected prenatally and 47% (355/748) of cases were not prenatally recognized. The effectiveness of CHD screening has improved progressively, from the initial 10% up to the current 74%. The best results were obtained using the basic four-chamber (4CH) scan; the results in practice gradually decreased, from the basic 4CH projection to the aortic arch. CONCLUSION: The effectiveness of prenatal detection of congenital heart defects gradually improves, namely in cases of hypoplasia and significant ventricular anomalies, with up to 100% prenatally detected cases in the past three years. The level of detection statistically decreases, from the four-chamber projection to out-flow tracts, great arteries and the aortic arch. Congenital heart defect is generally well detectable prenatally, and is usually observed as an isolated anomaly. The most important factors include a precise diagnosis, overall examination of the pregnancy and correct counselling provided for the affected family. PMID- 29510635 TI - [Various approaches of endometrial preparation for frozen-thawed embryo transfer]. AB - OBJECTIVE: Various approaches of endometrial preparation for frozen-thawed embryo transfer. DESIGN: Retrospective analysis. SETTING: Department of Obstetric and Gyneacology, Faculty of Medicine, Palacky University, University Hospital Olomouc. METHODS: Effectivity of frozen-thawed embryo transfers was carried out between January and August 2017 in the IVF unit at the University Hospital Olomouc. Results were compared among groups A, B, C with various approaches of endometrial preparation. Group A - natural ovulating cycle, group B - artificial cycle with oral estrogen, vaginal gestagen and group C - artificial cycle with transdermal estrogen and vaginal gestagen. One blastocyst (two blastocyst in five cycles) was transferred on day 6 post ovulation (group A) or after 6 days of using gestagens (group B, C). RESULTS: The highest pregnancy rate was observed in group C (56%), similar pregnancy rate was found in group B (52%) and the lowest was seen in group A (22%). All pregnancies in group A continued over 12 weeks, in group B continued 57 percent and in group C continued 56 percent of pregnancies. CONCLUSION: Frozen-thawed embryotransfers in natural cycles are highly time consuming. Our study has demonstrated the lowest effectivity of frozen embryotransfer in natural cycles. Artificial cycles managed by oral or transdermal form of estrogen have shown better results. PMID- 29510636 TI - [Validation of a new tool for identification of barriers to cervical cancer prevention in Slovakia]. AB - OBJECTIVE: The aim of the work was to validate the Slovak version of the CPC-28 questionnaire (Beliefs about Papanicolaou and Cervical Cancer). DESIGN: Original study. SETTING: Department of Public Health, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, in co-operation with gynaecological centers in University Hospital Martin and district Martin, Slovakia. METHODS: The original English version of the CPC-28 questionnaire was translated into Slovak language. The questionnaire consists of 28 statements divided into six domains. Cronbach's alpha coefficient was used to analyse the internal consistency of the questionnaire. Construction validity was evaluated by using Pearsons correlation coefficient. The results were processed in the statistical programs Epi Info 7.1.5. and Statistica 13, p-values < 0.05 were considered statistically significant. RESULTS: The Slovak version of the questionnaire was provided to 27 women. The women were given two questionnaires, and one of them was filled in immediately (test). After 14 days they filled in and returned second questionnaire (retest). The value of Cronbachs alpha was > 0.8 in all six domains which demonstrates the high internal consistency of the questionnaire. Pearsons coefficient was > 0.7 in all six domains and p-values < 0.001. CONCLUSION: The validated CPC-28 questionnaire in the Slovak language can be administered to women to collect data for identification of barriers to cervical cancer screening among women. PMID- 29510637 TI - [Vein of Galen aneurysmal malformation]. AB - OBJECTIVE: A case report of the pregnancy complicated by the presence of vein of Galen aneurysmal malformation in fetus. DESIGN: The case report. SETTING: Department of Obstetrics and Gynaecology, Masaryks Hospital, Jilemnice; Obstetrics and Gynecology Clinic, University Hospital in Hradec Kralove. CASE REPORT: The description of the pregnancy complicated by the presence of vein of Galen aneurysmal malformation in a fetus 32 weeks gestation which led to a progressive heart failure and the development of the hydrocephalus. CONCLUSION: The vein of Galen aneurysmal malformation is a rare cerebrovascular malformation of the fetus, the diagnosis of this malformation is usually detectable during prenatal ultrasound examination possibly also by magnetic resonance imaging. PMID- 29510638 TI - [Woman's subarachnoid hemmorage in pregnancy]. AB - OBJECTIVE: Diagnostics and solution to a case of subarachnoid hemorrhagie in a pregnant woman. Description of a subarachnoid hemmorage case in week 13 of pregnancy and pointing out to the insidiousness anamnestic examination. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, Uherskohradistska nemocnice a.s. CASE REPORT: The patient history describes a case of a 31-year-old hypertensive woman in week 38 of pregnancy, who experienced a complication during her pregnancy. Itinially the problem seemed to be gastroenteritis, which her son suffered from as well. Subsequently, the patient was diagnosed with subarachnoid hemorrhage, and a caesarean section and a neurosurgical operation was performed. CONCLUSION: Subarachnoid hemorrhage is weighty complication during pregnancy. It imminently threatens the woman's life, as well as the life of the fetus. An anamnestic and physical examination as its result may lead to a quick diagnosis and a solution to this acute disease and subsequently may rescue the life of both the mother and the fetus. PMID- 29510639 TI - [Non-Hodgkin's B-lymphoma of the ovaries with an unfavourable prognosis - incidental finding during caesarean section]. AB - OBJECTIVE: Presentation of a rare finding non-Hodgkin's B-lymphoma of the ovary in a patient during caesarean section. DESIGN: Case report. SETTINGS: Department of Obstetrics and Gynaecology, Regional Hospital Liberec, a.s.; First Internal Clinic - Clinic of Hematology, First Faculty of Medicine and General University Hospital, Charles University in Prague; Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University in Praque and Motol University Hospital. RESULTS: Pregnant woman, 31-years old, primiparous, with a history of caesarean section was examinated in our department due to nonspecific abdominal pain during her pregnancy. During the caesarean section of fetal indication we found bilateral ovarian tumours. We performed unilateral adnexectomy. Preliminary diagnosis from frozen section was thecoma, but final diagnosis (after definitive histology, imunohistochemistry and molecular investigation) was high-grade B-cell non-Hodgkin's lymphoma with c-myc and bcl-6 gene rearrangement (double-hit lymphoma) resulting in an unfavourable prognosis. The patient consequently completed 6 cycles of chemotherapy with a biological treatment, and achieved a complete remission. However, after 6 months, an early generalisation to the CNS appeared, leading to intracranial hypertension refractory to anithypertensive and anti-oedematous therapy, consequently leading to death. CONCLUSION: Non-Hodgkin's lymphoma of the ovary in pregnancy is a rare adnexal tumour whose treatment requires interdisciplinary cooperation. PMID- 29510640 TI - [Hysteroscopically assisted laparoscopic salpingostomy in the treatment of tubal pregnancy]. AB - OBJECTIVE: To present a case of conservative - Fallopian tube preserving - surgical therapy of tubal pregnancy. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, Strakonice Hospital. CASE DESCRIPTION: Due to the desire to preserve the Fallopian tube in a hemodynamically stable primigravida, we decided for laparoscopic salpingostomy using hysteroscopy for assisted removal of pregnancy tissue from the oviduct. CONCLUSION: In well-selected cases, this treatment is an effective method of choice and can be performed even under conditions of a smaller hospital performing a common spectrum of laparoscopic surgery. PMID- 29510641 TI - [Intravenous leiomyomatosis as a rare tumor of myometrium]. AB - AIM: To present a case of a woman diagnosed with intravenous leiomyomatosis of the uterus. TYPE OF STUDY: Case report. SETTING: Department of Obstetrics & Gynaecology, Stredomoravska nemocnicni a.s., Prerov Hospital. CASE REPORT: A 39 year old woman was referred to our unit with uterine fibroids, dysfunctional uterine bleeding and anaemia. Abdominal hysterectomy was performed. The histopathological analysis diagnosed the presence of intravenous leiomyomatosis. After a thorough literature review, we decided to perform an adnexectomy. It was not possible to perform this laparoscopically due to adhesions from previous operation. A conversion to open surgery was necessary. CONCLUSION: Intravenous leiomyomatosis is a rare clinical condition characterised by the ability of the leiomyoma to spread outside the uterus via the venous system. The diagnosis is difficult to obtain and can only be made after histopathological examination. There are no universal treatment guidelines in place at present. PMID- 29510643 TI - [Pregnancy in women with solid-organ transplants]. AB - OBJECTIVE: Evaluation of pregnancies and deliveries in women after solid organ transplantations with respect to the maternal and fetal risks. DESIGN: Overview article. SETTING: Department of Obstetrics and Gynaecology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague. METHODS: Literature search using the Web of Science, Ovid, Cochrane, Google Scholar and Medline databases with keywords (transplantation, pregnancy, immunosuppression) and analysis of articles published in impact and reviewed journals from 1958 to 2017. RESULTS: Pregnancy in patients after solid organ transplantions is associated with the higher risk of complications, particularly preeclampsia, and high incidence of comorbidities. Women after transplantation have an increased risk of premature deliveries and low birth weight newborns. The highest risk of complications is documented after lung transplantation. For immunosuppression in pregnancy inhibitors of calcineurin, azathioprine and prednisone are used. CONCLUSION: Pregnancies and deliveries in women after solid organ transplants are in a high risk. With early transplantation, adequate patient health compensation, properly planned pregnancy, adequate immunosuppressive therapy and specialized prenatal and obstetric care, women can give birth to healthy newborns after transplantation. PMID- 29510642 TI - [One-Step Nucleic Acid Amplification method - what is the future of sentinel lymph node management?] AB - OBJECTIVE: The article summarizes current possibilities of usage of the One-Step Nucleic Acid Amplification method (OSNA) in the perioperative management of sentinel lymph nodes in oncologic surgery. The principle of this method is the detection of cytokeratin 19 (CK19) in the lymphatic tissue as a marker of the metastatic spread. DESIGN: Review article. SETTINGS: Department of Obstetrics and Gynaecology, University Hospital Pilsen, Faculty of Medicine in Pilsen, Charles University, Prague; Department of Biology, Faculty of Medicine in Pilsen, Charles University, Prague; Department of Immunochemistry, University Hospital Pilsen, Faculty of Medicine in Pilsen, Charles University, Prague; Sikl's Department of Pathology, University Hospital Pilsen, Faculty of Medicine in Pilsen, Charles University, Prague. METHODS: The review of the literature published until the end of April 2017 available on the PubMed database was performed. The official abbreviation OSNA and the full name of the method One-Step Nucleic Acid Amplification was used for search in this database. CONCLUSION: The usage of the OSNA method with the detection of CK 19 in the sentinel lymph nodes as a marker of metastatic spread to the lymphatic tissue currently represents an acceptable form of perioperative sentinel lymph node management in patients with breast and colorectal cancer. Until now published data are pointing towards possible successful application of this method in sentinel lymph node management in patients with some other malignancies, such as thyroid carcinoma, gastric cancer, uterus cancer and head and neck cancer. More data is needed to establish this method also in those neoplasms. PMID- 29510644 TI - [Antibiotic therapy in pregnancy]. AB - OBJECTIVE: This article reviews up-to-date data on antibiotic therapy in pregnancy. DESIGN: Review article. SETTING: Department of Infectious Diseases, Military University Hospital Prague; Institute for the Care of Mother and Child, Prague. MATERIAL AND METHODS: Relevant literary sources have been considered, including articles in English indexed in Pubmed, monographies in English and articles in Czech. CONCLUSIONS: Antibiotic therapy in pregnancy must be rational. Antibiotics with favorable risk-benefit ratio should be used whenever possible. To achieve this, physicians must be well versed in the topic of toxicity and teratogenicity of the most commonly used antibiotics. Several pharmacokinetic parameters are altered in pregnant women. Thus, dosage of some antibiotics should be adjusted (usually increased) accordingly. Antibiotic therapy in perinatal period and in early childhood might increase the risk of developing atopy and obesity. PMID- 29510645 TI - RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice. AB - Titanium dioxide nanoparticles (TiO2 NPs) constitute the top five NPs in use today. In this study, oral administration of 50, 100, and 200 mg/kg body weight (b.w.) TiO2 NPs increases plasma glucose in mice, whereas 10 and 20 mg/kg b.w. TiO2 NPs did not. RNA sequencing (RNA-seq) technology was used to investigate genome-wide effects of TiO2 NPs. Clustering analysis of the RNA-seq data showed the most significantly enriched gene ontology terms and KEGG pathways related to the endoplasmic reticulum (ER) and ER stress. Molecular biology verification showed that 50 mg/kg b.w. and higher doses TiO2 NPs activated a xenobiotic biodegradation response and increased expression of cytochrome P450 family genes in mouse livers, thus inducing ER stress in mice. ER stress-activated MAPK and NF kappaB pathways and induced an inflammation response, resulting in phosphorylation of the insulin receptor substrate 1 and, consequently, insulin resistance. This was the main mechanism by which TiO2 NPs increased plasma glucose in mice. Meanwhile, ER stress disturbed the monooxygenase system, and thus generated reactive oxygen species (ROS). Relief of ER stress with 4 phenylbutyric acid inhibited all the above effects of TiO2 NPs, including the generation of ROS. Therefore, TiO2 NP-induced ER stress was a decisive factor with a central role in plasma glucose disturbance in mice. PMID- 29510646 TI - Maternal and neonatal outcomes associated with infertility. AB - OBJECTIVE: To investigate perinatal outcomes in a cohort of fertile and infertile nulliparous women. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: All nulliparous women delivering singletons >=24-week gestation at our center from 1 January 2012 to 31 December 2012 were included. Women were classified into two groups - fertile and infertile - based on a chart review at the time of delivery. OUTCOME MEASURE: Perinatal outcomes of interest included mode of delivery, gestational age at delivery, and birth weight. RESULTS: A total of 3293 mother/infant dyads fulfilled the inclusion criteria. Of these, 277 women (8.4%) were classified as infertile. Infertile women were significantly older than fertile women. In bivariate analyses, infertile women were more likely to undergo cesarean delivery (51.8 versus 36.1%, p < .001) and deliver at an earlier gestational age (38.9 +/- 2.3 versus 39.4 +/- 1.7 weeks, p < .0001). Infertility was no longer significantly associated with cesarean delivery after adjusting for maternal age. Infertility remained associated with an earlier gestational age at delivery after adjusting for maternal age and maternal race (beta coefficient 0.42, 95%CI -0.64, -0.2). There was no difference in infant birth weight. Late preterm deliveries (34-36 completed gestational weeks) accounted for 8.3% of deliveries for infertile women compared to 4.3% for fertile women (p = .032). CONCLUSIONS: We conclude that the increased risk of cesarean section associated with infertility is driven by maternal age. Late preterm infants represent a key cohort for further evaluation in the perinatal outcomes of infertile women. PMID- 29510647 TI - The genetic and clinical outcome of isolated fetal muscular ventricular septal defect (VSD). AB - INTRODUCTION: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD). MATERIAL AND METHODS: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients' medical records. RESULTS: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life. DISCUSSION: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome. PMID- 29510648 TI - Effects of physical activity on delayed memory measures in randomized controlled trials with nonclinical older, mild cognitive impairment, and dementia participants. AB - INTRODUCTION: Longitudinal studies have found that physical activity protects against Alzheimer disease, but the mechanism is unknown. The prevailing model derives from animal research and has physical activity directly affecting brain physiology by increasing brain volume, brain-derived neurotrophic factor (BDNF), and hippocampal neurogenesis with consequent gains in neuropsychological test scores. Supporting evidence has been mixed, with physical-activity-related gains across multiple neuropsychological domains considered indicative of the protective effect. Hippocampal-mediated delayed memory functioning is the first neurocognitive skill to be impaired in the early stages of Alzheimer disease, and physical-activity-related gains on delayed memory measures would provide the strongest support for the model. RESULTS: Review of 26 randomized controlled trials with nonclinical older, mild cognitive impairment, and dementia participants found only one with significant physical-activity-related gains in delayed memory compared to controls. This evidence does not support the physiological brain change model. Similarly, there is questionable support from those randomized controlled trials that have measured physical-activity-related brain volume and blood BDNF levels (neurogenesis having no valid labeling technique in living humans). CONCLUSION: Physical-activity-related protective effects against Alzheimer disease are likely mediated through pathways outside the central nervous system. PMID- 29510649 TI - The effects of letrozole and clomiphene citrate on ligands expression of Wnt3, Wnt7a, and Wnt8b in proliferative endometrium of women with Polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is a common endocrinologic disorder in women of reproductive age characterized by polycystic ovaries, oligo/anovulation, and hyperandrogenism. Not only anovulation but also endometrial dysfunction can reduce fertility in PCOS patients. Wnt pathway is responsible for endometrial proliferation which be strongly regulated by estradiol. To determine the effects of clomiphene citrate (CC) and letrozole, we measured the expression of some main ligands of Wnt/beta-catenin signaling including Wnt7a, Wnt3, and Wnt8b in the endometrial samples taken from PCOS women on day 12 of the menses who received 100 mg CC or 5 mg letrozole as well as from women without treatment. Significantly, the mean estrogen and progesterone concentration were lower and higher, respectively, in letrozole than CC. The mean endometrial thickness (ET) was significantly greater in letrozole compared to CC. Assessment of the mRNA and protein expression of Wnt7a, Wnt3, and Wnt8b showed significantly lower expression in CC than the letrozole and control groups. Collectively, letrozole provided a better molecular response in the endometrium of PCOS patients during the proliferative phase, similar to natural cycles, compared to CC. CC decreased the ligands expression of Wnt3, Wnt7a, and Wnt8b, resulting in endometrial dysfunction. PMID- 29510650 TI - Ultra-sonication application in biodiesel production from heterotrophic oleaginous microorganisms. AB - Utilization of microbial oil for biodiesel production has gained growing interest due to the increase in prices and the shortage of the oils and fats traditionally used in biodiesel production. However, it is still in the laboratory study stage due to the high cost of production. Employing organic wastes as raw materials to grow heterotrophic oleaginous microorganisms for further lipid production to produce biodiesel has been predicted to be a promising method for reducing costs. However, there are many obstacles including the low biodegradability of organic wastes, low lipid accumulation capacity of heterotrophic oleaginous microorganisms while using organic wastes, a great dependence on a high-energy consumption approach for biomass harvesting, utilization of toxic organic solvents for lipid extraction, and large amount of methanol required in trans esterification and in-situ trans-esterifications. Ultra-sonication as a green technology has been extensively utilized to enhance bio-product production from organic wastes. In this article, ultra-sonication applications in biodiesel production steps with heterotrophic oleaginous microorganisms have been reviewed, and its impact, potential, and limitations on the process have been discussed. PMID- 29510651 TI - Effects of group versus individual therapy for patients with memory disorder after an acquired brain injury: A randomized, controlled study. AB - INTRODUCTION: This randomized, controlled, single-blind study compared the efficacy of group versus individual memory rehabilitation therapy for patients with acquired brain injury (ABI). Subjects (N = 65) were assigned to individual (IT), group (GT), or no (NT) therapy during the three-week rehabilitation program. A neuropsychological assessment was conducted before treatment, immediately after completing treatment, and 4 months after completing treatment. Three levels of functioning were assessed: participation, disability, and impairment. The primary outcome measure was the Rivermead Behavioural Memory Test (RBMT). The results of the cognitive measures in the three groups at subsequent assessments were compared, and the effect sizes were calculated to investigate the magnitude of improvement. RESULTS: There were no significant changes in self reported patient memory problems for the participation-level measures. However, relatives of participants in the GT group reported a decreased frequency of memory failures (p = .026). According to the ability-level measure (RBMT), both therapeutic groups had similar significant improvements (p < .001), and the effect sizes were large in both groups. Although the NT group also improved (p = .015), the effect size was small. The differences between the three groups were not significant according to analysis of variance (ANOVA). However, after therapy was completed, only the GT group continued to improve (p = .013). For the impairment-level measures, the IT group showed significant improvement post treatment in three out of four measures (p < .05). This group had medium effect sizes, while the other groups showed a small or marginal effect. CONCLUSIONS: Cognitive rehabilitation - either in a group or individually - led to equally enhanced memory functioning in ABI patients, but the effects were not significantly different from those for patients in the NT group. GT and IT had specific effects on different levels of functioning. PMID- 29510652 TI - Kinematic Differences During Single-Leg Step-Down Between Individuals With Femoroacetabular Impingement Syndrome and Individuals Without Hip Pain. AB - Study Design Controlled laboratory study, case-control design. Background Despite recognition that femoroacetabular impingement syndrome (FAIS) is a movement related disorder, few studies have examined dynamic unilateral tasks in individuals with FAIS. Objectives To determine whether movements of the pelvis and lower extremities in individuals with FAIS differ from those in individuals without hip pain during a single-leg step-down, and to analyze kinematic differences between male and female participants within groups. Methods Individuals with FAIS and individuals without hip pain performed a single-leg step-down while kinematic data were collected. Kinematics were evaluated at 60 degrees of knee flexion. A linear regression analysis assessed the main effects of group, sex, and side, and the interaction of sex by group. Results Twenty individuals with FAIS and 40 individuals without hip pain participated. Individuals with FAIS performed the step-down with greater hip flexion (4.9 degrees ; 95% confidence interval [CI]: 0.5 degrees , 9.2 degrees ) and anterior pelvic tilt (4.1 degrees ; 95% CI: 0.9 degrees , 7.3 degrees ) than individuals without hip pain. Across groups, female participants performed the task with more hip flexion (6.1 degrees ; 95% CI: 1.7 degrees , 10.4 degrees ), hip adduction (4.8 degrees ; 95% CI: 2.2 degrees , 7.4 degrees ), anterior pelvic tilt (5.8 degrees ; 95% CI: 2.6 degrees , 9.0 degrees ), pelvic drop (1.4 degrees ; 95% CI: 0.3 degrees , 2.5 degrees ), and thigh adduction (2.7 degrees ; 95% CI: 1.3 degrees , 4.2 degrees ) than male participants. Conclusion The results of this study suggest that individuals with FAIS have alterations in pelvic motion during a dynamic unilateral task. The noted altered movement patterns in the FAIS group may contribute to the development of hip pain and may be due to impairments that are modifiable through rehabilitation. J Orthop Sports Phys Ther 2018;48(4):270 279. Epub 6 Mar 2018. doi:10.2519/jospt.2018.7794. PMID- 29510654 TI - Medical Teacher in Ten Minutes. PMID- 29510653 TI - Clinical Examination, Diagnostic Imaging, and Testing of Athletes With Groin Pain: An Evidence-Based Approach to Effective Management. AB - Synopsis Groin pain is common in athletes who participate in multidirectional sports and has traditionally been considered a difficult problem to understand, diagnose, and manage. This may be due to sparse historical focus on this complex region in sports medicine. Until recently, there has been little agreement regarding terminology, definitions, and classification of groin pain in athletes. This has made clear communication between clinicians difficult, and the results of research difficult to interpret and implement into practice. However, during the past decade, the field has evolved rapidly, and an evidence-based understanding is now emerging. This clinical commentary discusses the clinical examination (subjective history, screening, physical examination); imaging; testing of impairments, function, and performance; and management of athletes with groin pain in an evidence-based framework. J Orthop Sports Phys Ther 2018;48(4):239-249. Epub 6 Mar 2018. doi:10.2519/jospt.2018.7850. PMID- 29510655 TI - Top-rated AMEE MedEdPublish Papers - October 2017. PMID- 29510656 TI - Touching the base: heart-warming ads from the 2016 U.S. election moved viewers to partisan tears. AB - Some political ads used in the 2016 U.S. election evoked feelings colloquially known as being moved to tears. We conceptualise this phenomenon as a positive social emotion that appraises and motivates communal relations, is accompanied by physical sensations (including lachrymation, piloerection, chest warmth), and often labelled metaphorically. We surveyed U.S. voters in the fortnight before the 2016 U.S. election. Selected ads evoked the emotion completely and reliably, but in a partisan fashion: Clinton voters were moved to tears by three selected Clinton ads, and Trump voters were moved to tears by two Trump ads. Viewers were much less moved by ads of the candidate they did not support. Being moved to tears predicted intention to vote for the candidate depicted. We conclude that some contemporary political advertising is able to move its audience to tears, and thereby motivates support. PMID- 29510657 TI - Tangential Flow Filtration Technique: An Overview on Nanomedicine Applications. AB - Purification is a key step for different types of approaches, ranging from food, biotechnology to pharmaceutical fields. In biotechnology, tangential flow filtration (TFF) allows obtaining the separation of different components of cells without instability phenomena. In the food industry, TFF ensures the removal of contaminants or other substances that negatively affect visual appearance, organoleptic attributes, nutritional value and/or safety of ailments. In the pharmaceutical area, purification is also an important and necessary step controlling the quality of final product. In the field of research and development of nanomedicines, several techniques are used to purify and/or to concentrate the batches for in vitro and in vivo applications. Despite many approaches that exist; current data reveal continued unsatisfactory results. Between them, TFF showed promising results, even if, currently, its use is uncommon if compared with other purification techniques usually reported in "materials and methods" sections. This review represents an overview of the different applications of TFF from protein purification to food application, with particular attention to the field of nanomedicine from polymeric to metallic nanoparticles, highlighting advantages and dis-advantages in the use of this technique. The theoretical aspect of the process has been examined. PMID- 29510658 TI - Radiosensitizing Effect of Cerium Oxide Nanoparticles on Human Leukemia Cells. AB - BACKGROUND: Radiotherapy is an important protocol in the treatment of cancers, but radioresistance of cancerous cells is a challenge in cancer treatment. OBJECTIVE: The aim of this study was to evaluate the radiosensitizing effect of Cerium oxide Nanoparticles (CNPs) on human promyelocytic leukemia cells (HL-60). METHOD: HL-60 cells were treated with CNPs at different concentrations (10-100 MUg/ml) and exposed to Ionizing Radiation (IR). The genotoxicity effects of CNPs or/and IR were assessed by micronuclei assay in HL-60 cells. RESULTS: It was found that CNPs increased the frequencies of micronuclei in HL-60 cells. CNPs pretreatment to irradiation significantly increased the IR-induced micronuclei incidences in HL-60 cells. The present study demonstrates CNPs to be an effective sensitizer on DNA damage induced by IR in HL-60 cells. CONCLUSION: These findings suggest the potential application of CNPs as a highly effective radiosensitizer for the treatment of leukemia. PMID- 29510659 TI - Next generation sequencing based pathogen analysis in a patient with neurocysticercosis: a case report. AB - BACKGROUND: Accurate and early diagnosis of neurocysticercosis (NCC) remains a challenge due to the heterogeneity of its clinical, immunological and imaging characteristics. The presence of cysticercus DNA in cerebrospinal fluid (CSF) of NCC patients has been previously detected via conventional PCR assays. To the best of our knowledge, the use of CSF Next-Generation Sequencing (NGS) based pathogen analysis in patients with NCC infection has never been reported. CASE PRESENTATION: This study reports the clinical, imaging, and immunological features of a patient initially presenting with several months of headache who further developed a pure sensory stroke. NGS was used to detect the pathogen, and her CSF demonstrated the presence of Taenia solium-DNA. This finding was confirmed by a positive reaction to CSF cysticercosis antibodies. After antiparasitic treatment, secondary CSF NGS revealed the DNA index have dropped considerably compared to the initial NGS readings. CONCLUSIONS: NGS is a promising tool for the early and accurate diagnosis of central nervous system (CNS) infection, especially in the setting of atypical clinical manifestations. Further studies are required to evaluate the persistence of DNA in the CSF of patients. PMID- 29510660 TI - Loss of stomach, loss of appetite? Sequencing of the ballan wrasse (Labrus bergylta) genome and intestinal transcriptomic profiling illuminate the evolution of loss of stomach function in fish. AB - BACKGROUND: The ballan wrasse (Labrus bergylta) belongs to a large teleost family containing more than 600 species showing several unique evolutionary traits such as lack of stomach and hermaphroditism. Agastric fish are found throughout the teleost phylogeny, in quite diverse and unrelated lineages, indicating stomach loss has occurred independently multiple times in the course of evolution. By assembling the ballan wrasse genome and transcriptome we aimed to determine the genetic basis for its digestive system function and appetite regulation. Among other, this knowledge will aid the formulation of aquaculture diets that meet the nutritional needs of agastric species. RESULTS: Long and short read sequencing technologies were combined to generate a ballan wrasse genome of 805 Mbp. Analysis of the genome and transcriptome assemblies confirmed the absence of genes that code for proteins involved in gastric function. The gene coding for the appetite stimulating protein ghrelin was also absent in wrasse. Gene synteny mapping identified several appetite-controlling genes and their paralogs previously undescribed in fish. Transcriptome profiling along the length of the intestine found a declining expression gradient from the anterior to the posterior, and a distinct expression profile in the hind gut. CONCLUSIONS: We showed gene loss has occurred for all known genes related to stomach function in the ballan wrasse, while the remaining functions of the digestive tract appear intact. The results also show appetite control in ballan wrasse has undergone substantial changes. The loss of ghrelin suggests that other genes, such as motilin, may play a ghrelin like role. The wrasse genome offers novel insight in to the evolutionary traits of this large family. As the stomach plays a major role in protein digestion, the lack of genes related to stomach digestion in wrasse suggests it requires formulated diets with higher levels of readily digestible protein than those for gastric species. PMID- 29510661 TI - JAK/STAT3 regulated global gene expression dynamics during late-stage reprogramming process. AB - BACKGROUND: The generation of induced pluripotent stem cells (iPSCs) has underdefined mechanisms. In addition, leukemia inhibitory factor (LIF) activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is the master regulator for naive-state pluripotency achievement and maintenance. However, the regulatory process to attain naive pluripotent iPSCs is not well understood. RESULTS: We performed transcriptome analysis to dissect the genomic expression during mouse iPSC induction, with or without blocking the JAK/STAT3 activity. We describe JAK/STAT3 signaling-specific biological events such as gametogenesis, meiotic/mitotic cell cycle, and DNA repair, and JAK/STAT3 dependent expression of key transcription factors such as the naive pluripotency specific genes, developmental pluripotency associated (Dppa) family, along with histone modifiers and non-coding RNAs in reprogramming. We discover that JAK/STAT3 activity does not affect early phase mesenchymal to epithelial transition (MET) but is necessary for proper imprinting of the Dlk1-Dio3 region, an essential event for pluripotency achievement at late-reprogramming stage. This correlates with the JAK/STAT3-dependent stimulation of Dppa3 and Polycomb repressive complex 2 (PRC2) genes. We further demonstrate that JAK/STAT3 activity is essential for DNA demethylation of pluripotent loci including Oct4, Nanog, and the Dlk1-Dio3 regions. These findings correlate well with the previously identified STAT3 direct targets. We further propose a model of pluripotency achievement regulated by JAK/STAT3 signaling during the reprogramming process. CONCLUSIONS: Our study illustrates novel insights for JAK/STAT3 promoted pluripotency establishment, which are valuable for further improving the naive pluripotent iPSC generation across different species including humans. PMID- 29510662 TI - Successful use of whole genome amplified DNA from multiple source types for high density Illumina SNP microarrays. AB - BACKGROUND: The recommended genomic DNA input requirements for whole genome single nucleotide polymorphism microarrays can limit the scope of molecular epidemiological studies. We performed a large-scale evaluation of whole genome amplified DNA as input into high-density, whole-genome Illumina(r) Infinium(r) SNP microarray. RESULTS: Overall, 6622 DNA samples from 5970 individuals were obtained from three distinct biospecimen sources and genotyped using gDNA and/or wgaDNA inputs. When genotypes from the same individual were compared with standard, native gDNA input amount, we observed 99.94% mean concordance with wgaDNA input. CONCLUSIONS: Our results demonstrate that carefully conducted studies with wgaDNA inputs can yield high-quality genotyping results. These findings should enable investigators to consider expansion of ongoing studies using high-density SNP microarrays, currently challenged by small amounts of available DNA. PMID- 29510663 TI - Burden of severe RSV disease among immunocompromised children and adults: a 10 year retrospective study. AB - BACKGROUND: Respiratory syncytial virus (RSV) is associated with significant mortality rates amongst hematopoietic stem cell transplant (HSCT) recipients, with less known about other immunocompromised patients. METHODS: Ten-year retrospective cohort study of immunocompromised patients presenting with RSV disease documented at University Hospitals of Lausanne and Geneva. Severe RSV related outcomes referred to RSV documented respiratory conditions requiring hospital admission, presenting as lower respiratory tract infection (LRTI) or pneumonia. We used multivariable logistic regression to assess clinical and laboratory correlates of severe RSV disease. RESULTS: From 239 RSV-positive immunocompromised in and out-patients 175 were adults and 64 children of whom 111 (47.8%) presented with LRTI, which resulted in a 38% (89/239) admission rate to hospital. While immunocompromised children were more likely to be admitted to hospital compared to adults (75% vs 62.9%, p = 0.090), inpatients admitted to the intensive care unit (17/19) or those who died (11/11) were mainly adults. From multivariable analyses, adults with solid tumors (OR 5.2; 95% CI: 1.4-20.9 P = 0.015) or those requiring chronic immunosuppressive treatments mainly for rheumatologic conditions (OR 4.1; 95% CI: 1.1-16.0; P = 0.034) were significantly more likely to be admitted to hospital compared to hematopoietic stem cell (HSCT) recipients. Bacterial co-infection was significantly and consistently associated with viral LRTI and pneumonia. CONCLUSIONS: From our findings, RSV-related disease results in a significant burden among adults requiring chronic immunosuppressive treatments for rheumatological conditions and those with solid tumors. As such, systematic screening for respiratory viruses, should be extended to other immunocompromised populations than HSCT recipients. PMID- 29510664 TI - High seroprevalence of syphilis infection among pregnant women in Yiregalem hospital southern Ethiopia. AB - BACKGROUND: Despite availability of effective treatment and the implementation of focused antenatal care (ANC), still the prevalence of syphilis persists in Ethiopia. Yet, data is not found in southern Ethiopia. Therefore, this study was conducted to determine the seroprevalence and associated factors of syphilis among pregnant women in Yiregalem Hospital, Southern Ethiopia. METHODS: A cross sectional study was conducted among pregnant women from October 2015 to August 2016. Data on socio-demography and obstetric conditions of pregnant women were collected using a structured questionnaire. Serum samples were screened for syphilis using rapid plasma regain (RPR) test and those found seropositive were further confirmed by Treponema pallidum haemagglutination assay (TPHA) test following the manufacturer's instruction. HIV results were reviewed from records. The data were analyzed using SPSS version 20 software. RESULTS: Of 494 pregnant women, 204(41.3%) were first ANC visit attenders. Of these, 123(60.3%) were after the 12th gestational week. Sero-prevalence of syphilis and HIV was found to be 5.1% (25/494; 95 CI, 3.2-7.1%) and 10.3% (51/494; 95 CI, 7.7-13.2%), respectively. The overall prevalence of syphilis and HIV co-infection was 2.2% (11/494). Women with HIV infection were significantly more likely to be syphilis seropositive (AOR = 10.3, 95%CI, 4.213-25.185) than HIV negatives. CONCLUSIONS: High seroprevalence of syphilis particularly among HIV positive women and late first ANC visit attenders in the study area calls for further ramping up of current intervention measures. Like integration of syphilis testing and treatment to the already established HIV prevention program and creating awareness about early ANC visit and follow-up. PMID- 29510666 TI - Factors affecting time to sputum culture conversion and treatment outcome of patients with multidrug-resistant tuberculosis in China. AB - BACKGROUND: Few prospective cohort studies, none in China, have investigated the relationship between treatment outcomes of multidrug-resistant tuberculosis (MDR TB) patients and sputum culture conversion. Factors affecting the time of the culture conversion throughout the whole course of the treatment have rarely been investigated. METHODS: This study was performed in four cities in Jiangsu province, China. MDR-TB patients were consecutively enrolled between December 2011 and March 2014. Rates of sputum culture conversion were calculated and Cox proportional-hazards model was performed. Factors contributing to sputum culture conversion were investigated. RESULTS: In all, 139 MDR-TB patients with treatment outcomes were enrolled. Median time to culture conversion among those who converted was 91.5 days (interquartile range, 34.0-110.8 days). After multivariable analysis, smoking (HR = 0.44; 95% CI: 0.23-0.83), drinking (HR = 0.41; 95% CI: 0.21-0.81), ofloxacin resistance (HR = 0.43; 95% CI: 0.24-0.76) and sputum smear grade > 1 (HR = 0.51; 95% CI: 0.31-0.83) were less likely to have culture conversion. CONCLUSIONS: MDR-TB patients who smoke, drink, have ofloxacin resistance, or a high smear grade are less likely to respond to treatment and should be meticulously followed up. PMID- 29510665 TI - Characterization of the human RFX transcription factor family by regulatory and target gene analysis. AB - BACKGROUND: Evolutionarily conserved RFX transcription factors (TFs) regulate their target genes through a DNA sequence motif called the X-box. Thereby they regulate cellular specialization and terminal differentiation. Here, we provide a comprehensive analysis of all the eight human RFX genes (RFX1-8), their spatial and temporal expression profiles, potential upstream regulators and target genes. RESULTS: We extracted all known human RFX1-8 gene expression profiles from the FANTOM5 database derived from transcription start site (TSS) activity as captured by Cap Analysis of Gene Expression (CAGE) technology. RFX genes are broadly (RFX1 3, RFX5, RFX7) and specifically (RFX4, RFX6) expressed in different cell types, with high expression in four organ systems: immune system, gastrointestinal tract, reproductive system and nervous system. Tissue type specific expression profiles link defined RFX family members with the target gene batteries they regulate. We experimentally confirmed novel TSS locations and characterized the previously undescribed RFX8 to be lowly expressed. RFX tissue and cell type specificity arises mainly from differences in TSS architecture. RFX transcript isoforms lacking a DNA binding domain (DBD) open up new possibilities for combinatorial target gene regulation. Our results favor a new grouping of the RFX family based on protein domain composition. We uncovered and experimentally confirmed the TFs SP2 and ESR1 as upstream regulators of specific RFX genes. Using TF binding profiles from the JASPAR database, we determined relevant patterns of X-box motif positioning with respect to gene TSS locations of human RFX target genes. CONCLUSIONS: The wealth of data we provide will serve as the basis for precisely determining the roles RFX TFs play in human development and disease. PMID- 29510667 TI - Temporal and geographic variation in the systemic treatment of advanced prostate cancer. AB - BACKGROUND: Several systemic treatments have been shown to increase survival for patients with metastatic castration-resistant prostate cancer. This study sought to characterize variation in use of the six "focus drugs" (docetaxel, abiraterone, enzalutamide, sipuleucel-T, radium-223, and cabazitaxel) that have been approved by the Food and Drug Administration for the treatment of metastatic castration-resistant prostate cancer during the years 2010-2015. We hypothesized that the use of these treatments would vary over time and by region of the country. METHODS: We used Clinformatics DataMartTM Database (OptumInsight, Eden Prairie, MN), a de-identified claims database from a national insurance provider. Our sample included patients with prostate cancer who received any of the six drugs. We describe changes in usage patterns over time and geographic region of the United States via detailed descriptive statistics. We explore both patterns of first line therapy and sequence of treatments in our database. RESULTS: Our final analysis included 4275 patients with a mean age of 74 years. Docetaxel was the most commonly used first-line therapy in 2010 (97%), 2011 (66%), and 2012 (49%). Abiraterone was the most commonly used first-line therapy in 2013 (56%), 2014 (46%), and 2015 (34%). Approximately 14% of our study cohort received >=3 of the 6 drugs throughout their disease course. There was marked geographic variation in use of each of the drugs. CONCLUSION: Variation in treatment patterns were found with respect to both time and geographic location. Prescription rates of abiraterone outpaced docetaxel as the most commonly prescribed drug after 2013 when it became widely available. However, some regions of the country still lagged behind and prescribed less than would be expected. PMID- 29510668 TI - Building protein-protein interaction networks for Leishmania species through protein structural information. AB - BACKGROUND: Systematic analysis of a parasite interactome is a key approach to understand different biological processes. It makes possible to elucidate disease mechanisms, to predict protein functions and to select promising targets for drug development. Currently, several approaches for protein interaction prediction for non-model species incorporate only small fractions of the entire proteomes and their interactions. Based on this perspective, this study presents an integration of computational methodologies, protein network predictions and comparative analysis of the protozoan species Leishmania braziliensis and Leishmania infantum. These parasites cause Leishmaniasis, a worldwide distributed and neglected disease, with limited treatment options using currently available drugs. RESULTS: The predicted interactions were obtained from a meta-approach, applying rigid body docking tests and template-based docking on protein structures predicted by different comparative modeling techniques. In addition, we trained a machine-learning algorithm (Gradient Boosting) using docking information performed on a curated set of positive and negative protein interaction data. Our final model obtained an AUC = 0.88, with recall = 0.69, specificity = 0.88 and precision = 0.83. Using this approach, it was possible to confidently predict 681 protein structures and 6198 protein interactions for L. braziliensis, and 708 protein structures and 7391 protein interactions for L. infantum. The predicted networks were integrated to protein interaction data already available, analyzed using several topological features and used to classify proteins as essential for network stability. CONCLUSIONS: The present study allowed to demonstrate the importance of integrating different methodologies of interaction prediction to increase the coverage of the protein interaction of the studied protocols, besides it made available protein structures and interactions not previously reported. PMID- 29510669 TI - Clinical and epidemiological characteristics of cutaneous leishmaniasis in Sri Lanka. AB - BACKGROUND: Leishmaniasis, a vector borne tropical/subtropical disease caused by the protozoan Leishmania is transmitted to humans by sandfly vectors Phlebotomus and Lutzomyia. The principal form found in Sri Lanka is cutaneous leishmaniasis (CL) and is caused by Leishmania donovani. A rising trend in disease prevalence has been observed recently in Sri Lanka and the island is in fact the newest endemic focus in South Asia. Determining the prevalence of smear positivity among clinically suspected CL patients, identifying risk factors and specific clinical presentations of CL in order to implement preventive and early treatment strategies were the objectives of this study. METHODS: A sample of 509 clinically suspected cases of CL referred to the Department of Parasitology from all across Sri Lanka between 2005 and 2015 was selected consecutively. Diagnosis was confirmed by microscopic visualization of the Leishmania amastigote from the slit skin smear. A structured questionnaire was used to identify exposure related risk factors and a clinical examination was performed to identify lesion characteristics. RESULTS: Out of 509 clinical cases, 41.5% (n = 211) were smear positive. The study population ranged from ages 1 to 80 years (mean age = 34.76) and the most affected age group was 40-49. Of the smear positives, 58.85% were males. Majority (47.86%) were from the North Western region (Kurunegala) of the country and were exposed to scrub jungles. Sand fly exposure (p = 0.04) and positive contact history (p = 0.005) were significant risk factors for smear positivity. Erythema (p = 0.02), lack of pruritus (p = 0.02) and scaly appearance (p = 0.003) were significant lesion characteristics in smear positivity. Lesions were commonly found in the exposed areas and the commonest morphological type was papulo-nodular. CONCLUSIONS: An increasing trend in the spread of cutaneous leishmaniasis from endemic to non-endemic areas has become evident. Positive contact history and sandfly exposure were significant risk factors for smear positivity which may indicate the possibility of human reservoir hosts in infection transmission. Lack of pruritus, scaly appearance and erythema were highly significant lesion characteristics associated with Leishmania positive smears which can be used for the clinical diagnosis of CL. PMID- 29510671 TI - An unexpected, mild phenotype of glucocorticoid resistance associated with glucocorticoid receptor gene mutation case report and review of the literature. AB - BACKGROUND: Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue specific, or generalized partial insensitivity to glucocorticoids. CASE PRESENTATION: A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone. 24 h urinary cortisol was increased, but a normal midnight serum cortisol was detected suggesting a maintained circadian rhythm. Plasma dehydroepiandrosterone-sulfate and androstendione levels were also elevated. Repeated plasma ACTH measurements indicated slightly elevated or normal values. Bone mineral density was normal. All laboratory results confirmed the diagnosis of glucocorticoid resistance. Genetic counseling followed by Sanger sequencing of the coding region of the gene encoding human glucocorticoid receptor was performed and a missense mutation (Arg714Gln, R714Q) in a heterozygous form was detected. Following family screening, the same mutation was found in her clinically-healthy 35-year-old sister who had no fertility problems.This variant was not detected in more than 60 patients and controls tested either for glucocorticoid resistance or Cushing's syndrome in our Laboratory and it was absent in Exome Variant Server, HumanGene Mutation Database and ExAC databases. CONCLUSIONS: Our case fulfils the diagnostic criteria of glucocorticoid resistance, also named Chrousos syndrome. The glucocorticoid receptor gene mutation detected in our patient has been already reported in a 2-year-old child with hypoglycaemia, hypokalaemia, hypertension and premature puberty. These distinct phenotypes may suggest that other factors may modify the functional consequences of the R714Q variant of GR. PMID- 29510670 TI - Investigation of household contacts of pulmonary tuberculosis patients increases case detection in Mwanza City, Tanzania. AB - BACKGROUND: Tuberculosis (TB) contact tracing is a key strategy for containing TB and provides addition to the passive case finding approach. However, this practice has not been implemented in Tanzania, where there is unacceptably high treatment gap of 62.1% between cases estimated and cases detected. Therefore calls for more aggressive case finding for TB to close this gap. We aimed to determine the magnitude and predictors of bacteriologically-confirmed pulmonary TB among household contacts of bacteriologically-confirmed pulmonary TB index cases in the city of Mwanza, Tanzania. METHODS: This study was carried out from August to December 2016 in Mwanza city at the TB outpatient clinics of Tertiary Hospital of the Bugando Medical Centre, Sekou-Toure Regional Hospital, and Nyamagana District Hospital. Bacteriologically-confirmed TB index cases diagnosed between May and July 2016 were identified from the laboratory registers book. Contacts were traced by home visits by study TB nurses, and data were collected using a standardized TB screening questionnaire. To detect the bacterioriologically-confirmed pulmonary TB, two sputum samples per household contact were collected under supervision for all household contacts following standard operating procedures. Samples were transported to the Bugando Medical Centre TB laboratory for investigation for TB using fluorescent smear microscopy, GeneXpert MTB/RIF and Lowenstein-Jensen (LJ) culture. Logistic regression was used to determine predictors of bacteriologically-confirmed pulmonary TB among household contacts. RESULTS: During the study period, 456 household contacts from 93 TB index cases were identified. Among these 456 household contacts, 13 (2.9%) were GeneXpert MTB/RIF positive, 18 (3.9%) were MTB-culture positive and four (0.9%) were AFB-smear positive. Overall, 29 (6.4%) of contacts had bacteriologically-confirmed pulmonary TB. Predictors of bacteriologically confirmed pulmonary TB among household contacts were7being married (Odds ratio [OR], 3.3; 95% confidence interval [CI], 1.4-8.0; p = 0.012) and consuming less than three meals a day (OR, 3.7; 95% CI, 1.6-8.7; p = 0.009). CONCLUSIONS: Our data suggest that in Mwanza, Tanzania, seven in 100 contacts living in the same house with a TB patient develop bacteriologically-confirmed pulmonary TB. These results therefore underscore the need to implement routine TB contact tracing to control tuberculosis in high TB burden countries such as Tanzania. PMID- 29510672 TI - Quadruplex DNA in long terminal repeats in maize LTR retrotransposons inhibits the expression of a reporter gene in yeast. AB - BACKGROUND: Many studies have shown that guanine-rich DNA sequences form quadruplex structures (G4) in vitro but there is scarce evidence of guanine quadruplexes in vivo. The majority of potential quadruplex-forming sequences (PQS) are located in transposable elements (TEs), especially close to promoters within long terminal repeats of plant LTR retrotransposons. RESULTS: In order to test the potential effect of G4s on retrotransposon expression, we cloned the long terminal repeats of selected maize LTR retrotransposons upstream of the lacZ reporter gene and measured its transcription and translation in yeast. We found that G4s had an inhibitory effect on translation in vivo since "mutants" (where guanines were replaced by adenines in PQS) showed higher expression levels than wild-types. In parallel, we confirmed by circular dichroism measurements that the selected sequences can indeed adopt G4 conformation in vitro. Analysis of RNA-Seq of polyA RNA in maize seedlings grown in the presence of a G4-stabilizing ligand (NMM) showed both inhibitory as well as stimulatory effects on the transcription of LTR retrotransposons. CONCLUSIONS: Our results demonstrate that quadruplex DNA located within long terminal repeats of LTR retrotransposons can be formed in vivo and that it plays a regulatory role in the LTR retrotransposon life-cycle, thus also affecting genome dynamics. PMID- 29510673 TI - Analysis of low birth weight and its co-variants in Bangladesh based on a sub sample from nationally representative survey. AB - BACKGROUND: Low birth weight (LBW) remains a leading global cause of childhood morbidity and mortality. This study leverages a large national survey to determine current prevalence and socioeconomic, demographic and heath related factors associated with LBW in Bangladesh. METHODS: Data from the Multiple Indicator Cluster Survey (MICS) 2012-13 of Bangladesh were analyzed. A total of 2319 women for whom contemporaneous birth weight data was available and who had a live birth in the two years preceding the survey were sampled for this study. However, this analysis only was able to take advantage of 29% of the total sample with 71% missing birth weight for newborns. The indicator, LBW (< 2500 g) of infants, was examined as the outcome variable in association with different socioeconomic, demographic and health-related covariates. Mixed-effects logistic regression was performed to identify possible factors related to LBW. RESULTS: In the selected sub-sample, about 20% of infants were born with LBW, with lowest rates observed in Rajshahi (11%) and highest rates in Rangpur (28%). Education of mothers (adjusted odds ratio [AOR] 0.52, 95% confidence interval [CI] 0.39-0.68 for secondary or higher educated mother) and poor antenatal care (ANC) (AOR 1.40, 95% CI 1.04-1.90) were associated with LBW after adjusting for mother's age, parity and cluster effects. Mothers from wealthier families were less likely to give birth to an LBW infant. Further indicators that wealth continues to play a role in LBW were that place of delivery, ANC and delivery assistance by quality health workers were significantly associated with LBW. However there has been a notable fall in LBW prevalence in Bangladesh since the last comparable survey (prevalence 36%), and an evidence of possible elimination of rural/urban disparities. CONCLUSIONS: Low birth weight remains associated with key indicators not just of maternal poverty (notably adequate maternal education) but also markers of structural poverty in health care (notably quality ANC). Results based on this sub-sample indicate LBW is still a public health concern in Bangladesh and an integrated effort from all stakeholders should be continued and interventions based on the study findings should be devised to further reduce the risk of LBW. PMID- 29510674 TI - Evolutionary analysis of mitochondrially encoded proteins of toad-headed lizards, Phrynocephalus, along an altitudinal gradient. AB - BACKGROUND: Animals living at high altitude must adapt to environments with hypoxia and low temperatures, but relatively little is known about underlying genetic changes. Toad-headed lizards of the genus Phrynocephalus cover a broad altitudinal gradient of over 4000 m and are useful models for studies of such adaptive responses. In one of the first studies to have considered selection on mitochondrial protein-coding regions in an ectothermic group distributed over such a wide range of environments, we analysed nineteen complete mitochondrial genomes from all Chinese Phrynocephalus (including eight genomes sequenced for the first time). Initial analyses used site and branch-site model (program: PAML) approaches to examine nonsynonymous: synonymous substitution rates across the mtDNA tree. RESULTS: Ten positively selected sites were discovered, nine of which corresponded to subunits ND2, ND3, ND4, ND5, and ND6 within the respiratory chain enzyme mitochondrial Complex I (NADH Coenzyme Q oxidoreductase). Four of these sites showed evidence of general long-term selection across the group while the remainder showed evidence of episodic selection across different branches of the tree. Some of these branches corresponded to increases in altitude and/or latitude. Analyses of physicochemical changes in protein structures revealed that residue changes at sites that were under selection corresponded to major functional differences. Analyses of coevolution point to coevolution of selected sites within the ND4 subunit, with key sites associated with proton translocation across the mitochondrial membrane. CONCLUSIONS: Our results identify mitochondrial Complex I as a target for environment-mediated selection in this group of lizards, a complex that frequently appears to be under selection in other organisms. This makes these lizards good candidates for more detailed future studies of molecular evolution. PMID- 29510675 TI - Spatial variation in the use of reproductive health services over time: a decomposition analysis. AB - BACKGROUND: The paper argues that several Sub-Saharan African countries have recorded marked improvements in the use of reproductive health services. However, the literature has hardly highlighted such progress and the factors responsible for them. The current study uses Ghana as a case to examine progress in the consumption of reproductive health services over the last two decades and the factors responsible for such progress. METHODS: The study uses two rounds (1998 and 2014) of Demographic and Health Survey data from Ghana. Standard frequencies, a logit model and decomposition of the coefficients of the logit model (i.e. Oaxaca-type decomposition) was employed to examine changes in the use of reproductive health services (4+ antenatal visits and skilled attendance at birth) at national and sub-national levels (i.e the four ecological zones of Ghana) between 1998 and 2014 as well as factors explaining observed spatial changes between the two periods. RESULTS: Descriptive results suggest that the highest level of improvement occurred in resource-poor zones (i.e. northern belt followed by the southern belt) compared to the middle belt and Greater Accra, where access to resources and infrastructure is relatively better. Results from Oaxaca-type decomposition also suggest that women and partner's education, household wealth and availability and accessibility to health facilities are the key factors explaining spatial variation in reproductive health service consumption over the two periods. Most importantly, the marginal efficiency of investment in women and partner's education and access to health services were highest in the two resource poor zones. CONCLUSION: There is the need to target resource poor settings with existing or new pro-poor reproductive health interventions. Specifically, the northern and southern zones where the key drivers of education and availability of health facilities are the lowest, will be key to further improvements in the consumption of reproductive health services in Ghana. PMID- 29510676 TI - Signaling protein signature predicts clinical outcome of non-small-cell lung cancer. AB - BACKGROUND: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application. METHODS: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort. RESULTS: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P < 0.001) and SCC patients (27 months vs. not reached, HR 9.97; P < 0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018). CONCLUSIONS: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy. PMID- 29510677 TI - Summarizing performance for genome scale measurement of miRNA: reference samples and metrics. AB - BACKGROUND: The potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, designed with between-sample differences in the relative abundance of miRNAs, as process controls. RESULTS: Three pure total human RNA samples (brain, liver, and placenta) and two different mixtures of these components were evaluated as measurement assurance control samples on multiple measurement systems at multiple sites and over multiple rounds. In silico modeling of mixtures provided benchmark values for comparison with physical mixtures. Biomarker development laboratories using next-generation sequencing (NGS) or genome-scale hybridization assays participated in the study and returned data from the samples using their routine workflows. Multiplexed and single assay reverse-transcription PCR (RT-PCR) was used to confirm in silico predicted sample differences. Data visualizations and summary metrics for genome scale miRNA profiling assessment were developed using this dataset, and a range of performance was observed. These metrics have been incorporated into an online data analysis pipeline and provide a convenient dashboard view of results from experiments following the described design. The website also serves as a repository for the accumulation of performance values providing new participants in the project an opportunity to learn what may be achievable with similar measurement processes. CONCLUSIONS: The set of reference samples used in this study provides benchmark values suitable for assessing genome-scale miRNA profiling processes. Incorporation of these metrics into an online resource allows laboratories to periodically evaluate their performance and assess any changes introduced into their measurement process. PMID- 29510678 TI - Genetic and clinical characteristics of Chinese children with Glucokinase maturity-onset diabetes of the young (GCK-MODY). AB - BACKGROUND: There is scarcity of information on the clinical features and genetics of glucokinase-maturity-onset diabetes of the young (GCK-MODY) in China. The aim of the study was to investigate the clinical and molecular characteristics of Chinese children with GCK-MODY. METHODS: Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China. Clinical data were obtained from medical records. Blood was collected from the patients and their parents for glucokinase (GCK) gene analysis. Parents without diabetes were tested for fasting glucose and HbA1c. Clinical information and blood for GCK gene analysis were obtained from grandparents with diabetes. GCK gene mutational analysis was performed by polymerase chain reaction and direct sequencing. Patients without a GCK gene mutation were screened by targeted next-generation sequencing (NGS) technology for other MODY genes. RESULTS: Nine children tested positive for GCK gene mutations while two were negative. The nine GCK-MODY patients were from unrelated families, aged 1 month to 9 years and 1 month at first detection of hyperglycaemia. Fasting glucose was elevated (6.1-8.5 mmol/L), HbA1c 5.2-6.7% (33.3-49.7 mmol/mol), both remained stable on follow-up over 9 months to 5 years. Five detected mutations had been previously reported: p.Val182Met, c.679 + 1G > A, p.Gly295Ser, p.Arg191Gln and p.Met41Thr. Four mutations were novel: c.483 + 2 T > A, p.Ser151del, p.Met57GlyfsX29 and p.Val374_Ala377del. No mutations were identified in the other two patients, who were also tested by NGS. CONCLUSIONS: GCK gene mutations are detected in Chinese children and their family members with typical clinical features of GCK-MODY. Four novel mutations are detected. PMID- 29510679 TI - Case report: lipid inclusion in glomerular endothelial and mesangial cells in a patient after contrast medium injection. AB - BACKGROUND: It is well-recognized that injection of iodinated radiographic contrast media (CM) sometimes causes acute renal injury via multiple mechanisms, such as vasoconstriction, toxicity on glomerular endothelium and tubular epithelium and so forth. CASE PRESENTATION: A 51-year-old man developed acute renal injury with proteinuria after CM administration. To our surprise, in his renal biopsy sample the myelin figure like structure was observed in glomerular endothelium and mesangial cells by transmission electron microscopy. However the patient didn't has any clinic clues of Fabry disease and other lysosomal storage disorders. Moreover in vitro cultured glomerular endothelial and mesangial cells we found CM triggers lipid aggregation along with the increased CD36 and decreased ABCA1 abundance. Thus this patient was administrated statin to correct the aberrant lipid trafficking, 2 months later at his next visit we found his renal function partially recovered with reduced proteinuria. CONCLUSIONS: Besides the well-known underlying mechanisms, CM may cause renal impairment by triggering the dysregulated transportation of lipid. Furthermore statin is suggested to be a very promising medicine to decrease side effects of CM. PMID- 29510680 TI - A program to respond to otitis media in remote Australian Aboriginal communities: a qualitative investigation of parent perspectives. AB - BACKGROUND: Indigenous infants and children in Australia, especially in remote communities, experience early and chronic otitis media (OM) which is difficult to treat and has lifelong impacts in health and education. The LiTTLe Program (Learning to Talk, Talking to Learn) aimed to increase infants' access to spoken language input, teach parents to manage health and hearing problems, and support children's school readiness. This paper aimed to explore caregivers' views about this inclusive, parent-implemented early childhood program for 0-3 years in an Aboriginal community health context. METHODS: Data from in-depth, semi-structured interviews with 9 caregivers of 12 children who had participated in the program from one remote Aboriginal community in the Northern Territory are presented. Data were analysed thematically. Caregivers provided overall views on the program. In addition, three key areas of focus in the program are also presented here: speech and language, hearing health, and school readiness. RESULTS: Caregivers were positive about the interactive speech and language strategies in the program, except for some strategies which some parents found alien or difficult: such as talking slowly, following along with the child's topic, using parallel talk, or baby talk. Children's hearing was considered by caregivers to be important for understanding people, enjoying music, and detecting environmental sounds including signs of danger. Caregivers provided perspectives on the utility of sign language and its benefits for communicating with infants and young children with hearing loss, and the difficulty of getting young community children to wear a conventional hearing aid. Caregivers were strongly of the opinion that the program had helped prepare children for school through familiarising their child with early literacy activities and resources, as well as school routines. But caregivers differed as to whether they thought the program should have been located at the school itself. CONCLUSIONS: The caregivers generally reported positive views about the LiTTLe Program, and also drew attention to areas for improvement. The perspectives gathered may serve to guide other cross-sector collaborations across health and education to respond to OM among children at risk for OM-related disability in speech and language development. PMID- 29510681 TI - Association of depression and anxiety with cardiovascular co-morbidity in a primary care population in Latvia: a cross-sectional study. AB - BACKGROUND: Cardiovascular (CV) diseases (CVDs) are the leading cause of mortality worldwide. Globally, there is a growing interest in understanding and addressing modifiable psychosocial risk factors, particularly depression and anxiety, to prevent CVDs and to reduce morbidity and mortality. Despite the high premature mortality rate from CVDs in Latvia, this is the first Latvian study to examine the association of depression and anxiety with CVD morbidity in a primary care population. METHODS: This cross-sectional study was carried out in 2015 within the framework of the National Research Program BIOMEDICINE at 24 primary care facilities throughout Latvia. Consecutive adult patients during a one-week time period at each facility were invited to join the study. Assessments onsite included a 9-item Patient Health Questionnaire (PHQ-9) and a 7-item Generalized Anxiety Disorder scale (GAD-7) followed by a socio-demographic questionnaire and measurements of height, weight, waist circumference, blood pressure, and total cholesterol. The diagnostic Mini International Neuropsychiatric Interview (MINI) was conducted over the telephone within 2 weeks after the visit to the general practitioner. A multivariate model was developed using binary logistic regression. RESULTS: From the 1565 subjects (31.2% male), CVD was detected in 17.1%. Depression screening was positive (PHQ-9 >= 10) for 14.7%, and anxiety screening was positive (GAD-7 >= 10) for 10.1% of the study subjects. According to the MINI, 10.3% had current and 28.1% had lifetime depressive episode, and 16.1% had an anxiety disorder. Depression, not anxiety, was statistically significantly related to CVDs with an odds ratio (OR) of 1.52 (p = 0.04) for current depressive symptoms (PHQ-9 >= 10) and 2.08 (p = 0.002) for lifetime depressive episode (MINI). CONCLUSIONS: Current depressive symptoms (PHQ-9 >= 10) and a lifetime depressive episode (according to the MINI) were significantly associated with increased risk of CV morbidity. Therefore, CV patients should be screened and treated for depression to potentially improve the prognosis of CVDs. Enhanced training and integration of mental health treatment in Latvian primary care settings may improve clinical outcomes. PMID- 29510682 TI - Demand for family planning satisfied with modern methods among sexually active women in low- and middle-income countries: who is lagging behind? AB - BACKGROUND: Family planning is key for reducing unintended pregnancies and their health consequences and is also associated with improvements in economic outcomes. Our objective was to identify groups of sexually active women with extremely low demand for family planning satisfied with modern methods (mDFPS) in low- and middle-income countries, at national and subnational levels to inform the improvement and expansion of programmatic efforts to narrow the gaps in mDFPS coverage. METHODS: Analyses were based on Demographic and Health Survey and Multiple Indicator Cluster Survey data. The most recent surveys carried out since 2000 in 77 countries were included in the analysis. We estimated mDFPS among women aged 15-49 years. Subgroups with low coverage (mDFPS below 20%) were identified according to marital status, wealth, age, education, literacy, area of residence (urban or rural), geographic region and religion. RESULTS: Overall, only 52.9% of the women with a demand for family planning were using a modern contraceptive method, but coverage varied greatly. West & Central Africa showed the lowest coverage (32.9% mean mDFPS), whereas South Asia and Latin America & the Caribbean had the highest coverage (approximately 70% mean mDFPS). Some countries showed high reliance on traditional contraceptive methods, markedly those from Central and Eastern Europe, and the Commonwealth of Independent States (CEE & CIS). Albania, Azerbaijan, Benin, Chad and Congo Democratic Republic presented low mDFPS coverage (< 20%). The other countries had mDFPS above 20% at country-level, yet in many of these countries mDFPS coverage was low among women in the poorest wealth quintiles, in the youngest age groups, with little education and living in rural areas. Coverage according to marital status varied greatly: in Asia & Pacific and Latin America & the Caribbean mDFPS was higher among married women; the opposite was found in West & Central Africa and CEE & CIS countries. CONCLUSIONS: Almost half of the women in need were not using an effective family planning method. Subgroups requiring special attention include women who are poor, uneducated/illiterate, young, and living in rural areas. Efforts to increase mDFPS must address not only the supply side but also tackle the need to change social norms that might inhibit uptake of contraception. PMID- 29510683 TI - Options for sustaining solar-powered mosquito trapping systems on Rusinga Island, Western Kenya: a social dilemma analysis. AB - BACKGROUND: In 2012, a donor-supported proof of principle study was launched to eliminate malaria from Rusinga Island, western Kenya, using solar-powered mosquito trapping systems (SMoTS). SMoTS, which also provided power for room lighting and charging mobile telephones, were installed in houses. In view of the involvement of individual and collective benefits, as well as individual and collective maintenance solutions, this study qualitatively examined preferences of some project stakeholders towards SMoTS sustainability components to see if and how they related to social dilemma factors. METHODS: The data were collected through participant observation, semi-structured interviews and focus group discussions. RESULTS: The results show that respondents largely preferred individual solutions to various aspects of maintenance. Selective collective solutions such as table banking groups were considered positively for mobilising financial resources for maintenance, but respondents were hardly willing to contribute financially to a collective entity. Few people saw a meaningful role for a collective governing body; people preferred to rely on individual household responsibility and private service delivery for repairs and stocking spare parts. An overriding concern was that people lacked trust in other community members, leaders and/or technicians who would be employed by a governing body. Respondents also had little confidence that a governing body or saving group could effectively impose sanctions to misappropriation of funds, poor leadership, defecting group members or technicians that might abuse a salaried position. CONCLUSION: There seemed to be linkages between preferences towards organising various components of SMoTS sustainability and known hindrances to addressing social dilemmas. This posed considerable challenges to organising the sustainability of this innovative malaria control strategy. TRIAL REGISTRATION: NTR3496 . PMID- 29510684 TI - Community perception regarding childhood vaccinations and its implications for effectiveness: a qualitative study in rural Burkina Faso. AB - BACKGROUND: Vaccination has contributed to major reductions in global morbidity and mortality, but there remain significant coverage gaps. Better knowledge on the interplay between population and health systems regarding provision of vaccination information and regarding health staff organization during the immunization sessions appears to be important for improvements of vaccination effectiveness. METHODS: The study was conducted in the Nouna Health and Demographic Surveillance System (HDSS) area, rural Burkina Faso, from March to April 2014. We employed a combination of in-depth interviews (n = 29) and focus group discussions (n = 4) including children's mothers, health workers, godmothers, community health workers and traditional healers. A thematic analysis was performed. All material was transcribed, translated and analyzed using the software ATLAS.ti4.2. RESULTS: There was better social mobilization in the rural areas as compared to the urban area. Most mothers know the Expanded Program of Immunization (EPI) target diseases, and the importance to immunize their children. However, the great majority of informants reported that mothers don't know the vaccination schedule. There is awareness that some children are incompletely vaccinated. Mentioned reasons for that were migration, mothers being busy with their work, the practice of not opening vaccine vials unless a critical number of children are present, poor interaction between women and health workers during immunization sessions, potential adverse events associated with vaccination, geographic inaccessibility during rainy season, and lack of information. CONCLUSIONS: Well organized vaccination programs are a key factor to improve child health and there is a clear need to consider community perceptions on program performance. In Burkina Faso, a number of factors have been identified which need attention by the EPI managers for further improvement of program effectiveness. PMID- 29510685 TI - Case report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy. AB - BACKGROUND: After orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), recurrent HCC mostly develops within 2 years. All cases of de novo HCC described so far occurred later than 2 years after OLT. Prevention of post-transplantation HCC has usually been tried to achieve by curing or controlling recurrent liver disease. This has been rationale for treatment with interferon (IFN)/ribavirin of HCV-recurrence in patients after OLT, transplanted for advanced HCV-induced liver disease and/or HCC. The availability of new and more efficient drugs has improved chances also for previously difficult-to-treat HCV-positive patients. CASE PRESENTATION: A 75 year-old male patient who had undergone OLT for decompensated HCV-cirrhosis in 2009, and bilio-digestive surgery in 2011 under tracrolimus (0.5 mg/day) and prednisone (5 mg/day) immunosuppressive therapy, started to receive antiviral treatment for recurrent HCV-infection of graft with 200 mg/day ribavirin in combination with ledipasvir and sofosbuvir by the end of October 2015. Because of multiple side effects (anemia, asthenia, infections, and reduction of kidney functions - palliated by treatment with erythropoietin), treatment was stopped after 16 weeks. At the third control, a minimal increase in alpha-fetoprotein (AFP) serum level to 10 MUg/L was measured 8 months after therapy, whereas both liver sonography and serum transaminases were normal. The patient's general condition; however, remained poor, and a magnetic resonance imaging (MRI) of abdomen was performed 2 months later. A nodule of 3 cm in diameter with a pseudocapsule was found centrally in the liver. The patient had to be hospitalized for recurrent infections of the lung, overt ascites and peritonitis. Rapid tumor growth (10 cm) was detected during last stay in hospital (April 2017), concomitant with a rise of AFP-serum levels to 91 MUg/L. The family decided to take the patient home, and best supportive care was provided by a general practitioner, local nurses and the patient's dedicated wife until his death. CONCLUSION: Before treating OLT patients with HCV graft reinfection one should not only consider possible advantages of newly effective antiviral-therapies, but also life expectancy and possible side effects (difficult to manage at an outpatient service basis), including severe disadvantages such as the development of HCC. PMID- 29510686 TI - Fundus changes in type III membranoproliferative glomerulonephritis: a case report. AB - BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is characterized by mesangial cell proliferation and is classified into types I, II and III based on structural changes in the glomerular capillary walls. The drusen-like deposits of MPGN type II have been studied, but the fundus changes in MPGN type III have yet to be clarified. We report a case of MPGN type III with multiple deposits in the retinal pigment epithelium (RPE). CASE PRESENTATION: A 40-year-old Japanese woman with MPGN type III developed numerous yellow-white patches in the central macula of both eyes. Optical coherence tomography (OCT) showed deposits between the RPE and Bruch's membrane. Fluorescein angiography showed choroidal neovascularization (CNV) and OCT confirmed it as type 1 (sub RPE) CNV with fibrin tissue and subretinal fluid in the right eye. After 12 months, the CNV and subretinal fluid resolved spontaneously but the RPE deposits remained in both eyes. Her final visual acuity was 20/20 in the right eye and 20/16 in the left eye. CONCLUSION: We report a case of MPGN type III with multiple deposits in the RPE and CNV, suggesting that various fundus changes occur in MPGN type III and careful fundus follow-up is necessary to prevent vision loss. PMID- 29510687 TI - Bacterial risk factors for treatment failure and relapse among patients with isoniazid resistant tuberculosis. AB - BACKGROUND: Drug resistant tuberculosis (TB) is increasing in prevalence worldwide. Treatment failure and relapse is known to be high for patients with isoniazid resistant TB treated with standard first line regimens. However, risk factors for unfavourable outcomes and the optimal treatment regimen for isoniazid resistant TB are unknown. This cohort study was conducted when Vietnam used the eight month first line treatment regimen and examined risk factors for failure/relapse among patients with isoniazid resistant TB. METHODS: Between December 2008 and June 2011 2090 consecutive HIV-negative adults (>=18 years of age) with new smear positive pulmonary TB presenting at participating district TB units in Ho Chi Minh City were recruited. Participants with isoniazid resistant TB identified by Microscopic Observation Drug Susceptibility (MODS) had extended follow-up for 2 years with mycobacterial culture to test for relapse. MGIT drug susceptibility testing confirmed 239 participants with isoniazid resistant, rifampicin susceptible TB. Bacterial and demographic factors were analysed for association with treatment failure and relapse. RESULTS: Using only routine programmatic sputum smear microscopy for assessment, (months 2, 5 and 8) 30/239 (12.6%) had an unfavourable outcome by WHO criteria. Thirty-nine patients were additionally detected with unfavourable outcomes during 2 year follow up, giving a total of 69/239 (28.9%) of isoniazid (INH) resistant cases with unfavourable outcome by 2 years of follow-up. Beijing lineage was the only factor significantly associated with unfavourable outcome among INH-resistant TB cases during 2 years of follow-up. (adjusted OR = 3.16 [1.54-6.47], P = 0.002). CONCLUSION: One third of isoniazid resistant TB cases suffered failure/relapse within 2 years under the old eight month regimen. Over half of these cases were not identified by standard WHO recommended treatment monitoring. Intensified research on early identification and optimal regimens for isoniazid resistant TB is needed. Infection with Beijing genotype of TB is a significant risk factor for bacterial persistence on treatment resulting in failure/relapse within 2 years. The underlying mechanism of increased tolerance for standard drug regimens in Beijing genotype strains remains unknown. PMID- 29510688 TI - TIPE3 differentially modulates proliferation and migration of human non-small cell lung cancer cells via distinct subcellular location. AB - BACKGROUND: TIPE3 (TNFAIP8L3), a transfer protein for lipid second messengers, is upregulated in human lung cancer tissues. The most popular lung cancer is non small cell lung cancer (NSCLC) with high incidences and low survival rates, while the roles of TIPE3 in NSCLC remain largely unknown. METHODS: TIPE3 expression was examined in tissue chips from patients with NSCLC using immunohistochemistry; the correlation of plasma membrane expression of TIPE3 with T stage of NSCLC was analyzed. After endogenous TIPE3 was silenced via siRNA, or TIPE3 with N or C terminal flag was overexpressed via transient or stable transfection, human NSCLC cells were assayed for the proliferation and migration, respectively. NSCLC cells, in which TIPE3 with C-terminal flag was stably transfected, were inoculated into mice to establish xenograft tumors, the tumor growth and the expression of TIPE3 in tumor tissues were examined. RESULTS: TIPE3 was broadly expressed in lung tissues of patients with NSCLC. The plasma membrane expression of TIPE3 was positively correlated with the T stage of NSCLC. Knockdown of endogenous TIPE3, which was predominantly expressed in the plasma membrane, inhibited the proliferation and migration of NSCLC cells. While transient overexpression of TIPE3 with N-terminal flag, which was mostly trapped in the cytoplasm, inhibited the growth and migration of NSCLC cells accompanied by inactivation of AKT and ERK. In contrast, stable overexpression of TIPE3 with C terminal flag, which could be localized in the plasma membrane, markedly promoted the growth and migration of NSCLC cells through activation of AKT and ERK. Notably, in xenograft tumor models established with NSCLC cells, stable overexpression of TIPE3 with C-terminal flag in NSCLC cells significantly promoted the tumor growth and enhanced the expression and plasma membrane localization of TIPE3 in tumor tissues. CONCLUSION: This study demonstrates that human TIPE3 promotes the proliferation and migration of NSCLC cells depending on its localization on plasma membrane, whereas cytoplasmic TIPE3 may exert a negative function. Thus, manipulating the subcellular location of TIPE3 can be a promising strategy for NSCLC therapy. PMID- 29510689 TI - Comparison of discriminative motif optimization using matrix and DNA shape-based models. AB - BACKGROUND: Transcription factor (TF) binding site specificity is commonly represented by some form of matrix model in which the positions in the binding site are assumed to contribute independently to the site's activity. The independence assumption is known to be an approximation, often a good one but sometimes poor. Alternative approaches have been developed that use k-mers (DNA "words" of length k) to account for the non-independence, and more recently DNA structural parameters have been incorporated into the models. ChIP-seq data are often used to assess the discriminatory power of motifs and to compare different models. However, to measure the improvement due to using more complex models, one must compare to optimized matrix models. RESULTS: We describe a program "Discriminative Additive Model Optimization" (DAMO) that uses positive and negative examples, as in ChIP-seq data, and finds the additive position weight matrix (PWM) that maximizes the Area Under the Receiver Operating Characteristic Curve (AUROC). We compare to a recent study where structural parameters, serving as features in a gradient boosting classifier algorithm, are shown to improve the AUROC over JASPAR position frequency matrices (PFMs). In agreement with the previous results, we find that adding structural parameters gives the largest improvement, but most of the gain can be obtained by an optimized PWM and nearly all of the gain can be obtained with a di-nucleotide extension to the PWM. CONCLUSION: To appropriately compare different models for TF bind sites, optimized models must be used. PWMs and their extensions are good representations of binding specificity for most TFs, and more complex models, including the incorporation of DNA shape features and gradient boosting classifiers, provide only moderate improvements for a few TFs. PMID- 29510690 TI - Mannitol reduces nephron loss after warm renal ischemia in a porcine model. AB - BACKGROUND: Mannitol has been employed to ameliorate renal warm ischemia damage during partial nephrectomy, however, there is limited scientific evidence to support the use of mannitol during partial nephrectomy. The objective of the present study was to investigate the glomerular number after renal warm ischemia, with and without the use of mannitol in a Pig Model. METHODS: Twenty-four male pigs were assigned into three groups. Eight animals were allocated to the sham group that was subjected to laparoscopic dissection of the left renal hilum, without renal ischemia. Eight animals were allocated to the ischemia group that had the left renal hilum clamped for 30 min through laparoscopic access. Eight animals received mannitol (250 mg/kg) before the occlusion of renal hilum for 30 min. The kidneys were collected after the euthanasia of the pigs 21 days post surgery. The right kidney was utilized as a self-control for each animal. Serum creatinine, urea levels, the weight and volume of the kidneys were measured. Glomerular volumetric density, volume-weighted glomerular volume, and cortical volume were quantified through stereological methods and employed to determine the number of nephrons per kidney. Student's t test and ANOVA were used for statistical analysis. RESULTS: In the ischemia group, the left kidney recorded a reduction of 24.6% (290, 000 glomeruli) in the number of glomeruli in comparison to the right kidney. Kidneys subjected to ischemia also displayed decreased weight and volume in comparison to the sham and mannitol groups. No difference was observed between the left and right kidneys from the sham and mannitol groups. Further, no distinction in serum creatinine and urea among the groups was observed. CONCLUSION: The use of mannitol significantly reduces nephron loss during warm ischemia in pigs. PMID- 29510691 TI - A preliminary study evaluating cardiac output measurement using Pressure Recording Analytical Method (PRAM) in anaesthetized dogs. AB - BACKGROUND: Haemodynamic variations normally occur in anaesthetized animals, in relation to the animal status, administered drugs, sympathetic and parasympathetic tone, fluid therapy and surgical stimulus. The possibility to measure some cardiovascular parameters, such as cardiac output (CO), during anaesthesia would be beneficial for both the anaesthesia management and its outcome. New techniques for the monitoring of CO are aimed at finding methods which are non invasive, accurate and with good trending ability, which can be used in a clinical setting. The aim of this study was to compare the Pressure Recording Analytical Method (PRAM) with the pulmonary artery thermodilution (TD) for the measurement of cardiac output in 6 anaesthetized critically ill dogs. RESULTS: Fifty-four pairs of CO measurements were obtained with a median (range) of 3.33 L/min (0.81-7.21) for PRAM-CO and 3.48 L/min (1.41-6.56) for TD-CO. The Bland-Altman analysis showed a mean bias of 0.17 L/min with limits of agreement (LoA) of - 0.46 to 0.81 L/min. The percentage error resulted 18.2%. The 4 quadrant plot analysis showed an acceptable concordance (93%) between the 2 methods. The polar plot showed a good trending ability with the mean angular bias of 3.9 degrees and radial LoA +/- 12.1 degrees . CONCLUSIONS: The PRAM resulted in good precision, acceptable concordance and good trending ability for the measure of CO in the anaesthetized dog, representing a promising alternative to thermodilution for the measurement of CO. Among all the pulse contour methods available on the market it is the only one that does not require any calibration or adjustment of the measurement. Further studies are required to verify the ability of this method to accurately measure cardiac output even during unstable hemodynamic conditions. PMID- 29510693 TI - Biomechanical efficacy of AP, PA lag screws and posterior plating for fixation of posterior malleolar fractures: a three dimensional finite element study. AB - BACKGROUND: Clinically there are different fixation methods used for fixation of the posterior malleolar fractures (PMF), but the best treatment modality is still not clear. Few studies have concentrated on this issue, least of all using a biomechanical comparison. The purpose of this study was to carry out a computational comparative biomechanics of three different commonly used fixation constructs for the fixation of PMF by finite element analysis (FEA). METHODS: Computed tomography (CT) images were used to reconstruct three dimensional (3D) model of the tibia. Computer aided design (CAD) software was used to design 3D models of PMF. Finally, 3D models of PMF fixed with two antero-posterior (AP) lag screws, two postero-anterior (PA) lag screws and posterior plate were simulated through computational processing. Simulated loads of 500 N, 1000 N and 1500 N were applied to the PMF and proximal ends of the models were fixed in all degrees of freedom. Output results representing the model von Mises stress, relative fracture micro-motion and vertical displacement of the fracture fragment were analyzed. RESULTS: The mean vertical displacement value in the posterior plate group (0.52 mm) was lower than AP (0.68 mm) and PA (0.69 mm) lag groups. Statistically significant low amount of the relative micro-motion (P < 0.05) was observed in the posterior plate group. CONCLUSIONS: It was concluded that the posterior plate is biomechanically the most stable fixation method for fixation of PMF. PMID- 29510694 TI - Assessment of the alcohol consumption among outdoor bar drinkers in Nigeria by qualitative methods. AB - BACKGROUND: There are indications that drinking in outdoor bars, such as at motor parks, by the roadsides or street corners have become popular in Nigeria. METHOD: Three sets of qualitative assessments were carried out from three outdoor bars, randomly selected from 22 of such in Ibadan, Nigeria. The main sources of data were by direct observation and focus group discussion (FGD), conducted by a non probabilistic sample of outdoor bar drinkers, alcohol vendors and from community members. The qualitative assessments were recorded, followed by a thematic analysis of the contents of the qualitative assessments. RESULTS: Widespread use of alcohol was reported. Patrons of outdoor bars reported that their context of drinking was pleasurable to them. Use of local beverages usually called 'sepe' is increasing. The majority of them do not have adequate health information about the harmful consequences of alcohol. Alcohol and other substances of abuse were openly displayed, sold and consumed at the study sites. There were poor law provision and enforcement of laws prohibiting open display of alcohol and other substances. CONCLUSION: A high proportion of social drinkers in outdoor bars require intervention for their drinking behaviour. This is important because they have little or no information about the health hazards associated with excessive drinking. Presentation of these findings should contribute to increased awareness and improved response from the policy makers. PMID- 29510695 TI - CD133 expression in cancer cells predicts poor prognosis of non-mucin producing intrahepatic cholangiocarcinoma. AB - BACKGROUND: CD133 is a marker of stem cells as well cancer stem cells. This study investigated the association between CD133 expression in cancer cells and the clinical outcome of non-mucin producing intrahepatic cholangiocarcinoma (ICC). METHODS: Fifty-seven non-mucin producing ICC patients were enrolled in this study. Immunohistochemistry (IHC) and immunofluorescence staining for CD133 as well as other cancer-associated proteins, including cytokeratin 19, TGF-beta1, p Smad2 and epithelial-mesenchymal transition (EMT) markers S100A4, E-Cadherin and Vimentin were analyzed. RESULTS: IHC staining showed that tumor cells in 52.6% of patients expressed CD133. The CD133+ patients had significantly higher metastasis rate than those without CD133+ tumor cells (36.7% vs. 10.1%, p = 0.03). The CD133+ patients had shorter overall and disease-free survival time as compared to the CD133- patients. Furthermore, 90.9% of CD133+ patients developed cancer recurrence, as compared to 64.3% of CD133- patients (p = 0.02). As compared to CD133- patients, tumor cells in CD133+ patients demonstrated high levels of TGF beta/p-Smad2 as well as EMT-like alteration, characterized by loss of E-Cadherin and expression of Vimentin and S100A4. CONCLUSIONS: CD133 expression in ICC tumor cells indicates poor prognosis of the disease and might be associated with TGF beta related EMT alterations. PMID- 29510696 TI - Disparities in untreated caries among children and adults in the U.S., 2011-2014. AB - BACKGROUND: The Affordable Care Act of 2010 increased dental coverage for children in the United States, (U.S.) but not for adults. Few studies in current scholarship make use of up-to-date, nationally representative data to examine oral health disparities in the U.S. POPULATION: The purpose of this study is to use nationally representative data to determine the prevalence of untreated caries among children and adults of different socioeconomic and racial/ethnic groups and to examine the factors associated with untreated caries among children and adults. METHODS: This study used the 2011-2014 National Health and Nutrition Examination Survey (NHANES) demographic, oral health questionnaire, and oral health dentition examination data (n = 7008 for children; n = 9673 for adults). Participants that had a standardized oral health examination and at least one natural primary or permanent tooth considering 28 tooth spaces were included in this study. Our main outcome measure was untreated coronal caries defined as decay on the crown or enamel surface of a tooth that had not been treated or filled. Population estimates were calculated to determine the prevalence of untreated caries among children and adults in the United States. Frequencies and Pearson's chi-square tests were used to compare those with and without untreated caries. Multivariate logistic regression models were used to evaluate the factors associated with untreated caries. We conducted analyses among children and adults separately. RESULTS: From 2011 to 2014, 12.4 million children and 57.6 million adults in the United States had untreated caries. Age, family income level, recent dental visit, and financial and non-financial barriers were significantly associated with untreated caries in both children and adults. Race/ethnicity, gender and education level were also significantly associated with untreated caries among adults. The odds of untreated caries associated with financial barriers were 2.06 for children and 2.84 for adults while the odds of untreated caries associated with non-financial barriers were 2.86 for children and 1.67 for adults. CONCLUSIONS: Demographic and socio-economic disparities in untreated caries exist among children and adults. PMID- 29510697 TI - Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD 1 immunotherapy in melanoma patients. AB - BACKGROUND: While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling. METHODS: We used mass cytometry (CyTOF) to comprehensively profile peripheral blood of melanoma patients, in order to find predictive biomarkers of response to anti CTLA-4 or anti-PD-1 therapy. Using a panel of ~ 40 surface and intracellular markers, we performed in-depth phenotypic and functional immune profiling to identify potential predictive biomarker candidates. RESULTS: Immune profiling of baseline peripheral blood samples using CyTOF revealed that anti-CTLA-4 and anti PD-1 therapies have distinct sets of candidate biomarkers. The distribution of CD4+ and CD8+ memory/non-memory cells and other memory subsets was different between responders and non-responders to anti-CTLA-4 therapy. In anti-PD-1 (but not anti-CTLA-4) treated patients, we discovered differences in CD69 and MIP 1beta expressing NK cells between responders and non-responders. Finally, multivariate analysis was used to develop a model for the prediction of response. CONCLUSIONS: Our results indicate that anti-CTLA-4 and anti-PD-1 have distinct predictive biomarker candidates. CD4+ and CD8+ memory T cell subsets play an important role in response to anti-CTLA-4, and are potential biomarker candidates. For anti-PD-1 therapy, NK cell subsets (but not memory T cell subsets) correlated with clinical response to therapy. These functionally active NK cell subsets likely play a critical role in the anti-tumor response triggered by anti-PD-1. PMID- 29510692 TI - Are dementia with Lewy bodies and Parkinson's disease dementia the same disease? AB - BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD. Their morphological hallmarks - cortical and subcortical alpha-synuclein/Lewy body plus beta-amyloid and tau pathologies - are similar, but clinical differences at onset suggest some dissimilar profiles. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is provided herein. DISCUSSION: The clinical constellations of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and postmortem studies have revealed a more pronounced cortical atrophy, elevated cortical and limbic Lewy body pathologies, higher Abeta and tau loads in cortex and striatum in DLB compared to PDD, and earlier cognitive defects in DLB. Conversely, multitracer PET studies have shown no differences in cortical and striatal cholinergic and dopaminergic deficits. Clinical management of both DLB and PDD includes cholinesterase inhibitors and other pharmacologic and non-drug strategies, yet with only mild symptomatic effects. Currently, no disease-modifying therapies are available. CONCLUSION: DLB and PDD are important dementia syndromes that overlap in many clinical features, genetics, neuropathology, and management. They are currently considered as subtypes of an alpha-synuclein-associated disease spectrum (Lewy body diseases), from incidental Lewy body disease and non-demented Parkinson's disease to PDD, DLB, and DLB with Alzheimer's disease at the most severe end. Cognitive impairment in these disorders is induced not only by alpha synuclein-related neurodegeneration but by multiple regional pathological scores. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with Alzheimer's disease and other proteinopathies. While we prefer to view DLB and PDD as extremes on a continuum, there remains a pressing need to more clearly differentiate these syndromes and to understand the synucleinopathy processes leading to either one. PMID- 29510698 TI - Evolution of H9N2 avian influenza virus in embryonated chicken eggs with or without homologous vaccine antibodies. AB - BACKGROUND: Vaccines constitute a unique selective pressure, different from natural selection, drives the evolution of influenza virus. In this study, A/Chicken/Shanghai/F/1998 (H9N2) was continually passaged in specific pathogen free embryonated chicken eggs with or without selective pressures from antibodies induced by homologous maternal antibodies. Genetic mutations, antigenic drift, replication, and pathogenicity of the passaged virus were evaluated. RESULTS: Antigenic drift of the passaged viruses occurred in the 47th generation (vF47) under selective pressure on antibodies and in the 52nd generation (nF52) without selective pressure from antibodies. Seven mutations were observed in the vF47 virus, with three in PB2 and four in HA, whereas 12 mutations occurred in the nF52 virus, with three in PB2, two in PB1, four in HA, one in NP, one in NA, and one in NS. Remarkably, the sequences of the HA segment from vF47 were 100% homologous with those of the nF52 virus. Both the vF47 and nF52 viruses showed enhanced replication compared to the parental virus F/98, but higher levels of replication and pathogenicity were displayed by nF52 than by vF47. An inactive vaccine derived from the parental virus F/98 did not confer protection against challenges by either the vF47 or nF52 virus, but inactive vaccines derived from the vF47 or nF52 virus were able to provide protection against a challenge using F/98. CONCLUSION: Taken together, the passage of H9N2 viruses with or without selective pressure of the antibodies induced by homologous maternal antibodies showed genetic variation, enhanced replication, and variant antigenicity. Selective pressure of the antibody does not seem to play a key role in antigenic drift in the egg model but may impact the genetic variation and replication ability of H9N2 viruses. These results improve understanding of the evolution of the H9N2 influenza virus and may aid in selecting appropriate vaccine seeds. PMID- 29510699 TI - Physically active academic lessons: acceptance, barriers and facilitators for implementation. AB - BACKGROUND: To improve health and academic learning in schoolchildren, the Active School programme in Stavanger, Norway has introduced physically active academic lessons. This is a teaching method combining physical activity with academic content. The purpose of this paper was to evaluate the response to the physically active lessons and identify facilitators and barriers for implementation of such an intervention. METHODS: Five school leaders (principals or vice-principals), 13 teachers and 30 children from the five intervention schools were interviewed about their experiences with the 10-month intervention, which consisted of weekly minimum 2 * 45 minutes of physically active academic lessons, and the factors affecting its implementation. All interviews were transcribed and analysed using the qualitative data analysis program NVivo 10 (QSR international, London, UK). In addition, weekly teacher's intervention delivery logs were collected and analysed. RESULTS: On average, the physically active academic lessons in 18 of the 34 weeks (53%) were reported in the teacher logs. The number of delivered physically active academic lessons covered 73% of the schools' planned activity. Physically active lessons were well received among school leaders, teachers and children. The main facilitators for implementation of the physically active lessons were active leadership and teacher support, high self-efficacy regarding mastering the intervention, ease of organizing physically active lessons, inclusion of physically active lessons into the lesson curricula, and children's positive reception of the intervention. The main barriers were unclear expectations, lack of knowledge and time to plan the physiclly active lessons, and the length of the physically active lessons (15-20 min lessons were preferred over the 45 min lessons). CONCLUSION: Physically active academic lessons were considered an appropriate pedagogical method for creating positive variation, and were highly appreciated among both teachers and children. Both the principal and the teachers should be actively involved the implementation, which could be strengthened by including physical activity into the school's strategy. Barriers for implementing physically active lessons in schools could be lowered by increasing implementation clarity and introducing the teachers to high quality and easily organized lessons. TRIAL REGISTRATION: Clinicaltrail.gov ID identifier: NCT03436355 . Retrospectively registered: 16th of Feb, 2018. PMID- 29510700 TI - An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration. AB - BACKGROUND: Cell migration is essential for development and tissue repair, but it also contributes to disease. Rho GTPases regulate cell migration, but a comprehensive analysis of how each Rho signalling component affects migration has not been carried out. RESULTS: Through an RNA interference screen, and using a prostate cancer cell line, we find that approximately 25% of Rho network components alter migration. Some genes enhance migration while others decrease basal and/or hepatocyte growth factor-stimulated migration. Surprisingly, we identify RhoH as a screen hit. RhoH expression is normally restricted to haematopoietic cells, but we find it is expressed in multiple epithelial cancer cell lines. High RhoH expression in samples from prostate cancer patients correlates with earlier relapse. RhoH depletion reduces cell speed and persistence and decreases migratory polarity. Rac1 activity normally localizes to the front of migrating cells at areas of dynamic membrane movement, but in RhoH depleted cells active Rac1 is localised around the whole cell periphery and associated with membrane regions that are not extending or retracting. RhoH interacts with Rac1 and with several p21-activated kinases (PAKs), which are Rac effectors. Similar to RhoH depletion, PAK2 depletion increases cell spread area and reduces cell migration. In addition, RhoH depletion reduces lamellipodium extension induced by PAK2 overexpression. CONCLUSIONS: We describe a novel role for RhoH in prostate cancer cell migration. We propose that RhoH promotes cell migration by coupling Rac1 activity and PAK2 to membrane protrusion. Our results also suggest that RhoH expression levels correlate with prostate cancer progression. PMID- 29510701 TI - Access and adequate utilization of malaria control interventions in rural Malawi: a descriptive quantitative study. AB - BACKGROUND: Despite the availability of cost effective malaria control interventions, such as insecticide-treated bed nets (ITN), diagnosis and effective treatment of malaria, and intermittent preventive treatment during pregnancy (IPTp), the lack of equitable access and coverage affect utilization of these interventions in rural communities. Aggregated rates of access and utilization of malaria interventions in national surveys mask substantial variations in intervention coverage. Utilization of interventions and factors affecting utilization need investigation in rural communities. METHODS: One year of quantitative data collected from a rolling Malaria Indicator Survey (April 2015-April 2016) in Chikhwawa District, Malawi, before the ITN distribution campaign, were analysed. Univariate analyses were used to quantify rates of ITN usage, care-seeking for fever in children aged 6-59 months and women aged 15-49 years and IPTp uptake (for women aged 15-49 years with a recent delivery). Results were compared to national survey estimates; factors associated with these outcomes were determined using multivariate regression models. RESULTS: A total of 2046 participants were included from 1328 households; 56.6% were women aged 15 49 years and 43.4% were children aged 6-59 months. Reported ownership of at least one ITN per household and under-five children ITN use the previous night were 35.3 and 33.5% compared to 70.2 and 67.1%, respectively, in the national survey; ITN use was higher in high wealth quintile households than low quintile ones. For participants with recent fever, 37.6 and 19.5% sought care and sought care within 24 h, respectively. Care-seeking was lower for febrile women than febrile children [aOR, 95% CI 0.53 (0.35-0.81)]. Uptake of two and three or more doses of IPTp were 40.6 and 15.0%, respectively, among women with a pregnancy in the last 2 years. CONCLUSION: To achieve effective malaria control, fine-scale or district based surveillance should be used to identify and target communities requiring scaling up of interventions. Qualitative research and a participatory community approach should be used to address behavioural factors affecting how people make use of interventions. PMID- 29510702 TI - Ethical underpinnings for the development of health literacy in schools: ethical premises ('why'), orientations ('what') and tone ('how'). AB - BACKGROUND: Schools are seen as crucial environments to influence and develop the health literacy of new generations, but without sufficient reflection on the ethical underpinnings of intentions and interventions around health literacy. In contrast, we argue here that ethics are fundamental to all education. The article adopts a 'One world' approach that generalizes broadly across the so-called Global North and Global South. It also generalizes across various age groups among school pupils, advocating age appropriate application of the arguments advanced. MAIN TEXT: Our analysis examines why health literacy should be promoted in schools and argues that the purpose should embrace the values of social justice and should not stop at individual and national cost benefit analysis. Discussion about the orientation of health literacy highlights meta-cognitive skills around critical thinking, self-awareness and citizenship rather than lists of practical skills. Finally, approaches to health literacy in classrooms are presented with an ethical tone that draws attention to the power relations responsible for health inequities and that does not assume that such power relations are the given framework for health literacy interventions and activities. These arguments are reinforced by urging that related debates address dynamic social realities such as international migration. CONCLUSIONS: We reiterate the need for ethical questions to be consciously and systematically addressed from early on, beginning with intentions to promote health literacy even before these intentions are translated into action, within the political space where education meets public health and health promotion. We underline again the context of fluidity and dynamism, as new challenges emerge within pedagogies and curricula, especially in response to changing populations in the society around. PMID- 29510705 TI - Baseline assessment of patient safety culture in public hospitals in Kuwait. PMID- 29510704 TI - Effect of traditional yoga, mindfulness-based cognitive therapy, and cognitive behavioral therapy, on health related quality of life: a randomized controlled trial on patients on sick leave because of burnout. AB - BACKGROUND: To explore if health related quality of life(HRQoL) increased after traditional yoga(TY), mindfulness based cognitive therapy(MBCT), or cognitive behavioral therapy(CBT), in patients on sick leave because of burnout. METHODS: Randomized controlled trial, blinded, in ninety-four primary health care patients, block randomized to TY, MBCT or CBT (active control) between September 2007 and November 2009. Patients were living in the Stockholm metropolitan area, Sweden, were aged 18-65 years and were on 50%-100% sick leave. A group treatment for 20 weeks, three hours per week, with homework four hours per week. HRQoL was measured by the SWED-QUAL questionnaire, comprising 67 items grouped into 13 subscales, each with a separate index, and scores from 0 (worse) to 100 (best). SWED-QUAL covers aspects of physical and emotional well-being, cognitive function, sleep, general health and social and sexual functioning. Statistics: Wilcoxon's rank sum and Wilcoxon's sign rank tests, Bonett-Price for medians and confidence intervals, and Cohen's D. RESULTS: Twenty-six patients in the TY (21 women), and 27 patients in both the MBCT (24 women) and in the CBT (25 women), were analyzed. Ten subscales in TY and seven subscales in MBCT and CBT showed improvements, p < 0.05, in several of the main domains affected in burnout, e.g. emotional well-being, physical well-being, cognitive function and sleep. The median improvement ranged from 0 to 27 points in TY, from 4 to 25 points in CBT and from 0 to 25 points in MBCT. The effect size was mainly medium or large. Comparison of treatments showed no statistical differences, but better effect (small) of both TY and MBCT compared to CBT. When comparing the effect of TY and MBCT, both showed a better effect (small) in two subscales each. CONCLUSIONS: A 20 week group treatment with TY, CBT or MBCT had equal effects on HRQoL, and particularly on main domains affected in burnout. This indicates that TY, MBCT and CBT can be used as both treatment and prevention, to improve HRQoL in patients on sick leave because of burnout, reducing the risk of future morbidity. TRIAL REGISTRATION: July 22, 2012, retrospectively registered. ClinicalTrails.gov NCT01168661 . FUNDING: Stockholm County Council, grant 2003-5. PMID- 29510703 TI - A sophisticated, differentiated Golgi in the ancestor of eukaryotes. AB - BACKGROUND: The Golgi apparatus is a central meeting point for the endocytic and exocytic systems in eukaryotic cells, and the organelle's dysfunction results in human disease. Its characteristic morphology of multiple differentiated compartments organized into stacked flattened cisternae is one of the most recognizable features of modern eukaryotic cells, and yet how this is maintained is not well understood. The Golgi is also an ancient aspect of eukaryotes, but the extent and nature of its complexity in the ancestor of eukaryotes is unclear. Various proteins have roles in organizing the Golgi, chief among them being the golgins. RESULTS: We address Golgi evolution by analyzing genome sequences from organisms which have lost stacked cisternae as a feature of their Golgi and those that have not. Using genomics and immunomicroscopy, we first identify Golgi in the anaerobic amoeba Mastigamoeba balamuthi. We then searched 87 genomes spanning eukaryotic diversity for presence of the most prominent proteins implicated in Golgi structure, focusing on golgins. We show some candidates as animal specific and others as ancestral to eukaryotes. CONCLUSIONS: None of the proteins examined show a phyletic distribution that correlates with the morphology of stacked cisternae, suggesting the possibility of stacking as an emergent property. Strikingly, however, the combination of golgins conserved among diverse eukaryotes allows for the most detailed reconstruction of the organelle to date, showing a sophisticated Golgi with differentiated compartments and trafficking pathways in the common eukaryotic ancestor. PMID- 29510706 TI - Disparities in tobacco use by adolescents in southeast, Nigeria using Global Youth Tobacco Survey (GYTS) approach. AB - BACKGROUND: Tobacco use during adolescence is a substantial problem and adolescents are at higher risk of addiction and prolonged use. To reduce the burden of tobacco-related morbidity and mortality, monitoring of adolescent tobacco use is imperative. We aimed to determine the prevalence of tobacco use among adolescents in urban and rural secondary schools in Enugu State, southeast Nigeria. METHODS: A cross-sectional study of 4332 adolescents in 8th to 10th grades in 25 urban and 24 rural secondary schools in Enugu, Nigeria was done using Global Youth Tobacco Survey (GYTS) methodology. Students were asked about previous and current tobacco use, smoking cessation, and susceptibility to smoking initiation among non-smokers. Geographical, age and sex prevalence differences were examined. Analyses were performed for all adolescents (10-19 years) and for a subset of students, 13-15 years of age for comparison with previous GYTS surveys. All analyses were weighted to account for the complex survey design and for differential non-response at school, class and student levels. RESULTS: About 28.9% of students reported ever smoking cigarettes; 19.4% reported current tobacco use among all adolescents (13.3, 5.8 and 7.8% for cigarettes, other smoked tobacco, and smokeless tobacco, respectively) while 18.6% reported current tobacco use among 13-15 year olds (12.6, 5.2 and 7.5% for cigarettes, other smoked tobacco and smokeless tobacco respectively). Prevalence of all types of tobacco use was higher in rural schools (vs. urban schools), and among boys (vs. girls). Susceptibility to smoking initiation among non-smokers was 9.3% (95% CI: 8.1-10.7) among all adolescents, and 9% (95% CI: 7.6-10.7) among 13-15 year olds. About 88.1% of all adolescent smokers desired to quit and 57.9% of them had never received help to quit smoking. CONCLUSIONS: Nearly one in every five school-going adolescents currently uses at least one type of tobacco in Enugu State, southeast Nigeria. Prevalence of tobacco use is higher in rural schools and among boys in this setting. Most adolescent current smokers desire to quit and need smoking cessation support. PMID- 29510707 TI - A cross-sectional analysis of the associations between leisure-time sedentary behaviors and clustered cardiometabolic risk. AB - BACKGROUND: The aim of this study was to conduct a comprehensive investigation of the association between different types of leisure-time sedentary behavior (watching television, using a computer, reading and socializing) and clustered cardiometabolic risk in apparently healthy adults aged 40 to 65 years. METHODS: One hundred seventy-three participants from the general population (64% women; mean age = 54.4 years) consented to attend a cardiovascular examination program and to complete a questionnaire on leisure-time sedentary behaviors. Waist circumference, blood pressure, glucose, triglycerides, and high-density lipoprotein cholesterol of non-fasting blood samples were assessed, and a clustered cardiometabolic risk score [CMRS] was calculated. Data were collected between February and July 2015. Associations between leisure-time sedentary behaviors and CMRS were analyzed using linear and quantile regression, adjusted for socio-demographic variables and other types of leisure-time sedentary behavior (model 1) and additionally, adjusted for leisure-time physical activity and traveling in motor vehicles (model 2). RESULTS: Linear regression revealed that there was a positive association between watching television and CMRS (model 1: b = 0.27 [CI: 0.03; 0.52]; model 2: b = 0.30 [CI: 0.05; 0.56]). In addition, quantile regression analysis revealed that using a computer was negatively associated with the 50th (model 1: b = - 0.43 [CI: -0.79; - 0.07]) and the 75th percentiles (model 1: b = - 0.71 [CI: -1.27; - 0.14]) of CMRS. Reading and socializing were not associated with CMRS. CONCLUSIONS: Watching television was positively associated with a clustered cardiometabolic risk score, while time spent using a computer revealed inconsistent findings. Our results give reason to consider different types of behaviors in which individuals are sedentary and the associations between these behaviors and cardiometabolic risk, supporting the need for behavior-specific assessments as well as public health recommendations to maintain or enhance adults' health. TRIAL REGISTRATION: Clinical trial registration number: NCT02990039 , Retrospectively registered (December 12, 2016). PMID- 29510708 TI - A national public health programme on gambling policy development in New Zealand: insights from a process evaluation. AB - BACKGROUND: In New Zealand, a public health programme on gambling policy development is part of a national gambling harm reduction and prevention strategy mandated by the Gambling Act 2003. Funded by the Ministry of Health, the programme directs workplace/organisational gambling policies, non-gambling fundraising policies, and local council policies on electronic gaming machines (EGMs). We carried out a process evaluation of this programme to identify practical information (e.g. advocacy approaches; challenges and ameliorating strategies) that can be used by programme planners and implementers to reinforce programme effectiveness and serve to guide similar policy-focused public health initiatives elsewhere. METHODS: Evaluation criteria, based on the programme's official service specifications, guided our evaluation questions, analysis and reporting. To identify informative aspects of programme delivery, we thematically analysed over 100 six-monthly implementer progress reports (representing 3 years of programme delivery) and transcript of a focus group with public health staff. RESULTS: Identified output-related themes included purposeful awareness raising to build understanding about gambling harms and the need for harm-reduction policies and stakeholder relationship development. Outcome-related themes included enhanced community awareness about gambling harms, community involvement in policy development, some workplace/organisational policy development, and some influences on council EGM policies. Non-gambling fundraising policy development was not common. CONCLUSIONS: The programme offers an unprecedented gambling harm reduction approach. Although complex (due to its three distinct policy focus areas targeting different sectors) and challenging (due to the extensive time and resources needed to develop relationships and overcome counteractive views), the programme resulted in some policy development. Encouraging workplace/organisational policy development requires increased awareness of costs to employers and society and appreciation of policy value. Although encouraging non-gambling fundraising policies will likely remain challenging, public debate on ethical aspects could stimulate policy consideration. Influencing council EGM policy decisions will remain important for minimising EGM accessibility among vulnerable communities. Public involvement in EGM policy decisions has strong implications for policy effectiveness. Given the expanding range of gambling activities (including online gambling) presently accessible to communities worldwide, both organisational and public policies (as advocated through the programme) are needed to minimise gambling harms. PMID- 29510709 TI - A comparison of 10 accelerometer non-wear time criteria and logbooks in children. AB - BACKGROUND: There are many unresolved issues regarding data reduction algorithms for accelerometry. The choice of criterion for removal of non-wear time might have a profound influence on physical activity (PA) and sedentary time (SED) estimates. The aim of the present study was to compare 10 different non-wear criteria and a log of non-wear periods in 11-year-old children. METHODS: Children from the Active Smarter Kids study performed 7-days of hip-worn accelerometer monitoring (Actigraph GT3X+) and logged the number of non-wear periods each day, along with the approximate duration and reason for non-wear. Accelerometers were analyzed using 10 different non-wear criteria: >= 10, 20, 30, 45, 60, and 90 min of consecutive zero counts without allowance for interruptions, and >=60 and 90 min with allowance for 1 and 2 min of interruptions. RESULTS: 891 children provided 5203 measurement days, and reported 1232 non-wear periods ranging from 0 to 3 periods per day: on most days children reported no non-wear periods (77.1% of days). The maximum number of non-wear periods per day was 2 for the 90-min criterion, 3 to 5 for most criteria, 7 for the 20-min criterion, and 20 for the 10-min criterion. The non-wear criteria influenced overall PA (mean values across all criteria: 591 to 649 cpm; 10% difference) and SED time (461 to 539 min/day; 17% difference) estimates, especially for the most prolonged SED bouts. Estimates were similar for time spent in intensity-specific (light, moderate, vigorous, and moderate-to-vigorous) PA, but varied 6-9% among the non-wear criteria for proportions of time spent in intensity-specific PA (% of total wear time). CONCLUSIONS: Population level estimates of PA and SED differed between different accelerometer non-wear criteria, meaning that non-wear time algorithms should be standardized across studies to reduce confusion and improve comparability of children's PA level. Based on the numbers and reasons for non-wear periods, we suggest a 45 or 60-min consecutive zero count-criterion not allowing any interruptions to be applied in future pediatric studies, at least for children older than 10 years. TRIAL REGISTRATION: The study is registered in Clinicaltrials.gov with identification number NCT02132494 . Registered 7 April 2014. PMID- 29510710 TI - Substance use and self-harm: a cross-sectional study of the prevalence, correlates and patterns of medical service utilisation among patients admitted to a South African hospital. AB - BACKGROUND: Substance use is a potentially modifiable risk factor for suicidal behaviour. Little is known about the epidemiology of substance use among self harm patients in South Africa. This study set out to collect epidemiological data about the prevalence, correlates, and patterns of medical service utilisation among self-harm patients who used substances at the time of self-injury. METHODS: Data from 238 consecutive self-harm patients treated at an urban hospital in South Africa were analysed using bivariate and multivariate statistics. RESULTS: Approximately 20% of patients reported substance use at the time of self-harm. When compared to other self-harm patients, higher rates of patients who had used substances: had depressed levels of consciousness on admission; utilised more medical resources and required longer hospital admissions; cited relationship difficulties and financial concerns as reasons for their self-harm; reported a previous episode of self-harm; and intended to die as a result of their injuries. Although the observed differences were not statistically significant (p > 0.05), the proportional differences were congruent with international literature. CONCLUSION: Acute use of substances among self-harm patients warrants more focused research and clinical attention particularly in the context of reducing utilisation of scarce medical resources. PMID- 29510711 TI - The ethics of using placebo in randomised controlled trials: a case study of a Plasmodium vivax antirelapse trial. AB - BACKGROUND: The use of placebos in randomised controlled trials is a subject of considerable ethical debate. In this paper we present a set of considerations to evaluate the ethics of placebo controlled trials that includes: social value of the study; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and the harm benefit balance; clinical equipoise; and double standards. We illustrate the application of these considerations using a case study of a large ongoing multicentre, placebo controlled, double-blinded, randomised trial to determine primaquine anti-relapse efficacy in vivax malaria. MAIN BODY: There is an urgent need for primaquine anti relapse studies in order to rationalise the management of a potentially fatal disease. An ethical justification for the use of the placebo arm is provided on the grounds that the actual current applied standard of care in most endemic places does not include primaquine. It has also been argued that there is clinical equipoise among the primaquine study arms and that the risk of harms of being in the placebo arm is the risk of having relapse, which is no more than not being included in the trial, and that there are no double standards. CONCLUSION: Based on our set of considerations, we conclude that a placebo arm is not only justified but imperative in this study. We propose that similar considerations should be prospectively applied to other placebo controlled trials and observational control arms where no treatment is offered. PMID- 29510712 TI - Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: a randomized double-blind placebo-controlled single ascending dose study. AB - BACKGROUND: Cell therapies are being investigated as potential disease modifying treatment options for osteoarthritis (OA). Progenza (PRG) comprises in vitro expanded mesenchymal stem cells derived from human donor adipose tissue combined with cell culture supernatant. The primary objective of this first-in-human study was to evaluate the safety and tolerability of PRG. METHODS: We conducted a single centre, randomized, double-blind, placebo-controlled, single ascending dose study. Twenty patients aged 40-65 years with symptomatic Kellgren-Lawrence grade 1-3 knee OA were treated in two cohorts and randomized 4:1 to PRG or placebo. Cohort 1: 3.9 million cells (PRG 3.9M, n = 8) or placebo (n = 2) and cohort 2: 6.7 million cells (PRG 6.7M, n = 8) or placebo (n = 2). Each patient received a single intra-articular injection and was followed-up for 12 months. RESULTS: The study population comprised 20 patients (placebo, n = 4; PRG 3.9M, n = 8; PRG 6.7M, n = 8). All patients reported at least one treatment-emergent adverse event (TEAE). The majority of events [143/169 (84.6%)] were mild with 34 (20.1%) being considered by the investigator to be treatment related. There were no serious AEs or withdrawals due to AEs during the study. There was a statistically significant within group improvement in VAS pain scores from baseline at all timepoints for the PRG combined group, with highly significant improvements seen at months 3, 6, 9 and 12 (p <= 0.005) while VAS pain scores in the placebo group showed marginal improvement. A statistically significant improvement was also seen in WOMAC pain subscale scores from baseline at all timepoints for the PRG combined group while a marginal improvement in the placebo group was not statistically significant. Between screening and month 12, there was no decrease in average lateral tibial cartilage volume in the PRG 3.9M group while the placebo group showed a statistically significant cartilage loss. This difference between the placebo and PRG 3.9M group was statistically significant (LSM difference 106.47 mm3, 95% CI 13.56 mm3, 199.37 mm3, p = 0.028). CONCLUSION: When administered as a single intra-articular injection to patients with symptomatic knee OA, PRG was safe and well tolerated. Furthermore, measurable improvements in symptoms and knee structure outcomes warrant further studies on PRG's potential for disease modification in OA. Trial registration ANZCTR, ACTRN12615000439549. Date registered: 7th May 2015, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368355. PMID- 29510713 TI - Prevalence, risk factors and behavioural and emotional comorbidity of acute seizures in young Kenyan children: a population-based study. AB - BACKGROUND: Acute symptomatic seizures and febrile seizures are common in children admitted to hospitals in Africa and may be markers of brain dysfunction. They may be associated with behavioural and emotional problems, but there are no published community-based studies in Africa. METHODS: We screened 7047 children aged 1-6 years (randomly sampled from 50,000 in the community) for seizures (using seven questions) and invited those who screened positive and a proportion of negatives for a clinical assessment. Risk factors were identified using a parental questionnaire. Behavioural and emotional problems were examined using the Child Behaviour Checklist (CBCL) in 3273 children randomly selected from 7047. Generalised linear models with appropriate link functions were used to determine risk factors and associations between behavioural or emotional problems and acute seizures. Sobel-Goodman mediation tests were used to investigate if the association between acute seizures and CBCL scores was mediated by co-diagnosis of epilepsy. RESULTS: Acute seizures were identified in 429 (6.1%) preschool children: 3.2% (95% confidence interval CI: 2.9-3.5%) for symptomatic seizures, and 2.9% (95% CI: 2.6-3.3%) for febrile seizures. Risk factors for acute seizures included family history of febrile seizures (odds ratio OR = 3.19; 95% CI: 2.03 5.01) and previous hospitalisation (OR = 6.65; 95% CI: 4.60-9.63). Total CBCL problems occurred more frequently in children with acute seizures (27%; 95% CI: 21-34%) than for those without seizures (11%; 95% CI: 11-12%; chi-squared p <= 0.001). Acute seizures were associated with total CBCL problems (adjusted risk ratio (aRR) = 1.92; 95% CI: 1.34-2.77), externalising problems (aRR = 1.82; 95% CI: 1.21-2.75) and internalising problems (aRR = 1.57; 95% CI: 1.22-2.02), with the proportion of the comorbidity mediated by a co-diagnosis of epilepsy being small (15.3%; 95% CI: 4.5-34.9%). Risk factors for this comorbidity included family history of febrile seizures (risk ratio (RR) = 3.36; 95% CI: 1.34-8.41), repetitive acute seizures (beta = 0.36; 95% CI: 0.15-0.57) and focal acute seizures (RR = 1.80; 95% CI: 1.05-3.08). CONCLUSIONS: Acute seizures are common in preschool children in this area and are associated with behavioural and emotional problems. Both conditions should be assessed and addressed in children. PMID- 29510714 TI - Lipid profile and dyslipidemia among school-age children in urban Ghana. AB - BACKGROUND: Dyslipidemia during childhood has been associated with higher risk of atherosclerosis later in life. Information on the lipid profile of Ghanaian children is scarce. The aim of this study was to assess the lipid profiles of school children between the ages of 9-15 years, living in urban Ghana. METHODS: A total of 802 randomly selected school-age children participated in the Ghana School Survey implemented in Kumasi and Accra, Ghana. A structured questionnaire was used to collect information on child and maternal socio-demographic characteristics (including age, education, and occupation), 7-day food frequency, home and school activity, as well as measurement of weight and standing height. Weight, height, and age data were converted into BMI-for-age indices to determine weight status. Finger-prick fasting blood samples were taken from the school-age children. Total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol levels were determined using the CardioChek(r) PA Test System. Reference lipid levels based on the US National Cholesterol Education Program 2001 guidelines were used to determine the proportion of children with dyslipidemia. RESULTS: The mean TC, LDL-C, HDL-C, and TG levels were 149.0 +/- 57.0 mg/dl, 80.1 +/- 38.6 mg/dl, 53.5 +/- 19.4 mg/dl, and 71.4 +/- 54.7 mg/dl, respectively. Mean TC/HDL-C ratio was 3.0 +/- 1.0. The proportion of children with abnormal values were 12.1% for TC, 4.5% for TG, 28.4% for HDL-C, 9.2% for LDL-C, and 6.6% for TC/HDL-C ratio. The levels of dyslipidemia (HDL, LDL, and TC/HDL-C ratio) were higher among overweight/obese compared to normal-weight children. More frequent fruit consumption was also linked with lower LDL-C (p = 0.020) while watching television (TV) in the mornings was linked with both higher TC (p = 0.011) and TG (p = 0.006). CONCLUSIONS: Majority of urban-dwelling Ghanaian school children had normal lipid profiles. However, the higher levels of dyslipidemia observed among overweight and obese children suggest the need for population level physical activity and dietary interventions among children to reduce risk of cardiovascular diseases in adult life. PMID- 29510715 TI - Stand More AT Work (SMArT Work): using the behaviour change wheel to develop an intervention to reduce sitting time in the workplace. AB - BACKGROUND: Sitting (sedentary behaviour) is widespread among desk-based office workers and a high level of sedentary behaviour is a risk factor for poor health. Reducing workplace sitting time is therefore an important prevention strategy. Interventions are more likely to be effective if they are theory and evidence based. The Behaviour Change Wheel (BCW) provides a framework for intervention development. This article describes the development of the Stand More AT Work (SMArT Work) intervention, which aims to reduce sitting time among National Health Service (NHS) office-based workers in Leicester, UK. METHODS: We followed the BCW guide and used the Capability, Opportunity and Motivation Behaviour (COM B) model to conduct focus group discussions with 39 NHS office workers. With these data we used the taxonomy of Behaviour Change Techniques (BCTv1) to identify the most appropriate strategies for facilitating behaviour change in our intervention. To identify the best method for participants to self-monitor their sitting time, a sub-group of participants (n = 31) tested a number of electronic self-monitoring devices. RESULTS: From our BCW steps and the BCT-Taxonomy we identified 10 behaviour change strategies addressing environmental (e.g. provision of height adjustable desks,), organisational (e.g. senior management support, seminar), and individual level (e.g. face-to-face coaching session) barriers. The Darma cushion scored the highest for practicality and acceptability for self-monitoring sitting. CONCLUSION: The BCW guide, COM-B model and BCT Taxonomy can be applied successfully in the context of designing a workplace intervention for reducing sitting time through standing and moving more. The intervention was developed in collaboration with office workers (a participatory approach) to ensure relevance for them and their work situation. The effectiveness of this intervention is currently being evaluated in a randomised controlled trial. TRIAL REGISTRATION: ISRCTN10967042 . Registered on 2 February 2015. PMID- 29510716 TI - Oral health service utilization patterns among preschool children in Beijing, China. AB - BACKGROUND: The utilization of oral health services in children remains at a relatively low level in China. However, little is known about the utilization patterns and related factors. The objective of this study was to explore the patterns of oral health service utilization and to determine the related factors among preschool children in Beijing, China, based on the Andersen behavioral model. METHODS: A cross-sectional study of 1425 preschool children aged 2 to 6 years was carried out in five kindergartens in Beijing, China. A questionnaire investigation of parents/caregivers was performed to collect information on oral health service utilization. Oral health needs were evaluated through oral health examinations. Chi-square tests, t-tests, multivariate logistic regression and negative binomial regression were used in this study to identify the variables associated with oral health service utilization. RESULTS: In total, 648 (45.5%) children had utilized oral health services in the past 12 months, while 24.3% had utilized preventive oral health services. Routine checkups and receiving preventive measures accounted for 63.2% of the children who utilized oral health services in the past 12 months. Children were more likely to have utilized oral health services in the past 12 months if they attended kindergartens with regular oral health care resources, if their oral health status as perceived by their parents/parents was "fair" or "poor", if they had more decayed, missing and filled teeth (dmft) and if they had experienced more dental pain. In addition, children with more dental pain and more access to oral health services, whose oral health status was perceived by parents/caregivers as worse tended to have utilized oral health services more frequently in the past 12 months. CONCLUSIONS: In conclusion, we found a strong association between access to regular oral health care resources and oral health service utilization among preschool children. Children whose oral health status was perceived by parents/caregivers as worse and who had more dental pain were more likely to have utilized oral health services in China. PMID- 29510717 TI - Restrictive Versus Massive Fluid Resuscitation Strategy (REFILL study), influence on blood loss and hemostatic parameters in obstetric hemorrhage: study protocol for a randomized controlled trial. AB - BACKGROUND: Postpartum hemorrhage (PPH) is associated with maternal morbidity and mortality and has an increasing incidence in high-resource countries, despite dissemination of guidelines, introduction of skills training, and correction for risk factors. Current guidelines advise the administration, as fluid resuscitation, of almost twice the amount of blood lost. This advice is not evidence-based and could potentially harm patients. METHODS: All women attending the outpatient clinic who are eligible will be informed of the study; oral and written informed consent will be obtained. Where there is more than 500 ml blood loss and ongoing bleeding, patients will be randomized to care as usual, fluid resuscitation with 1.5-2 times the amount of blood loss or fluid resuscitation with 0.75-1.0 times the blood loss. Blood loss will be assessed by weighing all draping. A blood sample, for determining hemoglobin concentration, hematocrit, thrombocyte concentration, and conventional coagulation parameters will be taken at the start of the study, after 60 min, and 12-18 h after delivery. In a subgroup of women, additional thromboelastometric parameters will be obtained. DISCUSSION: Our hypothesis is that massive fluid administration might lead to a progression of bleeding due to secondary coagulation disorders. In non-pregnant individuals with massive blood loss, restrictive fluid management has been shown to prevent a progression to dilution coagulopathy. These data, however, cannot be extrapolated to women in labor. Our objective is to compare both resuscitation protocols in women with early, mild PPH (blood loss 500-750 ml) and ongoing bleeding, taking as primary outcome measure the progression to severe PPH (blood loss > 1000 ml). TRIAL REGISTRATION: Netherlands Trial Register, NTR 3789 . Registered on 11 January 2013. PMID- 29510718 TI - Barriers to reproductive health care for migrant women in Geneva: a qualitative study. AB - BACKGROUND: Migrant mothers in developed countries often experience more complicated pregnancy outcomes and less fewer women access preventive gynecology services. To enlighten health care providers to potential barriers, the objective of this paper is to explore barriers to reproductive health services in Geneva described by migrant women from a qualitative perspective. METHODS: In this qualitative study, thirteen focus groups (FG) involving 78 women aged 18 to 66 years were conducted in seven languages. All the FG discussions were audio recorded and later transcribed. The data was classified, after which the main themes and sub-themes were manually extracted and analyzed. RESULTS: Barriers were classified either into structural or personal barriers aiming to describe factors influencing the accessibility of reproductive health services vs. those influencing client satisfaction. The five main themes that emerged were financial accessibility, language barriers, real or perceived discrimination, lack of information and embarrassment. CONCLUSION: Structural improvements which might meet the needs of the emergent extremely diverse population are the (1) provision of informative material that is easy to understand and available in multiple languages, (2) provision of sensitive cultural training including competence skill for all health professionals, (3) provision of specifically trained nurses or social assistance to guide migrants through the health system and (4) inclusion of monitoring and evaluation programs for the prevention of personal and systemic discrimination. PMID- 29510719 TI - Survival benefit of a low ratio of visceral to subcutaneous adipose tissue depends on LDL clearance versus production in sepsis. AB - BACKGROUND: Patients with sepsis with a high ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) have increased mortality. Our goal was to investigate the mechanism of this effect, noting that low LDL levels are also associated with increased sepsis mortality. Accordingly we tested for association between VAT/SAT, low-density lipoprotein (LDL) levels, and mortality. Then we examined the effect of statin treatment, which decreases LDL production, and the effect of PCSK9 genotype, which increases LDL clearance. METHODS: We performed retrospective analysis of a cohort of patients with sepsis from a tertiary care adult intensive care unit in Vancouver, Canada, who underwent abdominal computed tomography (CT) (n = 75) for clinical reasons. We compared LDL levels in patients with sepsis according to high versus low VAT/SAT and 90-day survival. We next examined the effects of statin therapy and PCSK9 loss-of-function genotype on survival. RESULTS: Patients with a low VAT/SAT had increased 90-day survival and were relatively protected against low LDL levels in sepsis compared to high VAT/SAT. Statin treatment abrogated the beneficial effects of low VAT/SAT; eliminating the difference in LDL levels and survival between patients with low and high VAT/SAT. PSCK9 loss-of-function genotype similarly eliminated the increased LDL levels in low VAT/SAT patients but, in contrast, increased the survival advantage of low VAT/SAT compared to high VAT/SAT. CONCLUSIONS: Low LDL levels per se are not simply associated with decreased sepsis survival because lowering LDL levels by inhibiting LDL production (statin treatment) is associated with adverse outcomes, while increased LDL clearance (PCSK9 loss-of-function genotype) is associated with improved outcomes in patients with low VAT/SAT. PMID- 29510720 TI - The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. AB - BACKGROUND: Tumor hypoxia is an independent prognostic factor associated with poor patient survival. Emerging evidence suggests that hypoxia can potentially maintain or enhance the stem cell phenotype of both normal stem cells and cancer cells. However, it remains to be determined whether cell fate is regulated in vivo by the hypoxic tumor microenvironment (TME). METHODS: We established a hypoxia-sensing xenograft model to identify hypoxic tumor cell in vivo primarily using human breast cancer cell lines MDA-MB-231 and MCF7. Hypoxic tumor cells were identified in situ by fluorescence of green fluorescence protein. They were further isolated from xenografts, purified and sorted by flow cytometry for detailed analysis of their stem cell characteristics. RESULTS: We have found that hypoxic tumor cells freshly isolated from xenografts contain increased subpopulations of tumor cells with cancer stem cell (CSC)-like characteristics. The CSC characteristics of the hypoxic tumor cells are further enhanced upon re implantation in vivo, whereas secondary xenografts derived from the non-hypoxic tumor cells remain similar to the primary xenografts. Interestingly, the phenotypes exhibited by the hypoxic tumor cells are stable and remain distinctively different from those of the non-hypoxic tumor cells isolated from the same tumor mass even when they are maintained under the same ambient culture conditions. Mechanistically, the PI3K/AKT pathway is strongly potentiated in the hypoxic tumor cells and is required to maintain the CSC-like phenotype. Importantly, the differential cell fates between hypoxic and non-hypoxic tumor cells are only found in tumor cells isolated from the hypoxic TME in vivo and are not seen in tumor cells treated by hypoxia in vitro alone. CONCLUSIONS: These previously unknown observations suggest that the hypoxic TME may promote malignant progression and therapy resistance by coordinating induction, selection and/or preferential maintenance of the CSC-like phenotype in tumor cells. PMID- 29510722 TI - Recovery of facial expressions using functional electrical stimulation after full face transplantation. AB - BACKGROUND: We assessed the recovery of 2 face transplantation patients with measures of complexity during neuromuscular rehabilitation. Cognitive rehabilitation methods and functional electrical stimulation were used to improve facial emotional expressions of full-face transplantation patients for 5 months. Rehabilitation and analyses were conducted at approximately 3 years after full facial transplantation in the patient group. We report complexity analysis of surface electromyography signals of these two patients in comparison to the results of 10 healthy individuals. METHODS: Facial surface electromyography data were collected during 6 basic emotional expressions and 4 primary facial movements from 2 full-face transplantation patients and 10 healthy individuals to determine a strategy of functional electrical stimulation and understand the mechanisms of rehabilitation. A new personalized rehabilitation technique was developed using the wavelet packet method. Rehabilitation sessions were applied twice a month for 5 months. Subsequently, motor and functional progress was assessed by comparing the fuzzy entropy of surface electromyography data against the results obtained from patients before rehabilitation and the mean results obtained from 10 healthy subjects. RESULTS: At the end of personalized rehabilitation, the patient group showed improvements in their facial symmetry and their ability to perform basic facial expressions and primary facial movements. Similarity in the pattern of fuzzy entropy for facial expressions between the patient group and healthy individuals increased. Synkinesis was detected during primary facial movements in the patient group, and one patient showed synkinesis during the happiness expression. Synkinesis in the lower face region of one of the patients was eliminated for the lid tightening movement. CONCLUSIONS: The recovery of emotional expressions after personalized rehabilitation was satisfactory to the patients. The assessment with complexity analysis of sEMG data can be used for developing new neurorehabilitation techniques and detecting synkinesis after full-face transplantation. PMID- 29510721 TI - Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection. AB - BACKGROUND: Heme oxygenase-1 (HO-1) is a critical cytoprotective enzyme that limits oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. We previously demonstrated that HO-1 protein expression is decreased within the brains of HIV+ subjects and that this HO-1 reduction correlates with CNS immune activation and neurocognitive dysfunction. To define a potential CNS protective role for HO-1 against HIV, we analyzed a well-characterized HIV autopsy cohort for two common HO-1 promoter region polymorphisms that are implicated in regulating HO-1 promoter transcriptional activity, a (GT)n dinucleotide repeat polymorphism and a single nucleotide polymorphism (A(-413)T). Shorter HO-1 (GT)n repeats and the 'A' SNP allele associate with higher HO-1 promoter activity. METHODS: Brain dorsolateral prefrontal cortex tissue samples from an autopsy cohort of HIV-, HIV+, and HIV encephalitis (HIVE) subjects (n = 554) were analyzed as follows: HO-1 (GT)n polymorphism allele lengths were determined by PCR and capillary electrophoresis, A(-413)T SNP alleles were determined by PCR with allele specific probes, and RNA expression of selected neuroimmune markers was analyzed by quantitative PCR. RESULTS: HIV+ subjects with shorter HO-1 (GT)n alleles had a significantly lower risk of HIVE; however, shorter HO-1 (GT)n alleles did not correlate with CNS or peripheral viral loads. In HIV+ subjects without HIVE, shorter HO-1 (GT)n alleles associated significantly with lower expression of brain type I interferon response markers (MX1, ISG15, and IRF1) and T-lymphocyte activation markers (CD38 and GZMB). No significant correlations were found between the HO-1 (GT)n repeat length and brain expression of macrophage markers (CD163, CD68), endothelial markers (PECAM1, VWF), the T-lymphocyte marker CD8A, or the B-lymphocyte maker CD19. Finally, we found no significant associations between the A(-413)T SNP and HIVE diagnosis, HIV viral loads, or any neuroimmune markers. CONCLUSION: Our data suggest that an individual's HO-1 promoter region (GT)n polymorphism allele repeat length exerts unique modifying risk effects on HIV-induced CNS neuroinflammation and associated neuropathogenesis. Shorter HO-1 (GT)n alleles increase HO-1 promoter activity, which could provide neuroprotection through decreased neuroimmune activation. Therapeutic strategies that induce HO-1 expression could decrease HIV-associated CNS neuroinflammation and decrease the risk for development of HIV neurological disease. PMID- 29510723 TI - Correction to: Fraction of high-grade cervical intraepithelial lesions attributable to genotypes targeted by a nonavalent HPV vaccine in Galicia, Spain. AB - After publication of the article [1], it was brought to our attention that the author E. Lopez-Diez is missing their second affiliation. The author would also like to indicate an affiliation to "Universidade de Vigo, Pontevedra, Spain". PMID- 29510725 TI - Aging exacerbates development of cerebral microbleeds in a mouse model. AB - BACKGROUND: Cerebral microhemorrhages (CMH) are commonly found in the aging brain. CMH are also the neuropathological substrate of cerebral microbleeds (CMB), demonstrated on brain MRI. Recent studies demonstrate the importance of systemic inflammation in CMH development, but the relationships among inflammation, aging, and CMH development are not well-defined. In the current study, we hypothesized that the pathogenesis of inflammation-induced CMH in mice differs by age. METHODS: We studied young (3 months, n = 20) and old (18 months, n = 25) C57BL/6 mice injected with low-dose lipopolysaccharide (LPS; 1 mg/kg, i.p.) or saline at 0, 6, and 24 h. Seven days after the first LPS/saline injection, brains were harvested, sectioned, and stained with hematoxylin and eosin (H&E) and Prussian blue (PB) to estimate acute/fresh and sub-acute CMH development, respectively. The relationships between microglial/macrophage activation (ionized calcium-binding adapter molecule-1), astrocyte activation (glial fibrillary acidic protein), blood-brain barrier (BBB) disruption (brain immunoglobulin G), aging, and CMH development were examined using immunohistochemistry. RESULTS: Aging alone did not increase spontaneous H&E positive CMH development but significantly increased the number, size, and total area of LPS-induced H&E-positive CMH in mice. LPS- and saline-treated aged mice had significantly larger PB-positive CMH compared with young mice, but the total area of PB-positive CMH was increased only in LPS-treated aged mice. Aged mice had significantly increased microglial/macrophage activation, which correlated with H&E- and PB-positive CMH development. Aged mice treated with LPS had significantly increased astrocyte activation and BBB disruption compared with young LPS-treated mice. CONCLUSIONS: Aging makes the brain more susceptible to inflammation-induced CMH in mice, and this increase in CMH with aging is associated with microglial/macrophage activation. PMID- 29510726 TI - Correction to: Early-life exposure to PM2.5 and risk of acute asthma clinical encounters among children in Massachusetts: a case-crossover analysis. AB - After publication of the article [1], it was brought to our attention that a number in Table 1 is incorrect. PMID- 29510727 TI - EEF1D overexpression promotes osteosarcoma cell proliferation by facilitating Akt mTOR and Akt-bad signaling. AB - BACKGROUND: Dysregulation of eukaryotic translation elongation factor 1 delta (EEF1D) in cancers has been reported; however, the role and mechanisms of EEF1D in osteosarcoma remain poorly understood. The aim of this study is to investigate the expression and role of EEF1D in osteosarcoma and to elucidate its underlying mechanisms. METHODS: The expression of EEF1D in osteosarcomas and cell lines was evaluated by qRT-PCR, Western blotting and immunohistochemistry. EEF1D knockdown using small interfering RNA (siRNA) was employed to analyze the role of EEF1D in osteosarcoma cell proliferation and cell cycle progression. The host signaling pathways affected by EEF1D knockdown were detected using PathScan(r) intracellular signaling array kit. RESULTS: The expression of EEF1D was found to be up-regulated in human osteosarcoma tissues and cell lines. Its expression was positively correlated with Enneking stage and the tumor recurrence. EEF1D knockdown inhibited osteosarcoma cell proliferation, colony-forming ability, and cell cycle G2/M transition in vitro. In addition, EEF1D knockdown decreased the levels of phospho-Akt, phospho-mTOR, and phospho-Bad proteins. CONCLUSIONS: EEF1D is upregulated in osteosarcoma and plays a tumor promoting role by facilitating Akt-mTOR and Akt-Bad signaling pathways. Accordingly, EEF1D is a potential target for cancer therapy. PMID- 29510724 TI - Diversification of the muscle proteome through alternative splicing. AB - BACKGROUND: Skeletal muscles express a highly specialized proteome that allows the metabolism of energy sources to mediate myofiber contraction. This muscle specific proteome is partially derived through the muscle-specific transcription of a subset of genes. Surprisingly, RNA sequencing technologies have also revealed a significant role for muscle-specific alternative splicing in generating protein isoforms that give specialized function to the muscle proteome. MAIN BODY: In this review, we discuss the current knowledge with respect to the mechanisms that allow pre-mRNA transcripts to undergo muscle specific alternative splicing while identifying some of the key trans-acting splicing factors essential to the process. The importance of specific splicing events to specialized muscle function is presented along with examples in which dysregulated splicing contributes to myopathies. Though there is now an appreciation that alternative splicing is a major contributor to proteome diversification, the emergence of improved "targeted" proteomic methodologies for detection of specific protein isoforms will soon allow us to better appreciate the extent to which alternative splicing modifies the activity of proteins (and their ability to interact with other proteins) in the skeletal muscle. In addition, we highlight a continued need to better explore the signaling pathways that contribute to the temporal control of trans-acting splicing factor activity to ensure specific protein isoforms are expressed in the proper cellular context. CONCLUSIONS: An understanding of the signal-dependent and signal-independent events driving muscle-specific alternative splicing has the potential to provide us with novel therapeutic strategies to treat different myopathies. PMID- 29510728 TI - Uncemented three-dimensional-printed prosthetic reconstruction for massive bone defects of the proximal tibia. AB - BACKGROUND: Currently, it is challenging to treat massive bone defects of proximal tibia. Although numerous methods are available for reconstruction with epiphysis preservation, limitations in knee function and complications are noted with these methods. Our paper describes our attempt to reconstruct a marked defect in the proximal tibia with an uncemented three-dimensional (3D)-printed prosthesis and to evaluate the prosthesis design and short-term outcomes. CASE PRESENTATION: A 15-year-old boy with metaphyseal osteosarcoma of the tibia underwent intercalary allograft reconstruction following wide tumour resection with epiphysis preservation. However, chronic allograft rejection and/or infection occurred after the surgery and a sinus tract was formed. The rejection and/or infection process was successfully stopped by the removal of the graft and implantation of an antibiotic-loaded cement spacer; however, the limb function was poor. Because of the irregular shape of the defect and the excessively short length of the residual proximal tibia, we used the 3D printing technology to design and fabricate a personalised prosthesis to reconstruct the defect, with the preservation of the knee joint. At the last follow-up at 26 months, the patient had satisfactory limb function. CONCLUSIONS: The 3D-printed prosthesis may be a feasible option in the reconstruction of tibial metaphyseal defects with the preservation of the knee joint. Moreover, it can result in good postoperative function and low complication rates. However, a long-term follow-up is required to clarify its long-term outcomes. PMID- 29510729 TI - The role of the peritrophic matrix and red blood cell concentration in Plasmodium vivax infection of Anopheles aquasalis. AB - BACKGROUND: Plasmodium vivax is predominant in the Amazon region, and enhanced knowledge of its development inside a natural vector, Anopheles aquasalis, is critical for future strategies aimed at blocking parasite development. The peritrophic matrix (PM), a chitinous layer produced by the mosquito midgut in response to blood ingestion, is a protective barrier against pathogens. Plasmodium can only complete its life-cycle, and consequently be transmitted to a new host, after successfully passing this barrier. Interestingly, fully engorged mosquitoes that had a complete blood meal form a thicker, well-developed PM than ones that feed in small amounts. The amount of red blood cells (RBC) in the blood meal directly influences the production of digestive enzymes and can protect parasites from being killed during the meal digestion. A specific study interrupting the development of the PM associated with the proteolytic activity inhibition, and distinct RBC concentrations, during the P. vivax infection of the New World malaria vector An. aquasalis is expected to clarify whether these factors affect the parasite development. RESULTS: Absence of PM in the vector caused a significant reduction in P. vivax infection. However, the association of chitinase with trypsin inhibitor restored infection rates to those of mosquitoes with a structured PM. Also, only the ingestion of trypsin inhibitor by non chitinase treated mosquitoes increased the infection intensity. Moreover, the RBC concentration in the infected P. vivax blood meal directly influenced the infection rate and its intensity. A straight correlation was observed between RBC concentrations and infection intensity. CONCLUSIONS: This study established that there is a balance between the PM role, RBC concentration and digestive enzyme activity influencing the establishment and development of P. vivax infection inside An. aquasalis. Our results indicate that the absence of PM in the midgut facilitates digestive enzyme dispersion throughout the blood meal, causing direct damage to P. vivax. On the other hand, high RBC concentrations support a better and thick, well-developed PM and protect P. vivax from being killed. Further studies of this complex system may provide insights into other details of the malaria vector response to P. vivax infection. PMID- 29510730 TI - The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1. AB - BACKGROUND: Metabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis. MACC1, a transcriptional regulator of MET, was recognized as an oncogene in gastric cancer (GC); however, its transcriptional or post-translational regulation was not clear. We previously reported the metabolic role of MACC1 in glycolysis to promote GC progression. MACC1-AS1 is the antisense lncRNA of MACC1, yet its function was previously unknown. METHODS: We profiled and analyzed the expression of MACC1-AS1 utilizing the TCGA database as well as in situ hybridization using 123 pairs of GC tissues and matched adjacent normal gastric mucosa tissues (ANTs). The biological role of MACC1-AS1 in cell growth and metastasis was determined by performing in vitro and in vivo functional experiments. Glycolysis and antioxidant capabilities were assayed to examine its metabolic function. Further, the specific regulatory effect of MACC1-AS1 on MACC1 was explored transcriptionally and post transcriptionally. RESULTS: MACC1-AS1 was shown to be expressed significantly higher in GC tissues than in ANTs, which predicted poor prognosis in GC patients. MACC1-AS1 promoted GC cell proliferation and inhibited cell apoptosis under metabolic stress. Mechanistically, MACC1-AS1 stabilized MACC1 mRNA and post transcriptionally augmented MACC1 expression. Further, MACC1-AS1 was shown to mediate metabolic plasticity through MACC1 upregulation and subsequent enhanced glycolysis and anti-oxidative capabilities, and this was suggested to be coordinated by the AMPK/Lin28 pathway. CONCLUSIONS: Elevated expression of MACC1 AS1 in gastric cancer tissues is linked to poor prognosis and promotes malignant phenotype upon cancer cells. MACC1-AS1 is elevated under metabolic stress and facilitates metabolic plasticity by promoting MACC1 expression through mRNA stabilization. Our study implicates lncRNA MACC1-AS1 as a valuable biomarker for GC diagnosis and prognosis. PMID- 29510731 TI - miR-190 suppresses breast cancer metastasis by regulation of TGF-beta-induced epithelial-mesenchymal transition. AB - BACKGROUND: Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-beta (TGF-beta) pathway plays critical roles during breast cancer epithelial-mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-beta signaling, promotes breast cancer metastasis through induction of EMT. METHODS: The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. RESULTS: miR-190 down-regulation is required for TGF-beta-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. CONCLUSIONS: Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-beta network in breast cancer metastasis. PMID- 29510732 TI - Cross-linked hyaluronan gel inhibits the growth and metastasis of ovarian carcinoma. AB - BACKGROUND: The recurrence, metastasis and poor prognosis are important characteristics of ovarian carcinoma (OC), which are associated with exfoliation of cells from the primary tumor and colonization of the cells in pelvic cavity. On the other hand, the life quality of the patients undergoing surgical resection of OC was influenced by postoperative adhesions. Therefore, preventing postoperative implant tumor and adhesion may be effective methods to improve OC treatment. HyaRegen Gel, a cross-linked hyaluronan gel (CHAG), has been widely used as an anti-adhesive agent following pelvic operation in clinic. However, whether it can affect the implantation and growth of OC cells or not is still not clear. METHODS: Migration and invasion assays were applied to detect the effect of CHAG on migration and invasion of OC cells. Western blotting was performed to detect the phosphorylation/activation of EGFR and ERK, and the expression of PCNA and MMP7. Pull down assay was used to analyze the effect of CHAG on the activation of small G protein Rac1. Nude mice implantation tumor model was applied to observe the effect of CHAG on implantation tumor of OC cells. RESULTS: The results of in vitro experiments showed that CHAG suppressed both basic and EGF-induced migration and invasion of OC cells, blocked the activation of EGF initiated EGFR activation, inhibited downstream signal transduction of EGFR, and decreased expression of proliferation and migration/invasion related proteins. Meanwhile, results of in vivo experiments showed that CHAG not only inhibited the formation of implantation tumor of OC cells but also delayed the of the growth of the tumors. CONCLUSIONS: CHAG inhibited migration, invasion and proliferation of OC cells in vitro, and suppressed development of implantation tumor of OC in vivo. This made it as both anti-tumor and anti-adhesion agents. PMID- 29510733 TI - Income inequality and cardiovascular disease risk factors in a highly unequal country: a fixed-effects analysis from South Africa. AB - BACKGROUND: Chronic stress associated with high income inequality has been hypothesized to increase CVD risk and other adverse health outcomes. However, most evidence comes from high-income countries, and there is limited evidence on the link between income inequality and biomarkers of chronic stress and risk for CVD. This study examines how changes in income inequality over recent years relate to changes in CVD risk factors in South Africa, home to some of the highest levels of income inequality globally. METHODS: We linked longitudinal data from 9356 individuals interviewed in the 2008 and 2012 National Income Dynamics Study to district-level Gini coefficients estimated from census and survey data. We investigated whether subnational district income inequality was associated with several modifiable risk factors for cardiovascular disease (CVD) in South Africa, including body mass index (BMI), waist circumference, blood pressure, physical inactivity, smoking, and high alcohol consumption. We ran individual fixed-effects models to examine the association between changes in income inequality and changes in CVD risk factors over time. Linear models were used for continuous metabolic outcomes while conditional Poisson models were used to estimate risk ratios for dichotomous behavioral outcomes. RESULTS: Both income inequality and prevalence of most CVD risk factors increased over the period of study. In longitudinal fixed-effects models, changes in district Gini coefficients were not significantly associated with changes in CVD risk factors. CONCLUSIONS: Our findings do not support the hypothesis that subnational district income inequality is associated with CVD risk factors within the high-inequality setting of South Africa. PMID- 29510734 TI - Large gastric intramural hematoma mimicking a visceral artery aneurysm: a case report. AB - BACKGROUND: Gastric hematoma is a rare disorder. Here we report a case of a large gastric intramural hematoma mimicking an impending rupture of a visceral artery aneurysm. CASE PRESENTATION: A 60-year-old Japanese woman complained of left flank pain. Computed tomography with intravenously administered contrast agent showed a solid mass of 5 * 5 * 8 centimeter in the left middle abdominal quadrant. On completion of computed tomography, the working diagnosis was an impending rupture of an aneurysm located in a branch of the superior mesenteric artery. Transcatheter arterial embolization was performed, but angiography of the superior mesenteric artery and the inferior mesenteric artery did not indicate extravasation of the contrast agent and we did not observe any aneurysmal structure. We decided to perform surgery. The operational findings revealed that the mass was a gastric intramural hematoma. CONCLUSION: On encountering an intra abdominal mass found to be attached to a gastric wall, a gastric intramural hematoma should be considered. PMID- 29510735 TI - Comparative Efficacy and Mechanisms of a Single-Session Pain Psychology Class in Chronic Low Back Pain: Study Protocol for a Randomized Controlled Trial. AB - BACKGROUND: The Institute of Medicine (IOM) reported that chronic pain affects about 100 million U.S. adults, with chronic low back pain (CLBP) cited as the most prevalent type. Pain catastrophizing is a psychological construct shown to predict the development and trajectory of chronic pain and patient response to pain treatments. While effective treatment for pain catastrophizing typically includes eight-session groups of cognitive behavioral therapy (CBT), a single session targeted treatment class yielded promising results which, if replicated and extended, could prove to efficiently and cost-effectively reduce pain catastrophizing. In this trial, we seek to determine the comparative efficacy of this novel single-session pain catastrophizing class to an eight-session course of pain CBT and a single-session back pain health education class. We will also explore the psychosocial mechanisms and outcomes of pain catastrophizing treatment. METHODS: In this trial we will randomize 231 individuals with CLBP to one of three treatment arms: (1) pain-CBT (eight weekly 2-h group sessions with home exercises and readings); (2) a single 2-h pain catastrophizing class; or (3) a single 2-h back pain health education class (active control). For the primary outcome of pain catastrophizing, the trial is designed as a non-inferiority test between pain-CBT and the single-session pain catastrophizing class, and as a superiority test between the single-session pain catastrophizing class and the health education class. Team researchers masked to treatment assignment will assess outcomes up to six months post treatment. DISCUSSION: If the single session targeted pain catastrophizing class is found to be an effective treatment for patients with CLBP, this low cost and low burden treatment could dismantle many of the current barriers and burdens of effective pain care. Further, elucidation of the mechanisms of pain catastrophizing treatments will facilitate future research on the topic as well as further development and refinement of treatments. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03167086 . Registered on 22 May 2017. PMID- 29510736 TI - MicroRNA-1468 promotes tumor progression by activating PPAR-gamma-mediated AKT signaling in human hepatocellular carcinoma. AB - BACKGROUND: Accumulating evidence confirm that aberrant microRNAs (miRNAs) expression contributes to hepatocellular carcinoma (HCC) development and progression. Previous study reported that miR-1468 showed an up-regulated tendency and might be a potential prognostic biomarker in HCC samples derived from TCGA database. However, the role of miR-1468 and its underlying mechanisms involved in the growth and metastasis of HCC remain poorly investigated. METHODS: CCK-8, EdU, colony formation and flow cytometry were used to determine proliferation, cell cycle progression and apoptosis of HCC cells in vitro. The subcutaneous tumor model in nude mice was established to detect tumor growth of HCC in vivo. The direct binding of miR-1468 to 3'UTR of Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2) and Up frameshift protein 1 (UPF1) was confirmed by luciferase reporter assay. RESULTS: Here, we demonstrated that miR-1468 expression was up-regulated in HCC tissues and cell lines. Clinical analysis revealed that increased miR-1468 level was significantly correlated with malignant prognostic features and shorter survival. Gain- and loss-of-function experiments indicated that miR-1468 promoted cell proliferation, colony formation, cell cycle progression and induced apoptosis of HCC cells in vitro and in vivo. Moreover, CITED2 and UPF1 were identified as direct downstream targets of miR-1468 in HCC cells, and mediated the functional effects of miR-1468 in HCC, resulting in peroxisome proliferator-activated receptor-gamma (PPAR-gamma)/AKT signaling activation. In clinical samples of HCC, miR-1468 inversely correlated with the levels of CITED2 and UPF1, which were confirmed to be down-regulated in HCC. Restoration of CITED2 or UPF1 expression at least partially abolished the biological effects of miR-1468 on HCC cells. Moreover, alteration of PPAR-gamma or AKT phosphorylation could reverse the function of miR-1468 in HCC. CONCLUSIONS: Taken together, this research supports the first evidence that miR-1468 plays an oncogenic role in HCC via activating PPAR-gamma/AKT pathway by targeting CITED2 and UPF1, and represents a promising therapeutic strategy for HCC patients. PMID- 29510738 TI - Predicting the impact of selection for scrapie resistance on PRNP genotype frequencies in goats. AB - The European Union has implemented breeding programmes to increase scrapie resistance in sheep. A similar approach can be applied also in goats since the K222 allele provides a level of resistance equivalent to that of ARR in sheep. The European Food Safety Authority stated that breeding for resistance could be offered as an option for Member States to control classical scrapie in goats. We assessed the impact of different breeding strategies on PRNP genotype frequencies using a mathematical model that describes in detail the evolution of K222 in two goat breeds, Chamois Coloured and Saanen. Different patterns of age structure and replacement rate were modelled as factors affecting response to selection. Breeding for scrapie resistance can be implemented in goats, even though the initial K222 frequencies in these breeds are not particularly favourable and the rate at which the resistant animals increase, both breeding and slaughtered for meat production, is slow. If the goal is not to achieve the fixation of resistance allele, it is advisable to carry out selection only until a desired frequency of K222-carriers has been attained. Nucleus selection vs. selection on the overall populations is less expensive but takes longer to reach the desired output. The programme performed on the two goat breeds serves as a model of the response the selection could have in other breeds that show different initial frequencies and population structure. In this respect, the model has a general applicability. PMID- 29510737 TI - Effect of exposure to CeO2 nanoparticles on ram spermatozoa during storage at 4 degrees C for 96 hours. AB - BACKGROUND: Cerium oxide nanoparticles (CeO2 NPs) are able to store and release oxygen, conferring them scavenger activity against oxidative stress. However, their effects in reproductive systems are not yet well understood. The aim of the study was to investigate the effects of exposure of refrigerated ram semen to CeO2 NPs for 96 h on the main structural and kinematic parameters of spermatozoa. METHODS: The ejaculates of 5 Sarda rams were collected, pooled and diluted in a soybean lecithin extender. Samples were exposed to increasing doses of CeO2 NPs (0, 44 and 220 MUg/mL) and stored at 4 degrees C for 96 h. Analyses of kinematic parameters (computer assisted sperm analysis, CASA), integrity of membranes (PI/PSA staining), ROS production (H2DCFDA staining) and DNA damage (sperm chromatin structure assay with acridine orange, SCSA) were performed every 24 h (0, 24, 48, 72 and 96 h of incubation). The experiment was carried out in 6 replicates. Data were analysed by repeated measures ANOVA with Bonferroni's as post hoc test. When the assumption of normality was not met (ROS), non-parametric Kruskal-Wallis rank test was carried out. RESULTS: Exposure of ram spermatozoa to increasing doses of CeO2 NPs had a beneficial effect on the main motility parameters from 48 h of incubation onward. Velocity of sperm cells was enhanced in the groups exposed to CeO2 NPs compared to the control. Incubation with NPs had beneficial effects on the integrity of plasma membranes of spermatozoa, with higher percentage of damaged cells in the control group compared to the exposed ones. Production of ROS was not affected by exposure to NPs and its levels rose at 96 h of incubation. The integrity of DNA remained stable throughout the 96 h of storage regardless of co-incubation with NPs. CONCLUSIONS: We reported beneficial effects of CeO2 NPs on kinematic and morphologic parameters of ram semen, such as motility and membrane integrity following 96 h of exposure. Furthermore, we also proved no genotoxic effects of CeO2 NPs. These effects could not be related to an antioxidant activity of CeO2 NPs, since ROS levels in exposed cells were similar to those of unexposed ones. PMID- 29510739 TI - Measuring multiple parameters of CD8+ tumor-infiltrating lymphocytes in human cancers by image analysis. AB - BACKGROUND: Immuno-oncology and cancer immunotherapies are areas of intense research. The numbers and locations of CD8+ tumor-infiltrating lymphocytes (TILs) are important measures of the immune response to cancer with prognostic, pharmacodynamic, and predictive potential. We describe the development, validation, and application of advanced image analysis methods to characterize multiple immunohistochemistry-derived CD8 parameters in clinical and nonclinical tumor tissues. METHODS: Commercial resection tumors from nine cancer types, and paired screening/on-drug biopsies of non-small-cell lung carcinoma (NSCLC) patients enrolled in a phase 1/2 clinical trial investigating the PD-L1 antibody therapy durvalumab (NCT01693562), were immunostained for CD8. Additional NCT01693562 samples were immunostained with a CD8/PD-L1 dual immunohistochemistry assay. Whole-slide scanning was performed, tumor regions were annotated by a pathologist, and images were analyzed with customized algorithms using Definiens Developer XD software. Validation of image analysis data used cell-by-cell comparison to pathologist scoring across a range of CD8+ TIL densities of all nine cancers, relying primarily on 95% confidence in having at least moderate agreement regarding Lin concordance correlation coefficient (CCC = 0.88-0.99, CCC_lower = 0.65-0.96). RESULTS: We found substantial variability in CD8+ TILs between individual patients and across the nine types of human cancer. Diffuse large B-cell lymphoma had several-fold more CD8+ TILs than some other cancers. TIL densities were significantly higher in the invasive margin versus tumor center for carcinomas of head and neck, kidney and pancreas, and NSCLC; the reverse was true only for prostate cancer. In paired patient biopsies, there were significantly increased CD8+ TILs 6 weeks after onset of durvalumab therapy (mean of 365 cells/mm2 over baseline; P = 0.009), consistent with immune activation. Image analysis accurately enumerated CD8+ TILs in PD-L1+ regions of lung tumors using the dual assay and also measured elongate CD8+ lymphocytes which constituted a fraction of overall TILs. CONCLUSIONS: Validated image analysis accurately enumerates CD8+ TILs, permitting comparisons of CD8 parameters among tumor regions, individual patients, and cancer types. It also enables the more complex digital solutions needed to better understand cancer immunity, like analysis of multiplex immunohistochemistry and spatial evaluation of the various components comprising the tumor microenvironment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01693562 . Study code: CD-ON-MEDI4736-1108. Interventional study (ongoing but not currently recruiting). Actual study start date: August 29, 2012. Primary completion date: June 23, 2017 (final data collection date for primary outcome measure). PMID- 29510740 TI - A recombinant Fasciola gigantica 14-3-3 epsilon protein (rFg14-3-3e) modulates various functions of goat peripheral blood mononuclear cells. AB - BACKGROUND: The molecular structure of Fasciola gigantica 14-3-3 protein has been characterized. However, the involvement of this protein in parasite pathogenesis remains elusive and its effect on the functions of innate immune cells is unknown. We report on the cloning and expression of a recombinant F. gigantica 14 3-3 epsilon protein (rFg14-3-3e), and testing its effects on specific functions of goat peripheral blood mononuclear cells (PBMCs). METHODS: rFg14-3-3e protein was expressed in Pichia pastoris. Western blot and immunofluorescence assay (IFA) were used to examine the reactivity of rFg14-3-3e protein to anti-F. gigantica and anti-rFg14-3-3e antibodies, respectively. Various assays were used to investigate the stimulatory effects of the purified rFg14-3-3e protein on specific functions of goat PBMCs, including cytokine secretion, proliferation, migration, nitric oxide (NO) production, phagocytosis, and apoptotic capabilities. Potential protein interactors of rFg14-3-3e were identified by querying the databases Intact, String, BioPlex and BioGrid. A Total Energy analysis of each of the identified interaction was performed. Gene Ontology (GO) enrichment analysis was conducted using Funcassociate 3.0. RESULTS: Sequence analysis revealed that rFg14-3-3e protein had 100% identity to 14-3-3 protein from Fasciola hepatica. Western blot analysis showed that rFg14-3-3e protein is recognized by sera from goats experimentally infected with F. gigantica and immunofluorescence staining using rat anti-rFg14-3-3e antibodies demonstrated the specific binding of rFg14-3-3e protein to the surface of goat PBMCs. rFg14-3-3e protein stimulated goat PBMCs to produce interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta), corresponding with low levels of IL-4 and interferon gamma (IFN-gamma). Also, this recombinant protein promoted the release of NO and cell apoptosis, and inhibited the proliferation and migration of goat PBMCs and suppressed monocyte phagocytosis. Homology modelling revealed 65% identity between rFg14-3-3e and human 14-3-3 protein YWHAE. GO enrichment analysis of the interacting proteins identified terms related to apoptosis, protein binding, locomotion, hippo signalling and leukocyte and lymphocyte differentiation, supporting the experimental findings. CONCLUSIONS: Our data suggest that rFg14-3-3e protein can influence various cellular and immunological functions of goat PBMCs in vitro and may be involved in mediating F. gigantica pathogenesis. Because of its involvement in F. gigantica recognition by innate immune cells, rFg14-3-3e protein may have applications for development of diagnostics and therapeutic interventions. PMID- 29510743 TI - Review of "Ecology and prevention of Lyme borreliosis" edited by Marieta A. H. Braks, Sipke E. van Wieren, Willem Takken and Hein Sprong. AB - BOOK DETAILS: Marieta AH Braks, Sipke E van Wieren, Willem Takken and Hein Sprong, EditorsEcology and prevention of Lyme borreliosis. In: Ecology and control of vector-borne diseases Volume 4Wageningen: Wageningen Academic Publishers; 2016.462 pages, ISBN 1875-0699. PMID- 29510742 TI - Molecular and biochemical responses in the midgut of the silkworm, Bombyx mori, infected with Nosema bombycis. AB - BACKGROUND: Microsporidia are a group of eukaryotic intracellular parasites that infect almost all vertebrates and invertebrates. However, there is little information available of how microsporidia obtain nutrients and energy from host cells. The purpose of this study was to investigate the energy and material requirements of Nosema bombycis for the invasion procedure through analyzing the global variation of the gene expression, protein abundance, fatty acids level and ATP flux induced by the microsporidia N. bombycis infection in the midgut of the silkworm Bombyx mori. METHODS: A suppression subtractive hybridization (SSH) and quantitative real-time PCR (qPCR) analysis were performed to identify the genes upregulated in the midgut of B. mori 48 h following N. bombycis infection. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to annotate and summarize the differentially expressed genes, according to the categories 'molecular function', 'cellular component' and 'biological process'. To evaluate the nutrition material and energy costs in B.mori infected by N. bombycis, biochemical analysis was performed to determine the variation of protein abundance, fatty acid levels and ATP flux with or without the microsporidia N. bombycis infection in the midgut of the silkworm B. mori. RESULTS: A total of 744 clones were obtained, 288 clones were randomly selected for sequencing, and 110 unigenes were generated. Amongst these, 49.21%, 30.16% and 14.29% genes were involved in 19 molecular functions, 19 biological processes and nine cellular components, respectively. A total of 11 oxidative phosphorylation- and eight proton-coupled ATP synthesis-related genes were upregulated. Seven protein degradation-, three fat degradation-related genes were upregulated, and no genes related to the de novo synthesis of amino acids and fatty acids were significantly upregulated. The data from the biochemical analysis showed the contents of total protein and ATP of B. mori midgut tissues decreased significantly, whereas the fatty acid content did not significantly change after four days of N. bombycis infection. Microsporidia N. bombycis infection upregulated the expression level of genes involved in host ATP synthesis, protein and fat degradation, which eventually causes the obvious decline of protein content and ATP synthesis in the host midgut, whereas the fatty acids content did not change significantly. CONCLUSIONS: This study suggested to some extent that N. bombycis invasion can activate the host protein degradation and accelerate the production of host ATP. Microsporidia of N. bombycis show preference for proteins rather than fatty acids from the host to ensure the material preparation required by their parasitic life-cycle. Requirements of N. bombycis for energy were also mainly dependent on the host ATP production. This study provides a new data that may help our understanding of the molecular mechanisms of obtaining energy and nutrients from the host by the microsporidium N. bombycis. PMID- 29510741 TI - A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. AB - BACKGROUND: The cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The histopathologic hallmark of IMM is lymphocytic infiltration of myofibers. The purpose of this study was to identify putative functional variants associated with equine IMM. METHODS: A genome-wide association (GWA) study was performed on 36 IMM QHs and 54 breed matched unaffected QHs from the same environment using the Equine SNP50 and SNP70 genotyping arrays. RESULTS: A mixed model analysis identified nine SNPs within a ~ 2.87 Mb region on chr11 that were significantly (Punadjusted < 1.4 * 10- 6) associated with the IMM phenotype. Associated haplotypes within this region encompassed 38 annotated genes, including four myosin genes (MYH1, MYH2, MYH3, and MYH13). Whole genome sequencing of four IMM and four unaffected QHs identified a single segregating nonsynonymous E321G mutation in MYH1 encoding myosin heavy chain 2X. Genotyping of additional 35 IMM and 22 unaffected QHs confirmed an association (P = 2.9 * 10- 5), and the putative mutation was absent in 175 horses from 21 non-QH breeds. Lymphocytic infiltrates occurred in type 2X myofibers and the proportion of 2X fibers was decreased in the presence of inflammation. Protein modeling and contact/stability analysis identified 14 residues affected by the mutation which significantly decreased stability. CONCLUSIONS: We conclude that a mutation in MYH1 is highly associated with susceptibility to the IMM phenotype in QH-related breeds. This is the first report of a mutation in MYH1 and the first link between a skeletal muscle myosin mutation and autoimmune disease. PMID- 29510744 TI - Kala-azar in Darfur: Evidence for indigenous transmission in Al-Malha Locality, North Darfur, western Sudan. AB - BACKGROUND: Recent reports showed high numbers of visceral leishmaniasis cases in North Darfur, western Sudan. Due to a lack of previous studies, no information is available on local transmission of the disease in these areas. Therefore, a pilot entomological and epidemiological study was conducted in Al-Malha Locality during the year 2013, to investigate possibility of local transmission and places and times of the year where and when people contract the infection. METHODS: Kala azar incidence data were obtained from records of Ministry of Health, North Darfur; Al-Malha rural hospital; and the Federal Ministry of Health, Division of Communicable and Non-communicable Diseases. Sand flies were collected using sticky paper and rodent burrow traps from five different microhabitats during three different phases of the year. Species identification was undertaken using appropriate taxonomic keys. Data were statistically analyzed to determine the distribution of kala-azar among different age groups and between sexes, and to compare the species richness and distribution of different sandfly species between the different microhabitats. RESULTS: The most affected age groups with kala-azar during the period 2013-2016 were children between one and five years old and those under one year. Females were found to be more affected than males. A total of 918 sand fly specimens were collected using sticky paper and rodent burrow traps from five microhabitats. Identified specimens belong to 13 species; 5 Phlebotomus and 8 Sergentomyia. Phlebotomus orientalis, the principal vector of visceral leishmaniasis (VL) in Sudan and other East African countries, was found for the first time in the area. No other known vector of VL was found in the collection. The highest number of sand flies was recorded during the summer season (63%), with S. antennata (48%) and S. schwetzi (24.1%) being the most abundant species. Among Phlebotomus species, P. orientalis showed relatively high density (8.6%). A dry seasonal water course (called "Khor") seems to be the most preferred habitat for most of the sand fly species since most of the collections (41.2%) were made from this site, followed by the rodent burrows. CONCLUSIONS: The presence of P. orientalis and the high prevalence of VL in infants in the Al Malha area provide the first evidence for local transmission of the parasite causing kala-azar in Darfur. Transmission is probably occurring during summer near the woodland where a high density of the vector was recorded. As a pre requisite for designing effective control of VL in North Darfur, large scale entomological and epidemiological studies are recommended. PMID- 29510745 TI - Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses. AB - BACKGROUND: Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. METHODS: Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. RESULTS: Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. CONCLUSIONS: This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. TRIAL REGISTRATION: Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009. PMID- 29510746 TI - Sarcocystosis in South American camelids: The state of play revisited. AB - Members of the genus Sarcocystis (Apicomplexa: Sarcocystidae) are intracellular protozoan parasites that infect a wide range of domestic and wild animals, resulting in economic losses in production animals worldwide. Sarcocystis spp. have indirect life-cycles where canids and felids serve as main definitive hosts while a range of domestic and wild animals serve as intermediate hosts, including South American camelids (SACs) such as alpacas, llamas and guanacos. These animals primarily occur in South American countries on Andean, elevated plains but in recent years, alpacas and llamas have become emerging animal industries in other parts of the world such as Australia, Europe and the USA due to their high quality fiber, meat and hides. For instance, alpaca meat is becoming popular in many parts of the world due to its lower cholesterol content than other red meat, thereby it has the potential of a valuable product for both local and international markets. However, SAC meat can be degraded and/or even condemned due to the presence of macroscopic sarcocysts in skeletal muscles, leading to significant economic losses to farmers. The infection is generally asymptomatic, though highly pathogenic or even fatal Sarcocystis infections have also been reported in alpacas and llamas. Despite the economic importance of sarcocystosis in SACs, little is known about the life-cycle of parasites involved, disease transmission, epidemiology, pathogenesis, diagnosis, control and public health significance. This review article provides an in-depth analysis of the existing knowledge on the taxonomy, epidemiology, clinicopathology and diagnosis of Sarcocystis in SACs, highlights knowledge gaps and proposes future areas of research that could contribute to our better understanding of sarcocystosis in these animals. PMID- 29510747 TI - The left frontal cortex supports reserve in aging by enhancing functional network efficiency. AB - BACKGROUND: Recent evidence derived from functional magnetic resonance imaging (fMRI) studies suggests that functional hubs (i.e., highly connected brain regions) are important for mental health. We found recently that global connectivity of a hub in the left frontal cortex (LFC connectivity) is associated with relatively preserved memory abilities and higher levels of protective factors (education, IQ) in normal aging and Alzheimer's disease. These results suggest that LFC connectivity supports reserve capacity, alleviating memory decline. An open question, however, is why LFC connectivity is beneficial and supports memory function in the face of neurodegeneration. We hypothesized that higher LFC connectivity is associated with enhanced efficiency in connected major networks involved in episodic memory. We further hypothesized that higher LFC related network efficiency predicts higher memory abilities. METHODS: We assessed fMRI during a face-name association learning task performed by 26 healthy, cognitively normal elderly participants. Using beta-series correlation analysis, we computed task-related LFC connectivity to key memory networks, including the default mode network (DMN) and dorsal attention network (DAN). Network efficiency within the DMN and DAN was estimated by the graph theoretical small-worldness statistic. We applied linear regression analyses to test the association between LFC connectivity with the DMN/DAN and small-worldness of these networks. Mediation analysis was applied to test LFC connectivity to the DMN and DAN as a mediator of the association between education and higher DMN and DAN small worldness. Last, we tested network small-worldness as a predictor of memory performance. RESULTS: We found that higher LFC connectivity to the DMN and DAN during successful memory encoding and recognition was associated with higher small-worldness of those networks. Higher task-related LFC connectivity mediated the association between education and higher small-worldness in the DMN and DAN. Further, higher small-worldness of these networks predicted better performance in the memory task. CONCLUSIONS: The present results suggest that higher education related LFC connectivity to key memory networks during a memory task is associated with higher network efficiency and thus enhanced reserve of memory abilities in aging. PMID- 29510748 TI - Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease. AB - Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age. These findings may explain the previously observed neuroprotective properties of C6R mHTT. As the C6R mutation cannot be easily translated into a therapeutic approach, we show that a scheduled feeding paradigm is sufficient to lower mHTT levels in YAC128 mice expressing cleavable mHTT. This is consistent with a previous model, where the presence of cleavable mHTT impairs basal autophagy, while fasting-induced autophagy remains functional. In HD, mHTT clearance and autophagy may become increasingly impaired as a function of age and disease stage, because of gradually increased activity of mHTT-processing enzymes. Our findings imply that mHTT clearance could be enhanced by a regulated dietary schedule that promotes autophagy. PMID- 29510750 TI - Leaving patients to their own devices? Smart technology, safety and therapeutic relationships. AB - BACKGROUND: This debate article explores how smart technologies may create a double-edged sword for patient safety and effective therapeutic relationships. Increasing utilization of health monitoring devices by patients will likely become an important aspect of self-care and preventive medicine. It may also help to enhance accurate symptom reports, diagnoses, and prompt referral to specialist care where appropriate. However, the development, marketing, and use of such technology raise significant ethical implications for therapeutic relationships and patient safety. MAIN TEXT: Drawing on lessons learned from other direct-to consumer health products such as genetic testing, this article explores how smart technology can also pose regulatory challenges and encourage overutilization of healthcare services. In order for smart technology to promote safer care and effective therapeutic encounters, the technology and its utilization must be safe. CONCLUSION: This article argues for unified regulatory guidelines and better education for both healthcare providers and patients regarding the benefits and risks of these devices. PMID- 29510752 TI - Notes from a field hospital south of Mosul. AB - This short letter from the field is offered as a rapid communique of the emergency medical situation in Mosul and surrounding areas on the eve of the final onslaught to liberate the city. This letter is based on emergency medical work at two World Health Organization (WHO) and Ministry of Health (MoH) Iraq lead Role II+ Field Hospital facilities south of Mosul City from April to June 2017; these facilities are currently and temporarily managed and administered by private medical industry until full handover to MoH Iraq, with WHO support and expert facilitation. The prominence of non-state actors in the conflict, using hybrid warfare tactics that maximize casualties, makes health security a particular challenge for the global community. This challenge requires health leaders and other actors in the region to set clear strategic goals that support public health of the many millions displaced, maimed and affected by the war. Whether in clinical medicine, development, peace and stability operations, or global health diplomacy, the shared values and conviction to best serve vulnerable communities and mitigate morbidity must embrace the lessons of evidenced based practice derived from military medical experience. WHO is leading the charge in disaster response for the conflict in Iraq, and many challenges remain. This might also include developing a new process in emergency medical response that utilizes private contracting to improve efficiency in delivery and overall sustainability. PMID- 29510749 TI - Control of Lyme borreliosis and other Ixodes ricinus-borne diseases. AB - Lyme borreliosis (LB) and other Ixodes ricinus-borne diseases (TBDs) are diseases that emerge from interactions of humans and domestic animals with infected ticks in nature. Nature, environmental and health policies at (inter)national and local levels affect the risk, disease burden and costs of TBDs. Knowledge on ticks, their pathogens and the diseases they cause have been increasing, and resulted in the discovery of a diversity of control options, which often are not highly effective on their own. Control strategies involving concerted actions from human and animal health sectors as well as from nature managers have not been formulated, let alone implemented. Control of TBDs asks for a "health in all policies" approach, both at the (inter)national level, but also at local levels. For example, wildlife protection and creating urban green spaces are important for animal and human well-being, but may increase the risk of TBDs. In contrast, culling or fencing out deer decreases the risk for TBDs under specific conditions, but may have adverse effects on biodiversity or may be societally unacceptable. Therefore, in the end, nature and health workers together must carry out tailor-made control options for the control of TBDs for humans and animals, with minimal effects on the environment. In that regard, multidisciplinary approaches in environmental, but also medical settings are needed. To facilitate this, communication and collaboration between experts from different fields, which may include patient representatives, should be promoted. PMID- 29510751 TI - Impact of district mental health care plans on symptom severity and functioning of patients with priority mental health conditions: the Programme for Improving Mental Health Care (PRIME) cohort protocol. AB - BACKGROUND: The Programme for Improving Mental Health Care (PRIME) sought to implement mental health care plans (MHCP) for four priority mental disorders (depression, alcohol use disorder, psychosis and epilepsy) into routine primary care in five low- and middle-income country districts. The impact of the MHCPs on disability was evaluated through establishment of priority disorder treatment cohorts. This paper describes the methodology of these PRIME cohorts. METHODS: One cohort for each disorder was recruited across some or all five districts: Sodo (Ethiopia), Sehore (India), Chitwan (Nepal), Dr. Kenneth Kaunda (South Africa) and Kamuli (Uganda), comprising 17 treatment cohorts in total (N = 2182). Participants were adults residing in the districts who were eligible to receive mental health treatment according to primary health care staff, trained by PRIME facilitators as per the district MHCP. Patients who screened positive for depression or AUD and who were not given a diagnosis by their clinicians (N = 709) were also recruited into comparison cohorts in Ethiopia, India, Nepal and South Africa. Caregivers of patients with epilepsy or psychosis were also recruited (N = 953), together with or on behalf of the person with a mental disorder, depending on the district. The target sample size was 200 (depression and AUD), or 150 (psychosis and epilepsy) patients initiating treatment in each recruiting district. Data collection activities were conducted by PRIME research teams. Participants completed follow-up assessments after 3 months (AUD and depression) or 6 months (psychosis and epilepsy), and after 12 months. Primary outcomes were impaired functioning, using the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS), and symptom severity, assessed using the Patient Health Questionnaire (depression), the Alcohol Use Disorder Identification Test (AUD), and number of seizures (epilepsy). DISCUSSION: Cohort recruitment was a function of the clinical detection rate by primary health care staff, and did not meet all planned targets. The cross-country methodology reflected the pragmatic nature of the PRIME cohorts: while the heterogeneity in methods of recruitment was a consequence of differences in health systems and MHCPs, the use of the WHODAS as primary outcome measure will allow for comparison of functioning recovery across sites and disorders. PMID- 29510753 TI - Physical activity, obesity and sedentary behaviour and the risks of colon and rectal cancers in the 45 and up study. AB - BACKGROUND: Obesity and physical activity (PA) are predictors of colon (CC) and rectal (RC) cancers. Prolonged sitting is also emerging as a potential predictor for these cancers. Little knowledge exists about the interactive effects of obesity, PA and prolonged sitting on cancer risk. This analysis assessed independent and interactive effects of PA, body mass index (BMI) and sitting time on CC and RC risks. METHODS: This analysis used data from a prospective study of 226,584 participants aged 45 years and over in New South Wales (NSW), Australia, who joined the 45 and Up study between 2006 and 2009. Baseline data were linked with data relating to mortality, cancer registration, hospital admission and Department of Human Services to December 2010. Multivariable Cox regression was used to estimate adjusted hazard ratios (referred to as relative risks, RRs) and 95% confidence intervals (Cis). Statistical significance was defined as p < 0.05. RESULTS: There were 846 and 369 ascertained cases of CC and RC. BMI was positively associated with CC risk (p = 0.003, P-trend = 0.0006) but not with RC. CC risk was increased in participants in the highest BMI quartile (>=29.4-<=50 kg/m2) compared to the lowest (15- < 23.6 kg/m2), (RR = 1.32, 95% CI:1.08-1.63). PA was associated with CC risk (p = 0.02) but not with RC. Specifically, CC risk was lower in individuals partaking in any amount of vigorous activity (time/week) compared to participants with no engagement (RR = 0.78, 95% CI:0.65-0.93). Sitting time was not associated with CC or RC. We found no evidence of interactive effects of PA, BMI and prolonged sitting on cancer risk. CONCLUSION: This evidence suggests that a healthy weight and vigorous activity are essential to reduce CC risk since these factors may be independent of each other. PMID- 29510754 TI - Predictive factors for major postoperative complications related to gastric conduit reconstruction in thoracoscopic esophagectomy for esophageal cancer: a case control study. AB - BACKGROUND: Regardless of developments in thoracoscopic esophagectomy (TE), postoperative complications relative to gastric conduit reconstruction are common after esophagectomy. The aim of the present study was to evaluate the predictive factors of major complications related to gastric conduit after TE. METHODS: From 2006 to 2015, 75 patients with esophageal cancer who underwent TE were evaluated to explore the predictive factors of major postoperative complications related to gastric conduit. RESULTS: Patients with major complications related to gastric conduit had a significantly longer postoperative hospital stay than patients without these complications (P < 0.01). Multivariate analysis demonstrated that three-field lymph node dissection (3FLND) and high serum levels of creatine phosphokinase (CPK) and C-reactive protein (CRP) at 1 postoperative day (1POD) after TE were significant predictive factors of major complications related to gastric conduit [odds ratio (OR) 5.37, 95% confidence interval (CI) 1.41-24.33, P = 0.02; OR 5.40, 95% CI 1.60-20.20, P < 0.01; OR 5.07, 95% CI 1.47-20.25, P = 0.01, respectively]. The incidence rates of major complications related to gastric conduit for 0, 1, 2, and 3 predictive factors were 5.3%, 18.8%, 58.8%, and 85.7%, respectively (P < 0.01). CONCLUSIONS: Two or more factors in 3FLND and the high levels of CPK and CRP at 1POD after TE were identified as the risk model for major complications related to gastric conduit after TE. TRIAL REGISTRATION: UMIN Clinical Trials Registry, ID: UMIN000024436 , Registered date: Oct/17/2016. PMID- 29510756 TI - Evaluation of public subsidy for medical travel: does it protect against household impoverishment? AB - BACKGROUND: In resource-constrained health systems medical travel is a common alternative to seeking unavailable health services. This paper was motivated by the need to understand better the impact of such travel on households and health systems. METHODS: We used primary data from 344 subsidized and 471 non-subsidized inbound medical travellers during June to December 2013 drawn from the North, Centre and South regions of the Maldives where three international airports are located. Using a researcher-administered questionnaire to acquire data, we calculated annual out-of-pocket (OOP) spending on health, food and non-food items among households where at least one member had travelled to another country for medical care within the last year and estimated the poverty head count using household income as a living standard measure. RESULTS: Most of the socio demographic indicators, and costs of treatment abroad among Maldivian medical travellers were similar across different household income levels with no statistical difference between subsidized and non-subsidized travellers (p value: 0.499). The government subsidy across income quintiles was also similar indicating that the Maldivian health financing structure supports equality rather than being equity-sensitive. There was no statistical difference in OOP expenditure on medical care abroad and annual OOP expenditure on healthcare was similar across income quintiles. Diseases of the circulatory system, eye and musculoskeletal system had the most impoverishing effect - diseases for which half of the patients, or less, did not receive the public subsidy. Annually, 6 and 14% of the medical travellers in the Maldives fell into poverty ($2 per day) before and after making OOP payments to health care. CONCLUSION: Evidence of a strong association between predominant public financing of medical travel and equality was found. With universal eligibility to the government subsidy for medical travel, utilization of treatment abroad, medical expenditures abroad and OOP expenditures on health among Maldivian medical travellers were similar between the poor and the rich. However, we conclude mixed evidence on the linkages between public financing of medical travel and impoverishment which needs to be further explored with comparison of impoverishment levels between households with and without medical travel. PMID- 29510757 TI - Correction to: Metacognitive therapy vs. eye movement desensitization and reprocessing for posttraumatic stress disorder: study protocol for a randomized superiority trial. AB - CORRECTION TO: TRIALS (2018) 19: 16. HTTPS://DOI.ORG/10.1186/S13063-017-2404-7: In the original publication of this article [1] the SPIRIT figure for the study protocol was not included. In this Correction Article the SPIRIT figure (Fig. 1) is published. The original publication has been updated with the SPIRIT figure. PMID- 29510755 TI - Whole exome sequencing in three families segregating a pediatric case of sarcoidosis. AB - BACKGROUND: Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole exome sequencing (WES) methodology. METHODS: From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) ( https://clinicaltrials.gov ) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST - 2 - REF IRB 00009118 - September 21, 2016). RESULTS: We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. CONCLUSIONS: Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants. PMID- 29510758 TI - Garcin syndrome caused by sphenoid bone metastasis of lung cancer: a case study. AB - BACKGROUND: Garcin syndrome, which consists of unilateral palsies of almost all cranial nerves without either sensory or motor long-tract disturbances or intracranial hypertension, can be caused by malignant tumors at the skull base. The case of a patient with lung cancer that metastasized to the sphenoid bone and resulted in Garcin syndrome is presented. CASE PRESENTATION: A 76-year-old woman was diagnosed as having non-small cell lung cancer with pericardial and diaphragmatic infiltration, cT4N1M0, stage 3A. The left lower lobectomy with concomitant resection of the pericardium and diaphragm was performed. The pathological diagnosis was pleomorphic carcinoma, pT2bN0M0, stage 1B. She was then followed in the surgery clinic, and 2 months after surgery, she visited an emergency room complaining of headache and diplopia. Neurological examination showed the left IV, V1, and VI cranial nerve palsies. Metastatic tumor with bone destruction was found in the left sphenoid sinus on head computed tomography (CT) and contrast magnetic resonance imaging (MRI), and she was diagnosed with Garcin syndrome caused by sphenoid bone metastasis of lung cancer. Irradiation was performed as palliative treatment, but her neurological findings did not improve. Her general condition gradually worsened, and she died 5 months after surgery. CONCLUSIONS: Bone metastasis of lung cancer occurs frequently, but sphenoid bone metastasis is extremely rare. In this case report, Garcin syndrome caused by lung cancer is discussed in the context of the few previous reports. PMID- 29510759 TI - On the suitability of an allometric proxy for nondestructive estimation of average leaf dry weight in eelgrass shoots I: sensitivity analysis and examination of the influences of data quality, analysis method, and sample size on precision. AB - BACKGROUND: The effects of current anthropogenic influences on eelgrass (Zostera marina) meadows are noticeable. Eelgrass ecological services grant important benefits for mankind. Preservation of eelgrass meadows include several transplantation methods. Evaluation of establishing success relies on the estimation of standing stock and productivity. Average leaf biomass in shoots is a fundamental component of standing stock. Existing methods of leaf biomass measurement are destructive and time consuming. These assessments could alter shoot density in developing transplants. Allometric methods offer convenient indirect assessments of individual leaf biomass. Aggregation of single leaf projections produce surrogates for average leaf biomass in shoots. Involved parameters are time invariant, then derived proxies yield simplified nondestructive approximations. On spite of time invariance local factors induce relative variability of parameter estimates. This influences accuracy of surrogates. And factors like analysis method, sample size and data quality also impact precision. Besides, scaling projections are sensitive to parameter fluctuation. Thus the suitability of the addressed allometric approximations requires clarification. RESULTS: The considered proxies produced accurate indirect assessments of observed values. Only parameter estimates fitted from raw data using nonlinear regression, produced robust approximations. Data quality influenced sensitivity and sample size for an optimal precision. CONCLUSIONS: Allometric surrogates of average leaf biomass in eelgrass shoots offer convenient nondestructive assessments. But analysis method and sample size can influence accuracy in a direct manner. Standardized routines for data quality are crucial on granting cost-effectiveness of the method. PMID- 29510761 TI - Murine Gbp1 and Gbp2 are ubiquitinated independent of Toxoplasma gondii infection. AB - OBJECTIVE: The intracellular parasite Toxoplasma gondii can invade any nucleated cell residing inside a parasitophorous vacuole (PV). Upon infection, the cytokine interferon gamma (IFNgamma) is produced and elicits host defence mechanisms able to recognise the PV and destroy the parasite. Hereby, Guanylate binding proteins, ubiquitin and the E3 ubiquitin ligases Tripartite Motif Containing 21 (TRIM21) and TNF receptor associated factor 6 are targeted to the murine PV leading to its destruction. This study is the side product of research aiming to identify ubiquitinated substrates in a TRIM21-dependent fashion in murine cells infected with Toxoplasma. RESULTS: We infected IFNgamma-stimulated murine embryonic fibroblasts (MEFs) from either C57BL/6*129 wild-type (WT) mice or C57BL/6 TRIM21 /- mice with Toxoplasma. Using mass spectrometry, we analysed proteins in both cell backgrounds presenting with the di-glycine remnant of ubiquitination. In addition, we compared peptide levels between WT and TRIM21-/- cells. In line with earlier reports, Gbp1 was expressed to higher levels in the C57BL/6*129 WT MEFs compared to the C57BL/6-only background TRIM21-/- MEFs. Protein expression differences in these different murine backgrounds thus precluded identification of TRIM21-dependent ubiquitinated substrates. Nevertheless, we identified and confirmed Gbp1 and Gbp2 as being ubiquitinated in a Toxoplasma-infection independent manner. PMID- 29510760 TI - Cysteine peptidases of Eudiplozoon nipponicum: a broad repertoire of structurally assorted cathepsins L in contrast to the scarcity of cathepsins B in an invasive species of haematophagous monogenean of common carp. AB - BACKGROUND: Cysteine peptidases of clan CA, family C1 account for a major part of proteolytic activity in the haematophagous monogenean Eudiplozoon nipponicum. The full spectrum of cysteine cathepsins is, however, unknown and their particular biochemical properties, tissue localisation, and involvement in parasite-host relationships are yet to be explored. METHODS: Sequences of cathepsins L and B (EnCL and EnCB) were mined from E. nipponicum transcriptome and analysed bioinformatically. Genes encoding two EnCLs and one EnCB were cloned and recombinant proteins produced in vitro. The enzymes were purified by chromatography and their activity towards selected substrates was characterised. Antibodies and specific RNA probes were employed for localisation of the enzymes/transcripts in tissues of E. nipponicum adults. RESULTS: Transcriptomic analysis revealed a set of ten distinct transcripts that encode EnCLs. The enzymes are significantly variable in their active sites, specifically the S2 subsites responsible for interaction with substrates. Some of them display unusual structural features that resemble cathepsins B and S. Two recombinant EnCLs had different pH activity profiles against both synthetic and macromolecular substrates, and were able to hydrolyse blood proteins and collagen I. They were localised in the haematin cells of the worm's digestive tract and in gut lumen. The EnCB showed similarity with cathepsin B2 of Schistosoma mansoni. It displays molecular features typical of cathepsins B, including an occluding loop responsible for its exopeptidase activity. Although the EnCB hydrolysed haemoglobin in vitro, it was localised in the vitelline cells of the parasite and not the digestive tract. CONCLUSIONS: To our knowledge, this study represents the first complex bioinformatic and biochemical characterisation of cysteine peptidases in a monogenean. Eudiplozoon nipponicum adults express a variety of CLs, which are the most abundant peptidases in the worms. The properties and localisation of the two heterologously expressed EnCLs indicate a central role in the (partially extracellular?) digestion of host blood proteins. High variability of substrate-binding sites in the set of EnCLs suggests specific adaptation to a range of biological processes that require proteolysis. Surprisingly, a single cathepsin B is expressed by the parasite and it is not involved in digestion, but probably in vitellogenesis. PMID- 29510763 TI - Zika Virus Preparedness and Response Efforts Through the Collaboration Between a Health Care Delivery System and a Local Public Health Department. AB - The Zika virus was largely unknown to many health care systems before the outbreak of 2015. The unique public health threat posed by the Zika virus and the evolving understanding of its pathology required continuous communication between a health care delivery system and a local public health department. By leveraging an existing relationship, NYC Health+Hospitals worked closely with New York City Department of Health and Mental Hygiene to ensure that Zika-related processes and procedures within NYC Health+Hospitals facilities aligned with the most current Zika virus guidance. Support given by the public health department included prenatal clinical and laboratory support and the sharing of data on NYC Health+Hospitals Zika virus screening and testing rates, thus enabling this health care delivery system to make informed decisions and practices. The close coordination, collaboration, and communication between the health care delivery system and the local public health department examined in this article demonstrate the importance of working together to combat a complex public health emergency and how this relationship can serve as a guide for other jurisdictions to optimize collaboration between external partners during major outbreaks, emerging threats, and disasters that affect public health. (Disaster Med Public Health Preparedness. 2018;page 1 of 3). PMID- 29510764 TI - A cross-sectional survey of nutrition labelling use and its associated factors on parents of school students in Shanghai, China. AB - OBJECTIVE: To understand parents' knowledge and use of nutrition labelling and to explore its associated factors. DESIGN: Cross-sectional survey. SETTING: Two schools providing a nine-year educational programme in Putuo District, Shanghai, China, were selected for the study. Information was included on demographic data and knowledge of the Chinese Food Pagoda. SUBJECTS: Students and their parents (n 1770) participated in a questionnaire survey. RESULTS: Of questionnaires, 1766 were completed (response rate 99.8 %). Utilization rate of nutrition labelling was 19.3 %. Among 624 parents knowing nutrition labelling, 22.1 % understood all the information included, 70.7 % understood it partially and 7.2 % could not understand it at all. Use of nutrition labelling by parents was related to the following factors (OR; 95 % CI): high educational level of parent (1.465; 1.165, 1.841), parent's knowledge of the Chinese Food Pagoda (1.333; 1.053, 1.688), parent's consumption of top three snacks which are unhealthy (1.065; 1.023, 1.109), parent's assumption that nutrition labelling would affect their choice of food (1.522; 1.131, 2.048), student's willingness to learn about labels (1.449; 1.093, 1.920) and student's knowledge and use of labels (2.214; 1.951, 2.513). CONCLUSIONS: Parents' knowledge and use of nutrition labelling are still at a lower level, and some information included in the nutrition labels is not understood by parents. The forms of the existing nutrition labelling need to be continuously improved to facilitate their understanding and usefulness. It is necessary to establish nutrition projects focusing on education and use of nutrition labels which help parents and their children make the right choices in selecting foods. PMID- 29510762 TI - The Norwegian healthy body image programme: study protocol for a randomized controlled school-based intervention to promote positive body image and prevent disordered eating among Norwegian high school students. AB - BACKGROUND: Body dissatisfaction and disordered eating raise the risk for eating disorders. In the prevention of eating disorders, many programmes have proved partly successful in using cognitive techniques to combat such risk factors. However, specific strategies to actively promote a positive body image are rarely used. The present paper outlines a protocol for a programme integrating the promotion of a positive body image and the prevention of disordered eating. METHODS AND DESIGN: Using a cluster randomized controlled mixed methods design, 30 high schools and 2481 12th grade students were allocated to the Healthy Body Image programme or to a control condition. The intervention comprised three workshops, each of 90 min with the main themes body image, media literacy, and lifestyle. The intervention was interactive in nature, and were led by trained scientists. The outcome measures include standardized instruments administered pre-post intervention, and at 3 and 12 months follow-ups, respectively. Survey data cover feasibility and implementation issues. Qualitative interviews covers experiential data about students' benefits and satisfaction with the programme. DISCUSSION: The present study is one of the first in the body image and disordered eating literature that integrates a health promotion and a disease prevention approach, as well as integrating standardized outcome measures and experiential findings. Along with mediator and moderator analyses it is expected that the Healthy Body Image programme may prove its efficacy. If so, plans are made with respect to further dissemination as well as communicating the findings to regional and national decision makers in the education and health care services. TRIAL REGISTRATION: The study was registered and released at ClinicalTrials.gov 21th August 2016 with the Clinical Trial.gov ID: PRSNCT02901457 . In addition, the study is approved by the Regional Committee for Medical and Health Research Ethics. PMID- 29510765 TI - Enhancing Global Health Security: US Africa Command's Disaster Preparedness Program. AB - US Africa Command's Disaster Preparedness Program (DPP), implemented by the Center for Disaster and Humanitarian Assistance Medicine, partnered with US Government agencies and international organizations to promote stability and security on the African continent by engaging with African Partner Nations' (PN) civil and military authorities to improve disaster management capabilities. From 2008 to 2015, DPP conducted disaster preparedness and response programming with 17 PNs. DPP held a series of engagements with each, including workshops, strategic planning, developing preparedness and response plans, tabletop exercises, and prioritizing disaster management capability gaps identified through the engagements. DPP partners collected data for each PN to further capacity building efforts. Thus far, 9 countries have completed military pandemic plans, 10 have developed national pandemic influenza plans, 9 have developed military support to civil authorities plans, and 11 have developed disaster management strategic work plans. There have been 20 national exercises conducted since 2009. DPP was cited as key in implementation of Ebola response plans in PNs, facilitated development of disaster management agencies in DPP PNs, and trained nearly 800 individuals. DPP enhanced PNs' ability to prepare and respond to crises, fostering relationships between international agencies, and improving civil-military coordination through both national and regional capacity building. (Disaster Med Public Health Preparedness. 2018;page 1 of 11). PMID- 29510766 TI - Prematurity at birth and adolescent depressive disorder-CORRIGENDUM. PMID- 29510767 TI - Review: Principles of maximizing bull semen production at genetic centers. AB - Knowledge of the capabilities and limitations of the reproductive capacity of bulls is vital in maximizing reproductive efficiencies. Bull semen collection guidelines established by researchers and industry personnel to maximize the sperm harvest from bulls have been evolving for more than 60 years. Today, a mature artificial insemination industry employs those strategies to meet demands. These efficient management schemes exploit the reproductive potential of each sire while minimizing the associated risk of injury to bulls and reduce associated production costs. Personnel employed by a semen producing facility must be authorized to make effective and rational decisions based on principles of bull sexual behavior and reproductive physiology. Furthermore, collection facilities must be well planned to allow for the safe presentation of novel sexual situations while affording maximum safety for employees and proper footing for bulls. Normal bulls produce and ejaculate tremendous numbers of sperm. Most bulls have a sufficient libido for routine sexual activity, but become satiated to predictable stimulus situations. Frequent changes to the novelty should allow weekly harvest of four to six ejaculates per week for most bulls. Utilizing the physiological characteristics associated with each ejaculate to establish the collection frequency of each bull, and empowering an integrated collection and laboratory staff to monitor and make adjustments to the ejaculation frequency are necessary in maximizing the sperm harvest. Young bulls can ejaculate 10 to 20 billion sperm per week, and mature bulls should ejaculate 40 to 60 billion sperm per week. Semen collection management procedures should be reviewed when bulls do not meet production goals. PMID- 29510768 TI - Debate: The concept of culture has outlived its usefulness for psychiatry. AB - This paper presents a debate in which the authors participated at the World Psychiatric Association conference in Cape Town, South Africa in November 2016. Professor van Staden acted as chair and here, as at the debate, provides a rationale for debating a topic that many of those involved in mental health believe to be decided. The discussion that ensued demonstrated, however, that while the arguments have moved on they have not ceased. Who won? Well that depends how you look at it. A few in the audience shifted position towards the motion but the majority remained opposed. What do you think? Declaration of interest None. PMID- 29510769 TI - Parental perception of child weight and its association with weight-related parenting behaviours and child behaviours: a Chinese national study. AB - OBJECTIVE: Parents commonly fail to correctly recognize the weight status of their child. Whether parental perception of child weight is associated with weight-related parenting behaviours and child behaviours is unclear. The present study aimed to investigate the distribution of parental perception of child weight and its associations with weight-related parenting behaviours and child behaviours in China. DESIGN: Cross-sectional study. SETTING: Seven provinces in China. SUBJECTS: A total of 47 417 children aged 6-17 years and their parents were included from a national survey in 2013. Parental perception of child weight, weight-related parenting behaviours and child behaviours were self reported. Child's weight and height were objectively measured. RESULTS: A total of 30.5 % of parents underestimated and 8.7 % overestimated the child's weight. Parental underestimation was more common among younger children, boys and children with a lower BMI Z-score. Parents who perceived that their child had a healthy weight (accurately or inaccurately) were more likely to prepare breakfast for the child, exercise with him/her, set apart his/her exercise time, restrict his/her screen time, and were less likely to store soft drinks for the child. Children perceived to have a healthy weight, regardless of their actual weight status, behaved healthier on dietary intake, physical activity and homework time. CONCLUSIONS: Parental underestimation of their child's weight was prominent in China, especially among younger children, boys and children with a lower BMI Z score. Parental recognition of their child being overweight did not appear to translate into healthy changes in weight-related parenting behaviours or child behaviours. PMID- 29510770 TI - A Neuropsychological Profile for Agenesis of the Corpus Callosum? Cognitive, Academic, Executive, Social, and Behavioral Functioning in School-Age Children. AB - OBJECTIVES: Agenesis of the corpus callosum (AgCC), characterized by developmental absence of the corpus callosum, is one of the most common congenital brain malformations. To date, there are limited data on the neuropsychological consequences of AgCC and factors that modulate different outcomes, especially in children. This study aimed to describe general intellectual, academic, executive, social and behavioral functioning in a cohort of school-aged children presenting for clinical services to a hospital and diagnosed with AgCC. The influences of age, social risk and neurological factors were examined. METHODS: Twenty-eight school-aged children (8 to 17 years) diagnosed with AgCC completed tests of general intelligence (IQ) and academic functioning. Executive, social and behavioral functioning in daily life, and social risk, were estimated from parent and teacher rated questionnaires. MRI findings reviewed by a pediatric neurologist confirmed diagnosis and identified brain characteristics. Clinical details including the presence of epilepsy and diagnosed genetic condition were obtained from medical records. RESULTS: In our cohort, ~50% of children experienced general intellectual, academic, executive, social and/or behavioral difficulties and ~20% were functioning at a level comparable to typically developing children. Social risk was important for understanding variability in neuropsychological outcomes. Brain anomalies and complete AgCC were associated with lower mathematics performance and poorer executive functioning. CONCLUSIONS: This is the first comprehensive report of general intellectual, academic, executive social and behavioral consequences of AgCC in school-aged children. The findings have important clinical implications, suggesting that support to families and targeted intervention could promote positive neuropsychological functioning in children with AgCC who come to clinical attention. (JINS, 2018, 24, 445-455). PMID- 29510771 TI - Are Schemas Passed on? A Study on the Association Between Early Maladaptive Schemas in Parents and Their Offspring and the Putative Translating Mechanisms. AB - BACKGROUND: According to Young's schema theory, Early Maladaptive Schemas (EMSs) arise due to the violation of core emotional needs during childhood. It seems likely that parents have difficulties in satisfying their children's emotional needs if they have high levels of EMSs themselves. AIMS: This study investigated whether the extent of EMSs in parents is associated with the extent of EMSs in their offspring. Moreover, we tested for two putative mechanisms that account for this association: parental coping styles and parenting behaviour. METHODS: Sixty dyads of parents (mother or father) and their adult children (N = 120), recruited from the general population, completed the Young Schema Questionnaire. The parents rated their schema coping styles and the children retrospectively rated the parenting of the participating parent. RESULTS: As expected, parents' EMSs were significantly associated with EMSs in their offspring. This association was accounted for by the parental coping style Overcompensation and the adverse parenting that the child remembered. The parental coping style Avoidance did not account for the association. CONCLUSIONS: This study provides preliminary evidence for the notion that EMSs are passed on from one generation to the next via parental coping and parenting. Our findings thus support the assumption of schema theory that EMSs are connected to the family environment in terms of adverse parenting. If further confirmed, this has relevant implications for family-based interventions. PMID- 29510772 TI - Effect of exercise on apparent total tract digestibility of nutrients and faecal recovery of ADL and TiO2 in ponies. AB - Exercise and physical training are known to affect gastrointestinal function and digestibility in horses and can lead to inaccurate estimates of nutrient and energy digestibility when markers are used. The effect of exercise on apparent nutrient digestibility and faecal recoveries of ADL and TiO2 was studied in six Welsh pony geldings subjected to either a low- (LI) or high-intensity (HI) exercise regime according to a cross-over design. Ponies performing LI exercise were walked once per day for 45 min in a horse walker (5 km/h) for 47 consecutive days. Ponies submitted to HI exercise were gradually trained for the same 47 days according a standardized protocol. Throughout the experiment, the ponies received a fixed level of feed and the daily rations consisted of 4.7 kg DM of grass hay and 0.95 kg DM of concentrate. The diet was supplemented with minerals, vitamins and TiO2 (3.0 g Ti/day). Total tract digestibility of DM, organic matter (OM), CP, crude fat, NDF, ADF, starch, sugar and energy was determined with the total faeces collection (TFC) method. In addition, DM and OM digestibility was estimated using internal ADL and the externally supplemented Ti as markers. Urine was collected on the final 2 days of each experimental period. Exercise did not affect apparent digestibility of CP, crude fat, starch and sugar. Digestibility of DM (DMD), OM (OMD), ADF and NDF tended to be lower and DE was decreased when ponies received the HI exercise regime. For all treatments combined, mean faecal recoveries of ADL and Ti were 87.8+/-1.7% and 99.3+/-1.7%, respectively. Ti was not detected in the urine, indicating that intestinal integrity was maintained with exercise. Dry matter digestibility estimated with the TFC, ADL and Ti for ponies subjected to LI exercise were 66.3%, 60.3% and 64.8%, respectively, while DMD for HI ponies were 64.2%, 60.3% and 65.2%, respectively. In conclusion, physical exercise has an influence on the GE digestibility of the feed in ponies provided with equivalent levels of feed intake. In addition, the two markers used for estimating apparent DMD and OMD indicate that externally supplemented Ti is a suitable marker to determine digestibility of nutrients in horses performing exercise unlike dietary ADL. PMID- 29510773 TI - Why do People Overthink? A Longitudinal Investigation of a Meta-Cognitive Model and Uncontrollability of Rumination. AB - BACKGROUND: The meta-cognitive model of rumination is a theoretical model regarding the relationship between rumination and depression. Although meta cognitive therapy for rumination was established based on this model, insufficient longitudinal studies addressing this model have been conducted. Moreover, the uncontrollability of rumination, suggested to be driven by negative meta-beliefs about rumination, has not been examined using this meta-cognitive model. AIMS: We longitudinally examined the meta-cognitive model and its relationship with uncontrollability of rumination and depressive symptoms. METHOD: Undergraduate students (n = 117) were asked to complete two measurements (with a 6-month gap between them) of positive and negative meta-beliefs about rumination, causal analysis, understanding, uncontrollability of rumination and depression. RESULTS: Cross-lagged effect modelling revealed that positive meta beliefs predicted high causal analytic rumination. However, the results did not support the causal analytic and understanding aspects of how rumination predicted negative meta-beliefs. Negative meta-beliefs predicted high depressive symptoms, and depressive symptoms predicted high negative meta-beliefs. Negative meta beliefs predicted high uncontrollability of rumination, whereas uncontrollability of rumination did not predict depressive symptoms. CONCLUSIONS: The results partially supported the meta-cognitive model. The prediction of depressive symptoms on negative meta-beliefs suggests that depression-related cognition might be involved in increasing negative meta-beliefs, rather than the repetitive causal analytic and understanding aspects of rumination. In line with meta cognitive therapy, negative meta-beliefs could be a target for treating depression. PMID- 29510774 TI - Patient experience of nasal obstruction and its clinical assessment. AB - BACKGROUND: The correlation between objective and subjective nasal obstruction is poor, and dissatisfaction rates after surgery for nasal obstruction are high. Accordingly, novel assessment techniques may be required. This survey aimed to determine patient experience and preferences for the measurement of nasal obstruction. METHOD: Prospective survey of rhinology patients. RESULTS: Of 72 questionnaires distributed, 60 were completed (response rate of 83 per cent). Obstruction duration (more than one year) (chi2 = 13.5, p = 0.00024), but not obstruction severity, affected willingness to spend more time being assessed. Questionnaires (48 per cent) and nasal inspiratory peak flow measurement (53 per cent) are the most commonly used assessment techniques. Forty-nine per cent of participants found their assessment unhelpful in understanding their obstruction. Eighty-two per cent agreed or strongly agreed that a visual and numerical aid would help them understand their blockage. CONCLUSION: Many patients are dissatisfied with current assessment techniques; a novel device with visual or numerical results may help. Obstruction duration determines willingness to undergo longer assessment. PMID- 29510775 TI - Evaluation and Gap Analysis of Pediatric Disaster Preparedness Resources. AB - The goal of this research was to identify, summarize, and evaluate pediatric disaster preparedness resources in the United States and to identify areas that need improvement or further development. Using standard literature, gray literature and website reviews, relevant resources were identified and the 50 most relevant resources were studied in depth. Each resource was given a grade of A, B, or C based on content, format, quality, and thoroughness. These resources were divided into 3 categories: (1) hospital resources, (2) school resources, and (3) training/education resources. Half of the 50 resources (25) were given a grade of A, indicating the highest level of quality and thoroughness, with pertinent information presented in a clear format. Sixteen of the resources were given a rating of B, while 9 of the resources were given a rating of C. Over 60% of the resources did not contain culturally sensitive information and more than 60% of the resources did not contain preparedness information for children with disabilities. Resources specific to hospitals and schools were limited in number and quality available, while training/education resources were widely available. In addition, 60% of resources were not specific to schools, children's hospitals, or to certain occupations (ie, nurses, doctors, teachers, principals). Based on these results, gaps in cultural sensitivity were identified and limitations in resources for children with disabilities and for schools and hospitals currently exist. All these areas require further development in the field of pediatric disaster preparedness (Disaster Med Public Health Preparedness. 2018;page 1 of 8). PMID- 29510776 TI - MiR-126 functions as a tumor suppressor by targeting SRPK1 in human gastric cancer. AB - The expression of miR-126 and serine-arginine protein kinase 1 (SRPK1) are linked to tumor development; nevertheless, its role in tumor growth and invasion of gastric cancer (GC) and the underlying mechanism has not been clarified. Here, the expression and role of miR-126 and SRPK1 was investigated in GC tissues and cells by in-vitro assay, and then targets of miR-126 were identified by dual luciferase reporter assay. In this study, miR-126 expression was downregulated, and associated with lymph node metastasis and poor prognosis as well as SRPK1 expression. In vitro assay revealed that miR-126 obviously inhibited proliferation and invasive capability of GC cells. Dualluciferase reporter assay showed that miR-126 targets 3'-UTR of SRPK1 and downregulates its expression. Besides, SRPK1 over-expression promoted cell migration and invasion. In conclusion, we identified that miR-126 suppresses tumor growth and metastasis in GC by targeting SRPK1. The expression of miR-126 suggests GC recurrence and metastasis, which shed crucial light on how miR-126 functions in GC pathogenesis. PMID- 29510777 TI - LincRNA FEZF1-AS1 is associated with prognosis in lung adenocarcinoma and promotes cell proliferation, migration and invasion. AB - Long non-coding RNAs (lncRNA) have been reported to play important roles in tumorigenesis. In present study, we demonstrated long noncoding RNA (lncRNA) FEZF1 antisense RNA1 (FEZF1-AS1) is markedly upregulated in human lung adenocarcinoma (LAD) tissues, cell lines and associated with poor prognosis. Loss of-function revealed that deletion of FEZF1-AS1 expression significantly inhibited the LAD cells proliferation, invasion and migration. Further studies revealed that downregulation of FEZF1-AS1 reduced mRNA and protein expression of its sense-cognate gene FEZF1 (forebrain embryonic zinc finger protein 1) in LAD cells, and vice versa. Correlation analysis indicated that there was a positive correlation between FEZF1-AS1 and FEZF1 expression in LAD tissues. Additionally, rescue assay confirmed that the function of FEZF1-AS1 in LAD was mediated by FEZF1. Our findings suggested that dysregulation of FEZF1-AS1 contributed to the progression of LAD which might be a potential target for LAD therapy. PMID- 29510778 TI - Long non-coding RNA FEZF1-AS1 promotes osteosarcoma progression by regulating miR 4443/NUPR1 axis. AB - Long non-coding RNA (lncRNA) FEZF1-AS1 was demonstrated to facilitate cell proliferation and migration in some cancers.However, the functions of FEZF1-AS1 and its molecular mechanism in osteosarcoma remain to be elucidated. In our study, we found that the expression of FEZF1-AS1 was up-regulated in osteosarcoma samples and cell lines compared with normal tissues or cells. Besides, we showed that the expression levels of FEZF1-AS1 in osteosarcoma patients were positively correlated with tumor metastasis and TNM stage. Additionally, FEZF1-AS1 knockdown inhibited cell proliferation, migration and invasion in U2OS and MG63 cells, and vice versa in vitro. Moreover, FEZF1-AS1 depletion inhibited tumor growth and metastasis in vivo. In mechanism, we found that FEZF1-AS1 sponged miR-4443 to promote NUPR1 expression in U2OS and MG63 cells. Furthermore, knockdown of miR 4443 abrogated FEZF1-AS1 silence-induced inhibition of cell proliferation, migration and invasion in osteosarcoma. Finally, we found that restoration of NUPR1 rescued the proliferation, migration and invasion abilities of FEZF1-AS1 depleted U2OS and MG63 cells. In collection, our study indicated that FEZF1-AS1 could promote osteosarcoma progression by sponging miR-4443 to promote NUPR1 expression. The FEZF1-AS1/miR-4443/NUPR1 axis may act as a novel therapeutic strategy for osteosarcoma treatment. PMID- 29510779 TI - MicroRNA-331 inhibits proliferation and invasion of melanoma cells by targeting astrocyte-elevated gene-1. AB - Melanoma is characterised by aggressive invasion, early metastasis and resistance to existing chemotherapeutic agents.Accumulated studies have reported that microRNA (miRNA) is a potentially robust molecular tool for developing future therapeutic technologies. Therefore, examining the expression patterns, biological roles and associated mechanisms of cancer-related miRNAs in melanoma is essential for developing novel therapeutic targets for patients with this disease. In this study, miRNA-331 (miR-331) was underexpressed in melanoma tissues and cell lines. Functional assays revealed that the enforced expression of miR-331 inhibited cell proliferation and invasion. In addition, astrocyte elevated gene-1 (AEG-1) was identified as a novel target of miR-331 through bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction analysis, Western blot analysis, luciferase reporter assay and Spearman's correlation analysis. Furthermore, reintroduction of AEG-1 partially abrogated the inhibitory effects of miR-331 overexpression on the proliferation and invasion of melanoma cells. Moreover, miR-331 suppressed the activation of the PTEN/AKT signalling pathway in melanoma by inhibiting AEG-1. In short, miR 331 may play tumor-suppressive roles in melanoma by directly targeting AEG-1 and regulating the PTEN/AKT signalling pathway, suggesting that miR-331 could be investigated as a therapeutic strategy for patients with this malignancy. PMID- 29510780 TI - Hepatitis A outbreak since November 2016 affecting men who have sex with men (MSM) in Chile connected to the current outbreak in MSM in Europe, situation up to October 2017. AB - A hepatitis A outbreak has occurred in Chile since November 2016. Men are predominantly affected, with a large proportion of men who have sex with men (MSM). We describe 12 consecutive unrelated confirmed cases who presented at our healthcare institution in Santiago Metropolitan Area. Nine were men, all reporting having had sex with men. Ten viral sequences, genotyped as IA, clustered with the V16-25801 strain causing outbreaks mostly in MSM in Europe since mid-2016. PMID- 29510781 TI - Seroprevalence of Coxiella burnetii antibodies and chronic Q fever among post mortal and living donors of tissues and cells from 2010 to 2015 in the Netherlands. AB - BackgroundAfter a large Q fever outbreak in the Netherlands in the period from 2007 to 2010, the risk of Q fever transmission through tissue and cell transplantation from undiagnosed chronic Q fever cases became a potential issue. Aim: We aimed to evaluate the risk of Q fever transmission through tissue and cell transplantation. Methods: We performed a retrospective observational cohort study among 15,133 Dutch donors of tissues and stem cells from 2010 to 2015 to assess seroprevalence of Coxiella burnetii antibodies, to identify factors associated with presence of C. burnetii antibodies, and to assess the proportion of undiagnosed chronic Q fever cases. Results: The study population consisted of 9,478 (63%) femoral head donors, 5,090 (34%) post-mortal tissue donors and 565 (4%) cord blood donors. Seroprevalence of C. burnetii antibodies gradually decreased after the outbreak, from 2.1% in 2010 to 1.4% in 2015, with a significant trend in time (p < 0.001). Of 301 seropositive donors, seven (2.3%) were newly detected with chronic Q fever (0.05% of all screened donors). Conclusion: This study shows that seroprevalence of C. burnetii antibodies among donors of tissues and cells in the Netherlands after 2014 was similar to pre outbreak levels in the general population. The proportion of newly detected chronic Q fever patients among donors of tissues and cells was smaller than 0.1%. This study may prompt discussion on when to terminate the screening programme for chronic Q fever in donors of tissues and cells in the Netherlands. PMID- 29510784 TI - Posterior Ankle Impingement Syndrome and M. Flexor Hallucis Longus Tendinopathy in Dancers Results of Open Surgery. AB - Posterior ankle impingement syndrome (PAIS), the result of posterolateral soft tissue or bony impingement of the ankle, and tendinopathy of the flexor hallucis longus (FHL tendinopathy) in the ankle are common in dancers. If conservative treatment of these conditions fails to produce adequate results, surgical intervention might be necessary. However, outcomes of treatment by open surgery for these diagnoses have been described only in small series of dancers. For this study, data were extracted from clinical files and operative reports of an orthopaedic surgery clinic specialized in dance medicine. Prior to October 2016, 148 patients (82.1% female, median age 19 years) underwent 190 open procedures, 57 (30%) for FHL, 83 (43.7%) for PAIS, and 50 (26.3%) for a combination thereof. In 90.8% of cases, patients reported a "better" or "much better" postoperative outcome. There were only minor, transient complications that neither required re intervention nor influenced outcome. Patients were followed up for a median of 157 days (interquartile range: 91-245 days). Those operated on by a lateral approach were discharged from follow-up earlier (lateral 113 days vs. 190 for medial approach, p = 0.005), but there was no difference in outcome at discharge. It is concluded that the open surgical treatment of PAIS and FHL tendinopathy in dancers has a high success rate and can be considered a successful standard operative procedure. More detailed information is needed about dance-specific outcomes and the early postoperative course of rehabilitation. PMID- 29510783 TI - Prioritisation of food-borne parasites in Europe, 2016. AB - Background and aimsPriority setting is a challenging task for public health professionals. To support health professionals with this and in following a recommendation from the Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO), 35 European parasitologists attended a workshop from 8-12 February 2016 to rank food-borne parasites (FBP) in terms of their importance for Europe and regions within Europe. Methods: Countries were divided into European regions according to those used by the European Society of Clinical Microbiology and Infectious Diseases. We used the same multicriteria decision analysis approach as the FAO/WHO, for comparison of results, and a modified version, for better regional representation. Twenty-five FBP were scored in subgroups, using predefined decision rules. Results: At the European level, Echinococcus multilocularis ranked first, followed by Toxoplasma gondii and Trichinella spiralis. At the regional level, E. multilocularis ranked highest in Northern and Eastern Europe, E. granulosus in South-Western and South-Eastern Europe, and T. gondii in Western Europe. Anisakidae, ranking 17th globally, appeared in each European region's top 10. In contrast, Taenia solium, ranked highest globally but 10th for Europe. Conclusions: FBP of importance in Europe differ from those of importance globally, requiring targeted surveillance systems, intervention measures, and preparedness planning that differ across the world and across Europe. PMID- 29510785 TI - Operative Treatment of Posterior Ankle Impingement Syndrome and Flexor Hallucis Longus Tendinopathy in Dancers Open Versus Endoscopic Approach. AB - Posterior ankle impingement syndrome (PAIS) is a painful, usually limited plantar flexion of the ankle joint due to soft tissue impingement or a bony impediment often coinciding with tendinopathy of the flexor hallucis longus (FHL) behind the medial malleolus. In persistent complaints, the bony impediment is removed, the tunnel of the FHL tendon is released, or a combination of both procedures has traditionally been performed by open surgery. In 2000, an endoscopic surgical technique for PAIS and FHL tendinopathy was introduced. To date there is no evidence of the superiority of one surgical technique over the other in dancers; both the open and the endoscopic approach provide up to 90% good and excellent long-term results. We compared the first 20 consecutive open procedures with the first 19 consecutive endoscopic procedures in dancers, all operated by the same orthopaedic surgeon. The postoperative outcomes were reviewed by studying the patient files, clinical evaluation, American Orthopaedic Foot and Ankle Society (AOFAS) scoring, and we administered a dance-specific questionnaire. The results in the open group were: nine excellent, nine good, one moderate, and one poor (90% excellent and good). In the endoscopic group: nine excellent, six good, three moderate, one poor (79% excellent and good). Both groups returned to dance (barre) at a median of 8 weeks (IQR: 2). The direct postoperative morbidity in the endoscopic group was less favorable and was mainly related to hematomas and an inflammatory response or deep scar tissue formation. There were no major complications requiring re-intervention. Although the two small groups of patients and the retrospective character of our descriptive study do not allow firm conclusions or statistical analysis of subgroups, the results of this study indicate that the open approach seems to be better than the endoscopic approach in the surgical treatment of PAIS and FHL tendinopathy in dancers. PMID- 29510786 TI - Results of Treatment of Posterior Ankle Impingement Syndrome and Flexor Hallucis Longus Tendinopathy in Dancers: A Systematic Review. AB - Dancing on pointe and releve requires extreme plantar flexion of the talo-crural joint. Hence, these positions may lead to posterior ankle impingement syndrome (PAIS). PAIS often coincides with flexor hallucis longus tendinopathy (FHL tendinopathy, or "dancers' tendinitis"). Both injuries can appear in isolation as well. The goal of this review is to evaluate the results and the available levels of evidence of conservative and operative treatment (both open and endoscopic) of PAIS and FHL tendinopathy in dancers. It also offers an insight into the history of dance medical publications on this subject. In October 2016, a systematic search of PubMed, Embase, Cochrane, CINAHL, Web of Science, and (in French) ScienceDirect databases was undertaken. Five hundred and seventy-six publications were found, of which a total of 27 reported the results of operative treatment in 376 ankles (344 open, 32 endoscopic) in 324 dancers. The outcome was good to excellent in most cases (89%). The mean period of return to dance for all surgeries combined (PAIS and FHL tendinopathy, open and endo) was 11 weeks (range: 4 to 36 weeks), and for isolated FHL tendinopathy 16 weeks (range: 8 to 36 weeks). Only six publications reported the results of conservative treatment in 33 ankles (13 PAIS, 20 FHL tendinopathy) of 28 dancers, which does not allow for any evidence-based recommendations. Most studies failed to include dance specific baseline characteristics, like dance style and level of participation. We concluded that only retrospective studies with levels of evidence four and five show that operative treatment for PAIS and FHL tendinopathy is successful with few complications. Since isolated PAIS, PAIS combined with FHL tendinopathy, and isolated FHL injuries appear to be different pathological entities, more research taking into account demography, dance type, and level of participation is needed to find out in which cases early operative management should be considered or avoided. The same applies to defining the place of endoscopic surgery in dancers and being able better to predict which pathology is likely to produce worse outcomes or delay the return to dance. Future research should have a prospective design, including dance-specific outcome scores both preand post treatment. Furthermore, preferably a prospective randomized controlled design should be used to compare different conservative and operative treatment options. PMID- 29510787 TI - Kinematic and Kinetic Analysis of Repeated and Static Eleve in Adolescent Female Dance Students. AB - Eleve is a fundamental dance movement practiced routinely by dance students and serving as an integral component of screening in dance. It consists of ankle plantar flexion (PF) movement and is considered to be a frequent cause of foot and ankle injuries among dancers, with adolescent female dance students being at greatest risk for such injuries. Therefore, gaining additional knowledge regarding eleve functional range of motion (ROM) and inter-leg weightbearing distribution (WBD) properties among adolescent dance students is warranted for pedagogic, screening, injury prevention, and rehabilitation purposes. The aims of this study were three-fold: 1. to report and compare dance-specific, functional kinematic (ankle PF maximum angle and ankle PF ROM), kinetic (inter-leg WBD), and self-reported level of difficulty (balance, muscular force, and concentration) properties of repeated and static eleve among adolescent female dance students; 2. to look for correlations between eleve properties and participants' demographics (age, height, weight, dance experience, and leg dominance); and 3. to describe the relationships between the two kinematic properties in both eleve tasks. Twenty-three adolescent female dance students (mean age 13.57 +/- 0.50 years) were measured while performing two eleve tasks: 10 repetitions ("repeated eleve task") and 10 consecutive seconds hold ("static eleve task"). Data regarding ankle motion and WBD were collected and analyzed using three dimensional motion capture and two force plates. The data gained from this study expand our current understanding of eleve dance movement and may contribute to clinical relevancy and applicability of screening procedures being conducted in pre-professional dance settings. This may help to identify adolescent dance students with the potential to undertake a career in professional dance as well as to investigate the parameters associated with risk of ankle injuries in this population. PMID- 29510788 TI - Nutritional Considerations for the Vegetarian and Vegan Dancer. AB - Vegetarianism provides a catchall term for a variety of diets that exclude the consumption of some or all animal products. Contrary to popular claims, appropriately designed and managed vegetarian diets contain foods nutritionally sufficient for health, well-being, and physical performance. Vegetarian dancers can meet their protein needs from primarily or exclusively (vegan) plant-based sources when a variety of these foods are consumed daily and energy intake is adequate. However, the quality and timing of dietary intake is of key importance to meet the physical demands typical of high intensity, intermittent types of dance styles. Poorly planned, calorically restrictive, and nutrient poor diets confer a host of deficiencies that diminish health and ultimately performance. The recommendation for dietary macronutrient composition of carbohydrate, fat, and protein of 55%, 20% to 30%, and 12% to 15%, respectively, offers an acceptable baseline for all dancers across different dance styles. Vegetarians, in particular vegans, should ensure sufficient caloric and adequate intake of Vitamin B12, Vitamin D, omega-3 fatty acids, calcium, and zinc. Many of these micronutrients are derived from animal products, but, with sufficient knowledge, can be obtained from plantbased sources. However, the diminished bioavailability of iron from plants and lack of plant sources of Vitamin B12 in vegan type diets can have detrimental effects on physical performance. Thus, to prevent long-term deficiencies, vegan dancers require more diligence when preparing and managing dietary intake. This article reviews literature on vegetarian diets with regard to dance, gleaning findings from epidemiologic, clinical, and sport nutrition research. It also highlights potential micronutrient deficiencies that may occur in some plant-based diets and presents potential strategies to improve nutrient and caloric intake for dancers who opt for a plant-based diet. PMID- 29510782 TI - Interim 2017/18 influenza seasonal vaccine effectiveness: combined results from five European studies. AB - Between September 2017 and February 2018, influenza A(H1N1)pdm09, A(H3N2) and B viruses (mainly B/Yamagata, not included in 2017/18 trivalent vaccines) co circulated in Europe. Interim results from five European studies indicate that, in all age groups, 2017/18 influenza vaccine effectiveness was 25 to 52% against any influenza, 55 to 68% against influenza A(H1N1)pdm09, -42 to 7% against influenza A(H3N2) and 36 to 54% against influenza B. 2017/18 influenza vaccine should be promoted where influenza still circulates. PMID- 29510789 TI - Between-Day Reliability of Pre-Participation Screening Components in Pre Professional Ballet and Contemporary Dancers. AB - Critical appraisal of research investigating risk factors for musculoskeletal injury in dancers suggests high quality reliability studies are lacking. The purpose of this study was to determine between-day reliability of pre participation screening (PPS) components in pre-professional ballet and contemporary dancers. Thirty-eight dancers (35 female, 3 male; median age; 18 years; range: 11 to 30 years) participated. Screening components (Athletic Coping Skills Inventory-28, body mass index, percent total body fat, total bone mineral density, Foot Posture Index-6, hip and ankle range of motion, three lumbopelvic control tasks, unipedal dynamic balance, and the Y-Balance Test) were conducted one week apart. Intra-class correlation coefficients (ICCs: 95% confidence intervals), standard error of measurement, minimal detectable change (MDC), Bland Altman methods of agreement [95% limits of agreement (LOA)], Cohen's kappa coefficients, standard error, and percent agreements were calculated. Depending on the screening component, ICC estimates ranged from 0.51 to 0.98, kappa coefficients varied between -0.09 and 0.47, and percent agreement spanned 71% to 95%. Wide 95% LOA were demonstrated by Foot Posture Index-6 (right: -6.06, 7.31), passive hip external rotation (right: -9.89, 16.54), and passive supine turnout (left: -15.36, 17.58). The PPS components examined demonstrated moderate to excellent relative reliability with mean between-day differences less than MDC, or sufficient percent agreement, across all assessments. However, due to wide 95% limits of agreement, the Foot Posture Index-6 and passive hip range of motion are not recommended for screening injury risk in pre-professional dancers. PMID- 29510791 TI - The Impact of a Randomized Sleep Education Intervention for College Students. AB - STUDY OBJECTIVES: Sleep deprivation can impair attention, mood, and performance; however, few effective sleep education programs are available. The aim of this study was to assess the effect of a sleep education website, Sleep to Stay Awake (sleeptostayawake.org), on sleep behaviors of college students. METHODS: College students (age 18 years or older) attending a public Midwestern university were randomized to control or intervention groups. All subjects completed baseline surveys that included demographics, Pittsburgh Sleep Quality Index, Patient Health Questionnaire, sleep knowledge, and measures of sleepiness and circadian rhythm. The intervention group then undertook the online intervention. Surveys were repeated at 1 week and at 8 weeks. RESULTS: Students who participated included 295 controls and 254 intervention subjects. The mean age was 21.9 +/- 4.1 years and 41.7% were male. Survey results at 8 weeks showed that more intervention subjects reported improved sleep behaviors (50.3% versus 39.5%, P = .04). Intervention subjects were more likely to stop electronics use earlier (odds ratio [95% confidence interval] = 1.5 [1.0-2.4]), keep a more regular sleep schedule (1.6 [1.06-2.4]), have an earlier weekday rise time (2.4 [1.3-4.4]), and have a lower likelihood of insufficient sleep prior to examinations (0.46 [0.28 0.76]). The intervention group had improvement in mean sleep quality (odds ratio = 5.8 versus 6.6, P < .001) and depression scores (odds ratio = 4.6 versus 5.6, P = .03). No significant differences were found in the other measures. CONCLUSIONS: A brief and personalized online sleep education intervention improved sleep behaviors, sleep quality, and depressions scores. This novel approach to address sleep deprivation, poor sleep habits, and mood among college students may offer an effective and inexpensive remedy. PMID- 29510792 TI - Acetazolamide Reduces Blood Pressure and Sleep-Disordered Breathing in Patients With Hypertension and Obstructive Sleep Apnea: A Randomized Controlled Trial. AB - STUDY OBJECTIVES: The carbonic anhydrase inhibitor acetazolamide (AZT) modulates blood pressure at high altitude and reduces sleep-disordered breathing in patients with obstructive sleep apnea (OSA). We aimed to investigate the treatment effect of AZT and in combination with continuous positive airway pressure (CPAP) on blood pressure in patients with hypertension and OSA. METHODS: In a prospective, randomized, three-way crossover study, 13 male patients with hypertension and moderate to severe OSA (age 64 +/- 7 years, body mass index 29 +/- 4 kg/m2, and mean apnea-hypopnea index 37 +/- 23 events/h) received AZT, CPAP, or AZT plus CPAP for 2-week periods. Antihypertensive medication was washed out. Office and 24-hour blood pressure, arterial stiffness, polygraphic sleep study data, and blood chemistry were compared. RESULTS: AZT alone and AZT plus CPAP, but not CPAP alone, reduced office mean arterial pressure compared to baseline (-7 [95% CI -11 to -4], -7 [95% CI -11 to -4] and -1 [95% CI -5 to 4] mmHg, respectively; repeated- measures analysis of variance (RM-ANOVA; P = .015). Aortic systolic pressure and augmentation index, assessed by radial artery oscillatory tonometry, were unaffected by CPAP but decreased after AZT and AZT plus CPAP (RM-ANOVA P = .030 and .031, respectively). The apnea-hypopnea index was significantly reduced in all three treatment arms, most prominently by AZT plus CPAP (RM-ANOVA P = .003). The reduction of venous bicarbonate concentration following AZT was correlated with the change of apnea-hypopnea index (r = 0.66, P = .013). CONCLUSIONS: AZT reduced blood pressure, vascular stiffness, and sleep disordered breathing in patients with OSA and comorbid hypertension. Carbonic anhydrase inhibition may constitute a potential target for drug therapy in patients with sleep apnea and comorbid hypertension. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT02220803; Title: A Short Term Open, Randomized Cross-over Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension and Vascular Dysfunction; URL: https://clinicaltrials.gov/ct2/show/NCT02220803 and Registry: EU Clinical Trials Register; EudraCT Number: 2013-004866-33; Title: A short term open, randomized cross over trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004866-33. PMID- 29510793 TI - Symptom-Based Subgroups of Koreans With Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Recently, the Icelandic Sleep Apnea Cohort (ISAC) identified three subgroups in patients with obstructive sleep apnea (OSA) recruited from the sleep clinic based on clinical symptoms and comorbidities: excessively sleepy, minimally symptomatic, and disturbed sleep. This study sought to determine whether the three OSA subgroups are applicable to a population-based cohort in Korea. METHODS: Study subjects are participants of an ongoing cohort study in Korea. Of the 2,918 participants, 422 new moderate to severe OSA cases (apneahypopnea index [AHI] >= 15 events/h) were diagnosed by home sleep studies. All participants completed a detailed questionnaire on sleep-related symptoms, comorbidities, medication, and other information. A latent class analysis was performed. RESULTS: When examining solutions for up to 10 clusters, the a priori three-cluster solution was the optimal clustering solution. The three-cluster solution demonstrated a subgroup presentation similar to the clusters identified in the ISAC. The minimally symptomatic subgroup was most prevalent (55.7%) in the Korean cohort. Among the three subgroups, there were no differences in mean AHI and body mass index; however, the disturbed sleep subgroup was older and had more females. CONCLUSIONS: Combined with the ISAC data, we suggest that the three symptom cluster solution for patients with OSA may be more widely applicable, irrespective of ethnicity and study population. PMID- 29510794 TI - Daytime Sleep Disturbance in Night Shift Work and the Role of PERIOD3. AB - STUDY OBJECTIVES: Recent evidence indicates that daytime sleep disturbance associated with night shift work may arise from both circadian misalignment and sleep reactivity to stress. This presents an important clinical challenge because there are limited means of predicting and distinguishing between the two mechanisms, and the respective treatments differ categorically; however, there is support that a polymorphism in the PERIOD3 gene (PER3) may indicate differences in vulnerability to daytime sleep disturbance in shift workers. METHODS: We recruited 30 fixed night shift workers for laboratory assessments of circadian misalignment (dim light melatonin onset), sleep reactivity to stress (Ford Insomnia Response to Stress Test), daytime sleep disturbance (daytime Insomnia Severity Index), and PER3 genotype (PER34/4, PER35/-). The two mechanisms for daytime sleep disturbance (circadian misalignment and sleep reactivity to stress) were compared between PER3 genotypes. RESULTS: Disturbed daytime sleep in the PER34/4 group was more likely related to sleep reactivity to stress, whereas disturbed sleep in the PER35/- group was more likely related to circadian misalignment. Exploratory analyses also revealed a blunted melatonin amplitude in the PER34/4 genotype group. CONCLUSIONS: This study provides further evidence for multiple mechanisms (ie, circadian misalignment versus sleep reactivity to stress) associated with daytime sleep disturbances in shift workers. Additionally, it provides the new finding that PER3 genotype may play an important role in individual vulnerability to the different mechanisms of daytime sleep disturbance in night shift workers. PMID- 29510795 TI - Obstructive Sleep Apnea Severity is Directly Related to Suicidal Ideation in Posttraumatic Stress Disorder. AB - STUDY OBJECTIVES: Posttraumatic stress disorder (PTSD) is associated with suicidal ideation (SI) and obstructive sleep apnea (OSA). There are no studies of OSA diagnosed by sleep study and SI in patients with PTSD. METHODS: Forty consenting civilians with PTSD (38 female, mean +/- standard deviation age: 44.60 +/- 12.73) underwent a Level 3 home sleep apnea test (WatchPAT200; Itamar Medical, Israel). OSA severity was measured with the respiratory disturbance index (RDI) (number of apneas, hypopneas and respiratory effort related arousals per hour). SI was measured with Items 9, 35, 39, and 50 of the Brief Symptom Inventory (BSI). Other patient-rated measures included the Beck Depression Inventory, second edition (BDI-II), PTSD Checklist for DSM-5 (PCL-5), and the Pittsburgh Sleep Quality Index PTSD Addendum modified to include only Items 1c, 1e, 1f, and 1g that address nightmares. RESULTS: The RDI (r = .757, P < .001) and oxygen desaturation index (r = .633, P < .001) were directly correlated to SI. Multiple regression analysis using SI as the dependent variable and patient-rated measures as independent variables revealed only RDI (beta = .480, t = 4.167, P < .001) and BDI-II (beta = .469, t = 3.375, P = .002) as predictors of SI, with adjusted R2 = 0.718. In patients with RDI < 30 events/h (n = 37) correlation of SI with RDI (r = .511, P = .001) but not ODI (r = .312, P = .060) remained significant. Multiple regression analysis (when RDI < 30 events/h) revealed only BDI-II (beta = .603, t = 3.492, P = .002), and not RDI (beta = .247, t = 1.723, P = .096) as a significant predictor of SI. CONCLUSIONS: OSA severity in PTSD was directly related to SI. Depression was a significant mediator in the relationship between RDI and SI, with OSA-related intermittent hypoxemia possibly contributing to this relationship only in severe OSA. PMID- 29510796 TI - Nightmares in United States Military Personnel With Sleep Disturbances. AB - STUDY OBJECTIVES: Sleep disturbances are common in United States military personnel. Despite their exposure to combat and trauma, little is known about nightmares in this population. The purpose of this study was to describe the prevalence and associated clinical and polysomnographic characteristics of nightmares in United States military personnel with sleep disturbances. METHODS: Retrospective review of 500 active duty United States military personnel who underwent a sleep medicine evaluation and polysomnography at our sleep center. The Pittsburgh Sleep Quality Index and the Pittsburgh Sleep Quality Index Addendum were used to characterize clinically significant nightmares. Subjective and objective sleep attributes were compared between groups. RESULTS: At least weekly nightmares were present in 31.2%; yet, only 3.9% reported nightmares as a reason for evaluation. Trauma-related nightmares occurred in 60% of those patients with nightmares. Patients with nightmares had increased sleep onset latency (SOL) and rapid eye movement (REM) sleep latency (mean SOL/REM sleep latency 16.6/145 minutes, P = .02 and P = .01 respectively) compared to those without (mean SOL/REM sleep latency 12.5/126 minutes). The comorbid disorders of depression (P <= .01, relative risk [RR] 3.55 [95% CI, 2.52-4.98]), anxiety (P <= .01, RR 2.57 [95% CI, 1.93-3.44]), posttraumatic stress disorder (P <= .01, RR 5.11 [95% CI, 3.43-7.62]), and insomnia (P <= .01, RR 1.59 [95% CI, 1.42-1.79]) were all associated with nightmares. CONCLUSIONS: Clinically significant nightmares are highly prevalent in United States military personnel with sleep disturbances. Nightmares are associated with both subjective and objective sleep disturbances and are frequently comorbid with other sleep and mental health disorders. COMMENTARY: A commentary on this article appears in this issue on page 303. PMID- 29510797 TI - Time to Open Our Eyes? A Challenge to the Role of Polysomnography for Trials in Pediatric Sleep-Disordered Breathing. PMID- 29510798 TI - Does Perfectionism Increase the Risk for Dropout From Cognitive Behavioral Therapy for Insomnia? PMID- 29510799 TI - Targeted Delivery of Amantadine-loaded Methacrylate Nanosphere-ligands for the Potential Treatment of Amyotrophic Lateral Sclerosis. AB - PURPOSE: This study aimed to develop and analyse poly(DL-lactic acid)-methacrylic acid nanospheres bound to the chelating ligand diethylenetriaminepentaacetic acid (DTPA) for the targeted delivery of amantadine in Amyotrophic Lateral Sclerosis (ALS). METHODS: The nanospheres were prepared by a double emulsion solvent evaporation technique statistically optimized employing a 3-Factor Box-Behnken experimental design. Analysis of the particle size, zeta potential, polydispersity (Pdl), morphology, drug entrapment and drug release kinetics were carried out. RESULTS: The prepared nanospheres were determined to have particle sizes ranging from 68.31 to 113.6 nm (Pdl <= 0.5). An initial burst release (50% of amantadine released in 24 hr) was also obtained, followed by a prolonged release phase of amantadine over 72 hr. Successful conjugation of the chelating ligand onto the surface of the optimised nanospheres was thereafter achieved and confirmed by TEM. The synthesized modified nanospheres were spherical in shape, 105.6 nm in size, with a PdI of 0.24 and zeta potential of -28.0 mV. Conjugation efficiency was determined to be 74%. In vitro and ex vivo cell study results confirmed the intracellular uptake of the modified nanospheres by the NSC-34 cell line and the non-cytotoxicity of the synthesized nanospheres. CONCLUSIONS: Biocompatible amantadine-loaded nanospheres were successfully designed, characterized and optimized employing the randomized Box-Behnken statistical design. Delivery of amantadine over 72 hrs was achieved, with the nanospheres being of a size capable of internalization by the NSC- 34 cells. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29510800 TI - Microneedles as Enhancer of Drug Absorption Through the Skin and Applications in Medicine and Cosmetology. AB - The microneedles technology has found applications in many health-related fields. For example, their application in drugs and vaccines delivery as well, as the determination of biomarkers, has been reported. They also have a place in the dermatology and cosmetic areas such as the treatment of wounds from burns, scars, acne, depigmentation, and alopecia will be shown. Microneedles are used in therapeutic applications and are manufactured using materials such as metal (steel, titanium, nickel), polymer (oly-glycolic acid (PGA), poly-lactide-co glycolide acid (PLGA), poly-L-lactic acid (PLA), chitosan), glass, silicon, ceramic, carbohydrates (trehalose, sucrose, mannitol). Examples of application of microneedles and their advantages and disadvantages are discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29510801 TI - The Remarkable Cationic Peptides: A Boon to Pharmaceutical Sciences? AB - In this opinion article, the authors discuss a number of interesting, beneficial properties of naturally occurring and synthetic cationic antimicrobial peptides (AMPs) with the prospective aim of bringing these compounds into therapeutic use to avoid antibiotic resistance and utilize their numerous properties. The structural diversity and the conformational freedom of these compounds adversely affects their mechanistic elucidation. Our molecular level mechanistic exploration of these peptides has shown their ion carriage properties and systematically explains their antibiotic activity through disruption of bacterial cell homeostasis and inhibition of 14-alpha demethylase enzyme. We have also shown self-assemblage in AMPs in different nanoparticulate and tubular forms. Some AMPs possess cell penetration capability and their co-administration with drug enhances antibacterial activity through a non-disruptive mechanism. The anti HIV activity of AMPs has been explained based on their non-covalent, non-base pair base-pair type interactions with HIV viral ssRNA template. Design of peptidomimetic compounds with enhanced druggability based on our mechanistic explorations will definitely lead to better non-toxic drugs with antibacterial, anti-HIV activity and may contribute towards development of efficient drug delivery systems. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29510802 TI - The psychological impact of body contouring surgery. AB - INTRODUCTION: Body contouring surgery is associated with changes in body image and identity. The primary aim of the study was to investigate a multidisciplinary assessment of potential psychological challenges before and after body contouring surgery. METHODS: Eight pre- and post-operative patients undergoing plastic surgery, two surgeons and two nurses were investigated using semi-structured and focus group interviews to capture the perspectives of both the healthcare professionals and the patients. Data were analysed using an interpretive descriptive approach and coded line-by-line until all relevant codes had been extracted. RESULTS: A total of seven psychological themes were identified, indicating that surgery alone cannot improve the patients' psychological difficulties and that psychological care and management of the expected discomfort and body image is of considerable importance in providing continuity of care. CONCLUSIONS: The reported quality of life is of considerable importance to patients undergoing body contouring surgery after massive weight loss. Our findings may pro-vide useful information for surgeons and healthcare professionals allowing them to develop patient education programmes, reduce discrepancies in patient expectations and improve patient satisfaction. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29510803 TI - Preoperative inspiratory muscle training prevents pulmonary complications after cardiac surgery - a systematic review. AB - INTRODUCTION: Post-operative pulmonary complications are a common cause of morbidity and mortality in patients undergoing heart surgery. The aim of this systematic review was to determine if preoperative inspiratory muscle training could prevent the development of pneumonia and atelectasis in patients undergoing coronary artery bypass grafting (CABG) or heart valve surgery. METHODS: Systematic searches were performed in MEDLINE, Embase and the Cochrane Library. The included studies compared the development of pneumonia and atelectasis in CABG patients or heart valve surgery patients who were prescribed either preoperative inspiratory muscle training or usual care. The quality of the studies was assessed using the Cochrane Risk of Bias Tool. RESULTS: The search yielded 2,479 records. The inclusion criteria were fulfilled by five studies. All the studies were randomised controlled trials. We found that the development of both pneumonia and atelectasis was significantly reduced among patients who received inspiratory muscle training preoperatively compared with patients treated with usual care. CONCLUSIONS: Preoperative inspiratory muscle training may reduce the risk of developing pneumonia and atelectasis. However, more trials are needed to support and strengthen the evidence found in this systematic review before routine implementation of this kind of training preoperatively. PMID- 29510804 TI - Validity and reliability of an ultrasound measurement of the free length of the Achilles tendon. AB - INTRODUCTION: Valid length measurements of the different segments of the Achilles tendon are needed in order to investigate if differential elongation of the Achilles tendon takes place after rupture. The purpose of this paper was to present data concerning the accuracy and reliability of an ultrasound measurement of the free part of the Achilles tendon. METHODS: Both legs of 19 non-injured subjects were examined by magnetic resonance imagining (MRI) and ultrasound. The length from the distal tip of the soleus muscle to the tendon insertion on the calcaneus was measured by three independent ultrasound examiners. Repeated ultrasound measurements were performed and compared with MRI measurements. Intra rater and inter-rater reliability and the agreement between MRI and ultrasound were determined. Data were evaluated using the intraclass correlation coefficient (ICC), the standard error of the measurement (SEM) and the minimal detectable change (MDC). RESULTS: The measurement showed excellent intra-rater reliability (ICC = 0.94 (95% confidence interval (CI): 0.91-0.96), SEM = 5 mm and MDC = 13 mm) and inter-rater reliability (ICC = 0.96 (95% CI: 0.93-0.97), SEM = 4 mm and MDC = 11 mm). On average, ultrasound measurements exceeded the MRI measurements by 2 mm (non-significant), resulting in a measurement error of 5%. CONCLUSIONS: The ultrasound measurement of the free part of the Achilles tendon showed good reliability and accuracy. For comparison between groups of non-injured subjects, differences of > 5 mm can be detected. For repeated assessment of individual subject differences >= 13 mm can be detected. FUNDING: none. TRIAL REGISTRATION: Institutional Review Board of Zealand, Denmark, Ref. no: SJ-318. PMID- 29510805 TI - Thyroid fine-needle aspiration and The Bethesda Classification System. AB - INTRODUCTION: Fine-needle aspiration (FNA) is a cornerstone in diagnosing thyroid nodules. For decades, Danish FNA has been categorised into the groups: "FNA not performed", "Inadequate", "Cystic", "Inconclusive", "Benign", "Suspicious", "Malignant" and "Information missing". Internationally, The Bethesda Classification System (TBCS) is increasingly accepted, especially owing to a detailed specification of FNA suspicious for malignancy. The Danish "Suspicious" group is very broad and includes atypia, follicular neoplasia and FNA suspicious of other malignancies. The purpose of this study was to apply TBCS to the Danish "Suspicious" FNA group and to estimate the frequency of malignancy in the individual Bethesda groups (BG). METHODS: This descriptive study is based on a prospective cohort from the THYKIR database. It includes 479 patients with a "Suspicious" FNA and surgical treatment in The Region of Southern Denmark from 2001 to 2013. Based on pathology records, FNA was classified according to the TBCS. Malignancy was determined by the histological diagnosis from the THYKIR database. RESULTS: The Danish "Suspicious" group was allocated to the BG I, II, III, IV, V and VI with a malignancy risk of 36.4%, 13.3%, 17.2%, 16.1%, 55.3% and 88.2%, respectively. CONCLUSIONS: The Danish "Suspicious" group contains a broad spectrum of BG with varying malignancy risk. The results indicate a need for standardisation of the Danish FNA classification. A national introduction of the TBCS might secure an international and comparable standard. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29510806 TI - Testicular microlithiasis in patients with testicular cancer in the United Kingdom and in Denmark. AB - INTRODUCTION: Testicular cancer is the most common type of cancer in young Caucasian men. It has been suggested that testicular microlithiasis (TML) is a premalignant condition. This study's objective was to investigate TML histology prevalence in testicular cancer patients in two European populations. METHODS: We analysed archived histopathology orchiectomy specimens from 152 patients diagnosed with testicular cancer at Fredericia Hospital in Denmark from 2004 to 2014, and 106 patients diagnosed at St Thomas' Hospital in London from 2011 to 2015. RESULTS: The Danish patients' median age was 37 years (range: 16-74 years) and the English patients' 36 years (range: 18-78 years). In the Danish patients, 29 (19.1%) had TML, and in the English patients, 43 (40.6%) had TML (p < 0.001). Haematoxylin bodies were slightly more common in the English patients. Laminated calcification was more often seen in seminomas than in non-seminomas.? CONCLUSIONS: The English testicular cancer patients had a statistically significantly higher TML prevalence than the Danish patients. This observation questions the hypothesised biological association between TML and testicular ?cancer. FUNDING: The Region of Southern Denmark supported this study. TRIAL REGISTRATION: not relevant. PMID- 29510807 TI - Feasibility and safety of outpatient breast cancer surgery. AB - INTRODUCTION: Improvement in perioperative care programmes has facilitated post operative recovery and use of short-term or outpatient procedures. The aim of this study was to assess the feasibility and safety of an outpatient breast cancer programme in patients referred to a large breast cancer unit. METHODS: After an introduction period involving 554 consecutive patients, all patients operated from 1 November 2015 to 30 June 2016 (a total 483 patients) were treated with multimodal oral analgesia, preoperative high-dose glucocorticoids and no routine use of drains. Planned inpatient surgery included patients with mastectomy > 70 years, < 8 h in post-operative observation and < 2 h of observation after mobilisation. RESULTS: Of the 382 patients who were planned for outpatient surgery (79%), 90% received surgery in an outpatient setup. Among the 101 patients (21%) who were planned for inpatient surgery, 17% returned home on the day of surgery. Consequently, the overall outpatient rate was 72% and the overall mean length of stay was 0.3 days, ranging from 0.1 days for breast conserving surgery to 0.8 days for mastectomy. About 2% were readmitted within < 30 days, mostly due to wound problems.?Conclusion: Outpatient breast cancer surgery is feasible and safe in most patients in a socialised healthcare system. FUNDING: none. TRIAL REGISTRATION: not relevant.?. PMID- 29510808 TI - From acute to chronic postsurgical pain: the significance of the acute pain response. AB - The thesis comprises an overview and four papers, all published or submitted for publication in international peer-reviewed scientific journals.? ?Chronic pain after surgery is a common and debilitating complication after many types of surgery. The cause and pathology behind is still mainly uncovered, though several risk factors have been proposed. One of the strongest risk factors for persistent postsurgical pain is the intensity of the acute pain response though the mechanisms involved remain unsettled. The acute pain response consists of several different types of pain (i.e. somatic pain, visceral pain, referred pain, neuropathic pain). It's uncovered whether some components of the acute pain response are closer correlated to chronic pain than others and whether treatment of acute pain can change the risk of developing chronic pain.? The aim of the thesis was to investigate which components of the acute pain response, was correlated to chronic postsurgical pain in patients for cholecystectomy and lobectomy.? Furthermore, to study the type and time course of ipsilateral shoulder pain after lobectomy and whether an ultrasound-guided supraclavicular phrenic nerve block was effective in preventing acute and chronic shoulder pain after major thoracic surgery.? Paper I is based on a prospective, observational, multicenter, cohort study, in which 100 patients for cholecystectomy was examined preoperatively, 1 week postoperatively and 3, 6, and 12 months postoperatively for pain, psychological factors and signs of hypersensitivity.? Paper II and III are based on a prospective, observational, cohort study, in which 60 patients for lobectomy ware examined preoperatively, 4 days postoperatively and 12 months postoperatively for pain, psychological factors and signs of hypersensitivity. ?Paper IV is based on a prospective, randomized, double-blind and placebo controlled trial, where 76 patients were randomized to receive ultrasound guided supraclavicular phrenic nerve block with a blinded study solution (ropivacaine or saline). The primary endpoint was pain within the first 6 hours after surgery. Secondary endpoints included pain the following days and after 3 months.? ?Paper I: Nine patients developed chronic unexplained pain 12 months postoperatively. In a multivariate analysis, cumulated visceral pain during the first week and number of preoperative biliary pain attacks were identified as independent risk factors for unexplained pain 12 months after surgery. There were no consistent signs of increased hypersensitivity in the referred pain area before or after the operation in patients with chronic pain. ?Paper II: Sixteen patients developed chronic pain 12 months postoperatively. In a multivariate analysis thoracic pain during activity was the only significant predictor of chronic pain 12 months after surgery. Shoulder pain, referred pain and overall pain was not significant predictors. There were no signs of general hypersensitivity 12 months after surgery. ?Paper III: Forty-seven (78%) of patients experienced postoperative shoulder pain, but only 25 patients (42%) experienced clinically relevant pain (NRS > 3). On postoperative day 4, 19 (32%) of patients suffered shoulder pain, but only 4 (7%) suffered clinically relevant pain. Only 4 patients (8%) suffered chronic shoulder pain. Ipsilateral shoulder pain of the?? ?musculoskeletal type is more intense than referred ipsilateral shoulder pain, though referred shoulder pain is more common. Surgical approach was not related to incidence of shoulder pain or type of pain.? Paper IV: Shoulder pain within 6 hours of the operation was reported in 9 patients (24%) in the treatment group versus 26 (68%) in the placebo group (p<0.0001). Absolute and relative risk reductions were 44% (95% CI 22-67%) and 65% (95% CI 41-80%), respectively. No major complications, including respiratory compromise, were observed. Subsequent treatment with a nerve catheter was effective during the first 36 hours after surgery, but because of loss of nerve catheter or early submission of patients, data concerning pain the following days and after 3 months were inconclusive. PMID- 29510809 TI - Aetiology and treatment of severe postpartum haemorrhage. AB - This thesis is comprised of three studies focusing on severe postpartum haemorrhage (PPH). PPH is a major cause of maternal morbidity and mortality worldwide. Risk factors include retained placenta, prolonged duration of the third stage of labour, previous caesarean section, and operative vaginal delivery. Occurrence and development of PPH are, however, unpredictable and can sometimes give rise to massive haemorrhage or even hysterectomy and maternal death. Severe haemorrhage can lead to coagulopathy causing further haemorrhage and requiring substitution with blood transfusions. The aim of this thesis was to investigate causes of severe PPH and investigate methods of early prevention. ?The first study was a randomised controlled double-blinded trial investigating the effect of treatment with pre-emptive fibrinogen on women with severe PPH. The primary outcome was the need for red blood cell transfusion at 6 weeks postpartum. A total of 249 women were randomised to either 2 grams of fibrinogen or placebo. The mean concentration of fibrinogen increased significantly in the intervention group compared to the placebo group (0.40 g/l, confidence interval: 0.15-0.65), but there was no difference in the need for postpartum blood transfusions (relative risk 0.95, confidence interval: 0.15-1.54). No thromboembolic complications were detected.?The second study was a population based observational study including 245 women receiving >=10 red blood cell transfusion due to PPH. The cohort was identified by combining data from The Danish Transfusion Database with The Danish Medical Birth Registry, with further data extraction and validation through review of patient charts. The main causes of massive postpartum transfusion were atony (38%) and abnormal invasive placenta (25%). Two of the women in the cohort died, an additional six had a cardiac arrest, and a total of 128 women (52%) required a hysterectomy. Hysterectomy was associated with increased blood loss, increased number of blood transfusions, a higher fresh frozen plasma to red blood cell ratio (p=0.010), and an increased number of red blood cells before first platelet transfusion (p=0.023). Hysterectomy led to haemostasis in only 70% of cases.?The third study was a register-based cohort study, includ-ing 43,357 vaginal deliveries from two large Danish maternity units. Different cut-offs were used to define PPH. There was a difference in distribution of causes depending on the cut-off used, with atony playing a decreasing role and a retained placenta an increasing role the higher the cut-off used. In a multivariate linear regression model retained placenta was identified as a strong predictor of quantity of blood loss. The duration of the third stage of labour was a very weak predictor after adjusting for the influence of a retained placenta. ?In conclusion, an improved diagnosis of the causes of PPH especially retained placenta, together with an early recognition and treatment of coagulopathy, seem to be important in reducing severe PPH in an aim to minimize associated maternal morbidity. PMID- 29510810 TI - Structural joint damage and hand bone loss in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pain, swelling and progressive destruction of the joints leading to loss of function and invalidity. The bone destruction in RA is characterised by two distinct features: structural joint damage and hand bone loss, and their prevention is an important treatment goal. Inhibitors of tumour necrosis factor alpha (TNF inhibitors) have markedly improved the treatment options in RA patients who fail treatment with conventional synthetic Disease Modifying Anti Rheumatic Drugs (sDMARDS), but their effectiveness with regards to structural joint damage and hand bone loss, predictors thereof and the association with disease activity during treatment have mainly been investigated in randomized controlled trials (RCTs) with limited generalizability due to strict in- and exclusion criteria.? The main aim of the PhD thesis was to assess and predict structural joint damage and hand bone loss in patients with early and established RA treated with sDMARDs and TNF-inhibitors. This was investigated in two cohorts: A) The "DANBIO X-ray study": an observational, nationwide, longitudinal cohort study of established RA patients treated in clinical practice who initiated TNF-inhibitor treatment after failure of sDMARDs and B) The "OPERA study": a randomized controlled trial of sDMARD-naive patients with early RA treated with methotrexate (MTX) and intraarticular glucocorticoid injections in combination with adalimumab or placebo-adalimumab. Structural joint damage progression was assessed with the Sharp/van der Heijde radiographic method and hand bone loss was assessed with Digital X-ray Radiogrammetry. ?From the studies presented in the PhD thesis the following was concluded:? Structural joint damage progression and hand bone loss were significantly lower during two years of TNF-inhibitor treatment compared to the previous two years of sDMARD-treatment in the DANBIO X-ray Study. The majority of patients had no progression of structural joint damage during two years of TNF-inhibitor treatment, while hand bone loss remained increased compared to reference values from the general population in the majority of patients. Adalimumab had no impact on hand bone loss in the OPERA study.? Existing structural joint damage, older age, IgM-rheumatoid factor positivity and concomitant treatment with prednisolone were independent predictors of progression in structural joint damage in the DANBIO X-ray cohort, while high hand bone loss in the first 6 months of treatment and placebo treatment were independently associated with increase in structural joint damage scores in the OPERA study. A high hand bone mass and disease activity were independent predictors of increased hand bone loss in the DANBIO X-ray study, while older age and high functional disability predicted hand bone loss in the OPERA study. High disease activity during treatment was associated with structural joint damage progression during TNF-inhibitor treatment in the DANBIO X-ray study and with hand bone loss in the DANBIO X-ray and OPERA studies. PMID- 29510811 TI - Evaluation of new ultrasound techniques for clinical imaging in selected liver and vascular applications. AB - This PhD project is based on a longstanding collaboration between physicists and engineers from the Center of Fast Ultrasound Imaging (CFU) at the Technical University of Denmark and medical doctors from the department of Radiology at Rigshospitalet. The intent of this cooperation is to validate new ultrasonic methods for future clinical use. ?Study I compares two B-mode ultrasound methods: the new experimental technique Synthetic Aperture Sequential Beam-forming combined with Tissue Harmonic Imaging (SASB-THI), and a conventional technique combined with THI. While SASB reduces the amount of data transformation, thus enabling wireless transmission, THI can improve resolution and image contrast, and creates fewer artifacts. Thirty-one patients with verified liver tumors were scanned and recordings with and without visible pathology were performed. Subsequently, eight radiologists evaluated blinded to information about the technique, which B-mode images they preferred, as well as detection of pathology. Evaluation showed that the techniques were preferred equally and tumor could be detected equally well. ?Study II deals with the ability of vector flow imaging (VFI) to monitor patients with arteriovenous fistulas for hemodialysis for upcoming stenosis. VFI is an angle-independent method for determining blood flow direction and velocity. Volume can be determined by integrating the velocity profile multiplied by the cross-sectional area. Nineteen patients were monitored monthly over a period of six months, and VFI estimates were compared with the reference ultrasound dilution technique (UDT). VFI volume flow values were not significantly different from UDT and had a better precision. Concordance between VFI and UDT was high when large volume flow changes (greater than 25%) oc?curred between dialysis sessions. However, the methods could not be regarded as interchangeable. ?Study III deals with VFI's ability to determine peak velocity in the portal vein. The commonly used ultrasound method for this is spectral Doppler, which is known to overestimate peak velocity when the angle between the blood vessel and the beam is more than 70 degrees; this overestimation becomes even larger when the angle becomes larger. VFI can determine the peak velocity angle independently. Thirty-two healthy volunteers were scanned with spectral Doppler and VFI with two portal vein scan positions (intercostal and subcostal). The study showed that VFI estimates the same peak velocity as spectral Doppler. Furthermore, VFI has better precision and can estimate the same peak velocity with a scan position, where spectral Doppler cannot. Finally, inter- and intra observer agreement is higher for VFI. ?All three studies indicate that the techniques can be used in the clinic and probably will be part of everyday practice in the near future. PMID- 29510812 TI - Blowout fractures - clinic, imaging and applied anatomy of the orbit. AB - Isolated fractures of the orbital floor or medial wall are often referred to as blowout fractures (BOFs). Debilitating double vision and aesthetic deformity may affect the patients' quality of life and daily living skills, for instance, working or driving a car. The management of blowout fractures is, however, challenging, since not all fractures demand surgery. Some patients may have symptoms which subside, or may never develop symptoms. Due to a lack of evidence, there are still considerable differences in opinion on the criteria for surgery. The selection of patients for surgery is therefore crucial for optimal patient outcomes. ?The aims of this PhD project were to elucidate and investigate various clinical aspects of blowout fractures and to examine the anatomy of the orbital cavity, which included studying the symmetry of the two orbits, the location of orbital arteries, and the pathophysiology of blowout fractures. Several clinical specialties and basic research fields study the orbital cavity. The studies in this PhD project are based on collaboration between the Departments of Otorhinolaryngology, Ophthalmology and Radiology at the Copenhagen University Hospital Rigshospitalet and the Departments of Odontology and Anatomy (Cellular and Molecular Medicine) at the University of Copenhagen. ?We assessed the current treatment of blowout fractures at the Ear Nose and Throat (ENT) Department at our tertiary hospital in a retrospective study, and found that a third of the patients had persistent double vision 3 months post-trauma, irrespective of whether they had been managed surgically or conservatively (Paper I). We found that the left and right orbit are symmetrical with regards to various morphometrics of both the bony orbit and the intraorbital contents, e.g. volume, surface area and volume of fat and extraocular muscles, and distance to the ethmoidal arteries (Papers II, III and IV). This knowledge may be used in blowout fracture studies on surgical decision-making and orbital reconstruction and also in presurgical planning to avoid iatrogenic damage to the ethmoidal arteries in orbital surgery. In the first longitudinal MRI study of blowout fractures, dynamic post-traumatic changes in the intraorbital soft tissue were detected, i.e. to the best of our knowledge, for the first time indicative of an edema. We conclude that an edema subsides in the days following a blowout fracture and recommend a watchful waiting period before deciding on whether or not to operate (Paper III).? The 24-12-6 mm rule of thumb determines orbital distances from the anterior lacrimal crest to the ethmoidal arteries and the optic canal. We questioned the applicability of this rule to all patients and investigated whether or not it is feasible to measure the distances on CT images. We found large inter-individual differences in the distances to the ethmoidal arteries and found that preoperative measurements on CT images are feasible and produce results with a low intra- and inter-observer variability. PMID- 29510813 TI - Electronic monitoring in bipolar disorder. AB - Major reasons for the insufficient effects of current treatment options in bipolar disorder include delayed intervention for prodromal depressive and manic symptoms and decreased adherence to psychopharmacological treatment. The reliance on subjective information and clinical evaluations when diagnosing and assessing the severity of depressive and manic symptoms calls for less biased and more objective markers. By using electronic devices, fine-grained data on complex psychopathological aspects of bipolar disorder can be evaluated unobtrusively over the long term. Moreover, electronic data could possibly represent candidate markers of diagnosis and illness activity in bipolar disorder and allow for early and individualized intervention for prodromal symptoms outside clinical settings. ?The present dissertation concerns the use of electronic monitoring as a marker and treatment intervention in bipolar disorder and investigated the scientific literature and body of evidence within the area, which includes ten original study reports and two systematic reviews, one of which included a meta-analysis, conducted by the author of the dissertation. ?Taken together, the literature presented in this dissertation illustrates that 1) smartphone-based electronic self-monitoring of mood seems to reflect clinically assessed depressive and manic symptoms and enables the long-term characterization of mood??instability in bipolar disorder; 2) preliminary results suggest that smartphone-based automatically generated data (e.g. the number of text messages sent/day; the number of incoming and outgoing calls/day; the number of changes in cell tower IDs/day; and voice features) seem to reflect clinically assessed depressive and manic symptoms in bipolar disorder; 3) smartphone-based electronic self monitoring had no effects on the severity of depressive and manic symptoms in bipolar disorder, according to a randomized controlled trial; and 4) electronic monitoring of psychomotor activity and heart rate variability seems to reflect illness activity in bipolar disorder and differentiate between patients with bipolar disorder and healthy control individuals. ?These findings point toward the usefulness of electronic monitoring as a marker of illness in bipolar disorder. Using electronic monitoring as a treatment intervention could provide innovative and novel interventions on-demand with a potential global reach, filling the gap between availability and the need for treatment. However, future studies using rigorous methodology and more randomized controlled trials that carefully investigate the positive effects and possible harmful effects of electronic monitoring in bipolar disorder are needed. In addition, patient safety, privacy issues, data security and legal aspects are major concerns that must be considered and addressed when using electronic monitoring. PMID- 29510814 TI - von Hippel-Lindau disease: Diagnosis and factors influencing disease outcome. AB - von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition caused by mutations in the VHL tumor suppressor gene. VHL mutation-carriers are at life long risk of multi-organ tumor development. The mainstay of vHL management is close surveillance and surgical tumor removal. The disease has been reported to be fully penetrant at 60 years of age, and has a highly variable phenotype, which complicates vHL management and causes distress and uncertainty for affected families. vHL survival has historically been poorer than the survival of the general population, with a median life expectancy for vHL patients of only 49 years. vHL life expectancy is expected to be improved by better surveillance, tumor diagnosis, and treatment approaches, although this has not?yet been directly demonstrated. The prevalence of vHL is between 1 in 39,000 and 1 in 91,000 individuals, and the birth incidence is between 1 in 36,000 and 1 in 45,500 live births in different populations. Based on these estimates, vHL is underdiagnosed in Denmark, and many undiagnosed families are not offered genetic counseling or prophylactic surveillance.?We aimed to assess 1) how the rate of new manifestation development is influenced by age, sex, genotype, tumor location, and pregnancy, 2) how vHL survival has developed over time, and is affected by sex, genotype, and surveillance attendance, 3) to determine the prevalence and incidence of vHL, and 4) to calculate vHL penetrance based on an unselected national cohort. ?We included almost all diagnosed vHL patients in Denmark in a retrospective cohort study. We further used the national health registers to find individuals who had a missed vHL diagnosis despite fulfilling the clinical diagnostic criteria.?We found that the risk of new vHL manifestations varies with age, genotype, and tumor location. The risk of new retinal tumors is highest in the patients' teenage years, while cerebellar tumors developed at the highest rates in patients' thirties. Patients with truncating mutations had higher rates of new manifestation diagnosis than patients with missense mutations. Men tend to have higher manifestation rates in adulthood compared to women, and pregnancy was associated with a lower frequency of new manifestations. vHL survival has improved over time, and is getting closer to that of their siblings without vHL and the general population. Survival is significantly influenced by a patient's birth year, sex, and genotype. We estimate the mean life expectancy of VHL mutation-carriers born in 2000 to be 67 years for men and 60 years for women. We estimate the vHL prevalence to be about 1 in 46,900 individuals and the birth incidence to be about 1 in 27,300 live births. We found a penetrance at age 60 of 87%, and only 80% among pa-tients who have not attended surveillance prior to diagnosis, which is considerably lower than previous estimates. ?Our findings form the basis of a more targeted vHL surveillance and counseling. The lower age-related penetrance greatly influences risk assessment in a clinical genetic setting. Even though the prevalence has increased over recent years, vHL is still underdiagnosed, and there is a need for increased awareness about the disease. PMID- 29510815 TI - Onstep repair of inguinal hernias. AB - Inguinal hernias are a protrusion of the peritoneum through a weakening in the groin in which abdominal content (intestines or fat) can herniate and cause a bulge. Inguinal hernias can be painful and require surgery. Worldwide, approximately 20 million patients are operated each year, with 10,000 in Denmark. The repair of inguinal hernias causes pain and 16% of patients experience chronic pain six months after the standard, open, mesh-based Lichtenstein technique. Therefore, surgeons are trying to improve the techniques by finding new ways of operating. The Onstep method was a new method for the repair of inguinal hernias, presented along with excellent results regarding pain, recurrence and complications. However, the technique had not been tested outside the department of the inventors. ?The overall aim was to clarify whether the Onstep technique should be implemented on a larger scale outside the departments of the inventors. ?Six papers are included in this thesis: a systematic review, a protocol article, three reports on the Onstep versus Lichtenstein trial, and finally a focus group interview. ?The systematic review identified nine different methods of placing a preperitoneal mesh through and open anterior approach. In general, the techniques seem to provide good results regarding pain and discomfort, but more studies are needed. ?The protocol article describes the randomized, double blinded Onstep versus Lichtenstein study, with focus on the statistical analysis and sample size calculations. Four separate sample size calculations were conducted, making several primary outcomes possible. ?The three reports of the Onstep versus Lichtenstein study reported on early postoperative outcomes, on chronic pain, and lastly on sexual dysfunction. The overall findings from the trial demonstrated that there were no differences between the Onstep and the Lichtenstein technique regarding early and chronic pain (30 days, six months, and 12 months). However, for the group of patients operated with the Onstep technique, fewer patients experienced pain during sexual activity. ?The focus group interview was done with experienced surgeons teaching the Onstep technique. They described their experience, thoughts, and concerns regarding teaching the technique. The results from the focus group interview can be used to guide future trainings sessions. ?In this thesis the Onstep technique has been investigated in comparison with the Lichtenstein technique, but the results have not been as promising as the initial studies from the inventors. However, implementation of the Onstep technique outside the departments of the inventors is unlikely to result in increased risk of complications. Furthermore, the Onstep technique could possibly benefit patients by reducing the risk of pain during sexual activity. PMID- 29510816 TI - Adjuvant analgesics for spine surgery. AB - Increasing evidence indicate that pain is insufficiently treated following surgical procedures. It is essential that pain treatment is effective with a minimum of side effects in order to promote postoperative rehabilitation. Multimodal analgesia is most likely an important strategy in reducing postoperative pain. Combinations of different analgesics with different mechanisms of action may have an additive analgesic effect with fewer side effects compared to using a single drug. However, there is still a pronounced lack of documentation for the effect and side effects of these multimodal analgesic regimes. More than 6,000 spine surgeries are performed annually in Denmark and spine surgery has been associated with high levels of pain compared to other surgical procedures. Therefore, we considered spine surgery to pose a group of well-defined surgical procedures and we used this model to investigate the efficacy of 3 adjuvant analgesics aiming to improve the multimodal approach in pain management.? ?In study I and II we hypothesized that preoperative IV dexamethasone 16 mg would reduce acute postoperative pain, opioid consumption and persistent pain after lumbar disk surgery. We found that dexamethasone significantly reduced acute pain during mobilization. The clinical relevance is however debatable and we could not demonstrate an opioid sparing effect. Further, we discovered significantly higher pain levels in the dexamethasone group compared to placebo 1 year postoperatively.? ?In study III we explored the effect of 500 mg of oral chlorzoxazone on acute postoperative pain and opioid consumption in patients with moderate to severe pain after spine surgery and found no effect of chlorzoxazone compared to placebo.? ?In study IV we hypothesized that intraoperative ketamine would reduce postoperative opioid consumption and persistent pain after spinal fusion surgery in chronic pain patients with opioid dependency. We found a significantly reduced opioid consumption in the ketamine group and a reduced level of persistent pain 6 months postoperatively.? ?In conclusion, dexamethasone and ketamine are potential adjuvant analgesics for postoperative pain. Possibly ketamine also inhibits the development of persistent pain. Chlorzoxazone has no immediate effect as an adjuvant in acute pain management. PMID- 29510817 TI - Pulmonary artery perfusion versus no pulmonary per-fusion during cardiopulmonary bypass. AB - ?During conventional cardiopulmonary bypass (CPB) there is no active perfusion of the pulmonary circulation and the mechanical ventilation is ceased leaving the lungs exposed to warm ischemia.? ?Pulmonary dysfunction is seen in varying degrees after major surgery, but more severe in cardiac surgery patients probably due to the effects of CPB. The evidence for effect and safety are limited, but active pulmonary artery perfusion during CPB could be beneficial for the patients' postoperative oxygenation.?Our aim was in a randomised clinical trial to assess primarily the effect of pulmonary artery perfusion during CPB on postoperative oxygenation in patients diagnosed with chronic obstructive pulmonary disease (COPD), secondarily to assess other possible benefits and harms. Furthermore, we wanted in a systematic review with meta-analyses of all randomised clinical trials to investigate the pooled effects of pulmonary artery perfusion during CPB. ?We planned and conducted a randomised, partly blinded, clinical trial assigning cardiac surgery patients diagnosed with COPD to receive pulmonary artery perfusion with oxygenated blood or histidine-tryptophan ketoglutarate (HTK) solution compared to no pulmonary perfusion during CPB. The primary outcome was the oxygenation index measured during and after surgery. Secondary outcomes were intubation time, serious adverse events, days alive outside the intensive care unit and outside the hospital, 30- and 90-days mortality. ?Secondly, we conducted a systematic review of randomised clinical trials comparing benefits and harms of using pulmonary artery perfusion versus no pulmonary perfusion during CPB pooling results in meta-analyses and trial sequential analyses (TSA).? ?Of the 90 randomised patients 89 were included in analysis of the primary outcome, the inverse oxygenation index, measured at a single time point 21 hours after CPB start and longitudinally 1, 3, 5, 7, and 21 hours after CPB start. At 21 hours, patients randomised to pulmonary artery perfusion with oxygenated blood had a higher inverse oxygenation index compared to patients randomised to no pulmonary perfusion during CPB (mean difference (MD) 0.94; 95% confidence interval (CI), 0.05 to 1.83; P=0.04). The inverse oxygenation index was also significantly higher at 21 hours after CPB start (MD 0.99; CI, 0.29 to 1.69; P=0.007), and longitudinally (P=0.009), for patients receiving pulmonary artery perfusion with oxygenated blood compared to pulmonary artery perfusion with HTK solution. This corresponds to a PaO2 difference of 23 mmHg with a median FiO2 of 0.32. We found no additional significant differences for the remaining comparisons of the inverse oxygenation index neither for any of the secondary outcomes. ?The systematic review identified 4 trials with a total of 210 patients. In meta-analyses pulmonary artery perfusion with blood versus no pulmonary perfusion during CPB was not associated with relative risk of death (1.7; 95% CI, 0.4 to 6.9; 210 patients in three trials with high and one trial with low risk of bias), serious adverse events (1.2; 95% CI, 0.8 to 1.8; 180 patients in two trials with high and one trial with low risk of bias) or intubation time (-0.4 hours; 95% CI, -1.1 to 0.4; 176 patients in three trials with high and one trial with low risk of bias). TSA on mortality, serious adverse events, and PaO2/FiO2 ratio showed that required information sizes have not been reached, but pulmonary artery perfusion with blood was associated with a higher PaO2/FiO2 ratio (27.8 mmHg; 95% CI, 5.7 to 50.0 mmHg; 119 patients in two trials with high and one trial with low risk of bias). TSA on intubation time showed that the boundary for lack of superiority (futility) was crossed refuting a shorten intubation time of 1.5 hours or more. ?Our trial provided additional knowledge about the use of pulmonary artery perfusion during CPB in cardiac surgery patients with COPD, and improved oxygenation for patients receiving pulmonary artery perfusion with oxygenated blood. Pulmonary artery perfusion with HTK solution did not result in an improved oxygenation. In line with this, the systematic review including data from additional trials showed a possible association between pulmonary artery perfusion with blood and improved oxygenation, but no significant associations with mortality, serious adverse events or intubation time. However, all data are too sparse to be conclusive. PMID- 29510818 TI - Ultrasonography for diagnosis, monitoring and treatment of tenosynovitis in patients with rheumatoid arthritis. AB - Rheumatod arthritis is a chronic systemic autoimmune disease, characterized by inflammation in joints and tendon sheaths, which frequently leads to permanent and serious disability due to joint destruction, but also tendon and ligament ruptures. Clinical management of rheumatoid arthritis has traditionally been supported by biochemical and radiographic findings. However, imaging modalities like ultrasound and magnetic resonance imaging (MRI) have improved the possibility for better management of rheumatoid arthritis patients, due to higher sensitivity and specificity for detecting ongoing inflammation, this thesis is focusing on tenosynovitis as recent studies have shown that inflammation in tendon sheaths, i.e. tenosynovitis, is a very common manifestation of rheumatoid arthritis and may often be mistaken for synovitis. Furthermore, presence of ultrasonographic tenosynovitis may predict clinical flare and erosive progression. ?The main aim of this PhD thesis was to further develop and validate ultrasound as a tool for diagnosis, monitoring and treatment of tenosynovitis. This was investigated in four studies: ?Study I: 3D Doppler Ultrasound findings in healthy wrist and finger tendon sheaths - Can feeding vessels lead to misinterpretation in Doppler-detected tenosynovitis? ?Study II: Image fusion of Ultrasound and MRI and B-flow evaluation of tenosynovitis - A pilot study on new imaging techniques in rheumatoid arthritis patients. ?Study III: Validity and sensitivity to change of the semi-quantitative Outcome Measures in Rheumatology Clinical Trials (OMERACT) ultrasound scoring system for tenosynovitis in patients with rheumatoid arthritis and for the quantitative scoring system, pixel index. ?Study IV: Intramuscular versus ultrasound guided intratenosynovial glucocorticoid injection for tenosynovitis in patients with rheumatoid arthritis A randomised, double-blind, controlled study with ultrasound and clinical follow up at 4 and 12 weeks. ?From the studies presented in the PhD thesis the following was concluded:? Doppler findings in or in close proximity to the tendon sheaths were common in wrists and fingers in healthy participants. These feeding vessels may be a source of misinterpretation, i.e .wrong diagnosis of a low degree of tenosynovitis, not only due to their presence but also because they may be interpreted as being inside the tendon sheath due to blooming and reverberations artefacts.? Ultrasound and MRI had high agreement using image fusion for assessment of tenosynovitis when MRI partial volume artefacts were taken into account. In contrast, the agreement between B-flow and ultrasound was poor, since the quality of the b-flow images and the flow sensitivity were low.? The OMERACT ultrasound scoring system for tenosynovitis had an excellent intra- and interreader agreement between trained investigators and a high ability to detect change over time, similarly, the quantitative tenosynovitis assessment by pixel index had a very good intrareader agreement and moderate to good interreader agreement, but only a moderate ability to detect change over time. The ultrasound scores had a high responsiveness, indicating that the OMERACT ultrasound scoring system was useful for diagnosing and monitoring tenosynovitis in rheumatoid arthritis patients in clinical trials and practice. For treatment of tenosynovitis in rheumatoid arthritis patients, remission (ultrasound tenosynovitis grey scale score <=1 and Doppler score = 0) was achieved significantly more frequently in the ultrasound guided intratenosynovial glucocorticoid injection group than in the intramuscular glucocorticoid injection group, both at 4 and 12 week follow-ups. Furthermore, tenosynovitis responded significantly better clinically and by ultrasound assessment when treated with ultrasound guided intratenosynovial glucocorticoid injection com-pared to intramuscular glucocorticoid injection, both at 4 and 12 week follow-ups. PMID- 29510819 TI - Primary Empty Sella Syndrome and the Prevalence of Hormonal Dysregulation. AB - BACKGROUND: Empty sella is the neuroradiological or pathological finding of an apparently empty sella turcica containing no pituitary tissue. The prevalence of primary empty sella, i.e., empty sella without any discernible cause, is not precisely known; estimates range from 2% to 20%. Technical advances in neuroradiology have made empty sella an increasingly common incidental finding. It remains unclear whether, and to what extent, asymptomatic adult patients with an incidentally discovered empty sella should undergo diagnostic testing for hormonal disturbances. METHODS: To answer this question, the authors carried out a systematic search in the PubMed and Web of Science databases for publications that appeared in the period 1995-2016 and that contained the search term "empty sella" (registration: PROSPERO 2015: CRD42015024550). RESULTS: The search yielded 1282 hits. After the exclusion of duplicates, pediatric reports, case reports, and veterinary studies, 120 publications on primary empty sella syndrome (PES) were identified. 4 of these dealt with the prevalence of pituitary insufficiency in patients with PES as an incidental finding. Among patients with PES, the relative frequency of pituitary insufficiency in the pooled analysis was 52% (95% confidence interval [38; 65]). CONCLUSION: The data on PES as an incidental finding are too sparse to enable any evidence-based recommendation on the potential indications for hormone testing or its nature and extent. We advise basic neuroendocrinological testing (fasting cortisol, free thyroxine [fT4], estradiol or testosterone, insulin-like growth factor 1 [IGF-1], and prolactin). There is an unexplained discrepancy between the reported high prevalence of pituitary insufficiency among persons with PES and its low prevalence in epidemiologic studies. We suspect that the former may be high because of selection bias in the publications that we reviewed, or else the latter may be erroneously low. PMID- 29510821 TI - German Pregnancy Register "Rhekiss". PMID- 29510820 TI - The Interdisciplinary Diagnosis and Treatment of Intraocular Tumors. AB - BACKGROUND: Recent years have seen major changes in the diagnosis and treatment of solid intraocular tumors, mainly owing to an improved molecular biological understanding of their pathogenesis, new therapeutic approaches for the local treatment of tumors in children, and long-term follow-up observations in clinical trials. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed. RESULTS: Retinoblastoma is the most common type of primary intraocular tumor, with approximately 8000 new cases per year around the world, while malignant melanoma of the uvea is the most common primary intraocular tumor in adults, with approximately 7000 new cases per year around the world. Intraocular metastases of malignant tumors are ten times more common, in terms of incidence, than primary intraocular tumors and are therefore the most common intraocular tumors overall. Improved methods of intraocular biopsy, diagnostic imaging, and molecular genetic investigation have led to steady improvement in clinical and predictive diagnostic assessment. In the treatment of retinoblastoma, local techniques including brachytherapy and intra-arterial and intravitreal chemotherapy play a prominent role. Prognostic molecular-genetic testing now enables the highly selective identification of uveal melanomas that have a high potential to metastasize. Cutaneous and uveal melanomas differ both in their clinical behavior and in their basic biological features; to date, effective systemic treatment has been established for melanoma of the skin, but not for metastatic melanoma of the uvea. Intraocular metastases are common and often the initial manifestation of an extraocular tumor, particularly lung cancer. CONCLUSION: Modern diagnostic and therapeutic concepts for intraocular tumors can only be implemented through the close interdisciplinary collaboration of ophthal - mologists, oncologists, radiologists, radiotherapists, pathologists, and human geneticists. PMID- 29510822 TI - Anatomically Incorrect. PMID- 29510823 TI - Independent Measurement of PEF Values. PMID- 29510824 TI - In Reply. PMID- 29510825 TI - Central Problem is Equipoise. PMID- 29510826 TI - No Substitute for a Doctor's Intuition. PMID- 29510827 TI - Real-World Usefulness Is Missing. PMID- 29510828 TI - In Reply. PMID- 29510829 TI - Headache and Eye Pain in a Patient With Unusual Facial Morphology. PMID- 29510830 TI - A Rare Cause of Splenomegaly. PMID- 29510831 TI - Catheter washout solutions for long-term urinary catheterisation in adults: A Cochrane review summary. PMID- 29510832 TI - Simulated presence therapy for dementia: A Cochrane review summary. PMID- 29510833 TI - Correlation between elastic parameters and collagen fibre features in breast lesions. AB - AIM: To correlate elastic parameters with collagen fibre shape and arrangement features in breast lesions. MATERIALS AND METHODS: Shear-wave elastography (SWE) was used to measure the stiffness of breast lesions in 54 patients before surgical removal. The value of stiffness was expressed as the mean and maximum elasticity (Emean and Emax). Lesions were sliced and stained with picric acid sirius red to display the extracellular matrix (ECM) collagen fibre. The categories of the collagen fibres were based on the shape and arrangement features, i.e., category 0, wavy collagen fibres similar to normal breast tissue; category 1, taut parallel collagen fibres around tumour nests; category 2, straightened and aligned collagen fibres tending to be perpendicular to the tumour boundary; category 3, collagen fibre in a honeycomb arrangement. Bivariate correlation analysis was used to analyse the relationship between elastic parameters and collagen fibre category. RESULTS: For all 54 lesions, the correlation coefficient between Emean and category was 0.693 (p < 0.001), and between Emax and category was 0.794 (p < 0.001). For 36 malignant lesions, the correlation coefficient between Emean and category was 0.658 (p < 0.001), and between Emax and category was 0.771 (p < 0.001). CONCLUSION: Emean and Emax of breast lesions evaluated by SWE were positively correlated with ECM collagen fibre shape and arrangement category. Changes of ECM collagen fibre shape and arrangement may account for the stiffness variations of breast lesions. PMID- 29510834 TI - Definition: Asomatognosia. PMID- 29510835 TI - What is Health Equity? PMID- 29510836 TI - Black Lives Matter, but What About Our Health? AB - In the setting of the current social and political climate, the focus on protection of Black lives in America has come to the forefront. We evaluate how health in the Black community should be a paramount concern that can be addressed in three ways: 1. Connecting the medical community to the Black community, empowering patients with knowledge, and diversifying the medical workforce. These three initiatives will help to decrease the health disparities seen in Black health. PMID- 29510837 TI - Comparison of Self-Administered Post Traumatic Stress Disorder Tool vs. Researcher Administered Tool in the Emergency Department. AB - BACKGROUND: Recent studies have shown that there is a high rate of post traumatic stress disorder in the inner city. OBJECTIVE: The purpose of this study was to determine whether patients in the Emergency Department would use a post traumatic stress disorder (PTSD) assessment. Additionally, did the type of administration of the PTSD tool impact the usage of PTSD services? METHODS: The sample population was taken from patients, 12 years or older, who presented with a non psychiatric illness. This study was done at a level one inner city adult and pediatric Emergency Department. The PTSD validated survey, was randomized between being self or research fellow administered. Half of the patients completed the survey on their own and half were administered by a research fellow. Those who screen positive on the tool were contacted one week later. This was done to determine if they have scheduled an appointment or were seen for a follow-up appointment. This study was IRB approved. RESULTS: A total of 299 participants completed the survey. Half (149) of which used a PTSD tool that was self administered. The total amount of participants who tested positive for PTSD was 35% (105). There was a significant difference (0.01) between those who self administered the tool 26% (40) and those who had the tool administered 12% (18). This was seen in relationship to who was more likely to follow up with behavioral health referrals. CONCLUSIONS: These results reveal that 35% of the participants tested positive for PTSD. The majority of those that screened positive and used follow up services had self administered the tool. This indicates that they are more likely to seek out services based on their results. PMID- 29510838 TI - Strategies to Protect the Planet can Reduce Cancer, Too. PMID- 29510839 TI - Assessing the Effects of the Acting White Accusation Among Black Girls: Social Anxiety and Bullying Victimization. AB - One of the most harmful accusations one Black adolescent can hurl at another is the acting White accusation (AWA). The AWA is an attack against an individual's ethnic/racial identity and many have described it as a bullying experience. Those who experience the AWA frequently and are bothered by it might perceive the accusation as bullying for these reasons, and peer victimization has been associated with several negative outcomes including social anxiety. The present study examines the relationship between the acting White accusation, bullying victimization, and social anxiety. Thirty-one Black females between the ages of 10 and 18 years served as participants in the study. The findings indicated that all participants reported receiving the accusation at least once in their lifetime. The results also indicated that bother experienced when receiving the accusation was positively associated with social anxiety, while both bother and frequency of the accusation were positively associated with bullying victimization. These findings suggest that adolescents interpret the accusation as a negative evaluation. Additionally, the more an adolescent experiences the accusation and the more bothered he or she is by it, the more victimized they feel. PMID- 29510840 TI - African-American Medical Personnel in the US Army in the First World War. AB - In WWI, the United States was segregated by custom and law, and the Army obeyed the laws, reducing opportunities for Black medical professionals to serve their country in uniform. This article surveys African-American medical personnel serving in the US Army in World War I. It includes physicians, dentists, veterinarians, and other commissioned officers, as well as medical enlisted men. Overall, despite segregation and associated professional limitations, determined individuals still served with distinction in a variety of roles, opening doors for future advances. PMID- 29510841 TI - Visiting Black Patients: Racial Disparities in Security Standby Requests. AB - BACKGROUND: Structural inequalities exist within healthcare. Racial disparities in hospital security standby requests (SSRs) have not been previously explored. We speculated hospital SSRs varied based upon race with black patients and their visitors negatively impacted. METHODS: An 8-year retrospective study of hospital security dispatch information was performed. Data were analyzed to determine demographic information, and service location patterns for SSRs involving patients and their visitors. The race of the patient's visitors was imputed using the patient's race. The observed and expected (using hospital census data) number of patients impacted by SSRs was compared. Descriptive statistics were computed. Categorical data were analyzed using chi-square or Fisher exact test statistic. A p < 0.05 was statistically significant. RESULTS: The majority of the 1023 SSRs occurred for visitors of patients who were white (N = 642; 63%), female (56%), or < 21 years old (50.7%). However, SSRs differed significantly based upon the patient's race. Although Black patients represent 12% of the hospital population, they and their visitors were more than twice as likely (p < 0.0001) to have a SSR generated (N = 275; 27%) when compared to the visitors of both White and other (i.e., race unknown) patients (N = 106; 10%) combined (p < 0.0001). CONCLUSION: This study adds to the medical errors and healthcare disparities literature by being the first to describe racial disparities in SSRs for Black patients and their visitors. It also introduces the concept of "security intervention errors in healthcare environments." New metrics and continuous quality improvement initiatives are needed to understand and eliminate racial/ethnic based disparities in SSRs. PMID- 29510842 TI - The Violence Epidemic in the African American Community: A Call by the National Medical Association for Comprehensive Reform. AB - While much progress has occurred since the civil rights act of 1964, minorities have continued to suffer disparate and discriminatory access to economic opportunities, education, housing, health care and criminal justice. The latest challenge faced by the physicians and public health providers who serve the African American community is the detrimental, and seemingly insurmountable, causes and effects of violence in impoverished communities of color. According to statistics from the Centers for Disease Control (CDC), the number one killer of black males ages 10-35 is homicide, indicating a higher rate of violence than any other group. Black females are four times more likely to be murdered by a boyfriend or girlfriend than their white counterparts, and although intimate partner violence has declined for both black and white females, black women are still disproportionately killed. In addition, anxiety and depression that can lead to suicide is on the rise among African American adolescents and adults. Through an examination of the role of racism in the perpetuation of the violent environment and an exploration of the effects of gang violence, intimate partner violence/child maltreatment and police use of excessive force, this work attempts to highlight the repercussions of violence in the African American community. The members of the National Medical Association have served the African American community since 1895 and have been advocates for the patients they serve for more than a century. This paper, while not intended to be a comprehensive literature review, has been written to reinforce the need to treat violence as a public health issue, to emphasize the effect of particular forms of violence in the African American community and to advocate for comprehensive policy reforms that can lead to the eradication of this epidemic. The community of African American physicians must play a vital role in the treatment and prevention of violence as well as advocating for our patients, family members and neighbors who suffer from the preventable effects of violence. PMID- 29510843 TI - Lessons Learned Recruiting Minority Participants for Research in Urban Community Health Centers. AB - To help understand and mitigate health disparities, it is important to conduct research with underserved and underrepresented minority populations under real world settings. There is a gap in the literature detailing real-time research staff experience, particularly in their own words, while conducting in-person patient recruitment in urban community health centers. This paper describes challenges faced at the clinic, staff, and patient levels, our lessons learned, and strategies implemented by research staff while recruiting predominantly low income African-American women for an interviewer-administered survey study in four urban Federally Qualified Health Centers in New Jersey. Using a series of immersion-crystallization cycles, fieldnotes and research reflections written by recruiters, along with notes from team meetings during the study, were qualitatively analyzed. Clinic level barriers included: physical layout of clinic, very low or high patient census, limited private space, and long wait times for patients. Staff level barriers included: unengaged staff, overburdened staff, and provider and staff turnover. Patient level barriers included: disinterested patients, patient mistrust and concerns over confidentiality, no shows or lack of patient time, and language barrier. We describe strategies used to overcome these barriers and provide recommendations for in-person recruitment of underserved populations into research studies. To help mitigate health disparities, disseminating recruiters' experiences, challenges, and effective strategies used will allow other researchers to build upon these experience in order to increase recruitment success of underserved and underrepresented minority populations into research studies. PMID- 29510844 TI - Association Between Socioeconomic Status and Tumor Grade Among Black Men with Prostate Cancer. AB - BACKGROUND: Prostate cancer affects black men disproportionately. Black men have an increased incidence of prostate cancer diagnoses at earlier ages and higher grade as indicated by Gleason score, compared to other races. This study investigates the impact of socioeconomic status (SES) on prostate cancer tumor grade among black men. METHODS: Black men with a prostate cancer diagnosis during 1973-2011 were examined using individual-level data from the SEER NLMS database. Logistic regression model estimated the likelihood of receiving a diagnosis of high versus low grade prostate cancer based on self-reported SES status at the time of diagnosis. RESULTS: Men who completed high school only were statistically significantly more likely to have a higher prostate cancer grade than those with a bachelor's degree or higher. However, there was no dose-response effect across educational strata. Retirees were 30% less likely to have higher grade tumors compared to those who were employed. CONCLUSIONS: SES differences among black men did not fully explain the high grade of prostate cancer. Further research is needed on the biology of the disease and to assess access to medical care and prostate health education, discrimination, stress exposures, and social norms that might contribute to the aggressiveness of prostate cancer among black men. PMID- 29510846 TI - The Effectiveness of Self-care Program on the Life Quality of Patients with Multiple Sclerosis in 2015. AB - This study aimed to investigate the effectiveness of self-care plan on the life quality of patients with Multiple sclerosis (MS). The samples in this study included all the patients with MS under medical coverage of Iranian Association of supporting patients with MS in Tehran in 2015 who were studied as Convenience sampling and based on the inclusion and exclusion criteria. In this study, Dr. Madani's self-care program as an intervention and The World Health Organization Quality of Life (WHOQOL)-BREF for assessment of consequences were used. Spss software using Wilcoxon and ANOVA tests were used to analyze the data. Values are significant at P value less than 0.05. Before the intervention, the quality of life was 59.91 +/- 13.39 and after the intervention, it was 69.37 +/- 11.73 and there was a significant difference between them (P value < 0.001). Also, there was a significant difference between the items of life quality-including the physical, psychological and social relationships and living environment items before and after the interventions. Self-care program has an effect on the quality of life and physical, psychological and social relationships and living environment items. PMID- 29510845 TI - Challenges in Recruiting, Retaining and Promoting Racially and Ethnically Diverse Faculty. AB - BACKGROUND: Despite individual and institutional awareness of the inequity in retention, promotion and leadership of racially and ethnically underrepresented minority faculty in academic medicine, the number of such faculty remains unacceptably low. The authors explored challenges to the recruitment, retention and promotion of underrepresented faculty among a sample of leaders at academic medical centers. METHODS: Semi-structured interviews were conducted from 2011 to 2012 with 44 senior faculty leaders, predominantly members of the Group on Diversity and Inclusion (GDI) and/or the Group on Women in Medical Sciences (GWIMS), at the 24 randomly selected medical schools of the National Faculty Survey of 1995. All institutions were in the continental United States and balanced across public/private status and geographic region. Interviews were audio-taped, transcribed, and organized into content areas before conducting inductive thematic analysis. Themes expressed by multiple informants were studied for patterns of association. RESULTS: The climate for underrepresented minority faculty was described as neutral to positive. Three consistent themes were identified regarding the challenges to recruitment, retention and promotion of underrepresented faculty: 1) the continued lack of a critical mass of minority faculty; 2) the need for coordinated programmatic efforts and resources necessary to address retention and promotion; and 3) the need for a senior leader champion. CONCLUSION: Despite a generally positive climate, the lack of a critical mass remains a barrier to recruitment of racially and ethnically underrepresented faculty in medicine. Programs and resources committed to retention and promotion of minority faculty and institutional leadership are critical to building a diverse faculty. PMID- 29510847 TI - Comparative Characteristics of the Methods of Treatment of Chronic Periodontitis Using Antibacterial Photodynamic Therapy (Per One Visit) and Calasept Preparation. AB - BACKGROUND: The article describes the results of research on efficiency of using antimicrobial photodynamic therapy in treatment of chronic periodontitis. METHODS: 88 root canals in 84 patients were examined and treated. The diagnosis of chronic apical periodontitis was made based on anamnesis, data of clinical and instrumental examination, assessment of X-ray images. Patients were randomly selected to comply with the purity of the experiment. RESULTS: It was found that the use of antimicrobial photodynamic therapy leads to a reduction of medical cases accompanied by pain reaction after a one-stage treatment of chronic periodontitis when compared with data of the patients treated with calcium hydroxide preparation. Laser radiation in the course of preparation of the root canal for obturation allows reducing the number of complications almost 1.5 times, speeding up the recovery process of bone destruction foci, allowing to conduct endodontic treatment per one visit. CONCLUSION: The use of laser radiation in the course of preparation of the root canal for obturation when treating chronic periodontitis allows reducing the number of complications almost 1.5 times, accelerates recovery of bone destruction foci. PMID- 29510848 TI - Ethnic Manifestations of Gene Polymorphisms of Vitamin D Receptor (VDR) in Adolescents of Western Kazakhstan Region. AB - BACKGROUND (OBJECTIVES): The objective of the article is studying the connection of VDR gene polymorphisms with bone tissue mineral density and biochemical marker of 25-PO vitamin D in adolescents of both ethnic groups, living in Western Kazakhstan Region. METHODS: The study included 110 relatively healthy children aged 13-18 years of Aktobe, the representatives of Kazakh ethnic group e 66 (Kazakh children) and Slavonic e 44 (Russian children). The groups were formed according to BTMD data, ethnic affiliation and according to content of vitamin D and gene polymorphism of vitamin D (VDR). RESULTS: Genotype SS is negative marker in Kazakh adolescents of Western Kazakhstan Region for BTMD and 25-PO vitamin D; in children of Kazakh nationality with osteopathy sign, genotype SS occurs at almost twice the rate in comparison with Slavonic ethnic group and respectively by a factor of 2 less 25-PO vitamin D content. CONCLUSION: Disorders of bone mineralization and metabolism depend on ethnic affiliation and presence of defined polymorphic genotypes of VDR gene molecular markers. Genotype Tt is a normal variant of gene polymorphism and is characterized by significantly less 25 PO vitamin D content in adolescents of Kazakh ethnic group, in comparison with their age mates of Slavonic ethnic group. PMID- 29510849 TI - Anti-Vibriocholerae IgY Antibody Inhibits Mortality in Suckling Mice Model. AB - BACKGROUND: Regarding to the importance of cholera in Iran and the potential advantages of egg yolk antibody (IgY) for immunotherapy, the aim of this study was to produce IgY antibody against V. cholerae Lipopolysaccharide (LPS) and determine its potential for V. cholerae treatment. METHODS: LPS was prepared, and the Anti-V. cholerae LPS IgY was purified from egg yolk and serially diluted in phosphate-buffered saline (PBS), mixed with V. cholerae and then gavaged into several groups of suckling mice. RESULTS: The yield of Anti-LPS IgY extraction was 40 mg/Egg yolk. The results demonstrated that up to approximately 75 ng of IgY can detect specifically V. cholerae. The lowest protective dose of anti-V. cholerae LPS IgY was 2.5 MUg. CONCLUSIONS: The produced anti-Vibrio LPS specific IgY showed a good reactivity with its specific antigen and it may use as a complimentary oral immunotherapy for cholera disease. PMID- 29510850 TI - Characteristics of Mycobacterium Tuberculosis Positive Patients Screened for Drug Resistant Tuberculosis at a Tertiary Health Facility in Lagos, Nigeria. AB - BACKGROUND: Nigeria is one of the ten countries with the highest tuberculosis (TB) burden globally and is experiencing an increasing incidence of drug resistance. This study aimed to determine the prevalence of mycobacterium tuberculosis and rifampicin resistance (DR-TB) among patients screened at the TB clinic of a tertiary institution in Lagos, South-West, Nigeria. METHODS: A review of records of 840 patients with suspected drug-resistant TB was carried out from Gene Xpert test clinic register at a tertiary health facility from November 2013 to April 2015. The Data was analyzed with SPSS version 20, Chi square test was used to determine association between DR-TB and the factors examined and the level of significance was set at P < 0.05. RESULTS: MTB detection among all screened suspects was 43.3%. The prevalence of rifampicin resistance was 17.6% among patients that were investigated for DR-TB and this occurred more in the working age group (15-54 years) with male to female ratio of 1.8:1. However, only history of close contact with known DR-TB patient was associated with DR-TB (P < 0.01). CONCLUSION: The burden of DR-TB may be higher than previously thought. Drug resistance testing should be made more available to detect cases and thus control the emerging problem. PMID- 29510851 TI - Comparison of the Effects of Curcumin Mucoadhesive Paste and Local Corticosteroid on the Treatment of Erosive Oral Lichen Planus Lesions. AB - INTRODUCTION: Lichen planus is a prevalent chronic mucocutaneous condition, whose exact pathogenesis has not been elucidated yet and its standard treatment at present involves the use of local corticosteroids. Curcumin is a colored material extracted from Curcuma longa plant species and is used as an appetizer and for medical purposes. It has anti-inflammatory, antioxidative and anti-cancerous properties. In the present study, the effect of mucoadhesive pastes containing curcumin and local corticosteroids was evaluated for the treatment of erosive lichen planus lesions. MATERIALS AND METHODS: In this case-control study, 40 patients with oral lichen planus were evaluated. Twenty patients, as the cases, were given mucoadhesive pates containing curcumin and 20 patients, as the controls, were given local corticosteroids. The lesion sizes were recorded in the first session and during the follow-up sessions. Pain severities were measured and recorded using the visual analogue scale (VAS) on the first session and during the follow-up sessions. Data were analyzed with SPSS 19, using Student's t test and Mann-Whitney test. Data are significant P < 0.05. RESULTS: The lesion sizes, pain severities and changes in classification of the lesions exhibited significant differences at different follow-up sessions (weeks 1, 2, 4, 8 and 12) in the two groups (P < 0.05). However, there were no significant differences between the group treated with curcumin and the group treated with local corticosteroids (P > 0.05). CONCLUSION: Curcumin was effective in the treatment of oral lichen planus lesions and resulted in decreases in lesion sizes, pain and burning sensation severities and changes in classification of the lesions without any complications. PMID- 29510852 TI - Protective Role of Co-administration of Vitamin D in Monosodium Glutamate Induced Obesity in Female Rats. AB - PURPOSE: Obesity in females is an emerging health problem. The consumption of MSG has been considered as a risk factor for obesity. The tastemakers in Chinese and fast foods, such as fish sauce and soy sauce, contain very high levels of glutamate. The deficiency of Vitamin D is associated with obesity and metabolic syndrome. Therefore, the present study aimed to determine the effect of co administration of Vitamin D on body weight control in MSG-induced obese rats. METHODS: Eighteen adult female Wistar rats were randomly divided into three groups equally. The first group (Group I) was treated with saline served as the control; the second group (Group II) received a daily oral dose of 5 g/kg Body weight of MSG; the third group (Group III) received the same dose of MSG along with calcitriol (0.2 mcg/kg BW) for 15 days. RESULTS: The body weight, food, and water intake were measured. MSG treated rats showed a significant increase (P < 0.001) in the body weight, food, and water intake but significant decrease (P < 0.001) was observed in the rats treated with MSG along with Vitamin D. CONCLUSION: Ingestion of Vitamin D suppresses body weight gain in MSG-induced obese rats. Active agents in Vitamin D are useful for the prevention and treatment of obesity. Foods tested with high glutamate levels can be fortified with minute quantities of calcitriol to combat the adverse effects without compromising on the taste of the food processed. The fortification of junk foods might also combat largely prevalent Vitamin D deficiency in India. PMID- 29510854 TI - Reply to "Visibility of healthcare research institutes through the Web of Science database". PMID- 29510855 TI - Editorial. PMID- 29510856 TI - A prospective study with ten years follow-up of two-hundred patients with proximal femoral fracture. AB - BACKGROUND: The proximal femoral fracture is one of the most common injuries in the elderly. Nevertheless, no results beyond the second year post surgery have been reported in the literature. Therefore, the purpose of this study was to evaluate any revision and mortality within 10 years follow-up as well as the walking ability of still alive patients. METHODS: A total of 200 consecutive patients were included. A prospective database was first used to collect the demographic data. Exactly ten years after the surgery, a final evaluation was conducted by telephone for every patient. Any revision, any contralateral as well as other fractures and the date of death were recorded. For all patients who were still alive, the mobility score according to Parker was also surveyed. RESULTS: The average age was 79.0 years (SD: 12.5); women were affected at higher numbers (73.5%). The total surgical revision rate was 17.5% (35/200), due in particular to hematoma (9*) or infection (7*). A surgical revision later than two years was only needed in three patients (1.5%). The risk of another fracture caused by a fall was 19% (38/200), most often a contralateral femoral fracture (22/200; 11%) that happened on average 51.9 months (1-97) after the initial surgery. The risk of a contralateral femoral fracture was 15.4% (22/143) in patients who survived the first year post surgery. The postoperative mortality was 1, 2, 5 and 10 years or 23.5%, 32.5%, 55% as well as 81.5%, respectively. An average Parker's mobility score of 6.3 points (0-9) was determined for the 37 patients (18.5%) who were still alive at the time of the follow-up. CONCLUSION: The long-term study showed that revision surgery was only required in 3/200 patients (1.5%) beyond the second year of that surgery. On the other hand, more than half of all patients had already passed away five years after the initial surgery. The exact incidence of a contralateral femoral fracture was 11.9%, climbing to 15.4% if the patient survived at least one year. Nearly every fifth patient experienced another fall resulting in a severe fracture requiring treatment during the long-term course. PMID- 29510857 TI - Shoulder joint loadings in post total hip replacement surgery patients during assisted walking: The influence of the crutch setup. AB - A crutch is prescribed to permit the patient to walk safely and independently immediately after total hip replacement (THR) surgery. Purpose of this study is to evaluate the influence of the crutch setup on upper limbs biomechanics, including shoulder joint kinematics and kinetics parameters that will be evaluated to detect possible differences related to the crutch length. Thirty patients were randomly assigned to elbow flexed (EF) or elbow extended (EE) forearm crutch setup. Subjects were asked to walk on the laboratory path, instrumented with motion tracking system and force platforms. Spatiotemporal gait parameters, crutch ground reaction force (GRF) and crutch displacement (measured as the relative distance between the crutch position on the floor and the shoulder joint center), were evaluated. A three-dimensional (3D) biomechanical model was implemented to determine shoulder joint kinematics and kinetics during crutch walking. Results showed that the stride length significantly decreased, and base of support width increased for the EF group when compared to the EE group. Crutch forces and distance to the body significantly decreased in the EE group. Furthermore, shoulder joint moments in all planes of motion, vertical and lateral forces were significantly reduced in the EE group. The present study showed that crutch setup influenced performance and upper limb loading during walking, with EE setup allowing a more stable walking and reducing stress on the shoulder joint when compared to the EF setup. Results may help therapists in rationalizing crutch length adjustments for patients after THR surgery. PMID- 29510859 TI - [Statin treatment must be personalized]. PMID- 29510860 TI - Strategies for the cure of HIV infection. AB - The disadvantages of the long-term administration of antiretroviral therapy as well as the huge number of affected persons have placed the cure of HIV as a primary goal of Public Health. HIV may persist in the organism by at least four mechanisms: a latently infected cellular reservoir, the persistent replication of HIV in spite of ART, anatomic sanctuaries, and the immune dysfunction. Several strategies directed against these mechanisms have been developed. With all this, a complete eradication of HIV has been achieved in a patient using the transplantation of haemopoietic stem cells that were resistant to HIV-infection, and there are examples of functional cure either spontaneously (elite controllers) or after antiretroviral therapy (post-treatment controllers). However, no strategies have been successful in reducing the reservoir size, nor in achieving constant, uniform remissions. The failure of isolated strategies makes it likely that the combination of several of them may be the future solution. PMID- 29510858 TI - Masquelet technique: The effect of altering implant material and topography on membrane matrix composition, mechanical and barrier properties in a rat defect model. AB - The Masquelet technique is a surgical procedure to regenerate segmental bone defects. The two-phase treatment relies on the production of a vascularized foreign-body membrane to support bone grafts over three times larger than the traditional maximum. Historically, the procedure has always utilized a bone cement spacer to evoke membrane production. However, membrane formation can easily be effected by implant surface properties such as material and topology. This study sought to determine if the membrane's mechanical or barrier properties are affected by changing the spacer material to titanium or roughening the surface finish. Ten-week-old, male Sprague Dawley rats were given an externally stabilized, 6 mm femur defect which was filled with a pre-made spacer of bone cement (PMMA) or titanium (TI) with a smooth (~1 MUm) or roughened (~8 MUm) finish. After 4 weeks of implantation, the membranes were harvested, and the matrix composition, tensile mechanics, shrinkage, and barrier function was assessed. Roughening the spacers resulted in significantly more compliant membranes. TI spacers created membranes that inhibited solute transport more. There were no differences between groups in collagen or elastin distribution. This suggests that different membrane characteristics can be created by altering the spacer surface properties. Surgeons may unknowingly effecting membrane formation via bone cement preparation techniques. PMID- 29510861 TI - Comparison of two multiplex PCR techniques for the study of respiratory viruses in Mexican children with pneumonia. PMID- 29510862 TI - Association of prenatal antibiotics and the etiology of early neonatal sepsis in a neonatal care unit. PMID- 29510863 TI - Control of the spread of resistant pathogens in health centers: Beyond the standard prevention measures. PMID- 29510864 TI - Re: Human papillomavirus vaccine initiation in Asian Indians and Asian subpopulations: a case for examining disaggregated data in public health research. PMID- 29510865 TI - Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy. AB - BACKGROUND: Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases. PATIENTS AND METHODS: This study is based on a retrospective database of the DEGRO stereotactic working group, consisting of 637 patients with 858 treatments. Cox regression and logistic regression were used to analyze the association between the number of SBRT treatments or the number and the timing of repeat SBRT courses with overall survival (OS) and the risk of early death. RESULTS: Out of 637 patients, 145 patients were treated for multiple pulmonary metastases; 88 patients received all SBRT treatments within one month whereas 57 patients were treated with repeat SBRT separated by at least one month. Median OS for the total patient population was 23.5 months and OS was not significantly influenced by the overall number of SBRT treatments or the number and timing of repeat SBRT courses. The risk of early death within 3 and 6 months was not increased in patients treated with multiple SBRT treatments, and no grade 4 or grade 5 toxicity was observed in these patients. CONCLUSIONS: In appropriately selected patients, synchronous SBRT for multiple pulmonary oligometastases and repeat SBRT may have a comparable safety and efficacy profile compared to SBRT for one single oligometastasis. PMID- 29510866 TI - Immunohistochemical Analysis of Galectins-1, -3, and -7 in Periapical Granulomas, Radicular Cysts, and Residual Radicular Cysts. AB - INTRODUCTION: Galectins play important roles in immunoinflammatory responses, but their participation in the development of periapical lesions remains unclear. This study aimed to evaluate the expressions of galectins-1, -3, and -7 in periapical lesions, correlating them with the intensity of the inflammatory infiltrate and the pattern of the cystic epithelium. METHODS: Twenty periapical granulomas (PGs), 20 radicular cysts (RCs), and 20 residual radicular cysts (RRCs) were submitted to immunohistochemistry using anti-galectin-1, -3, and -7 antibodies. The percentage of immunopositive cells in epithelial and connective tissues was determined. RESULTS: In connective tissue, PGs exhibited higher cytoplasmic/membrane expression of galectins-1 and -7 than RCs and RRCs (P < .05). There was higher nuclear expression of galectin-1 in PGs compared with RCs and RRCs (P < .05). The expression of galectins-1 and -7 in connective tissue was higher in lesions with grade III inflammation (P < .05). No significant differences in galectin-3 immunoexpression were observed for any of the parameters evaluated (P > .05). In the epithelial component, a higher nuclear expression of galectin-7 was detected in RRCs (P < .05), and a higher cytoplasmic/membrane expression of this protein was found in cysts with hyperplastic epithelium (P < .05). Positive correlations were observed between the nuclear and cytoplasmic/membrane expression of galectin-1 in connective tissue (P < .05) as well as between the nuclear and cytoplasmic/membrane expression of galectin-7 in epithelial tissue of cysts (P < .05). CONCLUSIONS: Galectins-1 and -7 may play important roles in the pathogenesis of PGs, RCs, and RRCs. On the other hand, the present results suggest only a minor involvement of galectin-3 in the development of these lesions. PMID- 29510867 TI - Laparoscopic laterally extended endopelvic resection (LEER) for cervical carcinoma recurring at the pelvic sidewall after concurrent chemoradiotherapy: Our experience in three cases. AB - OBJECTIVE: Patients in whom laterally recurrent cervical carcinoma develops in the previously irradiated pelvis are usually abandoned because the resectability rate is low, and the 5-year survival rate is close to zero when complete margin negative resection is not achieved [1]. Hockel described laterally extended endopelvic resection (LEER) as an approach in which the line of resection extends to the pelvic sidewall [2]. Complete margin-negative resection (R0 resection) was achieved in all 100 patients who underwent LEER for laterally recurrent cervical carcinoma, and 5-year survival was very good at 62%. However, two procedure related deaths occurred, and morbidity was 70% [3]. When cervical carcinoma recurs in the previously irradiated pelvis, fibrosis and adhesion around the recurrent mass increase morbidity and mortality. Because laparoscopy optimizes visualization and thus provides for meticulous dissection, laparoscopic LEER can be advantageous over open LEER for treatment of such recurrent tumors. METHODS: We performed laparoscopic LEER in three cases of previously irradiated laterally recurrent cervical carcinoma under the following criteria: the recurrent tumor was solitary and without distant metastasis; no equally effective alternative treatment existed, preoperative evaluation of the tumor showed R0 resection to be achievable; and the patient provided informed consent for the procedure. RESULTS: In all three cases, R0 resection was achieved without the need for blood transfusion and without intraoperative or postoperative complications. There was no associated morbidity or mortality. One patient died from recurrent disease 24months after the operation, but neither of the other two patients has suffered recurrence during the respective 3 and 4months that have passed since the surgery. CONCLUSION: Laparoscopic LEER is a very complicated procedure; the surgeon must possess detailed knowledge of the pelvic anatomy and high-level technical skill. Our experience indicates that laparoscopic LEER is feasible for cervical carcinoma that recurs laterally after irradiation and that low morbidity and mortality can be expected. Oncologic outcomes of the procedure will become clear with an accumulation of cases and long-term follow-up data. PMID- 29510869 TI - Separating large microscale particles by exploiting charge differences with dielectrophoresis. AB - Dielectrophoresis (DEP), the migration of particles due to polarization effects under the influence of a nonuniform electric field, was employed for characterizing the behavior and achieving the separation of larger (diameter >5 MUm) microparticles by exploiting differences in electrical charge. Usually, electrophoresis (EP) is the method of choice for separating particles based on differences in electrical charge; however, larger particles, which have low electrophoretic mobilities, cannot be easily separated with EP-based techniques. This study presents an alternative for the characterization, assessment, and separation of larger microparticles, where charge differences are exploited with DEP instead of EP. Polystyrene microparticles with sizes varying from 5 to 10 MUm were characterized employing microdevices for insulator-based dielectrophoresis (iDEP). Particles within an iDEP microchannel were exposed simultaneously to DEP, EP, and electroosmotic (EO) forces. The electrokinetic behavior of four distinct types of microparticles was carefully characterized by means of velocimetry and dielectrophoretic capture assessments. As a final step, a dielectropherogram separation of two distinct types of 10 MUm particles was devised by first characterizing the particles and then performing the separation. The two types of 10 MUm particles were eluted from the iDEP device as two separate peaks of enriched particles in less than 80 s. It was demonstrated that particles with the same size, shape, surface functionalization, and made from the same bulk material can be separated with iDEP by exploiting slight differences in the magnitude of particle charge. The results from this study open the possibility for iDEP to be used as a technique for the assessment and separation of biological cells that have very similar characteristics (shape, size, similar make-up), but slight variance in surface electrical charge. PMID- 29510870 TI - A method for analysis of marker persistent organic pollutants in low-volume plasma and serum samples using 96-well plate solid phase extraction. AB - The objective of this study was to develop and validate a 96-well plate solid phase extraction method for analysis of 23 lipophilic persistent organic pollutants (POPs) in low-volume plasma and serum samples which is applicable for biomonitoring and epidemiological studies. The analysis of selected markers for internal exposure: 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and polybrominated diphenylether 47 (BDE 47) was evaluated by comparing two SPE sorbents and GC-HRMS or GC-MS/MS detection. The final method extracted 23 POPs from 150 MUL of serum and plasma using a 96-well extraction plate containing 60 mg Oasis HLB sorbent per well prior to GC-HRMS magnetic sector analysis. The extraction method was applied to 40 plasma samples collected for an epidemiological study. The recovery of selected POPs ranged from 31% to 63% (n = 48), and detection limits ranged from 2.2 to 45 pg/mL for PCBs, 4.2 to 167 pg/mL for OCPs, 7.8 pg/mL for OCDD and 6.1 pg/mL for BDE 47. This method showed good precision with relative standard deviations of selected POP concentrations in quality control samples (n = 48) ranging from 11% to 25%. The trueness was determined with standard reference material serum (n = 48) and the deviation from certified values ranged from 1 to 27%. Of the 23 POPs analyzed, 18 were detected in 43% to 100% of plasma samples collected for the epidemiological study. The method showed good robustness with low inter-well plate variation (11-31%) determined by twelve 96-well plate extractions, and can extract 96 samples, including quality controls and procedural blanks in 2-3 days. Comparison with GC-MS/MS analysis showed that similar concentrations (within 0.5% to 30%) of most POPs could be obtained with GC-APCI-MS/MS. Larger deviations were observed for PCB 194 (60%) and trans nonachlor (43%). The developed method produces accurate concentrations of low level marker POPs in plasma and serum, providing a suitable high-throughput sample preparation procedure for biomonitoring and epidemiological studies involving large sample size and limited sample volume. GC-HRMS was chosen over GC MS/MS, however the latter showed promising results, and could be used as an alternative to GC-HRMS analysis for most POPs. PMID- 29510871 TI - Safety and feasibility of same-day discharge for uncomplicated appendicitis: A prospective cohort study. AB - BACKGROUND: Appendicitis is the most common gastrointestinal pediatric surgical emergency. With the introduction of laparoscopic techniques in the 1990s, recovery, pain, and hospital stay after laparoscopic procedures have been significantly reduced. While many laparoscopic procedures are performed as outpatient surgeries, pediatric appendectomy patients continue to be hospitalized for postoperative observation. Our goal was to evaluate the safety and feasibility of same day discharge after laparoscopic appendectomy for uncomplicated appendicitis. METHODS: After IRB approval, all pediatric patients undergoing laparoscopic appendectomy during 2016 for noncomplicated appendicitis were eligible for the study. Decision for same day discharge was based on surgeon preference and parental agreement. Data regarding demographics, admission and discharge times, outcomes of complications, readmissions, return to the ED, and nonscheduled clinic visits were collected. RESULTS: A total of 1321 appendectomies were performed during the study period, of which 849 were uncomplicated and 382 were discharged same day. There were 2 readmissions, 4 superficial surgical site infections, 10 patients with nausea or vomiting, and 33 patients with pain control issues, 9 of whom presented to the ED. CONCLUSIONS: Same day discharge for laparoscopic noncomplicated appendectomy is a safe and feasible alternative to postoperative admission and observation. This has the potential to yield significant healthcare cost savings. LEVEL OF EVIDENCE: Level II, Prospective Cohort Study. PMID- 29510872 TI - Decision-Making Criteria for Observational Management of Congenital Pulmonary Airway Malformations (CPAMs). AB - PURPOSE: The purpose of this study was to determine practice patterns of Canadian surgeons managing congenital pulmonary airway malformations (CPAMs) and factors influencing practice. METHODS: Pediatric surgeons in Canada were surveyed regarding their experience, evaluation, and management CPAMs, and what factors they feel qualify patients for observation vs resection. Data were summarized, and Fisher's-Exact and Kruskal-Wallis Tests applied where appropriate. RESULTS: Sixty eight percent (n=46) of surgeons responded. However, three surveys were incomplete and excluded. The median age of initial assessment by a pediatric surgeon was one month. 98% (42/43) use CXR for initial imaging, and 83% (36/43) recommend CT scan for further evaluation. Observation is offered always, almost always, or sometimes by 2%, 35% and 37%, respectively. Only 16% almost never, and 9% never offer it. Years in practice was not associated with this decision (p=0.41). Of surgeons who offer observation, 78% (28/37) use morphology to guide their decision, and 63% (21/37) use lesion size (<1cm to <5cms). 68%(23/37) consider the number of lesions, and 61%(14/23) of those only offer observation to solitary lesions. CONCLUSION: Most pediatric surgeons in Canada offer observational management to patients with asymptomatic CPAMs. While practice variations exist, detailed imaging with a CT scan early in life to determine the morphology, size, and number of lesions guides practice. LEVEL OF EVIDENCE: V. PMID- 29510873 TI - The Shrinking Landscape of Pediatric Surgery: Is Less More? AB - The Fred MacLeod Lecture was given at the 49th Annual Canadian Association of Pediatric Surgeons meeting held October 5-7th, 2017, in Banff, Alberta, Canada. PMID- 29510874 TI - [Biomonitoring in exposure to pesticides, its contribution to epidemiological surveillance of pesticide applicators in Cordoba, Argentina]. AB - OBJECTIVE: To assess the level of exposure to pesticides and its correlation with perceived health indicators and injury biomarkers (genotoxic alterations and those caused by butyrylcholinesterase enzyme activity) in the population of pesticide applicators in extensive crops (PAEC) in Cordoba, Argentina. METHODS: Transversal study, in PAEC (n = 47) randomly selected from a sample of 2000, and non-exposed subject controls (n = 52). The sociodemographic variables, exposure conditioning, and perceived health were surveyed by means of a self-administered questionnaire; biological indicators of genotoxicity: micronuclei, chromosomal aberrations and kite assay, and butyrylcholinesterase activity. RESULTS: 40% of PAEC have over 10 years' length of service and almost 50% of them reside less than 500 m from the sprinkled fields; they report low rates of personal protective equipment use while mixing, applying, or repairing the equipment. General, cardio-respiratory, and dermatological symptoms were greater among PAEC (p <0.05) as well as indicators of genotoxic injury (p <0.001). The butyrylcholinesterase activity was negatively associated with levels of exposure to pesticides. CONCLUSIONS: The PAEC show an important negative impact on health linked to exposure to pesticides. The exposure scales associated to the use of biomarkers were a useful tool for monitoring pesticide applicators' health. PMID- 29510875 TI - When time affects space: Dispersal ability and extreme weather events determine metacommunity organization in marine sediments. AB - Community ecology has traditionally assumed that the distribution of species is mainly influenced by environmental processes. There is, however, growing evidence that environmental (habitat characteristics and biotic interactions) and spatial processes (factors that affect a local assemblage regardless of environmental conditions - typically related to dispersal and movement of species) interactively shape biological assemblages. A metacommunity, which is a set of local assemblages connected by dispersal of individuals, is spatial in nature and can be used as a straightforward approach for investigating the interactive and independent effects of both environmental and spatial processes. Here, we examined (i) how environmental and spatial processes affect the metacommunity organization of marine macroinvertebrates inhabiting the intertidal sediments of a biodiverse coastal ecosystem; (ii) whether the influence of these processes is constant through time or is affected by extreme weather events (storms); and (iii) whether the relative importance of these processes depends on the dispersal abilities of organisms. We found that macrobenthic assemblages are influenced by each of environmental and spatial variables; however, spatial processes exerted a stronger role. We also found that this influence changes through time and is modified by storms. Moreover, we observed that the influence of environmental and spatial processes varies according to the dispersal capabilities of organisms. More effective dispersers (i.e., species with planktonic larvae) are more affected by spatial processes whereas environmental variables had a stronger effect on weaker dispersers (i.e. species with low motility in larval and adult stages). These findings highlight that accounting for spatial processes and differences in species life histories is essential to improve our understanding of species distribution and coexistence patterns in intertidal soft-sediments. Furthermore, it shows that storms modify the structure of coastal assemblages. Given that the influence of spatial and environmental processes is not consistent through time, it is of utmost importance that future studies replicate sampling over different periods so the influence of temporal and stochastic factors on macrobenthic metacommunities can be better understood. PMID- 29510876 TI - Assessment of the use of Oblada melanura (L. 1758) otolith fluctuating asymmetry as environmental disturbance indicator. AB - Human impact on the environment is of widespread concern. The majority of anthropogenic impacts are centred on coastal ecosystems, so surveying them is an important step in the protection of the marine environment. We have tested Oblada melanura (L. 1758) otoliths' fluctuating asymmetry as a bioindicator in a Mediterranean coastal zone. The French Riviera is characterised by a summer population increase leading in particular to more yachting, and seasonal climatic changes with reduced, more concentrated waterway flows and storm events causing soil erosion. The present three-year study compares nine sites, situated in three zones, and characterised by three types of chemical pollutant states (low; waterway mouth; recreational harbour). For O. melanura juveniles, we have not shown any significant difference in the otoliths' fluctuating symmetry between zones or types of sites. We hypothesize that high stress levels are needed to induce significant fluctuating asymmetry variation. PMID- 29510868 TI - Multifunctional nanomedicine with silica: Role of silica in nanoparticles for theranostic, imaging, and drug monitoring. AB - The idea of multifunctional nanomedicine that enters the human body to diagnose and treat disease without major surgery is a long-standing dream of nanomaterials scientists. Nanomaterials show incredible properties that are not found in bulk materials, but achieving multi-functionality on a single material remains challenging. Integrating several types of materials at the nano-scale is critical to the success of multifunctional nanomedicine device. Here, we describe the advantages of silica nanoparticles as a tool for multifunctional nano-devices. Silica nanoparticles have been intensively studied in drug delivery due to their biocompatibility, degradability, tunable morphology, and ease of modification. Moreover, silica nanoparticles can be integrated with other materials to obtain more features and achieve theranostic capabilities and multimodality for imaging applications. In this review, we will first compare the properties of silica nanoparticles with other well-known nanomaterials for bio-applications and describe typical routes to synthesize and integrate silica nanoparticles. We will then highlight theranostic and multimodal imaging application that use silica based nanoparticles with a particular interest in real-time monitoring of therapeutic molecules. Finally, we will present the challenges and perspective on future work with silica-based nanoparticles in medicine. PMID- 29510877 TI - Placement of an arch bar for intermaxillary fixation using two wires for each dental arch. PMID- 29510878 TI - Support device for percutaneous endoscopic gastrostomy tube. PMID- 29510879 TI - Corrigendum to "Cyclic and non-cyclic breast-pain: A systematic review on pain reduction, side effects, and quality of life for various treatments" [Eur. J. Obstet. Gynecol. Reprod. Biol. 219 (2017) 74-93]. PMID- 29510880 TI - A chemically stable fluorescent marker of the ureter. AB - Surgical methods guided by exogenous fluorescent markers have the potential to define tissue types in real time. Small molecule dyes with efficient and selective renal clearance could enable visualization of the ureter during surgical procedures involving the abdomen and pelvis. These studies report the design and synthesis of a water soluble, net neutral C4'-O-alkyl heptamethine cyanine, Ureter-Label (UL)-766, with excellent properties for ureter visualization. This compound is accessed through a concise synthetic sequence involving an N- to O-transposition reaction that provides other inaccessible C4' O-alkyl heptamethine cyanines. Unlike molecules containing a C4'-O-aryl substituent, which have also been used for ureter visualization, UL-766 is not reactive towards glutathione and the cellular proteome. In addition, rat models of abdominal surgery reveal that UL-766 undergoes efficient and nearly exclusive renal clearance in vivo. In total, this molecule represents a promising candidate for visualizing the ureter during a variety of surgical interventions. PMID- 29510881 TI - An unusual esophageal endoscopic appearance. PMID- 29510882 TI - Single-case synthesis tools I: Comparing tools to evaluate SCD quality and rigor. AB - Tools for evaluating the quality and rigor of single case research designs (SCD) are often used when conducting SCD syntheses. Preferred components include evaluations of design features related to the internal validity of SCD to obtain quality and/or rigor ratings. Three tools for evaluating the quality and rigor of SCD (Council for Exceptional Children, What Works Clearinghouse, and Single-Case Analysis and Design Framework) were compared to determine if conclusions regarding the effectiveness of antecedent sensory-based interventions for young children changed based on choice of quality evaluation tool. Evaluation of SCD quality differed across tools, suggesting selection of quality evaluation tools impacts evaluation findings. Suggestions for selecting an appropriate quality and rigor assessment tool are provided and across-tool conclusions are drawn regarding the quality and rigor of studies. Finally, authors provide guidance for using quality evaluations in conjunction with outcome analyses when conducting syntheses of interventions evaluated in the context of SCD. PMID- 29510883 TI - The corticotropin releasing factor binding protein: A strange case of Dr. Jekyll and Mr. Hyde in the stress system? AB - The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP). Extensive literature suggests a role of CRF in alcohol use disorder (AUD). Less is known about the specific role, if any, of CRFBP in AUD. In this review, we summarize recent interdisciplinary efforts toward identifying the contribution of CRFBP in mediating CRF activation. The role of CRFBP in alcohol-related behaviors has been evaluated with the ultimate goal of designing effective novel therapeutic strategies for AUD. A series of in vitro, in vivo, ex vivo, and genetic studies presented here provides initial evidence that CRFBP may possess both inhibitory and excitatory roles, and supports the original hypothesis that it represents a novel pharmacological target for the treatment of AUD. This report summarizes the proceedings of one of the talks at the Young Investigator Award symposium at the Alcoholism and Stress: A Framework for Future Treatment Strategies Conference, Volterra, Italy. PMID- 29510885 TI - Drug supply indicators: Pitfalls and possibilities for improvements to assist comparative analysis. AB - Interventions to tackle the supply of drugs are seen as standard components of illicit drug policies. Therefore drug market-related administrative data, such as seizures, price, purity and drug-related offending, are used in most countries for policy monitoring and assessment of the drug situation. International agencies, such as the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and the UN Office of Drugs and Crime, also monitor and report on the drug situation cross-nationally and therefore seek to collect and make available key data in a uniform manner from the countries they cover. However, these data are not primarily collected for this purpose, which makes interpretation and comparative analysis difficult. Examples of limitations of these data sources include: the extent to which they reflect operational priorities rather than market changes; question marks over the robustness of and consistency in data collection methods, and issues around the timeliness of data availability. Such problems are compounded by cultural, social and contextual differences between countries. Making sense of such data is therefore challenging and extreme care needs to be taken using it. Nevertheless, these data provide an important window on a hidden area, so improving the quality of the data collected and expanding its scope should be a priority for those seeking to understand or monitor drug markets and supply reduction. In addition to highlighting some of the potential pitfalls in using supply indicators for comparative analysis, this paper presents a selection of options for improvements based on the current EMCDDA programme of work to improve their supply-related monitoring and analysis. The conceptual framework developed to steer this work may have wider application. Adopting this approach has the potential to provide a richer picture of drug markets, at both national and international levels, and make it easier to compare data between countries. PMID- 29510884 TI - Evaluation of a real-time PCR assay for detection of Mycoplasma genitalium and macrolide resistance-mediating mutations from clinical specimens. AB - Mycoplasma genitalium (MG) is a sexually transmitted pathogen for which there is no FDA-approved diagnostic test available in the United States. A modified real time polymerase chain reaction assay for detecting MG and simultaneously identifying macrolide resistance mutations from clinical specimens was evaluated and proved to be sensitive and accurate for diagnostic purposes. PMID- 29510886 TI - Pre- and postsynaptic ionotropic glutamate receptors in the auditory system of mammals. AB - The ionotropic glutamate receptors (iGluRs) concertedly mediate neurotransmission to convey, process, and integrate acoustic information along the auditory pathway. In order to ensure these challenging tasks, the iGluRs are variously expressed in auditory neurons in an age- and site-dependent manner. The subunit compositions of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) are altered with development, underlying the acceleration in kinetics of excitatory postsynaptic responses. AMPAR desensitization partly affects short-term synaptic plasticity upon repetitive stimuli in subsets of auditory neurons at a given period of maturation. NMDAR activation is required for long-term synaptic plasticity in a cerebellum-like microcircuit within the first auditory brainstem nucleus. Along with their postsynaptic functions, AMPARs and NMDARs fulfill essential roles in presynaptic modulation of auditory neurotransmission. Despite the expression of the kainate and delta receptors, their functions remain unknown. Here this review aims to discuss the diverse distribution and functions of pre- and postsynaptic iGluRs in the peripheral and central auditory systems. PMID- 29510887 TI - WASP (Write a Scientific Paper) using Excel 9: Analysis of variance. AB - Analysis of variance (ANOVA) may be required by researchers as an inferential statistical test when more than two means require comparison. This paper explains how to perform ANOVA in Microsoft Excel. PMID- 29510888 TI - Prediction of first-trimester preeclampsia: Relevance of the oxidative stress marker MDA in a combination model with PP-13, PAPP-A and beta-HCG. AB - OBJECTIVE: Early diagnosis of preeclampsia (PE) is very important and various parameters, individually or in combined models, are reported useful for prediction of PE. The objective of this study is to investigate the predictive value of pregnancy-associated plasma protein-A (PAPP-A), placental protein-13 (PP 13), human Chorionic Gonadotropin (B-HCG), and oxidative stress marker malondialdehyde (MDA), individually and in combination. MATERIALS AND METHODS: Maternal sera of 38 cases with PE and 122 controls were collected for first trimester screening and tested for PAPP-A and B-HCG by chemiluminescence, for PP 13 by using ELISA, and for MDA by high-performance liquid chromatography. Combined models of parameters were constituted as "MDA + PP-13", "PP-13 + PAPP-A + B-HCG" and "MDA + PP-13 + PAPP-A + B-HCG". The diagnostic performances of serum markers of preeclampsia were examined by nonparametric receiver-operator characteristics (ROC) analysis. RESULTS: PP-13 levels were significantly lower (p < 0.001) and MDA levels were significantly higher (p < 0.001) in PE. The area under the ROC curve (AUC) for MDA and PP-13 were greater than those for PAPP-A and B-HCG (p < 0.001). The AUCs of the combined models were significantly larger than those of individual parameters. The combined model "MDA + PP-13 + PAPP-A + B HCG" exhibited the best predictive outcome with an AUC of 0.91 [95% CI 0.86 0.95], 97% [95% CI 86.2-99.9] sensitivity and 75% [95% CI 66.5-82.6] specificity, and was significantly different from that of "PAPP-A + PP-13 + B-HCG" model, but similar to that of "MDA + PP-13" model. CONCLUSION: Combined models consisting of various parameters of different origin, may provide better predictive outcomes, and oxidative markers should be considered in combination with other placental biomarkers in prediction of PE. PMID- 29510889 TI - Anterolateral Ligament Injury in Knee Dislocations. AB - PURPOSE: The purpose of this study is to describe the prevalence and associated factors of anterolateral ligament (ALL) injury in knee dislocation (KD). METHODS: A retrospective review of charts and radiological images was done for patients who underwent multiligamentous knee reconstruction surgery for KD in the authors' institution from May 2008 to December 2016. The inclusion criteria were both genders, skeletally mature, and first dislocation. Previous anterior cruciate ligament injury or surgery were the exclusion criteria. Magnetic resonance imaging was used to describe the ALL injury. The association of ALL injury with other variables related to the injury and the patient's background features was examined. RESULTS: Forty-eight patients (49 knees) were included. The mean age of the patients was 32.3 +/- 10.6 years. High-energy trauma was the mechanism of dislocation in 28 (57.1%) knees. Thirty-one knees (63.3%) were classified as KD type IV. Forty-five (91.8%) knees had a complete ALL injury, and 3 (6.1%) knees had incomplete ALL injury. Forty (81.6%) knees had a complete ALL injury at the proximal fibers of the ALL, while 23 (46.9%) knees had complete distal ALL injury. None of the 46 (93.9%) knees with lateral collateral ligament injury had normal proximal ALL fibers (P = .012). Injury to the distal fibers of the ALL, as well as overall ALL injury, was not associated with any other variables (P > .05). Moreover, all patients with associated tibial plateau fractures (9; 18.4%) had abnormality of the proximal fibers of the ALL (P = .033). CONCLUSIONS: ALL injury is highly prevalent among dislocated knees. Most of the injuries are of high grade and involve the proximal, suprameniscal, fibers of the ligament. LEVEL OF EVIDENCE: Level IV, retrospective case series with no comparison group. PMID- 29510890 TI - Corrigendum to "Expression of CXCR1 (IL-8 receptor A) in splenic, peritoneal macrophages and resident bone marrow cells after acute live or heat killed Staphylococcus aureus stimulation in mice"[Microb. Pathog. 109 (2017) 131-150]. PMID- 29510891 TI - Lunate Grafting Into the Radius for Lunate Fossa Reconstruction in Madelung Deformity. AB - A 40-year-old woman presented with Madelung deformity and severe arthritic changes at both the radiocarpal and the distal radioulnar joints. She was treated by using her lunate as an osteochondral graft into the radius allowing reconstruction of the lunate fossa. The scaphoid and triquetrum were removed concomitantly and a Sauve-Kapandji procedure was performed. Complete bone healing was achieved. Ten years later, an excellent functional result was maintained, with a pain-free wrist, an acceptable wrist joint range of motion, as well as a favorable aesthetic appearance. This procedure may be indicated for patients with severe Madelung deformity with painful radiocarpal and distal radioulnar joints associated with severe arthritis changes. PMID- 29510892 TI - Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage. AB - BACKGROUND: Different strategies exist for dosing four-factor prothrombin complex concentrate (PCC4) for international normalized ratio (INR) reversal in the setting of life-threatening bleeding. Fixed doses ranging from 1000 IU to 1750 IU have demonstrated efficacy similar to weight-based dosing, however, few studies look exclusively at intracranial hemorrhage (ICH). OBJECTIVE: Our aim was to evaluate whether a fixed dose of 1000 IU of PCC4 achieves INR reversal similar to weight-based dosing in patients with ICH who were anticoagulated with warfarin. METHODS: We compared a weight-based dose vs. 1000 IU PCC4 between January 2014 and January 2017. The primary end point was achieving an INR < 1.5. Secondary end points included in-hospital mortality, patient disposition, and reversal defined by INR < 1.6. RESULTS: A total of 31 patients were included in the weight-based group and 30 were included in the fixed-dose group, with baseline INRs of 2.98 and 2.84, respectively (p = 0.39). Twenty-two patients (71%) achieved an INR < 1.5 in the weight-based group vs. 16 (53%) in the fixed-dose group (p = 0.15), while 25 (81%) achieved an INR < 1.6 in the weight-based group vs. 22 (73%) in the fixed-dose group (p = 0.49). There was no difference in the number of patients discharged to home (19% vs. 20%; p = 0.95) or in-hospital mortality (26% vs. 27%; p = 0.93). CONCLUSIONS: We found a non-statistically significant difference in warfarin reversal to an INR goal of < 1.5 when comparing a fixed dose of 1000 IU PCC4 and a weight-based dose for ICH. Further studies correlating clinical outcomes with INR reversal are needed. PMID- 29510893 TI - Denosumab as a potential treatment alternative for patients suffering from diffuse sclerosing osteomyelitis of the mandible-A rapid communication. AB - PURPOSE: Diffuse sclerosing osteomyelitis (DSO) is a rare disease of the jaw bone. Its treatment is challenging. Different medical and surgical treatment protocols have been proposed; however, none of these treatment protocols produce reliable results. Recently, ibandronate administration has been attempted as a treatment alternative in acute cases of DSO. Due to the similar antiresorptive effect, we sought to explore the application of the human monoclonal antibody to the receptor activator of nuclear factor kappaB ligand (RANKL), denosumab, in the treatment of DSO. MATERIALS AND METHODS: One female patient with histologically verified DSO received subcutaneous injections of denosumab (Prolia(r) 60 mg). The further course of the disease was followed clinically and by radiography and scintigraphy. RESULTS: In this case, the use of denosumab displayed promising results in aiding pain relief and reducing inflammatory activity. CONCLUSION: We suggest that antiresorptive treatment with denosumab can be considered as an alternative treatment for patients suffering from DSO. However further studies, with respect to clarifying the mechanisms of action and defining the necessary medication dose as well as application intervals, have to be conducted. PMID- 29510894 TI - A new type of hyperplastic anterior choroidal artery. AB - Hyperplastic anomaly of the anterior choroidal artery (hyperplastic AchA) and posterior communicating artery of duplicate origin (duplicated Pcom) are rare vessel anomalies. With some literature review, we here report three cases of hyperplastic AchA, one of which was considered a new type of hyperplastic AchA. This case was not categorized into Takahashi classification. PMID- 29510895 TI - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial. AB - INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. RESULTS: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (0/00) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.50/00 (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<=4.50/00; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). CONCLUSION: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. PMID- 29510896 TI - The prevalence of major drug-drug interactions in older adults with cancer and the role of clinical decision support software. AB - OBJECTIVES: Drug-drug interactions (DDIs) represent an escalating concern for older adults attributed to polypharmacy, multi-morbidity and organ dysfunction. Few studies have evaluated the prevalence of major DDIs and the variability between DDI detection software which confuses management. MATERIALS AND METHODS: Prevalence of major DDIs was examined as a secondary analysis of outpatients aged >=65 years. Demographic and clinical information was collected from electronic health records including age, sex, race, cancer type, comorbidities, and medications. All DDIs were screened by a clinical pharmacist using Lexi Interact(r) and Micromedex(r). Major DDIs were defined as Lexi-Interact(r) category D or X and/or Micromedex(r) category major or contraindication. Summary statistics of patient characteristics and DDIs were computed. RESULTS: Our cohort included 142 patients (mean age, 77.7 years; 56% women, 73% Caucasian). The mean medications was 9.8 including 6.7 prescriptions, 2.6 non-prescriptions, and 0.5 herbals. Lexi-Interact(r) identified 310 major DDIs in 69% of patients (n = 98) with an average of 2.2 DDIs per patient. Micromedex(r) identified 315 major DDIs in 61% of patients (n = 87) with an average of 2.2 DDIs per patient. DDIs mostly involved opioids, antiplatelets, electrolyte supplements, antiemetics, and antidepressants. Variability existed with the severity rating reporting of the clinical decision support software. CONCLUSIONS: There was a high prevalence of major DDIs in older adults with cancer. Utilizing clinical decision support software was beneficial for detecting DDIs however, variability existed with severity reporting. Future studies need to identify the relevant DDIs with clinical implications in order to optimize medication safety in this population. PMID- 29510897 TI - L1 Cell Adhesion Molecule and Its Soluble Form sL1 Exhibit Poor Prognosis in Primary Breast Cancer Patients. AB - INTRODUCTION: The L1 cell adhesion molecule (L1-CAM) and its soluble form sL1 play a prominent role in invasion and metastasis in several cancers. However, its association with breast cancer is still unclear. PATIENTS AND METHODS: We analyzed L1-CAM expression and serum sL1 levels in cancer and para-carcinoma tissues from 162 consecutive patients with primary invasive breast cancer (PBC) using immunohistochemistry and an enzyme-linked immunosorbent assay, respectively. The serum sL1 levels were also examined in 38 patients with benign breast disease and 36 healthy controls. RESULTS: L1-CAM was expressed more frequently in cancer tissues than in para-carcinoma tissues (24.1% vs. 5.6%; P < .001), and the mean sL1 levels were significantly greater in PBC than in those with benign breast disease and healthy controls (P = .027). Both L1-CAM+ expression and higher mean sL1 levels correlated significantly with larger tumor size, lymph node involvement, higher histologic grade, advanced TNM stage, and shorter disease-free survival for PBC patients. Moreover, higher mean sL1 levels were also significantly associated with estrogen receptor-alpha-negative expression, human epidermal growth factor receptor 2-positive (HER2+) expression, HER2-enriched and triple-negative molecular subtypes, and L1-CAM+ expression (P < .05). On multivariate analysis, larger tumor size, nodal involvement, HER2+, and higher sL1 levels (>= 0.7 ng/mL) were independent factors associated with L1-CAM+ expression (P < .05). No association was found between L1-CAM expression or sL1 level with age, gender, histologic type, or expression of progesterone receptor, Ki-67, p53, or vascular endothelial growth factor C (P > .05). CONCLUSION: These results indicate that L1-CAM and sL1 are elevated in PBC and both might affect the prognosis of PBC patients. In addition, sL1 might be a useful marker for screening and diagnosis. PMID- 29510898 TI - Critically Appraised Papers: An aerobic and resistance exercise program can improve glycaemic control in women with gestational diabetes mellitus [commentary]. PMID- 29510899 TI - Critically Appraised Papers: An aerobic and resistance exercise program can improve glycaemic control in women with gestational diabetes mellitus [synopsis]. PMID- 29510901 TI - Deprescription of benzodiazepines and Z drugs: A shared responsibility. PMID- 29510900 TI - Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment. AB - Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery. PMID- 29510902 TI - Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. AB - Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI. PMID- 29510903 TI - Subjective visual vertical assessment with mobile virtual reality system. AB - BACKGROUND AND OBJECTIVE: The subjective visual vertical (SVV) is a measure of a subject's perceived verticality, and a sensitive test of vestibular dysfunction. Despite this, and consequent upon technical and logistical limitations, SVV has not entered mainstream clinical practice. The aim of the study was to develop a mobile virtual reality based system for SVV test, evaluate the suitability of different controllers and assess the system's usability in practical settings. MATERIALS AND METHODS: In this study, we describe a novel virtual reality based system that has been developed to test SVV using integrated software and hardware, and report normative values across healthy population. Participants wore a mobile virtual reality headset in order to observe a 3D stimulus presented across separate conditions - static, dynamic and an immersive real-world ("boat in the sea") SVV tests. The virtual reality environment was controlled by the tester using a Bluetooth connected controllers. Participants controlled the movement of a vertical arrow using either a gesture control armband or a general purpose gamepad, to indicate perceived verticality. We wanted to compare 2 different methods for object control in the system, determine normal values and compare them with literature data, to evaluate the developed system with the help of the system usability scale questionnaire and evaluate possible virtually induced dizziness with the help of subjective visual analog scale. RESULTS: There were no statistically significant differences in SVV values during static, dynamic and virtual reality stimulus conditions, obtained using the two different controllers and the results are compared to those previously reported in the literature using alternative methodologies. The SUS scores for the system were high, with a median of 82.5 for the Myo controller and of 95.0 for the Gamepad controller, representing a statistically significant difference between the two controllers (P<0.01). The median of virtual reality-induced dizziness for both devices was 0.7. CONCLUSIONS: The mobile virtual reality based system for implementation of subjective visual vertical test, is accurate and applicable in the clinical environment. The gamepad-based virtual object control method was preferred by the users. The tests were well tolerated with low dizziness scores in the majority of patients. PMID- 29510904 TI - Real-time quantification of the next-generation matrix and age-dependent forecasting of pandemic influenza H1N1 2009 in Japan. AB - PURPOSE: To quantify the age-dependent next-generation matrix (NGM) for the 2009 H1N1 influenza pandemic and forecast the age-stratified cumulative incidence in Japan. METHODS: Using a renewal equation model that describes the time evolution of the 2009 H1N1 influenza pandemic, we derive the likelihood function to estimate parameters of the NGM and reporting coverage. Comparing the Akaike Information Criterion of models using empirically observed data from the 2009 pandemic in Gifu, Japan, we excluded redundant parameters and identified the three best models that were parameterized in different ways. RESULTS: The initial proportions of susceptible populations were suggested as redundant information to be inferred. The three models selected successfully captured the order of the age dependent cumulative incidence. We found that the time required for reliable estimation of age-dependent cumulative incidence was at least 180 days. CONCLUSIONS: To forecast the age-dependent cumulative incidence reliably following the estimation of the NGM and reporting coverage, we need empirically observed data for more than 5 months from the start of the epidemic, which is likely to be after the peak. To increase the practical efficacy in forecasting the cumulative incidence, additional data and approaches are required. PMID- 29510905 TI - Capturing the transmission dynamics of the 2009 Japanese pandemic influenza H1N1 in the presence of heterogeneous immunity. AB - PURPOSE: To explore the heterogeneous transmission dynamics for influenza and identify the optimal serum antibody titer cutoff values for estimating its cumulative incidence. METHODS: We constructed a mathematical model describing serologically dependent disease transmission. The diagnostic performances of two serum antibody titer tests (single serum test and paired sera test) were evaluated, and cumulative disease incidence estimators were formulated. The model simulated the 2009 Japanese influenza A/H1N1 epidemic and investigated the optimal cutoff values and cumulative incidence estimates for this epidemic. RESULTS: Our assumed model and parameters suggested that the optimal cutoffs for A/H1N1 influenza were 1:20 for the single serum test and a 2-fold increase for the paired sera test. Using these optimal cutoff values, the paired sera test was the most reliable. The cumulative incidence estimate for the pre- and post epidemic serological data showed that the paired serological data were also more accurately predictive. CONCLUSIONS: From a statistical perspective, the currently used cutoff values may be too strict for diagnosing influenza and estimating its incidence. The paired sera test, which was more accurate for diagnosis and cumulative incidence estimation, is the test recommended for seroepidemiological surveillance during an epidemic. PMID- 29510906 TI - Reconstruction of the repetitive antifreeze glycoprotein genomic loci in the cold water gadids Boreogadus saida and Microgadus tomcod. AB - Antifreeze glycoproteins (AFGPs) are a novel evolutionary innovation in members of the northern cod fish family (Gadidae), crucial in preventing death from inoculative freezing by environmental ice in their frigid Arctic and sub-Arctic habitats. However, the genomic origin and molecular mechanism of evolution of this novel life-saving adaptive genetic trait remained to be definitively determined. To this end, we constructed large insert genomic DNA BAC (bacterial artificial chromosome) libraries for two AFGP-bearing gadids, the high-Arctic polar cod Boreogadus saida and the cold-temperate Atlantic tomcod Microgadus tomcod, to isolate and sequence their AFGP genomic regions for fine resolution evolutionary analyses. The BAC library construction encountered poor cloning efficiency initially, which we resolved by pretreating the agarose-embedded erythrocyte DNA with a cationic detergent, a method that may be of general use to BAC cloning for teleost species and/or where erythrocytes are the source of input DNA. The polar cod BAC library encompassed 92,160 clones with an average insert size of 94.7 kbp, and the Atlantic tomcod library contained 73,728 clones with an average insert size of 89.6 kbp. The genome sizes of B. saida and M. tomcod were estimated by cell flow cytometry to be 836 Mbp and 645 Mbp respectively, thus their BAC libraries have approximately 10- and 9.7-fold genome coverage respectively. The inclusiveness and depth of coverage were empirically confirmed by screening the libraries with three housekeeping genes. The BAC clones that mapped to the AFGP genomic loci of the two gadids were then isolated by screening the BAC libraries with gadid AFGP gene probes. Eight minimal tiling path (MTP) clones were identified for B. saida, sequenced, and assembled. The B. saida AFGP locus reconstruction produced both haplotypes, and the locus comprises three distinct AFGP gene clusters, containing a total of 16 AFGP genes and spanning a combined distance of 512 kbp. The M. tomcod AFGP locus is much smaller at approximately 80 kbp, and contains only three AFGP genes. Fluorescent in situ hybridization with an AFGP gene probe showed the AFGP locus in both species occupies a single chromosomal location. The large AFGP locus with its high gene dosage in B. saida is consistent with its chronically freezing high Arctic habitats, while the small gene family in M. tomcod correlates with its milder habitats in lower latitudes. The results from this study provided the data for fine resolution sequence analyses that would yield insight into the molecular mechanisms and history of gadid AFGP gene evolution driven by northern hemisphere glaciation. PMID- 29510907 TI - Weight loss is associated with rapid striatal dopaminergic degeneration in Parkinson's disease. AB - INTRODUCTION: Weight loss in Parkinson's disease (PD) is associated with poorer clinical outcomes and rapid disease progression. However, it is unclear whether a longitudinal association between weight loss and striatal dopaminergic degeneration exists. METHODS: Using data from 171 PD patients in the Parkinson's Progression Markers Initiative (PPMI) cohort, we investigated longitudinal associations of change in body mass index (BMI) with striatal dopaminergic activity on 123I-N-3-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) single positron emission computed tomography (SPECT). We defined BMI loss as a reduction in BMI value > 5% of baseline, and categorized the PD patients into 2 subgroups (patients with and without BMI loss). Linear mixed model (LMM) analysis was employed to compare the progression of striatal dopaminergic degeneration. RESULTS: In LMM analyses, BMI values in PD patients were not correlated with clinical severities of parkinsonian motor deficits, cognitive impairment and depressive mood. However, BMI values were positively associated with changes in striatal 123I-FP-CIT binding over 24 months (caudate nucleus, estimate = 9.37 * 10-3, p = 0.009; putamen, estimate = 7.04 * 10-3, p = 0.031). Patients with BMI loss exhibited greater deterioration of striatal dopaminergic activity than those without (caudate nucleus, estimate = 3.35 * 10 3, p = 0.008; putamen, estimate = 2.34 * 10-3, p = 0.025). CONCLUSION: Our findings suggest a potential association between striatal dopaminergic activity with body weight or impairment in energy homeostasis. Body weight and its change may be a clinical biomarker reflecting striatal dopaminergic dysfunction in PD. PMID- 29510908 TI - Editorial overview: Early development of prosocial behavior: Revealing the foundation of human prosociality. PMID- 29510910 TI - Perceived exertion using two different EMS stretcher systems, report from a Swedish study. AB - BACKGROUND: Emergency medical services (EMS) facilitate out of hospital care in a wide variety of settings on a daily basis. Stretcher-related adverse events and long term musculoskeletal injuries are commonly reported. Novel stretcher mechanisms may facilitate enhanced movement of patients and reduce workload for EMS personnel. AIM: To describe EMS personnel's perceived exertion using two different stretcher systems. METHODS: The methodology of this explorative simulation study included enrolling twenty (n=20) registered nurses and paramedics who worked in ten pairs (n=10) to transport a conscious, 165lb. (75kg) patient using two different EMS stretcher systems: the Pensi stretcher labeled A and the ALLFA stretcher labeled B. The ten pairs (n=10) were randomized to use either an A stretcher or a B stretcher with subsequent crossover. The pairs performed six identical tasks with each stretcher, including conveying stretchers from an ambulance up to the first floor of a building via a staircase, loading a patient on to the stretcher, and using the stretcher to transport the patient back to the ambulance. The subjective Rating of Perceived Exertion (RPE) survey (Borg scale) was used to measure perceived exertion at predefined intervals during transport. RESULTS: No significant differences in workload were seen between stretcher groups A and B regarding unloading the stretcher (7.4 vs 8.2 p=0.3), transporting up a stairway (13.7 vs 12.5 p=0.06), lateral lift (12.1 vs 11.2 p=0.5), or flat ground transportation (10.4 vs 11.1 p=0.13). Pairs using stretcher A showed significantly less workload with regards to transporting down a stairway (11.0 vs 14.5 p<0.001) and loading into ambulance (11.1 vs 13.0 p<0.001). CONCLUSION: A structured methodology may be used for testing the exertion levels experienced while using different stretcher systems. The use of supporting stretcher system mechanisms may reduce perceived exertion in EMS personnel mainly during transports down stairs and during loading into ambulance vehicles. PMID- 29510909 TI - Insights into the neurochemical signature of the Innervation of Beige Fat. AB - OBJECTIVE: The potential for brown adipose tissue (BAT) to be targeted as a therapeutic option to combat obesity has been heightened by the discovery of a brown-like form of inducible "beige" adipose tissue in white fat which has overlapping structural and functional properties to "classical" BAT. The likelihood that both beige and brown fat are recruited functionally by neural mechanisms, taken together with the lack of a detailed understanding of the nature of changes in the nervous system when white adipose tissue (WAT) is transformed to brown, provides the impetus for this study. Here, we aim to identify whether there is a shift in the gene expression profile in neurons directly innervating inguinal white adipose tissue (iWAT) that has undergone "beiging" to a signature that is more similar to neurons projecting to BAT. METHODS: Two groups of rats, one housed at thermoneutrality (27 degrees C) and the other exposed to cold (8 degrees C) for 7 days, were killed, and their T13/L1 ganglia, stellate ganglion (T1/T2), or superior cervical ganglion (SCG, C2/3) removed. This approach yielded ganglia containing neurons that innervate either beiged white fat (8 degrees C for 7 days), inguinal WAT (27 degrees C for 7 days), BAT (both 27 degrees C and 8 degrees C for 7 days) or non-WAT (8 degrees C for 7 days), the latter included to isolate changes in gene expression that were more aligned with a response to cold exposure than the transformation of white to beige adipocytes. Bioinformatics analyses of RNA sequencing data was performed followed by Ingenuity Pathway Analysis (IPA) to determine differential gene expression and recruitment of biosynthetic pathways. RESULTS: When iWAT is "beiged" there is a significant shift in the gene expression profile of neurons in sympathetic ganglia (T13/L1) innervating this depot toward a gene neurochemical signature that is similar to the stellate ganglion projecting to BAT. Bioinformatics analyses of "beiging" related genes revealed upregulation of genes encoding neuropeptides proopiomelanocortin (POMC) and calcitonin-gene related peptide (CGRP) within ganglionic neurons. Treatment of differentiated 3T3L1 adipocytes with alphaMSH, one of the products cleaved from POMC, results in an elevation in lipolysis and the beiging of these cells as indicated by changes in gene expression markers of browning (Ucp1 and Ppargc1a). CONCLUSION: These data indicate that, coincident with beiging, there is a shift toward a "brown like" neurochemical signature of postganglionic neurons projecting to inguinal white fat, an increased expression of POMC, and, consistent with a causative role for this prohormone in beiging, an alphaMSH-mediated increase in beige gene markers in isolated adipocytes. PMID- 29510911 TI - Reply to the letter to the editor. PMID- 29510912 TI - Emergency services response to elder abuse and neglect - Then and now. PMID- 29510913 TI - Different manifestation of a familiar diagnosis: From anuria to acute appendicitis. AB - The differential diagnosis of anuria in emergency department (ED) is broad. Secondary to intraabdominal mass pressure or infections, symptoms of micturation difficulties or disuria accompanying to back pain may arise with the interruption of sacral nerve stimulation. Here, we report a patient who admitted to ED with back pain and anuria and diagnosed acute appendicitis (AA) after advanced investigation despite of not to have any abdominal pain. A 36-year-old man admitted to our ED with a 6-h history of back pain and urination difficulty. 750mL of clear urine output was observed after bladder catheterization. Abdominal computerized tomography with intravenous contrast was used and revealed acute appendicitis. The patient consulted with a general surgeon and hospitalized for operation. After the operation, back pain was disappeared, and spontaneous micturition was seen. This case not only represents an uncommon manifestation of AA, but also alerts us to the importance of anatomical considerations when interpreting disease extent with imaging. In the differential diagnosis of back pain and urination difficulty, the rare possibility of AA should be taken into account. Because the presence of unusual findings, such as those associated with the urinary tract or lumbosacral pathologies, may further obscure the diagnosis and delay appropriate therapy. PMID- 29510914 TI - Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center. AB - OBJECTIVE: The contemporary practice of testing for genetically triggered aortic and arterial aneurysms and dissections is not well described. This study aimed to describe this practice at a tertiary care academic center and to ascertain the yield of testing in establishing the diagnosis in patients referred on the basis of clinical suspicion. METHODS: This is a retrospective cohort study of patients referred for vascular genetic testing at an academic medical center between 2010 and 2015. Patients were identified by Current Procedural Terminology diagnostic codes 81405, 81408, and 81479 for genetic testing (Marfan syndrome, Loeys-Dietz syndrome, aneurysms-osteoarthritis syndrome, COL3A1, and familial thoracic aortic aneurysm panel [ACTA2, COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, MYLK, MYH11, and PRKG1 genes]) and by review of the collagen vascular laboratory database for genetic testing results. Data abstracted included demographics, clinical history, reason for referral, family history, referring provider type, and outcomes of genetic testing. RESULTS: Ninety-six patients (44.3% male; median age, 40.8 years) were referred for suspected genetic vascular disease. Genetic testing was performed in 75 cases thought to have heritable mutations related to aortic or arterial aneurysms and dissections. The most common reason for genetic testing was a personal history of aortic or arterial aneurysms and dissections (62.3%; mean age, 45.8 +/- 11.1 years), followed by a family history of aortic or arterial aneurysms and dissections without a personal history (26.6%; age, 28.8 +/- 17.9 years). The most common genetic testing performed was a familial thoracic aortic aneurysm gene panel (44%), followed by single gene testing for vascular Ehlers-Danlos syndrome (33.3%). Genetic testing identified a pathogenic mutation in 36% of the cases. The highest likelihood of identifying a pathogenic mutation was in those who had a family history with an already diagnosed mutation (57.1%), followed by patients with aortic root and ascending aortic aneurysm or dissection (42.3%). CONCLUSIONS: In patients with suspected genetically triggered vascular disease, the yield of clinical vascular genetic testing is reasonable when selective genetic testing is performed on the basis of personal or family history. These tests should be obtained with appropriate expertise in genetic counseling and interpretation of genetic testing results. Negative genetic test results in the setting of a positive family history demonstrate the limits of testing and known mutations leading to genetically triggered aortic and arterial aneurysms and dissections and support the need for novel gene discovery. PMID- 29510915 TI - Single-center experience with complex abdominal aortic aneurysms treated by open or endovascular repair using fenestrated/branched endografts. AB - OBJECTIVE: The objective of this study was to evaluate outcomes of patients with complex abdominal aortic aneurysms (cAAAs) treated with open repair (OR) or fenestrated/branched endovascular aneurysm repair (F/B-EVAR) from a single center. METHODS: A retrospective analysis of consecutive patients with cAAAs treated electively by OR or F/B-EVAR between January 2010 and February 2017 was conducted. Demographics of the patients, cardiovascular risk factors, procedure time, number of vessels incorporated, radiation dose, estimated blood loss, intensive care unit (ICU) length of stay (LOS), and hospital LOS were recorded. End points included target vessel patency, aneurysm rupture, freedom from reintervention, and major adverse events (MAEs). RESULTS: During this period, 153 patients (OR, 69; F/B-EVAR, 84) underwent repair of cAAA. The majority were male (OR, 55; F/B-EVAR, 64), with a mean age of 75.8 +/- 7.6 years (F/B-EVAR) and 71.2 +/- 7.9 years (OR). Patients in the F/B-EVAR group were more likely to be American Society of Anesthesiologists class 3 and 4 (60% vs 0%; P < .001) and had a higher median Society for Vascular Surgery/American Association for Vascular Surgery comorbidity severity score (15 vs 7; P < .001). A total of 235 vessels were targeted in the F/B-EVAR group, with a technical success of 97.6%. Thirty one patients in the OR group required concomitant renal artery revascularization. Transfusion requirements (100% vs 1.2%), MAEs (40.6% vs 13.1%), procedure length (304 minutes vs 140 minutes), estimated blood loss (2246 mL vs 165 mL), ICU LOS (3 days vs 1 day), and hospital LOS (7 days vs 2 days) were higher (P < .001) in the OR group compared with the F/B-EVAR group. The 30-day mortality was 2.9% and 2.4% (P = .84) in the OR group and F/B-EVAR group, respectively. Supraceliac clamp site was associated with increased incidence of postoperative renal insufficiency. A decrease in procedure time, contrast volume, fluoroscopy time, and fluoroscopy dose was noted in the F/B-EVAR group with increasing experience even as case complexity increased. More patients were discharged home after F/B EVAR (97.6% vs 59.4%; P < .001). With a mean follow-up of 31 months (F/B-EVAR, 17 months; OR, 48 months), the rate of secondary intervention was 3.7% and 5.8% (P = NS) for F/B-EVAR and OR, respectively. Freedom from branch instability and reintervention was 99% (95% confidence interval, 96.2%-99.8%) and 96% (95% confidence interval, 87.1%-98.6%), respectively. CONCLUSIONS: Results of this "real-world" experience suggest that the use of F/B-EVAR for the treatment of cAAAs in high-risk surgical patients is safe and effective and has comparable short-term results to those of low-risk patients undergoing OR. Patients treated by F/B-EVAR had shorter ICU and hospital LOS, lower MAEs, and faster convalescence. A decrease in procedure time and radiation dose was noted as experience was gained, even as complexity increased. PMID- 29510916 TI - A foot-and-mouth disease SAT2 vaccine protects swine against experimental challenge with a homologous virus strain, irrespective of mild pathogenicity in this species. AB - FMDV serotype SAT2 is most frequently associated with outbreaks in ruminants. However, the risk of it spreading from cattle to pigs cannot be excluded. To assess the efficacy of an SAT2-type FMD inactivated vaccine against homologous challenge in pigs, a suitable challenge strain adapted to pigs was produced. After two passages in two pigs each, a FMDV stock of SAT2 challenge strain was produced. This material was used to infect two groups of five pigs. The first group being vaccinated 28 days before challenge and the other one left as an unvaccinated control. Clinical signs were recorded, virus shedding was assessed on mouth swabs, and neutralising antibody titres were determined. At least 80% of the vaccinated pigs were protected against clinical disease. Furthermore, no virus shedding was observed in any of the vaccinated pigs. This study shows that experimentally inoculated pigs can become infected with a SAT2 serotype. Furthermore, vaccination offers protection against generalisation and viral excretion, confirming the potential of vaccination as an important tool in the control of FMD in pigs. PMID- 29510917 TI - Rotavirus is the leading cause of hospitalizations for severe acute gastroenteritis among Afghan children <5 years old. AB - BACKGROUND: Rotavirus gastroenteritis is estimated to cause approximately five thousand deaths annually among Afghan children under 5 years old. Because laboratory confirmation of rotavirus is not routinely performed in clinical settings, assessing the precise burden of disease attributable to severe rotavirus gastroenteritis typically requires active surveillance efforts. This study describes the current burden of pediatric hospitalizations attributable to rotavirus gastroenteritis among Afghan children using surveillance data collected from 2013 to 2015. METHODS: Rotavirus surveillance was conducted from January 2013 through December 2015 at two of the largest hospitals in the country, Indira Gandhi Children Hospital in Kabul and Herat Regional Hospital. Children between 1 and 60 months of age who were admitted to these hospitals for diarrhea were consented and enrolled. Information on age, gender, and seasonality were collected. Stool specimens were collected and tested by enzyme immunoassay for the presence of rotavirus at the central public health laboratory in Afghanistan. RESULTS: Overall, 1,413 of 2,737 (52%) of hospitalized children under five years old with diarrhea were rotavirus cases. The overwhelming majority of rotavirus hospitalizations occurred in children younger than two years of age (93%) while 42% of all rotavirus hospitalizations occurred in children between 6 and 11 months of age. Rotavirus transmission occurred year-round. CONCLUSIONS: Rotavirus is a major cause of severe acute gastroenteritis hospitalizations in young Afghan children, responsible for over half of diarrheal hospitalizations in this population. The Afghanistan Ministry of Public Health has prioritized reducing child mortality by 2020 and is actively working towards the introduction of rotavirus vaccination in Afghan children. These data will be instrumental in understanding the potential impact upon child health that may be achieved through the introduction of rotavirus vaccines in Afghanistan. PMID- 29510919 TI - Improving Incident ESRD Care Via a Transitional Care Unit. AB - Dialysis care in the United States continues to move toward an emphasis on continuous quality improvement and performance benchmarking. Government- and industry-sponsored programs have evolved to assess and incentivize outcomes for many components of end-stage renal disease care. One aspect that remains largely unaddressed at a systemic level is the high-risk transition period from chronic kidney disease and acute kidney injury to permanent dialysis dependence. Incident dialysis patients experience disproportionately high mortality and hospitalization rates coupled with high costs. This article reviews the clinical case for a special emphasis on this transition period, reviews published literature regarding prior transitional care programs, and proposes a novel iteration of the first 30 days of dialysis care: the transitional care unit (TCU). The goal of a TCU is to improve awareness of all aspects of renal replacement therapy, including modalities, access, transplantation options, and nutritional and psychosocial aspects of the disease. This enables patients to make truly informed decisions regarding their care. The TCU model is open to all patients, including incident patients with end-stage renal disease, those for whom peritoneal dialysis is failing, or those with failing transplants. This model may be especially beneficial to those who are deemed inadequately prepared or "crash start" patients. PMID- 29510918 TI - Seroprevalence of anti-polio antibodies in children from polio high risk area of Afghanistan: A cross sectional survey 2017. AB - BACKGROUND: Afghanistan is one of the remaining wild-poliovirus (WPV) endemic countries. We conducted a seroprevalence survey of anti-poliovirus antibodies in Kandahar Province. METHODS: Children in two age groups (6-11 months and 36-48 months) visiting Mirwais hospital in Kandahar for minor ailments unrelated to polio were enrolled. After obtaining informed consent, we collected venous blood and conducted neutralization assay to detect poliovirus neutralizing antibodies. RESULTS: A total of 420 children were enrolled and 409/420 (97%) were analysed. Seroprevalence to poliovirus type 1 (PV1) was 97% and 100% in the younger and older age groups respectively; it was 71% and 91% for PV2; 93% and 98% for PV3. Age group (RR = 3.6, CI 95% = 2.2-5.6) and place of residence outside of Kandahar city (RR = 1.8, CI 95% = 1.2-2.6) were found to be significant risk factors for seronegativity. CONCLUSIONS: The polio eradication program in Kandahar achieved high serological protection, especially against PV1 and PV3. Lower PV2 seroprevalence in the younger age group is a result of a withdrawal of live type 2 vaccine in 2016 and is expected. Ability to reach all children with poliovirus vaccines is a pre-requisite for achieving poliovirus eradication. PMID- 29510920 TI - Palliative Care Disincentives in CKD: Changing Policy to Improve CKD Care. AB - The dominant health delivery model for advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States, which focuses on provision of dialysis, is ill-equipped to address many of the needs of seriously ill patients. Although palliative care may address some of these gaps in care, its integration into advanced CKD care has been suboptimal due to several health system barriers. These barriers include uneven access to specialty palliative care services, underdeveloped models of care for seriously ill patients with advanced CKD, and misaligned policy incentives. This article reviews policies that affect the delivery of palliative care for this population, discusses reforms that could address disincentives to palliative care, identifies quality measurement issues for palliative care for individuals with advanced CKD and ESRD, and considers potential pitfalls in the implementation of new models of integrated palliative care. Reforming health care delivery in ways that remove policy disincentives to palliative care for patients with advanced CKD and ESRD will fill a critical gap in care. PMID- 29510921 TI - The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease. AB - Patients with both anti-glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against alpha3(IV)NC1 were detectable, with predominance of IgG1. In one patient with lymph node biopsy specimens available, sporadic plasma cells producing alpha3(IV)NC1-IgG were found, suggesting a causal relationship between the 2 diseases. One patient, who achieved remission with antibody clearance and normalization of serum creatinine and interleukin 6 concentrations after plasma exchange and 3 cycles of chemotherapy, experienced recurrence of anti-GBM antibodies and an increase in interleukin 6 concentration after chemotherapy discontinuation because of adverse effects, but both returned to normal after another cycle of chemotherapy. This clinical course and the pathologic findings support the hypothesis that the Castleman disease-associated tumor cells are the source of the anti-GBM autoantibodies. PMID- 29510923 TI - Low Heteroplasmy Rates of the m.8993T>G Variant May Not Be Pathogenic. PMID- 29510922 TI - Changes in Blood Pressure During Young Adulthood and Subsequent Kidney Function Decline: Findings From the Coronary Artery Risk Development in Young Adulthood (CARDIA) Study. AB - BACKGROUND: Many studies have focused on the association between a single blood pressure (BP) measurement and risk for adverse outcomes. However, the association of BP trajectories during young adulthood with subsequent decline in kidney function has not been well defined. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 3,429 participants in the Coronary Artery Risk Development in Young Adulthood (CARDIA) Study enrolled between the ages of 18 and 30 years. PREDICTORS: BP slope during the first 10 years of participation in CARDIA, derived from linear mixed models incorporating all repeated BP measures. OUTCOME: Decline in estimated glomerular filtration rate (eGFR) during the interval between years 10 and 20 of CARDIA participation using cystatin C measured at years 10, 15, and 20. RESULTS: Mean age of CARDIA participants at year 0 was 25.1 years, 56% were women, and 53% were white. Every 10-mmHg higher level of systolic (SBP) and diastolic BP (DBP) in year 10 was associated with change in eGFR of -0.09 (95% CI, -0.13 to -0.06) and -0.07 (95% CI, -0.12 to 0.03) mL/min/1.73m2 per year, respectively. Every 10-mmHg increase in SBP slope between years 0 and 10 was associated with a subsequent -0.52 (95% CI, -1.02 to 0.03) mL/min/1.73m2 per year change in kidney function after adjustment for comorbid conditions and SBP at year 10. Similarly, every 10-mmHg increase in DBP slope between years 0 and 10 was associated with a subsequent change in kidney function of -0.65 (95% CI, -1.23 to -0.07) mL/min/1.73m2 per year, after adjustment for comorbid conditions and DBP in year 10. LIMITATIONS: Observational design. CONCLUSIONS: During young adulthood, increasing SBP and DBP are associated with a higher rate of subsequent kidney function decline, independent of BP measured at the beginning of eGFR assessment. PMID- 29510924 TI - Schizophrenia-like olfactory dysfunction induced by acute and postnatal phencyclidine exposure in rats. AB - Deficits in olfactory abilities are frequently observed in schizophrenia patients. However, whether olfactory dysfunction is found in animal models is not known. Here, we examined whether two well-established schizophrenia rat models exhibit olfactory-relevant dysfunction that is similar to schizophrenia patients. Olfactory sensitivity was tested in rats that were acutely (3.3mg/kg) or postnatally (10mg/kg, at postnatal day 7, 9 and 11) treated with phencyclidine (PCP) as schizophrenia models. Electrophysiological recordings were conducted to measure the olfactory-relevant local field potential after acute PCP treatment. Olfactory-relevant neural connections were tested via virus tracing in rats postnatally treated with PCP. We also assessed the reversal effects of olanzapine (OLZ) treatment on both models. We found that acute PCP treatment induced a decline in olfactory sensitivity (p=0.01) and significantly lower beta- and higher gamma-band oscillations (p=0.03, and p=0.00 respectively) which were partly attenuated by OLZ treatment (2mg/kg and 4mg/kg). Postnatal PCP exposure also resulted in an olfactory sensitivity deficit during adulthood (p=0.012 for males and p=0.009 for females), and an abnormal development of neural circuits (p=0.000). Together, our research indicated that olfactory dysfunction found in schizophrenia patients can also be observed on animal models. PMID- 29510925 TI - Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophrenia. AB - BACKGROUND: Ketamine has been used to probe the biology of psychosis and cognitive dysfunction in humans. High levels of ketamine abuse are associated with persisting psychosis (KPP) in a minority of users. However, relatively little is known about cognitive function among KPP patients and whether the cognitive impairments associated with KPP resemble those of schizophrenia (SZ). METHODS: We recruited 149 treatment-seeking patients, including nonpsychotic ketamine users (KNP, n=51), KPP (n=23), and SZ (n=75) patients. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate psychopathology and the Cogstate Brief Battery to assess cognitive function including psychomotor processing speed, attention, working memory, verbal and visual learning and memory, spatial problem solving, and social-emotional cognition. RESULTS: Ketamine-dependent patients had an extensive history of ketamine use (average duration=7.1+/-4.2years, average consumption=3.8+/-2.7g per day). Although KPP patients used relatively less average ketamine daily dose than KNP patients, KPP patients exhibited significantly greater total PANSS score and subscale scores, while these scores in KPP and SZ patients did not differ significantly. After adjusting for demographic characteristics and antipsychotic dose, KPP and SZ patients showed impairments in spatial problem solving and verbal memory compared to KNP patients, but KPP and SZ patients did not significantly differ from each other. CONCLUSION: These data suggest that the symptom profile and cognitive impairments associated with persisting psychosis due to chronic heavy ketamine abuse resemble those of schizophrenia, while KNP patients showed significantly less severe symptom profile and cognitive impairment than KPP and SZ. PMID- 29510926 TI - Challenges of managing delirium and catatonia in a medically ill patient. AB - BACKGROUND: Untangling catatonia and delirium can be challenging. Furthermore, treatment of one syndrome can potentially worsen another. CASE PRESENTATION: We present the case of a 71-year-old patient with a history of schizoaffective disorder, bipolar subtype, who developed catatonia and delirium with prominent psychotic symptoms, during a single hospitalization. Treatment of this patient's catatonia with benzodiazepines exacerbated delirium, while treatment of psychotic symptoms precipitated by delirium with antipsychotics led to catatonia. Catatonia and psychotic symptoms were eventually successfully managed with electroconvulsive therapy (ECT). DISCUSSION: This case report highlights some of the treatment challenges faced when delirium and catatonia overlap in a medically ill patient. The use of benzodiazepines, valproic acid, antipsychotics, ECT and alternate medications to treat catatonia are also discussed. PMID- 29510928 TI - Is formal thought disorder in schizophrenia related to structural and functional aberrations in the language network? A systematic review of neuroimaging findings. AB - Formal thought disorder (FTD) is a core feature of schizophrenia, a marker of illness severity and a predictor of outcome. The underlying neural mechanisms are still a matter of debate. This study aimed at 1) reviewing the literature on the neural correlates of FTD in schizophrenia, and 2) testing the hypothesis that FTD correlates with structural and functional aberrations in the language network. Medline, PsychInfo, and Embase were searched for neuroimaging studies, which applied a clinical measure to assess FTD in adults with schizophrenia and were published in English or German in peer-reviewed journals until December 2016. Of 412 articles identified, 61 studies were included in the review. Volumetric studies reported bilateral grey matter deficits (L > R) to be associated with FTD in the inferior frontal gyrus, the superior temporal gyrus and the inferior parietal lobe. The same regions showed hyperactivity in resting state functional magnetic resonance imaging (fMRI) studies and both hyper- and hypoactivity in fMRI studies that employed semantic processing or free speech production tasks. Diffusion tensor imaging studies demonstrated white matter aberrations in fibre tracts that connect the frontal and temporo-parietal regions. FTD in schizophrenia was found to be associated with structural and functional aberrations in the language network. However, there are studies that did not find an association between FTD and neural aberrations of the language network and regions not included in the language network have been associated with FTD. Thus, future research is needed to clarify the specificity of the language network for FTD in schizophrenia. PMID- 29510929 TI - Altered proteomic profile in umbilical arterial serum from mothers with schizophrenia. PMID- 29510927 TI - Relationship between executive function, attachment style, and psychotic like experiences in typically developing youth. AB - Psychotic like experiences (PLE's) are common in the general population, particularly during adolescence, which has generated interest in how PLE's emerge, and the extent to which they reflect either risk for, or resilience to, psychosis. The "attachment-developmental-cognitive" (ADC) model is one effort to model the effect of risk factors on PLEs. The ADC model proposes attachment insecurity as an early environmental insult that can contribute to altered neurodevelopment, increasing the likelihood of PLE's and psychosis. In particular, early-life attachment disruptions may negatively impact numerous aspects of executive function (EF), including behavioral inhibition and emotion regulation. Yet despite the relationship of disrupted attachment to EF impairments, no studies have examined how these factors may combine to contribute to PLE's in adolescents. Here, we examined the relative contributions of daily life EF and attachment difficulties (avoidance and anxiety) to PLEs in typically developing youth (N=52; ages 10-21). We found that EF deficits and high attachment insecurity both accounted for a significant proportion of the variance in PLE's, and interacted to predict PLE manifestation. Specifically, positive PLEs were predicted by greater trouble monitoring behavioral impact, less difficulty completing tasks, greater difficulty regulating emotional reactions, greater difficulty controlling impulses and higher attachment anxiety. Negative PLEs were predicted by greater difficulty in alternating attention, transitioning across situations, and regulating emotional reactions as well as higher attachment anxiety. These results are consistent with the ADC model, providing evidence that early-life attachment disruptions may impact behavioral regulation and emotional control, which together may contribute to PLEs. PMID- 29510930 TI - Aortic diameter: The beginning of the end of an era. PMID- 29510931 TI - Pleural myopericytoma: A rare neoplasm in a difficult location. PMID- 29510933 TI - Discussion. PMID- 29510934 TI - Discussion. PMID- 29510932 TI - Long-term outcomes of expanded polytetrafluoroethylene conduits with bulging sinuses and a fan-shaped valve in right ventricular outflow tract reconstruction. AB - OBJECTIVE: Various types of conduits are available for right ventricular outflow tract (RVOT) reconstruction. We have developed an expanded polytetrafluoroethylene (ePTFE) conduit with bulging sinuses and a fan-shaped ePTFE valve. This study summarized the results of a multicenter study evaluating the valved ePTFE conduit. METHODS: The valve functions of 902 patients (median age, 3.9 years; median weight, 12.6 kg) who underwent RVOT reconstruction using valved ePTFE conduits (9 different sizes, 8-24 mm in diameter) at 65 hospitals between 2001 and 2015 were retrospectively investigated. Median follow-up time was 5.5 years. The valve functions were assessed using echocardiography, cardiac catheterization, and magnetic resonance angiography. RESULTS: There were no deaths related to the ePTFE conduit. The peak RVOT gradient was 16.5 +/- 13.1 mm Hg, and pulmonary insufficiency graded better than mild was 95.9% at the latest follow-up. Conduit replacement was performed in 55 patients, and in only 3 patients because of conduit infection. Freedom from intervention at 5 years and 10 years was 92.3% and 76.1%, respectively, with small conduits (8-16 mm in diameter) and 99.6% and 95.1%, respectively, with large conduits (18-24 mm in diameter). CONCLUSIONS: The long-term outcomes of the ePTFE conduit with a fan shaped valve and bulging sinuses appear clinically satisfactory. We believe that the longevity of small-sized conduits can yield sufficient time to exchange them to larger-sized conduits without any loss of their valve functions. Regarding longevity and resistance to infections, this ePTFE valved conduit can be one of the best ways to reconstruct the RVOT. PMID- 29510935 TI - Valve-sparing aortic root replacement after double-switch operation for corrected transposition of the great arteries in a patient with ulcerative colitis. PMID- 29510936 TI - Discussion. PMID- 29510937 TI - Edge-to-edge mitral valve repair with transapical neochord implantation. PMID- 29510938 TI - Think beyond the cell: Can we [tissue] engineer a solution to heart failure? PMID- 29510939 TI - Macroscopic complete resection is not associated with improved survival in patients with malignant pleural mesothelioma. AB - OBJECTIVE: Macroscopic complete resection (MCR) is the recommended surgical strategy in malignant pleural mesothelioma. Our objective was to analyze whether MCR influences survival in malignant pleural mesothelioma. METHODS: Between 2002 and 2016, 154 patients underwent pleurectomy decortication (n = 90), extrapleural pneumonectomy (n = 42), or exploratory/diagnostic procedures (n = 22) in a single institution. Patient data were recorded in a prospective database. Patients who underwent surgical resection (n = 132) were analyzed according to MCR as a whole group and after propensity score matching based on gender, age, histology, clinical T and N status, adjuvant chemotherapy, and trimodality treatment. Kaplan Meier survival and univariate and multivariate analyses were performed. RESULTS: Median age was 56 years (range, 26 to 80 years) and 62 were women. One hundred ten had epithelioid histology. MCR was achieved in 75 patients (49%). In-hospital mortality was seen in 7 patients (4.5%). Preoperative chemotherapy was applied in 32 patients. One hundred thirty-three patients underwent adjuvant treatment (45 had chemoradiation). Mean follow-up was 21 +/- 19 months. Overall median survival, 2-year, and 5-year survivals were 18.1 months, 36%, and 16%, respectively. There was no difference in median survival between patients who underwent MCR (21.4 months) and who did not (16.3 months) (P = .6). Following propensity score matching (23 patients in each group), median survivals were similar (13.3 vs 14.2 months; P = .63). CONCLUSIONS: MCR was not associated with improved survival in malignant pleural mesothelioma. We need to clearly define MCR and identify subgroups of patients who would benefit from this principle because minimal versus extensive and location of gross residual disease may have different influences on survival. PMID- 29510940 TI - Discussion. PMID- 29510941 TI - A continuous-flow external ventricular assist device for cardiogenic shock: Evolution over 10 years. AB - BACKGROUND: The use of percutaneous mechanical circulatory support (MCS) in the treatment of cardiogenic shock has increased. However, limitations in flow capability, ventricular unloading effect, durability, and mobility remain. We reviewed our single-center experience with continuous-flow external ventricular assist devices (VADs) to determine the role of temporary VADs for cardiogenic shock in the contemporary MCS era. METHODS: We retrospectively reviewed 252 patients who underwent continuous-flow external VAD insertion between January 2007 and December 2016. To investigate the change in indications, device configurations, and outcomes, we divided the cohort into 2 groups-2007 to 2011 (Era 1; n = 127) and 2012 to 2016 (Era 2; n = 125)-and compared early and late outcomes. RESULTS: Indications and device configurations changed significantly over time. The use of preoperative percutaneous MCS (53% vs 23%; P < .01) and use of minimally invasive VAD configurations (23% vs 6.7%; P < .01) were greater in Era 2 compared with Era 1. The rate of bridge to the next destinations, including myocardial recovery, transplantation, and durable VAD, was similar in the 2 groups. In-hospital mortality was significantly better in Era 2 (50% vs 37%; P = .04). Overall survival at 1 year was 57% in Era 2 versus 43% in Era 1 (P = .04). CONCLUSIONS: Better outcomes in the recent era could be associated with the changes in practice patterns using continuous-flow external VAD in patients with refractory cardiogenic shock. PMID- 29510942 TI - The importance and ways of exploring the entire chest before and after cardiac surgery: Chest radiography, lung ultrasonography, and computed tomography. PMID- 29510943 TI - Laryngeal ultrasound detects a high incidence of vocal cord paresis after aortic arch repair in neonates and young children. AB - OBJECTIVES: To determine the incidence of vocal cord paresis (VCP) after neonatal aortic arch repair/Norwood-type procedure, and the effectiveness of noninvasive laryngeal ultrasound in detecting VCP compared with gold standard invasive nasoendoscopy. METHODS: Fifty-two patients who underwent an arch repair (39 of 52; 75%) or Norwood-type procedure (13 of 52; 25%) via sternotomy between April 1, 2015, and April 30, 2017 underwent laryngeal ultrasound (50 of 52; 96%) and/or flexible fiber optic nasoendoscopy (39 of 52; 75%) at 48 to 72 hours after endotracheal extubation. Primary arch diagnoses were coarctation in 56% (29 of 52), hypoplastic left heart syndrome in 17% (9 of 52), isolated hypoplastic arch in 17% (9 of 52), and interrupted aortic arch in 10% (5 of 52). The median patient age at surgery was 5.5 days (interquartile range, 4.0-12.5 days). Fifteen patients (15 of 52; 29%) required preoperative intubation. RESULTS: Left VCP was present in 59% (23 of 39) of patients on nasoendoscopy and in 59% (27 of 46) of patients on laryngeal ultrasound, and 4 additional patients had inconclusive ultrasound results. There was agreement between the results of nasoendoscopy and conclusive ultrasound in all cases. The overall sensitivity, specificity, positive and negative predictive values, and Cohen's kappa coefficient of laryngeal ultrasound compared with nasoendoscopy for the detection of left VCP were 95%, 88%, 91%, 93%, and 0.83, respectively. On multivariable analysis, preoperative intubation and arch repair techniques other than the Norwood procedure were associated with left VCP (odds ratio, 12.7; P = .03; and 14.1; P = .03, respectively). CONCLUSIONS: There is a high incidence of VCP after arch repair via sternotomy. Laryngeal ultrasound seems to be an effective and noninvasive method for detecting VCP in neonates and young children. PMID- 29510944 TI - Rheological and mechanical properties of recycled polyethylene films contaminated by biopolymer. AB - Nowadays, with the increasing amount of biopolymers used, it can be expected that biodegradable polymers (e.g. PLA, PBAT) may appear in the petrol-based polymer waste stream. However, their impact on the recycling processes is not known yet; moreover, the properties of the products made from contaminated polymer blends are not easily predictable. Therefore, our goal was to investigate the rheological and mechanical properties of synthetic and biopolymer compounds. We made different compounds from regranulates of mixed polyethylene film waste and original polylactic acid (PLA) by extruison, and injection molded specimens from the compounds. We investigated the rheological properties of the regranulates, and the mechanical properties of the samples. When PLA was added, the viscosity and specific volume of all the blends decreased, and mechanical properties (tensile strength, modulus, and impact strength) changed significantly. Young's modulus increased, while elongation at break and impact strength decreased with the increase of the weight fraction of PLA. PMID- 29510945 TI - Selective reductive leaching of cobalt and lithium from industrially crushed waste Li-ion batteries in sulfuric acid system. AB - Recycling of valuable metals from secondary resources such as waste Li-ion batteries (LIBs) has recently attracted significant attention due to the depletion of high-grade natural resources and increasing interest in the circular economy of metals. In this article, the sulfuric acid leaching of industrially produced waste LIBs scraps with 23.6% cobalt (Co), 3.6% lithium (Li) and 6.2% copper (Cu) was investigated. The industrially produced LIBs scraps were shown to provide higher Li and Co leaching extractions compared to dissolution of corresponding amount of pure LiCoO2. In addition, with the addition of ascorbic acid as reducing agent, copper extraction showed decrease, opposite to Co and Li. Based on this, we propose a new method for the selective leaching of battery metals Co and Li from the industrially crushed LIBs waste at high solid/liquid ratio (S/L) that leaves impurities like Cu in the solid residue. Using ascorbic acid (C6H8O6) as reductant, the optimum conditions for LIBs leaching were found to be T = 80 degrees C, t = 90 min, [H2SO4] = 2 M, [C6H8O6] = 0.11 M and S/L = 200 g/L. This resulted in leaching efficiencies of 95.7% for Li and 93.8% for Co, whereas in contrast, Cu extraction was only 0.7%. Consequently, the proposed leaching method produces a pregnant leach solution (PLS) with high Li (7.0 g/L) and Co (44.4 g/L) concentration as well as a leach residue rich in Cu (up to 12 wt%) that is suitable as a feed fraction for primary or secondary copper production. PMID- 29510946 TI - Assessment of copper and zinc recovery from MSWI fly ash in Guangzhou based on a hydrometallurgical process. AB - Fly ash commonly accumulates a significant amount of heavy metals and most of these heavy metals are toxic and easily leached out to the environment, posing risks to human health. Thus, fly ash has been classified as a type of hazardous waste and requires proper treatment before disposal in specific landfill sites for hazardous waste. In this study, a hydrometallurgical process developed to recover copper and zinc performed in pilot scale close to industrial scale followed by a landfill compliance leaching test of the ash residue is evaluated. LIX860N-I and Cyanex 572 gave high selectively for extractions, a yield efficiency of 95% and 61% was achieved for copper and zinc respectively. Results of pilot experiments reveals that the combining metal recovery/recycling and landfill disposal of the ash residue in a local regular landfill was demonstrated to be a technically and economically effective strategy. Specifically, the economic and environmental aspects of a scenario, in which the fly ash generated in Guangzhou is processed were systematically assessed. the assessment results show that a 7.15 million US$ of total expense reduction, a less energy cost of 19k GJ as well as 2100 tons less CO2 emissions could be achieved annually comparing to the current alternative, direct disposal of the fly ash as hazardous waste. The results reveal that the hydrometallurgical process has industrial application potential on both economic and environmental aspects and further optimization of the process can give more accurate assessment of the cost and environment effect. In addition, leaching tests and evaluation of solid residue according to the regulations specific to the country should be studied in future. PMID- 29510947 TI - A combination of 19F NMR and surface plasmon resonance for site-specific hit selection and validation of fragment molecules that bind to the ATP-binding site of a kinase. AB - 19F NMR has recently emerged as an efficient, sensitive tool for analyzing protein binding to small molecules, and surface plasmon resonance (SPR) is also a popular tool for this purpose. Herein a combination of 19F NMR and SPR was used to find novel binders to the ATP-binding pocket of MAP kinase extracellular regulated kinase 2 (ERK2) by fragment screening with an original fluorinated fragment library. The 19F NMR screening yielded a high primary hit rate of binders to the ERK2 ATP-binding pocket compared with the rate for the SPR screening. Hit compounds were evaluated and categorized according to their ability to bind to different binding sites in the ATP-binding pocket. The binding manner was characterized by using isothermal titration calorimetry and docking simulation. Combining 19F NMR with other biophysical methods allows the identification of multiple types of hit compounds, thereby increasing opportunities for drug design using preferred fragments. PMID- 29510948 TI - Synthesis and SAR study of new hydroxy and chloro-substituted 2,4-diphenyl 5H chromeno[4,3-b]pyridines as selective topoisomerase IIalpha-targeting anticancer agents. AB - As part of our effort to develop potential topoisomerase IIalpha (topo IIalpha) targeting anticancer agents, we systematically designed a new series of hydroxy and chloro-substituted 2,4-diphenyl 5H-chromeno[4,3-b]pyridines. Total eighteen compounds were synthesized and tested for their ability to inhibit the function of topo I and IIalpha, and proliferation of human breast (T47D), colorectal (HCT15), and cervix (HeLa) cancer cells. Except compound 11, all of the tested compounds displayed selective topo IIalpha inhibitory activity. Compounds 8-18, 22, 24, and 25 showed excellent topo IIalpha inhibitory activity than a positive control, etoposide. Most of the compounds appeared to be superior to reference compounds in their antiproliferative activity. Structure-activity relationship (SAR) study has shown that it is better to place the hydroxyphenyl group at the 4 position of the central pyridine for superior topo IIalpha inhibition and antiproliferative activity. Similarly, the 3'-, or 4'-hydroxyphenyl substitution at the 2- and 4-positon of pyridine ring is important for better activity than 2' substitution. PMID- 29510949 TI - Reply to Woodward et al.: A standard mastectomy should not be the only recommended breast surgical treatment for non-metastatic inflammatory breast cancer. PMID- 29510950 TI - The Cost-Effectiveness of Preoperative Staphylococcus aureus Screening and Decolonization in Total Joint Arthroplasty. AB - BACKGROUND: This article presents a break-even analysis for preoperative Staphylococcus aureus colonization screening and decolonization protocols in total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Protocol costs, baseline infection rates after arthroplasty, and average revision costs were obtained from institutional records and the literature. The break-even analysis determined the absolute risk reduction (ARR) in infection rate required for cost-effectiveness. RESULTS: S aureus nasal screening ($144.07) was cost effective when initial infection rates of TKA (1.10%) and THA (1.63%) had an ARR of 0.56% and 0.45%, respectively. The most inexpensive decolonization treatment ($5.09) was cost effective with an ARR of 0.02% for both TKA and THA. The most expensive decolonization option ($37.67) was cost effective with ARRs of 0.15% (TKA) and 0.12% (THA). CONCLUSION: Preoperative S aureus decolonization can be highly cost effective, whereas colonization screening requires excessively high reductions in infection rate. PMID- 29510951 TI - Treatment of High-Grade Acetabular Defects: Do Porous Titanium Cups Provide Better Stability Than Traditional Titanium Cups When Combined With an Augment? AB - BACKGROUND: Revision total hip arthroplasty frequently faces challenges associated with deficient bone stock. Porous metal implants were developed to meet the challenge, but require rapid osseointegration for ultimate success. This study aims to assess relative motion as an indicator for primary stability and osseointegration of two different titanium cups each combined with a titanium augment. METHODS: In 14 cadaver hemipelvises, 2 types of titanium acetabular cups, a traditional sintered-bead cup (POROCOAT Acetabular Cup [PAC]) and a newer porous-coated cup (GRIPTION Acetabular Cup [GAC]) each associated with a porous augment, were subjected to 3-dimensional varying loads, replicating 30% of loads experienced during normal gait. Relative motion was measured at the cup/bone, augment/bone, and cup/augment interfaces. RESULTS: Only at the cup/bone interface was there a statistically significant difference in relative motion between the traditional PAC and the newer GAC, with PAC showing less relative motion (P = .0037). Bone mineral density (BMD) had a significant effect on relative motion (P = .0019) at the cup/bone interface of both cup types, with low BMD specimens showing more relative motion. CONCLUSION: Both cup types combined with augments displayed minimal relative motion that was within the accepted range thought to allow osseointegration, although the traditional surface proved superior to the newer surface. This difference was more pronounced at low BMD, with the well established PAC cup displaying less relative motion than the more porous GAC cup, consistent with better osseointegration than the more porous cup. This suggests that the more porous implant may be less advantageous than traditional PAC cups, particularly in cases with poorer bone stock. PMID- 29510952 TI - Comparison of Postoperative Complications Following Metal-on-Metal Total Hip Arthroplasty With Other Hip Bearings in Medicare Population. AB - BACKGROUND: The use of metal-on-metal (MoM) hip bearings has declined in the recent years due to strong evidence of their high complication rates and early failure. Hip implants with highly cross-linked polyethylene liners and ceramic bearings have become the modern implants of choice. We sought to determine if MoM implants are associated with higher complication and revision rates when compared to other hip bearings in the Medicare population. METHODS: We retrospectively reviewed a Medicare database (2005-2011) for patients who underwent a primary total hip arthroplasty with a MoM, metal-on-polyethylene (MoP), ceramic-on polyethylene (CoP), or ceramic-on-ceramic (CoC) implant (minimum 2 years of follow-up). Patient comorbidities and medical/surgical complication rates were analyzed at various time points postoperatively. RESULTS: We identified 288,118 patients, including 81,520 patients with a MoM implant, 162,881 with MoP, 33,819 with CoP, and 9898 with CoC implant. Surgical complication rates were higher for MoM implants including infection, osteolysis/polywear, mechanical complications, and need for hip irrigation and debridement. Overall revision rates were significantly higher for MoM implants (5.28%) compared to MoP (4.28%, odds ratio [OR] 1.26, P < .001) and CoP (3.52%, OR 1.55, P < .001) but only by one to two percent. MoM revision rates were similar to CoC implants (4.94%, OR 1.00, P = .096). CONCLUSIONS: MoM implants were associated with higher revision rates (5.28%) compared to MoP (4.28%) and CoP (3.52%) implants in the Medicare population. Both complication and revision rates were comparable to CoC implants. PMID- 29510953 TI - Comparing the Effect of Tourniquet vs Tourniquet-Less in Simultaneous Bilateral Total Knee Arthroplasties. AB - BACKGROUND: Total knee arthroplasty (TKA) is a commonly performed procedure worldwide for the treatment of knee joint disease. Tourniquet is frequently used during the entire procedure to reduce blood loss and increase surgical comfort. On the other hand, tourniquet-related complications exist, and there are still controversies whether benefits outweigh the risks. METHODS: Patients undergoing simultaneous TKAs had one knee assigned to group A (use of tourniquet during the entire procedure) and the other knee assigned to group B (use of tourniquet only during cementation). Blood loss, intraoperative complications, implant alignment, soft tissue swelling, pain score, and range of motion were analyzed. RESULTS: Fifty-four patients undergoing 108 TKAs were included in the study. Total blood loss was almost 2 times higher in group B knees compared with group A. No difference was observed between groups in implant alignment, soft tissue swelling, pain, range of motion, or other early postoperative complications. CONCLUSION: Tourniquet use in TKAs during the entire surgical procedure reduces total blood loss, without an increase in early postoperative complications. PMID- 29510954 TI - Increased survival might be an unexpected additional advantage of enhanced recovery after surgery programs. PMID- 29510955 TI - Effect of botulinum toxin type A treatment in children with cerebral palsy: Sequential physical changes for 3 months after the injection. AB - PURPOSE: This study investigated the sequential physical changes after botulinum toxin type A (BTX-A) injected in children with cerebral palsy. METHODS: Nine children with cerebral palsy were included. Measurements were performed before treatment and 4 weeks, 8 weeks, and 12 weeks after treatment. We used video recorded gait in the sagittal plane. The maximum flexion and extension angles of the hip, knee and ankle joints, step length, gait speed, and observational gait were measured using the Foot Contact Scale (FCS) and the Physician's Rating Scale (PRS). We also measured the lower limb range of motion (ROM), Modified Tardieu Scale (MTS), knee joint extension torque, and Gross Motor Function Measure-66 (GMFM-66). RESULTS: The ankle dorsiflexion ROM, GMFM-66, and the maximum dorsiflexion angle of the ankle during gait were significantly increased at 8 weeks after treatment, and knee joint extension torque was significantly increased at 12 weeks after treatment. CONCLUSION: Maximum effects of BTX-A treatment do not occur during the early stage after treatment. Therefore, long term intervention with rehabilitation between BTX-A treatment may be more effective than implementing rehabilitation for only a brief period. PMID- 29510956 TI - [Social problems in primary health care - prevalence, responses, course of action, and the need for support from a general practitioners' point of view]. AB - BACKGROUND: Very often patients utilize primary care services for health conditions related to social problems. These problems, which are not primarily medical, can severely influence the course of an illness and its treatment. Little is known about the extent to which problems like unemployment or loneliness occur in a general practice setting. OBJECTIVES: What are the most frequent health-related social problems perceived by general practitioners (GPs)? How are these problems associated with GP- or practice characteristics? How do general practitioners deal with the social problems they perceive and what kind of support do they need? MATERIALS AND METHODS: Cross-sectional, postal questionnaire survey with questions derived from "Chapter Z social problems" of the International Classification of Primary Care - 2nd edition. The questionnaire was mailed to available GP addresses in the federal states of Hamburg (n=1,602) and Schleswig-Holstein (n=1,242). RESULTS: N=489 questionnaires (17.2 %) were analyzed. At least three times a week, GPs were consulted by patients with poverty/financial problems (53.4 %), work/unemployment problems (43.7 %), patients with loneliness (38.7 %) as well as partnership issues (25.5 %). Only rarely did GPs report having perceived assault/harmful event problems (0.8 %). The highest frequency of problems was encountered by practices with a high proportion of a migrant population. CONCLUSIONS: Social problems are a common issue in routine primary care. GPs in Northwestern Germany usually try to find internal solutions for social problems but also indicated further interest in institutionalized support. A possible approach to solving these issues are community-based, locally organized networks. PMID- 29510957 TI - IDEAL 2a Phase II Study of Ultrafocal Brachytherapy for Low- and Intermediate risk Prostate Cancer. AB - PURPOSE: Focal therapy of prostate cancer requires precise positioning of therapeutic agents within well-characterized index tumors (ITs). We assessed the feasibility of low-dose-rate ultrafocal brachytherapy. METHODS AND MATERIALS: The present study was an institutional review board-approved European Clinical Trials Database-registered phase II protocol. Patients referred (October 2013 to August 2016) for active surveillance (prostate-specific antigen <10 ng/mL, cT1c-cT2a, Gleason score on referring biopsy specimens <=6 (3+3), <=3 positive biopsy cores, <=50% of cancer) were preselected. Inclusion was confirmed when complementary image-guided biopsy findings informed a single Prostate Imaging Reporting and Data System (PI-RADS) >=3, Gleason score <=7a (3+4) lesion. A ultrasound-visible ancillary marker was positioned within the IT using a magnetic resonance imaging (MRI)/3-dimensional transrectal ultrasound (TRUS) elastic fusion-guided system (Koelis). Ultrafocal transperineal delivery of 125I seeds used classic 2 dimensional TRUS (Bard-FlexFocus) and dose optimization (Variseed Treatment Planning System). Following Simon's optimal design, 17 patients were required to assess the feasibility of delivering >=95% of the prescribed dose (160 Gy) to the IT (primary objective). Adverse events (Common Terminology Criteria for Adverse Events) and quality of life (5-item International Index of Erectile Function, International Prostate Symptom Score) were recorded. One-year control biopsy specimens were obtained from the IT and untreated segments. RESULTS: Of the 44 preselected patients, 27 did not meet the inclusion criteria. Of the 17 ultrafocal brachytherapy-treated patients, 16 met the primary objective (per protocol success). The prescription dose was delivered to 14.5% +/- 6.4% of the prostate volume, resulting in negligible urethral and rectal irradiation and toxicity. No recurrence was evidenced on the 1-year follow-up MRI studies or IT biopsy specimens. Seven nonclinically significant cancers and one Gleason score 7a (3+4) cancer (salvage prostatectomy) were observed in the untreated parenchyma. CONCLUSIONS: Recent technology has allowed for selective and effective brachytherapy of small MRI targets. PMID- 29510958 TI - Task-dependent activation of distinct fast and slow(er) motor pathways during motor imagery. AB - BACKGROUND: Motor imagery and actual movements share overlapping activation of brain areas but little is known about task-specific activation of distinct motor pathways during mental simulation of movements. For real contractions, it was demonstrated that the slow(er) motor pathways are activated differently in ballistic compared to tonic contractions but it is unknown if this also holds true for imagined contractions. OBJECTIVE: The aim of the present study was to assess the activity of fast and slow(er) motor pathways during mentally simulated movements of ballistic and tonic contractions. METHODS: H-reflexes were conditioned with transcranial magnetic stimulation at different interstimulus intervals to assess the excitability of fast and slow(er) motor pathways during a) the execution of tonic and ballistic contractions, b) motor imagery of these contraction types, and c) at rest. RESULTS: In contrast to the fast motor pathways, the slow(er) pathways displayed a task-specific activation: for imagined ballistic as well as real ballistic contractions, the activation was reduced compared to rest whereas enhanced activation was found for imagined tonic and real tonic contractions. CONCLUSIONS: This study provides evidence that the excitability of fast and slow(er) motor pathways during motor imagery resembles the activation pattern observed during real contractions. The findings indicate that motor imagery results in task- and pathway-specific subliminal activation of distinct subsets of neurons in the primary motor cortex. PMID- 29510959 TI - Study by Monte Carlo methods of an explosives detection system made up with a D-D neutron generator and NaI(Tl) gamma detectors. AB - Detection of hidden explosives is of utmost importance for homeland security. Several configurations of an Explosives Detection System (EDS) to intercept hidden threats, made up with a Deuterium-Deuterium (D-D) compact neutron generator and NaI (Tl) scintillation detectors, have been evaluated using MCNP6 code. The system's response to various samples of explosives, such as RDX and Ammonium Nitrate, is analysed. The D-D generator is able to produce fast neutrons with 2.5 MeV energy in a maximum yield of 1010 n/s. It is surrounded by high density polyethylene to thermalize the fast neutrons and to optimize interactions with the sample inspected, whose emission of gamma rays gives a characteristic spectrum of the elements that constitute it. This procedure allows to determine its chemical composition and to identify the type of substance. The necessary shielding is evaluated to estimate its thicknesses depending on the admissible dose of operation, using lead and polyethylene. The results show that its functionality is promising in the field of national security for explosives inspection. PMID- 29510960 TI - New Mexico Cancer Center and the COME HOME Model: Pathways improving the value of community-based cancer care. PMID- 29510961 TI - ? AB - The therapy for invasive candidiasis related to biofilms infection remains a difficult medical problem. To overcome this problem, efforts have been made to search for novel antibiofilm agents from various sources. This study investigated the in vitro antibiofilm activity of (1)-N-2-methoxybenzyl-1,10-phenanthrolinium bromide (FEN) against Candida albicans. The minimum biofilm inhibitory concentration (MBIC) and minimum biofilm reduction concentration (MBRC) were determined using the MTT (3-(4-5-dimethylthiazol-2-yl)2,5-dyphenyl tetrazolium bromide) reduction assay. Biofilms on surfaces were visualized using scanning electron microscopy (SEM). This new compound inhibited the growth of C. albicans biofilms by 80 % with an MBIC80 range from 0.5-2.0MUg/mL. The ability of FEN to reduce 50 % of a preformed biofilm was demonstrated by defining a MBRC50 range from 6.25--12.5MUg/mL. To reduce 80 % of a preformed biofilm required higher concentrations >200MUg/mL. In addition, SEM images showed disruption of C. albicans biofilms matrix exposed to FEN. These results indicated that (1)-N-2 methoxybenzyl-1,10-phenanthrolinium bromide has the potential to be developed as a new antibiofilm agent against C. albicans. PMID- 29510962 TI - Coca-Cola allergy identified as fructose-induced anaphylaxis. PMID- 29510963 TI - [Conventional analgesics and non-pharmacological multidisciplinary therapeutic treatment in endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - : A major symptom of endometriosis is pelvic pain with a wide range of intensity, rhythm, type, and expression, without clearly established relationship between pain and the disease. Endometriosis-associated pain has physical, psychological/behavioral and social consequences with a significant impact on patient quality-of-life in relation with the biopsychosocial model of chronic pain. Pain assessment in all of its dimensions, as well as assessing the consequences of pain is therefore a crucial part of therapeutic management. Conventional analgesics are commonly used although studies demonstrating their efficacy in the treatment of endometriosis-related pelvic pain are lacking. Non steroid anti-inflammatory drugs (NSAIDs), known to be effective in dysmenorrhea unrelated to endometriosis, have not been recently re-assessed in patients with endometriosis. Following rigorous assessment, the characterization of neuropathic components of endometriosis-related pelvic pain may lead to treatment with antiepileptic of antidepressant drugs, although gabapentin and amitriptyline have yet to be specifically assessed in the setting of endometriosis-related pain. Other pharmacologically active compounds have been tested to treat endometriosis related pain but did not demonstrate efficacy with sufficient level of evidence. Diets, dietary supplements and herbal medicine are often proposed and/or used as adjuncts without any conclusive evidence. Although the effects on endometriosis related pain are methodologically difficult to assess, physical adjunctive therapies such as acupuncture, transcutaneous neurostimulation, osteopathy/chiropractics, physical therapy and physical activity, the long-term therapeutic relationship they establish may potentiate beneficial effects perceived by patients. However, it remains difficult to demonstrate significant effects of cognitive and/or behavioral interventions on endometriosis-related pain. CONCLUSION: The complexity of managing endometriosis-related pain requires a holistic approach with sustained attention to the patient. Treatments, either pharmacologic or non-pharmacologic, including adjuvant therapies, associate a technical expertise to which a human approach must be added in order to bring value to these treatments. Multidisciplinary and/or inter disciplinary approaches are therefore essential to the care of patients suffering from endometriosis. PMID- 29510964 TI - [Surgical management of endometrioma: Different alternatives in term of pain, fertility and recurrence. CNGOF-HAS Endometriosis Guidelines]. AB - Surgical management of ovarian endometrioma is most often part of a global approach of endometriosis pathology. Isolated endometrioma are rare. Laparoscopic cystectomy is the gold standard for surgical management of endometrioma. Nevertheless, this technique impacts the ovarian function. The hemostasis of the ovarian cyst bed should be performed to conserve the ovarian stroma. Ultrasonography-guided cyst aspiration, laparoscopic drainage and simple bipolar coagulation are not recommended as first line of treatment. Based on the actual literature, we cannot state the place of laser-vaporization and plasma-energy ablation in surgical management. Ethanol sclerotherapy could be an alternative to treat recurrent endometrioma. Uncompleted surgical removal of endometriosis lesions increases the recurrence rate. Endometriosis management should take into account the research and treatment of all the pelvic lesion, especially before surgical management of endometrioma. In this context, the evaluation of ovarian reserve could be useful before surgery. PMID- 29510965 TI - [Minimal and mild endometriosis: Impact of the laparoscopic surgery on pelvic pain and fertility. CNGOF-HAS Endometriosis Guidelines]. AB - Minimal and mild endometriosis (stage 1 and 2 AFSR) can lead to chronic pelvic pain and infertility but can also exist in asymptomatic patients. The prevalence of asymptomatic patients with minimal and mild endometriosis is not clear but typical endometriosis lesions are found in about 5 to 10% of asymptomatic women and more than 50% of painful and/or infertile women. Laparoscopic treatment of minimal and mild endometriotic lesions is justified in case of pelvic pain because their destruction decrease significatively the pain compared with diagnostic laparoscopy alone. In this context, ablation and excision give identical results in terms of pain reduction. Moreover, literature shows no interest in uterine nerve ablation in case of dysmenorrhea due to minimal and mild endometriosis. Then, it is recommended to treat these lesions during a laparoscopy realised as part of pelvic pain. On the other hand, it is not recommended to treat asymptomatic patients. With regard to treatment of minimal and mild endometriosis in infertile patients, only two studies can be selected and both show that laparoscopy with excision or ablation and ablation of adhesions is superior to diagnostic laparoscopy alone in terms of pregnancy rate. However, it is not recommended to treat these lesions when they are asymptomatic because there is no evidence that they can progress with symptomatic disease. There is no study assessing the interest to treat these lesions when they are found fortuitously. Adhesion barrier utilisation permits to reduce post-operative adhesions, however literature failed to demonstrate the clinical profit in terms of reduction of the risk of pain or infertility. PMID- 29510966 TI - [Medical treatment for the management of painful endometriosis without infertility: CNGOF-HAS Endometriosis Guidelines]. AB - OBJECTIVE: To provide clinical practice guidelines for the management of painful endometriosis in women without infertility. METHODS: Systematic review of the literature literature since 2006, level of evidence rating, external proofreading and grading of the recommendation grade by an expert group according to HAS methodology. RESULTS: Combined hormonal contraceptives (COP) and the levonorgestrel-releasing intra-uterin system (LNG-IUS) are recommended as first line hormonal therapies for the treatment of painful endometriosis (grade B). Second-line therapy relies on oral desogestrel microprogestative, etonogestrel releasing implant, GnRH analogs (GnRHa) and dienogest (grade C). It is recommended to use add-back therapy containing estrogen in association with GnRHa (grade B). After endometriosis surgery, hormonal treatment relying on COP or LNG IUS is recommended to prevent pain recurrence (grade B). COP is recommended to reduce the risk of endometrioma recurrence after surgery (grade B) but the prescription of GnRHa is not recommended (grade C). Continuous COP is recommended in case of dysmenorrhea (grade B). GnRHa is not recommended as first line endometriosis treatment for adolescent girl because of the risk of bone demineralization (grade B). The management of endometriosis-induced chronic pain requires an interdisciplinary evaluation. Physical therapies improving the quality of life such as yoga, relaxation or osteopathy can be proposed (expert agreement). Promising medical alternatives are currently under preclinical and clinical evaluation. PMID- 29510967 TI - Treatment with growth hormone in the prader-willi syndrome. AB - INTRODUCTION: The Prader-Willi syndrome (PWS) is a rare genetic disorder caused by absence of expression of the paternal alleles in region 15q11.2-q13. Obesity and hormonal deficiencies, especially of growth hormone (GH), are the most important signs from the therapeutic viewpoint. Recombinant GH (rGH) is effective in children and represents the mainstay in treatment; by contrast, little evidence in available in adult patients. OBJECTIVE: To review the reported evidence on the beneficial and adverse effects of treatment with rGH in children and adults. DESIGN: A review was made of 62 original articles published between 2000 and 2017 using the PubMed database. RESULTS: In pediatric and adult PWS, rGH improves body morphology and composition, physical performance, cognition, psychomotor development, respiratory function, and quality of life with few adverse effects. CONCLUSIONS: Treatment with rGH is effective and safe and improves quality of life in both children and adults with PWS. PMID- 29510968 TI - Technology and Social Media Use Among Patients Enrolled in Outpatient Addiction Treatment Programs: Cross-Sectional Survey Study. AB - BACKGROUND: Substance use disorder research and practice have not yet taken advantage of emerging changes in communication patterns. While internet and social media use is widespread in the general population, little is known about how these mediums are used in substance use disorder treatment. OBJECTIVE: The aims of this paper were to provide data on patients' with substance use disorders mobile phone ownership rates, usage patterns on multiple digital platforms (social media, internet, computer, and mobile apps), and their interest in the use of these platforms to monitor personal recovery. METHODS: We conducted a cross-sectional survey of patients in 4 intensive outpatient substance use disorder treatment facilities in Philadelphia, PA, USA. Logistic regressions were used to examine associations among variables. RESULTS: Survey participants (N=259) were mostly male (72.9%, 188/259), African American (62.9%, 163/259), with annual incomes less than US $10,000 (62.5%, 161/259), and averaged 39 (SD 12.24) years of age. The vast majority of participants (93.8%, 243/259) owned a mobile phone and about 64.1% (166/259) owned a mobile phone with app capabilities, of which 85.1% (207/243) accessed the internet mainly through their mobile phone. There were no significant differences in age, gender, ethnicity, or socio-economic status by computer usage, internet usage, number of times participants changed their phone, type of mobile phone contract, or whether participants had unlimited calling plans. The sample was grouped into 3 age groups (Millennials, Generation Xers, and Baby Boomers). The rates of having a social media account differed across these 3 age groups with significant differences between Baby Boomers and both Generation Xers and Millennials (P<.001 in each case). Among participants with a social media account (73.6%, 190/259), most (76.1%, 144/190) reported using it daily and nearly all (98.2%, 186/190) used Facebook. Nearly half of participants (47.4%, 90/190) reported viewing content on social media that triggered substance cravings and an equal percentage reported being exposed to recovery information on social media. There was a significant difference in rates of reporting viewing recovery information on social media across the 3 age groups with Baby Boomers reporting higher rates than Millennials (P<.001). The majority of respondents (70.1%, 181/259) said they would prefer to use a relapse prevention app on their phone or receive SMS (short message service) relapse prevention text messages (72.3%, 186/259), and nearly half (49.1%, 127/259) expressed an interest in receiving support by allowing social media accounts to be monitored as a relapse prevention technique. CONCLUSIONS: To our knowledge, this is the first and largest study examining the online behavior and preferences regarding technology-based substance use disorder treatment interventions in a population of patients enrolled in community outpatient treatment programs. Patients were generally receptive to using relapse prevention apps and text messaging interventions and a substantial proportion supported social media surveillance tools. However, the design of technology based interventions remains as many participants have monthly telephone plans which may limit continuity. PMID- 29510969 TI - Using Google Glass in Surgical Settings: Systematic Review. AB - BACKGROUND: In recent years, wearable devices have become increasingly attractive and the health care industry has been especially drawn to Google Glass because of its ability to serve as a head-mounted wearable device. The use of Google Glass in surgical settings is of particular interest due to the hands-free device potential to streamline workflow and maintain sterile conditions in an operating room environment. OBJECTIVE: The aim is to conduct a systematic evaluation of the literature on the feasibility and acceptability of using Google Glass in surgical settings and to assess the potential benefits and limitations of its application. METHODS: The literature was searched for articles published between January 2013 and May 2017. The search included the following databases: PubMed MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO (EBSCO), and IEEE Xplore. Two reviewers independently screened titles and abstracts and assessed full-text articles. Original research articles that evaluated the feasibility, usability, or acceptability of using Google Glass in surgical settings were included. This review was completed following the Preferred Reporting Results of Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of the 520 records obtained, 31 met all predefined criteria and were included in this review. Google Glass was used in various surgical specialties. Most studies were in the United States (23/31, 74%) and all were conducted in hospital settings: 29 in adult hospitals (29/31, 94%) and two in children's hospitals (2/31, 7%). Sample sizes of participants who wore Google Glass ranged from 1 to 40. Of the 31 studies, 25 (81%) were conducted under real-time conditions or actual clinical care settings, whereas the other six (19%) were conducted under simulated environment. Twenty-six studies were pilot or feasibility studies (84%), three were case studies (10%), and two were randomized controlled trials (6%). The majority of studies examined the potential use of Google Glass as an intraoperative intervention (27/31, 87%), whereas others observed its potential use in preoperative (4/31, 13%) and postoperative settings (5/31, 16%). Google Glass was utilized as a videography and photography device (21/31, 68%), a vital sign monitor (6/31, 19%), a surgical navigation display (5/31, 16%), and as a videoconferencing tool to communicate with remote surgeons intraoperatively (5/31, 16%). Most studies reported moderate or high acceptability of using Google Glass in surgical settings. The main reported limitations of using Google Glass utilization were short battery life (8/31, 26%) and difficulty with hands-free features (5/31, 16%). CONCLUSIONS: There are promising feasibility and usability data of using Google Glass in surgical settings with particular benefits for surgical education and training. Despite existing technical limitations, Google Glass was generally well received and several studies in surgical settings acknowledged its potential for training, consultation, patient monitoring, and audiovisual recording. PMID- 29510970 TI - The Optimization of an eHealth Solution (Thought Spot) with Transition-Aged Youth in Postsecondary Settings: Participatory Design Research. AB - BACKGROUND: Seventy percent of lifetime cases of mental illness emerge before the age of 24 years, but many youth are unable to access the support and services they require in a timely and appropriate way. With most youth using the internet, electronic health (eHealth) interventions are promising tools for reaching this population. Through participatory design research (PDR) engagement methods, Thought Spot, a Web- and mobile-based platform, was redeveloped to facilitate access to mental health services by transition-aged youth (aged 16-29 years) in postsecondary settings. OBJECTIVE: The aim of this study was to describe the process of engaging with postsecondary students through the PDR approaches, with the ultimate goal of optimizing the Thought Spot platform. METHODS: Consistent with the PDR approaches, five student-led workshops, attended by 41 individuals, were facilitated to obtain feedback regarding the platform's usability and functionality and its potential value in a postsecondary setting. Various creative engagement activities were delivered to gather experiences and opinions, including semistructured focus groups, questionnaires, personas, journey mapping, and a world cafe. Innovative technological features and refinements were also brainstormed during the workshops. RESULTS: By using PDR methods of engagement, participants knew that their ideas and recommendations would be applied. There was also an overall sense of respect and care integrated into each group, which facilitated an exchange of ideas and suggestions. CONCLUSIONS: The process of engaging with students to redesign the Thought Spot platform through PDR has been effective. Findings from these workshops will significantly inform new technological features within the app to enable positive help-seeking behaviors among students. These behaviors will be further explored in the second phase that involves a randomized controlled trial. PMID- 29510971 TI - Oncologic Therapy Support Via Means of a Dedicated Mobile App (OPTIMISE-1): Protocol for a Prospective Pilot Trial. AB - BACKGROUND: The increasing role of consumer electronics and Web-enabled mobile devices in the medical sector opens up promising possibilities for integrating novel technical solutions into therapy and patient support for oncologic illnesses. A recent survey carried out at Heidelberg University Hospital suggested a high acceptance among patients for an additional approach to patient care during radiotherapy based on patient-reported outcomes by a dedicated mobile app. OBJECTIVE: The aim of this trial (OPTIMISE-1: Oncologic Therapy Support Via Means of a Dedicated Mobile App - A Prospective Feasibility Evaluation) is to prospectively evaluate the feasibility of employing a mobile app for the systematic support of radiooncological patients throughout the course of their radiotherapy by monitoring symptoms and patient performance, and facilitating the background-exchange of relevant information between patient and physician. METHODS: The present single-center, prospective, exploratory trial, conducted at Heidelberg University Hospital, assesses the feasibility of integrating an app based approach into patient-care during radiotherapy. Patients undergoing curative radiotherapy for thoracic or pelvic tumors will be surveyed regarding general performance, treatment-related quality of life (QoL) and symptoms, and their need to personally consult a physician by means of a mobile app during treatment. The primary endpoint of feasibility will be reached when 80% of the patients have successfully answered 80% of their respective questions scheduled for each treatment day. Furthermore, treatment-related patient satisfaction and health-related QoL is assessed by the Patient Satisfaction Questionnaire Short Form (PSQ-18) and the European Organization for Research and Treatment of Cancer (EORTC) questionnaires at the beginning (baseline) and end of radiotherapy, and at the first follow-up. RESULTS: This trial will recruit 50 patients over a period of 12 months. Follow-up will be completed after 18 months, and publication of results is planned at 24 months after trial initiation. CONCLUSIONS: This study will serve as a basis for future studies aiming to exploit the constant innovation in mobile medical appliances and integrate novel patient-centered concepts into patient care in the context of radiotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03168048; https://clinicaltrials.gov/ct2/show/NCT03168048 (Archived at WebCite http://www.webcitation.org/6wtWGgi0X). PMID- 29510973 TI - NHS antidepressant prescribing: what do we get for L266m a year? PMID- 29510974 TI - Correction: AMSSM position statement on cardiovascular preparticipation screening in athletes: current evidence, knowledge gaps, recommendations and future directions. PMID- 29510975 TI - Surgeon who shared his experiences of inappropriate behaviour escapes sanction. PMID- 29510972 TI - Adapting the Wii Fit Balance Board to Enable Active Video Game Play by Wheelchair Users: User-Centered Design and Usability Evaluation. AB - BACKGROUND: Active video game (AVG) playing, also known as "exergaming," is increasingly employed to promote physical activity across all age groups. The Wii Fit Balance Board is a popular gaming controller for AVGs and is used in a variety of settings. However, the commercial off-the-shelf (OTS) design poses several limitations. It is inaccessible to wheelchair users, does not support the use of stabilization assistive devices, and requires the ability to shift the center of balance (COB) in all directions to fully engage in game play. OBJECTIVE: The aim of this study was to design an adapted version of the Wii Fit Balance Board to overcome the identified limitations and to evaluate the usability of the newly designed adapted Wii Fit Balance Board in persons with mobility impairments. METHODS: In a previous study, 16 participants tried the OTS version of the Wii Fit Balance Board. On the basis of observed limitations, a team of engineers developed and adapted the design of the Wii Fit Balance Board, which was then subjected to multiple iterations of user feedback and design tweaks. On design completion, we recruited a new pool of participants with mobility impairments for a larger study. During their first visit, we assessed lower-extremity function using selected mobility tasks from the International Classification of Functioning, Disability and Health. During a subsequent session, participants played 2 sets of games on both the OTS and adapted versions of the Wii Fit Balance Board. Order of controller version played first was randomized. After participants played each version, we administered the System Usability Scale (SUS) to examine the participants' perceived usability. RESULTS: The adapted version of the Wii Fit Balance Board resulting from the user-centered design approach met the needs of a variety of users. The adapted controller (1) allowed manual wheelchair users to engage in game play, which was previously not possible; (2) included Americans with Disabilities Act-compliant handrails as part of the controller, enabling stable and safe game play; and (3) included a sensitivity control feature, allowing users to fine-tune the controller to match the users' range of COB motion. More than half the sample could not use the OTS version of the Wii Fit Balance Board, while all participants were able to use the adapted version. All participants rated the adapted Wii Fit Balance Board at a minimum as "good," while those who could not use the OTS Wii Fit Balance Board rated the adapted Wii Fit Balance Board as "excellent." We found a significant negative correlation between lower-extremity function and differences between OTS and adapted SUS scores, indicating that as lower-extremity function decreased, participants perceived the adapted Wii Fit Balance Board as more usable. CONCLUSIONS: This study demonstrated a successful adaptation of a widely used AVG controller. The adapted controller's potential to increase physical activity levels among people with mobility impairments will be evaluated in a subsequent trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02994199; https://clinicaltrials.gov/ct2/show/NCT02994199 (Archived by WebCite at http://www.webcitation.org/6xWTyiJWf). PMID- 29510976 TI - Correction. PMID- 29510977 TI - Trump and health department diverge on how to deal with opioid crisis. PMID- 29510978 TI - Conflicting asthma guidelines reflect different motives. PMID- 29510979 TI - Immersive and interactive virtual reality to improve learning and retention of neuroanatomy in medical students: a randomized controlled study. AB - BACKGROUND: Spatial 3-dimensional understanding of the brain is essential to learning neuroanatomy, and 3-dimensional learning techniques have been proposed as tools to enhance neuroanatomy training. The aim of this study was to examine the impact of immersive virtual-reality neuroanatomy training and compare it to traditional paper-based methods. METHODS: In this randomized controlled study, participants consisted of first- or second-year medical students from the University of Saskatchewan recruited via email and posters displayed throughout the medical school. Participants were randomly assigned to the virtual-reality group or the paper-based group and studied the spatial relations between neural structures for 12 minutes after performing a neuroanatomy baseline test, with both test and control questions. A postintervention test was administered immediately after the study period and 5-9 days later. Satisfaction measures were obtained. RESULTS: Of the 66 participants randomly assigned to the study groups, 64 were included in the final analysis, 31 in the virtual-reality group and 33 in the paper-based group. The 2 groups performed comparably on the baseline questions and showed significant performance improvement on the test questions following study. There were no significant differences between groups for the control questions, the postintervention test questions or the 7-day postintervention test questions. Satisfaction survey results indicated that neurophobia was decreased. INTERPRETATION: Results from this study provide evidence that training in neuroanatomy in an immersive and interactive virtual reality environment may be an effective neuroanatomy learning tool that warrants further study. They also suggest that integration of virtual-reality into neuroanatomy training may improve knowledge retention, increase study motivation and decrease neurophobia. PMID- 29510980 TI - Hospital passports require standardisation to improve patient safety and person centred care for those with intellectual disability. PMID- 29510981 TI - Excess mortality associated with weekend hospital admissions may be due to patient-level differences, rather than reduced staffing or services. PMID- 29510982 TI - Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas. AB - BACKGROUND: Low-grade incomplete post-dexamethasone cortisol suppression in patients with adrenal incidentalomas - recently defined as possible autonomous cortisol secretion (pACS) - has been associated with increased cardiovascular events and mortality. However, prospective studies documenting cardiac abnormalities in these patients are lacking. SUBJECTS AND METHODS: Between July 2016 and September 2017, 71 consecutive patients with adrenal lesions were prospectively screened for hypercortisolism by dexamethasone suppression test (NCT 02611258). Complete anthropometric, metabolic and hormonal parameters were recorded along with full cardiac ultrasound assessment and noninvasive measurement of arterial stiffness. All patients underwent chemical-shift magnetic resonance imaging to characterize the lesions. Cardiovascular outcomes were recorded in blind. RESULTS: According to post-dexamethasone suppression cortisol values (post-DST), 34 patients had pACS and 37 non-functioning adenomas (NFA). The two groups were similar in sex, BMI, age distribution, cardiovascular risk factors and comorbidities. Left ventricular mass index (LVMIBSA) was increased in pACS compared to NFA (P = 0.006) and mildly correlated to the post-DST cortisol level (rho = 0.347; P = 0.004). The post-DST cortisol levels explained up to 13.7% of LVMIBSA variance (P = 0.002). Compared to NFA, patients with pACS had a higher prevalence of diastolic dysfunction (35.1% vs 82.6%; P = 0.001) and worse arterial stiffness assessed by pulse wave velocity (P = 0.033). CONCLUSIONS: In apparently asymptomatic patients, mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling, independently of other risk factors. The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition. PMID- 29510983 TI - Fifteen-minute consultation: Supporting colleagues through a serious incident or complaint. AB - Being involved in a complaint or serious incident can be a huge stress for a doctor, whether a trainee or consultant. When affected, it is important to be able to look for the support of a colleague or a more senior person, and just as importantly, those not directly involved need to know what to do to provide support. In this piece I consider what 'support' really means, I provide some tips on what to do and what not to do, and I consider how incidents and complaints can need different approaches. PMID- 29510986 TI - An end to bullying: five minutes with Alice Hartley. PMID- 29510984 TI - Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic alpha-helix. AB - Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding. PMID- 29510985 TI - Molecular architecture of LSM14 interactions involved in the assembly of mRNA silencing complexes. AB - The LSM domain-containing protein LSM14/Rap55 plays a role in mRNA decapping, translational repression, and RNA granule (P-body) assembly. How LSM14 interacts with the mRNA silencing machinery, including the eIF4E-binding protein 4E-T and the DEAD-box helicase DDX6, is poorly understood. Here we report the crystal structure of the LSM domain of LSM14 bound to a highly conserved C-terminal fragment of 4E-T. The 4E-T C-terminus forms a bi-partite motif that wraps around the N-terminal LSM domain of LSM14. We also determined the crystal structure of LSM14 bound to the C-terminal RecA-like domain of DDX6. LSM14 binds DDX6 via a unique non-contiguous motif with distinct directionality as compared to other DDX6-interacting proteins. Together with mutational and proteomic studies, the LSM14-DDX6 structure reveals that LSM14 has adopted a divergent mode of binding DDX6 in order to support the formation of mRNA silencing complexes and P-body assembly. PMID- 29510989 TI - Kite, Sangamo Partner on Gene-Edited Cell Therapies. AB - Kite and Sangamo signed a deal worth potentially more than $3 billion to jointly develop cellular immunotherapies using zinc finger nuclease gene-editing technologies. PMID- 29510990 TI - David Oliver: A manifesto for multimorbidity. PMID- 29510991 TI - Reduced fetal movements. PMID- 29510988 TI - Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma. AB - High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module-centered around a TEAD4-MYCN positive feedback loop-emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4-MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582-99. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517. PMID- 29510987 TI - Genetic Mechanisms of Immune Evasion in Colorectal Cancer. AB - To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy neutral loss of heterozygosity. WNT/beta-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/beta catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 663. PMID- 29510993 TI - Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo. AB - Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.Significance: Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. Cancer Res; 78(10); 2513-23. (c)2018 AACR. PMID- 29510992 TI - Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program. AB - CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two thirds of ErbB2+ and triple-negative breast cancers (TNBC) and in one third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and TNBC cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or downregulated by CHIP. We characterized myeloid zinc finger 1 (MZF1) as a CHIP target, given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L) mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression.Significance: These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1. Cancer Res; 78(10); 2524-35. (c)2018 AACR. PMID- 29510994 TI - Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells. AB - Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil-based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer.Significance: Claudin-2-mediated regulation of YAP activity and miR-222-3p expression drives CSC renewal in colorectal cancer, making it a potential target for therapy. Cancer Res; 78(11); 2925-38. (c)2018 AACR. PMID- 29510995 TI - Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche. AB - Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here, we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin beta1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/beta-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN-binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.Significance: These findings reveal a new mechanism by which ovarian CSCs interact with the tumor microenvironment, promoting cell proliferation and tumor initiation. Cancer Res; 78(11); 2990-3001. (c)2018 AACR. PMID- 29510996 TI - To trust or not to trust (in doctors)? That is the question. PMID- 29510997 TI - Endocarditis in children and adolescents with congenital heart defects: a Norwegian nationwide register-based cohort study. AB - OBJECTIVES: Congenital heart defects (CHD) are the most common birth defects worldwide and are an important cause of morbidity and early death. A significant number of deaths occur among patients with infections. CHDs predispose to the development of infective endocarditis (IE) and represent a risk factor for increased mortality due to IE. The aim of this study was to investigate the occurrence and outcomes of IE in children and adolescents with CHDs. METHODS: Data on all children with CHD and IE born in Norway between 1994 and 2016 were retrieved from the Oslo University Hospital's Clinical Registry for Congenital Heart Defects. Survivors were followed through 2016, and supplementary information was retrieved from medical records. RESULTS: In this nationwide register-based cohort study, which included all 1 357 543 live births in Norway between 1994 and 2016, the incidence of IE according to the European Society of Cardiology diagnostic criteria was 2.2 per 10 000 person-years among children and adolescents with CHDs. The incidence was stable throughout the period. Most patients with IE had severe CHDs (75%) and had undergone open chest cardiac surgery or catheter-based cardiac interventions the last year before IE. IE related mortality among children with CHDs and IE was 8% during the follow-up period (mean 12.4 years (+/-5.5 years)). CONCLUSIONS: The incidence of IE among children and adolescents with CHDs was higher than the reported incidence in the general population. IE was associated with severe CHDs and recent complex cardiac interventions, and had significant mortality. PMID- 29510999 TI - Abusive head trauma and the triad: a critique on behalf of RCPCH of 'Traumatic shaking: the role of the triad in medical investigations of suspected traumatic shaking'. AB - The Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) has recently published what they purported to be a systematic review of the literature on 'isolated traumatic shaking' in infants, concluding that 'there is limited evidence that the so-called triad (encephalopathy, subdural haemorrhage, retinal haemorrhage) and therefore its components can be associated with traumatic shaking'. This flawed report, from a national body, demands a robust response. The conclusions of the original report have the potential to undermine medico-legal practice. We have conducted a critique of the methodology used in the SBU review and have found it to be flawed, to the extent that children's lives may be put at risk. Thus, we call on this review to be withdrawn or to be subjected to international scrutiny. PMID- 29510998 TI - Hypothermia for perinatal asphyxia: trial-based quality of life at 6-7 years. AB - OBJECTIVE: To assess the impact of hypothermic neural rescue at birth on health related quality of life (HRQL) in middle childhood. DESIGN: Six-year to 7-year follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) Trial. SETTING: Community study including a single parental questionnaire to collect information on children's HRQL. PATIENTS: 145 children (70 in the control group, 75 in the hypothermia group) whose parents consented and returned the questionnaire. INTERVENTIONS: Intensive care with cooling of the body to 33.5 degrees C for 72 hours or intensive care alone. MAIN OUTCOME MEASURES: HRQL attributes and utility scores using the Health Utilities Index (HUI). RESULTS: At 6-7 years, speech appeared disproportionately affected when compared with other aspects of HRQL but levels of normal emotional functioning were similar in both groups. The mean (SE) HUI3 HRQL scores were 0.73 (0.05) in the hypothermia group and 0.62 (0.06) in the control group; mean difference (95% CI) 0.11 (-0.04 to 0.26). CONCLUSIONS: Findings of non-significant differences were not unexpected; the study used data from long-term survivors in a neonatal trial and was underpowered. However, results favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. The work provides further insight into the long-term HRQL impact of perinatal asphyxial encephalopathy and provides previously unavailable utility data with which to contemplate the longer term cost-effectiveness of hypothermic neural rescue. TRIAL REGISTRATION NUMBER: This study reports on the follow-up of the TOBY clinical trial: ClinicalTrials.gov number NCT01092637. PMID- 29511000 TI - Temporal Trends and Clinical Consequences of Wait-Times for Trans-Catheter Aortic Valve Replacement: A Population Based Study. AB - Background -Trans-catheter aortic valve replacement (TAVR) represents a paradigm shift in the therapeutic options for patients with severe aortic stenosis. However, rapid and exponential growth in TAVR demand may overwhelm capacity, translating to inadequate access and prolonged wait-times. Our objective was to evaluate temporal trends in TAVR wait-times and the associated clinical consequences. Methods -In this population-based study in Ontario, Canada, we identified all TAVR referrals from April 1st, 2010 to March 31st, 2016. The primary outcome was the median total wait-time from referral to procedure. Piecewise regression analyses were performed to assess temporal trends in TAVR wait-times, before and after provincial reimbursement in September 2012. Clinical outcomes included all-cause death and heart failure hospitalizations while on the wait-list. Results -The study cohort included 4,461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons and 11% remained on the wait list at the conclusion of the study. For patients who underwent a TAVR, the estimated median wait-time in the post-reimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability of wait-list mortality and heart failure hospitalization at 80 days was approximately 2% and 12% respectively, with a relatively constant increase in events with increased wait times. Conclusions -Post-reimbursement wait-time has remained unchanged for patients undergoing a TAVR procedure, suggesting the increase in capacity has kept pace with the increase in demand. The current wait-time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access. PMID- 29511002 TI - Pamela Hardy: the pre-hospital specialist. PMID- 29511001 TI - Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults. AB - BACKGROUND: Previous studies have demonstrated that earlier epinephrine administration is associated with improved survival from out-of-hospital cardiac arrest (OHCA) with shockable initial rhythms. However, the effect of epinephrine timing on patients with nonshockable initial rhythms is unclear. The objective of this study was to measure the association between time to epinephrine administration and survival in adults and children with emergency medical services (EMS)-treated OHCA with nonshockable initial rhythms. METHODS: We performed a secondary analysis of OHCAs prospectively identified by the Resuscitation Outcomes Consortium network from June 4, 2011, to June 30, 2015. We included patients of all ages with an EMS-treated OHCA and an initial nonshockable rhythm. We excluded those with return of spontaneous circulation in <10 minutes. We conducted a subgroup analysis involving patients <18 years of age. The primary exposure was time (minutes) from arrival of the first EMS agency to the first dose of epinephrine. Secondary exposure was time to epinephrine dichotomized as early (<10 minutes) or late (>=10 minutes). The primary outcome was survival to hospital discharge. We adjusted for Utstein covariates and Resuscitation Outcomes Consortium study site. RESULTS: From 55 568 EMS-treated OHCAs, 32 101 patients with initial nonshockable rhythms were included. There were 12 238 in the early group, 14 517 in the late group, and 5346 not treated with epinephrine. After adjusting for potential confounders, each minute from EMS arrival to epinephrine administration was associated with a 4% decrease in odds of survival for adults, odds ratio=0.96 (95% confidence interval, 0.95-0.98). A subgroup analysis (n=13 290) examining neurological outcomes showed a similar association (adjusted odds ratio, 0.94 per minute; 95% confidence interval, 0.89 0.98). When epinephrine was given late in comparison with early, odds of survival were 18% lower (odds ratio, 0.82; 95% confidence interval, 0.68-0.98). In a pediatric analysis (n=595), odds of survival were 9% lower (odds ratio, 0.91; 95% confidence interval, 0.81-1.01) for each minute delay in epinephrine. CONCLUSIONS: Among OHCAs with nonshockable initial rhythms, the majority of patients were administered epinephrine >10 minutes after EMS arrival. Each minute delay in epinephrine administration was associated with decreased survival and unfavorable neurological outcomes. EMS agencies should consider strategies to reduce epinephrine administration times in patients with initial nonshockable rhythms. PMID- 29511003 TI - Staff stress levels reflect rising pressure on NHS, says NHS leaders. PMID- 29511004 TI - Population-based analysis of patients with COPD in Catalonia: a cohort study with implications for clinical management. AB - BACKGROUND: Clinical management of patients with chronic obstructive pulmonary disease (COPD) shows potential for improvement provided that patients' heterogeneities are better understood. The study addresses the impact of comorbidities and its role in health risk assessment. OBJECTIVE: To explore the potential of health registry information to enhance clinical risk assessment and stratification. DESIGN: Fixed cohort study including all registered patients with COPD in Catalonia (Spain) (7.5 million citizens) at 31 December 2014 with 1-year (2015) follow-up. METHODS: A total of 264 830 patients with COPD diagnosis, based on the International Classification of Diseases (Ninth Revision) coding, were assessed. Performance of multiple logistic regression models for the six main dependent variables of the study: mortality, hospitalisations (patients with one or more admissions; all cases and COPD-related), multiple hospitalisations (patients with at least two admissions; all causes and COPD-related) and users with high healthcare costs. Neither clinical nor forced spirometry data were available. RESULTS: Multimorbidity, assessed with the adjusted morbidity grouper, was the covariate with the highest impact in the predictive models, which in turn showed high performance measured by the C-statistics: (1) mortality (0.83), (2 and 3) hospitalisations (all causes: 0.77; COPD-related: 0.81), (4 and 5) multiple hospitalisations (all causes: 0.80; COPD-related: 0.87) and (6) users with high healthcare costs (0.76). Fifteen per cent of individuals with highest healthcare costs to year ratio represented 59% of the overall costs of patients with COPD. CONCLUSIONS: The results stress the impact of assessing multimorbidity with the adjusted morbidity grouper on considered health indicators, which has implications for enhanced COPD staging and clinical management. TRIAL REGISTRATION NUMBER: NCT02956395. PMID- 29511005 TI - Effectiveness of implementation interventions in improving physician adherence to guideline recommendations in heart failure: a systematic review. AB - BACKGROUND: The uptake of guideline recommendations that improve heart failure (HF) outcomes remains suboptimal. We reviewed implementation interventions that improve physician adherence to these recommendations, and identified contextual factors associated with implementation success. METHODS: We searched databases from January 1990 to November 2017 for studies testing interventions to improve uptake of class I HF guidelines. We used the Cochrane Effective Practice and Organisation of Care and Process Redesign frameworks for data extraction. Primary outcomes included: proportion of eligible patients offered guideline-recommended pharmacotherapy, self-care education, left ventricular function assessment and/or intracardiac devices. We reported clinical outcomes when available. RESULTS: We included 38 studies. Provider-level interventions (n=13 studies) included audit and feedback, reminders and education. Organisation-level interventions (n=18) included medical records system changes, multidisciplinary teams, clinical pathways and continuity of care. System-level interventions (n=3) included provider/institutional incentives. Four studies assessed multi-level interventions. We could not perform meta-analyses due to statistical/conceptual heterogeneity. Thirty-two studies reported significant improvements in at least one primary outcome. Clinical pathways, multidisciplinary teams and multifaceted interventions were most consistently successful in increasing physician uptake of guidelines. Among randomised controlled trials (RCT) (n=10), pharmacist and nurse led interventions improved target dose prescriptions. Eleven studies reported clinical outcomes; significant improvements were reported in three, including a clinical pathway, a multidisciplinary team and a multifaceted intervention. Baseline assessment of barriers, staff training, iterative intervention development, leadership commitment and policy/financial incentives were associated with intervention effectiveness. Most studies (n=20) had medium risk of bias; nine RCTs had low risk of bias. CONCLUSION: Our study is limited by the quality and heterogeneity of the primary studies. Clinical pathways, multidisciplinary teams and multifaceted interventions appear to be most consistent in increasing guideline uptake. However, improvements in process outcomes were rarely accompanied by improvements in clinical outcomes. Our work highlights the need for improved research methodology to reliably assess the effectiveness of implementation interventions. PMID- 29511006 TI - Effects of five types of selenium supplementation for treatment of Kashin-Beck disease in children: a systematic review and network meta-analysis. AB - OBJECTIVE: To compare the effectiveness of five kinds of selenium supplementation for the treatment of patients with Kashin-Beck disease, and rank these selenium supplementations based on their performance. DESIGN: We searched for all publications between 1 January 1966 and 31 March 2017 using seven electronic databases. GRADE system to network meta-analyses (NMAs) was applied to rate the quality of the evidence. We conducted a random effects model NMA in STATA 12.1 to determine comparative effectiveness of each intervention. Rankings were obtained by using the surface under the cumulative ranking curve (SUCRA) values and mean ranks. RESULTS: A total of 15 randomised controlled trials involving 2931 patients were included. After assessment of the overall quality of the evidence, we downgraded our primary outcomes from high to low or very low quality. NMAs showed that all five kinds of selenium supplementation had higher metaphysis X ray improvement which were superior to placebo. Ranking on efficacy indicated that selenium salt was ranked the highest, followed by sodium selenite + vitamin E, selenium enriched yeast, sodium selenite and then sodium selenite + vitamin C. CONCLUSIONS: Based on the results of NMA, all five types of selenium supplements are more effective than placebo and so that selenium supplementation is of help in repairing metaphyseal lesions. Since the overall quality of the evidence was low or very low, the SUCRA values may be misleading and should be considered jointly with the The Grading of Recommendations Assessment, Development and Evaluation (GRADE) confidence in the estimates for each comparison. The quality of the evidence is insufficient to draw a conclusion about what method of selenium supplementation is most effective. PROSPERO REGISTRATION NUMBER: CRD42016051874. PMID- 29511008 TI - Relationship between stress-related psychosocial work factors and suboptimal health among Chinese medical staff: a cross-sectional study. AB - OBJECTIVES: The study aimed to develop and validate a model to measure psychosocial factors at work among medical staff in China based on confirmatory factor analysis (CFA). The second aim of the current study was to clarify the association between stress-related psychosocial work factors and suboptimal health status. DESIGN: The cross-sectional study was conducted using clustered sampling method. SETTING: Xuanwu Hospital, a 3A grade hospital in Beijing. PARTICIPANTS: Nine hundred and fourteen medical staff aged over 40 years were sampled. Seven hundred and ninety-seven valid questionnaires were collected and used for further analyses. The sample included 94% of the Han population. MAIN OUTCOME MEASURES: The Copenhagen Psychosocial Questionnaire (COPSOQ) and the Suboptimal Health Status Questionnaires-25 were used to assess the psychosocial factors at work and suboptimal health status, respectively. CFA was conducted to establish the evaluating method of COPSOQ. A multivariate logistic regression model was used to estimate the relationship between suboptimal health status and stress-related psychosocial work factors among Chinese medical staff. RESULTS: There was a strong correlation among the five dimensions of COPSOQ based on the first-order factor model. Then, we established two second-order factors including negative and positive psychosocial work stress factors to evaluate psychosocial factors at work, and the second-order factor model fit well. The high score in negative (OR (95% CI)=1.47 (1.34 to 1.62), P<0.001) and positive (OR (95% CI)=0.96 (0.94 to 0.98), P<0.001) psychosocial work factors increased and decreased the risk of suboptimal health, respectively. This relationship remained statistically significant after adjusting for confounders and when using different cut-offs of suboptimal health status. CONCLUSIONS: Among medical staff, the second-order factor model was a suitable method to evaluate the COPSOQ. The negative and positive psychosocial work stress factors might be the risk and protective factors of suboptimal health, respectively. Moreover, negative psychosocial work stress was the most associated factor to predict suboptimal health. PMID- 29511007 TI - A skin cancer prevention photoageing intervention for secondary schools in Brazil delivered by medical students: protocol for a randomised controlled trial. AB - INTRODUCTION: The incidence of melanoma is increasing faster than any other major cancer both in Brazil and worldwide. The Southeast of Brazil has especially high incidences of melanoma, and early detection is low. Exposure to UV radiation represents a primary risk factor for developing melanoma. Increasing attractiveness is a major motivation for adolescents for tanning. A medical student-delivered intervention that harnesses the broad availability of mobile phones as well as adolescents' interest in their appearance may represent a novel method to improve skin cancer prevention. METHODS AND ANALYSIS: We developed a free mobile app (Sunface), which will be implemented in at least 30 secondary school classes, each with 21 students (at least 30 classes with 21 students for control) in February 2018 in Southeast Brazil via a novel method called mirroring. In a 45 min classroom seminar, the students' altered three-dimensional selfies on tablets are 'mirrored' via a projector in front of their entire class, showing the effects of unprotected UV exposure on their future faces. External block randomisation via computer is performed on the class level with a 1:1 allocation. Sociodemographic data, as well as skin type, ancestry, UV protection behaviour and its predictors are measured via a paper-pencil questionnaire before as well as at 3 and 6 months postintervention. The primary end point is the group difference in the 30-day prevalence of daily sunscreen use at a 6-month follow up. Secondary end points include (1) the difference in daily sunscreen use at a 3 month follow-up, (2) if a self-skin examination in accordance with the ABCDE rule was performed within the 6-month follow-up and (3) the number of tanning sessions. ETHICS AND DISSEMINATION: Ethical approval was obtained from the ethics committee of the University of Itauna. Results will be disseminated at conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03178240; Pre-results. PMID- 29511010 TI - What is the value of fibre-endoscopic evaluation of swallowing (FEES) in neurological patients? A cross-sectional hospital-based registry study. AB - OBJECTIVES: Fibre-endoscopic evaluation of swallowing (FEES) to detect dysphagia is gaining more and more importance as a diagnostic tool. Therefore, we have investigated the impact of FEES in neurological patients in a clinical setting. DESIGN: Cross-sectional hospital-based registry. SETTING: Primary acute care in a neurological department of a German university hospital. PARTICIPANTS: 241patients with various neurological diseases who underwent FEES procedure. PRIMARY AND SECONDARY OUTCOME MEASURES: Dysphagia and related comorbidities. RESULTS: 267 FEES were performed in 241 patients with various neurological diagnoses. Dysphagia was diagnosed in 68.9% of the patients. In only 33.1% of the patients, appropriate oral diet was chosen prior to FEES. A relevant dysphagia occurred more often in patients with structural brain lesions (83.1% vs 65.3%, P=0.001), patients with dysphagia had a longer hospitalisation (median 18 (IQR 12 30) vs 15 days (IQR 9.75-22.75), P=0.005) and had a higher mortality (8.4% vs 1.3%, P=0.041). When the oral diet was changed, we observed a lower pneumonia rate (36% vs 50%, P=0.051) and a lower mortality (3.7% vs 11.3%, P=0.043) in comparison to no change of oral diet. A restriction of oral diet was identified more often in older patients (median 75 years (IQR 66.3-82 years) vs median 72 years (IQR 60-79 years), P=0.01) and in patients with structural brain lesions (86.8% vs 73.1%, P=0.05). CONCLUSION: On clinical investigation, dysphagia was misjudged for the majority of the patients. FEES might help to compensate this drawback, revising the diet regime in nearly 70% of the patients. PMID- 29511011 TI - The influence of hazardous drinking on psychological functioning, stress and sleep during and after treatment in patients with mental health problems: a secondary analysis of a randomised controlled intervention study. AB - OBJECTIVES: Hazardous drinking could negatively affect health and lead to alcohol use disorders, but it is unclear how hazardous drinking affects treatment outcomes of depression and anxiety and stress-related mental health problems. The aim of this study was to examine whether hazardous drinking, measured by Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), influences the outcomes of repeated assessments of psychological functioning (Outcome Questionnaire-45), stress (Perceived Stress Scale) and sleep (Karolinska Sleep Questionnaire), during and after treatment in patients with mental ill health. METHODS: The study was conducted within REGASSA, a randomised controlled trial aimed at comparing Internet-based cognitive-behaviour therapy and physical exercise with treatment as usual on primary care patients with mental ill health. The study involved 871 participants who completed the AUDIT at baseline and who were assessed repeatedly during and after treatment on psychological functioning, stress and sleep by interactive voice response, a computerised, automated telephone technology. RESULTS: At baseline, hazardous drinkers were more depressed and had lower scores on psychological functioning than non-hazardous drinkers, while there were no differences on stress and sleep. During the follow-ups, hazardous drinking negatively influenced perceived stress, that is, hazardous drinkers seemed to have less treatment effect on stress, and the results remained after controlling for depression. There were no differences during the follow-ups regarding psychological functioning and sleep. CONCLUSIONS: Hazardous drinking negatively influenced perceived stress. The findings of the study emphasise the importance of screening for alcohol habits in mental ill-health patients, since risky drinking may affect the outcomes of treatment. TRIAL REGISTRATION NUMBER: DRKS00008745; Post-results. PMID- 29511009 TI - Factor structure and convergent validity of the Derriford Appearance Scale-24 using standard scoring versus treating 'not applicable' responses as missing data: a Scleroderma Patient-centered Intervention Network (SPIN) cohort study. AB - OBJECTIVE: Valid measures of appearance concern are needed in systemic sclerosis (SSc), a rare, disfiguring autoimmune disease. The Derriford Appearance Scale-24 (DAS-24) assesses appearance-related distress related to visible differences. There is uncertainty regarding its factor structure, possibly due to its scoring method. DESIGN: Cross-sectional survey. SETTING: Participants with SSc were recruited from 27 centres in Canada, the USA and the UK. Participants who self identified as having visible differences were recruited from community and clinical settings in the UK. PARTICIPANTS: Two samples were analysed (n=950 participants with SSc; n=1265 participants with visible differences). PRIMARY AND SECONDARY OUTCOME MEASURES: The DAS-24 factor structure was evaluated using two scoring methods. Convergent validity was evaluated with measures of social interaction anxiety, depression, fear of negative evaluation, social discomfort and dissatisfaction with appearance. RESULTS: When items marked by respondents as 'not applicable' were scored as 0, per standard DAS-24 scoring, a one-factor model fit poorly; when treated as missing data, the one-factor model fit well. Convergent validity analyses revealed strong correlations that were similar across scoring methods. CONCLUSIONS: Treating 'not applicable' responses as missing improved the measurement model, but did not substantively influence practical inferences that can be drawn from DAS-24 scores. Indications of item redundancy and poorly performing items suggest that the DAS-24 could be improved and potentially shortened. PMID- 29511012 TI - Systematic review and meta-analysis of global birth prevalence of clubfoot: a study protocol. AB - INTRODUCTION: Clubfoot is a common congenital birth defect, with an average prevalence of approximately 1 per 1000 live births, although this rate is reported to vary among different countries around the world. If it remains untreated, clubfoot causes permanent disability, limits educational and employment opportunities, and personal growth. The aim of this systematic review and meta-analysis is to estimate the global birth prevalence of congenital clubfoot. METHODS AND ANALYSIS: Electronic databases including MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Global Health, Latin American & Caribben Health Science Literature (LILACS), Maternity and Infant Care, Web of Science, Scopus and Google Scholar will be searched for observational studies based on predefined criteria and only in English language from inception of database in 1946 to 10 November 2017. A standard data extraction form will be used to extract relevant information from included studies. The Joanna Briggs Institute appraisal checklist will be used to assess the overall quality of studies reporting prevalence. All included studies will be assessed for risk of bias using a tool developed specifically for prevalence studies. Forest plots will be created to understand the overall random effects of pooled estimates with 95% CIs. An I2 test will be done for heterogeneity of the results (P>0.05), and to identify the source of heterogeneity across studies, subgroup or meta-regression will be used to assess the contribution of each variable to the overall heterogeneity. A funnel plot will be used to identify reporting bias, and sensitivity analysis will be used to assess the impact of methodological quality, study design, sample size and the impact of missing data. ETHICS AND DISSEMINATION: This review will be conducted completely based on published data, so approval from an ethics committee or written consent will not be required. The results will be disseminated through a peer-reviewed publication and relevant conference presentations. PROSPERO REGISTRATION NUMBER: CRD42016041922. PMID- 29511014 TI - Protocol for a single-centre prospective observational study of postoperative delirium following total joint arthroplasties among South East Asians. AB - INTRODUCTION: Postoperative delirium is a serious and common complication in older adults following total joint arthroplasties (TJA). It is associated with increased risk of postoperative complications, mortality, length of hospital stay and postdischarge institutionalisation. Thus, it has a negative impact on the health-related quality of life of the patient and poses a large economic burden. This study aims to characterise the incidence of postoperative delirium following TJA in the South East Asian population and investigate any risk factors or associated outcomes. METHODS AND ANALYSIS: This is a single-centre prospective observational study recruiting patients between 65 and 90 years old undergoing elective total knee arthroplasty or total hip arthroplasty. Exclusion criteria included patients with clinically diagnosed dementia. Preoperative and intraoperative data will be obtained prospectively. The primary outcome will be the presence of postoperative delirium assessed using the Confusion Assessment Method on postoperative days 1, 2 and 3 and day of discharge. Other secondary outcomes assessed postoperatively will include hospital outcomes, pain at rest, knee and hip function, health-related quality of life and Postoperative Morbidity Survey-defined morbidity. Data will be analysed to calculate the incidence of postoperative delirium. Potential risk factors and any associated outcomes of postoperative delirium will also be determined. ETHICS AND DISSEMINATION: This study has been approved by the Singapore General Hospital Institutional Review Board (SGH IRB) (CIRB Ref: 2017/2467) and is registered on the ClinicalTrials.gov registry (Identified: NCT03260218). An informed consent form will be signed by all participants before recruitment and translators will be made available to non English-speaking participants. The results of this study will be presented at international conferences and submitted to a peer-reviewed journal. The data collected will also be made available in a public data repository. TRIAL REGISTRATION NUMBER: NCT03260218. PMID- 29511015 TI - Prevalence of multimorbidity in general practice: a cross-sectional study within the Swiss Sentinel Surveillance System (Sentinella). AB - OBJECTIVES: To estimate the prevalence of multimorbidity using a list of 75 chronic conditions derived from the International Classification for Primary Care, Second edition and developed specifically to assess multimorbidity in primary care. Our aim was also to provide prevalence data for multimorbidity in primary care in a country in which general practitioners (GPs) do not play a gatekeeping role in the health system. SETTING: A representative sample of GPs within the Swiss Sentinel Surveillance Network. PARTICIPANTS: 118 GPs completed a paper-based questionnaire about 25 consecutive patients of all ages between September and November 2015. There were no patient exclusion criteria. Recorded data included date of birth, gender and the patients' chronic conditions. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated the prevalence of multimorbidity, defined as >=2, and >=3 chronic conditions stratified by gender and age group, and adjusted for clustering by GPs. We also computed the prevalence of each chronic condition individually and grouped by system. RESULTS: Data from 2904 patients were included (mean age (SD)=56.5 (20.5) years; male=43.7%). Prevalence was 52.1% (95% CI 48.6% to 55.5%) for >=2 and 35.0% (95% CI 31.6% to 38.5%) for >=3 chronic conditions, with no significant gender differences. Prevalence of two or more chronic conditions was low (6.2%, 95% CI 2.8% to 13.0%) in those below 20 but affected more than 85% (85.8%, 95% CI 79.6% to 90.3%) of those above the age of 80. The most prevalent conditions were cardiovascular (42.7%, 95% CI 39.7% to 45.7%), psychological (28.5%, 95% CI 26.1% to 31.1%) and metabolic or endocrine disorders (24.1%, 95% CI 21.6% to 26.7%). Elevated blood pressure was the most prevalent cardiovascular condition and depression the most common psychological disorder. CONCLUSION: In a country in which GPs do not play a gatekeeping role within the health system, the prevalence of multimorbidity, as assessed using a list of chronic conditions specifically relevant to primary care, is high and increases with age. PMID- 29511013 TI - Clustering of risk factors and the risk of incident cardiovascular disease in Asian and Caucasian populations: results from the Asia Pacific Cohort Studies Collaboration. AB - OBJECTIVE: To assess the relationship between risk factor clusters and cardiovascular disease (CVD) incidence in Asian and Caucasian populations and to estimate the burden of CVD attributable to each cluster. SETTING: Asia Pacific Cohort Studies Collaboration. PARTICIPANTS: Individual participant data from 34 population-based cohorts, involving 314 024 participants without a history of CVD at baseline. OUTCOME MEASURES: Clusters were 11 possible combinations of four individual risk factors (current smoking, overweight, blood pressure (BP) and total cholesterol). Cox regression models were used to obtain adjusted HRs and 95% CIs for CVD associated with individual risk factors and risk factor clusters. Population-attributable fractions (PAFs) were calculated. RESULTS: During a mean follow-up of 7 years, 6203 CVD events were recorded. The ranking of HRs and PAFs was similar for Australia and New Zealand (ANZ) and Asia; clusters including BP consistently showed the highest HRs and PAFs. The BP-smoking cluster had the highest HR for people with two risk factors: 4.13 (3.56 to 4.80) for Asia and 3.07 (2.23 to 4.23) for ANZ. Corresponding PAFs were 24% and 11%, respectively. For individuals with three risk factors, the BP-smoking-cholesterol cluster had the highest HR (4.67 (3.92 to 5.57) for Asia and 3.49 (2.69 to 4.53) for ANZ). Corresponding PAFs were 13% and 10%. CONCLUSIONS: Risk factor clusters act similarly on CVD risk in Asian and Caucasian populations. Clusters including elevated BP were associated with the highest excess risk of CVD. PMID- 29511016 TI - Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: a cross-sectional study. AB - OBJECTIVE: To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. RESULTS: A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. CONCLUSION: The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA. PMID- 29511017 TI - 'Just an extra pair of hands'? A qualitative study of obstetric service users' and professionals' views towards 24/7 consultant presence on a single UK tertiary maternity unit. AB - OBJECTIVES: To explore the views of maternity service users and professionals towards obstetric consultant presence 24 hours a day, 7 days a week. DESIGN: Semistructured interviews conducted face to face with maternity service users and professionals in March and April 2016. All responses were analysed together (ie, both service users' and professionals' responses) using an inductive thematic analysis. SETTING: A large tertiary maternity unit in the North West of England that has implemented 24/7 obstetric consultant presence. PARTICIPANTS: Antenatal and postnatal inpatient service users (n=10), midwives, obstetrics and gynaecology specialty trainees and consultant obstetricians (n=10). RESULTS: Five themes were developed: (1) 'Just an extra pair of hands?' (the consultant's role), (2) the context, (3) the team, (4) training and (5) change for the consultant. Respondents acknowledged that obstetrics is an acute specialty, and consultants resolve intrapartum complications. However, variability in consultant experience and behaviour altered perception of its impact. Service users were generally positive towards 24/7 consultant presence but were not aware that it was not standard practice across the UK. Professionals were more pragmatic and discussed how the implementation of 24/7 working had affected their work, development of trainees and potential impacts on future consultants. CONCLUSIONS: The findings raised several issues that should be considered by practitioners and policymakers when making decisions about the implementation of 24/7 consultant presence in other maternity units, including attributes of the consultants, the needs of maternity units, the team hierarchy, trainee development, consultants' other duties and consultant absences. PMID- 29511018 TI - Treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: rationale and design of a prospective, randomised and multicentre DEFINITION II trial. AB - INTRODUCTION: Provisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs. METHODS AND ANALYSIS: This DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis. ETHICS AND DISSEMINATION: The study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT02284750; Pre-results. PMID- 29511019 TI - Randomised trial of coconut oil, olive oil or butter on blood lipids and other cardiovascular risk factors in healthy men and women. AB - INTRODUCTION: High dietary saturated fat intake is associated with higher blood concentrations of low-density lipoprotein cholesterol (LDL-C), an established risk factor for coronary heart disease. However, there is increasing interest in whether various dietary oils or fats with different fatty acid profiles such as extra virgin coconut oil may have different metabolic effects but trials have reported inconsistent results. We aimed to compare changes in blood lipid profile, weight, fat distribution and metabolic markers after four weeks consumption of 50 g daily of one of three different dietary fats, extra virgin coconut oil, butter or extra virgin olive oil, in healthy men and women in the general population. DESIGN: Randomised clinical trial conducted over June and July 2017. SETTING: General community in Cambridgeshire, UK. PARTICIPANTS: Volunteer adults were recruited by the British Broadcasting Corporation through their websites. Eligibility criteria were men and women aged 50-75 years, with no known history of cancer, cardiovascular disease or diabetes, not on lipid lowering medication, no contraindications to a high-fat diet and willingness to be randomised to consume one of the three dietary fats for 4 weeks. Of 160 individuals initially expressing an interest and assessed for eligibility, 96 were randomised to one of three interventions; 2 individuals subsequently withdrew and 94 men and women attended a baseline assessment. Their mean age was 60 years, 67% were women and 98% were European Caucasian. Of these, 91 men and women attended a follow-up assessment 4 weeks later. INTERVENTION: Participants were randomised to extra virgin coconut oil, extra virgin olive oil or unsalted butter and asked to consume 50 g daily of one of these fats for 4 weeks, which they could incorporate into their usual diet or consume as a supplement. MAIN OUTCOMES AND MEASURES: The primary outcome was change in serum LDL-C; secondary outcomes were change in total and high-density lipoprotein cholesterol (TC and HDL-C), TC/HDL-C ratio and non-HDL-C; change in weight, body mass index (BMI), waist circumference, per cent body fat, systolic and diastolic blood pressure, fasting plasma glucose and C reactive protein. RESULTS: LDL-C concentrations were significantly increased on butter compared with coconut oil (+0.42, 95% CI 0.19 to 0.65 mmol/L, P<0.0001) and with olive oil (+0.38, 95% CI 0.16 to 0.60 mmol/L, P<0.0001), with no differences in change of LDL-C in coconut oil compared with olive oil (-0.04, 95% CI -0.27 to 0.19 mmol/L, P=0.74). Coconut oil significantly increased HDL-C compared with butter (+0.18, 95% CI 0.06 to 0.30 mmol/L) or olive oil (+0.16, 95% CI 0.03 to 0.28 mmol/L). Butter significantly increased TC/HDL-C ratio and non-HDL-C compared with coconut oil but coconut oil did not significantly differ from olive oil for TC/HDL-C and non-HDL-C. There were no significant differences in changes in weight, BMI, central adiposity, fasting blood glucose, systolic or diastolic blood pressure among any of the three intervention groups. CONCLUSIONS AND RELEVANCE: Two different dietary fats (butter and coconut oil) which are predominantly saturated fats, appear to have different effects on blood lipids compared with olive oil, a predominantly monounsaturated fat with coconut oil more comparable to olive oil with respect to LDL-C. The effects of different dietary fats on lipid profiles, metabolic markers and health outcomes may vary not just according to the general classification of their main component fatty acids as saturated or unsaturated but possibly according to different profiles in individual fatty acids, processing methods as well as the foods in which they are consumed or dietary patterns. These findings do not alter current dietary recommendations to reduce saturated fat intake in general but highlight the need for further elucidation of the more nuanced relationships between different dietary fats and health. TRIAL REGISTRATION NUMBER: NCT03105947; Results. PMID- 29511021 TI - Visual Impairment Screening Assessment (VISA) tool: pilot validation. AB - OBJECTIVE: To report and evaluate a new Vision Impairment Screening Assessment (VISA) tool intended for use by the stroke team to improve identification of visual impairment in stroke survivors. DESIGN: Prospective case cohort comparative study. SETTING: Stroke units at two secondary care hospitals and one tertiary centre. PARTICIPANTS: 116 stroke survivors were screened, 62 by naive and 54 by non-naive screeners. MAIN OUTCOME MEASURES: Both the VISA screening tool and the comprehensive specialist vision assessment measured case history, visual acuity, eye alignment, eye movements, visual field and visual inattention. RESULTS: Full completion of VISA tool and specialist vision assessment was achieved for 89 stroke survivors. Missing data for one or more sections typically related to patient's inability to complete the assessment. Sensitivity and specificity of the VISA screening tool were 90.24% and 85.29%, respectively; the positive and negative predictive values were 93.67% and 78.36%, respectively. Overall agreement was significant; k=0.736. Lowest agreement was found for screening of eye movement and visual inattention deficits. CONCLUSIONS: This early validation of the VISA screening tool shows promise in improving detection accuracy for clinicians involved in stroke care who are not specialists in vision problems and lack formal eye training, with potential to lead to more prompt referral with fewer false positives and negatives. Pilot validation indicates acceptability of the VISA tool for screening of visual impairment in stroke survivors. Sensitivity and specificity were high indicating the potential accuracy of the VISA tool for screening purposes. Results of this study have guided the revision of the VISA screening tool ahead of full clinical validation. PMID- 29511020 TI - Reducing distress and improving social functioning in daily life in people with auditory verbal hallucinations: study protocol for the 'Temstem' randomised controlled trial. AB - INTRODUCTION: Auditory verbal hallucinations (AVH) are prevalent experiences that can induce distress and impede social functioning. While most voice hearers benefit from antipsychotic medication or cognitive-behavioural therapy, additional effective interventions are needed to reduce the burden of experiencing AVH. 'Temstem' is an easily accessible and useable smartphone application that was developed by designers in close cooperation with voice hearers and experts. By using language games, Temstem aims to reduce distress and improve social functioning. METHODS: This is a single-blind multicentre randomised controlled trial with two arms: 'Temstem+AVH monitoring' versus 'AVH monitoring' (total n=100). Participants are adult patients who suffer daily from AVH and will be recruited in outpatient units. Primary assessment in daily life is made by the Experience Sampling Method (ESM) and daily monitoring with the PsyMate app. During an ESM period of 6 days, participants assess their mental state (including AVH and context) several times a day by filling in short questionnaires. There are three 6-day ESM periods: at baseline (week 0-1), post treatment (weeks 5-6) and follow-up (weeks 9-10). In addition, during the entire 10-week study period, all participants monitor their AVH two times a day with a short assessment via the PsyMate app. Participants in the Temstem+AVH monitoring condition are provided with the Temstem app from week 1 to 6. Other assessments made at baseline, post-treatment and follow-up are based on questionnaires and a clinical interview. ETHICS AND DISSEMINATION: The results from this study will provide an evaluation of the effectiveness of Temstem, a non-invasive and easily accessible app for voice hearers, and insight into the determinants of optimal use. Results will be disseminated unreservedly, irrespective of the magnitude or direction of the effects. This study protocol was approved by the Medical Ethics Committee of the VU University Medical Centre (METC number: 2015.435/NL53684.029.15). TRIAL REGISTRATION NUMBER: ISRCTN75717636; Pre-results. PMID- 29511023 TI - Loss of Mob1a/b in mice results in chondrodysplasia due to YAP1/TAZ-TEAD dependent repression of SOX9. AB - Hippo signaling is modulated in response to cell density, external mechanical forces, and rigidity of the extracellular matrix (ECM). The Mps one binder kinase activator (MOB) adaptor proteins are core components of Hippo signaling and influence Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which are potent transcriptional regulators. YAP1/TAZ are key contributors to cartilage and bone development but the molecular mechanisms by which the Hippo pathway controls chondrogenesis are largely unknown. Cartilage is rich in ECM and also subject to strong external forces - two upstream factors regulating Hippo signaling. Chondrogenesis and endochondral ossification are tightly controlled by growth factors, morphogens, hormones, and transcriptional factors that engage in crosstalk with Hippo-YAP1/TAZ signaling. Here, we generated tamoxifen-inducible, chondrocyte-specific Mob1a/b-deficient mice and show that hyperactivation of endogenous YAP1/TAZ impairs chondrocyte proliferation and differentiation/maturation, leading to chondrodysplasia. These defects were linked to suppression of SOX9, a master regulator of chondrogenesis, the expression of which is mediated by TEAD transcription factors. Our data indicate that a MOB1-dependent YAP1/TAZ-TEAD complex functions as a transcriptional repressor of SOX9 and thereby negatively regulates chondrogenesis. PMID- 29511022 TI - L(3)mbt and the LINT complex safeguard cellular identity in the Drosophila ovary. AB - Maintenance of cellular identity is essential for tissue development and homeostasis. At the molecular level, cell identity is determined by the coordinated activation and repression of defined sets of genes. The tumor suppressor L(3)mbt has been shown to secure cellular identity in Drosophila larval brains by repressing germline-specific genes. Here, we interrogate the temporal and spatial requirements for L(3)mbt in the Drosophila ovary, and show that it safeguards the integrity of both somatic and germline tissues. l(3)mbt mutant ovaries exhibit multiple developmental defects, which we find to be largely caused by the inappropriate expression of a single gene, nanos, a key regulator of germline fate, in the somatic ovarian cells. In the female germline, we find that L(3)mbt represses testis-specific and neuronal genes. At the molecular level, we show that L(3)mbt function in the ovary is mediated through its co-factor Lint-1 but independently of the dREAM complex. Together, our work uncovers a more complex role for L(3)mbt than previously understood and demonstrates that L(3)mbt secures tissue identity by preventing the simultaneous expression of original identity markers and tissue-specific misexpression signatures. PMID- 29511024 TI - Genome-wide strategies identify downstream target genes of chick connective tissue-associated transcription factors. AB - Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc-finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling of chick limb micromass cultures revealed a set of common genes regulated by all five transcription factors, which we describe as a connective tissue core expression set. This common core was enriched with genes associated with axon guidance and myofibroblast signature, including fibrosis-related genes. In addition, each transcription factor regulated a specific set of signalling molecules and extracellular matrix components. This suggests a concept whereby local molecular niches can be created by the expression of specific transcription factors impinging on the specification of local microenvironments. The regulatory network established here identifies common and distinct molecular signatures of limb connective tissue subtypes, provides novel insight into the signalling pathways governing connective tissue specification, and serves as a resource for connective tissue development. PMID- 29511027 TI - Forward to the past: ultrasound might be necessary in some patients with rheumatoid arthritis. PMID- 29511025 TI - High-Resolution Analysis of the Efficiency, Heritability, and Editing Outcomes of CRISPR/Cas9-Induced Modifications of NCED4 in Lettuce (Lactuca sativa). AB - CRISPR/Cas9 is a transformative tool for making targeted genetic alterations. In plants, high mutation efficiencies have been reported in primary transformants. However, many of the mutations analyzed were somatic and therefore not heritable. To provide more insights into the efficiency of creating stable homozygous mutants using CRISPR/Cas9, we targeted LsNCED4 (9-cis-EPOXYCAROTENOID DIOXYGENASE4), a gene conditioning thermoinhibition of seed germination in lettuce. Three constructs, each capable of expressing Cas9 and a single gRNA targeting different sites in LsNCED4, were stably transformed into lettuce (Lactuca sativa) cvs. Salinas and Cobham Green. Analysis of 47 primary transformants (T1) and 368 T2 plants by deep amplicon sequencing revealed that 57% of T1 plants contained events at the target site: 28% of plants had germline mutations in one allele indicative of an early editing event (mono-allelic), 8% of plants had germline mutations in both alleles indicative of two early editing events (bi-allelic), and the remaining 21% of plants had multiple low frequency mutations indicative of late events (chimeric plants). Editing efficiency was similar in both genotypes, while the different gRNAs varied in efficiency. Amplicon sequencing of 20 T1 and more than 100 T2 plants for each of the three gRNAs showed that repair outcomes were not random, but reproducible and characteristic for each gRNA. Knockouts of NCED4 resulted in large increases in the maximum temperature for seed germination, with seeds of both cultivars capable of germinating >70% at 37 degrees . Knockouts of NCED4 provide a whole plant selectable phenotype that has minimal pleiotropic consequences. Targeting NCED4 in a co-editing strategy could therefore be used to enrich for germline edited events simply by germinating seeds at high temperature. PMID- 29511026 TI - Reduced Nonexercise Activity Attenuates Negative Energy Balance in Mice Engaged in Voluntary Exercise. AB - Exercise alone is often ineffective for treating obesity despite the associated increase in metabolic requirements. Decreased nonexercise physical activity has been implicated in this resistance to weight loss, but the mechanisms responsible are unclear. We quantified the metabolic cost of nonexercise activity, or "off wheel" activity (OWA), and voluntary wheel running (VWR) and examined whether changes in OWA during VWR altered energy balance in chow-fed C57BL/6J mice (n = 12). Energy expenditure (EE), energy intake, and behavior (VWR and OWA) were continuously monitored for 4 days with locked running wheels followed by 9 days with unlocked running wheels. Unlocking the running wheels increased EE as a function of VWR distance. The metabolic cost of exercise (kcal/m traveled) decreased with increasing VWR speed. Unlocking the wheel led to a negative energy balance but also decreased OWA, which was predicted to mitigate the expected change in energy balance by ~45%. A novel behavioral circuit involved repeated bouts of VWR, and roaming was discovered and represented novel predictors of VWR behavior. The integrated analysis described here reveals that the weight loss effects of voluntary exercise can be countered by a reduction in nonexercise activity. PMID- 29511028 TI - 'Deep Koebner' phenomenon of the flexor tendon-associated accessory pulleys as a novel factor in tenosynovitis and dactylitis in psoriatic arthritis. AB - OBJECTIVES: Skin and joint involvement in psoriasis (PsO) and psoriatic arthritis (PsA) are thought to relate to the so-called Koebner response. Given that dactylitis is non-randomly distributed in the digits, this study tested the hypothesis that the accessory pulleys linked to the flexor tendons were thickened in PsA and thus exhibited koebnerisation. METHODS: Ninety-six subjects (27 PsA, 27 rheumatoid arthritis (RA), 23 PsO and 19 healthy controls (HCs)) were enrolled. The A1, A2 and A4 pulley thickness was measured using a high-resolution probe (22 MHz). All patients were in remission or low disease activity with current dactylitis being excluded. RESULTS: Within 864 pulleys investigated, patients with PsA had thicker pulleys in every digit compared with both RA (P<0.001 and P=0.003) and HCs (P<0.001). RA and PsO groups had some pulleys in some digits thicker than HCs whereas some others were comparable. The second digit A1 pulley thickness was higher in patients with PsA with previous dactylitis (P=0.020). More pulleys were thickened in the PsA group (165/243, 68%) than RA (41/243, 17%; P<0.001) and HCs (13/171, 7.6%; P<0.001). CONCLUSIONS: In established PsA, the accessory pulleys are thickened compared with RA, PsO or HCs and especially in subjects with a history of dactylitis. These findings implicate the involvement of pulleys in PsA-related tenosynovitis and dactylitis supporting the idea of deep koebnerisation in dactylitis and sites of high physical stress. PMID- 29511029 TI - Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma. AB - Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives.Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in nondividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neurotoxicity evaluation of NG34 was tested by intracerebral inoculation.Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose-response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared with rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model.Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM. Clin Cancer Res; 24(11); 2574-84. (c)2018 AACR. PMID- 29511030 TI - Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma. AB - Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1-FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1-FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib.Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells.Results: Truncated FOSB significantly affected tumor growth in three dimensional (3D) on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (four fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1, and FLT4 signaling and downregulated SERPINE1, thereby affecting the self-regulation of the fusion gene.Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor could be a highly specific treatment option for patients with multifocal unresectable PHE. Clin Cancer Res; 24(11); 2678-87. (c)2018 AACR. PMID- 29511031 TI - Effect of Perioperative Opioids on Cancer-Relevant Circulating Parameters: Mu Opioid Receptor and Toll-Like Receptor 4 Activation Potential, and Proteolytic Profile. AB - Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of MU-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential.Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively.Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential.Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319-27. (c)2018 AACR. PMID- 29511032 TI - AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression. AB - AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models. Tumor control and survival benefit were associated with enhanced antitumor immunity. VIC-008 augmented mesothelin specific CD8+ T-cell responses in the spleen and lymph nodes and facilitated intratumoral lymphocytic infiltration. However, VIC-008 treatment was associated with increased programmed cell death protein-1 (PD-1) expression on intratumoral CD8+ T cells, likely due to high CXCL12 in the tumor microenvironment. AMD3100 alone and in combination with VIC-008 modulated immunosuppression in tumors and the immune system through suppression of PD-1 expression on CD8+ T cells and conversion of regulatory T cells (Tregs) into CD4+CD25-Foxp3+IL2+CD40L+ helper like cells. In mechanistic studies, we demonstrated that AMD3100-driven Treg reprogramming required T cell receptor (TCR) activation and was associated with loss of PTEN due to oxidative inactivation. The combination of VIC-008 augmentation of tumor-specific CD8+ T-cell responses with AMD3100 abrogation of immunosuppression conferred significant benefits for tumor control and animal survival. These data provide new mechanistic insight into AMD3100-mediated immunomodulation and highlight the enhanced antitumor effect of AMD3100 in combination with a tumor antigen-targeted therapy in mouse malignant mesothelioma, which could be clinically relevant to patients with this difficult to-treat disease. Cancer Immunol Res; 6(5); 539-51. (c)2018 AACR. PMID- 29511033 TI - Drug Distribution into Peripheral Nerve. AB - Little is known about the impact of the blood-nerve barrier (BNB) on drug distribution into peripheral nerves. In this study, we examined the peripheral nerve penetration in rats of 11 small-molecule drugs possessing diverse physicochemical and transport properties and ProTx-II, a tarantula venom peptide with molecular mass of 3826 Daltons. Each drug was administered as constant rate intravenous infusion for 6 hours (small molecules) or 24 hours (ProTx-II). Blood and tissues including brain, spinal cord, sciatic nerve, and dorsal root ganglion (DRG) were collected for drug concentration measurements. Unbound fractions of a set of compounds were determined by equilibrium dialysis method in rat blood, brains, spinal cords, sciatic nerves, and DRG. We also investigated the influence of N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy 9-oxo-10H-acridine-4-carboxamide (GF120918), a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor, on the peripheral nerve and central nervous system (CNS) tissue penetration of imatinib. We found that: 1) the unbound fraction in brain tissue homogenate highly correlates with that in the spinal cord, sciatic nerve, and DRG for a set of compounds and thus provides a good surrogate for spinal cord and peripheral nerve tissues, 2) small-molecule drugs investigated can penetrate the DRG and sciatic nerve, 3) P-gp and BCRP have a limited impact on the distribution of small-molecule drugs into peripheral nerves, and 4) DRG is permeable to ProTx-II, but its distribution into sciatic nerve and CNS tissues is restricted. These results demonstrate that small molecule drugs investigated can penetrate peripheral nerve tissues, and P-gp/BCRP may not be a limiting factor at the BNB. Biologics as large as ProTx-II can access the DRG but not sciatic nerve and CNS tissues. PMID- 29511034 TI - Measurement equivalence: a glossary for comparative population health research. AB - Comparative population health studies are becoming more common and are advancing solutions to crucial public health problems, but decades-old measurement equivalence issues remain without a common vocabulary to identify and address the biases that contribute to non-equivalence. This glossary defines sources of measurement non-equivalence. While drawing examples from both within-country and between-country studies, this glossary also defines methods of harmonisation and elucidates the unique opportunities in addition to the unique challenges of particular harmonisation methods. Its primary objective is to enable population health researchers to more clearly articulate their measurement assumptions and the implications of their findings for policy. It is also intended to provide scholars and policymakers across multiple areas of inquiry with tools to evaluate comparative research and thus contribute to urgent debates on how to ameliorate growing health disparities within and between countries. PMID- 29511035 TI - The association of polymorphisms in lncRNA-H19 with hepatocellular cancer risk and prognosis. AB - Hepatocellular cancer (HCC) is one of the major causes of cancer-related mortality. Genetic polymorphisms may affect the susceptibility and clinical outcomes of cancers. We aim to manifest the association of single nucleotide polymorphisms (SNPs) of lncRNA-H19 gene with the risk and prognosis of HCC. A total of 944 samples composed of 472 HCC patients and 472 matched controls were included in the risk analysis and amongst them 350 HCC samples were investigated in the prognosis analysis. KASP method was conducted for the SNP genotyping. The TT + CT genotype of rs2839698 was found to be associated with a 1.32-fold increased HCC risk (P=0.037, 95% confidence interval (CI) = 1.02-1.70). In the stratified analysis, rs2839698 (odds ratio (OR) = 1.57, P=0.007, 95% CI = 1.13 2.18) and rs3024270 (OR = 1.71, P=0.019, 95% CI = 1.09-2.68) were found to show more obvious increased HCC risk in the age <=60 subgroup. And we found that rs2839698 showed an increased HCC risk in the ever smoking subgroup. But in the male subgroup of rs2735971, it showed a decreased HCC risk. Furthermore, haplotype analysis showed that rs2735971-rs2839698-rs3024270 G-T-C significantly increased the risk of HCC (OR = 1.23, 95% CI = 1.01-1.51, P=0.043). Multilogistic analysis revealed no significant results of the interaction effects of the SNPs and environment factors. And in our study, rs2839698 showed a significant poor prognosis in the ever smoking subgroup (hazard rate (HR) = 5.19, 95% CI = 1.12 24.07, P=0.035). lncRNA-H19 rs2839698 SNP has the potential to be predictors for HCC risk and prognosis. PMID- 29511036 TI - A Modified Tie Technique for Securing Endotracheal Tubes. AB - BACKGROUND: Unintentional extubation is a well-documented and potentially life threatening phenomenon. There is little research into the factors that lead to unintentional extubation, and therefore how to prevent it. Endotracheal tubes (ETTs) are commonly secured with 1 cm twill tape, but there is little evidence on how to best tie them in place. We have devised a new knot for securing these tubes in place, and we have assessed its degree of slippage when exposed to both perpendicular and sliding forces in comparison with other commonly used knots. METHODS: We constructed a weighted apparatus to test the effects of these forces and measure whether conventional ETTs slipped. We tested the knots both wet and dry to better simulate the clinical environment. We also conducted a manual manipulation test in which a single operator attempted to slide the knot along the ETT. Each knot was tested 10 times for the weight test under both wet and dry conditions, and 8 times for the slip test. RESULTS: The normal knot slipped when weighted both wet and dry, while the clove hitch failed the weight test only when wet. Both the modified cow hitch and double hitch withstood all weights. Only the double hitch did not slip under any circumstances on either test. CONCLUSIONS: The new double hitch was superior to all conventional knots tested. It did not slip under any conditions and therefore may be of use to prevent unintentional extubation, particularly in the ICU setting. PMID- 29511037 TI - Analysis of a Pediatric Home Mechanical Ventilator Population. AB - BACKGROUND: The population of children requiring home mechanical ventilation has evolved over the years and has grown to include a variety of diagnoses and needs that have led to changes in the care of this unique population. The purpose of this study was to provide a descriptive analysis of pediatric patients requiring home mechanical ventilation after hospitalization and how the evolution of this technology has impacted their care. METHODS: A retrospective, observational, longitudinal analysis of 164 children enrolled in a university-affiliated home mechanical ventilation program over 26 years was performed. Data included each child's primary diagnosis, date of tracheostomy placement, duration of mechanical ventilation during hospitalization that consisted of home mechanical ventilator initiation, total length of pediatric ICU stay, ventilator settings at time of discharge from pediatric ICU, and disposition (home, facility, or died). Univariate, bivariate, and regression analysis was used as appropriate. RESULTS: The most common diagnosis requiring the use of home mechanical ventilation was neuromuscular disease (53%), followed by chronic pulmonary disease (29%). The median length of stay in the pediatric ICU decreased significantly after the implementation of a ventilator ward (70 d [30-142] vs 36 d [18-67], P = .02). The distribution of subjects upon discharge was home (71%), skilled nursing facility (24%), and died (4%), with an increase in the proportion of subjects discharged on PEEP and those going to nursing facilities over time (P = 0.02). CONCLUSIONS: The evolution of home mechanical ventilation has allowed earlier transition out of the pediatric ICU and with increasing disposition to skilled nursing facilities over time. There has also been a change in ventilator management, including increased use of PEEP upon discharge, possibly driven by changes in ventilators and in-patient practice patterns. PMID- 29511038 TI - Comparison of Biomarkers of Tobacco Exposure between Premium and Discount Brand Cigarette Smokers in the NHANES 2011-2012 Special Sample. AB - Background: Increased cigarette costs have inadvertently strengthened the appeal of discounted brands to price-sensitive smokers. Although smokers perceive discounted brands as having poorer quality, little is known about their delivery of toxic tobacco smoke constituents compared with premium-branded tobacco products.Methods: We investigated the differences between discount and premium brand smokers using the National Health and Nutrition Examination Survey 2011 2012 Special Smoker Sample. Our analyses focused on demographic differences and 27 biomarkers of harmful and potentially harmful constituents (HPHC) listed by the FDA, including volatile organic compounds, 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol and its glucuronide [4-(methylnitrosamino)-1-(3-pyridyl)-1 butanol glucuronide; reported as total NNAL (tNNAL)], metals, and polycyclic aromatic hydrocarbons (PAHs). Data were analyzed using linear regression models adjusting for potential confounders.Results: A total of 976 non-tobacco users and 578 recent cigarette smokers were eligible for analysis, of which 141 (26.0% weighted) smoked discount brand cigarettes and 437 (74.0% weighted) smoked premium. Discount brand smokers were older, predominantly non-Hispanic white, and had higher serum cotinine. Discount brand smokers had significantly higher levels of 13 smoking-related biomarkers, including tNNAL, uranium, styrene, xylene, and biomarkers of exposure to PAHs (naphthalene, fluorene, and phenanthrene), compared with premium brand smokers.Conclusions: These findings suggest that discount cigarette use is associated with higher exposure to several carcinogenic and toxic HPHCs.Impact: These results may have important regulatory implications for product standards, as higher exposures could lead to a greater degree of harm. Cancer Epidemiol Biomarkers Prev; 27(5); 601-9. (c)2018 AACR. PMID- 29511039 TI - Metformin Is Not Associated with Incidence Risk of Non-Hodgkin Lymphomas among Diabetic Patients. AB - Background: Several epidemiological studies have shown a positive association between diabetes and increased risk of non-Hodgkin lymphoma (NHL), but the effect of diabetic treatment drugs such as metformin on the risk is unknown.Methods: We conducted a population-based nested case-control study involving 878 NHL cases and 4,364 controls diagnosed with diabetes. Use of metformin and other medications before diagnosis and medical condition histories were assessed using administrative databases. We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for use of metformin, adjusting for confounders.Results: Risk of total NHLs is not associated with ever use of metformin (OR, 0.93; 95% CI, 0.79-1.10) among diabetic patients. NHL subtypes were also not associated with metformin use.Conclusions: Metformin use is not associated with overall or subtype NHL risk among diabetic patients.Impact: NHLs are etiologically heterogeneous and larger scale studies are warranted to test the potential effect of metformin by NHL subtype. Cancer Epidemiol Biomarkers Prev; 27(5); 610-2. (c)2018 AACR. PMID- 29511041 TI - From whom do physicians obtain consent for surgery? AB - OBJECTIVE: To evaluate the knowledge and performance of surgical residents regarding the person from whom informed consent should be taken for surgery and from whom the consent is taken in practice. MATERIALS AND METHODS: This study was done in 2013. The population of this study was all residents of urology, surgery, orthopaedic surgery and gynaecology of Tehran and Iran University of Medical Sciences. The study tool was a self-administered questionnaire, containing questions on their knowledge and performance regarding informed consent acquisition from patients with different conditions in terms of age, sex, marital status and their capacity to make treatment decisions. RESULTS: A total of 213 residents participated in the study (response rate=51.9%). The mean score of the participants' knowledge was 72.95 out of 100. There was no significant correlation between the residents' knowledge and performance. Regarding a competent married male patient, 98.2% of the residents knew that the person's consent was enough, but only 63.6% obtained informed consent only from the patient. These percentages were 69% and 19.7% for a competent married female patient, respectively. For a competent single male patient, 90.9% of the residents were aware that the patient's consent was enough, while only 40% of the residents obtained informed consent only from the patient. These percentages were 65.3% and 16% for a competent single female patient, respectively. CONCLUSION: Despite the residents' average knowledge of patient autonomy, this right is not observed for female patients, and their treatment is subject to consent acquisition from other family members. PMID- 29511042 TI - Chronic disease as risk multiplier for disadvantage. AB - This paper starts by establishing a prima facie case that disadvantaged groups or individuals are more likely to get a chronic disease and are in a disadvantaged position to adhere to chronic treatment despite access through Universal Health Coverage. However, the main aim of this paper is to explore the normative implications of this claim by examining two different but intertwined argumentative lines that might contribute to a better understanding of the ethical challenges faced by chronic disease health policy. The paper develops the argument that certain disadvantages which may predispose to illness might overlap with disadvantages that may hinder self-management, potentially becoming disadvantageous in handling chronic disease. If so, chronic diseases may be seen as disadvantages in themselves, describing a reproduction of disadvantage among the chronically ill and a vicious circle of disadvantage that could both predict and shed light on the catastrophic health outcomes among disadvantaged groups-or individuals-dealing with chronic disease. PMID- 29511040 TI - Estrogen Metabolism in Premenopausal Women Is Related to Early Life Body Fatness. AB - Background: Estrogen metabolism in premenopausal women may be related to early life body fatness.Methods: Premenopausal women participating in the Nurses' Health Study II recalled their body fatness at ages 5, 10, and 20 years using a validated 9-level pictogram. Fifteen estrogens and estrogen metabolites (EM) were measured using LC/MS-MS in luteal phase urines from 603 women ages 32-54 years. Geometric means of individual EM, metabolic pathway groups, and pathway ratios were examined by body fatness categories using linear mixed models.Results: Body fatness at each age was inversely associated with adult concentrations of all EM combined, parent estrogens (estrone, estradiol), and the 2-hydroxylation pathway. Women in the top (vs. bottom) category of body fatness at age 10 had 21% lower levels of all EM (Ptrend = 0.003), 24% lower parent estrogens (Ptrend = 0.002), and 36% lower 2-pathway (Ptrend = 0.0003). Body fatness at age 10 was inversely associated with 2-catechols (35% lower, Ptrend = 0.0004) and 2-methylated catechols (30% lower, Ptrend = 0.002). After adjusting for premenopausal body mass index (BMI), these associations remained inverse but were attenuated; only parent estrogens remained statistically significant (21% lower, Ptrend = 0.01). Body fatness at ages 5 and 20 were similarly, but more weakly, associated with estrogen pathways.Conclusions: Estimates of body fatness during early life were inversely associated with premenopausal levels of all EM combined, parent estrogens, and 2-pathway estrogen metabolites. These relationships were not fully explained by adult BMI.Impact: These findings inform investigations of diseases linked to early life body fatness and estrogen metabolism. Cancer Epidemiol Biomarkers Prev; 27(5); 585-93. (c)2018 AACR. PMID- 29511043 TI - Establishing objective benchmarks in robotic virtual reality simulation at the level of a competent surgeon using the RobotiX Mentor simulator. AB - BACKGROUND: To establish objective benchmarks at the level of a competent robotic surgeon across different exercises and metrics for the RobotiX Mentor virtual reality (VR) simulator suitable for use within a robotic surgical training curriculum. METHODS: This retrospective observational study analysed results from multiple data sources, all of which used the RobotiX Mentor VR simulator. 123 participants with varying experience from novice to expert completed the exercises. Competency was established as the 25th centile of the mean advanced intermediate score. Three basic skill exercises and two advanced skill exercises were used. SETTING: King's College London. PARTICIPANTS: 84 Novice, 26 beginner intermediates, 9 advanced intermediates and 4 experts were used in this retrospective observational study. RESULTS: Objective benchmarks derived from the 25th centile of the mean scores of the advanced intermediates provided suitably challenging yet also achievable targets for training surgeons. The disparity in scores was greatest for the advanced exercises. Novice surgeons are able to achieve the benchmarks across all exercises in the majority of metrics. CONCLUSION: We have successfully created this proof-of-concept study, which requires validation in a larger cohort. Objective benchmarks obtained from the 25th centile of the mean scores of advanced intermediates provide clinically relevant benchmarks at the standard of a competent robotic surgeon that are challenging yet also attainable. That can be used within a VR training curriculum allowing participants to track and monitor their progress in a structured and progressional manner through five exercises. Providing clearly defined targets, ensuring that a universal training standard has been achieved across training surgeons. PMID- 29511044 TI - Protein-protein interaction studies reveal the Plasmodium falciparum merozoite surface protein-1 region involved in a complex formation that binds to human erythrocytes. AB - Plasmodium falciparum merozoite surface protein (PfMSP) 1 has been studied extensively as a vaccine candidate antigen. PfMSP-1 undergoes proteolytic processing into four major products, such as p83, p30, p38, and p42, that are associated in the form of non-covalent complex(s) with other MSPs. To delineate MSP1 regions involved in the interaction with other MSPs, here we expressed recombinant proteins (PfMSP-165) encompassing part of p38 and p42 regions and PfMSP-119 PfMSP-165 interacted strongly with PfMSP-3, PfMSP-6, PfMSP-7, and PfMSP 9, whereas PfMSP-119 did not interact with any of these proteins. Since MSP-1 complex binds human erythrocytes, we examined the ability of these proteins to bind human erythrocyte. Among the proteins of MSP-1 complex, PfMSP-6 and PfMSP-9 bound to human erythrocytes. Serological studies showed that PfMSP-165 was frequently recognized by sera from malaria endemic regions, whereas this was not the case for PfMSP-119 In contrast, antibodies against PfMSP-119 showed much higher inhibition of merozoite invasion compared with antibodies against the larger PfMSP-165 fragment. Importantly, anti-PfMSP-119 antibodies recognized both recombinant proteins, PfMSP-119 and PfMSP-165; however, anti-PfMSP-165 antibody failed to recognize the PfMSP-119 protein. Taken together, these results demonstrate that PfMSP-1 sequences upstream of the 19 kDa C-terminal region are involved in molecular interactions with other MSPs, and these sequences may probably serve as a smoke screen to evade antibody response to the membrane-bound C-terminal 19 kDa region. PMID- 29511045 TI - The Effect of Malnutrition on the Risk of Unplanned 7-Day Readmission in Pediatrics. AB - BACKGROUND: Malnutrition is known to be associated with higher morbidity and a risk factor of readmissions in the adult population. In this study, we explore the effect of malnutrition in pediatrics because it may differ from the adult population. METHODS: Data for all inpatient encounters at a tertiary children's hospital within a 2-year period corresponding to 19 702 visits were obtained. The data included demographics, socioeconomic status, registered dietitian diagnosis of malnutrition, and variables of the LACE readmission model. We excluded all neonates and patients older than 21 years. A multivariable logistic model was obtained by implementing best subset regression on these variables, controlling for demographics and socioeconomic status, and considering all possible 2-way statistical interactions between malnutrition and the variables for demographics and socioeconomic status. RESULTS: We discovered a statistical interaction effect between a patient's age and malnutrition status (P value = .002) with respect to odds of unplanned 7-day readmission. It is indicated in this interaction term that patients who were malnourished had higher odds of readmission than patients who were not malnourished. Furthermore, younger patients who were malnourished were at increased odds of readmission than their older peers, whereas among patients who were not malnourished, younger patients were at reduced odds of readmission. CONCLUSIONS: The statistical interaction effect revealed that a patient's risk of readmission is jointly modified by the patient's age and malnutrition status. This finding advances our understanding of the complex picture of the simultaneous risk factor of unplanned 7-day readmissions in pediatrics. PMID- 29511047 TI - Streptococcus pyogenes Infection and the Human Proteome with a Special Focus on the Immunoglobulin G-cleaving Enzyme IdeS. AB - Infectious diseases are characterized by a complex interplay between host and pathogen, but how these interactions impact the host proteome is unclear. Here we applied a combined mass spectrometry-based proteomics strategy to investigate how the human proteome is transiently modified by the pathogen Streptococcus pyogenes, with a particular focus on bacterial cleavage of IgG in vivo In invasive diseases, S. pyogenes evokes a massive host response in blood, whereas superficial diseases are characterized by a local leakage of several blood plasma proteins at the site of infection including IgG. S. pyogenes produces IdeS, a protease cleaving IgG in the lower hinge region and we find highly effective IdeS cleavage of IgG in samples from local IgG poor microenvironments. The results show that IdeS contributes to the adaptation of S. pyogenes to its normal ecological niches. Additionally, the work identifies novel clinical opportunities for in vivo pathogen detection. PMID- 29511048 TI - Threading the needle: when embroidery was used to treat shell-shock. PMID- 29511046 TI - MicroRNA duplication accelerates the recruitment of new targets during vertebrate evolution. AB - The repertoire of miRNAs has considerably expanded during metazoan evolution, and duplication is an important mechanism for generating new functional miRNAs. However, relatively little is known about the functional divergence between paralogous miRNAs and the possible coevolution between duplicated miRNAs and the genomic contexts. By systematically examining small RNA expression profiles across various human tissues and interrogating the publicly available miRNA:mRNA pairing chimeras, we found that changes in expression patterns and targeting preferences are widespread for duplicated miRNAs in vertebrates. Both the empirical interactions and target predictions suggest that evolutionarily conserved homo-seed duplicated miRNAs pair with significantly higher numbers of target sites compared to the single-copy miRNAs. Our birth-and-death evolutionary analysis revealed that the new target sites of miRNAs experienced frequent gains and losses during function development. Our results suggest that a newly emerged target site has a higher probability to be functional and maintained by natural selection if it is paired to a seed shared by multiple paralogous miRNAs rather than being paired to a single-copy miRNA. We experimentally verified the divergence in target repression between two paralogous miRNAs by transfecting let 7a and let-7b mimics into kidney-derived cell lines of four mammalian species and measuring the resulting transcriptome alterations by extensive high-throughput sequencing. Our results also suggest that the gains and losses of let-7 target sites might be associated with the evolution of repressiveness of let-7 across mammalian species. PMID- 29511049 TI - LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk. AB - The connection between lipoprotein (a) [Lp(a)] levels and the risks of cardiovascular disease and diabetes remains poorly understood. Lp(a) is encoded by the LPA gene, and evidence suggests that the kringle IV type 2 (KIV-2) variant is particularly important to Lp(a) isoform size. A large isoform size, represented as a high number of KIV-2 repeats in LPA, is associated with low serum Lp(a) concentrations and an increased risk of type 2 diabetes. We investigated the associations among Lp(a) concentrations, LPA KIV-2 repeats, and type 2 diabetes in a Chinese population of 1,863 consecutive patients with very high cardiovascular risk, as identified by coronary angiography. Individuals with Lp(a) levels in the top tertile [67.86 (35.34-318.50) mg/dl] had a lower risk of diabetes compared with those in the bottom tertile [7.38 (0.60-12.91) mg/dl]. There was an inverse association between the number of KIV-2 repeats and serum Lp(a) concentrations. This study demonstrated that a high number of LPA KIV-2 repeats are associated with increased risk of type 2 diabetes in a Chinese population with very high cardiovascular risk, which suggests that large Lp(a) isoform size, associated with low Lp(a) concentration, has a causal effect on type 2 diabetes. PMID- 29511050 TI - Parenting in an Obesogenic Environment: Ghosts at the Dinner Table. PMID- 29511051 TI - Intergenerational Transmission of Parent Encouragement to Diet From Adolescence Into Adulthood. AB - BACKGROUND: Although previous cross-sectional research has revealed potential harmful outcomes associated with parent encouragement to diet, it is unclear whether these effects are long lasting and whether they are transmitted to the next generation. The main aim of the current study was to examine longitudinal associations between exposure to parent encouragement to diet in adolescence and weight-related and emotional health outcomes in adulthood and to examine whether intergenerational transmission of encouragement to diet occurs. METHODS: This is a longitudinal, population-based study (ie, Project Eating and Activity in Teens and Young Adults) of socioeconomically and racially and/or ethnically diverse adolescents managed into adulthood and/or parenthood (n = 556; mean age = 31.4; 64.6% female). Surveys and anthropometrics were completed at school by adolescents in 1998-1999 and surveys were completed online in 2015-2016 by young adults. RESULTS: Experiencing parent encouragement to diet as an adolescent was significantly associated with a higher risk of overweight or obesity, dieting, binge eating, engaging in unhealthy weight control behaviors, and lower body satisfaction 15 years later as a parent, after adjusting for sociodemographics and baseline measures of the outcomes (P < .05). Additionally, intergenerational transmission of encouragement to diet occurred and resulted in parents being more likely to report other weight-focused communication in the home environment. CONCLUSIONS: Exposure to parent encouragement to diet as an adolescent had long term harmful associations with weight-related and emotional health outcomes in parenthood and was transmitted to the next generation. It may be important for health care providers to educate parents about the potential harmful and long lasting consequences of engaging in encouragement to diet with their children. PMID- 29511052 TI - Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. AB - : Review evidence for cannabinoids as adjunctive treatments for treatment resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5-55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed. PROSPERO REGISTRATION NUMBER: CRD42017055412. PMID- 29511053 TI - A Plant Phytosulfokine Peptide Initiates Auxin-Dependent Immunity through Cytosolic Ca2+ Signaling in Tomato. AB - Phytosulfokine (PSK) is a disulfated pentapeptide that is an important signaling molecule. Although it has recently been implicated in plant defenses to pathogen infection, the mechanisms involved remain poorly understood. Using surface plasmon resonance and gene silencing approaches, we showed that the tomato (Solanum lycopersicum) PSK receptor PSKR1, rather than PSKR2, functioned as the major PSK receptor in immune responses. Silencing of PSK signaling genes rendered tomato more susceptible to infection by the economically important necrotrophic pathogen Botrytis cinerea Analysis of tomato mutants defective in either defense hormone biosynthesis or signaling demonstrated that PSK-induced immunity required auxin biosynthesis and associated defense pathways. Here, using aequorin expressing tomato plants, we provide evidence that PSK perception by tomato PSKR1 elevated cytosolic [Ca2+], leading to auxin-dependent immune responses via enhanced binding activity between calmodulins and the auxin biosynthetic YUCs. Thus, our data demonstrate that PSK acts as a damage-associated molecular pattern and is perceived mainly by PSKR1, which increases cytosolic [Ca2+] and activates auxin-mediated pathways that enhance immunity of tomato plants to B. cinerea. PMID- 29511055 TI - Patients, caregivers and health system costs of home ventilation. PMID- 29511054 TI - A Functional Study of AUXILIN-LIKE1 and 2, Two Putative Clathrin Uncoating Factors in Arabidopsis. AB - Clathrin-mediated endocytosis (CME) is a cellular trafficking process in which cargoes and lipids are internalized from the plasma membrane into vesicles coated with clathrin and adaptor proteins. CME is essential for many developmental and physiological processes in plants, but its underlying mechanism is not well characterized compared with that in yeast and animal systems. Here, we searched for new factors involved in CME in Arabidopsis thaliana by performing tandem affinity purification of proteins that interact with clathrin light chain, a principal component of the clathrin coat. Among the confirmed interactors, we found two putative homologs of the clathrin-coat uncoating factor auxilin previously described in non-plant systems. Overexpression of AUXILIN-LIKE1 and AUXILIN-LIKE2 in Arabidopsis caused an arrest of seedling growth and development. This was concomitant with inhibited endocytosis due to blocking of clathrin recruitment after the initial step of adaptor protein binding to the plasma membrane. By contrast, auxilin-like1/2 loss-of-function lines did not present endocytosis-related developmental or cellular phenotypes under normal growth conditions. This work contributes to the ongoing characterization of the endocytotic machinery in plants and provides a robust tool for conditionally and specifically interfering with CME in Arabidopsis. PMID- 29511056 TI - Geographical variations in the use of cancer treatments are associated with survival of lung cancer patients. AB - INTRODUCTION: Lung cancer outcomes in England are inferior to comparable countries. Patient or disease characteristics, healthcare-seeking behaviour, diagnostic pathways, and oncology service provision may contribute. We aimed to quantify associations between geographic variations in treatment and survival of patients in England. METHODS: We retrieved detailed cancer registration data to analyse the variation in survival of 176,225 lung cancer patients, diagnosed 2010 2014. We used Kaplan-Meier analysis and Cox proportional hazards regression to investigate survival in the two-year period following diagnosis. RESULTS: Survival improved over the period studied. The use of active treatment varied between geographical areas, with inter-quintile ranges of 9%-17% for surgical resection, 4%-13% for radical radiotherapy, and 22%-35% for chemotherapy. At 2 years, there were 188 potentially avoidable deaths annually for surgical resection, and 373 for radical radiotherapy, if all treated proportions were the same as in the highest quintiles. At the 6 month time-point, 318 deaths per year could be postponed if chemotherapy use for all patients was as in the highest quintile. The results were robust to statistical adjustments for age, sex, socio economic status, performance status and co-morbidity. CONCLUSION: The extent of use of different treatment modalities varies between geographical areas in England. These variations are not attributable to measurable patient and tumour characteristics, and more likely reflect differences in clinical management between local multi-disciplinary teams. The data suggest improvement over time, but there is potential for further survival gains if the use of active treatments in all areas could be increased towards the highest current regional rates. PMID- 29511057 TI - Hemodiafiltration to Address Unmet Medical Needs ESKD Patients. AB - Hemodiafiltration combines diffusive and convective solute removal in a single therapy by ultrafiltering 20% or more of the blood volume processed using a high flux hemodialyzer and maintaining fluid balance by infusing sterile nonpyrogenic replacement fluid directly into the patient's blood. In online hemodiafiltration, the large volumes of replacement fluid required are obtained by online filtration of standard dialysate through a series of bacteria- and endotoxin-retaining filters. Currently available systems for online hemodiafiltration are on the basis of conventional dialysis machines with added features to safely prepare and infuse replacement fluid and closely control fluid balance. Hemodiafiltration provides greater removal of higher molecular weight uremic retention solutes than conventional high-flux hemodialysis, and recently completed randomized, controlled clinical trials suggest better patient survival with online hemodiafiltration compared with standard high-flux hemodialysis when a high convection volume is delivered. Hemodiafiltration is also associated with improvements in other clinical outcomes, such as a reduction in intradialytic hypotension, and it is now used routinely to treat >100,000 patients, mainly in Europe and Japan. PMID- 29511058 TI - Regulatory Considerations for Hemodiafiltration in the United States. AB - Online hemodiafiltration provides greater removal of higher molecular weight uremic retention solutes than conventional high-flux hemodialysis. However, online hemodiafiltration is used sparsely in the United States in part because of a paucity of delivery systems cleared for clinical use by the US Food and Drug Administration. Although a pathway for regulatory approval exists in the United States, concerns remain, particularly regarding online production of the large volumes of sterile, nonpyrogenic substitution fluid infused directly into the bloodstream to maintain fluid balance. Clearly defined testing protocols, acceptable to Food and Drug Administration, will be useful to show that an online hemodiafiltration system is capable of routinely achieving a sterility assurance level of 10-6 and nonpyrogenic levels of endotoxin. Large-scale clinical experience has shown that systems providing this level of performance when combined with certain design features, such as redundancy, and an appropriate quality management process can routinely and safely produce substitution fluid for online hemodiafiltration. PMID- 29511059 TI - Association of Serious Fall Injuries among United States End Stage Kidney Disease Patients with Access to Kidney Transplantation. AB - BACKGROUND AND OBJECTIVES: Serious fall injuries in the setting of ESKD may be associated with poor access to kidney transplant. We explored the burden of serious fall injuries among patients on dialysis and patients on the deceased donor waitlist and the associations of these fall injuries with waitlisting and transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our analytic cohorts for the outcomes of (1) waitlisting and (2) transplantation included United States adults ages 18-80 years old who (1) initiated dialysis (n=183,047) and (2) were waitlisted for the first time (n=37,752) in 2010-2013. Serious fall injuries were determined by diagnostic codes for falls plus injury (fracture, joint dislocation, or head trauma) in inpatient and emergency department claims; the first serious fall injury after cohort entry was included as a time-varying exposure. Follow-up ended at the specified outcome, death, or the last date of follow-up (September 30, 2014). We used multivariable Cox proportional hazards models to determine the independent associations between serious fall injury and waitlisting or transplantation. RESULTS: Overall, 2-year cumulative incidence of serious fall injury was 6% among patients on incident dialysis; with adjustment, patients who had serious fall injuries were 61% less likely to be waitlisted than patients who did not (hazard ratio, 0.39; 95% confidence interval, 0.35 to 0.44). Among incident waitlisted patients (4% 2-year cumulative incidence), those with serious fall injuries were 29% less likely than their counterparts to be subsequently transplanted (hazard ratio, 0.71; 95% confidence interval, 0.63 to 0.80). CONCLUSIONS: Serious fall injuries among United States patients on dialysis are associated with substantially lower likelihood of waitlisting for and receipt of a kidney transplant. PMID- 29511060 TI - p16INK4a overexpression as a predictor of survival in ocular surface squamous neoplasia. AB - AIMS: To evaluate the expression and methylation status of the p16INK4a gene in early and advanced American Joint Committee on Cancer (AJCC) stages of ocular surface squamous neoplasia (OSSN) and to correlate its association with clinicopathological features and survival. METHODS: Sixty-four (35 early and 29 advanced AJCC stage) patients with OSSN formed part of this study and were followed up for 36-58 (mean 48+/-3.6) months. Immunohistochemical expression of the p16INK4a protein and methylation status of the p16INK4a gene were determined by methylation-specific PCR. RESULTS: Overexpression of p16INK4a was observed in 18/64 (28%) and hypermethylation in 35/64 (54.7%) OSSN cases. A gradual significant increase in the expression of p16INK4a (0%-48%, P=0.03) and decrease in its methylation (75%-16%, P=0.001) was observed with disease progression from early to advanced tumour stage. Overexpression of p16INK4a was significantly associated with palpebral location and diffuse growth pattern in both early and advanced T stage. Hypermethylation of p16INK4a was significantly associated with history of longer sunlight exposure in both early and advanced T stage of OSSN cases. In advanced T stage, p16INK4a overexpression was associated with reduced disease-free survival (P=0.02) and poor prognosis (HR, 0.2; P=0.03). CONCLUSIONS: OSSN patients presenting at an advanced AJCC stage with p16INK4a overexpression may require more aggressive treatment. Epigenetic inactivation of the p16INK4a gene due to sunlight exposure could be responsible for pathogenesis of OSSN. PMID- 29511061 TI - Population-based incidence of conjunctival tumours in Olmsted County, Minnesota. AB - AIM: To determine population-based incidence of conjunctival tumours in Olmsted County, Minnesota. METHODS: The Rochester Epidemiology Project medical record linkage system was used to identify patients with conjunctival tumours in Olmsted County (1 January 1980 to 31 December 2015). Records were reviewed for demographics, types of tumours, histopathology, treatment and clinical course. Incidence rate of all tumours was calculated per 1 000 000 person-years. Poisson regression analysis was used to assess changes in incidence over time. RESULTS: There were 504 patients with conjunctival tumours, giving an age-adjusted and sex adjusted incidence rate of 125 per 1 000 000 (CI 113.5 to 135.5). Incidence increased over time (P<0.001). Most tumours (474, 94%) were benign. Of benign lesions, melanocytic lesions accounted for the majority (431, 86%), with adjusted incidence rates of 10.8 (CI 7.7 to 13.9) for complexion-associated melanosis, 49.7 (CI 42.9 to 56.6) for nevus and 44.1 (37.5-50.8) for primary acquired melanosis. Malignant lesions were rare (30, 6%) with 6 cases of melanoma, 21 cases of ocular surface squamous neoplasia (OSSN), 1 case of Langerhans cell histiocytosis and 2 cases of lymphoma. Adjusted incidence rates of conjunctival melanoma and OSSN were 1.5 (CI 0.3 to 2.8) and 6.1 (CI 3.5 to 8.7), respectively. Outcomes for melanoma (mean follow-up 14 years, range 0-34) and OSSN (mean follow up 4 years, range 0-24) were favourable in 29 cases, with one fatality due to metastatic melanoma. CONCLUSIONS: In a population-based setting, most conjunctival tumours are benign, and the majority of lesions are melanocytic. While it is important to remain vigilant for malignancies, most conjunctival lesions in a community-based practice are not life-threatening. PMID- 29511062 TI - Neuroretinal atrophy following resolution of macular oedema in retinal vein occlusion. AB - BACKGROUND/AIMS: To characterise neuroretinal atrophy in retinal vein occlusion (RVO). METHODS: We included patients with central/branch RVO (CRVO=196, BRVO=107) who received ranibizumab according to a standardised protocol for 6 months. Retinal atrophy was defined as the presence of an area of retinal thickness (RT) <260 um outside the foveal centre. Moreover, the thickness of three distinct retinal layer compartments was computed as follows: (1) retinal nerve fibre layer to ganglion cell layer, (2) inner plexiform layer (IPL) to outer nuclear layer (ONL) and (3) inner segment/outer segment junction to retinal pigment epithelium. To characterise atrophy further, we assessed perfusion status on fluorescein angiography and best-corrected visual acuity (BCVA), and compared these between eyes with/without atrophy. RESULTS: 23 patients with CRVO and 11 patients with BRVO demonstrated retinal atrophy, presenting as sharply demarcated retinal thinning confined to a macular quadrant. The mean RT in the atrophic quadrant at month 6 was 249+/-26 um (CRVO) and 244+/-29 um (BRVO). Individual layer analysis revealed pronounced thinning in the IPL to ONL compartment. Change in BCVA at 6 months was similar between the groups (BRVO, +15 vs +18 letters; CRVO, +14 vs +18 letters). CONCLUSIONS: In this exploratory analysis, we describe the characteristics of neuroretinal atrophy in RVO eyes with resolved macular oedema after ranibizumab therapy. Our analysis shows significant, predominantly retinal thinning in the IPL to ONL compartment in focal macular areas in 11% of patients with RVO. Eyes with retinal atrophy did not show poorer BCVA outcomes. PMID- 29511063 TI - Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. AB - Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1-/- mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1-/-, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease. PMID- 29511064 TI - Mass cytometry reveals innate lymphoid cell differentiation pathways in the human fetal intestine. AB - Innate lymphoid cells (ILCs) are abundant in mucosal tissues and involved in tissue homeostasis and barrier function. Although several ILC subsets have been identified, it is unknown if additional heterogeneity exists, and their differentiation pathways remain largely unclear. We applied mass cytometry to analyze ILCs in the human fetal intestine and distinguished 34 distinct clusters through a t-SNE-based analysis. A lineage (Lin)-CD7+CD127-CD45RO+CD56+ population clustered between the CD127+ ILC and natural killer (NK) cell subsets, and expressed diverse levels of Eomes, T-bet, GATA3, and RORgammat. By visualizing the dynamics of the t-SNE computation, we identified smooth phenotypic transitions from cells within the Lin-CD7+CD127-CD45RO+CD56+ cluster to both the NK cells and CD127+ ILCs, revealing potential differentiation trajectories. In functional differentiation assays, the Lin-CD7+CD127-CD45RO+CD56+CD8a- cells could develop into CD45RA+ NK cells and CD127+RORgammat+ ILC3-like cells. Thus, we identified a previously unknown intermediate innate subset that can differentiate into ILC3 and NK cells. PMID- 29511065 TI - Unveiling skin macrophage dynamics explains both tattoo persistence and strenuous removal. AB - Here we describe a new mouse model that exploits the pattern of expression of the high-affinity IgG receptor (CD64) and allows diphtheria toxin (DT)-mediated ablation of tissue-resident macrophages and monocyte-derived cells. We found that the myeloid cells of the ear skin dermis are dominated by DT-sensitive, melanin laden cells that have been missed in previous studies and correspond to macrophages that have ingested melanosomes from neighboring melanocytes. Those cells have been referred to as melanophages in humans. We also identified melanophages in melanocytic melanoma. Benefiting of our knowledge on melanophage dynamics, we determined the identity, origin, and dynamics of the skin myeloid cells that capture and retain tattoo pigment particles. We showed that they are exclusively made of dermal macrophages. Using the possibility to delete them, we further demonstrated that tattoo pigment particles can undergo successive cycles of capture-release-recapture without any tattoo vanishing. Therefore, congruent with dermal macrophage dynamics, long-term tattoo persistence likely relies on macrophage renewal rather than on macrophage longevity. PMID- 29511066 TI - 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. AB - Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function. We hypothesized that 4-1BB signaling might provide metabolic support to tumor-infiltrating T cells. 4-1BB costimulation of CD8+ T cells results in enhanced mitochondrial capacity (suggestive of fusion) and engages PGC1alpha-mediated pathways via activation of p38-MAPK. 4-1BB treatment of mice improves metabolic sufficiency in endogenous and adoptive therapeutic CD8+ T cells. 4-1BB stimulation combined with PD-1 blockade results in robust antitumor immunity. Sequenced studies revealed the metabolic support afforded by 4-1BB agonism need not be continuous and that a short course of anti-4-1BB pretreatment was sufficient to provide a synergistic response. Our studies highlight metabolic reprogramming as the dominant effect of 4-1BB therapy and suggest that combinatorial strategies using 4-1BB agonism may help overcome the immunosuppressive metabolic landscape of the tumor microenvironment. PMID- 29511067 TI - Is previous azithromycin treatment associated with azithromycin resistance in Neisseria gonorrhoeae? A cross-sectional study using national surveillance data in England. AB - OBJECTIVES: It has been suggested that treatment of STIs with azithromycin may facilitate development of azithromycin resistance in Neisseria gonorrhoeae (NG) by exposing the organism to suboptimal doses. We investigated whether treatment history for non-rectal Chlamydia trachomatis (CT), non-gonococcal urethritis (NGU) or NG (proxies for azithromycin exposure) in sexual health (GUM) services was associated with susceptibility of NG to azithromycin. METHODS: Azithromycin susceptibility data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP 2013-2015, n=4606) and additional high-level azithromycin resistant isolates (HL-AziR) identified by the Public Health England reference laboratory (2013-2016, n=54) were matched to electronic patient records in the national GUMCAD STI surveillance dataset (2012-2016). Descriptive and regression analyses were conducted to examine associations between history of previous CT/NGU/NG and subsequent susceptibility of NG to azithromycin. RESULTS: Modal azithromycin minimum inhibitory concentration (MIC) was 0.25 mg/L (one dilution below the resistance breakpoint) in those with and without history of previous CT/NGU/NG (previous 1 month/6 months). There were no differences in MIC distribution by history of CT/NGU (P=0.98) or NG (P=0.85) in the previous 1 month/6 months or in the odds of having an elevated azithromycin MIC (>0.25 mg/L) (Adjusted OR for CT/NGU 0.97 (95% CI 0.76 to 1.25); adjusted OR for NG 0.82 (95% CI: 0.65 to 1.04)) compared with those with no CT/NGU/NG in the previous 6 months. Among patients with HL-AziR NG, 3 (4%) were treated for CT/NGU and 2 (3%) for NG in the previous 6 months, compared with 6% and 8%, respectively for all GRASP patients. CONCLUSIONS: We found no evidence of an association between previous treatment for CT/NGU or NG in GUM services and subsequent presentation with an azithromycin-resistant strain. As many CT diagnoses occur in non-GUM settings, further research is needed to determine whether azithromycin-resistant NG is associated with azithromycin exposure in other settings and for other conditions. PMID- 29511068 TI - Photoreceptor specialization and the visuomotor repertoire of the primitive chordate Ciona. AB - The swimming tadpole larva of Ciona has one of the simplest central nervous systems (CNSs) known, with only 177 neurons. Despite its simplicity, the Ciona CNS has a common structure with the CNS of its close chordate relatives, the vertebrates. The recent completion of a larval Ciona CNS connectome creates enormous potential for detailed understanding of chordate CNS function, yet our understanding of Ciona larval behavior is incomplete. We show here that Ciona larvae have a surprisingly rich and dynamic set of visual responses, including a looming-object escape behavior characterized by erratic circular swims, as well as negative phototaxis characterized by sustained directional swims. Making use of mutant lines, we show that these two behaviors are mediated by distinct groups of photoreceptors. The Ciona connectome predicts that these two behavioral responses should act through distinct, but overlapping, visuomotor pathways, and that the escape behavior is likely to be integrated into a broader startle behavior. PMID- 29511069 TI - Emersion behaviour underlies variation in gill morphology and aquatic respiratory function in the amphibious fish Kryptolebias marmoratus. AB - Fishes acclimated to hypoxic environments often increase gill surface area to improve O2 uptake. In some species, surface area is increased via reduction of an interlamellar cell mass (ILCM) that fills water channels between gill lamellae. Amphibious fishes, however, may not increase gill surface area in hypoxic water because these species can, instead, leave water and breathe air. To differentiate between these possibilities, we compared wild amphibious mangrove rivulus Kryptolebias marmoratus from two habitats that varied in O2 availability - a hypoxic freshwater pool versus nearly anoxic crab burrows. Fish captured from crab burrows had less gill surface area (as ILCMs were enlarged by ~32%), increased rates of normoxic O2 consumption and increased critical O2 tension compared with fish from the freshwater pool. Thus, wild mangrove rivulus do not respond to near-anoxic water by decreasing metabolism or increasing O2 extraction. Instead, fish from the crab burrow habitat spent three times longer out of water, which probably caused the observed changes in gill morphology and respiratory phenotype. We also tested whether critical O2 tension is influenced by genetic heterozygosity, as K. marmoratus is one of only two hermaphroditic vertebrate species that can produce both self-fertilized (inbred) or out-crossed (more heterozygous) offspring. We found no evidence for inbreeding depression, suggesting that self-fertilization does not impair respiratory function. Overall, our results demonstrate that amphibious fishes that inhabit hypoxic aquatic habitats can use a fundamentally different strategy from that used by fully aquatic water-breathing fishes, relying on escape behaviour rather than metabolic depression or increased O2 extraction ability. PMID- 29511070 TI - Conserved spatio-temporal patterns of suction-feeding flows across aquatic vertebrates: a comparative flow visualization study. AB - Suction feeding is a widespread prey capture strategy among aquatic vertebrates. It is almost omnipresent across fishes, and has repeatedly evolved in other aquatic vertebrates. By rapidly expanding the mouth cavity, suction feeders generate a fluid flow outside of their mouth, drawing prey inside. Fish and other suction-feeding organisms display remarkable trophic diversity, echoed in the diversity of their skull and mouth morphologies. Yet, it is unclear how variable suction flows are across species, and whether variation in suction flows supports trophic diversity. Using a high-speed flow visualization technique, we characterized the spatio-temporal patterns in the flow fields produced during feeding in 14 species of aquatic suction feeders. We found that suction-feeding hydrodynamics are highly conserved across species. Suction flows affected only a limited volume of ~1 gape diameter away from the mouth, and peaked around the timing of maximal mouth opening. The magnitude of flow speed increased with increasing mouth diameter and, to a lesser extent, with decreasing time to peak gape opening. Other morphological, kinematic and behavioral variables played a minor role in shaping suction-feeding dynamics. We conclude that the trophic diversity within fishes, and likely other aquatic vertebrates, is not supported by a diversity of mechanisms that modify the characteristics of suction flow. Rather, we suggest that suction feeding supports such trophic diversity owing to the general lack of strong trade-offs with other mechanisms that contribute to prey capture. PMID- 29511071 TI - Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection. AB - Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), including carbapenem-resistant Klebsiella pneumoniae (CRKP), which lead to mortality rates as high as 40 to 50%. Few treatment options are available to treat CRKP, and the polymyxin antibiotic colistin is often the "last-line" therapy. However, resistance to colistin is increasing. Here, we identify multidrug-resistant, carbapenemase-positive CRKP isolates that were classified as susceptible to colistin by clinical diagnostics yet harbored a minor subpopulation of phenotypically resistant cells. Within these isolates, the resistant subpopulation became predominant after growth in the presence of colistin but returned to baseline levels after subsequent culture in antibiotic-free media. This indicates that the resistance was phenotypic, rather than due to a genetic mutation, consistent with heteroresistance. Importantly, colistin therapy was unable to rescue mice infected with the heteroresistant strains. These findings demonstrate that colistin heteroresistance may cause in vivo treatment failure during K. pneumoniae infection, threatening the use of colistin as a last-line treatment for CRKP. Furthermore, these data sound the alarm for use of caution in interpreting colistin susceptibility test results, as isolates identified as susceptible may in fact resist antibiotic therapy and lead to unexplained treatment failures.IMPORTANCE This is the first report of colistin-heteroresistant K. pneumoniae in the United States. Two distinct isolates each led to colistin treatment failure in an in vivo model of infection. The data are worrisome, especially since the colistin heteroresistance was not detected by current diagnostic tests. As these isolates were carbapenem resistant, clinicians might turn to colistin as a last-line therapy for infections caused by such strains, not knowing that they in fact harbor a resistant subpopulation of cells, potentially leading to treatment failure. Our findings warn that colistin susceptibility testing results may be unreliable due to undetected heteroresistance and highlight the need for more accurate and sensitive diagnostics. PMID- 29511072 TI - Chikungunya Virus Strains Show Lineage-Specific Variations in Virulence and Cross Protective Ability in Murine and Nonhuman Primate Models. AB - Chikungunya virus (CHIKV) is a reemerging arbovirus capable of causing explosive outbreaks of febrile illness, polyarthritis, and polyarthralgia, inflicting severe morbidity on affected populations. CHIKV can be genetically classified into 3 major lineages: West African (WA); East, Central, and South African (ECSA); Indian Ocean (IOL); and Asian. Additionally, the Indian Ocean (IOL) sublineage emerged within the ECSA clade and the Asian/American sublineage emerged within the Asian clade. While differences in epidemiological and pathological characteristics among outbreaks involving different CHIKV lineages and sublineages have been suggested, few targeted investigations comparing lineage virulence levels have been reported. We compared the virulence levels of CHIKV isolates representing all major lineages and sublineages in the type I interferon receptor-knockout A129 mouse model and found lineage-specific differences in virulence. We also evaluated the cross-protective efficacy of the IOL-derived, live-attenuated vaccine strain CHIKV/IRESv1 against the Asian/American CHIKV isolate YO123223 in both murine and nonhuman primate models, as well as the WA strain SH2830 in a murine model. The CHIKV/IRES vaccine provided protection both in mice and in nonhuman primate cohorts against Caribbean strain challenge and protected mice against WA challenge. Taken together, our data suggest that Asian/American CHIKV strains are less virulent than those in the Asian, ECSA, and WA lineages and that despite differences in virulence, IOL-based vaccine strains offer robust cross-protection against strains from other lineages. Further research is needed to elucidate the genetic basis for variation in CHIKV virulence in the A129 mouse model and to corroborate this variation with human pathogenicity.IMPORTANCE Chikungunya virus (CHIKV) is a reemerging human pathogen capable of causing debilitating and disfiguring polyarthritis, which can last for months to years after initial fever has resolved. There are four major genetic lineages of CHIKV, as well as two recently emerged sublineages, none of which have been evaluated for differences in virulence. Moreover, the ability of chikungunya vaccines to cross-protect against heterologous CHIKV lineages has not been explored. Therefore, we sought to compare the virulence levels among CHIKV lineages, as well as to evaluate the cross-protective efficacy of the CHIKV/IRESv1 vaccine candidate, in two different models of CHIKV infection. Our results suggest that, although significant differences in virulence were observed among CHIKV lineages, the CHIKV/IRESv1 vaccine elicits cross-lineage protective immunity. These findings provide valuable information for predicting the severity of CHIKV-associated morbidity in future outbreaks, as well as vaccine development considerations. PMID- 29511073 TI - Diagnosis of Zika Virus Infection by Peptide Array and Enzyme-Linked Immunosorbent Assay. AB - Zika virus (ZIKV) is implicated in fetal stillbirth, microcephaly, intracranial calcifications, and ocular anomalies following vertical transmission from infected mothers. In adults, infection may trigger autoimmune inflammatory polyneuropathy. Transmission most commonly follows the bite of infected Aedes mosquitoes but may also occur through sexual intercourse or receipt of blood products. Definitive diagnosis through detection of viral RNA is possible in serum or plasma within 10 days of disease onset, in whole blood within 3 weeks of onset, and in semen for up to 3 months. Serological diagnosis is nonetheless critical because few patients have access to molecular diagnostics during the acute phase of infection and infection may be associated with only mild or inapparent disease that does not prompt molecular testing. Serological diagnosis is confounded by cross-reactivity of immune sera with other flaviviruses endemic in the areas where ZIKV has recently emerged. Accordingly, we built a high density microarray comprising nonredundant 12-mer peptides that tile, with one residue overlap, the proteomes of Zika, dengue, yellow fever, West Nile, Ilheus, Oropouche, and chikungunya viruses. Serological analysis enabled discovery of a ZIKV NS2B 20-residue peptide that had high sensitivity (96.0%) and specificity (95.9%) versus natural infection with or vaccination against dengue, chikungunya, yellow fever, West Nile, tick-borne encephalitis, or Japanese encephalitis virus in a microarray assay and an enzyme-linked immunosorbent assay (ELISA) of early convalescent-phase sera (2 to 3 weeks after onset of symptomatic infection).IMPORTANCE The emergence of Zika virus (ZIKV) as a teratogen is a profound challenge to global public health. Molecular diagnosis of infection is straightforward during the 3-week period when patients are viremic. However, serological diagnosis thereafter of historical exposure has been confounded by cross-reactivity. Using high-density peptide arrays that tile the proteomes of a selection of flaviviruses to identify a ZIKV-specific peptide, we established two assays that enable sensitive and specific diagnosis of exposure to ZIKV. These assays may be useful in guiding clinical management of mothers at risk for potential exposure to ZIKV and enable insights into the epidemiology of ZIKV infections. PMID- 29511074 TI - The Drosophila melanogaster Gut Microbiota Provisions Thiamine to Its Host. AB - The microbiota of Drosophila melanogaster has a substantial impact on host physiology and nutrition. Some effects may involve vitamin provisioning, but the relationships between microbe-derived vitamins, diet, and host health remain to be established systematically. We explored the contribution of microbiota in supplying sufficient dietary thiamine (vitamin B1) to support D. melanogaster at different stages of its life cycle. Using chemically defined diets with different levels of available thiamine, we found that the interaction of thiamine concentration and microbiota did not affect the longevity of adult D. melanogaster Likewise, this interplay did not have an impact on egg production. However, we determined that thiamine availability has a large impact on offspring development, as axenic offspring were unable to develop on a thiamine-free diet. Offspring survived on the diet only when the microbiota was present or added back, demonstrating that the microbiota was able to provide enough thiamine to support host development. Through gnotobiotic studies, we determined that Acetobacter pomorum, a common member of the microbiota, was able to rescue development of larvae raised on the no-thiamine diet. Further, it was the only microbiota member that produced measurable amounts of thiamine when grown on the thiamine-free fly medium. Its close relative Acetobacter pasteurianus also rescued larvae; however, a thiamine auxotrophic mutant strain was unable to support larval growth and development. The results demonstrate that the D. melanogaster microbiota functions to provision thiamine to its host in a low thiamine environment.IMPORTANCE There has been a long-standing assumption that the microbiota of animals provides their hosts with essential B vitamins; however, there is not a wealth of empirical evidence supporting this idea, especially for vitamin B1 (thiamine). To determine whether this assumption is true, we used Drosophila melanogaster and chemically defined diets with different thiamine concentrations as a model. We found that the microbiota does provide thiamine to its host, enough to allow the development of flies on a thiamine-free diet. The power of the Drosophila-microbiota system allowed us to determine that one microbiota member in particular, Acetobacter pomorum, is responsible for the thiamine provisioning. Thereby, our study verifies this long-standing hypothesis. Finally, the methods used in this work are applicable for interrogating the underpinnings of other aspects of the tripartite interaction between diet, host, and microbiota. PMID- 29511075 TI - Rapid Growth of Uropathogenic Escherichia coli during Human Urinary Tract Infection. AB - Uropathogenic Escherichia coli (UPEC) strains cause most uncomplicated urinary tract infections (UTIs). These strains are a subgroup of extraintestinal pathogenic E. coli (ExPEC) strains that infect extraintestinal sites, including urinary tract, meninges, bloodstream, lungs, and surgical sites. Here, we hypothesize that UPEC isolates adapt to and grow more rapidly within the urinary tract than other E. coli isolates and survive in that niche. To date, there has not been a reliable method available to measure their growth rate in vivo Here we used two methods: segregation of nonreplicating plasmid pGTR902, and peak-to trough ratio (PTR), a sequencing-based method that enumerates bacterial chromosomal replication forks present during cell division. In the murine model of UTI, UPEC strain growth was robust in vivo, matching or exceeding in vitro growth rates and only slowing after reaching high CFU counts at 24 and 30 h postinoculation (hpi). In contrast, asymptomatic bacteriuria (ABU) strains tended to maintain high growth rates in vivo at 6, 24, and 30 hpi, and population densities did not increase, suggesting that host responses or elimination limited population growth. Fecal strains displayed moderate growth rates at 6 hpi but did not survive to later times. By PTR, E. coli in urine of human patients with UTIs displayed extraordinarily rapid growth during active infection, with a mean doubling time of 22.4 min. Thus, in addition to traditional virulence determinants, including adhesins, toxins, iron acquisition, and motility, very high growth rates in vivo and resistance to the innate immune response appear to be critical phenotypes of UPEC strains.IMPORTANCE Uropathogenic Escherichia coli (UPEC) strains cause most urinary tract infections in otherwise healthy women. While we understand numerous virulence factors are utilized by E. coli to colonize and persist within the urinary tract, these properties are inconsequential unless bacteria can divide rapidly and survive the host immune response. To determine the contribution of growth rate to successful colonization and persistence, we employed two methods: one involving the segregation of a nonreplicating plasmid in bacteria as they divide and the peak-to-trough ratio, a sequencing-based method that enumerates chromosomal replication forks present during cell division. We found that UPEC strains divide extraordinarily rapidly during human UTIs. These techniques will be broadly applicable to measure in vivo growth rates of other bacterial pathogens during host colonization. PMID- 29511077 TI - Erratum for Fox et al., "A Herpesviral Immediate Early Protein Promotes Transcription Elongation of Viral Transcripts". PMID- 29511076 TI - Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. AB - Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs in vitro and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC50) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC50 The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS CoV resulted in the same in vitro resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.IMPORTANCE Coronaviruses (CoVs) cause severe human infections, but there are no approved antivirals to treat these infections. Development of nucleoside-based therapeutics for CoV infections has been hampered by the presence of a proofreading exoribonuclease. Here, we expand the known efficacy of the nucleotide prodrug remdesivir (GS-5734) to include a group beta 2a CoV. Further, GS-5734 potently inhibits CoVs with intact proofreading. Following selection with the GS-5734 parent nucleoside, 2 amino acid substitutions in the nsp12 polymerase at residues that are identical across CoVs provide low-level resistance to GS-5734. The resistance mutations decrease viral fitness of MHV in vitro and attenuate pathogenesis in a SARS-CoV animal model of infection. Together, these studies define the target of GS-5734 activity and demonstrate that resistance is difficult to select, only partial, and impairs fitness and virulence of MHV and SARS-CoV, supporting further development of GS 5734 as a potential effective pan-CoV antiviral. PMID- 29511078 TI - Correction for Sewell et al., "Homoacetogenesis in Deep-Sea Chloroflexi, as Inferred by Single-Cell Genomics, Provides a Link to Reductive Dehalogenation in Terrestrial Dehalococcoidetes". PMID- 29511079 TI - Large Blooms of Bacillales (Firmicutes) Underlie the Response to Wetting of Cyanobacterial Biocrusts at Various Stages of Maturity. AB - Biological soil crusts (biocrusts) account for a substantial portion of primary production in dryland ecosystems. They successionally mature to deliver a suite of ecosystem services, such as carbon sequestration, water retention and nutrient cycling, and climate regulation. Biocrust assemblages are extremely well adapted to survive desiccation and to rapidly take advantage of the periodic precipitation events typical of arid ecosystems. Here we focus on the wetting response of incipient cyanobacterial crusts as they mature from "light" to "dark." We sampled a cyanobacterial biocrust chronosequence before (dry) and temporally following a controlled wetting event and used high-throughput 16S rRNA and rRNA gene sequencing to monitor the dynamics of microbial response. Overall, shorter-term changes in phylogenetic beta diversity attributable to periodic wetting were as large as those attributable to biocrust successional stage. Notably, more mature crusts showed significantly higher resistance to precipitation disturbance. A large bloom of a few taxa within the Firmicutes, primarily in the order Bacillales, emerged 18 h after wetting, while filamentous crust-forming cyanobacteria showed variable responses to wet-up across the successional gradient, with populations collapsing in less-developed light crusts but increasing in later-successional-stage dark crusts. Overall, the consistent Bacillales bloom accompanied by the variable collapse of pioneer cyanobacteria of the Oscillatoriales order across the successional gradient suggests that the strong response of few organisms to a hydration pulse with the mortality of the autotroph might have important implications for carbon (C) balance in semiarid ecosystems.IMPORTANCE Desert biological soil crusts are terrestrial topsoil microbial communities common to arid regions that comprise 40% of Earth's terrestrial surface. They successionally develop over years to decades to deliver a suite of ecosystem services of local and global significance. Ecosystem succession toward maturity has been associated with both resistance and resilience to disturbance. Recent work has shown that the impacts of both climate change and physical disturbance on biocrusts increase the potential for successional resetting. A larger proportion of biocrusts are expected to be at an early developmental stage, hence increasing susceptibility to changes in precipitation frequencies. Therefore, it is essential to characterize how biocrusts respond to wetting across early developmental stages. In this study, we document the wetting response of microbial communities from a biocrust chronosequence. Overall, our results suggest that the cumulative effects of altered precipitation frequencies on the stability of biocrusts will depend on biocrust maturity. PMID- 29511080 TI - Novel (p)ppGpp Binding and Metabolizing Proteins of Escherichia coli. AB - The alarmone (p)ppGpp plays pivotal roles in basic bacterial stress responses by increasing tolerance of various nutritional limitations and chemical insults, including antibiotics. Despite intensive studies since (p)ppGpp was discovered over 4 decades ago, (p)ppGpp binding proteins have not been systematically identified in Escherichia coli We applied DRaCALA (differential radial capillary action of ligand assay) to identify (p)ppGpp-protein interactions. We discovered 12 new (p)ppGpp targets in E. coli that, based on their physiological functions, could be classified into four major groups, involved in (i) purine nucleotide homeostasis (YgdH), (ii) ribosome biogenesis and translation (RsgA, Era, HflX, and LepA), (iii) maturation of dehydrogenases (HypB), and (iv) metabolism of (p)ppGpp (MutT, NudG, TrmE, NadR, PhoA, and UshA). We present a comprehensive and comparative biochemical and physiological characterization of these novel (p)ppGpp targets together with a comparative analysis of relevant, known (p)ppGpp binding proteins. Via this, primary targets of (p)ppGpp in E. coli are identified. The GTP salvage biosynthesis pathway and ribosome biogenesis and translation are confirmed as targets of (p)ppGpp that are highly conserved between E. coli and Firmicutes In addition, an alternative (p)ppGpp degradative pathway, involving NudG and MutT, was uncovered. This report thus significantly expands the known cohort of (p)ppGpp targets in E. coliIMPORTANCE Antibiotic resistance and tolerance exhibited by pathogenic bacteria have resulted in a global public health crisis. Remarkably, almost all bacterial pathogens require the alarmone (p)ppGpp to be virulent. Thus, (p)ppGpp not only induces tolerance of nutritional limitations and chemical insults, including antibiotics, but is also often required for induction of virulence genes. However, understanding of the molecular targets of (p)ppGpp and the mechanisms by which (p)ppGpp influences bacterial physiology is incomplete. In this study, a systematic approach was used to uncover novel targets of (p)ppGpp in E. coli, the best-studied model bacterium. Comprehensive comparative studies of the targets revealed conserved target pathways of (p)ppGpp in both Gram-positive and -negative bacteria and novel targets of (p)ppGpp, including an alternative degradative pathway of (p)ppGpp. Thus, our discoveries may help in understanding of how (p)ppGpp increases the stress resilience and multidrug tolerance not only of the model organism E. coli but also of the pathogenic organisms in which these targets are conserved. PMID- 29511081 TI - Multisystem Analysis of Mycobacterium tuberculosis Reveals Kinase-Dependent Remodeling of the Pathogen-Environment Interface. AB - Tuberculosis is the leading killer among infectious diseases worldwide. Increasing multidrug resistance has prompted new approaches for tuberculosis drug development, including targeted inhibition of virulence determinants and of signaling cascades that control many downstream pathways. We used a multisystem approach to determine the effects of a potent small-molecule inhibitor of the essential Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB. We observed differential levels of phosphorylation of many proteins and extensive changes in levels of gene expression, protein abundance, cell wall lipids, and intracellular metabolites. The patterns of these changes indicate regulation by PknA and PknB of several pathways required for cell growth, including ATP synthesis, DNA synthesis, and translation. These data also highlight effects on pathways for remodeling of the mycobacterial cell envelope via control of peptidoglycan turnover, lipid content, a SigE-mediated envelope stress response, transmembrane transport systems, and protein secretion systems. Integrated analysis of phosphoproteins, transcripts, proteins, and lipids identified an unexpected pathway whereby threonine phosphorylation of the essential response regulator MtrA decreases its DNA binding activity. Inhibition of this phosphorylation is linked to decreased expression of genes for peptidoglycan turnover, and of genes for mycolyl transferases, with concomitant changes in mycolates and glycolipids in the cell envelope. These findings reveal novel roles for PknA and PknB in regulating multiple essential cell functions and confirm that these kinases are potentially valuable targets for new antituberculosis drugs. In addition, the data from these linked multisystems provide a valuable resource for future targeted investigations into the pathways regulated by these kinases in the M. tuberculosis cell.IMPORTANCE Tuberculosis is the leading killer among infectious diseases worldwide. Increasing drug resistance threatens efforts to control this epidemic; thus, new antitubercular drugs are urgently needed. We performed an integrated, multisystem analysis of Mycobacterium tuberculosis responses to inhibition of its two essential serine/threonine protein kinases. These kinases allow the bacterium to adapt to its environment by phosphorylating cellular proteins in response to extracellular signals. We identified differentially phosphorylated proteins, downstream changes in levels of specific mRNA and protein abundance, and alterations in the metabolite and lipid content of the cell. These results include changes previously linked to growth arrest and also reveal new roles for these kinases in regulating essential processes, including growth, stress responses, transport of proteins and other molecules, and the structure of the mycobacterial cell envelope. Our multisystem data identify PknA and PknB as promising targets for drug development and provide a valuable resource for future investigation of their functions. PMID- 29511082 TI - IgG Responses to Porins and Lipopolysaccharide within an Outer Membrane-Based Vaccine against Nontyphoidal Salmonella Develop at Discordant Rates. AB - Antibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens. Here we show that the response to immunization with GMMA from S Typhimurium (STmGMMA) provides B-cell-dependent protection and induces antibodies to two immunodominant antigens, lipopolysaccharide (LPS) and porins. Antibodies to LPS O antigen (O-Ag) markedly enhance protection in the spleen, but this effect is less marked in the liver. Strikingly, IgG responses to LPS and porins develop with distinct kinetics. In the first week after immunization, there is a dramatic T-cell-independent B1b-cell-associated induction of all IgG isotypes, except IgG1, to porins but not to LPS. In contrast, production of IgG1 to either antigen was delayed and T cell dependent. Nevertheless, after 1 month, cells in the bone marrow secreting IgG against porins or LPS were present at a similar frequency. Unexpectedly, immunization with O-Ag-deficient STmGMMA did not substantially enhance the anti-porin response. Therefore, IgG switching to all antigens does not develop synchronously within the same complex and so the rate of IgG switching to a single component does not necessarily reflect its frequency within the antigenic complex.IMPORTANCE Vaccines save millions of lives, yet for some infections there are none. This includes some types of Salmonella infections, killing hundreds of thousands of people annually. We show how a new type of vaccine, called GMMA, that is made from blebs shed from the Salmonella cell wall, works to protect against infection in mice by inducing host proteins (antibodies) specifically recognizing bacterial components (antigens). The rate of development of IgG antibody to antigens within GMMA occurred with different kinetics. However, the antibody response to GMMA persists and is likely to provide prolonged protection for those who need it. These results help show how antibody responses to bacterial antigens develop and how vaccines like GMMA can work and help prevent infection. PMID- 29511083 TI - Mechanism of Darunavir (DRV)'s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance. AB - Darunavir (DRV) has bimodal activity against HIV-1 protease, enzymatic inhibition and protease dimerization inhibition, and has an extremely high genetic barrier against development of drug resistance. We previously generated a highly DRV resistant HIV-1 variant (HIVDRVRP51). We also reported that four amino acid substitutions (V32I, L33F, I54M, and I84V) identified in the protease of HIVDRVRP51 are largely responsible for its high-level resistance to DRV. Here, we attempted to elucidate the role of each of the four amino acid substitutions in the development of DRV resistance. We found that V32I is a key substitution, which rarely occurs, but once it occurs, it predisposes HIV-1 to develop high level DRV resistance. When two infectious recombinant HIV-1 clones carrying I54M and I84V (rHIVI54M and rHIVI84V, respectively) were selected in the presence of DRV, V32I emerged, and the virus rapidly developed high-level DRV resistance. rHIVV32I also developed high-level DRV resistance. However, wild-type HIVNL4-3 (rHIVWT) failed to acquire V32I and did not develop DRV resistance. Compared to rHIVWT, rHIVV32I was highly susceptible to DRV and had significantly reduced fitness, explaining why V32I did not emerge upon selection of rHIVWT with DRV. When the only substitution is at residue 32, structural analysis revealed much stronger van der Waals interactions between DRV and I-32 than between DRV and V 32. These results suggest that V32I is a critical amino acid substitution in multiple pathways toward HIV-1's DRV resistance development and elucidate, at least in part, a mechanism of DRV's high genetic barrier to development of drug resistance. The results also show that attention should be paid to the initiation or continuation of DRV-containing regimens in people with HIV-1 containing the V32I substitution.IMPORTANCE Darunavir (DRV) is the only protease inhibitor (PI) recommended as a first-line therapeutic and represents the most widely used PI for treating HIV-1-infected individuals. DRV possesses a high genetic barrier to development of HIV-1's drug resistance. However, the mechanism(s) of the DRV's high genetic barrier remains unclear. Here, we show that the preexistence of certain single amino acid substitutions such as V32I, I54M, A71V, and I84V in HIV 1 protease facilitates the development of high-level DRV resistance. Interestingly, all in vitro-selected highly DRV-resistant HIV-1 variants acquired V32I but never emerged in wild-type HIV (HIVWT), and V32I itself rendered HIV-1 more sensitive to DRV and reduced viral fitness compared to HIVWT, strongly suggesting that the emergence of V32I plays a critical role in the development of HIV-1's resistance to DRV. Our results would be of benefit in the treatment of HIV-1-infected patients receiving DRV-containing regimens. PMID- 29511084 TI - Life Cycle, Ultrastructure, and Phylogeny of New Diplonemids and Their Endosymbiotic Bacteria. AB - Diplonemids represent a hyperdiverse and abundant yet poorly studied group of marine protists. Here we describe two new members of the genus Diplonema (Diplonemea, Euglenozoa), Diplonema japonicum sp. nov. and Diplonema aggregatum sp. nov., based on life cycle, morphology, and 18S rRNA gene sequences. Along with euglenozoan apomorphies, they contain several unique features. Their life cycle is complex, consisting of a trophic stage that is, following the depletion of nutrients, transformed into a sessile stage and subsequently into a swimming stage. The latter two stages are characterized by the presence of tubular extrusomes and the emergence of a paraflagellar rod, the supportive structure of the flagellum, which is prominently lacking in the trophic stage. These two stages also differ dramatically in motility and flagellar size. Both diplonemid species host endosymbiotic bacteria that are closely related to each other and constitute a novel branch within Holosporales, for which a new genus, "Candidatus Cytomitobacter" gen. nov., has been established. Remarkably, the number of endosymbionts in the cytoplasm varies significantly, as does their localization within the cell, where they seem to penetrate the mitochondrion, a rare occurrence.IMPORTANCE We describe the morphology, behavior, and life cycle of two new Diplonema species that established a relationship with two Holospora-like bacteria in the first report of an endosymbiosis in diplonemids. Both endosymbionts reside in the cytoplasm and the mitochondrion, which establishes an extremely rare case. Within their life cycle, the diplonemids undergo transformation from a trophic to a sessile and eventually a highly motile swimming stage. These stages differ in several features, such as the presence or absence of tubular extrusomes and a paraflagellar rod, along with the length of the flagella. These morphological and behavioral interstage differences possibly reflect distinct functions in dispersion and invasion of the host and/or prey and may provide novel insight into the virtually unknown function of diplonemids in the oceanic ecosystem. PMID- 29511085 TI - Sal-like 4 protein levels in breast cancer cells are post-translationally down regulated by tripartite motif-containing 21. AB - Sal-like 4 (SALL4) is a transcription factor that enhances proliferation and migration in breast cancer cells. SALL4 expression therefore has the potential to promote cancer malignancy. However, the regulatory mechanisms involved in SALL4 protein expression have not been thoroughly elucidated. In this study, we observed that treating MCF-7 and SUM159 breast cancer cell lines with a proteasome inhibitor increases SALL4 protein levels, suggesting that SALL4 is degraded by the ubiquitin-proteasome system. Using immunoprecipitation to uncover SALL4-binding proteins, we identified an E3 ubiquitin-protein ligase, tripartite motif-containing 21 (TRIM21). Using an EGFP reporter probe of the major SALL4 isoform SALL4B, we observed that shRNA-mediated knockdown of TRIM21 increases cellular SALL4B levels. Immunostaining experiments revealed that TRIM21 localizes to the nucleus, and a K64R substitution in the nuclear localization motif in SALL4B increased SALL4B levels in the cytoplasm. These results suggested that TRIM21 is involved in nuclear SALL4 degradation. To identify the amino acid residue that is targeted by TRIM21, we fragmented the SALL4B sequence, fused it to EGFP, and identified Lys-190 in SALL4B as TRIM21's target residue. Amino acid sequence alignments of SALL family members indicated that the region around SALL4 Lys-190 is conserved in both SALL1 and SALL3. Because SALL1 and SALL4 have similar functions, we constructed a SALL1-EGFP probe and found that the TRIM21 knockdown increases SALL1 levels, indicating that TRIM21 degrades both SALL1 and SALL4. Our findings extend our understanding of SALL4 and SALL1 regulation and may contribute to the development of SALL4-targeting therapies. PMID- 29511086 TI - Conformational dynamics of P-glycoprotein in lipid nanodiscs and detergent micelles reveal complex motions on a wide time scale. AB - P-glycoprotein (P-gp) is a highly substrate-promiscuous efflux transporter that plays a critical role in drug disposition. P-gp utilizes ATP hydrolysis by nucleotide-binding domains (NBDs) to drive transitions between inward-facing (IF) conformations that bind drugs and outward-facing (OF) conformations that release them to the extracellular solution. However, the details of the protein dynamics within either macroscopic IF or OF conformation remain uncharacterized, and the functional role of local dynamics has not been determined. In this work we measured the local dynamics of the IF state of P-gp in lipid nanodiscs and in detergent solution by hydrogen-deuterium (H/D) exchange MS. We observed "EX1 exchange kinetics," or bimodal kinetics, for several peptides distributed in both NBDs, particularly for P-gp in the lipid nanodiscs. Remarkably, the EX1 kinetics occurred on several time scales, ranging from seconds to hours, suggesting highly complex, and correlated, motions. The results indicate at least three distinct conformational states in the ligand-free P-gp and suggest a rough conformational landscape. Addition of excess ATP and vanadate, to favor the OF conformations, caused a generalized, but modest, decrease in H/D exchange throughout the NBDs and slowed the EX1 kinetic transitions of several peptides. The functional implications of the results are consistent with the possibility that conformational selection provides a source of substrate promiscuity. PMID- 29511087 TI - The AB loop and D-helix in binding site III of human Oncostatin M (OSM) are required for OSM receptor activation. AB - Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are closely related members of the interleukin-6 (IL-6) cytokine family. Both cytokines share a common origin and structure, and both interact through a specific region, termed binding site III, to activate a dimeric receptor complex formed by glycoprotein 130 (gp130) and LIF receptor (LIFR) in humans. However, only OSM activates the OSM receptor (OSMR)-gp130 complex. The molecular features that enable OSM to specifically activate the OSMR are currently unknown. To define specific sequence motifs within OSM that are critical for initiating signaling via OSMR, here we generated chimeric OSM-LIF cytokines and performed alanine-scanning experiments. Replacement of the OSM AB loop within OSM's binding site III with that of LIF abrogated OSMR activation, measured as STAT3 phosphorylation at Tyr-705, but did not compromise LIFR activation. Correspondingly, substitution of the AB loop and D-helix in LIF with their OSM counterparts was sufficient for OSMR activation. The alanine-scanning experiments revealed that residues Tyr-34, Gln-38, Gly-39, and Leu-45 (in the AB loop) and Pro-153 (in the D-helix) had specific roles in activating OSMR but not LIFR signaling, whereas Leu-40 and Cys-49 (in the AB loop), and Phe-160 and Lys-163 (in the D-helix) were required for activation of both receptors. Because most of the key amino acid residues identified here are conserved between LIF and OSM, we concluded that comparatively minor differences in a few amino acid residues within binding site III account for the differential biological effects of OSM and LIF. PMID- 29511088 TI - Concentration of 2'C-methyladenosine triphosphate by Leishmania guyanensis enables specific inhibition of Leishmania RNA virus 1 via its RNA polymerase. AB - Leishmania is a widespread trypanosomatid protozoan parasite causing significant morbidity and mortality in humans. The endobiont dsRNA virus Leishmania RNA virus 1 (LRV1) chronically infects some strains, where it increases parasite numbers and virulence in murine leishmaniasis models, and correlates with increased treatment failure in human disease. Previously, we reported that 2'-C methyladenosine (2CMA) potently inhibited LRV1 in Leishmania guyanensis (Lgy) and Leishmania braziliensis, leading to viral eradication at concentrations above 10 MUm Here we probed the cellular mechanisms of 2CMA inhibition, involving metabolism, accumulation, and inhibition of the viral RNA-dependent RNA polymerase (RDRP). Activation to 2CMA triphosphate (2CMA-TP) was required, as 2CMA showed no inhibition of RDRP activity from virions purified on cesium chloride gradients. In contrast, 2CMA-TP showed IC50 values ranging from 150 to 910 MUm, depending on the CsCl density of the virion (empty, ssRNA-, and dsRNA containing). Lgy parasites incubated in vitro with 10 MUm 2CMA accumulated 2CMA TP to 410 MUm, greater than the most sensitive RDRP IC50 measured. Quantitative modeling showed good agreement between the degree of LRV1 RDRP inhibition and LRV1 levels. These results establish that 2CMA activity is due to its conversion to 2CMA-TP, which accumulates to levels that inhibit RDRP and cause LRV1 loss. This attests to the impact of the Leishmania purine uptake and metabolism pathways, which allow even a weak RDRP inhibitor to effectively eradicate LRV1 at micromolar concentrations. Future RDRP inhibitors with increased potency may have potential therapeutic applications for ameliorating the increased Leishmania pathogenicity conferred by LRV1. PMID- 29511090 TI - Pathology of poverty: the need for quality improvement efforts to address social determinants of health. PMID- 29511089 TI - TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues. AB - Eukaryotic cells contain distinct organelles, but not all of these compartments are enclosed by membranes. Some intrinsically disordered proteins mediate membraneless organelle formation through liquid-liquid phase separation (LLPS). LLPS facilitates many biological functions such as regulating RNA stability and ribonucleoprotein assembly, and disruption of LLPS pathways has been implicated in several diseases. Proteins exhibiting LLPS typically have low sequence complexity and specific repeat motifs. These motifs promote multivalent connections with other molecules and the formation of higher-order oligomers, and their removal usually prevents LLPS. The intrinsically disordered C-terminal domain of TAR DNA-binding protein 43 (TDP-43), a protein involved in motor neuron disease and dementia lacks a dominant LLPS motif, however, and how this domain forms condensates is unclear. Using extensive mutagenesis of TDP-43, we demonstrate here that three tryptophan residues and, to a lesser extent, four other aromatic residues are most important for TDP-43 to undergo LLPS. Our results also suggested that only a few residues may be required for TDP-43 LLPS because the alpha-helical segment (spanning ~20 residues) in the middle part of the C-terminal domain tends to self-assemble, reducing the number of motifs required for forming a multivalent connection. Our results indicating that a self associating alpha-helical element with a few key residues regulates condensate formation highlight a different type of LLPS involving intrinsically disordered regions. The C-terminal domain of TDP-43 contains ~50 disease-related mutations, with no clear physicochemical link between them. We propose that they may disrupt LLPS indirectly by interfering with the key residues identified here. PMID- 29511091 TI - Measurement and monitoring of safety: impact and challenges of putting a conceptual framework into practice. AB - BACKGROUND: The Measurement and Monitoring of Safety Framework provides a conceptual model to guide organisations in assessing safety. The Health Foundation funded a large-scale programme to assess the value and impact of applying the Framework in regional and frontline care settings. We explored the experiences and reflections of key participants in the programme. METHODS: The study was conducted in the nine healthcare organisations in England and Scotland testing the Framework (three regional improvement bodies, six frontline settings). Post hoc interviews with clinical and managerial staff were analysed using template analysis. FINDINGS: Participants reported that the Framework promoted a substantial shift in their thinking about how safety is actively managed in their environment. It provided a common language, facilitated a more inquisitive approach and encouraged a more holistic view of the components of safety. These changes in conceptual understanding, however, did not always translate into broader changes in practice, with many sites only addressing some aspects of the Framework. One of the three regions did embrace the Framework in its entirety and achieved wider impact with a range of interventions. This region had committed leaders who took time to fully understand the concepts, who maintained a flexible approach to exploring the utility of the Framework and who worked with frontline staff to translate the concepts for local settings. CONCLUSIONS: The Measuring and Monitoring of Safety Framework has the potential to support a broader and richer approach to organisational safety. Such a conceptually based initiative requires both committed leaders who themselves understand the concepts and more time to establish understanding and aims than might be needed in a standard improvement programme. PMID- 29511092 TI - The ConCom Safety Management Scale: developing and testing a measurement instrument for control-based and commitment-based safety management approaches in hospitals. AB - BACKGROUND: Nursing management is considered important for patient safety. Prior research has predominantly focused on charismatic leadership styles, although it is questionable whether these best characterise the role of nurse managers. Managerial control is also relevant. Therefore, we aimed to develop and test a measurement instrument for control-based and commitment-based safety management of nurse managers in clinical hospital departments. METHODS: A cross-sectional survey design was used to test the newly developed questionnaire in a sample of 2378 nurses working in clinical departments. The nurses were asked about their perceptions of the leadership behaviour and management practices of their direct supervisors. Psychometric properties were evaluated using confirmatory factor analysis and reliability estimates. RESULTS: The final 33-item questionnaire showed acceptable goodness-of-fit indices and internal consistency (Cronbach's alpha of the subscales range: 0.59-0.90). The factor structure revealed three subdimensions for control-based safety management: (1) stressing the importance of safety rules and regulations; (2) monitoring compliance; and (3) providing employees with feedback. Commitment-based management consisted of four subdimensions: (1) showing role modelling behaviour; (2) creating safety awareness; (3) showing safety commitment; and (4) encouraging participation. Construct validity of the scale was supported by high factor loadings and provided preliminary evidence that control-based and commitment-based safety management are two distinct yet related constructs. The findings were reconfirmed in a cross-validation procedure. CONCLUSION: The results provide initial support for the construct validity and reliability of our ConCom Safety Management Scale. Both management approaches were found to be relevant for managing patient safety in clinical hospital departments. The scale can be used to deepen our understanding of the influence of patient safety management on healthcare professionals' safety behaviour as well as patient safety outcomes. PMID- 29511094 TI - Translocator protein and steroidogenesis. AB - Two interesting papers by Barren et al. and Owen et al. have been very recently published in Biochemical Journal, reporting the role of translocator protein (TSPO) in steroidogenesis. The involvement of TSPO in the steroid biosynthesis has been suggested by 30 years of researches, using biochemical, pharmacological and genetic experimental approaches. In the last 3 years, however, the TSPO involvement in steroidogenesis has been intensively and profoundly discussed. Using in vivo genetic manipulations aimed at deleting TSPO, some researchers have excluded its role in steroid production. Other research groups, using similar genetic manipulation techniques, have presented different results, corroborating the role of TSPO in steroidogenesis, in particular, when hormonal stimulation occurs. In this scenario, the publications by Barron et al. about 'Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male' and by Owen et al. about 'TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis' are part of this debate and provide further and more accurate information supporting the importance of TSPO as a steroidogenesis regulator. PMID- 29511095 TI - Molecular mobility and activity in an intravital imaging setting - implications for cancer progression and targeting. AB - Molecular mobility, localisation and spatiotemporal activity are at the core of cell biological processes and deregulation of these dynamic events can underpin disease development and progression. Recent advances in intravital imaging techniques in mice are providing new avenues to study real-time molecular behaviour in intact tissues within a live organism and to gain exciting insights into the intricate regulation of live cell biology at the microscale level. The monitoring of fluorescently labelled proteins and agents can be combined with autofluorescent properties of the microenvironment to provide a comprehensive snapshot of in vivo cell biology. In this Review, we summarise recent intravital microscopy approaches in mice, in processes ranging from normal development and homeostasis to disease progression and treatment in cancer, where we emphasise the utility of intravital imaging to observe dynamic and transient events in vivo We also highlight the recent integration of advanced subcellular imaging techniques into the intravital imaging pipeline, which can provide in-depth biological information beyond the single-cell level. We conclude with an outlook of ongoing developments in intravital microscopy towards imaging in humans, as well as provide an overview of the challenges the intravital imaging community currently faces and outline potential ways for overcoming these hurdles. PMID- 29511093 TI - Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases. AB - Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection - termed sterile inflammation - is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP-AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-kappaB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases. PMID- 29511096 TI - Clocking the difference: inverse relationship between epithelial and fibroblast clock regulation. PMID- 29511097 TI - Anthropogenic enrichment of mercury greater than that of vanadium. PMID- 29511099 TI - Noninvasive detection of macrophage activation with single-cell resolution through machine learning. AB - We present a method enabling the noninvasive study of minute cellular changes in response to stimuli, based on the acquisition of multiple parameters through label-free microscopy. The retrieved parameters are related to different attributes of the cell. Morphological variables are extracted from quantitative phase microscopy and autofluorescence images, while molecular indicators are retrieved via Raman spectroscopy. We show that these independent parameters can be used to build a multivariate statistical model based on logistic regression, which we apply to the detection at the single-cell level of macrophage activation induced by lipopolysaccharide (LPS) exposure and compare their respective performance in assessing the individual cellular state. The models generated from either morphology or Raman can reliably and independently detect the activation state of macrophage cells, which is validated by comparison with their cytokine secretion and intracellular expression of molecules related to the immune response. The independent models agree on the degree of activation, showing that the features provide insight into the cellular response heterogeneity. We found that morphological indicators are linked to the phenotype, which is mostly related to downstream effects, making the results obtained with these variables dose-dependent. On the other hand, Raman indicators are representative of upstream intracellular molecular changes related to specific activation pathways. By partially inhibiting the LPS-induced activation using progesterone, we could identify several subpopulations, showing the ability of our approach to identify the effect of LPS activation, specific inhibition of LPS, and also the effect of progesterone alone on macrophage cells. PMID- 29511098 TI - Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay. AB - Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized GrnR493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous GrnR493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP 43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival. Inhibition of nonsense-mediated mRNA decay (NMD) by genetic, pharmacological, or antisense oligonucleotide-based approaches showed that NMD contributes to the reduced mRNA levels in GrnR493X mice and cell lines and in fibroblasts from patients containing the GRNR493X mutation. Moreover, the expressed truncated R493X mutant protein was functional in several assays in progranulin-deficient cells. Together, these findings establish a murine model for in vivo testing of NMD inhibition or other therapies as potential approaches for treating progranulin deficiency caused by the R493X mutation. PMID- 29511100 TI - Vaccination can drive an increase in frequencies of antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae. AB - The bacterial pathogen Streptococcus pneumoniae is a major public health concern, being responsible for more than 1.5 million deaths annually through pneumonia, meningitis, and septicemia. Available vaccines target only a subset of serotypes, so vaccination is often accompanied by a rise in the frequency of nonvaccine serotypes. Epidemiological studies suggest that such a change in serotype frequencies is often coupled with an increase of antibiotic resistance among nonvaccine serotypes. Building on previous multilocus models for bacterial pathogen population structure, we have developed a theoretical framework incorporating variation of serotype and antibiotic resistance to examine how their associations may be affected by vaccination. Using this framework, we find that vaccination can result in a rapid increase in the frequency of preexisting resistant variants of nonvaccine serotypes due to the removal of competition from vaccine serotypes. PMID- 29511101 TI - Intermediate filament accumulation can stabilize microtubules in Caenorhabditis elegans motor neurons. AB - Neural circuits utilize a coordinated cellular machinery to form and eliminate synaptic connections, with the neuronal cytoskeleton playing a prominent role. During larval development of Caenorhabditis elegans, synapses of motor neurons are stereotypically rewired through a process facilitated by dynamic microtubules (MTs). Through a genetic suppressor screen on mutant animals that fail to rewire synapses, and in combination with live imaging and ultrastructural studies, we find that intermediate filaments (IFs) stabilize MTs to prevent synapse rewiring. Genetic ablation of IFs or pharmacological disruption of IF networks restores MT growth and rescues synapse rewiring defects in the mutant animals, indicating that IF accumulation directly alters MT stability. Our work sheds light on the impact of IFs on MT dynamics and axonal transport, which is relevant to the mechanistic understanding of several human motor neuron diseases characterized by IF accumulation in axonal swellings. PMID- 29511102 TI - Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine. AB - Monoterpenoid indole alkaloids (MIAs) possess a diversity of alkaloid skeletons whose biosynthesis is poorly understood. A bioinformatic search of candidate genes, combined with their virus-induced gene silencing, targeted MIA profiling and in vitro/in vivo pathway reconstitution identified and functionally characterized six genes as well as a seventh enzyme reaction required for the conversion of 19E-geissoschizine to tabersonine and catharanthine. The involvement of pathway intermediates in the formation of four MIA skeletons is described, and the role of stemmadenine-O-acetylation in providing necessary reactive substrates for the formation of iboga and aspidosperma MIAs is described. The results enable the assembly of complex dimeric MIAs used in cancer chemotherapy and open the way to production of many other biologically active MIAs that are not easily available from nature. PMID- 29511103 TI - Susceptibility of brain atrophy to TRIB3 in Alzheimer's disease, evidence from functional prioritization in imaging genetics. AB - The joint modeling of brain imaging information and genetic data is a promising research avenue to highlight the functional role of genes in determining the pathophysiological mechanisms of Alzheimer's disease (AD). However, since genome wide association (GWA) studies are essentially limited to the exploration of statistical correlations between genetic variants and phenotype, the validation and interpretation of the findings are usually nontrivial and prone to false positives. To address this issue, in this work, we investigate the functional genetic mechanisms underlying brain atrophy in AD by studying the involvement of candidate variants in known genetic regulatory functions. This approach, here termed functional prioritization, aims at testing the sets of gene variants identified by high-dimensional multivariate statistical modeling with respect to known biological processes to introduce a biology-driven validation scheme. When applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, the functional prioritization allowed for identifying a link between tribbles pseudokinase 3 (TRIB3) and the stereotypical pattern of gray matter loss in AD, which was confirmed in an independent validation sample, and that provides evidence about the relation between this gene and known mechanisms of neurodegeneration. PMID- 29511105 TI - Bifurcation-enhanced ultrahigh sensitivity of a buckled cantilever. AB - Buckling, first introduced by Euler in 1744 [Euler L (1744) Opera Omnia I 24:231], a sudden mechanical sideways deflection of a structural member under compressive stress, represents a bifurcation in the solution to the equations of static equilibrium. Although it has been investigated in diverse research areas, such a common nonlinear phenomenon may be useful to devise a unique mechanical sensor that addresses the still-challenging features, such as the enhanced sensitivity and polarization-dependent detection capability. We demonstrate the bifurcation-enhanced sensitive measurement of mechanical vibrations using the nonlinear buckled cantilever tip in ambient conditions. The cantilever, initially buckled with its tip pinned, flips its buckling near the bifurcation point (BP), where the buckled tip becomes softened. The enhanced mechanical sensitivity results from the increasing fluctuations, unlike the typical linear sensors, which facilitate the noise-induced buckling-to-flipping transition of the softened cantilever. This allows the in situ continuous or repeated single-shot detection of the surface acoustic waves of different polarizations without any noticeable wear of the tip. We obtained the sensitivity above 106 V(m/s)-1, a 1,000-fold enhancement over the conventional seismometers. Our results lead to development of mechanical sensors of high sensitivity, reproducibility, and durability, which may be applied to detect, e.g., the directional surface waves on the laboratory as well as the geological scale. PMID- 29511104 TI - Metabolic shift from glycogen to trehalose promotes lifespan and healthspan in Caenorhabditis elegans. AB - As Western diets continue to include an ever-increasing amount of sugar, there has been a rise in obesity and type 2 diabetes. To avoid metabolic diseases, the body must maintain proper metabolism, even on a high-sugar diet. In both humans and Caenorhabditis elegans, excess sugar (glucose) is stored as glycogen. Here, we find that animals increased stored glycogen as they aged, whereas even young adult animals had increased stored glycogen on a high-sugar diet. Decreasing the amount of glycogen storage by modulating the C. elegans glycogen synthase, gsy-1, a key enzyme in glycogen synthesis, can extend lifespan, prolong healthspan, and limit the detrimental effects of a high-sugar diet. Importantly, limiting glycogen storage leads to a metabolic shift whereby glucose is now stored as trehalose. Two additional means to increase trehalose show similar longevity extension. Increased trehalose is entirely dependent on a functional FOXO transcription factor DAF-16 and autophagy to promote lifespan and healthspan extension. Our results reveal that when glucose is stored as glycogen, it is detrimental, whereas, when stored as trehalose, animals live a longer, healthier life if DAF-16 is functional. Taken together, these results demonstrate that trehalose modulation may be an avenue for combatting high-sugar-diet pathology. PMID- 29511107 TI - Reply to Selin: Human impacts on the atmospheric burden of trace metals. PMID- 29511108 TI - Natural transmission of bovine viral diarrhoea virus-1c from a persistently infected neonate lamb to naive sheep and cattle. AB - This study investigated the transmission of bovine viral diarrhoea virus (BVDV) 1c from a persistently infected (PI) neonate lamb to naive sheep and cattle using three treatment groups: four naive ewes and their five lambs, which were copaddocked with the PI lamb; five steers, which were housed in a paddock adjacent to the PI lamb; and five steers, which had direct but limited exposure to the PI lamb. Serum samples were collected and tested for BVDV-specific antibodies. Serum samples from the PI lamb, from day of birth to eight weeks of age, were tested for BVDV-specific antibodies and antigen and submitted for quantitative PCR to determine the viral load present at each week of age. Only one lamb from the copaddocked group developed BVDV-specific antibodies following comingling while all the steers in both the cattle treatment groups remained BVDV antibody negative. Quantitative PCR results from the PI lamb showed lower viral loads from day of birth to six weeks of age, compared with the results at seven and eight weeks of age. This may reflect maternal colostral BVDV antibody concentrations in the neonate lamb or other viral properties. PMID- 29511106 TI - Towards an unconscious neural reinforcement intervention for common fears. AB - Can "hardwired" physiological fear responses (e.g., for spiders and snakes) be reprogramed unconsciously in the human brain? Currently, exposure therapy is among the most effective treatments for anxiety disorders, but this intervention is subjectively aversive to patients, causing many to drop out of treatment prematurely. Here we introduce a method to bypass the subjective unpleasantness in conscious exposure, by directly pairing monetary reward with unconscious occurrences of decoded representations of naturally feared animals in the brain. To decode physiological fear representations without triggering excessively aversive reactions, we capitalize on recent advancements in functional magnetic resonance imaging decoding techniques, and use a method called hyperalignment to infer the relevant representations of feared animals for a designated participant based on data from other "surrogate" participants. In this way, the procedure completely bypasses the need for a conscious encounter with feared animals. We demonstrate that our method can lead to reliable reductions in physiological fear responses, as measured by skin conductance as well as amygdala hemodynamic activity. Not only do these results raise the intriguing possibility that naturally occurring fear responses can be "reprogrammed" outside of conscious awareness, importantly, they also create the rare opportunity to rigorously test a psychological intervention of this nature in a double-blind, placebo-controlled fashion. This may pave the way for a new approach combining the appealing rationale and proven efficacy of conventional psychotherapy with the rigor and leverage of clinical neuroscience. PMID- 29511109 TI - Taeniid and other parasite ova in the faeces of working sheepdogs in south-west England. PMID- 29511110 TI - POEMS neuropathy: optimising diagnosis and management. AB - POEMS syndrome is a rare and disabling autoinflammatory condition characterised by a typical peripheral neuropathy and the presence of a monoclonal plasma cell disorder. The acronym 'POEMS' represents the complex and multisystem features of the disease, including polyneuropathy, organomegaly, endocrinopathy, a monoclonal plasma cell disorder and skin disease. The diagnosis of POEMS is a significant challenge because of the heterogeneity of clinical presentations and variation of POEMS features. Patients are often misdiagnosed with another cause of inflammatory neuropathy and receive one or more ineffective immunomodulatory medications, resulting in delayed diagnosis and further clinical deterioration before a diagnosis is made. University College London Hospitals sees one of the largest reported POEMS cohorts in Europe, and runs a multispecialist clinic to assist with diagnosis, treatment and ongoing support. This review draws upon our experience to present the typical features of POEMS syndrome and highlight diagnostic conundrums commonly experienced, supplemented with clinical cases. We provide an investigative guide for clinicians when considering POEMS as the diagnosis, and propose a treatment algorithm that centres on the site and degree of monoclonal cell proliferation. PMID- 29511112 TI - We AIM2 Inflame. PMID- 29511111 TI - Protein S Protects against Podocyte Injury in Diabetic Nephropathy. AB - Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear.Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN.Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose-induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose- and TNF-alpha-induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice.Conclusions Our results support a protective role of PS against glomerular injury in DN progression. PMID- 29511113 TI - Blood HER2 and Uromodulin as Causal Mediators of CKD. AB - Many biomarkers have been epidemiologically linked with CKD; however, the possibility that such associations are due to reverse causation or confounding limits the utility of these biomarkers. To overcome this limitation, we used a Mendelian randomization (MR) approach to identify causal mediators of CKD. We performed MR by first identifying genetic determinants of 227 serum protein biomarkers assayed in 4147 participants of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial who had early or prediabetes, and assessing the effects of these biomarkers on CKD in the CKD genetics consortium (n=117,165; 12,385 cases) using the inverse-variance weighted (fixed-effects) method. We then estimated the relationship between the serum concentration of each biomarker identified and incident CKD in ORIGIN participants. MR identified uromodulin (UMOD) and human EGF receptor 2 (HER2) as novel, causal mediators of CKD (UMOD: odds ratio [OR], 1.30 per SD; 95% confidence interval [95% CI], 1.25 to 1.35; P<5*10-20; HER2: OR, 1.30 per SD; 95% CI, 1.14 to 1.48; P=8.0*10-5). Consistent with these findings, blood HER2 concentration associated with CKD events in ORIGIN participants (OR, 1.07 per SD; 95% CI, 1.01 to 1.13; P=0.01). Additional exploratory MR analyses identified angiotensin-converting enzyme (ACE) as a regulator of HER2 levels (beta=0.13 per SD; 95% CI, 0.08 to 0.16; P=2.5*10-7). This finding was corroborated by an inverse relationship between ACE inhibitor use and HER2 levels. Thus, UMOD and HER2 are independent causal mediators of CKD in humans, and serum HER2 levels are regulated in part by ACE. These biomarkers are potential therapeutic targets for CKD prevention. PMID- 29511115 TI - Measurement of oxygen extraction fraction by blood sampling to estimate severe cerebral hemodynamic failure and anticipate cerebral hyperperfusion syndrome following carotid artery stenting. AB - BACKGROUND: Cerebral hyperperfusion syndrome (CHS) is likely to occur after carotid revascularization in patients with stage 2 hemodynamic failure (st2HF), in whom the oxygen extraction fraction (OEF) increases. OBJECTIVE: The purpose of our study was to investigate whether measurement of the global cerebral OEF (gcOEF) by blood sampling can be used to estimate st2HF and anticipate CHS following carotid artery stenting (CAS). METHODS: The OEF was calculated by blood sampling just before and after elective CAS. Data were collected prospectively. Patients who underwent elective CAS and gcOEF calculation were included in the study. Patients' baseline features, pre-CAS gcOEF, post-CAS gcOEF, and incidence of CHS (defined as headache, seizure, focal neurologic deficits, and/or restlessness) were evaluated. RESULTS: 141 patients met the inclusion criteria and 134 patients were analyzed. Median pre-CAS gcOEF and post-CAS gcOEF were 0.41 and 0.42, respectively. Nine patients developed CHS. Median pre-CAS gcOEF was higher in patients with than in those without CHS (Mann-Whitney U test, P<0.05), but median post-CAS gcOEF was not significantly higher in patients with CHS (P=0.058). Scattergrams of patients with and without CHS showed that the cut-off values of the pre-CAS gcOEF and post-CAS gcOEF for anticipation of CHS were 0.46 (P<0.01) and 0.49 (P<0.001), respectively. CONCLUSION: Elevation of the pre-CAS or post-CAS gcOEF by blood sampling allowed for anticipation of CHS following CAS. Elevation of the pre-CAS gcOEF might be associated with st2HF. PMID- 29511114 TI - The VITAL study and overall pooled analysis with the VIPS non-invasive stroke detection device. AB - INTRODUCTION: Effective triage of patients with emergent large vessel occlusion (ELVO) to endovascular therapy capable centers may decrease time to treatment and improve outcome for these patients. Here we performed a derivation study to evaluate the accuracy of a portable, non-invasive, and easy to use severe stroke detector. METHODS: The volumetric impedance phase shift spectroscopy (VIPS) device was used to assign a bioimpedance asymmetry score to 248 subjects across three cohorts, including 41 subjects presenting as acute stroke codes at a major comprehensive stroke center (CSC), 79 healthy volunteers, and 128 patients presenting to CSCs with a wide variety of brain pathology including additional stroke codes. Diagnostic parameters were calculated for the ability of the device to discern (1) severe stroke from minor stroke and (2) severe stroke from all other subjects. Patients with intracranial hardware were excluded from the analysis. RESULTS: The VIPS device was able to differentiate severe stroke from minor strokes with a sensitivity of 93% (95% CI 83 to 98), specificity of 92% (95% CI 75 to 99), and an area under the curve (AUC) of 0.93 (95% CI 0.85 to 0.97). The device was able to differentiate severe stroke from all other subjects with a sensitivity of 93% (95% CI 83 to 98), specificity of 87% (95% CI 81 to 92), and an AUC of 0.95 (95% CI 0.89 to 0.96). CONCLUSION: The VIPS device is a portable, non-invasive, and easy to use tool that may aid in the detection of severe stroke, including ELVO, with a sensitivity of 93% and specificity of 92% in this derivation study. This device has the potential to improve the triage of patients suffering severe stroke. PMID- 29511116 TI - Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. AB - OBJECTIVE: To identify the prevalence and therapeutic consequences of spontaneous intracranial artery dissection (IAD) at the acute phase of ischemic stroke. METHODS: We reviewed clinical and imaging data of consecutive patients attending our center for mechanical thrombectomy (MT) between January 2012 and November 2017. IAD was defined according to published criteria and our own angiographic criteria (no clot following MT, and normalization of the vessel caliber after stenting). RESULTS: IAD was retrospectively diagnosed in 13/391 (3%) patients (inter-rater agreement kappa=0.885, P<0.001). It was an extending of extracranial dissection in 7/13 (54%) patients. A total of 21 recanalization approaches (with or without IV tissue plasminogen activator) were analyzed in 13 patients. A medical approach was used in 7/21 (33%), MT in 7/21 (33%) (stent retriever=6, thromboaspiration=1), and permanent stenting in 7/21 (33%). A rescue recanalization was necessary after 8/14 (57%) approaches without stenting. Stenting was associated with a best rate of recanalization (P=0.001) and with a trend towards a lower rate of ischemic recurrence (P=0.057). Stenting of a circulating false lumen failed to recanalize the artery in two patients. At the last follow-up, no patient had developed a subarachnoid hemorrhage due to the dissection. The outcome at 3 months was favorable in 8/13 (62%) patients. One patient died at 3 weeks owing to a severe cerebellar infarction. CONCLUSION: IAD is a rare diagnosis that should be systematically considered in patients with intracranial large vessel occlusion, especially in patients with extracranial artery dissection and when MT does not retrieve any clot. Stenting of IAD as first-line approach should be assessed in further studies. PMID- 29511117 TI - Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia. AB - BACKGROUND: Optical coherence tomography (OCT) is a high-resolution, intra vascular diagnostic technique widely used for the characterization of vascular pathologies and optimization of stent implantation during percutaneous coronary intervention. OCT was used to investigate the in vivo vascular response to a new phosphorylcholine surface modified flow diverter (sPED). METHODS: In an in vivo rabbit aneurysmal model, we used two different types of flow diverters (classic Pipeline - cPED; and sPED) with or without dual antiplatelet therapy (four groups, n=10 per group). OCT cross-sectional area measurements were compared with histology in all animals. Neointimal hyperplasia (NIH) ratio was compared between OCT and histology at five different levels for each stent. The severity of NIH was also compared between the different stents, antiplatelet protocols, and vessel locations. RESULTS: OCT was used to calculate in-stent hyperplasia in 227 different locations corresponding to histology sections. OCT measurement strongly correlated with gold standard histology (r2=0.83; slope=0.988; P<0.0001). sPED had significantly less in-stent NIH than non-treated flow diverters (mean percent of lumen reduction 5.7% for sPED versus 8.9% for cPED; P<0.0001). The NIH ratio was slightly higher with dual antiplatelet therapy (DAPT) (NIH ratio=7.9% with DAPT versus 6.8% without DAPT; P<0.05). Complete and near complete occlusion rates of the aneurysms were not different with the cPED or sPED. CONCLUSION: OCT is a promising technique for immediate and long-term evaluation of flow diverter stent treatments. In an animal model, phosphorylcholine surface modified flow diverters induces less NIH after stent implant without reducing aneurysm occlusion rates. PMID- 29511118 TI - Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of "off target" pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor kappaB (NF-kappaB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders. PMID- 29511119 TI - Splenic leukocytes define the resolution of inflammation in heart failure. AB - Inflammation promotes healing in myocardial infarction but, if unresolved, leads to heart failure. To define the inflammatory and resolving responses, we quantified leukocyte trafficking and specialized proresolving mediators (SPMs) in the infarcted left ventricle and spleen after myocardial infarction, with the goal of distinguishing inflammation from its resolution. Our data suggest that the spleen not only served as a leukocyte reservoir but also was the site where SPMs were actively generated after coronary ligation in mice. Before myocardial infarction, SPMs were more abundant in the spleen than in the left ventricle. At day 1 after coronary ligation, the spleen was depleted of leukocytes, a phenomenon that was associated with greater numbers of leukocytes in the infarcted left ventricle and increased generation of SPMs at the same site, particularly resolvins, maresin, lipoxins, and protectin. In addition, the infarcted left ventricle showed increased expression of genes encoding lipoxygenases and enhanced production of SPMs generated by these enzymes. We found that macrophages were necessary for SPM generation. The abundance of SPMs in the spleen before myocardial infarction and increased SPM concentrations in the infarcted left ventricle within 24 hours after myocardial infarction were temporally correlated with the resolution of inflammation. Thus, the acute inflammatory response coincided with the active resolving phase in post myocardial infarction and suggests that further investigation into macrophage derived SPMs in heart failure is warranted. PMID- 29511120 TI - cAMPr: A single-wavelength fluorescent sensor for cyclic AMP. AB - Genetically encoded fluorescent sensors enable cell-specific measurements of ions and small molecules in real time. Cyclic adenosine monophosphate (cAMP) is one of the most important signaling molecules in virtually all cell types and organisms. We describe cAMPr, a new single-wavelength cAMP sensor. We developed cAMPr in bacteria and embryonic stem cells and validated the sensor in mammalian neurons in vitro and in Drosophila circadian pacemaker neurons in intact brains. Comparison with other single-wavelength cAMP sensors showed that cAMPr improved the quantitative detection of cAMP abundance. In addition, cAMPr is compatible with both single-photon and two-photon imaging. This enabled us to use cAMPr together with the red fluorescent Ca2+ sensor RCaMP1h to simultaneously monitor Ca2+ and cAMP in Drosophila brains. Thus, cAMPr is a new and versatile genetically encoded cAMP sensor. PMID- 29511121 TI - A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress. AB - Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders. We found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb. Through its receptor CRFR1 and subsequently protein kinase A (PKA), CRF application increased the intrinsic excitability of LHb neurons by affecting changes in small-conductance SK-type and large-conductance BK-type K+ channels. CRF also reduced inhibitory gamma-aminobutyric acid containing (GABAergic) synaptic transmission onto LHb neurons through endocannabinoid-mediated retrograde signaling. Maternal deprivation is a severe early-life stress that alters CRF neural circuitry and is likewise associated with abnormal mental health later in life. LHb neurons from pups deprived of maternal care exhibited increased intrinsic excitability, reduced GABAergic transmission, decreased abundance of SK2 channel protein, and increased activity of PKA, without any substantial changes in Crh or Crhr1 expression. Furthermore, maternal deprivation blunted the response of LHb neurons to subsequent, acute CRF exposure. Activating SK channels or inhibiting postsynaptic PKA activity prevented the effects of both CRF and maternal deprivation on LHb intrinsic excitability, thus identifying potential pharmacological targets to reverse central CRF circuit dysregulation in patients with associated disorders. PMID- 29511122 TI - Membrane protein recycling from the vacuole/lysosome membrane. AB - The lysosome (or vacuole in yeast) is the central organelle responsible for cellular degradation and nutrient storage. Lysosomes receive cargo from the secretory, endocytic, and autophagy pathways. Many of these proteins and lipids are delivered to the lysosome membrane, and some are degraded in the lysosome lumen, whereas others appear to be recycled through unknown pathways. In this study, we identify the transmembrane autophagy protein Atg27 as a physiological cargo recycled from the vacuole. We reveal that Atg27 is delivered to the vacuole membrane and then recycled using a two-step recycling process. First, Atg27 is recycled from the vacuole to the endosome via the Snx4 complex and then from the endosome to the Golgi via the retromer complex. During the process of vacuole-to endosome retrograde trafficking, Snx4 complexes assemble on the vacuolar surface and recognize specific residues in the cytoplasmic tail of Atg27. This novel pathway maintains the normal composition and function of the vacuole membrane. PMID- 29511124 TI - News Feature: Can predators have a big impact on carbon emissions calculations? PMID- 29511123 TI - Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization. AB - To relieve endoplasmic reticulum (ER) stress, IRE1 splices XBP1 messenger RNA (mRNA) or engages regulated IRE1-dependent decay (RIDD) of other mRNAs. Upon XBP1 deficiency, IRE1 switches to perform RIDD. We examined IRE1 in XBP1-deficient B cells and discovered that IRE1 undergoes phosphorylation at S729. We generated an anti-phospho-S729 antibody to investigate such phosphorylation. Compared with pharmacological ER stress inducers or Toll-like receptor ligands, the bacterial subtilase cytotoxin has an unusual capability in causing rapid and strong phosphorylation at S729 and triggering B cells to express spliced XBP1. To assess the function of S729 in IRE1, we generated S729A knock-in mice and found S729 is critically important for lipopolysaccharide-stimulated plasmablasts to respond to additional ER stress and for antibody production in response to immunization. We further crossed mice carrying an S729A mutation or DeltaIRE1 (missing the kinase domain) with B cell-specific XBP1-deficient mice to trigger RIDD and discovered a critical role for S729 in regulating RIDD in B cells. PMID- 29511127 TI - Telestroke for the Newly Minted Vascular Neurologist. PMID- 29511126 TI - Minocycline Effects on Intracerebral Hemorrhage-Induced Iron Overload in Aged Rats: Brain Iron Quantification With Magnetic Resonance Imaging. AB - BACKGROUND AND PURPOSE: Brain iron overload is a key factor causing brain injury after intracerebral hemorrhage (ICH). This study quantified brain iron levels after ICH with magnetic resonance imaging R2* mapping. The effect of minocycline on iron overload and ICH-induced brain injury in aged rats was also determined. METHODS: Aged (18 months old) male Fischer 344 rats had an intracerebral injection of autologous blood or saline, and brain iron levels were measured by magnetic resonance imaging R2* mapping. Some ICH rats were treated with minocycline or vehicle. The rats were euthanized at days 7 and 28 after ICH, and brains were used for immunohistochemistry and Western blot analyses. Magnetic resonance imaging (T2-weighted, T2* gradient-echo, and R2* mapping) sequences were performed at different time points. RESULTS: ICH-induced brain iron overload in the perihematomal area could be quantified by R2* mapping. Minocycline treatment reduced brain iron accumulation, T2* lesion volume, iron-handling protein upregulation, neuronal cell death, and neurological deficits (P<0.05). CONCLUSIONS: Magnetic resonance imaging R2* mapping is a reliable and noninvasive method, which can quantitatively measure brain iron levels after ICH. Minocycline reduced ICH-related perihematomal iron accumulation and brain injury in aged rats. PMID- 29511128 TI - Risk Factors for and Clinical Consequences of Multiple Intracranial Aneurysms: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Multiple intracranial aneurysms (MIAs) are common findings of cerebral angiographies; however, MIA prevalence varies in different patient cohorts. We sought to elucidate risk factors influencing MIA prevalence and the clinical consequences. METHODS: We systematically searched PubMed, Scopus, Embase, and Cochrane Library databases for publications before January 15, 2017, reporting MIA prevalence and risk factors. We used random-effects meta analysis and multivariate regression analysis to assess the impacts of individual, study, and population characteristics. RESULTS: We included 174 studies reporting on MIA (mean overall prevalence, 20.1%; range, 2%-44.9%) in 134 study populations with 86 989 intracranial aneurysm (IA) patients enrolled between 1950 and 2015. Studies from Europe and North America (P<0.001) and more recent enrolment years (P=0.046) were independently associated with higher MIA prevalence. In meta-analysis, MIA correlated with female sex (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.4-1.8), higher patient age (>40 years; OR, 1.6; 95% CI, 1.14-2.25), arterial hypertension (OR, 1.51; 95% CI, 1.17-1.94), smoking (OR, 1.89; 95% CI, 1.37-2.6) and familial IA (OR, 2.02; 95% CI, 1.47 2.77), and formation of de novo (OR, 3.92; 95% CI, 1.95-7.87) and growth of initial IA (OR, 3.47; 95% CI, 1.87-6.45). Risk of subarachnoid hemorrhage in MIA patients was higher only in longitudinal studies from Japan and Korea (OR, 2.08; 95% CI, 1.46-2.96). CONCLUSIONS: Female sex, higher age, arterial hypertension, smoking, and familial IA are major risk factors for MIA. In addition, MIA patients are at risk for enhanced IA formation. Further studies are needed to evaluate rupture risk and the role of ethnicity, especially in the context of increased MIA identification with improved neurovascular imaging. PMID- 29511129 TI - Increased Risk of Pregnancy Complications After Stroke: The FUTURE Study (Follow Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation). AB - BACKGROUND AND PURPOSE: The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack. METHODS: In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy. RESULTS: Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively (P<0.05). In nulliparous women after stroke (n=22), in comparison with Dutch population, there was a high prevalence of hypertensive disorders in pregnancy (33.3 versus 12.2%; P<0.05), hemolysis, elevated liver enzymes, low platelet count syndrome (9.5 versus 0.5%; P<0.05), and early preterm delivery <32 weeks (9.0 versus 1.4%; P<0.05). In primi/multiparous women (n=141) after stroke, 29 events occurred (20-year cumulative risk 35.2%; 95% confidence interval, 21.3 49.0), none during subsequent pregnancies, and a history of a hypertensive disorder in pregnancy did not modify this risk (log-rank P=0.62). CONCLUSIONS: When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications. PMID- 29511130 TI - Desirable Low-Density Lipoprotein Cholesterol Levels for Preventing Stroke Recurrence: A Post Hoc Analysis of the J-STARS Study (Japan Statin Treatment Against Recurrent Stroke). AB - BACKGROUND AND PURPOSE: To define desirable target low-density lipoprotein (LDL) cholesterol levels for the prevention of stroke recurrence, a post hoc analysis was performed in the J-STARS study (Japan Statin Treatment Against Recurrent Stroke). METHODS: Subjects (n=1578) were divided into groups based on mean value of postrandomized LDL cholesterol levels until the last observation in 20 mg/dL increments. Adjusted hazard ratios (HRs) and 95% confidence intervals were analyzed for each group, with adjustments for baseline LDL cholesterol, baseline body mass index, hypertension, diabetes mellitus, and statin usage. RESULTS: The postrandomized LDL cholesterol level until the last observation were 104.1+/-19.3 mg/dL in the pravastatin group and 126.1+/-20.6 mg/dL in the control group. The adjusted HRs for stroke and transient ischemic attack and all vascular events decreased in the postrandomized LDL cholesterol level of 80 to 100 mg/dL (P=0.23 and 0.25 for the trend, respectively). The adjusted HR for atherothrombotic infarction significantly reduced with the usage of statin after adjusting baseline LDL cholesterol levels (HR, 0.39; 95% confidence intervals, 0.19-0.83). The adjusted HR for atherothrombotic infarction and intracranial hemorrhage were similar among the postrandomized LDL-cholesterol-level subgroups (P=0.50 and 0.37 for the trend, respectively). The adjusted HR for lacunar infarction decreased in the postrandomized LDL cholesterol level of 100 to 120 mg/dL (HR, 0.45; 95% confidence intervals, 0.20-0.99; P=0.41 for the trend). CONCLUSIONS: The composite risk of stroke and transient ischemic attack reduced in the postrandomized LDL cholesterol level of 80 to 100 mg/dL after adjusting for statin usage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00221104. PMID- 29511131 TI - Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion. AB - BACKGROUND AND PURPOSE: Endothelial progenitor cells (EPCs) have been extensively investigated as a therapeutic approach for repairing the vascular system in cerebrovascular diseases. Beyond vascular regeneration per se, EPCs may also release factors that affect the entire neurovascular unit. Here, we aim to study the effects of the EPC secretome on oligovascular remodeling in a mouse model of white matter injury after prolonged cerebral hypoperfusion. METHODS: The secretome of mouse EPCs was analyzed with a proteome array. In vitro, the effects of the EPC secretome and its factor angiogenin were assessed on primary oligodendrocyte precursor cells and mature human cerebral microvascular endothelial cells (hCMED/D3). In vivo, mice were subjected to permanent bilateral common carotid artery stenosis, then treated with EPC secretome at 24 hours and at 1 week, and cognitive outcome was evaluated with the Y maze test together with oligodendrocyte precursor cell proliferation/differentiation and vascular density in white matter at 4 weeks. RESULTS: Multiple growth factors, cytokines, and proteases were identified in the EPC secretome, including angiogenin. In vitro, the EPC secretome significantly enhanced endothelial and oligodendrocyte precursor cell proliferation and potentiated oligodendrocyte precursor cell maturation. Angiogenin was proved to be a key factor since pharmacological blockade of angiogenin signaling negated the positive effects of the EPC secretome. In vivo, treatment with the EPC secretome increased vascular density, myelin, and mature oligodendrocytes in white matter and rescued cognitive function in the mouse hypoperfusion model. CONCLUSIONS: Factors secreted by EPCs may ameliorate white matter damage in the brain by boosting oligovascular remodeling. PMID- 29511133 TI - Ultra-thin and strong formvar-based membranes with controlled porosity for micro- and nano-scale systems. AB - We present a methodology for developing ultra-thin and strong formvar-based membranes with controlled morphologies. Formvar is a thin hydrophilic and oleophilic polymer inert to most chemicals and resistant to radiation. The formvar-based membranes are viable materials as support structures in micro- and macro-scale systems depending on thinness and porosity control. Tunable sub micron thick porous membranes with 20%-65% porosity were synthesized by controlling the ratios of formvar, glycerol, and chloroform. This synthesis process does not require complex separation or handling methods and allows for the production of strong, thin, and porous formvar-based membranes. An expansive array of these membrane characterizations including chemical compatibility, mechanical responses, wettability, as well as the mathematical simulations as a function of porosity has been presented. The wide range of chemical compatibility allows for membrane applications in various environments, where other polymers would not be suitable. Our formvar-based membranes were found to have an elastic modulus of 7.8 GPa, a surface free energy of 50 mN m-1 and an average thickness of 125 nm. Stochastic model simulations indicate that formvar with the porosity of ~50% is the optimal membrane formulation, allowing the most material transfer across the membrane while also withstanding the highest simulated pressure loadings before tearing. Development of novel, resilient and versatile membranes with controlled porosity offers a wide range of exciting applications in the fields of nanoscience, microfluidics, and MEMS. PMID- 29511132 TI - A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers. AB - LESSONS LEARNED: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma. BACKGROUND: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models. METHODS: Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit. RESULTS: Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days). CONCLUSION: OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors. PMID- 29511134 TI - Factors Associated with the Risk of Persistent Gastrostomy Site Infection Following Laparoscopic or Open Nissen Fundoplication. AB - Background: Gastrostomy for feeding disorders or swallowing dysfunctions can be complicated by persistent gastrostomy site infection (PGSI). PGSI causes nutrient leakage, with dilated PGSI requiring gastrostomy reconstruction. The purpose of this study was to evaluate the causes, patient characteristics, and perioperative management of PGSI after Nissen fundoplication and gastrostomy for patients with gastro-oesophageal reflux. Patients and Methods: The records of all patients who underwent Nissen fundoplication and gastrostomy for gastro-oesophageal reflux over the past 12 years were retrieved. Risk factors were analysed, including age at surgery, gender, operative procedure, use of postoperative ventilator management, gastrostomy tube migration towards the pylorus, bacterial culture results, and length of hospital stay. PGSI as a cause of inflammation was analysed statistically. Results: Forty patients were identified, ranging in age from 1 to 49 years (median, 11 years) surgically. Twenty each underwent laparoscopic and open surgery, with all undergoing gastrostomy using the Stamm technique. Four patients developed PGSI. Gastrostomy tubes had migrated postoperatively to the pyloric side in three of these four patients (P < 0.005), increasing intragastric pressure. Three of these four patients also required positive pressure ventilation during the perioperative period (P < 0.001). Conclusion: PGSI correlates with the perioperative management of positive pressure and with increased intragastric pressure resulting from pyloric obstruction, which is caused by aberrant distribution of the gastrostomy tube to the pyloric side. Statistical Analysis Used: Factors in the two groups were compared statistically by Mann-Whitney U-test to determine whether PGSI caused inflammation. Statistical significance was defined as P < 0.05. PMID- 29511135 TI - Retroperitoneoscopic Varicocelectomy in Adolescents: Long-term Follow-up in Two Italian Centres. AB - Background: The varicocele is the most commonly diagnosed pre-pubertal andrological condition with an incidence of 10%-15% between adolescents. The aim of this study was to evaluate the efficacy of retroperitoneoscopic varicocelectomy (RV) in two Italian centres with particular attention to post operative testicular volume and semen analysis after 18 years of life. Materials and Methods: From 1999 to 2010, 286 adolescents underwent retroperitoneoscopic left varicocelectomy. Of these patients, 67 were evaluated by clinical examination, ultrasound and semen analysis, allowing an adequate long-term follow up. Results: Surgery was performed at a mean age of 13 years (range 10-17) without intraoperative complications. There were two recurrences (3%), two left testis hypotrophy (3%) and four hydroceles (6%), not yet undergone surgery because asymptomatic or without tension. Currently, 44 patients accepted to perform semen analysis which showed a reduction in sperm motility in 12 cases, with associated morphological alterations in 3 and reducing number of spermatozoa in one case. Conclusions: In consideration of morphological and biomolecular spermatic alterations reported in adolescent varicocele that could interfere with cellular migration, differentiation and nutrition, it is fundamental to consider the correction of varicocele, not only for the classical indications, but also as a choice for arresting the progressive damage that inevitably acts for several years on the adolescent testis. The RV in adolescents is a safe and feasible procedure for experienced paediatric laparoscopic surgeons with early good clinical outcomes, but more studies occur to understand the real impact of adolescent varicocelectomy on testicular function. PMID- 29511136 TI - One or Two Stages Procedure for Repair of Rectovestibular Fistula: Which is Safer? (A Single Institution Experience). AB - Background: Rectovestibular fistula (RVF) is the most common type of anorectal malformations in females. The need for a diverting colostomy during correction of defect has ignited a heated debate. In this study, we reviewed the girls with RVF that had been treated by either one or two stage procedure in the past 10 years in our institution to define whether one stage or two stage procedures is safer and more beneficial for the patients. Materials and Methods: Seventy girls with RVF that had been operated from January 2005 to January 2015 were studied retrospectively. Data were obtained from medical hospital records. The cases were divided into two groups. Group A (46 patients): were operated by two stages technique (simultaneous sigmoid colostomy and anterior sagittal anorectoplasty [ASARP]). Group B (24 patients): were operated by one stage (ASARP without covering colostomy). The short-term outcome as regard wound infection, wound dehiscence, anal stenosis, anal retraction, recurrence of fistula as well as complications of colostomy was reported. The long-term outcome as regard soiling, constipation and voluntary bowel movement was evaluated. Results: The age of patients at the time of surgery ranged from 3 months to 2 years (mean; 9.5 months). In Group A, seven patients (15.2%) developed wound infection, two patients developed wound disruption. One patient developed anterior anal retraction and required redo-operation, anal stenosis was noticed in five (10.9%) patients. Complications from colostomy had occurred in nine patients (19.5%). In Group B, wound infection occurred in ten patients (41.7%). Seven patients (29.2%) developed wound disruption. Anal stenosis occurred in eight patients (33.3%). Five patients required redo-operation because of anal retraction in three patients and recurrence of fistula in the other two patients. Constipation recorded in 15 patients (32.6%) of Group A and in ten patients (41.3%) of Group B. Soiling was reported in six girls (13.04%) of Group A and five girls (20.8%) of Group B. Conclusion: The avoidance of colostomy is not outweighed achieving sound operation and continent child. Two stages correction of RVF is safer and more beneficial than one stage procedure, especially in our locality and for our paediatric surgeons during their learning curve. PMID- 29511137 TI - Unusual Ileal Anomalies Associated with Omphalomesenteric Duct Remnants. AB - The association between omphalomesenteric duct remnants and other digestive tract malformations is not rare. Most associated anomalies are reported with Meckel's diverticulum. We report two associated anomalies which were never reported: an ileal stenosis and an ileal duplication. Surgeons must be aware of associated anomalies to prevent post-operative complications. PMID- 29511138 TI - Reoperation of Anastomotic Stricture after Oesophageal Atresia Repair: An Uncommon Event. AB - Oesophageal atresia is a common malformation in which the survival rate in developed countries is around 90%, while its mortality remains very high in developing countries. Oesophageal stricture post-oesophageal atresia repair is traditionally treated by non-surgical approach. However, surgical resection of the oesophageal stricture may be necessary after the failure of dilations. We report one case of refractory oesophageal stricture post-EA repair in a 3-year old girl, who underwent oesophageal atresia Type III repair at 11-day-old. We performed an end-to-end oesophageal anastomosis with tracheal oesophageal fistula closure by extra-pleural approach. The patient was lost to follow-up for 3 years. She was seen later for anastomotic oesophageal stricture with the failure of oesophageal dilatations. Surgical resection of oesophageal stricture was performed with end-to-end oesophageal anastomosis. PMID- 29511140 TI - Type I interferon receptor knockout mice as models for infection of highly pathogenic viruses with outbreak potential. AB - Due to their inability to generate a complete immune response, mice knockout for type I interferon (IFN) receptors (Ifnar-/-) are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals. PMID- 29511141 TI - Animal models for filovirus infections. AB - The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates (NHPs), causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research. PMID- 29511143 TI - Development and characterization of a guinea pig model for Marburg virus. AB - The Angolan strain of Marburg virus (MARV/Ang) can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice (MARV/Ang-MA), with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold standard non-human primate (NHP) model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs (MARV/Ang-GA). Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1*10-1 TCID50 (median tissue culture infective dose). Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome. PMID- 29511142 TI - Animal models for the study of hepatitis B virus infection. AB - Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus (HBV) worldwide. Current antiviral therapies, including interferon and nucleot(s)ide analogues, rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection. PMID- 29511144 TI - Parasites may exit immunocompromised northern pig-tailed macaques (Macaca leonina) infected with SIVmac239. AB - Parasites can increase infection rates and pathogenicity in immunocompromised human immunodeficiency virus (HIV) patients. However, in vitro studies and epidemiological investigations also suggest that parasites might escape immunocompromised hosts during HIV infection. Due to the lack of direct evidence from animal experiments, the effects of parasitic infections on immunocompromised hosts remain unclear. Here, we detected 14 different parasites in six northern pig-tailed macaques (NPMs) before or at the 50th week of simian immunodeficiency virus (SIV) infection by ELISA. The NPMs all carried parasites before viral injection. At the 50th week after viral injection, the individuals with negative results in parasitic detection (i.e., 08247 and 08287) were characterized as the Parasites Exit (PE) group, with the other individuals (i.e., 09203, 09211, 10205, and 10225) characterized as the Parasites Remain (PR) group. Compared with the PR group, the NPMs in the PE group showed higher viral loads, lower CD4+ T cells counts, and lower CD4/CD8 rates. Additionally, the PE group had higher immune activation and immune exhaustion of both CD4+ and CD8+ T cells. Pathological observation showed greater injury to the liver, cecum, colon, spleen, and mesenteric lymph nodes in the PE group. This study showed more seriously compromised immunity in the PE group, strongly indicating that parasites might exit an immunocompromised host. PMID- 29511146 TI - Predicting mortality in patients with advanced heart failure: less is often more. PMID- 29511145 TI - Murine model of acute myocarditis and cerebral cortical neuron edema induced by coxsackievirus B4. AB - Globally, coxsackievirus B4 (CV-B4) has been continuously isolated and evidence suggests an association with the development of pancreatitis and type I diabetes. In addition, CV-B4 is also associated with myocarditis and severe central nervous system (CNS) complications, which remain poorly studied and understood. In the present study, we established an Institute for Cancer Research (ICR) mouse model of CV-B4 infection and examined whether CV-B4 infection resulted in a predisposition to myocarditis and CNS infection. We found high survival in both the treatment and control group, with no significant differences in clinical outcomes observed. However, pathological lesions were evident in both brain and heart tissue of the CV-B4-infected mice. In addition, high viral loads were found in the neural and cardiac tissues as early as 2 days post infection. Expressions of IFN-gamma and IL-6 in sera were significantly higher in CV-B4-infected mice compared to uninfected negative controls, suggesting the involvement of these cytokines in the development of histopathological lesions. Our murine model successfully reproduced the acute myocarditis and cerebral cortical neuron edema induced by CV-B4, and may be useful for the evaluation of vaccine candidates and potential antivirals against CV-B4 infection. PMID- 29511147 TI - E-learning, collaboration, and group support in medical education. PMID- 29511148 TI - Utility of left ventricular longitudinal strain in the diagnosis and treatment monitoring of cardiac sarcoidosis. PMID- 29511149 TI - Right atrial angiosarcoma in a pregnant woman: diagnostic and therapeutic dilemmas. PMID- 29511150 TI - Gastroscopy findings in a patient with signet ring cell carcinoma and late-onset hereditary hemochromatosis. PMID- 29511151 TI - Effect of extreme altitude mountaineering on iron status. PMID- 29511152 TI - Elevated C-reactive protein levels during cardiac implantations may increase the risk of early complications requiring transvenous lead removal: a preliminary report. PMID- 29511153 TI - Plasma fibrin clot structure and risk of thrombosis in rheumatoid arthritis. PMID- 29511154 TI - Plasma fibrin clot structure and risk of thrombosis in rheumatoid arthritis. Authors' reply. PMID- 29511155 TI - Primary Colonic Angiosarcoma Seen in a Patient on Calcium Channel Blocker: A Case Report with Summary Analysis of 32 Other Cases from the Literature. AB - BACKGROUND Angiosarcoma is a rare malignant mesenchymal tumor of vascular endothelial cell origin. Its occurrence in the colorectal region is extremely rare. Only 32 cases of primary colorectal angiosarcoma are reported in the current literature. Angiosarcoma in association with calcium channel blocker has been rarely reported. We present such a case of a patient who had been on levamlodipine besylate, a calcium channel blocker, for over 10 years. CASE REPORT A 53-year-old female with hypertension presented with a fever, a dry cough, and hematochezia. Computed tomography (CT) scan and angiography demonstrated a 6-cm vascular mass in the ileocecal region. The clinical symptoms stopped soon after a right hemicolectomy. The histopathology with immunohistochemical studies confirmed the diagnosis of angiosarcoma. Three months after surgery, the patient had evidence of recurrence of the tumor, however, she no longer presented with a fever or a dry cough. The patient was receiving chemotherapy at the time of the report. CONCLUSIONS Colorectal angiosarcoma is a rare malignancy of endothelial origin with uncertain etiology and often has a poor prognosis. Angiosarcoma seen in a patient taking calcium channel blocker is rare but alarming. CT scan and angiography are helpful tools to raise the suspicion of the diagnosis. A definitive pathological diagnosis relies on histopathology with immunohistochemical stains of endothelial markers. Surgical resection is still the best choice of the different treatment options. PMID- 29511156 TI - Outcome of Oocyte Vitrification Combined with Microdissection Testicular Sperm Extraction and Aspiration for Assisted Reproduction in Men. AB - BACKGROUND As a safety and efficacy protocol, oocyte vitrification has been widely used in IVF treatment. The aim of this study was to evaluate the outcome of ICSI-ET utilizing vitrified oocytes with sperm obtained from non-obstructive azoospermia (NOA) patients via micro-TESE. MATERIAL AND METHODS A total of 150 NOA patients underwent micro-TESE. Ten patients were unable to ejaculate and refused to accept TESA at the time of oocyte retrieval; later, these patients underwent TESA. A total of 174 obstructive azoospermia (OA) patients underwent TESA. Vitrified oocytes were used with micro-TESE in 35 cycles (group 1), and TESA in 10 cycles (group 2). Fresh oocytes were used with micro-TESE in 38 cycles (group 3) and TESA in 174 cycles (group 4). RESULTS The overall sperm retrieval rate of the 150 NOA patients was 48.7% (73/150). A total of 257 cycles of ICSI-ET were conducted with testicular spermatozoa; 212 cycles utilized fresh oocytes and 45 cycles utilized vitrified oocytes. No differences were observed with fertilization (73.8%, 77.2%,72.8%, 73.6%), implantation (33.3%, 34.7%, 33.8%, 37.5%), or clinical pregnancy rates (51.4%, 60%, 52.6%, 51.7%) for groups 1 through 4, respectively (P>0.05). Developmental competence was greatest among couples using sperm obtained via TESA rather than micro-TESE, not dependent on whether vitrified or fresh oocytes were utilized. Fertilization, implantation, and clinical pregnancy rates did not differ between using fresh vs. vitrified oocytes, nor did they differ between using testicular sperm derived from men with NOA vs. men with OA. CONCLUSIONS Vitrified oocytes combined with micro-TESE showed similar clinical efficacy when compared with fresh oocytes. PMID- 29511157 TI - Age-specific seroprevalence of human polyomavirus 12 and Saint Louis and New Jersey polyomaviruses. AB - The presence of specific antibodies against human polyomavirus 12, Saint Louis polyomavirus and New Jersey polyomavirus was investigated by using virus-like particle-based ELISAs with serum samples from 706 Italians aged 1- to 100-years old. The findings indicate that these polyomaviruses circulate widely in humans, with peak seroprevalence, observed at adulthood, of 97.3%, 93.3%, 57.5%, for human polyomavirus 12, Saint Louis polyomavirus and New Jersey polyomavirus, respectively. PMID- 29511158 TI - Cytokine-induced killer cells as a feasible adoptive immunotherapy for the treatment of lung cancer. AB - Most of the patients with lung cancer are diagnosed at advanced stage, and they often lose the opportunity of surgical therapy, most of whom fail to reach good prognosis after chemotherapy. Recently, a few clinical studies have confirmed the role of adoptive T-cell transfer in the maintenance therapy of cancer patients. Here, we provided statistical insights into the role of CIKs in advanced lung cancer from three different levels, cell model (in vitro co-culture system), mice model (in situ lung cancer), and clinical research (in lung cancer patients of different progression stages). We optimized the components of supplements and cytokines on activating and expanding CIK cells. Based on this, we explored a new serum-free medium for in vitro activation and expansion of CIK cells. Moreover, we found that activated CIK cells could efficiently kill lung cancer cells in cell-to-cell model in vitro and significantly reduce the tumor growth in mice. For the clinical research, the OS rates of patients received combination of chemotherapy and CIK treatment were significantly improved compared to the OS rates of patients only received chemotherapy. Additionally, CIK therapy represented good toleration in our study. All the results suggested that combination of immunotherapy with traditional therapy will be a feasible and promising method for the treatment of lung cancer. PMID- 29511159 TI - Marmota himalayana in the Qinghai-Tibetan plateau as a special host for bi segmented and unsegmented picobirnaviruses. AB - Wildlife has been considered the main source of novel viruses causing emerging infectious diseases. Marmota himalayana is endemic to the Qinghai-Tibetan Plateau, China. Here, based on a high-throughput method using Illumina RNA sequencing, we studied the RNA virome of M. himalayana and discovered multiple novel viruses, especially picobirnaviruses (PBVs), which have a bi-segmented genome and belong to the family Picobirnaviridae. A total of 63% of the viral contigs corresponded to PBVs, comprising 274 segment 1 and 56 segment 2 sequences. Unexpectedly, four unsegmented PBV genomes were also detected and confirmed by PCR and resequencing. According to the phylogenetic analysis, the following nine PBV assortment types are proposed: C1:GI, C2:GIV, C4:GI, C4:GV, C5:GI, C7:GI, C8:GIV, C8:GV and C8:GII. We hypothesize a model of segmentation for the PBV genome, mediated by a 6-bp direct repeat sequence, GAAAGG. The model is supported by detection of the segmentation-associated sequence GAAAGG not only in the 5' untranslated regions of segment 1 (221 in 289) and segment 2 (57 in 80) of bi-segmented PBVs but also in the 5' untranslated regions and junction sequences between the capsid and RdRp genes of unsegmented PBVs. Therefore, with RNA sequencing, we found an unexpected biodiversity of PBVs in M. himalayana, indicating that M. himalayana is a special host for PBVs. We also proposed a putative model of how bi-segmented PBVs could be converted into unsegmented PBVs, which sheds new light on the processes of RNA virus genome evolution. PMID- 29511160 TI - MiR34 inhibition induces human heart progenitor proliferation. AB - MiR34 involvement in myocardial injury repair and ageing has been well documented in mouse model. Our aim was to establish whether the inhibition of miR34 expression through locked nucleic acid (LNA) could be used as a pharmacological intervention to enhance human heart repair. Cardiac progenitor cells were obtained by right atrial specimen collection during intraoperative procedures. Our analysis revealed a direct correlation between miR34 expression and patient age, and its silencing by LNA promoted the cardiac progenitor growth rate up to twofold ( +/- 0.8). Our results confirmed the relevance of miR34a in human heart ageing, as previously demonstrated in mouse. Moreover, the decrease of miR34 expression in the cardiac progenitor cell population indicates its role in maintaining an undifferentiated status and consequently in a lower proliferation rate with the involvement of genes such as Notch-1, Numb, and p63. PMID- 29511161 TI - A multi-omic analysis reveals the regulatory role of CD180 during the response of macrophages to Borrelia burgdorferi. AB - Macrophages are cells of the innate immune system with the ability to phagocytose and induce a global pattern of responses that depend on several signaling pathways. We have determined the biosignature of murine bone marrow-derived macrophages and human blood monocytes using transcriptomic and proteomic approaches. We identified a common pattern of genes that are transcriptionally regulated and overall indicate that the response to B. burgdorferi involves the interaction of spirochetal antigens with several inflammatory pathways corresponding to primary (triggered by pattern-recognition receptors) and secondary (induced by proinflammatory cytokines) responses. We also show that the Toll-like receptor family member CD180 is downregulated by the stimulation of macrophages, but not monocytes, with the spirochete. Silencing Cd180 results in increased phagocytosis while tempering the production of the proinflammatory cytokine TNF. Cd180-silenced cells produce increased levels of Itgam and surface CD11b, suggesting that the regulation of CD180 by the spirochete initiates a cascade that increases CR3-mediated phagocytosis of the bacterium while repressing the consequent inflammatory response. PMID- 29511162 TI - Increased risk of venous thromboembolism in hospitalized patients with cirrhosis due to non-alcoholic steatohepatitis. AB - OBJECTIVE: Patients with cirrhosis are at increased risk for venous thromboembolism (VTE) and portal vein thrombosis (PVT). Cirrhosis due to non alcoholic steatohepatitis (NASH) appears to be particularly prothrombotic. We investigated hospitalized patients with NASH cirrhosis to determine if they are at increased risk for VTE. METHODS: Data on adult hospitalized patients with cirrhosis and VTE (deep vein thrombosis and/or pulmonary embolism) between November 1, 2010 and December 31, 2015 were obtained. Cases with VTE were matched by age, gender, and model for end stage liver disease (MELD) score to corresponding controls without VTE. RESULTS: Two hundred and ninety subjects (145 matched pairs) with mean age of 58.4 +/- 11.8 years and MELD score of 16.0 +/- 7.2 were included. Baseline characteristics were similar between cases and controls. Independent adjusted risk factors for VTE included NASH (OR: 2.46, 95% CI: 1.07-5.65, p = 0.034), prior VTE (OR: 7.12, 95% CI: 1.99-25.5, p = 0.003), and presence of PVT (OR: 2.18, 95% CI: 1.03-4.58, p = 0.041). Thrombocytopenia was associated with decreased risk (OR: 0.49, 95% CI: 0.26-0.95, p = 0.035). CONCLUSIONS: NASH is an independent risk factor for VTE among cirrhosis patients and provides further evidence that NASH is a hypercoagulable state. While all hospitalized patients with cirrhosis at risk for VTE should be considered for medical thromboprophylaxis, those with NASH cirrhosis are at particularly increased risk and therefore a high index of suspicion for VTE should be maintained even in the presence of thromboprophylaxis. PMID- 29511164 TI - Anisotropic photoemission time delays close to a Fano resonance. AB - Electron correlation and multielectron effects are fundamental interactions that govern many physical and chemical processes in atomic, molecular and solid state systems. The process of autoionization, induced by resonant excitation of electrons into discrete states present in the spectral continuum of atomic and molecular targets, is mediated by electron correlation. Here we investigate the attosecond photoemission dynamics in argon in the 20-40 eV spectral range, in the vicinity of the 3s-1np autoionizing resonances. We present measurements of the differential photoionization cross section and extract energy and angle-dependent atomic time delays with an attosecond interferometric method. With the support of a theoretical model, we are able to attribute a large part of the measured time delay anisotropy to the presence of autoionizing resonances, which not only distort the phase of the emitted photoelectron wave packet but also introduce an angular dependence. PMID- 29511163 TI - Wolfram syndrome: MAMs' connection? AB - Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca2+ transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed "mitochondria associated ER membranes" (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes. PMID- 29511165 TI - Food allergen triggers are increased in children with the TSLP risk allele and eosinophilic esophagitis. AB - OBJECTIVES: TSLP has been shown to be associated with eosinophilic esophagitis (EoE). Specifically, children with EoE often have the nucleotides AA or AG instead of GG at the single nucleotide polymorphism position RS3806932. Presently, the phenotypic characteristics in EoE children with the TSLP EoE risk allele are unknown. METHODS: A retrospective analysis was performed of all children with EoE who had TSLP genotyping at The Children's Hospital of Philadelphia from 2008-2014. EoE food allergen triggers, presence of atopic features, IgE mediated food allergy and skin prick testing results were reviewed. The number and type of EoE food allergen triggers were compared with genotype using chi-square analysis. Primary cell cultures from EoE patients with or without the risk allele were stimulated with ovalbumin and TSLP secretion was measured by ELISA. RESULTS: Fifty three of 309 patients were found to have no copies of the TSLP risk allele, whereas 256 patients were found to have one or more copies of the risk allele. There was an increase in the number of patients with three or more EoE food allergens among those who were either homozygous or heterozygous for the risk allele compared to those without the risk allele (P < 0.0001). This was independent of their atopic background. Primary cultures from patients homozygous for the risk allele had greater TSLP secretion than those isolated from heterozygous patients. CONCLUSIONS: The TSLP risk allele is associated with having multiple EoE food allergen triggers. This novel EoE genotypic-phenotypic correlation may guide future treatment for those with the TSLP risk allele. PMID- 29511166 TI - Gene-by-environment interactions in urban populations modulate risk phenotypes. AB - Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the G * E interactions in humans. We used an integrative approach to comprehensively assess the interactions between 1.6 million data points, encompassing a range of environmental exposures, health, and gene expression levels, coupled with whole-genome genetic variation. From ~1000 individuals of a founder population in Quebec, we reveal a substantial impact of the environment on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. Air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Finally, we capture four expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects disease risk phenotypes and that genetic variation, including less common variants, can modulate individual's response to environmental challenges. PMID- 29511167 TI - A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis. AB - Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large scale eQTL mapping study of human aortic valve tissues (n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS (P = 1.53 * 10 10) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options. PMID- 29511168 TI - The viscosity of atmospherically relevant organic particles. AB - The importance of organic aerosol particles in the environment has been long established, influencing cloud formation and lifetime, absorbing and scattering sunlight, affecting atmospheric composition and impacting on human health. Conventionally, ambient organic particles were considered to exist as liquids. Recent observations in field measurements and studies in the laboratory suggest that they may instead exist as highly viscous semi-solids or amorphous glassy solids under certain conditions, with important implications for atmospheric chemistry, climate and air quality. This review explores our understanding of aerosol particle phase, particularly as identified by measurements of the viscosity of organic particles, and the atmospheric implications of phase state. PMID- 29511169 TI - MiR-16-5p targets SESN1 to regulate the p53 signaling pathway, affecting myoblast proliferation and apoptosis, and is involved in myoblast differentiation. AB - The proliferation, apoptosis, and differentiation of myoblasts are essential processes in skeletal muscle development. During this developmental process, microRNAs (miRNAs) play crucial roles. In our previous RNA-seq study (accession number GSE62971), we found that miR-16-5p was differentially expressed between fast and slow growth in chicken. In this study, we report that miR-16-5p could inhibit myoblast proliferation, promote myoblast apoptosis, and repress myoblast differentiation by directly binding to the 3' UTR of SESN1, which is also differentially expressed. Overexpression of SESN1 significantly promoted the proliferation, inhibited apoptosis, and induced differentiation of myoblasts. Conversely, its loss of function hampered myoblast proliferation, facilitated myoblast apoptosis, and inhibited myoblast differentiation. Interestingly, we found SESN1 could regulate p53 by a feedback mechanism, thereby participating in the regulation of p53 signaling pathway, which suggests that this feedback is indispensable for myoblast proliferation and apoptosis. Altogether, these data demonstrated that miR-16-5p directly targets SESN1 to regulate the p53 signaling pathway, and therefore affecting myoblast proliferation and apoptosis. Additionally, SESN1 targets myogenic genes to control myoblast differentiation. PMID- 29511170 TI - Targeting intracellular signaling as an antiviral strategy: aerosolized LASAG for the treatment of influenza in hospitalized patients. AB - Influenza has been a long-running health problem and novel antiviral drugs are urgently needed. In pre-clinical studies, we demonstrated broad antiviral activity of D, L-lysine-acetylsalicylate glycine (LASAG) against influenza virus (IV) in cell culture and protection against lethal challenge in mice. LASAG is a compound with a new antiviral mode of action. It inhibits the NF-kappaB signal transduction module that is essential for IV replication. Our goal was to determine whether aerosolized LASAG would also show a therapeutic benefit in hospitalized patients suffering from severe influenza. The primary endpoint was time to alleviation of clinical influenza symptoms. The primary analysis was based on the modified intention-to-treat (MITT) population. This included all patients with confirmed influenza virus infection who received at least one treatment. The per protocol (PP) analysis set included all subjects from the MITT population who underwent at least 13 inhalations. In the MITT group, 48 (41.7%) participants (29 LASAG; 19 placebo) had severe influenza. The mean time to symptom alleviation was 56.2 h in the placebo group and 43.0 h in the LASAG group. The PP set consisted of 41 patients (24 LASAG; 17 placebo). The mean time to symptom alleviation in the LASAG group (38.3 h; P = 0.0365) was lower than that in the placebo group (56.2 h). In conclusion, LASAG improved the time to alleviation of influenza symptoms in hospitalized patients. The present phase II proof-of-concept (PoC) study demonstrates that targeting an intra-cellular signaling pathway using aerosolized LASAG improves the time to symptom alleviation compared to standard treatment. PMID- 29511171 TI - Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. AB - Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg2+ block. In addition, we provide new views on Mg2+ and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2BV618G unusually allowed Mg2+ permeation, whereas nearby N615I reduced Ca2+ permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease causing mutations. PMID- 29511172 TI - Rb is required for retinal angiogenesis and lamination. AB - Retinoblastoma tumor suppressor (Rb) promotes cell cycle exit, survival, differentiation, and tumor suppression in the retina. Here, we show it is also essential for vascularization and lamination. Despite minimal effects on Hif1a target expression, intraretinal vascular plexi did not form in the Rb -/- murine retina. Deleting adenovirus E2 promoter binding factor 3 (E2f3), which rescues starburst amacrine cell differentiation, or E2f2, had no effect, but deleting E2f1, which promotes neuronal cell cycle exit and survival, restored retinal vasculature. We specifically linked cell loss to the defect because removing Bax rescued rod and bipolar neurons and the vasculature, but not cell cycle exit. Despite rescuing Rb -/- neurons, Bax deletion exacerbated a delay in outer retina lamination, and exposed a requirement for Rb in inner retina lamination. The latter resembled Sem5 or FAT atypical cadherin 3 (Fat3) mutants, but expression of Sem5/Fat3 pathway components, or that of Neogenin, which perturbs migration in the Rb -/- cortex, was unchanged. Instead, lamination defects correlated with ectopic division, and were E2f1-dependent, implicating the cell cycle machinery. These in vivo studies expose new developmental roles for Rb, pinpoint aberrant E2f1 and Bax activity in neuronal death and vascular loss, and further implicate E2f1 in defective lamination. Links between Rb, angiogenesis and lamination have implications for the treatment of neovascularization, neurodegeneration and cancer. PMID- 29511173 TI - Rapid detection of MERS coronavirus-like viruses in bats: pote1ntial for tracking MERS coronavirus transmission and animal origin. AB - Recently, we developed a monoclonal antibody-based rapid nucleocapsid protein detection assay for diagnosis of MERS coronavirus (MERS-CoV) in humans and dromedary camels. In this study, we examined the usefulness of this assay to detect other lineage C betacoronaviruses closely related to MERS-CoV in bats. The rapid MERS-CoV nucleocapsid protein detection assay was tested positive in 24 (88.9%) of 27 Tylonycteris bat CoV HKU4 (Ty-BatCoV-HKU4) RNA-positive alimentary samples of Tylonycteris pachypus and 4 (19.0%) of 21 Pipistrellus bat CoV HKU5 (Pi-BatCoV-HKU5) RNA-positive alimentary samples of Pipistrellus abramus. There was significantly more Ty-BatCoV-HKU4 RNA-positive alimentary samples than Pi BatCoV-HKU5 RNA-positive alimentary samples that were tested positive by the rapid MERS-CoV nucleocapsid protein detection assay (P < 0.001 by Chi-square test). The rapid assay was tested negative in all 51 alimentary samples RNA positive for alphacoronaviruses (Rhinolophus bat CoV HKU2, Myotis bat CoV HKU6, Miniopterus bat CoV HKU8 and Hipposideros batCoV HKU10) and 32 alimentary samples positive for lineage B (SARS-related Rhinolophus bat CoV HKU3) and lineage D (Rousettus bat CoV HKU9) betacoronaviruses. No significant difference was observed between the viral loads of Ty-BatCoV-HKU4/Pi-BatCoV-HKU5 RNA-positive alimentary samples that were tested positive and negative by the rapid test (Mann Witney U test). The rapid MERS-CoV nucleocapsid protein detection assay is able to rapidly detect lineage C betacoronaviruses in bats. It detected significantly more Ty-BatCoV-HKU4 than Pi-BatCoV-HKU5 because MERS-CoV is more closely related to Ty-BatCoV-HKU4 than Pi-BatCoV-HKU5. This assay will facilitate rapid on-site mass screening of animal samples for ancestors of MERS-CoV and tracking transmission in the related bat species. PMID- 29511174 TI - Convergent genomic signatures of domestication in sheep and goats. AB - The evolutionary basis of domestication has been a longstanding question and its genetic architecture is becoming more tractable as more domestic species become genome-enabled. Before becoming established worldwide, sheep and goats were domesticated in the fertile crescent 10,500 years before present (YBP) where their wild relatives remain. Here we sequence the genomes of wild Asiatic mouflon and Bezoar ibex in the sheep and goat domestication center and compare their genomes with that of domestics from local, traditional, and improved breeds. Among the genomic regions carrying selective sweeps differentiating domestic breeds from wild populations, which are associated among others to genes involved in nervous system, immunity and productivity traits, 20 are common to Capra and Ovis. The patterns of selection vary between species, suggesting that while common targets of selection related to domestication and improvement exist, different solutions have arisen to achieve similar phenotypic end-points within these closely related livestock species. PMID- 29511176 TI - Identification of single amino acid differences in uniformly charged homopolymeric peptides with aerolysin nanopore. AB - There are still unmet needs in finding new technologies for biomedical diagnostic and industrial applications. A technology allowing the analysis of size and sequence of short peptide molecules of only few molecular copies is still challenging. The fast, low-cost and label-free single-molecule nanopore technology could be an alternative for addressing these critical issues. Here, we demonstrate that the wild-type aerolysin nanopore enables the size-discrimination of several short uniformly charged homopeptides, mixed in solution, with a single amino acid resolution. Our system is very sensitive, allowing detecting and characterizing a few dozens of peptide impurities in a high purity commercial peptide sample, while conventional analysis techniques fail to do so. PMID- 29511177 TI - Cytochrome c speeds up caspase cascade activation by blocking 14-3-3epsilon dependent Apaf-1 inhibition. AB - Apoptosis is a highly regulated form of programmed cell death, essential to the development and homeostasis of multicellular organisms. Cytochrome c is a central figure in the activation of the apoptotic intrinsic pathway, thereby activating the caspase cascade through its interaction with Apaf-1. Our recent studies have revealed 14-3-3epsilon (a direct inhibitor of Apaf-1) as a cytosolic cytochrome c target. Here we explore the cytochrome c / 14-3-3epsilon interaction and show the ability of cytochrome c to block 14-3-3epsilon-mediated Apaf-1 inhibition, thereby unveiling a novel function for cytochrome c as an indirect activator of caspase-9/3. We have used calorimetry, NMR spectroscopy, site mutagenesis and computational calculations to provide an insight into the structural features of the cytochrome c / 14-3-3epsilon complex. Overall, these findings suggest an additional cytochrome c-mediated mechanism to modulate apoptosome formation, shedding light onto the rigorous apoptotic regulation network. PMID- 29511175 TI - Low population serum microneutralization antibody titer against the predominating influenza A(H3N2) N121K virus during the severe influenza summer peak of Hong Kong in 2017. AB - The 2017 Hong Kong influenza A(H3N2) summer season was unexpectedly severe. However, antigenic characterization of the 2017 circulating A(H3N2) viruses using ferret antisera did not show significant antigenic drift. We analyzed the hemagglutinin amino acid sequences of A(H3N2) virus circulating in Hong Kong in 2017, and found that viruses with hemagglutinin N121K substitution, which was rare before 2017, emerged rapidly and dominated in 2017 (52.4% of A[H3N2] virus in 2017 contains N121K substitution). Microneutralization assay using archived human sera collected from mid-2017 showed that the geometric mean microneutralization titer was 3.6-fold lower against a 2017 cell culture-grown circulating A(H3N2)-N121K virus (3391/2017 virus) than that against the cell culture-grown 2016-2017 A(H3N2) seasonal influenza vaccine-like vaccine virus (4801/2014 virus) (13.4 vs 41.8, P < 0.0001). Significantly fewer serum specimens had a microneutralization titer of 40 or above against 3391/2017 virus than that against 4801/2014 virus (26.4% vs 60.0%, P < 0.0001). Conversely, the geometric mean hemagglutination inhibition titer was slightly higher against 3391/2017 virus than that against the 4801/2014 virus (96.9 vs 55.4, P < 0.0001). Moreover, 59.1% of specimens had a significantly lower microneutralization antibody titer (>=4-fold) against 3391/2017 virus than that against 4801/2014 virus, but none for hemagglutination titer (P < 0.0001). Similar results of microneutralization and hemagglutination titers were observed for day 21-post-vaccination sera. Hence, the 2017 A(H3N2) summer peak in Hong Kong was associated with a low microneutralization titer against the circulating virus. Our results support the use of microneutralization assay with human serum in assessing population susceptibility and antigenic changes of A(H3N2) virus. Novel and available immunization approach, such as topical imiquimod followed by intradermal vaccination, to broaden the neutralizing antibody response of influenza vaccine should be considered. PMID- 29511178 TI - Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen presenting cells. AB - In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer. PMID- 29511179 TI - Current-driven dynamics and inhibition of the skyrmion Hall effect of ferrimagnetic skyrmions in GdFeCo films. AB - Magnetic skyrmions are swirling magnetic textures with novel characteristics suitable for future spintronic and topological applications. Recent studies confirmed the room-temperature stabilization of skyrmions in ultrathin ferromagnets. However, such ferromagnetic skyrmions show an undesirable topological effect, the skyrmion Hall effect, which leads to their current-driven motion towards device edges, where skyrmions could easily be annihilated by topographic defects. Recent theoretical studies have predicted enhanced current driven behavior for antiferromagnetically exchange-coupled skyrmions. Here we present the stabilization of these skyrmions and their current-driven dynamics in ferrimagnetic GdFeCo films. By utilizing element-specific X-ray imaging, we find that the skyrmions in the Gd and FeCo sublayers are antiferromagnetically exchange-coupled. We further confirm that ferrimagnetic skyrmions can move at a velocity of ~50 m s-1 with reduced skyrmion Hall angle, |thetaSkHE| ~ 20 degrees . Our findings open the door to ferrimagnetic and antiferromagnetic skyrmionics while providing key experimental evidences of recent theoretical studies. PMID- 29511180 TI - Herbivorous turtle ants obtain essential nutrients from a conserved nitrogen recycling gut microbiome. AB - Nitrogen acquisition is a major challenge for herbivorous animals, and the repeated origins of herbivory across the ants have raised expectations that nutritional symbionts have shaped their diversification. Direct evidence for N provisioning by internally housed symbionts is rare in animals; among the ants, it has been documented for just one lineage. In this study we dissect functional contributions by bacteria from a conserved, multi-partite gut symbiosis in herbivorous Cephalotes ants through in vivo experiments, metagenomics, and in vitro assays. Gut bacteria recycle urea, and likely uric acid, using recycled N to synthesize essential amino acids that are acquired by hosts in substantial quantities. Specialized core symbionts of 17 studied Cephalotes species encode the pathways directing these activities, and several recycle N in vitro. These findings point to a highly efficient N economy, and a nutritional mutualism preserved for millions of years through the derived behaviors and gut anatomy of Cephalotes ants. PMID- 29511181 TI - Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis. AB - Group 2 innate lymphoid cells (ILC2) are one of three subgroups of innate lymphoid cells (ILC1, ILC2, and ILC3), and the major ILC population detected in the lungs. The function of ILC2 in the regulation of lung inflammation remains unclear. In the current study, we explored an important role of ILC2 in protecting lung endothelial cell (EC) from pyroptosis in sepsis-induced acute lung inflammation and the underlying mechanism. Using a cecal ligation and puncture (CLP) mouse sepsis model, we demonstrated that IL-33, which is released in response to sepsis, acting through its receptor ST2 mediates ILC2 expansion in the lungs. We further showed that the increased ILC2 in the lungs secrete IL-9, which in turn prevents lung EC from undergoing pyroptosis, a pro-inflammatory cell death form, by attenuating caspase-1 activation. These findings suggest a previously unidentified innate pathway that negatively regulates lung inflammation following sepsis. PMID- 29511182 TI - Asynchrony between Antarctic temperature and CO2 associated with obliquity over the past 720,000 years. AB - The deltaD temperature proxy in Antarctic ice cores varies in parallel with CO2 through glacial cycles. However, these variables display a puzzling asynchrony. Well-dated records of Southern Ocean temperature will provide crucial information because the Southern Ocean is likely key in regulating CO2 variations. Here, we perform multiple isotopic analyses on an Antarctic ice core and estimate temperature variations at this site and in the oceanic moisture source over the past 720,000 years, which extend the longest records by 300,000 years. Antarctic temperature is affected by large variations in local insolation that are induced by obliquity. At the obliquity periodicity, the Antarctic and ocean temperatures lag annual mean insolation. Further, the magnitude of the phase lag is minimal during low eccentricity periods, suggesting that secular changes in the global carbon cycle and the ocean circulation modulate the phase relationship among temperatures, CO2 and insolation in the obliquity frequency band. PMID- 29511183 TI - Nanowire arrays restore vision in blind mice. AB - The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 um. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices. PMID- 29511184 TI - The role of confined collagen geometry in decreasing nucleation energy barriers to intrafibrillar mineralization. AB - Mineralization of collagen is critical for the mechanical functions of bones and teeth. Calcium phosphate nucleation in collagenous structures follows distinctly different patterns in highly confined gap regions (nanoscale confinement) than in less confined extrafibrillar spaces (microscale confinement). Although the mechanism(s) driving these differences are still largely unknown, differences in the free energy for nucleation may explain these two mineralization behaviors. Here, we report on experimentally obtained nucleation energy barriers to intra- and extrafibrillar mineralization, using in situ X-ray scattering observations and classical nucleation theory. Polyaspartic acid, an extrafibrillar nucleation inhibitor, increases interfacial energies between nuclei and mineralization fluids. In contrast, the confined gap spaces inside collagen fibrils lower the energy barrier by reducing the reactive surface area of nuclei, decreasing the surface energy penalty. The confined gap geometry, therefore, guides the two dimensional morphology and structure of bioapatite and changes the nucleation pathway by reducing the total energy barrier. PMID- 29511185 TI - Inverted valley polarization in optically excited transition metal dichalcogenides. AB - Large spin-orbit coupling in combination with circular dichroism allows access to spin-polarized and valley-polarized states in a controlled way in transition metal dichalcogenides. The promising application in spin-valleytronics devices requires a thorough understanding of intervalley coupling mechanisms, which determine the lifetime of spin and valley polarizations. Here we present a joint theory-experiment study shedding light on the Dexter-like intervalley coupling. We reveal that this mechanism couples A and B excitonic states in different valleys, giving rise to an efficient intervalley transfer of coherent exciton populations. We demonstrate that the valley polarization vanishes and is even inverted for A excitons, when the B exciton is resonantly excited and vice versa. Our theoretical findings are supported by energy-resolved and valley-resolved pump-probe experiments and also provide an explanation for the recently measured up-conversion in photoluminescence. The gained insights might help to develop strategies to overcome the intrinsic limit for spin and valley polarizations. PMID- 29511186 TI - Context-dependent interactions and the regulation of species richness in freshwater fish. AB - Species richness is regulated by a complex network of scale-dependent processes. This complexity can obscure the influence of limiting species interactions, making it difficult to determine if abiotic or biotic drivers are more predominant regulators of richness. Using integrative modeling of freshwater fish richness from 721 lakes along an 11o latitudinal gradient, we find negative interactions to be a relatively minor independent predictor of species richness in lakes despite the widespread presence of predators. Instead, interaction effects, when detectable among major functional groups and 231 species pairs, were strong, often positive, but contextually dependent on environment. These results are consistent with the idea that negative interactions internally structure lake communities but do not consistently 'scale-up' to regulate richness independently of the environment. The importance of environment for interaction outcomes and its role in the regulation of species richness highlights the potential sensitivity of fish communities to the environmental changes affecting lakes globally. PMID- 29511187 TI - Flexibility in motor timing constrains the topology and dynamics of pattern generator circuits. AB - Temporally precise movement patterns underlie many motor skills and innate actions, yet the flexibility with which the timing of such stereotyped behaviors can be modified is poorly understood. To probe this, we induce adaptive changes to the temporal structure of birdsong. We find that the duration of specific song segments can be modified without affecting the timing in other parts of the song. We derive formal prescriptions for how neural networks can implement such flexible motor timing. We find that randomly connected recurrent networks, a common approximation for how neocortex is wired, do not generally conform to these, though certain implementations can approximate them. We show that feedforward networks, by virtue of their one-to-one mapping between network activity and time, are better suited. Our study provides general prescriptions for pattern generator networks that implement flexible motor timing, an important aspect of many motor skills, including birdsong and human speech. PMID- 29511188 TI - Direct observation of orbital hybridisation in a cuprate superconductor. AB - The minimal ingredients to explain the essential physics of layered copper-oxide (cuprates) materials remains heavily debated. Effective low-energy single-band models of the copper-oxygen orbitals are widely used because there exists no strong experimental evidence supporting multi-band structures. Here, we report angle-resolved photoelectron spectroscopy experiments on La-based cuprates that provide direct observation of a two-band structure. This electronic structure, qualitatively consistent with density functional theory, is parametrised by a two orbital ([Formula: see text] and [Formula: see text]) tight-binding model. We quantify the orbital hybridisation which provides an explanation for the Fermi surface topology and the proximity of the van-Hove singularity to the Fermi level. Our analysis leads to a unification of electronic hopping parameters for single-layer cuprates and we conclude that hybridisation, restraining d-wave pairing, is an important optimisation element for superconductivity. PMID- 29511189 TI - Saccade-synchronized rapid attention shifts in macaque visual cortical area MT. AB - While making saccadic eye-movements to scan a visual scene, humans and monkeys are able to keep track of relevant visual stimuli by maintaining spatial attention on them. This ability requires a shift of attentional modulation from the neuronal population representing the relevant stimulus pre-saccadically to the one representing it post-saccadically. For optimal performance, this trans saccadic attention shift should be rapid and saccade-synchronized. Whether this is so is not known. We trained two rhesus monkeys to make saccades while maintaining covert attention at a fixed spatial location. We show that the trans saccadic attention shift in cortical visual medial temporal (MT) area is well synchronized to saccades. Attentional modulation crosses over from the pre saccadic to the post-saccadic neuronal representation by about 50 ms after a saccade. Taking response latency into account, the trans-saccadic attention shift is well timed to maintain spatial attention on relevant stimuli, so that they can be optimally tracked and processed across saccades. PMID- 29511190 TI - ARMMs as a versatile platform for intracellular delivery of macromolecules. AB - Majority of disease-modifying therapeutic targets are restricted to the intracellular space and are therefore not druggable using existing biologic modalities. The ability to efficiently deliver macromolecules inside target cells or tissues would greatly expand the current landscape of therapeutic targets for future generations of biologic drugs, but remains challenging. Here we report the use of extracellular vesicles, known as arrestin domain containing protein 1 [ARRDC1]-mediated microvesicles (ARMMs), for packaging and intracellular delivery of a myriad of macromolecules, including the tumor suppressor p53 protein, RNAs, and the genome-editing CRISPR-Cas9/guide RNA complex. We demonstrate selective recruitment of these macromolecules into ARMMs. When delivered intracellularly via ARMMs, these macromolecules are biologically active in recipient cells. P53 delivered via ARMMs induces DNA damage-dependent apoptosis in multiple tissues in mice. Together, our results provide proof-of-principle demonstration that ARMMs represent a highly versatile platform for packaging and intracellular delivery of therapeutic macromolecules. PMID- 29511191 TI - Discrete energy levels of Caroli-de Gennes-Matricon states in quantum limit in FeTe0.55Se0.45. AB - Caroli-de Gennes-Matricon (CdGM) states were predicted in 1964 as low-energy excitations within vortex cores of type-II superconductors. In the quantum limit, the energy levels of these states were predicted to be discrete with the basic levels at +/-MUDelta2/EF (MU = 1/2, 3/2, 5/2, ...) with Delta the superconducting energy gap and EF the Fermi energy. However, due to the small ratio of Delta/EF in most type-II superconductors, it is very difficult to observe the discrete CdGM states, but rather a symmetric peak which appears at zero bias at the vortex center. Here we report the clear observation of these discrete energy levels of CdGM states in FeTe0.55Se0.45. The rather stable energies of these bound state peaks vs. space clearly validate our conclusion. Analysis based on the energies of these CdGM states indicates that the Fermi energy in the present system is very small. PMID- 29511192 TI - Toward a universal decoder of linguistic meaning from brain activation. AB - Prior work decoding linguistic meaning from imaging data has been largely limited to concrete nouns, using similar stimuli for training and testing, from a relatively small number of semantic categories. Here we present a new approach for building a brain decoding system in which words and sentences are represented as vectors in a semantic space constructed from massive text corpora. By efficiently sampling this space to select training stimuli shown to subjects, we maximize the ability to generalize to new meanings from limited imaging data. To validate this approach, we train the system on imaging data of individual concepts, and show it can decode semantic vector representations from imaging data of sentences about a wide variety of both concrete and abstract topics from two separate datasets. These decoded representations are sufficiently detailed to distinguish even semantically similar sentences, and to capture the similarity structure of meaning relationships between sentences. PMID- 29511193 TI - Photosystem II Subunit S overexpression increases the efficiency of water use in a field-grown crop. AB - Insufficient water availability for crop production is a mounting barrier to achieving the 70% increase in food production that will be needed by 2050. One solution is to develop crops that require less water per unit mass of production. Water vapor transpires from leaves through stomata, which also facilitate the influx of CO2 during photosynthetic assimilation. Here, we hypothesize that Photosystem II Subunit S (PsbS) expression affects a chloroplast-derived signal for stomatal opening in response to light, which can be used to improve water-use efficiency. Transgenic tobacco plants with a range of PsbS expression, from undetectable to 3.7 times wild-type are generated. Plants with increased PsbS expression show less stomatal opening in response to light, resulting in a 25% reduction in water loss per CO2 assimilated under field conditions. Since the role of PsbS is universal across higher plants, this manipulation should be effective across all crops. PMID- 29511195 TI - Publisher Correction: Intraskeletal histovariability, allometric growth patterns, and their functional implications in bird-like dinosaurs. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511196 TI - Author Correction: Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca2+ entry in mouse pancreatic beta-cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511194 TI - Genome-wide analysis yields new loci associating with aortic valve stenosis. AB - Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 * 10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 * 10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 * 10-10) and aortic root diameter (P = 1.30 * 10-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 * 10-3) and coronary artery disease (OR = 1.05, P = 9.3 * 10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high density lipoprotein cholesterol contribute substantially to the frequent co occurence of these diseases. PMID- 29511197 TI - Andean surface uplift constrained by radiogenic isotopes of arc lavas. AB - Climate and tectonics have complex feedback systems which are difficult to resolve and remain controversial. Here we propose a new climate-independent approach to constrain regional Andean surface uplift. 87Sr/86Sr and 143Nd/144Nd ratios of Quaternary frontal-arc lavas from the Andean Plateau are distinctly crustal (>0.705 and <0.5125, respectively) compared to non-plateau arc lavas, which we identify as a plateau discriminant. Strong linear correlations exist between smoothed elevation and 87Sr/86Sr (R2 = 0.858, n = 17) and 143Nd/144Nd (R2 = 0.919, n = 16) ratios of non-plateau arc lavas. These relationships are used to constrain 200 Myr of surface uplift history for the Western Cordillera (present elevation 4200 +/- 516 m). Between 16 and 26 degrees S, Miocene to recent arc lavas have comparable isotopic signatures, which we infer indicates that current elevations were attained in the Western Cordillera from 23 Ma. From 23-10 Ma, surface uplift gradually propagated southwards by ~400 km. PMID- 29511198 TI - Author Correction: Rev1 contributes to proper mitochondrial function via the PARP NAD+-SIRT1-PGC1alpha axis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511199 TI - Author Correction: PLK2 Plays an Essential Role in High D-Glucose-Induced Apoptosis, ROS Generation and Inflammation in Podocytes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511200 TI - Comparison of the virulence and transmissibility of canine H3N2 influenza viruses and characterization of their canine adaptation factors. AB - Recent canine influenza outbreaks have raised concerns about the generation of pathogenic variants that may pose a threat to public health. Here, we examine avian-like H3N2 canine influenza viruses (CIVs) isolated from 2009 to 2013 in South Korea from dogs. Phylogenetic analysis revealed that these viruses are closely related to strains previously isolated from dogs in Korea and China. However, molecular characterization demonstrated non-synonymous mutations between the canine viruses, particularly in the putative H3 antigenic sites, NA stalk regions, and in the internal genes of the 2012-2013 isolates compared with the 2009 isolate. Animal experiments showed that three representative isolates (A/canine/Korea/AS-01/2009(AS-01/09), A/canine/Korea/AS-05/2012(AS-05/12) and A/canine/Korea/AS-11/2013(AS-11/13), were readily droplet transmitted between dogs, whereas AS-05/12 induced more severe clinical disease and was lethal in dogs compared with AS-01/09. Although all viruses were able to infect ferrets, AS 05/12 consistently yielded higher nasal wash titers and was transmissible to ferrets via airborne droplets. Using reverse genetics, we show that the NA, NP, and M genes of CIV are critical for the adaptation of avian H3N2 viruses, and the resulting reassortant genotypes promote viral growth in dogs in a manner similar to that of the wild-type AS-01/09 virus. Taken together, these results demonstrate that CIVs continuously evolve in dogs thereby allowing them to gain a foothold in mammalian hosts. Importantly, we elucidated the genetic contributions of the NA, NP, and M genes to the adaptability of CIVs derived from the avian H3N2 virus. PMID- 29511201 TI - Linear magnetoresistivity in layered semimetallic CaAl2Si2. AB - According to an earlier Abrikosov model, a positive, nonsaturating, linear magnetoresistivity (LMR) is expected in clean, low-carrier-density metals when measured at very low temperatures and under very high magnetic fields. Recently, a vast class of materials were shown to exhibit extraordinary high LMR but at conditions that deviate sharply from the above-mentioned Abrikosov-type conditions. Such deviations are often considered within either classical Parish Littlewood scenario of random-conductivity network or within a quantum scenario of small-effective mass or low carriers at tiny pockets neighboring the Fermi surface. This work reports on a manifestation of novel example of a robust, but moderate, LMR up to ~100 K in the diamagnetic, layered, compensated, semimetallic CaAl2Si2. We carried out extensive and systematic characterization of baric and thermal evolution of LMR together with first-principles electronic structure calculations based on density functional theory. Our analyses revealed strong correlations among the main parameters of LMR and, in addition, a presence of various transition/crossover events based on which a P - T phase diagram was constructed. We discuss whether CaAl2Si2 can be classified as a quantum Abrikosov or classical Parish-Littlewood LMR system. PMID- 29511202 TI - Publisher Correction: Vimentin knockout results in increased expression of sub endothelial basement membrane components and carotid stiffness in mice. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511203 TI - Author Correction: A Systems Pharmacology Approach to Determine Active Compounds and Action Mechanisms of Xipayi Kuijie'an enema for Treatment of Ulcerative colitis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511204 TI - Author Correction: A method to generate small-scale, high-resolution sedimentary bedform architecture models representing realistic geologic facies. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511205 TI - Author Correction: High Energy Radical Chemistry Formation of HCN-rich Atmospheres on early Earth. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511206 TI - Author Correction: Unraveling the roles of CD44/CD24 and ALDH1 as cancer stem cell markers in tumorigenesis and metastasis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511207 TI - Author Correction: Circulating Biomarkers to Identify Responders in Cardiac Cell therapy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511208 TI - The influence of caging, bedding, and diet on the composition of the microbiota in different regions of the mouse gut. AB - Countless studies have identified differences between the gut microbiota of humans affected with myriad conditions and healthy individuals, and animal models are commonly used to determine whether those differences are causative or correlative. Recently, concerns have arisen regarding the reproducibility of animal models between institutions and across time. To determine the influence of three common husbandry-associated factors that vary between institutions, groups of weanling mice were placed in either static or ventilated microisolator caging, with either aspen or paperchip bedding, and with one of three commonly used rodent chows, in a fully crossed study design. After thirteen weeks, samples were collected from multiple regions of the gastrointestinal tract and characterized using culture-independent sequencing methods. Results demonstrated that seemingly benign husbandry factors can interact to induce profound changes in the composition of the microbiota present in certain regions of the gut, most notably the cecum, and that those changes are muted during colonic transit. These findings indicate that differences in factors such as caging and bedding can interact to modulate the gut microbiota that in turn may affect reproducibility of some animal models, and that cecal samples might be optimal when screening environmental effects on the gut microbiota. PMID- 29511209 TI - Author Correction: A strategy for effective latent HIV reactivation using subtherapeutic drug doses. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511210 TI - Publisher Correction: Total synthesis of the reported structure of 13a hydroxytylophorine. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511211 TI - Author Correction: Enhanced antiviral and antifibrotic effects of short hairpin RNAs targeting HBV and TGF-beta in HBV-persistent mice. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511212 TI - Author Correction: Dynamic Mechano-Regulation of Myoblast Cells on Supramolecular Hydrogels Cross-Linked by Reversible Host-Guest Interactions. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511214 TI - Author Correction: Nanomechanics of multidomain neuronal cell adhesion protein contactin revealed by single molecule AFM and SMD. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511215 TI - A Novel Nitrogen Enriched Hydrochar Adsorbents Derived from Salix Biomass for Cr (VI) Adsorption. AB - Hydrochars were prepared from Salix by hydrothermal carbonization, and characterized by FT-IR, 13C NMR, XPS, UV-vis, TG, SEM and BET techniques. The results showed that the hydrochars with molecular sieve-type open pore structure contained numbers of oxygen and nitrogen functional groups, which benefited the adsorption and diffusion of adsorbent Cr (VI). The hydrochar obtained from 26 h reaction (HC-26) was indicated an excellent adsorbent compared to the commercial activated carbon, and its maximum removal efficiency for Cr (VI) reaches up to 99.84% at pH 1. Langmuir's model is well fitted the experimental equilibrium adsorption data of total Cr. The bath experiment results showed that Cr (VI) could be removed rapidly in the first 300 min. Furthermore, the adsorption kinetics process of HC-26 could be described by pseudo-second-order model. Based on the above results, HC-26 could be acted as a potential efficient adsorbent for removal of Cr (VI) from aqueous solution. PMID- 29511213 TI - Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1. AB - BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency. PMID- 29511216 TI - Direct Detection of Unamplified Pathogen RNA in Blood Lysate using an Integrated Lab-in-a-Stick Device and Ultrabright SERS Nanorattles. AB - Direct detection of genetic biomarkers in body fluid lysate without target amplification will revolutionize nucleic acid-based diagnostics. However, the low concentration of target sequences makes this goal challenging. We report a method for direct detection of pathogen RNA in blood lysate using a bioassay using surface-enhanced Raman spectroscopy (SERS)-based detection integrated in a "lab in-a-stick" portable device. Two levels of signal enhancement were employed to achieve the sensitivity required for direct detection. Each target sequence was tagged with an ultrabright SERS-encoded nanorattle with ultrahigh SERS signals, and these tagged target sequences were concentrated into a focused spot for detection using hybridization sandwiches with magnetic microbeads. Furthermore, the washing process was automated by integration into a "lab-in-a-stick" portable device. We could directly detect synthetic target with a limit of detection of 200 fM. More importantly, we detected plasmodium falciparum malaria parasite RNA directly in infected red blood cells lysate. To our knowledge, this is the first report of SERS-based direct detection of pathogen nucleic acid in blood lysate without nucleic acid extraction or target amplification. The results show the potential of our integrated bioassay for field use and point-of-care diagnostics. PMID- 29511217 TI - Author Correction: Metabolic changes in Medaka fish induced by cyanobacterial exposures in mesocosms: an integrative approach combining proteomic and metabolomic analyses. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511218 TI - Publisher Correction: Factors influencing neurocognitive function in patients with neuroepithelial tumors. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511219 TI - Author Correction: Suppression of Transposable Elements in Leukemic Stem Cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511220 TI - Author Correction: Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511221 TI - Author Correction: Lithium chloride effectively kills the honey bee parasite Varroa destructor by a systemic mode of action. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511222 TI - Publisher Correction: Morphology and mechanics of fungal mycelium. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511223 TI - Rice intermediate filament, OsIF, stabilizes photosynthetic machinery and yield under salinity and heat stress. AB - Cytoskeleton plays a vital role in stress tolerance; however, involvement of intermediate filaments (IFs) in such a response remains elusive in crop plants. This study provides clear evidence about the unique involvement of IFs in cellular protection against abiotic stress in rice. Transcript abundance of Oryza sativa intermediate filament (OsIF) encoding gene showed 2-10 fold up-regulation under different abiotic stress. Overexpression of OsIF in transgenic rice enhanced tolerance to salinity and heat stress, while its knock-down (KD) rendered plants more sensitive thereby indicating the role of IFs in promoting survival under stress. Seeds of OsIF overexpression rice germinated normally in the presence of high salt, showed better growth, maintained chloroplast ultrastructure and favourable K+/Na+ ratio than the wild type (WT) and KD plants. Analysis of photosynthesis and chlorophyll a fluorescence data suggested better performance of both photosystem I and II in the OsIF overexpression rice under salinity stress as compared to the WT and KD. Under salinity and high temperature stress, OsIF overexpressing plants could maintain significantly high yield, while the WT and KD plants could not. Further, metabolite profiling revealed a 2-4 fold higher accumulation of proline and trehalose in OsIF overexpressing rice than WT, under salinity stress. PMID- 29511224 TI - Interplay between conformational selection and zymogen activation. AB - Trypsin-like proteases are synthesized as zymogens and activated through a mechanism that folds the active site for efficient binding and catalysis. Ligand binding to the active site is therefore a valuable source of information on the changes that accompany zymogen activation. Using the physiologically relevant transition of the clotting zymogen prothrombin to the mature protease thrombin, we show that the mechanism of ligand recognition follows selection within a pre existing ensemble of conformations with the active site accessible (E) or inaccessible (E*) to binding. Prothrombin exists mainly in the E* conformational ensemble and conversion to thrombin produces two dominant changes: a progressive shift toward the E conformational ensemble triggered by removal of the auxiliary domains upon cleavage at R271 and a drastic drop of the rate of ligand dissociation from the active site triggered by cleavage at R320. Together, these effects produce a significant (700-fold) increase in binding affinity. Limited proteolysis reveals how the E*-E equilibrium shifts during prothrombin activation and influences exposure of the sites of cleavage at R271 and R320. These new findings on the molecular underpinnings of prothrombin activation are relevant to other zymogens with modular assembly involved in blood coagulation, complement and fibrinolysis. PMID- 29511225 TI - Marker-assisted introgression of three dominant blast resistance genes into an aromatic rice cultivar Mushk Budji. AB - Modern high yielding rice varieties have replaced most of the traditional cultivars in recent past. Mushk Budji, is one such short grained landrace known for its aroma and exquisite quality, however, is highly susceptible to blast disease that has led to considerable decline in its area. Mushk Budji was crossed to a triple-gene donor line, DHMAS 70Q 164-1b and followed through marker assisted foreground and background selection in first and second backcross generations that helped to incorporate blast resistance genes Pi54, Pi1 and Pita. Marker-assisted background selection was carried out using 78 SSR and STS markers that helped to reduce linkage drag around the genes Pi54, Pi1 and Pita to 2.74, 4.60 and 2.03 Mb, respectively. The three-gene lines in BC2F2:3 were genotyped using 50 K SNP chip and revealed more than 92% genome similarity to the RP. 2-D gel assay detected differentially expressing 171 protein spots among a set of backcross derived lines, of which 38 spots showing match score of 4 helped us to calculate the proteome recovery. MALDI-TOF analysis helped to detect four significant proteins that were linked to quality and disease resistance. The improved lines expressed resistance to blast under artificial and natural field conditions. PMID- 29511226 TI - Publisher Correction: Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511227 TI - Tunable critical temperature for superconductivity in FeSe thin films by pulsed laser deposition. AB - Stabilized FeSe thin films in ambient pressure with tunable superconducting critical temperature would be a promising candidate for superconducting electronic devices. By carefully controlling the depositions on twelve kinds of substrates using a pulsed laser deposition technique single crystalline FeSe thin films were fabricated. The high quality of the thin films was confirmed by X-ray diffraction with a full width at half maximum of 0.515 degrees in the rocking curve and clear four-fold symmetry in phi-scan. The films have a maximum T c ~ 15 K on the CaF2 substrate and were stable in ambient conditions air for more than half a year. Slightly tuning the stoichiometry of the FeSe targets, the superconducting critical temperature becomes adjustable below 15 K with quite narrow transition width less than 2 K. These FeSe thin films deposited on different substrates are optimized respectively. The Tc of these optimized films show a relation with the out-of-plane (c-axis) lattice parameter of the FeSe films. PMID- 29511228 TI - Zerumbone reduces proliferation of HCT116 colon cancer cells by inhibition of TNF alpha. AB - Zerumbone is a known anti-cancer herbal compound. However, the actual protein target is not fully understood or known. This investigation focus on the association of zerumbone in HCT116 colon cancer cell proliferation and its link with TNF-alpha. The study shows that with the increasing concentration of zerumbone, there was a reduction of HCT116 cells proliferation based on the cell line study and hence higher TNF-alpha inhibition based on the TNF-alpha assay. The study also emphasizes on the computational aspect by investigating the molecular docking analysis of zerumbone against TNF-alpha. The docked complex was further validated using molecular dynamics simulation studies. The docking analysis observed that alpha-beta unsaturated carbonyl scaffold is an important moiety for the anti-cancer activity of zerumbone. Furthermore, the DFT analysis also confirms the reactivity nature of zerumbone based on the frontier molecular orbital analysis. PMID- 29511229 TI - Publisher Correction: Functionalized Non-vascular Nitinol Stent via Electropolymerized Polydopamine Thin Film Coating Loaded with Bortezomib Adjunct to Hyperthermia Therapy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511230 TI - A Triplet Parallelizing Spiral Microfluidic Chip for Continuous Separation of Tumor Cells. AB - Inertial and deformability- based particles separations gradually attract more significant attentions. In this work, we present a hybrid chip by combining the advantages of inertial and deformability -based principle. The chip is a triplet parallelizing spiral inertial microfluidic chip interconnected with numerable tilted slits (Spiral-Slits Chip) for continuous separation of circulating tumor cells. Utilizing the inertial lift and viscous drag forces, different sized particles achieve different equilibrium at distinct streamlines of the spiral microchannel. Numerable tilted slits are organized along the flow direction. They frequently transport segregated streamline particles into a paralleled smaller microchannel. These frequent dragging results in the amount of certain sized particles in the original microchannel gradually and dramatically reduced. Inertial separation of distinct sized particles could be achievable. Two arrays of numerable tilted slits function as bridges. This Spiral-Slits Chip could substitute for Red Blood Cells Lysis (RBCL) and is most effective for ultra-high throughput. The overall arrangement of this triplet parallelizing spiral inertial microfluidic reflects stable streamlines distribution in the first main microchannel. Combining with Ellipse filters, robust and reproducible capture of CTCs could be achieved at high flow rates. Optical absorption detection has been tentatively tested, and this could simplify the process. PMID- 29511231 TI - Publisher Correction: Multiple similarly effective solutions exist for biomedical feature selection and classification problems. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511233 TI - Author Correction: A role for small secreted proteins (SSPs) in a saprophytic fungal lifestyle: Ligninolytic enzyme regulation in Pleurotus ostreatus. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511232 TI - Cytokine and Chemokine Profiling in Patients with Hand, Foot and Mouth Disease in Singapore and Malaysia. AB - Hand, foot and mouth disease (HFMD) is a prevalent contagious childhood disease typically associated with fever, oral lesions and limb exanthema. While HFMD is caused by a plethora of serotypes of viruses under the genus Enterovirus within the Picornaviridae family, Coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV A71) are considered the main etiological agents. In recent years however, other viruses have also been isolated in considerable numbers from infected individuals in many regions, joining the legion commonly associated with HFMD. The present study investigated the cytokine and chemokine profiles of HFMD patients from Singapore and Malaysia for the first time. Comparative cohort studies of EV-A71 associated HFMD cases revealed that the Malaysia cohort had a distinct profile from the Singapore cohort, and this could be partly attributed by different EV A71 genotypes. As the isolation of CV-A6, instead of CV-A16, had become prevalent in the Singapore cohort, it was also of particular interest to study the differential cytokine and chemokine profiles. Our data revealed that overlapping as well as unique profiles exist between the two major causative clinical isolates in the Singapore cohort. Having a better understanding of the respective immunological profiles could be useful for more accurate HFMD diagnosis, which is imperative for disease transmission control until multi-valent vaccines and/or broad-spectrum anti-viral drugs become available. PMID- 29511235 TI - Publisher Correction: Acute Psychological Stress Disrupts Attentional Bias to Threat-Related Stimuli. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511234 TI - Single-cell RNA sequencing reveals developmental heterogeneity of blastomeres during major genome activation in bovine embryos. AB - Embryonic development is initially controlled by maternal RNAs and proteins stored in the oocyte, until gene products gradually generated by the embryo itself take over. Major embryonic genome activation (EGA) in bovine embryos occurs at the eight- to 16-cell stage. Morphological observations, such as size of blastomeres and distribution of microvilli, suggested heterogeneity among individual cells already at this developmental stage. To address cell heterogeneity on the transcriptome level, we performed single-cell RNA sequencing of 161 blastomeres from 14 in vitro produced bovine embryos at Day 2 (n = 6) and Day 3 (n = 8) post fertilization. Complementary DNA libraries were prepared using the Single-Cell RNA-Barcoding and Sequencing protocol and sequenced. Non supervised clustering of single-cell transcriptome profiles identified six clusters with specific sets of genes. Most embryos were comprised of cells from at least two different clusters. Sorting cells according to their transcriptome profiles resulted in a non-branched pseudo-time line, arguing against major lineage inclination events at this developmental stage. In summary, our study revealed heterogeneity of transcriptome profiles among single cells in bovine Day 2 and Day 3 embryos, suggesting asynchronous blastomere development during the phase of major EGA. PMID- 29511236 TI - Publisher Correction: Puerarin attenuates diabetic kidney injury through the suppression of NOX4 expression in podocytes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511237 TI - Publisher Correction: Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511238 TI - Corneal Curvature, Astigmatism, and Aberrations in Marfan Syndrome with Lens Subluxation: Evaluation by Pentacam HR System. AB - Marfan syndrome (MFS) is associated with abnormalities of corneal biometric characteristics. We conducted a retrospective case-control study including 55 eyes of the MFS patients with lens subluxation and 53 normal eyes of the control subjects to evaluate the corneal curvature, astigmatism and aberrations using a rotating Scheimpflug camera (Pentacam HR). Compared with the control group, the anterior, posterior, and total corneal curvature were flatter in the MFS group. The anterior and total corneal astigmatism were higher in the MFS patients, whereas the posterior corneal astigmatism was not significantly different between the two groups. Regarding the total corneal aberrations, the root mean square (RMS) aberrations, RMS higher-order aberrations and RMS lower-order aberrations increased, whereas the spherical aberration decreased in the MFS patients. Corneal parameters had potential diagnostic values for MFS patients with lens subluxation and the more reasonable cutoffs were the values of corneal curvature <41.35 D, corneal astigmatism >0.85 D and spherical aberration <0.188 MUm. Corneal biometric characteristics of MFS patients with lens subluxation include decreased corneal curvature, higher corneal astigmatism, larger corneal aberrations, and lower spherical aberration. Corneal curvature, corneal astigmatism, and spherical aberration are better diagnostic tools for suspicious MFS. PMID- 29511240 TI - Author Correction: The thiazide sensitive sodium chloride co-transporter NCC is modulated by site-specific ubiquitylation. AB - A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511239 TI - 1H NMR-based metabolomics reveals the effect of maternal habitual dietary patterns on human amniotic fluid profile. AB - Maternal diet may influence offspring's health, even within well-nourished populations. Amniotic fluid (AF) provides a rational compartment for studies on fetal metabolism. Evidence in animal models indicates that maternal diet affects AF metabolic profile; however, data from human studies are scarce. Therefore, we have explored whether AF content may be influenced by maternal diet, using a validated food-frequency questionnaire and implementing NMR-based metabolomics. Sixty-five AF specimens, from women undergoing second-trimester amniocentesis for prenatal diagnosis, were analysed. Complementary, maternal serum and urine samples were profiled. Hierarchical cluster analysis identified 2 dietary patterns, cluster 1 (C1, n = 33) and cluster 2 (C2, n = 32). C1 was characterized by significantly higher percentages of energy derived from refined cereals, yellow cheese, red meat, poultry, and "ready-to-eat" foods, while C2 by higher (P < 0.05) whole cereals, vegetables, fruits, legumes, and nuts. 1H NMR spectra allowed the identification of metabolites associated with these dietary patterns; glucose, alanine, tyrosine, valine, citrate, cis-acotinate, and formate were the key discriminatory metabolites elevated in C1 AF specimens. This is the first evidence to suggest that the composition of AF is influenced by maternal habitual dietary patterns. Our results highlight the need to broaden the knowledge on the importance of maternal nutrition during pregnancy. PMID- 29511241 TI - High-Throughput Sequencing and Linkage Mapping of a Clownfish Genome Provide Insights on the Distribution of Molecular Players Involved in Sex Change. AB - Clownfishes are an excellent model system for investigating the genetic mechanism governing hermaphroditism and socially-controlled sex change in their natural environment because they are broadly distributed and strongly site-attached. Genomic tools, such as genetic linkage maps, allow fine-mapping of loci involved in molecular pathways underlying these reproductive processes. In this study, a high-density genetic map of Amphiprion bicinctus was constructed with 3146 RAD markers in a full-sib family organized in 24 robust linkage groups which correspond to the haploid chromosome number of the species. The length of the map was 4294.71 cM, with an average marker interval of 1.38 cM. The clownfish linkage map showed various levels of conserved synteny and collinearity with the genomes of Asian and European seabass, Nile tilapia and stickleback. The map provided a platform to investigate the genomic position of genes with differential expression during sex change in A. bicinctus. This study aims to bridge the gap of genome-scale information for this iconic group of species to facilitate the study of the main gene regulatory networks governing social sex change and gonadal restructuring in protandrous hermaphrodites. PMID- 29511242 TI - The pharmacokinetic advantage of 5-methyltetrahydrofolate for minimization of the risk for birth defects. AB - Despite efforts to increase folic acid (FA) intake, even within countries mandating FA fortification, there remain pregnant women with folate levels inadequate to minimize congenital disorders (e.g., of the neural tube, heart, and lip/palate). The pharmacokinetics of FA and [6S]-5-methyltetrahydrofolate (5 MTHF) were examined to find a reliable and minimal dose for rapidly rescuing folate status prior to critical periods of embryonic development. Serum total folate increased much more rapidly over the first four days in insufficient women given 7.5 mg doses of 5-MTHF than the same regimen of FA (P for trend <0.0001). Nearly all women given 7.5 mg 5-MTHF (every 12 hours, five doses total) almost immediately reached 50 nM serum total folate. Moreover, this level could be maintained by subsequent administration of 0.4 mg/d of folic acid. Thus, 5-MTHF enables repletion of folate stores more quickly and uniformly than FA and without exposure to unmetabolized FA. PMID- 29511244 TI - Increased Glutamine Consumption in Cisplatin-Resistant Cells Has a Negative Impact on Cell Growth. AB - The emergence of drug-resistant subclones remains the primary reason for tumor treatment failure. Some theories suggest that drug-resistant cell growth can be suppressed by drug-sensitive cells because resistant cells are less fit than sensitive cells in the absence of drug. We investigated fitness differences and their underlying mechanisms in cisplatin (ddp)-resistant cells and parental cells. We found that glutamine (Gln) consumption was substantially higher in ddp resistant cells than that in sensitive cells, indicating that significantly fewer ddp-resistant cells than sensitive cells could be generated under the same Gln conditions. Interestingly, the antioxidant capacity of ddp-resistant cells was also significantly enhanced and was directly related to the presence of Gln. Then, we found that enhanced antioxidant capacity was sustained by accelerated Gln catabolism in resistant cells through oncogenic KRAS. Further analysis indicated that rapid Gln catabolism directly mediated ddp resistance through enhanced antioxidant capacity, but the maximum number of resistant cells that could be produced with the same amount of Gln was significantly reduced due to increased Gln catabolism. Collectively, our study revealed that rapid Gln catabolism provided ddp-resistant cells with the ability to tolerate cytotoxic treatment but also hindered the growth of ddp-resistant cells due to excessive Gln consumption. PMID- 29511245 TI - Author Correction: Volcanic influence on centennial to millennial Holocene Greenland temperature change. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511243 TI - Interaction between alcohol consumption and methylenetetrahydrofolate reductase polymorphisms in thyroid cancer risk: National Cancer Center cohort in Korea. AB - The effect of alcohol intake on thyroid cancer is unestablished, and its interaction effects with genetic susceptibility are unclear. In this case-control study, the relationship among alcohol intake, the methylenetetrahydrofolate reductase (MTHFR) gene, and thyroid cancer risk has been evaluated. In total, 642 cases and 642 controls of Korean origin were included, and the genetic variants C677T and A1298C of the MTHFR gene were analysed. The interactions between alcohol-consumption behaviour and genetic variants were analysed with a likelihood ratio test, wherein a multiplicative interaction term was added to a logistic regression model. There was an independent association between the C677T polymorphism and thyroid cancer risk but not for drinking history. For C677T C/C homozygotes, individuals with a history of alcohol consumption showed a protective OR (95% CI) of 0.42 (0.15-1.13) when never drinkers were used as the reference. However, this protective association was not observed among individuals with a T+ allele with an OR (95% CI) of 1.27 (0.89-1.82), showing different directions for the association between genotypes with a significant interaction (Pinteraction = 0.009). Based on the genetic characteristics of individuals included, an interaction between alcohol intake and MTHFR C677T may modify the risk of thyroid cancer. PMID- 29511246 TI - Stirring does not make populations well mixed. AB - In evolutionary dynamics, the notion of a 'well-mixed' population is usually associated with all-to-all interactions at all times. This assumption simplifies the mathematics of evolutionary processes, and makes analytical solutions possible. At the same time the term 'well-mixed' suggests that this situation can be achieved by physically stirring the population. Using simulations of populations in chaotic flows, we show that in most cases this is not true: conventional well-mixed theories do not predict fixation probabilities correctly, regardless of how fast or thorough the stirring is. We propose a new analytical description in the fast-flow limit. This approach is valid for processes with global and local selection, and accurately predicts the suppression of selection as competition becomes more local. It provides a modelling tool for biological or social systems with individuals in motion. PMID- 29511248 TI - Publisher Correction: Carbon nanowalls as a platform for biological SERS studies. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511247 TI - Interactions mediated by a public good transiently increase cooperativity in growing Pseudomonas putida metapopulations. AB - Bacterial communities have rich social lives. A well-established interaction involves the exchange of a public good in Pseudomonas populations, where the iron scavenging compound pyoverdine, synthesized by some cells, is shared with the rest. Pyoverdine thus mediates interactions between producers and non-producers and can constitute a public good. This interaction is often used to test game theoretical predictions on the "social dilemma" of producers. Such an approach, however, underestimates the impact of specific properties of the public good, for example consequences of its accumulation in the environment. Here, we experimentally quantify costs and benefits of pyoverdine production in a specific environment, and build a model of population dynamics that explicitly accounts for the changing significance of accumulating pyoverdine as chemical mediator of social interactions. The model predicts that, in an ensemble of growing populations (metapopulation) with different initial producer fractions (and consequently pyoverdine contents), the global producer fraction initially increases. Because the benefit of pyoverdine declines at saturating concentrations, the increase need only be transient. Confirmed by experiments on metapopulations, our results show how a changing benefit of a public good can shape social interactions in a bacterial population. PMID- 29511249 TI - A state-space modelling approach to wildlife monitoring with application to flying-fox abundance. AB - Monitoring flying-foxes is challenging as their extreme mobility produces highly dynamic population processes, considerable logistic difficulty, and variability in estimated population size. We report on methods for inferring population trend for the population of the spectacled flying-fox (Pteropus conspicillatus) in Australia. Monthly monitoring is conducted at all known roost sites across the species' range in the Wet Tropics Region. The proportion of animals in camps varies seasonally and stochastic environmental events appear to be influential. We develop a state-space model that incorporates these processes and enables inference on total population trends and uses early warning analysis to identify the causes of population dynamics. The model suggests that population growth rate is stable in the absence of cyclones, however, cyclones appear to impact on both survival and reproduction. The population recovered after two cyclones but declined after a third. The modelling estimates a population decline over 15 years of c. 75% (mean r = - 0.12yr-1 and belief of negative trend is c. 83%) suggesting that conservation action is warranted. Our work shows that a state space modelling approach is a significant improvement on inference from raw counts from surveys and demonstrates that this approach is a workable alternative to other methods. PMID- 29511250 TI - Publisher Correction: Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511251 TI - Author Correction: Poly-protein G-expressing bacteria enhance the sensitivity of immunoassays. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511252 TI - Author Correction: Quantitative inheritance of volatile pheromones and darcin and their interaction in olfactory preferences of female mice. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29511253 TI - Cooperative catalysis of cellulose nanofiber and organocatalyst in direct aldol reactions. AB - Cellulose nanofibers (CNFs) are finding a wide range of applications in the forthcoming sustainable society because of their carbon-neutral renewability and superior physicochemical properties. Here, we first show a cooperative organocatalysis by combining TEMPO-oxidized cellulose nanofiber (TOCN) and proline to enhance the catalytic efficiency in a direct aldol reaction. The yields of proline-catalyzed aldol products drastically increased in the presence of catalytically-inactive TOCN. This effect was also achieved by simply adding the TOCN to the reaction conditions where various proline analogues including structurally simple pyrrolidine and piperidine were used instead of proline. TOCN was superior to physically-pulverized CNF in the organocatalytic efficiency, and the nanofibrillation of cellulose microfibrils in reaction media was essential to induce the drastic enhancement in catalytic activity. The present finding will bring a new entry in the applications of CNFs, and open up a new phase in developing highly efficient molecular transformations in green chemical industries. PMID- 29511254 TI - Emergency department visits and unanticipated readmissions after liver transplantation: A retrospective observational study. AB - Improved survival after LT are likely to result in increased healthcare resource utilization. The pattern and risk factors of emergency department (ED) visits and unanticipated readmissions, associated cost, and predictors of healthcare resource utilization after liver transplantation (LT) patients who received LT between 2011 and 2014 were analyzed. A total of 430 LT recipients were enrolled and the 1 year all-cause mortality was 1.4%. ED visits occurred in 53% (229/430) and unanticipated readmissions occurred at least once in 58.6% (252/430) of the patients. Overall risk factors for ED visits after LT included emergency operation [OR 1.56 (95%CI 1.02-2.37), p = 0.038] and warm ischemic time of >15 minutes [OR 2.36 (95%CI 1.25-4.47), p = 0.015]. Risk factors for readmissions after LT included greater estimated blood loss during LT [OR 1.09 (95%CI 1.02 1.17), p = 0.012], warm ischemic time of >15 minutes [OR 1.98 (95%CI 1.04-3.78), p = 0.038], and hospital length of stay of >2 weeks. PMID- 29511255 TI - Black Sea outflow response to Holocene meltwater events. AB - During the Holocene, North American ice sheet collapse and rapid sea-level rise reconnected the Black Sea with the global ocean. Rapid meltwater releases into the North Atlantic and associated climate change arguably slowed the pace of Neolithisation across southeastern Europe, originally hypothesized as a catastrophic flooding that fueled culturally-widespread deluge myths. However, we currently lack an independent record linking the timing of meltwater events, sea level rise and environmental change with the timing of Neolithisation in southeastern Europe. Here, we present a sea surface salinity record from the Northern Aegean Sea indicative of two meltwater events at ~8.4 and ~7.6 kiloyears that can be directly linked to rapid declines in the establishment of Neolithic sites in southeast Europe. The meltwater events point to an increased outflow of low salinity water from the Black Sea driven by rapid sea level rise >1.4 m following freshwater outbursts from Lake Agassiz and the final decay of the Laurentide ice sheet. Our results shed new light on the link between catastrophic sea-level rise and the Neolithisation of southeastern Europe, and present a historical example of how coastal populations could have been impacted by future rapid sea-level rise. PMID- 29511256 TI - Intra-articular dexmedetomidine in knee arthroscopy: A systematic review and meta analysis. AB - The aim of this meta-analysis is to evaluate the analgesic effects of intra articular dexmedetomidine (DEX) in arthroscopic knee surgery. A comprehensive literature search was conducted to identify randomized controlled trials (RCTs) comparing intra-articular DEX versus control for postoperative analgesia in knee arthroscopy. Trial sequential analysis (TSA) was applied to determine the reliability of the evidence. Twelve RCTs including 594 patients met the eligibility criteria. DEX treatment significantly improved postoperative pain outcomes, with weighted mean differences (95% confidence interval) between the DEX and control groups of -1.57 (-1.94 to -1.20, P < 0.00001) for pain scores at rest at postoperative 1 h, -8.54 mg (-11.96 to -5.13, P < 0.00001) for morphine equivalents at postoperative 0-24 h, and 257.57 min (209.86 to 305.28, P < 0.00001) for time to first request for postoperative analgesia. TSA indicated there is sufficient evidence for these outcomes. Intra-articular DEX did not affect the incidence of postoperative nausea and vomiting, hypotension, bradycardia, or somnolence. This meta-analysis demonstrated that intra-articular administration of DEX improved pain outcomes in the early postoperative period after knee arthroscopy. Due to the limited number of trials and patients included in this meta-analysis, more evidence is required to confirm these findings. PMID- 29511257 TI - The temporal distribution of new H7N9 avian influenza infections based on laboratory-confirmed cases in Mainland China, 2013-2017. AB - In this study, estimates of the growth rate of new infections, based on the growth rate of new laboratory-confirmed cases, were used to provide a statistical basis for in-depth research into the epidemiological patterns of H7N9 epidemics. The incubation period, interval from onset to laboratory confirmation, and confirmation time for all laboratory-confirmed cases of H7N9 avian influenza in Mainland China, occurring between January 2013 and June 2017, were used as the statistical data. Stochastic processes theory and maximum likelihood were used to calculate the growth rate of new infections. Time-series analysis was then performed to assess correlations between the time series of new infections and new laboratory-confirmed cases. The rate of new infections showed significant seasonal fluctuation. Laboratory confirmation was delayed by a period of time longer than that of the infection (average delay, 13 days; standard deviation, 6.8 days). At the lags of -7.5 and -15 days, respectively, the time-series of new infections and new confirmed cases were significantly correlated; the cross correlation coefficients (CCFs) were 0.61 and 0.16, respectively. The temporal distribution characteristics of new infections and new laboratory-confirmed cases were similar and strongly correlated. PMID- 29511258 TI - BASIS: High-performance bioinformatics platform for processing of large-scale mass spectrometry imaging data in chemically augmented histology. AB - Mass Spectrometry Imaging (MSI) holds significant promise in augmenting digital histopathologic analysis by generating highly robust big data about the metabolic, lipidomic and proteomic molecular content of the samples. In the process, a vast quantity of unrefined data, that can amount to several hundred gigabytes per tissue section, is produced. Managing, analysing and interpreting this data is a significant challenge and represents a major barrier to the translational application of MSI. Existing data analysis solutions for MSI rely on a set of heterogeneous bioinformatics packages that are not scalable for the reproducible processing of large-scale (hundreds to thousands) biological sample sets. Here, we present a computational platform (pyBASIS) capable of optimized and scalable processing of MSI data for improved information recovery and comparative analysis across tissue specimens using machine learning and related pattern recognition approaches. The proposed solution also provides a means of seamlessly integrating experimental laboratory data with downstream bioinformatics interpretation/analyses, resulting in a truly integrated system for translational MSI. PMID- 29511259 TI - Plant-made Salmonella bacteriocins salmocins for control of Salmonella pathovars. AB - Salmonella enterica causes an estimated 1 million illnesses in the United States each year, resulting in 19,000 hospitalizations and 380 deaths, and is one of the four major global causes of diarrhoeal diseases. No effective treatments are available to the food industry. Much attention has been given to colicins, natural non-antibiotic proteins of the bacteriocin class, to control the related pathogen Escherichia coli. We searched Salmonella genomic databases for colicin analogues and cloned and expressed in plants five such proteins, which we call salmocins. Among those, SalE1a and SalE1b were found to possess broad antimicrobial activity against all 99 major Salmonella pathovars. Each of the two salmocins also showed remarkably high potency (>106 AU/ug recombinant protein, or >103 higher than colicins) against major pathogenic target strains. Treatment of poultry meat matrices contaminated with seven key pathogenic serovars confirmed salmocin efficacy as a food safety intervention against Salmonella. PMID- 29511260 TI - Cerebral blood flow predicts differential neurotransmitter activity. AB - Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans. PMID- 29511262 TI - Neutrophil-to-lymphocyte Ratio (NLR) as a predictor for recurrence in patients with stage III melanoma. AB - Neutrophil-to-lymphocyte ratio is a strong predictor for overall survival and disease free survival in many cancers. Our study is the first investigation aiming to determine the predictive value of neutrophil-to-lymphocyte ratio on prognosis of patients with stage III melanoma. This retrospective study utilized a cohort of 107 patients with stage III melanoma treated at Huntsman Cancer Institute, University of Utah, from May 2002 to March 2016. The optimal cutoff of neutrophil-to-lymphocyte ratio was determined by the significance of log-rank tests. A total of 97 log-rank tests were conducted to find the optimal cutoff. Disease free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of neutrophil-to-lymphocyte ratio. 2.5 was identified as the optimal cutoff. Kaplan Meier curve showed that the disease free survival rate of the low value group was significantly higher compared to that of high value group. After adjusting for confounders and other prognostic factors, the neutrophil-to-lymphocyte ratio >= 2.5 remained a strong predictor for disease recurrence in patients with stage III melanoma. PMID- 29511261 TI - Insights into the ubiquitin-proteasome system of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) exhibit high levels of proteasome activity, an intrinsic characteristic required for their self-renewal, pluripotency and differentiation. However, the mechanisms by which enhanced proteasome activity maintains hESC identity are only partially understood. Besides its essential role for the ability of hESCs to suppress misfolded protein aggregation, we hypothesize that enhanced proteasome activity could also be important to degrade endogenous regulatory factors. Since E3 ubiquitin ligases are responsible for substrate selection, we first define which E3 enzymes are increased in hESCs compared with their differentiated counterparts. Among them, we find HECT-domain E3 ligases such as HERC2 and UBE3A as well as several RING-domain E3s, including UBR7 and RNF181. Systematic characterization of their interactome suggests a link with hESC identity. Moreover, loss of distinct up-regulated E3s triggers significant changes at the transcriptome and proteome level of hESCs. However, these alterations do not dysregulate pluripotency markers and differentiation ability. On the contrary, global proteasome inhibition impairs diverse processes required for hESC identity, including protein synthesis, rRNA maturation, telomere maintenance and glycolytic metabolism. Thus, our data indicate that high proteasome activity is coupled with other determinant biological processes of hESC identity. PMID- 29511263 TI - The Use of Metabolomics and Inflammatory Mediator Profiling Provides a Novel Approach to Identifying Pediatric Appendicitis in the Emergency Department. AB - Multiplexed profiling approaches including various 'omics' platforms are becoming a new standard of biomarker development for disease diagnosis and prognosis. The present study applied an integrated metabolomics and cytokine profiling approach as a potential aid to the identification of pediatric appendicitis. Metabolic analysis using serum (n = 121) and urine (n = 102) samples, and cytokine analysis using plasma (n = 121) samples from children presenting to the Emergency Department with abdominal pain were performed. Comparisons between children with appendicitis vs. non-appendicitis abdominal pain, and with perforated vs. non perforated appendicitis were made using multivariate statistics. Serum and urine biomarker patterns were statistically significantly different between groups. The combined serum metabolomics and inflammatory mediator model revealed clear separation between appendicitis and non-appendicitis abdominal pain (AUROC: 0.92 +/- 0.03) as well as for perforated and non-perforated appendicitis (AUROC: 0.88 +/- 0.05). Urine metabolic analysis also demonstrated distinction between the groups appendicitis and non-appendicitis abdominal pain (AUROC: 0.85 +/- 0.04), and perforated and non-perforated appendicitis (AUROC: 0.98 +/- 0.02). In children presenting to the Emergency Department with abdominal pain, metabolomics and inflammatory mediator profiling are capable of distinguishing children with appendicitis from those without. The approach also differentiates between severities of disease. These results provide an important first step towards a potential aid for improving appendicitis identification. PMID- 29511264 TI - Author Correction: Quantifying the anisotropy and tortuosity of permeable pathways in clay-rich mudstones using models based on X-ray tomography. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511265 TI - Author Correction: Knowledge graph prediction of unknown adverse drug reactions and validation in electronic health records. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511266 TI - Publisher Correction: Intra-colony disease progression induces fragmentation of coral fluorescent pigments. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511267 TI - Publisher Correction: Phosphodiester backbone of the CpG motif within immunostimulatory oligodeoxynucleotides augments activation of Toll-like receptor 9. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511268 TI - Publisher Correction: TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511269 TI - Patient-derived conditionally reprogrammed cells maintain intra-tumor genetic heterogeneity. AB - Preclinical in vitro models provide an essential tool to study cancer cell biology as well as aid in translational research, including drug target identification and drug discovery efforts. For any model to be clinically relevant, it needs to recapitulate the biology and cell heterogeneity of the primary tumor. We recently developed and described a conditional reprogramming (CR) cell technology that addresses many of these needs and avoids the deficiencies of most current cancer cell lines, which are usually clonal in origin. Here, we used the CR cell method to generate a collection of patient derived cell cultures from non-small cell lung cancers (NSCLC). Whole exome sequencing and copy number variations are used for the first time to address the capability of CR cells to keep their tumor-derived heterogeneity. Our results indicated that these primary cultures largely maintained the molecular characteristics of the original tumors. Using a mutant-allele tumor heterogeneity (MATH) score, we showed that CR cells are able to keep and maintain most of the intra-tumoral heterogeneity, suggesting oligoclonality of these cultures. CR cultures therefore represent a pre-clinical lung cancer model for future basic and translational studies. PMID- 29511270 TI - Publisher Correction: Mass & secondary structure propensity of amino acids explain their mutability and evolutionary replacements. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511271 TI - Publisher Correction: Aspirin metabolite sodium salicylate selectively inhibits transcriptional activity of ATF6alpha and downstream target genes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511272 TI - Publisher Correction: A fossil species of the enigmatic early polypod fern genus Cystodium (Cystodiaceae) in Cretaceous amber from Myanmar. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511273 TI - Tadpoles respond to background colour under threat. AB - The ability to respond to background colour is an important feature of species that might benefit from background matching camouflage. Tadpole colour patterns vary and could be associated with several functions, including defense. Because tadpoles are exposed to a wide array of visually oriented predators, they represent good models to study defensive colouration and associated behaviours. We tested whether a potentially disruptively camouflaged tadpole with a dark body crossed by yellow bars (Ololygon machadoi) is able to respond differently to matching light and dark natural background colours and an artificial blue contrasting background. We used a syntopic contrasting black tadpole (Bokermannohyla martinsi) as a control, expecting it not to respond to background colour in search for camouflage. Ololygon machadoi tadpoles chose light over blue backgrounds under threat, as expected, however they did not show preferential use of dark vs. blue backgrounds. Bokermannohyla martinsi did not respond to any combination of background colours. Our results suggest that O. machadoi tadpoles are able to respond to background colour, and may favor matching backgrounds under some circumstances. The potentially disruptive colouration of O. machadoi tadpoles may increase their repertoire of escape strategies, background matching being one of the options to escape predation. PMID- 29511275 TI - Publisher Correction: A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells. AB - In the version of this Letter originally published, Michele S. Y. Tan was incorrectly listed as Michele Y. S. Tan due to a technical error. This has now been amended in all online versions of the Letter. PMID- 29511274 TI - Duck plague virus Glycoprotein J is functional but slightly impaired in viral replication and cell-to-cell spread. AB - To analyse the function of the duck plague virus (DPV) glycoprotein J homologue (gJ), two different mutated viruses, a gJ deleted mutant DeltagJ and a gJR rescue mutant gJR with US5 restored were generated. All recombinant viruses were constructed by using two-step of RED recombination system implemented on the duck plague virus Chinese virulent strain (DPV CHv) genome cloned into a bacterial artificial chromosome. DPV-mutants were characterized on non-complementing DEF cells compared with parental virus. Viral replication kinetics of intracellular and extracellular viruses revealed that the DeltagJ virus produce a 10-fold reduction of viral titers than the gJR and parental virus, which especially the production of extracellular infectivity was affected. In addition, the DeltagJ virus produced viral plaques on DEF cells that was on average approximately 11% smaller than those produced by the gJR and parental viruses. Electron microscopy confirmed that although DPV CHv without gJ could efficiently carry out viral replication, virion assembly and envelopment within infected cells, the DeltagJ virus produced and accumulated high levels of anuclear particles in the nuclear and cytoplasm. These results show that the gJ slightly impaired in viral replication, virion assembly and cell-to-cell spread, and is not essential in virion envelopment. PMID- 29511276 TI - A global mismatch in the protection of multiple marine biodiversity components and ecosystem services. AB - The global loss of biodiversity threatens unique biota and the functioning and services of ecosystems essential for human wellbeing. To safeguard biodiversity and ecosystem services, designating protected areas is crucial; yet the extent to which the existing placement of protection is aligned to meet these conservation priorities is questionable, especially in the oceans. Here we investigate and compare global patterns of multiple biodiversity components (taxonomic, phylogenetic and functional), ecosystem services and human impacts, with the coverage of marine protected areas across a nested spatial scale. We demonstrate a pronounced spatial mismatch between the existing degree of protection and all the conservation priorities above, highlighting that neither the world's most diverse, nor the most productive ecosystems are currently the most protected ecosystems. Furthermore, we show that global patterns of biodiversity, ecosystem services and human impacts are poorly correlated, hence complicating the identification of generally applicable spatial prioritization schemes. However, a hypothetical "consensus approach" would have been able to address all these conservation priorities far more effectively than the existing degree of protection, which at best is only marginally better than a random expectation. Therefore, a holistic perspective is needed when designating an appropriate degree of protection of marine conservation priorities worldwide. PMID- 29511277 TI - Silver and ultrasmall iron oxides nanoparticles in hydrocolloids: effect of magnetic field and temperature on self-organization. AB - Micro/nanostructures, which are assembled from various nanosized building blocks are of great scientific interests due to their combined features in the micro- and nanometer scale. This study for the first time demonstrates that ultrasmall superparamagnetic iron oxide nanoparticles can change the microstructure of their hydrocolloids under the action of external magnetic field. We aimed also at the establishment of the physiological temperature (39 degrees C) influence on the self-organization of silver and ultrasmall iron oxides nanoparticles (NPs) in hydrocolloids. Consequences of such induced changes were further investigated in terms of their potential effect on the biological activity in vitro. Physicochemical characterization included X-ray diffraction (XRD), optical microscopies (SEM, cryo-SEM, TEM, fluorescence), dynamic light scattering (DLS) techniques, energy dispersive (EDS), Fourier transform infrared (FTIR) and ultraviolet-visible (UV-Vis) spectroscopies, zeta-potential and magnetic measurements. The results showed that magnetic field affected the hydrocolloids microstructure uniformity, fluorescence properties and photodynamic activity. Likewise, increased temperature caused changes in NPs hydrodynamic size distribution and in hydrocolloids microstructure. Magnetic field significantly improved photodynamic activity that was attributed to enhanced generation of reactive oxygen species due to reorganization of the microstructure. PMID- 29511278 TI - Relationships of H. pylori infection and its related gastroduodenal morbidity with metabolic syndrome: a large cross-sectional study. AB - The few published studies on the relationship between Helicobacter pylori infection and metabolic homeostasis were relatively small and yielded inconsistent results. We examined the prevalence of metabolic syndrome in relation to H. pylori infection and its symptoms in a large and unselected population. Coded data from the computerised database of a large health maintenance organisation in Israel were accessed for 147,936 individuals 25-95 years of age who performed the urea breath test during 2002-2012. The classification of metabolic syndrome followed a modified definition of the international diabetes federation. Prevalences of H. pylori infection and metabolic syndrome were 52.0% and 11.4% respectively. H. pylori infected patients had increased likelihood of metabolic syndrome: adjusted odds ratio (aOR) 1.15 (95% confidence intervals (CI) 1.10-1.19), as did patients with gastric ulcer: aOR 1.15 (95% CI 1.03-1.28) vs patients without these conditions. Duodenal ulcer was associated with metabolic syndrome only in persons aged 25-34 years: aOR 1.59 (95% CI 1.19-2.13), but not in older persons (P = 0.001 for heterogeneity). In conclusion, the likelihood of metabolic syndrome appeared significantly increased in relation to H. pylori infection and gastric and duodenal ulcers. These findings suggest that H. pylori long-term gastric inflammation might play a role in metabolic homeostasis. PMID- 29511279 TI - Author Correction: White matter microstructural changes are related to cognitive dysfunction in essential tremor. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29511280 TI - Publisher Correction: Bacillus SEVA siblings: A Golden Gate-based toolbox to create personalized integrative vectors for Bacillus subtilis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511281 TI - Chemical & Nano-mechanical Study of Artificial Human Enamel Subsurface Lesions. AB - White lesions represent an early phase of caries formation. 20 human sound premolars were subjected to pH cycling procedure to induce subsurface lesions (SLs) in vitro. In addition, 2 teeth with naturally developed white spot lesions (WSLs) were used as references. All specimens characterized by confocal Raman microscopy being used for the first time in examining white & subsurface lesions and providing a high resolution chemical and morphological map based on phosphate peak intensity alterations at 960 cm-1. Nanoindentation technique was used to measure Hardness (H) and Young's modulus (E) of enamel. Phosphate map of examined samples exhibited presence of intact surface layer (ISL) followed by severe depletion in (PO43-) peak in the area corresponding to the body of the lesion. In all examined groups, the mechanical properties of enamel were decreased in lesion area and found to be inversely related to penetration depth of indenter owing to enamel hierarchical structure. By combining the above two techniques, we linked mechanical properties of enamel to its chemical composition and ensured that the two methods are highly sensitive to detect small changes in enamel composition. Further work is required to bring these two excellent tools to clinical application to perceive carious lesions at an early stage of development. PMID- 29511283 TI - Elucidating the genetics of craniofacial shape. PMID- 29511282 TI - Online proton therapy monitoring: clinical test of a Silicon-photodetector-based in-beam PET. AB - Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non invasive, promising in-vivo technique, which consists in the measurement of the beta+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy. PMID- 29511284 TI - The importance of cohort studies in the post-GWAS era. AB - The past decade has seen enormous success of wide-scale genetic studies in identifying genetic variants that modify individuals' predisposition to common diseases. However, the interpretation and functional understanding of these variants lag far behind. In this Perspective, we discuss opportunities for using large-scale cohort studies to investigate the downstream molecular effects of SNPs at different 'omics' data levels. We point to the pivotal role of population cohorts in establishing causality and advancing drug discovery. In particular, we focus on the breadth-versus-depth concepts of population studies, on data harmonization, and on the challenges, ethical aspects and future perspectives of cohort studies. PMID- 29511285 TI - Eggs sense high-fat diet. PMID- 29511286 TI - Contribution of the in-vehicle microenvironment to individual ambient-source nitrogen dioxide exposure: the Multi-Ethnic Study of Atherosclerosis and Air Pollution. AB - Exposure estimates that do not account for time in-transit may underestimate exposure to traffic-related air pollution, but exact contributions have not been studied directly. We conducted a 2-week monitoring, including novel in-vehicle sampling, in a subset of the Multi-Ethnic Study of Atherosclerosis and Air Pollution cohort in two cities. Participants spent the majority of their time indoors and only 4.4% of their time (63 min/day) in-vehicle, on average. The mean ambient-source NO2 concentration was 5.1 ppb indoors and 32.3 ppb in-vehicle during drives. On average, indoor exposure contributed 69% and in-vehicle exposure contributed 24% of participants' ambient-source NO2 exposure. For participants in the highest quartile of time in-vehicle (>=1.3 h/day), indoor and in-vehicle contributions were 60 and 31%, respectively. Incorporating infiltrated indoor and measured in-vehicle NO2 produced exposure estimates 5.6 ppb lower, on average, than using only outdoor concentrations. The indoor microenvironment accounted for the largest proportion of ambient-source exposure in this older population, despite higher concentrations of NO2 outdoors and in vehicles than indoors. In-vehicle exposure was more influential among participants who drove the most and for participants residing in areas with lower outdoor air pollution. Failure to characterize exposures in these microenvironments may contribute to exposure misclassification in epidemiologic studies. PMID- 29511287 TI - Residential mobility of pregnant women and implications for assessment of spatially-varying environmental exposures. AB - Health studies on spatially-varying exposures (e.g., air pollution) during pregnancy often estimate exposure using residence at birth, disregarding residential mobility. We investigated moving patterns in pregnant women (n = 10,116) in linked cohorts focused on Connecticut and Massachusetts, U.S., 1988 2008. Moving patterns were assessed by race/ethnicity, age, marital status, education, working status, population density, parity, income, and season of birth. In this population, 11.6% of women moved during pregnancy. Movers were more likely to be younger, unmarried, and living in urban areas with no previous children. Among movers, multiple moves were more likely for racial/ethnic minority, younger, less educated, unmarried, and lower income women. Most moves occurred later in pregnancy, with 87.4% of first moves in the second or third trimester, although not all cohort subjects enrolled in the first few weeks of pregnancy. Distance between first and second residence had a median value of 5.2 km (interquartile range 11.3 km, average 57.8 km, range 0.0-4277 km). Women moving larger distances were more likely to be white, older, married, and work during pregnancy. Findings indicate that residential mobility may impact studies of spatially-varying exposure during pregnancy and health and that subpopulations vary in probability of moving, and timing and distance of moves. PMID- 29511288 TI - Comparison of non-insulin antidiabetic agents as an add-on drug to insulin therapy in type 2 diabetes: a network meta-analysis. AB - We aimed to evaluate the comparative efficacy and safety of dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium glucose co-transporter 2 inhibitors (SGLT2i), or thiazolidinedione (TZD) as an adjunctive treatment in patients with poorly controlled type 2 diabetes mellitus (T2DM) on insulin therapy. We searched Medline, Embase, the Cochrane Library, and ClinicalTrials.gov through April 2016. Bayesian network meta-analyses were performed with covariate adjustment. The primary outcome was the change in glycated hemoglobin A1c (HbA1c) from baseline. Fifty randomized controlled trials covering 15,494 patients were included. GLP-1RA showed the greatest HbA1c lowering effect compared to the control (-0.84%; 95% credible interval, -1.00% to -0.69%), followed by TZD (-0.73%; -0.93 to -0.52%), SGLT2i (-0.66%; -0.84% to 0.48%), and DPP4i (-0.54%; -0.68% to -0.39%). SGLT2i showed the greatest fasting plasma glucose reduction. GLP-1RA and SGLT2i showed greater body weight reduction, whereas TZD increased body weight. TZD was ranked the highest in terms of insulin dose reduction. The risk of hypoglycemia was increased with TZD or GLP 1RA. The study provides the best available evidence on the comparative efficacy and safety of non-insulin anti-diabetic agents on top of pre-existing insulin therapy for inadequately controlled T2DM patients. PMID- 29511290 TI - Prognostic implication of appendicular skeleton bone marrow abnormalities detected using low-dose multidetector computed tomography in patients with myelodysplastic syndrome. PMID- 29511289 TI - Novel phosphorylated TAK1 species with functional impact on NF-kappaB and beta catenin signaling in human Cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sezary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF kappaB and beta-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex. Blocking PP1 activity, both pharmacologically and genetically, resulted in TAK1 hyperphosphorylation at residues T344, S389, T444, and T511, which have functional impact on canonical NF kappaB signaling. Inhibition of TAK1 precluded NF-kappaB and beta-catenin signaling and induced apoptosis of CTCL cell lines and primary Sezary syndrome cells both in vitro and in vivo. Detection of phosphorylated TAK1 at T444 and T344 is associated with the presence of lymphoma in a set of 60 primary human samples correlating with NF-kappaB and beta-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy. PMID- 29511291 TI - Publisher Correction: Exfoliated WS2-Nafion Composite based Electromechanical Actuators. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511292 TI - Publisher Correction: Composition, diversity and bioactivity of culturable bacterial endophytes in mountain-cultivated ginseng in Korea. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29511293 TI - Author Correction: Prevention of Retinal Degeneration in a Rat Model of Smith Lemli-Opitz Syndrome. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29511294 TI - Publisher Correction: The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast Pichia pastoris. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511295 TI - Publisher Correction: A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511296 TI - Characterization of gene regulation and protein interaction networks for Matrin 3 encoding mutations linked to amyotrophic lateral sclerosis and myopathy. AB - To understand how mutations in Matrin 3 (MATR3) cause amyotrophic lateral sclerosis (ALS) and distal myopathy, we used transcriptome and interactome analysis, coupled with microscopy. Over-expression of wild-type (WT) or F115C mutant MATR3 had little impact on gene expression in neuroglia cells. Only 23 genes, expressed at levels of >100 transcripts showed >=1.6-fold changes in expression by transfection with WT or mutant MATR3:YFP vectors. We identified ~123 proteins that bound MATR3, with proteins associated with stress granules and RNA processing/splicing being prominent. The interactome of myopathic S85C and ALS-variant F115C MATR3 were virtually identical to WT protein. Deletion of RNA recognition motif (RRM1) or Zn finger motifs (ZnF1 or ZnF2) diminished the binding of a subset of MATR3 interacting proteins. Remarkably, deletion of the RRM2 motif caused enhanced binding of >100 hundred proteins. In live cells, MATR3 lacking RRM2 (DeltaRRM2) formed intranuclear spherical structures that fused over time into large structures. Our findings in the cell models used here suggest that MATR3 with disease-causing mutations is not dramatically different from WT protein in modulating gene regulation or in binding to normal interacting partners. The intra-nuclear localization and interaction network of MATR3 is strongly modulated by its RRM2 domain. PMID- 29511297 TI - Ecrg4 peptide is the ligand of multiple scavenger receptors. AB - Esophageal cancer-related gene 4 (Ecrg4) encodes a hormone-like peptide that is believed to be involved in a variety of physiological phenomena, including tumour suppression. Recent progress in the study of Ecrg4 has shown that Ecrg4 is a proinflammatory factor and induces the expression of several cytokines and chemokines in macrophages/microglia. However, the detailed molecular mechanisms of Ecrg4 signalling, especially the Ecrg4 receptors, remain poorly understood. Here, using retrovirus-mediated expression cloning, we identified lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) as a membrane protein that binds amino acid residues 71-132 of Ecrg4 (Ecrg4(71-132)). Moreover, in addition to LOX-1, several scavenger receptors, such as Scarf1, Cd36 and Stabilin-1, facilitated the efficient internalisation of Ecrg4(71-132) into cells. A broad competitive inhibitor of scavenger receptors, polyinosinic acid, reduced both the binding of Ecrg4(71-132) and the activation of NF-kappaB in microglia. This activation was dependent on MyD88, an adaptor protein that recruits signalling proteins to Toll-like receptors (TLRs), with the consequent induction of various immune responses. These data suggest that multiple scavenger receptors recognise Ecrg4(71-132) and transduce its signals, together with TLRs, in microglia. PMID- 29511298 TI - Publisher Correction: Quaternary history, population genetic structure and diversity of the cold-adapted Alpine newt Ichthyosaura alpestris in peninsular Italy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511300 TI - Publisher Correction: Paracrine interactions between mesenchymal stem cells and macrophages are regulated by 1,25-dihydroxyvitamin D3. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511301 TI - Publisher Correction: Acoustic allometry revisited: morphological determinants of fundamental frequency in primate vocal production. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511302 TI - NLRP3 inflammasome inhibition ameliorates tubulointerstitial injury in the remnant kidney model. AB - Recent studies suggest that NLRP3 inflammasome activation is involved in the pathogenesis of chronic kidney disease (CKD). Allopurinol (ALLO) inhibits xanthine oxidase (XOD) activity, and, consequently, reduces the production of uric acid (UA) and reactive oxygen species (ROS), both of which can activate the NLRP3 pathway. Thus, ALLO can contribute to slow the progression of CKD. We investigated whether inhibition of XOD by ALLO reduces NLRP3 activation and renal injury in the 5/6 renal ablation (Nx) model. Adult male Munich-Wistar rats underwent Nx and were subdivided into the following two groups: Nx, receiving vehicle only, and Nx + ALLO, Nx rats given ALLO, 36 mg/Kg/day in drinking water. Rats undergoing sham operation were studied as controls (C). Sixty days after surgery, Nx rats exhibited marked albuminuria, creatinine retention, and hypertension, as well as glomerulosclerosis, tubular injury, and cortical interstitial expansion/inflammation/fibrosis. Such changes were accompanied by increased XOD activity and UA renal levels, associated with augmented heme oxigenase-1 and reduced superoxide dismutase-2 renal contents. Both the NF-kappaB and NLRP3 signaling pathways were activated in Nx. ALLO normalized both XOD activity and the parameters of oxidative stress. ALLO also attenuated hypertension and promoted selective tubulointerstitial protection, reducing urinary NGAL and cortical interstitial injury/inflammation. ALLO reduced renal NLRP3 activation, without interfering with the NF-kappaB pathway. These observations indicate that the tubulointerstitial antiinflammatory and antifibrotic effects of ALLO in the Nx model involve inhibition of the NLRP3 pathway, and reinforce the view that ALLO can contribute to arrest or slow the progression of CKD. PMID- 29511303 TI - Author Correction: Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511299 TI - Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. AB - Although synaptic loss is thought to be core to the pathophysiology of schizophrenia, the nature, consistency and magnitude of synaptic protein and mRNA changes has not been systematically appraised. Our objective was thus to systematically review and meta-analyse findings. The entire PubMed database was searched for studies from inception date to the 1st of July 2017. We selected case-control postmortem studies in schizophrenia quantifying synaptic protein or mRNA levels in brain tissue. The difference in protein and mRNA levels between cases and controls was extracted and meta-analysis conducted. Among the results, we found a significant reduction in synaptophysin in schizophrenia in the hippocampus (effect size: -0.65, p < 0.01), frontal (effect size: -0.36, p = 0.04), and cingulate cortices (effect size: -0.54, p = 0.02), but no significant changes for synaptophysin in occipital and temporal cortices, and no changes for SNAP-25, PSD-95, VAMP, and syntaxin in frontal cortex. There were insufficient studies for meta-analysis of complexins, synapsins, rab3A and synaptotagmin and mRNA measures. Findings are summarised for these, which generally show reductions in SNAP-25, PSD-95, synapsin and rab3A protein levels in the hippocampus but inconsistency in other regions. Our findings of moderate-large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and postsynaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia. However, they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent. PMID- 29511304 TI - Tunable Dielectric Properties of Poly(vinylidenefluoride-co-hexafluoropropylene) Films with Embedded Fluorinated Barium Strontium Titanate Nanoparticles. AB - Fluoropolymer nanocomposites of poly(vinylidene fluoride-co-hexafluoropropylene) (PVdF-HFP) were prepared using fluorinated barium strontium titanate (Ba1 xSrxTiO3, BSTO) nanoparticles (NPs) by low-temperature synthesis using a modified liquid-solid solution process. The exact stoichiometry of as-synthesized BSTO NPs was confirmed by X-ray diffraction analysis along with lattice parameter calculations. The synthesized BSTO NPs were fluorinated using 2,2,2 trifluoroacetic acid as a fluorous ligand. The BSTO NPs showed high solubility in the fluorous system (polymer and solvent) on account of their modified surface. The root-mean-square roughness of the fluorinated BSTO/PVdF-HFP nanocomposite was 76 times lower than that of the nonfluorinated BSTO/PVdF-HFP nanocomposite. The dielectric constant of the fluorinated BSTO/PVdF-HFP nanocomposite exhibited Curie temperature behavior. The dielectric constant of the nanocomposite predicted using the modified Kerner model at room temperature agreed well with the experimental values. PMID- 29511305 TI - Facile fabrication of superhydrophobic surfaces with hierarchical structures. AB - Hierarchical structures were fabricated on the surfaces of SUS304 plates using a one-step process of direct microwave irradiation under a carbon dioxide atmosphere. The surface nanostructures were composed of chrome-doped hematite single crystals. Superhydrophobic surfaces with a water contact angle up to 169 degrees were obtained by chemical modification of the hierarchical structures. The samples maintained superhydrophobicity under NaCl solution up to 2 weeks. PMID- 29511306 TI - Modeling of networks and globules of charged domain walls observed in pump and pulse induced states. AB - Experiments on optical and STM injection of carriers in layered MX2 materials revealed the formation of nanoscale patterns with networks and globules of domain walls. This is thought to be responsible for the metallization transition of the Mott insulator and for stabilization of a "hidden" state. In response, here we present studies of the classical charged lattice gas model emulating the superlattice of polarons ubiquitous to the material of choice 1T - TaS2. The injection pulse was simulated by introducing a small random concentration of voids which subsequent evolution was followed by means of Monte Carlo cooling. Below the detected phase transition, the voids gradually coalesce into domain walls forming locally connected globules and then the global network leading to a mosaic fragmentation into domains with different degenerate ground states. The obtained patterns closely resemble the experimental STM visualizations. The surprising aggregation of charged voids is understood by fractionalization of their charges across the walls' lines. PMID- 29511307 TI - Isolation of levoglucosan-utilizing thermophilic bacteria. AB - We previously developed an industrial production process for novel water-soluble indigestible polysaccharides (resistant glucan mixture, RGM). During the process, an anhydrosugar-levoglucosan -is formed as a by-product and needs to be removed to manufacture a complete non-calorie product. Here, we attempted to isolate thermophilic bacteria that utilize levoglucosan as a sole carbon source, to establish a removing process for levoglucosan at higher temperature. Approximately 800 natural samples were used to isolate levoglucosan-utilizing microorganisms. Interestingly, levoglucosan-utilizing microorganisms-most of which were filamentous fungi or yeasts-could be isolated from almost all samples at 25 degrees C. We isolated three thermophilic bacteria that grew well on levoglucosan medium at 60 degrees C. Two of them and the other were identified as Bacillus smithii and Parageobacillus thermoglucosidasius, respectively, by 16S rDNA sequence analysis. Using B. smithii S-2701M, which showed best growth on levoglucosan, glucose and levoglucosan in 5% (wt/vol) RGM were completely diminished at 50 degrees C for 144 h. These bacteria are known to have a biotechnological potential, given that they can ferment a range of carbon sources. This is the first report in the utilization of levoglucosan by these thermophiles, suggesting that our results expand their biotechnological potential for the unutilized carbon resources. PMID- 29511308 TI - Impact of growth rate on graphene lattice-defect formation within a single crystalline domain. AB - Chemical vapor deposition (CVD) is promising for the large scale production of graphene and other two-dimensional materials. Optimization of the CVD process for enhancing their quality is a focus of ongoing effort and significant progress has been made in decreasing the defectiveness associated with grain boundaries and nucleation spots. However, little is known about the quality and origin of structural defects in the outgrowing lattice which are present even in single crystalline material and represent the limit of current optimization efforts. We here investigate the formation kinetics of such defects by controlling graphene's growth rate over a wide range using nanoscale confinements. Statistical analysis of Raman spectroscopic results shows a clear trend between growth rate and defectiveness that is in quantitative agreement with a model where defects are healed preferentially at the growth front. Our results suggest that low growth rates are required to avoid the freezing of lattice defects and form high quality material. This conclusion is confirmed by a fourfold enhancement in graphene's carrier mobility upon optimization of the growth rate. PMID- 29511310 TI - Estimates of the precision of regional and whole body composition by dual-energy x-ray absorptiometry in persons with chronic spinal cord injury. AB - STUDY DESIGN: Repeated measures design. OBJECTIVES: To determine the reproducibility of total-body and regional-body composition assessments from a total-body scan using dual-energy x-ray absorptiometry (DXA) in persons with spinal cord injury (SCI). METHODS: Twenty-four individuals with SCI completed within-day short-term precision testing by repositioning study participants between scans. An additional and separate cohort of 22 individuals with SCI were scanned twice on a GE-Lunar DXA scanner separated by a 4-week interval to assess the long-term precision assessment. The root mean square coefficient of variation percent (RMS-CV%) values for the regional and total body composition was calculated. RESULTS: For the same day, short-term precision assessment, the RMS CV% for each region did not exceed 5.6, 2.7, 3.8, 6.5, 5.8, and 2.3% for arms, legs, trunk, android and gynoid regions, and total body mass, respectively. In the long-term precision assessment, the RMS-CV% for each region did not exceed 6.0, 3.0, 4.4, 8.2, 3.4, and 2.0% for arms, legs, trunk, android, gynoid, and total body mass. Moreover, the interclass-correlation coefficient in the long term precision group demonstrated excellent linear agreement between repeat scans for all regions (r > 0.97). CONCLUSIONS: The precision error of the total body composition variables in our SCI cohort was similar to those reported in the literature for nondisabled individuals, and the precision errors of the regional body composition compartments were notably higher, but similar to the regional precision errors reported in the general population. PMID- 29511309 TI - Prediction and characterization of human ageing-related proteins by using machine learning. AB - Ageing has a huge impact on human health and economy, but its molecular basis - regulation and mechanism - is still poorly understood. By today, more than three hundred genes (almost all of them function as protein-coding genes) have been related to human ageing. Although individual ageing-related genes or some small subsets of these genes have been intensively studied, their analysis as a whole has been highly limited. To fill this gap, for each human protein we extracted 21000 protein features from various databases, and using these data as an input to state-of-the-art machine learning methods, we classified human proteins as ageing-related or non-ageing-related. We found a simple classification model based on only 36 protein features, such as the "number of ageing-related interaction partners", "response to oxidative stress", "damaged DNA binding", "rhythmic process" and "extracellular region". Predicted values of the model quantify the relevance of a given protein in the regulation or mechanisms of the human ageing process. Furthermore, we identified new candidate proteins having strong computational evidence of their important role in ageing. Some of them, like Cytochrome b-245 light chain (CY24A) and Endoribonuclease ZC3H12A (ZC12A) have no previous ageing-associated annotations. PMID- 29511311 TI - Author Correction: Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29511312 TI - Application of maltose as energy source in protein-free CHO-K1 culture to improve the production of recombinant monoclonal antibody. AB - Oligosaccharides are generally considered to be un-utilized for growth of mammalian cells because their permeability across the cell membrane is low. However, in our previous study, we discovered that CHO and HEK293 cells consume maltose in culture media without serum and glucose. This is interesting because the transporter for maltose in mammalian cells has not been discovered to-date, and the only animal disaccharide transporter that is recently discovered is a sucrose transporter. The application of oligosaccharides in mammalian cell-based biopharmaceutical manufacturing can be beneficial, because it can theoretically increase carbohydrate content of the culture medium and decrease lactate production. Here, we first determined that specific maltose consumption rate in CHO cells was similar to galactose and fructose at 0.257 ng/cell/day. We then demonstrated that CHO cells can be cultivated with reasonable cell growth using higher maltose concentrations. After which, we evaluated the use of maltose supplementation in the production of a recombinant monoclonal antibody in batch and fed-batch cultures, demonstrating improvements in recombinant monoclonal antibody titer of 15% and 23% respectively. Finally, glycosylation profiles of the antibodies were analyzed. PMID- 29511313 TI - Evaluation of FOXC1 as a therapeutic target for basal-like breast cancer. AB - Basal-like breast cancer (BLBC) is a malignant carcinoma with aggressive motility and rapid growth. Accounting for 15% of breast cancers, BLBC often exhibits a poor prognosis and tends to metastasize to the brain and lungs. Because most BLBC display a triple-negative phenotype (ER-, PR-, and HER2-), conventional cytotoxic chemotherapy remains the only treatment option despite poor success and high rate of relapse. The overexpression of the forkhead-box transcription factor C1 (FOXC1) was recently identified as a biomarker of BLBC. Increased expression of FOXC1 was linked to excessive mobility and growth of BLBC cell lines, suggesting FOXC1 as a therapeutic target. In this study, siRNA-mediated knockdown of FOXC1 was confirmed to decrease the proliferation rate, migration, and invasion in a model BLBC-like cell line (4T1). 4T1 and 4T1-?FOXC1 cells lacking FOXC1 expression (generated by CRISPR/Cas9) were used to evaluate the effects of FOXC1 expression in an orthotopic murine model of BLBC. No statistically significant difference in tumor volume was observed between 4T1 and 4T1-?FOXC1 tumors. Furthermore, tumors metastasized to the liver and lungs to a similar degree regardless of FOXC1 expression. These data suggest that, despite positive results in vitro, FOXC1 may not be a promising therapeutic target for BLBC. PMID- 29511314 TI - Identification of Insulin Receptor Splice Variant B in Neurons by in situ Detection in Human Brain Samples. AB - Insulin and its receptor are widely expressed in a variety of tissues throughout the body including liver, adipose tissue, liver and brain. The insulin receptor is expressed as two functionally distinct isoforms, differentiated by a single 12 amino acid exon. The two receptor isoforms, designated IR/A and IR/B, are expressed in a highly tissue and cell specific manner and relative proportions of the different isoforms vary during development, aging and disease states. The high degree of similarity between the two isoforms has prevented detailed studies as differentiation of the two isoforms by traditional immunological methods cannot be achieved. We describe here a new in situ RT-PCR/ FISH assay that allows for the visualization of IR/A and IR/B in tissue along with tissue specific markers. We used this new method to show for the first time that IR/A and IR/B are both expressed in neurons in the adult human brain. Thus, we present a method that enables the investigation of IR/A and IR/B insulin receptor isoform expression in situ in various tissues. PMID- 29511315 TI - Publisher Correction: CODA: Integrating multi-level context-oriented directed associations for analysis of drug effects. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511316 TI - The early effects of external and internal strategies on working memory updating training. AB - The mechanisms underlying working memory training remain unclear, but one possibility is that the typically limited transfer effects of this training reflect adoption of successful task-specific strategies. Our pre-registered randomized controlled trial (N = 116) studied the early effects of externally given vs. internally generated strategies in an updating task (n-back) over a 5 day period with a single 30-minute training session. Three groups were employed: n-back training with strategy instruction (n = 40), n-back training without strategy instruction (n = 37), and passive controls (n = 39). We found that both external and internal strategy use was associated with significantly higher posttest performance on the trained n-back task, and that training with n-back strategy instruction yielded positive transfer on untrained n-back tasks, resembling the transfer pattern typically seen after the ordinary uninstructed 4 6-week working memory training. In the uninstructed participants, the level of detail and type of internally generated n-back strategies at posttest was significantly related to their posttest n-back performance. Our results support the view that adoption of task-specific strategies plays an important role in working memory training outcomes, and that strategy-based effects are apparent right at the start of training. PMID- 29511317 TI - Charge Berezinskii-Kosterlitz-Thouless transition in superconducting NbTiN films. AB - Three decades after the prediction of charge-vortex duality in the critical vicinity of the two-dimensional superconductor-insulator transition (SIT), one of the fundamental implications of this duality-the charge Berezinskii-Kosterlitz Thouless (BKT) transition that should occur on the insulating side of the SIT-has remained unobserved. The dual picture of the process points to the existence of a superinsulating state endowed with zero conductance at finite temperature. Here, we report the observation of the charge BKT transition on the insulating side of the SIT in 10 nm thick NbTiN films, identified by the BKT critical behavior of the temperature and magnetic field dependent resistance, and map out the magnetic field dependence of the critical temperature of the charge BKT transition. Finally, we ascertain the effects of the finite electrostatic screening length and its divergence at the magnetic field-tuned approach to the superconductor insulator transition. PMID- 29511318 TI - Publisher Correction: Learning the value of information and reward over time when solving exploration-exploitation problems. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29511320 TI - Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function. AB - BACKGROUND: Deterioration of the adipogenic potential of preadipocytes may contribute to adipose tissue dysfunction in obesity and type 2 diabetes (T2D). Here, we hypothesized that extracellular factors in obesity epigenetically reprogram adipogenesis potential and metabolic function of preadipocytes. METHODS: The transcriptomic profile of visceral adipose tissue preadipocytes collected from Lean, Obese and Obese with T2D was assessed throughout in vitro differentiation using RNA sequencing. Reduced Representation Bisulfite Sequencing was used to establish the genome-wide DNA methylation profile of human preadipocytes and 3T3-L1 preadipocytes treated by the inflammatory cytokine Tumour Necrosis Factor-alpha (TNF-alpha) or palmitate. RESULTS: While preadipocytes from all obese subjects (Obese+Obese T2D), compared to those of Lean, were transcriptionally different in response to differentiation in culture, preadipocytes from Obese T2D showed impaired insulin signalling and a further transcriptomic shift towards altered adipocyte function. Cultures with a lower expression magnitude of adipogenic genes throughout differentiation (PLIN1, CIDEC, FABP4, ADIPOQ, LPL, PDK4, APOE, LIPE, FABP3, LEP, RBP4 and CD36) were associated with DNA methylation remodelling at genes controlling insulin sensitivity and adipocytokine signalling pathways. Prior incubation of 3T3-L1 preadipocytes with TNF-alpha or palmitate markedly altered insulin responsiveness and metabolic function in the differentiated adipocytes, and remodelled DNA methylation and gene expression at specific genes, notably related to PPAR signalling. CONCLUSIONS: Our findings that preadipocytes retain the memory of the donor in culture and can be reprogrammed by extracellular factors support a mechanism by which adipocyte precursors are epigenetically reprogrammed in vivo. Epigenetic reprogramming of preadipocytes represents a mechanism by which metabolic function of visceral adipose tissue may be affected in the long term by past exposure to obesity- or T2D-specific factors. PMID- 29511319 TI - Cadmium exposure increases the risk of juvenile obesity: a human and zebrafish comparative study. AB - OBJECTIVE: Human obesity is a complex metabolic disorder disproportionately affecting people of lower socioeconomic strata, and ethnic minorities, especially African Americans and Hispanics. Although genetic predisposition and a positive energy balance are implicated in obesity, these factors alone do not account for the excess prevalence of obesity in lower socioeconomic populations. Therefore, environmental factors, including exposure to pesticides, heavy metals, and other contaminants, are agents widely suspected to have obesogenic activity, and they also are spatially correlated with lower socioeconomic status. Our study investigates the causal relationship between exposure to the heavy metal, cadmium (Cd), and obesity in a cohort of children and in a zebrafish model of adipogenesis. DESIGN: An extensive collection of first trimester maternal blood samples obtained as part of the Newborn Epigenetics Study (NEST) was analyzed for the presence of Cd, and these results were cross analyzed with the weight-gain trajectory of the children through age 5 years. Next, the role of Cd as a potential obesogen was analyzed in an in vivo zebrafish model. RESULTS: Our analysis indicates that the presence of Cd in maternal blood during pregnancy is associated with increased risk of juvenile obesity in the offspring, independent of other variables, including lead (Pb) and smoking status. Our results are recapitulated in a zebrafish model, in which exposure to Cd at levels approximating those observed in the NEST study is associated with increased adiposity. CONCLUSION: Our findings identify Cd as a potential human obesogen. Moreover, these observations are recapitulated in a zebrafish model, suggesting that the underlying mechanisms may be evolutionarily conserved, and that zebrafish may be a valuable model for uncovering pathways leading to Cd-mediated obesity in human populations. PMID- 29511321 TI - Re: "Widespread prevalence of a CREBRF variant among Maori and Pacific children is associated with weight and height in early childhood". PMID- 29511322 TI - Publisher Correction: Universal strategy for Ohmic hole injection into organic semiconductors with high ionization energies. AB - In the html version of this Article originally published, Paul W. M. Blom and Gert-Jan A. H. Wetzelaer were incorrectly listed as Paul M. W. Blom and Gert-Jan H. A. Wetzelaer, respectively, due to a technical error. This has now been amended in all online versions of the Article. PMID- 29511325 TI - JBS Haldane: an evolutionary geneticist not without controversy. PMID- 29511323 TI - Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy. AB - CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype-phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families. PMID- 29511326 TI - Doing your own thing. PMID- 29511327 TI - Twofold topology. PMID- 29511324 TI - Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice. AB - Several studies have identified copy number variants (CNVs) as responsible for cardiac diseases associated with sudden cardiac death (SCD), but very few exhaustive analyses in large cohorts of patients have been performed, and they have been generally focused on a specific SCD-related disease. The aim of the present study was to screen for CNVs the most prevalent genes associated with SCD in a large cohort of patients who suffered sudden unexplained death or had an inherited cardiac disease (cardiomyopathy or channelopathy). A total of 1765 European patients were analyzed with a homemade algorithm for the assessment of CNVs using high-throughput sequencing data. Thirty-six CNVs were identified (2%), and most of them appeared to have a pathogenic role. The frequency of CNVs among cases of sudden unexplained death, patients with a cardiomyopathy or a channelopathy was 1.4% (8/587), 2.3% (20/874), and 2.6% (8/304), respectively. Detection rates were particularly high for arrhythmogenic cardiomyopathy (5.1%), long QT syndrome (4.7%), and dilated cardiomyopathy (4.4%). As such large genomic rearrangements underlie a non-neglectable portion of cases, we consider that their analysis should be performed as part of the routine genetic testing of sudden unexpected death cases and patients with SCD-related diseases. PMID- 29511328 TI - Crystal casting. PMID- 29511329 TI - A frustrated solution. PMID- 29511330 TI - A reversible morphology. PMID- 29511332 TI - A different view of the environment. PMID- 29511331 TI - Quantum engineering of transistors based on 2D materials heterostructures. AB - Quantum engineering entails atom-by-atom design and fabrication of electronic devices. This innovative technology that unifies materials science and device engineering has been fostered by the recent progress in the fabrication of vertical and lateral heterostructures of two-dimensional materials and by the assessment of the technology potential via computational nanotechnology. But how close are we to the possibility of the practical realization of next-generation atomically thin transistors? In this Perspective, we analyse the outlook and the challenges of quantum-engineered transistors using heterostructures of two dimensional materials against the benchmark of silicon technology and its foreseeable evolution in terms of potential performance and manufacturability. Transistors based on lateral heterostructures emerge as the most promising option from a performance point of view, even if heterostructure formation and control are in the initial technology development stage. PMID- 29511333 TI - Relapse prediction in schizophrenia through digital phenotyping: a pilot study. AB - Among individuals diagnosed, hospitalized, and treated for schizophrenia, up to 40% of those discharged may relapse within 1 year even with appropriate treatment. Passively collected smartphone behavioral data present a scalable and at present underutilized opportunity to monitor patients in order to identify possible warning signs of relapse. Seventeen patients with schizophrenia in active treatment at a state mental health clinic in Boston used the Beiwe app on their personal smartphone for up to 3 months. By testing for changes in mobility patterns and social behavior over time as measured through smartphone use, we were able to identify statistically significant anomalies in patient behavior in the days prior to relapse. We found that the rate of behavioral anomalies detected in the 2 weeks prior to relapse was 71% higher than the rate of anomalies during other time periods. Our findings show how passive smartphone data, data collected in the background during regular phone use without active input from the subjects, can provide an unprecedented and detailed view into patient behavior outside the clinic. Real-time detection of behavioral anomalies could signal the need for an intervention before an escalation of symptoms and relapse occur, therefore reducing patient suffering and reducing the cost of care. PMID- 29511335 TI - Turning an old GADDget into a troublemaker. PMID- 29511334 TI - Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans. AB - Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn(r)), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants. PMID- 29511336 TI - Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition. AB - Myocardin is a transcriptional co-activator required for cardiovascular development, but also promotes cardiomyocyte survival through an unclear molecular mechanism. Mitochondrial permeability transition is implicated in necrosis, while pore closure is required for mitochondrial maturation during cardiac development. We show that loss of myocardin function leads to subendocardial necrosis at E9.5, concurrent with elevated expression of the death gene Nix. Mechanistically, we demonstrate that myocardin knockdown reduces microRNA-133a levels to allow Nix accumulation, leading to mitochondrial permeability transition, reduced mitochondrial respiration, and necrosis. Myocardin knockdown elicits calcium release from the endo/sarcoplasmic reticulum with mitochondrial calcium accumulation, while restoration of microRNA-133a function, or knockdown of Nix rescues calcium perturbations. We observed reduced myocardin and elevated Nix expression within the infarct border-zone following coronary ligation. These findings identify a myocardin-regulated pathway that maintains calcium homeostasis and mitochondrial function during development, and is attenuated during ischemic heart disease. Given the diverse role of Nix and microRNA-133a, these findings may have broader implications to metabolic disease and cancer. PMID- 29511337 TI - Post-translational modification of OCT4 in breast cancer tumorigenesis. AB - Recurrence and drug resistance of breast cancer are still the main reasons for breast cancer-associated deaths. Cancer stem cell (CSC) model has been proposed as a hypothesis for the lethality of breast cancer. Molecular mechanisms underlying CSC maintenance are still unclear. In this study, we generated mammospheres derived from breast cancer MDA-MB231 cells and MCF7 cells to enrich CSCs and performed DNA microarray analysis. We found that the expression of carboxy terminus of HSP70-interacting protein (CHIP) E3 ubiquitin ligase was significantly downregulated in breast CSCs. CHIP depletion increased mammosphere formation, whereas CHIP overexpression reversed this effect. We identified interactomes by mass spectrometry and detected CHIP directly interacted with OCT4, a stemness factor. CHIP overexpression decreased OCT4 stability through proteasomal degradation. CHIP induced OCT4 ubiquitination, whereas H260Q, a catalytic CHIP mutant, did not. Interestingly, we determined that OCT4 was ubiquitinated at lysine 284, and CHIP overexpression did not degrade K284R mutant OCT4. CHIP overexpression decreased the proliferation and side population of breast cancer cells, but these were not occurred in K284R mutant OCT4 overexpressed cells. Only 1000 cells showing CHIP depletion or OCT4 overexpression sufficiently generated breast tumors and lung metastases in xenografted mice. Ubiquitination-defective mutant of OCT4(K284R) overexpressed cells drastically generated tumor burdens in mice. Patients with breast cancer who showed low CHIP expression had poor survival probability. Taken together, we suggest that CHIP-induced OCT4 ubiquitination is important in breast CSCs. Regulation of CHIP expression and OCT4 protein stability is a considerable approach for breast cancer therapy. PMID- 29511338 TI - The cJUN NH2-terminal kinase (JNK) pathway contributes to mouse mammary gland remodeling during involution. AB - Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK has a key role in mammary gland involution post lactation. PMID- 29511339 TI - p73 coordinates with Delta133p53 to promote DNA double-strand break repair. AB - Tumour repressor p53 isoform Delta133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that Delta133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RAD51, LIG4 and RAD52 in a p53-independent manner. However, Delta133p53 lacks the transactivation domain of full-length p53, and the mechanism by which it exerts transcriptional activity independently of full-length p53 remains unclear. In this report, we describe the accumulation of high levels of both Delta133p53 and p73 (a p53 family member) at 24 h post gamma irradiation (hpi). Delta133p53 can form a complex with p73 upon gamma irradiation. The co-expression of Delta133p53 and p73, but not either protein alone, can significantly promote DNA DSB repair mechanisms, including homologous recombination (HR), non-homologous end joining (NHEJ) and single-strand annealing (SSA). p73 and Delta133p53 act synergistically to promote the expression of RAD51, LIG4 and RAD52 by joining together to bind to region containing a Delta133p53-responsive element (RE) and a p73-RE in the promoters of all three repair genes. In addition to its accumulation at 24 hpi, p73 protein expression also peaks at 4 hpi. The depletion of p73 not only reduces early-stage apoptotic frequency (4-6 hpi), but also significantly increases later-stage DNA DSB accumulation (48 hpi), leading to cell cycle arrest in the G2 phase and, ultimately, cell senescence. In summary, the apoptotic regulator p73 also coordinates with Delta133p53 to promote DNA DSB repair, and the loss of function of p73 in DNA DSB repair may underlie spontaneous and carcinogen-induced tumorigenesis in p73 knockout mice. PMID- 29511340 TI - LncRNA CASC9 promotes esophageal squamous cell carcinoma metastasis through upregulating LAMC2 expression by interacting with the CREB-binding protein. AB - Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM-integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment. PMID- 29511341 TI - The stiff RhoAd from mevalonate to mutant p53. PMID- 29511343 TI - Regeneration: Mending broken hearts. PMID- 29511344 TI - DNA Replication: Onco-agent provocateur. PMID- 29511342 TI - Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells. AB - Metabolically reactive formaldehyde is a genotoxin and a carcinogen. Mice lacking the main formaldehyde-detoxifying gene Adh5 combined with the loss of the Fanconi anemia (FA) DNA repair pathway rapidly succumbed to bone marrow failure (BMF) primarily due to the extensive ablation of the hematopoietic stem cell (HSC) pool. However, the mechanism by which formaldehyde mediates these toxic effects is still unknown. We uncover a detrimental role of tetrahydrofolic acid (THF) in cells lacking Adh5 or the FA repair pathway. We show that Adh5- or FA-deficient cells are hypersensitive to formaldehyde and to THF, presenting DNA damage and genome instability. THF cytotoxicity involved imbalance of the nucleotide pool by deregulation of the thymidylate synthase (TYMS) enzyme, which stalled replication forks. In mice, THF exposure had widespread effects on hematopoiesis, affecting the frequency and the viability of myeloid- and lymphoid-committed precursor cells. Moreover, the hematopoietic stem and progenitor cells (HSPC) showed genomic instability, reduced colony-forming capacity and increased frequency of cycling and apoptotic HSCs upon THF exposure. Overall, our data reveal that the physiological pool of THF and formaldehyde challenge the stability of the genome of HSPCs that might lead to blood disorders. PMID- 29511345 TI - Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor. AB - Resistance to the BCR-ABL tyrosine kinase inhibitor (TKI) remains a challenge for curing the disease in chronic myeloid leukemia (CML) patients as leukemia cells may survive through BCR-ABL kinase activity-independent signal pathways. To gain insight into BCR-ABL kinase activity-independent mechanisms, we performed an initial bioinformatics screen and followed by a quantitative PCR screen of genes that were elevated in CML samples. A total of 33 candidate genes were identified to be highly expressed in TKIs resistant patients. Among those genes, 6 phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), controlling the limiting step of glycolysis, was found to be strongly associated with TKIs resistance. PFKFB3 knockdown or pharmacological inhibition of its kinase activity markedly enhanced the sensitivity of CML cells to TKIs. Furthermore, pharmacological inhibition of PFKFB3 inhibited CML cells growth and significantly prolonged the survival of both allograft and xenograft CML mice. ChIP-seq data analysis combined with subsequent knockdown experiment showed that the Ets transcription factor PU.1 regulated the elevated expression of PFKFB3 in TKIs resistant CML cells. Therefore, our results showed that targeting PFKFB3 sensitizes CML cells to TKIs and PFKFB3 may be a potential BCR-ABL kinase activity-independent mechanism in CML. PMID- 29511346 TI - Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer. AB - Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES) upregulates hepatic CEBPA expression. Here we show how MTL-CEBPA therapy promotes disease reversal in rodent models of cirrhosis, fibrosis, hepatosteatosis, and significantly reduces tumor burden in cirrhotic HCC. Restoration of liver function markers were observed in a carbon-tetrachloride-induced rat model of fibrosis following 2 weeks of MTL-CEBPA therapy. At 14 weeks, animals showed reduction in ascites and enhanced survival rates. MTL-CEBPA reversed changes associated with hepatosteatosis in non-alcoholic methionine and cholic-deficient diet-induced steaotic liver disease. In diethylnitrosamine induced cirrhotic HCC rats, MTL CEBPA treatment led to a significant reduction in tumor burden. The data included here and the rapid adoption of MTL-CEBPA into a Phase 1 study may lead to new therapeutic oligonucleotides for undruggable diseases. PMID- 29511347 TI - PARP-1 inhibition with or without ionizing radiation confers reactive oxygen species-mediated cytotoxicity preferentially to cancer cells with mutant TP53. AB - Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1.22 to 2.27. Radiosensitization was correlated with the induction of potentially lethal DNA double-strand breaks (DSB) but not with RAD51 foci formation. The ability of olaparib to radiosensitize MIBC cells was linked to the extent of cell kill achieved with the drug alone. Unexpectedly, increased levels of reactive oxygen species (ROS) resulting from PARPi treatment were the cause of DSB throughout the cell cycle in vitro and in vivo. ROS originated from mitochondria and were required for the radiosensitizing effects of olaparib. Consistent with the role of TP53 in ROS regulation, loss of p53 function enhanced radiosensitization by olaparib in non-isogenic and isogenic cell line models and was associated with increased PARP-1 expression in bladder cancer cell lines and tumors. Impairment of ATM in addition to p53 loss resulted in an even more pronounced radiosensitization. In conclusion, ROS suppression by PARP-1 in MIBC is a potential therapeutic target either for PARPi combined with radiation or drug alone treatment. The TP53 and ATM genes, commonly mutated in MIBC and other cancers, are candidate biomarkers of PARPi-mediated radiosensitization. PMID- 29511348 TI - Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. AB - Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer. PMID- 29511349 TI - Pancreatic tumor microenvironment confers highly malignant properties on pancreatic cancer cells. AB - Tumor microenvironment plays a pivotal role in cancer progression; however, little is known regarding how differences in the microenvironment affect characteristics of cancer cells. Here, we investigated the effects of tumor microenvironment on cancer cells by using mouse tumor models. After three cycles of inoculation and extraction of human pancreatic cancer cells, including SUIT-2 and Panc-1 cells, from tumors, distinct cancer cell lines were established: 3P cells from the pancreas obtained using the orthotopic tumor model and 3sc cells from subcutaneous tissue obtained using the subcutaneous tumor model. On re inoculation of these cells, the 3sc cells and, more prominently, the 3P cells, exhibited higher tumorigenic activity than the parental cells. The 3P cells specifically exhibited low E-cadherin expression and high invasiveness, suggesting that they were endowed with the highest malignant characteristics. RNA sequence analysis demonstrated that distinct signaling pathways were activated in each cell line and that the 3P cells acquired a cancer stem cell-like phenotype. Among cancer stem cell-related genes, those specifically expressed in the 3P cells, including NES, may be potential new targets for cancer therapy. The mechanisms underlying the development of highly malignant cancer cell lines were investigated. Individual cell clones within the parental cells varied in tumor forming ability, indicating the presence of cellular heterogeneity. Moreover, the tumor-forming ability and the gene expression profile of each cell clone were altered after serial orthotopic inoculations. The present study thus suggests that both selection and education processes by tumor microenvironment are involved in the development of highly malignant cancer cells. PMID- 29511350 TI - TBX3 promotes proliferation of papillary thyroid carcinoma cells through facilitating PRC2-mediated p57KIP2 repression. AB - The T-box transcription factor TBX3 has been implicated in the patterning and differentiation of a number of tissues during embryonic development, and is overexpressed in a variety of cancers; however, the precise function of TBX3 in papillary thyroid carcinoma (PTC) development remains to be determined. In the current study, we report downregulation of TBX3 in PTC cells delays the G1/S phase transition, decreases cell growth in vitro, and inhibits tumor formation in vivo. We identified p57KIP2 as a novel downstream target that serves as the key mediator of TBX3's control over PTC cell proliferation. Reduced expression of TBX3 resulted in increased p57KIP2 level, while knockdown of p57KIP2 rescues the cell-cycle arrest phenotype. In clinical PTC specimens, the expression of TBX3 is markedly upregulated and significantly correlated with advanced tumor grade, but negatively correlated with the expression of p57KIP2. Mechanism investigation revealed that TBX3 directly binds to the CDKN1C gene promoter region, the coding gene of p57KIP2, and represses its transcription. Furthermore, recruitment of main components of the PRC2 complex as well as class I histone deacetylases, HDAC1 and HDAC2, is required for TBX3 to fulfill the transcriptional repression function. Our findings illustrate the previously unknown function and mechanism in cell proliferation regulation by the TBX3-p57KIP2 axis and provide evidence for the contribution of the PRC2 complex and HDAC1/2. Targeting of this pathway may present a novel and molecular defined strategy against PTC development. PMID- 29511351 TI - HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis. AB - Recent studies reveal the emerging functions of enhancer RNAs (eRNAs) in gene expression. However, the roles of eRNAs in regulating the expression of heparanase (HPSE), an established endo-beta-D-glucuronidase essential for cancer invasion and metastasis, still remain elusive. Herein, through comprehensive analysis of publically available FANTOM5 expression atlas and chromatin interaction dataset, we identified a super enhancer and its derived eRNA facilitating the HPSE expression (HPSE eRNA) in cancers. Gain-of-function and loss-of-function experiments indicated that HPSE eRNA facilitated the in vitro and in vivo tumorigenesis and aggressiveness of cancer cells. Mechanistically, as a p300-regulated nuclear noncoding RNA, HPSE eRNA bond to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with p300 and their enrichment on super enhancer, resulting in chromatin looping between super enhancer and HPSE promoter, p300-mediated transactivation of transcription factor early growth response 1 (EGR1), and subsequent elevation of HPSE expression. In addition, rescue studies in HPSE overexpressing or silencing cancer cells indicated that HPSE eRNA exerted oncogenic properties via driving HPSE expression. In clinical cancer tissues, HPSE eRNA was highly expressed and positively correlated with HPSE levels, and served as an independent prognostic factor for poor outcome of cancer patients. Therefore, these findings indicate that as a novel noncoding RNA, HPSE eRNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis. PMID- 29511353 TI - A Comprehensive Study of De Novo Genome Assemblers: Current Challenges and Future Prospective. AB - Background: Current advancements in next-generation sequencing technology have made possible to sequence whole genome but assembling a large number of short sequence reads is still a big challenge. In this article, we present the comparative study of seven assemblers, namely, ABySS, Velvet, Edena, SGA, Ray, SSAKE, and Perga, using prokaryotic and eukaryotic paired-end as well as single end data sets from Illumina platform. Results: Results showed that in case of single-end data sets, Velvet and ABySS outperformed in all the seven assemblers with comparatively low assembling time and high genome fraction. Velvet consumed the least amount of memory than any other assembler. In case of paired-end data sets, Velvet consumed least amount of time and produced high genome fraction after ABySS and Ray. In terms of low memory usage, SGA and Edena outperformed in all the assemblers. Ray also showed good genome fraction; however, extremely high assembling time consumed by the Ray might make it prohibitively slow on larger data sets of single and paired-end data. Conclusions: Our comparison study will provide assistance to the scientists for selecting the suitable assembler according to their data sets and will also assist the developers to upgrade or develop a new assembler for de novo assembling. PMID- 29511352 TI - Regulation of inside-out beta1-integrin activation by CDCP1. AB - Tumor metastasis depends on the dynamic regulation of cell adhesion through beta1 integrin. The Cub-Domain Containing Protein-1, CDCP1, is a transmembrane glycoprotein which regulates cell adhesion. Overexpression and loss of CDCP1 have been observed in the same cancer types to promote metastatic progression. Here, we demonstrate reduced CDCP1 expression in high-grade, primary prostate cancers, circulating tumor cells and tumor metastases of patients with castrate-resistant prostate cancer. CDCP1 is expressed in epithelial and not mesenchymal cells, and its cell surface and mRNA expression declines upon stimulation with TGFbeta1 and epithelial-to-mesenchymal transition. Silencing of CDCP1 in DU145 and PC3 cells resulted in 3.4-fold higher proliferation of non-adherent cells and 4.4-fold greater anchorage independent growth. CDCP1-silenced tumors grew in 100% of mice, compared to 30% growth of CDCP1-expressing tumors. After CDCP1 silencing, cell adhesion and migration diminished 2.1-fold, caused by loss of inside-out activation of beta1-integrin. We determined that the loss of CDCP1 reduces CDK5 kinase activity due to the phosphorylation of its regulatory subunit, CDK5R1/p35, by c-SRC on Y234. This generates a binding site for the C2 domain of PKCdelta, which in turn phosphorylates CDK5 on T77. The resulting dissociation of the CDK5R1/CDK5 complex abolishes the activity of CDK5. Mutations of CDK5-T77 and CDK5R1-Y234 phosphorylation sites re-establish the CDK5/CDKR1 complex and the inside-out activity of beta1-integrin. Altogether, we discovered a new mechanism of regulation of CDK5 through loss of CDCP1, which dynamically regulates beta1 integrin in non-adherent cells and which may promote vascular dissemination in patients with advanced prostate cancer. PMID- 29511354 TI - SWPhylo - A Novel Tool for Phylogenomic Inferences by Comparison of Oligonucleotide Patterns and Integration of Genome-Based and Gene-Based Phylogenetic Trees. AB - Modern phylogenetic studies may benefit from the analysis of complete genome sequences of various microorganisms. Evolutionary inferences based on genome scale analysis are believed to be more accurate than the gene-based alternative. However, the computational complexity of current phylogenomic procedures, inappropriateness of standard phylogenetic tools to process genome-wide data, and lack of reliable substitution models which correlates with alignment-free phylogenomic approaches deter microbiologists from using these opportunities. For example, the super-matrix and super-tree approaches of phylogenomics use multiple integrated genomic loci or individual gene-based trees to infer an overall consensus tree. However, these approaches potentially multiply errors of gene annotation and sequence alignment not mentioning the computational complexity and laboriousness of the methods. In this article, we demonstrate that the annotation and alignment-free comparison of genome-wide tetranucleotide frequencies, termed oligonucleotide usage patterns (OUPs), allowed a fast and reliable inference of phylogenetic trees. These were congruent to the corresponding whole genome super matrix trees in terms of tree topology when compared with other known approaches including 16S ribosomal RNA and GyrA protein sequence comparison, complete genome based MAUVE, and CVTree methods. A Web-based program to perform the alignment free OUP-based phylogenomic inferences was implemented at http://swphylo.bi.up.ac.za/. Applicability of the tool was tested on different taxa from subspecies to intergeneric levels. Distinguishing between closely related taxonomic units may be enforced by providing the program with alignments of marker protein sequences, eg, GyrA. PMID- 29511355 TI - Real-World Data on Health-Related Quality of Life Assessment in Patients With Breast Cancer Receiving Subcutaneous Trastuzumab. AB - Purpose: Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (anti-HER2) antibody delivered intravenously, has revolutionized the treatment of patients with breast cancer overexpressing HER2 protein. Recently, a newer subcutaneous formulation was shown to have comparable efficacy to the initial intravenous trastuzumab. In this study, we aimed to evaluate the impact of subcutaneous trastuzumab on the health-related quality of life (HRQoL) of patients diagnosed with early or metastatic HER2-overexpressing breast cancer. Methods: Patients were provided with the EORTC QLQ-C30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) and the BR-23 questionnaires. The scoring of questionnaires and patient's sociodemographic and clinicopathologic characteristics were recorded and analyzed by descriptive and correlation statistics employing t test and 2-way analysis of variance. Results: A total of 163 patients agreed to participate in the study. About 90 of 163 patients (55.21%) received subcutaneous trastuzumab and 21 patients intravenous trastuzumab (12.88%). A control group of 52 HER2+ patients received chemotherapy without trastuzumab (31.90%). Patients receiving subcutaneous trastuzumab were older and of more advanced disease stage compared with those receiving chemotherapy (58.5 vs 51 years, 39.8% vs 28.8% advanced disease). In univariate analysis, subcutaneous trastuzumab was associated with less nausea and vomiting (P = .002) but worse cognitive function (P = .013) and dyspnea (P = .042). Patients who have received >8 cycles of subcutaneous trastuzumab reported less diarrhea (P = .049) and systemic therapy side effects (P = .015). Multivariate analysis showed that patients without comorbidity receiving subcutaneous trastuzumab had less treatment side effects, less upset by hair loss, and higher emotional functioning. Of note, mastectomy and subcutaneous trastuzumab were associated with improved role functioning (P = .021). In metastatic disease, no negative impact of subcutaneous trastuzumab on HRQoL was found. Conclusions: The administration of subcutaneous trastuzumab improved certain symptoms and did not adversely affect most of the assessed functional scales. Particularly, in the metastatic setting, subcutaneous trastuzumab had no negative impact on HRQoL. PMID- 29511356 TI - Evaluation of Quantra Hologic Volumetric Computerized Breast Density Software in Comparison With Manual Interpretation in a Diverse Population. AB - Objective: Increased mammographic breast density is a well-established risk factor for breast cancer development, regardless of age or ethnic background. The current gold standard for categorizing breast density consists of a radiologist estimation of percent density according to the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) criteria. This study compares paired qualitative interpretations of breast density on digital mammograms with quantitative measurement of density using Hologic's Food and Drug Administration-approved R2 Quantra volumetric breast density assessment tool. Our goal was to find the best cutoff value of Quantra-calculated breast density for stratifying patients accurately into high-risk and low-risk breast density categories. Methods: Screening digital mammograms from 385 subjects, aged 18 to 64 years, were evaluated. These mammograms were interpreted by a radiologist using the ACR's BI-RADS density method, and had quantitative density measured using the R2 Quantra breast density assessment tool. The appropriate cutoff for breast density-based risk stratification using Quantra software was calculated using manually determined BI-RADS scores as a gold standard, in which scores of D3/D4 denoted high-risk densities and D1/D2 denoted low-risk densities. Results: The best cutoff value for risk stratification using Quantra-calculated breast density was found to be 14.0%, yielding a sensitivity of 65%, specificity of 77%, and positive and negative predictive values of 75% and 69%, respectively. Under bootstrap analysis, the best cutoff value had a mean +/- SD of 13.70% +/- 0.89%. Conclusions: Our study is the first to publish on a North American population that assesses the accuracy of the R2 Quantra system at breast density stratification. Quantitative breast density measures will improve accuracy and reliability of density determination, assisting future researchers to accurately calculate breast cancer risks associated with density increase. PMID- 29511357 TI - Childhood Tuberculosis in Nigeria: Disease Presentation and Treatment Outcomes. AB - Objectives: Understanding the factors that influence tuberculosis (TB) treatment outcomes in children is key to designing interventions to address them. This study aimed to determine the case category distribution of childhood TB in Nigeria and assess which clinical and demographic factors are associated with different treatment outcomes in childhood TB. Materials and methods: This was a retrospective cohort study involving a review of medical records of children (0 14 years) with TB in 3 states in Nigeria in 2015. Results: Of 724 childhood TB cases registered during the review period, 220 (30.4%) were aged 0-4 years. A high proportion of patients had pulmonary TB 420/724 (58.0%), new TB infection 713/724 (98.5%), and human immunodeficiency virus (HIV) coinfection 108/724 (14.7%). About 28% (n = 201) were bacteriologically diagnosed. The proportion of TB treatment success was 601/724 (83.0%). Treatment success was significantly higher in children aged 5-14 years than those 0-4 years (85.3% vs 77.7%, P = .01). Factors associated with unsuccessful outcomes in patients aged 0-4 years are male sex (adjusted odds ratio [aOR]: 1.2), HIV-positive status (aOR: 1.2), and clinical method of diagnosis (aOR: 5.6). Conclusions: Efforts should be made to improve TB treatment outcomes in children by ensuring early and accurate diagnosis, focused training of health workers on childhood TB-HIV care, and effective adherence counseling of caregivers. PMID- 29511358 TI - Neuronal Subtype Generation During Postnatal Olfactory Bulb Neurogenesis. AB - In the perinatal and adult forebrain, regionalized neural stem cells lining the ventricular walls produce different types of olfactory bulb interneurons. Although these postnatal stem cells are lineage related to their embryonic counterparts that produce, for example, cortical, septal, and striatal neurons, their output at the level of neuronal phenotype changes dramatically. Tiveron et al. investigated the molecular determinants underlying stem cell regionalization and the gene expression changes inducing the shift from embryonic to adult neuron production. High-resolution gene expression analyses of different lineages revealed that the zinc finger proteins, Zic1 and Zic2, are postnatally induced in the dorsal olfactory bulb neuron lineage. Functional studies demonstrated that these factors confer a GABAergic and calretinin-positive phenotype to neural stem cells while repressing dopaminergic fate. Based on these findings, we discuss the molecular mechanisms that allow acquisition of new traits during the transition from embryonic to adult neurogenesis. We focus on the involvement of epigenetic marks and emphasize why the identification of master transcription factors, that instruct the fate of postnatally generated neurons, can help in deciphering the mechanisms driving fate transition from embryonic to adult neuron production. PMID- 29511359 TI - Improving Reproducibility and Candidate Selection in Transcriptomics Using Meta analysis. AB - Transcriptomic experiments are often used in neuroscience to identify candidate genes of interest for further study. However, the lists of genes identified from comparable transcriptomic studies often show limited overlap. One approach to addressing this issue of reproducibility is to combine data from multiple studies in the form of a meta-analysis. Here, we discuss recent work in the field of circadian biology, where transcriptomic meta-analyses have been used to improve candidate gene selection. With the increasing availability of microarray and RNA Seq data due to deposition in public databases, combined with freely available tools and code, transcriptomic meta-analysis provides an ideal example of how open data can benefit neuroscience research. PMID- 29511360 TI - Stranger in a Strange Land: Using Heterotopic Transplantations to Study Nature vs Nurture in Brain Development. AB - The mammalian brain develops from a simple sheet of neuroepithelial cells into an incredibly complex structure containing billions of neurons with trillions of synapses. Understanding how intrinsic genetic programs interact with environmental cues to generate neuronal diversity and proper connectivity is one of the most daunting challenges in developmental biology. We recently explored this issue in forebrain GABAergic inhibitory interneurons, an extremely diverse population of neurons that are classified into distinct subtypes based on morphology, neurochemical markers, and electrophysiological properties. Immature interneurons were harvested from one brain region and transplanted into a different region, allowing us to assess how challenging cells in a new environment affected their fate. Do these grafted cells adopt characteristics of the host environment or retain features from the donor environment? We found that the proportion of interneuron subgroups is determined by the host region, but some interneuron subtypes maintain features attributable to the donor environment. In this commentary, I expound on potential mechanisms that could underlie these observations and explore the implications of these findings in a greater context of developmental neuroscience. PMID- 29511361 TI - Late Presentation of Infected Silicone Granulomas in the Lower Limb. AB - Introduction: Dermal fillers are used for multiple cosmetic indications including gluteal and thigh augmentation. Complications, although infrequent, are increasing due to the dramatic growth of dermal filler use. Our aim was to describe how the complication of infected silicone granulomas can present following lower limb augmentation. Methods: Two cases presented with pain, oedema, and erythema at the site of previous silicone filler injection, following a considerable delay after the last injection (range 4-7 years). We collected data on their biochemistry, haematology, histology, microbiology, and imaging at the time of presentation. Results: Complications included prolonged cellulitis with recurrent abscesses at sites of previous silicone dermal filler injection. Histology revealed infiltration of chronic inflammatory cells suggestive of silicone granuloma in both cases. Patients were reluctant to divulge use of cosmetic fillers or failed to recognise their significance given the time delay making diagnosis difficult. Delayed or recurring infections can suggest the presence of atypical organisms and we present the first reported case of silicone granuloma infection with Propionibacterium acnes. Conclusions: Microorganisms can induce immune-mediated hypersensitivity and are believed to be the trigger for delayed activation of a quiescent foreign body to a granulomatous reaction. The substantial time delay between injection and reaction must be recognised and may be attributable to atypical microorganisms or biofilm formation. Previous antibiotic use can affect expedient microbiological diagnosis and treatment requires close collaboration with microbiologists. It is important that clinicians are aware of these important complications which are becoming more common with increased use of filler augmentation. PMID- 29511363 TI - Application of a Causal Discovery Algorithm to the Analysis of Arthroplasty Registry Data. AB - Improving the quality of care for hip arthroplasty (replacement) patients requires the systematic evaluation of clinical performance of implants and the identification of "outlier" devices that have an especially high risk of reoperation ("revision"). Postmarket surveillance of arthroplasty implants, which rests on the analysis of large patient registries, has been effective in identifying outlier implants such as the ASR metal-on-metal hip resurfacing device that was recalled. Although identifying an implant as an outlier implies a causal relationship between the implant and revision risk, traditional signal detection methods use classical biostatistical methods. The field of probabilistic graphical modeling of causal relationships has developed tools for rigorous analysis of causal relationships in observational data. The purpose of this study was to evaluate one causal discovery algorithm (PC) to determine its suitability for hip arthroplasty implant signal detection. Simulated data were generated using distributions of patient and implant characteristics, and causal discovery was performed using the TETRAD software package. Two sizes of registries were simulated: (1) a statewide registry in Michigan and (2) a nationwide registry in the United Kingdom. The results showed that the algorithm performed better for the simulation of a large national registry. The conclusion is that the causal discovery algorithm used in this study may be a useful tool for implant signal detection for large arthroplasty registries; regional registries may only be able to only detect implants that perform especially poorly. PMID- 29511362 TI - Development of Molecularly Targeted Agents and Immunotherapies in Glioblastoma: A Personalized Approach. AB - Over the past decade, precision cancer medicine has driven major advances in the management of advanced solid tumours with the identification and targeting of putative driver aberrations transforming the clinical outcomes across multiple cancer types. Despite pivotal advances in the characterization of genomic landscape of glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. Immunotherapy strategies similarly have had limited success. Multiple deficiencies still exist in our knowledge of this complex disease, and further research is urgently required to overcome these critical issues. This review traces the path undertaken by the different therapeutics assessed in glioblastoma and the impact of precision medicine in this disease. We highlight challenges for precision medicine in glioblastoma, focusing on the issues of tumour heterogeneity, pharmacokinetic-pharmacodynamic optimization and outline the modern hypothesis testing strategies being undertaken to address these key challenges. PMID- 29511364 TI - Viola Yedoensis Suppresses Cell Invasion by Targeting the Protease and NF-kappaB Activities in A549 and Lewis Lung Carcinoma Cells. AB - Cancer metastasis is a vital trait in malignancies with complicated early diagnosis and therapeutic management. Therefore, the development of new remedies and the utilization of natural medicines that target metastasis are of great interest and have been studied extensively. Chinese medicinal herbs have various anti-carcinogenesis properties; however, the in vitro effect and mechanism of Viola yedoensis on cancer cell metastasis remains poorly understood. V. yedoensis extracts (VYE) can suppress the invasion of a highly metastatic human lung cancer cell line, A549 cells. According to gelatin zymography and casein zymography assays, VYE inhibited the activities of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (u-PA). The results of reverse transcription polymerase chain reaction and Western blotting revealed that VYE can alter the expression of proteinase inhibitor. VYE also suppressed the DNA binding activity of nuclear factor-kappa B. We concluded that VYE may inhibit tumor invasion by suppressing the activities of MMP and u-PA in lung cancer cells. PMID- 29511365 TI - SCAPs Regulate Differentiation of DFSCs During Tooth Root Development in Swine. AB - The tooth root transmits and balances occlusal forces through the periodontium to the alveolar bone. The periodontium, including the gingiva, the periodontal ligament, the cementum and the partial alveolar bone, derives from the dental follicle (DF), except for the gingiva. In the early developmental stages, the DF surrounds the tooth germ as a sphere and functions to promote tooth eruption. However, the morphological dynamics and factors regulating the differentiation of the DF during root elongation remain largely unknown. Miniature pigs are regarded as a useful experimental animal for modeling in craniofacial research because they are similar to humans with respect to dentition and mandible anatomy. In the present study, we used the third deciduous incisor of miniature pig as the model to investigate the factors influencing DF differentiation during root development. We found that the DF was shaped like a crescent and was located between the root apical and the alveolar bone. The expression levels of WNT5a, beta-Catenin, and COL-I gradually increased from the center of the DF (beneath the apical foramen) to the lateral coronal corner, where the DF differentiates into the periodontium. To determine the potential regulatory role of the apical papilla on DF cell differentiation, we co-cultured dental follicle stem cells (DFSCs) with stem cells of the apical papilla (SCAPs). The osteogenesis and fibrogenesis abilities of DFSCs were inhibited when being co-cultured with SCAPs, suggesting that the fate of the DF can be regulated by signals from the apical papilla. The apical papilla may sustain the undifferentiated status of DFSCs before root development finishes. These data yield insight into the interaction between the root apex and surrounding DF tissues in root and periodontium development and shed light on the future study of root regeneration in large mammals. PMID- 29511366 TI - Establishing an Animal Model of Secondary Osteoporosis by Using a Gonadotropin releasing Hormone Agonist. AB - Introduction: Orchidectomy is currently the preferred method to induce bone loss in preclinical male osteoporosis model. Gonadotropin-releasing hormone (GnRH) agonists used in prostate cancer treatment can induce testosterone deficiency but its effects on bone in preclinical male osteoporosis model are less studied. Objective: This study aimed to evaluate the skeletal effect of buserelin (a GnRH agonist) in male rats and compare it with orchidectomy. Methods: Forty-six three month-old male Sprague-Dawley rats were divided into three experimental arms. The baseline arm (n=6) was sacrificed at the onset of the study. In the buserelin arm, the rats received a daily subcutaneous injection of either normal saline (n=8), buserelin acetate at 25 ug/kg (n=8) or 75 ug/kg (n=8). In the orchidectomy arm, the rats were either sham-operated (n=8) or orchidectomized (n=8). All groups underwent in-vivo X-ray micro-computed tomography scanning at the left proximal tibia every month. Blood was collected at the beginning and the end of the study for testosterone level evaluation. The rats were euthanized after the three-month treatment. The femurs were harvested for biomechanical strength and bone calcium determination. Results: The results showed that buserelin at both doses caused a significant decline in testosterone level and deterioration in bone microstructure (p<0.05), but did not affect bone calcium content (p>0.05). Buserelin at 25 ug/kg decreased displacement and strain of the femur significantly (p<0.05). Similar changes were observed in the orchidectomized group compared to the sham-operated group but without any significant changes in biomechanical strength (p>0.05). Conclusion: Buserelin can induce testosterone deficiency and the associated deterioration of bone microarchitecture similar to orchidectomy in three months. However, it may require a longer time to show significant effects on bone strength and mineral content. PMID- 29511367 TI - While it is not deliberate, much of today's biomedical research contains logical and technical flaws, showing a need for corrective action. AB - Biomedical research has advanced swiftly in recent decades, largely due to progress in biotechnology. However, this rapid spread of new, and not always fully understood, technology has also created a lot of false or irreproducible data and artifacts, which sometimes have led to erroneous conclusions. When describing various scientific issues, scientists have developed a habit of saying "on one hand... but on the other hand...", because discrepant data and conclusions have become omnipresent. One reason for this problematic situation is that we are not always thoughtful enough in study design, and sometimes lack enough philosophical contemplation. Another major reason is that we are too rushed in introducing new technology into our research without assimilating technical details. In this essay, we provide examples in different research realms to justify our points. To help readers test their own weaknesses, we raise questions on technical details of RNA reverse transcription, polymerase chain reactions, western blotting and immunohistochemical staining, as these methods are basic and are the base for other modern biotechnologies. Hopefully, after contemplation and reflection on these questions, readers will agree that we indeed know too little about these basic techniques, especially about the artifacts they may create, and thus many conclusions drawn from the studies using those ever-more-sophisticated techniques may be even more problematic. PMID- 29511369 TI - Claudin-3 Inhibits Lung Squamous Cell Carcinoma Cell Epithelial-mesenchymal Transition and Invasion via Suppression of the Wnt/beta-catenin Signaling Pathway. AB - Altered expression of claudin-3 (CLDN3), a key cytoskeletal structural protein of the tight junctions in the epithelium, is associated with the development and metastasis of various human cancers. CLDN3 expression has been shown to be significantly associated with the prognosis of lung squamous cell carcinoma (SqCC). This study investigated the role of CLDN3 in inhibiting lung SqCC cell migration and invasion as well as the underlying molecular mechanisms. The CLDN3 levels were assessed between 20 paired lung SqCC tissues and adjacent normal tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The ectopic CLDN3 overexpression or knockdown was generated by using a plasmid carrying CLDN3 cDNA or shRNA, respectively. CLDN3 expression was significantly reduced in lung SqCC tissues vs. the adjacent normal tissues. The ectopic CLDN3 overexpression markedly inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of lung cancer H520 cells, whereas CLDN3 knockdown had an inverse effect on SK-MES-1 cells. However, cell viability and plate colony formation assays showed that both CLDN3 knockdown and overexpression did not affect SqCC cell proliferation. Both tissue and cell data revealed that CLDN3 expression was significantly associated with the expression of the EMT biomarkers E-cadherin and Vimentin. Furthermore, CLDN3-modulated EMT and expression of the EMT markers were through regulation of the Wnt/beta-catenin signaling pathway. In conclusion, this study identified reduced CLDN3 expression in lung SqCC tissues, which was associated with the progression and metastasis of lung SqCC and was attributed to EMT by activation of the Wnt pathway. Thus, CLDN3 could be further evaluated as a novel biomarker for predicting the prognosis of lung SqCC and as a target for the treatment of lung SqCC in the future. PMID- 29511368 TI - Bone Turnover Status: Classification Model and Clinical Implications. AB - Aim: To develop a practical model for classification bone turnover status and evaluate its clinical usefulness. Methods: Our classification of bone turnover status is based on internationally recommended biomarkers of both bone formation (N-terminal propeptide of type1 procollagen, P1NP) and bone resorption (beta C terminal cross-linked telopeptide of type I collagen, bCTX), using the cutoffs proposed as therapeutic targets. The relationships between turnover subtypes and clinical characteristic were assessed in1223 hospitalised orthogeriatric patients (846 women, 377 men; mean age 78.1+/-9.50 years): 451(36.9%) subjects with hip fracture (HF), 396(32.4%) with other non-vertebral (non-HF) fractures (HF) and 376 (30.7%) patients without fractures. Resalts: Six subtypes of bone turnover status were identified: 1 - normal turnover (P1NP>32 MUg/L, bCTX<=0.250 MUg/L and P1NP/bCTX>100.0[(median value]); 2- low bone formation (P1NP <=32 MUg/L), normal bone resorption (bCTX<=0.250 MUg/L) and P1NP/bCTX>100.0 (subtype2A) or P1NP/bCTX<100.0 (subtype 2B); 3- low bone formation, high bone resorption (bCTX>0.250 MUg/L) and P1NP/bCTX<100.0; 4- high bone turnover (both markers elevated ) and P1NP/bCTX>100.0 (subtype 4A) or P1NP/bCTX<100.0 (subtype 4B). Compared to subtypes 1 and 2A, subtype 2B was strongly associated with nonvertebral fractures (odds ratio [OR] 2.0), especially HF (OR 3.2), age>75 years and hyperparathyroidism. Hypoalbuminaemia and not using osteoporotic therapy were two independent indicators common for subtypes 3, 4A and 4B; these three subtypes were associated with in-hospital mortality. Subtype 3 was associated with fractures (OR 1.7, for HF OR 2.4), age>75 years, chronic heart failure (CHF), anaemia, and history of malignancy, and predicted post-operative myocardial injury, high inflammatory response and length of hospital stay (LOS) above10 days. Subtype 4A was associated with chronic kidney disease (CKD), anaemia, history of malignancy and walking aids use and predicted LOS>20 days, but was not discriminative for fractures. Subtype 4B was associated with fractures (OR 2.1, for HF OR 2.5), age>75 years, CKD and indicated risks of myocardial injury, high inflammatory response and LOS>10 days. Conclusions: We proposed a classification model of bone turnover status and demonstrated that in orthogeriatric patients altered subtypes are closely related to presence of nonvertebral fractures, comorbidities and poorer in-hospital outcomes. However, further research is needed to establish optimal cut points of various biomarkers and improve the classification model. PMID- 29511370 TI - Receptor for activated C kinase 1 in rats with ischemia-reperfusion injury: intravenous versus inhalation anaesthetic agents. AB - Background: The study examined the difference in the expression of the receptor for activated C kinase 1 (RACK1) between anaesthesia with propofol and isoflurane in rats with myocardial ischemia-reperfusion injury (IRI). Methods: Male Sprague Dawley rats were studied. Anaesthesia was induced with xylazine 20 ug/g by intraperitoneal injection and maintained with propofol or isoflurane. Myocardial IRI was induced by ligating the left anterior descending artery for 1 hour. Reactive oxygen species (ROS), cardiomyocyte apoptosis, the expression of RACK1 and toll-like receptor 4 (TLR4), and the heart injury score were compared between the two groups. Results: Cardiomyocyte apoptosis with ROS was significantly lower in the propofol group than in the isoflurane group. The propofol group had significantly higher RACK1 expression and lower TLR4 expression, compared with the isoflurane group (RACK1, 1970.50 +/- 120.50 vs. 1350.20 +/- 250.30, p<0.05; TLR4, 980.50 +/- 110.75 vs. 1275.50 +/- 75.35, p<0.05). However, the heart injury scores in the two groups did not differ significantly (3.56 +/- 0.29 vs. 4.33 +/- 0.23 in the propofol and isoflurane groups, respectively, p=0.33). Conclusion: There were significant differences in inflammation and apoptosis, including the expression of RACK1 and TLR4, after myocardial IRI between the propofol and isoflurane groups. However, both groups had similar heart injury scores. PMID- 29511371 TI - Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw. AB - The aim of the present study was to elucidate the role of osteoblasts in bisphosphonates-related osteonecrosis of the jaw (BRONJ). The specific objective was to evaluate the effect on osteoblasts of two nitrogen-containing BPs (zoledronate and alendronate) and one non-nitrogen-containing BP (clodronate) by analyzing modulations in their expression of genes essential for osteoblast physiology. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of zoledronate, alendronate, and clodronate at doses of 10-5, 10-7, or 10 9 M on the expression of Runx-2, OSX, ALP, OSC, OPG, RANKL, Col-I, BMP-2, BMP-7, TGF-beta1, VEGF, TGF-betaR1, TGF-betaR2, and TGF-betaR3 by primary human osteoblasts (HOBs) and MG-63 osteosarcoma cells. Expression of these markers was found to be dose-dependent, with no substantive differences between these cell lines. In general, results demonstrated a significant increase in TFG-beta1, TGF betaR1, TGF-betaR2, TGF-betaR3, and VEGF expressions and a significant reduction in RUNX-2, Col-1, OSX, OSC, BMP-2, BMP-7, ALP, and RANKL expressions, while OPG expression varied according to the dose and cell line. The results of this in vitro study of HOBS and MG-63 cell lines indicate that low BP doses can significantly affect the expression of genes essential for osteoblast growth and differentiation and of genes involved in regulating osteoblast-osteoclast interaction, possibly by increasing TGF-beta1 production. These findings suggest that osteoblasts may play an important role in BRONJ development, without ruling out other factors. PMID- 29511372 TI - Clinical importance of the anterior choroidal artery: a review of the literature. AB - The anterior choroidal artery (AChA) is a critical artery in brain physiology and function. The AChA is involved in many diseases, including aneurysm, brain infarct, Moyamoya disease (MMD), brain tumor, arteriovenous malformation (AVM), etc. The AChA is vulnerable to damage during the treatment of these diseases and is thus a very important vessel. However, a comprehensive systematic review of the importance of the AChA is currently lacking. In this study, we used the PUBMED database to perform a literature review of the AChA to increase our understanding of its role in neurophysiology. Although the AChA is a small thin artery, it supplies an extremely important region of the brain. The AChA consists of cisternal and plexal segments, and the point of entry into the choroidal plexus is known as the plexal point. During treatment for aneurysms, tumors, AVM or AVF, the AChA cisternal segments should be preserved as a pathway to prevent the infarction of the AChA target region in the brain. In MMD, a dilated AChA provides collateral flow for posterior circulation. In brain infarcts, rapid treatment is necessary to prevent brain damage. In Parkinson disease (PD), the role of the AChA is unclear. In trauma, the AChA can tear and result in intracranial hematoma. In addition, both chronic and non-chronic branch vessel occlusions in the AChA are clinically silent and should not deter aneurysm treatment with flow diversion. Based on the data available, the AChA is a highly essential vessel. PMID- 29511373 TI - SERPINB5 Expression: Association with CCRT Response and Prognostic Value in Rectal Cancer. AB - Background: Due to the varying characteristics and conflicting outcomes on the overall survival of rectal cancer patients, many studies have been undertaken to determine various prognostic and predictive factors for the mainstay treatment of CCRT followed by surgery. Cancer cell motility contributes to tumor invasion, migration and eventually metastasis. However, the genes associated with cell motility (i.e., GO:0048870) have not been systemically evaluated in rectal cancers. Methods: A comparative analysis of gene expression profiles was applied to the transcriptomic dataset (GSE35452) with a focus on genes associated with cell motility (GO:0048870), where SERPINB5 was recognized as the most significantly up-regulated gene. Tumor samples from 172 primary rectal cancer patients who underwent neoadjuvant CCRT followed by surgical resection were collected. Immunohistochemistry was used to semi-quantitatively assess the expression level of SERPINB5 protein. Statistical analyses of SERPINB5 expression and various clinicopathological features as well as survival were then performed. Results: High immunoreactivity of SERPINB5 was significantly linked to pre- and post-CCRT advanced disease, lymphovascular invasion, and poor response to CCRT (all P <= 0.015). SERPINB5 overexpression was not only negatively associated with disease-specific survival (DSS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS) rates in univariate analyses but also was an independent prognostic factor for DSS and MeFS in rectal cancer patients (all P <= 0.043). Conclusion: SERPINB5 may play an important role in rectal cancer progression and response to neoadjuvant CCRT and serve as a novel prognostic factor. PMID- 29511374 TI - Transgenic Expression of A Venous Malformation Related Mutation, TIE2-R849W, Significantly Induces Multiple Malformations of Zebrafish. AB - A TIE2 mutation causing arginine-to-tryptophan substitution at residue 849 (TIE2 R849W) is commonly identified in heredofamilial venous malformation. However, there is no in vivo model to confirm the pathogenic role of TIE2-R849W. Humanized TIE2-R849W plasmid was constructed via PCR-mediated site-directed mutagenesis. After transcription and micro-injection, TIE2-R849W significantly induces multiple malformations in zebrafish: caudal vein plexus (CVP) defect, eye abnormalities, forebrain formation perturbations, and mandibular malformation. Histologically, these phenotypes accompany aphakia, confused retina plexiform layer, abnormal mandibular cartilage, ectopic myelencephalon proliferation and aberrant location of neurogliocytes. According to qRT-PCR, except for high expression of egfl7, the other CVP-related genes cd146, nr2f1a, and s1pr1 are not significantly different from control. TIE2-R849W also induced upregulation of the wnt signaling pathway. Gene array in vitro shows that under the effect of TIE2 R849W, consistent with high expression of pik3 and foxo1, high levels of egfl7, wnt9a, lrp5 and dkk1 were partly confirmed. This in vivo model directly identifies the venous-related pathogenic role of TIE2-R849W. Under up-regulation of TIE2-R849W, egfl7 could be considered a potential reason for venous defects. Moreover, the wnt pathway may perform an important role as a key trigger for head multi-malformations. PMID- 29511375 TI - Distribution of Cytotoxic T Lymphocyte-Associated Antigen-4 Promoter Polymorphisms in Taiwanese Patients with Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) is associated with chronic inflammation, suggesting the metabolic abnormalities are originated from or exacerbated by cytokine overproduction. Cytokines and counter-regulatory molecules are crucial in keeping the balance of immune responses and, therefore, are potential candidates involved in T2DM etiology, development and complications. Our previous reports identify several significant associations between the genotypes of cytokine genes and T2DM and/or the clinical lipid parameters, which strongly suggest the participation of immune-regulatory molecules in lipid metabolism. The aim of this study is to determine the distribution of gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a T-cell negative regulator, in T2DM patients and health subjects. Genomic DNA was extracted from 287 Taiwanese T2DM patients and 278 ethnic- and age- matched healthy subjects, and two CTLA-4 polymorphisms (-318 C/T and +49 A/G) were analyzed by polymerase chain reaction restriction fragment length polymorphism. Intriguingly, CTLA-4 -318 genotype was associated with circulatory triglycerides in T2DM subjects (P=0.019) although no significant association between CTLA-4 -318 (P=0.119) and +49 (P=0.2) genotypes with T2DM was identified. In addition, CTLA-4 +49 genotype was significantly associated with the ratio between total cholesterol and high-density lipoprotein (P=0.004) in control subjects. Our results suggest that CTLA-4 may be involved in lipid metabolism and affect T2DM disease progression and/or the development of diabetic complications although this gene does not represent a major risk factor for T2DM. PMID- 29511377 TI - Differences in C-type lectin receptors and their adaptor molecules in the peritoneal fluid of patients with endometriosis and gynecologic cancers. AB - Endometriosis, although not malignant, has clinically demonstrated properties of invasiveness and metastasis. The pathogenesis of endometriosis, however, has not yet been elucidated. The immunological differences between endometriosis and malignant gynecologic tumors were analyzed by assessing C-type lectin receptors, which are associated with innate immunity, and immunoglobulin secretion, which is associated with B cell adaptive immunity, in the peritoneal fluid of these patients. Peritoneal fluid samples were obtained from 42 patients with benign masses (control group), 38 with endometriosis, and 43 with gynecologic (ovarian, uterine, and cervical) cancers. The levels of expression in these samples of mRNAs encoding the C-type lectin receptors Dectin-1, MR1, MR2, DC-SIGN, Syk, Card 9, Bcl 10, Malt 1, src, Dec 205, Galectin, Tim 3, Trem 1, and DAP 12, were measured by real-time reverse transcription polymerase chain reaction, and the concentrations of IgG, IgA and IgM were measured by enzyme-linked immunosorbent assays (ELISA). Findings in the three groups were compared. The level of galectin mRNA was significantly lower, and the levels of MR2 and DAP 12 mRNAs significantly higher, in the endometriosis than in the control group (p<0.05 each). Compared with the gynecologic cancer group, the level of Bcl 10 mRNA was significantly lower, and the levels of MR1, MR2, Syk, Card 9, Malt 1, Dec 205, Tim 3, and DAP 12 mRNAs significantly higher, in the endometriosis group (p<0.05 each). The levels of MR2 and DAP 12 mRNAs were significantly higher in the endometriosis than in the control group (p<0.05 each), whereas the level of galectin mRNA was similar in the endometriosis and gynecologic cancer groups. IgA and IgG concentrations in peritoneal fluid were significantly lower in the gynecologic cancer than in the control group (p<0.05 each). However, concentrations of all three immunoglobulins in the endometriosis group did not differ from those in the other two groups (p>0.05). C-type lectin receptors and immunoglobulins act cooperatively and are closely associated in the pathogenesis of endometriosis. The decreased expression of galectin mRNA in the peritoneal fluid of the endometriosis group suggests that endometriosis and gynecologic cancers have similar immunologic characteristics. PMID- 29511378 TI - Simultaneous Determination of Nitroimidazoles and Quinolones in Honey by Modified QuEChERS and LC-MS/MS Analysis. AB - This study reports an analytical method for the determination of nitroimidazole and quinolones in honey using liquid chromatography-tandem mass spectrometry (LC MS/MS). A modified QuEChERS methodology was used to extract the analytes and determine veterinary drugs in honey by LC-MS/MS. The linear regression was excellent at the concentration levels of 1-100 ng/mL in the solution standard curve and the matrix standard curve. The recovery rates of nitroimidazole and quinolones were 4.4% to 59.1% and 9.8% to 46.2% with relative standard deviations (RSDs) below 5.2% and the recovery rates of nitroimidazole and quinolones by the matrix standard curve ranged from 82.0% to 117.8% and 79% to 115.9% with relative standard deviations (RSDs) lower than 6.3% in acacia and jujube honey. The acacia and jujube honeys have stronger matrix inhibition effect to nitroimidazole and quinolones residue; the matrix inhibition effect of jujube honey is stronger than acacia honey. The matrix standard curve can calibrate matrix effect effectively. In this study, the detection method of antibiotics in honey can be applied to the actual sample. The results demonstrated that the modified QuEChERS method combined with LC-MS/MS is a rapid, high, sensitive method for the analysis of nitroimidazoles and quinolones residues in honey. PMID- 29511379 TI - Characterization of Fossil and Renewable Fuels. PMID- 29511376 TI - Cardiovascular Adaptations Induced by Resistance Training in Animal Models. AB - In the last 10 years the number of studies showing the benefits of resistance training (RT) to the cardiovascular system, have grown. In comparison to aerobic training, RT-induced favorable adaptations to the cardiovascular system have been ignored for many years, thus the mechanisms of the RT-induced cardiovascular adaptations are still uncovered. The lack of animal models with comparable protocols to the RT performed by humans hampers the knowledge. We have used squat exercise model, which is widely used by many others laboratories. However, to a lesser extent, other models are also employed to investigate the cardiovascular adaptations. In the subsequent sections we will review the information regarding cardiac morphological adaptations, signaling pathway of the cardiac cell, cardiac function and the vascular adaptation induced by RT using this animal model developed by Tamaki et al. in 1992. Furthermore, we also describe cardiovascular findings observed using other animal models of RT. PMID- 29511380 TI - Modeling and Synthesis of Ag and Ag/Ni Allied Bimetallic Nanoparticles by Green Method: Optical and Biological Properties. AB - In the quest for environmental remediation which involves eco-friendly synthetic routes, we herein report synthesis and modeling of silver nanoparticles (Ag NPs) and silver/nickel allied bimetallic nanoparticles (Ag/Ni NPs) using plant-extract reduction method. Secondary metabolites in the leaf extract of Canna indica acted as reducing agent. Electronic transitions resulted in emergence of surface plasmon resonance in the regions of 416 nm (Ag NPs) and 421 nm (Ag/Ni NPs) during optical measurements. Further characterizations were done using TEM and EDX. Antimicrobial activity of the nanoparticles against clinical isolates was highly significant as P < 0.05. These findings suggest application of Ag NPs as antibacterial agent against E. coli, S. pyogenes, and antifungal agent against C. albicans. Possible antibacterial drugs against S. pyogenes and E. coli can also be designed using Ag/Ni nanohybrid based on their strong inhibition activities. Similarly, the enhanced SPR in the nanoparticles is suggested for applications in optical materials, as good absorbers and scatters of visible light. Theoretical model clarified that the experiment observation on the relationship between metallic nanoparticles penetration through peptidoglycan layers and the activeness of microbial species depends on the nature of the nanoparticles and pore size of the layer. PMID- 29511381 TI - Could We Really Use Aloe vera Food Supplements to Treat Diabetes? Quality Control Issues. AB - Diabetes UK has recently listed a number of herbs and spices that have been clinically shown to improve blood glucose control in type-2 diabetes patients and the diabetes high-risk group. With Aloe vera being top in this list, its health benefit along with health and beauty/food retailers supplying it was illustrated in detail. Previous article from this laboratory scrutinised the merit of using A. vera as an alternative therapy to prescription antidiabetic drugs and the risk of using food supplements in the market which do not qualify as drug preparations. In continuation of this discussion, the present study assesses three Aloe Pura brands and one Holland and Barret brand of A. vera juice supplements in the UK market through chromatographic and spectroscopic analysis. While the polysaccharide active ingredient, acemannan, appears to be within the recommended limit, it was found that Aloe Pura (one of the best-selling brands for A. vera supplement) products have benzoate additive that does not appear in the supplement levels. Moreover, two of the Aloe Pura brand juices contain methanol, suggesting that the International Aloe Science Council (IASC) certification does not guarantee the medicinal quality of these products. The therapeutic fitness of such supplements is discussed. PMID- 29511382 TI - Management of multiple sclerosis patients in central European countries: current needs and potential solutions. AB - Multiple sclerosis (MS) experts in Europe are facing rapidly rising demands of excellence due to the increasing complexity of MS therapy and management. A central European expert board of MS experts met to identify needs and obstacles with respect to raising quality of MS care in central and Eastern European countries. There are substantial variations across countries regarding delivery of care and its cost structure, as well as access to treatment. To date, Eastern European countries are often less able to afford reimbursement of immunomodulatory agents than Western countries. Overall, approximately 40% of working-age patients are not working due to MS. Costs rise steeply with increasing disability; indirect costs constitute the bulk of the financial burden in patients with severe MS. Magnetic resonance imaging (MRI) assessment is meanwhile obligatory as the diagnostic interface in the management of MS patients. Recommended measures directed at improving quality of care include the collection of patient data in registries, enhanced education of healthcare professionals, implementation of national strategies aiming at reducing regional variation, optimization of approval processes, and removal of administrative barriers. Local partnerships with authorities such as those that represent the interests of employees can contribute to leverage the importance of epidemiological data. The need for education extends to (neuro)radiologists who are responsible for reporting MRI findings in expert quality. Dissemination of the Magnetic Resonance Imaging in MS (MAGNIMS) protocol would be an important step in this context. Also, clinical freedom of choice is rated as essential. Physicians should have access to a range of treatment options due to the complexity of disease. Guidelines such as the upcoming EAN-ECTRIMS clinical practice guideline also aim at providing a basis for argumentation in negotiations with national health authorities. PMID- 29511383 TI - Safety and efficacy of levodopa-carbidopa intestinal gel: results from an open label extension study in Japanese, Korean and Taiwanese patients with advanced Parkinson's disease. AB - Objectives: Levodopa-carbidopa intestinal gel (LCIG) was developed to reduce motor complications in Parkinson's disease (PD) caused by pulsatile levodopa plasma concentrations following oral levodopa administration. Dyskinesia and 'wearing off' symptoms can vary between Asian and Caucasian patients with PD, thus highlighting the importance of assessing the effectiveness of LCIG in an Asian population. Efficacy and safety of LCIG were previously assessed in a 12 week open-label study; we report the efficacy and safety of at least 52 weeks of LCIG treatment in Japanese, Taiwanese, and Korean patients with advanced PD in the ongoing extension study. Methods: In this interim analysis of a phase III, open-label, multicenter extension study in Japan, South Korea, and Taiwan [ClinicalTrials.gov identifier: NCT02082249/JapiCTI-142482], the mean change from baseline to final visit in 'off' time, as reported in the PD symptom diary, was normalized to a 16-h waking day. Changes in Parkinson's Disease Questionnaire-39 (PDQ-39) summary index and domains scores were also analyzed. Adverse events (AEs) were recorded. Results: Of the 28 patients enrolled (21 Japanese, 3 Taiwanese, 4 Korean), 27 completed at least 52 total weeks of treatment, and 25 patients were continuing in the study at data cutoff. The mean [standard deviation (SD)] 'off' time was significantly reduced by 4.6 (3.1) h/day (p < 0.001, n = 28). Patients experienced significant improvements in quality of life, as recorded by the mean change from baseline in PDQ-39 summary index (p < 0.001). All patients had at least one AE; three patients (11%) discontinued due to an AE. There were two deaths (sepsis and drowning), both of which the investigator considered unrelated to LCIG treatment. Conclusions: These data suggest that LCIG treatment is efficacious, safe, and well tolerated in Japanese, Taiwanese, and Korean patients with advanced PD, thus confirming the consistency of LCIG treatment in patients with advanced PD. PMID- 29511384 TI - Clinical course and outcome in patients with severe dysphagia after lateral medullary syndrome. AB - Background: The objective of this study was to investigate the clinical course and final outcome in patients afflicted with severe dysphagia following a diagnosis of lateral medullary syndrome (LMS). Methods: The patients with severe dysphagia after LMS admitted to a rehabilitation unit were included and their respective clinical data were prospectively collected. The criteria of 'severe dysphagia' was defined as the condition that showed decreased pharyngeal constriction with no esophageal passage in a videofluoroscopic swallowing study (VFSS) and initially required enteral tube feeding. The data included VFSS findings, types of diet and postural modification, penetration-aspiration scale (PAS) and functional oral intake scale (FOIS). Results: A total of 11 patients were included and VFSS was performed every 2 weeks after stroke onset. Esophageal passage began to show at an average 34.7 +/- 18.3 days, and the patients were able to begin consuming a partial oral diet with postural modification. It was 52.2 +/- 21.8 days till they were advanced to a full oral diet. PAS and FOIS were significantly improved over time. Conclusions: Patients with severe dysphagia after LMS were able to tolerate a partial oral diet at about 5 weeks following onset, and they were advanced to a normal diet after 10 weeks. This clinical course might help in predicting the prognosis, as well as assist in making practical decisions regarding a rehabilitation program. PMID- 29511386 TI - Clinical and electrophysiological impact of repetitive low-frequency transcranial magnetic stimulation on the sensory-motor network in patients with restless legs syndrome. AB - Background: Based on the hyperexcitability and disinhibition observed in patients with restless legs syndrome (RLS) following transcranial magnetic stimulation (TMS), we conducted a study with low-frequency repetitive TMS (rTMS) over the primary motor (M1) and somatosensory cortical areas (S1) in patients with RLS. Methods: A total of 13 right-handed patients and 10 age-matched controls were studied using clinical scales and TMS. Measurements included resting motor threshold (rMT), motor-evoked potentials (MEPs), cortical silent period (CSP), and central motor conduction time (CMCT). A single evening session of rTMS (1 Hz, 20 trains, 50 stimuli each) was administered over the left M1, left S1, and sham stimulation over M1 in a random order. Clinical and TMS measures were repeated after each stimulation modality. Results: Baseline CSP was shorter in patients than in controls and remained shorter in patients for both motor and somatosensory stimulation. The patients reported a subjective improvement of both initiating and maintaining sleep the night after the rTMS over S1. Patients exhibited a decrease in rMT after rTMS of S1 only, although the effect was smaller than in controls. MEP latency and CMCT changed only in controls after stimulation. Sham stimulation was without effect on the observed variables. Conclusions: rTMS on S1-M1 connectivity alleviated the sensory-motor complaints of RLS patients. The TMS indexes of excitation and inhibition indicate an intracortical and corticospinal imbalance, mainly involving gamma-aminobutyric acid (GABA)ergic and glutamatergic circuitries, as well as an impairment of the short-term mechanisms of cortical plasticity. The rTMS-induced activation of the dorsal striatum with the consequent increase of dopamine release may have contributed to the clinical and neurophysiological outcome. PMID- 29511388 TI - PROM and Labour Effects on Urinary Metabolome: A Pilot Study. AB - Since pathologies and complications occurring during pregnancy and/or during labour may cause adverse outcomes for both newborns and mothers, there is a growing interest in metabolomic applications on pregnancy investigation. In fact, metabolomics has proved to be an efficient strategy for the description of several perinatal conditions. In particular, this study focuses on premature rupture of membranes (PROM) in pregnancy at term. For this project, urine samples were collected at three different clinical conditions: out of labour before PROM occurrence (Ph1), out of labour with PROM (Ph2), and during labour with PROM (Ph3). GC-MS analysis, followed by univariate and multivariate statistical analysis, was able to discriminate among the different classes, highlighting the metabolites most involved in the discrimination. PMID- 29511389 TI - Clinical Significance of Hemostatic Parameters in the Prediction for Type 2 Diabetes Mellitus and Diabetic Nephropathy. AB - It would be important to predict type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). This study was aimed at evaluating the predicting significance of hemostatic parameters for T2DM and DN. Plasma coagulation and hematologic parameters before treatment were measured in 297 T2DM patients. The risk factors and their predicting power were evaluated. T2DM patients without complications exhibited significantly different activated partial thromboplastin time (aPTT), platelet (PLT), and D-dimer (D-D) levels compared with controls (P < 0.01). Fibrinogen (FIB), PLT, and D-D increased in DN patients compared with those without complications (P < 0.001). Both aPTT and PLT were the independent risk factors for T2DM (OR: 1.320 and 1.211, P < 0.01, resp.), and FIB and PLT were the independent risk factors for DN (OR: 1.611 and 1.194, P < 0.01, resp.). The area under ROC curve (AUC) of aPTT and PLT was 0.592 and 0.647, respectively, with low sensitivity in predicting T2DM. AUC of FIB was 0.874 with high sensitivity (85%) and specificity (76%) for DN, and that of PLT was 0.564, with sensitivity (60%) and specificity (89%) based on the cutoff values of 3.15 g/L and 245 * 109/L, respectively. This study suggests that hemostatic parameters have a low predicting value for T2DM, whereas fibrinogen is a powerful predictor for DN. PMID- 29511390 TI - Complementary evaluation of structure stability of perovskite oxides using bond valence and density-functional-theory calculations. AB - Estimation of structure stability is an essential issue in materials design and synthesis. Global instability index (GII) based on bond-valence method is applied as a simple indication, while density functional theory calculation is adopted for accurate evaluation of formation energy. We compare the GII and total energy of typical ABO3-type perovskite oxides and rationalize their relationship, proposing that the criteria for empirically unstable structures (GII > 0.2 valence unit) correspond to the difference in total energy of 50-200 meV per formula unit. PMID- 29511385 TI - Imaging in neuro-oncology. AB - Imaging plays several key roles in managing brain tumors, including diagnosis, prognosis, and treatment response assessment. Ongoing challenges remain as new therapies emerge and there are urgent needs to find accurate and clinically feasible methods to noninvasively evaluate brain tumors before and after treatment. This review aims to provide an overview of several advanced imaging modalities including magnetic resonance imaging and positron emission tomography (PET), including advances in new PET agents, and summarize several key areas of their applications, including improving the accuracy of diagnosis and addressing the challenging clinical problems such as evaluation of pseudoprogression and anti-angiogenic therapy, and rising challenges of imaging with immunotherapy. PMID- 29511391 TI - Oxygen surface exchange kinetics measurement by simultaneous optical transmission relaxation and impedance spectroscopy: Sr(Ti,Fe)O3-x thin film case study. AB - We compare approaches to measure oxygen surface exchange kinetics, by simultaneous optical transmission relaxation (OTR) and AC-impedance spectroscopy (AC-IS), on the same mixed conducting SrTi0.65Fe0.35O3-x film. Surface exchange coefficients were evaluated as a function of oxygen activity in the film, controlled by gas partial pressure and/or DC bias applied across the ionically conducting yttria-stabilized zirconia substrate. Changes in measured light transmission through the film over time (relaxations) resulted from optical absorption changes in the film corresponding to changes in its oxygen and oxidized Fe (~Fe4+) concentrations; such relaxation profiles were successfully described by the equation for surface exchange-limited kinetics appropriate for the film geometry. The kchem values obtained by OTR were significantly lower than the AC-IS derived kchem values and kq values multiplied by the thermodynamic factor (bulk or thin film), suggesting a possible enhancement in k by the metal current collectors (Pt, Au). Long-term degradation in kchem and kq values obtained by AC-IS was also attributed to deterioration of the porous Pt current collector, while no significant degradation was observed in the optically derived kchem values. The results suggest that, while the current collector might influence measurements by AC-IS, the OTR method offers a continuous, in situ, and contact-free method to measure oxygen exchange kinetics at the native surfaces of thin films. PMID- 29511392 TI - Carbon-neutral energy cycles using alcohols. AB - We demonstrated carbon-neutral (CN) energy circulation using glycolic acid (GC)/oxalic acid (OX) redox couple. Here, we report fundamental studies on both catalyst search for power generation process, i.e. GC oxidation, and elemental steps for fuel generation process, i.e. OX reduction, in CN cycle. The catalytic activity test on various transition metals revealed that Rh, Pd, Ir, and Pt have preferable features as a catalyst for electrochemical oxidation of GC. A carbon supported Pt catalyst in alkaline conditions exhibited higher activity, durability, and product selectivity for electrooxidation of GC rather than those in acidic media. The kinetic study on OX reduction clearly indicated that OX reduction undergoes successive two-electron reductions to form GC. Furthermore, application of TiO2 catalysts with large specific area for electrochemical reduction of OX facilitates the selective formation of GC. PMID- 29511393 TI - One-step growth of thin film SnS with large grains using MOCVD. AB - Thin film tin sulphide (SnS) films were produced with grain sizes greater than 1 MUm using a one-step metal organic chemical vapour deposition process. Tin-doped indium oxide (ITO) was used as the substrate, having a similar work function to molybdenum typically used as the back contact, but with potential use of its transparency for bifacial illumination. Tetraethyltin and ditertiarybutylsulphide were used as precursors with process temperatures 430-470 degrees C to promote film growth with large grains. The film stoichiometry was controlled by varying the precursor partial pressure ratios and characterised with energy dispersive X ray spectroscopy to optimise the SnS composition. X-ray diffraction and Raman spectroscopy were used to determine the phases that were present in the film and revealed that small amounts of ottemannite Sn2S3 was present when SnS was deposited on to the ITO using optimised growth parameters. Interaction at the SnS/ITO interface to form Sn2S3 was deduced to have resulted for all growth conditions. PMID- 29511394 TI - Morphological and optical properties of PdxAg1-x alloy nanoparticles. AB - Alloy nanoparticles (NPs) can offer a wide range of opportunities for various applications due to their composition and structure dependent properties such as multifunctionality, electronic heterogeneity, site-specific response, and multiple plasmon resonance bands. In this work, the fabrication of self-assembled PdxAg1-x NPs alloy nanostructures with distinct size, density, shape, and composition is demonstrated via the solid-state dewetting of sputtered Pd/Ag thin films on c-plane sapphire. The initial stage of bilayer dewetting exhibits the nucleation of voids, followed by the expansion of voids and cluster breakdown and finally shape transformation along with the temperature control. Bilayer composition shows a substantial influence on the dewetting such that the overall dewetting is enhanced along with the increased Ag composition, i.e. Pd0.25Ag0.75 > Pd0.5Ag0.5 > Pd0.75Ag0.25. On the other hand, the size and density of NPs can be efficiently controlled by varying the initial thickness of bilayers. Reflectance peaks in UV and near-infrared (NIR) regions and a wide absorption band in the visible region arisen from the surface plasmon resonance are observed in reflectance spectra. The peak intensity depends on the composition of PdxAg1-x NPs and the NIR peaks gradually blue-shift with the size decrement. PMID- 29511395 TI - Tunable near-infrared epsilon-near-zero and plasmonic properties of Ag-ITO co sputtered composite films. AB - Series of co-sputtered silver-indium tin oxide (Ag-ITO) films are systematically fabricated. By tuning the atomic ratio of silver, composite films are manifested to have different microstructures with limited silver amount (<3 at.%). Two stages for film morphology changing are proposed to describe different status and growth mechanisms. The introduction of silver improves the preferred orientations of In2O3 component significantly. Remarkably, dielectric permittivity of Ag-ITO films is highly adjustable, allowing the cross-over wavelengths lambdac to be changed by more than 300 nm through rapid post-annealing, and thus resulting in tunable epsilon-near-zero and plasmonic properties in the near-infrared region. Lower imaginary permittivity compared with pure metal films, as well as larger tunability in lambdac than pure ITO films suggest the potentiality of Ag-ITO films as substituted near-infrared plasmonic materials. Extended Maxwell-Garnett model is applied for effective medium approximation and the red-shifting of epsilon-near-zero region with the increase of silver content is well-fitted. Angle-variable prism coupling is carried out to reveal the surface plasmon polariton features of our films at optical communication wavelength. Broad dips in reflectance curves around 52-56 degrees correspond to the SPP in Ag-ITO films. PMID- 29511396 TI - High-pressure torsion for new hydrogen storage materials. AB - High-pressure torsion (HPT) is widely used as a severe plastic deformation technique to create ultrafine-grained structures with promising mechanical and functional properties. Since 2007, the method has been employed to enhance the hydrogenation kinetics in different Mg-based hydrogen storage materials. Recent studies showed that the method is effective not only for increasing the hydrogenation kinetics but also for improving the hydrogenation activity, for enhancing the air resistivity and more importantly for synthesizing new nanostructured hydrogen storage materials with high densities of lattice defects. This manuscript reviews some major findings on the impact of HPT process on the hydrogen storage performance of different titanium-based and magnesium-based materials. PMID- 29511397 TI - Photo-stability study of a solution-processed small molecule solar cell system: correlation between molecular conformation and degradation. AB - Solution-processed organic small molecule solar cells (SMSCs) have achieved efficiency over 11%. However, very few studies have focused on their stability under illumination and the origin of the degradation during the so-called burn-in period. Here, we studied the burn-in period of a solution-processed SMSC using benzodithiophene terthiophene rhodamine:[6,6]-phenyl C71 butyric acid methyl ester (BTR:PC71BM) with increasing solvent vapour annealing time applied to the active layer, controlling the crystallisation of the BTR phase. We find that the burn-in behaviour is strongly correlated to the crystallinity of BTR. To look at the possible degradation mechanisms, we studied the fresh and photo-aged blend films with grazing incidence X-ray diffraction, UV-vis absorbance, Raman spectroscopy and photoluminescence (PL) spectroscopy. Although the crystallinity of BTR affects the performance drop during the burn-in period, the degradation is found not to originate from the crystallinity changes of the BTR phase, but correlates with changes in molecular conformation - rotation of the thiophene side chains, as resolved by Raman spectroscopy which could be correlated to slight photobleaching and changes in PL spectra. PMID- 29511398 TI - A Review of Double Common Bile Duct and Its Sequelae. AB - A double or accessory common bile duct (ACBD) is a rare congenital anomaly. We report the case of a 60-year-old American Asian male, who was found to have a double or duplicated common bile duct after being admitted for evaluation of a pancreatic mass. A duplicated bile duct has the same mucosa histologically as a single bile duct. However, the opening of a duplicated bile duct lacks a sphincter allowing retrograde flow of gut contents which results in a higher probability of intraductal calculus formation. On rare occasions, it can predispose to liver abscesses, pancreatitis, pancreatic cancer, gallbladder cancer, gastric cancer, and ampullary cancer depending on the location of the opening of the ACBD. We present an integrative review of the limited cases of ACBD with correlation to the current case and discussion regarding the aspects of diagnosis and management. PMID- 29511399 TI - Clinical Implication of Enlarged Prostate in Patients with the Ileal Pouch-anal Anastomosis for Inflammatory Bowel Disease. AB - Background: Enlarged prostate is often noticed in patients with ileal pouch-anal anastomosis (IPAA) in our clinical practice. The aims were to identify the factors associated with enlarged prostate and to investigate its clinical implications. Methods: IPAA patients with available prostate imaging after IPAA were included. Prostate length and width were measured in the axial plane and height in coronal plane. Prostate volume was calculated with the formula (length * width * height) * pi/6. A volume greater than 40 cm3 was used to define enlarged prostate. Results: Prostate enlargement was found in 58 (24.8%) out of 234 patients. Factors associated with prostate enlargement included advanced age at imaging examination (55.6 +/- 11.5 vs. 41.3 +/- 13.6 years, P < 0.0001), age at pouch surgery (46.0 +/- 11.8 vs. 32.5 +/- 12.9 years, P<0.0001), and the presence of an S-pouch (6.9% vs. 1.1%, P = 0.03). Postoperative use of biologics was less common in patients with enlarged prostate (5.2% vs. 17%, P = 0.03). However, pouch duration was comparable (10.0 +/- 5.9 vs. 8.8 +/- 6.8 years, P = 0.2) and pouch failure rate was similar. A trend towards an increased risk for acute pouchitis in patients with enlarged prostate was noticed (19% vs. 9.1%, P = 0.06). The association of S-pouch (odds ratio: 7.2, 95% confidence interval: 1.1 46.4) and enlarged prostate remained significant after adjusting for age, acute pouchitis, and redo pouch on multivariate analysis. Conclusions: Prostate enlargement appears to be uncommon after IPAA and it was associated with S-pouch configuration and advanced age. Enlarged prostate in the setting of IPAA does not seem to have adverse impact on pouch outcomes, although there is a trend in correlation between enlarged prostate and acute pouchitis. PMID- 29511400 TI - Internists' Perceptions of Proton Pump Inhibitor Adverse Effects and Impact on Prescribing Practices: Results of a Nationwide Survey. AB - Background: Observational studies have linked proton pump inhibitors (PPIs) with serious adverse effects. The study aimed to evaluate internists' perceptions of PPI harms and effects on prescribing. Methods: This was an online survey of a representative sample of the American College of Physicians in 2013. We queried familiarity with and concern about PPI adverse effects (1 - 7 Likert-type scales, anchored by "not at all" and "extremely"). We also asked how frequently (often, sometimes, rarely, or never) participants used any of three "de-escalation" strategies to stop or reduce PPIs because of concern about adverse effects: reducing patients' PPI dose, switching to H2 blocker, or discontinuing PPI. We used multivariable logistic regression to evaluate associations between sometimes/often using any PPI de-escalation strategy and gender, time in practice, familiarity, and concern. Results: The response rate was 53% (487/914). Seventy percent were male, median time in practice was 11 - 15 years, and most practiced general medicine (58%). Ninety-nine percent reported at least some familiarity with reported adverse effects (mean 4.9, standard deviation (SD) 1.0), and 98% reported at least some concern (mean 4.6, SD 1.3). Sixty-three percent reported sometimes/often reducing the PPI dose, 52% switching to H2 blocker, and 44% discontinuing PPI. In multivariable analysis, familiarity with adverse effects (OR 1.66 (1.31 - 2.10) for 1-point increase, P < 0.001) and concern (OR 2.14 (1.76 - 2.61) for 1-point increase, P < 0.001) were independently associated with de-escalation. Gender and time in practice had no effects. Conclusion: Almost all internists report awareness and concern about PPI adverse effects, and most are de-escalating PPIs as a result. Research on which approach is most effective for which patients is critically important. PMID- 29511401 TI - Aquanet Bowel Cleansing Device Versus Oral Sodium Picosulfate for Pre-Endoscopy Bowel Preparation: Propensity Score Analysis for Interventional Effectiveness Evaluation. AB - Background: Colonoscopy procedures are commonly performed and have high success rates. However, poor or inadequate bowel preparation is one of the most common reasons for a repeated or failed colonoscopy. We therefore performed an observational study followed by propensity score modeling to evaluate and compare the quality of bowel preparation with the use of Aquanet bowel cleansing devices (BCDs) versus the use of oral sodium picosulfate solution. Methods: We performed a prospective cross-sectional study to compare the quality of pre-endoscopic bowel preparation using a BCD with oral solution. Our major outcome of interest was the quality of bowel preparation as measured through the Boston bowel preparation (BBP) scale. Our main predictor was the method of bowel preparation. The bowel was prepared using either sodium picosulfate or the BCD. Results: A total of 314 participants were part of this study. The average age of the participants was 54 years and most of the participants were females (81%). Sodium picosulfate was associated with better scores at each segment. After propensity scoring with a 1:1 match and further adjusting for the unbalanced variable (age), we found that despite the apparent superior cleansing performance of sodium picosulfate over the BCD, the difference was not statistically significant. Conclusion: This study reinforces previous reports regarding the quality, safety and comfort of BCDs, indicating that this technique should be considered for colonoscopy preparation. In the future, randomized controlled trials should be performed to validate these preliminary findings. PMID- 29511402 TI - Metastatic Renal Cell Carcinoma as Solitary Subcentimeter Polypoid Gastric Mucosal Lesions: Clinicopathologic Analysis of Five Cases. AB - Background: The stomach is an uncommon site for metastatic carcinoma. Approximately 6% of renal cell carcinomas (RCCs) may metastasize to the stomach. The majority of the reported metastatic RCCs in the stomach presented as large masses or ulcers greater than a centimeter in size. It is very rare to encounter metastatic RCC as a solitary small polypoid gastric mucosal lesion. Methods: In this study, we collected surgical pathology cases of gastric metastasis from RCC that measured 1.0 cm or less at the time of endoscopy. The clinicopathological characteristics were analyzed. Results: Five patients with subcentimeter metastatic RCC involving the gastric mucosa were identified. The clinical presentation for upper endoscopic examination was non-specific. Two of the five patients did not have a known history of RCC. In the three patients with a previous history of RCC, the interval from primary RCC diagnosis to the detection of gastric mucosal metastasis was 5, 6, and 10 years, respectively. Endoscopically, all the lesions were solitary, ranging in size from 0.4 to 1 cm. Histologically, all five cases were of the clear cell type consisting of a bland clear cell proliferation within the lamina propria. Although the tumor cells were relatively bland, the presence of clear cytoplasm, nuclear membrane irregularity, occasional enlarged hyperchromatic atypical nuclei, and destructive growth in the center of the lesion should promote immunohistochemical workup. Immunohistochemically, the RCC cells exhibited at least patchy immunoreactivity for cytokeratin and RCC markers. In two cases, there were many CD68 positive foamy histiocytes intermingled with the tumor cells. Conclusion: Metastatic RCC can rarely present as subcentimeter polypoid gastric mucosal lesions. The remote or unknown history of RCC, the non-specific endoscopic appearance, and the bland histological features may lead to a potential diagnostic pitfall. It is of importance to raise the awareness of such an unusual presentation of metastatic RCC in the stomach and to include metastatic RCC in the differential diagnosis for gastric mucosal polyps with clear cell morphology. PMID- 29511403 TI - Assessment of Knowledge, Attitudes, and Practices Regarding Chronic Hepatitis C Treatment and Its Challenges: A Survey of Internal Medicine Residents in a Community Hospital. AB - Background: Despite recent advances in chronic hepatitis C (CHC) treatment, only a small proportion of patients are connected with care and receive treatment. Internal medicine (IM) residents spend nearly one-third of their training in primary care settings and play a crucial role in diagnosing and counseling patients as well as linking patients with care and following up. Methods: IM residents in a community hospital completed an anonymous questionnaire regarding their knowledge, attitude, and practice associated with CHC treatment and its challenges. Results: Descriptive analysis of the survey showed that there is a substantial gap in knowledge regarding the newer treatment of CHC between IM residents' perceptions of patient awareness and IM residents. Conclusion: Updated education regarding CHC that is geared towards medical residents and focused on new modalities of treatment can narrow the gap and lead to considerable increases in the rates of diagnosis and treatment and decreases in morbidity and mortality. PMID- 29511404 TI - Outcomes of a Physician-Controlled Wire-Guided Cannulation of the Bile Duct Using a Novel Sphincterotome: A Single-Center, Prospective Study. AB - Background: Efficacy of a physician-controlled wire-guided cannulation of the bile duct has been reported. This study aimed to evaluate a novel sphincterotome with a short tip and a short wire, which can be bowed compactly compared to conventional sphincterotomes. Methods: This was a single-arm, single-center, prospective study. We enrolled patients with choledocholithiasis and/or obstructive jaundice and/or cholangitis for whom endoscopic sphincterotomy was planned. The main outcome measurement was the proportion of successful selective bile duct cannulation by physician-controlled wire-guided cannulation within 10 min. Results: The study cohort consisted of 40 patients. The proportion of successful selective bile duct cannulation within 10 min was 72.5% (n = 29). The proportion of post-endoscopic retrograde cholangiopancreatography pancreatitis was 2.5% (mild, n = 1) and the proportion of hemorrhage was 2.5% (moderate, n = 1). Conclusions: Although physician-controlled wire-guided cannulation using a novel sphincterotome with a short tip and a short wire was not superior to wire guided cannulation using conventional sphincterotomes reported in a previous study, it remains a safe and efficacious alternative in terms of successful biliary cannulation. PMID- 29511405 TI - Comparative Effectiveness of Vedolizumab vs. Infliximab Induction Therapy in Ulcerative Colitis: Experience of a Real-World Cohort at a Tertiary Inflammatory Bowel Disease Center. AB - Background: Vedolizumab (VDZ), an adhesion molecule inhibitor and infliximab (IFX), a tumor necrosis factor (TNF) blocker, are both approved as first-line induction agents in moderately to severely active ulcerative colitis (UC). However, there are no head-to-head studies comparing the relative effectiveness of the two agents. Here we provide a real-world comparison of these two agents. Methods: We conducted an ambidirectional cohort study of adult UC patients seen at our tertiary inflammatory bowel disease (IBD) center from 2012 to 2017. Each patient had moderately to severely active UC via partial Mayo score and was induced with IFX or VDZ. They were followed until assessment of clinical response. Poisson regression was used to calculate clinical response rates and rate ratios. Results: Of 59 patients who met inclusion criteria, 27 and 32 patients were induced with IFX and VDZ, respectively. Totally, 18/27 (66.7%) patients induced with IFX vs. 24/32 (78.1%) patients induced with VDZ were clinical responders. Response rates per 100 person-weeks (PW) were similar for VDZ (5.21) and IFX (5.38). The effectiveness in terms of induction of clinical response (incidence rate ratio, IRR) was not statistically significant for VDZ vs. IFX (IRR 0.97, 95% confidence interval (CI) 0.53 - 1.77). Among TNF blocker naive patients, IRR was also not statistically significant between VDZ (6.74/100 PW) and IFX (6.48/100 PW) (IRR 1.04, 95% CI 0.47 - 2.29). Among TNF blocker experienced patients, there was a higher response rate for VDZ (4.52) vs. IFX (2.29) per 100 PW, but the IRR did not reveal statistical significance (IRR 1.97, 95% CI 0.45 - 8.63) due to small sample size of TNF blocker experienced patients who received IFX. Five patients developed severe infection or adverse reaction during IFX induction requiring exclusion, whereas no VDZ patients were excluded for this reason. Conclusions: Our study revealed a higher proportion of patients who responded to VDZ vs. IFX; however when accounting for period between induction and assessment of clinical response, rates of clinical response were similar. A key difference between the two groups was the higher response rate in the VDZ group among TNF blocker experienced patients; however, a larger cohort is needed to further elaborate on this difference. VDZ held its own against IFX and this study strengthens its standing as a first-line agent among TNF blocker naive as well as TNF blocker experienced UC patients. PMID- 29511407 TI - Autologous Graft-Versus-Host Disease of the Gastrointestinal Tract in Patients With Multiple Myeloma and Hematopoietic Stem Cell Transplantation. AB - Multiple myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (HSCT) in North America. Despite occurring in up to 50% of patients undergoing allogeneic HSCT, the incidence of graft-versus-host disease (GVHD) after autologous HSCT is reportedly only 5-20%. Gastrointestinal involvement with graft-versus-host disease (GI GVHD) is a common and serious complication of allogeneic HSCT. GI GVHD after autologous transplant, which is referred to as autologous GVHD (auto-GVHD), has also been described. Auto-GVHD is usually less severe than allogeneic GVHD, and it can be one of the manifestations of engraftment syndrome with release of inflammatory cytokines and infiltration of auto-reactive T cells into affected tissue. Seventy-nine percent of patients respond well to corticosteroids without evidence of recurrence. However, cases of severe auto-GVHD lacking good response to corticosteroids have been reported, most notably in MM patients. Here we present two cases of autologous GI GVHD in recipients of autologous HSCT for treatment of MM. Our cases demonstrate two distinct clinical and endoscopic presentations of this uncommon entity. In the first case, the patient had more severe clinical symptoms accompanied by radiographic, endoscopic, and pathologic findings. The hospital course was complicated by cryptosporidium enteritis and acute cholecystitis in the setting of increased immunosuppression with a corticosteroid for presumed auto-GVHD. In contrast, the second case presented a patient with normal radiologic and endoscopic findings. Pathology revealing frequent apoptotic bodies led to auto GVHD as a diagnosis. Both our patients received similar courses of chemotherapy prior to autologous HSCT (four cycles of a proteasome inhibitor, lenalidomide, and dexamethasone). Our work highlights the importance of maintaining a high level of clinical suspicion for auto-GVHD in patients presenting with GI symptoms after autologous HSCT, as it is a potentially treatable pathology that may be easily confused with other conditions. Health care providers should be aware of the potential complications of auto-GVHD after autologous HSCT and should be suspicious of auto-GVHD if GI symptoms occur, especially in patients receiving immunomodulatory therapy for MM, even in the absence of gross endoscopic findings. PMID- 29511406 TI - Analysis of Helicobacter pylori Genotypes Amongst Jordanians' Dental Plaque Samples. AB - Background: Helicobacter pylori (H. pylori) infection has been associated with gastritis, gastric ulcer, mucosa-associated lymphoid tissue lymphoma and gastric cancer. The prevalence of H. pylori virulence genes have been studied in different populations and from different sources of samples but their prevalence has not been studied in dental plaque in Jordanian people; therefore, the aim of this study was to determine the genotypes of H. pylori isolated from dental plaque samples. Methods: Dental plaque samples were collected from 60 Jordanian volunteers. The genotypes of H. pylori virulence genes including the cytotoxin associated gene A (cagA) and the vacuolating toxin (vacA) were determined using polymerase chain reaction (PCR). Results: The cagA gene was detected in 14 (23.3%) samples, while vacA was detected in all volunteers enrolled in this study (100%). The most prevalent vacA alleles were m2 and s1 in 54 (90%) and 55 (91.7%) of volunteers, respectively. Compared to the other combinations including the most virulent vacA genotype s1/m1 which was detected in 11 (18.2%) of volunteers, the most prevalent vacA allelic combinations were s1/m2 and s2/m2 in 56 (93.3%) and 27 (45%) of volunteers, respectively. Conclusions: These results indicate a significant carriage of virulent H. pylori strains among Jordanian people in their dental plaques, which increases the possible transmission of these strains among them. In addition, the studying of the genotypic pattern of H. pylori virulence genes in the dental plaque could represent an essential tool for infection prevention and predicting the severity and prognosis of H. pylori gastric infection. PMID- 29511408 TI - Worsening of Acute Cholangitis Caused by a Bile Duct Stone After Hospitalization: A Case Series. AB - Acute cholangitis is a fatal condition if inadequately treated. It is possible to underestimate the severity of the condition because bacterial cultures are not immediately available. We evaluated the clinical features of patients with cholangitis due to bile duct stones who were diagnosed with severe bacteremia at the time of hospitalization, but not at the time of the initial visit. We conducted a retrospective analysis of cases of endoscopic retrograde cholangiopancreatography performed between January 2007 and October 2011 in patients with bile duct stones complicated by cholangitis. The severity of cholangitis was assessed based on the 2005 Japanese Evidence-Based Practice Guidelines for the Management of Acute Cholangitis and Cholecystitis (JG05). Of 130 cases, 23 were diagnosed as severe cholangitis, including 11 of bacterial cause. However, based on the JG05, two cases were classified as "mild" at initial assessment and nine cases as "moderate". A history of endoscopic sphincterotomy (EST) was identified in the two cases classified as "mild" cholangitis. Obstruction by a bile duct stone, possibly due to reflux from the duodenum, can lead to rapid progression to sepsis in a short time. For patients with a history of EST, early biliary drainage is necessary to prevent rapid progression of bacterial cholangitis. PMID- 29511409 TI - Fatal Acute Liver Failure With Intravenous Amiodarone: A Case Report and Literature Review. AB - Amiodarone is a drug which frequently causes elevated transaminases. However, acute liver failure has been rarely reported. Here, we present a case of fatal acute liver failure following the administration of intravenous amiodarone. It is important to be aware of this rare but potentially fatal complication of intravenous amiodarone so that it can be withdrawn immediately at the first sign of hepatic impairment. PMID- 29511410 TI - A Case of Adolescent Cronkhite-Canada Syndrome. AB - The Cronkhite-Canada syndrome (CCS) was first reported in 1955, since then more than 500 cases have been reported, indicating an estimated incidence of one case per 1 million inhabitants. The syndrome occurs predominantly in male, with a ratio of three males to two females. Because of the rarity of the syndrome, there are no evidence-based therapies and the treatments described include a combination of therapies, but none is consistently effective. Surgery is usually reserved for the treatment of complications. Herein, we present a case of adolescent CCS. The patient was a 15-year-old boy who presented with watery diarrhea with 20 episodes a day, vomiting and abdominal pain for 4 weeks, with a weight loss of 8.0 kg (15.0% of initial weight). Endoscopic examination revealed polyposis in the stomach, duodenum, and colon. CCS was diagnosed and the patient was treated with a combined corticosteroid and metronidazole. Followed up at 8 month after the diagnosis, the patient was asymptomatic. PMID- 29511411 TI - Gastric Diverticula: A Review and Report of Two Cases. AB - Gastric diverticula represent the rarest of gastrointestinal diverticula. While similar to duodenal, jejunal and colonic diverticula, gastric diverticula are found incidentally upon upper endoscopy and are mostly asymptomatic. However, larger diverticula can lead to symptoms such as upper abdominal pain, nausea, emesis, and dyspepsia. Some patients may present with dramatic presentations including ulceration, hemorrhage, or perforation. Clinicians should be aware that diagnostic imaging may not always detect the presence of gastric diverticula. Upper endoscopy is recommended for diagnosing gastric diverticula as it readily confirms the size and location of the lesion. Conservative treatment involves the use of antacids and may provide temporary relief. Surgical resection is recommended for treatment resistant gastric diverticula, or cases complicated by hemorrhage, perforation, or malignancy. Herein, we present two patients with antral gastric diverticula, and review the literature. PMID- 29511412 TI - Gastric Outlet and Duodenal Obstruction as a Complication of Migrated Gastrostomy Tube: Report of Two Cases and Literature Review. AB - Percutaneous endoscopic gastrostomy (PEG) is a well-recognized procedure for providing enteral feeding and long-term enteral nutritional support. Although it is mostly well tolerated, complications, sometimes mechanical in nature, do occur. Rare, and often initially unrecognized, late complications of PEG tube placement are gastric outlet obstruction and duodenal obstruction. Simple adjustment of the gastrostomy tube will lead to the improvement of the patient's clinical condition and prevent further complications. Physicians should be aware of and suspect gastric outlet and duodenal obstruction as rare late complications of PEG tube placement. Simple adjustment of the gastrostomy tube can resolve the problem without unnecessary medical tests and overly aggressive care. Here, we present two interesting cases of elderly women who developed mechanical obstruction after inadvertent migration of the gastrostomy tube. PMID- 29511413 TI - A Rare Cause of Abdominal Pain and Mass in an 18-Year-Old Patient: A Diagnostic Dilemma. AB - We present a case of an 18-year-old male who presented with complains of abdominal pain, nausea and vomiting for 2 years. An esophagogastroduodenoscopy (EGD) revealed a 3 mm nodule on the lesser curvature of the stomach and prominent gastric folds. Biopsy of the nodule revealed a well-differentiated neuroendocrine tumor (NET) in lamina prop with focal extension into muscularis mucosa consistent with a gastric carcinoid. Tumor cells stained with neuron-specific enolase (NSE), chromogranin and synaptophysin only. The prominent gastric fold biopsy revealed gastric fundic mucosa with mucosal edema and focal mild chronic inflammation. Serum gastrin level was found to be 2,083 pg/mL. Abdomen CT and endoscopic ultrasound (EUS) revealed a mass near the pancreatic neck. These findings were consistent with a functional gastrin producing well-differentiated grade 1 neuroendocrine neoplasm (gastrinoma). The patient underwent exploratory laparotomy with resection of the mass and resulting in normalization of gastrin levels. PMID- 29511414 TI - Histologic Characterization of Kratom Use-Associated Liver Injury. AB - Kratom is an herbal product derived from the leaves of Southeast Asian Mitragyna speciosa trees. It has traditionally been used by indigenous people to relieve fatigue and manage pain, diarrhea, or opioid withdrawal. The use of kratom has become more commonplace in the United States for similar purposes. Only rare reports of kratom liver toxicity exist in the literature but without histologic characterization. Herein, we report one case of kratom use-associated liver toxicity in a 38-year-old patient. The patient complained of dark colored urine and light colored stools after using kratom. He had unremarkable physical examination. Laboratory testing at presentation revealed elevated alanine aminotransferase (389 U/L), aspartate aminotransferase (220 U/L), total bilirubin (5.1 mg/dL), and alkaline phosphatase (304 U/L). There was no serology evidence of viral hepatitis A, B, and C. The acetaminophen level at presentation was below detectable limits. Ultrasound examination of the right upper quadrant revealed normal echogenicity and contour of the liver without bile ductal dilatation or disease of the gallbladder. The patient underwent liver biopsy 4 days after the initial presentation which revealed a pattern of acute cholestatic liver injury including zone 3 hepatocellular and canalicular cholestasis, focal hepatocyte dropout, mild portal inflammation, and bile duct injury. Kratom was stopped, the patient improved clinically and biochemically and was discharged 8 days after the initial presentation. To our best knowledge, this is the first case report detailing the histology of kratom use-associated liver injury. PMID- 29511416 TI - Functions of the Triceps Brachii in Humans: A Review. AB - The triceps brachii (TB) is the only muscle that lies along the posterior humerus, and its role in elbow extension has been the topic of investigation for many decades. The TB research has also included subjects such as strength training, effects of aging, training adaptions, etc. The purpose of this paper was to review some of the more unique investigations regarding the functions of the human TB. Specifically, this paper discusses articles that have explored the actions of the TB when manipulating the angles of the joints it crosses, the elbow and shoulder. PMID- 29511415 TI - An Improvement of Cardiovascular Risk Factors by Omega-3 Polyunsaturated Fatty Acids. AB - An epidemiological survey in the Northwest Greenland reported that the Greenlanders have a lower frequency of acute myocardial infarction and diabetes mellitus. The very low incidence of ischemic heart disease in the Greenlanders was explained by consumption of a diet rich in omega-3 polyunsaturated fatty acids (PUFAs). Possible anti-atherothrombotic effects of omega-3 PUFA include an improvement of lipid metabolism such as a reduction of triglyceride and an increase of high-density lipoprotein-cholesterol (HDL-C), and glucose metabolism, anti-platelet activity, anti-inflammatory effects, an improvement of endothelial function and stabilization of atherosclerotic plaque. The present study reviews an improvement of cardiovascular risk factors such as dyslipidemia and diabetes due to consumption of omega-3 PUFA. A sufficient number of studies suggest that omega-3 PUFA supplementation reduces serum triglyceride and increases HDL cholesterol. The mechanisms for omega-3 PUFA-mediated improvements of lipid metabolism have been partially elucidated. The studies using experimental animals, part of trials in humans, have shown the beneficial effects of omega-3 PUFA on glucose metabolism and insulin sensitivity. The meta-analysis showed that omega-3 PUFA might prevent development of diabetes in part of population. Further studies should be performed to elucidate the association of omega-3 PUFA supplementation with diabetes, in the future. PMID- 29511418 TI - Obstetrics at Decisive Crossroads Regarding Pattern-Recognition of Fetal Heart Rate Decelerations: Scientific Principles and Lessons From Memetics. AB - The survival of cardiotocography (CTG) as a tool for intrapartum fetal monitoring seems threatened somewhat unjustifiably and unwittingly despite the absence of better alternatives. Fetal heart rate (FHR) decelerations are center-stage (most important) in the interpretation of CTG with maximum impact on three-tier classification. The pattern-discrimination of FHR decelerations is inexorably linked to their nomenclature. Unscientific or flawed nomenclature of decelerations can explain the dysfunctional CTG interpretation leading to errors in detection of acidemic fetuses. There are three contrasting concepts about categorization of FHR decelerations: 1) all rapid decelerations (the vast majority) should be grouped as "variable" because they are predominantly due to cord-compression, 2) all decelerations are due to chemoreflex from fetal hypoxemia hence their timing is not important, and 3) FHR decelerations should be categorized into "early/late/variable" based primarily on their time relationship to contractions. These theoretical concepts are like memes (ideas/beliefs). Lessons from "memetics" are that the most popular, attractive or established beliefs may not necessarily be true, scientific, beneficial or even without harm. Decelerations coincident with contractions with trough corresponding to the peak of contractions cannot be explained by cord-compression or increasing hypoxia (from compromised uteroplacental perfusion, cord-compression or even cerebral hypoperfusion/anoxia purportedly conceivable from head-compression). Decelerations due to hypoxemia would be associated with delayed recovery of decelerations (lag phase). It is a scientific imperative to cast away disproven/falsified theories. Practices based on unscientific theories lead to patient harm. Clinicians should urgently adopt the categorization of FHR decelerations based primarily of the time relationship to contractions as originally proposed by Hon and Caldeyro-Barcia. This analytical review shows it to be underpinned by most robust physiological and scientific hypotheses unlike the other categorizations associated with untruthful hypotheses, irreconcilable fallacies and contradictions. Without truthful framework and meaningful pattern recognition of FHR decelerations, the CTG will not fulfil its true potential. PMID- 29511417 TI - Primary Small Intestinal Angiosarcoma: Epidemiology, Diagnosis and Treatment. AB - Angiosarcoma is an aggressive mesenchymal sarcoma of endothelial cell origin with high mortality. Its occurrence in the small intestine is exceedingly low. In addition to the rarity of small intestine angiosarcoma, the nonspecific early clinical symptoms obscure the suspicion of such tumors and thereby delay the diagnosis. In a hope to improve the knowledge of this rare but fatal neoplasm, we report one case of angiosarcoma of duodenum and jejunum in a 73-year-old man. Furthermore, we summarize and analyze the common clinical features, tumor markers, treatment, and survival of previous reported cases of this malignancy. Small bowel angiosarcoma occurs more often in men than women (1.6:1). The median age at diagnosis is 68.5 years. The overall median survival time is 150 days; the median survival time in female (300 days) is longer than that of male patients (120 days). Von Willebrand factor (vWF), CD31, CD34, vimentin, and Ulex europaeus agglutinin 1 appear to be the most useful markers for the diagnosis. The majority of the patients underwent surgical resection alone or surgery with subsequent chemotherapy. The patients treated with surgery plus chemotherapy survive longer than those underwent surgical resection only (median 420 days, n = 7 vs. 96.5 days, n = 26, respectively; P = 0.0275). Further studies of more cases are needed for a better understanding of this rare entity, as well as the development of effective strategies for prevention, early diagnosis, and treatment. PMID- 29511419 TI - Comparison of the Assessment of Orthostatic Hypotension Using Peripheral and Central Blood Pressure Measurements. AB - Background: Orthostatic hypotension (OH) is associated with falls and cardiovascular events. There is growing evidence that central blood pressure (CBP) is better than peripheral blood pressure (PBP) in predicting adverse outcomes. The objectives of this study were to assess 1) the prevalence of OH identified using PBP and CBP and the levels of agreement, 2) the respective associations between OH and falls and cardiovascular comorbidities, by PBP and CBP, and 3) the association of OH with arterial wall stiffness markers (augmentation pressure (AP) and augmentation index (AI)). Methods: An observational case-control study of subjects aged 50 years and above was conducted at the University of Alberta Hospital inpatient wards and outpatient clinics. This study used a non-invasive technology called SphygmoCor to assess changes in CBP between lying, 1, 3 and 6 min of standing. AP and AI, which are markers of arterial wall stiffness, were also measured in this study. Dementia, significant psychological problems, and isolation precautions were exclusion criteria. Both PBP and CBP were measured with arm cuffs in lying and standing positions. OH was diagnosed using consensus criteria. Results: Of the 71 participants recruited, mean age was 72.3 +/-10.3 years, 52% were males, 32% had a history of falls and 72% had hypertension. OH occurred within 1, 3 or 6 min of standing (transient OH) in 31% by PBP and 27% by CBP (kappa = 0.56). OH persisted for all 6 min (persistent OH) in 16% by both PBP and CBP (kappa = 0.68). A significant relationship was observed between transient OH by CBP and baseline hypertension (P = 0.05) and dyslipidemia (P = 0.02). There was a significant difference in the mean AP between subjects with and without central persistent OH (P = 0.02), but not between subjects with and without peripheral persistent OH. The mean AI was not significantly different between subjects with or without central or peripheral persistent OH and between subjects with and without peripheral or central transient OH. Conclusion: Prevalence of OH was similar between PBP and CBP. However, there was only moderate agreement with OH identified by PBP and CBP indicating some inconsistencies across the sample in identifying OH. PMID- 29511420 TI - Using Time-Driven Activity-Based Costing as a Key Component of the Value Platform: A Pilot Analysis of Colonoscopy, Aortic Valve Replacement and Carpal Tunnel Release Procedures. AB - Background: Time-driven activity-based costing (TDABC) is a methodology that calculates the costs of healthcare resources consumed as a patient moves along a care process. Limited data exist on the application of TDABC from the perspective of an anesthesia provider. We describe the use of TDABC, a bottom-up costing strategy and financial outcomes for three different medical-surgical procedures. Methods: In each case, a multi-disciplinary team created process maps describing the care delivery cycle for a patient encounter using the TDABC methodology. Each step in a process map delineated an activity required for delivery of patient care. The resources (personnel, equipment and supplies) associated with each step were identified. A per minute cost for each resource expended was generated, known as the capacity cost rate, and multiplied by its time requirement. The total cost for an episode of care was obtained by adding the cost of each individual resource consumed as the patient moved along a clinical pathway. Results: We built process maps for colonoscopy in the gastroenterology suite, calculated costs of an aortic valve replacement by comparing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve replacement (TAVR) techniques, and determined the cost of carpal tunnel release in an operating room versus an ambulatory procedure room. Conclusions: TDABC is central to the value based healthcare platform. Application of TDABC provides a framework to identify process improvements for health care delivery. The first case demonstrates cost savings and improved wait times by shifting some of the colonoscopies scheduled with an anesthesiologist from the main hospital to the ambulatory facility. In the second case, we show that the deployment of an aortic valve via the transcatheter route front loads the costs compared to traditional, surgical replacement. The last case demonstrates significant cost savings to the healthcare system associated with re-organization of staff required to execute a carpal tunnel release. PMID- 29511421 TI - The Celiac Trunk and Its Anatomical Variations: A Cadaveric Study. AB - Background: The celiac artery, celiac axis or celiac trunk is the first major abdominal branch of the aorta. Anatomic variations and accessory vessels have been reported with variable percentages. The purpose of this study was to report the pattern of the celiac trunk and its anatomic variations in a sample of Mexican population. Methods: Celiac trunk dissection was performed in 140 fresh cadavers. Cadavers of Mexican subjects aged 18 years and older were included. Cadavers with previous upper abdominal surgery, abdominal trauma, disease process that distorted the arterial anatomy or signs of putrefaction were excluded. Celiac trunk variations and external diameter, accessory vessels, and vertebral level of origin were described. Celiac trunk patterns were reported according to the Panagouli classification. This study was reviewed and approved by the Ethics Committee of our Hospital. Results: The celiac trunk derived in a common hepatic artery, a left gastric artery and a splenic artery (type I) in 43.6% of dissections. A true tripod was found in 7.1% and a false tripod in 36.4%. Celiac trunk bifurcation (type II) was found in 7.1%. Additional branches (type III) were observed in 47.9%. One or both phrenic arteries originated from the celiac trunk in 41.4% of dissections. Celiac trunk tetrafurcation was observed in 12.9%, pentafurcation in 12.9%, hexafurcation in 1.4%, and heptafurcation in 0.7%. The mean diameter of the celiac trunk ranged from 6 to 12 mm, with a mean diameter of 7.2 mm (SD = 1.39 mm). No significant difference was found between the diameters of the different types of celiac trunk (P > 0.05). The celiac trunk originated between the 12th thoracic and first lumbar vertebral bodies in 90% of dissections. Conclusions: Trifurcation of the celiac trunk was lower than previously reported. A high proportion of cases with additional vessels were found. PMID- 29511422 TI - Clinical Significance of Cardio-Ankle Vascular Index as a Cardiovascular Risk Factor in Elderly Patients With Type 2 Diabetes Mellitus. AB - Background: The cardio-ankle vascular index (CAVI) is a novel physiological marker of atherosclerosis that reflects systemic arterial stiffness. The aim of this study was to clarify the clinical significance of CAVI as a risk factor for cardiovascular diseases (CVDs) in elderly patients with type 2 diabetes mellitus. Methods: This cross-sectional study enrolled 216 elderly (>= 65 years) outpatients with type 2 diabetes mellitus who were undergoing antidiabetic treatment (96 males and 120 females; mean age, 75 +/- 7 years (mean +/- standard deviation)). Associations between CAVI and various clinical parameters were examined. Results: CAVI was significantly higher in patients with a history of CVD than in those without a history of CVD (10.4 +/- 1.4 vs. 9.5 +/- 1.0, respectively, P < 0.001). There were significantly positive correlations between CAVI and various clinical parameters, such as skin autofluorescence (r = 0.47, P < 0.001), high-sensitivity cardiac troponin T levels (r = 0.39, P < 0.001), and reactive oxygen metabolite levels (r = 0.28, P < 0.001). Furthermore, multiple regression analyses revealed that these clinical parameters ((skin autofluorescence (beta = 0.30, P < 0.001), high-sensitivity cardiac troponin T levels (beta = 0.18, P < 0.001), reactive oxygen metabolite levels (beta = 0.15, P < 0.01), and a history of CVD (beta = 0.19, P < 0.001)) were independent variables when CAVI was used as a subordinate factor. Conclusion: Findings of this study indicate that CAVI may be an important CVD risk factor in elderly patients with type 2 diabetes mellitus. Further investigations in a large number of prospective studies, including intervention therapies, are required to validate our results. PMID- 29511423 TI - Seroepidemiology of Cytomegalovirus Infection in Pregnant Women in the Central Mexican City of Aguascalientes. AB - Background: Infection with cytomegalovirus (CMV) during pregnancy may lead to congenital disease. Very little is known about the seroepidemiology of CMV infection in pregnant women in Mexico. We sought to determine the seroprevalence and correlates of CMV infection in pregnant women in Aguascalientes City, Mexico. Methods: Through a cross-sectional study design, 289 pregnant women were examined for anti-CMV IgG and IgM antibodies in Aguascalientes City, Mexico. A standardized questionnaire was used to obtain the socio-demographic, clinical and behavioral characteristics of the pregnant women. The association between CMV infection and the characteristics of the pregnant women was assessed by bivariate and multivariate analyses. Results: Anti-CMV IgG antibodies were detected in 259 (89.6%) of the 289 pregnant women studied. None of the 289 pregnant women were positive for anti-CMV IgM antibodies. Seroprevalence of CMV infection was significantly lower (P = 0.03) in pregnant women with reflex impairment (5/8: 62.5%) than in those without this clinical feature (246/272: 90.4%). Seroprevalence of CMV infection was significantly higher (P = 0.03) in pregnant women with 2 - 9 pregnancies (140/150: 93.3%) than in those with only one pregnancy (119/139: 86.2%). Logistic regression analysis of socio-demographic and behavioral variables showed that seropositivity to CMV was associated with contact with children (odds ratio (OR) = 3.56; 95% confidence interval (CI): 1.17 - 10.84; P = 0.02), whereas high (> 150 AU/mL) anti-CMV antibody levels were negatively associated with washing hands before eating (OR = 0.17; 95% CI: 0.05 - 0.63; P = 0.007). Conclusions: We found a high endemicity of CMV infection in pregnant women in Aguascalientes City, Mexico. Factors associated with CMV infection found in this study may be useful for an optimal planning of preventive measures against CMV exposure in pregnant women. PMID- 29511424 TI - The Relationship Between Mean Platelet Volume and Fasting Plasma Glucose and HbA1c Levels in a Large Cohort of Unselected Health Check-Up Participants. AB - Background: Larger platelets are more active and mean platelet volume (MPV) is an indicator of platelet activation and an independent risk factor of cardiovascular diseases. While MPV is reported to be higher in diabetic patients, the relationship between MPV and glycemic parameters in general population remains inconclusive. Methods: In this cross-sectional study, we studied relationship between MPV and fasting plasma glucose (FPG) and HbA1c levels in 38,204 unselected participants of general health check-up aged 20 years or older in the year of 2014 who were considered to be representative of the general population. Individuals with known diabetes, coronary artery disease and/or cerebrovascular disease who were on drug therapy and those with platelet counts below 100 * 109/L or above 400 * 109/L were excluded. Results: The mean age of the individuals was 52.3 +/- 12.1 years and 46.1% were male. There were positive associations between MPV and both FPG (r = 0.066; P < 0.001) and HbA1c (r = 0.025; P < 0.001) levels when all individuals were analyzed as a whole. While the association was only marginal in individuals with HbA1c levels below 6.5% (r = 0.009; P = 0.068), it was significant in those with HbA1c >= 6.5% (r = 0.138; P < 0.001). When the individuals were categorized into four groups according to the HbA1c values: HbA1c < 5.5%, 5.5% <= HbA1c < 6.0%, 6.0% <= HbA1c < 6.5%, and HbA1c >= 6.5%, the mean MPV was virtually same among groups with HbA1c level < 6.5% and that of the individuals with HbA1c >= 6.5 was significantly higher than groups with lower HbA1c levels. Multivariate analyses adjusted with age and sex showed the same results. Conclusion: FPG and HbA1c appeared to be associated with MPV in unselected health check-up participants; however, the association between glycemic state and MPV was apparent only in individuals with impaired glycemic control and only marginal in those with normal glycemic control. The clinical significance of the associations warrants further study. PMID- 29511425 TI - Cardiorespiratory Failure in Thyroid Storm: Case Report and Literature Review. AB - Thyroid storm is a potentially fatal manifestation of thyrotoxicosis. Cardiopulmonary failure is the most common cause of death in thyroid storm. Clinicians should keep in mind that thyroid storm complicated with cardiopulmonary failure can be the first presentation of thyrotoxicosis. As early intervention is associated with improved patient outcome, prompt diagnosis based on clinical grounds is of paramount importance in the management of thyrotoxicosis. A high index of suspicion and the ability of early recognition of impending thyroid storm depends on a thorough knowledge of both the typical and atypical clinical features of this illness. Herein, we report a case of thyroid storm presenting as cardiopulmonary failure in a 51-year-old woman with undiagnosed Grave's disease. Additionally, we review the pathophysiology of cardiopulmonary failure associated with thyrotoxicosis and various treatment modalities for thyroid storm. PMID- 29511426 TI - Isolated Adrenocorticotropic Hormone Deficiency and Severe Hypercalcemia After Destructive Thyroiditis in a Patient on Nivolumab Therapy With a Malignant Melanoma. AB - We describe a 58-year-old man with a malignant melanoma metastasis to the liver. After initiation of nivolumab therapy, he developed destructive thyroiditis and subsequently simultaneous isolated adrenocorticotropic hormone (ACTH) deficiency and severe hypercalcemia. Although isolated ACTH deficiency and hypercalcemia due to nivolumab therapy are both rare occurrences, these conditions can often cause a severe clinical course accompanied by a disturbance of consciousness. Therefore, clinicians should pay attention to these possible side effects of nivolumab if the patients have clinical symptoms, such as fatigue and a disturbance of consciousness. PMID- 29511427 TI - Clinical Significance of Pregnancy in Japanese Women Aged 15 Years. PMID- 29511428 TI - Multiple fractures in infants who have Ehlers-Danlos/hypermobility syndrome and or vitamin D deficiency: A case series of 72 infants whose parents were accused of child abuse and neglect. AB - Objective: To increase the level of awareness that Ehlers-Danlos/hypermobility syndrome (EDS) and vitamin D deficiency are associated with infantile fragility fractures and radiologic features that may be mistakenly reported to be caused by non-accidental trauma due to Child Abuse and Neglect (CAN). Patients and Methods: We constructed a case series, the largest to date, of infants with EDS who were vitamin D sufficient, insufficient and deficient and infants without EDS but with documented vitamin D deficiency and radiologic evidence of rickets who presented with multiple fractures originally diagnosed as being non-accidental and caused by child abuse. These infants were referred to the outpatient Bone Health Care Clinic at Boston University Medical Campus over a 6-year (2010-2015) period. We also present 6 index cases in which the court concluded that there was no convincing evidence of child abuse and the infants were returned to their parents. Institutional Review Board (IRB) approval was obtained. Results: We present 72 cases of infants with multiple fractures diagnosed to be caused by non accidental trauma. All infants were younger than one year of age. Among them, 93%(67) had clinical evidence of EDS and/or a family history with a confirmed clinical diagnosis of at least one parent having EDS and the other 7%(5) without evidence of EDS had vitamin D deficiency/infantile rickets. Three of the EDS infants were diagnosed as osteogenesis imperfecta (OI)/EDS overlap syndrome. The most common fractures noted at diagnosis were ribs and extremity fractures (including classic metaphyseal lesions). Serum levels of 25-hydroxyvitamin D [25(OH)D] were reported in 48 infants (18.0 +/- 8.5 ng/ml) and in 30 mothers (21.3 +/- 11.7 ng/ml). Sixty-three percent (27) of the EDS infants who had their serum 25(OH)D measured were vitamin D deficient 25(OH)D<20 ng/ml and 5 were vitamin D sufficient 25(OH)D>30 ng/ml. The mean serum level for infants with vitamin D deficiency/rickets was (10.2 +/- 3.0 ng/ml) Conclusion: EDS, OI/EDS and vitamin D deficiency/infantile rickets are associated with fragility fractures in infants that can be misinterpreted as caused by non-accidental trauma due to child abuse. PMID- 29511429 TI - High-voltage pulsed electric field plus photodynamic therapy kills breast cancer cells by triggering apoptosis. AB - This study evaluated the effects and mechanism of action of combining irreversible electroporation (IRE) and photodynamic therapy (PDT) in breast cancer cells in vitro and in vivo. Jin's formula was used to assess killing efficacy of different IRE+PDT dosing combinations in breast cancer MCF-7 cells. Flow cytometry, high-content imaging, and confocal laser scanning microscopy were used to detect apoptosis. qRT-PCR and western blotting were used to evaluate expression of apoptosis-related genes and proteins. IRE+PDT combination therapy was administered to BALB/C mice with breast cancer tumors in vivo; tumor size was used to assess treatment efficacy. Killing mechanisms were examined using transmission electron microscopy and immunohistochemistry. We found that IRE+PDT combination therapy produced significant synergistic killing effects in breast cancer cells (highest Jin q value of 1.32). Early apoptosis rates were significantly higher in the IRE+PDT group (16.0%) than in IRE-alone (7.6%) and PDT-alone (4.6%) groups (P<0.05). qRT-PCR showed higher Caspase-1, -3, -5, -6, 7, -8, and -9 and TNFRSF1A expression with IRE+PDT than with control. Western blots showed increased cleaved Caspase-3, -7, and -9, and PARP levels in the IRE+PDT group. In vivo tumor suppression rate for IRE (1200 V)+PDT (10 mg/kg) was 68.3%. Combination therapy produced the most obvious apoptosis effects. Compared with controls, the IRE+PDT group exhibited lower new blood vessel (VEGF, CD31), metastasis (TGF-beta), and cell proliferation (Ki-67) indicators and higher inflammation indicator (TNF-alpha) 1 day post-treatment. Thus, combining IRE and PDT enhanced their anti-tumor effects in breast cancer, and apoptosis played a key role in this process. PMID- 29511430 TI - The chemokine receptor CCR1 is identified in mast cell-derived exosomes. AB - Mast cells are important effector cells of the immune system, and mast cell derived exosomes carrying RNAs play a role in immune regulation. However, the molecular function of mast cell-derived exosomes is currently unknown, and here, we identify differentially expressed genes (DEGs) in mast cells and exosomes. We isolated mast cells derived exosomes through differential centrifugation and screened the DEGs from mast cell-derived exosomes, using the GSE25330 array dataset downloaded from the Gene Expression Omnibus database. Biochemical pathways were analyzed by Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on the online tool DAVID. DEGs-associated protein-protein interaction networks (PPIs) were constructed using the STRING database and Cytoscape software. The genes identified from these bioinformatics analyses were verified by qRT-PCR and Western blot in mast cells and exosomes. We identified 2121 DEGs (843 up and 1278 down-regulated genes) in HMC-1 cell-derived exosomes and HMC-1 cells. The up-regulated DEGs were classified into two significant modules. The chemokine receptor CCR1 was screened as a hub gene and enriched in cytokine-mediated signaling pathway in module one. Seven genes, including CCR1, CD9, KIT, TGFBR1, TLR9, TPSAB1 and TPSB2 were screened and validated through qRT-PCR analysis. We have achieved a comprehensive view of the pivotal genes and pathways in mast cells and exosomes and identified CCR1 as a hub gene in mast cell-derived exosomes. Our results provide novel clues with respect to the biological processes through which mast cell-derived exosomes modulate immune responses. PMID- 29511431 TI - Alantolactone plays neuroprotective roles in traumatic brain injury in rats via anti-inflammatory, anti-oxidative and anti-apoptosis pathways. AB - Traumatic brain injury (TBI) is a common disease associated with a high rate of morbidity and mortality. Secondary brain injury following TBI triggers pathological, physiological, and biological reactions that lead to neurological dysfunctions. Alantolactone (ATL) is a well-known Chinese medicine that possesses strong anti-inflammatory properties, but its role in TBI remains poorly understood. The objective of this study was to evaluate the protective effect of ATL in a rat model of controlled cortical impact (CCI). We observed the neurological scores, brain water content, oxidative stress, neuroinflammation and apoptosis by performing an enzyme-linked immunosorbent assay, western blotting, quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), immunohistochemical (IHC) staining and other methods after CCI. The neurological scores, brain water content, levels of oxidative stress and inflammatory cytokines, and apoptosis index were markedly decreased following the ATL treatment in rats after TBI. Moreover, the antioxidant and anti-inflammatory effects of ATL in TBI may be partially mediated by inhibition of the NF-kappaB pathway and suppression of Cyclooxygenase 2 (COX-2). In addition, ATL attenuated TBI-induced neuronal apoptosis by suppressing the cytochrome c/caspase-dependent apoptotic pathway. Thus, ATL could exert neuroprotection in rats in a TBI model. Importantly, ATL has great potential in the clinical treatment of TBI. PMID- 29511432 TI - Vitamin D enhances resistance to aspergillus fumigatus in mice via inhibition of excessive autophagy. AB - The role of vitamin D in the regulation of lung immune defense and inflammatory response has attracted more and more attention. Vitamin D deficiency is closely related to respiratory tract infections. However, few studies have elucidated the mechanism of vitamin D deficiency on host pulmonary resistance to Aspergillus fumigatus (A. fumigatus). In this paper, the role of autophagy and Treg regulation in the treatment of rat models of A. fumigatus infection with vitamin D was investigated. We intratracheally injected the A. fumigatus spores into Mice fed with sufficient vitamin D (VitD+) or deficient diets (VitD-). Mortality, fungal load and weight changes were evaluated. The conidia of lung tissue were isolated for analysis of viability. Alveolar macrophages (AMs) were stimulated with a viable A. fumigatus conidia for determining the formation of lysosomes in vitro. The autophagy-related proteins dectin-1, ROS and LC3BII expression in AMs were measured. Fluorescence and Western blot were performed to evaluate the autophagic flux and Treg cells were detected by flow cytometry. After inoculation with A. fumigatus, the vitamin D deficient mice exhibited a higher rate of death, more fungal growth, and more weight loss than its sufficient peers. The viability of A. fumigatus conidia in VitD+ mice was significantly lower than that in VitD- mice. In the case of A. fumigatus infection, vitamin D delays the formation of lysosomes against A. fumigatus through autophagy. The autophagy flow measurement experiment also found that the vitamin D group lowered autophagy levels in cells and a small number of Treg cells. In conclusion, Vitamin D deficiency can lead to impaired lung defense in mice, which may be associated with the formation of excessive autophagy-induced lysosomes and increased counts of Treg cells. PMID- 29511433 TI - A novel liver-targeted nitric oxide donor UDCA-Thr-NO protects against cirrhosis and portal hypertension. AB - Portal hypertension (PHT) is a common liver disease that is closely related to cirrhosis and has a high morbidity and mortality. The present study aimed to probe the efficacy of a novel nitric oxide (NO)-releasing agent with NO linked to ursodeoxycholic acid (UDCA) through threonine (UDCA-Thr-NO) as a liver-targeted therapy for cirrhosis and PHT. After intraperitoneal treatment of dimethyl nitrosamine-induced cirrhotic rats for 3 or 4 weeks, UDCA-Thr-NO could prevent ascites formation and reduce portal pressure instead of carotid artery pressure, when compared with UDCA or compound embryonic bovine liver extract tablets. Biochemical analysis of the rat sera also revealed that UDCA-Thr-NO improved the levels of alanine aminotransferase and total bilirubin and reduced the level of hydroxyproline (P < 0.05). Colorimetric analysis of the liver tissue by staining hematoxylin-eosin (HE) and Sirius red (SR) showed that UDCA-Thr-NO could improve pathological changes and reduce liver collagen deposition and intrahepatic resistance without affecting systemic circulation. It was concluded that UDCA-Thr NO had a protective effect on liver injury and could be utilized to improve cirrhosis and PHT. PMID- 29511434 TI - Augmenter of liver regeneration (ALR) regulates acute pancreatitis via inhibiting HMGB1/TLR4/NF-kappaB signaling pathway. AB - This research aimed to explore the effect of augmenter of liver regeneration (ALR) in acute pancreatitis (AP) of mice and the underlying mechanism. Caerulein were given to mice to get AP models. AP mice were given saline, ALR plasmids or negative control plasmids. Then, pancreas tissues were fixed and stained for histological examination. The levels of serum amylase, serum lipase, MPO, HMGB1, TNF-alpha, IL-1beta as well as MCP-1 were detected by ELISA assay. The mRNA levels of TLR4, p65, IkappaBalpha, iNOS, COX-2 and GAPDH were examined by RT qPCR. The protein levels of HMGB1, TLR4, MD2, MyD88, IkappaBalpha and GAPDH were detected by western blotting. ALR decreased serum amylase as well as lipase levels and alleviated the histopathological alterations of the pancreas in AP mice. ALR decreased the MPO activity of pancreas in AP Mice. ALR decreased the HMGB1/TLR4 signaling pathway in AP Mice. ALR decreased pancreas IL-1beta and MCP 1 in AP mice, and also decreased plasma TNF-alpha and IL-1beta in AP mice. ALR attenuated the cerulein-caused increase in p65 mRNA and protein levels, but had no effects on mRNA and protein levels of IkappaBalpha. The AP mice significantly promoted the mRNA levels of iNOS and COX-2 that was inhibited by ALR. HNE formation was also increased in AP mice, but it was decreased by ALR. ALR alleviates acute pancreatitis by inhibiting HMGB1/TLR4/NF-kappaB signaling pathway. It is promising to alleviate the syndromes of patients with acute via targeting ALR. PMID- 29511435 TI - Zhuangguguanjie formulation protects articular cartilage from degeneration in joint instability-induced murine knee osteoarthritis. AB - Zhuangguguanjie formulation (ZG) can provide noticeable relief from joint pain in patients suffering from knee osteoarthritis (OA). However, the underlying mechanism has not been fully described. Male C57BL/6 mice were administered either ZG or normal saline (NS) following surgical destabilization of the medial meniscus (DMM). At weeks 4, 6 and 8 (post-surgery), knee joints were harvested and assessed with Safranin-O staining. Blood serum was collected and tested. In vitro analysis was carried out to evaluate the effects of ZG on the expression of the OA-related genes. DMM mice indicated reduced cartilage destruction and lower blood serum biomarkers of OA (COMP1 and CTX-1) following ZG treatment. Moreover, the femoral condyle and tibial plateau histological scores were significantly reduced following ZG treatment of the DMM mice. ZG could markedly downregulate the expression of OA-related genes namely, ADAMTS5, MMP3 and MMP13, while it simultaneously upregulated collagen II as demonstrated by in vitro assays. Moreover, chondrocyte apoptosis was significantly decreased following ZG treatment. These results may be caused by the up-regulation of p-AKT expression levels, since the anti-apoptotic effects of ZG can be blocked by treatment with an AKT inhibitor. ZG is capable of preventing and/or reducing the progression of OA by inhibiting chondrocyte apoptosis via the p-AKT/Caspase 3 pathway. PMID- 29511436 TI - Dihydroartemisinin inhibits indoxyl sulfate (IS)-promoted cell cycle progression in mesangial cells by targeting COX-2/mPGES-1/PGE2 cascade. AB - Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin and has been used as an antimalarial drug. Recently, roles of artemisinin and its derivatives in treating diseases besides antimalarial effect were documented. Thus, this study was undertaken to investigate the role of DHA in indoxyl sulfate (IS)-promoted cell cycle progression in glomerular mesangial cells, as well as the potential mechanisms. Under the basal condition, DHA significantly retarded the cell cycle progression as shown by decreased cell percentage in S phase and increased cell percentage in G1/G0 phases in line with reduced cell cycle proteins cyclin A2 and cyclin D1. Interestingly, DHA also inactivated the COX 2/mPGES-1/PGE2 cascade which has been shown to play a critical role in promoting the mesangial cell cycle progression by our previous studies. Next, we investigated the role of DHA in IS-triggered cell cycle progression in this mesangial cell line. As expected, DHA treatment significantly retarded IS-induced cell cycle progression and inhibited the activation of COX-2/mPGES-1/PGE2 cascade induced by IS. In summary, these data indicated that DHA inhibited the cell cycle progression in glomerular mesangial cells under normal condition or IS challenge possibly through the inhibition of COX-2/mPGES-1/PGE2 cascade, suggesting a potential of DHA in treating glomerular diseases with mesangial cell proliferation. PMID- 29511437 TI - Mdivi-1 pretreatment mitigates isoflurane-induced cognitive deficits in developmental rats. AB - Accumulating evidence indicates that general anesthetics can cause acute neuroapoptosis and long-term cognitive deficit in models exposed to anesthetics during the brain growth-spurt period. Anesthetics-induced imbalance of mitochondrial fusion and fission preceded and contributed to developmental neuroapoptosis. Accordingly, the imbalance was accompanied by activation of dynamin-related protein (Drp)1 which was closely associated with synaptic degeneration in neurodegenerative diseases. Based on the neuroprotective role of mitochondrial division inhibitor-1 (mdivi-1) in neurodegeneration and stroke, we set out to examine whether mdivi-1 can mitigate developmental neurotoxicity induced by isoflurane. In the present study, we showed that 2% isoflurane exposure for 2 h triggered Drp1 dephosphorylation at serine 656 and increased translocation of Drp1 and Bax from cytosol to mitochondria, concomitant with cytochrome C leakage into the cytosol. Remarkably, pretreatment with mdivi-1 not only alleviated isoflurane-induced disturbed mitochondrial translocation of Drp1 and Bax and almost restored morphological changes, but also inhibited cytochrome C release, caspase9 and caspase3 activation in hippocampi. Furthermore, mdivi-1 mitigated the loss of synaptic proteins and long-lasting cognitive deficit in later life of rats neonatally exposed to isoflurane. Taken together, isoflurane induced Drp1 activation and translocation led to excessive mitochondrial fission and subsequently contributed to the synaptic injury and long-term cognitive impairment. However, mdivi-1 pretreatment prevented Drp1-dependent excessive mitochondrial fission and mitigated neuro-apoptosis and synaptic injury, and improved the long-term cognitive function. Thus mdivi-1 holds far-reaching insight for prophylaxis of developmental neurotoxicity induced by isoflurane. PMID- 29511438 TI - Multi-parameter evaluation of lumbar intervertebral disc degeneration using quantitative magnetic resonance imaging techniques. AB - Objective: To quantitatively evaluate lumbar disc degeneration with recently developed quantitative magnetic resonance imaging (MRI) techniques. A series of MRI parameters, including T2*, T1rho relaxation time, apparent diffusion coefficient and gagCEST, were compared and correlated with the Pfirrmann semi quantitative classification of lumbar intervertebral disc degeneration; the most accurate and relevant MRI parameters of lumbar disc degeneration were identified. Materials and Methods: Thirty-seven subjects (age range, 18-74 years) with non specific low back pain (LBP) for more than 6 months were enrolled. The L1/2-L5/S1 discs of each subject were measured and then analyzed. Results: The gagCEST value of the discs showed the best negative correlation with degeneration level (nucleus pulposus: r = -0.951, P < 0.001; annulus fibrosus: r = -0.938, P < 0.001). The discriminant analysis results showed that this parameter also had the highest correct rate using a single index (gagCEST discriminant accuracy = 82%). Conclusion: Early stage lumbar disc degeneration can be quantitatively evaluated with MRI using the chemical exchange saturation transfer technique. PMID- 29511439 TI - Knockout of the placenta specific 8 gene radiosensitizes nasopharyngeal carcinoma cells by activating the PI3K/AKT/GSK3beta pathway. AB - The present study investigated the radiosensitizing effect of placenta specific 8 (PLAC8) in nasopharyngeal carcinoma (NPC) cells. A PLAC8-knockout CNE2 cell line was constructed using the CRISPR/Cas9 system. The CCK-8 assay demonstrated knockout of PLAC8 significantly reduced cell proliferation and cell survival after irradiation compared to both control cells and non-irradiated PLAC8 knockout cells. The clonogenic assay showed knockout of PLAC8 enhanced the radiosensitivity of NPC cells. Flow cytometry revealed knockout of PLAC8 increased apoptosis and G2/M phase arrest after irradiation. Western blotting demonstrated knockout of PLAC8 was associated with increased levels of gammaHA2X, a higher BAX:BCL-2 ratio, and increased levels of phosphorylated-Akt and phosphorylated-GSK-3beta. Overall, this study indicates PLAC8 contributes to radioresistance in NPC by inhibiting the PI3K/AKT/GSK3beta pathway. PMID- 29511440 TI - Andrographolide presents therapeutic effect on ulcerative colitis through the inhibition of IL-23/IL-17 axis. AB - Ulcerative colitis (UC) is a chronic and nonspecific intestinal inflammatory disease, which may increase the risk of colon cancer. Andrographolide is a main active component of Andrographis paniculata. The anti-inflammatory ability of andrographolide suggested its potential therapeutic effect against UC. In the present study, elevated serum concentrations of proinflammatory factors, including (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-23, as well as increased percentages of Th17 cells (IL-17+CD4+ cells) in CD4+ cells were detected in UC patients compared to that in healthy donors. These data suggested that Th17 immune responses may involve in the pathogenesis of UC. Experimental colitis mouse model was then established. The results of hematoxylin and eosin staining demonstrated the therapeutic effect of andrographolide on colitis. Enzyme-linked immunosorbent assay (ELISA), flow cytometry and western blotting analyses showed that andrographolide could decreased the levels of proinflammatory factors TNF-alpha, IL-1beta, IL-6 and IL-17A in the serum and in the colon tissues, reduced the percentages of Th17 cells in CD4+ cells, and suppressed the levels of IL-23, IL-17A, ROR-gammat (key transcription factor of Th17 cells) and p-STAT3 in the colon tissues. Further, peripheral blood mononuclear cells (PBMCs) were isolated from UC patients and treated with various concentrations of andrographolide (0, 10, 20 and 30 MUg/ml). Andrographolide also showed inhibitory effects on the levels of proinflammatory factors, the percentages of Th17 cells and the expression of relative proteins. Similar results were obtained in lipopolysaccharide-treated normal PBMCs. These data suggested that andrographolide may inhibit Th17 immune response via STAT3 signaling. In conclusion, we demonstrated that andrographolide inhibited the activity of IL-23/IL-17 axis and down-stream pro-inflammatory factors so as to suppress inflammation response, resulting in the relieving of UC. PMID- 29511441 TI - A novel hybrid 3D-printed titanium scaffold for osteogenesis in a rabbit calvarial defect model. AB - The aim of this study was to explore an innovative method to improve the osteogenic ability of porous titanium. We used gelatin (Gel) and nano hydroxyapatite (nHA) to construct micro-scaffolds within the pores of porous titanium alloy. We compared three groups: control, Gel:nHA = 1:0, and Gel:nHA = 1:1. We assessed cell attachment, cell proliferation, and osteogenic (alkaline phosphatase [ALP] and collagen type 1 [Col-1]) and cytoskeletal (Talin) gene and protein expression in MC3T3-E1 cells. We also evaluated osteogenic abilities in a rabbit calvarial defect model. Our results showed that micro-scaffolds can improve new bone formation both in vitro and in vivo. Between the two micro scaffold groups, the Gel:nHA = 1:1 group exhibited the most satisfactory results. It had a multi-hierarchical pore structure with a mean pore size of 156+/-86 MUm. The Gel:nHA = 1:1 group exhibited significantly higher gene and protein expression of ALP, Col-1, and Talin. This group also exhibited the most new bone volume during in vivo experiments. The 3D micro-scaffold structure was an effective method of porous titanium modification that not only provided appropriate cell growth conditions but may also be used as a carrier of bioactive factors in the future. PMID- 29511442 TI - SRPX2 regulates colon cancer cell metabolism by miR-192/215 via PI3K-Akt. AB - Colon cancer is one of common cancer in the world and glycolysis is one of the major problems in colon cancer therapy. MicroRNAs (miRNAs) involve in colon cancer progression. Sushi repeat-containing protein X-linked 2 (SRPX2) is associated with poor prognosis in some cancer patients, however, the role of SRPX2 including glycolytic metabolism regulated by miRNAs is unclear in colon cancer. So, the purpose of the present study is to elucidate the underlying mechanism in colon cancer metabolism mediated by SRPX2. Our results revealed that miR-192-5p (miR-192) and miR-215-5p (miR-215) inhibited glycolysis by regulating SRPX2 expression in colon cancer cells. We also found that miR-192 and miR-215 were both regulated by PI3K-Akt. Our results indicate that SRPX2 facilitates colon cancer cell glycolysis by miR-192 and miR-215, which are down-regulated by PI3K-Akt. PMID- 29511443 TI - Anticancer effect of fufang yiliu yin on human hepatocellular carcinoma SMMC-7721 cells. AB - Chinese herbal medicine utilizes clinically effective adjuvants that can potentiate the effects of hepatectomy and molecule-targeted drugs for the treatment of hepatocellular carcinoma (HCC). The aim of this study was to investigate the possible molecular mechanisms underlying the antitumor effect of fufang yiliu yin (FYY) on HCC cells. We investigated the effects of FYY on the proliferation, migration, invasion, and apoptosis of SMMC-7721 cells in vitro and in mouse subcutaneous xenograft models in vivo. FYY significantly inhibited the proliferation of SMMC-7721 cells compared to that of normal hepatocytes; cell proliferation was blocked at the G2/M phase in accordance with reduced expression of proliferating cell nuclear antigen. FYY treatment resulted in the activation of caspase-8, caspase-3 and poly (ADP-ribose) polymerase, with reduced protein levels of tumor necrosis factor receptor-associated factor 2, indicating an induction of cell apoptosis. In addition, we observed decreases in the protein expression of matrix metalloproteinase-2 and -9 along with an inhibition of cell migration and invasion after FYY treatment. Furthermore, FYY treatment significantly inhibited the growth of tumors in vivo. These data demonstrate the strong inhibitory effects of FYY on SMMC-7721 cells, and we propose FYY as a novel potential anticancer adjuvant. PMID- 29511445 TI - Control of macrophage autophagy by miR-384-5p in the development of diabetic encephalopathy. AB - The molecular development of diabetic encephalopathy remains ill-defined. Recently, we reported that elimination of inflammatory macrophages alleviated the progress and severity of diabetic encephalopathy. Here, we studied the underlying mechanism. Inflammatory macrophages were isolated from the brain of the mice that received i.p. injection of streptozotocin (STZ) to develop diabetes 6 weeks before, and showed enhanced autophagy activity, seemingly through augmentation of Beclin-1 levels. However, the increases in Beclin-1 levels did not result from enhanced gene transcription, but appeared to result from suppression of a Beclin 1-inhibitory microRNA, miR-384-5p. Overexpression of miR-384-5p in the inflammatory macrophages through an adeno-associated virus mediated gene transfer system significantly reduced inflammatory macrophages in the diabetic brain, resulting in attenuation of the STZ-induced decreases in brain malondialdehyde, catalase and superoxidase anion-positive cells, and the STZ-induced increases in brain nitric oxide. Thus, these data suggest that downregulation of miR-384-5p in the inflammatory macrophages may enhance macrophage autophagy and contribute to the development of diabetic encephalopathy, which may be suppressed by re expression of miR-384-5p in macrophages. PMID- 29511446 TI - NudCD1 affects renal cell carcinoma through regulating LIS1/Dynein signaling pathway. AB - Renal cell carcinoma (RCC) is one of the most common malignant tumors in urogenital system with an incidence accounting for about 3% of the whole body malignant tumor. NudC domain containing 1 (NudCD1), a new member of NudC family distributed in nucleus, is found to be upregulated in multiple tumors. However, its expression and role in RCC tissue has not been elucidated. NudCD1 expression in RCC tissue was measured by western blot and immunohistochemistry (IHC). NudCD1 level was elevated by overexpression vector to investigate its regulatory role on LIS1/Dynein signaling pathway. Cell morphology, intracellular localization, and cell division were observed by immunofluorescence together with delayed microscope photograph. The impact of NudCD1 overexpression on cell migration was assessed by Transwell assay. NudCD1 expression was significantly increased in RCC tissue compared with that in adjacent normal control. NudCD1/LIS1/Dynein signaling pathway was obviously upregulated in RCC tissue. Overexpression of NudCD1 level in A498 cell line markedly elevated NudCD1/LIS1/Dynein signaling pathway, suggesting they might be involved in RCC process. NudCD1 upregulation also caused abnormal microtubule fasciculus structure with multinuclear morphology, and promoted cell migration. NudCD1 expression was obviously increased in RCC and affected RCC cell division and migration possibly through activating NudCD1/LIS1/Dynein signaling pathway, indicating therapeutic targeting NudCD1 might be a new approach to inhibit RCC cell migration. PMID- 29511444 TI - Functional peptides for cartilage repair and regeneration. AB - Cartilage repair after degeneration or trauma continues to be a challenge both in the clinic and for scientific research due to the limited regenerative capacity of this tissue. Cartilage tissue engineering, involving a combination of cells, scaffolds, and growth factors, is increasingly used in cartilage regeneration. Due to their ease of synthesis, robustness, tunable size, availability of functional groups, and activity, peptides have emerged as the molecules with the most potential in drug development. A number of peptides have been engineered to regenerate cartilage by acting as scaffolds, functional molecules, or both. In this paper, we will summarize the application of peptides in cartilage tissue engineering and discuss additional possibilities for peptides in this field. PMID- 29511447 TI - MiRNA-491-5p inhibits cell proliferation, invasion and migration via targeting JMJD2B and serves as a potential biomarker in gastric cancer. AB - Our previous work discovered that the histone demethylase JMJD2B (KDM4B) plays oncogenic roles in gastric carcinogenesis, but the regulatory mechanism of JMJD2B in gastric cancer has not been well defined. It has been revealed that microRNAs function as gene regulators by binding to the 3'UTR of mRNAs to inhibit gene expression. In this study, we found that miR-491-5p suppressed cell proliferation, invasion and migration by directly targeting the JMJD2B 3'UTR in gastric cancer. Moreover, miR-491-5p was decreased in GC tissues compared with adjacent normal tissues, and JMJD2B had the inverse expression pattern. In contrast to healthy individuals, GC patients had lower miR-491-5p expression in serum (P<0.0001). Our data indicate that miR-491-5p serves as a tumor suppressor in GC and might be a novel potential biomarker for the detection of gastric cancer. PMID- 29511448 TI - Co-injection of human adipose stromal cells and rhBMP-2/fibrin gel enhances tendon graft osteointegration in a rabbit anterior cruciate ligament reconstruction model. AB - The objective of this study was to investigate whether the co-injection of human adipose stromal cells (hASCs) and rhBMP-2/fibrin gel into the bone tunnels of anterior cruciate-ligament reconstructions can effectively enhance tendon graft osteointegration. We performed bilateral reconstructions using autologous semitendinosus tendons in 45 New Zealand rabbits, which we divided into three groups. We injected the bone tunnels with fibrin gel for group 1, rhBMP-2 (1 MUg/ml)/fibrin gel for group 2, and hASCs wrapped in rhBMP-2 (1 MUg/ml)/fibrin gel for group 3. We sacrificed five rabbits (two for histological assessment and three for biomechanical tests) from each group at 2, 4, and 8 weeks post surgery. At 2 and 4 weeks post surgery, histological analysis showed that fibro-cartilage had appeared in the tendon-bone interface in group 2. At 4 weeks post surgery, mature bone cells could be seen in group 3. There was new bone formed between the host bone and the graft in groups 2 and 3 at 8 weeks post surgery. Biomechanical testing showed that at 4 and 8 weeks post surgery, the ultimate failure loads in group 3 were significantly higher than those in groups 1 and 2 (both P=0.01). The tendon stiffness in group 3 was significantly higher than that in the other groups at 4 weeks post surgery (P=0.01). Our results indicate that co-injection of hASCs and rhBMP-2/fibrin gel has the potential to promote tendon-bone healing after anterior cruciate-ligament reconstruction. PMID- 29511449 TI - HDAC inhibitors suppressed small cell lung cancer cell growth and enhanced the suppressive effects of receptor-targeting cytotoxins via upregulating somatostatin receptor II. AB - Small cell lung cancer (SCLC) is a malignant human cancer and patients have very limited benefit from traditional anticancer treatments, with a poor five-year survival rate being 10% less. In present study, we observed that Notch signalling activation induced SCLC cell growth suppression via overexpressing Notch active fragments (ICN1, ICN2, ICN3 and ICN4), implying its tumor suppressive role. The histone deacetylase (HDAC) inhibitors also displayed their suppressive effects. Valproic acid (VPA) as a HDAC inhibitor was found to suppress SCLC cell growth and cell cycle arrest at phase G1, and observed to decrease HDAC4 and increase acetylation of histone H4 (AcH4) while activating Notch signalling with an increase of Notch1, Notch target gene HES1 and p21. Meanwhile, we also observed that VPA greatly stimulated the expression of somatostatin receptor type II (SSTR2) that is usually overexpressed in many cancer cells and is used as a target for anticancer drug development, providing a combination therapy with VPA and the SSTR2-targeting cytotoxins. Thus, VPA was investigated in combination with SSTR2-targeted cytotoxins captothecine-somatostatin conjugate (CPT-SST) and colchicine-somatostatin conjugate (COL-SST). Our assays showed that these combination treatments strongly led to a greater suppression as compared to each alone. In conclusion, we found that VPA suppressed SCLC cell growth and increased the expression of SSTR2. These may provide a novel clinical opportunity for enhanced anticancer therapy using the combination strategy of Notch signalling regulator and SSTR2-targeting cytotoxins in SCLC treatments. PMID- 29511450 TI - Genomic risk variants at 3q22.3 are associated with keloids in a Chinese Han population. AB - A keloid is the process of skin healing, collagen synthesis and metabolism of the loss of normal control in a sustained hyperactive state, resulting in excessive proliferation of collagen fibers. A large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in the 3q22.3 loci that are associated with keloids in a Japanese population. However, the associations of SNPs in 3q22.3 with keloids were not confirmed in a selected Chinese population by a replication study. Thus, in the present study, the relationships between keloids and 3q22.3 were assessed in another independent Chinese Han population, including 309 keloid patients and 1080 control subjects. The results displayed that rs940187 was associated with keloids (OR=1.88, 95% CI 1.27-2.78, P=1.35E-3) and remained significant after Bonferroni's correction for multiple testing, while rs1511412 showed only a trend association (OR=2.23, 95% CI 1.09-4.55, P=0.02) with keloids. In addition, we subsequently checked the annotation datasets for rs940187 with eQTLs and obtained two hits, trans-proteins SLC7A9 and LEMD3, with significant P values less than 1e-4. In summary, genomic risk variants at 3q22.3 are associated with keloids in a Chinese Han population and contribute to the development and deterioration of the keloids, together with environmental factors. PMID- 29511451 TI - lncRNA MALAT1/miR-205-5p axis regulates MPP+-induced cell apoptosis in MN9D cells by directly targeting LRRK2. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as a long chain non-coding RNA (lncRNA), has been reported to be upregulated in Parkinson's disease (PD). However, the mechanisms underlying this process remain unknown. Hence, to investigate the role of MALAT1 in PD, N-methyl-4-phenylpyridinium (MPP+) was used to induce PD in vitro in the MN9D dopaminergic neuronal cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD in vivo in C57BL/6 mice. Quantitative Real-Time PCR (qRT-PCR) and western blot assay showed that the expression levels of MALAT1 and leucine-rich repeat kinase (LRRK2) were increased, and that of miR-205-5p was decreased in the midbrains of mice in which PD was induced by MPTP. MALAT1 suppressed the expression of miR-205 5p in MN9D cells. The results of luciferase reporter assay indicated that LRRK2 was a direct target of miR-205-5p. Transfection with the miR-205-5p mimics decreased, whereas transfection with miR-205-5p inhibitor increased the expression levels of LRRK2 mRNA and protein. The cell counting kit-8 (CCK-8) and flow cytometry assays showed that overexpression of LRRK2 reduced the viability and promoted apoptosis in MN9D cells treated with MPP+. MALAT1 knockdown exerted a protective effect on the viability and apoptosis of MN9D cells treated with MPP+, which was abrogated by LRRK2 overexpression and miR-205-5p inhibition. Our study demonstrates that the MALAT1/miR-205-5p axis regulates MPP+-induced apoptosis in MN9D cells by targeting LRRK2, thereby improving our understanding of the molecular pathogenesis of PD. PMID- 29511452 TI - Expression of long non-coding RNA HOXA11-AS is correlated with progression of laryngeal squamous cell carcinoma. AB - Long noncoding RNA HOXA11 antisense RNA (HOXA11-AS) is involved in tumorigenesis and development of some human cancers. However, the role of HOXA11-AS in human laryngeal squamous cell cancer (LSCC) is yet unclear. In this study, we firstly investigated the expression of HOXA11-AS in LSCC. Microarray and qRT-PCR showed that the level of HOXA11-AS was significantly higher in LSCC than that in the corresponding adjacent non-neoplastic tissues. ISH revealed that HOXA11-AS was strongly expressed in the nucleus and closely related to the T grade, neck nodal metastasis, and clinical stage. Patients with T3-4 grade, neck nodal metastasis, or advanced clinical stage presented a high HOXA11-AS expression. Kaplan-Meier analysis showed that high HOXA11-AS expression could predict a poor prognosis in LSCC patients. Furthermore, HOXA11-AS knockdown significantly inhibited the growth, migration, and invasion of LSCC cells. Taken together, the current data indicated that HOXA11-AS plays an oncogenic role in the cellular processes of LSCC and serve as a novel marker and a potential therapeutic target in LSCC patients. PMID- 29511453 TI - Role of Kruppel-like factor 4 in cigarette smoke-induced pulmonary vascular remodeling. AB - Pulmonary hypertension (PH) is characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), leading to dysregulated vascular remodeling. Cigarette smoke (CS) is a common risk factor causing PH, and our previous study showed that CS extract (CSE) stimulated abnormal PASMC proliferation. However, the molecular mechanism remains unclear. In systemic circulation, vascular remodeling in some diseases is associated with upregulation of Kruppel-like factor 4 (KLF4), which stimulates the proliferation of vascular smooth muscle cells. We therefore hypothesized that upregulation of KLF4 may play a role in pulmonary vascular remodeling and the development of PH. Our results showed that KLF4 expression was increased significantly in remodeled pulmonary arteries from the rat smoking model of pulmonary vascular remodeling, compared with controls. In human PASMCs in vitro, KLF4 knockdown by gene silencing decreased proliferation and migration significantly. At the same time, it inhibited the CSE-induced increase of AKT phosphorylation. These results indicate that KLF4 contributes to CS-induced pulmonary vascular remodeling, and that KLF4 gene knockdown may be a useful therapeutic intervention for PH. PMID- 29511454 TI - Extensive profiling of circular RNAs and the potential regulatory role of circRNA 000284 in cell proliferation and invasion of cervical cancer via sponging miR 506. AB - Circular RNAs (circRNAs) are key regulators in the development and progression of human cancers, however its role in cervical cancer tumorigenesis is not well understood. The present study aims to investigate the expression profiles and potential modulation of circRNA on cervical cancer carcinogenesis. Human circRNA microarray was performed to screen for abnormally expressed circRNA in cervical cancer cells and circRNA-000284 was identified as one circRNA significantly upregulated in cervical cancer cells. Subsequent mechanistic investigations suggested that knockdown of circRNA-000284 suppressed cell proliferation and invasion, and caused G0/G1 phase cell cycle arrest. By performing anti-AGO2 RNA precipitation and luciferase reporter assay, we identified miR-506 as the circRNA 000284-associated miRNA. Furthermore, Snail-2 was identified as a direct target of miR-506, and circRNA-000284 could positively regulate the expression of Snail 2. Finally, the tumor promoting effect of circRNA-000284 was abolished by co expression of miR-506 mimics or Snail-2 silencing vector. In conclusion, circRNA 000284 promotes cell proliferation and invasion in cervical cancer, and may serve as a promising therapeutic target for cervical cancer patients. Therefore, silence of circRNA-000284 could be a future direction to develop a novel treatment strategy. PMID- 29511455 TI - Interplay between long noncoding RNA ZEB1-AS1 and miR-101/ZEB1 axis regulates proliferation and migration of colorectal cancer cells. AB - Long noncoding RNAs (lncRNAs) are dysregulated in many diseases. MicroRNA-101 (miR-101) functions as a tumor suppressor by directly targeting ZEB1 in various cancers. However, the potential mechanism of lncRNA ZEB1-AS1 and miR-101/ZEB1 axis in CRC remains unknown. In this study, we further investigated the potential interplay between miR-101/ZEB1 axis and lncRNA ZEB1-AS1 in colorectal cancer (CRC). Results showed that ZEB1-AS1 was upregulated in CRC tissues and cells. MiR 101 was downregulated in CRC tissues and negatively correlated with ZEB1-AS1 and ZEB1 expression levels in CRC. Functional experiments showed that, consistent with ZEB1-AS1 depletion, miR-101 overexpression and ZEB1 depletion inhibited the proliferation and migration of CRC cells. Overexpression of miR-101 partially abolished the effects of ZEB1-AS1 on the proliferation and migration of these cells. Moreover, combined ZEB1-AS1 depletion and miR-101 overexpression significantly inhibited cell proliferation and migration of the CRC cells. Hence, ZEB1-AS1 functioned as a molecular sponge for miR-101 and relieved the inhibition of ZEB1 caused by miR-101. This study revealed a novel regulatory mechanism between ZEB1-AS1 and miR-101/ZEB1 axis. The interplay between ZEB1-AS1 and miR 101/ZEB1 axis contributed to the proliferation and migration of CRC cells, and targeting this interplay could be a promising strategy for CRC treatment. PMID- 29511456 TI - MicroRNA-146b-3p regulates the development and progression of cerebral infarction with diabetes through RAF1/P38MAPK/COX-2 signaling pathway. AB - Diabetes has been considered as an independent risk factor for cerebral infarction. However, the pathological mechanism of cerebral infarction with diabetes (DMCI) is still rarely known. In this study, we try to explore the relationship between microRNA-146b-3p (miR-146b-3p) and DMCI patients. The peripheral blood mononuclear cells were separated after the patients were selected from our hospital. Firstly, the content of IL-6 and COX-2 was detected by ELISA. Then, the total RNAs were extracted and analyzed by microRNA (miRNA) microarray. Moreover, the target genes of miR-146b-3p were predicted by online miRNA target prediction algorithms. Meanwhile, luciferase reporter system was used for assaying the target gene for miRNA-146b-3p. Simultaneously, RT-PCR assay was used for the miRNA expression detection. Furthermore, western blot was applied to determine the expression of the signal pathway involved proteins. Our results demonstrated that expression of IL-6 and COX-2 were remarkably up regulated in peripheral blood of DMCI patients compared with that in normal control group. In addition, miRNA microarray data suggested that miR-146b-3p expression was significantly down-regulated in DMCI patients, with v-raf-1 expression negatively regulated. Moreover, miR-146b-3p regulated RAF1 expression was found to mediate P38MAPK signaling activation in thrombosis patients. The following research indicated that activation of RAF1 trough miR-146b-3p down regulation contributed to activation of RAF/P38MAPK/COX-2 signaling pathway in vascular infarction. Our data have implied that altered expression of miR-146b-3p is closely related to the progression and development of DCMI mediating the RAF/P38MAPK/COX-2 signal transduction pathway. PMID- 29511457 TI - Downregulation of FoxM1 inhibits cell growth and migration and invasion in bladder cancer cells. AB - The FoxM1 (Forkhead Box M1) transcription factor plays a key role in regulation of cell growth, cell cycle, and transformation. Higher expression of FoxM1 has been observed in various types of human cancers including bladder cancer. However, the exact function of FoxM1 in bladder cancer has not been elucidated. To investigate the cellular and molecular function of FoxM1 in bladder cancer, we measured the consequences of downregulation and upregulation of FoxM1 in bladder cancer cells using MTT assay, wound healing assay, and invasion assay. We found that downregulation of FoxM1 inhibited cell growth, but induced apoptosis in bladder cancer cells. Moreover, we found that inhibition of FoxM1 retarded cell migration and invasion. In line with this, upregulation of FoxM1 led to cell growth promotion and inhibited cell apoptosis in bladder cancer cells. Consistently, upregulation of FoxM1 led to increased cell migration and invasion. Our Western blotting results identified that downregulation of FoxM1 increased p27 level and inhibited VEGF, while overexpression of FoxM1 reduced p27 level and increased VEGF. Our findings suggest that FoxM1 could be a useful target for the treatment of bladder cancer. PMID- 29511458 TI - SOX2 inhibits cell proliferation and metastasis, promotes apoptotic by downregulating CCND1 and PARP in gastric cancer. AB - Inconsistent results of Sex-determining region Y-box2 (SOX2) expression have been reported in gastric cancer (GC) before. Our recent studies showed that SOX2 was significantly downregulated in GC cells compared with GES-1 at both mRNA and protein level. Transfected with pcDNA3.1-SOX2 resulted in enforced expression of SOX2 at mRNA and protein levels compared with NC group in undifferentiated cell lines including HGC27 and BGC823. MTT assay showed that exogenous expressed SOX2 suppressed cell proliferation. FC analysis revealed that SOX2-overexpressing cells exhibited cell-cycle arrest and apoptosis. Transwell assay showed the anti metastatic effect of SOX2 in GC cells. The subsequent results suggested CCND1 and PARP were downregulated in SOX2 overexpressed GC cells, and were responsible for the SOX2-induced anticancer effects. Thus, SOX2 proved to be an expected biomarker in GC diagnosis. PMID- 29511459 TI - Neutralizing antibodies against flaviviruses, Babanki virus, and Rift Valley fever virus in Ugandan bats. AB - Introduction: A number of arboviruses have previously been isolated from naturally-infected East African bats, however the role of bats in arbovirus maintenance is poorly understood. The aim of this study was to investigate the exposure history of Ugandan bats to a panel of arboviruses. Materials and methods: Insectivorous and fruit bats were captured from multiple locations throughout Uganda during 2009 and 2011-2013. All serum samples were tested for neutralizing antibodies against West Nile virus (WNV), yellow fever virus (YFV), dengue 2 virus (DENV-2), Zika virus (ZIKV), Babanki virus (BBKV), and Rift Valley fever virus (RVFV) by plaque reduction neutralization test (PRNT). Sera from up to 626 bats were screened for antibodies against each virus. Results and Discussion: Key findings include the presence of neutralizing antibodies against RVFV in 5/52 (9.6%) of little epauletted fruit bats (Epomophorus labiatus) captured from Kawuku and 3/54 (5.6%) Egyptian rousette bats from Kasokero cave. Antibodies reactive to flaviviruses were widespread across bat taxa and sampling locations. Conclusion: The data presented demonstrate the widespread exposure of bats in Uganda to arboviruses, and highlight particular virus-bat associations that warrant further investigation. PMID- 29511460 TI - Immunoaffinity-based isolation of melanoma cell-derived exosomes from plasma of patients with melanoma. AB - Tumour-derived exosomes (TEX) are a subset of extracellular vesicles (EVs) present in body fluids of patients with cancer. The role of this exosome subset in melanoma progression has been of interest ever since ex vivo studies of exosomes produced by melanoma cell lines were shown to suppress anti-melanoma immune responses. To study the impact of melanoma-derived exosomes (MTEX) present in patients' plasma on melanoma progression, isolation of MTEX from total plasma exosomes is necessary. We have developed an immunoaffinity-based method for MTEX capture from plasma of melanoma patients. Using mAb 763.74 specific for the CSPG4 epitope uniquely expressed on melanoma cells, we separated MTEX from non-tumour cell-derived exosomes and evaluated the protein cargo of both fractions by quantitative flow cytometry. Melanoma-associated antigens were carried by MTEX but were not detectable in exosomes produced by normal cells. Separation of plasma-derived MTEX from non-MTEX provides an opportunity for future evaluation of MTEX as potential biomarkers of melanoma progression and as surrogates of melanoma in tumour liquid biopsy studies. PMID- 29511461 TI - Extracellular vesicles: the growth as diagnostics and therapeutics; a survey. AB - This article aims to document the growth in extracellular vesicle (EV) research. Here, we report the growth in EV-related studies, patents, and grants as well as emerging companies with major intent on exosomes. Four different databases were utilized for electronic searches of published literature: two general databases - Scopus/Elsevier and Web of Science (WoS), as well as two specialized US government databases - the USA Patent and Trademark Office and National Institutes of Health (NIH) of the Department of Health and Human Services. The applied combination of key words was carefully chosen to cover the most commonly used terms in titles of publications, patents and grants dealing with conceptual areas of EVs. Within the time frame from 1 January 2000 to 31 December 2016, limited to articles published in English, we identified output using search strategies based upon Scopus/Elsevier and WoS, patent filings and NIH Federal Reports of funded grants. Consistently, USA and UK universities are the most frequent among the top 15 affiliations/organizations of the authors of the identified records. There is clear evidence of upward streaming of EV-related publications. By documenting the growth of the EV field, we hope to encourage a roster of independent authorities skilled to provide peer review of manuscripts, evaluation of grant applications, support of foundation initiatives and corporate long-term planning. It is important to encourage EV research to further identify biomarkers in diseases and allow for the development of adequate diagnostic tools that could distinguish disease subpopulations and enable personalized treatment of patients. PMID- 29511462 TI - Proteome profiling of extracellular vesicles captured with the affinity peptide Vn96: comparison of Laemmli and TRIzol(c) protein-extraction methods. AB - Sample amount is often a limiting factor for multi-parametric analyses that encompass at least three areas of '-omics' research: genomics, transcriptomics and proteomics. Limited sample amounts are also an important consideration when these multi-parametric analyses are performed on extracellular vesicles (EVs), as the amount of EVs (and EV cargo) that can be isolated is often very low. It is well understood that a monophasic solution of phenol and guanidine isothiocyanate (i.e. TRIzol(c)) can simultaneously isolate DNA, RNA and proteins from biological samples; however, it is most commonly used for the extraction of RNA. Validation of this reagent for the isolation of multiple classes of biological molecules from EVs would provide a widely applicable method for performing multi-parametric analyses of EV material. In this report, we describe a comparison of proteins identified from EVs processed with either TRIzol(c) or the conventional Laemmli buffer protein-extraction reagents. EVs were isolated from 3 mL of cell-culture supernatant derived from MCF-10A, MCF-7 and MDA-MB-231 cells using the Vn96 EV capture technology. For the TRIzol(c) extraction protocol, proteins were precipitated with acetone from the organic phase and then re-solubilized in a mixture of 8M urea, 0.2% SDS and 1 M Tris-HCl pH 6.8, followed by dilution in 5* loading buffer prior to fractionation with 1D SDS-PAGE. NanoLC-MS/MS of the trypsin-digested proteins was used to generate proteomic profiles from EV protein samples extracted with each method. Of the identified proteins, 57.7%, 69.2% and 57.0% were common to both extraction methods for EVs from MCF-10A, MCF-7 and MDA MB-231, respectively. Our results suggest that TRIzol(c) extraction of proteins from EVs has significant equivalence to the traditional Laemmli method. The advantage of using TRIzol PMID- 29511463 TI - Biocompatibility of highly purified bovine milk-derived extracellular vesicles. AB - Extracellular vesicles (EVs) deliver biologically active cargos from donor cells to recipient cells for intercellular communication. Since the existence of RNA cargo was discovered, EVs have been considered to be useful drug-delivery systems. Specifically, EVs from bovine milk (mEV) are one of the most promising platforms, since bovine milk is a scalable source of EVs for mass production. However, it is still difficult to isolate pure EVs from bovine milk owing to the complexity of raw materials. Furthermore, the biocompatibility and immunotoxicity of mEVs are still unclear. In this study, we developed a new method for isolating bovine milk-derived EVs by employing acid treatment and ultracentrifugation. Isolated mEVs are spherical in shape, measure 120 nm in diameter and contain typical EV marker proteins, such as tetraspanins. Compared with the previously reported method, our method can isolate purer mEVs. When mEVs are contacted with the mouse macrophage cell line Raw264.7, mEVs are readily taken up by the cells without a cytotoxic effect, suggesting that mEVs can deliver the cargo molecules into cells. While systemic administration of mEVs into mice resulted in the absence of systemic toxicity, certain types of cytokines were slightly induced. No anaphylaxis effect was observed after serial administration of mEVs in mice. Thus, mEVs isolated using our method are well tolerated in vivo and may be useful for the drug-delivery application. PMID- 29511464 TI - Type 2 diabetes mellitus and non-alcoholic fatty liver disease: a systematic review and meta-analysis. AB - Aim: The aim of this study was the evaluation of the prevalence of NAFLD in patients with type 2 diabetes mellitus. Background: Non-alcoholic fatty liver disease (NAFLD) is an emerging disease with high prevalence in patients with type 2 diabetes mellitus (T2DM). Many studies have reported the prevalence of NAFLD in type 2 diabetes mellitus patients. However, these results are inconsistent. Methods: A Literature search was conducted in PubMed, Scopus, web of science and Science Direct from 2005 to August 2017. The necessary information was extracted. Heterogeneity was evaluated using I2 statistic. Meta-regression analyses were performed to the estimation of the relationship between the year of study and sample size with the prevalence of NAFLD. Publication bias was assessed by both Begg rank correlation and Egger tests. Subgroup analysis was performed for identification of sources heterogeneity. Results: Seventeen studies involving 10897 type 2 diabetes mellitus patients with NAFLD were included in this meta analysis. The overall prevalence of NAFLD in type 2 diabetes mellitus patients by random effects models was 54% (95% CI, 45%- 64%). There is a significant heterogeneity across studies with (I2= 99%, p> 0.01). The funnel plot as graphically and Begg and Egger as statistically showed no publication bias among studies. Subgroup analysis indicated that the prevalence of NAFLD in type 2 diabetes mellitus patients differed in predictive factors such as lipid profile, BMI, HbA1c, AST, and ALT. This finding in spite of heterogeneity of documents is corresponding to the positive correlation between NAFLD and type 2 diabetes mellitus. Conclusion: The findings indicated that the overall prevalence of NAFLD among type 2 diabetes mellitus patients is significantly higher. It can be concluded that type 2 diabetes mellitus patients should be managed to prevent NAFLD. PMID- 29511465 TI - Management of multi-drug resistant Helicobacter pylori infection by supplementary, complementary and alternative medicine; a review. AB - Helicobacter pylori is recognized as the most common bacterial pathogens colonizing the gastric epithelium of nearly half of the world's population. This bacterium is the main etiological cause of gastroduodenal ulcers, and more importantly as the substantial risk factor for development of gastric cancer. The emergence and rapid increase in the prevalence of multi-drug resistant phenotypes have posed major pitfalls in effectiveness of various treatment regimens and eradication strategies against H. pylori infections. Several natural products and supplementary food components have been reported to have established anti-H. pylori activity. Herein, we review the application and efficacy of some specific natural products and foodstuffs such as milk, bee products (honey and propolis), fish oil, vitamins C and E, and also a nickel free-diet used as anti-H. pylori alternative treatment regimens. PMID- 29511466 TI - The effect of education on the knowledge of patients with celiac disease. AB - Aim: The aim of this study was to investigate the effects of education on patients' knowledge of celiac disease, in an Iranian population. Background: Education can increase patients' knowledge regarding their disease, leading to improvements in their health. Methods: This cross-sectional study was conducted on patients who had been diagnosed with celiac disease. The patients attended an educational meeting in September, 2016. During the educational meeting information regarding the epidemiology, diagnosis and treatment of celiac disease was provided to the study subjects. Each patient completed a questionnaire regarding celiac disease before and after the educational meeting. The questionnaires were scored. Study data was analyzed using SPSS version 20. Results: 90 patients were recruited (69 [77%] were women). Analysis of questionnaire responses showed that except for awareness of cross contamination with gluten, the education meeting significantly increased the knowledge of patients with celiac disease regarding epidemiology, diagnosis and treatment (p=0.001). Conclusion: The result of this study shows that an educational meeting can increase the knowledge of CD patients in treatment. Increasing patients' knowledge may lead to improvements in patients' health. PMID- 29511467 TI - Changing the cause of liver cirrhosis from hepatitis B virus to fatty liver in Iranian patients. AB - Aim: The objective of this study was to determine the epidemiologic characteristics of patients with liver cirrhosis. Background: Liver cirrhosis is an end-stage condition of chronic liver disease. Liver disease is an important cause of morbidity and mortality worldwide. Methods: In this cross-sectional study, demographic and epidemiologic characteristics of 203 patients with liver cirrhosis who were admitted in Taleghani Hospital over a period of two years were determined. Results: A total of 203 patients with liver cirrhosis consisted of 136 (67%) males and 67 (33%) females and the mean age was 53.7+/-15.2 years. No etiology were found in (59.6%) cirrhotic patients; therefore, they were labeled as cryptogenic cirrhosis, but according to clinical evidence and ultrasonography findings, (29.7%) of these patients were probable NAFLD. The other causes of liver cirrhosis in this study were HBV (20.2%), HCV (11.8%) and autoimmune hepatitis (AIH) (8.4%), respectively. Esophageal varices were present in (41.9%), ascites in (36.5%), variceal bleeding in (8.9%), encephalopathy in (7.4%) and spontaneous bacterial peritonitis (SBP) in (5.4%) of patients. When cirrhotic patients were grouped according to Child-Pugh classification, 26.1%, 54.7% and 19.2% were in classes A, B and C respectively. The mean MELD score was 16.16+/ 7.7. Conclusion: In this study we found that the leading etiology of cirrhosis is cryptogenic cirrhosis 59.6% (in all age groups) and followed by HBV. Noteworthy, according to the clinical and ultrasonography findings, 29.7% of patients who were labeled as cryptogenic cirrhosis were consistent with NAFLD. PMID- 29511468 TI - Detailed analysis of total colectomy on health-related quality of life in adult patients with ulcerative colitis. AB - Aim: The aim of this study was to explore the quality of life (QoL) in a group of patients who had an intractable disease on medical therapy including biologics and underwent surgery. Background: Quality of life of patients with ulcerative colitis (UC) has been measured with a series of multiple questionnaires. Methods: An observational cross sectional study was carried out on 68 patients with documented UC referring to an IBD clinic in a tertiary hospital. Patients with UC who had a colectomy because of intractable disease and were in remission for a year were eligible for enrollment Patients were instructed to fill the SF-36 Questionnaire (interviewer-administered) regarding quality of life. Side effects were evaluated with another questionnaire. Results were compared with the normal population of the community. Results: In comparison with normal population, patients having colectomy have better general QoL. Impotency and incontinency were most common adverse events after colectomy while the adverse events that decreased the QoL significantly were anal secretions and number of bowel movements per day without using antidiarrheal- drugs. Conclusion: In conclusion, our study showed a significant improvement of general QoL in a selected group of UC patients, who were in clinical remission following IPAA and only number of bowel movements per day and anal secretions significantly impaired their QoL. We suggest that a disease-specific questionnaire should be designed, making changes in health-related QOL more detectable over time, since it is more sensitive to these changes in IBD patients than a general questionnaire. PMID- 29511469 TI - The evaluation of functional results before and after laparoscopic Heller myotomy for achalasia: a single center experience. AB - Aim: The aim of this study was to evaluate and compare the functional results before and after laparoscopic Heller myotomy for Iranian patients with achalasia. Background: Achalasia is a severe neuromuscular disorder of the esophagus, characterized by the loss of peristalsis and an inability of the lower esophageal sphincter (LES) to reach optimal relaxation. Methods: In this cross sectional study, patients who underwent Heller myotomy for achalasia via laparoscopy in Taleghani Hospital Tehran, Iran were evaluated. Symptoms including pressure of residual, integrated relaxation sphincter (IRP), pressure of free drinking, pressure of LES, dysphasia score and peristalsis movement was measured and recorded by manometry before and after (2 months) treating with Heller myotomy. Results: In this study, 23 patients with achalasia (12 females and 11 males) with a mean age of 30+/-3.5 years (minimum 20, maximum 44 years) who met the inclusion criteria of the study were examined. Results of this study showed that, all the diagnostic criteria that were measured before the treatment was significantly different from after the treatment (P<0.05). The average decline in LES, IRP, Residual Pressure, Free drinking esophagus, and dysphasia score were 23.1 mmHg, 16.24 mmHg, 18,7 mmHg, 18.9 mmHg, and 5.0 unit, respectively. Also the average increase of the peristalsis movement was 8.26+/-13.7 in 8 patients. Conclusion: Considering the results of Heller myotomy surgery can be as a treatment of choice for achalasia. Free Drinking pressure can be a suitable criteria after treatment for evaluation and prediction of the reducing the dysphasia score after the surgery. PMID- 29511470 TI - Demographic changes of hepatitis B virus infection in Iran for the last two decades. AB - Aim: The objective of this study was to evaluate the impact of the hepatitis B virus (HBV) vaccination program, 24 years after its implementation, by analyzing patients with hepatitis B surface antigen (HBsAg) infection based on gender and age group. Background: Since the launch of the first universal vaccination program against HBV in Iran in 1993, the epidemiological pattern of HBV prevalence may have changed in our country. Methods: All data for this cross sectional study were collected from medical records of HBsAg positive patients, who were referred to the Golhak and Armin private laboratories and also to the Gastrointestinal Department of Tehran's Taleghani Hospital and Day Hospital in Iran over a period of 5 years (2011-2016). In total, 8,606 HBsAg positive subjects were assessed according to gender and age group. Results: The rates of HBsAg carriage were 0.8%, 7.8%, 49.3%, 27.9% and 14.1% among subjects under 14 years old, 15-24 years, 25-44 years, 45-59 years and those older than 60 years, respectively. According to the age subgroup analyses; the highest (26.2%) and lowest (0.6%) rate of HBsAg positivity was seen in the 31-40 age group and younger than 10 year old children, respectively. Conclusion: Global vaccination against hepatitis B has significantly reduced carrier rates among children and teenagers under 20 years old in this country. Nevertheless, HBsAg carriers still remain highly prevalent among 25-35-year age group. Therefore, the decline is limited to the younger population born after 1993, and it remains high in the middle-aged individuals. PMID- 29511471 TI - Diabetes mellitus and hypertension increase the risk of colorectal cancer mortality; a robust Bayesian adjustment analysis. AB - Aim: The aim of this study was to investigate the impact of diabetes and hypertension on colorectal cancer (CRC) mortality. Background: One of the methodology in epidemiological studies is to use self-report questionnaires to gather data, this is the easiest and cheapest method but involves with misclassification bias. We use robust Bayesian adjustment to correct this bias. Methods: One of the methodology in epidemiological studies is to use self-report questionnaires to gather data, this is the easiest and cheapest method but involves with misclassification bias. We use robust Bayesian adjustment to correct this bias. Results: The effect size with ignorance misclassification bias was 0.78 for diabetes and 0.94 for hypertension respectively which both of them were not significant. After adjusting the misclassification and performing the robust Bayesian analysis, we arrived at region (0.27, 3.4) for OR of diabetes and (0.21, 2.31) for hypertension. Conclusion: our study demonstrated that diabetes and hypertension increase the risk of mortality in CRC patients, using robust Bayesian analysis and misclassification in diagnosis these two exposure could change or confound the results of this association. PMID- 29511472 TI - Single Nucleotide Polymorphism (A870G) of the CCND1 gene: association with colorectal cancer susceptibility. AB - Aim: The aim of this study is to demonstrate the role of CCND1 gene polymorphism, A870G, in susceptibility to sporadic colorectal cancer in Iranian population. Background: It has been distinguished that CCND1 gene is one of the main genes in Wnt signaling pathway which involves in generating colorectal cancer. Nonetheless, there is no consistent result in terms of association between the genetic variations of this gene and colorectal cancer risk. Methods: We designed a case-control study consisting of 100 subjects with colorectal cancer (CRC) and 100 healthy controls to investigate the effect of A870G polymorphism on CRC susceptibility in an Iranian population. Genotype determination was performed by PCR-RFLP method. Results: The frequency of GG, AG and AA genotypes for cases were 24%, 51% and 25% respectively, while the genotype frequency for controls were 21%, 50% and 29% respectively. It was identified that there is no significant association between A870G polymorphism and risk of CRC, even after adjusting sex, age and smoking status variables (P = 0.777; OR=1.32 95% CI: 0.6-2.93).. Conclusion: Despite the well-known role of CCND1 gene in cell cycle regulation, our results revealed that A870G polymorphism could not be a potential predisposing risk factor in genetic susceptibility to CRC, at least in the studied population. PMID- 29511473 TI - Bayesian correction model for over-estimation and under-estimation of liver cancer incidence in Iranian neighboring provinces. AB - Aim: The aim of this study was to obtain more accurate estimates of the liver cancer incidence rate after correcting for misclassification error in cancer registry across Iranian provinces. Background: Nowadays having a thorough knowledge of geographic distribution of disease incidence has become essential for identifying the influential factors on cancer incidence. Methods: Data of liver cancer incidence was extracted from Iranian annual of national cancer registration report 2008. Expected coverage of cancer cases for each province was calculated. Patients of each province that had covered fewer cancer cases than 100% of its expectation, were supposed to be registered at an adjacent province which had observed more cancer cases than 100% of its expected coverage. For estimating the rate of misclassification in registering cancer incidence, a Bayesian method was implemented. Beta distribution was considered for misclassified parameter since its expectation converges to the misclassification rate. Parameters of beta distribution were selected based on the expected coverage of cancer cases in each province. After obtaining the misclassification rate, the incidence rates were re-estimated. Results: There was misclassification error in registering new cancer cases across the provinces of Iran. Provinces with more medical facilities such as Tehran which is the capital of the country, Mazandaran in north of the Iran, East Azerbaijan in north-west, Razavi Khorasan in north-east, Isfahan in central part, and Fars and Khozestan in south of Iran had significantly higher rates of liver cancer than their neighboring provinces. On the other hand, their neighboring provinces with low medical facilities such as Ardebil, West Azerbaijan, Golestan, South and north Khorasans, Qazvin, Markazi, Arak, Sistan & balouchestan, Kigilouye & boyerahmad, Bushehr, Ilam and Hormozgan, had observed fewer cancer cases than their expectation. Conclusion: Accounting and correcting the regional misclassification are necessary for identifying high risk areas of the country and effective policy making to cope with cancer. PMID- 29511474 TI - Identification of differentially-expressed of Olfactomedin-related proteins 4 and COL11A1 in Iranian patients with intestinal gastric cancer. AB - Aim: Due to limited information on these genes and to a better understanding of common biomarkers associated with cancer of the digestive tract routes, we aim to evaluated expression level of Olfactomedin4 (OLFM4) and (pro)collagen11A1/COL11A1 genes in people with gastric cancer in Iran. Background: Gastric cancer is one of the main cause of cancer death. The early prognosis of gastric cancer is still a matter of debate. Human olfactomedin4 (OLFM4) is a glycoprotein that generally known as the antiapoptotic protein. (pro) collagen11A1/COL11A1 codes for the alpha-1 subunit of type XI collagen which exists in extracellular minor fibrillar collagen. In most cases, OLFM4 and COL11A1 are found to be up-regulated in many types of human cancers including gastric cancer. Methods: 35 tissue samples were collected including 25 sample of patients with intestinal gastric cancer and 10 healthy controls. Expression level of OLFM4 and COL11A1 genes identified by using RGQ software. For analysis of real time-PCR products, Rotor-Gene Q series software was used. Results: Our finding showed that expression level of OLFM4 was significantly upregulated and COL11A1 did not show any significant difference in expression level in Iranian population with gastric cancer samples compared with those in normal samples. Conclusion: The results recommend that expression profiling of OLFM4 can be used for diagnosis of gastric cancer, and OLFM4 seems to be used as a biomarker for the diagnosis of gastric cancer. Regarding to our result, unlike some studies, COL11A1 did not show any significant difference between normal and tumor tissue which could explain ethological role in distribution of gastric cancer. PMID- 29511475 TI - Occurrence of Helicobacter pylori and its major virulence genotypes in dental plaque samples of patients with chronic periodontitis in Iran. AB - Aim: This study was aimed to investigate the presence of H. pylori and its virulence genotypes in dental plaques of Iranian patients with chronic periodontitis. Background: Helicobacter pylori is a Gram-negative bacterium that is associated with atrophic gastritis, peptic ulcer, and gastric cancer. Several studies have detected this bacterium in the oral cavity, suggesting it as a potential reservoir. Methods: A hundred individuals were divided in 2 groups: 50 patients with chronic periodontitis (case group), and 50 subjects in non periodontitis (control group). Supragingival and subgingival plaque samples were collected from the individuals using wood wedges and sterile paper points respectively, and prepared for PCR analysis. Results: Totally, H. pylori DNA was detected in 5 out of 100 (5%) dental plaques. Of 5 dental plaques positive for H. pylori, cagA gene was detected in 4 specimen, 3 in periodontitis group and one in non-periodontitis group. The H. pylori vacA s1m1 genotype was predominantly detected in 2/5 samples. The babA2 gene was detected in all (5/5) H. pylori positive dental plaques. There was no significant correlation between the presence of H. pylori genotypes from dental plaques and chronic periodontitis (P > 0.05). Conclusion: Our results revealed that the rate of H. pylori is very low in the dental plaques of Iranian patients with chronic periodontitis. Majority of H. pylori strains from oral cavity were highly virulent based on the main clinically virulence factors they carried. PMID- 29511476 TI - Evaluation of IL-17B and IL-17F mRNA expression in peripheral blood mononuclear cells and association with clinical outcome of IBD patients. AB - Aim: In this study, we determined the gene expression analysis of IL-17 gene family for early detection of subclinical inflammation among IBD patients. Background: Cytokines have a vital role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-17 is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17F is mainly involved in mucosal host defense mechanisms whereas the functions of IL-17B remain largely elusive. Methods: In this cross-sectional study, IBD patients divided into two active and inactive groups. Peripheral blood mononuclear cells (PBMCs) from 38 IBD patients which 20 inactive samples and 18 active individuals were collected. Changes of IL 17 F and IL-17B mRNA expression level evaluated by quantitative-real time-PCR. Results: mRNA expression level of IL-17B and IL-17F in CD, UC, active and inactive groups have been assessed and there were no significant differences (P>0.05). Patients were classified into five different categories as follows: i) 5ASA; ii) 5ASA + Pred; iii) 5ASA + AZA; iv) 5ASA + Pred + AZA; v) 5ASA + Pred + AZA + IFX according to medication usage, expression of IL-17F and IL-17B had no differences (p>0.05). Conclusion: Evaluation of IL-17B and IL-17F mRNA expression level illustrate no difference among active and inactive patients. Therefore, IL 17B and IL-17F are not biomarkers in an Iranian IBD patients. PMID- 29511477 TI - Pancreatic adenocarcinoma protein-protein interaction network analysis. AB - Aim: Gene assessment of pancreatic adenocarcinoma disease via protein-protein interaction (PPI) Network Analysis. Background: Diagnosis, especially early detection of pancreatic adenocarcinoma as a lethal disease implies more investigation. PPI Network Analysis is a suitable tool to discover new aspects of molecular mechanism of diseases. Methods: In the present study the related genes to pancreatic adenocarcinoma are studied in the interactome unit and the key genes are highlighted. The significant clusters were introduced by Cluster-ONE application of Cytoscape software 3.4.0. The genes are retrieved from STRING date base and analyzed by Cytoscape software. The crucial genes based on analysis of central parameters were determined and enriched by ClueGO v2.3.5 via gene ontology. Results: The number of 24 key genes among 794 initial genes were highlighted as crucial nodes in relationship with pancreatic adenocarcinoma. All of the key genes were organized in a cluster including 216 nodes. The main related pathways and cancer diseases were determined. Conclusion: It was concluded that the introduced 24 genes are possible biomarker panel of pancreatic adenocarcinoma. PMID- 29511479 TI - Study of prevalence, distribution and clinical significance of Blastocystis isolated from two medical centers in Iran. AB - Aim: This study aimed to survey prevalence and clinical significance of Blastocystis among symptomatic and asymptomatic groups. Background: Blastocystis is a prevalent microorganism that is found in intestine of human and majority of animals. However, most studies have failed to establish correlation between the presence of the parasite and clinical manifestations. Methods: from Dec 2016 to Jun 2017, 554 stool samples were collected from symptomatic and asymptomatic subjects referred to Imam Hossein Hospital and Gastroenterology and Liver Diseases Research Institute, Tehran, Iran. All samples were concentrated using conventional formalin-ethyl acetate concentration and then were microscopically examined using Lugol's iodine staining and light microscope. The fresh stool samples were also cultivated in DMEM medium and were examined for growth of Blastocystis every 48 hours with direct smear slides for 10 days. Results: Blastocystis was observed among 93 (16.8%) of stool samples cultivated in DMEM. The findings represented that 64/398 (16.08%) and 29/156 (18.58%) of asymptomatic and symptomatic patients were infected with Blastocystis, respectively. In addition, there was no significant correlation between presence of symptoms and carrying Blastocystis (P=0.528), although statistically significant association was observed between presence of urticaria and carrying Blastocystis (P<0.05). Furthermore, a statistically significant correlation between observing the parasite and different age groups was seen (P<0.05). Conclusion: Blastocystis is a prevalent parasitic eukaryote among symptomatic and asymptomatic populations despite the higher prevalence among symptomatic group that suggests the chance of infection with Blastocystis raises with age. PMID- 29511478 TI - Common and differential genetically pathways between ulcerative colitis and colon adenocarcinoma. AB - Aim: In the present study, genes of Ulcerative Colitis and Colon Adenocarcinoma (COAC) were extracted by string App in Cytoscape software version 3.5.1. Then protein- protein interaction (PPI) networks analyzed. Background: One of the most common chronic digestive problems is ulcerative colitis (UC) especially in developing countries. Prevalence of the disease is reported about 7.6 to 245 cases per 100,000 per year. UC can lead to colon cancer that is the third malignancy related death in the world. So awareness of the future of the patient with UC and the possibility of colon cancer is a very helpful approach. Methods: The analysis was based on centralities values. The goal is determining common gene pathways and differential gene pathways of the two diseases. Results: Results showed there are 11 and 29 central genes related to COAC and UC respectively. At least five common key genes between the two diseases were introduced. The number of 26 terms related to the common key genes were determined and clustered in seven clusters. Conclusion: ALB, AKT1, TP53, SRC and MYC are the common genes that play crucial roles in the related biological processes of UC and COAC. Besides introducing the common genes the differentiate genes related to the two diseases were proposed. PMID- 29511480 TI - ATP binding cassette and cholecystokinin A receptor genetic variations in gallstone susceptibility. AB - Aim: It was aimed to assess the association of four polymorphisms and relative haplotypes in the ATP binding cassettes and cholecystokinin A receptor (rs6720173, rs11887534, rs4148217, rs1800857) with the risk of gallstone. Background: Gallstone is a multifactorial disease. Besides high penetrance genes, low or moderate penetrance polymorphisms may increase susceptibility to gallstone. Methods: 200 gallstone patients and 251 healthy controls were analyzed in a case-control association model. Genotyping was carried out by restriction fragment length polymorphism. Randomly 10% of samples underwent for direct sequencing to confirm results. Results: Heterozygote variant of rs11887534 demonstrated protective effect on the risk of gallstone susceptibility in males (P=0.013; OR=0.125; CI95%=0.048-0.325). In contrast, C/C genotype associated with gallstone susceptibility in females (P=0.004; OR=5.555 CI95%=1.975-10.632). Moreover, rs1800857 showed association only in females (P=0.019; OR=0.283; CI95%=0.099-0.811). Haplotype analysis for rs1800857 showed GC, CC and CA association with gallstone. Conclusion: The most imperative polymorphisms of contributing genes to gallstone were analyzed in this study and rs11887534 and rs1800857 appeared to be associated with gallstone, which is expected to be further verified in a larger cohort in the future. PMID- 29511481 TI - Evaluation of promoter methylation status of MLH1 gene in Iranian patients with colorectal tumors and adenoma polyps. AB - Aim: The aim of this study was to evaluate the methylation status of the promoter region of MLH1 gene in colorectal cancer (CRC) and its precursor lesions as well as elucidate its association with various clinicopathological characteristics among Iranian population. Background: Epigenetic silencing of mismatch repair genes, such as MLH1, by methylation of CpG islands of their promoter region has been proved to be an important mechanism in colorectal carcinogenesis. Methods: Fifty colorectal cancer and polyp tissue samples including 13 Primary colorectal tumor and 37 Adenoma polyp samples were enrolled in this study. Methylation specific polymerase chain reaction (MSP) was performed to find the frequency of MLH1 Promoter Methylation. Results: Promoter methylation of MLH1 gene was detected in 5 out of 13 tumor tissues and 4 out of 37 adenoma polyp. The frequency of MLH1 methylation in tumor samples was significantly higher compared to that in polyp tissues (P= 0.026). No significant association was observed between MLH1 promoter methylation and clinicopathological characteristics of the patients. Conclusion: The frequency of MLH1 promoter methylation in CRC and colon polyp was 18%. Our findings indicated that methylation of MLH1 promoter region alone cannot be considered as a biomarker for early detection of CRC. PMID- 29511482 TI - Development of experimental fibrotic liver diseases animal model by Carbon Tetracholoride. AB - Aim: This study is presenting an effective method of inducing liver fibrosis by CCL4 as a toxin in two different breeds of rat models. Background: Liver fibrosis is a result of inflammation and liver injury caused by wound healing responses which ultimately lead to liver failure. Consequently, after liver fibrosis, the progression will be continued to liver cirrhosis and at the end stage hepatocellular carcinoma (HCC). Many studies have demonstrated that one of the most important causes of liver fibrosis is Non-alcoholic steatohepatitis (NASH). Fibrotic Liver is affected by an excessive accumulation of extracellular matrix (ECM) proteins like collagen and alpha-SMA. Methods: In two different experiments, male Vistar, and Sprague Dawley Rat models ranging from 200+/-60, corresponding to an age of approximately 10 weeks were utilized in order to induce CCL4 treated liver fibrosis. Results: After 6 weeks of CCL4 injection, different tests have been carried out to verify the liver fibrosis including serum markers such as Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT), molecular tests containing, laminin and alpha-SMA and also pathological observation by Hematoxylin and eosin staining in both fibrosis and control group. Conclusion: The results of Pathology and Real-time PCR showed that fibrosis was induced much more effectively in Sprague Dawley rat model compared with Wistar rats. PMID- 29511483 TI - Evaluation of involved proteins in colon adenocarcinoma: an interactome analysis. AB - Aim: Assessment of related genes to colon cancer to introduce crucial ones, was the aim of this research. Background: Colon cancer is one of the invasive colorectal diseases. This disease is preventable and manageable if it be diagnosed in early stage. The aggressive tools for its detection imply more investigation for new molecular diagnostic methods. Methods: Numbers of 300 genes from String database (SD) are analyzed via constructed Protein-protein interaction (PPI) network by Cytoscape software 3.4.0. Based on centrality parameters the main connected component of network was analyzed and the crucial genes were introduced. Cluster analysis of the network and gene ontology for the nodes of the main cluster revealed more details about the role of the key proteins related to colon cancer disease. Results: The constructed network was consisted of 300 genes which among them 68 genes were isolated and the 232 other genes formed the main connected component. Ten crucial genes related to colon adenocarcinoma were introduced that presented in cluster 1. Gene ontology analysis showed that cluster 1 is involved in 226 biological processes which are classified in 25 groups. Conclusion: In conclusion, results indicate that the identified key proteins play significant roles in colon adenocarcinoma. It may be possible to introduce a few diagnostic biomarker candidates for colon cancer disease. PMID- 29511484 TI - Protein profiling of infected human gastric epithelial cells with an Iranian Helicobacter pylori clinical isolate. AB - Aim: The main objective of this study was to use high throughput approach to characterize the response of human gastric epithelial cells to Helicobacter pylori (H. pylori) infection at protein level. Background: Alteration of host cell protein profiles occurs due to H.pylori infection. This alteration seems to be strain specific. High throughput approaches, such as proteomics, can describe changes that occurs at the protein levelin the infected cells in response to H.pylori infection. In accordance with this point of view, we used two dimensional electrophoresis (2-DE)/MS to determine changes in proteome profile of gastric epithelial cells infected with a clinical isolate of H. pylori from an Iranian patient. Methods: Human gastric epithelial cells (AGS) were infected by an Iranian H.pylori isolate (complete cagPAI, vacA s2m2, babA2, iceA1, sabA). The altered protein patterns separated by 2-DE were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis. Results: The results showed 40 spots with significantly different intensities between the 2-DE gels. Protein SETSIP and Endoplasmic reticulum resident protein 29 were identified by MALD-TOF and Mascot search. Proteomic analysis for functional roles of these proteins showed that mechanisms to deal with stress conditions and transcriptional activator related to cell reprogramming are involved in H. pylori infection. Conclusion: Using high throughput approaches, such as proteomics, we can provide further molecular details about interaction of H. pylori strains with the infected cells at protein level. PMID- 29511485 TI - Protein interaction mapping interpretation of none alcoholic fatty liver disease model of rats after fat diet feeding. AB - Aim: This study investigates the effect of fat diet on gene expression profile in rat liver via protein-protein interaction mapping analysis. Background: Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition of liver in the world. This progressive metabolic disease is representative with fat accumulation in the patients' liver that can led to advance stages, namely, cirrhosis and eventually cancer. Methods: Differentially expressed genes of NAFLD rat liver after 2, 4 and 6 weeks fat diet feeding were analyzed via GEO2R and protein protein interaction network by Cytoscape v3.6.0. and the related plug-ins. The important genes were assigned based on degree and betweenness centrality analysis and enriched using ClueGO+CluePedia Plug-in. Results: GAPDH, PRDM10, TP53, AKT1, INS, ALB, SRC, MAPK1, ACLY, ACACA, DECR1, ACACB, MBOAT4, TNF, EHHADH and JUN genes were introduced as key genes related to the fat diet fed NAFLD rats. Fatty acid biosynthesis and four other terms were introduced as the main related ones to the essential genes. Conclusion: The introduced critical genes and the related terms may describe NAFLD molecular condition and its progression to the other severe metabolic diseases. Moreover, these potential biomarkers may be monitored for diagnosis and treatment approaches after validation investigations. PMID- 29511486 TI - Interleukin-21 rs2055979 and Interleukin-21 receptor rs3093390 genetic variants and hepatitis C virus chronic infection. AB - Aim: The aim of this case-control study was to investigate association of G/T IL 21 (rs2055979) and C/T IL-21R (rs3093390) gene polymorphisms with chronic hepatitis C virus in Iranian Patients. Background: Interleukin 21 (IL-21) has a significant function in the regulation of cellular immune responses. Its exclusive receptor, IL-21R, expressed on the surface of T, B and NK cells and is important for the proliferation and differentiation of these immune cells. Hence, it was suggested to be involved in response to viral infections. Methods: This study follows a case-control study design and blood samples were collected from 290 patients with chronic HCV and 290 controls for both genes. Genomic DNA was extracted and then for each position, SNP was genotyped by the dedicated PCR and restriction fragment length polymorphism (RFLP) method. The results were analyzed by SPSS software using logistic regression and Chi-square tests. Results: Genotype frequencies of GG, GT and TT in IL21 gene (rs3093390) were found to be 27.6%, 48.3%, 24.1% and 25.2%, 55,5%, 19,3% respectively in HCV infected patients and control group. For IL21R gene (rs2055979) genotype frequencies of CC, CT and TT were 63.8%, 31.4%, 4.8% and 61.4%, 29.7%, 9.0% respectively in HCV infected patients and control group. P values for genotype and allele frequencies were p=0.188, p=0.769 for IL21 gene, and p=0.144, p=0.179 for IL21R gene respectively. Conclusion: As a result, there is no evidence for an association between IL-21 (rs2055979) and IL-21R (rs3093390) gene polymorphisms with chronic hepatitis C virus in Iranian Patients. PMID- 29511487 TI - Eosinophilic gastroenteritis; a report of two cases with different presentations. AB - Eosinophilic gastroenteritis is a rare inflammatory disease, defined by infiltration of eosinophils in gastrointestinal (GI) tract, but the etiology of this disorder is unknown. Depends on the involvement region of Eosinophilic gastroenteritis, GI symptoms are variable including abdominal pain, malabsorption, gastric and duodenal ulcer. Due to its non-specific symptoms, the diagnosis is based on upper GI endoscopy followed by histopathological examination of the biopsies, which shows eosinophilic infiltration in different layers of GI tract. In this article we report two cases with gastrointestinal disorders. The first case was a 52-year-old man with a history of peripheral edema over the past 3 months and low level of serum albumin. All the necessary evaluations were done and increase number of eosinophils were found in duodenal biopsies. The second case was a 42-year-old man presented with a history of chronic diarrhea over the past two years. Main causes of diarrhea were ruled out and small intestine biopsies confirmed submucosal eosinophilic infiltration. Therefore, corticosteroid therapy was administered for both patients then they were followed for a year. During this time all of the symptoms were disappeared and they did not recur in the first year of follow up. PMID- 29511488 TI - Amelioration of carbon tetrachloride-induced hepatic injury by emulsified Antrodia extract. AB - Objectives: Antrodia cinnamomea (AC) is found with anti-inflammatory and immunomodulatory biological activities. In this study, we investigated the anti hepatitis effect of the emulsified AC extract from RO water or supercritical fluid CO2 with ethanol co-solvent extract methods of AC preparations. Materials and Methods: Five groups of eight to ten weeks male rats with a count of ten for each group were studied to evaluate the protection of two kinds of AC extract from hepatic injury. Acute liver injury of rats was induced by injecting 40% carbon tetrachloride (CCl4) 1 mg/kg intraperitoneally. Positive and negative control groups rats were perfused with CCl4 or isotonic saline, respectively. Experimental groups received oral administration once/day of AC preparations before CCl4 treatment: water AC extract (WAE group), or emulsified AC extract from supercritical fluid extraction (EAE group) for 5 days, and sacrificed on the 6th day and the blood and liver samples were collected under chloral hydrate anesthesia. The anti-inflammatory, antioxidant markers, and relevant signaling pathways were measured (AST, ALT, ROS, IL-1, IL-6, NO, and COX-2, MAPKs, and caspase-3). Results: EAE at 50 mg/kg significantly decreased the serum AST, ALT, IL-1, IL-6, NO, and ROS levels. Both extracts reduced the activation of p-ERK in the liver samples, but EAE inhibited COX-2 and caspase-3 protein expression better than WAE. The EAE ameliorated CCl4-induced hepatic injury significantly; as compared with WAE and the positive control. Conclusion: The hepatoprotection of EAE could be attributed to the antioxidant and anti-inflammatory effects of Antrodia. PMID- 29511489 TI - The effect of bone marrow mesenchymal stem cells on recovery of skeletal muscle after neurotization surgery in rat. AB - Objectives: When the nerve is injured near its entrance to the muscle belly, we cannot perform conventional methods. One useful method in such a situation is neurotization surgery. In this study, Bone marrow mesenchymal stem cells (BMSCs) implanted into the paralyzed muscle after neurotization surgery. These cells can stimulate axon growth and motor endplate formation, also prevent muscle atrophy. Materials and Methods: Thirty-six adult male Sprague-Dawley rats were randomized into six groups: intact group, sham surgery group, control group, DMEM group, cell+DMEM group, denervated group. The motor nerve of the lateral head of gastrocnemius muscle was cut, and the proximal portion of the severed nerve was transplanted to the proximal third of the muscle paralysis. BMSCs with/or DMEM was injected into the site of injury. All animals were evaluated by withdrawal reflex latency (WRL), electromyography, muscle weight, histology and immunohistochemistry. Results: The WRL difference between the control and cell+DMEM groups at weeks 4 and 12 post-operation was statistically significant (P<0.05). The mean number of motor end plates in cell+DMEM group was more than control group (P<0.05). At 12 weeks post-operation, the difference of the mean nerve conduction velocity (NCV) between cell treated group and sham surgery groups were not statistically significant (P>0.05). In weeks 4 and 12 post operation, the mean fiber diameters in cell+DMEM group were more than control group (P<0.05). Conclusion: The results of this study demonstrate that transplantation of BMSCs after neurotization surgery, prevent muscle atrophy and improve muscle function. PMID- 29511490 TI - Chronic intermittent hypobaric hypoxia attenuates monocrotaline-induced pulmonary arterial hypertension via modulating inflammation and suppressing NF-kappaB/p38 pathway. AB - Objectives: Inflammation is involved in various forms of pulmonary arterial hypertension (PAH). Although the pathophysiology of PAH remains uncertain, NF kappaB and p38 mitogen-activated protein kinase (p38 MAPK) has been reported to be associated with many inflammatory mediators of PAH. This study aimed to evaluate the effect of chronic intermittent hypobaric hypoxia (CIHH) on pulmonary inflammation and remodeling in monocrotaline (MCT) induced PAH in rats. Materials and Methods: An in vivo model of PAH induced by MCT was employed. Statistical analyses were done using one-way analysis of variance (ANOVA) or Fisher's LSD test for multiple comparisons. Results: Four weeks of CIHH exposure following MCT injection resulted in significant reduction of mean pulmonary artery pressure (mPAP) level and improvement of right ventricular hypertrophy (RVH). Morphometric analyses showed decreased wall thickness of pulmonary arterioles in MCT+CIHH treated rats. These findings are consistent with the decrease in Ki-67 immunostaining. Following CIHH treatments, apoptotic analysis showed a consistent decrease in T lymphocytes together with lower levels of CD4+ T cell subset as measured in spleen and blood samples. Furthermore, CIHH treatment resulted in markedly reduced expression of TNF-alpha and IL-6 via the inhibition of NF-kappaB and p38 MAPK activity in rat lungs. Conclusion: Altogether, these results provide new evidence relating to the mode of action of CIHH in the prevention of PAH induced by MCT. PMID- 29511491 TI - The cucurbitacins D, E, and I from Ecballium elaterium (L.) upregulate the LC3 gene and induce cell-cycle arrest in human gastric cancer cell line AGS. AB - Objectives: Cucurbitacins exhibit a range of anti-cancer functions. We investigated the effects of cucurbitacins D, E, and I purified from Ecballium elaterium (L.) A. Rich fruits on some apoptotic and autophagy genes in human gastric cancer cell line AGS. Materials and Methods: Using quantitative reverse transcription PCR (qRT-PCR), the expression of LC3, VEGF, BAX, caspase-3, and c MYC genes were quantified in AGS cells 24 hr after treatment with cucurbitacins D, E, and I at concentrations 0.3, 0.1 and 0.5 MUg/ml, respectively. Cell cycle and death were analyzed by flflowcytometry. Results: Purified cucurbitacins induced sub-G1 cell-cycle arrest and cell death in AGS cells and upregulated LC3mRNA effectively, but showed a very low effect on BAX, caspase-3, and c-MYC mRNA levels. Also after treatment with cucurbitacin I at concentration 0.5 MUg/ml, VEGF mRNA levels were increased about 4.4 times. Pairwise comparison of the effect of cucurbitacins D, E, and I on LC3 mRNA expression showed that the cucurbitacin I effect is 1.3 and 1.1 times that of cucurbitacins E and D, respectively; cucurbitacin D effect is 1.2 times that of cucurbitacin E (P-value <0.05). In silico analysis showed that among autophagy genes, LC3 has an important gastric cancer rank relation. Conclusion: Cucurbitacins D, E, and I purified from E. elaterium fruits upregulate LC3 and induce sub-G1 cell-cycle arrest and cell death in human gastric cancer cell line AGS. Cucurbitacin I effect on LC3 mRNA expression is significantly more than that of cucurbitacins E and D. PMID- 29511492 TI - Design of a humanized anti vascular endothelial growth factor nanobody and evaluation of its in vitro function. AB - Objectives: Nanobodies, the single domain antigen binding fragments of heavy chain-only antibodies occurring naturally in camelid sera, are the smallest intact antigen binding entities. Their minimal size assists in reaching otherwise largely inaccessible regions of antigens. However, their camelid origin raises a possible concern of immunogenicity when used for human therapy. Humanization is a promising approach to overcome the problem. Materials and Methods: Here, we designed a humanized version of previously developed nanobody (anti vascular endothelial growth factor nanobody), evaluated and compared its predicted 3D structure, affinity and biological activity with its original wild type nanobody. Results: Our in silico results revealed an identical 3D structure of the humanized nanobody as compare to original nanobody. In vitro studies also demonstrated that the humanization had no significant visible effect on the nanobody affinity or on its biological activity. Conclusion: The humanized nanobody could be developed and proposed as a promising lead to target pathologic angiogenesis. PMID- 29511493 TI - Protective effect of scutellarin on myocardial infarction induced by isoprenaline in rats. AB - Objectives: Scutellarin (Scu) is the main effective constituent of Erigeron breviscapus which has anti-oxidant, anti-apoptotic, anti-inflammatory and other therapeutic properties. The purpose of this study was to investigate the protective effect of Scu on myocardial infarction (MI) induced by isoprenaline (ISO). Materials and Methods: The rats were subcutaneously injected with ISO (45 mg/kg) on the first day, then single tail-intravenously injected with different doses of Scu (10 mg/kg, 20 mg/kg, 40 mg/kg) for 7 consecutive days. The protective effect of Scu on ISO-induced MI was evaluated by measuring markers of heart injury in serum, levels of lipid peroxidation, and antioxidants in heart tissue, observing pathological changes of tissue, and detecting quantified expression of apoptotic-related family members and inflammation. Results: Compared with the model group, the concentration of troponin T (CTn-T) and troponin I (CTn-I), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the serum all decreased in the Scu high dose group. The activities of superoxide dismutase (SOD), catalase (CAT), and the content of reduced glutathione (GSH) in heart increased, and the content of malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) decreased. In addition, the histopathologic aspects showed that pathological heart change was found in the model group, and was reduced to varying degrees in the Scu group. Moreover, the expression of Bax, P53, Caspase3, Caspase9, cytochrome C, NGAL, NFkappaB, IL 1beta and IL-6 in the heart decreased, while the expression of Bcl2 increased. Conclusion: Scu could reduce the degree of MI induced by ISO by improving the antioxidant, anti-apoptotic, and anti-inflammatory capacities of the body. PMID- 29511494 TI - MiR-9-5p and miR-106a-5p dysregulated in CD4+ T-cells of multiple sclerosis patients and targeted essential factors of T helper17/regulatory T-cells differentiation. AB - Objectives: Multiple sclerosis (MS) is considered as a chronic type of an inflammatory disease characterized by loss of myelin of CNS. Recent evidence indicates that Interleukin 17 (IL-17)-producing T helper cells (Th17 cells) population are increased and regulatory T cells (Treg cells) are decreased in MS. Despite extensive research in understanding the mechanism of Th17 and Treg differentiation, the role of microRNAs in MS is not completely understood. Thereby, as a step closer, we analyzed the expression profile of miR-9-5p and miR 106a-5p, and protein level of retinoic acid receptor (RAR)-related orphan receptor C (RORC; Th17 master transcription factor) as direct target of miR-106a 5p and forkhead box P3 (FOXP3; Treg master transcription factor) as indirect target of miR-9-5p in CD4+ T cells in two groups of relapsing and remitting in our relapsing-remitting MS (RR-MS) patients. Materials and Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to assess the expression of miRNAs and mRNAs, in 40 RR-MS patients and 11 healthy individuals. Thus, FOXP3 and RAR-related orphan receptor gammat (RORgammat) was assessed in CD4+T-cells by flow cytometry. We also investigated the role of these miRNAs in Th17/Treg differentiation pathway through bioinformatics tools. Results: An up-regulation of miR-9-5p and down-regulation of miR-106a-5p in relapsing phase of MS patients were observed compared to healthy controls. RORC and FOXP3 were up-regulated in relapsing and remitting phases of MS, respectively. Conclusion: Expression pattern of miR-9-5p and miR-106a-5p and their targets suggest a possible inducing role of miR-9-5p and suppressing role of miR-106a-5p in differentiation pathway of Th17 cells during MS pathogenesis. PMID- 29511495 TI - Immunogenicity of enterotoxigenic Escherichia coli outer membrane vesicles encapsulated in chitosan nanoparticles. AB - Objectives: Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrheal disease in humans, particularly in children under 5 years and travelers in developing countries.To our knowledge, no vaccine is licensed yet to protect against ETEC infection. Like many Gram-negative pathogens, ETEC can secrete outer membrane vesicles (OMVs). These structures contain various immunogenic virulence proteins such as LT and therefore can be used as vaccine candidates. In this study we attempted to isolate the OMVs of ETEC cultivated at different temperatures and evaluate their immunogenicity and protective efficacy in a murine model of infection. Materials and Methods: OMVs was purified from bacterial supernatant by ultracentrifugation. OMVs were encapsulated in chitosan nanoparticles prepared by ionic gelation method within a layer of Eudragit L100 for oral delivery. Female BALB/c mice of 9 weeks' old were immunized by parenteral injection and oral administration with free and encapsulated OMVs obtained from bacteria cultivated at 37 degrees C and 42 degrees C. The serum samples were collected and the antibody titers were measured by an enzyme-linked immunosorbent assay (ELISA). Results: The protein concentrations of OMVs were 3.47 mg/ml and 2.46 mg/ml for bacteria grown at 37 degrees C and 42 degrees C respectively. OMVs loaded into nanoparticles (NP-OMVs) were homogeneous and spherical in shape, with a size of 532 nm. The encapsulation efficiency of NP was 90%. Mice immunized with OMVs, inhibited the ETEC colonization in their small intestine and induced production of antibodies against LT toxin. Conclusion: The results obtained in this research place OMVs among promising candidates to be used for vaccination. PMID- 29511496 TI - MiR-103 alleviates autophagy and apoptosis by regulating SOX2 in LPS-injured PC12 cells and SCI rats. AB - Objectives: Recent studies revealed that microRNAs (miRNAs) may play crucial roles in the responses and pathologic processes of spinal cord injury (SCI). This study aimed to investigate the effect and the molecular basis of miR-103 on LPS induced injuries in PC12 cells in vitro and SCI rats in vivo. Materials and Methods: PC12 cells were exposed to LPS to induce cell injuries to mimic the in vitro model of SCI. The expression of miR-103 and SOX2 in PC12 cells were altered by transient transfections. Cell viability and apoptotic cell rate were measured by CCK-8 assay and flow cytometry assay. Furthermore, Western blot analysis was performed to detect the expression levels of apoptosis- and autophagy- related proteins, MAPK/ERK pathway- and JAK/STAT pathway-related proteins. In addition, we also assessed the effect of miR-103 agomir on SCI rats. Results: LPS exposure induced cell injuries in PC12 cells. miR-103 overexpression significantly increased cell viability, reduced cell apoptosis and autophagy, and opposite results were observed in miR-103 inhibition. miR-103 attenuated LPS-induced injuries by indirect upregulation of SOX2. SOX2 overexpression protected PC12 cells against LPS-induced injuries, while SOX2 inhibition expedited LPS-induced cell injuries. Furthermore, miR-103 overexpression inhibited MAPK/ERK pathway and JAK/STAT pathway through upregulation of SOX2. We also found that miR-103 agomir inhibited cell apoptosis and autophagy in SCI rats. Conclusion: This study demonstrates that miR-103 may represent a protective effect against cell apoptosis and autophagy in LPS-injured PC12 cells and SCI rats by upregulation of SOX2 expression. PMID- 29511497 TI - Role of melatonin receptors in the effect of estrogen on brain edema, intracranial pressure and expression of aquaporin 4 after traumatic brain injury. AB - Objectives: Traumatic brain injury (TBI) is one of the most common causes of death and disability in modern societies. The role of steroids and melatonin is recognized as a neuroprotective factor in traumatic injuries. This study examined the role of melatonin receptors in the neuroprotective effects of estrogen. Materials and Methods: Seventy female ovariectomized Wistar rats were divided into five groups and two subgroups. All animals underwent brain trauma. The groups were as follow: 1) trauma, 2) melatonin receptor antagonist vehicle + estrogen, 3) MT1 melatonin receptor antagonist + estrogen, 4) MT2 melatonin receptor antagonist+ estrogen, 5) MT3 melatonin receptor antagonist+ estrogen. Brain edema (24 hr), intracranial pressure (ICP) (-1, 0, 1, 4 and 24 hr) and blood-brain barrier (BBB) permeability (5 hr) and aquaporin (AQP4) expression (24 hr) were evaluated after TBI. Results: MT1, MT2 and MT3 melatonin receptors had anti-edema effects while MT1 and MT2 have a role in protecting BBB by estrogen. Furthermore, the activity of MT3 and MT2 melatonin receptors weakened the effect of estrogen on ICP. However, melatonin receptors had no role in the effect of estrogen on AQP4 protein. Conclusion: Based on the above results, it seems that melatonin receptors appear to influence the effect of estrogen in TBI without altering AQP4 expression. The role of the receptors is different in this interaction. PMID- 29511498 TI - The inhibitory effects of 20(R)-ginsenoside Rg3 on the proliferation, angiogenesis, and collagen synthesis of hypertrophic scar derived fibroblasts in vitro. AB - Objectives: Therapeutic effect of many selectable methods applied in clinical practice for treating hypertrophic scar (HS) is not still so satisfactory. Meanwhile, a few medicines may lead to several undesirable complications. The traditional Chinese medicine, Rg3, has been reported for multiple antitumor effects previously. We have conducted series of animal experiments and confirmed the inhibitory effect of Rg3 in HS before. The aim of this study was to further verify the conclusions of previous studies and reveal the specific functional mechanisms of Rg3. Materials and Methods: The HS specimens were obtained from the patients aged from 15 to 36 years without systemic diseases and the primary cultured cells were isolated from the scar tissue and expanded in vitro. In every experiment, hypertrophic scar fibroblasts (HSFs) were divided into three groups and respectively cultured in medium with or without different Rg3 concentrations (50, 100 MUg/ml). Cell viability assay, flow cytometry analysis (FCM), quantitative PCR, cell migration assay, immunofluorescence staining, western blot and ELISA were employed. Results: The outcomes demonstrated that Rg3 could suppress cell proliferation, vascularization and extracellular matrix (ECM) deposition of HSFs in vitro by TGF-beta/SMAD and Erk signaling pathways. Significant statistical differences were between control group and Rg3-treated groups (P<0.05). Conclusion: This study provides sufficient in vitro evidences for Rg3 as a promising drug in the treatment of human HS. PMID- 29511499 TI - MiR-103 regulates the angiogenesis of ischemic stroke rats by targeting vascular endothelial growth factor (VEGF). AB - Objectives: To investigate the effect of miR-103 on the angiogenesis of ischemic stroke rats via targeting vascular endothelial growth factor (VEGF) at the molecular level. Materials and Methods: Rat models had received the middle cerebral artery occlusion (MCAO) or sham operation before grouping, and cell models of oxygen-glucose deprivation (OGD) were performed. FITC-dextran, matrigel, and Trans-well assays were used to evaluate the vascular density, tube formation, and cell migration respectively. The expression levels of miR-103 and VEGF were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Dual-luciferase assay was used for analyzing the targeting relationship between miR-103 and VEGF. Results: We found the reduced miR-103 in rats after MCAO. Down-regulating miR-103 with the miR-103 inhibitor enhanced VEGF, ameliorated the neurological scores, decreased infarct volume, and increased vascular density in rats after MCAO. Besides, in OGD human umbilical vein endothelial cells (HUVECs), inhibition of miR-103 could promote the increase of tube length and the migration of cells. Additionally, we found that miR-103 could directly target VEGF and thereby lead to the down-expression of VEGF. Meanwhile, si-VEGF could reverse the effect of miR-103 inhibitor on angiogenesis in rats subjected to MCAO. Conclusion: Inhibition of miR-103 could promote ischemic stroke angiogenesis and reduce infarction volume via enhancing VEGF, which provides a new target for the clinical treatment of ischemic stroke. PMID- 29511500 TI - Bax/Bcl-2 expression ratio in prediction of response to breast cancer radiotherapy. AB - Objectives: Radiotherapy is one of the most effective modalities of cancer therapy, but clinical responses of individual patients varies considerably. To enhance treatment efficiency it is essential to implement an individual-based treatment. The aim of present study was to identify the mechanism of intrinsic apoptosis pathway on radiosensitivity and normal tissue complications caused by the radiotherapy. Materials and Methods: Peripheral blood mononuclear cells from ten breast cancer patients were exposed to 6MV X-rays to deliver 1 and 2 Gy. Expression levels of Bax, Bcl-2, and Bax/Bcl-2 ratio were examined by relative quantitative RT-PCR. All the patients received similar tangential irradiation of the whole breast and conventional fractionation. Skin dosimetry was done by GAFChromic EBT-3 film and clinical radiosensitivity was determined using the acute reactions to radiotherapy of the skin according to Radiation Therapy Oncology Group score. All statistical analyses were performed using GraphPad Prism, version 7.01. Results: In the in-vitro experiment, Bax and Bax/Bcl-2 ratios were significantly increased with 1 and 2 Gy doses (P<0.001 and P<0.0001, respectively). Herein, the notable result was a significant correlation between dose-response curve slope (as an in-vitro radiosensitivity index) and acute skin toxicity score following irradiation (as a clinical radiosensitivity index). There was no significant relationship between skin dose and reactions (P>0.05 for all patients). Conclusion: Significant correlation between Bax/Bcl-2 ratio determined before radiation therapy and clinical response in the patients, can be used as a biomarker to identify radiosensitive individuals. However, further studies are required to validate radiation-induced apoptotic biomarkers. PMID- 29511501 TI - The first case of NSHL by direct impression on EYA1 gene and identification of one novel mutation in MYO7A in the Iranian families. AB - Objectives: Targeted next-generation sequencing (NGS) provides a consequential opportunity to elucidate genetic factors in known diseases, particularly in profoundly heterogeneous disorders such as non-syndromic hearing loss (NSHL). Hearing impairments could be classified into syndromic and non-syndromic types. This study intended to assess the significance of mutations in these genes to the autosomal recessive/dominant non-syndromic genetic load among Iranian families. Materials and Methods: Two families were involved in this research and two patients were examined by targeted next-generation sequencing. Here we report two novel mutations in the MYO7A and EYA1 genes in two patients detected by targeted NGS. They were confirmed by Sanger sequencing and quantitative real-time PCR techniques. Results: In this investigation, we identified a novel mutation in MYO7A, c.3751G>C, p.A1251P, along with another previously identified mutation (c.1708C>T) in one of the cases. This mutation is located in the MYTH4 protein domain which is a pivotal domain for the myosin function. Another finding in this research was a novel de-novo deletion which deletes the entire EYA1 coding region (EX1-18 DEL). Mutations in EYA1 gene have been found in branchiootorenal (BOR) syndrome. Interestingly the patient with EYA1 deletion did not show any other additional clinical implications apart from HL. This finding might argue for the sole involvement of EYA1 function in the mechanism of hearing. Conclusion: This investigation exhibited that the novel mutations in MYO7A, c.3751G>C, p.A1251P, and EYA1, EX1-18 DEL, were associated with NSHL. Our research increased the mutation spectrum of hearing loss in the Iranian population. PMID- 29511502 TI - Anti-diabetic effects of Sargassum oligocystum on Streptozotocin-induced diabetic rat. AB - Objectives: Diabetes is a metabolic syndrome which is associated with the worldwide major public health problems. There are many natural compounds from the sea-market, as a valuable aquatic source, along with the variety of health and therapeutic benefits. In the present research, with respect to the traditional and ethnic uses of Sargassum oligocystum algae for healing of some diseases which have similar metabolic mechanism to the diabetes, its anti-diabetic effects in animal model was proposed. Materials and Methods: The animals (rat) were divided into the normal control, diabetic control, positive control and, the test groups. The test groups were gavaged with oral doses of 150 and 300 mg/kg of algae hydroalcoholic extracts. After 30 days of intervention the serum glucose, cholesterol, triglyceride, HDLC, LDLC, insulin, insulin resistance, beta-cells function and, the histopathology of pancreatic tissue were evaluated. Results: In animals that were fed with algae extracts a significant decrease in the fasting blood glucose, triglyceride and HOMA-IR and an increase in the HOMA-B with no significant impacts on the insulin, cholesterol and HDL were observed. Also, the histopathology evaluations in the groups which were treated with algae extract revealed the regeneration and reconstitution of damaged pancreatic beta-cells. Conclusion: The results give evidence that, the S. oligocystum algae extract has a healing effect on diabetes which can be considered as a new research prospect for the natural therapy of diabetes. PMID- 29511503 TI - New advances in the understanding and treatment of axial spondyloarthritis: from chance to choice. AB - Axial spondyloarthritis (axSpA) is a chronic inflammatory condition that encompasses ankylosing spondylitis (AS) as well as non-radiographic axial disease (nr-axSpA) and can lead to chronic pain, structural damage and disability. The introduction of tumour necrosis factor inhibitor (TNFi) drugs for AS heralded a new era of drug therapeutics for what was previously a largely untreatable disease. This has now been expanded with the licensing of secukinumab, an interleukin 17A (IL-17A) inhibitor for the treatment of AS. Although biologic disease modifying antirheumatic drugs (bDMARDs) are not a first line treatment option in AS or axSpA, they are highly effective following incomplete or no response to physiotherapy and non-steroidal anti-inflammatory drugs (NSAIDs). Current research strategies aim to test whether the desired treatment goal of disease remission may now be achievable with early and stratified use of bDMARDs in both AS and nr-axSpA. This review summarizes the current literature on axSpA including pathophysiology, treatment indications, radiographic progression and the evidence for new developments in the treatment of both AS and nr-axSpA. PMID- 29511504 TI - Spatial imaging of carbon reactivity centers in Pd/C catalytic systems. AB - Gaining insight into Pd/C catalytic systems aimed at locating reactive centers on carbon surfaces, revealing their properties and estimating the number of reactive centers presents a challenging problem. In the present study state-of-the-art experimental techniques involving ultra high resolution SEM/STEM microscopy (1 A resolution), high brilliance X-ray absorption spectroscopy and theoretical calculations on truly nanoscale systems were utilized to reveal the role of carbon centers in the formation and nature of Pd/C catalytic materials. Generation of Pd clusters in solution from the easily available Pd2dba3 precursor and the unique reactivity of the Pd clusters opened an excellent opportunity to develop an efficient procedure for the imaging of a carbon surface. Defect sites and reactivity centers of a carbon surface were mapped in three-dimensional space with high resolution and excellent contrast using a user-friendly nanoscale imaging procedure. The proposed imaging approach takes advantage of the specific interactions of reactive carbon centers with Pd clusters, which allows spatial information about chemical reactivity across the Pd/C system to be obtained using a microscopy technique. Mapping the reactivity centers with Pd markers provided unique information about the reactivity of the graphene layers and showed that >2000 reactive centers can be located per 1 MUm2 of the surface area of the carbon material. A computational study at a PBE-D3-GPW level differentiated the relative affinity of the Pd2 species to the reactive centers of graphene. These findings emphasized the spatial complexity of the carbon material at the nanoscale and indicated the importance of the surface defect nature, which exhibited substantial gradients and variations across the surface area. The findings show the crucial role of the structure of the carbon support, which governs the formation of Pd/C systems and their catalytic activity. PMID- 29511505 TI - Diindeno[1,2-b:2',1'-n]perylene: a closed shell related Chichibabin's hydrocarbon, the synthesis, molecular packing, electronic and charge transport properties. AB - Diindeno[1,2-b:2',1'-n]perylene, a new derivative of the indenoacene family was synthesized, and its electronic, electrochemical, and electrical properties were investigated. This material has a closed shell electronic configuration which corresponds to a quinoidal structure with a low band gap of 1.35 eV. Molecular packing in the single crystal was studied by single-crystal X-ray structural analysis, and this information was subsequently used in the determination of the charge transfer integrals via density functional theory methods. The charge carrier transport properties of the diindeno[1,2-b:2',1'-n]perylene-5,12-dione and diindeno[1,2-b:2',1'-n]perylene derivatives were investigated through the fabrication and characterization of field-effect transistors via both vacuum deposited and solution-processed films, respectively. Diindeno[1,2-b:2',1' n]perylene exhibited a field-effect behaviour with a hole mobility up to 1.7 * 10 3 cm2 V-1 s-1 when the active layer was solution-processed. PMID- 29511506 TI - Nickel-catalyzed reductive cleavage of aryl alkyl ethers to arenes in absence of external reductant. AB - The reductive cleavage of the C-O bonds of aryl ethers has great potential in organic synthesis. Although several catalysts that can promote the reductive cleavage of aryl ethers have been reported, all such systems require the use of an external reductant, e.g., hydrosilane or hydrogen. Here, we report the development of a new nickel-based catalytic system that can cleave the C-O bonds of ethers in the absence of an external reductant. The hydrogen atom required in this new reductive cleavage reaction is provided by the alkoxy group of the substrate, which serves as an internal reductant. The absence of an external reductant enables the unique chemoselectivity, i.e., the selective reduction of an alkoxy group over alkenes and ketones. PMID- 29511507 TI - Pd-catalyzed asymmetric hydrogenation of fluorinated aromatic pyrazol-5-ols via capture of active tautomers. AB - An efficient palladium-catalyzed asymmetric hydrogenation of fluorinated aromatic pyrazol-5-ols has been developed via capture of the active tautomers. A wide variety of 2,5-disubstituted and 2,4,5-trisubstituted pyrazolidinones have been synthesized with up to 96% and 95% ee, respectively. The hydrogenation pathway includes Bronsted acid promoted tautomerization of pyrazol-5-ols and Pd-catalyzed asymmetric hydrogenation of the active tautomer. PMID- 29511508 TI - Mixed-ligand complexes of paddlewheel dinuclear molybdenum as hydrodehalogenation catalysts for polyhaloalkanes. AB - We developed a hydrodehalogenation reaction of polyhaloalkanes catalyzed by paddlewheel dimolybdenum complexes in combination with 1-methyl-3,6 bis(trimethylsilyl)-1,4-cyclohexadiene (MBTCD) as a non-toxic H-atom source as well as a salt-free reductant. A mixed-ligated dimolybdenum complex Mo2(OAc)2[CH(NAr)2]2 (3a, Ar = 4-MeOC6H4) having two acetates and two amidinates exhibited high catalytic activity in the presence of n Bu4NCl, in which [ n Bu4N]2[Mo2{CH(NAr)2}2Cl4] (9a), derived by treating 3a with ClSiMe3 and n Bu4NCl, was generated as a catalytically-active species in the hydrodehalogenation. All reaction processes, oxidation and reduction of the dimolybdenum complex, were clarified by control experiments, and the oxidized product, [ n Bu4N][Mo2{CH(NAr)2}2Cl4] (10a), was characterized by EPR and X-ray diffraction studies. Kinetic analysis of the hydrodehalogenation reaction as well as a deuterium-labelling experiment using MBTCD-d8 suggested that the H-abstraction was the rate-determining step for the catalytic reaction. PMID- 29511509 TI - Biosynthesis of trioxacarcin revealing a different starter unit and complex tailoring steps for type II polyketide synthase. AB - Trioxacarcins (TXNs) are highly oxygenated, polycyclic aromatic natural products with remarkable biological activity and structural complexity. Evidence from 13C labelled precursor feeding studies demonstrated that the scaffold was biosynthesized from one unit of l-isoleucine and nine units of malonyl-CoA, which suggested a different starter unit in the biosynthesis. Genetic analysis of the biosynthetic gene cluster revealed 56 genes encoding a type II polyketide synthase (PKS), combined with a large amount of tailoring enzymes. Inactivation of seven post-PKS modification enzymes resulted in the production of a series of new TXN analogues, intermediates, and shunt products, most of which show high anti-cancer activity. Structural elucidation of these new compounds not only helps us to propose the biosynthetic pathway, featuring a type II PKS using a novel starter unit, but also set the stage for further characterization of the enzymatic reactions and combinatorial biosynthesis. PMID- 29511510 TI - Extending the biocatalytic scope of regiocomplementary flavin-dependent halogenase enzymes. AB - Flavin-dependent halogenases are potentially valuable biocatalysts for the regioselective halogenation of aromatic compounds. These enzymes, utilising benign inorganic halides, offer potential advantages over traditional non enzymatic halogenation chemistry that often lacks regiocontrol and requires deleterious reagents. Here we extend the biocatalytic repertoire of the tryptophan halogenases, demonstrating how these enzymes can halogenate a range of alternative aryl substrates. Using structure guided mutagenesis we also show that it is possible to alter the regioselectivity as well as increase the activity of the halogenases with non-native substrates including anthranilic acid; an important intermediate in the synthesis and biosynthesis of pharmaceuticals and other valuable products. PMID- 29511512 TI - Designing efficient photochromic dithienylethene dyads. AB - Aiming at designing more efficient multiphotochromes, we investigate with the help of ab initio tools the impact of the substitution on a series of dimers constituted of two dithienylethene (DTE) moieties, strongly coupled to each other through an ethynyl linker. The electronic structure and the optical properties of a large panel of compounds, substituted on different positions by various types of electroactive groups, have been compared with the aim of designing a dyad in which the three possible isomers (open-open, closed-open, closed-closed) can be reached. We show that appending the reactive carbons atoms of the DTE core with electroactive groups on one of the two photochromes allows cyclisation to be induced on a specific moiety, which leads to the formation of the desired closed open isomer. Substituting the lateral positions of the thiophene rings provides further control of the topology of the frontier molecular orbitals, so that the electronic transition inducing the second ring closure stands out in the spectrum of the intermediate isomer. PMID- 29511511 TI - Three-phase junction for modulating electron-hole migration in anatase-rutile photocatalysts. AB - The heterophase solid-solid junction as an important type of structure unit has wide applications for its special mechanics and electronic properties. Here we present a first three-phase atomic model for the anatase-rutile TiO2 heterophase junction and determine its optical and electronic properties, which leads to resolution of the long-standing puzzles on the enhanced photocatalytic activity of anatase-rutile photocatalysts. By using a set of novel theoretical methods, including crystal phase transition pathway sampling, interfacial strain analysis and first principles thermodynamics evaluation of holes and electrons, we identify an unusual structurally ordered three-phase junction, a layer-by-layer "T-shaped" anatase/TiO2-II/rutile junction, for linking anatase with rutile. The intermediate TiO2-II phase, although predicted to be only a few atomic layers thick in contact with anatase, is critical to alleviate the interfacial strain and to modulate photoactivity. We demonstrate that the three-phase junction acts as a single-way valve allowing the photogenerated hole transfer from anatase to rutile but frustrating the photoelectron flow in the opposite direction, which otherwise cannot be achieved by an anatase-rutile direct junction. This new model clarifies the roles of anatase, rutile and the phase junction in achieving high photoactivity synergistically and provides the theoretical basis for the design of better photocatalysts by exploiting multi-phase junctions. PMID- 29511513 TI - Can the study of self-assembly in solution lead to a good model for the nucleation pathway? The case of tolfenamic acid. AB - To further our understanding of the role of solution chemistry in directing nucleation processes new experimental and computational data are presented on the solution and crystallisation chemistry of tolfenamic acid (TA), a benchmark polymorphic compound. With these, and previously published data, we were able to establish that TA is rapidly fluctuating between conformers in solution with either solvated monomers or dimers present depending on the solvent. Hence, despite the fact that conformational polymorphs can be obtained from crystallisations in ethanol, we found no links between solution chemistry and crystallisation outcomes. We discuss the implications of these conclusions for the nature of the nucleation pathway via dimers and clusters and raise experimental questions about how best to undertake relevant crystallisation studies. PMID- 29511514 TI - Polymorph crystal packing effects on charge transfer emission in the solid state. AB - Condensation of 1,8-naphthalic anhydride with N,N-(dimethylamino)aniline produced the donor-acceptor compound DMIM, which crystallised from a chloroform-diethyl ether mixture to afford two different coloured crystal polymorphs. Crystals for one polymorph are small and green, whereas the other crystals are orange and needle-like. X-ray crystal structures for both polymorphs were determined. The donor N,N-dimethylaniline and acceptor naphthalimide groups are twisted with respect to each other; the degree of twist is marginally different for the two structures. The orange crystal polymorph crystallises in the monoclinic space group C2/c and contains two slightly different molecular conformers in the unit cell (calculated density is 1.410 g cm-3). The green crystal polymorph crystallises in the triclinic space group P1 and contains only one type of molecule in the unit cell (calculated density is 1.401 g cm-3). The crystal packing motifs for the two polymorphs are subtly different, explaining the small variance in the observed densities. Very weak room temperature emission was observed for DMIM in a CHCl3 solution, but crystals deposited on a glass slide glowed when irradiated at 488 nm using a fluorescence microscope. Disparate solid state emission spectra and lifetimes for the two polymorphic crystal forms are observed for the dyad. The emission is assigned to charge recombination fluorescence from a charge transfer state. PMID- 29511515 TI - Addressing, amplifying and switching DNAzyme functions by electrochemically triggered release of metal ions. AB - The design of artificial cells, which mimic the functions of native cells, is an ongoing scientific goal. The development of stimuli-responsive chemical systems that stimulate cascaded catalytic transformations, trigger chemical networks, and control vectorial branched transformations and dose-controlled processes, are the minimum requirements for mimicking cell functions. We have studied the electrochemical programmed release of ions from electrodes, which trigger selective DNAzyme-driven chemical reactions, cascaded reactions that self assemble catalytic DNAzyme polymers, and the ON-OFF switching and dose-controlled operation of catalytic reactions. The addressable and potential-controlled release of Pb2+ or Ag+ ions into an electrolyte that includes a mixture of nucleic acids, results in the metal ion-guided selection of nucleic acids yielding the formation of specific DNAzymes, which stimulate orthogonal reactions or activate DNAzyme cascades. PMID- 29511516 TI - Enantioselective synthesis of bicyclo[3.n.1]alkanes by chiral phosphoric acid catalyzed desymmetrizing Michael cyclizations. AB - 2,2-Disubstituted cyclic 1,3-diketones containing a tethered electron-deficient alkene undergo chiral phosphoric acid-catalyzed desymmetrizing Michael cyclizations to give bridged bicyclic products in high enantioselectivities. Both bicyclo[3.2.1]octanes and bicyclo[3.3.1]nonanes are accessible using this methodology. PMID- 29511517 TI - Can acyclic conformational control be achieved via a sulfur-fluorine gauche effect? AB - The gauche conformation of the 1,2-difluoroethane motif is known to involve stabilising hyperconjugative interactions between donor (bonding, sigmaC-H) and acceptor (antibonding, sigma*C-F) orbitals. This model rationalises the generic conformational preference of F-Cbeta-Calpha-X systems (phiFCCX ~ 60 degrees ), where X is an electron deficient substituent containing a Period 2 atom. Little is known about the corresponding Period 3 systems, such as sulfur and phosphorus, where multiple oxidation states are possible. Conformational analyses of beta fluorosulfides, -sulfoxides and -sulfones are disclosed here, thus extending the scope of the fluorine gauche effect to the 3rd Period (F-C-C-S(O) n ; phiFCCS ~ 60 degrees ). Synergy between experiment and computation has revealed that the gauche effect is only pronounced in structures bearing an electropositive vicinal sulfur atom (S+-O-, SO2). PMID- 29511518 TI - Edge overgrowth of spiral bimetallic hydroxides ultrathin-nanosheets for water oxidation. AB - The structure of edges may dramatically influence the properties of nanomaterials, so the rational design or control over the structures of the edges is required. Here we synthesized spiral ultrathin-nanosheets with overgrown edges (SUNOE) of NiFe, CoNi and CoFe bimetallic hydroxides by governing the growth rates of different directions in screw dislocation driven growth (SDDG) in nonaqueous solvents. The driving force for the SDDG is supersaturation, which could be controlled by the concentration of the different precursors, thus achieving non-uniform structures of the edges and inner sheets. NiFe, CoNi and CoFe bimetallic hydroxides possess layered structures, in which overgrown edges may prevent them from re-stacking. The as prepared SUNOE all show good performance for the oxygen evolution reaction (OER) in the electrolysis of water, and the lowest onset potential was 1.45 V (vs. RHE) (the lowest potential when the current density reached 10 mA cm-2 was 1.51 V (vs. RHE)). PMID- 29511519 TI - Two dimensional inorganic electride-promoted electron transfer efficiency in transfer hydrogenation of alkynes and alkenes. AB - A simple and highly efficient transfer hydrogenation of alkynes and alkenes by using a two-dimensional electride, dicalcium nitride ([Ca2N]+.e-), as an electron transfer agent is disclosed. Excellent yields in the transformation are attributed to the remarkable electron transfer efficiency in the electride mediated reactions. It is clarified that an effective discharge of electrons from the [Ca2N]+.e- electride in alcoholic solvents is achieved by the decomposition of the electride via alcoholysis and the generation of ammonia and Ca(OiPr)2. We found that the choice of solvent was crucial for enhancing the electron transfer efficiency, and a maximum efficiency of 80% was achieved by using a DMF mixed isopropanol co-solvent system. This is the highest value reported to date among single electron transfer agents in the reduction of C-C multiple bonds. The observed reactivity and efficiency establish that electrides with a high density of anionic electrons can readily participate in the reduction of organic functional groups. PMID- 29511520 TI - Fluoride binding to an organoboron wire controls photoinduced electron transfer. AB - We demonstrate that the rates for long-range electron transfer can be controlled actively by tight anion binding to a rigid rod-like molecular bridge. Electron transfer from a triarylamine donor to a photoexcited Ru(bpy)32+ acceptor (bpy = 2,2'-bipyridine) across a 2,5-diboryl-1,4-phenylene bridge occurs within less than 10 ns in CH2Cl2 at 22 degrees C. Fluoride anions bind with high affinity to the organoboron bridge due to strong Lewis base/Lewis acid interactions, and this alters the electronic structure of the bridge drastically. Consequently, a large tunneling barrier is imposed on photoinduced electron transfer from the triarylamine to the Ru(bpy)32+ complex and hence this process occurs more than two orders of magnitude more slowly, despite the fact that its driving force is essentially unaffected by fluoride addition. Electron transfer rates in proteins could potentially be regulated via a similar fundamental principle, because interactions between charged amino acid side chains and counter-ions can modulate electronic couplings between distant redox partners. In artificial donor-bridge acceptor compounds, external stimuli have been employed frequently to control electron transfer rates, but the approach of exploiting strong Lewis acid/Lewis base interactions to regulate the tunneling barrier height imposed by a rigid rod like molecular bridge is conceptually novel and broadly applicable, because it is largely independent of the donor and the acceptor, and because the effect is not based on a change of the driving-force for electron transfer. The principle demonstrated here can potentially be used to switch between conducting and insulating states of molecular wires between electrodes. PMID- 29511521 TI - Controlling the activity of quorum sensing autoinducers with light. AB - Bacteria use a communication system, called quorum sensing (QS), to organize into communities and synchronize gene expression to promote virulence and secure survival. Here we report on a proof-of-principle for externally interfering with this bacterial communication system, using light. By employing photoswitchable small molecules, we were able to photocontrol the QS-related bioluminescence in an Escherichia coli reporter strain, and the expression of target QS genes and pyocyanin production in Pseudomonas aeruginosa. PMID- 29511522 TI - Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (-)-psychotriasine and (+) pestalazine B. AB - We report a unified strategy for the total syntheses of (-)-psychotriasine and (+)-pestalazine B based on the advanced intermediates of 3alpha-amino hexahydropyrrolo[2,3-b]indole. To construct these structural motifs, a cascade reaction involving a BINOL-derived phosphoric anion-paired catalyst for enantioselective or diastereoselective azo-coupling/iminium-cyclizations was developed. The remaining key steps of the synthesis involve a sterically hindered amination via hypervalent iodine reagents and the Larock annulation. These transformations enable a general approach to the syntheses of indole alkaloids containing a 3alpha-amino-hexahydropyrrolo[2,3-b]indole motif and could be further applied to build a natural product-based library. PMID- 29511523 TI - A prochelator peptide designed to use heterometallic cooperativity to enhance metal ion affinity. AB - A peptide has been designed so that its chelating affinity for one type of metal ion regulates its affinity for a second, different type of metal ion. The prochelator peptide (PCP), which is a fusion of motifs evocative of calcium loops and zinc fingers, forms a 1 : 2 Zn : peptide complex at pH 7.4 that increases its affinity for Zn2+ ~3-fold in the presence of Tb3+ (log beta2 from 13.8 to 14.3), while the 1 : 1 luminescent complex with Tb3+ is brighter, longer lived, and 20 fold tighter in the presence of Zn2+ (log K from 6.2 to 7.5). This unique example of cooperative, heterometallic allostery in a biologically compatible construct suggests the possibility of designing conditionally active metal-binding agents that could respond to dynamic changes in cellular metal status. PMID- 29511524 TI - Asymmetric C-H functionalization of cyclopropanes using an isoleucine-NH2 bidentate directing group. AB - The systematic investigation of substrate-bound alpha-amino acid auxiliaries has resulted in catalytic asymmetric C-H functionalization of cyclopropanes enabled by amino acid amides as chiral bidentate directing groups. The use of an Ile-NH2 auxiliary embedded in the substrate provided excellent levels of asymmetric induction (diastereomeric ratio of up to 72 : 1) in the Pd(ii)-catalyzed beta methylene C(sp3)-H bond activation of cyclopropanes and cross-coupling with aryl iodides. PMID- 29511526 TI - False-positive radioiodine accumulation in a huge pelvic mass after thyroidectomy for papillary carcinoma, a case report from Syria. AB - Iodine has always been connected to thyroid gland, and the fact that thyroid tissue traps, organificates and stores iodine more than other tissues is well known, hence the use of radioiodine as a diagnostic and therapeutic tool for thyroid disorders. However, false-positive cases do occur. We present a case of a 34-year-old patient who underwent total thyroidectomy for papillary carcinoma. Results of follow up TSH, thyroglobulin and thyroglobulin antibody tests after surgery lead to two rounds of radioactive iodine. After that, a radioiodine whole body scan showed high uptake in the pelvis above bladder. Computed tomography scan showed a pelvic heterogeneous mass with some calcifications. Surgical removal and subsequent pathology confirmed the absence of metastasis. The final pathological diagnosis was serous cystadenoma, endometriosis cyst and leiomyoma. As the real cause behind false-positive iodine uptake by these tissues has yet to be determined, careful assessment should be considered in any suspicious case. PMID- 29511527 TI - Clinically diagnosed cholecystitis: a case series. AB - In patients presenting with classic signs and symptoms of cholecystitis, the diagnosis is made based on confirmatory imaging studies. However, the most commonly utilized imaging studies lack accuracy, especially in the case of acalculous disease. Here we discuss four cases of patients presenting with symptoms of cholecystitis. All four patients underwent multiple imaging studies, which yielded negative results. Due to persistent symptoms, the decision was made to proceed with cholecystectomy. Each patient underwent uncomplicated cholecystectomy, with resolution of symptoms post-operatively, and continued symptoms relief 6-10 months post-operatively. Cholecystitis is a clinical diagnosis. Negative imaging studies should not influence the management in a patient presenting with classic signs and symptoms of cholecystitis. PMID- 29511528 TI - Bowel endometriosis treated with simultaneous ileocecal and rectal resection. AB - A 43-year-old female noticed hematochezia and lower-right abdominal pain during menstruation. Her family doctor detected a mass by computed tomography at the ileocecum. She was referred to our hospital and colonoscopy was performed. We observed extrinsic pressure resulting in mucosal change at the ileocecum. We also observed a submucosal tumor-like lesion at the rectosigmoid. We performed biopsy from both lesions, both were benign. Ileocecal resection and rectal low anterior resection were performed for diagnosis. Redness, induration and serosal dimpling were recognized at the ileocecum, rectosigmoid and upper rectum. All lesions had endometorial tissue in muscular layer, so pathological diagnosis was bowel endometriosis. Bowel endometriosis occurring in multiple parts and where two colectomies were performed simultaneously is very rare. To determine the optimal method of treatment for the bowel endometriosis, detailed preoperative examination must be performed, specifically complete surgical resection of the lesion for definite diagnosis. PMID- 29511529 TI - In silico analysis of single nucleotide polymorphisms (SNPs) in human FOXC2 gene. AB - Introduction: Lymphedema is abnormal accumulation of interstitial fluid, due to inefficient uptake and reduced flow, leading to swelling and disability, mostly in the extremities. Hereditary lymphedema usually occurs as an autosomal dominant trait with allelic heterogeneity. Methods: We identified single nucleotide polymorphisms (SNPs) in the FOXC2 gene using dbSNP, analyzed their effect on the resulting protein using VEP and Biomart, modelled the resulting protein using Project HOPE, identified gene - gene interactions using GeneMANIA and predicted miRNAs affected and the resulting effects of SNPs in the 5' and 3' regions using PolymiRTS. Results: We identified 448 SNPs - 429 were nsSNPs and 44 SNPs were in the 5' and 3' UTRs. In total, 2 SNPs have deleterious effects on the resulting protein, and a 3D model confirmed those effects. The gene - gene interaction network showed the involvement of FOXC2 protein in the development of the lymphatic system. hsa-miR-6886-5p, hsa-miRS-6886-5p , hsa-miR-6720-3p, which were affected by the SNPs rs201118690, rs6413505, rs201914560, respectively, were the most important miRNAs affected, due to their high conservation score. Conclusions: rs121909106 and rs121909107 were predicted to have the most harmful effects, while hsa-miR-6886-5p, hsa-miR-6886-5p and hsa-miR-6720-3p were predicted to be the most important miRNAs affected. Computational biology tools have advantages and disadvantages, and the results they provide are predictions that require confirmation. PMID- 29511530 TI - Two center experience of capsule endoscopy in Iran: Report on 101 cases. AB - Background: Capsule endoscopy (CE) is a minimally invasive method for the visual examination of the small intestine, which may be for the evaluation and follow-up of patients with Crohn's disease. It can also be used to look at mucosal inflammation. Methods: This cross sectional study was used to determine the diagnostic efficacy of the CE system by performing a cross-sectional study of cases from 2011-2014. This study involved a total of 101 Iranian patients who were referred to the gastrointestinal and liver diseases outpatient clinics in Guilan (northern Iran) and in Isfahan (central Iran) for complaints of gastrointestinal problems. For all patients, definitive diagnosis had failed with the use of other diagnostic tools and CE was performed. Descriptive analysis was used. The patient population was represented by men and women equally, and the mean age of the patients was 42.3 +/- 17.2 years (range: 16-89 years). Results: The final diagnoses were: non-specific enteritis (30.6%), Crohn's disease (20.7%), ulcers caused by aspirin or non-steroidal anti-inflammatory drugs (8.9%), mucosal erosion (5.9%) and angioectasia (4.9%); nearly 10% of the patients had normal findings. Analysis of the distribution of chief presenting complaints with patients stratified by the final diagnosis of Crohn's disease showed that the most frequently presented chief complaint was abdominal pain 42.9% and the least frequently presented chief complaint was diarrhea (4.8%). Conclusions: Small bowel evaluation by CE was well tolerated and capable of diagnosing Crohn's disease and gastrointestinal bleeding in patients who failed other diagnostic tests. PMID- 29511531 TI - netSmooth: Network-smoothing based imputation for single cell RNA-seq. AB - Single cell RNA-seq (scRNA-seq) experiments suffer from a range of characteristic technical biases, such as dropouts (zero or near zero counts) and high variance. Current analysis methods rely on imputing missing values by various means of local averaging or regression, often amplifying biases inherent in the data. We present netSmooth, a network-diffusion based method that uses priors for the covariance structure of gene expression profiles on scRNA-seq experiments in order to smooth expression values. We demonstrate that netSmooth improves clustering results of scRNA-seq experiments from distinct cell populations, time course experiments, and cancer genomics. We provide an R package for our method, available at: https://github.com/BIMSBbioinfo/netSmooth. PMID- 29511532 TI - Non-headache symptoms in migraine patients. AB - Migraine is one of the most common neurological disorders. In addition to severe headaches, non-headache symptoms associated with migraine attacks as well as co morbid disorders frequently aggravate the disabling of migraine patients. Some of these symptoms are related to poor outcomes. In this review, we update the advances of studies on certain non-headache symptoms, including visual disturbance, gastrointestinal symptoms, allodynia, vestibular symptoms, and symptoms of co-morbid restless legs syndrome and psychiatric disorders. PMID- 29511533 TI - Antibiotic treatment of acute gastroenteritis in children. AB - Antibiotic therapy is not necessary for acute diarrhea in children, as rehydration is the key treatment and symptoms resolve generally without specific therapy. Searching for the etiology of gastroenteritis is not usually needed; however, it may be necessary if antimicrobial treatment is considered. The latter is left to the physician evaluation in the absence of clear indications. Antimicrobial treatment should be considered in severely sick children, in those who have chronic conditions or specific risk factors or in specific settings. Traveler's diarrhea, prolonged diarrhea, and antibiotic-associated diarrhea may also require antibiotic therapy. Depending on the severity of symptoms or based on risk of spreading, empiric therapy may be started while awaiting the results of microbiological investigations. The choice of antibiotic depends on suspected agents, host conditions, and local epidemiology. In most cases, empiric therapy should be started while awaiting such results. Empiric therapy may be started with oral co-trimoxazole or metronidazole, but in severe cases parenteral treatment with ceftriaxone or ciprofloxacin might be considered. PMID- 29511535 TI - Surgeon symptoms, strain, and selections: Systematic review and meta-analysis of surgical ergonomics. AB - Background: Many surgeons experience work-related pain and musculoskeletal symptoms; however, comprehensive reporting of surgeon ailments is lacking in the literature. We sought to evaluate surgeons' work-related symptoms, possible causes of these symptoms, and to report outcomes associated with those symptoms. Materials and methods: Five major medical indices were queried for articles published between 1980 and 2014. Included articles evaluated musculoskeletal symptoms and ergonomic outcomes in surgeons. A meta-analysis using a fixed-effect model was used to report pooled results. Results: Forty articles with 5152 surveyed surgeons were included. Sixty-eight percent of surgeons surveyed reported generalized pain. Site-specific pain included pain in the back (50%), neck (48%), and arm or shoulder (43%). Fatigue was reported by 71% of surgeons, numbness by 37%, and stiffness by 45%. Compared with surgeons performing open surgery, surgeons performing minimally invasive surgery (MIS) were significantly more likely to experience pain in the neck (OR 2.77 [95% CI 1.30-5.93]), arm or shoulder (OR 4.59 [2.19-9.61]), hands (OR 2.99 [1.33-6.71], and legs (OR 12.34 [5.43-28.06]) and experience higher odds of fatigue (8.09 [5.60-11.70]) and numbness (6.82 [1.75-26.65]). Operating exacerbated pain in 61% of surgeons, but only 29% sought treatment for their symptoms. We found no direct association between muscles strained and symptoms. Conclusions: Most surgeons report work related symptoms but are unlikely to seek medical attention. MIS surgeons are significantly more likely to experience musculoskeletal symptoms than surgeons performing open surgery. Symptoms experienced do not necessarily correlate with strain. PMID- 29511534 TI - Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC. AB - Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer's disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed. PMID- 29511536 TI - Skeletal metastasis in renal cell carcinoma: A review. AB - Background: Renal cell carcinoma account for 3% of all cancers, with peak incidence between 60 and 70 years of age predominantly affecting male population. Renal carcinoma is the most common malignancy of kidney constitutes for 80-90% of renal neoplasm with an overall 45% five years survival rate. Majority are diagnosed incidentally during investigation for other disease process of abdomen. Classical triad of gross hematuria, pain and palpable mass in abdomen is rare accounting to only 6-10%. Treatment of early stages of disease i.e. localized disease is partial or radical nephrectomy. Most common metastasis in RCC occurs to lung, followed by bone involvement in 20-35%, lymph nodes, liver, adrenal gland and brain. In metastatic disease median survival rate of patient is about eight months with 50% mortality rate within first year of life, five years survival rate is 10%. Skeletal metastasis are very destructive in patients with renal cell carcinoma compromising bone integrity leading to skeletal related events including pains, impending fractures, nerve compressions, hypercalcemia and even pathological fractures which may require surgical interventions and other therapy. In addition to skeletal complications, presence of bone metastases in RCC has negative impact on progression free survival and overall survival of patients treated with systemic therapies. Objective: In this review we discuss pathophysiology of tumor metastasis, diagnosis, management and Case examples of metastatic renal cell carcinoma. Conclusion: Incidence of metastatic renal carcinoma is increasing. Overall prognosis of patient with advanced RCC is poor, emphasizing the importance of early detection and prompt treatment of primary lesion in its early stage. Advancement in targeted therapy in recent decades had made some improvement in treatment of SREs and has helped in improving patent's quality of life but still we are in need of further improvement in treatment modalities to cure disease thereby decreasing morbidity and mortality. PMID- 29511537 TI - Pre-hospital National Early Warning Score (NEWS) is associated with in-hospital mortality and critical care unit admission: A cohort study. AB - Background: National Early Warning Score (NEWS) is increasingly used in UK hospitals. However, there is only limited evidence to support the use of pre hospital early warning scores. We hypothesised that pre-hospital NEWS was associated with death or critical care escalation within the first 48 h of hospital stay. Methods: Planned secondary analysis of a prospective cohort study at a single UK teaching hospital. Consecutive medical ward admissions over a 20 day period were included in the study. Data were collected from ambulance report forms, medical notes and electronic patient records. Pre-hospital NEWS was calculated retrospectively. The primary outcome was a composite of death or critical care unit escalation within 48 h of hospital admission. The secondary outcome was length of hospital stay. Results: 189 patients were included in the analysis. The median pre-hospital NEWS was 3 (IQR 1-5). 13 patients (6.9%) died or were escalated to the critical care unit within 48 h of hospital admission. Pre-hospital NEWS was associated with death or critical care unit escalation (OR, 1.25; 95% CI, 1.04-1.51; p = 0.02), but NEWS on admission to hospital was more strongly associated with this outcome (OR, 1.52; 95% CI, 1.18-1.97, p < 0.01). Neither was associated with hospital length of stay. Conclusion: Pre-hospital NEWS was associated with death or critical care unit escalation within 48 h of hospital admission. NEWS could be used by ambulance crews to assist in the early triage of patients requiring hospital treatment or rapid transport. Further cohort studies or trials in large samples are required before implementation. PMID- 29511538 TI - Injury patterns and outcomes in late middle age (55-65): The intersecting comorbidity with high-risk activity - A retrospective cohort study. AB - Background: Late middle age (LMA), is a watershed between youth and old age, with unique physical and social changes and declines in vitality, but a desire to remain active despite increasing comorbidity. While post-injury outcomes in the elderly are well studied, little is known regarding LMA patients. We analyzed the injured LMA population admitted to a rural, regional Level 1 Trauma Center relative to outcomes for both younger and older patients. Materials and methods: Our registry was queried retrospectively for patients admitted 7/2008- 12/2015; they were divided into three cohorts: 18-54, 55-65, and >65 years. Demographics, injury details, comorbidities, and outcomes were compiled and compared using ANOVA and Chi-square; p < 0.05 was significant. Results: During the study period, 10,543 were admitted; 1419 (14%) were LMA who experienced overall injury mechanisms, severities and patterns that mirrored the younger cohort. However comorbidity rates were high (56.4%) and comparable to the elderly. LMA patients had the highest rates of alcohol abuse, morbid obesity, and psychiatric illness (p < 0.0001) and suffered the poorest outcomes: highest complications and hospital charges, and longest ICU and hospital LOS. LMA mortality (4.1%) was 41% higher than younger patients (2.9%; p < 0.02) and similar to the older cohort (4.7%; p = 0.32). Conclusions: The LMA population has similar mechanisms and injury patterns to younger patients, while exhibiting comorbidity rates similar to the elderly. High-energy injuries exact a greater toll in LMA with poorer outcomes and greater resource utilization. Targeted outreach for injury prevention, and future studies, are needed to address high-risk behavior, substance abuse, and societal contributors. PMID- 29511539 TI - A case report of acute pulmonary hypertension after hyperthermic intraperitoneal chemotherapy (HIPEC) and review of the literature. AB - Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) poses a widely used and accepted treatment option for patients with peritoneal carcinomatosis of gastrointestinal tumors. In contrast to the well-described risks and complications of intravenous cytostatic drugs, literature offers only scarce information of serious complications following HIPEC. To our knowledge no other description of rapid progressive pulmonary hypertension (PH) and consecutive respiratory failure following HIPEC have been described in current literature. Case presentation: A 48-year-old female suffering from a recurrent appendix carcinoma developed progressive dyspnea and fatigue six weeks after multivisceral abdominal resection and HIPEC. Medical examinations included laboratory-checks, non-invasive imaging, scintigraphy as well as invasive examinations (left-/right heart-catheterization) and confirmed PH of unknown origin to be the cause of dyspnea. The patient died nine days after admission of respiratory failure and rapid deterioration as a result of aggravating PH. Conclusion: Rapid progressive respiratory insufficiency due to PH following HIPEC procedure might represent a rare complication, but must be considered because of the high clinical impact. Further studies are necessary to investigate the correlation between HIPEC and PH. PMID- 29511540 TI - A systematic review of gallstone sigmoid ileus management. AB - Introduction: Gallstone sigmoid ileus is a rare although serious complication of cholelithiasis resulting in large bowel obstruction. The condition accounts for 4% of all gallstone ileus patients. There are no recognized management guidelines currently. Management strategies range from minimally invasive endoscopy and lithotripsy to substantial surgery. We aim to identify trends when managing patients with gallstone sigmoid ileus to help improve outcomes. Methods: Literature searches of EMBASE, Medline and by hand were conducted. All English language papers published from 2000 to 2017(Oct) were included. The terms 'gallstone', 'sigmoid', 'colon', 'ileus', 'coleus' and 'large bowel obstruction' were used. Results: 38 papers included, male:female ratio was 8:30. Average age was 81.11 (SD +/- 7.59). Average length of preceding symptoms was 5.31days (+/ SD3.16). 20/38 (59%) had diverticulosis. 89% of patients had significant comorbidities documented. 34/38 patients underwent computerized tomography. 31 stones were located within sigmoid colon, 4 at rectosigmoid junction and 2 within descending colon. Average impacted gallstone size was 4.14 cm (2.3-7 cm range). 23/38 (61%) patients' initial management was conservative or with endoscopy +/- lithotripsy. Conservative management successfully treated 26% of patients. 28/38 (74%) patients ultimately underwent surgical intervention. 5/38 patients died post-operatively. Patients treated non-operatively had shorter hospital stays (4:12.3days) although not significant (p-value = 0.0056). Conclusions: There is no management consensus from the literature. Current evidence highlights endoscopy and lithotripsy as practical firstline strategies. However, surgical intervention should not be delayed if non-operative measures fail or in emergency. Given the complexity of such patients, less invasive timesaving surgery appears practical, avoiding bowel resection and associated complications. PMID- 29511541 TI - Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study. AB - Background: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs. Methods and Results: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057 US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234). Conclusion: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities. PMID- 29511542 TI - Fertility potential in a man with ankylosing spondylitis as revealed by semen analysis by light, electron and fluorescence microscopy. AB - Ankylosing spondylitis affects 0.1%-0.5% of the adult population. The aim was to investigate the possible effects of both the disease and its treatment on semen quality by performing a highly detailed analysis in a man with ankylosing spondylitis, presenting for infertility. Sperm characteristics were evaluated by light microscopy, morphology by electron microscopy (transmission electron microscopy), DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling using fluorescence microscopy and chromosomal abnormalities by fluorescence in situ hybridisation using probes for chromosomes 13,15,16,18,21,22,X and Y. There was no evidence for an effect of either ankylosing spondylitis or its treatment with celecoxib and sulphasalazine on sperm quality as all parameters including concentration, motility, DNA fragmentation and aneuploidy incidence were within normal limits. Transmission electron microscopy, however, revealed a high incidence of head, neck and tail abnormalities, as well as the presence of immature sperm and phagocytes. Hysteroscopic removal of an endometrial polyp enabled the achievement of a spontaneous pregnancy and the delivery of a healthy boy. PMID- 29511543 TI - Total retroperitoneal approach to aortic reconstruction: A novel technique for aorto-enteric fistulae and graft infections. AB - Aorto-enteric fistulae pose a challenging negative outcome of aortic intervention. Treatment involves graft excision, and recently, more enthusiasm has met in situ revascularization over extra-anatomic bypass. This has been traditionally performed through the transperitoneal approach via a midline abdominal incision. We propose an exclusively total retroperitoneal technique in managing this complication with regard to both the vascular and alimentary tract technical aspects of the procedure. This involves exclusion and bypass of the affected segment followed by en-mass resection of the affected segment with the duodenum, and finally, bowel anastomosis. We present a case of an aorto-enteric fistulae illustrating classical radiological findings treated via a flank incision and retroperitoneal technique after a temporizing endovascular stent placement at an outside institution. Peri-operative course was uneventful. The retroperitoneal approach has been shown to be equivalent to its transperitoneal counterpart in many aspects of treating aortic disease. It has also been shown to be superior in others, including but not limited to, faster return of bowel function, decreased respiratory complications, less blood loss and shorter length of stay in the intensive care unit (ICU) and hospital. We recommend adding this approach to every vascular surgeons operative armamentarium when it comes to managing aorto-enteric fistulae. This might be especially helpful in avoiding re operative planes, thus minimizing blood loss and iatrogenic bowel injury, better aortic exposure, and adequate access to the duodenum. PMID- 29511544 TI - Radial neuropathy following arterial line removal: A rare complication from a routine ICU procedure. AB - Radial artery thrombosis is a rare complication of cannulation. There are no reported cases of acute thrombosis and severe acute neuropathy in the setting of cannula discontinuation. We report a case of acute radial nerve mono-neuropathy following thrombosis after radial arterial line removal. The thrombus was immediately evident on exam and diagnostic imaging after cannula discontinuation. The patient was consented and promptly taken to OR for immediate repair. Mild radial neuropathy persisted despite immediate repair. Immediate recognition of signs and symptoms is essential for diagnosis and management, especially in the high-risk population. PMID- 29511545 TI - Ligation of the aorta for a mycotic abdominal aortic aneurysm in an infant. AB - Mycotic aortic aneurysms are exceedingly uncommon in infants and they have a high risk of rupture. Their surgical management is extremely challenging. We report a case of a 22-month-old girl who presented with abdominal pain and fever revealing a ruptured mycotic aneurysm of the infrarenal aorta. The surgical treatment consisted of a ligature of the proximal and distal ends of the aneurysm. Postoperative course was significant for hypertension. A year and a half follow up showed no other complications. Limited data are available concerning our chosen technique, but the reported cases showed a good short-term outcome. PMID- 29511546 TI - Intraorbital ancient pilocytic astrocytoma of the optic nerve in neurofibromatosis type 1 patient presenting with sudden ocular pain. AB - Optic nerve pilocytic astrocytoma is an uncommon but well-known entity; however, intraorbital ancient pilocytic astrocytoma of the optic nerve is extremely rarely reported. To our knowledge, this is the first detailed description regarding the intraorbital ancient pilocytic astrocytoma, reported in available English literature, to date. We presented an extremely unusual neurofibromatosis type 1 case of a 17-year-old male's sudden ocular pain secondary to intraorbital pilocytic astrocytoma of the optic nerve with markedly cystic degeneration, fluid production, and hemorrhage, due to ancient and possibly ruptured glioma. Future prospective studies are required to validate the significance of intraorbital ancient pilocytic astrocytoma arising from the optic nerve and the close correlation with ruptured cystic degeneration and ocular pain, after collecting and investigating a larger number of its cases examined. PMID- 29511547 TI - Comparative efficacy and tolerability of probiotics for antibiotic-associated diarrhea: Systematic review with network meta-analysis. AB - Background: Probiotics are commonly used for the prevention of antibiotic associated diarrhea (AAD). However, the optimum regimen remains controversial. Objective: The objective of this article is to compare and rank the relative efficacy and tolerability among all available probiotic agents for AAD through a network meta-analysis. Methods: Eligible studies were identified by searching PubMed, Embase, Medline, Cochrane library and Web of Science for randomized controlled trials (RCTs) that examined the efficacy of probiotic therapy for AAD. A random-effects model was applied within a frequentist framework. Quality of evidence was performed by the GRADE approach. The project was prospectively registered with PROSPERO (CRD 42016050776). Results: Fifty-one articles (60 comparisons, 9569 participants), including 10 probiotic interventions, were identified. Lactobacillus rhamnosus GG (LGG) had the highest probability of being ranked best both in effectiveness (odds ratio (OR), 95% confidence interval (CI) = 0.28 (0.17, 0.47)) and tolerance (0.44 (0.23, 0.84)) on prevention of AAD. With regard to reducing Clostridium difficile infection rate, Lactobacillus casei (L. casei) was considered better efficacy (0.04 (0.00, 0.77)) and medium tolerance (0.56 (0.19, 1.66)). Strain combination reported no superiority over single strain in either efficacy or tolerability. Conclusions: LGG is probably the best option to consider when AAD is indicated. L. casei appears to be the most efficacious choice when associated with severe C. difficile-related cases. PMID- 29511548 TI - Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis. AB - Background: Citrulline has been described as a marker of intestinal function or absorption but evidence varies according to clinical settings. Objective: The objective of this article is to examine the evidence of plasma citrulline as a marker of intestinal function and absorption in various clinical settings. Methods: Studies were examined for p values, means and standard deviations, correlation coefficients or other metrics depicting the association of citrulline with intestinal function. A random effects model was used to produce a pooled estimate. A hierarchical summary receiver operating curve model was fitted for diagnostic accuracy measures. Results: Citrulline levels are correlated strongly with small bowel length in short bowel syndrome patients (r = 0.67). Citrulline is strongly negatively correlated (r = -0.56) with intestinal disease severity with regards to enteropathies (coeliac disease, tropical enteropathy, Crohn's disease, mucositis, acute rejection in intestinal transplantation). Citrulline cut-off levels have an overall sensitivity and specificity of 80% and 84% respectively. Citrulline levels in untreated coeliac patients compared to controls were reduced by 10 umol/l. Citrulline levels increase with gluten-free diet and with improvement of enteropathy. Citrulline is decreased in critical illness and sepsis. Conclusion: These findings allow us to advocate quite reasonably that citrulline is a marker of acute and chronic intestinal insufficiency. PMID- 29511549 TI - Endoscopic screening for gastric cancer: A cost-utility analysis for countries with an intermediate gastric cancer risk. AB - Background: Endoscopic screening for gastric cancer is debatable in countries with an intermediate risk. Objective: The objective of this article is to determine the cost-utility of screening strategies for gastric cancer in a European country. Methods: We conducted a cost-utility analysis using a Markov model comparing three screening strategies versus no screening: stand-alone upper endoscopy, endoscopy combined with a colorectal cancer screening colonoscopy after a positive faecal occult blood test or pepsinogens serologic screening. Clinical data were collected from systematic reviews, costs from published national data and utilities as quality-adjusted life years (QALY). The primary outcome was the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were performed. The threshold was set at ?37,000 (2016 prices). Results: Upper endoscopy combined with screening colonoscopy (every 10 or 5 years) had an ICER of 15,407/QALY and ?30,908/QALY respectively, stand-alone endoscopic screening (every five years) an ICER of ?70,693/QALY and pepsinogens screening an ICER of ?143,344/QALY. Sensitivity analyses revealed that only endoscopic costs 25/100,000 would make stand alone endoscopic screening cost-effective. Conclusion: Endoscopic gastric cancer screening in Europe can be cost-effective if combined with a screening colonoscopy in countries with a gastric cancer risk >=10 per 100,000. PMID- 29511550 TI - Endoscopic submucosal dissection of gastric superficial neoplastic lesions: a single Western center experience. AB - Background: Endoscopic submucosal dissection (ESD) allows "en bloc" resection of superficial gastric lesions. Objective: The aim of this study is to report "en bloc" resection rate, procedure results, post resection features, analysis of complications, and relapses at mid-long term follow-up on an Italian center case series of patients with superficial gastric neoplastic lesions treated with ESD. Methods: This is a retrospective evaluation of a prospectively collected series of patients diagnosed with gastric superficial lesions who underwent ESD between November 2007 and May 2015. The analysis included demographic, clinical, endoscopic, and histological data. In detail, the following features were analyzed: (1) "en bloc" resection rate; (2) R0, R1, and RX rate; (3) complication rate; and (4) neoplastic recurrence during follow-up. A comparison was performed between lesions treated according to standard and to extended criteria. Results: In the analysis, therefore, 70 superficial lesions and 70 endoscopic procedures were considered.Overall, 53 (76%) procedures were performed according to the extended-ESD criteria. The remaining 17 (24%) cases were performed according to standard criteria. In 68/70 (97%) procedures "en bloc" resection was successful. Forty-four (65.6%) patients had a R0 resection, while 15 (22%) patients had a R1 and the remaining 8 (12.4%) patients were RX. Two patients (2.8%) experienced a major complication. Overall, 7 patients (10.4%) required surgery: in two cases because of local recurrence, in one case for an intraprocedural complication not amenable to endoscopic treatment, in three patients with R1 vertical margins, and in the last patient because of an aggressive pathology (i.e. signet ring cell adenocarcinoma). The mean follow-up of patients with neoplastic lesions was 36.6 +/- 13.1 months. Conclusion: ESD for early gastric cancer is a safe and effective technique when performed by experienced Endoscopists also in Western setting. When comparing the outcomes of the ESD in patients with standard and extended indication there is no significant difference in terms of complete resection, complications and local recurrence rates. Larger Western studies are needed to clearly define the role and the outcomes of ESD in regions at low incidence for gastric neoplasia. PMID- 29511551 TI - Treatment of hepatitis C genotype 1 infection in Germany: effectiveness and safety of antiviral treatment in a real-world setting. AB - Background: In pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%. Objective: The objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study. Methods: The German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician. Results: A total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24-1.43); p < 0.001), negatively associated with presence of liver cirrhosis (OR 0.71 (0.56-0.89); p < 0.003) and positively associated with female gender (OR 1.52 (1.21-1.91); p < 0.001). Conclusion: Data from this real world registry show SVR12 rates close to those obtained in clinical studies. Discontinuation rates are low, confirming good tolerance of the regimens and good adherence of patients (Trial registration number DRKS00009717, German Clinical Trials Register, DRKS). PMID- 29511552 TI - Optimization of direct anti-viral agent treatment schedule: Focus on HCV genotype 3. AB - Background and aim: Direct antiviral agents (DAAs) have led to high sustained virological responses (SVR) in hepatitis C virus (HCV) patients. However, genotype 3 patients respond to treatment in a suboptimal way. This study aims to identify which of the several treatment schedules recommended for genotype 3 would constitute the best option. Methods: Twenty-four Italian centers were involved in this real-life study of HCV genotype 3 patients treated with DAAs. To expand the number of cases, we conducted a systematic review of the literature on the outcome of genotype 3 patients treated with DAAs. Results: A total of 233 patients with HCV genotype 3 were enrolled. Cirrhotic patients accounted for 83.7%. Overall, the SVR12 rate was achieved by 205 patients (88.0%); the SVR rates were 78.8% after sofosbuvir/ribavirin, 92.5% after sofosbuvir/daclatasvir +/- ribavirin, and 100% after sofosbuvir/ledipasvir (seven patients). No difference in rate of SVR was observed in cirrhotic and non-cirrhotic patients (92.2 vs 94.4) using a combination regimen of NS5A and NS5B inhibitors.The systematic review of the literature provided data of 3311 patients: The mean weighted SVR12 rate was 84.4% (CI: 80.4-87.8); the rates varied from 79.0% (CI: 70.9-85.3) with sofosbuvir/ribavirin, to 83.7% (CI: 66.2-93.1) with sofosbuvir/ledispavir, and to 88.2% (CI: 83.3-91.7) with sofosbuvir/daclatasvir. Conclusions: Our results reinforce the concept that patients with HCV genotype 3 should no longer be considered difficult-to-treat individuals. The optimal therapeutic regimen for these patients appears to be the combination sofosbuvir/daclatasvir, administered for 12 weeks without the use of RBV in non cirrhotic patients. In cirrhotics the meta-analytic approach suggests extending therapy to 24 weeks. PMID- 29511553 TI - Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease. AB - Background: Sorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE. Methods: A total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis. Results: Patients with liver cirrhosis, higher extrahepatic tumor burden and/or infiltration of adjacent organs/structures were significantly more often treated with sorafenib. Median overall survival (OS) was similar for sorafenib- and TACE-treated patients (7 versus 8 months, p = 0.312). In a propensity score analysis matched for demographic differences, median OS remained similar with 4 versus 8 months for sorafenib versus TACE (p = 0.613). Conclusion: Treatment with TACE is not inferior to treatment with sorafenib in patients with limited EHD of HCC. TACE represents an effective therapeutic option in selected patients with EHD. PMID- 29511554 TI - Suitability of the simplified autoimmune hepatitis score for the diagnosis of autoimmune hepatitis in a German cohort. AB - Background: Several years ago the International Autoimmune Hepatitis Group simplified the previous revised original scoring system for diagnosis of autoimmune hepatitis (AIH) into a scoring system based on only four instead of 13 parameters. Objective: We aimed to evaluate the suitability of the simplified AIH score for diagnosis of AIH in a German cohort with chronic liver diseases. Methods: In this retrospective single-center study, we compared the accuracy of both AIH scores in 70 patients with AIH and 211 patients with chronic liver diseases (PBC (n = 52), PSC (n = 27), NASH (n = 67), DILI (n = 15), CHB/C (n = 50)). Sensitivity, specificity and predictability of each scoring system were calculated. Results: Using the simplified AIH score, the sensitivity and specificity of detecting a probable AIH (scores >= 6) were 96% and 97% with a positive and negative predictive value of 92% and 99%, respectively. For diagnosis of definite AIH (scores >= 7), the sensitivity and specificity were 43% and 100% with a positive and negative predictive value of 97% and 84%, respectively. The concordance with the revised original criteria was 63%. The specificity for excluding AIH was excellent in both scoring system. Conclusion: The simplified diagnostic criteria allow a reliable diagnosis of AIH in a German cohort. PMID- 29511555 TI - Impact of age at diagnosis on disease progression in patients with primary sclerosing cholangitis. AB - Background: The median age of diagnosis of primary sclerosing cholangitis (PSC) is ~30-40 years. Objective: We aimed to analyse disease progression and liver dependent survival in patients diagnosed with PSC after 50 years of age. Methods: Patients with PSC were analysed with regard to their age at diagnosis. Patients with a first diagnosis of PSC after the age of 50 years were considered as the late-onset group. Results: A total of 32/215 (14.9%) patients were diagnosed with PSC after 50 years of age. The proportion of females was significantly higher among patients with late-onset PSC (48.4 vs. 27.3%; p = 0.02). Patients with later diagnosis required dilatation therapy more often due to dominant stenosis (84.2 vs. 53.1%; p = 0.01) and suffered from recurrent cholangitis more often (48.3 vs. 21.0%; p = 0.003). Patients with late-onset PSC had reduced transplantation-free survival (10.5 +/- 0.6 years vs. 20.8 +/- 1.7 years, p < 0.0001), with progredient liver failure and cholangiocarcinoma as the leading causes of death. Conclusions: Patients with later age at diagnosis of PSC displayed a different clinical phenotype with a different sex ratio, immune status and an increased risk for progressive liver failure and biliary malignancies. PMID- 29511556 TI - Preoperative prediction of curative surgery of perihilar cholangiocarcinoma by combination of endoscopic ultrasound and computed tomography. AB - Background: Perihilar cholangiocarcinomas are often considered incurable. Late diagnosis is common. Advanced disease therefore frequently causes questioning of curative surgical outcome. Aim: This study aimed to develop a prediction model of curative surgery in patients suffering from perihilar cholangiocarcinomas based on preoperative endosonography and computer tomography. Methods: A cohort of 81 patients (median age 67 (54-75) years, 62% male) with perihilar cholangiocarcinoma was retrospectively analyzed. Multivariate logistic regression analysis of staging variables taken from the European Staging System was performed and applied to ROC analysis. Results: The correlation of predicted rates of eligibility for surgery with actual rates reached AUC values between 0.652 and 0.758 for endosonography and computer tomography (p < 0.05 each). Best prediction for curative surgical option was achieved by combining endosonography and computer tomography (AUC: 0.787; 95% CI 0.680-0.893, p < 0.0001). A predictive model (pSurg) was developed using multivariate analysis. Conclusions: Our predictive web-based model pSurg with inclusion of T, N, M, B, PV, HA and V stage of the recently published European Staging System for perihilar cholangiocarcinoma results in highly significant predictability for curative surgery when combining preoperative endosonography and computer tomography, thus allowing for better patient selection in terms of possibility of curative surgery. PMID- 29511557 TI - Bach2 repression mediates Th17 cell induced inflammation and associates with clinical features of advanced disease in chronic pancreatitis. AB - Objectives: Altered immune homeostasis and involvement of T cells has been reported in chronic pancreatitis (CP). We evaluated the role of Bach2 (BTB and CNC homology basic leucine zipper transcription factor 2), a key regulator of immune homeostasis in the chronicity of CP. Methods: Expression of Bach2 and T cell transcription factors, enumeration of BACH2+/CD4+ T-lymphocytes were performed by qRT-PCR and flow cytometry respectively. Bach2silenced human CD4+ T lymphocytes were exposed to CP tissue extract to assess T-cell lineage commitment. Aryl hydrocarbon receptor (Ahr) and Deubiquitinase enzyme A (DUBA/OTUD5gene) were evaluated as markers of persistent Th17 cell differentiation. Bach2 gene (exons) was sequenced to identify risk variants and functionally validated. Results: Decrease in Bach2 (p < 0.0001) and increase (p < 0.001) in TBX21, RORC, Ahr, PRDM1, IL23R mRNA were noted in pancreatic tissues, while BACH2+/CD4+ T-lymphocytes were decreased (p < 0.01) in circulation and tissues. Exposure of Bach2 silenced CD4+ T-lymphocytes to CP tissue extract showed increased Ahr, decreased OTUD5, and enhanced Th17 cell differentiation. Sequencing of Bach2 gene revealed association of novel variant (rs9111 in 5'-UTR) with advanced disease and luciferase assay confirmed its role in Bach2 repression. Conclusion: Bach2 repression mediates Th17 cell induced inflammation and rs9111-TT in individuals with primary genetic susceptibility to CP is associated with clinical features of advanced disease. PMID- 29511558 TI - Educational strategies for colonoscopy bowel prep overcome barriers against split dosing: A randomized controlled trial. AB - Background: A split-dose (SD) regimen is crucial for colonoscopy quality. Compliance with SD for early morning colonoscopy is generally poor. The present study evaluated whether pre-colonoscopy counselling, in addition to a dedicated leaflet, might increase SD uptake. Methods: Consecutive 50-69-year-old patients undergoing screening colonoscopy before 10 a.m. were randomized to either receive written information only on bowel preparation (Written Group, WG) or written and oral instructions (Written and Oral Group, WaOG). The leaflet strongly encouraged SD adoption. The primary endpoint was the number of patients adopting SD in each group. The secondary endpoints were predictors of SD uptake, compliance with preparation schemes and cleansing adequacy. Results: A total of 286 patients (143 WG, 143 WaOG) were enrolled (mean age 59.6 +/- 6.1 years, men 49.3%). SD was adopted by 114 and 125 patients in the WG and WaOG, respectively (79.7% versus 87.4%, p = 0.079). No significant differences were observed for the proportion of patients with full compliance with preparation scheme (97.9% versus 97.2%, p = 0.99) and of procedures with adequate bowel cleansing (95.6% versus 95.1%, p = 0.77). At multivariate analysis, a > 1 h travel time to the endoscopy service was inversely correlated with SD uptake (odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09-0.98). Conclusions: Our leaflet guaranteed satisfactory uptake of SD and excellent adherence to the preparation scheme for early morning colonoscopy. Its use might marginalize the need for additional oral instructions, particularly in open-access settings. PMID- 29511559 TI - Genetic Biopsy for Prediction of Surveillance Intervals after Endoscopic Resection of Colonic Polyps: Results of the GENESIS Study. AB - Background and objective: Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub groups at risk. Methods: One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina)). Genetic and histopathological analyses were done blinded to other data. Results: In 100 patients, 224 polyps were removed. Significant associations of genetic alterations with endoscopic or histological polyp characteristics were observed for BRAF, KRAS, TCF7L2, FBXW7 and CTNNB1 mutations. Multivariate analysis revealed that polyps >= 10 mm have a significant higher relative risk for harbouring oncogene mutations (relative risk 3.467 (1.742-6.933)). Adenomas and right-sided polyps are independent risk factors for CTNNB1 mutations (relative risk 18.559 (2.371-145.245) and 12.987 (1.637-100.00)). Conclusions: Assessment of the mutational landscape of polyps can be integrated in the workflow of current colonoscopy practice. There are distinct genetic patterns related to polyp size and location. These results suffice to optimise individual risk calculation and may help to better define surveillance intervals. PMID- 29511560 TI - Relationships between psychological state, abuse, somatization and visceral pain sensitivity in irritable bowel syndrome. AB - Background and objective: Psychological states may interfere with visceral sensitivity. Here we investigate associations between psychosocial factors and visceral sensitivity in irritable bowel syndrome (IBS). Methods: Two IBS patient cohorts (Cohort 1: n = 231, Rome II; Cohort 2: n = 141, Rome III) underwent rectal barostat testing, and completed questionnaires for anxiety, depression, somatization, and abuse. The associations between questionnaire measures and visceral sensitivity parameters were analyzed in three-step general linear models (step1: demographic and abuse variables; step 2: anxiety and depression; step 3: somatization). Results: Cohort 1. Pain threshold was positively associated with age and female gender, and negatively with adult sexual abuse and somatization. Pain referral area was negatively associated with age and positively with somatization and GI-specific anxiety, the latter effect mediated by somatization. Cohort 2. Pain threshold was positively associated with age and male gender, and negatively with adult sexual abuse. Pain intensity ratings were positively associated with somatization, female gender and depression, the latter effect mediated by somatization. Conclusion: Somatization is associated with most visceral sensitivity parameters, and mediates the effect of some psychological factors on visceral sensitivity. It may reflect a psychobiological sensitization process driving symptom generation in IBS. In addition, abuse history was found to independently affect some visceral sensitivity parameters. PMID- 29511561 TI - Cost-effectiveness of biological treatment sequences for fistulising Crohn's disease across Europe. AB - Background: In clinical practice, treatment sequences of biologicals are applied for active fistulising Crohn's disease, however underlying health economic analyses are lacking. Objective: The purpose of this study was to analyse the cost-effectiveness of different biological sequences including infliximab, biosimilar-infliximab, adalimumab and vedolizumab in nine European countries. Methods: A Markov model was developed to compare treatment sequences of one, two and three biologicals from the payer's perspective on a five-year time horizon. Data on effectiveness and health state utilities were obtained from the literature. Country-specific costs were considered. Calculations were performed with both official list prices and estimated real prices of biologicals. Results: Biosimilar-infliximab is the most cost-effective treatment against standard care across the countries (with list prices: ?34684-?72551/quality adjusted life year; with estimated real prices: ?24364-?56086/quality adjusted life year). The most cost-effective two-agent sequence, except for Germany, is the biosimilar infliximab-adalimumab therapy compared with single biosimilar-infliximab (with list prices: ?58533-?133831/quality adjusted life year; with estimated prices: ?45513-?105875/quality adjusted life year). The cost-effectiveness of the biosimilar-infliximab-adalimumab-vedolizumab three-agent sequence compared wit biosimilar-infliximab -adalimumab is ?87214-?152901/quality adjusted life year. Conclusions: The suggested first-choice biological treatment is biosimilar infliximab. In case of treatment failure, switching to adalimumab then to vedolizumab provides meaningful additional health gains but at increased costs. Inter-country differences in cost-effectiveness are remarkable due to significant differences in costs. PMID- 29511563 TI - Young GI angle: Boosting your career development with fellowship experience. PMID- 29511562 TI - Prevalence and risk factors for colorectal adenomas in patients with ulcerative colitis. AB - Background: Patients with ulcerative colitis (UC) have an increased risk of colorectal cancer. Scarce data regarding the development of adenomas in these patients are available both for normal and colitic mucosa. Objective: The objective of this article is to evaluate the prevalence of adenomatous polyps and associated risk factors in patients with UC. Methods: Patients with UC were identified from the databases of two tertiary referral centers. Medical, endoscopic and histologic reports were reviewed. Results: A total of 403 patients were included (53% male; 33% extensive colitis) and 1065 colonoscopies (median per patient, 2) were recorded and analyzed. Seventy-four adenomas in 47 patients (11.7%) and three cases of colorectal cancer were found during a median follow-up of 6.3 years. The cumulative risk of colorectal adenoma was 4.7%, 16.7%, 23.6% and 34.4% at 10, 20, 30 and 40 years from UC diagnosis, respectively. The cumulative risk of developing metachronous colorectal adenoma was 66.7%, 87.9%, and 90.9% at 5, 10, and 15 years from first adenoma detection. Older age at UC diagnosis and longer disease duration were independent risk factors for colorectal adenoma development. Conclusions: The prevalence of colorectal adenomas among UC patients seems to be higher than previously reported, although lower than in the background population. PMID- 29511565 TI - Combination immune checkpoint inhibitor therapy nivolumab and ipilimumab associated with multiple endocrinopathies. AB - : Immune checkpoint inhibitors are the mainstay of treatment for advanced melanoma, and their use is being increasingly implicated in the development of autoimmune endocrinopathies. We present a case of a 52-year-old man with metastatic melanoma on combination nivolumab and ipilumimab therapy who developed concurrent hypophysitis, type 1 diabetes mellitus (T1DM) and diabetes insipidus. He presented prior to third cycle of combination treatment with a headache, myalgias and fatigue. Biochemistry and MRI pituitary confirmed anterior pituitary dysfunction with a TSH: 0.02 mU/L (0.5-5.5 mU/L), fT4: 5.2 pmol/L (11-22 pmol/L), fT3: 4.0 pmol/L (3.2-6.4 pmol/L), cortisol (12:00 h): <9 nmol/L (74-286 nmol/L), FSH: 0.7 IU/L (1.5-9.7 IU/L), LH: <0.1 IU/L (1.8-9.2 IU/L), PRL: 1 mIU/L (90-400 mIU/L), SHBG: 34 nmol/L (19-764 nmol/L) and total testosterone: <0.4 nmol/L (9.9 27.8 nmol/L). High-dose dexamethasone (8 mg) was administered followed by hydrocortisone, thyroxine and topical testosterone replacement. Two weeks post administration of the third cycle, he became unwell with lethargy, weight loss and nocturia. Central diabetes insipidus was diagnosed on the basis of symptoms and sodium of 149 mmol/L (135-145 mmol/L). Desmopressin nasal spray was instituted with symptom resolution and normalization of serum sodium. Three weeks later, he presented again polyuric and polydipsic. His capillary glucose was 20.8 mmol/L (ketones of 2.4 mmol), low C-peptide 0.05 nmol/L (0.4-1.5 nmol/L) and HbA1c of 7.7%. T1DM was suspected, and he was commenced on an insulin infusion with rapid symptom resolution. Insulin antibodies glutamic acid decarboxylase (GAD), insulin antibody-2 (IA-2) and zinc transporter-8 (ZnT8) were negative. A follow-up MRI pituitary revealed findings consistent with recovering autoimmune hypophysitis. Immunotherapy was discontinued based on the extent of these autoimmune endocrinopathies. Learning points: The most effective regime for treatment of metastatic melanoma is combination immunotherapy with nivolumab and ipilumimab, and this therapy is associated with a high incidence of autoimmune endocrinopathies.Given the high prevalence of immune-related adverse events, the threshold for functional testing should be low.Traditional antibody testing may not be reliable to identify early-onset endocrinopathy.Routine screening pathways have yet to be adequately validated through clinical trials. PMID- 29511564 TI - Management of patients with high-risk pulmonary embolism: a narrative review. AB - High-risk pulmonary embolism (PE) is a life-threatening disorder associated with high mortality and morbidity. Most deaths in patients with shock occur within the first few hours after presentation, and rapid diagnosis and treatment is therefore essential to save patients' lives. The main manifestations of major PE are acute right ventricular (RV) failure and hypoxia. RV pressure overload is predominantly related to the interaction between the mechanical pulmonary vascular obstruction and the underlying cardiopulmonary status. Computed tomography angiography allows not only adequate visualization of the pulmonary thromboemboli down to at least the segmental level but also RV enlargement as an indicator of RV dysfunction. Bedside echocardiography is an acceptable alternative under such circumstances. Although it does not usually provide a definitive diagnosis or exclude pulmonary embolism, echocardiography can confirm or exclude severe RV pressure overload and dysfunction. Extracorporeal membrane oxygenation support can be an effective procedure in patients with PE-induced circulatory collapse. Thrombolysis is generally accepted in unstable patients with high-risk PE; however, thrombolytic agents cannot be fully administered to patients with a high risk of bleeding. Conversely, catheter-directed treatment is an optimal treatment strategy for patients with high-risk PE who have contraindications for thrombolysis and is a minimally invasive alternative to surgical embolectomy. It can be performed with a minimum dose of thrombolytic agents or without, and it can be combined with various procedures including catheter fragmentation or embolectomy in accordance with the extent of the thrombus on a pulmonary angiogram. Hybrid catheter-directed treatment can reduce a rapid heart rate and high pulmonary artery pressure and can improve the gas exchange indices and outcomes. Surgical embolectomy is also performed in patients with contraindications for or an inadequate response to thrombolysis. Large hospitals having an intensive care unit should preemptively establish diagnostic and therapeutic protocols and rehearse multidisciplinary management for patients with high-risk PE. Coordination with a skilled team comprising intensivists, cardiologists, cardiac surgeons, radiologists, and other specialists is crucial to maximize success. PMID- 29511566 TI - Assessment of self-reporting reading of medicine's labels and the resources of information about medicines in general public in Malaysia. AB - This study was undertaken to assess the people's self-reported reading of medicine labels and its associated factors and to assess the sources of information about medicines among general public. A cross-sectional study was carried out among general public in the State of Penang, Malaysia. A total of 888 participants were conveniently selected and completed the survey. A self administered questionnaire was used to obtain the data from all the participants. Most of the participants (74.2%) reported that they have adequate information about medicines provided on their medicine labels. In addition, 86.9% of them reported that they read their medicine's label for the directions of usage and 84.3% for the dosage instruction. However, 42.1% of the participants do not read their medicine's label for the active ingredients, and 33% of them do not read their medicine's label for the safety information. In addition, 36.5% of the respondents did not read the label of medicine for the symptoms which can be used for. However, females, Malay respondents, and higher education level (college/university) were more likely to self-reported the reading medicine's label. Females were more likely to read the labels of medicines compared with males (OR = 1.6, 95% CI 1.20-2.13, P = .001). The reading of medicine labels was predicted by females, Malay respondents, and higher educated people. Health educational programs are needed to clarify label's information that can help in concept of patient safety. PMID- 29511567 TI - RNA expression profiling in sulfamethoxazole-treated patients with a range of in vitro lymphocyte cytotoxicity phenotypes. AB - The lymphocyte toxicity assay (LTA) is a proposed surrogate marker of sulfonamide antibiotic hypersensitivity. In the LTA, peripheral blood mononuclear cells (PBMCs) undergo apoptosis more readily in hypersensitive versus tolerant patients when exposed to drug-hydroxylamine metabolites in vitro. The purpose of this study was to identify key gene transcripts associated with increased cytotoxicity from sulfamethoxazole-hydroxylamine in human PBMCs in the LTA. The LTA was performed on PBMCs of 10 patients hypersensitive to trimethoprim-sulfamethoxazole (HS) and 10 drug-tolerant controls (TOL), using two cytotoxicity assays: YO-PRO (n = 20) and MTT (n = 12). mRNA expression profiles of PBMCs, enriched for CD8+ T cells, were compared between HS and TOL patients. Transcript expression was interrogated for correlation with % cytotoxicity from YO-PRO and MTT assays. Correlated transcripts of interest were validated by qPCR. LTA results were not significantly different between HS and TOL patients, and no transcripts were found to be differentially expressed between the two groups. 96 transcripts were correlated with cytotoxicity by YO-PRO (r = +/-.63-.75, FDR 0.188). Transcripts were selected for validation based on mechanistic plausibility and three were significantly over-expressed by qPCR in high cytotoxicity patients: multi specific organic anion transporter C (ABCC5), mitoferrin-1 (SLC25A37), and Porimin (TMEM123). These data identify novel transcripts that could contribute to sulfonamide-hydroxylamine induced cytotoxicity. These include SLC25A37, encoding a mitochondrial iron transporter, ABCC5, encoding an arylamine drug transporter, and TMEM123, encoding a transmembrane protein that mediates cell death. PMID- 29511568 TI - Chlamydiae in febrile children with respiratory tract symptoms and age-matched controls, Ghana. AB - Members of the Chlamydiales order are obligate intracellular pathogens causing acute and chronic infectious diseases. Chlamydiaceae are established agents of community- and zoonotically acquired respiratory tract infections, and emerging pathogens among the Chlamydia-related bacteria have been implicated in airway infections. The role of both in airway infections in Africa is underexplored. We performed a case -control study on the prevalence of Chlamydiaceae and Chlamydia related emerging pathogens in children with febrile respiratory tract infections in West Africa, Ghana. Using a pan-Chlamydiales broad-range real-time PCR, we detected chlamydial DNA in 11 (1.9%) of 572 hospitalized febrile children with respiratory tract symptoms and in 24 (4.3%) of 560 asymptomatic age-matched controls (p 0.03). Chlamydiaceae were found to be common among both symptomatic and healthy Ghanaian children, with Chlamydia pneumoniae being the most prevalent species. Parachlamydiaceae were detected in two children without symptoms but not in the symptomatic group. We identified neither Chlamydia psittaci nor Simkania negevensis but a member of a new chlamydial family that shared 90.2% sequence identity with the 16S rRNA gene of the zoonotic pathogen Chlamydia pecorum. In addition, we found a new Chlamydia-related species that belonged to a novel family sharing 91.3% 16S rRNA sequence identity with Candidatus Syngnamydia venezia. The prevalence and spectrum of chlamydial species differed from previous results obtained from children of other geographic regions and our study indicates that both, Chlamydiaceae and Chlamydia-related bacteria, are not clearly linked to clinical symptoms in Ghanaian children. PMID- 29511569 TI - Vascular Access Practice Patterns in Canada: A National Survey. AB - Background: One of the mandates of the Canadian Society of Nephrology's (CSN) Vascular Access Working Group (VAWG) is to inform the nephrology community of the current status of vascular access (VA) practice within Canada. To better understand VA practice patterns across Canada, the CSN VAWG conducted a national survey. Objectives: (1) To inform on VA practice patterns, including fistula creation and maintenance, within Canada. (2) To determine the degree of consensus among Canadian clinicians regarding patient suitability for fistula creation and to assess barriers to and facilitators of fistula creation in Canada. Design: Development and implementation of a survey. Setting: Community and academic VA programs. Participants: Nephrologists, surgeons, and nurses who are involved in VA programs across Canada. Measurements: Practice patterns regarding access creation and maintenance, including indications and contraindications to fistula creation, as well as program-wide facilitators of and barriers to VA. Methods: A small group of CSN VAWG members determined the scope and created several VA questions which were then reviewed by 5 additional VAWG members (4 nephrologists and 1 VA nurse) to ensure that questions were clear and relevant. The survey was then tested by the remaining members of the VAWG and refinements were made. The final survey version was submitted electronically to relevant clinicians (nephrologists, surgeons, and nurses) involved or interested in VA across Canada. Questions centered around 4 major themes: (1) Practice patterns regarding access creation (preoperative assessment and maturation assessment), (2) Practice patterns regarding access maintenance (surveillance and salvage), (3) Indications and contraindications for arteriovenous (AV) access creation, and (4) Facilitators of and barriers to fistula creation and utilization. Results: Eighty two percent (84 of 102) of invited participants completed the survey; the majority were nurses or VA coordinators (55%) with the remainder consisting of nephrologists (21%) and surgeons (20%). Variation in practice was noted in utility of preoperative Doppler ultrasound, interventions to assist nonmaturing fistulas, and procedures to salvage failing or thrombosed AV-access. Little consensus was seen regarding potential contraindications to AV-access creation (with the exception of limited life expectancy and poor vasculature on preoperative imaging, which had high agreement). Frequent barriers to fistula utilization were primary failure (77% of respondents) and long maturation times (73%). Respondents from centers with low fistula prevalence also cited long surgical wait times as an important barrier to fistula creation, whereas those from centers with high fistula prevalence cited access to multidisciplinary teams and interventional radiology as keys to successful fistula creation and utilization. Conclusions: There is significant variation in VA practice across Canada and little consensus among Canadian clinicians regarding contraindications to fistula creation. Further high-quality studies are needed with regard to appropriate fistula placement to help guide clinical practice. PMID- 29511570 TI - Protocol for the STAR (Sheffield Treatments for ADHD) project: an internal pilot study assessing the feasibility of the Trials within Cohorts (TwiCs) design to test the effectiveness of interventions for children with ADHD. AB - Background: Attention deficit hyperactivity disorder (ADHD) is a common and growing problem and a leading cause of child referrals to Child and Adult Mental Health Services (CAMHS). It is a drain on resources across nationally funded support agencies and associated with negative outcomes such as early criminality, school disruption and antisocial behaviour. Mainstream interventions (pharmacological and behavioural) demonstrate effectiveness whilst implemented, but are costly, often have unwanted side effects and do not appear to be affecting long-term outcomes.Development of a robust evidence base for the effectiveness of current and novel interventions and their impact over the long term is required. The aim of the Sheffield Treatments for ADHD Research (STAR) project is to facilitate a rigorous evidence base in order to provide information about the comparative (cost) effectiveness and acceptability of multiple interventions to key stakeholders. Methods: The Trials within Cohorts (TwiCs) design was used to build a cohort of children with a diagnosis of ADHD and conduct a three-armed pilot trial of the clinical and cost effectiveness of two novel interventions: (a) treatment by nutritional therapists and (b) treatment by homoeopaths, compared to (c) treatment as usual.Participants are recruited to the STAR long-term observational cohort, and their outcomes of interest (ADHD symptoms, health-related quality of life, school disruption, resource use and criminality) are measured every 6 months by carers and (blinded) teachers. Two promising interventions were identified for the first randomised controlled trial embedded in the cohort. A random selection of eligible participants is offered treatments (a) and (b). The outcomes of those offered treatment are compared to those not offered treatment using intention to treat (ITT) analysis.The feasibility of recruiting to the cohort and the trial, delivering the interventions, the effectiveness of the interventions and the appropriateness, sensitivity and collectability of outcomes is trialled. Discussion: The results of this trial will provide information on the feasibility of the TwiCs design to facilitate multiple trials of potential interventions for children with ADHD, and the acceptability, clinical and cost effectiveness of two potential interventions for ADHD to ADHD stakeholders including service providers. Future stages of the STAR project will test other treatments informed by the results in stage 1. Trial registration: ISRCTN number 17723526. 10.1186/ISRCTN17723526. Date assigned 27/4/15. PMID- 29511571 TI - Private collection: high correlation of sample collection and patient admission date in clinical microbiological testing complicates sharing of phylodynamic metadata. AB - Infectious pathogens are known for their rapid evolutionary rates with new mutations arising over days to weeks. The ability to rapidly recover whole genome sequences and analyze the spread and evolution of pathogens using genetic information and pathogen collection dates has lead to interest in real-time tracking of infectious transmission and outbreaks. However, the level of temporal resolution afforded by these analyses may conflict with definitions of what constitutes protected health information (PHI) and privacy requirements for de identification for publication and public sharing of research data and metadata. In the United States, dates and locations associated with patient care that provide greater resolution than year or the first three digits of the zip code are generally considered patient identifiers. Admission and discharge dates are specifically named as identifiers in Department of Health and Human Services guidance. To understand the degree to which one can impute admission dates from specimen collection dates, we examined sample collection dates and patient admission dates associated with more than 270,000 unique microbiological results from the University of Washington Laboratory Medicine Department between 2010 and 2017. Across all positive microbiological tests, the sample collection date exactly matched the patient admission date in 68.8% of tests. Collection dates and admission dates were identical from emergency department and outpatient testing 86.7% and 96.5% of the time, respectively, with >99% of tests collected within 1 day from the patient admission date. Samples from female patients were significantly more likely to be collected closer to admission date that those from male patients. We show that PHI-associated dates such as admission date can confidently be imputed from deposited collection date. We suggest that publicly depositing microbiological collection dates at greater resolution than the year may not meet routine Safe Harbor-based requirements for patient de identification. We recommend the use of Expert Determination to determine PHI for a given study and/or direct patient consent if clinical laboratories or phylodynamic practitioners desire to make these data available. PMID- 29511572 TI - Estimating evolutionary rates in giant viruses using ancient genomes. AB - Pithovirus sibericum is a giant (610 Kpb) double-stranded DNA virus discovered in a purportedly 30,000-year-old permafrost sample. A closely related virus, Pithovirus massiliensis, was recently isolated from a sewer in southern France. An initial comparison of these two virus genomes assumed that P. sibericum was directly ancestral to P. massiliensis and gave a maximum evolutionary rate of 2.60 * 10-5 nucleotide substitutions per site per year (subs/site/year). If correct, this would make pithoviruses among the fastest-evolving DNA viruses, with rates close to those seen in some RNA viruses. To help determine whether this unusually high rate is accurate we utilized the well-known negative association between evolutionary rate and genome size in DNA microbes. This revealed that a more plausible rate estimate for Pithovirus evolution is ~2.23 * 10-6 subs/site/year, with even lower estimates obtained if evolutionary rates are assumed to be time-dependent. Hence, we estimate that Pithovirus has evolved at least an order of magnitude more slowly than previously suggested. We then used our new rate estimates to infer a time-scale for Pithovirus evolution. Strikingly, this suggests that these viruses could have diverged at least hundreds of thousands of years ago, and hence have evolved over longer time scales than previously suggested. We propose that the evolutionary rate and time scale of pithovirus evolution should be reconsidered in the light of these observations and that future estimates of the rate of giant virus evolution should be carefully examined in the context of their biological plausibility. PMID- 29511573 TI - Selective venous sampling supports localization of adenoma in primary hyperparathyroidism. AB - Background: Selective venous sampling (SVS) is an invasive localization study for persistent or recurrent hyperparathyroidism. Purpose: To assess the role of SVS in addition to non-invasive imaging for primary hyperparathyroidism (pHPT). Material and Methods: This study was approved by the institutional review board and included 14 patients who underwent SVS and subsequent parathyroidectomy between January 2014 and April 2017 following a clinical diagnosis of pHPT. All patients underwent pre-SVS non-invasive imaging, including ultrasound, computed tomography (CT), and 99mTc-MIBI scintigraphy, and sensitivity was assessed using the operative and pathological findings. Results: In all but one case, a single parathyroid adenoma was responsible for the pHPT; the remaining case exhibited a chemical response following surgical removal of parathyroid tissue. The sensitivity (%) for ultrasound, CT, 99mTc-MIBI scintigraphy, and SVS was 76.9, 84.6, 69.2, and 76.9, respectively. SVS yielded positive results in four patients with discordant results and one patient with non-detectable results on imaging. In seven patients, a significant increase in the intact parathyroid hormone level was recognized only in the thyroid veins. The procedure time was in the range of 52-183 min (median = 89.5 min). Conclusion: The addition of SVS to a non-invasive imaging study would be helpful to locate the responsible lesion of pHPT with discordant or non-detectable results on imaging for initial surgical treatment as well. PMID- 29511574 TI - Comparison of Glycomacropeptide with Phenylalanine Free-Synthetic Amino Acids in Test Meals to PKU Patients: No Significant Differences in Biomarkers, Including Plasma Phe Levels. AB - Introduction: Management of phenylketonuria (PKU) is achieved through low phenylalanine (Phe) diet, supplemented with low-protein food and mixture of free synthetic (FS) amino acid (AA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese-making and does not contain Phe. Lacprodan(r) CGMP-20 used in this study contained a small amount of Phe due to minor presence of other proteins/peptides. Objective: The purpose of this study was to compare absorption of CGMP-20 to FSAA with the aim of evaluating short term effects on plasma AAs as well as biomarkers related to food intake. Methods: This study included 8 patients, who had four visits and tested four drink mixtures (DM1-4), consisting of CGMP, FSAA, or a combination. Plasma blood samples were collected at baseline, 15, 30, 60, 120, and 240 minutes (min) after the meal. AA profiles and ghrelin were determined 6 times, while surrogate biomarkers were determined at baseline and 240 min. A visual analogue scale (VAS) was used for evaluation of taste and satiety. Results: The surrogate biomarker concentrations and VAS scores for satiety and taste were nonsignificant between the four DMs, and there were only few significant results for AA profiles (not Phe). Conclusion: CGMP and FSAA had the overall same nonsignificant short-term effect on biomarkers, including Phe. This combination of FSAA and CGMP is a suitable supplement for PKU patients. PMID- 29511575 TI - Mirror Syndrome in Monochorionic Twin Pregnancy with Acardiac Fetus. AB - We report the case of a 20-year-old patient, primigravida, with twin monochorionic pregnancy, with a weight gain of 6 kg in one week and increased blood pressure. During the ultrasound diagnostic investigation, placental edema and hydrops were identified in both fetuses, which, in association with maternal anasarca and pressure control, constitute the triad for mirror syndrome, also known as triple edema. In addition to being hydropic, one of the twins was an acardiac fetus, which is a rare combination of events. Gestation was terminated at 22 weeks and five days because of high maternal risk. The patient progressed with clinical and laboratory improvement. Our study is relevant in that it documents an extremely rare case and discusses relevant aspects of the symptoms and diagnosis of mirror syndrome. It also systematically reviews the condition. PMID- 29511576 TI - Multiparametric magnetic resonance imaging: Overview of the technique, clinical applications in prostate biopsy and future directions. AB - Multiparametric magnetic resonance imaging (mpMRI) has managed to change the paradigms on prostate cancer detection and risk classification. The most clear cut indication of mpMRI in guidelines is the patients with a history of negative biopsy/increasing prostate-specific antigen (PSA), and presence of additional findings supporting its use in non biopsied patients and active surveillance. mpMRI complements standard clinical exam, PSA measurements, and systematic biopsy, and will miss some tumors that lack enough size or change in tissue density. Use of mpMRI is likely to increase, and further developments in the technique will be important for safe adoption of focal therapy concepts. Here we present a brief summary about mpMRI and its use in detection, risk classification and follow-up of prostate cancer. PMID- 29511578 TI - Male infertility, azoozpermia and cryptozoospermia incidence among three infertility clinics in Turkey. AB - Objective: Semen parameters are directly correlated with the infertility of the male. Incidence rates of male factor infertility, azoospermia and cryptozoospermia differ according to many factors such as geographic region, age, occupation and body weight. The aim of the present study is to determine the incidence of male factor infertility, azoospermia and cryptozoospermia among patients who have been admitted to three separate infertility clinics in Turkey for infertility investigation and analyze the outcomes of these patients. Material and methods: A total of 9733 men, who have been admitted to 3 infertility clinics in Turkey due to infertility between March 2011 and October 2016, were included in the study. Male infertility, azoozpermia and cryptozoospermia incidence were calculated according to WHO criteria. Results: Male factor infertility was determined in 3114 (32%) of the patients including cases with azoospermia and cryptozoospermia. Azoospermia cases were observed in 570 (5.85%) and cryptozoospermia in 850 (8.73%) men. Azoospermic, and cryptozoospermic patients constitute 18.3%, and 27.2% of the male infertility cases. Sperm retrieval rates in diagnostic or oocyte pick-up plus testicular sperm extraction groups were found to be comparable (16.39%, and 41.3%, respectively). Conclusion: The data obtained may help to estimate the number of in vitro fertilization cycles and testicular sperm extraction cases, to determine social security policies, and reproductive potential, and in the light of these data to establish social insurance policies. These data will help patients to decide on treatment alternatives, and guide the urologists about the issue. PMID- 29511577 TI - The relationship between lipoprotein-associated phospholipase A2 with cardiovascular risk factors in testosterone deficiency. AB - Objective: Lipoprotein-associated phospholipase A2 (Lp-PLA2) which is believed to play a role in atherosclerotic inflammatory process due to its function in hydrolysis of phospholipids and release of pro-inflammatory products, is considered as a novel biomarker for vascular risk. In this study we aimed to investigate the alterations in Lp-PLA2 and its relationship with other cardiovascular risk factors in patients with testosterone deficiency. Material and methods: Forty hypogonadic male and 30 healthy male aged between 18-50 years were enrolled in this study. Height-weight, waist-to-hip circumference, body mass index (BMI) blood pressure, and body fat measurements were performed in all subjects. Blood glucose, albumin, total cholesterol, HDL-cholesterol, LDL cholesterol, triglycerides, high sensitive C-reactive protein (hs-CRP), apo-A1, apo-B, fibrinogen, insulin, total testosterone, sex hormone binding globulin (SHBG), small dense low-density lipoprotein (sd-LDL), paraoxonase 1, oxidized low density lipoprotein (ox-LDL) and Lp-PLA 2 values were measured. Free and bioavailable testosterone levels were calculated. Data management was carried out with the statistical program SAS Version 9.2. Statistical evaluations were performed using Analysis of Variance (ANOVA), Kruskal-Wallis test, Wilcoxon test, correlation analysis and chi-square analysis. P values <0.05 were considered statistically significant. Results: In patients with hypogonadism, significant increase in Lp-PLA2 levels were accompanied with risk factors of atherosclerosis, such as increase in total cholesterol, apo-B, sd-LDL, weight, BMI, body fat percentage, and decrease in paraoxonase 1 levels. Although the differences were not significant, similarly ox-LDL, hs-CRP, triglyceride, LDL-cholesterol levels were found to be higher in patients with hypogonadism compared to the control group. The mean level of Lp-PLA2 was the highest when compared with the group of secondary hypogonadism with the lowest testosterone level. Conlusion: Our study has demonstrated that the testosterone deficiency increases cardiovascular risk via its effects on lipid metabolism and Lp-PLA2 can be used to assess this risk. PMID- 29511579 TI - Robotic perineal radical prostatectomy and robotic pelvic lymph node dissection via a perineal approach: The Tugcu Bakirkoy Technique. AB - Objective: To describe The Tugcu Bakirkoy robotic perineal radical prostatectomy and pelvic lymph node dissection technique, and present the results of seven patients. Material and methods: We performed seven robotic perineal radical prostatectomy and pelvic lymph node dissection operation using Da Vinci Xi HD Surgical System (Intuitive Surgical, Inc., Sunnyvale, California, USA) on single Gel-port platform. The operation is completed in 4 stages: stage 1 open perineal dissection and gel port placement, stage 2 robotic perineal radical prostatectomy, stage 3 robotic pelvic lymph node dissection, stage 4 vesico urethral anastomosis. In addition to describing the operation technique step by step, we aimed to present the perioperative and postoperative findings of the seven patients who underwent The Tugcu Bakirkoy Technique. Results: All operations were successfully completed without any complications in fully the robotic procedure by a single surgeon. Demographic data of the patients were as follows: Mean age (62.1+/-8 years), mean body mass index (28.2+/-0.7 kg/m2), mean prostate specific antigen value (10.7+/-3 ng/mL), and mean prostate volume (64.2+/-15.3 cc). Mean operative time (184.1+/-20.2 mins), blood loss (64.2+/ 15.3 cc), hospitalization time (2.1+/-0.6 days), and time to withdrawal of the urethral catheter (7.8+/-0.8 days) were also estimated. According to the pathology results, lymph node metastasis was detected in 3 patients while the surgical margin was positive in one. Conclusion: We demonstrated for the first time that a new The Tugcu Bakirkoy robotic perineal radical prostatectomy technique which was previously tested in a cadaveric model, can be safely applied for the first time in vivo, and presented our results. On the basis of this, for problems that can not be overcome by traditional methods, this method is a good alternative as a way out. In this regard, it is necessary to carry out advanced studies so that this method can be applied to daily practice. PMID- 29511580 TI - Predictive role of neutrophil-to-lymphocyte ratio on upstaging of organ-confined invasive urothelial bladder cancer to non-organ-confined disease. AB - Objective: The aim of this study is to examine the usefulness of preoperative neutrophile-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to monocyte ratios to predict pathological upstaging of invasive bladder cancer who underwent radical cystectomy. Material and methods: A total of 126 patients who underwent radical cystectomy at our clinic between January 2006 and March 2015 were retrospectively analysed. One hundred and twelve patients with organ confined invasive bladder tumors (T2) detected at histopathological examination of transuretral resection material were included in the study. Upstaging was seen at histopathological examination of radical cystectomy specimens of 42 patients. We compared preoperative neutrophile-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio between upstaged and not-upstaged groups. Results: There were no statistically significant correlation between age, time to radical cystectomy, gender, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio ratios and carcinoma in situ in upstaged and non-upstaged groups. Statistical analyses showed that preoperative neutrophile-to-lymphocyte ratio was higher in upstaged patients (p=0.009). In multivariate analysis preoperative neutrophile-to-lymphocyte ratio and positive surgical margin were significantly higher in upstaged group. Conclusion: In organ-confined muscle invasive bladder cancer neutrophile-to-lymphocyte ratio seems to be an acceptable parameter to predict locally advanced disease. PMID- 29511581 TI - Detection of CYP1A1 and GSTP1 gene polymorphisms in bladder cancer patients in a Turkish population using a polymerase chain reaction-restriction fragment length polymorphism method. AB - Objective: Understanding genetic polymorphisms might facilitate the analysis of differences between individuals in their susceptibility to developing cancers as a result of environmental carcinogens. Skin, lung, colon and bladder cancers emerge from biological defects in GSTM1, GSTT1 and GSTP1 gene expressions. In this study, we aimed to investigate whether there was an association between CYP1A1 and GSTP1 gene polymorphisms and bladder cancer in a Turkish population. Material and methods: Blood samples were collected from 120 individuals (60 patients with bladder cancer and 60 healthy individuals), and their DNAs were isolated. A polymerase chain reaction-restriction fragment length polymorphism (PCR - RFLP) method was used to detect the frequencies of CYP1A1 NM_000499.3: c.*1189T > C and GSTP1 NM_000852.3: c.313A > G polymorphisms in bladder cancer patients. Results: The frequency of the CYP1A1: c.*1189 TC genotype and C allele were significantly different between bladder cancer patients and healthy individuals (p=0.001 and p=0.005, respectively). However, there was no significant difference for the GSTP1: c.313 AG genotype or G allele between both study groups (p=0.699 and p=0.360, respectively). Conclusion: A polymorphic site of the CYP1A1 gene might be involved in the development of bladder cancer. However, the investigated GSTP1 polymorphic site did not represent an important risk factor for the development of bladder cancer in a Turkish population. PMID- 29511582 TI - Prognostic influence of 5 alpha reductase inhibitors in patients with localized prostate cancer under active surveillance. AB - Objective: The incidence of prostate adenocarcinoma (PCa) is increased with the use of prostate-specific antigen (PSA). In the current study, we aimed to investigate the impact of 5- alpha- reductase inhibitors (5-ARI) on pathological progression in patients followed by active surveillance (AS). Material and methods: Records of 69 patients with localized prostate cancer under AS (PSA <=15 ng/mL, PSAD <=0.20, <=cT2c, Gleason sum <=3+3, the number of cancer positive cores <=3) were evaluated retrospectively. Patients were followed-up with quarterly PSA testing and semiannual digital rectal examination during the first 2 years, and semiannual PSA testing thereafter. Repeat biopsies were done annually and whenever indicated by clinical findings. Pathological progression was defined as increasing Gleason grade, number of cancer-positive cores, and/or increasing percentage of cancer in any core. Results: Patients using (29/69: 42%) and not using (40/69: 58%) 5-ARI were followed for a median of 39 (IQR: 23-45) and 23.5 (IQR: 17-37.5) months, respectively. Pathological progression was observed in 32% (22/69) of the patients at a median of 25 (IQR: 18-39) months. Pathological progression was observed in 34.5% (10/29) and 30% (12/40) of the patients using and not using 5-ARI, respectively (Log-rank p=0.4151). Definitive treatment was done in 31% (9/29) and 47.5% (19/40) of the patients using and not using 5-ARI, respectively. Patients who did not use 5-ARI received definitive treatment earlier than 5-ARI users (Log-rank p=0.0342). On multivariate analysis, more than 2 cancer-positive cores (HR: 11.62) and age (HR: 0.94) were independently associated with pathological progression (p<0.05), rather than 5 ARI use (p=0.148). Conclusion: More than 2 cancer- positive cores at the initial biopsy was the strongest covariate associated with pathological progression; these patients should not be offered AS. There was no impact of 5-ARI use on pathological progression in AS. PMID- 29511583 TI - Choosing the appropriate size of Amplatz sheath during percutaneous nephrolithotomy-a novel method. AB - Objective: To choose appropriate size Amplatz sheath during percutaneous nephrolithotomy (PCNL) based on retrograde pyelogram. Material and methods: We performed standard PCNL in prone position in 20 patients. All these patients had placement of appropriate size of Amplatz sheath based on retrograde pyelogram images. All patients had nephrostomy tubes postoperatively. The preoperative and postoperative renal parameters, hemoglobin, mean operating time and mean hospitalisation stay were measured. Results: There was no significant difference between the pre-operative and postoperative hemoglobin and creatinine levels. Median operating time was 60.5 mins (45 to 98 mins). The median hospitalisation stay was 4.6 days (3 to 7 days). There was no intraoperative pelvic wall or infundibular injury. Conclusion: Choosing correct size of Amplatz sheath lowers the incidence of kidney hemorrhage and renal function impairment. PMID- 29511584 TI - Efficacy of antegrade and retrograde warm saline pyeloperfusion during renal cryoablation for ureteral preservation. AB - Objective: Cryoablation of renal tumors adjacent to the ureter or pelvicalyceal system carries risks for thermal injury of the collecting system. Although cold antegrade perfusion has been described for radiofrequency ablation, warm saline perfusion for renal cryoablation has not been well-characterized. The purpose of this study was to determine the safety and feasibility of antegrade and retrograde warm saline perfusions during percutaneous renal cryoablation. Material and methods: A retrospective review was performed on 136 patients treated with percutaneous renal cryoablation at a single academic institution between 2009 and 2015. Six patients undergoing antegrade (n=3) or retrograde (n=3) warm saline perfusion for protection of the collecting system were identified. Warm saline was perfused through a 4 French nephrostomy tube in the antegrade technique and through a 6 French end-hole catheter in the retrograde technique. Outcome measures were tumor recurrence rates, success of urothelial preservation, hospital stay, blood loss and procedural time. Results: Four tumors were in the lower pole and two tumors in the middle pole. The mean distance from tumor to ureter was 6.8 mm (0.8-11.5 mm) and no patient developed ureteral stricture. There was no tumor recurrence at a median follow-up of 37.3 months (7 65). The median procedural time was 3 hours and 13 minutes. One patient in each group developed minor complications (Clavien I and II) and there were no major complications. Conclusion: This study demonstrates the feasibility of antegrade and retrograde warm saline perfusion for ureteral preservation during cryoablation, without compromising oncologic outcomes. PMID- 29511585 TI - The outcome of percutaneous nephrolithotomy on >=50 mm staghorn and multiple calyceal stones. AB - Objective: To determine the success rate of percutaneous nephrolithotomy (PNL) in kidney stones over 50 milimeters. Material and methods: Twenty-four patients with a renal stone size of >50 mm between January 2007 and December 2016 were enrolled. Stone-free and complication rates were investigated. Results: Twenty one (87.5%) patients were male and 3 (12.5%) were female. Fifteen (62.5%) stones were located in the right, and 9 (37.5%) in the left kidney. Twenty-one (87.5%) patients were operated using single-access, and three (12.5%) patients were double-access. Thirteen (54%) patients were found to have no stone after operation and 11 (46%) patients had residual stones. Extracorporal shock wave lithotripsy was applied to 5 of 11 patients with residual stones, while flexible ureteroscopy was applied to 6 of them. After additional treatments, 8 (33.5%) patients were observed to be stone free. The stone-free rate was 87.5%. The mean operation time was 135.43 (85-240) minutes. Hemoglobin levels before and after operation were 14.8 (12-16.7) and 12.6 (9.3-15.5), respectively (p=0.001). The hospital stay was 6.04 (4-8) days. Complications were observed in four patients (16.6%). Conclusion: PNL has high stone-free rate on staghorn type large stones compared with multiple calyceal scattered large stones. PMID- 29511586 TI - Investigating knowledge levels of university students about infertility. AB - Objective: The aim of this study was to determine the knowledge levels of university students about infertility and investigate the differences in knowledge levels according to sociodemographic variables and some lifestyle factors. Material and methods: The sample of the study consisted of 9693 undergraduate students (5002 females, 4691 males) from 12 regions. Regions were determined according to Statistical Region Units Classification-1 criteria. Infertility Knowledge Test (IKT) was used as a data collection tool. Results: It was found that university students' IKT scores significantly differed according to gender (p<0.01); age (p<0.05); body mass index (p<0.05); reproductive health education status (p<0.001), presence of infertile individuals around (p<0.001); having sexual intercourse (p<0.001); smoking (p<0.001) and alcohol consumption frequency (p<0.05). Conclusion: University students' lack of knowledge about family planning, effects of age and sexual intercourse timing on infertility was remarkable. However, it was determined that the knowledge level of infertility risk factors related to substance use and body mass index was high. It is believed that increasing the level of knowledge about infertility among individuals will positively effect their awareness of risk factors and facilitate their search for timely medical assistance. Sexual health education can be effective in increasing university students' knowledge of infertility. PMID- 29511587 TI - Long term follow up of proximal hypospadias repair-urethral stricture should be excluded in adults who present with epididymo-orchitis. AB - Objective: Epididymo-orchitis (EO) is a well-known complication of urinary tract infections (UTI) in children. This is commonly seen in children who had hypospadias repair or in those who had surgery for anorectal malformation especially when it results in urethral stricture. However EO occurring as a complication of urethral stricture in adults operated for hypospadias in childhood is not well documented in the literature. Material and methods: This is a retrospective review of four adults who had proximal hypospadias repair in childhood. All four men presented to us with EO. They were thoroughly investigated to rule out presence of urethral stricture. Results: Three patients had urethral stricture of which two responded well to dilatation and one required cystoscopy and visual internal urethrotomy. The fourth patient did not have urethral stricture. EO in this patient is thought to be due to excessive straining during micturition causing reflux into seminal vesicles. Conclusion: Urethral stricture should be excluded in any adult who had a hypospadias repair and presents with EO. Urethral strictures after hypospadias surgery respond well to dilatation and to endoscopic urethrotomy. PMID- 29511588 TI - Management of the patients with persistent Mullerian duct syndrome: Is the ultimate goal testicular descent? AB - Objective: Persistent Mullerian duct syndrome (PMDS) is a rare congenital disease characterized by the presence of rudimentary Mullerian structures within an intra abdominal or hernial sac in a virilized male, often presenting as undescended testes. In this study, we aim to present a series of the PMDS patients who were managed by orchiopexy without removal of Mullerian remnants (MR). Material and methods: Between May 2010 and June 2017, we treated six cases diagnosed as PMDS in our department. Laparoscopy and gonadal biopsy were performed in all patients, and vessel ligation was done in four patients for the first session of Stephen Fowler orchiopexy. After initial diagnosis, genetic analyses and endocrine investigations were performed. Demographic and clinical features of the patients, operative methods and follow-up data were analyzed retrospectively. Results: Mean age of the patients was 5.5 years. Three boys had undergone inguinal surgery due to hernia or undescended testis, while others were diagnosed during laparoscopic investigation of nonpalpable testis. As a definitive operation, testes and MR were completely removed in an adult patient, and the remaining patients were treated with laparoscopic or open orchiopexy with or without utero-cervical splitting and the MRs were left in situ. Two testes atrophied during follow-up period. Conclusion: The goal of the approach in PMDS patients is to preserve testes, as well as carry them to their natural location. Leaving the MR in place is a suitable option for blood circulation of the testes but the long-term results are still unknown. PMID- 29511589 TI - The outcomes of transurethral incision/resection of the prostate (TUIP/TURP) performed early after renal transplantation. AB - Objective: In the early period after renal transplantation, urinary retention stemming from bladder outlet obstruction (BOO) may directly affect graft success. The aim of this study was to evaluate the early and long-term outcomes of transurethral resection of the prostate (TURP) and transurethral incision of prostate (TUIP) procedures performed in the first month following RT due to BOO. Material and methods: Between February 2009 and March 2016, 38 male patients underwent TURP/TUIP due to BOO within the first 30 days of renal transplantation. The urodynamic and renal function assessment results of all patients were collected during the pre-and postoperative periods. All patients were followed up for a minimum of 12 months for short and long-term complications. The results were evaluated retrospectively. Results: The mean age of the patients who underwent operations was 59.2+/-12 years. The median duration of dialysis was 41 months (range 0-180). Before the operation the mean serum creatinine (sCr) level was 1.8+/-0.7 mg/dL, the mean total PSA level was 1.6+/-1.1 ng/mL. Of the voiding parameters, the mean Qmax and Qave were measured as 8.2+/-4.5 mL/sec and 4.6+/ 2.5 mL/sec, respectively. The median post-micturition residual urine (PMR) was 105 mL (range 10-400). TURP/TUIP operations were performed at a median of 19 days (range 8-30) after renal transplantations. None of the patients experienced major complications. In the early postoperative period, 5 patients (13.1%) developed urinary tract infection. The mean decrease in sCr in the first month following TURP/TUIP was 1.4+/-0.4 mg/dL (p<0.001). The mean Qmax (22.4+/-11.1 mL/sec), and Qave (11.7+/-5.4 mL/sec) increased significantly (p<0.001), while the median PMR (15 mL, range 0-205) decreased significantly (p<0.001). The mean follow-up period after the procedure was 46.8+/-23.3 months. During the follow-up period, 3 (7.8%) patients suffered from urethral stricture and 2 (5.2%) patients from bladder neck obstruction. Conclusion: In the surgical treatment of urinary retention arising from BOO in the first month following renal transplantation, TURP/TUIP yield safe and successful results. In addition, regarding the short and long term outcomes, these procedures may be safely performed with low morbidity. PMID- 29511590 TI - Primary high grade testicular leiomyosarcoma: A rare malignancy in a young male. AB - A 27-year-old male presented with a gradually increasing left scrotal mass. There was no significant past medical history. Ultrasonography of the left scrotum showed a hypoechoic, intratesticular mass with solid and cystic components. Laboratory investigations revealed normal serum levels of alpha-fetoprotein, beta human chorionic gonadotropin and lactate dehydrogenase. He underwent left high inguinal orchidectomy due to suspicion of testicular malignancy. After histopathologic examination and immunostaining, a diagnosis of high-grade primary testicular leimyosarcoma was ascertained. Only a few cases of primary intratesticular leiomyosarcoma have been reported in literature with the mean age of presentation of 50 years. In younger individuals, these tumors have been reported in a setting of predisposing factors like anabolic steroid use, testicular germ cell tumors, chronic inflammation of testis and testicular field radiation for treatment of leukemia. We present a case of high grade leiomyosarcoma of testis in a young male without any known predisposing factors. PMID- 29511591 TI - Scrotal Kaposi's Sarcoma in HIV-negative patient: A case report and review of the literature. AB - Kaposi's Sarcoma (KS) is a malignancy that generally effects the skin, and can be systemic with internal organ involvement. It originates from the vascular endothelium. KS's relationship with human immunodeficiency virus (HIV) infection is well known. Isolated scrotal KS in the urogenital system is quite rare and scrotal KS in an HIV-negative patient is limited to a few cases. In this case report, the biopsy result from the violescent nodular lesions on the scrotum of the HIV-negative 81-year-old patient was found compatible with KS and a pathology was not detected in the systemic screening. With a diagnosis of isolated scrotal KS, the patient underwent surgical excision aimed at the lesions on the scrotum. KS is rare in HIV-negative patients and it is associated with human herpes virus 8 infection. PMID- 29511592 TI - Management of a patient with vesicocutaneous fistula presenting 13 years after radiotherapy performed for cervical cancer. AB - A vesicocutaneous fistula (VCF) is a tract that is formed abnormally between the bladder and the external surface of the body. VCF results in a great deal of inconvenience, discomfort, and physical disability for the affected patient. This condition can be caused by extensive trauma with pelvic bone fracture, radical pelvic surgery, irradiation of pelvic malignancies, hip arthroplasty, a large bladder calculus, and various other pathologies. The management of VCF should be approached on a case-by-case basis because of the complexity of the disease. In this report, we present a case of VCF that was managed by using vacuum-assisted closure therapy. A 72-year-old female was diagnosed with VCF as a late complication after radiotherapy for cervical cancer. After radiotherapy, she had lower urinary tract symptoms and was diagnosed as a neurogenic bladder. She started to perform clean intermittent catheterization (CIC). She was subsequently diagnosed as chronic kidney disease stage 5 due to hypertensive nephrosclerosis, and started to receive hemodialysis. Recently, she avoided CIC because of decreased urine output. Despite urinary diversion and surgical debridement, the surgical wound had not healed after several days. After vacuum assisted closure therapy, the surgical wound healed and filled with granulation tissue. This case shows that vacuum-assisted closure therapy is efficient for complicated wound healing of a VCF after radiotherapy. PMID- 29511594 TI - Imbalance of a KLF4-miR-7 auto-regulatory feedback loop promotes prostate cancer cell growth by impairing microRNA processing. AB - The microRNA-transcription factor auto-regulatory feedback loop is a pivotal mechanism for homeostatic regulation of gene expression, and dysregulation of the feedback loop is tightly associated with tumorigenesis and progression. However, the mechanism underlying such dysregulation is still not well-understood. Here we reported that Kruppel-like factor 4 (KLF4), a stemness-associated transcription factor, promotes the transcription of miR-7 to repress its own translation so that a KLF4-miR-7 auto-regulatory feedback loop is established for mutual regulation of their expression. Interestingly, this feedback loop is unbalanced in prostate cancer (PCa) cell lines and patient samples due to an impaired miR-7 processing, leading to decreased mature miR-7 production and attenuated inhibition of KLF4 translation. Mechanistically, enhanced oncogenic Yes associated protein (YAP) nuclear translocation mediates sequestration of p72, a co-factor of the Drosha/DGCR8 complex for pri-miR-7s processing, leading to attenuation of microprocessors' efficiency. Knockdown of YAP or transfection with a mature miR-7 mimic can significantly recover miR-7 expression to restore this feedback loop, and in turn to inhibit cancer cell growth by repressing KLF4 expression in vitro. Thus, our findings indicate that targeting the KLF4-miR-7 feedback loop might be a potential strategy for PCa therapy. PMID- 29511593 TI - Next generation sequencing-based emerging trends in molecular biology of gastric cancer. AB - Gastric cancer (GC) is one of the leading causes of cancer related mortality in the world. Being asymptomatic in nature till advanced stage, diagnosis of gastric cancer becomes difficult in early stages of the disease. The onset and progression of gastric cancer has been attributed to multiple factors including genetic alterations, epigenetic modifications, Helicobacter pylori and Epstein Barr Virus (EBV) infection, and dietary habits. Next Generation Sequencing (NGS) based approaches viz. Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), RNA-Seq, and targeted sequencing have expanded the knowledge base of molecular pathogenesis of gastric cancer. In this review, we highlight recent NGS based advances covering various genetic alterations (Microsatellite Instability, Single Nucleotide Variations, and Copy Number Variations), epigenetic changes (DNA methylation, histone modification, microRNAs) and differential gene expression during gastric tumorigenesis. We also briefly discuss the current and future potential biomarkers, drugs and therapeutic approaches available for the management of gastric cancer. PMID- 29511595 TI - Long noncoding RNA CCAT2 is activated by E2F1 and exerts oncogenic properties by interacting with PTTG1 in pituitary adenomas. AB - Pituitary adenomas, arising from the pituitary gland cells, are one of the most frequent tumors found in the sella region. However, the molecular mechanisms involved in the carcinogenesis and progression of pituitary adenomas is still not understood in detail. Long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2), a newly identified lncRNA, has been reported to be abnormally expressed in some cancers. In the present study, we found that CCAT2 was significantly upregulated in pituitary adenomas tissues. Elevated CCAT2 expression was correlated with poor prognosis in patients with pituitary adenomas. Moreover, CCAT2 expression was activated by E2F1. Loss-of-function and gain-of-function assays showed that CCAT2 positively regulated pituitary adenoma cell proliferation, migration, and invasion. Further investigation demonstrated that CCAT2 interacted with PTTG1, and promoted its stability. Furthermore, CCAT2 affected the expression of downstream genes regulated by PTTG1, including SOX2, DLK1, MMP2, and MMP13. Cumulatively, CCAT2 functions as an oncogene in pituitary adenomas and its overexpression contributes to pituitary adenoma carcinogenesis and progression. PMID- 29511596 TI - High expression of WWP1 predicts poor prognosis and associates with tumor progression in human colorectal cancer. AB - WWP1 (WW domain-containing E3 ubiquitin protein ligase 1), which is frequently up regulated in multiple human malignancies, has been demonstrated to play a critical function in cell proliferation, apoptosis and invasion. However, limited knowledge is known about the expression pattern and prognostic value of WWP1 in colorectal cancer (CRC). In this study, we firstly observed that WWP1 mRNA and protein is commonly up-regulated in CRC tissues compared with normal counterparts. Furthermore, by immunohistochemical analysis in 348 cases of CRC specimens, we demonstrated that the WWP1 protein expression is up-regulated in 58.91% (205/348) samples and detected increasing WWP1 expression is closely correlated with enhanced tumor size (P=0.022), CEA level (P=0.021), T classification (P=0.010), distant metastasis (P=0.021) and TNM stage (P=0.005). Meanwhile, Kaplan-Meier survival analysis showed CRC patients with a high WWP1 expression have a poorer overall survival (P<0.001) and disease-free survival (P=0.001) than those with a low WWP1 expression. Multivariate Cox regression analysis revealed WWP1 is the independent prognostic factors for overall survival rate of CRC patients. What's more, by CCK-8 assays and Transwell assays, we found WWP1 depletion markedly inhibited tumor proliferation and invasion in CRC cells, and cells with WWP1 overexpression had a prominently higher proliferative and invasive capacity. Most notably, we illuminated WWP1 downregulation inactivated PTEN/Akt pathway in CRC cells. Taken together, our studies revealed the prognostic value of WWP1 in CRC and support that WWP1 may act as a molecular target for CRC treatment. PMID- 29511597 TI - AQP8 inhibits colorectal cancer growth and metastasis by down-regulating PI3K/AKT signaling and PCDH7 expression. AB - Colorectal cancer (CRC) is one of the most common malignant cancers and the leading cause of cancer-related deaths in worldwide. Although the monoclonal antibody therapy is prescribed for CRC, the metastasis resistant to therapy is the major cause of death of patients with CRC, which indicating the urgent demands for new therapeutic targets discovery. Aquaporin 8 (AQP8) has been identified alter expressed in several cancers including breast cancer, lung cancer and prostatic carcinoma. Our study demonstrated the functional significance of AQP8 in CRC cells growth and metastasis. Over-expression of AQP8 remarkably decreased growth, aggressiveness and colony formation in the CRC SW480 and HT-29 cells. Mechanistically, AQP8 over-expression inhibited tumorigenic phenotype by inactivating PI3K/AKT signaling and inhibiting PCDH7 expression. Furthermore, in vivo studies using nude mice xenograft and metastasis model identified the pivotal role of AQP8 in CRC cells growth and metastasis. Taken together, the present study verifies the vital role of the endogenous AQP8 in colorectal cancer progression. PMID- 29511598 TI - miR-34a increases the sensitivity of colorectal cancer cells to 5-fluorouracil in vitro and in vivo. AB - : This study was designed to investigate the significance of the effect of miR 34a on 5-fluorouracil (5-FU) sensitivity in vitro and in vivo. miR-34a expression in tumor tissues or serum was determined by quantitative polymerase chain reaction. CRC cell lines HCT116 and SW480 were used to evaluate cell viability, cell apoptosis, and the cell cycle using a cell proliferation assay, flow cytometry, and Western blotting, respectively. For the in vivo studies, xenografts derived from SW480 cells were established to assess the antitumor activity between miR-34a and 5-FU. Patients with high levels of miR-34a expression were found to benefit more from 5-FU-based chemotherapy than patients with low levels of miR-34a expression, regardless of disease stage. Ectopic expression of miR-34a alone or 5-FU alone was found to inhibit CRC cell growth in vitro and in vivo. Moreover, cell growth in vitro and in vivo was further inhibited when miR-34a combined with 5-FU through increasing the rate of cell apoptosis. The potential targets of miR-34a, including CREB1, Bcl-2, Notch 1, Sirt1, and E2F3, were predicted and preliminarily validated and merit further study. CONCLUSION: miR-34a might function as a predictor of fluorouracil chemosensitivity in CRC, and a combination strategy of miR-34a with fluorouracil was expected to be more beneficial for CRC patients. PMID- 29511599 TI - MicroRNA-1294 inhibits the proliferation and enhances the chemosensitivity of glioma to temozolomide via the direct targeting of TPX2. AB - MicroRNA-1294 (miR-1294) has been reported to be involved in the progression of esophageal squamous cell carcinoma. However, the function and the mechanisms of miR-1294 in glioma remain unclear. In this study, we explore the potential biological roles of miR-1294 in glioma cell lines. First, we detected the aberrant down-regulation of miR-1294 in glioma tissues and cell lines. Second, we determined that miR-1294 suppresses the proliferation, migration and invasiveness and enhances the chemosensitivity of glioma cells lines to temozolomide. Third, we found that the targeting protein for Xenopus kinesin-like protein 2 (TPX2) is the functional target of miR-1294; miR-1294 acts through TPX2 to exert an important biological effect in glioma. Importantly, TPX2 knockdown had the same effect on glioma cell lines as miR-1294 overexpression. In addition, when TPX2 was up-regulated in these cells, the effects of miR-1294 on glioma cell lines were suppressed. Moreover, the effect of miR-1294 on glioma was verified using a xenograft model. These findings demonstrated that miR-1294 inhibits the development of glioma by targeting TPX2. These findings provide a new potential therapeutic target for glioma treatment. PMID- 29511600 TI - Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. AB - In this study, we investigated the role of cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC) progression. We showed that CAFs secrete high levels of IL-6, which promoted stem cell-like properties in HCC cells by activating Notch signaling through STAT3 Tyr705 phosphorylation. These effects were abolished by Notch1 shRNA knockdown in HCC cells or treatment with an IL-6 neutralizing antibody or the p-STAT3 (Tyr705) inhibitor cryptotanshinone. Xenografted liver tumors were larger in nude mice injected with HCC cells and CAFs than in those receiving HCC cells alone. Moreover, immunohistochemical analysis of liver tissue specimens from 88 HCC patients revealed that high nuclear Notch intracellular domain (nNICD) levels in HCC cells correlated with poor prognosis in patients. These findings suggest that IL-6 secreted by CAFs promotes stem cell-like properties in HCC cells by enhancing STAT3/Notch signaling. PMID- 29511601 TI - The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. AB - Drug repositioning is a highly studied alternative strategy to discover and develop anticancer drugs. This drug development approach identifies new indications for existing compounds. Ivermectin belongs to the group of avermectins (AVM), a series of 16-membered macrocyclic lactone compounds discovered in 1967, and FDA-approved for human use in 1987. It has been used by millions of people around the world exhibiting a wide margin of clinical safety. In this review, we summarize the in vitro and in vivo evidences demonstrating that ivermectin exerts antitumor effects in different types of cancer. Ivermectin interacts with several targets including the multidrug resistance protein (MDR), the Akt/mTOR and WNT-TCF pathways, the purinergic receptors, PAK-1 protein, certain cancer-related epigenetic deregulators such as SIN3A and SIN3B, RNA helicase, chloride channel receptors and preferentially target cancer stem-cell like population. Importantly, the in vitro and in vivo antitumor activities of ivermectin are achieved at concentrations that can be clinically reachable based on the human pharmacokinetic studies done in healthy and parasited patients. Thus, existing information on ivermectin could allow its rapid move into clinical trials for cancer patients. PMID- 29511602 TI - Infectious Disease Risk and Vaccination in Northern Syria after 5 Years of Civil War: The MSF Experience. AB - Introduction: In 2015, following an influx of population into Kobane in northern Syria, Medecins Sans Frontieres (MSF) in collaboration with the Kobane Health Administration (KHA) initiated primary healthcare activities. A vaccination coverage survey and vaccine-preventable disease (VPD) risk analysis were undertaken to clarify the VPD risk and vaccination needs. This was followed by a measles Supplementary Immunization Activity (SIA). We describe the methods and results used for this prioritisation activity around vaccination in Kobane in 2015. Methods: We implemented a pre-SIA survey in 135 randomly-selected households in Kobane using a vaccination history questionnaire for all children <5 years. We conducted a VPD Risk Analysis using MSF 'Preventive Vaccination in Humanitarian Emergencies' guidance to prioritize antigens with the highest public health threat for mass vaccination activities. A Measles SIA was then implemented and followed by vaccine coverage survey in 282 randomly-selected households targeting children <5 years. Results: The pre-SIA survey showed that 168/212 children (79.3%; 95%CI=72.7-84.6%) had received one vaccine or more in their lifetime. Forty-three children (20.3%; 95%CI: 15.1-26.6%) had received all vaccines due by their age; only one was <12 months old and this child had received all vaccinations outside of Syria. The VPD Risk Analysis prioritised measles, Haemophilus Influenza type B (Hib) and Pneumococcus vaccinations. In the measles SIA, 3410 children aged 6-59 months were vaccinated. The use of multiple small vaccination sites to reduce risks associated with crowds in this active conflict setting was noted as a lesson learnt. The post-SIA survey estimated 82% (95%CI: 76.9-85.9%; n=229/280) measles vaccination coverage in children 6-59 months. Discussion: As a result of the conflict in Syria, the progressive collapse of the health care system in Kobane has resulted in low vaccine coverage rates, particularly in younger age groups. The repeated displacements of the population, attacks on health institutions and exodus of healthcare workers, challenge the resumption of routine immunization in this conflict setting and limit the use of SIAs to ensure sustainable immunity to VPDs. We have shown that the risk for several VPDs in Kobane remains high. Conclusion: We call on all health actors and the international community to work towards re-establishment of routine immunisation activities as a priority to ensure that children who have had no access to vaccination in the last five years are adequately protected for VPDs as soon as possible. PMID- 29511603 TI - Levels of Patient Satisfaction on Integrative Medicine Before and After Implementation of Diagnosis-related Groups. AB - Objectives: The aim of this article is to study patient satisfaction with complementary and alternative medicine (CAM) in an in-hospital setting before and after the introduction of diagnosis-related groups (DRGs). Methods: Patients were interviewed regarding a general evaluation of their hospital stay, the psychological talking therapy, the nutrition therapy, and the overall success of the treatment. Results: The medical treatment was evaluated by 1158 patients. A very good success was reported by 347, a good by 609, a moderate by 181, and none by 21 patients. DRG implementation showed no significant effects. Psychological talking therapy was evaluated as "very good" (P <= .05). With regard to the success of the medical talking and nutrition therapy, there were no significant differences (P >= .05) between the time before and after DRG implementation. Conclusion: Broadening conventional medical treatment with CAM practices can lead to a parallel treatment of DRGs in hospitals working with complementary medicine. This results in very patient-centered therapies, which may impact patient satisfaction. PMID- 29511604 TI - Genetic variation and DNA fingerprinting of durian types in Malaysia using simple sequence repeat (SSR) markers. AB - Durian (Durio zibethinus) is one of the most popular tropical fruits in Asia. To date, 126 durian types have been registered with the Department of Agriculture in Malaysia based on phenotypic characteristics. Classification based on morphology is convenient, easy, and fast but it suffers from phenotypic plasticity as a direct result of environmental factors and age. To overcome the limitation of morphological classification, there is a need to carry out genetic characterization of the various durian types. Such data is important for the evaluation and management of durian genetic resources in producing countries. In this study, simple sequence repeat (SSR) markers were used to study the genetic variation in 27 durian types from the germplasm collection of Universiti Putra Malaysia. Based on DNA sequences deposited in Genbank, seven pairs of primers were successfully designed to amplify SSR regions in the durian DNA samples. High levels of variation among the 27 durian types were observed (expected heterozygosity, HE = 0.35). The DNA fingerprinting power of SSR markers revealed by the combined probability of identity (PI) of all loci was 2.3*10-3. Unique DNA fingerprints were generated for 21 out of 27 durian types using five polymorphic SSR markers (the other two SSR markers were monomorphic). We further tested the utility of these markers by evaluating the clonal status of shared durian types from different germplasm collection sites, and found that some were not clones. The findings in this preliminary study not only shows the feasibility of using SSR markers for DNA fingerprinting of durian types, but also challenges the current classification of durian types, e.g., on whether the different types should be called "clones", "varieties", or "cultivars". Such matters have a direct impact on the regulation and management of durian genetic resources in the region. PMID- 29511605 TI - Hypothermia in a Rural Setting: An Emergency Medicine Simulation Scenario. AB - Patients presenting with hypothermia in a rural emergency department can be quite challenging to manage without significant mortality and morbidity. Standard medical school curricula do not fully prepare trainees for the unique aspects of practice in northern rural and remote communities. Training opportunities on site may provide a solution to this lack of experience. However, these communities often have limited simulation-based resources and expertise for conducting and developing simulation scenarios. In this technical report, we outline a hypothermia simulation that utilizes only basic resources and is, thus, practical for rural and remote facilities. The aim of this report is to better equip trainees, clinicians, and emergency department staff who may encounter such a scenario in their practice. While the simulation is specifically designed for medical students, resident doctors, and emergency department staff, it could also be applicable in other low-resource settings, such as military bases, search and rescue stations, and arctic travel and tourism infirmaries. PMID- 29511606 TI - Antioxidant and antiplatelet potential of different methanol fractions and flavonols extracted from onion (Allium cepa L.). AB - In this study, we reported the potential of various methanol fractions of onion (MFO) and its components quercetin and quercetin glucosides on platelet aggregation and antioxidant activity. The onion extracts were separated into several fractions using methanol and water. Further, these extracts were analyzed using simple high-performance liquid chromatography-diode array detector method to separate quercetin (Q), quercetin-4'-O-monoglucoside and quercetin-3, 4'-O diglucoside from onion sample. It was observed that the bioactive compounds were accumulated in the non-polar portions rather than in the polar one. MFO and flavonol glucosides inhibited collagen-induced platelet aggregation, and the anti aggregatory effects were comparatively studied using rat PRP (platelet-rich plasma). Among the extracted compounds, quercetin was found as a potent inhibitor of platelet aggregation compared to quercetin glucosides, whereas quercetin glucosides showed high antioxidant activities. These results suggest that MFO, quercetin and quercetin glucosides have powerful antiplatelet and antioxidant activities. These studies provide possible information leading to the intake of onions rich in these flavonols as a dietary supplement and functional food ingredient to prevent thrombosis and cardiovascular and oxidative stress-related diseases and might be utilized as a real source of valuable phytochemicals for the pharmaceutical and food industries for the development of antioxidant, anticoagulant and antiplatelet agents. PMID- 29511607 TI - Antimicrobial and anticancer activity of AgNPs coated with Alphonsea sclerocarpa extract. AB - The synthesis and characterization of an aggregate of AgNPs coated with plant extract (PE) from Alphonsea sclerocarpa and its significant antimicrobial activity and inhibition on K562 (blood cancer) cells have been appended in the article. Synthesis of aggregate [(AgNPs)-(PE)] has been followed by a facile eco friendly approach without using any harmful chemicals. The morphology of an aggregate [(AgNPs)-(PE)] was confirmed by TEM and SEM microscopic characterizations. Properties like solid state, the presence of functional groups, and elemental composition have been characterized through the XRD, FTIR, and EDAX. The biocompatibility of synthesized aggregate of [(AgNPs)-(PE)] was confirmed by the MTT assay. An in vitro cell (HEK293)-based studies were performed for the biocompatibility tests and it is found that the aggregate [(AgNPs)-(PE)] is not harmful to normal/healthy cells. Even though A. sclerocarpa show the antimicrobial (antibacterial and antifungal) activity, it has been further enhanced with the developed aggregate of [(AgNPs)-(PE)]. Furthermore, it has been extended to examine the cellular inhibition on K562 cells and obtained > 75% cell inhibition for 24 h treated cells. PMID- 29511608 TI - Ligand complex structures of l-amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813 and its conformational change. AB - : l-Amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813 (l-AAO/MOG) catalyzes both the oxidative deamination and oxidative decarboxylation of the alpha-group of l-Lys to produce a keto acid and amide, respectively. l-AAO/MOG exhibits limited specificity for l-amino acid substrates with a basic side chain. We previously determined its ligand-free crystal structure and identified a key residue for maintaining the dual activities. Here, we determined the structures of l-AAO/MOG complexed with l-Lys, l-ornithine, and l-Arg and revealed its substrate recognition. Asp238 is located at the ceiling of a long hydrophobic pocket and forms a strong interaction with the terminal, positively charged group of the substrates. A mutational analysis on the D238A mutant indicated that the interaction is critical for substrate binding but not for catalytic control between the oxidase/monooxygenase activities. The catalytic activities of the D238E mutant unexpectedly increased, while the D238F mutant exhibited altered substrate specificity to long hydrophobic substrates. In the ligand-free structure, there are two channels connecting the active site and solvent, and a short region located at the dimer interface is disordered. In the l-Lys complex structure, a loop region is displaced to plug the channels. Moreover, the disordered region in the ligand-free structure forms a short helix in the substrate complex structures and creates the second binding site for the substrate. It is assumed that the amino acid substrate enters the active site of l-AAO/MOG through this route. Database: The atomic coordinates and structure factors (codes 5YB6, 5YB7, and 5YB8) have been deposited in the Protein Data Bank (http://wwpdb.org/). EC numbers: 1.4.3.2 (l-amino acid oxidase), 1.13.12.2 (lysine 2-monooxygenase). PMID- 29511609 TI - miR-373 regulates inflammatory cytokine-mediated chondrocyte proliferation in osteoarthritis by targeting the P2X7 receptor. AB - Inflammatory cytokines commonly initiate extreme changes in the synovium and cartilage microenvironment of osteoarthritis (OA) patients, which subsequently cause cellular dysfunction, especially in chondrocytes. It has been reported that induction of the purinergic P2X7 receptor (P2X7R) can regulate the expression of a variety of inflammatory factors, including interleukin (IL)-6 and -8, leading to OA pathogenesis. However, knowledge of the mechanism of upregulation of P2X7R in OA is still incomplete, and its role in chondrocyte proliferation is also not clear. It was reported previously that the expression of P2X7R was controlled by certain microRNAs, and so we tested the expression of several microRNAs and found that microRNA-373 (miR-373) was downregulated in the chondrocytes from OA patients. Regarding the mechanism of action, miR-373 inhibited chondrocyte proliferation by suppressing the expression of P2X7R, as well as inflammatory factors such as IL-6 and IL-8. Furthermore, the proliferative and pro inflammatory effects of miR-373 on the chondrocytes could be suppressed by a P2X7R antagonist, further suggesting that miR-373 mediates chondrocyte proliferation and inflammation by targeting P2X7R. Generally, our results suggest a novel method for OA treatment by targeting the miR-373-P2X7R pathway. PMID- 29511610 TI - Aberrant Ki-67 expression through 3'UTR alternative polyadenylation in breast cancers. AB - Ki-67 (MKI67) is a marker of cellular proliferation of cancer. Here, we show that Ki-67 is post-transcriptionally regulated through alternative polyadenylation (APA) and microRNAs in breast cancer. We show that shortening of the Ki-67 3'UTR results in the loss of the binding sites for the suppressive miRNAs and thus renders the transcript with a shortened 3'UTR insusceptible to miRNA-mediated suppression. This APA-mediated shortening of the Ki-67 3'UTR contributes to increased mRNA stability and enhanced translational efficiency. In summary, our results not only highlight the post-transcriptional regulation of Ki-67 involving APA and microRNAs but also suggest that Ki-67 3'UTR disruption could serve as a molecular marker in breast cancer. PMID- 29511611 TI - miR-322-5p targets IGF-1 and is suppressed in the heart of rats with pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here, we show that miR-322-5p (the rodent orthologue of miR-424-5p) expression is decreased in the right ventricle of monocrotaline-treated rats, a model of PAH, whereas a putative target insulin-like growth factor 1 (IGF-1) is increased. IGF-1 mRNA was enriched 16-fold in RNA immunoprecipitated with Ago2, indicating binding to miR 322-5p. In cell transfection experiments, miR-322-5p suppressed the activity of a luciferase reporter containing a section of the IGF-1 3' untranslated region (UTR) as well as IGF-1 mRNA and protein levels. Taken together, these data suggest that miR-322 targets IGF-1, a process downregulated in PAH-related RV hypertrophy. PMID- 29511612 TI - Regucalcin confers resistance to amyloid-beta toxicity in neuronally differentiated PC12 cells. AB - Amyloid-beta (Abeta), a primary component of amyloid plaques, has been widely associated with the pathogenesis of Alzheimer's disease. The Ca2+-binding protein regucalcin (RGN) plays multiple roles in maintaining cell functions by regulating intracellular calcium homeostasis, various signaling pathways, and gene expression systems. Here, we investigated the functional role of RGN against Abeta-induced cytotoxicity in neuronally differentiated PC12 cells. Overexpression of RGN reduced Abeta-induced apoptosis by reducing mitochondrial dysfunction and caspase activation. It also attenuated Abeta-induced reactive oxygen species production and oxidative damage and decreased Abeta-induced nitric oxide (NO) overproduction, upregulation of inducible NO synthase by nuclear factor-kappaB, and nitrosative damage. Interestingly, the genetic disruption of RGN increased the susceptibility of neuronally differentiated PC12 cells to Abeta toxicity. Thus, RGN possesses antioxidant activity against Abeta-induced oxidative and nitrosative stress and may play protective roles against Abeta induced neurotoxicity in Alzheimer's disease. PMID- 29511613 TI - ULBP1 is induced by hepatitis C virus infection and is the target of the NK cell mediated innate immune response in human hepatocytes. AB - Natural killer (NK) cells through their NK group 2 member D (NKG2D) receptors recognize NKG2D ligands such as UL16-binding proteins (ULBPs) on virus-infected cells and subsequently trigger the host innate immune response. In the present study, we demonstrated that hepatitis C virus (HCV) induced the cell surface expression of ULBP1 in human immortalized hepatocyte PH5CH8 cells and human hepatoma HuH-7 cell-derived RSc cells. Interestingly, NK cell line NK-92 induced cytotoxicity and interferon-gamma mRNA expression and subsequently reduced the levels of HCV RNA replication during co-culture with HCV-infected RSc cells. From these results, we conclude that ULBP1 is a target of the NK cell-mediated innate immune response in HCV-infected human hepatocytes. PMID- 29511614 TI - The combined effect of Pdx1 overexpression and Shh manipulation on the function of insulin-producing cells derived from adipose-tissue stem cells. AB - Pancreatic and duodenal homeobox 1 (Pdx1) and Sonic hedgehog (Shh) are the key regulators of beta-cell function. In vitro experiments have shown that there is significant cooperation between Pdx1 and Shh with regard to the production and maintenance of insulin-producing cells (IPCs). In this study, the combined effect of Pdx1 overexpression and Shh manipulation on the function of adipose tissue derived IPCs was determined. A eukaryotic expression vector (Pdx1- pCDNA3.1(+)) was constructed and transfected into a Chinese hamster ovary (CHO) cell line. Adipose tissue-derived mesenchymal stem cells (ADMSCs) obtained from rats were assigned to two groups [control (C) and manipulated (M)] and differentiated into IPCs. Manipulated cells were treated with a mixture of FGF-beta and cyclopamine and recombinant Shh protein at days 3 and 11, respectively, and transfected with Pdx1- pCDNA3.1(+) at day 10. The expression of multiple genes related to function of beta cells was analyzed using real-time PCR. The functionality of IPCs in vitro was analyzed through dithizone (DTZ) staining and ELISA. IPCs were injected into the tail vein of diabetic rats, and blood glucose and insulin concentrations were measured. CHO cells transfected with Pdx1- pCDNA3.1(+) showed a significantly higher expression of Pdx1 compared with nontransfected cells. Manipulated IPCs exhibited a significantly higher expression of MafA, Nkx2.2, Nkx6.1, Ngn3, insulin, and Isl1 and a higher insulin secretion in response to glucose challenge in relation to control cells. Rats that received manipulated IPCs exhibited a higher ability to normalize blood glucose and insulin secretion when compared to controls. Our protocol might be used for more efficient cell therapy of patients with diabetes in the future. PMID- 29511615 TI - Divalent metal modulation of Japanese flounder (Paralichthys olivaceus) purinergic P2X7 receptor. AB - Paralichthys olivaceus P2X7 receptor (poP2X7R) is a recently identified as a P2X7 purinergic receptor involved in innate immunity of the Japanese flounder Paralichthys olivaceus. Divalent metals are allosteric modulators of mammalian P2XRs, but there is no information for fish P2XRs. Here, we characterized the effects of divalent metals on poP2X7R channel activity by electrophysiology and molecular biology techniques. Copper, zinc and mercury inhibited poP2X7R-mediated currents with different maximal inhibition potency, while cadmium had no effect on poP2X7R activity. Mercury-induced inhibition was irreversible, but the inhibitory effects of copper and zinc were reversed after washout. Cooper and zinc also reduced poP2X7R-mediated interleukin-1 mRNA production. These findings suggest that divalent metals have potential effects on the Japanese flounder innate immune response through modulation of poP2X7R activity. PMID- 29511616 TI - Biophysical characterisation of the recombinant human frataxin precursor. AB - Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81 210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1-210). We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes. His6-TAT-FXN1-210 was expressed in Escherichia coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing. The protein was found to be stable and monomeric, with the N-terminal stretch (residues 1-89) mostly unstructured and the C-terminal domain properly folded. The experimental data suggest a complex picture for the folding process of full-length frataxin in vitro: the presence of the N-terminal region increased the tendency of FXN to aggregate at high temperatures but this could be avoided by the addition of low concentrations of GdmCl. The purified precursor was translocated through cell membranes. In addition, immune response against His6-TAT-FXN1-210 was measured, suggesting that the C-terminal fragment was not immunogenic at the assayed protein concentrations. Finally, the recognition of recombinant FXN by cellular proteins was studied to evaluate its functionality. In this regard, cysteine desulfurase NFS1/ISD11/ISCU was activated in vitro by His6-TAT-FXN1-210. Moreover, the results showed that His6-TAT-FXN1-210 can be ubiquitinated in vitro by the recently identified frataxin E3 ligase RNF126, in a similar way as the FXN1-210, suggesting that the His6-TAT extension does not interfere with the ubiquitination machinery. PMID- 29511617 TI - Histone methylation regulates Hif-1 signaling cascade in activation of hepatic stellate cells. AB - Liver fibrosis is characterized by deposition of excessive extracellular matrix (ECM). The major source of ECM is activated hepatic stellate cells (HSCs). Previously, we reported that hypoxia-inducible factor-1 (Hif-1) regulates activation of HSCs through autophagy. In current work, human HSC cell line LX-2 was used as cell model. It was determined that trimethylation of H3 histone on lysine 4 (H3K4me3) occurred in the Hif-1 transcriptional complex. Inhibition of modifications of histone methylation suppressed Hif-1 nuclear transport, autophagosome formation, and activation of LX-2 cells. These data suggest that histone methylation modification plays an important role in the Hif-1 signaling cascade regulating HSC activation. PMID- 29511618 TI - Suboptimal extracellular pH values alter DNA damage response to induced double strand breaks. AB - Conditions leading to unrepaired DNA double-stranded breaks are potent inducers of genetic instability. Systemic conditions may lead to fluctuation of hydrogen ions in the cellular microenvironment, and we show that small variations in extracellular pH, termed suboptimal pHe, can decrease the efficiency of DNA repair in the absence of intracellular pH variation. Recovery from bleomycin induced DNA double-stranded breaks in fibroblasts proceeded less efficiently at suboptimal pHe values ranging from 7.2 to 6.9, as shown by the persistence of repair foci, reduction of H4K16 acetylation, and chromosomal instability, while senescence or apoptosis remained undetected. By allowing escape from these protective mechanisms, suboptimal pHe may therefore enhance the genotoxicity of double-stranded breaks, leading to genetic instability. PMID- 29511619 TI - Normal development of mice lacking PAXX, the paralogue of XRCC4 and XLF. AB - DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR). Inactivation of NHEJ factors Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, and Artemis impairs V(D)J recombination and blocks lymphocyte development. Paralogue of XRCC4 and XLF (PAXX) is an accessory NHEJ factor that has a significant impact on the repair of DNA lesions induced by ionizing radiation in human, murine, and chicken cells. However, the role of PAXX during development is poorly understood. To determine the physiological role of PAXX, we deleted part of the Paxx promoter and the first two exons in mice. Further, we compared Paxx-knockout mice with wild-type (WT) and NHEJ-deficient controls including Ku80- and Dna-pkcs-null and severe combined immunodeficiency mice. Surprisingly, Paxx-deficient mice were not distinguishable from the WT littermates; they were the same weight and size, fertility status, had normal spleen, thymus, and bone marrow. Paxx-deficient mice had the same number of chromosomal and chromatid breaks as WT mice. Moreover, Paxx-deficient primary B lymphocytes had the same level of CSR as lymphocytes isolated from WT mice. We concluded that PAXX is dispensable for normal mouse development. PMID- 29511620 TI - Serum amyloid A1 (SAA1) protein in human colostrum. AB - Proteins of the serum amyloid A (SAA) family have been remarkably conserved in evolution. Their biologic function(s) are not fully defined but they are likely to be a part of primordial host defense. We have detected a ~ 12-kDa protein reacting with antibodies against serum amyloid A (SAA) in human colostrum by western blotting. Mass spectrometry identified the reactive species as SAA1, previously identified as a prominent member of the acute-phase response in serum. Our finding SAA1 in human colostrum contrasts with bovine, caprine and ovine colostrum where a species corresponding to putative SAA3 is uniformly present. SAA1 protein in human colostrum presumably contributes to neonatal protection. PMID- 29511621 TI - Robust DNA repair in PAXX-deficient mammalian cells. AB - To ensure genome stability, mammalian cells employ several DNA repair pathways. Nonhomologous DNA end joining (NHEJ) is the DNA repair process that fixes double strand breaks throughout the cell cycle. NHEJ is involved in the development of B and T lymphocytes through its function in V(D)J recombination and class switch recombination (CSR). NHEJ consists of several core and accessory factors, including Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, Artemis, and XLF. Paralog of XRCC4 and XLF (PAXX) is the recently described accessory NHEJ factor that structurally resembles XRCC4 and XLF and interacts with Ku70/Ku80. To determine the physiological role of PAXX in mammalian cells, we purchased and characterized a set of custom-generated and commercially available NHEJ-deficient human haploid HAP1 cells, PAXXDelta, XRCC4Delta , and XLFDelta . In our studies, HAP1 PAXXDelta cells demonstrated modest sensitivity to DNA damage, which was comparable to wild type controls. By contrast, XRCC4Delta and XLFDelta HAP1 cells possessed significant DNA repair defects measured as sensitivity to double-strand break inducing agents and chromosomal breaks. To investigate the role of PAXX in CSR, we generated and characterized Paxx-/- and Aid-/- murine lymphoid CH12F3 cells. CSR to IgA was nearly at wild-type levels in the Paxx-/- cells and completely ablated in the absence of activation-induced cytidine deaminase (AID). In addition, Paxx-/- CH12F3 cells were hypersensitive to zeocin when compared to wild-type controls. We concluded that Paxx-deficient mammalian cells maintain robust NHEJ and CSR. PMID- 29511622 TI - Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract. AB - The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration. PMID- 29511623 TI - A novel mutation in exon 9 of Cullin 3 gene contributes to aberrant splicing in pseudohypoaldosteronism type II. AB - Pseudohypoaldosteronism type II (PHAII) is a rare renal tubular disease that is inherited in an autosomal dominant manner. Mutations in four genes (WNK1,WNK4,CUL3, and KLHL3) have been identified to be responsible for this disease. Cullin 3 (CUL3) and KLHL3 are subunits of Cullin-RING E3 ubiquitin ligase complexes, and the serine-threonine kinases WNK1 and WNK4 are substrates of this ubiquitin ligase. For CUL3, all mutations associated with PHAII exclusively lead to exon 9 skipping. In this study, we identified a Chinese PHAII kindred caused by a novel synonymous mutation (c.1221A > G p.Glu407Glu) in CUL3, and explored its effects on exon 9 abnormal splicing through an in vitro splicing assay and study of the patients' RNA. We obtained evidence that this synonymous mutation leads to complete exon 9 skipping, and in silico bioinformatics analysis demonstrated that the CUL3 c.1221A > G mutation might decrease the ratio of exonic splicing enhancers and silencers. This is the first report of PHAII in Chinese patients with a novel CUL3 mutation. Our findings add a novel pathogenic splicing variant to the CUL3 mutational spectrum and provide reference for further research on mechanisms of splicing modulation and development of potential therapeutic reagents for PHAII. PMID- 29511624 TI - p62/SQSTM1 promotes rapid ubiquitin conjugation to target proteins after endosome rupture during xenophagy. AB - Autophagy is a bulk degradation pathway, and selective autophagy to remove foreign entities is called xenophagy. The conjugation of ubiquitin to target pathogens is an important process in xenophagy but when and where this ubiquitination occurs remains unclear. Here, we analyzed the temporal sequence and subcellular location of ubiquitination during xenophagy using time-lapse observations, with polystyrene beads mimicking invading pathogens. Results revealed accumulation of a ubiquitination marker around the beads within 3 min after endosome rupture. Recruitment of ubiquitin to the beads was significantly delayed in p62-knockout murine embryonic fibroblast cells, and this delay was rescued by ectopic p62 expression. Ectopic expression of a phosphorylation mimicking p62 mutated at serine residue 405 (equivalent to human serine residue 403) rescued this delay, but its unphosphorylated form did not. These results indicate that ubiquitination mainly occurs after endosome rupture and suggest that p62, specifically the phosphorylated form, promotes ubiquitin conjugation to target proteins in xenophagy. PMID- 29511625 TI - A standardized fold change method for microarray differential expression analysis used to reveal genes involved in acute rejection in murine allograft models. AB - Murine transplantation models are used extensively to research immunological rejection and tolerance. Here we studied both murine heart and liver allograft models using microarray technology. We had difficulty in identifying genes related to acute rejections expressed in both heart and liver transplantation models using two standard methodologies: Student's t test and linear models for microarray data (Limma). Here we describe a new method, standardized fold change (SFC), for differential analysis of microarray data. We estimated the performance of SFC, the t test and Limma by generating simulated microarray data 100 times. SFC performed better than the t test and showed a higher sensitivity than Limma where there is a larger value for fold change of expression. SFC gave better reproducibility than Limma and the t test with real experimental data from the MicroArray Quality Control platform and expression data from a mouse cardiac allograft. Eventually, a group of significant overlapping genes was detected by SFC in the expression data of mouse cardiac and hepatic allografts and further validated with the quantitative RT-PCR assay. The group included genes for important reactions of transplantation rejection and revealed functional changes of the immune system in both heart and liver of the mouse model. We suggest that SFC can be utilized to stably and effectively detect differential gene expression and to explore microarray data in further studies. PMID- 29511626 TI - Incidence, risk factors and prognostic characteristics of bone metastases and skeletal-related events (SREs) in breast cancer patients: A systematic review of the real world data. AB - Purpose: The aim was to systematically extrapolate the occurrence, risk factors, prognostic characteristics, management and outcome of bone metastases (BM) and skeletal related events (SREs) of breast cancer survivors in the real world clinical setting. Methods: A systematic literature search of PubMed, Web of Science, EMBASE OvidSP and EBSCO Academic Search Complete was conducted. Published prospective and retrospective papers investigating BM and SREs in breast cancer patients in non-trial settings were identified and systematically reviewed. Results: Twenty-four studies met the inclusion criteria. Incidences of BM based on new diagnosis, length of BM-free interval (BMFI) and number and sites of BM were detected by 17 of 24 studies. Seven studies included in the review were subjected to analyses of risk factors for BM. Developments of SREs regarding the occurrence ratio of total and specific SREs, SERs-free interval (SREFI) and the first-line therapy for SREs were observed in 16 of 24 studies. Out of 5 studies, we extracted uni- and multivariate analysis of risk factor for SREs and out of 16 studies - predictors for survival in breast cancer patients with BM. Conclusions: BM and SREs are common problems in non-trial breast cancer populations. Patient demographics, clinical stage, tumor pathological type, molecular receptors status are significantly risk factors for incidence of BM, SREs and the survival. The unique characteristics of BM and SREs in breast cancer patients should be taken into account in future randomized controlled trials, as to optimize individual treatment options and assure a maximally long good quality of life. PMID- 29511628 TI - Osteitis in the vertebral body due to Treponema pallidum. AB - The patient was referred to us for suspected Bechet's disease and was finally diagnosed with osteitis and skin lesions caused by secondary syphilis. The syphilitic osteitis was confirmed by PCR using a biopsy of the spinal lesion. PMID- 29511629 TI - Introducing the Asian Journal of Urology. PMID- 29511630 TI - Introduction to manuscript by Prof. Donald S. Coffey. PMID- 29511631 TI - Comment on the discovery of prostate specific antigen. PMID- 29511632 TI - Evolution: Back to the future to understand and control prostate cancer. PMID- 29511627 TI - Neonatal brain resting-state functional connectivity imaging modalities. AB - Infancy is the most critical period in human brain development. Studies demonstrate that subtle brain abnormalities during this state of life may greatly affect the developmental processes of the newborn infants. One of the rapidly developing methods for early characterization of abnormal brain development is functional connectivity of the brain at rest. While the majority of resting-state studies have been conducted using magnetic resonance imaging (MRI), there is clear evidence that resting-state functional connectivity (rs-FC) can also be evaluated using other imaging modalities. The aim of this review is to compare the advantages and limitations of different modalities used for the mapping of infants' brain functional connectivity at rest. In addition, we introduce photoacoustic tomography, a novel functional neuroimaging modality, as a complementary modality for functional mapping of infants' brain. PMID- 29511633 TI - History of the discovery and clinical translation of prostate-specific antigen. PMID- 29511636 TI - Locally advanced and high risk prostate cancer: The best indication for initial radical prostatectomy? AB - High risk prostate cancer is a deadly disease that needs aggressive treatment. High risk prostate cancer is often treated with androgen deprivation therapy or combined radiohormonotherapy while there is a place for surgery in cases of operable and resectable locally advanced or high risk disease. This review summarises the results of the different treatment strategies for locally advanced and high risk prostate cancer. Radical prostatectomy monotherapy or in combination with radiotherapy and/or hormonal treatment are analysed. They show that radical prostatectomy is an effective treatment modality for these tumours. After surgery, the results of the pathology and the follow-up of serum PSA may indicate the need of additional adjuvant or salvage treatment strategies. PMID- 29511635 TI - Novel anti-androgen receptor signaling agents: Understanding the mechanisms of resistance. AB - Prostate cancer remains an intractable threat to the lives of men worldwide. Although deaths from prostate cancer (PCa) in the United States have declined in recent years, in other parts of the world Pca mortality is increasing. The introduction of 2nd generation anti-androgen receptor agents into the therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has resulted in modestly increased survival advantages as demonstrated by initial clinical trials. However, analysis of the molecular pathways affected by these agents may lead to new insight into mechanisms of resistance that drive mCRPC, including proliferation and survival signaling pathways that are derepressed by maximum repression of androgen signaling. Combination therapies that involve anti AR signaling agents together with agents that target these pathways establish a paradigm for the development of more effective treatment of mCRPC. In this review, we briefly summarize the current clinical trial literature with regard to novel anti-AR signaling agents such as abiraterone acetate and enzalutamide. We discuss observational data that point to mechanisms of resistance that emerged from these studies. We further present and discuss recent experimental studies that address the mechanisms of resistance to these treatments. Finally, we discuss novel and rational therapeutic approaches, including combination therapy, for patients with mCRPC. PMID- 29511634 TI - Prostate cancer in Asia: A collaborative report. AB - The incidence of prostate cancer (PCa) within Asian population used to be much lower than in the Western population; however, in recent years the incidence and mortality rate of PCa in some Asian countries have grown rapidly. This collaborative report summarized the latest epidemiology information, risk factors, and racial differences in PCa diagnosis, current status and new trends in surgery management and novel agents for castration-resistant prostate cancer. We believe such information would be helpful in clinical decision making for urologists and oncologists, health-care ministries and medical researchers. PMID- 29511638 TI - Robotic assisted laparoscopic simple suprapubic prostatectomy - The Smith Institute for Urology experience with an evolving technique. AB - Objective: Despite a multitude of minimally invasive surgical options available for benign prostatic enlargement, open simple prostatectomy (OSP) remains the standard for large prostates (typically greater than 100 g). OSP, however, is associated with significant morbidity. Recently, a few reports touting robotic application to simple prostatectomy have been published. Herein, we reviewed our series of robotic assisted laparoscopic simple suprapubic prostatectomy (RALSSP) and detailed modifications in our technique as our experience increased. Methods: All RALSSP cases performed between January 2013 and January 2014 were reviewed for demographics, pre-operative features, and perioperative outcomes. All parameters were tabulated and mean values were calculated. Student's t-test was utilized with p < 0.05 deemed significant. Details regarding surgical technique were reviewed and highlighted. Results: Fifteen patients underwent RALSSP during this period. Mean age of these men was 68.7 years. Mean body mass index (BMI) was 28.5 kg/m2. American Society of Anesthesiologists (ASA) score was on average 2.6. Average International Prostate Symptom Score (IPSS) was 16.2 with the majority of men experiencing some adverse clinical sequela of such benign prostatic hyperplasia (BPH). For those patients not in retention, preoperative post-void residual (PVR) was 428 mL. All patients underwent successful RALSSP without need for conversion or need for blood transfusion. Mean estimated blood loss (EBL) was 290 mL. Five patients underwent other concurrent procedures (e.g., cystolithotomy). Mean length of hospital stay (LOS) was 2.4 days and only five patients required continuous bladder irrigation (CBI) postoperatively. Postoperative PVR improved to a mean of 33 mL and IPSS improved to 4.5 (p < 0.001). No major complications were identified. Adaptation of low transverse cystotomy, utilization of a robotic tenaculum in the #3 arm with its control by a surgeon on a second console, and the utilization of mucosal advancement have all subjectively aided in performance of RALSSP and perioperative outcomes. Conclusion: RALSSP allows for feasible performance of prostate adenoma enucleation with low risk of blood transfusion, short LOS, and significant improvement in IPSS and PVR; all while maintaining a minimally invasive approach. The use of a robotic tenaculum controlled by the secondary console and the mucosal advancement facilitate excellent outcomes and may play a role in minimizing hematuria and need for CBI. PMID- 29511637 TI - Current trends in urethral stricture management. AB - The recent International Consultation on Urological Disease (ICUD) panel 2010 confirmed that a urethral stricture is defined as a narrowing of the urethra consequent upon ischaemic spongiofibrosis, as distinct from sphincter stenoses and a urethral disruption injury. Whenever possible, an anastomotic urethroplasty should be performed because of the higher success rate as compared to augmentation urethroplasty. There is some debate currently regarding the critical stricture length at which an anastomotic procedure can be used, but clearly the extent of the spongiofibrosis and individual anatomical factors (the length of the penis and urethra) are important, the limitation for this being extension of dissection beyond the peno-scrotal junction and the subsequent production of chordee. More recently, there has been interest in whether to excise and anastomose or to carry out a stricturotomy and reanastomosis using a Heineke Miculicz technique. Augmentation urethroplasty has evolved towards the more extensive use of oral mucosa grafts as compared to penile skin flaps, as both flaps and grafts have similar efficacy and certainly the use of either dorsal or ventral positioning seems to provide comparable results. It is important that the reconstructive surgeon is well versed in the full range of available repair techniques, as no single method is suitable for all cases and will enable the management of any unexpected anatomical findings discovered intra-operatively. PMID- 29511639 TI - Systematic evaluation of a holmium:yttrium-aluminum-garnet laser lithotripsy device with variable pulse peak power and pulse duration. AB - Objective: The Holmium:yttrium-aluminum-garnet (Ho:YAG) laser is the standard lithotrite for ureteroscopy. This paper is to evaluate a Ho:YAG laser with a novel effect function in vitro, which allows a real-time variation of pulse duration and pulse peak power. Methods: Two types of phantom calculi with four degrees of hardness were made for fragmentation and retropulsion experiments. Fragmentation was analysed at 5 (0.5 J/10 Hz), 10 (1 J/10 Hz), and 20 (2 J/10 Hz) W in non-floating phantom calculi, retropulsion in an ureteral model at 10 (1 J/10 Hz) and 20 (2 J/10 Hz) W using floating phantom calculi. The effect function was set to 25%, 50%, 75%, and 100% of the maximum possible effect function at each power setting. Primary outcomes: fragmentation (mm3), the distance of retropulsion (cm); >=5 measurements for each trial. Results: An increase of the effect feature (25% vs. 100%), i.e., an increase of pulse peak power and decrease of pulse duration, improved Ho:YAG laser fragmentation. This effect was remarkable in soft stone composition, while there was a trend for improved fragmentation with an increase of the effect feature in hard stone composition. Retropulsion increased with increasing effect function, independently of stone composition. The major limitations of the study are the use of artificial stones and the in vitro setup. Conclusion: Changes in pulse duration and pulse peak power may lead to improved stone fragmentation, most prominently in soft stones, but also lead to increased retropulsion. This new effect function may enhance Ho:YAG laser fragmentation when maximum power output is limited or retropulsion is excluded. PMID- 29511640 TI - Ureteric pyogenic granuloma: A peculiar case of ureteric obstruction. PMID- 29511643 TI - Microsurgical technique for tracheostomy in the rat. AB - Tracheostomy is used to obtain airway access to allow for mechanical ventilation in experimental animal models. We present a microsurgical atlas of our technique for tracheostomy in the adult rat. PMID- 29511641 TI - The consequence of NAC on sodium arsenite-induced uterine oxidative stress. AB - Arsenic consumption through drinking water is a worldwide major health problem. Management of arsenic intoxication with invasive, painful therapy using metal chelators is usually used as a conventional treatment strategy in human. In this present study, we examined the efficacy of oral administration of N-acetyl l cysteine (NAC) in limiting arsenic-mediated female reproductive disorders and oxidative stress in female Wistar rats. The treatment was continued for 8 days (2 estrus cycles) on rats with sodium arsenite (10 mg/Kg body weight) orally. We examined the electrozymographic imprint of three different enzymatic antioxidants in uterine tissue. Rats fed with sodium arsenite exhibited a significant lessening in the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). Uterine DNA breakage, necrosis, ovarian and uterine tissue damage, disruption in steroidogenesis were also found in arsenic treated rats. Co-administration of NAC at different doses (50 mg/kg body weight, 100 mg/kg body weight, respectively) significantly reversed the action of uterine oxidative stress markers like malondialdehyde (MDA), conjugated dienes (CD) and non protein soluble thiol (NPSH); and noticeably improved antioxidant status of the arsenic fed rats. This ultimately resulted in the uterine tissue repairing followed by improvement of ovarian steroidogenesis. However, this effective function of NAC might be crucial for the restoration of arsenic-induced female reproductive organ damage in rats. PMID- 29511644 TI - Considering on the exercise rehabilitation and the Journal of Exercise Rehabilitation. PMID- 29511642 TI - Bioaccumulation of heavy metals in fish species from the Meiliang Bay, Taihu Lake, China. AB - In the present study, the bioaccumulation of heavy metals (Cr, Cu, Cd, Pb) content were determined in freshwater edible fishes Cyprinus carpio Linnaeus and Pelteobagrus fluvidraco, which were caught from the Meiliang Bay, Taihu Lake, a large, shallow and eutrophic lake of China. The results showed that the Cr, Cu, Cd and Pb content in the edible parts of the two fish species were much lower than Chinese Food Health Criterion (1994). However, the results showed marked differences in the four analyzed metal content between the two species and different tissues as well as significant variations. Pb content were the highest in the liver of fishes, Cd contents were almost the same in all organs of fishes, Cr contents mainly enriched in the kidney and liver, Cu contents were the highest in gills, However, the total metal bioaccumulation were greatest in the liver, gills and the lowest in the muscle. Although the total accumulations were highest in P. fluvidraco compare then C.carpio. This investigation indicated that fish products in Meiliang Bay, Taihu Lake were still safe for human consumption, but the amount consumed should be controlled under the Chinese Food Health Criterion to avoid excessive intake of Pb. Further, this is the first report on seasonal distribution of heavy metals and proximate compositions of commercialized important edible fishes from Meiliang Bay, Taihu Lake, China. PMID- 29511645 TI - Anabolic steroid-induced hypogonadism: a challenge for clinicians. PMID- 29511646 TI - Treadmill exercise activates PI3K/Akt signaling pathway leading to GSK-3beta inhibition in the social isolated rat pups. AB - Social isolation is known to precipitate depression-like symptoms in rodents and has emerged as a dependable paradigm to screen the behavioral and neurobiological changes observed in humans. In the present study, the undying mechanisms of treadmill exercise on social isolation-induced depression was evaluated. The rat pups in the social isolation groups were housed individually. The social isolation procedures started on the postnatal day 14. The rat pups in the exercise groups were forced to run on treadmill for 30 min once a day from postnatal day 21 to postnatal day 34. The expression of phosphoinositide 3 kinase (PI3K), tyrosine kinase B (Akt), and glycogen synthase kinase 3beta (GSK-3beta) in the hippocampus were determined by using western blot analysis. The ratio phosphorylated PI3K (p-PI3K)/PI3K and phosphorylated Akt (p-Akt)/Akt were decreased and the ratio of phosphorylated-GSK-3 (p-GSK-3beta)/GSK-3beta was increased by social isolation. Treadmill exercise increased the ratio p-PI3K/PI3K and p-Akt/Akt and suppressed the ratio of p-GSK-3beta/GSK-3beta in the hippocampus of social isolated rat pups. Treadmill exercise activates PI3K/Akt signaling pathway leading to GSK-3beta inhibition in social isolated rats. These results suggested that treadmill exercise may improve depressive symptoms via activation of PI3K/Akt signaling pathway. PMID- 29511647 TI - Effects of exercise on sexual function and central mechanism in the streptozotocin-induced diabetic rats. AB - Diabetes mellitus is associated with the impairment of sexual function including desire and orgasmic dysfunction. Sexual dysfunction in the diabetes mellitus is due to a selective defect of the nitric oxide synthase (NOS) within paraventricular nucleus (PVN). c-Fos is an immediate early gene and c-Fos expression represents neuronal activity in response to various stimuli. In the present study, we investigated the effects of treadmill exercise on sexual behaviors and the expressions of NOS and c-Fos in the PVN were evaluated using streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ. The rats in the treadmill exercise groups were made to run on a treadmill for 30 min once a day during 4 weeks. Male sexual behaviors were evaluated by recording the number of mounting, intromission, and ejaculation frequency. The present results revealed that treadmill exercise ameliorated sexual dysfunction in the STZ-induced diabetic rats. Treadmill exercise restored the contents of NOS and c-Fos in the PVN. The improving effect of treadmill exercise on sexual function can be considered as the neuronal activating effect of exercise through increasing expressions of NO and c-Fos. PMID- 29511648 TI - Exercise training regulates angiogenic gene expression in white adipose tissue. AB - White adipose tissue (WAT) expansion is associated with angiogenesis. Although, activation of lipolysis by exercise induces adipocyte hypotrophy and reduction of fat mass, it is poorly understood whether exercise regulates angiogenesis by altering angiogenic gene expression in WAT. Therefore, the purpose of this study was to evaluate the effect of 6 weeks voluntary wheel running exercise on angiogenic gene expression in adipose tissues. Male C57BL/6J mice performed voluntary wheel running for 6 weeks. At 24 hr after the last exercise training, tibialis anterior (TA), soleus (Sol), epididymal WAT (eWAT), inguinal WAT (iWAT), and brown adipose tissue (BAT) were isolated and then the expressions of vascular endothelial growth factor A (VEGFA), angiopoietin1 (Ang1), Ang2, platelet-derived growth factor B (PDGF-B) and their corresponding receptors were analyzed by reverse transcription-polymerase chain reaction. In skeletal muscles, VEGFA expression was upregulated in TA and Sol and PDDGF-B expression was increased in Sol after exercise training. In eWAT, the expressions of VEGFA and Flk-1 were dramatically downregulated, whereas Ang2 and PDGFRbeta was upregulated after exercise training. In iWAT, VEGF expression was increased with the downregulation of Ang1. However, there was no alteration of any of these genes in BAT. These results suggest that angiogenic gene expression is altered by exercise training and voluntary wheel running regulates VEGFA, Ang1, and Ang2 expressions in a fat depot specific manner. PMID- 29511649 TI - Association of sericin and swimming on the phenotype, motor plate, and functionality of the denervated plantar muscle of Wistar rats. AB - Physical exercise may help maintain muscle properties and functional improvement after peripheral nerve lesion, which may be enhanced by using biocompatible substances, such as sericin. The aim of this study was analyse the effect of sericin associated with swimming exercise on the phenotype, innervation, and functionality of the plantar muscle of Wistar rats. Forty randomly divided adult rats were used in five groups of eight animals: control, injury, sericin, exercise, exercise and sericin. The application of sericin was done on the spot, 100 MUL, shortly after nerve compression. Three days after sciatic nerve compression, the swimming and swimming and sericin groups were submitted to physical swimming exercise for 21 days. Afterwards, the animals were euthanised and the plantar muscle was dissected and submitted to histochemical and histoenzymological techniques. The grip strength test did not show alterations in muscular functionality, and the control presented greater muscle mass in relation to the other groups, the same did not occur for muscle length. Polymorphic neuromuscular junctions were detected in the groups, although without significant morphometric alterations of the area, major and minor diameters. The percentage of type I fibres was lower in the lesion group and there was no difference in fibres IIa and IIb between groups. The area of fibres I, IIa and IIb remained constant between groups. Sericin biopolymer combined with swimming exercise did not affect plantar muscle function, submitted to experimental axonotmosis, whose contractile properties were altered by nerve injury. PMID- 29511650 TI - Effects of regular-moderate exercise on high-fat diet-induced intramyocellular lipid accumulation in the soleus muscle of Sprague-Dawley rats. AB - Previously, we monitored the expression level of the pro-apoptotic proteins caspase-3 and cleaved poly-ADP-ribose polymerase in the skeletal muscle of high fat diet-induced obese rats in order to assess muscle damage. In this study, we analyzed whether exercise or dietary adjustment was more effective at preventing high-fat diet-induced muscle damage. High-fat diet-induced obese rats were divided into three groups: the high-fat diet (HFD), the combined high-fat diet and exercise (HFD+EXE), and the dietary adjustment (DA) groups. For 6 weeks, the HFD+EXE group was subjected to exercise on an animal treadmill. Capsase-3 protein was quantified, and histopathology of the soleus muscle was performed. Both the HFD+EXE and DA interventions resulted in a reduction of lipid accumulation in the soleus muscle, and nucleus infiltration was significantly lower in the DA group. The inflammatory response, caspase-3 level, and relative muscle weight were significantly higher in the HFD+EXE group compared to the HFD group. An increase in intramyocellular lipids in the soleus muscle by obesity and exercise stimulated apoptosis. When the rats exercised, muscle growth was normal and unrelated to the effects of lipid accumulation. These data indicate that exercise was more effective than dietary adjustment in reducing lipid accumulation and increasing muscle metabolism. PMID- 29511651 TI - Effects of virtual reality exercise for Korean adults with schizophrenia in a closed ward. AB - The purpose of this study was to examine the effects of virtual reality exercise (VRE) using Nintendo Wii-Fit on physical fitness of Korean adults with schizophrenia living in a mental health facility located in South Korea. Two male participants diagnosed with schizophrenia, ages 53 and 61, were recruited and selected for inclusion in this study. The intervention using the Nintendo Wii-Fit consisted of 35-min sessions, 3 times per week for 8 weeks and was facilitated by the primary researcher and two graduate students. The senior fitness test and 10 m walking test were used to measure the physical functioning, specifically, physical fitness and mobility, of the participants. The study was divided into three phases using an A-B-A single-subject design and involved multiple repeated measures of functional physical fitness. Both participants were evaluated each week for the duration of 18 weeks. Both participants exhibited measureable improvement in some of the physical fitness measures, but not in the mobility. These results thus provide preliminary evidence to support the use of VRE to improve physical function for Korean adults with schizophrenia as an alternative exercise regimen to the conventional exercise. PMID- 29511652 TI - The efficacy and safety of whole-body electromyostimulation in applying to human body: based from graded exercise test. AB - Recently, whole body-electromyostimulation (WB-EMS) has upgraded its functions and capabilities and has overcome limitations and inconveniences from past systems. Although the efficacy and safety of EMS have been examined in some studies, specific guidelines for applying WB-EMS are lacking. To determine the efficacy and safety of applying it in healthy men to improve cardiopulmonary and psychophysiological variables when applying WB-EMS. Sixty-four participants were randomly grouped into control group (without electrical stimuli) or WB-EMS group after a 6-week baseline period. The control group (n=33; female. 15; male, 18) wore the WB-EMS suit as much as the WB-EMS group (n=31; female, 15; male, 16). There were no abnormal changes in the cardiopulmonary variables (heart rate, systolic blood pressure [SBP], diastolic blood pressure, and oxygen uptake) during or after the graded exercise test (GXT) in both groups. There was a significant decrease in SBP and an increase of oxygen uptake from stages 3 to 5 of the GXT in the WB-EMS group. The psychophysiological factors for a WB-EMS group, which consisted of soreness, anxiety, fatigability, and sleeplessness were significantly decreased after the experiment. The application of WB-EMS in healthy young men did not negatively affect the cardiopulmonary and psychophysiological factors. Rather, the application of WB-EMS improved SBP and oxygen uptake in submaximal and maximal stages of GXT. This study also confirmed that 6 weeks of WB-EMS training can improve psychophysiological factors. PMID- 29511653 TI - Feasibility online survey to estimate physical activity level among the students studying professional courses: a cross-sectional online survey. AB - The aim of the study was to estimate the physical activity (PA) level among the professional college students in North India. One hundred three professional college students in the age group of 18-25 years were recruited by simple random sampling for this cross-sectional online survey. The survey was advertised on the social networking sites (Facebook, WhatsApp) through a link www.surveymonkey.com/r/MG-588BY. A Short Form of International Physical Activity Questionnaire was used for this survey study. The questionnaire included total 8 questions on the basis of previous 7 days. The questionnaire consists of 3 main categories which were vigorous, moderate and high PA. Time spent in each activity level was multiplied with the metabolic equivalent of task (MET), which has previously set to 8.0 for vigorous activity, 4.0 for moderate activity, 3.3 for walking, and 1.5 for sitting. By multiplying MET with number of days and minutes performed weekly, amount of each activity level was calculated and measured as MET-min/wk. Further by adding MET minutes for each activity level, total MET min/wk was calculated. Total number of 100 students participated in this study, and it was shown that all professional course students show different levels in PA. The total PA level among professional college students, which includes, physiotherapy, dental, medical, nursing, lab technician, pharmacy, management, law, engineering, were 434.4 (0-7,866), 170.3 (0-1,129), 87.7 (0-445), 102.8 (0 180), 469 (0-1,164), 0 (0-0), 645 (0-1,836), 337 (0-1,890), 396 (0-968) MET min/wk respectively. PA levels among professional college students in North India have been established. PMID- 29511654 TI - Injury survey in Choi Kwang Do (CKD) martial art practitioners around the world: CKD is a safe form of training for adults. AB - Among the many sports and activities to choose from, martial arts are becoming increasingly popular for health and fitness. Due to the different nature of the various styles of martial arts, injuries are not uncommon. Though there have been studies on the injury rates of several martial art styles, there have been none regarding Choi Kwang Do (CKD), a noncompetitive martial art with relaxed and fluid movements designed to promote health and fitness for people of all ages. The purpose of this study was to examine the rate of injury for adults training in CKD to find out whether this is a safe style of martial art for adults. This study found the prevalence, causes, severity, and types of injuries from CKD practitioners around the world through an online survey targeting adults (n=122), aged 18 or older, with varying years of training experience. The annual rate of injury was 11.73 for every 100 CKD practitioners. There was no correlation between the length of training experience and injury. Training frequency and duration had no significant relationship with injury rates. A significant positive relationship between training intensity and injury existed (P=0.009). The results of the study found that CKD can be an attractive option for adults of any age who are looking to learn a martial art or choose a physical activity with a low risk of injury, however the training intensity should be kept at a level that is not excessively high. PMID- 29511655 TI - Comparison of isokinetic trunk flexion and extension torques and powers between athletes and nonathletes. AB - This study is aimed to perform and compare maximal concentric isokinetic trunk extension and flexion torques and powers between high-level athletes and a control population. In addition, the ratio of isokinetic trunk extension and flexion torques was measured, and compared between groups. Eighteen high-level male athletes and 15 male nonathletes without low back pain were recruited. Subjects performed isokinetic trunk extension and flexion at 60 degrees /sec, 90 degrees /sec, and 120 degrees /sec through a maximal range of motion in a dynamometer. Trunk extension torque of athletes was significantly higher than in nonathletes at 60 degrees /sec and 90 degrees /sec but not at 120 degrees /sec. Trunk extension power of athletes was significantly higher than the control group at 90 degrees /sec and 120 degrees /sec but not at 60 degrees /sec. There was no difference between the athlete and nonathlete groups in respect of trunk flexion torque or power at any angular velocity. Consequently, the ratio of trunk flexion to extension strength was greater in nonathletes than in athletes. Trunk extension and flexion torques tended to decrease, and trunk extension and flexion powers tended to increase, with increasing angular velocity. High-level athletes seem to display preferentially greater trunk extension strength and power in comparison with trunk flexion strength, compared to nonathletes. This could be caused by the use of strength training exercises such as squats and deadlifts, or it may be associated with greater athletic performance. PMID- 29511656 TI - The effect of warm-ups with stretching on the isokinetic moments of collegiate men. AB - Performing warm-ups increases muscle temperature and blood flow, which contributes to improved exercise performance and reduced risk of injuries to muscles and tendons. Stretching increases the range of motion of the joints and is effective for the maintenance and enhancement of exercise performance and flexibility, as well as for injury prevention. However, stretching as a warm-up activity may temporarily decrease muscle strength, muscle power, and exercise performance. This study aimed to clarify the effect of stretching during warm-ups on muscle strength, muscle power, and muscle endurance in a nonathletic population. The subjects of this study consisted of 13 physically active male collegiate students with no medical conditions. A self-assessment questionnaire regarding how well the subjects felt about their physical abilities was administered to measure psychological readiness before and after the warm-up. Subjects performed a non-warm-up, warm-up, or warm-up regimen with stretching prior to the assessment of the isokinetic moments of knee joints. After the measurements, the respective variables were analyzed using nonparametric tests. First, no statistically significant intergroup differences were found in the flexor and extensor peak torques of the knee joints at 60 degrees /sec, which were assessed to measure muscle strength. Second, no statistically significant intergroup differences were found in the flexor and extensor peak torques of the knee joints at 180 degrees /sec, which were assessed to measure muscle power. Third, the total work of the knee joints at 240 degrees /sec, intended to measure muscle endurance, was highest in the aerobic-stretch-warm-ups (ASW) group, but no statistically significant differences were found among the groups. Finally, the psychological readiness for physical activity according to the type of warm-up was significantly higher in ASW. Simple stretching during warm-ups appears to have no effect on variables of exercise physiology in nonathletes who participate in routine recreational sport activities. However, they seem to have a meaningful effect on exercise performance by affording psychological stability, preparation, and confidence in exercise performance. PMID- 29511657 TI - Effect of rapid weight loss and glutamine supplementation on immunosuppression of combat athletes: a double-blind, placebo-controlled study. AB - The role of plasma glutamine concentration and glutamine supplementation on immunosuppression was investigated in combat athletes. Twenty-three male athletes were randomly assigned to receive glutamine (21 g/day, n=12) or placebo (ovalbumin, n=11) for 10 days. Six athletes who did not lose weight served as controls. Athletes were assessed 21 days before (-21d), 1 day before (-1d) and 5 days after (+5d) a competition. Weight reduction was similar between glutamine ( 8.2%+/- 4.1%) and placebo (-8.5%+/-2.4%) and negligible in control (-0.6%+/ 1.4%). In both weight-loss groups, the majority of athletes reported symptoms of upper respiratory symptoms, as assessed by the Wisconsin upper respiratory symptom survey questionnaire. Only two athletes reported symptoms in the control group. Immune cell function remained unchanged throughout the study except for an increase in neutrophil phagocytic activity (placebo: -21d=5,251+/-2,986; 1d=17,428+/-22,374; +5d=21,125+/-21,934; glutamine: -21d=6,096+/-3,549; 1d=11,029+/-17,113; +5d=28,186+/-21,032 FI) and a minor change in monocyte phagocytic activity (placebo: -21d=4,421+/-3,634; -1d=3,329+/-6,283; +5d=3,243+/- 2,553; glutamine: -21d=4,051+/-3,186; -1d=3,106+/-2,625; +5d=4,981+/- 4,598) in both glutamine and placebo after weight loss. Plasma glutamine and cortisol remained unchanged across the study. creatine kinase levels were increased in placebo (-21d=125.2+/-54.1; -1d=187.2+/- 73.5; +5d=111.3+/-59.1 U/L) but not in glutamine (-21d=136.2+/-58.2; -1d= 168.8+/-65.0; +5d=129.7+/-64.0 U/L). Rapid weight loss increased the frequency and severity of infection symptoms, but this was neither associated with plasma glutamine depletion nor counteracted by glutamine supplementation. PMID- 29511658 TI - Effect of official judo matches on handgrip strength and perceptual responses. AB - This study aimed to verify the effect of judo matches on handgrip strength and perceptual responses during an official tournament in medalists and nonmedalists. Thirty-four male judo athletes participated in an official judo tournament. Before the first match and immediately after each match, maximum isometric handgrip strength and rate of perceived exertion overall and in specific areas were assessed. Analysis of variance for repeated measures was used to compare variables before the first match and after each match, and t-test was used to compare medalists and nonmedalists with the level of significance set at 5%. Also, effect size (ES) analysis was used. The results showed decrease in handgrip strength in both hands from the third match (P<0.05). The rate of perceived exertion (RPE) increased from the first match and remained high over the subsequent matches (P<0.001). A very large effect for nonmedalist group (ES=3.44) and large effect for medalist group (ES=1.94) was found in the third match compared to prematch. Forearm and fingers were the body regions most cited by athletes in both groups. We concluded that an official judo competition induced significant drop in handgrip strength from the third match and increased the RPE from first match. Medalists seem to have better recovery after the third match compared to nonmedalists. PMID- 29511659 TI - Changes of gait pattern, muscle activity, and perceived comfort in response to variations of height-elevating insoles in young adults. AB - The purpose of this study was to investigate changes of gait pattern, muscle activity, and perceived comfort in response to variations of height-elevating insoles (HEIs) in young adults. The subjects of this study were 30 young adults who voluntarily consented to participate in this experiment after listening to its purpose and method. They were divided into 3 groups who wore HEIs height (0, 3, and 7 cm). Each group consisted of 10 young adults and wore the HEIs for 4 hr a day. Electromyographic signals were collected from the tibialis anterior, the gastrocnemius, the hamstring, and the right and the left erector spinae (ES) before and after walking with the HEI. Gait pattern was measured before and after walking with the HEI. Perceived comfort was measured after a subject wore the insoles for 4 hr. The activities of ES showed significant differences among the three groups. The activity of the left ES was significantly different between groups 1 (0 cm) and 2 (3 cm) and groups 1 and 3 (7 cm). The activity of the right ES was significantly different between groups 1 and 3. The left stride length and the left step length showed significant differences between groups 1 and 3. Perceived comfort was significantly different among the three groups. As the HEIs increased, the activities of ES were gradually increased and the left step length and stride were decreased. Using of higher HEIs over 4 hr may be occurred excessive activities of the ES, abnormal gait patterns, and perceived discomfort. PMID- 29511660 TI - Sprint interval training on the vertical treadmill improves aerobic and anaerobic running performance. AB - The vertical treadmill (VertiRun) is an unresearched mode of exercise where users engage in a "running-like" action whilst body weight is supported by a recumbent bench and overhanging resistance cables are tethered to the user's ankles. The purpose of this study was to determine the effects of training on a VertiRun and any cross-training effect on running performance. Thirty active males (age, 22+/ 4 years; stature, 1.79+/-0.08 m; body mass, 78.5+/-12.6 kg) volunteered for this study. Participants' aerobic and anaerobic running performance were determined by incremental maximum rate of oxygen consumption (VO2max) treadmill test and a maximum anaerobic running test (MART), respectively. Participants were matched and then randomly assigned to either a VertiRun group, 20-m shuttle sprint group or control group. The intervention consisted of 4-6, 30-sec all-out efforts with 4-min recovery between bouts, 3 days a week for 6 weeks. The pre- and postintervention VO2max and MART were analysed using a mixed repeated measures analysis of variance. MART increased by 4.5% in the VertiRun group (P=0.006) and 4% in the sprint group (P<0.001). VO2max increased by 6.2% in the VertiRun group (P=0.009) and 5.5% in the sprint group (P=0.020). The MART and VO2max of the control group were unchanged (P=0.910 and P=0.915, respectively). These data suggest that the VertiRun could be an effective cross-training mode for running and could supplement training programmes. Also, as VertiRun is a low-impact exercise it might be useful in the physical preparation of athletes returning to sport following lower limb injury. PMID- 29511661 TI - Acute effects of endurance exercise on nocturnal autonomic functions in sedentary subjects: a pilot study. AB - Nocturnal heart rate variability (HRV) is thought to reflect healthy recovery function of the autonomic nervous system. Although exercise is recommended for health promotion, exercise itself decreases HRV. We studied acute effect of daytime exercise on nocturnal HRV in 5 healthy adults (age, 22-40 years; 2 female subjects) without regular exercise habit. Using a treadmill, they performed 30 min walking at 4 km/hr and 30-min running at 9 km/hr from 11 a.m. on different days at an interval of 2 weeks. On these days and a day without exercise (control), Holter electrocardiograms were recorded from 9 a.m. for 24 hr. The amplitudes of low-frequency (LF, 0.04-0.15 Hz) and high-frequency (HF, 0.15-0.45 Hz) components of HRV were measured continuously by complex demodulation and were averaged over periods of 11:00-11:30 a.m., 3 hr after going to bed, and time in bed at night. Exercise intensities of the walking and running were at 10% to 44% and 55% to 67% of heart rate reserve, respectively. During exercise, heart rate increased and LF and HF amplitudes decreased with exercise intensity. Nocturnal heart rate and LF and HF amplitude, however, showed no consistent changes with exercise intensity and their averages on the days of walking and running did not differ significantly from those of the control day. In conclusion, 30-min walking and running exercises performed in the morning had no significant acute effects on nocturnal heart rate or HRV. PMID- 29511662 TI - Impact of a 12-week high-intensity interval training without caloric restriction on body composition and lipid profile in sedentary healthy overweight/obese youth. AB - Although High-intensity interval training (HIIT) has shown its effectiveness in improving body composition, cardio-respiratory fitness and lipid profile in obese adults, evidences remain limited in overweight/obese youth. This study was conducted to investigate the effect of a 12-week HIIT program without caloric restriction on body composition and lipid profile among young overweight/obese men. Twenty healthy obese youth were randomly allocated into two groups; experimental group (HIIT) and control group. The HIIT program consisted in 3 exercises sessions per week (30 sec of work at 100% maximal aerobic velocity [MAV]) interspersed by 30 sec of active recovery at 50% MAV, starting by 15 repetitions to reach 27 by the end of the program. Aerobic capacity (MAV and maximum oxygen uptake [VO2max]), body composition (body mass index [BMI], waist circumference [WC], and fat mass percent) and lipid profile (triglycerides [TG] and total, high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol) were determined before and after the HIIT program. Following 12 weeks of HIIT, WC, BMI (P<0.01), and fat mass percent (P<0.05) were significantly decreased. MAV and VO2max were significantly improved in the HIIT group, only. Total cholesterol (P<0.05) and TG (P<0.05) decreased significantly in the HIIT group, while LDL and HDL cholesterol levels remained unchanged in both groups. HIIT may be particularly useful in overweight/obese youth to improve body composition, aerobic fitness and lipid profile. PMID- 29511663 TI - Effects of ninety minutes per week of continuous aerobic exercise on blood pressure in hypertensive obese humans. AB - The main objective of this study was to examine the effect of continuous aerobic training (CAT) in hypertensive, obese people. Seven patients of average age (45.3+/-3.9 years), height (1.63+/-0.1 m), body weight (89.09+/-22.0 kg), and body mass index (33.44+/-8.6 kg/m2) were subjected to the training. CAT was performed in thrice-weekly nonconsecutive sessions (90 min per week) with intervals of 48 hr between each session. The training sessions entailed 30 min of walking at an intensity of 70%-80% of the maximum heart rate (MHR) on a treadmill over a period of eight weeks, giving a total of 24 sessions. Through correlation analyses, we found significant improvement in the systolic pressure (R=0.5675, P=0.0253) and diastolic pressure (R=0.7083, P=0.0088) when the last session was compared to the first session of training. We found no differences in the diastolic pressure and systolic pressure before, during and after 15 min of the protocol exercise. The program showed a large effect size (ES) for systolic pressure (ES=0.85) and a small ES for diastolic pressure (ES=0.33). We found no differences in the blood pressure (BP) and heart rate (HR) during and after the training of obese hypertensive humans, but we found a positively significant correlation between HR and BP in the last session and a large ES, suggesting that this protocol exercise might have significance effect in the long term. PMID- 29511664 TI - Relationship between ankle range of motion and Biodex Balance System in females and males. AB - This study examined whether there are differences between range of motion (ROM) and balance in lower extremities according to gender. A total of 31 male and 28 female students measured plantar flexion (PF), dorsiflexion, inversion (IV), eversion (EV), hip flexion (HF), hip internal rotation (HIR), and hip external rotation (HER) and tested on the Biodex Balance System. ROM of PF and HF were significantly high the female group and ROMs of IV, EV, HIR, and HER were significantly higher the male group than in the female group. Low ROM of PF may be more negative related to overall balance, especially, back balance in males; therefore, it is necessary to assess and plan the training program for PF ROM in male students. PMID- 29511665 TI - Acute effects of one session dry needling on a chronic golfer's elbow disability. AB - A 40-year-old retired male elite athlete with more than 20 years' experience in wrestling and bodybuilding with mild elbow pain and disability of 2 years presented to our clinic reporting an acute pain in medial aspect of the elbow. Physical examination revealed symptoms of left Golfer's elbow during target directed movements. The results of sonography in left elbow showed low level of hypo echo irregularity and increased blood flow in color Doppler mode in the common flexor origin. The pain amplitude was moderate at rest and extremely high during kinetic and intentional movements. During last 2 years, the patient tried different types of therapy including manual therapy, Transcutaneous electrical nerve stimulation and also received a variety of injections none of which were effective for reducing pain and disability. This is the first study showed that one sessions of dry needling improved both pain and disability and helped to return to a normal life and exercise training. PMID- 29511666 TI - Pre- and postoperative postural regulation following anterior cruciate ligament reconstruction. AB - There are currently no longitudinal data describing the pre- and postoperative postural regulation and stability of patients with anterior cruciate ligament (ACL) damage. Therefore, the aim of this study was to evaluate postural regulation and stability prior to and during rehabilitation following surgery of the ACL. Fifty-four physically active subjects (age: 30.5+/-10.9 years, 29 male subjects) were examined with the Interactive Balance System pre-, 6, and at 12 weeks following surgical reconstruction of the ACL using a hamstring tendon graft. The average period of time from injury to surgery was 27 days. Data were calculated with unifactorial and univariate analysis of variance. Significant effects were found for the somatosensory system (eta2=0.115), stability indicator (eta2=0.123), weight distribution index (eta2=0.176), and synchronization (foot coordination) (eta2=0.249). Involved side weight distribution (parameter: left) increased significantly (patients with left-sided/right-sided injury: eta2=0.234/0.272). Load distribution to the heel remained stable during all three examination periods (eta2=0.035 and eta2=0.071), although a remarkable load at forefoot was observed. In seven out of 10 parameters partial effects were seen during the first 6 weeks after surgery. The results of this study indicated that injury of the ACL and subsequent surgical reconstructions result in postural regulation, with improvements in somatosensory system function, postural stability, weight distribution index, and foot coordination. Also, overloading of the injured side on the feet reduces significantly during rehabilitation. Thus, the initial phase of rehabilitation (weeks 1 to 6) seems to be more effective than the second period (weeks 6 to 12) postoperatively. PMID- 29511667 TI - Effect of wearing positions of load on the dynamic balance during gait. AB - The study aim to analyze the influence on dynamic stability relative to positions carrying with weight during gait, for which experiment participated with healthful adult males (n=9), were performed under three-dimensional (3D) conditions of no load (NL), right of trunk (RT), and front of trunk (FT). The kinematic and kinetic conclusions obtained from 3D cinematography and ground reaction force system were as follows; 1-step time elapsed showed longest in NL of all, and maximum velocity of RT showed slower than NL and FT, which resulted in significant level at (P<0.05) respectively. While NL showed slower average velocity than RT and FT, RT showed larger incline angle (extrapolated center of mass theta) than NL and FT, which resulted in significant level at (P<0.01) respectively. Also FT showed larger peak vertical force than NL and RT, which resulted in significant level at (P<0.001). Because gait pattern is regarded it as a success when fulfilled both forward propulsive force and dynamic stability, we may ensure that each other active strategy for securement and performance in a situation carrying with 20 kg of the same weight in forward and lateral plane was mobilized. However, participants in pathological gait such as leg injury, and exercise rehabilitation during walking should avoid carrying loads bag to ensure dynamic stability. PMID- 29511668 TI - Transcriptome Analysis of the Thymus in Short-Term Calorie-Restricted Mice Using RNA-seq. AB - Calorie restriction (CR), which is a factor that expands lifespan and an important player in immune response, is an effective protective method against cancer development. Thymus, which plays a critical role in the development of the immune system, reacts to nutrition deficiency quickly. RNA-seq-based transcriptome sequencing was performed to thymus tissues of MMTV-TGF-alpha mice subjected to ad libitum (AL), chronic calorie restriction (CCR), and intermittent calorie restriction (ICR) diets in this study. Three cDNA libraries were sequenced using Illumina HiSeqTM 4000 to produce 100 base pair-end reads. On average, 105 million clean reads were mapped and in total 6091 significantly differentially expressed genes (DEGs) were identified (p < 0.05). These DEGs were clustered into Gene Ontology (GO) categories. The expression pattern revealed by RNA-seq was validated by quantitative real-time PCR (qPCR) analysis of four important genes, which are leptin, ghrelin, Igf1, and adinopectin. RNA-seq data has been deposited in NCBI Gene Expression Omnibus (GEO) database (GSE95371). We report the use of RNA sequencing to find DEGs that are affected by different feeding regimes in the thymus. PMID- 29511669 TI - Ethanol Extract from Ulva prolifera Prevents High-Fat Diet-Induced Insulin Resistance, Oxidative Stress, and Inflammation Response in Mice. AB - Ulva prolifera is the major causative species in the green tide, a serious marine ecological disaster, which bloomed in the Yellow Sea and the Bohai Sea of China. However, it is also a popular edible seaweed and its extracts exerts anti inflammatory and antioxidant effects. The present study investigated the effects of ethanol extract of U. prolifera (EUP) on insulin sensitivity, inflammatory response, and oxidative stress in high-fat-diet- (HFD-) treated mice. HFD-treated mice obtained drinking water containing 2% or 5% EUP. The results showed that EUP supplementation significantly prevented HFD-induced weight gain of liver and fat. EUP supplementation also improved glucose tolerance and insulin resistance in HFD treated mice. Moreover, EUP supplementation prevented the increased expression of genes involved in triglyceride synthesis and proinflammatory genes and the decreased expression of genes involved in fatty acid oxidation in liver of HFD treated mice. Furthermore, EUP supplementation decreased reactive oxygen species content, while increasing glutathione content and glutathione peroxidase activity in HFD-treated mice. In conclusion, our results showed that EUP improved insulin resistance and had antilipid accumulation and anti-inflammatory and antioxidative effects on HFD-treated mice. We suggested that U. prolifera extracts may be regarded as potential candidate for the prevention of nonalcoholic fatty liver disease. PMID- 29511670 TI - Whole-Exome Sequencing Identified a Novel Compound Heterozygous Mutation of LRRC6 in a Chinese Primary Ciliary Dyskinesia Patient. AB - Primary ciliary dyskinesia (PCD) is a clinical rare peculiar disorder, mainly featured by respiratory infection, tympanitis, nasosinusitis, and male infertility. Previous study demonstrated it is an autosomal recessive disease and by 2017 almost 40 pathologic genes have been identified. Among them are the leucine-rich repeat- (LRR-) containing 6 (LRRC6) codes for a 463-amino-acid cytoplasmic protein, expressed distinctively in motile cilia cells, including the testis cells and the respiratory epithelial cells. In this study, we applied whole-exome sequencing combined with PCD-known genes filtering to explore the genetic lesion of a PCD patient. A novel compound heterozygous mutation in LRRC6 (c.183T>G/p.N61K; c.179-1G>A) was identified and coseparated in this family. The missense mutation (c.183T>G/p.N61K) may lead to a substitution of asparagine by lysine at position 61 in exon 3 of LRRC6. The splice site mutation (c.179-1G>A) may cause a premature stop codon in exon 4 and decrease the mRNA levels of LRRC6. Both mutations were not present in our 200 local controls, dbSNP, and 1000 genomes. Three bioinformatics programs also predicted that both mutations are deleterious. Our study not only further supported the importance of LRRC6 in PCD, but also expanded the spectrum of LRRC6 mutations and will contribute to the genetic diagnosis and counseling of PCD patients. PMID- 29511671 TI - High Expression of ITGA3 Promotes Proliferation and Cell Cycle Progression and Indicates Poor Prognosis in Intrahepatic Cholangiocarcinoma. AB - Integrin subunit alpha 3 (ITGA3) interacts with a beta 1 subunit to form a member of the integrin family. Integrins are heterodimeric integral membrane proteins that serve as cell surface adhesion proteins. In this research, we investigated the biological function of this protein in human intrahepatic cholangiocarcinoma (ICC) for the first time. Here, using Western blotting and immunohistochemistry assays, we discovered that ITGA3 was overexpressed in ICC cell lines and ICC patients. Moreover, we found ITGA3 expression correlated with several clinicopathological features, including tumor size, lymph node metastasis, and the TNM stage. Patients with high ITGA3 expression underwent a worse prognosis after complete resection compared with patients with low ITGA3 expression in terms of overall survival. Furthermore, we demonstrated that ITGA3 could significantly promote ICC cell proliferation and cell cycle progression in vitro. However, as a classical cell surface adhesion molecule, we found ITGA3 correlated negatively with the migration and invasion of ICC cell lines, which differs from other malignant tumors. Generally, these findings suggest that ITGA3 may play a role as a potential oncogene in ICC and suppression of ITGA3 expression may establish a novel target for guiding the therapy of ICC patients. PMID- 29511672 TI - Percutaneous High Frequency Microwave Ablation of Uterine Fibroids: Systematic Review. AB - Uterine fibroids are the most common benign pelvic tumor of the female genital tract and tend to increase with age; they cause menorrhagia, dysmenorrhea, pelvic pressure symptoms, back pain, and subfertility. Currently, the management is based mainly on medical or surgical approaches. The nonsurgical and minimally invasive therapies are emerging approaches that to the state of the art include uterine artery embolization (UAE), image-guided thermal ablation techniques like magnetic resonance-guided focused ultrasound surgery (MRgFUS) or radiofrequency ablation (RF), and percutaneous microwave ablation (PMWA). The purpose of the present review is to describe feasibility results and safety of PMWA according to largest studies available in current literature. Moreover technical aspects of the procedure were analyzed providing important data on large scale about potential efficacy of PMWA in clinical setting. However larger studies with international registries and randomized, prospective trials are still needed to better demonstrate the expanding benefits of PMWA in the management of uterine fibroids. PMID- 29511673 TI - Structural and Morselized Allografting Combined with a Cementless Cup for Acetabular Defects in Revision Total Hip Arthroplasty: A 4- to 14-Year Follow-Up. AB - Using morselized and structural allograft to restore bone stock for massive acetabular bone defect in revision total hip arthroplasty (THA) is an appealing procedure. However, concerns about inability to achieve long-term stability following allograft resorption remained. From 2003 to 2012, 59 hips in 58 patients undergoing revision THA for Paprosky type II or III acetabular defects were retrospectively reviewed. The acetabular defects were managed with deep frozen morselized and structural allografts, and a press-fit cementless cup along with supplementary screws. Clinical outcomes and radiographic results were analyzed with a mean follow-up of 8.7 years. The clinical successful rate was 100% for hips with Paprosky type II defect, 95.2% for IIIA defect, and 92.8% for IIIB defect. Three hips with type III defect failed at 4, 7, and 9 years, respectively. Harris Hip Score improved significantly from 60.1 preoperatively to 91.3 at the latest follow-up. All hips with good clinical results showed trabecular bridging in the allograft-host bone interface. Deep-frozen structural and morselized allograft in combination with a press-fit cementless cup represented a viable option to reconstruct acetabular defects in revision THA. PMID- 29511674 TI - Advances in Localized Prostate Cancer Management. PMID- 29511675 TI - Regulation of Spontaneous Contractions in Intact Rat Bladder Strips and the Effects of Hydrogen Peroxide. AB - Enhanced spontaneous contractions are associated with overactive bladder. Elevated levels of reactive oxygen species might contribute to enhanced spontaneous contractions. We investigated the regulation of spontaneous contractions and the effects of hydrogen peroxide (H2O2) in intact rat bladder strips. The spontaneous contractions were measured using a tissue bath system. The vehicle or the specific activators/blockers were applied and followed by the application of 0.003 g% H2O2. The basal tension, amplitude, and frequency of spontaneous contractions were quantified. Nisoldipine and bisindolylmaleimide 1 had no effects on spontaneous contractions. SKF96365 and Y27632 decreased basal tension and amplitude. Ryanodine slightly increased frequency. Both iberiotoxin and NS-1619 increased amplitude. Apamin reduced frequency but increased amplitude. NS-309 inhibited both the amplitude and frequency. The basal tension and amplitude increased when H2O2 was applied. Pretreatment with NS-309 inhibited H2O2-elicited augmented amplitude and frequency, while pretreatment with Y-27632 inhibited the augmented basal tension. The combined application of NS-309 and Y27632 almost eliminated spontaneous contractions and its augmentation induced by H2O2. In conclusion, Ca2+ influx, Rho kinase activation, and SK channel inactivation play important roles in spontaneous contractions in intact bladder strips, whereas only latter two mechanisms may be involved in H2O2-elicited increased spontaneous contractions. PMID- 29511677 TI - Saccharomyces cerevisiae-Derived Mannan Does Not Alter Immune Responses to Aspergillus Allergens. AB - Severe asthma with fungal sensitization predominates in the population suffering from allergic asthma, to which there is no cure. While corticosteroids are the mainstay in current treatment, other means of controlling inflammation may be beneficial. Herein, we hypothesized that mannan from Saccharomyces cerevisiae would dampen the characteristics of fungal allergic asthma by altering the pulmonary immune responses. Using wild-type and transgenic mice expressing the human mannose receptor on smooth muscle cells, we explored the outcome of mannan administration during allergen exposure on the pathogenesis of fungal asthma through measurement of cardinal features of disease such as inflammation, goblet cell number, and airway hyperresponsiveness. Mannan treatment did not alter most hallmarks of allergic airways disease in wild-type mice. Transgenic mice treated with mannan during allergen exposure had an equivalent response to non-mannan treated allergic mice except for a prominent granulocytic influx into airways and cytokine availability. Our studies suggest no role for mannan as an inflammatory regulator during fungal allergy. PMID- 29511678 TI - The Assessment of Static Balance in Patients after Total Hip Replacement in the Period of 2-3 Years after Surgery. AB - Introduction: The aim of this study was to assess static balance of patients after Total Hip Replacement (THR) compared with the age-matched, asymptomatic control group, considering the subject's gender and the time since the surgery. Materials and Methods: The Total Hip Replacement (THR) group consisted of 55 subjects (mean age: 56.3 +/- 8.7 years) and the control group consisted of 48 subjects (mean age: 58 +/- 6.2 years). For the assessment of static balance, a stabilometric force platform was used. All subjects performed two 30-second trials in the double-leg stance position with eyes opened and closed. In the study group, the stabilometric assessment was performed once within the period of 24 to 36 months after the surgery. Results: Subjects from the study group had significantly increased mediolateral COP velocity in the test with eyes opened, as well as the values of most of the COP parameters (excluding COP path area) in the test with eyes closed, compared to the control group. Higher values of the selected COP parameters were observed in the male subjects from the study group. Conclusion: In contrast to a number of papers, our study revealed some deficits in static balance in patients after THR up to 2-3 years after surgery. PMID- 29511676 TI - Effect of Riociguat and Sildenafil on Right Heart Remodeling and Function in Pressure Overload Induced Model of Pulmonary Arterial Banding. AB - Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and a rise in right ventricular (RV) afterload. The increased RV afterload leads to right ventricular failure (RVF) which is the reason for the high morbidity and mortality in PAH patients. The objective was to evaluate the therapeutic efficacy and antiremodeling potential of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil and the soluble guanylate cyclase stimulator riociguat in a model of pressure overload RV hypertrophy induced by pulmonary artery banding (PAB). Mice subjected to PAB, one week after surgery, were treated with either sildenafil (100 mg/kg/d, n = 5), riociguat (30 mg/kg/d, n = 5), or vehicle (n = 5) for 14 days. RV function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometry. Both sildenafil and riociguat prevented the deterioration of RV function, as determined by a decrease in RV dilation and restoration of the RV ejection fraction (EF). Although both compounds did not decrease right heart mass and cellular hypertrophy, riociguat prevented RV fibrosis induced by PAB. Both compounds diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Treatment with either riociguat or sildenafil prevented the progression of pressure overload-induced RVF, representing a novel therapeutic approach. PMID- 29511679 TI - Prostaglandin E1 Preconditioning Attenuates Liver Ischemia Reperfusion Injury in a Rat Model of Extrahepatic Cholestasis. AB - The aim of this study is to explore the hepatoprotective effect of intraportal prostaglandin E1 (PGE1) on liver ischemia reperfusion (IR) injury using an extrahepatic cholestatic model, observing oxidative stress markers, proinflammatory factors, apoptotic marker proteins, and an adhesion molecule. The extrahepatic cholestatic model was induced by common bile duct ligation. After seven days, rats were subjected to ischemia by Pringle maneuver for 15 min, followed by 1, 6, or 24 h of reperfusion. Prostaglandin E1 (PGE group) or normal saline (NS group) was continuously infused from 15 min before liver ischemia to 1 h after reperfusion. After reperfusion, histopathological evaluation of the liver was performed, as were measurements of bilirubin, biochemical enzymes, oxidative stress markers (GSH and MDA), proinflammatory factors (MPO, TNF-alpha, and IL 1beta), apoptotic marker proteins (Bcl-2 and Bax), and the adhesion molecule (ICAM-1). PGE1 pretreatment attenuated IR injury in extrahepatic cholestatic liver probably by suppressing MDA, MPO, TNF-alpha, IL-1beta, ICAM-1, and Bax levels and improving GSH and Bcl-2 levels. In conclusion, PGE1 protects extrahepatic cholestatic liver from IR injury by improving hepatic microcirculation and reducing oxidative stress damage, intrahepatic neutrophil infiltration, and hepatocyte apoptosis. PMID- 29511680 TI - The Effect of Muscle Direction on the Predictions of Finite Element Model of Human Lumbar Spine. AB - The normal physiological loads from muscles experienced by the spine are largely unknown due to a lack of data. The aim of this study is to investigate the effects of varying muscle directions on the outcomes predicted from finite element models of human lumbar spine. A nonlinear finite element model of L3-L5 was employed. The force of the erector spinae muscle, the force of the rectus abdominis muscle, follower loads, and upper body weight were applied. The model was fixed in a neural standing position and the direction of the force of the erector spinae muscle and rectus abdominis muscle was varied in three directions. The intradiscal pressure, reaction moments, and intervertebral rotations were calculated. The intradiscal pressure of L4-L5 was 0.56-0.57 MPa, which agrees with the in vivo pressure of 0.5 MPa from the literatures. The models with the erector spinae muscle loaded in anterior-oblique direction showed the smallest reaction moments (less than 0.6 Nm) and intervertebral rotations of L3-L4 and L4 L5 (less than 0.2 degrees). In comparison with loading in the vertical direction and posterior-oblique direction, the erector spinae muscle loaded in the anterior oblique direction required lower external force or moment to keep the lumbar spine in the neutral position. PMID- 29511681 TI - Prevalence of Low Birth Weight before and after Policy Change to IPTp-SP in Two Selected Hospitals in Southern Nigeria: Eleven-Year Retrospective Analyses. AB - Background: In 2005, Nigeria changed its policy on prevention of malaria in pregnancy to intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP). Indicators of impact of effective prevention and control of malaria on pregnancy (MIP) are low birth weight (LBW) and maternal anaemia by parity. This study determined the prevalence of LBW for different gravidity groups during periods of pre- and postpolicy change to IPTp-SP. Methods: Eleven-year data were abstracted from the delivery registers of two hospitals. Study outcomes calculated for both pre- (2000-2004) and post-IPTp-SP-policy (2005-2010) years were prevalence of LBW for different gravidity groups and risk of LBW in primigravidae compared to multigravidae. Results: Out of the 11,496 singleton deliveries recorded within the 11-year period, the prevalence of LBW was significantly higher in primigravidae than in multigravidae for both prepolicy (6.3% versus 4%) and postpolicy (8.6% versus 5.1%) years. The risk of LBW in primigravidae compared to multigravidae increased from 1.62 (1.17-2.23) in the prepolicy years to 1.74 (1.436-2.13) during the postpolicy years. Conclusion: The study demonstrated that both the prevalence and risk of LBW remained significantly higher in primigravidae even after the change in policy to IPTp-SP. PMID- 29511682 TI - Noncaloric Sweeteners in Children: A Controversial Theme. AB - Noncaloric sweeteners (NCS) are food additives used to provide sweetness without adding calories. Their consumption has become more widespread around the world in all age groups, including children. The aim of this study is to show the state of the art about the intake of noncaloric sweeteners in children, as well as their benefits and consumption risk. Scientific searchers were used (PUBMED, Scopus, and Scielo) to analyze articles that included keywords (noncaloric sweeteners/saccharin/cyclamate/acesulfame potassium/aspartame/sucralose/stevia/children) in English, Spanish, and Portuguese. Authors conclude that it is imperative that health professionals judiciously and individually evaluate the overall benefits and risks of NCS use in consumers before recommending their use. Different subgroups of the population incorporate products containing NCS in their diet with different objectives, which should be considered when recommending a diet plan for the consumer. In childhood, in earlier age groups, this type of additives should be used as a dietary alternative when other forms of prevention in obesity are not sufficient. PMID- 29511683 TI - Circulating CD3+CD4+CD161+ Cells Are Associated with Early Complications after Autologous Stem Cell Transplantation in Multiple Myeloma. AB - The aim of this study was to explore if measurement of pretransplant circulating CD161-expressing cells, in addition to clinical risk factors, could predict mucositis and infections in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). To determine if CD161-expressing cells are likely to predict early complications, namely, mucositis (>=grade 3), infections, and cytomegalovirus (CMV) reactivation, we prospectively examined CD161-expressing cells (CD3+CD4+CD161+ and CD3+CD8+CD161+) in peripheral blood samples from 108 patients with MM undergoing ASCT. After adjusting for factors identified by univariate analysis that predicted mucositis (>=grade 3), infection before engraftment, and CMV reactivation, multivariate analyses revealed that the low proportion of CD3+CD4+CD161+ cells in peripheral blood was an independent predictor of mucositis (>=grade 3) (P = 0.020), infections before engraftment (P = 0.014), and CMV reactivation (P = 0.010). In addition, we found that female sex and decreased glomerular filtration rate were independent factors for predicting mucositis. Female sex and severe pulmonary comorbidity were independent factors for predicting infection before engraftment. We found that the proportion of circulating CD3+CD4+CD161+ cells is useful for predicting the occurrence of early complications, including mucositis and infections, after ASCT in patients with MM. PMID- 29511685 TI - A Simple Scatter Reduction Method in Cone-Beam Computed Tomography for Dental and Maxillofacial Applications Based on Monte Carlo Simulation. AB - The quality of images obtained from cone-beam computed tomography (CBCT) is important in diagnosis and treatment planning for dental and maxillofacial applications. However, X-ray scattering inside a human head is one of the main factors that cause a drop in image quality, especially in the CBCT system with a wide-angle cone-beam X-ray source and a large area detector. In this study, the X ray scattering distribution within a standard head phantom was estimated using the Monte Carlo method based on Geant4. Due to small variation of low-frequency scattering signals, the scattering signals from the head phantom can be represented as the simple predetermined scattering signals from a patient's head and subtracted the projection data for scatter reduction. The results showed higher contrast and less cupping artifacts on the reconstructed images of the head phantom and real patients. Furthermore, the same simulated scattering signals can also be applied to process with higher-resolution projection data. PMID- 29511684 TI - Oncogenic N-Ras Stimulates SRF-Mediated Transactivation via H3 Acetylation at Lysine 9. AB - Signal transduction pathways regulate the gene expression by altering chromatin dynamics in response to mitogens. Ras proteins are key regulators linking extracellular stimuli to a diverse range of biological responses associated with gene regulation. In mammals, the three ras genes encode four Ras protein isoforms: H-Ras, K-Ras4A, K-Ras4B, and N-Ras. Although emerging evidence suggests that Ras isoforms differentially regulate gene expressions and are functionally nonredundant, the mechanisms underlying Ras specificity and Ras signaling effects on gene expression remain unclear. Here, we show that oncogenic N-Ras acts as the most potent regulator of SRF-, NF-kappaB-, and AP-1-dependent transcription. N Ras-RGL2 axis is a distinct signaling pathway for SRF target gene expression such as Egr1 and JunB, as RGL2 Ras binding domain (RBD) significantly impaired oncogenic N-Ras-induced SRE activation. By monitoring the effect of Ras isoforms upon the change of global histone modifications in oncogenic Ras-overexpressed cells, we discovered that oncogenic N-Ras elevates H3K9ac/H3K23ac levels globally in the chromatin context. Importantly, chromatin immunoprecipitation (ChIP) assays revealed that H3K9ac is significantly enriched at the promoter and coding regions of Egr1 and JunB. Collectively, our findings define an undocumented role of N-Ras in modulating of H3 acetylation and in gene regulation. PMID- 29511686 TI - Case-Control Study on Occupational Exposure to Extremely Low-Frequency Electromagnetic Fields and the Association with Meningioma. AB - Objective: Exposure to extremely low-frequency electromagnetic fields (ELF-EMF) was in 2002 classified as a possible human carcinogen, Group 2B, by the International Agency for Research on Cancer at WHO based on an increased risk for childhood leukemia. In case-control studies on brain tumors during 1997-2003 and 2007-2009 we assessed lifetime occupations in addition to exposure to different agents. The INTEROCC ELF-EMF Job-Exposure Matrix was used for associating occupations with ELF-EMF exposure (MUT) with meningioma. Cumulative exposure (MUT years), average exposure (MUT), and maximum exposed job (MUT) were calculated. Results: No increased risk for meningioma was found in any category. For cumulative exposure in the highest exposure category 8.52+ MUT years odds ratio (OR) = 0.9, 95% confidence interval (CI) = 0.7-1.2, and p linear trend = 0.45 were calculated. No statistically significant risks were found in different time windows. Conclusion: In conclusion occupational ELF-EMF was not associated with an increased risk for meningioma. PMID- 29511688 TI - Optical Surface Management System for Patient Positioning in Interfractional Breast Cancer Radiotherapy. AB - Background: The Optical Surface Management System (OSMS) is a simple, fast, reproducible, and accurate solution for patient set-up and can minimize random day-to-day set-up errors. However, studies in breast cancer patients are rare. Objective: To analyze 200 patient set-ups in 20 patients with breast cancer by comparing the OSMS with the conventional cone-beam computed tomography (CBCT). Method: Displacements from concurrent OSMS and CBCT registrations were compared in a total of 200 setups of 20 patients to analyze the interfractional displacement and positioning displacement in three dimensions (lateral, longitudinal, and vertical directions). Results: The interfractional displacement on the lateral, longitudinal, and vertical directions for OSMS versus CBCT was 0.049 +/- 0.254 versus 0.041 +/- 0.244 centimeters (cm); 0.018 +/- 0.261 versus 0.040 +/- 0.242 cm; 0.062 +/- 0.254 versus 0.065 +/- 0.240 cm, respectively, without any significant difference (all P > 0.05). The duration for CBCT scan was about 60 seconds (s), while that for image processing, matching, and couch displacement was at least 5 minutes (min). The average scanning time with OSMS was less than 20 s, and the total duration for positioning was less than 1 min. Conclusion: OSMS is an efficient tool to improve the accuracy and increase the speed for verifying the patient positioning in radiotherapy for breast cancer. PMID- 29511689 TI - Evaluation of Cerebral White Matter in Prelingually Deaf Children Using Diffusion Tensor Imaging. AB - This study compared white matter development in prelingually deaf and normal hearing children using a tract-based spatial statistics (TBSS) method. Diffusion tensor imaging (DTI) was performed in 21 prelingually deaf (DEAF group) and 20 normal-hearing (HEAR group) subjects aged from 1.7 to 7.7 years. Using TBSS, we evaluated the regions of significant difference in fractional anisotropy (FA) between the groups. Correlations between FA values and age in each group were also analyzed using voxel-wise correlation analyses on the TBSS skeleton. Lower FA values of the white matter tract of Heschl's gyrus, the inferior frontooccipital fasciculus, the uncinate fasciculus, the superior longitudinal fasciculus, and the forceps major were evident in the DEAF group compared with those in the HEAR group below 4 years of age, while the difference was not significant in older subjects. We also found that age-related development of the white matter tracts may continue until 8 years of age in deaf children. These results imply that development of the cerebral white matter tracts is delayed in prelingually deaf children. PMID- 29511687 TI - Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management. AB - The discovery of circulating antibodies specific for native podocyte antigens has transformed the diagnostic workup and greatly improved management of idiopathic membranous nephropathy (iMN). In addition, their identification has clearly characterized iMN as a largely autoimmune disorder. Anti-PLA2R1 antibodies are detected in approximately 70% to 80% and anti-THSD7A antibodies in only 2% of adult patients with iMN. The presence of anti-THSD7A antibodies is associated with increased risk of malignancy. The assessment of PLA2R1 and THSD7A antigen expression in glomerular immune deposits has a better sensitivity than measurement of the corresponding autoantibodies. Therefore, in the presence of circulating anti-podocytes autoantibodies and/or enhanced expression of PLA2R1 and THSD7A antigens MN should be considered as primary MN (pMN). Anti-PLA2R1 or anti-THSD7A autoantibodies have been proposed as biomarkers of autoimmune disease activity and their blood levels should be regularly monitored in pMN to evaluate disease activity and predict outcomes. We propose a revised clinical workup flow for patients with MN that recommends assessment of kidney biopsy for PLA2R1 and THSD7A antigen expression, screening for circulating anti-podocytes antibodies, and assessment for secondary causes, especially cancer, in patients with THSD7A antibodies. Persistence of anti-podocyte antibodies for 6 months or their increase in association with nephrotic proteinuria should lead to the introduction of immunosuppressive therapies. Recent data have reported the efficacy and safety of new specific therapies targeting B cells (anti-CD20 antibodies, inhibitors of proteasome) in pMN which should lead to an update of currently outdated treatment guidelines. PMID- 29511690 TI - A Decision for Predicting Successful Extubation of Patients in Intensive Care Unit. AB - Approximately 40% of patients admitted to the medical intensive care unit (ICU) require mechanical ventilation. An accurate prediction of successful extubation in patients is a key clinical problem in ICU due to the fact that the successful extubation is highly associated with prolonged ICU stay. The prolonged ICU stay is also associated with increasing cost and mortality rate in healthcare system. This study is retrospective in the aspect of ICU. Hence, a total of 41 patients were selected from the largest academic medical center in Taiwan. Our experimental results show that predicting successful rate of 87.8% is obtained from the proposed predicting function. Based on several types of statistics analysis, including logistic regression analysis, discriminant analysis, and bootstrap method, three major successful extubation predictors, namely, rapid shallow breathing index, respiratory rate, and minute ventilation, are revealed. The prediction of successful extubation function is proposed for patients, ICU, physicians, and hospital for reference. PMID- 29511692 TI - Quinolone-Induced Painful Peripheral Neuropathy: A Case Report and Literature Review. AB - We present a case report of a 20-year-old male with diabetes mellitus type 1, who developed severe painful peripheral neuropathy while on the second of a 10-day course with levofloxacin for the treatment of epididymitis. The intensity of the pain rapidly reached scores of 10/10 in a numeric scale 0/10, and the patient was transferred to an inpatient pain unit where he was treated aggressively with minimal improvement. A skin biopsy revealed small fiber neuropathy. Then the patient was treated with intravenous immunoglobulin, which improved the pain. Now the patient is on outpatient intravenous immunoglobulin infusions bimonthly and making a slow recovery. PMID- 29511691 TI - Coronary Atherosclerosis Assessment by Coronary CT Angiography in Asymptomatic Diabetic Population: A Critical Systematic Review of the Literature and Future Perspectives. AB - The prognostic impact of diabetes mellitus (DM) on cardiovascular outcomes is well known. As a consequence of previous studies showing the high incidence of coronary artery disease (CAD) in diabetic patients and the relatively poor outcome compared to nondiabetic populations, DM is considered as CAD equivalent which means that diabetic patients are labeled as asymptomatic individuals at high cardiovascular risk. Lessons learned from the analysis of prognostic studies over the past decade have challenged this dogma and now support the idea that diabetic population is not uniformly distributed in the highest risk box. Detecting CAD in asymptomatic high risk individuals is controversial and, what is more, in patients with diabetes is challenging, and that is why the reliability of traditional cardiac stress tests for detecting myocardial ischemia is limited. Cardiac computed tomography angiography (CCTA) represents an emerging noninvasive technique able to explore the atherosclerotic involvement of the coronary arteries and, thus, to distinguish different risk categories tailoring this evaluation on each patient. The aim of the review is to provide a wide overview on the clinical meaning of CCTA in this field and to integrate the anatomical information with a reliable therapeutic approach. PMID- 29511693 TI - Unmasking a Case of Asymptomatic Charcot-Marie-Tooth Disease (CMT1A) With Vincristine. AB - Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating disease of the peripheral nervous system that results in sensory and motor dysfunction. CMT includes a spectrum of diseases with different types of mutations in the genes encoding myelin protein, resulting in a variety of dysfunctions in its life cycle. In CMT subtype 1A there is duplication mutation of peripheral myelin protein 22 gene on chromosome 17. Incomplete penetrance, gene-dosage effect, and variable expressivity can attribute to the asymptomatic nature of the disease in some subset of patients. Vincristine administration is contraindicated in patients who are alrea?dy diagnosed with CMT disease. We report a case of asymptomatic CMT disease unmasked only by the neurotoxic effects of vincristine. Genetic testing for a patient with a preexisting family background of inherited diseases before starting vincristine therapy can potentially prevent a disability. PMID- 29511694 TI - Aerococcus urinae Mitral Valve Endocarditis-Related Stroke: A Case Report and Literature Review. AB - Background. Aerococcus urinae is a rare causative pathogen of infective endocarditis that results in a high risk of embolic events. The mortality rate for A urinae endocarditis is high. Old age and underlying urologic conditions are the best-known risk factors for infection. Case Description. We report the clinical course of the disease in a 49-year-old man who presented symptoms of a urinary tract infection. A few days later, transthoracic echocardiography showed a conspicuous mitral valve with myxomatous alterations. Following the detection of a cerebral embolism with associated stroke symptoms, as well as at the beginning of cardiac failure, the emergency indication for the surgical treatment of mitral valve endocarditis was given. On the second day following the operation, circulatory collapse rapidly developed. Following an unsuccessful attempt at cardiopulmonary resuscitation, the patient died. Review of the Literature. From 1991 to 2017, 29 cases of A urinae-induced endocarditis have been described in PubMed and Medline. One or 2 new cases are published annually. We review all reported cases of A urinae endocarditis, with an emphasis on the predisposing factors, course, and outcomes of the disease. Conclusion. A urinae endocarditis is a rare disease primarily affecting elderly men with urinary tract pathologies and comorbidities. The course of the disease is severe, and the outcome is often fatal. A 16S rDNA polymerase chain reaction investigation of bacterial genome provides proof of the presence of A urinae. Because of the high risk of embolism, rapid treatment should focus on the diseased heart valve. Based on existing data and the experience gained from handling cases, treatment with beta-lactam and aminoglycosides is recommended. It is also recommended that operative therapy take place as soon as possible. PMID- 29511695 TI - Dynamic Course of Serratia marcescens Pulmonic Valve Endocarditis Resulting in Submassive PE and Valve Replacement. AB - This report illustrates a case of a 42-year-old male with a history of intravenous drug abuse who presented with septic shock. Diagnostic studies, including a transthoracic echocardiogram, chest computed tomography angiography, transesophageal echocardiogram, and blood cultures ultimately revealed Serratia marcescens pulmonic valve infective endocarditis that was treated with intravenous antibiotics. In addition to the rare form of endocarditis and bacterium involved, this case brings into awareness the dynamic nature of the hospital course that requires vigilance in responding to hypotensive episodes for consideration of pulmonary embolism. Surgical valve replacement was opted for due to such a complication in addition to the large size of the vegetation, 2.5 cm. PMID- 29511698 TI - State-Level Implementation of Health and Safety Policies to Prevent Sudden Death and Catastrophic Injuries Within Secondary School Athletics: Letter to the Editor. PMID- 29511696 TI - Protein-Losing Enteropathy in the Setting of Severe Iron Deficiency Anemia. AB - A 20-month-old boy presented with a 2-week history of pallor and progressive abdominal distention. Nutritional history revealed long-standing excessive cow milk intake. He was subsequently found to be profoundly iron deficient and hypoproteinemic, with an elevated fecal alpha-1-antitrypsin level and occult blood positive stool, consistent with protein-losing enteropathy. He was treated with cow milk restriction and oral iron supplements, which resulted in resolution of his edema and laboratory anomalies. While small numbers of previous case reports have described the potential association between excessive cow milk intake and severe iron deficiency and protein-losing enteropathy, this constellation of clinical symptoms is infrequently recognized in clinical practice. As iron deficiency is recognized as the most common nutritional deficiency in the United States, it is important to keep excessive cow milk intake in mind when evaluating young children presenting with severe iron deficiency and protein-losing enteropathy. PMID- 29511699 TI - State-Level Implementation of Health and Safety Policies to Prevent Sudden Death and Catastrophic Injuries Within Secondary School Athletics: Response. PMID- 29511700 TI - Variability of United States Online Rehabilitation Protocols for Proximal Hamstring Tendon Repair. AB - Background: The optimal postoperative rehabilitation protocol following repair of complete proximal hamstring tendon ruptures is the subject of ongoing investigation, with a need for more standardized regimens and evidence-based modalities. Purpose: To assess the variability across proximal hamstring tendon repair rehabilitation protocols published online by United States (US) orthopaedic teaching programs. Study Design: Cross-sectional study. Methods: Online proximal hamstring physical therapy protocols from US academic orthopaedic programs were reviewed. A web-based search using the search term complete proximal hamstring repair rehabilitation protocol provided an additional 14 protocols. A comprehensive scoring rubric was developed after review of all protocols and was used to assess each protocol for both the presence of various rehabilitation components and the point at which those components were introduced. Results: Of 50 rehabilitation protocols identified, 35 satisfied inclusion criteria and were analyzed. Twenty-five protocols (71%) recommended immediate postoperative bracing: 12 (34%) prescribed knee bracing, 8 (23%) prescribed hip bracing, and 5 (14%) did not specify the type of brace recommended. Fourteen protocols (40%) advised immediate nonweightbearing with crutches, while 16 protocols (46%) permitted immediate toe-touch weightbearing. Advancement to full weightbearing was allowed at a mean of 7.1 weeks (range, 4-12 weeks). Most protocols (80%) recommended gentle knee and hip passive range of motion and active range of motion, starting at a mean 1.4 weeks (range, 0-3 weeks) and 4.0 weeks (range, 0-6 weeks), respectively. However, only 6 protocols (17%) provided specific time points to initiate full hip and knee range of motion: a mean 8.0 weeks (range, 4-12 weeks) and 7.8 weeks (range, 0-12 weeks), respectively. Considerable variability was noted in the inclusion and timing of strengthening, stretching, proprioception, and cardiovascular exercises. Fifteen protocols (43%) required completion of specific return-to-sport criteria before resuming training. Conclusion: Marked variability is found in both the composition and timing of rehabilitation components across the various complete proximal hamstring repair rehabilitation protocols published online. This finding mirrors the variability of proposed rehabilitation protocols in the professional literature and represents an opportunity to improve patient care. PMID- 29511702 TI - Position Statement of the Arthroscopy Association of Canada (AAC) Concerning Arthroscopy of the Knee Joint-September 2017. PMID- 29511701 TI - Existing Evidence on Ultrasound-Guided Injections in Sports Medicine. AB - Office-based ultrasonography has become increasingly available in many settings, and its use to guide joint and soft tissue injections has increased. Numerous studies have been conducted to evaluate the use of ultrasound-guided injections over traditional landmark-guided injections, with a rapid growth in the literature over the past few years. A comprehensive review of the literature was conducted to demonstrate increased accuracy of ultrasound-guided injections regardless of anatomic location. In the upper extremity, ultrasound-guided injections have been shown to provide superior benefit to landmark-guided injections at the glenohumeral joint, the subacromial space, the biceps tendon sheath, and the joints of the hand and wrist. Ultrasound-guided injections of the acromioclavicular and the elbow joints have not been shown to be more efficacious. In the lower extremity, ultrasound-guided injections at the knee, ankle, and foot have superior efficacy to landmark-guided injections. Conclusive evidence is not available regarding improved efficacy of ultrasound-guided injections of the hip, although landmark-guided injection is performed less commonly at the hip joint. Ultrasound-guided injections are overall more accurate than landmark-guided injections. While current studies indicate that ultrasound guidance improves efficacy and cost-effectiveness of many injections, these studies are limited and more research is needed. PMID- 29511703 TI - Shoulder MRI Abnormalities in Asymptomatic Little League Baseball Players. AB - Background: Youth baseball is extremely popular in the United States, but it has been associated with shoulder pain and injury. The incidence of shoulder abnormalities in this athletic population has yet to be defined. Purpose: To examine abnormalities noted on magnetic resonance imaging (MRI) in the shoulders of asymptomatic Little League baseball players and to correlate these findings with the players' throwing history and physical examinations. Study Design: Case control study; Level of evidence, 3. Methods: A total of 23 Little League baseball players aged 10 to 12 years were recruited. All players underwent a comprehensive physical examination and responded to a questionnaire addressing their playing history and any arm or shoulder pain. Bilateral shoulder MRIs were performed and read in a blinded manner by 2 radiologists. Responses on the questionnaire and physical examination findings were compared between participants with and without positive MRI findings through use of chi-square test and analysis of variance. Results: The dominant arm was 8.5 times more likely to have an abnormality on MRI compared with the nondominant arm. In all, 12 players (52%) had 17 positive MRI findings in their throwing shoulder that were not present in their nondominant shoulder. These findings included edema or widening of the proximal humeral physis (n = 5), labral tear (n = 4), partial rotator thickness tear (n = 4), acromioclavicular joint abnormality (n = 2), subacromial bursitis (n = 1), and cystic change of the greater tuberosity (n = 1). Two primary risk factors were associated with an abnormal MRI: year-round play and single-sport athletes focusing solely on baseball (P < .05). Players with no risk factors, 1 risk factor, and both risk factors had a 25%, 71%, and 100% chance, respectively, of having an abnormal MRI. A majority of players (61%) had previously experienced shoulder pain, especially pitchers throwing curveballs and sliders (P < .05), but this was not associated with an abnormal MRI. Conclusion: Abnormalities seen on MRI involving the shoulder are common in Little League baseball players, especially those who are single-sport athletes playing year-round. PMID- 29511704 TI - Shoulder Injuries in National Collegiate Athletic Association Quarterbacks: 10 Year Epidemiology of Incidence, Risk Factors, and Trends. AB - Background: Up to 50% of National Collegiate Athletic Association (NCAA) football players have a history of shoulder injuries. The quarterback position has been shown to have a high prevalence of these injuries because of its unique exposures. There is little information regarding the shoulder injury type and mechanism in NCAA quarterbacks. Purpose: To understand the 10-year epidemiology of specific shoulder injury rates in NCAA quarterbacks. Study Design: Descriptive epidemiology study. Methods: Shoulder injury data for collegiate football quarterbacks from the 2004 through 2014 academic years were analyzed using the NCAA Injury Surveillance Program (ISP) data set. Results: Over the 10-year study period, a total of 133 shoulder injuries to collegiate quarterbacks were reported, with 157,288 quarterback exposures. There was approximately 1 shoulder injury per 1221 exposures. The most common injuries noted were acromioclavicular sprains (45.1%, n = 60), followed by shoulder contusions (9.0%, n = 12), clavicular fractures (7.5%, n = 10), and anterior instability (5.3%, n = 7). The majority of injuries were caused by contact with a player (60.2%, n = 80) or contact with a playing surface (28.6%, n = 38), and 88% (n = 117) were deemed nonsurgical in nature. Conclusion: NCAA ISP data analysis suggests that collegiate quarterbacks sustain acute contact injuries 89% of the time and that they typically occur while being tackled, resulting in a time loss of less than 2 weeks. These injuries are commonly treated nonsurgically. PMID- 29511706 TI - Effective treatment of CLIPPERS with long-term use of rituximab. PMID- 29511705 TI - Treatment choices and neuropsychological symptoms of a large cohort of early MS. AB - Objective: To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods: The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. Results: Of 1,124 patients, with a 2.2:1 female-to male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion: Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients. PMID- 29511707 TI - Thymectomy lowers the myasthenia gravis biomarker miR-150-5p. AB - Objective: The aim of the study was to analyze the effect of thymectomy on the proposed disease-specific microRNA (miRNA) biomarkers miR-150-5p and miR-21-5p in patients from the prospective randomized trial of thymectomy in myasthenia gravis (MGTX trial) and to evaluate the longitudinal changes in clinical patterns compared with these miRNA levels. Methods: Serum samples were obtained from 80 patients with MG who were included in the MGTX trial. Thirty-eight patients were randomized to thymectomy plus prednisone treatment, and 42 patients were randomized to prednisone treatment. Serum samples were analyzed for the expression of miR-150-5p and miR-21-5p, with quantitative reverse transcriptase PCR at baseline and at 12, 24, and 36 months after randomization. The inclusion criteria for participation in the MGTX trial were age 18-65 years, generalized myasthenia gravis (Myasthenia Gravis Foundation of America Class II-IV), disease duration of less than 5 years, and seropositivity for acetylcholine receptor antibodies (AChR+). Results: Patients treated with thymectomy had lower levels of miR-150-5p at 24 months, both compared with baseline values (p = 0.0011) and the prednisone group (p = 0.04). No change in miRNA levels was found in the prednisone group. Levels of miR-21-5p displayed a negative correlation with the prednisone dose within the prednisone-only group (p <= 0.001). Conclusions: Thymectomy lowers the levels of the proposed biomarker miR-150-5p, which strengthens its position as a potential disease-specific biomarker for AChR+ MG. PMID- 29511708 TI - Parent-Reported Mild Head Injury History in Children: Long-Term Effects on Attention-Deficit Hyperactivity Disorder. AB - Objective. Consequences of mild head injury for behavioral adjustment have not been well researched, and little is known about the long-term effects of mild head injury for attention-deficit hyperactivity disorder (ADHD). Methods. In this longitudinal study of 418 children in Jintan City, China, parents reported children's history of head injury at age 6 years, and the Child Behavior Checklist was used to measure child iDSM-IV-oriented ADHD at ages 6 (Wave I) and 12 years (Wave II). Regression models were used to calculate the long-term (Wave II) effect of mild head injury on diagnosed ADHD, while controlling for diagnosed ADHD in Wave I. Results. Fifty-seven children (13.6%) had a single injury and 42 (10.0%) had multiple injuries before the age of 6 years. The long-term effect of multiple mild injury on ADHD at age 12 years was significant (R2 = 0.103, P < .05), even after controlling for ADHD at age 6 years. Conclusions. Multiple, but not single, mild head injuries before the age of 6 years had a significant long term effect on ADHD. Thus, injuries traditionally overlooked and underreported still pose significant risks to children's long-term behavioral development. PMID- 29511709 TI - Nasogastric Hydration for Bronchiolitis: Sustaining Change in Practice. PMID- 29511710 TI - Distinct CCL2, CCL5, CCL11, CCL27, IL-17, IL-6, BDNF serum profiles correlate to different job-stress outcomes. AB - Chronic psychosocial stress at workplace is an important factor in the development of physical and mental illness. Objective biological measures of chronic stress are still lacking, but inflammatory response and growth factors are increasingly considered as potential stress biomarkers. Therefore, we investigated the relationship between psychophysical strain and serum levels of 48 chemokines, cytokines and growth factors measured using a multiplex immunoassay, and serum brain-derived neurotrophic factor (BDNF) measured by ELISA. Severity of psychophysical strain was scored in 115 healthy hospital workers using specific scales for anxiety, depression-like emotion, gastrointestinal or cardiac disturbances, and ergonomic dysfunction. Multivariate analysis revealed that higher anxiety scale scores were correlated with lower serum chemokine C-C motif ligand-2 (CCL2/MCP-1), chemokine C-C motif ligand-5 (CCL5/RANTES), chemokine C-C motif ligand-27 (CCL27/CTACK), chemokine C-C motif ligand-11 (CCL11/Eotaxin) and interleukin-6 (IL-6); gastrointestinal disturbances correlated with increased levels of interleukin-17 (IL-17) and reduced CCL11/Eotaxin, CCL27/CTACK and CCL2/MCP-1; while cardiac dysfunctions associate only to reduced CCL27/CTACK, and ergonomic dysfunction correlated with increased BDNF and reduced CCL11/Eotaxin and CCL5/RANTES. Thus, these 7 serum factors may provide a distinct signature for each different stress-related psychophysical outcome giving indications on individual vulnerabilities. PMID- 29511712 TI - Data on antibiogram and resistance genes harboured by Salmonella strains and their Pulsed-field gel electrophoresis clusters. AB - This article describes the Pulsed-field gel electrophoresis clustering of the predominant Salmonella strains (Salmonella ser. Albany, Salmonella ser. Brancaster, and Salmonella ser. Corvallis) isolated from poultry and processing environment in wet market and small-scale processing plant in Penang and Perlis, the northern states of Malaysia. Agar disk diffusion assay was performed to determine the phenotypic antibiotic resistance of these Salmonella strains. The most common antibiograms among the three predominant Salmonella serovars were reported. The presence of integrase genes and antibiotic resistance genes conferring to resistance against beta-lactams, aminoglycosides, tetracyclines, quinolones, sulphonamides and chloramphenicol, was detected via PCR amplification. PMID- 29511711 TI - Data in support of sustained upregulation of adaptive redox homeostasis mechanisms caused by KRIT1 loss-of-function. AB - This article contains additional data related to the original research article entitled "KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: implication for Cerebral Cavernous Malformation disease" (Antognelli et al., 2017) [1]. Data were obtained by si-RNA-mediated gene silencing, qRT-PCR, immunoblotting, and immunohistochemistry studies, and enzymatic activity and apoptosis assays. Overall, they support, complement and extend original findings demonstrating that KRIT1 loss-of-function induces a redox-sensitive and JNK-dependent sustained upregulation of the master Nrf2 antioxidant defense pathway and its downstream target Glyoxalase 1 (Glo1), and a drop in intracellular levels of AP-modified Hsp70 and Hsp27 proteins, leading to a chronic adaptive redox homeostasis that sensitizes cells to oxidative DNA damage and apoptosis. In particular, immunoblotting analyses of Nrf2, Glo1, AP-modified Hsp70 and Hsp27 proteins, HO 1, phospho-c-Jun, phospho-ERK5, and KLF4 expression levels were performed both in KRIT1-knockout MEF cells and in KRIT1-silenced human brain microvascular endothelial cells (hBMEC) treated with the antioxidant Tiron, and compared with control cells. Moreover, immunohistochemistry analysis of Nrf2, Glo1, phospho JNK, and KLF4 was performed on histological samples of human CCM lesions. Finally, the role of Glo1 in the downregulation of AP-modified Hsp70 and Hsp27 proteins, and the increase in apoptosis susceptibility associated with KRIT1 loss of-function was addressed by si-RNA-mediated Glo1 gene silencing in KRIT1 knockout MEF cells. PMID- 29511713 TI - Data on processing of Ti-25Nb-25Zr beta-titanium alloys via powder metallurgy route: Methodology, microstructure and mechanical properties. AB - The data presented in this article are related to the research article entitled "Cyclic Shear behavior of conventional and harmonic structure-designed Ti-25Nb 25Zr beta-titanium alloy: Back-stress hardening and twinning inhibition" (Dirras et al., 2017) [1]. The datasheet describes the methods used to fabricate two beta titanium alloys having conventional microstructure and so-called harmonic structure (HS) design via a powder metallurgy route, namely the spark plasma sintering (SPS) route. The data show the as-processed unconsolidated powder microstructures as well as the post-SPS ones. The data illustrate the mechanical response under cyclic shear loading of consolidated alloy specimens. The data show how electron back scattering diffraction(EBSD) method is used to clearly identify induced deformation features in the case of the conventional alloy. PMID- 29511714 TI - Dataset on the effects of spermidine on linking number differences between histone H1-free and histone H1-bound circular polynucleosomes. AB - The data presented in this article are related to the research article entitled "Quantitative determination of linking number differences between circular polynucleosomes and histone H1-bound circular polynucleosomes" Zhang et al. (in press) [1]. DNA linking number differences between histone H1-free and histone H1 bound circular polynucleosomes at various spermidine concentrations was quantitatively determined by chloroquine-based gel electrophoretic analysis in this work, which provides information on the topological effects of histone H1 and spermidine on the linker DNA between nucleosomes. PMID- 29511715 TI - Data supporting the assessment of biomass based electricity and reduced GHG emissions in Cuba. AB - Assessing the biomass based electricity potential of developing nations like Cuba can help to reduce the fossil fuels dependency and the greenhouse gas emissions. The data included in this study present the evolution of electricity production and greenhouse gas emissions in Cuba. Additionally, the potentialities to produce biomass based electricity by using the most significant biomass sources in Cuba are estimated. Furthermore, estimations of the potential reductions of greenhouse gas emissions, resulting from implementing the biomass based electricity potential of the different sources discussed in the study, are included. Results point to the most promising biomass sources for electricity generation and their potential to reduce GHG emissions. PMID- 29511716 TI - Data supporting the prediction of the properties of eutectic organic phase change materials. AB - The data presented in this article include the molar masses, melting temperatures, latent heats of fusion and temperature-dependent heat capacities of fifteen fatty acid phase change materials (PCMs). The data are used in conjunction with the thermodynamic models discussed in Kahwaji and White (2018) [1] to develop a computational tool that calculates the eutectic compositions and thermal properties of eutectic mixtures of PCMs. The computational tool is part of this article and consists of a Microsoft Excel(r) file available in Mendeley Data repository [2]. A description of the computational tool along with the properties of nearly 100 binary mixtures of fatty acid PCMs calculated using this tool are also included in the present article. The Excel(r) file is designed such that it can be easily modified or expanded by users to calculate the properties of eutectic mixtures of other classes of PCMs. PMID- 29511717 TI - Systematic review of Australian policing interventions to reduce alcohol-related violence - A maxillofacial perspective. AB - Alcohol-related violence remains to be a health concern, and the oral and maxillofacial surgeons are routinely exposed to its impact on the victims and the healthcare system. At a community level, various policing interventions have been implemented to address this violent crime in and around licensed premises. Current study sought to examine the effectiveness of these interventions in Australia. Ten eligible studies, that evaluated the impact of 15 Australian policing interventions on reducing alcohol-related violence in the night-time economy, were included in this systematic review. Due to the heterogeneity of the study designs and the insufficiency of the reported data, quantitative meta analysis of the findings was precluded. Instead, a critical narrative approach was used. Police-recorded assault rate was the primary outcome measured to assess the level of alcohol-related violence, which was influenced by the level of police duties implemented during the intervention period. The overall evidence base to support Australian policing interventions was found to be poor and was limited by the low-quality study design observed in the majority of the included studies. However, there is some evidence to suggest interventions involving proactive policing to be more effective than traditional reactive policing. There was also an increased emphasis on developing policing interventions in collaborative partnerships, demonstrating the synergistic benefits in crime prevention through community partnerships, where communities were encouraged to take ownerships of their own problems and develop targeted responses to alcohol related violence rather than a one-size-fits-all approach. Further research is required to define their effectiveness with the use of more appropriate and robust methodologies. PMID- 29511718 TI - Age-related changes in the relationship between alcohol use and violence from early adolescence to young adulthood. AB - Background: Despite the accumulation of studies examining the link between alcohol use and violence, no studies to our knowledge have systematically set out to detect age-related differences in these relationships. This limitation inhibits important insights into the stability of the relationship between alcohol use and violence among youth across varying ages. Method: Study findings are based on repeated, cross-sectional data collected annually as part of the National Survey on Drug Use and Health between 2002 and 2013. We combined a series of nationally representative cross-sections to provide a multi-year string of data that, in effect, reflects a nationally representative non-traditional cohort. We conducted logistic regression analyses to examine the cross-sectional association between non-binge and binge drinking and violent attacks among youth between ages 12 (2002) and 24/25 (2013). Results: With respect to the association between non-binge alcohol use and violence, the only significant relationship identified-while controlling for sociodemographic and drug use factors-was for youth at age 13 (2003; OR = 1.97, 95% CI = 1.04-3.72). For binge drinking, we identified a distinct pattern of results. Controlling for sociodemographic, drug use factors, and school enrollment, binge drinking was significantly associated with violence between ages 13 (2003) and 20 (2010) with the largest odds ratios observed during the early adolescent period. Conclusions: Non-binge drinking is associated with violent behavior at age 13. Binge drinking was found to be associated with violence among youth through age 20; however, the relationship dissipates when youth arrive at the legal drinking age of 21. PMID- 29511719 TI - Substance use among adolescent sexual minority athletes: A secondary analysis of the youth risk behavior survey. AB - Aims: While a robust literature exists regarding substance use patterns among adolescent athletes, no studies have examined substance use among adolescent sexual minority athletes; a subpopulation of adolescents that may experience greater rates of substance use due to their marginalized status within the context of sport. Methods: This study uses data from the Youth Risk Behavior Survey (2009-2013). Adolescents (N = 26,940) from four states were included in the analyses that assessed past 30-day cigarette use, alcohol use, binge drinking and marijuana use among sexual minority athletes, heterosexual athletes, heterosexual non-athletes, and sexual minority non-athletes. Results: Approximately 4% of the sample included athletes who identified as a sexual minority (3.7% males and 5.3% females). While the bivariate analyses found that sexual minority athletes had higher past 30-day prevalence rates of substance use when compared to heterosexual athletes and non-athletes, these rates were similar to sexual minority non-athletes. Moreover, when demographic characteristics and history of substance use were included in the multivariate analytic models, many of these differences were no longer statistically significant. These results were generally consistent for both males and females. Conclusions: The results of the study suggest that the context of sport may not be an additional site for stress among adolescent athletes who identify as a sexual minority, and subsequently may have little impact on substance use behaviors. However, participating in sport may not serve as a protective context for adolescent sexual minorities given that substance use behaviors may be learned and reinforced. PMID- 29511720 TI - Trajectories of abstinence-induced Internet gaming withdrawal symptoms: A prospective pilot study. AB - Internet Gaming Disorder (IGD) is positioned in the appendix of the DSM-5 as a condition requiring further study. The IGD criteria refer to withdrawal symptoms, including irritability, anxiety, or sadness, that follow cessation of Internet gaming (APA, 2013). The aim of this study was to prospectively examine the nature of Internet gaming withdrawal symptoms, if they occur, under gaming abstinence conditions. This study employed a repeated-measures protocol to examine the cognitive-affective reactions of participants undertaking an 84-h Internet gaming abstinence period. The sample included individuals who met the IGD criteria as well as those who regularly played Internet games but did not meet the IGD criteria. Outcome variables included affect (positive and negative), psychological distress (depression, anxiety, stress), and Internet gaming withdrawal symptoms (craving/urge, thoughts about gaming, inability to resist gaming). A total of 24 participants (Mage = 24.6 years, SD = 5.8) were recruited from online gaming communities, and completed a series of online surveys before, during, and after abstaining from Massively Multiplayer Online (MMO) games. Both the IGD group and the non-IGD group experienced an abstinence-induced decline in withdrawal symptomatology, negative affect, and psychological distress. The IGD group experienced its largest decline in withdrawal symptomatology within the first 24 h of abstinence. These preliminary data suggest that gaming withdrawal symptoms may follow, at least initially, negative linear and quadratic trends. Further prospective work in larger samples involving longer periods of abstinence is required to verify and expand upon these observations. PMID- 29511721 TI - Prospective recovery of cannabis use in a psychotic population: A qualitative analysis. AB - Introduction: There is growing evidence for natural recovery from cannabis use by people with psychosis, but mechanisms underpinning it need further exploration. This study prospectively explored this issue. Method: Twenty-two people with psychosis and cannabis misuse were recruited: 19 provided data for at least one follow-up assessment, and 13 of these (68%) reduced or ceased using cannabis. A semi-structured interview with the latter group explored reasons for initiating the attempt, strategies they employed, and context/s where any relapse occurred. Interpretative phenomenological analysis was used to identify themes. Results: Participants who reduced or ceased cannabis use had fewer negative symptoms at Baseline, and were more likely to only use cannabis. Major reasons for starting an attempt were worsening mental health, relationship and lifestyle difficulties. Effective strategies fell into psychological, relationship, lifestyle and medication themes. Only three participants reported a relapse: triggers involved substance-using peers, relationship difficulties, and problems with negative emotions including ones from past trauma. Conclusions: An encouragingly high rate of maintained reductions in cannabis use was seen. Increased awareness of the benefits across multiple life domains from addressing cannabis use may be critical to the initiation and maintenance of attempts, both to maximise motivation, and avoid over-dependence on improvements in any single domain. Negative symptoms, multiple substance use, dysphoria and pressure from substance using peers clearly offer additional challenges for control. PMID- 29511722 TI - Exploring the alcohol-behaviour link: Myopic self-enhancement in the absence of alcohol consumption as a function of past alcohol use. AB - Dual process accounts of the alcohol-behaviour link hypothesise that differences in drinking patterns will moderate the effects of exposure to alcohol-related cues on behaviour, such as when a placebo is administered. We test this hypothesis by adapting a paradigm used in alcohol myopia research to examine the effects of alcohol-related priming on self-enhancement behaviour amongst social drinkers. Participants were asked to engage in a computerised self-rating task prior to being exposed to alcohol related and/or motivational primes. A staged computer error then occurred, and participants were then asked to complete their self ratings again - this method allowed for an immediate assessment of the impact of alcohol and motivational primes on self enhancement. As predicted by alcohol myopia theory, the overall effect of priming with alcohol-related cues was not significant irrespective of response-conflict manipulations. However, drinker type moderated this effect such that heavier drinkers self-enhanced more after exposure to alcohol-related cues, but only in high-conflict conditions. This suggests that the efficacy of a placebo may be significantly moderated by individual differences in reactions to alcohol-related stimuli, and that dual process accounts of the effects of alcohol on behaviour better explains this variation than alcohol myopia theory. PMID- 29511723 TI - Confirmatory factor analysis of the Spanish version of the Gamblers' Beliefs Questionnaire in a sample of Argentinean gamblers. AB - INTRODUCTION: Cognitive distortions are related to gambling frequency and gambling severity. Having a culturally sensitive measure to assess cognitive distortions will facilitate the early detection of people who might be at risk of developing problematic gambling behaviors. The Gamblers' Beliefs Questionnaire was translated into Spanish (GBQ-S) but no previous study explored the structure of the GBQ-S in a non-US sample with different levels of gambling involvement. AIM: The present study examined the factor structure of the GBQ-S in a community sample of gamblers from Argentina. It also analyzed the association between cognitive distortions and type of gambling activity and frequency of gambling behaviors and the predictive utility of the GBQ-S on gambling severity. PARTICIPANTS: 508 youth and adults completed the GBQ-S. RESULTS: The CFA showed an overall acceptable fit to the data confirming the proposed two-factor model. Scores of the two GBQ sub-scales were positively and significantly correlated with scores on gambling severity. Cognitive distortions have a significant effect on gambling severity after controlling for frequency of engagement in gambling activities. Luck and perseverance, but not illusion of control, was positively related to gambling severity. DISCUSSION: scores measured by the GBQ-S exhibit adequate psychometric properties for the accurate assessment of cognitive distortions across adults and youth from the general community of Argentina. PMID- 29511724 TI - Effects of repetitive imagination of alcohol consumption on craving in alcohol dependent patients: A pilot study. AB - Background: In the majority of patients with alcohol use disorder (AUD), the clinical course is characterized by multiple relapses to drinking, frequently preceded by intense craving for alcohol. The present pilot study aimed to assess the effects of a repetitive imaginary cue-exposure protocol in reducing craving in recently abstinent alcohol-dependent patients. Methods: Sixty-four patients were randomly assigned to six intervention groups and were instructed to repetitively imagine: i) drinking a glass of their preferred alcoholic drink (low vs. high number of repetitions); or ii) drinking a glass of water (low vs. high number of repetitions); or iii) performing an analogous movement or performed no imagination. Additionally, 10 healthy controls were instructed to repetitively imagine drinking a glass of their preferred alcoholic drink (high number of repetitions). The levels of craving before and after intervention were measured using the Alcohol Urge Questionnaire (AUQ) and the Visual Analogue Scale for Craving (VASC). Results: Repetitive imagination of alcohol consumption did not lead to a significant decrease in craving in alcohol-dependent patients as measured by the AUQ and VASC. In contrast, healthy controls showed a nearly significant decrease of the urge to drink alcohol after applying the protocol with a high number of repetitions. Conclusions: The findings of this pilot study might indicate an aberrant ability to habituate to alcohol-related stimuli in patients with AUD compared to healthy subjects. Future studies in larger samples are needed to further explore the effectiveness of imaginary cue-exposure interventions in alcohol dependence. PMID- 29511725 TI - Internet use and problematic Internet use among adolescents in Japan: A nationwide representative survey. AB - Introduction: Japan is assumed to have serious health and social problems due to Internet overuse, but little is known about the actual conditions. This study was conducted to investigate the prevalence of problematic Internet use (PIU) and associated Internet use in adolescents in Japan. Methods: A nationwide survey of adolescent Internet use was conducted in 2012 and 2013. The participants were 100,050 students from randomly selected junior and senior high schools nationwide who gave valid responses to a self-reported questionnaire. The questionnaire included questions on Internet use and the Japanese version of the Young's Diagnostic Questionnaire (YDQ) as well as other questions related to lifestyle habits. Internet users were classified by gender according to three categories on the basis of their YDQ scores: adaptive use, maladaptive use, and PIU. Results: The estimated prevalence of PIU was 6.2% in males, 9.8% in females, and 7.9% in total; it closely correlated with female gender, school grades, and number of Internet hours. The following common and gender-specific applications that conferred a risk of PIU were identified: downloading (both genders), online gaming (males), social networking services, blogs, and bulletin boards (females). Conclusions: A cross-sectional survey using YDQ of a large number of high school students yielded a PIU prevalence of 7.9% in Japan. This study showed that problems associated with Internet overuse have already become serious; therefore, planning and implementation of prevention and control measures is urgently required. PMID- 29511726 TI - Hopelessness and alcohol use: The mediating role of drinking motives and outcome expectancies. AB - Introduction: Heavy drinking is a considerable public health concern. There is a broad evidence-base examining the separate contributions of personality characteristics, motives and alcohol-expectancies on subsequent alcohol use to identify those at risk. However, little is known about the complex relationships by which these variables may interact to predict drinking behavior. Feelings of hopelessness and anxiety sensitivity are hypothesized to be distal predictors of alcohol use, with outcome expectancies and drinking motives more proximal. Therefore, the aim of the current study was to examine whether hopelessness and anxiety sensitivity influenced alcohol use via drinking to cope and alcohol - outcome expectancies. Methods: We recruited 230 participants to complete an online questionnaire consisting of the brief drinking motives questionnaire, the Substance Use Risk Profile scale and Brief Comprehensive Effects of Alcohol scale. We conducted path analyses using structural equation modelling. Results: We demonstrated a significant direct effect of anxiety sensitivity on alcohol use, and a significant serial indirect effect of hopelessness through coping motives and alcohol outcome expectancies. Conclusions: These findings suggest feelings of hopelessness may predict alcohol consumption through a complex pathway and future research should use these findings to identify individuals at risk of increased alcohol use. PMID- 29511727 TI - Associations between social identity diversity, compatibility, and recovery capital amongst young people in substance use treatment. AB - : This study explored associations between group memberships and recovery capital amongst 20 young adults aged 18 to 21 years in residential alcohol and drug treatment. Method: Participants completed an interviewer administered research interview based on measures of recovery capital and a social networks assessment mapping group memberships, group substance use, and relationships between groups. Results: Higher personal and social recovery capital was associated with lower diversity of group memberships, a higher number of positive links between groups, and greater compatibility of lower substance-using groups with other groups in the network. Higher compatibility of heavier-using groups was also associated with having a higher number of negative, antagonistic ties between groups. Conclusions: These findings indicate that it is higher compatibility of a lower substance-using social identity and lower-using group memberships that contributes to recovery capital. Further, positive ties between groups and lower diversity of group memberships appear to be key aspects in how multiple social identities that are held by young adults relate to personal and social recovery capital. PMID- 29511728 TI - The importance of social identities in the management of and recovery from 'Diabulimia': A qualitative exploration. AB - Introduction: A significant barrier to recovery for individuals with co-morbid eating disorders and type 1 diabetes is the way in which group members self categorise. Nonetheless, identity issues are neglected during the recovery process. The aim of this paper is to explore how group memberships (and the associated identities) both contribute to and hinder recovery in this cohort. Method: Transcripts from five online focus groups with 13 members of an online support group for individuals with 'Diabulimia' were thematically analysed. Results: Findings suggested that those with whom one shares a recovery identity can be well placed to provide psychological resources necessary for successful recovery although such connections can be damaging if group norms are not managed. Members recognised that other important relationships (including family and friends and health professionals) are also key to recovery; these other group memberships (and the associated identities) can be facilitated through the recovery identity group membership, which allows for external validation of the recovery identity, provides encouragement to disclose the illness to supportive others, and provides information to facilitate positive service interactions. Conclusions: While clinical interventions typically focus on eliminating disordered behaviours, we suggest that these should also include strengthening important group memberships that promote recovery. PMID- 29511729 TI - People Control Their Addictions: No matter how much the "chronic" brain disease model of addiction indicates otherwise, we know that people can quit addictions - with special reference to harm reduction and mindfulness. AB - The world, led by the United States, is hell bent on establishing the absence of choice in addiction, as expressed by the defining statement that addiction is a "chronic relapsing brain disease" (my emphasis). The figure most associated with this model, the director of the American National Institute on Drug Abuse, Nora Volkow, claims that addiction vitiates free will through its effects on the brain. In reality, while by no means a simple task, people regularly quit their substance addictions, often by moderating their consumption, usually through mindfulness-mediated processes (Peele, 2007). Ironically, the brain disease model's ascendance in the U.S. corresponds with epidemic rises in opiate addiction, both painkillers (Brady et al., 2016) and heroin (CDC, n.d.), as well as heroin, painkiller, and tranquilizer poisoning deaths (Rudd et al., 2016). More to the point, the conceptual and treatment goal of eliminating choice in addiction and recovery is not only futile, but iatrogenic. Indeed, the National Institute on Alcohol Abuse and Alcoholism's epidemiological surveys, while finding natural recovery for both drug and alcohol disorders to be typical, has found a decline in natural recovery rates (Dawson et al., 2005) and a sharp increase in AUDs (Grant et al., 2015). PMID- 29511730 TI - Colorectal polyp characterization: Is my computer better than me? PMID- 29511731 TI - Endoscopic perforation during ERM or ESD: who should take care of the patient? PMID- 29511732 TI - Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability. AB - High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%-80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation. PMID- 29511733 TI - On-chip dual-comb source for spectroscopy. AB - Dual-comb spectroscopy is a powerful technique for real-time, broadband optical sampling of molecular spectra, which requires no moving components. Recent developments with microresonator-based platforms have enabled frequency combs at the chip scale. However, the need to precisely match the resonance wavelengths of distinct high quality-factor microcavities has hindered the development of on chip dual combs. We report the simultaneous generation of two microresonator combs on the same chip from a single laser, drastically reducing experimental complexity. We demonstrate broadband optical spectra spanning 51 THz and low noise operation of both combs by deterministically tuning into soliton mode locked states using integrated microheaters, resulting in narrow (<10 kHz) microwave beat notes. We further use one comb as a reference to probe the formation dynamics of the other comb, thus introducing a technique to investigate comb evolution without auxiliary lasers or microwave oscillators. We demonstrate high signal-to-noise ratio absorption spectroscopy spanning 170 nm using the dual comb source over a 20-MUs acquisition time. Our device paves the way for compact and robust spectrometers at nanosecond time scales enabled by large beat-note spacings (>1 GHz). PMID- 29511734 TI - High-capacity aqueous zinc batteries using sustainable quinone electrodes. AB - Quinones, which are ubiquitous in nature, can act as sustainable and green electrode materials but face dissolution in organic electrolytes, resulting in fast fading of capacity and short cycle life. We report that quinone electrodes, especially calix[4]quinone (C4Q) in rechargeable metal zinc batteries coupled with a cation-selective membrane using an aqueous electrolyte, exhibit a high capacity of 335 mA h g-1 with an energy efficiency of 93% at 20 mA g-1 and a long life of 1000 cycles with a capacity retention of 87% at 500 mA g-1. The pouch zinc batteries with a respective depth of discharge of 89% (C4Q) and 49% (zinc anode) can deliver an energy density of 220 Wh kg-1 by mass of both a C4Q cathode and a theoretical Zn anode. We also develop an electrostatic potential computing method to demonstrate that carbonyl groups are active centers of electrochemistry. Moreover, the structural evolution and dissolution behavior of active materials during discharge and charge processes are investigated by operando spectral techniques such as IR, Raman, and ultraviolet-visible spectroscopies. Our results show that batteries using quinone cathodes and metal anodes in aqueous electrolyte are reliable approaches for mass energy storage. PMID- 29511735 TI - Synthetic electromagnetic knot in a three-dimensional skyrmion. AB - Classical electromagnetism and quantum mechanics are both central to the modern understanding of the physical world and its ongoing technological development. Quantum simulations of electromagnetic forces have the potential to provide information about materials and systems that do not have conveniently solvable theoretical descriptions, such as those related to quantum Hall physics, or that have not been physically observed, such as magnetic monopoles. However, quantum simulations that simultaneously implement all of the principal features of classical electromagnetism have thus far proved elusive. We experimentally realize a simulation in which a charged quantum particle interacts with the knotted electromagnetic fields peculiar to a topological model of ball lightning. These phenomena are induced by precise spatiotemporal control of the spin field of an atomic Bose-Einstein condensate, simultaneously creating a Shankar skyrmion a topological excitation that was theoretically predicted four decades ago but never before observed experimentally. Our results reveal the versatile capabilities of synthetic electromagnetism and provide the first experimental images of topological three-dimensional skyrmions in a quantum system. PMID- 29511737 TI - Optical manipulation of work function contrasts on metal thin films. AB - Work function is a crucial metric in every optoelectronic device to ensure a specific charge transport scheme. However, the number of stable conductive materials available in a given work function range is scant, necessitating work function modulation. As opposed to all the previous chemical methods of work function modulation, we introduce here an alternative approach involving optical modulation. The work function is the minimum energy needed to eject an electron from a solid into vacuum and is known to be light-intensity-independent. A "light intensity dependent" change in work function was observed in metallic thin films coated on a semiconductor. This new phenomenon, contrasting the existing notions on work function, was tested and affirmed with three different systems, namely, Au/n-Si, Pt/n-Si, and W/n-Si. A work function shift of 0.22 eV is achieved in the Pt/n-Si system merely by tuning the illumination intensity from 0 to 18 mW/cm2. Continuous tuning of work functions to a specified range is now possible just by tuning the light intensity with a few discrete metals in hand. Moreover, selective illumination creates a work function contrast on the metal film, enabling in-plane charge transport. This throws new light on the design and understanding of the optoelectronic devices. In light of this, we also present a simple photodetector design that is sensitive to illumination direction. PMID- 29511736 TI - Oxide-mediated recovery of field-effect mobility in plasma-treated MoS2. AB - Precise tunability of electronic properties of two-dimensional (2D) nanomaterials is a key goal of current research in this field of materials science. Chemical modification of layered transition metal dichalcogenides leads to the creation of heterostructures of low-dimensional variants of these materials. In particular, the effect of oxygen-containing plasma treatment on molybdenum disulfide (MoS2) has long been thought to be detrimental to the electrical performance of the material. We show that the mobility and conductivity of MoS2 can be precisely controlled and improved by systematic exposure to oxygen/argon plasma and characterize the material using advanced spectroscopy and microscopy. Through complementary theoretical modeling, which confirms conductivity enhancement, we infer the role of a transient 2D substoichiometric phase of molybdenum trioxide (2D-MoO x ) in modulating the electronic behavior of the material. Deduction of the beneficial role of MoO x will serve to open the field to new approaches with regard to the tunability of 2D semiconductors by their low-dimensional oxides in nano-modified heterostructures. PMID- 29511738 TI - Critical behavior within 20 fs drives the out-of-equilibrium laser-induced magnetic phase transition in nickel. AB - It has long been known that ferromagnets undergo a phase transition from ferromagnetic to paramagnetic at the Curie temperature, associated with critical phenomena such as a divergence in the heat capacity. A ferromagnet can also be transiently demagnetized by heating it with an ultrafast laser pulse. However, to date, the connection between out-of-equilibrium and equilibrium phase transitions, or how fast the out-of-equilibrium phase transitions can proceed, was not known. By combining time- and angle-resolved photoemission with time resolved transverse magneto-optical Kerr spectroscopies, we show that the same critical behavior also governs the ultrafast magnetic phase transition in nickel. This is evidenced by several observations. First, we observe a divergence of the transient heat capacity of the electron spin system preceding material demagnetization. Second, when the electron temperature is transiently driven above the Curie temperature, we observe an extremely rapid change in the material response: The spin system absorbs sufficient energy within the first 20 fs to subsequently proceed through the phase transition, whereas demagnetization and the collapse of the exchange splitting occur on much longer, fluence-independent time scales of ~176 fs. Third, we find that the transient electron temperature alone dictates the magnetic response. Our results are important because they connect the out-of-equilibrium material behavior to the strongly coupled equilibrium behavior and uncover a new time scale in the process of ultrafast demagnetization. PMID- 29511739 TI - Near-field strong coupling of single quantum dots. AB - Strong coupling and the resultant mixing of light and matter states is an important asset for future quantum technologies. We demonstrate deterministic room temperature strong coupling of a mesoscopic colloidal quantum dot to a plasmonic nanoresonator at the apex of a scanning probe. Enormous Rabi splittings of up to 110 meV are accomplished by nanometer-precise positioning of the quantum dot with respect to the nanoresonator probe. We find that, in addition to a small mode volume of the nanoresonator, collective coherent coupling of quantum dot band-edge states and near-field proximity interaction are vital ingredients for the realization of near-field strong coupling of mesoscopic quantum dots. The broadband nature of the interaction paves the road toward ultrafast coherent manipulation of the coupled quantum dot-plasmon system under ambient conditions. PMID- 29511740 TI - Effects of environmental change on population nutrition and health: A comprehensive framework with a focus on fruits and vegetables. AB - Environmental changes are likely to affect agricultural production over the next 20-30 years. The interactions between environmental change, agricultural yields and crop quality, and the critical pathways to future diets and health outcomes remain largely undefined. There are currently no quantitative models to test the impact of multiple environmental changes on nutrition and health outcomes. Using an interdisciplinary approach, we developed a framework to link the multiple interactions between environmental change, agricultural productivity and crop quality, population-level food availability, dietary intake and health outcomes, with a specific focus on fruits and vegetables. The main components of the framework consist of: i) socio-economic and societal factors, ii) environmental change stressors, iii) interventions and policies, iv) food system activities, v) food and nutrition security, and vi) health and well-being outcomes. The framework, based on currently available evidence, provides an overview of the multidimensional and complex interactions between environmental change, diets and health, and forms the analytical baseline for future modelling and scenario testing. The framework identifies the inter-sectoral datasets and models that need to be defined and populated to assess the impacts of environmental change on agricultural production, food availability, nutrition and population health. PMID- 29511741 TI - Evaluating healthcare priority setting at the meso level: A thematic review of empirical literature. AB - Background: Decentralization of health systems has made sub-national/regional healthcare systems the backbone of healthcare delivery. These regions are tasked with the difficult responsibility of determining healthcare priorities and resource allocation amidst scarce resources. We aimed to review empirical literature that evaluated priority setting practice at the meso level of health systems. Methods: We systematically searched PubMed, ScienceDirect and Google scholar databases and supplemented these with manual searching for relevant studies, based on the reference list of selected papers. We only included empirical studies that described and evaluated, or those that only evaluated priority setting practice at the meso-level. A total of 16 papers were identified from LMICs and HICs. We analyzed data from the selected papers by thematic review. Results: Few studies used systematic priority setting processes, and all but one were from HICs. Both formal and informal criteria are used in priority setting, however, informal criteria appear to be more perverse in LMICs compared to HICs. The priority setting process at the meso-level is a top-down approach with minimal involvement of the community. Accountability for reasonableness was the most common evaluative framework as it was used in 12 of the 16 studies. Efficiency, reallocation of resources and options for service delivery redesign were the most common outcome measures used to evaluate priority setting. Limitations: Our study was limited by the fact that there are very few empirical studies that have evaluated priority setting at the meso-level and there is likelihood that we did not capture all the studies. Conclusions: Improving priority setting practices at the meso level is crucial to strengthening health systems. This can be achieved through incorporating and adapting systematic priority setting processes and frameworks to the context where used, and making considerations of both process and outcome measures during priority setting and resource allocation. PMID- 29511742 TI - Extracranial Vertebral Artery Aneurysm Rupture Complicated by Extrapleural Haematoma. AB - Introduction: Extracranial vertebral artery aneurysm (EVAA) and extrapleural haematoma (EH) are rare clinical findings most often associated with blunt or penetrating trauma. However, EVAA rupture can be complicated by development of a large EH. Report: A 50 year old man underwent an emergency thrombectomy followed by graft reconstruction of an aorto-bi-femoral bypass. The post-operative course was complicated by respiratory failure and severe anaemia. Computed tomography revealed EVAA rupture and EH, so ligation of EVAA was performed with thoracotomy. Discussion: In a patient with extensive peripheral vascular disease and rapid development of EH, the rupture of a supra-aortic vessel aneurysm might be considered. PMID- 29511743 TI - Spatial distribution patterns of illegal artisanal small scale gold mining (Galamsey) operations in Ghana: A focus on the Western Region. AB - Recently, there have been efforts by stakeholders to monitor illegal mining (galamsey) activities, foster their formalization and reclaim the many abandoned wastelands in Ghana. However, limited information exists on the locations, abundance, scope and scale of galamsey types, which hinders the development of effective policy response. This study attempts to map and analyze the distribution patterns, abundance, activity statuses and the extents of nine (9) galamsey types within eleven (11) Municipal and District Assemblies (MDAs) of Ghana's Western Region. It explores the utility of field-based survey, using the Open Data Kit (ODK) system, ArcGIS and Google Earth Imagery to map and visualize different galamsey types under a hostile working environment. A total of 911 galamsey sightings, of which 547 were found in clusters (corresponding to approximately 7106 individual operational units) and 364 in stand-alone mode. Overall, a total of 7470 individual galamsey operations were encountered in 312 different communities (towns and villages). Operationally, the Alluvial Washing Board, Mill-House and Chamfi were found to be the three most popular and practiced galamsey types. The three main galamsey hotspot districts (out of the 11) are the Tarkwa Nsuaem (294 sightings and 3648 individual galamsey sites), Amenfi East (223 sightings and 1397 individual galamsey sites) and Prestea Huni Valley Districts (156 sightings and 1130 individual galamsey sites). In terms of their activity statuses, 199 abandoned operations (entailing 1855 individual operations), 664 active (entailing 5055 individuals operations) and 48 semi active (comprising 560 individuals within clusters) galamsey operations were sighted at the time of the study. While galamsey is generally acknowledged to be widespread in Ghana, the results suggest a scale that probably surpasses any previous estimate or expectation. The findings will adequately inform the prioritization of reclamation efforts. PMID- 29511744 TI - Impedance spectroscopy as a tool to monitor the adsorption and removal of nitrate ions from aqueous solution using zinc aluminum chloride anionic clay. AB - In this study, Zn3AlCl ionic clay was used to investigate the adsorption mechanism of the nitrate ions in solutions containing nitrate ions at different contact time. The clay was synthesized by coprecipitation method at room temperature, and this sample was characterized by XRD, Fourier transform-infrared (FT-IR) and inductively coupled plasma (ICP). This sample was crystallized in a rhombohedral symmetry (Space group: R-3 m). Impedance spectroscopy was used as a tool to evaluate and monitor the adsorption process at different contact time 5; 10; 20; 30; 60 min and the clay alone. The impedance measurement was well analyzed and fitted with an equivalent circuit containing both (R//CPE) connected in series. Furthermore, the sigmaac conductivity was also investigated as a function of frequency. It was analyzed and fitted using double power law: [Formula: see text] This study reveals the existence of two relaxation processes with different relaxation times, which could be attributed to the grain and grain boundaries, and exhibit high values of dielectric constant at low frequencies. PMID- 29511745 TI - Combination nivolumab- and cabiralizumab-associated acute bilateral anterior and posterior scleritis and anterior uveitis. AB - Purpose: To report on a case of uveitis and scleritis resulting as an immune mediated side effect of cancer immunotherapy with nivolumab and cabiralizumab. Observations: Bilateral anterior nongranulomatous anterior uveitis and bilateral diffuse anterior and posterior scleritis occurred following the use of combination cancer immunotherapy. The uveitis and scleritis resolved following temporary discontinuation of nivolumab and cabiralizumab as well as systemic prednisone. Conclusions and importance: Ophthalmologists should be aware of the possibility of acute ocular inflammation developing with cancer immunotherapy. Systemic corticosteroids play a first-line role in managing such immune-mediated side effects. PMID- 29511746 TI - Retinal pigment epithelium changes in Kartagener syndrome. AB - Purpose: We present the first case in the literature of a patient with Kartagener syndrome and ocular findings of nonexudative age-related macular degeneration. Observations: A 55-year-old woman with Kartagener syndrome and chronic angle closure glaucoma presented for evaluation of the retina. Optos ultra-widefield imaging of the fundus showed glaucomatous cupping, drusen, and retinal pigment epithelium changes within the macular region. Humphrey visual field testing confirmed glaucomatous changes. Drusenoid pigment epithelial detachments were observed bilaterally with optical coherence tomography. Conclusions and importance: We hypothesize that in addition to the lungs, spermatozoa and the Fallopian tubes, the retinal pigment epithelium may also be affected by ciliary dysfunction in individuals with Kartagener syndrome. Given recent advances in our knowledge of retinal ciliopathies, further studies are needed to understand how ciliary dysfunction affects the retina in Kartagener syndrome. PMID- 29511747 TI - A theoretical study on the mechanism of hydrogen evolution on non-precious partially oxidized nickel-based heterostructures for fuel cells. AB - It is desirable, yet challenging, to utilize non-precious metals instead of noble metals as efficient catalysts in the renewable energy manufacturing industry. Using first principles calculations, we study the structural characteristics of partially oxidized nickel-based nanoheterostructures (NiO/Ni NHSs), and the interfacial effects on hydrogen evolution. The origin of the enhanced hydrogen evolution performance is discussed at the microscopic level. This study identifies two types of active sites of the exposed Ni surface available for the hydrogen evolution reaction (HER). One is the hcp-hollow sites near the perimeter boundary that exhibit a more excellent HER performance than platinum (Pt), and the other the second nearest neighbor fcc-hollow sites away from the boundary that exhibit a similar performance to Pt. The interfacial effects result from the competitive charge transfer between NiO and Ni surfaces in NHSs, and enhance the reactivity of NiO/Ni NHSs by shifting the d-states of surface atoms down in energy. The illumination of the mechanism would be helpful for the design of more efficient and cheap transition metal-based catalysts. PMID- 29511748 TI - Electrically enhanced hot hole driven oxidation catalysis at the interface of a plasmon-exciton hybrid. AB - In this work, an electro-optical device based on a graphene-Ag nanoparticle hybrid is fabricated as the substrate of graphene mediated surface enhanced Raman scattering (G-SERS) manipulated by the gate and bias voltages. Plasmon-exciton coupling promotes co-driven surface catalytic reactions, where the density of states (DOS) of holes and electrons on graphene is well controlled by the gate voltage, and the kinetic energy of holes and electrons is driven by the bias voltage (or current). Our experimental results reveal that the hot holes on graphene mainly contribute to plasmon-exciton co-driven oxidation reactions. The contribution of hot electrons to oxidation reactions is less important. Our novel electro-optical device can be potentially applied in controlling plasmon-exciton co-driven oxidation or reduction reactions by tuning the gate and bias voltages. PMID- 29511749 TI - Spinach-based fluorescent light-up biosensors for multiplexed and label-free detection of microRNAs. AB - A novel Spinach-based fluorescent light-up biosensor utilizing the T7 in vitro transcription process to generate unmodified Spinach sequences for multiplexed microRNA detection has been developed. PMID- 29511750 TI - The coordinative state of aluminium alkyls in Ziegler-Natta catalysts. AB - The most commonly used cocatalyst species in Ziegler-Natta catalysts are aluminium alkyls. In this study we aim to find the interaction between aluminium centres of these activators and other components in the ZNC system. Initially we look at binary systems of Al-alkyl/MgCl2 and ternary systems of Al alkyl/MgCl2/TiCl4, followed by donor containing systems. The aluminium alkyls prove to be very reactive species and only in the case of trimethylaluminium the alkyl is strongly present in the sample. This species appears to convert, however, over time. 1H NMR proves to be an efficient method to detect the presence of the Al-alkyl species. The use of high magnetic field strengths and 27Al MQMAS NMR alleviates signal overlap and gives insight in the dominant line broadening mechanisms thus providing an in-depth view of the cocatalyst. Various Al species with different coordinations can be identified in the samples. The heterogeneity of the samples turns out to have a larger effect on the 27Al NMR spectra than the quadrupolar interaction, which argues against the presence of highly distorted sites with mixed coordinations. Nevertheless for the samples indicating the presence of alkyls in the 1H NMR spectra, we observe an aluminium site at 97 ppm in the 27Al spectra that might be coordinated to an organic group. PMID- 29511751 TI - A self-powered porous ZnS/PVDF-HFP mechanoluminescent composite film that converts human movement into eye-readable light. AB - This study reports on a self-powered mechanoluminescent flexible film that converts human movement into green, yellow, and white light that are visible to the naked eye. The film is simply a highly porous composite material that was prepared using a piezoelectric polymer and ZnS luminescent powders. The highly effective mechanoluminescence capabilities stem from both the film's porous structure and the strong interactions between poly(vinylidene fluoride-co hexafluoropropylene) (PVDF-HFP) and ZnS particles. The porous film's sensitivity helps the conversion of mechanical disturbances into electrical energies and induces the electroluminescence of ZnS particles. The particle-film interactions induced a high beta-phase, which is the most effective piezoelectric phase, in the PVDF-HFP film. Similar to polymeric materials, the composite film is highly processable and can be written into arbitrary shapes or patterns using a pipette or stamping techniques. Finger rubbing or ultrasonication makes the mechanoluminescence patterns readable. This composite mechanoluminescent film provides high potential for future applications in electronic skins, smart electronics, and information encryption techniques. PMID- 29511752 TI - A metal-free and mild approach to 1,3,4-oxadiazol-2(3H)-ones via oxidative C-C bond cleavage using molecular oxygen. AB - A mild metal-free approach to 1,3,4-oxadiazol-2(3H)-ones via 1,3,4-oxadiazin 5(6H)-ones is described. This novel transformation, promoted by the electron withdrawing p-substituents on the phenyl group at the alpha-carbonyl position, features a tandem reaction consisting of oxidative hydroxylation and C-C bond cleavage using molecular oxygen. The method utilizes K2CO3 in CH3CN without any oxidants, transition metals, or additives, enabling the tunable synthesis of 1,3,4-oxadiazin-5(6H)-ones, 1,3,4-oxadiazol-2(3H)-ones, and alpha-ketoamides under mild aerobic conditions. PMID- 29511753 TI - Modulating the rigidity of nanoparticles for tumor penetration. AB - How the rigidity of nanoparticles affects their penetration into tumors is unclear. Core-shell nanoparticles were prepared with amphipathic poly(ethylene glycol)-b-(poly epsilon-caprolactone-g-poly butyl acrylate) (PEG-(PCL-g-PBA)) so that the mechanical stiffness of their cores could be varied in order to test the relationship between their rigidity and penetration through tumors. The rigidity of the nanoparticles was adjusted by the changeable crystallinity of the core, which was altered by varying the ratio of epsilon-caprolactone and butyl acrylate. PMID- 29511754 TI - A robust tissue laser platform for analysis of formalin-fixed paraffin-embedded biopsies. AB - Laser emission-based detection and imaging technology has attracted significant interest in biomedical research due to its high sensitivity, narrow linewidth, and superior spectral and spatial resolution. Recent advances have further revealed the potential to use laser emission to investigate chromatin dynamics, as well as to diagnose cancer tissues based on nuclear biomarkers. To move the laser emission based detection technology a step further towards practical use, in this work, we developed a highly robust tissue laser platform by microfabricating an SU8 spacer with a fixed height on the top mirror of the Fabry Perot (FP) cavity, which allows generation of reproducible and stable lasing results regardless of tissue thickness. Then we applied this platform to achieve lasing emission from formalin-fixed, paraffin-embedded (FFPE) lung tissues, which account for an overwhelming fraction of tissues collected for research and clinical use worldwide. We further showed that the cancer and normal FFPE lung tissues can be distinguished by their respective lasing thresholds. Two different tissue thicknesses (10 MUm and 5 MUm) commonly used in pathological labs were explored. Finally, we tested three additional types of tissues (colon, stomach, and breast) that were prepared independently by lab technicians in a pathology lab in China and shipped to the US in order to validate the general applicability and practicality of the laser emission-based technology as well as the corresponding sample preparation protocol and the tissue laser platform. Our work will not only vastly broaden the applications of laser emission-based detection/imaging technology but also help translate it from the laboratory to an automated system for clinical practice that may eventually benefit biomedicine and biological research. PMID- 29511755 TI - Ultrathin silver telluride nanowire films and gold nanosheet electrodes for a flexible resistive switching device. AB - We demonstrated a flexible resistive switching device based on ultrathin Ag2Te nanowire (NW) films and Au nanosheet (NS) electrodes by exploiting a monolayer assembly on the water surface for macroscale two-dimensional structures. Firstly, ultrathin TeNWs (diameter ~ 10 nm) are rapidly assembled on the water surface as a form of monolayer and transferred to fabricate TeNW films on various substrates with any available size. An assembled TeNW film was used as a template to produce a Ag2TeNW film through chemical transformation. A well-aligned Ag2TeNW film device showed reversible resistive switching properties when the Ag composition of the silver telluride NW becomes stoichiometric Ag2Te. Additionally, a non stoichiometric Ag2+deltaTeNW film shows an increased On/Off ratio. For a flexible memory device, ultrathin AuNSs (thickness <=20 nm) were adopted as working electrodes, since thermally deposited gold electrodes tend to crack under strain, which can fail to maintain the electrical properties. A paper-like flexibility of AuNS proved its capability as optimal electrodes of ultrathin Ag2TeNW film-based resistive memory devices. PMID- 29511756 TI - Label-free in-flow detection of receptor recognition motifs on the biomolecular corona of nanoparticles. AB - Nanomedicine, nanotargeting and nanotherapeutics have in the last few years faced several difficulties in translating the promising results obtained in vitro to an in vivo scenario. The origin of this discrepancy might be found in the lack of a detailed and realistic characterization of the biological surface of nanoparticles. Despite the capability to engineer nanomaterials with a great variety and a precise control of the surface functionalization, the targeting capability is lost when the nanoparticles are embedded in complex biological media, due to the formation of a biological layer (biomolecular corona). This biological layer represents the ultimate nanoparticle surface, likely to interact with the cell machinery. Therefore, in addition to traditional nanoparticle characterization techniques, a more insightful investigation of the biomolecular corona is needed, including the capability to assess the orientation and functionality of specific key molecular features. Here we present a method for the rapid screening of exposed protein recognition motifs on the surface of nanoparticles exploiting quartz crystal microbalance (QCM). We quantify accessible functional epitopes of transferrin-coated nanoparticles and correlate them to differences in nanoparticle size and functionalization. The target recognition occurs label free in flow, thereby pushing our investigation into a more in vivo-like scenario. Our method is applicable to a wide array of nanoparticles and therefore holds the potential to become an advanced technique for the classification of all kinds of nanobioconstructs based on their biological external functionality. PMID- 29511757 TI - Formation of a large gap quantum spin Hall phase in a 2D trigonal lattice with three p-orbitals. AB - The quantum spin Hall (QSH) phase in a trigonal lattice requires typically a minimal basis of three orbitals with one even parity s and two odd parity p orbitals. Here, based on first-principles calculations combined with tight binding model analyses and calculations, we demonstrate that depositing 1/3 monolayer Bi or Te atom layers on an existing experimental Ag/Si(111) surface can produce a QSH phase readily but with three p-orbitals (px, py and pz). The essential mechanism can be understood by the fact while in 3D, the pz orbital has an odd parity, its parity becomes even when it is projected onto a 2D surface so as to act in place of the s orbital in the original minimum basis. Furthermore, non-trivial large gaps, i.e., 275.0 meV for Bi and 162.5 meV for Te systems, arise from a spin-orbit coupling induced quadratic px-py band opening at the Gamma point. Our findings will significantly expand the search for a substrate supported QSH phase with a large gap, especially in the Si surface, to new orbital combinations and hence new elements. PMID- 29511758 TI - Engineering ellipsoidal cap-like hydrogel particles as building blocks or sacrificial templates for three-dimensional cell culture. AB - Hydrogel particles that can be engineered to compartmentally culture cells in a three-dimensional (3D) and high-throughput manner have attracted increasing interest in the biomedical area. However, the ability to generate hydrogel particles with specially designed structures and their potential biomedical applications need to be further explored. This work introduces a method for fabricating hydrogel particles in an ellipsoidal cap-like shape (i.e., ellipsoidal cap-like hydrogel particles) by employing an open-pore anodic aluminum oxide membrane. Hydrogel particles of different sizes are fabricated. The ability to produce ellipsoidal cap-like magnetic hydrogel particles with controlled distribution of magnetic nanoparticles is demonstrated. Encapsulated cells show high viability, indicating the potential for using these hydrogel particles as structure- and remote-controllable building blocks for tissue engineering application. Moreover, the hydrogel particles are also used as sacrificial templates for fabricating ellipsoidal cap-like concave wells, which are further applied for producing size controllable cell aggregates. The results are beneficial for the development of hydrogel particles and their applications in 3D cell culture. PMID- 29511759 TI - The evolution of size, shape, and surface morphology of gold nanorods. AB - We investigate the transformation of single crystal gold nanorod surface morphology over extended growth times. After initial rapid anisotropic growth and disappearance of {111} bridging facets, the aspect ratios converge across AgNO3 concentrations. The surface morphology transitions from faceted to curved. These observations imply the final aspect ratio has little dependence on the AgNO3 concentration, consistent with primary control of the AgNO3 over aspect ratio occurring at the symmetry breaking point. PMID- 29511760 TI - Novel indeno[2,1-b]carbazole donor-based organic dyes for dye-sensitized solar cells. AB - Four novel metal-free organic dyes (CFB1, CFB2, CFT1 and CFT2) based on indeno[2,1-b]carbazole donors were synthesized and their absorption spectra, photovoltaic performances, and electrochemical properties were evaluated. The differences in linking mode and the number of thiophene units led to variations in absorptivity, electron injection efficiency, and charge recombination. Among the four dyes, CFT1 with a pi-bridge at the indeno[2,1-b]carbazole ring and a bridge of thiophene showed the best photovoltaic performance with a JSC of 12.34 mA cm-2, VOC of 0.71 V, and FF of 0.68, corresponding to an overall conversion efficiency eta of 5.97% under standard AM 1.5 G irradiation. PMID- 29511766 TI - Selective extraction of semiconducting single-walled carbon nanotubes with a thermoresponsive polymer. AB - The extraction of single-walled carbon nanotubes by exploiting the phase transition of poly(N-isopropylacrylamide), a thermoresponsive polymer, was performed to obtain homogenous electronic properties. The semiconducting single walled carbon nanotubes were selectively extracted into the aqueous phase of a PNIPAM solution above the lower critical solution temperature. PMID- 29511767 TI - Water decontamination by polyoxometalate-functionalized 3D-printed hierarchical porous devices. AB - The design of organic-inorganic hybrid composites has revolutionized application driven materials design. Here, we show how hierarchically structured, 3D-printed ABS polymers can be surface-functionalized with lacunary polyoxometalate anions ([alpha-PW9O34]9-) featuring heavy-metal binding sites. The resulting composite is highly porous and can be used for the removal of transition-metal pollutants from water. Thus, a facile blueprint for decentralized production of water filtration devices is reported. PMID- 29511768 TI - Metal-catalyzed direct heteroarylation of C-H (meso) bonds in porphyrins: facile synthesis and photophysical properties of novel meso-heteroaromatic appended porphyrins. AB - A simple and rapid microwave-assisted synthesis of heteroaromatic appended porphyrins using the Pd/Cu-catalyzed C-C coupling of meso-bromoporphyrins with various five- and six-membered heteroaromatic azoles has been successfully developed. The prepared heteroaromatic porphyrins 7a-lNi were found to exhibit slightly red-shifted (~5-10 nm) Soret and Q bands. The developed reaction conditions are useful for the preparation of diversely substituted heteroaromatic porphyrins (A3B- and A2B2-types). PMID- 29511769 TI - [Rudolf Happle celebrates his 80th birthday]. PMID- 29511770 TI - [Inflammatory bowel disease : What does the clinician want to know from the radiologist?] AB - BACKGROUND: Inflammatory bowel disease is a complex and challenging disease. In diagnosis and the course of disease both radiology and endoscopy play a vital role. OBJECTIVES: The purpose of this review is to provide an overview of the questions asked by the clinician. Depending on the situation (clinical presentation of the patient, laboratory results) these questions can vary considerably and should be answered using the most appropriate imaging technique. Therefore, in the authors' view, a close cooperation between the clinician and the radiologist is imperative to provide optimal care for the patients. PMID- 29511771 TI - Risk of hysterectomy and salpingectomy or oophorectomy compared to repair after pelvic gynecologic trauma. AB - PURPOSE: Pelvic gynecologic trauma (PGT) includes injury to the uterus, ovaries or fallopian tubes. We hypothesized Injury Severity Score (ISS) >= 25, hypotension on admission and age >= 51 (average age for menopause) would be independent risk factors for resection compared to repair. METHODS: A retrospective analysis of the National Trauma Data Bank was performed between 2007 and 2015. RESULTS: Of 2,040,235 female patients, 1938 (< 0.1%) presented with PGT with the majority sustaining injury to the ovary or fallopian tubes (52.9%). Most patients were managed nonoperatively (77.1 vs 22.9%). On multivariable analysis, in patients with injury to the uterus, ISS >= 25 (OR 3.52, CI 1.67-7.48, p < 0.05) was associated with higher risk for hysterectomy compared to repair. In patients with injury to the ovaries or fallopian tubes, gunshot wound (OR 3.73, CI 1.43-9.68, p < 0.05) was associated with a higher risk for salpingectomy or oophorectomy compared to repair. Age >= 51 and hypotension on admission were not independent risk factors for resection in patients with PGT. Operative treatment was associated with a lower risk for mortality in patients with an injury to the uterus (OR 0.27, CI 0.14-0.51, p < 0.001) or ovaries/fallopian tubes (OR 0.37, CI 0.19-0.72, p < 0.001) compared to those managed nonoperatively. CONCLUSION: In the largest study reported, PGT occurred in < 0.1% of traumas involving women. Patients with ISS >= 25 have higher risk for hysterectomy compared to repair. Gunshot injuries have higher risk for salpingectomy or oophorectomy compared to repair. Hypotension on arrival or age >= 51 are not independent risk factors for resection in PGT. Operative management is associated with lower risk of mortality in PGT patients. PMID- 29511773 TI - [The quiet evolution]. PMID- 29511772 TI - [Neurodegenerative diseases]. AB - Neurodegenerative diseases are sporadic and rare hereditary disorders of the central nervous system, which cause a slowly progressive loss of function of specific neuron populations and their connections. Severe impairments and care dependency can be the sequelae. Neurodegenerative disorders are diseases of older people; therefore, the demographic shift leads to an increase in the number of affected patients. Radiologists will also become more involved. For this reason important neurodegenerative diseases are presented in this article. In addition to Alzheimer's and Parkinson's diseases these also include frontotemporal lobar degeneration, Lewy body dementia, vascular dementia, Creutzfeldt-Jakob disease and Huntington's chorea. The clinical symptoms and diagnostics are described, whereby the focus lies on typical results of morphological imaging. PMID- 29511775 TI - Stenotic Breast Malformation and Its Reconstructive Surgical Correction: A New Concept from Minor Deformity to Tuberous Breast-Author Response. PMID- 29511776 TI - Trait Mapping Approaches Through Association Analysis in Plants. AB - Previously, association mapping (AM) methodology was used to unravel genetic complications in animal science by measuring the complex traits for candidate and non-candidate genes. Nowadays, this statistical approach is widely used to clarify the complexity in plant breeding program-based genome-wide breeding strategies, marker development, and diversity analysis. This chapter is particularly focused on methodologies with limitations and provides an overview of AM models and software used up to now. Association or linkage disequilibrium mapping has become a very popular method for discovering candidate and non candidate genes and confirmation of quantitative trait loci (QTL) on various parts of the genome and in marker-assisted selection for breeding. Previously, various QTL investigations were carried out for different plants exclusively by linkage mapping. To help to understand the basics of modern molecular genetic techniques, in this chapter we summarize previous studies done on different crops. AM offers high-resolution power when there is large genotypic diversity and low linkage disequilibrium (LD) for the germplasm being investigated. The benefits of AM, compared with traditional QTL mapping, include a relatively detailed mapping resolution and a far less time-consuming approach since no mapping populations need to be generated. The advancements in genotyping and computational techniques have encouraged the use of AM. AM provides a fascinating approach for genetic investigation of QTLs, due to its resolution and the possibility to study the various genomic areas at the same time without construction of mapping populations. In this chapter we also discuss the advantages and disadvantages of AM, especially in the dicotyledonous crops Fabaceae and Solanaceae, with various genome-size reproductive strategies (clonal vs. sexual), and statistical models. The main objective of this chapter is to highlight the uses of association genetics in major and minor crop species that have trouble being analyzed for dissection of complex traits by identification of the factor responsible for controlling the effect of trait. Graphical Abstract. PMID- 29511777 TI - Intensity-modulated radiotherapy of prostate cancer with simultaneous integrated boost after molecular imaging with 18F-choline-PET/CT : Clinical results and quality of life. AB - PURPOSE: To analyze clinical results and quality of life of patients with localized prostate cancer after irradiation of the prostate with an 18F-choline PET/CT-based simultaneous integrated boost (SIB) in comparison to a control group without SIB. METHODS: A total of 134 patients underwent intensity-modulated radiotherapy from 2007-2010. All patients received a total dose of 76 Gy with 2 Gy fractions to the prostate; 67 patients received an additional SIB of 80 Gy. The median follow-up was 65 months. Quality of life was evaluated with the EPIC (Expanded Prostate Cancer Index Composite) questionnaire. RESULTS: Baseline characteristics were similar in both groups (prostate-specific antigen 11 ng/ml vs. 8 ng/ml, p = 0.20, Gleason score <6 in 36% vs. 46%, p = 0.22, with vs. without SIB). No prostate cancer-related death was observed. No significant difference of quality of life scores was found. The largest difference after 5-6 years in comparison to baseline was reported for sexual bother (mean 15 vs. 17 points with vs. without SIB). Mean urinary scores did not decrease. Bowel bother scores changes were larger in the SIB group (mean 5 vs. 2 points, dependent on SIB volume), with increased bowel problems (15 vs. 2% big/moderate problem with bowel movements, p = 0.03). However, a trend towards higher efficacy with SIB resulted (biochemical recurrence-free survival of 92% vs. 85%, p = 0.17). CONCLUSIONS: The first long-term analysis of patients treated with SIB based on molecular imaging with 18-F-choline-PET/CT showed an excellent biochemical recurrence-free survival, but a larger percentage of bowel problems in comparison to the control group. PMID- 29511778 TI - [Regulatory dysfunctions in nasal polyposis]. AB - Chronic rhinosinusitis is a heterogeneous group of inflammatory diseases with significant annual costs for the health care system. To date, there is no distinct signaling pathway known that explains the entire process from the beginning to tissue transformation. Due to the diversity of chronic rhinosinusitis, no uniform treatment has yet been developed. With a focus on chronic rhinosinusitis with nasal polyps (CRSwNP), molecular biologic gene expression studies have been performed to identify specific characteristics of nasal polyps that might allow the development of new therapeutic procedures. Microarray analysis revealed alterations in cell adhesion and differentiation as well as blood vessels. Further examinations identified two mechanisms that could play an important role in the pathogenesis of nasal polyps. In the context of the underlying disease, i.e., Th2-mediated chronic inflammation with predominantly eosinophilic cell infiltration, these findings might explain the pathogenesis of nasal polyps and allow development of new therapeutic strategies. PMID- 29511779 TI - Defining outcomes for beta cell replacement therapy: a work in progress. AB - Defined outcomes for beta cell replacement therapy in the treatment of diabetes are critically needed. Progress towards the clinical acceptance of pancreas and islet transplantation has been hampered by the lack of clear definitions of functional and efficacy outcomes, as well as a lack of consistently applied glycaemic control metrics, together with poor alignment with the field of artificial insulin delivery/artificial pancreas development. To address this problem, the International Pancreas & Islet Transplant Association (IPITA) collaborated with the European Pancreas and Islet Transplant Association (EPITA) to develop a consensus for a joint statement on the definition of function and failure of beta cell replacement therapies, which is summarised in this commentary. PMID- 29511781 TI - An acute dyspnea. PMID- 29511780 TI - Evaluation of pharmacokinetic and pharmacodynamic parameters following single dose of sitagliptin in healthy Indian males. AB - PURPOSE: Sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes, is reported to be more efficacious in Indian patients than non-Indian patient population. The objective of the study was to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of single-dose sitagliptin 100 mg (Januvia) in healthy Indian male participants. METHOD: In a randomised, single-dose, open-label, three-treatment, three-period, three sequence, crossover bioavailability study, 18 healthy male participants received single-dose of sitagliptin under fasted and fed conditions. PK parameters (Cmax, Tmax, AUC0-infinity and t1/2) were determined using Phoenix WinNonlin software. PD parameters [DPP-IV inhibition, active glucagon-like peptide-1 (GLP-1) and insulin] were determined using established methods. RESULTS: PK parameters expressed in mean (SD) were Cmax 491.7 (135.9) ng/mL; AUC0-infinity 4256.1 (509.9) ng. hr/mL, Tmax 2.9 (1.0) hr and t1/2 10.4 (3.0) hr. The weighted average (WA) plasma DPP-4 inhibition over 24 h was 89.6% and WA of plasma active GLP-1 over 2 h after standardised meal (geometric mean ratio) was 11.1 (9.9) pM/L which is two- to- four fold higher compared to that reported in other populations. The mean average (SD) AUC of plasma insulin over 2 h of standardised meal was 47.9 (24.9) MUIU/mL. CONCLUSION: Although, there are differences in pharmacokinetic parameters, no clinically meaningful differences were observed with respect to DPP-IV inhibition between Indian and non-Indian population. PMID- 29511782 TI - Epigenome-wide association study for 28-day survival of acute respiratory distress syndrome. PMID- 29511783 TI - Ultrasound-guided central venous catheter placement in children: what is a really good practice? PMID- 29511784 TI - Simultaneous improvement of grain yield and protein content in durum wheat by different phenotypic indices and genomic selection. AB - KEY MESSAGE: Simultaneous improvement of protein content and grain yield by index selection is possible but its efficiency largely depends on the weighting of the single traits. The genetic architecture of these indices is similar to that of the primary traits. Grain yield and protein content are of major importance in durum wheat breeding, but their negative correlation has hampered their simultaneous improvement. To account for this in wheat breeding, the grain protein deviation (GPD) and the protein yield were proposed as targets for selection. The aim of this work was to investigate the potential of different indices to simultaneously improve grain yield and protein content in durum wheat and to evaluate their genetic architecture towards genomics-assisted breeding. To this end, we investigated two different durum wheat panels comprising 159 and 189 genotypes, which were tested in multiple field locations across Europe and genotyped by a genotyping-by-sequencing approach. The phenotypic analyses revealed significant genetic variances for all traits and heritabilities of the phenotypic indices that were in a similar range as those of grain yield and protein content. The GPD showed a high and positive correlation with protein content, whereas protein yield was highly and positively correlated with grain yield. Thus, selecting for a high GPD would mainly increase the protein content whereas a selection based on protein yield would mainly improve grain yield, but a combination of both indices allows to balance this selection. The genome-wide association mapping revealed a complex genetic architecture for all traits with most QTL having small effects and being detected only in one germplasm set, thus limiting the potential of marker-assisted selection for trait improvement. By contrast, genome-wide prediction appeared promising but its performance strongly depends on the relatedness between training and prediction sets. PMID- 29511786 TI - [Anatomical total shoulder replacement in glenohumeral osteoarthritis : Indications, current implants, and clinical results]. AB - IMPLANT DESIGNS: Within the last 50 years, implants for shoulder replacement have developed rapidly. Monobloc-stems in few sizes were changed to modular implant systems that allow for an individual adaption of the stem, as well as adaption of the humeral head component according to the specific anatomic situation of the patient. Moreover, stemless und short stem implants are available, which may highly simplify primary implantation, especially in posttraumatic cases as well as in revision cases with a need for removal or change of the implants. Concerning the glenoid component, cemented PE-inlays were further modified to increase long-term survival rates. Moreover, cement-free modular "metal-backs" allow for a conversion to a reverse total shoulder arthroplasty without removal of the "metal back" component. RESULTS: Long-term survival rates of total shoulder arthroplasties achieve comparable survival rates to knee and hip arthroplasties with good to excellent clinical long-term results. In addition to an experienced surgeon, the key to a successful surgical result is the correct and timely indication, as massive contractures of the soft tissues as well as excessive abrasion of the glenoid bone may significantly impair the functional results. PMID- 29511785 TI - The ipsilateral corticospinal responses to cross-education are dependent upon the motor-training intervention. AB - This study aimed to identify the ipsilateral corticospinal responses of the contralateral limb following different types of unilateral motor-training. Three groups performing unilateral slow-paced strength training (SPST), non-paced strength training (NPST) or visuomotor skill training (VT) were compared to a control group. It was hypothesised that 4 weeks of unilateral SPST and VT, but not NPST, would increase ipsilateral corticospinal excitability (CSE) and reduce short-interval cortical inhibition (SICI), resulting in greater performance gains of the untrained limb. Tracking error of the untrained limb reduced by 29 and 41% following 2 and 4 weeks of VT. Strength of the untrained limb increased by 8 and 16% following 2 and 4 weeks of SPST and by 6 and 13% following NPST. There was no difference in cross-education of strength or tracking error. For the trained limb, SPST and NPST increased strength (28 and 26%), and VT improved by 47 and 58%. SPST and VT increased ipsilateral CSE by 89 and 71% at 2 weeks. Ipsilateral CSE increased 105 and 81% at 4 weeks following SPST and VT. The NPST group and control group showed no changes at 2 and 4 weeks. SPST and VT reduced ipsilateral SICI by 45 and 47% at 2 weeks; at 4 weeks, SPST and VT reduced SICI by 48 and 38%. The ipsilateral corticospinal responses are determined by the type of motor training. There were no differences in motor performance between SPST, NPST and VT. The data suggests that the corticospinal responses to cross-education are different and determined by the type of motor-training. PMID- 29511787 TI - HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical Surgical Centers in Italy. AB - Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches. PMID- 29511788 TI - Effects of Oxalic Acid on Arsenic Uptake and the Physiological Responses of Hydrilla verticillata Exposed to Different Forms of Arsenic. AB - A hydroponic experiment was conducted to investigate the effects of oxalic acid (OA) on arsenic (As) uptake and the physiological responses of Hydrilla verticillata exposed to 3 mg L-1 of As in different forms. Plant As(III) uptake was significantly increased by 200-2000 ug L-1 OA. However, an increase of As(V) uptake was only shown with 1000 ug L-1 OA, and no significant difference was observed with dimethylarsinate treatment. Peroxidase and catalase activities, and the contents of photosynthetic pigments, soluble sugar and proline, were significantly increased by 1000 ug L-1 OA during As(III) treatment. Superoxide dismutase and proline were also increased significantly by 1000 ug L-1 OA when plants were exposed to As(V). In DMA treatment, proline was significantly increased by 500 ug L-1 OA. Therefore, As-induced oxidative stress is relieved by OA, but it depends on OA concentration and the form of As. Our results may be useful for the phytoremediation of waste water containing As and OA. PMID- 29511790 TI - Annual Scientific Meeting Abstracts of the European Society of Musculoskeletal Radiology (ESSR) 2018, Amsterdam, The Netherlands. PMID- 29511789 TI - Correction to: Triple elastofibromas located in the supra- and infrascapular regions-a case report. AB - The original version of this article unfortunately contained mistakes. The authornames of Matias de Albert, Manuel Perez, and Rosa Dominguez Oronoz as well as the affiliation of Dr. Perez are now corrected in this article. PMID- 29511791 TI - Early vulnerabilities for psychiatric disorders in elementary schoolchildren from four Brazilian regions. AB - PURPOSE: The purpose of the study is to identify early vulnerabilities for psychiatric disorders among Brazilian elementary school children, controlling for familial and community adversities. METHODS: This is a cross-sectional study examining the association between child psychiatric disorders and potential early vulnerabilities (disability, low intellectual quotient, and negative dimensions of the temperament trait self-directedness (low resourcefulness, low purposefulness, low enlightened second nature), controlling for the potential confounders: familial and community adversities. SAMPLE: Four probabilistic samples of second-to-sixth grade students from public schools in four towns from different Brazilian regions (N = 1620). The following instruments were applied: the K-SADS-PL (to assess child/adolescent psychiatric disorders); the Ten Question Screen (to measure child disability); three structured questions used as proxy of self-directedness; and the reduced version of the WISC-III to measure IQ. To evaluate familial/community adversities: Self-Report Questionnaire-SRQ-20 (to assess maternal/primary caretaker anxiety/depression); questions derived from structured questionnaires (to measure child abuse, marital physical violence, neighborhood violence); Brazilian Association of Research Companies questionnaire (to evaluate poverty/socioeconomic status). Trained psychologists interviewed mothers/primary caretakers and evaluated children/adolescents individually. RESULTS: A final logistic regression model showed that children/adolescents with low resourcefulness, low purposefulness, low enlightened second nature, lower IQ and disability were more likely to present any child psychiatric disorders. CONCLUSION: Early vulnerabilities such as low IQ, presence of disability, and dimensions of temperament were associated with psychiatric disorders among Brazilian elementary school children, after controlling for familial and ecological confounders. These early vulnerabilities should be considered in mental health prevention/intervention programs in low-middle-income countries like Brazil. PMID- 29511793 TI - Calcifying nanoparticles induce cytotoxicity mediated by ROS-JNK signaling pathways. AB - Calcifying nanoparticles (CNPs) play an important role in kidney stone formation, but the mechanism(s) are unclear. CNPs were isolated and cultured from midstream urine of patients with kidney stones. CNP morphology and characteristics were examined by electron microscopy and electrophoresis analysis. Chemical composition was analyzed using energy-dispersive X-ray microanalysis and Western blotting. Human renal proximal convoluted tubule cell (HK-2) cultures were exposed to CNPs for 0, 12 and 72 h, and production of reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis levels were evaluated. CNPs isolated from patients showed classical morphology, the size range of CNPs were 15-500 nm and negative charge; they were found to contain fetuin-A. Exposure of HK-2 cells to CNPs induced ROS production, decreased mitochondrial membrane potential and decreased cell viability. Transmission electron microscopy showed that CNPs can enter the cell by phagocytosis, and micrographs revealed signs of apoptosis and autophagy. CNPs increased the proportion of apoptotic cells, down regulated Bcl-2 expression and up-regulated Bax expression. CNPs also up regulated expression of LC3-B, Beclin-1and p-JNK.CNPs are phagocytosed by HK-2 cells, leading to autophagy, apoptosis and ROS production, in part through activation of JNK signaling pathways. ROS and JNK pathways may contribute to CNP induced cell injury and kidney stone formation. PMID- 29511792 TI - The positive association of total protein intake with femoral neck strength (KNHANES IV). AB - : Data gathered from a nationally representative cohort demonstrate that higher dietary protein intake was positively associated with the composite indices of femoral neck strength in both men and women, suggesting that higher protein intake may contribute to lower risk of hip fracture through the improvement of bone strength. INTRODUCTION: Despite the general belief that higher protein intake may be helpful for bone homeostasis, its impact on human bone health is still debated. Furthermore, the association of dietary protein intake with femoral neck (FN) strength, which can predict fracture risk independently of bone mineral density (BMD), has not been thoroughly studied. METHODS: This is a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys, including 592 men aged 50 years or older and 590 postmenopausal women. The composite indices of FN strength, such as the compression strength index (CSI), bending strength index (BSI), and impact strength index (ISI), were generated by combining BMD, body weight, and height with the femoral axis length and width, which were measured by dual-energy X-ray absorptiometry. RESULTS: After adjustment for confounders, total protein intake (g/kg/day) positively correlated with all three FN composite indices in both genders (P = 0.006 to 0.035), except for BSI showing marginal significance in postmenopausal women (P = 0.093). Consistently, compared with subjects in lowest total protein intake quartile, those in the highest quartile showed markedly higher CSI, BSI, and ISI values (P = 0.043 to < 0.001), with a dose-response manner across increasing total protein intake quartile categories in both men and women (P for trend = 0.028 to < 0.001). CONCLUSIONS: These findings provide the clinical evidence that higher dietary protein intake can play a beneficial role on bone health through the increase of FN strength relative to load in adults. PMID- 29511794 TI - Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers. AB - PURPOSE: It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy. EXPERIMENTAL DESIGN: Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients' primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration. RESULTS: There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005). CONCLUSIONS: Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy. PMID- 29511795 TI - Mitteilungen DGKFO. PMID- 29511796 TI - Pharmacokinetics of intravenous mycophenolate mofetil in allogeneic hematopoietic stem cell-transplanted Japanese patients. AB - PURPOSE: Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation. METHODS: Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow transplanted patients, and every 12 h in cord blood-transplanted patients. MMF was administered orally at the same dose from day 11. Plasma concentrations of mycophenolic acid (MPA) were measured by high-performance liquid chromatography. RESULTS: The MPA AUC0 - tau was 31.9 +/- 3.4, 26.2 +/- 2.4, and 21.0 +/- 2.2 ug*h/mL, the mean Ctrough was 0.25, 0.35, and 0.37 ug/mL, and the Cmax was 10.8, 9.2, and 5.5 ug/mL on days 2, 9, and 16, respectively. The AUC0 - tau and Cmax were significantly higher after intravenous MMF dosing than after oral MMF dosing. All patients exhibited successful neutrophil engraftments in a median time of 18 days. Grade II acute graft-versus-host disease (GvHD) of the skin was observed in two patients, and one patient developed limited chronic GvHD. Individual cases of transient and curable grade III oral mucositis and diarrhea were observed; however, MMF was not discontinued. No other severe complications or infections were observed. CONCLUSIONS: Intravenously administered MMF was safe and possibly effective in achieving higher MPA plasma concentrations for GvHD prophylaxis after allo-SCT in Japanese patients. PMID- 29511797 TI - Benign multicystic mesothelioma and peritoneal inclusion cysts: are they the same clinical and histopathological entities? A systematic review to find an evidence based management. AB - PURPOSE: Peritoneal mesothelial cysts (PMC) are a clinical dilemma because of their true pathogenic nature. Many definitions have been associated with PMC, including "benign multicystic mesothelioma", "cystic mesothelioma", "multilocular peritoneal inclusion cysts", ''inflammatory cysts of the peritoneum" or "postoperative peritoneal cyst". METHODS: We herein performed a systematic review of the literature focusing on clinical and histopathological aspects of PMC, diagnosis, and therapies. Moreover, we described our experience with a case of PMC in a young female. RESULTS: Since there is often a history of prior surgery or inflammatory disease, most authors consider PMC of reactive origin. However, in some cases they occur without any documentable signs of disease or injury. A variety of clinical findings can complicate the preoperative assessment and a multitude of histological pictures may potentially lead to a misdiagnosis. The absence of a uniform treatment strategy and lack of long-term follow-up often hinder the accurate definition leading to unnecessary or unnecessarily aggressive therapy. CONCLUSIONS: PMC are more common than had previously been thought. Most authors consider them non-neoplastic; thus the designation of "peritoneal inclusion cyst" is preferable. The term "mesothelioma" should be used only in cases of histological evidences of atypia. The high rates of recurrence suggest that the goal of treatment should not be necessarily complete eradication, but symptomatic relief through individualized treatment. This is a topic of particular importance, especially in young female where recurrence rates could be lower than those reported in adults and where an improperly aggressive treatment could have repercussions on fertility. PMID- 29511800 TI - Hypothenar hammer syndrome: caused by a muscle anomaly? A case report with review of the literature. AB - The hypothenar hammer syndrome (HHS) is a rare entity of secondary Raynaud's phenomenon. The blunt hypothenar trauma causes a lesion of the vessel wall with a consecutive thrombosis or aneurysm of the ulnar artery at the Guyon's canal. Different risk factors are discussed such as nicotine abuse, or a muscle anomaly in the Guyon's canal. To date, there are five case reports published about muscle anomalies and HHS. We present a case of a 51-year-old shipbuilder with a unilateral HHS on his right dominant hand with a bilateral muscle anomaly. We successfully treated the patient by resection of the aneurysm without a resection of the atypical muscle. PMID- 29511799 TI - Overexpression of VpPR10.1 by an efficient transformation method enhances downy mildew resistance in V. vinifera. AB - KEY MESSAGE: Putrescine and spermidine increase the transformation efficiency of Vitis vinifera L. cv. Thompson seedless. Accumulation of VpPR10.1 in transgenic V. vinifera Thompson seedless, likely increases its resistance to downy mildew. A more efficient method is described for facilitating Agrobacterium-mediated transformation of Vitis vinifera L. cv. Thompson Seedless somatic embryogenesis using polyamines (PAs). The efficacies of putrescine, spermidine and spermine are identified at a range of concentrations (10 uM, 100 uM and 1 mM) added to the culture medium during somatic embryo growth. Putrescine (PUT) and spermidine (SPD) promote the recovery of proembryonic masses (PEM) and the development of somatic embryos (SE) after co-cultivation. Judging from the importance of the time-frame in genetic transformation, PAs added at the co-cultivation stage have a stronger effect than delayed selection treatments, which are superior to antibiotic treatments in the selection stage. Best embryogenic responses are with 1 mM PUT and 100 uM SPD added to the co-culture medium. Using the above method, a pathogenesis-related gene (VpPR10.1) from Chinese wild Vitis pseudoreticulata was transferred into Thompson Seedless for functional evaluation. The transgenic line, confirmed by western blot analysis, was inoculated with Plasmopara viticola to test for downy mildew resistance. Based on observed restrictions of hyphal growth and increases in H2O2 accumulation in the transgenic plants, the accumulation of VpPR10.1 likely enhanced the transgenic plants resistance to downy mildew. PMID- 29511798 TI - Advanced genetic tools enable synthetic biology in the oleaginous microalgae Nannochloropsis sp. AB - Nannochloropsis is a genus of fast-growing microalgae that are regularly used for biotechnology applications. Nannochloropsis species have a high triacylglycerol content and their polar lipids are rich in the omega-3 long-chain polyunsaturated fatty acid, eicosapentaenoic acid. Placed in the heterokont lineage, the Nannochloropsis genus has a complex evolutionary history. Genome sequences are available for several species, and a number of transcriptomic datasets have been produced, making this genus a facile model for comparative genomics. There is a growing interest in Nannochloropsis species as models for the study of microalga lipid metabolism and as a chassis for synthetic biology. Recently, techniques for gene stacking, and targeted gene disruption and repression in the Nannochloropsis genus have been developed. These tools enable gene-specific, mechanistic studies and have already allowed the engineering of improved Nannochloropsis strains with superior growth, or greater bioproduction. PMID- 29511801 TI - Efficiency and predictive parameters of outcome of a multimodal pain management concept with spinal injections in patients with low back pain: a retrospective study of 445 patients. AB - Low back pain is one of the most common diseases of modern civilization. Multimodal pain management (MPM) represents a central approach to avoiding surgery. Short-term results are published rarely and often incomparable because of different treatment concepts. This study compared the subjective and objective parameters as well as the anamnestic and clinical parameters of 445 patients with low back pain before and after inpatient MPM to investigate the influence of this type of therapy on short-term outcome. The majority of patients were very satisfied (39%) or satisfied (58%) with the treatment outcome. The median pain reduction for back pain was 3.0 (IQR 2.88) (numeric rating scale, NRS), thus 66% and 2.75 (IQR 3.38, 62%) for leg pain. The main pain reduction occurred within the first 10 days of treatment and was clinically significant from day 5 onwards. The outcome for patients with hospitalization of more than 10 days was significantly worse. The parameters female sex, BMI of > 30, local pain, and pain duration of 3-24 months had a significantly better outcome. In contrast, age, treatment cause, depression, anxiety, and other diseases had no statistically significant influence on outcome. MPM therapy for more than 5 days seems to be an efficient short-term approach to treating low back pain. Knowledge of some of the outcome predictors helps to early identify patients who require more intensive individual care. In the case of no clear indication for surgery, MPM can be an appropriate treatment option. PMID- 29511802 TI - Effects of testosterone supplement treatment in hypogonadal adult males with T2DM: a meta-analysis and systematic review. AB - PURPOSE: Testosterone supplement treatment (TST) is a classic therapy for hypogonadal men with type 2 diabetes mellitus (T2DM), but the effects of TST in different studies are inconsistent. We conducted this meta-analysis to evaluate the precise role of TST in hypogonadal men with T2DM. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched to identify qualified randomized controlled trials (RCTs). Pooled mean differences (MDs) with 95% confidence intervals (CIs) were calculated to measure the specific effects of TST. Trial sequential analysis was performed to verify the pooled results. RESULTS: A total of eight RCTs were enrolled in our meta-analysis, including 596 hypogonadal participants with T2DM. Compared with comparators, TST can significantly improve glycemic control by reducing homeostatic model assessment of insulin resistance (MD - 0.79, 95% CI - 1.23 to - 0.34), fasting glucose (MD - 0.98, 95% CI - 1.13 to - 0.54), fasting insulin (MD - 2.47, 95% CI - 3.99 to - 0.95) and HbA1c% (MD - 0.45, 95% CI - 0.73 to - 0.16). In addition, TST can result in a decline in cholesterol (MD - 0.29, 95% CI - 0.38 to - 0.19) and triglyceride (MD - 0.37, 95% CI - 0.59 to - 0.15). CONCLUSION: Our results indicated that TST can improve glycemic control and decrease TC and TG in hypogonadal patients with T2DM. We recommend TST during the anti-diabetic therapy in these patients. PMID- 29511803 TI - TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling. AB - Sinoatrial node fibrosis is involved in the pathogenesis of sinus sick syndrome (SSS). Transient receptor potential (TRP) subfamily M member 7 (TRPM7) is implicated in cardiac fibrosis. However, the mechanisms underlying the regulation of sinoatrial node (SAN) fibrosis in SSS by TRPM7 remain unknown. The aim of this study was to investigate the role of angiotensin II (Ang II)/TRPM7/Smad pathway in the SAN fibrosis in rats with SSS. The rat SSS model was established with sodium hydroxide pinpoint pressing permeation. Forty-eight rats were randomly divided into six groups: normal control (ctrl), sham operation (sham), postoperative 1-, 2-, 3-, and 4-week SSS, respectively. The tissue explant culture method was used to culture cardiac fibroblasts (CFs) from rat SAN tissues. TRPM7 siRNA or encoding plasmids were used to knock down or overexpress TRPM7. Collagen (Col) distribution in SAN and atria was assessed using PASM Masson staining. Ang II, Col I, and Col III levels in serum and tissues or in CFs were determined by ELISA. TRPM7, smad2 and p-smad2 levels were evaluated by real time PCR, and/or western blot and immunohistochemistry. SAN and atria in rats of the SSS groups had more fibers and higher levels of Ang II, Col I and III than the sham rats. Similar findings were obtained for TRPM7 and pSmad2 expression. In vitro, Ang II promoted CFs collagen synthesis in a dose-dependent manner, and potentiated TRPM7 and p-Smad2 expression. TRPM7 depletion inhibited Ang II induced p-Smad2 expression and collagen synthesis in CFs, whereas increased TRPM7 expression did the opposite. SAN fibrosis is regulated by the Ang II/TRPM7/Smad pathway in SSS, indicating that TRPM7 is a potential target for SAN fibrosis therapy in SSS. PMID- 29511805 TI - Correction to: Depressive residual symptoms are associated with illness course characteristics in a sample of outpatients with bipolar disorder. AB - Depressive residual symptoms are. PMID- 29511804 TI - Correlation between electrical conductivity and apparent diffusion coefficient in breast cancer: effect of necrosis on magnetic resonance imaging. AB - OBJECTIVES: To investigate the correlation between conductivity and ADC in invasive ductal carcinoma according to the presence of necrosis on MRI. METHODS: Eighty-one women with invasive ductal carcinoma >=1 cm on T2-weighted fast spin echo sequence of preoperative MRI were included. Phase-based MR electric properties tomography was used to reconstruct conductivity. Mean ADC was measured. Necrosis was defined as an area with very high T2 signal intensity. The relationship between conductivity and ADC was examined using Spearman's correlation coefficient (r). Multiple linear regression analysis was performed to identify factors associated with conductivity or ADC. RESULTS: In the total group, conductivity showed negative correlation with ADC (r = -0.357, p = 0.001). This correlation was maintained in the subgroup without necrosis (n = 53, r = 0.455, p = 0.001), but not in the subgroup with necrosis (n = 28, r = -0.080, p = 0.687). The correlation between the two parameters was different according to necrosis (r = -0.455 vs -0.080, p = 0.047). HER2 enriched subtype was independently associated with conductivity (p = 0.029). Necrosis on MRI was independently associated with ADC (p = 0.027). CONCLUSIONS: Conductivity shows negative correlation with ADC that is abolished by the presence of necrosis on MRI. KEY POINTS: * Electric conductivity showed negative correlation with ADC * However, the correlation was abolished by the presence of necrosis on MRI * HER2 enriched subtype was independently associated with conductivity * Necrosis on MRI was independently associated with ADC. PMID- 29511806 TI - Alcohol, psychomotor-stimulants and behaviour: methodological considerations in preclinical models of early-life stress. AB - BACKGROUND: In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant. OBJECTIVES: The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour. METHODS: The protocols employed for exploring early-life stress were investigated and summarised. Experimental variables include animals, stress models, and endpoints employed. RESULTS: The findings in this paper suggest that there is little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. CONCLUSION: The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic. PMID- 29511808 TI - Oral dosing of rodents using a palatable tablet. AB - RATIONALE: Delivering orally bioavailable drugs to rodents is an important component to investigating that route of administration in novel treatments for humans. However, the traditional method of oral gavage requires training, is stressful, and can induce oesophageal damage in rodents. OBJECTIVES: To demonstrate a novel administrative technique-palatable gelatine tablets-as a stress-free route of oral delivery. METHODS: Twenty-four male Lister hooded rats were sacrificed for brain tissue analysis at varying time-points after jelly administration of 30 mg/kg of the wake-promoting drug modafinil. A second group of 22 female rats were tested on locomotor activity after 30 mg/kg modafinil, or after vehicle jellies, with the locomotor data compared to the brain tissue concentrations at the corresponding times. RESULTS: Modafinil was present in the brain tissue at all time-points, reducing in concentration over time. The pattern of brain tissue modafinil concentration is comparable to previously reported results following oral gavage. Modafinil-treated rats were more active than control rats, with greater activity during the later time-periods-similar to that previously reported following intraperitoneal injection of 40 mg/kg modafinil. CONCLUSIONS: Palatable jelly tablets are an effective route of administration of thermally stable orally bioavailable compounds, eliminating the stress/discomfort and health risk of oral gavage and presenting as an alternative to previously reported palatable routes of administration where high protein and fat levels may adversely affect appetite for food reward, and uptake rate in the gastrointestinal tract. PMID- 29511807 TI - Acute effects of lisdexamfetamine and D-amphetamine on social cognition and cognitive performance in a placebo-controlled study in healthy subjects. AB - RATIONALE: Amphetamines are used as medications but are also misused as cognitive enhancers by healthy subjects and may have additional effects on social cognition. METHODS: We investigated the acute effects of single, high, equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg) on social cognition and cognitive performance using a randomized, placebo-controlled, double-blind, cross-over design in 24 healthy volunteers. Effects on social cognition were assessed using the Facial Emotion Recognition Task (FERT), Multifaceted Empathy Test (MET), and Sexual Arousal Task (SAT). Cognitive performance was measured using the Digit Symbol Substitution Test (DSST), Digit Span (DS), Stop-Signal Task (SST), and Mackworth Clock Test (MCT). RESULTS: D-Amphetamine and lisdexamfetamine had small effects on measures of social cognition. There were no effects on emotion recognition on the FERT. D-Amphetamine increased direct empathy on the MET, but only for positive stimuli. Both amphetamines increased ratings of pleasantness and attractiveness on the SAT in response to sexual but also to neutral stimuli. D-Amphetamine and lisdexamfetamine increased cognitive performance (go-accuracy and vigilance on the SST and MCT, respectively). Lisdexamfetamine increased processing speed on the DSST. Neither drug had an effect on the DS. CONCLUSION: Single, high, equimolar doses of D-amphetamine and lisdexamfetamine enhanced certain aspects of cognitive performance in healthy non sleep-deprived subjects. Both amphetamines also slightly altered aspects of social cognition. Whether these small effects also influence social interaction behavior in amphetamine users remains to be investigated. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT02668926). PMID- 29511809 TI - Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy. AB - PURPOSE: Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality. METHODS: From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7 years (range 0.9-18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6 mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort. RESULTS: All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9 years (range 0-7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001). CONCLUSION: There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE. PMID- 29511811 TI - [Structural endpoints for glaucoma studies]. AB - BACKGROUND: Structural endpoints have been discussed as surrogate endpoints for the approval of neuroprotective drugs in glaucoma. OBJECTIVE: Is the evidence strong enough to establish structural endpoints as surrogate endpoints? MATERIAL AND METHODS: Review of current understanding between structure and function in glaucoma. RESULTS: The introduction of optical coherence tomography has revolutionized imaging in glaucoma patients. Clinically either the nerve fiber layer thickness can be measured along a circle centered in the optic nerve head or the ganglion cell layer thickness can be assessed in the macular region, the latter being quantified in combination with other inner retinal layers. On a microscopic level there is a strong correlation between structural and functional loss but this relation can only partially be described with currently available clinical methods. This is particularly true for longitudinal course of the disease in glaucoma patients. Novel imaging techniques that are not yet used clinically may have the potential to increase our understanding between structure and function in glaucoma but further research in this field is required. CONCLUSION: The current evidence does not allow the establishment of structural endpoints as surrogate endpoints for phase 3 studies in glaucoma. Neuroprotective drugs have to be approved on the basis of visual field data because this is the patient-relevant endpoint. Structural endpoints can, however, play an important role in phase 2 and proof of concept studies. PMID- 29511810 TI - Techniques of cadaver perfusion for surgical training: a systematic review. AB - PURPOSE: The objective of this study was to identify the most appropriate cadaver perfusion techniques for surgical training through a systematic review with a description of the protocols used. METHODS: The search strategy included PubMed and reference tracking. Studies were identified by searching the electronic Medline databases. The search concepts included perfusion, cadavers and simulation training, and the protocol used is reported. This resulted in a qualitative review of 12 articles out of 250 articles consulted. We collected all the important data from these 12 articles. RESULTS: Regarding the characteristics of the studies and the declotting or perfusion techniques, the results were heterogeneous. Indeed, in several studies, a good deal of information was unclear or insufficiently precise, making it unfeasible to summarize the data. The methods used were not sufficiently explicit and detailed. However, a majority of the fresh cadavers used tap water for declotting. Perfusion, type of fluid, number of pumps, pressure, pulsatility, and arterial or venous approaches differed greatly. Only two studies fulfilled five of our six realism criteria for surgical simulation. CONCLUSIONS: This systematic review provided an overview of all the different cadaver perfusion techniques. It could be used to establish a reference method of a simulation model. PMID- 29511813 TI - Correction to: Arrhythmia-free survival and pulmonary vein reconnection patterns after second-generation cryoballoon and contact-force radiofrequency pulmonary vein isolation. AB - The name of the author Jaap Jan J. Smit was rendered wrongly in the original publication. The original article has been corrected. PMID- 29511812 TI - Light microscopic study of four plagiorchiid trematodes infecting marine fish in the south-eastern Mediterranean Sea, Alexandria City, with descriptions of two new species. AB - During the present investigation, a total of 220 fish specimens belonging to three different species, namely, little tunny Euthynnus alletteratus, African snook Lates niloticus, and striped red mullet Mullus surmuletus, were collected from January-November 2016 from the coasts off Abu Qir landing site, Alexandria City, south-eastern Mediterranean Sea, Egypt. The collected fish samples were dissected and examined for the presence of helminth parasites. Twenty-three out of 220 (10.45%) fish specimens were found to be naturally infected with four species of trematode parasites belonging to three different families of the order Plagiorchiida. The recovered parasite species were collected and identified by applying light microscopic examinations. The present study recorded two new parasite species, namely, Stephanostomum alletterani sp. nov. and Bathycreadium mulli sp. nov., belonging to the families Acanthocolpidae and Opecoelidae and infecting E. alletteratus and M. surmuletus, respectively and re-descriptions of the two remaining species, namely, Acanthostomum spiniceps and Aponurus mulli of the families Acanthostomatidae and Opecoelidae, respectively, to clarify the measurements of some body parts. Morphological and morphometric characterizations revealed some differences between the present species and other related species detected previously. Future studies are recommended to include advanced molecular characteristics for these species. PMID- 29511815 TI - Analysis and Tendencies of Metals and POPs in a Sediment Core from the Alvarado Lagoon System (ALS), Veracruz, Mexico. AB - This study focused on dating of a sediment core from the Alvarado Lagoon System, Veracruz, Mexico, calculating the sedimentation rate by using 210Pb to determine the tendency towards pollution by polycyclic aromatic hydrocarbons, organochlorides, the metals Cd, Cr, Cu, Hg, Ni, Pb, and V, and organic matter content. The activity of total Pb and supported Pb in the samples was 83.1 and 29.5 Bq kg-1, respectively, whereas the average estimated sedimentation rate was 0.48 +/- 0.09 cm per year-1. The organic matter values exhibited linear behavior throughout the historical profile, with values under 2.5%. Metal concentrations followed the order V > Cr > Ni > Cu > Pb > Hg > Cd. Variations found in Cr, Ni, Pb, and V concentrations are basically due to three meteorological phenomena that hit the region: hurricanes Gladys, Hilda, and Janet in September of 1955. V, Ni, and Hg input comes from anthropogenic and lithogenic sources. The presence of individual polycyclic aromatic hydrocarbons showed no ascending accumulation pattern over time, nor did it show any significant statistical correlation to OM. As for the organochlorine pesticides, 63.61% of the total sum of these compounds were from the ciclodienics family. Concentration of p,p'-DDT was observed only in the earliest profile, from 1929. PMID- 29511816 TI - Greater body mass index and hip abduction muscle strength predict noncontact anterior cruciate ligament injury in female Japanese high school basketball players. AB - PURPOSE: This 3-year prospective study assessed risk factors for noncontact anterior cruciate ligament (ACL) injuries in female Japanese high school basketball players. Players suffering noncontact ACL injuries were assumed to demonstrate poorer hip abductor, knee flexor, and knee extensor muscle strength, as well as static balance, than those without injuries. METHODS: One hundred and ninety-five new female high school basketball players underwent baseline examinations for various parameters during their first year of high school. After the baseline data were collected, all ACL injuries occurring over the subsequent 3 years were recorded. The assessment parameters between the noncontact ACL injury group and the control group were compared. RESULTS: Of the 195 players, 24 were excluded due to pre-existing injuries present during the initial examination, quitting the basketball club during the follow-up period, or missing data. The remaining 171 players were observed for 3 years; unilateral noncontact ACL injuries were occurred in 12 players. Significantly lower general joint laxity and greater hip abductor strength were observed in the ACL injury group than in the control group. Body mass index (BMI) and hip abductor strength were significantly greater in the ACL injury group than in the control group, based on logistic regression analysis. CONCLUSIONS: Greater BMI and hip abductor muscle strength were independent risk factors for noncontact ACL injuries in female Japanese high school basketball players. Although performing complete screens may be difficult, attention should be given to ACL injuries, particularly in highly competitive players with strong muscles. LEVEL OF EVIDENCE: III. PMID- 29511814 TI - An oilseed rape WRKY-type transcription factor regulates ROS accumulation and leaf senescence in Nicotiana benthamiana and Arabidopsis through modulating transcription of RbohD and RbohF. AB - MAIN CONCLUSION: Overexpression of BnaWGR1 causes ROS accumulation and promotes leaf senescence. BnaWGR1 binds to promoters of RbohD and RbohF and regulates their expression. Manipulation of leaf senescence process affects agricultural traits of crop plants, including biomass, seed yield and stress resistance. Since delayed leaf senescence usually enhances tolerance to multiple stresses, we analyzed the function of specific MAPK-WRKY cascades in abiotic and biotic stress tolerance as well as leaf senescence in oilseed rape (Brassica napus L.), one of the important oil crops. In the present study, we showed that expression of one WRKY gene from oilseed rape, BnaWGR1, induced an accumulation of reactive oxygen species (ROS), cell death and precocious leaf senescence both in Nicotiana benthamiana and transgenic Arabidopsis (Arabidopsis thaliana). BnaWGR1 regulates the transcription of two genes encoding key enzymes implicated in production of ROS, that is, respiratory burst oxidase homolog (Rboh) D and RbohF. A dual luciferase reporter assay confirmed the transcriptional regulation of RbohD and RbohF by BnaWGR1. In vitro electrophoresis mobility shift assay (EMSA) showed that BnaWGR1 could bind to W-box cis-elements within promoters of RbohD and RbohF. Moreover, RbohD and RbohF were significantly upregulated in transgenic Arabidopsis overexpressing BnaWGR1. In summary, these results suggest that BnaWGR1 could positively regulate leaf senescence through regulating the expression of RbohD and RbohF genes. PMID- 29511817 TI - Meniscus repairs can be saved in the event of postoperative septic arthritis. AB - PURPOSE: No systematic studies on optimal treatment of postoperative septic arthritis following arthroscopic meniscus repair are available. The purpose of this study was to retrospectively evaluate the fate of repaired menisci in cases of postoperative septic arthritis, with treatment for infection focused on arthroscopic irrigation and debridement (I&D) and intention to maintain the meniscus. METHODS: Data of two sports orthopedics centers of the last 10 years were pooled (approximately 25,000 arthroscopic procedures of the knee). All cases of septic arthritis following arthroscopic meniscus repair were identified. These cases were retrospectively evaluated with regard to clinical course and management, especially the number of necessary I&Ds, if eradication was achieved, and if the repaired meniscus was retained or a partial resection was necessary ('early failure'). Patients with initially maintained meniscus repairs were contacted if further meniscus surgery was performed in further follow-up ('late failure'). RESULTS: 20 patients with 23 repaired menisci were included. In 65% (13 cases), a concomitant anterior cruciate ligament reconstruction was performed. A mean of 2.0 +/- 1.0 (1-4) arthroscopic I&Ds were performed in the treatment of septic arthritis. In two cases, additional open surgery was performed (after outside-in sutures). Eradication was achieved in all cases. Four repaired menisci (17.4%) showed loosened fixation or substantial degradation and were consequently partially resected within treatment for septic arthritis (early failures). The follow-up rate for the 19 initially maintained menisci was 94.7% after 3.0 +/- 2.2 years (median 2.8, 0.4-7.8). Three of these underwent further partial resection (13.0%). Cumulative 3-year survival rate (Kaplan-Meier method) of all repairs was 70.7% (95% CI 50.3-91.1%), and for the subgroup of initially maintained menisci 85.6% (95% CI 67.0-100.0%), respectively. CONCLUSION: Septic arthritis following meniscus repair can be successfully treated with (sequential) arthroscopic I&Ds. There is a considerable rate of early failures, however, in a mid-term follow-up the failure rate of initially retained menisci is low and comparable to what we know from the literature for cases without infection. Therefore, it is generally recommended to try to save the repaired menisci in these cases. LEVEL OF EVIDENCE: IV, therapeutic case series. PMID- 29511818 TI - Medial meniscus extrusion increases with age and BMI and is depending on different loading conditions. AB - PURPOSE: Meniscus extrusion has always been described as an indirect sign of meniscus pathology and is associated with a loss of function of the affected meniscus. The current cut-off value of 3 mm displacement is indicated as abnormal and has been determined on magnetic resonance images (MRI) and ultrasound (US). However, it has to be considered that there is no description of the physiological meniscus extrusion in healthy knees depending on age or different weight-bearing conditions. It was hypothesized that in healthy knees there is a physiological age and BMI dependent meniscal extrusion, and meniscus extrusion depends on different loading conditions. METHODS: Healthy volunteers with non symptomatic knee, and no history of knee injuries or operations were included in this prospective cross-sectional study. Exclusion criteria were age < 18years, subjective or objective instability, malalignment and positive medial meniscus test. Secondary exclusion criteria were osteoarthritis ICRS grade 3-4 or signs of meniscus tear on MRI. Every patient underwent standard knee examination following measurement of medial meniscus extrusion (MME) using US. In US extrusion was determined in supine position (unloaded) and in standing position with full weight-bearing and 20 degrees of flexion (loaded). MRI was performed in a neutral knee position to compare ultrasound measurements with the current gold standard. Based on the power calculation of preliminary results a minimum of 70 volunteers was needed. RESULTS: 75 patients were enrolled to this study. The mean US MME was 1.1 mm +/- 0.5 mm in supine position and 1.9 mm +/- 0.9 mm under full weight-bearing. The mean US Delta-extrusion was 0.8 mm +/- 0.6 mm. With rising age, a significant increased MME in US and MRI could be demonstrated (p < 0.001). Furthermore, elevated BMI was significantly correlated to increased US MME under full weight-bearing (p = 0.002) and to US Delta-extrusion (p = 0.003). CONCLUSION: Based on the results of this study, medial meniscus extrusion is an age-depending phenomenon in healthy knees and depends on various load-bearing conditions. Ultrasound examination of the MME might be favorable compared to MRI due to the ability of dynamic evaluation. As a consequence, the current cut-off value of 3 mm for meniscus pathologies should be reconsidered. LEVEL OF EVIDENCE: III. PMID- 29511819 TI - Intra-articular injections of expanded mesenchymal stem cells with and without addition of platelet-rich plasma are safe and effective for knee osteoarthritis. AB - PURPOSE: To compare the effectiveness and safety of intra-articular injections of autologous expanded mesenchymal stromal stem cells alone (MSCs), or in combination with platelet-rich plasma (MSCs + PRP), in patients with knee osteoarthritis. METHODS: Eighteen patients (57.6 +/- 9.6 years) with radiographic symptomatic knee osteoarthritis (Dejour grades II-IV) were randomized to receive intra-articular injections of MSCs (n = 9) or MSCs + PRP (n = 9). Injections were performed 2-3 weeks after bone marrow aspiration (+/- 80-100 ml) which was obtained from both posterior iliac crests. RESULTS: The Knee Injury and Osteoarthritis Outcome Score (KOOS) improved significantly throughout the 12 months for both groups (p < 0.05). No statistically significant differences between groups were found in KOOS subscales and global score improvements at 12 month end-point (n.s.). The MSCs group showed significant improvements in the pain, function and daily living activities, and sports and recreational activities subscales (p < 0.05). Similarly, the MSCs + PRP group showed significant improvements in the pain, function and daily living activities and quality of life subscales (p < 0.05). The average number of fibroblast colony forming units (CFU-F) was 56.8 + 21.9 for MSCs group and 50.7 +/- 21.7 for MSCs + PRP group. Minimal adverse effects were seen in both groups (10 adverse events, in 5 patients). CONCLUSIONS: Intra-articular injections of expanded MSCs alone or in combination with PRP are safe and have a beneficial effect on symptoms in patients with symptomatic knee osteoarthritis. Adding PRP to the MSCs injections did not provide additional benefit. These results are encouraging and support the recommendation of this minimally invasive procedure in patients with knee osteoarthritis, without requiring hospitalization. The CFU-F results may be used as reference for future research. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 29511821 TI - Correction to: Estrogen and muscle stiffness have a negative relationship in females. AB - In the original publication the name of the fourth reviewer was incorrectly published. PMID- 29511820 TI - No evidence for the most appropriate postoperative rehabilitation protocol following anterior cruciate ligament reconstruction with concomitant articular cartilage lesions: a systematic review. AB - PURPOSE: Anterior cruciate ligament (ACL) rupture commonly occurs in conjunction with articular cartilage injury. However, there is no consensus on the most appropriate rehabilitation which should be carried out for ACL reconstruction (ACLR) and the surgical management of articular cartilage lesions of the knee. The purpose of this study was to systematically review the literature to investigate the recommended rehabilitation protocol for patients undergoing ACLR with concomitant articular cartilage injury with a view to develop guidelines on the most appropriate treatment. METHODS: Two reviewers independently searched five database for randomised controlled trials (RCTs), non-randomised comparative and retrospective cohort studies (CS) describing the management of concomitant ACL rupture and articular cartilage injury and the postoperative rehabilitation regimen. Risk of bias was performed using a modified Downs & Black's checklist. The primary outcome was specific rehabilitation protocols including weight bearing status, immobilisation, continuous passive motion (CPM), and return to play criteria. Secondary outcomes included patient-reported outcomes. A best evidence synthesis was performed. RESULTS: The review yielded six studies which reported on rehabilitation techniques. All studies were of low methodological quality. There was considerable variability in not only the chondral lesion reported but also the treatment techniques utilised and especially the rehabilitation regimes. No consensus was found on weight-bearing status, postoperative immobilisation, the use of CPM, or return to play criteria. Given the quality of the papers, there was no evidence to recommend any specific rehabilitation regime in the postoperative management of concomitant ACLR and articular cartilage lesions. CONCLUSION: This systematic review revealed that despite how common concomitant ACL rupture and articular cartilage injury is, there is no evidence to support one, most appropriate rehabilitation protocol. From a clinical perspective, decisions on postoperative rehabilitation for patients undergoing ACLR and treatment of articular cartilage lesions should be made on a case-by-case basis with criteria-based progression until more robust evidence becomes available. A list of specific rehabilitation protocols based on the cartilage restoration technique is provided. LEVEL OF EVIDENCE: IV. PMID- 29511822 TI - [Restricted mobility in nursing home residents : The role of pain and cognitive capacity]. AB - BACKGROUND: Pain, restriction of mobility and cognitive impairment are often present in old age and intensify each other. OBJECTIVES: Is there a relationship between mobility, pain, cognitive capacity, diagnoses and number of prescribed medication for residents of nursing homes? METHODS: Subgroup analysis of the baseline data from an intervention study for optimization of the medication safety of 120 nursing home residents. RESULTS: Pain was presumed in 77.8% of the residents. Persons with cognitive impairment were more frequently affected. The results of the observational and self-reported pain assessment in cognitively impaired patients did not agree for two-thirds of the cases. A correlation between prevalence of pain, pain intensity and mobility could only be shown for persons without cognitive impairment. Half of the persons were unable to walk; 80% of the residents with analgesics as a permanent medication were more restricted in their mobility. CONCLUSIONS: Cognitive impairment is associated with pain and reduced mobility, whereby self-rated pain did not concur with the observational pain assessment for two-thirds of the residents with cognitive impairment. This illustrates the difficulty of observational pain assessment. PMID- 29511823 TI - Theoretical study of the heats of formation, detonation properties, and bond dissociation energies of substituted bis-1,2,4-triazole compounds. AB - The heats of formation (HOFs), detonation properties, and bond dissociation energies (BDEs) of a series of energetic bis-1,2,4-trizaole compounds with different substituents were studied using density functional theory at the 6-311 + G(2df, 2p) level. The HOF results indicated that the presence of the substituents -NH2, -NO2, -NHNO2, and -N3 markedly increases the HOFs of bis-1,2,4 trizaole compounds. The calculated detonation velocities and detonation pressures indicated that the presence of the substituents -NH2, -NO2, -NHNO2, -CH(NO2)2, and -OH strongly enhances the detonation properties of bis-1,2,4-trizaole compounds. The BDEs results indicated that the presence of the substituents -H, NH2, and -OH substituent groups greatly improves the thermal stabilities of bis 1,2,4-trizaole compounds. Based on its detonation properties and BDEs, one of the bis-1,2,4-trizaole compounds (B6) is a potential alternative explosive to 1,3,5 trinitro-1,3,5-triazacyclohexane (RDX). PMID- 29511824 TI - Minimally invasive total hip arthroplasty using Hueter's direct anterior approach. AB - For many years the Hueter anterior approach has been performed exclusively in Paris. Robert and Jean Judet described it for the first time in 1950 in relation to total hip arthroplasty. They started using an orthopaedic surgery table in 1985. The approach was only taught within the capital's orthopaedic units and was relatively unknown before. In the last 10 years there has been widespread renewed interest in this approach which preserves the muscles. The technique is described in detail with its tricks and risks. It appeals to the surgeon in its minimally invasive form and provides particulary effective treatment for the patient. PMID- 29511825 TI - AFD: an application for bi-molecular interaction using axial frequency distribution. AB - Conformational flexibility and generalized structural features are responsible for specific phenomena existing in biological pathways. With advancements in computational chemistry, novel approaches and new methods are required to compare the dynamic nature of biomolecules, which are crucial not only to address dynamic functional relationships but also to gain detailed insights into the disturbance and positional fluctuation responsible for functional shifts. Keeping this in mind, axial frequency distribution (AFD) has been developed, designed, and implemented. AFD can profoundly represent distribution and density of ligand atom around a particular atom or set of atoms. It enabled us to obtain an explanation of local movements and rotations, which are not significantly highlighted by any other structural and dynamical parameters. AFD can be implemented on biological models representing ligand and protein interactions. It shows a comprehensive view of the binding pattern of ligand by exploring the distribution of atoms relative to the x-y plane of the system. By taking a relative centroid on protein or ligand, molecular interactions like hydrogen bonds, van der Waals, polar or ionic interaction can be analyzed to cater the ligand movement, stabilization or flexibility with respect to the protein. The AFD graph resulted in the residual depiction of bi-molecular interaction in gradient form which can yield specific information depending upon the system of interest. PMID- 29511826 TI - Efficacy and safety of amantadine for the treatment of L-DOPA-induced dyskinesia. AB - L-DOPA induced dyskinesias (LIDs) may affect up to 40% of Parkinson's disease (PD) and impact negatively health-related quality of life. Amantadine has demonstrated significant antidyskinetic effects in animal PD models and in randomized double-blind placebo-controlled trials (RCTs) in patients with PD. These effects are thought to be related to the blockade of NMDA receptors modulating cortico-striatal glutamatergic-dopaminergic interactions involved in the genesis of LIDs. There are three pharmaceutical forms of amantadine currently available in the market: an oral immediate-release (IR) formulation, which is widely available; an extended-release (ER) formulation (ADS-5102) which has been recently developed and approved by the FDA; and an intravenous infusion (IV) solution, which is not commonly used in clinical practice. RCTs with amantadine IR or ER, involving more than 650 patients have shown consistent and long-lasting reductions in LIDs. Interestingly, ADS-5102 not only reduced LIDs, but also reduced significantly at the same time the duration of daily OFF-time, a unique finding compared with other antiparkinsonian medications that usually reduce time spent OFF at the cost of worsening of LIDs. Amantadine IR might also have possible effects on other PD symptoms such as apathy or fatigue. The most common adverse reactions with amantadine are constipation, cardiovascular dysfunction including QT prolongation, orthostatic hypotension and edema, neuropsychiatric symptoms such as hallucinations, confusion and delirium, nausea and livedo reticularis. Corneal degeneration is rare but critical. In summary, amantadine immediate and extended-release are effective and safe for the treatment of LIDs. PMID- 29511828 TI - Urinary sucrose and fructose to validate self-reported sugar intake in children and adolescents: results from the I.Family study. AB - PURPOSE: Excessive consumption of free sugar increases the risk for non communicable diseases where a proper assessment of this intake is necessary to correctly estimate its association with certain diseases. Urinary sugars have been suggested as objective biomarkers for total and free sugar intake in adults but less is known about this marker in children and adolescents. Therefore, the aim of this exploratory study is to evaluate the relative validity of self reported intake using urinary sugars in children and adolescents. METHODS: The study was conducted in a convenience subsample of 228 participants aged 5-18 years of the I.Family study that investigates the determinants of food choices, lifestyle and health in European families. Total, free and intrinsic sugar intake (g/day) and sugar density (g/1000 kcal) were assessed using 24-h dietary recalls (24HDRs). Urinary sucrose (USUC) and urinary fructose (UFRU) were measured in morning urine samples and corrected for creatinine excretion (USUC/Cr, UFRU/Cr). Correlation coefficients, the method of triads and linear regression models were used to investigate the relationship between intake of different types of sugar and urinary sugars. RESULTS: The correlation between usual sugar density calculated from multiple 24HDRs and the sum of USUC/Cr and UFRU/Cr (USUC/Cr + UFRU/Cr) was 0.38 (p < 0.001). The method of triads revealed validity coefficients for the 24HDR from 0.64 to 0.87. Linear regression models showed statistically significant positive associations between USUC/Cr + UFRU/Cr and the intake of total and free sugar. CONCLUSIONS: These findings support the relative validity of total and free sugar intake assessed by self-reported 24HDRs in children and adolescents. PMID- 29511829 TI - A novel approach to producing uniform 3-D tumor spheroid constructs using ultrasound treatment. AB - Producing three-dimensional (3-D) multicellular tumor spheroids (TSs) is valuable for characterizing anticancer drugs since they provide a more representative model of the 3-D in vivo tumor than conventional two-dimensional (2-D) monolayer culture. The interaction of tumor cells with the extracellular matrix (ECM) in a 3-D culture environment is more similar to a tumor in vivo than in a 2-D environment; cell-cell and cell-ECM interaction can influence cell behaviour, such as in response to drug treatment. In vitro tumor spheroid models have been developed using microfluidic systems to generate 3-D hydrogel beads containing components of alginate and ECM protein, such as collagen, with high uniformity and throughput. Cell-laden hydrogel droplets are formed using a flow focusing process wherein the hydrogel precursors should be a homogeneous mixture. During gelation of the droplets into beads, the alginate acts as a fast gelling component helping to maintain the spherical shape of beads and preventing coalescence as the temperature-sensitive collagen I component gels more slowly. To produce uniform hydrogel droplets using the microfluidic flow focusing system, the mixtures must be homogeneous. However, collagen's sensitivity to temperature can lead to formation of chunks of collagen gel inside of the mixture, causing the mixture to become non-uniform and risking chip clogging. In order to overcome this limitation, previous approaches have used a cooling system during bead encapsulation while tumor cells were also present in the mixture, but this procedure can contribute to a delay in cell proliferation. Here a novel yet simple method is developed to prepare homogeneous pre-bead-encapsulation-mixtures containing collagen type I through ultrasonication. This method allows the cultivation of homogenous TS cultures with high uniformity and compact structure, and not only maintains cell viability but also the proliferation of cells in alginate/collagen hydrogel bead cultures. Depending on the sonication parameters, time and temperature, collagen can form small sized fibrils to thick fibers. Here, the mixtures containing collagen are assessed for morphology of collagen fibers/fibrils, cell viability, and proliferation. Human source Michigan Cancer Foundation-7 (MCF-7) breast cancer cells are successfully incorporated into alginate/collagen mixtures, followed by sonication, and then bead production. After bead gelation, the encapsulated MCF-7 cells remained viable and proliferated to form uniform TSs when the beads contained alginate and collagen. Results indicate that ultrasound treatment (UST) provides a powerful technique to change the structure of collagen from fiber to fibril, and to disperse collagen fibers in the mixture homogeneously for an application to generate uniform hydrogel beads and spheroids while not inhibiting cell proliferation. PMID- 29511827 TI - Impulse control disorders in Parkinson's disease. AB - Impulse control disorders (ICD) are frequent side effects of dopamine replacement therapy (DRT) used in Parkinson's disease (PD) with devastating consequences on the patients and caregivers. ICD are behavioural addictions including compulsive gambling, shopping, sexual behaviour, and binge eating that are mainly associated with dopamine D2/D3 agonists. Their management is a real clinical challenge due to the lack of therapeutic alternative. Clinical studies have identified demographic and clinical risk factors for ICD such as younger age at disease onset, male gender, prior history of depression or substance abuse, REM sleep behaviour disorders and higher rate of dyskinesia. PD patients with ICD may also have a specific pattern of dopaminergic denervation in the ventral striatum. Specific evaluation tools have now been designed to better evaluate the severity and impact of ICD in PD. Patients with ICD display altered processing of reward and loss, and decisional bias associated with altered activity in cortical and subcortical areas such as the orbitofrontal cortex, amygdala, insula, anterior cingular cortex, and ventral striatum. Preclinical studies have demonstrated that D2/D3 agonists induce impairments in behavioural processes likely relevant to ICD such as risk-taking behaviour, preference for uncertainty, perseverative responding and sustained drive to engage in gambling-like behaviour. Whether interactions between dopamine denervation and DRT significantly contribute to the pathogenesis of ICD remains poorly understood so far, although features unique to PD have been identified in patients with ICD. Large-scale longitudinal studies are needed to better identify subjects with increased risk to develop ICD and develop therapeutic options. PMID- 29511830 TI - Recovery of mycobacteriophages from archival stocks stored for approximately 50 years in Japan. AB - Mycobacteriophage archival stocks have been kept for ca. 20-50 years in Japan. In this study, we attempted to recover mycobacteriophages from 50 archival stocks and briefly analyzed the recovered phages. The phages were recovered from 72.2% (13/18) of the lyophilized stocks that had been stored for 47-56 years. Moreover, the analysis of 12 representative recovered phages led to their classification as belonging to the family Siphoviridae, and seven of them were typed by polymerase chain reaction (PCR) targeting the gene that encodes the tape measure protein. Considering these results, lyophilization seems to be suitable for phage archival storage. PMID- 29511831 TI - Experiences of being diagnosed with osteoporosis: a meta-synthesis. AB - : This systematic review provides synthesised knowledge and guidance to health professionals on the experiences and perspectives of being diagnosed with osteoporosis from the patient's point of view. Using individuals' experiences and meanings can promote tailored and targeted information and guidance on osteoporosis, bone care and treatment at different stages of the osteoporosis trajectory. INTRODUCTION: To be diagnosed with osteoporosis with or without fragility fractures affects individuals differently. The aim of this review was firstly to aggregate existing qualitative evidence regarding an individual's experience of being diagnosed with osteoporosis at different stages, and secondly, to use a systematic approach to develop a conceptual understanding of central issues relevant for health professionals in order to provide support and guidance to patients/individuals. METHODS: This study used a systematic review methodology and methods for qualitative synthesis as recommended by Cochrane and integrated the findings of qualitative research from eight databases (Medline, PubMed, CINAHL, Embase, SweMed+, PsycINFO, ERIC, Web of Science) to July 2016. Selection and assessment were performed by three authors while four authors were involved in the analysis. Findings were cross-checked with the original article to ensure consistency with the individual's accounts. RESULTS: Our findings have revealed that individuals diagnosed with osteoporosis do not perceive osteoporosis as a biomedical trajectory but as a self-perceived continuum of severity and health. To be diagnosed with osteoporosis affects individuals differently depending on, for example, personal experience, pre-conceived notions of or knowledge about the disease, fragility fractures or pain. Hence, individuals will create a meaning of the diagnosis based on self-perceived fracture risk, self-perceived severity of osteoporosis and at the same time, self perceived health. CONCLUSIONS: This meta-synthesis provides knowledge for health professionals on the experiences and perspectives of being diagnosed with osteoporosis from the patient's point of view. The experience, meaning and significance of osteoporosis must be taken into consideration and can be used to promote tailored and targeted information and guidance on osteoporosis, bone care and treatment at different stages of the osteoporosis trajectory. PMID- 29511832 TI - Iron-sulfur clusters: from metals through mitochondria biogenesis to disease. AB - Iron-sulfur clusters are ubiquitous inorganic co-factors that contribute to a wide range of cell pathways including the maintenance of DNA integrity, regulation of gene expression and protein translation, energy production, and antiviral response. Specifically, the iron-sulfur cluster biogenesis pathways include several proteins dedicated to the maturation of apoproteins in different cell compartments. Given the complexity of the biogenesis process itself, the iron-sulfur research area constitutes a very challenging and interesting field with still many unaddressed questions. Mutations or malfunctions affecting the iron-sulfur biogenesis machinery have been linked with an increasing amount of disorders such as Friedreich's ataxia and various cardiomyopathies. This review aims to recap the recent discoveries both in the yeast and human iron-sulfur cluster arena, covering recent discoveries from chemistry to disease. PMID- 29511834 TI - Pollen ultrastructure in Aristolochia manshuriensis and A. contorta (Aristolochiaceae). AB - Pollen ultrastructure has been studied in two relict and rare species of the genus Aristolochia, A. contorta Bunge and A. manshuriensis Kom. (Aristolochiaceae). Both species have inaperturate, spheroidal, sometimes distally monocolpate or distally bicolpate pollen grains. The equatorial and polar axes of pollen grain in A. manshuriensis are 48.5 and 44.0 MUm, respectively. The percentage of defective pollen grains in A. manshuriensis is 3.4%. The fossulate, perforated exine is up to 2.3 MUm in thickness; the sexine and the nexine are almost equal in thickness. In A. contorta, the equatorial axis of pollen grain is 36.6 MUm: the defectiveness percentage, 24.5%. The exine is verrucate, up to 0.3 MUm in thickness, while the sexine is two to three times thicker than the nexine. The pollen germination experiments have shown that pollen of A. manshuriensis, in contrast to A. contorta, can germinate in 10-20% sucrose at 22 degrees S. These data and the high percentage of pollen defectiveness in A. contorta indicate that the androecium function in this species is reduced. The reduction of the androecium function is evidenced by a small amount of pollen grains in anthers or empty anthers and a high percentage of defective pollen grains. PMID- 29511833 TI - Reactive oxygen species and nitric oxide are involved in polyamine-induced growth inhibition in wheat plants. AB - Polyamines (PAs) produce H2O2 and nitric oxide (NO) during their normal catabolism and modulate plant growth and development. To explore the biochemical basis of PAs-induced growth inhibition in Triticum aestivum L seedlings, we examined the role of O2.-, H2O2 or NO in shoot and root development. Although all PA treatments resulted in a variable reduction of root and shoot elongation, spermine (Spm) caused the greater inhibition in a similar way to that observed with the NO donor, sodium nitroprusside (SNP). In both cases, O2.- production was completely blocked whereas H2O2 formation was high in the root apex under SNP or Spm treatments. Catalase recovered root and shoot growth in SNP but not in Spm treated plants, revealing the involvement of H2O2 in SNP-root length reduction. The addition of the NO scavenger, cPTIO, restored root length in SNP- or Spm treated plants, respectively, and partially recovered O2.- levels, compared to the plants exposed to PAs or SNP without cPTIO. A strong correlation was observed between root growth restoration and O2.- accumulation after treating roots with SNP + aminoguanidine, a diamine oxidase inhibitor, and with SNP + 1,8 diaminoctane, a polyamine oxidase inhibitor, confirming the essential role of O2. formation for root growth and the importance of the origin and level of H2O2. The differential modulation of wheat growth by PAs through reactive oxygen species or NO is discussed. Graphical abstract Polyamines, nitric oxide and ROS interaction in plants during plant growth. PMID- 29511835 TI - Biological aspects of tissue-engineered cartilage. AB - Cartilage regenerative medicine has been progressed well, and it reaches the stage of clinical application. Among various techniques, tissue engineering, which incorporates elements of materials science, is investigated earnestly, driven by high clinical needs. The cartilage tissue engineering using a poly lactide scaffold has been exploratorily used in the treatment of cleft lip-nose patients, disclosing good clinical results during 3-year observation. However, to increase the reliability of this treatment, not only accumulation of clinical evidence on safety and usefulness of the tissue-engineered products, but also establishment of scientific background on biological mechanisms, are regarded essential. In this paper, we reviewed recent trends of cartilage tissue engineering in clinical practice, summarized experimental findings on cellular and matrix changes during the cartilage regeneration, and discussed the importance of further studies on biological aspects of tissue-engineered cartilage, especially by the histological and the morphological methods. PMID- 29511836 TI - An effervescence-assisted switchable fatty acid-based microextraction with solidification of floating organic droplet for determination of fluoroquinolones and tetracyclines in seawater, sediment, and seafood. AB - This study developed a new effervescence-assisted switchable fatty acid-based microextraction combined with solidification of a floating organic-droplet (EA SFAM-SFO) for simple and rapid determination of fluoroquinolones and tetracyclines in seawater, sediment, and seafood. Five medium-chain fatty acids (pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, and nonanoic acid) were tested as an extraction solvent, given their ability to change between hydrophobic and hydrophilic forms by pH adjustment. As nonanoic acid had the highest extraction recovery (>92%) for the six antibiotics and the ability to transform from liquid to a solidified floating state at low temperature, it was selected as the optimum extraction solvent. The prominent advantages of the newly developed method are: (1) reaction between the procedures salt and fatty acid changed extraction solvent from the hydrophobic to hydrophilic state; (2) bubbling with CO2 greatly increased the contact area between fatty acid and analytes resulting in improved extraction recovery; and (3) solidification of the fatty acid at a low temperature provided good separation and avoided the use of specialized equipment. Single-factor screening and optimization of the main factors were conducted using Plackett-Burman design and central composite design, respectively. The main parameters were optimized as follows: 258 MUL fatty acid, 406 MUL H2SO4 (98%), 3.9 min vortex time, and 354 MUL Na2CO3 (2 mol L-1). Under optimized conditions, limits of detection were 0.007-0.113 MUg L-1 or MUg kg-1 and extraction recoveries were 82.2%-116.7% for six fluoroquinolone and tetracycline antibiotics in seawater, sediments, and seafood. The newly developed method combines the advantages of effervescence-assisted dispersion, hydrophobic/hydrophilic switchable solvent, and liquid/solid transition induced by low temperature. Overall, the new method is simple, quick, and environment friendly with low detection limits and high recoveries. Thus, the newly developed method has excellent prospects for sample pretreatment and analysis of antibiotics in marine environmental and food samples. Graphical Abstract ?. PMID- 29511837 TI - Novel capsule phase microextraction in combination with liquid chromatography tandem mass spectrometry for determining personal care products in environmental water. AB - A novel sample preparation technique named capsule phase microextraction (CPME) is presented here. The technique utilizes a miniaturized microextraction capsule (MEC) as the extraction medium. The MEC consists of two conjoined porous tubular polypropylene membranes, one of which encapsulates the sorbent through sol-gel technology, while the other encapsulates a magnetic metal rod. As such, MEC integrates both the extraction and stirring mechanisms into a single device. The aim of this article is to demonstrate the application potential of CPME as sample preparation technique for the extraction of a group of personal care products (PCPs) from water matrices. Among the different sol-gel sorbent materials (UCON(r), poly(caprolactone-dimethylsiloxane-caprolactone) (PCAP-DMS-CAP) and Carbowax 20M (CW-20M)) evaluated, CW-20M MEC demonstrated the best extraction performance for the selected PCPs. The extraction conditions for sol-gel CW-20M MEC were optimized, including sample pH, stirring speed, addition of salt, extraction time, sample volume, liquid desorption solvent, and time. Under the optimal conditions, sol-gel CW-20M MEC provided recoveries, ranging between 47 and 90% for all analytes, except for ethylparaben, which showed a recovery of 26%. The method based on CPME with sol-gel CW-20M followed by liquid chromatography-tandem mass spectrometry was developed and validated for the extraction of PCPs from river water and effluent wastewater samples. When analyzing different environmental samples, some analytes such as 2,4 dihydroxybenzophenone, 2,2-dihydroxy-4-4 methoxybenzophenone and 3-benzophenone were found at low ng L-1. PMID- 29511838 TI - The roles of 11C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral glioma. AB - PURPOSE: This prospective study aimed to evaluate the clinical values of 11C acetate positron emission tomography/computed tomography (PET/CT) in predicting histologic grades and survival in patients with cerebral glioma. METHODS: Seventy three patients with surgically confirmed cerebral gliomas (19 grade II, 21 grade III, and 33 grade IV) who underwent 11C-acetate PET/CT before surgery were included. Tumor-to-choroid plexus ratio (TCR), which was defined as the maximum standardized uptake value (SUV) of tumors to the mean SUV of choroid plexus, was compared between three World Health Organization (WHO) grade groups. Moreover, metabolic tumor volumes (MTV) were calculated. Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan-Meier method, and differences in survival between groups were assessed using the log-rank test. RESULTS: Median TCR was 1.20 (interquartile range [IQR], 1.14 to 1.4) in grade II, 1.65 (IQR, 1.26 to 1.79) in grade III, and 2.53 (IQR, 1.93 to 3.30) in grade IV gliomas. Significant differences in TCR were seen among the three WHO grade groups (P < 0.001). In Cox regression analysis including TCR, MTV, molecular markers, and other clinical factors, TCR was prognostic for PFS (P = 0.016) and TCR and MTV were prognostic for OS (P = 0.024 [TCR], P = 0.030 [MTV]). PFS and OS were significantly shorter in patients with a TCR >= 1.6 than in those with a TCR < 1.6. OS were significantly shorter in patients with a MTV >= 1 than in those with a TCR < 1. CONCLUSIONS: TCR on 11C-acetate PET/CT significantly differed between low- and high-grade cerebral gliomas, and it showed the capability to further differentiate grade III from grade IV tumors. TCR and MTV were independent prognostic factors and predicted survival better than did the WHO grade. PMID- 29511839 TI - Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers. AB - PURPOSE: Cardiac involvement in familial transthyretin (TTR) amyloidosis is of major prognostic value, and the development of early-diagnostic tools that could trigger the use of new disease-modifying treatments is crucial. The aim of our study was to compare the respective contributions of 99mTc-diphosphonate scintigraphy (DPD, detecting amyloid deposits) and 123I-MIBG (MIBG, assessing cardiac sympathetic denervation) in patients with genetically proven TTR mutation referred for the assessment of cardiac involvement. METHODS: We prospectively studied 75 consecutive patients (classified as symptomatic or asymptomatic carriers), using clinical evaluation, biomarkers (troponin and BNP), echocardiography, and nuclear imaging. Patients were classified as having normal heart-to-mediastinum (HMR) MIBG uptake ratio 4 h after injection (defined by HM4 >= 1.85) or abnormal HM4 < 1.85, and positive DPD uptake (grade >= 1 of Perugini classification) or negative DPD uptake. RESULTS: Among 75 patients, 49 (65%) presented with scintigraphic sympathetic cardiac denervation and 29 (39%) with myocardial diphosphonate uptake. When MIBG was normal, DPD was negative except for two patients. Age was an independent predictor of abnormal scintigraphic result of both MIBG and DPD (HR 1.08 and 1.15 respectively), whereas echocardiographic-derived indicators of increased left ventricular filling pressure (E/e' ratio) was an independent predictor of abnormal MIBG (HR 1.33) and global longitudinal strain of positive DPD (HR 1.45). In asymptomatic patients (n = 31), MIBG was abnormal in 48% (n = 15) among whom 50% had a normal DPD; all those with a normal MIBG (n = 16) had a normal DPD. CONCLUSIONS: In TTR mutation carriers, cardiac sympathetic denervation evidenced by decreased MIBG uptake is detected earlier than amyloid burden evidenced by DPD. These results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value. PMID- 29511840 TI - Soil Inoculation with Bacillus spp. Modifies Root Endophytic Bacterial Diversity, Evenness, and Community Composition in a Context-Specific Manner. AB - The use of microbial inoculants containing plant growth-promoting rhizobacteria as a promoter of plant fitness and health is becoming increasingly popular in agriculture. However, whether and how these bacteria affect indigenous bacterial communities in field conditions is sparsely explored. We studied the effects of seed inoculation and field soil application of ubiquitous soil bacteria, B. cereus, B. subtilis, and B. amyloliquefaciens, on the diversity, evenness, and richness of endophytic bacterial communities in sprouting broccoli roots using high-throughput metagenome sequencing. The multiple operational taxonomic units (OTUs) assigned to different bacterial taxa clearly showed changes in ecological measures and relative abundances of certain taxa between control and treatment groups. The Bacillus inocula, themselves, failed to flourish as endophytes; however, the effects they extended on the endophytic bacterial community were both generic as well as species specific. In each case, Pseudomonadales, Rhizobiales, Xanthomonadales, and Burkholderiales were the most abundant orders in the endosphere. B. amyloliquefaciens drastically reduced the most abundant genus, Pseudomonas, while increasing the relative abundance of a range of minor taxa. The Shannon-Weiner diversity and Buzas and Gibson's evenness indices showed that the diversity and evenness were increased in both B. amyloliquefaciens and mixed treated plants. The UniFrac measurement of beta diversity showed that all treatments affected the specific composition of the endophytic bacterial community, with an apparent interspecies competition in the mixed treatment. Taken together, Bacillus species influenced the diversity, evenness, and composition of the endophytic bacterial community. However, these effects varied between different Bacillus spp. in a context-specific manner. PMID- 29511841 TI - New perspectives on the long-term outcome of segmental colectomy for Crohn's colitis: an observational study on 200 patients. AB - BACKGROUND AND AIMS: Surgical management of Crohn's colitis represents one of the most complex situations in colorectal surgery. Segmental colectomy (SC) and total abdominal colectomy with ileorectal anastomosis (TAC-IRA) are the most common procedures, but there are few available data on their long-term outcome. The aim of the present study was to analyze the long-term outcome of patients who underwent segmental colectomy for Crohn's colitis, with regard to the risk for total abdominal colectomy. METHODS: In this observational, monocentric, retrospective analysis, we analyzed patients who received a segmental colectomy for Crohn's colitis at our institution. The database was updated by asking patients to complete a questionnaire by telephone or at the outpatient clinic. Only patients followed up at our Hospital were included. Patients were followed up by a specialized multidisciplinary team (IBD Unit). The primary endpoint was the interval between segmental colectomy and, when performed, total abdominal colectomy. RESULTS: Between 1973 and 2014, 200 patients underwent segmental colectomy for Crohn's colitis. The median follow-up was 13.5 years (interquartile range [IQR] 7.8-21.5). Overall, 62 patients (31%) had a surgical recurrence, of these, 42 (21%) received total abdominal colectomy. At multivariate analysis, the presence of >= 3 sites (HR = 2.47; 95% CI 1.22-5.00; p = 0.018) and perianal disease (HR = 3.23; 95% CI 1.29-8.07; p = 0.006) proved to be risk factors for total abdominal colectomy. CONCLUSIONS: The risk for surgical recurrence after SC for Crohn's colitis is acceptable. We recommend a bowel-sparing policy for the treatment of Crohn's colitis in any case in which the extent of the disease at the moment of surgery makes the conservative approach achievable. PMID- 29511842 TI - Long-term mortality and recurrence in patients treated for colonic diverticulitis with abscess formation: a nationwide register-based cohort study. AB - PURPOSE: The study aimed to investigate long-term mortality, recurrence, and death related to recurrence for patients admitted with acute diverticulitis with abscess formation (Hinchey stage Ib-II). METHODS: The cohort was identified by linking administrative registers for all Danish citizens in years 2000-2012. Patients were identified from ICD-10 discharge codes and stratified according to treatment (antibiotics, percutaneous abscess drainage, or surgery). RESULTS: From 6,641,672 persons, 3148 patients were identified with acute diverticulitis with abscess formation. Survival was comparable between treatment groups with a 1-year survival of 81-83% and a 5-year survival of 66-67% (p = 0.66). Glucocorticoid usage prior to admission increased risk of mortality with hazard ratio 1.64 (95%CI 1.39-1.93), 1.77 (1.20-2.63), and 1.92 (1.07-3.44) for the antibiotics, drainage, and operative treatment group, respectively. Drainage treatment increased risk of recurrence with sub-distribution hazard (SDH) of 1.52 (1.19 1.95) and operative treatment decreased risk with a SDH of 0.55 (0.32-0.93), both compared with antibiotic treatment (p = 0.0001). Recurrence occurred in 23.6% (18.5-30.1%) of patients in the drainage group, 15.5% (13.9-17.3%) in the antibiotics group, and 9.1% (5.1-16.1%) in the operative group. Recurrence related mortality was 2.0% (0.9-4.4%) for the drainage group, 1.1% (0.7-1.8%) for the antibiotics group, and 0.6% (0.1-4.3%) for the operative group (p = 0.24). Most recurrences and recurrence-related mortality occurred within the first year after primary admission. CONCLUSIONS: This study with complete national data revealed a high mortality and recurrence rate after diverticular abscesses. Survival was comparable between treatment groups, but patients treated with drainage had significantly higher risk of recurrence. PMID- 29511843 TI - PET Assessment of Immune Cell Activity and Therapeutic Monitoring Following Myocardial Infarction. AB - PURPOSE OF REVIEW: Local inflammation after myocardial infarction (MI) plays a role in subsequent ventricular remodeling, influences cardiac outcome, and has emerged as a therapeutic target. Preclinical and clinical PET imaging studies have employed a variety of radiotracers to target inflammatory leukocytes in the early stages after MI. RECENT FINDINGS: Imaging of enhanced metabolism in activated macrophages with 18F-FDG is feasible and has been associated with cardiac outcome in a small prospective study. Novel targeted PET agents show higher specificity for inflammatory leukocytes and can identify therapeutic response with limited background. While PET imaging of acute inflammation after MI has grown in recent years, significant challenges remain to widespread clinical application, including the complex cellular composition of the imaging signal and unclear association with functional outcome. Future studies must address the prognostic value of post-MI inflammation imaging and the ability to discern response to targeted, expensive, and personalized therapies. PMID- 29511844 TI - Functional identification of the prnABCD operon and its regulation in Serratia plymuthica. AB - The antibiotic pyrrolnitrin (PRN) is a tryptophan-derived secondary metabolite that plays an important role in the biocontrol of plant diseases due to its broad spectrum of antimicrobial activities. The PRN biosynthetic gene cluster remains to be characterised in Serratia plymuthica, though it is highly conserved in PRN producing bacteria. To better understand PRN biosynthesis and its regulation in Serratia, the prnABCD operon from S. plymuthica G3 was cloned, sequenced and expressed in Escherichia coli DH5alpha. Furthermore, an engineered strain prnind which is a conditional mutant of G3 prnABCD under the control of the Ptac promoter was constructed. This mutant was able to overproduce PRN with isopropylthiogalactoside (IPTG) induction by overexpressing prnABCD, whilst behaving as a conditional mutant of G3 prnABCD in the absence of IPTG. These results confirmed that prnABCD is responsible for PRN biosynthesis in strain G3. Further experiments involving lux-/dsRed-based promoter fusions, combined with site-directed mutagenesis of the putative sigmaS extended -10 region in the prnA promoter, and liquid chromatography-mass spectrometry (LC-MS) analysis extended our previous knowledge about G3, revealing that quorum sensing (QS) regulates PRN biosynthesis through cross talk with RpoS, which may directly activated prnABCD transcription. These findings suggest that PRN in S. plymuthica G3 is produced in a tightly controlled manner, and has diverse functions, such as modulation of cell motility, in addition to antimicrobial activities. Meanwhile, the construction of inducible mutants could be a powerful tool to improve PRN production, beyond its potential use for the investigation of the biological function of PRN. PMID- 29511845 TI - Magnetic graphene oxide inlaid with silver nanoparticles as antibacterial and drug delivery composite. AB - A three-component composite consisted of graphene oxide, cobalt ferrite, and silver nanoparticles has been prepared by a facile method and fully characterized. The antibacterial activity of this composite has been greatly enhanced after being combined with ciprofloxacin drug. This clearly showed the occurrence of a strong synergistic effect between ciprofloxacin and the Ag NPs in the composite. The ciprofloxacin-conjugated composite was found to be a potent antimicrobial agent while having rather low cytotoxicity and high stability. The studies based on field emission scanning electron microscopy (FESEM) analysis and zeta potential measurement have revealed that the composite sticks to the bacterial cell wall causing irreversible cell damage. This multifunctional magnetic nanocomposite was also examined as drug delivery system for ciprofloxacin in solutions with different pH. It was observed that the release of ciprofloxacin in this system is pH-sensitive with gradual and controlled manner. Mechanisms for the synergistic effect and drug release behavior, as well as explanation for the antibacterial action, of the nanocomposite were also demonstrated. PMID- 29511846 TI - Surface engineering of polyester-degrading enzymes to improve efficiency and tune specificity. AB - Certain members of the carboxylesterase superfamily can act at the interface between water and water-insoluble substrates. However, nonnatural bulky polyesters usually are not efficiently hydrolyzed. In the recent years, the potential of enzyme engineering to improve hydrolysis of synthetic polyesters has been demonstrated. Regions on the enzyme surface have been modified by using site directed mutagenesis in order to tune sorption processes through increased hydrophobicity of the enzyme surface. Such modifications can involve specific amino acid substitutions, addition of binding modules, or truncation of entire domains improving sorption properties and/or dynamics of the enzyme. In this review, we provide a comprehensive overview on different strategies developed in the recent years for enzyme surface engineering to improve the activity of polyester-hydrolyzing enzymes. PMID- 29511847 TI - Characterization of novel roles of a HMG-box protein PoxHmbB in biomass-degrading enzyme production by Penicillium oxalicum. AB - High-mobility group (HMG)-box proteins are involved in chromatin organization in eukaryotes, especially in sex determination and regulation of mitochondrial DNA compaction. Although a novel HMG-box protein, PoxHmbB, had been initially identified to be required for filter paper cellulase activity by Penicillium oxalicum, the biological roles of HMG-box proteins in biomass-degrading enzyme production have not been systematically explored. The P. oxalicum mutant ?PoxHmbB lost 34.7-86.5% of cellulase (endoglucanase, p-nitrophenyl-beta-cellobiosidase, and p-nitrophenyl-beta-glucopyranosidase) activities and 60.3% of xylanase activity following Avicel induction, whereas it exhibited about onefold increase in amylase activity following soluble corn starch induction. Furthermore, ?PoxHmbB presented delayed conidiation and hyphae growth. Transcriptomic profiling and real-time quantitative reverse transcription-PCR revealed that PoxHmbB regulated the expression of major genes encoding plant biomass-degrading enzymes such as PoxCel7A-2, PoxCel5B, PoxBgl3A, PoxXyn11B, and PoxGA15A, as well as those involved in conidiation such as PoxBrlA. In vitro binding experiments further confirmed that PoxHmbB directly binds to the promoter regions of these major genes. These results further indicate the diversity of the biological functions of HMG-box proteins and provide a novel and promising engineering target for improving plant biomass-degrading enzyme production in filamentous fungi. PMID- 29511848 TI - Enriching ruminal polysaccharide-degrading consortia via co-inoculation with methanogenic sludge and microbial mechanisms of acidification across lignocellulose loading gradients. AB - Using lignocellulosic materials as substrates, ruminal microbiota were co inoculated with anaerobic sludge at different loading rates (LR) to study the microbial community in the semi-continuous mode. The results indicated that the highest CH4 yield reached 0.22 L/g volatile solid at LR of 4 g/L/day, which obtained 56-58% of the theoretical value. In the steady stage with LR of 2-4 g/L/day and slurry recirculation, copies of total archaea increased. Especially the Methanobacteriales increased significantly (p < 0.05) to 3.30 * 108 copies/mL. The microbial communities were examined by MiSeq 16S rRNA sequencing. Enriched hydrolytic bacteria mainly belonged to Clostridiales, including Ruminococcus, Ruminiclostridium, and Ruminofilibacter settled in the rumen. High active cellulase and xylanase were excreted in the co-inoculated system. Acid producing bacteria by fermentation were affiliated with Lachnospiraceae and Bacteroidales. The acidogen members were mainly Spirochaetaceae and Clostridiales. Syntrophic oxidation bacteria mainly consisted of Synergistetes, propionate oxidizers (Syntrophobacter and Pelotomaculum), and butyrate oxidizers (Syntrophus and Syntrophomonas). There had no volatile fatty acid (VFA) accumulation and the pH values varied between 6.94 and 7.35. At LR of 6 g/L/day and a recirculation ratio of 1:1, the hardly degradable components and total VFA concentrations obviously increased. The total archaea and Methanobacteriales then deceased significantly to 8.56 * 105 copies/mL and 4.14 * 103 copies/mL respectively (p < 0.05), which resulted in the inhibition of methanogenic activities. Subsequently, microbial diversity dropped, and the hydrolytic bacteria and syntrophic oxidizers obviously decreased. In contrast, the abundances of Bacteroidales increased significantly (p < 0.05). Acetate, propionate, and butyrate concentrations reached 2.02, 6.54, and 0.53 g/L, respectively, which indicated "acidification" in the anaerobic reactor. Our study illustrated that co-inoculated anaerobic sludge enriched the ruminal function consortia and hydrogenotrophic methanogens played an important role in anaerobic digestion of lignocelluloses. PMID- 29511849 TI - Role of MDCT Imaging in Planning Mitral Valve Intervention. AB - PURPOSE OF REVIEW: Recent advancements in transcatheter valvular interventions have resulted in a growing demand for advanced cardiac imaging to help guide these procedures. RECENT FINDINGS: Both echocardiography and multi-detector computed tomography have played essential roles in the maturation of transcatheter aortic valve replacement and are now building on these experiences and helping inform the nascent field of transcatheter mitral interventions. Advanced imaging is essential to aid in the diagnosis and determination of the mechanism of mitral regurgitation. In addition, they are integral to annular sizing, determination of the suitability of patient anatomy for specific devices and increasingly important in the determination of the risk of left ventricular outflow tract obstruction and providing appropriate patient-specific fluoroscopic angulation in advance of the procedure. PMID- 29511852 TI - Inference of maternal uniparental disomy of the entire chromosome 2 from a paternity test. AB - Atypical situations arise during the constant resolution of paternity cases, which constitute challenges requiring additional genetic systems and non-standard methods. We report a paternity case presenting three alleged father (AF)-child incompatibilities for the markers TPOX, D2S441, and the indel locus B02 (11/11 vs 8/8; 14/14 vs 10/10; 2/2 vs1/1, respectively). Considering the presence of mutations/null alleles, the residual paternity indexes (PI) obtained with 23 autosomal short tandem repeats (STRs) and 38 indels suggest that the AF is the father (PI = 1.94e+011). Although the presence of few incompatibilities also could imply paternity of the AF brother, this hypothesis was less probable (PI = 3.20e+9) (W = 98.4 vs 1.6%, respectively). The inclusion of 23 Y-STR loci confirmed the paternity relationship in this case (global PI = 6.08e+15). However, the two multistep STRs and one indel incompatibilities allow discarding the mutation possibility. On the other hand, the confirmation of the homozygous STR genotypes with two different human identification kits and the low probability to find three null alleles (3.10e-8) allow rejecting the null allele presence hypothesis. Conversely, the child's homozygous genotype for maternal alleles in four markers located in the p and q arms of the chromosome 2 (TPOX, D2S441, D2S1338, and B02) suggests that maternal uniparental isodisomy better explains the relationship despite the presence of three paternal incompatibilities. In brief, when multiple incompatibilities are observed in paternity testing, the chromosomal location of the excluding loci and the use of additional genetic systems can be crucial to get confident kinship conclusions. PMID- 29511853 TI - Wounding potential of 4.4-mm (.173) caliber steel ball projectiles. AB - From time to time, severe or fatal injuries caused by small caliber air rifle projectiles are seen. In forensic sciences, the theoretical wounding potential of these weapons and projectiles is widely known. Usually, shots against the skull were reported and, in these cases, penetrating the eyes or thin bone layers of the temporal region. Amongst a huge number of different projectiles available for air guns, sub-caliber 4.4-mm (.173) caliber steel ball projectiles were used in an unusual suicide case. This case led to fundamental questions concerning wound ballistics. An 82-year-old man shot once against his right temporal region and twice into his mouth with a 4.5-mm (.177) caliber air rifle. Because of the exceptionally deep penetration of the base of the skull and the use of spherical shaped sub-caliber air rifle projectiles, terminal ballistic features were analyzed and compared to results published in forensic literature. Test shots using the same weapon and similar projectiles were fired into ballistic gelatin to measure and calculate basic wound ballistic variables of cal. 4.4-mm (.173) steel balls. In comparison, further test shots with cal. 4.5-mm (.177) steel balls BB (ball bearing), flat-headed and pointed air rifle pellets ("diabolos") were carried out. The theoretical penetration depth in solid bone was calculated with 36.4 mm, and test shots in gelatin from hard contact produced an on-average wound track of 120 mm underlining the potential wounding effect. Furthermore, spherical projectiles could roll back and forth within the barrel, and an air cushion between projectile and breechblock can reduce muzzle velocity by more than half, explaining the retained missile in the temporal region. PMID- 29511850 TI - Using Information Technology in the Assessment and Monitoring of Geriatric Oncology Patients. AB - PURPOSE OF REVIEW: Older adults with cancer have complex medical needs and often experience higher rates of treatment-related toxicities compared to their younger counterparts. The advent of health information technologies can address multiple gaps in the care of this population. We review the role of existing and emerging technologies in facilitating the use of comprehensive geriatric assessment (CGA) in routine clinics, promoting symptom reporting, and monitoring medication adherence. RECENT FINDINGS: Increasingly, studies demonstrate the feasibility of implementing electronic CGA in routine oncology practices. Evidence also suggests that electronic symptom reporting can improve outcomes in patients with cancer. In addition, technology devices can be used to promote adherence to cancer therapy. There are many opportunities for information technology to be integrated into the management and treatment of older adults with cancer. However, further evaluation of these technologies is needed to ensure that they meet the needs of the targeted end users. PMID- 29511851 TI - Patterns of cell death in the embryonic antenna of the grasshopper Schistocerca gregaria. AB - We have investigated the pattern of apoptosis in the antennal epithelium during embryonic development of the grasshopper Schistocerca gregaria. The molecular labels lachesin and annulin reveal that the antennal epithelium becomes subdivided into segment-like meristal annuli within which sensory cell clusters later differentiate. To determine whether apoptosis is involved in the development of such sensory cell clusters, we examined the expression pattern of the cell death labels acridine orange and TUNEL in the epithelium. We found stereotypic, age-dependent, wave-like patterns of cell death in the antenna. Early in embryogenesis, apoptosis is restricted to the most basal meristal annuli but subsequently spreads to encompass almost the entire antenna. Cell death then declines in more basal annuli and is only found in the tip region later in embryogenesis. Apoptosis is restricted throughout to the midregion of a given annulus and away from its border with neighboring annuli, arguing against a causal role in annular formation. Double-labeling for cell death and sensory cell differentiation reveals apoptosis occurring within bands of differentiating sensory cell clusters, matching the meristal organization of the apical antenna. Examination of the individual epithelial lineages which generate sensory cells reveals that apoptosis begins peripherally within a lineage and with age expands to encompass the differentiated sensory cell at the base. We conclude that complete lineages can undergo apoptosis and that the youngest cells in these lineages appear to die first, with the sensory neuron dying last. Lineage-based death in combination with cell death patterns in different regions of the antenna may contribute to odor-mediated behaviors in the grasshopper. PMID- 29511854 TI - Correction to: Treatment Strategies for the Opioid-Dependent Patient. AB - The original version of this article contains an error in the gender listing of the first author in the Conflict of Interest statement. PMID- 29511855 TI - Shifting stream planform state decreases stream productivity yet increases riparian animal production. AB - In the Colorado Front Range (USA), disturbance history dictates stream planform. Undisturbed, old-growth streams have multiple channels and large amounts of wood and depositional habitat. Disturbed streams (wildfires and logging < 200 years ago) are single-channeled with mostly erosional habitat. We tested how these opposing stream states influenced organic matter, benthic macroinvertebrate secondary production, emerging aquatic insect flux, and riparian spider biomass. Organic matter and macroinvertebrate production did not differ among sites per unit area (m-2), but values were 2 *-21 * higher in undisturbed reaches per unit of stream valley (m-1 valley) because total stream area was higher in undisturbed reaches. Insect emergence was similar among streams at the per unit area and per unit of stream valley. However, rescaling insect emergence to per meter of stream bank showed that the emerging insect biomass reaching the stream bank was lower in undisturbed sites because multi-channel reaches had 3 * more stream bank than single-channel reaches. Riparian spider biomass followed the same pattern as emerging aquatic insects, and we attribute this to bottom-up limitation caused by the multi-channeled undisturbed sites diluting prey quantity (emerging insects) reaching the stream bank (riparian spider habitat). These results show that historic landscape disturbances continue to influence stream and riparian communities in the Colorado Front Range. However, these legacy effects are only weakly influencing habitat-specific function and instead are primarily influencing stream-riparian community productivity by dictating both stream planform (total stream area, total stream bank length) and the proportional distribution of specific habitat types (pools vs riffles). PMID- 29511856 TI - Correction to: Root-colonizing bacteria enhance the levels of (E)-beta caryophyllene produced by maize roots in response to rootworm feeding. AB - Unfortunately, family name of author "Xavier Chiriboga M" was incorrectly identified in the original publication and the same is corrected here. The original article has been corrected. PMID- 29511857 TI - The impact of exclusion processes on angiogenesis models. AB - Angiogenesis is the process by which new blood vessels form from existing vessels. During angiogenesis, tip cells migrate via diffusion and chemotaxis, new tip cells are introduced through branching, loops form via tip-to-tip and tip-to sprout anastomosis, and a vessel network forms as endothelial cells, known as stalk cells, follow the paths of tip cells (a process known as the snail-trail). Using a mean-field approximation, we systematically derive one-dimensional non linear continuum models from a lattice-based cellular automaton model of angiogenesis in the corneal assay, explicitly accounting for cell volume. We compare our continuum models and a well-known phenomenological snail-trail model that is linear in the diffusive, chemotactic and branching terms, with averaged cellular automaton simulation results to distinguish macroscale volume exclusion effects and determine whether linear models can capture them. We conclude that, in general, both linear and non-linear models can be used at low cell densities when single or multi-species exclusion effects are negligible at the macroscale. When cell densities increase, our non-linear model should be used to capture non linear tip cell behavior that occurs when single-species exclusion effects are pronounced, and alternative models should be derived for non-negligible multi species exclusion effects. PMID- 29511858 TI - The referee who agrees to review and never responds again (NERO): a series of 37 cases of an emerging entity. PMID- 29511859 TI - Grey-matter network disintegration as predictor of cognitive and motor function with aging. AB - Loss of grey-matter volume with advancing age affects the entire cortex. It has been suggested that atrophy occurs in a network-dependent manner with advancing age rather than in independent brain areas. The relationship between networks of structural covariance (SCN) disintegration and cognitive functioning during normal aging is not fully explored. We, therefore, aimed to (1) identify networks that lose GM integrity with advancing age, (2) investigate if age-related impairment of integrity in GM networks associates with cognitive function and decreasing fine motor skills (FMS), and (3) examine if GM disintegration is a mediator between age and cognition and FMS. T1-weighted scans of n = 257 participants (age range: 20-87) were used to identify GM networks using independent component analysis. Random forest analysis was implemented to examine the importance of network integrity as predictors of memory, executive functions, and FMS. The associations between GM disintegration, age and cognitive performance, and FMS were assessed using mediation analyses. Advancing age was associated with decreasing cognitive performance and FMS. Fourteen of 20 GM networks showed integrity changes with advancing age. Next to age and education, eight networks (fronto-parietal, fronto-occipital, temporal, limbic, secondary somatosensory, cuneal, sensorimotor network, and a cerebellar network) showed an association with cognition and FMS (up to 15.08%). GM networks partially mediated the effect between age and cognition and age and FMS. We confirm an age-related decline in cognitive functioning and FMS in non-demented community-dwelling subjects and showed that aging selectively affects the integrity of GM networks. The negative effect of age on cognition and FMS is associated with distinct GM networks and is partly mediated by their disintegration. PMID- 29511860 TI - DJ-1 is involved in epigenetic control of sphingosine-1-phosphate receptor expression in vascular neointima formation. AB - DJ-1 and sphingosine-1-phosphate (S1P) receptors (S1PRs) are implicated in the control of physiology and pathophysiology of cardiovascular systems such as blood pressure, atherosclerosis, and restenosis. Here, we investigated whether DJ-1 with antioxidant function participates in the regulation of S1PR1 and S1PR2 expression in vascular smooth muscle cells (VSMCs) and whether this response is related to vascular neointima formation. In vitro studies used cellular migration assay, western blot, reverse transcriptase and real-time PCR analysis, and immunocytochemistry. In vivo studies were performed using the carotid artery ligation model together with immunohistochemistry in DJ-1 knockout (DJKO) and corresponding wild-type (DJWT) mice. S1P stimulated migration of VSMCs from DJKO and DJWT mice. VSMC migration was suppressed by S1PR1 inhibitor but was elevated by S1PR2 inhibitor. Compared with DJWT mice, S1PR1 expression was higher in VSMCs and neointimal plaque from DJKO mice, but S1PR2 expression was lower. Overexpression of DJ-1 in DJKO VSMCs reduced S1PR1 expression and elevated S1PR2 expression. Compared with DJWT mice, histone deacetylase-1 recruitment and histone H3 acetylation at the S1PR1 promoter region were lower and higher, respectively, but this pattern was reversed at the S1PR2 promoter region in DJKO VSMCs. S1PR expressions and epigenetic changes at S1PR promoter regions in DJWT VSMCs treated with H2O2 showed similar patterns to those in DJKO VSMCs. Our findings suggest that DJ-1 may be involved in the regulation of S1PR1 and S1PR2 expression via H2O2-mediated histone modification in VSMCs. Consequently, this modification may affect S1P-induced VSMC migration and be related to vascular neointima formation. PMID- 29511861 TI - Myocardial Extracellular Volume Quantification by Cardiovascular Magnetic Resonance and Computed Tomography. AB - PURPOSE OF REVIEW: This review article discusses the evolution of extracellular volume (ECV) quantification using both cardiovascular magnetic resonance (CMR) and computed tomography (CT). RECENT FINDINGS: Visualizing diffuse myocardial fibrosis is challenging and until recently, was restricted to the domain of the pathologist. CMR and CT both use extravascular, extracellular contrast agents, permitting ECV measurement. The evidence base around ECV quantification by CMR is growing rapidly and just starting in CT. In conditions with high ECV (amyloid, oedema and fibrosis), this technique is already being used clinically and as a surrogate endpoint. Non-invasive diffuse fibrosis quantification is also generating new biological insights into key cardiac diseases. CMR and CT can estimate ECV and in turn diffuse myocardial fibrosis, obviating the need for invasive endomyocardial biopsy. CT is an attractive alternative to CMR particularly in those individuals with contraindications to the latter. Further studies are needed, particularly in CT. PMID- 29511862 TI - Adult normative values for the PATA Rate Test. AB - BACKGROUND: During neurological evaluation, dysarthria is not rated using quantitative measures, but rather using a qualitative approach. OBJECTIVE: Aim of our study was to validate and acquire normative values for the PATA Rate Task (PRT), a quantitative test used to measure the severity of dysarthria. METHODS: For the PRT probands are invited to repeat the syllables "PA-TA" as quickly as possible during a 10-s interval. The score consists in the number of correct repetition of both syllables. RESULTS: We enrolled 232 healthy controls (118 males, 114 females), mean and standard deviation of the PRT was 28.84 +/- 6.6 (range 14-52). The PRT showed good inter-rater reliability (R = 0.783; p < 0.001), as well as test-retest reliability (R = 0.927; p < 0.001), and intra rater reliability (R = 0.888; p < 0.001). Higher age correlated with lower scores (R = - 0.368; p < 0.001). CONCLUSIONS: The PRT showed good reliability and could be easily added to the evaluation of movement disorders where a speech evaluation is essential. PMID- 29511863 TI - The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis. AB - Some patients with primary central nervous system lymphoma (PCNSL) may initially present with similar clinical, magnetic resonance imaging, and routine cerebrospinal fluid (CSF) findings as those observed in multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, appears to be the most specific CSF marker for MS. This study aimed to determine whether a positive MRZR and other routine CSF markers help differentiate between MS and PCNSL. Data regarding brain biopsy, CSF routine tests, cytopathological examination and immunophenotyping of CSF cells were assessed in 68 PCNSL patients. MRZR was determined, as possible, in PCNSL patients (n = 37) and in those with MS (n = 74; age and sex matched to PSCNL patients) and psychiatric disorders (PD; n = 78). Two stringency levels for a positive antibody index (AI) evaluation (AI >= 1.5 and 2.0) were applied, and MRZR was considered positive in cases with >= 2 positive AIs (MRZR-2). Using the common AI threshold of >= 1.5, MS patients exhibited positive MRZR-2 (58.1%) more frequently than PCNSL (8.1%) and PD patients (2.6%; p < 0.0001 for each comparison with the MS group) corresponding to a positive predictive value (PPV) of 89.6% and a negative predictive value (NPV) of 78.0%. On applying the stricter AI threshold of >= 2.0, 37.8% of MS patients were MRZR-2 positive; however, all patients with PCNSL and PD were MRZR 2 negative (p < 0.0001 for each comparison with the MS cohort) resulting in a PPV of 100% and an NPV of 71.4%. Consequently, a positive MRZR-2 result may contribute toward the distinction between MS and PCNSL owing to its high specificity and PPV for MS in the context of the present study. Among the other CSF parameters only a quantitative intrathecal IgG synthesis (present in 49.3% of MS patients but in none of the PCNSL or PD patients; p < 0.0001 for each comparison with the MS group) reliably indicated MS rather than PCNSL. PMID- 29511864 TI - Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation. AB - B-cell depleting anti-CD20 monoclonal antibody therapies are being increasingly used as long-term maintenance therapy for neuroinflammatory disease compared to many non-neurological diseases where they are used as remission-inducing agents. While hypogammaglobulinaemia is known to occur in over half of patients treated with medium to long-term B-cell-depleting therapy (in our cohort IgG 38, IgM 56 and IgA 18%), the risk of infections it poses seems to be under-recognised. Here, we report five cases of serious infections associated with hypogammaglobulinaemia occurring in patients receiving rituximab for neuromyelitis optica spectrum disorders. Sixty-four per cent of the whole cohort of patients studied had hypogammaglobulinemia. We discuss the implications of these cases to the wider use of anti-CD20 therapy in neuroinflammatory disease. PMID- 29511866 TI - Complications and Reinterventions After Fenestrated and Branched EVAR in Patients with Paravisceral and Thoracoabdominal Aneurysms. AB - The application of endovascular strategies to treat aneurysms involving the abdominal and thoracoabdominal aorta has evolved significantly since the inception of endovascular aneurysm repair. Advances in endograft technology and operator experience have enabled the management of a wider spectrum of challenging aortic anatomy. Fenestrated endovascular and branched endovascular aneurysm repair represent two technical innovations, which have expanded endovascular treatment options to include patients with paravisceral and thoracoabdominal aortic aneurysms. Although similar in many ways to standard aortic endografts, fenestrated and branched endografts have specific short- and long-term complications due to their unique modular endograft design and their sophisticated deployment mechanisms. This article aims to examine the commonly encountered complications with these devices and the endovascular reintervention strategies. PMID- 29511867 TI - Endovascular Treatment of Congenital Arterioportal Fistulas. AB - PURPOSE: To characterize anatomy of congenital arterioportal fistulas (CAPF) and correlate this with technique and outcomes of transcatheter embolization (TCE). MATERIALS AND METHODS: Retrospective review was conducted of children with CAPF that underwent TCE in a 10-year period. Medical records, imaging and procedure details were reviewed. TCE was performed via transarterial (n = 5), portal (n = 5) or patent ductus venosus (n = 1) approach. Embolic agents used were coils (n = 10), Onyx (n = 1) and Amplatzer septal occluder (n = 1). RESULTS: A total of 7 patients were included (4 female). Median age at treatment was 4 months (2 month 3 year). Most common symptoms were GI bleeding (n = 4), anemia (n = 4) and ascites (n = 3). Hepatopetal flow was seen in all on pre-procedure sonography. On angiography, a simple lesion, with direct fistulous connections, from hepatic arterial (HA) branches to portal venous (PV) system was seen in 3. A complex lesion with multiple connections was identified in 4. In simple lesions, cessation of shunting was achieved in 1 procedure, with embolization of afferent vessels. In complex lesions, multiple procedures were required in 3 of 4 patients. All 4 with complex connections required embolization of the aneurysmal PV segment. There were no major complications. Two minor complications were noted: localized biliary leak in 1 and femoral pseudoaneurysm in 1. There was resolution of symptoms in 6. CONCLUSIONS: TCE is effective as primary treatment of CAPF. Patients with simple arteriovenous connections can be treated with embolization of afferent vessels, but children with multiple complex connections usually require embolization of the dilated PV segment. PMID- 29511865 TI - Deep brain stimulation in uncommon tremor disorders: indications, targets, and programming. AB - BACKGROUND: In uncommon tremor disorders, clinical efficacy and optimal anatomical targets for deep brain stimulation (DBS) remain inadequately studied and insufficiently quantified. METHODS: We performed a systematic review of PubMed.gov and ClinicalTrials.gov. Relevant articles were identified using the following keywords: "tremor", "Holmes tremor", "orthostatic tremor", "multiple sclerosis", "multiple sclerosis tremor", "neuropathy", "neuropathic tremor", "fragile X-associated tremor/ataxia syndrome", and "fragile X." RESULTS: We identified a total of 263 cases treated with DBS for uncommon tremor disorders. Of these, 44 had Holmes tremor (HT), 18 orthostatic tremor (OT), 177 multiple sclerosis (MS)-associated tremor, 14 neuropathy-associated tremor, and 10 fragile X-associated tremor/ataxia syndrome (FXTAS). DBS resulted in favorable, albeit partial, clinical improvements in HT cases receiving Vim-DBS alone or in combination with additional targets. A sustained improvement was reported in OT cases treated with bilateral Vim-DBS, while the two cases treated with unilateral Vim-DBS demonstrated only a transient effect. MS-associated tremor responded to dual-target Vim-/VO-DBS, but the inability to account for the progression of MS associated disability impeded the assessment of its long-term clinical efficacy. Neuropathy-associated tremor substantially improved with Vim-DBS. In FXTAS patients, while Vim-DBS was effective in improving tremor, equivocal results were observed in those with ataxia. CONCLUSIONS: DBS of select targets may represent an effective therapeutic strategy for uncommon tremor disorders, although the level of evidence is currently in its incipient form and based on single cases or limited case series. An international registry is, therefore, warranted to clarify selection criteria, long-term results, and optimal surgical targets. PMID- 29511868 TI - Technical Note: Dissection Flap Perforation with Use of a TIPS-Needle During Fenestrated Endografting for Post-dissection Thoracoabdominal Aneurysms. AB - INTRODUCTION: Fenestrated/branched thoracic endovascular aneurysm repair (F/Br TEVAR) is a new minimal invasive treatment option for patients with post dissection thoracoabdominal aortic aneurysms. This specific pathology is challenging to F/Br-TEVAR, especially when target vessels originate from the false lumen. Crossing from the true lumen into the false lumen to catheterize such target vessels may prove cumbersome in the usually thickened dissection flap. TECHNIQUE: We describe a bailout technique when standard catheterization techniques fail, by using a transjugular intrahepatic portosystemic shunt (TIPS) needle to perforate the dissection flap. The fenestration is subsequently dilated using balloon angioplasty to allow for insertion and deployment of the bridging stent graft. CONCLUSION: When other catheterization techniques fail in vessel originating from the false lumen, TIPS-needle perforation of the dissection flap is a useful bailout tool. PMID- 29511869 TI - Is Redo Vertebroplasty an Effective Treatment on the Same Vertebra? AB - OBJECTIVE: Redo vertebroplasty is rarely reported. Previous studies on redo vertebroplasty included a small number of patients and lacked radiographic analysis. The purpose of this study was to assess the radiographic outcomes (restoration of vertebral body) and clinical outcomes (pain relief) in patients with recurrent or unrelieved pain after vertebroplasty with a minimum follow-up duration of 12 months. MATERIALS AND METHODS: The records of 22 patients (23 cases), who underwent redo vertebroplasty between March 2001 and February 2014, were analyzed. Vertebral height loss (VHL) and wedge angle (WA) were measured before and after redo vertebroplasty. Subjective back pain was assessed via the numeric rating scale (NRS) score. RESULTS: VHL after the initial vertebroplasty was 18.7%. Preoperative and final VHL of redo vertebroplasty were 32.3 and 18.3%, respectively. WA after initial vertebroplasty was 9.5 degrees . Preoperative and final WA of redo vertebroplasty was 13.9 degrees and 9 degrees , respectively. Changes of VHL and WA values at each time point were significant (p < 0.01). The change of NRS pain score at each time point, including the period between post initial vertebroplasty and final follow-up, was statistically significant (p < 0.01); 18 patients (82%) showed marked pain relief and 4 patients (18%) showed partial pain relief. CONCLUSIONS: Redo vertebroplasty seems to be an effective way to achieve pain relief and vertebral body height restorations without major complications in patients with unrelieved or recurrent back pain after vertebroplasty. LEVEL OF EVIDENCE: Level 4, case series. PMID- 29511870 TI - Stromal PDGFR-beta Expression is Associated with Postoperative Survival of Non Small Cell Lung Cancer Patients Receiving Preoperative Chemo- or Chemoradiotherapy Followed by Surgery. AB - BACKGROUND: PDGFR-beta is used as a stromal biomarker and is functional in mesenchymal cells of the tumor microenvironment. The significance of stromal PDGFR-beta expression in non-small cell lung cancer (NSCLC) in patients undergoing preoperative chemo- or chemoradiotherapy had not been determined. METHODS: Patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy between 1996 and 2014 were assessed for expression of stromal PDGFR-beta by immunohistochemistry using resected specimens. Relationships between stromal PDGFR-beta expression and survival after operation were analyzed. Forty-three patients who underwent surgery without preoperative treatment in 2005 were also analyzed as a chemo-naive control group. RESULTS: The mean age of the 92 patients was 60.2 years. Seventy-eight (85%) were male, and 14 (15%) were female. Fifty four patients (59%) underwent preoperative chemoradiotherapy, and 38 patients (41%) underwent preoperative chemotherapy. Regimens for preoperative chemotherapy were cisplatin (CDDP) based in 48 patients (52%) and carboplatin (CBDCA) based in 43 (42%). While stromal cells expressed PDGFR-beta in 21 chemo-naive patients (49%), stromal cells expressed PDGFR-beta in 65 patients who underwent preoperative therapy (p = 0.02). The 5-year disease-free survival rate (DFS) of the PDGFR-beta-positive group was significantly worse than that of the negative group (27 vs. 48%, p = 0.04). The 5-year disease-specific survival rate (DSS) in the stromal PDGFR-beta-positive group was also significantly worse than in the negative group (43 vs. 70%, p = 0.01). On the other hand, stromal PDGFR-beta expression did not influence survival in chemo-naive patients. CONCLUSIONS: Stromal PDGFR-beta expression is negatively associated with DFS and DSS in patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy. PMID- 29511871 TI - Risk Factors of Postoperative Delirium in the Intensive Care Unit After Liver Transplantation. AB - BACKGROUND: Postoperative delirium after liver transplantation is relatively common, especially due to preexisting conditions such as hepatic encephalopathy. Most studies of delirium after liver transplantation were based on ICU practices using deep hypnosedation. Therefore, risk factors and consequences of postoperative delirium after liver transplantation were evaluated in the light sedation era. METHODS: A total of 253 liver transplantation patients were evaluated for postoperative delirium. Clinical outcomes including mortality were compared between patients who suffered delirium and those who did not. Risk factors for postoperative delirium were analyzed with subgroup analysis depending on MELD scores and type of liver transplantation. RESULTS: Post-liver transplant delirium developed in 17% of the patients, 88% of which occurred within the first postoperative day. Alcoholic liver cirrhosis, class C Child-Pugh score, higher MELD scores, higher proportion of deceased donor liver transplantation, and reintubation were more frequent in patients who developed delirium, but there was no difference in mortality. Higher preoperative MELD group (15-24 vs. <15; OR 4.10, 95% Cl [1.67-10.09], P = 0.002, >=25 vs. <15; OR 5.59, 95% CI [2.06-15.19], P < 0.01), higher APACHE II scores (OR 5.59, 95% CI [2.06-15.19], P < 0.01), and reintubation (OR 6.46, 95% CI [2.10-19.88], P < 0.01) were identified as significant risk factors for postoperative delirium. CONCLUSION: Postoperative delirium after liver transplantation was associated with worse clinical outcomes. MELD scores greater than 15 were predictive of postoperative delirium in both living and deceased donor liver transplantation. PMID- 29511872 TI - Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma. AB - OBJECTIVE: Surgical resection is the only available treatment for achieving long term survival in cholangiocarcinoma. The purpose of this study is to elucidate the utility of chemoradiotherapy for initially unresectable locally advanced cholangiocarcinoma. METHODS: Unresectable locally advanced cholangiocarcinoma was defined as those in which radical surgery could not be achieved even with aggressive surgical procedure. Fifteen candidates (7 intrahepatic cholangiocarcinomas and 8 hilar cholangiocarcinomas) underwent chemoradiotherapy. Fourteen of the 15 patients received oral S-1 chemotherapy. Radiotherapy was administered with 50 Gy for each patient. After chemoradiotherapy, the resectability of each cholangiocarcinoma was reexamined. RESULTS: Of the 15 patients with initially unresectable locally advanced cholangiocarcinoma, 11 (73.3%) were judged to have resectable cholangiocarcinoma after chemoradiotherapy, and received radical hepatectomy (R0 resection in 9 patients). Among the 11 patients who underwent surgical resection, 4 had recurrence-free survival and the median survival time (MST) was 37 months. The overall 1-, 2-, and 5-year survival rates were 80.8, 70.7 and 23.6%, respectively. Among the 4 patients who were unable to receive surgery, 3 died of the primary disease and the MST was 10 months. The overall 1- and 2-year survival rates were 37.5 and 0%, respectively. Patients who received radical surgery had significantly longer survival time than those who were unable to receive surgery (p = 0.027). CONCLUSIONS: Chemoradiotherapy allowed patients with initially unresectable locally advanced cholangiocarcinomas to be reclassified as surgical candidates in a substantial proportion. Chemoradiotherapy might be one of the treatment options for similarly advanced cholangiocarcinomas. PMID- 29511873 TI - Aflatoxin B1 and Zearalenone-Detoxifying Profile of Rhodococcus Type Strains. AB - Aflatoxin B1 (AFB1) and zearalenone (ZON) are dangerous mycotoxins due to their carcinogenicity or oestrogenicity. To alleviate negative effects on humans and animals, successful detoxification tools are needed. The application of microorganisms to biodegrade mycotoxins can be an effective way in food and feed industry enhancing food safety. Several Rhodococcus strains are effective in the degradation of aromatic mycotoxins and their application in mycotoxin biodetoxification processes is a promising field of biotechnology. In this study, we investigated the AFB1 and ZON detoxification ability of 42 type strains of Rhodococcus species. Samples were analysed by high-performance liquid chromatograph equipped with fluorescence detector for mycotoxin concentration and SOS-chromotest was used for monitoring remaining genotoxicity. Out of the 42 Rhodococcus strains, 18 could eliminate more than 90% of the applied AFB1 and the genotoxicity was ceased by 15 strains in 72 h (R. imtechensis JCM 13270T, R. erythropolis JCM 3201T, R. tukisamuensis JCM 11308T, R. rhodnii JCM 3203T, R. aerolatus JCM 19485T, R. enclensis DSM 45688T, R. lactis DSM 45625T, R. trifolii DSM 45580T, R. qingshengii DSM 45222T, R. artemisiae DSM 45380T, R. baikonurensis DSM 44587T, R. globerulus JCM 7472T, R. kroppenstedtii JCM 13011T, R. pyridinivorans JCM 10940T, R. corynebacterioides JCM 3376T). In case of ZON, only R. percolatus JCM 10087T was able to degrade more than 90% of the compound and to reduce the oestrogenicity with 70%. PMID- 29511874 TI - Groundwater monitoring of an open-pit limestone quarry: groundwater characteristics, evolution and their connections to rock slopes. AB - Groundwater flow and its geochemical evolution in mines are important not only in the study of contaminant migration but also in the effective planning of excavation. The effects of groundwater on the stability of rock slopes and other mine constructions especially in limestone quarries are crucial because calcite, the major mineral component of limestone, is moderately soluble in water. In this study, evolution of groundwater in a limestone quarry located in Chichibu city was monitored to understand the geochemical processes occurring within the rock strata of the quarry and changes in the chemistry of groundwater, which suggests zones of deformations that may affect the stability of rock slopes. There are three distinct geological formations in the quarry: limestone layer, interbedded layer of limestone and slaty greenstone, and slaty greenstone layer as basement rock. Although the hydrochemical facies of all groundwater samples were Ca-HCO3 type water, changes in the geochemical properties of groundwater from the three geological formations were observed. In particular, significant changes in the chemical properties of several groundwater samples along the interbedded layer were observed, which could be attributed to the mixing of groundwater from the limestone and slaty greenstone layers. On the rainy day, the concentrations of Ca2+ and HCO3- in the groundwater fluctuated notably, and the groundwater flowing along the interbedded layer was dominated by groundwater from the limestone layer. These suggest that groundwater along the interbedded layer may affect the stability of rock slopes. PMID- 29511875 TI - Evolocumab: Considerations for the Management of Hyperlipidemia. AB - PURPOSE OF REVIEW: To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. RECENT FINDINGS: PCSK9 inhibitors are a class of lipid lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non-high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins. Patients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone. PMID- 29511876 TI - Actigraphy as an objective intra-individual marker of activity patterns in acute phase bipolar disorder: a case series. AB - BACKGROUND: Actigraphy could be an objective alternative to clinical ratings of motor activity in bipolar disorder (BD), which is of importance now that increased activity and energy are added as cardinal symptoms of (hypo)mania in the DSM-5 and commonly used rating scales give inadequate information about motor symptoms. To date, most actigraphy studies have been conducted in groups and/or used mean activity levels as the variable of interest. The novelty of this case series is therefore to indicate the potential of actigraphy and non-parametric analysis as an objective and personalized marker of intra-individual activity patterns in different phases of BD. To our knowledge, this is the first case series that provides an objective assessment of non-linear dynamics in within person activity patterns during acute BD episodes. RESULTS: We report on three cases of bipolar I disorder with 24-h actigraphy recordings undertaken during the first few days of two or more separate admissions for an acute illness episode, including admissions for individuals in different phases of BD, or with different levels of severity in the same phase of illness. For each recording, we calculated mean activity levels over 24 h, but especially focused on key measures of variability and complexity in activity. Intra-individual activity patterns were found to be different according to phase of illness, but showed consistency within the same phase. With increasing psychotic symptoms, there was evidence of a lower overall level and greater irregularity in activity. As such, sample entropy (a measure of irregularity) may have particular utility in characterizing mania and psychotic symptoms, while assessment of the distribution of rest versus activity over 24 h may distinguish between phases of BD within an individual. CONCLUSIONS: This case series indicates that objective, intra-individual, real time recordings of patterns of activity may have clinical impact as a valuable adjunct to clinical observation and symptom ratings. We suggest that actigraphy combined with detailed mathematical analysis provides a biological variable that could become an important tool for developing a personalized approach to diagnostics and treatment monitoring in BD. PMID- 29511877 TI - The use of acellular dermal matrix in immediate two-stage prosthetic breast reconstruction provides protection from postmastectomy radiation therapy: a clinicopathologic perspective. AB - Although there is ample evidence showing that radiation therapy increases the risk of complications of breast reconstruction, the efficacy of human acellular dermal matrix (CGCryoDerm(r)) in immediate tissue expander breast reconstruction in the setting of postmastectomy radiation therapy has not been fully elucidated. In this study, we report our institutional experience with pertinent refined surgical technique, and determine whether acellular dermal matrices have a protective effect in this increasingly prevalent clinical setting. Twenty-six patients who underwent immediate two-stage breast reconstruction in the setting of postmastectomy radiation therapy with at least 2 years of follow-up were retrieved. Fifteen patents were reconstructed with ADM, whereas 11 patients were reconstructed without ADM. The occurrence of complications was assessed according to the reconstruction type (with ADM vs without ADM). Furthermore, in patients reconstructed with ADM (n = 15), immunohistochemistry was performed to analyze the breast capsule with ADM compared with that without ADM in the same patient, according to the expression of alpha-smooth muscle actin (alpha-SMA). The occurrence of complications was significantly associated with the reconstruction type (with ADM vs. without ADM, p = 0.015). On the basis of the results of alpha SMA staining, alpha-SMA+ myofibroblasts were relatively highly expressed throughout the breast capsule without ADM. On the contrary, alpha-SMA+ myofibroblasts present at the breast capsule adjacent to the ADM were scarce and irregularly scattered. Use of an acellular dermal matrix may be recommended to patients who are concerned about complications after immediate two-stage breast reconstruction in the setting of postmastectomy radiation therapy. PMID- 29511879 TI - Scientific Session of the 16th World Congress of Endoscopic Surgery, jointly hosted by Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) & Canadian Association of General Surgeons (CAGS), Seattle, Washington, USA, 11-14 April 2018: Exhibit Hall Videos. PMID- 29511878 TI - Biomineralization-Inspired Synthesis of Cerium-Doped Carbonaceous Nanoparticles for Highly Hydroxyl Radical Scavenging Activity. AB - Cerium oxide nanoparticles recently have received extensive attention in biomedical applications due to their excellent anti-oxidation performance. In this study, a simple, mild, and green approach was developed to synthesize cerium doped carbonaceous nanoparticles (Ce-doped CNPs) using bio-mineralization of bull serum albumin (BSA) as precursor. The resultant Ce-doped CNPs exhibited uniform and ultrasmall morphology with an average size of 14.7 nm. XPS and FTIR results revealed the presence of hydrophilic group on the surface of Ce-doped CNPs, which resulted in excellent dispersity in water. The CCK-8 assay demonstrated that Ce doped CNPs possessed favorable biocompatibility and negligible cytotoxicity. Using H2O2-induced reactive oxygen species (ROS) as model, Ce-doped CNPs showed highly hydroxyl radical scavenging capability. Furthermore, flow cytometry and live-dead staining results indicated that Ce-doped CNPs protected cells from H2O2 induced damage in a dose-dependent effect, which provided a direct evidence for anti-oxidative performance. These findings suggest that Ce-doped CNPs as novel ROS scavengers may provide a potential therapeutic prospect in treating diseases associated with oxidative stress. PMID- 29511880 TI - Scientific Session of the 16th World Congress of Endoscopic Surgery, jointly hosted by Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) & Canadian Association of General Surgeons (CAGS), Seattle, Washington, USA, 11-14 April 2018: Resident Fellow Abstracts. PMID- 29511881 TI - Optimal time of resuming anticoagulant after endoscopic sphincterotomy in patients at risk for thromboembolism: a retrospective cohort study. AB - BACKGROUND: One major adverse event of endoscopic sphincterotomy (EST) is bleeding, which could be more common and severe in patients receiving anticoagulant therapy. However, the cessation of anticoagulants for long periods could lead to thromboembolic events. We aimed to evaluate the optimal timing of resumption of anticoagulants after EST in patients at risk for thromboembolism. MATERIALS AND METHODS: From January 2010 through October 2017, a retrospective cohort at risk for thromboembolism who had taken warfarin and bridging therapy with heparin around EST from three tertiary hospitals in South Korea was investigated. The primary outcome was to compare the incidence of post-EST delayed bleeding according to the resumption time of anticoagulant. The secondary outcome was to investigate any thromboembolic adverse events related to interruption of the anticoagulant. RESULTS: A total of 96 patients (46 males and 50 females; median age 75 years [range, 24-91 years]) were enrolled. Overall, the patient numbers of very early (< 24 h), early (24-48 h), and late resumption (> 48 h) of anticoagulant after EST were 56, 23, and 17, respectively. The baseline characteristics were similar between groups except resumption time of anticoagulant. There was no significant difference in the rate of post-EST delayed bleeding (5% in very early group vs. 9% in early group vs. 0 in late group, p = 0.47). The rate of thromboembolic adverse events was significantly higher in the late resumption of anticoagulant group (0 vs. 0 vs. 24%, p < 0.001). CONCLUSION: There was no significant difference in the incidence of post EST delayed bleeding according to the resuming time of anticoagulant. Since long cessation of anticoagulant could increase the risk of thrombotic adverse events, the early resumption of anticoagulant seems to be preferred. PMID- 29511882 TI - Cardiometabolic Effects of Anti-obesity Pharmacotherapy. AB - PURPOSE OF REVIEW: We review recent studies discussing the impact of pharmacologic agents for weight loss on clinical cardiovascular events, as well as cardiometabolic risk factors. RECENT FINDINGS: Pharmacotherapy with current FDA-approved medications for weight loss can significantly improve known risk factors for the development of cardiovascular disease such as hypertension, hyperlipidemia, insulin resistance, inflammatory biomarkers, and the quantity of visceral fat, as well as non-alcoholic fatty liver disease. However, data regarding the actual reduction in clinical cardiovascular events with the use of weight loss medications is scarce. Pharmacotherapy for weight loss may have additional benefit in optimizing patient's cardiometabolic comorbidities and improving their clinical cardiovascular outcomes, but each drug should be carefully selected based upon individual patient characteristics. PMID- 29511883 TI - Validation of a 10-gene molecular signature for predicting biochemical recurrence and clinical metastasis in localized prostate cancer. AB - PURPOSE: To validate a previously characterized 10-gene signature in prostate cancer with implication to distinguish aggressive and indolent disease within low and intermediate patients' risk groups. METHODS: A case-control study design used to select 545 patients from the Mayo clinic tumor registry who underwent radical prostatectomy. A training set from this cohort (n = 359) was used to build a 10 gene model, based on high-dimensional discriminant analysis (HDDA10) to predict several endpoints of clinical patients' outcome. An independent set (n = 219) from the same institution was used as validation set. RESULTS: HDDA10 showed significant performance for predicting metastasis (Mets) (AUC 0.68, p = 6.4E - 6) and biochemical recurrence (BCR) (AUC = 0.65, p = 0.003) in the validation set outperforming Gleason grade grouping (GG) for BCR (AUC 0.57, p = 0.03) and with comparable performance for Mets endpoint (GG AUC 0.66, p = 8.1E - 5). HDDA10 prognostic significance was superior to any clinical-pathological parameter within GG2 + 3 (GS7) patients achieving an AUC of 0.74 (p = 0.0037) for BCR compared to Gleason pattern 4 (AUC 0.64) (p = 0.015) and AUC for Mets of 0.68 versus AUC of 0.65 for Gleason pattern 4 (p = 0.01). HDDA10 remained significant for both BCR and Mets in multivariate analysis, suggesting that it can be used to increase accuracy in stratifying patients eligible for active surveillance. CONCLUSION: HDDA10 is of added value to GG and other clinical-pathological parameters in predicting BCR and Mets endpoint, especially in the low to intermediate patients' risk groups. HDDA10 prognostic value should be further validated prospectively in stratifying patients specifically in low to intermediate GS (GG1-2), such as active surveillance programs. PMID- 29511886 TI - Influence of the flow field on alpha-cyclodextrin glycosyltransferase production by Escherichia coli BL21. AB - The computational fluid dynamics (CFD) software package Fluent was utilized to simulate the flow field of Escherichia coli (E. coli) BL21 fermentation in a 50 L automatic bioreactor for producing alpha-cyclodextrin glycosyltransferase (alpha CGTase) in this study. 4-down-pumping propeller (4DPP), 6-curved-blade disc turbine (6CBDT), and Rushton turbine (RT) were assembled to form eight impeller combinations (C1-C8). Through flow field simulating, four referential impeller combinations, in which C6, C7, and C8 were three layers stirring blades and C1 as a control, were selected to carry out batch fermentation experiments (TC1, TC6, TC7, and TC8) for validation. The correlation analysis between simulation results and experimental measurements indicated that TC6 (tank equipped with C6 impeller combination) exhibited lower enzymatic activity though it had the better mixing effect, fastest oxygen uptake rate (OUR), and maximum specific growth rate (u) in the initial stage, which was just to the contrary in TC8. It was revealed by next fed-batch fermentation experiments in TC6 and TC8 that TC6 was considered as excellent flow field properties brought about the higher u of E. coli BL21 and fast acetic acid (HAc) accumulation, which resulting in a serious inhibition on alpha-CGTase expression and this negative effect could not be removed. As a result, there should be a threshold of HAc accumulation rate which brought about a terrible inhibitory effect on alpha-CGTase expression. Moreover, the yield of alpha-CGTase activity reached 231.38 U mL- 1 in TC8, which elevated 31.74% compared to that obtained in TC1. PMID- 29511885 TI - Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations. AB - Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA based and CoMSIA-based QSAR models, the cross-validated coefficients (r2cv) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r2) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors. PMID- 29511884 TI - Podoplanin-positive cancer-associated fibroblast recruitment within cancer stroma is associated with a higher number of single nucleotide variants in cancer cells in lung adenocarcinoma. AB - PURPOSE: Podoplanin-positive cancer-associated fibroblasts (CAFs) play an essential role in tumor progression. However, it is still unclear whether specific genomic alterations of cancer cells are required to recruit podoplanin positive CAFs. The aim of this study was to investigate the relationship between the mutation status of lung adenocarcinoma cells and the presence of podoplanin positive CAFs. METHODS: Ninety-seven lung adenocarcinomas for which whole exome sequencing data were available were enrolled. First, we analyzed the clinicopathological features of the cases, and then, evaluated the relationship between genetic features of cancer cells (major driver mutations and the number of single nucleotide variants, SNVs) and the presence of podoplanin-positive CAFs. RESULTS: The presence of podoplanin-positive CAFs was associated with smoking history, solid predominant subtype, and lymph node metastasis. We could not find any significant correlations between major genetic mutations (EGFR, KRAS, TP53, MET, ERBB2, BRAF, and PIC3CA) in cancer cells and the presence of podoplanin-positive CAFs. However, cases with podoplanin-positive CAFs had a significantly higher number of SNVs in cancer cells than the podoplanin-negative CAFs cases (median 84 vs 37, respectively; p = 0.001). This was also detected in a non-smoker subgroup (p = 0.037). Multivariate analyses revealed that the number of SNVs in cancer cells was the only statistically significant independent predictor for the presence of podoplanin-positive CAFs (p = 0.044). CONCLUSIONS: In lung adenocarcinoma, the presence of podoplanin-positive CAFs was associated with higher numbers of SNVs in cancer cells, suggesting a relationship between accumulations of SNVs in cancer cells and the generation of a tumor-promoting microenvironment. PMID- 29511887 TI - Attention profiles in autism spectrum disorder and subtypes of attention deficit/hyperactivity disorder. AB - Attention problems are observed in attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most neuropsychological studies that compared both disorders focused on complex executive functions (EF), but missed to contrast basic attention functions, as well as ASD- and ADHD subtypes. The present study compared EF as well as basic attention functioning of children with the combined subtype (ADHD-C), the predominantly inattentive subtype (ADHD-I), and autism spectrum disorder without ADHD (ASD-) with typically developing controls (TD). Basic attention functions and EF profiles were analysed by testing the comprehensive attention function model of van Zomeren and Brouwer using profile analysis. Additionally, neurocognitive impairments in ASD- and ADHD were regressed on dimensional measures of attention- and hyperactive-impulsive symptoms across and within groups. ADHD-C revealed a strong impairment across measures of EF compared to ASD- and TD. The ADHD-C profile furthermore showed disorder specific impairments in interference control, whereas the ASD- profile showed a disorder specific impairment in basic attention component divided attention. Attention- and hyperactive-impulsive symptom severity did not predict neurocognitive impairments across- or within groups. Study findings thus support disorder and subtype specific attention/EF profiles, which refute the idea of a continuum of ADHD-I, ADHD-C, and ASD with increasing neurocognitive impairments. PMID- 29511889 TI - Kidney injury biomarkers 5 years after AKI due to pediatric cardiac surgery. AB - BACKGROUND: We previously reported that children undergoing cardiac surgery are at high risk for long-term chronic kidney disease (CKD) and hypertension, although postoperative acute kidney injury (AKI) is not a risk factor for worse long-term kidney outcomes. We report here our evaluation of renal injury biomarkers 5 years after cardiac surgery to determine whether they are associated with postoperative AKI or long-term CKD and hypertension. METHODS: Children aged 1 month to 18 years old undergoing cardiopulmonary bypass were recruited to this prospective cohort study. At 5 years after cardiac surgery, we measured urine interleukin-18, kidney injury molecule-1, monocyte chemoattractant protein-1, YKL 40, and neutrophil gelatinase-associated lipocalin (NGAL). Biomarker levels were compared between patients with AKI and those without. We also performed a cross sectional analysis of the association between these biomarkers with CKD and hypertension. RESULTS: Of the 305 subjects who survived hospitalization, four (1.3%) died after discharge, and 110 (36%) participated in the 5-year follow-up. Of these 110 patients, 49 (45%) had AKI. Patients with versus those without postoperative AKI did not have significantly different biomarker concentrations at 5 years after cardiac surgery. None of the biomarker concentrations were associated with CKD or hypertension at 5 years of follow-up, although CKD and hypertension were associated with a higher proportion of participants with abnormal NGAL levels. CONCLUSIONS: Postoperative pediatric AKI is not associated with urinary kidney injury biomarkers 5 years after surgery. This may represent a lack of chronic renal injury after AKI, imprecise estimation of the glomerular filtration rate, the need for longer follow-up to detect chronic renal damage, or that our studied biomarkers are inadequate for evaluating subclinical chronic renal injury. PMID- 29511890 TI - Urinary clusterin-a novel urinary biomarker associated with pediatric lupus renal histopathologic features and renal survival. AB - BACKGROUND: Lupus nephritis (LN) is a major risk factor for systemic lupus erythematous (SLE)-related morbidity and mortality. With the aim of bypassing renal biopsy, we analyzed urinary biomarkers for their ability to predict renal histopathologic features and end-stage kidney disease (ESKD). METHODS: Urinary albumin, beta2-microglobulin (B2M), cystatin C, kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), clusterin, calbindin, interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), trefoil factor 3 (TFF3), osteopontin, and glutathione S-transferase pi (GST-pi) levels were measured at time of renal biopsy. Renal histopathologies were carefully reviewed. RESULTS: Urine from 60 pediatric SLE cases with LN, 29 without and 22 healthy controls were collected. Median age at SLE diagnosis was 12.92 years (range = 4.27-17.30 years) and 10 cases progressed to ESKD during a period of 4.12 +/- 2.17 years. Urinary albumin and clusterin were significantly elevated (p = 0.035 and 0.048, respectively) in patients with tubulointerstitial renal lesions. Urinary clusterin among all urinary markers, performed best at predicting ESKD with cutoff of 0.61 * 10-4 (AUC = 0.804; p = 0.002). Interestingly, elevation of urinary clusterin likely resulted from local over-expression in tubulointerstitial tissue since the level of serum clusterin was not concomitantly higher (p = 0.424). CONCLUSION: Urinary biomarkers are emerging as non-invasive indicators for lupus-related renal histopathology and renal outcome prediction in pediatric SLE patients. Urinary clusterin, a newly identified biomarker, is an indicator that shows an association with tubulointerstitial renal lesions and demonstrates the best ability to predict ESKD. PMID- 29511891 TI - Diaphragmatic paralysis in obese patients in arthroscopic shoulder surgery: consequences and causes. AB - PURPOSE: Ambulatory process in arthroscopic shoulder surgery has boomed over past decades. Some anesthetic techniques such as interscalene block (ISB) and its surrogates are associated with diaphragmatic paralysis and might compromise outpatient procedure. HYPOTHESIS: This study aims to assess consequences of diaphragmatic paralysis in obese patients. METHODS: This prospective observational study screened patients with body mass index (BMI) >= 30 kg/m2 undergoing acromioplasty or supraspinatus tendon repair. Surgery was performed using brachial plexus block, and the method of brachial plexus block was left at the discretion of attending anesthesiologists. Post-operative hemidiaphragmatic paralysis was evaluated using M-mode ultrasonography and its consequences on patient ventilation were assessed: occurrence of hypoxic episode defined as oxygen saturation less than 90% (by pulse oximeter) in room air, dyspnea and failure of ambulatory procedure. Causes of diaphragmatic paralysis were also analyzed. RESULTS: Ninety-one patients were screened, 82 patients were included in this study and 37 patients (45%) presented diaphragmatic paralysis. Compared to patients without diaphragmatic paralysis, diaphragmatic paralysis was associated with dyspnea [10 (27%) versus 1 (2%); p = 0.0019], occurrence of patients presenting at least one hypoxic episode [6 (16%) versus 1 (2%); p = 0.02] and failure of ambulatory process [10 (27%) versus 1 (2%); p = 0.009]. The combination of axillary and suprascapular nerve blocks, but also low volume ISB, was found to be protective against diaphragmatic paralysis when compared to high volume ISB [Odds ratios 0.0019 (0.001-0.026) and 0.0482 (0.008-0.27), respectively; p < 0.001]. CONCLUSION: In patients with BMI >= 30 kg/m2 undergoing arthroscopic shoulder surgery, diaphragmatic paralysis is associated with dyspnea, occurrence of hypoxic episodes and failure of ambulatory procedure. High volume ISB and also, to a lesser extent, low volume ISB were found to be responsible for diaphragmatic paralysis. TRIAL REGISTRY NUMBER: Registration n degrees 2014-202. PMID- 29511893 TI - Higher step count is associated with greater bone mass and strength in women but not in men. AB - : In this cross-sectional study, peripheral bone traits were examined relative to total daily steps measured with pedometer. Higher number of steps was associated with greater bone values at the calcaneus and tibia in women, but not in men. In women, dose-dependent associations at the radius were congruent with the weight bearing bones. INTRODUCTION: Habitual physical activity measured as daily steps may contribute to bone density and strength at the calcaneus and other weight bearing bones. METHODS: Subgroups of 705-837 women and 480-615 men aged 31-46 years from the Cardiovascular Risk in Young Finns Study participated in the present study. Participants were instructed to use pedometer for 1 week, and the total daily steps, divided into tertiles, were evaluated relative to quantitative ultrasound-measured bone traits at the calcaneus and peripheral quantitative computed tomography-measured bone traits at the tibia and radius. Analysis of covariance was used to examine the between-group differences. RESULTS: In women, significant dose-dependent between-group differences were found in the weight bearing bones and in non-weight-bearing radius. The differences in broadband ultrasound attenuation and speed of sound at the calcaneus were 3.8 and 0.5% greater in women within the highest tertile of daily steps compared to the lowest tertile (p values for trend <= 0.04). In tibia, women in the highest tertile (> 8765 steps/day) had on average 1-5.4% greater bone cross-sectional area, bone mineral content (BMC), trabecular density, and bone strength index at the distal site and 1.6-2.7% greater bone areas, BMC and strength strain index (SSI) at the shaft compared to women with less daily steps (p values for trend <= 0.02). Similarly, in radius, BMC and BSI at the distal site, and bone cross-sectional areas, BMC and SSI at the shaft were 1.7-3.4% greater in women within the highest tertile of daily steps compared to their peers (p values for trend <= 0.04). In men, the differences in calcaneal, tibial, and radial bone traits were mainly non significant between the tertiles of daily steps. CONCLUSION: Observed significant positive associations between daily steps and various bone traits at the calcaneus, tibia, and radius in women suggest that habitual physical activity may benefit skeletal health in adulthood. PMID- 29511894 TI - Comparative Analysis of Polyethyleneimine Efficiency for Improvement of Plasmid DNA Bioavailability. AB - We studied the influence of the type and structure of polyethyleneimine on bioavailability and expression of plasmid DNA carrying IGF-1 gene. Polymers with different molecular weights (2.5, 10, 25, and 60 kDa) of linear and branching structure were studied. It was found that the time of polyplex circulation in the blood did not exceed 24 h and the maximum concentration of plasmid DNA was attained with complexes with a molecular weight of 60 kDa. Analysis of liver samples showed that administration of 60-kDa branched polyethyleneimine complex provides DNA protection from degradation for 4 h; in 24 h from the start of the experiment, its concentration was significantly higher than the concentration of other studied polyethyleneimines. The expression of plasmid IGF-1 DNA for this complex attained maximum in 4 h and was equal to 15.50 (7.98; 21.98) arb. units/ml. These results allow us to recommend using polyethyleneimines with branched structure and a molecular weight of 60 kDa for improving plasmid DNA protection and bioavailability. PMID- 29511897 TI - Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis). AB - PURPOSE: Hereditary transthyretin amyloidosis (hATTR amyloidosis) is a progressive disease primarily characterized by adult-onset sensory, motor, and autonomic neuropathy. In this article, we discuss the pathophysiology and principal findings of autonomic neuropathy in hATTR amyloidosis, the most common methods of assessment and progression, and its relation as a predictive risk factor or a measure of progression in the natural history of the disease. METHODS: A literature search was performed using the terms "autonomic neuropathy," "dysautonomia," and "autonomic symptoms" in patients with hereditary transthyretin amyloidosis and familial amyloid polyneuropathy. RESULTS: Various scales to measure autonomic function have been employed, particularly within the major clinical trials, to assess novel therapies for the disease. Most of the evaluations were taken from diabetic clinical trials. Questionnaires include the COMPASS-31 and Norfolk QOL autonomic nerve function domain, whereas clinical evaluations comprise HRDB and the orthostatic tolerance test. Several treatment options are being employed although only diflunisal and tafamidis have reported improvement in the autonomic abnormalities. CONCLUSIONS: Autonomic nerves are often affected before motor nerve impairment, and dysautonomia may support the diagnosis of hATTR amyloidosis when differentiating from other adult-onset progressive neuropathies and from other types of amyloidosis. Most of the progression of autonomic dysfunction is seen in early stages of the disease, commonly before motor impairment or affection of the overall quality of life. Unfortunately, there is no current single standardized approach to evaluate dysautonomia in hATTR amyloidosis. PMID- 29511895 TI - Loneliness Mediates the Relationship Between Pain During Intercourse and Depressive Symptoms Among Young Women. AB - Previous research suggests that women who experience pain during intercourse also experience higher rates of depressive symptoms. Loneliness might be one factor that contributes to this relationship. We hypothesized that women who experience more severe and interfering pain during intercourse would report higher rates of loneliness and higher rates of depressive symptoms. Further, we hypothesized that loneliness would mediate the relationship between pain during intercourse and depressive symptoms. A total of 104 female participants (85.6% white, 74.03% partnered, 20.9 [3.01] years old) completed an online survey including demographic information, PROMIS Vaginal Discomfort Measure, PROMIS Depression Measure, and Revised UCLA Loneliness Scale. Pearson correlations and bootstrapped mediation analysis examined the relationships among pain during intercourse, loneliness, and depressive symptoms. Pain during intercourse, loneliness, and depressive symptoms were all significantly correlated (p < .05). Results of the mediation analysis indicated that loneliness was a significant mediator of the relationship between pain during intercourse and depressive symptoms (indirect effect = 0.077; 95% CI 0.05-0.19). After accounting for loneliness, pain during intercourse was not significantly related to depressive symptoms, suggesting that loneliness fully mediated the relationship between pain during intercourse and depressive symptoms. These findings are consistent with previous studies highlighting that pain during intercourse is related to depressive symptoms. The current study adds to that literature and suggests that more frequent and severe pain during intercourse leads to more loneliness, which then leads to increased depressive symptoms. This line of work has important implications for treating women who experience depressive symptoms and pain during intercourse. PMID- 29511896 TI - Redefining biomarkers in heart failure. AB - Heart failure (HF) is the end result of many different cardiac and non-cardiac abnormalities leading to a complex clinical entity. In this view, the use of biomarkers in HF should be deeply reconsidered; indeed, the same biomarker may carry a different significance in patients with preserved or reduced EF. The aim of this review is to reconsider the role of biomarkers in HF, based on the different clinical characteristics of this syndrome. The role of cardiac and non cardiac biomarkers will be reviewed with respect of the different clinical manifestations of this syndrome. PMID- 29511898 TI - Relationship Between Abdominal Symptoms and Fructose Ingestion in Children with Chronic Abdominal Pain. AB - BACKGROUND: Limited valid data are available regarding the association of fructose-induced symptoms, fructose malabsorption, and clinical symptoms. AIM: To develop a questionnaire for valid symptom assessment before and during a carbohydrate breath test and to correlate symptoms with fructose breath test results in children/adolescents with functional abdominal pain. METHODS: A Likert type questionnaire assessing symptoms considered relevant for hydrogen breath test in children was developed and underwent initial validation. Fructose malabsorption was determined by increased breath hydrogen in 82 pediatric patients with functional abdominal pain disorders; fructose-induced symptoms were quantified by symptom score >=2 and relevant symptom increase over baseline. The results were correlated with clinical symptoms. The time course of symptoms during the breath test was assessed. RESULTS: The questionnaire exhibited good psychometric properties in a standardized assessment of the severity of carbohydrate-related symptoms. A total of 40 % (n = 33) had malabsorption; symptoms were induced in 38 % (n = 31), but only 46 % (n = 15) with malabsorption were symptomatic. There was no significant correlation between fructose malabsorption and fructose-induced symptoms. Clinical symptoms correlated with symptoms evoked during the breath test (p < 0.001, r2 = 0.21) but not with malabsorption (NS). Malabsorbers did not differ from non-malabsorbers in terms of symptoms during breath test. Symptomatic patients had significantly higher pain and flatulence scores over the 9-h observation period (p < 0.01) than did nonsymptomatic patients; the meteorism score was higher after 90 min. CONCLUSIONS: Fructose-induced symptoms but not fructose malabsorption are related to increased abdominal symptoms and have distinct timing patterns. PMID- 29511899 TI - Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes. METHODS: We conducted a nationwide epidemiological survey of clinically diagnosed aHUS patients and examined 118 patients enrolled from 1998 to 2016 in Japan. We screened variants of seven genes related to complement and coagulation, as well as positivity for anti-CFH antibodies, and assessed clinical manifestations, laboratory findings, and clinical course. RESULTS: The most frequent genetic abnormalities were in C3 (31%) and the frequency of CFH variants was relatively low (10%) compared to Western countries. The predominant variant in this cohort was C3 p.I1157T (23%), which was related to favorable outcomes despite frequent relapses. A total of 72% of patients received plasma therapy, while 42% were treated with eculizumab. The prognosis of Japanese aHUS patients was relatively favorable, with a total mortality rate of 5.4% and a renal mortality rate of 15%. CONCLUSIONS: The common occurrence of genotype C3, especially the p.I1157T variant was the characteristic of the genetic backgrounds of Japanese aHUS patients that differed from those of Caucasian patients. In addition, the favorable prognosis of patients with the unique C3 p.I1157T variant indicates that understanding the clinical characteristics of individual gene alterations is important for predicting prognosis and determining therapeutic strategies in aHUS. PMID- 29511900 TI - Routine Angiographic Follow-Up After Coronary Artery Disease Revascularization: Is Seeing Believing? AB - PURPOSE OF THE REVIEW: Coronary artery disease is a major cause of mortality and morbidity in the world, and PCI and CABG account for over a million procedures performed annually in the USA. The goal of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is to achieve complete revascularization (CR) if at all possible. However, restenosis and stent thrombosis (ST) remain the Achilles heel of contemporary PCI with restenosis rates between 10 and 30% with bare metal stents to 5-15% after drug-eluting stents and ST rates of around 0.8 vs 1.2%, respectively. Routine angiography after revascularization seems theoretically attractive as this may allow intervention before clinical events occur. In this manuscript, we review the literature regarding routine angiography after PCI or CABG and its outcomes. RECENT FINDINGS: According to the 2016 update from the American Heart Association (AHA), 15.5 million people above the age of 20 have coronary heart disease (CHD) in the USA. The prevalence of CHD is now almost similar in both men and women, and one American suffers from a myocardial infarction (MI) every 42 s. Recent data from randomized clinical trials and observational studies does not support the use of routine coronary angiography after revascularization in asymptomatic patients. There are some studies which show that routine angiography may have a role in left main or complex coronary interventions; however, these findings are exploratory and were not seen in randomized trials. After reviewing the data on routine angiography after coronary revascularization, we came to the conclusion that current data does not support the use of routine angiography for asymptomatic patients. However, there is a lack of randomized controlled trial in this field with only one recent trial reporting negative outcomes. PMID- 29511901 TI - Tie one on: 'nest tying' by wild chimpanzees at Bulindi-a variant of a universal great ape behavior? AB - With data accumulating from a growing pool of chimpanzee field studies, new behaviors as well as novel variants on common behaviors continue to be described. Nest construction is a universal behavior in wild great apes. Among chimpanzee populations, reported variation in nest building behavior mostly reflects environmental constraints. Despite the ubiquity of nest making by chimpanzees, only ground nesting has been recognized as a behavioral variant, potentially determined by both environmental and social factors. In a study of nests made by chimpanzees (Pan troglodytes schweinfurthii) in Bulindi, Uganda, I identified a hitherto undescribed nest construction technique, termed 'nest tying'. Five observed nests lacked strong weight-bearing structures beneath them, such as large branches or a supporting trunk. Instead, the nests appeared 'tied' (or 'tethered') to an adjacent trunk by looping leafy stems or palm fronds around it and interweaving these into the nest mattress, securing the nest against the trunk; thus, nest tying presumably functions to provide added stability and support. This preliminary report presents a description of the observed nests. Irrespective of whether nest tying constitutes true knot making-commonly considered absent in wild great apes-this nest construction technique would seem to require advanced dexterity and a sophisticated understanding of the mechanical properties of the plants used. Forest fragments in Bulindi are highly degraded. Thus, nest tying-and construction of integrated nests (i.e., utilizing multiple plants, often small trees and shrubs) generally-may be promoted by a relative paucity of suitable nesting trees at this site. Still, insofar as nest building is learned in chimpanzees, different construction techniques including nest tying are potentially acquired through social learning. Further investigation is required to ascertain the prevalence and acquisition of this nest construction technique at Bulindi, and to verify its presence or absence in other habitats. PMID- 29511902 TI - Incidence and Management of Immune-Related Adverse Events in Patients Undergoing Treatment with Immune Checkpoint Inhibitors. AB - PURPOSE OF REVIEW: The unleashing of the immune system in an effort to fight cancer has proven to be an incredible advance in the war on cancer. However that breakthrough has come with a price in the form of serious and potentially fatal immune-related adverse events (irAEs). RECENT FINDINGS: Rapid recognition and early intervention is imperative to avoid significant morbidity and mortality. Additionally, providers need to be aware that there are still new, rare, and long term emerging irAEs that were not previously reported in clinical trials. Because of the significant difference between irAEs and those caused by chemotherapy and/or targeted therapy, providers must have a thorough understanding of which events would be considered immune related and require treatment. This review will cover descriptions of the most common and uncommon but serious irAEs experienced by patients on immunotherapy, as well as management of these irAEs. PMID- 29511903 TI - How Temperature, Pond-Drying, and Nutrients Influence Parasite Infection and Pathology. AB - The rapid pace of environmental change is driving multi-faceted shifts in abiotic factors that influence parasite transmission. However, cumulative effects of these factors on wildlife diseases remain poorly understood. Here we used an information-theoretic approach to compare the relative influence of abiotic factors (temperature, diurnal temperature range, nutrients and pond-drying), on infection of snail and amphibian hosts by two trematode parasites (Ribeiroia ondatrae and Echinostoma spp.). A temperature shift from 20 to 25 degrees C was associated with an increase in infected snail prevalence of 10-20%, while overall snail densities declined by a factor of 6. Trematode infection abundance in frogs was best predicted by infected snail density, while Ribeiroia infection specifically also declined by half for each 10% reduction in pond perimeter, despite no effect of perimeter on the per snail release rate of cercariae. Both nutrient concentrations and Ribeiroia infection positively predicted amphibian deformities, potentially owing to reduced host tolerance or increased parasite virulence in more productive environments. For both parasites, temperature, pond drying, and nutrients were influential at different points in the transmission cycle, highlighting the importance of detailed seasonal field studies that capture the importance of multiple drivers of infection dynamics and the mechanisms through which they operate. PMID- 29511904 TI - Performance and economy of production of broilers fed Siam weed (Chromolaena odorata) leaf meal (SWLM). AB - A 49-day feeding trial was conducted to determine the effect of Siam weed leaf meal (SWLM)-based diets on growth, organ, and carcass weight characteristics and economics of production of broilers. Proximate biochemical composition of SWLM and the appropriate inclusion level of SWLM for optimum productivity were also determined. Ninety-six-day-old Chi broiler chicks were randomly divided into 4 groups of 24 birds, and each group replicated three times. Each group was assigned to one experimental diet in a completely randomized design marked T1 (0%), T2 (4%), T3 (8%), and T4 (12%). Proximate biochemical results revealed that SWLM is rich in protein (20.52%) and minerals (9.29%). Birds on diets T1 and T2 had similar (p > 0.05) final live weights (FLW), which were higher (p < 0.05) than those on diets T3 and T4. Birds on diet T2 had the highest (p < 0.05) daily feed intake (DFI) and daily weight gain (DWG), while birds on diet T1 had the best feed conversion ratio (FCR) followed by birds on diet T2. The result of quadratic model regression analyses showed that SWLM levels of 1.48, 1.50, 1.47, and 1.56% supported optimum final live weight, DFI, DWG, and FCR. There were no significant (p > 0.05) differences in the dressing percentage, but there were significant differences in the carcass weight between birds on diet T4 and the other three diets. Similarly, pancreas and spleen had similar (p > 0.05) weights across the treatments. There was significant difference (p < 0.05) between birds on diets T1 and T4 in gizzard weight. Cost-benefit ratio was influenced (p < 0.05) with T4 birds having better income of US$1 per US$10.18 invested. It is concluded that SWLM is rich in essential nutrients and therefore suitable for inclusion in broiler diets at level not beyond 2% for best final live weight, daily weight gain, and thigh weight. PMID- 29511905 TI - The value of metastasectomy in stage IV cutaneous melanoma. AB - Cutaneous melanoma is an aggressive neoplasia of melanocytes. Prognosis is dependent on tumor stage. Stage IV melanoma is characterized by the occurrence of distant metastases. Response of metastases to classical chemotherapy is limited and toxicity of treatment is high. In recent years, new developments in immunotherapy and targeted therapies improved prognosis of stage IV melanoma patients with better tolerability of treatment. There is no dispute about surgical treatment of primary melanoma. But what is the value of metastasectomy in the era of new systemic treatments? This review aims to discuss available data for surgical removal of distant metastases for several organs and tissues. The available evidence suggests that for selected patients with possible complete resection of all tumor metastases, metastasectomy remains an effective treatment option with a benefit in overall survival. PMID- 29511906 TI - Survivorship care plans have a negative impact on long-term quality of life and anxiety through more threatening illness perceptions in gynecological cancer patients: the ROGY care trial. AB - PURPOSE: Prior results from the registration system oncological gynecology (ROGY) care trial showed that survivorship care plans (SCPs) increased threatening illness perceptions in gynecological cancer survivors, but it remained unclear whether this would result in poorer physical and psychosocial outcomes. The aim of the current study is to assess the direct and indirect effects of SCPs on health-related quality of life (HRQoL) and anxiety and depression, through illness perceptions. METHODS: Twelve hospitals in the South of the Netherlands were randomized to providing 'SCP care' or 'usual care.' Newly diagnosed endometrial and ovarian cancer patients completed questionnaires after initial treatment (endometrial, 221 [75%]; ovarian, 174 [71%]) and after 6, 12, and 24 months. SCPs were automatically generated after initial treatment by the oncology providers through the web-based ROGY. Illness perceptions were measured after initial treatment and HRQoL and anxiety and depression after 6, 12, and 24 months. RESULTS: Structural equation models showed that endometrial cancer patients who experienced more symptoms or concern due to the SCP reported worse social functioning (beta = - 0.82; p = 0.01) and more fatigue, insomnia, pain, and anxiety (beta = 0.58-0.86, p < 0.05) within 12 months after treatment. Ovarian cancer patients who had lower trust that the treatment would cure their disease due to the SCP reported worse emotional functioning 6 months after treatment (beta = 0.27, p = 0.02). CONCLUSIONS: Current results show that SCPs may have negative effects on HRQoL and anxiety in patients who experience more threatening illness perceptions due to the SCP. We should be aware of the potential negative consequences of SCPs. Trial Registration clinicaltrials.gov Identifier: NCT01185626. PMID- 29511907 TI - Cardiovascular Risk in Patients with Prehypertension and the Metabolic Syndrome. AB - Prehypertension (pHTN) and metabolic syndrome (MetS) are both lifestyle diseases that are potentiated by increased adiposity, as both disease processes are closely related to weight. In the case of pHTN, increased adiposity causes dysregulation of the renin-angiotensin-aldosterone-system (RAAS) as well as adipokine- and leptin-associated increases in adrenergic tone. In MetS, excess weight potentiates hyperglycemia and insulin resistance which causes positive feedback into the RAAS system, activates an inflammatory cascade that potentiates atherosclerosis, and causes lipid dysregulation which together contribute to cardiovascular disease, especially coronary heart disease (CHD) and heart failure (HF). The relationship with all-cause mortality is not as clear-cut in part because of some protective effects associated with the obesity paradox in chronic diseases such as CHD and HF. However, in healthy populations, the absence of excess weight and its associated effects on prehypertension and MetS are associated with a longer absolute and disease-free lifespan. PMID- 29511908 TI - QTL mapping and candidate gene analysis of peduncle vascular bundle related traits in rice by genome-wide association study. AB - BACKGROUND: The vascular bundle especially in the peduncle is one of crucial limiting factors of rice yield, and it determines how plants efficiently transport photosynthetic products, mineral nutrients and water from leaf and root to panicle. However, the genetic base of rice vascular bundle related traits in the peduncle still remains unknown. RESULTS: The 423 panel showed substantial natural variations of peduncle vascular bundle. In total, 48 quantitative trait loci/locus (QTL) affecting the eight traits were identified throughout the genome by applying a significance threshold of P < 1.0 * 10- 4. Combined determining linkage disequilibrium (LD) blocks associated with significant SNPs and haplotype analyses allowed us to shortlist six candidate genes for four important QTL regions affecting the peduncle vascular bundle traits, including one cloned gene (NAL1) and three newly identified QTL (qLVN6, qSVN7, and qSVA8.1). Further the most likely candidate genes for each important QTL were also discussed based on functional annotation. CONCLUSIONS: Genetic base on peduncle vascular bundle related traits in rice was systematically dissected, and most likely candidate genes of the known gene NAL1 and the three newly identified QTL (qLVN6, qSVN7, and qSVA8.1) were analyzed. The results provided valuable information for future functional characterization and rice breeding for high yield through optimizing transportation efficiency of photosynthetic products by marker-assisted selection. PMID- 29511911 TI - Electric Field Tuning Non-volatile Magnetism in Half-Metallic Alloys Co2FeAl/Pb(Mg1/3Nb2/3)O3-PbTiO3 Heterostructure. AB - We reported the non-volatile electric field-mediated magnetic properties in the half-metallic Heusler alloy Co2FeAl/Pb(Mg1/3Nb2/3)O3-PbTiO3 heterostructure at room temperature. The remanent magnetization with different applied electric field along [100] and [01-1] directions was achieved, which showed the non volatile remanent magnetization driven by an electric field. The two giant reversible and stable remanent magnetization states were obtained by applying pulsed electric field. This can be attributed to the piezostrain effect originating from the piezoelectric substrate, which can be used for magnetoelectric-based memory devices. PMID- 29511910 TI - Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3). AB - High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin + etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter- and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n = 236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n = 170), short infusion (<= 5 h, n = 33) or oral etoposide (n = 33) according to hospital tradition. PFS and OS were analyzed with Kaplan Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP NEN, G3 patients scheduled for cisplatin/carboplatin + etoposide therapy. PMID- 29511909 TI - Resistance Trends and Treatment Options in Gram-Negative Ventilator-Associated Pneumonia. AB - PURPOSE OF REVIEW: Hospital-acquired and ventilator-associated pneumonia (VAP) are frequent causes of infection among critically ill patients. VAP is the most common hospital-acquired bacterial infection among mechanically ventilated patients. Unfortunately, many of the nosocomial Gram-negative bacteria that cause VAP are increasingly difficult to treat. Additionally, the evolution and dissemination of multi- and pan-drug resistant strains leave clinicians with few treatment options. VAP patients represent a dynamic population at risk for antibiotic failure and under-dosing due to altered antibiotic pharmacokinetic parameters. Since few antibiotic agents have been approved within the last 15 years, and no new agents specifically targeting VAP have been approved to date, it is anticipated that this problem will worsen. Given the public health crisis posed by resistant Gram-negative bacteria, it is essential to establish a firm understanding of the current epidemiology of VAP, the changing trends in Gram negative resistance in VAP, and the current issues in drug development for Gram negative bacteria that cause VAP. RECENT FINDINGS: Rapid identification technologies and phenotypic methods, new therapeutic strategies, and novel treatment paradigms have evolved in an attempt to improve treatment outcomes for VAP; however, clinical data supporting alternative treatment strategies and adjunctive therapies remain sparse. Importantly, new classes of antimicrobials, novel virulence factor inhibitors, and beta-lactam/beta-lactamase inhibitor combinations are currently in development. Conscientious stewardship of new and emerging therapeutic agents will be needed to ensure they remain effective well into the future. PMID- 29511912 TI - Single-institution experience with selective internal radiation therapy (SIRT) for the treatment of unresectable colorectal liver metastases. AB - BACKGROUND: Liver metastases are the commonest cause of death for patients with colorectal cancer. Growing evidence supports the use of selective internal radiation therapy (SIRT) in combination with conventional chemotherapy regimens for liver-only or liver-dominant unresectable metastatic colorectal cancer. AIMS: To measure and evaluate outcomes of the first 20 consecutive patients with unresectable colorectal liver metastasis selected for SIRT in addition to their chemotherapy at a single Irish institution. METHODS: Retrospective case series was performed. Patient charts and medical records were reviewed. RESULTS: All 20 patients (100%) selected for angiographic workup were subsequently successfully treated with radioembolization. All patients were discharged 1 day post-SIRT. At initial imaging evaluation, 12 (60%) had a partial response in their liver, 2 (10%) had stable disease, and 6 (30%) had liver-specific progressive disease. Median follow up was 10 months (range 6-26). At last follow up, 14 (70%) patients were alive and 6 (30%) deceased. Most recent imaging demonstrated 2 (10%) with a complete response, 7 (35%) had a partial response, 2 (10%) had stable disease, and 9 (45%) had progressive disease within their liver. One patient was downstaged to hepatic resection, and one with a complete hepatic response had his primary sigmoid tumor resected 11 months post-SIRT. CONCLUSIONS: SIRT is a safe and effective therapy for certain patients with unresectable colorectal liver metastases. This case series supports our opinion that selected patients should be offered SIRT in concert with their medical oncologist, concomitant with their chemotherapy. Larger multi-center studies are required to more clearly define the patient groups that will derive most benefit from SIRT. PMID- 29511914 TI - Revealing proteins associated with symbiotic germination of Gastrodia elata by proteomic analysis. AB - BACKGROUND: Gastrodia elata, a mycoheterotrophic orchid, is a well-known medicinal herb. In nature, the seed germination of G. elata requires proper fungal association, because of the absence of endosperm. To germinate successfully, G. elata obtains nutrition from mycorrhizal fungi such as Mycena. However, Mycena is not able to supply nutrition for the further development and enlargement of protocorms into tubers, flowering and fruit setting of G. elata. To date, current genomic studies on this topic are limited. Here we used the proteomic approach to explore changes in G. elata at different stages of symbiotic germination. RESULTS: Using mass spectrometry, 3787 unique proteins were identified, of which 599 were classified as differentially accumulated proteins. Most of these differentially accumulated proteins were putatively involved in energy metabolism, plant defense, molecular signaling, and secondary metabolism. Among them, the defense genes (e.g., pathogenesis-/wound-related proteins, peroxidases, and serine/threonine-protein kinase) were highly expressed in late-stage protocorms, suggesting that fungal colonization triggered the significant defense responses of G. elata. CONCLUSIONS: The present study indicated the metabolic change and defensive reaction could disrupt the balance between Mycena and G. elata during mycorrhizal symbiotic germination. PMID- 29511913 TI - HIF1alpha deletion facilitates adipose stem cells to repair renal fibrosis in diabetic mice. AB - Adipose stem cell (ASC) transplantation is a promising therapeutic strategy for diabetic renal fibrosis. Hypoxia-inducible factor 1alpha (HIF1alpha) is a negative regulatory factor of mitochondrial function. In the current study, we aimed to explore if HIF1alpha deletion protects against hyperglycemia-induced ASC damage and enhances the therapeutic efficiency of ASCs in diabetic renal fibrosis. Our data indicated that HIF1alpha was upregulated in ASCs in response to high glucose stimulation. Higher HIF1alpha expression was associated with ASC apoptosis and proliferation arrest. Loss of HIF1alpha activated mitophagy protecting ASCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting HIF1alpha-deleted ASCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c, and inflammatory markers. In addition, the engraftment of HIF1alpha-modified ASCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that HIF1alpha-modified ASCs reduced renal fibrosis. Collectively, our results demonstrate that ASCs may be a promising therapeutic treatment for ameliorating diabetes and the development of renal fibrosis and that the loss of HIF1alpha in ASCs may further increase the efficiency of stem cell-based therapy. These findings provide a new understanding about the protective effects of HIF1alpha silencing on ASCs and offer a new strategy for promoting the therapeutic efficacy of ASCs in diabetic renal fibrosis. PMID- 29511915 TI - Developing an Iranian ELT Context-Specific Grit Instrument. AB - Grit as an interesting and significant topic in psychology has been associated with better study habits and higher grades through perseverance and passion for long term goals. The only available measurement instrument of grit (Duckworth et al. in J Personal Soc Psychol 92:1087-1101, 2007) is general both in terms of its subject matter and context. Thus, this study aims to develop and validate an English as a foreign language (EFL) grit instrument whose items are specific to EFL context to obtain a more detailed view of its components for Iranian EFL learners, and to tap on other grit related factors in the EFL context. A four component model of EFL grit was developed through reviewing the existing literature and exploring EFL experts' perspectives. This tentative theoretical model of EFL grit encompasses overarching construct of effort including the following main components: Trying hard to learn English (THLE) having interest in learning English (ILE) practicing a lot in order to learn English (PLE) and having goal for learning English (HGLE). The model was then cross checked against the results of the interviews, and evolved into a scenario-based, 5 point Likert scale EFL grit instrument. It was later operationalized by an instrument consisting of 26 items, i.e. 6 items for each component plus 2 items for themes 1 and 3. The piloting and testing of the tentative model through exploratory and confirmatory data analyses on a sample of 306 EFL learners indicated the reliability of 0.833 and an acceptable validity. The findings called for a more meaningful interpretation of the concept of grit in relation to Iranian EFL context and offered new insights for higher education administrators considering student academic performance. PMID- 29511916 TI - Implementation and Evaluation of a Recurring Interdisciplinary Community Health Fair in a Remote U.S.-Mexico Border Community. AB - The purpose of this project was to design, implement, and assess a recurring interdisciplinary community health fair in an underserved border town. University of California San Diego (UCSD) medical and pharmacy students, under faculty supervision, worked alongside community partners in Calexico, California to implement a health fair two miles from the U.S.-Mexico border. Demographic and screening data were described from 293 participants from 2014 to 2016. Over 90% (269/293) listed Mexico as their country of birth, 82.9% (243/293) were monolingual Spanish speakers, 75.4% (221/293) had an annual household income of <= $20,000, and 58.7% (172/293) described their health as fair or poor. Screening revealed 91.1% (265/291) were overweight or obese, 37.8% (109/288) had hypertension, 9.3% (27/289) had elevated blood sugar, and 11.4% (33/289) had elevated total cholesterol levels. This model could be replicated in other training settings to increase exposure to border health issues and connect patients to local health services. PMID- 29511917 TI - The role of mitochondria in cellular toxicity as a potential drug target. AB - Mitochondrial malfunction is related to aging and to the onset of many diseases, such as obesity/diabetes, cancer, and cardiovascular and neurodegenerative diseases. The molecular principles of biological and toxicological processes the mitochondria can regulate should be disease-specific, cell type-specific, and drug targetable. Mitochondrial biology and toxicology is evolving and undergoing a revolution through fast-developing biotechnologies garnering increasing attention due to the importance of targeted therapies. Mitochondrial energy production and metabolism are conducted via post-mitochondrial signaling, and are controlled by extra-mitochondrial pathways. Mitochondrial biology and toxicology has a history spanning over 30 years and is one of the main scientific focuses at Cell Biology and Toxicology. It is our aim to pioneer innovations of mitochondrial biology and toxicology to improve the understanding, highlight the latest development, and find mitochondria-based targets for therapies. It is expected to know how drugs can initiate mitochondrial dysfunction, the role of nuclear messages in regulating mitochondrial DNA (MtDNA), and how mitochondria communicate between or with other cells. Further studies are crucial to discover how mitochondria control the process of immune response, autophagy/mitophagy, genome activation, and cell interaction. It is also needed to innovate how the transcription is started and terminated within mitochondria, the cytosolic proteins and other organelles interact with mitochondria, and MtDNA regulates the function of mitochondrial respiratory megacomplexes. PMID- 29511919 TI - Cardiorespiratory and perceptual responses to self-regulated and imposed submaximal arm-leg ergometry. AB - PURPOSE: This study compared cardiorespiratory and perceptual responses to exercise using self-regulated and imposed power outputs distributed between the arms and legs. METHODS: Ten males (age 21.7 +/- 3.4 years) initially undertook incremental arm-crank ergometry (ACE) and cycle ergometry (CYC) tests to volitional exhaustion to determine peak power output (Wpeak). Two subsequent tests involved 20-min combined arm-leg ergometry (ALE) trials, using imposed and self-regulated protocols, both of which aimed to elicit an exercising heart rate of 160 beats min-1. During the imposed trial, arm and leg intensity were set at 40% of each ergometer-specific Wpeak. During the self-regulated trial, participants were asked to self-regulate cadence and resistance to achieve the target heart rate. Heart rate (HR), oxygen uptake ([Formula: see text]), pulmonary ventilation ([Formula: see text]), and ratings of perceived exertion (RPE) were recorded continuously. RESULTS: As expected, there were no differences between imposed and self-regulated trials for HR, [Formula: see text], and [Formula: see text] (all P >= 0.05). However, central RPE and local RPE for the arms were lower during self-regulated compared imposed trials (P <= 0.05). Lower RPE during the self-regulated trial was related to preferential adjustments in how the arms (33 +/- 5% Wpeak) and legs (46 +/- 5% Wpeak) contributed to the exercise intensity. CONCLUSIONS: This study demonstrates that despite similar metabolic and cardiovascular strain elicited by imposed and self-regulated ALE, the latter was perceived to be less strenuous, which is related to participants doing more work with the legs and less work with the arms to achieve the target intensity. PMID- 29511922 TI - Education Moderates the Relationship Between Spirituality with Quality of Life and Stress Among Malay Muslim Women with Breast Cancer. AB - The purpose of this study was to investigate the relationship between spirituality with quality of life and stress of Malay Muslim breast cancer patients in Malaysia. In addition, the moderating role of education on this relationship was examined. Participants consisted of 145 conveniently selected Malay breast cancer patients. The results indicated that the more spiritual respondents reported a higher level of quality of life and lower level of stress. Moreover, education weakened the relationship between spirituality with quality of life and stress. PMID- 29511920 TI - The acute effect of Quercetin on muscle performance following a single resistance training session. AB - PURPOSE: To examine the effect of acute quercetin (Q) ingestion on neuromuscular function, biomarkers of muscle damage, and rate of perceived exertion (RPE) in response to an acute bout of resistance training. METHODS: 10 young men (22.1 +/- 1.8 years, 24.1 +/- 3.1 BMI) participated in a randomized, double-blind, crossover study. Subjects consumed Q (1 g/day) or placebo (PLA) 3 h prior to a resistance training session which consisted of 3 sets of 8 repetitions at 80% of the one repetition maximum (1RM) completed bilaterally for eight different resistance exercises. Electromyographic (EMG) signals were recorded from the knee extensor muscles during maximal isometric (MVIC) and isokinetic voluntary contractions, and during an isometric fatiguing test. Mechanical and EMG signals, biomarkers of cell damage, and RPE score were measured PRE, immediately POST, and 24 h (blood indices only) following the resistance exercise. RESULTS: After a single dose of Q, the torque-velocity curve of knee extensors was enhanced and after the resistance exercise, subjects showed a lower MVIC reduction (Q: 0.91 +/ 6.10%, PLA: 8.66 +/- 5.08%) with a greater rate of torque development (+ 10.6%, p < 0.005) and neuromuscular efficiency ratio (+ 28.2%, p < 0.005). Total volume of the resistance exercises was significantly greater in Q (1691.10 +/- 376.71 kg rep) compared to PLA (1663.65 +/- 378.85 kg rep) (p < 0.05) with a comparable RPE score. No significant differences were found in blood marker between treatments. CONCLUSIONS: The acute ingestion of Q may enhance the neuromuscular performance during and after a resistance training session. PMID- 29511923 TI - What Can Be Learned from Health-Related Tensions and Disparities in Ultra Orthodox Jewish Families? AB - Promoting healthy lifestyle from early childhood is a key objective in public health, yet health behaviors are often culturally driven, especially in closed religious communities. This study aims to reveal key cultural-religious aspects of attitudes and behaviors regarding lifestyle in one such closed community-the ultra-orthodox Jewish community. In-depth interviews were conducted with 20 participants: religious leaders, educational figures, psycho-medical professionals from two major ultra-orthodox communities in Israel. A thematic analysis was used to reveal key themes in the interviews. We found tensions between conflicting themes in the parenting, nutrition and physical activity domains, while the sleep domain illustrated cultural solution for a tension. By illuminating the perceptional components of lifestyle, the study contributes to better foundations of health promotion in closed-religious communities. PMID- 29511921 TI - Increased rate of force development during periodized maximum strength and power training is highly individual. AB - Maximum strength training induces various improvements in the rate of force development (RFD) on a group level, but no study has investigated inter individual adaptations in RFD. Fourteen men (28 +/- 6 years old) performed the same 10-week maximum strength and then a 10-week power training program. Maximal force and RFD were recorded during maximal isometric leg extension voluntary contractions repeatedly before every 7th training session (2 sessions/week). After the intervention, subjects were retrospectively divided into three groups based on their RFD improvements: (1) improved only during the maximum strength period (MS-responders, + 100 +/- 35%), (2) improved only during the power period (P-responders, + 53 +/- 27%) or (3) no improvement at all (non-responders, + 3 +/ 9%). All groups increased dynamic 1RM equally, but baseline 1RM was greater (p < 0.05) in responder vs non-responder groups. MS-responders had higher electrical stimulation-induced torque at baseline and they improved (+ 35 +/- 28%) power production at 50% 1RM load more than P- (- 7 +/- 20%, p = 0.052) and non responders (+ 3 +/- 6%, p = 0.066) during the maximum strength training period. MS-responders increased vastus lateralis cross-sectional area (+ 12 +/- 9%, p < 0.01) as did P-responders (+ 10 +/- 7%, p = 0.07), whereas non-responders were unchanged. Free androgen index (FAI) in responders was higher (+ 34%, p < 0.05) compared to non-responders at baseline. The maximum strength period decreased testosterone (- 17 +/- 12; 17 +/- 22%), FAI ratio (- 12 +/- 14; - 21 +/- 23%) and testosterone/cortisol ratio (- 17 +/- 25; - 31 +/- 20%) in MS and P-responders, respectively. During the P-period hormonal levels plateaued. To conclude, periodized strength training induced different inter-individual physiological responses, and thus RFD development may vary between individuals. Therefore, RFD seems to be a useful tool for planning and monitoring strength training programs for individual neuromuscular performance needs. PMID- 29511924 TI - Citation classics in pediatrics: a bibliometric analysis. AB - BACKGROUND: Citation analysis provides insights into the history and developmental trajectory of scientific fields. Our objective was to perform an analysis of citation classics in the journals of pediatric specialty and to examine their characteristics. METHODS: Initially, all the journals listed under the category of pediatrics (n = 120) were identified using Journal Citation Reports. Web of science database was then searched (1950-2016) to select the top 100 cited articles in the above identified pediatric journals. The top-100 cited article were categorized according the study design, sub-specialty, country, institutional affiliation, and language. RESULTS: The top-100 articles were published in 18 different journals, with Pediatrics having the highest numbers (n = 40), followed by The Journal of Pediatrics (n = 17). The majority (n = 62) of classics were published after 1990. The most cited article had citation count of 3516 and the least cited had a citation count of 593. The USA (n = 71) was the most commonly represented country, and 60 institutions contributed to 100 articles. Fifteen authors contributed to more than one classic as first or second author. Observational study (n = 55) was the commonest study design across all decades, followed by reviews (n = 12), scale development studies (n = 11), and guidelines (n = 11). Among the pediatric sub-specialties, growth and development articles were highly cited (n = 24), followed by pediatric psychiatry and behavior (n = 21), endocrinology (n = 15), and neonatology (n = 12). CONCLUSIONS: The top-100 cited articles in pediatrics identify the impactful authors, journals, institutes, and countries. Observational study design was predominant implying that inclusion among citation classics is not related to soundness of study design. PMID- 29511926 TI - Editor-in-Chief Round-up: JNC's top performers of 2017, JNC/ASNC Podcast, Manuscript Transfer Service and our new section 'Basic and Translational Preclinical Studies'. PMID- 29511927 TI - Computed tomography continues to be the preferred tomographic imaging technology for patients with cardiac implantable electronic devices despite a potential risk of electrical interference by irradiation. PMID- 29511925 TI - Hematopoietic stem cell transplantation for children with beta-thalassemia major: multicenter experience in China. AB - BACKGROUND: beta-Thalassemia major (beta-TM) has become a public health problem in mainland China. Hematopoietic stem cell transplantation (HSCT) has remained the only cure for beta-TM in mainland China since 1998. METHODS: This multicenter retrospective study provides a comprehensive review of the outcomes of 50 pediatric patients with beta-TM who received HSCT between 1998 and 2009 at five centers in mainland China. Both related (n = 35) and unrelated donors (n = 15) with complete human leukocyte antigen matches were included. The stem cell sources included bone marrow (BM), peripheral blood stem cells, umbilical cord blood (UCB) and a combination of BM and UCB or a combination of BM and peripheral blood stem cells from a single sibling donor. RESULTS: The probabilities of 5 year overall survival (OS) and thalassemia-free survival (TFS) after the first HSCT were 83.1 and 67.3%, respectively. Graft failure (GF) occurred in 17 patients. Univariate analyses showed that umbilical cord blood transplantation (UCBT) was one of the potential risk factors for decreased OS (P = 0.051), and that UCBT (P = 0.002) was potentially related to TFS. GF incidence was distinct between the UCBT and non-UCBT groups (P = 0.004). Four cases of UCB-BM combined transplantation led to decreased risks of mortality and recurrence. In the UCBT group, related donor transplantation produced more favorable results than unrelated donor transplantation in OS (P = 0.009) but not in TFS (P = 0.217). CONCLUSIONS: GF was the primary cause of UCBT failure. Though UCBT from related donors was not favorable, the combined transplantation of UCB and BM could improve the prognosis of UCBT. PMID- 29511928 TI - Do we need diagnostic strategies enhanced with genetic information for ischemic heart disease? PMID- 29511929 TI - The never-ending story of cardiac biomarkers: A further step toward a very early detection of ischemic patients? PMID- 29511930 TI - Dual isotope stress Tl-201 and rest Tc-99m CZT SPECT: Are we truly leveraging CZT technology? PMID- 29511931 TI - Muscle-strengthening and aerobic activities and mortality among 3+ year cancer survivors in the U.S. AB - PURPOSE: This study examined the association between adherence to American College of Sports Medicine and American Cancer Society guidelines on aerobic and muscle-strengthening activities and mortality risks among 3+ year cancer survivors in the U.S. METHODS: The observational study was based on 1999-2009 National Health Interview Survey Linked Mortality Files with follow-up through 2011. After applying exclusion criteria, there were 13,997 observations. The hazard ratios (HRs) for meeting recommendations on muscle-strengthening activities only, on aerobic activities only, and on both types of physical activity (i.e., adhering to complete guidelines) were calculated using a reference group of cancer survivors engaging in neither. Unadjusted and adjusted HRs of all-cause, cancer-specific, and cardiovascular disease-specific mortalities were estimated using Cox proportional hazards models. RESULTS: In all models, compared to the reference group, cancer survivors adhering to complete guidelines had significantly decreased all-cause, cancer-specific, and cardiovascular disease-specific mortalities (HRs ranged from 0.37 to 0.64, p's < 0.05). There were no statistically significant differences between hazard rates of cancer survivors engaging in recommended levels of muscle-strengthening activities only and the reference group (HRs ranged from 0.76 to 0.94, p's > 0.05). Wald test statistics suggested a significant dose-response relationship between levels of adherence to complete guidelines and cancer-specific mortality. CONCLUSIONS: While muscle-strengthening activities by themselves do not appear to reduce mortality risks, such activities may provide added cancer-specific survival benefits to 3+ year cancer survivors who are already aerobically active. PMID- 29511932 TI - Neonatal lethality and recycling defect of transferrin receptor in mice with Syntaxin12/13 disruption. PMID- 29511933 TI - UQCRFS1N assembles mitochondrial respiratory complex-III into an asymmetric 21 subunit dimer. PMID- 29511934 TI - The scalographic pattern of Morlet continuous wavelet transform can differentiate bileaflet valve function. AB - The authors have discussed the significance of the Morlet continuous wavelet transform of bileaflet mechanical heart valve (BLMHV) sound for detecting its malfunction: consecutive single patterns on the scalogram alway suggested its malfunction, whereas the tandem pattern with two steepled figures was demonstrated in both normal and malfunctioning valves. Therefore, authors have tried to distinguish this pattern between them by manually calculated multiple scalographic parameters. Although only the sum of wavelet coefficients (SWC) is supposed to be closer to valve sound property than other parameters, its calculation was not available in the original wavelet application. Therefore, the application was customized in the current study to semi-automatically calculate the SWC ratio between two figures for classifying the scalographic pattern of malfunctioning valves, and its efficacy to distinguish valve function was compared to other parameters. Among 155 BLMHVs, 6 valves with consecutive single patterns (type-I) and other 6 with two similar needle-like narrow figures (type II) were confirmed to be a malfunction by fluoroscopic examination, whereas 14 malfunctioning valves with the tandem pattern which showed a great difference between two figure sizes (type-III) were distinguished from 129 normal valves by the cutoff point of the SWC ratio < 0.482 with the highest AUC (0.960) compared to other parameters by the ROC analysis. PMID- 29511935 TI - Serum from the Human Fracture Hematoma Contains a Potent Inducer of Neutrophil Chemotaxis. AB - A controlled local inflammatory response is essential for adequate fracture healing. However, the current literature suggests that local and systemic hyper inflammatory conditions after major trauma induce increased influx of neutrophils into the fracture hematoma (FH) and impair bone regeneration. Inhibiting neutrophil chemotaxis towards the FH without compromising the hosts' defense may therefore be a target of future therapies that prevent impairment of fracture healing after major trauma. We investigated whether chemotaxis of neutrophils towards the FH could be studied in vitro. Moreover, we determined whether chemotaxis of neutrophils towards the FH was mediated by the CXCR1, CXCR2, FPR, and C5aR receptors. Human FHs were isolated during an open reduction internal fixation (ORIF) procedure within 3 days after trauma and spun down to obtain the fracture hematoma serum. Neutrophil migration towards the FH was studied using IbidiTM Chemotaxis3D MU-Slides and image analysis of individual neutrophil tracks was performed. Our study showed that the human FH induces significant neutrophil chemotaxis, which was not affected by blocking CXCR1 and CXCR2. In contrast, neutrophil chemotaxis towards the FH was significantly inhibited by chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS), which blocks FPR and C5aR. Blocking only C5aR with CHIPSDelta1F also significantly inhibited neutrophil chemotaxis towards the FH. Our finding that neutrophil chemotaxis towards the human FH can be blocked in vitro using CHIPS may aid the development of therapies that prevent impairment of fracture healing after major trauma. PMID- 29511936 TI - Efficacy and Tolerability of a Medical Device Repairing Emollient Cream Associated with a Topical Corticosteroid in Adults with Atopic Dermatitis: An Open-label, Intra-individual Randomized Controlled Study. AB - INTRODUCTION: Medical device repairing emollient creams (MDRECs) are designed to repair and protect the skin barrier. In this study, we examined the added clinical benefit and tolerability of a MDREC when used in association with a moderately potent topical corticosteroid (TCS) for adults with atopic dermatitis (AD). METHODS: This was an intra-individual randomized controlled trial in adults with moderate to severe AD (EudraCT no. 2014-002,194-10). Symmetrical lesions on each arm of the subjects were randomized to treatment for 10 days with twice daily TCS (desonide) cream alone or with combined TCS + MDREC. Subjects were then included in a following 2-week maintenance phase if the AD on at least one test area had sufficiently improved so that the treatment was no longer needed. During the maintenance phase, treatment with the TCS cream was stopped, but twice-daily application of the MDREC was continued on the same test area previously assigned to receive it. The primary outcome measure was the change in local Scoring Atopic Dermatitis (SCORAD) index between day 1 and 3 based on investigators' assessment. Secondary measures of lesion severity included changes in the local patient oriented SCORAD index, pruritus intensity according to subjects' assessments, and global assessments by subjects and investigators. RESULTS: The study included 54 subjects. The change in investigator-observed local SCORAD index between day 1 and 3 was - 14.4% with TCS alone and - 24.5% for TCS + MDREC (p = 0.0005). Between baseline and the end of the treatment phase, all secondary measures of lesion severity decreased more with the combined TCS + MDREC treatment than with the TCS cream alone. The MDREC also reduced the relapse of AD lesions during the maintenance phase. Tolerability was very good, and the product was well accepted by subjects. CONCLUSION: These results support using the MDREC in association with TCS during AD flares and as a maintenance therapy after treatment with TCS has stopped. FUNDING: Laboratoires Dermatologiques Ducray, Pierre Fabre. PMID- 29511937 TI - Using an in vitro system for maintaining Varroa destructor mites on Apis mellifera pupae as hosts: studies of mite longevity and feeding behavior. AB - Varroa destructor mites (varroa) are ectoparasites of Apis mellifera honey bees, and the damage they inflict on hosts is likely a causative factor of recent poor honey bee colony performance. Research has produced an arsenal of control agents against varroa mites, which have become resistant to many chemical means of their control, and other means have uncertain efficacy. Novel means of control will result from a thorough understanding of varroa physiology and behavior. However, robust knowledge of varroa biology is lacking; mites have very low survivability and reproduction away from their natural environment and host, and few tested protocols of maintaining mites in vitro are available as standardized methods for varroa research. Here, we describe the 'varroa maintenance system' (VMS), a tool for maintaining in vitro populations of varroa on its natural host, and present best practices for its use in varroa and host research. Additionally, we present results using the VMS from research of varroa and host longevity and varroa feeding behavior. Under these conditions, from two trials, mites lived an average of 12 and 14 days, respectively. For studies of feeding behavior, female mites inflicted wounds located on a wide range of sites on the host's integument, but preferred to feed from the host's abdomen and thorax. Originally in the phoretic phase, female mites in VMS had limited reproduction, but positive instances give insights into the cues necessary for initiating reproduction. The VMS is a useful tool for laboratory studies requiring long-term survival of mites, or host parasite interactions. PMID- 29511938 TI - Modeling Relationships Involving Perceived Recovery Orientation of Mental Health Teams Among Quebec Mental Health Professionals. AB - While mental health (MH) services are expected to support client recovery, very little is known about services provided by MH teams in relation to this goal. This study explored relationships between a comprehensive collection of team effectiveness variables and the perspectives of MH professionals regarding the recovery orientation of their teams. A model developed by path analysis revealed eight team-related variables that were significantly and positively associated with recovery-oriented teams: primary care versus specialized MH services; greater proportions of clients with severe mental disorders or with suicide ideation on caseloads; knowledge sharing and knowledge production among team members; team climate; work role performance; and trust in coworkers. Results underline the importance of building knowledge and professional competence on MH teams, and the need for a positive team climate that offers flexibility and innovation for addressing the complex needs of people in MH recovery living in the community. PMID- 29511939 TI - Hepatectomy for oligo-recurrence of non-small cell lung cancer in the liver. AB - BACKGROUND: The prognosis of metastatic recurrent non-small cell lung cancer (NSCLC) is poor, and chemotherapy improves survival by only a few months. The concept of oligo-recurrence, defined as a small number of new lesions at a distant site theoretically curable by local therapy, has recently been proposed for several cancers. To evaluate the possible benefits of surgical resection for oligo-recurrence, we report the outcomes of seven patients who underwent hepatic resection for oligo-recurrence of NSCLC in the liver. METHODS: Among the 2038 patients who underwent resection for NSCLC between January 1997 and December 2015 at the Department of Chest Surgery, Chiba Cancer Center, 7 (0.34%) with oligo recurrence in the liver underwent hepatectomy. Perioperative data were retrospectively reviewed, including recurrence-free and overall survival. RESULTS: Primary tumor histopathological types included five cases of squamous cell carcinoma, one case of adenocarcinoma, and one case of large-cell carcinoma. All patients underwent complete tumor resection without complication. The median survival duration following hepatectomy was 24.0 (range 15.2-30.2) months. Four patients were alive at the end of follow-up (23.4-30.2 months), whereas three died between 15.2 and 24.5 months. There was no evidence of second recurrence in two patients. CONCLUSIONS: Hepatectomy may be equally effective as multidisciplinary therapy for oligo-recurrence of NSCLC in the liver. PMID- 29511940 TI - Retrospective analysis on the clinical outcomes of recombinant human soluble thrombomodulin for disseminated intravascular coagulation syndrome associated with solid tumors. AB - BACKGROUND: Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs. METHODS: Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration. RESULTS: The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS. CONCLUSIONS: rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible. PMID- 29511941 TI - The Modification of Cell Wall Properties by Expression of Recombinant Resilin in Transgenic Plants. AB - Plant tissue is composed of many different types of cells. Plant cells required to withstand mechanical pressure, such as vessel elements and fibers, have a secondary cell wall consisting of polysaccharides and lignin, which strengthen the cell wall structure and stabilize the cell shape. Previous attempts to alter the properties of the cell wall have mainly focused on reducing the amount of lignin or altering its structure in order to ease its extraction from raw woody materials for the pulp and paper and biorefinery industries. In this work, we propose the in vivo modification of the cell wall structure and mechanical properties by the introduction of resilin, an elastic protein that is able to crosslink with lignin monomers during cell wall synthesis. The effects of resilin were studied in transgenic eucalyptus plants. The protein was detected within the cell wall and its expression led to an increase in the elastic modulus of transgenic stems. In addition, transgenic stems displayed a higher yield point and toughness, indicating that they were able to absorb more energy before breaking. PMID- 29511942 TI - The evaluation of the transport medium for extracted premolars prior to cryopreservation: a systematic literature review. AB - Prior to cryopreservation, a tooth is transported from a contaminated oral environment to the tooth bank. Our objective was to identify all studies reporting or investigating a transport protocol prior to the cryopreservation of teeth, in terms of decontamination of the subjects. The systematic literature search (1970-2017) was based on MEDLINE via PubMed, Web of Science and the Cochrane Library. The reference lists of the included studies and the Science Citation Index were used for hand searching (snowballing). Only studies reporting the transport conditions of the transplant were included. Language restrictions for English, Dutch or French were applied. The search led to 14 eligible studies. Almost all studies were laboratory studies, so the methodological quality of evidence was low. The majority of the included studies was performed by only five different research groups and the number of subjects varied between 1 and 120 teeth. In general, the teeth were stored in a tissue culture medium supplemented with fetal calf serum and/or different combinations of antibiotics and/or antimycotics. The teeth were transported cooled (4 degrees C) or at room temperature, for a period of time not exceeding 24 h. Only three studies reported the irrigation of the teeth with phosphate buffered saline prior to the transport. The optimisation of the decontamination during transport was investigated in three studies (from 1971, 1980 and 1982). It was concluded that the literature on this topic is scarce, and the decontamination protocol for teeth, prior to cryopreservation has not been validated recently. PMID- 29511943 TI - Proactive behavior, but not inhibitory control, predicts repeated innovation by spotted hyenas tested with a multi-access box. AB - Innovation is widely linked to cognitive ability, brain size, and adaptation to novel conditions. However, successful innovation appears to be influenced by both cognitive factors, such as inhibitory control, and non-cognitive behavioral traits. We used a multi-access box (MAB) paradigm to measure repeated innovation, the number of unique innovations learned across trials, by 10 captive spotted hyenas (Crocuta crocuta). Spotted hyenas are highly innovative in captivity and also display striking variation in behavioral traits, making them good model organisms for examining the relationship between innovation and other behavioral traits. We measured persistence, motor diversity, motivation, activity, efficiency, inhibitory control, and neophobia demonstrated by hyenas while interacting with the MAB. We also independently assessed inhibitory control with a detour cylinder task. Most hyenas were able to solve the MAB at least once, but only four hyenas satisfied learning criteria for all four possible solutions. Interestingly, neither measure of inhibitory control predicted repeated innovation. Instead, repeated innovation was predicted by a proactive syndrome of behavioral traits that included high persistence, high motor diversity, high activity and low neophobia. Our results suggest that this proactive behavioral syndrome may be more important than inhibitory control for successful innovation with the MAB by members of this species. PMID- 29511944 TI - Author Correction to: Dynamic Scheduling for Veterans Health Administration Patients Using Geospatial Dynamic Overbooking. AB - The original version of this article unfortunately contained a mistake. The name of Matthew Gerber was incorrectly spelled as Mathew Gerber. The correct spelling is now presented correctly in this correction article. PMID- 29511945 TI - Investigating the establishment of primary cultures of hemocytes from Mytilus edulis. AB - Anthropogenic influences on the environment have been become a focal point for many social and political endeavors. With an ever-increasing rate of new contaminants being introduced into the environment every year, regulatory policies have begun to shift to prevention rather than mitigation. However, current in vivo testing strategies, in addition to ethical considerations, are too expensive and time consuming to adequately screen potential contaminants within a realistic timeframe. As a result, in vitro testing on cell cultures has been identified as an ideal alternative testing strategy for emerging contaminants. In the context of ecotoxicology, in vitro testing has had limited use particularly with marine invertebrates like the marine mussel Mytilus edulis mainly due to difficulties in establishing longer term cell cultures and cell lines. The aim of this study was to define an optimal technique (extraction and maintenance) for establishing a primary cell culture on M. edulis hemocytes that could be used for screening contaminants. PMID- 29511946 TI - Adipose tissue extract shows potential for wound healing: in vitro proliferation and migration of cell types contributing to wound healing in the presence of adipose tissue preparation and platelet rich plasma. AB - Growth factors are the key elements in wound healing signaling for cell migration, differentiation and proliferation. Platelet-rich plasma (PRP), one of the most studied sources of growth factors, has demonstrated to promote wound healing in vitro and in vivo. Adipose tissue is an alternative source of growth factors. Through a simple lipoaspirate method, adipose derived growth factor-rich preparation (adipose tissue extract; ATE) can be obtained. The authors set out to compare the effects of these two growth factor sources in cell proliferation and migration (scratch) assays of keratinocyte, fibroblast, endothelial and adipose derived stem cells. Growth factors involved in wound healing were measured: keratinocyte growth factor, epidermal growth factor, insulin-like growth factor, interleukin 6, platelet-derived growth factor beta, tumor necrosis factor alfa, transforming growth factor beta and vascular endothelial growth factor. PRP showed higher growth factor concentrations, except for keratinocyte growth factor, that was present in adipose tissue in greater quantities. This was reflected in vitro, where ATE significantly induced proliferation of keratinocytes at day 6 (p < 0.001), compared to plasma and control. Similarly, ATE-treated fibroblast and adipose stem cell cultures showed accelerated migration in scratch assays. Moreover, both sources showed accelerated keratinocyte migration. Adipose tissue preparation has an inductive effect in wound healing by proliferation and migration of cells involved in wound closure. Adipose tissue preparation appears to offer the distinct advantage of containing the adequate quantities of growth factors that induce cell activation, proliferation and migration, particularly in the early phase of wound healing. PMID- 29511947 TI - Long-term crude probabilities of death among breast cancer patients by age and stage: a population-based survival study in Northeastern Spain (Girona-Tarragona 1985-2004). AB - BACKGROUND: We provide population-based long-term survival indicators of breast cancer patients by quantifying the observed survival, and the probabilities of death due to breast cancer and to other causes by age and tumor stage at diagnosis. METHODS: We included a total of 10,195 female patients diagnosed before 85 years with invasive primary breast cancer in Girona and Tarragona during the periods 1985-1994 and 1995-2004 and followed-up until December 31st 2014. The survival indicators were estimated at 5, 10, 15 and 20 years of follow up comparing diagnostic periods. RESULTS: Comparing diagnostic periods: I) the probability of death due to other causes did not change; II) the 20-year survival for women diagnosed <= 49 years increased 13% (1995-2004 = 68%; 1985-1994:55%), whereas their probability of death due to breast cancer decreased at the same pace (1995-2004 = 29%; 1985-1994 = 42%); III) at 10 years of follow-up, decreases in the probabilities of death due to breast cancer across age groups switched from 11 to 17% resulting in a risk of death reduction of 19% after adjusting by stage. During 1995-2004, the stage-specific 10-year probabilities of death due to breast cancer switched from: 3-6% in stage I, 18-20% in stage II, 34-46% in stage III and surpassed 70% in stage IV beyond 5 years after diagnosis. CONCLUSIONS: In our study, women diagnosed with breast cancer had higher long-term probability to die from breast cancer than from other causes. The improvements in treatment and the lead-time bias in detecting cancer in an early stage resulted in a reduction of 19% in the risk of death between diagnostic periods. PMID- 29511948 TI - Current Information and Recommendations on the Discontinuation of TKI Inhibitors in Chronic Myeloid Leukemia. AB - PURPOSE OF REVIEW: Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic phase chronic myeloid leukemia (CP-CML) patients has become a reality. Treatment-free remission (TFR) is the term that identifies success after discontinuation. RECENT FINDINGS: Several trials have demonstrated that with imatinib about 40% of patients discontinuing treatment in deep and stable molecular response remain disease-free. Second-generation TKIs have improved the rate of deep molecular responses and allowed to increase the percentage of patients attempting treatment discontinuation. We hereby review the current information based on the available published data and discuss the current suggestions on how to move TFR into the clinical practice. PMID- 29511949 TI - Ophthalmic Manifestations in Children with Periventricular Leukomalacia. PMID- 29511950 TI - Regional Genotyping of Rotavirus: Role in Vaccine Development. PMID- 29511951 TI - Predictors of response to fixed-dose vasopressin in adult patients with septic shock. AB - BACKGROUND: Vasopressin is often utilized for hemodynamic support in patients with septic shock. However, the most appropriate patient to initiate therapy in is unknown. This study was conducted to determine factors associated with hemodynamic response to fixed-dose vasopressin in patients with septic shock. METHODS: Single-center, retrospective cohort of patients receiving fixed-dose vasopressin for septic shock for at least 6 h with concomitant catecholamines in the medical, surgical, or neurosciences intensive care unit (ICU) at a tertiary care center. Patients were classified as responders or non-responders to fixed dose vasopressin. Response was defined as a decrease in catecholamine dose requirements and achievement of mean arterial pressure >= 65 mmHg at 6 h after initiation of vasopressin. RESULTS: A total of 938 patients were included: 426 responders (45%), 512 non-responders (55%). Responders had lower rates of in hospital (57 vs. 72%; P < 0.001) and ICU mortality (50 vs. 68%; P < 0.001), and increased ICU-free days at day 14 and hospital-free days at day 28 (2.3 +/- 3.8 vs. 1.6 +/- 3.3; P < 0.001 and 4.2 +/- 7.2 vs. 2.8 +/- 6.0; P < 0.001, respectively). On multivariable analysis, non-medical ICU location was associated with increased response odds (OR 1.70; P = 0.0049) and lactate at vasopressin initiation was associated with decreased response odds (OR 0.93; P = 0.0003). Factors not associated with response included APACHE III score, SOFA score, corticosteroid use, and catecholamine dose. CONCLUSION: In this evaluation, 45% responded to the addition of vasopressin with improved outcomes compared to non responders. The only factors found to be associated with vasopressin response were ICU location and lactate concentration. PMID- 29511952 TI - Prostate cancer and the impact on couples: a qualitative metasynthesis. AB - PURPOSE: To review and interpret existing qualitative literature on the experiences of couples affected by prostate cancer (PCa). METHODS: A metasynthesis was carried out which included a systematic search of seven databases between 2000 and 2016. A modified version of Noblit and Hare's meta ethnographic approach was used to synthesise qualitative study findings and inform overarching interpretations. RESULTS: Thirty-seven studies focusing on the experiences of men with PCa and their partner dyad were included producing seven interconnected constructs. The construct accepting change vs seeking continuity reflects the range of ways individuals within the dyad and couples adjust to the diagnosis. Cultivating connection vs disengaging illustrates how couples seek to manage the impact of PCa and its treatment on their relationship, which may lead to a threatened identity, including sexual insecurities. Shielding me, you and us reflects the ways in which couples strive to protect themselves as individuals and/or each other from the impact of PCa. Being a partner and its challenges highlights the responsibilities partners assume and the impact of their supporting role. Yet, partners sometimes report feeling unsupported and side lined both by the man they are caring for and by healthcare professionals. Couples often recognise the value of facing PCa together. CONCLUSIONS: PCa affects both members of the dyad as individuals, as well as the couple's relationship. How best to support couples and how to overcome difficulties in expressing their concerns to one another requires further consideration. Healthcare professionals should endeavour to employ a couple-focused approach where appropriate. PMID- 29511953 TI - Associations between workability and patient-reported physical, psychological and social outcomes in breast cancer survivors: a cross-sectional study. AB - PURPOSE: Workability is of increasing importance especially in Asia given the increasing incidence rates and young age of onset of breast cancer. This study explores the determinants of employment and suboptimal workability. And evaluate the association between workability and patient-reported physical, psychological, and social outcomes. METHODS: In a hospital-based cross-sectional study, 327 breast cancer survivors, < 65 years of age and > 1 year post-diagnosis were recruited. Employed survivors filled out the workability index, which measures a person's capacity to meet work demands in relation to current health status. The EORTC-QLQ-C30, EORTC-QLQ-BR23, hospital anxiety and depression scale, multidimensional fatigue inventory, and brief pain index were administered. Fisher's exact test and Kruskal-Wallis test were used to test for associations of workability and employment status with demographic, clinical characteristics, and patient-reported outcomes. Linear models with standardised scores for patient reported outcomes were fitted to study the associations of workability with patient-reported outcomes. RESULTS: Of the 327 survivors, < 65 years of age (working age), 140 (43%) were in full-time and 34 (10%) in part-time employment. Employed survivors were younger at time of diagnosis and at time of survey. Employment status was not associated with time since diagnosis, ethnicity, or clinical characteristics. Suboptimal workability was present in 37% of employed survivors of the working age, and more common in jobs that include physical work activities. Higher level of depression, financial difficulty and physical fatigue, more breast symptoms, and poorer global health status were independently associated with poorer workability. CONCLUSIONS: Lower employment and reduced workability in breast cancer survivors is common, and reduced workability is associated with higher levels of depression, financial difficulty and physical fatigue, more breast symptoms, and poorer global health status. Longitudinal research on psychosocial support with workability in Asia may find tailored approach to improve or maintain workability in employed breast cancer patients. PMID- 29511954 TI - 25(OH) vitamin D deficiency in lymphoid malignancies, its prevalence and significance. Are we fully aware of it? AB - INTRODUCTION: Vitamin D has a role in cellular differentiation, proliferation, apoptosis, and angiogenesis and therefore is studied as a prognostic factor in cancer. The aim of our study was to assess the prevalence and significance of 25(OH)D deficiency in patients with lymphoid malignancies. METHODOLOGY: Between January 2014 and June 2016 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade, the pretreatment serum level of 25(OH)D was determined in 133 (62 women/71 men, median age 58 (18-84) years) previously untreated patients with lymphoid malignancy using a chemiluminescent immunoassay. From their medical records, we noted the age, clinical stage, Eastern Cooperative Oncology Group Performance Scale (ECOG PS), nutritional status using the Nutritional Risk Score 2002 (NRS2002), the time of year, comorbidity index, progression, and progression free survival (PFS) for a median of 20 (1-32) months. The optimal cutoff point for prediction of outcome was determined using the Maximally Selected Rank Statistics. RESULTS: There were 37 (27.8%) patients with the severe 25(OH)D deficiency <= 25 nmol/l, 80 (60.2%) with 25(OH)D deficiency 25-50 nmol/l, and 16 (12%) with 25(OH)D insufficiency 50-75 nmol/l. None of the patients had the desired normal level. There were significant differences between groups in regard to ECOG PS, NRS2002, type of lymphoma, and progression. The severely 25(OH)D deficient patients had a shorter mean time until progression (P = 0.018). Cox regression analysis showed that 25(OH)D < 19.6 nmol/l remained the only significant parameter for PFS (HR = 2.921; 95% CI 1.307-6.529). CONCLUSION: The prevalence of 25(OH)D deficiency in the analyzed group of patients with lymphoid malignancies is high and greater in malnourished individuals. Patients with pretreatment serum 25(OH)D < 19.6 nmol/l had a significantly shorter PFS. PMID- 29511956 TI - Selective isolation and characterisation of novel members of the family Nocardiopsaceae and other actinobacteria from a marine sediment of Tioman Island. AB - Tioman Island is one of many sources for underexplored actinobacterial diversity in Malaysia. Selective isolation, molecular profiling, 16S rRNA gene sequencing and phylogenetic analyses were carried out to highlight the diversity of the marine actinobacterial community in a sediment collected off Tioman Island. A high number of diverse actinobacteria were recovered using skim milk/HEPES pre treatment on a mannitol-based medium. A total of 123 actinobacterial strains were isolated, including thirty obligate marine actinobacteria putatively identified as Salinispora spp. Molecular fingerprinting profiles obtained with a double digestion approach grouped the remaining non-Salinispora-like strains into 24 different clusters, with Streptomyces and Blastococcus as the major clusters. A total of 17 strains were identified as novel actinobacterial species within the genera Streptomyces (n = 6), Blastococcus (n = 5), Marinactinospora (n = 3), Nocardiopsis (n = 1), Agromyces (n = 1) and Nonomuraea (n = 1) based on 16S rRNA gene sequence analyses. Polyphasic data from three putative Marinactinospora spp. showed that the strains represent a new genus in the Nocardiopsaceae family. Crude extracts from the strains were also found to inhibit the growth of Gram positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Providencia alcalifaciens) pathogens. Hierarchical clustering of the bioactivities of an active fraction revealed a unique profile, which is closely related that of fosfomycin. PMID- 29511955 TI - Analysis of evolutionary rate of HIV-1 subtype B using blood donor samples in Japan. AB - There are few reports on HIV-1 intra-host evolutionary rate in asymptomatic treatment-naive patients. Here, the HIV-1 intra-host evolutionary rate was estimated based on HIV-1 RNA sequences from plasma samples of blood donors in Japan. Blood donors were assumed to have received no treatment for and have no symptoms of HIV-1 infection because they were healthy, and declared no risky behaviors of HIV-1 infection on a self-reported questionnaire or interview followed by donation. HIV-1 RNA was obtained from 85 plasma samples from 36 blood donors who donated blood multiple times and were HIV-1-positive. The C2V3C3 region which encodes for a part of the envelope protein, and the V3 loop in the C2V3C3 region were analyzed by RT-PCR and direct sequencing, and the sequences were compared. The nucleotide substitution rate was calculated by linear regression. All HIV-1 samples analyzed were classified as subtype B. The mean nucleotide substitution rate in C2V3C3 was calculated to be 6.2 * 10-3-1.8 * 10 2/site/year (V3: 4.5 * 10-3-2.3 * 10-2/site/year). The mean non-synonymous substitution rate in C2V3C3 was calculated to be 5.2 * 10-3-1.7 * 10-2/site/year (V3: 4.5 * 10-3-2.1 * 10-2/site/year). The mean synonymous substitution rate in C2V3C3 was calculated to be 1.1 * 10-4-2.3 * 10-3/site/year (V3: 2.9 * 10 3/site/year). Among HIV-1 subtype B RNA-positive blood donors in Japan, the nucleotide substitution rate in C2V3C3 was estimated to be higher than that of reported cases using HIV-1 samples mainly obtained from AIDS patients. Compared to AIDS patients, immune responses against HIV-1 are probably more effective in HIV-1 RNA-positive blood donors. Consequently, immune pressure presumably promotes mutation of the virus genome. PMID- 29511957 TI - Aureobasidium mangrovei sp. nov., an ascomycetous species recovered from Hara protected forests in the Persian Gulf, Iran. AB - A new ascomycetous black yeast-like species was recovered from healthy plant (Avicennia marina) of Hara protected mangrove forests at Qeshm Island, Iran. Morphological, physiological analysis as well as a molecular analysis of the internal transcribed spacer (ITS) and partial large ribosomal subunit (D1/D2 domains) confirmed the placement of this strain in the genus Aureobasidium and based on considerable sequence divergence, distinguishable cardinal growth temperatures and salt tolerance a new species Aureobasidium mangrovei sp. nov. is proposed. However, the type strain micro-morphologically is not clearly distinguishable from other members of the genus. The type strain, Aureobasidium mangrovei was preserved in a metabolically inactive state at the Iranian Biological Resource Centre, Tehran, Iran as IBRC-M 30265T and the ex-type culture is deposited in the CBS yeast collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands as CBS 142205T. The GenBank accession numbers for the nucleotide sequences of the large subunit ribosomal DNA and ITS region are KY089084 and KY089085, respectively. The MycoBank number of the new species is MB 823444. PMID- 29511958 TI - Are RAN deficits in university students with dyslexia due to defective lexical access, impaired anchoring, or slow articulation? AB - The purpose of this study was to examine different hypotheses in relation to RAN deficits in dyslexia. Thirty university students with dyslexia and 32 chronological-age controls were assessed on RAN Digits and Colors as well as on two versions of RAN Letters and Objects (one with five items repeated 16 times and one with 20 items repeated four times). In addition, participants were tested on discrete letter and object naming, phonological awareness, orthographic knowledge, and speed of processing, and the RAN Letters and Objects total times were partitioned into pause times and articulation times. Results showed first that the dyslexia group was slower than the control group on all RAN tasks and the differences remained significant after controlling for discrete naming time. Second, both groups were slower in the large item set condition (20 * 4) than in the small set condition (5 * 16). Third, the dyslexia group was slower than the control group in both the pause and the articulation times. Although none of the processing skills was sufficient on its own to eliminate group differences in RAN Letters components, phonological awareness, and orthographic processing were sufficient on their own to eliminate group differences in the RAN Objects pause time. Taken together, our findings suggest that the deficits in RAN are not due to impaired anchoring, but rather due to subtle impairments in lexical access (specific to alphanumeric RAN), serial processing, and articulation. PMID- 29511959 TI - Patient perceptions regarding the use of smart devices for medical photography: results of a patient-based survey. AB - AIM: To assess patient perceptions regarding medical photography and the use of smart devices, namely mobile phones and tablets for medical photography. METHODS: A questionnaire-based survey was conducted among 280 consecutive adult patients who presented to the oculoplastics clinic at a tertiary eye care centre. The responses were tabulated and analysed. RESULTS: Of the 280 patients surveyed, 68% felt that medical photography had a positive impact on their understanding of their illnesses and 72% felt that the use of smartphones for medical photography was acceptable. Respondents below the age of 40 years were more likely to approve of the use of mobile phones for photography as compared to those over 40. Most patients (74%) preferred a doctor to be the person photographing them. While a majority approved of doctors and trainee physicians having access to their photographs, they felt non-physician healthcare personnel should not have access to clinical photographs. Also, 72% of the respondents felt that the patient's consent should be taken before using their photographs. It was noted that patient identification and breach of confidentiality could be some of the potential issues with using smart devices as cameras in the clinic. CONCLUSIONS: Clinical photography in general and, specifically, using smart devices for clinical photographs have gained acceptance among patients. The outcomes of this study may be utilized to create policy guidelines for the use of smart devices as photography tools in the clinics. The findings of this survey can also help to create standardized, uniform patient consent forms for clinical photography. PMID- 29511960 TI - Aberrant default mode network in amnestic mild cognitive impairment: a meta analysis of independent component analysis studies. AB - Independent component analysis (ICA) is one of the most popular and valid methods to investigate the default mode network (DMN), an intrinsic network which attracts particular attention in amnestic mild cognitive impairment (aMCI). However, previous studies present inconsistent results regarding the topographical organization of the DMN in aMCI. Therefore, we conducted a quantitative, voxel-wise meta-analysis of resting-state ICA studies using Seed based d Mapping to establish the most consistent pattern of DMN functional connectivity alterations in aMCI. Twenty studies, comprising 23 independent datasets involving 535 patients and 586 healthy controls, met the inclusion criteria. Patients with aMCI exhibited reliably lower DMN functional connectivity than the healthy controls in the bilateral precuneus/posterior cingulate cortices and medial temporal lobes, which are implicated in episodic memory deficits. Moreover, an exploratory meta-regression analysis revealed that greater severity of global cognitive impairment in the patient groups was associated with stronger functional connectivity in the bilateral medial frontal cortices (including the anterior cingulate cortices), left angular gyrus, and right temporal pole extending to the middle temporal gyrus, likely reflecting a compensatory mechanism for maintaining cognitive efficiency. This meta-analysis identifies a consistent pattern of aberrant DMN functional connectivity in aMCI, which facilitates understanding of the neurobiological substrates of this disease. PMID- 29511961 TI - Levofloxacin-induced hemichorea-hemiballism in a patient with previous thalamic infarction. PMID- 29511962 TI - Lower uric acid is associated with poor short-term outcome and a higher frequency of posterior arterial involvement in ischemic stroke. AB - Uric acid has neuroprotective properties in experimental and clinical studies of neurodegenerative disease. It is, however, associated with increased risk of stroke, yet, despite some inconsistent findings, increasing evidence suggests it may also be related to improved stroke outcomes. We have determined whether there is an effect of plasma uric acid on the short-term outcome of stroke patients in a general hospital setting using the modified Rankin Scale (mRS). We also investigated the relationship of uric acid with other clinical correlates. Plasma uric acid was determined in 108 acute ischemic stroke patients and their mRS scores measured. Patients with a poor outcome (mRS > 2) had significantly lower uric acid than those with a better outcome; this remained after correcting for the effect of sex on uric acid concentrations. There was no significant association with other epidemiological factors or with cognitive function determined by Mini-Mental State Examination. An association between uric acid and the cerebral circulation was also found in which lower uric acid occurs with posterior artery involvement. These findings demonstrate in a naturalistic cohort of patients the association of uric acid with short-term disability following ischemic stroke. They also raise the question of whether uric acid may influence the regional brain involvement in stroke. PMID- 29511964 TI - Dose-dependent effect of mammographic breast density on the risk of contralateral breast cancer. AB - PURPOSE: Increased mammographic breast density is a significant risk factor for breast cancer. It is not clear if it is also a risk factor for the development of contralateral breast cancer. METHODS: The data were obtained from Breast Cancer Surveillance Consortium and included women diagnosed with invasive breast cancer or ductal carcinoma in situ between ages 18 and 88 and years 1995 and 2009. Each case of contralateral breast cancer was matched with three controls based on year of first breast cancer diagnosis, race, and length of follow-up. A total of 847 cases and 2541 controls were included. The risk factors included in the study were mammographic breast density, age of first breast cancer diagnosis, family history of breast cancer, anti-estrogen treatment, hormone replacement therapy, menopausal status, and estrogen receptor status, all from the time of first breast cancer diagnosis. Both univariate analysis and multivariate conditional logistic regression analysis were performed. RESULTS: In the final multivariate model, breast density, family history of breast cancer, and anti-estrogen treatment remained significant with p values less than 0.01. Increasing breast density had a dose-dependent effect on the risk of contralateral breast cancer. Relative to 'almost entirely fat' category of breast density, the adjusted odds ratios (and p values) in the multivariate analysis for 'scattered density,' 'heterogeneously dense,' and 'extremely dense' categories were 1.65 (0.036), 2.10 (0.002), and 2.32 (0.001), respectively. CONCLUSION: Breast density is an independent and significant risk factor for development of contralateral breast cancer. This risk factor should contribute to clinical decision making. PMID- 29511963 TI - High serum levels of malondialdehyde and antioxidant enzymes are associated with post-stroke anxiety. AB - Post-stroke anxiety (PSA) is a common neuropsychiatric affective disorder occurring after stroke. The purpose of this study was to investigate the association between anxiety and the serum levels of oxidative stress markers at admission. First-ever or recurrent ischemic stroke patients were consecutively recruited into the study and followed up 1 month. Patients were divided into PSA and non-PSA group according DSM-IV criteria for anxiety due to stroke. Overall, 49 patients (24.1%) were diagnosed anxiety. Serum GPX (glutathione peroxidase), CAT (catalase), SOD (superoxide dismutase), and MDA (malondialdehyde) were significantly higher in patients with anxiety than patients without anxiety. The HAM-A scores had a significant positive association with MDA levels. In multivariate logistic regression analysis, serum antioxidant enzymes and MDA were independent predictors of PSA. An increased risk of PSA was associated with serum MDA levels >= 3.0 nmol/ml (adjusted OR 8.68, 95% CI 3.02-24.95; P < 0.001) after adjusting for relevant confounders such as social support and treatments at admission. Elevated serum levels of lipid oxidation products and antioxidant enzymes at admission were associated with anxiety 1 month after stroke, suggesting that these alterations might participate in the pathophysiology of anxiety symptoms in stroke patients. PMID- 29511965 TI - Exercise and weight loss interventions and miRNA expression in women with breast cancer. AB - PURPOSE: Obesity and weight gain are associated with comorbidities including a higher risk of tumor recurrence and cancer-related deaths among breast cancer (BC) survivors; however, the underlying mechanisms linking obesity and cancer are poorly understood. Given the lack of clinically validated BC biomarkers, obesity and weight-loss studies utilize serum biomarkers as the intermediary outcomes of tumor recurrence. Studies have indicated microRNAs (miRNA)s are reliable biomarkers for cancer. We hypothesized that miRNA expression correlates with obesity and weight loss amongst BC survivors. This would yield insight into the biological pathways by which this association occurs, enabling more precise development of therapeutics. PATIENTS AND METHODS: We correlated baseline body mass index (BMI) with serum miRNA expression in 121 BC survivors enrolled in the Hormones and Physical Exercise (HOPE) trial. We then analyzed expression of the 35 most abundant miRNAs from HOPE in a six-month randomized controlled weight loss trial (Lifestyle, Exercise, and Nutrition; LEAN) in 100 BC survivors. Ingenuity pathway analysis (IPA) software was used to identify biological pathway targets of the BMI-associated and intervention-responsive miRNAs using predictive biomarkers. RESULTS: Pearson correlations in HOPE identified eight miRNAs associated with BMI, including miR-191-5p (r = - 0.22, p = 0.016) and miR-122-5p (r = 0.25, p = 0.0048). In the LEAN validation study, levels of miR-191-5p significantly increased during the six-month intervention (p = 0.082). Ingenuity Pathway Analysis identified "Estrogen-mediated S-phase entry" (HOPE p = 0.003; LEAN p < 0.001) and "Molecular mechanisms of cancer" (HOPE p = 0.02; LEAN p < 0.001) as the top canonical pathways that significantly correlated with BMI associated and intervention-responsive miRNAs and contain obesity and cancer relevant genes including the E2F family of transcription factors and CCND1, which have been implicated in sporadic BC. CONCLUSION: While the association between obesity and BC recurrence and mortality has been demonstrated in the literature, mechanisms underlying the link between weight gain and cancer are unclear. Using two independent clinical trials, we identified novel miRNAs associative to BMI and weight loss that contribute to the development of cancer. Predictive modeling of miRNA targets identified multiple canonical pathways associated with cancer, highlighting potential mechanisms explaining the link between BMI and increased cancer risk. PMID- 29511966 TI - Evaluating Personalized Feedback Intervention Framing with a Randomized Controlled Trial to Reduce Young Adult Alcohol-Related Sexual Risk Taking. AB - The purpose of this study was to evaluate personalized feedback intervention (PFI) framing with two web-delivered PFIs aimed to reduce young adult alcohol related risky sexual behavior (RSB). Combined PFIs typically use an additive approach whereby independent components on drinking and components on RSB are presented without the discussion of the influence of alcohol on RSB. In contrast, an integrated PFI highlights the RSB-alcohol connection by presenting integrated alcohol and RSB components that focus on the role of intoxication as a barrier to risk reduction in sexual situations. In a randomized controlled trial, 402 (53.98% female) sexually active young adults aged 18-25 were randomly assigned to a combined PFI, an integrated PFI, or attention control. All assessment and intervention procedures were web-based. At the 1-month follow-up, those randomly assigned to the integrated condition had a lower likelihood of having any casual sex partners compared to those in the control group. At the 6-month follow-up, the combined condition had a lower likelihood of having any casual sex partners compared to those in the control group. When examining alcohol-related RSB, at the 1-month follow-up, both interventions showed a lower likelihood of any drinking prior to sex compared to the control group. When examining alcohol related sexual consequences, results showed a reduction in the non-zero count of consequences in the integrated condition compared to the control at the 1-month follow-up. For typical drinks per week, those in the combined condition showed a greater reduction in the non-zero count of drinks than those in the control condition at the 1-month follow-up. While there were no significant differences between the two interventions, the current findings highlight the utility of two efficacious web-based alcohol and RSB interventions among a national sample of at risk young adults. PMID- 29511967 TI - Efficacy of a new delivery system based on solid lipid microparticles for the oral administration of the non-conventional antioxidant IAC on a diabetes mouse model. AB - PURPOSE: We previously showed the positive effects of the new antioxidant molecule bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) in reducing basal hyperglycaemia and relieving glucose intolerance in a diabetes model. However, the chemical properties of IAC did not allow an efficient oral administration, thus representing the main failing of that study. Here, we tested the effect of a new oral delivery system based on solid lipid microparticles (SLMs) in a diabetes mouse model. METHODS: The diabetes model was induced in C57B1/6J mice using streptozotocin and nicotinamide. Only the animals that overcame the glycaemic threshold of 180 mg/dL were enrolled in the study. Diabetic animals were then randomly assigned to 4 groups (n = 9) and treated once a day for 5 consecutive weeks with IAC (50, 100, and 150 mg/kg b.w.). The control group was composed of (n = 7) healthy mice that received only the vehicle. Glucose level was weekly monitored during the treatment period and up to 3 weeks after the suspension of the treatment. Glucose tolerance and insulin-resistance test were carried out. RESULTS: Our results showed that SLMs maintained the IAC effect in reducing basal hyperglycaemia as well as improving the insulin sensitivity and glucose tolerance. CONCLUSION: The present study confirms that SLMs are promising drug carriers, which allow the oral administration of IAC ensuring its therapeutic efficacy. The concrete possibility to administer IAC per os represents a significant breakthrough in the putative consideration of this multi-radical scavenger in the diabetes therapeutic approach. PMID- 29511968 TI - Amphetamine Neurotoxicity in PC12 Cells through the PP2A/AKT/GSK3beta Pathway. AB - Amphetamine (AMPH) abuse can influence neuropsychiatric disorders and cell apoptosis by interfering with the protein kinase B/ glycogen synthase kinase 3 beta (AKT/GSK3beta) pathway. However, the mechanisms underlying this regulation are poorly understood. Using PC12 cells, we found that AMPH inhibited AKT and GSK 3beta phosphorylation levels and increased total GSK-3beta levels. Furthermore, AMPH caused an increase in the activity of protein phosphatase 2 (PP2A), a signaling protein upstream of AKT, which in turn inhibited phosphorylated AKT levels. Okadaic acid, a PP2A inhibitor, protected PC12 cells against AMPH-induced apoptosis. Together, our results suggest that the PP2A/AKT/GSK3beta pathway plays an important role in AMPH-induced neurotoxicity. PMID- 29511970 TI - Substance Use in Medical Trainees: Current Problems and Future Directions. PMID- 29511969 TI - Ionic liquids as biocompatible stabilizers of proteins. AB - Ionic liquids (ILs) have recently emerged as versatile solvents and additives in the field of biotechnology, particularly as stabilizers of proteins and enzymes. Of interest to the biotechnology industry is the formulation of stable biopharmaceuticals, therapeutic proteins, and vaccines which have revolutionized the treatment of many diseases including debilitating conditions such as cancers and auto-immune diseases. The stabilization of therapeutic proteins is typically achieved using additives that prevent unfolding and aggregation of these proteins during manufacture, transport, and long-term storage. To determine if ILs could be used in the formulation of stable therapeutic proteins, a thorough understanding of the effects of ILs on protein stability is needed, as well as understanding the toxicity of ILs on humans, and other considerations for formulation development such as viscosity and osmolality. In this review, we summarize recent developments on the stabilization of proteins and enzymes using ILs, with emphasis on identifying biocompatible ILs that may be suitable for the formulation of stable biopharmaceuticals in the future. PMID- 29511971 TI - Impact of continuous non-invasive blood pressure monitoring on hemodynamic fluctuation during general anesthesia: a randomized controlled study. AB - This study assessed the ability of a continuous non-invasive blood pressure (BP) monitoring system to reduce intra-anesthetic hemodynamic fluctuation compared with intermittent BP cuff measurement. Forty patients undergoing total knee arthroplasty under general anesthesia were enrolled and randomly divided into two groups (Control and CS group). BP management was performed using the same protocol with BP measured by intermittent BP cuff in the Control and that by continuous non-invasive BP monitoring in the CS group. We assessed the accuracy and precision of the continuous non-invasive BP monitoring compared with BP cuff measurement using Bland-Altman, four-quadrant plot, and polar-plot analyses. Additionally, the occurrence of hypotension and hypertention during general anesthesia was compared between the two groups. The continuous non-invasive BP monitoring showed excellent accuracy of - 1.1 +/- 8.1 mmHg during surgery and an acceptable trending ability with a concordance rate of 95.1% according to the four-quadrant plot analysis and an angular concordance rate of 86.7% by polar plot analysis. Hypotension was less common in the CS group during induction of anesthesia (p = 0.002) and surgery (p = 0.008). Hypertension occurred more frequently in the Control group during emergence from anesthesia (p = 0.037). The duration of hemodynamic stability (systolic BP 80-110% of baseline) intraoperatively was longer in the CS group than in the Control group (87.7 vs. 61.9%; p < 0.001). Accuracy and trending ability of the continuous non-invasive BP monitoring was clinically acceptable, and lead to hemodynamic stability and reduction of intra-anesthetic hypotension and hypertension intraoperatively. PMID- 29511972 TI - Optimizing peripheral venous pressure waveforms in an awake pediatric patient by decreasing signal interference. AB - The purpose of this technological notes paper is to describe our institution's experience collecting peripheral venous pressure (PVP) waveforms using a standard peripheral intravenous catheter in an awake pediatric patient. PVP waveforms were collected from patients with hypertrophic pyloric stenosis. PVP measurements were obtained prospectively at two time points during the hospitalization: admission to emergency department and after bolus in emergency department. Data was collected from thirty-two patients. Interference in the PVP waveforms data collection was associated with the following: patient or device motion, system set-up error, type of IV catheter, and peripheral intravenous catheter location. PVP waveforms can be collected in an awake pediatric patient and adjuncts to decrease signal interference can be used to optimize data collection. PMID- 29511974 TI - Reprogramming of Aged Cells into Pluripotent Stem Cells by Nuclear Transfer. AB - Stem cells have the potential to differentiate into specialized cell types under specific conditions in vivo or in vitro, which are used to cure many diseases related to aging. Somatic cell nuclear transfer (SCNT) can reprogram differential somatic cells into cloned embryos and embryonic stem cells can be derived from these cloned embryos. Recipient oocytes have healthier mitochondria and can improve the metabolism competence, lessen the ROS damage, and rejuvenate mitochondrial function of aged cells during reprogramming. Here, we describe a protocol to isolate aged somatic cells and reprogram them into embryonic stem cells by SCNT. These stem cells can be used to differentiate into regenerative somatic cells and replace the aged cells. PMID- 29511973 TI - Very long-term outcomes after a single catheter ablation procedure for the treatment of atrial fibrillation-the protective role of antiarrhythmic drug therapy. AB - BACKGROUND: Pulmonary vein isolation (PVI) is the cornerstone of AF ablation, but its long-term clinical outcomes, predictors of relapse, and optimal pharmacological treatment remain controversial. OBJECTIVE: The objectives of this paper were to (1) assess very long-term AF recurrence, (2) identify predictors of relapse, and (3) evaluate the impact of continued antiarrhythmic drug (AAD) treatment after ablation. METHODS: Multicenter observational registry including all consecutive patients with drug-resistant AF who underwent a first PVI between 2006 and 2008 (n = 253 (age 55 years (IQR 48-63)), 80% males, 64% with paroxysmal AF. Endpoint was AF/AT/AFL relapse after a 3-month blanking period. Predictors and protective factors of AF relapse were assessed with multivariate Cox regression. RESULTS: A total of 144 patients (57%) relapsed over a median 5-year (IQR 2-9) follow-up-annual relapse rate of 10%/year. Female sex (aHR 1.526, 95% CI 1.037-2.246, P = 0.032), non-paroxysmal AF (aHR 1.410, 95% CI 1.000-1.987, P = 0.050), and LA volume/BSA (aHR 1.012, 95% CI 1.003-1.021, P = 0.008) were identified as independent predictors of relapse. A total of 139 patients (55%) continued AAD (55% on amiodarone) after blanking period. One-year overall PVI success rate of patients under AAD was 86 vs 76% with no AAD (P < 0.001)-annual relapse rates were 8%/year vs 14%/year (P < 0.001), respectively. AAD was associated with a long-term reduction in AF relapse (aHR 0.673, 95% CI 0.509 0.904 P = 0.004). CONCLUSION: Half the patients remained free from AF 5 years after a single procedure. Female sex, non-paroxysmal AF, and LA volume/BSA independently predicted recurrence, whereas continuing AAD after the 3-month blanking period reduced relapse. In a multicenter registry of AF patients undergoing a first PVI, 57% relapsed over a median 5-year follow-up. Female sex, non-paroxysmal AF and LA volume/BSA were identified as independent predictors of relapse. Maintaining AAD therapy after the blanking period was associated with a long-term reduction in AF relapse. PMID- 29511976 TI - Mining the preferences of patients for ubiquitous clinic recommendation. AB - A challenge facing all ubiquitous clinic recommendation systems is that patients often have difficulty articulating their requirements. To overcome this problem, a ubiquitous clinic recommendation mechanism was designed in this study by mining the clinic preferences of patients. Their preferences were defined using the weights in the ubiquitous clinic recommendation mechanism. An integer nonlinear programming problem was solved to tune the values of the weights on a rolling basis. In addition, since it may take a long time to adjust the values of weights to their asymptotic values, the back propagation network (BPN)-response surface method (RSM) method is applied to estimate the asymptotic values of weights. The proposed methodology was tested in a regional study. Experimental results indicated that the ubiquitous clinic recommendation system outperformed several existing methods in improving the successful recommendation rate. PMID- 29511975 TI - 18F-FDG-PET/CT Imaging to Diagnose Septic Emboli and Mycotic Aneurysms in Patients with Endocarditis and Cardiac Device Infections. AB - PURPOSE OF REVIEW: This review analyzes recent studies evaluating the diagnostic value of 18F-FDG-PET/CT for the detection of peripheral emboli and secondary infectious foci in patients with infective endocarditis and cardiac device infections. RECENT FINDINGS: Detection of extracardiac septic localizations in patients with infective endocarditis and cardiac device infections is crucial, as it may impact the diagnosis, prognosis, and therapeutic management. Recent literature substantiated the clinical usefulness of 18F-FDG-PET/CT in this setting. 18F-FDG-PET/CT has proven its high diagnostic value for the detection of peripheral emboli in patients with infective endocarditis and cardiac device infections, substantially affecting patients' outcome and treatment. A multimodal approach, combining the high sensitivity of 18F-FDG-PET/CT with morphological imaging seems promising. PMID- 29511977 TI - Patterns of relapse for children with localized intracranial ependymoma. AB - We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age <= 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted. PMID- 29511978 TI - Hypoglossal nerve involvement in Lewis-Sumner syndrome: a case report. PMID- 29511979 TI - Pros and Cons of Intensive Systolic Blood Pressure Lowering. AB - PURPOSE OF REVIEW: The Systolic Blood Pressure Intervention Trial demonstrated significant decreases in cardiovascular events and total mortality with intensive systolic blood pressure lowering in adults with high cardiovascular risk in the absence of diabetes but benefits were accompanied by increased risk of adverse events. RECENT FINDINGS: Over 100,000 deaths and 46,000 cases of heart failure may be prevented annually if intensive systolic blood pressure lowering is implemented in 17 million US adults who are age 50 years and older, and have high cardiovascular risk in the absence of diabetes and meet eligibility for the Systolic Blood Pressure Intervention Trial. However, the benefits of intensive SBP lowering will be accompanied by an excess of 43,000 cases of electrolyte abnormalities and 88,000 cases of acute kidney injury. Physicians should consider implementation of intensive systolic blood pressure lowering in appropriate patients who understand the risks and benefits of this intervention. PMID- 29511981 TI - Paravalvular Leak in Structural Heart Disease. AB - PURPOSE OF REVIEW: This review will summarize the growing importance of diagnosing and managing paravalvular leak associated with surgical and transcatheter valves. RECENT FINDINGS: The burden of paravalvular leak is increasing; however, advanced imaging techniques and high degree of clinical suspicion are required for diagnosis and management. The latest data from pivotal clinical trials in the field of transcatheter aortic valve replacement suggest that any paravalvular leak greater than mild was associated with worse clinical outcomes. Percutaneous techniques for paravalvular leak closure are now the preferred approach, and surgical repair is reserved for contraindications and unsuccessful procedures. Recent data from studies evaluating paravalvular leak closure outcomes report a greater than 90% success rate with a significant improvement in patient symptoms. Paravalvular leak is a growing problem in the structural heart disease arena. Percutaneous closure is successful in more than 90% of the procedures with a low complication rate. PMID- 29511980 TI - Principles of quantitative water and electrolyte replacement of losses from osmotic diuresis. AB - Osmotic diuresis results from urine loss of large amounts of solutes distributed either in total body water or in the extracellular compartment. Replacement solutions should reflect the volume and monovalent cation (sodium and potassium) content of the fluid lost. Whereas the volume of the solutions used to replace losses that occurred prior to the diagnosis of osmotic diuresis is guided by the clinical picture, the composition of these solutions is predicated on serum sodium concentration and urinary sodium and potassium concentrations at presentation. Water loss is relatively greater than the loss of sodium plus potassium leading to hypernatremia which is seen routinely when the solute responsible for osmotic diuresis (e.g., urea) is distributed in body water. Solutes distributed in the extracellular compartment (e.g., glucose or mannitol) cause, in addition to osmotic diuresis, fluid transfer from the intracellular into the extracellular compartment with concomitant dilution of serum sodium. Serum sodium concentration corrected to euglycemia should be substituted for actual serum sodium concentration when calculating the composition of the replacement solutions in hyperglycemic patients. While the patient is monitored during treatment, the calculation of the volume and composition of the replacement solutions for losses of water, sodium and potassium from ongoing osmotic diuresis should be based directly on measurements of urine volume and urine sodium and potassium concentrations and not by means of any predictive formulas. Monitoring of clinical status, serum sodium, potassium, glucose, other relevant laboratory values, urine volume, and urine sodium and potassium concentrations during treatment of severe osmotic diuresis is of critical importance. PMID- 29511982 TI - Understanding Interactions of Smoking on Prognosis of HPV-Associated Oropharyngeal Cancers. AB - The new 8th edition AJCC/UICC staging system for human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC), developed to account for improved survival outcomes over HPV-negative cancers, includes anatomic features strictly associated with tumor-node-metastasis (TNM) and does not account for patient-specific characteristics that may impact prognosis. This commentary evaluates the evidence of smoking as an adverse prognostic factor in HPV-associated OPSCC. We review the multifactorial biological, clinical, and social/behavioral characteristics of smokers with OPSCC that impact outcomes, discuss current challenges with incorporating smoking history in prognostic classifications, and consider opportunities for future investigation. PMID- 29511983 TI - Local Interleukin-2 Immunotherapy of Breast Cancer: Benefit and Risk in a Spontaneous Mouse Model. AB - Earlier, naturally arising mammary cancer in BLRB female mice was shown to reproduce some key pathological characteristics of the familial set of human breast cancer. Then we advanced a novel 3S-paradigm of anticancer research that helped to develop selection criteria and to estimate benefit/risk of local interleukin-2 (IL-2) effects in this spontaneous mouse model. In this paper, the efficacy of single and triple local IL-2 doses is compared using properly selected murine BLRB females based on our previously published data. Only BLRB females bearing spontaneous mammary tumors without subclinical period were used. The tumor growth rate and recipient survival of single and triple IL-2 applications were compared with corresponding parameter values of untreated control. Tumor growth rate was decreased in both experimental groups versus control parameter values. Single IL-2 application resulted in a significant prolongation of the average survival time while triple application caused acute tumor rejection in some females decreasing the survival time of the rest of the recipients. As a result, proper treatment protocol in accurately selected females allowed increasing the complete response rate to 14% in spontaneous mouse model of breast cancer. In conclusion, our approaches may demonstrate the principle methodology developing preselection procedure for breast cancer patients for local IL-2 therapy application. PMID- 29511984 TI - Analysis of the function of KIF3A and KIF3B in the spermatogenesis in Boleophthalmus pectinirostris. AB - Spermatogenesis represents one of the most complicated morphological transformation procedures. During this process, the assembly and maintenance of the flagella and intracellular transport of membrane-bound organelles required KIF3A and KIF3B. Our main goal was to test KIF3A and KIF3B location during spermatogenesis of Boleophthalmus pectinirostris. We cloned complete cDNA of KIF3A/3B from the testis of B. pectinirostris by PCR and rapid amplification of cDNA ends (RACE). The predicted secondary and tertiary structures of B. pectinirostris KIF3A/3B contained three domains: (a) the head region, (b) the stalk region, and (c) the tail region. Real-time quantitative PCR (qPCR) results revealed that KIF3A and KIF3B mRNA were presented in all the tissues examined, with the highest expression seen in the testis. In situ hybridization (ISH) showed that KIF3A and KIF3B were distributed in the periphery of the nuclear in the spermatocyte and the early spermatid. In the late spermatid and mature sperm, the KIF3A and KIF3B mRNA were gradually gathered to one side where the flagella formed. Immunofluorescence (IF) showed that KIF3A, tubulin, and mitochondria were co-localized in different stages during spermiogenesis in B. pectinirostris. The temporal and spatial expression dynamics of KIF3A/3B indicate that KIF3A and KIF3B might be involved in flagellar assembly and maintenance at the mRNA and protein levels. Moreover, these proteins may transport the mitochondria resulting in flagellum formation in B. pectinirostris. PMID- 29511987 TI - Ethnic Differences for Public Health Knowledge, Health Advocacy Skills, and Health Information Seeking Among High School Students: Community Agents of Change. AB - Although adult health advocacy programs have been examined in communities, little is known about integrated adolescent health advocacy programs in high schools. The purpose of this study was to examine the health advocacy program impact and ethnic differences among high school students. Using a cross-sectional study, high school students participating in the school-based program completed evaluation surveys. The program domains included upstream causes of health, community assets, and public health advocacy. Bivariate analyses were conducted to examine ethnic differences for public health knowledge, health advocacy skills, and health information seeking behaviors. Using thematic analysis, open ended survey item responses were coded to identify themes for students' perceptions of community health. Non-Hispanic (n = 72) and Hispanic high school students (n = 182) in ten classes reported owning smartphones (95%) and laptops (76%). Most students (72%) reported seeking online health information. Non Hispanic students reported significantly higher health advocacy skills for speaking with the class about health issues, identifying community services, or creating health awareness at school than Hispanic students. Non-Hispanic students were more likely to seek health information from fathers and television than Hispanic students. Hispanic students were more likely to seek health information from hospital or clinic staff than non-Hispanic students. Emergent themes included health advocacy skills, community awareness, and individual and community health changes. High schools benefit from integrating health advocacy programs into the core curriculum. Adolescents gain important skills to improve their individual health and engage in changing community health. PMID- 29511985 TI - Effects of dietary inclusions of red beet and betaine on the acute stress response and muscle lipid peroxidation in rainbow trout. AB - This study evaluates the effects of red beet (RB) and betaine on rainbow trout submitted to an acute stress challenge. A control diet was compared with four experimental diets in which red beet (14 and 28%) and betaine (0.9 and 1.63%) were incorporated in different concentrations according to a factorial design. Cortisol in plasma and fin, glucose and lactate plasma levels, and malondialdehide (MDA) in muscle were all measured before the stress challenge and 30 min and 6 and 12 h after the stress challenge as parameters to determine the diet effects. RB and betaine had no effect on cortisol, glucose, and MDA basal levels. However, lactate basal levels were significantly lower on fish fed with RB and betaine. Thirty minutes after the stress challenge, there was a significant increase in plasma and fin cortisol, glucose and lactate concentrations, although fish fed with diets containing RB and betaine showed significantly higher plasma cortisol values. MDA values of fish fed with 14% RB and 0.9% betaine were significantly higher than MDA values from fish fed with 28% RB and 1.63% betaine. After 6 and 12 h, plasma and fin cortisol and lactate levels recovered in a similar trend. Glucose plasma levels recovered in almost all groups 12 h after the stress. Also, MDA values recovered basal levels after 6 and 12 h. RB and betaine did not enhance the tolerance to the stress challenge compared to the control group, although the presence of these ingredients had no negative effect on any of the stress indicators. PMID- 29511988 TI - A Descriptive Analysis of a Community Clinic Providing Hepatitis C Treatment to Poor and Uninsured Patients. AB - This study describes clinical characteristics of poor and uninsured patients living with hepatitis C virus (HCV) who received care from a multidisciplinary HCV clinic, reports treatment completion and cure rates, and estimates the cost of HCV medications provided at no cost to uninsured patients. A retrospective chart review was performed and identified 69 uninsured HCV patients who received medical care at Mercy Health Center, a small non-profit community clinic, between January 2008 and March 2015. Three-fourths of the patients were unemployed, a third had multiple HCV exposures, nearly half acquired HCV due to illicit drug use, and more than half had active psychiatric disorders. Of those who received HCV treatment, 81% completed treatment and 85% were achieved virological cure. The multidisciplinary community clinic provided > $1.4 million of HCV antivirals at no cost to uninsured patients. Findings suggest a multidisciplinary community clinic comprised of a social worker, pharmacist, gastroenterologist, nurse, nurse practitioner, psychologist, and dietitian can help patients achieve HCV treatment completion and cure rates comparable to traditional physician-led clinics, and successfully manage uninsured and underserved HCV patients-who are often regarded as "difficult-to-treat" patients. Public health social workers and other health professionals are encouraged to advocate for treatment and care of poor and uninsured patients living with HCV in health agencies and health systems, otherwise population-wide reductions in HCV morbidity and mortality will not be realized. PMID- 29511989 TI - Arterial inflow line equipped with a side arm for circulatory support and catheter insertion during transcatheter aortic valve implantation for limited vascular access. AB - Transcatheter aortic valve implantation was performed on a 78-year-old patient. Elective circulatory support with cardiopulmonary bypass was planned because of left ventricular function impairment and hemodynamic instability. Limited vascular access was due to a severe atherosclerotic aorta distal to the origin of the left carotid artery. The right arm was the only safe vascular access site. However, at least 2 vascular access sites for angiographic catheter and inflow of circulatory support were required. An arterial inflow line equipped with a side arm was developed to enable single access to the right axillary artery to be used for the above purposes. PMID- 29511990 TI - On the Regularities of the Polar Profiles of Proteins Related to Ebola Virus Infection and their Functional Domains. AB - The number of fatalities and economic losses caused by the Ebola virus infection across the planet culminated in the havoc that occurred between August and November 2014. However, little is known about the molecular protein profile of this devastating virus. This work represents a thorough bioinformatics analysis of the regularities of charge distribution (polar profiles) in two groups of proteins and their functional domains associated with Ebola virus disease: Ebola virus proteins and Human proteins interacting with Ebola virus. Our analysis reveals that a fragment exists in each of these proteins-one named the "functional domain"-with the polar profile similar to the polar profile of the protein that contains it. Each protein is formed by a group of short sub sequences, where each fragment has a different and distinctive polar profile and where the polar profile between adjacent short sub-sequences changes orderly and gradually to coincide with the polar profile of the whole protein. When using the charge distribution as a metric, it was observed that it effectively discriminates the proteins from their functional domains. As a counterexample, the same test was applied to a set of synthetic proteins built for that purpose, revealing that any of the regularities reported here for the Ebola virus proteins and human proteins interacting with Ebola virus were not present in the synthetic proteins. Our results indicate that the polar profile of each protein studied and its corresponding functional domain are similar. Thus, when building each protein from its functional domai-adding one amino acid at a time and plotting each time its polar profile-it was observed that the resulting graphs can be divided into groups with similar polar profiles. PMID- 29511991 TI - Glucosylation of T-2 and HT-2 toxins using biotransformation and chemical synthesis: Preparation, stereochemistry, and stability. AB - Plant-derived phase II metabolites of T-2 toxin (T2) and HT-2 toxin (HT2) were first described in 2011 and further characterized in the following years. Since then, some efforts have been made to understand their biosynthesis, occurrence, toxicity, toxicokinetics, and finally relevance for consumers. Thus, the probably most important question is whether and how these metabolites contribute to toxicity upon hydrolysis either during food processing or the gastrointestinal passage. To answer this question, firstly, knowledge on the correct stereochemistry of T2 and HT2 glucosides is important as this affects hydrolysis and chemical behavior. So far, contradictory results have been published concerning the number and anomericity of occurring glucosides. For this reason, we set up different strategies for the synthesis of mg-amounts of T2, HT2, and T2 triol glucosides in both alpha and beta configuration. All synthesized glucosides were fully characterized by NMR spectroscopy as well as mass spectrometry and used as references for the analysis of naturally contaminated food samples to validate or invalidate their natural occurrence. Generally, 3-O-glucosylation was observed with two anomers of HT2 glucoside being present in contaminated oats. In contrast, only one anomer of T2 glucoside was found. The second aspect of this study addresses the stability of the glucosides during thermal food processing. Oat flour was artificially contaminated with T2 and HT2 glucosides individually and extruded at varying initial moisture content and temperature. All four glucosides appear to be more stable during food extrusion than the parent compounds with the glucosidic bond not being hydrolyzed. PMID- 29511992 TI - Major Reduction in Axillary Lymph Node Dissections After Neoadjuvant Systemic Therapy for Node-Positive Breast Cancer by combining PET/CT and the MARI Procedure. AB - BACKGROUND: Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy. METHODS: All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node. RESULTS: The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment. CONCLUSION: Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN + breast cancer patients. PMID- 29511993 TI - Pulmonary Arterial Hypertension: Combination Therapy in Practice. AB - Combination therapy is now regarded as the standard of care in pulmonary arterial hypertension (PAH) and is becoming widely used in clinical practice. Given the inherent complexities of combining medications, there is a need for practical advice on implementing this treatment strategy in the clinic. Drawing on our experience and expertise, within this review, we discuss some of the challenges associated with administration of combination therapy in PAH and how these can be addressed in the clinic. Despite their differing modes of action, all of the currently available classes of PAH therapy induce systemic vasodilation. In initial combination therapy regimens in particular, this may lead to additive side effects and reduced tolerability compared with monotherapy. However, approaches such as staggered treatment initiation and careful up-titration may reduce the risk of additive side effects and have been used successfully in clinical practice, as well as in clinical trials and registry studies. When combination therapy regimens are initiated, it is important that patients are monitored regularly for the presence of any side effects and that these are then managed promptly and appropriately. For patients to attain the best outcomes, the treatment regimen must be tailored to the individual's specific needs, including consideration of PAH etiology, the presence of comorbidities and concomitant medications beyond PAH therapy, and patient lifestyle and preference. It is also vital that individuals are managed at expert care centers, where multidisciplinary teams have a wealth of specialist experience in treating PAH patients. Adherence to therapy can be a concern in a chronic disease such as PAH, and as treatment regimens become increasingly complex, maintaining good treatment adherence may become more challenging. It is essential that patients are educated on the importance of treatment adherence, and this is a key role for the PAH nurse specialist. For patients who are managed carefully in expert centers with combination therapy regimens that are tailored to their specific needs, a favorable benefit-risk ratio can be achieved. With individual and carefully managed approaches, the excellent results observed with combination therapy in clinical trials can be obtained by patients in a real-world setting. PMID- 29511994 TI - Effect of Oral Branched-Chain Amino Acids on Serum Albumin Concentration in Heart Failure Patients with Hypoalbuminemia: Results of a Preliminary Study. AB - BACKGROUND: We conducted a randomized, controlled trial to determine whether supplementation with oral branched-chain amino acids (BCAAs) improves serum albumin and clinical outcomes in heart failure (HF) patients with hypoalbuminemia. METHODS AND RESULTS: We randomly assigned 18 in-hospital HF patients with serum albumin < 3.5 g/dL to receive oral BCAA granules (LIVACT(r)) for 28 days during their hospital stay or until discharge (BCAA group; N = 9) or to receive no supplementation (controls; N = 9), in addition to recommended HF therapy. The primary endpoints were changes from baseline in serum albumin and cardiothoracic ratio (CTR). Sixteen patients completed the study. The mean (+/- standard deviation) period of BCAA supplementation was 18.4 +/- 8.4 days. Serum albumin significantly increased in the BCAA group [mean difference vs baseline, 0.44 g/dL; 95% confidence interval (CI) 0.13-0.76; P = 0.014] and did not change in controls (0.18 g/dL; 95% CI - 0.05 to 0.40; P = 0.108). CTR significantly decreased in the BCAA group (- 2.3%; 95% CI - 3.8 to - 0.8; P = 0.014) and did not change in controls (- 1.0%; 95% CI - 2.3 to 0.3; P = 0.111). CONCLUSION: In hospital HF patients with hypoalbuminemia supplemented with BCAAs showed increased serum albumin and decreased CTR. Clinical trial registration number UMIN000004488 [ http://www.umin.ac.jp/ctr/index.htm ]. PMID- 29511996 TI - Risk Factors of Post-traumatic Stress and Depressive Disorders in Longmenshan Adolescents After the 2013 Lushan Earthquake. AB - This study examined the severity of post-traumatic stress and depressive disorders in Longmenshan adolescents after the 2013 Lushan earthquake, as well as relationships among earthquake-related exposure, post-earthquake negative factors, previous exposure to the 2008 Wenchuan earthquake, and level of earthquake impact (city). A cross-sectional survey was conducted among adolescents in Lushan (n = 1416), Baoxing (n = 1102) and Tianquan (n = 1265) at 3 years after the Lushan earthquake. Respondents were evaluated using the Earthquake Experience Scale, the Adolescent Self-rating Life Events Checklist (ASLEC), the Children's Revised Impact of Event Scale (CRIES-13), and the Depression Self-Rating Scale (KADS-6). High levels of post-traumatic stress and depression symptoms were found among adolescents in the most heavily affected cities, and these symptoms were more severe in respondents exposed to the 2008 earthquake. PTSD correlated most strongly with earthquake exposure, whereas depression correlated most strongly with psychosocial stressors following the event. PMID- 29511997 TI - The Roles of Socioeconomic Status, Occupational Health and Job Rank on the Epidemiology of Different Psychiatric Symptoms in a Sample of UK Workers. AB - There is a considerable gap in epidemiological literature about community mental health showing how psychiatric symptoms are associated with job rank, socioeconomic status, and occupational health. We examine data from 4596 employees collected in the United Kingdom's Psychiatric Morbidity among Adults Living in Private Households Survey. There were 939 workers in managerial jobs, 739 in supervisory jobs and 2918 employees in lower ranking jobs. Of the 4596 workers, 2463 had depressive symptoms and 2133 no depressive symptoms. Job rank, household gross income, social class, personal gross income and socio-economic group were significantly associated with general health, occupational health and depressive and avoidant symptoms. Job rank, occupational and physical health also explained the variance in paranoid and avoidant symptoms among the employees. This study shows that severe psychopathology is related to workers' job rank. PMID- 29511995 TI - Is 60 the New 50? Examining Changes in Biological Age Over the Past Two Decades. AB - Increasing life expectancy has been interpreted as improving health of a population. However, mortality is not always a reliable proxy for the pace of aging and could instead reflect achievement in keeping ailing people alive. Using data from NHANES III (1988-1994) and NHANES IV (2007-2010), we examined how biological age, relative to chronological age, changed in the United States between 1988 and 2010, while estimating the contribution of changes in modifiable health behaviors. Results suggest that biological age is lower for more recent periods; however, the degree of improvement varied across age and sex groups. Overall, older adults experienced the greatest improvement or decreases in biological age. Males, especially those in the youngest and oldest groups, experienced greater declines in biological age than females. These differences were partially explained by age- and sex-specific changes in behaviors, such as smoking, obesity, and medication use. Slowing the pace of aging, along with increasing life expectancy, has important social and economic implications; thus, identifying modifiable risk factors that contribute to cohort differences in health and aging is essential. PMID- 29511998 TI - Comparative transcriptome analysis provides key insights into gene expression pattern during the formation of nodule-like structures in Brachypodium. AB - Auxins can induce the formation of nodule-like structures (NLS) in plant roots even in the absence of rhizobia and nitrogen-fixing bacteria can colonize these structures. Interestingly, NLS can be induced in roots of both legumes and non legumes. However, our understanding of NLS formation in non-legumes at a molecular level is limited. This study aims to investigate NLS formation at a developmental and molecular level in Brachypodium distachyon. We treated Brachypodium roots with the synthetic auxin, 2,4-D, to induce NLS at a high frequency (> 80%) under controlled conditions. A broad base and a diffuse meristem characterized these structures. Next, we performed a comprehensive RNA sequencing experiment to identify differentially expressed genes (DEGs) in Brachypodium roots during NLS formation. We identified 618 DEGs; several of which are promising candidates for control of NLS based on their biological and molecular functions. We validated the expression pattern of several genes via RT PCR. Next, we compared the expression profile of Brachypodium roots with rice roots during NLS formation. We identified 76 single-copy ortholog pairs in rice and Brachypodium that are both differentially expressed during this process. Some of these genes are involved in auxin signaling, root development, and legume rhizobia symbiosis. We established an experimental system to study NLS formation in Brachypodium at a developmental and genetic level, and used RNA-sequencing analysis to understand the molecular mechanisms controlling this root organogenesis program. Furthermore, our comparative transcriptome analysis in Brachypodium and rice identified a key set of genes for further investigating this genetic pathway in grasses. PMID- 29512000 TI - Evaluation of the AJCC 8th Edition Staging System for Pathologically Versus Clinically Staged Intrahepatic Cholangiocarcinoma (iCCA): a Time to Revisit a Dogma? A Surveillance, Epidemiology, and End Results (SEER) Analysis. AB - BACKGROUND: Recently, the AJCC has released its 8th edition changes to the staging system for intrahepatic cholangiocarcinoma (iCCA). This study sought to validate the proposed changes to the 8th edition of AJCC system for T and N classification of iCCA using a population-based data set. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database (1998-2013), patients undergoing resection or non-surgical management for non-metastatic iCCA were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-indices) calculated from Cox proportional hazards models were calculated to evaluate discriminatory power. RESULTS: The study included 2630 patients resected (37%) or non-surgically managed (63%) for iCCA. Nodal staging was performed in 56%, of whom 31% had positive nodes. For all patients with iCCA, the median 5-year survival by AJCC T classification for T1a, T1b, T2, T3, and T4 was 32, 21, 14, 10, and 10 months, respectively (p < 0.001). The concordance index for the staging system was 0.57 for all patients, 0.62 for those who underwent resection, and 0.54 for patients who did not undergo resection. CONCLUSION: In summary, the new AJCC 8th edition staging system is comparable to the 7th edition and valid in stratifying patients with iCCA. However, the performance of the staging system is better in patients undergoing surgical resection than those undergoing non-surgical management. These findings further highlight the need for improved accuracy of radiological imaging in clinically staging patients to guide prognosis. PMID- 29512001 TI - Evaluating the Ability of the New Subclassification to Prognosticate Outcomes Following Hepatectomy for Patients with HBV-Related HCC. AB - BACKGROUND: Recently, experts proposed subclassification for BCLC B patients. In this study, we aimed to evaluate the efficient of subclassification of patients with hepatitis B virus-related hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) staging system. METHODS: Seven hundred twenty-nine consecutive hepatitis B virus-related HCC patients with BCLC stage B classification who underwent hepatectomy in the period 2006-2012 were retrospectively analyzed. Patients were reclassified based on the new proposed subclassification of the BCLC B stage from B1 to B4. The prognosis of subclassification was tested using Kaplan-Meier statistics analysis. RESULTS: There were 145 (19.9%), 480 (65.8%), 62 (8.5%), and 42 (5.8%) patients in B1, B2, B3, and B4, respectively. The result suggested that overall and tumor-free survival rates among the B1, B2, and B3 subclassification in the Bolondi system had significant difference (P < 0.05). However, no significant difference was found between B3 and B4 subclassifications. Cox regression showed that BCLC B subclassification, largest/smallest diameter, and anatomic liver resection were independent predictors of tumor-free survival. BCLC B subclassification and anatomic liver resection were independent predictors of overall survival. CONCLUSIONS: The subclassification of BCLC stage B can be used in patients with HBV-related HCC who underwent curative intent hepatectomy. Patients in BCLC B1 and B2 subgroups should be treated more aggressively than patients in B3 and B4 subgroups. B3 and B4 groups should be merged for patients with HBV-related HCC who underwent curative intent hepatectomy. PMID- 29511999 TI - MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype. AB - Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition. PMID- 29512003 TI - Subacute Upper GI Bleeding Due To Infected Aortic Graft with Aorto-Duodenal Fistula. PMID- 29512002 TI - Hepatic Artery Resection for Bismuth Type III and IV Hilar Cholangiocarcinoma: Is Reconstruction Always Required? AB - OBJECTIVE: The objective of the study is to examine the feasibility of hepatic artery resection (HAR) without subsequent reconstruction (RCS) in specified patients of Bismuth type III and IV hilar cholangiocarcinoma. METHODS: We retrospectively reviewed 63 patients who underwent hepatic artery resection for Bismuth type III and IV hilar cholangiocarcinoma. These patients were subsequently enrolled into two groups based on whether the artery reconstruction was conducted. Postoperative morbidity and mortality, and long-term survival outcome were compared between the two groups. RESULTS: There were 29 patients in HAR group and 34 patients in the HAR + RCS group. Patients with hepatic artery reconstruction tended to have longer operative time (545.6 +/- 143.1 min vs. 656.3 +/- 192.8 min; P = 0.013) and smaller tumor size (3.0 +/- 1.1 cm vs. 2.5 +/ 0.9 cm; P = 0.036). The R0 resection margin was comparable between the HAR group and HAR + RCS group (86.2 vs. 85.3%; P > 0.05). Twelve patients (41.4%) with 24 complications in HAR group and 13 patients (38.2%) with 25 complications in HAR + RCS group were recorded (P = 0.799). The postoperative hepatic failure rate (13.8 vs. 5.9%) and postoperative mortality rate (3.4% vs. 2.9%) were also comparable between the two groups. In the HAR group, the overall 1-, 3-, and 5-year survival rates were 72, 41, and 19%, respectively; while in the HAR + RCS group, the overall 1-, 3-, and 5-year survival rates were 79, 45, and 25%, respectively (P = 0.928). CONCLUSIONS: Hepatic artery resection without reconstruction is also a safe and feasible surgical procedure for highly selected cases of Bismuth type III and IV hilar cholangiocarcinoma. PMID- 29512004 TI - Gallstone Ileus. PMID- 29512005 TI - The wild bootstrap for multivariate Nelson-Aalen estimators. AB - We rigorously extend the widely used wild bootstrap resampling technique to the multivariate Nelson-Aalen estimator under Aalen's multiplicative intensity model. Aalen's model covers general Markovian multistate models including competing risks subject to independent left-truncation and right-censoring. This leads to various statistical applications such as asymptotically valid confidence bands or tests for equivalence and proportional hazards. This is exemplified in a data analysis examining the impact of ventilation on the duration of intensive care unit stay. The finite sample properties of the new procedures are investigated in a simulation study. PMID- 29512006 TI - Convolution neural networks for real-time needle detection and localization in 2D ultrasound. AB - PURPOSE: We propose a framework for automatic and accurate detection of steeply inserted needles in 2D ultrasound data using convolution neural networks. We demonstrate its application in needle trajectory estimation and tip localization. METHODS: Our approach consists of a unified network, comprising a fully convolutional network (FCN) and a fast region-based convolutional neural network (R-CNN). The FCN proposes candidate regions, which are then fed to a fast R-CNN for finer needle detection. We leverage a transfer learning paradigm, where the network weights are initialized by training with non-medical images, and fine tuned with ex vivo ultrasound scans collected during insertion of a 17G epidural needle into freshly excised porcine and bovine tissue at depth settings up to 9 cm and [Formula: see text]-[Formula: see text] insertion angles. Needle detection results are used to accurately estimate needle trajectory from intensity invariant needle features and perform needle tip localization from an intensity search along the needle trajectory. RESULTS: Our needle detection model was trained and validated on 2500 ex vivo ultrasound scans. The detection system has a frame rate of 25 fps on a GPU and achieves 99.6% precision, 99.78% recall rate and an [Formula: see text] score of 0.99. Validation for needle localization was performed on 400 scans collected using a different imaging platform, over a bovine/porcine lumbosacral spine phantom. Shaft localization error of [Formula: see text], tip localization error of [Formula: see text] mm, and a total processing time of 0.58 s were achieved. CONCLUSION: The proposed method is fully automatic and provides robust needle localization results in challenging scanning conditions. The accurate and robust results coupled with real-time detection and sub-second total processing make the proposed method promising in applications for needle detection and localization during challenging minimally invasive ultrasound-guided procedures. PMID- 29512007 TI - Correction to: Can in vivo surface dental enamel microbiopsies be used to measure remote lead exposure? AB - To accomplish the aim A, lead from 90 bovine incisor crowns was determined by graphite furnace atomic absorption spectrometer as a function of exposure time and lead concentration. PMID- 29512008 TI - Occurrence of sweet refuse at disposal sites: rainwater retention capacity and potential breeding opportunities for Aedes aegypti. AB - Nectar is the staple diet of adult mosquitoes in the wild, but its availability is inconsistent and can be affected by rainfall. In urban centers, Aedes vectors commonly use man-made containers as their major habitat; however, they can colonize any items replenished by rainfall. Garbage output has increased significantly in recent years, at a time when collection frequency is reducing. Such garbage usually includes organic components, some of which are sweet and can be fed upon by other animals or become can containers for rainwater. Despite evidence that Aedes larvae can thrive in containers comprised of organic waste material, which can be produced by rodents gnawing on fruits or vegetables, and that adults can survive on sweet waste fluids, the capacity of organic waste materials to accumulate rainwater and act as egg deposition sites has not been examined. It is also unknown for how long sweet extracts can sustain the life of adult vectors. Here, we investigated the abundance of sweet leftovers at garbage sites and the rainwater retention capacity of some organic materials through a field survey and laboratory bioassays. We also examined whether sweet waste fluids impact egg hatching success and longevity of Aedes aegypti. The results of this study indicated that sweet products with leftovers are highly prevalent in garbage. When exposed to rain, food items (BAFrc, banana fruit resembling container; and BSPrc, boiled sweet potato resembling container) and the packaging of sweet foods (SMIc, sweetened condensed milk can) retained water. When provided an opportunity to oviposit in cups containing BAF extract (BAFex), BSP extract (BSPex), and SMI extract (SMIex), eggs were deposited in all media. Egg maturation in the BAFex environment resulted in similar larval eclosion success to that resulting from embryo development in a water milieu. Adults maintained on sweet waste extracts had long lifespans, although shorter than that of their sugar solution (SUS)-fed counterparts. Taken together, these results indicated that sweet waste materials are useful to dengue mosquitoes, acting both as oviposition sites and energy sources. PMID- 29512009 TI - Seasonal drought effects on the water quality of the Biobio River, Central Chile. AB - Quantifying the effect of droughts on ecosystem functions is essential to the development of coastal zone and river management under a changing climate. It is widely acknowledged that climate change is increasing the frequency and intensity of droughts, which can affect important ecosystem services, such as the regional supply of clean water. Very little is understood about how droughts affect the water quality of Chilean high flow rivers. This paper intends to investigate the effect of an, recently identified, unprecedented drought in Chile (2010-2015), on the Biobio River water quality, (36 degrees 45'-38 degrees 49' S and 71 degrees 00'-73 degrees 20' W), Central Chile. This river is one of the largest Chilean rivers and it provides abundant freshwater. Water quality (water temperature, pH, dissolved oxygen, electrical conductivity, biological oxygen demand, total suspended solids, chloride, sodium, nutrients, and trace metals), during the drought (2010-2015), was compared with a pre-drought period (2000-2009) over two reaches (upstream and downstream) of the river. Multivariate analysis and seasonal Mann-Kendall trend analyses and a Theil-Sen estimator were employed to analyze trends and slopes of the reaches. Results indicated a significant decreased trend in total suspended solids and a slightly increasing trend in water temperature and EC, major ions, and trace metals (chrome, lead, iron, and cobalt), mainly in summer and autumn during the drought. The reduced variability upstream suggested that nutrient and metal concentrations were more constant than downstream. The results evidenced, due to the close relationship between river discharge and water quality, a slightly decline of the water quality downstream of the Biobio River during drought period, which could be attenuated in a post drought period. These results displayed that water quality is vulnerable to reductions in flow, through historical and emerging solutes/contaminants and induced pH mobilization. Consequently, seasonal changes and a progressive reduction of river flow affect the ecosystem functionality in this key Chilean river. The outcomes from this research can be used to improve how low flow conditions and the effects of a reduction in the river volume and discharge are assessed, which is the case under the scenario of more frequent drought periods. PMID- 29512010 TI - Purification of arsenic-contaminated water with K-jarosite filters. AB - The high toxicity and potential arsenic accumulation in several environments have encouraged the development of technologies for its removal from contaminated waters. However, the arsenic released into aquatic environment comes mainly from extremely acidic mining effluents, making harder to find stable adsorbents to be used in these conditions. In this work, K-jarosite particles were synthesized as a stable adsorbent in acidic medium for eliminating arsenic from contaminated water. The adsorption capacities of K-jarosite for As3+, As5+, and monomethylarsonic acid were 9.45, 12.36, and 8.21 mg g-1, respectively. Most arsenic in water was adsorbed within the first 10 min, suggesting the fast arsenic adsorption kinetics of K-jarosite particles. Because of that, a K jarosite filter was constructed for purifying water at a constant flow. The K jarosite filter was highly efficient to treat arsenic-contaminated water from a Brazilian river, reducing the concentration of arsenic in water to near zero. These data suggest the K-jarosite filter can be used as a low-cost technology for purifying arsenic-contaminated water in acidic medium. PMID- 29512012 TI - Solar light-driven photocatalysis using mixed-phase bismuth ferrite (BiFeO3/Bi25FeO40) nanoparticles for remediation of dye-contaminated water: kinetics and comparison with artificial UV and visible light-mediated photocatalysis. AB - Mixed-phase bismuth ferrite (BFO) nanoparticles were prepared by co-precipitation method using potassium hydroxide as the precipitant. X-ray diffractogram (XRD) of the particles showed the formation of mixed-phase BFO nanoparticles containing BiFeO3/Bi25FeO40 phases with the crystallite size of 70 nm. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed the formation of quasi-spherical particles. The BFO nanoparticles were uniform sized with narrow size range and with the average hydrodynamic diameter of 76 nm. The band gap energy of 2.2 eV showed its ability to absorb light even in the visible range. Water contaminated with Acid Yellow (AY-17) and Reactive Blue (RB-19) dye was treated by photocatalysis under UV, visible, and solar light irradiation using the BFO nanoparticles. The BFO nanoparticles showed maximum photocatalytical activity under solar light as compared to UV and visible irradiations, and photocatalysis was favored under acidic pH. Complete degradation of AY-17 dyes and around 95% degradation of RB-19 could be achieved under solar light at pH 5. The kinetics of degradation followed the Langmuir Hinshelhood kinetic model showing that the heterogeneous photocatalysis is adsorption controlled. The findings of this work prove the synthesized BFO nanoparticles as promising photocatalysts for the treatment of dye-contaminated industrial wastewater. PMID- 29512011 TI - Ecotoxicological impacts of surface water and wastewater from conventional and advanced treatment technologies on brood size, larval length, and cytochrome P450 (35A3) expression in Caenorhabditis elegans. AB - Anthropogenic micropollutants and transformation products (TPs) negatively affect aquatic ecosystems and water resources. Wastewater treatment plants (WWTP) represent major point sources for (micro)pollutants and TPs in urban water cycles. The aim of the current study was to assess the removal of micropollutants and toxicity during conventional and advanced wastewater treatment. Using wild type and transgenic Caenorhabditis elegans, the endpoint reproduction, growth, and cytochrome P450 (CYP) 35A3 induction (via cyp-35A3::GFP) were assessed. Samples were collected at four WWTPs and a receiving surface water. One WWTP included the advanced treatments: ozonation followed by granular activated carbon (GAC) or biological filtration (BF), respectively. Relevant micropollutants and WWTP parameters (n = 111) were included. Significant reproductive toxicity was detected for one WWTP effluent (31-83% reduced brood size). Three of four effluents significantly promoted the growth of C. elegans larvae (49-55% increased lengths). This effect was also observed for the GAC (34-41%) and BF (30%) post-treatments. Markedly, significant cyp-35A3::GFP induction was detected for one effluent before and after ozonation, being more pronounced for the ozonated samples (5- and 7.4-fold above controls). While the advanced treatments decreased the concentrations of most micropollutants, the observed effects may be attributed to effects of residual target compounds and/or compounds not included in the target chemical analysis. This highlights the need for an integrated assessment of (advanced) wastewater treatment covering both biological and chemical parameters. PMID- 29512013 TI - Total mercury concentration in two marine fish species, mackerel (Scomberomorus sp.) and snapper (Lutjanus sp.), from several Mexican fishing ports. AB - Mercury and methylmercury concentrations were evaluated in two marine fish species captured and consumed in Mexico, snapper (Lutjanus sp.) and mackerel (Scomberomorus sp.), obtained from several fish ports on the Pacific Ocean and the Gulf of Mexico. Significant differences were found between the median total mercury concentrations in snapper and mackerel, which were 0.187 and 0.125 MUg/g (ww), respectively. Differences in the total mercury concentration in snapper were observed between the different oceans; snappers from the Gulf of Mexico registered a higher median mercury concentration (0.233 MUg/g) than those caught in the Pacific Ocean (0.150 MUg/g). Ninety-three percent of all samples presented had mercury concentrations that did not exceed the maximum limit (0.5 MUg/g) specified by Mexican regulations, although 21% exceeded the US EPA limit of 0.3 MUg/g, and three samples had mercury concentrations that were above the FDA recommended limit of 1 MUg/g. Mackerel and snapper collected in the ports of Tampico and Mazatlan (economically important industrial cities and fishing sites) had the highest concentrations of total mercury, compared with those obtained from Acapulco and Ensenada (important touristic centers), which showed the lowest values. Recommendations should be made for the maximum allowed consumption of these fish in Mexico, especially for populations settled in shorelines where fish is essential for the daily diet. PMID- 29512014 TI - Mercury in the feathers of bird scavengers from two areas of Patagonia (Argentina) under the influence of different anthropogenic activities: a preliminary study. AB - Mercury (Hg) is a global pollutant that bioaccumulates and biomagnifies in food chains and is associated with adverse effects in both humans and wildlife. We used feather samples from bird scavengers to evaluate Hg concentrations in two different areas of Northern Patagonia. Hg concentrations were analyzed in feathers obtained from turkey vultures (Cathartes aura), Black Vultures (Coragyps atratus), and southern crested caracaras (Caracara plancus) from the two areas of Northern Patagonia (Argentina): Bariloche and El Valle. Hg was detected in all the samples analyzed, but the concentrations can be considered low for the three species in both sampling areas. The mean concentration of Hg in Bariloche was 0.22 +/- 0.16 mg/kg dry weight (d.w.) in black vulture, 0.13 +/- 0.06 mg/kg d.w. in turkey vulture, and 0.13 +/- 0.09 mg/kg d.w. in southern crested caracara; in El Valle, the mean concentration of Hg was 1.02 +/- 0.89 mg/kg d.w. in black vulture, 0.53 +/- 0.82 mg/kg d.w. in turkey vulture, and 0.54 +/- 0.74 mg/kg d.w. in southern crested caracara. Hg concentrations in feathers were explained by the sampling area but not by the species. The concentrations of Hg contamination were comparable to those obtained in other studies of terrestrial raptors and aquatic bioindicator raptors. The species of the present study occur throughout much of North and South America. Thus, they may be appropriate bioindicators across the species' range, which is particularly useful as a surrogate, especially in distribution areas shared with endangered scavengers such as the California condor (Gymnopsys californianus) and the Andean Condor (Vultur gryphus). PMID- 29512016 TI - Sustainable environmental chemistry and technology with focus on the Mediterranean area. PMID- 29512015 TI - NO3-/NH4+ proportions affect cadmium bioaccumulation and tolerance of tomato. AB - With the growth of the world population, cadmium (Cd) concentration in the environment has increased considerably as a result of human activities such as foundry, battery disposal, mining, application of fertilizers containing toxic elements as impurities, and disposal of metal-containing waste. Higher plants uptake N as ammonium (NH4+), nitrate (NO3- ), and many other water-soluble compounds such as urea and amino acids, and nourishing plants with N, providing part of it as NH4+, is an interesting alternative to the supply of this nutrient in the exclusive form of NO3- under Cd toxicity. The objective was to evaluate the influence of NO3- /NH4+ proportions on the development and tolerance of tomato plants grown under the presence of Cd in the culture medium. The experiment was conducted in a completely randomized block design in a 3 * 3 factorial arrangement consisting of three Cd rates (0, 50, and 100 MUmol L-1) and three NO3-/NH4+ proportions (100/0, 70/30, and 50/50) in the nutrient solution. To this end, we quantified the responses of the antioxidant enzymatic system and productive and functional changes in Solanum lycopersicum var. esculentum (Calabash Rouge). Shoot biomass production decreased with the maximum Cd rate (100 MUmol L-1) tested in the growth medium, whereas the NO3- /NH4+ proportions and other Cd rates did not significantly influence this variable. The lowest SPAD values were observed at the 100/0 NO3- /NH4+ proportion and in plants exposed to Cd. The largest accumulation of the metal occurred in the shoots at the NO3- /NH4+ proportion of 70/30 and at 100 MUmol L-1 Cd and in the roots at 100/0 NO3 /NH4+ and with 50 and 100 MUmol L-1 Cd. The concentration and accumulation of NO3 were highest at the NO3-/NH4+ proportion of 100/0 in the shoots and at 50/50 NO3 /NH4+ in the roots, whereas for NH4+, values were higher as the proportion of N supplied in the form of NH4+ was increased. The nitrate reductase enzyme activity decreased with the Cd supply in the nutrient solution. The antioxidant system enzymes were activated as we increased the NO3-/NH4+ proportion and/or Cd rates added to the nutrient solution in both shoots and roots of the tomato plant, except for ascorbate peroxidase. Based on the results obtained, if the plant is to be used as a food source as is the case of tomato, the 100/0 NO3-/NH4+ proportion is the better alternative because it resulted in higher Cd accumulation in the root system over the translocation to the shoots and consequently to the fruit. PMID- 29512017 TI - Emotion Control Predicts Internalizing and Externalizing Behavior Problems in Boys With and Without an Autism Spectrum Disorder. AB - Children and adolescents with Autism Spectrum Disorder (ASD) often show comorbid emotional and behavior problems. The aim of this longitudinal study is to examine the relation between emotion control (i.e., negative emotionality, emotion awareness, and worry/rumination) and the development of internalizing and externalizing problems. Boys with and without ASD (N = 157; age 9-15) were followed over a period of 1.5 years (3 waves). We found that baseline levels of worry/rumination was a specific predictor of later externalizing problems for boys with ASD. Furthermore, the developmental trajectory of worry/rumination predicted the development of internalizing and externalizing problems in both groups. Our findings suggest that worry/rumination may constitute a transdiagnostic factor underlying both internalizing and externalizing problems in boys with and without ASD. PMID- 29512018 TI - Do Children with Autism Spectrum Disorder Share Fairly and Reciprocally? AB - This study investigated whether children with autism spectrum disorder (ASD) and typically developing children matched on receptive language share resources fairly and reciprocally. Children completed age-appropriate versions of the Ultimatum and Dictator Games with real stickers and an interactive partner. Both groups offered similar numbers of stickers (preferring equality over self interest), offered more stickers in the Ultimatum Game, and verbally referenced 'fairness' at similar rates. However, children with ASD were significantly more likely to accept unfair offers and were significantly less likely to reciprocate the puppet's offers. Failure to reciprocate fair sharing may significantly impact on social cohesion and children's ability to build relationships. These important differences may be linked to broader deficits in social-cognitive development and potentially self-other understanding. PMID- 29512019 TI - An external validation of the HEART pathway among Emergency Department patients with chest pain. AB - The impact of an outpatient disposition strategy for patients with HEART score 0 3 (HEART pathway) on HEART score prognostic accuracy is unclear. Our objective is to perform an external validation the HEART score in the setting of recent implementation of the HEART pathway. We conducted an external validation study of the HEART pathway among patients presenting to our ED with chest pain 6 weeks after institutional implementation of a HEART pathway outpatient disposition pathway. We reviewed the charts of 625 consecutive patients with chest pain. Data abstracted included all elements of the HEART score to include history, electrocardiogram (ECG) read, patient age, patient risk factors, and troponin levels. We also reviewed each patient's record for evidence of major adverse cardiac events (MACE) to include mortality, myocardial infarction, or coronary revascularization over 6 weeks following their initial ED visit. We double abstracted 10% of the charts for quality assurance purposes. Of 625 charts, 449 patients met all criteria for study inclusion. Of these, 25 subjects (5.56%) experience 6-week MACE. No subject with a score of 3 or less has a MACE at 6 weeks (100% sensitivity, 38.7% specificity). The area under the receiver operator curve (AUROC) is 0.898 (95% confidence interval 0.847-0.950). Kappa coefficients for inter-rater reliability range from 0.62 for the history component of the HEART score to 1.0 for troponin. A low HEART score (0-3) maintains excellent sensitivity for predicting 6-week MACE in the setting of an outpatient disposition pathway for these patients. PMID- 29512020 TI - Noninvasive auto-titrating ventilation (AVAPS-AE) versus average volume-assured pressure support (AVAPS) ventilation in hypercapnic respiratory failure patients. AB - Auto-titrating noninvasive ventilation (NIV) has been developed as a new mode applying variable expiratory-positive airway pressure (EPAP) in addition to variable inspiratory pressures (IPAP), both to deliver targeted tidal volume (VT) and to eliminate upper airway resistance. The purpose of this study is to evaluate whether NIV with auto-titrating mode will decrease more PaCO2 within a shorter time compared to volume-assured mode in hypercapnic intensive care unit (ICU) patients. The hypercapnic respiratory failure patients treated with average volume assured pressure support- automated EPAP mode (group1) were compared with those treated with average volume-assured pressure support mode (group2). Two groups were matched with each other according to baseline diagnoses, demographic characteristics, arterial blood gas values, target VT settings and daily NIV usage times. Built-in software was used to gather the ventilatory parameters. Twenty-eight patients were included in group 1, and 22 in group 2. The decrease in PaCO2 had been achieved within a shorter time period in group 1 (p < 0.05). This response was more pronounced within the first 6 h (mean reduction in PaCO2 was 7 +/- 7 mmHg in group 1 and 2 +/- 5 mmHg in group 2, p = 0.025), and significantly greater reductions in PaCO2 (18 +/- 11 mmHg in group 1 and 9 +/- 8 mmHg in group 2, p = 0.008) and plasma HCO3 levels (from 32 to 30 mEq and from 35 to 35 mEq, p = 0.007) took place within first 4 days. While mean IPAP was similar in both groups, maximum EPAP, mean VT and leak were significantly higher in group 1 than in group 2 (p < 0.05). Results of this preliminary study suggest that, this new auto-titrating NIV mode may provide additional benefit on volume-assured mode in decreasing PaCO2 more efficiently and rapidly in hypercapnic ICU patients. PMID- 29512022 TI - Small intestine strictures in opium addicts: An unrecognized cause of intestinal obstruction. AB - Strictures of the small intestine have been attributed many causes of Crohn's disease, nonsteroidal anti-inflammatory drugs, neoplastic, post-surgical, and corrosive ingestion. Opium as a cause of small intestine strictures has not been described. Six cases of opium addicts diagnosed with small intestine strictures were selected after excluding the possible etiology of strictures. Investigations like upper gastrointestinal endoscopy, colonoscopy (in patients with small intestinal obstruction), barium meal follow-through, and histopathology of strictures were done in all patients. Among the six cases, two patients were diagnosed with small intestinal obstruction and four patients with gastric outlet obstruction. Histopathology of the strictures revealed marked thickening of submucosa with infiltration by lymphocytes, plasma cells, and plenty of eosinophils. There was dilatation of vessels and lymphatics. The granulomatous reaction was not seen. These histological features are suggestive of concentric fibrous thickening in submucosa with stricture formation possibly as a result of drug abuse like opioids and opioid-like products resulting in transient ischemia of the small intestine leading to fibrosis. Patients were managed by surgery and deaddiction treatment was given to prevent further complications. Opium and opioid-like drugs can cause small intestinal strictures causing ulceration and fibrosis in opioid-dependent patients. PMID- 29512021 TI - The protective effects of metformin in an in vitro model of aging 3T3 fibroblast under the high glucose conditions. AB - Metformin is the most widely used anti-diabetic drug in the world. It reduces advanced glycation end product (AGEs)-induced ROS generation in high glucose condition. Protein glycation contributes to skin aging as it deteriorates the existing collagen by crosslinking. The progressive increase of AGE during aging not only causes oxidative damage to cellular macromolecules but also modulates the activation of transcription factors nuclear factor kappa-B(NF-kB). However, it is still unclear whether metformin can change collagen production and NF-kB activity induced by high glucose conditions in 3T3 fibroblast. The effects of metformin on proliferation, apoptosis, and collagen levels and NF-kB activity of in vitro cell aging model of 3T3 fibroblast cells in high glucose conditions. At first, we investigated the effects of 50 mM high glucose concentration, with or without metformin, on 3T3 fibroblast proliferation, by BrdU immunostaining for cell proliferation. Apoptotic levels were analyzed by flow cytometric assay. NF kB(p65) activity was measured by transcription factor assay kit and collagen I and III levels by Collagen Estimation Assay through ELISA. We observed that metformin exposure leads to decreased apoptosis levels and increased proliferation of 3T3 fibroblast in high glucose media. We also determined that metformin exposure leads to increased production of collagen I-III and decreased activation of NF-kB(p65) activity. The data are consistent with the observation that metformin has a protective effect in this in vitro model of aging 3T3 fibroblasts under high glucose conditions inducing cell proliferation, collagen I and III production, protection from apoptosis, and reducing NF-kB(p65) activity. PMID- 29512024 TI - Spongiotic Gingival Hyperplasia Synchronously Involving Multiple Sites: Case Report and Review of the Literature. AB - Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a gingival lesion with unique clinicopathologic features that may involve synchronously multiple sites. We present a case with lesions clinically consistent with LJSGH in four jaw quadrants, confirmed by biopsy and review the English literature on multifocal LJSGH cases. A 19 year-old woman presented with circumscribed, erythematous overgrowths on the right and left maxillary and mandibular gingiva. With the provisional diagnosis of multifocal LJSGH, total excision of four maxillary lesions was performed. Clinical, microscopic and immunohistochemical examination with cytokeratin 19 confirmed the diagnosis of LJSGH in multiple sites. The excised lesions showed partial to complete recurrence after 4 months, while spontaneous regression of all but one lesion was observed after 15 months. Twenty cases with synchronous involvement of the gingiva of at least two teeth were previously reported. Their clinical features were comparable to that of solitary LJSGH. Only one case involved all four jaw quadrants. Spontaneous remission has not been documented before. The recognition of multiple lesions with clinicopathologic features diagnostic of LJSGH in the same adult patient argue against the designations "localized" and "juvenile". Recurrences are common, while remission might occur. PMID- 29512023 TI - Rate of recurrence in Indian patients presenting with acute pancreatitis and identification of chronicity on follow up: Possible risk factors for progression. AB - BACKGROUND: To study the profile and long-term outcome of Indian patients presenting with acute pancreatitis and the possible risk factors for progression. METHODS: Consecutive patients with acute or recurrent acute pancreatitis seen in our department during July 2013 to December 2014 were included. Details of past episodes were collected and patients were followed up till March 2015. RESULTS: In the 97 patients included (mean age 47.2 [SD 16.9] years; 74 men), gallstones (37 [38.1%]) and alcohol (19 [19.6%]) were the major identified etiologies; the idiopathic (31 [32%]) group constituted a third of patients. Recurrences were more common with idiopathic etiology (14 patients out of 30 had recurrences [46.7%]) as compared to alcoholic (5 out of 19 [26.3%]) and biliary (4 out of 37 [10.8%]) pancreatitis and with mild index episode. Following the episode of acute pancreatitis, identification of chronic pancreatitis was more common with alcoholic (6 out of 18 [33%]) and idiopathic (9 out of 30 [30%]) etiology as compared to other etiologies. Longer duration of follow up, but not number of recurrent episodes, was associated with identification of chronicity in patients presenting as acute pancreatitis. CONCLUSIONS: Out of 97 patients with acute pancreatitis, 27 (27.8%) developed recurrences with risk factors being idiopathic etiology and mild index episode. Eighteen of 97 (18.6%) patients had evidence of chronic pancreatitis on follow up, risk factors being the alcoholic and idiopathic varieties, and longer duration of follow up. PMID- 29512025 TI - Ubiquitin Immunostaining in Thyroid Neoplasms Marks True Intranuclear Cytoplasmic Pseudoinclusions and May Help Differentiate Papillary Carcinoma from NIFTP. AB - Papillary thyroid carcinoma (PTC) is defined by an invasive growth pattern and classic nuclear features: enlarged, grooved, overlapping nuclei with chromatin clearing and intranuclear cytoplasmic pseudoinclusions (INCP). True INCPs are characteristic of PTC, but may infrequently be seen in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Nuclear abnormalities that mimic INCP ("pseudo-pseudoinclusions") are common in a variety of thyroid lesions. H&E and ubiquitin-stained whole tissue sections of classic PTC (n = 25) and NIFTP (n = 35) were evaluated. On H&E, true INCPs were present in all (100%) PTCs and absent in all NIFTPs (0%). Pseudo-pseudoinclusions were present in 13 (37%) NIFTPs. In 24 (96%) PTCs, ubiquitin was strongly expressed within INCPs. In NIFTPs, optically clear nuclei or pseudo-pseudoinclusions did not express ubiquitin (0/35). Occasionally, nuclear vacuoles in NIFTP demonstrated a marginated staining pattern, in which strong ubiquitin expression was seen at the periphery of the nucleus, but the central pale area was negative. In addition, 2 NIFTPs demonstrated intrafollicular psammomatoid calcifications which were strongly ubiquitin-positive. Psammoma bodies in PTC were ubiquitin negative in the majority of cases. We report a previously undescribed finding: strong ubiquitin expression in true INCPs in PTC, absence of true INCPs in NIFTP, and absence of ubiquitin expression in pseudo-pseudoinclusions in NIFTP. This finding supports the difference between true INCPs (found only in PTC) and pseudo pseudoinclusions (found in NIFTP). Using strict histologic criteria and ubiquitin immunostaining, the presence of true pseudoinclusions may exclude a diagnosis of NIFTP. Caution should be exercised when interpreting nuclear vacuoles or pseudo pseudoinclusions. PMID- 29512026 TI - Patch-Based Label Fusion with Structured Discriminant Embedding for Hippocampus Segmentation. AB - Automatic and accurate segmentation of hippocampal structures in medical images is of great importance in neuroscience studies. In multi-atlas based segmentation methods, to alleviate the misalignment when registering atlases to the target image, patch-based methods have been widely studied to improve the performance of label fusion. However, weights assigned to the fused labels are usually computed based on predefined features (e.g. image intensities), thus being not necessarily optimal. Due to the lack of discriminating features, the original feature space defined by image intensities may limit the description accuracy. To solve this problem, we propose a patch-based label fusion with structured discriminant embedding method to automatically segment the hippocampal structure from the target image in a voxel-wise manner. Specifically, multi-scale intensity features and texture features are first extracted from the image patch for feature representation. Margin fisher analysis (MFA) is then applied to the neighboring samples in the atlases for the target voxel, in order to learn a subspace in which the distance between intra-class samples is minimized and the distance between inter-class samples is simultaneously maximized. Finally, the k-nearest neighbor (kNN) classifier is employed in the learned subspace to determine the final label for the target voxel. In the experiments, we evaluate our proposed method by conducting hippocampus segmentation using the ADNI dataset. Both the qualitative and quantitative results show that our method outperforms the conventional multi-atlas based segmentation methods. PMID- 29512027 TI - Strain-Specific Quantification of Native Probiotic Bacillus spp. and Their Effect on Liver Function and Gut Microflora of Experimental Rats. AB - Safety and efficacy was investigated for two candidate probiotic B. flexus MCC2427 and B. licheniformis MCC2512 via in vivo studies on albino Wistar rats. In acute toxicity assay, rats were fed with single dose of 1010 cfu mL-1 of probiotics. The follow-up studies for next 14 days did not reveal any toxicity related criteria indicating the non-toxicity nature of probiotics. In 90-day repeated dosage studies, the cultures were administered in three doses (106, 107, 108 cfu mL-1). Results showed no overt toxic effect and no drastic treatment related changes pertaining to histopathology of vital organs. DNA fingerprinting indicated the lack of bacterial translocation. Superoxide dismutase and catalase activity indicated their antioxidant potential. Reduced serum cholesterol with improved HDL-cholesterol specified the cholesterol-reducing ability of the cultures, which was also apparent with increased excretion of cholic acid in feces. Both probiotic cultures positively altered the gut microbial environment, retained lactic acid bacterial effect, and simultaneously reduced pathogenic strains. A sensitive and rapid tool was developed using strain-specific qPCR primers, which facilitated appropriate estimation of test culture in feces. The data strongly advocate the safety of tested probiotics at levels used in the study. PMID- 29512028 TI - Essentials in the management of S. aureus bloodstream infection. AB - AIMS: Staphylococcus aureus bloodstream infection is one of the most common serious bacterial infections worldwide. It represents a heterogenous clinical entity with a high risk of metastatic complications and a high in-hospital mortality ranging between 20 and 30%. The outcome can be improved by optimised diagnostic and therapeutic management. Thus, our minireview should provide important and often missed pieces of information in the management of S. aureus bloodstream infection. METHODS: We describe the essentials in the management of S. aureus bloodstream infection. RESULTS: Five essentials were identified: 1) S. aureus bacteremia should always be considered clinically significant. 2) Length of bacteremia and fever is relevant for diagnostic workup, duration of therapy and prognosis. 3) Prompt identification and eradication of portal of entry and infective/metastatic foci are essential. 4) Infective endocarditis should be excluded. 5) Intravenous treatment for at least two weeks up to 4-6 weeks with antistaphylococcal penicillins for MSSA and vancomycin or daptomycin for MRSA bloodstream infection is indicated. CONCLUSION: Further efforts should be undertaken to increase the adherence to the essentials in the management of S. aureus bloodstream infection. PMID- 29512029 TI - The Protective Role of Selenium in AFB1-Induced Tissue Damage and Cell Cycle Arrest in Chicken's Bursa of Fabricius. AB - Aflatoxin B1 (AFB1) is a naturally occurring secondary metabolites of Aspergillus flavus and Aspergillus parasiticus, and is the most toxic form of aflatoxins. Selenium (Se) with antioxidant and detoxification functions is one of the essential trace elements for human beings and animals. This study aims to evaluate the protective effects of Se on AFB1-induced tissue damage and cell cycle arrest in bursa of Fabricius (BF) of chickens. The results showed that a dietary supplement of 0.4 mg.kg-1 Se alleviated the histological lesions induced by AFB1, as demonstrated by decreasing vacuoles and nuclear debris, and relieving oxidative stress. Furthermore, flow cytometry studies showed that a Se supplement protected AFB1-induced G2M phase arrest at 7 days and G0G1 phase arrest at 14 and 21 days. Moreover, the mRNA expression results of ATM, Chk2, p53, p21, cdc25, PCNA, cyclin D1, cyclin E1, cyclin B3, CDK6, CDK2, and cdc2 indicated that Se supplement could restore these parameters to be close to those in the control group. It is concluded that a dietary supplement of 0.4 mg kg-1 Se could diminish AFB1-induced immune toxicity in chicken's BF by alleviating oxidative damage and cell cycle arrest through an ATM-Chk2-cdc25 route and the ATM-Chk2-p21 pathway. PMID- 29512030 TI - Task-dependent evaluative processing of moral and emotional content during comprehension: An ERP study. AB - Recently, we showed that when participants passively read about moral transgressions (e.g., adultery), they implicitly engage in the evaluative (good bad) categorization of incoming information, as indicated by a larger event related brain potential (ERP) positivity to immoral than to moral scenarios (Leuthold, Kunkel, Mackenzie, & Filik in Social, Cognitive, and Affective Neuroscience, 10, 1021-1029, 2015). Behavioral and neuroimaging studies indicated that explicit moral tasks prioritize the semantic-cognitive analysis of incoming information but that implicit tasks, as used in Leuthold et al. (Social, Cognitive, and Affective Neuroscience, 10, 1021-1029, 2015), favor their affective processing. Therefore, it is unclear whether an affective categorization process is also involved when participants perform explicit moral judgments. Thus, in two experiments, we used similarly constructed morality and emotion materials for which their moral and emotional content had to be inferred from the context. Target sentences from negative vs. neutral emotional scenarios and from moral vs. immoral scenarios were presented using rapid serial visual presentation. In Experiment 1, participants made moral judgments for moral materials and emotional judgments for emotion materials. Negative compared to neutral emotional scenarios elicited a larger posterior ERP positivity (LPP) about 200 ms after critical word onset, whereas immoral compared to moral scenarios elicited a larger anterior negativity (500-700 ms). In Experiment 2, where the same emotional judgment to both types of materials was required, a larger LPP was triggered for both types of materials. These results accord with the view that morality scenarios trigger a semantic-cognitive analysis when participants explicitly judge the moral content of incoming linguistic information but an affective evaluation when judging their emotional content. PMID- 29512032 TI - Using Discrete-Choice Experiment Methods to Estimate the Value of Informal Care: The Case of Children with Intellectual Disability. AB - OBJECTIVES: This research produces a preference-based monetary valuation of informal care provided to children with intellectual disability (ID) that can be directly applied in economic evaluations. METHODS: A discrete-choice experiment (DCE) was designed to elicit an individual's willingness to accept compensation for different care tasks. Respondents were presented choice sets that included a care package comprising different amounts and types of care and asked to choose between the care package provided free of charge or providing that care themselves and receiving cash compensation. The care package included personal care, social support, household errands and housework, with the value of compensation, number of care hours provided and types of care varied across the choice sets. Choices were analysed using a generalised multinomial logit model and latent class model. RESULTS: A representative sample of 198 caregivers completed the survey (response rate 52%). Participants were recruited in Australia. Overall, caregivers would accept a minimum of Australian dollars ($A)20.61 to provide 1 h of care. The preferences for assistance varied significantly with different types of care tasks. Individuals placed the highest value on receiving assistance with social support ($A35.96) and the least value on receiving assistance with household errands ($A-0.92) CONCLUSIONS: This study produces a value of informal care provided to children with ID that can be directly applied in economic evaluations. The study shows that informal care tasks are not valued equally. Caregivers placed the most value on receiving assistance with social support, which may reflect the time spent by caregivers on these tasks. PMID- 29512031 TI - A Preliminary Study of the Relationship between Perceived Racism and Cardiovascular Reactivity and Recovery in Native Hawaiians. AB - Native Hawaiians, compared to other ethnic groups in Hawai'i, have significantly higher mortality rates and die at a younger average age from cardiovascular disease (CVD). This may be partially explained by elevated cardiovascular responses to racial stressors. Our study examined the degree to which blood pressure (BP) and heart rate (HR) reactivity and recovery, and ratings of subjective distress to racial stressors, differ as a function of Native Hawaiian college students' levels of perceived racism. This study had three phases. Phase 1 involved the development of a blatant and subtle racial stressor. Phase 2 involved assigning 132 students into high- or low-perceived racism groups based on scores on two perceived interpersonal racism measures. Phase 3 involved a psychophysiology laboratory experiment conducted with 35 of the 132 students. BP, HR, and subjective distress were measured during exposure to the blatant and subtle racial stressors. Systolic blood pressure (SBP) recovery following exposure to both stressors was significant for both groups. Although not significant, three trends were observed among the high-perceived racism group, which included: (1) greater reactivity to exposure to the subtle stressor than to the blatant stressor, (2) incomplete HR recovery following exposure to both stressors, and (3) incomplete SBP and diastolic blood pressure recovery following exposure to the subtle stressor. Participants also reported significantly greater subjective distress following exposure to the blatant than to the subtle stressor. Specific interventions, such as increased self-awareness of physiological responses to racial stressors, targeted at at-risk individuals are necessary to reduce a person's risk for CVD. PMID- 29512035 TI - Defining Short-term, Medium-term, Long-term, and Very Long-term Follow-up After Bariatric Surgery. PMID- 29512034 TI - Effectiveness, Tolerability, and Safety of Belimumab in Patients with Refractory SLE: a Review of Observational Clinical-Practice-Based Studies. AB - To date, belimumab is the only biological drug approved for the treatment of patients with active refractory SLE. We compared and critically analyzed the results of 11 observational clinical-practice-based studies, conducted in SLE referral centers. Despite the differences in endpoints and follow-up duration, all studies remarked that belimumab provides additional benefits when used as an add-on to existing treatment, allowing a higher rate of patients to reach remission and to taper or discontinue corticosteroids. In the OBSErve studies, 2 9.6% of patients discontinued corticosteroids and 72-88.4% achieved a >= 20% improvement by physician's judgment at 6 months. In Hui-Yuen's study, 51% of patients attained response by simplified SRI at month 6. In Sthoeger's study, 72.3% of patients discontinued corticosteroids and 69.4% achieved clinical remission by PGA after a median follow-up of 2.3 years. In the multicentric Italian study, 77 and 68.7% of patients reached SRI-4 response at months 6 and 12, respectively. In all the studies, disease activity indices decreased over time. Retention rates at 6, 9, and 12 months were 82-94.1, 61.2-83.3, and 56.7 79.2%, respectively. The main limitations of these studies include the lack of a control group, the short period of observation (6-24 months) and the lack of precise restrictions regarding concomitant medication management. This notwithstanding, these experiences provide a more realistic picture of real-life effectiveness of the drug compared with the randomized controlled clinical trials, where stringent inclusion/exclusion criteria and changes in background therapy could limit the inference of data to the routine clinical care. PMID- 29512036 TI - Does Bariatric Surgery Affect the Incidence of Endometrial Cancer Development? A Systematic Review. AB - Obesity has been linked to an increased prevalence in multiple cancers. Studies have suggested a reduction in the overall risk of cancer after bariatric surgery. We reviewed the evidence for bariatric surgery reducing the risk of endometrial cancer. Data was extracted from PubMed, EMBASE, and Medline to perform a systematic review. Thirty-one full text articles were identified from 265 abstracts. Nine observational studies were relevant to endometrial cancer. In the five controlled studies, 462 of 113,032 (0.4%) patients receiving bariatric surgery versus 11,997 of 848,864 (1.4%) controls developed endometrial cancer, odds ratio of 0.317 (95% CI 0.161 to 0.627) using random effects model (P < 0.001). Bariatric surgery seems to reduce the risk of endometrial cancer; however, more research is required. PMID- 29512037 TI - Weight Loss and Timing of J Tube Removal in Biliopancreatic Diversion with Duodenal Switch Patients Who Report Physical or Sexual Abuse. AB - BACKGROUND: Bariatric surgery patients who report physical or sexual abuse form a sizeable cohort that stands out due to psychological comorbidity. Their possible vulnerability to suboptimal weight loss remains of interest. Their risk for malnutrition due to inadequate oral intake following surgery is underexplored. OBJECTIVES: Study aims were to determine the effect of self-reported physical or sexual abuse in patients undergoing open biliopancreatic diversion with duodenal switch (BPD/DS) on (a) 3-year weight loss trajectories and (b) timing of feeding jejunostomy tube (J tube) removal. Delayed J tube removal served as an indicator for inadequate oral intake. METHODS: In this retrospective cohort study, the sample (N = 189) consisted of all patients who underwent primary BPD/DS by the same surgeon during 2009 and 2010 at a Midwestern health system. All patients had a J tube placed during surgery. Longitudinal mixed models were used for testing differences in weight loss trajectories by abuse status. RESULTS: There were no significant differences in weight loss trajectories by abuse status. The abused group had the J tube in place a mean of 61.9 days (SD = 39.5) compared to 44.8 days (SD = 32.8) for the not abused group, a significant difference. CONCLUSIONS: Our use of the best available statistical methods lends validity to previous findings that suggest physical or sexual abuse does not affect weight loss after bariatric surgery. Increased likelihood of persistent inadequate oral intake in the abused group suggests the need for early multidisciplinary interventions that include mental health and nutrition experts. PMID- 29512038 TI - Which Bariatric Procedure Is the Most Popular in the World? A Bibliometric Comparison. AB - OBJECTIVE: This study aims to make a bibliometric analysis of the most commonly performed bariatric procedures between the years 2006 and 2016 and identify the most popular procedure in the field of bariatric surgery (BS). BACKGROUND: Despite the fact that BS popularity has been increasing considerably in recent years, the literature indicates insufficient information regarding the comparison of the methods used in BS. METHODS: The terms "Sleeve Gastrectomy," "Gastric Bypass," or "Gastric Band" were searched in Web of Science for the years between 1980 and 2016. All the publications found were subjected to bibliometric analysis. RESULTS: WoS database included 3501 publications about the sleeve gastrectomy keyword, 7278 publications about the gastric bypass keyword, and 2692 publications about the gastric band keyword. USA was found to be the most active country in all methods, and the authors who had most publications were Gagner M (64, 1.8%) for sleeve gastrectomy, Le Roux CW (83, 1.1%) for gastric bypass, and O'brien PE (50, 1.9%) for gastric band. "Obesity Surgery" was the journal that contributed most to the literature in all three obesity surgery procedures. CONCLUSION: Despite the fact that the top procedure was Roux-en-Y gastric bypass in terms of bibliometrics, the most popular procedure was found to be sleeve gastrectomy. According to the percentage of the increase in publications and citations, sleeve gastrectomy was found to be the method which showed the highest increase rates in recent years. PMID- 29512039 TI - The Obituary of Routine Roux-en-Y Reconstruction in Bariatric Surgery. PMID- 29512040 TI - A Population-Based Study of Early Postoperative Outcomes in Patients with Heart Failure Undergoing Bariatric Surgery. AB - BACKGROUND: Weight loss following bariatric surgery can improve cardiac function among patients with heart failure (HF). However, perioperative morbidity of bariatric surgery has not been evaluated in patients with HF. STUDY DESIGN: The National Surgical Quality Improvement Project (NSQIP) database for 2006-2014 was queried to identify patients undergoing adjustable gastric band, gastric bypass, sleeve gastrectomy, and biliopancreatic diversion-duodenal switch. Patients with HF were propensity matched to a control group without HF (1:5). Univariate analyses evaluated differences in complications, and multivariate analysis was completed to predict all-cause morbidity. RESULTS: There were 237 patients identified with HF (mean age 52.8 years, 59.9% female, mean body mass index 50.6 kg/m2) matched to 1185 controls without HF who underwent bariatric surgery. Preoperatively, patients with HF were more likely to be taking antihypertensive medication and have undergone prior percutaneous cardiac intervention and cardiac surgery. There was no difference in operative time, surgical site infections, acute renal failure, re-intubation, or myocardial infarction. HF was associated with increased likelihood of length of stay more than 7 days, likelihood to remain ventilated > 48 h, venous thromboembolism, and reoperation. For patients with HF, the adjusted odds ratio for all-cause morbidity was 2.09 (1.32-3.22). CONCLUSION: The NSQIP definition of HF, which includes recent hospitalization for HF exacerbation or new HF diagnosis 30 days prior to surgery, predicts a more than two-fold increase in odds of morbidity following bariatric surgery. This must be balanced with the longer-term potential benefits of weight loss and associated improvement in cardiac function in this population. PMID- 29512041 TI - Tai Chi for older adults with chronic multisite pain: a randomized controlled pilot study. AB - BACKGROUND: Chronic pain is associated with poorer cognition and mobility, and fall risk in older adults. AIMS: To investigate the feasibility of a randomized controlled trial of mind-body exercise (Tai Chi) versus light physical exercise in older adults with multisite pain. METHODS: Adults aged >= 65 years with multisite pain who reported falling in the past year or current use of an assistive device were recruited from Boston area communities. Participants were randomized to either a Tai Chi or a light physical exercise program, offered twice weekly for 12 weeks. The primary outcomes were feasibility and acceptability. Secondary outcomes included pain characteristics, cognition, physical function, gait mobility, fear of falling, and fall rate. RESULTS: Of 176 adults screened, 85 were eligible, and 54 consented and enrolled (average age 75 +/- 8 years; 96.30% white; 75.93% female). The dropout rate was 18% for Tai Chi and 12% for light physical exercise. For those completing the study, exercise class attendance rate was 76% for Tai Chi and 82% for light physical exercise. There were no significant group differences in most secondary outcomes. Tai Chi significantly lowered pain severity (4.58 +/- 1.73 to 3.73 +/- 1.79, p < 0.01) and pain interference (4.20 +/- 2.53 to 3.16 +/- 2.28, p < 0.05), reduced fear of falling (90.82 +/- 9.59 to 96.84 +/- 10.67, p < 0.05), and improved several single-task and dual-task gait variables, while light physical exercise did not change these measures. DISCUSSION AND CONCLUSIONS: This study demonstrated the feasibility and acceptability of conducting a larger randomized controlled trial in older adults with multisite pain. Study findings and challenges encountered will inform future research. PMID- 29512042 TI - Functional status improves in hypertensive older adults: the long-term effects of antihypertensive therapy combined with multicomponent exercise intervention. AB - BACKGROUND: The increasing prevalence of functionally-limited hypertensive individuals highlights the need for interventions to reduce the burden of hypertension-aging-disability and to maximize the chances of healthy aging. AIM: This study aims to compare the effects of multicomponent exercise and different pharmacological treatments on functional status and cardiovascular risk outcomes in hypertensive older adults with comorbidities. METHODS: Participants (n = 96) engage in a 3 days/week multicomponent (aerobic + resistance) exercise program and for one of the following three conditions: (1) thiazide-related diuretics (TDs; n = 33, 69.9 +/- 9.5 years); (2) calcium channel blockers (CCBs; n = 23, 67.0 +/- 9.0 years); (3) and beta-blockers (betaBs; n = 40, 65.6 +/- 7.2 years) medication. Baseline and 2-year follow-up evaluations included the Senior Fitness Test battery, anthropometrics and hemodynamic profile, health-related quality of life (HRQoL; Short-Form Health Survey 36) and health history questionnaires. RESULTS: All groups have significantly improved the physical functional status; particularly upper and lower body strength and aerobic endurance and systolic blood pressure. The TDs and betaBs groups have diminished the waist circumference and body mass. The CCBs decreased total cholesterol (P = 0.028), perceived better physical functioning, physical component score but also augmented bodily pain (P < 0.05). The betaB group decreased triglycerides (P = 0.013). No group differences were found. CONCLUSION: Multicomponent exercise training has improved functional status regardless of the antihypertensive medication options. Hypertensive older adults should add exercise training to pharmacological antihypertensive therapy to reduce the rate of physical disability. PMID- 29512043 TI - Decision-making about surgery in the elderly. PMID- 29512033 TI - Assessement of Awareness of, Concerns and Attitudes Towards HIV-Related Court Case Sentences in France in a Representative Sample of People Living with HIV (ANRS VESPA2 Survey). AB - Some of the 12 criminal trials and sentences in France for HIV transmission in 1998-2011 attracted substantial public attention, with a possible negative impact on people living with HIV (PLWH) through reinforced stigma and discrimination. This analysis aimed to characterize PLWH enrolled in the representative ANRS VESPA2 survey, aware of and concerned about convictions for HIV transmission. Being a migrant from Sub-Saharan Africa, having difficult socio-economic conditions, having unprotected sex with one's main partner and concealing one's HIV status were all factors statistically associated with concern about the sentences. Participants tempted to press charges against someone for infecting them were more likely to be younger, women, not living in a couple, unemployed, and to report a major depressive disorder. Concern about HIV-related criminal proceedings among the most vulnerable PLWH do not reflect the actual risk of prosecution they are exposed to. PMID- 29512044 TI - Mercury-associated diagnoses among children diagnosed with pervasive development disorders. AB - Nelson and Bauman (Pediatrics 111:674-679, 2003) previously hypothesized that pervasive developmental disorder (PDD) was not associated with mercury (Hg) exposure because the medical conditions associated with Hg exposure were not associated with PDD. A hypothesis-testing longitudinal case-control study evaluated the frequency of medically diagnosed conditions previously associated with Hg poisoning, including: epilepsy, dysarthria, failure to thrive, cerebral palsy, or contact dermatitis and other eczema among children preceding their eventual PDD diagnosis (cases) compared to controls. A retrospective examination of medical records within the Vaccine Safety Datalink (VSD) was undertaken. Cases diagnosed with PDD (n = 534) were born from 1991 to 2000 and continuously enrolled until their PDD diagnosis. Controls (n = 26,367) were born from 1991 to 1993 and continuously enrolled from birth for 7.22 years. Within the first 5 years of life, cases compared to controls were significantly (p < 0.0001) more likely to be assigned a diagnosis of contact dermatitis and other eczema (odds ratio (OR) = 2.033), dysarthria (OR = 23.992), epilepsy (OR = 5.351), failure to thrive (OR = 25.3), and cerebral palsy (OR = 4.464). Similar results were observed when the data were separated by gender. Overall, the results of the present study and recently published studies provide direct evidence supporting a link in twelve of twelve categories (100%) of Hg poisoning associated symptoms as defined by Nelson and Bauman (Pediatrics 111:674-679, 2003) and symptoms observed in those with a PDD diagnosis. The results of this study support the biological plausibility of Hg poisoning to induce PDD diagnoses and rejection of the Nelson and Bauman (Pediatrics 111:674-679, 2003) hypothesis because those with a PDD diagnosis have an increased frequency of conditions previously associated with Hg poisoning. PMID- 29512046 TI - Preliminary experience with umbilical stoma in transumbilical single-port colorectal surgery. AB - BACKGROUND: The umbilicus, an embryological natural orifice, is increasingly used as the only access route during single-incision laparoscopic surgery (SILS) for colorectal disease. As a part of some of these procedures, a temporary, diverting ostomy could be exteriorized through the umbilicus itself. Theoretical advantages include better preservation of the abdominal wall and potentially superior cosmetic results. The aim of the present study was to evaluate our preliminary experience in SILS colorectal resection with umbilical stoma (u-stoma). METHODS: We retrospectively reviewed all colorectal patients operated using SILS for benign or malignant disease at Paris Poissy Medical Center. Patients were selected for consideration of u-stoma with our stoma therapists. RESULTS: Between January 2010 and December 2016, 234 patients underwent colorectal SILS procedures. In 74 patients (31.6%), an ileostomy (n = 41) or a colostomy (n = 33) was fashioned. Of these, 20 (27% of all ostomies) were umbilical stomas. The 20 u stoma patients, 10 men and 10 women, received either a loop ileostomy (n = 14) or an end (n = 4) or loop (n = 2) colostomy. The mean age was 52 years (range 29-81 years). There was no mortality. Operative stoma-related morbidity occurred in only 5% of patients (n = 1: ileal torsion volvulus). Median follow-up after stoma formation was 30 months (range 12-59 months). Adjustment to the stoma and quality of life were satisfactory as estimated by both the patient and the stoma therapist. All stomas were reversed. At a median follow-up of 27.5 months (range 7-55 months) after stoma reversal, two patients had reoperation for incisional hernia. CONCLUSION: This preliminary experience showed that u-stoma is a feasible and safe alternative to more conventional ostomy after SILS. PMID- 29512045 TI - What to consider when designing a laparoscopic colorectal training curriculum: a review of the literature. AB - Multiple studies have demonstrated the benefits of laparoscopic colorectal surgery (LCS), but in several countries it has still not been widely adopted. LCS training is associated with several challenges, such as patient safety concerns and a steep learning curve. Current evidence may facilitate designing of efficient training curricula to overcome these challenges. Basic training with virtual reality simulators has witnessed meteoric advances and may be essential during the early parts of the learning curve. Cadaveric and animal model training still constitutes an indispensable training tool, due to a higher degree of difficulty and greater resemblance to real operative conditions. In addition, recent evidence favors the use of novel training paradigms, such as proficiency based training, case selection and modular training. This review summarizes the recent advances in LCS training and provides the evidence for designing an efficient training curriculum to overcome the challenges of LCS training. PMID- 29512047 TI - Perioperative hyperglycemia: an unmet need within a surgical site infection bundle. AB - BACKGROUND: The aim of this study was to determine whether perioperative stress hyperglycemia is correlated with surgical site infection (SSI) rates in non diabetes mellitus (DM) patients undergoing elective colorectal resections within an SSI bundle. METHODS: American College of Surgeons National Surgical Quality Improvement Program data of patients treated at a single institution in 2006-2012 were supplemented by institutional review board-approved chart review. A multifactorial SSI bundle was implemented in 2009 without changing the preoperative 8-h nil per os, and in the absence of either a carbohydrate loading strategy or hyperglycemic management protocol. Hyperglycemia was defined as blood glucose level > 140 mg/dL. The primary endpoint was SSI defined by the Centers for Disease Control National Nosocomial Infections Surveillance. RESULTS: Of 690 patients included, 112 (16.2%) had pre-existing DM. Overall SSI rates were significantly higher in DM patients as compared to non-DM patients (28.7 vs. 22.3%, p = 0.042). Postoperative hyperglycemia was more frequently seen in non-DM patients (46 vs. 42.9%). The SSI bundle reduced SSI rates (17 vs. 29.3%, p < 0.001), but the rate of hyperglycemia remained unchanged for DM or non-DM patients (pre-bundle 59%; post-bundle 62%, p = 0.527). Organ/space SSI rates were higher in patients with pre- and postoperative hyperglycemia (12.6%) (p = 0.017). Overall SSI rates were higher in DM patients with hyperglycemia as compared to non-DM patients with hyperglycemia (35.6 vs. 20.8%, p = 0.002). At multivariate analysis DM, chronic steroid use, chemotherapy and SSI bundle were predictive factors for SSI. CONCLUSIONS: This study showed that non-DM patients have a postoperative hyperglycemia rate as high as 46% in spite of the SSI bundle. A positive correlation was found between stress hyperglycemia and organ/space SSI rates regardless of the DM status. These data support the need for a strategy to prevent stress hyperglycemia in non-DM patients undergoing colorectal resections. PMID- 29512048 TI - The clinical value of magnetic resonance defecography in males with obstructed defecation syndrome. AB - BACKGROUND: The aim of the present study was to assess the relationship between symptoms of obstructed defecation and findings on magnetic resonance (MR) defecography in males with obstructed defecation syndrome (ODS). METHODS: Thirty six males with ODS who underwent MR defecography at our institution between March 2013 and February 2016 were asked in a telephone interview about their symptoms and subsequent treatment, either medical or surgical. Patients were divided into 2 groups, one with anismus (Group 1) and one with prolapse without anismus (Group 2). The interaction between ODS type and symptoms with MR findings was assessed by multivariate analysis for categorical data using a hierarchical log-linear model. MR imaging findings included lateral and/or posterior rectocele, rectal prolapse, intussusception, ballooning of levator hiatus with impingement of pelvic organs and dyskinetic puborectalis muscle. RESULTS: There were 21 males with ODS due to anismus (Group 1) and 15 with ODS due to rectal prolapse/intussusception (Group 2). Mean age of the entire group was 53.6 +/- 4.1 years (range 18-77 years). Patients in Group 1 were slightly older than those in Group 2 (age peak, sixth decade in 47.6 vs 20.0%, p < 0.05). Symptoms most frequently associated with Group 1 patients included small volume and hard feces (85.0%, p < 0.01), excessive strain at stool (81.0%, p < 0.05), tenesmus and fecaloma formation (57.1 and 42.9%, p < 0.05); symptoms most frequently associated with Group 2 patients included mucous discharge, rectal bleeding and pain (86.7%, p < 0.05), prolonged toilet time (73.3%, p < 0.05), fragmented evacuation with or without digitation (66.7%, p < 0.005). Voiding outflow obstruction was more frequent in Group 1 (19.0 vs 13.3%; p < 0.05), while non bacterial prostatitis and sexual dysfunction prevailed in Group 2 (26.7 and 46.7%, p < 0.05). At MR defecography, two major categories of findings were detected: a dyskinetic pattern (Type 1), seen in all Group 1 patients, which was characterized by non-relaxing puborectalis muscle, sand-glass configuration of the anorectum, poor emptying rate, limited pelvic floor descent and final residue >= 2/3; and a prolapsing pattern (Type 2), seen in all Group 2 patients, which was characterized by rectal prolapse/intussusception, ballooning of the levator hiatus with impingement of the rectal floor and prostatic base, excessive pelvic floor descent and residue <= 1/2. Posterolateral outpouching defined as perineal hernia was present in 28.6% of patients in Group 1 and were absent in Group 2. The average levator plate angle on straining differed significantly in the two patterns (21.3 degrees +/- 4.1 in Group 1 vs 65.6 degrees +/- 8.1 in Group 2; p < 0.05). Responses to the phone interview were obtained from 31 patients (18 of Group 1 and 13 of Group 2, response rate, 86.1%). Patients of Group 1 were always treated without surgery (i.e., biofeedback, dietary regimen, laxatives and/or enemas) which resulted in symptomatic improvement in 12/18 cases (66.6%). Of the patients in Group 2, 2/13 (15.3) underwent surgical repair, consisting of stapled transanal rectal resection (STARR) which resulted in symptom recurrence after 6 months and laparoscopic ventral rectopexy which resulted in symptom improvement. The other 11 patients of Group 2 were treated without surgery with symptoms improvement in 3 (27.3%). CONCLUSIONS: The appearance of various abnormalities at MR defecography in men with ODS shows 2 distinct patterns which may have potential relevance for treatment planning, whether conservative or surgical. PMID- 29512049 TI - Target-Controlled Continuous Infusion for Antibiotic Dosing: Proof-of-Principle in an In-silico Vancomycin Trial in Intensive Care Unit Patients. AB - OBJECTIVES: In this in-silico study, we investigate the clinical utility of target-controlled infusion for antibiotic dosing in an intensive care unit setting using vancomycin as a model compound. We compared target-controlled infusion and adaptive target-controlled infusion, which combines target controlled infusion with data from therapeutic drug monitoring, with conventional (therapeutic drug monitoring-based) vancomycin dosing strategies. METHODS: A clinical trial simulation was conducted. This simulation was based on a comprehensive database of clinical records of intensive care unit patients and a systematic review of currently available population-pharmacokinetic models for vancomycin in intensive care unit patients. Dosing strategies were compared in terms of the probability of achieving efficacious concentrations as well as the potential for inducing toxicity. RESULTS: Adaptive target-controlled infusion outperforms rule-based dosing guidelines for vancomycin. In the first 48 h of treatment, the probability of target attainment is significantly higher for adaptive target-controlled infusion than for the second-best method (Cristallini). Probability of target attainments of 54 and 72% and 47 and 59% for both methods after 24 and 48 h, respectively. Compared to the Cristallini method, which is characterized by a probability of attaining concentrations above 30 mg.L 1 > 65% in the first few hours of treatment, adaptive target-controlled infusion shows negligible time at risk and a probability of attaining concentrations above 30 mg.L-1 not exceeding 25%. Finally, in contrast to the other methods, the performance of target-controlled infusion is consistent across subgroups within the population. CONCLUSIONS: Our study shows that adaptive target-controlled infusion has the potential to become a practical tool for patient-tailored antibiotic dosing in the intensive care unit. PMID- 29512052 TI - Examining the Relationship Between Individual Characteristics, Community-Level Traits, Multidimensional Empowerment, and Maternal Health Care Utilization in the Islamic Republic of Pakistan. AB - Introduction The Islamic Republic of Pakistan's maternal mortality ratio is particularly high, and the nation ranks 126 out of 149 countries on the Human Development Report-Gender Inequality Index. This is because Pakistani women have low levels of empowerment, make limited economic contributions, and underutilization of maternal health care. The aim of this study is to create a multidimensional index of women's empowerment and assess the association between this index and maternal health care utilization in Pakistan, controlling for individual characteristics and community-level traits. Methods Data from the 2012 2013 Pakistan Demographic and Health Surveys were employed to investigate the relationship between this index and the latent construct of maternal health care utilization. Results Using exploratory factor analysis, four indicators of maternal health care utilization were loaded onto a single latent factor. Multivariate analyses found support for the association between empowerment and health care utilization, despite adjustments for individual and area level factors. Positive associations between education, wealth, and maternal health care utilization were found. Conclusions Although we find support for the association of educational attainment with maternal health care utilization, the multidimensional women's empowerment index was independently a consistent associate of maternal health care utilization. This illustrates a complex mechanism with both-education and empowerment, being necessary for improved maternal health care utilization. Policy makers seeking to improve outcomes should expand their focus beyond simply improving rates of education to examining effects of cultural norms which constrain the independence of women in making decisions about their own health care. PMID- 29512053 TI - Reproductive Life Planning: Raising the Questions. AB - Introduction Unintended pregnancy has been a concerning public health problem for decades. As we begin to understand the complexities of pregnancy intention and how women experience these pregnancies, reproductive life planning offers a paradigm shift. Methods Reproductive life planning is a patient-centered approach that places a patient's reproductive preferences-whether concrete or ambivalent at the forefront of her clinical care. Results This process grants women and men the opportunity to consider how reproduction fits within the context of their broader lives. Within a clinical encounter, reproductive life planning allows counseling and care to be tailored to patient preferences. Discussion Although there is great potential for positive public health impacts in unintended pregnancy, contraceptive use and improved preconception health, the true benefit lies within reinforcing reproductive empowerment. Despite recommendations for universal adoption, many questions remain regarding implementation, equity and outcomes. PMID- 29512051 TI - Characterization of ELISA Antibody-Antigen Interaction using Footprinting-Mass Spectrometry and Negative Staining Transmission Electron Microscopy. AB - We describe epitope mapping data using multiple covalent labeling footprinting mass spectrometry (MS) techniques coupled with negative stain transmission electron microscopy (TEM) data to analyze the antibody-antigen interactions in a sandwich enzyme-linked immunosorbant assay (ELISA). Our hydroxyl radical footprinting-MS data using fast photochemical oxidation of proteins (FPOP) indicates suppression of labeling across the antigen upon binding either of the monoclonal antibodies (mAbs) utilized in the ELISA. Combining these data with Western blot analysis enabled the identification of the putative epitopes that appeared to span regions containing N-linked glycans. An additional structural mapping technique, carboxyl group footprinting-mass spectrometry using glycine ethyl ester (GEE) labeling, was used to confirm the epitopes. Deglycosylation of the antigen resulted in loss of potency in the ELISA, supporting the FPOP and GEE labeling data by indicating N-linked glycans are necessary for antigen binding. Finally, mapping of the epitopes onto the antigen crystal structure revealed an approximate 90 degrees relative spatial orientation, optimal for a noncompetitive binding ELISA. TEM data shows both linear and diamond antibody antigen complexes with a similar binding orientation as predicted from the two footprinting-MS techniques. This study is the first of its kind to utilize multiple bottom-up footprinting-MS techniques and TEM visualization to characterize the monoclonal antibody-antigen binding interactions of critical reagents used in a quality control (QC) lot-release ELISA. Graphical Abstract ?. PMID- 29512054 TI - Peripartum Care for Mothers Diagnosed with Hepatitis B During Pregnancy: A Survey of Provider Practices. AB - Objectives Hepatitis B (HBV) remains a significant public health burden, despite effective therapy. Routine HBV screening is recommended during pregnancy to reduce the risk of vertical transmission, but the rates of follow-up care peri partum are low. The aim of this study was to evaluate physician practices and knowledge regarding HBV in women diagnosed perinatally. Methods A survey was distributed to obstetricians and midwives within the Partners HealthCare system at Brigham and Women's Hospital and Massachusetts General Hospital. Results Of 118 survey respondents (response rate 56%), 97% reported that they always tested for hepatitis B, and 77% referred new diagnoses of HBV during pregnancy to a HBV specialist for further care. Only 10% of respondents reported that there was formal referral mechanism in place to facilitate follow-up care for mothers diagnosed with hepatitis B infection. 91% of survey respondents selected hepatitis B surface antigen as the correct screening test, and 76% selected hepatitis B immune globulin with vaccination for the newborn as the correct prophylaxis regimen. Only 40 and 51% of respondents accurately identified serologies that were consistent with acute and chronic infection, respectively. Conclusions for Practice Routine screening for HBV in this population presents an important opportunity to identify cases and to reduce the public health burden of this disease. Providers were somewhat knowledgeable about HBV, but the lack of formal referral mechanism may explain why HBV follow-up is suboptimal in this healthcare system. Supplemental provider education and formal linkage to care programs may increase rates of follow-up HBV care. PMID- 29512055 TI - Association of Pre-pregnancy BMI and Postpartum Weight Retention Before Second Pregnancy, Washington State, 2003-2013. AB - Background Maternal overweight and obesity is one of the most common high-risk obstetric conditions associated with adverse birth outcomes. Smaller studies have suggested that pre-pregnancy body mass index (BMI) is associated with postpartum weight retention. Objective The primary objective of this study was to examine the association between pre-pregnancy BMI status and maternal weight retention. Study design We conducted a population-based retrospective cohort study using Washington State birth certificate data from 2003-2013. We included women who had two sequential births during this time period, with the second birth occurring within 18-36 months of the first singleton delivery date. BMI before a women's first pregnancy ("pre-pregnancy BMI") was categorized as normal (18.5-24.9 kg/m2) and overweight/obese (25-40 kg/m2). Women were classified as having returned to first pre-pregnancy BMI if their BMI before their second pregnancy was no more than 1 kg/m2 more compared to their BMI before their first pregnancy. Analyses were stratified by gestational weight gain during the first pregnancy (below, met, exceeded recommended gestational weight gain). Results A total of 49,132 mothers were included in the study. Among women who met their recommended gestational weight gain, compared to mothers with a normal BMI, obese/overweight mothers were less likely to return to their pre-pregnancy BMI (76.5 vs 72.3%; RRObese/Overweight = 0.88; 95% CI: 0.85-0.92). A similar pattern was observed among women who exceeded their recommended gestational weight gain (62.6 vs 53.2%; RRObese/Overweight = 0.79, 95% CI: 0.78-0.80). Conclusion Pre-pregnancy BMI in the overweight/obese range is associated with a decreased likelihood of returning to pre-pregnancy BMI. Further research to support women during and after their pregnancy to promote behavior changes that prevent excessive weight gain during pregnancy and weight retention after birth is needed. PMID- 29512050 TI - Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease. AB - According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries. PMID- 29512056 TI - Quantitative T1 and T2* carotid atherosclerotic plaque imaging using a three dimensional multi-echo phase-sensitive inversion recovery sequence: a feasibility study. AB - Magnetic resonance imaging (MRI) is widely used to detect carotid atherosclerotic plaques. Although it is important to evaluate vulnerable carotid plaques containing lipids and intra-plaque hemorrhages (IPHs) using T1-weighted images, the image contrast changes depending on the imaging settings. Moreover, to distinguish between a thrombus and a hemorrhage, it is useful to evaluate the iron content of the plaque using both T1-weighted and T2*-weighted images. Therefore, a quantitative evaluation of carotid atherosclerotic plaques using T1 and T2* values may be necessary for the accurate evaluation of plaque components. The purpose of this study was to determine whether the multi-echo phase-sensitive inversion recovery (mPSIR) sequence can improve T1 contrast while simultaneously providing accurate T1 and T2* values of an IPH. T1 and T2* values measured using mPSIR were compared to values from conventional methods in phantom and in vivo studies. In the phantom study, the T1 and T2* values estimated using mPSIR were linearly correlated with those of conventional methods. In the in vivo study, mPSIR demonstrated higher T1 contrast between the IPH phantom and sternocleidomastoid muscle than the conventional method. Moreover, the T1 and T2* values of the blood vessel wall and sternocleidomastoid muscle estimated using mPSIR were correlated with values measured by conventional methods and with values reported previously. The mPSIR sequence improved T1 contrast while simultaneously providing accurate T1 and T2* values of the neck region. Although further study is required to evaluate the clinical utility, mPSIR may improve carotid atherosclerotic plaque detection and provide detailed information about plaque components. PMID- 29512057 TI - Comments on "Novel real-time tumor-contouring method using deep learning to prevent mistracking in X-ray fluoroscopy" by Terunuma et al. PMID- 29512058 TI - Physiopathological relationship between chronic obstructive pulmonary disease and insulin resistance. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is characterized by persistent and progressive airflow obstruction that is associated with an abnormal chronic inflammatory response in the airways and lungs to noxious particles. COPD often leads to physical inactivity and deconditioning that added to inappropriate/excessive inflammatory responses leads to systemic consequences. Studies have shown that metabolic syndrome and manifested diabetes are more frequent in COPD than in healthy subjects; a possible explanation is that different pathophysiological aspects of COPD can lead to insulin resistance. Thus, this mini-review aims to present the main studies suggesting a pathophysiological relationship between COPD and insulin resistance. METHODS: A review of literature was conducted using PubMed and Web of Science databases with the aim of searching for studies supporting a relationship between COPD and insulin resistance. RESULTS: A physiopathological relationship between COPD and insulin resistance was found, supported in part due to common risk factors presented by these two conditions, such as smoking and physical inactivity. Also, systemic effects (worsening of physical inactivity and sedentary behavior, inflammation and oxidative stress, body composition abnormalities) and the corticosteroid treatment of patients with COPD may play a role. CONCLUSION: Patients with COPD should be screened for abnormalities in insulin sensitivity in order to reduce morbidity and improve health status in this population. PMID- 29512059 TI - Patient-Specific Cardiovascular Computational Modeling: Diversity of Personalization and Challenges. AB - Patient-specific computer models have been developed representing a variety of aspects of the cardiovascular system spanning the disciplines of electrophysiology, electromechanics, solid mechanics, and fluid dynamics. These physiological mechanistic models predict macroscopic phenomena such as electrical impulse propagation and contraction throughout the entire heart as well as flow and pressure dynamics occurring in the ventricular chambers, aorta, and coronary arteries during each heartbeat. Such models have been used to study a variety of clinical scenarios including aortic aneurysms, coronary stenosis, cardiac valvular disease, left ventricular assist devices, cardiac resynchronization therapy, ablation therapy, and risk stratification. After decades of research, these models are beginning to be incorporated into clinical practice directly via marketed devices and indirectly by improving our understanding of the underlying mechanisms of health and disease within a clinical context. PMID- 29512060 TI - Review and Comparison of Electronic Patient-Facing Family Health History Tools. AB - Family health history (FHx) is one of the most important pieces of information available to help genetic counselors and other clinicians identify risk and prevent disease. Unfortunately, the collection of FHx from patients is often too time consuming to be done during a clinical visit. Fortunately, there are many electronic FHx tools designed to help patients gather and organize their own FHx information prior to a clinic visit. We conducted a review and analysis of electronic FHx tools to better understand what tools are available, to compare and contrast to each other, to highlight features of various tools, and to provide a foundation for future evaluation and comparisons across FHx tools. Through our analysis, we included and abstracted 17 patient-facing electronic FHx tools and explored these tools around four axes: organization information, family history collection and display, clinical data collected, and clinical workflow integration. We found a large number of differences among FHx tools, with no two the same. This paper provides a useful review for health care providers, researchers, and patient advocates interested in understanding the differences among the available patient-facing electronic FHx tools. PMID- 29512061 TI - Living with Merkel Cell Carcinoma (MCC): Development of a Conceptual Model of MCC Based on Patient Experiences. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with limited treatment options at advanced stages. There is a paucity of data available regarding the impact of MCC and its management on patients' lives. This study aimed to address this gap by interviewing patients with metastatic MCC entering a trial of an immunotherapy (avelumab). METHODS: In a single-arm, open label, international, phase 2 trial in patients with stage IV, chemotherapy refractory, histologically confirmed MCC, patients were invited to participate in semi-structured phone interviews. These were conducted before avelumab administration. Interview transcripts were analysed qualitatively to identify concepts important to patients relating to their experience of metastatic MCC and its management. RESULTS: Nineteen patients were interviewed. Most reported MCC to be painless and asymptomatic. They reported being often misdiagnosed and described a long process before receiving the correct diagnosis. They also reported a feeling of "shock" after being informed of the severity and seriousness of their cancer. Overall, patients did not report impaired physical and cognitive capacities or impact on daily lives, either before or after diagnosis. However, patients and their relatives reported feelings of "worry" and "fear" about the unknown outcome of the disease. Chemotherapy and radiotherapy negatively affected patients physically and psychologically in their everyday lives. CONCLUSIONS: MCC disease was not perceived by the interviewed patients to result in severe functional limitations or to severely impact everyday activities, but was associated with substantial negative psychological impact. In contrast, chemotherapy and radiotherapy for MCC are highly debilitating and disrupt patients' lives. CLINICALTRIALS. GOV IDENTIFIER: NCT02155647. PMID- 29512062 TI - Epidemiology of Dementia: The Burden on Society, the Challenges for Research. AB - Dementia is among the leading causes of death and disability. Due to the ageing population, its prevalence is expected to nearly triple worldwide by 2050, urging the development of preventive and curative interventions. Various modifiable risk factors have been identified in community-based cohort studies, but insight into the underlying pathophysiological mechanisms is lacking. Clinical trials have thus far failed in the development of disease-modifying therapy in patients with dementia, thereby triggering a shift of focus toward the presymptomatic phase of disease. The extensive preclinical disease course of Alzheimer's disease warrants reliable, easily obtainable biomarkers to aid in timely application of preventive strategies, selecting participants for neuroprotective trials, and disease monitoring in trials and clinical practice. Biomarker and drug discovery may yield the fruits from technology-driven developments in the field of genomics, epigenetics, metabolomics, and brain imaging. In that context, bridging the gap between translational and population research may well prove a giant leap toward development of successful preventive and curative interventions against dementia. PMID- 29512063 TI - Population-Based Approaches to Alzheimer's Disease Prevention. AB - Progress in prevention and treatment of Alzheimer's disease (AD) and dementia is hampered by the restricted understanding of the biological and environmental causes underlying pathophysiology. It is widely accepted that certain genetic factors are associated with AD and a number of lifestyle and other environmental characteristics have also been linked to dementia risk. However, interactions between genes and the environment are not yet well understood, and coordinated global action is required to utilize existing cohorts and other resources effectively and efficiently to identify new avenues for dementia prevention. This chapter provides a brief summary of current research on risk and protective factors and opportunities and challenges in relation to population-based approaches are discussed. PMID- 29512064 TI - Systems Biology Methods for Alzheimer's Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials. AB - Alzheimer's disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases particularly AD-is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest genome editing and single-cell technologies. Their progressive incorporation into basic research, cohort studies, and trials is beginning to provide novel insights into AD essential mechanisms, molecular signatures, and markers toward mechanism-based classification and staging, and tailored interventions. Selected methods which can be applied in cohort studies and trials, with the European Prevention of Alzheimer's Dementia (EPAD) project as a reference example, are presented and discussed. PMID- 29512065 TI - CSF Lipidomics Analysis: High-Resolution Mass Spectrometry Analytical Platform. AB - High-resolution mass spectrometry provides the resolution required for direct infusion allowing detection and characterization of a vast array of lipids with a single injection. This chapter presents the methodology utilized for both unbiased and targeted lipidomics of cerebrospinal fluid. PMID- 29512066 TI - CSF N-Glycomics Using MALDI MS Techniques in Alzheimer's Disease. AB - In this chapter, we present the methodology currently applied in our laboratory for the structural elucidation of the cerebrospinal fluid (CSF) N-glycome. N glycans are released from denatured carboxymethylated glycoproteins by digestion with peptide-N-glycosidase F (PNGase F) and purified using both C18 Sep-Pak(r) and porous graphitized carbon (PGC) HyperSepTM HypercarbTM solid-phase extraction (SPE) cartridges. The glycan pool is subsequently permethylated to increase mass spectrometry sensitivity. Molecular assignments are performed through matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis considering either the protein N-linked glycosylation pathway or MALDI TOF MS/MS data. Each stage has been optimized to obtain high-quality mass spectra in reflector mode with an optimal signal-to-noise ratio up to m/z 4800. This method has been successfully adopted to associate specific N-glycome profiles to the early and the advanced phases of Alzheimer's disease. PMID- 29512067 TI - MicroRNA Profiling of Alzheimer's Disease Cerebrospinal Fluid. AB - MicroRNAs (miRNAs) are a class of small, highly conserved, and noncoding RNAs that modulate gene expression by regulating the activity and stability of target mRNAs. MiRNAs play significant roles by controlling fundamental cellular processes and its deregulation is associated with various diseases. Ubiquitous expression and its release into circulation make them interesting biomarkers, which can be measured by different platforms. In this book chapter, we provide a specific protocol that describes the detection of circulating miRNAs in CSF by using RT-qPCR. PMID- 29512068 TI - Validation of a Chemiluminescence Immunoassay for Measuring Amyloid-beta in Human Blood Plasma. AB - The technical performance of immunological assays and their suitability for the intended use should be carefully validated before implementation in research, clinical studies or routine. We describe here the evaluation of a sandwich electrochemiluminescence immunoassay for measuring total Amyloid-beta levels in human blood plasma as an example of a laboratory protocol for a partial "fit for purpose" assay performance validation. We tested two different assay protocols and addressed impact of sample dilution, parallelism, intra- and inter-assay variance, lower limit of quantification, lower limit of detection, and analytical spike recoveries. PMID- 29512069 TI - Mass Spectrometry-Based Metabolomic Multiplatform for Alzheimer's Disease Research. AB - The integration of complementary analytical platforms has emerged as a suitable strategy to perform a comprehensive metabolomic characterization of complex biological systems. In this work, we describe the most important issues to be considered for the application of a mass spectrometry multiplatform in Alzheimer's disease research, which combines direct analysis with electrospray and atmospheric pressure photoionization sources, as well as orthogonal hyphenated approaches based on reversed-phase ultrahigh-performance liquid chromatography and gas chromatography. These procedures have been optimized for the analysis of multiple biological samples from human patients and transgenic animal models, including blood serum, various brain regions (e.g., hippocampus, cortex, cerebellum, striatum, olfactory bulbs), and other peripheral organs (e.g., liver, kidney, spleen, thymus). It is noteworthy that the metabolomic pipeline here detailed has demonstrated a great potential for the investigation of metabolic perturbations underlying Alzheimer's disease pathogenesis. PMID- 29512070 TI - Blood-Based Biomarker Screening with Agnostic Biological Definitions for an Accurate Diagnosis Within the Dimensional Spectrum of Neurodegenerative Diseases. AB - The discovery, development, and validation of novel candidate biomarkers in Alzheimer's disease (AD) and other neurodegenerative diseases (NDs) are increasingly gaining momentum. As a result, evolving diagnostic research criteria of NDs are beginning to integrate biofluid and neuroimaging indicators of pathophysiological mechanisms. More than 10% of people aged over 65 suffer from NDs. There is an urgent need for a refined two-stage diagnostic model to first initiate an early, sensitive, and noninvasive process in primary care settings. Individuals that meet detection criteria will then be channeled to more specific, costly (positron-emission tomography), and invasive (cerebrospinal fluid) assessment methods for confirmatory biological characterization and diagnosis.A reliable and sensitive blood test for AD and other NDs is not yet established; however, it would provide the golden screening gate for an efficient primary care management. A limitation to the development of a large-scale blood-screening biomarker-based test is the traditional application of clinically descriptive criteria for the categorization of single late-stage ND constructs. These are genetically and biologically heterogeneous, reflected in multiple pathophysiological mechanisms and subsequent pathologies throughout a dimensional continuum. Evidence suggests that a shared, "open-source" integrated multilevel categorization of NDs that clusters individuals based on descriptive clinical phenotypes and pathophysiological biomarker signatures will provide the next incremental step toward an improved diagnostic process of NDs. This intermediate objective toward unbiased biomarker-guided early detection of individuals at risk for NDs is currently carried out by the international pilot Alzheimer Precision Medicine Initiative Cohort Program (APMI-CP). PMID- 29512071 TI - Functional Magnetic Resonance Imaging in Alzheimer' Disease Drug Development. AB - While now commonly applied for studying human brain function the value of functional magnetic resonance imaging in drug development has only recently been recognized. Here we describe the different functional magnetic resonance imaging techniques applied in Alzheimer's disease drug development with their applications, implementation guidelines, and potential pitfalls. PMID- 29512072 TI - Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies. AB - Among others, the existence of pathophysiological biomarkers such as cerebrospinal fluid (CSF) Abeta-42, t-tau, and p-tau preceding the onset of Alzheimer's disease (AD) symptomatology have shifted the conceptualization of AD as a continuum. In addition, magnetic resonance imaging (MRI) enables the study of structural and functional cross-sectional correlates and longitudinal changes in vivo and, therefore, the combination of CSF data and imaging analyses emerges as a synergistic approach to understand the structural correlates related with specific AD-related biomarkers. In this chapter, we describe the methods used in neuroimaging that will allow researchers to combine data on CSF metabolites with imaging analyses. PMID- 29512073 TI - Hybrid PET-MRI in Alzheimer's Disease Research. AB - Multiple factors, namely amyloid, tau, inflammation, metabolic, and perfusion changes, contribute to the cascade of neurodegeneration and functional decline occurring in Alzheimer's disease (AD). These molecular and cellular processes and related functional and morphological changes can be visualized in vivo by two imaging modalities, namely positron emission tomography (PET) and magnetic resonance imaging (MRI). These imaging biomarkers are now part of the diagnostic algorithm and of particular interest for patient stratification and targeted drug development.In this field the availability of hybrid PET/MR systems not only offers a comprehensive evaluation in a single imaging session, but also opens new possibilities for the integration of the two imaging information. Here, we cover the clinical protocols and practical details of FDG, amyloid, and tau PET/MR imaging as applied in our institutions. PMID- 29512074 TI - Amyloid PET Imaging: Standardization and Integration with Other Alzheimer's Disease Biomarkers. AB - Amyloid plaques are a neuropathologic hallmark of Alzheimer's disease (AD), which can be imaged through positron emission tomography (PET) technology using radiopharmaceuticals that selectively bind to the fibrillar aggregates of amyloid beta plaques (Amy-PET). Several radiotracers for amyloid PET have been investigated, including 11C-Pittsburgh compound B and the 18F-labeled compounds such as 18F-florbetaben, 18F-florbetapir, and 18F-flutemetamol. Besides the injected radiotracer, images can be interpreted by means of visual/qualitative, semiquantitative, and quantitative criteria. Here we summarize the main differences between the available radiotracers for Amy-PET, the proposed interpretation criteria, and analytical methods. PMID- 29512075 TI - The Use of 18F-FDG PET in the Diagnostic Workup of Alzheimer's Dementia. AB - The diagnosis of dementia probably due to Alzheimer's disease is still primarily a clinical one. In cases that remain clinically unclear, however, biomarkers for amyloid deposition and neuronal injury can help to identify the underlying cause. One biomarker even for early neuronal injury in the stage of mild cognitive impairment is cerebral glucose hypometabolism measured by 18F-FDG PET. Distinct patterns of hypometabolism can be seen, for example, in dementia due to Alzheimer's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. This makes it possible to distinguish between different neurodegenerative diseases as well as major depressive disorder. While the sensitivity of 18F-FDG PET to detect Alzheimer's disease is high, specificity is low and the additional use of biomarkers for amyloid deposition might be beneficial in some cases. In conclusion, 18F-FDG PET is a useful tool when the cause for dementia remains unclear and different diagnosis would lead to different treatment approaches. Due to the lack of treatment options in pre-dementia stages, the use of 18F-FDG PET is currently not recommended for these cases in a purely clinical setting. PMID- 29512076 TI - Quantification of Tau Load in Alzheimer's Disease Clinical Trials Using Positron Emission Tomography. AB - Alzheimer's disease is a neurodegenerative condition that is neuropathologically characterized by the presence of amyloid-beta plaques and neurofibrillary tangles consisting of tau. Recently, several positron emission tomography (PET) tracers have been developed that yielded promising initial results. In this chapter, we discuss how tau PET can be used in the context in clinical trials. We argue that simplified reference tissue models based on dynamic data acquisition are most suitable for accurately measuring changes in tau pathology in trials tailored to reduce cerebral tau load. Therefore, we discuss the importance of tracer kinetic modeling and describe in detail how a reliable measurement of specific binding can be obtained. PMID- 29512077 TI - Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach. AB - The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed, and how clinical trials are designed today. Alzheimer's disease (AD)-the most common neurodegenerative disorder-is characterized by a complex neuropathology involving the deposition of extracellular amyloid-beta (Abeta) plaques and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells-astrocytes and microglia-and neuroinflammatory responses, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers are available to selectively target the different pathophysiological processes of AD. Along with the success of Abeta PET and the more recent tau PET imaging, there is also a great interest to develop PET tracers to image glial activation and neuroinflammation. While most research to date has focused on imaging microgliosis, recent studies using 11C-deuterium-L-deprenyl (11C-DED) PET imaging suggest that astrocytosis may be present from very early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Abeta deposition, and glucose metabolism in patients at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial responses in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial activation and neuroinflammation as biomarkers with clinical application, and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases. PMID- 29512078 TI - Unbiased Lipidomics and Metabolomics of Human Brain Samples. AB - Mass spectrometry (MS)-based lipidomics and metabolomics approaches have been used to discover new diagnostic and therapeutic targets of neurodegenerative disorders. Here, we describe a protocol to conduct an integrated metabolomics and lipidomics profiling of postmortem brains of frozen tissue samples from clinically characterized patients and age-matched controls. Metabolites and lipids can be extracted from each brain tissue sample, using a biphasic liquid/liquid extraction method. An unbiased liquid chromatography MS-based lipidomics and metabolomics workflows allows to screen for the content and composition of lipids and polar metabolites for each brain tissue. Data processing and statistical analysis are then used to compare the molecular content of all the samples, grouping them into cluster based on molecular similarities. The final results highlight classes of metabolites and biochemical pathways that are altered in brain samples from diseased brains compared to those from healthy subjects, helping to generate novel hypotheses on their mechanistic and functional significance. PMID- 29512079 TI - Neuropathological Assessment as an Endpoint in Clinical Trial Design. AB - Different neurodegenerative conditions can have complex, overlapping clinical presentations that make accurate diagnosis during life very challenging. For this reason, confirmation of the clinical diagnosis still requires postmortem verification. This is particularly relevant for clinical trials of novel therapeutics where it is important to ascertain what disease and/or pathology modifying effects the therapeutics have had. Furthermore, it is important to confirm that patients in the trial actually had the correct clinical diagnosis as this will have a major bearing on the interpretation of trial results. Here we present a simple protocol for pathological assessment of neurodegenerative changes. PMID- 29512080 TI - Analysis of Micro-RNA Expression by qPCR on a Microfluidics Platform for Alzheimer's Disease Biomarker Discovery. AB - Changes associated with neurodegeneration at the cellular level are manifestations of deregulated biochemical pathways, and typically precede neuronal loss. Incorporation of molecular markers in the diagnostic process could aid detection of early changes, prior to extensive neuronal loss, as early as the presymptomatic stages of the disorder, thus enabling improved patient stratification for targeted drug development. Such biomarkers should be sufficiently sensitive and specific to distinguish AD from other disorders with overlapping symptoms. Easily accessible biosamples, simple methodology, and low overall cost would enable population screening, which would not be feasible with other modalities. Non-coding (nc)RNAs have a crucial role in the entire spectrum of cellular processes, from development and differentiation to homeostatic maintenance, and have been implicated in different diseases; micro-RNAs (miRNAs) are a family of ncRNA molecules with an important role in posttranscriptional gene silencing. The early advances in the study of miRNAs as noninvasive biomarkers in cancer inspired their study for other conditions, including AD. Several deregulated miRNAs in brain, CSF, and blood have been associated with AD and other brain disorders. Their high stability makes miRNAs attractive for biomarker development, and a number of platforms are currently available for their analysis. qPCR is a technology characterized by high sensitivity and is suitable for focused analysis of specific candidates (assays) in a large number of samples. Microfluidic-based qPCR platforms have minimal RNA requirements and can yield thousands of datapoints in one qPCR experiment. Here, I present the use of miScript qPCR miRNA assays with the Fluidigm BioMark HD System. PMID- 29512081 TI - Telomere Length Shortening in Alzheimer's Disease: Procedures for a Causal Investigation Using Single Nucleotide Polymorphisms in a Mendelian Randomization Study. AB - Measuring the length of telomeres, repetitive nucleotide sequences capping the chromosomes which shortens by each cell division, has become a popular way of attaining a marker of biological aging processes. Several observational studies have investigated the associations between telomere length and Alzheimer's disease (AD) with the overall conclusion being shorter telomeres provide an increased risk for AD development. Here we present an alternative approach for addressing the topic where additional evidence on causality can be drawn. To do so, we include information on single nucleotide polymorphisms (SNPs) using nature's own experiment with random segregation of alleles at conception. The protocol describes the full process of the so-called Mendelian Randomization by selecting appropriate SNPs for the analysis, discussing different data sources that can be used and inform about methods, assumptions and suitable software packages including Stata code. PMID- 29512082 TI - Quantifying miRNA Deregulation in Alzheimer's Disease. AB - Analysis of miRNA expression in circulating immune cells, such as monocytes, using qRT-PCR arrays, allows the quantification of a wide range of miRNAs in easily accessible biosamples from Alzheimer's disease patients. This technique enables the identification of differentially expressed miRNAs and provides important clues for the discovery of new miRNA-based biomarkers. Here we describe how to isolate a specific lymphocyte population from human blood samples, CD14+ monocytes, and how to extract total RNA, containing short RNAs, from these cells, transcribe the RNA into cDNA and quantify a pre-set of specific miRNAs using customizable PCR plates of 96 or 384 wells. PMID- 29512083 TI - Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET. AB - Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [11C]PBR28 provides an opportunity for accurate visualization and quantification of changes in microglial density in transgenic mouse models of Alzheimer's disease (AD). Here, we describe the methodology for the in vivo use of [11C]PBR28 in AD patients and the 5XFAD transgenic mouse model of AD and compare the results against healthy individuals and wild-type controls. To confirm the results, autoradiography with [3H]PBR28 and immunochemistry was carried out in the same mouse brains. Our data shows that [11C]PBR28 is suitable as a tool for in vivo monitoring of microglial activation and may be useful to assess treatment response in future studies. PMID- 29512084 TI - In Vivo Two-Photon Calcium Imaging of Hippocampal Neurons in Alzheimer Mouse Models. AB - The use of in vivo two-photon microscopy in mouse models of Alzheimer's disease (AD) has propelled studies of disease mechanisms and treatments. For instance, this approach allowed for the first time to study in the intact brain the dynamics of individual amyloid plaques, and the effects of anti-amyloid therapies on plaque formation and growth. Moreover, by combining two-photon microscopy with fluorescent calcium indicators, an amyloid-dependent abnormal hyperactivity of cortical and hippocampal neurons was revealed as a primary neuronal impairment, which was not predicted from previous in vitro analyses. Here, a method for in vivo two-photon calcium imaging with single-cell and single-action potential accuracy in the hippocampus of Alzheimer mouse models is presented. PMID- 29512085 TI - Cognitive Assessment in Alzheimer's Disease Clinical Trials. AB - Many tests are available for the assessment of cognitive function. This chapter describes the common features and practical requirements of test administration, key considerations in the selection and interpretation of tests, and their application in Alzheimer's disease drug development. PMID- 29512086 TI - Data Mining and Machine Learning Methods for Dementia Research. AB - Patient data in clinical research often includes large amounts of structured information, such as neuroimaging data, neuropsychological test results, and demographic variables. Given the various sources of information, we can develop computerized methods that can be a great help to clinicians to discover hidden patterns in the data. The computerized methods often employ data mining and machine learning algorithms, lending themselves as the computer-aided diagnosis (CAD) tool that assists clinicians in making diagnostic decisions. In this chapter, we review state-of-the-art methods used in dementia research, and briefly introduce some recently proposed algorithms subsequently. PMID- 29512087 TI - Reply to "Comments on the Cerebral Edema After CPR: A Therapeutic Target Following Cardiac Arrest?" PMID- 29512088 TI - Sexual Dysfunction in Married Women With Urinary Incontinence. AB - PURPOSE: This study was conducted in descriptive and cross-sectional design in order to determine prevalence of urinary incontinence severity in women with urinary incontinence (UI), correlation between UI and sexual dysfunctionMaterials and Methods: The study had descriptive and cross-sectional design. In sample selection, four Family Health Centers areas were determined by lot and totally 384 women with UI were reached by making home visits in these regions. As data collection tool, severity index in female urinary incontinence determining UI condition and Female Sexual Function index determining sexual functioning were used. RESULTS: Average age of the women participating in the study was 37.3 +/- 1.02. Mean body mass index of the women was 26.3 +/- 5.41. It was determined that 22.1% of the women participating in the study had UI for 3-5 years and 15.1% had UI for six years and a longer time. It was determined that 53.9% of the women participating in study had mild incontinence, 40.6% had moderate incontinence, 3.6% had severe incontinence, and 1.8% had very severe incontinence. A significant correlation was found between severity index in female urinary incontinence (ISI) score and Female Sexual Function Index (FSFI) score (p < 0.05). There was a positive and weak correlation between ISI scores and age, duration of marriage, and number of pregnancy of the women who participating in the study; and a positive and very weak correlation between ISI scores and body mass index and spontaneous abortion (p < 0.05). CONCLUSION: Almost half of women with UI were determined to have moderate and more severe urinary incontinence. A significant correlation was found between ISI and FSFI score. PMID- 29512089 TI - Calculi in the Prostatic Surgical Bed as a complication after Holmium Laser Enucleation of the Prostate. AB - PURPOSE: To report de novo calculi in the prostatic surgical bed as a complication of Holmium laser enucleation of the prostate (HoLEP). MATERIALS AND METHODS: Patients who underwent HoLEP and were enrolled in our Benign Prostatic Hyperplasia (BPH) Database Registry from July 2008 to December 2015 were reviewed. Cases of calculi removal in the prostatic surgical bed were identified. Clinical data, including preoperative evaluation, postoperative symptoms with a detailed history, urinalysis, pathology, cystourethroscopy, and stone analysis were collected and described. RESULTS: Eight patients were identified including one patient who underwent HoLEP at another hospital. Among the 877 patients in our BPH database, 7 (0.8%) underwent calculi removal in the prostatic surgical bed. Median age was 67.0 years. Median prostatic volume was 75.5mL. The most common symptom was severe stabbing urethral pain (n = 4), with a median of 13 months after HoLEP. Calculi were pedunculated in the prostatic surgical bed or in the bladder neck with a small mucosal connection. Pathology of the resected tissue showed granulation tissueformation and dystrophic calcification. CONCLUSION: Calculi in the prostatic surgical bed or the bladder neck after HoLEP have never been reported previously. Although it is very rare, recurrent urethral pain, persistent pyuria, and recurrent gross haematuria are signs for further investigation. Cystourethroscopy should be performed to rule out the presence of stones. Careful history taking and having an index of suspicion are important for the diagnosis. PMID- 29512090 TI - Predicting functional mitral stenosis after restrictive annuloplasty for ischemic mitral regurgitation. AB - BACKGROUND: Although it has been realized that restrictive mitral valve annuloplasty (MVA) may result in clinically significant functional mitral stenosis (MS), it still cannot be predicted. The purpose of this study was to identify risk factors for clinically significant functional MS following restrictive MVA surgery for chronic ischemic mitral regurgitation (CIMR). METHODS: 114 patients who underwent restrictive MVA with coronary artery bypass grafting (CABG) for treatment of CIMR were retrospectively reviewed. Clinically significant functional MS was defined as resting transmitral peak pressure gradient (PPG) >= 13 mmHg. RESULTS: During the follow-up period (range 6-12 months), 28 (24.56%) patients developed clinically significant functional MS. The PPG at follow-up was significantly higher than that measured in the early postoperative stage (3-5 days after surgery). Moreover, there was a linear correlation between the two measurements (r = 0.398, p < 0.001). Annuloplasty size <= 27 mm and early postoperative PPG >= 7.4 mmHg could predict clinically significant functional MS at 6-12 months postoperatively. CONCLUSIONS: Chronic ischemic mitral regurgitation patients treated with restrictive MVA and CABG have significant increases in PPG postoperatively. Annuloplasty size <= 27 mm and early postoperative PPG >= 7.4 mmHg can predict clinically significant functional MS at 6-12 months after surgery. PMID- 29512091 TI - Hyperuricemia and severity of coronary artery disease: An observational study in adults 35 years of age and younger with acute coronary syndrome. AB - BACKGROUND: Coronary artery disease (CAD) in adults <= 35 years of age is rare, but the incidence is on the rise and the risk factors for this age group are largely uncertain. Previous studies have shown that hyperuricemia (HUA) is an independent risk factor for CAD in the general population, whereas the role in adults <= 35 years of age with acute coronary syndrome (ACS) is unclear. METHODS: Patients, 18-35 years of age, diagnosed with ACS for the first time at the documented institution between January 2005 and December 2015, were enrolled in the current study. The severity of CAD was assessed by the Gensini score. Patients were divided into two groups according to the definition of HUA. The relationship between HUA and CAD severity was assessed based on multi-variate analysis. RESULTS: Seven hundred seventy-one participants fulfilling the criteria were included in this study (mean age, 31.6 years; 94.4% male). HUA, which was defined as a serum uric acid level >= 7.0 mg/dL (420MUmol/L) in males and >= 6.0 mg/dL (357 MUmol/L) in females, accounted for 37% of the participants. Multivariate analysis identified that HUA is an independent risk factor of CAD severity, as assessed by the Gensini score, in very young adults with ACS (OR, 8.28; 95% CI, 1.96-14.59; P = 0.01), and the effect of HUA on CAD severity was second only to diabetes mellitus. CONCLUSIONS: HUA was shown to be an independent risk factor for CAD severity in young adults with ACS (18-35 years of age). PMID- 29512092 TI - Optical coherence tomography-guided versus angiography-guided implantation of everolimus-eluting bioresorbable vascular scaffolds: Comparison of coverage, apposition and clinical outcome. The ALSTER-OCT ABSORB registry. AB - BACKGROUND: Suboptimal implantation of everolimus-eluting bioresorbable vascular scaffolds (EE-BVS) leading to strut malapposition and lack of neointima coverage has been hypothesized to be linked to late BVS-thrombosis. Optical coherence tomography (OCT) allows assessing subtle differences in BVS-healing. We aimed to link 6-months OCT-data on EE-BVS coverage and malapposition to implantation technique and clinical outcome. METHODS: Twenty-nine consecutive EE-BVS-patients were included. EE-BVS-implantation was guided by angiography in the first 17 patients (group 1). Vessel sizing prior to implantation and implantation result was assessed by OCT in the 12 following patients (group 2). EE-BVS-implantation was performed in both groups with adequate lesion preparation, sizing and systematic high-pressure post-dilatation. All patients received 6-months invasive control including OCT-analysis and clinical follow-up for 2 years. RESULTS: The rate of uncovered struts was group 1: 10.8 +/- 10.0%; group 2: 10.6 +/- 8.2%, p = 0.934. Target lesion failure due to BVS-thrombosis occurred in 2/17 patients at 9 and 18 months (11.8%, group 1), and no patients in group 2 (p = 0.218). CONCLUSIONS: Optical coherence tomography analysis at 6-months following EE-BVS implantation finds almost 90% of struts to be covered. No difference between OCT vs. angiography-guided EE-BVS-implantation was observed. OCT at 6-months was not able to predict late BVS-thrombosis of EE-BVS. PMID- 29512093 TI - Predictive and protective role of high-density lipoprotein cholesterol in acute myocardial infarction. AB - BACKGROUND: It is unclear whether high-density lipoprotein cholesterol (HDL-C) level predicts cardiovascular events and has a protective effect in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) and statin treatment. METHODS: A total of 15,290 AMI patients receiving statins were selected from the Korean Myocardial Infarction Registry. Baseline HDL-C level was used to identify patients with low (Group A), normal (B), and high (C) HDL-C levels according to the Adult Treatment Panel III criteria. Clinical outcomes were compared in propensity-adjusted and matched cohorts. The primary endpoint was a composite of cardiovascular death and recurrent myocardial infarction. RESULTS: At the median follow-up of 11.5 months, the primary endpoint occurred in 2.7% (112/4098), 1.4% (54/3910), and 1.2% (8/661) of patients in groups A, B, and C, respectively. In the propensity-adjusted cohort, low HDL-C level increased the risk of primary endpoint (hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.274-2.417, p = 0.001), whereas high HDL-C level did not reduce this risk (HR 0.562, 95% CI 0.275-1.146, p = 0.113). In the propensity matched cohort, low HDL-C level increased the risk of primary endpoint (HR 1.716, 95% CI 1.210-2.434, p = 0.002), whereas high HDL-C level reduced this risk (HR 0.449, 95% CI 0.214 - 0.946, p = 0.035). CONCLUSIONS: In AMI patients treated with PCI and statins, low HDL-C level increases the risk of cardiovascular death and recurrent myocardial infarction, whereas high HDL-C level likely reduces the risk of cardiovascular events, especially for ST-elevation myocardial infarction. PMID- 29512094 TI - Two-dimensional versus three-dimensional transesophageal echocardiography in percutaneous left atrial appendage occlusion. AB - BACKGROUND: Real-time three-dimensional transesophageal echocardiography (RT3D TEE) enables better visualization of the left atrial appendage (LAA) and may be superior to real-time two-dimensional transesophageal echocardiography (RT2D TEE) for LAA occlusion (LAAO). The aim of this study was to assess inter- and intra observer variability of RT2D TEE and RT3D TEE measurements of LAA, and to assess the accordance of RT2D TEE and RT3D TEE with appropriate occluder selection. METHODS: Transesophageal echocardiography was performed in 40 patients during LAAO. RT2D TEE and RT3D TEE measurements of the ostium and landing zone were performed independently by 2 echocardiographers. The appropriate choice of occluder was confirmed with fluoroscopic criteria. After the procedures, RT2D TEE and RT3D TEE evaluation were repeated separately by the same echocardiographers. RESULTS: The mean ostium diameters by RT2D TEE obtained by the 2 observers were 23.6 +/- 4.2 vs. 24.8 +/- 5.2 (p = 0.04), and the mean landing zone diameters were 17.7 +/- 4.4 vs. 19.4 +/- 3.9 (p < 0.01). In the case of RT3D TEE, the ostium diameters were 29.6 +/- 5.3 vs. 29.4 +/- 6.4 (p = not significant [NS]) and the landing zone diameters were 21.4 +/- 3.8 vs. 21.6 +/- 3.9 (p = NS). Intra observer differences were absent in the case of RT3D TEE. The comparison of RT2D TEE vs. RT3D TEE analyses performed by the same echocardiographer revealed significant differences in the ostium and landing zone measurements (both p < 0.01). Agreement between the suggested device size was better for RT3D TEE (weighted Kappa was 0.62 vs. 0.28, respectively). CONCLUSIONS: The results obtained with RT3D TEE showed significantly larger dimensions of the ostium and the landing zone. RT3D TEE showed lesser inter- and intra-observer variability and better agreement with the implanted device. PMID- 29512095 TI - Mast cell derived carboxypeptidase A3 is decreased among patients with advanced coronary artery disease. AB - BACKGROUND: Coronary artery disease (CAD) affects milions of people and can result in myocardial infarction (MI). Previously, mast cells (MC) have been extensively investigated in the context of hypersensitivity, however as regulators of the local inflammatory response they can potentially contribute to CAD and/or its progression. The aim of the study was to assess if serum concentration of MC proteases: carboxypeptidase A3, cathepsin G and chymase 1 is associated with the extension of CAD and MI. METHODS: The 44 patients with angiographically confirmed CAD (23 subjects with non-ST segment elevation MI [NSTEMI] and 21 with stable CAD) were analyzed. Clinical data were obtained as well serum concentrations of carboxypeptidase A3, cathepsin G and chymase 1 were also measured. RESULTS: Patients with single vessel CAD had higher serum concentration of carboxypeptidase than those with more advanced CAD (3838.6 +/- 1083.1 pg/mL vs. 2715.6 +/- 442.5 pg/mL; p = 0.02). There were no significant differences in levels of any protease between patients with stable CAD and those with NSTEMI. Patients with hypertension had ~2-fold lower serum levels of cathepsin G than normotensive individuals (4.6 +/- 0.9 pg/mL vs. 9.4 +/- 5.8 pg/mL; p = 0.001). Cathepsin G levels were also decreased in sera of the current smokers as compared with non-smokers (3.1 +/- 1.2 ng/mL vs. 5.8 +/- 1.2 ng/mL, p = 0.02). CONCLUSIONS: 1. Decreased serum level of carboxypeptidase is a hallmark of more advanced CAD. 2. Lower serum levels of carboxypeptidase A3 and catepsin G are associated with risk factors of blood vessel damage suggesting a protective role of these enzymes in CAD. PMID- 29512096 TI - Predictive value of CHA2DS2-VASc and CHA2DS2-VASc-HS scores for failed reperfusion after thrombolytic therapy in patients with ST-elevation myocardial infarction. AB - BACKGROUND: Thrombolytic therapy is recommended for patients with acute ST segment elevation myocardial infarction (STEMI) who cannot undergo primary percutaneous coronary intervention within the first 120 min. The aim of this study wasz to demonstrate the value of CHA2DS2-VASc and CHA2DS2-VASc-HS scores in predicting failed reperfusion in STEMI patients treated with thrombolytic therapy. METHODS: A total of 537 consecutive patients were enrolled in the study; 139 had failed thrombolysis while the remaining 398 fulfilled the criteria for successful thrombolysis. Thrombolysis failure was defined with the lack of symptom relief, < 50% ST resolution-related electrocardiography within 90 min from initiation of the thrombolytic therapy, presence of hemodynamic or electrical instability or in-hospital mortality. CHA2DS2-VASc and CHA2DS2-VASc-HS scores, which incorporate hyperlipidemia, smoking, switches between female and male gender, were previously shown to be markers of the severity of coronary artery disease (CAD). RESULTS: History of hypertension, diabetes mellitus, hyperlipidemia, heart failure, smoking, and CAD were significantly common in failed reperfusion patients (for all; p < 0.05). For prediction of failed reperfusion, the cut-off value of CHA2DS2-VASc score was >= 2 with a sensitivity of 80.90% and a specificity of 41.01% (area under curve [AUC] 0.660; 95% confidence interval [CI] 0.618-0.700; p < 0.001) and the cut-off value of CHA2DS2 VASc-HS score was >= 3 with a sensitivity of 76.13% and a specificity of 67.63% (AUC 0.764; 95% CI 0.725-0.799; p < 0.001). The CHA2DS2-VASc-HS score was found to be statistically and significantly better than CHA2DS2-VASc score to predict failed reperfusion (p < 0.001). CONCLUSIONS: The findings suggest that the CHA2DS2-VASc and especially CHA2DS2-VASc-HS scores could be considered as predictors of risk of failed reperfusion in STEMI patients. PMID- 29512097 TI - Patent foramen ovale closure versus medical therapy after cryptogenic stroke: An updated meta-analysis of all randomized clinical trials. AB - BACKGROUND: Cryptogenic strokes can be attributed to paradoxical emboli through patent foramen ovale (PFO). However, the effectiveness of PFO closure in preventing recurrent stroke is uncertain and the results of previous randomized clinical trials (RCTs) have been inconclusive. Hence, this study provides an updated meta-analysis of all RCTs comparing PFO closure with medical therapy for secondary prevention of cryptogenic stroke. METHODS: All RCTs were identified by a comprehensive literature search of PubMed, Embase, the Cochrane Collaboration Central Register of Controlled Trials, Scopus, and Clinicaltrials.gov. The primary outcome was recurrent ischemic stroke and secondary outcomes were transient ischemic attack (TIA), all-cause mortality, new-onset atrial fibrillation (AF), serious adverse events, and major bleeding. RESULTS: 5 RCTs with 3440 participants were included in the present study (1829 patients underwent PFO closure and 1611 were treated medically). Pooled analysis showed a statistically significant reduction in the rate of recurrent stroke with PFO closure in comparison to medical therapy (OR 0.41; 95% CI 0.19-0.90; p = 0.03). However, there were no statistically significant reductions of recurrent TIAs (OR 0.77; 95% CI 0.51-1.14; p = 0.19) or all-cause mortality (OR 0.76; 95% CI 0.35 1.65; p = 0.48). The risk of developing new-onset AF was increased significantly with PFO closure (OR 4.74; 95% CI 2.33-9.61; p < 0.0001), but no significant differences in terms of serious adverse events or major bleeding between both groups. CONCLUSION: Patent foramen ovale closure in adults with recent cryptogenic stroke was associated with a lower rate of recurrent strokes in comparison with medical therapy alone. PMID- 29512098 TI - Effects of hyperbaric oxygen on vascular endothelial function in patients with slow coronary flow. AB - BACKGROUND: To improve therapy for slow coronary flow (SCF), the effects of hyperbaric oxygen (HBO) therapy on vascular endothelial function in SCF patients is the focus of this investigation. METHODS: Ninety-eight patients who exhibited chest discomfort were retrospectively analyzed, and di-agnosed with SCF by coronary artery angiography at the Third Hospital of Hebei Medical University, Shijiazhuang, China from 2014 to 2016. The patients were divided into two groups according to the following treatment: HBO group (n = 48) and the control group (n = 50). Patients in the control group were administrated with conventional treatment, while those in the HBO group were administrated HBO therapy for 4 weeks in addition to conventional treatment. To evaluate the effects of HBO on vas-cular endothelial functions, plasma levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), endothelin-1 (ET-1), high sensitivity C-reactive protein (hsCRP) as well as endothelial-dependent flow-mediated vasodilation (FMD) of the brachial artery were measured in both groups before and after their respective treatments. RESULTS: There were no significant differences in plasma levels of NO, ET-1, CGRP, hsCRP nor in FMD measurements between the two groups before treatment (p > 0.05). Moreover, the levels of all the parameters measured showed no significant changes before and after treatment in the control group. However, when comparing the control group, FMD and plasma NO and CGRP levels were significantly increased in the HBO group after treatment (p < 0.01), whereas hsCRP and ET-1 levels decreased dramatically (p < 0.001). CONCLUSIONS: The HBO treatment in addition to conventional therapy may significantly improve the vascular endothelial function in SCF patients. (Cardiol J 2018; 25, 1: 106-112). PMID- 29512099 TI - Sealing a large double lobe left atrial appendage with two Occlutech occluders. PMID- 29512100 TI - Self-apposing stent fracture in the context of myocardial bridging leading to in stent chronic total occlusion: When the muscle trumps the metal. PMID- 29512101 TI - Diagnostic dilemma regarding the extent of implantable cardioverter-defibrillator infection: Pocket infection alone or pocket infection with concomitant lead dependent infective endocarditis? PMID- 29512102 TI - Impact of post-dilatation on strut apposition of second-generation bioresorbable vascular scaffolds: Key role for scaffold thrombosis and prognosis? PMID- 29512103 TI - Intra-ventricular thrombus resolution after anticoagulation therapy with rivaroxaban in patient with poor anticoagulation quality. PMID- 29512104 TI - Delayed cerebral fat embolism occurring after off-pump coronary artery bypass grafting. PMID- 29512105 TI - hPSC-derived Midbrain Dopaminergic Neurons Generated in a Scalable 3-D Biomaterial. AB - Human pluripotent stem cell (hPSC)-derived midbrain dopaminergic (mDA) neurons may facilitate the development of therapies for Parkinson's disease via disease modeling, drug screening, and cell replacement therapy. However, large numbers of cells are typically needed for these applications, and 2-D culture-based approaches typically used for mDA differentiation are difficult to scale up and require a long time for mDA maturation. Here we present a protocol to rapidly generate functional mDA neurons in a fully defined, scalable, thermoresponsive 3 D biomaterial. Resource-efficient and accelerated differentiation of large numbers of mDA neurons may thus facilitate studying and treating PD. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512106 TI - CRISPR-Cas9-Based Genome Editing of Human Induced Pluripotent Stem Cells. AB - Human induced pluripotent stem cells (hiPSCs) are the ideal cell source for autologous cell replacement. However, for patients with Mendelian diseases, genetic correction of the original disease-causing mutation is likely required prior to cellular differentiation and transplantation. The emergence of the CRISPR-Cas9 system has revolutionized the field of genome editing. By introducing inexpensive reagents that are relatively straightforward to design and validate, it is now possible to correct genetic variants or insert desired sequences at any location within the genome. CRISPR-based genome editing of patient-specific iPSCs shows great promise for future autologous cell replacement therapies. One caveat, however, is that hiPSCs are notoriously difficult to transfect, and optimized experimental design considerations are often necessary. This unit describes design strategies and methods for efficient CRISPR-based genome editing of patient- specific iPSCs. Additionally, it details a flexible approach that utilizes positive selection to generate clones with a desired genomic modification, Cre-lox recombination to remove the integrated selection cassette, and negative selection to eliminate residual hiPSCs with intact selection cassettes. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512107 TI - Fluid accumulation during acute kidney injury in the intensive care unit. AB - INTRODUCTION: Fluid therapy is a ubiquitous intervention in patients admitted to the intensive care unit, but positive fluid balance may be associated with poor outcomes and particular in patients with acute kidney injury. Studies describing this have defined fluid overload either at specific time points or considered patients with a positive mean daily fluid balance as fluid overloaded. We wished to detail this further and performed joint model analyses of the association between daily fluid balance and outcome represented by mortality and renal recovery in patients admitted with acute kidney injury. METHOD: We did a retrospective cohort study of patients admitted to the intensive care unit with acute kidney injury during a 2-year observation period. We used serum creatinine measurements to identify patients with acute kidney injury and collected sequential daily fluid balance during the first 5 days of admission to the intensive care unit. We used joint modelling techniques to correlate the development of fluid overload with survival and renal recovery adjusted for age, gender and disease severity. RESULTS: The cohort contained 863 patients with acute kidney injury of whom 460 (53%) and 254 (29%) developed 5% and 10% fluid overload, respectively. We found that both 5% and 10% fluid overload was correlated with reduced survival and renal recovery. CONCLUSION: Joint model analyses of fluid accumulation in patients admitted to the intensive care unit with acute kidney injury confirm that even a modest degree of fluid overload (5%) may be negatively associated with both survival and renal recovery. PMID- 29512108 TI - Direct Conversion of Human Pluripotent Stem Cells to Osteoblasts With a Small Molecule. AB - Human pluripotent stem cells (hPSCs), which exhibit unlimited self-renewal ability and can differentiate into all cell types in the human body, are a promising cell source for cell-based therapies and regenerative medicine. Small molecules hold great potential in the derivation of tissue-specific cells from hPSCs owing to their cost-effectiveness and scalability. Here, we describe a protocol for deriving osteoblasts from hPSCs by using a single, natural small molecule: adenosine. This simple and effective experimental protocol allows one to obtain large numbers of osteoblasts or osteoprogenitor cells, with the ability to form functional bone tissues, from hPSCs, including human embryonic stem cells and induced pluripotent stem cells. This protocol could potentially enable studies of tissue regeneration and skeletal diseases. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512109 TI - Fatal propofol infusion syndrome in a young man with status epilepticus. PMID- 29512111 TI - Derivation of Multipotent Mesenchymal Stromal Cells from Ovine Bone Marrow. AB - In the field of orthopedics, translational research of novel therapeutic approaches involves the use of large animal models (such as sheep, goat, pig, dog, and horse) due to the similarities with humans in weight, size, joint structure, and bone/cartilage healing mechanisms. Particularly in the development of cell-based therapies, the lack of manageable immunocompromised preclinical large animal models prevents the use of human cells, which makes it necessary to produce equivalent homologous cell types for the study of their pharmacodynamics, pharmacokinetics, and toxicology. The methods described herein allow for the isolation, expansion, manipulation, and characterization of fibroblastic-like ovine bone marrow-derived multipotent mesenchymal stromal cells (BM-MSC) that, similar to human BM-MSC, adhere to standard plastic surfaces; express specific surface markers such as CD44, CD90, CD140a, CD105, and CD166; and display trilineage differentiation potential in vitro. Homogeneous cell cultures result from a 3-week bioprocess yielding cell densities in the range of 2-4 * 104 MSC/cm2 at passage 2, which corresponds to ~8 cumulative population doublings. Large quantities of BM-MSC resulting from following this methodology can be readily used in proof of efficacy and safety studies in the preclinical development stage. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512110 TI - The efficacy of functional gait training in children and young adults with cerebral palsy: a systematic review and meta-analysis. AB - AIM: The aim of this systematic review was to investigate the effects of functional gait training on walking ability in children and young adults with cerebral palsy (CP). METHOD: The review was conducted using standardized methodology, searching four electronic databases (PubMed, Embase, CINAHL, Web of Science) for relevant literature published between January 1980 and January 2017. Included studies involved training with a focus on actively practising the task of walking as an intervention while reporting outcome measures relating to walking ability. RESULTS: Forty-one studies were identified, with 11 randomized controlled trials included. There is strong evidence that functional gait training results in clinically important benefits for children and young adults with CP, with a therapeutic goal of improved walking speed. Functional gait training was found to have a moderate positive effect on walking speed over standard physical therapy (effect size 0.79, p=0.04). Further, there is weaker yet relatively consistent evidence that functional gait training can also benefit walking endurance and gait-related gross motor function. INTERPRETATION: There is promising evidence that functional gait training is a safe, feasible, and effective intervention to target improved walking ability in children and young adults with CP. The addition of virtual reality and biofeedback can increase patient engagement and magnify effects. WHAT THIS PAPER ADDS: Functional gait training is a safe, feasible, and effective intervention to improve walking ability. Functional gait training shows larger positive effects on walking speed than standard physical therapy. Walking endurance and gait-related gross motor function can also benefit from functional gait training. Addition of virtual reality and biofeedback shows promise to increase engagement and improve outcomes. PMID- 29512112 TI - Molecular Genetic Manipulation of Sarcocystis neurona. AB - Sarcocystis neurona is a member of the important phylum Apicomplexa and the primary cause of equine protozoal myeloencephalitis (EPM). Moreover, S. neurona is the best-studied species in the genus Sarcocystis, one of the most successful parasite taxa, as virtually all vertebrate animals may be infected by at least one species. Consequently, scientific investigation of S. neurona will aid in the control of EPM and neurologic disease in sea mammals, while also improving our understanding of a prominent branch on the apicomplexan phylogenetic tree. These protocols describe methods that expand the capabilities to study this prominent member of the Apicomplexa. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512113 TI - Porcine Reproductive and Respiratory Syndrome Virus: Propagation and Quantification. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a member of the family Arteriviridae, order Nidovirale. PRRSV is an enveloped, single-stranded, positive-sense RNA virus with a genome around 15 kb in length. For propagation of PRRSV in vitro, the MARC-145 cell line is the most often used in a laboratory setting. Infectious cDNA clones of many PRRSV strains have been established, from which these viruses can be recovered. PRRSV titration is generally done in MARC 145 cells. PRRSV RNA copy numbers can be assessed by reverse transcription and real-time PCR. Here, protocols for PRRSV propagation, virus recovery from infectious cDNA clones, and quantification are presented. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512114 TI - Poliovirus Replicon RNA Generation, Transfection, Packaging, and Quantitation of Replication. AB - Poliovirus is a prototype member of the Enterovirus genus of the Picornaviridae family of small positive strand RNA viruses, which include important human and animal pathogens. Quantitative assessment of viral replication is very important for investigation of the virus biology and the development of anti-viral strategies. The poliovirus genome structure allows replacement of structural genes with a reporter protein, such as a luciferase or a fluorescent protein, whose signals can be detected and quantified in vivo, thus permitting observation of replication kinetics in live cells. This paper presents protocols for poliovirus replicon RNA production, purification, packaging and transfection, as well as techniques for monitoring Renilla luciferase replication signal in living cells. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512115 TI - Hepatitis E Virus: Isolation, Propagation, and Quantification. AB - Hepatitis E virus (HEV) predominantly causes acute liver disease in humans and is transmitted via the fecal-oral route. HEV infection in pregnant women can result in grave consequences, with up to 30% fatality. The HEV strains infecting humans mainly belong to four genotypes. Genotypes 1 and 2 are restricted to human infection, while genotypes 3 and 4 are zoonotic. HEV genotype 3 (HEV-3) can cause both acute and chronic liver diseases. Several cell lines (mainly hepatocytes) have been developed for HEV propagation and biological study. However, HEV production in these cell lines is suboptimal and inefficient. Here, we present methods for the isolation, propagation, and quantification of HEV. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512116 TI - Sporulation and Germination of Paenibacillus larvae Cells. AB - Endospores are metabolically dormant cells formed by a variety of Gram-positive bacteria within the phylum Firmicutes in response to nutrient limiting or otherwise unfavorable growth conditions. American foulbrood disease (AFB) is a serious disease of honeybees that is caused by the introduction of Paenibacillus larvae endospores into a honeybee colony. Progression to fulminant disease and eventual collapse of the colony requires multiple rounds of endospore germination, vegetative replication, endospore formation, and subsequent spread within the colony. This unit includes protocols for the in vitro sporulation and germination of P. larvae to assist investigators in the study of these processes. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512117 TI - Growth and Laboratory Maintenance of Paenibacillus larvae. AB - Paenibacillus larvae is a Gram-positive, spore-forming bacterium and the causative agent of American foulbrood disease (AFB), a highly contagious, fatal disease affecting managed honeybee (Apis mellifera) colonies. As the etiological agent of American foulbrood disease, P. larvae is the most economically significant bacterial pathogen infecting honeybees. This unit includes protocols for the in vitro growth and laboratory maintenance of P. larvae. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512118 TI - Analyzing Chemotaxis and Related Behaviors of Azospirillum Brasilense. AB - Bacteria of the genus A. brasilense are motile and capable of chemotaxis and aerotaxis (taxis in gradient of oxygen) using a single polar flagellum that propels the cells in aqueous environments. Responses to attractants and repellents have been described and spatial gradient assays that permit the visualization of these responses are detailed in this unit. These assays are simple and can be readily implemented with minimum set ups. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512119 TI - Reverse Genetics for Newcastle Disease Virus as a Vaccine Vector. AB - Newcastle disease virus (NDV) is an economically important pathogen in the poultry industry worldwide. Recovery of infectious NDV from cDNA using reverse genetics has made it possible to manipulate the genome of NDV. This has greatly contributed to our understanding of the molecular biology and pathogenesis of NDV. Furthermore, NDV has modular genome and accommodates insertion of a foreign gene as a transcriptional unit, thus enabling NDV as a vaccine vector against diseases of humans and animals. Avirulent NDV strains (e.g., LaSota and B1) have been commonly used as vaccine vectors. In this protocol, we have described reverse genetics of NDV to be used as a vaccine vector by exemplifying the recovery of NDV vectored avian influenza virus vaccine. Specifically, cloning and recovery of NDV expressing the hemagglutinin protein of highly pathogenic influenza virus were explained. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512120 TI - Medical Costs of Fatal and Nonfatal Falls in Older Adults. AB - OBJECTIVES: To estimate medical expenditures attributable to older adult falls using a methodology that can be updated annually to track these expenditures over time. DESIGN: Population data from the National Vital Statistics System (NVSS) and cost estimates from the Web-based Injury Statistics Query and Reporting System (WISQARS) for fatal falls, quasi-experimental regression analysis of data from the Medicare Current Beneficiaries Survey (MCBS) for nonfatal falls. SETTING: U.S. population aged 65 and older during 2015. PARTICIPANTS: Fatal falls from the 2015 NVSS (N=28,486); respondents to the 2011 MCBS (N=3,460). MEASUREMENTS: Total spending attributable to older adult falls in the United States in 2015, in dollars. RESULTS: In 2015, the estimated medical costs attributable to fatal and nonfatal falls was approximately $50.0 billion. For nonfatal falls, Medicare paid approximately $28.9 billion, Medicaid $8.7 billion, and private and other payers $12.0 billion. Overall medical spending for fatal falls was estimated to be $754 million. CONCLUSION: Older adult falls result in substantial medical costs. Measuring medical costs attributable to falls will provide vital information about the magnitude of the problem and the potential financial effect of effective prevention strategies. PMID- 29512121 TI - Randomized controlled trial of intra-articular ketorolac on pain and inflammation after minor arthroscopic knee surgery. AB - BACKGROUND: Ketorolac is an effective non-steroidal anti-inflammatory drug, commonly used with local anaesthetics as part of local infiltration analgesia protocols following orthopaedic surgery. However, systemic uptake and drug action may be the major mechanism after local infiltration. The aims of this project were to study the effects of a small, systemically ineffective dose of ketorolac given intra-articularly for post-operative pain and also to study synovial inflammatory biomarkers. We investigated whether ketorolac affects pro inflammatory biomarkers in an in vitro model, as well. METHODS: In this placebo controlled, blind, randomized study, we analysed intra-articular ketorolac (5 mg) in ambulatory minor knee surgery patients with moderate or severe pain (n = 44). We assessed post-operative pain intensity (n = 44) and analysed microdialysis samples taken from knee synovial tissue every 20 min (n = 34). We also tested cyclooxygenase-independent effects of ketorolac in synovial cells stimulated by prostaglandin E2 and chondroitin sulphate in vitro. RESULTS: Intra-articular ketorolac (5 mg) administration did not reduce pain or synovial pro-inflammatory cytokines CXCL1, IL-8, and MCP-1, 0-120 min after knee arthroscopy. Female gender was a risk factor for moderate or severe pain (relative risk 1.45, 95% confidence interval 1.04-2.01). Paradoxically, ketorolac increased the release of CXCL1 and IL-8 in prostaglandin E2 and chondroitin sulphate-stimulated synovial cells in vitro. CONCLUSION: Ketorolac prescribed at a low dose intra-articularly does not produce any detectable analgesic effect after minor knee surgery. PMID- 29512122 TI - Phenotypic and Functional Evaluation of Hematopoietic Stem and Progenitor Cells in Toxicology of Heavy Metals. AB - All blood cells are differentiated from hematopoietic stem and progenitor cells (HSPCs), a process known as hematopoiesis that can be influenced by a variety of environmental factors. In this unit, we introduce a couple of protocols including phenotypic analysis, mixed bone marrow (BM) chimera and rescue assays, colony forming unit (CFU), and in vitro OP9 stromal cell differentiation assays for evaluating HSPCs in the BM of mice, and provide some examples of their implications in mouse models treated with heavy metals. The protocols for evaluating hematopoietic stem cells (HSCs) comprise phenotypic analysis and functional transplantation assays. The protocols for assessing hematopoietic progenitor cells (HPCs) consist of phenotypic analysis and in vitro differentiation assays. The main techniques applied in these protocols include flow cytometry (phenotypic analysis and sorting), irradiation, transplantation, and cell culture. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512123 TI - Preparation of Human Primary Colon Tissue-Derived Organoid Using Air Liquid Interface Culture. AB - In vitro analysis of intestinal epithelium has been hindered by a lack of suitable culture systems useful for gastrointestinal research. To overcome the problem, an air liquid interface (ALI) method using a collagen gel was established to culture three-dimensional primary cells containing both primary epithelial and mesenchymal components from mouse gastrointestinal tissues. ALI organoids accurately recapitulate organ structures, multilineage differentiation, and physiology. Since ALI organoids from human tissues have not been produced, we modified the previous protocol for mouse ALI organoid culture to establish the culture system of ALI organoids from normal and tumor colorectal tissues of human patients. The current unit presents a protocol for preparation of the ALI organoid culture from normal and tumor colorectal tissues of human patients. ALI organoid culture from human tissues might be useful for examining not only resistance to chemotherapy in a tumor microenvironment but also toxic effects on organoids. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512124 TI - Development of an In Vitro Method to Estimate the Sensitization Induction Level of Contact Allergens. AB - Recently, an in vitro procedure, which combines the epidermal equivalent potency assay with assessment of IL-18 to provide a single test for identification and classification of skin sensitizers, was developed and validated. This unit will describe a simple in vitro method for estimation of the expected sensitization induction level interpolating in vitro EC50 and IL-18 SI2 values to predict LLNA EC3 and/or human NOEL from standards curves generated using reference contact allergens, based on the use of Reconstituted human Epidermis (RhE).(c) 2018 by John Wiley & Sons, Inc. PMID- 29512125 TI - Evaluation of Marijuana Compounds on Neuroimmune Endpoints in Experimental Autoimmune Encephalomyelitis. AB - Cannabinoid compounds refer to a group of more than 60 plant-derived compounds in Cannabis sativa, more commonly known as marijuana. Exposure to marijuana and cannabinoid compounds has been increasing due to increased societal acceptance for both recreational and possible medical use. Cannabinoid compounds suppress immune function, and while this could compromise one's ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases. It is critical, therefore, to understand the effects and mechanisms by which cannabinoid compounds alter immune function, especially immune responses induced in autoimmune disease. Therefore, this unit will describe induction and assessment of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and its potential alteration by cannabinoid compounds. The unit includes three approaches to induce EAE, two of which provide correlations to two forms of MS, and the third specifically addresses the role of autoreactive T cells in EAE. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512126 TI - A Real-Time Image-Based Approach to Distinguish and Discriminate Apoptosis from Necrosis. AB - Recent cell biology studies reveal that a cell can die through multiple pathways via distinct signaling mechanisms. Among these, apoptosis and necrosis are two distinct cell death pathways, and their detection and discrimination is vital in the drug discovery process and in understanding diverse biological processes. Although sensitive assays for apoptosis and necrosis are available, it is extremely difficult to adapt any of these methods to discriminate apoptosis inducing stimuli from necrosis-inducing stimuli because of the acquisition of secondary necrosis by apoptotic cells when they are not phagocytosed. Essentially, any assay for discriminating apoptosis and necrosis needs to be carried out in real-time kinetic mode. Caspase 3 or 7 activation is observed in the majority of apoptotic cell death. Similarly, the absence of caspase 3/7 activation and cell membrane leakage are the two prominent indicators for necrotic cell death or necroptosis. The programmed form of necrosis, called pyroptosis, is also accompanied by membrane leakage and most often associated with activation of specific caspases such as caspase 1, 4, or 11, but not through caspase 3/7 activation. Here, a robust and sensitive real-time method is described to distinguish and discriminate apoptosis from necrosis. The assay utilizes stable integration of a genetically encoded fluorescence resonance energy transfer (FRET) probe for caspase 3/7 activation and the mitochondrion targeted DsRed to identify necrotic cells. Caspase activation is determined by cleavage of the FRET probe; loss of soluble FRET probe with retention of mitochondrial red fluorescence indicates necrosis. This unit describes an important protocol for the generation of sensor cells expressing both probes, followed by detailed analysis of apoptosis and necrosis by microscopy imaging, confocal imaging, high-throughput imaging, and flow cytometry. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512127 TI - Determination of Mycophenolic Acid and Mycophenolic Acid Glucuronide Using Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS). AB - Mycophenolic acid (MPA) is an immunosuppressant that is used in renal, liver, and heart transplantation. Due to its narrow therapeutic range, monitoring of MPA levels is essential to avoid toxicity and organ rejection. Although immunoassays are available for the determination of MPA, due to their higher specificity, mass spectrometry methods are preferred. In this unit, we describe a liquid chromatography tandem mass spectrometry (LC/MS/MS) method utilizing positive ionization electrospray and multiple reaction monitoring (MRM) for the quantification of levels of MPA and its conjugate MPA glucuronide (MPAG). Blood collected in a plain, EDTA, or heparin-containing tube is centrifuged to separate the serum or plasma. Proteins are precipitated using a solution containing zinc sulfate and acetonitrile that has been spiked with deuterated internal standards. The resulting protein-free supernatant is injected into the LC/MS/MS system for analysis. The chromatography involves the use of a C18 column and ammonium acetate/water/formic acid and ammonium acetate/methanol/formic acid mobile phases. Quantification of MPA and MPAG levels is achieved by comparing the MRM peak area ratios of analytes and internal standards, consisting of specific precursor/product pairs, with those of calibrators at various concentrations. Calibration curves are constructed from the MRM peak area ratios of calibrators and internal standards versus concentration. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512128 TI - Use of Human Embryoid Bodies for Teratology. AB - Human birth defects are relatively common and can be caused by exposure to environmental teratogens or to pharmaceuticals with teratogenic activities. Human embryonic stem cells (hESCs), by virtue of their pluripotent nature, provide an excellent cellular platform for teratogen detection and risk assessment. This unit describes detailed protocols for the preparation and validation of highly pluripotent hESCs, the production of large quantities of aggregated multicellular spheroids composed of hESCs, and these spheroids' differentiation into embryoid bodies (EBs). EBs contain a variety of cells of endodermal, ectodermal, and mesodermal origin and can be subjected to compound exposure in vitro. Hence, they are useful for the detection of chemicals with teratogenic activities. Beyond describing protocols to assemble and culture EBs, this unit details methods to exploit the EB system for teratological assessment. In addition, strategies to distinguish compounds with bona fide teratogenic activity versus simple toxicity are discussed. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512129 TI - Controlling the Effective Oxygen Tension Experienced by Cells Using a Dynamic Culture Technique for Hematopoietic Ex Vivo Expansion. AB - Clinical hematopoietic stem/progenitor cell (HSPC) transplantation outcomes are strongly correlated with the number of cells infused. Hence, to generate sufficient HSPCs for transplantation, the best culture parameters for expansion are critical. It is generally assumed that the defined oxygen (O2 ) set for the incubator reflects the pericellular O2 to which cells are being exposed. Studies have shown that low O2 tension maintains an undifferentiated state, but the expansion rate may be constrained because of limited diffusion in a static culture system. A combination of low ambient O2 and dynamic culture conditions has been developed to increase the reconstituting capacity of human HSPCs. In this unit, the protocols for serum-free expansion of HSPCs at 5% and 20% O2 in static and dynamic nutrient flow mode are described. Finally, the impact of O2 tension on HSPC expansion in vitro by flow cytometry and colony forming assays and in vivo through engraftment using a murine model is assessed. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512130 TI - Conditional Manipulation of Gene Function in Human Cells with Optimized Inducible shRNA. AB - The difficulties involved in conditionally perturbing complex gene expression networks represent major challenges toward defining the mechanisms controlling human development, physiology, and disease. We developed an OPTimized inducible KnockDown (OPTiKD) platform that addresses the limitations of previous approaches by allowing streamlined, tightly-controlled, and potent loss-of-function experiments for both single and multiple genes. The method relies on single-step genetic engineering of the AAVS1 genomic safe harbor with an optimized tetracycline-responsive cassette driving one or more inducible short hairpin RNAs (shRNAs). OPTiKD provides homogeneous, dose-responsive, and reversible gene knockdown. When implemented in human pluripotent stem cells (hPSCs), the approach can be then applied to a broad range of hPSC-derived mature cell lineages that include neurons, cardiomyocytes, and hepatocytes. Generation of OPTiKD hPSCs in commonly used culture conditions is simple (plasmid based), rapid (two weeks), and highly efficient (>95%). Overall, this method facilitates the functional annotation of the human genome in health and disease. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512131 TI - B cells in multiple sclerosis therapy-A comprehensive review. AB - For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS. PMID- 29512132 TI - A novel technique for endobronchial blocker placement for one-lung ventilation in children under 2 years. AB - BACKGROUND: The present study aimed to report our clinical experience with intraluminal calculated distance for endobronchial blocker placement (ICEB) and to find out whether ICEB could reduce the number of hypoxemia episodes during blocker placement compared with extraluminal blocker placement for one-lung ventilation in children under the age of 2 years. METHODS: The medical records of all children under the age of 2 years with a 5 French (F) or 4F WeiLi (WeiLi medical Inc, Guangzhou, China) endobronchial blocker for one-lung ventilation in thoracic surgery from July 2015 through July 2016 were retrospectively reviewed. After November 2015, one-lung ventilation was achieved using the ICEB technique, while before November 2015, extraluminal blocker placement was used. The success rate of blocker placement, quality of lung deflation, number of hypoxemia episodes, blocker dislodgement, and successful reposition after dislodgement were compared between the two groups. RESULT: The incidence of hypoxemia episodes during blocker placement was lower in the ICEB group compared to the extraluminal placement group. Moreover, the success rate of blocker reposition during the operation was higher in the ICEB group than the extraluminal placement group. The success rate of endobronchial blocker placement was similar between the two groups. CONCLUSIONS: Intraluminal calculated distance for endobronchial blocker placement is a feasible method to achieve lung isolation and could reduce hypoxemia episodes during blocker placement in children under the age of 2 years. PMID- 29512134 TI - Funding the Training of Future Health Services Researchers. PMID- 29512135 TI - Familiar Object Salience Affects Novel Word Learning. AB - Children use the presence of familiar objects with known names to identify the correct referents of novel words. In natural environments, objects vary widely in salience. The presence of familiar objects may sometimes hinder rather than help word learning. To test this hypothesis, 3-year-olds (N = 36) were shown novel objects paired with familiar objects that varied in their visual salience. When the novel objects were labeled, children were slower and less accurate at fixating them in the presence of highly salient familiar objects than in the presence of less salient familiar objects. They were also less successful in retaining these word-referent pairings. While familiar objects may facilitate novel word learning in ambiguous situations, the properties of familiar objects matter. PMID- 29512136 TI - Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression. AB - Mood disorders are a spectrum of neuropsychiatric disorders characterized by changes in the emotional state. In particular, major depressive disorder is expected to have a worldwide prevalence of 20% in 2020, representing a huge socio economic burden. Currently used antidepressant drugs have poor efficacy with only 30% of the patients in remission after the first line of treatment. Importantly, mood disorder patients present uncoupling of circadian rhythms. In this regard, melatonin (5-methoxy-N-acetyltryptamine), an indolamine synthesized by the pineal gland during the night, contributes to synchronization of body rhythms with the environmental light/dark cycle. In this review, we describe evidence supporting antidepressant-like actions of melatonin related to the circadian modulation of neuroplastic changes in the hippocampus. We also present evidence for the role of melatonin receptors and their signalling pathways underlying modulatory effects in neuroplasticity. Finally, we briefly discuss the detrimental consequences of circadian disruption on neuroplasticity and mood disorders, due to the modern human lifestyle. Together, data suggest that melatonin's stimulation of neurogenesis and neuronal differentiation is beneficial to patients with mood disorders. PMID- 29512137 TI - Discrete-choice experiment to analyse preferences for centralizing specialist cancer surgery services. AB - BACKGROUND: Centralizing specialist cancer surgery services aims to reduce variations in quality of care and improve patient outcomes, but increases travel demands on patients and families. This study aimed to evaluate preferences of patients, health professionals and members of the public for the characteristics associated with centralization. METHODS: A discrete-choice experiment was conducted, using paper and electronic surveys. Participants comprised: former and current patients (at any stage of treatment) with prostate, bladder, kidney or oesophagogastric cancer who previously participated in the National Cancer Patient Experience Survey; health professionals with experience of cancer care (11 types including surgeons, nurses and oncologists); and members of the public. Choice scenarios were based on the following attributes: travel time to hospital, risk of serious complications, risk of death, annual number of operations at the centre, access to a specialist multidisciplinary team (MDT) and specialist surgeon cover after surgery. RESULTS: Responses were obtained from 444 individuals (206 patients, 111 health professionals and 127 members of the public). The response rate was 52.8 per cent for the patient sample; it was unknown for the other groups as the survey was distributed via multiple overlapping methods. Preferences were particularly influenced by risk of complications, risk of death and access to a specialist MDT. Participants were willing to travel, on average, 75 min longer in order to reduce their risk of complications by 1 per cent, and over 5 h longer to reduce risk of death by 1 per cent. Findings were similar across groups. CONCLUSION: Respondents' preferences in this selected sample were consistent with centralization. PMID- 29512138 TI - Changes in filaggrin degradation products and corneocyte surface texture by season. AB - BACKGROUND: During the winter in northern countries, the risk of dermatitis is increased due to low temperature and humidity. Dermatitis is particularly common on weather-exposed skin such as the cheeks and hands. Recently, increased numbers of unidentified nanosized protrusions on the corneocyte surface were associated with dermatitis and deficiency of natural moisturizing factor (NMF). OBJECTIVES: To investigate the effect of season on NMF levels and corneocyte surface texture in cheek and hand skin of healthy adults. METHODS: Eighty healthy volunteers (40 male and 40 female) were recruited: 40 aged 18-40 years and 40 aged >= 70 years. Cheek and dorsal hand skin was tape stripped in the winter and summer. Analysis for NMF and corneocyte surface texture was done (Dermal Texture Index, DTI). Potential confounders were registered and adjusted for. RESULTS: In cheek skin, NMF levels were reduced and DTI elevated during the winter compared with the summer. Older participants had higher NMF levels than younger participants. In the summer, DTI level was dependent on self-reported ultraviolet exposure. In hand skin, NMF levels were higher during the winter than in the summer, and female participants had higher NMF levels than male participants. CONCLUSIONS: Seasonal effects on NMF and DTI on the cheeks and hands were found, suggesting an influence of climatic factors at the biochemical and ultrastructural levels. Significant variations were also observed regarding age and sex, making it difficult to draw firm conclusions. Our study adds new pieces to the puzzle of seasonal differences in xerosis and dermatitis. PMID- 29512139 TI - Should impaired mobility on presentation be a vital sign? AB - INTRODUCTION: Vital signs are routinely used to assess acutely ill patients, but they do not detect all patients at risk of death. This retrospective multicenter cohort study compares the prediction of death by impaired mobility with age, co morbidities, and vital sign changes. METHODS: On first assessment, patients from a combined cohort of 9684 Danish and Irish patients and a separate cohort of 1010 Ugandan patients were stratified by impaired mobility on presentation (IMOP), vital sign changes assessed by the National Early Warning Score (NEWS), the Charlson Co-morbidity Index, and age. RESULTS: Fourteen percent of Danish and Irish patients had IMOP compared with 42% of Ugandan patients. The odds ratios of IMOP for 7-day mortality were similar for both cohorts (i.e. 11.8, 95% CI 5.8 24.0 for Ugandan patients versus 6.7, 95% CI 5.0-9.0 for Danish and Irish patients). Univariate analysis of Ugandan patients showed that none of the parameters tested (i.e. low blood pressure, pulse, elevated respiratory rate, hypothermia, low oxygen saturation, old age, and coma) had a statistically higher odds ratio for either 7-day mortality than IMOP. Multivariate logistic regression analysis of Danish and Irish patients also showed that none of these parameters or the Charlson Co-morbidity Index had a statistically higher odds ratio than IMOP for either 7-day or 30-day mortality. CONCLUSION: Immobility on presentation is a vital sign and predicts mortality for acutely ill patients independently of the traditional vital signs, age, and co-morbidities. PMID- 29512140 TI - Autoimmune Pancreatitis Mouse Model. AB - Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. However, extensive clinico-pathological analyses have revealed that AIP is, in reality, a pancreatic manifestation of a newly described systemic disease known as IgG4-related disease (IgG4-RD). IgG4-RD is characterized by enhanced local and systemic IgG4 antibody (Ab) responses as well as inflammation involving multiple organs, including the pancreas, bile ducts, and salivary glands. Although mice lack the IgG4 Ab subtype, autoimmune-prone MRL/Mp mice treated with repeated injection with polyinosinic-polycytidylic acid (poly (I:C)) provide an experimental model of AIP. These mice exhibit massive destruction of pancreatic architecture associated with pancreatic immune cell infiltration and fibrosis. Moreover, this experimental AIP may be accompanied by involvement of multiple organs as well as elevation of serum levels of autoAbs, resembling humans with IgG4-RD. Thus, elucidation of the molecular mechanisms accounting for the development of experimental AIP can potentially provide new insights into the immuno-pathogenesis of human IgG4-related AIP. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512141 TI - Flow Cytometry: An Overview. AB - Flow cytometry is a technology that provides rapid multi-parametric analysis of single cells in solution. Flow cytometers utilize lasers as light sources to produce both scattered and fluorescent light signals that are read by detectors such as photodiodes or photomultiplier tubes. These light signals are converted into electronic signals that are analyzed by a computer and written to a standardized format (.fcs) data file. Cell populations can be analyzed and/or purified based on their fluorescent or light scattering characteristics. A variety of fluorescent reagents are utilized in flow cytometry. These include fluorescently conjugated antibodies, nucleic acid binding dyes, viability dyes, ion indicator dyes, and fluorescent expression proteins. Flow cytometry is a powerful tool that has applications in immunology, molecular biology, bacteriology, virology, cancer biology, and infectious disease monitoring. It has seen dramatic advances over the last 30 years, allowing unprecedented detail in studies of the immune system and other areas of cell biology. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512142 TI - Liposome Preparation for the Analysis of Lipid-Receptor Interaction and Efferocytosis. AB - Efficient phagocytosis of apoptotic cells (efferocytosis) is essential for immune homeostasis. Phospholipids exposed on the surface of apoptotic cells, such as phosphatidylserine, supply important "eat-me" signals. Liposomes are lipid bilayer vesicles that can be generated from one or several types of phospholipids of interest. Thus, these vesicles offer versatility, flexibility, and, importantly, a three-dimensional structure for studying the interaction between lipids and their receptors as well as the lipid-receptor interaction-mediated signaling events controlling efferocytosis by cells like professional phagocytes. Here, we describe methods to prepare liposomes, perform liposome-based lipid receptor binding assays, use liposomes to block efferocytosis, and utilize liposome-coated beads as apoptotic cell surrogates for phagocytosis. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512143 TI - Isolation of Conventional Murine Lung Dendritic Cell Subsets. AB - The lungs are continuously exposed to environmental threats, requiring an adequate and stringent immune response of a heterogeneous set of effector cells. Dendritic cells (DCs) form a dense network in the respiratory mucosa and act as the central regulators of the different components of this response, both sensing the nature of the threats and precisely coordinating the effector mechanisms best suited for overcoming it. The DCs are classically subdivided in two main groups, plasmacytoid DCs (pDCs) and conventional DCs (cDCs), the latter being further subdivided into cDC1s and cDC2s based on ontogeny and their distinct non redundant functions. This protocol provides different enrichment methods and represents an up-to-date, universal framework that uses a minimal set of highly specific lineage markers to discriminate and sort pure cDC subsets from the murine lung but also across tissues and species which is an added value in intra- and interspecies comparative research. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512144 TI - Thy1-YFP-H Mice and the Parallel Rod Floor Test to Evaluate Short- and Long-Term Progression of Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a leading cause of death and disability and is a risk factor for the later development of neuropsychiatric disorders and neurodegenerative diseases. Many models of TBI have been developed, but their further refinement and a more detailed long-term follow-up is needed. We have used the Thy1-YFP-H transgenic mouse line and the parallel rod floor test to produce an unbiased and robust method for the evaluation of the multiple effects of a validated model of controlled cortical injury. This approach reveals short- and long-term progressive changes, including compromised biphasic motor function up to 85 days post-lesion, which correlates with neuronal atrophy, dendrite and spine loss, and long-term axonal pathology evidenced by axon spheroids and fragmentation. Here we present methods for inducing a controlled cortical injury in the Thy1-YFP-H transgenic mouse line and for evaluating the resulting deficits in the parallel rod floor test. This technique constitutes a new, unbiased, and robust method for the evaluation of motor and behavioral alterations after TBI. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512145 TI - Induction and Measurement of Cytotoxic T Lymphocyte Activity. AB - Cytotoxic T cells (CTLs) are important immune effector cells in the adaptive immune response. It has been well documented that CTLs are important in host immune responses to viral and bacterial intracellular pathogens, tumors, and transplanted tissues. The properties of CTLs have been studied extensively in murine models, and their roles validated in the human setting. Frequently, the presence of these cells correlates well with protective immunity, so the ability to readily measure the activity of these cells is an important immunological measurement. In this unit, several assays are described that are commonly utilized to induce CTLs and to measure CTL activity both in vitro and in vivo. These assays are adaptable to many experimental and/or disease models, and in the case of the in vitro assays can be applied to measure CTL activity in human samples. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512146 TI - Intravital Imaging of Neuroimmune Interactions Through a Thinned Skull. AB - Innate and adaptive immune interactions within the central nervous system (CNS) and surrounding meninges contribute significantly to neural homeostasis as well as a variety of different neurological disorders. Two-photon laser scanning microscopy is a deep tissue imaging technique that provides a means to image immune cell dynamics and interactions in the living CNS with high spatial and temporal resolution. Optical access to the brain and meninges can be achieved through the creation of thinned skull windows, which can be made without inducing damage and inflammation in the underlying tissue. This protocol provides guidance on how to create a thinned skull window without causing CNS injury. We also describe a highly reproducible method to induce a mild traumatic brain injury using the thinned skull approach. (c) 2018 by John Wiley & Sons, Inc. PMID- 29512148 TI - Eicosanoids in platelets and the effect of their modulation by aspirin in the cardiovascular system (and beyond). AB - Platelets are important players in thrombosis and haemostasis with their function being modulated by mediators in the blood and the vascular wall. Among these, eicosanoids can both stimulate and inhibit platelet reactivity. Platelet Cyclooxygenase (COX)-1-generated Thromboxane (TX)A2 is the primary prostanoid that stimulates platelet aggregation; its action is counter-balanced by prostacyclin, a product of vascular COX. Prostaglandin (PG)D2 , PGE2 and 12 hydroxyeicosatraenoic acid (HETE), or 15-HETE, are other prostanoid modulators of platelet activity, but some also play a role in carcinogenesis. Aspirin permanently inhibits platelet COX-1, underlying its anti-thrombotic and anti cancer action. While the use of aspirin as an anti-cancer drug is increasingly encouraged, its continued use in addition to P2 Y12 receptor antagonists for the treatment of cardiovascular diseases is currently debated. Aspirin not only suppresses TXA2 but also prevents the synthesis of both known and unknown antiplatelet eicosanoid pathways, potentially lessening the efficacy of dual antiplatelet therapies. PMID- 29512147 TI - Influences on Care Preferences of Older People with Advanced Illness: A Systematic Review and Thematic Synthesis. AB - OBJECTIVES: To determine and explore the influences on care preferences of older people with advanced illness and integrate our results into a model to guide practice and research. DESIGN: Systematic review using Medline, Embase, PsychINFO, Web of Science, and OpenGrey databases from inception to February 2017 and reference and citation list searching. Included articles investigated influences on care preference using qualitative or quantitative methodology. Thematic synthesis of qualitative articles and narrative synthesis of quantitative articles were undertaken. SETTING: Hospital and community care settings. PARTICIPANTS: Older adults with advanced illness, including people with specific illnesses and markers of advanced disease, populations identified as in the last year of life, or individuals receiving palliative care (N = 15,164). MEASUREMENTS: The QualSys criteria were used to assess study quality. RESULTS: Of 12,142 search results, 57 articles were included. Family and care context, illness, and individual factors interact to influence care preferences. Support from and burden on family and loved ones were prominent influences on care preferences. Mechanisms by which preferences are influenced include the process of trading-off between competing priorities, making choices based on expected outcome, level of engagement, and individual ability to form and express preferences. CONCLUSION: Family is particularly important as an influence on care preferences, which are influenced by complex interaction of family, individual, and illness factors. To support preferences, clinicians should consider older people with illnesses and their families together as a unit of care. PMID- 29512149 TI - Diagnostic performance of body mass index to identify excess body fat in children with cerebral palsy. AB - AIM: To assess the diagnostic performance of body mass index (BMI) cut-off values according to recommendations of the World Health Organization (WHO), the World Obesity Federation (WOF), and the German Society for Adiposity (DAG) to identify excess body fat in children with cerebral palsy (CP). METHOD: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation programme. Excess body fat was defined as a body fat percentage above the 85th centile assessed by dual-energy X-ray absorptiometry. RESULTS: In total, 329 children (181 males, 148 females) with CP were eligible for analysis. The mean age was 12 years 4 months (standard deviation 2y 9mo). The BMI cut-off values for 'overweight' according to the WHO, WOF, and DAG showed the following sensitivities and specificities for the prediction of excess body fat in our population: WHO: sensitivity 0.768 (95% confidence interval [CI] 0.636-0.870), specificity 0.894 (95% CI 0.851-0.928); WOF: sensitivity 0.696 (95% CI 0.559 0.812), specificity 0.934 (95% CI 0.898-0.960); DAG: sensitivity 0.411 (95% CI 0.281-0.550), specificity 0.993 (95% CI 0.974-0.999). INTERPRETATION: Body mass index showed high specificity, but low sensitivity in children with CP. Thus, 'normal-weight obese' children with CP were overlooked, when assessing excess body fat only using BMI. WHAT THIS PAPER ADDS: Excess body fat in children with cerebral palsy (CP) is less common than previously reported. Body mass index (BMI) had high specificity but low sensitivity in detecting excess body fat in children with CP. BMI evaluation criteria of the German Society for Adiposity could be improved in children with CP. PMID- 29512150 TI - Neurobiological Basis of Migraine. PMID- 29512151 TI - Long-term pragmatic use of stiripentol for Dravet syndrome. PMID- 29512152 TI - Decision-makers are resilient in the face of social exclusion. AB - A growing body of evidence suggests that social exclusion impairs people's capacity for active deliberation and logical reasoning. Building on this finding and on the postulate from the dual-process theory that analytical thinking is essential in order to make good judgements and decisions, we hypothesized that social exclusion will alter judgement and choice behaviour. We tested this hypothesis in three experiments in which social exclusion was manipulated using the Cyberball paradigm, an online ball-tossing game in which participants either received the ball a fair number of times or were excluded by the other two players. We focused on a range of tasks designed to be sensitive to participants' ability to engage in analytical thinking and careful deliberation, including the cognitive reflection test (Experiment 1) and a set of anchoring, intertemporal preference, disjunction, and confidence tasks (experiments 2 and 3). Our results unanimously failed to support the hypothesis that social exclusion influences people's judgements and decision-making. We discuss the implications of our findings for social exclusion theory. PMID- 29512153 TI - Further evaluation of differential exposure to establishing operations during functional communication training. AB - Recent research findings (DeRosa, Fisher, & Steege, ) suggest that minimizing exposure to the establishing operation (EO) for destructive behavior when differential reinforcement interventions like functional communication training (FCT) are introduced may produce more immediate reductions in destructive behavior and prevent or mitigate extinction bursts. We directly tested this hypothesis by introducing FCT with extinction in two conditions, one with limited exposure to the EO (limited EO) and one with more extended exposure to the EO (extended EO) using a combined reversal and multielement design. Results showed that the limited-EO condition rapidly reduced destructive behavior to low levels during every application, whereas the extended-EO condition produced an extinction burst in five of six applications. We discuss these findings in relation to the effects of EO exposure on the beneficial and untoward effects of differential reinforcement interventions. PMID- 29512154 TI - Understanding Trends in Medicare Spending, 2007-2014. AB - OBJECTIVES: To analyze the sources of per-beneficiary Medicare spending growth between 2007 and 2014, including the role of demographic characteristics, attributes of Medicare coverage, and chronic conditions. DATA SOURCES: Individual level Medicare spending and enrollment data. STUDY DESIGN: Using an Oaxaca Blinder decomposition model, we analyzed whether changes in price-standardized, per-beneficiary Medicare Part A and B spending reflected changes in the composition of the Medicare population or changes in relative spending levels per person. DATA EXTRACTION METHODS: We identified a 5 percent sample of fee-for service Medicare beneficiaries age 65 and above from years 2007 to 2014. RESULTS: Mean payment-adjusted Medicare per-beneficiary spending decreased by $180 between the 2007-2010 and 2011-2014 time periods. This decline was almost entirely attributable to lower spending levels for beneficiaries. Notably, declines in marginal spending levels for beneficiaries with chronic conditions were associated with a $175 reduction in per-beneficiary spending. The decline was partially offset by the increasing prevalence of certain chronic diseases. Still, we are unable to attribute a large share of the decline in spending levels to observable beneficiary characteristics or chronic conditions. CONCLUSIONS: Declines in spending levels for Medicare beneficiaries with chronic conditions suggest that changing patterns of care use may be moderating spending growth. PMID- 29512155 TI - Teaching children with autism to explain how: A case for problem solving? AB - Few studies have applied Skinner's (1953) conceptualization of problem solving to teach socially significant behaviors to individuals with developmental disabilities. The current study used a multiple probe design across behavior (sets) to evaluate the effects of problem-solving strategy training (PSST) on the target behavior of explaining how to complete familiar activities. During baseline, none of the three participants with autism spectrum disorder (ASD) could respond to the problems presented to them (i.e., explain how to do the activities). Tact training of the actions in each activity alone was ineffective; however, all participants demonstrated independent explaining-how following PSST. Further, following PSST with Set 1, tact training alone was sufficient for at least one scenario in sets 2 and 3 for all 3 participants. Results have implications for generative responding for individuals with ASD and further the discussion regarding the role of problem solving in complex verbal behavior. PMID- 29512157 TI - The songs of silence: cortical suppression and synchronization by layer-specific activation. PMID- 29512156 TI - NMDA receptor-gated visual responses in hippocampal CA1 neurons. AB - KEY POINTS: Sensory information processing in hippocampal circuits is critical for numerous hippocampus-dependent functions, but the underlying synaptic mechanism remains elusive. We performed whole-cell recording in vivo to examine visually evoked synaptic activity in hippocampal CA1 pyramidal cells (PCs). We first found that at resting potentials, ~30% of CA1 PCs showed synaptic responses to a flash of visual stimulation. Interestingly, at depolarizing potentials, nearly all CA1 PCs were found to exhibit NMDA receptor-dependent responses, indicating the presence of NMDA receptor-mediated gating of CA1 responses. The NMDA receptor-gated CA1 responses may play important roles in the hippocampal function that depends on sensory information processing. ABSTRACT: Hippocampal processing of environmental information is critical for hippocampus-dependent brain functions that result from experience-induced hippocampal plasticity, such as memory acquisition and storage. Hippocampal responses to sensory stimulation have been extensively investigated, particularly with respect to spike activity. However, the synaptic mechanism for hippocampal processing of sensory stimulation has been much less understood. Here, we performed in vivo whole-cell recording on hippocampal CA1 pyramidal cells (PCs) from adult rodents to examine CA1 responses to a flash of visual stimulation. We first found in recordings obtained at resting potentials that ~30% of CA1 PCs exhibited significant excitatory/inhibitory membrane-potential (MP) or membrane-current (MC) responses to the flash stimulus. Remarkably, in the other (~70%) CA1 PCs, although no responses could be detected at resting potentials, clear excitatory MP or MC responses to the same flash stimulus were observed at depolarizing potentials, and these responses were further found to depend on NMDA receptors. Our findings demonstrate the presence of NMDA receptor-mediated gating of visual responses in hippocampal CA1 neurons, a synaptic mechanism for hippocampal processing of sensory information that may play important roles in hippocampus-dependent functions such as learning and memory. PMID- 29512158 TI - Ready, set, go: the bridging of attention to action by acetylcholine in prefrontal cortex. PMID- 29512159 TI - Anti-inflammatory effect of diterpenes-enriched fractions from Pterodon polygalaeflorus through inhibition of macrophage migration and cytokine production. AB - OBJECTIVES: To evaluate the anti-inflammatory potential of Pterodon polygalaeflorus hexane extract (HE) and its fractions on macrophage migration in vitro and in vivo. METHODS: Hexane extract from P. polygalaeflorus fruits was fractionated and yielded four fractions. RAW 264.7 cells were treated with samples to evaluate cell viability (MTT assay), cell migration (wound healing and transwell assays), CD14 expression (flow cytometry), iNOS and cytokine mRNA expression (RT-qPCR), NO (Griess reaction) and cytokine (ELISA) production. In vivo migration was evaluated on the thioglycollate-induced peritonitis model. Qualitative analysis was performed by GC-MS. KEY FINDINGS: All fractions inhibited the NO production by LPS-stimulated RAW 264.7 cells. Fr3 and Fr4 presented the lowest IC50 values. The expressions of iNOS and IL-1beta, TNF-alpha and IL-10 cytokines were inhibited by Fr3 and Fr4, whereas the CD14 expression was only inhibited by Fr3. All the samples inhibited RAW 264.7 migration in the wound healing and transwell assays. Fr3 and Fr4 reduced the migration of Mac-1+ Gr-1- cells to the peritoneum and presented in their compositions: 6alpha-hydroxy 7beta-acetoxyvouacapan-17beta-oate, methyl 6alpha,7beta-dihydroxyvouacapan-17beta oate, methyl 6alpha-acetoxy-7beta-hydroxyvouacapan-17beta-oate, geranylgeraniol and 14,15-epoxy-geranylgeraniol. CONCLUSIONS: The anti-inflammatory effects of Fr3 and Fr4 involve inhibition of cell migration, iNOS expression and NO production, cytokine expression (mRNA and proteins) and CD14 expression (Fr3). PMID- 29512160 TI - Mannose receptor (MR) and Toll-like receptor 2 (TLR2) influence phagosome maturation during Leishmania infection. AB - Leishmania enter macrophages through receptor-mediated phagocytosis and survive the harsh environment of a phagolysosome. Here, we investigated the interaction between mannose receptor (MR), Toll-like receptor 2 (TLR2), and Leishmania, and the subsequent impact on phagosome maturation. Leishmania parasites are able to delay phagosome maturation, not reaching full maturation until 5 hours post engulfment. Here, maturation of Leishmania major- and Leishmania donovani containing phagosomes proceeded as expected in the WT macrophages becoming LAMP1 positive by 6 hours. Interestingly, MR-/- macrophages become LAMP1 positive by ~2 hours and ~4 hours post-infection Leishmania-containing phagosomes lost LAMP1 expression and gained the early marker EEA1. LAMP1 expression was again observed by 6 hours. Leishmania LPG was essential for the delay in both WT and MR-/- macrophages but was not essential for the early maturation (2 hours) observed in MR-/- macrophages. Serum opsonization of Leishmania prior to infection induced identical phagosome maturation patterns in WT and MR-/- macrophages. In the absence of MyD88 or TLR2 on macrophages, Leishmania phagosomes matured significantly faster, becoming LAMP1 positive by ~1-2 hours. These studies add to the knowledge that phagosome maturation is influenced by multiple receptor-ligand interactions and signalling pathways. PMID- 29512161 TI - Extending shelf life of dithiothreitol-treated panel RBCs to 28 days. AB - BACKGROUND: Daratumumab (DARA) causes non-specific results in indirect agglutination testing (IAT). Dithiothreitol (DTT) treatment of panel red blood cells (RBCs) abolishes DARA interference. The objective of our study was to extend stability of DTT-treated panel RBCs to 28 days through application of a commercially available panel RBC stabilizer. MATERIALS AND METHODS: Serological antigen typing and IAT using DARA sera and DARA plasma spiked with weakly reacting alloantibodies was performed up to 28 days after DTT treatment and stabilization. RESULTS: DTT treatment resulted in loss of Fy-antigen expression on some panel RBCs. Antigen profiles of stabilized, DTT-treated panel RBCs remained stable. Alloantibodies in DARA sera and DARA plasma were reliably detected. CONCLUSIONS: Application of a commercially available RBC stabilizer extends shelf life of DTT-treated panel RBCs to 28 days. PMID- 29512162 TI - Nitrogen deposition increases root production and turnover but slows root decomposition in Pinus elliottii plantations. AB - Fine roots of woody plants comprise multiple root orders, which can be functionally partitioned into two pools: absorptive fine roots (AFRs, orders 1, 2) and transport fine roots (TFRs, orders 3-5). However, the function-based fine root dynamics and especially their responses to increased nitrogen (N) availability remain unclear. We explored dynamic responses of both AFRs and TFRs of Pinus elliottii to N addition in subtropical China based on a 4-yr minirhizotron experiment and a two-stage - early (0.5 yr) vs late (4 yr) - decomposition experiment. N addition increased the production, mortality, and turnover of AFRs but not TFRs. High rates of N persistently inhibited AFR decomposition but affected TFR decomposition differentially at the early (no effect) and late (negative effect) stages. The increased production of AFRs was driven by N-induced decrease in foliar and soil phosphorus (P) concentrations. The decreased decomposition of AFRs might be due to the increased acid unhydrolyzable residues in decomposing roots. AFRs are the resource-acquiring module, the increased carbon allocation to AFRs may represent a P-acquiring strategy when N no longer limits growth of P. elliottii. Our results suggest that AFRs and TFRs respond differently to N deposition, both in terms of production, mortality, and turnover and in terms of decomposition. PMID- 29512164 TI - Maternal red blood cell alloimmunization requiring intrauterine transfusion: a comparative study on management and outcome depending on the type of antibody. AB - BACKGROUND: The antibody primarily responsible for fetal anemia may influence treatment and prognosis. The primary objective was to compare ante- and postnatal management and the outcomes of maternal red blood cell (RBC) alloimmunizations according to the antibody involved. The secondary objective was to compare anti-D alloimmunizations according to associated number of antibodies. STUDY DESIGN AND METHODS: A single-center study from 1999 to 2015 including maternal RBC alloimmunizations requiring intrauterine transfusion (IUT) was conducted. Patients were classified according to the antibody involved: anti-D, other Rh (anti-c and anti-E), and anti-K1. Obstetric data, IUT characteristics, and neonatal outcome were compared. A specific study on the anti-D, when isolated or associated, was then conducted. RESULTS: There were 106 pregnancies included, with 77.4% having anti-D, 9.4% having another anti-Rh (Rh group), and 13.2% having anti-K1. No significant difference between the anti-D and Rh groups was found for management and prognosis. The hemoglobin level in the first IUT was higher in the anti-D group than in the Kell group (6.8 vs. 4.7 g/dL, p = 0.008). Newborns in the anti-D group had significantly higher bilirubin levels and phototherapy duration than those in the Kell group. The mean estimated daily decrease in hemoglobin and that between the first two IUTs were lower with an isolated anti-D, compared with anti-D associated with two antibodies (p = 0.04). CONCLUSION: Anti-K1 alloimmunizations seem to cause more severe fetal anemia than anti-D alloimmunizations. Moreover, a decrease in hemoglobin appears to be more rapid when anti-D is associated with other antibodies. PMID- 29512163 TI - Toward a better noninvasive assessment of preejection period: A novel automatic algorithm for B-point detection and correction on thoracic impedance cardiogram. AB - Impedance cardiography is the most common clinically validated, noninvasive method for determining the timing of the opening of the aortic valve, an important event used for measuring preejection period, which reflects sympathetic beta-adrenergic influences on the heart. Automatic detection of the exact time of the opening of the aortic valve (B point on the impedance cardiogram) has proven to be challenging as its appearance varies between and within individuals and may manifest as a reversal, inflection, or rapid slope change of the thoracic impedance derivative's (dZ/dt) rapid rise. Here, a novel automatic algorithm is proposed for the detection of the B point by finding the main rapid rise of the dZ/dt signal, which is due to blood ejection. Several conditions based on zero crossings, minima, and maxima of the dZ/dt signal and its derivatives are considered to reject any unwanted noise and artifacts and select the true B-point location. The detected B-point locations are then corrected by modeling the B point time data using forward and reverse autoregressive models. The proposed algorithm is validated against expert-detected B points and is compared with different conventional methods; it significantly outperforms them by at least 54% in mean error, 30% in mean absolute error, and 27% in standard deviation of error. This algorithm can be adopted in ambulatory studies requiring beat-to-beat evaluation of cardiac hemodynamic parameters over extended time periods where expert scoring is not feasible. PMID- 29512165 TI - Rhizosphere priming effects on soil carbon and nitrogen dynamics among tree species with and without intraspecific competition. AB - Rhizosphere priming effects (RPEs) play a central role in modifying soil organic matter mineralization. However, effects of tree species and intraspecific competition on RPEs are poorly understood. We investigated RPEs of three tree species (larch, ash and Chinese fir) and the impact of intraspecific competition of these species on the RPE by growing them at two planting densities for 140 d. We determined the RPE on soil organic carbon (C) decomposition, gross and net nitrogen (N) mineralization and net plant N acquisition. Differences in the RPE among species were associated with differences in plant biomass. Gross N mineralization and net plant N acquisition increased, but net N mineralization decreased, as the RPE on soil organic C decomposition increased. Intraspecific competition reduced the RPE on soil organic C decomposition, gross and net N mineralization, and net plant N acquisition, especially for ash and Chinese fir. Microbial N mining may explain the overall positive RPEs across species, whereas intensified plant-microbe competition for N may have reduced the RPE with intraspecific competition. Overall, the species-specific effects of tree species play an important role in modulating the magnitude and mechanisms of RPEs and the intraspecific competition on soil C and N dynamics. PMID- 29512166 TI - Occupational exposure to asphalt fume can cause oxidative DNA damage among road paving workers. AB - OBJECTIVES: We designed the present study to determine the effect of occupational exposure to asphalt fumes on oxidative status and DNA damage in road paving workers. METHODS: Sixty road paving workers exposed to asphalt fumes and forty non-exposed control subjects were recruited. Occupational exposure to PAHs was assessed by urinary 1-hydroxypyrene (1-OHP) excretion. Serum thiol disulfide homeostasis (TDH), total oxidant status (TOS) and total antioxidant status (TAS) and urinary 8-hydro-deoxyguanosine (8-OH-dG) level were evaluated by automated colourimetric method. RESULTS: The urinary concentrations of 1-OHP and 8-OH-dG were significantly higher in the exposed group than in the control group (P < 0.001). Disulfide/thiol ratio, TOS, and TAS were also significantly higher for the asphalt workers. A positive correlation existed between urinary 1-OHP and 8 OH-dG, TOS and TAS. CONCLUSION: Study results indicate that exposure to PAHs induces oxidative stress and causes genotoxic effects in asphalt workers. PMID- 29512167 TI - Ovine Leukocyte Microparticles Generated by the CentriMag Ventricular Assist Device In Vitro. AB - Ventricular assist devices (VADs) are a life-saving form of mechanical circulatory support in heart failure patients. However, VADs have not yet reached their full potential due to the associated side effects (thrombosis, bleeding, infection) related to the activation and damage of blood cells and proteins caused by mechanical stress and foreign materials. Studies of the effects of VADs on leukocytes are limited, yet leukocyte activation and damage including microparticle generation can influence both thrombosis and infection rates. Therefore, the aim was to develop a multicolor flow cytometry assessment of leukocyte microparticles (LMPs) using ovine blood and the CentriMag VAD as a model for shear stress. Ovine blood was pumped for 6 h in the CentriMag and regular samples analyzed for hemolysis, complete blood counts and LMP by flow cytometry during three different pump operating conditions (low flow, standard, high speed). The high speed condition caused significant increases in plasma-free hemoglobin; decreases in total leukocytes, granulocytes, monocytes, and platelets; increases in CD45+ LMPs as well as two novel LMP populations: CD11bbright /HLA-DR- and CD11bdull /HLA-DR+ , both of which were CD14- /CD21- . CD11bbright /HLA-DR- LMPs appeared to respond to an increase in shear magnitude whereas the CD11bdull /HLA-DR+ LMPs significantly increased in all pumping conditions. We propose that these two populations are released from granulocytes and T cells, respectively, but further research is needed to better characterize these two populations. PMID- 29512168 TI - Role of cell stress signaling networks in cancer cell death and antitumor immune response following proteotoxic injury inflicted by photodynamic therapy. AB - The insult delivered by photodynamic therapy (PDT) in treated cells is oxidative stress. The main burden threatening survival of PDT-treated cells is proteotoxic damage that jeopardizes proteostasis in these cells. For dealing with this type of proteostasis impairment, cells have developed protection mechanisms operating by signaling networks. This review will outline various components of signaling networks that can be engaged in stressed cells with highlighting the emerging aspects relevant to response to PDT. It will be also shown how the well known inflammatory/immune response associated with PDT is also based on the activity of these stress signaling networks. Lasers Surg. Med. 50:491-498, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29512169 TI - Improvement in sperm functional competence through modified low-dose packaging in French mini straws of bull semen. AB - To achieve the targeted artificial insemination coverage with the current rate of semen production, without affecting the conception rate, it needs to reduce the number of spermatozoa per insemination dose in India as per international practice. Therefore, this study was planned to perform different levels of semen dilution, compare in vitro post-thaw semen quality and develop a modified low dose semen packaging method in French mini straw to minimise semen dilution effect. Sixteen ejaculates were collected from Karan Fries bulls (n = 4). The mean percentage post-thaw motility, viability, membrane integrity, acrosome integrity, lipid peroxidation and capacitation status were estimated as post-thaw sperm function assays in semen sample diluted to 20, 15, 10 and 5 million spermatozoa per 0.25 ml and filled in the French mini straw by conventional packaging. No significant (p > .05) difference in post-thaw sperm quality was observed between 15 and 20 million doses; however, below 15 million sperm quality get reduced. There was no significant difference in post-thaw semen quality traits between 20 million conventional packaging and 5 million spermatozoa/dose in modified packaging. In conclusions, the modified packaging is a very effective method for low-dose cryopreservation with acceptable post-thaw semen quality. PMID- 29512170 TI - Importance of baseline heart rate as a predictor of cardiac functional recovery in newly diagnosed heart failure with reduced ejection fraction. AB - BACKGROUND: Left ventricular ejection fraction (LVEF) has shown to predict outcomes in patients with heart failure (HF). Left ventricular recovery (LVR) has shown to improve prognosis. HYPOTHESIS: Guideline-directed medical therapy will predict LVR in patients with HF and reduced LVEF. METHODS: We studied 244 patients with newly diagnosed HF and an LVEF <=35%. LVR was defined as an increase in LVEF >=40%. Patients who experienced LVR were compared with those who had persistent left ventricular dysfunction. RESULTS: Population characteristics included ischemic etiology, 38.1%; baseline LVEF, 23% +/-6%; and mean baseline heart rate (HR), 75 +/-13 bpm. Guideline-directed medical therapy was achieved as follows: angiotensin-converting enzyme inhibitors, 74.3%; beta-blockers (BB), 95.4%; target dosing of angiotensin-converting enzyme inhibitors, 33.7%; target dosing of BB, 40.2%. LVR occurred in 154/244 patients (63.1%). By multivariable analysis, baseline HR <=70 bpm was the only independent predictor of LVR (odds ratio: 3.39, 95% confidence interval: 1.5-7.5, P = 0.003). Target dosing of BB therapy was predictive of LVR only in the univariate analysis (odds ratio: 1.9, 95% confidence interval: 1.1-3.4, P = 0.03). Furthermore, the composite endpoint of HF hospitalization or mortality occurred less frequently in those who did vs those who did not achieve target BB doses (5.4% vs 16.7%, respectively; P = 0.023). CONCLUSIONS: The novel findings of our analysis reveal that the only predictor of LVR in this study was a low baseline HR. Early modulation of HR in newly diagnosed HF patients may increase the rates of LVR. PMID- 29512171 TI - Exogenous recombinant human thioredoxin-1 prevents acetaminophen-induced liver injury by scavenging oxidative stressors, restoring the thioredoxin-1 system and inhibiting receptor interacting protein-3 overexpression. AB - Thioredoxin-1 (Trx-1) is a potent therapeutic agent against a variety of diseases because of its actions as an antioxidant and regulator of apoptosis. N-acetyl-p aminophenol (APAP), commonly known as acetaminophen, generates excessive oxidative stress and triggers hepatocyte cell death, exemplified by regulated necrosis. In the present study, we investigated whether APAP-induced liver injury in a mouse model is associated with "necroptosis," and if pretreatment with recombinant Trx-1 prevents the hepatic injury caused by APAP overdose. We also explored the mechanism underlying the preventive action of Trx-1 against APAP induced hepatic injury. In a prevention study, C3H/he mice received different doses (0, 10, 50 or 100 mg kg-1 body weight) of recombinant human Trx-1 intraperitoneally, followed by a single oral dose of 300 mg kg-1 of APAP. In this experimental paradigm, liver injury and lethality were markedly decreased in rhTrx-1-pretreated mice. In survival experiments, mice received rhTrx-1 followed by oral administration of a lethal dose of APAP. APAP overdose caused a series of liver toxicity-associated events, beginning with overexpression of c-fos, excessive production of reactive oxygen species and reactive nitrogen species (RNS) and leading to decreased endogenous Trx-1 expression and activation of JNK signaling pathways. Pretreatment with rhTrx-1 inhibited all of these toxicological manifestations of APAP. In addition, rhTrx-1 significantly reduced the expression of RIP-3, a critical necrosome component. Taken together, our findings indicate that rhTrx-1 prevents APAP-induced liver injury through multiple action mechanisms, including scavenging reactive oxygen species and reactive nitrogen species, restoring endogenous Trx-1 levels and inhibiting RIP-3 overexpression. PMID- 29512172 TI - Semen parameters are unaffected by statin use in men evaluated for infertility. AB - The effects of statin use on conventional semen parameters in humans are largely unknown and have not been previously studied in subfertile men. We retrospectively reviewed data from 10,140 patients seen at our fertility clinic between 2002 and 2013 to assess the effects of statin use on semen parameters. Men who used any statins for >3 months before semen sample collection were included as cases. Data were gathered on patient age, medication use and conventional semen parameters. A total of 118 patients (126 samples) used statins for at least 3 months before semen sample collection. Data from 7698 patients (8,760 samples), who were not using any medications, were used as controls. In age-adjusted regression models, statin use was not associated with statistically significant changes in semen parameters. When used in combination with other nonspermatotoxic medications, it was associated with 0.3 ml decrease in semen volume (95% confidence interval: 0.02 to 0.58 ml, p-value = .04). In conclusion, statin use was not adversely associated with semen parameters other than semen volume in subfertile patients. These findings from our large-scale retrospective study suggest that there are no clinically relevant deleterious effects from statin use on conventional semen parameters. PMID- 29512173 TI - Practical management of ibrutinib in the real life: Focus on atrial fibrillation and bleeding. AB - The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB-related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life-saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma. PMID- 29512174 TI - Carbohydrate-based vaccines for oncotherapy. AB - Cancer is still one of the most serious threats to human worldwide. Aberrant patterns of glycosylation on the surface of cancer cells, which are correlated with various cancer development stages, can differentiate the abnormal tissues from the healthy ones. Therefore, tumor-associated carbohydrate antigens (TACAs) represent the desired targets for cancer immunotherapy. However, these carbohydrate antigens may not able to evoke powerful immune response to combat with cancer for their poor immunogenicity and immunotolerance. Different approaches have been developed to address these problems. In this review, we want to summarize the latest advances in TACAs based anticancer vaccines. PMID- 29512175 TI - Microbial Diversity in the Eukaryotic SAR Clade: Illuminating the Darkness Between Morphology and Molecular Data. AB - Despite their diversity and ecological importance, many areas of the SAR Stramenopila, Alveolata, and Rhizaria-clade are poorly understood as the majority (90%) of SAR species lack molecular data and only 5% of species are from well sampled families. Here, we review and summarize the state of knowledge about the three major clades of SAR, describing the diversity within each clade and identifying synapomorphies when possible. We also assess the "dark area" of SAR: the morphologically described species that are missing molecular data. The majority of molecular data for SAR lineages are characterized from marine samples and vertebrate hosts, highlighting the need for additional research effort in areas such as freshwater and terrestrial habitats and "non-vertebrate" hosts. We also describe the paucity of data on the biogeography of SAR species, and point to opportunities to illuminate diversity in this major eukaryotic clade. See also the video abstract here: https://youtu.be/_VUXqaX19Rw. PMID- 29512176 TI - Three case reports of involuntary muscular movements as adverse reactions to sacubitril/valsartan. PMID- 29512179 TI - Angiosarcoma arising in a traumatic scar. PMID- 29512177 TI - Patterns and profiles of methylphenidate use both in children and adults. AB - AIM: The aim of the present study was to characterize patterns of use of methylphenidate (MPH), a prescription stimulant medication recommended in the treatment of attention deficit hyperactivity disorder (ADHD) and of narcolepsy, in France, both in children and adults, over a 3-year period. METHODS: Using the French General Health Insurance database, limited to two areas covering approximately 4 million individuals, we made up a cohort of incident MPH users between July 2010 and June 2013. Splitting them into distinct age groups (18-24, 25-49 and >=50 years of age for adults and <6, 6-11 and 12-17 years of age for children), we established the characteristics of these populations at MPH initiation and during follow-up according to the duration of treatment, quantities dispensed and coprescription with central nervous system (CNS) drugs. RESULTS: We included a cohort of 3534 incident users, involving 30 238 dispensings of MPH, leading to an annual rate of 29 incident users per 100 000 in 2013. Children (66% of new users) were characterized by long-term use of MPH with few comedications. The group of 25-49-year-old patients were dispensed MPH more frequently than other groups, had the highest mean dose and were more often coprescribed other CNS drugs. The >=50 year-old group was more often coprescribed antidepressants and antiparkinsonian drugs. CONCLUSIONS: Our pharmacoepidemiological study involving incident MPH users with a large number of characteristics showed different patterns of MPH use among children and adults. The results from the 25-49-year-old group suggested that MPH might be being used for medical conditions other than ADHD or narcolepsy in adults, and that it might be subject to misuse and/or abuse. PMID- 29512178 TI - Klinefelter syndrome and fertility-Impact of X-chromosomal inheritance on spermatogenesis. AB - With the use of testicular sperm extraction (TESE), spermatozoa can be retrieved in about 30%-50% of men with Klinefelter syndrome (KS). The reason for the absence or presence of spermatozoa in half of the men with KS remains unknown. Therefore, the search for an objective marker for a positive prediction in finding spermatozoa is of significant clinical value to avoid unnecessary testicular biopsies in males with (mostly) low testicular volume and impaired testosterone. The objective of this study was to determine whether paternal or maternal inheritance of the additional X-chromosome can predict the absence or presence of spermatogenesis in men with KS. Men with KS who have had a testicular biopsy for diagnostic fertility workup TESE were eligible for inclusion. Buccal swabs from nine KS patients and parents (trios) were taken to compare X chromosomal inheritance to determine the parental origin of both X-chromosomes in the males with KS. Spermatozoa were found in TESE biopsies 8 of 35 (23%) patients after performing a unilateral or bilateral TESE. Different levels of spermatogenesis (from the only presence of spermatogonia, up to maturation arrest or hypospermatogenesis) appeared to be present in 19 of 35 (54%) men, meaning that the presence of spermatogenesis not always yields mature spermatozoa. From the nine KS-trios that were genetically analysed for X-chromosomal inheritance origin, no evidence of a correlation between the maternal or paternal origin of the additional X-chromosome and the presence of spermatogenesis was found. In conclusion, the maternal or paternal origin of the additional X-chromosome in men with KS does not predict the presence or absence of spermatogenesis. PMID- 29512180 TI - Lichen planus hypertrophicus-inversus occurring in a patient with Bannayan-Riley Ruvalcaba syndrome. PMID- 29512181 TI - Effectiveness of and factors associated with clinical response to methotrexate under daily life conditions in Asian patients with psoriasis: A retrospective cohort study. AB - Given the relative scarcity of data concerning the efficacy of methotrexate under daily life conditions in psoriasis, this study aimed to investigate the effectiveness of methotrexate in Asian psoriatic patients and to identify factors associated with clinical response. This observational retrospective cohort study included adult psoriatic patients who had been treated with or were going to start methotrexate. Psoriasis Area and Severity Index (PASI) scores at baseline and at 3, 6 and 12 months were recorded. At 3 months, patients achieving 50% or more reduction from baseline PASI score were defined as responders. One hundred, 74 and 61 patients were followed for 3, 6 and 12 months, respectively. Mean follow-up time was 15.3 +/- 10.2 months. A reduction in PASI score of at least 75% was achieved in 26%, 32.5% and 45.2% at 3, 6 and 12 months, respectively. At 12 and 24 months, Kaplan-Meier analysis showed 68.7% and 52.1% probability of drug survival, respectively. Male sex, body mass index (BMI) of less than 25 kg/m2 and absence of abdominal obesity were factors associated with response to treatment in univariate analysis. Male sex was the only significant factor in multivariate analysis. The effectiveness of methotrexate in clinical practise seemed to be lower than in clinical trials, but effectiveness increased with longer duration of treatment. Problems associated with methotrexate use in clinical practise may be due to medication adherence rather than lack of medication effectiveness. Female sex, abdominal obesity and BMI of 25 kg/m2 or more might decrease response to methotrexate. PMID- 29512183 TI - Persistent pruritus in psoriatic patients during administration of biologics. PMID- 29512182 TI - Atypical chronic myeloid leukaemia: A case of an orphan disease-A multicenter report by the Polish Adult Leukemia Group. AB - Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 * 109 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 * 109 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses. PMID- 29512184 TI - Case of pityriasis rubra pilaris with focal acantholytic dyskeratosis. PMID- 29512185 TI - Tufted angioma of the finger: A case of an uncommon location with unique dermoscopic features. PMID- 29512186 TI - Color-transition sign: A useful trichoscopic finding for differentiating alopecia areata incognita from telogen effluvium. PMID- 29512187 TI - Bariatric surgery is associated with increased risk of new-onset inflammatory bowel disease: case series and national database study. AB - BACKGROUND: Case series suggest a possible association between bariatric surgery and incident IBD. AIM: The aim of this study was to evaluate the association between bariatric surgery and new-onset IBD. METHODS: We first conducted a multi institutional case series of patients with a history of IBD and bariatric surgery. We next conducted a matched case-control study using medical and pharmacy claims from 2008 to 2012 in a US national database from Source Healthcare Analytics LLC. Bariatric surgery was defined by ICD-9 or CPT code. Bariatric surgery was evaluated as recent (code in database timeframe), past (past history V code) or no history. Conditional logistic regression was used to estimate odds ratios (OR) and 95% CI for new-onset IBD, CD and UC. RESULTS: A total of 15 cases of IBD (10 CD, 4 UC, 1 IBD, type unclassified) with a prior history of bariatric surgery were identified. Most cases were women, had Roux-en Y surgery years prior to diagnosis and few IBD-related complications. A total of 8980 cases and 43 059 controls were included in our database analysis. Adjusting for confounders, a past history of bariatric surgery was associated with an increased risk of new-onset IBD (OR 1.93, 95% CI 1.34-2.79). However, patients who had recent bariatric surgery did not appear to be at shorter term risk of IBD (OR 0.94, 95% CI 0.58-1.52). CONCLUSION: New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies. PMID- 29512188 TI - Current husbandry situation of red pandas in Japan. AB - The red panda (Ailurus fulgens) is an endangered semi-arboreal folivore with a specialized diet of bamboo leaves. Zoos worldwide maintain red pandas under a variety of housing environments and husbandry procedures that may affect the reproductive success and longevity of captive red pandas. The aims of the present study were to investigate how red pandas are kept in Japan and to obtain useful insights to increase their longevity by comparing the results from a questionnaire sent to Japanese zoos and those from a previous survey conducted in other countries. We received responses from 42 out of 52 zoos, holding a total of 219 individual red pandas, in Japan. The age-sex distribution indicated that red panda populations in Japan need close attention to be maintained sustainably. Of the husbandry aspects surveyed, the number of individuals in the same zoo, enclosure size, and the frequency of bamboo feeding factors indicated to affect reproductive success. Frequent monitoring of body weight, implementation of husbandry training, and bamboo feeding were also suggested as the reasons for the longevity of red pandas in Japan. Zoos were provided with sufficient physical features in on-exhibit enclosures, close monitoring for health status, and proper feeding, but other aspects of husbandry such as enclosure size and structures in off-exhibit spaces were insufficient and might compromise animal welfare. PMID- 29512189 TI - Validation of 3D skin imaging for objective repeatable quantification of severity of atrophic acne scarring. AB - BACKGROUND: One major sequelae of acne is atrophic scarring, yet objective tools to assess scars are lacking. Neither depth nor volume of atrophic scars is readily evaluable clinically and standard 2D photography is significantly affected by lighting and shadows. The aim of our study was to define and evaluate parameters of 3D imaging that can be used to assess severity of atrophic acne scarring. METHODS: Single center study of 31 patients with acne scarring. A target area of 3 * 3 cm was defined on the face. The global severity of atrophic acne scarring in the target area was evaluated by 5 dermatologists and scars were counted and categorized by size (scars < 2 mm, 2-4 mm, and > 4 mm in diameter). Three dimensional images of the target area were acquired with the LifeViz Micro(r) system and analysis was performed using MountainsMaps(r) software. An algorithm was developed to quantify the scar volume loss: shape removal step, with an order 5 polynomial, and to calculate the Valley void volume 80% (Vvv 80%) defined in the ISO-25178 standard for 3D surface texture. RESULTS: Correlation coefficient of the Vvv parameter to mean global severity at the target area rating was 0.77. The volume of scars evaluated with the Vvv parameter was mainly impacted by scars > 2 mm. The evaluations demonstrated good repeatability (with an intra-class correlation coefficient ICC = 0.98). CONCLUSIONS: We demonstrate convergent validation to clinical assessment and repeatability of 3D skin imaging in atrophic acne scarring. Image analysis is straightforward and can be integrated into an automated workflow. PMID- 29512190 TI - Comparison of the effect of gel used in two different serum separator tubes for thyroid function tests. AB - BACKGROUND: Selection and verification of blood collection tubes is an important preanalytical issue in clinical laboratories. Today, gel tubes are commonly used with many advantages, although they are known to cause interference in immunoassay methods. In this study, we aimed to compare SSTs of two different suppliers (Ayset clot activator & Gel and Becton Dickinson (BD) Vacutainer SST II advance) with reference tubes and evaluate the effect of storage time in terms of commonly used endocrine tests such as thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3). METHODS: Fifty-five volunteers were included in the study. Samples were taken into three different tubes and analyzed for serum TSH, fT4, and fT3 on Architect ci8200 Immunoassay System. Clinical decision levels were estimated using total allowable error (TEa). RESULTS: No difference was found between tubes in terms of TSH, fT3, and fT4 levels. From a statistical standpoint, TSH and fT4 levels were no longer stable during 24, 48, and 72 hours storage time periods. However, their variations were not clinically significant. CONCLUSION: Ayset clot activator & Gel tubes and BD Vacutainer SST II advance tubes have comparable results with glass tube in terms of TSH, fT3, and fT4 levels on Architect ci8200 Immunoassay Systems. From a clinical standpoint, serum TSH, fT4, and fT3 concentrations may be considered as stable when storing these tubes over 72 hours. PMID- 29512191 TI - Application of high-resolution array platform for genome-wide copy number variation analysis in patients with nonsyndromic cleft lip and palate. AB - BACKGROUND: Although more than 14 loci may be involved in the development of nonsyndromic cleft lip and palate (NSCLP), the etiology has not been fully elucidated due to genetic and environmental risk factor interactions. Despite advances in identifying genes associated with the NSCLP development using traditional genetic mapping strategies of candidate genes, genome-wide studies, and epidemiologic and linkage analysis, microarray techniques have become important complementary tools in the search for potential causative oral clefts genes in genetic studies. Microarray hybridization enables scanning of the whole genome and detecting copy number variants (CNVs). Although common benign CNVs are often smaller, with sizes smaller than 20 kb, here we reveal small exonic CNVs based on the importance of the encompassed genes in cleft lip and palate phenotype. METHODS: Microarray hybridization analysis was performed in 15 individuals with NSCLP. RESULTS: We identified 11 exonic CNVs affecting at least one exon of the candidate genes. Thirteen candidate genes (COL11A1-1p21; IRF6 1q32.3; MSX1-4p16.2; TERT-5p15.33; MIR4457-5p15.33; CLPTM1L-5p15.33; ESR1-6q25.1; GLI3-7p13; FGFR-8p11.23; TBX1-22q11.21; OFD-Xp22; PHF8-Xp11.22; and FLNA-Xq28) overlapped with the CNVs identified. CONCLUSIONS: Considering the importance to NSCLP, the microdeletions that encompass MSX1, microduplications over TERT, MIR4457, CLPTM1L, and microduplication of PHF8 have been identified as small CNVs related to sequence variants associated with oral clefts susceptibility. Our findings represent a preliminary study on the clinical significance of small CNVs and their relationship with genes implicated in NSCLP. PMID- 29512192 TI - The clinical phenotype and a novel COL7A1 mutation in a Chinese family with dystrophic epidermolysis bullosa pruriginosa. PMID- 29512193 TI - The author's reply to comment on 'psoriasis/inflammatory bowel diseases: a time to solve the liaison'. PMID- 29512194 TI - 'Dermohscopy' mapping: correlating dermoscopic findings with histology in Mohs micrographic surgery. PMID- 29512195 TI - Bullous pemphigoid with the deposition of IgG2 but not IgG1, IgG3 nor IgG4 autoantibodies at the basement membrane zone. PMID- 29512196 TI - Patient-reported symptoms and signs of moderate-to-severe psoriasis treated with guselkumab or adalimumab: results from the randomized VOYAGE 1 trial. AB - BACKGROUND: How patients experience the symptoms/signs of psoriasis is highly relevant for assessing treatment response. OBJECTIVES: Compare outcomes with guselkumab, placebo and adalimumab utilizing the novel, validated Psoriasis Symptoms and Signs Diary (PSSD). METHODS: VOYAGE 1 is an ongoing, phase III, double-blinded, controlled trial of patients with moderate-to-severe psoriasis. Patients were randomized to guselkumab 100 mg every 8 weeks; placebo-to guselkumab 100 mg every 8 weeks; or adalimumab 40 mg every 2 weeks. The PSSD was self-administered to assess symptoms (i.e. itch, skin tightness, burning, stinging and pain) and signs (i.e. dryness, cracking, scaling, shedding/flaking, redness and bleeding) of psoriasis (0-10 [absent-to-worst-imaginable]) every 24 h. Symptom and sign summary scores were derived (0-100) based on average scores of the individual symptoms and signs. Proportions of patients with clinically meaningful improvements and symptom- and sign-free scores of 0 were evaluated across treatment groups at weeks 16, 24 and 48. RESULTS: At baseline, 652 of 837 randomized patients had PSSD scores. The proportion of patients achieving clinically meaningful improvements in PSSD summary scores was significantly higher in the guselkumab group compared with the placebo group at week 16 (P < 0.001) and compared with the adalimumab group at weeks 24 (P = 0.002) and 48 (P < 0.001). The proportions of patients achieving PSSD symptom and sign summary scores of 0 (i.e. symptom- and sign-free) were significantly higher for guselkumab vs. placebo at week 16 and vs. adalimumab at weeks 24 and 48 (all P < 0.001). CONCLUSIONS: Based on PSSD scores, greater improvements in symptoms and signs of psoriasis were reported by patients treated with guselkumab compared with placebo at week 16 or adalimumab through 48 weeks. PMID- 29512197 TI - Utility of whole-exome sequencing in detecting novel compound heterozygous mutations in COL7A1 among families with severe recessive dystrophic epidermolysis bullosa in India - implications on diagnosis, prognosis and prenatal testing. PMID- 29512198 TI - Design and Development of Biomimetic Nanovesicles Using a Microfluidic Approach. AB - The advancement of nanotechnology toward more sophisticated bioinspired approaches has highlighted the gap between the advantages of biomimetic and biohybrid platforms and the availability of manufacturing processes to scale up their production. Though the advantages of transferring biological features from cells to synthetic nanoparticles for drug delivery purposes have recently been reported, a standardizable, batch-to-batch consistent, scalable, and high throughput assembly method is required to further develop these platforms. Microfluidics has offered a robust tool for the controlled synthesis of nanoparticles in a versatile and reproducible approach. In this study, the incorporation of membrane proteins within the bilayer of biomimetic nanovesicles (leukosomes) using a microfluidic-based platform is demonstrated. The physical, pharmaceutical, and biological properties of microfluidic-formulated leukosomes (called NA-Leuko) are characterized. NA-Leuko show extended shelf life and retention of the biological functions of donor cells (i.e., macrophage avoidance and targeting of inflamed vasculature). The NA approach represents a universal, versatile, robust, and scalable tool, which is extensively used for the assembly of lipid nanoparticles and adapted here for the manufacturing of biomimetic nanovesicles. PMID- 29512199 TI - Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management. AB - DISEASE OVERVIEW AND DIAGNOSIS: Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of >= 25 x 109 /L of which >= 80% are neutrophils, with < 10% circulating neutrophil precursors with blasts rarely observed. In addition, there is no dysplasia, nor clinical or molecular criteria for other myeloproliferative neoplasms. UPDATE ON DIAGNOSIS: Previously the diagnosis of CNL was often as one of exclusion based on no identifiable cause for physiologic neutrophilia in patients fulfilling the aforementioned criteria. The 2016 WHO classification now recognizes somatic activating mutations of CSF3R (most commonly CSF3RT618I) as diagnostic, allowing for an accurate diagnosis for the majority of suspected cases through molecular testing. These mutations are primary driver mutations, accounting for the characteristic clinical phenotype and potential susceptibility to molecularly targeted therapy. RISK STRATIFICATION: Concurrent mutations, common to myeloid neoplasms and their precursor states, most frequently in SETBP1 and ASXL1, are frequent and appear to be of prognostic significance. Although data are evolving on the full genomic profile, the rarity of CNL has delayed complete understanding of its full molecular pathogenesis and individual patient prognosis. PMID- 29512200 TI - Improvement in itch and other psoriasis symptoms with brodalumab in phase 3 randomized controlled trials. AB - BACKGROUND: Patients with psoriasis have lesional symptoms, including itch, which can reduce quality of life. The efficacy and safety of brodalumab, an interleukin 17 receptor A antagonist, in treating moderate-to-severe psoriasis have been reported in three randomized, controlled, phase 3 trials (AMAGINE-1/-2/-3). OBJECTIVE: The effect of brodalumab on lesional symptoms was assessed using the psoriasis symptom inventory (PSI), a validated patient-reported instrument. METHODS: Patients were randomized to receive brodalumab (140 or 210 mg every 2 weeks [Q2W]), placebo (AMAGINE-1/-2/-3), or ustekinumab (AMAGINE-2/-3) during a 12-week induction phase, followed by a maintenance phase through week 52. Patients electronically rated the severity of PSI items (itch, burning, stinging, pain, redness, scaling, cracking and flaking) during the previous 24 h on a scale of 0 (not at all severe) to 4 (very severe). At each visit, the PSI total score responder status was assessed, with responders defined as having an average weekly total inventory score <=8 with no item score >1 at week 12. RESULTS: Across AMAGINE-1/-2/-3, brodalumab was associated with improvements in PSI total scores and itch scores vs. placebo from week 2 through week 12 (P < 0.001 in both domains). In AMAGINE-2/-3, brodalumab 210 mg Q2W demonstrated faster onset of PSI total score and itch responses (week 2, 22.1% and 36.4%, respectively) vs. ustekinumab (week 2, 6.9% and 17.1%, respectively) and was associated with improved itch responses vs. ustekinumab after 52 weeks of constant treatment. CONCLUSION: Brodalumab demonstrated rapid, robust improvements in symptoms assessed by the PSI, including itch, vs. placebo and ustekinumab. PMID- 29512201 TI - Isotretinoin treatment and peanut allergy: a new case report and review of the literature. PMID- 29512202 TI - Mucocutaneous manifestations of cocaine abuse: a review. AB - Cocaine is an alkaloid extracted from the leaves of the Erythroxylum coca plant that emerged in the 1970s as a fashionable drug among members of certain social backgrounds. Cocaine abuse is a problem of current interest, which is mostly hidden and underdiagnosed, but dramatically widespread among all socio-economic strata, and with an incidence which is increasing at an alarming rate. There are 1.5 million cocaine consumers in the USA. In Spain, the prevalence of consumption among the population between 15 and 65 years old is higher, reaching 3.1%. Because of this, it seems important to understand and recognize all the mucocutaneous manifestations of cocaine abuse which have been reported in the literature to clarify and to help dermatologists in their daily practice. In this article, we describe the principal mucocutaneous manifestations of cocaine abuse and we review isolated case reports which have been published in the literature. Because the dermatologist may deal with an unknown problem as well as with an already well-known history of cocaine abuse, it seems logical to separate the mucocutaneous manifestations into those which are frequent and highly suggestive, such as those caused by vascular injury, damage to mucosal membranes, infectious diseases or neutrophilic dermatosis, especially when suffered by young people and in consonance with other systemic manifestations and, those which have been reported in the literature as isolated case reports. We also summarize the main aspects of its pathogeny, principal pharmacodynamic and pharmacokinetic characteristics, and diagnostic tools. PMID- 29512203 TI - Risk of developing pressure sore in amyotrophic lateral sclerosis patients - a nationwide cohort study. AB - BACKGROUND: Prior investigations with few cases have disclosed lack of pressure sore (PrS) formation was characteristic in amyotrophic lateral sclerosis (ALS) patients. However, studies with larger samples are lacking to ascertain this concept. OBJECTIVE: To investigate whether patients with ALS have higher risk of PrS. METHODS: Utilizing a Taiwan National Insurance claims data set with 23 million participants, we extracted 514 patients with ALS and 2056 controls from 1 January 2000 to 31 December 2008. Both groups were followed up until PrS occurrence during study period (2000-2011). The PrS risk was calculated with Cox proportional regression model. RESULTS: The patients with ALS had a greater PrS risk (adjusted hazard ratio [aHR] = 8.82, 95% confidence interval [CI] = 4.90 15.9, P < 0.001) than the controls did. PrS risk was much higher in ALS women (aHR = 26.6, 95% CI = 9.05-78.2, P < 0.001) than in ALS men (aHR = 4.38, 95% CI = 1.99-9.68, P < 0.001). Besides, in people aged 20-54, ALS was linked with a much greater PrS risk (aHR = 27.7, 95% CI = 5.79-132, P < 0.001) than in those aged >=55 (aHR = 6.10, 95% CI = 3.10-12.0, P < 0.001). CONCLUSIONS: Amyotrophic lateral sclerosis is discovered to be correlated with an enhanced PrS risk. For PrS prevention, it is needed to pay more attention to the management of the patients with ALS, particularly in women and those with relatively younger age. Further investigations are needed to confirm the findings in this study. PMID- 29512204 TI - Psoriasis/Inflammatory bowel diseases: a time to solve the liaison. PMID- 29512205 TI - The Impact of Atmosphere on the Local Luminescence Properties of Metal Halide Perovskite Grains. AB - Metal halide perovskites are exceptional candidates for inexpensive yet high performing optoelectronic devices. Nevertheless, polycrystalline perovskite films are still limited by nonradiative losses due to charge carrier trap states that can be affected by illumination. Here, in situ microphotoluminescence measurements are used to elucidate the impact of light-soaking individual methylammonium lead iodide grains in high-quality polycrystalline films while immersing them with different atmospheric environments. It is shown that emission from each grain depends sensitively on both the environment and the nature of the specific grain, i.e., whether it shows good (bright grain) or poor (dark grain) luminescence properties. It is found that the dark grains show substantial rises in emission, while the bright grain emission is steady when illuminated in the presence of oxygen and/or water molecules. The results are explained using density functional theory calculations, which reveal strong adsorption energies of the molecules to the perovskite surfaces. It is also found that oxygen molecules bind particularly strongly to surface iodide vacancies which, in the presence of photoexcited electrons, lead to efficient passivation of the carrier trap states that arise from these vacancies. The work reveals a unique insight into the nature of nonradiative decay and the impact of atmospheric passivation on the microscale properties of perovskite films. PMID- 29512206 TI - A Highly Sensitive Fluorogenic Probe for Imaging Glycoproteins and Mucine Activity in Live Cells in the Near-Infrared Region. AB - A novel fluorescent molecular probe is reported, which is able to detect glycoproteins, especially mucins, with high sensitivity and with a turn-on response along with a large Stokes shift (>130 nm), within the biologically active window. The probe contains an aminotricarbocyanine as the fluorescent reporter with a linked benzoboroxole as the recognition unit, which operates through a dynamic covalent reaction between the boronic hemiester residue of the receptor and cis-diols of the analyte. The superior selectivity of the probe is displayed by the labeling of mucins present in Calu-3 cells. The new benzoboroxole fluorescent derivative gathers together key properties to make it a highly rated molecular probe: specificity, excellent solubility in water, and off on near infrared emission. This probe is expected to be an excellent tool for imaging intracellular mucin to evaluate mucus-related diseases as well as a sensing strategy towards glycosylated structures with a high potential for theranostics approaches in biological samples. PMID- 29512207 TI - An impact of Deoxynivalenol produced by Fusarium graminearum on broiler chickens. AB - Deoxynivalenol (DON) is a major mycotoxin from the trichothecene family of mycotoxins produced by Fusarium fungi that cause disease in grains. Food and feed contaminated with DON cause a variety of adverse health effects in humans and farm animals. However, the fermentation conditions of DON for toxicological study remain to be optimised. Deoxynivalenol levels were increased in a constant temperature of 20 degrees C after fermentation for 7 and 14 days compared with cycling temperatures between 10-20 degrees C and 15-20 degrees C. We have established that optimum conditions for DON production on rice-based medium is constant temperature at 20 degrees C. In feeding experiments, the villus height and the ratio of villus height and crypt depth were reduced in the duodenum of DON-fed broiler chickens, whereas a mycotoxin degradation agent efficiently reversed the abnormal morphology of the small intestine in the DON-fed broilers. The expression of pro-inflammatory gene, COX-2, was induced in the spleen and bursa of Fabricius of DON-fed broilers. This effect was alleviated in the presence of mycotoxin degradation agent. DON produced in solid-state fermentation is able to cause toxic effects in broilers and induce an abnormal morphology of the small intestine, particularly the duodenum. PMID- 29512208 TI - Printable Superelastic Conductors with Extreme Stretchability and Robust Cycling Endurance Enabled by Liquid-Metal Particles. AB - Stretchable conductors are vital and indispensable components in soft electronic systems. The development for stretchable conductors has been highly motivated with different approaches established to address the dilemma in the conductivity and stretchability trade-offs to some extent. Here, a new strategy to achieve superelastic conductors with high conductivity and stable electrical performance under stretching is reported. It is demonstrated that by electrically anchoring conductive fillers with eutectic gallium indium particles (EGaInPs), significant improvement in stretchability and durability can be achieved in stretchable conductors. Different from the strategy of modulating the chemical interactions between the conductive fillers and host polymers, the EGaInPs provide dynamic and robust electrical anchors between the conductive fillers. A superelastic conductor which can achieve a high stretchability with 1000% strain at initial conductivity of 8331 S cm-1 and excellent cycling durability with about eight times resistance change (compared to the initial resistance at 0% strain before stretching) after reversibly stretching to 800% strain for 10 000 times is demonstrated. Applications of the superelastic conductor in an interactive soft touch device and a stretchable light-emitting system are also demonstrated, featuring its promising applications in soft robotics or soft and interactive human-machine interfaces. PMID- 29512209 TI - Exploring Critical Factors Affecting Strain Distribution in 1D Silicon-Based Nanostructures for Lithium-Ion Battery Anodes. AB - Despite the advantage of high capacity, the practical use of the silicon anode is still hindered by large volume expansion during the severe pulverization lithiation process, which results in electrical contact loss and rapid capacity fading. Here, a combined electrochemical and computational study on the factor for accommodating volume expansion of silicon-based anodes is shown. 1D silicon based nanostructures with different internal spaces to explore the effect of spatial ratio of voids and their distribution degree inside the fibers on structural stability are designed. Notably, lotus-root-type silicon nanowires with locally distributed void spaces can improve capacity retention and structural integrity with minimum silicon pulverization during lithium insertion and extraction. The findings of this study indicate that the distribution of buffer spaces, electrochemical surface area, as well as Li diffusion property significantly influence cycle performance and rate capability of the battery, which can be extended to other silicon-based anodes to overcome large volume expansion. PMID- 29512210 TI - A Voltage-Boosting Strategy Enabling a Low-Frequency, Flexible Electromagnetic Wave Absorption Device. AB - Nowadays, low-frequency electromagnetic interference (<2.0 GHz) remains a key core issue that plagues the effective attenuation performance of conventional absorption devices prepared via the component-morphology method (Strategy I). According to theoretical calculations, one fundamental solution is to develop a material that possesses a high epsilon' but lower epsilon". Thus, it is attempted to control the dielectric values via applying an external electrical field, which inducts changes in the macrostructure toward a performance improvement (Strategy II). A sandwich-structured flexible electronic absorption device is designed using a carbon film electrode to conduct an external current. Simultaneously, an absorption layer that is highly responsive to an external voltage is selected via Strategy I. Relying on the synergistic effects from Strategies I and II, this device demonstrates an absorption value of more than 85% at 1.5-2.0 GHz with an applied voltage of 16 V while reducing the thickness to ~5 mm. In addition, the device also shows a good absorption property at 25-150 degrees C. The method of utilizing an external voltage to break the intrinsic dielectric feature by modifying a traditional electronic absorption device is demonstrated for the first time and has great significance in solving the low-frequency electromagnetic interference issue. PMID- 29512211 TI - Polypyrenes as High-Performance Cathode Materials for Aluminum Batteries. AB - The pressing need for low-cost and large-scale stationary storage of electricity has led to a new wave of research on novel batteries made entirely of components that have high natural abundances and are easy to manufacture. One example of such an anode-electrolyte-cathode architecture comprises metallic aluminum, AlCl3 :[EMIm]Cl (1-ethyl-3-methylimidazolium chloride) ionic liquid and graphite. Various forms of synthetic and natural graphite cathodes have been tested in recent years in this context. Here, a new type of compelling cathode based on inexpensive pyrene polymers is demonstrated. During charging, the condensed aromatic rings of these polymers are oxidized, which is accompanied by the uptake of aluminum tetrachloride anions (AlCl4- ) from the chloroaluminate ionic liquid. Discharge is the fast inverse process of reduction and the release of AlCl4- . The electrochemical properties of the polypyrenes can be fine-tuned by the appropriate chemical derivatization. This process is showcased here by poly(nitropyrene-co-pyrene), which has a storage capacity of 100 mAh g-1 , higher than the neat polypyrene (70 mAh g-1 ) or crystalline pyrene (20 mAh g-1 ), at a high discharge voltage (~1.7 V), energy efficiency (~86%), and cyclic stability (at least 1000 cycles). PMID- 29512213 TI - The role of the dermatologist in Raynaud's phenomenon: a clinical challenge. AB - Raynaud's phenomenon (RP) is a functional vascular disorder involving extremities. In his practice, the dermatologist may frequently encounter RP which affects mainly women and is categorized into a primary benign form and a secondary form associated with different diseases (infections, drugs, autoimmune and vascular conditions, haematologic, rheumatologic and endocrinologic disorders). Still today, the differential diagnosis is a clinical challenge. Therefore, a careful history and a physical examination, together with laboratory tests and nailfold capillaroscopy, is mandatory. RP is generally benign, but a scheduled follow-up for primary RP patients should be established, due to risk of evolution to secondary RP. A combination of conservative measures and medications can help in the management of RP. The importance of avoiding all potential physical, chemical and emotional triggers, as well as quitting smoking, should be strongly suggested to the patient. As first-line treatment, dihydropyridine calcium channel blockers should be used. If this approach is not sufficient, prostacyclin derivatives, phosphodiesterases inhibitors and endothelin receptor antagonists can be considered as second-line treatment. In cases of acute ischaemia, nifedipine and intravenous prostanoids are helpful. In refractory cases, botulinum injections have shown a significant benefit. The approach to the RP patients requires therefore a coordinated care of specialists together with the primary care physician. PMID- 29512212 TI - Oxygen Diode Formed in Nickelate Heterostructures by Chemical Potential Mismatch. AB - Deliberate control of oxygen vacancy formation and migration in perovskite oxide thin films is important for developing novel electronic and iontronic devices. Here, it is found that the concentration of oxygen vacancies (VO ) formed in LaNiO3 (LNO) during pulsed laser deposition is strongly affected by the chemical potential mismatch between the LNO film and its proximal layers. Increasing the VO concentration in LNO significantly modifies the degree of orbital polarization and drives the metal-insulator transition. Changes in the nickel oxidization state and carrier concentration in the films are confirmed by soft X-ray absorption spectroscopy and optical spectroscopy. The ability to unidirectional control the oxygen flow across the heterointerface, e.g., a so-called "oxygen diode", by exploiting chemical potential mismatch at interfaces provides a new avenue to tune the physical and electrochemical properties of complex oxides. PMID- 29512214 TI - Enhancing the Performance of Polymer Solar Cells via Core Engineering of NIR Absorbing Electron Acceptors. AB - In order to utilize the near-infrared (NIR) solar photons like silicon-based solar cells, extensive research efforts have been devoted to the development of organic donor and acceptor materials with strong NIR absorption. However, single junction organic solar cells (OSCs) with photoresponse extending into >1000 nm and power conversion efficiency (PCE) >11% have rarely been reported. Herein, three fused-ring electron acceptors with varying core size are reported. These three molecules exhibit strong absorption from 600 to 1000 nm and high electron mobility (>1 * 10-3 cm2 V-1 s-1 ). It is proposed that core engineering is a promising approach to elevate energy levels, enhance absorption and electron mobility, and finally achieve high device performance. This approach can maximize both short-circuit current density ( JSC ) and open-circuit voltage (VOC ) at the same time, differing from the commonly used end group engineering that is generally unable to realize simultaneous enhancement in both VOC and JSC . Finally, the single-junction OSCs based on these acceptors in combination with the widely polymer donor PTB7-Th yield JSC as high as 26.00 mA cm-2 and PCE as high as 12.3%. PMID- 29512215 TI - Nanostructuring Multilayer Hyperbolic Metamaterials for Ultrafast and Bright Green InGaN Quantum Wells. AB - Semiconductor quantum well (QW) light-emitting diodes (LEDs) have limited temporal modulation bandwidth of a few hundred MHz due to the long carrier recombination lifetime. Material doping and structure engineering typically leads to incremental change in the carrier recombination rate, whereas the plasmonic based Purcell effect enables dramatic improvement for modulation frequency beyond the GHz limit. By stacking Ag-Si multilayers, the resulting hyperbolic metamaterials (HMMs) have shown tunability in the plasmonic density of states for enhancing light emission at various wavelengths. Here, nanopatterned Ag-Si multilayer HMMs are utilized for enhancing spontaneous carrier recombination rates in InGaN/GaN QWs. An enhancement of close to 160-fold is achieved in the spontaneous recombination rate across a broadband of working wavelengths accompanied by over tenfold enhancement in the QW peak emission intensity, thanks to the outcoupling of dominating HMM modes. The integration of nanopatterned HMMs with InGaN QWs will lead to ultrafast and bright QW LEDs with a 3 dB modulation bandwidth beyond 100 GHz for applications in high-speed optoelectronic devices, optical wireless communications, and light-fidelity networks. PMID- 29512216 TI - Copper-Catalyzed Regio- and Enantioselective Aminoboration of Unactivated Terminal Alkenes. AB - A CuCl/(R,R)-PTBP-BDPP-catalyzed regioselective and enantioselective aminoboration of simple and unactivated terminal alkenes with bis(pinacolato)diboron (pinB-Bpin) and hydroxylamines has been developed. The amino group and boryl group were incorporated at the internal position and terminal position, respectively, and the corresponding chiral beta borylalkylamines were obtained with good to high enantiomeric ratios. The asymmetric copper catalysis allows rapid and concise transformation of readily available olefinic feedstock-like materials into functionalized chiral alkylamines of high potential in medicinal and pharmaceutical chemistry. PMID- 29512217 TI - Partnering with insiders: A review of peer models across community-engaged research, education and social care. AB - Within community-engaged research, education and social care, peer models that partner with local "insiders" are increasingly common. Peer models are composed of insider "lay" community members who often share similarities or background with a project's target population. Peers are not academically trained, but work alongside researchers and professionals to carry out specific tasks within a project, or in the truest sense of partnership, peers collaborate throughout the project from start to finish as an equal member of the team. Although peer models are used widely, the literature lacks consistency and clarity. This systematic review of literature used a qualitative thematic synthesis to examine and report how, where and why peer models have been used in research, education and social care. We examined the language and titles used to describe the peers, details of their involvement in community-engaged projects, the setting, content/topic of study, level of engagement and related benefits/outcomes of such models. Focusing on the last 10 years, we conducted a comprehensive literature search twice between September 2016 and June 2017. The search resulted in 814 articles which were assessed for eligibility. Overall, 251 articles met our inclusion criteria and were categorised into three categories: empirical (n = 115); process/descriptive (n = 93); and "about" peers (n = 43). Findings suggest that there is a wide variety of peers, titles and terminology associated with peer models. There is inconsistency in how these models are used and implemented in research studies and projects. The majority of articles used an employment peer model, while only a handful involved peers in all phases of the project. The results of this literature review contribute to understanding the use, development and evolution of peer models. We highlight potential benefits of peer models for peers, their communities and community-engaged work, and we offer recommendations for future implementation of peer models. PMID- 29512218 TI - "I see so much in them": Australian Chaplains telling an alternative narrative of adolescents in the justice system. AB - This qualitative study aims to provide insight into the impact of chaplaincy in the Australian juvenile justice system. Semi-structured qualitative interviews were conducted with six chaplains and managers of chaplaincy services in the juvenile justice system in Victoria, Australia. Interviews were analysed thematically using deductive and inductive coding. Four themes emerged relating to the role and impact of the chaplain: to establish a safe and trusting relationship with the adolescents, to convey love and belonging, to engage the adolescents in meaning making, and to help adolescents to realise their full potential. These themes are consistent with Maslow's Hierarchy of Needs. Two themes emerged regarding how to increase the reach of chaplaincy: through recognising chaplaincy as an integral part of the justice system and enabling chaplains to work with the adolescents and their families post-release. While limited by a small sample, this study represents all organisations that provide chaplaincy in the juvenile justice system in Victoria, Australia. Future research could include the voices of the adolescents in juvenile justice, to gain their perspective on the role and impact of chaplaincy services. PMID- 29512219 TI - Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents. AB - A nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct-acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long-term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016-2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale-up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879. PMID- 29512220 TI - Study on the molecular recognition action of lamivudine by human serum albumin. AB - In this work, the interaction of an anti-HIV drug lamivudine and human serum albumin (HSA) was studied by multispectroscopic and molecular modeling methods. The fluorescence emission spectra showed that the fluorescence of HSA was quenched by lamivudine through static mechanism with HSA-lamivudine complex produced at ground state. According to the binding equilibriums observed at 4 different temperatures, the number of binding site, binding constant, enthalpy change, entropy change, and Gibbs free energy change of the interaction were calculated. The results indicated that there was only 1 main binding site under present concentration condition, and then, the location of this binding site was ascertained by molecular probe experiments using warfarin and ibuprofen as site markers. The interaction was a spontaneous and exothermic process. Hydrogen bonds and van der Waals force were the major power that fixed lamivudine on Sudlow's site I in subdomain IIA of HSA molecule. The distance between donor and acceptor was determined by Forster's nonradiative fluorescence resonance energy transfer theory. Circular dichroism spectra exhibited the alteration of HSA's secondary structures. Molecular modeling investigation revealed the structure of HSA lamivudine complex, including the conformation of lamivudine in binding site, the amino residues close to lamivudine, and the interaction forces between receptor and ligand. The study may be beneficial to therapists in understanding the distribution of lamivudine in vivo and explaining its drug-resistant mechanism in clinical diagnosis. PMID- 29512221 TI - Challenges to reproductive rights. PMID- 29512222 TI - Nearly half of the adolescents in an Italian school-based study exceeded the recommended upper limits for daily caffeine consumption. AB - AIM: No data are available on caffeine consumption among Italian adolescents. We investigated caffeine intake from coffee, soft drinks and energy drinks in a sample of Italian adolescents and determined if they exceeded the recommended limits. METHODS: The study comprised 1213 adolescents with a mean age of 15.1 years (range 12-19) from four schools in Foggia, southern Italy. Caffeine intake was assessed using an anonymous self-reported questionnaire during the 2013/2014 school year. We calculated the percentage of daily caffeine consumers, their mean intake of caffeine from beverages and the contribution of each beverage category to the total caffeine intake. RESULTS: Approximately 76% of the sample consumed caffeine every day, amounting to 125.5 +/- 69.2 mg/day and 2.1 +/- 1.2 mg/kg/day. When we applied the reference values from the Academy of Pediatrics, we found that 46% of the adolescents exceeded the recommended upper limits. Coffee was the most frequently consumed caffeinated drink and the main contributor to daily caffeine intake. CONCLUSION: More than three quarters (76%) of the Italian adolescents in our study drank coffee on a daily basis and nearly half (46%) exceeded the recommended upper limits. Strategies are needed to reduce caffeine consumption by adolescents. PMID- 29512223 TI - Pseudomonas aeruginosa infection alters the macrophage phenotype switching process during wound healing in diabetic mice. AB - Macrophages play critical roles in wound healing process. They switch from "classically activated" (M1) phenotype in the early inflammatory phase to "alternatively activated" (M2) phenotype in the later healing phase. However, the dynamic process of macrophage phenotype switching in diabetic wounds burdened with bacteria is unclear. In this report, Pseudomonas aeruginosa, frequently detected in diabetic foot ulcers, was inoculated into cutaneous wounds of db/db diabetic mice to mimic bacterium-infected diabetic wound healing. We observed that P. aeruginosa infection impaired diabetic wound healing and quickly promoted the expression of pro-inflammatory genes (M1 macrophage markers) tumor necrosis factor-alpha (tnf-alpha), interleukin-1beta (il-1beta) and il-6 in wounds. The expression of markers of M2 macrophages, including il-10, arginase-1, and ym1 were also upregulated. In addition, similar gene expression patterns were observed in macrophages isolated directly from wounds. Immunostaining showed that P. aeruginosa infection increased both the ratios of M1 and M2 macrophages in wounds compared with that in control groups, which was further confirmed by in vitro culturing macrophages with P. aeruginosa and skin fibroblast conditioned medium. However, the ratios of the expression levels of pro-inflammatory genes to anti-inflammatory gene il-10 was increased markedly in P. aeruginosa infected wounds and macrophages compared with that in control groups, and P. aeruginosa prolonged the presence of M1 macrophages in the wounds. These data demonstrated that P. aeruginosa in diabetic wounds activates a mixed M1/M2 macrophage phenotype with an excessive activation of M1 phenotype or relatively inadequate activation of M2 phenotype. PMID- 29512224 TI - Physiology of static breath holding in elite apneists. AB - NEW FINDINGS: What is the topic of this review? This review provides an up-to date assessment of the physiology involved with extreme static dry-land breath holding in trained apneists. What advances does it highlight? We specifically highlight the recent findings involved with the cardiovascular, cerebrovascular and metabolic function during a maximal breath hold in elite apneists. ABSTRACT: Breath-hold-related activities have been performed for centuries, but only recently, within the last ~30 years, has it emerged as an increasingly popular competitive sport. In apnoea sport, competition relates to underwater distances or simply maximal breath-hold duration, with the current (oxygen-unsupplemented) static breath-hold record at 11 min 35 s. Remarkably, many ultra-elite apneists are able to suppress respiratory urges to the point where consciousness fundamentally limits a breath-hold duration. Here, arterial oxygen saturations as low as ~50% have been reported. In such cases, oxygen conservation to maintain cerebral functioning is critical, where responses ascribed to the mammalian dive reflex, e.g. sympathetically mediated peripheral vasoconstriction and vagally mediated bradycardia, are central. In defence of maintaining global cerebral oxygen delivery during prolonged breath holds, the cerebral blood flow may increase by ~100% from resting values. Interestingly, near the termination of prolonged dry static breath holds, recent studies also indicate that reductions in the cerebral oxidative metabolism can occur, probably attributable to the extreme hypercapnia and irrespective of the hypoxaemia. In this review, we highlight and discuss the recent data on the cardiovascular, metabolic and, particularly, cerebrovascular function in competitive apneists performing maximal static breath holds. The physiological adaptation and maladaptation with regular breath-hold training are also summarized, and future research areas in this unique physiological field are highlighted; particularly, the need to determine the potential long-term health impacts of extreme breath holding. PMID- 29512225 TI - Mapping repetitive activation in atrial fibrillation: Active drivers or passengers along for the ride? PMID- 29512226 TI - Conundrum of the Tpeak-Tend interval. PMID- 29512227 TI - Synthesis and characterization of four novel palladium(II) and platinum(II) complexes with 1-(2-aminoethyl)pyrrolidine, diclofenac and mefenamic acid: In vitro effect of these complexes on human serum paraoxanase1 activity. AB - In this study, the effects of four novel mononuclear palladium(II) and platinum(II) complexes on the activity of human serum paraoxanase1 were examined. First, four novel mononuclear palladium(II) and platinum(II) complexes were synthesized with a nitrogen donor ligand 1-(2-aminoethyl)pyrrolidine and nonsteroidal anti-inflammatory drugs diclofenac, mefenamic acid. These complexes were characterized by spectroscopic, thermal, and elemental analyses. The crystal structures of complex [Pd(2-amepyr)2 ](dicl)2 1 and [Pd(2-amepyr)2 ](mef)2 3 were determined by X-ray crystallography. Then, paraoxonase1 enzyme was purified from human serum. The effects of these complexes on enzyme were evaluated in vitro. The complexes consist of the cationic unit and the counterions. The diclofenac and mefenamic acid acted as a counterion in the complexes. It was observed that all the complexes were stable up to high temperatures. These complexes, even at low doses, inhibited the activity of the enzyme with different inhibition mechanisms. PMID- 29512228 TI - Bombyx mori cyclin-dependent kinase inhibitor is involved in regulation of the silkworm cell cycle. AB - Cyclin-dependent kinase inhibitors (CKIs) are negative regulators of the cell cycle. They can bind to cyclin-dependent kinase (CDK)-cyclin complexes and inhibit CDK activities. We identified a single homologous gene of the CDK interacting protein/kinase inhibitory protein (Cip/Kip) family, BmCKI, in the silkworm, Bombyx mori. The gene transcribes two splice variants: a 654-bp-long BmCKI-L (the longer splice variant) encoding a protein with 217 amino acids and a 579-bp-long BmCKI-S (the shorter splice variant) encoding a protein with 192 amino acids. BmCKI-L and BmCKI-S contain the Cip/Kip family conserved cyclin binding domain and the CDK-binding domain. They are localized in the nucleus and have an unconventional bipartite nuclear localization signal at amino acid residues 181-210. Overexpression of BmCKI-L or BmCKI-S affected cell cycle progression; the cell cycle was arrested in the first gap phase of cell cycle (G1). RNA interference of BmCKI-L or BmCKI-S led to cells accumulating in the second gap phase and the mitotic phase of cell cycle (G2/M). Both BmCKI-L and BmCKI-S are involved in cell cycle regulation and probably have similar effects. The transgenic silkworm with BmCKI-L overexpression (BmCKI-L-OE), exhibited embryonic lethal, larva developmental retardation and lethal phenotypes. These results suggest that BmCKI-L might regulate the growth and development of silkworm. These findings clarify the function of CKIs and increase our understanding of cell cycle regulation in the silkworm. PMID- 29512229 TI - The anti-inflammatory effect of topical tofacitinib on immediate and late-phase cutaneous allergic reactions in dogs: a placebo-controlled pilot study. AB - BACKGROUND: Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans. OBJECTIVES: To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs. ANIMALS: Five healthy laboratory beagle dogs. METHODS: Topical tofacitinib (total daily dosage: 0.5 mg/cm2 ) or its gel vehicle were applied on either the left or right lateral thorax of each dog for eight days. Three days before application and after eight days of topical treatment, intradermal injections of histamine and anticanine-IgE antibodies were performed on both sides; they were evaluated by an investigator blinded to the interventions. RESULTS: The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P <= 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes. CONCLUSIONS: Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs. PMID- 29512230 TI - Non-pharmacological interventions during childbirth for pain relief, anxiety, and neuroendocrine stress parameters: A randomized controlled trial. AB - AIM: This study aimed to investigate the effect of warm shower hydrotherapy and perineal exercises with a ball on pain, anxiety, and neuroendocrine stress parameters during childbirth. METHODS: This randomized controlled trial was conducted with 128 women during childbirth, admitted for hospital birth in Sao Paulo, Brazil, from June 2013 to February 2014. The participants were randomly assigned into one of the following intervention groups: received warm shower hydrotherapy (GA); performed perineal exercises with a ball (GB); and combined intervention group, which received warm shower hydrotherapy and perineal exercises with a ball (GC) (n = 39). Pre-and post-intervention parameters were evaluated using visual analogue scales for pain and anxiety, and salivary samples were collected for the stress hormones analysis. RESULTS: Pain, anxiety, and epinephrine release decreased in the group performing perineal exercises with a ball (GB). beta-endorphin levels increased in this group (GB) after the intervention and showed significant difference in capacity to cause this effect (P = .007). However, no significant differences were observed in cortisol, epinephrine, and norepinephrine levels. CONCLUSIONS: Warm showers and perineal exercises could be considered as adjunct therapy for women suffering from pain, anxiety, and stress during childbirth. Clinical Trial Registry RBR-84xprt. PMID- 29512232 TI - Management of haemophilia carriers around the time of their delivery: Phenotypic variation requiring customization of management. PMID- 29512231 TI - Direct-acting antivirals and hepatitis B virus (HBV) reactivation in co-infected HBV/HCV kidney-transplant recipients. AB - Direct-acting agents (DAAs) are highly efficient at treating hepatitis C virus (HCV) infections after kidney transplantation. Although drug agencies have recently warned of the risk of hepatitis B virus (HBV) reactivation after patients have received DAAs, reports have discrepant results in HBsAg-positive and HBsAg-negative patients. We report on 3 cases of HBV reactivation that were detected after achieving a DAA-associated sustained virological response in 3 kidney-transplant recipients initially HBsAg-negative. In the first case, retrospective virological analysis revealed that HBsAgs had become positive and HBV DNA was detectable before initiating DAA therapy. In the second and third cases, HBV reactivation occurred 2 months and more than 1 year after stopping anti-HCV therapy. These cases underline the discrepancies and highlight the need for comprehensive information before making definitive conclusions regarding the causal link between DAAs and HBV reactivation. PMID- 29512233 TI - Screening recipients of increased risk donor organs: A multicenter retrospective study. AB - Organ Procurement & Transplantation Network policy requires post-transplant screening of recipients of organs from donors at increased risk for transmission of HIV, hepatitis B virus, and hepatitis C virus. Available data suggest that follow-up testing of recipients is not routinely conducted. Data on increased risk donors and recipients of their organs from 2008 to 2012 were retrospectively collected from 6 transplant centers after IRB approval. Descriptive statistics were performed. About 363 (60%) recipients were screened for transmission of HIV, HBV, and/or HCV at some time point; 257 (70.8%) within 90 days of transplant. The type of test used to screen for infection was variable with many recipients (25% 43%) screened with serology alone. Our results reveal that post-transplant screening for HIV, HBV, and HCV in recipients of increased risk donor organs did not universally occur and testing methods were variable. PMID- 29512234 TI - Seroresponses and safety of 13-valent pneumococcal conjugate vaccination in kidney transplant recipients. AB - BACKGROUND: Conjugated pneumococcal vaccine is recommended for kidney transplant recipients, however, their immunogenicity and potential to trigger allograft rejection though generation of de novo anti-human leukocyte antigen antibodies has not been well studied. METHODS: Clinically stable kidney transplant recipients participated in a prospective cohort study and received a single dose of 13-valent conjugate pneumococcal vaccine. Anti-pneumococcal IgG was measured for the 13 vaccine serotypes pre and post vaccination and functional anti pneumococcal IgG for 4 serotypes post vaccination. Anti-human leukocyte antigen antibodies antibodies were measured before and after vaccination. Kidney transplant recipients were followed clinically for 12 months for episodes of allograft rejection or invasive pneumococcal disease. RESULTS: Forty-five kidney transplant recipients participated. Median days between pre and post vaccination serology was 27 (range 21-59). Post vaccination, there was a median 1.1 to 1.7 fold increase in anti-pneumococcal IgG antibody concentrations for all 13 serotypes. Kidney transplant recipients displayed a functional antibody titer >=1:8 for a median of 3 of the 4 serotypes. Post vaccination, there were no de novo anti-human leukocyte antigen antibodies, no episodes of biopsy proven rejection or invasive pneumococcal disease. CONCLUSION: A single dose of 13 valent conjugate pneumococcal vaccine elicits increased titers and breadth of functional anti-pneumococcal antibodies in kidney transplant recipients without stimulating rejection or donor-specific antibodies. PMID- 29512235 TI - Glycaemic control and treatment of type 2 diabetes in adults aged 75 years or older. AB - AIM: The aim of this study was to assess glycaemic control and prescribing practices of antihyperglycaemic treatment in patients with diabetes mellitus type 2 aged 75 years or older. METHODS: We analysed data from health electronic records from 4,581 persons attended at primary healthcare centres of the Institut Catala de la Salut (ICS), in the Girona Sud area of Catalonia, Spain, during 2013 and 2016. Variables such as age, gender, body mass index (BMI), diabetes duration, age at diabetes diagnosis, glycated haemoglobin (HbA1c), creatinine, glomerular filtrate rate and the albumin/creatinine ratio in urine were collected. A descriptive analysis of the study variables was done to determinate the percentage of persons on antidiabetic treatment. RESULTS: We identified 4,421 persons aged 75 years or older who provided data on HbA1c and antidiabetic treatment. Mean age was 82.3 (5.1) years. In 58.1% of patients, the level of HbA1c was below 7.0%, while in 36.8% it was below 6.5%. Between patients with HbA1c below 7.0%, antidiabetic drugs were taken by 70.2%, where 15.2% were either on insulin, sulphonylureas or repaglinide therapy. CONCLUSION: Intensive treatment among older adults with diabetes mellitus type 2 is common in primary care clinical practice in our area. Intensive glycaemic control confers an increased risk of hypoglycaemia and little benefit among older individuals with diabetes. Physicians should take care more not to harm those populations and treatment should be de-intensified to reduce the risk of hypoglycaemia. PMID- 29512236 TI - Risk stratification in acute heart failure: reply. PMID- 29512237 TI - Polymer on Top: Current Limits and Future Perspectives of Quantitatively Evaluating Surface Grafting. AB - Well-defined polymer strands covalently tethered onto solid substrates determine the properties of the resulting functional interface. Herein, the current approaches to determine quantitative grafting densities are assessed. Based on a brief introduction into the key theories describing polymer brush regimes, a user's guide is provided to estimating maximum chain coverage and-importantly examine the most frequently employed approaches for determining grafting densities, i.e., dry thickness measurements, gravimetric assessment, and swelling experiments. An estimation of the reliability of these determination methods is provided via carefully evaluating their assumptions and assessing the stability of the underpinning equations. A practical access guide for comparatively and quantitatively evaluating the reliability of a given approach is thus provided, enabling the field to critically judge experimentally determined grafting densities and to avoid the reporting of grafting densities that fall outside the physically realistic parameter space. The assessment is concluded with a perspective on the development of advanced approaches for determination of grafting density, in particular, on single-chain methodologies. PMID- 29512239 TI - The changing vista of pleural effusion management: Indwelling pleural catheters (IPC). PMID- 29512238 TI - N-Type 2D Organic Single Crystals for High-Performance Organic Field-Effect Transistors and Near-Infrared Phototransistors. AB - Organic field-effect transistors and near-infrared (NIR) organic phototransistors (OPTs) have attracted world's attention in many fields in the past decades. In general, the sensitivity, distinguishing the signal from noise, is the key parameter to evaluate the performance of NIR OPTs, which is decided by responsivity and dark current. 2D single crystal films of organic semiconductors (2DCOS) are promising functional materials due to their long-range order in spite of only few molecular layers. Herein, for the first time, air-stable 2DCOS of n type organic semiconductors (a furan-thiophene quinoidal compound, TFT-CN) with strong absorbance around 830 nm, by the facile drop-casting method on the surface of water are successfully prepared. Almost millimeter-sized TFT-CN 2DCOS are obtained and their thickness is below 5 nm. A competitive field-effect electron mobility (1.36 cm2 V-1 s-1 ) and high on/off ratio (up to 108 ) are obtained in air. Impressively, the ultrasensitive NIR phototransistors operating at the off state exhibit a very low dark current of ~0.3 pA and an ultrahigh detectivity (D*) exceeding 6 * 1014 Jones because the devices can operate in full depletion at the off-state, superior to the majority of the reported organic-based NIR phototransistors. PMID- 29512240 TI - Fatal Fusarium infection manifesting as osteomyelitis following previous treatment with amphotericin B in a multi-visceral transplant: Case report and review of Fusarium infections in solid organ transplantation. AB - Invasive fusariosis in solid organ transplant is uncommon and usually presents as localized infection with favorable outcomes compared to hematologic malignancies or bone marrow transplants. We report the first case of Fusarium osteomyelitis in a patient following multi-visceral transplant and review Fusarium in organ transplant recipients and Fusarium bone and joint infections. Our case underscores the importance of early recognition and multidisciplinary approach to treatment and highlights potential failure to eradicate with amphotericin B monotherapy. PMID- 29512241 TI - Controlled Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides. AB - A chemoenzymatic approach has been developed for the preparation of diverse libraries of heparan sulfate (HS) oligosaccharides. It employs chemically synthesized oligosaccharides having a chemical entity at a GlcN residue, which in unanticipated manners influences the site of modification by NST, C5-Epi/2-OST and 6-OST1 /6-OST3 , thus resulting in oligosaccharides differing in N/O sulfation and epimerization pattern. The enzymatic transformations defined fine substrate requirements of NST, C5-Epi, 2-OST, and 6-OST. PMID- 29512242 TI - Organ donor screening practices for Strongyloides stercoralis infection among US organ procurement organizations. AB - BACKGROUND: Targeted donor screening for strongyloidiasis performed at the time of organ procurement can prevent this life-threatening donor-derived infection. METHOD: The Association of Organ Procurement Organizations surveyed members to determine the number of US organ procurement organizations (OPOs) performing donor screening for Strongyloides infection and their screening practices. RESULTS: All 58 OPOs responded to the survey. Only 6 (10%) currently screen donors for strongyloidiasis; most OPOs started 6-36 months before the survey and one started 6 years prior. All used risk-based criteria to determine which donors to screen, though the criteria varied among OPOs. A median of 56 donors have been screened at each OPO since initiating their screening programs, with a median of 2 infected donors (range 0-13) identified. Overall, 53 organs have been transplanted from 22 infected donors, including hearts, lungs, kidneys, and livers. Of 52 OPOs not currently screening, 20 had considered screening and one plans to start screening in the near future. Of those considering risk-based screening, most had not decided on the criteria. Uncertainty about the benefits of and guidelines for screening and misconceptions about the interpretation of test results were concerns shared by non-screening OPOs. CONCLUSION: Continued education and advocacy on the importance of targeted donor screening are needed. PMID- 29512243 TI - Recurrent bacterial pneumonia due to immunoglobulin G2 subclass deficiency after allogeneic hematopoietic stem cell transplantation: Efficacy of immunoglobulin replacement. AB - Immunoglobulin (Ig) G2 subclass deficiency is known to be associated with recurrent bacterial respiratory infections caused by capsulated bacteria. We encountered a case of recurrent pneumonia due to Streptococcus pneumoniae after allogeneic hematopoietic stem cell transplantation (HSCT). IgG2 subclass level was specifically low, and prophylactic Ig replacement successfully prevented subsequent infections. However, the cessation of Ig replacement resulted in subsequent pneumonia. These findings suggested that IgG2 deficiency could be a cause of recurrent pneumococcal infection after allogeneic HSCT. PMID- 29512244 TI - Comparison of outcomes with vancomycin or metronidazole for mild-to-moderate Clostridium difficile associated diarrhea among solid organ transplant recipients: A retrospective cohort study. AB - BACKGROUND: Current guidelines recommend oral vancomycin or fidaxomicin for the treatment of mild-to-moderate Clostridium difficile associated diarrhea (CDAD), while metronidazole is recommended as an alternative when oral vancomycin and fidaxomicin are unavailable. However, data are lacking among the solid organ transplant (SOT) population. METHODS: This single center, retrospective cohort study evaluated adult SOT recipients with mild-to-moderate CDAD. Analysis 1 evaluated patients receiving initial therapy with metronidazole vs oral vancomycin for at least 72 hours. Analysis 2 evaluated patients receiving metronidazole vs oral vancomycin for at least 70% of the treatment duration. The primary outcome was treatment failure. Secondary outcomes included CDAD recurrence and all-cause mortality. RESULTS: Analysis 1 included 71 patients (metronidazole n = 50, oral vancomycin n = 21) and analysis 2 included 75 patients (metronidazole n = 42, oral vancomycin n = 33). No significant differences in C. difficile risk factors were observed between groups in either analysis. However, in both analyses, more patients in the oral vancomycin arm received antibiotics during the CDAD episode (analysis 1, 52% vs 26%, P = .03; analysis 2, 55% vs 32%, P < .01). Neither analysis demonstrated differences in treatment failure (analysis 1, metronidazole 16%, oral vancomycin 10%, P = .71; analysis 2, metronidazole 2%, oral vancomycin 6%, P = .58). CDAD recurrence and all-cause mortality were similar across groups in both analyses. CONCLUSIONS: Results suggest that both metronidazole and oral vancomycin are reasonable options for the treatment of mild-to-moderate CDAD in patients with SOT. No difference in treatment failure was observed; however, oral vancomycin may be preferred for higher risk patients, such as those receiving concurrent antibiotics. PMID- 29512245 TI - A Multi-signal Fluorescent Probe with Multiple Binding Sites for Simultaneous Sensing of Cysteine, Homocysteine, and Glutathione. AB - A novel fluorescent probe was developed by integrating chlorinated coumarin and benzothiazolylacetonitrile and exploited for simultaneous detection of cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). Featuring four binding sites and different reaction mechanisms for different biothiols, this probe exhibited rapid fluorescence turn-on for distinguishing Cys, Hcy, and GSH with 108-, 128-, 30-fold fluorescence increases at 457, 559, 529 nm, respectively, across different excitation wavelengths. Furthermore, the probe was successfully applied to the fluorescence imaging of endogenous Cys and GSH and exogenous Cys, Hcy, and GSH in living cells. PMID- 29512246 TI - Vertical 1T-TaS2 Synthesis on Nanoporous Gold for High-Performance Electrocatalytic Applications. AB - 2D metallic TaS2 is acting as an ideal platform for exploring fundamental physical issues (superconductivity, charge-density wave, etc.) and for engineering novel applications in energy-related fields. The batch synthesis of high-quality TaS2 nanosheets with a specific phase is crucial for such issues. Herein, the successful synthesis of novel vertically oriented 1T-TaS2 nanosheets on nanoporous gold substrates is reported, via a facile chemical vapor deposition route. By virtue of the abundant edge sites and excellent electrical transport property, such vertical 1T-TaS2 is employed as high-efficiency electrocatalysts in the hydrogen evolution reaction, featured with rather low Tafel slopes ~67-82 mV dec-1 and an ultrahigh exchange current density ~67.61 uA cm-2 . The influence of phase states of 1T- and 2H-TaS2 on the catalytic activity is also discussed with the combination of density functional theory calculations. This work hereby provides fundamental insights into the controllable syntheses and electrocatalytic applications of vertical 1T-TaS2 nanosheets achieved through the substrate engineering. PMID- 29512247 TI - A 61-year-old man with erythematous forearm papules three months after liver transplantation. AB - A 61-year-old Caucasian man presented with papules on his left forearm and hand three months after liver transplantation: images from physical exam, pathology, and microbiology are presented. Skin biopsy confirmed the presence of fungal elements within the hair shaft, which is consistent with Majocchi granuloma, also known as nodular granulomatous perifolliculitis. A combination of fungal culture, microscopic morphology, and gene sequencing was used to identify the causative organism. The patient recovered with appropriate systemic antifungal therapy. PMID- 29512248 TI - Consumer input into health care: Time for a new active and comprehensive model of consumer involvement. AB - BACKGROUND: To ensure the provision of patient-centred health care, it is essential that consumers are actively involved in the process of determining and implementing health-care quality improvements. However, common strategies used to involve consumers in quality improvements, such as consumer membership on committees and collection of patient feedback via surveys, are ineffective and have a number of limitations, including: limited representativeness; tokenism; a lack of reliable and valid patient feedback data; infrequent assessment of patient feedback; delays in acquiring feedback; and how collected feedback is used to drive health-care improvements. OBJECTIVES: We propose a new active model of consumer engagement that aims to overcome these limitations. This model involves the following: (i) the development of a new measure of consumer perceptions; (ii) low cost and frequent electronic data collection of patient views of quality improvements; (iii) efficient feedback to the health-care decision makers; and (iv) active involvement of consumers that fosters power to influence health system changes. PMID- 29512250 TI - An Easily Accessible Ionic Aggregation-Induced Emission Luminogen with Hydrogen Bonding-Switchable Emission and Wash-Free Imaging Ability. AB - Ionic fluorophores are powerful tools for the study of environmental science and bio-imaging. However, traditional ionic dyes usually require long synthetic steps and suffer from a quenching effect caused by aggregation. A water-soluble ionic aggregation-induced emission luminogen called DBTA is presented, which is readily accessed by a one-step reaction. The switchable emission manipulated by hydrogen bonding provided solid evidence for the restriction of intramolecular motions as the mechanism of aggregation-induced emission. DBTA can not only differentiate solvents with different H-bond donor acidities but also capable of wash-free imaging in living HeLa cells and fish larva. PMID- 29512249 TI - Low-dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti-thymocyte globulin. AB - BACKGROUND: Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. OBJECTIVE: We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. METHODS: Hundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900 mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450 mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis. RESULTS: All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P = .001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients. CONCLUSIONS: The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis. PMID- 29512251 TI - Thirty-day outcomes in Indigenous Australians following coronary artery bypass grafting. AB - BACKGROUND: Indigenous Australians have higher rates of cardiovascular disease and comorbidities compared to their non-indigenous counterparts. AIMS: We sought to evaluate whether indigenous status per se portends a worse prognosis following isolated coronary artery bypass grafting (CABG). METHODS: The outcomes of 778 Indigenous Australians (55 +/- 10 years; 32% female) enrolled in the Australian and New Zealand Society of Cardiac and Thoracic Surgeons registry were compared to 36 124 non-Indigenous Australians (66 +/- 10 years; 21% female) following isolated CABG. In a secondary analysis, patients were propensity-matched by age, sex, renal function, diabetes and ejection fraction (778 individuals in each group). RESULTS: Indigenous Australians were younger and more likely to be female and current smokers and to have diabetes, hypertension, renal impairment, heart failure and previous CABG (all P < 0.04). Indigenous patients had fewer bypasses with arterial conduits (including less internal mammary artery use) and a higher number of distal vein anastomoses (P < 0.001). Postoperative bleeding rates were higher in indigenous patients (P = 0.001). However, in-hospital and 30-day all cause mortality and rates of 30-day readmission were similar between both groups, although cardiac mortality was higher in the indigenous cohort (1.5% vs 0.8%, P = 0.02). With propensity-matching, rates of postoperative complications were similar among the two groups, with the exception of bleeding, which remained higher in Indigenous Australians (P = 0.03). CONCLUSIONS: Despite procedural differences and higher rates of baseline comorbidities, Indigenous Australians do not have worse short-term outcomes following isolated CABG. Given the higher rates of baseline comorbidities and lower rates of arterial conduit use, it will be essential to determine long-term outcomes. PMID- 29512252 TI - Decarboxylative Benzylation of Aryl and Alkenyl Boronic Esters. AB - The copper-catalyzed decarboxylative benzylation of aryl and alkenyl boronic esters with electron-deficient aryl acetates is reported. The oxidative coupling proceeds under mild, aerobic conditions and tolerates a host of potentially reactive electrophilic functional groups that would be problematic with traditional benzylation methods (aryl iodides and bromides, protic heteroatoms, aldehydes, Michael acceptors). A reaction pathway in which a benzylic nucleophile is generated by aryl acetate decarboxylation and in turn is intercepted by the catalyst to form diarylmethane products is supported by mechanistic studies. PMID- 29512253 TI - Palladium-Catalyzed Enantioselective C-H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization. AB - The first example of PdII -catalyzed enantioselective C-H olefination with non chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity (up to 99 %) through both desymmetrization and parallel kinetic resolution (PKR). This is the first report of PdII -catalyzed enantioselective C(sp2 )-H functionalization through PKR, and it represents a novel strategy to construct sulfur chiral centers. PMID- 29512254 TI - Formation of Agostic Structures Driven by London Dispersion. AB - Agostic interactions between a C-H bond and a transition metal are commonly crucial in catalytic polymerization processes. Herein, a quantitative study of the nature of beta-agostic interactions in a series of systems of importance in C H bond activation reactions is reported. The analysis, characterized by the use of a coupled-cluster-based energy decomposition scheme, demonstrates that short range London dispersion between the agostic C-H bond and the metal center plays a fundamental role in affecting the structural stability of these systems, contrary to a widely held view. These results are used to rationalize a series of previously published experimental findings. PMID- 29512255 TI - Differences among patients with Alzheimer's disease, older adults with mild cognitive impairment and healthy older adults in finger dexterity. AB - AIM: We have developed a smart terminal device for screening finger function, and investigated the capability of this tool for detecting abnormalities of finger dexterity. METHODS: Finger dexterity was measured for 31 patients with Alzheimer's disease (AD group), 15 people diagnosed with mild cognitive impairment (MCI group) and 48 family members (healthy older adult group) as the control. Cognitive function was assessed using the Mini-Mental State Examination. RESULTS: There were significant differences between the AD and control group in response time, rhythm and contact duration (P <= 0.05), and a negative correlation was identified between contact duration and Mini-Mental State Examination score (-0.36 to -0.5; P <= 0.05). Also, there were significant differences between the AD and MCI group in response time and contact duration (P <= 0.05). DISCUSSION: These results show that declines in finger dexterity can reflect declining cognitive function, and that measurement of finger dexterity using our smart terminal device can facilitate screening of large groups for MCI or AD. Geriatr Gerontol Int 2018; 18: 907-914. PMID- 29512256 TI - Ibuprofen reduces cell proliferation through inhibiting Wnt/beta catenin signaling pathway in gastric cancer stem cells. AB - Nowadays, most studies focused on cancer stem cells (CSCs) through their abilities to cause tumorigenicity, drug resistance, and cancer recurrence. On the other side, nonsteroidal anti-inflammatory drugs (NSAIDs) have been taken into consideration because of cheapness and availability. For the reasons mentioned above, we have studied the effect of ibuprofen as an NSAID on CSCs derived from AGS and MKN-45 gastric cancer cell lines to perform effective cancer therapy. We evaluated cell viability, spheroid body formation, monolayer, and soft agar colony formation to express the anti-cancer effect of ibuprofen on CSCs. Also, real-time RT-PCR data of stemness markers and genes affected on, or downstream of Wnt signaling pathway were evaluated. Our findings suggest that ibuprofen at 1,000 MUM for 48 h can reduce cell proliferation, stemness features in CSCs by changing the expression level of CD44, OCT3/4, SOX2, Nanog, and KLF4 as stemness markers. Furthermore, ibuprofen can have an inhibitory role in Wnt signaling pathway by changing the expression level of some genes, including CTNNB1, CTNNBIP1, SMARCD1, PYGO2, SUFU, CASK, and KREMEN1. According to our study, ibuprofen has an anti-proliferative effect on CSCs derived from AGS and MKN-45 cells. PMID- 29512257 TI - Down-regulation of the non-coding RNA H19 and its derived miR-675 is concomitant with up-regulation of insulin-like growth factor receptor type 1 during neural like differentiation of human bone marrow mesenchymal stem cells. AB - The differentiation of human bone marrow mesenchymal stem cells (BMSCs) into specific lineages offers new opportunities to use the therapeutic efficiency of these pluripotent cells in regenerative medicine. Multiple lines of evidence have revealed that non-coding RNAs play major roles in the differentiation of BMSCs into neural cells. Here, we applied a cocktail of neural inducing factors (NIFs) to differentiate BMSCs into neural-like cells. Our data demonstrated that during neurogenic induction, BMSCs obtained a neuron-like morphology. Also, the results of gene expression analysis by qRT-PCR showed progressively increasing expression levels of neuron-specific enolase (NSE) as well as microtubule-associated protein 2 (MAP-2) and immunocytochemical staining detected the expression of these neuron specific markers along differentiated BMSC bodies and cytoplasmic processes, confirming the differentiation of BMSCs into neuronal lineages. We also compared differences in the expression levels of the long non-coding RNA (lncRNA) H19 and H19-derived miR-675 between undifferentiated and neurally differentiated BMSCs and found that during neural differentiation down-regulation of the lncRNA H19/miR-675 axis is concomitant with up-regulation of insulin-like growth factor type-1 (IGF-1R), a well-established target of miR-675 involved in neurogenesis. The findings of the current study provide support for the hypothesis that miR-675 may confer functionality to H19, suggesting a key role for this miRNA in the neural differentiation of BSMCs. However, further investigation is required to gain deeper insights into the biological roles of this miRNA in the complex process of neurogenesis. PMID- 29512258 TI - Fifth Chinese National Consensus Report on the management of Helicobacter pylori infection. AB - BACKGROUND: Since the 'Fourth Chinese National Consensus Report on the management of H. pylori infection' was published in 2012, three important consensuses (Kyoto global consensus report on H. pylori gastritis, The Toronto Consensus for the Treatment of H. pylori Infection in Adults and Management of H. pylori infection the Maastricht V/Florence Consensus Report) have been published regarding the management of H. pylori infection. MATERIALS AND METHODS: A Delphi method was adopted to develop the consensus of relevant 'statements'. First, the established 'statements' were sent to experts via email. Second, after undergoing two rounds of consultation, the initial statements were discussed face to face and revised in the conference item by item on 16 December 2016. Finally, 21 core members of conferees participated in the final vote of statements. Voting for each statement was performed using an electronic system with levels of agreements shown on the screen in real time. RESULTS: Consensus contents contained a total of 48 "statements" and related 6 parts, including indications for H. pylori eradication, diagnosis, treatment, H. pylori and gastric cancer, H. pylori infection in special populations, H. pylori and gastrointestinal microbiota. CONCLUSIONS: Recommendations are provided on the basis of the best available evidence. PMID- 29512260 TI - Catalytic Asymmetric [2+3] Cyclizations of Azlactones with Azonaphthalenes. AB - The first catalytic asymmetric [2+3] cyclization of azlactones with azonaphthalenes has been established. This strategy allowed the synthesis of a variety of chiral isatin derivatives in generally good yields and excellent enantioselectivities (up to 99 % yield, 98 % ee). The developed reaction has not only established a catalytic enantioselective [2+3] cyclization using azlactones as two-carbon building blocks, but also enriches the chemistry of catalytic asymmetric cyclizations of azonaphthalenes. In addition, this protocol will provide a useful method for constructing enantioenriched 3,3'-disubstituted isatin-type frameworks. PMID- 29512259 TI - Prevalence of diabetes in Australia: insights from the Fremantle Diabetes Study Phase II. AB - BACKGROUND: Accurate diabetes prevalence estimates are important for health service planning and prioritisation. Available data have limitations, suggesting that the contemporary burden of diabetes in Australia is best assessed from multiple sources. AIMS: To use systematic active detection of diabetes cases in a postcode-defined urban area through the Fremantle Diabetes Study Phase II (FDS2) to complement other epidemiological and survey data in estimating the national prevalence of diabetes and its types. METHODS: People with known diabetes in a population of 157 000 were identified (n = 4639) from a variety of sources and those providing informed consent (n = 1668 or 36%) were recruited to the FDS2 between 2008 and 2011. All FDS2 participants were assigned a type of diabetes based on clinical and laboratory (including serological and genetic) features. Data from people identified through the FDS2 were used to complement Australian Health Survey and National Diabetes Services Scheme prevalence estimates (the proportions of people well controlled on no pharmacotherapy and registering with the National Diabetes Services Scheme respectively) in combination with Australian Bureau of Statistics data to generate the prevalence of diabetes in Australia. RESULTS: Based on data from multiple sources, 4.8% or 1.1 million Australians had diabetes in 2011-2012, of whom 85.8% had type 2 diabetes, 7.9% type 1 diabetes and 6.3% other types (latent autoimmune diabetes of adults, monogenic diabetes and secondary diabetes). CONCLUSIONS: Approximately 1 in 20 Australians has diabetes. Although most have type 2 diabetes, one in seven has other types that may require more specialised diagnosis and/or management. PMID- 29512261 TI - Initial experience with robotic hepatectomy in Singapore: analysis of 48 resections in 43 consecutive patients. AB - BACKGROUND: Presently, the adoption of laparoscopic hepatectomy is rapidly increasingly worldwide. However, the application of robotic hepatectomy (RH) remains limited and its role remains undefined today. METHODS: A retrospective review of 43 consecutive patients who underwent RH at two institutions in the Singapore Health Services Group. RESULTS: Forty-three consecutive patients underwent 48 resections during the study period. Seven (16.3%) patients underwent major resections and seven (16.3%) underwent right posterior sectionectomies. Nineteen (44.2%) patients had tumours located in the difficult posterosuperior segments, five had multiple resections and three underwent repeat resections for recurrent tumours. RH was performed for malignant tumours in 32 (74%) patients and 16 (37.2%) had cirrhosis. Seven RH was performed with other concomitant procedures including three colectomies, three hilar lymphadenectomies and one portal vein ligation. The median operation time was 360 min (range 75-825) and the median blood loss was 300 mL (range 25-4500). There was one (2.3%) open conversion for bleeding. The median post-operative stay was 4 days (range 2-33) and there was one (2.3%) readmission. There was one (2.3%) major (>grade 2 morbidity) in a patient with concomitant anterior resection who underwent reoperation for anastomotic leak. There was no 90 day/in-hospital mortality. Comparison between RH for tumours in the anterolateral segments versus posterosuperior segments demonstrated no significant difference in perioperative outcomes. CONCLUSION: Our initial experience demonstrated that RH is safe, feasible and associated with excellent post-operative outcomes. It can be performed successfully with low morbidity even for complex resections such as major hepatectomies, posterior sectionectomies, tumours in difficult posterosuperior segments and repeat liver resections. PMID- 29512262 TI - An Ethylenediamine-based Switch to Render the Polyzwitterion Cationic at Tumorous pH for Effective Tumor Accumulation of Coated Nanomaterials. AB - Polyzwitterions are employed as coating polymers for biomaterials to induce an antifouling property on the surface. Fine-tuning the betaine structure switches the antifouling property to be interactive with anionic tissue constituents in response to a tumorous pH gradient. The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the di-protonation process around tumorous pH (6.5). The net charge of the developed polyzwitterion (PGlu(DET-Car)) was thus neutral at pH 7.4 for antifouling, but was cationic at pH 6.5 for interaction with anionic constituents. Quantum dots coated with PGlu(DET-Car) exhibited comparable stealth and enhanced tumor accumulation relative to the PEG system. The present study provides a novel design of smart switchable polyzwitterion based on a precise control of the net charge. PMID- 29512263 TI - Risk of sudden sensorineural hearing loss in adults using phosphodiesterase type 5 inhibitors: Population-based cohort study. AB - PURPOSE: The objective of the study was to determine the risk of sudden sensorineural hearing loss (SNHL) associated with use of phosphodiesterase type 5 (PDE5) inhibitors. METHODS: We conducted a retrospective cohort study in the MarketScan Commercial Claims and Encounters Database including adult men who initiated a PDE5 inhibitor (n = 377,722) and 1,957,233 nonusers between 1998 and 2007. Periods of drug exposure were assessed on a weekly basis based on pharmacy billing records, assuming use of 1 dose per week (current use). Incident sudden SNHL was defined based on inpatient or outpatient visits with International Classification of Diseases, Ninth Revision, Clinical Modification codes 389.1x, 389.2x, or 388.2 plus >=2 procedure codes for audiometric hearing testing within +/-30 days of sudden SNHL diagnosis. We used age- and propensity score-adjusted Cox proportional hazards model to evaluate the risk of sudden SNHL during periods of current or recent use compared with that of nonuse. We conducted sensitivity analyses by varying the assumed drug utilization frequency and sudden SNHL case definition. RESULTS: We evaluated 1233 sudden SNHL cases, resulting in an incidence of 4.35, 5.58, and 2.38 per 10,000 person-years for current, recent, and nonuse of PDE5 inhibitors, respectively. Compared with nonuse, the adjusted hazard ratio was 1.25 (1.01-1.55) for current use with a risk difference of 1.97 (1.12-2.82) per 10,000 person-years. For recent use, the adjusted hazard ratio was 1.60 (1.33-1.94) and risk difference was 3.19 (2.24-4.14). Estimates were consistent across the sensitivity analyses. CONCLUSIONS: Use of PDE5 inhibitors is associated with a small but significantly increased risk of sudden SNHL. PMID- 29512264 TI - Small dense low-density lipoprotein cholesterol is a promising biomarker for secondary prevention in older men with stable coronary artery disease. AB - AIM: The study objective was to investigate whether small dense low-density lipoprotein cholesterol (sdLDL-C) is superior to low-density lipoprotein cholesterol (LDL-C) and other biomarkers to predict future cardiovascular events (CE) in secondary prevention. METHODS: sdLDL-C measured by a homogeneous assay, remnant lipoprotein cholesterol, LDL particle diameter and other biomarkers were compared in 345 men aged >=65 years with stable coronary artery disease. Baseline LDL-C was 100.5 +/- 30.1 mg/dL. CE including cardiovascular death, onset of acute coronary syndrome, need for arterial revascularization, hospitalization for heart failure, surgery procedure for cardiovascular disease and hospitalization for stroke were monitored for 5 years. RESULTS: CE occurred in 96 patients during the study period. LDL-C, sdLDL-C non-high-density lipoprotein cholesterol, apolipoprotein B, remnant lipoprotein cholesterol, glucose, glycated hemoglobin and brain natriuretic peptide were significantly higher; LDL particle diameter and apolipoprotein A-1 were significantly lower in patients with than in those without CE. Age-adjusted Cox regression analysis showed that sdLDL-C per 10 mg/dL, but not LDL-C, was significantly associated with CE (HR 1.206, 95% CI 1.006-1.446). A significant association of sdLDL-C and incident CE was observed in statin users (HR 1.252, 95% CI 1.017-1.540), diabetes patients (HR 1.219, 95% CI 1.018-1.460), patients without diabetes (HR 1.257, 95% CI 1.019-1.551) and patients with hypertriglyceridemia (HR 1. 376, 95% CI 1.070-1.770). CONCLUSIONS: sdLDL-C was the most effective predictor of residual risk of future CE in stable coronary artery disease patients using statins and in high-risk coronary artery disease patients with diabetes or hypertriglyceridemia. Geriatr Gerontol Int 2018; 18: 965-972. PMID- 29512265 TI - Relationship between number of drugs and duration of hospital stay in older patients with neuromuscular diseases. AB - AIM: Older patients are considered to be at high risk for developing adverse drug reactions (ADR), because they commonly receive multidrug therapy despite changes in pharmacokinetic function with age. In the present study, we assessed the relationship between the number of prescribed drugs and the incidence of ADR or the time to discharge in older patients with neuromuscular disease. METHODS: A retrospective study was carried out among 135 older patients (aged >=65 years) who were admitted to the neurology ward from October 2007 through December 2011. Drugs that possess a high risk for initiation of grade >=2 ADR were determined using logistic regression analysis. RESULTS: A total of 38 patients (28.1%) experienced grade >=2 ADR. Multivariate logistic regression analysis showed that corticosteroids, antibiotics, enteric nutrients and insulin were significant risks for grade >=2 ADR. Notably, the time to discharge extended as the grade of ADR increased, with mean values of 24.4 days for grade 0, 38.3 days for grade 1, 47.5 days for grade 2 and 73.1 days for grade 3-4 events. Furthermore, the number of high-risk drugs for grade >=2 ADR correlated well with the incidence of grade >=2 events (R = 0.964, P = 0.008), as well as with the time to discharge (R = 0.473, P < 0.001). CONCLUSIONS: Older patients receiving multidrug therapy using corticosteroids, antibiotics, enteric nutrients, or insulin were at high risk for grade >=2 ADR and prolongation of hospital stay. Geriatr Gerontol Int 2018; 18: 1018-1024. PMID- 29512266 TI - Will teenagers today live with and care for their aged parents tomorrow? AB - AIMS: Older adults who live alone are vulnerable physically, emotionally and socially. However, there is a trend towards children not living with their parents. We studied the willingness of teenagers today to live with and care for their aged parents tomorrow, and the reasons for their decision. METHODS: A convenient sample of 1405 teenage students (M age = 14.9 +/- 1.30) in the north region of Singapore completed a purpose-designed questionnaire. Structural equation modeling was used to explore the relationships between teenagers' closeness to grandparents, challenges faced living with grandparents, positive and negative perceptions towards aging, and willingness to stay with aged parents in the future, stratified by sex. Thematic analysis was used to understand the reasons for their choice. RESULTS: The majority (85.6%) chose to live with their parents, and the significant predictors were "closeness to grandparents" (P = 0.034) and "positive perceptions towards aging" (P < 0.01), but not "challenges in living with grandparents" (P = 0.391) or "negative perceptions" (P = 0.302). Among teenagers with positive perceptions, boys were more likely to live with their parents (P < 0.01). Conversely, among teenagers with negative perceptions, girls were more likely to do so (P = 0.026). Primary reasons for willingness included: "desire to care," "expression of love," "sense of responsibility" and "prompted by moral values." CONCLUSIONS: Efforts should be undertaken to strengthen teenagers' relationships with grandparents, and promote positive perceptions towards aging to better sustain the family as a social safety net for aging and frail older adults. Geriatr Gerontol Int 2018; 18: 957-964. PMID- 29512267 TI - Characterization of an Anthracene Intermediate in Dynemicin Biosynthesis. AB - Despite the identification of a beta-hydroxyhexaene produced by the enediyne polyketide synthases (PKSs), the post-PKS biosynthetic steps to the individual members of this antitumor and antibiotic family remain largely unknown. The massive biosynthetic gene clusters (BGCs) that direct the formation of each product caution that many steps could be required. It was recently demonstrated that the enediyne PKS in the dynemicin A BGC from Micromonospora chersina gives rise to both the anthraquinone and enediyne halves of the molecule. We now present the first evidence for a mid-pathway intermediate in dynemicin A biosynthesis, an iodoanthracene bearing a fused thiolactone, which was shown to be incorporated selectively into the final product. This unusual precursor reflects just how little is understood about these biosynthetic pathways, yet constrains the mechanisms that can act to achieve the key heterodimerization to the anthraquinone-containing subclass of enediynes. PMID- 29512268 TI - Telechelic, Antimicrobial Hydrophilic Polycations with Two Modes of Action. AB - Telechelic antimicrobial poly(2-oxazoline)s with quaternary ammonium (quat) end groups are shown to be potent antimicrobial polymers against Gram-positive bacterial strains. In this study, the activity against the Gram-negative bacterium Escherichia coli is additionally implemented by hydrolyzing the poly(2 methyl-2-oxazoline) with two quart end groups to poly(ethylene imine) (PEI). The resulting telechelic polycations are active against Staphylococcus aureus and E. coli. The contribution of the PEI backbone is determined by measuring the antimicrobial activity in the presence of calcium ions. The influence of PEI on the overall activity strongly depends on the molecular weight and increases with higher mass. The PEI dominates the activity against E. coli at lower masses than against S. aureus. The quart end groups require an alkyl substituent of dodecyl or longer to dominate the antimicrobial activity. Additionally, PEI and quart end groups act synergistically. PMID- 29512269 TI - From gene to structure: Lactobacillus bulgaricus D-lactate dehydrogenase from yogurt as an integrated curriculum model for undergraduate molecular biology and biochemistry laboratory courses. AB - We have developed an integrated, project-oriented curriculum for undergraduate molecular biology and biochemistry laboratory courses spanning two semesters that is organized around the ldhA gene from the yogurt-fermenting bacterium Lactobacillus bulgaricus, which encodes the enzyme d-lactate dehydrogenase. The molecular biology module, which consists of nine experiments carried out over eleven sessions, begins with the isolation of genomic DNA from L. bulgaricus in yogurt and guides students through the process of cloning the ldhA gene into a prokaryotic expression vector, followed by mRNA isolation and characterization of recombinant gene expression levels using RT-PCR. The biochemistry module, which consists of nine experiments carried out over eight sessions, begins with overexpression of the cloned ldhA gene and guides students through the process of affinity purification, biochemical characterization of the purified LdhA protein, and analysis of enzyme kinetics using various substrates and an inhibitor, concluding with a guided inquiry investigation of structure-function relationships in the three-dimensional structure of LdhA using molecular visualization software. Students conclude by writing a paper describing their work on the project, formatted as a manuscript to be submitted for publication in a scientific journal. Overall, this curriculum, with its emphasis on experiential learning, provides hands-on training with a variety of common laboratory techniques in molecular biology and biochemistry and builds experience with the process of scientific reasoning, along with reinforcement of essential transferrable skills such as critical thinking, information literacy, and written communication, all within the framework of an extended project having the look and feel of a research experience. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):270-278, 2018. PMID- 29512270 TI - Re: Pregnancy-associated plasma protein-A is positively correlated with first trimester skin microvascular reactivity. C. Iacobaeus, T. Kahan, G. Jorneskog, K. Bremme, E. Andolf and M. Thorsell. Ultrasound Obstet Gynecol 2018; 51: 361-367. PMID- 29512271 TI - Reply. PMID- 29512272 TI - 3D to boldly go where no 2D has gone before? Pitfalls in 3D reconstruction of the fetal palate. PMID- 29512273 TI - Reply. PMID- 29512274 TI - Re: Cavum septi pellucidi (CSP) ratio: a marker for partial agenesis of the fetal corpus callosum. PMID- 29512275 TI - Reply. PMID- 29512276 TI - Re: Impaired maternal hemodynamics in morbidly obese women: a case-control study. PMID- 29512277 TI - Re: Predicting delivery of a small-for-gestational-age infant and adverse perinatal outcome in women with suspected pre-eclampsia. M. Griffin, P. T. Seed, S. Duckworth, R. North, J. Myers, L. Mackillop, N. Simpson, J. Waugh, D. Anumba, L. C. Kenny, C. W. G. Redman, A. H. Shennan and L. C. Chappell. Ultrasound Obstet Gynecol 2018; 51: 387-395. PMID- 29512278 TI - Common germline haplotypes and genotypes identified in BRCA2 exon 11 of dogs with mammary tumours and histopathological analyses. AB - The canine BRCA2 is a tumor supressor gene which encodes the BRCA2 protein, involved in DNA repair through interaction with the RAD51 recombinase. This process is mediated by eigth BRC repeats that are encoded by BRCA2 exon 11. Two variants corresponding to human mutations in human BRC3 repeat have been reported in canine BRC3 repeat. In addition, other variants have also been described in canine BRCA2 exon 11. Considering the importance of polymorphisms in human BRCA2 to breast cancer development, this study aimed to investigate the frequency of variants in BRCA2 exon 11 in 48 blood and tissue DNA samples from bitches with canine mammary tumors (CMT), as well as, to analyze tumor stage and histopathological features. Seven Single Nucleotide Polymorphisms (SNPs) were identified, three of which were evaluated as possibily or probably deleterious variant. Interestingly, almost all the 22 mammary tumors (except one) which presented a clinical staging equal to or greater than III carried at least one mutant allele of these three variants. Besides that, no statistically significant correlation was observed between any of the reported SNPs in heterozygosis or homozygosis and either dogs data (such as breed, age or disease stage) or mammary tumors histopathological characteristics. A total of 97.9% of bitches had one to three polymorphisms of the seven identified in this study, which suggests a possibly correlation between the canine BRCA2 exon 11 polymorphisms and mammary carcinogenesis. PMID- 29512279 TI - A course-based undergraduate research experience investigating the consequences of nonconserved mutations in lactate dehydrogenase. AB - There is a growing movement to involve undergraduate students in authentic research experiences. A variety of studies have indicated the strength of this approach in developing scientific aptitude, confidence, critical thinking skills, and increasing the likelihood to become career scientists. Course-based undergraduate research experiences (CUREs) foster opportunities for students to carry out authentic research at both primarily undergraduate and large research institutions. Here, we describe a novel CURE-based biochemistry laboratory course to explore the consequences of mutagenesis of non-conserved amino acid sites in the structure and function of the lactate dehydrogenase enzyme and demonstrate how collaborations between institutions can facilitate real research experiences at any type of institution. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):285-296, 2018. PMID- 29512281 TI - Determinants of health-related quality of life among outpatients with acute coronary artery disease after percutaneous coronary intervention. AB - AIM: This study aimed to identify health-related quality of life (HRQoL) and its determinants in outpatients with acute coronary syndrome (ACS) after percutaneous coronary intervention. METHODS: A cross-sectional design was used and a total of 124 Korean participants was enrolled. The HRQoL (physical limitations, treatment satisfaction, and disease perception), symptom experience (frequency, severity, and distress), physiological (left ventricular ejection fraction and lipids), psychological (depression and anxiety), and situational (social support) factors were measured, selected on the basis of the theory of unpleasant symptoms. The HRQoL was assessed by using the Seattle Angina Questionnaire-Korean, designed to evaluate disease-specific health outcomes in patients with coronary artery disease. Descriptive statistics and multiple linear regression analyses were conducted. RESULTS: The mean age of the participants was 61.73 years. The HRQoL was moderate. Among the HRQoL domains, disease perception showed the lowest level. The most intense symptoms that were experienced by the participants were fatigue, shortness of breath, and chest discomfort. More than half of the participants had depression and anxiety. The determinants of worse HRQoL were severe symptom experience, higher depression, higher low-density lipoprotein cholesterol, a lower educational level, and lower social support. CONCLUSION: This study proposes a comprehensive approach to health care that incorporates symptom experience, as well as the physiological, psychological, and situational aspects based on the theory of unpleasant symptoms, to improve the HRQoL among outpatients with ACS. Nurses should play a key role to help patients with ACS to deal with the symptoms, low-density lipoprotein cholesterol, and depression and to promote social support, particularly in less-educated patients, in order to improve their HRQoL. PMID- 29512280 TI - Reduction in mortality associated with secondary cytomegalovirus prophylaxis after solid organ transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) is the most important viral pathogen in solid organ transplant (SOT) recipients. The role of secondary CMV prophylaxis in this population remains unclear. METHODS: Retrospective cohort study in a single center. SOT recipients treated for CMV infection from 2007 to 2014 were studied to determine the efficacy and safety of secondary prophylaxis and its impact on graft loss and mortality. The outcome variable was CMV replication in the first 3 months after the end of therapy. Secondary variables were crude mortality and graft lost censored at 5 years after transplantation. Propensity score for the use of secondary prophylaxis was used to control selection bias. RESULTS: Of the 126 treated patients, 103 (83.1%) received CMV secondary prophylaxis. CMV relapse occurred in 44 (35.5%) patients. The use of secondary prophylaxis was not associated with fewer relapses (34.0% in patients with prophylaxis vs 42.9% in those without prophylaxis, P = .29). After a mean follow-up of 32.1 months, graft loss was not different between both groups but patient mortality was significantly lower in patients who received secondary prophylaxis (5.8% vs 28.6%, P = .003). CONCLUSION: Secondary prophylaxis did not prevent CMV infection relapse but it was associated with improved patient survival. PMID- 29512282 TI - A randomized, placebo-controlled phase I trial of live, attenuated herpes zoster vaccine in subjects with end-stage renal disease immunized prior to renal transplantation. AB - BACKGROUND: Solid organ transplant recipients are at increased risk for reactivation of herpes zoster, or shingles, and have a higher frequency of serious complications including post-herpetic neuralgia. A live, attenuated shingles vaccine is effective and approved for individuals 50 years and older. The vaccine is contraindicated following transplantation, but may be used in patients with renal failure. Utilization of the vaccine has been poor in patients with end-stage renal disease, including those awaiting transplant, owing to concerns for safety, efficacy, and potential sensitization prior to transplant. METHODS: We conducted a phase I, randomized, placebo-controlled study of the safety and immunogenicity of live, attenuated Oka strain shingles vaccine in subjects prior to or awaiting renal transplant at 3 US centers. Subjects received vaccine a minimum of 4 weeks prior to transplant. RESULTS: The vaccine was safe and well-tolerated. There were no cases of herpes zoster or rash illness. There was no change in donor-specific antibody or calculated panel reactive antibody after vaccination during the follow-up period. There were no rejection episodes. There was a significant 2.1-fold rise in geometric mean titer of anti-VZV antibody at 5 weeks post-vaccine. CONCLUSIONS: The data suggest that the shingles vaccine is safe in subjects with ESRD awaiting transplant. Antibody responses were similar to those seen previously in adults >50 years of age and are consistent with a protective response. PMID- 29512285 TI - Blood biomarkers for neuropsychiatric diseases. PMID- 29512284 TI - The chaperone protein HSP47: a platelet collagen binding protein that contributes to thrombosis and hemostasis. AB - : Essentials Heat shock protein 47 (HSP47), a collagen specific chaperone is present on the platelet surface. Collagen mediated platelet function was reduced following blockade or deletion of HSP47. GPVI receptor regulated signalling was reduced in HSP47 deficient platelets. Platelet HSP47 tethers to exposed collagen thus modulating thrombosis and hemostasis. SUMMARY: Objective Heat shock protein 47 (HSP47) is an intracellular chaperone protein that is vital for collagen biosynthesis in collagen secreting cells. This protein has also been shown to be present on the surface of platelets. Given the importance of collagen and its interactions with platelets in triggering hemostasis and thrombosis, in this study we sought to characterize the role of HSP47 in these cells. Methods and Results The deletion of HSP47 in mouse platelets or its inhibition in human platelets reduced their function in response to collagen and the GPVI agonist (CRP-XL), but responses to thrombin were unaltered. In the absence of functional HSP47, the interaction of collagen with platelets was reduced, and this was associated with reduced GPVI-collagen binding, signalling and platelet activation. Thrombus formation on collagen, under arterial flow conditions, was also decreased following the inhibition or deletion of HSP47, in the presence or absence of eptifibatide, consistent with a role for HSP47 in enhancing platelet adhesion to collagen. Platelet adhesion under flow to von Willebrand factor was unaltered following HSP47 inhibition. Laser-induced thrombosis in cremaster muscle arterioles was reduced and bleeding time was prolonged in HSP47-deficient mice or following inhibition of HSP47. Conclusions Our study demonstrates the presence of HSP47 on the platelet surface, where it interacts with collagen, stabilizes platelet adhesion and increases collagen-mediated signalling and therefore thrombus formation and hemostasis. PMID- 29512287 TI - Mindfulness-based weekend retreats for people bereaved by suicide (Panta Rhei): A pilot feasibility study. AB - OBJECTIVES: This study investigates whether a programme of mindfulness-based weekend retreats (Panta Rhei) is able to improve mood states, mindfulness qualities, and self-compassion in family members and friends of suicide victims (suicide survivors). DESIGN: Longitudinal prospective study. METHODS: Sixty-one suicide survivors participated in a mindful-self-compassion retreat. The Five Facet Mindfulness Questionnaire, the Profile of Mood States (POMS), and the Self Compassion Scale were administered 4-6 days before and after the retreat. RESULTS: A significant reduction in all dimensions of the POMS (except Vigor Activity) and lower levels of overidentification were observed after the retreat. CONCLUSIONS: Although further research is warranted, this study highlights the potential beneficial effect of brief mindfulness-based weekend retreats on the well-being of suicide survivors. PRACTITIONER POINTS: Mindfulness-based weekend retreats seem to be effective in alleviating the psychological distress of suicide survivors in the short term. The benefit may depend on standard mindfulness practices and on more tailored interventions aimed at promoting acceptance of loss, forgiveness and rage management, and thus reducing rumination. Since there is no established treatment for this population, this type of intervention, which seems feasible and well accepted by participants, paves the way for future research in this area. PMID- 29512286 TI - Transthyretin Mimetics as Anti-beta-Amyloid Agents: A Comparison of Peptide and Protein Approaches. AB - beta-Amyloid (Abeta) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Abeta agents. We developed two compounds based on the Abeta-binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Abeta, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of alpha-synuclein. They both bind more Abeta aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Abeta binding to human neurons. When mTTR was co-incubated with Abeta under oligomer-forming conditions, Abeta morphology was drastically changed and Abeta-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Abeta deposited. These results provide guidance for further evolution of TTR mimetic anti-amyloid agents. PMID- 29512288 TI - Expectations vs reality: The expectations and experiences of psychiatric treatment reported by young adults at a mood and anxiety outpatient mental health program. AB - AIM: To compare young adults' expectations of psychiatric treatment to their actual experiences and identify myths and assumptions that youth might hold prior to receiving care. METHODS: We interviewed youth who engaged in at least 4 months of treatment at the First Episode Mood and Anxiety Program to theme saturation (N = 20). They were asked about their experience of treatment and the expectations they had prior to care. Transcribed interviews were analysed for themes. RESULTS: Results indicated that participants often expected a cold, serious atmosphere, a "quick fix," and a directive therapeutic relationship. Although most patients had a negative experience at some point in their care, they overall described a welcoming environment with engaged providers and a collaborative therapeutic relationship. Participants found treatment more complex than they had anticipated, but ultimately experienced strengthening of agency and a change in perspective. CONCLUSIONS: These results identify a need to recognize assumptions held by young adults seeking treatment for mental health symptoms. Addressing these preconceptions might reduce apprehension and improve readiness for treatment. This research provides direction on how to dispel myths and better prepare youth for the work involved in effective psychiatric care. PMID- 29512289 TI - Disseminated blastomycosis in a transplant patient. AB - A 51-year-old woman from Wisconsin with past medical history of kidney transplantation from her sibling 8 weeks prior, presented with symptoms of shortness of breath, cough, and a new skin rash over a 2-week period. PMID- 29512290 TI - Underdiagnosed and undertreated psoriasis: Nuances of treating psoriasis affecting the scalp, face, intertriginous areas, genitals, hands, feet, and nails. AB - Psoriasis of the scalp, face, intertriginous areas, genitals, hands, feet, and nails is often underdiagnosed, and disease management can be challenging. Despite the small surface area commonly affected by psoriasis in these locations, patients have disproportionate levels of physical impairment and emotional distress. Limitations in current disease severity indices do not fully capture the impact of disease on a patient's quality of life, and, combined with limitations in current therapies, many patients do not receive proper or adequate care. In this review, we discuss the clinical manifestations of psoriasis in these less commonly diagnosed areas and its impact on patient quality of life. We also examine clinical studies evaluating the effectiveness of therapies on psoriasis in these regions. This article highlights the need to individualize treatment strategies for psoriasis based on the area of the body that is affected and the emerging role of biologic therapy in this regard. PMID- 29512291 TI - Healthcare providers' experiences of assessing and performing oral care in older adults. AB - AIMS AND OBJECTIVES: The purpose of this study was to describe healthcare providers' experiences, knowledge and attitudes in relation to the assessment of oral health in older adults. BACKGROUND: Oral health is an important element in the care of older adults. An increasing proportion of older people need the help and support of community-based healthcare services, which are responsible for providing oral health assessment for this group. Although oral care is an important part of nursing care, studies show that it is often an overlooked area in the care of older people. DESIGN: An inductive qualitative description design was used. METHODS: The participating healthcare providers were selected from a municipality in western Sweden. Purposeful sampling was employed and data were collected through focus-group interviews and were analysed with content analysis. RESULTS: The analysis resulted in four categories: healthcare providers' knowledge and attitudes to oral health; routines affect flexibility; challenges in assessing and performing oral care and ethical dilemmas. The results showed that oral health was neglected because of several factors. Lack of knowledge, inadequate procedures and time constraints were most prominent. The healthcare providers' own attitudes affected the performing of oral health assessments. Ethical dilemmas related to the attitudes of those people in receipt of care and their relatives, and their integrity and autonomy, could be seen as complicating factors. CONCLUSIONS: The healthcare providers expressed that they did not have the necessary knowledge of oral health that was required in their area of responsibility. In addition, they described their own attitudes as being important when attending to the patients' oral health. IMPLICATIONS FOR PRACTICE: The healthcare providers themselves identified lack of knowledge and their own attitudes as being especially important factors in the oral care of older adults, and further research in this area is needed. PMID- 29512292 TI - Platelet function testing: dead or alive. AB - : Essentials Pharmacodynamic response to antiplatelet medication is heterogeneous. Platelet reactivity to dual antiplatelet therapy was analyzed by three platelet function assays. The prevalence of high and low platelet reactivity differed significantly between assays. Future trials are needed to determine the best assay to analyze platelet function. SUMMARY: Background High on-treatment platelet reactivity (HTPR) to antiplatelet medication leads to ischemic events, whereas low on-treatment platelet reactivity (LTPR) increases bleeding risk. However, various trials have failed to demonstrate superiority of tailored antiplatelet regimens (ARCTIC, ANTARCTIC, Trigger-PCI, and GRAVITAS). TROPICAL-ACS was the first study that demonstrated the benefit of tailoring antiplatelet medication according to platelet function analysis. A potential reason may be that different platelet function assays were used in these trials. Objectives To evaluate whether the results of platelet function tests are comparable. Patients/Methods We tested three commonly used assays - light transmission aggregometry (LTA), (Multiplate impedance aggregometry [MP]), and vasodilator-stimulated phosphoprotein phosphorylation assay (VASP) - in 23 patients receiving dual antiplatelet therapy with aspirin and clopidogrel. Results With LTA, HTPR occurred in 57% of patients; with VASP, it occurred in 43% of patients; and with MP, it occurred in 13% of patients. According to LTA, only 35% of patients were in the therapeutic window; according to VASP, 57% of patients were in the therapeutic window; and according to MP, 48% of patients were in the therapeutic window. With LTA, LTPR occurred in 9% of patients; with VASP, it occurred in 0% of patients; and with MP, it occurred in 39% of patients. Therefore, the prevalences of HTPR and LTPR differed significantly between assays. Remarkably, in 17% of patients, one assay showed HTPR whereas another showed LTPR. Conclusions The results of different platelet function assays differ substantially. Up to now, only TROPICAL-ACS had demonstrated a benefit of tailoring antiplatelet medication according to platelet function analysis. Future trials are needed to evaluate whether the platelet function assay used in TROPICAL-ACS is the 'correct' one and revives platelet function testing. PMID- 29512293 TI - Adaptation to acute pulmonary hypertension in pigs. AB - The extent of right ventricular compensation compared to the left ventricle is restricted and varies among individuals, which makes it difficult to define. While establishing a model of acute pulmonary hypertension in pigs we observed two different kinds of compensation in our animals. Looking deeper into the hemodynamic data we tried to delineate why some animals could compensate and others could not. Pulmonary hypertension (mean pressure 45 mmHg) was induced gradually by infusion of a stable thromboxane A2 analogue U46619 in a porcine model (n = 22). Hemodynamic data (pressure-volume loops, strain-analysis of echocardiographic data and coronary flow measurements) were evaluated retrospectively for the short-term right ventricular compensatory mechanisms and limits (Roehl et al. [2012] Acta Anaesthesiol. Scand., 56:449-58) 10 animals showed stable arterial blood pressures, whereas 12 pigs exhibited a significant drop of 16.4 +/- 9.9 mmHg. Cardiac output and heart rate were comparable in both groups. In contrast, right ventricular contractility and coronary flow only rose in the stable group. The unchanging values in the decrease group correlated with an increasing ST-segment depression and a loss of ventricular synchronism and resulted in a larger septum bulging to the right ventricle. Simultaneously, a reduced left-ventricular end-diastolic volume and a missing improvement in contractility in the posterior septal and inferior free wall of the left ventricle have been observed. Our findings suggest that right ventricular compensation during acute pulmonary hypertension is strongly dependent on the individual capability to increase coronary flow. The cause for inter-individual variability could be the dimension and reactivity of the coronary system. PMID- 29512294 TI - Nomograms forecasting long-term overall and cancer-specific survival of patients with oral squamous cell carcinoma. AB - Our aim was to establish a "nomogram" model to forecast the overall survival (OS) and cancer-specific survival (CSS) of oral squamous cell carcinoma (OSCC) patients. The clinicopathological data for the 10,533 OSCC patients were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used a credible random split-sample method to divide 10,533 patients into two cohorts: 7046 patients in the modeling cohort and 3487 patients in the external validation cohort (split-ratio = 2:1). The median follow-up period was 32 months (1-119 months). We developed nomograms to predict 5- and 8-year OS and CSS of OSCC patients with a Cox proportional hazards model. The precision of the nomograms was assessed by the concordance index (C-index) and calibration curves through internal and external validation. The C-indexes of internal validation regarding 5- and 8-year OS and CSS were 0.762 and 0.783, respectively. In addition, the external validation's C-indexes were 0.772 and 0.800. Based on a large-sample analysis targeting the SEER database, we established two nomograms to predict long-term OS and CSS for OSCC patients successfully, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations. PMID- 29512295 TI - Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings. AB - The principal symptoms of Huntington's disease (HD), chorea, cognitive deficits, and psychiatric symptoms are associated with the massive loss of striatal and cortical projection neurons. As current drug therapies only partially alleviate symptoms, finding alternative treatments has become peremptory. Cell replacement using stem cells is a rapidly expanding field that offers such an alternative. In this review, we examine recent studies that use mesenchymal cells, as well as pluripotent, cell-derived products in animal models of HD. Additionally, we provide further electrophysiological characterization of a human neural stem cell line, ESI-017, which has already demonstrated disease-modifying properties in two mouse models of HD. Overall, the field of regenerative medicine represents a viable and promising avenue for the treatment of neurodegenerative disorders including HD. PMID- 29512296 TI - Formation of Supramolecular Nanotubes by Self-assembly of a Phosphate-linked Dimeric Anthracene in Water. AB - The assembly of supramolecular polymers from a phosphodiester-linked dimeric anthracene is described. AFM and TEM imaging reveals that the supramolecular polymers self-assemble into nanotubes in water. Subsequent photodimerization experiments indicate that the supramolecular polymerization occurs via end-to-end stacking rather than an interdigitation arrangement of the building blocks. PMID- 29512297 TI - Tear of the entire length of the rectum with haemoperitoneum: an unusual cause of the acute abdomen. PMID- 29512298 TI - True left-sided gallbladder: a rare anatomical anomaly and its associated surgical challenges. PMID- 29512299 TI - Translocation and protein complex co-localization of mTOR is associated with postprandial myofibrillar protein synthesis at rest and after endurance exercise. AB - Translocation and colocalization of mechanistic target of rapamycin complex 1 (mTORC1) with regulatory proteins represents a critical step in translation initiation of protein synthesis in vitro. However, mechanistic insight into the control of postprandial skeletal muscle protein synthesis rates at rest and after an acute bout of endurance exercise in humans is lacking. In crossover trials, eight endurance-trained men received primed-continuous infusions of L-[ring-2 H5 ]phenylalanine and consumed a mixed-macronutrient meal (18 g protein, 60 g carbohydrates, 17 g fat) at rest (REST) and after 60 min of treadmill running at 70% VO2peak (EX). Skeletal muscle biopsies were collected to measure changes in phosphorylation and colocalization in the mTORC1-pathway, in addition to rates of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis. MyoPS increased (P < 0.05) above fasted in REST (~2.1-fold) and EX (~twofold) during the 300 min postprandial period, with no corresponding changes in MitoPS (P > 0.05). TSC2/Rheb colocalization decreased below fasted at 60 and 300 min after feeding in REST and EX (P < 0.01). mTOR colocalization with Rheb increased above fasted at 60 and 300 min after feeding in REST and EX (P < 0.01), which was consistent with an increased phosphorylation 4E-BP1Thr37/46 and rpS6ser240/244 at 60 min. Our data suggest that MyoPS, but not MitoPS, is primarily nutrient responsive in trained young men at rest and after endurance exercise. The postprandial increase in MyoPS is associated with an increase in mTOR/Rheb colocalization and a reciprocal decrease in TSC2/Rheb colocalization and thus likely represent important regulatory events for in vivo skeletal muscle myofibrillar mRNA translation in humans. PMID- 29512300 TI - Co-Evolutionary Fitness Landscapes for Sequence Design. AB - Efficient and accurate models to predict the fitness of a sequence would be extremely valuable in protein design. We have explored the use of statistical potentials for the coevolutionary fitness landscape, extracted from known protein sequences, in conjunction with Monte Carlo simulations, as a tool for design. As proof of principle, we created a series of predicted high-fitness sequences for three different protein folds, representative of different structural classes: the GA (all-alpha) and GB (alpha/beta) binding domains of streptococcal protein G, and an SH3 (all-beta) domain. We found that most of the designed proteins can fold stably to the target structure, and a structure for a representative of each for GA, GB and SH3 was determined. Several of our designed proteins were also able to bind to native ligands, in some cases with higher affinity than wild type. Thus, a search using a statistical fitness landscape is a remarkably effective tool for finding novel stable protein sequences. PMID- 29512301 TI - Differential response of adipose tissue gene and protein expressions to 4- and 8 week administration of beta-guanidinopropionic acid in mice. AB - beta-Guanidinopropionic acid (beta-GPA) feeding inhibits growth-associated gain of body mass. It remains unknown, however, whether and how beta-GPA feeding affects growth-associated increase in white adipose tissue (WAT) mass. We examined the effects of 4- and 8-week beta-GPA feeding on serum myostatin levels and expression of genes and proteins related to adipogenesis, lipolysis, and liposynthesis in epididymal WAT (eWAT) and brown adipose tissue (BAT) in 3-week old, juvenile male mice. Body, eWAT, and muscle weights were significantly lower in beta-GPA-fed mice than in controls after feeding. Four- but not 8-week-beta GPA feeding increased the serum myostatin level. Incubation of C2C12 myotubes with beta-GPA (1 mM) significantly promoted myostatin mRNA expression. The protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) and peroxisome proliferator-activated receptor alpha (PPARalpha) was up-regulated in GPAF eWAT at week 4, but down-regulated at week 8. There was no significant difference in the protein expression of adipocyte triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) between groups in eWAT. In BAT, no significant difference was found in the protein expression of PGC-1alpha, PPARalpha, ATGL, and HSL between beta-GPA-fed and control mice, whereas that of FAS and ACC was significantly lower in beta-GPA-fed mice at week 8. Uncoupling protein 1 was expressed higher in beta-GPA-fed mice both at weeks 4 and 8 than that in controls. Thus, the mechanism by which beta-GPA feeding in early juvenile mice inhibits growth-associated increase in eWAT mass may differ between early and later periods of growth. PMID- 29512302 TI - Aluminium foil as an alternative substrate for the spectroscopic interrogation of endometrial cancer. AB - Biospectroscopy has the potential to investigate and characterize biological samples and could, therefore, be utilized to diagnose various diseases in a clinical environment. An important consideration in spectrochemical studies is the cost-effectiveness of the substrate used to support the sample, as high expense would limit their translation into clinic. In this paper, the performance of low-cost aluminium (Al) foil substrates was compared with the commonly used low-emissivity (low-E) slides. Attenuated total reflection-Fourier transform infrared spectroscopy was used to analyse blood plasma and serum samples from women with endometrial cancer and healthy controls. The 2 populations were differentiated using principal component analysis with support vector machines with 100% sensitivity in plasma samples (endometrial cancer = 70; healthy controls = 15) using both Al foil and low-E slides as substrates. The same sensitivity results (100%) were achieved for serum samples (endometrial cancer = 60; healthy controls = 15). Specificity was found higher using Al foil (90%) in comparison to low-E slides (85%) and lower using Al foil (70%) in comparison to low-E slides in serum samples. The establishment of Al foil as low-cost and highly performing substrate would pave the way for large-scale, multicentre studies and potentially for routine clinical use. PMID- 29512303 TI - Occupational transmission of an Orthopoxvirus infection during an outbreak in a colony of Macaca tonkeana in Lazio Region, Italy, 2015. AB - Orthopoxviruses spill over from animal reservoirs to accidental hosts, sometimes causing human infections. We describe the surveillance and infection control measures undertaken during an outbreak due to an Orthopoxvirus occurred in January 2015 in a colony of Macaca tonkeana in the province of Rieti, Latio, Italy, which caused a human asymptomatic infection. According to the epidemiological investigation, the human transmission occurred after an unprotected exposure. The contacts among wild, captive and domestic animals and humans, together with decreased immunity against Orthopoxviruses in the community, may put animal handlers at risk of infection, especially after the cessation of smallpox vaccination. To reduce these threats, standard precautions including respiratory hygiene and transmission-based precautions should be carefully applied also in veterinary medicine. PMID- 29512304 TI - Cutaneous ulcerations caused by Paecilomyces variotii in a renal transplant recipient. AB - Skin infections caused by Paecilomyces species have been rarely described in patients with solid organ transplantation. Cutaneous manifestations are highly variable and include erythematous macules, nodules, pustules, and vesicular and necrotic lesions. The diagnosis of these infections is generally made by examination of a skin biopsy. Management of these fungal infections is difficult due to the immunocompromised state of the patients. Moreover, antifungal therapy and immunosuppressive drug interactions should be considered during treatment management. Herein, we reported a case of cellulitis caused by Paecilomyces variotii in a 56-year-old man who had undergone a kidney transplantation. Erythematous macular and nodular lesions on the left hand and left foot appeared first; within 2 months the skin lesions became ulcerated, hemorrhagic, and progressively painful and the patient was admitted to our hospital. The diagnosis was made by skin biopsy and tissue culture. The skin lesions resolved by the sixth week of the treatment with voriconazole. PMID- 29512305 TI - Financial impact and effect on the outcome of preoperative tests for at-risk older hip fracture patients. AB - AIM: Older patients with proximal femoral fractures often undergo preoperative tests due to coexisting morbidities. Our aim was to evaluate these tests and their impact on patient outcome and medical expenses. METHODS: This retrospective study includes data on head computed tomography, carotid ultrasound, echocardiography and pulmonary functional tests calculated according to the type of surgery (osteosynthesis or hip arthroplasty) carried out on 2798 patients. Time-to-surgery, test repeated postoperatively, American Society of Anesthesiology Physical Status score, additional procedures, hospitalization time, 30-day mortality and associated medical expenses were evaluated. RESULTS: A total of 921 preoperative tests were carried out in 780 (28%) patients, and 375 postoperative tests were carried out in 329 (12%) patients (P < 0.001). A total of 23 procedures were carried out after surgery, none related to the originally carried out tests. Significant group differences were found for American Society of Anesthesiology Physical Status score, days to surgery, hospitalization time (days) and mortality rates. The medical expenses of these tests were 1.3% of the average income per case, and 0.6% of the average study group income. CONCLUSIONS: Non-routine preoperative tests prolong time-to-surgery, increased hospitalization time and contribute to 30-day mortality. No postoperative procedure was related to preoperative test findings. The financial cost for these tests does not burden the medical expenses per procedure. Geriatr Gerontol Int 2018; 18: 937-942. PMID- 29512307 TI - Preparation of Optically Enriched Secondary Alkyllithium and Alkylcopper Reagents Synthesis of (-)-Lardolure and Siphonarienal. AB - Optically enriched secondary alkyl iodides were converted into secondary alkyllithium and secondary alkylcopper compounds with very high retention of configuration. Quenching with various electrophiles, including chiral epoxides, provided a range of chiral molecules with high enantiomeric purity (>90 % ee). This method has been applied in an iterative fashion in the total synthesis of ( )-lardolure in 13 steps and 5.4 % overall yield (>99 % ee, dr>99:1) and siphonarienal in 15 steps and 5.6 % overall yield (>99 % ee, dr>99:1) starting from commercially available ethyl (R)-3-hydroxybutyrate (>99 % ee). PMID- 29512306 TI - Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin-3 down-regulation. AB - BACKGROUND: A global consensus on the loss of skeletal muscle mass and function in humans refers as sarcopenia and cachexia including diabetes, obesity, renal failure, and osteoporosis. Despite a current improvement of sarcopenia or cachexia with exercise training and supportive therapies, alternative and specific managements are needed to discover for whom are unable or unwilling to embark on these treatments. Alendronate is a widely used drug for osteoporosis in the elderly and postmenopausal women. Osteopenic menopausal women with 6 months of alendronate therapy have been observed to improve not only lumbar bone mineral density but also handgrip strength. However, the effect and mechanism of alendronate on muscle strength still remain unclear. Here, we investigated the therapeutic potential and the molecular mechanism of alendronate on the loss of muscle mass and strength in vitro and in vivo. METHODS: Mouse myoblasts and primary human skeletal muscle-derived progenitor cells were used to assess the effects of low-dose alendronate (0.1-1 MUM) combined with or without dexamethasone on myotube hypertrophy and myogenic differentiation. Moreover, we also evaluated the effects of low-dose alendronate (0.5 and 1 mg/kg) by oral administration on the limb muscle function and morphology of mice with denervation-induced muscle atrophy and glycerol-induced muscle injury. RESULTS: Alendronate inhibited dexamethasone-induced myotube atrophy and myogenic differentiation inhibition in mouse myoblasts and primary human skeletal muscle derived progenitor cells. Alendronate significantly abrogated dexamethasone-up regulated sirtuin-3 (SIRT3), but not SIRT1, protein expression in myotubes. Both SIRT3 inhibitor AKG7 and SIRT3-siRNA transfection could also reverse dexamethasone-up-regulated atrogin-1 and SIRT3 protein expressions. Animal studies showed that low-dose alendronate by oral administration ameliorated the muscular malfunction in mouse models of denervation-induced muscle atrophy and glycerol-induced muscle injury with a negative regulation of SIRT3 expression. CONCLUSIONS: The putative mechanism by which muscle atrophy was improved with alendronate might be through the SIRT3 down-regulation. These findings suggest that alendronate can be a promising therapeutic strategy for management of muscle wasting-related diseases and sarcopenia. PMID- 29512308 TI - Oral contraceptives augment the exercise pressor reflex during isometric handgrip exercise. AB - We sought to determine whether oral contraception alters the gender-related differences observed in the exercise pressor reflex during isometric handgrip exercise. Fifteen men, fifteen normally menstruating women (WomenNM), and fifteen women taking monophasic oral contraceptives (WomenOC) completed two trials of a 3 min isometric handgrip exercise protocol performed at 30% of their maximal voluntary contraction: (1) where arterial occlusion was applied to the previously exercising arm during a 3-min recovery period (Occlusion trial); (2) where no arterial occlusion was applied during recovery (Control trial). Handgrip exercise elicited greater increases in mean arterial pressure (MAP) in MEN compared to both female groups (P < 0.05), and in WomenOC compared to WomenNM in both trials (P = 0.01, P = 0.03). After 3 min of recovery, sBP was 12% (P = 0.01) and 9% (P = 0.02) higher in the Occlusion trial when compared to the Control trial for MEN and WomenOC. Conversely, arterial occlusion in recovery from handgrip did not sustain elevated sBP in the Occlusion trial, and sBP returned to recovery levels not different to the Control trial, in WomenNM (P = 0.41). These data indicate that gender-related differences in the metaboreflex during isometric handgrip exercise exist between men and normally menstruating women, but are blunted when men are compared to women taking oral contraceptives. We conclude that the suppression of 17beta-estradiol and/or progestogen in women via the administration of oral contraceptives attenuates sex-related differences in the metaboreflex during isometric handgrip exercise. PMID- 29512309 TI - Appearance of reassortant European avian-origin H1 influenza A viruses of swine in Vietnam. AB - Three subtypes-H1N1, H1N2 and H3N2-of influenza A viruses of swine (IAVs-S) are currently endemic in swine worldwide, but there is considerable genotypic diversity among each subtype and limited geographical distribution. Through IAVs S monitoring in Vietnam, two H1N2 influenza A viruses were isolated from healthy pigs in Ba Ria-Vung Tau Province, Southern Vietnam, on 2 December 2016. BLAST and phylogenetic analyses revealed that their HA and NA genes were derived from those of European avian-like H1N2 IAVs-S that contained avian-origin H1 and human-like N2 genes, and were particularly closely related to those of IAVs-S circulating in the Netherlands, Germany or Denmark. In addition, the internal genes of these Vietnamese isolates were derived from human A(H1N1)pdm09 viruses, suggesting that the Vietnamese H1N2 IAVs-S are reassortants between European H1N2 IAVs-S and human A(H1N1)pdm09v. The appearance of European avian-like H1N2 IAVs-S in Vietnam marks their first transmission outside Europe. Our results and statistical analyses of the number of live pigs imported into Vietnam suggest that the European avian-like H1N2 IAVs-S may have been introduced into Vietnam with their hosts through international trade. These findings highlight the importance of quarantining imported pigs to impede the introduction of new IAVs-S. PMID- 29512311 TI - Nitrite as a pharmacological intervention for the successful treatment of crush syndrome. AB - Crush syndrome is characterized by ischemia/reperfusion injury (IRI). The protective effect of nitrite on experimentally induced IRI has been demonstrated in the heart, kidney, liver, and skeletal muscle. IRI in tissues and systemic organs occurs due to the massive generation of reactive oxygen species and subsequent systemic inflammation. Therefore, ischemic pre and postconditioning are performed in clinical practice. Intravenous administration of nitrite inhibits IRI through nitric oxide-mediated mechanisms. In this paper, we discuss the utility of nitrite as a pharmacological postconditioning agent in the treatment of crush syndrome. PMID- 29512310 TI - Caffeine consumption disrupts hippocampal long-term potentiation in freely behaving rats. AB - Caffeine, one of the most commonly consumed psychoactive substances in the world, has long been known to alter neurological functions, such as alertness, attention, and memory. Despite caffeine's popularity, systematic investigations of its effects on synaptic plasticity in the brain are still lacking. Here we used a freely behaving rodent model of long-term potentiation (LTP), a frequently studied form of synaptic plasticity, to assess the effects of caffeine consumption on hippocampal plasticity. LTP, which is a persistent increase in the strength of synaptic connections between neurons, is a cellular mechanism widely considered to underlie the processes of learning and memory. A group of 10-week old Sprague-Dawley rats were administered caffeine (1 g/L) in their drinking water 3 weeks prior to collection of electrophysiological data. Another group of age-matched animals received tap water and served as controls. Stimulating and recording electrodes were chronically implanted in the perforant pathway (PP) and dentate gyrus (DG) region of the hippocampus, respectively, to permit stable electrophysiological recordings of synaptic transmission at this synapse. Population spike amplitude (PSA) measures of LTP induction and duration were acquired in vivo while animals were freely behaving using a well-established electrophysiological recording protocol. Results indicate caffeine-treated rats (n = 9) had a significantly (P < 0.05) reduced level of LTP induction compared with controls (n = 10). More studies are needed to identify the exact mechanism through which caffeine alters LTP induction in this freely behaving model of synaptic plasticity. PMID- 29512312 TI - Discharges from an early intervention in psychosis service: The effect of patient characteristics on discharge destination. AB - AIM: The present study aimed to determine the influence of demographic and clinical features on the likelihood of patients being discharge to primary vs secondary care. The overarching aim of this service evaluation is to assess factors affecting discharge and determine important modulators of discharge destination to inform care planning in services. METHOD: Clinical and demographic data were extracted from patient notes of those discharged from the Psychosis Intervention and Early Recovery (PIER) service in Leicestershire between January 2005 and December 2013. A total of 508 records were analysed and logistic regression was used to assess the impact of diagnostic, demographic and other clinical factors on the discharge destination of patients. RESULTS: Of the 508 patients, 241 (47.44%) had been discharged to primary care and 267 (52.55%) to secondary psychiatric services. The factors which increased the likelihood of patients being discharged to secondary care were diagnoses of enduring psychoses, being referred from inpatient services and longer time spent with the PIER team. CONCLUSIONS: Diagnosis and duration of treatment were significant predictors of discharge destination. Patients with diagnoses of enduring psychotic illness, were more likely to be discharged to a secondary psychiatric service irrespective of gender, ethnicity and geographical location. These data may suggest the possibility to predict the discharge destination when patients are taken on to the caseload of an early intervention in psychosis (EIP) team and have important implications for psychoeducation, preparing the patient for future after EIP and distribution of resources. PMID- 29512313 TI - Pb2 BO3 I: A Borate Iodide with the Largest Second-Harmonic Generation (SHG) Response in the KBe2 BO3 F2 (KBBF) Family of Nonlinear Optical (NLO) Materials. AB - Borate halides are an ideal materials class from which to design high-performance nonlinear optical (NLO) materials. Currently, borate fluorides, chlorides, and bromides are extensively investigated while borate iodide materials discovery remains rare because of the perceived synthetic challenges. We report a new borate iodide, Pb2 BO3 I, synthesized by a straightforward hydrothermal method. The Pb2 BO3 I chemical formula conceals that the compound exhibits a structure similar to the well-established KBe2 BO3 F2 (KBBF), which we show supports the highest second-harmonic generation (SHG) at 1064 nm in the KBBF family, 10 * KH2 PO4 (KDP), arising from the inclusion of Pb2+ and I- and the crystal chemistry. Our work shows that KBBF-related compounds can be synthesized incorporating iodide and exhibit superior NLO responses. PMID- 29512314 TI - Exploring functional impairment in young people at ultra-high risk for psychosis: A qualitative study. AB - AIM: Many young people at ultra-high risk (UHR) of developing psychosis exhibit marked and persistent impairments in social and occupational functioning. We aimed to explore UHR patients' subjective experiences of these difficulties and their causes. METHODS: We conducted semi-structured interviews with 20 UHR individuals recruited from Early Detection and Intervention Teams in Northwest England. Topics covered included how participants spent their time, their interpersonal relationships, academic and occupational performance, premorbid functioning and clinical treatment. Thematic analysis was used to examine the prevailing themes. RESULTS: The sample included individuals with varying degrees of functional impairment, ranging from mild to severe difficulties in functioning. Analysis of the qualitative data elicited themes around 2 topics: breadth of functional difficulties and subjective reasons for poor functioning. Participants reported a range of impairments in their social and occupational functioning which they attributed to a combination of clinical, cognitive and psychological factors. These included variables previously identified in the quantitative literature such as psychiatric symptoms, adverse life experiences and cognitive deficits. However, our findings also included other factors which have received comparably little attention such as self-stigmatizing attitudes and dysfunctional metacognitive beliefs. CONCLUSIONS: We propose a model that attempts to explain how these variables interact to drive and sustain functional impairment in the UHR population. This will assist in the development of clinical interventions aimed at promoting functional recovery among UHR individuals. PMID- 29512315 TI - Vascular risk factors for male and female urgency urinary incontinence at age 68 years from a British birth cohort study. AB - OBJECTIVE: To investigate the prevalence of urgency urinary incontinence (UUI) at age 68 years and the contribution of vascular risk factors to male and female UUI pathogenesis in addition to the associations with raised body mass index (BMI). SUBJECTS AND METHODS: In all, 1 762 participants from the Medical Research Council (MRC) National Survey for Health and Development birth cohort who answered the International Consultation on Incontinence Questionnaire short form (ICIQ-SF), at age 68 years, were included. Logistic regression was used to estimate associations between UUI and earlier life vascular risk factors including: lipid status, diabetes, hypertension, BMI, previous stroke or transient ischaemic attack (TIA) diagnosis; adjusting for smoking status, physical activity, co-presentation of stress UI symptoms, educational attainment; and in women only, type of menopause, age at period cessation, and use of hormone replacement therapy (HRT). RESULTS: UUI was reported by 12% of men and 19% of women at age 68 years. Female sex, previous stroke or TIA diagnosis, increased BMI and hypertension (in men only) at age 60-64 years were independent risk factors for UUI. Female sex, increased BMI, and a previous diagnosis of stroke/TIA increased the relative risk of more severe UUI symptoms. Type and timing of menopause and HRT use did not alter the estimated associations between UUI and vascular risk factors in women. CONCLUSION: Multifactorial mechanisms lead to UUI and vascular risk factors may contribute to the pathogenesis of bladder overactivity in addition to higher BMI. Severe UUI appears to be a distinct presentation with more specific contributory mechanisms than milder UUI. PMID- 29512317 TI - Will a chlorhexidine-fluoride mouthwash reduce plaque and gingivitis? AB - FOCUS QUESTION: What is the efficacy of a chlorhexidine (CHX) mouthwash (MW) containing sodium fluoride (NaF) compared to a CHX - MW alone on the parameters of plaque, gingivitis and discoloration? MATERIAL AND METHODS: MEDLINE-PubMed, Cochrane-CENTRAL, and EMBASE were searched for papers from inception to December 2017. The inclusion criteria were (randomized) controlled clinical trials conducted in human subjects with good general health and without removable prosthesis. Papers evaluating the effect of a MW containing CHX + NaF compared to a CHX alone were included. From the eligible studies, data were extracted, a descriptive analysis was performed and a meta-analysis when feasible. RESULTS: Independent screening of 412 unique papers resulted in 9 eligible publications presenting 10 clinical trials comparing the effect of CHX + NaF to CHX - MW and provided 13 comparisons. Five evaluated the MW as an adjunct to brushing and 8 were non-brushing comparisons of which 4 used an experimental gingivitis model. No significant difference was observed for plaque score reduction in the brushing studies the end scores (diffM; -0.04, P = .36; 95%CI: [-0.13, 0.05]) nor the differences (diffM; 0.11, P = .33; 95%CI: [-0.12, 0.24]). In the descriptive analysis, none of the experiments demonstrated a statistical significant difference regarding Gingival Index (GI), Bleeding Score and Discoloration Scores. For the GI, a meta-analysis of the difference of Means was not significant when included experimental gingivitis model studies end scores (0.01, P = .78; 95%CI: [-0.08, 0.11]) and the difference (0.01, P = .81; 9 5%CI: [-0.08, 0.10]) either for the end scores of brushing studies (diffM; -0.01, P = .82; 95%CI: [-0.10, 0.08]). CONCLUSION: From this study, it can be concluded that NaF and CHX may be present in the same MW without reducing CHX efficacy with respect to plaque and gingivitis scores. Moreover, no difference in the development of tooth discoloration was observed. PMID- 29512316 TI - Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence-based lens. AB - : Based on prediction models and expert opinion, most obstetric venous thromboembolism guidelines recommend low-molecular-weight heparin for many postpartum women, including most delivering by caesarean. Scrutiny reveals major oversights: prediction models are based on studies that report asymptomatic deep vein thrombosis; risk estimates are not adjusted for time exposure; and harm caused by heparin has been overlooked. The benefits of heparin are exaggerated and its harms are under-appreciated. Estimates of the numbers-needed-to-treat and harm are universally lacking. This paper critically reviews the evidence and quantifies the benefit and harm from low-molecular-weight heparin in postpartum women with common risk factors. FUNDING: This work was unsponsored and unfunded. TWEETABLE ABSTRACT: Randomised trials should demonstrate more benefit than harm before widespread postpartum low-molecular-weight heparin is recommended. PMID- 29512319 TI - Author reply. PMID- 29512318 TI - Prevalence of restless legs syndrome in a tertiary cohort of ambulant patients with chronic liver disease. AB - A cross-sectional survey of 188 ambulant patients with chronic liver disease was performed to determine the prevalence of restless legs syndrome (RLS) using a validated patient completed questionnaire. Patient responses were verified by standardised telephone interview. RLS was identified in 64 (34%) patients. Significantly, more patients with cirrhosis had RLS than patients without RLS (43.9 vs 23.3%, P = 0.003, respectively). Cirrhotic patients with a history of hepatic encephalopathy were also more likely to have RLS than patients without hepatic encephalopathy (odds ratio = 4.33, 95% confidence interval = 1.40-13.37, P = 0.011). Patients with chronic liver disease may be at risk for RLS; early detection and treatment may improve patient outcomes. PMID- 29512320 TI - Severe methanol poisoning with neurological sequelae: implications for diagnosis and management. AB - A 22-year-old woman presented with methanol toxicity manifesting as headache, reduced conscious state and visual change after consuming home-made grappa. She progressed to a coma with fixed mydriasis and severe acidaemia (pH 6.55). She was treated with empirical antidote administration (intravenous ethanol) and enhanced elimination through haemodialysis. She survived despite her delayed presentation but developed significant neurological sequelae, including visual impairment. We provide an overview of key elements of diagnosis and recent updates in treatment recommendations. PMID- 29512321 TI - More needs to be spent on hepatitis C treatment, not less. PMID- 29512322 TI - Routine vaccinations as a precipitant of adrenal crisis in adrenal insufficiency. PMID- 29512323 TI - A case of malignant hypertension with thrombotic microangiopathy. PMID- 29512324 TI - Depression and suicide among medical practitioners in Australia. AB - This review will provide an overview of the prevalence of, and risk factors for, depression and suicide in medical practitioners. It will also discuss the barriers to accessing appropriate care and potential interventions for this population. PMID- 29512325 TI - Use of extracorporeal membrane oxygenation in cystic fibrosis in an Australian cystic fibrosis centre. AB - Extracorporeal membrane oxygenation (ECMO) support is used in selected patients with cystic fibrosis (CF) as a bridge to transplantation. Our aim was to describe briefly treatment and outcomes of six CF patients who received ECMO. One patient received a lung transplant and another recovered from acute respiratory failure. Four died despite ECMO support. Lack of timely availability of suitable donor lungs and patient selection are contributing factors. PMID- 29512326 TI - Dapsone-induced drug reaction with eosinophilia and systemic symptoms associated with HLA-B*13:01. PMID- 29512327 TI - P-value. What value? PMID- 29512328 TI - National Disability Insurance Scheme, health, hospitals and adults with intellectual disability. AB - Preventable poor health outcomes for adults with intellectual disability in health settings have been known about for years. Subsequent analysis and the sorts of reasonable adjustments required in health and disability support settings to address these health gaps are well described, but have not really been embedded in practice in any significant way in either setting. As far as health is concerned, implementation of the National Disability Insurance Scheme (NDIS, the Scheme) affords an opportunity to recognise individual needs of people with intellectual disability to provide reasonable and necessary functional support for access to mainstream health services, to build capacity of mainstream health providers to supply services and to increase individual capacity to access services. Together these strands have potential to transform health outcomes. Success of the Scheme, however, rests on as yet incompletely defined operational interaction between NDIS and mainstream health services and inherently involves the disability sector. This interaction is especially relevant for adults with intellectual disability, known high users of hospitals and for whom hospital outcomes are particularly poor and preventable. Keys to better hospital outcomes are first, the receiving of quality person-centred healthcare from physicians and hospitals taking into account significance of intellectual disability and second, formulation of organised quality functional supports during hospitalisation. Achieving these require sophisticated engagement between consumers, the National Disability Insurance Agency, Commonwealth, State and Territory government leaders, senior hospital and disability administrators, NDIS service providers and clinicians and involves cross fertilisation of values, sharing of operational policies and procedures, determination of boundaries of fiscal responsibility for functional supports in hospital. PMID- 29512329 TI - Results of a 10-year follow-up study of botulinum toxin A therapy for primary axillary hyperhidrosis in Australia. AB - Primary hyperhidrosis has a prevalence of 3-5% in the United States. It is a psychosocially disabling condition leading to low self-esteem, chronic stress and depressive symptoms. Several medical and surgical treatments exist, including botulinum toxin A, which internationally, has been shown effectively and safely to treat this condition achieving high patient satisfaction. In Australia, botulinum toxin A has been available under the Medicare benefits scheme for axillary hyperhidrosis since 2013, but efficacy and treatment satisfaction had not been evaluated. We present the results of the first Australian study on efficacy and patient satisfaction with botulinum toxin A in primary axillary hyperhidrosis with evaluation of possible prognostic factors. PMID- 29512330 TI - Pituitary surgery in Australia: time to address the elephant in the room. PMID- 29512332 TI - Laparoscopic management of gastric perforation secondary to mesenteroaxial volvulus in a patient with laparoscopic adjustable gastric banding. AB - A 54-year-old woman was admitted to the emergency department with a 2-week history of alimentary vomiting. She had undergone laparoscopic adjustable gastric banding 6 years earlier. CT revealed a mesenteroaxial gastric volvulus and ischemia on the gastric wall. Emergent diagnostic laparoscopy was performed, and severe peritonitis and gastric necrosis caused by volvulation was found. After band removal, a fundal perforation was noted, but a viable lesser curvature enabled laparoscopic sleeve gastrectomy to be performed. The postoperative course was uneventful. Laparoscopic adjustable gastric banding is considered a safe and effective method for the surgical treatment of obesity, but it is associated with a number of complications, such as pouch dilatation and band slippage. Although infrequent, ischemic complications are life-threatening conditions that require urgent surgery. This is the first report of this unusual complication managed laparoscopically. PMID- 29512331 TI - Dentinogenesis imperfecta type II- genotype and phenotype analyses in three Danish families. AB - BACKGROUND: Dentinogenesis imperfecta (DI) is a rare debilitating hereditary disorder affecting dentin formation and causing loss of the overlying enamel. Clinically, DI sufferers have a discolored and weakened dentition with an increased risk of fracture. The aims of this study were to assess genotype phenotype findings in three families with DI-II with special reference to mutations in the DSPP gene and clinical, histological, and imaging manifestations. METHODS: Nine patients participated in the study (two from family A, four from family B, and three from family C). Buccal swab samples were collected from all participants and extracted for genomic DNA. Clinical and radiographic examinations had been performed longitudinally, and the dental status was documented using photographic images. Four extracted and decalcified tooth samples were prepared for histological analysis to assess dysplastic manifestations in the dentin. Optical coherence tomography (OCT) was applied to study the health of enamel tissue from in vivo images and the effect of the mutation on the function and structure of the DSPP gene was analyzed using bioinformatics software programs. RESULTS: The direct DNA sequence analysis revealed three distinct mutations, one of which was a novel finding. The mutations caused dominant phenotypes presumably by interference with signal peptide processing and protein secretion. The clinical and radiographic disturbances in the permanent dentition indicated interfamilial variability in DI II manifestations, however, no significant intrafamilial variability was observed. CONCLUSION: The different mutations in the DSPP gene were accompanied by distinct phenotypes. Enamel defects suggested deficit in preameloblast function during the early stages of amelogenesis. PMID- 29512333 TI - Study design and baseline characteristics of inpatients with diabetes mellitus in a tertiary hospital in China: A database study based on electronic medical records. AB - AIM: To describe the characteristics of inpatients with diabetes in a tertiary hospital in China using an electronic medical record (EMR)-based database. METHODS: We identified the medical records of all patients with diabetes from nonpediatric departments of West China Hospital, Sichuan University (from February 2009 to December 2013), and extracted information on demographic, diagnosis, discharge outcome, department of discharge, laboratory test, and prescription from the EMR system. The quality of the database was assessed by analyzing missing data and extreme data and by reviewing the International Classification of Diseases 10th Revision (ICD-10) coding. RESULTS: Among 683,267 discharged patients, 56,784 (8.3%) patients diagnosed with diabetes were identified from all departments. Among the patients with diabetes, the average age was 63.5 +/- 13.1 years and the overall death in hospital was 2.2%. Laboratory test results were highly completed in our database with no extreme or discrepant value identified. Anthropometric parameters were of a relatively low quality as 62.2% body-mass index data were missing. HbA1c levels at admission were available for 36.7% patients with diabetes. The ICD-10 coding of the diagnosis of diabetes was accurate in 88.6% records reviewed. Dyslipidemia (76.5%), hypertension (51.3%), chronic kidney disease (22.1%), and hyperuricemia (16.2%) were the most commonly presented comorbidities among inpatients with diabetes. CONCLUSIONS: Our study indicated a wide distribution of diabetes throughout the inpatients in a tertiary hospital in southwest China. This EMR based database of diabetes could be potentially useful in further investigations. PMID- 29512334 TI - Causes of Death in Rheumatoid Arthritis: How Do They Compare to the General Population? AB - OBJECTIVE: To compare mortality rates, underlying causes of death, excess mortality, and years of potential life lost (YPLL) among patients with rheumatoid arthritis (RA) relative to the general population. METHODS: We studied an inception cohort of 87,114 Ontario-based RA patients and 348,456 age/sex/area matched general population comparators from years 2000 to 2013. All-cause, cause specific, and excess mortality rates, mortality rate ratios (MRRs), and the YPLL were estimated. RESULTS: A total of 11,778 RA patients (14%) and 32,472 comparators (9%) died during 508,385 and 1,769,365 patient-years of follow-up, respectively, for corresponding mortality rates of 232 (95% confidence interval [95% CI] 228-236) and 184 (95% CI 182-186) per 10,000 patient-years. The leading causes of death in both groups were diseases of the circulatory system, cancer, and respiratory conditions. Increased mortality for all-cause and specific causes was observed in RA patients relative to the general population. MRRs were elevated for most causes of death. Age-specific mortality ratios illustrated a high excess mortality among RA patients <45 years of age for respiratory disease and circulatory disease. The YPLL for RA patients was 7,436 per 10,000 persons, compared with 4,083 YPLL among those without RA. CONCLUSION: Among most causes of death, mortality rates were increased in RA patients relative to the general population. The potential life years lost (before the age of 75 years) among RA patients was roughly double that among those without RA, reflecting higher rate ratios for most causes of death and RA patients dying at earlier ages. PMID- 29512335 TI - Synthesis of a Bis-Urea Dimer and Its Effects on the Physical Properties of an Amphiphilic Tris-Urea Supramolecular Hydrogel. AB - The successful development of stiff supramolecular gels is an important goal toward their practical application. One approach to stiffen supramolecular gels is to introduce covalent cross-links. The bis-urea dimer 2, having a structure similar to that of the low-molecular-weight gelator 1, was synthesized. Supramolecular hydrogels were formed from mixtures of 1 and 2 in appropriate ratios, with 2 acting as a covalent cross-linker to connect the fibrous aggregates formed by the self-assembly of 1. The introduction of these covalent cross-links greatly influenced the dynamic viscoelasticity of the supramolecular hydrogels. In the supramolecular hydrogel of 1 mixed with 5 % 2, the storage modulus was 1.35 times higher than that of the supramolecular hydrogel of 1 alone, and the crossover strain was extended from 5 % to over 20 %. The supramolecular hydrogel of 1 and 2 was free-standing and supported 13 times its own weight. PMID- 29512336 TI - Success rates and factors associated with failure of temporary anchorage devices: A prospective clinical trial. AB - AIM: The objective of the present study was to investigate success rates and associated factors affecting temporary anchorage device (TAD) failure in different biomechanical applications. METHODS: A total of 180 TADs were used as a part of 82 patients' treatment plan (24 males and 58 females); their mean age was 21.41 years. Three types of TADs were used: 50 (3M ESPE, Neuss, Germany), 56 (Bone screw; Jeil Medical, Seoul, Korea), and 74 (Morelli, Sorocaba, Brazil). Eight maxillary and four mandibular sites were selected for insertion. Three different lengths (6, 8, and 10 mm) and three different diameters (1.5, 1.6, and 1.8 mm) were used. The force levels were set at 50, 100, 150, 200, and 250 g. Patient-, implant-, and operator-dependent factors were evaluated throughout the 266 days of function. Qualitative variables were described by proportions and percentages and analyzed using chi2 test. RESULTS: The overall success rate was 82.2%. The higher age group showed a significantly higher success rate. Oral hygiene showed a statistically-significant (P ? .05) difference between both success and failure groups. All other patient-related factors showed no significant differences. Regarding force levels used, the highest success rate was in 250 g and the lowest was in 100 g. There were no significant differences between both groups regarding other implant- and operator-related factors. CONCLUSIONS: Temporary anchorage devices have a good success rate and are beneficial to be integrated in orthodontic treatment planning. Patient age, oral hygiene, and force level are the most significant factors affecting TAD success. PMID- 29512337 TI - Ultra-fast liquid chromatography coupled with electrospray ionization time-of flight mass spectrometry for the rapid phenolic profiling of red maple (Acer rubrum) leaves. AB - The red maple (Acer rubrum) species is economically important to North America because of its sap, which is used to produce maple syrup. In addition, various other red maple plant parts, including leaves, were used as a traditional medicine by the Native Americans. Currently, red maple leaves are being used for nutraceutical and cosmetic applications but there are no published analytical methods for comprehensive phytochemical characterization of this material. Herein, a rapid and sensitive method using liquid chromatography with electrospray ionization time-of-flight tandem mass spectrometry was developed to characterize the phenolics in a methanol extract of red maple leaves and a proprietary phenolic-enriched red maple leaves extract (MaplifaTM). Time-of flight mass spectrometry and tandem mass spectrometry experiments led to the identification of 106 phenolic compounds in red maples leaves with the vast majority of these compounds also detected in MaplifaTM. The compounds included 68 gallotannins, 25 flavonoids, gallic acid, quinic acid, catechin, epicatechin, and nine other gallic acid derivatives among which 11 are potentially new and 75 are being reported from red maple for the first time. The developed method to characterize red maple leaves phenolics is rapid and highly sensitive and could aid in future standardization and quality control of this botanical ingredient. PMID- 29512338 TI - Impact of sexual debut on culturable human seminal microbiota. AB - Micro-organisms are tightly integrated into host-microbiota ecosystem. Microbiota of human semen has been studied so far mostly in case of infertility or prostatitis. We aimed to reveal possible impact of sexual debut on seminal microbiota in healthy young men. The study group included 68 young healthy men, of them 12 men without sexual experience, 11 men with single lifetime sexual partner and 45 men with multiple lifetime sexual partners. Basic semen parameters were similar for all subgroups, and no correlation between sexual experience and WBC counts in semen was found. A man could harbour one to nine different bacteria in his semen; the total concentration of bacteria ranged from 2.3 to 7.3 log10 CFU/mL of semen. Lower total bacterial concentration and lower bacterial diversity was observed in men without sexual experience than in sexually experienced men (p < 0.05), with significant positive correlation between these two parameters (r = 0.54; p < 0.0001). In conclusion, the sexual debut is associated with the enrichment of seminal microbiota but not with the influx of WBC or changes in basic seminal parameters. PMID- 29512339 TI - Future-proofing academic surgery in Australia and New Zealand: the Annual RACS Joint Academic Meeting. PMID- 29512340 TI - Restricted venous access after lymph node dissection: no evidence (voodoo). PMID- 29512341 TI - Re: Recurrent sigmoid volvulus in pregnancy. PMID- 29512342 TI - What's in a title: does it really matter? PMID- 29512343 TI - Re: Internal herniation through the foramen of Winslow: a rare cause of bowel obstruction. PMID- 29512346 TI - Arterio-ureteric fistula: a rare but important cause of haematuria. PMID- 29512345 TI - Re: Subhepatic appendicitis masquerading as acute cholecystitis: a lesson learnt! PMID- 29512347 TI - Idiopathic colonic perforation in adults. PMID- 29512348 TI - Preventing hypoparathyroidism after total thyroidectomy. PMID- 29512349 TI - Electric scooter burns and the danger of personal mobility device battery. PMID- 29512350 TI - Inferior vena cava filters: recent controversies. PMID- 29512351 TI - Is single port laparoscopic cholecystectomy a new gold standard? PMID- 29512352 TI - What is the non-inflammed appendix? PMID- 29512353 TI - Medicine in small doses. PMID- 29512354 TI - Spontaneous splenic rupture in an intravenous drug abuser. PMID- 29512355 TI - Management of colorectal cancer patients with brain metastases. PMID- 29512356 TI - Meals, Mindfulness, & Moving Forward: A feasibility study to a multi-modal lifestyle approach in early psychosis. AB - AIM: The primary aim was to demonstrate adherence to a novel 6-week lifestyle intervention program ("Meals, Mindfulness, & Moving Forward" [M3 ]) designed to help improve lifestyle practices of youth with a history of at least 1 psychotic episode. METHODS: M3 used a non-equivalent control group design involving clients from a community early intervention program. Seventeen individuals in the active M3 program and 16 controls were assessed for secondary outcomes at baseline, 6 weeks, and 12-weeks (6 weeks post-intervention) on cardiometabolic and symptomatic outcomes. RESULTS: The program met its primary aim with 88% (15/17) of participants meeting adherence criteria. Compared with the controls, M3 participants showed significant improvement in positive psychotic symptoms (P = .002). CONCLUSION: This pilot study showed that young people involved in a community early intervention program adhered to an activity-based lifestyle program which included mindfulness meditation, yoga and nutrition education, warranting further evaluation with a larger sample size. PMID- 29512357 TI - A newly identified lncRNA MAR1 acts as a miR-487b sponge to promote skeletal muscle differentiation and regeneration. AB - BACKGROUND: Skeletal muscle atrophy induced by either aging (sarcopenia) or mechanical unloading is associated with serious health consequences. Long non coding RNAs (lncRNAs) are implicated as important regulators in numerous physiological and pathological processes. METHODS: Microarray analysis was performed to identify the differentially expressed lncRNAs in skeletal muscle between adult and aged mice. The most decreased lncRNA in aged skeletal muscle was identified. The C2C12 mouse myoblast cells were used to assess the biological function of the lncRNA in vitro. The target microRNA of lncRNA and the target protein of microRNA were predicted by bioinformatics analysis and validated in vitro. Furthermore, the biology function of the lncRNA in vivo was investigated by local overexpression or knockdown the lncRNA in skeletal muscle. The therapeutic effect of the lncRNA overexpression in age-related or mechanical unloading-induced muscle atrophy was also evaluated. RESULTS: We identified a novel lncRNA (muscle anabolic regulator 1, MAR1) which was highly expressed in mice skeletal muscle and positively correlated with muscle differentiation and growth in vitro and in vivo. We predicted and validated that microRNA-487b (miR 487b) was a direct target of MAR1. We also predicted and validated that Wnt5a, an important regulator during myogenesis, was a target of miR-487b in C2C12 cells. Our findings further demonstrated that enforced MAR1 expression in myoblasts led to derepression of Wnt5a. Moreover, MAR1 promoted skeletal muscle mass/strength and Wnt5a protein level in mice. Enforced MAR1 expression in mice attenuated muscle atrophy induced by either aging or unloading. CONCLUSIONS: The newly identified lncRNA MAR1 acts as a miR-487b sponge to regulate Wnt5a protein, resulting in promoting muscle differentiation and regeneration. MAR1 could be a novel therapeutic target for treating muscle atrophy induced by either aging or mechanical unloading. PMID- 29512358 TI - Challenges and opportunities in clinical translation of biomedical optical spectroscopy and imaging. AB - Medical devices face many hurdles before they enter routine clinical practice to address unmet clinical needs. This is also the case for biomedical optical spectroscopy and imaging systems that are used here to illustrate the opportunities and challenges involved. Following initial concept, stages in clinical translation include instrument development, preclinical testing, clinical prototyping, clinical trials, prototype-to-product conversion, regulatory approval, commercialization, and finally clinical adoption and dissemination, all in the face of potentially competing technologies. Optical technologies face additional challenges from their being extremely diverse, often targeting entirely different diseases and having orders-of-magnitude differences in resolution and tissue penetration. However, these technologies can potentially address a wide variety of unmet clinical needs since they provide rich intrinsic biochemical and structural information, have high sensitivity and specificity for disease detection and localization, and are practical, safe (minimally invasive, nonionizing), and relatively affordable. PMID- 29512360 TI - Fitness differences according to BMI categories: a new point of view. AB - BACKGROUND: Many studies have reported negative association between fitness level and BMI categories but the lack of body weight correction and and the systematic use of physical endurance test made these differences controversial. Thus, the aim of this study was the assessment of physical fitness level associated to BMI using alternative tests. METHODS: BMI was calculated as body mass/stature2 while fitness level was assessed using field test. In particular, Sit and Reach (SAR), Standing Broad Jump (SBJ), Shuttle Run Test 5mx 10 (SHR), Sit ups (SUP), Bent arm hang (BAH) were assessed in 2545 students. Subsequently, normal weight/overweight/obesity/underweight/thinness students were classified according to the cut-off points defined in literature and then the relative fitness results. RESULTS: The performances in SBJ showed very low differences between BMI categories such as for SUP test. The effects size in SHR were low or close to moderate while in BAH thin students revealed high performance than normal/overweight peers. In SAR test no clear trends in the BMI categories were observed. CONCLUSIONS: All test (exluding BAH) were similar for normal, overweight and thin students. This finding can be useful to teachers to encourage over/under-weighted students to adopt active life style because they are close to normal weight counterparts. PMID- 29512359 TI - Nondestructive assessment of collagen hydrogel cross-linking using time-resolved autofluorescence imaging. AB - We investigate the use of a fiber-based, multispectral fluorescence lifetime imaging (FLIm) system to nondestructively monitor changes in mechanical properties of collagen hydrogels caused by controlled application of widely used cross-linking agents, glutaraldehyde (GTA) and ribose. Postcross-linking, fluorescence lifetime images are acquired prior to the hydrogels being processed by rheological or tensile testing to directly probe gel mechanical properties. To preserve the sterility of the ribose-treated gels, FLIm is performed inside a biosafety cabinet (BSC). A pairwise correlation analysis is used to quantify the relationship between mean hydrogel fluorescence lifetimes and the storage or Young's moduli of the gels. In the GTA study, we observe strong and specific correlations between fluorescence lifetime and the storage and Young's moduli. Similar correlations are not observed in the ribose study and we postulate a reason for this. Finally, we demonstrate the ability of FLIm to longitudinally monitor dynamic cross-link formation. The strength of the GTA correlations and deployment of our fiber-based FLIm system inside the aseptic environment of a BSC suggests that this technique may be a valuable tool for the tissue engineering community where longitudinal assessment of tissue construct maturation in vitro is highly desirable. PMID- 29512361 TI - Transcatheter aortic valve implantation in bicuspid anatomy: procedural results with two different types of valves. AB - BACKGROUND: It is well known that bicuspid valve stenosis can be treated with transcatheter aortic valve implantation (TAVI) even if specific issues can cause problems: dilatation of ascending aorta, possible aorthopathy, eccentricity of the valve and calcium distribution in leaflets and in commissures. We classified Bicuspid aortic valve (BAV) in type 0 (2 cusps and no raphe), and type 1 (2 cusps and one or more raphes). The aim of the present study was to report the results of two types of valve (CoreValve from 2009 to 2016 and Lotus valve from 2014 to 2017) in a consecutive series of BAV patients treated in 2 Italian centers. METHODS: A total of 30 patients with BAV underwent TAVI from September 2009 to March 2017. RESULTS: Mean age was 78+/-8 years, 54.5% were males and 7.4% had peripheral vasculopathy, 6.5% previous stroke or TIA, 15.6% previous PCI and 9.4% previous coronary artery bypass grafting. Ten patients (30.3%) had a type 1; mean aortic valvular gradient was 57.7+/-17.7 mmHg; aortic valvular area was 0.7+/-0.2 mm2, left ventricular ejection fraction was 51.4+/-10.0% and ascending aorta was 41.0+/-5.6 mm. Among these 30 patients, 16 of them (group 1) undergone CoreValve implantation and 14 (group 2) undergone Lotus valve implantation. Patients in the first group had a higher Logistic Euroscore (P<0.001) and higher AVA (P=0.026) and valve area CT (P=0.003). Device size in group1 was more often bigger than in group 2 (P<0.001) and postdilatation was never used in the last group. Group 1 had a significant more frequent aortic regurgitation >=2 assessed with angiography (28.6% vs. 0%; P=0.05). A non-statistically significant higher rate of second valve implantation (6.2% vs. 0%; P=1.00) was also observed. New permanent pacemaker implantation (40.0% vs. 35.7%; P=0.812) was equal in both valves. CONCLUSIONS: Postprocedural aortic regurgitation is still an issue in BAV undergone TAVI when: 1) the annulus is big; 2) when we are using self-expandable valves; and 3) in type 0 valves. Lotus valve, with a higher radial force put in a small annuls seems associated to better procedural outcomes in this subset of patients. PMID- 29512363 TI - Irreversible left atrium dilatation preceding left ventricular dysfunction during trastuzumab therapy. PMID- 29512362 TI - Long-haul flights, edema, and thrombotic events: prevention with stockings and Pycnogenol(r) supplementation (LONFLIT Registry Study). AB - BACKGROUND: This registry study evaluated the effects of Pycnogenol(r) on edema and thrombotic complications in long-haul flights; jet lag was also evaluated. METHODS: Four hundred and fifty subjects at different risk levels for thrombosis, flying in economy class twice a week for more than 8 hours, were included; 295 completed the registry study and were subdivided in 3 groups according to their risk level - low, moderate, or high. The high-risk group also received Aspirin(r). A standard management (SM) was used in all groups. In each risk category, three groups were made according to patient management: a Pycnogenol group, a SM group (control), and a stockings group. The groups were comparable at inclusion. No side effects were observed. RESULTS: In the low risk group edema were reduced more (P<0.05) with Pycnogenol and stockings compared to control. Ankle circumference was smaller with Pycnogenol (P<0.05). No thrombosis was detected. D-dimer was negative in Pycnogenol subjects; one subject in the control group had increased values, as did two of the 36 subjects in the stockings group. In the group with moderate risk, edema and ankle circumference were lower in the Pycnogenol group (P<0.05). One deep vein thrombosis (DVT) and one minimal superficial vein thrombosis (SVT) were seen in controls. D-dimer was normal in the Pycnogenol group. In high-risk subjects, edema, and ankle circumference were significantly reduced in the Pycnogenol group (P<0.05). There were no SVT or DVT in the Pycnogenol group. One minimal DVT and one SVT were observed in controls. D dimer was negative in all Pycnogenol subjects (P<0.05); three post-flight values increased in controls and in four of the 32 subjects in the stockings group. The jet lag score was lower in low-, medium-, and high-risk Pycnogenol subjects (P<0.05). CONCLUSIONS: This registry study indicates that Pycnogenol supplementation reduces edema and may control some thrombotic events. PMID- 29512364 TI - Glucocorticoid Receptor Nuclear Translocation in CD4 T Cells from Severe and Moderate Asthmatic Patients Treated with Fluticasone/Vilanterol. AB - Different phenotypes of asthma from mild to severe are categorized based on diverse clinical features. A guideline for the recognition and treatment of asthma has been provided by Global Initiative for Asthma (GINA). To control symptoms and prevent asthma exacerbation in most patients combinational therapy with inhaled corticosteroids (ICS) and a long acting B2-adrenreceptor agonist (LABA) are recommended. Understanding asthma phenotypes would be helpful to improve asthma diagnosis and treatment. The aim of this study was to verify glucocorticoid receptor glcococorticoid receptor (GR) nuclear translocation in CD4 T cells treated with fluticasone furoate (FF), vilanterol (V) and FF/V combination in severe asthmatic patients compare to patients with moderate asthma and healthy controls using Immunocytochemistry (ICC). After taking blood and separating PBMCs from each subject, CD4 T cells were isolated from PBMCs using CD4+ T cell isolation kit. Isolated CD4 T cells were cultured in presence of FF, V and FF/V combination for 1 hour and after cytocentrifugation, cells were incubated with anti GR-antibody and subsequently stained with FITC bound secondary antibody and GR nuclear translocation was observed under microscope. The results showed significant increasing in GR nuclear translocation in treated CD4 T cells from patients with moderate asthma and controls compare to those severe asthmatic patients, along with treating cells with FF/V combination no significant GR nuclear translocation was observed compare to that of using mono treatment of cells with FF and V. Based on our findings, it can be concluded different mechanisms are responsible for severe asthma and moderate asthma. PMID- 29512365 TI - Regulatory Effects of Estradiol on Peripheral Blood Mononuclear Cells Activation in Patients with Asthma. AB - Asthma prevalence and severity are greater in women than in men, and mounting evidence suggests this is in part related to female steroid sex hormones. Conflicting data are reported regarding pro- and anti-inflammatory properties of estradiol. This study was designed to clarify whether estradiol may contribute to enhanced T helper (Th) 17-associated cytokines production by peripheral blood mononuclear cells (PBMC) in asthmatic patients and healthy individuals. PBMCs from patients with asthma and healthy donors were cultured with 17-beta estradiol (E2) and phytohemagglutinin (PHA). The quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure IL-6, IL-17, IL-23 and TGF-beta. We observed a significant increased IL-17, IL-23 and TGF-beta expression in PBMCs of patients compared to the healthy individuals. In addition, our findings indicated that IL-6 and IL-17 expressions in PBMCs were induced, following E2 treatment. Our results identified an impact of E2 in stimulation of Th17 phenotype, and upon hormonal oscillations and hormone replacement therapy (HRT), asthma inflammation may be mediated by Th17-associated cytokines. PMID- 29512366 TI - Clinical Course and Factors Associated with Asthma Control in Children under Control-based Asthma Management: A Prospective Study. AB - In the current study, we sought to track the clinical course of children under control-based asthma management and focused on respiratory pathogens monitoring. We prospectively explored influencing factors for asthma control. 121 children with uncontrolled asthma between 3-14 years of age were recruited. Common respiratory pathogens were detected with pharyngeal swabs and serum aeroallergen specific IgE was measured. Numeric asthma control scores, airway resistance and fractional concentrations of exhaled nitric oxide (FENO) were evaluated. A proper control-based asthma management plan was established by the study physician. Regular reviews were performed, with the above measurements retested at set time intervals. The proportion of patients achieving asthma control at 1 month and 3 months were 59% and 76% ; respectively (p=0.013). These patients exhibited significant improvement in numeric scores and lung function parameters. The prevalence of common respiratory pathogens did not significantly differ between reviews. The number of sensitized aeroallergens significantly increased with age (r=0.235, p=0.010). Children with a high visual analogue scale (VAS) score for asthma at baseline were less likely to achieve asthma control after 1 month, while those sensitized to more aeroallergens were more likely to achieve asthma control after 1 month (p=0.016 and 0.012). In summary, children with asthma showed significant improvements in control rates and lung function during control based asthma management, independent of respiratory pathogens testing reults. Patients with high VAS scores and fewer sensitizations to aeroallergens had difficulty achieving short-term asthma control. PMID- 29512367 TI - Effects of Connexin 43 Inhibition in an Ovalbumin-induced Mouse Model of Asthma. AB - Connexion 43 (Cx43), a gap junction protein, is expressed abundantly in the airway and has been implicated in the pathogenesis of asthma. However, the effects of blocking Cx43 in asthma remain unclear. We investigated the therapeutic effects of two specific Cx43 inhibitors (Gap26 and Gap27) on the development of allergic airway disease in mice. Allergic asthma was induced in BALB/c mice by sensitization and challenge with ovalbumin (OVA). Different doses of Cx43 inhibitors were administered by aerosol inhalation 1 h after OVA challenge on days 21 and 23. Airway hyperresponsiveness (AHR), lung pathology, mucus production, and inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were examined. We found that Gap26 significantly inhibited OVA induced AHR, inflammatory cell infiltration surrounding the bronchia, mucus production, inflammatory cells and cytokines in BALF, and OVA-specific IgE in the serum in a dose-dependent manner. Gap27 showed effects similar to those of Gap26 in inhibiting inflammatory cytokine production in BALF. We conclude Cx43 inhibitor inhalation alleviates asthma featuresin mice and may be a promising therapy for clinical asthma. PMID- 29512368 TI - Regulatory Effect of Xiaoqinglong Decoction on Thymic Stromal Lymphopoietin (TSLP) Inflammation Promoter in Mice with Cold Asthma. AB - Allergic asthma is a complex and chronic inflammatory airway disease. The thymic stromal lymphopoietin (TSLP) signaling pathway plays an important role in asthma. Xiaoqinglong Decoction (XQL) is the first choice to treat cold asthma in clinical settings. In this study, the role of the TSLP pathway in the onset of asthma and the protective mechanism of XQL were investigated. A total of 50 female mice were randomly divided into the following groups: the blank group (A), the model group (B), the XQL group (C), the dexamethasone group (D), and the XQL + dexamethasone group (E). Asthma was induced with ovalbumin, and corresponding drug intervention was carried out for 7 days, after which serum and lung tissue end points were analyzed. Serum interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNF alpha), nuclear factor kappaB (NF-kappaB), and TSLP levels were higher in group B than in group A (p<0.05). However these levels were lower in group C and D than in group B (p<0.05), and there was no significant difference between groups C and D (p>0.05). Interestingly, these end points were significantly lower in group E than in groups C and D (p<0.05). Regarding pathologic changes, the inflammatory infiltrate in the lungs of groups C, D, and E was lower than that of group B, especially in group E. We conclude that the TSLP pathway plays an important role in the course of asthma, and can be used as an important target for asthma treatment; XQL may play a role in reducing inflammation and relieving asthma by regulating the TSLP signaling pathway. PMID- 29512369 TI - Myeloid-derived Suppressor Cells Elimination by 5-Fluorouracil Increased Dendritic Cell-based Vaccine Function and Improved Immunity in Tumor Mice. AB - Myeloid-derived suppressor cells (MDSCs) are capable of suppressing the immune response. 5-Fluorouracil (5-FU) compared to other chemotherapy drugs have shown considerable decreases in the number of MDSCs without visible effects on T, B and natural killer cells, as well as dendritic cells (DCs). DC-based vaccines considered to be appropriate candidates for cancer immunotherapy. However, due to the presence of various factors like MDSCs in tumor microenvironment, DC vaccine cannot effectively perform its function. The purpose of this study was to evaluate the effect of low doses of 5-FU on the efficacy of DC-based vaccines in preventing and treating of melanoma tumor model. This research was performed on 28 melanoma tumor bearing C57BL/6 female mice. The mice were randomly divided to 4 groups, group 1 is control population while group 2 and 3 were treated with DC vaccine and 5-FU respectively and group 4 was treated with both DC Vaccine and 5 FU. The mice survival, tumor growth rate, number of MDSC and CD8+/ CD107a+ T cells in mice spleen were evaluated in each group with maximum result in group 4. Our results revealed that combination of DC vaccine and 5-FU reduced number of MDSCs (3%) and also tumor growth rate(10%)(p<0.05) and increased mice survival (70%) and increased CD8+ /CD107a+ T cells (25%). This study have shown that combinational therapy with DC vaccine improved immunity in tumor mice compared to the therapy consisting of DC vaccine or 5-FU only. PMID- 29512370 TI - Indoleamine 2, 3-dioxygenase Up-regulates Hypoxia-inducible Factor-1alpha Expression by Degrading L-tryptophan but Not Its Activity in Human Alloreactive T cells. AB - Indoleamine 2, 3-dioxygenase (IDO) suppresses T-cell function at least in part by altering cell metabolism. Hypoxia-inducible factor-1 (HIF-1) increases upon T cell activation and alters cell metabolism favoring their differentiation to effector cells. The effect of IDO on HIF-1alpha expression and activity was evaluated. For this purpose, mixed lymphocyte reaction (MLR) was performed using the IDO inhibitor 1-DL-methyl-tryptophan and the p53 inhibitor pifithrin-alpha. L tryptophan degradation and cell proliferation were assessed by enzyme-linked immunosorbent assay, whereas the expression of proteins of interest by western blotting. IDO inhibited cell proliferation, and in MLR-derived T-cells increased HIF-1alpha and p53, whereas it decreased c-Myc. Inhibition of p53 abrogated IDO induced HIF-1alpha upregulation. IDO increased the p53 transcriptional targets p21 and TP53-induced glycolysis and apoptosis regulator. The transcriptional targets of both HIF-1alpha and c-Myc, hexokinase II and lactate dehydrogenase-A were decreased by IDO. Phosphorylated pyruvate dehydrogenase remained unaffected indicating that pyruvate dehydrogenase kinase, a transcriptional target of HIF 1alpha, is not affected by IDO. In human alloreactive T-cells, IDO up-regulates HIF-1alpha, by inducing p53 overexpression. However, HIF-1alpha remains transcriptionally inactive. PMID- 29512371 TI - Th1-Th17 Ratio as a New Insight in Rheumatoid Arthritis Disease. AB - The Th17, Th1 and dual Th17/Th1 cells are important players in rheumatoid arthritis (RA) disease. To assess their roles, the frequency and impact of these cells were investigated in patients with different disease activity. In 14 new cases and 41 established RA patients in comparison with 22 healthy controls, the percentages of Th17, Th1 and dual Th17/Th1 cells were determined by flow cytometry and their correlations were investigated with disease activity score (DAS28). Moreover, serum levels of IL-6 and IL-17 as inducer and functional cytokines for Th17 were investigated. Finally, serum levels of anti citrullinated protein antibody (ACPA) and rheumatoid factor (RF) were assessed. Percentage of Th17 cells in RA patients were increased in comparison with healthy controls (p<0.01). In correlation with this finding, IL-17 and IL-6 cytokines in RA patients also increased (p<0.01). The Th1 cells in RA patients were less than healthy group (p<0.05) and showed negative correlation with disease activity (r= 0.328, p<0.01). Dual Th17/Th1 cell only in new cases of RA were more than healthy control groups (p<0.01). The Th1/Th17 ratio in RA patients is statistically different with healthy control group (p<0.01) and it has negative correlation with disease activity (r=-264, p<0.05). The levels of ACPA and RF were increased with disease progression. Decreasing of Th1/Th17 ratio in RA patient suggested a new paradigm in the field of autoimmune disease and indicated that imbalance or plasticity between these subsets can be important in progress, diagnosis and therapy of RA disease. PMID- 29512372 TI - The Correlation between the Numerical Status of Th22 Cells and Serum Level of IL 22 with Severity of Ulcerative Colitis. AB - Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease, yet its etiology as well as pathogenesis remain poorly understood. There is increasing evidence that aberrant expression of CD4+T lymphocytes plays an essential role in the progression of different pathologies such as UC. This study aimed to evaluate the circulatory frequency of T-helper 22 (Th22), a subset of CD4+ T cells, and serum level of its signature cytokine, IL-22, in patients with UC. Blood samples from 30 patients with UC and 30 controls (n=30) were tested for IL-22 level and circulatory Th22-cell count by ELISA and Flow cytometric analysis, respectively. Our results revealed higher serum level of IL-22 as well as circulatory frequency of Th22 cells in patients with UC compared to those in healthy controls. Notably, effective factors on severity of the disease were age, Th22, IL-22, ESR and CRP. We conclude that elevated circulating Th22 cells and their signature cytokine, IL-22, may be implicated in the pathogenesis of UC. These findings may provide preliminary experimental clues for the development of new therapies for UC and its severity judgment. PMID- 29512373 TI - Good's Syndrome-Association of the Late Onset Combined Immunodeficiency with Thymoma: Review of Literature and Case Report. AB - Good's syndrome, the adult onset hypogammaglobulinemia associated with thymoma has been explained about six decades ago. It generally presents with recurrent infections and several paraneoplastic syndromes including myasthenia gravis, pure red cell aplasia, connective tissue disorders, superior vena cava, Horner's syndrome, lichen planus and inflammatory bowel disease. Lack of B cell, dysfunction of T cell, CD4+ T cell lymphopenia, reversed CD4/CD8+ T cell ratio, autoantibodies against Th17 related cytokines have been respected as the pathogenesis of the immune dysregulation this syndrome. A 57-year-old man was admitted to our hospital with a history of thymectomy due to thymoma (Type A) 6 years ago. He developed weight loss and recurrent persistent diarrhea caused by isospora belli. His chest CT scan revealed bilateral bronchiectasis. His laboratory data showed hypogammaglobulinemia and he was treated by monthly IVIG with the diagnosis of good's syndrome. Nevertheless he referred again with left sided loss of vision because of CMV retinitis and he also developed nail candidiasis. Good's syndrome should be considered in every patient with a history of thymoma and recurrent infection. Immunologic evaluation of these patients including measurement of the serum level of immunoglobulin as well as B cell and T cell subgroups should be performed. Physicians must be aware and think about this entity in patients with adult onset immunodeficiency. PMID- 29512374 TI - A Case of Anaphylaxis to Intramuscular but Not to Oral Application of Thiamine (Vitamin B1). AB - We report a 78 year-old non-atopic female with polyneuropathy who started to receive monthly intramuscular injections of thiamine hydrochloride. She had an anaphylaxis after the fourth injection. Skin prick test (SPT) with pure commercially available aqueous preparations was positive for thiamine hydrochloride. A titrated, single blinded, placebo-controlled oral provocation test with thiamine hydrochloride was well tolerated. The patient was then diagnosed as compartment allergy with hypersensitivity to parenteral but not to oral thiamine. Because in our patient, oral intake of thiamine has never been reported to lead to any adverse reaction. Oral tolerability might be due to the uptake mechanism of thiamine in the gastrointestinal system. PMID- 29512375 TI - Angioedema Due to Lamiaceae Allergy. AB - We present a 13-year-old male childallergic to three different plants (Salvia officinalis, Mentha piperita and Origanum onites L.) of Lamiaceae family. The patient developed angioedema 20-30 minutes after eating chicken meat with cheddar cheese. There was no history of allergy. Oral food challenge (OFC) with both cheddar cheese and chicken meat was negative. Skin tests for inhalant allergens were negative. 3 weeks later, the patient was admitted with angioedema after drinking sage tea. OFC with sage was applied and angioedema was observed. It was recognized that the first trigger, chicken meat with cheddar cheese, included oregano (Origanum onites L.). OFC for oregano was positive. Prick to prick test for Lamiaceae herbs (oregano, sage, mint) was performed. A positive reaction was observed only to mint. OFC was repeated with fresh mint and angioedema developed after 16 hours. Diagnose of Lamiaceae allergy is complicated and cross sensitivity is common. Skin prick test (prick to prick)revealed a positive response only to mint but not to oregano and sage. Commercial radioallergosorbent (RAST) tests are available only for a few members of the family. Finally, thediagnose is based mainly on OFC. Spices from Lamiaceae group should be considered as potential triggers of allergic reactions. PMID- 29512376 TI - A Comparison of the Cyanide-Scavenging Capabilities of Some Cobalt-Containing Complexes in Mice. AB - Four cobalt-containing macrocyclic compounds previously shown to ameliorate cyanide toxicity have been comparatively evaluated with an acute sublethal toxicity model in conscious (unanesthetized) adult male Swiss-Webster mice. All of the compounds (the cobalt-corrins cobalamin and cobinamide, a cobalt porphyrin, plus a cobalt-Schiff base macrocycle) given 5 min prior to the toxicant dose significantly decreased the righting-recovery time of cyanide intoxicated mice, but the doses required for maximal antidotal effect varied. Additionally, all of the compounds tested significantly reduced the righting recovery time when administered at either 1 or 2 min after cyanide intoxication, but none of the compounds tested significantly reduced the righting-recovery time when delivered 5 min after the toxicant dose. Using the lowest effective dose of each compound determined during the first (prophylactic) set of experiments, neuromuscular recovery following cyanide intoxication in the presence/absence of the cobalt-based antidotes was assessed by RotaRod testing. All the compounds tested accelerated recovery of neuromuscular coordination, and no persistent impairment in any group, including those animals that received toxicant and no antidote, was apparent up to 2 weeks postexposures. The relative effectiveness of the cobalt compounds as cyanide antidotes are discussed and rationalized on the basis of the cyanide-binding stoichiometries and stability constants of the Co(III) cyano adducts, together with consideration of the rate constants for axial ligand substitutions by cyanide in the Co(II) forms. PMID- 29512377 TI - Parabens and Their Metabolites in Pet Food and Urine from New York State, United States. AB - The exposure of pets, such as dogs and cats, to a wide range of chemicals present in the indoor environment and the concomitant increase in noninfectious diseases in these companion animals are a concern. Nevertheless, little is known about the sources and pathways of exposure to chemicals in pets. In this study, we determined the concentrations of parabens in commercially available cat and dog foods as well as in urine samples from these pets collected from the Albany area of the state of New York in the United States. Parabens, especially methyl paraben (MeP), and their metabolites were found in all pet food and urine samples. The mean concentrations of total parabens (i.e., sum of parabens and their metabolites) in dog ( n = 23) and cat ( n = 35) food were 1350 and 1550 ng/g fresh wt, respectively. Dry food contained higher concentrations of parabens and their metabolites than did wet food, and cat food contained higher concentrations of target chemicals than did dog food. The mean concentrations of total parabens found in dog ( n = 30) and cat ( n = 30) urine were 7230 and 1040 ng/mL, respectively. In both pet food and urine, MeP (among parabens) and 4 hydroxy benzoic acid (4-HB) (among metabolites) were the dominant compounds. The metabolites of parabens accounted for ~99% (~99.1% in food and ~98.9% in urine) of the total concentrations in both food and urine. The profiles of parabens and their metabolites in the urine of dogs and cats varied. In addition to diet, other sources of paraben exposures were found for dogs, whereas, for cats, the majority of exposures was identified as related to diet. PMID- 29512378 TI - Systematic Characterization of the Metabolism of Acetoin and Its Derivative Ligustrazine in Bacillus subtilis under Micro-Oxygen Conditions. AB - Bacillus subtilis is an important microorganism for brewing of Chinese Baijiu, which contributes to the formation of flavor chemicals including acetoin and its derivative ligustrazine. The first stage of Baijiu brewing process is under micro oxygen conditions; however, there are few studies about B. subtilis metabolism under these conditions. Effects of various factors on acetoin and ligustrazine metabolism were investigated under these conditions, including key genes and fermentation conditions. Mutation of bdhA (encoding acetoin reductase) or overexpression of glcU (encoding glucose uptake protein) increased acetoin concentration. Addition of Vigna angularis powder to the culture medium also promoted acetoin production. Optimal culture conditions for ligustrazine synthesis were pH 6.0 and 42 degrees C. Ammonium phosphate was shown to promote ligustrazine synthesis in situ. This is the first report of acetoin and ligustrazine metabolism in B. subtilis under micro-oxygen conditions, which will ultimately promote the application of B. subtilis for maintaining Baijiu quality. PMID- 29512379 TI - Rapid Assessment of Site Specific DNA Methylation through Resistive Pulse Sensing. AB - Many diseases are defined by patterns of DNA methylation which result in aberrant gene expression. We present a rapid assay based upon resistive pulse sensing, RPS, to characterize sequence specific DNA methylation sites in genomic DNA. We modify the surface of superparamagnetic beads, SPBs, with DNA (capture probe). The particles are added to solution where they bind to and extract sequence specific DNA (target DNA). The target loaded SPBs are then incubated with antibodies which bind to the methylation sites, and the velocity of the SPBs through the nanopore reveals the number and location of the epigenetic markers within the target. The approach is capable of distinguishing between different methylation sites within a DNA promoter region. Crucially the approach is not dependent on accurate sequencing of assayed DNA, with genomic regions targeted through complementary probes. As such the number of stages and reagents costs are low and the assay is complete in under 60 min which includes the incubation and run times. The format also allows simultaneous quantification of number of copies of methylated DNA, and we illustrate this with a dose response curve. PMID- 29512380 TI - Highly Sensitive Electrochemical Detection of Tumor Exosomes Based on Aptamer Recognition-Induced Multi-DNA Release and Cyclic Enzymatic Amplification. AB - Sensitive and specific detection of tumor exosomes is of great significance for early cancer diagnosis. In this paper, we report an aptamer strategy for exosome detection based on aptamer recognition-induced multi-DNA release and cyclic enzymatic amplification. First, we use aptamer-magnetic bead bioconjugates to capture tumor exosomes derived from LNCaP cells, leading to the release of three kinds of messenger DNAs (mDNAs). After magnetic separation, the released mDNAs hybridized with the probe DNAs immobilized on a gold electrode. Electroactive Ru(NH3)63+ was used as the signal reporter because of its electrostatic attraction to DNA. Subsequent Exo III cyclic digestion caused the electrochemical signal to "turn off". Because the electrochemical signal reflects the concentration of Ru(NH3)63+ and the concentration of Ru(NH3)63+ is correlated with the mDNA concentration, which is correlated with the exosome concentration, the tumor exosomes can be detected by examining the decrease in the peak current of Ru(NH3)63+. In this paper, the signal was amplified by the numerous mDNAs released from the magnetic bead and the Exo III-assisted mDNA recycling. Under the optimal conditions, a detection limit down to 70 particles/MUL was achieved, which is lower than the LODs of most currently available methods. Furthermore, this assay can be used to detect tumor exosomes in complex biological samples, demonstrating potential application in real sample diagnosis. PMID- 29512381 TI - 2- O- N-Benzylcarbamoyl as a Protecting Group To Promote beta-Selective Glycosylation and Its Applications in the Stereoselective Synthesis of Oligosaccharides. AB - This study examines the utility of the N-benzylcarbamoyl (BnCar) protecting group in glycosylation reactions of the parent O-2 protected carbohydrate donor. It was found that the BnCar group imparted exclusively beta-selectivity with primary and secondary alcohols. A mechanistic study revealed the activated intermediate to be the glycosyl triflate in a skew conformation, which results in beta-selective glycosylation via an SN2-like pathway. The BnCar group can be readily cleaved using tetrabutylammonium nitrite, without affecting ester and ether protecting groups. Taken together, these results show BnCar to be useful for the synthesis of complex oligosaccharides, an undertaking that requires delicate chemical differentiation of various protecting groups. PMID- 29512382 TI - Polycytosine DNA Electric-Current-Generated Immunosensor for Electrochemical Detection of Human Epidermal Growth Factor Receptor 2 (HER2). AB - A polycytosine DNA-based immunosensor for electrochemical detection was developed and tested for detection of human epidermal growth factor receptor 2 (HER2), a breast cancer biomarker. We utilized gold nanoparticles (AuNPs) as supporting matrix to immobilize polycytosine DNA sequence (dC20) for electrochemical current generation and anti-HER2 antibodies. In the presence of target HER2, a sandwiched immunocomplex forms between a peptide specific to HER2 immobilized on the gold electrode and the anti-HER2 antibodies on the AuNPs. The HER2 captured by the sensor is detected because of the reaction of the dC20 phosphate backbone with molybdate, forming redox molybdophosphate precipitate that generates an electrochemical current on the surface of the electrode. The assay is sensitive: the calculated limit of detection of HER2 was as low as 0.5 pg/mL and the detection was linear to HER2 from 1 pg/mL to 1 ng/mL. The sensor's specificity is high, and there is no cross reactivity with several potential interferents, such as human IgG, human IgA, p53, carcinoembryonic antigen, and protein kinase. The sensor's performance with HER2 in clinical serum samples is similar to the performance of commercial ELISA assays. The configuration of polycytosine DNA as electrochemical current generating label and anti-HER2 antibodies on AuNPs is versatile and can be reconfigured to detect low levels of different analytes, or made more sensitive by amplifying the DNA to produce more phosphate to react with Na2MoO4. PMID- 29512383 TI - Spontaneous Interfacial Dipole Orientation Effect of Acetic Acid Solubilized PFN. AB - Poly[(9,9-dioctyl-2,7-fluorene)- alt-(9,9-bis(3'-( N, N-dimethylamino)propyl)-2,7 fluorene)] (PFN) is a very important interfacial modifier in organic photovoltaic and organic light-emitting diodes to improve device performance, where their molecular dipole has been regarded to play a key role. In this work, we have reported a spontaneous interfacial dipole orientation effect in acetic acid dissolved PFN, which is strongly related to the interfacial dipole and the corresponding device performance. In direct spin-coating, the interfacial dipole is 1.08 Debye with interfacial contact angle 84.8 degrees , whereas after self assembly of 10 min, the interfacial dipole is balanced at 4.21 Debye, with the interfacial contact angle decreasing to 76.8 degrees . Without strong interaction with the substrate, the energy of upward amine groups is much lower than that of downward ones in theoretical simulation, which would be the driving force of this spontaneous process. The preferred conformations of PFN molecules on hydroxylated substrates have over 99% amine groups outward, and the theoretical average dipole calculated from the weight of these conformations is 4.48 Debye, which is close to the experimental result and indicates a high ratio of upward amine groups in self-assembled films. This effect obviously changes the device performance, such as an obvious positive threshold voltage shift in transistors and a distinct increase of the short-circuit current/open-circuit voltage in organic solar cells. This effect provides a deeper understanding of the PFN interlayer mechanism and has potential application in optoelectronic devices. PMID- 29512384 TI - Maximizing the Public Health Benefits from Climate Action. PMID- 29512385 TI - Catalysis of Methyl Transfer Reactions by Oriented External Electric Fields: Are Gold-Thiolate Linkers Innocent? AB - Oriented external electric fields (OEEFs) are potent effectors of chemical change and control. We show that the Menshutkin reaction, between substituted pyridines and methyl iodide, can be catalyzed/inhibited at will, by just flipping the orientation of the EEF ( F Z) along the "reaction axis" ( Z), N---C---I. A theoretical analysis shows that catalysis/inhibition obey the Bell-Evans-Polanyi principle. Significant catalysis is predicted also for EEFs oriented off the reaction axis. Hence, the observation of catalysis can be scaled up and may not require orienting the reactants vis-a-vis the field. It is further predicted that EEFs can also catalyze the front-side nucleophilic displacement reaction, thus violating the Walden-inversion paradigm. Finally, we considered the impact of gold-thiolate linkers, used experimentally to deliver the EEF stimuli, on the Menshutkin reaction. A few linkers were tested and proved not to be innocent. In the presence of F Z, the linkers participate in the electronic reorganization of the molecular system. In so doing, these linkers induce local electric fields, which map the effects of the EEF and induce catalysis/inhibition at will, as in the pristine reaction. However, as the EEF becomes more negative than -0.1 V/A, an excited charge transfer state (CTS), which involves one-electron transfer from the 5p lone pair of iodine to an antibonding orbital of the gold cluster, crosses below the closed-shell state of the Menshutkin reaction and causes a mechanistic crossover. This CTS catalyzes nucleophilic displacement of iodine radical from the CH3I*+ radical cation. The above predictions and others discussed in the text are testable. PMID- 29512386 TI - Mimicking a Dog's Nose: Scrolling Graphene Nanosheets. AB - Inspired by the densely covered capillary structure inside a dog's nose, we report an artificial nanostructure, i. e., poly(sodium p-styrenesulfonate) functionalized reduced graphene oxide nanoscrolls (PGNS), with high structural perfection and efficient gas sensing applications. A facile supramolecular assembly is introduced to functionalize graphene with the functional polymer, combined with the lyophilization technique to massively transform the planar graphene-based nanosheets to nanoscrolls. Detailed characterizations reveal that the bioinspired nanoscrolls exhibit a wide-open tubular morphology with uniform dimensions that is structurally distinct from the previously reported ones. The detailed morphologies of the graphene-based nanosheets in each scrolling stage during lyophilization are monitored by cryo-SEM. This unravels an asymmetric polymer-induced graphene scrolling mechanism including the corresponding scrolling process, which is directly presented by molecular dynamics simulations. The fabricated PGNS sensors exhibit superior gas sensing performance with reliable repeatability, excellent linear sensibility, and, especially, an ultrahigh response ( Ra/ Rg = 5.39, 10 ppm) toward NO2. The supramolecular assembly combined with the lyophilization technique to fabricate PGNS provides a strategy to design biomimetic materials for gas sensors and chemical trace detectors. PMID- 29512388 TI - Empirical Analysis of the Photoelectrochemical Impedance Response of Hematite Photoanodes for Water Photo-oxidation. AB - Photoelectrochemical impedance spectroscopy (PEIS) is a useful tool for the characterization of photoelectrodes for solar water splitting. However, the analysis of PEIS spectra often involves a priori assumptions that might bias the results. This work puts forward an empirical method that analyzes the distribution of relaxation times (DRT), obtained directly from the measured PEIS spectra of a model hematite photoanode. By following how the DRT evolves as a function of control parameters such as the applied potential and composition of the electrolyte solution, we obtain unbiased insights into the underlying mechanisms that shape the photocurrent. In a subsequent step, we fit the data to a process-oriented equivalent circuit model (ECM) whose makeup is derived from the DRT analysis in the first step. This yields consistent quantitative trends of the dominant polarization processes observed. Our observations reveal a common step for the photo-oxidation reactions of water and H2O2 in alkaline solution. PMID- 29512387 TI - Asymmetric Organocatalytic Sulfa-Michael Addition to Enone Diesters. AB - An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane thiourea organocatalyst and provides a range of alpha-sulfaketones in high yields and enantioselectivities. Leveraging the gem-diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters. PMID- 29512389 TI - Enzyme-Free Amplification Strategy for Biosensing Using Fe3+-Poly(glutamic acid) Coordination Chemistry. AB - In this work, we outline a signal amplification strategy using the coordination chemistry between Fe3+ and poly(glutamic acid) (PGA) for biosensing applications. The theoretical calculation based on density functional theory shows that PGA has a much higher binding affinity with Fe3+ than the other metal ions. Guided by this rationale, we prepare a PGA-mediated signal probe through conjugating PGA onto polystyrene (PS) nanoparticles to form a brushlike nanostructure for Fe3+ coordination. This PGA-PS brush (PPB) has a large loading capacity of Fe3+ with a number of 1.92 * 108 Fe atoms per nanoparticle that greatly amplifies the signals for assays in an enzyme-free way. Combined with ferrozine coloration-based readout, this PPB-mediated amplification is further applied for the enzyme-free immunoassay that shows an ultrahigh sensitivity for detection of microcystins-LR (12 pg/mL), a 5-fold enhancement compared with that of traditional enzyme-linked immunosorbent assay (ELISA) (60 pg/mL). In addition, the good stability, rapid response, and long shelf life make this enzyme-free amplification strategy a promising platform for point-of-care biosensing applications. PMID- 29512390 TI - Role of Zinc and Magnesium Ions in the Modulation of Phosphoryl Transfer in Protein Tyrosine Phosphatase 1B. AB - While the majority of phosphatases are metalloenzymes, the prevailing model for the reactions catalyzed by protein tyrosine phosphatases does not involve any metal ion, yet both metal cations and oxoanions affect their enzymatic activity. Mg2+ and Zn2+ activate and inhibit, respectively, protein tyrosine phosphatase 1B (PTP1B). Molecular dynamics simulations, metadynamics, and quantum chemical calculations in combination with experimental investigations demonstrate that Mg2+ and Zn2+ compete for the same binding site in the active site only in the closed conformation of the enzyme in its phosphorylated state. The two cations have different effects on the arrangements and activities of water molecules that are necessary for the hydrolysis of the phosphocysteine intermediate in the second catalytic step of the reaction. Remarkable differences between the established structural enzymology of PTP1B investigated ex vivo and the function of PTP1B in vivo become evident. Different reaction pathways are viable when the presence of metal ions and their cellular concentrations are considered. The findings suggest that the substrate delivers the inhibitory Zn2+ ion to the active site. The inhibition and activation can be ascribed to the different coordination chemistries of Zn2+ and Mg2+ ions and the orientation of the metal coordinated water molecules. Metallochemistry adds an additional dimension to the regulation of PTP1B and presumably other members of this enzyme family. PMID- 29512391 TI - Insights into the Rb-Mg-N-H System: an Ordered Mixed Amide/Imide Phase and a Disordered Amide/Hydride Solid Solution. AB - The crystal structure of a mixed amide-imide phase, RbMgND2ND, has been solved in the orthorhombic space group Pnma ( a = 9.55256(31), b = 3.70772(11) and c = 10.08308(32) A). A new metal amide-hydride solid solution, Rb(NH2) xH(1- x), has been isolated and characterized in the entire compositional range. The profound analogies, as well as the subtle differences, with the crystal chemistry of KMgND2ND and K(NH2) xH1- x are thoroughly discussed. This approach suggests that the comparable performances obtained using K- and Rb-based additives for the Mg(NH2)2- 2LiH and 2LiN H2-MgH2 hydrogen storage systems are likely to depend on the structural similarities of possible reaction products and intermediates. PMID- 29512392 TI - Human herpesvirus 6A and 6B and NK cells. AB - Human herpesvirus 6 (HHV-6) comprises two viral species, HHV-6A and HHV-6B, closely related but differing for pathogenic and biological characteristics. Both viral species are predominantly lymphotropic, infecting T lymphocytes and other lymphoid cells, including natural killer (NK) cells. The interactions between HHV 6 and NK cells have been scarcely studied, but it has become clear that NK cells are not only crucial in immune protection during the early phases of infection, but also that HHV-6 infection can affect NK cell functions. In this report, we shortly summarize the interactions between HHV-6 and NK cells. PMID- 29512393 TI - Value of the eazyplex(r) CSF direct assay in rapid diagnosis of invasive meningococcal disease - Case report. AB - There is a need for easy-to-use molecular assays for diagnosis of invasive meningococcal disease. Here, we report the rapid identification of Neisseria meningitidis in a cerebrospinal fluid sample from a patient with purulent meningitis using a commercially available loop-mediated isothermal amplification assay, resulting in a prompt de-escalation of the initial empiric antibiotic therapy. PMID- 29512394 TI - Usefulness of ultrasound assessment of median nerve mobility in carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common peripheral compression neuropathy of the upper extremity. Recently, dynamic ultrasound (US) imaging has shown differences in median nerve mobility between the affected and unaffected sides in CTS. PURPOSE: The present study was performed to compare the median nerve mobility between patients with CTS and healthy individuals, and to correlate median nerve mobility with the severity of CTS. MATERIAL AND METHODS: A total of 101 patients (128 wrists) with CTS and 43 healthy individuals (70 wrists) were evaluated. Electrodiagnostic studies were initially conducted to determine the neurophysiological grading scale (NGS). The cross-sectional area (CSA) of the median nerve and the grade of median nerve mobility were measured using US. RESULTS: The mean grade of median nerve mobility in the CTS group (1.9) was significantly lower than that in the control group (2.6; P < 0.001). There were significant negative correlations between the grade of median nerve mobility and distal motor latency of the median nerve (r = -0.218, P = 0.015), NGS (r = 0.207, P = 0.020) and CSA of the median nerve (r = -0.196, P = 0.028). CONCLUSION: The grade of median nerve mobility was negatively correlated with the severity of CTS. US assessment of median nerve mobility may be useful in diagnosing and determining the severity of CTS. PMID- 29512395 TI - Fifteen-Year Journey to High Reliability in Pathology and Laboratory Medicine. AB - Many high-reliability organizations in industries outside of health care have sustained high levels of excellence and prevention of harm while managing complex systems and risk. To date, no health care organizations has organized its efforts to achieve highly reliable results despite several decades of improvement science. Laboratorians were early adopters of quality initiatives and process improvements. In the late 1990s, the Division of Pathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center embarked on a major effort to improve quality and patient safety and to reduce waste. This article describes the institution's journey toward approaching high reliability with the intent to share not only the tools and best practices, but also the ongoing reassessment of the problems detected on the journey. The authors hope that their experience will help the reader develop interventions to adapt in their own environment to facilitate more optimal patient care. PMID- 29512397 TI - Characterization of anti-interferon-gamma antibodies in HIV-negative immunodeficient patients infected with unusual intracellular microorganisms. AB - A major characteristic of immunodeficiency associated with life-threatening intracellular infection in adults is the presence of anti-interferon-gamma antibodies. Although little is known about the mechanism underlying this syndrome, it is believed that the antibodies inhibit the activity of downstream signaling pathway of interferon-gamma. In this study, the characteristics of these antibodies in patients who presented, or have a history of, intracellular infection and were positive to anti-interferon-gamma antibodies were investigated. The antibodies exhibited mainly the IgG1 and the IgG4 subtypes and recognized the C-terminal of the interferon-gamma linear epitope containing the KRKR motif, which is required for the biological activity of interferon-gamma. The antibodies bound to recombinant interferon-gamma with significantly lower avidity than antibodies to a recall antigen, tetanus toxoid, suggesting that the antibodies might have not undergone affinity maturation. The data from this study may provide fundamental information to better understand the properties of anti interferon-gamma antibodies, which can be useful for future studies. Impact statement An increase in the number of immunodeficient patients related to autoantibodies to interferon (IFN)-gamma has been observed particularly in East Asian adults. These patients are often presented with opportunistic infections caused by intracellular pathogens, including non-tuberculous mycobacteria (NTM), Cryptococcus neoformans, Penicillium marneffei (now called Talaromyces marneffei), and non-typhoidal Salmonella spp. The mortality rate for this syndrome is relatively high with 32% patients dying at the median time of 25 months after diagnosis. Characterization of these autoantibodies may promote better understanding of the syndrome, an emerging health problem affecting East Asia populations and impeding their welfare and economic development. PMID- 29512396 TI - High acute phase protein levels correlate with pulmonary and skin involvement in patients with diffuse systemic sclerosis. AB - Objective This study was performed to evaluate the serum amyloid A (SAA) and C reactive protein (CRP) levels in patients with diffuse systemic sclerosis (dSSc) in relation to a control group, disease duration, and skin and pulmonary involvement. Methods This case-control study included 18 patients with early dSSc, 15 patients with late dSSc, and 15 healthy controls. The SAA and CRP levels, modified Rodnan skin score (mRSS), and diffusing capacity of the lungs for carbon monoxide (DLCO) were determined in all patients. Results The SAA and CRP levels were significantly higher in patients with early and late dSSc than in healthy controls. The frequency of detection of elevated SAA and CRP levels was approximately 66% and 85%, respectively. A significant correlation was found between the SAA and CRP levels in patients with dSSc. The SAA and CRP levels were inversely correlated with DLCO. The CRP level was positively correlated with the mRSS. Conclusions High SAA and CRP levels could serve as biomarkers for pulmonary involvement. The serum CRP level accurately reflects the extension of skin thickening in patients with dSSc. PMID- 29512399 TI - Electrocardiography-controlled central venous catheter tip positioning in patients with atrial fibrillation. AB - INTRODUCTION:: A significant increase of the p-wave of a real-time intracavitary electrocardiography is a reliable and safe method to confirm the central venous catheter tip position close to the atrium. However, conflicting data about the feasibility of electrocardiography exist in patients with atrial fibrillation. METHODS:: An observational prospective case-control cohort study was set up to study the feasibility and accuracy of the electrocardiography-controlled central venous catheter tip placement in 13 patients with atrial fibrillation versus 10 patients with sinus rhythm scheduled for elective surgery. Each intervention was crosschecked with ultrasound-guided positioning via right supraclavicular fossa view and chest radiography. Ultrasound-guided supraclavicular venipuncture of the right subclavian vein and guidewire advancement were performed. A B-mode view of the superior vena cava and the right pulmonary artery was obtained to visualize the J-tip of the guidewire. The central venous catheter was advanced over the guidewire and the electrocardiography was derived from the J-tip of the guidewire protruding from the central venous catheter tip. Electrocardiography was read for increased p- and atrial fibrillation waves, respectively, and insertion depth was compared with the ultrasound method. RESULTS:: Electrocardiography indicated significantly increasing fibrillation and p-waves, respectively, in all patients and ultrasound-guided central venous catheter positioning confirmed a tip position within the lower third of the superior vena cava. CONCLUSION:: Electrocardiography-guided central venous catheter tip positioning is a feasible real-time method for patients with atrial fibrillation. Combined with ultrasound, the electrocardiography-controlled central venous catheter placement may eliminate the need for postinterventional radiation exposure. PMID- 29512398 TI - Analysis of factors associated with development of Bacille Calmette-Guerin inoculation site change in patients with Kawasaki disease. AB - Objective The present study was performed to identify factors associated with a Bacille Calmette-Guerin (BCG) inoculation site change in patients with Kawasaki disease (KD). Methods Among patients who had received BCG vaccination and treatment for KD at our hospital from 2005 through 2016, 177 patients born in 2005 through 2016 were enrolled. The patients were divided into those with (n = 83, change group) and without (n = 94, no-change group) a BCG site change, and the patient demographics, clinical severity, blood examination results, and echocardiographic findings were compared between the two groups. Results The change group was younger at onset and had a shorter interval from vaccination to onset. A BCG site change was observed in patients who developed the onset of KD symptoms from 31 to 806 days after BCG vaccination. Multivariate analysis showed that the interval from vaccination was closely and positively associated with the BCG site change (hazard ratio = 0.995, 95% confidence interval = 0.993-0.997). Conclusion A BCG site change in patients with KD is most closely associated with the interval from BCG vaccination to onset. PMID- 29512400 TI - Adiponectin receptor 1-mediated micro RNA-323-3p regulates functions of the MIN6 cell line via the AMP-activated protein kinase/sirtuin-1 pathway. AB - Background The development of an effective treatment for type 2 diabetes mellitus is urgently needed. This study aimed to investigate the role of micro RNA (miR) 323-3p in regulating the expression of adiponectin receptor 1 (AdipoR1), as well as the insulin secretion and cell function of pancreatic MIN6 beta-cells. Methods MIN6 cells were treated with miR-323-3p mimics or inhibitors, and the effects on cell growth, proliferation, mitosis, and insulin secretion were studied. The expression levels of sirtuin-1 (SIRT-1) and AMP-activated protein kinase (AMPK) genes were also assessed. Results miR-323-3p directly targeted AdipoR1, and suppressed its expression at mRNA and protein levels. It also regulated the protein expression of SIRT-1 and AMPK, which are downstream target genes of the AdipoR1 signaling pathway. miR-323-3p suppressed cell growth, proliferation, mitosis, and insulin secretion of MIN6 cells. Conclusions miR-323-3p appears to be a crucial diabetes factor that mediates its functions by inhibiting the AdipoR1/AMPK/SIRT-1 signaling pathway. Our findings suggest that targeting AdipoR1 with inhibitors of miR-323-3p is a potential approach to improve the function of islet cells. PMID- 29512401 TI - GENIPAC: A Genomic Information Portal for Head and Neck Cancer Cell Systems. AB - Head and neck cancer (HNC)-derived cell lines represent fundamental models for studying the biological mechanisms underlying cancer development and precision therapies. However, mining the genomic information of HNC cells from available databases requires knowledge on bioinformatics and computational skill sets. Here, we developed a user-friendly web resource for exploring, visualizing, and analyzing genomics information of commonly used HNC cell lines. We populated the current version of GENIPAC with 44 HNC cell lines from 3 studies: ORL Series, OPC 22, and H Series. Specifically, the mRNA expressions for all the 3 studies were derived with RNA-seq. The copy number alterations analysis of ORL Series was performed on the Genome Wide Human Cytoscan HD array, while copy number alterations for OPC-22 were derived from whole exome sequencing. Mutations from ORL Series and H Series were derived from RNA-seq information, while OPC-22 was based on whole exome sequencing. All genomic information was preprocessed with customized scripts and underwent data validation and correction through data set validator tools provided by cBioPortal. The clinical and genomic information of 44 HNC cell lines are easily assessable in GENIPAC. The functional utility of GENIPAC was demonstrated with some of the genomic alterations that are commonly reported in HNC, such as TP53, EGFR, CCND1, and PIK3CA. We showed that these genomic alterations as reported in The Cancer Genome Atlas database were recapitulated in the HNC cell lines in GENIPAC. Importantly, genomic alterations within pathways could be simultaneously visualized. We developed GENIPAC to create access to genomic information on HNC cell lines. This cancer omics initiative will help the research community to accelerate better understanding of HNC and the development of new precision therapeutic options for HNC treatment. GENIPAC is freely available at http://genipac.cancerresearch.my/ . PMID- 29512402 TI - Trans-popliteal access for treatment of life-threatening hyperkalemia when all other conventional access fails. PMID- 29512403 TI - General practitioners: Between integration and co-location. The case of primary care centers in Tuscany, Italy. AB - Healthcare systems have followed several strategies aimed at integrating primary care services and professionals. Medical homes in the USA and Canada, and primary care centres across Europe have collocated general practitioners and other health and social professionals in the same building in order to boost coordination among services and the continuity of care for patients. However, in the literature, the impact of co-location on primary care has led to controversial results. This article analyses the possible benefits of the co-location of services in primary care focusing on the Italian model of primary care centres (Case della Salute) in terms of general practitioners' perception. We used the results of a web survey of general practitioners in Tuscany to compare the experiences and satisfaction of those general practitioners involved and not involved in a primary care centre, performed a MONAVA and ANOVA analysis. Our case study highlights the positive impact of co-location on the integration of professionals, especially with nurses and social workers, and on organizational integration, in terms of frequency of meeting to discuss about quality of care. Conversely, no significant differences were found in terms of either clinical or system integration. Furthermore, the collaboration with specialists is still weak. Considering the general practitioners' perspective in terms of experience and satisfaction towards primary care, co-location strategies is a necessary step in order to facilitate the collaboration among professionals and to prevent unintended consequences in terms of an even possible isolation of primary care as an involuntary 'disintegration of the integration'. PMID- 29512404 TI - Medication Errors: The School Nurse as Second Victim. AB - Medication errors occur in the school setting as they do in other healthcare settings. In this article, three accounts of school nurse medication errors are presented. School nurses often undergo emotional trauma after a mistake is made. Other fields of healthcare are incorporating the second victim phenomena in their responses to errors, with the patient as the first victim and the caregiver who made the mistake as the second. Researchers have identified six stages of the second victim's journey. School nurses and administrators would benefit from understanding and utilizing this model. PMID- 29512405 TI - Symptom attribution and treatment seeking in Australian veterans. AB - To understand the role of symptom attribution in treatment-seeking behaviours, survey results of 1356 veterans (age = 38-72 years) were analysed. Controlling for symptom frequency, significant relationships were found for specialist and psychological-related consultations. Those who favoured psychological explanations for symptoms were more likely to attend specialist and psychology related consultations and filled significantly more prescriptions than people who predominantly explained symptoms by situational factors (normalisers). Veterans who favoured somatic explanations attended more general practitioner consultations than normalisers. Attributional style should be considered part of the constellation of factors influencing healthcare usage. Normalisers, the predominant group, used fewest health services and filled fewest prescriptions; this may have important implications for healthcare considering their tendency to minimise or downplay symptoms. PMID- 29512406 TI - Cytokine signaling in multiple sclerosis: Lost in translation. AB - Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical studies delineate abnormal expression of specific cytokines over the course of disease. Preclinical studies using animal models of MS have yielded promising results in manipulating the activity of certain cytokines to improve the clinical outcome. However, the translation of these findings into the clinic is often disappointing. The reason for this might be the complex nature of cytokine networks and the pathogenesis of neuroinflammation, as well as an oversimplified interpretation of preclinical observations. This review presents an overview on cytokines that potentially contribute to the development of MS and provides examples of success and failure in translating basic science into clinical benefit for people with MS. PMID- 29512407 TI - The association of genotype polymorphisms with vascular access patency in hemodialysis patients. AB - Some hemodialysis patients suffer from repeat dysfunction of dialysis vascular access and need procedures of angioplasty, thrombectomy, and even temporary catheter use. Why these patients are vulnerable to vascular access dysfunction and how to improve its patency are imperative to be discovered. Traditional risk factors for vascular access function had been widely investigated but could not fully explain this question. Several genotype polymorphisms were demonstrated to increase the incidence of cardiovascular disease and might also be linked to higher risk of vascular access dysfunction. As the major causes of arteriovenous access thrombosis are hypercoagulable status and arteriovenous access stenosis, the investigated genes mainly focus on the mediators of the coagulation cascade, inflammatory process, and endothelial dysfunction. The reported polymorphisms of genes significantly associated with arteriovenous access dysfunction included genes encoding methylene tetrahydrofolate reductase, coagulation factors, heme oxygenase-1, matrix metalloproteinase, transforming growth factor-beta1, tumor necrosis factor-alpha, vascular endothelial growth factor-A, renin-angiotensin aldosterone system, and protein methyl transferase. However, further prospective study is indispensable to elucidate the association between the genotype polymorphisms and the outcome of vascular access. More and more therapeutic options that focus on genotype polymorphisms may generate a great benefit to the patency of vascular access of uremic patients. PMID- 29512408 TI - Supporting autonomy of nursing home residents with dementia in the informed consent process. AB - Background In studies involving people with dementia, researchers have historically defaulted to seeking consent from a proxy, the assumption being that people with dementia are unable to provide their own informed consent. This choice denies people with dementia a voice in the consent process, thus disregarding their autonomy and agency. Recently, other options for improving the consent process have been explored. Objective This study aimed to determine whether nursing home residents with dementia could demonstrate an ability to provide their own informed consent as determined by the Evaluation to Sign Consent instrument. Methods As part of a larger study on the quality of life of nursing home residents, the Evaluation to Sign Consent was administered to 392 people diagnosed with dementia. Data on demographic variables, such as gender and age, as well as level of cognitive impairment, were also collected. Results Just over one-fifth (22%) of the residents with dementia were judged as having the capacity to provide their own informed consent to participate in this specific research project. Consistent with existing literature, capacity to consent was significantly, and negatively, associated with cognitive impairment. Conclusion This study demonstrates that assuming all people diagnosed with dementia are unable to provide informed consent for research on the basis of cognitive test scores, or on clinical assessment alone, potentially denies them the autonomy to make a decision that they may be capable of making. Research involving people with mild-to-moderate dementia needs to consider evaluating whether potential participants have the capacity to provide their own consent. PMID- 29512409 TI - 'Living together with dementia' - Conceptual validation of training programme for family caregivers: Innovative practice. AB - This article presents results from a conceptual validation of the programme 'Living Together with Dementia', through an e-Delphi study carried out during April/May, 2015 with 26 Portuguese and Spanish experts. The programme consists of seven individual weekly sessions and two group sessions over a seven-week period. It covers dementia, communication and behaviour; demands and expectations of the caregiver role; basic activities of daily living; coping and problem solving strategies; physical and mental health of the caregiver and community support. The programme methods mainly consist of discussion sessions, practical examples/simulations and skill training. PMID- 29512410 TI - Experimental measurement and numerical modelling of dye washout for investigation of blood residence time in ventricular assist devices. AB - Ventricular assist devices have become the standard therapy for end-stage heart failure. However, their use is still associated with severe adverse events related to the damage done to the blood by fluid dynamic stresses. This damage relates to both the stress magnitude and the length of time the blood is exposed to that stress. We created a dye washout technique which combines experimental and numerical approaches to measure the washout times of ventricular assist devices. The technique was used to investigate washout characteristics of three commercially available and clinically used ventricular assist devices: the CentriMag, HVAD and HeartMate II. The time taken to reach 5% dye concentration at the outlet (T05) was used as an indicator of the total residence time. At a typical level of cardiac support, 5 L/min and 100 mmHg, T05 was 0.93, 0.28 and 0.16 s for CentriMag, HVAD and HeartMate II, respectively, and increased to 5.06, 1.64 and 0.96 s for reduced cardiac support of 1 L/min. Regional variations in washout characteristics are described in this article. While the volume of the flow domain plays a large role in the differences in T05 between the ventricular assist devices, after standardising for ventricular assist device volume, the secondary flow path was found to increase T05 by 35%. The results explain quantitatively, for the first time, why the CentriMag, which exerts low shear stress magnitude, has still been found to cause acquired von Willebrand Syndrome in patients. PMID- 29512411 TI - Socioeconomic correlates of dietary diversity and its association with adherence and psychosocial functioning of people living with HIV in rural Zambia. AB - BACKGROUND: The intersection of nutrition and HIV underscores the importance of adequate food and a diverse diet. In communities with high prevalence of food insecurity and HIV, there is a substantial co-occurrence of low dietary diversity, undernutrition, and adverse health outcomes. AIM: The aim of this study was to identify correlates of individual dietary diversity (IDD) and its association with health outcomes for people living with HIV (PLHIV) in rural Zambia. METHODS: The study used a cross-sectional design using data from 101 PLHIV. We calculated IDD using a composite score based on dietary diversity, food frequency, and the relative nutritional importance of different food groups. Adherence was measured using the visual analog scale. Psychosocial functioning was measured using the Structural Barriers to Medication-taking Scale and the Perceived Stress Scale. Data were analyzed using linear and logistic regressions. Multiple imputation was conducted to address missing data. RESULTS: Staples were the most commonly consumed food group. Income and household size were negatively associated with IDD scores. Assets were positively associated with IDD scores. Residing in Lundazi and having a poor or fair self-rated health were associated with lower IDD scores. IDD was also associated, albeit not significant, with desirable health outcomes, including adherence and lower levels of perceived barriers to pill taking and stress. CONCLUSIONS: Findings suggest a heterogeneous effect of socioeconomic variables on IDD. Understanding this heterogeneity is important for the design of interventions. Interventions that combine opportunities to generate economic resources with food and nutrition coaching may be appropriate and effective. PMID- 29512413 TI - Evaluation of brain lesion distribution criteria at disease onset in differentiating MS from NMOSD and MOG-IgG-associated encephalomyelitis. AB - OBJECTIVES:: We aimed to evaluate the utility of the recently described brain lesion distribution criteria to differentiate multiple sclerosis (MS) from aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein immunoglobulin G-associated encephalomyelitis (MOG-EM) at disease onset in an Asian cohort. METHODS:: A total of 214 patients who fulfilled the published criteria for MS, NMOSD, or MOG-EM and underwent brain magnetic resonance imaging (MRI) within 3 months of disease onset were enrolled. The brain lesion distribution criteria were defined as the presence of a lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe, or an S-shaped U-fiber lesion, or a Dawson's finger-type lesion. RESULTS:: Brain lesions were identified in the initial MRI scans of 166/214 patients. The distribution criteria were applied to these scans (MS ( n = 94), NMOSD ( n = 64), and MOG-EM ( n = 8)). The sensitivity, specificity, and positive and negative predictive values of the criteria for MS versus NMOSD were 79.8%, 87.5%, 90.4%, and 74.7%, and for MS versus MOG-EM these were 79.8%, 100%, 100%, and 29.6%, respectively. CONCLUSION:: These findings suggest that the brain lesion distribution criteria are helpful in distinguishing MS from NMOSD and MOG EM in an Asian population, even at disease onset. PMID- 29512412 TI - Optical Characterization of Paper Aging Based on Laser-Induced Fluorescence (LIF) Spectroscopy. AB - Paper aging and degradation are growing concerns for those who are responsible for the conservation of documents, archives, and libraries. In this study, the paper aging was investigated using laser-induced fluorescence spectroscopy (LIFS), where the fluorescence properties of 47 paper samples with different ages were explored. The paper exhibits fluorescence in the blue-green spectral region with two peaks at about 448 nm and 480 nm under the excitation of 405 nm laser. Both fluorescence peaks changed in absolute intensities and thus the ratio of peak intensities was also influenced with the increasing ages. By applying principal component analysis (PCA) and k-means clustering algorithm, all 47 paper samples were classified into nine groups based on the differences in paper age. Then the first-derivative fluorescence spectral curves were proposed to figure out the relationship between the spectral characteristic and the paper age, and two quantitative models were established based on the changes of first-derivative spectral peak at 443 nm, where one is an exponential fitting curve with an R squared value of 0.99 and another is a linear fitting curve with an R-squared value of 0.88. The results demonstrated that the combination of fluorescence spectroscopy and PCA can be used for the classification of paper samples with different ages. Moreover, the first-derivative fluorescence spectral curves can be used to quantitatively evaluate the age-related changes of paper samples. PMID- 29512414 TI - Withdrawn: An assessment of the dementia CQUIN - An audit of improving compliance. PMID- 29512415 TI - A younger onset dementia toolkit: Innovative practice. AB - A diagnosis of younger onset dementia requires specific care tailored to the individual and the family. Dementia care workers often do not have the skills and experience necessary to offer this care within the residential and community environment. This article reports the development of an interactive resource to educate those employed to care for people living with younger onset dementia. Prescription for Life, a talking e-Flipbook was developed and piloted in two states of Australia. Feedback from the pilots was incorporated in the resource prior to a national rollout. The project was supported by an expert panel, including experts from national aged care providers. PMID- 29512416 TI - A cost-effective alternative formulation of ultrasound phantom for vascular access instruction: Cost-effective hands-on procedural training. PMID- 29512417 TI - Comparison of surgical and radiological interventions for thrombosed arteriovenous access. AB - INTRODUCTION:: To compare open surgical and radiological interventions for thrombosed arteriovenous access for dialysis. METHODS:: A retrospective analysis of access procedures and dialysis episodes from 1 December 2002 to 30 November 2015 with follow-up up to 1 August 2016. Hospital records and dialysis database interrogated for further interventions and length of functional use. RESULTS:: Some 128 surgical and 27 radiological thrombectomies were compared. Radiological treatment was successful in 24 (89%) cases and surgical interventions in 65 cases (51%; p < 0.001). In all, 82 (64%) of the 128 surgical thrombectomies had no additional treatment, 43 (34%) had a surgical revision and 3 cases (2%) had an on table balloon angioplasty. All 27 interventional thrombectomies had an additional balloon angioplasty. Success rate was significantly increased after a surgical revision (74%) or balloon angioplasty (87%) compared to no adjuvant procedure (38%; p < 0.001). There was a trend towards higher primary failure rates of arteriovenous fistula thrombectomies in the upper arm (57%) compared to the arteriovenous fistula thrombectomies in forearm (40%) and arteriovenous graft thrombectomies (33%; p = 0.056). Assisted primary patency was better after interventional treatment compared to surgery (p = 0.02) and significantly better after thrombectomy with additional treatment (p = 0.005). Patency after surgical revision or balloon angioplasty of the access was similar (p = 0.15). More procedures were required to maintain the access after balloon angioplasty than after surgical revision, and intervention-free survival was better after surgical revision (p = 0.02). CONCLUSION:: Revision procedures significantly increase success rate of access thrombectomies. Radiological thrombectomies have higher success rates but lower intervention-free survival and need more additional procedures to maintain patency. PMID- 29512418 TI - Effect of decrease in radial inclination of distal radius fractures on distal radioulnar joint stability: a biomechanical study. AB - We investigated the relationship between the radial inclination of the distal radius and distal radioulnar joint stability. Six fresh-frozen upper extremities were used. Radial inclination was decreased by 10 degrees and 20 degrees and increased by 10 degrees from the original radial inclination. Distal radioulnar joint stiffness was assessed with an intact radioulnar ligament and after partial and then complete sectioning of the radioulnar ligament. Radial angulation deformities significantly increased distal radioulnar joint stiffness when the radioulnar ligament is totally or partially attached to the ulnar fovea. After complete sectioning of the radioulnar ligament, distal radioulnar joint stiffness decreased significantly; additional radial angulation deformity slightly increased distal radioulnar joint stiffness, but the distal radioulnar joint never recovered to the original stiffness. Based on the results, radial angulation deformities of the distal radius should be corrected within 10 degrees when the radioulnar ligament is intact, to reduce the risk of symptomatic distal radioulnar joint instability. PMID- 29512419 TI - Effect of Heliox on Respiratory Outcomes during Rigid Bronchoscopy in Term Lambs. AB - Objective To (1) compare physiologic changes during rigid bronchoscopy during spontaneous and mechanical ventilation and (2) evaluate the efficacy of a helium oxygen (heliox) gas mixture as compared with room air during rigid bronchoscopy. Study Design Crossover animal study evaluating physiologic parameters during rigid bronchoscopy. Outcomes were compared with predicted computational fluid analysis. Setting Simulated ventilation via computational fluid dynamics analysis and term lambs undergoing rigid bronchoscopy. Methods Respiratory and physiologic outcomes were analyzed in a lamb model simulating bronchoscopy during foreign body aspiration to compare heliox with room air. The main outcome measures were blood oxygen saturation, heart rate, blood pressure, partial pressure of oxygen, and partial pressure of carbon dioxide. Computational fluid dynamics analysis was performed with SOLIDWORKS within a rigid pediatric bronchoscope during simulated ventilation comparing heliox with room air. Results For room air, lambs desaturated within 3 minutes during mechanical ventilation versus normal oxygen saturation during spontaneous ventilation ( P = .01). No improvement in respiratory outcomes was seen between heliox and room air during mechanical ventilation. Computational fluid dynamics analysis demonstrates increased turbulence within size 3.5 bronchoscopes when comparing heliox and room air. Meaningful comparisons could not be made due to the intolerance of the lambs to heliox in vivo. Conclusion During mechanical ventilation on room air, lambs desaturate more quickly during rigid bronchoscopy on settings that should be adequate. Heliox does not improve ventilation during rigid bronchoscopy. PMID- 29512421 TI - Isotretinoin-induced urethritis versus non-gonococcal urethritis in a man who has sex with men: an open debate. AB - This is the case of a young man presenting with urethritis despite a negative infectious work-up. Careful history taking elucidated a strong correlation between symptom onset and a recent dose escalation of isotretinoin for treatment of his refractory cystic acne. The urethral symptoms quickly resolved with dose reduction, suggesting urethritis as a rare adverse reaction of isotretinoin. PMID- 29512420 TI - Advanced Cancer Patients' Perceptions of Dignity: The Impact of Psychologically Distressing Symptoms and Preparatory Grief. AB - PURPOSE: The present study assesses the relationship between patient dignity in advanced cancer and the following variables: psychological distress, preparatory grief, and sociodemographic and clinical characteristics. METHODS: The sample consisted of 120 patients with advanced cancer. The self-administered questionnaires were as follows: the Preparatory Grief in Advanced Cancer Patients (PGAC), the Patient Dignity Inventory-Greek (PDI-Gr), the Greek Schedule for Attitudes toward Hastened Death (G-SAHD), and the Greek version of the Hospital Anxiety and Depression Scale (G-HADS). RESULTS: Moderate to strong statistically significant correlations were found between the 4 subscales of PDI-Gr (psychological distress, body image and role identity, self-esteem, and social support) with G-HADS, G-SAHD, and PGAC ( P < .005), while physical distress and dependency was moderately correlated with depression. Multifactorial analyses showed that preparatory grief, depression, and age influenced psychological distress, while preparatory grief, depression, and performance status influenced body image and role identity. CONCLUSIONS: Preparatory grief, psychological distress, and physical symptoms had significant associations with perceptions of dignity among patients with advanced cancer. Clinicians should assess and attend to dignity-distressing factors in the care of patients with advanced cancer. PMID- 29512422 TI - Endovascular treatment of post-thrombotic and non-thrombotic iliofemoral venous outflow obstructions with self-expanding nitinol stents. AB - BACKGROUND: The aim of the study was to investigate venous patency and clinical outcomes for endovascular treatment of iliofemoral venous obstruction in patients with post-thrombotic syndrome (PTS) and non-thrombotic iliac vein lesion (NIVL) with dedicated self-expanding nitinol stents. PATIENTS AND METHODS: Data were collected from the prospective Swiss Venous Stent Registry, enrolling consecutive patients with a standardized follow-up procedure since January 2008. Patency was evaluated by duplex sonography and clinical outcome by various scores including the Villalta score at baseline, three, six, and 12 months, and then annually after endovascular therapy. RESULTS: Overall, 93 patients (64 PTS, 29 NIVL) were analysed. Mean follow-up time was 20 +/- 16 (range 3-70) months. A total of 11 (12 %) patients had a stent occlusion, all of which occurred in the PTS group, and 13 (14 %) patients had a symptomatic stent stenosis. Primary patency was 79 % (95 % CI 68-87 %) at 12 months and 72 % (95 % CI 59-82 %) at 24 months. In PTS patients, primary patency at 12 months was 75 % (95 % CI 61-84 %) vs. 89 % (95 % CI 63-97 %) in NIVL patients (p = 0.10). Secondary patency at 24 months was 94 % (95 % CI 84-98 %) in PTS and 100 % in NIVL, p = 0.19). Overall, 62 (67 %) patients were free from PTS at the latest follow-up with a Villalta score < 5 points. Predictive factors for the loss of primary patency were stents placed below the inguinal ligament (OR 2.59, 95 % CI, 0.99-6.84, p = 0.05). CONCLUSIONS: In symptomatic patients with chronic iliofemoral vein obstruction, endovascular therapy with self-expanding nitinol stents was associated with favourable patency rates and clinical improvement in the majority of patients. PMID- 29512423 TI - A cross-linguistic comparison of category and letter fluency: Mandarin and English. AB - Verbal fluency tasks are widely applied in a variety of languages, but whether the quality and quantity of responses are comparable across structurally different writing systems is debatable. For example, since there are no letters in a logographic, non-alphabetic language such as Chinese, the mechanisms speakers use to generate a list of words in a letter fluency task might be structurally different than those used by speakers of alphabetic languages. In this study, we investigated lexical retrieval strategies and approaches in letter and category fluency tasks among monolingual Mandarin speakers compared to monolingual English speakers. We found that the responses of Mandarin speakers are both qualitatively and quantitatively different in letter fluency, and qualitatively different in category fluency. These results suggest that differences in task completion among non-English-speaking populations are important to consider when using this extensively utilised cognitive and linguistic measure in research and clinic. PMID- 29512424 TI - Chlamydia trachomatis infection influences the clinical course of acute bronchiolitis. AB - The frequency of Chlamydia trachomatis infection among young infants admitted with acute bronchiolitis was analysed to determine whether the former affects the clinical course of the latter. A total of 92 infants aged <6 months admitted with acute bronchiolitis were tested for C. trachomatis by a cell culture technique, obtaining nasal smears from each infant's nostrils. A second nasal sampling was taken for respiratory viruses from the study group and tested with real-time polymerase chain reaction. Clinical characteristics of C. trachomatis-positive and -negative cases were compared. C. trachomatis was detected in 22.8% of the infants, mostly as coinfection with respiratory viral agents. Infection with C. trachomatis affected the clinical outcome in acute bronchiolitis and such infants tended to have severe bronchiolitis. PMID- 29512425 TI - Improving Measurement Efficiency of the Inner EAR Scale with Item Response Theory. AB - Objectives (1) To assess the 11-item Inner Effectiveness of Auditory Rehabilitation (Inner EAR) instrument with item response theory (IRT). (2) To determine whether the underlying latent ability could also be accurately represented by a subset of the items for use in high-volume clinical scenarios. (3) To determine whether the Inner EAR instrument correlates with pure tone thresholds and word recognition scores. Design IRT evaluation of prospective cohort data. Setting Tertiary care academic ambulatory otolaryngology clinic. Subjects and Methods Modern psychometric methods, including factor analysis and IRT, were used to assess unidimensionality and item properties. Regression methods were used to assess prediction of word recognition and pure tone audiometry scores. Results The Inner EAR scale is unidimensional, and items varied in their location and information. Information parameter estimates ranged from 1.63 to 4.52, with higher values indicating more useful items. The IRT model provided a basis for identifying 2 sets of items with relatively lower information parameters. Item information functions demonstrated which items added insubstantial value over and above other items and were removed in stages, creating a 8- and 3-item Inner EAR scale for more efficient assessment. The 8 item version accurately reflected the underlying construct. All versions correlated moderately with word recognition scores and pure tone averages. Conclusion The 11-, 8-, and 3-item versions of the Inner EAR scale have strong psychometric properties, and there is correlational validity evidence for the observed scores. Modern psychometric methods can help streamline care delivery by maximizing relevant information per item administered. PMID- 29512426 TI - End-of-Life Care for an Undocumented Mexican Immigrant: Resident Perspective. AB - The immigrant population in the United States has grown over the past years. Undocumented immigrants account for 14.6% of the uninsured population in the United States. Decisions about end-of-life treatment are often difficult to reach in the best of situations. We present a 43-year-old undocumented Mexican female immigrant with metastatic sarcomatoid squamous cell cervical cancer and discuss the barriers that she faced during her treatment. Limited English proficiency, living below the poverty line, low level of education, and lack access to Medicare, Medicaid, or other insurance coverage under the Affordable Care Act are major causes of decreased health-care access and service utilization by the immigrant population. Latinos are less likely to be referred to hospice by oncologists, and nearly a third of hospice agencies offer limited or no services to undocumented immigrants. Undocumented immigrants with terminal diagnoses generally do not have access to comprehensive or multidisciplinary follow-up treatment. Instead, one of their few options is to return to their home countries without any long-term treatment. This article discusses the many barriers and proposes areas for reform. PMID- 29512427 TI - The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis. AB - BACKGROUND: Episodic memory loss is one of the most common cognitive symptoms in patients with multiple sclerosis (MS), but the pathophysiology of this symptom remains unclear. Both the hippocampus and thalamus have been implicated in episodic memory and show regional atrophy in patients with MS. OBJECTIVE: In this work, we used functional magnetic resonance imaging (fMRI) during a verbal episodic memory task, lesion load, and volumetric measures of the hippocampus and thalamus to assess the relative contributions to verbal and visual-spatial episodic memory. METHODS: Functional activation, lesion load, and volumetric measures from 32 patients with MS and 16 healthy controls were used in a predictive analysis of episodic memory function. RESULTS: After adjusting for disease duration, immediate recall performance on a visual-spatial episodic memory task was significantly predicted by hippocampal volume ( p < 0.003). Delayed recall on the same task was significantly predicted by volume of the left thalamus ( p < 0.003). For both memory measures, functional activation of the thalamus during encoding was more predictive than that of volume measures ( p < 0.002). CONCLUSION: Our results suggest that functional activation may be useful as a predictive measure of episodic memory loss in patients with MS. PMID- 29512428 TI - Attitudes of radiation oncologists to percutaneous endoscopic gastrostomy in patients with head and neck cancer and eating difficulties: A survey in China. AB - Objective To investigate the attitudes of radiation oncologists towards using percutaneous endoscopic gastrostomy (PEG) to solve nutritional problems in patients with head and neck cancer (HNC) undergoing radiotherapy. Methods A self reported questionnaire was developed and used to assess the willingness of radiation oncologists from 26 hospitals throughout several provinces in China to use the nutritional method. Results Of the 433 radiation oncologists who were contacted and returned questionnaires, 361 were completed correctly and used in the study (83.4% completion rate). Years of working and degree of understanding PEG were significantly related to the willingness of oncologists to use PEG in patients with HNC. Radiation oncologists who were willing to accept PEG training were more willing to use PEG. Main reasons for unwillingness to use PEG were poor understanding of the operation or cost and fear of side effects causing medical disputes. Conclusions The findings of the survey suggest that attitudes of radiation oncologists in China towards using PEG in patients with HNC requiring nutritional support may be improved by providing accessible training in the technique. PMID- 29512429 TI - Comparison of two intramuscular sedation protocols on sedation, recovery and ease of venepuncture for cats undergoing blood donation. AB - Objectives The aim of this study was to compare the quality of sedation and recovery, and ease of venepuncture following sedation for feline blood donation using two intramuscular (IM) sedation protocols: alfaxalone/butorphanol (AB) and dexmedetomidine/butorphanol (DB). Methods This was an experimental randomized, blinded, crossover study. Ten client-owned healthy cats were recruited to participate in the study. Cats were sedated with AB (alfaxalone 2 mg/kg and butorphanol 0.2 mg/kg) for one donation and DB (dexmedetomidine 10 MUg/kg and butorphanol 0.2 mg/kg) for another. Reaction to injection, quality of sedation and quality of recovery were assessed by a blinded observer. Time to lateral recumbency, number of venepuncture attempts, time required for blood collection and time to return to sternal recumbency were recorded. Cats were monitored for evidence of gastrointestinal distress. Each donation consisted of a maximum of 53 ml whole blood drawn over 3-22 mins. Donors received 100 ml subcutaneous lactated Ringer's solution in recovery. Owners, unaware of sedation protocol, were asked to complete a questionnaire evaluating their cat's behavior following sedation. Results IM injections were well tolerated by both treatment groups. There was no significant difference between treatment groups in sedation scores for posture ( P = 0.30) or behavior ( P = 0.06). Cats sedated with DB had significantly higher muscle relaxation scores ( P = 0.03) compared with AB. There was no significant difference between treatment groups in time to lateral recumbency ( P = 0.12), number of venepuncture attempts ( P = 0.91) and time for blood draw ( P = 0.29). There was no difference in quality of recoveries between treatment groups based on simple descriptive scores ( P = 0.18) and owner evaluation 24 h following sedation. One cat vomited following administration of DB. Conclusions and relevance Alfaxalone is a suitable alternative to dexmedetomidine when combined with butorphanol and used as part of an IM sedation protocol for cats undergoing blood donation. PMID- 29512431 TI - What Does It Take To Be a School Nurse? PMID- 29512430 TI - Infection of totally implantable venous access devices: A review of the literature. AB - Totally implantable venous access devices, or ports, are essential in the therapeutic management of patients who require long-term intermittent intravenous therapy. Totally implantable venous access devices guarantee safe infusion of chemotherapy, blood transfusion, parenteral nutrition, as well as repeated blood samples. Minimizing the need for frequent vascular access, totally implantable venous access devices also improve the patient's quality of life. Nonetheless, totally implantable venous access devices are not free from complications. Among those, infection is the most relevant, affecting patients' morbidity and mortality-both in the hospital or outpatient setting-and increasing healthcare costs. Knowledge of pathogenesis and risk factors of totally implantable venous access device-related infections is crucial to prevent this condition by adopting proper insertion bundles and maintenance bundles based on the best available evidence. Early diagnosis and prompt treatment of infection are of paramount importance. As a totally implantable venous access device-related infection occurs, device removal or a conservative approach should be chosen in treating this complication. For both prevention and therapy, antimicrobial lock is a major matter of controversy and a promising field for future clinical studies. This article reviews current evidences in terms of epidemiology, pathogenesis and risk factors, diagnosis, prevention, and treatment of totally implantable venous access device-related infections. PMID- 29512432 TI - Full Coverage Sports Physicals: School Nurses' Untapped Role in Health Promotion Among Student Athletes. AB - Pre-participation physical exams (PPEs) hold great potential for addressing adolescents' health-risk behaviors. School nurses may be well positioned to assist with PPEs, yet little is known about their involvement. In this mixed methods study conducted in 2015, we collected data from school nurses in Texas (surveys, n = 208; key informant interviews, n = 10) to explore their roles and attitudes toward being involved in PPEs and addressing health-risk behaviors. Most respondents described minimal involvement in PPEs or were not involved to their full scope of practice. Most (69%) felt that school nurses are an untapped resource for addressing health-risk behaviors among student athletes. Interview participants felt that student athletes saw nurses as a "safe space" to talk about health-risk behaviors. Barriers included a lack of time, resources for follow-up, parental approval, and legal concerns. Study findings identify potential opportunities to support nurses' involvement in addressing health-risk behaviors among student athletes. PMID- 29512433 TI - Victimization by Bullying and Physical Symptoms Among South Korean Schoolchildren. AB - This study examined the relationship between victimization by bullying and physical symptoms among South Korean schoolchildren. Data were analyzed from a nationally representative sample of 2006 schoolchildren across South Korea aged 9 17 years. Multiple logistic regression analysis was used to estimate the associations between victimization by bullying and physical symptoms in the children. Schoolchildren bullied 4 or more times by peers in the previous year were approximately 3 times more likely to report recurrent stomachache or dizziness and twice as likely to report headache and sleep difficulties than students who were never victimized by peers. These risk estimates were calculated by controlling for confounding variables. School nurses, teachers, and school counselors or school social workers should consider frequent physical symptoms (headache, stomachache, dizziness, and sleep difficulties) as potential indicators of victimization through bullying and then provide prompt intervention and support using a multidisciplinary approach when harm is confirmed. PMID- 29512434 TI - Variations in Adolescent Purpose in Life and Their Association With Lifetime Substance Use. AB - Purpose in life (PIL) promotes positive development and is associated with decreased substance use. However, to our knowledge, researchers have not investigated how different categories of PIL are associated with substance use behavior among youth. Therefore, we sought to explore categories of PIL and how they are related to substance use in a sample of adolescents. Ninth through 12th grade students from a high school in a Midwest suburban community completed a paper-and-pencil survey ( n = 408, Mage = 15.36, SD = 1.21; 50% female; 72% White). Measures included lifetime substance use and categories of PIL. Exploratory factor analyses suggest that there are three categories of PIL. Alcohol and other drug (ATOD) use was inversely related with broad other promoting PIL, while a broad self-promoting PIL was positively associated with ATOD use. These findings suggest that exploring PIL with students may reduce substance use behavior. PMID- 29512436 TI - The 38th BMSS Annual Meeting, Royal Northern College of Music Manchester: 5th to 7th September 2017. PMID- 29512437 TI - Profile likelihood-based analyses of infectious disease models. AB - Ordinary differential equation models are frequently applied to describe the temporal evolution of epidemics. However, ordinary differential equation models are also utilized in other scientific fields. We summarize and transfer state-of the art approaches from other fields like Systems Biology to infectious disease models. For this purpose, we use a simple SIR model with data from an influenza outbreak at an English boarding school in 1978 and a more complex model of a vector-borne disease with data from the Zika virus outbreak in Colombia in 2015 2016. Besides parameter estimation using a deterministic multistart optimization approach, a multitude of analyses based on the profile likelihood are presented comprising identifiability analysis and model reduction. The analyses were performed using the freely available modeling framework Data2Dynamics (data2dynamics.org) which has been awarded as best performing within the DREAM6 parameter estimation challenge and in the DREAM7 network reconstruction challenge. PMID- 29512440 TI - Serendipity and margin of safety. PMID- 29512441 TI - Editorial: Brain Basis of Resilience and its Effect on Mood Disorders in the Aging. PMID- 29512442 TI - The Diabetic Foot. PMID- 29512443 TI - Editorial: Advanced Antimicrobial Materials and Interfaces. PMID- 29512444 TI - Pharmacokinetic and Toxicological Characteristics of Tripterigium Glycosides and Their Derivatives. AB - BACKGROUND: Tripterigium wilfordii glycosides (TWG) demonstrate paramount bioactive effectiveness in the management of many autoimmune diseases. However, its side effects on the hepatic, nephrotic, reproductive, and cardiovascular systems have limited its immense therapeutic potentials. Triptolide (TP) and Celastrol (CL), the leading bioactive as well as toxic constituents of TWG, have been widely studied. This review aims to summarize the key mechanisms that TWG trigger the toxic reactions and the precautionary measures that could prevent and reduce such reactions. METHOD: We undertook a systemic search of bibliographic databases for peer-reviewed research literature about the toxic mechanisms and pharmacokinetic profiles of TWG. The key points of screened papers were described and combined together to make up whole. RESULTS: Totally 125 papers were referred in this paper, the majority were from Chinese academic associations. It has been reported that reactive oxygen species generation, mitochondrial respiratory chain inhibition, and metabolizing enzyme inhibition are the leading factors of the toxic reactions. The bioactive effects and toxicities of TWG are closely related to its metabolic profiles. It has been confirmed that TP and CL inhibit CYP450 and the transporters. This paper reviews and summarizes the pharmacokinetic parameters of TWG. Antioxidants, polymeric micelle and topical nanoparticle formulations have exhibited potentials in toxicity circumvention. CONCLUSION: A thorough understanding of the pharmacokinetic and toxicological characteristics of TWG combined with further in-depth study will enhance the efficacy and safety in using TWG, which would augment and improve its clinical application in the future. PMID- 29512445 TI - An Insight into the Therapeutic Potential of Major Coffee Components. AB - BACKGROUND: The popular drink, coffee (Coffea arabica) is under the great attention of late because of its promising pharmacological potential. Caffeine (the major constituent of coffee) is known for its prominent psychoactive impact. This review aims at highlighting the therapeutic potentials of caffeine and other five coffee components viz. caffeic acid, chlorogenic acids, cafestol, ferulic acid and kahweol and their mechanisms of action. METHODS: An up-to-date search was made with selected keywords in PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society and miscellaneous databases (e.g., Google Scholar) for the published literature on the selected topic. RESULTS: A number of pharmacological activities are attributed to these components that include anti oxidant, antiinflammatory, immunomodulatory, anti-microbial, anti-cancer, cardioprotective and neuroprotective effects. In addition, osteogenesis (kahweol), anti-diabetic (caffeine, chlorogenic acid and ferulic acid) and hepatoprotective (chlorogenic acid) activities have also been reported by some of these components in the scientific literature. Caffeine has also been noted for adverse effect on the development of the brain at early stages and reproductive systems. CONCLUSION: A more advanced pre-clinical and clinical trials are recommended to investigate the safety profiles of these coffee components before their use as possible therapeutics. PMID- 29512446 TI - A Synopsis on the Role of Human Papilloma Virus Infection in Cervical Cancer. AB - BACKGROUND: Understanding of cervical cancer severity is still an important health issue across the world, especially for developing countries. Cancer or abnormal growth of the cell is one of the major health problems of the world. There are about two hundred types of malignancies reported till date. An updated statistic of all the main types of cancer and pathophysiology of cervical cancer is a significant need for designing the future treatment strategy. OBJECTIVE: In this review, a brief update on cancer, its causes and different types has been discussed along with updated statistics of patient's mortality. A brief overview of cervical cancer and its pathophysiology has been discussed with special emphasis on its causative agent, human papilloma virus (HPV). A brief introduction and update on genetics, molecular pathogenesis and prevalence of HPV and its role in cervical cancer have been added. CONCLUSION: This review delivered an updated status of cervical cancer and provide novel therapeutic approaches for targeting HPV. The detailed molecular and genomic information of the HPV help the researchers to develop more effective and efficacious therapeutic strategies and preventive vaccines that will significantly contribute to the control and anticipation of cervical cancer. Ultimately this may open new vistas to get rid of this deadly disease and may offer significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer in the affected nations. PMID- 29512447 TI - Current Therapeutic Approaches for Targeting Inflammation in Depression and Cardiovascular Disease. AB - BACKGROUND: Cardiovascular disease (CVD) and depression are extremely prevalent and debilitating conditions. Evidence suggest that there is a two-way relationship between depression and CVD. Inflammation is implicated in the pathophysiology of both conditions, thus representing a central candidate mediating the link between these disorders. Depression is consistently associated with increased inflammation and increased blood levels of inflammatory molecules. In recent years, studies have shown that depression significantly increases the risk of developing inflammatory-related diseases such as CVD, precipitated by the same inflammatory pathways involved in the pathophysiology of CVD. OBJECTIVE AND METHOD: The aim of this work is to discuss the role of inflammation in depression and CVD and review the evidence of the benefits and side effects of anti inflammatory drugs in both the diseases. RESULTS: Drugs with anti-inflammatory properties have shown benefit in alleviating signs and symptoms in CVD and in depression. This was shown to be particularly true for the following classes of drugs: non-steroidal antiinflammatory drugs (NSAIDS), polyunsaturated fatty acids (PUFAs) statins and cytokine inhibitors. Finally, antidepressant drugs initially used exclusively to treat depression also lead to improvement in CVD indicators, while lowering inflammation markers in patients at the same time. This evidence further strengthens the suggestion of the biological link between depression and CVD through inflammation. CONCLUSION: Strategies that can mitigate this risk profile are highly needed in the clinical setting, and these particular groups of drugs have the possibility of becoming increasingly important in treatment strategies aiming to improve both the conditions. PMID- 29512449 TI - Sodium Oxybate Treatment in Pediatric Type 1 Narcolepsy. AB - BACKGROUND: Narcolepsy type 1 (NT1) is a chronic neurologic disorder defined by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, typically with onset during childhood/ adolescence. Pediatric NT1 is associated with limitations on children's activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. Sodium oxybate (SO) is a sodium salt of gamma-hydroxybutyric (GHB) acid and is greatly effective in treating cataplexy and excessive daytime sleepiness in NT1 and it can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients. METHOD: We conducted a research of literature into bibliographic databases regarding NT1 features in childhood and the possible option treatment with SO in this kind of patient population. RESULTS: We reported sixteen papers focusing on symptom presentation and on clinical and metabolic features of children affected with NT1. Furthermore, we reported 24 manuscripts focusing on SO biological actions and pharmacological properties and on the few but important available studies (8) conducted in NT1 children under SO therapy. CONCLUSION: Although in the majority of patients develop NT1 during childhood, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Ongoing pediatric therapy is based only on observational data shared among sleep disorders clinicians. PMID- 29512448 TI - Frontier View on Nanotechnological Strategies for Neuro-therapy. AB - BACKGROUND: Nanotechnology exploits materials and devices with a functional organization that has been engineered at the nanometre scale. The application of nanotechnology in neuroscience involves specific interactions with neurons and glial cells. This property is used for delivering drugs and other small molecules (such as genes, oligonucleotides and contrasting agents) across the blood brain barrier (BBB), an important requirement for delivering the drug successfully to the brain. OBJECTIVE: Nanotechnology based approaches (NBA) favours transcytosis mediated delivery of nanoparticles to the brain by crossing the BBB. The last five years have witnessed the successful applications of NBA to treat neurological disorders. It is expected that the development of novel NBA will result in important insights on the brain mechanisms, and eventually provide better medical care to patients suffering from neurological disorders. CONCLUSION: This review introduces the emerging work in this area and summarizes the successful NBA used in recent past for treating various neurological disorders ike Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, meningitis and glioblastoma. PMID- 29512450 TI - Pharmacokinetics, Metabolism, Distribution and Permeability of Nanomedicine. AB - BACKGROUND: Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nanoparticles with less than 1nm in size have been used as drug delivery and gene delivery systems to accelerate the drug action in humans. Size of nanomaterials is akin to that of biomolecules and expected to have better interactions. Hence, its utility for various biomedical applications is explored. OBJECTIVE: Pharmacokinetics, metabolism, permeability, distribution and elimination studies of nanoparticles are essential to understand its potency, toxicity threshold and confirm its safe use in humans. Reports were available for toxicity studies on nanoparticles, but work on metabolism, pharmacokinetics, distribution and permeability of nanomedicine is limited. Hence, the main focus of this review article is about metabolism, pharmacokinetics, permeability and biodistribution of nanomaterials used in nanomedicine. CONCLUSION: Nanomedicine is increasingly becoming important in the treatment of diseases and diagnosis. Size of the particle plays an important role. As the particle size decreases its effect to cure the disease increases. Pharmacokinetics, bioavailability, half-life, metabolism, biodistribution and permeability of nanomedicine were found to be better than that of microsized drugs. In vitro and In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies are mandatory for pharmaceutical organic drugs. Similarly, nanomaterials should be subjected to both in vitro and in vivo ADME studies. Thus, nanomedicine can assist in the development of safe personalized medicine in humans. PMID- 29512451 TI - Potentiating Effect of Ethnomedicinal Plants Against Proliferation on Different Cancer Cell Lines. AB - BACKGROUND: There is a long history of traditional medicine for serving the world population. For the prevention and treatment of cancer, herbal remedies have played a significant role. In this review, we have summarized medicinal herbs from the entire world, including India, that are used traditionally for various cancer treatment. Whenever we talk about cancer treatment, medicinal plants always have been on the priority. OBJECTIVE: In this article, we have summarized the flora used in earlier times and recently identified for pre-clinical anticancer treatment. The present paper is a comprehensive review of different literature sources with discussion being made on the therapeutic value of diverse medicinal herbs in the treatment of various kinds of cancer by using different in vitro cancer cell lines. Countless anticancer plants have been recognized with the help of innovative techniques including isolation and structure elucidation that implement their beneficial effect by increasing the immunity of the body, inducing antioxidant action, endorsing making of shielding enzymes, hindering cancer triggering enzymes and hormones, and exciting DNA restoration mechanism. CONCLUSION: Finally, we have concluded that Argemone mexicana shows maximum anti cancer activity on various cancer cell lines in comparison to other medicinal plants. PMID- 29512452 TI - Formulations, Pharmacodynamic and Clinical Studies of Nanoparticles for Lung Cancer Therapy - An Overview. AB - BACKGROUND: Nanoparticles play an important role in the area of drug delivery and have been applied in lung cancer treatments for the purpose of controlled release and cancer cell targeting. METHOD: A review covering various nanoparticle formulations for lung cancer therapy is presented. The pharmacodynamic models for evaluating anti-lung cancer drugs are summarized upon drug administration routes. Moreover, the current clinical applications of nano-drugs for lung cancer treatments are also reviewed, including the administration routes, dose forms and clinical trials. RESULTS: The preparation methods of anti-lung cancer nanoparticles varied from different formulations. Owing to the improvement of their bioavailability, stability and residency at lung, the anti-lung cancer drugs encapsulated by nanoparticles showed better therapeutic effects than the naked drug. Likewise, characterization including pharmacology, physical and chemical properties should be taken into consideration. More importantly, different pharmacological animal models should be correctly selected for the pharmacodynamics assessment. Finally, the investigation of anti-lung cancer nanoparticles in clinical trials provided experience on further related research. CONCLUSION: Nanoparticle delivery system for lung cancer therapy is still in its early stage and expecting numerous challenges. PMID- 29512453 TI - Medicinal Plants in Neurodegenerative Diseases: Perspective of Traditional Persian Medicine. AB - BACKGROUND: Neurodegenerative diseases are a progressive loss of structure and/or function of neurons. Weak therapeutic response and progressive nature of the diseases, as well as a wide range of side effects caused by conventional therapeutic approaches make patients seek for complementary and alternative medicine. OBJECTIVE: The aim of the present paper is to discuss the neuropharmacological basis of medicinal plants and their principle phytochemicals which have been used in traditional Persian medicine for different types of neurodegenerative diseases. RESULTS: Medicinal plants introduced in traditional Persian medicine perform beneficial effects in neurodegenerative diseases via various cellular and molecular mechanisms including suppression of apoptosis mediated by an increase in the expression of anti-apoptotic agents (e.g. Bcl-2) as well as a decrease in the expression and activity of proapoptotic proteins (e.g. Bax, caspase 3 and 9). Alleviating inflammatory responses and suppressing the expression and function of pro-inflammatory cytokines like Tumor necrosis factor alpha and interleukins, as well as improvement in antioxidative performance mediated by superoxide dismutase and catalase, are among other neuroprotective mechanisms of traditional medicinal plants. Modulation of transcription, transduction, intracellular signaling pathways including ERK, p38, and MAPK, with upstream regulatory activity on inflammatory cascades, apoptosis and oxidative stress associated pathways, play an essential role in the preventive and therapeutic potential of the plants in neurodegenerative diseases. CONCLUSION: Medicinal plants used in traditional Persian medicine along with their related phytochemicals by affecting various neuropharmacological pathways can be considered as future drugs or adjuvant therapies with conventional pharmacotherapeutics; though, further clinical studies are necessary for the confirmation of their safety and efficacy. PMID- 29512454 TI - A System Pharmacology Study for Deciphering Anti Depression Activity of Nardostachys jatamansi. AB - BACKGROUND: The plant Nardostachys jatamansi from Valerianaceae family is a well known antidepressant plant and has historically been used in traditional medicine. As N. jatamansi contains many different compounds, to identify its mechanisms of action, we need a network-based study. Network-based studies are becoming an increasingly important tool in understanding the mechanisms of actions of drugs. Systems pharmacology (SP) and bioinformatics are two emerging tools that use computation to develop an understanding of drug actions in molecular and cellular levels. SP can provide mechanistic understanding of protein-protein (drug-target) interaction involved in a common biological pathway. The present study was undertaken to identify unknown targets and mechanisms of antidepressant activity of N. jatamansi according to a systems pharmacology approach. METHOD: First of all a list of all the targets (receptors and metabolites) involved in depression process were provided based on KEGG database. The 3D structures of protein targets were collected as PDB files and their active sites coordinates were found. In the next step the structures of known compounds of N. jatamansi were collected. For identifying the protein lagand interactions, a docking process was run in AutoDock and an output was received. To complete our study, the similarity between antidepressant conventional drugs and N. jatamansi compounds was analyzed. A SP map figured by Cytoscape Software, shows the relations between herbal compounds, molecular targets and depression. RESULTS: According to the docking results, we can suggest several important targets that we have no drugs for, or several natural compounds that play an important role in depression process. According to the similarity results we can suggest several molecules for extraction or synthesis that need more researches for their therapeutic effects. This study shows that how N. jatamansi can effect on depression by multiple molecular targeting with multiple compounds. PMID- 29512455 TI - Phytotherapy for the Prevention of Atherosclerosis-Associated Early Cerebral Ischemia. AB - BACKGROUND: Cerebrovascular disease caused by atherosclerosis affecting cerebral and pre-cerebral arteries is one of the leading causes of morbidity and mortality in high-income countries. Medications of botanical origin are often characterized by good tolerability and are suitable for long-term treatment. Therefore, phytotherapy provides an interesting possibility for developing new therapies for the prevention of atherosclerosis and its complications that could be used at preclinical stages of the disease. OBJECTIVE: We reviewed the current literature studying the potential of various plant-based medications for prevention and treatment of early cerebral ischemia induced by atherosclerosis. METHODS: Literature search was performed in PubMed, Scopus, and Cochrane library to find trials on phytotherapy in cerebrovascular prevention and treatment. RESULTS: The present review covers the recent data on the prevention of cerebral ischemia with natural preparations and demonstrates the effect of anti-atherosclerotic therapy on the dynamics of minor neurological changes. CONCLUSION: Phytotherapy appears to have a great potential for cerebrovascular disease prevention, combining good safety profiles with pleiotropic effects on different mechanisms atherosclerosis related cerebral ischemia development. PMID- 29512456 TI - A Review of Herbal Remedies for Multiple Sclerosis-Like Disorders in Traditional Persian Medicine (TPM). AB - BACKGROUND: Among various neurological disorders, multiple sclerosis (MS) is an expanding global immune- related inflammatory disease with complex etiologies. There is increasing demand for the use and administration of natural medicaments for this disorder. Traditional Persian Medicine (TPM) is a school of medicine and a medicinal plants-based resource for clinical studies put forward by Persian scholars. OBJECTIVE: This paper aims to gather and study the effectiveness of all medicinal plants from the most popular Persian pharmacopeias. Five main Persian pharmacopeias from the 9th to the 18th century A.D. have been studied to identify the remedial plants for this disorder. Moreover, PubMed, and Scopus databases have been checked to derive relevant activities for these plants. Khaddar (numbness), Esterkha (Palsy) and Falej (quadriplegia) are traditional definitions; these are clinically close to what is known as MS in today's medicine. CONCLUSION: In all, 118 medicinal plants, related to 65 families, have been authenticated out of 157 chosen medicaments. Apiaceae is the most frequent family (13 reports). Fruits and roots of plants have been the most reported botanical parts (34 and 32 items). The employed routes of administration are topical, oral, or a combination of the two (27, 57, and 34 sequentially). Fifteen medicines have been reported for Khaddar, Esterkha, and Falej simultaneously. Antioxidant activities, immunomodulatory, and anti-inflammatory properties of medicines are known as some main mechanisms to manage MS. These functions are possessed by 81%, 36%, and 48% of the studied plants, respectively. Hence, conducting adducible clinical trials and highly approved experimental tests on animals may lead to novel drugs with lesser undesirable and much more therapeutic effects on controlling MS. PMID- 29512457 TI - Topical Discoveries on Multi-Target Approach to Manage Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) is recognized as progressive multifaceted and multi-factorial neurodegenerative disorder which causes dementia among elderly people. Although, researchers in this field have put considerable efforts for the investigation of novel and appropriate therapeutic measures towards the cure of AD, unfortunately, no effective prevention therapy for this disease is available till date. In fact, various aspects involved in the onset and progression of AD are still disputed or uncovered. However, to achieve definite and direct cure of AD, researcher's attention has been drawn towards exploration of new therapeutics targets. In this review, we have discussed the current progress of various aspects of pathophysiological mechanisms behind AD, together with recent investigational therapeutic approaches and present tools with an emphasis on Multi Target Directed Drugs approach. METHOD: We have scrutinized numerous peer-reviewed research articles to assemble and discuss significant research findings and success achieved in the last decade pertinent to the application of Multi-Target Directed Drugs in the treatment of AD. RESULTS: The main emphasis of the review was to understand the various aspects of pathophysiological mechanisms involved in AD, along with the recent developments on potential AD targets and application of Multi-Target Directed Drugs approach against AD. In addition, a brief overview of major drawbacks of conventional anti AD drugs has also been included. We found that several strategies including in silico approach could be used for multi-target drug designing against AD. However, various synthetic/natural compounds and nano-formulations have the ability to be developed as multi-target drugs for AD. CONCLUSION: The present review comprises imperative information regarding AD pathology and disease process along with recent researches going on to develop treatment strategies against AD. Thus, this review might be helpful for physician, neurologist and scientist in understanding the diverse roots of AD for designing primary cure skills and scaffold of pharmacological treatment to manage AD. PMID- 29512458 TI - New Bioactive Metabolites from the Marine-derived Fungi Aspergillus. AB - Recently, the marine-derived Aspergillus present as producers of a large number of structurally novel secondary metabolites. Some of these metabolites have shown antitumor, antimicrobial, anti-inflammatory, antioxidant and enzymatic activities, and may be promising resources for new therapeutic drugs. This review sums up 232 new bioactive metabolites from the marine-derived Aspergillus with classification through their biological activities and chemical structures in 2006-2016. Besides, structure-activity relationships of some compounds are explored. PMID- 29512459 TI - Withdrawn: Quercetin: A plant-derived polyphenol with tremendous cardioprotective effects. PMID- 29512460 TI - Potential Anti-Malarial Agents from Endophytic Fungi: A Review. AB - Malaria is one of the major infectious diseases and foremost cause of mortality and morbidity in many subtropical and tropical regions. In the last years, the situation has become worst in many ways, due to increase in the parasites resistance to various available antimalarial agents. Furthermore, malaria's control is beginning to be more sophisticated by the parallel spread of mosquito vector's resistance to the available insecticides. Recently, there is a wide consensus to seek for target specific, safe, affordable, and effective new antimalarial agents, which can compete with synthetic ones. Endophytic fungi are of a growing interest as prominent sources of structurally unique bioactive natural products. The bio-metabolites isolated from endophytic fungi, possessing antimalarial potential may compose the base for the synthesis of novel drugs that might be utilized to withstand malaria and its resistance. For getting information on the various studies, PubMed, Google Scholar, ScienceDirect, SpringerLink, Scopus, and Wiley search was done using keywords (malaria, endophytic fungi, and antimalarial activity). The present review covers the literature published from 1996 to 2017 and highlights the metabolites for which antimalarial activities have been reported. Overall, 135 fungal metabolites and 72 references are cited. In addition, their structure, chemical class, fungal source, host, and activity have been presented. This review shows the significance of endophytic fungi as a wealthy pool of antimalarial agents. PMID- 29512461 TI - Multicomponent Pharmaceutical Cocrystals: A Novel Approach for Combination Therapy. AB - Cocrystallization is a technique for modifying the physicochemical and pharmacokinetic properties of an active pharmaceutical ingredient (API) embodying the concept of supramolecular synthon. Most of the examples cited in the literature are of cocrystals formed between an API and a coformer chosen from the generally recognized as safe (GRAS) substance list; however few examples exist where a cocrystal consists of two or more APIs. These cocrystals are commonly known as multi API, multi-drug or drug- drug cocrystals. The formation of such cocrystals is feasible by virtue of non covalent interactions between the APIs, which help them in retaining their activity. In addition, drugdrug cocrystals also offer potential solution to the limitations such as solubility, stability differences and chemical interaction between the APIs which is often faced during the traditional combination therapy. Cocrystallization of two or more APIs can be employed for delivery of combination drugs for the better and efficacious management of many complex disorders where existing monotherapies do not furnish the desired therapeutic effect. This review on the existing drug-drug cocrystals is to gain an insight for better designing of multi API cocrystals with improved physicochemical and pharmacokinetic profile and its application in multiple target therapy. PMID- 29512462 TI - Dysfunction in Brain-Derived Neurotrophic Factor Signaling Pathway and Susceptibility to Schizophrenia, Parkinson's and Alzheimer's Diseases. AB - Brain-Derived Neurotrophic Factor (BDNF) is a dominant neurotrophic factor in the brain which plays a crucial role in differentiation, regeneration and plasticity mechanisms. Binding of the BDNF to its high-affinity Tropomyosin-related kinase B (TrkB) receptor leads to phosphorylation of TrkB, thus activating the three important downstream intracellular signaling cascades within the neural cells including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Phospholipase C-gamma (PLCgamma), and mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathways. Transcription of these pathways is regulated by cAMP Response Element-Binding protein (CREB) transcription factor, which can upregulate gene expression. In this review, we attempted to explore the role of BDNF and its associated pathways in susceptibility to Schizophrenia (Scz), Alzheimer's (AD), and Parkinson's (PD) diseases. Furthermore, we discuss dysfunction in BDNF signaling pathway and the therapeutic potential of BDNF in the treatment of these disorders. The review covers various therapeutic strategies including BDNF gene therapy, transplantation of BDNFexpressing cell grafts, epigenetic manipulation, and intraparenchymal BDNF protein infusion as well. This review seeks to achieve these goals by reviewing recent studies on BDNF and examining the details of BDNF pathway in any of the above-mentioned diseases. PMID- 29512463 TI - Application of Optogenetics in Gene Therapy. AB - The optogenetics approach uses a combination of genetic and optical methods to initiate and control functions in specific cells of biological tissues. Since the high-speed control of neuronal activity by irradiating channelrhodopsin-2 with blue light was reported in 2005, tremendous advancement and application of optogenetics in the field of neuroscience, such as in studies that associate neuronal activity with behaviors, have been initiated. Optogenetics is not only used as a research tool, but is also started to apply in the diagnosis of a disease or as therapy in various studies. Here, we summarize reports on therapy using a typical photoreceptor used in optogenetics, channelrhodopsin-2. PMID- 29512464 TI - Insight into the emerging role of striatal neurotransmitters in the pathophysiology of Parkinson's disease and Huntington's disease: A review. AB - Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson's disease and Huntington's disease. Dopamine is important neurotransmitter which play critical role in coordinated body movements. Alteration in level of brain dopamine and receptor radically contribute to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson's disease and Huntington's disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Though the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson's disease and Huntington's disease. Therefore, there is urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration. PMID- 29512465 TI - Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. AB - As a result of ischemia or hemorrhage, blood supply to neurons is disrupted which subsequently promotes a cascade of pathophysiological responses resulting in cell loss. Many mechanisms are involved solely or in combination in this disorder including excitotoxicity, mitochondrial death pathways, and the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy and inflammation. Besides neuronal cell loss, damage to and loss of astrocytes as well as injury to white matter contributes also to cerebral injury. The core problem in stroke is the loss of neuronal cells which makes recovery difficult or even not possible in the late states. Acute treatment options that can be applied for stroke are mainly targeting re-establishment of blood flow and hence, their use is limited due to the effective time window of thrombolytic agents. However, if the acute time window is exceeded, neuronal loss starts due to the activation of cell death pathways. This review will explore the most updated cellular death mechanisms leading to neuronal loss in stroke. Ischemic and hemorrhagic stroke as well as subarachnoid hemorrhage will be debated in the light of cell death mechanisms and possible novel molecular and cellular treatment options will be discussed. PMID- 29512466 TI - Mitochondria: A Connecting Link In The Major Depressive Disorder Jigsaw. AB - BACKGROUND: Depression is a widespread phenomenon with varying degrees of pathology in different patients. Various hypotheses have been proposed for the cause and continuance of depression. Some of these include, but not limited to, the monoamine hypothesis, the neuroendocrine hypothesis, and the more recent epigenetic and inflammatory hypotheses. OBJECTIVE: In this article, we review all the above hypotheses with a focus on the role of mitochondria as the connecting link. Oxidative stress, respiratory activity, mitochondrial dynamics and metabolism are some of the mitochondria-dependent factors which are affected during depression. We also propose exogenous ATP as a contributing factor to depression. RESULT: Literature review shows that pro-inflammatory markers are elevated in depressive individuals. The cause for elevated levels of cytokines in depression is not completely understood. We propose exogenous ATP activates purinergic receptors which in turn increase the levels of various pro inflammatory factors in the pathophysiology of depression. CONCLUSION: Mitochondria are integral to the function of neurons and undergo dysfunction in major depressive disorder patients. This dysfunction is reflected in all the various hypotheses that have been proposed for depression. Among the newer targets identified, which also involve mitochondria, includes the role of exogenous ATP. The diversity of purinergic receptors, and their differential expression among various individuals in the population, due to genetic and environmental (prenatal) influences, may influence the susceptibility and severity of depression. Identifying specific receptors involved and using patient specific purinergic receptor antagonist may be an appropriate therapeutic course in the future. PMID- 29512467 TI - The delicate equilibrium between oxidants and antioxidants in brain glioma. AB - Gliomas are the most frequent brain tumors in adult population and unfortunately the adjuvant therapies are not effective. Brain tumorigenesis has been related both with the increased levels of free radicals as inductors of severe damages in healthy cells, but also with the reduced response of endogenous enzyme and non enzymatic antioxidant defenses. In turn, both processes induce the change to malignant cells. In this review we analyzed the role of the imbalance between free radicals production and antioxidant mechanism in the development and progression of gliomas but also the influence of redox status on the two major distinctive forms of programmed cell death related to cancer: apoptosis and autophagy. These data may be the reference to the development of new pharmacological options based on redox microenvironment for glioma treatment. PMID- 29512468 TI - Effects of Intensive Blood Pressure Control in Patients with Evident Cardiovascular Disease: An investigation using the SPRINT study data. AB - BACKGROUND: Recent data advocate adoption of a more intensive treatment strategy for management of blood pressure (BP). OBJECTIVE: We investigated whether the overall effects of the Systolic Blood Pressure Intervention Trial (SPRINT) are applicable to cardiovascular disease (CVD) patients. METHOD: In a post-hoc analysis we analyzed data from SPRINT that randomly assigned 9361 individuals to a systolic BP (SBP) target of <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). 1562 patients had clinically evident CVD (age=70.3+/-9.3 years, 24% females) at study entry and were followed for 3.1 years. Further, we assessed the effect of low (<150 mmHg) baseline SBP on outcome. RESULTS: In CVD patients, there was no benefit from the intensive treatment regarding all endpoints, except for a marginally significant benefit on all-cause mortality (hazard ratio [HR]: 0.67; 95% confidence interval [CI], 0.45 to 1.00; p=0.0509). Further, while there was no increase in serious adverse events (SAE) in the intensive group, there was increased risk for study-related SAE, acute renal failure and electrolyte abnormalities. In patients with low baseline SBP there was a beneficial effect on all-cause mortality (HR: 0.56; 95% CI: 0.33 to 0.96; p=0.033), but with greater stroke incidence (HR: 2.94; 95% CI: 1.04 to 8.29; p=0.042). CONCLUSION: We confirm the beneficial effect of the intensive strategy in SPRINT study on all-cause mortality and the harmful effect on specific adverse outcomes in patients with CVD. However, in patients with low baseline SBP stroke may increase. PMID- 29512469 TI - Stemness Phenotype in Tamoxifen Resistant Breast Cancer Cells May be Induced by Interactions Between Receptor Tyrosine Kinases and ERalpha-66. AB - BACKGROUND: Tamoxifen is widely administered for patients with estrogen receptor positive breast cancer. Despite many patients benefiting from Tamoxifen as an effective anti-hormonal agent in adjuvant therapy, a noticeable number of patients tend to develop resistance. OBJECTIVE: The aim of this study was to shed light upon the molecular mechanisms associated with Tamoxifen resistance which can help improve current treatment strategies available for stimulating responsiveness and combating resistance. METHODS: Relevant articles were obtained from PubMed and google scholar, nearly all dated from 2010 to 2017. Articles were screened to select the ones meeting the objective. The molecular interactions in the resistant network were extracted from the appropriate articles. RESULTS: The mechanisms of developing Tamoxifen resistance were briefly outlined. Overactivation of Receptor Tyrosine Kinases (RTKs) pathways, commonly known as alternative growth cascades, is one of the main players in acquired cancer cell stemness, which can induce unrestricted proliferation in the presence of Tamoxifen. There are seven recent patents including 6291496B1 as an anti-HER2, 8143226B2 as an inhibitor of RTK phosphorylation, 9062308B2 as an anti-HOXB7, Lapatinib functioning as an anti-EGFR/HER2, Everolimus as an inhibitor of mTOR, Exemestane as an aromatase inhibitor and Perifosine as an AKT inhibitor. CONCLUSION: Altogether, it seems that tumor cells express a stemness phenotype which tends to override anti-hormonal adjuvant therapies. Since RTKs are overactivated and overexpressed in such cells, specialized targeted therapies suppressing RTKs would be a novel and effective way in restoring Tamoxifen sensitivity in resistant breast cancer tumor cells. PMID- 29512470 TI - PARP Inhibitors in Ovarian Cancer. AB - BACKGROUND: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. OBJECTIVES: The study aimed to highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. METHODS: We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google. com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. RESULTS: Olaparib, Niraparib and Rucaparib are already approved for the treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum sensitive and resistant disease). CONCLUSION: PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. PMID- 29512472 TI - A Rare Case of Tricuspid Valve Endocarditis Caused by Enterococcus Gallinarum in a Patient with Recurrent Urinary Tract Infection. AB - OBJECTIVE: Infective endocarditis due to Enterococus Gallinarum is a rare clinical condition. We present a case of an 85 years old male with a history of the valvular disease and permanent pace maker with past medical history of repetitive urinary tract infections in the previous months, who presented to the emergency department with fever, urinary disturbances, general malaise and positive blood cultures for Enterococcus Gallinarum. METHODS: Echocardiography was a useful diagnostic method in the present case, showing the vegetation on the tricuspid valve. RESULTS: This case is notable because tricuspid valve endocarditis due to Enterococcus Gallinarum is a rare clinical condition and improves knowledge of disease and management in patients with endocarditis. PMID- 29512471 TI - TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients. AB - BACKGROUND: Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. OBJECTIVE: To evaluate the association of pharmacokinetic parameter TC > 0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. METHODS: A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxelTM kit. The patients' PTX TC > 0.05 (the time during which PTX plasma concentration exceed 0.05umol/L) were calculated based on pharmacokinetic analysis. RESULTS: The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358 0.127 umol/L; (2) the PTX TC > 0.05 ranged from 14 to 38h with a median time of 27h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC > 0.05 between CR+PR and SD+PD; (4) with the increasing value of TC > 0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC > 0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC > 0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC > 0.05 at 26 to 30h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. CONCLUSION: PTX TC > 0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors. PMID- 29512473 TI - Cholesterol Homeostasis and Liver X Receptor (LXR) in Atherosclerosis. AB - Cholesterol is an important lipid for maintaining cell membrane fluidity and generation of various hormones and bile acids. Thus, it is critical to maintain cholesterol homeostasis including absorption, trafficking, biosynthesis, and efflux; dysregulation of cholesterol homeostasis may lead to human disorders such as atherosclerosis. As a cholesterol sensor, nuclear receptor liver X receptor (LXR) is an important factor regulating cholesterol homeostasis. Extensive research has been carried out to examine the roles of LXR in atherosclerosis. In this review, we summarize our current understanding of the mechanisms how LXR regulates cholesterol synthesis, efflux, absorption, and conversion of cholesterol esters to cholesterol in the context of atherosclerosis. In addition, we also discuss the possibility of targeting LXR and cholesterol homeostasis as a potential interventional strategy for treating atherosclerosis. PMID- 29512474 TI - Open access: is there a predator at the door? PMID- 29512475 TI - Prevention of pharyngocutaneous fistula in salvage total laryngectomy: role of the pectoralis major flap and peri-operative management. AB - OBJECTIVE: This study aimed to evaluate the impact of an onlay pectoralis major flap in reducing the incidence of pharyngocutaneous fistula after salvage total laryngectomy and determine the complications of pectoralis major flap reconstruction. METHODS: A retrospective study was conducted of consecutive patients who underwent salvage total laryngectomy between 1995 and 2016. The pharyngeal defects were primarily closed with or without the pectoralis major flap. RESULTS: Of 64 patients, 34 had primary pharyngeal closure alone (control group) and 30 received an onlay pectoralis major flap (pectoralis major flap group). The overall fistula rate was 15.6 per cent, with 17.6 per cent occurring in the control group and 13.3 per cent in the pectoralis major flap group (p = 0.74). The incidence rates of voice failure (p = 0.02) and shoulder disability (p < 0.001) were significantly higher in the pectoralis major flap group. CONCLUSION: The pectoralis major flap in salvage total laryngectomy did not decrease the pharyngocutaneous fistula rate, and the incidence of flap-related complications was high. Appropriate surgical technique and post-operative care may reduce the incidence of pharyngocutaneous fistula. PMID- 29512476 TI - Vestibular rehabilitation using video gaming in adults with dizziness: a pilot study. AB - OBJECTIVE: To determine the effectiveness of vestibular rehabilitation using the Wii Fit balance platform, in adults with dizziness. METHODS: A single-site prospective clinical trial was conducted in a university hospital in the UK. Forty patients with dizziness, who would normally be candidates for vestibular rehabilitation, were identified and considered as potential participants. Participants were randomised into either the treatment group (the Wii Fit group) or the control group (standard customised vestibular rehabilitation protocol). Participants were assessed over a 16-week period using several balance and quality of life questionnaires. RESULTS: Both exercise regimes resulted in a reduction of dizziness and an improvement in quality of life scores over time, but no statistically significant difference between the two interventions was identified. CONCLUSION: This pilot study demonstrated that use of the Wii Fit balance platform resulted in a statistically significant improvement in balance function and quality of life. Furthermore, outcomes were comparable to a similar group of individuals following a standard customised vestibular rehabilitation protocol. The study provides useful information to inform the design and execution of a larger clinical trial. PMID- 29512477 TI - Setting up a parathyroid multidisciplinary team meeting: one year's experience, outcomes and learning points. AB - OBJECTIVE: A parathyroid multidisciplinary team meeting was set up at East Sussex Healthcare Trust, from November 2014 to November 2015, in order to improve and streamline services for patients with parathyroid pathology. METHODS: Data were collected on all new referrals for hyperparathyroidism, and on the outcomes for each patient discussed at the meeting, including the number of operations and management outcomes. A survey was sent out to the members of the multidisciplinary team meeting to determine their perception of its effectiveness. RESULTS: Seventy-nine new referrals were discussed throughout the year; 43 per cent were recommended for surgery, 41 per cent had a trial of conservative or medical management before re-discussion, and 16 per cent required further imaging. Ninety-two per cent of patients underwent an ultrasound, single photon emission computed tomography/computed tomography or nuclear medicine (sestamibi) scan prior to the meeting. All ultrasound scans were performed by a consultant radiologist. CONCLUSION: The multidisciplinary team meeting has been successful, with perceived benefits for patients, improved imaging evaluation and efficiency of referral pathways, leading to more appropriate patient management. PMID- 29512478 TI - Pediatric Acute Severe Neurologic Illness and Injury in an Urban and a Rural Hospital in the Democratic Republic of the Congo. AB - Empirical knowledge suggests that acute neurologic disorders are common in sub Saharan Africa, but studies examining the true burden of these diseases in children are scarce. We performed this prospective, observational study to evaluate the prevalence, clinical characteristics, treatment approaches, and outcomes of children suffering acute neurologic illness or injury (ANI) in an urban and rural site in the Democratic Republic of the Congo. Over 12 months, 471 out of 6,563 children admitted met diagnostic criteria for ANI, giving a hospital based prevalence of 72/1,000 admissions. Two hundred and seventy-two children had clinical findings consistent with central nervous system infection but lacked complete diagnostic evaluation for definitive classification. Another 151 children were confirmed to have cerebral malaria (N = 109, 23% of admissions), bacterial meningitis (N = 38, 8% of admissions), tuberculous meningitis (N = 3, 0.6% of admissions), or herpes encephalitis (N = 1, 0.21% of admissions). Febrile convulsions, traumatic brain injury, and epilepsy contributed less significantly to overall hospital prevalence of ANI (3.19/1,000, 1.37/1,000, and 1.06/1,000, respectively). Overall mortality for the cohort was 21% (97/471). Neurologic sequelae were seen in another 31% of participants, with only 45% completing the study with a normal neurologic examination. This type of data is imperative to help plan effective strategies for illness and injury prevention and control, and to allow optimal use of limited resources in terms of provision of acute care and rehabilitation for these children. PMID- 29512479 TI - Evaluation of Malaria Urban Risk Using an Immuno-Epidemiological Biomarker of Human Exposure to Anopheles Bites. AB - Urban malaria is an underestimated serious health concern in African countries. This study aimed to evaluate the risk of malaria transmission in an urban area by evaluating the level of human exposure to Anopheles bites using an Anopheles salivary biomarker (gambiae Salivary Gland Protein-6 peptide 1 [gSG6-P1] peptide). Two multidisciplinary cross-sectional studies were undertaken in five sites of Bouake city (three urban districts and two surrounding villages, used as control; Cote d'Ivoire) during the rainy season and the dry season. Blood samples were obtained from children 6 months to 14 years of age for immunological tests. The level of anti-gSG6-P1 immunoglobulin G (IgG) antibodies was significantly higher in the rainy season than the dry season in both urban and rural sites (P < 0.0001). Interestingly, children with the highest anti-gSG6-P1 IgG responses in the rainy season were infected by Plasmodium falciparum. Surprisingly, no difference of anti-gSG6-P1 IgG level was observed between urban and rural areas, for either season. The current data suggest that children in the urban city of Bouake could be as highly exposed to Anopheles bites as children living in surrounding villages. The immunological biomarker of human exposure to Anopheles bites may be used to accurately assess the potential risk of malaria transmission in African urban settings. PMID- 29512480 TI - Knowledge and Adherence to the National Guidelines for Malaria Diagnosis in Pregnancy among Health-Care Providers and Drug-Outlet Dispensers in Rural Western Kenya. AB - Prompt diagnosis and effective treatment of acute malaria in pregnancy (MiP) is important for the mother and fetus; data on health-care provider adherence to diagnostic guidelines in pregnancy are limited. From September to November 2013, a cross-sectional survey was conducted in 51 health facilities and 39 drug outlets in Western Kenya. Provider knowledge of national diagnostic guidelines for uncomplicated MiP were assessed using standardized questionnaires. The use of parasitologic testing was assessed in health facilities via exit interviews with febrile women of childbearing age and in drug outlets via simulated-client scenarios, posing as pregnant women or their spouses. Overall, 93% of providers tested for malaria or accurately described signs and symptoms consistent with clinical malaria. Malaria was parasitologically confirmed in 77% of all patients presenting with febrile illness at health facilities and 5% of simulated clients at drug outlets. Parasitological testing was available in 80% of health facilities; 92% of patients evaluated at these facilities were tested. Only 23% of drug outlets had malaria rapid diagnostic tests (RDTs); at these outlets, RDTs were offered in 17% of client simulations. No differences were observed in testing rates by pregnancy trimester. The study highlights gaps among health providers in diagnostic knowledge and practice related to MiP, and the lack of malaria diagnostic capacity, particularly in drug outlets. The most important factor associated with malaria testing of pregnant women was the availability of diagnostics at the point of service. Interventions that increase the availability of malaria diagnostic services might improve malaria case management in pregnant women. PMID- 29512481 TI - Phase I Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico. AB - The safety and immunogenicity of four adjuvanted formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV) were evaluated in a predominantly dengue-primed population in Puerto Rico. In this placebo-controlled, randomized, observer-blind, phase I trial, 100 healthy adults were randomized 1:1:1:1:1 to receive DPIV at Day (D)0 and D28 (1 MUg per dengue virus [DENV] type 1-4 adjuvanted with either alum, AS01E or AS03B, or 4 MUg per DENV type adjuvanted with alum) or saline placebo. Functional antibody responses were assessed using a microneutralization assay at D56, Month (M)7, and M13. All DPIV formulations were well tolerated and no safety signals were identified through M13. The M13 according-to-protocol (ATP) immunogenicity cohort included 83 participants. The ATP analysis of immunogenicity was performed only on the 78 subjects seropositive for >= 1 DENV type at baseline: 69 tetravalent, three trivalent, two bivalent, and four monovalent. In all DPIV groups, geometric mean antibody titers (GMTs) increased from D0 to D56 and waned modestly through M13, while remaining well above prevaccination levels. The 4 MUg + alum and the AS01E- and AS03B-adjuvanted formulations were highly immunogenic, with M13-neutralizing antibody GMTs against all four DENV types above 1,000. M13/D0 GMT ratios were highest in the 1 MUg + AS03B group (ranging 3.2-3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857). PMID- 29512483 TI - Dried Blood Spot RNA Transcriptomes Correlate with Transcriptomes Derived from Whole Blood RNA. AB - Obtaining RNA from clinical samples collected in resource-limited settings can be costly and challenging. The goals of this study were to 1) optimize messenger RNA extraction from dried blood spots (DBS) and 2) determine how transcriptomes generated from DBS RNA compared with RNA isolated from blood collected in Tempus tubes. We studied paired samples collected from eight adults in rural Tanzania. Venous blood was collected on Whatman 903 Protein Saver cards and in tubes with RNA preservation solution. Our optimal DBS RNA extraction used 8 * 3-mm DBS punches as the starting material, bead beater disruption at maximum speed for 60 seconds, extraction with Illustra RNAspin Mini RNA Isolation kit, and purification with Zymo RNA Concentrator kit. Spearman correlations of normalized gene counts in DBS versus whole blood ranged from 0.887 to 0.941. Bland-Altman plots did not show a trend toward over- or under-counting at any gene size. We report a method to obtain sufficient RNA from DBS to generate a transcriptome. The DBS transcriptome gene counts correlated well with whole blood transcriptome gene counts. Dried blood spots for transcriptome studies could be an option when field conditions preclude appropriate collection, storage, or transport of whole blood for RNA studies. PMID- 29512482 TI - The Burden of Dengue Fever and Chikungunya in Southern Coastal Ecuador: Epidemiology, Clinical Presentation, and Phylogenetics from the First Two Years of a Prospective Study. AB - Here, we report the findings from the first 2 years (2014-2015) of an arbovirus surveillance study conducted in Machala, Ecuador, a dengue-endemic region. Patients with suspected dengue virus (DENV) infections (index cases, N = 324) were referred from five Ministry of Health clinical sites. A subset of DENV positive index cases (N = 44) were selected, and individuals from the index household and four neighboring homes within 200 m were recruited (N = 400). Individuals who entered the study, other than the index cases, are referred to as associates. In 2014, 70.9% of index cases and 35.6% of associates had acute or recent DENV infections. In 2015, 28.3% of index cases and 12.8% of associates had acute or recent DENV infections. For every DENV infection captured by passive surveillance, we detected an additional three acute or recent DENV infections in associates. Of associates with acute DENV infections, 68% reported dengue-like symptoms, with the highest prevalence of symptomatic acute infections in children aged less than 10 years. The first chikungunya virus (CHIKV) infections were detected on epidemiological week 12 in 2015; 43.1% of index cases and 3.5% of associates had acute CHIKV infections. No Zika virus infections were detected. Phylogenetic analyses of isolates of DENV from 2014 revealed genetic relatedness and shared ancestry of DENV1, DENV2, and DENV4 genomes from Ecuador with those from Venezuela and Colombia, indicating the presence of viral flow between Ecuador and surrounding countries. Enhanced surveillance studies, such as this, provide high-resolution data on symptomatic and inapparent infections across the population. PMID- 29512484 TI - Exploring Droughts and Floods and Their Association with Cholera Outbreaks in Sub Saharan Africa: A Register-Based Ecological Study from 1990 to 2010. AB - Cholera outbreaks in Africa have been attributed to both droughts and floods, but whether the risk of a cholera outbreak is elevated during droughts is unknown. We estimated the risk of cholera outbreaks during droughts and floods compared with drought- and flood-free periods in 40 sub-Saharan African countries during 1990 2010 based on data from Emergency Events Database: the Office of Foreign Disaster Assistance /Centre for Research on the Epidemiology of Disasters International Disaster Database (www.emdat.be). A cholera outbreak was registered in one of every three droughts and one of every 15 floods. We observed an increased incidence rate of cholera outbreaks during drought periods (incidence rate ratio [IRR] = 4.3, 95% confidence interval [CI] = 2.9-7.2) and during flood periods (IRR = 144, 95% CI = 101-208) when compared with drought/flood-free periods. Floods are more strongly associated with cholera outbreaks, yet the prevalence of cholera outbreaks is higher during droughts because of droughts' long durations. The results suggest that droughts in addition to floods call for increased cholera preparedness. PMID- 29512485 TI - Frequent Community Use of Antibiotics among a Low-Economic Status Population in Manila, the Philippines: A Prospective Assessment Using a Urine Antibiotic Bioassay. AB - The widespread unregulated use of antibiotics without medical consultation contributes to the burden of antibiotic resistance in Southeast Asian countries. This study investigated antibiotic use before hospital consultation. In a prospective observational study from February 2, 2015, to July 2, 2015, we enrolled febrile patients attending the emergency room in San Lazaro Hospital, Manila, the Philippines. A urine sample was collected and a bioassay was used to detect antibiotic activity in urine using Bacillus stearothermophilus (ATCC7953), Escherichia coli (ATCC25922), and Streptococcus pyogenes (ATCC19615). Patients or caregivers reported their medication history, clinical information, and socioeconomic status. During the study period, 410 patients were enrolled. The median (interquartile range) age was 14 (7-23) years and 158 (39%) reported prior antibiotic use, predominantly a beta-lactam antibiotic. A total of 164 (40%, 95% confidence interval [CI]: 35-45) patients were urine bioassay positive with any of three organisms. The Bacillus assay was the most sensitive, detecting 162 (99%, 95% CI: 96-100) cases. Among bioassay positive patients, dengue (N = 91, 55%, 95% CI: 48-63) was the most frequent diagnosis, followed by other viral infections, including measles, rubella, and mumps (N = 17, 10%, 95% CI: 6-16). Patients with a positive bioassay were significantly more likely to be from the lowest-income group (adjusted odds ratio [AOR]: 1.7; 95% CI: 1.1-2.6) and required hospital admission (AOR: 2.1; 95% CI: 1.3-3.5). Unnecessary antibiotic use for febrile illnesses before hospital consultation is common in a low-income, highly populated urban community in Manila. Education targeting this group should be implemented to reduce unnecessary antibiotic use. PMID- 29512487 TI - Retraction: Protein kinase C is a calcium sensor for presynaptic short-term plasticity. PMID- 29512486 TI - Safety Analysis of Leishmania Vaccine Used in a Randomized Canine Vaccine/Immunotherapy Trial. AB - In Leishmania infantum-endemic countries, controlling infection within dogs, the domestic reservoir, is critical to public health. There is a need for safe vaccines that prevent canine progression with disease and transmission to others. Protective vaccination against Leishmania requires mounting a strong, inflammatory, Type 1 response. Three commercially available canine vaccines on the global veterinary market use saponin or inflammatory antigen components (Letifend) as a strong pro-inflammatory adjuvant. There is very little information detailing safety of saponin as an adjuvant in field trials. Safety analyses for the use of vaccine as an immunotherapeutic in asymptomatically infected animals are completely lacking. Leishmania infantum, the causative agent of canine leishmaniasis, is enzootic within U.S. hunting hounds. We assessed the safety of LeishTec(r) after use in dogs from two different clinical states: 1) without clinical signs and tested negative on polymerase chain reaction and serology or 2) without clinical signs and positive for at least one Leishmania diagnostic test. Vaccine safety was assessed after all three vaccinations to quantify the number and severity of adverse events. Vaccinated animals had an adverse event rate of 3.09%, whereas placebo animals had 0.68%. Receiving vaccine was correlated with the occurrence of mild, site-specific, reactions. Occurrence of severe adverse events was not associated with having received vaccine. Infected, asymptomatic animals did not have a higher rate of adverse events. Use of vaccination is, therefore, likely to be safe in infected, asymptomatic animals. PMID- 29512488 TI - S2P: A software tool to quickly carry out reproducible biomedical research projects involving 2D-gel and MALDI-TOF MS protein data. AB - BACKGROUND AND OBJECTIVE: 2D-gel electrophoresis is widely used in combination with MALDI-TOF mass spectrometry in order to analyze the proteome of biological samples. For instance, it can be used to discover proteins that are differentially expressed between two groups (e.g. two disease conditions, case vs. control, etc.) thus obtaining a set of potential biomarkers. This procedure requires a great deal of data processing in order to prepare data for analysis or to merge and integrate data from different sources. This kind of work is usually done manually (e.g. copying and pasting data into spreadsheet files), which is highly time consuming and distracts the researcher from other important, core tasks. Moreover, engaging in a repetitive process in a non-automated, handling based manner is prone to error, thus threatening reliability and reproducibility. The objective of this paper is to present S2P, an open source software to overcome these drawbacks. METHODS: S2P is implemented in Java on top of the AIBench framework, and relies on well-established open source libraries to accomplish different tasks. RESULTS: S2P is an AIBench based desktop multiplatform application, specifically aimed to process 2D-gel and MALDI-mass spectrometry protein identification-based data in a computer-aided, reproducible manner. Different case studies are presented in order to show the usefulness of S2P. CONCLUSIONS: S2P is open source and free to all users at http://www.sing group.org/s2p. Through its user-friendly GUI interface, S2P dramatically reduces the time that researchers need to invest in order to prepare data for analysis. PMID- 29512489 TI - Assessment of hand superficial oxygenation during ischemia/reperfusion in healthy subjects versus systemic sclerosis patients by 2D near infrared spectroscopic imaging. AB - BACKGROUND AND OBJECTIVE: Patients affected by systemic sclerosis (SSc) develop functional and structural microcirculatory dysfunction, which progressively evolves towards systemic tissue fibrosis (sclerosis). Disease initially affects distal extremities, which become preferential sites of diagnostic scrutiny. This pilot investigation tested the hypothesis that peripheral microcirculatory dysfunction in SSc could be non-invasively assessed by 2D Near Infrared Spectroscopic (NIRS) imaging of the hand associated with Vascular Occlusion Testing (VOT). NIRS allows measurement of hemoglobin oxygen saturation (StO2) in the blood perfusing the volume tissue under scrutiny. METHODS: In five normal volunteers and five SSc patients we applied a multispectral oximetry imaging device (Kent camera, Kent Imaging, Calgary, Canada) to acquire StO2 2D maps of the whole hand palm during baseline, ischemia and reperfusion phase. RESULTS: We found significant differences between controls and SSc patients in basal StO2 (82.80 +/- 2.51 vs 65.44 +/- 7.96%, p = 0.0016), minimum StO2 (59.35 +/- 4.29 vs 40.73 +/- 6.47%, p = 0.0007), final StO2 (83.83 +/- 4.09 vs 68.84 +/- 11.41%, p = 0.02) and time to maximum StO2 (40 +/- 12.25 vs 62 +/- 4.47 s, p = 0.005). CONCLUSIONS: This is, to our knowledge, the first application of 2D NIRS imaging of the whole hand to the investigation of microvascular dysfunction in systemic sclerosis. The image processing presented here considered the StO2 in the entire hand allowing a comprehensive view of the spatial heterogeneity of microvascular dysfunction. PMID- 29512490 TI - Automated quantification of renal interstitial fibrosis for computer-aided diagnosis: A comprehensive tissue structure segmentation method. AB - : Interstitial fibrosis in renal biopsy samples is a scarring tissue structure that may be visually quantified by pathologists as an indicator to the presence and extent of chronic kidney disease. The standard method of quantification by visual evaluation presents reproducibility issues in the diagnoses. This study proposes an automated quantification system for measuring the amount of interstitial fibrosis in renal biopsy images as a consistent basis of comparison among pathologists. The system extracts and segments the renal tissue structures based on colour information and structural assumptions of the tissue structures. The regions in the biopsy representing the interstitial fibrosis are deduced through the elimination of non-interstitial fibrosis structures from the biopsy area and quantified as a percentage of the total area of the biopsy sample. A ground truth image dataset has been manually prepared by consulting an experienced pathologist for the validation of the segmentation algorithms. The results from experiments involving experienced pathologists have demonstrated a good correlation in quantification result between the automated system and the pathologists' visual evaluation. Experiments investigating the variability in pathologists also proved the automated quantification error rate to be on par with the average intra-observer variability in pathologists' quantification. BACKGROUND AND OBJECTIVE: Interstitial fibrosis in renal biopsy samples is a scarring tissue structure that may be visually quantified by pathologists as an indicator to the presence and extent of chronic kidney disease. The standard method of quantification by visual evaluation presents reproducibility issues in the diagnoses due to the uncertainties in human judgement. METHODS: An automated quantification system for accurately measuring the amount of interstitial fibrosis in renal biopsy images is presented as a consistent basis of comparison among pathologists. The system identifies the renal tissue structures through knowledge-based rules employing colour space transformations and structural features extraction from the images. In particular, the renal glomerulus identification is based on a multiscale textural feature analysis and a support vector machine. The regions in the biopsy representing interstitial fibrosis are deduced through the elimination of non-interstitial fibrosis structures from the biopsy area. The experiments conducted evaluate the system in terms of quantification accuracy, intra- and inter-observer variability in visual quantification by pathologists, and the effect introduced by the automated quantification system on the pathologists' diagnosis. RESULTS: A 40-image ground truth dataset has been manually prepared by consulting an experienced pathologist for the validation of the segmentation algorithms. The results from experiments involving experienced pathologists have demonstrated an average error of 9 percentage points in quantification result between the automated system and the pathologists' visual evaluation. Experiments investigating the variability in pathologists involving samples from 70 kidney patients also proved the automated quantification error rate to be on par with the average intra-observer variability in pathologists' quantification. CONCLUSIONS: The accuracy of the proposed quantification system has been validated with the ground truth dataset and compared against the pathologists' quantification results. It has been shown that the correlation between different pathologists' estimation of interstitial fibrosis area has significantly improved, demonstrating the effectiveness of the quantification system as a diagnostic aide. PMID- 29512492 TI - Finite element investigation of human maxillary incisor under traumatic loading: Static vs dynamic analysis. AB - BACKGROUND AND OBJECTIVE: Traumatic loading is the main form of injury sustained in dental injuries. In spite of the prevalence of dental trauma, little information is available on traumatic dental damage and the evaluation of tooth behavior under traumatic loading. Due to the short period of traumatic loading, at first sight, a dynamic analysis needs to be performed to investigate the dental trauma. However, it was hypothesized that dental traumatic loading could be regarded as quasi-static loading. Thus, the aim of the present study was to examine this hypothesis. METHODS: Static and dynamic analyses of the human maxillary incisor were carried out under traumatic loading using a 3D finite element method. Also, modal analysis of the tooth model was performed in order to evaluate the assumption of the dental traumatic loading as a quasi-static one. RESULTS: It was revealed that the static analysis of dental trauma is preferred to the dynamic analysis when investigating dental trauma, mainly due to its lower computational cost. In fact, it was shown that including the inertia of the tooth structure does not influence the results of the dental trauma simulation. Furthermore, according to the modal analysis of the tooth structure, it was found that the mechanical properties and geometry of the periodontal ligament play significant roles in the classification of dental traumatic loading as a quasi static one, in addition to the time duration of the applied load. CONCLUSIONS: This paper provides important biomechanical insights into the classification of dental loading as quasi-static, transient or impact loading in future dental studies. PMID- 29512491 TI - Methods for classifying depression in single channel EEG using linear and nonlinear signal analysis. AB - BACKGROUND AND OBJECTIVE: Depressive disorder is one of the leading causes of burden of disease today and it is presumed to take the first place in the world in 2030. Early detection of depression requires a patient-friendly inexpensive method based on easily measurable objective indicators. This study aims to compare various single-channel electroencephalographic (EEG) measures in application for detection of depression. METHODS: The EEG recordings were performed on a group of 13 medication-free depressive outpatients and 13 gender and age matched controls. The recorded 30-channel EEG signal was analysed using linear methods spectral asymmetry index, alpha power variability and relative gamma power and nonlinear methods Higuchi's fractal dimension, detrended fluctuation analysis and Lempel-Ziv complexity. Classification accuracy between depressive and control subjects was calculated using logistic regression analysis with leave-one-out cross-validation. Calculations were performed separately for each EEG channel. RESULTS: All calculated measures indicated increase with depression. Maximal testing accuracy using a single measure was 81% for linear and 77% for nonlinear measures. Combination of two linear measures provides the accuracy of 88% and two nonlinear measures of 85%. Maximal classification accuracy of 92% was indicated using mixed combination of three linear and three nonlinear measures. CONCLUSIONS: The results of this preliminary study confirm that single-channel EEG analysis, employing the combination of measures, can provide discrimination of depression at the level of multichannel EEG analysis. The performed study shows that there is no single superior measure for detection of depression. PMID- 29512494 TI - A novel fuzzy rough selection of non-linearly extracted features for schizophrenia diagnosis using fMRI. AB - BACKGROUND AND OBJECTIVES: Schizophrenia is a severe brain disorder primarily diagnosed through externally observed behavioural symptoms due to the dearth of established clinical tests. Functional magnetic resonance imaging (fMRI) can capture the distortions caused by schizophrenia in the brain activation. Hence, it can be useful for developing a decision model that performs computer-aided diagnosis of schizophrenia. But, fMRI data is huge in dimension. Therefore dimension reduction is indispensable. It is additionally required to identify the discriminative brain regions. Hence, we aim to build an effective decision model that incorporates suitable dimension reduction and also identifies discriminative brain regions. METHODS: We propose a three-phase dimension reduction. First phase involves spatially-constrained fuzzy clustering of 3-dimensional spatial maps (obtained from general linear model and independent component analysis). In the second phase, non-linear features are extracted from each cluster using a generalized discriminant analysis. In the third phase, a novel fuzzy rough feature selection is proposed. The features obtained after the third phase are used for learning a decision model by the help of support vector machine classifier. This complete method is implemented within leave-one-out cross validation on two balanced datasets (respectively acquired on 1.5Tesla and 3Tesla scanners). Both these datasets are created using Function Biomedical Informatics Research Network multisite data and contain fMRI data acquired during auditory oddball task performed by age-matched schizophrenia patients and healthy subjects. A permutation test is also carried out to ensure that no bias is involved in the learning. RESULTS: The results indicate that the proposed method achieves maximum classification accuracy of 97.1% and 98.0% for the two datasets respectively. The proposed method outperforms the state-of-the-art methods. The results of the permutation test show that p-values are lesser than the significance level i.e. 0.05. Therefore, the classifier has found a significant class structure and does not involve any bias. Further, discriminative brain regions are identified and are in agreement with the findings in related literature. CONCLUSION: The proposed method is able to derive suitable non-linear features and the related brain regions for effective computer-aided diagnosis. The fuzzy and rough set based approaches help in handling uncertainty and ambiguity in real data. PMID- 29512495 TI - Spatiotemporal features of DCE-MRI for breast cancer diagnosis. AB - BACKGROUND AND OBJECTIVE: Breast cancer is a major cause of mortality among women if not treated in early stages. Previous works developed non-invasive diagnosis methods using imaging data, focusing on specific sets of features that can be called spatial features or temporal features. However, limited set of features carry limited information, requiring complex classification methods to diagnose the disease. For non-invasive diagnosis, different imaging modalities can be used. DCE-MRI is one of the best imaging techniques that provides temporal information about the kinetics of the contrast agent in suspicious lesions along with acceptable spatial resolution. METHODS: We have extracted and studied a comprehensive set of features from spatiotemporal space to obtain maximum available information from the DCE-MRI data. Then, we have applied a feature fusion technique to remove common information and extract a feature set with maximum information to be used by a simple classification method. We have also implemented conventional feature selection and classification methods and compared them with our proposed approach. RESULTS: Experimental results obtained from DCE-MRI data of 26 biopsy or short-term follow-up proven patients illustrate that the proposed method outperforms alternative methods. The proposed method achieves a classification accuracy of 99% without missing any of the malignant cases. CONCLUSIONS: The proposed method may help physicians determine the likelihood of malignancy in breast cancer using DCE-MRI without biopsy. PMID- 29512493 TI - Wakefulness evaluation during sleep for healthy subjects and OSA patients using a patch-type device. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is a major sleep disorder that causes insufficient sleep, which is linked with daytime fatigue and accidents. Long-term sleep monitoring can provide meaningful information for patients with OSA to prevent and manage their symptoms. Even though various methods have been proposed to objectively measure sleep in ambulatory environments, less reliable information was provided in comparison with standard polysomnography (PSG). Therefore, this paper proposes an algorithm for distinguishing wakefulness from sleep using a patch-type device, which is applicable for both healthy individuals and patients with OSA. METHODS: Electrocardiogram (ECG) and 3-axis accelerometer signals were gathered from the single device. Wakefulness was determined with six parallel methods based on information about movement and autonomic nervous activity. The performance evaluation was conducted with five-fold cross validation using the data from 15 subjects with a low respiratory disturbance index (RDI) and 10 subjects with high RDI. In addition, wakefulness information, including total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), and wake after sleep onset (WASO), were extracted from the proposed algorithm and compared with those from PSG. RESULTS: According to epoch-by-epoch (30 s) analysis, the performance results of detecting wakefulness were an average Cohen's kappa of 0.60, accuracy of 91.24%, sensitivity of 64.12%, and specificity of 95.73%. Moreover, significant correlations were observed in TST, SE, SOL, and WASO between the proposed algorithm and PSG (p < 0.001). CONCLUSIONS: Wakefulness related information was successfully provided using data from the patch-type device. In addition, the performance results of the proposed algorithm for wakefulness detection were competitive with those from previous studies. Therefore, the proposed system could be an appropriate solution for long-term objective sleep monitoring in both healthy individuals and patients with OSA. PMID- 29512496 TI - Symtosis: A liver ultrasound tissue characterization and risk stratification in optimized deep learning paradigm. AB - Background and ObjectiveFatty Liver Disease (FLD) - a disease caused by deposition of fat in liver cells, is predecessor to terminal diseases such as liver cancer. The machine learning (ML) techniques applied for FLD detection and risk stratification using ultrasound (US) have limitations in computing tissue characterization features, thereby limiting the accuracy.MethodsUnder the class of Symtosis for FLD detection and risk stratification, this study presents a Deep Learning (DL)-based paradigm that computes nearly seven million weights per image when passed through a 22 layered neural network during the cross-validation (training and testing) paradigm. The DL architecture consists of cascaded layers of operations such as: convolution, pooling, rectified linear unit, dropout and a special block called inception model that provides speed and efficiency. All data analysis is performed in optimized tissue region, obtained by removing background information. We benchmark the DL system against the conventional ML protocols: support vector machine (SVM) and extreme learning machine (ELM).ResultsThe liver US data consists of 63 patients (27 normal/36 abnormal). Using the K10 cross validation protocol (90% training and 10% testing), the detection and risk stratification accuracies are: 82%, 92% and 100% for SVM, ELM and DL systems, respectively. The corresponding area under the curve is: 0.79, 0.92 and 1.0, respectively. We further validate our DL system using two class biometric facial data that yields an accuracy of 99%.ConclusionDL system shows a superior performance for liver detection and risk stratification compared to conventional machine learning systems: SVM and ELM. PMID- 29512497 TI - Immunohistochemical quantification of expression of a tight junction protein, claudin-7, in human lung cancer samples using digital image analysis method. AB - BACKGROUND AND OBJECTIVES: Tight junction proteins are correlated with cancer development. As the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies. We have previously reported that claudin-7 was strongly expressed in benign bronchial epithelial cells at the cell-cell junction while expression of claudin-7 was either altered with discontinued weak expression or completely absent in lung cancers. Based on these results, we continued working on the expression pattern of claudin-7 and its relationship with lung cancer development. We herein proposed a new Digital Image Classification, Fragmentation index, Morphological analysis (DICFM) method for differentiating the normal lung tissues and lung cancer tissues based on the claudin-7 immunohistochemical staining. METHODS: Seventy-seven lung cancer samples were obtained from the Second Affiliated Hospital of Zhejiang University and claudin-7 immunohistochemical staining was performed. Based on C++ and Open Source Computer Vision Library (OpenCV, version 2.4.4), the DICFM processing module was developed. Intensity and fragmentation of claudin-7 expression, as well as the morphological parameters of nuclei were calculated. Evaluation of results was performed using Receiver Operator Characteristic (ROC) analysis. RESULTS: Agreement between these computational results and the results obtained by two pathologists was demonstrated. The intensity of claudin-7 expression was significantly decreased while the fragmentation was significantly increased in the lung cancer tissues compared to the normal lung tissues and the intensity was strongly positively associated with the differentiation of lung cancer cells. Moreover, the perimeters of the nuclei of lung cancer cells were significantly greater than that of the normal lung cells, while the parameters of area and circularity revealed no statistical significance. CONCLUSIONS: Taken together, our DICFM approach may be applied as an appropriate approach to quantify the immunohistochemical staining of claudin-7 on the cell membrane and claudin-7 may serve as a marker for identification of lung cancer. PMID- 29512498 TI - surrosurv: An R package for the evaluation of failure time surrogate endpoints in individual patient data meta-analyses of randomized clinical trials. AB - BACKGROUND AND OBJECTIVE: Surrogate endpoints are attractive for use in clinical trials instead of well-established endpoints because of practical convenience. To validate a surrogate endpoint, two important measures can be estimated in a meta analytic context when individual patient data are available: the Rindiv2 or the Kendall's tau at the individual level, and the Rtrial2 at the trial level. We aimed at providing an R implementation of classical and well-established as well as more recent statistical methods for surrogacy assessment with failure time endpoints. We also intended incorporating utilities for model checking and visualization and data generating methods described in the literature to date. METHODS: In the case of failure time endpoints, the classical approach is based on two steps. First, a Kendall's tau is estimated as measure of individual level surrogacy using a copula model. Then, the Rtrial2 is computed via a linear regression of the estimated treatment effects; at this second step, the estimation uncertainty can be accounted for via measurement-error model or via weights. In addition to the classical approach, we recently developed an approach based on bivariate auxiliary Poisson models with individual random effects to measure the Kendall's tau and treatment-by-trial interactions to measure the Rtrial2. The most common data simulation models described in the literature are based on: copula models, mixed proportional hazard models, and mixture of half normal and exponential random variables. RESULTS: The R package surrosurv implements the classical two-step method with Clayton, Plackett, and Hougaard copulas. It also allows to optionally adjusting the second-step linear regression for measurement-error. The mixed Poisson approach is implemented with different reduced models in addition to the full model. We present the package functions for estimating the surrogacy models, for checking their convergence, for performing leave-one-trial-out cross-validation, and for plotting the results. We illustrate their use in practice on individual patient data from a meta-analysis of 4069 patients with advanced gastric cancer from 20 trials of chemotherapy. CONCLUSIONS: The surrosurv package provides an R implementation of classical and recent statistical methods for surrogacy assessment of failure time endpoints. Flexible simulation functions are available to generate data according to the methods described in the literature. PMID- 29512500 TI - Breast cancer data analysis for survivability studies and prediction. AB - BACKGROUND: Breast cancer is the most common cancer affecting females worldwide. Breast cancer survivability prediction is challenging and a complex research task. Existing approaches engage statistical methods or supervised machine learning to assess/predict the survival prospects of patients. OBJECTIVE: The main objectives of this paper is to develop a robust data analytical model which can assist in (i) a better understanding of breast cancer survivability in presence of missing data, (ii) providing better insights into factors associated with patient survivability, and (iii) establishing cohorts of patients that share similar properties. METHODS: Unsupervised data mining methods viz. the self organising map (SOM) and density-based spatial clustering of applications with noise (DBSCAN) is used to create patient cohort clusters. These clusters, with associated patterns, were used to train multilayer perceptron (MLP) model for improved patient survivability analysis. A large dataset available from SEER program is used in this study to identify patterns associated with the survivability of breast cancer patients. Information gain was computed for the purpose of variable selection. All of these methods are data-driven and require little (if any) input from users or experts. RESULTS: SOM consolidated patients into cohorts of patients with similar properties. From this, DBSCAN identified and extracted nine cohorts (clusters). It is found that patients in each of the nine clusters have different survivability time. The separation of patients into clusters improved the overall survival prediction accuracy based on MLP and revealed intricate conditions that affect the accuracy of a prediction. CONCLUSIONS: A new, entirely data driven approach based on unsupervised learning methods improves understanding and helps identify patterns associated with the survivability of patient. The results of the analysis can be used to segment the historical patient data into clusters or subsets, which share common variable values and survivability. The survivability prediction accuracy of a MLP is improved by using identified patient cohorts as opposed to using raw historical data. Analysis of variable values in each cohort provide better insights into survivability of a particular subgroup of breast cancer patients. PMID- 29512499 TI - Histogram analysis of T2*-based pharmacokinetic imaging in cerebral glioma grading. AB - BACKGROUND AND OBJECTIVE: To investigate the feasibility of histogram analysis of the T2*-based permeability parameter volume transfer constant (Ktrans) for glioma grading and to explore the diagnostic performance of the histogram analysis of Ktrans and blood plasma volume (vp). METHODS: We recruited 31 and 11 patients with high- and low-grade gliomas, respectively. The histogram parameters of Ktrans and vp, derived from the first-pass pharmacokinetic modeling based on the T2* dynamic susceptibility-weighted contrast-enhanced perfusion-weighted magnetic resonance imaging (T2* DSC-PW-MRI) from the entire tumor volume, were evaluated for differentiating glioma grades. RESULTS: Histogram parameters of Ktrans and vp showed significant differences between high- and low-grade gliomas and exhibited significant correlations with tumor grades. The mean Ktrans derived from the T2* DSC-PW-MRI had the highest sensitivity and specificity for differentiating high grade gliomas from low-grade gliomas compared with other histogram parameters of Ktrans and vp. CONCLUSIONS: Histogram analysis of T2*-based pharmacokinetic imaging is useful for cerebral glioma grading. The histogram parameters of the entire tumor Ktrans measurement can provide increased accuracy with additional information regarding microvascular permeability changes for identifying high grade brain tumors. PMID- 29512501 TI - A clinical nutritional information system with personalized nutrition assessment. AB - BACKGROUND AND OBJECTIVE: Traditional nutrition evaluations not only require the use of numerous tables and lists to provide sufficient recommendations for patients' diets but are also very time-consuming due to cross-referencing and calculations. METHODS: To personalize patient assessments, this study implemented a Clinical Nutritional Information System (CNIS) to help hospital dietitians perform their daily work more effectively in terms of time management and paper work. The CNIS mainly targets in-patients who require cancer-nutrition counselling. The development of the CNIS occurred in three phases. Phase 1 included system design and implementation based on the Nutrition Care Process and Model (NCPM) and the Patient Nutrition Care Process. Phase 2 involved a survey to characterize the efficiency, quality and accuracy of the CNIS. In Phase 3, a second survey was conducted to determine how well dietitians had adapted to the system and the extent of improvement in efficiency after the CNIS had been available online for three years. RESULTS: The work time requirements decreased by approximately 58% with the assistance of the CNIS. Of the dietitians who used the CNIS, 95% reported satisfaction, with 91.66% indicating that the CNIS was really helpful in their work. However, some shortcomings were also evident according to the results. CONCLUSIONS: Dietitians favoured the standardization of nutritional intervention and monitoring. The CNIS meets the needs of dietitians by increasing the quality of nutritional interventions by providing accurate calculations and cross-referencing for information regarding patients' conditions, with the benefit of decreasing the processing time, such as handwritten documentation. In addition, the CNIS also helps dietitians statistically analyse each patient's personal nutritional needs to achieve nutritional improvement. PMID- 29512502 TI - A new near-term breast cancer risk prediction scheme based on the quantitative analysis of ipsilateral view mammograms. AB - PURPOSE: To help improve efficacy of screening mammography and eventually establish an optimal personalized screening paradigm, this study aimed to develop and test a new near-term breast cancer risk prediction scheme based on the quantitative analysis of ipsilateral view of the negative screening mammograms. METHODS: The dataset includes digital mammograms acquired from 392 women with two sequential full-field digital mammography examinations. All the first ("prior") sets of mammograms were interpreted as negative during the original reading. In the sequential ("current") screening, 202 were proved positive and 190 remained negative/benign. For each pair of the "prior" ipsilateral mammograms, we adaptively fused the image features computed from two views. Using four different types of image features, we built four elastic net support vector machine (EnSVM) based classifiers. Then, the initial prediction scores form the 4 EnSVMs were combined to build a final artificial neural network (ANN) classifier that produces the final risk prediction score. The performance of the new scheme was evaluated by using a 10-fold cross-validation method and an assessment index of the area under the receiver operating characteristic curve (AUC). RESULTS: A total number of 466 features were initially extracted from each pair of ipsilateral mammograms. Among them, 51 were selected to build the EnSVM based prediction scheme. The AUC = 0.737 +/- 0.052 was yielded using the new scheme. Applying an optimal operating threshold, the prediction sensitivity was 60.4% (122 of 202) and the specificity was 79.0% (150 of 190). CONCLUSION: The study results showed moderately high positive association between computed risk scores using the "prior" negative mammograms and the actual outcome of the image detectable breast cancers in the next subsequent screening examinations. The study also demonstrated that quantitative analysis of the ipsilateral views of the mammograms enabled to provide useful information in predicting near-term breast cancer risk. PMID- 29512503 TI - Improved binary dragonfly optimization algorithm and wavelet packet based non linear features for infant cry classification. AB - BACKGROUND AND OBJECTIVE: Infant cry signal carries several levels of information about the reason for crying (hunger, pain, sleepiness and discomfort) or the pathological status (asphyxia, deaf, jaundice, premature condition and autism, etc.) of an infant and therefore suited for early diagnosis. In this work, combination of wavelet packet based features and Improved Binary Dragonfly Optimization based feature selection method was proposed to classify the different types of infant cry signals. METHODS: Cry signals from 2 different databases were utilized. First database contains 507 cry samples of normal (N), 340 cry samples of asphyxia (A), 879 cry samples of deaf (D), 350 cry samples of hungry (H) and 192 cry samples of pain (P). Second database contains 513 cry samples of jaundice (J), 531 samples of premature (Prem) and 45 samples of normal (N). Wavelet packet transform based energy and non-linear entropies (496 features), Linear Predictive Coding (LPC) based cepstral features (56 features), Mel-frequency Cepstral Coefficients (MFCCs) were extracted (16 features). The combined feature set consists of 568 features. To overcome the curse of dimensionality issue, improved binary dragonfly optimization algorithm (IBDFO) was proposed to select the most salient attributes or features. Finally, Extreme Learning Machine (ELM) kernel classifier was used to classify the different types of infant cry signals using all the features and highly informative features as well. RESULTS: Several experiments of two-class and multi-class classification of cry signals were conducted. In binary or two-class experiments, maximum accuracy of 90.18% for H Vs P, 100% for A Vs N, 100% for D Vs N and 97.61% J Vs Prem was achieved using the features selected (only 204 features out of 568) by IBDFO. For the classification of multiple cry signals (multi-class problem), the selected features could differentiate between three classes (N, A & D) with the accuracy of 100% and seven classes with the accuracy of 97.62%. CONCLUSION: The experimental results indicated that the proposed combination of feature extraction and selection method offers suitable classification accuracy and may be employed to detect the subtle changes in the cry signals. PMID- 29512504 TI - Study on digital teeth selection and virtual teeth arrangement for complete denture. AB - BACKGROUND AND OBJECTIVE: In dentistry, the complete denture is a conventional treatment for edentulous patients. The computer-aided design and computer-aided manufacturing (CAD/CAM) has been applied on the digital complete denture which is developed rapidly. Tooth selection and arrangement is one of the most important parts in digital complete denture. In this paper, we propose a new method of personalized teeth arrangement. METHODS: This paper presents a method of arranging teeth virtually for a complete denture. First, scan and extract the feature points of the 3D triangular mesh data of artificial teeth (PLY format), then establish a tooth selection system. Second, scan and mark the anatomic characteristics of the maxillary and mandibular cast surfaces, such as facial midline, the curve of the arches. With the enter information, the study calculates the common arrangement lines of artificial teeth. Third, select the preferred artificial teeth and automatically arrange them virtually in the correct position by using our own software. After that, design the gingival part of the dentures on the basic of the arranged teeth on the screen and then fabricated it by using Computerized Numerical Control (CNC) technology, Rapid Prototyping (RP) technology or 3D printer technology. Finally, select artificial teeth were embedded in wax rims. RESULTS: This system can choose artificial teeth reasonably and the teeth placement can meet the dentist's request to a certain extent, whereas all the operations are based on the medical principles. CONCLUSIONS: The study performed here involves computer sciences, medicine, and dentistry, a teeth selection system was proposed and virtual teeth arrangement was described. This study has the capacity of helping operators to select teeth, which improved the accuracy of tooth arrangement, and customized complete denture. PMID- 29512505 TI - Detection of multipoint pulse waves and dynamic 3D pulse shape of the radial artery based on binocular vision theory. AB - BACKGROUND AND OBJECTIVE: Pulse signals contain a wealth of human physiological and pathological information. How to get full pulse information is especially challenging, and most of the traditional pulse sensors can only get the pulse wave of a single point. This study is aimed at developing a binocular pulse detection system and method to obtain multipoint pulse waves and dynamic three dimensional pulse shape of the radial artery. METHODS: The proposed pulse detection approach is image-based and implemented by two steps. First, a new binocular pulse detection system is developed based on the principle of pulse feeling used in traditional Chinese medicine. Second, pulse detection is achieved based on theories and methods of binocular vision and digital image processing. In detail, the sequences of pulse images collected by the designed system as experimental data are sequentially processed by median filtering, block binarization and inversion, area filtering, centroids extraction of connected regions, to extract the pattern centroids as feature points. Then stereo matching is realized by a proposed algorithm based on Gong-shape scan detection. After multipoint spatial coordinate calculation, dynamic three-dimensional reconstruction of the thin film shape is completed by linear interpolation. And then the three-dimensional pulse shape is achieved by finding an appropriate reference time. Meanwhile, extraction of multipoint pulse waves of the radial artery is accomplished by using a suitable reference origin. The proposed method is analyzed from three aspects, which are pulse amplitude, pulse rate and pulse shape, and compared with other detection methods. RESULTS: Analysis of the results shows that the values of pulse amplitude and pulse rate are consistent with the characteristics of pulse wave of the radial artery, and pulse shape can correctly present the shape of pulse in space and its change trend in time. The comparison results with the other two previously proposed methods further verify the correctness of the presented method. CONCLUSIONS: The designed binocular pulse detection system and proposed algorithm can effectively detect pulse information. This tactile visualization-based pulse detection method has important scientific significance and broad application prospects and will promote further development of objective pulse diagnosis. PMID- 29512506 TI - Automation of a DXA-based finite element tool for clinical assessment of hip fracture risk. AB - Finite element analysis of medical images is a promising tool for assessing hip fracture risk. Although a number of finite element models have been developed for this purpose, none of them have been routinely used in clinic. The main reason is that the computer programs that implement the finite element models have not been completely automated, and heavy training is required before clinicians can effectively use them. By using information embedded in clinical dual energy X-ray absorptiometry (DXA), we completely automated a DXA-based finite element (FE) model that we previously developed for predicting hip fracture risk. The automated FE tool can be run as a standalone computer program with the subject's raw hip DXA image as input. The automated FE tool had greatly improved short-term precision compared with the semi-automated version. To validate the automated FE tool, a clinical cohort consisting of 100 prior hip fracture cases and 300 matched controls was obtained from a local community clinical center. Both the automated FE tool and femoral bone mineral density (BMD) were applied to discriminate the fracture cases from the controls. Femoral BMD is the gold standard reference recommended by the World Health Organization for screening osteoporosis and for assessing hip fracture risk. The accuracy was measured by the area under ROC curve (AUC) and odds ratio (OR). Compared with femoral BMD (AUC = 0.71, OR = 2.07), the automated FE tool had a considerably improved accuracy (AUC = 0.78, OR = 2.61 at the trochanter). This work made a large step toward applying our DXA-based FE model as a routine clinical tool for the assessment of hip fracture risk. Furthermore, the automated computer program can be embedded into a web-site as an internet application. PMID- 29512507 TI - R package to estimate intracluster correlation coefficient with confidence interval for binary data. AB - BACKGROUND AND OBJECTIVE: The Intracluster Correlation Coefficient (ICC) is a major parameter of interest in cluster randomized trials that measures the degree to which responses within the same cluster are correlated. There are several types of ICC estimators and its confidence intervals (CI) suggested in the literature for binary data. Studies have compared relative weaknesses and advantages of ICC estimators as well as its CI for binary data and suggested situations where one is advantageous in practical research. The commonly used statistical computing systems currently facilitate estimation of only a very few variants of ICC and its CI. To address the limitations of current statistical packages, we developed an R package, ICCbin, to facilitate estimating ICC and its CI for binary responses using different methods. METHODS: The ICCbin package is designed to provide estimates of ICC in 16 different ways including analysis of variance methods, moments based estimation, direct probabilistic methods, correlation based estimation, and resampling method. CI of ICC is estimated using 5 different methods. It also generates cluster binary data using exchangeable correlation structure. RESULTS: ICCbin package provides two functions for users. The function rcbin() generates cluster binary data and the function iccbin() estimates ICC and it's CI. The users can choose appropriate ICC and its CI estimate from the wide selection of estimates from the outputs. CONCLUSIONS: The R package ICCbin presents very flexible and easy to use ways to generate cluster binary data and to estimate ICC and it's CI for binary response using different methods. The package ICCbin is freely available for use with R from the CRAN repository (https://cran.r-project.org/package=ICCbin). We believe that this package can be a very useful tool for researchers to design cluster randomized trials with binary outcome. PMID- 29512508 TI - Vertebral body segmentation in wide range clinical routine spine MRI data. AB - BACKGROUND AND OBJECTIVE: In this work we propose a 3D vertebral body segmentation approach for clinical magnetic resonance (MR) spine imaging. So far, vertebrae segmentation approaches in MR spine imaging are either limited to particular MR imaging sequences or require minutes to compute, which can be hindering in clinical routine. The major contribution of our work is a reasonably precise segmentation result, within seconds and with minimal user interaction, for spine MR imaging commonly used in clinical routine. Our focus lies on the applicability towards a large variety of clinical MR imaging sequences, dealing with low image quality, high anisotropy and spine pathologies. METHODS: Our method starts with a intensity correction step to deal with bias field artifacts and a minimal user-assisted initialization. Next, appearance-based vertebral body probability maps guide a subsequent hybrid level-set segmentation. RESULTS: We tested our method on different MR imaging sequences from 48 subjects. Overall, our evaluation set contains 63 datasets including 419 vertebral bodies, which differ in age, sex and presence of spine pathologies. This is the largest set of reference segmentations of clinical routine spine MR imaging so far. We achieved a Dice coefficient of 86.0%, a mean Euclidean surface distance error of 1.59 +/- 0.24 mm and a Hausdorff distance of 6.86 mm. CONCLUSIONS: These results illustrate the robustness of our segmentation approach towards the variety of MR image data, which is a pivotal aspect for clinical usefulness and reliable diagnosis. PMID- 29512509 TI - Improving access to state of the art statistical methods for use in applied clinical research. PMID- 29512510 TI - Adaptive treatment-length optimization in spatiobiologically integrated radiotherapy. AB - Recent theoretical research on spatiobiologically integrated radiotherapy has focused on optimization models that adapt fluence-maps to the evolution of tumor state, for example, cell densities, as observed in quantitative functional images acquired over the treatment course. We propose an optimization model that adapts the length of the treatment course as well as the fluence-maps to such imaged tumor state. Specifically, after observing the tumor cell densities at the beginning of a session, the treatment planner solves a group of convex optimization problems to determine an optimal number of remaining treatment sessions, and a corresponding optimal fluence-map for each of these sessions. The objective is to minimize the total number of tumor cells remaining (TNTCR) at the end of this proposed treatment course, subject to upper limits on the biologically effective dose delivered to the organs-at-risk. This fluence-map is administered in future sessions until the next image is available, and then the number of sessions and the fluence-map are re-optimized based on the latest cell density information. We demonstrate via computer simulations on five head-and neck test cases that such adaptive treatment-length and fluence-map planning reduces the TNTCR and increases the biological effect on the tumor while employing shorter treatment courses, as compared to only adapting fluence-maps and using a pre-determined treatment course length based on one-size-fits-all guidelines. PMID- 29512511 TI - High pressure phase transformations revisited. AB - High pressure phase transformations play an important role in the search for new materials and material synthesis, as well as in geophysics. However, they are poorly characterized, and phase transformation pressure and pressure hysteresis vary drastically in experiments of different researchers, with different pressure transmitting media, and with different material suppliers. Here we review the current state, challenges in studying phase transformations under high pressure, and the possible ways in overcoming the challenges. This field is critically compared with fields of phase transformations under normal pressure in steels and shape memory alloys, as well as plastic deformation of materials. The main reason for the above mentioned discrepancy is the lack of understanding that there is a fundamental difference between pressure-induced transformations under hydrostatic conditions, stress-induced transformations under nonhydrostatic conditions below yield, and strain-induced transformations during plastic flow. Each of these types of transformations has different mechanisms and requires a completely different thermodynamic and kinetic description and experimental characterization. In comparison with other fields the following challenges are indicated for high pressure phase transformation: (a) initial and evolving microstructure is not included in characterization of transformations; (b) continuum theory is poorly developed; (c) heterogeneous stress and strain fields in experiments are not determined, which leads to confusing material transformational properties with a system behavior. Some ways to advance the field of high pressure phase transformations are suggested. The key points are: (a) to take into account plastic deformations and microstructure evolution during transformations; (b) to formulate phase transformation criteria and kinetic equations in terms of stress and plastic strain tensors (instead of pressure alone); (c) to develop multiscale continuum theories, and (d) to couple experimental, theoretical, and computational studies of the behavior of a tested sample to extract information about fields of stress and strain tensors and concentration of high pressure phase, transformation criteria and kinetics. The ideal characterization should contain complete information which is required for simulation of the same experiments. PMID- 29512512 TI - Highly sensitive MoS2 photodetectors with graphene contacts. AB - Two-dimensional materials such as graphene and transition metal dichalcogenides (TMDs) are ideal candidates to create ultra-thin electronics suitable for flexible substrates. Although optoelectronic devices based on TMDs have demonstrated remarkable performance, scalability is still a significant issue. Most devices are created using techniques that are not suitable for mass production, such as mechanical exfoliation of monolayer flakes and patterning by electron-beam lithography. Here we show that large-area MoS2 grown by chemical vapor deposition and patterned by photolithography yields highly sensitive photodetectors, with record shot-noise-limited detectivities of 8.7 * 1014 Jones in ambient condition and even higher when sealed with a protective layer. These detectivity values are higher than the highest values reported for photodetectors based on exfoliated MoS2. We study MoS2 devices with gold electrodes and graphene electrodes. The devices with graphene electrodes have a tunable band alignment and are especially attractive for scalable ultra-thin flexible optoelectronics. PMID- 29512513 TI - Induced Forster resonance energy transfer by encapsulation of DNA-scaffold based probes inside a plant virus based protein cage. AB - Insight into the assembly and disassembly of viruses can play a crucial role in developing cures for viral diseases. Specialized fluorescent probes can benefit the study of interactions within viruses, especially during cell studies. In this work, we developed a strategy based on Forster resonance energy transfer (FRET) to study the assembly of viruses without labeling the exterior of viruses. Instead, we exploit their encapsulation of nucleic cargo, using three different fluorescent ATTO dyes linked to single-stranded DNA oligomers, which are hybridised to a longer DNA strand. FRET is induced upon assembly of the cowpea chlorotic mottle virus, which forms monodisperse icosahedral particles of about 22 nm, thereby increasing the FRET efficiency by a factor of 8. Additionally, encapsulation of the dyes in virus-like particles induces a two-step FRET. When the formed constructs are disassembled, this FRET signal is fully reduced to the value before encapsulation. This reversible behavior makes the system a good probe for studying viral assembly and disassembly. It, furthermore, shows that multi-component supramolecular materials are stabilized in the confinement of a protein cage. PMID- 29512514 TI - Magnetism of the 35 K superconductor CsEuFe4As4. AB - The results of ab initio hyperfine-interaction parameters calculations, and of x ray diffraction and 57Fe and 151Eu Mossbauer spectroscopy study of the new 35 K superconductor CsEuFe4As4 are reported. The superconductor crystallizes in the tetragonal space group P4/mmm with the lattice parameters [Formula: see text] A and [Formula: see text] A. It is demonstrated unequivocally that there is no magnetic order of the Fe magnetic moments down to 2.1 K and that the ferromagnetic order is associated with the Eu magnetic moments. The Curie temperature [Formula: see text] K determined from the temperature dependence of the hyperfine magnetic field at 151Eu nuclei is shown to be compatible with the temperature dependence of the transferred hyperfine magnetic field at 57Fe nuclei that is induced by the ferromagnetically ordered Eu sublattice. The Eu magnetic moments are shown to be perpendicular to the crystallographic c-axis. The temperature dependence of the principal component of the electric field gradient tensor, both at Fe and Eu sites, is well described by a T 3/2 power-law relation. Good agreement between the calculated and measured hyperfine-interaction parameters is observed. The Debye temperature of CsEuFe4As4 is found to be 295(3) K. PMID- 29512515 TI - Receiver operating characteristic (ROC) curves: review of methods with applications in diagnostic medicine. AB - Receiver operating characteristic (ROC) analysis is a tool used to describe the discrimination accuracy of a diagnostic test or prediction model. While sensitivity and specificity are the basic metrics of accuracy, they have many limitations when characterizing test accuracy, particularly when comparing the accuracies of competing tests. In this article we review the basic study design features of ROC studies, illustrate sample size calculations, present statistical methods for measuring and comparing accuracy, and highlight commonly used ROC software. We include descriptions of multi-reader ROC study design and analysis, address frequently seen problems of verification and location bias, discuss clustered data, and provide strategies for testing endpoints in ROC studies. The methods are illustrated with a study of transmission ultrasound for diagnosing breast lesions. PMID- 29512516 TI - Efficient organ localization using multi-label convolutional neural networks in thorax-abdomen CT scans. AB - Automatic localization of organs and other structures in medical images is an important preprocessing step that can improve and speed up other algorithms such as organ segmentation, lesion detection, and registration. This work presents an efficient method for simultaneous localization of multiple structures in 3D thorax-abdomen CT scans. Our approach predicts the location of multiple structures using a single multi-label convolutional neural network for each orthogonal view. Each network takes extra slices around the current slice as input to provide extra context. A sigmoid layer is used to perform multi-label classification. The output of the three networks is subsequently combined to compute a 3D bounding box for each structure. We used our approach to locate 11 structures of interest. The neural network was trained and evaluated on a large set of 1884 thorax-abdomen CT scans from patients undergoing oncological workup. Reference bounding boxes were annotated by human observers. The performance of our method was evaluated by computing the wall distance to the reference bounding boxes. The bounding boxes annotated by the first human observer were used as the reference standard for the test set. Using the best configuration, we obtained an average wall distance of [Formula: see text] mm in the test set. The second human observer achieved [Formula: see text] mm. For all structures, the results were better than those reported in previously published studies. In conclusion, we proposed an efficient method for the accurate localization of multiple organs. Our method uses multiple slices as input to provide more context around the slice under analysis, and we have shown that this improves performance. This method can easily be adapted to handle more organs. PMID- 29512517 TI - Investigation of iron spin crossover pressure in Fe-bearing MgO using hybrid functional. AB - Pressure-induced spin crossover behaviors of Fe-bearing MgO were widely investigated by using an LDA + U functional for describing the strongly correlated Fe-O bonding. Moreover, the simulated spin crossover pressures depend on the applied U values, which are sensitive to environments and parameters. In this work, the spin crossover pressures of (Mg1-x ,Fe x )O are investigated by using the hybrid functional with a uniform parameter. Our results indicate that the spin crossover pressures increase with increasing iron concentration. For example, the spin crossover pressure of (Mg0.03125,Fe0.96875)O and FeO was 56 GPa and 127 GPa, respectively. The calculated crossover pressures agreed well with the experimental observations. Therefore, the hybrid functional should be an effective method for describing the pressure-induced spin crossover behaviors in transition metal oxides. PMID- 29512518 TI - Universal and idiosyncratic characteristic lengths in bacterial genomes. AB - In condensed matter physics, simplified descriptions are obtained by coarse graining the features of a system at a certain characteristic length, defined as the typical length beyond which some properties are no longer correlated. From a physics standpoint, in vitro DNA has thus a characteristic length of 300 base pairs (bp), the Kuhn length of the molecule beyond which correlations in its orientations are typically lost. From a biology standpoint, in vivo DNA has a characteristic length of 1000 bp, the typical length of genes. Since bacteria live in very different physico-chemical conditions and since their genomes lack translational invariance, whether larger, universal characteristic lengths exist is a non-trivial question. Here, we examine this problem by leveraging the large number of fully sequenced genomes available in public databases. By analyzing GC content correlations and the evolutionary conservation of gene contexts (synteny) in hundreds of bacterial chromosomes, we conclude that a fundamental characteristic length around 10-20 kb can be defined. This characteristic length reflects elementary structures involved in the coordination of gene expression, which are present all along the genome of nearly all bacteria. Technically, reaching this conclusion required us to implement methods that are insensitive to the presence of large idiosyncratic genomic features, which may co-exist along these fundamental universal structures. PMID- 29512519 TI - [Homeostasis and Disorder of Musculoskeletal System.Pathogenesis of musculoskeletal diseases and strategies for their treatment.] AB - Decline of homeostasis in musculoskeletal locomotive organs such as bone and muscle with age leads to age-related diseases such as osteoporosis and muscle atrophy. To date, various findings underlying the pathogenesis of these tissues were accumulated. In this review, we discuss regarding the recent advances in the findings in the treatment for osteoporosis and the strategy for muscle atrophy, and our recent findings on the mechanisms underlying these diseases. PMID- 29512520 TI - [Homeostasis and Disorder of Musculoskeletal System.Humoral factors produced by osteocytes as druggable targets for skeletal diseases.] AB - Osteocytes have several functions such as sensing mechanical load to bone and regulating osteoclastic bone resorption. In addition, osteocytes secrete several humoral factors that affect bone and other organs. FGF23 produced by osteocytes works as a hormone that reduces serum phosphate level. Sclerostin suppresses bone formation by inhibiting Wnt signals. Drugs that inhibit the activities of these factors are now under investigation as new therapeutic measures. PMID- 29512521 TI - [Homeostasis and Disorder of Musculoskeletal System.BMP and TGF signaling and locomotive tissues.] AB - BMP(bone morphogenetic protein)and TGF-beta(transforming growth factor-beta)form a family and play an important role from formation of bone, cartilage and skeletal muscle to their homeostasis. BMP and TGF-beta transduce their signals through the cell surface type I and type II serine/threonine kinase receptors and the intracellular Smad proteins. Several factors regulate BMP and TGF-beta signals including activation mechanisms and antagonist outside the cell, co receptor in the cell membrane, and dephosphorylation by phosphatase and modification/degradation by the ubiquitin-proteasome system in the cell. In this section, we outline the functions, roles and related diseases of BMP and TGF betafamily molecules and signal transduction in locomotive tissues. PMID- 29512522 TI - [Homeostasis and Disorder of Musculoskeletal System.Transplantation of synovial mesenchymal stem cells for cartilage and meniscus regeneration.] AB - Cartilage injury remains one of the common clinical problems due to its limited regeneration capacities. Meniscectomy commonly performed for meniscus injury leads to osteoarthritis, but the indication of meniscus repair is limited. We have identified that synovial mesenchymal stem cells(MSCs)are superior to MSCs derived from other tissues in proliferation capacity and in vitro/in vivo chondrogenic potentials. When suspension of synovial MSCs was placed on the cartilage defect for 10 minutes, 60% of the cells attached to the defect site. Based on these basic researches, we started a clinical study for cartilage regeneration by arthroscopic transplantation of synovial MSCs. Additionally, we transplanted synovial MSCs for meniscus injury after meniscus repair. We obtained good clinical results of cartilage regeneration and meniscus healing without any serious side effects. Transplantation of synovial MSCs will be useful for cartilage or meniscus injuries. PMID- 29512523 TI - [Homeostasis and Disorder of Musculoskeletal System.Molecular mechanism underlying muscle development and regeneration.] AB - Skeletal muscle composes 30-40% of our body weight and is formed by multinuclear cells called myofibers. The formation of myofiber depends on the dynamic proliferation, differentiation and fusion of the myogenic progenitors during development. In the adult stage, the skeletal muscle exhibits excellent regeneration ability as well, depended on the muscle stem(satellite)cells that generate and repair myofibers. In this review, we would like to introduce 1 the mechanisms of myogenic progenitor-dependent myofiber formation in myogenesis, 2 the common fusion mechanism for myogenesis and muscle regeneration, and 3 the current status and prospects for clinical application utilizing satellite cells. PMID- 29512524 TI - [Homeostasis and Disorder of Musculoskeletal System.Enthesis formation and repair:Current understanding and perspectives for the future regenerative therapy.] AB - Tendons and ligaments are dense fibrous connective tissues mainly composed of type I collagen, aligned in highly ordered arrays along the axis of the tendon and ligament. The enthesis is defined as the attachment site of a tendon, ligament, joint capsule, or fascia to bone. During morphogenesis, the cell population co-expressing Scleraxis(Scx)and the SRY-box containing gene 9(Sox9)contributes to the formation of fibrocartilaginous entheses. Scx regulates tendon and ligament maturation, while Sox9 is a key regulatory factor for cartilage formation. The considerable mechanical forces transmitted through the enthesis and avascular properties of the tissue make it more prone to injuries and degenerative changes. Thus, integration of tendons or ligaments with bone following surgical repair remains a clinical challenge. In this review, we summarize the current knowledge regarding the formation, maintenance, damage, and repair of fibrocartilaginous entheses, focusing on the rotator cuff tendon-to bone attachment sites. PMID- 29512525 TI - [Homeostasis and Disorder of Musculoskeletal System.Molecular mechanism of bone metabolism and future therapeutic strategies.] AB - Recent studies of mouse genetics and human gene mutations has greatly contributed to clarifying the molecular mechanism of bone metabolism. Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. Bone remodeling is stringently regulated by communication among bone component cells such as osteoclasts, osteoblasts, osteocytes and endothelial cells. An imbalance of this process is often linked to various bone diseases. Thus, the elucidation of the molecular mechanisms involved in bone remodeling is critical for a deeper understanding of the maintenance of healthy skeleton and bone disease. PMID- 29512526 TI - [Homeostasis and Disorder of Musculoskeletal System.Mechanisms of cartilage development and homeostasis.] AB - Chondrocytes, which are originated from undifferentiated mesenchymal stem cells, play roles in skeletal development and growth in mammal, and smooth movement of joints. Endochondral ossification is necessary for skeletal development, and the multiple and complex biological events are precisely regulated by several hormones, cytokines, and their downstream signaling and transcriptional regulation. On the other hands, articular chondrocytes physiologically retains their features during a lifetime. Numerous molecules involved in endochondral ossification have been identified and investigation of the molecular mechanisms have amazingly progressed. Although GDF5 and Prg4 were identified as important molecules associated with articular cartilage development and its homeostasis, the molecular mechanisms are very unclear to date. PMID- 29512527 TI - [Homeostasis and Disorder of Musculoskeletal System.Molecular signaling and its pathogenic alterations in neuromuscular junction formation.] AB - The neuromuscular junction(NMJ)is the synapse between a motor neuron and the skeletal muscle that is essential for muscle contraction. Impairments at the NMJ lead to neuromuscular-transmission pathologies characterized by fatigable muscle weakness. Muscle-specific receptor tyrosine kinase MuSK plays key roles in NMJ formation. Over the past decade, studies examining the NMJ formation signals have identified molecules involved in the signaling pathways and have promoted a better understanding of characteristic molecular mechanisms for MuSK activation. Unlike many other receptor tyrosine kinases, MuSK is regulated by the cytoplasmic activator Dok-7 in addition to the extracellular activator agrin. It is well established that all of these molecules are indispensable in the formation and maintenance of the NMJ. In this chapter, we review molecular signaling, particularly MuSK signaling, in the formation of the NMJ and the altered molecular signaling associated with neuromuscular disorders. PMID- 29512528 TI - [Homeostasis and Disorder of Musculoskeletal System.Cellular dynamics in musculoskeletal system visualized by intravital imaging techniques.] AB - Bone is continually remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. Although it has long been believed that bone homeostasis is tightly regulated by communication between osteoclasts and osteoblasts, the fundamental process and dynamics have remained elusive. We originally established an advanced imaging system to visualize living bone tissues using intravital two-photon microscopy. By means of this system, we revealed the in vivo behavior of bone resorbing osteoclasts and bone-forming osteoblasts in bone tissues. This approach facilitates investigation of cellular dynamics in the pathogenesis of musculoskeletal disorders, and would thus be useful for evaluating the efficacy of novel therapeutic agents. PMID- 29512529 TI - [Homeostasis and Disorder of Musculoskeletal System.Roles of the motor system in systemic metabolism and the aging-related disorders.] AB - Among the tissues involved in the motor system, skeletal muscle plays an important role in systemic metabolism and is the largest organ in terms of glucose uptake. Insulin promotes anabolism of nutrients in skeletal muscle, as in other insulin-targeted organs, and maintains muscle volume, in cooperation with insulin-like growth factor-1. In humans, along with aging, insulin resistance is induced in skeletal muscle, which could lead to systemic insulin resistance, and circulating IGF-1 levels are lowered. These changes contribute to the development of sarcopenia, in which function and volume of skeletal muscle are impaired, and modulation of the insulin/IGF-1 signaling could be promising in treatment of sarcopenia. PMID- 29512530 TI - [Homeostasis and Disorder of Musculoskeletal System.Diagnosis and Treatment of Congenital Musculoskeletal Diseases.] AB - Congenital skeletal dysplasias have been considered to be fundamentally untreatable diseases. However, molecular diagnosis by genetic testing has become more prevalent, and efforts are being made to develop novel therapies based on the pathogenesis. As treatments for osteogenesis imperfecta, in addition to anti resorptive agents, neutralizing antibodies against sclerostin and transforming growth factor(TGF)-beta and chemical chaperones can be beneficial. Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has been recently developed to treat hypophosphatasia and has much improved the prognosis of the patients affected with severe forms of the disease. To treat the severe short stature in achondroplasia, drugs targeting the fibroblast growth factor receptor 3(FGFR3)-mediated signal are in development for clinical use. PMID- 29512531 TI - [Homeostasis and Disorder of Musculoskeletal System.Research of Osteoarthritis Therapeutics.] AB - Since the establishment of murine surgical knee osteoarthritis(OA)models, many of the key molecules and signalling pathways responsible for OA development have been identified. In vivo experiments using murine models indicate that inhibition or activation of these molecules and pathways may be useful for modifying OA pathophysiology. Here we review previous research about molecular mechanisms and therapeutics for OA. PMID- 29512532 TI - [Homeostasis and Disorder of Musculoskeletal System.Progress in the treatment of rheumatoid arthritis.] AB - Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammation and joint damage that causes significant morbidity and mortality. Rapid and appropriate intervention using disease-modifying anti-rheumatic drugs(DMARDs)is prerequisite to halt joint destruction and long-term functional disabilities. Recent progress in the treatment strategy has brought about paradigm shift for the management of the disease, namely, the combined use of methotrexate, a synthetic DMARD, and a biologic DMARD targeting TNF, IL-6 and T cells has revolutionized treatment of rheumatoid arthritis. Clinical remission is now realistic targets for the treatment, achieved by a large proportion of rheumatoid arthritis patients, which leads to structural remission without damage in bone and cartilage as well as functional remission. Furthermore, orally available small but strong molecules targeting Janus kinase(JAK)are emerging. When DMARDs are prescribed, appropriate selection of DMARDs, adequate screening, regular monitoring and systemic management are required. PMID- 29512533 TI - [Homeostasis and Disorder of Musculoskeletal System.Influence of steroid therapy on muscuoskeletal system.] AB - Muscle atrophy occurs when glucocorticoid steroids are administered in pharmacological doses or in Cushing syndrome, and such pathological condition is termed as steroid myopathy. Its molecular mechanism is clarified from the study of the gene expression regulation mechanism mediated by steroid receptors in skeletal muscle, progressing to translational research and also addressing the mechanism by which steroids participate in the regulation of whole body energy metabolism via skeletal muscle. PMID- 29512534 TI - [Optogenetics sheds light on memory research.Development and application of photoactivatable CaMKII inhibitory peptide to the study of synaptic plasticity.] AB - In the past decade, the various types of genetically-encoded optogenetic tools using blue-light sensitive LOV2 domain have been developed and applied in a wide range of areas including neuroscience field. Recently, we succeeded in developing a photoactivatable inhibitory peptide, a genetically-encoded light inducible CaMKII inhibitory peptide. Using this new optogenetic tool, we found that the 1 min of CaMKII activation is sufficient for triggering structural plasticity of synapses(spines)in hippocampal neurons. Furthermore, using passive avoidance test, we found that transient CaMKII activity, but not sustained activity, is only required for fear memory formation/maintenance in amygdala of mice. PMID- 29512535 TI - Thrombolytic therapy in ischaemic stroke [Editorial] [Erratum appears in Neurology India, 1997 Dec, 45(4) :286]. PMID- 29512536 TI - CNS tuberculosis. PMID- 29512537 TI - Recurrence of supratentorial gliomas. AB - Two hundred patients treated for supratentorial gliomas and for whom a follow up of one to sixteen years was available have been reviewed retrospectively for recurrence of tumor. All patients were initially treated with radical surgical tumour removal followed by radiotherapy. The series consisted of 82 cases of astrocytomas, 46 cases of mixed gliomas (oligoastrocytomas), 8 of oligodendrogliomas, 33 cases of malignant astrocytomas and 31 glioblastomas. However, period of recurrence could not be correlated to histological grade or presence or absence of residual tumour in a postoperative CT scan. Illustrated cases have been described. Problems of diagnosis and therapy have been discussed. PMID- 29512538 TI - Characterisation of agglutination properties of myelin basic protein. AB - Myelin basic protein (MBP) from one month old rat brain was purified by CM-52 cellulose chromatography and heparin sepharose chromatography. It's lectin properties were studied and conditions for optimum agglutination were observed. MBP behaved likea heparin binding lectin. Carbohydrade binding specificity studies showed that on molar basis MBP was feebly inhibited by lactose and strongly inhibited by heparin. Inhibition due to heparin was not due to electrostatic forces as evidenced by no inhibition due to other glycosaminoglycans. Argine and lysine residues were involved in the agglutination activity of MBP. PMID- 29512539 TI - A Software programme for data analysis of cerebral aneurysms. AB - Research by traditional methods of collection of data from case files, proformas, registers and master charts is laborious and cumbersome process. Case files in the hospital record section are often not easily accessible and can get lost. Moreover manually recorded and analysed data occupies lot of space. This entire tedious business is highly simplified by using computer software for record keeping and its analysis. We describe the development of a comprehensive, user friendly software programme for neurosurgeons using FoxPro to analyse data of cerebral aneurysm patients. Data entry is done with the help of prompted picklist instead of codes, the selection of which is tapping a key without the need to type it. This entered data is automatically converted into a computer database which generates more than 75 tables and graphs of predetermined nature and covers most of the parameters a neurosurgeon would be interested in. This coded database also generates a discharge summary in a flowing text. The prototype of programme has been used in our first hundred patients of cerebral aneurysm and debugged while analysing the next fifty. PMID- 29512540 TI - Brachial plexus and related lesions after median sternotomy. AB - A prospective study was undertaken in 459 cases, undergoing open heart surgery which necessitated media sternotomy, to see the frequency of brachial plexus and peripheral nerve related complications in the upper limbs. Seven cases (1.53) had such complications. These included lower trunk injury (3 cases), ulnar neuropathy at the elbow (3 cases), and radical neuropathy at the level of radical groove (one case). The youngest patient was aged 12 years and the remaining 6 patients were more than 30 years of age. There was no relation between the type of heart disease and these complications. The difference between patients with or without preparation of the internal mammary artery for graft was not significant. All the complications occurred on the left side. Ulnar and radical nerve palsy could be due to the positioning of the left limb. The barchial plexus injury was related to retraction of the sternum during operation. AA : Y. PMID- 29512541 TI - Peritumoural oedema in meningiomas : a radiological and histological correlation. AB - One hundred and six patients with intracranial meningiomas were evaluated retrospectively, and the degree of peritumoural oedema as noticed on CT, was correlated with the histological features and site and size of the tumour. 89 of the tumours which were 4.5 cms or more and all angioblastic and haemangiopericytic subtypes were associated with significant peritumoural oedema. PMID- 29512542 TI - Auditory function after lumbar puncture. AB - This study was undertaken to evaluate the incidence and degree of hearing loss by clinical and audiometric analysis after lumbar puncture and to determine the site of involvement in brainstem auditory evoked response (BAER) studies. We also wanted to determine whether the degree of hearing loss is related to the size of the spinal needle used. Twenty patients were randomised for lumbar puncture into 2 groups, one using 20G and the other using 24G needle. Audiometry and brainstem auditory evoked response studies were carried out before and 24 hours after lumbar puncture. There was no statistically significant change in the hearing levels (on audiometry), before and after lumbar puncture, in cases belonging to both the groups (20G and 24G). There was no statistically significant change in the latency of each wave (on BAER) before and after lumbar puncture in cases belonging to both the groups (20G and 24G). No significant change either in hearing level on audiometry or in latency of BAER waves was noted when the two groups (20G, 24G) were compared with each other. In the present study, there was no indicator to suggest that the size of the lumbar puncture needle influenced auditory function. PMID- 29512543 TI - Leigh's disease : analysis of clinical and imaging characteristics with possible therapeutic implications. AB - The symptoms and signs of Leigh's disease are so variable that the diagnosis is extremely difficult. The disease was so far being confirmed only at autopsy. Antemortem clinical diagnosis, however, is important, as some of these patients may respond to high dose of vitamin B-1. We report two patients of Leigh's disease suspected clinically and confirmed on MR imaging. Both the patients responded partially to parenteral thiamine and subsequently remained stable on convenient oral dosage during one year of observation. Follow-up MRI done on patient showed resolution of some of the lesions, no change in some and appearance of some new lesions. There was no definite correlation between the thiamine related clinical recovery and the structural changes observed on MRI. The extreme rarity of involvement of medulla and cervical spinal cord as observed in one of the patients and of external capsule as seen in the other patient, is highlighted. PMID- 29512544 TI - Cerebral parenchymal calcification in a child with vein of galen malformation : role of medullary veins. AB - A child with vein of Galen malformation whose CT scan showed extensive parenchymal calcification on follow-up, is presented. The possible role of differential venous pressures and medullary veins in the pathogenesis of cerebral calcification in our patient is discussed. PMID- 29512545 TI - Spinal extradural angiolipomas : report of three cases. AB - Three cases of extrdural spinal agiolipomas of dorsal region presenting as compressive myelopathy are reported. All of them recovered fully following surgery. The role of modern imaging techniques in detecting such lesions along with review of literature is presented. Histopathology in case 2 showed areas suggestive of haemingioma and predominant areas of angiolipoma supporting the hypothesis of common origin of al these from the same pluripotential stem cells. PMID- 29512546 TI - Large exophytic chondrosarcoma of cervicodorsal spine without spinal cord compression : a case report with review of literature. AB - A case of well differentiated chondrosarcoma arising from the laminae and spinous processes of cervicodorsal spine is reported in a 22-years-old patient. He had presented with a painless progressive mass in the cervicodorsal region, without any neurological deficit. The tumour had a large exophytic growth without any intraspinal component. Radiological appearance of cartilaginous calcification suggested the diagnosis of a cartilaginous tumour. Fine needle aspiration cytology (FNAC) from the mass failed to differentiate between a chondroma and a well differentiated chondrosarcoma. The final histopathological diagnosis of the surgically excised tumour was possible only after a detailed radiological and clinicopathological correlation. Total surgicalexcision of the tumour was followed by radiation therapy. A review of literature is included in view of the rarity of this condition and scarcity of similar reports in the Indian literature. PMID- 29512547 TI - Electrophysiologic study of spraymen exposed to insecticide Lambda-cyhalothrin. AB - Lambda-cyhalothrin ia a potent insecticide which acts by producing prolonging the duration of opening of sodium channels in neurons. While it is being used in several countries, no extensive neurophysiologic study of toxic effects in humans is available. We performed multimodality electro-physiologic studies in 15 spraymen in the age range of 19-48 years, before and after the exposure to this insecticide, with a view to detect any neurotoxic manifestation. Facial nerve conduction, blink response, repetitive stimulation test and visual, auditory and somatosensory evoked potentials were normal. Six subjects had mild changes in peripheral nerve conduction parameters. Comparison of mean values of the various nerve conduction studies in three subjects showed normal findings. We conclude that Lambda-cyhalothrin may produce transient, subclinical, electrophysiologic changes in the nerves of upper limb, possibly as a local toxic manifestation. PMID- 29512548 TI - Infantile facioscapulohumeral muscular dystrophy with Coat's syndrome. AB - A case of facioscapulohumeral dystrophy (FSH) with several unusual feature is being presented. It's early onset in infancy as against commonly occurring onset in second decade, the relentless progressive course without abortive or apparent arrest phase as is often seen, the calf hypertrophy, marked skeletal changes and associated retinal changes seen in Coat's disease are the noteworthy features of this unusual case. PMID- 29512549 TI - Dumb-bell schwannoma of brachial plexus. AB - A rare case of extradural dumb-bell schwannoma of brachial plexus, arising from C6 root is reported along with review of literature. The clinical and radiological features useful in diagnosing the lesion are presented. The treatment policy to be adopted and the importance of adequate surgical exposure is discussed. PMID- 29512550 TI - Botulinum toxin injections for dystonias. PMID- 29512551 TI - Non-compressive cervical myelopathy associated with monoclonal gammopathy. PMID- 29512553 TI - Hypothyroidism with hypokalemic periodic paralysis. PMID- 29512552 TI - Multiple brain tumours : a case report. PMID- 29512554 TI - Depression as the initial manifestation of Parkinson's disease. PMID- 29512555 TI - Iatrogenic brain abscess. PMID- 29512556 TI - Painful cervical dystonia due to caudate nucleus infarction in Behcet's disease. PMID- 29512557 TI - Tracking India's Progress in Health Sector after 70 Years of Independence. PMID- 29512558 TI - An epidemiological study on home injuries among children of 0-14 years in South Delhi. AB - Background: Injuries are an important public health problem worldwide, accounting for 5 million deaths, of which unintentional injuries account for 0.8 million deaths in children. Though there are many factors responsible for injury in the home, the environment plays an important role. Objectives: The objectives were to study the magnitude and pattern of home injuries in children aged 0-14 years and to assess the environmental risk associated with home injuries. Methods: A community-based, cross-sectional study was conducted in 2015 in a ward of Mehrauli containing 20,800 households, and the total sample of children was selected from 400 households by systematic random sampling, with sampling interval being 52. Information was taken using a predesigned, semi-structured, pretested proforma from both the parents and children. The data collected were analyzed using SPSS version 12. Results: : The prevalence of home injury was found to be 39.7% in the last 1 year, significantly higher in the age group of 1 3 years (54.3%) followed by 5-10 years (45.1%) (P = 0.000). The total number of injuries and the average number of injuries in girls were significantly higher than those of boys. The most common type of home injury was falls (59.5%) followed by injury with sharps and burn injury. The environmental risk was assessed using standard and working definitions and found unsafe electrical points (95.3%), unsafe stairs (100%), unsafe kitchen with access to sharps (29.3%), access to active fire (19.3%), and unsafe furniture and objects (22.8%). Conclusion: Though home injury did not occur in 60% of the children during the study period, the risk of injury in the future is high. Educating the parents and the children at schools and environmental modification are important strategies for prevention of home injury. PMID- 29512559 TI - Perceived role and its enhancing factors among the village health volunteers regarding malaria control in rural myanmar. AB - Background: Village health volunteers (VHVs) are key agents for malaria control in community. The Myanmar Medical Association-Malaria (MMA-Malaria) Project has promoted effective malaria control in endemic and high-risk townships by supporting roles of VHVs. Objectives: To assess the roles of VHVs on malaria control and factors enhancing their roles in rural Myanmar. Methods: : A cross sectional study was conducted in five townships where the MMA-Malaria Project has been implemented. One hundred and fifty VHVs were sampled from five townships by simple random sampling. Data were collected by trained interviewers using structured questionnaires, which covered sociodemographic, supportive, motivational factors, and roles of malaria control. Studied variables were described by proportions, means, and standard deviations and were analyzed for their association by odds ratio with 95% confidence interval and Chi-square tests. Results: Most of VHVs (96%) expected to demonstrate good roles on malaria control, but only 44.0% exhibited current roles at a good level. Factors enhancing their roles were female (P = 0.037), family income >=50,001 kyat/month (P < 0.015), time serving as a volunteer 1-2 years (P = 0.006), good knowledge of malaria control (P < 0.001), good family support (P < 0.001), good community support (P < 0.001), and good motivational factors (P = 0.002). Conclusion: VHVs are key agents for malaria control in community. Most of VHVs expected to demonstrate good roles on malaria control, but less than half of them exhibited current roles at a good level. The systems and program for improving VHVs' knowledge, encouraging family and community support, and promoting motivation are essential for their better roles. PMID- 29512560 TI - Stigma towards mental illness: A hospital-based cross-sectional study among caregivers in West Bengal. AB - Background: Stigma among caregivers of people with mental illness has a serious impact on the disease outcome and lives of people with mental illness as well as other family members. Objectives: The objectives of this study were (i) To determine the level of self-perceived stigma toward mental illness, (ii) To measure perception to it among caregivers of people with mental illness, and (iii) To identify the factors associated with self-perceived stigma of caregivers. Methods: In this cross-sectional study, a structured interview was conducted among 200 caregivers of people with mental illness in the psychiatry outpatient department of a tertiary care hospital in West Bengal, India. Stigma and perception regarding mental illness were assessed with a validated 12-item Explanatory Model Interview Catalogue and 20-item perception scale, respectively. Information on their sociodemographic characteristics was also collected. Results: Average stigma score (53.3 +/- 13.2) was higher than 50% of maximum attainable score. Caregivers of higher age, female gender, low income, higher education, manual job, rural residence, and those who are single or widowed scored higher in stigma scale. Caregivers with female gender (P = 0.007) and rural residence (P = 0.01) were more likely to have stigma while the perception score was negatively associated (P < 0.001) with stigma score. Conclusion: The study highlighted that health-care providers can play a pivotal role to address caregivers' stigma in order to alleviate its effect on the course of illness and improve family life. PMID- 29512561 TI - Influences of Gender, Religion, Dietary Patterns, and Mixed-sex Education on Aggressiveness in Children: A Sociodemographic Study in Municipal Primary Schools of South Delhi. AB - Background: Increasing antisocial and violent behaviors in adolescents and young adults present serious challenges for public health. Children with persistent high levels of aggressiveness are often associated with developing conduct disorders later in life. Early detection of highly aggressive children and sociodemographic risk-modifying factors are important for developing effective preventive strategies. Objectives: The present study was undertaken to assess levels of aggressiveness for detecting highly aggressive children in sample populations of primary school children in an urban setting and determine significant biosociocultural risk-modifying factors in this scenario. Methods: The study was conducted during August-September, 2015 in 5 primary schools of South Delhi Municipal Corporation. Sociodemographic data on 2080 students were collected. Overall aggressiveness scores (OA-Scores) were estimated using a self report questionnaire in Hindi. Results: Categorizing students according to their OA-Scores, the data revealed that highly aggressive children constituted 4.3% of the study population. Analysis showed significant influence of (a) gender: boys displayed higher levels of aggressiveness compared to girls; (b) dietary pattern: omnivores showed higher aggressiveness than vegetarians; and (c) school environment: boys in mixed-sex (coeducational) schools displayed lower aggressiveness than from single-sex schools. Statistically significant influences of religion (Hindu/Muslim) and family type (joint/nuclear) on aggressiveness profiles were not noticeable. Conclusions: Vegetarian diets and mixed-sex education act as protective factors in the development of aggressiveness in children, especially among boys. Extending investigations to populations differing in geography and cultural backgrounds are warranted to verify present results. PMID- 29512562 TI - Correlation among perceived stress, emotional intelligence, and burnout of resident doctors in a medical college of West Bengal: A mediation analysis. AB - Background: Perceived stress and burnout are by-products of powerless responsibility imposed on resident doctors. Emotional intelligence (EI) works as an adapting and coping tool. Objective: The objective of this study is to find out the role of work-related perceived stress on burnout and influence of EI on it. Methods: : A descriptive cross-sectional study was conducted from February to April 2016 among 63 resident doctors of different departments of Bankura Sammilani Medical College and Hospital. Data were collected through a self administered questionnaire for background characteristics and work-related variables. Cohen perceived stress scale, Trait EI, and Shirom-Melamed burnout questionnaire were applied for measuring perceived stress, EI, and burnout, respectively. Statistical analysis was done with of SPSS version 22.0, and for mediation analysis, Andrew F. Hyne's SPSS macro was adopted. Nonparametric bootstrapping was done assuming small sample. Results: Out of complete responses, 67%, 22.9%, and 9.8% were from clinical, paraclinical, and preclinical specialties, respectively. Burnout had a significant positive correlation with perceived stress and in negative correlation with EI-well-being and positive correlation with EI-self-control and sociability. Physical fatigue factor of burnout had a significant positive correlation with EI-emotionality. Perceived stress had a negative correlation with EI-well-being. On mediation analysis, assuming EI as a mediator, total, direct, and indirect effects of perceived stress on burnout were significant (<0.05). Mediation was proved to act with percent mediation of 0.07. Conclusion: There was definite mitigating effect of EI on burnout by perceived stress among resident doctors. This necessitates more attention by decision-makers toward this burning problem for the sake of care of caregivers. PMID- 29512563 TI - Spatio-temporal assessment of infant mortality rate in India. AB - Background: Infant mortality rate (IMR) is globally identified by the policymakers as the marker of health of a population. Objectives: This study aimed to detect the change in hotspots of IMR in Indian states from the year 2000 to 2012, identify hotspots of IMR at district level in selected states from each of the six regions of India and determine the potential predictors of IMR after accounting for spatial autocorrelation. Methods: Ecological study design was used to analyze state and district level data on IMR of India. For the first objective, the data were obtained from Sample Registration System. For the second objective, we classified India into six regions and selected a state in each region that had the highest IMR. The district level data on IMR and potential predictors were obtained from surveys, namely, Annual Health Survey, District Level Household and Facility Survey and Census. Spatio-temporal hotspots of IMR were examined using local indicators of spatial association statistic. Spatial regression was used to identify the potential predictors of IMR after accounting for spatial autocorrelation. Results: Temporal hotspots of IMR were found in the central part of India. Spatial hotspots were identified in districts of Uttar Pradesh. A negative association of IMR existed with female literacy rate, mothers receiving antenatal checkup (%), and people living in urban areas (%). Conclusion: IMR continues to be a problem in the states that have previously shown to be poor performing. Certain districts within these states need emphasis for focused activities. PMID- 29512564 TI - Medicosocial characteristics as predictors of school achievements in students with intellectual and developmental disabilities: A follow-up study in ujjain and shajapur districts of Madhya Pradesh, India. AB - Background: For a long time, there have been arguments about which factors influence the skill development of students with intellectual disability in rehabilitation centers. Objective: The present follow-up study was thus planned to analyze the effect of the demographic variables related to disabled child, his/her parents and the family; their schooling pattern and types of study settings and the associated comorbidities on improvement in the performance score of students attending these study settings in one academic year. Methods: The study was conducted among children (n = 204) with intellectual disability receiving rehabilitation services in centers run by a nongovernmental organization in two districts of Central India. Results: : Application of regression analysis concluded that among various hypothesized factors higher birth order, more time spent by parents for child's development at home, high performing classes, absence of epilepsy, psychiatric comorbidities, and associated physically challenged were significantly associated with improvement in overall mean performance score. Conclusions: : The study delineates the need to motivate parents, so that they can involve themselves to develop their child's full potential. Identification of associated comorbidities is recommended and parents need to be appraised accordingly. PMID- 29512565 TI - The effect of a newly established urban diarrhea treatment facility in Bangladesh: Changing patient characteristics and etiologies. AB - Background: Mirpur treatment centre (MTC), Dhaka of the International Centre for Diarrhoeal Disease Research, Bangladesh, was established as a consequence of an outbreak of diarrheal disease during the summer month of April 2007 in Mirpur area. Objective: The present study aimed to evaluate the impact of this new facility on patient load, common etiology, and other characteristics of patient population who sought treatment at Dhaka Hospital. Methods: As part of the Diarrheal Disease Surveillance System (DDSS), 10% patients (every 10th) seeking care irrespective of age, sex, sociodemographic background, and severity of disease were enrolled at MTC as opposed to 2% (every 50th) at Dhaka Hospital following identical methodology from 2010 to 2013. Moreover, enrolled DDSS patients from 2005 to 2009 at Dhaka Hospital were also included in analysis to further examine the impact of MTC on Dhaka Hospital. Results: Patient load from Mirpur area attending the Dhaka Hospital reduced from 13% during epidemic in 2010 to 6% in 2013 (53% reduction), whereas attendance in MTC increased substantially by 33%. This changing trend was also observed among children <5 years old. A significant reduction of patients presenting with moderately severe disease from Mirpur area at Dhaka Hospital was observed (69% reduction); however, attendance at MTC increased by 26% during same period. Conclusion: The number of patients from Mirpur area in Dhaka Hospital reduced but increased at MTC explaining the need for establishment of a set up for early treatment and control of diarrheal disease when consistent increase in annual number of cases or at the time of upsurge of cases is observed. PMID- 29512566 TI - Congenital rubella syndrome: A brief review of public health perspectives. AB - Congenital rubella syndrome (CRS) is one of the most devastating congenital infections and yet the only one which is vaccine preventable and is a public health challenge for clinicians and policymakers across the developing world including India. The clinical manifestations of CRS include growth retardation, cardiac defects, cataracts, and hearing impairment. The World Health Organization (WHO) estimates that worldwide over 100,000 babies are born with CRS every year despite the availability of safe and inexpensive vaccines, thus highlighting the need for broader vaccination coverage programs. This article briefly reviews the importance of CRS, the proposed strategies for prevention by the WHO, and the "Rubella initiative" that Government of India is launching in view of the recognition of CRS as a significant problem in India. PMID- 29512567 TI - War against tobacco: Where do we stand? AB - India has launched war against tobacco epidemic for the past few decades but with partial success; hence, challenges are still there which need to be identified and addressed for winning the battle. Targeted approach directed at motivating smoking cessation of female smokers, frequent changing of pictorial warnings depicting variety of health consequences in cigarette packets and devoid of logos and colors in conjunction with plain packaging, and display of toll-free number for quitting are expected to dissuade tobacco consumers to quit and save themselves from the devastating health, social, environmental, and economic consequences of tobacco consumption. Online reporting system for violating legal enforcements can also be implemented easily. Moreover, guidance from success stories of countries/states who have achieved smoke-free status along with concerted efforts such as innovative anti-tobacco campaigns, involvement of religious leaders in anti-tobacco propaganda, strict legislations, and overall strong political commitment would further aid in winning the war. PMID- 29512568 TI - Factors associated with maternal near miss: A study from Kerala. AB - Severe life-threatening situations leading to a "near-miss" event may arise unexpectedly in pregnancy. Delay in seeking help, delayed access to care, and poor quality of emergency obstetric services can lead to undesirable outcomes. Women meeting the WHO "near-miss" criteria were assessed using a cross-sectional study design. These women were interviewed to evaluate the circumstances leading to a near-miss event. Reasons for delays in getting proper care were studied using the "3 delays' model." Thirty-two women met the criteria for "near miss" during the 15-month study period, with a maternal near-miss incidence ratio of 9.27/1000 live births. One or more delays were identified in 21 (65.6%) near-miss cases. Delayed access to care was the most important factor for delay. A review of near-miss cases can be used to improve and optimize the existing obstetric services. PMID- 29512569 TI - Evaluation of competency and skills of skilled birth attendants in Madhya Pradesh, central India. AB - The National Health Mission tracks the proportion of women delivered by skilled birth attendants (SBAs). We assessed SBAs competence in Madhya Pradesh, India, using structured evaluation tools. It is a cross-sectional study conducted from 2014 to 2015. We evaluated 335 trained SBAs using multistage stratified random sampling. Of total, 335 skilled births attendant selected 41.8% were auxiliary nurse midwife, 47.8% were staff nurse, and 10.4% were lady health visitors. Grouping all provider and knowledge test versions, SBAs were correct on 75.4% of the questions. By topic, results ranged from 77.9% correct for the management of normal pregnancy and childbirth to 70.2% correct for intranatal care. The skill evaluation score was 88.1% of infection prevention practices to 74.3% for postnatal care. The present study found significant variations in knowledge and skill competency scores of the SBAs. There is a critical need to improve the training quality of skill birth attendants. PMID- 29512570 TI - Consumption of junk foods by school-aged children in rural Himachal Pradesh, India. AB - There has been an increase in the consumption of junk food (JF) among school-aged children (SAC) possibly leading to obesity and diet-related diseases among them. We do not have evidence on consumption of JF in rural areas; hence, we conducted a study to assess the consumption of JF by SAC in rural, Himachal Pradesh. A total of 425 children in the age group of 12-18 years studying in 30 government schools (clusters) were included. The clusters were selected using population proportionate to size sampling methodology. We found high prevalence (36%) of consumption of JF among SAC during the last 24 h. Efforts should be taken to reduce the consumption of JF by promotion of healthy dietary habits and educating children about the ill effects of JF. PMID- 29512571 TI - A comment on "nomophobic behaviors among smartphone using medical and engineering students in two colleges of West Bengal" letter by dasgupta et alx. (2017). PMID- 29512572 TI - Author's reply for article "nomophobic behaviors among smartphone using medical and engineering students in two colleges of West Bengal". PMID- 29512573 TI - Kaleidoscopic view of intracranial aneurysms. PMID- 29512574 TI - Neuromuscular disorders in infancy and childhood. AB - Thirty five floppy children seen during two year period, were subjected to clinical examination, electroneuromyography and muscle biopsy. The muscle biopsy was sent for routine histology, histochemistry and electron microscopy. Using muscle pathology as the 'gold standard' for diagnosis, the aetiological entities were spinal muscular atrophy (16), congenital muscular dystrophy (6), mitochondrial myopathy (3), congenital fibre type disproportion (2), acid mutase deficiency (1) and benign congenital hypotonia (6). Mental subnormality, seizures, ptosis and ophthalmoplegia suggested mitochondrial disease (n=2). Macroglossia, hepatomegaly and cardiomegaly along with the dive bomber effect on electromyography were useful clues to the diagnosis of Pompe's disease (n=1). Positive decremental test established the diagnosis of congenital myasthenia in one patient. Contrary to most previously published reports, infantile onset of spinal muscular atrophy did not always spell a poor prognosis on follow up. 'Floppy infant syndrome' has varied etiology. Comprehensive evaluation including clinical, electrophysiological and detailed histological examination is necessary for proper diagnosis and prognosis of this heterogenous entity. PMID- 29512575 TI - Efficacy of bupivacaine infiltration in preventing haemodynamic changes during craniotomy. AB - This study was carried out in sixty adult patients of either sex, to assess the efficacy of bupivacaine infiltration in different concentrations to prevent haemodynamic responses during craniotomy. The patients were randomly divided into 4 groups of15 each and scalp was infiltrated along the line of skin incision using either normal saline or 0.5, 0.25 or 0.125 bupivacaine. Patients were premedicated with morphine and promethazine and were anaestetised using conventional general anaesthesia technique including 02, N20 vecuronium and morphine. Ventilation was controlled so as to maintain PaCO2 between 25-30 mm Hg. EKG, heart rate and direct arterial pressure were monitored at various events during craniotomy. In control group there was a statistically significant increase in systolic arterial pressure and heart rate after scalp infiltration, scalp incision, during scalp flap reflection, burr hole formation, giglisaw operation and dural incision. In bupivacaine groups there was no significant alteration in arterial blood pressure or heart rate through out the period of study. On comparing the four groups it was observed that rise in arterial pressure and heart rate was significantly more in control group. Similarly a significantly more increasein systolic arterial pressure was observed in bupivacaine (0.125) group as compared to other trial groups. We recommend the haemodynamic changes during craniotomy. PMID- 29512576 TI - Chronic inflammatory demyelinating polyneuropathy : clinical, electrophysiological and morphological study. AB - Twelve patients (M:F 9:3) who fulfilled diagnostic criteria of chronic inflammatory demyelinating polyneuropathy (CIDP) were seen at NIMHANS over a period of three years (1987-1990). Their ages ranged from 20 yrs to 71 yrs and the mean duration of symptoms was 30 months (range 3 months to 6 yrs). Symptoms at the onset were dependent on the duration of disease. These included paraesthesia (7), weakness (4) and ataxia in lower limbs (1). Salient features on examintion were: distal weakness (10), proximal weakness (6), impaired touch and pain (12), impaired joint position and vibration sense (6), distal areflexia (12), bilateral impaired hearing (2) and thickened nerves (4). Electrophysiological evidence of demyelination was present in all and albumino cytological dissociation in CSF was noted in 55 of the patients. Sural nerve biopsy revealed significant loss of myelinated fibres in all the five patients studied. Increase in endo and perineural collagen, remyelination and schwann cell proliferation were also seen. Inflammatory infiltrates were conspicuously absent. Steroids were given in 10 patients. The therapeutic response was good in 5 and moderate in 5. Two patients had remitting relapsing course. Response to steroids could not be predicted on the basis of clinical or laboratory features. The recent diagnostic criteria and their therapeutic relevance are discussed. PMID- 29512577 TI - Peripheral neuropathy in tetanus : a clinical, neuroelectrophysiological and histological evaluation. AB - Nineteen patients (14 males and 5 females), who had tetanus were evaluated for polyneuropathy by clinical examination, neuroelectromyography and sural nerve biopsy. Three patients (16) had clinically evident distal symmetrical polyneuropathy. Therewas a significant prolongation of mean median motor distal latency (p<0.02) peroneal motor distal latency (p<0.001) and reduction of sural sensory nerve action potentials (p<0.001) in these patients in comparison to controls. Electromyographic sampling of tibialis anterior muscle revealed wide variation in motor unit action potential duration and amplitude. Denervation phenomena including fibrilations and positive sharp waves were present in 4 patients (21) and complex repetitive discharges were present in 9 patients (47.4). Sural nerve histology was performed in 9 patients. It revealed mild to moderate loss of myelinated fibres in 4 cases (44.4). There is evidence that in tetanus there is a distal predominantly sensory polyneuropathy. PMID- 29512578 TI - Mitochondrial neurogastrointestinal encephalopathy (MNGIE) in a South Indian family with two affected siblings. AB - We report a South Indian family in which two living members were affected by a progressive neurogasrointestinal disorder characterized by dysmotility. Evidence for mitochondrial dysfunction was provided by increased arterial blood lactate, and ragged red fibres in muscle biopsy. Our report is believed to be the first description of the autosomal recessively inherited multisystem mitochondrial disease, mitochondrial neurogastrointestinal encephalopathy (MNGIE), from India. PMID- 29512579 TI - Ventral screw fixation of odontoid fracture, using single fluoroscope. AB - This paper is a detailed description of an improvised operative technique used by us, for ventral screw fixation in a case of type II odontoid fracture. PMID- 29512580 TI - Spontaneous resolution of chronic subdural haematoma secondary to chronic idiopathic thrombocytopenic purpura. AB - Chronic subdural haematoma (SDH) complicating chronic idiopathic thrombocytopenic purpura (ITP), in an adult is extremely rare. There are only four such case reports available in the literature and all these patients had surgical evacuation of the haematoma. We report an elderly female with chronic ITP presenting with a chronic SDH which resolved spontaneously. This is possibly the first report of its kind in the world literature. The possible pathogenesis is discussed and pertinent literature reviewed. PMID- 29512581 TI - High cervical intraspinal enterogenous cyst. AB - A case of histologically verified ventro-laterally placed enterogenous cyst in the upper cervical region is reported. PMID- 29512582 TI - Cortical sensory loss : is it always cortical? AB - A 38 year male suffering from cardioembolic stroke developed acute left hemiplegia and cortical sensory loss, which included graphanesthesia, impairment of two point discrimination and tactile inattention. CT scan revealed haemorrhagic infarction inright corona radiata and anterior limb of internal capsule. On day 13, cortical SEPS were absent and there was bifrontal and left parietal hypoperfusion on SPECT studies. Both the sensory loss, and SEP improved on day 28, which correlated with improvement in regional cerebral blood flow (rCBF). The cortical sensory loss, therefore, can also occur in subcortical lesion and may be due to cerebral diaschisis. PMID- 29512583 TI - Claudicatory penile erection in lumbar canal stenosis with prolapsed disc : a case report of 2 cases. AB - Two adult male patients having lumbar canal stenosis with prolapsed disc, developed claudicatory priapism along with classical symptoms of claudication, are reported in this article. The first patient complained of severe claudicatory pain in anal canal along with other symptoms. The second patient had a protruded bony rim at the lower margin of L4 vertebra in addition to the prolapsed disc. All the symptoms totally subsided after relieving the compression. PMID- 29512584 TI - Bilateral basal ganglia germinoma in an Indian boy. AB - Germ cell tumours are rare intracranial tumours. The basal ganglionic location of these tumours comprise a rare group. Bilateral involvement of the basal ganglia by germ cell tumours is distinctly rare and have only been reported in Japanese patients. We present the first report of bilateral basal ganglionic germ cell tumour in a non-Japanese patient. PMID- 29512585 TI - Episodic headache in a non-epileptic patient having disappearing single (ring enhancing) CT lesion. PMID- 29512586 TI - Skull tongs : an unusual cause of cerebral abscess. PMID- 29512588 TI - Abscess within a metastatic tumour. PMID- 29512587 TI - Oculomotor paresis in unruptured anterior communicating artery aneurysm. PMID- 29512589 TI - Long segment cervico-dorsal intradural lipoma. PMID- 29512590 TI - Management of posterior fossa tumours with severe hydrocephalus. PMID- 29512591 TI - Hereditary multiple exostoses with thoracic cord compression. PMID- 29512593 TI - Cerebellar ataxia in patients of falciparum malaria. PMID- 29512592 TI - Thalamic tumour presenting with only deteriorating mental functions. PMID- 29512594 TI - Postmortem examination of the nervous system. PMID- 29512595 TI - Women & diabetes: Our right to a healthy future. PMID- 29512596 TI - Age of onset of alcoholism: Improving samples & design to inform policy. PMID- 29512597 TI - Early warning systems for the detection of malaria outbreaks. PMID- 29512599 TI - Zika virus: Current concerns in India. AB - With confirmation of Zika virus (ZIKV) presence in India, screening of a large number of febrile illness samples yielded only four positive cases. In this review, we address the current concern with context to India. The possible reasons for low level of Zika prevalence in India have been discussed, by extracting some probable explanations from previous experience of chikungunya virus-vector model/studies. In the current context, it is hypothesized that Indian mosquito strains have lower susceptibility gradient/threshold for ZIKV. The very low positivity in the humans also indicates low levels of mosquito-human mosquito transmission cycle. There is also a need to look for the existence of any such animal cycle/sylvatic involvement in India. The recently detected four cases in India show local transmission of ZIKV suggesting that ZIKV might have been present in India since long time. The earlier vector-virus relationship studies with chikungunya suggested that in due course of time, ZIKV might become a major public health concern in the future. PMID- 29512598 TI - Prognostic & predictive factors for planning adjuvant chemotherapy of early-stage breast cancer. AB - Breast cancer is a heterogeneous disease and may present with different clinical and biological characteristics. At present, breast cancer is divided into molecular subgroups besides its histopathological classification. Decision for adjuvant chemotherapy is made based on not only histopathological characteristics but also molecular and genomic characteristics using indices, guidelines and calculators in early-stage breast cancer. Making a treatment plan through all these prognostic and predictive methods according to risk categories aims at preventing unnecessary or useless treatments. In this review, an attempt to make a general assessment of prognostic and predictive methods is made which may be used for planning individualized therapy and also the comments of the guidelines used by the oncologists worldwide on these methods. PMID- 29512601 TI - National sample survey to assess the new case disease burden of leprosy in India. AB - A national sample survey of leprosy was undertaken in partnership with Indian Council of Medical Research (ICMR) institutions, National Leprosy Eradication Programme (NLEP), Panchayati Raj members, and treated leprosy patients to detect new cases of leprosy in India. The objectives of the survey were to estimate the new leprosy case load; record both Grade 1 and Grade 2 disabilities in the new cases; and to assess the magnitude of stigma and discrimination prevalent in the society. A cluster based, cross-sectional survey involving all States was used for the door-to-door survey using inverse sampling methodology. Rural and urban clusters were sampled separately. The population screened for detecting 28 new cases in rural and 30 in urban clusters was enumerated, recorded and analyzed. Data capture and analysis in different schedules were the main tools used. For quality control three tiers of experts were utilized for the confirmation of cases and disabilities. Self-stigma was assessed in more than half of the total new patients detected with disabilities by the approved questionnaire. A different questionnaire was used to assess the stigma in the community. A population of 14,725,525 (10,302,443 rural; 4,423,082 urban) was screened and 2161 new cases - 1300 paucibacillary (PB) and 861 multibacillary (MB) were detected. New case estimates for leprosy was 330,346 (95% Confidence limits, 287,445-380,851). Disabilities observed in these cases were 2.05/100,000 population and 13.9 per cent (302/2161) in new cases. Self-stigma in patients with disabilities was reduced, and the patients were well accepted by the spouse, neighbour, at workplace and in social functions. PMID- 29512600 TI - A meta-analysis to assess usefulness of procalcitonin-guided antibiotic usage for decision making. AB - Background & objectives: Development of antibacterial resistance and its association with antibiotic overuse makes it necessary to identify a specific and sensitive biomarker for the diagnosis of bacterial infection and guiding antibiotic therapy. Procalcitonin (PCT), as a sepsis biomarker, may play a role in guiding antibiotics treatment in hospital settings. The aim of the current meta-analysis was to analyze the utility of PCT on various outcomes of interest in inpatients. Methods: Different databases were searched for randomized controlled trials comparing PCT-guided therapy with standard therapy in admitted patients with bacterial infections. Twenty six articles were found suitable for full text search and of these, 16 studies were considered finally for data extraction. Results: There were no significant differences found in total mortality [pooled odds ratio (OR) 1.04, 95% confidence interval (CI) 0.89-1.22, P=0.63], 28-day mortality (pooled OR 0.97, 95% CI 0.80-1.19, P=0.79), need of Intensive Care Unit admission (OR=0.80, 95% CI 0.59-1.09, P=0.16) and duration of stay in hospital (pooled mean difference -0.01, 95% CI -0.50-0.49, P=0.98) between treatment and control groups. PCT-guided treatment significantly decreased the duration of antibiotic treatment (pooled mean difference -2.79, 95% CI -3.52--2.06, P<0.00001). Interpretation & conclusions: PCT-guided therapy significantly decreased antibiotics exposure and thus treatment cost. However, the hard endpoints did not demonstrate any significant benefits, possibly due to low power to detect differences and/or the presence of comorbidities. PMID- 29512602 TI - Relation between age at first alcohol drink & adult life drinking patterns in alcohol-dependent patients. AB - Background & objectives: Age at first drink has its influence on later life drinking patterns. The association between age at first drink and adult alcohol consumption has not been studied in clinical population. This study was aimed to determine the age at first drink and its correlation with adult life drinking patterns in alcohol-dependent patients. Methods: Adult participants with alcohol dependence were included from the inpatient and outpatient wards of a tertiary care de-addiction facility in India. Questionnaires administered were National Institute on Alcohol Abuse and Alcoholism-Quantity Frequency for alcohol and the Fagerstrom Test for Nicotine Dependence for tobacco. Results: Of the 99 participants (92% males) with mean age 37+/-8.36 yr, mean age at first drink was 21.14+/-5.33 yr. After controlling for age, satisfaction with life scores and smoking, age at first drink showed a significant negative correlation with drinking days per week (r=-0.259, P=0.012), typical drink per day (r=-0.218, P=0.035) and maximum drinks in the previous month/year (r=-0.233, -0.223 and P=0.024, 0.031, respectively). Interpretation & conclusions: Our study suggested that earlier age of first drink correlated with chronic heavy drinking patterns in later adult life in alcohol-dependent patients. This may have implications for alcohol control policies determining the age for legal consumption. PMID- 29512603 TI - Devising a method towards development of early warning tool for detection of malaria outbreak. AB - Background & objectives: Uncertainty often arises in differentiating seasonal variation from outbreaks of malaria. The present study was aimed to generalize the theoretical structure of sine curve for detecting an outbreak so that a tool for early warning of malaria may be developed. Methods: A 'case/mean-ratio scale' system was devised for labelling the outbreak in respect of two diverse districts of Assam and Rajasthan. A curve-based method of analysis was developed for determining outbreak and using the properties of sine curve. It could be used as an early warning tool for Plasmodium falciparum malaria outbreaks. Result: In the present method of analysis, the critical Cmax(peak value of sine curve) value of seasonally adjusted curve for P. falciparum malaria outbreak was 2.3 for Karbi Anglong and 2.2 for Jaisalmer districts. On case/mean-ratio scale, the Cmax value of malaria curve between Cmaxand 3.5, the outbreak could be labelled as minor while >3.5 may be labelled as major. In epidemic years, with mean of case/mean ratio of >=1.00 and root mean square (RMS) >=1.504 of case/mean ratio, outbreaks can be predicted 1-2 months in advance. Interpretation & conclusions: The present study showed that in P. falciparum cases in Karbi Anglong (Assam) and Jaisalmer (Rajasthan) districts, the rise in Cmaxvalue of curve was always followed by rise in average/RMS or both and hence could be used as an early warning tool. The present method provides better detection of outbreaks than the conventional method of mean plus two standard deviation (mean+2 SD). The identified tools are simple and may be adopted for preparedness of malaria outbreaks. PMID- 29512604 TI - In vitro susceptibility of Indian Plasmodium falciparum isolates to different antimalarial drugs & antibiotics. AB - Background & objectives: : The in vitro assays for susceptibility of Plasmodium falciparum to antimalarial drugs are important tools for monitoring drug resistance. During the present study, efforts were made to establish long-term continuous in vitro culture of Indian field isolates of P. falciparum and to determine their sensitivity to standard antimalarial drugs and antibiotics. Methods: Four (MZR-I, -II, -III and -IV) P. falciparum isolates were obtained from four patients who showed artemisinin-based combination therapy (ACT) from Mizoram, a north-eastern State of India, and characterized for their in vitro susceptibility to chloroquine diphosphate (CQ), quinine hydrochloride dehydrate, mefloquine, piperaquine, artemether, arteether, dihydro-artemisinin (DHA), lumefantrine and atovaquone and antibiotics, azithromycin and doxycycline. These patients showed ACT treatment failure. Two-fold serial dilutions of each drug were tested and the effect was evaluated using the malaria SYBR Green I fluorescence assay. K1 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) reference strains were used as controls. Results: Growth profile of all field isolates was identical to that of reference parasites. The IC50 values of all the drugs were also similar against field isolates and reference parasite strains, except K1, exhibited high IC50 value (275+/-12.5 nM) of CQ for which it was resistant. All field isolates exhibited higher IC50 values of CQ, quinine hydrochloride dihydrate and DHA compared to reference strains. The resistance index of field isolates with respect to 3D7 ranged between 260.55 and 403.78 to CQ, 39.83 and 46.42 to quinine, and 2.98 and 4.16 to DHA, and with respect to K1 strain ranged between 6.51 and 10.08, 39.26 and 45.75, and 2.65 and 3.71. MZR-I isolate exhibited highest resistance index. Interpretation & conclusions: As the increase in IC50 and IC90 values of DHA against field isolates of P. falciparum was not significant, the tolerance to DHA-piperaquine (PPQ) combination might be because of PPQ only. Further study is required on more number of such isolates to generate data for a meaningful conclusion. PMID- 29512605 TI - Protective effect of antigen excess immune complex in guinea pigs infected with Mycobacterium tuberculosis. AB - Background & objectives: : Immune complexes (ICs) play a crucial role which can either be beneficial or pathological to the host. Involvement of circulating immune complexes (CICs) has been shown in tuberculosis (TB) cases (adults and neonates form), but its immunomodulatory effect has not been studied in vivo. Hence, this study was carried out to understand and explore the prognostic therapeutic potential of CICs on the host immune system in guinea pigs animal TB model. Methods: In this study, the guinea pigs (group I) were immunized with in vitro synthesized antigen excess IC (AgX-IC), group II with antibody excess IC (AbX-IC) and group III with phosphate-buffered saline. All these animals were sensitized with Mycobacterium tuberculosis H37Rv before immunization and subsequently infected with M. tuberculosis H37Rv strain post-immunization with IC. Results: Mortality was observed in animals belonging of groups II and III, while all animals in group I survived. A steady increase in the body weight of animals immunized with AgX-IC was observed when compared to the other groups. The infection load in the spleen and lungs was less in animals from group I when compared to the other groups. The CICs were found to be in higher concentration in serum of IC-immunized guinea pigs when compared to ICs non-immunized animals. Interpretation & conclusions: Based on our findings, it can be speculated that the ICs may have a protective immunomodulatory role pertaining to disease progression and development of pathology. As a new perspective, with further insight into the underlying mechanism of action and correlation with clinical data, ICs may also be used as a potential tool for assessing the immune status of the infected individuals, especially the close contacts of TB patients. PMID- 29512606 TI - Molecular strain typing of Trichophyton mentagrophytes (T. mentagrophytes var. interdigitale) using non-transcribed spacer region as a molecular marker. AB - Background & objectives: : Dermatophytes are keratinophilic fungi that infect keratinized tissues of human and animal origin. Trichophyton mentagrophytes is considered to be a species complex composed of several strains, which include both anthropophiles and zoophiles. Accurate discrimination is critical for comprehensive understanding of the clinical and epidemiological implications of the genetic heterogeneity of this complex. Molecular strain typing renders an effective way to discriminate each strain. The objective of the study was to characterize T. mentagrophytes clinical isolates to sub-species level using molecular techniques and non-transcribed spacer (NTS) region as marker. Methods: Sixty four T. mentagrophytes clinical isolates were identified by phenotypic methods. These were subjected to polymerase chain reaction targeting three sub repeat elements (SREs), TmiS0, TmiS1 and TmiS2 of the NTS region. Sequence analysis of internal transcribed spacer (ITS) region of different types was also done. Results: Strain-specific polymorphism was observed in all three loci. Totally, 13 different PCR types were obtained on combining all the three SREs loci. No variation was observed in the ITS region. Interpretation & conclusions: The study described the usefulness of molecular strain typing technique for the discrimination of the T. mentagrophytes isolates. This will help for the future explorations into the epidemiology of T. mentagrophytes and its complex. PMID- 29512607 TI - Seroprevalence & changing trends of transfusion-transmitted infections amongst blood donors in a Regional Blood Transfusion Centre in north India. AB - Background & objectives: Transfusion-transmitted infections (TTIs) are the major problem associated with blood transfusion. Accurate estimates of risk of TTIs are essential for monitoring the safety of blood supply. The present study was undertaken to determine the percentage of voluntary donors (VDs) and replacement donors (RDs) and also, to estimate and compare the seroprevalence and changing trends of TTIs amongst VDs and RDs in a regional blood transfusion centre in north India. Methods: This retrospective study was based on the records of all voluntary and replacement donations which were collected from January 2008 to December 2014 in a Regional Blood Transfusion Centre placed in a tertiary care hospital in Delhi, India. Results: Of the total 220,482 donations, 163,540 (74.17%) were voluntary and 56,942 (25.83%) were replacement donation. The overall seroprevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis and malaria were 0.32, 1.61, 0.73, 1.62 and 0.06 per cent, respectively. Furthermore, the TTIs were more frequently encountered in RDs in comparison to VDs. Interpretation & conclusions: The increase in public awareness regarding voluntary blood donation, meticulous donor screening, counselling and use of highly sensitive tests can help in reducing the risk of TTIs. PMID- 29512608 TI - Preclinical evaluation of hydrogel sealed fluropassivated indigenous vascular prosthesis. AB - Background & objectives: Polyethylene terephthalate (PET) graft, designed and developed at our institute for vascular reconstruction, is porous to promote optimal incorporation and neointima formation, requiring pre-clotting or biomodification by sealing the pores before implantation. The objective of this study was to characterize, test and perform preclinical evaluation of hydrogel (alginate dialdehyde cross-linked gelatin) sealed fluoropassivated PET vascular prosthesis in pig model, so as to avoid pre-clotting, for its safety and efficacy before employing the indigenous and less expensive graft for clinical use. Methods: Hydrogel sealed, fluoropassivated PET vascular prosthesis were tested for haemocompatibility and toxicity followed by small animal toxicology tests and in vivo experiments in pigs receiving implantation at thoracic aorta. All 33 animals received test as well as control grafts with a plan for phased explantation at 2, 12 and 26 weeks. All animals underwent completion angiogram at the end of procedure as well as before graft explantation. Results: Haemocompatibility tests for haemolysis and toxicity tests showed no adverse events in tested mice and rabbits. Completion angiogram showed intact anastamosis and patent graft in each animal in post-operative period and at explantation. Gross and histopathological examination showed well-encapsulated grafts, clean glistening neointima and no evidence of thrombus in both test and control grafts. Interpretation & conclusions: Hydrogel sealed, fluoropassivated PET vascular prosthesis was found non-toxic, haemocompatible and remained patent in in vivo studies at planned intervals. PMID- 29512609 TI - Socio-demographic determinants of out-of-pocket health expenditure in a rural area of Wardha district of Maharashtra, India. AB - Background & objectives: In India, health expenditure accounts for less than 5 per cent of the Gross Domestic Product and the level of out-of-pocket (OOP) spending is 69.5 per cent of total health expenditures. OOP expenditure exacerbates poverty and has a negative impact on equity and can increase the risk of vulnerable groups slipping into poverty. This study was conducted to estimate the OOP expenditure on health and catastrophic health expenditure and their socio demographic determinants in a rural area of Maharashtra, India. Methods: This was a prospective observational study involving monthly follow up visits, done in 180 households of three villages under a primary health centre in Wardha district, India. Results: Of the 180 families, 18.9 per cent had catastrophic health expenditure over a period of one year. The median total out-of-pocket health expenditure was '1105.00 with median medical expenditure being '863.85 and median non-medical health expenditure being '100.00. A total of 151 (83.9%) had enough money, 27 (15%) borrowed money and two (1.1%) of them sold assets. The significant correlates for the ratio of out-of-pocket health expenditure to total annual income of the family were the occupation of head of family, caste category and type of village. The significant correlate for catastrophic health expenditure was type of village. Interpretation & conclusions: Around one-fifth of the households had catastrophic health expenditure. People with no healthcare facility located in their village had higher odds of having catastrophic health expenditure. Private providers were preferred for the treatment of acute illnesses and medical college hospitals for hospitalization. PMID- 29512610 TI - Genetic characterization of dengue virus types 1 and 2 in India, with emphasis on the viruses circulating in Karnataka. PMID- 29512611 TI - Lumpy body & starry sky: A case of disseminated cysticercosis. PMID- 29512612 TI - The association between serum hepcidin-25 level and subclinical atherosclerosis in peritoneal dialysis patients. AB - OBJECTIVE: Recently, the role of hepcidin as a cardiovascular marker in the chronic kidney disease (CKD) population has gained interest. The aim of this study was to investigate the relationship between serum hepcidin-25, inflammation, iron parameters, and carotid intima-media thickness (CIMT) in peritoneal dialysis (PD) patients. METHODS: A total of 58 patients (30 male, 51.3%; mean age: 46.8+/-13.6 years; mean dialysis duration: 69.2+/-39.1 months) were included in this cross-sectional study. Clinical and routine laboratory data were recorded and the CIMT and hepcidin values were determined. The study population was divided into 2 groups according to the median hepcidin value of 60 ng/mL. Correlation analysis and logistic regression analysis were performed to determine the relationship between the hepcidin level and other parameters. RESULTS: Age (p=0.003), systolic blood pressure (p=0.039), body mass index (p=0.031), glucose (p=0.028) level, C-reactive protein (CRP) level (p<0.001), and CIMT (p=0.011) were found to be statistically significantly higher in the high hepcidin group. In correlation analysis, hepcidin was positively correlated with age (p<0.001), dialysis duration (p=0.041), glucose (p=0.015), ferritin (p=0.005), CRP (p<0.001), and CIMT (p=0.035). In multivariate linear regression analysis, age (p<0.001) and CRP (p=0.005) were found to be related to CIMT. CONCLUSION: Hepcidin-25 was strongly associated with both age and CRP in patients undergoing PD treatment. The results suggest that hepcidin may be involved in the pathophysiology of atherosclerosis. Prospective studies should be carried out in this patient population to determine whether hepcidin has an effect on atherosclerosis. PMID- 29512613 TI - Neutrophil-to-lymphocyte ratio predicts functionally significant coronary artery stenosis in patients with stable coronary artery disease. AB - OBJECTIVE: The aim of this study was to determine the relationship between the neutrophil-to-lymphocyte ratio (NLR) and the functional severity of coronary stenosis assessed according to the fractional flow reserve (FFR) in stable coronary artery disease (CAD). METHODS: The clinical and laboratory data of 420 patients who underwent index coronary angiography for stable angina pectoris were analyzed retrospectively. The functional severity of an intermediate lesion was determined by FFR. An FFR value of >0.80 was considered non-significant (Group 1), whereas <=0.80 was accepted as significant stenosis (Group 2). RESULTS: A total of 137 (32.6%) patients had functionally significant coronary artery stenosis. The median NLR value was significantly greater in Group 2 compared with Group 1 [3.13 (0.93-9.75) vs 2.22 (0.75-6.02); p<0.001]. In multivariable logistic regression analysis, the Gensini score [odds ratio (OR): 1.04; 95% confidence interval (CI): 1.02-1.06; p<0.001], diabetes mellitus (OR: 2.56; 95% CI: 1.38-4.75; p=0.003), smoking (OR: 2.09; 95% CI: 1.12-3.94; p=0.021), and NLR (OR: 1.62; 95% CI:1.26-2.09; p<0.001) were found to be independent predictors of the presence of functionally significant coronary stenosis using an FFR value of <=0.80. The optimal cut-off value of NLR for predicting functionally significant coronary stenosis was 2.3. An NLR value greater than 2.3 had a sensitivity of 72% and a specificity of 61% to predict stenosis with an FFR value of <=0.80. CONCLUSION: The pre-angiographic NLR is a simple, noninvasive, and inexpensive biomarker that was significantly higher in patients with functionally significant coronary stenosis; it can be used to predict the hemodynamic severity of intermediate coronary stenosis in patients with stable CAD. PMID- 29512614 TI - Heparin-induced thrombocytopenia after MitraClip: A case report. AB - Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis are potentially fatal adverse reactions to heparin therapy caused by the formation of polyclonal antibodies against the platelet factor 4-heparin complex. Fatal limb and organ damage or death may occur as a result of this immunological drug reaction. Described in this case report is the management of a patient who developed HIT after undergoing a MitraClip transcatheter mitral valve repair. The aim was to encourage clinicians to pay special attention to a frail patient who receives heparin therapy and to advise clinicians that clinical scores and laboratory tests should be used as a complement for certain diagnosis. The decision about continuation or cessation of heparin therapy is an important cornerstone for hospitalized patients with HIT. PMID- 29512615 TI - Contrast-induced encephalopathy after percutaneous peripheral intervention. AB - Contrast-induced encephalopathy (CIE) is a rare complication of angiography. Presently reported is the case of a patient diagnosed with CIE following peripheral angioplasty with the non-ionic contrast agent, iohexol. A 66-year-old male patient described intermittent claudication and peripheral arterial disease was suspected. Lower extremity angiography was performed, and following dilation of a 7.0x150-mm balloon, a 9.0x57-mm stent was placed in the lesioned vessel. The patient subsequently developed confusion and cortical blindness, and a seizure occurred 1 hour after the procedure. An emergency cerebral computed tomography scan did not reveal any signs of intracerebral hemorrhage. The neurological symptoms disappeared within 24 hours after hydration and sedative medication. CIE was diagnosed based on the patient's clinical course findings and cerebral imaging. PMID- 29512616 TI - Successful treatment of massive pulmonary embolism with reteplase. AB - Unexpected and unexplained out-of-hospital cardiac arrests have a poor prognosis. Difficulties encountered during the differential diagnosis phase may delay the administration of specific treatment for treatable and reversible causes of cardiac arrest. Massive pulmonary embolism is a reversible cause of cardiac arrest, but without proper management it has a high mortality rate. Presently described is the case of a 53-year-old female patient with a massive pulmonary embolism. PMID- 29512617 TI - Infective endocarditis of a bicuspid aortic valve complicated by septal aneurysm and mitral-aortic intervalvular fibrosa pseudoaneurysm. AB - Aortic valve endocarditis can lead to the destruction or perforation of the leaflets, ring abscess, fistula, or perivalvular regurgitation; less commonly, the regurgitation itself may result in secondary damage to subaortic structures. Pseudoaneurysm of the mitral-aortic intervalvular fi brosa is a rare complication of native aortic valve endocarditis. This region is a relatively avascular area and is prone to endocarditis infection and subsequent aneurysm formation. Herein, the case of a 33-year-old man who was diagnosed with bicuspid aortic valve endocarditis complicated by a pseudoaneurysm, an aneurysm, and aortic valve rupture is described. PMID- 29512618 TI - The hemostatic power of fat: An effective, inexpensive, and biocompatible method to achieve hemostasis in cardiac surgery. AB - Postoperative bleeding with its important socioeconomic cost is associated with an increased morbidity and mortality. It causes hemodynamic instability, increases blood loss, and multiplies the number of transfusions required. Especially in vascular or aortic surgery, postoperative bleeding can become a life-threatening complication due to anticoagulant or antiaggregation preoperative status or postoperative coagulation dysfunction after a high level of heparinization. Presently described is the case of a patient who underwent an aortic valve and ascending aorta replacement. A simple but effective method to achieve hemostasis, designed particularly for aortic surgery and the use of Dacron grafts, is presented. No residual adherence or contraindications exist, and it can potentially be applied to any kind of surgical process. This method offers a cheap, biocompatible, and highly effective means to achieve complete hemostasis without the use of extra sutures, or expensive synthetic or allogeneic hemostatic agents or sealants. PMID- 29512619 TI - A practical and case-based approach to thrombocytopenia in cardiology practice. AB - In cardiology practice, anticoagulation and antiplatelet therapies are essential for most patients. As of yet, there is no high quality evidence regarding these treatments in thrombocytopenic patients, which continues to be an issue. Thrombocytopenia is defined as a platelet count of <150x109/L and is classified as severe when the platelet count is <50x109/L. Pseudothrombocytopenia, drug induced thrombocytopenia, immune thrombocytopenia, heparin-induced thrombocytopenia, and thrombotic thrombocytopenic purpura are some of the main causes of thrombocytopenia. The current treatment suggestions are conservative, as a result of the lack of evidence, built on defensive treatment strategies and the fear of bleeding complications. Many patients with acute myocardial infarction with thrombocytopenia have undergone percutaneous coronary intervention successfully with adjunctive antiplatelet and anticoagulant use, as has been described in case reports. A risk-benefit ratio should be evaluated for antiplatelet therapy. In the relevant guidelines, while full dose low-molecular weight heparin (LMWH) is recommended for patients with a thrombocyte count of >50x109/L, a half-dose of LMWH is recommended in patients with thrombocytopenia between 25 and 50x109/L. According to the current guidelines, avoiding antiplatelet and anticoagulant treatment should be restricted to patients with very severe thrombocytopenia (i.e., a platelet count <25x109/L), but new data and recommendations are needed. PMID- 29512620 TI - Case Image: Hybrid aortic repair for a massive aneurysm. PMID- 29512621 TI - Case Image: Left ventricular pseudoaneurysm as a silent complication of non-ST segment elevation myocardial infarction. PMID- 29512622 TI - Case Image: Bovine-type aortic arch and compression of the kissing carotid arteries by a retrosternal goiter: An uncommon cause of carotid bruit. PMID- 29512623 TI - Influences of cardiac resynchronization therapy on cardiac biomarkers in patients with chronic heart failure. PMID- 29512624 TI - Association between reverse electrical remodeling and cardiac fibrosis markers in patients with cardiac resynchronization therapy. AB - OBJECTIVE: Cardiac resynchronization therapy (CRT) induces structural and electrical reverse remodeling of the failing heart. However, the association between native QRS narrowing and cardiac fibrosis markers has not been investigated in patients with an implanted CRT device. METHODS: A total of 41 symptomatic patients diagnosed with systolic heart failure who underwent CRT implantation were included in this study. Electrocardiogram findings and cardiac fibrosis marker levels [galectin-3, growth-differentiation factor-15 (GDF-15) and procollagen III N-terminal propeptide (P3TD)] were collected before and 12 months after initiation of biventricular pacing. Reverse electrical remodeling was defined as a decrease in 12-month intrinsic QRS (iQRS) duration by >=20 milliseconds after CRT implantation. RESULTS: The median QRS duration decreased from 155 milliseconds (interquartile range [IQR]: 142-178 milliseconds) before CRT to 142 milliseconds (IQR: 130-161 milliseconds) (p=0.001) after 12 months of CRT. According to the predefined criteria, electrical remodeling was detected in 16 (39.0%) patients. The median galectin-3, GDF-15, and P3TD levels were significantly decreased after CRT implantation in patients with electrical remodeling [27.65 ng/mL (IQR: 24.4-35.2 ng/mL) vs 23.00 ng/mL (IQR: 16.0-36.7 ng/mL), p=0.017; 3104 pg/mL (IQR: 2923-4825 pg/mL) vs 2276 pg/mL (IQR: 1294-3209 pg/mL), p=0.002; 0.43 ng/mL (IQR: 0.23-0.64) vs 0.15 ng/mL (IQR: 0.04-0.29 ng/mL), p=0.034, respectively]. The galectin-3, GDF-15, and P3TD levels were not significantly changed in patients without electrical remodeling [26.80 ng/mL (IQR: 23.9-31.5 ng/mL) vs 28.80 ng/mL (IQR: 23.0-34.8 ng/mL), p=0.211; 4221 pg/mL (IQR: 2709-4995 pg/mL) vs 3035 pg/mL (IQR: 2038-4872 pg/mL), p=0.143; and 0.34 ng/mL (IQR: 0.11-0.68 ng/mL) vs 0.21 ng/mL (IQR: 0.09-0.37 ng/mL), p=0.112, respectively]. CONCLUSION: The results from the small sample used in this study indicated that electrical reverse remodeling after CRT was associated with a decrease in cardiac fibrosis. PMID- 29512625 TI - Clinical practices of the management of nonvalvular atrial fibrillation and outcome of treatment: A representative prospective survey in tertiary healthcare centers across Turkey. AB - OBJECTIVE: The goal of this study was to define clinical practice patterns for assessing stroke and bleeding risks and thromboprophylaxis in nonvalvular atrial fibrillation (NVAF) and to evaluate treatment outcomes and patient quality of life. METHODS: A clinical surveillance study was conducted in 10 tertiary healthcare centers across Turkey. Therapeutic approaches and persistence with initial treatment were recorded at baseline, the 6th month, and the 12th month in NVAF patients. RESULTS: Of 210 patients (57.1% male; mean age: 64.86+/-12.87 years), follow-up data were collected for 146 patients through phone interviews at the 6th month and 140 patients at the 12th month. At baseline, most patients had high CHADS2 score (>=2: 48.3%) and CHA2DS2-VASc (>=2: 78.7%) risk scores but a low HAS-BLED (0-2: 83.1%) score. Approximately two-thirds of the patients surveyed were using oral anticoagulants as an antithrombotic and one-third were using antiplatelet agents. The rate of persistence with initial treatment was approximately 86%. Bleeding was reported by 22.6% and 25.0% of patients at the 6th and 12th month, respectively. The proportion of patients with an INR of 2.0 3.0 was 41.8% at baseline, 65.7% at the 6th month, and 65.9% at the 12th month. The time in therapeutic range was 61.0% during 1 year of follow-up. The median EuroQol 5-dimensional health questionnaire (EQ-5D) score of the patients at baseline and the 12th month was 0.827 and 0.778, respectively (p<0.001). The results indicated that patient quality of life declined over time. CONCLUSION: In atrial fibrillation, despite a high rate of persistence with initial treatment, the outcomes of stroke prevention and patient quality of life are not at the desired level. National health policies should be developed and implemented to better integrate international guidelines for the management of NVAF into clinical practice. PMID- 29512626 TI - Iron deficiency and hematinic deficiencies in atrial fibrillation: A new insight into comorbidities. AB - OBJECTIVE: Iron deficiency (ID) is the most common nutritional deficiency, and iron metabolism becomes further deteriorated in the presence of certain conditions, such as heart failure (HF). Atrial fibrillation (AF) has many similarities to HF, including a chronic inflammatory pathophysiology; however, the prevalence of ID and other hematinic deficiencies in AF patients have not been determined. METHODS: In this study, the prevalence of iron (serum ferritin <100 ug/L or ferritin 100-299 ug/L with transferrin saturation <20%), vitamin B12 (<200 pg/mL), and folate deficiency (<4.0 ng/mL) was evaluated in 101 patients with non-valvular AF with preserved left ventricular ejection fraction and no signs of HF, and the results were compared with 35 age- and gender-matched controls. RESULTS: Anemia was detected in 26% of the patients. A total of 48 (47.6%) patients had ID, 10 (9.9%) had a vitamin B12 deficiency, and 13 (12.9%) had a folate deficiency. The prevalence of ID was similar in the controls and the paroxysmal AF patients, but increased gradually in persistent and permanent AF. Univariate logistic regression analysis demonstrated that permanent vs. paroxysmal AF [Odds ratio (OR): 2.17; 95% confidence interval (CI): 0.82-5.69; p=0.011], high sensitive C-reactive protein (OR: 1.47; 95% CI: 0.93-2.36; p=0.019), N-terminal pro b-type natriuretic peptide (OR: 1.24; 95% CI: 0.96-1.71; p=0.034), and white blood cell count (OR: 1.21; 95% CI: 0.95-1.58; p=0.041) were associated with ID. In multivariable analysis, permanent AF remained as an independent clinical associate of ID (OR: 4.30; 95% CI: 0.83-12.07; p=0.039). CONCLUSION: ID is common in permanent AF, as in HF. Inflammation and neurohormonal activation seem to contribute to its development. PMID- 29512627 TI - Evaluation of the association between serum uric acid level andthe predicted risk score of sudden cardiac death in five years in patients with hypertrophic cardiomyopathy. AB - OBJECTIVE: The aim of this study was to determine the relationship between serum uric acid (UA) level and the predicted risk score for sudden cardiac death in 5 years (the HCM Risk-SCD), galectin-3 level, and positive fragmented QRS (fQRS) on electrocardiography (ECG) in patients with hypertrophic cardiomyopathy (HCM). METHODS: This was a prospective, observational study. In all, 115 consecutive patients (age >17 years) with HCM and 80 healthy participants were included in the study. The HCM Risk-SCD score (%), galectin-3 level, and fQRS on ECG were evaluated in all patients. RESULTS: The serum UA, galectin-3 level, UA/Creatinine ratio, incidence of ventricular tachycardia (VT) and syncope, and some echocardiographic parameters were significantly higher in the patient group than in the control group (all p<0.05). The UA value was significantly higher in patients with a high score on the HCM Risk-SCD, a positive fQRS, a high galectin 3 level, VT incidence, and need for implantable cardioverter defibrillator (ICD) implantation or cardiopulmonary resuscitation (CPR) than in those without (HCM Risk-SCD >6%. Namely, HCM Risk-SCD >6%, UA: 6.71+/-1.29 mg/dL, HCM Risk-SCD <=5.9%, UA: 5.84+/-1.39 mg/dL, p=0.001; fQRS(+), UA: 6.56+/-1.20 mg/dL, fQRS(-), UA: 5.63+/-1.49 mg/dL, p<0.001; galectin-3 >6.320 pg/mL, UA: 6.56+/-1.27 mg/dL, galectin-3 <=6.310 pg/mL, p=0.016; left atrium anterior-posterior dimension (LAAPD) >36 mm, UA: 6.31+/-1.33 mg/dL, LAAPD <36 mm, UA: 5.20+/-1.60 mg/dL, p=0.005; VT(+), UA: 6.83+/-1.19 mg/dL, VT(-), UA: 5.97+/-1.42 mg/dL, p=0.008; ICD(+), UA: 7.08+/-0.88 mg/dL, ICD(-), UA: 6.06+/-1.42 mg/dL, p=0.022; CPR(+), UA: 7.03+/-0.96 mg/dL, CPR(-), UA: 6.04+/-1.42 mg/dL, p=0.018. A statistically significant correlation was observed between UA and HCM Risk-SCD, galectin-3 level, LAAPD, and left ventricular (LV) mass (LVM) (r and p values, respectively: 0.355, <0.001; 0.297, 0.002; 0.309, 0.001; 0.276, 0.003. CONCLUSION: The serum UA level was significantly higher in patients with HCM compared with the control group. A high UA level was associated with a higher HCM Risk-SCD score, positive fQRS, higher galectin-3 level, greater LAAPD, VT incidence, and the need for ICD implantation and CPR in patients with HCM. PMID- 29512628 TI - Analysis of Chronic Illnesses and Disability in a Community-Based Sample of Elderly People in South-Eastern Poland. AB - BACKGROUND The proportion of elderly people living in Poland has risen in recent years. With rising life expectancy, there is likely to be a concurrent increase in the incidence of chronic diseases and disabilities. Therefore, this study aimed to analyze the prevalence of chronic diseases and disability of the elderly in order to help guide strategies of prevention and public health control. MATERIAL AND METHODS This was a cross-sectional study of 1,000 randomly-selected residents living in the Podkarpackie region of Poland. The WHODAS 2.0 questionnaire was used to assess the disability and functioning of the participants across six domains of functioning using the following scores: no disability (0-4%), mild disability (5-24%), moderate disability (25-49%), severe disability (50-95%), and extreme disability (96-100%). RESULTS The presence of at least one chronic disease was identified in 84.1% of participants. The most common diseases were: circulatory diseases (59.10%), spinal pain syndromes (51.50%), degenerative joint diseases (50.30%), and rheumatic diseases (23.90%). Severe or extreme disability was found in 8.46% of patients with circulatory disease, 9.32% of patients with spinal pain syndromes, 9.34% of patients with degenerative joint diseases, and 12.13% of patients with rheumatic diseases. CONCLUSIONS Based on our findings, we recommend an emphasis be placed on early diagnosis of chronic diseases. We also recommend implementing methods of primary and secondary prevention aimed at reducing or eliminating disability resulting from chronic diseases. Our research highlights the need to plan targeted support and prevention programs using strategies that optimize social participation of older people with various chronic diseases. PMID- 29512629 TI - [Bacteriophage T5 Mutants Carrying Deletions in tRNA Gene Region]. AB - A new series of heat-stable (st) mutants of bacteriophage T5, which contains deletions in the tRNA gene region, has been isolated. An accurate mapping of the deletion boundaries for more than 30 mutants of phage T5 has been carried out. As a result of the analysis of nucleotide sequences flanking the deleted regions in wild-type phage DNA, it has been shown that they all contain short, direct repeats of different lengths (2-35 nucleotide residues), and that only one repetition is retained in the mutant phage DNA. On the basis of the obtained results, it was suggested that deletion mutants of the phage T5 are formed as a result of illegal recombination occurring with the participation of short repeats in DNA (SHDIR). Based on the example of two mutants, it has been shown that the resistance to thermal inactivation depends on the size of the deleted region. PMID- 29512630 TI - [Glycyl-tRNA Synthetase as a Potential Universal Regulator of Translation Initiation at IRES-I]. AB - A full analysis has been conducted of the sequences and secondary structures of viral type-I or related IRESs identified in all of the elements that correspond to the previously described minimal fragment of the enterovirus C IRES, which mimics the glycine tRNA anticodon hairpin in the IRES structure and is necessary for the specific binding of glycyl-tRNA synthetase. Experiments on human glycyl tRNA synthetase binding with the mRNA fragments of several taxonomically distant viruses showed that the binding constants of these complexes are similar. These results indicate that the regulation of translation initiation via glycyl-tRNA synthetase must be a universal mechanism for these viruses and the corresponding parts of their mRNAs must have similar spatial structures. Furthermore, at least one additional mRNA hairpin with the glycyl anticodon loop has been found in all analyzed viral type-I IRESs. It seems plausible that this extra hairpin is associated with the second RNA-binding site of the glycyl-tRNA synthetase dimer and stabilizes its complex with the viral mRNA. PMID- 29512631 TI - [Stimulation of the Translation of Reporter mRNA in the Presence of Another mRNA in a Cell-Free System Based on Wheat Germ Extract]. AB - The translation of uncapped mRNAs encoding luciferase and green fluorescent protein in a cell-free translation system based on wheat germ extract has been studied. It turned out that two simultaneously translated (in one tube) different templates in a certain range of concentrations not only do not compete, but mutually enhance each other's translation. It has been shown that the synthesis of luciferase in the presence of mRNA that encodes green fluorescent protein is much more effective than in the translation of only luciferase mRNA at the same concentration. Similarly, the efficiency of the synthesis of green fluorescent protein increases in the presence of the template that encodes luciferase. It follows that the total effect of the concurrent translation of two different mRNAs exceeds the sum of the effects of the translation of each mRNA separately. PMID- 29512632 TI - [Mutant Initiation Factor eIF4A (R362Q) Does Not Suppress the Assembly of the 48S Preinitiation Complex on mRNA with the Leader Sequence of mRNA That Encodes for Obelin]. AB - The formation of ribosomal 48S initiation complexes at the start codon of the mRNA leader sequence that encodes obelin has been studied using the method of primer extension inhibition (toeprinting). Experiments have been performed in a system composed of purified individual components required to initiate translation. The influence of the dominant negative mutant of factor eIF4A (R362Q) on translation initiation has been studied. It has been shown that the presence of the mutant in reaction mixture has no effect on efficiency of formation of the 48S complexes at start codon of the template studied. PMID- 29512633 TI - [Incorporation of Copper Ions into T2/T3 Centers of Two-Domain Laccases]. AB - Laccase belongs to the family of copper-containing oxidases. A study was made of the mechanism that sustains the incorporation of copper ions into the T2/T3 centers of recombinant two-domain laccase Streptomyces griseoflavus Ac-993. The occupancy of the T3 center by copper ions was found to increase with an increasing copper content in the culture medium and after dialysis of the protein preparation against a copper sulfate-containing buffer. The T2 center was filled only when overproducer strain cells were grown at a higher copper concentration in the medium. Two-domain laccases were assumed to possess a channel that serves to deliver copper ions to the T3 center during the formation of the three dimensional laccase conformation and dialysis of the protein preparation. A narrower channel leads to the T2 center in two-domain laccases compared with three-domain ones, rendering the center less accessible for copper atoms. The incorporation of copper ions into the T2 center of two-domain laccases is likely to occur in the course of their biosynthesis or the formation of a functional trimer. PMID- 29512634 TI - [Lysozyme Stabilization under High Pressure: Differential Scanning Microcalorimetry]. AB - The heat denaturation of lysozyme has been studied by high-pressure differential scanning microcalorimetry. It has been demonstrated that an increase in pressure has different influence on denaturation temperature and enthalpy at different pH values. It has been established that the pressure increase has no appreciable effect on the transition cooperativity. The experimental data have been analyzed using an equilibrium model of transition between two states. Partial molar volume changes accompanying the denaturation as well as isothermal compressibility and thermal expansibility coefficients have been assessed. In contrast to the denaturation of most globular proteins, the lysozyme denaturation under conditions of the experiment was accompanied by positive volume changes. Possible reasons for this unusual behavior have been discussed. PMID- 29512635 TI - [Unique Combinations of betaalphabeta-Units and Pi-Like Modules in Proteins and Specific Features of Their Amino Acid Sequences]. AB - Possible combinations of betaalphabeta-units and Pi-like modules in proteins in both right- and left-handed forms have been analyzed in detail. The correlation between the mutual arrangement of the structural elements in the polypeptide chain and their handedness has been shown. In the betaalphabetaP combinations, which is encountered most frequently in proteins, the P-module follows the betaalphabeta unit along the chain and both elements are right-handed. In the Pbetaalphabeta combinations, where the P-module is located at the N end and the betaalphabeta-unit follows it, the former is left-handed and the latter is right handed. In relatively rare combinations of the left-handed betaalphabeta-units and right-handed P-modules, the betaalphabeta-unit follows P-module in the chain. The combinations of left-handed P-modules and the left-handed betaalphabeta-units are unobservable in proteins. It has also been shown that the P-modules with a beta-strand-alpha-helix-arch-beta-strand structure are observed in proteins only in a right-handed form and half of them (51%) contains cis-prolines in their arches. These arches of nonhomologous proteins, as well as the positions of cis prolines, nearly coincide when superimposed. The superimposed P-modules also demonstrate that their overall folds are very similar. Structural alignment of their amino acid sequences has shown that the P-modules have very similar sequence patterns of the key hydrophobic, hydrophilic, glycine, and cis-proline residues. PMID- 29512636 TI - [Amyloid Core Wild-Type Apomyoglobin and Its Mutant Variants Is Formed by Different Regions of the Polypeptide Chain]. AB - As has been recently shown, the toxicity of protein aggregates is determined by their structure. Therefore, special attention has been focused on the search for factors that specify the structural features of formed amyloid fibrils. The effect of amino acid substitutions in apomyoglobin on the structural characteristics of its amyloid aggregates has been analyzed. The morphology and secondary structure of amyloids of the wild-type protein and its mutant variants Val10Ala, Val10Phe, and Trp14Phe have been compared, and the regions involved in intermolecular interactions in fibrils have been determined using limited proteolysis and mass spectrometry. No considerable differences have been found in the morphology (shape, length, or diameter) or the content (percentage) of the cross-beta structure of apomyoglobin amyloids and its mutant variants. Amyloid cores of wild-type apomyoglobin and variants with Val10Phe and Trp14Phe substitutions have been formed by different regions of the polypeptide chain. The case study of apomyoglobin demonstrates that the location of amyloidogenic regions in the polypeptide chain of wild-type protein and its mutant forms can differ. Thus, possible structural changes in amyloids resulting from amino acid substitutions should be taken into account when studying phenotype aggregation. PMID- 29512637 TI - [Effect of Substitutions in Surface Amino Acid on Energy Profile of Apomyoglobin]. AB - Studies on the process of spontaneous protein folding into a unique native state are an important issue of molecular biology. Apomyoglobin from the sperm whale is a convenient model for these studies in vitro. Here, we present the results of equilibrium and kinetic experiments carried out in a study on the folding and unfolding of eight mutant apomyoglobin forms of with hydrophobic amino acid substitutions on the protein surface. Calculated values of apparent constants of folding/unfolding rates, as well as the data on equilibrium conformational transitions in the urea concentration range of 0-6 M at 11 degrees C are given. Based on the obtained information on the kinetic properties of the studied proteins, a Phi-value analysis of the transition state has been performed and values of urea concentrations corresponding to the midpoint of the transition from the native to intermediate state have been determined for the given forms of mutant apomyoglobin. It has been found that a significant increase in the stability of the native state can be achieved by a small number of amino acid substitutions on the protein surface. It has been shown that the substitution of only one amino acid residue exclusively affects the height of the energy barrier that separates different states of apomyoglobin. PMID- 29512638 TI - [Anomalous Kinetics of Amyloidogenesis Suggest a Competition between Oligomers and Fibrils]. AB - Meisl et al. have recently observed an anomalous dependence of the amyloid formation rate on the protein concentration. A novel mechanism of fibril growth has been proposed by Meisl et al. to explain the abnormality; it consists in the fibril-catalyzed initiation of fibril formation with saturation of catalytic sites at high concentrations of substrates. Our article describes an alternative explanation of the anomalous kinetics, assuming that the formation of metastable oligomers competes with fibril formation by decreasing the concentration of free monomers. Oligomers are indeed observed in the course of amyloid formation, but are usually considered as seeds of amyloid fibrils rather as their competitors. However, the oligomers visually detectable by electron microscopy were shown to be close in size to those that can be derived from the anomalous dependence of the amyloid growth rate on the protein concentration, given that the anomaly results from competition between oligomer formation and amyloidogenesis. PMID- 29512639 TI - [Limited Trypsinolysis of GroES: The Effect on the Interaction with GroEL and Assembly In Vitro]. AB - GroES is a heptameric partner of tetradecameric molecular chaperone GroEL, which ensures the correct folding and assembly of numerous cellular proteins both in vitro and in vivo. This work demonstrates the results of a study of structural aspects of GroES that affect its interaction with GroEL and reassembly. The effect of limited trypsinolysis of GroES on these processes has been studied. It has been shown that limited trypsinolysis of GroES is only strongly pronounced outside the complex with GroEL and results in the cleavage of the peptide bond between Lys20 and Ser21. The N-terminal fragment (~2 kDa) is retained in the GroES particle, which maintains its heptaoligomeric structure but loses the ability to interact with GroEL and dissociates upon a change in the pH from 7 to 8. Trypsin-nicked GroES cannot reassemble after urea-induced unfolding, while the urea-induced unfolding of intact GroES is fully reversible. The reported results indicate the important role of the N-terminal part of GroES subunit in the assembly of its heptameric structure and the interaction with GroEL. PMID- 29512640 TI - [Artificial Cysteine Bridges on the Surface of Green Fluorescent Protein Affect Hydration of Its Transition and Intermediate States]. AB - Studying the effect of cysteine bridges on different energy levels of multistage folding proteins will enable a better understanding of the process of folding and functioning of globular proteins. In particular, it will create prospects for directed change in the stability and rate of protein folding. In this work, using the method of differential scanning microcalorimetry, we have studied the effect of three cysteine bridges introduced in different structural elements of the green fluorescent protein on the denaturation enthalpies, activation energies, and heat-capacity increments when this protein passes from native to intermediate and transition states. The studies have allowed us to confirm that, with this protein denaturation, the process hardly damages the structure initially, but then changes occur in the protein structure in the region of 4-6 beta sheets. The cysteine bridge introduced in this region decreases the hydration of the second transition state and increases the hydration of the second intermediate state during the thermal denaturation of the green fluorescent protein. PMID- 29512641 TI - [Identification of Ribosomal Protein L1-Binding Sites in Thermus thermophilus and Thermotoga maritima mRNAs]. AB - The conserved two-domain ribosomal protein (r-protein) L1 is a structural part of the L1 stalk of the large ribosomal subunit and regulates the translation of the operon that comprises its own gene. The regulatory properties of the bacterial r protein L1 have only been studied in detail for Escherichia coli; however, there were no such studies for other bacteria, in particular, Thermus thermophilus and Thermotoga maritima, which are more evolutionarily ancient. It is known that domain I of the r-protein L1 might have regulatory properties of the whole protein. The aim of this study was to identify regulatory sites on the mRNA of T. thermophilus and T. maritima that interact with r-proteins L1, as well as with their domains I from the same organisms. An analysis of the mRNA of the L11 operon T. thermophilus showed the presence of one potential binding site of the L1 r-protein, two such regions were found also in the mRNA sequence of the L11 operon of T. maritima. The dissociation constants for the L1 proteins from T. thermophilus and T. maritima and their domains I with mRNA fragments from the same organisms that contain the supposed L1-binding sites were determined by surface plasmon resonance. It has been shown that the ribosomal proteins L1 as their domains I bind specific fragments of mRNA from the same organisms that may suggest regulatory activity of the L1 protein in the T. thermophilus and T. maritima and conservatism of the principles of L1-RNA interactions. PMID- 29512642 TI - [Influence of Nonconserved Regions of L1 Protuberance of Thermus thermophilus Ribosome on the Affinity of L1 Protein to 23s rRNA]. AB - The L1 protuberance of the ribosome includes two domain ribosomal protein L1 and three helices of 23S rRNA (H76, H77, and H78) with interconnecting loops A and B. Helix 78 consists of two parts, i.e., H78a and H78b. A comparison of the available structural data of L1-RNA complexes with the obtained kinetic data made it possible to determine the influence of the nonconserved regions of Thermus thermophilus L1-protuberance on the mutual affinity of the L1 protein and 23S rRNA. It has been shown that the N-terminal helix of the protein and 78b helix of 23S rRNA are essential for the formation of an additional intermolecular contact, which is separated in the protein from the main site of L1-rRNA interaction by a flexible connection. This results in a rise in the TthL1-rRNA affinity. At the same time, the elongation of the 76 helix has no effect on rRNA-protein binding. PMID- 29512643 TI - [Model of the Complex of the Human Glycyl-tRNA Synthetase Anticodon-Binding Domain with IRES I Fragment]. AB - The currently available structural information is insufficient for a detailed analysis of interactions between human glycyl-tRNA synthetase (GARS) and enterovirus IRESs. At the same time, this information is required in order to understand how this IRES trans-acting factor (ITAF) functions during viral mRNA translation, which is in turn crucial for the development of direct-action antiviral agents. In this paper, a theoretical model of the complex between a cadicivirus A IRES fragment and the anticodon-binding domain of human GARS is constructed using molecular dynamics simulation based on all of the available structural and biochemical data. The proposed model enables the structural interpretation of the previously obtained biochemical data. PMID- 29512644 TI - [Ligand-Induced Reassembly of GroEL/ES Chaperone In Vitro: Visualization by Electron Microscopy]. AB - The products of the reassembly reaction of tetradecameric two-ring quaternary structure of GroEL chaperonin under the pressure of its heptameric co-chaperonin GroES have been visualized by electron microscopy. It has been shown that one ring heptameric oligomers of GroEL have been formed at the beginning (after ~5 min) of the reaction, while at the final stage of the reaction (after ~70 min), both one-ring heptamers in complex with one GroES and two-rings tetradecamers in complexes with one (asymmetrical complex) or two (symmetrical complex) GroES heptamers are present. The relationship between the data of light scattering, native electrophoresis, and electron microscopy obtained earlier has been discussed. PMID- 29512645 TI - [Evaluation of the Accuracy of Calculation of the Standard Binding Entropy of Molecules from their Average Mobility in Molecular Crystals]. AB - One of the main problems in attempts to predict the binding constants of molecules (or free energies of their binding) is the correct evaluation of configurational binding entropy. This evaluation is possible by methods of molecular dynamics simulation, but these simulations require a lot of computational time. Earlier, we have developed an alternative approach which allows the fast calculation of the binding entropy from summarizing the available data on sublimation of crystals. Our method is based on evaluating the mean amplitude of the movements that are restricted in the bound molecule, e.g., in a crystal, but are not restricted in the free state, e.g., in vapor. In this work, it is shown that the standard entropy of binding of molecules by crystals under standard conditions (1 atm, 25 degrees C) can be assessed rather accurately from geometric and physical parameters of the molecule and the average amplitude of the molecule motions in crystals estimated in our previous work. PMID- 29512646 TI - [Search for Functionally Significant Motifs and Amino Acid Residues of Actin]. AB - The scientific interest to the structural and functional properties of actin is determined by its abundance in cells. Being an important component of the cytoskeleton, actin is involved in many protein-protein interactions. Using crystal structures and molecular models, we have mapped the amino acid residues that are involved in these interactions and form the ATP-binding site of the actin monomer. Moreover, using mass spectrometry and high-performance liquid chromatography methods, we have discovered the regions of the amino acid sequence of actin that form the core of the actin fibril. According to the bioinformatic analysis, these regions are amyloidogenic and are located in the C-terminal region and in the hinge between the first and third subdomains. The data obtained are applicable to chordate actin, because multiple alignment revealed highly conserved amino acid sequences. In turn, the comparison of the chordate actin with the bacterial homologs showed the presence of numerous amino acid substitutions and insertions. PMID- 29512647 TI - Probiotics, bile acids and gastrointestinal carcinogenesis. PMID- 29512648 TI - Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis: a role for bifidobacteria and lactobacilli? PMID- 29512649 TI - Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management. AB - Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management. PMID- 29512650 TI - Modular assembly of the nucleolar pre-60S ribosomal subunit. AB - Early co-transcriptional events during eukaryotic ribosome assembly result in the formation of precursors of the small (40S) and large (60S) ribosomal subunits. A multitude of transient assembly factors regulate and chaperone the systematic folding of pre-ribosomal RNA subdomains. However, owing to a lack of structural information, the role of these factors during early nucleolar 60S assembly is not fully understood. Here we report cryo-electron microscopy (cryo-EM) reconstructions of the nucleolar pre-60S ribosomal subunit in different conformational states at resolutions of up to 3.4 A. These reconstructions reveal how steric hindrance and molecular mimicry are used to prevent both premature folding states and binding of later factors. This is accomplished by the concerted activity of 21 ribosome assembly factors that stabilize and remodel pre ribosomal RNA and ribosomal proteins. Among these factors, three Brix-domain proteins and their binding partners form a ring-like structure at ribosomal RNA (rRNA) domain boundaries to support the architecture of the maturing particle. The existence of mutually exclusive conformations of these pre-60S particles suggests that the formation of the polypeptide exit tunnel is achieved through different folding pathways during subsequent stages of ribosome assembly. These structures rationalize previous genetic and biochemical data and highlight the mechanisms that drive eukaryotic ribosome assembly in a unidirectional manner. PMID- 29512651 TI - Unconventional superconductivity in magic-angle graphene superlattices. AB - The behaviour of strongly correlated materials, and in particular unconventional superconductors, has been studied extensively for decades, but is still not well understood. This lack of theoretical understanding has motivated the development of experimental techniques for studying such behaviour, such as using ultracold atom lattices to simulate quantum materials. Here we report the realization of intrinsic unconventional superconductivity-which cannot be explained by weak electron-phonon interactions-in a two-dimensional superlattice created by stacking two sheets of graphene that are twisted relative to each other by a small angle. For twist angles of about 1.1 degrees -the first 'magic' angle-the electronic band structure of this 'twisted bilayer graphene' exhibits flat bands near zero Fermi energy, resulting in correlated insulating states at half filling. Upon electrostatic doping of the material away from these correlated insulating states, we observe tunable zero-resistance states with a critical temperature of up to 1.7 kelvin. The temperature-carrier-density phase diagram of twisted bilayer graphene is similar to that of copper oxides (or cuprates), and includes dome-shaped regions that correspond to superconductivity. Moreover, quantum oscillations in the longitudinal resistance of the material indicate the presence of small Fermi surfaces near the correlated insulating states, in analogy with underdoped cuprates. The relatively high superconducting critical temperature of twisted bilayer graphene, given such a small Fermi surface (which corresponds to a carrier density of about 1011 per square centimetre), puts it among the superconductors with the strongest pairing strength between electrons. Twisted bilayer graphene is a precisely tunable, purely carbon-based, two dimensional superconductor. It is therefore an ideal material for investigations of strongly correlated phenomena, which could lead to insights into the physics of high-critical-temperature superconductors and quantum spin liquids. PMID- 29512652 TI - Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. AB - A key limitation of the use of the CRISPR-Cas9 system for genome editing and other applications is the requirement that a protospacer adjacent motif (PAM) be present at the target site. For the most commonly used Cas9 from Streptococcus pyogenes (SpCas9), the required PAM sequence is NGG. No natural or engineered Cas9 variants that have been shown to function efficiently in mammalian cells offer a PAM less restrictive than NGG. Here we use phage-assisted continuous evolution to evolve an expanded PAM SpCas9 variant (xCas9) that can recognize a broad range of PAM sequences including NG, GAA and GAT. The PAM compatibility of xCas9 is the broadest reported, to our knowledge, among Cas9 proteins that are active in mammalian cells, and supports applications in human cells including targeted transcriptional activation, nuclease-mediated gene disruption, and cytidine and adenine base editing. Notably, despite its broadened PAM compatibility, xCas9 has much greater DNA specificity than SpCas9, with substantially lower genome-wide off-target activity at all NGG target sites tested, as well as minimal off-target activity when targeting genomic sites with non-NGG PAMs. These findings expand the DNA targeting scope of CRISPR systems and establish that there is no necessary trade-off between Cas9 editing efficiency, PAM compatibility and DNA specificity. PMID- 29512655 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2325967117750105.]. PMID- 29512653 TI - Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. AB - The insulin receptor is a dimeric protein that has a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels. Insulin receptor dysfunction has been associated with many diseases, including diabetes, cancer and Alzheimer's disease. The primary sequence of the receptor has been known since the 1980s, and is composed of an extracellular portion (the ectodomain, ECD), a single transmembrane helix and an intracellular tyrosine kinase domain. Binding of insulin to the dimeric ECD triggers auto-phosphorylation of the tyrosine kinase domain and subsequent activation of downstream signalling molecules. Biochemical and mutagenesis data have identified two putative insulin-binding sites, S1 and S2. The structures of insulin bound to an ECD fragment containing S1 and of the apo ectodomain have previously been reported, but details of insulin binding to the full receptor and the signal propagation mechanism are still not understood. Here we report single-particle cryo-electron microscopy reconstructions of the 1:2 (4.3 A) and 1:1 (7.4 A) complexes of the insulin receptor ECD dimer with insulin. The symmetrical 4.3 A structure shows two insulin molecules per dimer, each bound between the leucine-rich subdomain L1 of one monomer and the first fibronectin-like domain (FnIII-1) of the other monomer, and making extensive interactions with the alpha-subunit C-terminal helix (alpha-CT helix). The 7.4 A structure has only one similarly bound insulin per receptor dimer. The structures confirm the binding interactions at S1 and define the full S2 binding site. These insulin receptor states suggest that recruitment of the alpha-CT helix upon binding of the first insulin changes the relative subdomain orientations and triggers downstream signal propagation. PMID- 29512654 TI - Correlated insulator behaviour at half-filling in magic-angle graphene superlattices. AB - A van der Waals heterostructure is a type of metamaterial that consists of vertically stacked two-dimensional building blocks held together by the van der Waals forces between the layers. This design means that the properties of van der Waals heterostructures can be engineered precisely, even more so than those of two-dimensional materials. One such property is the 'twist' angle between different layers in the heterostructure. This angle has a crucial role in the electronic properties of van der Waals heterostructures, but does not have a direct analogue in other types of heterostructure, such as semiconductors grown using molecular beam epitaxy. For small twist angles, the moire pattern that is produced by the lattice misorientation between the two-dimensional layers creates long-range modulation of the stacking order. So far, studies of the effects of the twist angle in van der Waals heterostructures have concentrated mostly on heterostructures consisting of monolayer graphene on top of hexagonal boron nitride, which exhibit relatively weak interlayer interaction owing to the large bandgap in hexagonal boron nitride. Here we study a heterostructure consisting of bilayer graphene, in which the two graphene layers are twisted relative to each other by a certain angle. We show experimentally that, as predicted theoretically, when this angle is close to the 'magic' angle the electronic band structure near zero Fermi energy becomes flat, owing to strong interlayer coupling. These flat bands exhibit insulating states at half-filling, which are not expected in the absence of correlations between electrons. We show that these correlated states at half-filling are consistent with Mott-like insulator states, which can arise from electrons being localized in the superlattice that is induced by the moire pattern. These properties of magic-angle-twisted bilayer graphene heterostructures suggest that these materials could be used to study other exotic many-body quantum phases in two dimensions in the absence of a magnetic field. The accessibility of the flat bands through electrical tunability and the bandwidth tunability through the twist angle could pave the way towards more exotic correlated systems, such as unconventional superconductors and quantum spin liquids. PMID- 29512657 TI - A multifunctional nanoplatform for cancer chemo-photothermal synergistic therapy and overcoming multidrug resistance. AB - The integration of various therapy strategies into a single nanoplatform for synergistic cancer treatment has presented a great prospect. Herein, docetaxel (DTX)-loaded poly lactic-co-glycolic acid (PLGA)-coated polydopamine modified with d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) was synthesized for chemo-photothermal synergistic therapy against cancer. Firstly, the DTX loaded PLGA NPs were prepared by a facile and robust nanoprecipitation method. Then, they were coated with dopamine to achieve the photothermal effects and to be further modified with TPGS, which can inhibit the P-glycoprotein-mediated multidrug resistance (MDR). The near-infrared (NIR) laser irradiation triggered DTX release from DTX-loaded PLGA NPs@PDA-TPGS, and then the chemo-photothermal therapy effect could be enhanced. The in vitro experimental results illustrated that DTX-loaded PLGA NPs@PDA-TPGS exhibits excellent photothermal conservation properties and remarkable cell-killing efficiency. In vivo antitumor studies further confirmed that DTX-loaded PLGA NPs@PDA-TPGS could present an outstanding synergistic antitumor efficacy compared with any monotherapy. This work exhibits a novel nanoplatform, which could not only load chemotherapy drugs efficiently, but could also improve the therapeutic effect of chemotherapy drugs by overcoming MDR and light-mediated photothermal cancer therapy. PMID- 29512658 TI - Inertial manipulation of bubbles in rectangular microfluidic channels. AB - Inertial microfluidics is an active field of research that deals with crossflow positioning of the suspended entities in microflows. Until now, the majority of the studies have focused on the behavior of rigid particles in order to provide guidelines for microfluidic applications such as sorting and filtering. Deformable entities such as bubbles and droplets are considered in fewer studies despite their importance in multiphase microflows. In this paper, we show that the trajectory of bubbles flowing in rectangular and square microchannels can be controlled by tuning the balance of forces acting on them. A T-junction geometry is employed to introduce bubbles into a microchannel and analyze their lateral equilibrium position in a range of Reynolds (1 < Re < 40) and capillary numbers (0.1 < Ca < 1). We find that the Reynolds number (Re), the capillary number (Ca), the diameter of the bubble (D[combining macron]), and the aspect ratio of the channel are the influential parameters in this phenomenon. For instance, at high Re, the flow pushes the bubble towards the wall while large Ca or D[combining macron] moves the bubble towards the center. Moreover, in the shallow channels, having aspect ratios higher than one, the bubble moves towards the narrower sidewalls. One important outcome of this study is that the equilibrium position of bubbles in rectangular channels is different from that of solid particles. The experimental observations are in good agreement with the performed numerical simulations and provide insights into the dynamics of bubbles in laminar flows which can be utilized in the design of flow based multiphase flow reactors. PMID- 29512659 TI - An amplification-free electrochemical detection of exosomal miRNA-21 in serum samples. AB - Recent evidence suggests that small non-coding RNAs such as microRNA (miRNA) encapsulated in exosomes represent an important mechanism of communication between the cells. Exosomal miRNAs play an important role in carcinogenesis via enhancing the cell to cell communication and targeting the cell growth molecular pathways which in turn facilitate metastasis in cancers. Despite progressive advances, the current methods for the exosomal miRNA detection mostly rely on labor-intensive sequencing approaches which are often prone to amplification bias and require costly and bulky equipment. Herein, we report an electrochemical approach for the detection of cancer-derived exosomal miRNAs in human serum samples by selectively isolating the target miRNA using magnetic beads pre functionalized with capture probes and then directly adsorbing the targets onto a gold electrode surface. The level of adsorbed miRNA is detected electrochemically in the presence of an [Fe(CN)6]4-/3- redox system. This method enabled an excellent detection sensitivity of 1.0 pM with a relative standard deviation (%RSD) of <5.5% in cancer cells and serum samples (n = 8) collected from patients with colorectal adenocarcinoma (CRC). We believe that our approach could be useful in clinical settings for the quantification of exosomal miRNA in cancer patients. PMID- 29512660 TI - Adaptive immune cells are necessary for the enhanced therapeutic effect of sorafenib-loaded nanoparticles. AB - Sorafenib is a kinase inhibitor approved for the treatment of primary kidney cancer, advanced primary liver cancer, and radioactive iodine resistant advanced thyroid carcinoma. However, sorafenib usually causes serious side effects, which limit its antitumor effect. Nanoparticle based drug delivery systems have been widely used to enhance the therapeutic effects and reduce the side effects of this drug by the enhanced permeability and retention (EPR) effect. Herein, to improve the therapeutic effect of sorafenib, we developed poly(ethylene glycol)-b poly(lactic acid-co-glycolic acid) (PEG-PLGA) based nanoparticles by a dialysis method for sorafenib encapsulation. After intravenous injection of the sorafenib loaded nanoparticles (NPsorafenib), the tumor growth of mice bearing B16-F10, MC38 and LLC tumor was significantly inhibited. Meanwhile, the dose of sorafenib was reduced to one ninth and the side effects on the hematopoietic system and immune system were abrogated. More importantly, the tumor growth inhibition effect of NPsorafenib was dramatically reduced in B16-F10 bearing Rag1-/- mice which are adaptive immune cell defective, indicating that the antitumor effects of NPsorafenib are dependent on the adaptive immune cells. These results emphasize the indispensable role of the adaptive immune system in nano-drug mediated antitumor effects and the adaptive immune system should be considered as an important factor for clinical applications. PMID- 29512661 TI - Topographical changes in photo-responsive liquid crystal films: a computational analysis. AB - Switchable materials in response to external stimuli serve as building blocks to construct microscale functionalized actuators and sensors. Azobenzene-modified liquid crystal (LC) polymeric networks, that combine liquid crystalline orientational order and elasticity, reversibly undergo conformational changes powered by light. We present a computational framework to describe photo-induced topographical transformations of azobenzene-modified LC glassy polymer coatings. A nonlinear light penetration model is combined with an opto-mechanical constitutive relation to simulate various ordered and corrugated topographical textures resulting from aligned or randomly distributed LC molecule orientations. Our results shed light on the fundamental physical mechanisms of light-triggered surface undulations and can be used as guidelines to optimize surface modulation and roughness in emerging fields that involve haptics interfacing, friction control and wetting manipulation. PMID- 29512662 TI - Control of triplet state generation in heavy atom-free BODIPY-anthracene dyads by media polarity and structural factors. AB - A family of heavy atom-free BODIPY-anthracene dyads (BADs) exhibiting triplet excited state formation from charge-transfer states is reported. Four types of BODIPY scaffolds, different in the alkyl substitution pattern, and four anthracene derivatives have been used to access BADs. Fluorescence and intersystem crossing (ISC) in these dyads depend on donor-acceptor couplings and can be accurately controlled by substitution or media polarity. Under conditions that do not allow charge transfer (CT), the dyads exhibit fluorescence with high quantum yields. Formation of charge-transfer states triggers ISC and the formation of long-lived triplet excited states in the dyads. The excited state properties were studied by steady-state techniques and ultrafast pump-probe spectroscopy to determine the parameters of the observed processes. Structural information for various BADs was derived from single crystal X-ray structure determinations alongside DFT molecular geometry optimization, revealing the effects of mutual orientation of subunits on the photophysical properties. The calculations showed that alkyl substituents on the BODIPY destabilize CT states in the dyads, thus controlling the charge transfer between the subunits. The effect of the dyad structure on the ISC efficiency was considered at the M06-2X level of theory, and a correlation between mutual orientation of the subunits and the energy gap between singlet and triplet CT states was studied using a multireference CASSCF method. PMID- 29512663 TI - Target-responsive DNA hydrogel for non-enzymatic and visual detection of glucose. AB - We have successfully developed a target-responsive aptamer cross-linked hydrogel for the visual detection of glucose, an important biomedical analyte. In this work, the glucose-responsive hydrogel was prepared using the target aptamer and its two short complementary DNA strands grafted onto a linear polyacrylamide chain as cross-linkers. Gold nanoparticles (AuNPs) modified with thiol-PEG were encapsulated in the gel and used as the output signal for visible detection. The complex of glucose and its ligand of boronic acid derivatives (Shinkai's receptor) can bind with the aptamer to disrupt the hydrogel, leading to the release of AuNPs with a distinct red colour in the supernatant. By this method glucose can be detected with the naked eye, and the sensor has a detection limit of 0.44 mM in buffer with the help of UV-Vis spectrophotometry. Furthermore, glucose spiked in 50% urine and 30% serum could also be detected respectively with the naked eye, and glucose was quantitatively detected in 50% urine. The hydrogel system provides a non-enzymatic and visual method for glucose detection, and offers promising applications in biotechnology and biomedicine. PMID- 29512664 TI - Binding sites for luminescent amyloid biomarkers from non-biased molecular dynamics simulations. AB - A very stable binding site for the interaction between a pentameric oligothiophene and an amyloid-beta(1-42) fibril has been identified by means of non-biased molecular dynamics simulations. In this site, the probe is locked in an all-trans conformation with a Coulombic binding energy of 1200 kJ mol-1 due to the interactions between the anionic carboxyl groups of the probe and the cationic epsilon-amino groups in the lysine side chain. Upon binding, the conformationally restricted probes show a pronounced increase in molecular planarity. This is in line with the observed changes in luminescence properties that serve as the foundation for their use as biomarkers. PMID- 29512665 TI - Multifunctional monomers based on vinyl sulfonates and vinyl sulfonamides for crosslinking thiol-Michael polymerizations: monomer reactivity and mechanical behavior. AB - Multifunctional vinyl sulfonates and vinyl sulfonamides were conveniently synthesized and assessed in thiol-Michael crosslinking polymerizations. The monomer reactivities, mechanical behavior and hydrolytic properties were analyzed and compared with those of analogous thiol-acrylate polymerizations. Materials with a broad range of mechanical properties and diverse hydrolytic stabilities were obtained. PMID- 29512666 TI - Is ReO3 a mixed ionic-electronic conductor? A DFT study of defect formation and migration in a BVIO3 perovskite-type oxide. AB - Density-functional-theory (DFT) calculations within the generalised gradient approximation (GGA) were used to examine the behaviour of point defects in the cubic BVIO3 perovskite-type oxide, ReO3. Energies of reduction and of hydration were calculated, and the results are compared with literature data for ABO3 perovskite oxides. The activation energies of migration were determined for O2-, H+, Li+, Na+, K+ and H3O+. An occupied A site in ReO3 is found to be beneficial to oxide-ion migration by a vacancy mechanism as well as to proton migration by a Grotthuss mechanism. Na+, K+ and H3O+ exhibit activation energies of migration higher than 2 eV, whereas Li+ is characterised by a very low migration barrier of 0.1 eV. Reasons for this behaviour are discussed. Our results suggest that H+, O2 , and especially Li+, are highly mobile ions in ReO3. PMID- 29512667 TI - Secondary structure-induced aggregation by hydrogen peroxide: a stimuli-triggered open/close implementation by recombination. AB - The fabrication of reactive aggregation nanomaterials through assemblies in a facile and cost-effective manner is much desired but remains to be well explored. Here we show that exquisite and ultra-long (>2 MUm) hybrid polymer nanorods (NRs) can be formed by a simple self-assembly of a phenylboronic acid modified genistein crosslinker (Ge-di(HMPBA-pin)) and d-alpha-tocopheryl polyethylene glycol 1000 (TPGS). The obtained NRs exhibit quantitative and sensitive colorimetric detection of H2O2 with a remarkable detection limit for different stromal materials. More significantly, the presence of H2O2 triggers a distinct morphological transformation of the polymer NR assembly into the secondary structure of micelles via the oxidative deboronation of boronate moieties in HMPBA-pin-SA. It spontaneously induces the aggregation of metal nanoparticles (Au NPs), metal nanorods (Au NRs), quantum dots (MoS2 QDs), metal ions (Cu2+), protein (ferritin) and tetraphenylethene (TPE) molecules, giving rise to a dramatic stimuli-triggered open/close switchable complexation and apparent colorimetric transitions in vitro. This study, for the first time, showcases the fascinating advantages of such unprecedented secondary structure-induced aggregation and uncovers the immense potential to design a plethora of other sensing systems by virtue of the alternate trigger-specific, sacrifice-aggregated building moieties. PMID- 29512669 TI - A smartphone-based double-channel fluorescence setup for immunoassay of a carcinoembryonic antigen using CuS nanoparticles for signal amplification. AB - Sensitive detection of cancer biomarkers is valuable for clinical diagnosis and treatment assessment of cancers. Herein, we report a simple smartphone-based double-channel fluorescence setup for immunoassay. Not including the smartphone, the total cost of the detection device itself is about 80 $, including a laser pointer, a twinning measurement cell, a collective lens, and an outside box. The fluorescence images of the sample and reference areas were captured by the camera in the smartphone and the brightness ratio was calculated using a user-edited smartphone app. By using 2,3-diaminophenazine (DAP) as the model luminophore, the influence of exposure time and photosensitivity on the sensitivity was tested. The brightness ratio offers high stability of the fluorescence signal, which is helpful to improve the sensitivity. The applicability of this device was demonstrated by a catalytic fluorimetric method for Cu2+ determination, which is based on the oxidation of o-phenylenediamine (non-fluorescent) to DAP (strong fluorescent) by dissolved oxygen using Cu2+ as the catalyst. Accordingly, by using a CuS nanoparticle-conjugated second antibody as the signal tag, the immunoassay for a carcinoembryonic antigen was performed with the detection limit of 0.05 pg mL-1. This smartphone-based double-channel fluorescence device offers the advantages of high sensitivity, inexpensive and miniaturization. PMID- 29512668 TI - Immobilization of gold nanoparticles on folate-conjugated dendritic mesoporous silica-coated reduced graphene oxide nanosheets: a new nanoplatform for curcumin pH-controlled and targeted delivery. AB - In the present study, a new sandwich-like nanocomposite as a multifunctional smart nanocarrier for curcumin (Cur) targeted delivery and cell imaging was prepared by immobilization of gold nanoparticles on folic acid-modified dendritic mesoporous silica-coated reduced graphene oxide nanosheets (AuNPs@GFMS). The physical and chemical properties of the nanocomposite were investigated by atomic force microscopy (AFM), transmission electron microscopy (TEM), X-ray diffraction (XRD), UV-Vis, field-emission scanning electron microscopy (FE-SEM), Fourier transformation infrared (FT-IR), and Brunauer-Emmett-Teller (BET) surface area analysis. The nanocarrier exhibits a number of interesting properties, including good biocompatibility, biodegradability, and suitable surface area, which results in high drug loading capacity. In addition, this new drug delivery system showed sustained-release and pH-responsive properties. The in vitro cytotoxicity test of the free curcumin, free nanocarrier (AuNPs@GFMS), curcumin-loaded folate conjugated nanocarriers (Cur-AuNPs@GFMS), and curcumin-loaded nanocarriers without folate-conjugation (Cur-AuNPs@GAMS) against two human cancer cell lines, including MCF-7 (human breast carcinoma cell lines) and A549 (human lung carcinoma cell lines) demonstrated that the therapeutic efficacy of Cur AuNPs@GFMS is significantly greater than those of other compounds because the cancerous cells can uptake the folate-conjugated drug nanocarrier via a receptor mediated mechanism. Fluorescence microscopic images and different staining techniques were also used to visualize the cellular uptake, anticancer activity, specific targeting ability, and photothermal potency of Cur-AuNPs@GFMS toward the MCF-7 cancer cells. The obtained results proved that the proposed system, Cur AuNPs@GFMS, can be used as a potent anticancer agent in targeted cancer therapies for breast cancer. PMID- 29512670 TI - Biocatalysis with the milk protein beta-lactoglobulin: promoting retroaldol cleavage of alpha,beta-unsaturated aldehydes. AB - Enzymes with a hydrophobic binding site and an active site lysine have been suggested to be promiscuous in their catalytic activity. beta-Lactoglobulin (BLG), the principle whey protein found in milk, possesses a central calyx that binds non-polar molecules. Here, we report that BLG can catalyze the retro-aldol cleavage of alpha,beta-unsaturated aldehydes making it a naturally occurring protein capable of catalyzing retro-aldol reactions on hydrophobic substrates. Retroaldolase activity was seen to be most effective on substrates with phenyl or naphthyl side-chains. Use of a brominated substrate analogue inhibitor increases the product yield by a factor of three. BLG's catalytic activity and its ready availability make it a prime candidate for the development of commercial biocatalysts. PMID- 29512671 TI - The effect of ether-functionalisation in ionic liquids analysed by DFT calculation, infrared spectra, and Kamlet-Taft parameters. AB - The effect of ether-functionalisation on ionic liquids (ILs) is discussed based on Kamlet-Taft parameters and the infrared (IR) spectra of N-ethoxyethyl-N methylpiperidinium bis(trifluoromethanesulfonyl)imide ([P1,2O2][TFSI]) and N ethoxyethyl-N-methylmorpholinium bis(trifluoromethanesulfonyl)imide ([M1,2O2][TFSI]). The results are analysed taking into consideration their ion conformers, electronegativity and hardness, and the IR active vibrations obtained by means of DFT calculations. From the evaluation of Kamlet-Taft parameters, the ether-functionalisation in the cationic ring is found to improve the polarity and hydrogen bond acidity of the ILs. This correlates with the computational result which designates that the oxygen atom in the cationic ring increases the electronegativity of the cation. The comparison with the IR spectra, which were obtained experimentally and computationally, revealed that trans-[TFSI] was preferably formed in [M1,2O2][TFSI] compared to [P1,2O2][TFSI]. Although the Kamlet-Taft parameters indicate that [M1,2O2][TFSI] has a higher polarity, this IL preferably adopts trans-[TFSI], which is normally stabilised with the cations having a lower polarity. This may be due to the presence of the oxygen in the cationic ring which delocalises the electron density of the lowest unoccupied molecular orbitals (LUMO) and increases the conformational freedom of the hydrogen bonds between cations and anions. Moreover, the mixtures of pure ILs with a suitable Li-salt were also investigated to analyze the effect of the Li salt on the polarity and the ion conformers. PMID- 29512672 TI - PhI(OAc)2-mediated dearomative C-N coupling: facile construction of the spiro[indoline-3,2'-pyrrolidine] skeleton. AB - A facile construction of the spiro[indole-3,2'-pyrrolidine] skeleton, through diacetoxyiodobenzene (PIDA) mediated C-N bond-forming dearomatization of C3 sulfonamide linked indole derivatives, has been developed. A variety of spiro indolepyrrolidines were obtained in moderate to excellent yields under mild conditions. PMID- 29512673 TI - Correction: Guest-regulated chirality switching of planar chiral pseudo[1]catenanes. AB - Correction for 'Guest-regulated chirality switching of planar chiral pseudo[1]catenanes' by Ya-Fen Yang et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c8ob00156a. PMID- 29512674 TI - General strategies for effective capture and separation of noble gases by metal organic frameworks. AB - In this frontier article, we provide a brief overview of recent progress in capture and separation of noble gases by microporous metal-organic framework based adsorbents, with an emphasis on xenon and krypton. Our discussions include separation mechanisms and strategies applied to enhance the MOF performance. Existing issues are also reviewed and potential solutions are proposed. PMID- 29512675 TI - Diarylethene-based xerogels: the fabrication of more entangled networks driven by isomerization and acidofluorochromism. AB - Fully-conjugated styrylbenzoxazoles and styrylbenzothiazoles of BOAF24, BOACl24, BOACl35, BOABr24, BOABr35, BTAF24, BTACl24 and BTABr24 without traditional gelation groups could form organogels. It was found that introduction of chlorine atoms in the 2,4-positions of the phenyl group would improve gelation abilities, and benzothiazole derivatives exhibited better gelation abilities than benzoxazoles with a similar pi-skeleton due to better pi-electron delocalization. Interestingly, the organogel of BTACl24 could change into solution by UV light due to trans-cis isomerization, which could also induce morphological changes in xerogels. The smooth organogel nanofibers stretched out lots of thin 'arms' to hold together or to catch other nanofibers upon UV irradiation, so more entangled networks were generated. Moreover, TFA (trifluoroacetic acid) could induce a gel sol transformation on account of the protonation of the benzoxazole or benzothiazole unit, accompanied by emission quenching. BTACl24 exhibited higher performance than BOACl24 in the detection of TFA because of its strong basicity. The decay time and the detection limit of BTACl24 in xerogel-based film towards TFA vapor were of 0.7 s and 0.3 ppm, respectively. Therefore, organogelation of non-traditional organogelators is a powerful approach to the fabrication of multi stimuli-responsive soft materials, and provides a new method to generate more entangled 3D networks through photochemical reactions in xerogels. PMID- 29512676 TI - Magnesium bis(trifluoromethanesulfonyl)amide complexes with triglyme and asymmetric homologues: phase behavior, coordination structures and melting point reduction. AB - The phase behavior of binary mixtures of triglyme (G3) and Mg[TFSA]2 (TFSA: bis(trifluoromethanesulfonyl)amide) was investigated, towards the development of a Mg2+-based room-temperature solvate ionic liquid (SIL) electrolyte. In a 1 : 1 molar ratio, G3 and Mg[TFSA]2 form a thermally stable complex (decomposition temperature, Td: 240 degrees C) with a melting point (Tm) of 70 degrees C, which is considerably lower than that of the analogous tetraglyme (G4) system (137 degrees C). X-ray crystallography of a single crystal of [Mg(G3)][TFSA]2 revealed that a single Mg2+ cation is coordinated by a single, distorted, tetradentate G3 molecule from one side, and two monodentate [TFSA]- anions, with transoid conformation, from the reverse side to form an ion pair. Raman spectra of [Mg(G3)][TFSA]2 in the molten state revealed the presence of different coordination structures, as the liquid exhibits changes in the vibrational modes corresponding to G3 and the [TFSA]- anion compared to those observed for the solid. Investigation of the ion pair stabilization energies by DFT calculations suggests that higher stability cation complexes and ion pairs co-exist in the molten state than those observed in the crystalline state. These results imply that the coordination structures of the ion pairs play a key role in providing SILs with low Tm. To decrease the Tm further, several asymmetric homologues of G3, which have higher conformational flexibility than G3, were investigated. Notably, a 1 : 1 mixture of Mg[TFSA]2 with G3Bu (where one of the terminal methyl groups of G3 is substituted for a butyl group) formed a thermally stable complex (Td: 251 degrees C) without any distinct Tm and showed reasonable ionic conductivity at room-temperature, indicating partial dissociation of ions. In this electrolyte, which showed high oxidative stability, quasi-reversible Mg deposition/dissolution was achieved, indicating that Mg2+-based room-temperature SILs can be utilized as a new class of Mg electrolyte. PMID- 29512677 TI - Exploiting the benefit of S0-> T1 excitation in triplet-triplet annihilation upconversion to attain large anti-stokes shifts: tuning the triplet state lifetime of a tris(2,2'-bipyridine) osmium(ii) complex. AB - Os(ii) complexes are particularly interesting for triplet-triplet annihilation (TTA) upconversion, due to the strong direct S0-> T1 photoexcitation, as in this way, energy loss is minimized and large anti-Stokes shift can be achieved for TTA upconversion. However, Os(bpy)3 has an intrinsic short T1 state lifetime (56 ns), which is detrimental for the intermolecular triplet-triplet energy transfer (TTET), one of the crucial steps in TTA upconversion. In order to prolong the triplet state lifetime, we prepared an Os(ii) tris(bpy) complex with a Bodipy moiety attached, so that an extended T1 state lifetime is achieved by excited state electronic configuration mixing or triplet state equilibrium between the coordination center-localized state (3MLCT state) and Bodipy ligand-localized state (3IL state). With steady-state and time-resolved transient absorption/emission spectroscopy, we proved that the 3MLCT is slightly above the 3IL state (by 0.05 eV), and the triplet state lifetime was prolonged by 31-fold (from 56 ns to 1.73 MUs). The TTA upconversion quantum yield was increased by 4 fold as compared to that of the unsubstituted Os(ii) complex. PMID- 29512678 TI - Graphene hybridization for energy storage applications. AB - Graphene has attracted considerable attention due to its unique two-dimensional structure, high electronic mobility, exceptional thermal conductivity, excellent optical transmittance, good mechanical strength, and ultrahigh surface area. To meet the ever increasing demand for portable electronic products, electric vehicles, smart grids, and renewable energy integrations, hybridizing graphene with various functions and components has been demonstrated to be a versatile and powerful strategy to significantly enhance the performance of various energy storage systems such as lithium-ion batteries, supercapacitors and beyond, because such hybridization can result in synergistic effects that combine the best merits of involved components and confer new functions and properties, thereby improving the charge/discharge efficiencies and capabilities, energy/power densities, and cycle life of these energy storage systems. This review will focus on diverse graphene hybridization principles and strategies for energy storage applications, and the proposed outline is as follows. First, graphene and its fundamental properties, followed by graphene hybrids and related hybridization motivation, are introduced. Second, the developed hybridization formulas of using graphene for lithium-ion batteries are systematically categorized from the viewpoint of material structure design, bulk electrode construction, and material/electrode collaborative engineering; the latest representative progress on anodes and cathodes of lithium-ion batteries will be reviewed following such classifications. Third, similar hybridization formulas for graphene-based supercapacitor electrodes will be summarized and discussed as well. Fourth, the recently emerging hybridization formulas for other graphene based energy storage devices will be briefed in combination with typical examples. Finally, future prospects and directions on the exploration of graphene hybridization toward the design and construction of viable, high-class, and even newly-featured (e.g., flexible) energy storage materials, electrodes, and systems will be presented. PMID- 29512679 TI - Preparation of pyrrolizinone derivatives via sequential transformations of cyclic allyl imides: synthesis of quinolactacide and marinamide. AB - A facile synthetic route has been developed for the preparation of pyrrolizinone derivatives employing N-allyl imides as starting materials. The nucleophilic addition of a vinyl Grignard reagent/RCM/elimination sequence afforded pyrrolizinones in good yields and has been applied for the preparation of naturally occurring quinolactacide and marinamide. PMID- 29512680 TI - Graphene delamination using 'electrochemical methods': an ion intercalation effect. AB - The mechanism of graphene delamination from a Pt catalyst growth surface with electrochemical methods is studied. After a water intercalation step, an electrochemical graphene delamination process is done with a variety of different electrolytes. It is shown that (hydrogen or oxygen) bubble formation is not the main driving force to decouple graphene from its catalyst growth substrate. Ion intercalation is identified as the primary component for a fast graphene delamination process from its catalytic growth substrate. When the Pt/graphene sample is negatively charged, cations will intercalate, assuming they do not reduce within the electrochemical window of the solvent. This cation intercalation does result in graphene delamination. In the same way, anions intercalate in positively charged Pt/graphene samples when they do not react within the electrochemical window of the solvent. Furthermore, it is shown that applying a potential is sufficient (current is not needed) to induce ion intercalation and, as a result, graphene delamination. These findings open the door to avoid Na+ or K+ contamination introduced during currently described electrochemical graphene delamination. Alternative electrolytes (i.e. ammonium hydroxide and tetraethylammonium hydroxide) are proposed, due to the absence of alkali contaminants and rapid cation intercalation to delaminate graphene. PMID- 29512681 TI - Triptolide reduces ischemia/reperfusion injury in rats and H9C2 cells via inhibition of NF-kappaB, ROS and the ERK1/2 pathway. AB - Myocardial ischemia/reperfusion (I/R) induces cardiac cell injury; however, the mechanism underlying cardiac damage remains unclear. A previous study demonstrated that triptolide (TP) exerts protective effects against I/R in cerebral cells. The present study aimed to evaluate the protective effects of TP on cardiac cells, and investigated the potential mechanisms involved in I/R induced damage. Rats and cardiac H9C2 cells undergoing I/R were pretreated with TP, and cell damage was assessed in vivo and in vitro. Hematoxylin and eosin and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining were employed to evaluate I/R injury in rat cardiac tissue. Inflammatory factors, including tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6, were detected by ELISA. Biochemical analyses were performed to evaluate the bioactivity of superoxide dismutase, malondialdehyde and catalase. In addition, viability of H9C2 cells was measured using the Cell Counting kit 8 assay. Flow cytometry was used to evaluate cell apoptosis and reactive oxygen species (ROS) generation. Furthermore, the expression levels of proteins associated with apoptosis, peroxide and inflammation were measured using western blot analysis. H9C2 cells were also treated with N-acetylcysteine and pyrrolidine dithiocarbamate, and cell injury was assessed after peroxidation or I/R. The results demonstrated that TP exerted a significant protective effect on cardiac cells in vivo and in vitro. TP reduced the inflammatory response, as determined by nuclear factor-kappaB inhibition. In addition, TP decreased ROS-mediated lipid peroxidation, and reduced ROS generation. TP also inhibited cell apoptosis by activating the extracellular signal-regulated kinase 1/2 pathway. In conclusion, TP may protect cardiac cells from I/R injury; the potential protective mechanisms of TP against I/R include anti-inflammatory action, antioxidation and apoptotic resistance. PMID- 29512682 TI - Cyclic mechanical tension reinforces DNA damage and activates the p53-p21-Rb pathway to induce premature senescence of nucleus pulposus cells. AB - Intervertebral disc (IVD) degeneration (IDD) is a widely recognized contributor to low back pain. Mechanical stress is a crucial etiological factor of IDD. During the process of IDD, a vicious circle is formed between abnormal mechanical stress and the damage of disc structure and function. Notably, the pathological process of IDD is mediated by the phenotypic shift of IVD cells from an extracellular matrix anabolic phenotype to a catabolic and pro-inflammatory phenotype. Therefore, the effects of mechanical stress on the initiation and progression of IDD depend on the mechanobiology of IVD cells. Recently, disc cell senescence was identified as a new hallmark of IDD. However, the senescent response of disc cells to mechanical stress remains unknown. In this study, we found that prolonged exposure of cyclic mechanical tension (CMT) with unphysiological magnitude generated by the Flexercell tension system markedly induced premature senescence of nucleus pulposus (NP) cells. CMT augmented the DNA damage of NP cells, but did not affect the redox homeostasis of NP cells. Moreover, the p53-p21-retinoblastoma protein (Rb) pathway was activated by CMT to mediate the CMT-induced premature senescence of NP cells. The findings are beneficial to understanding the mechanism of disc cell senescence and the mechanobiology of disc cells further. It suggests that prolonged abnormal mechanical stress accelerates the establishment and progression of disc cell senescence and consequently impairs the structural and functional homeostasis of IVDs to cause IDD. Preventing the pro-senescent effect of mechanical stress on IVD cells is a promising approach to delay the process of IDD. PMID- 29512683 TI - A novel psoralen derivative-MPFC enhances melanogenesis via activation of p38 MAPK and PKA signaling pathways in B16 cells. AB - As an active compound, psoralen is present in various Chinese herbal medicines and has exhibited significant activity in skin disease treatment. Its derivative 8-methoxypsoralan (8-MOP) is the most commonly used drug to induce repigmentation of vitiligo. In our previous screening assays, 4-methyl-6-phenyl-2H-furo[3,2 g]chromen-2-one (MPFC), a psoralen derivative, was identified as more effective tyrosinase and melanin activator than the positive control 8-MOP in consideration of low doses, as well as low toxicity. The overall purpose of this study was to characterize the melanogenic effect and mechanisms of MPFC in B16 cells. The melanin biosynthesis effects of MPFC were determined by examination of cellular melanin contents, tyrosinase activity assay, cyclic adenosinemonophosphate (cAMP) assay, and western blotting of MPFC-stimulated B16 mouse melanoma cells. Our results showed that MPFC enhanced both melanin synthesis and tyrosinase activity in a concentration-dependent manner as well as significantly activated the expression of melanogenic proteins such as tyrosinase, tyrosinase-related protein 1 and tyrosinase-related protein-2. Western blot analysis showed that MPFC increased the phosphorylation of p38 mitogen-activated protein kinase and cAMP response element-binding protein (CREB) as well as the expression of microphthalmia-associated transcription factor (MITF). Moreover, MPFC stimulated intracellular cAMP levels and induced tyrosinase activity and melanin synthesis were attenuated by H89, a protein kinase A inhibitor. These results indicated that MPFC-mediated activation of the p38 MAPK and the protein kinase A (PKA) pathway may shed light on a novel approach for an effective therapy for vitiligo. PMID- 29512684 TI - Valproic acid prevents glucocorticoid-induced osteonecrosis of the femoral head of rats. AB - Glucocorticoids (GCs) are the most common cause of atraumatic osteonecrosis of the femoral head (ONFH) because their effect compromises the osteogenic capability of bone marrow-derived mesenchymal stem cells (BMSCs). Valproic acid (VPA) is a widely used anti-epileptic and anti-convulsant drug. Previous studies have reported that VPA promotes osteogenic differentiation of MSCs in vitro and osteogenesis in vivo as a histone deacetylase (HDAC) inhibitor. The purpose of the present study was to investigate the efficacy of VPA as a precautionary treatment of ONFH after GC treatment in rats. In vitro, the effect of VPA, dexamethasone or a combination treatment of the two on the proliferation and osteogenic differentiation of human BMSCs was assessed using a Cell Counting Kit 8 and apoptosis assays, and by measuring the expression of proteins associated with osteogenesis. In vivo, a GC-induced ONFH model was established in rats and VPA was added during GC treatment to investigate the preventive effect of VPA against ONFH. Rat BMSCs were also extracted to investigate the osteogenic capacity. The results of micro-computed tomography scanning, angiography of the femoral head and histological and immunohistochemical analyses indicated that 11 of 15 rats induced with methylprednisolone (MP) presented with ONFH, while only 2 of 15 rats treated with a combination of MP and VPA developed ONFH. VPA produced beneficial effects on subchondral bone trabeculae in the femoral head with significant preservation of bone volume and blood supply, as well as improved osteogenic capability of BMSCs compared with those in rats treated with GC alone. In conclusion, VPA attenuated the inhibitory effect of GC on BMSC proliferation and osteogenesis by inhibiting apoptosis and elevating the expression of proteins associated with osteogenesis, which may contribute to the prevention of GC induced ONFH in rats. PMID- 29512685 TI - Deguelin exerts anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro. AB - During the pathogenesis of gastric cancer, Akt signaling is considered as a pivotal inducer of gastric cancer development. Here we report the identification of anticancer activities of deguelin, a natural agent that inhibits Akt signaling. When applied to MGC-803 and MKN-45 cells, deguelin suppressed the proliferation and arrested cell cycle by p21-mediated inhibition of cyclin E. We further present in vitro evidence that deguelin promoted apoptosis of cancer cells by decreasing the phospho-Akt signaling and affecting expression of the apoptosis-associated genes Bax and Bcl-2. Additionally, deguelin was found to suppress the migration and invasion of gastric cancer cells. Taken together, these results indicated that deguelin exerted anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro. PMID- 29512686 TI - REG3A overexpression suppresses gastric cancer cell invasion, proliferation and promotes apoptosis through PI3K/Akt signaling pathway. AB - Gastric cancer (GC) is the second most common cause of cancer-related deaths. In recent years some essential factors for resolution were identified, but the clinical trials still lack the effective methods to treat or monitor the disease progression. Regenerating islet-derived 3alpha (REG3A) is a member of REG protein family. Previous studies have investigated the altered expression of REG3A in various cancers. In this investigtion we aimed at the biological function and the underlying molecular mechanism of REG3A in GC. We found that REG3A was significantly downregulated in GC and closely related with patient prognoses. REG3A overexpression suppressed the invasion and proliferation promoting apoptosis of GC cells. While REG3A knockdown promoted the invasion, and proliferation suppressing apoptosis of GC cells. It was further found that REG3A performed its biological functions mainly through phosphatidylinositol 3 kinase (PI3K)/Akt-GSK3beta signaling pathway axis. REG3A may be a promising therapeutic strategy for GC. PMID- 29512687 TI - Transcriptomic and proteomic analysis of potential therapeutic target genes in the liver of metformin-treated Sprague-Dawley rats with type 2 diabetes mellitus. AB - The main actions of metformin are as follows: To reduce hyperglycemia via the suppression of gluconeogenesis, improve glucose uptake and insulin sensitivity, and stimulate activation of adenosine monophosphate-activated protein kinase during the treatment of diabetes mellitus. It is well known that metformin acts via complex mechanisms, including multitarget and multipathway mechanisms; however, the multitargeted antidiabetic genes of metformin remain obscure. The present study aimed to perform transcriptomic and proteomic analysis of potential therapeutic target genes in the liver of metformin-treated Sprague-Dawley rats with type 2 diabetes mellitus. The type 2 diabetes rat model was established using streptozotocin. Fasting blood glucose, hemoglobin A1c, serum insulin and biological parameters were subsequently measured. Differentially expressed genes (DEGs) and proteins were identified in the rat livers by expression profile analysis and isobaric tags for relative and absolute quantitation (iTRAQ). A 1.5 fold alteration in gene expression, as determined using chip-based expression profile analysis, and a 1.2-fold alteration in protein expression, as determined using iTRAQ, were considered physiologically significant benchmarks, which were used to identify DEGS in metformin-treated rats with type 2 diabetes mellitus. The DEGs were verified using quantitative polymerase chain reaction (qPCR) and western blot analysis. Numerous hepatic genes involved in various metabolic pathways were affected by metformin; in particular, genes associated with lipid metabolism were markedly affected. Expression profile analysis and iTRAQ analysis suggested that carboxylesterase 1C subunit (Ces1C) and cholesterol 7alpha hydroxylyase (Cyp7a1) may serve as important DEGs, which were validated by qPCR and western blot analysis. Ces1C and Cyp7a1 are the main enzymes in cholesterol metabolism, yet the result of western blotting was not consistent with qPCR. The present study demonstrated that metformin may affect the expression of numerous hepatic genes involved in metabolic pathways, particularly the lipid and cholesterol metabolic pathways. Ces1C and Cyp7a1 may be considered novel therapeutic target genes in the liver, which are involved in the antidiabetic effects of metformin. PMID- 29512688 TI - In vivo effects of the NLRP1/NLRP3 inflammasome pathway on latent respiratory virus infection. AB - The present study aimed to investigate the effects of nucleotide-binding domain leucine-rich repeat protein (NLRP)1/NLRP3 inflammasome pathways on latent viral infection of the respiratory tract. A total of 55 BALB/c mice were assigned to the control, bleomycin (BLM)-treated, murine cytomegalovirus (MCMV), MCMV+BLM and MCMV+BLM+CD4+ T-cell groups. The viral loads were detected in the salivary glands, kidney, liver and lung tissues via polymerase chain reaction (PCR). The weight, lung coefficient and hydroxyproline (HYP) were detected. HE and Masson staining were performed to score for alveolitis and degree of pulmonary fibrosis. Reverse transcription-quantitative PCR and western blot were applied to assess the expression levels of the NLRP inflammasome components caspase-1, interleukin (IL)-1beta and IL-18. ELISA was used to evaluate the expression levels of caspase 1, tumor necrosis factor (TNF)-alpha, IL-1beta and IL-18. The weight of the mice decreased, and the lung coefficient and HYP content increased in the BLM, MCMV, MCMV+BLM and MCMV+BLM+CD4+ T-cell groups compared with those in the control group. Compared with the control group, mice in the BLM, MCMV+BLM and MCMV+BLM+CD4+ T-cell groups had obviously increased alveolitis and degrees of pulmonary fibrosis, increased mRNA expression levels of caspase-1, IL-1beta and IL-18, and increased protein expression levels of caspase-1(p20), mature IL-1beta and mature IL-18. The values in the MCMV+BLM group were also higher than those in the BLM group and those in the MCMV+BLM+CD4+ T-cell group. The serum levels of caspase-1, TNF-alpha, IL-1beta and IL-18 in the serum of mice in the MCMV+BLM group were significantly higher than those in the BLM group. Compared with the MCMV+BLM group, the MCMV+BLM+CD4+ T-cell group had decreased levels of caspase-1, TNF-alpha, IL-1beta and IL-18 (all P<0.05). These results demonstrated that the activation of the NLRP1 and NLRP3 inflammasome pathways may contribute to pulmonary fibrosis caused by latent MCMV infection in mice. PMID- 29512690 TI - Daidzein exerts anticancer activity towards SKOV3 human ovarian cancer cells by inducing apoptosis and cell cycle arrest, and inhibiting the Raf/MEK/ERK cascade. AB - Ovarian cancer is the main cause of gynecological cancer-associated mortality around the world. Despite initial responses to chemotherapy, frequent relapse occurs. Daidzein is an important flavonoid and has been shown to exhibit a diversity of pharmacological properties, including antimicrobial and anticancer activities. However, information on the anticancer activity of daidzein against ovarian cancer remains limited. Therefore, the present study evaluated the anticancer activity of daidzein against a panel of human ovarian cancer cell lines and one normal ovarian cell line (Moody). The results revealed that daidzein exhibited potent anticancer activity against SKVO3 cells with a half maximal inhibitory concentration (IC50) of 20 uM. However, it exhibited comparatively lower activity against normal ovarian Moody cells, which had an IC50 of 100 uM. Daidzein induced morphological changes in SKOV3 cells and mitochondrial apoptosis, as evident from DAPI, AO/EB and Annexin V/propidium iodide staining. This was associated with the upregulation of B-cell lymphoma 2 associated X protein, cytochrome c, cleaved caspase-3 and -9, and cleaved poly (ADP-ribose) polymerase. Daidzein also triggered G2/M cell arrest through the downregulation of pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1. The effect of daidzein on the migration of SKOV3 cells was also determined, the results of which indicated that daidzein inhibited cell migration in a concentration dependent manner and was coupled with concomitant decrease in the expression of matrix metalloproteinase (MMP)-2 and -9. Additionally, daidzein-inhibited cell growth was simultaneous with suppression of the expression of phosphorylated mitogen-activated protein kinase kinase and phosphorylated extracellular signal regulated kinase. The present study also examined whether daidzein exerts similar activity against SKOV3 cells in nude mouse xenograft models and it was revealed that daidzein considerably reduced the tumorigenesis in vivo, indicative of the potential for daidzein as a lead molecule in the development of ovarian cancer chemotherapy. PMID- 29512689 TI - MicroRNA-155 inhibits the osteogenic differentiation of mesenchymal stem cells induced by BMP9 via downregulation of BMP signaling pathway. AB - Previous studies have indicated that bone morphogenetic protein 9 (BMP9) can promote the osteogenic differentiation of mesenchymal stem cells (MSCs) and increase bone formation in bone diseases. However, the mechanisms involved remained poorly understood. It is necessary to investigate the specific regulatory mechanisms of osteogenic differentiation that were induced by BMP9. During the process of osteogenic differentiation induced by BMP9, the expression of microRNA-155 (miR-155) exhibited a tendency of increasing at first and then decreasing, which made us consider that miR-155 may have a modulatory role in this process, but the roles of this process have not been elucidated. This study aimed to uncover miR-155 capable of concomitant regulation of this process. mmu miR-155 mimic (miR-155) was transfected into MSCs and osteogenesis was induction by using recombinant adenovirus expressing BMP9. Overexpressed miR-155 in MSCs led to a decrease in alkaline phosphatase (ALP) staining and Alizarin red S staining during osteogenic differentiation, and reduced the expression of osteogenesis-related genes, such as runt-related transcription factor 2 (Runx2), osterix (OSX), osteocalcin (OCN) and osteopontin (OPN). On protein levels, overexpressed miR-155 markedly decreased the expression of phosphorylated Smad1/5/8 (p-Smad1/5/8), Runx2, OCN and OPN. Luciferase reporter assay revealed Runx2 and bone morphogenetic protein receptor 9 (BMPR2) are two direct target genes of miR-155. Downregulation of the expression of Runx2 and BMPR2, respectively could offset the inhibitory effect of miR-155 in the osteogenesis of MSCs. In vivo, subcutaneous ectopic osteogenesis of MSCs in nude mice showed miR 155 inhibited osteogenic differentiation. In conclusion, our results demonstrated that miR-155 can inhibit the osteogenic differentiation induced by BMP9 in MSCs. PMID- 29512691 TI - Effect of lithocholic acid on biologically active alpha,beta-unsaturated aldehydes induced by H2O2 in glioma mitochondria for use in glioma treatment. AB - Lithocholic acid (LCA) is known to kill glioma cells while sparing normal neuronal cells. However, the anti-glioma mechanism of LCA is unclear at present. Although malondialdehyde (MDA) is not specific to detect tumors, biologically active alpha,beta-unsaturated aldehydes can be used to detect the outcome of gliomas, especially the mitochondria, as a research tool. The purpose of this research was to determine the optimum conditions for a lipid peroxidation model, according to changes in the aldehydes formed from the reaction between 2 thiobarbituric acid and biologically active alpha,beta-unsaturated aldehydes. Experimental methods and procedures were successfully established for a model of lipid peroxidation induced by H2O2 in glioma mitochondria for glioma treatment and optimum conditions for LCA treatment were determined. The optimal conditions for the model were a glioma mitochondrial concentration of 1.5 mg/ml, H2O2 concentration of 0.3 mg/ml, duration of action of 30 min, and addition of 4.0 ml of 46 mM thiobarbituric acid. The effect of LCA, as determined by changes in the UV peaks at 450, 495, and 532 nm, was optimal at a concentration of 100 uM, a duration of action of 15 min, and in an acidic microenvironment. The study concluded that a suitable concentration of LCA has anti-glioma effects as determined by the effect on changes in the UV peaks at 450, 495 and 532 nm and the mitochondrial model developed should be conducive to further in-depth research. PMID- 29512693 TI - IL-17 induces NSCLC A549 cell proliferation via the upregulation of HMGA1, resulting in an increased cyclin D1 expression. AB - Non-small cell lung cancer (NSCLC) is considered to be an inflammation-associated carcinoma. Although interleukin-17 (IL-17) production contributes to the proliferation and growth of NSCLC, the mechanisms underlying IL-17-induced NSCLC cell proliferation have not been fully elucidated. In the present study, by using ELISA and immunohistochemical analyses, we first found that the expression levels of IL-17, IL-17 receptor (IL-17R), high-mobility group A1 (HMGA1) and cyclin D1 were elevated in the samples of patients with NSCLC. Subsequently, by RT-qPCR, western blot analysis and cell proliferation assay in vitro, we revealed that stimulation with recombinant human IL-17 (namely IL-17A) markedly induced the expression of HMGA1 and cyclin D1 in the A549 cells (a human lung adenocarcinoma cell line) and promoted cell proliferation. Furthermore, luciferase reporter and ChIP assays confirmed that upregulated HMGA1 directly bound to the cyclin D1 gene promoter and activated its transcription. Notably, the response element of HMGA1 binding to the cyclin D1 promoter was disclosed for the first time, at least to the best of our knowledge. Taken together, our findings indicate that the IL 17/HMGA1/cyclin D1 axis plays an important role in NSCLC cell proliferation and may provide new insight into NSCLC pathogenesis and may thus aid in the development of novel therapeutic targets for NSCLC. PMID- 29512692 TI - PEDF protects cardiomyocytes by promoting FUNDC1-mediated mitophagy via PEDF-R under hypoxic condition. AB - Pigment epithelial-derived factor (PEDF) is known to exert diverse physiological activities. Previous studies suggest that hypoxia could induce mitophagy. Astoundingly, under hypoxic condition, we found that PEDF decreased the mitochondrial density of cardiomyocytes. In this study, we evaluated whether PEDF could decrease the mitochondrial density and play a protective role in hypoxic cardiomyocytes via promoting mitophagy. Immunostaining and western blotting were used to analyze mitochondrial density and mitophagy of hypoxic cardiomyocytes. Gas chromatography-mass spectrometry and ELISA were used to analyze levels of palmitic acid and diacylglycerol. Transmission Electron Microscopy was used to detect mitophagy and the mitochondrial density in adult male Sprague-Dawley rat model of acute myocardial infarction. Compared to the control group, we observed that PEDF decreased mitochondrial density through promoting hypoxic cardiomyocyte mitophagy. PEDF increased the levels of palmitic acid and diacylglycerol, and then upregulated the levels of protein kinase Calpha (PKC-alpha) and its activation. Furthermore, inhibition of PKC-alpha by Go6976 could effectively suppress PEDF-induced mitophagy. Besides, we found that PEDF promoted FUNDC1 mediated cardiomyocyte mitophagy via ULK1, which depended on the activation of PKC-alpha. Finally, we discovered that mitophagy was increased and mitochondrial density was reduced in adult male Sprague-Dawley rat model of acute myocardial infarction. We concluded that PEDF promotes mitophagy to protect hypoxic cardiomyocytes, through PEDF/PEDF-R/PA/DAG/PKC-alpha/ULK1/FUNDC1 pathway. PMID- 29512694 TI - Screening for key lncRNAs in the progression of gallbladder cancer using bioinformatics analyses. AB - The present study aimed to investigate key long non-coding RNAs (lncRNAs) and genes, and to obtain insights into their roles in the progression of gallbladder cancer (GBC). The gene expression profile and non-coding RNA profile of GSE62335, which included five separate GBC tissue samples and five matched adjacent gallbladder normal tissue samples, was downloaded from the Gene Expression Omnibus database. The differentially expressed lncRNAs and mRNAs in the GBC tissues were identified, following which RNA binding protein analysis was performed using starBase v2.0 and the co-expressed lncRNA-mRNA pairs were predicted. Gene Ontology enrichment analysis for mRNAs was performed using the Database for Annotation Visualization and Integrated Discovery online tool. In addition, upstream microRNAs (miRNAs) were predicted for the co-expressed lncRNAs and mRNAs. The results revealed that a total of 89 upregulated (13 lncRNAs and 76 mRNAs) and 261 downregulated transcripts (27 lncRNAs and 234 mRNAs) were identified in the GBC tissues. Only 9 lncRNAs had co-expressed mRNAs, and lncRNA forkhead box P2 (FOXP2) was co-expressed with the highest number of mRNAs, which were significant associated with the function of cell adhesion. In addition, the analysis of upstream miRNAs showed that FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) had common upstream miRNAs, including miR-18b-5p, with another 119 differentially expressed genes, and that FENDRR was co-expressed with adenomatosis polyposis coli downregulated 1 (APCDD1) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT). Taken together, the results suggested that the lncRNAs FOXP2 and FENDRR may be crucial in promoting the progression of GBC via cell adhesion and regulating miR-18b-5p, or through interactions with KIT and APCDD1, respectively. PMID- 29512695 TI - SUMO2 modification of Aurora B and its impact on follicular development and atresia in the mouse ovary. AB - In the mammalian ovary, >99% follicles fail to ovulate due to apoptosis in granulosa cells. Aurora B, a core subunit enzyme of the chromosomal passenger complex, exerts a crucial role in microtubule-kinetochore attachment, and has been reported to be modified by small ubiquitin-related modifier (SUMO) proteins. However, the details of how Aurora B and its SUMOylation impact on follicular development have yet to be fully elucidated. The aim of the present study was to explore the roles, and possible molecular mechanism, of Aurora B and its SUMOylation in the granulosa cells of the mouse follicle. It was revealed that the protein level of Aurora B increased with follicular development and the growth of the granulosa cells. Aurora B impacted follicular development and atresia through mediating the p38 mitogen-activated protein kinase and FasL/Fas pathways, and caused the downregulation of cyclin-dependent kinase 4, proliferating cell nuclear antigen, Bcl-2, and upregulation of caspases-3 and -8 to modulate the viability of the granulosa cells. In addition, Aurora B undergoes modification by SUMO2, but not by SUMO1, in vivo and in vitro, and Lys-207 is a major modification site. SUMOylation modulates follicular development through an increase in Aurora B localization in the nucleus, and by stabilizing the protein level of Aurora B and keeping the viability of the granulosa cells. Taken together, Aurora B and its SUMOylation are important for follicular development and atresia in the ovaries of mice. PMID- 29512696 TI - Identification of key genes and long non-coding RNAs in celecoxib-treated lung squamous cell carcinoma cell line by RNA-sequencing. AB - Celecoxib is an inhibitor of cyclooxygenase-2, a gene that is often aberrantly expressed in the lung squamous cell carcinoma (LSQCC). The present study aims to provide novel insight into chemoprevention by celecoxib treatment. The human LSQCC cell line SK-MES-1 was treated with or without celecoxib and RNA-sequencing (RNA-seq) was performed on the Illumina HiSeq 2000 platform. Expression levels of genes or long non-coding RNAs (lncRNAs) were calculated by Cufflinks software. Subsequently, differentially expressed genes (DEGs) and differentially expressed lncRNAs (DE-LNRs) between the two groups were selected using the limma package and LNCipedia 3.0, respectively; followed by co-expression analysis based on their expression correlation coefficient (CC). Enrichment analysis for the DEGs and co-expressed DE-LNRs were performed. Protein-protein interaction (PPI) network analysis for DEGs was performed using STRING database. A set of 317 DEGs and 25 DE-LNRs were identified between celecoxib-treated and non-treated cell lines. A total of 12 pathways were enriched by the DEGs, including 'protein processing in endoplasmic reticulum' for activating transcription factor 4 (ATF4), 'mammalian target of rapamycin (mTOR) signaling pathway' for vascular endothelial growth factor A (VEGFA) and 'ECM-receptor interaction' for fibronectin 1 (FN1). Genes such as VEGFA, ATF4 and FN1 were highlighted in the PPI network. VEGFA was linked with lnc-AP000769.1-2:10 (CC= -0.99227), whereas ATF4 and FN1 were closely correlated with lnc-HFE2-2:1 (CC=0.996159 and -0.98714, respectively). lncRNAs were also enriched in pathways such as 'mTOR signaling pathway' for lnc-HFE2-2:1. Several important molecules were identified in celecoxib-treated LSQCC cell lines, such as VEGFA, ATF4, FN1, lnc-AP000769.1-2:10 and lnc-HFE2-2:1, which may enhance the anti-cancer effects of celecoxib on LSQCC. PMID- 29512697 TI - Ephrin-b3 modulates hippocampal neurogenesis and the reelin signaling pathway in a pilocarpine-induced model of epilepsy. AB - Ephrin-B3 is important in the regulation of cell proliferation, differentiation and migration via cell-cell contact, and can activate the reelin pathway during brain development. However, the effect of ephrin-B3 on hippocampal neurogenesis and the reelin pathway in epilepsy remains to be fully elucidated. In the present study, the expression of ephrin-B3 in pilocarpine-induced status epilepticus (SE) rats was investigated. SYBR Green-based reverse transcription-quantitative polymerase chain reaction analysis, immunohistochemical labeling and western blot analysis were used to detect the gene and protein expression levels of ephrin-B3 and reelin pathway proteins. Immunofluorescence staining of doublecortin (DCX) was utilized to analyze hippocampal neurogenesis. The data revealed that the mRNA and protein expression levels of ephrin-B3 in the hippocampus decreased during the spontaneous seizure period. Of note, the expression of reelin and its downstream phosphorylation disabled 1 (p-Dab1) were also notably decreased during the spontaneous seizure period, which showed similar dynamic changes as in the expression of ephrin-B3. In addition, it was found that the number of DCX-labeled neuronal progenitor cells was increased in the hippocampus following pilocarpine induced SE. To further clarify the role of ephrin-B3 in neurogenesis and the reelin pathway in epilepsy, an exogenous ephrin-B3 clustering stimulator, EphB3 Fc, was infused into the bilateral hippocampus of the rats post-SE. Following EphB3-Fc injection, it was found that the expression levels of reelin and p-Dab1 were significantly increased in the epileptic rats following EphB3-Fc injection. The number of DCX-labeled neuronal progenitor cells was reduced in the hippocampus of the epileptic rats. Furthermore, the intensity and frequency of spontaneous recurrent seizures and electroencephalographic seizures were attenuated in the epileptic rats post-injection. These results demonstrated the critical role of ephrin-B3 in regulation of the reelin pathway and hippocampal neurogenesis in epilepsy, providing experimental evidence that ephrin-B3 functions as a potential protective factor in epilepsy, at least in animals. PMID- 29512698 TI - Downregulation of SIRT6 by miR-34c-5p is associated with poor prognosis and promotes colon cancer proliferation through inhibiting apoptosis via the JAK2/STAT3 signaling pathway. AB - Sirtuin 6 (SIRT6) is a member of the nicotinamide adenine dinucleotide positivity dependent class III deacetylase sirtuin family. The present study aimed to explore the expression and function of SIRT6 in colon cancer. Furthermore, the partial mechanism underlying the dysregulation of SIRT6 was investigated. The results of immunohistochemistry demonstrated that SIRT6 was markedly downregulated in colon cancer tissues, and patients with high SIRT6 expression had a better prognosis than those who did not. The proliferation and apoptotic assays demonstrated that SIRT6 was able to suppress colon cancer cell proliferation and induce apoptosis via the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. MicroRNAs (miRNAs/miRs) are important non-coding RNAs, which have a critical role in the negative regulation of their target genes. Through bioinformatics analysis and further experiments, the results demonstrated that miR-34c-5p was not only dysregulated in colon cancer tissues but may also regulate SIRT6 expression via interaction with the 3'-untranslated region of SIRT6 mRNA. The proliferation and apoptotic assays indicated that miR-34c-5p could directly promote cell growth and inhibit apoptosis via activation of the JAK2/STAT3 signaling pathway, which was similar to silencing SIRT6. In conclusion, the results of the present study demonstrated that miR-34c-5p promoted colon cancer cell proliferation by targeting SIRT6 via activation of the JAK2/STAT3 signaling pathway. It may be hypothesized that SIRT6 is a potential biomarker for colon cancer prognosis, and the miR-34c-5p/SIRT6/JAK2/STAT3 axis may provide novel insights into colon cancer treatment. PMID- 29512699 TI - High expression of active ATF6 aggravates endoplasmic reticulum stress-induced vascular endothelial cell apoptosis through the mitochondrial apoptotic pathway. AB - Activating transcription factor 6 (ATF6), one of three sensor proteins in the endoplasmic reticulum (ER), is an important regulatory factor in the ER stress induced apoptosis pathway. Although recent studies have made some progress in elucidating the regulation mechanism of ATF6, the specific regulatory mechanism of ER stress-induced vascular endothelial cell (VEC) apoptosis is still unclear. The present study was designed to investigate the role of ATF6 in VECs under thapsigargin (TG)-induced ER stress. ATF6 (1-366aa; ATF6 high-expressed plasmid) and ATF6 (151-366aa; plasmid without transcriptional activity) were transfected into VECs to yield an ATF6 high-expression model and a positive control model, respectively. High expression of ATF6 decreased viability and aggravated ER stress-induced apoptosis in VECs. Increased expression of apoptosis-related genes, including those encoding caspase-3, caspase-9, C/EBP homologous protein (CHOP), cytochrome c and B-cell lymphoma-associated protein X (Bax)/B-cell lymphoma (Bcl-)2, was detected by polymerase chain reaction and western blotting in the ATF6 (1-366aa) + TG group. No significant effect of TG treatment and high ATF6 expression was indicated on the expression of death receptor-related genes, including those encoding caspase-8 and Fas. The results demonstrated that high expression of activated ATF6 aggravates ER stress-induced VEC apoptosis through the mitochondrial apoptotic pathway. Furthermore, in response to ER stress, ATF6 upregulates the expression of caspase-3, caspase-9, CHOP, cytochrome c and Bax/Bcl-2. PMID- 29512700 TI - Increased interleukin-17A levels promote rituximab resistance by suppressing p53 expression and predict an unfavorable prognosis in patients with diffuse large B cell lymphoma. AB - Rituximab resistance has become increasingly common in patients with diffuse large B cell lymphoma (DLBCL). However, the mechanisms involved remain unclear. In this study, we aimed to examine the effect of rituximab on interleukin (IL) 17A and to investigate the role of IL-17A in rituximab resistance and its prognostic value in patients with DLBCL. Our retrospective analysis revealed that rituximab increased IL-6 expression levels in patients with DLBCL, and the increased IL-6 levels in turn induced the differentiation of Th17 and IL 17+Foxp3+ Treg cells, which secreted IL-17A both in vivo and in vitro. We then examined the effects of IL-17A on the apoptosis and proliferation of, and p53 expression in DLBCL cells, and found that IL-17A prevented rituximab-induced apoptosis and promoted the proliferation of DLBCL cells by suppressing p53 expression in vitro. The survival data of 73 patients with DLBCL suggested that high peripheral blood levels of IL-17A predicted an unfavorable survival. On the whole, our data indicate that rituximab promotes Th17 and IL-17+Foxp3+ Treg cells to secrete IL-17A, which in turn promotes rituximab resistance, partially by suppressing p53 expression and inhibiting rituximab-induced DLBCL cell apoptosis. IL-17A may thus prove to be a useful prognostic marker in patients with DLBCL. PMID- 29512701 TI - Low expression of PTEN is essential for maintenance of a malignant state in human gastric adenocarcinoma via upregulation of p-AURKA mediated by activation of AURKA. AB - Gastric adenocarcinoma remains a life-threatening disease, emphasizing the importance of gaining an improved understanding of signaling pathways involved in this disease, which can lead to the development of novel therapeutic methods targeting common molecular pathways shared across different types of gastric adenocarcinoma. The present study revealed phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and aurora kinase A (AURKA) gene alterations, which were involved in changes in the phenotypes of gastric cancer cells, including increased proliferation by cell counting kit-8 assay and invasion capacity by Transwell invasion assay, and predicted survival rates by KM Plotter database in gastric cancer. The present study investigated the association between PTEN and AURKA. Western blotting revealed that phosphorylated (p)-AURKA correlated with two target genes, PTEN and AURKA. The downregulation of PTEN by small interfering (si)RNA not only increased the expression of AURKA at the mRNA and protein levels by western blotting and by reverse transcription-quantitative PCR, but also increased the expression of p-AURKA by western blotting and immunofluorescence analysis. In addition, western blotting and reverse transcription-quantitative PCR revealed that the downregulation of AURKA affected the expression level of PTEN. Furthermore, PTEN suppressed the malignant phenotypic changes of gastric adenocarcinoma cells by regulating the expression of AURKA inhibited by p-AURKA, suggesting that p-AURKA may be the key mediator of the PTEN-associated activation of AURKA and may be key in maintaining the PTEN-induced malignant state of gastric adenocarcinoma cells. This hypothesis was confirmed by western blotting, and changes were observed in the protein expression of p-AURKA and AURKA under conditions in which cells were treated with either MLN8237 or si-PTEN transfection only, or with si-PTEN transfection and MLN8237. Knockdown of the expression of PTEN altered the expression of p-AKT, p-glycogen synthase kinase 3beta and beta-catenin, which are genes that have been reported to be involved in the development of gastric adenocarcinoma. The present study confirmed that p AURKA is important in the development of gastric adenocarcinoma and revealed a novel functional link between PTEN, AURKA and p-AURKA activation. The results also suggest a novel drug design strategy in targeting PTEN and AURKA for more specific gastric cancer cell death that spares normal cells. PMID- 29512702 TI - c-Myc regulates the CDK1/cyclin B1 dependent-G2/M cell cycle progression by histone H4 acetylation in Raji cells. AB - Overexpression of c-Myc is involved in the tumorigenesis of B-lineage acute lymphoblastic leukemia (B-ALL), but the mechanism is not well understood. In the present study, a c-Myc-knockdown model (Raji-KD) was established using Raji cells, and it was indicated that c-Myc regulates the expression of genes associated with cell cycle progression in G2/M-phase, cyclin D kinase (CDK)1 and cyclin B1, by modulating 60 kDa Tat-interactive protein (TIP60)/males absent on the first (MOF)-mediated histone H4 acetylation (AcH4), which was then completely restored by re-introduction of the c-Myc gene into the Raji-KD cells. The expression of CDK1 and cyclin B1 was markedly suppressed in Raji-KD cells, resulting in G2/M arrest. In comparison to Raji cells, the proliferation of Raji KD cells was significantly reduced, and it was recovered via re-introduction of the c-Myc gene. In the tumorigenesis assays, the loss of c-Myc expression significantly suppressed Raji cell-derived lymphoblastic tumor formation. Although c-Myc also promotes Raji cell apoptosis via the caspase-3-associated pathway, CDK1/cyclin B1-dependent-G2/M cell cycle progression remains the major driving force of c-Myc-controlled tumorigenesis. The present results suggested that c-Myc regulates cyclin B1- and CDK1-dependent G2/M cell cycle progression by TIP60/MOF-mediated AcH4 in Raji cells. PMID- 29512703 TI - Transcriptome and alternative splicing analysis of nucleus pulposus cells in response to high oxygen tension: Involvement of high oxygen tension in the pathogenesis of intervertebral disc degeneration. AB - High oxygen tension caused by neovascularization in the microenvironment of intervertebral discs (IVDs) is associated with the pathogenesis of IVD degeneration (IDD). Pre-mRNAs undergo alternative splicing (AS) to produce structurally and functionally diverse mRNA and proteins. However, the precise role of high oxygen tension in IDD and the relationship between AS and high oxygen tension in disc cells remain unknown. To investigate the effect of high oxygen tension on disc cells, Affymetrix Rat Transcriptome Array 1.0 was used to determine differentially expressed genes (DEGs) and alternative splicing genes (ASGs) in rat nucleus pulposus (NP) cells treated with 20% O2. NP cells at 1% O2 served as the control. PCR was used for validation. GO and KEGG pathway analysis was performed. Furthermore, the reactive oxygen species (ROS) production, growth, cell cycle and matrix metabolism of NP cells were also investigated. In total, 2499 DEGs and 8451 ASGs were identified. Various GO terms and KEGG pathways were potently associated with IDD, including autophagy, mTOR signaling pathway and angiogenesis. Especially, high oxygen tension increased ROS production in NP cells. It also accelerated the matrix metabolism of NP cells and induced NP cell cycle arrest to retard cell growth. This study, for the first time, analyzes the transcriptome and AS of NP cells in response to high oxygen tension, indicating that high oxygen tension is involved in the establishment and progression of IDD through its wide effects on the viability and function of disc cells. PMID- 29512704 TI - Intravenous administration of DPSCs and BDNF improves neurological performance in rats with focal cerebral ischemia. AB - Dental pulp stem cells (DPSCs) are considered as an ideal stem cell source for the treatment of neurological diseases. In this study, we evaluated the therapeutic potency of DPSCs and brain-derived neurotrophic factor (BDNF) in focal cerebral ischemia using animal models. Following middle cerebral artery occlusion (MCAO), rats were randomized into four groups: the BDNF, DPSCs, DPSCs+BDNF and the controls injected with saline. DPSCs were transplanted and BDNF was injected into the DPSCs+BDNF group via the tail vein. The fate of the transplanted DPSCs in rat brains was evaluated using immunofluorescence, immunohistochemistry, western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Adhesive removal tests and the modified neurological severity scores were used to estimate the restoration of neurological function. Proliferation of intravenously transplanted DPSCs was observed in the peripheral ischemic regions of the MCAO models. A green fluorescent dye PKH67 was used to label cells. PKH67-labeled DPSCs were co-localized with neuronal cell markers and 4',6-diamidino-2-phenylindole (DAPI). DPSC transplantation combined with BDNF induced the expression of neural differentiation markers such as nestin, doublecortin (DCX) and neuronal specific filament (NF-H), suggesting that BDNF enhances the survival of DPSCs and differentiation into neuronal cells. Treatment with DPSCs combined with BDNF promoted the recovery of neurological function more effectively compared with BDNF injection or DPSC transplantation alone. In conclusion, treatment with DPSCs combined with BDNF enhances neurological recovery after stroke suggesting a novel therapeutic strategy against cerebral ischemia. PMID- 29512705 TI - Interferon regulatory factor 3 mediates Poly(I:C)-induced innate immune response and apoptosis in non-small cell lung cancer. AB - Immunotherapy is considered one of the most promising treatments for lung cancer. The cell signalling molecules melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I protein (RIG-I) are essential receptors that recognise intracellular pathogen-associated nucleic acids, whereas interferon regulatory factor 3 (IRF3) controls the expression of innate immunity associated genes in macrophages. However, the innate immune response to polyinosinic:polycytidylic acid [Poly(I:C)] in lung cancer remains to be elucidated. In the present study, western blot analysis, reverse transcription quantitative polymerase chain reaction, RNA interference, IRF3 plasmid construction, ELISA and apoptosis analysis were employed to study the innate immune response and apoptosis of non-small cell lung cancer (NSCLC) cells. Poly(I:C) transfection in NSCLC cells triggered apoptosis via the extrinsic apoptotic pathway, and activated the innate immune response by promoting interferon-beta and C-X-C motif chemokine ligand 10 expression. Treatment with the IkappaB kinase epsilon/tumour necrosis factor receptor-associated factor family member-associated nuclear factor-kappaB activator-binding kinase 1 inhibitor BX795, which inhibits IRF3 phosphorylation, or transfection with small interfering RNA/short hairpin RNA to downregulate MDA5, RIG-I or IRF3, prior to Poly(I:C) transfection inhibited the innate immune response and apoptotic pathway. Conversely, IRF3 overexpression promoted activation of the apoptotic pathway, thus indicating that the MDA5/RIG-I/IRF3 axis may mediate responses to Poly(I:C) transfection. Furthermore, phosphorylation of the transcription factor signal transducer and activator of transcription 1 (STAT1) was associated with the alterations in IRF3 phosphorylation and apoptosis, thus suggesting that STAT1 may be involved in Poly(I:C)-induced apoptosis. In NSCLC surgical samples, MDA5, RIG-I and IRF3 were highly expressed, whereas the expression levels of phosphorylated-IRF3 were reduced. These findings indicated that the function of the MDA5/RIG-I/IRF3 axis may be impaired in some lung cancers. In conclusion, the present findings suggested that the MDA5/RIG-I/IRF3 axis, which is associated with innate immunity, is intact in NSCLC cells, and IRF3 is involved in regulating the apoptotic pathway in NSCLC cells. PMID- 29512706 TI - Upregulation of SIRT1 inhibits H2O2-induced osteoblast apoptosis via FoxO1/beta catenin pathway. AB - Osteoporosis is a disease that significantly influences life expectancy and quality in humans. Oxidative stress may stimulate bone marrow osteoclast differentiation and inhibit osteoblast (OB) differentiation. OB proliferation and differentiation are affected by the forkhead box O (FoxO)1/beta-catenin signaling pathway. The osteogenic differentiation of mesenchymal stem cells (MSCs) may be promoted by silent information regulator type-1 [sirtuin (SIRT)1]. However, the molecular mechanism of SIRT1 regulation of osteogenic differentiation of MSCs remains unclear, and further elucidation is needed. The present study investigated the role of SIRT1 in the FoxO1/beta-catenin signaling pathway in oxidative stress and its mechanism in the osteoblastic progenitor cell line (MC3T3-E1). The results demonstrated that OB apoptosis and elevated oxidative stress in cells were simulated by H2O2, which was inhibited by moderate SIRT1 overexpression through reducing the oxidative stress. Further studies revealed that FOXO1 and beta-catenin pathway activity was downregulated by SIRT1 and eventually resulted in inhibition of target genes, including the proapoptotic gene B cell lymphoma-2 interacting mediator of cell death, DNA repair gene growth arrest and DNA damage inducible protein 45 and the OB differentiation suppressor gene peroxisome proliferator activated receptor (PPAR)-gamma. Furthermore, beta catenin and PPAR-gamma were inhibited by SIRT1. Overall, the results of the present study suggest that moderate overexpression of SIRT1 (~3-fold of normal level) may directly or indirectly inhibit apoptosis of OBs via the FOXO1 and beta catenin signaling pathway. PMID- 29512707 TI - Apigenin induces apoptosis by suppressing Bcl-xl and Mcl-1 simultaneously via signal transducer and activator of transcription 3 signaling in colon cancer. AB - Apigenin is a natural flavonoid that exhibits anti-proliferative activity and induces apoptosis in various types of cancer, including colon cancer. The aim of the present study was to determine the mechanism underlying the apoptosis inducing effect of apigenin in colon cancer. Apigenin reduced the proliferation of colon cancer cell lines, stimulated the cleavage of PARP and induced apoptosis in a dose-dependent manner. Apigenin treatment also suppressed the expression of the anti-apoptotic proteins Bcl-xL and Mcl-1. Small interfering RNA was used to knockdown Bcl-xL and Mcl-1 expression alone and in concert, and the proliferation and apoptosis of cancer cells were subsequently measured. The knockdown of Bcl-xL and Mcl-1 expression together markedly suppressed cell proliferation and induced apoptosis. Apigenin treatment also inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which targets Bcl-xL and Mcl 1. The results of the current study therefore determined that apigenin induces the apoptosis of colon cancer cells by inhibiting the phosphorylation of STAT3 and consequently downregulates the anti-apoptotic proteins Bcl-xL and Mcl-1. PMID- 29512708 TI - Pterostilbene modulates the suppression of multidrug resistance protein 1 and triggers autophagic and apoptotic mechanisms in cisplatin-resistant human oral cancer CAR cells via AKT signaling. AB - Pterostilbene is a natural polyphenolic compound that is primarily found in fruits, such as blueberries and has a similar structure to resveratrol. Pterostilbene exhibits antioxidant, anti-inflammatory and antitumor activity but the effects of pterostilbene on drug-resistant oral cancer cells and its underlying mechanisms of action have not yet been explored. Therefore, the present study was performed to clarify the anticancer effects of pterostilbene on cisplatin-resistant human oral cancer CAR cells. The results demonstrated that CAR cells exhibited marked shrinkage, cell membrane breakage and autophagic vacuole formation following treatment with pterostilbene. Pterostilbene also effectively inhibited cell viability and suppressed cell confluence in a time- and concentration-dependent manner. Probing with acridine orange, monodansylcadaverine and LysoTracker Red demonstrated that the number of acidic vesicular organelles was increased, indicating increased autophagy. Furthermore, Heochst 33342 staining determined that DNA condensation, a characteristic of apoptosis, was enhanced following treatment with pterostilbene. Furthermore, pterostilbene upregulated mRNA levels of LC3-II and Atg12, as well as the expression of Atgs/Beclin-1/LC3-associated signaling, suggesting that it enhances autophagy. The autophagy inhibitors 3-methyladenine and chloroquine were used to confirm that pterostilbene induces autophagy. It was also determined that pterostilbene triggered caspase-dependent apoptosis by directly testing DNA breakage and using the pan-caspase inhibitor carbobenzoxyvalyl-alanyl-aspartyl fluoromethyl ketone. The results demonstrated that pterostilbene mediates the apoptosis of CAR cells via the intrinsic apoptotic cascade. In addition, pterostilbene inhibited MDR1 expression and the phosphorylation of AKT on the Ser473 site in CAR cells. Therefore, pterostilbene may elicit an oral anticancer response in drug-resistant cells and may be used as a chemotherapeutic adjuvant to treat patients with oral cancer. PMID- 29512710 TI - Enhanced rapamycin delivery to hemangiomas by lipid polymer nanoparticles coupled with anti-VEGFR antibody. AB - The most common tumors in children are infantile hemangiomas which could cause morbidity and severe complications. The development of novel alternative drugs to treat infantile hemangiomas is necessary, since Hemangeol is the only US Food and Drug Administration-approved drug for infantile hemangiomas. However, Hemangeol has several disadvantages, including a high frequency of administration and adverse effects. Rapamycin is a well-established antiangiogenic drug, and we have previously developed rapamycin lipid polymer nanoparticles (R-PLNPs) as a local sustained-release drug delivery system to achieve controlled rapamycin release and to decrease the frequency of administration and side effects of rapamycin. To improve the targeting of R-PLNPs to infantile hemangiomas in the present study, R PLNPs were modified to include an antibody against vascular endothelial growth factor receptor (VEGF). The characteristics, and the anti-hemangioma activity of the resulting R-PLNPs coupled with the anti-VEGFR2 antibody (named R-PLNPs-V) were examined in vitro and in vivo. R-PLNPs-V possessed a small size (115 nm) and sustained drug release for 6 days. The anti-VEGFR2 antibody promoted the targeting and cytotoxic effect of R-PLNPs-V to human hemangioma endothelial cells and human umbilical vein endothelial cells. Using a subcutaneous infantile hemangioma xenograft in mice, the in vivo therapeutic effect (evaluated with hemangioma weight, volume, and microvessel density) of R-PLNPs-V was demonstrated to be superior compared with rapamycin alone and other non-targeted nanoparticles, without any total body weight loss. In summary, R-PLNPs-V could facilitate targeted delivery and sustained release of rapamycin to infantile hemangiomas, and thus may represent a promising candidate treatment for infantile hemangiomas. PMID- 29512711 TI - MicroRNA-383 suppresses cell proliferation and invasion in colorectal cancer by directly targeting paired box 6. AB - Colorectal cancer (CRC) is the third-most prevalent cancer and the fourth-most common cause of cancer-associated fatality worldwide. The expression and biological roles of microRNAs (miRNAs/miRs) in tumourigenesis, and their regulatory function in a number of biological processes correlated with cancer have been investigated. miR-383 has been reported to be deregulated in several human cancer types. However, the involvement and effects of miR-383 on CRC progression and its underlying mechanism remain unknown. Therefore, the present study aimed to examine miR-383 expression, investigate the biological functions of miR-383 and identify its mechanism of action in CRC cells. In the present study, miR-383 was significantly downregulated in CRC tissues and cell lines. Low miR-383 expression was negatively associated with tumour size, lymph node metastasis and TNM stage. Function experiments demonstrated that miR-383 upregulation inhibited the proliferation and invasion of CRC cells. Paired box 6 (PAX6) was confirmed as a direct target of miR-383. PAX6 was upregulated in CRC tissues and was negatively correlated with miR-383 expression. Induced PAX6 overexpression effectively rescued the tumour-suppressing roles of miR-383 on CRC cell proliferation and invasion. These findings suggested that miR-383 may act as a tumour suppressor in CRC by directly targeting PAX6 and may serve as a promising therapeutic target for CRC treatment. PMID- 29512709 TI - RP105 alleviates myocardial ischemia reperfusion injury via inhibiting TLR4/TRIF signaling pathways. AB - The Toll-like receptor 4 (TLR4) signal pathway- induced inflammation is considered to be a crucial link to myocardial ischemia reperfusion injury (MIRI). Our previous study proved that radioprotective 105 kDa protein (RP105), a negative regulator of TLR4, performed a protective role in MIRI by anti-apoptosis approach. However, the mechanism of RP105 cardioprotection of anti-inflammation is still unclear. This study aimed to explore the underlying mechanism of RP105 anti-inflammation effect in MIRI. We established a rat model of MIRI induced by ligation of the left anterior descending coronary artery for 30 min followed by 2 h reperfusion. Animals were pre-infected with Ad-EGFP-RP105, Ad-EGFP or saline at the apex of the heart. All rats were sacrificed to collect blood samples and myocardial tissue and assessed by immunofluorescence, blood biochemical analysis, Evans blue/triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E) staining, enzyme-linked immuno sorbent assay (ELISA), western blot analysis, quantitative PCR and electrophoretic mobility shift assay (EMSA). RP105 overexpression with adenovirus vectors reduced serum myocardial enzyme (CK-MB and LDH) activities, decreased myocardial infarct size, mitigated inflammatory factors interferon-beta and tumor necrosis factor-alpha during MIRI. We also found that Ad-RP105 group exerted distinct repression of TLR4/TRIF signal pathway related proteins and mRNAs (TRIF, TBK-1, IRF3 and p-IRF3) with a low transcriptional activity of IRF3. These findings first expounded that RP105 could alleviate the ischemia reperfusion induced inflammatory status in heart via inhibiting TLR4/TRIF signaling pathway and provided a theoretical foundation of RP105 gene in MIRI. PMID- 29512713 TI - Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts. AB - Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy (DCM), which leads to cardiac remodeling, dilated cardiomyopathy and congestive heart failure. Human cardiac fibroblasts (HCF) constitute the predominant cell type in the heart and matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are also involved in cardiac fibrosis. However, it is unclear whether high glucose levels affect the expression of MMPs and TIMPs in HCF. Sodium-glucose cotransporter (SGLT) inhibitors have been developed as therapeutic agents and the anti-DCM effect of SGLT inhibitors has been demonstrated by previous studies. However, whether SLGT inhibitors protect the diabetic heart by directly inhibiting the SGLTs in HCF in addition to lowering the blood glucose levels, has not yet been determined. In the present study, increased MMP-2 expression was noted in HCFs in response to high glucose levels, which may be reversed by phlorizin (inhibits both SGLT1 and SGLT2), but not dapagliflozin (inhibits SGLT2). In addition, SGLT1 was revealed to be present in the HCFs and high glucose level was demonstrated to increase SGLT1 expression, which may be attenuated by phlorizin. Therefore it was concluded that high glucose levels induced MMP-2 expression in the HCFs, potentially by upregulating SGLT1. SGLT1 inhibition may be a novel strategy for the treatment of DCM. PMID- 29512712 TI - Identification of COL4A1 as a potential gene conferring trastuzumab resistance in gastric cancer based on bioinformatics analysis. AB - Trastuzumab, the first targeted antibody against human epidermal growth factor receptor 2 (HER2), has been used to treat gastric cancer patients with HER2 overexpression. However, trastuzumab resistance often occurs following an initial period of benefits, and the underlying mechanisms remain largely unclear. The present study revealed that collagen type IV alpha1 chain (COL4A1), whose expression is upregulated in gastric cancer tissues and trastuzumab-resistant gastric cancer cells, may potentially confer trastuzumab resistance in gastric cancer. By performing bioinformatics analysis of 2 microarray datasets, the present study initially identified COL4A1, overexpressed in gastric cancer tissues and trastuzumab-resistant gastric cancer cells, as a potential candidate for inducing trastuzumab resistance. The drug resistance function of COL4A1 in gastric cancer was then validated by performing protein/gene interactions and biological process annotation analyses, and further validated by analyzing the functionality of microRNAs that target COL4A1 mRNA. Collectively, these data indicated that COL4A1 may confer trastuzumab resistance in gastric cancer. PMID- 29512714 TI - Downregulated CDK10 expression in gastric cancer: Association with tumor progression and poor prognosis. AB - The tumor suppressor characteristics of cyclin-dependent kinase 10 (CDK10) in nasopharyngeal carcinoma and breast cancer have been previously demonstrated. In the present study the expression status of CDK10 and its prognostic significance in gastric cancer was determined, as well as its role in cell proliferation and invasion. Immunoblot analysis revealed that CDK10 protein expression was notably decreased in gastric cancer compared with normal tissues. Immunohistochemistry demonstrated that the loss of CDK10 expression, which was observed in 50.8% of primary gastric cancer tissues (n=128), significantly correlated with advanced tumor stage (P<0.001), frequent lymph node metastasis (P<0.001), distant metastasis (P=0.013), tumor differentiation (P=0.004) and unfavorable overall survival (P<0.001). Multivariate analysis suggested that CDK10 expression may serve as an independent prognostic predictor (P=0.001) for the progression of gastric cancer. In addition, ectopic CDK10 expression inhibited gastric cancer cell proliferation, migration and invasion, while knockdown of CDK10 promoted these phenotypes. Collectively, the results of the present study indicated that CDK10 expression may serve as a novel prognostic biomarker that holds therapeutic promise for gastric cancer. PMID- 29512715 TI - miR-377 targets CUL4A and regulates metastatic capability in ovarian cancer. AB - The incidence and recurrence rates of ovarian cancer are still high, and once the disease metastasizes, it is nearly always fatal. Cullin 4A (CUL4A) serves a significant role in tumourigenesis and tumour progression; however, the effect and mechanisms underlying CUL4A overexpression are still unknown. The role of microRNAs (miRs) in the regulation of metastatic capability in ovarian cancer cell lines was investigated. The interaction between miR-377 and CUL4A was investigated using bioinformatics analyses and dual-luciferase reporter assays. Furthermore, miR-377 mRNA and protein levels were detected using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively and cell migration and invasion were detected using a Transwell assay. Results revealed that CUL4A expression was negatively associated with miR 377 levels in ovarian cancer tissues and cell lines. Through in silico analysis, the targeting effect of miR-377 on CUL4A was verified. Ectopic expression of miR 377 in SKOV3 cells downregulated the level of CUL4A, and significantly reduced the migratory ability of the cells. miR-377 overexpression led to reduced activity of the Wnt/beta-catenin signaling pathway, and regulated the expression of matrix metalloproteinase-2, and 9, and epithelial-mesenchymal transition (EMT) associated protein. These results suggested that miR-377 is a significant negative regulator of CUL4A that controls cancer cell progression in ovarian cancer cell lines. PMID- 29512716 TI - High fish oil diet promotes liver inflammation and activates the complement system. AB - Diets rich in n-3 polyunsaturated fatty acid (n-3 PUFA) fish oil (FO) have beneficial effects in obesity-associated metabolic disease. However, contradictory roles in inflammatory disease intervention have been reported. Our previous work revealed that a high-FO diet promoted myeloid cell differentiation by modifying the bone marrow microenvironment; however, its effects on liver inflammation and complement system activation remain unknown. By performing ELISA, reverse transcription-quantitative polymerase chain reaction, flow cytometry and histology on mice fed with high-FO and low-fat diets, the present study demonstrated that a 4-week high-FO diet promoted liver inflammation in mice without affecting body or liver weight. The livers of high-FO diet mice exhibited increased infiltration of T cells and CD11b+ Gr-1+ myeloid cells. Additionally, a higher level of IL-1beta and MCP-1 mRNA expression was detected, suggesting that the high-FO diet promoted liver inflammation. Further experiments indicated that the high-FO diet increased the total hemolytic complement activity (CH50), promoted the production of the membrane attack complex and increased the levels of various complement proteins in vivo, including complement components C3, C4b, C1qb and factor B. Furthermore, higher concentrations of triglyceride were detected in the peripheral blood of high-FO diet mice, indicating the potential protective roles of n-3 PUFAs in FO against lipotoxicity in hyperlipidemia. Collectively, the present study demonstrated that high FO intake induced inflammation and activated the complement system in the liver. However, further study is required to determine the exact mechanisms. PMID- 29512717 TI - Sodium selenite induces apoptosis and inhibits autophagy in human synovial sarcoma cell line SW982 in vitro. AB - The present study aimed to examine the effects of sodium selenite on the SW982 human synovial sarcoma cell line in relation to cell viability, apoptosis and autophagy. The results indicated that sodium selenite reduced cell viability and induced apoptosis by activating caspase-3 and members of the poly (ADP-ribose) polymerase and Bcl-2 protein families in SW982 cells. Furthermore, autophagy was also suppressed by sodium selenite treatment in SW982 cells, and apoptosis was upregulated in cells co-treated with sodium selenite and the autophagy inhibitor 3-methyladenine. By contrast, apoptosis was downregulated when sodium selenite was combined with rapamycin, an inducer of autophagy. The results indicated that autophagy may protect cells from the cytotoxicity of sodium selenite. The present study results demonstrated that sodium selenite induced apoptosis and inhibited autophagy and autophagy-protected cells from death by antagonizing sodium selenite-induced apoptosis in SW982 cells in vitro. PMID- 29512718 TI - Oxidative damage and mitochondrial injuries differ following pneumoperitoneum pressure in rabbit models of varying degrees of hydronephrosis. AB - The influence of intraabdominal pressure which is necessary to maintain the operating area during the surgery cannot be ignored especially on the kidneys. Many articles have reported the effect of intraabdominal pressure on normal kidneys. However, the influence of intraabdominal pressure on hydronephrosis kidneys is rarely studied. The aim of the present study was to clarify whether intraabdominal pressure tolerance is modified in various degrees of kidney hydronephrosis by evaluating oxidative damage and mitochondrial injuries. A total of 72 rabbits were randomly divided into three groups (groups N, M and S, which represented rabbits with no, mild and severe hydronephrosis, respectively). Rabbits in groups M (n=24) and S (n=24) underwent a surgical procedure inducing mild or severe hydronephrosis, respectively. Subsequently, rabbits in all groups were allocated to 4 subgroups (N0-N3, M0-M3 and S0-S3) consisting of 6 rabbits each. Groups 0 to 3 were, respectively, subjected to intraabdominal pressures of 0, 5, 10 and 15 mmHg. Oxidative damage was assessed by analyzing levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), catalase (CAT) and lactate (LD). Mitochondrial injuries were assessed based on mitochondrial membrane potential (MMP) alterations, mitochondrial structure and cytochrome c (cytc) protein expression, as measured by JC-1 staining, electron microscopy and western blotting, respectively. Oxidative damage and mitochondrial injuries were noticeably exacerbated in group N and M with increased levels of ROS, MDA and LD, decreased levels of SOD, GSH-Px, CAT and MMP, mitochondrial vacuolization and higher expression of cytc when the intraabdominal pressure reached 15 mmHg. In group S, these alterations occurred at pressures of 10 and 15 mmHg. Therefore, it was concluded that in rabbits exposed to pneumoperitoneal pressure, kidneys with severe hydronephrosis were more likely to suffer from oxidative damage and mitochondrial injuries compared with kidneys with mild hydronephrosis and normal kidneys. PMID- 29512719 TI - Neuroprotective effect of berberine agonist against impairment of learning and memory skills in severe traumatic brain injury via Sirt1/p38 MAPK expression. AB - Berberine has multiple clinical applications, including the treatment of tumors, diabetes, cardiovascular diseases, hyperlipidemia, inflammation, bacterial and viral infections, cerebral ischemic injuries, mental diseases, Alzheimer's disease and osteoporosis. In the present study, the neuroprotective effect of berberine agonist rescue learning and memory in severe traumatic brain injury (TBI), and the possible mechanism underlying these observations was explored. The protective effect of berberine agonist significantly recovered learning and memory skills, attenuated brain edema and inhibited matrix metalloproteinase-3 and -9 protein expression in mice with severe TBI. Berberine agonist significantly reduced inflammation, oxidative stress and apoptosis levels in mice with severe TBI. Berberine agonist promoted choline acetyltransferase activity and inhibited the activity of acetylcholinesterase. Collectively, results of the present study revealed that the neuroprotective effect of berberine agonist rescues learning and memory skills in severe TBI. PMID- 29512720 TI - Alogliptin alleviates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease by promoting CPT1a expression via Thr172 phosphorylation of AMPKalpha in the liver. AB - Pioglitazone (PIO) has been reported to be effective for nonalcoholic fatty liver disease (NAFLD) and alogliptin (ALO) may have efficacy against NAFLD progression in patients with type 2 diabetes mellitus (T2DM). The present study examined the effectiveness of ALO in a rodent model of NAFLD and diabetes mellitus. KK-Ay mice were used to produce an NAFLD model via administration of a choline-deficient (CD) diet. To examine the effects of alogliptin, KK-Ay mice were provided with a CD diet with 0.03% ALO and/or 0.02% PIO orally for 8 weeks. Biochemical parameters, pathological alterations and hepatic mRNA levels associated with fatty acid metabolism were assessed. Severe hepatic steatosis was observed in KK Ay mice fed with a CD diet, which was alleviated by the administration of ALO and/or PIO. ALO administration increased the hepatic carnitine palmitoyltransferase 1a (CPT1a) mRNA expression level and enhanced the Thr172 phosphorylation of AMP-activated protein kinase alpha (AMPKalpha) in the liver. PIO administration tended to decrease the hepatic fatty acid synthase mRNA expression level and increase the serum adiponectin level. Homeostasis model of assessment-insulin resistance values tended to improve with ALO and PIO administration. ALO and PIO alleviated hepatic steatosis in KK-Ay mice fed with a CD diet. ALO increased hepatic mRNA expression levels associated with fatty acid oxidation. In addition, the results of the present study suggested that ALO promotes CPT1a expression via Thr172 phosphorylation of AMPKalpha. PMID- 29512721 TI - HIF-1-mediated expression of Foxo1 serves an important role in the proliferation and apoptosis of osteoblasts derived from children's iliac cancellous bone. AB - Activation of the transcription factor hypoxia inducible factor-1alpha (HIF 1alpha) is considered critical for the stimulation of osteogenic markers including runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin, which are closely associated with forkhead boxclass O1 (Foxo1) levels in osteoblasts. The present study explored the associations between HIF 1alpha and Foxo1 in the regulation of cell viability, proliferation and apoptosis of osteoblasts. Osteoblasts obtained from children's iliac cancellous bone were used in the present study, which were confirmed by immunofluorescence staining for the osteoblast marker osteocalcin. The results revealed that the levels of reactive oxygen species and apoptosis were markedly increased in cells with knockdown of HIF-1alpha. By contrast, these were reduced in response to overexpressed HIF-1alpha. In addition, HIF-1alpha overexpression significantly stimulated cell viability, which was suppressed by silencing HIF-1alpha. HIF 1alpha overexpression also significantly increased the transcriptional and translational levels of Foxo1. Conversely, silencing HIF-1alpha markedly suppressed the expression levels of Foxo1. Furthermore, silencing HIF-1alpha reduced the expression of osteogenic markers, including Runx2, ALP and osteocalcin. Runx2 and ALP expression induced by HIF1alpha were markedly reversed by Foxo1 small interfering (si)RNA, whereas osteocalcin was not significantly affected by Foxo1 siRNA. Therefore, the cooperation of and interactions between HIF-1alpha and Foxo1 may be involved in the regulation of osteoblast markers, and serve a pivotal role in the proliferation and apoptosis of osteoblast. The HIF1alpha-induced expression of Runx2 and ALP may be completely dependent on the expression levels of Foxo1, and in turn, osteocalcin may be partially dependent on Foxo1 expression. PMID- 29512722 TI - Expression of immunoglobulin G in human podocytes, and its role in cell viability and adhesion. AB - Podocyte injury occurs during the initiation and development of numerous forms of glomerular disease, and antibodies targeting podocytes have become a biomarker for diagnosis and monitoring treatment response. Accumulating evidence has suggested that immunoglobulin (Ig) is expressed in non-B lineage cells, including epithelial cancer cells, myeloid cells and several types of normal cells. The main aim of the present study was to ascertain the expression of IgG in human podocytes and to determine its potential role in cellular bioactivity. The present study detected positive staining for IgG heavy chain (Iggamma) and its subtype gamma4, and the light chains kappa and lambda in the cytoplasm or on the membrane by immunofluorescence. In addition, positive bands were detected for Iggamma, gamma1, gamma3, gamma4, kappa and lambda in the lysates of a podocyte cell line by western blotting. Mass spectrometry confirmed IgG1 as an intact tetramer in the culture supernatant. Constant region transcripts of Iggamma, gamma1, gamma3, gamma4, kappa and lambda were identified by reverse transcription polymerase chain reaction, and DNA sequencing of these transcripts revealed 96 99% similarity with Ig mRNAs in the National Center for Biotechnology Information database. Compared with the diverse gene rearrangements from B cell-derived Ig, podocyte-derived Ig exhibited conservative V(D)J patterns in the variable regions of Iggamma and kappa chains. Furthermore, the present study investigated the mechanism underlying IgG production in these cells by examining the expression of recombination activating gene (RAG)1, RAG2 and activation-induced cytidine deaminase. The expression levels of these proteins suggested that podocyte derived Ig and traditional Ig may be generated in a similar manner. Furthermore, small interfering RNA-mediated downregulation of IgG expression reduced podocyte viability and adhesive capabilities. These findings suggested that IgG is expressed in podocytes and that this expression may be associated with podocyte function. Due to its potential biological and clinical significance, this phenomenon warrants further investigation. PMID- 29512723 TI - Susceptibilities of epicardial and subcutaneous fat tissue for browning-gene expression and diet-induced volume reduction are different. AB - The upregulation of brown or brown-like beige adipocytes is a potential strategy for the prevention or treatment of diabetes and coronary artery diseases in obese patients. Epicardial adipose tissue (EAT) differs significantly from subcutaneous fat tissue (SAT) in metabolic properties. To investigate properties of EAT further, thermogenesis gene expression was investigated in human autopsy and murine samples, and adipocytes differentiated from EAT mesenchymal cells. Subsequently, analyzed EAT volume alterations were observed to be associated with weight reduction in obese patients by imaging. Gene expression analyses of autopsy samples revealed that UCP-1 mRNA levels in EAT were significantly increased compared with SAT, and beta3-adrenergic receptor (AR) levels tended to be increased; this finding was verified in comparing EAT with SAT in mice. Browning stimulation of human EAT-derived MCs increased uncoupling protein-1 and beta3-AR levels by 3.2 fold- and 12.6-fold compared with SAT-derived MCs, respectively. Subsequent imaging for EAT volume measurement using multi-detector computed tomography in 10 obese patients revealed that mean EAT volumes did not significantly decrease following weight loss therapy. The EAT volume alterations were not correlated with weight changes, whereas positive correlations were observed in SAT and visceral adipose tissue. Therefore, the studies in man and mouse on EAT properties demonstrated that susceptibilities of EAT and SAT for browning-gene expression and diet-induced volume reduction were grossly different. The data suggest a potential association of EAT with local thermogenetic and metabolic homeostasis in cardiac and/or cardiovascular cells, in conjunction with systemic energy metabolism. PMID- 29512724 TI - A novel polysaccharide derived from algae extract inhibits cancer progression via JNK, not via the p38 MAPK signaling pathway. AB - Cancer has long been one of the most malignant diseases worldwide. Processes in cancer cells are often mediated by Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (p38 MAPK) and other signaling pathways. Traditional therapies are often problematic. Recently, a novel polysaccharide derived from algae extract was investigated due to the increasing interest in biological activities of compounds from marine organisms. The effect of this novel polysaccharide on human MKN45 gastric carcinoma cells was determined previously. The current aimed to determine whether the polysaccharide affects other types of cancer, and the deeper mechanisms involved in the process. Human MCF-7 breast cancer cells were used to investigate the novel polysaccharide for its role in the cell growth and migration, and determine the mechanisms affected. MTT assay, nuclear staining and fluorescence activated cell sorting analysis demonstrated that the novel polysaccharide reduced the viability of MCF-7 cells by inducing cell apoptosis and arresting the cells at G2/M phase. Results of western blot analysis demonstrated that phosphorylation of JNK and expression of p53, caspase 9 and caspase-3 were upregulated in the polysaccharide-treated MCF-7 cells. SP600125, an inhibitor of JNK, maintained MCF-7 cell viability, prevented cell apoptosis and cycle arrest, and downregulated the polysaccharide-induced protein phosphorylation/expression. However, a migration assay demonstrated that the novel polysaccharide did not change the migration of MCF-7 cells, as well as the expression of p38 MAPK, and matrix metalloproteinase-9 and -2. Taken together, the current study demonstrated that the novel polysaccharide suppressed cancer cell growth, induced cancer cell apoptosis and cell cycle arrest via JNK signaling, but had no effect on cancer cell migration and p38 MAPK signaling. PMID- 29512725 TI - ML-7 attenuates airway inflammation and remodeling via inhibiting the secretion of Th2 cytokines in mice model of asthma. AB - Previous studies have indicated that smooth muscle myosin light chain kinase (MLCK) has a prominent role in the regulation of smooth muscle contraction, which tends to be upregulated in asthma. In recent years, numerous studies have reported that MLCK is intimately connected with the immunoregulatory mechanism of T cells. The imbalance of T helper type 1 cells (Th1)/Th2 constitutes the immune associated pathological basis of chronic asthma. Th2-associated cytokines, including interleukin-4, -5, -13, -25 and -33, are involved in airway inflammation, hyperresponsiveness and remodeling, which leads to a progressive decline in lung function. The purpose of the present study was to verify whether inhibition of bronchial MLCK attenuated the expression Th2-associated cytokines in asthmatic mice, including the above-mentioned ones. Female BALB/c mice were used to establish an ovalbumin (OVA)-induced model of asthma, of which one group was treated with the MLCK inhibitor (5-iodonaphthalene-1-sulfonyl) homopiperazine (ML-7). The inhibitor of MLCK, ML-7 attenuated airway inflammation and remodeling by reducing inflammatory cell infiltration and the secretion of Th2 cytokines in mice model of asthma, which may represent a promising therapeutic strategy for asthma. PMID- 29512726 TI - Ginsenoside Rg1 ameliorates testicular senescence changes in D-gal-induced aging mice via anti-inflammatory and antioxidative mechanisms. AB - With the growing population, aging, extended lifespans and anti-aging have become popular areas of research in the life and social sciences. With increasing age, the structure and function of the testes, the spermatogenetic and androgen producing organ in the male reproductive system, gradually declines. Ginsenoside Rg1 is an extract of Panax ginseng in traditional Chinese medicine. The extract facilitates anti-aging through its anti-inflammatory and antioxidant properties. However, it has not been reported whether ginsenoside Rg1 delays testicular aging. The present study established D-galactose (D-gal)-induced aging mouse models to examine the protective effects of ginsenoside Rg1 on the structure and function of the testes, and the underlying mechanism. A total of 60 healthy specific pathogen-free male C57BL/6 mice were randomly divided into four groups: Control group; Rg1 group; D-gal + Rg1 group; and D-gal group. The tissues of the mice were used for further experiments. The present study further investigated the effects of Rg1 on the volume of serum testosterone, the testicular index, testicular microscopic structures, the senescence of spermatogenetic cells, the apoptosis of spermatogenetic cells, the activity of the antioxidant enzymes, the levels of inflammatory cytokines, and the levels of S-phase kinase-associated protein (p19), cyclin-dependent kinase inhibitor 1 (p21) and cellular tumor antigen p53 (p53) in D-gal-induced aging mice. In general, compared with the D gal group, the treatment of Rg1 increased the testis index, serum testosterone level and the active content of superoxide dismutase and the total antioxidant capacity. The percentage of senescence-associated beta-galactosidase-positive cells, the level of apoptosis and the volume of methane dicarboxylic aldehyde, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6 in testicular tissues were significantly decreased, and the expression of p19, p53 and p21 was downregulated due to the treatment with Rg1. The results of the present study demonstrated that ginsenoside Rg1 was able to protect the testes against D-gal induced aging in mice. In addition, the protective effect of Rg1 may be achieved via antioxidation and downregulation of the p19/p53/p21 signaling pathway. PMID- 29512727 TI - Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC), defined as breast cancer lacking estrogen- and progesterone-receptor expression and human epidermal growth factor receptor 2 (HER2) amplification, is a heterogeneous disease. RNA-sequencing analysis of 15 TNBC specimens and The Cancer Genome Atlas-TNBC dataset analysis identified the frequent downregulation of leucine-rich repeat-containing 26 (LRRC26), which negatively regulates nuclear factor-kappaB (NF-kappaB) signaling, in TNBC tissues. Quantitative polymerase chain reaction and bisulfite pyrosequencing analyses revealed that LRRC26 was frequently silenced in TNBC tissues and cell lines as a result of promoter methylation. LRRC26 expression was restored by 5 aza-2'-deoxycytidine (5'-aza-dC) treatment in HCC1937 TNBC cells, which lack LRRC26 expression. Notably, small interfering RNA-mediated knockdown of LRRC26 expression significantly enhanced the anchorage-independent growth, invasion and migration of HCC70 cells, whereas ectopic overexpression of LRRC26 in BT20 cells suppressed their invasion and migration. Conversely, neither knockdown nor overexpression of LRRC26 had an effect on cell viability in the absence of tumor necrosis factor-alpha (TNF-alpha) stimulation. Meanwhile, overexpression of LRRC26 caused the reduction of TNF-alpha-mediated NF-kappaB luciferase reporter activity, whereas depleting LRRC26 expression resulted in the upregulation of TNF alpha-mediated NF-kappaB downstream genes [interleukin-6 (IL-6), IL-8 and C-X-C motif chemokine ligand-1]. Taken together, these findings demonstrate that LRRC26 is frequently downregulated in TNBC due to DNA methylation and that it suppresses the TNF-alpha-independent anchorage-independent growth, invasion and migration of TNBC cells. Loss of LRRC26 function may be a critical event in the aggressiveness of TNBC cells through a TNF-alpha/NF-kappaB-independent mechanism. PMID- 29512728 TI - Comparison of the common bacteria in human and mouse tumours using high throughput sequencing. AB - Evidence has indicated that gut bacteria may serve an important role in cancer development and therapy, while little work has been done to explore the microbial diversity inside tumours. In the present study, high-throughput sequencing was first used to identify and compare the microbial diversity in human and mouse tumours. Principal component analysis (PCA) and beta-diversity indicated a low microbial similarity among mouse artificial tumours (M.AT group), mouse spontaneous tumours (M.T group) and human tumours (H.T group), and Serratia (35.85 vs. 32.64 vs. 73.32%), Pseudomonas (24.10 vs. 16.62 vs. 1.72%) and Ochrobactrum (6.28 vs. 11.08 vs. 11.90%) were identified as dominant bacteria at the genus level. In addition, Venn results indicated 103 common operational taxonomic units (OTUs) in the M.AT, M.T and H.T groups, and only 2 and 1 OTUs belonged to Lactobacillus and Escherichia, respectively, while no OTUs belonging to Salmonella, Bifidobacteria or Clostridium were identified. In the present study, the common bacteria between human and mouse tumours were identified, which may serve as potential strains for bacteriotherapy of cancers. PMID- 29512729 TI - Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-kappaB pathway in pancreatic cancer cells. AB - Curcumin is a natural polyphenol compound derived from turmeric. It possesses multiple pharmacological properties, including antioxidant, anti-inflammatory and anti-tumor progression properties. Our recent study demonstrated that superoxide dismutase (SOD)-dependent production of hydrogen peroxide (H2O2) promoted the invasive and migratory activity of pancreatic cancer cells. However, whether curcumin suppresses SOD-induced cancer progression and the related mechanisms remains unclear. Since epithelial-to-mesenchymal transition (EMT) plays a key role in tumor metastasis, the aim of the present study was to examine whether curcumin intervenes with SOD-induced EMT in pancreatic cancer and the underlying mechanism. The human pancreatic cancer cells BxPC-3 and Panc-1 were exposed to SOD in the presence or absence of curcumin, catalase (CAT, a scavenger of H2O2), or LY 294002 [a phosphoinositide-3 kinase (PI3K) inhibitor]. Intracellular reactive oxygen species (ROS) and H2O2 were evaluated by 2,7 dichlorodihydrofluorecein diacetate and H2O2 assay, respectively. The activation of p-Akt and p-nuclear factor (NF)-kappaB were examined by western blotting. The migratory and invasive abilities of pancreatic cancer cells were tested by the wound healing and Transwell invasion assays. The expression of E-cadherin, N cadherin and vimentin (EMT-related genes) were measured by reverse transcription quantitative polymerase chain reaction and western blotting at the mRNA and protein levels, respectively. The findings of the present study demonstrated that curcumin decreased SOD-induced production of ROS and H2O2 in BxPC-3 and Panc-1 cells. Curcumin was able to suppress SOD-induced invasion and migration, and it also regulated the expression of the above-mentioned EMT-related genes and cell morphology. SOD-induced cell invasion was also inhibited by catalase and LY 294002. Furthermore, the levels of p-Akt and p-NF-kappaB caused by SOD could be offset by treatment with curcumin and LY 294002. To summarize, these results demonstrated that curcumin was able to prevent SOD-driven H2O2-induced pancreatic cancer metastasis by blocking the PI3K/Akt/NF-kappaB signaling pathway. The use of curcumin to inhibit the H2O2/Akt/NF-kappaB axis may be a promising therapeutic approach to the treatment of patients with pancreatic cancer. PMID- 29512730 TI - PTBP1 knockdown in renal cell carcinoma inhibits cell migration, invasion and angiogenesis in vitro and metastasis in vivo via the hypoxia inducible factor 1alpha pathway. AB - Polypyrimidine tract-binding protein 1 (PTBP1), a heterogeneous nuclear ribonucleoprotein, is a multi-functional RNA-binding protein. PTBP1 participates in a number of biological processes, including maintaining cell structure and motility, immunity, protein metabolism and the cell cycle. The present study aimed to investigate the association between PTBP1 expression and the prognosis and clinicopathological characteristics of patients with renal cell cancer (RCC). The potential mechanism of action of PTBP1 in the metastasis of RCC was also investigated. The results demonstrated that PTBP1 was overexpressed in RCC tissues compared with normal renal tissues. Furthermore, PTBP1 expression was negatively associated with patient prognosis and positively associated with tumor size, pathological tumor (pT) and pathological metastasis (pM) status and tumor lymph node metastasis (TNM) stage. PTBP1 knockdown in vitro inhibited RCC cell migration, invasion, proliferation and angiogenesis, and it was demonstrated that PTBP1 affected RCC cells primarily via the hypoxia inducible factor-1alpha pathway. Furthermore, PTBP1 knockdown decreased RCC lung metastasis in vivo. The present study demonstrated that PTBP1 knockdown suppresses tumor progression and metastasis, indicating that PTBP1 is an important prognostic factor in RCC and that it may be developed as a novel method of treating patients with RCC. PMID- 29512731 TI - The mRNA, miRNA and lncRNA networks in hepatocellular carcinoma: An integrative transcriptomic analysis from Gene Expression Omnibus. AB - Research advances and analysis in the non-protein coding part of the human genome have suggested that microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are associated with tumor initiation, growth and metastasis. Accumulating studies have demonstrated that a class of miRNAs and lncRNAs are dysregulated in hepatocellular carcinoma (HCC) and closely associated with tumorigenesis, diagnosis and prognosis. In the present study, integrative analysis of published data on multi-level Gene Expression Omnibus (GEO) and a bioinformatics computational approach were used to predict regulatory mechanism networks among differentially expressed mRNAs, miRNAs, and lncRNAs. Firstly, nine microarray expression data sets of mRNAs, miRNAs, and lncRNAs associated with HCC were collected from GEO datasets. Secondly, a total of 628 mRNAs, 15 miRNAs, and 49 lncRNAs were differentially expressed in this integrative analysis. Following this, mRNA, miRNA and lncRNA regulatory or co-expression networks were constructed. From the construction of the regulatory networks, five miRNAs and ten lncRNAs were identified as key differentially expressed noncoding RNAs associated with HCC progression. Finally, the regulatory effects of ten lncRNAs and miRNAs were validated. The study provides a novel insight into the understanding of the transcriptional regulation of HCC, and differentially expressed lncRNAs targeted and regulated by miRNAs were identified and validated in HCC specimens and cell lines. PMID- 29512733 TI - Autophagy inhibition enhanced 5-FU-induced cell death in human gastric carcinoma BGC-823 cells. AB - The exact molecular mechanism of 5-fluorouracil (5-FU) in human gastric cancer cells remains to be elucidated. Cultured BGC-823 human gastric carcinoma and AGS cell lines were treated with 5-FU. Autophagosome formation was investigated through multiple approaches, including the quantification of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (LC3) puncta, LC3 conversion and electron microscopy observations. Additionally, autophagy was inhibited using 3-methyladenine (3-MA) and beclin-1 ablation, to determine its role in 5-FU-mediated cell death. In addition, the present study assessed alterations in sirtuin expression following 5-FU treatment with reverse transcription-quantitative polymerase chain reaction. 5-FU treatment induced apoptosis and inhibited proliferation in BGC-823 and AGS gastric cancer cells. It is of note that the 5-FU treatment only promoted autophagy in BGC-823 cells. Additionally, inhibition of autophagy by either 3-MA or beclin-1 ablation increased 5-FU-induced cell death in BGC-823 cells. The present study quantified changes in sirtuin (SIRT1, SIRT3, SIRT5, and SIRT6) expression following 5-FU treatment and using a specific inhibitor, sirtinol, the present study investigated their involvement in 5-FU-mediated autophagy. Autophagy inhibition through manipulation of sirtuin proteins may increase the therapeutic efficacy of the 5-FU chemotherapeutic drug against gastric carcinoma. PMID- 29512732 TI - Construction of a ceRNA network reveals potential lncRNA biomarkers in rectal adenocarcinoma. AB - Competing endogenous RNAs (ceRNAs) render the functions of long non-coding RNAs (lncRNAs) more complicated during cancer processes. Potential lncRNA biomarkers and their roles as ceRNAs have not been clearly described for rectal adenocarcinoma (READ). In the present study, we extracted data from The Cancer Genome Atlas (TCGA) including data from 167 tumor samples and 10 adjacent non tumor samples. A total of 202 lncRNAs, 190 microRNAs (miRNAs) and 1,530 mRNAs were identified as READ-specific RNAs [log2(fold-change)>2, FDR<0.01]. The Gene Ontology (GO) biological processes and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways were analysed for 1,530 specific mRNAs. Among 202 READ specific lncRNAs, 7 lncRNAs were identified as being associated with overall survival of READ patients. Then, a ceRNA network was constructed with 34 key lncRNAs, 25 miRNAs and 65 mRNAs. A total of 7 lncRNAs from the network were revealed to be linked to clinical features. The results of qRT-PCR ascertained that our analysis was credible. Overall, this research provides a novel perspective from which to study the lncRNA-related ceRNA network in READ and assists in the identification of new potential biomarkers to be used for diagnostic and prognostic purposes. PMID- 29512734 TI - miR-3147 serves as an oncomiR in vulvar squamous cell cancer via Smad4 suppression. AB - The incidence of vulvar squamous cell carcinoma (VSCC) has increased annually over the last decade. MicroRNAs (miRNAs/miRs) serve an important role in tumor progression and development. Our previous microarray studies have revealed that miR-3147 was overexpressed in VSCC. However, its function and underlying mechanism in VSCC remain unknown. In the present study, it was confirmed by reverse transcription-quantitative polymerase chain reaction that the expression of miR-3147 was markedly upregulated in VSCC tissues. The increased expression of miR-3147 was positively associated with the depth of invasion. The overexpression of miR-3147 resulted in the promotion of vulvar cancer cell proliferation, migration, invasion, G1/S progression and invasion-associated gene expression. miR-3147 may participate in the process of epithelial-mesenchymal transition and reduce the expressions of downstream target genes in the transforming growth factor-beta/Smad signaling pathway in A431 cells. The knockdown of Smad4 by small interfering RNA promoted malignant behaviours in A431 cells. In addition, miR 3147 regulated Smad4 by directly binding to its 3' untranslated region. In conclusion, the results indicated that miR-3147 may serve an oncogenic role in VSCC by targeting Smad4. miR-3147 may represent a novel potential therapeutic target marker for VSCC. PMID- 29512735 TI - The role of molecular breast imaging in predicting complete tumor response to treatment and residual tumor extent following neoadjuvant therapy. AB - The aim of the present study was to investigate the usefulness of molecular breast imaging (MBI) in predicting complete tumor response to treatment and residual tumor extent following neoadjuvant therapy. A consecutive series of 43 female patients with large or locally advanced primary breast cancer, scheduled for surgery following neoadjuvant therapy, was retrospectively reviewed. Prior to surgery, all patients underwent MBI using a high-resolution semiconductor-based device for image acquisition. MBI data were correlated with surgical histopathological findings. Spearman's correlation coefficient was calculated to assess differences in residual tumor size with MBI and histopathological examination. From the images obtained using MBI, 7 patients were negative for residual tumors with pathological complete response (specificity, 100%) and positive in 34/36 patients with residual disease (sensitivity, 94.4%), including 26/27 patients with unifocal and 8/9 patients with multicentric/multifocal tumors, 5 of which exhibited multiple microscopic foci scattered in a fibrotic area. Overall accuracy was 95.3% and the positive predictive value (PPV) and negative predictive value (NPV) were 100 and 77.8%, respectively. MBI was false negative in one patient with a 2.5-cm invasive ductal carcinoma located close to the chest wall and in one patient with microscopic foci of epithelial carcinoma. In the patients with unifocal residual tumors, correlation of tumor size between MBI and histopathology was r=0.981 (P<0.0001); however, MBI overestimated the number of lesions in one of these cases. In the patients with multifocal/multicentric tumors, MBI adequately assessed residual tumor extent in 5/8 positive cases, overestimating the number of lesions in one case and underestimating tumor extent in 2 further cases with microscopic foci scattered in a fibrotic area. MBI proved to be a highly accurate diagnostic tool in predicting complete tumor response to neoadjuvant therapy and residual tumor extent, correlating with surgical histopathological findings in 86% of overall cases. A positive result was always associated with the presence of residual disease and MBI tumor size was strongly correlated with histopathological analysis mainly in unifocal residual tumors. PMID- 29512736 TI - Development of podophyllotoxin-loaded nanostructured lipid carriers for the treatment of condyloma acuminatum. AB - Condyloma acuminatum (CA) is a common sexually transmitted disease caused by human papillomavirus (HPV). Podophyllotoxin (POD), a cytotoxic compound, is able to effectively treat HPV; however, the severe irritation side effects of POD restrict its use as a treatment for CA. The aim of the present study was to construct novel POD-loaded nanostructured nanolipid carriers (POD-NLCs) and evaluate their physicochemical characteristics and cytotoxicity. POD-NLCs (0.5%) were prepared using emulsion-evaporation and low temperature-solidification methods with optimized conditions and preparations. Subsequently, the POD-NLCs were physicochemically characterized and their in vitro and in vivo release efficiencies and in vitro cytotoxicity were studied. The prepared POD-NLCs had an average particle size, zeta potential, polydispersity index and encapsulation efficacy of 178.5+/-20 nm, -27+/-0.5 mV, 0.18+/-0.01 and 82.9+/-2%, respectively. In vitro and in vivo release studies demonstrated that POD-NLCs are able to provide sustained drug delivery for 72 h in vitro and 10 h in the mucosa. Compared with a tincture formulation of POD (POD-T), POD-NLC induced less inflammatory cytokine production in the cervical mucous and led to a decreased histopathological score. In addition, a cytotoxicity assay demonstrated that inhibition of the POD-NLCs was 98.4% at 24 h and remained >98% up to 72 h. Furthermore, more cells were arrested in the G2/M phase of the cell cycle following POD-NLC treatment compared with the POD-T treatment. The present study provides evidence that POD-NLC is a promising delivery system for the treatment of CA. PMID- 29512737 TI - Overexpression of adrenomedullin protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the Akt/GSK3beta and Bcl-2 signaling pathways. AB - The poor survival rate of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Adrenomedullin (ADM) has been identified as a potent apoptotic inhibitor. The present study aimed to investigate the protective effects of ADM on MSCs against hypoxia and serum deprivation (H/SD)-induced apoptosis, and to determine the potential underlying mechanisms. In the present study, a recombinant adenovirus expressing the ADM gene was established and was infected into MSCs. The infection rate was determined via microscopic detection of green fluorescence and flow cytometric analysis. The mRNA expression levels of ADM were detected by reverse transcription-polymerase chain reaction. In addition, a model of H/SD was generated. The MSCs were randomly separated into six groups: Control, enhanced green fluorescent protein (EGFP)-Adv, EGFP-ADM, H/SD, EGFP-Adv + H/SD and EGFP ADM + H/SD. Cell viability and proliferation were determined using the Cell Counting kit-8 assay. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated-dUTP nick-end labeling assay and flow cytometric analysis using Annexin V-phycoerythrin/7-aminoactinomycin D staining. The protein expression levels of total protein kinase B (Akt), phosphorylated (p)-Akt, total glycogen synthase kinase (GSK)3beta, p-GSK3beta, B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), caspase-3 and cleaved caspase-3 were detected by western blot analysis. The results indicated that ADM overexpression could improve MSC proliferation and viability, and protect MSCs against H/SD-induced apoptosis. In addition, ADM overexpression increased Akt and GSK3beta phosphorylation, and Bcl-2/Bax ratio, and decreased the activation of caspase-3. These results suggested that ADM protects MSCs against H/SD-induced apoptosis, which may be mediated via the Akt/GSK3beta and Bcl-2 signaling pathways. PMID- 29512738 TI - Poly(ADP-ribose) polymerase inhibitor olaparib hampers placental growth factor driven activation of myelomonocytic cells. AB - The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor activated by the angiogenic factors VEGF-A and placental growth factor (PlGF). While VEGF-A binds to both VEGFR-1 and VEGFR-2, PlGF interacts exclusively with VEGFR-1 triggering a signaling pathway involved in: i) tumor associated angiogenesis; ii) chemotaxis and invasion of the extracellular matrix (ECM) by cancer cells; and iii) mobilization of bone marrow-derived myeloid cells that generate tumor-associated macrophages. By using a novel anti-VEGFR-1 monoclonal antibody (D16F7 mAb), which hampers receptor activation without avoiding ligand binding, we recently demonstrated that VEGFR-1 blockade reduced myeloid progenitor mobilization and monocyte/macrophage cell infiltration of tumor grafts in vivo. Since poly(ADP-ribose) polymerase (PARP)-1 exerts a pro inflammatory role favoring monocyte activation, in the present study we investigated whether the PARP inhibitor (PARPi) olaparib hampers PlGF-induced activation of human myelomonocytic cells. HL-60 cells induced to differentiate towards the monocytic/macrophage lineage were tested and the results were confirmed in freshly isolated monocytes obtained from healthy donors. Cells were treated with olaparib, at clinically achievable concentrations, before exposure to PlGF and were analyzed for migration and ECM invasion in response to PlGF. Olaparib effects were compared to those obtained with D16F7 mAb used as single agent or in combination with the PARPi. The results indicate that differentiated HL-60 cells and monocytes expressed VEGFR-1 and migrated in response to PlGF. Moreover, olaparib and D16F7 inhibited PlGF-induced chemotaxis and ECM invasion in a dose-dependent manner and with similar efficacy. However, in combination studies the PARPi and D16F7 did not exert synergistic effects. Olaparib also hampered PlGF-induced monocyte adhesion to fibronectin, while it did not affect NF-kappaB activation in response to the angiogenic factor. These data suggest that olaparib likely interferes with the same pathway affected by the anti-VEGFR 1 mAb and that inhibition of PlGF-induced monocyte activation may contribute to PARPi antitumor activity. PMID- 29512739 TI - [6]-Gingerol enhances the radiosensitivity of gastric cancer via G2/M phase arrest and apoptosis induction. AB - Ionizing radiation (IR) is the main modality for locoregional control of unresectable gastric cancer (GC). [6]-Gingerol is an active major phenolic compound isolated from ginger (Zingiber officinale Roscoe), and it has been demonstrated to possess antitumor activity in previous studies. In the present study, we aimed to evaluate the potential activity of [6]-gingerol as a radiosensitizer and to further explore the underlying mechanism. A CCK-8 assay revealed that [6]-gingerol inhibited the cell viability of HGC-27 cells in a dose dependent manner (P<0.05). Colony formation assay indicated that pretreatment of [6]-gingerol prior to IR decreased the clonogenic survival of HGC-27 cells. Notably, the combination of [6]-gingerol with IR enhanced IR-induced cell cycle arrest at the G2/M phase compared with IR alone (41.3% in IR alone vs. 53.5% in [6]-gingerol+IR; P=0.006), and increased IR-induced apoptosis compared with IR alone (9.6% in IR alone group vs. 15.1% in [6]-gingerol+IR; P=0.07). DAPI staining detected the apoptotic nuclear morphological changes in the cells treated with [6]-gingerol and/or IR. Furthermore, western blotting and qRT-PCR revealed that [6]-gingerol pretreatment following IR downregulated the protein expression of cyclin B1, cyclin A2, CDC2 and cyclin D1, upregulated the mRNA expression of p27, and induced active caspase-9, active caspase-3 and cytochrome c. In conclusion, the present study demonstrated that [6]-gingerol enhanced radiosensitivity of GC cells, and that the mechanisms involved at least G2/M phase arrest and apoptosis induction. PMID- 29512740 TI - Programmed cell death 4 overexpression enhances sensitivity to cisplatin via the JNK/c-Jun signaling pathway in bladder cancer. AB - The aim of the present study was to evaluate the effects of programmed cell death 4 (PDCD4) on cell proliferation and apoptosis, and to elucidate the potential role of the Jun N-terminal kinase (JNK)/c-Jun pathway in human bladder cancer (BCa) cells. Mixed BCa cells were transfected with plasmids containing PDCD4 (PDCD4-pcDNA3). The sensitivity to cisplatin was analyzed using cell viability, invasion/migration, apoptosis, flow cytometry, wound healing and Transwell assays at different transfection times. Furthermore, epithelial-to-mesenchymal transition (EMT) markers were detected by immunofluorescence staining, and the protein expression of c-Jun, and phosphorylated Jun N-terminal kinase (p-JNK) and c-Jun (p-c-Jun, Ser-73) were also tested using western blotting. It was observed that BCa cell proliferation and invasion and tumor growth were significantly inhibited, whereas apoptosis was enhanced in PDCD4-transfected cells treated with cisplatin compared with controls. Moreover, the western blotting and immunofluorescence results demonstrated that PDCD4 upregulated the expression of epithelial cell markers, but downregulated the expression of mesenchymal cell markers. Furthermore, overexpression of PDCD4 reduced the protein levels of p-JNK and p-c-Jun. Taken together, the findings of the present study indicate that PDCD4 enhances the sensitivity of BCa cells to cisplatin, partially via regulation of the JNK/c-Jun pathway, and reverses EMT. In conclusion, the results of the present study suggested that PDCD4, a nuclear/cytoplasmic shuttling protein with multiple functions, plays an important role in the development and progression of human BCa. PMID- 29512741 TI - Macrophage migration inhibitory factor antagonist (S,R)3-(4-hydroxyphenyl)-4,5 dihydro-5-isoxazole acetic acid methyl ester attenuates inflammation and lung injury in rats with acute pancreatitis in pregnancy. AB - Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine involved in many acute and chronic inflammatory diseases. However, its role in acute lung injury associated with acute pancreatitis in pregnancy (APIP) has not yet been elucidated. The present study was undertaken to clarify the effect and potential mechanism of MIF antagonist (S,R)3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) in the development of acute lung injury in rats with APIP. Eighteen late-gestation SD rats were randomly assigned to three groups: Sham operation (SO) group, APIP group, and ISO-1 group. All the rats were sacrificed 6 h after modeling. The severity of pancreatitis was evaluated by serum amylase (AMY), lipase (LIPA), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 and assessing the histopathological score. Lung injury was determined by performing histology and inflammatory cell infiltration investigations. Western blot analysis was used to detect the protein expression of MIF, phosphorylated and total P38 and nuclear factor-kappaB (NF-kappaB) protein in lungs. The results showed that MIF was upregulated in the lung of APIP rats. Compared with APIP group, the intervention of ISO-1 alleviated the pathological injury of the pancreas and lungs, decreased serum AMY and LIPA, attenuated serum concentrations of TNF-alpha, IL-1beta, and IL-6, reduced the number of MPO-positive cells in the lung and inhibited the activation of P38MAPK and NF-kappaB. These results suggest that MIF is activated in lung injury induced by APIP. Furhtermore, the present findings indicate that the MIF antagonist ISO-1 has a protective effect on lung injury and inflammation, which may be associated with deactivating the P38MAPK and NF-kappaB signaling pathway. PMID- 29512742 TI - Mangiferin induces islet regeneration in aged mice through regulating p16INK4a. AB - Previous studies by our group on mangiferin demonstrated that it exerts an anti hyperglycemic effect through the regulation of cell cycle proteins in 3-month old, partially pancreatectomized (PPx) mice. However, beta-cell proliferation is known to become severely restricted with advanced age. Therefore, it is unknown whether mangiferin is able to reverse the diabetic condition and retain beta-cell regeneration capability in aged mice. In the present study, 12-month-old C57BL/6J mice that had undergone PPx were subjected to mangiferin treatment (90 mg/kg) for 28 days. Mangiferin-treated aged mice exhibited decreased blood glucose levels and increased glucose tolerance, which was accompanied with higher serum insulin levels when compared with those in untreated PPx control mice. In addition, islet hyperplasia, elevated beta-cell proliferation and reduced beta-cell apoptosis were also identified in the mice that received mangiferin treatment. Further studies on the mRNA transcript and protein expression levels indicated comparatively increased levels of cyclins D1 and D2 and cyclin-dependent kinase 4 in mangiferin-treated mice, while the levels of p27Kip1 and p16INK4a were decreased relative to those in the untreated PPx controls. Of note, mangiferin treatment improved the proliferation rate of islet beta-cells in adult mice overexpressing p16INK4a, suggesting that mangiferin induced beta-cell proliferation via the regulation of p16INK4a. In addition, the mRNA transcription levels of critical genes associated with insulin secretion, including pancreatic and duodenal homeobox 1, glucose transporter 2 and glucokinase, were observed to be upregulated after mangiferin treatment. Taken together, it was indicated that mangiferin treatment significantly induced beta-cell proliferation and inhibited beta-cell apoptosis by regulating cell cycle checkpoint proteins. Furthermore, mangiferin was also demonstrated to regulate genes associated with insulin secretion. Collectively these, results suggest the therapeutic potential of mangiferin in the treatment of diabetes in aged individuals. PMID- 29512743 TI - Leigh syndrome T8993C mitochondrial DNA mutation: Heteroplasmy and the first clinical presentation in a Vietnamese family. AB - Leigh syndrome is a rare inherited, heterogeneous and progressive neurometabolic disorder that is mainly caused by specific mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). The present study reported a case of childhood Leigh syndrome with a point mutation at bp 8,993 in the mitochondrial ATPase6 gene. A 21-month-old male child had developed epilepsy, muscular weakness and vomiting, which was accompanied by high fever. Magnetic resonance imaging indicated typical characteristics of Leigh syndrome, including a symmetric abnormal signal in the dorsal medulla oblongata and Sylvian fissure enlargement in association with an abnormal signal in the periventricular white matter and in the putamina and caudate heads. The diagnosis was further supported with genetic tests including polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), sequencing, and quantitative PCR. The patient was found to carry a mitochondrial T8993C (m.T8993C) mutation in peripheral blood with 94.00+/-1.34% heteroplasmy. Eight of his relatives were also subjected to quantification of the m.T8993C mutation. The percentages of heteroplasmy in samples taken from the grandmother, mother, aunt, cousin 1, and cousin 2 were 16.33+/-1.67, 66.81+/-0.85, 71.66+/ 3.22, 87.00+/-1.79, and 91.24+/-2.50%, respectively. The mutation was not found in samples taken from the father, the husband of the aunt, or the grandfather of the patient. The obtained data showed that the mutation was maternally inherited and accumulated through generations. Even though the heteroplasmy levels of his mother, aunt, cousin 1, and cousin 2 were relatively high (66.81-91.24%), they remained asymptomatic, indicating that the threshold at which this mutation shows effects is high. To the best of our knowledge, this is the first report of a case of Leigh syndrome in a Vietnamese individual harboring a mtDNA mutation at the 8,993 bp site, and showing a correlation between the heteroplasmy and clinical phenotype. These findings may be useful in helping to improve the clinical diagnosis and treatment of Leigh syndrome. PMID- 29512744 TI - Therapeutic effects of antimicrobial peptide on malignant ascites in a mouse model. AB - The primary objective of the treatment of malignant ascites in advanced stages is to alleviate symptoms using procedures such as diuresis, paracentesis of subretinal fluid and vena cava anastomosis. The effectiveness of systemic or intraperitoneal chemotherapy treatment is limited, and more efficacious therapies are required. The authors of the present study demonstrated that an antimicrobial peptide, cecropinXJ, isolated from the larvae of Bombyx mori, selectively inhibits the proliferation of gastric cancer cells. However, the effects of antibacterial peptides on gastric ascites tumor remains unclear. In the present study, the therapeutic effects of cecropinXJ were investigated in mice bearing malignant ascites. Compared with bovine serum albumin treatment, cecropinXJ and doxorubicin (Dox) significantly inhibited the formation and growth of malignant ascites, and prolonged the survival time of ascites tumor-bearing mice. In addition, cecropinXJ treatment normalized the hematological and biochemical phenotypes, induced tumor cell apoptosis in ascites and improved the survival of mice bearing malignant ascites when compared with Dox treatment. These results suggested that cecropinXJ might be a promising therapeutic candidate for the treatment of gastric cancer-associated ascites. PMID- 29512745 TI - Tumor necrosis factor-alpha downregulates the REIC/Dkk-3 tumor suppressor gene in normal human skin keratinocytes. AB - Our previous studies revealed that REIC/Dkk-3 was expressed various tissues, including skin keratinocytes. The aim of the present study was to identify the factors that regulate the expression of the dickkopf Wnt signaling pathway inhibitor 3 (REIC/Dkk-3) tumor suppressor gene in normal human skin keratinocytes (NHKs). Several growth factors and cytokines that have previously been reported to be involved in the growth and differentiation of keratinocytes were screened as potential regulators. Western blot analysis was performed using protein from NHKs cultured with/without various factors including the epidermal growth factor, tumor necrosis factor-alpha, transforming growth factor-beta, interleukin (IL) 1F9, IL-6, IL-8 and Ca2+. The results indicated that only TNF-alpha downregulated REIC/Dkk-3 expression in NHKs. Subsequently, TNF-alpha was confirmed to reduce the expression levels of REIC/Dkk-3 in mouse skin tissue and hair culture models. TNF-alpha-mediated downregulation of REIC/Dkk-3 expression in NHKs was abrogated by the addition of a TNF-alpha-specific antibody. In conclusion, the results indicate that TNF-alpha downregulates REIC/Dkk-3 expression in normal skin keratinocytes. PMID- 29512747 TI - Isolation, culture and biological characteristics of multipotent porcine tendon derived stem cells. AB - Tendon-derived stem cells (TDSCs), a postulated multi-potential stem cell population, play significant role in the postnatal replenishment of tendon injuries. However, the majority of experimental materials were obtained from horse, rat, human and rabbit, but rarely from pig. In this research, 1-day-old pig was chosen as experimental sample source to isolate and culture TDSCs in vitro. Specific markers of TDSCs were then characterized by immunofluorescence and reverse transcription polymerase chain reaction (RT-PCR) assays. The results showed that TDSCs could be expanded for 11 passages in vitro. The expression of specific markers, such as collagen I, collagen III, alpha-smooth muscle actin (alpha-SMA), CD105 and CD90 were observed by immunofluorescence and RT-PCR. TDSCs were induced to differentiate into adipocytes, osteoblasts and chondrocytes, respectively. These results suggest that TDSCs isolated from porcine tendon exhibit the characteristics of multipotent stem cells. TDSCs, therefore, may be potential candidates for cellular transplantation therapy and tissue engineering in tendon injuries. PMID- 29512748 TI - miR-130b promotes bladder cancer cell proliferation, migration and invasion by targeting VGLL4. AB - Bladder cancer (BCa) is the most common urological cancer, and more and more evidence suggests that microRNAs (miRNAs) play an important role in BCa pathogenesis. Aberrant miR-130b expression has been reported in several types of cancers. The aim of the present study was to elucidate the effects of miR-130b on BCa progression. miR-130b expression in BCa cell lines and tissues was detected using real-time PCR (RT-PCR), and vestigial-like protein 4 (VGLL4) expression in tissue specimens and BCa cells that had been transfected with miR-130b mimics and inhibitors was detected using western blotting. Dual-luciferase reporter assay was performed to confirm whether the VGLL4 gene is a direct target of miR-130b, and in vitro cell function testing, Cell Counting Kit-8 (CCK-8) assay, colony formation assay, wound healing and Transwell assays were performed to examine BCa cell proliferation, migration and invasion ability after the cells were transfected with miR-130b mimics and inhibitors and VGLL4 siRNA. miR-130b was found to be upregulated in BCa cells and tissues. miR-130b overexpression promoted BCa cell proliferation, migration and invasion, whereas miR-130b inhibition had the opposite effects. Dual-luciferase reporter assay confirmed that the VGLL4 gene was a direct target of miR-130b and that VGLL4 suppression was crucial for miR-130b-induced BCa cell proliferation, migration and invasion. The present study showed that miR-130b was significantly upregulated in BCa and may play an oncogenic role in BCa occurrence and development by targeting VGLL4. miR-130b may be a potential therapeutic target in the treatment of BCa. PMID- 29512746 TI - MicroRNA-4284 promotes gastric cancer tumorigenicity by targeting ten-eleven translocation 1. AB - Increasing evidence has shown that abnormal expression of miR-4284 participates in the progression of several types of cancer. However, the expression and the role of miR-4284 in gastric cancer remain largely unknown. Therefore, in the present study the miR-4284 expression levels in gastric cancer tissues and cell lines, was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and found that miR-4284 was significantly upregulated in 40 pairs of gastric cancer tissues and five gastric cancer cell lines compared to the corresponding normal tissues and GES-1 cell line. In addition, increased miR 4284 expression was positively associated with TNM stage (P=0.035), distal metastasis (P=0.022) and poor prognosis in gastric cancer patients. Furthermore, the overexpression of miR-4284 expression was shown to promote cell proliferation, clone formation, invasion and migration, while the suppression of miR-4284 expression induced opposite effects. Additionally, luciferase reporter assay was conducted and showed that ten-eleven translocation 1 (TET1), a tumor suppressor gene that regulating cell survival and metastasis, was a direct target of miR-4284. Upregulated miR-4284 decreased the mRNA and protein levels of TET1 in SGC-7901 cells and downregulated miR-4284 increased the mRNA and protein levels of TET1 in AGS cells. In addition, miR-4284 expression was negatively correlated with the TET1 expression in gastric cancer tissues. Moreover, inhibition of TET1 suppressed the effect of miR-4284 inhibitors on cell proliferation in AGS cells. Therefore, data demonstrated that miR-4284 could promote tumor cell growth, migration and invasion by directly targeting TET1 in gastric cancer, which may provide a potential therapeutic target for gastric cancer treatment. PMID- 29512749 TI - Allicin attenuates lipopolysaccharide-induced acute lung injury in neonatal rats via the PI3K/Akt pathway. AB - Allicin is an oxygenated carotenoid derivative that exhibits strong antioxidant activity, which effectively removes reactive oxygen species from the body and has important roles in disease prevention and treatment. Therefore, the present study aimed to investigate whether allicin attenuates lipopolysaccharide (LPS)-induced acute lung injury (ALI) in neonatal rats and the potential underlying mechanisms. An LPS-induced ALI neonatal rat model was utilized to assess the therapeutic value and mechanisms of allicin. Following allicin treatment, increases in lung wet/dry ratio and the lung protein concentration were significantly suppressed in LPS-induced ALI neonatal rats. Furthermore, ELISA results demonstrated that allicin significantly reduced the levels of malondialdehyde, tumor necrosis factor-alpha and interleukin-6, and increased superoxide dismutase activity, in the bronchoalveolar lavage fluid of LPS-treated rats. Additionally, allicin administration increased the protein expression of Bcl-2 and reduced the activity of caspase-3/-9, as determined by western blotting or ELISA, respectively, and increased phosphatidylinositol 3-kinase (PI3K) and phosphorylated-Akt protein levels, in LPS-treated ALI neonatal rats. The results of the present study indicate that allicin attenuate LPS-induced ALI in neonatal rats by ameliorating oxidative stress, inflammation and apoptosis via the PI3K/Akt pathway. Allicin may be used for development of a novel drug for treatment of ALI. PMID- 29512751 TI - Tegillarca granosa extract Haishengsu inhibits tumor activity via a mitochondrial mediated apoptotic pathway. AB - Haishengsu (HSS) is an active natural extract isolated from Tegillarca granosa, which has previously been demonstrated to inhibit the proliferation of several types of cancer cells in vitro. Our previous study indicated that HSS may induce apoptosis to suppress growth of human hepatocellular carcinoma BEL-7402 cells by activating Fas pathway. The present study demonstrated that HSS treatment induces the in vitro apoptosis of BEL-7402 cells via the mitochondrial-mediated apoptotic pathway detected by DNA fragmentation assay, caspase activity assay and transmission electron microscopy assay, and inhibits tumor xenograft growth in vivo. Alterations in apoptotic regulatory proteins were detected, including decreased expression of B-cell lymphoma2 (Bcl-2), upregulation of Bcl-2 associated X protein and mitochondrial cytochrome c release, and downstream activation of apoptotic signaling. Furthermore, apoptotic induction was caspase dependent, as indicated by cleavage of the caspase substrate, poly (ADP-ribose) polymerase. Oral administration of 62.5-250 mg/kg HSS markedly educed the growth of hepatocellular carcinoma tumor xenografts in nude mice. In addition, immunohistochemical staining for caspase-3 protein and transmission electron microscopy further indicated the induction of apoptosis in these tumor tissues. Taken together, the present study demonstrated that HSS may effectively induce apoptosis to suppress the growth of BEL-7402 cells in vitro and in vivo, and therefore may hold promise for further development as a novel cancer therapy. PMID- 29512750 TI - Transplantation of human matrix metalloproteinase-1 gene-modified bone marrow derived mesenchymal stem cell attenuates CCL4-induced liver fibrosis in rats. AB - It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs) alleviated liver fibrosis. We investigated whether BMSCs transfected with human matrix metalloproteinase 1 (BMSCs/MMP1) would improve their therapeutic effect in liver fibrosis induced by carbon tetrachloride (CCl4) in rats. BMSCs were transfected with an adenovirus carrying enhanced green fluorescence protein (GFP) and human MMP1 gene. BMSCs or BMSCs/MMP1 were directly injected into fibrotic rats via the tail vein. GFP-labeled cells appeared in the fibrotic liver after BMSC transplantation. The expression of BMSCs/MMP1 elevated levels of MMP1 in vitro. Although BMSC administration reduced liver fibrosis, transplantation of BMSCs/MMP1 enhanced the reduction of liver fibrosis to a higher level. Treatment with BMSCs/MMP1 not only decreased collagen content but also suppressed activation of hepatic stellate cells (HSCs) in fibrotic liver, which led to subsequent improvement of both liver injury and fibrosis. Treatment with BMSCs/MMP1 resulted in an improved therapeutic effect compared with BMSCs alone, which is probably because of the sustainably expressed MMP1 level in the liver. BMSCs/MMP1 transplantation not only improved biochemical parameters but also attenuated progression of liver fibrosis, suggesting that BMSCs may be a potential cell source in preventing liver fibrosis and MMP1 gene may enhance the anti-fibrotic effect of BMSCs. PMID- 29512752 TI - MicroRNA-29c inhibits proliferation and promotes apoptosis in non-small cell lung cancer cells by targeting VEGFA. AB - Non-small cell lung cancer (NSCLC) is a primary sub-type of lung cancer with a high incidence rate and poor prognosis. The primary therapeutic treatment for NSCLC is chemotherapy, which is considered to be ineffective and excessively toxic. Novel therapeutic methods, particularly molecular targeted therapy, have attracted considerable attention. MicroRNAs (miRs) are reported to be potential biomarkers and targeted agents with roles in various types of tumors. Herein, the present study presented the observation of aberrant low expression of miR-29c and associated overexpression of vascular endothelial growth factor A (VEGFA) in NSCLC tumor tissues. The effects of miR-29c upon NSCLC tumor progression, including cell proliferation and cellular apoptosis, were investigated. The possible regulatory mechanism of action of miR-29c on its direct target VEGFA and the phosphatidylinositol 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (Akt) signaling pathway was examined using multiple methods, including reverse transcription-quantitative polymerase chain reaction analysis, dual luciferase assay and western blot analysis. The results demonstrated that miR-29c expression was downregulated in NSCLC tumor tissues compared with normal tissues. A marked negative correlation in the expression of miR-29c and VEGFA was observed in clinical NSCLC tissues and cultured NSCLC cells. Overexpression of miR-29c may inhibit cell proliferation and accelerate the cellular apoptosis rate of NSCLC tumor cells. Furthermore, the overexpression of miR-29c was demonstrated to be able to downregulate the expression levels of VEGFA and PI3K/Akt signaling pathway-associated proteins. The results of the present study suggested that miR 29c might regulate NSCLC tumor progression by targeting VEGFA. PMID- 29512754 TI - 3,5,4'-Tri-O-acetylresveratrol attenuates seawater inhalation-induced acute respiratory distress syndrome via thioredoxin 1 pathway. AB - The protecting effects of 3,5,4'-tri-O-acetylresveratrol (AC-Res) on seawater inhalation-induced acute respiratory distress syndrome (ARDS) by interfering with the activation of thioredoxin-1 (Trx-1) pathway were evaluated. Seawater inhalation-induced ARDS was assessed by magnitude of pulmonary edema and lung inflammation. Oxidative stress was tested by T-SOD activity and MDA content in lungs and cells. Besides, Trx-1, nuclear factor erythroid 2-related factor 2 (Nrf2) and Txnip expression were measured to explore how seawater induced oxidative stress and the mechanism by which AC-Res attenuated seawater inhalation induced ARDS. The results showed that seawater inhalation increased wet-to-dry (W/D) ratios of lung tissues, enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and disturbed the oxidative distress balance probably through interfering the activity of Trx-1 pathway. While treatment of AC-Res in vivo and Res in vitro reduced W/D ratios of lung tissues, decreased cytokines in lungs and maintained the oxidative stress balance through Trx-1 pathway. In conclusion, AC-Res treatment attenuated seawater inhalation induced ARDS via Trx-1 pathway. PMID- 29512753 TI - Identification of genes and pathways associated with MDR in MCF-7/MDR breast cancer cells by RNA-seq analysis. AB - Multidrug resistance (MDR) is a major problem in the treatment of breast cancer. In the present study, next-generation sequencing technology was employed to identify differentially expressed genes in MCF-7/MDR cells and MCF-7 cells, and aimed to investigate the underlying molecular mechanisms of MDR in breast cancer. Differentially expressed genes between MCF-7/MDR and MCF-7 cells were selected using software; a total of 2085 genes were screened as differentially expressed in MCF-7/MDR cells. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID database. Finally, a protein-protein interaction network was constructed and the hub genes in the network were analyzed using the STRING database. GO annotation demonstrated that the differentially expressed genes were enriched in various biological processes, including 'regulation of cell differentiation', 'cell development', 'neuron development', 'movement of cell or subcellular component' and 'cell morphogenesis involved in neuron differentiation'. Cellular component analysis by GO revealed that differentially expressed genes were enriched in 'plasma membrane region' and 'extracellular matrix' terms. Furthermore, KEGG analysis demonstrated that the target genes were enriched in various pathways, including 'cell adhesion molecules (CAMs)', 'calcium signaling pathway', 'tight junction', 'Wnt signaling pathway' and 'pathways in cancer' terms. A protein-protein interaction network demonstrated that certain hub genes, including cyclin D1, nitric oxide synthase 3 (NOS3), NOTCH3, brain-derived neurotrophic factor (BDNF), paired box 6, neuropeptide Y, phospholipase C beta (PLCB) 4, PLCB2 and actin alpha cardiac muscle 1, may be associated with MDR in breast cancer. Subsequently, RT-qPCR confirmed that the expression of these 9 hub genes was higher in MCF-7/MDR cells compared with MCF-7 cells, consistent with the RNA-sequencing analysis. Additionally, a Cell Counting Kit-8 assay demonstrated that specific inhibitors of NOS3 and BDNF/neurotrophic receptor tyrosine kinase, type 2 signaling reduced the IC50 of MCF-7/MDR cells in response to various anticancer drugs, including adriamycin, cisplatin and 5-fluorouracil. The results of the present study provide novel insights into the mechanism underlying MDR in MCF-7 cells and may identify novel targets for the treatment of breast cancer. PMID- 29512755 TI - Effects of HAD-B1 on the proliferation of A549 cisplatin-resistant lung cancer cells. AB - The present study investigated the toxicity of HangAmDan-B1 (HAD-B1) on A549 Cisplatin resistant (A549CR) cells. HAD-B1 inhibited the growth of A549CR cells in a concentration-dependent manner; HAD-B1 was more effective at inhibiting A549CR cell viability compared with vehicle-treated cells. The reduction in viability may be due to S-phase cell cycle arrest and the induction of apoptosis in HAD-B1-treated cells. Cell cycle protein profile analysis of HAD-B1-treated A549CR cells using an InnoPharmaScreen (IPS) ProteoChip-based antibody microarray chip indicated downregulation of signal transducer and activator of transcription 3. The activities of caspase-3, -8 and -9 were significantly increased in HAD-B1 treated cells when compared with the vehicle-treated control group. Furthermore, the HAD-B1-treated group exhibited similarly increased caspase levels when compared with the Afatinib-treated group. Taken together, these observations suggest that HAD-B1 may be a promising candidate for further research into the therapeutic management of cisplatin-resistant lung cancer. PMID- 29512757 TI - Ubiquitin-specific peptidase 5 and ovarian tumor deubiquitinase 6A are differentially expressed in p53+/+ and p53-/- HCT116 cells. AB - Most proteins undergo ubiquitination, a process by which ubiquitin proteins bind to their substrate proteins; by contrast, deubiquitination is a process that reverses ubiquitination. Deubiquitinating enzymes (DUBs) function to remove ubiquitin proteins from the protein targets and serve an essential role in regulating DNA repair, protein degradation, apoptosis and immune responses. Abnormal regulation of DUBs may affect a number of cellular processes and may lead to a variety of human diseases, including cancer. Therefore, it is important to identify abnormally expressed DUBs to identify DUB-related diseases and biological mechanisms. The present study aimed to develop a multiplex polymerase chain reaction screening platform comprising primers for various DUB genes. This assay was used to identify p53-related DUBs in HCT116 p53+/+ and p53-/- cells. The results demonstrated that ubiquitin-specific peptidase 5 (USP5) and ovarian tumor deubiquitinase 6A (OTUD6A) were differentially expressed in p53+/+ and p53 /- HCT116 cells. Based on the data obtained through DUB screening, the protein expression levels of USP5 and OTUD6A were examined by western blotting, which confirmed that both of these DUBs were also expressed differentially in p53+/+ and p53-/- HCT116 cells. In conclusion, results from the DUB screening performed by the present study revealed that the expression of USP5 and OTUD6A may be affected by p53, and this method may be useful for the rapid and cost-effective identification of possible biomarkers. PMID- 29512758 TI - BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-kappaB signaling. AB - Breast cancer suppressor candidate-1 (BCSC-1; also termed von Willebrand factor A domain containing 5A and LOH11CR2A) is a newly identified candidate tumor suppressor gene that has been implicated in several types of cancer in previous studies. However, there have been few reports about the association between BCSC 1 and human breast cancer in recent years. In the present study, the expression of BCSC-1 in breast cancer was determined by immunohistochemistry (IHC) staining of tissue microarrays and clinical tissue specimens. Subsequently, BCSC-1 gene expression was evaluated in different breast cancer cell lines by quantitative polymerase chain reaction and the MDA-MB-231 cell line was selected for further use in subsequent experiments, due to its low BCSC-1 expression. An MDA-MB-231 cell line with stable overexpression of BCSC-1 was established through transfection with plasmid containing the BCSC-1 gene, and then screening for G418 resistance. Wound-healing, migration and invasion assays were conducted to detect the effect of BCSC-1 on MDA-MB-231 cells. Furthermore, changes in matrix metalloproteinases (MMPs), osteopontin (OPN) and the nuclear factor-kappaB (NF kappaB) pathway were detected in the current study. Additionally, stable silencing of BCSC-1 expression in MCF-7 cells was performed using a lentivirus. The results of IHC indicated that BCSC-1 is expressed at low levels in breast cancer tissues compared with in normal breast tissue. Results of the wound healing, migration and invasion assays demonstrated that BCSC-1 overexpression reduced the metastasis ability of MDA-MB-231 cells in vitro. Further research confirmed that the BCSC-1 overexpression reduced the expression levels of MMP7, MMP9 and OPN, and the phosphorylation of NF-kappaB p65. Furthermore, inhibition of BCSC-1 via lentivirus-mediated RNA interference revealed that the downregulation of BCSC-1 increased the invasive ability of MCF-7 cells. In summary, the results demonstrated that BCSC-1 is expressed at low levels in breast cancer tissues, and that it can suppress human breast cancer cell migration and invasion, potentially altering the expression of MMP7, MMP9, OPN, and the activity of the NF-kappaB pathway. Therefore, BCSC-1 may be useful as a biomarker for the treatment of breast cancer in the future. PMID- 29512756 TI - Expression profiles of long noncoding RNAs and mRNAs in post-cardiac arrest rat brains. AB - To investigate long noncoding (lnc)-RNA and mRNA expression profiles in post cardiac arrest (CA) brains, an external transthoracic electrical current was applied for 8 min to induce CA (the CA group). A total of 4 rats received sham operations and served as the blank control (BC) group. Upon return of spontaneous circulation (ROSC), lncRNA and mRNA expression in the rat cerebral cortex was assayed with high-throughput Agilent lncRNA and mRNA microarrays. In total, 37 lncRNAs were upregulated and 21 lncRNAs were downregulated in the CA group, and 258 mRNA transcripts were differentially expressed with 177 mRNAs upregulated and 81 mRNAs downregulated in the CA group. The differentially expressed lncRNAs in the CA group were co-expressed with thousands of mRNAs. The differentially expressed lncRNAs could be clustered into >100 signaling pathways and processes according to Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. The most common predicted functions involved metabolic pathways, protein synthesis, transport and degradation during CA-ROSC. CA-ROSC led to significant alterations in cerebral lncRNA and mRNA expression profiles. Thus, lncRNA-mRNA network interactions have the potential to regulate vital metabolic pathways and processes involved in CA-ROSC. PMID- 29512759 TI - Selection of reference genes for expression analysis in mouse models of acute alcoholic liver injury. AB - Investigations of hepatic gene expression are crucial for determining the molecular factors involved in acute alcoholic liver injury. The results of liver molecular investigations may reveal etiologically important genomic alterations. Therefore, it is necessary to normalize gene expression data to identify stable genes, which may be used as a reference under different experimental conditions. The aim of the present study was to apply reverse transcription-quantitative polymerase chain reaction analysis and use analysis software to investigate the expression stability of candidate reference genes in hepatic tissues from mice with acute alcoholic liver injury. The acute alcoholic liver injury models were established by the intragastric administration of alcohol (5 mg/kg) in Imprinting Control Region mice. Total RNA was isolated from the mouse livers, following which the expression levels of seven reference genes, beta-actin, glyceraldehyde 3-phosphate dehydrogenase (Gadph), glucuronidase beta, hypoxanthine phosphoribosyltransferase 1 (Hprt1), 18S ribosomal RNA, TATA binding protein and beta-2 microglobulin, were examined, and gene expression stability was assessed using the geNorm, NormFinder and BestKeeper tools. The geNorm analysis revealed that the gene with the lowest variability was Hprt1. Hprt1 and Gapdh were validated as the optimal reference gene pair in all samples from all groups. The NormFinder and BestKeeper results showed that Hprt1 was the most stable gene in all samples. Alcohol induces endoplasmic reticulum (ER) stress, causing changes in the expression levels of ER stress-associated genes. The stability of Hprt1 was verified by the expression analysis of ER stress-associated genes, and gene expression levels in the ethanol groups were upregulated, with a significant difference in expression, compared with those in the control group. Therefore, Hprt1 was selected as the most stable gene, and Hprt1 and Gapdh were determined to be the optimum gene pair in mouse models of acute alcoholic liver injury. The reliability of the Hprt1 gene was confirmed by expression analysis of ER stress associated genes. PMID- 29512760 TI - Artesunate suppresses oxidative and inflammatory processes by activating Nrf2 and ROS-dependent p38 MAPK and protects against cerebral ischemia-reperfusion injury. AB - Artesunate is a semi-synthetic derivative of artemisinin that is used in the treatment of patients with malaria. Artesunate has also been reported to exert immune-regulatory, antitumor, hepatoprotective, anti-inflammatory and smooth muscle relaxing functions. The present study aimed to investigate the putative protective effects of artesunate against cerebral ischemia/reperfusion injury (CIRI), and to elucidate the molecular mechanisms underlying its effects. A CIRI mouse model was created via middle cerebral artery occlusion for 2 h, followed by 22 h of reperfusion. Mice were treated with 10-40 mg/kg artesunate. The present results demonstrated that treatment with artesunate significantly reduced the cerebral infarct volume and potentiated the recovery of neurological function in CIRI mice. Oxidative stress and inflammation markers were revealed to be significantly downregulated following treatment with artesunate in CIRI mice. Furthermore, artesunate was demonstrated to activate nuclear factor erythroid 2 related factor 2 (Nrf2), inhibit caspase-3 activity, reduce the apoptosis regulator BAX/apoptosis regulator Bcl-2 expression ratio and suppress the phosphorylation of the mitogen-activated protein kinase (MAPK) p38 in CIRI mice. In conclusion, the present findings suggested that artesunate may exert protective effects against CIRI through the suppression of oxidative and inflammatory processes, via activating Nrf2 and downregulating ROS-dependent p38 MAPK in mice. PMID- 29512761 TI - Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma. AB - Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag-2 family of ligands for the Notch receptor and plays a role in Notch signaling. We have previously revealed that the expression of DLL3 is silenced by aberrant DNA methylation and that overexpression of DLL3 in the HuH2 hepatocellular carcinoma (HCC) cell line induced apoptosis. In the present study, we first confirmed the methylation of DLL3 in HuH2 cells and analyzed the methylation status of the DLL3 promoter region by bisulfite sequencing. Furthermore, we investigated whether other epigenetic modifications, such as histone acetylation and histone methylation, affected the expression of DLL3. Treatment with the DNA methylation inhibitor, 5 azadeoxycytidine (5-Aza-dC) slightly reactivated DLL3 mRNA expression and bisulfite sequencing revealed that CpG sites in the DLL3 promoter region of the HuH2 cells were densely-methylated. In addition, a significant increase in the expression of DLL3 was observed when the cells were treated with 5-Aza-dC in combination with the histone deacetylase inhibitor trichostatin A. However, an inhibitor of the dimethylation of histone H3 lysine 9 (H3K9me2) or the trimethylation of histone H3 lysine 27 (H3K27me3), modifications that are associated with gene silencing, had no effect on DLL3 reactivation. In combination with the findings from our previous study, these results indicated that DLL3 expression was silenced in HCC cells by DNA methylation and was more readily affected by histone acetylation than histone methylation (H3K9me2 or H3K27me3). PMID- 29512762 TI - Inhibition of autophagy promotes cisplatin-induced apoptotic cell death through Atg5 and Beclin 1 in A549 human lung cancer cells. AB - Recent studies have indicated that autophagy contributes to tumorigenesis and participates in acquired chemotherapeutic resistance. The present study aimed to determine the function and underlying mechanism of cisplatin-induced autophagy in A549 human lung cancer cells. Autophagy was measured by LC3B-I/II conversion, LC3B puncta and autophagosomes formation. Apoptotic cell death was measured by caspase-3 activity, caspase-3 cleavage and LDH release. The transcriptional and expressional level of autophagy related proteins were measured by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Beclin 1 and Atg 5 siRNA transfection was used to explore the function of cisplatin-induced autophagy. The results demonstrated that cisplatin induces apoptotic cell death in A549 cells and triggers an autophagic response, as indicated by increased microtubule-associated protein 1 light chain 3beta (LC3B) I/II conversion, increased LC3B puncta and autophagosome formation. Mechanisms underlying cisplatin-induced autophagic responses were also investigated. Cisplatin induced autophagy by upregulating the mRNA and protein expression levels of autophagy protein (Atg)5 and Beclin 1, whereas the mRNA and protein expression levels of serine/threonine-protein kinase ULK1, Atg3, Atg7, Atg12, and sequestosome-1 were not markedly upregulated. In addition, knockdown of Atg5 and Beclin 1 by small interfering RNA transfection impaired cisplatin-induced activation of autophagic responses, increased caspase-3 cleavage and inhibited cell viability. These findings suggested that disruption of autophagy via the inhibition of Atg5 and Beclin 1 may promote cisplatin-induced apoptotic cell death in A549 human lung cancer cells. In conclusion, the present study demonstrated that targeting autophagy may be used in the future for the treatment of lung cancer. PMID- 29512763 TI - Studying the mechanism of PLAGL2 overexpression and its carcinogenic characteristics based on 3'-untranslated region in colorectal cancer. AB - Pleomorphic adenoma gene like-2 (PLAGL2) is a zinc finger protein transcription factor, which is upregulated and serves an oncogenic function in multiple human malignancies, including colorectal cancer (CRC). First, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of PLAGL2 in CRC tissues and normal tissues. Then, bioinformatics analysis, RT-qPCR, western blotting, luciferase reporter assays and RNA-binding protein immunoprecipitation assays were performed to explore whether the underlying mechanisms, including copy number variation (CNV), microRNAs (miRNAs/miRs) and RNA-binding proteins (RBPs) led to the abnormal expression of PLAGL2. Finally, cell counting kit-8 assays, Transwell assays and xenograft models were used to detect carcinogenesis-associated characteristics based on the 3'-untranslated region (3'-UTR) of PLAGL2. In the present study, PLAGL2 was revealed to be upregulated in CRC tissues compared with normal CRC tissues. CNV was one of the causes leading to the upregulation of PLAGL2. miRNA, including downregulated miR-486-5p, and RBPs, including upregulated human antigen R (HuR), were other key underlying causes. In addition, PLAGL2 3'-UTR was revealed to promote the progression of CRC in vitro and in vivo, and to regulate the expression of C-MYC and CD44. To conclude, these results suggested that high expression of PLAGL2 in CRC was associated with CNV, miR-486-5p and HuR expression, whose 3'-UTR may promote colon carcinogenesis and serve as a novel potential biomarker for CRC therapies. PMID- 29512764 TI - Investigation of the expressions of MMPs and TIMPs between isogeneic and allogeneic rat aortic transplantation. AB - The present study investigated the effects of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in transplantation-associated arteriosclerosis by observing their expression in transplanted aortas in rats. Allogenic and isogenic abdominal aortic transplantations were performed and grafts were removed from the recipients at the designated time points (day 7, 14, 28 and 56 post transplantation). Hematoxylin and eosin staining, immunohistochemistry, immunofluorescence and western blot analysis were used to evaluate the grafts. Significant proliferation of the intima was observed in the allogenic transplantation groups (P<0.05). The expressions of MMPs and TIMPs in the allografts were significantly increased compared with the isografts, and the suppression of MMP2 in allografts reduced injury after transplantation. The present study concluded that the imbalance of MMPs and TIMPs led to the disturbance of synthesis and the degradation of the extracellular matrix and it may represent a key cause of chronic rejection. PMID- 29512765 TI - Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro. AB - KMT5A (known as PR-Set7/9, SETD8 and SET8), a member of the SET domain containing methyltransferase family specifically targeting H4K20 for methylation, has been implicated in multiple biological processes. In the present study, we identified that KMT5A was elevated in 50 pairs of papillary thyroid cancer tissue samples and in cell lines K1 and TPC-1 by qRT-PCR and western blotting, as well as by immunohistochemical staining. CCK-8 assay and flow cytometric analysis revealed that inhibition of KMT5A attenuated proliferation and induced apoptosis. Transwell assays revealed that cell migration and invasion were suppressed in KMT5A-knockdown cells. Moreover, the inhibition of KMT5A arrested the cell cycle in the G1/S phase of papillary thyroid cancer cells. The TCGA data revealed that elevated KMT5A expression was significantly correlated with extrathyroidal extension, lymph node metastasis and advanced pathological stage of papillary thyroid cancer. Furthermore, we observed that inhibition of KMT5A suppressed the expression of SREBP1, SCD, FASN and ACC, key molecules involved in lipid metabolism and decreased the level of malondialdehyde in papillary thyroid cancer cells. In conclusion, KMT5A may be a novel oncogenic factor, specifically a regulator for lipid metabolism in papillary thyroid carcinoma. PMID- 29512766 TI - TNF-alpha and RANKL promote osteoclastogenesis by upregulating RANK via the NF kappaB pathway. AB - Although tumor necrosis factor alpha (TNF-alpha) is known to serve a critical role in the pathogenesis of inflammatory osteolysis, the exact mechanisms underlying the effects of TNF-alpha on osteoclast recruitment and differentiation remain unclear. To investigate the mechanisms by which TNF-alpha influences osteoclast differentiation, mouse bone marrow-derived macrophages (BMMs) were used as osteoclast precursors, and osteoclastogenesis was induced by macrophage colony-stimulating factor and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) with or without TNF-alpha for 4 days. Then, NF-kappaB was inhibited using the inhibitor, BAY 11-7082. The results indicated that treatment with TNF-alpha alone did not induce osteoclastogenesis of BMMs. However, TNF alpha in combination with RANKL dramatically stimulated the differentiation of osteoclasts and positively regulated the expression of mRNA markers of osteoclasts. Finally, treatment of BMMs with BAY 11-7082 prevented the formation of mature osteoclasts by BMMs treated with TNF-alpha only or with RANKL, as well as the upregulation of osteoclast marker genes. Therefore, although TNF-alpha does not induce osteoclastogenesis alone, it does work with RANKL to induce osteoclastic differentiation, and the NF-kappaB pathway may serve an important role in this process. PMID- 29512767 TI - Knockdown of ZEB1 suppressed the formation of vasculogenic mimicry and epithelial mesenchymal transition in the human breast cancer cell line MDA-MB-231. AB - Breast cancer is a common malignant tumor in women. It has been suggested that a type of microcirculation pattern that does not rely on host microvascular endothelial cells known as vasculogenic mimicry (VM) may contribute to the poor effect of anti-angiogenesis treatment on some patients with breast cancer. However, the formation and regulatory mechanism of VM in breast cancer are unclear and still require further investigation. The present study examined whether decreasing the expression of zinc finger E-box binding homeobox (ZEB1) using siRNA can inhibit the formation of VM in Triple Negative Breast Cancer (TNBC), and its specific function and molecular mechanism. mRNA and protein expression were detected by RT-qPCR and western blotting. Invasion assay and tube formation assay were also performed. The results demonstrated that ZEB1 small hairpin (sh)RNA inhibited the formation of VM. Knockdown of ZEB1 markedly inhibited the expression of vimentin in MDA-MB-231 cells and markedly increased the expression of E-cadherin. It was suggested that ZEB1 shRNA may have inhibited the epithelial-mesenchymal transition (EMT). In addition, ZEB1 shRNA inhibited the invasion of MDA-MB-231 cells and suppressed the expression of fetal liver kinase 1 (flk-1). The flk-1 inhibitor Semaxanib inhibited the formation of VM; thus, ZEB1 shRNA inhibited EMT and cell invasion, and may have inhibited the formation of VM through flk-1. The present study contributed further understanding on the theory of tumor angiogenesis and provided theoretical basis for novel targeted therapy of TNBC. PMID- 29512768 TI - Anthocyanin complex exerts anti-cholangiocarcinoma activities and improves the efficacy of drug treatment in a gemcitabine-resistant cell line. AB - Cholangiocarcinoma (CCA) is a deleterious bile duct tumor with poor prognosis and is relatively resistant to chemotherapy. Therefore, alternative or supplementary agents with anticancer and chemosensitizing activities may be useful for the treatment of CCA. A novel anthocyanin complex (AC) nanoparticle, developed from extracts of cobs of purple waxy corn and petals of blue butterfly pea, has exhibited chemopreventive potential in vivo. In the present study, the anti-CCA activities of AC and their underlying molecular mechanisms were investigated further in vitro using a CCA cell line (KKU213). The potential use of AC as a chemosensitizer was also evaluated in a gemcitabine-resistant CCA cell line (KKU214GemR). It was demonstrated that AC treatment suppressed proliferation of KKU213 CCA cells in dose- and time-dependent manners. AC treatment also induced apoptosis and mitochondrial superoxide production, decreased clonogenicity of CCA cells, and downregulated forkhead box protein M1 (FOXM1), nuclear factor-kappaB (NF-kappaB) and pro-survival protein B-cell lymphoma-2 (Bcl-2). The expression of endoplasmic reticulum (ER) stress-response proteins, including protein kinase RNA like ER kinase, phosphorylated eIF2alpha, eukaryotic initiation factor 2alpha and activating transcription factor 4, also decreased following AC treatment. It was also identified that AC treatment inhibited KKU214GemR cell proliferation in dose and time-dependent manners. Co-treatment of KKU214GemR cells with low doses of AC together with gemcitabine significantly enhanced efficacy of the latter against this cell line. Therefore, it is suggested that AC treatment is cytotoxic to KKU213 cells, possibly via downregulation of FOXM1, NF-kappaB, Bcl-2 and the ER stress response, and by induction of mitochondrial superoxide production. AC also sensitizes KKU214GemR to gemcitabine treatment, which may have potential for overcoming drug resistance of CCA. PMID- 29512769 TI - Novel mutations of the SERPINF1 and FKBP10 genes in Chinese families with autosomal recessive osteogenesis imperfecta. AB - The aim of the present study was to characterize the clinical manifestations and identify the mutations of Serpin family F member 1 (SERPINF1) and FK506 binding protein 10 (FKBP10) genes in Chinese patients with osteogenesis imperfecta (OI). Using whole-exome sequencing in the first and third probands, a novel mutation was identified in SERPINF1 and a novel compound heterozygous mutation was revealed in FKBP10. Using Sanger sequencing, an additional novel mutation in SERPINF1 was identified in a proband of family 2. In family 1, the proband presented with a novel homozygous missense mutation of the SERPINF1 gene, c.1067T>A (V356E). In family 2, the proband had a novel homozygous deletion mutation of the SERPINF1 gene, c.283+473_643+104del (p.Ala96_Gly215del). Serum pigment-epithelium-derived factor concentration was not detected in probands with OI type VI. For both families, the proband's father was demonstrated to have a heterozygous mutation of SERPINF1, whereas no mutations was detected in the probands' mothers. An assessment of allelic copy numbers revealed a deletion of SERPINF1 in the mother of family 1. The results of the present study demonstrate that patients may have mild symptoms of OI with a large fragment deletion in the SERPINF1 gene. Thus, the phenotype of Chinese patients with type VI OI is milder than that of Caucasian and Korean patients. In family 3, the proband displayed a novel compound heterozygous mutation in FKBP10, c.813_814delGA (p.Glu271AspfsX101) and c.831delC (p.Gly278AlafsX20), and did not have Bruck syndrome. Codon 831 of the FKBP10 gene may represent a mutation hotspot for human OI. These results extend both the phenotypic and the genotypic contents of OI patients with SERPINF1 or FKBP10 mutations. PMID- 29512770 TI - Inhibition effects of total flavonoids from Sculellaria barbata D. Don on human breast carcinoma bone metastasis via downregulating PTHrP pathway. AB - It is abundantly clear that tumor-derived parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) are central contributors in promoting osteolytic process of breast carcinoma bone metastasis. Forcusing on this molecular basis, the study was undertaken to explore the inhibition effects of total flavonoids from Scutellaria barbata D. Don (TF-SB) on human breast carcinoma bone metastasis. MDA MB-231 cells and nude mouse models of breast cancer bone metastasis were given TF SB in different concentrations. The proliferation, migration and invasion potentials of MDA-MB-231 cells were respectively tested. The effects of TF-SB on tumor weights and bone destruction were investigated. The mRNA and protein expression of PTHrP, OPG and RANKL were assessed by qPCR and western blot analysis. In vitro, TF-SB inhibited the proliferation, migration and invasion of MDA-MB-231 cells in a dose-dependent manner. In vivo, TF-SB prevented bone metastasis of breast cancer by decreasing the number of osteoclast cells per field in a dose-dependent manner, but not affecting tumor growth or mouse survival. Molecular analysis revealed that TF-SB controled the secretion of osteolysis-related factors PTHrP and its downstream RANKL/OPG. Together, by controlling the expression of PTHrP and its downstream OPG/RANKL, TF-SB has significant inhibition effects on breast cancer bone metastasis, which indicates a new therapeutic method. PMID- 29512771 TI - Screening pathogenic genes in oral squamous cell carcinoma based on the mRNA expression microarray data. AB - Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and its survival rate has barely improved over the past few decades. The purpose of this study was to screen pathogenic genes of OSCC via microarray analysis. The mRNA expression microarray datasets (GSE2280 and GSE3524) were downloaded from the Gene Expression Omnibus (GEO) database. In GSE2280, there were 22 OSCC samples without metastasis and 5 OSCC samples with lymph node metastasis. In GSE3524, there were 16 OSCC samples and 4 normal tissue samples. The differentially expressed genes (DEGs) in OSCC samples with lymph node metastasis compared with those without metastasis (named as DEGs-1), and the DEGs in OSCC samples compared with normal tissue samples (named as DEGs-2), were obtained via limma package. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform the functional enrichment analyses of DEGs 1 and DEGs-2. The miRNA-gene pairs of overlaps among DEGs were screened out with the TargetScan database, and the miRNA-gene regulated network was constructed by Cytoscape software. A total of 233 and 410 DEGs were identified in the sets of DEGs-1 and DEGs-2, respectively. DEGs-1 were enriched in 188 Gene Ontology (GO) terms and 8 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and DEGs-2 were enriched in 228 GO terms and 6 KEGG pathways. In total, 126 nodes and 135 regulated pairs were involved in the miRNA-gene regulated network. Our study indicated that transglutaminase 2 (TGM2) and Islet 1 (ISL1) may be biomarkers of OSCC and their metastases. Moreover, it provided some potential pathogenic genes (e.g. P2RY2 and RAPGEFL1) in OSCC. PMID- 29512772 TI - Protective effect of alpha-mangostin against CoCl2-induced apoptosis by suppressing oxidative stress in H9C2 rat cardiomyoblasts. AB - Garcinia mangostana (a fruit) has been commonly used as a traditional drug in the treatment of various types of diseases. The aim of the present study was to evaluate the potential protective effect of alpha-mangostin (alpha-MG), a primary constituent extracted from the hull of the G. mangostana fruit (mangosteen), against CoCl2-induced apoptotic damage in H9C2 rat cardiomyoblasts. alpha-MG was demonstrated to significantly improve the viability of the CoCl2-treated cells by up to 79.6%, attenuating CoCl2-induced damage. Further studies revealed that alpha-MG exerted a positive effect in terms of decreased reactive oxygen species generation, malondialdehyde concentration, cellular apoptosis, and increased superoxide dismutase activity. Furthermore, treatment with CoCl2 increased the cleavage of caspase-9, caspase-3 and apoptosis regulator BAX, and reduced apoptosis regulator Bcl-2 in H9C2 cells, as measured by reverse transcription quantitative polymerase chain reaction and western blotting, which were significantly reversed by co-treatment with alpha-MG (0.06 and 0.3 mM). In conclusion, these results demonstrated that alpha-MG protects H9C2 cells against CoCl2-induced hypoxic injury, indicating that alpha-MG is a potential therapeutic agent for cardiac hypoxic injury. PMID- 29512773 TI - Emodin inhibits TGF-beta2 by activating the FOXD3/miR-199a axis in ovarian cancer cells in vitro. AB - Ovarian cancer is a highly metastatic malignancy and a leading cause of cancer related death in postmenopausal women. Emodin is a natural anthraquinone isolated from several traditional Chinese medicines including Rhubarb and Polygonum cuspidatum. Recently, emodin was demonstrated to reduce the growth of human ovarian carcinoma cells. However, the mechanism remains unclear. In the present study, we identified that transforming growth factor (TGF)-beta2 was significantly affected by emodin treatment in A2780 cells using microarray analysis. MicroRNA (miR)-199a was predicted as a potential miRNA targeting TGF beta2 by in silico prediction using TargetScan. The mRNA and protein levels of TGF-beta2 were both significantly reduced by miR-199a. Spearman's correlation analysis revealed a significant correlation between the expression level of miR 199a and TGF-beta2 in human ovarian cancer specimens. Silencing of miR-199a with miR-199a inhibitor significantly restored the reduction in TGF-beta2 expression induced by emodin. Additionally, cell viability and colony formation of A2780 cells were markedly inhibited by emodin treatment, which was mediated by miR 199a. We analyzed the primary mature miR-199a-1 and miR-199a-2 transcripts in A2780 cells treated with emodin or dimethyl sulfoxide (DMSO) and found that only pri-miR-199a-1 was regulated by emodin. A conserved binding site of Forkhead box D3 (FOXD3) was identified within pri-miR-199a-1. We further revealed that miR 199a expression was significantly regulated by FOXD3. Taken together, the present study demonstrated that emodin may directly promote FOXD3 expression and sequentially activates miR-199a, which in turn suppresses the expression of TGF beta2 to reduce cell viability and colony formation of A2780 cells. PMID- 29512774 TI - Knockdown of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) enhances tumorigenesis both in vivo and in vitro in bladder cancer. AB - Bladder cancer is the most common tumor of the urinary tract. Tyrosine 3 monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3zeta protein, has been observed to be frequently amplified in bladder cancer. However, the role of 14-3-3zeta in various types of cancer is controversial. With reproduction of The Cancer Genome Atlas database, we searched the correlation of YWHAZ expression with survival outcomes of multiple cancers in silico. Our results revealed that only in bladder cancer was there a positive survival trend with YWHAZ overexpression. To study its role in bladder cancer, YWHAZ was successfully downregulated by lentivirus in 5637 and T24 cells. MTT and colony-formation assays showed that YWHAZ downregulation increased cell proliferation. Wound healing and Transwell assays showed that YWHAZ downregulation enhanced cell migration and invasiveness. FACS analysis showed that YWHAZ induced cell cycle arrest, but not apoptosis. A xenograft tumor model revealed that YWHAZ knockdown enhanced tumor growth. Gene set enrichment analysis confirmed that the cell cycle pathway plays a vital role in the function of the YWHAZ gene. In conclusion, knockdown of YWHAZ promoted both in vitro and in vivo tumorigenesis in bladder cancer and may be a novel biomarker for bladder cancer deserving further study. PMID- 29512775 TI - SOX6 is downregulated in osteosarcoma and suppresses the migration, invasion and epithelial-mesenchymal transition via TWIST1 regulation. AB - Transcription factor SOX6 (SOX6) has been reported to serve essential roles in numerous types of cancers. However, the expression and functions of SOX6 in osteosarcoma (OS) have not been analyzed. In the present study, the patterns of SOX6 expression in OS cell lines and tissues were investigated by reverse transcription-quantitative polymerase chain reaction and western blotting. The results of the present study revealed that SOX6 was notably downregulated in OS tissues and cell lines. Subsequently, gain- and loss-of-function studies demonstrated that SOX6 inhibited OS cell migration and invasion. In addition, SOX6 may have suppressed epithelial-mesenchymal transition via twist-related protein 1 (TWIST1) modulation. Chromatin immunoprecipitation (ChIP), quantitative ChIP and dual luciferase activity assays were used to confirm the binding of SOX6 to the promoter region of TWIST1. Additionally, colony formation assays and Cell Counting Kit-8 assays demonstrated that SOX6 suppressed cell proliferation. The findings of the present study indicated that SOX6 serves as a tumor suppressor in OS and may be a potential therapeutic target for OS. PMID- 29512776 TI - miR-367 enhances the proliferation and invasion of cutaneous malignant melanoma by regulating phosphatase and tensin homolog expression. AB - Melanoma presents a serious threat to human health but the underlying mechanisms have not been fully identified. Increasing evidence indicates that microRNAs exert a significant influence on the tumorigenesis and metastasis of different types of cancer. The present study aimed to identify the role of microRNA (miR) 367 in the initiation and progression of melanoma and investigate its potential target. A total of 50 melanoma samples and 25 benign nevi tissues were used in the present study. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to determine the expression of mRNA and protein, respectively. Cell proliferation and invasion were assessed by CCK-8, wound healing and Transwell assays. A proposed target mRNA of miR-367 was determined using a luciferase reporter assay and an in vivo xenograft model was used to evaluate the function of miR-367 in the progression of melanoma. It was revealed that miR-367 was overexpressed in melanoma tissues and cell lines. The miR-367 level in tumor tissues was positively correlated with tumor thickness, tumor stage, lymph node involvement, distant metastasis and the patient survival rate. A high miR-367 level was observed to enhance the growth, migration and invasion of melanoma cells. Conversely, low miR-367 levels suppressed the proliferation and invasion of melanoma cells. Furthermore, miR-367 was revealed to bind directly to phosphatase and tensin homolog (PTEN) mRNA and regulate the expression of the PTEN protein. miR-367 markedly increased the growth and invasion of melanoma cells, whereas the cotransfection of PTEN vectors limited the promoting function of miR-367 in the proliferation and invasion of A375 cells. The upregulation of miR-367 promoted tumor growth in vivo. In conclusion, the results revealed that miR-367 serves a positive role in the development of melanoma and may be an important target for the treatment of cutaneous melanoma. PMID- 29512777 TI - CFTR ameliorates high glucose-induced oxidative stress and inflammation by mediating the NF-kappaB and MAPK signaling pathways in endothelial cells. AB - Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive production of oxidative stress and pro-inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regulator (CFTR). However, little information is available about the role of CFTR in hyperglycemia-induced endothelial cell oxidative stress and inflammation. In the present study, a high glucose-treatment was applied in human umbilical vein endothelial cells with CFTR overexpression or inhibition, and the oxidative and inflammatory characteristics were measured. It was shown that CFTR protein and mRNA expression were reduced by glucose in a concentration-dependent manner. Overexpression of CFRT via adenoviral infection significantly inhibited the production of reactive oxygen species and inflammatory biomediators induced by high glucose. Conversely, pharmacological inhibition of CFTR led to the opposite effects. Mechanistically, nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling were activated following high glucose treatment, which were inhibited by CFTR overexpression and enhanced by CFTR inhibition. The pro-inflammatory effect of CFTR inhibition was abolished by pharmacological inhibition of the NF kappaB or MAPK pathways. Moreover, inhibition of MAPK abrogated CFTR inhibition induced NF-kappaB nuclear translocation, whereas NF-kappaB inhibitor produced no effects on MAPK activation. Additionally, antioxidant treatment inhibited the high glucose-induced decrease in CFTR expression and the increase in inflammatory responses. Collectively, these findings revealed that CFTR attenuates high glucose-induced endothelial cell oxidative stress and inflammation through inactivation of NF-kappaB and MAPK signaling, indicating that elevation of CFRT expression may be a novel strategy in preventing endothelial dysfunction in diabetes. PMID- 29512778 TI - MCMV triggers ROS/NLRP3-associated inflammasome activation in the inner ear of mice and cultured spiral ganglion neurons, contributing to sensorineural hearing loss. AB - Congenital cytomegalovirus (CMV) infection is the most common infectious cause of sensorineural hearing loss in children. While the importance of CMV-induced SNHL has been described, the mechanisms underlying its pathogenesis and the role of inflammatory responses remain elusive. The present study established an experimental model of hearing loss after systemic infection with murine CMV (MCMV) in newborn mice. Auditory brainstem responses were tested to evaluate hearing at 3 weeks, expression of inflammasome--associated factors was assessed by immunofluorescence, western blot analysis, reverse transcription-quantitative polymerase chain reaction and ELISA. MCMV sequentially induced inflammasome associated factors. Furthermore, the inflammasome-associated factors were also increased in cultured spiral ganglion neurons infected with MCMV for 24 h. In addition, MCMV increased the content of reactive oxygen species (ROS). These results suggest that hearing loss caused by MCMV infection may be associated with ROS-induced inflammation. PMID- 29512779 TI - Suppression of YAP by DDP disrupts colon tumor progression. AB - Colon cancer is a commonly diagnosed cancer that often has a poor prognosis. Combined with the development of drug resistance to cancer treatment agents the treatment efficacy of colon cancer can be limited. Activation of the oncogene YAP has been shown to be related to colon cancer progression and is associated with poor prognosis, drug resistance and metastasis, even under treatment. Cisplatin (DDP) is a commonly used drug that can control carcinoma progression, although its mechanisms are poorly understood. In the present study, we examined whether DDP specifically suppressed YAP in order to inhibit colon carcinoma progression. Our data revealed that Mst/Yap signaling was unusually activated in colon cancers, promoting cell proliferation and invasion. DDP treatment decreased the expression of YAP at both the transcriptional and post-translational levels, leading to cell cycle arrest, apoptosis and senescence in cancer cells, in addition to decreasing epithelial-to-mesenchymal transition, cell motility and in vitro cell invasion and migration. Ultimately, DDP increased the expression of E cadherin and decreased the expression of vimentin. The present study also revealed that post-translational regulation of YAP phosphorylation controlled the subcellular distribution between the nucleus and the cytoplasm. In conclusion, the findings of the present study revealed that DDP was a suitable therapeutic candidate for colon cancer that specifically targets the Mst/Yap signaling pathway. PMID- 29512781 TI - Keratin 5/14-mediated cell differentiation and transformation are regulated by TAp63 and Notch-1 in oral squamous cell carcinoma-derived cells. AB - Keratins 5/14 (K5/14) are intermediate filament proteins expressed in the basal layer of stratified epithelial cells and are known targets of p63. Previous research in our laboratory showed that upon K5/14 downregulation in oral squamous cell carcinoma (OSCC)-derived cells, there was an increase in intracellular Notch 1 levels and differentiation markers such as involucrin, keratin 1 and a decrease in tumorigenic potential in vivo. However, the molecules involved in the K14 regulated cell differentiation and transformation are not known to date. In order to understand the possible role of TAp63, we downregulated TAp63 in a K14 knockdown background. We observed that there was a decrease in the expression of Notch-1. Expression levels of differentiation markers such as involucrin, K1, loricrin and filaggrin were also decreased. Furthermore, TAp63 downregulation led to an increase in invasion, migration and in vivo tumorigenic potential of these cells. We observed a decrease in beta-catenin signaling in K14-downregulated cells. Notably, when TAp63 was downregulated in K14-knockdown cells, there was increase in non-phospho beta-catenin levels. Hence, this study indicates that TAp63 plays an important role in K14-downregulated cells possibly by regulating the Notch-1 expression. K14 regulates the expression of TAp63 which in turn regulates expression of Notch-1. The present study is a step forward in our quest to understand the functional significance of molecules that regulate the process of differentiation and tumorigenesis in stratified epithelial cells. PMID- 29512780 TI - An adenosine A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-kappaB and CREB phosphorylation. AB - Microglial activation-mediated inflammatory damage to oligodendrocytes is a key step in the etiology of ischemic white matter lesions. The adenosine A1 receptor (A1R) and adenosine A2a receptor (A2aR) have been reported to regulate the activation of microglia, however, the underlying mechanisms remain elusive. Thus, the present study used a microglia/oligodendrocyte co-culture model exposed to low glucose/hypoxia, and treated with agonists/antagonists of A1R and A2aR to investigate the role of A1R and A2aR. Changes in A1R and A2aR expression and inflammatory cytokine secretion by the microglia, and oligodendrocyte damage, after exposure were examined. Low glucose/hypoxia induced a higher elevation of A1R than A2aR. In addition, activation of A1R inhibited A2aR protein expression and vice versa. The A1R antagonist DPCPX (100 nM) and A2aR agonist CGS 21680 (100 nM) inhibited microglial activation, reduced the production of inflammatory cytokines and attenuated oligodendrocyte damage, along with elevating the levels of phosphorylated nuclear factor (NF)-kappaB and cyclic adenosine monophosphate response element binding protein (CREB). These data indicate that an A1R-A2aR imbalance is able to modulate low glucose-induced microglial activation and the cellular immune response through altering NF-kappaB and CREB phosphorylation. This suggests that rebalancing A1R-A2aR is a promising approach for treating white matter injury. PMID- 29512782 TI - Eruca sativa seed extract: A novel natural product able to counteract neuroinflammation. AB - Certain nutrients are able to exert health promoting effects. The consumption of Brassicaceae vegetables has increased given their reported beneficial effects on human health, due to their high content of nutraceutical compounds. The health benefits appear to be associated with the presence of glucosinolates and flavonoids. Certain nutraceutics have been revealed to have anti-inflammatory action. In the present study, the anti-inflammatory properties of Eruca sativa seed extract (ESE) were evaluated in NSC-34 motor neurons exposed to the cell culture medium of lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Treatment with LPS-stimulated RAW 264.7 medium induced apoptosis and the expression of Toll-like receptor 4 (TLR4) and cyclooxygenase 2 (COX2) in NSC-34 motor neurons. Additionally, the stimulation of NSC-34 motor neurons with the medium of LPS-treated macrophages triggered the expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome proteins and the production of pro inflammatory cytokines. Pre-treatment with ESE counteracted the apoptosis and production of pro-inflammatory cytokines in NSC-34 motor neurons treated with the medium of LPS-treated RAW 264.7. It also eliminated COX2 and TLR4/NLRP3 inflammasome expression. In addition, pre-treatment with ESE was able to restore interleukin 10 expression in NSC-34 cells. These results demonstrate the anti inflammatory and neuroprotective effects of ESE. PMID- 29512783 TI - Therapeutic window for YC-1 following glutamate-induced neuronal damage and transient focal cerebral ischemia. AB - 3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), has been demonstrated to inhibit platelet aggregation, vascular contraction and hypoxia-inducible factor 1 activity in vitro and in vivo. The present study investigated the neuroprotective efficacy of YC-1 in cultured neurons exposed to glutamate-induced excitotoxicity and in an animal model of stroke. In a cortical neuronal culture model, YC-1 demonstrated neurotoxicity at a concentration >100 uM, and YC-1 (10-30 uM) achieved potent cytoprotection against glutamate-induced neuronal damage. Additionally, YC-1 (30 uM) effectively attenuated the increase in intracellular Ca2+ levels. Delayed treatment of YC-1 (30 uM) also protected against glutamate induced neuronal damage and cell swelling in cultured neurons, though only at 4 h post-treatment. In addition, immediate treatment of YC-1 (30 uM) following the exposure of cortical neurons to glutamate (300 uM) produced a marked reduction in intracellular pH. Delayed treatment of YC-1 (25 mg/kg) protected against ischemic brain damage in vivo, though only when administered at 3 h post-insult. Thus, YC 1 exhibited neuroprotection against glutamate-induced neuronal damage and in mice subjected to transient focal cerebral ischemia. This neuroprotection may be mediated via its ability to limit the glutamate-induced excitotoxicity. However, the neuroprotective therapeutic window of YC-1 is only at 3 h in vivo and 4 h in vitro, which may, at least in part, be attributed to its ability to reduce the intracellular pH in the early phase of ischemic stroke. Although YC-1 provided the potential for clinical therapy, the treatment time point must be carefully evaluated following ischemia. PMID- 29512784 TI - Transdermal estrogen gel and oral aspirin combination therapy improves fertility prognosis via the promotion of endometrial receptivity in moderate to severe intrauterine adhesion. AB - Intrauterine adhesion (IUA) is one of the most common gynecological diseases in women of reproductive age. IUA, particularlyin moderate to severe forms, accounts for a large percentage of infertility cases. Clinically, the first-line treatment strategy for IUA is transcervical resection of adhesion (TCRA), followed by adjuvant postoperative treatment. Estrogen is one of the classic chemotherapies used following TCRA and contributes to preventing re-adhesion following surgery. However, estrogen has limited effects in promoting pregnancy, which is the ultimate goal for IUA management. In the present study, a transdermal estrogen gel and oral aspirin combination therapy was used in patients with IUA following TCRA. Compared with in the control group (transdermal estrogen only therapy), the combination therapy significantly increased endometrial receptivity marker (alphavbeta3 and laminin) expression in endometrium tissues. Additionally, ultrasonic examination revealed the pulsatility index and resistant index of the uterine artery were lower in the combination therapy group. Combination therapy promoted angiogenesis and prevented fibrosis following TCRA more effectively than estrogen-only therapy. Collectively, the evaluation indices, including American Fertility Society score, endometrial parameters and pregnancy rate, indicated that patients with combination therapy had better prognoses in endometrial repair and pregnancy. In conclusion, postoperative combination therapy with transdermal estrogen gel and oral aspirin may be more efficacious in enhancing endometrial receptivity by increasing uterine blood and angiogenesis, contributing to improved fertility prognosis. The findings of the present study may provide novel guidance to the clinical treatment of IUA. PMID- 29512785 TI - Identification of potential genes and miRNAs associated with sepsis based on microarray analysis. AB - Sepsis is a type of systemic inflammatory response syndrome caused by infection. The present study aimed to examine key genes and microRNAs (miRNAs) involved in the pathogenesis of sepsis. The GSE13205 microarray dataset, downloaded from the Gene Expression Omnibus was analyzed using bioinformatics tools, and included muscle biopsy specimens of 13 patients with sepsis and eight healthy controls. The differentially expressed genes (DEGs) in samples from patients with sepsis were identified using the Linear Models for Microarray package in R language. Using the Database for Annotation, Visualization and Integration Discovery tool, functional and pathway enrichment analyses were performed to examine the potential functions of the DEGs. The protein-protein interaction (PPI) network was constructed with the DEGs using the Search Tool for the Retrieval of Interacting Genes, and the network topology was analyzed using CytoNCA. Subsequently, MCODE in Cytoscape was used to identify modules in the PPI network. Finally, the integrated regulatory network was constructed based on the DEGs, miRNAs and transcription factors (TFs). A total of 259 upregulated DEGs (MYC and BYSL) and 204 downregulated DEGs were identified in the patients with sepsis. NOP14, NOP2, AATF, GTPBP4, BYSL and TRMT6 were key genes in the MCODE module. In the integrated DEG-miRNA-TF regulatory network, hsa-miR-150 (target gene MYLK3) and 21 TFs, comprising 14 upregulated DEGs (including MYC) and seven downregulated DEGs, were identified. The results suggested that NOP14, NOP2, AATF, GTPBP4, BYSL, MYC, MYLK3 and miR-150 may be involved in the pathogenesis of sepsis. PMID- 29512786 TI - Dioscin prevents LPS-induced acute lung injury through inhibiting the TLR4/MyD88 signaling pathway via upregulation of HSP70. AB - Dioscin, as a type of important natural steroidal saponin, has widespread sources, primarily from the fenugreek plant, which is an important raw material in the production of synthetic steroid hormone drugs. Dioscin has anti-tumor, anti-inflammatory, antioxidant and other significant pharmacological effects with high medicinal value. The present work aimed to research the protective effect and underlying mechanisms by which dioscin prevents acute lung injury (ALI). Mice were injected with 5 mg/kg LPS to induce lung injury. Mice were treated with dioscin (20, 40 and 60 mg/kg) following LPS-induced lung injury. Treatment with dioscin significantly decreased total number of alveolar macrophages, water content of lung and total protein concentration in ALI mice. Dioscin treatment significantly suppressed the ALI-induced interleukin (IL)-1B, IL-6, tumor necrosis factor-alpha, nuclear factor (NF)-kappaB, myeloperoxidase, interferon gamma and intercellular adhesion molecule-1 activities in ALI rats. Following this, the authors identified that dioscin significantly also suppressed cyclooxygenase-2, heat shock protein 70, Toll-like receptor 4, MyD88 and NF kappaB protein expression in ALI rats. The results suggested that dioscin prevents LPS-induced ALI through inhibiting the TLR4/MyD88 signaling pathway via upregulation of HSP70. PMID- 29512787 TI - BMP7 regulates lung fibroblast proliferation in newborn rats with bronchopulmonary dysplasia. AB - The present study investigated the expression of bone morphogenetic protein (BMP) 7 in a newborn rat model of bronchopulmonary dysplasia (BPD) and the biological effects of BMP7 on newborn rat lung fibroblast (LF) cells. For this purpose, a total of 196 newborn rats were randomly and equally assigned to a model group and a control group. Lung tissue was collected at days 3, 7, 14 and 21 for histological analysis. The location and expression of BMP7 was examined by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. A total of 38 full-term newborn rats on the day of birth were sacrificed and LF cells were isolated and treated with BMP7. The biological effects of BMP7 on LF cells were assessed by cell proliferation and cell cycle analysis. The findings demonstrated that abnormal alveolar development due to BPD was gradually intensified in the model group over time. Immunohistochemical staining revealed that the location of BMP7 in lung tissue was altered. Immunohistochemistry and RT-qPCR assays demonstrated a gradual decrease in BMP7 expression in the model group induced by hyperoxia. MTT assays demonstrated that BMP7 inhibited LF cells and the inhibitory effect was dose dependent and time-dependent. Flow cytometry revealed that the inhibitory effect of BMP7 in LF cells was causing cell cycle arrest at the G1 phase. The present study demonstrated that BMP7 may serve an important role in alveolar development in a BPD model. BMP7 may be involved in abnormal alveolar development through the regulation of LF proliferation. PMID- 29512788 TI - Upregulated plasmacytoma variant translocation 1 promotes cell proliferation, invasion and metastasis in colorectal cancer. AB - Emerging evidence indicates that the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is associated with tumourigenesis in various types of cancer. However, its specific effects on the proliferation, invasion and metastasis of colorectal cancer (CRC) are still poorly understood. The present study aimed to investigate PVT1 expression in CRC and explore its role in CRC pathogenesis. The reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) technique was used to assess PVT1 expression in CRC cell lines. Gene Expression Omnibus (GEO) database analysis and measurement of clinical samples was used to analyse the correlation between PVT1 expression, CRC metastasis and overall survival (OS). In addition, knockdown of PVT1 expression was performed using short interfering RNA (siRNA) and RT-qPCR, western blotting, CCK-8 assays, tumour cell clone-formation and Matrigel invasion assays were used to observe its biological functions in HCT116 cells. The present study demonstrated that the expression of PVT1 in CRC cell lines was higher than that in normal colon mucosal cell lines. Using GEO database analysis and the measurement of clinical samples, it was revealed that CRC patients with high PVT1 expression demonstrated poor OS. Multivariate analysis indicated that high PVT1 expression is an independent risk factor for patients with CRC. In addition, PVT1 knockdown suppressed the proliferation, invasion and metastasis of CRC cells in vitro, which were associated with decreasing vimentin, cyclin D1 and cyclin-dependent kinase 4 expression and enhanced E-cadherin expression. The results of the present study suggest that PVT1 may serve a critical role in CRC progression and metastasis and may serve as a potential prognostic biomarker for CRC. PMID- 29512789 TI - Protective effects of tetrahydropalmatine against ketamine-induced learning and memory injury via antioxidative, anti-inflammatory and anti-apoptotic mechanisms in mice. AB - Tetrahydropalmatine exerts numerous pharmacological activities, including analgesic and narcotic effects; anti-arrhythmic, blood pressure lowering and cardioprotective effects; protective effects against cerebral ischemia reperfusion injury; inhibition of platelet aggregation; prevention of ulcerative diseases and inhibition of gastric acid secretion; antitumor effects; and beneficial effects on the withdrawal symptoms associated with drug addiction. The present study aimed to investigate the protective effects of tetrahydropalmatine against ketamine-induced learning and memory impairment in mice. The Morris water maze test and open field test were used to analyzed learning and memory impairment in mice. ELISA kits and western blotting were used to analyze oxidative stress, inflammation factors, caspease-3 and caspase-9, iNOS, glial fibrillary acidic protein (GFAP), glial cell-derived neurotrophic factor (GDNF), cytochrome c and phospholipase C (PLC)-gamma1 protein expression. The results demonstrated that tetrahydropalmatine treatment significantly decreased escape latency in the learning phase and increased the number of platform site crossings in ketamine-induced mice. In addition, tetrahydropalmatine significantly inhibited oxidative stress, inflammation and acetylcholinesterase activity, and decreased acetylcholine levels in ketamine-induced mice. Tetrahydropalmatine also suppressed iNOS protein expression, weakened caspase-3 and caspase-9 activation, inhibited nuclear factor-kappaB, glial fibrillary acidic protein, cytochrome c and phospholipase C-gamma1 protein expression, and induced glial cell-derived neurotrophic factor protein expression in ketamine-induced mice. Taken together, these results indicated that tetrahydropalmatine may protect against ketamine induced learning and memory impairment in mice via antioxidative, anti inflammatory and anti-apoptotic mechanisms. The present study provided an experimental basis for the clinical application of tetrahydropalmatine to reduce the severe side effects associated with ketamine therapy in future studies. PMID- 29512790 TI - Neuroprotective effects of N-acetyl cysteine on primary hippocampus neurons against hydrogen peroxide-induced injury are mediated via inhibition of mitogen activated protein kinases signal transduction and antioxidative action. AB - N-acetyl cysteine (NAC) has been extensively reported to exert neuroprotective effects on the central nervous system. Oxidative stress may contribute to the underlying mechanisms causing Alzheimer's disease (AD). The effect of NAC against oxidative stress injury was investigated in a cellular model of AD in the present study and the underlying mechanisms were revealed. The neuroprotective action of NAC (1, 10, 100 and 1,000 umol/l) on a cellular model of AD [hydrogen peroxide (H2O2)-induced (3, 30 and 300 umol/l) toxicity in primary rat hippocampus neurons] demonstrated the underlying mechanisms. Cytotoxicity was measured using the MTT assay, and light microscopy and the dichloro-dihydro-fluorescein diacetate method were used to detect the reactive oxygen species (ROS) levels. Furthermore, the levels of mitogen-activated protein kinases (MAPKs) signal transduction and tau protein phosphorylation were measured via western blotting. NAC (100 umol/l) protected hippocampus neurons against H2O2-mediated toxicity, as evidenced by enhanced cell viability. Using MTT assay and light microscopy for the observation of cell death, NAC ameliorated cell viability, which was induced by H2O2 injury (P<0.05). NAC was found to mitigate the excessive production of ROS (P<0.05). Another mechanism involved in the neuroprotective action of NAC may be its ability to inhibit MAPK signal transduction following H2O2 exposure. In addition, NAC may protect cells against H2O2-induced toxicity by attenuating increased tau phosphorylation. Thus, the protective ability of NAC is hypothesized to result from inhibition of oxidative stress and downregulation of MAPK signal transduction and tau phosphorylation. PMID- 29512792 TI - Legal responsibility of the pathologist in Tunisia. AB - The role of the pathologist has been highlighted by the medias since the recent years and the Tunisian law system suffers from a huge and there are no rules or jury verdicts concerning the e responsability of the doctors in general with emphasis on pathologists. One might think that the lack of laws benefits to the pathologist, on the other hand, we can consider this as dangerous either for the patients or the pathologists. This lack of laws makes the judge dependant on the expert view. Other countries like European ones and the United States, has available data furnished by the insurance bodies that enrich the jury verdicts and the different laws that are available. Our aim was to help the pathologists understand their legal responsibilities and the law system. The latter may seem as complex for the pathologist as a pathologic report for a judge. PMID- 29512791 TI - Occurrence of substance P and neurokinin receptors during the early phase of spinal fusion. AB - Spinal fusion is widely used for patients with spinal disorders; however, patients often suffer from back pain following fusion surgery. Substance P (SP) acts as a pain neurotransmitter via the sensory nerve afferent fibres up to the spinal cord, and is involved in the conduction and modulation of pain. The use of specific SP neurokinin receptor (NKR) antagonists may decrease postoperative pain. In the present study, the effects of alterations in the quantity of SP and NKRs in the early spinal fusion process were investigated. The results of the present study revealed that SP and NKRs began to appear 1 week post-surgery in fibrous tissues. The abundance of SP and NKRs peaked at 3 weeks post-surgery; the majority of SP and NKRs were distributed around the allograft and the new microvessels. In conclusion, SP and NKRs are involved in early spinal fusion, a finding that may facilitate the development of novel strategies to promote spinal fusion from a neurogenesis perspective. PMID- 29512793 TI - Gastrointestinal neuro-endocrine tumors: retrospective study of 36 cases. AB - BACKGROUND: Neuroendocrine tumors (NETs) of the gastrointestinal tract are a heterogeneous group of tumors which have different malignant potential and evolution. The World Health Organization (WHO) has set up a new classification of gastrointestinal NETs in 2010. However, it does not evaluate the risk of malignancy for each tumor. AIM: To evaluate the prognostic impact of the WHO classification in 2010 by reclassifying the tumor according to new recommendations and to identify histoprognostic factors to better predict changes. METHODS: This is a descriptive retrospective study of 36 cases of gastrointestinal NETs, collected at the pathological anatomy department in Rabta hospital, over a period of 11 years from 2003 to 2013. RESULTS: Our series included 11 NETs of Appendix, nine of the pancreas, seven of the small bowel, four of the stomach, three of the rectum, one of the colon and one of the esophagus. The mean age of patients across all sites, was 50.3 years old and the sex ratio was 0,44. The tumors were classified according to the 2010 WHO classification. They were divided into: G1 in 27 cases (75%); G2 in three cases (8.3%); G3 small cell carcinoma in two cases (5.6%); G3 large cell carcinoma in one case (2.8%) and mixed adeno-neuroendocrine carcinoma in three cases (8.3%). CONCLUSION: Our study has shown limits of the latest 2010 WHO classification of NETs. The prognosis of these tumors could be better predicted by the evaluation of other histoprognostic factors and by the improvement of criteria defining histological degrees including tumor size. PMID- 29512794 TI - Evaluation of the work satisfaction of the teaching physicians practicing in the hospitals of Tunis. AB - BACKGROUND: Job satisfaction is a key element in managing human resources despite the scope of practice. It is intimately linked to motivation but acts independently. AIM: To evaluate the degree of job satisfaction of the teaching physicians practicing in the hospitals of Tunis. METHODS: It was a descriptive study including a sample of 75 teaching physicians practicing in Tunis hospitals, selected randomly and anonymously with a 1:20 scale with a matching based on the grade and the speciality. The evaluation was carried out by the Saphora-Job satisfaction questionnaire. RESULTS: The 75 physicians who participated had a sex ratio (M / F) of 0.42. The Median seniority was of seven years. The majority of physicians who participated in the study had a professional experience of less than 10 years (72%) and were mostly Assistant Professors (57.3%). The overall job satisfaction rating of participants in the study was 3.13 +/- 1.2. Indicators that were related to relatively high satisfaction were represented by the relationship between colleagues, the nature of work and the adequacy of work and personal life. Indicators that were linked to the lowest satisfaction were represented by knowledge and access to regulation, remuneration and knowledge of the organization of the institution. CONCLUSION: Our study suggested the need for serious discussions between the different stakeholders about teaching physicians' salary ranges and opportunities for personal development as well as reward system for hospital-based physicians. PMID- 29512795 TI - Inhaled nitrous oxide during the make stitches : Randomized double blind prospective study. AB - INTRODUCTION: Inhaled nitrous oxide (MEOPA) ensures short-term analgesia of a patient in spontaneous ventilation through a mask. It ensures analgesic coverage during the painful gesture while saving to the patient the phenomena of memorization. AIM: To study the efficacy and safety of the use of MEOPA during the make stitches. METHODS: Randomized double blind prospective study including any patient aged > 16 years admitted to the emergency for make stitches during a period of 3 months. After consent, patients were randomized to 2 groups (MEOPA versus placebo). When the stitches were made, if the patient has a VAS (visual analog scale) > 30%, an emergency analgesia with 2% subcutaneous xylocaine is performed. The primary endpoint was the degree of analgesia according to VAS. The secondary endpoints were the occurrence of side effects, patient and operator satisfaction. RESULTS: We collected 115 patients comparable in age, sex and pain at baseline. The mean of the VAS during suturing was 11.1+/-5.8% (MEOPA) versus 47.8+/-13.9% (placebo); and the mean at the end of the procedure was 5.2+/-5% (MEOPA) versus 27.6+/-12.8% (placebo) with p=0.000. Only minor adverse events (22% versus 16%) were observed with P = 0.306. CONCLUSION: We affirm the interest of this non-invasive, safe, innocuous analgesic technique that satisfies caregivers, patients and caregivers in suturing. PMID- 29512796 TI - Adult's congenital bile duct cysts. AB - INTRODUCTION: Congenital bile duct cysts (CBDC) is a rare congenital malformation. It results from an anomaly of the biliopancreatic junction (AJBP). This condition is often diagnosed at a young age. Although, it can be asymptomatic and discovered only at an advanced age. The aim of our work was to describe the diagnosis, therapeutic and evolutionary aspects of BVCD through a series of 11 cases diagnosed in adult cases. METHODS: This is a descriptive, retrospective and monocentric study. It collects patients operated for CBDC between 01/08/1999 and 30/06/2009. RESULTS: The mean age was 45.3 years. Two men and nine women. The right hypochondria pain has been reported by all patients. On physical examination, jaundice was noted in five cases and the rest of the examination was normal. Biology showed cholestasis in six cases and cytolysis in four cases. Only one patient had hyperamylasaemia (five times normal). The preoperative diagnosis of a VBCD was reported in eight cases. Peroperative cholangiography (OCP) allowed to make the diagnosis and classify the CBDC according to the classification of Todani. Microscopic examination demonstrated three cases of associated gallbladder adenocarcinoma. The operative follow-up was simple for ten cases. A case of surgical recovery was necessary due to infection of necrotic pancreatitis. The mean follow-up was 40.6 months with extremes from one month to seven years. Only one case of death has been reported. No patient has presented a later biliary tract degeneration. Only one case of secondary biliary cirrhosis due to repeated attacks of angiocholitis has been reported. CONCLUSION: CBDC is rare. It must be suspected at any age. It is characterized by the increased risk of degeneration. Radiological examinations can suspect the diagnosis in younger and asymptomatic patients to ensure a well-conducted and timely surgical treatment. PMID- 29512797 TI - Epidemiological, clinical and pronostic aspects of multiple myeloma eligible for therapeutic intensification followed by autologous hematopoietic stem cell in the Algerian West: report of 147 cases. AB - BACKGROUND: Multiple Myeloma (MM) represent about 1 to 2% of cancers and 15% of all hematological malignancies. It is characterized by malignant proliferation of plasmocytes in bone marrow and an excess of secreted monoclonal immunoglobulins (Ig) Objective: Describe the epidemiological, clinical, biological and prognosis of patients with MM treated with autologous peripheral hematopoietic stem cell transplantation (APHSCT) in the Algerian West. METHODS: It is a retrospective descriptive study covering all MM patients treated with APHSCT over a period of 7 years (2008-2015) at service of Haematology and Cell Therapy of the EHU "1er November 1954 of Oran, Algeria. RESULTS: During the study, we collected 147 MM patients treated with APHSCT. The median age of the population was 53 years with a male predominance and a sex ratio of 1.53. Clinically, bone syndrome was found in 75.51% of cases. Paraclinaclly, anemia was found in 78.52% of patients, hyperprotidemy in 59.06%. A monoclonal peak in serum protein electrophoresis was noted in 80.54% of cases. Isotype repartition was: IgG (61.04%), IgA (19.17%), monoclonal light chains (16.11%). A plasmocytosis more than 10% was detected in 89.79% of cases. According to the Durie and Salmon classification, all of our patients were classified as stage III. The average survival time was thirty months. CONCLUSION: The majority of our patients had advanced stage of MM to the presentation and the median survival was not reached thus emphasizing a high rate of remission and marks an important advance in the care of MM in Algeria. PMID- 29512798 TI - Death certificate accuracy in a Tunisian Emergency Department. AB - OBJECTIVE: Assess Death Certificates accuracy (DCs) issued by a teaching emergency department in Tunis. METHODS: It is a descriptive study. We included all death certificates issued in the Emergency Department of a teaching Hospital in Tunis over 17 months period (October 2013 - March 2014). Twenty-one errors have been predefined and classified as "Editing errors" or "Medical analysis error" then as major or minor errors. RESULTS: 757 certificates were studied; all DCs had at least three errors with an average number of errors of 6.92+/-1.55. The mechanism of death was inadequate in 20% of the DCs. The cause of death was "unacceptable" in 21% of the DCs. CONCLUSION: The results are similar to those reported in international literature. Therefore, it is urgent to start working on further and regular training on how to fulfil a death certificate for undergraduate and postgraduate medical students. PMID- 29512799 TI - Cardiac metastases: 4 cases report. AB - Cardiac metastases are rare. They are found in one to 10% of autopsies of patients withmalignant neoplasm. Adenocarcinoma represents the most common histologicaltype. The most common neoplasms that metastasize to the heart are lung andbreast cancers, melanoma, mesothelioma and lymphoma. However, Cardiacinvolvement is unusual in Hepatic, cutaneous and gastric cancer. We reportedthese three primary localizations in our cases. PMID- 29512800 TI - Extracapsular involvement in nodal metastasis as a prognostic factor in colorectal cancer. AB - BACKGROUND: Extracapsular extension of nodal metastasis has recently emerged as an important prognostic factor in different malignancies. In colorectal cancer (CRC), only a limited number of studies have been published and its prognostic value has not yet been completely established. AIMS: To assess the incidence of extracapsular invasion (ECI) in lymph node (LN) metastasis in colorectal adenocarcinoma and to investigate the correlation between this parameter and other clinico-pathological factors. Furthermore, its effect on overall and disease free survival were evaluated. METHODS: Seventy-five patients who underwent colorectal resection for adenocarcinoma with node metastasis were included in this study. Extracapsular invasion was evaluated by two pathologists. Associations between clinicopathologic factors, survival, and the nodal findings were evaluated. The 2009 pTNM staging of CRC was used. RESULTS: Extracapsular invasion was identified in 45 patients (60 %). Average follow-up time was 25 months. Extracapsular invasion was correlated with pT stage> pT2 (p=0,015), pN stage > pN1 (p= 0,014), distant metastasis at diagnosis (p=0,005) and later (p=0,01) and with local recurrences (p=0,0001). Univariate analysis indicated that ECI tends to decrease overall survival but not significantly. Multivariate analysis showed that age and synchronic metastasis were independent prognostic factors (HR = 2,03 and 2,24; p= 0,039 and 0,012 respectively). Patients with ECI had a significantly worse five-year disease-free survival than ECI-negative groups. CONCLUSION: In patients with CRC, ECI in regional LNs would reflect an aggressive behavior. It would therefore be useful to include this parameter in standardized pathologic reports and future staging systems. PMID- 29512801 TI - Long term results of laparoscopic gastric band. AB - BACKGROUND: Laparoscopic gastric band (LAGB) has gained popularity among the surgical community since its first description in the early 90'. Actually, it is the third most practiced bariatric procedure in the world. The mean advantage of LAGB is a low rate of early postoperative morbidity. These satisfactory early results are in complete opposition with relatively high long term morbidity and a high rate of weight loss failure. AIM: Long term morbidity, weight loss and life quality index after LAGB were analyzed. METHODS: Data of patients eligible for LAGB between January 2005 and November 2016 in the surgical department of La Rabta teaching hospital were retrospectively analyzed. Weight loss curves, long term complications and quality of life were evaluated. RESULTS: Between 2004 and 2008, 28 patients had LAGB. Mean preoperative BMI was 44.6 Kg/m2. No immediate complications occurred. Mean EWL were 39% and 37% respectively after 24 and 60 months. EWL was above 50% in only 4 patients. Coming to long term morbidity, 10 (35%) patients had complications. Reintervention rate was 39%. The gastric band was removed in 9 (32%) patients. Mean quality of life BAROS score was 4.21. CONCLUSIONS: Judging for its long term morbidity with a high reintervention rate, the LAGB raises the question of its valuable position as a surgical procedure against morbid obesity. PMID- 29512802 TI - Unilateral proptosis revealing a fronto-ethmoidal mucocele. AB - : Backgroud: The fronto-ethmoidal mucocele is a benign condition leading commonly to limited eye movement or ocular pain but it could also induce visual acuity impairment by compressing the optic nerve Aim: To discuss, through a case report, different ophthalmologic manifestations of the fronto-ethmoidalmucocele. Reported case: A 46-years-old man with no general history consulted for a bilateral ocular redness and itching. He reported, however, a mild protrusion of his left globe evolving for oneyear. The clinical examination revealed a unilateral proptosis in the left eye with a discrete limitation of theadduction. A brain and orbital computer tomography (CT)and a magnetic resonance imaging(MRI)revealed a grade I exophthalmos caused by an oval formation of fluid density in the left anterior and posterior ethmoidal cells in addition to the frontal sinus,driving theeyeball and internal oculomotor muscles back and out.The patient was referred to otorhinolaryngology department for a precocious surgical management. CONCLUSION: The ophtalmologic manifestations of the disease depend on the location, the size of the formation and involvement of adjacent structures. The loss of vision and the apex syndrome due to the compressionof the ocular globe are the most serious complications. PMID- 29512803 TI - Attempted suicide by Flecainide overdose: A case report. AB - Class Ic antiarrythmic overdose is associated with a relatively high mortality. We presenta case report regarding a suicidal intoxication of an 18-year old female with a medical history of Wolff-Parkinson-White syndrome. The preliminary examination highlighted a profound cardiovascular collapse. The electrocardiogram showed a PR interval extended to 360 ms. The QRS complexes were enlarged to 360 ms with a right bundle brunch block appearance associated with left posterior hemibloc. There were repolarization abnormalities such as elevation of the J point, convex ST segment and biphasic T wave in the right precordial leads ("Brugada-Like ECG pattern"). Sodium bicarbonate was administered. A rapid decrease in the duration of the QRS complexes was noted as well as a slowing of the heart rate. The electrocardiogram aspect on the 4th day showed the reappearance of the ventricular pre-excitation. The severity and lethal potential of Flecainide poisoning are linked to the cardiotoxic effects of these molecules. The prognosis remains poor despite progress in intensive care procedures. PMID- 29512804 TI - Malignant transformation of nasal inverted papilloma into sarcomatoid carcinoma. AB - A 57 year-old, male presented with a chronic unilateral nasal obstruction and epistaxis. Intranasal endoscopy showed multiple polypoid lesions. The computed tomography exam revealed a heterogeneous mass that occupied the right nasal cavity with osteolysis of the middle and lower cone causing fluid retention of the right maxillary sinus. He underwent resection of these lesions. Pathological examination revealed malignant transformation of nasal inverted papilloma into sarcomatoid carcinoma. This case report highlights the importance of considering malignant transformation in the differential diagnosis of polypoid lesions. PMID- 29512805 TI - Warthin-like papillary carcinoma associated with Hashimoto thyroiditis and systemic granulomatosis: a case report. PMID- 29512806 TI - A severe anti MDA-5 antibodies associated amyopathic dermatomyositis. AB - BACKGROUND: Lung damage during amyopathic dermatomyositis (ADM) associated with auto antibodies anti MDA-5 is serious. We report a rare observation of a severe ADM associated to anti MDA-5 antibodies complicated with diffuse interstitial lung disease (ILD) rapidly extensive and fatal. OBSERVATION: We report the observation of a Tunisian adult who was admitted for ADM. The anti MDA-5 antibodies were detected. He developed an ILD rapidly extensive to fibrosis. Corticosteroids were unefficient and he deceded of pneumomediastin and refractory respiratory distress. CONCLUSION: This observation illustrates the severity of ADM with anti MDA-5 antibodies. Every clinician should detect any ILD to avoid the progression to fibrosis. PMID- 29512807 TI - Fistulizing nodular lymphoid hyperplasia. AB - BACKGROUND: Nodular lymphoid hyperplasia (NLH) of the gastrointestinal (GI) tract is a rare condition in adults. It is usually asymptomatic. Few complications have been described. AIM: We report an unusual clinical presentation of focal lymphoid hyperplasia of the GI. CASE REPORT: A 23-year-old female patient presented with a fistulizingdisease of the terminal ileum and the caecum complicated with an abscess of the lower right quadrant if the abdomen. CT-guided drainage with antibiotic therapy failed to control the abscess. Thus, surgery was undertaken and ileocaecal resection was performed. Focal lymphoid hyperplasia was confirmed by the pathology of the specimen. CONCLUSIONS: NLH is an uncommon condition in adults. To the best of our knowledge, no previous cases have been reported with fistulizing NLH. The management should follow the same algorithm as fistulizing ileitis. Surgery is indicated only in cases of complicated disease after the failure of medical treatment. PMID- 29512808 TI - Urethral funneling visualized during pelvic floor sonography - analysis of occurrence among urogynecological patients. AB - OBJECTIVES: There are different diagnostic methods used in women with urinary incontinence symptoms such as: medical history, voiding diary, cough test, pad test, urodynamic testing. None of them is optimal. The aim of this study is to analyze the correlation between urethral funneling visualized during pelvic floor sonography and symptoms of stress urinary incontinence. MATERIAL AND METHODS: We have performed a retrospective analysis of 657 complete datasets of patients who attended our urogynecological clinic for diagnostics. Women with wet overactive bladder were excluded from the analysis. Tests used in our clinic included: standardized interview and questionnaire, clinical exam, cough test. Pelvic floor sonography with a transvaginal probe in women with filled bladder was performed to assess the urethral length and the urethral funneling during maximal Valsalva maneuver. RESULTS: In all patients with clinical SUI symptoms and with a positive cough test the urethral funneling length during Valsalva maneuver was > 50% of urethral length (long urethral funneling). In 83.7% of women without SUI the urethral funneling was absent. In the remaining 16.3% funneling was visible but its relative length was less than 50% of urethral length and urine flow was not observed (short urethral funneling). CONCLUSIONS: Long urethral funneling (> 50% of urethral length) seems to be a characteristic sign for SUI in women. The presence of urethral funneling shorter than 50% of urethral length (short urethral funneling) is not a SUI symptom - it is probably a sign of asymptomatic funneling of bladder neck. PMID- 29512809 TI - The prevelance of human papillomavirus (HPV) genotypes detected by PCR in women with normal and abnormal cervico-vaginal cytology. AB - OBJECTIVES: Cervical cancer is the second most common type of cancer for women worldwide with a great proportion proved to be related to human papillomavirus (HPV) infection. As infection with HPV is the strongest risk factor for cervical neoplasia, detection of HPV genotypes in cervical and vaginal specimens of women with normal and abnormal cytology seems to be of paramount importance in cervical cancer screening. The objective of the study is to evaluate the prevalence and HPV genotypes among women with normal or abnormal Pap smear tests. MATERIAL AND METHODS: This retrospective study was conducted in a tertiary care university hospital in western Turkey. A total of 201 patients in whom both HPV typing and Pap test was performed between 2012 and 2016 in our obstetrics and gynecology department were enrolled in this study. Clinical and laboratory data were obtained for all participants. Cervical smears of the patients were classified by the Bethesda system and HPV analyses were done using the polymerase chain reaction (PCR) method. RESULTS: This study included 201 women, 72 of whom had normal and 129 of whom had abnormal Pap smear results. HPV DNA was detected in 91 (45.2%) of the 201 investigated women. Out of 72 patients with normal cervico vaginal cytology, HPV positivity was detected in 35 (49%) patients, whereas 33 (35%) patients out of 94 with ASCUS , 18 (62%) patients out of 29 with LSIL and 5 (83%) patients out of 6 with HSIL had HPV positivity. Out of 35 HPV positive women that had normal pap test results, 25 (75%) were found to have high risk HPV (HR-HPV) genotypes. In women with ASCUS, LSIL and HSIL, HR-HPV genotype rates were found to be 94%, 89% and 100% respectively. The most common identified HPV types were HPV58, HPV16, HPV31, HPV33, HPV11 and HPV35. CONCLUSIONS: The frequency of HPV infection was found to be higher in our study compared to previous reports. Moreover, although HR-HPV genotypes were also detected in patients with normal cervical cytology, a majority of patients with HR-HPV genotypes were associated with abnormal cervical smear cytology including high rates of atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion. PMID- 29512810 TI - Barriers to cervical cancer screening exist despite integrating HIV and gynaecological services for HIV-positive women in Poland. AB - OBJECTIVES: HIV-positive women are at increased risk of HPV infection and cervical cancer. European and national guidelines advise yearly screening for cervical cancer, however due to the lack of a central registration of HIV infected persons there is a gap in offering such care through general healthcare services in many countries, including Poland. MATERIAL AND METHODS: In response to the above limitations, integrated gynaecological care (IGC) was established at the HIV Out-Patient Clinic in Warsaw. We analysed data from January 2007 to May 2014. Logistic regression models were used to identify factors associated with not using IGC by patients. RESULTS: Two hundred and forty women were registered in the observation period:59.6% infected through sexual contact, 18.7% through IDUs, 19.2 % through unknown causes and 2.5% by other (two were vertically infected). The median follow-up time was 2.35 (IQR 0.9-4.5) years and 78.3% were on combination antiretroviral therapy (cART). In total 145 of the women (60.4%) used IGC, from 72.1% of those registered in 2007 to 27.3% registered in 2014. There were in total 1075 gynaeco-logical visits and 254 cervical cytology tests performed. Seventy-five (51.7%) women were tested for HPV infection. Fac-tors decreasing the odds of not using IGC identified by multivariate regression models were being on cART (OR 0.25 [IQR: 0.10-0.59]; p = 0.003) and longer time of observation (0.69 [0.58-0.83]; p = 0.0001). CONCLUSIONS: The utilisation of IGC was very high, but with a delay in commencing the IGC. Women on cART and with longer periods of follow-up had lower odds of not using IGC. A screening approach for women not yet on cART, or newly registered in the clinics, needs special attention. PMID- 29512811 TI - Planning and preparation for pregnancy among women with and without a history of infertility. AB - OBJECTIVES: Preconception counseling, maternal health-related habits, diet, folic acid consumption, substances abuse, may all impact the outcome of pregnancy. The aim of this study was to compare the planning and preparation for pregnancy among pregnant women with and without infertility. MATERIAL AND METHODS: A survey of health behaviors prior to and during pregnancy that could affect pregnancy outcomes, including laboratory tests performed, stimulant usage, initiation of prenatal care, and folic acid intake, was conducted among 400 pregnant women. The study group included 121 women (30.25%) diagnosed with prior infertility, while the control group included 279 women (69.74%) who did not report any problems conceiving. RESULTS: All patients (100%) from the study group and 70,97% from the control group planned their pregnancy(p < 0.0001). Patients in the study group performed significantly more laboratory tests prior to pregnancy, including: complete blood count, urine analysis, fasting blood glucose concentration, testing for toxoplasmosis, and Pap smear, compared with the control group (p < 0.0001). There was no difference between groups regarding the knowledge of when and why folic acid supplementation is required (p > 0.05). CONCLUSIONS: Effective education of women, regarding pregnancy planning and behaviours, that may impact pregnancy outcome is still a serious challange to public health in Poland. Our study indicates that reaching general population with the education is most important to achieve best results in preconceptional care. PMID- 29512812 TI - The impact of physical activity during pregnancy on maternal weight and obstetric outcomes. AB - OBJECTIVES: The goal of the paper was to compare weight gain in pregnant women in relation to the week of gestation at birth, the delivery method, and the occurrence of macrosomia and low birth weights for patients with different durations of physical activity during pregnancy. MATERIALS AND METHODS: The full course of study was completed by 57 pregnant women enrolled in an 18-week physical activity programme during their second and third trimesters. The actual duration of their physical activity was monitored with the ActiGraph GT3X monitor. The patients were divided into two groups: L_MPA (n = 28) - pregnant women with daily physical activity of over 21.38 minutes and S_MPA (n = 29) - pregnant women who exercised less than 21.38 minutes a day. The study compared obstetric results in both groups. RESULTS: Significantly more patients in the S_MPA group exhibited excess weight gain as compared with the L_MPA group (p = 0.01). There was found to be no significant impact from the duration of physical activity on the occurrence of macrosomia or low birth weight, the gestation age at birth or the delivery method. However, there were two times fewer cases of macrosomia in the L_MPA group. CONCLUSIONS: The results demonstrate that physical activity during pregnancy for at least 21 minutes per day in the second half of the pregnancy reduces the risk of excess weight gain during pregnancy. PMID- 29512814 TI - Diastasis recti abdominis - a review of treatment methods. AB - Diastasis recti abdominis is a condition in which both rectus abdominis muscles disintegrate to the sides, this being ac-companied by the extension of the linea alba tissue and bulging of the abdominal wall. DRA may result in the herniation of the abdominal viscera, but it is not a hernia per se. DRA is common in the female population during pregnancy and in the postpartum period. There is a scant knowledge on the prevalence, risk factors, prevention or management of the abovemen-tioned condition. The aim of this paper is to present the methods of DRA treatment based on the results of recent studies. PMID- 29512813 TI - Evaluation of the effectiveness of the Quadratus Lumborum Block type I using ropivacaine in postoperative analgesia after a cesarean section - a controlled clinical study. AB - OBJECTIVES: Quadratus Lumborum Block in contrast to Transversus Abdominis Plane Block contains a unique component which not only stops somatic pain but also inhibits visceral pain by spreading the local anesthetic to the paravertebral space. This study was designed to determine whether performing the Quadratus Lumborum Block type I in patients un-dergoing cesarean section would be associated with both decreased morphine consumption and decreased pain levels in the postoperative 48-hour period. MATERIAL AND METHODS: Sixty patients undergoing caesarean section under spinal anesthesia were randomly and equally assigned to one or other of two groups: QLB I (who received Bilateral Quadratus Lumborum Block type I with the use of 24 mL 0.375% ropivacaine per side) or a Control group. In both groups, on-demand morphine analgesia was administered postoperatively within the first 48 hours. The following were measured: the morphine consumption; the time elapsed from the C-section until the first dose of morphine; and the levels of pain intensity among patients in rest (numeral pain rating scale). RESULTS: There were no statistically significant demographic data differences between the QLB I and Control groups. The following significant differences were observed in the 48-hour postoperative period: morphine consumption was higher in the Control group (p = 0.000); the time elapsed from the C-section until the first dose of morphine was longer in QLB I group (p < 0.05); and the median of the pain numeric rating scale was higher in the Control group (p < 0.05). CONCLUSIONS: Quadratus Lumborum Block type I significantly reduces morphine consumption and pain levels up to 48 hours postoperatively. PMID- 29512815 TI - The phenomenon of pregnancy - a psychological view. AB - Pregnancy is a very specific and complex period in a woman's life. The accompanying changes are observed not only on the biological/physiological plane but also in her psychological and social functioning. Altered psychological functioning can occur from the very beginning to the end of pregnancy, including the postpartum period. During pregnancy, visible changes occur in the body's appearance, as well as in femininity, affections, and sexuality, whereas the woman's position and role are gaining new qualities. To a greater or lesser degree, every expectant mother experiences psychological am-bivalence, frequent mood changes from exhaustion to exaltation, emotional disturbances, and/or mixed anxiety-depressive disorder. In addition, pregnancy causes a number of specific apprehensions concerning the course and outcome, which makes the woman particularly vulnerable and requires adequate treatment, depending on the adaptive capacities of her personality. Furthermore, from a psychosocial aspect, pregnancy could be considered a specific highly emotional state, which may be a potent stressor. Perinatal maternal stress can lead to different complications that may have far-reaching consequences for both somatic and psychic functioning of the newborn. This review considers pregnancy as a complex psychological phenomenon and explores multiple changes in the woman's psychological functioning in both normal and psychologically complicated courses of pregnancy. PMID- 29512816 TI - The practical use of acetylsalicylic acid in the era of the ASPRE trial. Update and literature review. AB - It is now well established that acetylsalicylic acid - one of the most widely prescribed drugs today - has brought a new era in maternal-fetal medicine. The History of medicine mentions several antecedents. Extracts made from willow contained in clay tablets are reported in both ancient Sumer and Egypt. In 400 BC, Hippocrates referred to the use of salicylic tea to reduce fevers. In the 1950s, acetylsalicylic acid entered the Guinness Book of Records as the highest selling painkiller. There is little doubt that acetylsalicylic acid - one of the first drugs to enter common usage - remains one of the most researched drugs in the world. PMID- 29512817 TI - Treatment of congenital nephrogenic diabetes insipidus in pregnancy. PMID- 29512818 TI - Antibiotics at the time of removal of central venous catheter to reduce morbidity and mortality in newborn infants. AB - BACKGROUND: Late-onset sepsis is associated with increased rates of mortality and morbidity in newborn infants, in addition to poorer long-term developmental outcomes and increased length of stay and hospital costs. Central line-associated blood stream infection (CLABSI) is the most common cause of late-onset sepsis in hospitalised infants, and prevention of CLABSI is a key objective in neonatal care. Increased frequency of CLABSI around the time of removal of central venous catheters (CVCs) has been reported, and use of antibiotics at the time of removal may reduce the incidence and impact of late-onset sepsis in vulnerable newborn infants. OBJECTIVES: To determine the efficacy and safety of giving antibiotics at the time of removal of a central venous catheter (CVC) for reduction of morbidity and mortality in newborn infants, in particular effects on late-onset sepsis. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group without language restriction to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3), MEDLINE via PubMed (1966 to 6 April 2017), Embase (1980 to 6 April 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 6 April 2017). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised, quasi-randomised, and cluster-randomised trials considering use of any antibiotic or combination of antibiotics at the time of CVC removal in newborn infants compared with placebo, no antibiotics, or another antibiotic or combination of antibiotics. DATA COLLECTION AND ANALYSIS: We extracted data using standard methods of the Cochrane Neonatal Review Group. Two review authors independently selected, assessed the quality of, and extracted data from the included study. MAIN RESULTS: Only one randomised controlled trial was eligible for inclusion in this analysis. Forty-four of a total of 88 infants received two doses of cephazolin at the time of removal of CVC compared with no antibiotics at the time of removal of CVC in the control group. No infant in the intervention group developed late-onset sepsis after CVC removal compared with five of 44 (11%) in the control group (risk ratio (RR) 0.09, 95% confidence interval (CI) 0.01 to 1.60). Cephazolin given at the time of removal of CVC did not statistically significantly alter late-onset sepsis rates and led to no significant differences in any of the prespecified outcomes. Review authors judged the study to be of low quality because of high risk of bias and imprecision. AUTHORS' CONCLUSIONS: Randomised controlled trials have provided inadequate evidence for assessment of the efficacy or safety of antibiotics given at the time of CVC removal. The single identified trial was underpowered to address this question. Future research should be directed towards targeting use of antibiotics upon removal of CVC for those at greatest risk of complications from CVC removal-related CLABSI. Researchers should include safety data such as impact upon antibiotic use and resistance patterns. This investigation would best occur as part of a bundle of quality improvement care interventions provided by neonatal networks. PMID- 29512819 TI - Maternal steroid therapy for fetuses with second-degree immune-mediated congenital atrioventricular block: a systematic review and meta-analysis. AB - INTRODUCTION: The aim of this study was to explore the effect of maternal fluorinated steroid therapy on fetuses affected by second-degree immune-mediated congenital atrioventricular block. MATERIAL AND METHODS: Studies reporting the outcome of fetuses with second-degree immune-mediated congenital atrioventricular block diagnosed on prenatal ultrasound and treated with fluorinated steroids compared with those not treated were included. The primary outcome was the overall progression of congenital atrioventricular block to either continuous or intermittent third-degree congenital atrioventricular block at birth. Meta analyses of proportions using random effect model and meta-analyses using individual data random-effect logistic regression were used. RESULTS: Five studies (71 fetuses) were included. The progression rate to congenital atrioventricular block at birth in fetuses treated with steroids was 52% (95% confidence interval 23-79) and in fetuses not receiving steroid therapy 73% (95% confidence interval 39-94). The overall rate of regression to either first degree, intermittent first-/second-degree or sinus rhythm in fetuses treated with steroids was 25% (95% confidence interval 12-41) compared with 23% (95% confidence interval 8-44) in those not treated. Stable (constant) second-degree congenital atrioventricular block at birth was present in 11% (95% confidence interval 2-27) of cases in the treated group and in none of the newborns in the untreated group, whereas complete regression to sinus rhythm occurred in 21% (95% confidence interval 6-42) of fetuses receiving steroids vs. 9% (95% confidence interval 0-41) of those untreated. CONCLUSIONS: There is still limited evidence as to the benefit of administered fluorinated steroids in terms of affecting outcome of fetuses with second-degree immune-mediated congenital atrioventricular block. PMID- 29512820 TI - Attitudes toward surrogacy among doctors working in reproductive medicine and obstetric care in Sweden. AB - INTRODUCTION: The aim of this study was to investigate attitudes and opinions towards surrogacy among physicians working within obstetrics and reproductive medicine in Sweden. MATERIAL AND METHODS: Physicians working within medically assisted reproduction (MAR), antenatal care and obstetrics were invited to participate in a cross-sectional nationwide survey study. The study-specific questionnaire measured attitudes and experiences in three domains: attitudes towards surrogacy, assessment of prospective surrogate mothers, and antenatal and obstetric care for surrogate mothers. RESULTS: Of the 103 physicians who participated (response rate 74%), 63% were positive or neutral towards altruistic surrogacy being introduced in Sweden. However, only 28% thought that it should be publicly financed. Physicians working at fertility clinics were more positive towards legalization as well as public financing of surrogacy compared than were those working within antenatal and delivery care. The majority of the physicians agreed that surrogacy involves the risk of exploitation of women's bodies (60%) and that there is a risk that the commissioning couple might pay the surrogate mother "under the table" (82%). They also expressed concerns about potential surrogate mothers not being able to understand fully the risks of entering pregnancy on behalf of someone else. CONCLUSION: There is a relatively strong support among physicians working within obstetrics and reproductive medicine for the introduction of surrogacy in Sweden. However, the physicians expressed concerns about the surrogate mothers' health as well as the risk of coercion. Further discussions about legalization of surrogacy should include views from individuals within a wide field of different medical professions and laymen. PMID- 29512821 TI - Photocycle of Sensory Rhodopsin II from Halobacterium salinarum (HsSRII): Mutation of D103 Accelerates M Decay and Changes the Decay Pathway of a 13-cis O like Species. AB - Aspartic acid 103 (D103) of sensory rhodopsin II from Halobacterium salinarum (HsSRII, or also called phoborhodopsin) corresponds to D115 of bacteriorhodopsin (BR). This amino acid residue is functionally important in BR. This work reveals that a substitution of D103 with asparagine (D103N) or glutamic acid (D103E) can cause large changes in HsSRII photocycle. These changes include (1) shortened lifetime of the M intermediate in the following order: the wild-type > D103N > D103E; (2) altered decay pathway of a 13-cis O-like species. The 13-cis O-like species, tentatively named Px, was detected in HsSRII photocycle. Px appeared to undergo branched reactions at 0 degrees C, leading to a recovery of the unphotolyzed state and formation of a metastable intermediate, named P370, that slowly decayed to the unphotolyzed state at room temperature. In wild-type HsSRII at 0 degrees C, Px mainly decayed to the unphotolyzed state, and the decay reaction toward P370 was negligible. In mutant D103E at 0 degrees C, Px decayed to P370, while the recovery of the unphotolyzed state became unobservable. In mutant D103N, the two reactions proceeded at comparable rates. Thus, D103 of HsSRII may play an important role in regulation of the photocycle of HsSRII. PMID- 29512822 TI - Mean Streets and Mental Health: Depression and Post-Traumatic Stress Disorder at Crime Hot Spots. AB - This study explores the relationship between mental health and place at microgeographic units of analysis. We examine self-reported symptomology for depression and PTSD for 2,724 survey respondents interviewed in three types of randomly selected street segments: violent crime hot spots, cool spots, and cold spots. We find that the mean symptomology score is 61% higher for depression in violent crime hot spots than cold spots, and 85% higher for PTSD. Overall, we estimate that 14.8% of residents of violent crime hot spots meet thresholds for moderate depression or a diagnosis of PTSD. This can be compared to only 6.5% of residents at the cold spots. Using PSM and weighted negative binomial regression approaches we show that observable selection factors are not responsible for the relationships identified. Examining geographic influences, we find an important area effect of violent crime for both mental health measures, and an additional impact of the specific street of residence for PTSD. PMID- 29512823 TI - Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: Implications for B-cell selection. AB - Autoreactive B cells have a central role in the pathogenesis of rheumatoid arthritis (RA), and recent findings have proposed that anti-citrullinated protein autoantibodies (ACPA) may be directly pathogenic. Herein, we demonstrate the frequency of variable-region glycosylation in single-cell cloned mAbs. A total of 14 ACPA mAbs were evaluated for predicted N-linked glycosylation motifs in silico, and compared to 452 highly-mutated mAbs from RA patients and controls. Variable region N-linked motifs (N-X-S/T) were strikingly prevalent within ACPA (100%) compared to somatically hypermutated (SHM) RA bone marrow plasma cells (21%), and synovial plasma cells from seropositive (39%) and seronegative RA (7%). When normalized for SHM, ACPA still had significantly higher frequency of N linked motifs compared to all studied mAbs including highly mutated HIV broadly neutralizing and malaria-associated mAbs. The Fab glycans of ACPA-mAbs were highly sialylated, contributed to altered charge, but did not influence antigen binding. The analysis revealed evidence of unusual B-cell selection pressure and SHM-mediated decrease in surface charge and isoelectric point in ACPA. It is still unknown how these distinct features of anti-citrulline immunity may have an impact on pathogenesis. However, it is evident that they offer selective advantages for ACPA+ B cells, possibly through non-antigen driven mechanisms. PMID- 29512824 TI - Improved cardiac outcomes with combined atenolol and diazepam intervention in seizure. AB - OBJECTIVE: Altered autonomic activity has been implicated in the development of cardiac dysfunction during seizures. This study investigates whether intervening in seizure progression with diazepam will reduce seizure-induced cardiomyopathy. Second, this study examines the hypothesis that combining atenolol with diazepam, as an intervention after seizure onset, will combat cardiac injury during status epilepticus. METHODS: Male Sprague-Dawley rats were implanted with electroencephalographic/electrocardiographic electrodes to allow simultaneous recordings during seizures induced by intrahippocampal (2 nmol, 1 MUL) kainic acid (KA). Subcutaneous saline, atenolol (5 mg.kg-1 ), diazepam (5 mg.kg-1 ), or atenolol and diazepam (n = 12/group) were administered at 60 minutes post-KA and daily for 7 days, at which point echocardiography, susceptibility to aconitine induced arrhythmias, and histology were evaluated. RESULTS: Seizure activity was associated with immediately increased heart rate, QTc interval, and blood pressure (BP; 10%-30% across indices). Seven days postseizure, saline-treated animals were found to have reduced left ventricular function, increased fibrotic scarring, and an elevated risk of aconitine-induced arrhythmias. Diazepam treatment significantly reduced cumulative seizure behaviors by 79% compared to saline-treated animals but offered no cardiac protection. Diazepam significantly raised BP (35%) and increased the risk of bigeminal arrhythmias (36%) compared to saline-treated animals. Atenolol administration, either alone or with diazepam, reduced heart rate, QTc interval, and BP back to control levels. Atenolol also preserved cardiac morphology and reduced arrhythmia risk. SIGNIFICANCE: Attenuation of seizure with diazepam offered no cardiac protection; however, coadministration of atenolol with diazepam prevented the development of seizure induced cardiac dysfunction. This study demonstrates that atenolol intervention should be strongly considered as an adjunct clinical treatment to reduce cardiomyopathy during seizures. PMID- 29512825 TI - Authors' Reply. PMID- 29512826 TI - Risk factors for discontinuation of thyroid hormone replacement therapy in early pregnancy: a study from the Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway. AB - INTRODUCTION: Approximately 3-5% of pregnant women have hypothyroidism. Despite the potential impact of untreated hypothyroidism on infant neurodevelopment, few studies have investigated the risk factors associated with discontinuation of thyroid hormone replacement therapy (THRT) in pregnancy. We aimed to identify such factors in a population of women using THRT prior to pregnancy. MATERIAL AND METHODS: Data from the Norwegian Mother and Child Cohort Study were linked to records in the Medical Birth Registry of Norway. Pregnant women with hypothyroidism prior to pregnancy were categorized as discontinuers or continuers of THRT in pregnancy. The main analysis used generalized estimating equations based on multiply imputed data. RESULTS: Of 86 848 enrolled pregnant women, 2720 (3.2%) had a medically confirmed thyroid disorder and/or reported use of thyroid therapy. More than half (n = 1587; 57.8%) used THRT prior to pregnancy; of these, 207 (13.0%) discontinued and 1380 (86.9%) continued THRT during early pregnancy. Having a non-medicated mental disorder [odds ratio (OR) 1.64, 95% CI 1.03-2.63] and non-compliance with recommended nutritional supplementation (OR 2.51, 95% CI 1.82-3.47) increased the odds of discontinuing THRT. Women medicated for somatic comorbidities (OR 0.56, 95% CI 0.33-0.98) had a 44% decreased odds of discontinuing THRT. CONCLUSIONS: In Norway, around 13% of women with hypothyroidism discontinue THRT in early pregnancy. For discontinuers, non medicated mental comorbidity and non-compliance with nutritional supplements presented increased risk, whereas having a medicated somatic disorder was protective. Health professionals advising women with hypothyroidism should be aware of risk factors associated with THRT discontinuation. PMID- 29512828 TI - Strategies and dental care in the treatment of patients with myelomeningocele. AB - Myelomeningocele (MMC) is a congenital malformation that occurs in the embryonic period, characterized by failure in closure of the caudal portion of the neural tube during central nervous system formation. Alterations and complications can be associated with this condition, such as hydrocephalus, neurogenic bladder, orthopedic problems, and motor and cognitive impairment. This patients with MMC also have predisposition to develop latex allergy and high caries risk and activity due to deficient oral hygiene, fermentable carbon hydrate-rich diet and prolonged use of sugar-containing oral medications. This paper reports the oral findings and dental treatment in a 15-year-old female patient diagnosed with MMC and describes the strategies used to improve dental treatment conditions and reduce the impact of associated risks to her health. The measures and precautions adopted in this case could be useful to reduce the barriers for patients with the same condition to access oral health care: regular visits to the dentist, initiating as early as possible; frequent reinforcement of oral homecare instructions and diet counseling; minor adaptions to the dental chair and dental office to improve ease of access due to patients' mobility problems; prevention of latex-related allergic reactions; reduction of gag reflex during dental procedures. PMID- 29512827 TI - Short course of grass allergen peptides immunotherapy over 3 weeks reduces seasonal symptoms in allergic rhinoconjunctivitis with/without asthma: A randomized, multicenter, double-blind, placebo-controlled trial. AB - BACKGROUND: Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 MUg LPP administered subcutaneously over 3 weeks. METHODS: In a randomized, double-blind, placebo-controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 MUg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) was assessed as secondary endpoints. RESULTS: The mean reduction in CSMS in the LPP vs placebo group was 15.5% (P = .041) during the peak period and -17.9% (P = .029) over the entire pollen season. LPP-treated group had a reduced reactivity to CPT (P < .001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed <=30 minutes in 10.5% of LPP-treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication. CONCLUSION: Lolium perenne pollen peptides administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms and was generally safe and well-tolerated. PMID- 29512829 TI - Hepatic angiomyolipoma: mutation analysis and immunohistochemical pitfalls in diagnosis. AB - AIMS: Hepatic angiomyolipoma (AML) often shows epithelioid morphology with inconspicuous fat. Epithelioid component can mimic hepatocellular adenoma (HCA) or carcinoma (HCC). The aims of this study were to examine the expression of commonly used markers for HCA or HCC in hepatic AML and highlight pitfalls in diagnosis. METHODS AND RESULTS: Resected hepatic AMLs (n = 16) were reviewed; reticulin stain, immunohistochemistry for glutamine synthetase (GS), beta-catenin and liver fatty acid binding protein (LFABP) were performed along with Sanger sequencing of exon 3 of CTNNB1 and next-generation sequencing (NGS). Predominant epithelioid component (>=50%) was seen in 80% of cases. Foamy macrophage was present in 33% of cases. High-risk histological features were often present in tumours with benign outcome: marked atypia (19%), mitoses (20%) and necrosis (33%). GS staining (>=10% of tumour) was seen in epithelioid components in 13 (87%) cases, and was diffuse (>50% of tumour) in six (40%) cases. LFABP staining or nuclear beta-catenin staining was not seen in any case. Sanger sequencing and NGS did not reveal CTNNB1 mutation in any tested case. NGS demonstrated TSC2 mutations in all five cases tested. CONCLUSIONS: The predominance of epithelioid component resembling HCA or HCC is common in hepatic AML. Absence of LFABP and presence of fat can be mistaken for HNF1alpha-inactivated HCA. Diffuse GS staining can be mistaken for beta-catenin-activated HCA or HCC. Diffuse GS expression is not related to CTNNB1 mutation. All tested cases showed TSC2 mutation, supporting this as the driving genetic event for hepatic AML. PMID- 29512830 TI - Tumor-stage mycosis fungoides in palmoplantar localization with large-cell transformation and partial CD30 expression shows complete response to brentuximab vedotin. AB - Mycosis fungoides in palmoplantar localization (MFPP) is a rare variant of MF that is confined to the hands and feet. Patients commonly receive treatment over many years for suspected palmoplantar dermatitis before the diagnosis is made. Most MFPP patients remain at patch or plaque stage, and often respond to treatment with radiotherapy. Herein, we describe a 77-year-old man who suffered 6 years of hand and foot dermatitis that failed multiple treatments, most notably TNF-alpha inhibitors and mycophenolate mofetil. He eventually developed a tumor on the hand, which was biopsied to reveal a dense dermal infiltrate of large lymphocytes (CD3+/CD4-/CD8-/TCR-BetaF1+/partial CD30+). A subsequent biopsy of an eczematous patch from his hand revealed an epidermotropic and syringotropic infiltrate comprised of smaller lymphocytes with a concordant immunophenotype and matching clonal peak with TCR gene rearrangement. He was diagnosed with MFPP and started on radiotherapy with a modest response; therefore, a decision was made to start brentuximab vedotin, which resulted in a complete response. MFPP is an exceedingly rare variant of MF that can show large-cell transformation and progress in stage. We highlight a possible association between disease progression and immunosuppressants and the potential role for treatment with brentuximab. PMID- 29512831 TI - Quercetin and rutin ameliorates sulphasalazine-induced spermiotoxicity, alterations in reproductive hormones and steroidogenic enzyme imbalance in rats. AB - Certain dietary flavonoids exhibit protective potentials against drug-induced male reproductive toxicities. We investigated the protective effects of quercetin and rutin on sulphasalazine-induced alterations in steroidogenic enzyme activity, hormone profile and spermiotoxicity in rats. Sulphasalazine (SASP, 600 mg/kg bw) was administered alone or in combination with quercetin (20 mg/kg bw) or rutin (10 mg/kg bw) for 14 days. SASP treatment significantly increased relative weights of the epididymis and seminal vesicles. Also, testicular and epididymal sperm numbers (TSN, ESN), motility, daily sperm production (DSP) and acrosome reaction (AR) significantly decreased. SASP altered plasma testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels while testicular cholesterol levels, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities were decreased. Elevated malondialdehyde levels and concomitant decrease in reduced glutathione, glutathione-S-transferase, peroxidase and superoxide dismutase activities were evident in testis and epididymis of SASP-treated rats. Quercetin or rutin co treatment with SASP significantly reversed organ weights, preserved sperm integrity, restored plasma hormone levels and increased cholesterol levels, 3beta HSD and 17beta-HSD activities in testis. Both flavonoids also prevented oxidative stress in testis and epididymis of SASP-treated rats. Quercetin and rutin protect against the negative effects of SASP treatment on reproductive capacity in male rats. PMID- 29512832 TI - A Preliminary Validation Study of Two Ultra-Brief Measures of Suicide Risk: The Suicide and Perceived Burdensomeness Visual Analog Scales. AB - The advent of rapid-acting suicide-focused interventions and longitudinal research designs employing high-frequency, repeated measurement of suicide risk has resulted in a need to quantify suicide risk during very brief windows of time (e.g., minutes, hours, days). This has rapidly outpaced traditional methods for assessing suicide risk, which often focus on measuring indicators of suicide risk during much broader intervals of time (e.g., weeks to months). Valid and practical methods for rapidly assessing suicide risk during small time intervals are therefore needed. This study reports a preliminary examination of the Suicide Visual Analog Scale (S-VAS) and the Perceived Burdensomeness Visual Analog Scale (PB-VAS) in a clinical sample of suicidal adults. Results support the convergent validity, predictive validity, responsiveness, and clinical utility of both scales, suggesting the S-VAS and PB-VAS are valid methods for rapidly quantifying two dimensions of suicide risk. PMID- 29512833 TI - Improvement of Photodynamic Activity of Lipid-Membrane-Incorporated Fullerene Derivative by Combination with a Photo-Antenna Molecule. AB - The weak absorbance of pristine C60 , C70 , and fullerene derivatives at wavelengths over 600 nm hampers the use of these molecules as photosensitizers (PSs) for photodynamic therapy (PDT). The coexistence of light-harvesting antenna molecules with a fullerene derivative in lipid membrane bilayers solved this issue. By controlling the location of the C60 derivative in the lipid membrane, the liposomal dyad system for PDT improved the photodynamic activity via an efficient photoenergy transfer from antenna molecules to the fullerene derivative. The photodynamic activity was found to be much higher than those of dyad systems using pristine C60 and C70 . PMID- 29512834 TI - Suicide Among Health Care Practitioners and Technicians in Colorado: An Epidemiological Study. AB - Suicide is a public health concern with risks that vary between occupation groups. Many suicide victims with a health care occupation die by poisoning, but few studies have epidemiologically studied this association. The objective of this study was to quantify the increased risk of suicide death by poisoning among health care professionals in Colorado. Eleven years (2004-2014, N = 8,753) of suicide deaths in Colorado were compiled from the Colorado Violent Death Reporting System. A retrospective cohort study using multivariate logistic regression was conducted to examine the risk associated with having a health care occupation and eventual suicide death by poisoning, compared independently to firearm and hanging methods. Suicide victims with a health care occupation were more likely to die by poisoning rather than by hanging (RR 1.54, 95% CI: 1.41 1.68) or firearm (RR 1.79, 95% CI: 1.60-2.01), when compared to suicide victims without a health care occupation. The association between health care occupation and suicide method was significantly (p = .032) modified by gender. The results show that health care workers who die by suicide have an increased risk of eventual suicide death by poisoning rather than by firearm or hanging. These results can be used to inform tailored suicide prevention efforts in health care professionals. PMID- 29512835 TI - Childhood asthma and smoking exposures before conception-A three-generational cohort study. AB - BACKGROUND: Some human and animal studies have recently shown that maternal grandmother's smoking during pregnancy increases the risk of asthma in the grandchildren. We have investigated whether sex of the exposed parent and/or grandchild modifies the association between grandmaternal smoking and grandchild asthma. METHODS: We formed a cohort study based on linkage of national registries with prospectively collected data over three generations. Smoking habits in early pregnancy were registered since 1982 and purchases of prescribed medication since 2005. In all, 10 329 children born since 2005 had information on maternal and grandmaternal smoking on both sides and were followed from birth up to 6 years of age. Ages when medication was purchased were used to classify the cohort into never, early transient (0-3 years), early persistent (0-3 and 4-6 years), and late-onset (4-6 years) phenotypes of childhood asthma. RESULTS: Maternal grandmother's smoking was associated with an increased odds of early persistent asthma after adjustment for maternal smoking and other confounders (odds ratio 1.29, 95% confidence interval 1.10-1.51). Grandchild sex did not modify the association. Paternal grandmother's smoking was not associated with any of the asthma phenotypes. CONCLUSION: Maternal but not paternal exposure to nicotine before conception was related to an increased risk of early persistent childhood asthma, but not other asthma phenotypes. Our findings are possibly consistent with a sex-specific mode of epigenetic transfer. PMID- 29512836 TI - Can oxytocin augmentation modify the risk of epidural analgesia by maternal age in cesarean sections? AB - INTRODUCTION: Maternal age is an established risk factor for cesarean section; epidural analgesia and oxytocin augmentation may modify this association. We investigated the effects and interactions of oxytocin augmentation, epidural analgesia and maternal age on the risk of cesarean section. MATERIAL AND METHODS: In all, 416 386 nulliparous women with spontaneous onset of labor, >=37 weeks of gestation and singleton infants with a cephalic presentation during 2000-2011 from Norway and Denmark were included [Ten-group classification system (Robson) group 1]. In this case-control study the main exposure was maternal age; epidural analgesia, oxytocin augmentation, birthweight and time period were explanatory variables. Chi-square test and logistic regression were used to estimate associations and interactions. RESULTS: The cesarean section rate increased consistently with advancing maternal age, both overall and in strata of epidural analgesia and oxytocin augmentation. We observed strong interactions between maternal age, oxytocin augmentation and epidural analgesia for the risk of cesarean section. Women with epidural analgesia generally had a reduced adjusted odds ratio when oxytocin was used compared with when it was not used. In Norway, this applied to all maternal age groups but in Denmark only for women >=30 years. Among women without epidural, oxytocin augmentation was associated with an increased odds ratio for cesarean section in Denmark, whereas no difference was observed in Norway. CONCLUSIONS: Oxytocin augmentation in nulliparous women with epidural analgesia is associated with a reduced risk of cesarean section in labor with spontaneous onset. PMID- 29512838 TI - Efficacy of stabilisation splint treatment on the oral health-related quality of life-A randomised controlled one-year follow-up trial. AB - The aim of this randomised controlled trial was to assess the efficacy of stabilisation splint treatment on the oral health-related quality of life OHRQoL during a 1-year follow-up. Originally, the sample consisted of 80 patients (18 men, 62 women) with temporomandibular disorders (TMD) who had been referred to the Oral and Maxillofacial Department, Oulu University Hospital, Finland, for treatment. Patients were randomly designated into splint (n = 39) and control group (n = 41). Patients in the splint group were treated with a stabilisation splint. Additionally, patients in both groups received counselling and instructions on masticatory muscle exercises. The patients filled in the Oral Health Impact Profile-14 (OHIP-14) questionnaire before treatment and at 3 months, 6 months and 1 year. At total, 67 patients (35 in the splint group vs. 32 in the control group) completed the questionnaire at baseline. The outcome variables were OHIP prevalence, OHIP severity and OHIP extent. Linear mixed effect regression model was used to analyse factors associated with change in OHIP severity during the 1-year follow-up, taking into account treatment time, age, gender and group status. OHIP prevalence, severity and extent decreased in both groups during the follow-up. According to linear mixed-effect regression, decrease in OHIP severity did not associate significantly with group status. Compared to masticatory muscle exercises and counselling alone, stabilisation splint treatment was not more beneficial on self-perceived OHRQoL among TMD patients over a 1-year follow-up. PMID- 29512839 TI - YouTube and food allergy: An appraisal of the educational quality of information. AB - BACKGROUND: Food allergy affects an estimated 8% of children and 3% of adults in the United States. Food-allergic individuals increasingly use the web for medical information. We sought to determine the educational quality of food allergy YouTube videos. METHODS: We performed a YouTube search using keywords "food allergy" and "food allergies". The 300 most viewed videos were included and analyzed for characteristics, source, and content. Source was further classified as healthcare provider, alternative medicine provider, patient, company, media, and professional society. A scoring system (FA-DQS) was created to evaluate quality (-10 to +34 points). Negative points were assigned for misleading information. Eight reviewers scored each video independently. RESULTS: Three hundred videos were analyzed, with a median of 6351.50 views, 19 likes, and 1 dislike. More video presenters were female (54.3%). The most common type of video source was alternative medicine provider (26.3%). Alternative treatments included the following: water fast, juicing, Ayurveda, apple cider, yoga, visualization, and sea moss. Controversial diagnostics included kinesiology, IgG testing, and pulse test. Almost half of the videos depicted a non-IgE-mediated reaction (49.0%).Videos by professional societies had the highest FA-DQS (7.27). Scores for videos by professional societies were significantly different from other sources (P < .001). There was a high degree of agreement among reviewers (ICC = 0.820; P < .001). CONCLUSION: YouTube videos on food allergy frequently recommend controversial diagnostics and commonly depict non-IgE-mediated reactions. There is a need for high-quality, evidence-based, educational videos on food allergy. PMID- 29512840 TI - Letter in response to: McAlpine J, Leon-Castillo A, Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol 2018; 244: 538-549. PMID- 29512837 TI - Natural killer cell cytotoxicity and its regulation by inhibitory receptors. AB - Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity. PMID- 29512841 TI - Electrochemical C-O Bond Formation: Facile Access to Aromatic Lactones. AB - An efficient and robust methodology based on electrochemical techniques for the direct synthesis of aromatic lactones through dehydrogenative C-O cyclization is described. This new and useful electrochemical reaction can tolerate a variety of functional groups, and is scalable to 100 g under mild conditions. Remarkably, heterocycle-containing substrates can be employed, thus expanding the scope of radical C-O cyclization reactions. PMID- 29512843 TI - Neural capacity limits during unconscious semantic processing. AB - A growing body of neuroimaging data suggests that direct measurements of brain activity can reveal subliminal effects that remain invisible with behavior measures alone. We examined whether sentence comprehension processes could be triggered by a sequence of masked words. On each trial, participants viewed a rapid sequence of masked or unmasked words, including a subject noun, three adverbs and followed by a visible target verb. To probe the capacity limits of unconscious processing, we measured event-related potentials associated with the semantic congruency between the noun and the verb, while varying the subject position in each sentence. Unmasked sentences produced significant behavioral effects of congruency, paralleled by robust N400 effects, independently of subject-verb distance. By contrast, masked sentences produced no behavioral effect and elicited N400 effects only when subjects and verbs were separated by 0 or 1 word. The present results suggest that semantic integration of multiple words can occur unconsciously only if the distance between the words to be integrated does not exceed two words. Although the possibility remains that even longer sequence of invisible words may produce similar neural effects in different experimental settings, our ERP data show that only conscious perception gives access to a buffer that enables robust sentence-level processing independently of temporal distance. PMID- 29512842 TI - Super-resolution structural analysis of dendritic spines using three-dimensional structured illumination microscopy in cleared mouse brain slices. AB - Three-dimensional (3D) super-resolution microscopy technique structured illumination microscopy (SIM) imaging of dendritic spines along the dendrite has not been previously performed in fixed tissues, mainly due to deterioration of the stripe pattern of the excitation laser induced by light scattering and optical aberrations. To address this issue and solve these optical problems, we applied a novel clearing reagent, LUCID, to fixed brains. In SIM imaging, the penetration depth and the spatial resolution were improved in LUCID-treated slices, and 160-nm spatial resolution was obtained in a large portion of the imaging volume on a single apical dendrite. Furthermore, in a morphological analysis of spine heads of layer V pyramidal neurons (L5PNs) in the medial prefrontal cortex (mPFC) of chronic dexamethasone (Dex)-treated mice, SIM imaging revealed an altered distribution of spine forms that could not be detected by high-NA confocal imaging. Thus, super-resolution SIM imaging represents a promising high-throughput method for revealing spine morphologies in single dendrites. PMID- 29512844 TI - Experience modulates motor imagery-based brain activity. AB - Whether or not brain activation during motor imagery (MI), the mental rehearsal of movement, is modulated by experience (i.e. skilled performance, achieved through long-term practice) remains unclear. Specifically, MI is generally associated with diffuse activation patterns that closely resemble novice physical performance, which may be attributable to a lack of experience with the task being imagined vs. being a distinguishing feature of MI. We sought to examine how experience modulates brain activity driven via MI, implementing a within- and between-group design to manipulate experience across tasks as well as expertise of the participants. Two groups of 'experts' (basketball/volleyball athletes) and 'novices' (recreational controls) underwent magnetoencephalography (MEG) while performing MI of four multi-articular tasks, selected to ensure that the degree of experience that participants had with each task varied. Source-level analysis was applied to MEG data and linear mixed effects modelling was conducted to examine task-related changes in activity. Within- and between-group comparisons were completed post hoc and difference maps were plotted. Brain activation patterns observed during MI of tasks for which participants had a low degree of experience were more widespread and bilateral (i.e. within-groups), with limited differences observed during MI of tasks for which participants had similar experience (i.e. between-groups). Thus, we show that brain activity during MI is modulated by experience; specifically, that novice performance is associated with the additional recruitment of regions across both hemispheres. Future investigations of the neural correlates of MI should consider prior experience when selecting the task to be performed. PMID- 29512845 TI - Dealing with stroke: Perspectives from stroke survivors and stroke caregivers from an underserved Hispanic community. AB - Globally, stroke is the leading cause of death and disease burden. While post stroke studies have been conducted, they excluded survivors and caregivers from underserved communities. It can be argued that the impact of stroke on survivors and caregivers from underserved communities may be greater. Using qualitative exploratory research design, the purpose of this study was to examine the lived experiences of post-stroke recovery and readjustment among stroke survivors and stroke caregivers from an underserved community. Two separate focus groups were conducted, one each for stroke survivors and caregivers. Thematic analysis was used to analyze the data. Finding meaning in life is the general theme of stroke survivors' and stroke caregivers' journey of post-stroke recovery and readjustment. For stroke survivors, the transition to stroke recovery required time, life goal reconfiguration, willpower, humor, and network support. Post stroke caregiving is a daily navigation and negotiation influenced by internal and external processes. Personal, economic, and socio-cultural nuances play a role in how post-stroke recovery is lived and experienced. Study findings highlight the importance of policies to support family-centered and system-level advocacy in post-stroke care. PMID- 29512847 TI - High-density mapping of atrial tachycardias: Importance of interpolation. PMID- 29512846 TI - Progressive multifocal leukoencephalopathy after allogeneic stem cell transplantation: Case report and review of the literature. AB - Progressive multifocal leukoencephalopathy (PML) is a rare, yet typically fatal complication of allogeneic stem cell transplantation. It is caused by reactivation of the John Cunningham (JC) virus in an immunocompromised host. This report describes an unfortunate case of PML in a recipient of an allogeneic stem cell transplant for acute myelogenous leukemia. The JC virus was undetectable in the patient's cerebrospinal fluid by polymerase chain reaction (PCR); however, a positive diagnosis was made after a brain biopsy. This and other published cases demonstrate that recipients of allogeneic stem cells can develop PML. Moreover, early diagnosis of the disease is often difficult and, as demonstrated in this case, screening with PCR does not appear to have strong diagnostic significance. With no effective treatment presently available, restoration of immune function is the only intervention that can affect prognosis. Further prospective studies are needed to understand the pathophysiology and treatment of this disease. PMID- 29512848 TI - Metformin ameliorates the age-related changes of d-galactose administration in ovariectomized mice. AB - Metformin (Met) has been shown to have pleiotropic effects such as neuroprotective, antioxidant, and anti-inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. This study was designed to investigate the possible effect of Met on the d galactose (d-gal)-induced aging in ovariectomized mice. The female mice underwent bilateral ovariectomy. d-gal was administered orally at a dose of 500 mg/kg, and Met was administrated orally at doses of 1 and 10 mg/kg for 6 weeks. Anxiety-like behavior was evaluated by the elevated plus-maze. Physical power was assessed by vertical grid holding test and forced swimming capacity test. The brains were assessed for the level of superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). Ovariectomy caused anxiety and declined the physical power as well as BDNF and SOD levels. d-gal administration in ovariectomized mice exacerbated these deleterious effects. Met hampered the anxiety-like behavior and strengthened the physical power of d-gal-treated ovariectomized mice. Met also increased the SOD and BDNF levels in the brains of d-gal-treated ovariectomized animals. Based on the obtained results, we suggest Met administration as a novel therapeutic approach for the treatment of age-related conditions in the absence of female sex hormones. PMID- 29512849 TI - Phenotypic and virulence traits of Escherichia coli and Salmonella strains isolated from vegetables and fruits from India. AB - AIMS: The present study was designed to assess the phenotypic traits and virulence determinants of vegetable-/fruit-origin Escherichia coli and Salmonella strains. METHODS AND RESULTS: A total of 520 fresh vegetables/fruits samples were analysed for the presence of E. coli, including Shiga toxin-producing E. coli (STEC), and Salmonella. The vegetable-/fruit-origin E. coli and Salmonella strains were further assessed for antimicrobial resistance, biofilm formation, extracellular matrix production and in vitro invasion/intracellular survivability assays. A total of 73 E. coli, including four STEC, and 26 Salmonella strains were recovered from vegetables/fruits in the present study. Most of the E. coli and Salmonella isolates were able to form biofilm with higher production of cellulose/curli-fimbriae. Furthermore, more resistance was observed in E. coli isolates (61.6%) than in Salmonella isolates (38.5%) against tested antimicrobials. Additionally, invasion/intracellular survival results showed that majority of the E. coli and Salmonella isolates were able to efficiently invade/replicate intracellularly in the human epithelial cells. CONCLUSIONS: Our results demonstrate that vegetable-/fruit-origin E. coli and Salmonella significantly exhibited distinct phenotypic/virulence traits which could be linked to their plant-associated lifestyle with food safety issues. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study provides valuable baseline information that E. coli and Salmonella may use plants as an alternative host with significant clinical importance. PMID- 29512850 TI - High-density mapping of atrial tachycardias: Importance of interpolation. PMID- 29512851 TI - TIGIT expression levels on CD4+ T cells are correlated with disease severity in patients with psoriasis. AB - BACKGROUND: T-cell immunoglobulin and ITIM domain (TIGIT), a co-inhibitory receptor, suppresses CD4+ T-cell responses by triggering CD155. TIGIT shifts the balance of cytokines, including interferon (IFN)-gamma, interleukin (IL)-10 and IL-17A, and affects the proliferation of CD4+ T cells. AIM: To investigate TIGIT expression and its effects on CD4+ T-cell function in psoriasis. METHODS: In total, 28 patients with psoriasis vulgaris PV and 14 healthy controls (HCs) were enrolled. TIGIT expression on CD4+ T cells was evaluated by flow cytometry analysis and quantitative real-time PCR. Production of IFN-gamma, IL-10 and IL-17 was measured with cytometry bead arrays, while CD4+ T cell proliferation was measured using a permeable assay. RESULTS: IGIT expression on CD4+ T cells and mRNA level were significantly lower in patients with PV compared with HCs. TIGIT expression was negatively correlated with Psoriasis Area and Severity Index. Activation of TIGIT with recombinant human CD155/Fc protein significantly inhibited psoriatic CD4+ T-cell proliferation, decreased production of IFN-gamma and IL-17A, and increased IL-10. After blockade with a functional anti-human TIGIT antibody, TIGIT produced the opposite effect on IFN-gamma and IL-17A, but had no significant effect on IL-10 or cell proliferation. Furthermore, the frequency of TIGIT+CD4+ T cells was significantly increased in patients with PV after 2 months of treatment with acitretin, with associated significant changes in IFN-gamma, IL-10and IL-17A plasma levels. CONCLUSIONS: Downregulation of TIGIT on CD4+ T cells may contribute to the pathogenesis of psoriasis, and activation of the TIGIT signalling pathway may be a potential therapeutic target. PMID- 29512852 TI - Purinergic receptor types in the hypothalamic-neurohypophysial system. AB - Many different types of purinergic receptors are present in the Hypothalamic Neurohypophysial System (HNS), which synthesizes and releases vasopressin and oxytocin. The specific location of purinergic receptor subtypes has important functional repercussions for neuronal activity and synaptic output. Yet, until the advent of receptor KOs, this had been hindered by the low selectivity of the available pharmacological tools. The HNS offers an excellent opportunity to differentiate the functional properties of these purinergic receptors in cell bodies vs. terminals of the same physiological system. P2X2, P2X3, P2X4 and P2X7 receptors are present in vasopressin terminals while oxytocin terminals exclusively express the P2X7 subtype. The latter is not functional in the cell bodies of the HNS. These purinergic receptor subtypes are permeable to sodium vs. calcium in varying amounts and this could play an important role in the release of vasopressin vs. oxytocin during bursting activity. Endogenous ATP and its metabolite, adenosine, have autocrine and paracrine modulatory effects on the release of these neuropeptides during physiological stimulation. Finally, we hypothesize that during such action potential bursts, ATP potentiates the release of vasopressin but not of oxytocin, and that adenosine, via A1 receptors, inhibits the release of both neuropeptides. This article is protected by copyright. All rights reserved. PMID- 29512853 TI - Dengue fever in renal allograft recipients: Clinical course and outcome. AB - BACKGROUND: There are annual outbreaks of dengue infection in tropical and subtropical countries. This retrospective study aimed to assess the clinical manifestation of dengue and outcome in renal transplant recipients. METHODS: Renal transplant recipients diagnosed with dengue in the nephrology department during the outbreak from August 2015 to December 2015 were included in the study. RESULTS: Twenty patients developed dengue presenting during the outbreak. Mean age was 31.9 +/- 8.8 years and all were males. Two patients had severe dengue (dengue hemorrhagic fever, dengue shock syndrome). Clinical presentation included febrile illness (95%), myalgia (65%), headache (30%), retro-orbital pain (10%), and mucocutaneous bleeding manifestations (10%). Three (15%) had third space fluid accumulation and 2 (10%) had hypotension. Ninety percent patients had thrombocytopenia, with 4 requiring platelet transfusion. Leucopenia (WBC < 4000/mm3 ) developed in 50% patients. About 60% had transient transaminitis. One patient with severed dengue expired and 1 recovered with IV immunoglobulin therapy. About 40% patients had rise in serum creatinine, with complete recovery in all patients. CONCLUSION: Clinical manifestations of dengue infection in renal transplant recipients were similar to that in general population. However, leucopenia necessitating temporary withdrawal of immunosuppression was common. Renal dysfunction was frequent but completely reversible. PMID- 29512855 TI - Site-specificity of serine integrase demonstrated by the attB sequence preference of phiBT1 integrase. AB - Serine integrases mediate site-specific recombination and are extensively applied in genetic engineering and synthetic biology. However, which regions of the attachment sites determine site-specificity and how these regions function in recombination remain elusive. Here, we explored the sequence features of attB attachment sites recognized by phiBT1 integrase, a representative serine integrase. A 34-bp DNA motif is found that displays distinct base-specific preference for every position. Further investigation of mutations at different positions within the attB sequence shows different recombination efficiencies and binding affinities. We found four conserved regions within the attB motif that coincide with the results of recombination assays, and mutations in the attB sequence that hamper recombination almost all cause reduced binding affinity. PMID- 29512854 TI - Contribution of repeated infections in asthma persistence from preschool to school age: Design and characteristics of the PreDicta cohort. AB - BACKGROUND: The PreDicta cohort was designed to prospectively evaluate wheeze/asthma persistence in preschoolers in association with viral/microbial exposures and immunological responses. We present the cohort design and demographic/disease characteristics and evaluate unsupervised and predefined phenotypic subgroups at inclusion. METHODS: PreDicta is a 2-year prospective study conducted in five European regions, including children 4-6 years with a diagnosis of asthma as cases and healthy age-matched controls. At baseline, detailed information on demographics, asthma and allergy-related disease activity, exposures, and lifestyle were recorded. Lung function, airway inflammation, and immune responses were also assessed. Power analysis confirmed that the cohort is adequate to answer the initial hypothesis. RESULTS: A total of 167 asthmatic children (102 males) and 66 healthy controls (30 males) were included. Groups were homogeneous in respect to most baseline characteristics, with the exception of male gender in cases (61%) and exposure to tobacco smoke. Comorbidities and number and duration of infections were significantly higher in asthmatics than controls. 55.7% of asthmatic children had at least one positive skin prick test to aeroallergens (controls: 33.3%, P = .002). Spirometric and exhaled nitric oxide values were within normal limits; only baseline FEV0.5 and FEV1 reversibility values were significantly different between groups. Viral infections were the most common triggers (89.2%) independent of severity, control, or atopy; however, overlapping phenotypes were also common. Severity and control clustered together in an unsupervised analysis, separating moderate from mild disease. CONCLUSIONS: The PreDicta cohort presented no differences in non asthma related measures; however, it is well balanced regarding key phenotypic characteristics representative of "preschool asthma". PMID- 29512856 TI - Analysis of psoriasis-relevant gene expression and exon usage alterations after silencing of SR-rich splicing regulators. AB - In our recent cDNA microarray experiment, three SR-rich splicing factors-SFRS18, PPIG and LUC7L3-were shown to exert altered responsiveness upon T-lymphokine stimulation of psoriatic non-involved and healthy epidermis samples. We have also demonstrated that double silencing LUC7L3 and SFRS18 efficiently decreased production of the psoriasis-associated EDA+ fibronectin isoform. These findings prompted the further investigation of signalling pathways affected by LUC7L3 and SFRS18. To detect gene expression and splicing pattern alterations upon double silencing of LUC7L3 and SFRS18 in an HPV-immortalised keratinocyte cell culture, paired-end RNA sequencing was carried out. Marked changes in exon usage were revealed, in contrast to the modest alterations detected in gene expression, providing a closer delineation of the potential targets of the examined splicing factors. The most prominent gene expression change was detected for IFI6, an interferon-inducible gene highly expressed in psoriasis. Interacting partners of IFI6 and certain psoriasis-associated transcripts also exhibited significantly increased expression upon silencing. In addition to elevated abundance of the EDA+ fibronectin interactor ITGA5, we confirmed decreased EDA domain inclusion, which agrees well with our prior experimental data. Furthermore, differential exon usage was established for the transcription element CREB1, along with HERC6 and CUL1, which are implicated in ubiquitination. Although immortalised keratinocytes express low levels of TINCR, a long non-coding RNA involved in terminal differentiation of keratinocytes, splicing alterations were successfully demonstrated for this RNA as well. We believe that the targeted investigation of mRNA maturation disturbances may help us gain deeper insight into the molecular pathogenesis of psoriasis. PMID- 29512858 TI - A novel use of indocyanine green to identify the plane of dissection during abdominoperineal resection by the transperineal approach - a video vignette. PMID- 29512857 TI - Serum 25-hydroxyvitamin D, metabolome, and bronchiolitis severity among infants-A multicenter cohort study. PMID- 29512859 TI - CNS progression during vinblastine or targeted therapies for high-risk relapsed ALK-positive anaplastic large cell lymphoma: A case series. AB - Vinblastine and targeted therapies induce remissions in patients with relapsed or progressive anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). Central nervous system (CNS) prophylaxis often is not included during re-induction in CNS-negative relapse patients. We report on five patients with progressive or early relapsed ALK-positive ALCL who developed CNS progression during re-induction with vinblastine, crizotinib, or brentuximab vedotin given for bridging to allogeneic blood stem cell transplantation. These observations suggest that CNS prophylaxis should be considered in ALCL patients suffering progression during initial therapy who receive re-induction using agents with limited CNS penetration. PMID- 29512860 TI - Lipoprotein Transport: Greasing the Machines of Outer Membrane Biogenesis: Re Examining Lipoprotein Transport Mechanisms Among Diverse Gram-Negative Bacteria While Exploring New Discoveries and Questions. AB - The Gram-negative outer membrane (OM) is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals the existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. PMID- 29512861 TI - Tooth fragment reattachment techniques-A systematic review. AB - BACKGROUND/AIM: Several strategies have been developed for tooth fragment reattachment following fracture. Although many techniques have been reported, there is no consensus on which one has the best results in terms of the bond strength between the fragment and the dentin over time. The aim of this study was to assess the currently reported tooth fragment reattachment techniques for fractured crowns of anterior teeth. MATERIALS AND METHODS: The PubMed, LILACS, Web of Science, Cochrane, and Scopus databases were searched in October 2016, and the search was updated in February 2017. A search of the gray literature was performed in Google Scholar and OpenGrey. Reference lists of eligible studies were cross-checked to identify additional studies; gray literature and ongoing trials were investigated. Two authors assessed studies to determine inclusion and undertook data extraction. Case reports/series of three or more cases, cross sectional studies, cohort studies, and in vivo clinical trials in all languages were included. RESULTS: Five articles remained after screening. These studies predominantly reported on fragment reattachment with composite resin and resin cement. There was little consistency among the studies in regard to the technique used for tooth fragment reattachment and length of the follow-up period. CONCLUSIONS: According to the evidence found in the studies included in this review, simple tooth fragment reattachment was the preferred reattachment technique. An increase in the bond strength between tooth fragment and dentin was observed when an intermediate material was used. Further investigation is needed, using standard follow-up periods and larger samples. PMID- 29512862 TI - MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IkappaBalpha pathway. AB - Vascular endothelial senescence contributes to atherosclerosis and coronary artery disease (CAD), but the mechanisms are yet to be clarified. We identified that microRNA-216a (miR-216a) significantly increased in senescent endothelial cells. The replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established to explore the role of miR-216a in endothelial ageing and dysfunction. Luciferase assay indicated that Smad3 was a direct target of miR 216a. Stable expression of miR-216a induced a premature senescence-like phenotype in HUVECs with an impairment in proliferation and migration and led to an increased adhesion to monocytes by inhibiting Smad3 expression and thereafter modulating the degradation of NF-kappaB inhibitor alpha (IkappaBalpha) and activation of adhesion molecules. Conversely, inhibition of endogenous miR-216a in senescent HUVECs rescued Smad3 and IkappaBalpha expression and inhibited monocytes attachment. Plasma miR-216a was significantly higher in old CAD patients (>50 years) and associated with increased 31% risk for CAD (odds ratio 1.31, 95% confidence interval 1.03-1.66; P = .03) compared with the matched healthy controls (>50 years). Taken together, our data suggested that miR-216a promotes endothelial senescence and inflammation as an endogenous inhibitor of Smad3/IkappaBalpha pathway, which might serve as a novel target for ageing related atherosclerotic diseases. PMID- 29512863 TI - Re-emergent tremor in Parkinson's disease: the effect of dopaminergic treatment. AB - BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) with resting tremor may be affected by a tremor that appears after a varying latency while a posture is maintained, a phenomenon referred to as re-emergent tremor (RET). The aim of the study was to evaluate the occurrence and clinical features of RET in patients with PD tested off and on treatment, and to compare the effect of dopaminergic treatment on RET with the effect on resting and action tremor. METHODS: We consecutively enrolled 100 patients with PD. Patients were clinically evaluated 24 h after withdrawal of therapy (off-treatment phase) and 60 min after therapy administration (on-treatment phase). We collected the demographic and clinical data of patients with PD. The severity of the disease was assessed by means of the Hoehn and Yahr scale and Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III. We evaluated the latency, severity and body side affected both off and on treatment in patients with RET. RESULTS: Re-emergent tremor was present in 24% of the patients with PD off treatment and in 19% of the patients on treatment. Dopaminergic treatment reduced the clinical severity of RET. Dopaminergic treatment increased the number of patients with unilateral RET and reduced the number of those who had bilateral RET. RET and resting tremor responded similarly to dopaminergic treatment, whereas action tremor was less responsive. Patients with RET had milder motor symptoms than patients without RET both off and on treatment. CONCLUSIONS: Dopaminergic treatment modified RET occurrence, severity and body distribution. Dopaminergic depletion plays a role in the pathophysiology of RET. PMID- 29512864 TI - Treatment of Langerhans cell histiocytosis with a modified risk-adapted protocol experience from a tertiary cancer institute in India. AB - BACKGROUND: Involvement of risk-organs (RO+) in Langerhans cell histiocytosis (LCH) and inadequate early response identifies patients at high risk for relapse and mortality requiring intensive salvage therapy including stem cell transplant, adding cost and toxicity. To mitigate this, we used a standard induction, augmented with metronomic etoposide, and prolonged maintenance-similarly augmented for RO+, and retrospectively analyzed its impact. PROCEDURE: LCH patients from 2009 through 2014 were included. Patients received standard vinblastine and prednisolone therapy weekly till week 25 for RO+. Single site (SS) and multisystem (MS) without risk organ involvement (RO-) received 3-weekly pulses from week 13 till week 25. Maintenance was 3-weekly vinblastine and 5-day prednisolone pulses, daily 6-mercaptopurine (60 mg/m2 ) and weekly methotrexate (15 mg/m2 ) for 18 and 9 months for RO+ and MSRO-, respectively. RO+ also received oral etoposide (50 mg/m2 ) for 21 of every 28-day cycle for the first year. RESULTS: Fifty consecutive patients were analyzed. Median age was 36 months (4-189 months). SS, MSRO-, and RO+ were 29 (58%), 12 (24%), and nine (18%), respectively. Four were lost to follow-up and excluded from further evaluation. On response evaluation at week 6, 24 (52%) had no active disease (NAD), 17 (37%) had AD-better (where AD is active disease), and one (2%) had AD-worse. In RO+, eight (66.6%) had AD-better and three (25%) had NAD. Forty-five patients had NAD by week 12. Three patients relapsed. With median follow-up of 39 months (8-84), 5 year event free survival was 85.6% (RO- and SS), and 100% for RO+. One patient's death in remission from unrelated causes resulted in overall survival of 97%. CONCLUSIONS: RO+LCH receiving oral etoposide augmented induction and maintenance had early and durable responses. Prolonging maintenance lowered reactivation rates in RO+ and RO-LCH, resulting in excellent survival. PMID- 29512865 TI - Malignant progression of a peripheral nerve sheath tumor in the setting of rhabdoid tumor predisposition syndrome. AB - Malignant progression of a benign or low-grade tumor in individuals with germline alteration of SMARCB1 gene is not well characterized. In a family in which two carrier children had germline SMARCB1 mutations and atypical teratoid rhabdoid tumor, we report malignant progression of a nerve sheath tumor over a 7-year period in an affected adult family member. Prompt identification of the germline SMARCB1 alteration and the resultant rhabdoid tumor predisposition syndrome can help guide genetic counseling and surveillance in affected family members. PMID- 29512866 TI - Exposure to childhood adversity and deficits in emotion recognition: results from a large, population-based sample. AB - BACKGROUND: Emotion recognition skills are essential for social communication. Deficits in these skills have been implicated in mental disorders. Prior studies of clinical and high-risk samples have consistently shown that children exposed to adversity are more likely than their unexposed peers to have emotion recognition skills deficits. However, only one population-based study has examined this association. METHODS: We analyzed data from children participating in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort (n = 6,506). We examined the association between eight adversities, assessed repeatedly from birth to age 8 (caregiver physical or emotional abuse; sexual or physical abuse; maternal psychopathology; one adult in the household; family instability; financial stress; parent legal problems; neighborhood disadvantage) and the ability to recognize facial displays of emotion measured using the faces subtest of the Diagnostic Assessment of Non-Verbal Accuracy (DANVA) at age 8.5 years. In addition to examining the role of exposure (vs. nonexposure) to each type of adversity, we also evaluated the role of the timing, duration, and recency of each adversity using a Least Angle Regression variable selection procedure. RESULTS: Over three-quarters of the sample experienced at least one adversity. We found no evidence to support an association between emotion recognition deficits and previous exposure to adversity, either in terms of total lifetime exposure, timing, duration, or recency, or when stratifying by sex. CONCLUSIONS: Results from the largest population-based sample suggest that even extreme forms of adversity are unrelated to emotion recognition deficits as measured by the DANVA, suggesting the possible immutability of emotion recognition in the general population. These findings emphasize the importance of population-based studies to generate generalizable results. PMID- 29512868 TI - Lymphopenia is associated with late onset Pneumocystis jirovecii pneumonia in solid organ transplantation. AB - BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) affected 5%-15% of solid organ transplant (SOT) recipients prior to universal prophylaxis, classically with trimethoprim-sulfamethoxazole (TMP-SMX). Guidelines generally recommend 6-12 months of prophylaxis post-SOT, yet optimal duration and robust PJP risk stratification have not been established. METHODS: A retrospective, single center, case-control study of PJP among SOT recipients from January 1998 to December 2013 was conducted. Cases had positive PJ direct fluorescent antibody assay of respiratory specimens. Controls were matched 4:1 by nearest date of SOT. Univariate testing and multivariate logistic regressions were performed. RESULTS: Fifteen cases were identified among 5505 SOT recipients (0.27% rate) and analyzed vs 60 controls. PJP occurred on average 6.1 years (range 0.9-13.8) post-SOT; no case was receiving PJP prophylaxis at diagnosis. Most were treated with reduced immunosuppression and TMP-SMX plus steroids (80%). Six patients (40%) required critical care; 3 (20%) died. There were no significant demographic differences, though cases tended to be older at SOT (54 vs 48 years, P = .1). In univariate analysis, prior viral infection was more common among cases (67% vs 37%, P = .08). Lower absolute lymphocyte count (ALC) at diagnosis date was strongly associated with PJP (400 vs 1230 * 106 cells/MUL, P < .001); odds of infection were high with ALC <= 500 * 106 cells (OR 18.7, P < .01). CONCLUSION: Pneumocystis jirovecii pneumonia is a rare, late complication of SOT with significant morbidity and mortality. Severe lymphopenia may be useful in identifying SOT recipients who warrant continued or reinstated PJP prophylaxis. PMID- 29512867 TI - Resveratrol protects mice against SEB-induced acute lung injury and mortality by miR-193a modulation that targets TGF-beta signalling. AB - Staphylococcal enterotoxin B (SEB) is a potent superantigen produced by Staphylococcus aureus that triggers a strong immune response, characterized by cytokine storm, multi-organ failure, and often death. When inhaled, SEB can cause acute lung injury (ALI) and respiratory failure. In this study, we investigated the effect of resveratrol (RES), a phytoallexin, on SEB-driven ALI and mortality in mice. We used a dual-exposure model of SEB in C3H/HeJ mice, which caused 100% mortality within the first 5 days of exposure, and treatment with RES resulted in 100% survival of these mice up to 10 days post-SEB exposure. RES reduced the inflammatory cytokines in the serum and lungs, as well as T cell infiltration into the lungs caused by SEB. Treatment with RES also caused increased production of transforming growth factor-beta (TGF-beta) in the blood and lungs. RES altered the miRNA profile in the immune cells isolated from the lungs. Of these, miR-193a was strongly induced by SEB and was down-regulated by RES treatment. Furthermore, transfection studies and pathway analyses revealed that miR-193a targeted several molecules involved in TGF-beta signalling (TGFbeta2, TGFbetaR3) and activation of apoptotic pathways death receptor-6 (DR6). Together, our studies suggest that RES can effectively neutralize SEB-mediated lung injury and mortality through potential regulation of miRNA that promote anti-inflammatory activities. PMID- 29512869 TI - Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management. PMID- 29512870 TI - DW2008S and its major constituents from Justicia procumbens exert anti-asthmatic effect via multitargeting activity. AB - Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A3 (A3 AR), which mediates mast cell-dependent inflammation and bronchoconstriction. DW2008S and JB inhibited human phosphodiesterase 4 (PDE4), which is known to cause bronchoconstriction; however, the required concentrations were higher than those needed to affect TIGIT . These findings suggest that DW2008S can potentially ameliorate Th2-driven airway inflammation and bronchoconstriction through negative regulation of TIGIT and blockade of A3 AR and PDE4 activities. PMID- 29512871 TI - Flunarizine in migraine-related headache prevention: results from 200 patients treated in the UK. AB - BACKGROUND AND PURPOSE: For over 20 years, as a group we have been using flunarizine in primary headache disorders. Flunarizine is widely used in Europe, but not licensed in the UK. In September 2014, the National Institute for Clinical Excellence published supportive guidelines for flunarizine use in migraine, based on randomized controlled evidence that it is as effective as propranolol and topiramate in adults. METHODS: We reviewed a cohort of adult patients (n = 200) treated with flunarizine from our practice. The clinical information of these patients, i.e. diagnosis, dose, efficacy, side effects and duration of treatment, was collected. RESULTS: The most common indication for flunarizine use was chronic migraine, followed by migraine with aura, sporadic hemiplegic migraine, familial hemiplegic migraine and new daily persistent headache with migrainous features. Flunarizine was generally effective, with only 24% (n = 47) of patients reporting no clinical effect. The most common dose used was 10 mg per day. Duration of treatment information was available for 39% (n = 78) of patients. Of these patients, 64% (n = 50) continued treatment for more than 1 year. Doses up to 15 mg were generally well tolerated, with only 10.5% (n = 21) of patients stopping treatment due to adverse effects. The most common adverse events were tiredness, mood change and weight gain. CONCLUSION: The data provide supportive evidence from tertiary headache practice in the UK for the use of flunarizine in migraine. The data encourages development of future guidance regarding flunarizine use in headache centres in countries where its use is not routine. PMID- 29512872 TI - Hydroxyurea (hydroxycarbamide) genotoxicity in pediatric patients with sickle cell disease. AB - BACKGROUND: Hydroxyurea (HU) reduces the severity of sickle cell disease (SCD) in children; nevertheless, its long-term safety is an important concern. This paper evaluates HU genotoxicity at dose <= 30 mg/kg/day after over 2 years of treatment. PROCEDURE: The study included 76 children: 32 SCD patients treated with HU, 27 SCD patients not treated with HU, and 17 unaffected children. HU patients were classified as good or poor responders according to their clinical response. Comet assay allows the comparison of DNA damage between both groups of patients and unaffected children. Maximal concentration (Cmax ) of HU in plasma was determined after drug administration. RESULTS: Mean values of DNA in the comet tail were 5.13 +/- 6.84 for unaffected children, 5.80 +/- 7.78 for patients with SCD treated with HU, and 5.61 +/- 6.91 for patients with SCD not treated with HU. Significant differences were observed between unaffected children and children with SCD. No difference was evident between comets from SCD patients treated and not treated with HU. In the case of HU, mean DNA in the comet tail was significantly lower in good responders than in poor responders: 5.54 +/- 7.77 and 6.69 +/- 8.43, respectively. Mean Cmax value on plasma was 39.08 +/- 15.65 mg/l; N = 31. CONCLUSIONS: SCD increases, slightly but significantly, DNA damage in lymphocytes from patients with SCD. Patients with SCD treated with HU do not present more nucleoid damage than patients with SCD not treated with HU. Good responders to the HU treatment have significantly less nucleoid damage than poor responders. HU treatment at <=30 mg/kg/day does not expose patients to a genotoxic plasma concentration. PMID- 29512873 TI - Liquid biopsy to monitor melanoma patients. AB - During the last six years, several innovative, systemic therapies for the treatment of metastatic malignant melanoma (MM) have emerged. Conventional chemotherapy has been superseded by novel first-line therapies, including systemic immunotherapies (anti-CTLA4 and anti-PD1; authorization of anti-PDL1 is anticipated) and therapies targeting specific mutations (BRAF, NRAS, and c-KIT). Thus, treating physicians are confronted with new challenges, such as stratifying patients for appropriate treatments and monitoring long-term responders for progression. Consequently, reliable methods for monitoring disease progression or treatment resistance are necessary. Localized and advanced cancers may generate circulating tumor cells and circulating tumor DNA (ctDNA) that can be detected and quantified from peripheral blood samples (liquid biopsy). For melanoma patients, liquid biopsy results may be useful as novel predictive biomarkers to guide therapeutic decisions, particularly in the context of mutation-based targeted therapies. The challenges of using liquid biopsy include strict criteria for the phenotypic nature of circulating MM cells or their fragments and the instability of ctDNA in blood. The limitations of liquid biopsy in routine diagnostic testing are discussed in this review. PMID- 29512874 TI - Repetitive transcranial magnetic stimulation reveals a role for the left inferior parietal lobule in matching observed kinematics during imitation. AB - Apraxia (a disorder of complex movement) suggests that the left inferior parietal lobule (IPL) plays a role in kinematic or spatial aspects of imitation, which may be particularly important for meaningless (i.e. unfamiliar intransitive) actions. Mirror neuron theories indicate that the IPL is part of a frontoparietal system that can support imitation by linking observed and stored actions through visuomotor matching, and have less to say about different subregions of the left IPL, or how different types of action (i.e. meaningful or meaningless) are processed for imitation. We used repetitive transcranial magnetic stimulation (rTMS) to bridge this gap and better understand the roles of the left supramarginal gyrus (SMG) and left angular gyrus (AG) in imitation. We also examined whether these areas are differentially involved in meaningful and meaningless action imitation. We applied rTMS over the left SMG, over the left AG or during a no-rTMS baseline condition, and then asked participants to imitate a confederate's actions whilst the arm and hand movements of both individuals were motion-tracked. rTMS over both the left SMG and the left AG reduced the velocity of participants' finger movements relative to the actor during imitation of finger gestures, regardless of action meaning. Our results support recent claims in apraxia and confirm a role for the left IPL in kinematic processing during gesture imitation, regardless of action meaning. PMID- 29512875 TI - Stability of complete blood count in different storage conditions using the ABX PENTRA 60 analyzer. AB - INTRODUCTION: Sample stability is essential to obtain reliable results in the clinical laboratory. This study was conducted to investigate the reliability of hematological parameters using ABX Pentra 60 in samples stored for up to 72 hours at different temperatures. METHODS: A total of 651 blood samples were analyzed at different analysis times: 2, 24, 48, and 72 hours and forms and storage: room temperature (25 degrees C) and at 4 degrees C. The imprecision of the results was evaluated by the analytical coefficient of variation (CVa%) obtained by the typical error (TE) and Kruskal-Wallis analysis, to compare the averages. The reliability of the results was evaluated by the CVa (%) within the maximum allowable analytical variation and by the difference of means of the results in relation to the baseline sample (2 hours). RESULTS: Red blood count, hemoglobin, and MCH parameters showed stability up to 72 hours at room temperature and at 4 degrees C. The other complete blood count parameters showed imprecision results emitted by the ABX Pentra 60 from 24 hours of sample storage, independent of the storage temperature. In addition, there were significant oscillations in the mean values, particularly for the samples stored at room temperature, with the exception of platelet parameters that exhibited mean changes also at 4 degrees C. CONCLUSION: The results demonstrate the importance of the clinical analyst's knowledge about the behavior of the CBC parameters over time under different storage conditions, and mainly the imprecision of the hematological equipment used, for the suitable interpretation of the results. PMID- 29512876 TI - How Many People Are Exposed to Suicide? Not Six. AB - It has long been stated that six people are left behind following every suicide. Despite a lack of empirical evidence, this has been extensively cited for over 30 years. Using data from a random-digit dial survey, a more accurate number of people exposed to each suicide is calculated. A sample of 1,736 adults included 812 lifetime suicide-exposed respondents who reported age and number of exposures. Each suicide resulted in 135 people exposed (knew the person). Each suicide affects a large circle of people, who may be in need of clinician services or support following exposure. PMID- 29512877 TI - Rhythm and melody as social signals for infants. AB - Infants typically experience music through social interactions with others. One such experience involves caregivers singing to infants while holding and bouncing them rhythmically. These highly social interactions shape infant music perception and may also influence social cognition and behavior. Moving in time with others interpersonal synchrony-can direct infants' social preferences and prosocial behavior. Infants also show social preferences and selective prosociality toward singers of familiar, socially learned melodies. Here, we discuss recent studies of the influence of musical engagement on infant social cognition and behavior, highlighting the importance of rhythmic movement and socially relevant melodies. PMID- 29512878 TI - Platelet impedance adhesiometry: A novel technique for the measurement of platelet adhesion and spreading. AB - INTRODUCTION: Thrombogenesis plays an important role in today's morbidity and mortality. Antithrombotics are among the most frequently prescribed drugs. Thorough knowledge of platelet function is needed for optimal clinical care. Platelet adhesion is a separate subprocess of platelet thrombus formation; still, no well-standardized technique for the isolated measurement of platelet adhesion exists. Impedimetry is one of the most reliable, state-of-art techniques to analyze cell adhesion, proliferation, viability, and cytotoxicity. We propose impedimetry as a feasible novel method for the isolated measurement of 2 significant platelet functions: adhesion and spreading. METHODS: Laboratory reference platelet agonists (epinephrine, ADP, and collagen) were applied to characterize platelet functions by impedimetry using the xCELLigence SP system. Platelet samples were obtained from 20 healthy patients under no drug therapy. Standard laboratory parameters and clinical patient history were also analyzed. RESULTS: Epinephrine and ADP increased platelet adhesion in a concentration dependent manner, while collagen tended to have a negative effect. Serum sodium and calcium levels and age had a negative correlation with platelet adhesion induced by epinephrine and ADP, while increased immunoreactivity connected with allergic diseases was associated with increased platelet adhesion induced by epinephrine and ADP. ADP increased platelet spreading in a concentration dependent manner. CONCLUSION: Impedimetry proved to be a useful and sensitive method for the qualitative and quantitated measurement of platelet adhesion, even differentiating between subgroups of a healthy population. This novel technique is offered as an important method in the further investigation of platelet function. PMID- 29512880 TI - Nature of Bonding in Bowl-Like B36 Cluster Revisited: Concentric (6pi+18pi) Double Aromaticity and Reason for the Preference of a Hexagonal Hole in a Central Location. AB - The bowl-shaped C6v B36 cluster with a central hexagon hole is considered an ideal molecular model for low-dimensional boron-based nanosystems. Owing to the electron deficiency of boron, chemical bonding in the B36 cluster is intriguing, complicated, and has remained elusive despite a couple of papers in the literature. Herein, a bonding analysis is given through canonical molecular orbitals (CMOs) and adaptive natural density partitioning (AdNDP), further aided by natural bond orbital (NBO) analysis and orbital composition calculations. The concerted computational data establish the idea of concentric double pi aromaticity for the B36 cluster, with inner 6pi and outer 18pi electron counting, which both conform to the (4n+2) Huckel rule. The updated bonding picture differs from existing knowledge of the system. A refined bonding model is also proposed for coronene, of which the B36 cluster is an inorganic analogue. It is further shown that concentric double pi aromaticity in the B36 cluster is retained and spatially fixed, irrespective of the migration of the hexagonal hole; the latter process changes the system energetically. The hexagonal hole is a destabilizing factor for sigma/pi CMOs. The central hexagon hole affects substantially fewer CMOs, thus making the bowl-shaped C6v B36 cluster the global minimum. PMID- 29512881 TI - Parent pain catastrophizing predicts child depressive symptoms in youth with sickle cell disease. AB - BACKGROUND: Youth with sickle cell disease (SCD) are at risk for recurrent pain and depressive symptoms, both of which contribute to poorer health outcomes. Furthermore, youth and family coping with child pain, including pain catastrophizing, is known to be associated with poorer psychosocial adjustment and greater functional disability among youth with SCD. In particular, child catastrophizing about pain and parent catastrophizing about their child's pain have been linked to increased pain and depressive symptoms in youth with chronic pain conditions. Despite this, the impact of child and parent pain catastrophizing on depressive symptoms remains unexplored in pediatric SCD. PROCEDURE: The current study evaluated the predictive value of child and parent pain catastrophizing on child depressive symptoms in a sample of 100 youth with SCD. Differences in child and parent pain catastrophizing across youth with and without clinically elevated depressive symptoms were also examined. RESULTS: Pain frequency and parent and child pain catastrophizing accounted for 35.9% of variance in child depressive symptoms, with only pain frequency and parent pain catastrophizing emerging as unique predictors of clinically elevated depressive symptoms. Additionally, parents of youth with clinically elevated depressive symptoms showed increased helplessness relative to parents of youth with minimal to mild depressive symptoms. CONCLUSIONS: Findings support the value of depression screening and interventions to promote parent self-efficacy in managing childhood SCD pain. PMID- 29512882 TI - Sulfinate-Salt-Mediated Radical Relay Cyclization of Cyclic Ethers with 2 Alkynylbenzonitriles toward 3-Alkylated 1-Indenones. AB - A new sulfinate salt-mediated radical relay for the completion of C(sp3 )-H bond indenylation of cyclic ethers with readily available 2-alkynylbenzonitriles by combining silver/tert-butyl peroxide (TBHP) was established, providing a wide range of 3-alkylated 1-indenones with generally good yields. Interestingly, the current reaction system can tolerate an S-centered radical and a C-centered radical in one pot, in which the S-centered radical promotes the formation of the C-centered radical to induce a radical cascade without disturbing the reaction process. A reaction mechanism is also proposed based on control experiments. PMID- 29512883 TI - Genetic counseling: Growth of the profession and the professional. AB - Growth of the profession of genetic counseling has gone hand-in-hand with professional development of individual genetic counselors. Genetic counseling has achieved most of the typical early milestones in the development of a profession. The profession is maturing at a time when the number of practitioners is predicted to vastly expand. The last two decades have seen a proliferation of genetic counselor roles and practice areas, and a distinct professional identity. It is likely that the next two decades will see an increase in educational paths, practice areas, and possibilities for professional advancement. How this maturation proceeds will be impacted by overall trends in healthcare, decisions made by international genetic counseling organizations, and thousands of individual decisions about career trajectories. PMID- 29512884 TI - Design of Modular G-quadruplex Ligands. AB - Guanine-rich nucleic acid sequences able to form four-stranded structures (G quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug-like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure-G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes. PMID- 29512885 TI - Altered vaccine-induced immunity in children with Dravet syndrome. AB - Dravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium-adjuvanted vaccine of children with DS to sex- and age matched heathy children. Using ex vivo cytokine responses of peripheral-blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome. PMID- 29512886 TI - A quality improvement initiative to increase access to food challenges. PMID- 29512887 TI - Opioid and nondopamine reward circuitry and state-dependent mechanisms. AB - A common notion is that essentially all addictive drugs, including opioids, activate dopaminergic pathways in the brain reward system, and the inappropriate use of such drugs induces drug dependence. However, an opioid reward response is reportedly still observed in several models of dopamine depletion, including in animals that are treated with dopamine blockers, animals that are subjected to dopaminergic neuron lesions, and dopamine-deficient mice. The intracranial self stimulation response is enhanced by stimulants but reduced by morphine. These findings suggest that dopaminergic neurotransmission may not always be required for opioid reward responses. Previous findings also indicate the possibility that dopamine-independent opioid reward may be observed in opioid-naive states but not in opioid-dependent states. Therefore, a history of opioid use should be considered when evaluating the dopamine dependency of opioid reward. PMID- 29512888 TI - The past, present and future of service delivery in genetic counseling: Keeping up in the era of precision medicine. AB - Precision medicine aims to approach disease treatment and prevention with consideration of the variability in genes, environment, and lifestyle for each person. This focus on the individual is also key to the practice of genetic counseling, whereby foundational professional values prioritize informed and autonomous patient decisions regarding their genetic health. Genetic counselors are ideally suited to help realize the goals of the precision medicine. However, a limited genetic counseling workforce at a time in which there is a rapidly growing need for services is challenging the balance of supply and demand. This article provides historical context to better understand what has informed traditional models of genetic counseling and considers some of the current forces that require genetic counselors to adapt their practice. New service delivery models can improve access to genetic healthcare by overcoming geographical barriers, allowing genetic counselors to see a higher volume of patients and supporting other healthcare providers to better provide genetic services to meet the needs of their patients. Approaches to genetic counseling service delivery are considered with a forward focus to the challenges and opportunities that lie ahead for genetic counselors in this age of precision health. PMID- 29512889 TI - The dawn of consumer-directed testing. AB - As the public's interest in genetics and genomics has increased, there has been corresponding and unprecedented growth in direct-to-consumer genetic testing (DTC GT). Although regulatory concerns have limited true DTC-GT available without a physician order, the paradigm has shifted to a model of consumer-directed genetic testing (CD-GT) in which patients are researching testing options and requesting specific genetic testing from their health-care providers. However, many nongenetics health-care providers do not have the background, education, interest, or time to order and/or interpret typical clinical genetic testing, let alone DTC-GT. The lines between CD-GT, DTC-GT, and traditional clinical genetic testing are also blurring with the same types of tests available in different settings (e.g., carrier screening) and tests merging medical and nonmedical results, increasing the complexity for consumer decision-making and clinician management. The genetics community has the training to work with CD-GT, but there has been a hesitancy to commit to working with these results and questions about what to do when consumers have more complicated asks, like interpretation of raw data. Additionally, at the rate with which CD-GT is growing, there are questions about having sufficient genetics professionals to meet the potential genetic counseling demand. While there are many complex questions and challenges, this market represents a chance for the genetics community to address and unmet need. We will review the history of the CD-GT/DTC-GT market and outline the issues and opportunities our profession is facing. PMID- 29512891 TI - Resisting resistance to cancer immunotherapy. PMID- 29512890 TI - Nucleolin mediated pro-angiogenic role of Hydroxysafflor Yellow A in ischaemic cardiac dysfunction: Post-transcriptional regulation of VEGF-A and MMP-9. AB - Hydroxysafflor Yellow A (HSYA), a most representative ingredient of Carthamus tinctorius L., had long been used in treating ischaemic cardiovascular diseases in China and exhibited prominently anticoagulant and pro-angiogenic activities, but the underlying mechanisms remained largely unknown. This study aimed to further elucidate the pro-angiogenic effect and mechanism of HSYA on ischaemic cardiac dysfunction. A C57 mouse model of acute myocardial infarction (AMI) was firstly established, and 25 mg/kg HSYA was intraperitoneally injected immediately after operation and given once, respectively, each morning and evening for 2 weeks. It was found that HSYA significantly improved ischaemia-induced cardiac haemodynamics, enhanced the survival rate, alleviated the myocardial injury and increased the expressions of CD31, vascular endothelial growth factor-A (VEGF-A) and nucleolin in the ischaemic myocardium. In addition, HSYA promoted the migration and tube formation of human umbilical vein endothelial cells (HUVECs), enhanced the expressions of nucleolin, VEGF-A and matrix metalloproteinase-9 (MMP 9) in a dose- and time-dependent manner. However, down-regulation of nucleolin expression sharply abrogated the effect mentioned above of HSYA. Further protein RNA coimmunoprecipitation and immunoprecipitation-RT-PCR assay showed that nucleolin binded to VEGF-A and MMP-9 mRNA and overexpression of nucleolin up regulated the mRNA expressions of VEGF-A and MMP-9 in the HUVECs through enhancing the stability of VEGF-A and MMP-9 mRNA. Furthermore, HSYA increased the mRNA expressions of VEGF-A and MMP-9 in the extract of antinucleolin antibody precipitated protein from the heart of AMI mice. Our data revealed that nucleolin mediated the pro-angiogenic effect of HSYA through post-transcriptional regulation of VEGF-A and MMP-9 expression, which contributed to the protective effect of HSYA on ischaemic cardiac dysfunction. PMID- 29512892 TI - Discovery of Benzimidazole-Quinolone Hybrids as New Cleaving Agents toward Drug Resistant Pseudomonas aeruginosa DNA. AB - A series of benzimidazole-quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2 fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities. PMID- 29512894 TI - Veteran Participation in Intensive Suicide Research Protocols: No Evidence of Iatrogenic Effects. AB - Suicide research remains fraught with ethical and methodological issues, including researchers' reservations about conducting intensive suicide research protocols due to potential iatrogenic effects and liability concerns. Such issues significantly impede scientific inquiry related to suicide. To date, no research has explored potential iatrogenic effects of intensive, nontreatment suicide research among Veterans. This study aimed to fill this gap. It was hypothesized that participation in suicide-specific protocols would not significantly increase risk among Veterans. Veterans completed self-reports, structured interviews, and rigorous suicide-specific tasks (Study A, N = 34; Study B, N = 18; Study C, N = 119). Findings indicated there were no significant differences in pre- and postassessment suicide risk variables (all ps > .05). Estimated mean change for "urge to harm self" was -0.24 (95% confidence interval [CI]: -0.60, 0.13), -0.28 (CI: -0.56, 0.01), and -0.01 (CI: -0.09, 0.07) and "intent to harm self" was 0.18 (95% CI: -0.45, 0.10), 0 (CI: -0.17, 0.17), and 0.01 (CI: -0.04, 0.06) for Studies A, B, and C, respectively. Results indicated the respective protocols did not produce iatrogenic effects. The current findings are discussed with attention to safety-monitoring techniques that may reduce iatrogenic effects and considerations for future researchers. PMID- 29512893 TI - Outcome evaluation of a pharmacy-based therapy management program for patients with cystic fibrosis. AB - OBJECTIVE: To compare medication adherence, pulmonary exacerbations, healthcare utilization, and costs for patients with cystic fibrosis (CF) who utilized a pharmacy-based therapy management program to a matched control group. We hypothesized that patient management services would be associated with better medication adherence, and thus require fewer visits to the emergency room or hospitalizations. METHODS: This retrospective, observational cohort study used claims data from the MORE2 claims Registry(r). The sample consisted of CF patients, aged 6+, who had >=1 pharmacy claim for inhaled tobramycin, inhaled aztreonam, ivacaftor, or dornase alfa from 6/2/2014-5/31/2015. Adherence was measured as proportion of days covered (PDC). Propensity score matching and multivariable regression techniques were used to compare outcomes in program participants to matched controls. RESULTS: Of the 236 intervention and 724 control patients meeting selection criteria, 202 were propensity-matched from each cohort. Relative to the control cohort, program patients had 23% higher mean PDC for tobramycin (IRR = 1.23, P = 0.01) and were twice as likely to be adherent to tobramycin (PDC >= 80%) than matched controls (OR = 2.14, P = 0.04). Program patients had fewer ER visits (IRR = 0.52, P < 0.01) and slightly lower ER costs (IRR = 0.66, P = 0.06) than the control patients. CONCLUSION: A pharmacy-based therapy management program for CF patients was associated with higher adherence to inhaled tobramycin and lower ER rates. Pharmacies that provide therapy management can support effective CF care management. PMID- 29512895 TI - The Dynamics of Chemical Reactions: Atomistic Visualizations of Organic Reactions, and Homage to van 't Hoff. AB - Jacobus Henricus van 't Hoff was the first Nobel Laureate in Chemistry. He pioneered in the study of chemical dynamics, which referred at that time to chemical kinetics and thermodynamics. The term has evolved in modern times to refer to the exploration of chemical transformations in a time-resolved fashion. Chemical dynamics has been driven by the development of molecular dynamics trajectory simulations, which provide atomic visualization of chemical processes and illuminate how dynamic effects influence chemical reactivity and selectivity. In homage to the legend of van 't Hoff, we review the development of the chemical dynamics of organic reactions, our area of research. We then discuss our trajectory simulations of pericyclic reactions, and our development of dynamic criteria for concerted and stepwise reaction mechanisms. We also describe a method that we call environment-perturbed transition state sampling, which enables trajectory simulations in condensed-media using quantum mechanics and molecular mechanics (QM/MM). We apply the method to reactions in solvent and in enzyme. Jacobus Henricus van 't Hoff (1852, Rotterdam-1911, Berlin) received the Nobel Prize for Chemistry in 1901 "in recognition of the extraordinary services he has rendered by the discovery of the laws of chemical dynamics and osmotic pressure in solutions". van 't Hoff was born the Netherlands, and earned his doctorate in Utrecht in 1874. In 1896 he moved to Berlin, where he was offered a position with more research and less teaching. van 't Hoff is considered one of the founders of physical chemistry. A key step in establishing this new field was the start of Zeitschrift fur Physikalische Chemie in 1887. PMID- 29512896 TI - Media pH and media type can significantly affect the reliability of in vitro copper tolerance assessments of Pseudomonas syringae pv. tomato. AB - AIMS: There are inconsistencies with in vitro copper tolerance screening methodology for Pseudomonas syringae pv. tomato in the current literature, particularly in relation to the appropriate medium to use, copper tolerance thresholds and reporting medium pH and/or pH adjustment steps. This study investigates the effect of medium and pH on copper tolerance results, including the potential use of 2-(N-morpholino)ethanesulfonic acid (MES) buffer to stabilize medium pH. METHODS AND RESULTS: Copper tolerance methodology was investigated through in vitro and in vivo testing of P. syringae pv. tomato. Four different media were tested, nutrient agar, Casitone yeast extract glycerol agar, King's B medium and potato dextrose agar. Highly variable copper tolerance profiles were observed for different isolates on the media tested. A pH range of 5.8-7.0 produced consistent copper tolerance data; outside of this range the data were unreliable. Addition of MES to media buffered the pH to within the acceptable levels. CONCLUSIONS: Copper tolerance thresholds with different media can vary significantly and the lowering effect of copper sulphate on media pH must be considered in media preparation. SIGNIFICANCE AND IMPACT OF THE STUDY: Methodology presented in the study can be extrapolated to copper tolerance testing for other pathogenic plant bacteria, particularly other pseudomonads. PMID- 29512897 TI - Arteriovenous differences in cord blood gas analysis and the prediction of adverse neonatal outcome. AB - INTRODUCTION: The aim of this paper was to determine whether arteriovenous differences of pH and pCO2 are useful predictors of adverse neonatal outcome in acidemic neonates. MATERIAL AND METHODS: An established database of 8759 term, singleton, non-anomalous neonates with validated cord gases and outcomes [Encephalopathy (Grade 2/3), Apgar <7 at five minutes and composite neonatal outcomes of neurological and systemic involvement] was used. Analysis was of the cohort of the 520 acidemic (arterial pH <7.10) neonates. Chi-square tests with odds ratio (OR), 95% CI were calculated for dichotomous cut-offs of differences; hierarchical logistic regression was used to examine the predictive performance over and above arterial pH. RESULTS: Arteriovenous hydrogen ion concentration ([H+ ion]) differences do not predict neonatal outcomes except low Apgar scores, and large pCO2 differences are associated with worse neonatal outcomes. Nevertheless, neonates with large arteriovenous [H+ ion] and pCO2 differences have lower arterial pH values. Hierarchical regression demonstrates that arteriovenous pCO2 differences do not add predictive value beyond arterial pH and arteriovenous [H+ ion] adds only to the prediction of low Apgar scores. CONCLUSIONS: Arteriovenous differences of [H+ ion] and pCO2 are not useful independent predictors of adverse neonatal outcomes in acidemic neonates. PMID- 29512898 TI - Structural and genetic analysis of START superfamily protein MSMEG_0129 from Mycobacterium smegmatis. AB - Mycobacterium tuberculosis is a notorious pathogen that continues to threaten human health. Rv0164, an antigen of both T- and B cells conserved across mycobacteria, and MSMEG_0129, its close homolog in Mycobacterium smegmatis, are predicted members of the START domain superfamily, but their molecular function is unknown. Here, gene knockout studies demonstrate MSMEG_0129 is essential for bacterial growth, suggesting Rv0164 may be a potential drug target. The MSMEG_0129 crystal structure determined at 1.95 A reveals a fold similar to that in polyketide aromatase/cyclases ZhuI and TcmN from Streptomyces sp. Structural comparisons and docking simulations, however, infer that MSMEG_0129 and Rv0164 are unlikely to catalyze polyketide aromatization/cyclization, but probably play an irreplaceable role during mycobacterial growth, for example, in lipid transfer during cell envelope synthesis. PMID- 29512900 TI - Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high-grade and diffuse intrinsic pontine glioma. AB - BACKGROUND: Progressive/recurrent high-grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed. METHODS: We conducted a phase 1 study (rolling-six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet-derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c-Met inhibitor, in such patients. Pharmacokinetics of both agents were performed. Biomarkers of cellular pathway activation in peripheral blood mononuclear cells (PBMC) were evaluated before and after administration of dasatinib. PDGFRA and MET amplification, and PDGFRA mutations were studied in tumor samples. RESULTS: Twenty-five patients were enrolled in this study (median age: 11.9 years). Eleven patients had DIPG. Glioblastoma accounted for 40% of cases. Dasatinib at 50 mg/m2 and crizotinib at 130 mg/m2 or 100 mg/m2 were poorly tolerated when administered twice daily. Drug administration was then switched to once daily. Dasatinib administered at 50 mg/m2 and crizotinib at 215 mg/m2 once daily was the MTD. Dose-limiting toxicities consisted of diarrhea, fatigue, proteinuria, hyponatremia, rash, and grade 4 neutropenia. Only two patients received therapy for at least 6 months. No objective radiologic responses were observed. Pharmacokinetics of dasatinib and crizotinib were comparable to previous studies. A statistically significant decrease in the ratio of p AKT/total AKT in PBMC occurred after dasatinib administration. PDGFRA and MET amplification were found in four and two cases, respectively. Only one of 10 tumors harbored a PDGFRA mutation. CONCLUSIONS: This drug combination was poorly tolerated and its activity was minimal. We do not recommend further testing of this combination in children. PMID- 29512899 TI - Integrating Proteomics and Targeted Metabolomics to Understand Global Changes in Histone Modifications. AB - The chromatin fiber is the control panel of eukaryotic cells. Chromatin is mostly composed of DNA, which contains the genetic instruction for cell phenotype, and histone proteins, which provide the scaffold for chromatin folding and part of the epigenetic inheritance. Histone writers/erasers "flag" chromatin regions by catalyzing/removing covalent histone post-translational modifications (PTMs). Histone PTMs chemically contribute to chromatin relaxation or compaction and recruit histone readers to modulate DNA readout. The precursors of protein PTMs are mostly small metabolites. For instance, acetyl-CoA is used for acetylation, ATP for phosphorylation, and S-adenosylmethionine for methylation. Interestingly, PTMs such as acetylation can occur at neutral pH also without their respective enzyme when the precursor is sufficiently concentrated. Therefore, it is essential to differentially quantify the contribution of histone writers/erasers versus the effect of local concentration of metabolites to understand the primary regulation of histone PTM abundance. Aberrant phenotypes such as cancer cells have misregulated metabolism and thus the composition and the modulation of chromatin is not only driven by enzymatic tuning. In this review, the latest advances in mass spectrometry (MS) to analyze histone PTMs and the most adopted quantification methods for related metabolites, both necessary to understand PTM relative changes, are discussed. PMID- 29512902 TI - A phase 3 multicenter, open-label, prospective study designed to evaluate the effectiveness and ease of use of nasal glucagon in the treatment of moderate and severe hypoglycemia in children and adolescents with type 1 diabetes in the home or school setting. AB - OBJECTIVE: This multicenter, open-label study was designed to evaluate real-world effectiveness and ease of use of nasal glucagon (NG) in treating moderate or severe hypoglycemic events in children and adolescents with type 1 diabetes (T1D). METHODS: Caregivers were trained to administer NG (3 mg) to the child/adolescent with T1D during spontaneous, symptomatic moderate or severe hypoglycemic events, observe treatment response (defined as awakening or returning to normal status within 30 minutes), and measure blood glucose (BG) levels every 15 minutes. Data regarding adverse events and ease of use were solicited using questionnaires. RESULTS: The analysis population included 14 patients who experienced 33 moderate hypoglycemic events with neuroglycopenic symptoms and BG level <=70 mg/dL. Patients returned to normal status within 30 minutes of NG administration in all 33 events. Mean BG levels increased from 55.5 mg/dL (range 42-70 mg/dL) at baseline to 113.7 mg/dL (range 79-173 mg/dL) within 15 minutes of NG administration. In most hypoglycemic events (93.9%), caregivers reported that NG administration was easy or very easy; they could administer NG within 30 seconds in 60.6% of events. There were no serious adverse events. CONCLUSIONS: A single 3-mg dose of NG was effective in treating moderate, symptomatic, hypoglycemic events in children and adolescents with T1D in a real world setting. It was easy-to-use and reasonably well tolerated. NG shows promise as an effective, needle-free, and user-friendly alternative to injectable glucagon. PMID- 29512901 TI - Regulation of autoimmune and anti-tumour T-cell responses by PTPN22. AB - A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22 (that encodes a tyrosine phosphatase) has been associated with the development of several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types, including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T cell activation and effector responses. We discuss progress in our understanding of the impact of PTPN22 in autoimmune disease in humans and mouse models, as well as recent evidence suggesting that genetic manipulation of PTPN22 expression might enhance the efficacy of anti-tumour T-cell responses. PMID- 29512903 TI - Tracking Down a New Steroid-Hydroxylating Promiscuous Cytochrome P450: CYP154C8 from Streptomyces sp. W2233-SM. AB - CYP154C8 from Streptomyces sp. has been identified as a new cytochrome P450 with substrate flexibility towards different sets of steroids. In vitro treatment of these steroids with CYP154C8 revealed interesting product formation patterns with the same group of steroids. NMR study revealed the major product of corticosterone to be hydroxylated at the C21 position, whereas progesterone, androstenedione, testosterone, and 11-ketoprogesterone were exclusively hydroxylated at the 16alpha position. However, the 16alpha-hydroxylated product of progesterone was further hydroxylated to yield dihydroxylated products. 16 hydroxyprogesterone was hydroxylated at two positions to yield dihydroxylated products: 2alpha,16alpha-dihydroxyprogesterone and 6beta,16alpha dihydroxyprogesterone. To the best of our knowledge, this is the first report of generation of such products through enzymatic hydroxylation by a CYP450. In view of the importance of modified steroids as pharmaceutical components, CYP154C8 has immense potential for utilization in bioproduction of hydroxylated derivative compounds to be directly employed for pharmaceutical applications. PMID- 29512904 TI - EBV transformation induces overexpression of hMSH2/3/6 on B lymphocytes and enhances gammadeltaT-cell-mediated cytotoxicity via TCR and NKG2D. AB - The engagement of Epstein-Barr virus (EBV)-induced protein ligands in gammadelta T-cell-mediated anti-EBV immunity, especially in EBV-associated B-cell malignancies, has not been fully elucidated. Previously we reported the overexpression of human MutS homologue 2 (hMSH2), a stress-inducible protein ligand for human gammadelta T-cells, on EBV-transformed B lymphoblastic cell lines (B-LCLs). In this study, we first generated EBV-transformed B-LCLs from peripheral blood mononuclear cells of healthy volunteers with B95-8 cellular supernatant and cyclosporine A. Secondly, we demonstrated the significantly elevated cell surface protein expression and mRNA transcription of hMSH2 in EBV transformed B-LCLs, 3D5 and EBV-positive B lymphoma cell line Daudi and Raji. Thirdly, hMSH2-mediated recognition of EBV-transformed B malignant cells by human gammadelta T-cells was confirmed by specific antibody blocking and siRNA interference. Both TCRgammadelta and NKG2D participated in hMSH2-mediated recognition of EBV-transformed B malignant cells. Furthermore, hMSH3 and hMSH6, the companion proteins of hMSH2, along with CD98, were found overexpressed on the surface of EBV-transformed malignant B-cells. We concluded that the induced overexpression of hMSH proteins might serve as early alerting biomarkers emerged in EBV-related B-cell malignances or as potential targets for establishing gammadelta T-cell-based therapeutic immunotherapies towards EBV infection. PMID- 29512905 TI - Geniposide prevents H2 O2 -induced oxidative damage in melanocytes by activating the PI3K-Akt signalling pathway. AB - BACKGROUND: Oxidative stress is one possible pathogenic event in vitiligo that induces melanocyte destruction. Geniposide exerts certain antioxidant effects on various cells by activating the phosphoinositol 3-kinase (PI3K)-Akt signalling pathway. However, researchers have not clearly determined whether geniposide protects human melanocytes from oxidative stress or identified the underlying mechanism of such protection. AIM: To determine whether geniposide protects melanocytes from H2 O2 -induced oxidative damage and to explore the role of the PI3K-Akt signalling pathway in this protective effect. METHODS: The antioxidant effects of geniposide on human melanocytes were examined by measuring cell viability, apoptosis rates, reactive oxygen species (ROS) production and activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). We examined expression of Akt, phosphorylated Akt (p-Akt), Bcl-2, Bax, and cleaved caspase 3 and cleaved caspase 9 proteins to determine the involvement of the PI3K-Akt pathway. RESULTS: Pretreatment with geniposide 5, 25, 125 or 625 MUmol/L increased cell viability and decreased the apoptosis rate of H2 O2 treated melanocytes. In addition, geniposide enhanced the antioxidant activity of SOD and CAT, and decreased intracellular ROS accumulation. Furthermore, geniposide increased the levels of p-Akt and regulated the expression of downstream proteins in the PI3K-Akt pathway, such as Bcl-2, Bax, and cleaved caspase 3 and 9, in H2 O2 -treated melanocytes. Notably, these effects were largely blocked by treatment with LY294002 prior to H2 O2 treatment. CONCLUSIONS: Based on these results, geniposide protects human melanocytes from H2 O2 -induced oxidative damage, and the PI3K-Akt signalling pathway is involved in its antioxidant effect. PMID- 29512906 TI - Letter: predicting azathioprine-associated pancreatitis in IBD-phenotype or genotype? Authors' reply. PMID- 29512907 TI - Letter: using a placebo as a comparator to rifaximin for the primary prophylaxis of spontaneous bacterial peritonitis-is there really an ethical concern? PMID- 29512908 TI - Letter: extensive intestinal metaplasia is associated with the presence of incomplete intestinal metaplasia subtype and could be an easier marker for high risk of gastric cancer Authors' reply. PMID- 29512909 TI - Editorial: NAFLD in Asia-clinical associations with advanced disease become clearer. Authors' reply. PMID- 29512910 TI - Editorial: weight change, liver histology and the metabolic effects of obeticholic acid in NASH. PMID- 29512911 TI - Letter: extensive intestinal metaplasia is associated with the presence of incomplete intestinal metaplasia subtype and could be an easier marker for high risk of gastric cancer. PMID- 29512912 TI - Editorial: ulcerative colitis submucosal fibrosis and inflammation: more than just strictures. PMID- 29512913 TI - Editorial: NAFLD in Asia-clinical associations with advanced disease become clearer. PMID- 29512914 TI - Letter: the addition of an immunosuppressant in patients with unsatisfactory response to vedolizumab-Authors' reply. PMID- 29512916 TI - Editorial: older-onset inflammatory bowel disease-is it time to start looking beyond a number? PMID- 29512915 TI - Letter: the addition of an immunosuppressant in patients with unsatisfactory response to vedolizumab. PMID- 29512917 TI - Editorial: clinical trials in IBD-how much of a difference is enough? PMID- 29512918 TI - Letter: predicting azathioprine-associated pancreatitis in IBD-phenotype or genotype? PMID- 29512919 TI - Corrigendum. PMID- 29512920 TI - Perceived Burdensomeness Predicts Outcomes of Short-Term Psychological Treatment of Young People at Risk of Suicide. AB - The interpersonal-psychological theory of suicide (IPTS; Joiner, ) provides a model for understanding the mechanisms underlying suicide risk, but there is limited research measuring change in the constructs over the course of treatment. This study aimed to test whether changes in perceived burdensomeness (PB) and thwarted belongingness (TB) mediated the effects of changes in depression and hopelessness on suicide risk. The sample comprised 226 Australian young people (aged 12-24; 67.7% female; 5.7% Aboriginal and Torres Strait Islander) receiving short-term psychological treatment for suicide-related behaviors. Change scores over the course of therapy were generated using admission and discharge measures of PB, TB, depression, hopelessness, and suicide risk. Results revealed partial support for the theory. The relationship between changes in depression and hopelessness on suicide risk was fully mediated by changes in PB. However, changes in TB did not mediate these relationships. This study offers encouragement for the potential use of the IPTS in the context of psychological treatment of young people. Assessment of the IPTS constructs may be helpful in assessing change in suicide risk and further assist in treatment. PMID- 29512922 TI - Bilateral sensory disturbance after cortical spreading depression revealed by fluorescence imaging of voltage-sensitive dye. AB - Cortical spreading depression (CSD), a propagation wave of transient neuronal and glial depolarization followed by suppression of spontaneous brain activity, has been hypothesized to be the underlying mechanism of migraine aura and triggers the headache attack. Evidence from various animal models accumulates since its first discovery in 1944 and provides support for this hypothesis. In this paper, alterations of bilateral cortical responses are investigated in a mice migrainous model of CSD using voltage-sensitive dye imaging under hindlimb and cortical stimulation. After CSD induction in the right hemisphere, bilateral sensory responses evoked by left hindlimb stimulation dramatically decreases, whereas right hindlimb stimulation can still activate bilateral responses with an increased response of the left hemisphere and a well-preserved response of the right hemisphere. In addition, cortical neural excitability remains after CSD assessed by direct activation of the right hemisphere in spite of the sensory deficit under contralateral hindlimb stimulation. These results depict the sensory disturbance of bilateral hemispheres after CSD, which may be helpful in understanding how sensory disturbance occur during migraine aura. PMID- 29512921 TI - ETS1 and SP1 drive DHX15 expression in acute lymphoblastic leukaemia. AB - DHX15 plays a role in leukaemogenesis and leukaemia relapse. However, the mechanism underlying the transcriptional regulation of DHX15 in ALL has not been elucidated. Our present study aimed to explore the functional promoter region of DHX15 and to investigate the transcription factors controlling the transcription of this gene. A luciferase assay performed with several truncated constructs identified a 501-bp region as the core promoter region of DHX15. Site-directed mutagenesis, electrophoretic mobility shift and chromatin immunoprecipitation assays showed that ETS1 and SP1 occupied the DHX15 promoter. Furthermore, knockdown of ETS1 and SP1 resulted in suppression of DHX15, whereas the overexpression of these genes led to up-regulation of DHX15. Interestingly, in samples obtained from patients with ALL at diagnosis, both ETS1 and SP1 correlated positively with DHX15 expression. Additionally, differences in methylation of the DHX15 core promoter region were not observed between the patients and controls. In conclusion, we identified the core promoter region of DHX15 and demonstrated that ETS1 and SP1 regulated DHX15 expression in ALL. PMID- 29512925 TI - Isolated central nervous system relapse of maxillary rhabdomyosarcoma presenting with neoplastic meningitis. PMID- 29512923 TI - Modulation of the oxidative plasmatic state in gastroesophageal reflux disease with the addition of rich water molecular hydrogen: A new biological vision. AB - Gastroesophageal reflux disease (GERD), a clinical condition characterized by reflux of gastroduodenal contents in the oesophagus, has proved to demonstrate a strong link between oxidative stress and the development of GERD. Proton pump inhibitors (PPIs) have been universally accepted as first-line therapy for management of GERD. The potential benefits of electrolysed reduced water (ERW), rich in molecular hydrogen, in improving symptoms and systemic oxidative stress associated with GERD was assessed. The study was performed on 84 GERD patients undergoing control treatment (PPI + tap water) or experimental treatment (PPI + ERW) for 3 months. These patients were subjected to the GERD-Health Related Quality of Life Questionnaire as well as derivatives reactive oxigen metabolites (d-ROMs) test, biological antioxidant potential (BAP) test, superoxide anion, nitric oxide and malondialdehyde assays, which were all performed as a proxy for the oxidative/nitrosative stress and the antioxidant potential status. Spearman's correlation coefficient was used to evaluate the correlation between scores and laboratory parameters. Overall results demonstrated that an optimal oxidative balance can be restored and GERD symptoms can be reduced rapidly via the integration of ERW in GERD patients. The relative variation of heartburn and regurgitation score was significantly correlated with laboratory parameters. Thus, in the selected patients, combination treatment with PPI and ERW improves the cellular redox state leading to the improvement of the quality of life as demonstrated by the correlation analysis between laboratory parameters and GERD symptoms. PMID- 29512924 TI - Down-regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer. AB - Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non-muscle-invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down-regulation of PKM2 on THP efficiency. Via inhibitor or siRNA, the effects of reduced PKM2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT, cologenic and fluorescence approaches. Molecular mechanisms of PKM2 on THP sensitization were explored by probing p-AMPK and p-STAT3 levels via WB. Syngeneic orthotopic bladder tumour model was applied to evaluate this efficiency in vivo, analysed by Kaplan-Meier survival curves, body and bladder weights plus immunohistochemistric tumour biomarkers. PKM2 was overexpressed in bladder cancer cells and tissues, and down-regulation of PKM2 enhanced the sensitivity of THP in vitro. Activation of AMPK is essential for THP to exert anti-bladder cancer activities. On the other hand, down-regulating PKM2 activates AMPK and inhibits STAT3, correlated with THP sensitivity. Compared with THP alone (400 MUmol L-1 , 50 MUL), the combination with metformin (60 mmol L-1 , 50 MUL) stopped growth of bladder cancer completely in vivo (combination group VS normal group P = .078). Down-regulating the expression of PKM2 enhances the anticancer efficiency of THP. This study provides a new insight for improving the chemotherapeutic effect of THP. PMID- 29512926 TI - Age distribution and metabolic disorders in people with Type 1 diabetes in Beijing and Shantou, China: a cross-sectional study. AB - AIMS: To examine whether the age profile of people with Type 1 diabetes differs from that of the general population and in what manner, and to study the clinical characteristics related to metabolic disorders among people with Type 1 diabetes in China. METHODS: We sequentially enrolled 849 people with Type 1 diabetes from hospital records review, inpatient wards and outpatient clinics. Data were collected via face-to-face interviews, medical records and venous blood samples. Beijing census data for 2011 were used to provide the general population statistics. Descriptive analysis of the results and tests for differences were performed. RESULTS: The median (interquartile range) age at diagnosis of diabetes was 16 (9-28) years and the duration of diabetes was 4 (1-8) years. The mean +/- sd HbA1c concentration was 76+/-28 mmol/mol (9.1+/-2.5%). Compared with the general population, the population with Type 1 diabetes comprised more young individuals and fewer elderly individuals. The overall prevalence of metabolic syndrome among those with Type 1 diabetes was 10.1% (95% CI 7.9-12.2). People with metabolic syndrome were older and were diagnosed with diabetes at an older age. Hypertension and dyslipidaemia were more common in obese individuals with Type 1 diabetes than in their non-obese counterparts. CONCLUSIONS: Compared with the general population, people with Type 1 diabetes comprised more young and fewer elderly individuals. The prevalence of metabolic syndrome in the Type 1 diabetes population was 10.1%. Hypertension and dyslipidaemia were more prevalent in obese than non-obese individuals. PMID- 29512927 TI - Influences of photic stress on postsubicular head-directional processing. AB - The stress response serves vital adaptive functions. However, acute stress episodes often negatively impact cognitive processing. Here, we aimed to elucidate whether stress detrimentally affects the head-direction cells of the postsubiculum, which may in turn impair downstream spatial information processing. We recorded neurons in the rats' postsubiculum during a pellet chasing task during baseline non-stress conditions and after a 30-min acute photic stress exposure. Based on their baseline firing rate, we identified a subpopulation of head-direction cells that drastically decreased its firing rate as a response to stress while preserving their head directionality. The remaining population of head-direction cells as well as other neurons recorded in the postsubiculum were unaffected. The observed altered activity in the subpopulation might be the basis for spatial processing deficits observed following acute stress episodes. PMID- 29512928 TI - Association between impaired renal function and stroke outcome in patients with versus without atrial fibrillation. AB - BACKGROUND AND PURPOSE: Chronic kidney disease and atrial fibrillation (AF) are two commonly coexisting risk factors of stroke. The aim of this study was to compare the association between impaired renal function and poor prognosis in ischaemic stroke patients with versus without AF. METHODS: Patients with ischaemic stroke in the China National Stroke Registry were included. Low estimated glomerular filtration rate (eGFR) on admission was defined as <60 ml/min/1.73 m2 . Outcomes included stroke recurrence, death, poor outcome defined as 3-6 on the modified Rankin Scale (mRS) and ordinal mRS at 12 months. RESULTS: Of 9154 patients included, 1143 (12.5%) patients had a low eGFR. Patients with a low eGFR had more presence of AF compared with those with an eGFR of >=90 ml/min/1.73 m2 [21.5% vs. 6.9%; odds ratio (OR) 1.77, 95% confidence interval (CI) 1.43-2.20]. An interaction of eGFR category by AF was observed for poor outcome and ordinal mRS (P for interaction = 0.04 and 0.002). In patients with AF, the OR with 95% CI of low eGFR was 1.86 (1.19-2.92) for stroke recurrence, 2.87 (1.82-4.52) for death, 1.83 (1.09-3.05) for poor outcome and 2.20 (1.52 3.18) for ordinal mRS. In patients without AF, low eGFR was only associated with death and ordinal mRS (OR 1.61, 95% CI 1.28-2.02; common OR 1.20, 95% CI 1.04 1.38; respectively). CONCLUSIONS: Stroke patients with lower eGFR had more presence of AF. The associations of low eGFR with risk of poor prognosis in stroke patients with AF were stronger than those without AF. PMID- 29512930 TI - Isavuconazole pharmacokinetics in a patient with cystic fibrosis following bilateral orthotopic lung transplantation. AB - Previous studies of patients with cystic fibrosis (CF) treated with azole antifungals have shown altered pharmacokinetics relative to healthy patients. Data regarding the pharmacokinetic profile of isavuconazole in patients with CF undergoing lung transplantation are currently not available. Serum trough concentrations assessed in a single CF patient following transplant revealed significantly lower values relative to available literature. Larger studies are required to validate CF population pharmacokinetics of isavuconazole. PMID- 29512931 TI - Risk of epilepsy after a single seizure in multiple sclerosis. AB - BACKGROUND AND PURPOSE: The 2014 International League Against Epilepsy clinical definition of epilepsy allows diagnosis after a single unprovoked seizure if the 10-year recurrence risk exceeds 60%. Multiple sclerosis (MS) carries an increased risk of epilepsy, but the risk after a first seizure is unknown. We aimed to investigate the risk of epilepsy in patients with MS who had suffered a first seizure. METHODS: We cross-referenced data from the Swedish MS register with the national patient register for 15 810 patients with MS and 43 635 controls and included 289 patients with MS and 222 controls with a first diagnosis of seizure or status epilepticus (SE) without prior epilepsy or presumed symptomatic aetiology. Kaplan-Meier curves were used to estimate the risk of epilepsy. RESULTS: The 10-year risk of epilepsy was 51.4% [95% confidence interval (CI), 44.0-58.9] for patients with MS and 41.3% (95% CI, 33.5-49.1) for controls. The risk was 46.1% (95% CI, 35.3-56.9) for patients with relapsing-remitting MS and 60.7% (95% CI, 46.6-74.8) for patients with secondary progressive MS. For patients with MS with SE, the 10-year risk of epilepsy was 85.9% (95% CI, 67.9 100). CONCLUSIONS: Our data indicate that patients with relapsing-remitting MS have a similar risk as controls of developing epilepsy after a single seizure. Patients with secondary progressive MS could run a greater risk of subsequent epilepsy, but our data do not indicate a risk that, with certainty, exceeds the threshold specified by the International League Against Epilepsy. Patients with SE have a high risk of epilepsy, possibly motivating diagnosis and treatment. PMID- 29512932 TI - Modified conditioning regimen improves outcomes of unrelated donor peripheral blood stem cell transplantation for beta-thalassaemia major patients. AB - BACKGROUND: The objective of this study was to evaluate the feasibility of a modified conditioning regimen for the treatment of patients with beta thalassaemia major (TM), using unrelated donor peripheral blood stem cell transplantation (UD-PBSCT). METHODS: A modified conditioning regimen based on intravenous busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin was performed in 50 consecutive childhood patients with beta-TM and a median age of 4.6 years (range, 2-12 years). According to Pesaro's classification, three classes of risk are identified using the criteria of degree of hepatomegaly, portal fibrosis, and quality of the chelation treatment. Patients with three adverse criteria constituted class III, none of the adverse criteria constituted class I, and one or two of the adverse criteria formed class II. Ten patients were class I, 36 class II, and four class III. All patients were transplanted with UDs containing 37 of 10/10 human leukocyte antigen (HLA)-matched pairs, 11 of 9/10 matched pairs, and two of 8/10 matched pairs. The median follow-up was 36 months (range, 9-96 months). RESULTS: All patients successfully achieved engraftment, two of whom developed persistent thrombocytopaenia. The incidence of acute graft-versus-host disease (aGVHD) grade III-IV and chronic graft-versus host disease (cGVHD) were 12% and 8%, respectively. However, 8.3% of HLA-matched and 15.4% of HLA-mismatched patients developed aGVHD. The incidence of severe bacterial infections and fungal pneumonia was 12% and 20%, respectively. The 3 year overall survival, disease-free survival, graft rejection, and transplant related mortality were 94%, 92%, 2%, and 6%, respectively. CONCLUSION: This modified conditioning protocol effectively improved outcomes of UD-PBSCT for patients with beta-TM. PMID- 29512933 TI - Genetic counselor training for the next generation: Where do we go from here? PMID- 29512934 TI - Interaction of Beauveria bassiana and Metarhizium anisopliae with chlorpyrifos ethyl and spinosad in Spodoptera frugiperda larvae. AB - BACKGROUND: The high natural resistance of the fall armyworm (FAW) to entomopathogenic fungi and the speed at which it develops resistance to chemical insecticides make it difficult to control in several crops where it is a key pest. The aim of the study was to improve mortality by combining a 50% lethal concentration of chlorpyrifos ethyl or spinosad with the entomopathogenic fungus Beauveria bassiana (Bb88) or Metarhizium anisopliae (ETL). RESULTS: Three main results were obtained. (i) Both insecticides improved the performance of the fungus when the insecticide and fungus were applied simultaneously and when spinosad preceded fungi. In control larvae treated with fungi, <1% of larvae showed fungal sporulation, but under simultaneous application of the fungus with chlorpyrifos or spinosad, 31 and 47% did so, with 68 and 93% of cadavers showing sporulation, respectively. (ii) Synergistic mortality was observed when Bb88 and spinosad were applied simultaneously, which resulted in 34% more dead larvae than the spinosad control (44%). Finally, (iii) antagonism occurred when Bb88 was applied before chlorpyrifos, when Bb88 and chlorpyrifos were applied simultaneously, and when ETL was applied before chlorpyrifos, which reduced larval mortality by 27, 31 and 19%, respectively. CONCLUSION: The synergistic mortality and improved fungal performance observed here support the hypothesis that combinations of low insecticide doses and entomopathogenic fungi can enhance integrated pest management programs and reduce the environmental impact of insecticides. Antagonism shows that some particular combinations and application sequences may produce disadvantages in pest control. (c) 2018 Society of Chemical Industry. PMID- 29512935 TI - Cytomegalovirus infections in lung and hematopoietic cell transplant recipients in the Organ Transplant Infection Prevention and Detection Study: A multi-year, multicenter prospective cohort study. AB - BACKGROUND: Most studies of post-transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these 2 groups. METHODS: Patients were followed up for 30 months in a 6-center prospective cohort study. Data on demographics, CMV infections, tissue-invasive disease, recurrences, rejection, and immunosuppression were recorded. RESULTS: The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (P = .0706). Tissue-invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (P = .087). Median time to CMV infection was longer in the lung transplant group (236 vs 40 days, P < .0001), likely reflecting the effects of prophylaxis vs preemptive therapy. Total IgG levels of < 350 mg/dL in lung recipients and graft vs host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (P = .008), although duration of viremia was not significantly different between the 2 groups. CMV infection was not associated with reduced overall survival in either group. CONCLUSIONS: Current CMV prevention strategies have resulted in a low incidence of tissue-invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era. PMID- 29512937 TI - The future is now: Technology's impact on the practice of genetic counseling. AB - Smartphones, artificial intelligence, automation, digital communication, and other types of technology are playing an increasingly important role in our daily lives. It is no surprise that technology is also shaping the practice of medicine, and more specifically the practice of genetic counseling. While digital tools have been part of the practice of medical genetics for decades, such as internet- or CD-ROM-based tools like Online Mendelian Inheritance in Man and Pictures of Standard Syndromes and Undiagnosed Malformations in the 1980s, the potential for emerging tools to change how we practice and the way patients consume information is startling. Technology has the potential to aid in at-risk patient identification, assist in generating a differential diagnosis, improve efficiency in medical history collection and risk assessment, provide educational support for patients, and streamline follow-up. Here we review the historic and current uses of technology in genetic counseling, identify challenges to integration, and propose future applications of technology that can shape the practice of genetic counseling. PMID- 29512936 TI - PCSK9 inhibitor valuation: A science-based review of the two recent models. AB - Low-density lipoprotein cholesterol (LDL-C) has been extensively evaluated. Prospective cohort studies, randomized controlled trials, biology, pathophysiology, genetics, and Mendelian randomization studies, have clearly taught us that LDL-C causes atherosclerotic cardiovascular disease. The newest class of drugs to lower LDL-C, the proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, have been found to safely reduce LDL-C approximately 60% when added to high-intensity statin therapy. Because their cost is much greater than that of the currently available agents, their value has been questioned. In late August, 2017, two groups assessed the value of this class of drugs looking at cost-effectiveness; however, the Institute for Clinical and Economic Review and Fonarow and colleagues found disparate results when assessing PCSK9 valuation. Herein, we review the evolution of LDL-C from hypothesis to fact, and then attempt to adjudicate the 2 models, shedding light on the complex modeling process. We find that models of cost-effectiveness are helpful adjuncts to decision making, but that their conclusions depend on many assumptions. Ultimately, clinician judgment regarding their clinical benefit, balanced by some estimation of cost, may be more productive to target the right patients for whom the benefits can be well-justified. PMID- 29512938 TI - FGF1 improves functional recovery through inducing PRDX1 to regulate autophagy and anti-ROS after spinal cord injury. AB - Fibroblast growth factor 1 (FGF1) is thought to exert protective and regenerative effects on neurons following spinal cord injury (SCI), although the mechanism of these effects is not well understood. The use of FGF1 as a therapeutic agent is limited by its lack of physicochemical stability and its limited capacity to cross the blood-spinal cord barrier. Here, we demonstrated that overexpression of FGF1 in spinal cord following SCI significantly reduced tissue loss, protected neurons in the ventricornu, ameliorated pathological morphology of the lesion, dramatically improved tissue recovery via neuroprotection, and promoted axonal regeneration and remyelination both in vivo and in vivo. In addition, the autophagy and the expression levels of PRDX1 (an antioxidant protein) were induced by AAV-FGF1 in PC12 cells after H2 O2 treatment. Furthermore, the autophagy levels were not changed in PRDX1-suppressing cells that were treated by AAV-FGF1. Taken together, these results suggest that FGF1 improves functional recovery mainly through inducing PRDX1 expression to increase autophagy and anti ROS activity after SCI. PMID- 29512939 TI - Changing trends in inducer drugs of fixed drug eruption: a 20-year cross sectional study from Turkey. PMID- 29512940 TI - Engaging populations underrepresented in research through novel approaches to consent. AB - The lack of diversity of populations included in genomics databases is an important inhibitor of genomic discovery from bench to bedside. One way to increase the diversity of participants is to ensure that informed consent processes are designed for cultural and linguistic concordance for non-majority populations. This article describes two case studies of genomics research studies that are using novel approaches to informed consent to increase recruitment and retention of participants from traditionally underrepresented populations: The Cancer Health Assessments Reaching Many (CHARM) study, part of the Clinical Sequencing Evidence-Generating Research (CSER) consortium, and the All of Us Research Program, part of the Precision Medicine Initiative. We conclude by proposing a community of practice among researchers seeking to improve informed consent to increase diversity in genomics research. PMID- 29512941 TI - Selective Hydrodeoxygenation of Vegetable Oils and Waste Cooking Oils to Green Diesel Using a Silica-Supported Ir-ReOx Bimetallic Catalyst. AB - High yields of diesel-range alkanes are prepared by hydrodeoxygenation of vegetable oils and waste cooking oils over ReOx -modified Ir/SiO2 catalysts under mild reaction conditions. The catalyst containing a Re/Ir molar ratio of 3 exhibits the best performance, achieving 79-85 wt % yield of diesel-range alkanes at 453 K and 2 MPa H2 . The yield is nearly quantitative for the theoretical possible long-chain alkanes on the basis of weight of the converted oils. The catalyst retains comparable activity upon regeneration through calcination. Control experiments using probe molecules as model substrates suggest that C=C bonds of unsaturated triglycerides and free fatty acids are first hydrogenated to their corresponding saturated intermediates, which are then converted to aldehyde intermediates through hydrogenolysis of acyl C-O bonds and subsequently hydrogenated to fatty alcohols. Finally, long-chain alkanes without any carbon loss are formed by direct hydrogenolysis of the fatty alcohols. Small amounts of alkanes with one carbon fewer are also formed by decarbonylation of the aldehyde intermediates. A synergy between Ir and partially reduced ReOx sites is discussed to elucidate the high activity of Ir-ReOx /SiO2. PMID- 29512942 TI - Haemin attenuates intermittent hypoxia-induced cardiac injury via inhibiting mitochondrial fission. AB - Obstructive sleep apnoea (OSA) characterized by intermittent hypoxia (IH) is closely associated with cardiovascular diseases. IH confers cardiac injury via accelerating cardiomyocyte apoptosis, whereas the underlying mechanism has remained largely enigmatic. This study aimed to explore the potential mechanisms involved in the IH-induced cardiac damage performed with the IH-exposed cell and animal models and to investigate the protective effects of haemin, a potent haeme oxygenase-1 (HO-1) activator, on the cardiac injury induced by IH. Neonatal rat cardiomyocyte (NRC) was treated with or without haemin before IH exposure. Eighteen male Sprague-Dawley (SD) rats were randomized into three groups: control group, IH group (PBS, ip) and IH + haemin group (haemin, 4 mg/kg, ip). The cardiac function was determined by echocardiography. Mitochondrial fission was evaluated by Mitotracker staining. The mitochondrial dynamics-related proteins (mitochondrial fusion protein, Mfn2; mitochondrial fission protein, Drp1) were determined by Western blot. The apoptosis of cardiomyocytes and heart sections was examined by TUNEL. IH regulated mitochondrial dynamics-related proteins (decreased Mfn2 and increased Drp1 expressions, respectively), thereby leading to mitochondrial fragmentation and cell apoptosis in cardiomyocytes in vitro and in vivo, while haemin-induced HO-1 up-regulation attenuated IH-induced mitochondrial fragmentation and cell apoptosis. Moreover, IH resulted in left ventricular hypertrophy and impaired contractile function in vivo, while haemin ameliorated IH-induced cardiac dysfunction. This study demonstrates that pharmacological activation of HO-1 pathway protects against IH-induced cardiac dysfunction and myocardial fibrosis through the inhibition of mitochondrial fission and cell apoptosis. PMID- 29512943 TI - Neural substrates for allocentric-to-egocentric conversion of remembered reach targets in humans. AB - Targets for goal-directed action can be encoded in allocentric coordinates (relative to another visual landmark), but it is not known how these are converted into egocentric commands for action. Here, we investigated this using a slow event-related fMRI paradigm, based on our previous behavioural finding that the allocentric-to-egocentric (Allo-Ego) conversion for reach is performed at the first possible opportunity. Participants were asked to remember (and eventually reach towards) the location of a briefly presented target relative to another visual landmark. After a first memory delay, participants were forewarned by a verbal instruction if the landmark would reappear at the same location (potentially allowing them to plan a reach following the auditory cue before the second delay), or at a different location where they had to wait for the final landmark to be presented before response, and then reach towards the remembered target location. As predicted, participants showed landmark-centred directional selectivity in occipital-temporal cortex during the first memory delay, and only developed egocentric directional selectivity in occipital-parietal cortex during the second delay for the 'Same cue' task, and during response for the 'Different cue' task. We then compared cortical activation between these two tasks at the times when the Allo-Ego conversion occurred, and found common activation in right precuneus, right presupplementary area and bilateral dorsal premotor cortex. These results confirm that the brain converts allocentric codes to egocentric plans at the first possible opportunity, and identify the four most likely candidate sites specific to the Allo-Ego transformation for reaches. PMID- 29512944 TI - Development and clinical application of a bioluminescence enzyme immunoassay for oxytocin. AB - The development of a highly sensitive analytical method for oxytocin could be useful in the diagnosis and treatment of autistic spectrum disorder. We previously developed a colorimetric enzyme immunoassay (EIA) for plasma oxytocin measurement. In this study, we developed a method to measure oxytocin concentrations using a higher sensitivity bioluminescent EIA. Biotinylated oxytocin bridged with five lysine residues was used in a competitive format. The standard curve range for oxytocin was 1.0 to 1000 pg/assay. In addition, there was good correlation between the colorimetric and bioluminescent immunoassays in terms of measured oxytocin concentration (r = 0.9665, n = 48). The bioluminescent EIA for plasma oxytocin was more rapid and provided higher sensitivity than the colorimetric immunoassay, making it suitable for clinical application. PMID- 29512945 TI - Chronic, persistent angioedema and sinusitis-like presentation of multibacillary leprosy. PMID- 29512946 TI - ? PMID- 29512947 TI - [Septic arthritis diagnosis : the role of microbiology]. AB - Septic arthritis is a medical and surgical emergency. It is therefore essential to promptly differentiate an infectious from a non-infectious origin in order to improve the prognostic (mortality and morbidity). To do so the clinician needs not only to know which tests are available but also how to adequately use them and interpret their results. In this article, we review the various tests in use for the evaluation of acute arthritis, highlighting the most useful ones for the diagnosis of septic arthritis. We will also have a quick look at the use of intra articular injection of corticosteroid. PMID- 29512948 TI - [Management of septic arthritis]. AB - Native joint septic arthritis is a medical emergency requiring urgent joint drainage and antibiotic therapy. In the absence of an artificial joint or a foreign body, the " rheumatological approach " with repetitive arthrocentesis yields similar outcomes in the literature when compared to surgical drainage. Arthrocentesis could therefore be viewed as the preferential method of joint drainage as it is associated both with reduced morbidity for patients and decreased costs for the healthcare system. In case of failure with arthrocentesis, surgical arthroscopic drainage becomes necessary. In addition, the prescription of systemic steroids is promising but requires further studies, especially in adult patient populations. PMID- 29512949 TI - [Viral arthritis]. AB - Arthritis and arthralgia during a viral infection are often polyarticular and symmetric and can mimic rheumatoid arthritis. Depending on germs, others signs and symptoms as fever, cutaneous rash (Parvovirus B19) or jaundice (hepatitis) can be present. Worldwide most common germs are Parvovirus B19, hepatitis B and C, HIV and alphavirus. There are significant differences throughout the world and epidemiology continues to evolve with a progression of vector-borne infections. Diagnosis of viral arthritis is often difficult and is based on epidemiological, clinical and serological data. PMID- 29512950 TI - [Rheumatic manifestations of Lyme disease : questions and controversies]. AB - Osteoarticular manifestations of Lyme disease are well known features, although a number of controversies persist. These concern both the diagnosis, in particular the interpretation of serology results and the management, notably the role of antibiotics. In the article, we review a number of issues, and strive to shed light on the current evidence based Swiss and international data. PMID- 29512951 TI - [Reactive arthritis]. AB - Reactive arthritis is usually regarded as a form of spondylarthritis. Patients generally present with an acute asymmetrical oligoarthritis following an episode of diarrhea or urethritis. The most frequent involved pathogens are Salmonella, Shigella, Campylobacter and Chlamydia trachomatis. Additional causative pathogens have been described. Non-steroidal anti-inflammatory drugs are the first line treatment for reactive arthritis, associated with physiotherapy. Occasionally, a short course of glucocorticoids or an intra-articular injection is needed. Chlamydia induced reactive arthritis should be treated with antibiotics. Some patients experience chronic persistent arthritis. These patients could benefit from a treatment with DMARDs such as sulfasalazine. In refractory cases, TNF inhibitors are sometimes used. PMID- 29512952 TI - [Microbiota and inflammatory rheumatisms]. AB - The microbiota and dysbiosis are involved in various diseases. Many studies in mice and humans demonstrate its influence on inflammatory rheumatisms. In rheumatoid arthritis (RA), Prevotella copri, a Gram-negative bacteria of the intestinal flora, is found to be more prevalent in the early stages of the disease. Specific antibodies against this germ have been identified in RA patients, suggesting a role of this bacteria in the initiation of the disease. Oral microorganisms involved in periodontitis have also been associated with the development and the activity of RA. These discoveries imply new targets in the management of inflammatory rheumatisms. PMID- 29512954 TI - ? PMID- 29512953 TI - ? PMID- 29512955 TI - ? PMID- 29512956 TI - ? PMID- 29512957 TI - ? PMID- 29512958 TI - ? PMID- 29512959 TI - ? PMID- 29512960 TI - An overview of mechanical ventilation in the intensive care unit. AB - This article discusses the history, types and essential components of mechanical ventilation. It addresses the potential complications associated with mechanical ventilation and outlines the nurse's role in the recognition and prevention of such complications. This article provides an overview of some of the advances in mechanical ventilation and emphasises the importance of patient safety through an awareness of the associated risks and limiting or avoiding mechanical ventilation where possible. PMID- 29512961 TI - Aetiology, clinical presentation and treatment of testicular cancer. AB - Testicular cancer is a highly treatable and curable malignancy. It typically affects men aged 15-35 years and is the most common malignancy in this age group. Nurses have an important role in assisting patients to cope with the diagnosis and understand the treatment options. It is also important for nurses to provide psychological support, because testicular cancer can have a significant effect on a man's fertility, sexuality and body image. This article examines the epidemiology and aetiology of the disease, together with its clinical presentation and treatment options. It emphasises the importance of early detection of testicular cancer to improve its prognosis, through awareness of the signs and symptoms of the disease and undertaking regular testicular self examination. PMID- 29512962 TI - Acute burns management: placement reflections of a children's nursing student. AB - Reflection can help nurses make sense of their clinical surroundings and understand risks, challenges and opportunities. Learning the art required for reflective practice begins as a student when critical reflection is particularly important during practice placements. A suitable reflective framework is provided by Rolfe et al ( 2011 ). Adopting this framework, this article draws on the placement experiences of a second-year undergraduate children's nursing student in an acute setting, caring for a toddler with 13% partial and full-thickness burns. The decisions made about assessing and monitoring homeostasis, overall fluid and pain management, infection prevention and potential safeguarding concerns are explored. Reflecting on clinical experience provides students with invaluable transferable skills. PMID- 29512963 TI - Adrenal insufficiency, steroid sick day rules and the paediatric endocrine nurse. AB - Clinical governance processes are important for improving patient care. Patients with adrenal insufficiency are at significant risk if they have an adrenal crisis and require steroid therapy. Families should receive education on managing illness or stress, that is, steroid sick day rules. Most of this education is delivered by children's nurses. Two local cases of mortality related to adrenal insufficiency were reviewed and a questionnaire audit was undertaken to compare the steroid sick day rules education provided to patients and their families with published standards. Most training (75%) was delivered by nurses. Most families/patients (94%) had received written information on oral dosing for steroid sick day rules, and were confident about when/how to double up oral steroid doses (78%). Fewer families recalled being given written information about the emergency hydrocortisone injection (53%), and fewer were confident about how to give the injection (46%). Several important changes and modifications to clinical practice have been implemented in response to the clinical governance findings. These include setting up notification 'red flags' on patients' electronic records and holding specialist family teaching sessions on steroid sick day rules. PMID- 29512964 TI - Collaboration challenges faced by nurses when premature infants are discharged. AB - AIM: To explore the collaboration challenges faced by neonatal intensive care unit (NICU) nurses and public health nurses when preparing premature infants for transition home and to explore the culture of cooperation between the two professional groups. METHOD: Qualitative individual interviews were undertaken with two NICU nurses and two public health nurses. A qualitative content analysis was used to analyse the data. FINDINGS: Three main themes were identified: different expectations and lack of communication between NICU nurses and public health nurses; responsibilities and interactions between the two professional groups were not clearly defined; and the public health nurses' competence was not recognised by the NICU nurses and parents. CONCLUSION: There is a need of clear guidelines about the discharge process from the NICU. This issue must be given further attention. PMID- 29512965 TI - Leadership and management influences on personal and professional development and group dynamics: a student's experience. AB - The ever-evolving nature of nursing requires professionals to keep their knowledge up to date and uphold the Nursing and Midwifery Council (NMC) Code by engaging themselves in ongoing personal and professional development (PPD). This article aims to highlight the importance of good leadership and management in healthcare and to explore the literature surrounding leadership and management, such as the current NHS healthcare leadership model ( NHS Leadership Academy 2013 ), the Leading Change, Adding Value Framework underpinned by the 10 commitments and 6Cs ( NHS England 2016 ) and the NMC Code ( NMC 2015a ) in relation to PPD. It examines how nurses can be supported in their PPD by their team leader and or managers using examples experienced in a clinical setting while caring for children and young people (CYP). Furthermore, the importance of team working and group processes in the context of leadership will be deliberated, using examples of formative group work to illustrate principles described in the literature. Finally, reflections will be discussed on how learning from this experience can influence future practice when caring for CYP. PMID- 29512966 TI - [Whole-cell bacterial biosensors for the detection of aromatic hydrocarbons and their chlorinated derivatives]. AB - The review summarizes the data on new directions in biosensor technologies based on whole bacterial cells. Biosensors for the monitoring of mono(poly)aromatic hydrocarbons and their chlorinated derivatives, which are constructed with genetically modified bacterial cells bearing a reporter gene fusion, are considered. The operating principle of these biosensors is based on the expression of reporter genes (luc, lux, gfp, rfp) under the control of a promoter and a regulator that specifically respond to a detected compound. PMID- 29512967 TI - [Physicochemical and catalytic properties of NAD+- dependent malate dehydrogenase isoforms from maize mesophyll0. AB - Malate dehyrogenase isoforms (46- and 70-fold purifications) with specific activities of the 640 and 990 U/mg protein were obtained in an electrophoretically homogeneous state from maize mesophyll. The physicochemical and catalytic properties of these isoforms were studied. The molecular weight and the Michaelis constants were determined; the effect of hydrogen ions on the forward and reverse MDH reaction was studied. The results of SDS-PAGE demonstrated that malate dehydrogenase isoforms have an oligomeric structure comprised of identical subunits. The first isoform with a molecular weight of 126.58 kDa is tetramer, and the second isoform with a molecular weight of 63.3 is dimer. PMID- 29512968 TI - [Production of humanized F(ab')2 fragment of rabies blocking antibodies in Pichia pastoris yeast]. AB - The yeast strain Pichia pastoris, a producer of humanized F(ab')2 fragments of rabies-blocking antibodies, has been obtained. Human chaperone BiP coexpression caused a twofold increase of the immunoglobulins secretion level. The use of Fos and Jun zippers in the composition of heavy chains facilitated the dimerization of F(ab')2 fragments of the shared pool of secreted immunoglobulins up to 75%. PMID- 29512969 TI - [Biosynthesis of silver nanoparticles with the participation of extracellular Mn dependent peroxidase from Azospirillum]. AB - The accumulation of nanoparticles of colloidal silver with spherical shape in culture liquid of Azospirillum brasilense has been shown by transmission electron microscopy. Bacterial extracellular Mn-peroxidases were found to participate in silver reduction from silver nitrate with the formation of nanoparticles. A mechanism of extracellular biosynthesis of silver nanoparticles by A. brasilense bacteria was proposed PMID- 29512970 TI - Plenty of challenges, great opportunities. AB - Under the Presidency of Greg Markham, who took up the role two years ago this month, IHEEM has continued to significantly raise its profile among key opinion formers, strengthening its ties with influential bodies such as the Department of Health, the Sustainable Development Unit, The Department for Business, Innovation & Skills, ProCure21+, and the Engineering Council, and with parliamentarians, senior civil servants, its international counterparts, and the architectural and construction supply chains. Taking over the Presidency this month, highly experienced public health engineer, Chris Northey, will thus have much to build on. As he told HEJ editor, Jonathan Baillie, during a recent meeting at his employer, ChapmanBDSP's London offices, he is particularly looking forward to 'giving something back to the building services profession and the wider healthcare estates sector', having 'come a long way professionally' since beginning his working life, aged 17, as an apprentice plumbing and heating engineer in his father's Cornwall-based company. PMID- 29512971 TI - CHP systems to save money and cut carbon. AB - According to Ian Hopkins, a director of ENER-G Combined Power--which has delivered more than 50 CHP-led energy services contracts within the healthcare sector, having, for the past 30 years, designed and manufactured CHP systems at its global headquarters and R&D centre in Salford--'the energy cost and carbon saving benefits of combined heat and power are difficult to match where there is a large heating/cooling demand over extended periods'. In this article, he explains how hospitals and other busy healthcare facilities thus 'make ideal bedfellows' for CHP, and outlines the key criteria and considerations, such as sizing, for healthcare engineers, when looking to specify such a system. PMID- 29512972 TI - Efficacy of a cosmetic phyto-caffeine shampoo in female androgenetic alopecia. AB - BACKGROUND: Androgenetic alopecia (AGA) is the most common type of hair loss in both males as well as females, occurring in up to 57% of women by the age of 80 years. Androgenetic alopecia is associated with a high psychological burden and often results in substantially reduced quality of life, poor body image and low self-esteem, particularly in women. Caffeine-based products have shown promise, both in vitro and in vivo, as potential treatments for AGA. This study was performed to determine the efficacy of a phyto-caffeine- containing shampoo used over a 6-month period in female subjects with AGA. METHODS: This was a single centre, double-blind parallel trial in which female subjects with AGA were randomized to either a phyto-caffeine-containing shampoo or a control shampoo. The primary endpoint was the change from baseline in the number of hairs pulled in a hair pull test at 6 months. Hair loss intensity, hair strength, subject satisfaction and tolerability were also assessed. RESULTS: Subjects using the phyto-caffeine-containing shampoo had significantly fewer hairs pulled in a hair pull test at 6 months, compared with subjects using the control shampoo (-3.1 vs 0.5 hairs; p<0.001). The majority of pre-specified secondary endpoints were also significantly improved for subjects using the phyto-caffeine- containing shampoo, compared with controls. Both products were very well tolerated. CONCLUSIONS: Compared with a control shampoo, a phyto-caffeine-containing shampoo was more efficacious, with respect to the number of hairs being pulled out at 6 months, hair loss intensity and hair strength in subjects with AGA. PMID- 29512973 TI - Down-regulation of IL-10 in patients with mild psoriasis and metabolic syndrome. PMID- 29512974 TI - Acral melanoma: correlating the clinical presentation to the mutational status. AB - Acral lentiginous melanoma (ALM) is the most common type of malignant melanoma (MM) in Asians, Afro-Americans and Middle-Easterns. It represents 1.5-10% of all MM cases, being the most common histological type of MM arising on palms, soles and nail apparatus, which is more generically defined as acral MM. To date no risk factors have been officially established, however a history of trauma may be involved in the pathogenesis of acral MM. This shows heterogeneous clinical features and frequently presents with advanced stage and aggressive behaviour, often as a result of misdiagnosis or delayed identification. Dermoscopy is helpful for an early diagnosis of ALM: the most characteristic dermoscopic patterns are the parallel ridge and the irregular diffuse pigmentation. On histopathology ALM displays a lentiginous growth pattern, with melanocytes arranged as solitary units along the basilar epidermis, without notable pagetoid growth in the early stage. Not all acral MMs present a lentiginous pattern: superficial spreading melanoma (SSM) and nodular melanoma (NM) patterns are possible, too. Novel studies investigating the biologic characteristics of acral MM reported variable results: the overall mutational rates ranged respectively between 8.5 and 23% for KIT, between 3.6 and 33.3% for BRAF and between 3 and 47% for NRAS in ALMs. Increasing attention has been recently given to other genes, such as telomerase reverse transcriptase (TERT), platelet-derived growth factor receptor alfa (PDGFRA) and cyclin D1 (CCND1). Larger molecular investigations urge to describe the molecular profile of acral MM, to allow the development of specific targeted therapies. PMID- 29512975 TI - Basal cell carcinoma in post-traumatic scar successfully treated with thulium laser and photodynamic therapy. PMID- 29512976 TI - Herpes simplex reactivation after photodynamic therapy for actinic cheilitis in a patient with Non-Hodgkin Lymphoma: a possible indication for prophylaxis. PMID- 29512977 TI - Cutis Marmorata Telangiectatica Congenita: a diagnostic challenge. PMID- 29512978 TI - Dermoscopic features of Milia-Like calcinosis cutis. PMID- 29512979 TI - Clinical research in dermatology: resources and activities associated with a higher scientific productivity. AB - BACKGROUND: Clinical research papers and their derived metrics can be useful to assess the scientific production of medical and research centers. Diverse factors are probably associated to differences in scientific production. But there are scarce studies analyzing them. Resources are limited and have to be distributed efficiently. AIMS: The objective of this study is to explore what resources and activities are potentially associated with a higher scientific productivity. MATERIAL AND METHODS: A bibliometric study was performed to obtain information about scientific productivity. Papers included had to meet criteria to be considered clinical research in dermatology, additionally had to be published between the years 2005-2014, had to be included in Pubmed or Embase and had to include a Spanish center of dermatology as the correspondence address. Information about research resources and activities of the year 2015 was gathered by means of an online survey sent to the authors identified in the bibliometric study. RESULTS: The search strategy returned 8617 papers and only 1104 of them (12.81%) met the inclusion criteria. 63 out of 113 centers responded to the survey (55.75%). Factors associated with a higher scientific productivity were: the size of the resident program, the amount of time specifically dedicated to research, a lower clinical workload, and the number of clinical trials performed in the last year. CONCLUSIONS: We have demonstrated that some factors are associated with a higher scientific productivity. Residency program, more research staff, clinical workload redistribution and research motivation/initiatives are key strategies that could improve scientific productivity of a center. PMID- 29512980 TI - Oral pemphigus. AB - The involvement of the oral mucosa in patients affected by pemphigus vulgaris (PV), paraneoplastic, IgA pemphigus, and in some cases iatrogenic pemphigus is common and often a prelude to skin lesions. Intraepidermal bullae are caused by acantholysis, induced by IgG autoantibodies directed against the desmosomes and the domain of numerous keratinocytes self-antigens desmogleins (namely cadherins), thus supporting the autoimmune nature of the disease. Apoptosis may contribute to the acantholysis. Oral mucosal lesions are more commonly refractory to treatment compared to skin lesions and have been associated with disease duration, disease location and possibly the presence of HSV DNA in the oral cavity. Recent publications have stressed the positive role of Rituximab in early disease treatment. PMID- 29512981 TI - Fibronectin interaction with growth factors in the context of general ways extracellular matrix molecules regulate growth factor signaling. AB - Wound healing is a complex cascade of molecular events centered on the extracellular matrix (ECM). Early research viewed ECM in wounds as a simple scaffold for repair. Subsequently, this perception was extended to providing cells with discrete surface adhesion sites and then to providing a reservoir for growth factors (GF). However, over the past decade, research has revealed that ECM interactions with GF are far more complex and exquisite than previously thought. Chief among ECM components during the early phases of wound healing is a ~250kDa glycoprotein, fibronectin (FN). This review outlines ways in which FN interacts with GF as a model for studying ECM-GF interactions. Additionally, we present evidence to suggest that FN contains bioactive peptides that enhance or bias GF activity and thereby can be used as pharmacologic interventions for wound healing. PMID- 29512982 TI - [Thermotolerant oil-degrading bacteria isolated from soil and water of geographically distant regions]. AB - Oil-degrading bacteria were isolated from soil and water samples taken in Russia, Kazakhstan, and the Antarctic; 13 of 86 strains proved to be thermotolerant. These bacteria utilized crude oil at 45-50 degrees C; their growth optimum (35-37 degrees C) and range (20-53 degrees C) differ from those of mesophilic bacteria. Thermotolerant strains were identified as representatives of the genera Rhodococcus and Gordonia. It was shown that their ability to degrade petroleum products does not differ at 24 and 45 degrees C. The strains Rhodococcus sp. Par7 and Gordonia sp. 1D utilized 14 and 20% of the oil, respectively, in 14 days at 45 degrees C. All of the isolated thermotolerant bacteria grew in a medium containing 3% NaCl; the medium for the strains Gordonia amicalis 1B and Gordonia sp. 1D contained up to 10% NaCl. The bacteria G. amicalis and Rhodococcus erythropolis were able to utilize crude oil and individual hydrocarbons at higher (up to 50 degrees C) temperatures. PMID- 29512983 TI - [Biooxidation of gold-bearing sulfide ore and subsequent biological treatment of cyanidation residues]. AB - The percolation biooxidation parameters of ore from the Bakyrchik deposit were studied. An investigation of the technological parameters (such as the concentration of leaching agents, irrigation intensity, and pauses at various stages of the leaching) revealed the optimal mode for precious metal extraction. The stages of the ore processing were biooxidation, gold extraction by cyanidation or thiosulfate leaching, and biological destruction of cyanide. The gold and silver recovery rates by cyanidation were 64.0 and 57.3%, respectively. The gold and silver recovery rates by thiosulfate leaching were 64.0 and 57.3%, respectively. Gold and silver recovery rates from unoxidized ore (control experiment) by cyanidation were 20.9 and 26.8%, respectively. Thiosulfate leaching of unoxidized ore allowed the extraction of 38.8 and 24.2% of the gold and silver, respectively. Cyanidation residues were treated with bacteria of the genus Alcaligenes in order to destruct cyanide. PMID- 29512984 TI - Better prepared for 'extreme events'. AB - Kristen Guida, chair of directors and co-founder of Climate UK, a not-for-profit community interest company and a national network of 12 climate change partnerships in England, Northern Ireland, Scotland, and Wales, discusses improving resilience planning, to enable estates teams in hospitals and other healthcare facilities to be better prepared to deal with, and mitigate the effects of, flooding and other severe weather events. She highlights a number of useful guidance publications and information sources on the subject, discusses recent research, and focusses on where key lessons may be learned from past experience. PMID- 29512985 TI - [The obtainment and characteristics of Kalanchoe pinnata L. plants expressing the artificial gene of the cecropin P1 antimicrobial peptide]. AB - Kalanchoe pinnata L. plants bearing an artificial CP1 gene encoding the cecropin P1 antimicrobial peptide have been obtained. The presence of the CP1 gene in the plant genome has been confirmed by PCR. Cecropin P1 synthesis in transgenic plants has been shown by MALDI mass spectrometry and Western blotting. The obtained plants have been highly resistant to bacterial and fungal phytopathogens, and their extracts have demonstrated antimicrobial activity towards human and animal pathogens. It has been shown that transgenic plants bearing the CP1 gene can be colonized by the beneficial associative microorganisms Methylovorus mays. PMID- 29512986 TI - [Impossible mechanisms of germatranol influence on the thermal stability of wheat germs]. AB - The influence of biologically active substance germatranol in low and very low doses on the respiration rate and the content of reactive oxygen species (ROS) in wheat roots under conditions of high stress was investigated. The results showed that solutions of the studied substance in concentrations of from 10-5 M to 10-10 M (depending on the temperature) increase the thermotolerance of wheat germs and affect the ROS content and respiration rate. It is assumed that germatranol can have a positive impact on plant growth and development and act as antioxidants in plant cells. PMID- 29512987 TI - [The effect of 3,5-dicarbomethoxyphenylbiguanide on the activity of antioxidant enzymes]. AB - The effect of 3,5-dicarbomethoxyphenylbiguanide, which was selected with the Prediction of Activity Spectra of Substances (PASS) computer program, on the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione transferase in the heart and the blood serum of rats with experimental rheumatoid arthritis was investigated. The studied parameters changed towards control values when the tested compound was injected in animals with the pathology. These results can be explained by the cardioprotective and antioxidant activity of the compound. The data obtained during the study may be used for the development of new preventive and therapeutic agents for the treatment of the rheumatoid arthritis. PMID- 29512988 TI - [Neutralization of anticoagulant activity of heparin by N-[(2-hydroxy-3 trimethylammonium) propyl] chloride derivatives of chitosan]. AB - Alkylated derivatives of low molecular weight chitosan with different substitution degrees of 98, 40, and 9% (I, II, and III respectively) have been synthesized. The structure of the obtained derivatives was defined by spectral assays (IR-spectroscopy and proton magnetic resonance). Chitosan derivatives were characterized with positive zeta-potential (33-51 mV) and solubility from 2 to 100 mg/mL in pH 7.4 and 25 degrees C. It was shown that, at a concentration of 0.0014-0.0029 mg/mL, derivative I, as well as protamine sulfate, could be used to neutralize the anticoagulant activity of unfractionated or low molecular weight heparin. At a concentration of 0.0029-0.58 mg/mL, derivative I enhanced platelet aggregation, which would be necessary when hemostatic compounds or materials were used. Derivatives II and III enhanced platelet aggregation to a lesser extent. PMID- 29512989 TI - Aspergillus fumigatus--a ubiquitous foe. AB - Aspergillus, a fungus whose spores are ubiquitous in the environment, and are normally found in air, can be a significant issue in healthcare premises, and especially in hospital ventilation systems. Here Andrew Poplett, an engineer with over 28 years' healthcare building services engineering experience, and an Authorised Engineer for both specialist ventilation and water quality, explains its occurrence, spread, and prevalence. He discusses how estates and facilities personnel, in conjunction with their clinical and infection control counterparts, can act to control and manage Aspergillus, and thus help safeguard patients, staff, and visitors, in hospitals and other healthcare facilities, against its negative impact on health. PMID- 29512990 TI - Flexible BEMS for Basildon hospital. AB - HEJ reports on the major benefits seen at Basildon University Hospital in Essex through the installation of a sophisticated building energy management system, which also integrates features such as access control, security, and lighting control, and whose advantages are increasingly being experienced by an ever broader range of Trust users. PMID- 29512991 TI - Managing a highly important service. AB - As facilities managers take more responsibility for the hospital laundries, Murray Simpson, chief executive of the TSA (Textile Services Association), the trade association for the laundry, dry cleaning, and textile rental industries in the UK, highlights the major issues that need to be addressed--ranging from effective stock control, to making sure nurses' uniforms are washed at sufficiently high temperatures to prevent them harbouring bacteria, to ensure that Government targets on hygiene and efficiency are met. PMID- 29512992 TI - [Dihydroquercetin polymerization using laccase immobilized into an ionic liquid]. AB - It was shown that the laccase (LC) included into hydrophobic ionic liquid (IL) can be reused for the biotransformation of dihydroquercetin (DHQ). The physicochemical characteristics of DHQ oligomers synthesized using LC/IL did not differ from the characteristics of the oligomers obtained with native laccase. The synthesized oligomers have a number average molecular weight of 1050 g/mol and a polydispersity index of 1.41. Oligomers possess higher antioxidant activity than the monomer. PMID- 29512993 TI - [Immunodetection of bacteriophages by a piezoelectric resonator with lateral electric field]. AB - It has been demonstrated that electroacoustic analysis with polyclonal antibodies can be used for bacteriophage detection. The frequency dependences of the real and imaginary parts of electrical impedance of a resonator with a viral suspension with antibodies were shown to be essentially different from the dependences of a resonator with control viral suspension without antibodies. It was shown that PhiAl-Sp59b bacteriophages were detected with the use of antibodies in the presence of foreign virus particles. The PhiAl-Sp59b bacteriophage content in the analyzed suspension was ~1010-106 phages/mL; the time of analysis was no more than 5 min. The optimally informative parameter for obtaining reliable information was the change in the real or imaginary part of electrical impedance at a fixed frequency near the resonance upon the addition of specific antibodies to the analyzed suspension. It was demonstrated that the interaction between bacteriophages and antibodies can be recorded, offering good prospects for the development of a biological sensor for liquid-phase identification and virus detection. PMID- 29512994 TI - Less jargon, more common ground. AB - June Lancaster, a nurse by background, who has spent 35 years working within healthcare and facilities management companies, and now runs her own consultancy, Asset Wisdom, and Steve Goodchild, an engineer with over 40 years' healthcare engineering experience, and a director at estates and facilities solutions consultancy, CPA, argue that better teamwork and communication between clinicians and estates and facilities professionals, and a greater understanding of each other's roles, would contribute significantly to an even safer, more efficient, patient care environment. PMID- 29512995 TI - Unveiling the Different Emission Behavior of Polytriazoles Constructed from Pyrazine-Based AIE Monomers by Click Polymerization. AB - Polymers with aggregation-induced emission (AIE) characteristics have aroused tremendous interest because of their potential applications in large-area flexible display and luminescent self-assembling, and as stimuli-responsive and porous materials. However, the design of AIE-active polymers is always not as easy as that of small molecules because their properties are hard to predict. In some cases, the polymers prepared from the AIE-active monomers show the aggregation-caused quenching (ACQ) instead of AIE effect. To understand the structure-property relationship of the polymers constructed from the AIE monomers, in this paper, two pyrazine-containing AIE monomers were utilized to construct luminescent polymers by click polymerization. The photophysical property investigation indicates that the polytriazole containing tetraphenylpyrazine units is AIE-active, whereas that bearing 2,3-dicyano-5,6 diphenylpyrazine units suffers from the ACQ effect. Through systematical investigation, the cause for such difference was unveiled. Thus, this work provides a useful guidance for further design of AIE-active polymers. PMID- 29512996 TI - High-Performance Microsupercapacitors Based on Bioinspired Graphene Microfibers. AB - The miniaturization of portable electronic devices has fueled the development of microsupercapacitors that hold great potential to complement or even replace microbatteries and electrolytic capacitors. In spite of recent developments taking advantage of printing and lithography, it remains a great challenge to attain a high energy density without sacrificing the power density. Herein, a new protocol mimicking the spider's spinning process is developed to create highly oriented microfibers from graphene-based composites via a purpose-designed microfluidic chip. The orientation provides the microfibers with an electrical conductivity of ~3 * 104 S m-1, which leads to a high power density; the energy density is sustained by nanocarbons and high-purity metallic molybdenum disulfide. The microfibers are patterned in-plane to fabricate asymmetric microsupercapacitors for flexible and on-chip energy storage. The on-chip microsupercapacitor with a high pattern resolution of 100 MUm delivers energy density up to the order of 10-2 W h cm-3 and retains an ultrahigh power density exceeding 100 W cm-3 in an aqueous electrolyte. This work provides new design of flexible and on-chip asymmetric microsupercapacitors based on microfibers. The unique biomimetic microfluidic fabrication of graphene microfibers for energy storage may also stimulate thinking of the bionic design in many other fields. PMID- 29512997 TI - Glycosylated Peptoid Nanosheets as a Multivalent Scaffold for Protein Recognition. AB - Glycoproteins adhered on the cellular membrane play a pivotal role in a wide range of cellular functions. Their importance is particularly relevant in the recognition process between infectious pathogens (such as viruses, bacteria, toxins) and their host cells. Multivalent interactions at the pathogen-cell interfaces govern binding events and can result in a strong and specific interaction. Here we report an approach to mimic the cell surface presentation of carbohydrate ligands by the multivalent display of sugars on the surface of peptoid nanosheets. The constructs provide a highly organized 2D platform for recognition of carbohydrate-binding proteins. The sugars were displayed using different linker lengths or within loops containing 2-6 hydrophilic peptoid monomers. Both the linkers and the loops contained one alkyne-bearing monomer, to which different saccharides were attached by copper-catalyzed azide-alkyne cycloaddition reactions. Peptoid nanosheets functionalized with different saccharide groups were able to selectively bind multivalent lectins, Concanavalin A and Wheat Germ Agglutinin, as observed by fluorescence microscopy and a homogeneous Forster resonance energy transfer (FRET)-based binding assay. To evaluate the potential of this system as sensor for threat agents, the ability of functionalized peptoid nanosheets to bind Shiga toxin was also studied. Peptoid nanosheets were functionalized with globotriose, the natural ligand of Shiga toxin, and the effective binding of the nanomaterial was verified by the FRET based binding assay. In all cases, evidence for multivalent binding was observed by systematic variation of the ligand display density on the nanosheet surface. These cell surface mimetic nanomaterials may find utility in the inactivation of pathogens or as selective molecular recognition elements. PMID- 29512998 TI - Reactivity Studies of [Co@Sn9]4- with Transition Metal Reagents: Bottom-Up Synthesis of Ternary Functionalized Zintl Clusters. AB - The binary cluster [Co@Sn9]4- (1) was extracted directly from ethylenediamine (en) solutions of an intermetallic precursor with nominal composition "K5Co3Sn9", and its reactions with various organometallic reagents were explored. Reaction with Ni(PPh3)2(CO)2 gives [Co@Sn9Ni(CO)]3- (2), a Co-centered closo-Sn9Ni bicapped square antiprism. Analogous reactions with Ni(COD)2, Pt(PPh3)4, and Au(PPh3)Ph led to the isolation of [Co@Sn9Ni(C2H4)]3- (3), [Co@Sn9Pt(PPh3)]3- (4), and [Co@Sn9AuPh]3- (5), respectively. 3 is structurally similar to 2 but significantly distorted from a closo-cluster with one open square face. The coordination of [CoSn9]3- by PtPPh3 (4) or AuPh (5) induces a structural transformation in the CoSn9 core, from a monocapped square antiprism ( C4 v) to a tricapped trigonal prismatic structure ( pseudo- C3 v), with the transition metal fragment capping a triangular face. The four trimetallic anions presented here represent a new family of ternary functionalized Zintl clusters incorporating a d9 transition metal center. All clusters were characterized by single-crystal X ray diffraction and electrospray ionization mass spectrometry (ESI-MS). PMID- 29512999 TI - Determination of the Subcellular Localization and Mechanism of Action of Ferrostatins in Suppressing Ferroptosis. AB - Ferroptosis is a form of nonapoptotic cell death characterized by the unchecked accumulation of lipid peroxides. Ferrostatin-1 and its analogs (ferrostatins) specifically prevent ferroptosis in multiple contexts, but many aspects of their molecular mechanism of action remain poorly described. Here, we employed stimulated Raman scattering (SRS) microscopy coupled with small vibrational tags to image the distribution of ferrostatins in cells and found that they accumulate in lysosomes, mitochondria, and the endoplasmic reticulum. We then evaluated the functional relevance of lysosomes and mitochondria to ferroptosis suppression by ferrostatins and found that neither is required for effective ferroptosis suppression. PMID- 29513000 TI - Labeling RNAs in Live Cells Using Malachite Green Aptamer Scaffolds as Fluorescent Probes. AB - RNAs mediate many different processes that are central to cellular function. The ability to quantify or image RNAs in live cells is very useful in elucidating such functions of RNA. RNA aptamer-fluorogen systems have been increasingly used in labeling RNAs in live cells. Here, we use the malachite green aptamer (MGA), an RNA aptamer that can specifically bind to malachite green (MG) dye and induces it to emit far-red fluorescence signals. Previous studies on MGA showed a potential for the use of MGA for genetically tagging other RNA molecules in live cells. However, these studies also exhibited low fluorescence signals and high background noise. Here we constructed and tested RNA scaffolds containing multiple tandem repeats of MGA as a strategy to increase the brightness of the MGA aptamer-fluorogen system as well as to make the system fluoresce when tagging various RNA molecules, in live cells. We demonstrate that our MGA scaffolds can induce fluorescence signals by up to ~20-fold compared to the basal level as a genetic tag for other RNA molecules. We also show that our scaffolds function reliably as genetically encoded fluorescent tags for mRNAs of fluorescent proteins and other RNA aptamers. PMID- 29513001 TI - Time-Gated Raman Spectroscopy for Quantitative Determination of Solid-State Forms of Fluorescent Pharmaceuticals. AB - Raman spectroscopy is widely used for quantitative pharmaceutical analysis, but a common obstacle to its use is sample fluorescence masking the Raman signal. Time gating provides an instrument-based method for rejecting fluorescence through temporal resolution of the spectral signal and allows Raman spectra of fluorescent materials to be obtained. An additional practical advantage is that analysis is possible in ambient lighting. This study assesses the efficacy of time-gated Raman spectroscopy for the quantitative measurement of fluorescent pharmaceuticals. Time-gated Raman spectroscopy with a 128 * (2) * 4 CMOS SPAD detector was applied for quantitative analysis of ternary mixtures of solid-state forms of the model drug, piroxicam (PRX). Partial least-squares (PLS) regression allowed quantification, with Raman-active time domain selection (based on visual inspection) improving performance. Model performance was further improved by using kernel-based regularized least-squares (RLS) regression with greedy feature selection in which the data use in both the Raman shift and time dimensions was statistically optimized. Overall, time-gated Raman spectroscopy, especially with optimized data analysis in both the spectral and time dimensions, shows potential for sensitive and relatively routine quantitative analysis of photoluminescent pharmaceuticals during drug development and manufacturing. PMID- 29513002 TI - NiOOH Exfoliation-Free Nickel Octahedra as Highly Active and Durable Electrocatalysts Toward the Oxygen Evolution Reaction in an Alkaline Electrolyte. AB - A layered beta-NiOOH crystal with undercoordinated facets is an active and economically viable nonnoble catalyst for the oxygen evolution reaction (OER) in alkaline electrolytes. However, it is extremely difficult to enclose the beta NiOOH crystal with undercoordinated facets because of its inevitable crystal transformation to gamma-NiOOH, resulting in the exfoliation of the catalytic surfaces. Herein, we demonstrate {111}-faceted Ni octahedra as the parent substrates whose surfaces are easily transformed to catalytically active beta NiOOH during the alkaline OER. Electron microscopic measurements demonstrate that the horizontally stacked beta-NiOOH on the surfaces of Ni octahedra has resistance to further oxidation to gamma-NiOOH. By contrast, significant crystal transformation and thus the exfoliation of the gamma-NiOOH sheets can be observed on the surfaces of Ni cubes and rhombic dodecahedra (RDs). Electrocatalytic measurements show that the beta-NiOOH formed on Ni octahedra exhibits highly enhanced OER durability compared to the Ni cubes, Ni RDs, and the state-of-the art Ir/C catalysts. PMID- 29513003 TI - Radiation-Induced Changes in Quartz, A Mineral Analog of Nuclear Power Plant Concrete Aggregates. AB - Quartz single-crystal samples consisting of alpha-quartz crystal structure were neutron irradiated to fluences of 5 * 1018, 4 * 1019, and 2 * 1020 n/cm2 (E > 0.1 MeV) at two temperatures (52 and 95 degrees C). The changes in the alpha-quartz phase as a function of these two conditions (temperature and fluence) were studied using X-ray powder diffraction (XRD), Raman spectroscopy, and transmission electron microscopy (TEM), and the results acquired using these complementary techniques are presented in a single place for the first time. XRD studies showed that the lattice parameters of alpha-quartz increased with increasing neutron flux. The lattice growth was larger for the samples that were neutron irradiated at 52 degrees C than at 95 degrees C. Moreover, an amorphous content was determined in the quartz samples neutron irradiated at 4 * 1019 n/cm2, with the greater amount being in the 52 degrees C irradiated sample. Complete amorphization of quartz was observed at a fluence of 2 * 1020 n/cm2 (E > 0.1 MeV) using XRD and confirmed by TEM characterization and Raman spectroscopic studies. The cause for alpha-quartz lattice expansion and sample amorphization was also explored using XRD and Raman spectroscopic studies. PMID- 29513004 TI - SET-LRP of the Hydrophobic Biobased Menthyl Acrylate. AB - Cu(0) wire-catalyzed single electron transfer-living radical polymerization (SET LRP) of (-)-menthyl acrylate, a biobased hydrophobic monomer, was investigated at 25 degrees C in ethanol, isopropanol, ethyl lactate, 2,2,2-trifluoroethanol (TFE), and 2,2,3,3-tetrafluoropropanol (TFP). All solvents are known to promote, in the presence of N ligands, the mechanistically required self-regulated disproportionation of Cu(I)Br into Cu(0) and Cu(II)Br2. Both fluorinated alcohols brought out their characteristics of universal SET-LRP solvents and showed the proper polarity balance to mediate an efficient polymerization of this bulky and hydrophobic monomer. Together with the secondary alkyl halide initiator, methyl 2 bromopropionate (MBP), and the tris(2-dimethylaminoethyl)amine (Me6-TREN) ligand, TFE and TPF mediated an efficient SET-LRP of MnA at room temperature that proceeds through a self-generated biphasic system. The results presented here demonstrate that Cu(0) wire-catalyzed SET-LRP can be used to target polyMnA with different block lengths and narrow molecular weight distribution at room temperature. Indeed, the use of a combination of techniques that include GPC, 1H NMR, MALDI-TOF MS performed before and after thioetherification of bromine terminus via "thio-bromo" click chemistry, and in situ reinitiation copolymerization experiments supports the near perfect chain end functionality of the synthesized biobased hydrophobic polymers. These results expand the possibilities of SET-LRP into the area of renewable resources where hydrophobic compounds are widespread. PMID- 29513005 TI - Influence of Geometries on the Assembly of Snowman-Shaped Janus Nanoparticles. AB - The self-assembly of micro/nanoparticles into suprastructures is a promising way to develop reconfigurable materials and to gain insights into the fundamental question of how matter organizes itself. The geometry of particles, especially those deviating from perfectly spherical shapes, is of significant importance in colloidal assembly because it influences the particle "recognition", determines the particle packing, and ultimately dictates the formation of assembled suprastructures. In order to organize particles into desired structures, it is of vital importance to understand the relationship between the shape of the colloidal building blocks and the assembled suprastructures. This fundamental issue is an enduring topic in the assembly of molecular surfactants, but it remained elusive in colloidal assembly. To address this issue, we use snowman shaped Janus nanoparticles (JNPs) as a model to systematically study the effect of colloidal geometries on their assembled suprastructures. Ten types of JNPs with identical chemical compositions but with different geometries were synthesized. Specifically, the synthesized JNPs differ in their lobe size ratios, phase separation degrees, and overall sizes. We show that by altering these parameters, both finite suprastructures, such as capsules with different curvatures, and nonfinite suprastructures, including free-standing single-layered or double-layered JNPs sheets, can be obtained via self-assembly. All these different types of suprastructures are constituted by highly oriented and hexagonally packed JNPs. These findings demonstrate the significance of geometries in colloidal assembly, such that slightly changing the building block geometries could result in a large variety of very different assembled structures, without altering the chemistry of the particles. PMID- 29513006 TI - Top-Down Analysis of Branched Proteins Using Mass Spectrometry. AB - Post-translational modifications by the covalent attachment of Rub1 (NEDD8), ubiquitin, SUMO, and other small signaling proteins have profound impacts on the functions and fates of cellular proteins. Investigations of the relationship of these bioactive structures and their functions are limited by analytical methods that are scarce and tedious. A novel strategy is reported here for the analysis of branched proteins by top-down mass spectrometry and illustrated by application to four recombinant proteins and one synthetic peptide modified by covalent bonds with ubiquitin or Rub1. The approach allows an analyte to be recognized as a branched protein; the participating proteins to be identified; the site of conjugation to be defined; and other chemical, native, and recombinant modifications to be characterized. In addition to the high resolution and high accuracy provided by the mass spectrometer, success is based on sample fragmentation by electron-transfer dissociation assisted by collisional activation and on software designed for graphic interpretation and adapted for branched proteins. The strategy allows for structures of unknown, two-component branched proteins to be elucidated directly the first time and can potentially be extended to more complex systems. PMID- 29513007 TI - A Potential Bone-Targeting Hypotoxic Platinum(II) Complex with an Unusual Cytostatic Mechanism toward Osteosarcoma Cells. AB - Osteosarcoma (OS) is the most common primary pediatric bone tumor lethal to children and adolescents. Chemotherapeutic agents such as cisplatin are not effective for OS because of their poor accessibility to this cancer and severe systemic toxicity. In this study, a lipophilic platinum(II) complex bearing a bisphosphonate bone-targeting moiety, cis-[PtL(NH3)2Cl]NO3 {BPP; L = tetraethyl [2-(pyridin-2-yl)ethane-1,1-diyl]bisphosphonate}, was prepared and characterized by NMR, electrospray ionization mass spectrometry, and single-crystal X-ray crystallography. The cytotoxicity of BPP toward OS cell lines U2OS and MG-63 was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. BPP exhibits moderate inhibition against U2OS cells through a mechanism involving both DNA binding and a mevalonate pathway. The acute toxicity of BPP to mice is 7-fold lower than that of cisplatin. The relative low systemic toxicity may result from the steric hindrance of the ligand, which blocks BPP approaching the bases of DNA. The results suggest that incorporating bisphosphonates into a platinum complex not only enhances its bone-targeting property but also minimizes its reactivity toward DNA and thereby lowers the systematic toxicity of the complex. The diminished cytotoxicity of BPP could be compensated for by increasing the therapeutic dose with marginal harm. This strategy provides a new possibility for overcoming the ineffectiveness and systemic toxicity of platinum drugs in the treatment of OS. PMID- 29513008 TI - Optimization of the Microwave-Assisted Ethanosolv Extraction of Lignocellulosic Compounds from the Bagasse of Agave angustifolia Haw Using the Response Methodology. AB - The main objective of this work was to optimize the process of fractionation of the bagasse of Agave angustifolia Haw, applying organosolv assisted with microwaves. The DCC was used to evaluate the effect of independent variables such as ethanol concentration (40, 50, and 60%) and reaction time (1, 1.5, and 2 h) on yield, cellulose and lignin percentages. Lignocellulosic fractions (F1 and F2) were obtained by means of organosolv assisted with microwave in an open system (atmospheric pressure) and a closed system (controlled pressure). The lignocellulosic fractions were microstructurally characterized. The highest extraction yields (70.39%) were reached in the open system at 50% ethanol for 1.5 h. The highest percentages of LK (5.05%) were obtained in the closed system at 60% ethanol for 2 h. The SEM photomicrograph showed that the microstructure of F1 was retained even after treatment with 60% ethanol for 2 h, and the exposure of the fibrillar part was observed obtaining the disposition of pectin. PMID- 29513009 TI - Structural Correlation to Piezoelectric and Ferroelectric Mechanisms in Rhombohedral Pb(Zr,Ti)O3 Ceramics by in-Situ Synchrotron Diffraction. AB - The evidence of fundamental lattice strain and domain switching contribution to the piezoelectric and ferroelectric responses of ceramics has been well studied, while the contribution from crystal structure variation has been rarely reported in terms of the existence of intergranular stress/strain and crystallographic texture. In the present study, the detailed electric field induced structure evolution in rhombohedral PbZr0.55Ti0.45O3 (PZT55) has been investigated by in situ high-energy synchrotron diffraction. The phase of PZT55 is stable in the rhombohedral one against bipolar electrical loading. It is interesting to find that both spontaneous polarization and unit cell volume exhibit a butterfly shape in response to electric field. Direct evidence has revealed that the lattice strain and volume expansion show similar variation tendency to the piezoelectric response in the rhombohedral PZT55. The macro-polarization of PZT55 derives from the combination of domain switching and spontaneous polarization change. PMID- 29513010 TI - Ultralight, Recoverable, and High-Temperature-Resistant SiC Nanowire Aerogel. AB - Ultralight ceramic aerogels with the property combination of recoverable compressibility and excellent high-temperature stability are attractive for use in harsh environments. However, conventional ceramic aerogels are usually constructed by oxide ceramic nanoparticles, and their practical applications have always been limited by the brittle nature of ceramics and volume shrinkage at high temperature. Silicon carbide (SiC) nanowire offers the integrated properties of elasticity and flexibility of one-dimensional (1D) nanomaterials and superior high-temperature thermal and chemical stability of SiC ceramics, which makes it a promising building block for compressible ceramic nanowire aerogels (NWAs). Here, we report the fabrication and properties of a highly porous three-dimensional (3D) SiC NWA assembled by a large number of interweaving 3C-SiC nanowires of 20 50 nm diameter and tens to hundreds of micrometers in length. The SiC NWA possesses ultralow density (~5 mg cm-3), excellent mechanical properties of large recoverable compression strain (>70%) and fatigue resistance, refractory property, oxidation and high-temperature resistance, and thermal insulating property (0.026 W m-1 K-1 at room temperature in N2). When used as absorbents, the SiC NWAs exhibit an adsorption selectivity of low-viscosity organic solvents with high absorption capacity (130-237 g g-1). The successful fabrication of such an attractive material may provide promising perspectives to the design and fabrication of other compressible and multifunctional ceramic NWAs. PMID- 29513011 TI - Iron Mesh-Based Metal Organic Framework Filter for Efficient Arsenic Removal. AB - Efficient oxidation from arsenite [As(III)] to arsenate [As(V)], which is less toxic and more readily to be adsorbed by adsorbents, is important for the remediation of arsenic pollution. In this paper, we report a metal organic framework (MIL-100(Fe)) filter to efficiently remove arsenic from synthetic groundwater. With commercially available iron mesh as a substrate, MIL-100(Fe) is implanted through an in situ growth method. MIL-100(Fe) is able to capture As(III) due to its microporous structure, superior surface area, and ample active sites for As adsorption. This approach increases the localized As concentration around the filter, where Fenton-like reactions are initiated by the Fe2+/Fe3+ sites within the MIL-100(Fe) framework to oxidize As(III) to As(V). The mechanism was confirmed by colorimetric detection of H2O2, fluorescence, and electron paramagnetic resonance detection of .OH. With the aid of oxygen bubbling and Joule heating, the removal efficiency of As(III) can be further boosted. The MIL 100(Fe)-based filter also exhibits satisfactory structural stability and recyclability. Notably, the adsorption capacity of the filter can be regenerated satisfactorily. Our results demonstrate the potential of this filter for the efficient remediation of As contamination in groundwater. PMID- 29513012 TI - Unforeseen 1,2-Aryl Shift in Tetraarylpyrrolo[3,2- b]pyrroles Triggered by Oxidative Aromatic Coupling. AB - Tetraarylpyrrolo[3,2- b]pyrroles (TAPPs) possessing [1,1'-biphenyl]-2-yl substituents attached to the pyrrolic nitrogen atoms undergo selective double dehydrogenative cyclization accompanied by twofold 1,2-aryl migration under oxidative aromatic coupling conditions. The structure of the product of the rearrangement has been unambiguously confirmed by X-ray crystallography, and the reaction pathway is supported by density functional theory (DFT) calculations. Six-membered ring formation (requiring rearrangement of aryl substituents around the core) is energetically preferred over seven-membered ring closure, and a 1,2 aryl shift occurs via arenium cation intermediate. PMID- 29513013 TI - Structural Coloration of a Colloidal Amorphous Array is Intensified by Carbon Nanolayers. AB - In this study, we introduce the possibility of applying a colloidal amorphous array composed of fine silica particles as a structural-color material to invisible information technology. The appearance of a thick filmlike colloidal amorphous array formed from fine silica particles is considerably influenced by incoherent light scattering across the entire visible region. Therefore, regardless of the diameter of the fine silica particles, the thick colloidal amorphous array exhibits a white color to the naked eye. When carbon is uniformly deposited in the colloidal amorphous array by a pressure-pulsed chemical vapor deposition method, incoherent light scattering in the colloidal amorphous array is suppressed. As a result, coherent light scattering due to the short-range order in the colloidal amorphous array becomes conspicuous and the array exhibits a vivid structural color. As structures, such as letters and pictures, can be drawn using this technology, the colloidal amorphous array as a structural colored material may also be applicable for invisible information technology. PMID- 29513014 TI - RNA and Protein Interactors with TDP-43 in Human Spinal-Cord Lysates in Amyotrophic Lateral Sclerosis. AB - The TAR DNA-binding protein of 43 kDa (TDP-43) is a dual function RNA- and DNA binding protein with varied cellular functions. In degenerating motor neurons in amyotrophic lateral sclerosis (ALS), TDP-43 relocalizes from the nucleus to the cytosol, where it is sequestered into inclusions. It is likely that the pathogenic role of TDP-43 in ALS can involve either a gain or a loss of function, depending on the nature of its RNA or protein interactor. However, while TDP-43 binding partners have been identified in a range of model systems and from the human brain, interactors from human spinal-cord tissue have not. In this study, we have characterized both protein and RNA TDP-43 interactors from neuropathologically normal (control) and ALS-affected ventral lumbar spinal cord, including sporadic ALS (sALS) and familial cases harboring either a A4T mutant SOD1 or a 3' UTR *c.41G>A mutant FUS/TLS or expressing pathological c9orf72 expanded repeats. RNA interactors with TDP-43 were similar between the control and ALS spinal cords examined regardless of genotype. In contrast, protein interactors with TDP-43 did demonstrate differences, with the sALS and mtSOD1 harboring cases examined differing from the protein interactors identified in the FUS 3' UTR mutation and c9orf72 repeat-positive cases. PMID- 29513015 TI - Application of Clustering Algorithms to Partitioning Configuration Space in Fitting Reactive Potential Energy Surfaces. AB - A large number of energy points add great difficulty to construct reactive potential energy surfaces (PES). To alleviate this, exemplar-based clustering is applied to partition the configuration space into several smaller parts. The PES of each part can be constructed easily and the global PES is obtained by connecting all of the PESs of small parts. This divide and conquer strategy is first demonstrated in the fitting of PES for OH3 with Gaussian process regression (GPR) and further applied to construct PESs for CH5 and O+CH4 with artificial neural networks (NN). The accuracy of PESs is tested by fitting errors and direct comparisons with previous PESs in dynamically important regions. As for OH3 and CH5, quantum scattering calculations further validate the global accuracy of newly fitted PESs. The results suggest that partitioning the configuration space by clustering provides a simple and useful method for the construction of PESs for systems that require a large number of energy points. PMID- 29513016 TI - Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan Skeleton. AB - The aldol condensation of naltrexone with various aryl aldehydes gives the corresponding 7-benzylidenenaltrexone derivatives in high yields. However, novel C-ring-contracted morphinan compounds were produced when 2-pyridinecarboxaldehyde or its related analogues were used as a coupling partner. The key structural feature was the existence of the tetrahydrofuran ring (4,5-epoxy ring, E-ring) of the morphinan skeleton. The time-resolved in situ IR spectroscopy of the reaction system indicated the short-lived absorption of the distorted cyclopropanone intermediate. PMID- 29513017 TI - Broadband Terahertz Spectroscopy of Imidazolium-Based Ionic Liquids. AB - Ionic liquids are liquid salts at ambient temperature composed of organic cations and organic/inorganic anions. Outstanding physical and chemical properties of ionic liquids lead to increasing application in scientific and industrial field. Ionic liquids have been already investigated by different spectroscopic techniques, including terahertz (THz) time-domain spectroscopy. The usual THz frequency range extends up to 2-3 THz, a relatively narrow band, which can only show the intermolecular vibrational modes. Here, we report about broadband THz spectroscopy of ionic liquids up to 13 THz. Bandwidth of intermolecular absorption band presents an unexpected behavior and strong sharp intramolecular absorptions are shown. In addition, we found violation of the approximation of harmonic oscillator used to predict the peak shift of intermolecular absorption band. PMID- 29513018 TI - Divergent Synthesis of Oxindolylidene Acetates and Spirooxindolopyrrolidones from Arynes. AB - A novel process for the preparation of various ( E)-oxindolylidene acetates using arynes and carbamoylpropiolates has been developed. The utility of this protocol is also further extended to the one-pot synthesis of complex spirooxindolopyrrolidones. This method provides a milder and transition-metal free access to both of the target scaffolds in moderate to good yields. PMID- 29513019 TI - Catalytic Asymmetric beta-C-H Functionalizations of Ketones via Enamine Oxidation. AB - A chiral primary amine catalyzed oxidative beta-C-H functionalization of ketone is described. The reaction proceeds via ketone enamine oxidation by IBX and enables highly enantioselective remote C-H functionalization of both cyclic and acyclic ketones, generating chiral ketones bearing beta-stereocenters. PMID- 29513020 TI - Phosphole-Thiophene Hybrid: A Dual Role of Dithieno[3,4- b:3',4'- d]phosphole as Electron Acceptor and Electron Donor. AB - We have synthesized dithieno[3,4- b:3',4'- d]phosphole derivatives as a new type of thiophene-fused phospholes. These dithienophospholes were found to show intramolecular charge transfer interactions by introducing electron-donating or withdrawing groups on the peripheral aryl groups. Namely, they exhibit the unique hybrid character of electron-withdrawing phosphole and electron-donating thiophene. PMID- 29513021 TI - Comparison of early treatment outcomes rendered in three different types of malocclusions. AB - OBJECTIVE: To evaluate the outcome of early treatment in Class I, II, and III malocclusions based on the reduction of weighted Peer Assessment Rating (PAR) scores. MATERIALS AND METHODS: Two hundred thirty subjects (female = 105; male = 125) selected from 400 cases were divided into three groups based on their malocclusions (Class I, II, and III). The PAR index was evaluated prior to early treatment (T0), at the end of phase I (T1), and after completion of phase II therapy (T2). The reliability of overall PAR scores was assessed by Bland-Altman plot and intraclass correlation coefficient. The starting age, total weighted PAR scores and their changes after phase I and II treatments, treatment time, and the percentage of correction in the three different malocclusions were assessed by repeated-measures analysis of variance with post hoc analysis. The level of significance was set at P < .05. RESULTS: More than 30% reduction of the weighted PAR scores and less than 10 points of the remaining weighted PAR scores were observed in all malocclusion groups at T1. The Class III group had the highest percentage of correction during phase I treatment. CONCLUSIONS: Early treatment effectively reduced the complexity of Class I, II, and III malocclusions and accounted for 57%, 64%, and 76% of the total correction, respectively, after phase I treatment, as indicated by an overall reduction in weighted PAR scores. The Class III group responded most favorably to early treatment followed by the Class II group. PMID- 29513022 TI - Recent developments in suicide prevention among the Indigenous peoples of Australia. AB - OBJECTIVES: Suicide is an Aboriginal and Torres Strait Islander (hereafter 'Indigenous') population health issue. Over 2015-2016, the Aboriginal and Torres Strait Islander Suicide Prevention Project (ATSISPEP) aimed to identify success factors in Indigenous suicide prevention. CONCLUSIONS: For non-Indigenous practitioners working with indigenous clients at risk of suicide, ATSISPEP identified important considerations to make treatment more effective. The start is acknowledging the differences in the historical, cultural, political, social and economic experiences of Indigenous peoples, and their greater exposure to trauma, psychological distress and risks to mental health. These mental health difficulties are specific and more prevalent amongst Indigenous peoples and communities due to the ongoing impacts of colonisation in Australia including a range of social determinants impacting on the well-being of Indigenous peoples today. Working effectively with Indigenous clients also includes being able to establish culturally safe work environments, and the ability of non-Indigenous practitioners to work in a culturally competent and trauma-informed manner. There are also considerations regarding time protocols and client follow-up. Further, postvention responses might be required. Supporting selective suicide prevention activity among younger people (and other groups at increased risk) and community level work is an important complement to working with Indigenous individuals at risk of suicide. PMID- 29513023 TI - Apical Takotsubo syndrome versus anterior acute myocardial infarction: findings from the Tokyo Cardiovascular Care Unit network registry. AB - BACKGROUND: Although the typical apical form of Takotsubo syndrome and anterior acute myocardial infarction have similar electrocardiographic and echocardiographic presentations, data on the clinical differences between the two disorders are limited. METHODS: Using the Tokyo Cardiovascular Care Unit network registry, we identified patients hospitalised with apical Takotsubo syndrome ( n=540; 2010-2014) or anterior acute myocardial infarction ( n=2,806; 2013-2014) and created 522 age and sex-matched pairs (mean age 74.1 years; women 78.5%). We compared the clinical characteristics and inhospital outcomes between the two groups. RESULTS: On admission, patients with apical Takotsubo syndrome showed a lower body mass index, less frequent chest pain/tightness, lower systolic blood pressure, higher heart rate, lower creatine kinase, higher C-reactive protein and brain natriuretic peptide, and less frequent ST-elevation than patients with anterior acute myocardial infarction. Patients with apical Takotsubo syndrome received catecholamine (12.8% vs. 24.5%, P<0.001) and intra-aortic balloon pumping (5.9% vs. 15.1%, P<0.001) less frequently. Despite similar all-cause mortality (5.4% vs. 7.9%, P=0.134), patients with apical Takotsubo syndrome showed lower cardiac mortality (2.1% vs. 6.7%, P<0.001; risk difference -4.6% (95% confidence interval -7.1% to -2.1%)) but higher non-cardiac mortality (3.3% vs. 1.1%, P=0.033; 2.1% (0.3%-3.9%)). In subgroup comparisons, patients with physically triggered Takotsubo syndrome had higher non-cardiac mortality (7.0%) than those with non-physically triggered Takotsubo syndrome (1.2%, P=0.001) or anterior acute myocardial infarction (1.1%, P<0.001). CONCLUSIONS: This study found that cardiac and non-cardiac mortality risks differed significantly between apical Takotsubo syndrome and anterior acute myocardial infarction. Our findings underscore the importance of differentiating between the two disorders for appropriate management. PMID- 29513024 TI - Radical changes to the investigation of stable chest pain following the 2016 NICE update. AB - The 2016 National Institute for Health and Care Excellence (NICE) guidelines mark a radical change in the diagnosis of patients with stable chest pain. Quantitative assessments of the disease probability are no longer considered necessary to determine the need and type of diagnostic testing. Instead, the recommendation is for no diagnostic test if the chest pain is judged to be "non anginal" and CT coronary angiography (CTCA) in patients with "typical" or "atypical" chest pain. The new emphasis on anatomical, rather than functional testing is driven by the accuracy, safety and cost effectiveness of the different investigations as evaluated by NICE. Despite inevitable resource implications NICE calculates that annual savings will be significant. PMID- 29513028 TI - Biomechanical analysis of lumbar interbody fusion cages with various lordotic angles: a finite element study. AB - Inappropriate lordotic angle of lumbar fusion cage could be associated with cage damage or subsidence. The biomechanical influence of cage lordotic angle on lumbar spine has not been fully investigated. Four surgical finite element models were constructed by inserting cages with various lordotic angles at L3-L4 disc space. The four motion modes were simulated. The range of motion (ROM) decreased with increased lordotic angle of cage in flexion, extension, and rotation, whereas it was not substantially changed in bending. The maximum stress in cage decreased with increased lordotic angle of cage in all motion modes. The maximum stress in endplate at surgical level increased with increased lordotic angle of cage in flexion and rotation, whereas it was not substantially changed in extension and bending. The facet joint force (FJF) was much smaller than that for the intact conditions in extension, bending, and rotation, while it was not substantially changed in flexion. In conclusion, the ROM, stresses in the cage and endplate at surgical level are sensitive to the lordotic angle of cage. The increased cage lordotic angle may provide better stability and reduce the risk of cage damage, whereas it may increase the risk of subsidence in flexion and rotation. PMID- 29513031 TI - Updated ASTRO guidelines on accelerated partial breast irradiation (APBI): to whom can we offer APBI outside a clinical trial? AB - The American Society of Radiation Oncology has recently updated its guidelines on the role of accelerated partial breast irradiation in the management of breast cancer. This commentary discusses the new recommendations and how we might advise patients in the light of existing data. PMID- 29513032 TI - Tumor oxygenation and cancer therapy-then and now. AB - In 2012, cancer affected 14.1 million people worldwide and was responsible for 8.2 million deaths. The disease predominantly affects aged populations and is one of the leading causes of death in most western countries. In tumors, the aggressive growth of the neoplastic cell population and associated overexpression of pro-angiogenic factors lead to the development of disorganized blood vessel networks that are structurally and functionally different from normal vasculature. A disorganized labyrinth of vessels that are immature, tortuous and hyperpermeable typifies tumor vasculature. Functionally, the ability of the tumor vasculature to deliver nutrients and remove waste products is severely diminished. A critical consequence of the inadequate vascular networks in solid tumors is the development of regions of hypoxia [low oxygen tensions typically defined as oxygen tensions (pO2 values) < 10 mm Hg]. Tumor cells existing in such hypoxic environments have long been known to be resistant to anticancer therapy, display an aggressive phenotype, and promote tumor progression and dissemination. This review discusses the physiological basis of hypoxia, methods of detection, and strategies to overcome the resulting therapy resistance. PMID- 29513033 TI - HLA-DQB1*03 and DRB1*07 alleles increase the risk of cervical cancer among Uighur and Han women in Xinjiang, China. AB - AIM: To explore the association between the determinant factors including HLA DQB1*03, DRB1-*07, -*13 and high-risk HPV infection, the cervical squamous cell carcinoma (CSCC) pathogenesis among Chinese Uighur and Han population. MATERIALS & METHODS: HLA alleles were genotyped by PCR sequence-specific primers. RESULTS: HPV16 infection rate was significantly higher among the Uighurs and Hans with CSCC as compared with healthy controls, respectively. HLA-DQB1*03 significantly increased among Uighurs with CSCC, while HLA-DRB1*07 significantly increased among Hans with CSCC. Similar tendencies were observed for DQB1*03 with HPV16 positive Uighurs CSCC and DRB1*07 with HPV16-positive Hans CSCC. CONCLUSION: This study suggests that HLA-DQB1*03 and DRB1*07 alleles may influence the immune response to HPV16 infection and increase the risk of CSCC among the Uighurs and Hans in China. PMID- 29513037 TI - Lagoecia cuminoides L., its antioxidant activity and polyphenolic constituents from Iran. AB - Lagoecia cuminoides L. belongs to the family of Umbelliferae (Apiaceae), and known also as common wild cumin. The aerial parts of L. cuminoides were collected at the flowering stage and dried, then the methanolic extract was analyzed for polyphenol compounds identified by HPLC-DAD and antioxidant activity (DPPH(2,2 diphenyl-1-picrylhydrazyl) radical scavenging assay). It was found that the predominant phenolic constituents were chlorogenic acid, hesperidin, rosmarinic acid, hesperetin and vanillin. The antioxidant activity of methanolic extract from L. cuminoides was found 1597 MUg/mL in DPPH scavenging assay. There is no strict positive relationship between the polyphenolic content and antioxidant activity of extracts. PMID- 29513036 TI - A randomized controlled trial of manual therapy and pneumatic compression for recovery from prolonged running - an extended study. AB - Manual therapy (MT) and intermittent pneumatic compression (IPC) are recovery methods used by endurance athletes with little evidence supporting effectiveness. This randomized controlled trial evaluated effectiveness of four daily post-race treatments of a specific MT protocol and IPC compared with supine rest on recovery following an ultramarathon among 56 ultramarathoners. Groups were comparable across all characteristics examined, including post-race plasma creatine kinase concentration. Subject completed timed 400 m runs before the race and on days three, five, seven and 14 post- race, and also provided muscle pain and soreness ratings and fatigue scores immediately before and after treatments, and during the 14 days post- race. Daily subjective measures and 400 m run times were not improved by either treatment, but both treatments reduced (p < .05) muscular fatigue scores acutely after treatment following the race and on post race day 1, and MT improved (p < .05) muscle pain and soreness acutely following the race. PMID- 29513038 TI - Hypoxia gene expression signatures as predictive biomarkers for personalising radiotherapy. AB - Hypoxia is a generic micro-environmental factor of solid tumours. High levels of hypoxia lead to resistance to radiotherapy, which can be targeted by adding hypoxia-modifying therapy to improve clinical outcomes. Not all patients benefit from hypoxia-modifying therapy, and there is a need for biomarkers to enable progression to biologically personalised radiotherapy. Gene expression signatures are a relatively new category of biomarkers that can reflect tumour hypoxia. This article reviews the published hypoxia gene signatures, summarising their development and validation. The challenges of gene signature derivation and development, and advantages and disadvantages in comparison with other hypoxia biomarkers are also discussed. Current evidence supports investment in gene signatures as a promising hypoxia biomarker approach for clinical utility. PMID- 29513039 TI - Retreatment with peptide receptor radionuclide therapy in patients with progressing neuroendocrine tumours: efficacy and prognostic factors for response. AB - OBJECTIVE:: To evaluate the efficacy and toxicity of a repeat peptide receptor radionuclide therapy (PRRT) course in neuroendocrine tumour patients who have progressed following previous PRRT and to identify factors contributing to retreatment outcomes. METHODS:: This was a retrospective analysis of 47 consecutive patients who had been treated with PRRT (PRRT1) and following disease progression were retreated with a second course of PRRT (PRRT2). We reviewed patient, tumour and treatment characteristics, time to progression after PRRT1 and PRRT2, overall survival and toxicity. We evaluated Kaplan-Meier survival plots, multiple regression analysis on factors predictive of time to progression and toxicity. RESULTS:: PRRT1: 45/47 patients were initially were treated with 90Y-DOTATATE, with two patients treated with 177Lu-DOTATATE. The median progression free survival (PFS) following PRRT1 was 30 months [95% confidence interval (CI) (26.9-36.6 months)]. Two patients developed Grade 1 renal toxicity. 3/47 patients had bone marrow toxicity, with 1 of these patients having Grade 3 toxicity. PRRT2: At the second course of treatment, 29 patients were treated with 90Y-DOTATATE and 18 patients with 177Lu-DOTATATE. Of the 44 patients with evaluable survival data, 41 patients developed disease progression. The median PFS after PRRT2 was 17.5 months [95% CI (11-23.8 months)]. There was no statistically significant difference in median PFS dependent on the choice of radiopharmaceutical: median PFS for 177Lu-DOTATATE = 17.2 months, median PFS for 90Y-DOTATATE = 17.3 months. Male sex and high burden of liver metastases were associated with shorter PFS following a PRRT retreatment course. 17/41 (41%) patients had bone marrow toxicity (2/17 had Grade 3 toxicity; no Grade 4 toxicity was seen). One patient developed myelodysplastic syndrome. 6/41 (14.6%) developed Grade 1 renal toxicity and 1/41 (2.4%) had Grade 4 renal toxicity. The median overall survival from commencement of first PRRT cycle was 71 months. CONCLUSION:: PRRT retreatment is safe and offers patients, who had progressed following initial PRRT course, a reasonably good PFS. Extra consideration is needed in patients with multiple comorbidities, as they may be at greater risk of renal and haematological toxicity. Male sex and high burden of liver metastases seem to be associated with shorter PFS following PRRT retreatment. ADVANCES IN KNOWLEDGE:: The majority of studies on PRRT have shown that it is effective as an initial treatment. This study with long-term follow-up demonstrates that PRRT is safe and effective retreatment option in patients that have progressed following initial PRRT course. PMID- 29513040 TI - Mangostanaxanthone VIII, a new xanthone from Garcinia mangostana and its cytotoxic activity. AB - A new prenylated xanthone, mangostanaxanthone VIII (7) and six known metabolites: gartanin (1), 1,3,8-trihydroxy-2-(3-methyl-2-butenyl)-4-(3-hydroxy-3 methylbutanoyl)-xanthone (2), rubraxanthone (3), 1,3,6,7-tetrahydroxy-8 prenylxanthone (4), garcinone C (5), and xanthone I (9-hydroxycalabaxanthone) (6) were separated from the EtOAc-soluble fraction of the air-dried pericarps of Garcinia mangostana (Clusiaceae). Their structures have been verified on the basis of spectroscopic data analysis as well as comparison with the literature. The cytotoxic activity of 7 was assessed against MCF7, A549, and HCT116 cell lines using sulforhodamine B (SRB) assay. Compound 7 showed significant cytotoxic potential against MCF7 and A549 cell lines with IC50s 3.01 and 1.96 MUM, respectively compared to doxorubicin (0.06 and 0.44 MUM, respectively). However, it exhibited moderate activity towards HCT116 cell line. PMID- 29513041 TI - VEGF-mediated angiogenesis and vascularization of a fumarate-crosslinked polycaprolactone (PCLF) scaffold. AB - PURPOSE: Revascularization of natural and synthetic scaffolds is a critical part of the scaffold's incorporation and tissue ingrowth. Our goals were to create a biocompatible polymer scaffold with 3D-printing technology, capable of sustaining vascularization and tissue ingrowth. METHODS: We synthesized biodegradable polycaprolactone fumarate (PCLF) scaffolds to allow tissue ingrowth via large interconnected pores. The scaffolds were prepared with Poly(lactic-co-glycolic acid)(PLGA) microspheres seeded with or without different growth factors including VEGF,FGF-2, and/or BMP-2. Scaffolds were implanted into the subcutaneous tissues of rats before undergoing histologic and microCT angiographic analysis. RESULTS: At harvest after 12 weeks, scaffolds had tissue infiltrating into their pores without signs of scar tissue formation, fibrous capsule formation, or immune responses against PCLF. Histology for M1/M2 macrophage phenotypes confirmed that there were no overt signs of immune responses. Both microCT angiography and histologic analysis demonstrated marked tissue and vessel ingrowth throughout the pores traversing the body of the scaffolds. Scaffolds seeded with microspheres containing VEGF or VEGF with either BMP-2 or FGF-2 had significantly higher vascular ingrowth and vessel penetration than controls. All VEGF-augmented scaffolds were positive for Factor-VIII and exhibited collagen tissue infiltration throughout the pores. Furthermore, scaffolds with VEGF and BMP-2 had high levels of mineral deposition throughout the scaffold that are attributable to BMP-2. CONCLUSIONS: PCLF polymer scaffold can be utilized as a framework for vascular ingrowth and regeneration of multiple types of tissues. This novel scaffold material has promise in tissue regeneration across all types of tissues from soft tissue to bone. PMID- 29513042 TI - Bioactive cyclic molecules and drug design. PMID- 29513044 TI - Pain chronification: what should a non-pain medicine specialist know? AB - OBJECTIVE: Pain is one of the most common reasons for an individual to consult their primary care physician, with most chronic pain being treated in the primary care setting. However, many primary care physicians/non-pain medicine specialists lack enough awareness, education and skills to manage pain patients appropriately, and there is currently no clear, common consensus/formal definition of "pain chronification". METHODS: This article, based on an international Change Pain Chronic Advisory Board meeting which was held in Wiesbaden, Germany, in October 2016, provides primary care physicians/non-pain medicine specialists with a narrative overview of pain chronification, including underlying physiological and psychosocial processes, predictive factors for pain chronification, a brief summary of preventive strategies, and the role of primary care physicians and non-pain medicine specialists in the holistic management of pain chronification. RESULTS: Based on currently available evidence, we propose the following consensus-based definition of pain chronification which provides a common framework to raise awareness among non-pain medicine specialists: "Pain chronification describes the process of transient pain progressing into persistent pain; pain processing changes as a result of an imbalance between pain amplification and pain inhibition; genetic, environmental and biopsychosocial factors determine the risk, the degree, and time-course of chronification." CONCLUSIONS: Early intervention plays an important role in preventing pain chronification and, as key influencers in the management of patients with acute pain, it is critical that primary care physicians are equipped with the necessary awareness, education and skills to manage pain patients appropriately. PMID- 29513043 TI - Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid. AB - Pharmacological interventions targeting mitochondria present several barriers for a complete efficacy. Therefore, a new mitochondriotropic antioxidant (AntiOxBEN3) based on the dietary antioxidant gallic acid was developed. AntiOxBEN3 accumulated several thousand-fold inside isolated rat liver mitochondria, without causing disruption of the oxidative phosphorylation apparatus, as seen by the unchanged respiratory control ratio, phosphorylation efficiency, and transmembrane electric potential. AntiOxBEN3 showed also limited toxicity on human hepatocarcinoma cells. Moreover, AntiOxBEN3 presented robust iron-chelation and antioxidant properties in both isolated liver mitochondria and cultured rat and human cell lines. Along with its low toxicity profile and high antioxidant activity, AntiOxBEN3 strongly inhibited the calcium-dependent mitochondrial permeability transition pore (mPTP) opening. From our data, AntiOxBEN3 can be considered as a lead compound for the development of a new class of mPTP inhibitors and be used as mPTP de-sensitiser for basic research or clinical applications or emerge as a therapeutic application in mitochondria dysfunction related disorders. PMID- 29513045 TI - Isothiocyanates: cholinesterase inhibiting, antioxidant, and anti-inflammatory activity. AB - Finding a new type of cholinesterase inhibitor that would overcome the brain availability and pharmacokinetic parameters or hepatotoxic liability has been a focus of investigations dealing with the treatment of Alzheimer's disease. Isothiocyanates have not been previously investigated as potential cholinesterase inhibitors. These compounds can be naturally produced from their glucosinolate precursors, secondary metabolites widely distributed in our daily Brassica vegetables. Among 11 tested compounds, phenyl isothiocyanate and its derivatives showed the most promising inhibitory activity. 2-Methoxyphenyl ITC showed best inhibition on acetylcholinesterase with IC50 of 0.57 mM, while 3-methoxyphenyl ITC showed the best inhibition on butyrylcholinesterase having 49.2% at 1.14 mM. Assessment of the antioxidant efficacy using different methods led to a similar conclusion. The anti-inflammatory activity was also tested using human COX-2 enzyme, ranking phenyl isothiocyanate, and 3-methoxyphenyl isothiocyanate as most active, with ~99% inhibition at 50 MUM. PMID- 29513047 TI - Reference values of inspiratory spirometry for Finnish adults. AB - Inspiratory spirometry is used in evaluation of upper airway disorders e.g. fixed or variable obstruction. There are, however, very few published data on normal values for inspiratory spirometry. The main aim of this study was to produce reference values for inspiratory spirometry for healthy Finnish adults. Inspiratory spirometry was preplanned to a sample of the Finnish spirometry reference values sample. Data was successfully retrieved from 368 healthy nonsmoking adults (132 males) between 19 and 83 years of age. Reference equations were produced for forced inspiratory vital capacity (FIVC), forced inspiratory volume in one second (FIV1), FIV1/FIVC, peak inspiratory flow (PIF) and the ratios of FIV1/forced expiratory volume in one second and PIF/peak expiratory flow. The present values were compared to PIF values from previously used Finnish study of Viljanen et al. (1982) reference values and Norwegian values for FIV1, FIVC and FIV1/FIVC presented by Gulsvik et al. (2001). The predicted values from the Gulsvik et al. (2001), provided a good fit for FIVC, but smaller values for FIV1 with mean 108.3 and 109.1% of predicted values for males and females, respectively. PIF values were 87.4 and 91.2% of Viljanen et al. (1982) predicted values in males and females, respectively. Differences in measurement methods and selection of results may contribute to the observed differences. Inspiratory spirometry is technically more demanding and needs repeatability criteria to improve validity. New reference values are suggested to clinical use in Finland when assessing inspiratory spirometry. Utility of inspiratory to expiratory values indices in assessment of airway collapse need further study. PMID- 29513046 TI - A microemulsion of puerarin-phospholipid complex for improving bioavailability: preparation, in vitro and in vivo evaluations. AB - Puerarin is a phytochemical with various pharmacological effects, but poor water solubility and low oral bioavailability limited usage of puerarin. The purpose of this study was to develop a new microemulsion (ME) based on phospholipid complex technique to improve the oral bioavailability of puerarin. Puerarin phospholipid complex (PPC) was prepared by a solvent evaporation method and was characterized by X-ray diffraction and infrared spectroscopy. Pseudo-ternary phase diagrams were constructed to investigate the effects of different oil on the emulsifying performance of the blank ME. Intestinal mucosal injury test was conducted to evaluate safety of PPC-ME, and no sign of damage on duodenum, jejunum and ileum of rats was observed using hematoxylin-eosin staining. In pharmacokinetic study of PPC-ME, a significantly greater Cmax (1.33 ug/mL) was observed when compared to puerarin (Cmax 0.55 ug/mL) or PPC (Cmax 0.70 ug/mL); the relative oral bioavailability of PPC-ME was 3.16-fold higher than puerarin. In conclusion, the ME combined with the phospholipid complex technique was a promising strategy to enhance the oral bioavailability of puerarin. PMID- 29513048 TI - Transient plasma cobalamin elevation in patients with pneumonia - two case reports. AB - We report two cases of transient significantly elevated plasma cobalamin (B12) in geriatric patients acutely admitted with fever, increased C-reactive protein and X-ray verified pneumonia. Extensive diagnostic workup did not reveal kidney or liver disease, neither any signs of cancer. Furthermore, none of the patients had received therapeutic B12 supplementation prior to admission. In both cases, plasma B12 normalized at an out-patient control few months later. We were not able to identify the reason for the initial B12 elevation in any of the patients, since none of the usually recognized causes were evident. Since both patients had an infection and temporarily elevated B12, we suggest a possible inflammatory response or a vitamin B12 production by the infectious agents as the cause. Both suggestions, however, need further exploration. PMID- 29513051 TI - Spinal cord injury rehabilitation and pressure ulcer prevention after the 2005 South Asian Earthquake: a CBR case study from Pakistan. AB - BACKGROUND: The 2005 South Asian earthquake led to large-scale injuries and disabilities in northern Pakistan, which were dealt with using various approaches. In this regard, a community-based rehabilitation approach was initiated in the Muzaffarabad district of Pakistan in early 2006, focused on preventing complications among persons with Spinal Cord Injury. This case study briefly describes its development, aims and service provision components, in addition to the distribution of injuries from the disaster. Pressure ulcer prevention education, its recall and decrease in prevalence over a year are presented as key outcomes and illuminate the process of implementing rehabilitation in this context. METHODS: This case study presents findings from a larger internal program evaluation in 2010-11. The study design was cross sectional, to elicit recall of education components and the resulting prevalence of pressure ulcers over the year, in 33 randomly selected persons with Spinal Cord Injury. Outcomes included retention of knowledge about pressure ulcer prevention, practices and reduction in the prevalence of pressure ulcers over the last year. We also conducted a narrative literature review on the types of injuries and complications in the Spinal Cord population from Northern Pakistan. RESULTS: Hospital cohort studies reported "spine" injuries at 5%, while persons with spinal cord injury were identified as the most underserved needing rehabilitation services after the quake. Results from the evaluation of prevention education revealed that all 33 respondents were trained in detection of pressure ulcers, while 32 recalled "danger signs" for which they would seek immediate help. All correctly recalled postural change timings, however, their actual practices differed. Twenty-seven respondents (82%) reported no pressure ulcers over the last year. CONCLUSION: The decrease in pressure ulcer prevalence over the last year in persons with spinal cord injury highlights the strengths of the community-based rehabilitation approach, particularly preventive education in geographically challenging and highly resource constrained settings. The research also begins to fill a critical gap in the present literature as most research is limited to hospital based interventions from the first year of the 2005 earthquake. Implications for Rehabilitation Prevention education for targeting pressure ulcers can be effective in reducing incidence of this important complication in persons with spinal cord injury. Community-based rehabilitation approaches can prove beneficial in post-disaster settings, especially in resource constrained settings and difficult hilly terrain. Rehabilitation programs should consider nutrition interventions to reduce multiple pressure ulcers, especially in lower middle income countries. PMID- 29513050 TI - Detection of cytomegalovirus by immunohistochemistry of colonic biopsies and quantitative blood polymerase chain reaction: evaluation of agreement in ulcerative colitis. AB - OBJECTIVES: Cytomegalovirus (CMV) often reactivates in ulcerative colitis (UC). In diagnostics, along with immunohistochemistry (IHC) of colonic biopsies, blood CMV polymerase chain reaction (PCR) is gaining increasing application. We aimed to assess agreement between the density of infected colonic cells by IHC and the viral load in the blood by PCR. MATERIAL AND METHODS: We retrospectively identified patients with active UC or indeterminate colitis in whom blood CMV PCR had been performed while biopsies had been taken simultaneously. The latter were re-evaluated and the numbers of IHC-positive cells per square millimetre counted. RESULTS: The analyses extended to 234 sample pairs, among which there were 184 cases (78.6% of the total) in which IHC was equal to 0. The median among the remaining 50 non-zero values for IHC was 1.7 cells/mm2. PCR was equal to 0 in 192 cases (82.1%), while the median among the remaining 42 non-zero values was 4995.3 IU/ml. The Spearman correlation coefficient was 0.43 (p < .001). The area under the curve (AUC) values did not differ significantly between different IHC cut offs. The highest AUC of 0.753 was obtained while predicting if IHC would be above the 3rd quartile (>5.6 cells/mm2), where PCR > 0 had a sensitivity of 0.615 and a specificity of 0.846. CONCLUSIONS: In active CMV colitis, the specificity and negative predictive value of blood PCR are high, while the sensitivity grows with the intensity of colon infection. A highly positive result could justify the administration of antiviral treatment being brought forward in selected patients. PMID- 29513049 TI - Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo. AB - Mitochondrial-targeting therapy was considered to be a promising approach for the efficient treatment of cancer while positive charge induced nonspecific cytotoxicity severely limits its application. To overcome this drawback, a novel mitochondria targeted conjugate triphenylphosphine-docetaxel (TD) has been synthesized successfully and incorporated it into liposomes (EPSLP/TD), which possessed excellent pH-sensitive characteristic, EphA 10 mediated active targetability as well as mitochondria-targeting capability. EPSLP/TD was characterized to have a small particle size, high-encapsulation efficiency and excellent pH-sensitive characteristic. Compared with DTX-loaded liposomes (EPSLP/DTX), EPSLP/TD possessed higher cytotoxicity against MCF-7 cell line. Mitochondrial-targeting assay demonstrated mitochondria-targeting moiety triphenylphosphine (TPP) could efficiently deliver DTX to mitochondria. Western immunoblotting assay indicated that EPSLP/TD could efficiently deliver antitumor drug to mitochondria and induce cell apoptosis via mitochondria-mediated apoptosis pathway. In vivo antitumor study demonstrated EPSLP/TD owed excellent in vivo antitumor activity. Histological assay demonstrated EPSLP/TD showed strongly apoptosis inducing effect, anti-proliferation effect and anti angiogenesis effect. This work investigated the potential of hierarchical targeting pH-sensitive liposomes is a suitable carrier to activate mitochondria mediated apoptosis pathway for cancer therapy. PMID- 29513052 TI - Experiences of therapists using feedback-based technology to improve physical function in rehabilitation settings: a qualitative systematic review. AB - PURPOSE: To synthesise therapist experiences of using feedback-based technology for physical rehabilitation through a systematic review of qualitative studies. METHODS: Ten electronic databases were searched up to March 2017. Peer reviewed studies that provided qualitative data that met the inclusion criteria were selected. The methodological quality of included studies was assessed using the Critical Appraisal Skills Programme. Relevant text from each study was extracted including quotes and the author's interpretations. Data were imported into NVivo for analysis. Text was coded for content, then categorised using a thematic synthesis approach. RESULTS: The search yielded 50,379 records. Of 340 full text articles assessed for eligibility, 12 publications (10 studies) were included. Themes that emerged relating to therapists' experience of using feedback-based technology in practice were: (1) the benefits of using technology; (2) practicalities of using technology in practice; (3) the need for support; and (4) design to support the use of technology in rehabilitation. CONCLUSIONS: Therapists perceive many benefits to using feedback-based technologies in rehabilitation but view it as an addition rather than an alternative to usual therapy. Input from therapists was perceived to be needed for technology to achieve therapeutic benefit. Technology use in practice may be influenced by design limitations or the available support to access and use the technology. Implications for Rehabilitation Therapists perceive technology can be used for benefit as an adjunct to usual therapy with the skilled input of a therapist to assess and monitor patient performance to ensure the "right" quality and quantity of movements for recovery. Technology prescription requires an investment of time and a tailored approach so that its use meets the needs of the individual patient. Support for training, evidence of effectiveness and access to technology is imperative for implementation in practice. Therapists need to work collaboratively with technology developers to improve the design and usability of technologies to better support the rehabilitation process. PMID- 29513053 TI - Reforms in VUmc School of Medical Sciences Amsterdam: Student engagement, a Minor elective semester and stakeholder collaboration in improving the quality of assessments. AB - BACKGROUND: At VUmc School of Medical Sciences, major curricular reforms occurred in 2005 and 2015, related to the introduction of a Bachelor-Master structure, a new legislation from the Ministry of Education, the changing societal context, and taking note of students' and teachers' needs. Summary of work: Along with the introduction of the Bachelor-Master system, the period between 2005 and 2009 saw the movement from traditional lecture-based teaching to small group teaching in a competency-based curriculum, in which the students were responsible for their learning. Student engagement grew through students' designing learning modules and conducting some of the teaching. In the Bachelor program, an elective "Minor", was designed to broaden and deepen the knowledge of our students beyond the core learning outcomes, in a discipline of their choice. The examination board (EB), responsible for maintaining the quality of assessment, was split into the General EB, which handled overall strategy issues, and the Executive EB, which handled student requests and monitored the quality of assessments. LESSONS LEARNED: Students develop a sense of what education is about if they are provided opportunities in designing teaching and conducting it. A Minor elective in the medical study can provide the students with an opportunity to learn outside the medical field. Collaborative working between different stakeholders in a medical school is crucial for safeguarding the quality of assessments. Curricular reforms need time to be accepted and integrated into the culture of the medical school. The educational vision needs to be refreshed regularly in alignment with the changing societal context. PMID- 29513054 TI - Influence of inter-observer delineation variability on radiomics stability in different tumor sites. AB - BACKGROUND: Radiomics is a promising methodology for quantitative analysis and description of radiological images using advanced mathematics and statistics. Tumor delineation, which is still often done manually, is an essential step in radiomics, however, inter-observer variability is a well-known uncertainty in radiation oncology. This study investigated the impact of inter-observer variability (IOV) in manual tumor delineation on the reliability of radiomic features (RF). METHODS: Three different tumor types (head and neck squamous cell carcinoma (HNSCC), malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC)) were included. For each site, eleven individual tumors were contoured on CT scans by three experienced radiation oncologists. Dice coefficients (DC) were calculated for quantification of delineation variability. RF were calculated with an in-house developed software implementation, which comprises 1404 features: shape (n = 18), histogram (n = 17), texture (n = 137) and wavelet (n = 1232). The IOV of RF was studied using the intraclass correlation coefficient (ICC). An ICC >0.8 indicates a good reproducibility. For the stable RF, an average linkage hierarchical clustering was performed to identify classes of uncorrelated features. RESULTS: Median DC was high for NSCLC (0.86, range 0.57-0.90) and HNSCC (0.72, 0.21-0.89), whereas it was low for MPM (0.26, 0-0.9) indicating substantial IOV. Stability rate of RF correlated with DC and depended on tumor site, showing a high stability in NSCLC (90% of total parameters), acceptable stability in HNSCC (59% of total parameters) and low stability in MPM (36% of total parameters). Shape features showed the weakest stability across all tumor types. Hierarchical clustering revealed 14 groups of correlated and stable features for NSCLC and 6 groups for both HNSCC and MPM. CONCLUSION: Inter-observer delineation variability has a relevant influence on radiomics analysis and is strongly influenced by tumor type. This leads to a reduced number of suitable imaging features. PMID- 29513055 TI - Intravitreal chemotherapy and laser for newly visible subretinal seeds in retinoblastoma. AB - BACKGROUND: There has been no effective method for treating newly visible ("new") subretinal seeding in retinoblastoma except enucleation. The objective of this report is to determine whether intravitreal chemotherapy combined with 810 nm indirect laser can successfully treat retinoblastoma eyes with "new" subretinal seeding which appeared after intra-arterial chemotherapy (ophthalmic arterial chemosurgery: OAC). MATERIAL AND METHODS: Single center retrospective study from a tertiary cancer hospital of a case series of 14 eyes treated with combined intravitreal chemotherapy and laser from 2012 to 2017. Ocular salvage, patient survival, recurrence-free ocular survival, metastases, and extraocular extension were assessed. RESULTS: A total of 14 eyes in 13 unilateral or bilateral retinoblastoma patients with "new" subretinal seeding after initial eye salvage therapy were treated with combined intravitreal injection of melphalan (30 ug) or melphalan (30 ug) and topotecan (20 ug) and with 810 nm indirect continuous wave laser. All eyes were salvaged. Only two eyes (14%) recurred again for subretinal seeds after 6 and 8 months, respectively, and required additional cycles of intravitreal injections and laser. Combined intravitreal injection of melphalan or melphalan plus topotecan with 810 nm indirect continuous wave laser was not associated with any metastatic events, patient deaths, extraocular extension, or need for enucleation. CONCLUSION: There has been no effective treatment for "new" subretinal seeding after OAC except enucleation or second course OAC. Combined intravitreal chemotherapy with 810 nm indirect laser may be an effective and safe alternative to enucleation. PMID- 29513056 TI - l-N-acetylcysteine protects outer hair cells against TNFalpha initiated ototoxicity in vitro. AB - OBJECTIVE: The present study is aimed at determining the efficacy and exploring the mechanisms by which l-N-acetylcysteine (l-NAC) provides protection against tumor necrosis factor-alpha (TNFalpha)-induced oxidative stress damage and hair cell loss in 3-day-old rat organ of Corti (OC) explants. Previous work has demonstrated a high level of oxidative stress in TNFalpha-challenged OC explants. TNFalpha can potentially play a significant role in hair cell loss following an insult to the inner ear. l-NAC has shown to provide effective protection against noise-induced hearing loss in laboratory animals but mechanisms of this otoprotective effect are not well-defined. DESIGN: Rat OC explants were exposed to either: (1) saline control (N = 12); (2) TNFalpha (2 MUg/ml, N = 12); (3) TNFalpha+l-NAC (5 mM, N = 12); (4) TNFalpha+l-NAC (10 mM, N = 12); or (5) l-NAC (10 mM, N = 12). Outer hair cell (OHC) density, levels of reactive oxygen species (ROS), lipid peroxidation of cell membranes, gluthathione activity, and mitochondrial viability were assayed. RESULTS: l-NAC (5 and 10 mM) provided protection for OHCs from ototoxic level of TNFalpha in OC explants. Groups treated with TNFalpha+l-NAC (5 mM) showed a highly significant reduction of both ROS (p < 0.01) and 4-hydroxy-2-nonenal immunostaining (p < 0.001) compared to TNFalpha-challenged explants. Total glutathione levels were low in TNFalpha challenged explants compared to control and TNFalpha+l-NAC (5 mM) treated explants (p < 0.001). CONCLUSIONS: l-NAC is a promising treatment for protecting auditory HCs from TNFalpha-induced oxidative stress and subsequent loss via programmed cell death. PMID- 29513057 TI - Effect of the cross-linking agent and drying method on encapsulation efficiency of orange essential oil by complex coacervation using whey protein isolate with different polysaccharides. AB - Orange essential oil was microencapsulated by complex coacervation with whey protein isolate (WPI): carboxymethylcellulose (CMC), WPI:sodium alginate (SA) and WPI:chitosan (CH). Effect of pH, protein:polysaccharide ratio and solid concentration on coacervation efficiency were selected for the best coacervation conditions. Tannic acid (TA), sodium tripolyphosphate, oxidised tannic acid and transglutaminase enzyme (TG) were used as cross-linking agents. Highest encapsulation efficiency (EE) for wet coacervated microcapsules ranged from 88% to 94%. Microcapsules were freeze and spray dried to evaluate their effect on its integrity. EE was higher than 80% in freeze dried coacervated microcapsules with and without cross-linking agent, but they formed a solid cake. Spray-dried samples formed a free fluid solid (10-20 um), where the systems WPI:CMC and WPI:CH cross-linked with TA and TG, respectively showed the highest EE (47% and 50% respectively), representing 400% improvement compared to the samples without cross-linking. PMID- 29513058 TI - Evaluation of the relationship between compliance with the follow-up and treatment protocol and health literacy in bladder tumor patients. AB - OBJECTIVE: To investigate the relationship between the compliance of bladder cancer patients with cystoscopic follow-up and the treatment protocol, and their health literacy. METHODS: Patients who underwent transurethral resection surgery for bladder tumor were found to have non-muscular invasive bladder carcinoma on pathology examination and then underwent cystoscopic follow-up for 1 year or more were included in the study. Cystoscopic follow-up was recommended to the low- and high-risk groups in terms of progression and recurrence. The patients were evaluated with the Health Literacy Survey-European Union scale. RESULTS: The mean age of the patients was 67.13 +/- 10.77 years. The treatment continuity rate was 80.50% (n = 33) in the adequate health literacy group (n = 41) and significantly higher than the 56.50% (n = 48) rate in the inadequate health literacy group (n = 85) (p = .008). The health literacy results revealed that the health promotion and general index score was higher in the group of patients under the age of 65. CONCLUSIONS: Adequate health literacy in bladder cancer patients is associated with better compliance with the treatment protocol. Young patients show better compliance with the follow-up protocol recommended by the physician. Increasing the follow-up protocol compliance of elderly patients with inadequate health literacy is necessary. PMID- 29513059 TI - Response to: Feedback: Form over function? PMID- 29513060 TI - Exploitation of microbial forensics and nanotechnology for the monitoring of emerging pathogens. AB - Emerging infectious diseases remain among the leading causes of global mortality. Traditional laboratory diagnostic approaches designed to detect and track infectious disease agents provide a framework for surveillance of bio threats. However, surveillance and outbreak investigations using such time-consuming approaches for early detection of pathogens remain the major pitfall. Hence, reasonable real-time surveillance systems to anticipate threats to public health and environment are critical for identifying specific aetiologies and preventing the global spread of infectious disease. The current review discusses the growing need for monitoring and surveillance of pathogens with the same zeal and approach as adopted by microbial forensics laboratories, and further strengthening it by integrating with the innovative nanotechnology for rapid detection of microbial pathogens. Such innovative diagnostics platforms will help to track pathogens from high risk areas and environment by pre-emptive approach that will minimize damages. The various scenarios with the examples are discussed where the high risk associated human pathogens in particular were successfully detected using various nanotechnology approaches with potential future prospects in the field of microbial forensics. PMID- 29513061 TI - Response to: Factors influencing the educational impact of mini-CEX and DOPS: A qualitative synthesis. PMID- 29513063 TI - Acid-base and me. PMID- 29513062 TI - Relevance of barriers and facilitators in the use of health technology assessment in Colombia. AB - OBJECTIVES: Several studies, mostly from developed countries, have identified barriers and facilitators with regard to the uptake of health technology assessment (HTA). This study elicited, using best-worst scaling (BWS), what HTA experts in Colombia consider to be the most important barriers and facilitators in the use of HTA, and makes a comparison to results from the Netherlands. METHODS: Two object case surveys (one for barriers, one for facilitators) were conducted among 18 experts (policymakers, health professionals, PhD students, senior HTA-researchers) from Colombia. Seven respondents were employees of the national HTA agency Instituto de Evaluacion Tecnologica de Salud (IETS). In total, 22 barriers and 19 facilitators were included. In each choice task, participants were asked to choose the most and least important barrier/facilitator from a set of five. Hierarchical Bayes modeling was used to compute the mean relative importance scores (RIS) for each factor, and a subgroup analysis was conducted to assess differences between IETS and non-IETS respondents. The final ranking was further compared to the results from a similar study conducted in the Netherlands. RESULTS: The three most important barriers (RIS >6.00) were "Inadequate presentation format", "Absence of policy networks", and "Insufficient legal support". The six most important facilitators (RIS >6.00) were "Appropriate timing", "Clear presentation format", "Improving longstanding relation", "Appropriate incentives", "Sufficient qualified human resources", and "Availability to relevant HTA research". The perceived relevance of the barriers and facilitators differed slightly between IETS and non-IETS employees, while the differences between the rankings in Colombia and the Netherlands were substantial. CONCLUSION: The study suggests that barriers and facilitators related to technical aspects of processing HTA reports and to the contact and interaction between researchers and policymakers had the greatest importance in Colombia. PMID- 29513064 TI - Contribution of intratympanic steroids in the primary treatment of sudden hearing loss. AB - OBJECTIVE: The primary objective is to investigate the contribution of intratympanic steroids in the primary treatment of idiopathic sudden sensorineural hearing loss (ISSNHL). The secondary objective is to compare methylprednisolone (MP) and dexamethasone in terms of their effectiveness and injection-site pain. METHODS: Two hundred and four patients with ISSNHL, 144 patients underwent systemic steroid therapy (SST) alone and 60 patients underwent combined therapy (CT). The effectiveness of the treatment was assessed according to the Furuhashi criteria. Injection-site pain after the procedure was assessed at 5 and 60 min on a visual analog scale (VAS). RESULTS: Successful recovery was 55% in the CT group and 34% in the SST alone group (p = .004). Patients whose initial hearing level is severe, the success rate was statistically significantly higher with CT (p = .0001). Hearing improvement differed significantly between the MP and dexamethasone (p = .015). Injection-site pain at 5 min after the procedure, higher VAS scores were obtained with MP (p = .002). CONCLUSION: In the primary treatment of sudden hearing loss, in which the level of hearing loss is 70-89 dB HL, the addition of ITS to the treatment significantly increased the success rate. The pain occurring in the middle ear was high but tolerable in the first few minutes by MP. PMID- 29513065 TI - Learning about discharging. PMID- 29513066 TI - Adolescent insightfulness toward a close friend: its roots in maternal insightfulness and child attachment in infancy. AB - Two antecedents of the insightfulness of adolescents into a close friend's experience were examined: The insightfulness of the mother and the attachment of the child, both measured when the adolescent was an infant. We hypothesized that both antecedents would be associated with adolescent insightfulness. Maternal insightfulness was assessed using the Insightfulness Assessment (IA) in which mothers are interviewed about their children's thoughts and feelings after viewing short video segments of their interactions with their children, and infant attachment was assessed using the Strange Situation Procedure. Adolescent insightfulness was assessed using an adaptation of the IA in which the adolescents were interviewed about their friend's thoughts and feelings after viewing short video segments of their interactions with them. As predicted, the results showed that adolescents were more likely to show insightfulness toward their friend when their mothers had been insightful toward them when they were infants and when they had secure attachment with their mothers. When both predictors were considered together, maternal insightfulness remained predictive of adolescent insightfulness but infant attachment was no longer significant. PMID- 29513067 TI - Preclinical stress research: where are we headed? An early career investigator's perspective. AB - Stress is a major risk factor in the development of various psychiatric disorders such as depression, anxiety and post-traumatic stress disorder. The use of stress paradigms in preclinical contexts is essential to advance our understanding of the pathophysiology of these disorders. However, they are not without their limitations and in this commentary, we have examined some of the practical issues associated with their use. We also highlight some of the latest techniques to identify their neuromolecular correlates as well as the potentially important and integrative role of computational neuroscience. Finally, we share our perspective on future directions in the field of preclinical stress research. PMID- 29513068 TI - Testing the redintegration hypothesis by a single probe recognition paradigm. AB - The lexicality effect in verbal short-term memory (STM), in which word lists are better recalled than nonwords lists, is considered to reflect the influence of linguistic long-term memory (LTM) knowledge on verbal STM performance. The locus of this effect remains, however, a matter of debate. The redintegrative account considers that degrading phonological traces of memoranda are reconstructed at recall by selecting lexical LTM representations that match the phonological traces. According to a strong version of this account, redintegrative processes should be strongly reduced in recognition paradigms, leading to reduced LTM effects. We tested this prediction by contrasting word and nonword memoranda in a fast encoding probe recognition paradigm. We observed a very strong lexicality effect, with better and faster recognition performance for words as compared to nonwords. These results do not support a strong version of the redintegrative account of LTM effects in STM which considers that these LTM effects would be the exclusive product of reconstruction mechanisms. If redintegration processes intervene in STM recognition tasks, they must be very fast, which at the same time provides support for models considering direct activation of lexico-semantic knowledge during verbal STM tasks. PMID- 29513069 TI - Glucose dilates renal afferent arterioles via glucose transporter-1. AB - Glomerular hyperfiltration occurs during the early stage of diabetes. An acute glucose infusion increases glomerular filtration rate. The involvement of tubuloglomerular feedback response and direct effect of glucose on the afferent arterioles (Af-Arts) have been suggested. However, the signaling pathways to trigger Af-Art dilatation have not been fully identified. Therefore, in the present study we tested our hypothesis that an increase in glucose concentration enhances endothelial nitric oxide synthesis activity and dilates the Af-Arts via glucose transporter-1 (GLUT1) using isolated mouse Af-Arts with perfusion. We isolated and microperfused the Af-Arts from nondiabetic C57BL/6 mice. The Af-Arts were preconstricted with norepinephrine (1 uM). When we switched the d-glucose concentration from low (5 mM) to high (30 mM) in the perfusate, the preconstricted Af-Arts significantly dilated by 37.8 +/- 7.1%, but L-glucose did not trigger the dilation. GLUT1 mRNA was identified in microdisserted Af-Arts measured by RT-PCR. Changes in nitric oxide (NO) production in Af-Art were also measured using fluorescent probe when ambient glucose concentration was increased. When the d-glucose concentration was switched from 5 to 30 mM, NO generation in Af-Art was significantly increased by 19.2 +/- 6.2% (84.7 +/- 4.1 to 101.0 +/- 9.3 U/min). l-Glucose had no effect on the NO generation. The GLUT1 selective antagonist 4-[({[4-(1,1-Dimethylethyl)phenyl]sulfonyl}amino)methyl]- N 3-pyridinylbenzamide and the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester blocked the high glucose-induced NO generation and vasodilation. In conclusion, we demonstrated that an increase in glucose concentration dilates the Af-Art by stimulation of the endothelium-derived NO production mediated by GLUT1. PMID- 29513070 TI - Endothelial progenitor cells accelerate endothelial regeneration in an in vitro model of Shigatoxin-2a-induced injury via soluble growth factors. AB - Endothelial injury with consecutive microangiopathy and endothelial dysfunction plays a central role in the pathogenesis of the postenteropathic hemolytic uremic syndrome (D + HUS). To identify new treatment strategies, we examined the regenerative potential of endothelial progenitor cells (EPCs) in an in vitro model of Shiga toxin (Stx) 2a-induced glomerular endothelial injury present in D + HUS and the mechanisms of EPC-triggered endothelial regeneration. We simulated the proinflammatory milieu present in D + HUS by priming human renal glomerular endothelial cells (HRGECs) with tumor necrosis factor-alpha before stimulation with Stx2a. This measure led to a time- and concentration-dependent decrease of HRGEC viability of human renal glomerular endothelial cells as detected by a colorimetric assay. Coincubation with EPCs (104-105 cells/ml) under dynamic flow conditions led to a significant improvement of cell viability in comparison to untreated monolayers (0.45 +/- 0.06 vs. 0.16 +/- 0.04, P = 0.003). A comparable regenerative effect of EPCs was observed in a coculture model using cell culture inserts (0.41 +/- 0.05 vs. 0.16 +/- 0.04, P = 0.003) associated with increased concentrations of vascular endothelial growth factor, insulin-like growth factor I, fibroblast growth factor-2, and hepatocyte growth factor in the supernatant. Treatment of Stx2a-injured monolayers with a combination of these growth factors imitated this effect. EPCs did not show distinct sings of migration and angiogenic tube formation in functional assays. These data demonstrate that EPCs significantly improve endothelial viability after Stx2a-induced injury in vitro and that this effect is associated with the release of growth factors by EPCs. PMID- 29513073 TI - Modulation of tubular solute reuptake in UMOD knockout mice. PMID- 29513072 TI - Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1. AB - Nitric oxide prevents hypertension yet enhances proximal tubule Na+ reabsorption. Nitric oxide synthase is inhibited by asymmetric dimethylarginine (ADMA) that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) whose type 1 isoform is expressed abundantly in the proximal tubule (PT). We hypothesize that ADMA metabolized by DDAH-1 inhibits fluid reabsorbtion (Jv) by the proximal tubule. S2 segments of the PT were microperfused between blocks in vivo to assess Jv in anesthetized rats. Compared with vehicle, microperfusion of ADMA or Nomega nitro-l-arginine methyl ester (l-NAME) in the proximal tubule reduced Jv dose dependently. At 10-4 mol/l both reduced Jv by ~40% (vehicle: 3.2 +/- 0.7 vs. ADMA: 2.1 +/- 0.5, P < 0.01 vs. l-NAME: 1.9 +/- 0.4 nl.min-1.mm-1, P < 0.01; n = 10). Selective inhibition of DDAH-1 in rats with intravenous L-257 (60 mg/kg) given 2 h before and L-257 (10-5 mol/l) perfused in the proximal tubule for 5 min reduced Jv by 32 +/- 4% (vehicle: 3.2 +/- 0.5 vs. L-257: 2.2 +/- 0.5 nl.min-1.mm 1; P < 0.01) and increased plasma ADMA by ~50% (vehicle: 0.46 +/- 0.03 vs. L-257: 0.67 +/- 0.03 umol/l, P < 0.0001) without changing plasma symmetric dimethylarginine. Compared with nontargeted control small-interference RNA, knock down of DDAH-1 in mice by 60% with targeted small-interference RNAs (siRNA) reduced Jv by 29 +/- 5% (nontargeted siRNA: 2.8 +/- 0.20 vs. DDAH-1 knockdown: 1.9 +/- 0.31 nl.min-1.mm-1, P < 0.05). In conclusion, fluid reabsorption in the proximal tubule is reduced by tubular ADMA or by blocking its metabolism by DDAH 1. L-257 is a novel regulator of proximal tubule fluid reabsorption. PMID- 29513071 TI - Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening, highly prevalent monogenic disease caused by mutations in polycystin-1 (PC1) in 85% of patients. We have previously identified a COOH-terminal cleavage fragment of PC1, PC1-p30, which interacts with the transcription factor STAT6 to promote transcription. STAT6 is aberrantly active in PKD mouse models and human ADPKD, and genetic removal or pharmacological inhibition of STAT6 attenuates disease progression. High levels of IL-13, a STAT6-activating cytokine, are found in the cyst fluid of PKD mouse models and increased IL-13 receptors in ADPKD patient tissue, suggesting that a positive feedback loop exists between IL-13 and STAT6 is activated in cystic epithelial cells and contributes to disease progression. In this study, we aimed to identify genes aberrantly regulated by STAT6 to better understand how increased IL-13/STAT6 signaling may contribute to PKD progression. We demonstrate that the expression of periostin, galectin-3, and IL-24 is upregulated in various forms of PKD and that their aberrant regulation is mediated by IL-13 and STAT6 activity. Periostin and galectin-3 have previously been implicated in PKD progression. We support these findings by showing that periostin expression is increased after IL-13 treatment in kidney epithelial cells, that galectin-3 expression is increased after injecting IL-13 in vivo and that IL-24 expression is upregulated by both IL-13 treatment and PC1-p30 overexpression in mouse and human kidney cells. Overall, these findings provide insight into the possible mechanisms by which increased IL-13/STAT6 signaling contributes to PKD progression and suggest potential therapeutic targets. PMID- 29513074 TI - Triptolide delays disease progression in an adult rat model of polycystic kidney disease through the JAK2-STAT3 pathway. AB - The aim of our current study was to investigate the long-term effect and the mechanism of triptolide in an adult nonorthologous rat model of polycystic kidney disease (PKD). Male wild-type (+/+) and Cy/+ cystic Han:SPRD rats were treated with vehicle or triptolide from 4 to 16 wk of age. Rats were killed at 16 wk of age for blood, urine, and organ collection. Human-derived WT9-12 PKD cells were treated with triptolide with or without IL-6 pretreatment. Cell proliferation, apoptosis, and cytotoxicity were determined. Western blotting and immunohistochemistry analysis were performed to evaluate the activation of IL-6 JAK2-STAT3 pathway. Renal function was protected by 12 wk of triptolide treatment in cystic Han:SPRD rats as shown by reduced blood urea nitrogen, serum creatinine, and proteinuria levels. Cyst and kidney growth were also retarded by triptolide treatment in Cy/+ rats. We further found that the proliferation index was reduced by triptolide in cystic rats, which was correlated with the reduced expression of IL-6/IL-6 receptor, decreased phosphorylation of JAK2-STAT3, and increased expression of suppressor of cytokine signaling 3 (SOCS3). The inhibitory effect of triptolide was further studied in WT9-12 cells. Triptolide inhibited cell proliferation and the activation of JAK2-STAT3 pathway in PKD cells, but it increased the expression of SOCS3. Pretreatment with IL-6 attenuated the inhibitory effect of triptolide on STAT3 phosphorylation. Our study revealed a long-term beneficial effect of triptolide in PKD that was probably through inhibition of the JAK2-STAT3 pathway. PMID- 29513075 TI - Understanding health food messages on Twitter for health literacy promotion. AB - AIMS: With the popularity of social media, Twitter has become an important tool to promote health literacy. However, many health-related messages on Twitter are dead-ended and cannot reach many people. This is unhelpful for health literacy promotion. This article aims to examine the features of online health food messages that people like to retweet. METHODS: We adopted rumour theory as our theoretical foundation and extracted seven characteristics (i.e. emotional valence, attractiveness, sender's authoritativeness, external evidence, argument length, hashtags, and direct messages). A total of 10,025 health-related messages on Twitter were collected, and 1496 messages were randomly selected for further analysis. Each message was treated as one unit and then coded. All the hypotheses were tested with logistic regression. RESULTS: Emotional valence, attractiveness, sender's authoritativeness, argument length, and direct messages in a Twitter message had positive effects on people's retweet behaviour. The effect of external evidence was negative. Hashtags had no significant effect after consideration of other variables. CONCLUSION: Online health food messages containing positive emotions, including pictures, containing direct messages, having an authoritative sender, having longer arguments, or not containing external URLs are more likely to be retweeted. However, a message only containing positive or negative emotions or including direct messages without any support information will not be retweeted. PMID- 29513076 TI - Occult teratoma in a case of N-methyl-D-aspartate receptor encephalitis. AB - N-methyl-D-aspartate receptor encephalitis (NMDARe) is one of 13 autoimmune mediated encephalitides that have been discovered over the last decade. This case report describes the course of a 26-year-old female who presented with new-onset seizures and insomnia, complicated by encephalitis. The initial workup ruled out common causes of encephalitis, while a transvaginal ultrasound (TVUS), and computed tomography (CT) scans of the chest, abdomen, and pelvis did not identify a mass. Based on the suspicion that she may have autoimmune encephalitis, the patient was treated with intravenous immunoglobulins and plasma exchange, but continued to deteriorate. Whole-body positron emission tomography (PET) scan identified a small hypermetabolic pelvic mass. Shortly thereafter serum and cerebral spinal fluid NMDAR antibody titers were reported as positive, prompting repetition of the TVUS, which confirmed the presence of an ovarian teratoma. The patient had a laparoscopic oophorectomy with subsequent resolution of her symptoms, further confirming the diagnosis. Despite the sensitivities of TVUS and CT of up to 94% and 98%, respectively, the teratoma was unusually small, necessitating the addition of a PET scan to identify the lesion. These neoplasms are thought to have low uptake on PET; however, it is possible that focal inflammation may have enhanced the detection. It is unlikely that the teratoma grew during hospitalization as the average growth rate is 1.8 mm per year. Regardless, the lesson that can be learned is that imaging modalities beyond CT and TVUS, such as PET, can be helpful, as identification of a resectable tumor may alter management and ultimately improve outcomes. PMID- 29513077 TI - Re-treatment of residual aneurysms after flow diversion: An experimental study. AB - Aim Flow diverters are increasingly used to treat aneurysms, but treatment is not always effective. The management of aneurysms that fail to occlude following flow diversion is problematic. We aimed to reproduce failures in an animal model and study re-treatment with additional flow diverters alone or with flow diverters and liquid embolic agent. Material and methods Twenty wide-necked aneurysms were created at the carotid-lingual bifurcation in 10 dogs, and were treated with flow diverters 4-6 weeks later. Follow-up angiography was performed at three months. Suitable residual aneurysms were randomly allocated: re-treatment with flow diverters alone ( n = 6), or with the injection of liquid embolic between two layers of flow diverters ( n = 4) or no re-treatment ( n = 2). Angiography was repeated three months later, followed by euthanasia, photography and pathology. Results Patent wide-necked aneurysms were produced in 17/20 attempts (85%); three months after flow diversion there were 15/17 (88%) residual aneurysms. In three cases, re-treatment was not possible because the flow diverter had prolapsed into the aneurysm, leaving 12 aneurysms to study. Re-treated aneurysms showed improved angiographic results at six months (median score of 2; P = 0.03), but residual aneurysms were present in all cases. Parent artery occlusion occurred in two aneurysms treated with flow diverter plus liquid embolic. At pathology, aneurysms were only partially filled with thrombus; leaks through the flow diverters were found in the neointima connecting the arterial lumen to residual aneurysms. Conclusion Re-treatment of residual flow-diverted experimental aneurysms with additional flow diverters did not lead to aneurysm occlusion. PMID- 29513078 TI - Early childhood trauma in high-risk families: associations with caregiver emotional availability and insightfulness, and children's social information processing and social behavior. AB - The links between exposure to adverse childhood experiences (ACEs), caregiver insightfulness and emotional availability, and the child's social information processing (SIP) and social behavior were examined in a sample of 15 preschool children enrolled in a Therapeutic Nursery Program (TNP). Children are typically referred to the TNP due to significant delays in their social emotional development that often result in difficulty functioning in typical childcare, home, and community settings. Caregiver insightfulness was measured via an interview with the caregiver. Emotional availability was coded based on observations of caregiver-child interactions. The child's SIP patterns were measured in an interview, and the child's behavior in preschool was assessed by teacher reports. Higher levels of exposure to ACE were hypothesized to be related to lower levels of caregiver emotional availability and insightfulness and to higher levels of the children's perceptual (i.e. SIP) and behavioral maladjustment. It was also hypothesized that caregiver emotional availability and insightfulness would be associated with one another and significantly associated with children's perceptions and behaviors. Caregivers reporting higher levels of exposure exhibited lower levels of insightfulness and emotional availability. No such associations were found between the child's exposure to ACE and the caregivers' perceptions and behaviors. In addition, more insightful caregivers showed higher levels of emotional availability. Finally, children with more emotionally available caregivers showed more competent SIP and social behavior. PMID- 29513079 TI - Executive, language, or both? An examination of the construct validity of verbal fluency measures. AB - The purpose of the present study was to evaluate whether phonemic and semantic verbal fluency were more related to aspects of language processing than executive functioning (EF). An exploratory factor analysis was performed on a college-aged sample of 320 healthy participants using principle axis factoring and promax rotation on nine measures of EF. The first three factors, labeled: working memory, fluid reasoning, and shifting/updating, were extracted and used as latent executive variables. Participants were also split into low, medium, and high phonemic and semantic verbal fluency ability groups. Phonemic and semantic fluency correlated similarly across all three extracted EF factors and word knowledge. Using one-way analysis of variance (ANOVAs), there was a main effect for both phonemic and semantic verbal fluency groups and all outcome variables (i.e., the EF factors and word knowledge). Tukey HSD post hoc analyses showed that those in the low verbal fluency ability groups had significantly lower scores across all outcome measures compared to the high verbal fluency ability groups. Across all analyses, semantic fluency had stronger relations with the EF factors, signifying a large executive component involved in the task. Both phonemic and semantic fluency were similarly related to multiple dimensions of EF and word knowledge and should be considered executive language tasks. PMID- 29513080 TI - Synthesis and inhibitory activity of deoxy-d-allose amide derivative against plant growth. AB - 1,2,6-Trideoxy-6-amido-d-allose derivative was synthesized and found to exhibit higher growth-inhibitory activity against plants than the corresponding deoxy-d allose ester, which indicates that an amide group at C-6 of the deoxy-d-allose amide enhances inhibitory activity. In addition, the mode of action of the deoxy d-allose amide was significantly different from that of d-allose which inhibits gibberellin signaling. Co-addition of gibberellin GA3 restored the growth of rice seedlings inhibited by the deoxy-d-allose amide, suggesting that it might inhibit biosynthesis of gibberellins in plants to induce growth inhibition. PMID- 29513081 TI - Implementacion de un modelo de capacitacion multimedial para brindar orientacion alimentaria a los beneficiarios de un programa de ayuda social en Mexico. AB - Introduccion: Se implemento un modelo de capacitacion en orientacion alimentaria para la poblacion beneficiaria y el personal operativo del Programa de Abasto Rural (PAR) de Diconsa, el cual es una iniciativa social de ayuda alimentaria que abastece productos basicos y complementarios, ademas de brindar capacitacion en localidades de alta marginacion en Mexico. Objetivo: Documentar la utilizacion de la Metodologia de Capacitacion Multimedial (MCM) en el desarrollo de un esquema de capacitacion sobre orientacion alimentaria y su implementacion en la poblacion beneficiaria del PAR, a traves de la propia estructura operativa del PAR. Metodologia: El modelo se fundamenta en la MCM, integrada por cuatro elementos didacticos e indivisibles que conforman el paquete pedagogico multimedial (PPM), compuesto a su vez por tres videos y rotafolios, material impreso, practicas y las relaciones interpersonales. Los ejes tematicos fueron: alimentacion correcta para una vida saludable, alimentacion materno-infantil, elecciones saludables y gasto familiar. El modelo fue replicado en cascada en los tres niveles operativos del PAR (responsables de capacitacion, supervisores operativos y beneficiarios del PAR), con un componente de multiplicacion horizontal, e implementado como piloto en cuatro estados de Mexico. Resultados: Se observo un cambio positivo sobre los conocimientos en alimentacion correcta en todos los niveles de capacitacion, principalmente en los beneficiarios del PAR. La evaluacion del proceso mostro conocimientos previos de los responsables de capacitacion en los temas, buen desempeno como facilitadores, y habilidades de presentacion y manejo del grupo de los supervisores operativos. A partir de las evaluaciones y del acompanamiento en la prueba piloto, fueron modificados las actividades, las estrategias y los materiales educativos del PPM. Conclusiones: La capacitacion multimedial y la educacion nutricional promueven procesos de cambio y desarrollo comunitario, posibles a traves de la toma de conciencia y la puesta en practica de acciones que favorecen la salud. PMID- 29513083 TI - Multicenter Assessment of Antibiotic Prophylaxis Spectrum on Surgical Infections in Head and Neck Cancer Microvascular Reconstruction. AB - Objective To characterize and identify risk factors for 30-day surgical site infections (SSIs) in patients with head and neck cancer who underwent microvascular reconstruction. Study Design Cross-sectional study with nested case control design. Setting Nine American tertiary care centers. Subjects and Methods Hospitalized patients were included if they underwent head and neck cancer microvascular reconstruction from January 2003 to March 2016. Cases were defined as patients who developed 30-day SSI; controls were patients without SSI at 30 days. Postoperative antibiotic prophylaxis (POABP) regimens were categorized by Gram-negative (GN) spectrum: no GN coverage, enteric GN coverage, and enteric with antipseudomonal GN coverage. All POABP regimens retained activity against anaerobes and Gram-positive bacteria. Thirty-day prevalence of and risk factors for SSI were evaluated. Results A total of 1307 patients were included. Thirty day SSI occurred in 189 (15%) patients; median time to SSI was 11.5 days (interquartile range, 7-17). Organisms were isolated in 59% of SSI; methicillin resistant Staphylococcus aureus (6%) and Pseudomonas aeruginosa (9%) were uncommon. A total of 1003 (77%) patients had POABP data: no GN (17%), enteric GN (52%), and antipseudomonal GN (31%). Variables independently associated with 30 day SSI were as follows: female sex (adjusted odds ratio [aOR], 1.6; 95% CI, 1.1 2.2), no GN POABP (aOR, 2.2; 95% CI, 1.5-3.3), and surgical duration >=11.8 hours (aOR, 1.9; 95% CI, 1.3-2.7). Longer POABP durations (>=6 days) or antipseudomonal POABP had no association with SSI. Conclusions POABP without GN coverage was significantly associated with SSI and should be avoided. Antipseudomonal POABP or longer prophylaxis durations (>=6 days) were not protective against SSI. Antimicrobial stewardship interventions should be made to limit unnecessary antibiotic exposures, prevent the emergence of resistant organisms, and improve patient outcomes. PMID- 29513082 TI - Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation. AB - Endocrine disrupting chemicals (EDCs) pose a public health risk through disruption of normal biological processes. Identifying toxicoepigenetic mechanisms of developmental exposure-induced effects for EDCs, such as phthalates or bisphenol A (BPA), is essential. Here, we investigate whether maternal exposure to EDCs is predictive of infant DNA methylation at candidate gene regions. In the Michigan Mother-Infant Pairs (MMIP) cohort, DNA was extracted from cord blood leukocytes for methylation analysis by pyrosequencing (n = 116) and methylation changes related to first trimester levels of 9 phthalate metabolites and BPA. Growth and metabolism-related genes selected for methylation analysis included imprinted (IGF2, H19) and non-imprinted (PPARA, ESR1) genes along with LINE-1 repetitive elements. Findings revealed decreases in methylation of LINE-1, IGF2, and PPARA with increasing phthalate concentrations. For example, a log unit increase in SigmaDEHP corresponded to a 1.03 [95% confidence interval (CI): -1.83, -0.22] percentage point decrease in PPARA methylation. Changes in DNA methylation were also inversely correlated with PPARA gene expression determined by RT-qPCR (r = -0.34, P = 0.02), thereby providing evidence in support of functional relevance. A sex-stratified analysis of EDCs and DNA methylation showed that some relationships were female-specific. For example, urinary BPA exposure was associated with a 1.35 (95%CI: -2.69, -0.01) percentage point decrease in IGF2 methylation and a 1.22 (95%CI: -2.27, -0.16) percentage point decrease in PPARA methylation in females only. These findings add to a body of evidence suggesting epigenetically labile regions may provide a conduit linking early exposures with disease risk later in life and that toxicoepigenetic susceptibility may be sex specific. PMID- 29513084 TI - Barriers to Advance Care Planning in End-Stage Renal Disease: Who is to Blame, and What Can be Done? AB - Patients with end-stage renal disease experience significant mortality and morbidity, including cognitive decline. Advance care planning has been emphasized as a responsibility and priority of physicians caring for patients with chronic kidney disease in order to align with patient values before decision-making capacity is lost and to avoid suffering. This emphasis has proven ineffective, as illustrated in the case of a patient treated in our hospital. Is this ineffectiveness a consequence of failure in the courtroom or the clinic? Through our own experience we affirm what has been written before: that legal precedent favors intensive treatment in virtually all cases without 'clear and convincing evidence' of a patient's previously declared wishes to the contrary. Equally clear is that more than 20 years of support in the clinical literature suggesting advance care planning early in the course of disease can address challenges in the legal system for those lacking capacity. However, many physicians fail to recognize the need for advance care planning in a timely manner and lack the necessary training to provide it. The need for more training and new tools to recognize opportunities for advance care planning in daily practice remains unmet. PMID- 29513085 TI - The prognostic impact of long noncoding RNA HOTAIR in leukemia and lymphoma: a meta-analysis. AB - OBJECTIVES: Multiple studies have shown that the expression level of Homeobox (HOX) transcript antisense RNA (HOTAIR) has a correlation with the diagnosis and prognosis of acute leukemia (AL) and lymphoma. The prognostic significance of HOTAIR on AL and lymphoma has been controversial. Our study thus was performed to further reveal its prognostic value in leukemia and lymphoma. METHODS: By literature searching in some common electronic databases, five studies covering a number of 531 patients were included in this meta-analysis. We extracted useful data to calculate the pooled hazard ratio (HR) and p-value. RESULTS: The combined HR estimated for overall survival (OS) was 1.87 (95% confidence interval (CI): 1.03-3.47; p = .041) when comparing patients with high HOTAIR with those low. For event/disease/relapse-free survival, the HR was 1.53 (95%CI: 0.58-4.06; p = .39). Subgroup analyses showed that the HR for OS was 2.32 (95%CI: 1.56-3.44; p = .000) in patients with AL and 1.24 (95%CI: 0.21-7.45; p = .817) in lymphoma. Additionally, the Ann-Arbor stage (p = .0009) and the international prognostic index score (p = .0065) were found to be statistically significant between patients with high and low HOTAIR expression. Also, the hemoglobin (HGB) level (p = .008), platelet (PLT) count (p = .001) and blasts in bone marrow (p = .001), but not the French-American-British classification, were found statistically significant. DISCUSSION: Although our analysis has its limitation, it showed that high expression of HOTAIR had a significantly inferior impact on OS and some clinical parameter of leukemia and lymphoma patients. CONCLUSION: HOTAIR played an important prognostic role in leukemia and lymphoma and might serve as a potential target for therapeutic intervention in those patients. PMID- 29513086 TI - Challenges in chemotherapy delivery: comparison of standard chemotherapy delivery to locoregional vascular mass fluid transfer. AB - Standard intravenous chemotherapy delivery to neoplasms relies on simple diffusion gradients from the intravascular to the interstitial space. Systemic perfusion creates untoward effects on normal tissue limiting both concentration and exposure times. Regional intra-arterial therapy is limited by drug recirculation and vascular isolation repeatability and does not address the interstitial microenvironment. Barriers to delivery relate to chaotic vascular architecture, heterogeneous fluid flux, increased interstitial and variable solid tumor pressure and ischemia. To address these difficulties, a delivery system was developed allowing mass fluid transfer of chemotherapeutic agents into the interstitium. This implantable, reusable system is comprised of multiple independently steerable balloons and catheters capable of controlling the locoregional hydraulic and oncotic forces across the vascular endothelium. PMID- 29513087 TI - Nutrient removal from piggery wastewater by Desmodesmus sp.CHX1 and its cultivation conditions optimization. AB - Combination of microalgae cultivation and piggery wastewater treatment has become a hot topic in recent years. Nutrient removal from aerated piggery wastewater (APW) by Desmodesmus sp. CHX1 and the optimization of cultivation conditions were investigated in this study. Results indicated that Desmodesmus sp. CHX1 showed an efficient growth in APW, with specific growth rate of 0.26-0.56 d-1. The biomass yield based on nutrient consumption was 9.65 g biomass/g NH4-N and 209.15 g biomass/g total phosphorus (TP) respectively. Desmodesmus sp. CHX1 performed well in nutrient removal from APW, with ammonium nitrogen (NH4-N) and TP removal efficiency (RE) of 78.46% and 91.66% respectively after 7 days of culture. Nutrient removal process fitted the pseudo-first-order kinetic equations well, with removal rate (RR) constant of 0.24 d-1 for NH4-N and 0.28 d-1 for TP. The optimum conditions for nutrient removal from APW by Desmodesmus sp. CHX1 were light intensity of 150 MUmol photons m-2 s-1 in the photoperiod for 24 h when the temperature was set at 35 degrees C with alga cell inoculation concentration of 30%. The removal efficiencies of NH4-N and TP were 88.26% and 95.06% respectively under the optimal conditions after 7 days of culture. Our results can be a good reference for enhancement of microalga production and the nutrient RE and further extend the application of the large-scale piggery wastewater treatment under a controlled environment. PMID- 29513088 TI - Ingestion of coffee polyphenols suppresses deterioration of skin barrier function after barrier disruption, concomitant with the modulation of autonomic nervous system activity in healthy subjects. AB - The aim of this study was to evaluate the effect of consumption of coffee polyphenols (CPPs) on the autonomic nervous system activity and decreased skin barrier function caused by sodium dodecyl sulfate (SDS) treatment. In this single blind, placebo-controlled study, ten healthy male subjects consumed either a beverage containing CPPs or a placebo beverage for four weeks. CPPs significantly suppressed the deterioration in skin barrier function and skin moisture content induced by SDS treatment after the third week. Furthermore, in the heart rate variability analysis, CPPs significantly produced an increase in parasympathetic nervous activity, and a decrease in sympathetic nervous activity after the four weeks of beverage consumption. These results suggest that CPPs might influence the regulation of the autonomic nervous system and contribute to the suppressive effect on deterioration of skin barrier function. PMID- 29513090 TI - Nigericin and grisorixin methyl ester from the Algerian soil-living Streptomyces youssoufiensis SF10 strain: a computational study on their epimeric structures and evaluation of glioblastoma stem cells growth inhibition. AB - The present work describes the metabolites produced by a strain identified as Streptomyces youssoufiensis, whose secondary metabolites profile has not been studied so far. The crude ethyl acetate extract was analyzed by high performance liquid chromatography-electrospray ionization mass spectrometry, leading to the detection of the ionophoric polyethers nigericin, epinigericin, abierixin and the newly isolated grisorixin methyl ester. The presence of epimeric forms of nigericin/epinigericin and grisorixin/epigrisorixin has spurred density functional theory computational calculations. This analysis was able to provide the relative stability of the most favored epimers, setting the basis for general structural considerations applicable to several other polyethers. Both nigericin sodium salt and grisorixin methyl ester showed to affect glioblastoma stem cells proliferation in a dose-dependent manner, with a higher activity for the more lipophilic grisorixin methyl ester (GI50 values of 3.85 and 3.05 MUM for VIPI and COMI human glioblastoma stem cells, respectively). PMID- 29513091 TI - The Impact of Intimate Partner Violence Exposure in Adolescence and Emerging Adulthood: A Developmental Psychopathology Approach. AB - Despite increased attention on parental intimate partner violence (IPV) exposure, a relative paucity of research has examined the developmental consequences of this traumatic experience within a life span approach. The aim of the present study was to examine how parental IPV exposure may relate to mental health during the transition from adolescence to emerging adulthood. Furthermore, we examined whether the impact of parental IPV exposure was unique from more commonly studied maltreatment experiences, specifically neglect and physical abuse. A large, racially and ethnically diverse sample (Nbaseline = 1,042; 56% female; Mage = 15.1, SD = 0.79; 31.4% Hispanic, 29.4% White, 27.9% African American, 3.6% Asian, 7.7% biracial or other) of adolescents completed a baseline assessment for parental physical IPV exposure and maltreatment as well as measures for symptoms of depression, posttraumatic stress, and substance use, annually for 6 consecutive years. Mixed-level modeling was used to examine how parental IPV exposure was uniquely associated with different patterns of mental health across developmental epochs. Findings demonstrated a multifaceted relation with mental health. For internalizing symptoms, the effect was pronounced during adolescence, and neglect increased the risk for depression symptomatology. Meanwhile, parental IPV-exposed adolescents were at increasing risk for substance use as they aged into adulthood. Symptom levels and trajectories were independent and distinct from maltreatment experiences. This study helps illuminate parental IPV exposure's unique influence on well-being during vulnerable developmental periods. It also calls attention to the importance of developing suitable intervention/prevention programs to target this vulnerable population. PMID- 29513089 TI - An empirical assessment of the short-term impacts of a reading of Deborah Zoe Laufer's drama Informed Consent on attitudes and intentions to participate in genetic research. AB - OBJECTIVE: This study assessed the short-term impact of the play "Informed Consent" by Deborah Zoe Laufer (a fictionalized look at the controversy over specimens collected from the Havasupai Tribe for diabetes research in 1989) on perceptions of trust, willingness to donate biospecimens, and attitudes toward harm and privacy among the medical and undergraduate students, faculty, and the public in the Intermountain West. METHODS: Surveys were administered before and after a staged reading of the play by professional actors. Survey items included the short form Trust in Medical Researchers, and single-item questions about group identity, ethics of genetic testing in children, and willingness to donate biospecimens. In addition, respondents were given the option to answer open-ended questions through e-mail. RESULTS: Out of the 481 who attended the play, 421 completed both the pre and post surveys, and 166 participants completed open ended questions online approximately 1 week after the play. Across all participants, there were significant declines for trust in medical researchers and for the survey item "is it ethical for investigators to test children for adult onset diseases" (p < .001 for both) following the play. There was a significant increase in agreement to improve group identity protections (p < .001) and there were no differences on willingness to donate biospecimens to research (p = .777). Qualitative data provided extensive contextual data supporting these perspectives. DISCUSSION: This is one of the first studies to document short-term impacts of a theatrical performance on both attitudes and behavioral intentions toward research ethics and clinical research participation. Future research should continue to explore the impact of theatrical performances among public and investigators on the ethical issues and complexities in clinical research. PMID- 29513092 TI - Effects of Aerobic Exercise on Cognitive Performance Among Young Adults in a Higher Education Setting. AB - PURPOSE: Acute benefits of aerobic exercise on executive functioning have been reported frequently under laboratory conditions. However, to date, a beneficial effect on long-term memory has been less well supported and no data are available regarding nonlaboratory conditions in young adults. The aim of the current study was to investigate acute effects of aerobic exercise on cognitive functioning in a university classroom setting. METHOD: Using a cross-over design, 51 participants performed a bout of moderately intense running (RUN) and read an article while seated (CON). Afterwards, they completed free-recall tests, followed by a Flanker task and an n-back task. RESULTS: Participants in the RUN condition compared with those in the CON condition showed shorter reaction time on the inhibition task, F(1, 50) = 5.59, p = .022, eta2 = .101, and recalled more words in the immediate- and delayed-recall tests, F(1, 50) = 8.40, p = .006, eta2 = .144. CONCLUSION: The present findings suggest that a moderately intense bout of aerobic exercise benefits verbal short-term and long-term memory as well as inhibitory control among students in a classroom setting. PMID- 29513093 TI - Kicking Performance in Young U9 to U20 Soccer Players: Assessment of Velocity and Accuracy Simultaneously. AB - PURPOSE: The purpose of this study was to compare the kicking performance of young soccer players in the U9 to U20 age groups. METHOD: Three hundred and sixty six Brazilian players were evaluated on an official pitch using three-dimensional kinematics to measure (300 Hz) ball velocity (Vball), foot velocity (Vfoot), Vball/Vfoot ratio, last stride length, and distance between the support foot and the ball. Simultaneously, a two-dimensional procedure was also conducted to compute (60 Hz) the mean radial error, bivariate variable error, and accuracy. Possible age-related differences were assessed through one-way analysis of variance and magnitude-based inferences. RESULTS: Ball velocity increased by 103% (p < .001, eta2 = .39) from the U11 age group (48.54 +/- 8.31 km/hr) to the U20 age group (98.74 +/- 16.35 km/hr). Foot velocity presented a 59% increase (p < .001, eta2 = .32) from the U11 age group (49.08 +/- 5.16 km/hr) to U20 (78.24 +/- 9.49 km/hr). This finding was due to improvement in the quality of foot-ball impact (Vball/Vfoot ratio) from U11 (0.99 +/- 0.13 a.u.) to U20 (1.26 +/- 0.11 a.u.; p < .001, eta2 = .25). Parameters such as mean radial error and accuracy appeared to be impaired during the growth spurt (U13-U15). Last stride length was correlated, low to moderately high, with Vball in all age groups (r = .36-.79). CONCLUSIONS: In summary, we concluded that simple biomechanical parameters of kicking performance presented distinct development. These results suggest that different training strategies specific for each age group could be applied. We provide predictive equations to aid coaches in the long-term monitoring process to develop the kick in soccer or search for talented young players. PMID- 29513094 TI - Haematemesis related to orthodontic treatment with Nance palatal arch: a case report. AB - Haematemesis is a worrying sign, generally related to acute upper gastrointestinal bleeding and potentially life-threatening condition. We present a case of a 15-year-old Caucasian girl who was belatedly diagnosed with oral bleeding because it was not related to the most common aetiologic factors. In fact, she was undergoing orthodontic treatment with a Nance palatal arch, an appliance used to reinforce anchorage during teeth movements. In her case haematemesis was a sign of inflammation and necrosis occurring in the palatal mucosa, under the acrylic button of palatal arch. The appliance was removed; antibiotic and Chlorhexidine 0.12% were recommended. After a 6-week follow-up, no pathological signs were present and the orthodontic treatment was resumed. Both physicians and dentists should be aware of the possible side effect of the Nance palatal arch use; this could help in achieving a diagnosis and providing a correct treatment. Orthodontists should avoid excessive compression over the palatal mucosa and check the appliance condition during every follow-up in order to avoid necrosis of the palatal mucosa. PMID- 29513095 TI - Catalytic efficiency of laterite-based FeNPs for the mineralization of mixture of herbicides in water. AB - In this work, low cost, locally available laterite-based iron nanoparticles were synthesized using Tectona Grandis extract (Teak extract) with an average size of 75 nm. The synthesized FeNPs were applied as a heterogeneous Fenton catalyst for the oxidation of mixture herbicides, namely ametryn, dicamba and 2,4-D in water. The FeNPs were characterized for various analytical methods (field emission scanning electron microscopy-X-ray energy-dispersive spectrophotometer, XRD, FTIR and BET) and the effect of different variables (FeNPs dosage, H2O2, pH) was studied using the responses surface methodology. The initial herbicide concentration was considered as 25, 3.5 and 94 mg L-1 for 2,4-D, ametryn and dicamba, respectively, with the COD value of 172 mg L-1. The 100% degradation and mineralization was achieved in 135 min and >85% in 45 min (optimum dosage: FeNPs = 25.29 mg L-1, H2O2 = 430 mg L-1 and pH = 5). The degradation kinetics were performed for both pseudo-first order and second order, it was observed that first-order kinetics (R2 > 0.85) was well fitted in the treatment process. Recycling of FeNPs in five cycles was performed at optimum conditions and 10-40% of reduction in degradation efficiency was achieved. Finally, the whole treatment process was validated with a contour overlay plot and analysis of variance. PMID- 29513096 TI - Patients with liver cirrhosis show worse survival if decompensation occurs later during course of disease than at diagnosis. AB - OBJECTIVES: Liver cirrhosis is characterized by a silent phase until decompensation, which is defined by onset of ascites, variceal bleeding, or encephalopathy. Although it is presumed that the survival of decompensated patients is the same regardless of when decompensation occurs, data to support this are scarce. We aimed to study the impact of time of decompensation on the clinical course and survival of patients with cirrhosis in a large population based cohort. MATERIALS AND METHODS: We used medical registries to define a 10 year cohort of 1317 patients with incident liver cirrhosis in the Scania region of Sweden. Medical records were reviewed. Patients were followed until December 2011, and for death or transplantation until December 2014. RESULTS: In the cohort, 629 patients were decompensated at diagnosis, of which 505 had ascites and 44 variceal bleeding only. During follow-up, 228 patients developed ascites and 39 variceal bleeding as first complication. Patients with ascites as first complication showed worse survival than patients who had ascites at diagnosis. (5 year survival 33% vs. 15%, HR 1.60 (95% CI 1.34-1.90)). This difference persisted after adjustment for confounders, including hepatocellular cancer (HR 1.38 (95% CI 1.15-1.67)). Worse survival was also seen when bleeding from varices occurred during follow-up rather than at diagnosis. CONCLUSIONS: Our results provide evidence for an association between transplantation-free survival after decompensation and the time of decompensation in liver cirrhosis, with worse survival when decompensation occurs during follow-up, thus challenging the generally held, view that the survival after decompensation is independent of when decompensation occurs. PMID- 29513097 TI - Leisure and health benefits among Korean adolescents with visual impairments. AB - PURPOSE: The purpose of the study was to explore health benefits through leisure engagement among Korean adolescents with visual impairments. METHOD: Using semi structured interviews, a total of 14 adolescents with visual impairments participated in this study. RESULTS: Two salient themes were captured as health benefits as a result of leisure engagement: psychological wellbeing and personal growth. CONCLUSIONS: The findings suggest that leisure provides a venue for the development of self-expression, leisure skills, perseverance, and positive affects. It also indicates that leisure can serve as a vehicle for promoting health and life satisfaction among Korean adolescents with visual impairments. PMID- 29513098 TI - Five-year survival, disability, and recurrence after first-ever stroke in a middle-income country: A population-based study in Joinvile, Brazil. AB - Background Information about long-term outcomes after stroke in developing countries provided by population-based methodologies is scarce. Aim This study aimed to know outcomes five years after a first-ever stroke in Joinville, Brazil. Methods Data were extracted from the Joinville Stroke Registry about all patients who had strokes in Joinville in 2010 and were followed up to 2015. Stroke recurrence, Kaplan-Meier survival probabilities, functional outcomes, and causes of death were ascertained at 30 days, six months, one and five years. Results A total of 399 strokes were studied. The mean age was 64 (standard deviation 16) years. After five years, 52% (95% confidence interval: 47-57%) survived and 20% (95% confidence interval: 15-26%) of the survivors had modified Rankin scale scores >2. More than half of these patients were institutionalized in nursing or home care settings. The average risk of death per year was ~7%. Survival rates were significantly lower for subarachnoid hemorrhage and primary intracerebral hemorrhage than for ischemic stroke. The five-year recurrence rate was 12% (95% confidence interval: 9-15%). The index stroke was the cause of death in three quarters of the patients. Conclusions The results showed that 68% of the patients with stroke were either dead or disabled five years after first-ever stroke. This percentage is similar to proportions of other recent cohorts from developed countries, despite the lower age of the patients in this study. PMID- 29513099 TI - Application of Monte Carlo cross-validation to identify pathway cross-talk in neonatal sepsis. AB - To explore genetic pathway cross-talk in neonates with sepsis, an integrated approach was used in this paper. To explore the potential relationships between differently expressed genes between normal uninfected neonates and neonates with sepsis and pathways, genetic profiling and biologic signaling pathway were first integrated. For different pathways, the score was obtained based upon the genetic expression by quantitatively analyzing the pathway cross-talk. The paired pathways with high cross-talk were identified by random forest classification. The purpose of the work was to find the best pairs of pathways able to discriminate sepsis samples versus normal samples. The results found 10 pairs of pathways, which were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways were identified according to analysis of extensive literature. Impact statement To find the best pairs of pathways able to discriminate sepsis samples versus normal samples, an RF classifier, the DS obtained by DEGs of paired pathways significantly associated, and Monte Carlo cross-validation were applied in this paper. Ten pairs of pathways were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways ((7) IL-6 Signaling and Phospholipase C Signaling (PLC); (8) Glucocorticoid Receptor (GR) Signaling and Dendritic Cell Maturation) were identified according to analysis of extensive literature. PMID- 29513100 TI - Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice. AB - Low linoleic acid concentration is a common finding in patients with cystic fibrosis and associated with severe clinical phenotype. Low docosahexaenoic and arachidonic acids are more inconsistently found in patients, but arachidonic/docosahexaenoic ratio is usually high. In animal models with cftr mutations or KO animals for the cftr gene, linoleic acid deficiency has not been consistently reported and some report docosahexaenoic deficiency as the major fatty acid abnormality. We hereby describe fatty acid profile in a severe clinical cystic fibrosis phenotype in mice with a duplication of exon 3 generated in the cystic fibrosis gene of C57B1/6J mice ( cftrm1Bay allele). In 43/50 animals, plasma phospholipid fatty acids were repeatedly analyzed (mean three times/animal) covering ages between 7 and 235 days. Linoleic acid concentrations were significantly lower in cftr-/- mice compared to heterozygotes ( P = 0.03) and wild type mice ( P < 0.001). Females had significantly lower linoleic acid than males, not related to age. Arachidonic acid did not differ but docosahexaenoic acid was higher in cftr-/- than in wild type mice ( P < 0.001). The arachidonic/docosahexaenoic acid ratio did not differ but arachidonic/linoleic acid ratio was higher in cftr-/- mice compared to wild type mice ( P = 0.007). Similar to clinical studies, type of mutation is important for lipid abnormality with low linoleic acid most consistently found in the animals. Rodents differ in metabolism by synthesizing docosahexaenoic acid more efficiently comparing to humans, suggesting greater influence by diet. Precaution seems important when comparing animal and humans. Impact statement In translational research, animal models are important to investigate the effect of genetic mutations in specific diseases and their metabolism. Special attention has to be given to differences in physiology and metabolism between species and humans, which otherwise can hazard the conclusions. Our work illustrates that the different synthesis capacity in mice and humans for DHA would explain different results in different models for cystic fibrosis and different influences of diets. To avoid disappointing clinical results, these facts have to be considered before extensive clinical studies are started based on results from single animal studies. PMID- 29513101 TI - RIP140/PGC-1alpha axis involved in vitamin A-induced neural differentiation by increasing mitochondrial function. AB - Vitamin A deficiency and mitochondrial dysfunction are both associated with neural differentiation-related disorders, such as Alzheimer's disease (AD) and Down syndrome (DS). The mechanism of vitamin A-induced neural differentiation and the notion that vitamin A can regulate the morphology and function of mitochondria in its induction of neural differentiation through the RIP140/PGC 1alpha axis are unclear. The aim of this study was to investigate the roles and underlying mechanisms of RIP140/PGC-1alpha axis in vitamin A-induced neural differentiation. Human neuroblastoma cells (SH-SY5Y) were used as a model of neural stem cells, which were incubated with DMSO, 9-cis-retinoic acid (9-cis RA), 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (at-RA). Neural differentiation of SH-SY5Y was evaluated by Sandquist calculation, combined with immunofluorescence and real-time polymerase chain reaction (PCR) of neural markers. Mitochondrial function was estimated by ultrastructure assay using transmission electron microscopy (TEM) combined with the expression of PGC-1alpha and NEMGs using real-time PCR. The participation of the RA signaling pathway was demonstrated by adding RA receptor antagonists. Vitamin A derivatives are able to regulate mitochondrial morphology and function, and furthermore to induce neural differentiation through the RA signaling pathway. The RIP140/PGC-1alpha axis is involved in the regulation of mitochondrial function in vitamin A derivative induced neural differentiation. PMID- 29513102 TI - Comparison of Salmonella Prevalence Rates in Bovine Lymph Nodes across Feeding Stages. AB - Peripheral lymph nodes (LNs) located in the fatty tissues of beef carcasses have been shown to harbor Salmonella and, thus, potentially contaminate ground beef. Salmonella prevalence within LNs is known to differ among feedlots. Two South Texas feeding operations (identified as locations A and B) known to harbor salmonellae in the feedlot environment, while historically producing cattle with opposing rates (one "high" and one "low") of Salmonella prevalence in LNs, were used in this study. To determine whether this difference was due to cattle source or factors associated with different stages of feeding, weanling steers of common and known origin were followed through normal feeding stages at both operations. Eighty Angus-sired beef steers were harvested at each of four feeding stages: 1, postweaning; 2, background or stocker; 3, 60 days on feed; and 4, 120 days on feed. Left and right subiliac and superficial cervical LNs ( n = 304) were collected from each carcass, and similar node types were pooled by animal ( n = 152). Results showed a difference ( P < 0.05) in prevalence of Salmonella in bovine lymph nodes between location A and location B and among feeding stages in location B. Salmonella was not isolated from any feeding stage 1 (postweaning) or location A LN samples. Within location B, there was an increase in Salmonella prevalence as cattle moved into later stages of feeding: at 22.2% (4 of 18), 77.8% (14 of 18), and 94.4% (17 of 18) for feeding stages 2, 3, and 4, respectively. Although the reasons for the differences seen between feeding operations and for increased Salmonella prevalence in LNs at later feeding stages remain unexplained, these results indicate that factors other than cattle source are likely influencing Salmonella prevalence in LNs. PMID- 29513103 TI - Characterization of Toxin Genes and Antimicrobial Susceptibility of Staphylococcus aureus from Retail Raw Chicken Meat. AB - The aim of this study was to investigate the toxin gene profile and antimicrobial resistance of Staphylococcus aureus isolates from raw chicken in the People's Republic of China. In total, 289 S. aureus isolates were characterized by antimicrobial susceptibility testing, and genes encoding enterotoxins, exfoliative toxins, Panton-Valentine leukocidin, and toxic shock syndrome toxin were revealed by PCR. Overall, 46.0% of the isolates were positive for one or more toxin genes. A high proportion of toxin genes were pvl (26.6%), followed by sej (12.5%), sea (9.0%), seh (8.3%), seb (6.9%), sec (6.9%), sed (4.8%), sei (3.1%), and see (2.4%). None of the isolates harbored seg, tsst-1, or exfoliative toxin genes. In total, 29 toxin gene profiles were obtained, and pvl (10.7%) was the most frequent genotype, followed by sea (5.9%), seb (4.8%), and sej (4.2%). Furthermore, 99.7% of the strains were resistant to at least one of the tested antimicrobial agents, and 87.2% of them displayed multidrug resistance. Resistance was most frequently observed to trimethoprim-sulfamethoxazole and erythromycin (86.2% for each), followed by tetracycline (69.9%), amoxicillin clavulanic acid (45.0%), and ampicillin (42.6%). None of the strains were resistant to vancomycin. This study indicates that S. aureus isolates from raw chicken harbored multiple toxin genes and exhibited multiple antimicrobial resistance, which represents a potential health hazard for consumers. PMID- 29513104 TI - Evaluation of Hot Water, Gaseous Chlorine Dioxide, and Chlorine Treatments in Combination with an Edible Coating for Enhancing Safety, Quality, and Shelf Life of Fresh-Cut Cantaloupes. AB - Fresh-cut cantaloupes have been implicated in numerous foodborne outbreaks of salmonellosis. Commercial aqueous wash treatments are limited in their ability to inactivate Salmonella enterica. Our objective was to evaluate the efficacy of hot water, gaseous chlorine dioxide, and chlorine on enhancing microbial safety and sensory qualities of fresh-cut cantaloupes. Cantaloupes were inoculated with an S. enterica cocktail (serovars Michigan, Mbandaka, and Poona) and treated with chlorine (200 ppm of free chlorine) for 40 min, 5 mg/L gaseous chlorine dioxide for 4.5 h, and hot water (76.1 degrees C) for 3 min. Fresh-cut cantaloupes were prepared from treated whole cantaloupes and divided into two sets; one set of samples was treated with NatureSeal to evaluate its effect on shelf life and sensory quality and the second set (control) was packed without further treatment. Fresh-cut samples were stored at 4 degrees C for up to 21 days. For the sensory quality parameters analyzed (color, water loss, and texture), the samples treated with NatureSeal had significantly better quality ( P < 0.05) than did the control samples. All treatments significantly reduced ( P < 0.05) the pathogen populations on the rind of the whole melons and on the fresh-cut samples prepared from the treated melons. All fresh-cut samples prepared from melons treated with hot water were negative for Salmonella throughout the storage period except for the samples treated with hot water and NatureSeal and evaluated on day 7. The fresh-cut samples prepared from melons treated with chlorine dioxide and chlorine were negative for Salmonella after 21 days of storage. These results provide a framework to producers of fresh-cut cantaloupes for the potential use of hot water as an intervention treatment in combination with NatureSeal for enhancing the microbiological safety and quality of this commodity. PMID- 29513105 TI - Survival of Salmonella during Production of Partially Sprouted Pumpkin, Sunflower, and Chia Seeds Dried for Direct Consumption. AB - Ready-to-eat foods based on dried partially sprouted seeds have been associated with foodborne salmonellosis. Whereas research has focused on the potential for Salmonella initially present in or on seeds to grow and survive during fresh sprout production, little is known about the potential for growth and survival of Salmonella associated with seeds that have been partially sprouted and dried. The goal of this study was to determine the growth of Salmonella during soaking for partial germination of pumpkin, sunflower, and chia seeds and subsequent survival during drying and storage. Pumpkin, sunflower, and chia seeds were inoculated with a four-serotype Salmonella cocktail by the dry transfer method and were soaked in sterile water at 25 or 37 degrees C for 24 h. During the soaking period, Salmonella exhibited growth rates of 0.37 +/- 0.26, 0.27 +/- 0.12, and 0.45 +/- 0.19 log CFU/h at 25 degrees C and 0.94 +/- 0.44, 1.04 +/- 0.84, and 0.73 +/- 0.36 log CFU/h at 37 degrees C for chia, pumpkin, and sunflower seeds, respectively. Soaked seeds were drained and dried at 25, 51, and 60 degrees C. Drying resulted in >5 log CFU/g loss at both 51 and 60 degrees C and ~3 log CFU/g loss at 25 degrees C on partially sprouted pumpkin and sunflower seeds. There was no decrease in Salmonella during drying of chia seeds at 25 degrees C, and only drying at 60 degrees C provided losses >5 log CFU/g. Dried seeds were stored at 37 and 45 degrees C at 15 and 76% relative humidity (RH) levels. The combination of temperature and RH exerted a stronger effect than either factor alone, such that rates at which Salmonella decreased generally followed this order: 37 degrees C at 15% RH < 45 degrees C at 15% RH < 37 degrees C at 76% RH < 45 degrees C at 76% RH for all seeds tested. Rates differed based on seed type, with chia seeds and chia seed powder having the smallest rate of Salmonella decrease, followed by sunflower and pumpkin seeds. Drying at higher temperatures (50 and 61 degrees C) or storing at elevated temperature and humidity (45 degrees C and 76% RH) resulted in significantly different rates of Salmonella decrease. PMID- 29513106 TI - Frequency of Enteroparasites and Bacteria in the Leafy Vegetables Sold in Brazilian Public Wholesale Markets. AB - The consumption of raw vegetables is related to health benefits. However, these foods might be source of foodborne diseases. The objective of the present study was to perform a microbiological and parasitological evaluation of the leafy vegetables commercially sold in five regions of Brazil at public wholesale markets. The 12 types of leafy vegetables (144 samples) were curly lettuce, looseleaf lettuce, red lettuce, chives, coriander, kale, basil, arugula, parsley, iceberg lettuce, chicory, and bean sprouts. The prevalences of total coliforms (88 to 100%) and thermotolerant coliforms (37 to 100%) were high, but Salmonella was not detected in any of the analyzed samples. All open markets sold vegetables contaminated with enteroparasites, mainly Entamoeba sp., Balantidium coli, Strongyloides sp., Ascaris sp., Enterobius vermicularis, and Ancylostomidae. Contamination was detected in all the regions (north, northeast, central west, southeast, and south) and types of vegetables, with higher prevalences in the northeast region, mainly in basil, lettuce, and chives. Contamination of vegetables by potentially pathogenic microorganisms is a national problem, and the distribution centers should improve quality control of these commercial vegetables. Considering the high frequency of enteroparasites and bacteria and the potential risk of disease transmitted by vegetables, we suggest greater enforcement of the sanitary surveillance of food offered to the public. PMID- 29513107 TI - Evaluation of Coregulation as a Governance Option To Manage Aflatoxin Risk in Texas Maize. AB - Coregulation as a form of risk management relies upon a government-private partnership in regulation using government-backed codes of practice or action plans. In Texas, implementation of coregulation to manage aflatoxin risk has been practiced since 2011 and operates under the program title One Sample Strategy (OSS). Aflatoxin-contaminated cereals and oilseeds that contain greater than 20 MUg/kg of the toxin (B1, B2, G1, and G2) are adulterated as defined by the Texas Commercial Feed Rules and regulated by the Texas Feed and Fertilizer Control Service of the Office of the Texas State Chemist. The present study was intended to evaluate the implementation and effectiveness of the coregulation program for 3 years based on selected evaluation criteria aiming to improve aflatoxin risk management and thus reduce market and food safety risk in Texas. In 2013, 124 analysts qualified to participate in the program at 23 grain elevators. During the 2013 harvest, use of control samples to ensure testing accuracy revealed that the average relative standard deviation among all participants was 14.5%. In 2014 and 2015, 129 and 151 analysts, respectively, qualified to measure aflatoxin, and the average relative standard deviation values for the working control across the 29 and 30 participating firms were 16.2 and 13.7%, respectively. All firms demonstrated the capability to grind maize to the OSS-prescribed particle size (70% passing through a 20-mesh sieve) in all 3 years. The Texas Feed and Fertilizer Control Service verified testing accuracy of OSS participants analyzing 612, 693, and 482 retained samples in 2013, 2014, and 2015, respectively. Results were plotted in an operating curve to depict type I and type II errors. The implementation of the OSS built upon a quality system-based code of practice successfully managed aflatoxin risk in Texas by using coregulation as a governance option. PMID- 29513108 TI - Hereditary angioedema due to C1-inhibitor deficiency in Macedonia: clinical characteristics, novel SERPING1 mutations and genetic factors modifying the clinical phenotype. AB - OBJECTIVE: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by swellings. We aimed to characterize on a clinical and molecular basis C1-INH-HAE patients in the Republic of Macedonia. RESULTS: All 15 patients from six unrelated families were diagnosed with C1-INH-HAE type I, with a mean age of symptom onset of 11 years and an average delay of diagnosis of seven years. Patients reported on average 31 angioedema attacks/year, with a median clinical severity score (CSS) of 7. We identified three known mutations and two new mutations (c.813_818delCAACAA and c.1488T > G) that were reported for the first time. To address the genotype-phenotype association, a pooled analysis including 78 C1-INH-HAE south-eastern European patients was performed, with additional analysis of F12-46C/T and KLKB1-428G/A polymorphisms. We demonstrated that patients with nonsense and frameshift mutations, large deletions/insertions, splicing defects and mutations at Arg444 exhibited an increased CSS compared with missense mutations, excluding mutations at Arg444. In addition, the CC F12-46C/T polymorphism was suggestive of earlier disease onset. DISCUSSION: Genetic analysis helped identify the molecular basis of C1-INH-HAE given that causative mutations in SERPING1 were detected in all patients, including an infant before the appearance of clinical symptoms. We identified two novel mutations and further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and CC F12-46C/T predisposes patients to earlier disease onset. KEY MESSAGES * In the present nationwide study, we aimed to characterize on a clinical and molecular basis patients with hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) in the Republic of Macedonia. * Causative mutations in SERPING1 were detected in all 15 C1-INH-HAE patients from six Macedonian families, including an infant, before the appearance of clinical symptoms. * We identified three known mutations and two novel mutations (c.813_818delCAACAA and c.1488T > G). These findings further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and the CC F12 46C/T polymorphism predisposes patients to earlier disease onset. PMID- 29513109 TI - Anterior-Segment Optical Coherence Tomography for Predicting Postoperative Outcomes After Trabeculectomy. AB - PURPOSE: To determine whether anterior-segment optical coherence tomography (AS OCT) can be used to predict post-trabeculectomy bleb outcomes. MATERIALS AND METHODS: We divided 58 eyes of 47 trabeculectomy patients into success or failure groups based on their status at 12 months after surgery. We then compared various AS-OCT measurement parameters between the two groups at 1 and 2 weeks and 1, 3, 6, and 12 months. We also analyzed the early post-trabeculectomy bleb parameters with multiple logistic regression, stepwise multiple regression, and the receiver operating characteristic (ROC) curve, to evaluate the power of these parameters to predict long-term outcomes. RESULTS: Intraocular pressure 3 or more months after trabeculectomy was significantly lower in the success group than the failure group (all: P < 0.0016). Cleft volume was significantly higher 6 or more months after trabeculectomy in the success group than the failure group (P = 0.0027 and <0.0016). Reflectivity of the bleb wall was significantly higher in the failure group than the success group at 2 weeks and all later time points (all: P < 0.0016). Reflectivity of the bleb wall at 2 weeks after trabeculectomy was a risk factor for failure, with an odds ratio (OR) for failure of 2.48 (95% confidence interval, 1.31-4.68, increasing per 10 AU). The area under the ROC curve for reflectivity of the bleb wall at 2 weeks after trabeculectomy was 0.775 when the cutoff value was set at 122.8, with sensitivity, specificity, and OR of 78.3%, 80.0%, and 14.4, respectively. A stepwise multiple regression analysis showed that reflectivity of the bleb wall at 2 weeks was an independent factor indicating postoperative bleb survival period (beta = -0.39, P = 0.007). CONCLUSIONS: Reflectivity of the bleb wall, measured by AS-OCT, may be an early post-trabeculectomy predictor of bleb outcome. PMID- 29513110 TI - Effects of fucoidan on diabetic rat testicular tissue. AB - Increased reactive oxygen species (ROS) resulting from hyperglycemia and inadequate endogenous antioxidant systems are responsible for the complications of diabetes. ROS accumulate in the cell and stimulate apoptosis, which compromises sperm quality and function. We investigated the possible effects of fucoidan, a potent antioxidant with a regulatory effect on blood glucose homeostasis, on the testicular tissues of rats with experimental diabetes. Diabetes was induced by administering 40 mg/kg streptozotocin (STZ) on five consecutive days. Twenty-four Wistar albino male rats were divided into four groups: group 1, control group (CG); group 2, diabetes group (DG); group 3, early fucoidan group (EFG) treated with 50 mg/kg fucoidan after diabetes induction; group 4, late fucoidan group (LFG) treated with the same dose of fucoidan 15 days after diabetes induction. Fucoidan was administered intraperitoneally every two days for four weeks. Basement membrane thickness and Johnsen scores were higher in the DG than in the CG; no difference was found for either the EFG or LFG compared to the CG. Seminiferous tubule diameters of EFG were significantly greater than for the DG. Apoptotic tubule and apoptotic cell indexes were significantly greater in the DG and significantly less in the EFG and LFG groups compared to the CG. Early use of fucoidan in diabetic individuals may minimize damage to testicular tissue. PMID- 29513111 TI - Granulocyte/monocyte adsorptive apheresis for the treatment of therapy-refractory chronic active ulcerative colitis. AB - OBJECTIVES: Current options for patients with steroid-dependent, chronic-active ulcerative colitis (UC) with insufficient response/intolerance to immunosuppressants (ISs) and/or biologics are limited. The aim of this study was to assess the long-term outcome of granulocyte/monocyte adsorptive (GMA) apheresis (Adacolumn(r)) in this population. MATERIALS AND METHODS: Ninety five adults with steroid-dependent active UC and insufficient response/intolerance to IS and/or TNF inhibitors received 5-8 aphereses in a single induction series of <=10 weeks. Endpoints included rates of remission (clinical activity index [CAI] <= 4) at weeks 24 and 48. RESULTS: Of 94 patients (ITT population), remission and response rates were 34.0% and 44.7% at week 24, and 33.0% and 39.4% at week 48. Among 30 patients with prior failure of IS and biologics, 33.3% and 20.0% were in remission at weeks 24 and 48. At both weeks, 19.2% of patients achieved steroid free remission. Sustained remission or response occurred in 27.7% of patients at 48 weeks. The cumulative colectomy rate at week 96 was 23.4%. Safety was consistent with previous findings. CONCLUSIONS: This study confirms findings of the 12-week interim analysis and demonstrates that GMA apheresis provides a safe and beneficial long-term outcome for patients with chronic active UC resistant/intolerant to IS and/or TNF inhibitors. PMID- 29513112 TI - Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation. AB - Familial hemiplegic migraine type 2 (FHM2) is associated with inherited point mutations in the Na,K-ATPase alpha2 isoform, including G301R mutation. We hypothesized that this mutation affects specific aspects of vascular function, and thus compared cerebral and systemic arteries from heterozygote mice bearing the G301R mutation (Atp1a2+/-G301R) with wild type (WT). Middle cerebral (MCA) and mesenteric small artery (MSA) function was compared in an isometric myograph. Cerebral blood flow was assessed with Laser speckle analysis. Intracellular Ca2+ and membrane potential were measured simultaneously. Protein expression was semi quantified by immunohistochemistry. Protein phosphorylation was analysed by Western blot. MSA from Atp1a2+/-G301R and WT showed similar contractile responses. The Atp1a2+/-G301R MCA constricted stronger to U46619, endothelin and potassium compared to WT. This was associated with an increased depolarization, although the Ca2+ change was smaller than in WT. The enhanced constriction of Atp1a2+/-G301R MCA was associated with increased cSrc activation, stronger sensitization to [Ca2+]i and increased MYPT1 phosphorylation. These differences were abolished by cSrc inhibition. Atp1a2+/-G301R mice had reduced resting blood flow through MCA in comparison with WT mice . FHM2-associated mutation leads to elevated contractility of MCA due to sensitization of the contractile machinery to Ca2+, which is mediated via Na,K-ATPase/Src-kinase/MYPT1 signalling. PMID- 29513113 TI - Biogenesis of silver nanoparticles using leaf extract of Indigofera hirsuta L. and their potential biomedical applications (3-in-1 system). AB - The present study reports the biosynthesis of silver nanoparticles (IH-AgNPs) using aqueous leaf extract of Indigofera hisruta L. The biosynthesized IH-AgNPs were found to be FCC crystals, 5-10 nm in size, spherical in shape and stable. The biosynthesized IH-AgNPs showed dose-dependant cytotoxicity against prostate cancer (PC3) (IC50 = 68.5 MUg/mL), colon cancer (COLO205) (IC50 = 85.2 MUg/mL), and mouse melanoma (B16F10) (IC50 = 80.9 MUg/mL). IH-AgNPs were found to be nontoxic towards normal CHO (Chinese hamster ovary) cells. The biosynthesized IH AgNPs showed effective in vitro antioxidant activity against DPPH (IC50 = 63.43 MUg/mL) and H2O2 (IC50 = 89.93 MUg/mL) radicals. IH-AgNPs exhibited effective antibacterial activity against both Gram+ve and Gram-ve bacteria. MIC values of IH-AgNPs against S. aureus, B. subtilis, P. aeruginosa and E. coli were found to be 7.8 MUg/mL, 3.9 MUg/mL, 15.6 MUg/mL and 15.6 MUg/mL respectively. IH-AgNPs also showed inhibitory activity against fungal pathogens including C. albicans, C. nonalbicans and C. tropicalis. Considering the results together, we demonstrate that IH-AgNPs exhibits three different bioactivities (3-in-1 system) and they could be employed as future antimicrobial, antioxidant and anticancer agents/drug delivery vehicles in the field of biomedicine. PMID- 29513115 TI - Editorial. PMID- 29513114 TI - Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF3-Phe Asp]NH2. AB - Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe Asp]NH2 (C-36) and Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2 (F-81). The ability of these peptides to cross the blood-brain barrier was tested in the parallel artificial membrane permeability (PAMPA) assay. On the basis of the hot-plate test in mice after central and peripheral administration, analog F-81 was selected for the anti-nociceptive and anti-inflammatory activity assessment after peripheral administration. PMID- 29513116 TI - Risk factors and treatment of refractory anaphylaxis - a review of case reports. AB - INTRODUCTION: Patients experiencing anaphylaxis who do not recover after treatment with intramuscular adrenaline are regarded as suffering from refractory anaphylaxis. The incidence of refractory anaphylaxis is estimated to range between 3-5% of anaphylaxis cases. The risk factors for refractory anaphylaxis are unknown. Areas covered: In the present analysis, we aimed to evaluate the management and risk factors of refractory anaphylaxis to highlight possible clinical implications for updating current management algorithms. Expert commentary: According to international guidelines, adrenaline given through the intramuscular (i.m.) route is a rapid and safe treatment but may be insufficient. Therefore, defined standardized treatment protocols for such cases of refractory anaphylaxis are needed to optimize the treatment. Point-of-care diagnostics may enable doctors to identify patients experiencing severe, refractory anaphylaxis early in order to initiate intensified critical care treatment. PMID- 29513117 TI - A debt of gratitude for newly established guidelines. PMID- 29513118 TI - Associations of coffee consumption with circulating level of adiponectin and leptin. A meta-analysis of observational studies. AB - The association between coffee consumption and the circulating level of adiponectin and leptin has been evaluated in several epidemiological studies with conflicting results. Therefore, the aim of this study was to examine the associations of coffee consumption with the circulating level of adiponectin and leptin. A comprehensive literature search up to January 2018, using PUBMED, EMBASE and Web of Science databases, was conducted to identify the relevant observational studies that examined the associations of coffee consumption with the circulating level of adiponectin and leptin. A total of twelve cross sectional studies were included in this meta-analysis. According to the combined standard mean difference (SMD) between the highest and the lowest coffee intake category, coffee consumption was associated with a higher circulating adiponectin level (SMD = 0.11, 95%CI: 0.06-0.17; P < .001). Subgroup analysis confirmed such findings in females (SMD = 0.11, 95%CI: 0.02-0.20; P = .01), but not in males (SMD = 0.03, 95%CI: -0.08 to 0.14; P = .59). In addition, the combined SMD showed that coffee consumption was negatively associated with the circulating level of leptin (SMD = -0.19, 95%CI: -0.28 to -0.10; P < .001). The results of this meta analysis suggested that coffee consumption was associated with a higher circulating level of adiponectin. Additionally, we showed that coffee consumption was inversely associated with the circulating level of leptin. More well-designed prospective cohort studies and randomised controlled trials are needed to further elaborate the concerned issues. PMID- 29513119 TI - Undergraduate students' perspectives of healthcare professionals' use of shared decision-making skills. AB - Essential for future healthcare professionals (HCPs) to delivering ethical and empathetic patient-centred care (PCC) as a team is the understanding of appropriate shared decision-making (SDM) responses when facilitating discussions with patients and family members. The purpose of this study was to evaluate undergraduate students' perspectives about HCPs' use of SDM as described in a case-study reflection assignment. An exploratory qualitative approach was used to analyse student-reflection assignments. The sample included 42 undergraduate students enrolled in an interprofessional education (IPE) course at a Midwest university based in the United States. Data consisted of student responses in a course reflection assignment that captured their perspectives about recommended SDM responses by HCPs. Student assignments were randomly selected using stratified sampling to provide representation of eight HCP roles. Analysis revealed two themes related to students' use of SDM responses. Results provide evidence supporting the tenet that through IPE, healthcare students can develop an understanding of SDM and ethical principles related to PCC. PMID- 29513120 TI - Assessment of lingual sentinel lymph nodes metastases using dual-modal indirect CT/MR lymphography with gold-gadolinium-based nanoprobes in a tongue VX2 carcinoma model. AB - OBJECTIVE: To evaluate the capability of indirect computed tomography and magnetic resonance lymphography (CT/MR-LG) with gadolinium-loaded, polyethylenimine-entrapped gold nanoprobes (Gd-Au PENPs) for assessing lingual sentinel lymph node (SLN) metastasis in a tongue VX2 carcinoma model. MATERIALS AND METHODS: Seventeen rabbits were used to establish a metastatic cervical lymph node model by implanting VX2 carcinoma suspension into the ventral tongue muscle. CT and MR images were acquired one hour after Gd-Au PENPs injection into the tongue submucosa bilaterally, on 1w (n = 4), 2w (n = 6) and 3w (n = 7) tumour bearing rabbits after carcinoma transplantation. Then, the filling defects and enhancement features of the lingual SLN on indirect CT/MR-LG were assessed. RESULTS: The enhanced lingual SLNs were observed bilaterally in all rabbits using indirect CT/MR-LG. In total, 15 enhanced SLNs displayed oval or round shape with uniform density and no filling defects or only local small filling defects, and all nodes were metastasis-negative, while 19 enhanced SLNs demonstrated irregular morphologies with filling defects, non-uniform densities and unclear borders, of which 14 nodes were metastatic. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value when using SLN enhancement with irregular morphology, filling defects, non-uniform density and unclear border as diagnostic criteria for metastasis were 100%, 75.0%, 85.3%, 73.7% and 100%, respectively. CONCLUSIONS: Indirect CT/MR-LG with Gd-Au PENPs can be used for the metastatic diagnosis of lingual SLN in tongue cancer. PMID- 29513121 TI - Serum relaxin-2 as a novel biomarker for prostate cancer. PMID- 29513122 TI - Treatment of secondary brain injury by perturbing postsynaptic density protein-95 NMDA receptor interaction after intracerebral hemorrhage in rats. AB - Postsynaptic density protein-95 (PSD95) plays important roles in the formation, differentiation, remodeling, and maturation of neuronal synapses. This study is to estimate the potential role of PSD95 in cognitive dysfunction and synaptic injury following intracerebral hemorrhage (ICH). The interaction between PSD95 and NMDA receptor subunit NR2B-neurotransmitter nitric oxide synthase (nNOS) could form a signal protein complex mediating excitatory signaling. Besides NR2B nNOS, PSD95 also can bind to neurexin-1-neuroligin-1 to form a complex and participates in maintaining synaptic function. In this study, we found that there were an increase in the formation of PSD95-NR2B-nNOS complex and a decrease in the formation of neurexin-1-neuroligin-1-PSD95 complex after ICH, and this was accompanied by increased neuronal death and degeneration, and behavior dysfunction. PSD95 inhibitor Tat-NR2B9c effectively inhibited the interaction between PSD95 and NR2B-nNOS, and promoted the formation of neurexin-1-nueuroligin 1-PSD95 complex. In addition, Tat-NR2B9c treatment significantly reduced neuronal death and degeneration and matrix metalloproteinase 9 activity, alleviated inflammatory response and neurobehavioral disorders, and improved the cognitive and learning ability of ICH rats. Inhibition of the formation of PSD95-NR2B-nNOS complex can rescue secondary brain injury and behavioral cognitive impairment after ICH. PSD95 is expected to be a target for improving the prognosis of patients with ICH. PMID- 29513123 TI - Broccoli and human health: immunomodulatory effect of sulforaphane in a model of colon cancer. AB - The favourable properties of broccoli on human health are due to their abundant content of vitamins, minerals and isothiocyanates, the sulforaphane (SFN) being the most important. SFN is created from its precursor glucoraphanin and it is released by myrosinase enzymes produced during crushing of the plant. SFN has been shown to possess anti-inflammatory and anticancer properties. The aim of the study was to determine if SFN may affect the immune dialogue between human peripheral blood mononuclear cells (PBMCs) and HT-29 and RKO human colon cancer cells lines. Non- or mitogen-stimulated PBMCs were incubated with various concentrations of SFN, and the secretion of TNFalpha, IL-1beta, IL-6, IFNgamma, IL-2, IL-10 and IL-1ra was determined. In addition, the effect of SFN on the production of these cytokines by PBMCs co-cultured with colon carcinoma cells was examined. SFN exerted a concentration-dependent inhibitory effect on the inflammatory cytokine production by the immune cells. The impact of SFN on the interaction between immune and colon cancer cells underscores its capacity for cancer prevention and development. PMID- 29513124 TI - A rational approach to identifying newborns with hearing loss caused by congenital cytomegalovirus infection by dried blood spot screening. AB - OBJECTIVE: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection, with the majority of infected newborns having no detectable signs. The aim of this study was to examine the accuracy of our newly developed DBS-based assay as an appropriate mass screening method for cCMV infection. METHODS: Between May 2011 and October 2016, newborns delivered at six hospitals in Nagano Prefecture, Japan were enrolled prospectively. We employed dried blood spot (DBS)-based assays with real-time quantitative PCR (qPCR). RESULTS: Prior to the clinical study, confirmation analysis was carried out using positive and negative controls. The sensitivity and specificity of this DBS-based qPCR assay for the detection of CMV DNA were 83 and 97%, respectively. During the study period, 9675 newborns were enrolled. The total recovery rate of DBS was 99.92% (9,667/9,675). From our analysis of the 9,667 samples, 47 DBS samples were found positive by the qPCR test (0.48%), and 9620 (99.5%) DBS samples were CMV negative. CONCLUSIONS: The risk of neural disorders associated with cCMV infection is thought likely to increase with CMV viral load in the blood. DBS screening for cCMV may be sufficient in a clinical setting, and offers a realistic and feasible option for universal mass screening. PMID- 29513126 TI - 1994 NASPSPA Conference Abstracts. PMID- 29513127 TI - Free Communications. PMID- 29513125 TI - A Coincidental Discovery of a New Stable Variant (Hb Hachioji or HBB: c.187C>T) in a Patient with Chronic Hemolytic Anemia of Unexplained Origin. AB - We report a new hemoglobin (Hb) variant, Hb Hachioji (HBB: c.187C>T), which was detected in a 32-year-old male with hemolytic anemia. The proband had undergone splenectomy in his childhood after being diagnosed with hereditary spherocytosis (HS) with no clinical improvement. A recent study showed that Heinz bodies were frequently observed in his red cells, however, no abnormal band was separated by isoelectric focusing (IEF), and the isopropanol (instability) test was negative. Direct sequencing revealed that the proband was a heterozygous carrier of a novel mutation (GCT>GTT) at codon 62 of the beta-globin gene, leading to an alanine to valine substitution. This variant was named Hb Hachioji. Characterization at the mRNA level by cDNA sequencing detected betaHachioji mRNA, as well as betaA mRNA. Subsequently, study of the proband's family indicated that his father was a carrier of this Hb variant, although unexpectedly, the father was asymptomatic and clinically healthy. Oxygen affinity measurement of total Hb showed no alteration in the P50 and oxygen equilibrium curve. The presence of Hb Hachioji was confirmed by mass spectrometry (MS). Hb Hachioji comprised approximately 50.0% of the total Hb and was a stable variant. The phenotypic discrepancy between these two carriers suggests that Hb Hachioji may not be associated with the hemolytic involvement in the proband. P4.2Nippon, which is the primary cause of most cases of Japanese HS, was absent in the proband's parents. The coexistence of glucose-6-phosphate dehydrogenase (G6PD) deficiency was ruled out. Thus, the cause of hemolytic involvement in this patient remains unclear. PMID- 29513128 TI - From Boreli (1680) and Bell (1826) to the Dynamics of Action and Perception. AB - Recent developments in the study of action and perception have their roots in the contemplations of Giovanni Borelli, a 17th-century Italian mathematician and physicist, and Sir Charles Bell, and 18th-century English physiologist and neuroanatomist. When Borelli looked at muscle and its functional achievements, he saw dynamics with its attendant laws and principles; when Bell looked at muscle, he saw information about muscular states and a smart mechanism for its measurement. Research and theory on the dynamics of coordination and locomotion, and on the perceptual achievements of the haptic subsystem of dynamic touch, are providing affirmation of these visions of Borelli and Bell. PMID- 29513130 TI - Fairy chemicals - a candidate for a new family of plant hormones and possibility of practical use in agriculture. AB - 2-Azahypoxanthine (AHX, 1) and imidazole-4-carboxamide (ICA, 2) were isolated from a fairy-ring forming fungus Lepista sordida. AHX was converted into a metabolite, 2-aza-8-oxohypoxanthine (AOH, 3), in plants. Afterward, it turned out that these three compounds, fairy chemicals (FSc), endogenously exist in plants and are biosynthesized via a new purine metabolic pathway. Furthermore, FCs increased the yields of rice, wheat and other crops in the filled experiments. PMID- 29513129 TI - In vivo anti-ulcerogenic effect of okra (Abelmoschus esculentus) on ethanol induced acute gastric mucosal lesions. AB - CONTEXT: Okra, Abelmoschus esculentus (L.) (Malvaceae), is a medicinal plant widely used in Turkish traditional medicine for the treatment of various diseases such as ulcers and gastritis. OBJECTIVE: In the present study, we evaluated the gastroprotective effect of okra against ethanol-induced acute gastric mucosal injury in animal models. MATERIALS AND METHODS: Wistar rats were treated with 500, 250 or 100 mg/kg okra; 20 mg/kg famotidine (Fam); and 75 mg/kg quercetin (Que). Following a 60 min period, all the rats were given 1 mL of ethanol (80%). One hour after the administration of ethanol, all groups were sacrificed. RESULTS: At 5000 mg/kg, the extract produced (okra) no signs of toxicity in animals. Okra 500, 250, 100, Fam 20 and Que 75 inhibited ulcer formation by 81.0, 67.5, 67.0, 76.3 and 72.4%, respectively. Okra 500 significantly decreased edema, hemorrhage and inflammation scores compared with the ethanol group (p < 0.05). The oxidant levels decreased significantly in the all study groups compared within ethanol group (p < 0.001). Serum beta-carotene and retinol levels significantly increased 40.2 and 45.4% in the okra 500 group. In okra 500, 250 and Fam 20 groups, apoptosis significantly decreased (p < 0.001), while okra 500, 250 and Fam 20 groups showed a higher percentage of cell proliferation compared with the ethanol group (p < 0.001). DISCUSSION AND CONCLUSIONS: Our in vivo data indicate that okra has a gastroprotective effect against ethanol and could reduce the gastric ulcer as seen from biochemical and histopathological results. We suggest that okra could be a possible therapeutic antiulcer agent. PMID- 29513131 TI - Dolutegravir with boosted darunavir treatment simplification for the transmitted HIV thymidine analog resistance in Manitoba, Canada. PMID- 29513132 TI - Parent coaching increases the parents' capacity for reflection and self evaluation: results from a clinical trial in autism. AB - Family-centered parent coaching interventions in autism strive to encourage family engagement and support parent reflection and self-evaluation. This includes the parents' capacity to: (1) carefully observe the child's behavior; (2) reflect upon the child's thoughts, motives, and feelings; (3) consider links between the child's internal experiences and observable behavior; and (4) grapple with the complex interplay among the child's experiences and behaviors, contextual factors, parenting strategies, as well as parental goals and emotions. The current study reports data from a clinical trial of Focused Playtime Intervention (FPI), a parent coaching intervention targeting responsive parental behaviors and child communication. Seventy children with autism between 2 and 6 years and their parents were randomly assigned to participate in FPI for 12 weeks or an active control intervention. The Insightfulness Assessment was administered and used (a) to classify parents' baseline capacity for reflection and self evaluation as either established (i.e., positively insightful) or emerging, and (b) to capture longitudinal change in the parents' capacity between baseline, exit (~5 months after baseline), and follow up (~14 months after exit) using a dimensional composite subscale score. Results revealed a significant treatment effect of FPI on growth in the parents' capacity for reflection and self evaluation, conditional on the parents' classification at baseline. That is, parents whose capacity for reflection and self-evaluation was classified as emerging at baseline (n = 42) showed higher rates of growth when assigned to FPI, compared to the control condition. A similar treatment effect was not found for parents whose baseline capacity for reflection and self-evaluation was classified as established (i.e., positively insightful). This is the first study to show that a family-centered parent coaching intervention effectively increases the capacity for reflection and self-evaluation in parents of young children with autism. This capacity may enable parents to adapt and implement intervention strategies flexibly across contexts, daily routines, and interactions. PMID- 29513133 TI - QT prolongation and sudden cardiac death risk in hypertrophic cardiomyopathy. AB - INTRODUCTION: Risk assessment for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains complex. The goal of this study was to assess electrocardiogram (ECG)-derived risk factors on SCD in a large HCM population Methods: Retrospective review of adults with HCM evaluated at Mayo Clinic, Rochester, MN from 1 December 2002 to 31 December 2012 was performed. Data inclusive of ECG and 24-hour ambulatory Holter monitor were assessed. SCD events were documented by ventricular fibrillation (VF) noted on implantable cardioverter defibrillator (ICD), or appropriate VT or VF-terminating ICD shock. RESULTS: Overall, 1615 patients (mean age 53.7 +/- 15.2 years; 943 males, 58.4%) were assessed, with mean follow-up 2.46 years and 110 SCD events. Via logistic regression (n = 820), the odds of SCD increased with increasing number of conventional risk factors. With one risk factor the OR was 4.88 (p < .0001; CI 2.22-10.74), two risk factors the OR was 6.922 (p < .0001; CI 2.94-16.28) and three or more risk factors, the OR was 13.997 (p < .0001; CI 5.649-34.68). Adding QTc > 450 to this logistic regression model had OR 1.722 (p = .04, CI 1.01-2.937) to predict SCD. QTc >= 450 was a significant predictor for death (HR 1.88, p = .021, CI 1.10-3.20). There was no correlation between sinus bradycardia, sinus tachycardia, first degree AV block, atrial fibrillation, left bundle branch block, right bundle branch block, premature atrial complexes, premature ventricular complexes, supraventricular tachycardia, PR interval, QRS interval and SCD. CONCLUSIONS: Prolonged QTc was a risk factor for SCD and death even when controlling for typical risk factors. PMID- 29513134 TI - Belfast Agar-a simple laboratory medium to separate Pseudomonas aeruginosa from pan-resistant Burkholderia cenocepacia isolated from the sputum of patients with cystic fibrosis (CF). PMID- 29513135 TI - Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis. AB - The preservation of tissue and organ architecture and function depends on tightly regulated interactions of cells with the extracellular matrix (ECM). These interactions are maintained in a dynamic equilibrium that balances intracellular, myosin-generated tension with extracellular resistance conferred by the mechanical properties of the extracellular matrix. Disturbances of this equilibrium can lead to the development of fibrotic lesions that are associated with a wide repertoire of high prevalence diseases including obstructive cardiovascular diseases, muscular dystrophy and cancer. Mechanotransduction is the process by which mechanical cues are converted into biochemical signals. At the core of mechanotransduction are sensory systems, which are frequently located at sites of cell-ECM and cell-cell contacts. As integrins (cell-ECM junctions) and cadherins (cell-cell contacts) have been extensively studied, we focus here on the properties of the discoidin domain receptor 1 (DDR1), a tyrosine kinase that mediates cell adhesion to collagen. DDR1 expression is positively associated with fibrotic lesions of heart, kidney, liver, lung and perivascular tissues. As the most common end-point of all fibrotic disorders is dysregulated collagen remodeling, we consider here the mechanical signaling functions of DDR1 in processing of fibrillar collagen that lead to tissue fibrosis. PMID- 29513136 TI - Training in office-based opioid treatment with buprenorphine in US residency programs: A national survey of residency program directors. AB - BACKGROUND: The prevalence of opioid use disorder (OUD) has increased sharply. Office-based opioid treatment with buprenorphine (OBOT) is effective but often underutilized because of physicians' lack of experience prescribing this therapy. Little is known about US residency training programs' provision of OBOT and addiction medicine training. METHODS: The authors conducted a survey of residency program directors (RPDs) at all US residency programs in internal medicine, family medicine, and psychiatry to assess the frequency with which their residents provide care for OUD, presence and features of curricula in OBOT and addiction medicine, RPDs' beliefs about OBOT, and potential barriers to providing OBOT training. RESULTS: The response rate was 49.5% (476 of 962). Although 76.9% of RPDs reported that residents frequently manage patients with OUD, only 23.5% reported that their program dedicates 12 or more hours of curricular time to addiction medicine, 35.9% reported that their program encourages/requires training in OBOT, and 22.6% reported that their program encourages/requires obtaining a Drug Enforcement Administration (DEA) waiver to prescribe buprenorphine. Most RPDs believe that OBOT is an important treatment option for OUD (88.1%) and that increased residency training in OBOT would improve access to OBOT (73.7%). The authors also found that programs whose RPD had favorable views of OBOT were more likely to provide OBOT and addiction medicine training. Psychiatry programs were most likely to provide OBOT training and their RPDs most likely to have beliefs about OBOT that were positive. Commonly cited barriers to implementing OBOT training include a lack of waivered preceptors (76.9%), competing curricular priorities (64.1%), and a lack of support (social work and counseling) services (54.0%). CONCLUSIONS: Internal medicine, family medicine, and psychiatry residents often care for patients with OUD, and most RPDs believe that increased residency training in OBOT would increase access to this treatment. Yet, only a minority of programs offer training in OBOT. PMID- 29513137 TI - Epigenetic modification of the oxytocin and glucocorticoid receptor genes is linked to attachment avoidance in young adults. AB - Attachment in the context of intimate pair bonds is most frequently studied in terms of the universal strategy to draw near, or away, from significant others at moments of personal distress. However, important interindividual differences in the quality of attachment exist, usually captured through secure versus insecure anxious and/or avoidant - attachment orientations. Since Bowlby's pioneering writings on the theory of attachment, it has been assumed that attachment orientations are influenced by both genetic and social factors - what we would today describe and measure as gene by environment interaction mediated by epigenetic DNA modification - but research in humans on this topic remains extremely limited. We for the first time examined relations between intra individual differences in attachment and epigenetic modification of the oxytocin receptor (OXTR) and glucocorticoid receptor (NR3C1) gene promoter in 109 young adult human participants. Our results revealed that attachment avoidance was significantly and specifically associated with increased OXTR and NR3C1 promoter methylation. These findings offer first tentative clues on the possible etiology of attachment avoidance in humans by showing epigenetic modification in genes related to both social stress regulation and HPA axis functioning. PMID- 29513139 TI - Effect of pre-ozonation-enhanced coagulation on dissolved organic nitrogen in municipal wastewater treatment plant effluent. AB - Municipal wastewater treatment plant (WWTP) effluent is increasingly used as reclaimed water and as water sources for downstream areas. Effluent dissolved organic nitrogen (DON) is considered to be the precursor to nitrogen disinfection by-products (N-DBPs). Here, we investigated DON removal by pre-ozonation-enhanced coagulation and found that (1) pre-ozonation significantly enhanced the removal of DON, dissolved organic carbon (DOC), and UV254 by coagulation. (2) pH had an important impact on the pre-ozonation-enhanced coagulation. At lower pH, the removal of DON, DOC, and UV254 is higher. (3) As ozone dosage increased, zeta potential gradually increased, while dissolved calcium concentrations declined and there was a strong correlation between zeta potential and dissolved calcium concentrations. (4) Small (<6 kDa) molecular weight DON was dominant in the effluent. Hydrophilic and hydrophobic DON accounted for 58.5% and 30.8% of the total, respectively. (5) Coagulation reduced overall DBP formation potentials to less than 20%. In contrast, overall DBP formation potentials increased after ozonation. However, pre-ozonation-enhanced coagulation not only removed 71% DON, but also reduced overall DBP formation potentials by more than 40%. (6) 3-DEEM spectra indicated that DBP formation potentials and DON concentrations were related to three main peaks, which corresponded to tryptophan-based proteins, aromatic proteins, and fulvic acids. PMID- 29513140 TI - The neuroprotective effects of an ethanolic turmeric (Curcuma longa L.) extract against trimethyltin-induced oxidative stress in rats. AB - INTRODUCTION: Oxidative stress is known to contribute to the pathogenesis of neurodegenerative disorders. An ethanolic turmeric (Curcuma longa L.) extract containing curcumin has been reported to produce antioxidant effects. OBJECTIVE: The present study aims to investigate the possible neuroprotective effects of the ethanolic turmeric extract against trimethyltin (TMT)-induced oxidative stress in Sprague Dawley rats. METHODS: The ethanolic turmeric extract and citicoline were administered to the TMT exposed rats from day 1 to day 28 of the experiment. The TMT injection was administered on day 8 of the experiment. The plasma and brain malondialdehyde (MDA) and reduced glutathione (GSH) levels, and the activities of the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzymes in the brain were examined at the end of the experiment. RESULTS: The administration of 200 mg/kg bw of the ethanolic turmeric extract prevented oxidative stress by decreasing the plasma and brain MDA levels and increasing the SOD, CAT, and GPx enzyme activities and GSH levels in the brain. These effects seem to be comparable to those of citicoline. DISCUSSION: The ethanolic turmeric extract at a dose of 200 mg/kg bw may exert neuroprotective effects on TMT exposed Sprague Dawley rats by preventing them from oxidative stress. PMID- 29513141 TI - Seasonal distribution characteristics and health risk assessment of typical antibiotics in the Harbin section of the Songhua River basin. AB - A method was established for coupled solid phase extraction-ultra performance liquid chromatography and mass spectrometry, to simultaneously detect 12 common antibiotics belonging to 4 types (sulfonamides, macrolides, fluoroquinolones and cephalosporins) in the Harbin section of the Songhua River basin, Northeastern China. The results showed that the 12 antibiotics monitored were all detected to varying degrees, with 100% detection rates for sulfamethoxazole (SMX), cefazolin (CFZ), ofloxacin (OFL), flumequine (FLU), azithromycin (AZI) and roxithromycin (ROX), and the highest levels were in winter, the lowest in summer. The total concentrations of all 12 antibiotics in spring, summer, autumn and winter, were 39.7, 9.6, 27.5 and 136.2 ng L-1, respectively. Seasonality was also observed in antibiotic distribution along the riverbank, with winter concentrations of all antibiotics detected upstream of the Harbin section being lower than the downstream section; in summer, except for CFZ, the concentrations of all antibiotics detected were higher upstream, than downstream of the Harbin section. Finally, the health risks to people of different ages caused by residual antibiotic contamination in the Songhua River were evaluated, and the results showed that the risk of antibiotics was far lower than 1, with no direct threat to human health established. PMID- 29513142 TI - Faster, higher, stronger, older: Relative age effects are most influential during the youngest age grade of track and field athletics in the United Kingdom. AB - The relative age effect (RAE) is a common phenomenon in youth sport, whereby children born early in the selection year are more likely to experience success and to sustain participation. There is a lack of research investigating variables which influence RAEs within track and field athletics. Such information is vital to guide policies in relation to competition structure, youth development squads and coach education. A database of competition results was analysed to determine the extent to which RAEs were present in track and field athletics in the United Kingdom. Subsequent analyses examined whether age, sex, event and skill level influenced the RAE. Examination of 77,571 records revealed that RAEs were widespread, but most pronounced during Under 13 (U13) competitions; that is, during athletes' first exposure to formal track and field competition. Sex, event and skill level further influenced the existence and magnitude of RAEs at different age grades. Relative age is a key influencing factor within track and field athletics, especially at the youngest age category. Consequently, national governing bodies need to consider what administrative and stakeholder initiatives are necessary to minimise the effects of RAEs on young athletes' early experiences of competition. PMID- 29513143 TI - Combined use of polymeric ferric sulfate and chitosan as a conditioning aid for enhanced digested sludge dewatering. AB - In this study, the effects of polymeric ferric sulfate (PFS) and chitosan (CTS) on the dewatering characteristics of the digested activated sludge (e.g. filtrate turbidity, specific resistance of filtration (SRF), and cake moisture content) were investigated. The combined conditioning of PFS and CTS improved the settleability of the digested sludge more effectively than when using of PFS alone. The SRF value of the digested sludge decreased to 2.08 * 1012 m/kg after conditioning with 50 mg/g PFS and 10 mg/g CTS. Furthermore, a minimum moisture content of 68% was obtained when 40 mg/g PFS and 10 mg/g CTS were used to condition the digested sludge. At a fixed dose of PFS, the concentrations of extracellular polymeric substances, including polysaccharides (C/C0 = 2.1), proteins (C/C0 = 2.7), and deoxyribonucleic acids (C/C0 = 7.8) in the supernatant were increased considerably with an increase in CTS dose (0-10 mg/g). Phosphorus could be recovered efficiently as a result of charge neutralization and the adsorption-bridging effects of CTS, which promote the release of phosphorus from the digested activated sludge. The concentrations of heavy metals in the digested sludge conditioned with 40 mg/g PFS and 10 mg/g CTS satisfied the agricultural safety requirements. These results indicate that conditioning the digested sludge with combinations of PFS and CTS improves its dewatering performance and enables its direct use as a fertilizer. PMID- 29513144 TI - An interprofessional patient assessment involving medical and nursing students: a qualitative study. AB - Interprofessional collaboration is fundamental to providing optimal patient care. The readiness of the team entering a framework of interprofessional collaborative practice is critical to its success. In this study, we conducted an interprofessional education (IPE) activity for medical and nursing students in an acute care setting. Over nine occasions, 21 student pairs (one nursing and one medical student per pair) jointly assessed a patient and created a list of problems and interventions to achieve the patient's goals. Immediately after the activity, students were debriefed to gain insight into their experiences. Debriefing sessions were audiotaped and analysed using a phenomenological approach and four major themes were identified. Overall, students felt responsible for representing their profession and were initially apprehensive about the interprofessional task. Nevertheless, they identified their own shortcomings and recognized the value in their partner's approach. These realizations promoted convergence on a shared vision to provide optimal care for patients as a team. Acknowledging and understanding these perceptions may help design better ways to improve patient care. This educational model may be utilized by others who are seeking IPE activities in acute care. PMID- 29513138 TI - Protein kinase C: perfectly balanced. AB - Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are "receptors" for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: PKC isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer's disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: "to go beyond is as wrong as to fall short." PMID- 29513145 TI - New insights into the formation and the function of lamellipodia and ruffles in mesenchymal cell migration. AB - Lamellipodia and ruffles are veil-shaped cell protrusions composed of a highly branched actin filament meshwork assembled by the Arp2/3 complex. These structures not only hallmark the leading edge of cells adopting the adhesion based mesenchymal mode of migration but are also thought to drive cell movement. Although regarded as textbook knowledge, the mechanism of formation of lamellipodia and ruffles has been revisited in the last years leveraging new technologies. Furthermore, recent observations have also challenged our current view of the function of lamellipodia and ruffles in mesenchymal cell migration. Here, I review this literature and compare it with older studies to highlight the controversies and the outstanding open issues in the field. Moreover, I outline simple and plausible explanations to reconcile conflicting results and conclusions. Finally, I integrate the mechanisms regulating actin-based protrusion in a unifying model that accounts for random and ballistic mesenchymal cell migration. PMID- 29513147 TI - Postoperative seizure outcome-guided machine learning for interictal electrocorticography in neocortical epilepsy. AB - The objective of this study was to introduce a new machine learning guided by outcome of resective epilepsy surgery defined as the presence/absence of seizures to improve data mining for interictal pathological activities in neocortical epilepsy. Electrocorticographies for 39 patients with medically intractable neocortical epilepsy were analyzed. We separately analyzed 38 frequencies from 0.9 to 800 Hz including both high-frequency activities and low-frequency activities to select bands related to seizure outcome. An automatic detector using amplitude-duration-number thresholds was used. Interictal electrocorticography data sets of 8 min for each patient were selected. In the first training data set of 20 patients, the automatic detector was optimized to best differentiate the seizure-free group from not-seizure-free-group based on ranks of resection percentages of activities detected using a genetic algorithm. The optimization was validated in a different data set of 19 patients. There were 16 (41%) seizure-free patients. The mean follow-up duration was 21 +/- 11 mo (range, 13-44 mo). After validation, frequencies significantly related to seizure outcome were 5.8, 8.4-25, 30, 36, 52, and 75 among low-frequency activities and 108 and 800 Hz among high-frequency activities. Resection for 5.8, 8.4-25, 108, and 800 Hz activities consistently improved seizure outcome. Resection effects of 17-36, 52, and 75 Hz activities on seizure outcome were variable according to thresholds. We developed and validated an automated detector for monitoring interictal pathological and inhibitory/physiological activities in neocortical epilepsy using a data-driven approach through outcome-guided machine learning. NEW & NOTEWORTHY Outcome-guided machine learning based on seizure outcome was used to improve detections for interictal electrocorticographic low- and high frequency activities. This method resulted in better separation of seizure outcome groups than others reported in the literature. The automatic detector can be trained without human intervention and no prior information. It is based only on objective seizure outcome data without relying on an expert's manual annotations. Using the method, we could find and characterize pathological and inhibitory activities. PMID- 29513149 TI - Motor action of the frontal eye field on the eyes and neck in the monkey. AB - Focal stimulation in the frontal eye field (FEF) evoked eye movements that were often accompanied by neck movements. Experiments were performed with concurrent recording of both movements in trained monkeys. We recorded neck forces under a head-restrained condition with a force-measuring system. With the system, we measured forces along the x-, y-, and z-axes and torque about the z-axis. Torque about the z-axis that represented yaw rotation of the head was significantly affected by stimulation. We found that stimulation generated two types of motor actions of the eyes and neck. In the first type, contraversive neck forces were evoked by stimulation of the medial part of the FEF, where contraversive saccadic eye movements with large amplitudes were evoked. When the stimulus intensity was increased, saccades were evoked in an all-or-none manner, whereas the amplitude of neck forces increased gradually. In the second type, contraversive neck forces were evoked by stimulation of the medial and caudal part of the FEF, where ipsiversive slow eye movements were evoked. The depth profiles of amplitudes of neck forces were almost parallel to those of eye movements in individual stimulation tracks. The present results suggest that the FEF is involved in the control of motor actions of the neck as well as the eyes. The FEF area associated with contraversive saccades and contraversive neck movements may contribute to a gaze shift process, whereas that associated with ipsiversive slow eye movements and contraversive neck movements may contribute to a visual stabilization process. NEW & NOTEWORTHY Focal stimulation in the frontal eye field (FEF) evoked eye and neck movements. We recorded neck forces under a head-restrained condition with a force-measuring system. Taking advantage of this approach, we could analyze slow eye movements that were dissociated from the vestibuloocular reflex. We found ipsiversive slow eye movements in combination with contraversive neck forces, suggesting that the FEF may be a source of a corollary discharge signal for compensatory eye movements during voluntary neck movements. PMID- 29513148 TI - Meridian interference reveals neural locus of motion-induced position shifts. AB - When a Gabor patch moves along a path in one direction while its internal texture drifts orthogonally to this path, it can appear to deviate from its physical path by 45 degrees or more. This double-drift illusion is different from other motion induced position shift effects in several ways: it has an integration period of over a second; the illusory displacement that accumulates over a second or more is orthogonal to rather than along the motion path; the perceptual deviations are much larger; and they have little or no effect on eye movements to the target. In this study we investigated the underlying neural mechanisms of the motion integration and position processing for this double-drift stimulus by testing possible anatomical constraints on its magnitude. We found that the illusion was reduced at the vertical and horizontal meridians when the perceptual path would cross or be driven toward the meridian, but not at other locations or other motion directions. The disruption of the accumulation of the position error at both the horizontal and vertical meridians suggests a central role of quadrantic areas in the generation of this type of motion-induced position shift. NEW & NOTEWORTHY The remarkably strong double-drift illusion is disrupted at both the vertical and horizontal meridians. We propose that this finding is the behavioral consequence of the anatomical gaps at both meridians, suggesting that neural areas with quadrantic representations (e.g., V2, V3) are the initial locus of this motion-induced position shift. This result rules out V1 as the source of the illusion because it has an anatomical break only at the vertical meridian. PMID- 29513150 TI - Structural modularity and grid activity in the medial entorhinal cortex. AB - Following the groundbreaking discovery of grid cells, the medial entorhinal cortex (MEC) has become the focus of intense anatomical, physiological, and computational investigations. Whether and how grid activity maps onto cell types and cortical architecture is still an open question. Fundamental similarities in microcircuits, function, and connectivity suggest a homology between rodent MEC and human posteromedial entorhinal cortex. Both are specialized for spatial processing and display similar cellular organization, consisting of layer 2 pyramidal/calbindin cell patches superimposed on scattered stellate neurons. Recent data indicate the existence of a further nonoverlapping modular system (zinc patches) within the superficial MEC layers. Zinc and calbindin patches have been shown to receive largely segregated inputs from the presubiculum and parasubiculum. Grid cells are also clustered in the MEC, and we discuss possible structure-function schemes on how grid activity could map onto cortical patch systems. We hypothesize that in the superficial layers of the MEC, anatomical location can be predictive of function; thus relating functional properties and neuronal morphologies to the cortical modules will be necessary for resolving how grid activity maps onto cortical architecture. Imaging or cell identification approaches in freely moving animals will be required for testing this hypothesis. PMID- 29513152 TI - Effect of moisture condition on the immobilization of Cd in red paddy soil using passivators. AB - In this study, the immobilization of cadmium (Cd) was evaluated in red paddy soil amended with four different passivators (biochar, lime (CaO), calcium dihydrogen phosphate (Ca(H2PO4)2) and zeolite (modified with NaOH)) for three moisture regimes (70% water-holding capacity (WHC), continuous flooding (CF) and wetting drying cycle (WDC)). The results showed that: the pH of the soil was obviously influenced by the moisture regimes and decreased in the general order of CF > WDC > 70% WHC, and the addition of lime and Ca(H2PO4)2 could obviously enhance and reduce the values to some extent, respectively. Flooding condition could enhance soil pH and increase the content of free Fe-oxides, amorphous Fe-oxides and water soluble organic/inorganic carbon in paddy soil. The efficiency in decreasing the exchangeable Cd of different moisture regimes followed the order: CF > 70%WHC > WDC. CF combined with lime was the most effective treatment for reducing exchangeable Cd. The transformation of Cd fractions mainly occurred between the acid-extractable and reducible fractions in the immobilization experiments. The most effective passivator is Ca(H2PO4)2, and CF is the most favorable regime in promoting the transformation of Cd in red paddy soil from acid-extractable to reducible fraction. PMID- 29513151 TI - Systemic inflammation inhibits serotonin receptor 2-induced phrenic motor facilitation upstream from BDNF/TrkB signaling. AB - Although systemic inflammation induced by even a low dose of lipopolysaccharide (LPS, 100 MUg/kg) impairs respiratory motor plasticity, little is known concerning cellular mechanisms giving rise to this inhibition. Phrenic motor facilitation (pMF) is a form of respiratory motor plasticity elicited by pharmacological agents applied to the cervical spinal cord, or by acute intermittent hypoxia (AIH; 3, 5-min hypoxic episodes); when elicited by AIH, pMF is known as phrenic long-term facilitation (pLTF). AIH consisting of moderate hypoxic episodes (mAIH, arterial Po2 = 35-55 mmHg) elicits pLTF via the Q pathway to pMF, a mechanism that requires spinal serotonin (5HT2) receptor activation and new brain-derived neurotrophic factor (BDNF) protein synthesis. Although mild systemic inflammation attenuates mAIH-induced pLTF via spinal p38 MAP kinase activation, little is known concerning how p38 MAP kinase activity inhibits the Q pathway. Here, we confirmed that 24 h after a low LPS dose (100 MUg/kg ip), mAIH induced pLTF is greatly attenuated. Similarly, pMF elicited by intrathecal cervical injections of 5HT2A (DOI; 100 MUM; 3 * 6 MUl) or 5HT2B receptor agonists (BW723C86; 100 MUM; 3 * 6 MUl) is blocked 24 h post-LPS. When pMF was elicited by intrathecal BDNF (100 ng, 12 MUl), pMF was actually enhanced 24 h post-LPS. Thus 5HT2A/2B receptor-induced pMF is impaired downstream from 5HT2 receptor activation, but upstream from BDNF/TrkB signaling. Mechanisms whereby LPS augments BDNF-induced pMF are not yet known. NEW & NOTEWORTHY These experiments give novel insights concerning mechanisms whereby systemic inflammation undermines serotonin-dependent, spinal respiratory motor plasticity, yet enhances brain-derived neurotrophic factor (BDNF)/TrkB signaling in phrenic motor neurons. These insights may guide development of new strategies to elicit functional recovery of breathing capacity in patients with respiratory impairment by reducing (or bypassing) the impact of systemic inflammation characteristic of clinical disorders that compromise breathing. PMID- 29513153 TI - Biomarkers identify the Binswanger type of vascular cognitive impairment. AB - Binswanger's disease is a form of subcortical ischemic vascular disease (SIVD-BD) with extensive white matter changes. To test the hypothesis that biomarkers could improve classification of SIVD-BD, we recruited 62 vascular cognitive impairment and dementia (VCID) patients. Multimodal biomarkers were collected at entry into the study based on clinical and neuropsychological testing, multimodal magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. The patients' diagnoses were confirmed by long-term follow-up, and they formed a "training set" to test classification methods, including (1) subcortical ischemic vascular disease score (SIVDS), (2) exploratory factor analysis (EFA), (3) logistic regression (LR), and (4) random forest (RF). A subsequently recruited cohort of 43 VCID patients with provisional diagnoses were used as a "test" set to calculate the probability of SIVD-BD based on biomarkers obtained at entry. We found that N-acetylaspartate (NAA) on proton magnetic resonance spectroscopy (1H MRS) was the best variable for classification, followed by matrix metalloproteinase-2 in CSF and blood-brain barrier permeability on MRI. Both LR and RF performed better in diagnosing SIVD-BD than either EFA or SIVDS. Two-year follow-up of provisional diagnosis patients confirmed the accuracy of statistically derived classifications. We propose that biomarker-based classification methods could diagnose SIVD-BD patients earlier, facilitating clinical trials. PMID- 29513154 TI - Dietary inflammatory index, bone health and body composition in a population of young adults: a cross-sectional study. AB - Diet quality has been postulated as a relevant factor in disorders like obesity and osteoporosis as it modulates inflammatory biomarkers. The aim of this study was to investigate whether the dietary inflammatory index (DII) is associated with bone health status and body composition parameters in a population of young adults. The study population consisted of 599 young adults (aged 20.41 +/- 2.72). Linear regression analysis revealed that weight and fat-free mass (FFM) were significantly associated with the DII after adjustments for age, sex and total energy (beta = -0.91, 95% CI -1.782, -0.213, p = .013 and beta = -0.059, 95% CI 0.842, -0.107, p = .011, respectively). Our results suggest that the inflammatory potential of diet, measured using the DII, is associated with obesity-related parameters such as FFM and weight, although it may not contribute to osteoporosis in early adulthood. PMID- 29513155 TI - Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake, clinically normal cats. AB - Objectives The aim of this study was to compare the effects of multiple once- or twice-daily oral dosage rates of the angiotensin II, type-1 receptor blocker, telmisartan (TEL), or placebo (PLA) on indirect systolic arterial blood pressure (SBP) in awake, clinically normal cats. Methods Utilizing an incomplete crossover design and following a 14 day acclimation period, 28 healthy laboratory cats were randomized to undergo treatment with three of the following 14 day treatment protocols, each separated by a 1 week washout period: oral PLA q24h, oral TEL at a dosage of 1, 1.5, 2 or 3 mg/kg q24h, or oral TEL at a dosage of 1 or 1.5 mg/kg q12h. Using the Doppler ultrasound method, indirect SBP was measured daily during each treatment period, and daily during the first 5 days of each washout period, approximately 3 h after administration of the morning treatment. Results Each treatment protocol was administered to a total of 12 cats. A statistically significant effect of treatment period was identified for the entire study; therefore, only data from the first treatment period (four cats per treatment group) were used for further analysis. Compared with PLA, during the first treatment period, SBP values were significantly lower in cats treated with TEL at all tested dosages by the second week of treatment. SBP remained significantly lower than in PLA-treated animals for 2 days following administration of the last dose in all TEL treatment groups. No clinical signs of hypotension were noted in any group. Conclusions and relevance These results suggest that treatment with TEL at a total daily dose of 1-3 mg/kg - administered as a single dose, or split into two equal doses administered 12 h apart - results in a significant, relatively long-lasting reduction of SBP in clinically normal cats. TEL appears to be well tolerated by normal cats at the dosages tested. PMID- 29513156 TI - Pretreatment Histoplasma capsulatum urine enzymatic immunoassay concentrations do not correlate with outcome but may be influenced by renal function in cats with histoplasmosis. AB - OBJECTIVES: The objective of this study was to determine if urine Histoplasma antigen (HAg) enzyme immunoassay (EIA) concentrations at the time of diagnosis and prior to the administration of antifungal agents are predictive of outcome for cats infected with Histoplasma capsulatum and to determine if compromised renal function affects urine HAg EIA measurements. METHODS: Medical records at four institutions were searched to identify cats diagnosed with histoplasmosis between April 2012 and December 2015. Pretreatment urine Histoplasma EIA values were recorded, along with patient signalment, serum creatinine concentration, urine specific gravity, site(s) of infection and survival data. RESULTS: Pretreatment urine HAg EIA measurements were available for 50 cats, and ranged from 0-19.1 ng/ml (median 6.3 ng/ml). Thirty-five cats were alive at day 180, 12 had died or were euthanized (median survival time 24 days; range 2-124 days) and three were lost to follow-up. The median urine HAg EIA at the time of diagnosis for cats alive at 6 months was 5 ng/ml (range 0-19.1); this was similar to findings for the non-survivors (median 7.29 ng/ml; range 0.78-19.1; P = 0.54). Surviving cats were significantly younger (mean age 6.9 years) than non-survivors (mean age 9.9 years; P = 0.03) but median body weights (3.8 kg vs 3.6 kg) and rates of pulmonary involvement (22/35 vs 9/12) were similar for the two groups. Median urine HAg EIA concentration was lower in cats with evidence of renal compromise than cats with acceptable renal function (0.54 ng/ml vs 7.2 ng/ml; P <0.013). CONCLUSIONS AND RELEVANCE: Urine HAg EIA concentrations at the time of diagnosis are not predictive of outcome in cats with histoplasmosis and should not be used as a prognostic indicator in this species. Renal function may influence urine HAg EIA concentrations in cats; further investigation is needed to see if concurrent kidney disease impacts test sensitivity. PMID- 29513157 TI - Use of lispro insulin for treatment of diabetic ketoacidosis in cats. AB - Objectives The aim of this study was to evaluate the efficacy and safety of lispro insulin for the treatment of feline diabetic ketoacidosis (DKA). Times to resolution of hyperglycaemia, ketosis and acidosis were compared between cats treated with continuous rate infusion (CRI) of lispro insulin and cats treated with CRI of regular insulin. Methods Client-owned cats with naturally occurring DKA, newly diagnosed with diabetes mellitus (DM) or already receiving treatment for DM, were included. Diagnosis of DKA involved the presence of at least two clinical signs consistent with DKA (eg, polyuria/polydipsia, anorexia, severe lethargy, vomiting and dehydration), blood glucose (BG) concentration >13.9 mmol/l (>250 mg/dl), blood beta hydroxybutyrate (BHB) concentration >2.5 mmol/l and venous pH <7.3 or bicarbonate <15 mEq/l. Cats were treated with a standard protocol of an intravenous (IV) CRI of regular insulin (group R) or lispro insulin (group L). The time to resolution of DKA was defined as the time interval from when the IV CRI of insulin began until marked hyperglycaemia (BG >13.9 mmol/l [>250 mg/dl]), ketosis (BHB concentration >1 mmol/l) and acidosis (venous pH <7.3 and/or bicarbonate <15 mEq/l) resolved. Results Eighteen DKA cases (nine per group) were enrolled into the study. There were no significant differences in the median time to resolution of three variables (hyperglycaemia, ketosis and acidosis) between the two groups. Two cats in group R developed hypoglycaemia during the CRI of insulin. One cat in group L and three cats in group R developed hypophosphataemia, which required phosphate supplementation. Conclusions and relevance IV CRI of lispro insulin has few side effects and appears to be as effective as IV CRI of regular insulin in the treatment of cats with DKA. PMID- 29513146 TI - The Biology of Regeneration Failure and Success After Spinal Cord Injury. AB - Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI. PMID- 29513158 TI - One size fits all? Disentangling the effects of tobacco taxes, laws, and control spending on adult subgroups in the United States. AB - BACKGROUND: To determine the relative impact of each of the 3 state-level tobacco control policies (cigarette taxation, tobacco control spending, and smoke-free air [SFA] laws) on adult smoking rate overall and separately for adult subgroups in the United States. METHODS: A difference-in-differences analysis was conducted with generalized propensity scores. State-level policies were merged with the individual-level Behavioral Risk Factor Surveillance System in 1995-2009. RESULTS: State cigarette taxation was the only policy that significantly impacted smoking among the general adult population, with a 1-standard deviation increase in taxes (i.e., $0.68 in constant 2014 dollars) lowering the adult smoking rate by about a quarter of a percentage point. The taxation impact was consistent, regardless of the presence of, or interactions with, other policies. Taxation was also the only policy that significantly reduced smoking for some adult subgroups, including females, non-Hispanic whites, adults aged 51 or older, and adults with more than a high school education. However, other adult subgroups responded to the other 2 types of policies, either by mediating the taxation effect or by reducing smoking independently. Specifically, tobacco control spending reduced smoking among young adults (ages 18-25 years) and Hispanics. SFA laws affected smoking among men, young adults, non-Hispanic blacks, and Hispanics. CONCLUSIONS: State cigarette taxation is the single most important policy for reducing smoking among the general adult population. However, adult subgroups' reactions to taxes are diverse and mediated by tobacco control spending and SFA laws. PMID- 29513159 TI - Elucidating the interaction of ticlopidine with serum albumin and its role in bilirubin displacement in vitro. AB - Ticlopidine is an anti-platelet drug that functions as a P2Y12 receptor antagonist. The present study provides a detailed characterization of interaction of ticlopidine with a model transport protein, bovine serum albumin (BSA) as well as an assessment of its bilirubin displacing ability using a multi-spectroscopic approach in combination with isothermal titration calorimetry. The value of binding constant determined using ITC studies was found to be 3.03 * 103 M-1 with a binding stoichiometry of approximately 1:1. Competitive site marker experiments indicate that ticlopidine binds to Sudlow site I, located in subdomain IIA of BSA. In addition, Circular dichroism and 3D fluorescence spectroscopy indicated structural and conformational changes in BSA on interaction with ticlopidine. Thermodynamic parameters suggested that the reaction was spontaneous, exothermic, entropically driven, and involved hydrophobic interactions. These results were well supported by those obtained through molecular docking studies. Additionally, the effect of ticlopidine on bilirubin and albumin interaction was evaluated using the peroxidase method as well as through fluorescence spectroscopy. Ticlopidine was found to displace bilirubin from serum albumin. Moreover, the binding constant of bilirubin-serum albumin interaction also decreased in presence of ticlopidine. The results indicated that ticlopidine is a competitive displacer of bilirubin in vitro and may contribute to the incidences hyperbilirubinemia associated with the usage of this drug. PMID- 29513160 TI - Prognostic value of serum levels of soluble MICA (sMICA) in patients with prostate cancer. PMID- 29513161 TI - The Digest. PMID- 29513162 TI - Erratum: Mahoney et al. (2014). AB - In the article "Mental Toughness in Sport: Motivational Antecedents and Associations With Performance and Psychological Health," by John W. Mahoney, Daniel F. Gucciardi, Nikos Ntoumanis, and Cliff J. Mallett, in the Journal of Sport & Exercise Psychology, 36(3), 281-292, http://dx.doi.org/10.1123/jsep.2013 0260, the fourth author's surname was inadvertently misspelled twice on page 281. Under the article title, the correct spelling should be Mallett. Likewise, in the footnote, the first sentence should read "John W. Mahoney and Cliff J. Mallett are with the School of Human Movement Studies, University of Queensland." PMID- 29513164 TI - Erratum. PMID- 29513163 TI - Electrical stimulation promotes regeneration and re-myelination of axons of injured facial nerve in rats. AB - Objective To investigate the effects of electrical stimulation (ES) on the nerve regeneration and functional recovery of facial expression muscles in facial nerve defect rats. Methods Sixty rats were surgically introduced with a 1-cm defect on the right facial nerves and evenly divided into the Surgery group (Group A, the main trunk of the right facial nerve was surgically cut-off with a 1.0 cm at the foramina stylomastoideum) and the Surgery + ES group (Group B). Twenty normal rats were as normal control group (without receiving surgery or ES). For rats in group B, the orbicularis oris muscle of the right paralyzed face was stimulated with an electrical pulse of 3 V, 20 Hz and 0.3 mA for 1 h each day. The effects of ES on the facial muscle movement, compound muscle action potentials (CMAPs), histological structure, and the expression levels of S100B and NF200 proteins were comparatively studied. Results In group A, facial paralysis scores were slightly improved from day 1 to 28; the facial nerve trunks had swelled and malformed till day 14; and CMAPs could be induced in fewer animals and were abnormal, resulting in a slow recovery of the facial muscle movement. In group B, facial paralysis scores were improved from 4 to 2.6 during the 4 weeks; more rats showed a higher amplitude and shorter latency of CMAPs from day 14 to 28 after surgery; and increased axons and the expression of S100B and NF200 proteins and gradually decreased swelling in the injured facial nerve. Conclusion ES promotes outgrowth and myelination of axons and a partial functional recovery of facial muscles in injured facial nerve rats. PMID- 29513165 TI - Experimental research on bypass evaporation tower technology for zero liquid discharge of desulfurization wastewater. AB - Zero liquid discharge (ZLD) of wastewater has become the trend of environmental governance after the implementation of 'The Action Plan for Prevention and Treatment of Water Pollution' in China, desulfurization wastewater has gained more attention due to its complex composition and heavy metals. However, current technologies for ZLD have some shortcomings such as high cost and insufficient processing capacity, ZLD cannot be achieved actually. This paper proposes a new evaporation drying technology. An independent bypass evaporation tower was built, part of the hot flue gas before the air preheater was introduced into the evaporation tower for desulfurization wastewater evaporation, and the generated dust after evaporation was discharged back to the flue duct before electrostatic precipitator. This paper reports on the performance of desulfurization wastewater evaporation and the characteristics of evaporation products in depth and makes a comprehensive discussion of the impact on the existing equipment based on the self-designed evaporation tower. Research suggests that this technology has high system reliability and little effect on subsequent equipment and provides theoretical and practical data. Due to environmental policies and huge market demand for ZLD of desulfurization wastewater, bypass evaporation tower technology has a great application prospect in the future. PMID- 29513192 TI - SkipCPP-Pred: an improved and promising sequence-based predictor for predicting cell-penetrating peptides. AB - BACKGROUND: Cell-penetrating peptides (CPPs) are short peptides (5-30 amino acids) that can enter almost any cell without significant damage. On account of their high delivery efficiency, CPPs are promising candidates for gene therapy and cancer treatment. Accordingly, techniques that correctly predict CPPs are anticipated to accelerate CPP applications in future therapeutics. Recently, computational methods have been reportedly successful in predicting CPPs. Unfortunately, the predictive performance of existing methods is not satisfactory and reliable so as to accurately identify CPPs. RESULTS: In this study, we propose a novel computational predictor called SkipCPP-Pred to further improve the predictive performance. The novelty of the proposed predictor is that we present a sequence-based feature representation algorithm called adaptive k-skip n-gram that sufficiently captures the intrinsic correlation information of residues. By fusing the proposed adaptive skip features with a random forest (RF) classifier, we successfully construct the prediction model of SkipCPP-Pred. The various jackknife results demonstrate that the proposed SkipCPP-Pred is 3.6% higher than state-of-the-art CPP predictors in terms of accuracy. Moreover, we construct a high-quality benchmark dataset by reducing the data redundancy and enhancing the similarity between the positive and negative classes. Using this dataset to build prediction models, we can successfully avoid the performance bias lying in existing methods and yield a promising predictive model. CONCLUSIONS: The proposed SkipCPP-Pred is a simple and fast sequence-based predictor featured with the adaptive k-skip-n-gram model for the improved prediction of CPPs. Currently, SkipCPP-Pred is publicly available from an online webserver ( http://server.malab.cn/SkipCPP-Pred/Index.html ). PMID- 29513193 TI - Semantic biclustering for finding local, interpretable and predictive expression patterns. AB - BACKGROUND: One of the major challenges in the analysis of gene expression data is to identify local patterns composed of genes showing coherent expression across subsets of experimental conditions. Such patterns may provide an understanding of underlying biological processes related to these conditions. This understanding can further be improved by providing concise characterizations of the genes and situations delimiting the pattern. RESULTS: We propose a method called semantic biclustering with the aim to detect interpretable rectangular patterns in binary data matrices. As usual in biclustering, we seek homogeneous submatrices, however, we also require that the included elements can be jointly described in terms of semantic annotations pertaining to both rows (genes) and columns (samples). To find such interpretable biclusters, we explore two strategies. The first endows an existing biclustering algorithm with the semantic ingredients. The other is based on rule and tree learning known from machine learning. CONCLUSIONS: The two alternatives are tested in experiments with two Drosophila melanogaster gene expression datasets. Both strategies are shown to detect sets of compact biclusters with semantic descriptions that also remain largely valid for unseen (testing) data. This desirable generalization aspect is more emphasized in the strategy stemming from conventional biclustering although this is traded off by the complexity of the descriptions (number of ontology terms employed), which, on the other hand, is lower for the alternative strategy. PMID- 29513194 TI - An uncertain model-based approach for identifying dynamic protein complexes in uncertain protein-protein interaction networks. AB - BACKGROUND: Recently, researchers have tried to integrate various dynamic information with static protein-protein interaction (PPI) networks to construct dynamic PPI networks. The shift from static PPI networks to dynamic PPI networks is essential to reveal the cellular function and organization. However, it is still impossible to construct an absolutely reliable dynamic PPI networks due to the noise and incompletion of high-throughput experimental data. RESULTS: To deal with uncertain data, some uncertain graph models and theories have been proposed to analyze social networks, electrical networks and biological networks. In this paper, we construct the dynamic uncertain PPI networks to integrate the dynamic information of gene expression and the topology information of high-throughput PPI data. The dynamic uncertain PPI networks can not only provide the dynamic properties of PPI, which are neglected by static PPI networks, but also distinguish the reliability of each protein and PPI by the existence probability. Then, we use the uncertain model to identify dynamic protein complexes in the dynamic uncertain PPI networks. CONCLUSION: We use gene expression data and different high-throughput PPI data to construct three dynamic uncertain PPI networks. Our approach can achieve the state-of-the-art performance in all three dynamic uncertain PPI networks. The experimental results show that our approach can effectively deal with the uncertain data in dynamic uncertain PPI networks, and improve the performance for protein complex identification. PMID- 29513195 TI - Improving somatic variant identification through integration of genome and exome data. PMID- 29513196 TI - Phylogeny analysis from gene-order data with massive duplications. AB - BACKGROUND: Gene order changes, under rearrangements, insertions, deletions and duplications, have been used as a new type of data source for phylogenetic reconstruction. Because these changes are rare compared to sequence mutations, they allow the inference of phylogeny further back in evolutionary time. There exist many computational methods for the reconstruction of gene-order phylogenies, including widely used maximum parsimonious methods and maximum likelihood methods. However, both methods face challenges in handling large genomes with many duplicated genes, especially in the presence of whole genome duplication. METHODS: In this paper, we present three simple yet powerful methods based on maximum-likelihood (ML) approaches that encode multiplicities of both gene adjacency and gene content information for phylogenetic reconstruction. RESULTS: Extensive experiments on simulated data sets show that our new method achieves the most accurate phylogenies compared to existing approaches. We also evaluate our method on real whole-genome data from eleven mammals. The package is publicly accessible at http://www.geneorder.org . CONCLUSIONS: Our new encoding schemes successfully incorporate the multiplicity information of gene adjacencies and gene content into an ML framework, and show promising results in reconstruct phylogenies for whole-genome data in the presence of massive duplications. PMID- 29513197 TI - An improved burden-test pipeline for identifying associations from rare germline and somatic variants. AB - BACKGROUND: Identifying rare germline and somatic variants associated with cancer progression is an important research topic in cancer genomics. Although many approaches are proposed for rare variant association study, they are not fit for cancer sequencing data due to multiple issues, such as overly relying on pre selection, losing sight of interacting hotspots, etc. RESULTS: In this article, we propose an improved pipeline to identify germline variant and somatic mutation interactions influencing cancer susceptibility from pair-wise cancer sequencing data. The proposed pipeline, RareProb-C performs an algorithmic selection on the given variants by incorporating the variant allelic frequencies. The interactions among the variants are considered within the regions which are limited by a four gamete test. Then it filters singular cases according to the posterior probability at each site. Finally, it outputs the selected candidates that pass a collapse test. CONCLUSIONS: We apply RareProb-C on a series of carefully constructed simulation cases and it outperforms six existing genetic model-free approaches. We also test RareProb-C on 429 TCGA ovarian cancer cases, and RareProb-C successfully identifies the known highlighted variants which are considered increasing disease susceptibilities. PMID- 29513198 TI - Epistasis analysis of microRNAs on pathological stages in colon cancer based on an Empirical Bayesian Elastic Net method. AB - BACKGROUND: Colon cancer is a leading cause of worldwide cancer death. It has become clear that microRNAs (miRNAs) play a role in the progress of colon cancer and understanding the effect of miRNAs on tumorigenesis could lead to better prognosis and improved treatment. However, most studies have focused on studying differentially expressed miRNAs between tumor and non-tumor samples or between stages in tumor tissue. Limited work has conducted to study the interactions or epistasis between miRNAs and how the epistasis brings about effect on tumor progression. In this study, we investigate the main and pair-wise epistatic effects of miRNAs on the pathological stages of colon cancer using datasets from The Cancer Genome Atlas. RESULTS: We develop a workflow composed of multiple steps for feature selection based on the Empirical Bayesian Elastic Net (EBEN) method. First, we identify the main effects using a model with only main effect on the phenotype. Second, a corrected phenotype is calculated by removing the significant main effect from the original phenotype. Third, we select features with epistatic effect on the corrected phenotype. Finally, we run the full model with main and epistatic effects on the previously selected main and epistatic features. Using the multi-step workflow, we identify a set of miRNAs with main and epistatic effect on the pathological stages of colon cancer. Many of miRNAs with main effect on colon cancer have been previously reported to be associated with colon cancer, and the majority of the epistatic miRNAs share common target genes that could explain their epistasis effect on the pathological stages of colon cancer. We also find many of the target genes of detected miRNAs are associated with colon cancer. Go Ontology Enrichment Analysis of the experimentally validates targets of main and epistatic miRNAs, shows that these target genes are enriched for biological processes associated with cancer progression. CONCLUSION: Our results provide a set of candidate miRNAs associated with colon cancer progression that could have potential translational and therapeutic utility. Our analysis workflow offers a new opportunity to efficiently explore epistatic interactions among genetic and epigenetic factors that could be associated with human diseases. Furthermore, our workflow is flexible and can be applied to analyze the main and epistatic effect of various genetic and epigenetic factors on a wide range of phenotypes. PMID- 29513199 TI - Apes, skulls and drums: using images to make ethnographic knowledge in imperial Germany. AB - In this paper, I discuss the development and use of images employed by the Dresden Royal Museum for Zoology, Anthropology and Ethnography to resolve debates about how to use visual representation as a means of making ethnographic knowledge. Through experimentation with techniques of visual representation, the founding director, A.B. Meyer (1840-1911), proposed a historical, non essentialist approach to understanding racial and cultural difference. Director Meyer's approach was inspired by the new knowledge he had gained through field research in Asia-Pacific as well as new forms of imaging that made highly detailed representations of objects possible. Through a combination of various techniques, he developed new visual methods that emphasized intimate familiarity with variations within any one ethnic group, from skull shape to material ornamentation, as integral to the new disciplines of physical and cultural anthropology. It is well known that photographs were a favoured form of visual documentation among the anthropological and ethnographic sciences at the fin de siecle. However, in the scholarly journals of the Dresden museum, photographs, drawings, tables and etchings were frequently displayed alongside one another. Meyer sought to train the reader's eye through organized arrangements that represented objects from multiple angles and at various levels of magnification. Focusing on chimpanzees, skulls and kettledrums from Asia-Pacific, I track the development of new modes of making and reading images, from zoology and physical anthropology to ethnography, to demonstrate how the museum visually historicized humankind. PMID- 29513200 TI - Utopian biologies. AB - In 1924, the British biologist J.B.S. Haldane acknowledged that anyone who tried to predict where science was taking us was obliged to mention H.G. Wells, since '[t]he very mention of the future suggests him'. Nevertheless, Haldane complained that Wells was 'a generation behind the time', having been raised when flying and radiotelegraphy were genuinely scientific questions, but they were now mere 'commercial problems', Haldane asserted, and 'I believe that the centre of scientific interest lies in biology'. Haldane's conviction that biology was the key to the future was widely shared, and lies in the background of both these books. Helen Curry examines the early history of the dream of engineering new kinds of plants, using first X-rays, then colchicine (a chemical mutagen), and then the new sources of intense radioactivity that were created by the early nuclear reactors. By contrast, Ewa Luczak is interested in the influence of eugenics on American literature, focusing particularly on Jack London, Charlotte Perkins Gilman and George Schuyler. What unites these books (and the diverse topics they address) is new ways of imagining the future, specifically a future based in biology. PMID- 29513201 TI - Involvement of patients and parents in research generated by the Australian and New Zealand Fontan Registry. PMID- 29513202 TI - Transcatheter closure of ventricular septal defect with Occlutech Duct Occluder. AB - Patent ductus arteriosus occluders are used for transcatheter closure of ventricular septal defects, as well as for closure of patent ductus arteriosus. The Occlutech Duct Occluder is a newly introduced device for transcatheter closure of patent ductus arteriosus. Here, we present a case in which the Occlutech Duct Occluder was successfully used on a patient for the closure of a perimembraneous ventricular septal defect. PMID- 29513203 TI - Disopyramide use in infants and children with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy has a range of clinical severity in children. Treatment options are limited, mainly on account of small patient size. Disopyramide is a sodium channel blocker with negative inotropic properties that effectively reduces left ventricular outflow tract gradients in adults with hypertrophic cardiomyopathy, but its efficacy in children is uncertain. A retrospective chart review of patients ?21 years of age with hypertrophic cardiomyopathy at our institution and treated with disopyramide was performed. Left ventricular outflow tract Doppler gradients before and after disopyramide initiation were compared as the primary outcome measure. Nine patients received disopyramide, with a median age of 5.6 years (range 6 days-12.9 years). The median left ventricular outflow tract Doppler gradient before initiation of disopyramide was 81 mmHg (range 30-132 mmHg); eight patients had post-initiation echocardiograms, in which the median lowest recorded Doppler gradient was 43 mmHg (range 15-100 mmHg), for a median % reduction of 58.2% (p=0.002). With median follow-up of 2.5 years, eight of nine patients were still alive, although disopyramide had been discontinued in six of the nine patients. Reasons for discontinuation included septal myomectomy (four patients), heart transplantation (one patient), and side effects (one patient). Disopyramide was effective for the relief of left ventricular outflow tract obstruction in children with hypertrophic cardiomyopathy, although longer-term data suggest that its efficacy is not sustained. In general, it was well tolerated. Further study in larger patient populations is warranted. PMID- 29513204 TI - Rare presentation of Candida albicans: infective endocarditis and a pulmonary coin lesion. AB - We present a case of a rare association of infective endocarditis and a coin lesion in the lung caused by Candida albicans. The lesion disappeared after 6 weeks of treatment with 5 mg/kg/day amphotericin B. PMID- 29513206 TI - Open Reduction with Internal Fixation of Mandibular Angle Fractures: A Retrospective Study. AB - OBJECTIVE: The goal of this project was to report the complications associated with mandibular angle fractures and identify variables affecting their occurrence. METHODS: We retrospectively reviewed the charts of patients with a mandibular angle fracture treated at the Centre hospitalier universitaire de Quebec between 2009 and 2013. RESULTS: Seventy-eight patients (73 males) aged 15 59 years (mean 25.2 years) met our inclusion criteria. A wisdom tooth was present in 85.9% (n = 67) of the cases and it was removed 62.7% (n = 42) of the time. Thirty-four patients (43.6%) had other mandibular fractures. Most fractures were fixated with a sagittal split osteotomy plate (n = 32; 41.0%) or a 2.0-mm plate on the lateral aspect of the mandible (n = 20; 25.6%). The overall complication rate was 42.3% (n = 33); of these 37.2% were infections, 26.9% involved plate removal and 6.4% were associated with non-union. Older patients had more infections (p = 0.03) and more plates removed (p = 0.03). When a wisdom tooth was extracted, more infections (p = 0.04) and overall complications (p = 0.02) were observed. CONCLUSION: This study confirms that, when treating a mandibular angle fracture in a healthy patient, it may be beneficial to leave a wisdom tooth in the line of fracture in place, if there is no indication to remove it. PMID- 29513205 TI - Validation of the Brief Developmental Assessment in pre-school children with heart disease. AB - : Introduction The objective of this study was to prospectively validate the "Brief Developmental Assessment", which is a new early recognition tool for neurodevelopmental abnormalities in children with heart disease that was developed for use by cardiac teams. METHODS: This was a prospective validation study among a representative sample of 960 pre-school children with heart disease from three United Kingdom tertiary cardiac centres who were analysed grouped into five separate age bands. RESULTS: The "Brief Developmental Assessment" was successfully validated in the older four age bands, but not in the youngest representing infants under the age of 4 months, as pre-set validation thresholds were met - lower 95% confidence limit for the correlation coefficient above 0.75 in terms of agreement of scores between two raters and with an external measure the "Mullen Scales of Early Learning". On the basis of American Association of Pediatrics Guidelines, which state that the sensitivity and specificity of a developmental screening tool should fall between 70 and 80%, "Brief Developmental Assessment" outcome of Red meets this threshold for detection of Mullen scores >2 standard deviations below the mean. CONCLUSION: The "Brief Developmental Assessment" may be used to improve the quality of assessment of children with heart disease. This will require a training package for users and a guide to action for abnormal results. Further research is needed to determine how best to deploy the "Brief Developmental Assessment" at different time points in children with heart disease and to determine the management strategy in infants younger than 4 months old. PMID- 29513207 TI - Can Dentists Help Patients Quit Smoking? The Role of Cessation Medications. AB - BACKGROUND: Clinical trials show the efficacy of dentists' counseling in smoking cessation. However, little is known about the effectiveness of such advice in the general population of smokers. OBJECTIVE: To examine the association between dentists' advice, use of cessation medications and quitting behaviours in the general population of adult smokers in Ontario, Canada. METHODS: Data were from the Ontario Tobacco Survey panel study, which followed people who were smokers in July 2005 semi-annually for up to 3 years until June 2011. Baseline smokers, who were seen by a dentist during the study, were included in the analysis (n = 2714 with 7549 observations). Logistic regression analysis with generalized estimating equations was used to examine associations among dentists' advice, use of cessation medications and quitting outcomes (quit attempts and short-term quitting >= 30 days). RESULTS: Those who received dentists' advice were more addicted to tobacco, compared with those who did not receive dentists' advice (self-perceived addiction to tobacco: 96% vs. 89%, p < 0.001). Dentists' advice alone was not associated with making an attempt to quit smoking or short-term quitting. However, receiving dentists' advice in conjunction with cessation medications was associated with a higher likelihood of quit attempts (adjusted odds ratio [OR] 9.85, 95% confidence interval [CI] 7.77-12.47) and short-term quitting (adjusted OR 3.19, 95% CI 2.20-4.62), compared with not receiving dentists' advice and not using cessation medications. CONCLUSION: Dentists play an important role in smoking cessation, because they can encourage patients to stop smoking and promote success by advising patients to use cessation medications. PMID- 29513208 TI - Use of and Access to Deep Sedation and General Anesthesia for Dental Patients: A Survey of Ontario Dentists. AB - OBJECTIVE: This study aims to assess barriers to the use of deep sedation/general anesthesia (DS/GA) identified by dentists in Ontario. METHODS: An email invitation to a web-based survey was distributed to all licensed dentists and specialists who have provided an email address to the provincial regulator (n = 5507). Descriptive and regression analyses were performed to explore practice and demographic factors associated with the use of DS/GA. RESULTS: The response rate was 18.3%. A quarter (24.8%) of respondents reported inadequate access to DS/GA. Access was poorest in rural communities and greatest in the Greater Toronto Area (GTA). Overall, 74.5% of dentists indicated that they had used DS/GA in the past 12 months. Use was defined as having provided the service or referred a patient in the past 12 months. Non-use was most likely among general dentists, part-time dentists, dentists > 64 years and dentists in urban locations. Wait times and travel distances were reported as longer for medically complex patients. The most common reasons for non-use of DS/GA were a lack of perceived demand and additional costs to patients. For DS/GA users, the greatest barrier was additional costs to patients. CONCLUSION: Access to DS/GA in Ontario is not uniform; it remains a challenge in rural communities and regions outside the GTA, especially in the north. Use is lowest among general dentists and urban dentists despite adequate access, with dentists' perception of need for DS/GA and cost to the patient acting as major barriers. Education for dentists and better insurance coverage for patients may improve access for these patients. PMID- 29513209 TI - Pharmacotherapy in Temporomandibular Disorders: A Review. AB - Temporomandibular disorder (TMD) is a collective term that includes disorders of the temporomandibular joint (TMJ) and of the masticatory muscles and their associated structures. TMDs are characterized by pain, joint sounds and restricted mandibular movement, and drugs are widely used in the management of that pain. Pharmacological agents commonly used for the treatment of TMDs include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, corticosteroids, muscle relaxants, antidepressants, anticonvulsants and benzodiazepines. In this paper, we discuss these agents and the potential adverse drug reactions and interactions associated with their use. Temporomandibular disorder (TMD) is a collective term used for a number of clinical problems that involve the masticatory muscle complex, the temporomandibular joint (TMJ) and associated structures. TMD is one of the most common disorders in the maxillofacial region. Signs and symptoms of TMD may include pain, impaired jaw function, malocclusion, deviation from the midline on opening or closing the jaw, limited range of motion, joint noises and locking.1 Among other signs and symptoms, headaches and sleep disturbances can appear concomitantly.2 This disorder is most prevalent in people aged 20-40 years.3 Approximately 33% of the population have at least 1 TMD symptom, and 3.6 7.0% of the population have TMD with sufficient severity to seek treatment.3 There is some evidence to suggest that anxiety, stress and other emotional disturbances exacerbate TMD.4 As many as 75% of patients with TMD have a significant psychological abnormality.5 Most TMD symptoms resolve over time, but, for a significant number of patients, this may take a year or more.3 Treatment is directed toward reducing pain and improving function. Many non-invasive therapies, such as self-care, physical therapy and appliance therapy, are commonly used for the treatment of TMD.3 Pharmacological intervention has been used for many years, and the most effective pharmacological agents for the treatment of TMD include analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, corticosteroids, anxiolytics, muscle relaxants, antidepressants, anticonvulsants and benzodiazepines. However, we found only 1 relevant Cochrane study, which included 11 randomized controlled trials of pharmacotherapy for TMD.6 In this article, we review the pharmacology and research supporting the use of a host of pharmacologic agents that have been prescribed for patients who have TMD. The decision to select any of these agents depends on a full understanding of the drug's risks and benefits. PMID- 29513210 TI - Antibiotic and Opioid Analgesic Prescribing Patterns of Dentists in Vancouver and Endodontic Specialists in British Columbia. AB - AIM: To assess the prescribing decisions of general dentists in Vancouver and endodontists in British Columbia regarding analgesics and antibiotics for patients with endodontic disease. An additional aim was to determine whether gender, clinical experience or practice location have an impact on such decisions. METHODS: A 4-page survey was developed and distributed to approximately half the general dentists in Vancouver (n = 259) and all of the endodontists in British Columbia (n = 50). Basic demographic questions were followed by 7 clinical scenarios and a list of endodontic diagnoses. Participants were asked questions regarding their decisions to prescribe analgesics and antibiotics. RESULTS: The overall response rate was 49%: 72% of endodontists responded, compared with 45% of general dentists. A substantial proportion of clinicians prescribed opioid analgesics and antibiotics in the various clinical scenarios. The rate of prescription of opioid analgesics ranged from 4%-47% for the various scenarios; the rate of prescription of antibiotics was 5%-88%. General dentists reported prescribing opioid analgesics and antibiotics more often than endodontists. Gender, clinical experience and practice location did not seem to have an impact on the decision to prescribe opioid analgesics or antibiotics. CONCLUSIONS: Based on the results of our survey, a significant proportion of dental professionals in British Columbia prescribe opioid analgesics and antibiotics during endodontic procedures when they are likely not required. General dentists tend to prescribe these medications more often than endodontists. We found no apparent differences in terms of gender, clinical experience or practice location. Dentists must be conscientious when prescribing these medications as over-prescription has negative consequences. PMID- 29513211 TI - Sterilization of Ceramic Sharpening Stones. AB - Traditionally, periodontal hand instruments are honed or sharpened during patient care as they dull easily during contact with enamel, calculus and cementum. This approach is taught in dental and hygiene schools around the world and remains the standard of care. Recently, some professional organizations have questioned whether this practice should be abandoned because of safety issues. Questions have been raised whether sharpening stones can be properly sterilized and whether the sharpening of contaminated instruments poses a health hazard for the provider. Using bacteria culture techniques and scanning electron microscopy, we tested whether contaminated ceramic sharpening stones can be sterilized. Our results demonstrate that the stones were sterile after being subjected to the manufacturer's sterilization protocol. In addition, over the last year, no incidents related to periodontal instrument sharpening have been reported among nearly 400 students at the faculty of dentistry, University of British Columbia, where chair-side sharpening is taught. Therefore, we conclude that ceramic sharpening stones can be sterilized using normal office protocols and that chair side sharpening adds little risk beyond routine handling of operatory or periodontal instruments during patient care when proper protocols are followed. PMID- 29513213 TI - Culturally adapted musical intervention for patient-centred health care. PMID- 29513212 TI - The Perfect Storm: What's Pushing Canadians Abroad for Dental Care? AB - We examine the perspectives of 14 key informants with extensive knowledge of dental care provision in Canada regarding systemic factors that could push Canadians to participate in dental tourism. Drawing on interview discussions about Canadians' access to dental care and their participation in dental tourism, we identify systemic factors related to how dental care is financed and delivered, rising costs of dental care and consumerism in terms of their potential role in Canadians' decisions to purchase dental care abroad. Further research on individual experiences accessing and using dental care, both in Canada and abroad, could help provide a better understanding of how these factors are informing Canadians' decision-making regarding dental care and, as a result, access to needed care. PMID- 29513214 TI - Biochemical Stability and Interactions of Dental Resin Composites and Adhesives with Host and Bacteria in the Oral Cavity: A Review. AB - The use of resin composites and adhesives in dental restorations is ubiquitous. However, the longevity of resin composites is less than that of comparable restorative materials, mainly because of higher fracture rates and greater prevalence of secondary caries. Dental resin composites and adhesives contain ester links, which are vulnerable to biochemical hydrolysis by esterase activity from human saliva and bacteria. In this article, we review biodegradation processes that occur in the oral cavity and their contribution to the premature failure of resin composites. Biodegradation causes deterioration of resin composite bulk and the composite-tooth interface and releases by-products, such as methacrylic acid, triethylene glycol and bishydroxy-propoxy-phenyl-propane. These by-products have been shown to affect cariogenic bacterial growth and virulence. A compromised restoration-tooth interface allows saliva and oral bacteria to infiltrate the spaces between the tooth and the composite, exacerbating the effects of biodegradation, undermining the restoration and leading to recurrent caries, hypersensitivity and pulpal inflammation. It is important to consider the biochemical stability of these materials to advance their chemistry beyond the current formulations and conceive more biochemically stable and better-performing dental resin composites and adhesives. PMID- 29513215 TI - The sweet side of vimentin. AB - A protein modification called O-linked glycosylation regulates the interactions between vimentin molecules under normal conditions, and the ability of Chlamydia bacteria to replicate after they infect cells. PMID- 29513216 TI - cisTEM, user-friendly software for single-particle image processing. AB - We have developed new open-source software called cisTEM (computational imaging system for transmission electron microscopy) for the processing of data for high resolution electron cryo-microscopy and single-particle averaging. cisTEM features a graphical user interface that is used to submit jobs, monitor their progress, and display results. It implements a full processing pipeline including movie processing, image defocus determination, automatic particle picking, 2D classification, ab-initio 3D map generation from random parameters, 3D classification, and high-resolution refinement and reconstruction. Some of these steps implement newly-developed algorithms; others were adapted from previously published algorithms. The software is optimized to enable processing of typical datasets (2000 micrographs, 200 k - 300 k particles) on a high-end, CPU-based workstation in half a day or less, comparable to GPU-accelerated processing. Jobs can also be scheduled on large computer clusters using flexible run profiles that can be adapted for most computing environments. cisTEM is available for download from cistem.org. PMID- 29513217 TI - Drosophila Fezf coordinates laminar-specific connectivity through cell-intrinsic and cell-extrinsic mechanisms. AB - Laminar arrangement of neural connections is a fundamental feature of neural circuit organization. Identifying mechanisms that coordinate neural connections within correct layers is thus vital for understanding how neural circuits are assembled. In the medulla of the Drosophila visual system neurons form connections within ten parallel layers. The M3 layer receives input from two neuron types that sequentially innervate M3 during development. Here we show that M3-specific innervation by both neurons is coordinated by Drosophila Fezf (dFezf), a conserved transcription factor that is selectively expressed by the earlier targeting input neuron. In this cell, dFezf instructs layer specificity and activates the expression of a secreted molecule (Netrin) that regulates the layer specificity of the other input neuron. We propose that employment of transcriptional modules that cell-intrinsically target neurons to specific layers, and cell-extrinsically recruit other neurons is a general mechanism for building layered networks of neural connections. PMID- 29513218 TI - TANGO1 builds a machine for collagen export by recruiting and spatially organizing COPII, tethers and membranes. AB - Collagen export from the endoplasmic reticulum (ER) requires TANGO1, COPII coats, and retrograde fusion of ERGIC membranes. How do these components come together to produce a transport carrier commensurate with the bulky cargo collagen? TANGO1 is known to form a ring that corrals COPII coats, and we show here how this ring or fence is assembled. Our data reveal that a TANGO1 ring is organized by its radial interaction with COPII, and lateral interactions with cTAGE5, TANGO1-short or itself. Of particular interest is the finding that TANGO1 recruits ERGIC membranes for collagen export via the NRZ (NBAS/RINT1/ZW10) tether complex. Therefore, TANGO1 couples retrograde membrane flow to anterograde cargo transport. Without the NRZ complex, the TANGO1 ring does not assemble, suggesting its role in nucleating or stabilising this process. Thus, coordinated capture of COPII coats, cTAGE5, TANGO1-short, and tethers by TANGO1 assembles a collagen export machine at the ER. PMID- 29513219 TI - Distinct contributions of functional and deep neural network features to representational similarity of scenes in human brain and behavior. AB - Inherent correlations between visual and semantic features in real-world scenes make it difficult to determine how different scene properties contribute to neural representations. Here, we assessed the contributions of multiple properties to scene representation by partitioning the variance explained in human behavioral and brain measurements by three feature models whose inter correlations were minimized a priori through stimulus preselection. Behavioral assessments of scene similarity reflected unique contributions from a functional feature model indicating potential actions in scenes as well as high-level visual features from a deep neural network (DNN). In contrast, similarity of cortical responses in scene-selective areas was uniquely explained by mid- and high-level DNN features only, while an object label model did not contribute uniquely to either domain. The striking dissociation between functional and DNN features in their contribution to behavioral and brain representations of scenes indicates that scene-selective cortex represents only a subset of behaviorally relevant scene information. PMID- 29513220 TI - Orbitofrontal neurons signal sensory associations underlying model-based inference in a sensory preconditioning task. AB - Using knowledge of the structure of the world to infer value is at the heart of model-based reasoning and relies on a circuit that includes the orbitofrontal cortex (OFC). Some accounts link this to the representation of biological significance or value by neurons in OFC, while other models focus on the representation of associative structure or cognitive maps. Here we tested between these accounts by recording OFC neurons in rats during an OFC-dependent sensory preconditioning task. We found that while OFC neurons were strongly driven by biological significance or reward predictions at the end of training, they also showed clear evidence of acquiring the incidental stimulus-stimulus pairings in the preconditioning phase, prior to reward training. These results support a role for OFC in representing associative structure, independent of value. PMID- 29513223 TI - A creative team. PMID- 29513222 TI - Acquired Chiari I Malformation Secondary to Spontaneous Intracranial Hypotension Syndrome and Persistent Hypoglycemia: A Case Report AB - Spontaneous intracranial hypotension (SIH) is a rare and potentially serious condition in childhood. Cerebrospinal fluid (CSF) volume depletion is thought to be the main causative feature for intracranial hypotension and results from a spontaneous CSF leak, often at the spine level. SIH is increasingly diagnosed in clinical practice, although it manifests a varied symptomatology. The downward displacement of the brain, sometimes mimicking a Chiari I malformation, has rarely been reported. We present a case of a SIH with Chiari I malformation accompanied by an unusual clinical presentation of persistent hypoglycemia. PMID- 29513224 TI - Horse or zebra? PMID- 29513221 TI - Site-specific glycosylation regulates the form and function of the intermediate filament cytoskeleton. AB - Intermediate filaments (IF) are a major component of the metazoan cytoskeleton and are essential for normal cell morphology, motility, and signal transduction. Dysregulation of IFs causes a wide range of human diseases, including skin disorders, cardiomyopathies, lipodystrophy, and neuropathy. Despite this pathophysiological significance, how cells regulate IF structure, dynamics, and function remains poorly understood. Here, we show that site-specific modification of the prototypical IF protein vimentin with O-linked beta-N-acetylglucosamine (O GlcNAc) mediates its homotypic protein-protein interactions and is required in human cells for IF morphology and cell migration. In addition, we show that the intracellular pathogen Chlamydia trachomatis, which remodels the host IF cytoskeleton during infection, requires specific vimentin glycosylation sites and O-GlcNAc transferase activity to maintain its replicative niche. Our results provide new insight into the biochemical and cell biological functions of vimentin O-GlcNAcylation, and may have broad implications for our understanding of the regulation of IF proteins in general. PMID- 29513225 TI - Beyond restorative dentistry: preventive and interim care for underserved populations. PMID- 29513227 TI - Surrogate decision-making. PMID- 29513226 TI - Considerations for the management of patients with generalized anxiety disorder in the dental setting. PMID- 29513228 TI - The retread procedure: a new hybrid appliance with fewer appointments and less cost. PMID- 29513229 TI - Creating the foundation: minimally invasive periodontal therapy. PMID- 29513230 TI - What do you really need to know about bisphosphonates? PMID- 29513231 TI - Recurrent palatal swelling and Radiopaque mass of the mandibular condyle. PMID- 29513232 TI - Mouthwashes: an in vitro study of their action on microbial biofilms and cytotoxicity to gingival fibroblasts. AB - This study evaluated the in vitro antibiofilm effect of 5 different commercial mouthwashes (Cepacol Traditional, Colgate Plax Fresh Mint, Listerine Cool Mint, Oral-B Complete, and Sensodyne) on Candida albicans, Staphylococcus aureus, Enterococcus faecalis, Streptococcus mutans, Escherichia coli, and Pseudomonas aeruginosa. The cytotoxic effect of the mouthwashes on gingival fibroblasts was also analyzed. A colorimetric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) was used to investigate the viability of biofilms after 48 hours and gingival fibroblasts after 24 hours. The biofilms were exposed to the mouthwashes for 2 different lengths of time: T1, the time recommended by the manufacturer (30 or 60 seconds); and T2, double the recommended time (60 or 120 seconds). All antiseptic mouthwashes caused a significant reduction of biofilm (P < 0.05) as well as a significant reduction of viable gingival fibroblasts (P < 0.05) with both exposure times (T1 and T2). It can be concluded that the commercial mouthwashes demonstrated effective antibiofilm activity; they were more effective on bacteria than on C albicans. A significant cytotoxic effect on gingival fibroblasts was also observed. PMID- 29513233 TI - Effect of composite warming on shear bond strength. AB - Several manufacturers produce devices designed to warm composite resins used in restorative dentistry. Previous investigators have examined the effects of heating composite restorative resins prior to placement and polymerization. Heating has been reported to reduce viscosity, improve ease of placement, enhance monomer conversion, and reduce microleakage. The aim of the present study was to compare shear bond strengths of room temperature (22 degrees C) and prewarmed (54 degrees C) restorative composite resin. Extracted bovine mandibular incisors were sectioned sagittally and embedded in acrylic cylinders. Enamel was selectively etched with 37% phosphoric acid, rinsed, and dried. Self-etching primer was applied to both enamel and dentin. Self-etching adhesive was then applied and photopolymerized. Composite resin capsules were then divided into prewarmed and room temperature groups. Fourteen composite specimens prewarmed in an incubator were applied to the prepared enamel and dentin and photopolymerized. Fourteen room temperature composite specimens were likewise placed. After storage in water for 24 hours, all composite specimens were subjected to shear stress testing. The resulting data were analyzed with a t test (P = 0.05). There was no statistically significant difference between the shear bond strengths of the prewarmed and room temperature composite resin specimens. Warming does not appear to affect bond strength of composite resin bonded to both dentin and enamel. PMID- 29513234 TI - Medication use and medical history of 155 patients with oral lichenoid lesions: a retrospective study. AB - Several medications have been reported as possible etiologic factors for oral lichen planus (OLP) and oral lichenoid lesions (OLLs). This study investigated the medication profile and medical history of patients with biopsy-proven OLP or OLLs, also classified by the clinically nonspecific term oral lichenoid mucositis (OLM), in a busy oral medicine clinic. The University of Florida College of Dentistry records from 2009 to 2014 were searched retrospectively for all patients with a biopsy-proven diagnosis of OLP, OLLs, or OLM. Patients were excluded if dysplasia or carcinoma was diagnosed concurrently at the same biopsy site. The demographics, clinical parameters, systemic diseases, histologic diagnosis, and direct immunofluorescence testing results were recorded. Medication category use was recorded based on both commonly used medications and those that have been reportedly linked to lichenoid disease in the literature. A total of 155 patients with an average age of 63.6 years were included. The majority of patients were women (76.8%) and Caucasian (91.8%). Most of the lesions were multifocal and mixed (white-red) in appearance. The most common systemic conditions were hypertension (n = 80; 51.6%) followed by thyroid disease (n = 52; 33.5%) and diabetes (n = 26; 16.8%). Antihypertensives were the most common medication category followed by, in descending order, nonsteroidal anti inflammatory drugs, cholesterol-lowering medications, psychiatric medications, and thyroid replacement drugs. The records revealed that 87.7% of the patients took at least 1 medication from 1 of the categories studied. Medication use is common in patients with biopsy-proven OLP or OLLs. Although causation cannot be assessed from the results of this study, the clinician should consider the possibility of medication as a complicating factor in patients with OLP or OLLs. PMID- 29513235 TI - Use of trichloroacetic acid for management of oral lesions caused by human papillomavirus. AB - The human papillomavirus (HPV) has an affinity for squamous cells of stratified keratinized epithelium, thus affecting the lower genital, nasal, and oral tracts. In the oral cavity, HPV is associated with pathoses such as the verruca vulgaris (common wart), squamous cell papilloma, condyloma acuminatum (venereal wart), and focal epithelial hyperplasia (Heck disease). Among the treatments available for these lesions are cryotherapy, electrosurgery, surgical removal, laser therapy, and trichloroacetic acid (TCA). The objective of this research was to determine the behavior of HPV-associated oral pathoses treated with TCA. A prospective cohort study was performed in 20 patients who attended a dental consultation at 2 universities in Cartagena, Colombia. Among the patients, 65% were diagnosed as having focal epithelial hyperplasia, 20% as having verrucae vulgares, and 15% as having condylomata acuminata. Application of TCA to HPV-associated oral lesions proved to be a useful nonsurgical alternative treatment, as the resolution of the lesions was achieved atraumatically in a span of 45 days with 3 applications of 30-60 seconds each. PMID- 29513236 TI - Conservative management of a rootless premolar: a case report with 4-year follow up. AB - Any disturbance in the primary tooth can lead to an altered eruption pattern of the corresponding permanent tooth. This article presents a case of a carious permanent second premolar with an immature root that erupted prematurely following extraction of the infected primary second molar. The carious premolar was treated with a stepwise excavation, and a primary stainless steel crown was adapted to prevent microleakage and restoration failure. A follow-up evaluation at 4 years showed remarkable healing and complete root formation. To the authors' knowledge, this is the first case report in the literature that describes successful conservative management of a rootless premolar treated by pulp capping and restored with a primary stainless steel crown. PMID- 29513237 TI - The effect of endodontic access on the failure load of lithium disilicate and resin nanoceramic CAD/CAM crowns. AB - Currently, there is no consensus on whether crowns fabricated via computer-aided design/computer-aided manufacturing (CAD/CAM) need to be replaced following an endodontic procedure. The aim of this in vitro study was to evaluate the effect of endodontic access preparation and repair on the failure load of lithium disilicate and resin nanoceramic crowns. The hypothesis was that there would be no difference in the failure load between the intact and repaired crowns. Eighty identical mandibular CAD/CAM crowns (40 lithium disilicate glass ceramic [IPS e.max CAD] and 40 resin nanoceramic [Lava Ultimate]) were milled and cemented on 80 identical polymethyl methacrylate resin dies. A standardized endodontic access preparation was made in half the specimens and restored with composite resin. All crowns were subjected to an occlusal load with a hydraulic testing machine until failure. Based on the Wilcoxon rank sum test, the load to failure was significantly higher for the lithium disilicate crowns than for resin nanoceramic crowns in both the intact and repaired groups (P < 0.001). For the lithium disilicate crowns, the failure load was significantly higher for intact than for repaired specimens (P = 0.002). However, there was no significant difference between intact and repaired specimens for resin nanoceramic. The repair of lithium disilicate and resin nanoceramic CAD/CAM crowns may provide a serviceable restoration under normal occlusal loads. However, replacement would be prudent in cases where parafunctional occlusal loading is suspected, the crown was not adhesively cemented, or there is an obvious defect in the existing crown. PMID- 29513238 TI - Piezoelectric ridge split and immediate implant placement in an atrophic mandible: a 3-year follow-up. AB - Anatomical variations often present a challenge in the placement of an implant in its optimal location. A ridge split procedure, which had been recommended for narrow alveolar ridges, has recently undergone a number of modifications, making the procedure simpler and providing more predictable outcomes. This article reports the 3-year follow-up of 2 implants placed using a ridge split procedure with a piezoelectric surgical unit for the rehabilitation of the mandibular posterior ridge. PMID- 29513239 TI - The effect of time between curing and tea immersion on composite resin discoloration. AB - One common cause for the replacement of a composite restoration is discoloration. This in vitro study evaluated the effect of tea solution on the discoloration of 3 types of composites at different timepoints after curing. For this study, 150 disc-shaped specimens of 3 types of composite resin-a nanohybrid (Filtek Z350), a microhybrid (Filtek Z250), and a microfilled material (Heliomolar)-were prepared. Specimens were randomly divided into 5 subgroups (n = 10) according to the type of composite and the time from curing to immersion in a tea solution (none [immersed immediately], 1 hour, 6 hours, 12 hours, or 24 hours postcuring). The color for all specimens was measured before and after immersion in tea. Color change (DeltaE*) for all specimens was measured, and a DeltaE* value of less than 3.3 was considered clinically acceptable. Analysis of variance and a post hoc Tukey test were used to analyze the data (alpha = 0.05). Immediately after curing, the levels of composite discoloration were deemed clinically acceptable (DeltaE* < 3.3). In all composites, the greatest color change was found immediately after curing (P < 0.05). With each subsequent timepoint, the color stability increased. When the groups were immersed in tea 6 hours postcuring, the mean DeltaE* value of the Filtek Z350 composite resin specimens was significantly greater than that of Heliomolar specimens (P < 0.05). The mean DeltaE* value for specimens immersed 12 hours postcuring was also greater in the Filtek Z250 composite group than in the Heliomolar group (P < 0.05). The DeltaE* values of Filtek Z350 and Filtek Z250 composites were not significantly different from each other (P > 0.05), except with 12-hour postcure immersion. The results suggest that patients should avoid the intake of staining foods or beverages for at least 12 hours after placement of a composite resin restoration, although this restriction may be reduced to 1 hour for microfilled composite resins. PMID- 29513240 TI - Photobiomodulation versus direct restoration in a patient presenting with dentinal hypersensitivity: a 6-month follow-up. AB - Despite nearly a century of research, the treatment of cervical dentinal hypersensitivity (DH) remains challenging. This case report discusses the indications for different approaches to the treatment of DH in a single patient; the chosen alternatives took into account the different degrees of tooth wear and levels of pain at different sites. A 31-year-old woman reported DH in the maxillary right canine and first premolar and the maxillary left lateral incisor and canine in response to thermal, tactile, and osmotic stimuli. Clinical examination revealed that the teeth on the right side presented noncarious cervical lesions deeper than 1 mm, while the teeth on the left side presented only minimal wear. Therefore, the right canine and premolar were restored with composite resin to create a mechanical barrier against stimuli and reestablish form, function, and esthetics. Prior to restoration, the teeth on the right side were irradiated with a low-power laser (808 nm, 100 mW, 1.1 J/point, 10 seconds), which was applied in a single session at 2 locations on each tooth. In contrast, the left lateral incisor and canine were irradiated in 3 sessions with the low power laser, which reduces pain levels and depolarizes nerve fibers by means of cell biomodulation, and received no restorations. A visual analog scale (0.0 10.0) was used to record the patient's pain, and it was found that pain levels for the restored teeth decreased from 9.4 initially to 0.0 immediately after restoration, and pain levels for the irradiated teeth decreased from 5.4 initially to 2.0 after 3 sessions. After 6 months of clinical evaluation, both sets of teeth showed scores of 0.0 (no pain). Based on the results presented, it can be concluded that both treatments provided satisfactory outcomes when applied for the appropriate indication. PMID- 29513241 TI - The influence of dental implants in periapical and panoramic radiographs and cone beam computed tomography images: a clinical study. AB - The aim of this study was to analyze the influence of dental implants on the radiographic density of the peri-implant region in tomographic and radiographic examinations. A sample of 21 dental implants from 10 patients with Branemark protocol prostheses was evaluated based on postoperative control images, including periapical radiography (paralleling technique), panoramic radiography, and cone beam computed tomography (CBCT). The density means of 6 defined areas near dental implants were calculated and compared considering their locations and the different imaging examinations. The CBCT examinations showed significantly different densities among the measured areas (P < 0.001), while there were no significant differences among the density means of the various areas in periapical radiographs (P = 0.430) and panoramic radiographs (P = 0.149). The highest mean densities were observed in areas closer to the implants in all the examinations: CBCT (127.88 and 120.71), panoramic (106.51 and 106.09), and periapical (120.32). The sagittal CBCT images were measured in 2 different sections, and in both sections those areas closer to implants showed mean densities that were significantly higher than means from more distant areas (P < 0.001). Means from distant areas on CBCT slice imaging were significantly lower than the densities of the same areas on periapical and panoramic examinations. The changes in mean radiographic density values in the peri-implant region confirmed the interference of dental implants in radiographic and tomographic images. CBCT images suffered the greatest interference from dental implants. PMID- 29513242 TI - Effectiveness of whitening mouthwashes on tooth color: an in vitro study. AB - Products for tooth whitening (or tooth color maintenance) that improve smile esthetics have become increasingly popular due to their easy accessibility and low cost. This in vitro study assessed the effect of whitening mouthwash on bovine tooth color. Forty-eight bovine teeth were divided into 3 immersion groups: SL, artificial saliva (control); CLW, Colgate Luminous White; and OBW, Oral-B 3D White. After prophylaxis with pumice, the initial color was measured using the CIE L*a*b* system. Teeth were immersed in the solutions for 2 minutes, 3 times per day, for 30 days. Changes in color (DeltaE*, DeltaL*, Deltaa*, and Deltab*) were measured at days 14 and 30. Data were analyzed with 2-way analysis of variance and Tukey test (P < 0.05). At day 30, values of DeltaE* had significantly decreased in group SL and increased in group OBW; in addition, at day 30, the DeltaE*values in group CLW were significantly greater than those in group SL. The DeltaL* values for groups SL and OBW significantly decreased from day 14 to day 30. At day 30, the Deltaa* and Deltab* values were lower in all 3 groups. The results showed that the whitening mouthwashes did not improve color after 14 and 30 days. PMID- 29513243 TI - Influence of plasma-based dry etching on the bond strength of Y-TZP ceramic. AB - The aim of this study was to evaluate the bond strength between an yttria stabilized tetragonal zirconia polycrystal (Y-TZP) ceramic and a luting agent when submitted to plasma etching surface treatment before and after thermocycling (TC) with 3000 cycles of 5 degrees C-55 degrees C. The null hypothesis was that the surface treatments and thermocycling would not influence the bond strength. A total of 160 Y-TZP ceramic blocks in 2 sizes (10 size 1 and 10 size 2 blocks in each group) were distributed into 8 groups: group C (control), no surface treatment; group C-TC, TC without prior surface treatment; group SAO, sandblasting with aluminum oxide (Al2O3); group SAO-TC, sandblasting with Al2O3 followed by TC; group SAOS, sandblasting with silica-coated Al2O3; group SAOS-TC, sandblasting with silica-coated Al2O3 followed by TC; group PE, plasma etching; and group PE-TC, plasma etching followed by TC. In each group, size 1 blocks were cemented to size 2 blocks to fabricate specimens for microshear bond strength testing (n = 10 per group). Cementation followed surface treatments (except in control groups) and preceded any TC. All specimens were cemented using a luting agent that contained 10-meth-acryloyloxydecyl dihydrogen phosphate (MDP). The specimens were submitted to a microshear bond strength test and the means were analyzed with a 2-factor analysis of variance and Tukey test. Group PE showed the highest bond strength value before thermocycling (17.31 MPa). After thermocycling, the highest value was observed in the SAO-TC group (9.73 MPa), and statistically significant differences were observed between SAOS-TC and SAO-TC (P < 0.05) and PE-TC and SAO-TC (P < 0.05). Plasma etching improved the bond strength values between the Y-TZP ceramic and MDP-containing luting agent before thermocycling. After thermocycling, all groups showed lower bond strength values. PMID- 29513244 TI - Clostridium difficile infection in patients hospitalized in the gastroenterology ward - retrospective analysis. AB - INTRODUCTION: Clostridium difficile associated colitis became over last years a worldwide medical issue. It involves patients of the Polish hospitals too. The aim of the study was the analysis of CDAD incidence and the course of infection in Gastroenterology Ward of Regional Specialist Hospital of Zgierz, 2012-2015. MATERIAL AND METHODS: Retrospective analysis of the medical documentation of 79 patients with CDAD was performed. Demographic and epidemiological data and the clinical course of infection were analyzed. RESULTS: The study group comprised of women in 59,5% and men in 40,5%. The patients' average age was 70,5 years. The average hospitalization period was 10,3 days. CDAD infection seasonality was proved, with statistically significant peak in springtime. 73% of patients were previously hospitalized and 85% - had co-morbidities. 76% of patients underwent antibiotherapy, whilst 29% - used PPI prior to CDAD diagnosis. 50,6% of patients had severe CDAD diagnosed. The recurrence reached 14%. In 19% of patients CDAD resulted in death. DISCUSSION: The results of the study confirm increase of the incidence of the patients with CDAD in Gastroenterology Ward over 4-years' observation. The prevalence was higher among 65+ patients, after prior hospitalization and antibiotherapy. The co-morbidities was a significant risk factor, especially common in severe cases. CONCLUSION: The results we obtained confirm substantial importance of Clostridium difficile infection leading to antibiotherapy- associated diarrhea among adults, causing prolonged hospitalization, increased prevalence and mortality of patients. Getting to know and minimizing the risk factors will prevent the future outbreak of the disease. PMID- 29513245 TI - Characteristics and results of treatment of patients treated surgically with colorectal cancer in old and senile age. AB - Colorectal cancer (CC) in Poland is the type of cancer with the highest dynamics of disease growth and is epidemiologically related to age. The analysis involved 353 patients operated on due to CC in senile and old age and compared with younger patients. It was found that people at this age are more often diagnosed with CC They were more often women, the patients did not differ in the stage of cancer, while they were significantly more often qualified for surgery due to urgent indications. In patients with colonic cancer, the resectability and radicality of the procedures in comparison with patients with rectal cancer was significantly higher, while there were more complications and deaths in the 30 day follow-up in this group. The overall survival in senile and old age was significantly worse. In the first year of follow-up after surgical treatment of patients in this group, complications and deaths were more frequently observed. However, in patients who survived 12 months after the operation, the overall survival rate did not significantly differ. PMID- 29513246 TI - Can the surgeon live his whole life? Analysis of the risk of death related to the profession. AB - More than half of physicians in Poland are over 50 years old. This raises concerns about the risk of lack of continuity of health care services due to the generational gap, particularly marked among interventional specialties. The physical and mental burden of general surgery affects those doctors in particular. The aim of the study is to assess whether the type of the profession pursued influences the average lifetime of a physician in Poland and the impact of the surgeon's occupation on life expectancy compared to the rest of the population according to gender. Demographic data was obtained from official publications of the Central Statistical Office. Data on 189,459 physicians in Poland were obtained from the Central Register of Doctors. A total of 6,496 physicians and dentists deaths in the period from January 1st, 2010 to June 30th, 2014, including 722 surgeons, were analyzed. In general, both male physicians and dentists died at an older age than the mean population (74.9 years and 74.7 years vs. 68.9 years; p <0.05). Among women, only dentists lived longer (78.5 years) p <0.05), while women physicians died at a younger age than the average in the general population (76.4 vs. 77.2 years; p <0.05). The average lifetime of both male and female surgeons was 74.2 and 77.5 years, respectively. The average life expectancy of people aged 25 years with college/university education is 80.3 years for men and 86.6 years for women. Male surgeons live significantly longer than the average life expectancy in the general population of men. The average length of life of women surgeons is significantly lower than the average lifespan of women in the general population. The actual lifetime of surgeons in Poland is significantly lower than the expected average life expectancy for other people aged 25 with tertiary education. The average lifespan of surgeons in Poland does not differ significantly from the average life expectancy of other Polish physicians. PMID- 29513247 TI - Acceptance of disease and the quality of life in patients with enteric stoma. AB - INTRODUCTION: The main reason of the emergence of enteric stoma is colorectal cancer. Enteric stoma is a serious health, as well as life problem. In Poland, there are about 6,000 stoma surgeries yearly. It changes the functioning of patients, restricts their daily activity and influences their quality of life significantly. Therefore, in the modern treatment process, all spheres of human life and its surroundings are considered. The evaluation of the quality of life and the level of acceptance of the disease enables us to identify the regions in which patients require attention and help, as well as places to which health promotion among patients with a stoma should be directed. The aim of the study was the evaluation of the acceptance of the disease and the quality of life in patients with colostomy. MATERIAL AND METHODS: The study conducted between February 2015 and February 2016 included101 patients with enteric stoma of the Provincial Specialist Hospital in Wroclaw at Kamienskiego St. in the departments of General Surgery with the Subdivision of Traumatology and Orthopedic Surgery, Subdivision of Metabolic Surgery, Subdivision of Endocrine Surgery and Oncological Surgery . Two anonymous questionnaires, i.e., health-related quality of life (HRQoL) and acceptance of illness scale (AIS), were used. 60% (61 people) were women, and 40% (40 people) were men. The mean age was 48; the youngest respondent was 20 years old, and the oldest was 79 years old. 17% of the respondents had primary education, 25% - vocational, 33% - secondary and 26% - university-level. RESULTS: The most common reason for the emergence of a stoma among the respondents was colon cancer (44%), followed by: mechanical bowel onstruction (26%), intestinal damage following injuries (25%), inflammatory bowel disease (6%). The quality of life of patients with colostomy was evaluated in view of their health condition, postoperative recovery, everyday limitations, and self-evaluation. The majority of participants pointed to the deterioration of their quality of life. A higher level of acceptance of the disease was revealed in men as 75% of men, and 61% of women acceptted their health status. The education level also influences the acceptance of the disease, as 41% participants with higher education, and only 6% participants with primary education did not accept their health status. We revealed some social factors influencing the quality of life and the acceptance of the disease, i.e., gender, age, education, job, and place of living. CONCLUSIONS: Gender and education have an impact on the level of the acceptance of the disease, but they do not influence the quality of life. The acceptance of the disease is connected with the quality of life in patients with a stoma. The higher the level of acceptance of the disease, the better the quality of life. Research indicates the need to deepen patients' education regarding their functioning in society. PMID- 29513248 TI - Sclerotherapy of esophageal varices in hemophilia patients with liver cirrhosis - a prospective, controlled clinical study. AB - INTRODUCTION: Bleeding from esophageal varices is a serious clinical condition in hemophilia patients due to congenital deficiency or lack of clotting factors VIII (in hemophilia A) and IX (in hemophilia B), decreased clotting factor II, VII, IX, X synthesis in the course of chronic liver disease and hipersplenic thrombocytopenia. The aim of this study was to assess the efficacy and safety of endoscopic sclerotherapy in acute esophageal variceal bleeding and in secondary prophylaxis of hemorrhage. The aim was also to investigate the optimal activity of deficiency factors VIII or IX and duration of replacement therapy required to ensure proper hemostasis after sclerotherapy procedures. MATERIAL AND METHODS: 22 hemophilia patients (A-19, B-4) with coexistent liver cirrhosis and active esophageal variceal bleeding treated with endoscopic sclerotherapy were subjected to prospective analysis. The patients who survived were qualified to repeated sclerotherapy procedures every 3 weeks within secondary prophylaxis of bleeding (investigated group). A 3-day substitution therapy enhanced the infusion of the deficient or lacking factor in doses allowing to reach 80-100% of normal value activity of factor VIII on the 1st day and 60-80% in the next two days. The desired activity of factor IX was 60- 80% and 40-60% respectively. The control group consisted of 20 non-hemophiliac patients with liver cirrhosis comparable in terms of age, sex, stage of advancement of liver cirrhosis, who underwent the same medical proceedings as the investigated group. RESULTS: Active esophageal bleeding was stopped in 21 of 22 (95%) hemophilia patients. Complications were observed in 3 patients; 2 patients died. The rate of hemostasis, complications and deaths in the control group were comparable and no statistical differences were found. In hemophilia patients subjected to secondary prophylaxis of hemorrhage, in 18 of 20 (80%), complete eradication of esophageal varices was achieved after 4 to 7 sclerotherapy procedures in 1 patient (average 5.4). Recurrent bleeding was observed in 15% of patients, complication in 20%; 1 patient died. Time lapse from bleeding to eradication was 12-21 weeks (average 15.2). In the control group the rate of variceal eradication, complication and deaths was comparable and no statistical differences were found. The usage of factor VIII concentrates was as follows: in hemophilia A, in a severe form - 80.9 U/kg b.w./day, in hemophilia A in a severe form with an inhibitor <5 BU - 95.2 U/kg b.w./day, in mild form - 64.2 U/kg b.w./day and in severe hemophilia B - 91.6 U/kg b.w./day. CONCLUSIONS: Sclerotherapy is an effective method in the management of esophageal variceal bleeding in hemophilia patients. It is also effective for total eradication of varices when applied as a secondary prophylaxis of hemorrhage. In our opinion, a 3-day replacement therapy at the applied doses is sufficient to ensure hemostasis and avoid bleeding complications. PMID- 29513249 TI - Comparison of objective and subjective evaluation of breast symmetrization results in patients with Poland syndrome. AB - INTRODUCTION: There are many methods of analyzing the appearance of the breasts, but most of them are based on the patient's subjective assessment or on the opinion of a specialist panel. Anthropometric measurements enable objective breast evaluation. The aim of the study was to compare the objective and subjective evaluation of aesthetic results of breast symmetrization in patients with Poland syndrome. MATERIAL AND METHODS: The analysis of the results of the treatment was performed in 7 patients treated surgically due to unilateral breast underdevelopment in Poland syndrome. In the postoperative assessment, the following features were considered: 1 - breast volume, symmetry of: 2 - nipple areola-complexes (NAC), 3 - inframammary folds (IMF), 4 - upper poles (UP). The subjective assessment performed by the patient included each of the listed features and the overall satisfaction with the results of symmetrization on the 10-point Likert scale. Then, objective metric breast analysis was performed. RESULTS: Overall assessment of postoperative breast asymmetry (mean 8.1) indicates a high level of patients' satisfaction with breasts symmetrization. An objective analysis showed that the average breasts' difference in volume was about 36 cc and the difference in NAC location was about 1.2 cm. CONCLUSION: 3D imaging is helpful in planning breast symmetrization procedures, especially in breast prostheses' selection. Combination of this method with clinical experience results in good postoperative effects. PMID- 29513250 TI - Role of crossmatch testing when Luminex-SAB is negative in renal transplantation. AB - The human leukocyte antigen (HLA) system plays an important role in the acceptance of renal graft. Long and better graft survival has been reported in patients with HLA-identical siblings and a nonreactive cytotoxicity assay (CDC). New methods of HLA-typing and anti-HLA antibody detection techniques such as flow cytometry, solid-phase immunoassays, or antigen bead assays have further improved the outcomes of renal transplant recipients. In the present review, the explicit details of these methodologies are discussed in detail. PMID- 29513251 TI - The use of rifaximin in pre-operative period of patients with tumors of the gastrointestinal tract - a retrospective study (2013-2016). AB - : ntroduction: One of the most important goals of preparing a patient for elective gastrointestinal cancer surgery is prevention of postoperative complications. The literature gives many ways to prepare for surgery, but only a few suggests that pre-operative use of rifaximin provides benefits in the form of fewer perioperative complications and reduces the severity of pain during this period. O bjective: The presented project is a retrospective analysis of the effectiveness of rifaximin in the prevention of perioperative complications in patients treated in the Unit of General Surgery with the Orthopedic and Urology in the Hospital of the Ministry of the Interior and Administration in Lublin, and a review of international literature in this subject. MATERIALS AND METHODS: A retrospective analysis of the results of pre-operative use of rifaximin was performed in 181 patients scheduled for rectal and colorectal cancer between 2013 and 2016 in the General Surgery Unit with the Orthopedic and Urology in the Hospital of the Ministry of Interior and Administration in Lublin. Patients undergoing urgent surgery were excluded from the study. Patients were divided into 2 groups. The first group of 139 patients - patients operated on for rectal and colorectal cancer in 2013 until 2015, in whom rifaximine was not used in the preoperative period. The second group is 42 patients, operated on in 2016, in which the rifaximin was used in the pre-operative period at a dose of 2x2 tablets (400 mg) per day, 12-hour interval, for 7 days before the planned operation. Additionally, a probiotic was administered for 7 days. Drugs were ordained at the Oncological Outpatient Clinic as part of the pre-hospitalization check. R esults: The use of rifaximin in the preoperative period in patients with colorectal cancer had an effect on shortening the time of post-operative hospitalization and reduced post-surgical pain in comparison with the control group. The analysis of the cynumber and intensity of surgical complications in both groups did not differ. C onclusions: Large studies on the influence of rifaximin on the development of colorectal cancer have not been published so far. Only single reports suggest that its use has a positive effect on the perioperative period of patients treated for colorectal cancer including rectum and our retrospective analysis confirms these observations. PMID- 29513252 TI - Overtreatment in surgery - does it concern also the patients with ductal breast carcinoma in situ. AB - Overtreatment means treatment that goes beyond current standards, and patients with any disease can be overtreated. Overtreatment is also given to patients with cancer, including those who need surgery. Overtreatment is closely related to the problem of overdiagnosis. In patients with cancer, unnecessary surgery may cause complications and generates unnecessary costs. The size of the problem of unnecessary surgery in patients with cancer can best be shown among patients with the most common cancers, which dedicated screening programs. Breast cancer patients, particularly those with pre-invasive types of the tumor, who typically have ductal carcinoma in situ (80%), are likely to undergo unnecessary surgery. We describe the most common clinical problems caused by overtreating patients with ductal carcinoma in situ. PMID- 29513253 TI - A rare cause of gastrointestinal obstruction. Drug poisoning as a surgical disorder? AB - A patient had intestinal obstruction due to a rare cause. The patient presented unusual signs and symptoms. Although we performed a thorough diagnostic workup (CT, ultrasound, radiography, endoscopy), only laparotomy revealed that a bezoar caused the intestinal obstruction. The bezoar consisted of a herbal preparation, which was mentioned by the patient twice as a possible cause of his symptoms. All in all, the patient was right. PMID- 29513254 TI - Yersiniosis or Lesniowski-Crohn's disease. AB - Yersiniosis is zoonotic disease caused by infection with Yersinia enterocolictica. The variety of clinical signs and the similarity to other diseases causes major diagnostics and therapeutics difficulties. The authors present a case of Yersinia enterocolitica infection in a 38-year-old patient, mimicking Lesniowski Crohn's disease. PMID- 29513255 TI - Rehabilitation in elderly patients with dizziness and balance unsteadiness. AB - Rehabilitation in elderly patients with dizziness and balance unsteadiness. PMID- 29513256 TI - Vertical partial frontolateral laryngectomy with simultaneous pedunculated sternothyroid muscle flap reconstruction of the vocal fold - surgical procedure and treatment outcomes. AB - PURPOSE OF THE STUDY: The aim of the study was to present the treatment outcomes after vertical partial laryngectomy with or without pedunculated sternothyroid muscle flap reconstruction following the resection of neoplasm-infiltrated vocal fold. The procedure was used in a patient with glottic cancer. Oncological outcomes, morphology of neo-vocal fold and the act of swallowing were evaluated. MATERIAL AND METHODS: 45 patients with T1-T2 glottic cancer were subjected to vertical partial laryngectomy with 26 patients undergoing a procedure with pedunculated sternothyroid muscle flap reconstruction and the remaining 19 patients undergoing a procedure without such a reconstruction. Two female and 43 male patients aged 35-82 years (mean age of 62.5 years) were enrolled in the study. Local tumor spread and the condition of reconstructed vocal fold were assessed in sequential videofiberoscopy examination conducted each month after surgery whereas the regional spread was assessed in ultrasound scans. Postoperative aspiration was graded according to the Pearson's scale. RESULTS: Six patients experienced local recurrence while 2 patients experienced regional recurrence of the tumor. The pedunculated sternothyroid muscle flap neo-fold was structurally resemblant of the non-affected vocal fold. Episodic, daily dysphagia was observed in 1 patient while normal act of swallowing with no Pearson's scale symptoms was observed in the remaining 44 patients. No necrosis of pedunculated flap was observed. CONCLUSIONS: Vertical partial laryngectomy with or without pedunculated sternothyroid muscle flap reconstruction is a good method for the treatment of low- or intermediate-stage glottic cancer, especially when endoscopic access to the tumor is limited and when CO2 laser cannot be used. No significant functional disorders were observed in operated larynges. PMID- 29513257 TI - Association of breathing patterns and quality of life in patients with nasal obstruction. AB - INTRODUCTION: In the general population, nasal obstruction is a common complaint. However, an objective evaluation of nasal obstruction is difficult. Nose examination, computed tomography (CT), acoustic rhinometry, and anterior rhinomanometry do not accurately reflect the discomfort reported by patients with nasal obstruction. In patients with nasal obstruction, this study evaluated nasal breathing with a unique device for continuous nasal-oral spirometry - a nasal oral flow analyzer (NOFA); moreover, quality of life was compared between patients with normal nasal breathing on NOFA and of those with impaired nasal breathing on NOFA. METHODS: Of 181 adult patients admitted to an ENT department due to nasal obstruction that were enrolled in the study, 97 (53.6%) completed all per-protocol assessments, including the SF-36 questionnaire and 3-hour, continuous nasal-oral spirometry with NOFA. Based on the presence of normal nasal breathing defined as >=95% of nasal flow, the 97 patients were divided into those with normal nasal breathing (n=31) and impaired nasal breathing (n=66). RESULTS: Patients with normal nasal breathing differed from those with impaired nasal breathing with respect to all SF-36 subscales (physical functioning, p=0.004; role-physical, p=0.009; bodily pain, p<0.001; general health, p=0.007; vitality, p=0.002; social functioning, p=0.008; mental health, p=0.009; physical component summary, p<0.001; mental component summary, p=0.02), except for the role emotional subscale (p=0.1). CONCLUSIONS: Among patients with symptoms of nasal obstruction, compared to patients with normal nasal breathing, those with impaired nasal breathing had significantly lower quality of life in the physical and mental domains. Further research needs to determine whether NOFA can be used to diagnose nasal obstruction. PMID- 29513258 TI - The report of the Polish Universal Neonatal Hearing Screening Program in 2016. AB - The Polish Universal Neonatal Hearing Screening Program (PUNHSP) has been carried out in Poland for 14 years. The main aim of this Program is to organize hearing screening tests and to gather the information about risk factors of hearing loss in almost all newborns in Poland. It consists of 496 centers at 3 referral levels. A total of 5 458 114 children had been registered in the Central Database (CDB) of PUNHSP by the 22nd of August 2017. Bilateral sensorineural hearing loss was the most frequently appearing hearing impairment in children. It was diagnosed in 260 cases in 2016. This report presents the most important results and conclusions concerning the running of the PUNHSP in 2016. PMID- 29513259 TI - Assessment of cortical auditory evoked potentials in children with specific language impairment. AB - The proper course of speech development heavily influences the cognitive and personal development of children. It is a condition for achieving preschool and school successes - it facilitates socializing and expressing feelings and needs. Impairment of language and its development in children represents a major diagnostic and therapeutic challenge for physicians and therapists. Early diagnosis of coexisting deficits and starting the therapy influence the therapeutic success. One of the basic diagnostic tests for children suffering from specific language impairment (SLI) is audiometry, thus far referred to as a hearing test. Auditory processing is just as important as a proper hearing threshold. Therefore, diagnosis of central auditory disorder may be a valuable supplementation of diagnosis of language impairment. Early diagnosis and implementation of appropriate treatment may contribute to an effective language therapy. PMID- 29513260 TI - Otolaryngological symptoms in patients treated for tick-borne diseases. AB - : infections are borreliosis (Lyme disease) and tick-borne encephalitis (TBE). Lately there is growing incidence of Bartonella, Babesia, Anaplasma and Brucella co-infections. The similarity between the symptoms of tick-borne diseases and other pathologies causes serious diagnostic issues. MATERIAL AND METHODS: 216 patients aged 18-55, who presented to the outpatient clinic for tick-borne diseases in the years 2014-2016, were enrolled in the study. The patients had been diagnosed with Lyme disease and co-infections. The principal diagnostic tests to confirm the infections included ELISA, Western-Blot and circulating immune complexes (CIC). RESULTS: In the group of 216 patients, 162 presented with otolaryngological symptoms. The most common complaint was tinnitus (76,5%) accompanied by vertigo and dizziness (53,7%), headache (39%), unilateral sensorineural hearing loss (16,7%). The patients also had tick-borne coinfections, among them the most common was Bartonella henselae (33,4%) and Bartonella quintana (13%). CONCLUSIONS: Otolaryngological symptoms are a common manifestation of tick-borne diseases. They are most frequently observed in Lyme disease and Bartonella spp. infections. The symptoms in the head and neck region are usually occur in chronic Lyme disease with predominant IgG antibodies nad VlsE antigen. PMID- 29513261 TI - Uniformly coated highly porous graphene/MnO2 foams for flexible asymmetric supercapacitors. AB - Supercapacitors are called to play a prominent role in the newly emerging markets of electric vehicles, flexible displays and sensors, and wearable electronics. In order to compete with current battery technology, supercapacitors have to be designed with highly conductive current collectors exhibiting high surface area per unit volume and uniformly coated with pseudocapacitive materials, which is crucial to boost the energy density while maintaining a high power density. Here, we present a versatile technique to prepare thickness-controlled thin-film micro graphene foams (MUGFs) with pores in the lower micrometer range grown by chemical vapor deposition which can be used as highly conductive current collectors in flexible supercapacitors. To fabricate the MUGF, we use porous metallic catalytic substrates consisting of nickel/copper alloy synthesized on nickel foil by electrodeposition in an electrolytic solution. Changing the duration of the electrodeposition allows the control of the thickness of the metal foam, and thus of the MUGF, ranging from a few micrometers to the millimeter scale. The resulting MUGF with a thickness and pores in the micrometer regime exhibits high structural quality which leads to a very low intrinsic resistance of the devices. Transferred onto flexible substrates, we demonstrate a uniform coating of the MUGFs with manganese oxide, a pseudocapacitively active material. Considering the porous structure and the thickness of the MUGFs, square wave potential pulses are used to ensure uniform coverage by the oxide material boosting the volumetric and areal capacitance to 14 F cm-3 and 0.16 F cm-2. The MUGF with a thickness and pores in the micrometer regime in combination with a coating technique tuned to the porosity of the MUGF is of great relevance for the development of supercapacitors based on state-of-the-art graphene foams. PMID- 29513262 TI - Should patients with brain implants undergo MRI? AB - Patients suffering from neuronal degenerative diseases are increasingly being equipped with neural implants to treat symptoms or restore functions and increase their quality of life. Magnetic resonance imaging (MRI) would be the modality of choice for the diagnosis and compulsory postoperative monitoring of such patients. However, interactions between the magnetic resonance (MR) environment and implants pose severe health risks to the patient. Nevertheless, neural implant recipients regularly undergo MRI examinations, and adverse events are rarely reported. However, this should not imply that the procedures are safe. More than 300 000 cochlear implant recipients are excluded from MRI, unless the indication outweighs the excruciating pain. For 75 000 deep brain stimulation (DBS) recipients quite the opposite holds true: MRI is considered an essential part of the implantation procedure and some medical centres deliberately exceed safety regulations, which they refer to as crucially impractical. Permanent MRI related neurological dysfunctions in DBS recipients have occurred in the past when manufacturer recommendations were exceeded. Within the last few decades, extensive effort has been invested to identify, characterise and quantify the occurring interactions. Yet today we are still far from a satisfying solution concerning a safe and beneficial MR procedure for all implant recipients. To contribute, we intend to raise awareness of the growing concern, summon the community to stop absurdities and instead improve the situation for the increasing number of patients. Therefore, we review implant safety in the MRI literature from an engineering point of view, with a focus on cochlear and DBS implants as success stories of neural implants in clinical practice. We briefly explain fundamental phenomena which can lead to patient harm, and point out breakthroughs and errors made. Then, we end with conclusions and strategies to avoid future implants from being contraindicated in MR examinations. We believe that implant recipients should enter MRI, but before doing so, it should be made sure that the procedure is reasonable. PMID- 29513263 TI - Wrinkle-free atomically thin CdS nanosheets for photocatalytic hydrogen evolution. AB - Two-dimensional (2D) nanosheets of atomic thickness have attracted extensive research interest recently. In this work, atomically thin (0.7 nm) flat CdS (F CdS) nanosheets of several tens of micrometers in lateral size were synthesized by a solvent-thermal method. The as-synthesized F-CdS could maintain flat morphology well in solution, while irreversible wrinkles could be generated after drying, forming wrinkled CdS (W-CdS) samples. It was revealed that the formation of wrinkles could reduce light absorbance, narrow the band gap, move down the conduction band position and accelerate electron-hole recombination. As photocatalysts, the F-CdS achieved a photocatalytic H2 evolution rate of 138.7 mmol g-1 h-1 without any co-catalyst under visible light, which was much higher than that of the W-CdS sample (with an H2 evolution rate of only 52.8 mmol g-1 h 1). This work demonstrates that great attention should be paid to the wrinkles in 2D materials as photocatalysts. PMID- 29513265 TI - Graphene-like monolayer InSe-X: several promising half-metallic nanosheets in spintronics. AB - Several half-metallic graphene-like nanosheets, namely halogen atom adsorbed InSe X (X = F, Cl, Br and I) nanosheets, are predicted by first-principles calculations. Then, their structural, electric and magnetic properties are studied in detail. The calculated negative adsorption energies of these InSe-X nanosheets ensure that they attain stable adsorption structures, which suggests that they may be prepared experimentally. The pristine InSe monolayer is a typical semi-conductor, whereas it is interesting that the X ion (X = F, Cl, Br and I) adsorbed InSe-X nanosheets are electronically conductive. They can be promising and good candidates for applications of half-metallic 2D materials. The calculated magnetic moments of these nanosheets are close to 1.0 u B. In the InSe F nanosheet, there are sp2 hybridized orbitals due to the crystal field effect, and its electroconductibility, half-metallicity and magnetic moments originate from the In and Se ions, not the F ion. However, in InSe-X (X = Cl, Br and I) nanosheets, there are sp3 hybridized orbitals, and their electroconductibility, half-metallicity and magnetic moments originate mainly from X ions, together partially with the In and Se ions. PMID- 29513266 TI - Trioctylphosphine-assisted morphology control of ZnO nanoparticles. AB - This study investigates the morphological change in colloidal ZnO nanoparticles (NPs) synthesized with trioctylphosphine (TOP). The addition of TOP to the synthesis causes an evolution in the shape of ZnO NPs to tadpole-like particles from quasi-spherical particles at 300 degrees C. The total length of the tadpole like ZnO NPs can be modified by controlling the molar ratio of TOP to oleylamine (OLAM). The tadpole-like particles are elongated as the concentration of TOP increased but decreased when the addition of TOP is excessive. These tadpole-like ZnO NPs transform to quasi-spherical NPs regardless of the amount of TOP at a reaction time of 3 h at 300 degrees C. At 200 degrees C, the effect of TOP on the ZnO NP synthesis differs from that at 300 degrees C. The ZnO NPs synthesized by controlling the molar ratios of surfactant ligands (TOP:OLAM = 2:100 and 70:100) at 200 degrees C share similar amorphous structures, while a crystalline ZnO phase is formed when the reaction time is 3 h. X-ray photoelectron spectroscopy analysis shows that TOP influences the oxidation of ZnO and suggests that a combination of OLAM and TOP plays a role in controlling the shape of ZnO NPs. These results provide critical insights to the utilization of TOP for a shape controlling ligand in ZnO NPs and suggest a new route to design oxide NPs. PMID- 29513264 TI - Associations of sex, age and adiposity in endothelium-independent dilation in children. AB - OBJECTIVE: To examine the association of age, sex, and obesity status on endothelial-independent dilation (EID) among children and adolescents. STUDY DESIGN: This study examined 264 children (143 males) between 8 to 18 years old (mean +/- SD: age = 14.3 +/- 2.7 years). Endothelial-independent dilation was assessed via ultrasound imaging of the brachial artery following administration of 0.3 milligrams of sublingual nitroglycerin. A one-way analysis of variance with Bonferroni post hoc comparisons assessed sex-differences in percent peak EID dilation (EID%-peak) and EID area under the curve (EID%-AUC), while analysis of covariance (ANCOVA) adjusted for race, age, body mass index percentile (BMI-percentile), and brachial artery diameter. Multiple linear regression evaluated the association of sex, age, BMI-percentile, percent body fat (%BF), and brachial artery diameter on EID. RESULTS: Prior to adjustment, EID%-peak was significantly higher among females than males (mean +/- SE: 26.9 +/- 0.5% versus 22.9 +/- 0.6%, p < 0.001, respectively); similar findings for EID%-AUC (4214% +/- 105%.s versus 3398% +/- 97%.s, p < 0.001) were observed. After adjusting for covariates, EID%-AUC remained consistent (p = 0.03) while EID%-peak was not significantly different between sexes (p = 0.21). EID%-peak was significantly higher among normal weight compared to obese participants (p = 0.04), while no differences were observed between obesity status after adjustment for brachial artery diameter (p = 0.64). Both unadjusted (p = 0.16) and adjusted EID%-AUC (p = 0.24) was not significantly different between obesity status. BMI-percentile was not associated with EID% peak (p = 0.76) or EID%-AUC (p = 0.30). Additionally, %BF was not associated with EID%-peak (p = 0.56) or EID%-AUC (p = 0.15). After adjusting for brachial artery diameter, BMI-percentile, and age, males had lower EID%-AUC (p = 0.03) and lower but not significant EID%-peak (p = 0.21). SIGNIFICANCE: Vascular smooth muscle function was significantly lower among male children and adolescents, which is suggestive that impaired EID and increased cardiovascular disease risk among males may begin in childhood. Interestingly, obesity status and BMI-percentile was not associated with EID in children and adolescents after adjusting for brachial artery diameter. PMID- 29513267 TI - Tetrazole amphiphile inducing growth of conducting polymers hierarchical nanostructures and their electromagnetic absorption properties. AB - Conducting polymers (CPs) at nano scales endow materials with special optical, electrical, and magnetic properties. The crucial factor to construct and regulate the micro-structures of CPs is the inducing reagent, particular in its chemical structure, such active sites, self-assembling properties. In this paper, we design and synthesize an amphiphile bearing tetrazole moiety on its skeleton, and use this amphiphile as an inducing reagent to prepare and regulate the micro structures of a series of CPs including polypyrrole, polyaniline, poly(3,4 ethylenedioxythiophene) and poly(p-phenylenediamine). Because of the unique electric properties of CPs and size effect, we next explored the electromagnetic absorption performances of these CPs nanostructures. A synergetic combination of electric loss and magnetic loss is used to explain the absorption mechanism of these CPs nano-structures. PMID- 29513268 TI - Magnetic micro scavengers: highly porous Ni1-x Co x Fe2O4 microcubes for efficient disintegration of nitrophenol. AB - The fabrication of functional materials in patterned morphology is focused to obtain remarkable physiognomies of the materials for certain applications. Instead of randomly distributed agglomerated nanoparticles, it is highly desirable to arrange them in a motif, as this directed formation of nanomaterials can have a substantial influence on their performance and activity in various applications. With this perspective, MOF derived hollow cubes of nickel cobalt ferrites have been synthesized via a facile process using sacrificial templates at 600 degrees C. Microcubes, composed of tiny grains in a size range from 10 nm +/- 2 nm were obtained in pure form as a polycrystalline material. The high specific surface area (1185 m2 g-1) and mesoporous nature of hollow cubic ferrites were found to be excellent adsorbents for nitrophenol at room temperature. The equilibrium quantity of adsorbed nitrophenol was calculated as 47 mg g-1 ferrite, accomplished in 7 min. Their large surface area, mesopores and hollow nature, in combination with controlled size distribution of grains, have enabled this remarkable utilization of nanoferrites for removal of nitrophenol from water. PMID- 29513269 TI - Outstanding features of Cu-doped ZnS nanoclusters. AB - ZnS and their Cu-doped nanoclusters (NCs) were synthesized successfully using the wet chemical route with different Cu content. The crystalline structure was investigated using x-ray powder diffraction which assured the single-phase formation in cubic symmetry. High-resolution transmission electron microscope indicated the microstructure of NCs with a size ranging from 2-4 nm. A butterfly hysteresis (M-H) loop was observed at room temperature with large values of coercivity for the Cu content of x = 0.05. Photoluminescence emission spectra were recorded from 500-615 nm for pure and Cu-doped ZnS NCs at a 350 nm excitation wavelength. The sample exhibited green fluorescence bands peaking at 535, 544, 552.5, 558.2, and 560.6 nm, which confirmed the characteristic feature of Zn2+ as luminescent centers in the lattice. The additional yellow and orange emissions are due to defect levels or/and impurity centers. The dielectric constant as well as the conductivity values increased with increasing Cu content. PMID- 29513270 TI - Fabrication of CuO-Pt core-shell nanohooks by in situ reconstructing the Pt shells. AB - The design of various nanostructures with specific compositions and shapes is highly demanded due to the widespread use of micro/nano electro-mechanical systems. In this work, one-dimensional CuO-Pt core-shell nanowires (NWs) are acquired by depositing Pt nanoparticles onto CuO NWs and then mechanically-shaped into nanohooks. Subsequently, the hook-like shape is maintained by the Pt-shell which is reconstructed via Joule heat and re-solidified after cooling down, during which the elastic strain energy is stored in the CuO-core. The results provide a simple strategy to design nanostructures with various compositions and shapes, implying the potential applications in mechanical energy storage and shape memory nanodevices. PMID- 29513271 TI - Feasibility of using thermal response to Ka band millimeter wave heating to assess skin blood flow. AB - OBJECTIVE: Implementation of clinical guidelines for diagnosing peripheral artery disease will demand screening many millions of patients who are considered at risk. This will require faster, easier screening technologies to identify patients with compromised blood flow to the extremities. APPROACH: The feasibility of using surface temperature response to Ka band (26.5-40 GHz) near field irradiation to assess skin blood flow was explored using an animal model. Ears of domestic rabbits were subjected to low-power continuous wave radio frequency heating from an open-ended waveguide (WR-28) at f = 35 GHz. Three flow conditions were evaluated: (1) a baseline flow condition, (2) occluded flow and (3) reactive hyperemia. Surface temperatures were monitored continuously by means of an infrared thermography camera during each 2 min exposure. MAIN RESULTS: Ensemble average results showed significant differences (p < .05) at exposure times 30, 60, 90 and 120 s between baseline and occluded conditions, and between baseline and reactive hyperemia conditions. The occluded condition (N = 12) resulted in an average temperature increase of 21.4 degrees C +/- 3.9 after 2 min, compared with an average increase of 12.1 degrees C +/- 1.6 for baseline conditions (N = 9) and 4.7 degrees C +/- 3.6 for post occlusion/hyperemic conditions (N = 8). SIGNIFICANCE: Results are compared with the results of a simple two parameter mathematical model. These results suggest a method for non-invasive skin blood flow assessment to screen for peripheral artery disease and associated risk of cardiovascular events. PMID- 29513272 TI - Thickness-controlled direct growth of nanographene and nanographite film on non catalytic substrates. AB - Metal-catalyzed chemical vapor deposition (CVD) has been broadly employed for large-scale production of high-quality graphene. However, a following transfer process to targeted substrates is needed, which is incompatible with current silicon technology. We here report a new CVD approach to form nanographene and nanographite films with accurate thickness control directly on non-catalytic substrates such as silicon dioxide and quartz at 800 degrees C. The growth time is as short as a few seconds. The approach includes using 9 bis(diethylamino)silylanthracene as the carbon source and an atomic layer deposition (ALD) controlling system. The structure of the formed nanographene and nanographite films were characterized using atomic force microscopy, high resolution transmission electron microscopy, Raman scattering, and x-ray photoemission spectroscopy. The nanographite film exhibits a transmittance higher than 80% at 550 nm and a sheet electrical resistance of 2000 ohms per square at room temperature. A negative temperature-dependence of the resistance of the nanographite film is also observed. Moreover, the thickness of the films can be precisely controlled via the deposition cycles using an ALD system, which promotes great application potential for optoelectronic and thermoelectronic devices. PMID- 29513273 TI - The origin and reduction of spurious extrahepatic counts observed in 90Y non-TOF PET imaging post radioembolization. AB - Our literature survey revealed a physical effect unknown to the nuclear medicine community, i.e. internal bremsstrahlung emission, and also the existence of long energy resolution tails in crystal scintillation. None of these effects has ever been modelled in PET Monte Carlo (MC) simulations. This study investigates whether these two effects could be at the origin of two unexplained observations in 90Y imaging by PET: the increasing tails in the radial profile of true coincidences, and the presence of spurious extrahepatic counts post radioembolization in non-TOF PET and their absence in TOF PET. These spurious extrahepatic counts hamper the microsphere delivery check in liver radioembolization. An acquisition of a 32P vial was performed on a GSO PET system. This is the ideal setup to study the impact of bremsstrahlung x-rays on the true coincidence rate when no positron emission and no crystal radioactivity are present. A MC simulation of the acquisition was performed using Gate-Geant4. MC simulations of non-TOF PET and TOF-PET imaging of a synthetic 90Y human liver radioembolization phantom were also performed. Internal bremsstrahlung and long energy resolution tails inclusion in MC simulations quantitatively predict the increasing tails in the radial profile. In addition, internal bremsstrahlung explains the discrepancy previously observed in bremsstrahlung SPECT between the measure of the 90Y bremsstrahlung spectrum and its simulation with Gate-Geant4. However the spurious extrahepatic counts in non-TOF PET mainly result from the failure of conventional random correction methods in such low count rate studies and poor robustness versus emission-transmission inconsistency. A novel proposed random correction method succeeds in cleaning the spurious extrahepatic counts in non-TOF PET. Two physical effects not considered up to now in nuclear medicine were identified to be at the origin of the unusual 90Y true coincidences radial profile. TOF reconstruction removing of the spurious extrahepatic counts was theoretically explained by a better robustness against emission-transmission inconsistency. A novel random correction method was proposed to overcome the issue in non-TOF PET. Further studies are needed to assess the novel random correction method robustness. PMID- 29513274 TI - High sensitive detection of copper II ions using D-penicillamine-coated gold nanorods based on localized surface plasmon resonance. AB - In this paper, we describe the development of a nanoplasmonic biosensor based on the localized surface plasmon resonance (LSPR) effect that enables a sensitive and selective recognition of copper II ions. First, we fabricated the nanoplasmonics as LSPR substrates using gold nanorods (GNR) and the nano adsorption method. The LSPR sensitivity of the nanoplasmonics was evaluated using various solvents with different refractive indexes. Subsequently, D-penicillamine (DPA)-a chelating agent of copper II ions-was conjugated to the surface of the GNR. The limit of detection (LOD) for the DPA-conjugated nanoplasmonics was 100 pM. Furthermore, selectivity tests were conducted using various divalent cations, and sensitivity tests were conducted on the nanoplasmonics under blood-like environments. Finally, the developed nanoplasmonic biosensor based on GNR shows great potential for the effective recognition of copper II ions, even in human blood conditions. PMID- 29513275 TI - Soft-type trap-induced degradation of MoS2 field effect transistors. AB - The practical applicability of electronic devices is largely determined by the reliability of field effect transistors (FETs), necessitating constant searches for new and better-performing semiconductors. We investigated the stress-induced degradation of MoS2 multilayer FETs, revealing a steady decrease of drain current by 56% from the initial value after 30 min. The drain current recovers to the initial state when the transistor is completely turned off, indicating the roles of soft-traps in the apparent degradation. The noise current power spectrum follows the model of carrier number fluctuation-correlated mobility fluctuation (CNF-CMF) regardless of stress time. However, the reduction of the drain current was well fitted to the increase of the trap density based on the CNF-CMF model, attributing the presence of the soft-type traps of dielectric oxides to the degradation of the MoS2 FETs. PMID- 29513276 TI - Emergence EEG pattern classification in sevoflurane anesthesia. AB - OBJECTIVE: Significant spectral electroencephalogram (EEG) pattern characteristics exist in individual patients during the re-establishment of consciousness after general anesthesia. However, these EEG patterns cannot be quantitatively identified using commercially available depth of anesthesia (DoA) monitors. This study proposes an effective classification method and indices to classify these patterns among patients. APPROACH: Four types of emergence EEG patterns were identified based on the EEG data set from 52 patients undergoing sevoflurane general anesthesia from two hospitals. Then, the relative power spectrum density (RPSD) of five frequency sub-bands of clinical interest (delta, theta, alpha, beta and gamma) were selected for emergence state analysis. Finally, a genetic algorithm support vector machine (GA-SVM) was used to identify the emergence EEG patterns. The performance was reported in terms of sensitivity (SE), specificity (SP) and accuracy (AC). MAIN RESULTS: The combination of the mean and mode of RPSD in the delta and alpha band (P (delta)/P (alpha) performed the best in the GA-SVM classification. The AC indices obtained by GA-SVM across the four patterns were 90.64 +/- 7.61, 81.79 +/- 5.84, 82.14 +/- 7.99 and 72.86 +/- 11.11 respectively. Furthermore, the emergence time of the patients with EEG emergence patterns I and III increased as the patients' age increased. However, for patients with EEG emergence pattern IV, the emergence time positively correlates with the patients' age when they are under 50, and negatively correlates with it when they are over 50. SIGNIFICANCE: The mean and mode of P (delta)/P (alpha) is a useful index to classify the different emergence EEG patterns. In addition, these patterns may correlate with an underlying neural substrate which is related to the patients' age. Highlights ? Four emergence EEG patterns were found in gamma-amino-butyric acid (GABA)-ergic anesthetic drugs. ? A genetic algorithm combined with a support vector machine (GA-SVM) was proposed to identify the emergence EEG patterns. ? The relative power spectrum density (RPSD) was used as a feature to classify the emergence EEG patterns and good accuracy was achieved. ? The statistics shows that the emergence EEG patterns are age-related and may have value in assessing postoperative brain states. PMID- 29513277 TI - Posteroventral pallidotomy : a treatment option for advanced Parkinson's disease. PMID- 29513278 TI - Neurocysticercosis in the Indian context : with special reference to solitary parenchymatous cyst. PMID- 29513279 TI - Cranial computed tomography and TIA. AB - Transient ischaemic attack (TIA) is a focal neurological deficit of vascular deficit of vascular etiology, the evidence of which completely resolves within 24 hours. TIAs were thought to cause no permanent damage to the brain before the introductionof cranial computed tomography (CCT) in 1975. Thereafter, some patients with typical TIA were found to have had cerebral infarction. Though CCT has been extensively used for establishing the diagnosis of TIA and stroke, the factors determining infarctionand prognostic significance of CCT abnormalities has not been analysed. Variables such as image quality, generation of CCT equipment, duration of the TIA, timing of CCT in relation to the event, territory of TIA, degree of arterial stenosis, plaque characteristics, age of the patient - all affect the likelihood of unrecognized (silent) cerebral infarction. The chance of secondary stroke and premature vascular death are increased, if silent infarction is found. PMID- 29513280 TI - Complications of transsphenoidal pituitary surgery. AB - Two hundred and sixty four transsphenoidal procedure for excision for pituitary adenomas were performed in the Christian Medical College Hospital at Vellore between 1983 and 1994. These were reviewed to evaluate the complications and their management. There were four operative deaths (1.5). Major morbidity included cerebrospinal fluid (CSF) rhinorrhoea, meningitis, diabetes insipidus, visual deterioration and Addisonian crisis. Intraopertive CSF leak had a high association with postoperative diabetes insipidus. PMID- 29513281 TI - Normal pressure hydrocephalus role of radionuclide cisternography. AB - Seventeen patients with clinical and radiological features of normal pressure hydrocephalus (NPH) underwent isotope cisternography after instilling 2-3 mCi 99m Technetium labelled Diethylene triamine pentacetic acid (DTPA) through lumbar puncture. Detailed analysis of the images taken by Gamma camera at 1,2,4 and 24 hours was done. Features of early ventricular reflux, absent or patchy radioactivity at the surface of brain and persistent ventricular reflex at 24 hours (suggesting NPH) were looked for. Depending upon patient's response to repeated CSF taps, shunt surgery was offered to the responsive group. All these patients were followed for a mean period of 11 months. Gait apraxia preceding dementia, presence of urinary incontinence and CT head picture of increased periventricular lucency predicted good response to shunt. Presence of associated diseases predicted the opposite. The sensitivity of persistent ventricular reflux at 24 hours in predicting a good response to shunt surgery was 87.5 and specificity was 77.8. Significant loss or absence of activity at surface of the brain had a sensitivity of 62.5 and specificity of 88.89. Our study indicates that radionuclide cisternography is a useful investigation for NPH in combination with clinical and radiologic studies. PMID- 29513282 TI - Sodium valproate monotherapy and sex hormones in men. AB - Antiepileptic drugs affect various endocrinal functions including sex hormones. In this study, the effect of sodium valproate monotherapy on sex hormones has been evaluated in sexually asymptomatic patients of primary generalised tonic clonic epilepsy. Twenty-six newly diagnosed young male patients with epilepsy and twenty controls were subjects in this study. Sodium valproate monotherapy (20-30 mg/kg) was administered in patients to control the seizures. None of the patients had recurrence of seizure during one year of follow up. Serum levels of sodium valproate, total serum testosterone, leutinizing hormone (LH), follicle stimulating hormone (FSH) were estimated initially, before starting valproate therapy. These were repeated at 3 month intervals for one year. Patients on sodium valproate therapy showed minor changes in serum sex hormone level. The total testosterone level fell significantly (p<0.05) at the end of 1 year, however LH, FSH and serum prolactin levels remained unaltered. It was concluded that sodium valproate has potential for altering balance of testosterone after prolonged administration. PMID- 29513283 TI - Clinical study of neurological cretinism in Sikkim. AB - Sikkim is a small hilly state in the eastern Himalayas. Iodine deficiency disorders constitute a major public health problem for the state. High prevalence of endemic goitre (54.7) and endemic cretinism (3.7) exist in the state. A total of 119 neurological cretins were studied to define the pattern and extent of neurological involvement in endimic cretinism. There were 65 men (54.6) and 54 women (45.4). Goitre was seen in 57 (47.9). Grade-I goitre was the most frequent type of goitre seen in 52.6 of the goitrous cretins. All the endemic cretins had moderate to severe neurological deficits. The most salient neurological feature was deaf-mutism which was seen in 91 cases (76.5). Examination of motor system revealed rigidity,more marked in lower limbs, patellar hyper-reflexia in 106 (89.2) and Babinnski's sign in 40 hypothyroidism. Audiometry done in a subset of 38 cretins revealed that only two cretins had normal hearing. The hearing loss was found to be bilateral and equal and was sever toprofound in 22 cretins; mild to moderate in 9 cretins and was bilateral but unequal in 5 cretins. Neurological cretinism is a distinct and easily identifiable clinical entity. It is an important indicator of severity of iodine deficiency in a community. PMID- 29513284 TI - Sleep deprivation in anaesthetists : effect on cognitive functions. AB - Sleep deprivation is one of the various stress factors which may affect the efficiency of an anaesthitist. Cognitive functions play a vital role in safe anaesthetic practice. To assess the effect of sleep deprivation on cognitive functions, forty anaesthesia residents were tested using various tests in two planned situations. 'Situation I' comprised of non sleep deprived state and 'Situation II' was the sleep deprived state defined as 'less than 4 hours of sleep in the last 24 hours'. The tests used were Trail making task, Digit symbol test, Letter comparison test and Standard progressive matrices. There was a statistically significant decrease in the performance scores after sleep deprivation. It is concluded that acute sleep deprivation adversely affects cognitive functions. PMID- 29513285 TI - Visual and brain stem auditory evoked responses in opioid dependence. AB - Visual evoked response (VER) and Brain stem auditory response (BAER) were performed on 19 opioid dependent subjects and results compared with 20 control subjects of similar age group. The opioid dependent subjects revealed significant decrease in VER amplitude (P<0.001) and also prolonged latencies of wave III, V, and inter-peak latencies (I-III, III-IV, I-V) suggesting impaired auditory conduction in the brain stem. PMID- 29513286 TI - Giant cell tumour of sphenoid : a review and report of three cases. AB - Giant cell tumour of sphenoid is a rare tumour. Clinical manifestations are as for any other pituitary region tumour, though endocrinopathy is not common. Radiological diagnosis is often not possible. On histopathology, they have to be distinguishedfrom other lesions containing giant cells. Radical excision followed by radiotherapy is recommended for good long term results. PMID- 29513287 TI - Hereditary liability to pressure palsy : a clinical electrophysiological and histomorphometric case study. AB - An 18 years old female patient presenting with a peroneal nerve palsy after trivial pressure has been reported. A diagnosis of hereditary liability to pressure palsy was not suspected until electrodiagnostic studies were performed. These revealed the presence of a demyelinating polyneuropathy with conduction block and differential affection of various segments of the nerves. Sural nerve histology was charcterised by the presence of suasage like swellings and segmental demyelination and remyelination in teased fibres and mild loss of large myelinated fibres. PMID- 29513288 TI - Aspergilloma : an unusual differential diagnosis for an intradural extramedullary cervical cord tumour in a healthy man. AB - This is a case of Aspergillus infection in a twenty year old male presenting as an insidiously growing intradural spinal cord tumour with signs of cord compression. There was no definite portal of entry and the patient had no signs of immunsuppression. It is believed that such a case has not been previously reported. The lesion resembled a benign tumour on preoperative imaging and intraoperative consistency and vascularity. The lesion was successfully and completely resected. MR images of this unusual lesion are presented. PMID- 29513289 TI - Sequestrated lateral ventricle due to tuberculosis. AB - A twenty-six year man presented with a short history of raised intracranial pressure. He had papilloedema and long tract signs in both the lower limbs. CT scan of the head revealed unilateral dilatation of the right lateral ventricle. Ventriculography showed block of right foramen of Mono. Patient was treated by right vrentriculoperitoneal shunt and antitubercular drugs. However symptoms recurred within six weeks. MRI done at this stage revealed a sequestrated left lateral ventricle with dilatationof the cut off part of the ventricle. CSF findings were suggestive of tubercular pathology. Such a pathological manifestation has described only once before. The pathogenesis and management is being discussed. PMID- 29513290 TI - Spinal muscular atrophy and Ehlers-Danlos syndrome : a rare association. AB - Ehlers-Danlos Syndrome (EDS) is a group of heritable connective tissue disorders characterised by hyperelasticity of the skin and hypermobile joints. In addition to those features it is often associated with many systemic complications. Though many neurological complications have been described, an association of spinal muscular atrophy (SMA) has not been reported. We are reporting this rare association - a case of EDS with Kugelberg-Welander disease (type III SMA). PMID- 29513292 TI - Excess trinucleotide repeats and neurogenetic disorders. PMID- 29513291 TI - Unusual MRI findings in young onset Parkinson's disease. AB - A case of young onset Parkinson's disease is presented, who had MRI finding usually described in Parkinson plus syndrome. PMID- 29513293 TI - Spinal subdural abscess. PMID- 29513294 TI - Bilateral ischaemic lesions of basal ganglia in children after minor head trauma. PMID- 29513295 TI - Spontaneous intracerebral haematoma from an atypical meningioma. PMID- 29513297 TI - Neurology : a public health problem. PMID- 29513296 TI - Beevor's sign in amyotrophic lateral sclerosis. PMID- 29513298 TI - NOD2: Activation During Bacterial and Viral Infections, Polymorphisms and Potential as Therapeutic Target. AB - Nucleotide-binding domain (NBD) leucine-rich repeat (LRR)-containing receptors or NLRs are a family of receptors that detect both, molecules associated to pathogens and alarmins, and are located mainly in the cytoplasm. NOD2 belongs to the NLR family and is a dynamic receptor capable of interacting with multiple proteins and modulate immune responses in a stimuli-dependent manner. The experimental evidence shows that interaction between NOD2 structural domains and the effector proteins shape the overall response against bacterial or viral infections. Other reports have focused on the importance of NOD2 not only in infection but also in maintaining tissue homeostasis. However, not only protein interactions relate to function but also certain polymorphisms in the gene that encodes NOD2 have been associated with inflammatory diseases, such as Crohn's disease. Here, we review the importance and general characteristics of NOD2, discussing its participation in infections caused by bacteria and viruses as well as its interaction with other pathogen recognition receptors or effectors to induce antibacterial and antiviral responses. Finally, the role of NOD2 in chronic inflammatory conditions and its potential to be targeted therapeutically are examined. PMID- 29513299 TI - Cytotoxic Activity of a Black Bean (Phaseolus vulgaris L.) Extract and its Flavonoid Fraction in Both In Vitro and In Vivo Models of Lymphoma. AB - Background: Black bean (Phaseolus vulgaris L.) is a very common legume seed in Mexican diet. Flavonoids and crude extracts from different plants have been reported as effective agents for chemoprevention and cytotoxicity in several cancer cell lines. We investigated the effects of black bean hulls extract (BBE) and its flavonoid fraction (FF) on lymphoma cells. Methods: BBE and FF were characterized by high-performance liquid chromatography. Viability and flow cytometry assays were carried out. Finally, a mouse model was generated to test the in vivo effect of both fractions. Results: Both BBE and FF inhibited cell proliferation in a dose-dependent way. In addition, cells underwent apoptosis, and the cellular population at S-phase increased after exposure to these fractions. Furthermore, mice treated with BBE or FF increased the overall survival by 5 or 6 days, respectively, in comparison with a placebo group (p = 0.056). Discussion: BBE and FF had cytotoxic action by driving OCI-Ly7 cells into apoptosis as well as blocking progression to G2/M phase. In addition, BBE and FF treatments were effective in xenograft models. PMID- 29513300 TI - Heading Toward the Elimination of Hepatitis C Virus. AB - Chronic hepatitis C is often asymptomatic and may progress over the years to cirrhosis and hepatocellular carcinoma. Although the prevalence and incident cases are decreasing, the peak mortality of hepatitis C virus (HCV)-related complications is ahead of us in most countries. The economic impact of this burden is enormous. Scaling up the identification of new opportunities to facilitate the road toward HCV elimination includes increasing screening, awareness, and the number of prescribing physicians. Screening should occur within the context of linkage-to-care and patient retention across the care continuum. Awareness and access to treatment in different countries are not systematic as countries have diverse healthcare organizations so that treatment eligibility and availability criteria vary significantly. The simplicity of oral regimens with direct-acting antiviral drugs that are effective across HCV genotypes expands the number of physicians who can prescribe them with accessible treatment models. The ultimate aim is the elimination of HCV by 2030. PMID- 29513301 TI - Changing Trends in Gastric Polyps. AB - Background: The prevalence of gastric polyps varies around the world reflecting regional associations. We describe demographic features of patients with gastric polyp diagnosis treated between 1980 and 2016 at a referral center in Mexico City and analyzed trends of polyp subtype. Materials and Methods: We conducted a blind review of archival slides of gastric biopsies with polyp diagnosis from the years 1980, 1990, 2000, 2010, and 2016. Initial diagnosis; patient's gender, age and symptoms; and number and location of lesions were recorded. Blind slide review and trend analysis were performed. Results: In 3887 gastric biopsies, 192 patients (4.93%) with epithelial polyps were identified. The median age of patients was 58 years; 73% were female. Polyps were single in 143/192 cases (74.4%), almost 67% in the oxyntic mucosa, and 85% were associated with dyspepsia. The prevalence was 0.5%, 1.6%, 1.9%, 4.6%, and 9.6% for the years 1980, 1990, 2000, 2010, and 2016, respectively, resulting in a rising trend in the prevalence of epithelial polyps of 380% in 46 years. Fundic gland polyps (FGPs) had a global frequency of 66.6% (128/192). They were identified for the first time in the third period of the study, with a frequency of 28.6% (6/21), 66.6% (35/53), and 78.3% (87/111) for the years 2000, 2010, and 2016, respectively. Contrary, hyperplastic polyps (HPs) decreased 20%. A relative prevalence of 3.29%, 0.97%, and 0.15% was observed for FGP, HP, and gastric adenoma, respectively. Discussion: The 1400% change of FGP explains the increased prevalence of gastric polyps. Chronic treatment with proton pump inhibitors and Helicobacter pylori eradication are possible explanations. PMID- 29513302 TI - Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis. AB - Atherosclerosis is a chronic, progressive, and multifactorial disease modulated by genetic and environmental factors. In recent years, the paradigm that explained atherosclerosis as resulting from a complex interaction between factors not accessible to medical intervention, and modifiable risk factors has changed. In this paradigm, alterations in lipid metabolism were the pivotal concept of atherosclerosis as a chronic degenerative disease. In the last years, an increasing number of observations have shown that the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall significantly influence atherosclerosis. Currently, it is well recognized that the pathogenesis of atherosclerosis and its complications involves the inflammatory process, which includes the participation of several cytokines. Besides the classic cytokines involved in this process, the role of the interleukin-12 (IL-12) family has been recently demonstrated. This review describes our current understanding about the role of the family of IL-12 in atherosclerosis considering the participation of the genes that encode these cytokines in the genetic susceptibility to developing this disease. PMID- 29513303 TI - Chewing Xylitol Gum could Accelerate Bowel motility Recovery after Elective Open Proctectomy for Rectal Cancer. AB - Background: A number of studies with conflicting results have evaluated the effect of chewing gum on post-operative gastrointestinal recovery in patients after major colorectal surgery. Objective: The objective of the study was to study the efficacy of chewing gum in patients with rectal cancer after elective open proctectomy only. Methods: A randomized controlled clinical trial was performed. We recruited patients who would undergo elective open proctectomy for rectal cancer in Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital. Patients in the intervention arm received chewing gum 3 times a day postoperatively. All patients in the trial were placed on the same perioperative management and standardized post-operative care plans. The primary outcome was time to the first peristalsis sounds, time to first flatus and the first defecation. Results: A total of 89 patients were recruited. The time to the first flatus was 42.33 +/- 3.46 h in the gum group and 49.20 +/- 1.42 h in the control group (p < 0.05). The time to the first defecation was significantly shorter in the gum-chewing group than in the control group (66.07 +/- 2.36 vs. 78.37 +/- 1.62 h; p < 0.05). Post-operative ileus (POI) was confirmed in 2 patients in the gum-chewing group and in 7 in the control group (7.0% vs. 23.9%; p = 0.028). Discussion: The present study suggests that chewing gum is a method to reduce the time to first flatus, time to first defecation and POI in patients undergoing elective open proctectomy for rectal cancer. PMID- 29513304 TI - A prognostic score for survival in patients older than 65 years with Diffuse Large B-Cell Lymphoma. AB - Background: Available prognosis scores for patients with diffuse large B-cell lymphoma (DLBCL) included a limited number of patients >= 65 years of age, and most of them did not include comorbidities. Here, we propose a prognostic score for overall survival (OS) for this group of patients. Materials and Methods: Patients >= 65 years with DLBCL treated at a single national reference center were included. Clinical features including comorbidities and biochemical parameters were analyzed. Results: We included 141 patients. Response rate in the whole group was 77%. Based on multivariate analysis, the presence of the European Cooperative Oncology Group (ECOG) > 2, elevated levels of beta-2 microglobulin, bulky disease, and anemia (hemoglobin < 10 g/dL) had a significant effect on OS. These parameters were considered when computing the prognostic score, which identified three groups with differential survival: Low, intermediate, and high risk of death, with a probability of survival at 60 months of 80.05%, 55.5%, and 29.84%, respectively. Discussion: This score may select patients to optimize treatment. The presence of high levels of beta-2 microglobulin, bulky disease, and hemoglobin < 10 g/dL, and ECOG > 2 was associated with poor OS in elderly patients with DLBCL. PMID- 29513305 TI - Electro-nucleation of water nano-droplets in No Man's Land to fault-free ice Ic. AB - Elucidating water-to-ice freezing, especially in "No Man's Land" (150 K < T < 235 K), is fundamentally important (e.g., predicting upper-troposphere cirrus-cloud formation) - and elusive. An oft-neglected aspect of tropospheric ice-crystallite formation lies in inevitably-present electric fields' role. Exploring nucleation in No Man's Land is technically demanding, owing to rapid nucleation rates, to mention nothing of difficulties of applying relevant electric fields thereto. Here, we tackle these intriguing open questions, via non-equilibrium molecular dynamics simulations of sub-microsecond formation of rhombus-shaped ice Ic nano crystallites from aggressively-quenched supercooled water nano-droplets in the gas phase, in external static electric fields. We explore droplets' nano-confined geometries and the entropic-ordering agent of external electric fields as a means of realising cubic-ice formation, especially with very few stacking faults and defects. PMID- 29513306 TI - Interfacial engineering in graphene bandgap. AB - Graphene exhibits superior mechanical strength, high thermal conductivity, strong light-matter interactions, and, in particular, exceptional electronic properties. These merits make graphene an outstanding material for numerous potential applications. However, a graphene-based high-performance transistor, which is the most appealing application, has not yet been produced, which is mainly due to the absence of an intrinsic electronic bandgap in this material. Therefore, bandgap opening in graphene is urgently needed, and great efforts have been made regarding this topic over the past decade. In this review article, we summarise recent theoretical and experimental advances in interfacial engineering to achieve bandgap opening. These developments are divided into two categories: chemical engineering and physical engineering. Chemical engineering is usually destructive to the pristine graphene lattice via chemical functionalization, the introduction of defects, doping, chemical bonds with substrates, and quantum confinement; the latter largely maintains the atomic structure of graphene intact and includes the application of an external field, interactions with substrates, physical adsorption, strain, electron many-body effects and spin-orbit coupling. Although these pioneering works have not met all the requirements for electronic applications of graphene at once, they hold great promise in this direction and may eventually lead to future applications of graphene in semiconductor electronics and beyond. PMID- 29513307 TI - All-phosphorus flexible devices with non-collinear electrodes: a first principles study. AB - With the continuous expansion of the family of two-dimensional (2D) materials, flexible electronics based on 2D materials have quickly emerged. Theoretically, predicting the transport properties of the flexible devices made up of 2D materials using first principles is of great importance. Using density functional theory combined with the non-equilibrium Green's function formalism, we calculated the transport properties of all-phosphorus flexible devices with non collinear electrodes, and the results predicted that the device with compressed metallic phosphorene electrodes sandwiching a P-type semiconducting phosphorene shows a better and robust conducting behavior against the bending of the semiconducting region when the angle between the two electrodes is less than 45 degrees , which indicates that this system is very promising for flexible electronics. The calculation of a quantum transport system with non-collinear electrodes demonstrated in this work will provide more interesting information on mesoscopic material systems and related devices. PMID- 29513308 TI - Quantification of biomolecules responsible for biomarkers in the surface-enhanced Raman spectra of bacteria using liquid chromatography-mass spectrometry. AB - Recently, specific biomarkers in the surface-enhanced Raman scattering (SERS) spectra of bacteria have been successfully exploited for rapid bacterial antibiotic susceptibility testing (AST) - dubbed SERS-AST. The biomolecules responsible for these bacterial SERS biomarkers have been identified as several purine derivative metabolites involved in bacterial purine salvage pathways (W. R. Premasiri, J. C. Lee, A. Sauer-Budge, R. Theberge, C. E. Costello and L. D. Ziegler, Anal. Bioanal. Chem., 2016, 408, 4631). Here we quantified these metabolites in the SERS spectra of Staphylococcus aureus and Escherichia coli using ultra-performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS). The time dependences of the concentrations of these molecules were measured using 13C- or 12C-purine derivatives as internal and external standards respectively in UPLC/ESI-MS measurements. Surprisingly, a single S. aureus and an E. coli cell were found to release millions of adenine and hypoxanthine into a water environment in an hour respectively. Furthermore, simulated SERS spectra of bacterial supernatants based on the mixtures of purine derivatives with measured concentrations also show great similarity with those of the corresponding bacterial samples. Our results not only provide a quantitative foundation for the emerging SERS-AST method but also suggest the potential of exploiting SERS for in situ monitoring the changes in bacterial purine salvage processes in response to different physical and chemical challenges. PMID- 29513309 TI - Synthesis of medium-sized aryl-fused nitrogenous heterocycles via sequential aryne aza-Claisen rearrangement/ring-closing metathesis. AB - The reaction of arynes and secondary allylamines furnished ortho-allyl substituted N-arylanilines via an aza-Claisen rearrangement. In this transformation, the sequential formation of C-C and C-N bonds occurred by involving two aryne molecules under metal-free reaction conditions to provide moderate to good yields of the products. The obtained ortho-allyl-substituted N arylaniline derivatives were further converted into aryl-fused medium-sized (7-9) nitrogenous heterocyclic molecules such as azepines, azocines and azonines via ring-closing metathesis (RCM). PMID- 29513310 TI - Inertio-capillary cross-streamline drift of droplets in Poiseuille flow using dissipative particle dynamics simulations. AB - We find using dissipative particle dynamics (DPD) simulations that a deformable droplet sheared in a narrow microchannel migrates to steady-state position that depends upon the dimensionless particle capillary number , which controls the droplet deformability (with Vmax the centerline velocity, MUf the fluid viscosity, Gamma the surface tension, R the droplet radius, and H the gap), the droplet (particle) Reynolds number , which controls inertia, where rho is the fluid density, as well as on the viscosity ratio of the droplet to the suspending fluid kappa = MUd/MUf. We find that when the Ohnesorge number is around 0.06, so that inertia is stronger than capillarity, at small capillary number Cap < 0.1, the droplet migrates to a position close to that observed for hard spheres by Segre and Silberberg, around 60% of the distance from the centerline to the wall, while for increasing Cap the droplet steady-state position moves smoothly towards the centerline, reaching around 20% of the distance from centerline to the wall when Cap reaches 0.5 or so. For higher Oh, the droplet position is much less sensitive to Cap, and remains at around 30% of the distance from centerline to the wall over the whole accessible range of Cap. The results are insensitive to viscosity ratios from unity to the highest value studied here, around 13, and the drift towards the centerline for increasing Cap is observed for ratios of droplet diameter to gap size ranging from 0.1 to 0.3. We also find consistency between our predictions and existing perturbation theory for small droplet or particle size, as well as with experimental data. Additionally, we assess the accuracy of the DPD method and conclude that with current computer resources and methods DPD is not readily able to predict cross-stream-line drift for small particle Reynolds number (much less than unity), or for droplets that are less than one tenth the gap size, owing to excessive noise and inadequate numbers of DPD particles per droplet. PMID- 29513311 TI - Quadratic and cubic hyperpolarizabilities of nitro-phenyl/-naphthalenyl/ anthracenyl alkynyl complexes. AB - 1-Nitronaphthalenyl-4-alkynyl and 9-nitroanthracenyl-10-alkynyl complexes [M](C[triple bond, length as m-dash]C-4-C10H6-1-NO2) ([M] = trans-[RuCl(dppe)2] (6b), trans-[RuCl(dppm)2] (7b), Ru(PPh3)2(eta5-C5H5) (8b), Ni(PPh3)(eta5-C5H5) (9b), Au(PPh3) (10b)) and [M](C[triple bond, length as m-dash]C-10-C14H8-9-NO2) ([M] = trans-[RuCl(dppe)2] (6c), trans-[RuCl(dppm)2] (7c), Ru(PPh3)2(eta5-C5H5) (8c), Ni(PPh3)(eta5-C5H5) (9c), Au(PPh3) (10c)) were synthesized and their identities were confirmed by single-crystal X-ray diffraction studies. Electrochemical studies and a comparison to the 1-nitrophenyl-4-alkynyl analogues [M](C[triple bond, length as m-dash]C-4-C6H4-1-NO2) ([M] = trans-[RuCl(dppe)2] (6a), trans-[RuCl(dppm)2] (7a), Ru(PPh3)2(eta5-C5H5) (8a), Ni(PPh3)(eta5-C5H5) (9a), Au(PPh3) (10a)) reveal a decrease in oxidation potential for ruthenium and nickel complexes on proceeding from the phenyl- to naphthalenyl- and then anthracenyl-containing bridge. HOMO -> LUMO transitions characteristic of MC[triple bond, length as m-dash]C-1-C6H4 to 4-C6H4-1-NO2 charge transfer red shift and gain in intensity on proceeding to the ruthenium complexes; the low energy transitions have increasing ILCT character on proceeding from the phenyl- to naphthalenyl- and then anthracenyl-containing bridge. Spectroelectrochemical studies of the Ru-containing complexes reveal the appearance of low-energy bands corresponding to chloro-to-RuIII charge transfer that red-shift on proceeding from the phenyl- to naphthalenyl- and then anthracenyl-containing bridge. Second order nonlinear optical (NLO) studies at 1064 nm employing ns pulses and the hyper-Rayleigh scattering technique reveal an increase in quadratic optical nonlinearity upon introduction of metal to the precursor alkyne to afford alkynyl complexes and on proceeding from ligated-gold to -nickel and then to -ruthenium for a fixed alkynyl ligand. Quadratic NLO data of the gold complexes optically transparent at the second-harmonic wavelength reveal an increase in betaHRS on proceeding from the phenyl- to the naphthalenyl-containing complex. Broad spectral range third-order nonlinear optical studies employing fs pulses and the Z-scan technique reveal an increase in two-photon absorption cross-section on replacing ligated-gold by -nickel and then -ruthenium for a fixed alkynyl ligand. Computational studies undertaken using time-dependent density functional theory have been employed to assign the nature of the key optical transitions and suggest that the significant optical nonlinearities observed for the ruthenium containing complexes correlate with the low-energy formally Ru -> NO2 band which possesses strong MLCT character, while the more moderate nonlinearities of the gold complexes correlate with a band higher in energy that is primarily ILCT in character. PMID- 29513312 TI - Electrochemical and surface plasmon insulin assays on clinical samples. AB - Diabetes is a complex immune disorder that requires extensive medical care beyond glycemic control. Recently, the prevalence of diabetes, particularly type 1 diabetes (T1D), has significantly increased from 5% to 10%, and this has affected the health-associated complication incidences in children and adults. The 2012 statistics by the American Diabetes Association reported that 29.1 million Americans (9.3% of the population) had diabetes, and 86 million Americans (age >=20 years, an increase from 79 million in 2010) had prediabetes. Personalized glucometers allow diabetes management by easy monitoring of the high millimolar blood glucose levels. In contrast, non-glucose diabetes biomarkers, which have gained considerable attention for early prediction and provide insights about diabetes metabolic pathways, are difficult to measure because of their ultra-low levels in blood. Similarly, insulin pumps, sensors, and insulin monitoring systems are of considerable biomedical significance due to their ever-increasing need for managing diabetic, prediabetic, and pancreatic disorders. Our laboratory focuses on developing electrochemical immunosensors and surface plasmon microarrays for minimally invasive insulin measurements in clinical sample matrices. By utilizing antibodies or aptamers as the insulin-selective biorecognition elements in combination with nanomaterials, we demonstrated a series of selective and clinically sensitive electrochemical and surface plasmon immunoassays. This review provides an overview of different electrochemical and surface plasmon immunoassays for insulin. Considering the paramount importance of diabetes diagnosis, treatment, and management and insulin pumps and monitoring devices with focus on both T1D (insulin-deficient condition) and type 2 diabetes (insulin-resistant condition), this review on insulin bioassays is timely and significant. PMID- 29513313 TI - Bioimaging of isosteric osmium and ruthenium anticancer agents by LA-ICP-MS. AB - Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to study the spatial distribution of two metallodrugs with anticancer activities in vivo, namely the organoruthenium plecstatin-1 (1) and its isosteric osmium analogue (2), in liver, kidneys, muscles and tumours of treated mice bearing a CT 26 tumour after single-dose i.p. administration. To the best of our knowledge, this is the first time that the spatial distribution of an osmium drug candidate has been investigated using LA-ICP-MS in tissues. Independent measurements of the average ruthenium and osmium concentration via microwave digestion and ICP-MS in organs and tumours were in good agreement with the LA-ICP-MS results. Matrix matched standards (MMS) ranging from 1 to 30 MUg g-1 were prepared to quantify the spatial distributions of the metals and the average metal content of the MMS samples was additionally quantified by ICP-MS after microwave digestion. The recoveries for osmium and ruthenium in the MMS were 105% and 101% on average, respectively, validating the sample preparation procedure of the MMS. Preparation of MMS was carried out under an argon atmosphere to prevent oxidation of osmium species to the volatile OsO4. The highest metal concentrations were found in the liver, followed by kidney, lung and tumour tissues, while muscles displayed only very low quantities of the respective metal. Both metallodrugs accumulated in the cortex of the kidneys more strongly compared to the medulla. Interestingly, osmium from 2 was largely located at the periphery and tissue edges, whereas ruthenium from 1 was observed to penetrate deeper into the organs and tumours. PMID- 29513314 TI - High resolution visualization of the redox activity of Li2O2 in non-aqueous media: conformal layer vs. toroid structure. AB - A strong relationship between the surface structure and the redox activity of Li2O2 is visualized directly using scanning electrochemical cell microscopy, employing a dual-barrel nanopipette containing a unique gel polymer electrolyte. These measurements reveal considerable local heterogeneity with significantly enhanced electrochemical activity at toroidal Li2O2 structures when compared to the conformal layer that is usually formed on the cathode of Li-O2 batteries. PMID- 29513315 TI - Viscoelastic multistable architected materials with temperature-dependent snapping sequence. AB - When an architected material with snap-through instabilities is loaded, the unit cells of the architected material snap sequentially to a series of deformed configurations. In this paper, we propose the novel concept of multimaterial viscoelastic architected materials whose snapping sequence can be tuned using temperature as a control parameter. Because different polymers have different temperature-dependent properties, it is possible that one polymer that is stiffer than another polymer at one temperature becomes softer at a higher temperature. A 3D printing inverse molding process is used to fabricate soft multimaterial architected materials that consist of two different polymers. Using finite element simulations and experiments, we demonstrate that the snapping sequence of these multimaterial architected materials depends on temperature. The influence of the geometrical parameters of the design on the critical temperature at which the snapping sequence switches from one sequence to another sequence is systematically analyzed using simulations and experiments. Being able to tune the snapping sequence using temperature makes it possible to obtain a large number of distinct stable configurations in response to compressive loads. To illustrate a potential application, we demonstrate that these materials can be used as soft reconfigurable metamaterials with tunable stiffness. PMID- 29513316 TI - The direct observation of electron backflow in an organic heterojunction formed by two n-type materials. AB - Many physical processes such as exciton interfacial dissociation, exciton interfacial recombination, and exciton-electron and exciton-hole interactions coexist at the interface of organic solar cells (OSC). In this study, the direction of free charge generation is defined as the direction from the interface to the side where free charges are left. For a p-n type device, the direction of free electron (hole) generation from exciton dissociation at the donor/accepter (D/A) interface is the same as the subsequent transportation direction under the built-in electric field. However, the direction of free electron (hole) generation from exciton-exciton recombination across the D/A interface is opposite to the direction of free charge transportation. Both free charges generated from exciton interfacial dissociation and recombination are contributed to the photocurrent for a p-n type device. In a device with a heterojunction formed by two n-type materials (here it is defined as an n-n type device), the direction of free electron (hole) generation from exciton recombination across the interface is also the same as the subsequent free charge transportation. At the same time, there are also some free electrons (free holes) generated by exciton interfacial dissociation. The direction of free charge generation from exciton dissociation for this n-n type device is also opposite to the direction of free charge transportation. However, only free charges generated from exciton interfacial recombination are contributed to the photocurrent for an n-n type device. But so far there has been no direct experimental evidence to prove the above theories. In this work, an NPB interfacial layer with a high LUMO was introduced in an n-n type OSC to inhibit the backflow of electrons, which are generated from exciton dissociation at the heterojunction formed by two n-type materials, enhancing the device performance accordingly. This work is conducive to interfacial engineering in an OSC to further improve its performance. PMID- 29513321 TI - Unique chemistry of non-heme iron enzymes in fungal biosynthetic pathways. AB - Covering: up to 2018 Non-heme iron enzymes are a versatile family of oxygenases that catalyze remarkable types of chemistry. This review highlights the intriguing chemistry of non-heme iron enzymes, especially those utilizing alpha ketoglutarate (alpha-KG) as a co-substrate, in fungal secondary metabolism and aims to summarize how nature diversifies and complexifies natural products. PMID- 29513319 TI - The neuroprotective and antioxidant profiles of selenium-containing polysaccharides from the fruit of Rosa laevigata. AB - Rosa laevigata fruit has been known as a functional foodstuff for a long time. Recently, increasing attention has been given to polysaccharides from R. laevigata fruit due to their numerous medicinal and nutritional properties. In this study, a rapid and effective approach for the extraction and separation of polysaccharides from the title fruit was developed using microwave-assisted aqueous two-phase extraction (MA-ATPE) with a PEG/ammonium sulfate system. After analysis of the response surface methodology (RSM) data based on a Box-Behnken design (BBD), a model was proposed and was found to predict an optimum yield value of 258.99 mg g-1 which is in good agreement with the experimental value (258.59 mg g-1). Two selenium (Se)-containing polysaccharides, Se-RLFP-1 and Se RLFP-2, were isolated from R. laevigata fruit. Their chemical structures were elucidated by acid hydrolysis, weight-average molecular mass and Se-content analysis, along with UV, FT-IR, 1H and 13C NMR spectroscopy. As a result, Se-RLFP 1 was found to be mainly composed of mannose, glucose, galactose and xylose in a molar ratio of 1.4 : 7.9 : 1.0 : 1.5, while Se-RLFP-2 was composed of mannose, rhamnose, glucose, galactose and xylose (12.6 : 1.0 : 38.3 : 5.6 : 19.6). Furthermore, the antioxidant properties of the polysaccharides were investigated on the basis of FRAP, ABTS and DPPH radical scavenging assays. The results showed that the two polysaccharides had a noticeable effect on the radical scavenging of ABTS and DPPH, especially at high concentrations. In addition, the neuroprotective effect of Se-RLFP-1 and Se-RLFP-2 against oxidative stress induced by H2O2 in SH-SY5Y neuroblastoma cells was also investigated. In particular, Se-RLFP-1 exhibited obvious neuroprotective activity at a concentration of 100 MUg mL-1. PMID- 29513322 TI - Charge driven lateral structural evolution of ions in electric double layer capacitors strongly correlates with differential capacitance. AB - Electric double layers (EDLs) play a decisive role in the energy storage of supercapacitors. Recently, voltage/charge driven ordering transitions of ions in the lateral direction of the EDL were found to dramatically affect the capacitance in experiments and molecular dynamics (MD) simulations. However, the correlation between the lateral structure of the ions and the capacitance was not well understood. In this work, all-atom MD simulations were applied to investigate the lateral ordering of the [BMIM][PF6] ionic liquid on both anode and cathode surfaces. The lateral ordering of ions was systematically characterized using the 2D structure factor, radial distribution function and coordination number. It was found that the disorder to order transition of PF6- ions on the anode occurs when the number of first nearest neighboring ions converges to six. What's more, the local maximum of the differential capacitance profile not only appears at the disorder-order transition point, but also occurs at the splitting point of the radial distribution function peak and where the number of second and third nearest neighboring ions become converged and stable. On the cathode side, a long range ordered phase of BMIM+ ions does not exist due to its multi-adsorption states on the electrode. To understand the origin of the correlation between the lateral structure and the differential capacitance, the correlation between the structures in the lateral and normal directions was investigated. Such a structural correlation is closely related to the three dimensional characteristics of the EDL structure and the over-screening phenomenon. PMID- 29513326 TI - FTIR spectroscopy of chronic venous leg ulcer exudates: an approach to spectral healing marker identification. AB - Chronic venous leg ulcer (CVLU) arises as a chronic venous insufficiency complication and is a major cause of morbidity throughout the world. Our hypothesis is that the CVLU exudate composition is a biochemical representation of the wound clinical state. Then, Fourier Transform Infrared (FTIR) spectroscopy could be a useful and less-invasive technique to study the clinical state of the ulcer. For this, the aim of this work was to perform a spectral characterization of the exudate from CVLU using FTIR spectroscopy to identify potential healing markers. 45 exudate samples from CVLU, 95% of the strains isolated from CVLU in planktonic and biofilm phenotypes and other related biological samples such as human plasma, serum, urine, blood cells, urea, creatinine, glucose and albumin were studied by FTIR spectroscopy. According to the vibration frequency of biomolecules' (lipids, proteins, nucleic acids and carbohydrates) characteristic bonds in the infrared region, different spectral windows were selected and spectral areas of each window were measured. Besides, Savitzky-Golay second derivatives were obtained for all spectra and peaks from each standardized window were detected. FTIR spectroscopy allowed identification of sample types (exudate, plasma, serum, urine) as each one presents a unique relative composition and ratios range. Also, this technique could be useful to identify bacteria in the phenotypic-ulcer state and allows differentiation of whether bacteria are in the biofilm or planktonic form which is unlikely by conventional methods. In this work we found some spectral markers (areas, peaks) that allow identification of several parameters in the exudate such as (a) total cellularity, (b) inflammatory cell load, (c) bacterial load, (d) fibrin amount, and (e) inflammatory proteins. Because the measured areas or founded peaks are concentration-dependent this method could also serve to measure them. Therefore, FTIR spectroscopy could be useful to evaluate patient evolution as all these exudate parameters represent critical negative markers for wound healing. PMID- 29513327 TI - Low-valent magnesium(i)-catalyzed cyanosilylation of ketones. AB - The magnesium(i) complex [(XylNacnac)Mg]2 was employed as a highly efficient catalyst for the cyanosilylation of a variety of ketones with trimethylsilyl cyanide under mild conditions. In contrast to the traditional stoichiometric use of magnesium(i) complexes, 1 provides the first example of a truly catalytic application of Mg(i) complexes. PMID- 29513328 TI - Gaussian curvature directs the distribution of spontaneous curvature on bilayer membrane necks. AB - Formation of membrane necks is crucial for fission and fusion in lipid bilayers. In this work, we seek to answer the following fundamental question: what is the relationship between protein-induced spontaneous mean curvature and the Gaussian curvature at a membrane neck? Using an augmented Helfrich model for lipid bilayers to include membrane-protein interaction, we solve the shape equation on catenoids to find the field of spontaneous curvature that satisfies mechanical equilibrium of membrane necks. In this case, the shape equation reduces to a variable coefficient Helmholtz equation for spontaneous curvature, where the source term is proportional to the Gaussian curvature. We show how this latter quantity is responsible for non-uniform distribution of spontaneous curvature in minimal surfaces. We then explore the energetics of catenoids with different spontaneous curvature boundary conditions and geometric asymmetries to show how heterogeneities in spontaneous curvature distribution can couple with Gaussian curvature to result in membrane necks of different geometries. PMID- 29513329 TI - Reentrant phase behavior and coexistence in asymmetric block copolymer electrolytes. AB - It is known that the addition of salts to symmetric block copolymers leads to stabilization of ordered phases and an increase in domain spacing; both trends are consistent with an increase in the effective Flory-Huggins interaction parameter between the blocks, chi. In this work, we show that the addition of salt to a disordered asymmetric block copolymer first leads to the formation of coexisting ordered phases which give way to a reentrant disordered phase at a higher salt concentration. The coexisting phases are both body centered cubic (BCC) with different domain spacings, stabilized by partitioning of the salt. Further increase in salt concentration results in yet another disorder-to-order transition; hexagonally packed cylinders are obtained in the high salt concentration limit. The coexisting phases formed at intermediate salt concentration, elucidated by electron tomography, showed the absence of macroscopic regions with distinct BCC lattices. A different asymmetric block copolymer with composition in the vicinity of the sample described above only showed only a single disorder-to-order transition. However, the dependence of domain spacing on salt concentration was distinctly non-monotonic, and similar to that of the sample with the reentrant phase behavior. This dependence appears to be an announcement of reentrant phase transitions in asymmetric block copolymer electrolytes. These results cannot be mapped on to the traditional theory of block copolymer electrolyte self-assembly based on an effective chi. PMID- 29513330 TI - CuO/CeO2 catalysts for glycerol selective conversion to lactic acid. AB - Ceria supported copper oxide catalysts were produced by a deposition precipitation method, at a high copper loading (up to >25 wt%). These materials demonstrated excellent properties for glycerol selective conversion to lactic acid, with a conversion reaching up to 87% with a selectivity to lactic acid of 74% (8 h reaction, 220 degrees C, under N2 pressure). These catalysts also exhibited high stability upon 5 successive reaction cycles. The formation of a crystalline CuO phase was demonstrated in the nanocomposites at a high Cu loading, with elongated shaped particles formed on the cerium oxide surface. Such particles were however, not observed at low Cu loadings. XPS analysis revealed that Cu(ii) was the main Cu species on the fresh catalyst, and that this species was reduced to Cu(i) during the reaction. Complementary characterization over the spent catalyst clearly showed the morphological modifications of the CuO phase, however, did not impact significantly either glycerol conversion or selectivity to lactic acid upon recycling. For instance, apparently, the catalytic activity of CuO largely depends on the Cu(ii) species. PMID- 29513332 TI - Repeated roll-to-roll transfer of two-dimensional materials by electrochemical delamination. AB - Two-dimensional (2D) materials such as graphene (Gr), molybdenum disulfide and hexagonal boron nitride (hBN) hold great promise for low-cost and ubiquitous electronics for flexible displays, solar cells or smart sensors. To implement this vision, scalable production, transfer and patterning technologies of 2D materials are needed. Recently, roll-to-roll (R2R) processing, a technique that is widely used in industry and known to be cost-effective and scalable, was applied to continuously grow and transfer graphene. However, more work is needed to understand the possibilities and limitations of this technology to make R2R processing of 2D materials feasible. In this work, we fabricated a custom R2R transferring system that allows the accurate control of the process parameters. We employ continuous electrochemical delamination, known as "bubble transfer", to eliminate chemical etchant waste and enable the continuous transfer of 2D materials from metal foils. This also makes our transfer method a renewable and environmentally friendly process. We investigate the surface topology as well as the electrical parameters of roll-to-roll transferred graphene on polyethylene terephthalate (PET) coated with ethylene-vinyl acetate (EVA). Furthermore, we demonstrate for the first time the stacking of two layers of graphene or graphene on hBN by repeated lamination and delamination onto EVA/PET. These results are an important contribution to creating low-cost, large scale and flexible electronics based on 2D materials. PMID- 29513333 TI - HIV-related DNA detection through switching on hybridized quenched fluorescent DNA-Ag nanoclusters. AB - In this paper, DNA containing six cytosines as the formation site for silver nanoclusters (Ag NCs) was adopted as a template for preparing fluorescent DNA-Ag NCs. For the first time, it was found that the fluorescence of DNA-Ag NCs could be quenched after hybridization with their complementary sequence. On the basis of this new phenomenon, we designed a sequence C1 that was completely complementary to human immunodeficiency virus (HIV) DNA, and probe DNA which was partially complementary to C1 for the synthesis of DNA-Ag NCs. The fluorescence of DNA-Ag NCs was quenched after hybridization with C1 and the DNA-Ag NCs/C1 composite was formed, while C1 could be dissociated away from the DNA-Ag NCs by HIV DNA through a strand exchange reaction due to the stronger affinity between HIV DNA and C1, which could switch on the quenched Ag NCs, thus a new "off-on" fluorescence method for HIV DNA detection was developed. In the experiment, the Ag NCs formation site of DNA, the number of base pairs, and the pH and salt concentration of binding buffer were optimized. Under the optimum conditions, the limit of detection for HIV DNA was obtained to be 3.18 nM (3sigma/N, n = 7) with the linear range of 15-150 nM for the 150 nM DNA-Ag NCs/C1 probe. Besides, the probe showed excellent specificity to HIV DNA, and even distinguished one nucleotide mismatched HIV DNA. PMID- 29513334 TI - DNA-templated copper nanoparticles for voltammetric analysis of endonuclease activity. AB - DNA endonucleases play critical roles in medicinal chemistry, which are also commonly used in molecular biology investigation. Sensitive quantification of endonuclease activity is of great significance. In this study, a reliable electrochemical approach for endonuclease activity sensing is developed with the adoption of copper nanoparticles (CuNPs) as electrochemical reporters. Firstly, a DNA duplex is designed and modified on a gold electrode, which acts as the template for the synthesis of CuNPs. Subsequently, the formed NPs are dissolved and then electrodeposited on a glassy carbon electrode for DPV measurements. With the effect of target endonuclease, the DNA duplex is specifically recognized and cleaved. Thus, CuNPs cannot be synthesized and a declined DPV peak is obtained to reveal the level of endonuclease activity. This developed sensor has a wide linear range from 10-3 to 10 U mL-1, and the limit of detection is 10-3 U mL-1, which is extremely low. High stability and excellent reproducibility are also researched. Besides, this sensor shows good selectivity, which can successfully distinguish target endonuclease from possible interferences. PMID- 29513335 TI - Shapes within shapes: how particles arrange inside a cavity. AB - We calculate the configurational entropy of hard particles confined in a cavity using Monte Carlo integration. Multiple combinations of particle and cavity shapes are considered. For small numbers of particles N, we show that the entropy decreases monotonically with increasing cavity aspect ratio, regardless of particle shape. As N increases, we find ordered regions of high and low particle density, with the highest density near the boundary for all particle and cavity shape combinations. Our findings provide insights relevant to engineering particles in confined spaces, entropic barriers, and systems with depletion interactions. PMID- 29513336 TI - On the relevance of thermophysical characterization in the microwave treatment of legumes. AB - This study is focused on the characterization of the thermal behavior and physical properties of the most consumed legumes in the daily diet such as beans, lentils and chickpeas. Because of a lack of information in the literature about the effect of microwave treatments on legumes, characterization protocols have been applied before and after subjecting them to microwave irradiation suitable for pest disinfestation. The effects of two different radiative treatments, one suitable for inactivating the infesting fauna and the other simulating uncontrolled treatments, characterized by very high temperatures, were tested. The impacts of microwave treatments on legumes, in terms of thermal behavior, germination capability, tannin and total polyphenol composition and other physical properties (water uptake capability, texture change, mineral losses), after typical soaking cooking processes, are also studied. The thermal properties of the examined legumes were found to be comparable for all samples. Similarly, no significant differences in antinutritional factors, polyphenol and tannin content among all samples were detected. From the structural point of view, samples exposed to high temperatures showed texture degradation and in turn, loss of mineral nutrients during soaking processes. Moreover, their germination capability was drastically reduced. These latter results highlighted why it is important to correctly perform the radiative microwave process in order to both ensure effective and safe disinfestation and avoid nutritional value loss and the worsening of physical properties. PMID- 29513338 TI - Constrained saccharides: a review of structure, biology, and synthesis. AB - Review primarily covers from 1995-2018Carbohydrate function, recognized in a multitude of biological processes, provides a precedent for developing carbohydrate surrogates that mimic the structure and function of bioactive compounds. In order to constrain highly flexible oligosaccharides, synthetic tethering techniques like those exemplified by stapled peptides are utilized to varying degrees of success. Naturally occurring constrained carbohydrates, however, exist with noteworthy cytotoxic and chemosensitizing properties. This review highlights the structure, biology, and synthesis of this intriguing class of molecules. PMID- 29513341 TI - Redox fusion of metal particles using deep eutectic solvents. AB - Alternating anodic and cathodic current pulses have been applied to a metal powder on an electrode surface to fuse the particles together. It is shown that homogeneous films can be electroformed with different morphologies depending on the size of the powder and the experimental conditions. PMID- 29513342 TI - The influence of dietary fat and intestinal pH on calcium bioaccessibility: an in vitro study. AB - In vivo studies measuring true fractional calcium (Ca) absorption have shown that dietary fat is a significant predictor of absorption and is influenced by luminal pH levels. However, whether changes in Ca bioaccessibility (CaB) can explain the effects on absorption has not been examined. In the current study, we examined two high fat diets enriched in either monounsaturated fatty acids or saturated fatty acids (SFA), and a low-fat diet (LFD), each with 50 mg Ca, and measured CaB at different intestinal regions during normal acidic or higher (pH = 7) gastrointestinal conditions using an in vitro gastrointestinal model. During normal pH conditions in the jejunum, there was an interaction between diet and time for CaB (P < 0.02), and CaB during the SFA diet was higher than LFD (P = 0.05). CaB was reduced by 90 +/- 3% during higher compared with normal pH under all dietary conditions (P < 0.001). These findings indicate that fat intake, especially SFA enriched, is associated with a greater CaB in the jejunum, and may explain the higher Ca absorption in previous studies. In addition, the marked reduction in CaB under higher pH conditions could have implications in persons taking medications to reduce gastric acid. PMID- 29513343 TI - Electrochemically driven host-guest interactions on patterned donor/acceptor self assembled monolayers. AB - Here, on ITO//Au patterned substrates SAMs of ferrocene (Fc) on the Au regions and of anthraquinone (AQ) on the ITO areas are prepared, exhibiting three stable redox states. Furthermore, by selectively oxidizing or reducing the Fc or AQ units, respectively, the surface properties are locally modified. As a proof-of concept, such a confinement of the properties is exploited to locally form host guest complexes with beta-cyclodextrin on specific surface regions depending on the applied voltage. PMID- 29513344 TI - Antioxidant activity and inhibitory effects of 2-hydroxy-3-methylcyclopent-2 enone isolated from ribose-histidine Maillard reaction products on aldose reductase and tyrosinase. AB - This study aimed to better understand the functional properties of ribose and 20 amino acid Maillard reaction products (MRPs). The ABTS+ radical scavenging ability of the ribose-20 amino acid MRPs was evaluated. Among the MRPs, ribose histidine MRPs (RH-MRPs) showed the highest inhibitory activities on the ABTS+ radical scavenging ability, aldose reductase (AR), and tyrosinase compared to other MRPs. Functional compounds with antioxidant and AR inhibitory activities have been recognized as an important strategy in the prevention and treatment of diabetic complications, and the search for tyrosinase inhibitors is important for the treatment of hyperpigmentation, development of skin-whitening agents, and use as preservatives in the food industry. On this basis, we sought to isolate and identify compounds with inhibitory activities against AR and tyrosinase. RH-MRPs were heated at 120 degrees C for 2 h and fractionated using four solvents: methylene chloride (MC), ethyl acetate, n-butanol, and water. The highest inhibitions were found in the MC fraction. The two compounds from this fraction were purified by silica gel column and preparative thin layer chromatography, and identified as 2-hydroxy-3-methylcyclopent-2-enone and furan-3-carboxylic acid. AR inhibition, tyrosinase inhibition, and ABTS+ scavenging (IC50) of 2-hydroxy-3 methylcyclopent-2-enone were 4.47, 721.91 and 9.81 MUg mL-1, respectively. In this study, inhibitory effects of 2-hydroxy-3-methylcyclopent-2-enone isolated from RH-MRP were demonstrated on AR, tyrosinase, and its antioxidant activity for the first time. RH-MRP and its constituents can be developed as beneficial functional food sources and cosmetic materials and should be investigated further as potential functional food sources. PMID- 29513345 TI - Versatility of chlorination-promoted skeletal transformation pathways in C76 fullerene. AB - We present the synthesis and crystal structure of a new chlorinated non-IPR isomer of C76 fullerene, 18387C76Cl30. The new chloride is formed from IPR-D2 C76via a sequence of chlorination-promoted Stone-Wales rearrangements concurrently with the previously known non-IPR compound 18917C76Cl24. A considerable difference between the two simultaneously forming non-IPR compounds suggests that higher fullerenes can exhibit a much higher versatility of skeletal transformations than the presently known compounds. Our theoretical analysis identifies yet further favorable Stone-Wales pathways in C76 and predicts several stable non-IPR and non-classical (i.e. heptagon-containing) C76 chlorides that may await experimental isolation. PMID- 29513347 TI - A tetraphenylethylene-based acylhydrazone gel for selective luminescence sensing. AB - A supramolecular gel based on dynamic covalent acylhydrazone bonding assembled from small molecules has been reported. The gel shows aggregation-induced emission for selective and sensitive Cu2+ and subsequent CN- detection. PMID- 29513348 TI - Super strong dopamine hydrogels with shape memory and bioinspired actuating behaviours modulated by solvent exchange. AB - Dopamine-containing hydrogels were synthesized by copolymerization of dopamine methacrylamide (DMA), N,N-dimethylacrylamide (DMAA), and an N,N' methylenebisacrylamide (BIS) crosslinker in a mixed solvent of water and DMSO. The association of DMA was formed by simply immersing in water to facilely reinforce the hydrogel due to the introduction of the second physical crosslinking. The tensile strength of the hydrogels was increased greatly and regulated in a wide range from 200 kPa to over 2 MPa. The association of DMA was destroyed upon immersing in DMSO. This reversible formation and dissociation of the association structure endowed the hydrogel with shape memory and actuating capabilities. Rapid shape fixing in water and complete shape recovery in DMSO was realized within several minutes. Bioinspired functional soft actuators were designed based on the reversible association and metal ion coordination of DMA, including fast responsive hydrogel tentacles, programable multiple shape change, reversible and versatile painting and writing "hydrogel paper". The facile preparation and strength regulation provide a new way to design novel soft actuators through solvent exchange, and will inspire more complex applications upon combining the association with other properties of mussel inspired dopamine derivatives. PMID- 29513349 TI - Editorial. PMID- 29513350 TI - The Perfect Enzyme : Revisiting the Modelling of Initial Proton Transfer in Triosephosphate Isomerase. AB - DESCRIPTION: The understanding of the factors governing the enzyme catalysis is one of the most important goals of biochemistry and biophysics. In this context the contribution of theoretical research might be of high relevance. However, despite the huge amount of proposed approaches, the modelling of enzyme reactions still represents a very difficult task and a definitive and conclusive theoretical-computational strategy is still far from being available. In this study, after a presentation of the main difficulties associated to a coherent and possibly rigorous modelling of these processes, we present a computational theoretical method specifically designed for addressing complex molecular systems eventually applied to a benchmark reaction: the initial proton transfer in Triosephosphate Isomerase. This latter species, termed as the 'perfect enzyme' because of its exceptional ability as catalyst, provides an excellent test for evaluating the different environmental and intrinsic determinants at the basis of enzyme activity. PMID- 29513351 TI - Master equation and relative species abundance distribution for Lotka-Volterra models of interacting ecological communities. AB - DESCRIPTION: Understanding the factors that control the dynamics of interacting species is a fundamental problem in ecology. The nature of the interactions among different species is usually not completely understood, but it is assumed that the species interaction plays an important role in the ecosystem properties as predicted by the niches models for an ecosystem. However, recent studies point out as the neutral hypothesis proposed by Hubbell of non-interacting species with an external source from the surrounding environment, allows to explain the relative species abundance distribution when the ecosystem has reached a stationary situation. In this paper we use the concept of fitness landscape to introduce a random dynamical model that describes the evolution of different communities near a stationary situation. The average dynamics can be associated to a system of Lotka-Volterra equations with mutualistic interactions. Then we derive a Master equation that satisfies the detailed balance condition of thermodynamical equilibria and allows to analytically compute the relative species abundance distribution near the stationary state as a multinomial negative distribution. These results suggest a possible approach to a synthetic theory that joins the niche theories and the Hubbell's neutral theory for RSA distribution. PMID- 29513352 TI - Cherry-picking functionally relevant substates from long md trajectories using a stratified sampling approach. AB - DESCRIPTION: Classical Molecular Dynamics (MD) simulations can provide insights at the nanoscopic scale into protein dynamics. Currently, simulations of large proteins and complexes can be routinely carried out in the ns-MUs time regime. Clustering of MD trajectories is often performed to identify selective conformations and to compare simulation and experimental data coming from different sources on closely related systems. However, clustering techniques are usually applied without a careful validation of results and benchmark studies involving the application of different algorithms to MD data often deal with relatively small peptides instead of average or large proteins; finally clustering is often applied as a means to analyze refined data and also as a way to simplify further analysis of trajectories. Herein, we propose a strategy to classify MD data while carefully benchmarking the performance of clustering algorithms and internal validation criteria for such methods. We demonstrate the method on two showcase systems with different features, and compare the classification of trajectories in real and PCA space. We posit that the prototype procedure adopted here could be highly fruitful in clustering large trajectories of multiple systems or that resulting especially from enhanced sampling techniques like replica exchange simulations. PMID- 29513353 TI - Early metazoan development: the origin of the Cambrian exuberance. AB - DESCRIPTION: A number of common features can be observed in the earliest developing embryos of all animal phyla. A simple extant model of morphogenesis is outlined here, with the aim of giving a model of the relatively rapid appearance of Cambrian animals, 541-515 mya. Developmental patterning, elucidated by a simple linear model with only short-range diffusion of ligands, is given as the origin of the most primitive animals. The key aspect of the model involves the interaction between the emergence of the Wnt and Hedgehog (Hh) signaling pathways. The non-canonical Wnt pathway is crucial in first establishing a sphere of cells, by way of cell-cell connection fi bers. A mutation in the Wnt pathway at the dawn of multicellular organisms is argued to have given rise to the early Hh pathway, and their interaction gives two spatially separate gene determination regions, the key goal of biological patterning. PMID- 29513354 TI - A (historical) remark on the Darwin-Schiaparelli evolution theory. AB - DESCRIPTION: The aim of this paper is a free interpretation and reconstruction of a part of Giovanni Virginio Schiaparelli's essay (1898) where the author presents some ideas about a correspondence between living organisms and geometrical curves. From our analysis we derive a new approach to the ago-antagonist conception of the Darwinian evolution theory which is a continuation of [2]. PMID- 29513355 TI - Order is present at every level but is not total. AB - INCIPIT: It may sound as a truism but it may be necessary to recall that science is not made by instruments, or by well equipped laboratories, but by the unique personalities that use them. As a consequence their intellect, their emotional experiences and their physical ability, cannot be separated from their achievements - being they minor or profound. PMID- 29513356 TI - L'etat, c'est moi. Fifty years of history and philosophy of evolutionary biology. AB - DESCRIPTION: I reflect on my fifty-year history as a philosopher of biology, showing how it has taken me from rather narrow analytic studies, through the history of ideas, and now on to issues to do with science and religion. I argue that moral concerns were and still are a major motivation behind what I do and write. PMID- 29513357 TI - Beyond the neo-Darwinist paradigm. AB - DESCRIPTION: Ever since Darwin, there have been challenges to the claim that the natural selection of small random variations is a sufficient explanation of evolution. Even mainstream evolutionists are now beginning to accept that something more is required. The question is whether this will be merely a few add ons that leave the paradigm unaltered, or whether the whole framework of explanation, including its application to other disciplines, will be changed. PMID- 29513358 TI - Two dynamical models for cholera. AB - DESCRIPTION: In this essay the researcher modeled contagious cholera illness by geometrical dynamic methods in two forms, seasonal variables and without seasonal variables. In modeling the illness without seasonal variables geometric points and dynamical results are acquired. Disease free equilibrium of this model is considered. The model which is made by seasonal variables is a complicated model from geometrical point of view. So it is considered numerically. The numerical results are given in six figures and the figures are studied biologically. PMID- 29513359 TI - Cancer is the chaotic search for adaptation to previously unknown environments. AB - DESCRIPTION: Cancer may be the most important global public health problem. The effort of understanding carcinogenesis has been accelerating over the last years on account of its high incidence and impact on the lives of individuals' affected. There are a number of theories of carcinogenesis and these theories may be used to justify various alternative cancer treatments. The small variations in cancer mortality observed during the previous years indicate that the clinical applications of these theories have been very limited. In this article, we tried to explain carcinogenesis based on complex adaptive system (CAS) theory. PMID- 29513360 TI - Agile Implementation: A Blueprint for Implementing Evidence-Based Healthcare Solutions. AB - OBJECTIVES: To describe the essential components of an Agile Implementation (AI) process, which rapidly and effectively implements evidence-based healthcare solutions, and present a case study demonstrating its utility. DESIGN: Case demonstration study. SETTING: Integrated, safety net healthcare delivery system in Indianapolis. PARTICIPANTS: Interdisciplinary team of clinicians and administrators. MEASUREMENTS: Reduction in dementia symptoms and caregiver burden; inpatient and outpatient care expenditures. RESULTS: Implementation scientists were able to implement a collaborative care model for dementia care and sustain it for more than 9 years. The model was implemented and sustained by using the elements of the AI process: proactive surveillance and confirmation of clinical opportunities, selection of the right evidence-based healthcare solution, localization (i.e., tailoring to the local environment) of the selected solution, development of an evaluation plan and performance feedback loop, development of a minimally standardized operation manual, and updating such manual annually. CONCLUSION: The AI process provides an effective model to implement and sustain evidence-based healthcare solutions. PMID- 29513362 TI - A Multisite Intervention for Pediatric Community-acquired Pneumonia in Community Settings. AB - OBJECTIVES: The majority of children with community-acquired pneumonia (CAP) are primarily evaluated in community hospital emergency departments (EDs); however, studies on the management of pediatric CAP have largely targeted care provided in freestanding children's hospital EDs or inpatient settings. The objectives of this study were to examine whether implementation of a CAP pathway within three community hospital EDs and inpatient units improved process measures related to appropriate laboratory testing and antibiotic prescribing and to compare performance on these measures between the community hospitals and a freestanding children's hospital. METHODS: Through a multidisciplinary approach (including general emergency medicine [EM] providers, pediatric fellowship-trained EM providers, and pediatric hospitalists), a CAP pathway was designed and implemented at three community hospitals in January and February 2016. Diagnostic and therapeutic process measures were collected using administrative data and medical record abstraction 1 year pre- and postintervention. Chi-square statistics and statistical process control P-charts were used to examine adherence to these process measures. RESULTS: Across the community hospitals, 544 patients preintervention and 321 patients postintervention met inclusion criteria, with 290 children's hospital patients meeting criteria in the postintervention period. Adherence to process measures increased postintervention for appropriate laboratory testing, narrow-spectrum antibiotic stewardship and macrolide stewardship by 10.8% (95% confidence interval [CI] = 4.7% to 16.9%), 8.3% (95% CI = 21.5% to 15.2%), and 3.1% (95% CI = -4.3% to 10.4%), respectively. Statistical process control P-charts demonstrated special cause variation immediately after implementation of the intervention in regards to appropriate laboratory testing. CONCLUSION: Implementation of a CAP pathway through a multisite community hospital intervention improved adherence to evidence-based recommendations for laboratory testing and antibiotic stewardship. Similar interventions may improve the quality of care for children with CAP on a population level, as community hospitals are where these patients are seen most frequently. PMID- 29513361 TI - A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation. AB - Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL 6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2 years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation. PMID- 29513363 TI - Impaired autophagy correlates with golden retriever muscular dystrophy phenotype. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) and golden retriever muscular dystrophy (GRMD) are X-linked disorders caused by mutations in the DMD gene. Autophagy was recently identified as a secondary therapeutic target for DMD. We hypothesized that autophagy would be reduced in GRMD. METHODS: Autophagic gene and protein expression was assessed in normal and GRMD skeletal muscles and correlated with phenotypic biomarkers. RESULTS: Muscles were differentially affected. Autophagy gene levels were lower than normal in the GRMD cranial sartorius (CS) but similar in the vastus lateralis (VL). Protein markers of autophagic flux, LC3B-II and p62, were higher in both GRMD muscles, in keeping with impaired autophagy. Protein levels correlated with a more severe phenotype. Autophagic structures were found in necrotic, fast-twitch GRMD myofibers. DISCUSSION: Our data suggest that autophagy is impaired in certain GRMD muscles. Differential GRMD CS involvement emphasizes that therapeutic modulation of autophagy could require specific muscle targeting. Muscle Nerve 58: 418-426, 2018. PMID- 29513364 TI - UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies. AB - A series of glycomimetics of UDP-GlcNAc, in which the beta-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures. Their affinities for human O-GlcNAc transferase (hOGT) have been evaluated and studied both spectroscopically and computationally. The binding epitopes of the best ligands have been determined in solution by means of saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic, and computational results are in agreement, pointing out the essential role of the binding of beta-phosphate. We have found that the loss of interactions from the beta-phosphate can be counterbalanced by the presence of hydrophobic groups at a pyrroline ring acting as a surrogate of the carbohydrate unit. Two of the prepared glycomimetics show inhibition at a micromolar level. PMID- 29513365 TI - Ventricular septal rupture complicating acute myocardial infarction: Incidence, treatment, and outcomes among medicare beneficiaries 1999-2014. AB - OBJECTIVES: The present study was designed to assess whether the incidence and outcomes of VSR-AMI have changed in the era of timely primary PCI. BACKGROUND: Ventricular septal rupture (VSR) is a rare but frequently fatal complication of acute myocardial infarction (AMI). METHODS: We conducted a retrospective cohort study of all Medicare fee-for-service beneficiaries from 1999 to 2014 to examine trends in the incidence, surgical and percutaneous repair, and 30-day and 1-year mortality of VSR-AMI. RESULTS: The annual incidence of VSR-AMI hospitalization declined by 41.6% from 197 patients per 100,000 AMIs in 1999 to 115 patients per 100,000 AMIs in 2014 (P < 0.001). The 30-day VSR-AMI repair rate decreased from 49.9% in 1999 to 33.3% in 2014 (P < 0.001). In 2014, 82.9% of repairs were performed surgically and 17.1% percutaneously. VSR-AMI mortality rates were high (60.2% at 30 days; 68.5% at 1 year) and changed minimally over the study period with adjusted 30-day mortality per year Odds Ratio (OR) 0.99 (95% confidence interval [CI] 0.98-1.01) and adjusted 1-year mortality per year OR 0.98 (95% CI 0.97-1.00). Across the 16 years of data, unadjusted mortality rates were lower in patients undergoing repair than in unrepaired patients at 30 days (mean 51.7% and 65.7%, P <= 0.01) and 1 year (mean 62.0% and 72.8%, P < 0.01). CONCLUSIONS: In the era of increased timely primary PCI, the incidence of VSR-AMI hospitalization declined but its associated mortality rate remained high. Rates of VSR repair decreased from 1999 to 2014 despite increased use of percutaneous repair. PMID- 29513366 TI - Changes in chromatin accessibility between Arabidopsis stem cells and mesophyll cells illuminate cell type-specific transcription factor networks. AB - Cell differentiation is driven by changes in the activity of transcription factors (TFs) and subsequent alterations in transcription. To study this process, differences in TF binding between cell types can be deduced by probing chromatin accessibility. We used cell type-specific nuclear purification followed by the assay for transposase-accessible chromatin (ATAC-seq) to delineate differences in chromatin accessibility and TF regulatory networks between stem cells of the shoot apical meristem (SAM) and differentiated leaf mesophyll cells in Arabidopsis thaliana. Chromatin accessibility profiles of SAM stem cells and leaf mesophyll cells were very similar at a qualitative level, yet thousands of regions having quantitatively different chromatin accessibility were also identified. Analysis of the genomic regions preferentially accessible in each cell type identified hundreds of overrepresented TF-binding motifs, highlighting sets of TFs that are probably important for each cell type. Within these sets, we found evidence for extensive co-regulation of target genes by multiple TFs that are preferentially expressed in each cell type. Interestingly, the TFs within each of these cell type-enriched sets also showed evidence of extensively co regulating each other. We further found that preferentially accessible chromatin regions in mesophyll cells tended to also be substantially accessible in the stem cells, whereas the converse was not true. This observation suggests that the generally higher accessibility of regulatory elements in stem cells might contribute to their developmental plasticity. This work demonstrates the utility of cell type-specific chromatin accessibility profiling for the rapid development of testable models of regulatory control differences between cell types. PMID- 29513369 TI - March 2018. PMID- 29513367 TI - The familial aggregation of atopic diseases and depression or anxiety in children. AB - BACKGROUND: Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases has strong genetic and environmental components; therefore, it seems likely that there is a shared liability rather than causative risk. OBJECTIVE: To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety. METHODS: Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n = 14 197. Current and ever asthma, eczema, hay fever and food allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic (MZ) twins and same-sex dizygotic (DZ) twins for atopic disease in 1 twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth. RESULTS: Familial co-aggregation analysis found that if 1 twin had at least 1 current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations, suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates. CONCLUSIONS AND CLINICAL RELEVANCE: Atopic diseases and depression or anxiety tend to occur together in families; therefore, when treating for 1 disease, the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity, and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation. PMID- 29513368 TI - On-Surface Synthesis of Carbon Nanostructures. AB - Novel carbon nanomaterials have aroused significant interest owing to their prospects in various technological applications. The recently developed on surface synthesis strategy provides a route toward atomically precise fabrication of nanostructures, which paves the way to functional molecular nanostructures in a controlled fashion. A plethora of low-dimensional nanostructures, challenging to traditional solution chemistry, have been recently fabricated. Within the last few decades, an increasing interest and flourishing studies on the fabrication of novel low-dimensional carbon nanostructures using on-surface synthesis strategies have been witnessed. In particular, carbon materials, including fullerene, carbon nanotubes, and graphene nanoribbons, are synthesized with atomic precision by such bottom-up methods. Herein, starting from the basic concepts and progress made in the field of on-surface synthesis, the recent developments of atomically precise fabrication of low-dimensional carbon nanostructures are reviewed. PMID- 29513370 TI - Mechanism of Phosphine-Catalyzed Allene Coupling Reactions: Advances in Theoretical Investigations. AB - Organocatalysis has emerged as an effective strategy for chemical synthesis. Within this area, phosphine-catalyzed coupling reactions have attracted considerable attention because of their versatility and wide range of applications in the construction of new C-C bonds. Recently, various experimental studies on the phosphine-catalyzed coupling reaction of allenes have been reported, and mechanistic and computational studies have also progressed considerably. As a nucleophile, phosphine can react with an allene to form a zwitterionic phosphoniopropenide intermediate. After stepwise cycloaddition and proton transfer, the phosphine catalyst can be regenerated by C-P bond cleavage. Alternatively, the zwitterionic phosphoniopropenide intermediate could also be protonated by a Bronsted acid to generate a phosphonium intermediate, which can be used to construct new C-C bonds by electrophilic addition. In this review, we have summarized details of mechanistic studies of phosphine-catalyzed allene coupling reactions that follow these two reaction modes. In addition to detailing the reaction pathway, the regioselectivity and diastereoselectivity of the phosphine-catalyzed allene coupling reaction are also discussed in this review. PMID- 29513371 TI - Changes in arachidonic acid metabolism during liver ischemia triggers induction of inflammatory injury. PMID- 29513372 TI - The "opportunity costs" of kidney transplantation. PMID- 29513373 TI - Balanced Partnership between Donor and Acceptor Components in Nonfullerene Organic Solar Cells with >12% Efficiency. AB - Relative to electron donors for bulk heterojunction organic solar cells (OSCs), electron acceptors that absorb strongly in the visible and even near-infrared region are less well developed, which hinders the further development of OSCs. Fullerenes as traditional electron acceptors have relatively weak visible absorption and limited electronic tunability, which constrains the optical and electronic properties required of the donor. Here, high-performance fullerene free OSCs based on a combination of a medium-bandgap polymer donor (FTAZ) and a narrow-bandgap nonfullerene acceptor (IDIC), which exhibit complementary absorption, matched energy levels, and blend with pure phases on the exciton diffusion length scale, are reported. The single-junction OSCs based on the FTAZ:IDIC blend exhibit power conversion efficiencies up to 12.5% with a certified value of 12.14%. Transient absorption spectroscopy reveals that exciting either the donor or the acceptor component efficiently generates mobile charges, which do not suffer from recombination to triplet states. Balancing photocurrent generation between the donor and nonfullerene acceptor removes undesirable constraints on the donor imposed by fullerene derivatives, opening a new avenue toward even higher efficiency for OSCs. PMID- 29513374 TI - Programmable Self-Locking Origami Mechanical Metamaterials. AB - Developing mechanical metamaterials with programmable properties is an emerging topic receiving wide attention. While the programmability mainly originates from structural multistability in previously designed metamaterials, here it is shown that nonflat-foldable origami provides a new platform to achieve programmability via its intrinsic self-locking and reconfiguration capabilities. Working with the single-collinear degree-4 vertex origami tessellation, it is found that each unit cell can self-lock at a nonflat configuration and, therefore, possesses wide design space to program its foldability and relative density. Experiments and numerical analyses are combined to demonstrate that by switching the deformation modes of the constituent cell from prelocking folding to postlocking pressing, its stiffness experiences a sudden jump, implying a limiting-stopper effect. Such a stiffness jump is generalized to a multisegment piecewise stiffness profile in a multilayer model. Furthermore, it is revealed that via strategically switching the constituent cells' deformation modes through passive or active means, the n layer metamaterial's stiffness is controllable among 2n target stiffness values. Additionally, the piecewise stiffness can also trigger bistable responses dynamically under harmonic excitations, highlighting the metamaterial's rich dynamic performance. These unique characteristics of self-locking origami present new paths for creating programmable mechanical metamaterials with in situ controllable mechanical properties. PMID- 29513376 TI - Barriers to Implementation of Geriatric Medicine Programs: When Advocacy Meets Reality. PMID- 29513375 TI - Increased salt exposure affects both lymphoid and myeloid effector functions, influencing innate-associated disease but not T-cell-associated autoimmunity. AB - High salt consumption has since long been associated with elevated blood pressure and cardiovascular disease. Recently, mouse studies suggested that a high dietary salt intake exacerbates the clinical manifestations of autoimmunity. Using naive cells ex vivo after pre-exposure of mice to high salt intake, we showed that increased salt exposure affects the viability and effector functions of immune cells. CD4+ T-cells evidenced a pro-inflammatory phenotype characterized by increased secretion of IFNgamma and IL-17A, when exposed to high salt concentrations in vitro. Interestingly, this phenotype was associated with osmotic pressure, as replacing salt for d-mannitol resulted in similar observations. However, high salt intake did not alter the development of T-cell dependent autoimmunity. Instead, recruitment of peritoneal macrophages was increased in mice pre-exposed to high salt concentrations. These cells had an increased production of both TNFalpha and IL-10, suggesting that salt stimulates expansion and differentiation of different subsets of macrophages. Moreover, mice pre-exposed to high salt intake developed exacerbated symptoms of colitis, when induced by dextran sulphate sodium. The aggravated colitis in salt-exposed animals was associated with a higher frequency of CD4+ T-cells and CD11b+ CD64+ macrophages producing TNFalpha. These phenotypes correlated with elevated titres of faecal IgA and higher lymphocytic cellularity in the colon, mesenteric lymph nodes and spleen. In conclusion, we report here that high salt intake affects both lymphoid and myeloid cells ex vivo. However, the effects of high salt intake in vivo seem less pronounced in terms of CD4+ T-cell responses, whereas macrophage-dependent pathologies are significantly influenced. PMID- 29513377 TI - Quantitative analysis of hepatic iron in patients suspected of coexisting iron overload and steatosis using multi-echo single-voxel magnetic resonance spectroscopy: Comparison with fat-saturated multi-echo gradient echo sequence. AB - BACKGROUND: The coexistence of hepatic iron and fat is common in patients with hyperferritinemia, which plays an interactive and aggressive role in the progression of diseases (fibrosis, cirrhosis, and hepatocellular carcinomas). PURPOSE: To evaluate a modified high-speed T2 -corrected multi-echo, single voxel spectroscopy sequence (HISTOV) for liver iron concentration (LIC) quantification in patients with hyperferritinemia, with simultaneous fat fraction (FF) estimation. STUDY TYPE: Retrospective cohort study. POPULATION: Thirty-eight patients with hyperferritinemia were enrolled. FIELD STRENGTH/SEQUENCE: HISTOV, a fat-saturated multi-echo gradient echo (GRE) sequence, and a spin echo sequence (FerriScan) were performed at 1.5T. ASSESSMENT: R2 of the water signal and FF were calculated with HISTOV, and R2* values were derived from the GRE sequence, with R2 and LIC from FerriScan serving as the references. STATISTICAL TESTS: Linear regression, correlation analyses, receiver operating characteristic analyses, and Bland-Altman analyses were conducted. RESULTS: Abnormal hepatic iron load was detected in 32/38 patients, of whom 10/32 had coexisting steatosis. Strong correlation was found between R2* and FerriScan-LIC (R2 = 0.861), and between HISTOV-R2_ water and FerriScan-R2 (R2 = 0.889). Furthermore, HISTOV-R2_ water was not correlated with HISTOV-FF. The area under the curve (AUC) for HISTOV-R2_ water was 0.974, 0.971, and 1, corresponding to clinical FerriScan-LIC thresholds of 1.8, 3.2, and 7.0 mg/g dw, respectively. No significant difference in the AUC was found between HISTOV-R2_ water and R2* at any of the LIC thresholds, with P-values of 0.42, 0.37, and 1, respectively. HISTOV-LIC showed excellent agreement with FerriScan-LIC, with a mean bias of 0.00 +/- 1.18 mg/g dw, whereas the mean bias between GRE-LIC and FerriScan-LIC was 0.53 +/- 1.49 mg/g dw. DATA CONCLUSION: HISTOV is useful for the quantification and grading of liver iron overload in patients with hyperferritinemia, particularly in cases with coexisting steatosis. HISTOV-LIC showed no systematic bias compared with FerriScan-LIC, making it a promising alternative for iron quantification. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29513378 TI - Incidence and predictors of target lesion failure in a multiethnic Asian population receiving the SYNERGY coronary stent: A prospective all-comers registry. AB - OBJECTIVES: To evaluate the target lesion failure (TLF) rate of the SYNERGY stent in all-comers, multiethnic Asian population. BACKGROUND: Currently, most drug eluting stents deliver anti-proliferative drugs from a durable polymer which is associated with a risk of late stent thrombosis. The novel everolimus-eluting, platinum chromium SYNERGY stent is coated with a bioabsorbable abluminal polymer that resolves within 4 months. METHODS: This was a prospective, single center registry of consecutive patients treated with the SYNERGY stent between December 2012 and April 2015. The primary outcome was the incidence of TLF, defined as the combination of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization (TLR) at 1 year. RESULTS: A total of 807 patients received the SYNERGY stent during the study period. One-year clinical outcome data was available for 765 patients (94.8%) and were considered for statistical analysis. The mean age was 60.7 +/- 10.8 years, and 83.4% were males. Patients with acute myocardial infarction consisted of 50.3% (ST-segment elevation myocardial infarction: 23.0%, Non-ST-segment elevation myocardial infarction: 27.3%) of the study population. The treated lesions were complex (ACC/AHA type B2/C: 72.7%). The primary end point of TLF at 1 year was 5.8%. Rates of cardiac mortality, target vessel myocardial infarction, and TLR were 4.2, 1.0, and 1.3%, respectively, at 1 year. Predictors of the incidence and time to early TLF were female gender, Malay ethnicity, diabetes mellitus, acute myocardial infarction at presentation, a prior history of coronary artery bypass surgery and the presence of lesion calcification. The incidence of definite stent thrombosis was 0.4% at 1 year. CONCLUSIONS: In this registry, the use of the SYNERGY stent was associated with low rates of TLF at 1 year. PMID- 29513379 TI - Changing demographics of heart donors: The impact of donor drug intoxication on posttransplant survival. AB - Recent reports have shown an increase in the number of organ donors from drug intoxication. The impact of donor drug use on survival after cardiac transplant remains unclear. The aim of our study was to illustrate changes in donor death mechanisms and assess the impact on posttransplant survival. We queried United Network of Organ Sharing thoracic transplant and deceased donor databases to identify patients undergoing heart transplantation between 2005 and 2015. We evaluated annual trends in donor death mechanisms. Recipients were propensity matched (drug-intoxicated-non-drug-intoxicated = 1:2) and posttransplant survival was compared using Kaplan-Meier curves. In total, 19 384 donor hearts were used for transplant during the period (donor age 31.6 +/- 11.8 years, 72% male). Use of drug-intoxicated donors increased from 2% (2005) to 13% (2015) and decreased from blunt injury (40%-30%) and intracranial hemorrhage (29%-25%). After propensity matching, posttransplant survival of drug-intoxicated donor hearts was 90%, 82%, and 76% at 1, 3, and 5 years, which was similar to non-drug intoxicated. Heart transplants using drug-intoxicated donors have significantly increased; however, they have not adversely affected posttransplant survival. Hearts from drug-intoxicated donors should be carefully evaluated and considered for transplant. PMID- 29513380 TI - Infectious disease risks in xenotransplantation. AB - Hurdles exist to clinical xenotransplantation including potential infectious transmission from nonhuman species to xenograft recipients. In anticipation of clinical trials of xenotransplantation, the associated infectious risks have been investigated. Swine and immunocompromised humans share some potential pathogens. Swine herpesviruses including porcine cytomegalovirus (PCMV) and porcine lymphotropic herpesvirus (PLHV) are largely species-specific and do not, generally, infect human cells. Human cellular receptors exist for porcine endogenous retrovirus (PERV), which infects certain human-derived cell lines in vitro. PERV-inactivated pigs have been produced recently. Human infection due to PERV has not been described. A screening paradigm can be applied to exclude potential human pathogens from "designated pathogen free" breeding colonies. Various microbiological assays have been developed for screening and diagnosis including antibody-based tests and qualitative and quantitative molecular assays for viruses. Additional assays may be required to diagnose pig-specific organisms in human xenograft recipients. Significant progress has been made in the evaluation of the potential infectious risks of clinical xenotransplantation. Infectious risk would be amplified by intensive immunosuppression. The available data suggest that risks of xenotransplant-associated recipient infection are manageable and that clinical trials can be performed safely. Possible infectious risks of xenotransplantation to the community at large are undefined but merit consideration. PMID- 29513381 TI - The Association between Daily Posttraumatic Stress Symptoms and Pain over the First 14-days after Injury: An Experience Sampling Study. AB - OBJECTIVES: Psychosocial factors and responses to injury modify the transition from acute to chronic pain. Specifically, posttraumatic stress disorder symptoms (PTSS; reexperiencing, avoidance, and hyperarousal symptoms) exacerbate and co occur with chronic pain. Yet no study has prospectively considered the associations among these psychological processes and pain reports using experience sampling methods (ESM) during the acute aftermath of injury. This study applied ESM via daily text messaging to monitor and detect relationships among psychosocial factors and post-injury pain across the first 14-days after emergency department (ED) discharge. METHODS: We recruited 75 adults (59% male; M age = 33) who experienced a potentially traumatic injury (i.e., involving life threat or serious injury) in the past 24-hours from the EDs of two Level 1 trauma centers. Participants received 5 questions per day via text messaging from Day-1 to Day-14 post-ED discharge; three questions measured PTSS, one question measured perceived social support, and one question measured physical pain. RESULTS: Sixty seven participants provided sufficient data for inclusion in the final analyses, and the average response rate per subject was 86%. Pain severity score decreased from a mean of 7.2 to 4.4 over 14 days and 50% of the variance in daily pain scores was within-person. In multilevel structural equation models, pain scores decreased over time, and daily fluctuations of hyperarousal (b = 0.22, 95% CI [0.08, 0.36]) were uniquely associated with daily fluctuations in reported pain level within each person. CONCLUSIONS: Daily hyperarousal symptoms predict same day pain severity over the acute post-injury recovery period. We also demonstrated feasibility to screen and identify patients at risk for pain chronicity in the acute aftermath of injury. Early interventions aimed at addressing hyperarousal (e.g. anxiolytics) could potentially aid in reducing experience of pain. This article is protected by copyright. All rights reserved. PMID- 29513382 TI - A randomized, controlled trial of magnetic therapy for carpal tunnel syndrome. AB - INTRODUCTION: Magnet therapy has been proposed as a treatment for neurologic conditions. In this this trial we assessed the feasibility and efficacy of a magnet inserted into a wristband for carpal tunnel syndrome (CTS). METHODS: Twenty-two patients with mild to moderate CTS were randomized to wear a high-dose or low-dose "sham" magnetic wristband for 6 weeks. The primary outcome was the Symptom Severity Scale (SSS) of the Boston Carpal Tunnel Questionnaire. Secondary measures were nerve conduction studies (NCS), median nerve ultrasound, and compliance. RESULTS: Compliance for both groups was >90%. Improvements in the mean SSS, NCS, and median nerve ultrasound did not reach statistical significance. DISCUSSION: Magnet therapy via wristband is well-tolerated. Further investigations in larger populations are needed to determine efficacy. Muscle Nerve 58: 310-313, 2018. PMID- 29513383 TI - Combination of Tetrabutylammonium Iodide (TBAI) with tert-Butyl Hydroperoxide (TBHP): An Efficient Transition-Metal-Free System to Construct Various Chemical Bonds. AB - In this account, we describe our recent progress on transition-metal-free catalyzed cross-coupling reactions using tetrabutylammonium iodide (TBAI) as the catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant. A rich variety of important organic compounds including alpha-acyloxy ethers, tert-butyl peresters, allylic esters, amides, alpha-amino nitriles, fully substituted pyrazoles, N sulfonyl formamidines, alpha-amino acid esters, cyanomethyl esters, N nitrosamines, and 3-acyloxy-2,3-dihydrobenzofurans have been successfully achieved in high chemoselectivity. Mechanistic studies suggested that TBAI could decompose TBHP to t BuO. and t BuOO. or be oxdized to (hypo)iodite by TBHP. PMID- 29513384 TI - Fitness decline under osmotic stress in Caenorhabditis elegans populations subjected to spontaneous mutation accumulation at varying population sizes. AB - The consequences of mutations for population fitness depends on their individual selection coefficients and the effective population size. An earlier study of Caenorhabditis elegans spontaneous mutation accumulation lines evolved for 409 generations at three population sizes found that Ne = 1 populations declined significantly in fitness whereas the fitness of larger populations (Ne = 5, 50) was indistinguishable from the ancestral control under benign conditions. To test if larger MA populations harbor a load of cryptic deleterious mutations that are obscured under benign laboratory conditions, we measured fitness under osmotic stress via exposure to hypersaline conditions. The fitness of Ne = 1 lines exhibited a further decline under osmotic stress compared to benign conditions. However, the fitness of larger populations remained indistinguishable from that of the ancestral control. The average effects of deleterious mutations in Ne = 1 lines were estimated to be 22% for productivity and 14% for survivorship, exceeding values previously detected under benign conditions. Our results suggest that fitness decline is due to large effect mutations that are rapidly removed via selection even in small populations, with implications for conservation practices. Genetic stochasticity may not be as potent and immediate a threat to the persistence of small populations as other demographic and environmental stochastic factors. PMID- 29513385 TI - Quality-of-Life Metrics Correlate With Disease Severity in Idiopathic Subglottic Stenosis. AB - OBJECTIVES: Idiopathic subglottic stenosis (ISGS) can have significant impacts on quality of life (QOL), but it remains unclear how patients' subjective responses correlate with objective measurement of disease severity. Peak expiratory flow percentage (PEF%) has been shown to be an effective measure of disease severity in subglottic stenosis. This study aims to identify the key QOL questions correlated with PEF% and proposes a statistical model for prediction of disease severity. METHODS: Patients with ISGS presenting to an academic laryngologist were included retrospectively from 2012 to 2016. Peak expiratory flow percentage (age, sex, and height adjusted) was recorded for each visit, along with four validated QOL instruments (European QOL-Five Dimensions; RAND 36-Item Health Survey; Clinical COPD [Chronic Obstructive Pulmonary Disease] Questionnaire; and the Airway, Dyspnea, Voice, and Swallowing Summary Assessment). A stepwise multiple linear regression was used to identify statistically significant independent variables correlated with PEF%, and a model was built with these variables. RESULTS: Thirty-two patients were included, with a total of 271 patient encounters. Overall scores from each of the four QOL instruments were correlated with PEF% values recorded each visit (P < 0.05). Question responses correlating most positively included overall breathlessness, difficulty catching breath, cough within the past week, dyspnea with moderate activity, perception that voice changes are restricting social life, and overall general health (all P < 0.01). A model constructed using six nonoverlapping questions yielded an adjusted R2 of 0.58. CONCLUSION: Quality of life is correlated to PEF% in ISGS. Using a limited number of QOL questions, clinicians can predict objective worsening or improvement of disease severity, as measured by spirometry. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2017. PMID- 29513386 TI - Facial sinus endoscopic evaluation, radiologic assessment, and classification. AB - OBJECTIVES: To describe facial sinus anatomy from an endoscopic perspective and present a radiologic classification. METHODS: Facial sinus was studied by endoscopy and high-resolution computed tomography (HRCT) scan in 39 temporal bones that underwent exclusive transcanal endoscopic approach. A radiomorphologic classification based on the relationship between the facial sinus and the mastoid portion of the facial nerve is created as follows. In type A facial sinus, the pneumatization of the facial sinus did not extend medially or posteriorly to the mastoid portion of the facial nerve. In type B facial sinus, the pneumatization extended posteriorly to the mastoid portion of the facial nerve. In type C facial sinus, the pneumatization extended posteriorly and medially to the mastoid portion of the facial nerve. RESULTS: In all the specimens that underwent HRCT (n = 31), facial sinus could be identified, and its depth classified, in relation to the facial nerve. In this group, 58% type A, 29% type B, and 13% type C facial sinuses were identified. In all the specimens (n = 39), the facial sinus could be assessed by means of an exclusive endoscopic transcanal approach, and anatomical variants of the chordiculus, previously known as chordal ridge, could be described: ridge (39%), bridge (18%), incomplete (15%), and absent (28%). CONCLUSION: Endoscopic exploration of the retrotympanum guarantees a very good exposure of the facial sinus, allowing detailed anatomic descriptions of its conformation and relationships with other structures. Improvement in our knowledge of its anatomy might decrease the possibility of residual disease during cholesteatoma surgery. Angled endoscopes (e.g. 45 degrees , 70 degrees ) can guarantee a better view of the facial sinus. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:2397-2402, 2018. PMID- 29513387 TI - Increasing tacrolimus time-in-therapeutic range is associated with superior one year outcomes in lung transplant recipients. AB - Calcineurin inhibitors (CNIs) are the backbone of traditional immunosuppressive regimens for lung transplant recipients (LTR). The CNIs are both narrow therapeutic index drugs with significant interpatient and intrapatient variability that require therapeutic drug monitoring to ensure safety and effectiveness. We hypothesized that tacrolimus time-in-therapeutic range (TTR) affects acute and chronic rejection rates in LTRs. This was a single-center, observational, cross-sectional study of 292 adult LTRs. Subjects who received tacrolimus posttransplant for the first year were included. TTR was calculated at 1 year using protocol goal ranges (12-15 mg/mL months 0-6; 10-12 mg/mL for months 7-12). The primary outcome was acute cellular rejection (ACR) burden at 1 year. Chronic lung allograft dysfunction (CLAD), mortality, and infection rate were assessed as secondary outcomes at 1 year. Primary and secondary outcomes were assessed using logistic regression. Increasing TTR by 10% was associated with a significantly lower likelihood of high-burden ACR at 1 year on univariable (OR 0.46, 95% CI 0.40-0.54, P < .001) and multivariable (OR 0.64, 95% CI 0.47-0.86, P = .003) assessment, controlling for age and induction agent. Increasing TTR by 10% was also associated with lower rates of CLAD (P < .001) and mortality (P < .001) at 1 year. Prospective studies confirming these findings appear warranted. PMID- 29513388 TI - Integration of danger peptide signals with herbivore-associated molecular pattern signaling amplifies anti-herbivore defense responses in rice. AB - Plant defense against herbivores is modulated by herbivore-associated molecular patterns (HAMPs) from oral secretions (OS) and/or saliva of insects. Furthermore, feeding wounds initiate plant self-damage responses modulated by danger associated molecular patterns (DAMPs) such as immune defense-promoting plant elicitor peptides (Peps). While temporal and spatial co-existence of both patterns during herbivory implies a possibility of their close interaction, the molecular mechanisms remain undetermined. Here we report that exogenous application of rice (Oryza sativa) peptides (OsPeps) can elicit multiple defense responses in rice cell cultures. Specific activation of OsPROPEP3 gene transcripts in rice leaves by wounding and OS treatments further suggests a possible involvement of the OsPep3 peptide in rice-herbivore interactions. Correspondingly, we found that simultaneous application of OsPep3 and Mythimna loreyi OS significantly amplifies an array of defense responses in rice cells, including mitogen-activated protein kinase activation, and generation of defense related hormones and metabolites. The induction of OsPROPEP3/4 by OsPep3 points to a positive auto-feedback loop in OsPep signaling which may contribute to additional enhancement of defense signal(s). Finally, the overexpression of the OsPep receptor OsPEPR1 increases the sensitivity of rice plants not only to the cognate OsPeps but also to OS signals. Our findings collectively suggest that HAMP-DAMP signal integration provides a critical step in the amplification of defense signaling in plants. PMID- 29513389 TI - A prospective, multi-center study of the chocolate balloon in femoropopliteal peripheral artery disease: The Chocolate BAR registry. AB - The Chocolate BAR study is a prospective multicenter post-market registry designed to evaluate the safety and performance of the Chocolate percutaneous transluminal angioplasty balloon catheter in a broad population with symptomatic peripheral arterial disease. The primary endpoint is acute procedural success (defined as <=30% residual stenosis without flow-limiting dissection); secondary long-term outcomes include freedom from target lesion revascularization (TLR), major unplanned amputation, survival, and patency. A total of 262 patients (290 femoropopliteal lesions) were enrolled at 30 US centers between 2012 and 2014. The primary endpoint of procedure success was achieved in 85.1% of cases, and freedom from stenting occurred in 93.1%. Bail out stenting by independent adjudication occurred in 1.6% of cases and there were no flow limiting dissections. There was mean improvement of 2.1 Rutherford classes (+/-1.5) at 12 months, with 78.5% freedom from TLR, 97.2% freedom from major amputation, and 93.3% freedom from all-cause mortality. Core Lab adjudicated patency was 64.1% at 12 months. Use of the Chocolate balloon in an "all-comers" population achieved excellent procedural outcomes with low dissection rates and bailout stent use. PMID- 29513390 TI - Fabrication of a Stable New Polymorph Gold Nanowire with Sixfold Rotational Symmetry. AB - Gold is known as the most noblest metal with only face-centered cubic (fcc) structure in ambient conditions. Here, stable hexagonal non-close-packed (ncp) gold nanowires (NWs), having a diameter of about 50 nm and aspect ratios of well over 400, are reported. Au NWs are grown in the confined system of nanotubular TiO2 arrays via photoelectrochemical reduction of HAuCl4 precursors. Some of the resulting Au NWs are proved to have sixfold rotational symmetry, observed by transmission electron microscopy tilting experiments. This new polymorph is identified as a hexagonal ncp-structure with lattice parameters of a = 2.884 A and c = 7.150 A, showing quite a large interplanar spacing (c/a ~ 2.48). That is, Au atoms are close-packed along the ab plane, but each plane is not closely stacked along the c axis like in graphite. The structure is usually expected to be unstable, but the present ncp-2H gold is stable under ambient conditions and intense electron beam irradiation, and shows thermal stability up to 400 degrees C. Moreover, the resulting physical properties as a result of the corresponding change in electronic structures are investigated by comparing the optical properties of fcc and ncp-2H Au NWs. PMID- 29513391 TI - Lifestyle and overall health in high school children: Results from the Toyama birth cohort study, Japan. AB - BACKGROUND: The aim of this study was to investigate the relationship between lifestyle and overall health in high school children. METHODS: Subjects were from the Toyama Birth Cohort Study, a prospective, longitudinal study of children born between 1989 and 1990, and who lived in Toyama Prefecture, Japan, at the time of the survey. This investigation used data from phase 5 of the Birth Cohort Study, which was conducted in 2005, when the children were in high school. Participants included 4,966 children (2,449 boys and 2,517 girls) aged 15-16 years old. A questionnaire was designed to measure lifestyle factors such as eating habits, physical activity, sedentary behavior, and sleeping pattern. A question from a validated Japanese version of the Dartmouth Primary Care Cooperative Information Project was used to evaluate overall health in children. Logistic regression analysis was used to determine if lifestyle factors are associated with overall health in high school children. RESULTS: Boys who skipped breakfast and had short night-time sleep duration (<=6 h per night) were more likely to have poor health status. Girls who skipped breakfast, and had night-time eating patterns, personal computer use >4 h per day, and short night-time sleep duration (<=6 h/night) were more likely to have poor health status. CONCLUSIONS: Undesirable lifestyle was associated with poor health status in high school boys and girls. Further understanding of these relationships is needed to facilitate the development of interventions that will help children with poor health status. PMID- 29513393 TI - Oral water soluble contrast for malignant bowel obstruction. AB - BACKGROUND: Malignant bowel obstruction (MBO) is a common problem in patients with intra-abdominal cancer. Oral water soluble contrast (OWSC) has been shown to be useful in the management of adhesive small bowel obstruction in identifying patients who will recover with conservative management alone and also in reducing the length of hospital stay. It is not clear whether the benefits of OWSC in adhesive small bowel obstruction are also seen in patients with MBO. OBJECTIVES: To determine the reliability of OWSC media and follow-up abdominal radiographs in predicting the success of conservative treatment in resolving inoperable MBO with conservative management.To determine the efficacy and safety of OWSC media in reducing the duration of obstruction and reducing hospital stay in people with MBO. SEARCH METHODS: We identified studies from searching Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE in Process, Embase, CINAHL, Science Citation Index (Web of Science) and Conference Proceedings Citation Index - Science (Web of Science). We also searched registries of clinical trials and the CareSearch Grey Literature database. The date of the search was the 6 June 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs), or prospective controlled studies, that evaluated the diagnostic potential of OWSC in predicting which malignant bowel obstructions will resolve with conservative treatment.RCTs, or prospective controlled studies, that assessed the therapeutic potential of OWSC in managing MBO at any level compared with placebo, no intervention or usual treatment or supportive care. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed risk of bias and assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We found only one RCT meeting the selection criteria for the second objective (therapeutic potential) of this review. This study recruited nine participants. It compared the use of gastrografin versus placebo in adult patients with MBO with no indication for further intervention (surgery, endoscopy) apart from standardised conservative management.The overall risk of bias for the study was high due to issues with low numbers of participants, selective reporting of outcomes and a high attrition rate for the intervention arm.Primary outcomesThe included trial was a pilot study whose primary outcome was to test the feasibility for a large study. The authors reported specifically on the number of patients screened, the number recruited and reasons for exclusion; this was not the focus of our review.Due to the low number of participants, the authors of the study decided not to report on our primary outcome of assessing the ability of OWSC to predict the likelihood of malignant small bowel obstruction resolving with conservative treatment alone (diagnostic effect). It also did not report on our primary outcome of rate of resolution of MBO in patients receiving OWSC compared with those not receiving it (therapeutic effect).The study reported that no issues regarding safety or tolerability of either gastrografin or placebo were identified. The overall quality of the evidence for the incidence of adverse events with OWSC was very low, downgraded twice for serious limitations to study quality (high risk of selective reporting and attrition bias) and downgraded once for imprecision (sparse data).Secondary outcomesThe study planned to report on this review's secondary outcome measures of length of hospital stay and time from administration of OWSC to resolution of MBO. However the authors of the study decided not to do so due to the low numbers of patients recruited. The study did not report on our secondary outcome measure of survival times from onset of inoperable MBO until death. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to determine the place of OWSC in predicting which patients with inoperable MBO will respond with conservative treatment alone. There is also insufficient evidence from RCTs to determine the therapeutic effects and safety of OWSC in patients with malignant small bowel obstruction. PMID- 29513394 TI - Probing the Outstanding Local Hydrophobicity Increases in Peptide Sequences Induced by Incorporation of Trifluoromethylated Amino Acids. AB - In order to achieve accurate determination of the local hydrophobicity increases in peptide sequences produced by incorporation of trifluoromethylated amino acids (TfmAAs), the chromatographic hydrophobicity indexes (phi0 ) of three series of tripeptides containing three unnatural trifluoromethylated amino acids have been measured and compared with those of their non-fluorinated analogues. The hydrophobic contribution of each fluorinated amino acid was quantified by varying the position and the protection of (R)- and (S)-alpha-trifluoromethylalanine (TfmAla), (R)-trifluoromethylcysteine (TfmCys), and (S)-trifluoromethionine (TFM) in a short peptide sequence. As a general trend, strong increases in hydrophobicity were precisely measured, even exceeding the high hydrophobic contribution of the natural amino acid isoleucine. This study validates the incorporation of trifluoromethylated amino acids into peptide sequences as a rational strategy for the fine-tuning of hydrophobic peptide-protein interactions. PMID- 29513392 TI - Cannabis-based medicines for chronic neuropathic pain in adults. AB - BACKGROUND: This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain. OBJECTIVES: To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults. SEARCH METHODS: In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.Primary outcomesCannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).Secondary outcomesCannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low quality evidence).We found no information about long-term risks in the studies analysed.Subgroup analysesWe are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). AUTHORS' CONCLUSIONS: The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes. PMID- 29513395 TI - Linc-9432 is a novel pterygium lincRNA which regulates differentiation of fibroblasts. AB - Long intergenic noncoding RNAs (lincRNAs) are not fully characterized in disease, although many are involved in controlling differentiation. We discovered and sequenced a novel 4.4 kb human lincRNA called linc-9432 in pterygium, an ocular disease characterized by a wedge lesion. This transcript inhibited differentiation-induced cell death, promoted expression of stem cell markers, and decreased expression of epithelial and mesenchymal differentiation markers. This lincRNA regulated 30 differentiation-related genes in transcriptome analysis and 17/30 gene products were known to be directly associated in a network. When the lincRNA was silenced with pooled siRNA, the levels of these transcripts decreased in accordance with their predicted binding affinity for the lincRNA. TBC1D8B had the strongest affinity, interacting in-vitro at positions 269-292 within TBC1D8B. PMID- 29513396 TI - Fuel Cell Measurements with Cathode Catalysts of Sputtered Pt3 Y Thin Films. AB - Fuel cells are foreseen to have an important role in sustainable energy systems, provided that catalysts with higher activity and stability are developed. In this study, highly active sputtered thin films of platinum alloyed with yttrium (Pt3 Y) are deposited on commercial gas diffusion layers and their performance in a proton exchange membrane fuel cell is measured. After acid pretreatment, the alloy is found to have up to 2.5 times higher specific activity than pure platinum. The performance of Pt3 Y is much higher than that of pure Pt, even if all of the alloying element was leached out from parts of the thin metal film on the porous support. This indicates that an even higher performance is expected if the structure of the Pt3 Y catalyst or the support could be further improved. The results show that platinum alloyed with rare earth metals can be used as highly active cathode catalyst materials, and significantly reduce the amount of platinum needed, in real fuel cells. PMID- 29513397 TI - Anticoagulation use and clinical outcomes after catheter ablation in patients with persistent and longstanding persistent atrial fibrillation. AB - INTRODUCTION: Whether successful catheter ablation for atrial fibrillation (AF) reduces risk of cerebrovascular events (CVEs) remains controversial and whether oral anticoagulation therapy (OAT) can be safely discontinued in patients rendered free of AF recurrences remains unknown. We evaluated OAT use patterns and examined long-term rates of CVEs (stroke/TIA) and major bleeding episodes (MBEs) in patients with nonparoxysmal AF treated with catheter ablation. METHODS AND RESULTS: Four hundred patients with nonparoxysmal AF (200 persistent, 200 longstanding persistent; mean age 60.3 +/- 9.7 years, 82% male) undergoing first AF ablation were followed for 3.6 +/- 2.4 years. OAT discontinuation during follow-up was permitted in selected patients per physician discretion. At last follow-up, allowing for multiple ablations, 172 (43.0%) patients were free of AF recurrence. Two hundred and seven (51.8%) discontinued OAT at some point; 174 (43.5%) were off OAT at last follow-up. Patients without AF recurrence were more likely to remain off OAT (HR 0.23 [95% CI 0.17-0.33]). Patients with persistent (versus longstanding persistent) AF type prior to ablation (HR 0.6 [CI 0.44 0.83]) and those with CHA2 DS2 -VASc score <2 (HR 0.56 [0.39-0.80]) were less likely to continue OAT. Seven patients had CVEs (incidence: 0.49/100 patient years) and 14 experienced MBE during follow-up (incidence: 0.98/100 patient years). Older age (P = 0.001) and coronary artery disease (P = 0.028) were associated with CVE. CONCLUSION: Anticoagulation discontinuation in well selected, closely monitored patients following successful ablation of nonparoxysmal AF was associated with a low rate of clinical embolic CVEs. Prospective studies are required to confirm safety of OAT discontinuation after successful AF ablation. PMID- 29513398 TI - A flow cytometry-based assay to determine the phagocytic activity of both clinical and nonclinical antibody samples against Chlamydia trachomatis. AB - Globally, an estimated 131 million new cases of chlamydial infection occur annually. Chlamydia trachomatis infection can cause permanent damage to the fallopian tubes in woman, resulting in infertility and a risk of ectopic pregnancy. There is a great need for a vaccine against Chlamydia trachomatis and as a result there is a need for assays to evaluate functional immune responses for use in future clinical trials and epidemiological studies. Antibodies play a crucial role in the defense against infection and can be protective by several functions, including phagocytosis and neutralization. Vaccine development could greatly benefit from a method to measure functional C. trachomatis-specific antibodies in a large number of samples. In the current in vitro antibody protection assays, which measure the capacity of antibodies to facilitate phagocytic uptake of C. trachomatis, the phagocytosed bacteria have to be counted manually. This is both labor demanding, time consuming, and it prevents high throughput usage of this method. In this study, we, therefore, developed a simple and rapid flow cytometry based assay to measure the capacity of antibodies to mediate Fc-receptor dependent phagocytosis. This method is highly reproducible and suitable to analyze large numbers of clinical and nonclinical samples. (c) 2018 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC. PMID- 29513399 TI - Solvent-Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII -Catalyzed C-H Activation. AB - The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N methoxy benzamides and alpha,alpha-difluoromethylene alkynes is enabled by C-H activation with a chiral CpRhIII catalyst. Remarkably, product formation is solvent-dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in i PrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E-configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z-configured monofluoroalkene upon protonation in the i PrCN system and into an alkyne by an unusual anti beta-F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes. PMID- 29513401 TI - Novel innate and adaptive lymphocytes: The new players in the pathogenesis of inflammatory upper airway diseases. AB - Host immunity (innate and adaptive immunity) plays essential roles in the pathogenesis of inflammatory upper airway diseases, including allergic rhinitis and chronic rhinosinusitis. Recently, the discovery of novel innate immune cells, particularly innate lymphoid cells, has renewed our view on the role of innate immunity in inflammatory upper airway diseases. Meanwhile, the identification of new subsets of T helper (Th) cells, including Th22, Th9 and follicular Th cells, and regulatory B cells in the adaptive immunity, has broadened our knowledge on the complex immune networks in inflammatory upper airway diseases. In this review, we focus on these newly identified innate and adaptive lymphocytes with their contributions to the immunological disturbance in allergic rhinitis and chronic rhinosinusitis. We further discuss the perspective for future research and potential clinical utility of regulating these novel lymphocytes for the treatment of allergic rhinitis and chronic rhinosinusitis. PMID- 29513400 TI - The Molecular Industrial Revolution: Automated Synthesis of Small Molecules. AB - Today we are poised for a transition from the highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of different types of molecules with the push of a button. Creating machines that are capable of making many different types of small molecules on demand, akin to that which has been achieved on the macroscale with 3D printers, is challenging. Yet important progress is being made toward this objective with two complementary approaches: 1) Automation of customized synthesis routes to different targets by machines that enable the use of many reactions and starting materials, and 2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale. PMID- 29513403 TI - Absorb bioresorbable vascular scaffold vs. everolimus-eluting metallic stent in small vessel disease: A propensity matched analysis of COMPARE II, RAI, and MAASSTAD-ABSORB studies. AB - BACKGROUND: Patients with small vessel disease (SVD) are at higher risk of adverse events after PCI compared to non-SVD patients. In this subset, the use of bioresorbable vascular scaffolds (BVS) has raised particular concern. OBJECTIVE: We aimed to compare outcomes of Absorb BVS versus a 2nd-generation metallic everolimus-eluting stents (EES) in the SVD setting, by pooling patients from three large, prospective studies. METHODS: Patients with SVD (reference vessel diameter <=2.75 mm by QCA) and treated with Absorb BVS were identified in the Italian RAI and the MAASSTAD-Absorb registries. EES controls were identified in the COMPARE II Trial. We performed a propensity-score matching using several clinical and angiographic variables. Implantation technique was not object of matching, being device-specific. RESULTS: Out of 4635 enrolled subjects, 1147 belonged to the SVD population. After matching, we obtained 337 pairs of patients. High clinical and angiographic complexity was found in both groups. Predilation and postdilation rates were significantly higher in BVS patients. No differences were found in terms of the device-oriented composite end-point at 1 year (HR = 1.08, 95%CI 0.5-2.3, P = .8) and 2-years (HR = 1.28, 95% CI: 0.68 2.43, P = .5). Notwithstanding, higher incidence of definite/probable stent thrombosis was observed in the BVS group at 1 year (HR 4.7, 95%CI 0.8-31.4, P = .08) and 2-years (HR = 8.34 95%CI 1.1-60.2, P = .04). CONCLUSION: In this propensity-matched analysis pooling SVD patients of three large prospective studies, incidence of composite device-related events was comparable between BVS and EES up to 2 years follow-up. However, higher rates of stent thrombosis were found in the BVS group. PMID- 29513404 TI - Enantioselective Alkylation of 2-Oxindoles Catalyzed by a Bifunctional Phase Transfer Catalyst: Synthesis of (-)-Debromoflustramine B. AB - A new bifunctional phase-transfer catalyst that employs hydrogen bonding as a control element was developed to promote efficient enantioselective SN 2 reactions for the construction all-carbon quaternary stereocenters in high yield and excellent enantioselectivity (up to 97 % ee) utilizing the alkylation of a malleable oxindole substrate. The utility of the methodology was demonstrated through a concise and highly enantioselective synthesis of (-)-debromoflustramine B. PMID- 29513405 TI - Proteoglycans in brain development and pathogenesis. AB - Proteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio active functions attributed to proteoglycans. Increasingly, attention has been paid to the roles of proteoglycans in nervous tissue development due to their highly regulated spatio/temporal expression patterns, whereby they promote/inhibit neurite outgrowth, participate in specification and maturation of various precursor cell types, and regulate cell behaviors like migration, axonal pathfinding, synaptogenesis and plasticity. These functions emanate from both the environments proteoglycans create around cells by retaining ions and water or serving as scaffolds for cell shaping or motility, and from dynamic interactions that modulate signaling fields for cytokines, growth factors and morphogens, which may bind to either the protein or GAG portions. Also, genetic abnormalities impacting proteoglycan synthesis during critical steps of brain development and response to environmental insults and injuries, as well as changes in microenvironment interactions leading to tumors in the central nervous system, all suggest roles for proteoglycans in behavioral and intellectual disorders and malignancies. PMID- 29513402 TI - Inflammation in CNS neurodegenerative diseases. AB - Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases. PMID- 29513406 TI - Relative importance of long-term changes in climate and land-use on the phenology and abundance of legume crop specialist and generalist aphids. AB - Insect populations are prone to respond to global changes through shifts in phenology, distribution and abundance. However, global changes cover several factors such as climate and land-use, the relative importance of these being largely unknown. Here, we aim at disentangling the effects of climate, land-use, and geographical drivers on aphid abundance and phenology in France, at a regional scale and over the last 40 years. We used aerial data obtained from suction traps between 1978 and 2015 on five aphid species varying in their degree of specialization to legumes, along with climate, legume crop area and geographical data. Effects of environmental and geographical variables on aphid annual abundance and spring migration dates were analyzed using generalized linear mixed models. We found that within the last four decades, aphids have advanced their spring migration by a month, mostly due to the increase in temperature early in the year, and their abundance decreased by half on average, presumably in response to a combination of factors. The influence of legume crop area decreased with the degree of specialization of the aphid species to such crops. The effect of geographical variation was high even when controlling for environmental variables, suggesting that many other spatially structured processes act on aphid population characteristics. Multifactorial analyses helped to partition the effects of different global change drivers. Climate and land-use changes have strong effects on aphid populations, with important implications for future agriculture. Additionally, trait-based response variation could have major consequences at the community scale. PMID- 29513407 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 12/2018. PMID- 29513408 TI - [Mechanisms of the interaction of chitosan and its derivatives with the cell]. AB - The review summarizes the data on the mechanisms of the interaction of chitosan and other molecules, as well as the drug delivery systems based on them, with mammalian cells. The mechanisms of binding, endocytosis, and the further distribution of chitosan and nanoparticles with different physic-chemical properties in cells remain unclear at the present time. PMID- 29513409 TI - [Determination of residual protein and endotoxins in chitosan ]. AB - Methods for the determination of residual protein and endotoxins in chitosan preparations, which can be used as vectors for biologically active compounds delivery, are discussed. The limits of their use for the determination of residual impurities in chitosan preparations associated with the structure of the biopolymer are estimated. PMID- 29513410 TI - [Cytokine-inducing and anti-inflammatory activity of chitosan and its low molecular derivative]. AB - A low-molecular derivative of the polysaccharide (5 kDa) was obtained and its cytokine-inducing and anti-inflammatory activity was studied by free radical depolymerization of chitosan (110 kDa). It was shown that high-molecular chitosan in vitro inhibited the synthesis of anti-inflammatory cytokine, the tumor necrosis factor alpha induced by endotoxin. In the case of peroral introduction to experimental animals, high- and low-molecular chitosans stimulated synthesis of the anti-inflammatory cytokine IL-10 in the blood serum of mice; in this case, the activity of the high-molecular derivative was two times higher as compared with the initial polysaccharide. With peroral introduction, the initial polysaccharide (50 mg/kg) and its derivative inhibited the development of chemically induced inflammation of experimental animals' large intestines, which was manifested as a decrease in the affected area and the degree of damage to the large intestine wall, as well as a two-fold reduction of myeloperoxidase activity. According to morphological and biochemical characteristics, the effect of chitosans was similar to that of a hormone anti-inflammatory drug, prednisolone. PMID- 29513411 TI - [Analysis of toxicity and biocompatibility of chitosan derivatives with different physico-chemical properties]. AB - A comparative study of the toxicity and hemocompatibility of chitosan and its derivatives with different acetylation degrees, molecular masses, charges, and hydrophobicity has been performed. It has been shown that only positively charged chitosan derivatives activate platelets and suppress cell proliferation, regardless of the acetylation degree, molecular mass, and hydrophobicity. Chitosan quaternization decreases toxicity at a low degree of substitution and abruptly increases it at a high one. Negatively charged chitosan derivatives were nontoxic and compatible with blood components. It was concluded that the toxicity of chitosan and its derivatives is defined by their charge and solubility at a neutral pH. PMID- 29513412 TI - [Antimutagenic systems based on chitosan conjugates with plant antioxidants]. AB - It was shown using various methods that the radical scavenging and radical scavenging activities of chitosan conjugates with phenolic antioxidants of plant origin significantly exceed the corresponding values of their low molecular weight analogs (gallic and syringic acids, quercetin and dihydroquercetin). Cytogenetic analysis of human peripheral blood lymphocytes demonstrated that the conjugates showed pronounced antimutagenic efficiency when the cells were gamma irradiated in vitro at a dose of 2 Gy. PMID- 29513413 TI - [Antibacterial effect of peptide conjugates with a quaternized chitosan derivative and its estimation by the method of atomic force microscopy]. AB - We obtained a number of conjugates based on a quaternized chitosan derivative and antimicrobial peptides (melittin and warnerin) crosslinked by microbial transglutaminase. We determined the optimal conditions for the synthesis (30 minutes, with a mole ratio of peptides and chitosan derivative of 1.4: 100) and studied the antibacterial properties of obtained conjugates. The antibacterial effect of the conjugates was found to be greater than that of their components. The antibacterial activity of the conjugates was determined by the double dilution method and by atomic force microscopy. PMID- 29513414 TI - [Determination of antibacterial activity of chitosan]. AB - A method for the determination of the antimicrobial activity of chitosan with the use of organic salts for the production of pH in the range of 5.5-8.2 was studied. The double-dilution method demonstrated the effectiveness of the determination of the antimicrobial activity of chitosan samples with different molecular weights and solubilities. It was found that the antibacterial activity of chitosan samples with different molecular weights and solubilities. It was found that the antibacterial activity increased at low pH values with increasing molecular weight, but chitosan with a molecular weight of 5-6 kDa showed higher activity at neutral and slightly alkaline pH levels. Determination of the antimicrobial activity of various chitosan samples at different pH values allowed a more reliable assessment of the potential biological activity of chitosan. PMID- 29513415 TI - [Compatibility of cells of the nervous system with structured biodegradable chitosan-based hydrogel matrices]. AB - Hydrogel matrices for cell cultivation have been generated by two-photon laser polymerization of unsaturated chitosan derivatives and methacrylated hyaluronic acid. The adhesive and toxic properties of the matrices have been assessed, and the matrices have been shown to have a good compatibility with primary hippocampal cell cultures. The formation of morphologically normal neural networks by cells of the nervous system cultured on the surface of hydrogel matrices has been observed. The metabolic status of dissociated hippocampal cells cultured on the matrices was similar to that of the control cultures, as shown by the results of MTT reductase activity assay. Thus, matrices based on unsaturated polysaccharide derivatives crosslinked by laser irradiation showed good compatibility with differentiated cells of the nervous system and considerable potential for use in neurotransplantation. PMID- 29513416 TI - [Biodegradablescaffolds based on chitosan: Preparation, properties, and use for the cultivation of animal cells]. AB - The influence of the conditions of the formation of chitosan hydrogels crosslinked with glutaraldehyde (GA) or genipin (the polysaccharide molecular weight, pH level, and concentration of the chitosan solution) on the gel time and the properties of biopolymer scaffolds for tissue engineering obtained by the freeze-drying of hydrogels was studied. The resulting scaffolds had different structures (morphology, degree of anisotropy, average pore size) and moisture retaining capacities. The cytotoxicity of biodegradable scaffolds based on chitosan with a low content of genipin and GA was studied for the first time. Using the L929 mouse fibroblasts model line, we demonstrated that scaffolds based on chitosan with a molecular weight of 320 and 190 kDa crosslinked with genipin and GA (0.005 and 0.01 mol/mol of chitosan amino groups) are biocompatible. Using confocal laser microscopy, we demonstrated that the cells are uniformly distributed in all scaffold samples and they successfully grew and proliferated when cultured in vitro for 4 days. PMID- 29513417 TI - [Enzymatic hydrolysis of chitosan films in water and physiological solution]. AB - It was shown that the processes of enzymatic hydrolysis of chitosan in aqueous acetic acid and on the surface of chitosan films in a solution of hyaluronidase in acetic acid are described by uniform kinetic constants. Kinetic parameters of enzymatic hydrolysis of the chitosan film samples in water and in physiological solution (Ringer-Locke's solution) were determined. It was found that the introduction of medicinal agents and low-molecular-weight electrolytes to a chitosan-based film material reduces the rate of enzymatic hydrolysis of the films, which may indicate a possible increase in their service life when used on the wound surface. PMID- 29513418 TI - [Synthesis of exo-beta-glucosaminidase BY FUNGUS Penicillium sp. IB-37-2]. AB - A new strain Penicillium sp. IB-37-2, which actively hydrolyzes chitosan (SD ~80 85%) but possesses low activity against colloidal chitin, was isolated. The fungus was observed to have a high level chitosanase biosynthesis (1.5-3.0 U/mL) during submerged cultivation at 28 degrees C, with a pH of 3.5-7.0 and 220 rpm in nutrient media containing chitosan or chitin from shells of crabs. Purification of the chitosanase enzyme complex from Penicillium sp. IB-37-2 by ultrafiltration and hydrophobic chromatography, followed by denaturing electrophoresis, revealed two predominant proteins with molecular weights of 89 and 41 kDa. The purified enzyme complex demonstrated maximal activity (maximal rate of hydrolysis of dissolved chitosan) and stability at 50-55 degrees C and a pH of 3.5-4.0. The enzyme preparation also hydrolyzed laminarin, beta-(1,3)-(1,4)-glycan, and colloidal chitin. Exohydrolysis of chitosan by the preparation isolated from Penicillium sp. IB-37-2 resulted in the formation of single product, D glucosamine. PMID- 29513419 TI - [The effect of chitosan- and vanillin-based immune modulators on the formation of plant resistance to dark-brown blotch]. AB - The effect of chitosan- and vanillin-based immune modulators on the development of the phytopathogen Cochliobolus sativus (S. Ito & Kurib.) Drechsler ex Dastur, which induces dark-brown blotch (helminthosporiosis) in wheat, has been studied. It was shown that treatment with these substances led to a decreased injured area in leaves and an increase in the biotrophic period of pathogen development. It was found that vanillin-modified chitosan effectively provided wheat resistance to hemibiotrophic pathogen C. sativus. Changes in leaf peroxidase activity correlated with the manifestation of disease symptoms. PMID- 29513420 TI - [Signal molecules involved in the regulation of the wheat defense response to Septoria nodorum infection]. AB - The response of Triticum aestivum L. to infection by Septoria nodorum Berk, a pathogen causing speckled leaf blotch, was studied. The effect of salicylic acid (SA) and jasmonic acid (JA) signal molecules, as well as chitooligosaccharides (COSs) with different acetylation degrees (ADs), on the accumulation of hydrogen peroxide (N2O2) in wheat leaves and the pathogenesis-related (PR) proteins of oxalate oxidase (AJ556991.1), peroxidase (TC 151917), and proteinase inhibitor (EU293132.1) was investigated. Treatment with the signal molecules inhibited S. nodorum growth and stimulated N2O2 accumulation, as well as PR gene expression. SA and COS with 65% AD are found to be more efficient in N2O2 induction and elevation of the transcriptional level of the oxalate oxidase and peroxidase genes. At the same time, JA and COS with 30% AD stimulated transcription of the proteinase inhibitor gene. The results suggest the existence of differential means of defense response induction by signal molecules with more prospects for the regulation of plant immunity. PMID- 29513421 TI - Avoiding the pitfalls of leakage testing. AB - Peter Rogers, chairman of the B&ES (Building and Engineering Services Association) Ductwork Group technical committee, reveals how crucial leakage testing is in hospitals because of the health risk posed to patients if ventilation systems do not achieve and maintain the required standards. PMID- 29513424 TI - Capacity planning for a different future. AB - As NHS waiting lists in England top three million,(1) the highest figure since waiting list 'targets' were created, estates teams have a key role to play in ensuring that infrastructure is best placed to meet demand. Working across Europe, operator of mobile healthcare facilities, Vanguard Healthcare Solutions, claims to have 'a unique insight' into the variety of estates policies and solutions being adopted by our European neighbors. Here Rob van Liefland, European representative, takes a look at the situation in Belgium and the Netherlands, and considers how the UK compares. PMID- 29513425 TI - Maintaining staff and patient safety in 'ED'. AB - Drawing on his own considerable experience and expertise in the field, including in the UK, the US, and Canada, Jon Huddy, architect, and President of Huddy HealthCare Solutions, headquartered in Fort Mill, South Carolina, examines optimizing security measures in hospital Emergency Departments. PMID- 29513426 TI - Minimising infection--from floor to ceiling. AB - Dr Sarah Peake, product sustainability manager at specialty chemicals company, Sika--which provides solutions for concrete, waterproofing, roofing, flooring, refurbishment, sealing and bonding, and industry--looks at the fundamentals for keeping floors, walls, and ceilings in hospitals and other healthcare facilities 'in excellent health'. PMID- 29513427 TI - Case 37-2017: A Man with Unintentional Opioid Overdose. PMID- 29513428 TI - Case 37-2017: A Man with Unintentional Opioid Overdose. PMID- 29513429 TI - Protecting people and valuable 'assets'. AB - A physical security breach in a healthcare facility can have serious consequences for staff, patients, and the general public, especially if that breach occurs in a high risk area, such as a server room, pharmaceutical storage unit, or radiological room. Here, Mike McColl, managing director of high security panel manufacturer, Securiclad, highlights the importance of a 'last line of defence' when protecting both people, and a wide range of equipment and 'assets', in healthcare facilities. PMID- 29513430 TI - Polio eradication - just one final sprint to the finish. PMID- 29513431 TI - ? PMID- 29513432 TI - Diabetes, coronary artery disease and collaboration. PMID- 29513433 TI - ? PMID- 29513434 TI - While we await a new method of determining the age of young asylum seekers. PMID- 29513435 TI - ? PMID- 29513436 TI - ? PMID- 29513438 TI - ? PMID- 29513437 TI - ? PMID- 29513439 TI - ? PMID- 29513440 TI - ? PMID- 29513441 TI - ? PMID- 29513442 TI - The follow-up after myocardial infarction - is it good enough? PMID- 29513443 TI - ? PMID- 29513444 TI - Genuine protection for whistleblowers - also in the health services. PMID- 29513446 TI - ? PMID- 29513445 TI - ? PMID- 29513447 TI - ? PMID- 29513448 TI - ? PMID- 29513449 TI - ? PMID- 29513450 TI - ? PMID- 29513452 TI - ? PMID- 29513451 TI - ? PMID- 29513453 TI - ? PMID- 29513454 TI - ? PMID- 29513455 TI - Atraumatic knee pain. AB - BAKGRUNN: Knesmerter er blant de vanligste arsaker til konsultasjoner for muskel- og skjelettplager. Siktemalet med denne artikkelen er dels a gi en oversikt over de siste par tiars forskning pa atraumatiske og degenerativt betingede kneplager, dels a vurdere hvorvidt den sedvanlige praksis for utredning og behandling er i samsvar med denne forskningen. KUNNSKAPSGRUNNLAG: Artikkelen er basert pa et utvalg av engelskspraklige studier av atraumatiske og degenerative knelidelser funnet ved sok i Medline, manuelle sok i artiklenes litteraturlister og litteraturforslag fra Mendeley. Studier av gonartrose, degenerativ meniskskade og kneplagers psykososiale kontekst ble vektlagt. RESULTATER: Det er ofte darlig samsvar mellom bildediagnostiske funn og det kliniske bildet, og ekstraartikulaert utgangspunkt kan lett overses. Symptomgivende gonartrose kan som regel diagnostiseres klinisk. Ved behov for bildediagnostikk er staende rontgenbilder forstevalget. MR-undersokelse benyttes ofte ukritisk ved mistanke om artrose og meniskskade, men undersokelsen gir sjelden klinisk nyttig informasjon. Aktivitetsbaserte behandlingsformer gir minst like gode resultater som artroskopisk kirurgi ved degenerative knelidelser og bor vaere forstevalget. Atraumatiske kneplager er ofte assosiert med psykososiale problemer, saerlig der det er beskjedne kliniske og radiologiske funn. FORTOLKNING: Mange pasienter med kneplager blir utsatt for utredninger og behandlinger som samsvarer darlig med nyere forskningsresultater. Bade pasient og samfunn vil vaere tjent med en mer kunnskapsbasert tilnaerming. PMID- 29513456 TI - ? AB - BACKGROUND: In 2009, the Norwegian Directorate of Health published the national guidelines 'Decision-making processes in the limitation of life-prolonging treatment' (1). It is not known whether the recommendations in the guidelines are followed in clinical practice. The purpose of this study was to investigate the decision-making process when a DNR order has been issued to refrain from resuscitation and the patient group for whom such an order is made. MATERIAL AND METHOD: The patients studied were hospitalised in the medical ward of a local hospital in 2012. Patients with a DNR order were identified through searches in 'critical information' in the DIPS patient record system. The study was conducted by means of a retrospective review of patient records with a follow-up time of two years. When competence to give informed consent was not recorded in the patient records, this was assessed based on other information in the records. RESULTS: A total of 363 out of 12 522 patients hospitalised in 2012 were registered with DNR orders. Their average age was 82.5 years. Hospital mortality was 37 % and 30-day mortality 66 %. The DNR order was based on the patient's own wishes in 116 out of 363 patients. Altogether 64 % of these were women. Competence to give informed consent was never explicitly noted in the patient records. A total of 27 % of the patients who were assessed as competent to give informed consent were not involved in the decision. INTERPRETATION: Patients with DNR orders are characterised by advanced age, mortality and morbidity. Clearer documentation of the assessment of competence to give informed consent, as well as better involvement of the patient, are necessary. PMID- 29513457 TI - ? PMID- 29513458 TI - ? PMID- 29513459 TI - ? PMID- 29513461 TI - ? PMID- 29513462 TI - ? PMID- 29513463 TI - ? PMID- 29513464 TI - ? PMID- 29513467 TI - ? PMID- 29513466 TI - Prevalence of diabetes before and after first diagnosis of coronary artery disease. AB - BAKGRUNN: Diabetes er assosiert med koronarsykdom, og kardiovaskulaer sykdom er viktigste dodsarsak hos mennesker med sykdommen. I denne studien har vi undersokt forekomsten av kjent diabetes og ikke-erkjent diabetes hos pasienter ved forste gangs hjerteinfarkt, perkutan koronar intervensjon eller koronar bypasskirurgi samt forekomsten av nye kardiovaskulaere hendelser i inntil fem ar etterpa. MATERIALE OG METODE: Alle pasienter < 80 ar uten tidligere kjent koronarsykdom innlagt ved Sorlandet sykehus Arendal i forbindelse med forste gangs hjerteinfarkt, perkutan koronar intervensjon eller koronar bypasskirurgi i perioden 2007-16 ble fortlopende inkludert i studien og fulgt i inntil fem ar (median oppfolgingstid tre ar). RESULTATER: Av totalt 1 259 inkluderte pasienter hadde 178 (14 %) kjent diabetes ved innleggelsestidspunktet og 49 (4 %) ikke erkjent diabetes. I lopet av oppfolgingsperioden utviklet ytterligere 102 pasienter (8 %) diabetes. Omtrent halvparten av dem med diabetes hadde en HbA1c verdi <= 7 %. Risikoen for utvikling av nye kardiovaskulaere hendelser var hoyere hos pasienter med diabetes enn hos pasienter uten diabetes (alders- og kjonnsjustert hasardratio 1,5; 95 % konfidensintervall: 1,1-2,1, p = 0,005). FORTOLKNING: Studien viser at det er hoy forekomst av diabetes hos pasienter med forste gangs koronarsykdom og hoy risiko for nye kardiovaskulaere hendelser hos pasienter med diabetes. Regelmessig undersokelse med tanke pa utvikling av diabetes og god forebyggende behandling av pasienter med diabetes og koronarsykdom er viktig. PMID- 29513468 TI - ? PMID- 29513470 TI - ? PMID- 29513469 TI - Maternity waiting homes - an effective instrument for global maternal health. PMID- 29513471 TI - [Inhibition of IAA oxidase activity of wheat anionic peroxidase by chitooligosaccharides]. AB - The study demonstrated that chitooligosaccharides with a molecular weight of 5-10 kDa and a degree of acetylation of 65% exhibited an auxin-like effect in wheat plants and also played an important role in regulating the activity of polysaccharide (chitin)-specific anion isoenzymes of peroxidase oxidizing indole acetic acid. Changes in the kinetic parameters of the interaction of the wheat anionic chitin-specific peroxidase with pI ~3.5 with chitin oligomers in the presence of indoleacetic acid were pH-depended and indicated that chitooligosaccharides significantly impair the ability of the enzyme for oxidation at pH levels of 4.2 and 6.0. It can be assumed that chitooligosaccharides not only induce protective plant systems but also increase the accumulation of auxin in plant tissues, thus adversely affecting a number of components of the plant protective system against pathogens. PMID- 29513472 TI - [The effect of high-molecular weight chitosans on the antioxidant and immune systems of the honeybee]. AB - High-molecular weight chitosan (200 kDa, 75% deacetylated) and N-succinoyl chitosan (300 kDa, 75% deacetylated) were shown to have a preadaptive effect and increase the lifespan of honeybees due to the induction of protective antioxidant and immune mechanisms. Chitosan with a molecular weight of 200 kDa had a fungistatic effect on a pathogenic fungus that causes ascospherosis, a disease of bee larvae and pupae. PMID- 29513473 TI - [The role of microorgansisms in maintaining the chitin balance in the Barents Sea]. AB - In this study, we investigated chitin hydrolysis by the bacteria inhabiting the ground of the Barents Sea. Four microbial cultures isolated from the ground were described as the genera of Rhodococcus sp., Bacillus sp., Pseudomonas sp., and Acinetobacter sp. Protein complexes with endochitinase and exochitinase activities were purified from the culture liquid. These microorganisms can participate in chitin degradation in sea water. The average molecular weight of the protein fraction with the chitinolytic activity constituted 92-135 kDa. The ratio of the endo-/exochitinase activities of the enzymatic systems was increased in the order Pseudomonas sp. < Bacillus sp. < Acinetobacter sp. < Rhodococcus sp. PMID- 29513474 TI - [Lignin: Chemical structure, biodegradation, and practical application]. AB - The review describes the natural biopolymer lignin, which is second in plant biomass abundance. It is evident now that lignin is considerably undervalued and insufficiently studied in the applied area. The review focuses on the history of the lignin discovery, methods for its extraction from plant objects, its biodegradation by fungi, the enzymes degrading lignin, and the prospects of its application in current biotechnology. PMID- 29513475 TI - [Catalytic properties of lipase adsorbed on nanocarbon-containing mesoporous silica in esterification and transesterification reactions]. AB - Nanocarbon-containing mesoporous silica covered with a varying amounts of nanostructured carbon of different morphologies were used as supports to immobilize Thermomyces lanuginosus lipase. The catalytic properties of the prepared biocatalysts were studied in both the transesterification of vegetable (linseed) oil in the presence of ethyl acetate and the esterification of the fatty acid (capric C10:0) in the presence of secondary (isopropyl or isoamyl) alcohols. The physico-chemical characteristics, such as the amount of adsorbed lipase, its specific activity, and the dependence of the activity and stability of the prepared biocatalysts on the support type were evaluated. The Michaelis Menten kinetics was studied in the esterification of capric acid with isoamyl alcohol. The prepared biocatalysts were shown to retain up to 90% activity for >1000 h in the synthesis of isoamyl caprate. The half-time of the biocatalysts inactivation in the transesterification of linseed oil was found to be more than 700 h at 40 degrees C. PMID- 29513476 TI - ISO 55000 promotes 'joined-up' approach. AB - Keith Hamer, an asset management system specialist, currently group vice president, Asset Management and Engineering, at Sodexo, and Kevin Main, marketing director at asset management solutions learning consultancy, Asset Wisdom, look at an important new international asset management standard, launched earlier this year, that they believe many in the healthcare estates and facilities management community managers may, as yet, have little, if any, knowledge of. PMID- 29513477 TI - [VapC toxin inhibition as a method for prevention of the formation of resting forms of mycobacteria]. AB - It has been shown that inactivation of the VapC toxin from the VapVS toxin antitoxin system prevents mycobacterial cells from transitioning to an ovoid state that meets the criteria of dormancy. The results indicate a potential target for medicines that prevent the development of latent tuberculosis infection and provide a basis to obtain bacterial cells for the testing of compounds that are active towards dormant forms of mycobacteria. PMID- 29513478 TI - Improving provision, thinking ahead. AB - Phillip Herring, managing director at VINCI Park UK--a parking operator which develops and manages integrated parking solutions across a wide range of sectors- examines some of the key issues facing those working within healthcare estates and facilities teams responsible for parking policy and operations in their hospital or other healthcare facility, and discusses how the company has deployed its expertise to 'ease some of the pressures'. PMID- 29513479 TI - Time to take action to meet GS1 mandate. AB - A recent paper, NHS eProcurement Strategy,(1) published earlier this year by the Department of Health, mandated the use of GS1 standards throughout the NHS in England. The Strategy requires all NHS Trusts in England to produce a Board approved adoption plan. Chris Doyle, head of Healthcare at independent global supply chain standards organization, GS1 UK, explains the next steps to becoming compliant. PMID- 29513480 TI - [Resistance to cellobiose lipids and specific features of lipid composition in yeast]. AB - The significance of the fatty acid composition and ergosterol content in cells for resistance to cellobiose lipids has been investigated in the cells of mutant Saccharomyces cerevisiae strains that are unable to produce ergosterol or sphingomyelin and in the cells of microorganisms that produce cellobiose lipids. S. cerevisiae mutants were shown to be less sensitive to cellobiose lipids from Cryptococcus humicola than the wild-type strain, and the strains that produced cellobiose lipids were virtually insensitive to this compound as well. The sensitivity of Pseudozyma fusiformata yeast to its own cellobiose lipids was reduced under conditions that favored the production of these compounds. No correlation between the content of ergosterol and sensitivity to cellobiose lipids was observed in S. cerevisiae or in the strains that produced cellobiose lipids. The ratio between the levels of saturated and unsaturated fatty acids in the cells of the mutant strains was correlated to the sensitivity of the cells to cellobiose lipids. PMID- 29513481 TI - [Degradation of fluorene and fluoranthene by the basidiomycete Pleurotus ostreatus]. AB - The dependence of the degree of fluorene and fluoranthene degradation by the fungus Pleurotus ostreatus D1 on the culture medium composition has been studied. Polycyclic aromatic hydrocarbons (PAHs) have been transformed in Kirk's medium (under conditions of laccase production) with the formation of a quinone metabolite and 9-fluorenone upon the use of fluoranthene and fluorene as substrates, respectively. More complete degradation with the formation of an intermediate metabolite, phthalic acid that has undergone subsequent utilization, has occurred in basidiomycete-rich medium (under the production of both laccase and versatile peroxidase). The formation of phthalic acid as a metabolite of fluoranthene degradation by lignolytic fungi has been revealed for the first time. The data allow the supposition that both extracellular laccase and laccase on the mycelium surface can participate in the initial stages of PAH metabolism, while versatile peroxidase is necessary for the oxidation of the formed metabolites. A scheme of fluorene metabolism by Pleurotus ostreatus D1 is suggested. PMID- 29513482 TI - Touchscreen device to 'calm and de-stress'. AB - A highly experienced former psychiatric nurse until recently innovation manager at the Geestelijke Gezondheidszorg Eindhoven (GGZe)--the Eindhoven Mental Health Institute in the Netherlands, and a PhD holder in physics who spent several years at Philips Healthcare, have jointly developed an interactive 'communication wall' designed primarily as a communication tool for, and as a means to help 'de stress', patients in inpatient mental health facilities during periods of acute anxiety. Erik Kuijpers and Cor Datema will show a version of their 'Cowall' on the Britplas stand at this month's Healthcare Estates 2014. As HEJ editor, Jonathan Baillie, discovered, when he met them during one of their recent trips to the UK, late in 2013 they formed a company, Recornect, to market the system, and to provide consultancy to those keen to specify the latest technology for mental and acute healthcare settings. Their Cowall has already seen installations in mainland Europe, and the pair are now seriously targeting the UK. PMID- 29513483 TI - [Oil degradation by basidiomycetes in soil and peat at low temperatures]. AB - A total of 17 basidiomycete strains causing white rot and growing on oil contaminated substrates have been screened. Three strains with high (Steccherinum murashkinskyi), average (Trametes maxima), and low (Pleurotus ostreatus) capacities for the colonization of oil-contaminated substrates have been selected. The potential for degrading crude oil hydrocarbons has been assessed with the use of fungi grown on nonsterile soil and peat at low temperatures. Candida sp. and Rhodococcus sp. commercial strains have been used as reference organisms with oil-degrading ability. All microorganisms introduced in oil contaminated soil have proved to be ineffective, whereas the inoculation of peat with basidiomycetes and oil-degrading microorganisms accelerated the destruction of oil hydrocarbons. The greatest degradation potential of oil-aliphatic hydrocarbons has been found in S. murashlinskyi. T. maxima turned out to be the most successful in degrading aromatic hydrocarbons. It has been suggested that aboriginal microflora contributes importantly to the effectiveness of oil destructing microorganisms. T. maxima and S. murashkinskyi strains are promising for further study as oil-oxidizing agents during bioremediation of oil contaminated peat soil under conditions of low temperatures. PMID- 29513485 TI - Designing facilities for the future, today. AB - Cassandra Coleman, business development manager at international healthcare consultancy, MJ Medical, discusses the challenges of designing healthcare facilities today that will cope well with, and adapt to, the changing clinical demands, patient care pathways, and advances in both diagnostics and treatment, that will inevitably characterise healthcare in the next 2-3 decades and beyond. PMID- 29513484 TI - [New strains of basidiomycetes that produce bioethanol from lignocellulose biomass]. AB - Sixty six isolates were screened for ability of bioethanol production; dynamics of product accumulation and substrate utilization were investigated for two selected strains Trametes hirsuta MT-24.24 and Trametes versicolor IT-1. The strains' efficiency was evaluated as bioethanol production by 1 g biomass. Strain T. versicolor IT-1 producing over 33 g/L of the ethanol for 9 d was selected. Direct conversion of Na-carboxymethyl cellulose, microcrystalline cellulose and straw was shown with ethanol yields of 2.1, 1.6 and 1.7 g/L, respectively, for 9 d fermentation time. PMID- 29513486 TI - [Formation of protodioscin and deltoside isomers in suspension cultures of Nepal yam (Dioscorea deltoidea Wall.) cells]. AB - Changes in the content of the furostanol glycosides protodioscin and deltoside, particularly that of the (25S)-isomers of the glycosides, during suspension cultivation of different lines of Nepal yam (Dioscorea deltoidea Wall.) cells of the strain IFR-DM-0.5 has been investigated. The composition of furostanol glycosides has been characterized, and the dynamics of the accumulation of individual glycosides during lengthy subcultivation of cells maintained in flasks or in a barbotage bioreactor has been analyzed. A positive correlation between the growth and accumulation of substances that belonged to the class of furostanol glycosides has been demonstrated for cultured dioscorea cells, whereas the content of some of the individual glycosides varied considerably between the lines of the strain, cultures maintained under different conditions, and even between cells in different phases of the growth cycle. The increased content of (25R)-forms of the glycosides (protodioscin and deltoside) was correlated with a decrease in the cellular growth rate, whereas an increase in culture growth intensity occurred concomitantly to an increase of the amount of (25S)-isomers. This may be indicative of the specific stimulatory effect of (25S)-glycosides, but not the (25R)-forms, on cell proliferation in vitro. Thus, the concentration of (25S)-forms may increase due to the autoselection of cells capable of intensive division during prolonged cultivation. PMID- 29513487 TI - [Genetic system for maintaining the mitochondrial human genome in yeast Yarrowia lipolytica]. AB - For the first time, the possibility of maintaining an intact human mitochondrial genome in a heterologous system in the mitochondria of yeast Yarrowia lipolytica is shown. A method for introducing directional changes into the structure of the mitochondrial human genome replicating in Y. lipolytica by an artificially induced ability of yeast mitochondria for homologous recombination is proposed. A method of introducing and using phenotypic selection markers for the presence or absence of defects in genes tRNA-Lys and tRNA-Leu of the mitochondrial genome is developed. The proposed system can be used to correct harmful mutations of the human mitochondrial genome associated with mitochondrial diseases and for preparative amplification of intact mitochondrial DNA with an adjusted sequence in yeast cells. The applicability of the new system for the correction of mutations in the genes of Lys- and Leu-specific tRNAs of the human mitochondrial genome associated with serious and widespread human mitochondrial diseases such as myoclonic epilepsy with lactic acidosis (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF) is shown. PMID- 29513488 TI - Competition should open up savings. AB - Mark Powles, chief executive of Business Stream, which says it has helped Scottish businesses and public sector organisations save over L100 million on their water bills since retail competition in this area was introduced in Scotland in April 2008, explains how, thanks to legislation that came into effect earlier this year, NHS Trusts in England will, from April 2017, be able to benefit from similar 'full competition' in their choice of water supplier. Here he advises on some of the steps that healthcare estates teams and others responsible for their organization's water supply should be taking in preparation. PMID- 29513489 TI - [Fluorescence polarization immunoassay of ractopamine]. AB - A technique was developed for fluorescence polarization immunoassay (FPIA) of ractopamine, a toxic low molecular weight nonsteroidal growth regulator belonging to the most controlled contaminants of food products of animal origin. The assay is based on the competition between a sample containing ractopamine and ractopamine-fluorophore conjugate for binding to antibodies. The competition is monitored via changes in the degree of fluorescence polarization for plane polarized excitation light, which differs for the free and antibody-bound forms of the conjugate. The optimal assay conditions were established, ensuring a high accuracy and minimal detection limit. The developed assay demonstrated a detection limit of 1 ng/mL and a range of detectable concentrations of 2.3-50 ng/mL, which met the requirements of sanitary control. The duration of the analysis was 10 min. The possible application of the developed FPIA was demonstrated with testing of turkey meat. The speed and simplicity of the proposed assay define its efficiency as a screening tool for safety of foods. PMID- 29513510 TI - Lateral Non-covalent Clamping of Graphene at the Edges Using a Lipid Scaffold. AB - Developing a clean handling and transfer process, capable of preserving the integrity of two-dimensional materials, is still a challenge. Here, we present a flexible, dynamic, and lipid-based scaffold that clamps graphene at the edges providing a practical, simple, and clean graphene manipulation and transfer method. Lipid films with different surface pressures are deposited at the air/copper-etchant interface immediately after placing the graphene samples. We show that at surface pressures above 30 mN/m, the lateral support prevents graphene movement and cracking during all etching and transfer. The method provides new insights into the handling of graphene and can yield efficient, sensitive, and clean graphene-based devices. PMID- 29513511 TI - Shedding Light on the Oxygen Reduction Reaction Mechanism in Ether-Based Electrolyte Solutions: A Study Using Operando UV-Vis Spectroscopy. AB - Using UV-vis spectroscopy in conjunction with various electrochemical techniques, we have developed a new effective operando methodology for investigating the oxygen reduction reactions (ORRs) and their mechanisms in nonaqueous solutions. We can follow the in situ formation and presence of superoxide moieties during ORR as a function of solvent, cations, anions, and additives in the solution. Thus, using operando UV-vis spectroscopy, we found evidence for the formation of superoxide radical anions during oxygen reduction in LiTFSI/diglyme electrolyte solutions. Nitro blue tetrazolium (NBT) was used to indicate the presence of superoxide moieties based on its unique spectral response. Indeed, the spectral response of NBT containing solutions undergoing ORR could provide a direct indication for the level of association of the Li cations with the electrolyte anions. PMID- 29513512 TI - Binding CO2 from Air by a Bulky Organometallic Cation Containing Primary Amines. AB - The organometallic cation 1 (Fe(bipy-NH2)32+, bipy-NH2 = 4,4'-diamino-2,2' bipyridine), which was constructed in situ in solution, can bind CO2 from air effectively with a stoichiometric ratio of 1:4 (1/CO2), through the formation of "H-bonded CO2" species: [CO2-OH-CO2]- and [CO2-CO2-OH]-. These two species, along with the captured individual CO2 molecules, connected 1 into a novel 3D (three dimensional) architecture, that was crystal 1.2(OH-).4(CO2). The adsorption isotherms, recycling investigations, and the heat capacity of 1 have been investigated; the results revealed that the organometallic cation 1 can be recycled at least 10 times for the real-world CO2 capture applications. The strategies presented here may provide new hints for the development of new alkanolamine-related absorbents or technologies for CO2 capture and sequestration. PMID- 29513513 TI - Diffusion-Controlled Faradaic Charge Storage in High-Performance Solid Electrolyte-Gated Zinc Oxide Thin-Film Transistors. AB - An electrochemical device capable of manifesting reversible charge storage at the interface of an active layer offers formidable advantages, such as low switching energy and long retention time, in realizing synaptic behavior for ultralow power neuromorphic systems. Contrary to a supercapacitor-based field-effect device that is prone to low memory retention due to fast discharge, a solid electrolyte-gated ZnO thin-film device exhibiting a battery-controlled charge storage mechanism via mobile charges at its interface with tantalum oxide is demonstrated. Analysis via cyclic voltammetry and chronoamperometry uniquely distinguishes the battery behavior of these devices, with an electromotive force generated due to polarization of charges strongly dependent on the scan rate of the applied voltage. The Faradaic-type diffusion-controlled charge storage mechanism exhibited by these devices is capable of delivering robust enhancement in the channel conductance and leads to a superior ON-OFF ratio of 108-109. The nonvolatile behavior of the interface charge storage and slow diffusion of ions is utilized in efficiently emulating spike timing-dependent plasticity (STDP) at similar time scales of biological synapses and unveils the possibility of STDP behavior using multiple in-plane gates that alleviate additional requirement of waveform-shaping circuits. PMID- 29513514 TI - Nanopore Opening at Flat and Nanotip Conical Electrodes during Vesicle Impact Electrochemical Cytometry. AB - The oxidation of catecholamine at a microelectrode, following its release from individual vesicles, allows interrogation of the content of single nanometer vesicles with vesicle impact electrochemical cytometry (VIEC). Previous to this development, there were no methods available to quantify the chemical load of single vesicles. However, accurate quantification of the content is hampered by uncertainty in the proportion of substituent molecules reaching the electrode surface (collection efficiency). In this work, we use quantitative modeling to calculate this collection efficiency. For all vesicles except those at the very edge of the electrode, modeling shows that ~100% oxidation efficiency is achieved when employing a 33 MUm diameter disk microelectrode for VIEC, independent of the location of the vesicle release pore. We use this to experimentally determine a precise distribution of catecholamine in individual vesicles extracted from PC12 cells. In contrast, we calculate that when a nanotip conical electrode (~4 MUm length, ~1.5 MUm diameter at the base) is employed, as in intracellular VIEC (IVIEC), the current-time response depends strongly on the position of the catecholamine-releasing pore in the vesicle membrane. When vesicle release occurs with the pore opening occurring far from the electrode, lower currents and partial oxidation (~75%) of the catecholamine are predicted, as compared to higher currents and ~100% oxidation, when the pore is close to/at the electrode surface. As close agreement is observed between the experimentally measured vesicular content in intracellular and extracted vesicles from the same cell line using nanotip and disk electrodes, respectively, we conclude that pores open at the electrode surface. Not only does this suggest that electroporation of the vesicle membrane is the primary driving force for catecholamine release from vesicles at polarized electrodes, but it also indicates that IVIEC with nanotip electrodes can directly assess vesicular content without correction. PMID- 29513515 TI - Oxidation of Microcystin-LR via Activation of Peroxymonosulfate Using Ascorbic Acid: Kinetic Modeling and Toxicity Assessment. AB - Advanced oxidation processes (AOPs) have been widely used for the destruction of organic contaminants in the aqueous phase. In this study, we introduce an AOP on activated peroxymonosulfate (PMS) by using ascorbic acid (H2A) to generate sulfate radicals (SO4*-). Sulfate radicals, hydroxyl radicals (HO*), and ascorbyl radicals (A*-) were found using electron spin resonance (ESR). But we found A*- is negligible in the degradation of microcystin-LR (MCLR) due to its low reactivity. We developed a first-principles kinetic model to simulate the MCLR degradation and predict the radical concentrations. The MCLR degradation rate decreased with increasing pH. The scavenging effect of natural organic matter (NOM) on SO4*- was relatively small compared to that for HO*. Considering both energy consumption and MCLR removal, the optimal H2A and PMS doses for H2A/PMS process were determined at 1.0 * 10-6 M and 1.6 * 10-5 M, respectively. In addition, we determined the toxicity using the protein phosphatase 2A (PP2A) test and the results showed that MCLR was readily detoxified and its oxidation byproducts were not hepatotoxic. Overall, our work provides a new type of AOP and a promising, efficient, and environmental-friendly method for removing microcystins in algae-laden water. PMID- 29513517 TI - Interpenetrated Binary Supramolecular Nanofibers for Sensitive Fluorescence Detection of Six Classes of Explosives. AB - In this work, we develop a sequential self-assembly approach to fabricate interpenetrated binary supramolecular nanofibers consisting of carbazole oligomer 1-cobalt(II) (1-Co2+) coordination nanofibers and oligomer 2 nanofibers for the sensitive detection of six classes of explosives. When exposed to peroxide explosives (e.g., H2O2), Co2+ in 1-Co2+ coordination nanofibers can be reduced to Co+ that can transfer an electron to the excited 2 nanofibers and thereby quench their fluorescence. On the other hand, when exposed to the other five classes of explosives, the excited 2 nanofibers can transfer an electron to explosives to quench their fluorescence. On the basis of the distinct fluorescence quenching mechanisms, six classes of explosives can be sensitively detected. Herein, we provide a new strategy to design broad-band fluorescence sensors for a rich identification of threats. PMID- 29513518 TI - Panoply of Fluorescence Polarization/Anisotropy Signaling Mechanisms for Functional Nucleic Acid-Based Sensing Platforms. AB - Fluorescence polarization/anisotropy is a very popular technique that is widely used in homogeneous-phase immunoassays for the small molecule quantification. In the present Feature, we discuss how the potential of this signaling approach considerably expanded during the last 2 decades through the implementation of a myriad of original transducing strategies that use functional nucleic acid recognition elements as a promising alternative to antibodies. PMID- 29513516 TI - Prairie Voles as a Model for Understanding the Genetic and Epigenetic Regulation of Attachment Behaviors. AB - Over a lifetime, humans build relationships with family, friends, and partners that are critically important for our mental and physical health. Unlike commonly used laboratory mice and rats, Microtine rodents provide a unique model to study the neurobiology underlying pair bonding and the selective attachments that form between adults. Comparisons between monogamous prairie voles and the closely related but nonmonogamous meadow and montane voles have revealed that brain region-specific neuropeptide receptor patterning modulates social behavior between and within species. In particular, diversity in vasopressin 1a receptor (V1aR) distribution has been linked to individual and species differences in monogamy-related behaviors such as partner preference, mate guarding, and space use. Given the importance of differential receptor expression for regulating social behavior, a critical question has emerged: What are the genetic and epigenetic mechanisms that underlie brain-region-specific receptor patterns? This review will summarize what is known about how the vasopressin (AVP)-V1aR axis regulates social behaviors via signaling in discrete brain regions. From this work, we propose that brain-region-specific regulatory mechanisms facilitate robust evolvability of V1aR expression to generate diverse sociobehavioral traits. Translationally, we provide a perspective on how these studies have contributed to our understanding of human social behaviors and how brain-region specific regulatory mechanisms might be harnessed for targeted therapies to treat social deficits in psychiatric disorders such as depression, complicated grief, and autism spectrum disorder. PMID- 29513519 TI - Light-Driven Sodium-Pumping Rhodopsin: A New Concept of Active Transport. AB - Ion pumps perform active transport of ions by using energy. The active transport mechanism can be illustrated by the Panama Canal model, which considers two gates and a gain in energy. The Panama Canal model is consistent with the alternating access model that is used to describe active transport, in which the substrate ion is bound, energized, and released. It was generally accepted that energization occurs only for an ion-bound protein but not for an ion-unbound protein. Light-driven proton and chloride pumps, two of the best studied pumps, are represented by the Panama Canal model. In this case, light absorption takes place for the bound state of ions (proton and chloride ions) in the active center (protonated Schiff base of the retinal chromophore). In contrast, a recently discovered light-driven sodium pump, Krokinobacter eikastus rhodopsin 2 (KR2), is a unique active transporter that does not bind the transport substrate, the sodium ion, in its resting state. The molecular architecture and photoreaction cycle of the light-driven sodium pump are very similar to those of proton and chloride pumps, although sodium ions are actively transported without initial binding. Sodium uptake is a diffusive process, but the presence of two gates allows the unidirectional transport of sodium ions. In this sense, the light driven sodium pump is also represented by a modified Panama Canal model. Current understanding of the light-driven sodium pump is reviewed. PMID- 29513520 TI - Multilayer Functional Tapes Cofired at 450 degrees C: Beyond HTCC and LTCC Technologies. AB - This paper reports the first ultralow sintering temperature (450 degrees C) cofired multifunctional ceramic substrate based on a commercial lead zirconium titanate (PZ29)-glass composite, which is fabricated by tape casting, isostatic lamination, and sintering. This substrate was prepared from a novel tape casting slurry composition suitable for cofiring at low temperatures with commercial Ag electrodes at 450 degrees C. The green cast tape and sintered substrate showed a surface roughness of 146 and 355 nm, respectively, suitable for device-level fabrication by postprocessing. Additionally, the ferroelectric and piezoelectric studies disclosed low remnant polarization due to the dielectric glass matrix with average values of piezoelectric coefficient (+ d33) and voltage coefficient (+ g33) of 17 pC/N and 30 mV/N, respectively. The dielectric permittivity and loss value of the sintered substrates were 57.8 and 0.05 respectively, at 2.4 GHz. The variation of relative permittivity on temperature dependence in the range of -40 to 80 degrees C was about 23%, while the average linear coefficient of thermal expansion was 6.9 ppm/ degrees C in the measured temperature range of 100-300 degrees C. Moreover, the shelf life of the tape over 28 months was studied through measurement of the stability of the dielectric properties over time. The obtained results open up a new strategy for the fabrication of next generation low-cost functional ceramic devices prepared at an ultralow temperature in comparison to the high-temperature cofired ceramic and low temperature cofired ceramic technologies. PMID- 29513521 TI - The Double-Edged Sword Profile of Redox Signaling: Oxidative Events As Molecular Switches in the Balance between Cell Physiology and Cancer. AB - The intracellular redox state in the cell depends on the balance between the level of reactive oxygen species (ROS) and the activity of defensive systems including antioxidant enzymes. This balance is a dynamic process that can change in relation to many factors and/or stimuli induced within the cell. ROS production is derived from physiological metabolic events. For instance, mitochondria represent the major ROS sources during oxidative phosphorylation, but other systems, such as NADPH oxidase or specific enzymes in certain metabolisms, may account for ROS production as well. Whereas high levels of ROS perturb the cell environment, causing oxidative damage to biological macromolecules, low levels of ROS can exert a functional role in the cell, influencing the activity of specific enzymes or modulating some intracellular signaling cascades. Of particular interest appears to be the role of ROS in tumor systems not only because ROS are known to be tumorigenic but also because tumor cells are able to modify their redox state, regulating ROS production to sustain tumor growth and proliferation. Overall, the scope of this review was to critically discuss the most recent findings pertaining to ROS physiological roles as well as to highlight the controversial involvement of ROS in tumor systems. PMID- 29513522 TI - Light-Trigerred Cellular Epigenetic Molecule Release To Reverse Tumor Multidrug Resistance. AB - Owing to the high spatial and temporal resolution of light, light-related biotechnologies, for example, optogenetics, has wide ranging applications in neuroscience to control a subject's behavior. Applying light to control tumors' genetic behavior directly was still a challenge so far. Herein, we put forward a strategy of chemical optoepigenomics, in which an epigenetic regulator (vorinostat) and paclitaxel (PTX) were conjugated onto a light-sensitive chemical molecule. The activity of vorinostat could be precisely controlled by the light, which could minimize the off-target effect. After UV irradiation under 350 nm, the photocaged epigenetic regulator (vorinostat) was selectively released from the conjugate in a spatiotemporal manner, inhibiting the activity of histone deacetylase and then reversing the PTX resistance of tumor cells effectively. PMID- 29513523 TI - Design of a New Near-Infrared Ratiometric Fluorescent Nanoprobe for Real-Time Imaging of Superoxide Anions and Hydroxyl Radicals in Live Cells and in Situ Tracing of the Inflammation Process in Vivo. AB - The superoxide anion (O2*-) and hydroxyl radical (*OH) are important reactive oxygen species (ROS) used as biomarkers in physiological and pathological processes. ROS generation is closely related to the development of a variety of inflammatory diseases. However, the changes of ROS are difficult to ascertain with in situ tracing of the inflammation process by real-time monitoring, owing to the short half-lives of ROS and high tissue autofluorescence in vivo. Here we developed a new near-infrared (NIR) ratiometric fluorescence imaging approach by using a Forster resonance energy transfer (FRET)-based ratiometric fluorescent nanoprobe for real-time monitoring of O2*- and *OH generation and also by using in situ tracing of the inflammation process in vivo. The proposed nanoprobe was composed of PEG functionalized GQDs as the energy donor connecting to hydroIR783, serving as both the O2*-/*OH recognizing ligand and the energy acceptor. The nanoprobe not only exhibited a fast response to O2*- and *OH but also presented good biocomapatibility as well as a high photostability and signal-to-noise ratio. We have demonstrated that the proposed NIR ratiometric fluorescent nanoprobe can monitor the changes of O2*- and *OH in living RAW 264.7 cells via a drug mediating inflammation model and further realized visual monitoring of the change of O2*- and *OH in mice for in situ tracing of the inflammation process. Our design may provide a new paradigm for long-term and real-time imaging applications for in vivo tracing of the pathological process related to the inflammatory diseases. PMID- 29513524 TI - Estradiol-Loaded Poly(epsilon-caprolactone)/Silk Fibroin Electrospun Microfibers Decrease Osteoclast Activity and Retain Osteoblast Function. AB - Estrogen, a steroid hormone, plays an important role in modulating osteoclast proliferation and development. Estrogen deficiency boosts osteoclast activity, leading to osteoporosis in elderly women. In this study, 17-beta estradiol (E2) loaded poly(epsilon-caprolactone) (PCL)/silk fibroin (SF) electrospun microfibers were developed as a proposed localized E2 delivery system to treat osteoporotic fractures. PCL is a synthetic polymer known for its biocompatibility and excellent mechanical properties. The bioactivity of PCL was enhanced by mixing it with a natural SF polymer that has low immunogenicity and inherent bioactivity. Different ratios of PCL/SF blends were electrospun and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and water contact angle measurement. PCL and SF at a ratio of 50:50 (PCL50/SF50) augmented cell proliferation of murine preosteoblast MC3T3-E1 cells and murine preosteoclast RAW 264.7 cells. Hence, PCL50/SF50 was selected and mixed with three concentrations of E2 to produce electrospun fiber mesh (0.1% E2@PCL/SF, 1% E2@PCL/SF, and 5% E2@PCL/SF). Sustained release of E2 was obtained for about 3 weeks at higher E2 concentration 5% E2@PCL/SF. An E2-loaded PCL50/SF50 elecrospun microfiber (1% E2@PCL/SF and 5% E2@PCL/SF) reduced tartrate-resistant acid phosphate activity, total DNA, and multinucleated cell formation of osteoclasts. On the other hand, the alkaline phosphatase activity and collagen I expression of osteoblasts were retained on all E2-loaded electrospun microfibers. The E2@PCL/SF system shows potential to be used for localized E2 delivery for the treatment of osteoporotic fractures. PMID- 29513525 TI - Zwitterion-like, Charge-Balanced Ultrathin Layers on Polymeric Membranes for Antifouling Property. AB - Zwitterions of charge-balanced units have super-low fouling properties induced by ionic solvation, but their extensive applications in polymeric substrates are strictly constrained by current constructing strategies. A zwitterion-like, charge-balanced ultrathin layer with high antifouling capacity was covalently constructed on delicate aromatic polyamide (PA) reverse osmosis (RO) membranes via a mild and solvent-free grafting-to strategy. Two oppositely charged commercial short-chain carbonyl alkenes, 2-acrylamido-2-methylpropanesulfonic acid (AMPS) and methacryloxyethyltrimethylammonium chloride (DMC), were directly mixed-grafted with amino groups on PA RO membrane surface via Michael addition. Under ambient temperature and pressure, these oppositely charged compounds were assembled into a zwitterion-like, charge-balanced ultrathin layer. The dynamic fouling experiments indicated that the modified membrane exhibited strong antifouling properties and excellent permeation recovery abilities. Surface characterization revealed that the selective layer thickness and surface roughness were not measurably changed. More meaningful is that the typical ridge and-valley surface structure and the excellent separation performance were both well preserved after modification. This opens a universal avenue to construct a zwitterion-like, ultrathin antifouling layer on the delicate polymer substrate without compromising its original matrix structure and performance, which has promising application in areas of biosensors, tissue engineering, and biomaterials. PMID- 29513526 TI - Natural Deep Eutectic Solvents: Properties, Applications, and Perspectives. AB - As functional liquid media, natural deep eutectic solvent (NADES) species can dissolve natural or synthetic chemicals of low water solubility. Moreover, the special properties of NADES, such as biodegradability and biocompatibility, suggest that they are alternative candidates for concepts and applications involving some organic solvents and ionic liquids. Owing to the growing comprehension of the eutectic mechanisms and the advancing interest in the natural eutectic phenomenon, many NADES applications have been developed in the past several years. However, unlike organic solvents, the basic structural unit of NADES media primarily depends on the intermolecular interactions among their components. This makes NADES matrices readily influenced by various factors, such as water content, temperature, and component ratio and, thus, extends the metabolomic challenge of natural products (NPs). To enhance the understanding of the importance of NADES in biological systems, this review focuses on NADES properties and applications in NP research. The present thorough chronological and statistical analysis of existing report adds to the recognition of the distinctiveness of (NA)DES, involves a discussion of NADES-related observations in NP research, and reportes applications of these eutectic mixtures. The work identifies potential areas for future studies of (NA)DES by evaluating relevant applications, including their use as extraction and chromatographic media as well as their biomedical relevance. The chemical diversity of natural metabolites that generate or participate in NADES formation highlights the growing insight that biosynthetically primordial metabolites (PRIMs) are as essential to the biological function and bioactivity of unrefined natural products as the biosynthetically more highly evolutionary metabolites (HEVOs) that can be isolated from crude mixtures. PMID- 29513527 TI - Li6M(SeO3)4 (M = Co, Ni, and Cd) and Li2Zn(SeO3)2: Selenites with Late Transition Metal Cations. AB - A series of lithium metal selenites, Li6M(SeO3)4 (M = Co, Ni, and Cd) and Li2Zn(SeO3)2, were synthesized by hydrothermal and solid-state reactions. Li6M(SeO3)4 is composed of Li+ cations, MO6 octahedra, and SeO3 polyhedra, while Li2Zn(SeO3)2 consists of Li+, Zn(Li)O4 tetrahedra, and SeO3 polyhedra. Isostructural Li6Co(SeO3)4 and Li6Ni(SeO3)4 crystallize in the rhombohedral space group R3, forming a three-dimensional distorted cubic lattice. Li2Zn(SeO3)2 crystallizes in the orthorhombic space group Pbam and reveals a layered structure in the bc plane. Li6Cd(SeO3)4 revealing a unidimensional structure crystallizes in the polar non-centrosymmetric space group C2, attributed to the parallel alignment of distorted CdO6 octahedra. The direct-current magnetic susceptibility measurements unveil that Li6Co(SeO3)4 is a canted antiferromagnet with TN = 25 K, while Li6Ni(SeO3)4 undergoes an antiferromagnetic transition at TN = 54 K, having a negligible canted moment. The weak ferromagnetism observed in Li6Co(SeO3)4 indicates the significance of spin-orbit coupling, bringing about anisotropic exchange interactions. Li6Cd(SeO3)4 reveals a second harmonic generation (SHG) efficiency of 10 * alpha-SiO2. Dipole moment calculations on Li6Cd(SeO3)4 indicate that the cooperative interaction of CdO6 and SeO3 is responsible for the observed SHG properties. Band gaps of the compounds are enlarged as atomic number increases. The effect of late transition-metal cations with different coordination numbers on the framework structures and the subsequent physical properties will be also discussed. PMID- 29513528 TI - Hydrothermal Growth of Centimeter-Scale CuO Plates: Planar Chromium(III) Oligomer as a Facet-Directing Agent. AB - In this work, a simple hydrothermal method was developed to synthesize CuO plates in centimeter scale for the first time. Plates of up to 20 MUm thickness and several square millimeters in area have been prepared. The unusual size was obtained under ultrahigh-concentration NaOH and a planar chromium(III) oligomer, which served as a new kind of inorganic facet-directing agent. The obtained CuO plates were glossy black, free-standing, and crack-free. The chromium(III) oligomer offered ideal chemically active sites for adsorbing and confining Cu2+ ions. They could be adsorbed on the surface of Cu(OH)42- clusters via hydrogen bonding interaction, which thus modified the growth orientation. The as synthesized centimeter-scale CuO plates could possibly serve as substrates and electronic materials with potential applications. PMID- 29513529 TI - Pentaminomycins A and B, Hydroxyarginine-Containing Cyclic Pentapeptides from Streptomyces sp. RK88-1441. AB - Two new cyclic peptides, pentaminomycins A (1) and B (2), were isolated from cultures of Streptomyces sp. RK88-1441. Based on the interpretation of the NMR, UV, IR, and MS data, the planar structures of 1 and 2 were elucidated as cyclic pentapeptides with a modified amino acid residue, N5-hydroxyarginine (N5-OH-Arg). The absolute configurations of the constituent amino acid residues were determined by the advanced Marfey's method. Localization of l- and d-amino acids in the sequence was ascertained by chiral analysis of the fragment peptide obtained from a partial hydrolysate; amino acids were identified by LC-MS. Pentaminomycin A (1) reduced alpha-MSH-stimulated melanin synthesis by suppressing the expression of melanogenic enzymes including tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). PMID- 29513530 TI - An Extensive Description of the Peptidomic Repertoire of the Hen Egg Yolk Plasma. AB - Hen egg is a raw material widely used for the preparation of food, pharmaceutical and cosmetoceutical products. Dedicated proteomic studies were accomplished on eggshell membrane, egg white, and yolk, identifying the most abundant proteins. No similar peptidomic studies have been performed so far. Only preliminary investigations on bioactive peptides in egg fractions and digestates were accomplished through functional screening assays, characterizing antioxidant, antibacterial, antiviral, immunomodulatory, and antihypertensive preparations and isolated components. This study fills this gap and provides a comprehensive picture of the peptides present in the yolk plasma of different hen egg types after 24 and 264 h of laying, taking advantage of a procedure based on a two-step fractionation followed by combined MALDI-TOF-TOF-MS- and nanoLC-ESI-Q Orbitrap-MS/MS-based analysis. Six hundred and twenty-eight peptides were characterized as deriving from the proteolytic processing of larger protein components after the physiological action of chicken chymotrypsin-like and pepsin like enzymes. Structural details on their post-translational modifications were also provided. Identified peptides were subjected to bioinformatic analysis and further compared with available data from the literature, ascertaining 198 peptides associable with putative antihypertensive, antimicrobial, anticancer, antiviral, antibiofilm, anorectic, calcium-binding, and anti-inflammatory activities. This analysis was often confirmative of previous experimental evidence on functional properties of unfractionated preparations or isolated molecules. These results further emphasize the bioactive action of yolk-derived peptides as related to egg consumption, and the potential use of these molecules as additive ingredients in the preparation of functional foods and cosmetics. PMID- 29513531 TI - Assessment of Real-Time Time-Dependent Density Functional Theory (RT-TDDFT) in Radiation Chemistry: Ionized Water Dimer. AB - Ionization in the condensed phase and molecular clusters leads to a complicated chain of processes with coupled electron-nuclear dynamics. It is difficult to describe such dynamics with conventional nonadiabatic molecular dynamics schemes since the number of states swiftly increases as the molecular system grows. It is therefore attractive to use a direct electron and nuclear propagation such as the real-time time-dependent density functional theory (RT-TDDFT). Here we report a RT-TDDFT benchmark study on simulations of singly and doubly ionized states of a water monomer and dimer as a prototype for more complex processes in a condensed phase. We employed the RT-TDDFT based Ehrenfest molecular dynamics with a generalized gradient approximate (GGA) functional and compared it with wave function-based surface hopping (SH) simulations. We found that the initial dynamics of a singly HOMO ionized water dimer is similar for both the RT TDDFT/GGA and the SH simulations but leads to completely different reaction channels on a longer time scale. This failure is attributed to the self interaction error in the GGA functionals and it can be avoided by using hybrid functionals with large fraction of exact exchange (represented here by the BHandHLYP functional). The simulations of doubly ionized states are reasonably described already at the GGA level. This suggests that the RT-TDDFT/GGA method could describe processes following the autoionization processes such as Auger emission, while its applicability to more complex processes such as intermolecular Coulombic decay remains limited. PMID- 29513532 TI - CO2 Capture by Injection of Flue Gas or CO2-N2 Mixtures into Hydrate Reservoirs: Dependence of CO2 Capture Efficiency on Gas Hydrate Reservoir Conditions. AB - Injection of flue gas or CO2-N2 mixtures into gas hydrate reservoirs has been considered as a promising option for geological storage of CO2. However, the thermodynamic process in which the CO2 present in flue gas or a CO2-N2 mixture is captured as hydrate has not been well understood. In this work, a series of experiments were conducted to investigate the dependence of CO2 capture efficiency on reservoir conditions. The CO2 capture efficiency was investigated at different injection pressures from 2.6 to 23.8 MPa and hydrate reservoir temperatures from 273.2 to 283.2 K in the presence of two different saturations of methane hydrate. The results showed that more than 60% of the CO2 in the flue gas was captured and stored as CO2 hydrate or CO2-mixed hydrates, while methane rich gas was produced. The efficiency of CO2 capture depends on the reservoir conditions including temperature, pressure, and hydrate saturation. For a certain reservoir temperature, there is an optimum reservoir pressure at which the maximum amount of CO2 can be captured from the injected flue gas or CO2-N2 mixtures. This finding suggests that it is essential to control the injection pressure to enhance CO2 capture efficiency by flue gas or CO2-N2 mixtures injection. PMID- 29513534 TI - PAH/Aromatic Tar and Coke Precursor Formation in the Early Stages of Triglyceride (Triolein) Pyrolysis. AB - There has been a limited understanding of high MW polycyclic aromatic hydrocarbon (PAH) product chemistry in the pyrolysis of triglycerides (TGs), though the subject has important implications for both fuel production from TGs and food science. Previous TG pyrolysis studies have been able to identify only relatively low MW GC-elutable aromatics occurring in the bulk liquid phase; products occurring in the solid phase have remained inaccessible to chemical analysis. In contrast, cold gas expansion molecular beam methods, where pyrolysis products are analyzed in real time as they are entrained in gas expansions, remove product collection difficulties, thereby allowing for analysis of coke/tar PAH precursors. In this study, the model TG triolein was heated and the ensuing products in the molecular beam were soft photoionized, enabling time-of-flight mass detection. Use of 266 nm pulses enabled selective photoionization of aromatic products. Unlike previous work on analysis of the liquid phase TG cracking products, a different and distinct pattern of rather large PAHs, up to 444 amu, was observed, at nontrivial relative product fractions. With an increase of temperature to ~350 degrees C, a small number of PAHs with MW >= 276 amu increasingly dominated the aromatic product distribution. Surprisingly, PAH product detection ensued at rather low temperatures, as low as ~260 degrees C. For tentative PAH product identification and product chemistry rationalization, we observed the product homology pattern and applied a stoichiometric analysis. The latter, combined with the known homology profiles of TG cracking products, indicated specific patterns of intermediate fragment association that facilitated large-MW PAH formation as a result of TG cracking. PMID- 29513535 TI - Methanol-Assisted Phthalimide Ring Opening: Concerted or Stepwise Mechanism? AB - The opening of the five-membered ring is the essential step for phthalimide and its derivatives to be used as the reactants in many chemical synthetic routes. Reportedly, such ring opening follows the concerted mechanism in methanol solvent, which, however, has an unreasonably high energy barrier (36.3 kcal mol-1 at the M06-2X/6-311++G(d,p) level of theory). By density functional theory calculations, we report that this ring opening prefers the alternatively stepwise mechanism. The stepwise mechanism has a much lower energy barrier (21.0 kcal mol 1 at the same level of theory) and thus is much more completive than the concerted one. The stepwise mechanism should be considered as the dominant mechanism responsible for the phthalimide ring opening when studying the kinetics of the relevant synthetic reactions in the future. PMID- 29513533 TI - Structure-Property Relationships for Tailoring Phenoxazines as Reducing Photoredox Catalysts. AB - Through the study of structure-property relationships using a combination of experimental and computational analyses, a number of phenoxazine derivatives have been developed as visible light absorbing, organic photoredox catalysts (PCs) with excited state reduction potentials rivaling those of highly reducing transition metal PCs. Time-dependent density functional theory (TD-DFT) computational modeling of the photoexcitation of N-aryl and core modified phenoxazines guided the design of PCs with absorption profiles in the visible regime. In accordance with our previous work with N, N-diaryl dihydrophenazines, characterization of noncore modified N-aryl phenoxazines in the excited state demonstrated that the nature of the N-aryl substituent dictates the ability of the PC to access a charge transfer excited state. However, our current analysis of core modified phenoxazines revealed that these molecules can access a different type of CT excited state which we posit involves a core substituent as the electron acceptor. Modification of the core of phenoxazine derivatives with electron-donating and electron-withdrawing substituents was used to alter triplet energies, excited state reduction potentials, and oxidation potentials of the phenoxazine derivatives. The catalytic activity of these molecules was explored using organocatalyzed atom transfer radical polymerization (O-ATRP) for the synthesis of poly(methyl methacrylate) (PMMA) using white light irradiation. All of the derivatives were determined to be suitable PCs for O-ATRP as indicated by a linear growth of polymer molecular weight as a function of monomer conversion and the ability to synthesize PMMA with moderate to low dispersity (dispersity less than or equal to 1.5) and initiator efficiencies typically greater than 70% at high conversions. However, only PCs that exhibit strong absorption of visible light and strong triplet excited state reduction potentials maintain control over the polymerization during the entire course of the reaction. The structure property relationships established here will enable the application of these organic PCs for O-ATRP and other photoredox-catalyzed small molecule and polymer syntheses. PMID- 29513536 TI - Quantum-Chemical Approach to NMR Chemical Shifts in Paramagnetic Solids Applied to LiFePO4 and LiCoPO4. AB - A novel protocol to compute and analyze NMR chemical shifts for extended paramagnetic solids, accounting comprehensively for Fermi-contact (FC), pseudocontact (PC), and orbital shifts, is reported and applied to the important lithium ion battery cathode materials LiFePO4 and LiCoPO4. Using an EPR-parameter based ansatz, the approach combines periodic (hybrid) DFT computation of hyperfine and orbital-shielding tensors with an incremental cluster model for g- and zero-field-splitting (ZFS) D-tensors. The cluster model allows the use of advanced multireference wave function methods (such as CASSCF or NEVPT2). Application of this protocol shows that the 7Li shifts in the high-voltage cathode material LiCoPO4 are dominated by spin-orbit-induced PC contributions, in contrast with previous assumptions, fundamentally changing interpretations of the shifts in terms of covalency. PC contributions are smaller for the 7Li shifts of the related LiFePO4, where FC and orbital shifts dominate. The 31P shifts of both materials finally are almost pure FC shifts. Nevertheless, large ZFS contributions can give rise to non-Curie temperature dependences for both 7Li and 31P shifts. PMID- 29513537 TI - Fluid Flow and Thin-Film Evolution near the Triple Line during Droplet Evaporation of Self-Rewetting Fluids. AB - The microscopic region near the triple line plays an important role in the heat and mass transfer of droplets, although the mechanisms of evaporation and internal flow remain unclear. This paper describes an experimental study of fluid flow and thin-film evolution near the triple line in sessile droplets of self rewetting fluids, aqueous solutions of alcohols with the number of carbon atoms varying from 1 to 7, to analyze the influence of various factors on the mesoscale flows. The mechanism of internal flow for self-rewetting fluid droplets was different from that of conventional fluids, and hence, a novel expression of the in-plane average velocity was fitted for them. The temporal and spatial evolution of the thin-film thickness near the triple line during droplet evaporation was obtained by using a proposed subregion method, which was developed from an evanescent-wave-based multilayer nanoparticle image velocimetry technique. The self-rewetting fluids are conducive to increase the microscopic critical contact angle and the energy barrier of the contact line, which reduces the rate of thin film thickness variation. The inhibited impact of self-rewetting fluids on evaporation increases gradually with an increasing number of carbon atoms. PMID- 29513538 TI - Influence of Polymer and Drug Loading on the Release Profile and Membrane Transport of Telaprevir. AB - During the dissolution of amorphous solid dispersions (ASDs), various phase transformations can occur, which will ultimately impact the degree of supersaturation. This study employed dissolution and diffusion measurements to compare the performance of various ASD formulations based on the maximum amount of free drug in the solution that was able to permeate through a cellulose-based membrane. Telaprevir (TPV) was used as the model drug compound, and ASDs were prepared with different drug loadings and with four different polymers. Four possible scenarios that can influence TPV mass flow rates upon ASD dissolution were described and supported with experimental data: (1) a system dissolves readily and completely undergoes phase separation via glass-liquid phase separation (GLPS), forming drug-rich aggregates, and reaches the maximum anticipated mass flow rate; (2) where the maximum mass flow rate decreases due to substantial mixing of the polymer into the drug-rich phase, and/or due to the formation of soluble polymer-drug complexes; (3) a system does not undergo GLPS due to slow drug release and/or matrix crystallization; and (4) a system does not undergo GLPS due to rapid crystallization from the supersaturated solution generated during dissolution. The results described herein support the importance of the combined use of the dissolution-diffusion measurements to determine the maximum level of supersaturation achievable for diverse drug formulations. PMID- 29513539 TI - Correction to Asymmetric Construction of Fluoroalkyl Tertiary Alcohols through a Three-Component Reaction of (Bpin)2, 1,3-Enynes, and Fluoroalkyl Ketones Catalyzed by a Copper(I) Complex. PMID- 29513540 TI - A Copper-Catalyzed Reductive Defluorination of beta-Trifluoromethylated Enones via Oxidative Homocoupling of Grignard Reagents. AB - An efficient copper-catalyzed reductive defluorination of beta trifluoromethylated enones via an oxidative homocoupling of Grignard reagents is reported. The reaction proceeded smoothly with a wide range of substrates, including the ones bearing aromatic heterocycles, such as furyl and thienyl ring systems in high yields (80-92%, except one example) under mild conditions. This provides a practical method for synthesis of gem-difluoroolefin ketones. It is also worth noting that this homocoupling process of Grignard reagents using beta trifluoromethylated enones as "oxidizing reagents" is effective for both the Csp2 Csp2 and Csp3-Csp3 bond formations, including for substrates whose beta-hydride elimination of the corresponding transition metal alkyl complex is particularly facile, affording coupling products with high yields (83-95%), simultaneously. PMID- 29513541 TI - DNA-Templated N(Me)-Alkoxyamine Glycosylation. AB - The potential of N(Me)-alkoxyamine glycosylation as a DNA-templated ligation has been studied. On a hairpin stem-template model, a notable rate enhancement and an increased equilibrium yield are observed compared to the corresponding reaction without a DNA catalyst. The N-glycosidic connection is dynamic at pH 5, whereas it becomes irreversible at pH 7. The N(Me)-alkoxyamine glycosylation may hence be an attractive pH controlled reaction for the assembly of DNA-based dynamic products. PMID- 29513542 TI - Metabolic Engineering-Based Rapid Characterization of a Sesquiterpene Cyclase and the Skeletons of Fusariumdiene and Fusagramineol from Fusarium graminearum. AB - The potential power of sesquiterpene synthase FgJ03939 from Fusarium graminearum was fully exploited in a farnesyl diphosphate-overexpressing Saccharomyces cerevisiae chassis to produce the novel sesquiterpenes fusariumdiene (1), epi fusagramineol (2), and fusagramineol (3) with 5/7 bicyclic and 5/6/3 tricyclic ring systems, respectively, as well as five known sesquiterpenes (4-8). The structure of the unusual skeletons was characterized, and an absolute configuration was proposed. A mechanism for the biosynthesis of 1-8 was also proposed. PMID- 29513543 TI - Revisiting the Critical Condition for the Cassie-Wenzel Transition on Micropillar Structured Surfaces. AB - Biological and engineering applications of superhydrophobic surfaces are limited by the stability of the wetting state determined by the transition from the Cassie-Baxter state to the Wenzel state (C-W transition). In this paper, we performed water droplet squeeze tests to investigate the critical conditions for the C-W transition for solid surfaces with periodic micropillar arrays. The experimental results indicate that the critical transition pressures for the samples with varying micropillar dimensions are all significantly higher than the theoretical predictions. Through independent measurements, we attributed the disparity to the incorrect assessment of the contact angle on the sidewall surfaces of the micropillars. We also showed that the theoretical models are still applicable when the correct contact angle of the sidewall surfaces is adopted. Our work directly validates and improves the theoretical models regarding the C-W transition and suggests a potential route of tuning superhydrophobicity using finer scale surface features. PMID- 29513544 TI - Magnesium Bisamide-Mediated Halogen Dance of Bromothiophenes. AB - A magnesium bisamide-mediated halogen dance of bromothiophenes is described. The thienylmagnesium species generated in situ is more stable than the corresponding thienyllithium species, which was applied to trap the transient anion species with several electrophiles, such as allyl iodide, phenyl isocyanate, and tributylstannyl chloride. The utility of the magnesium bisamide-mediated halogen dance is useful in the concise synthesis of a medicinally advantageous compound via a one-pot, ester-directed halogen dance/Negishi cross coupling. PMID- 29513545 TI - Split-Channel Ballistic Transport in an InSb Nanowire. AB - We report an experimental study of one-dimensional (1D) electronic transport in an InSb semiconducting nanowire. A total of three bottom gates are used to locally deplete the nanowire, creating a ballistic quantum point contact with only a few conducting channels. In a magnetic field, the Zeeman splitting of the corresponding 1D sub-bands is revealed by the emergence of conductance plateaus at multiples of e2/h, yet we find a quantized conductance pattern largely dependent on the configuration of voltages applied to the bottom gates. In particular, we can make the first plateau disappear, leaving a first conductance step of 2 e2/ h, which is indicative of a remarkable 2-fold sub-band degeneracy that can persist up to several tesla. For certain gate voltage settings, we also observe the presence of discrete resonant states producing conductance features that can resemble those expected from the opening of a helical gap in the sub band structure. We explain our experimental findings through the formation of two spatially separated 1D conduction channels. PMID- 29513546 TI - Some Methods for Calculating Competition Coefficients from Resource-Utilization Spectra. AB - When relative frequencies of resource kinds in the diet are known, the competition coefficient giving the effect of competitor j on i may be computed as ?documentclass{aastex} ?usepackage{amsbsy} ?usepackage{amsfonts} ?usepackage{amssymb} ?usepackage{bm} ?usepackage{mathrsfs} ?usepackage{pifont} ?usepackage{stmaryrd} ?usepackage{textcomp} ?usepackage{portland,xspace} ?usepackage{amsmath,amsxtra} ?usepackage{wasysym} ?pagestyle{empty} ?DeclareMathSizes{10}{9}{7}{6} ?begin{document}$$?alpha_{ij}=?left(?frac{T_{j}}{T_{i}}?right)?left[?frac{{?sum?l mits_{k=1}^{m}}(d_{ik}/f_{k})?:(d_{jk}/f_{k})?:b_{ik}}{?sum?limits_{k=1}^{m}(d_{i }/f_{k})^{2}?:b_{ik}}?right],$$?end{document} where Tj/Ti= the ratio of the number of items consumed by an individual of competitor j to that consumed by an individual of competitor i, measured over an interval of time that includes all regular fluctuations in consumption for both species; dik = the frequency of resource k in the diet of competitor i (and similarly for djk); fk = the standing frequency of resource k in the environment; bik = the net calories gained by an individual of competitor i from an item of resource k, or more approximately the calories contained in an item of resource k, or still more approximately the weight or volume of an item of resource k; and the summations are taken over all resources eaten by at least one of the competing species. The coefficient follows from MacArthur's (1968) consumer-resource system when the ratio of the carrying capacity to intrinsic rate of increase is constant for all resources. When relative frequencies of time spent foraging in habitat kinds are known, the competition coefficient may be computed as ?documentclass{aastex} ?usepackage{amsbsy} ?usepackage{amsfonts} ?usepackage{amssymb} ?usepackage{bm} ?usepackage{mathrsfs} ?usepackage{pifont} ?usepackage{stmaryrd} ?usepackage{textcomp} ?usepackage{portland,xspace} ?usepackage{amsmath,amsxtra} ?usepackage{wasysym} ?pagestyle{empty} ?DeclareMathSizes{10}{9}{7}{6} ?begin{document}$$?alpha_{ij}=?left(?frac{T_{j}}{T_{i}}?right)^{?prime} ?frac{?sum?limits^{m}_{k=1}p_{ik}p_{jk}b_{ik}}{?sum?limits^{m}_{k=1}p_{ik}{}^2b_{ k}}$$?end{document} where (Tj/Ti)' = the ratio of the total time spent searching for food by an individual of competitor j in all habitats to that spent by an individual of competitor i; bik = as above, except resource k is the average food item in habitat k; and summations are taken as before. This coefficient, with the same resource restrictions and assuming equal consumption rates per unit search time for the competitor species, follows also from MacArthur's system. It equals the Levins-MacArthur alpha (eq. [3]) when it is assumed or known that (Tj/Ti)' = 1 and the b 's are equal. PMID- 29513547 TI - Medial Elbow Joint Space Increases With Valgus Stress and Decreases When Cued to Perform A Maximal Grip Contraction. AB - BACKGROUND: Previous research indicates that the amount of valgus torque placed on the elbow joint during overhead throwing is higher than the medial ulnar collateral ligament (UCL) can tolerate. Wrist and finger flexor muscle activity is hypothesized to make up for this difference, and in vitro studies that simulated activity of upper extremity musculature, specifically the flexor digitorum superficialis and flexor carpi ulnaris, support this hypothesis. PURPOSE: To assess the medial elbow joint space at rest, under valgus stress, and under valgus stress with finger and forearm flexor contraction by use of ultrasonography in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: Participants were 22 healthy males with no history of elbow dislocation or UCL injury (age, 21.25 +/- 1.58 years; height, 1.80 +/- 0.08 m; weight, 79.43 +/- 18.50 kg). Medial elbow joint space was measured by use of ultrasonography during 3 separate conditions: at rest (unloaded), under valgus load (loaded), and with a maximal grip contraction under a valgus load (loaded-contracted) in both limbs. Participants lay supine with their arm abducted 90 degrees and elbow flexed 30 degrees with the forearm in full supination. A handgrip dynamometer was placed in the participants' hand to grip against during the contracted condition. Images were reduced in ImageJ to assess medial elbow joint space. A 2-way (condition * limb) repeated-measures analysis of variance and Cohen's d effect sizes were used to assess changes in medial elbow joint space. Post hoc testing was performed with a Bonferroni adjustment to assess changes within limb and condition. RESULTS: The medial elbow joint space was significantly larger in the loaded condition (4.91 +/- 1.16 mm) compared with the unloaded condition (4.26 +/- 1.23 mm, P < .001, d = 0.712) and the loaded-contracted condition (3.88 +/- 0.94 mm, P < .001, d = 1.149). No significant change was found between the unloaded and loaded-contracted conditions ( P = .137). CONCLUSION: Medial elbow joint space increases under a valgus load and then decreases when a maximal grip contraction is performed. This indicates that wrist and finger flexor muscle contraction may assist in limiting medial elbow joint space, a result similar to findings of previous research in vitro. CLINICAL RELEVANCE: Muscle activation of the upper extremity limits the medial elbow joint space, suggesting that injury prevention programs for throwing athletes should incorporate exercises for the elbow, wrist, and hand to limit excessive medial elbow joint space gapping during activities that create high valgus load. PMID- 29513548 TI - The Rate of Change of a Character Correlated with Fitness. AB - An extended form of Fisher's Fundamental Theorem of Natural Selection gives the rate of change of the mean value, [Formula: see text], of a measured character. For a character determined by multiple alleles at two loci, this is [Formula: see text] where the Newtonian superior dot means the time derivative and the circle is the time derivative of the logarithm. Covg (m, gamma) is the genic (additive genetic) covariance of the character and fitness. Specifically, it is the covariance of the average excess of an allele for fitness and its average effect on the character. [Formula: see text] is the average rate of change of the value of the character for individual genotypes, weighted by their frequencies. The value could be nonzero because of changing environments or change in the age distribution of the population. The third term on the right is the average over all pairs of alleles at both loci of the product of the dominance deviation and the rate of change of ln theta(n), where theta(n) is a measure of departure from random proportions. The last term is a similar expression for epistatic interactions. If selection is much weaker than recombination, after several generations, the last two terms are much smaller than the first. When the measured character is fitness, our result reduces to Kimura's generalization of Fisher's Fundamental Theorem of Natural Selection. PMID- 29513549 TI - Reliability and Normative Reference Values for the Vestibular/Ocular Motor Screening (VOMS) Tool in Youth Athletes. AB - BACKGROUND: The Vestibular/Ocular Motor Screening (VOMS) measure is a newly developed vestibular and ocular motor symptom provocation screening tool for sport-related concussions. Baseline data, psychometric properties, and reliability of the VOMS are needed to further understand the applications of this tool, especially in the youth population, where research is scarce. PURPOSE: To establish normative data and document the internal consistency and false-positive rate of the VOMS in a sample of nonconcussed youth athletes. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: A total of 423 youth athletes (male = 278, female = 145) between the ages of 8 and 14 years completed baseline VOMS screening before the start of their respective sport seasons. Internal consistency was measured with Cronbach alpha and inter-item correlations. RESULTS: Approximately 60% of youth athletes reported no symptom provocation on baseline VOMS assessment, with 9% to 13% scoring over the cutoff levels (score of >=2 for any individual VOMS symptom, near point convergence distance of >=5 cm). The VOMS displayed a high internal consistency (Cronbach alpha = .97) at baseline among youth athletes. CONCLUSION: The current findings provide preliminary support for the implementation of VOMS baseline assessment into clinical practice, due to a high internal consistency, strong relationships between VOMS items, and a low false-positive rate at baseline in youth athletes. PMID- 29513550 TI - Gene Frequency Clines in the Presence of Selection Opposed by Gene Flow. AB - Suppose we have a cline in gene frequency which results from spatially varying selection forces (which tend to establish the cline) opposed by gene flow (which tends to blur the cline). The characteristic width, W, of this gene frequency cline can be assessed qualitatively in terms of the parameters characterizing the selection and gene flow processes. We define Delta as the transition distance in the selection gradient, s as the maximum selection intensity (see fig. 1), l as the root-mean-square gene flow distance (see eq. [3]), and lc = l/ $$?sqrt s$$ (see eq. [5]): then for Delta < lc we have W ~ lc, and consequently W > Delta (as discussed fully by Slatkin 1973); conversely for Delta > lc we have W ~ (lc2 Delta)1/3, and consequently lc < W < Delta. The former circumstance may be thought of as relatively strong gene flow and a relatively blurred cline (W > Delta); the latter circumstance as relatively weak gene flow and a relatively sharp cline (W < Delta). The above qualitative results pertain to all situations where the fitness of the heterozygotes, Aa, is intermediate between (or, in the event of a dominant allele A or a, coincident with one of) the homozygotes AA and aa. In particular, the detailed results of table 1 apply if the heterozygotes are of precisely intermediate fitness and table 2 applies if there is dominance, so that the heterozygote fitness coincides with one of the homozygotes. More generally, if the heterozygotes are at a strong disadvantage, measured by the selection parameter h of equation (15), the gene frequency cline is steepened and has typical width W ~ l/ $$?sqrt{-h}$$ . Conversely, strong heterozygous advantage leads to a very smooth cline and eventually to essentially equal frequencies of A and a at all points. The presence of asymmetry in the gene flow, as may easily arise from a prevailing wind or other environmental effect, can substantially modify the slope and position of a gene frequency cline. This can happen even when the characteristic scale length of the asymmetry (see eq. [22]) is relatively small. These results unify a large number of numerical simulations of such situations, some of which have been done for a stepped environmental gradient (effectively Delta < lc) and others for a continuous selection gradient (effectively Delta > lc). Some studies on real clines produced by the tension between selection and gene flow contain enough data to permit rough comparison with theory. The agreement between nature and qualitative theory is surprisingly good in several cases (see table 3). Field data of this sort are rare, as quantitative information about gene flow and about selective forces is difficult to get. The main aim of this paper is to present an orderly framework within which to assemble such data. PMID- 29513551 TI - The Community Matrix and the Number of Species in a Community. AB - In this paper I am concerned with the number of species that will be held in stable equilibrium in a community of competing organisms, using the general form of the Lotka-Volterra competition equations for m species. Defining Ki as the saturation density for the ith species and alphaij as the competition coefficient between species i and j, and Ni as the equilibrium density of species i, the number of species will be determined by N, K, $$?overline{?alpha}$$ , var (K), the covariances among the alpha's, and the covariance between alpha and N. In particular, the number of species increases as K increases but as N, $$?overline{?alpha}$$ , cov (alpha), cov (alpha,N) and variance of K decrease. PMID- 29513552 TI - A Model of Mating Behavior in Flies. AB - A model of mating behavior is developed to characterize geographic variation in flies. Normally distributed sexual vigor parameters [Formula: see text] and [Formula: see text] are defined for males and females, respectively. When there is no sexual isolation present, the success and duration of a courtship is determined by the linear difference between the vigors of courting pairs. Sexual isolation is represented as an angle (theta) separating the vigor vectors of courting pairs, and the effectiveness of the male vigor assumes its projection onto the female vector ([Formula: see text]), where cos theta is the correlation between the courtship patterns of the two populations. The corroboration of the basic tenets of mating success implicit in our formulation agrees remarkably well with extant data in percentage of copulations in single pairs, distribution of mating times, the balance between sexes, and the correspondence of the isolation parameter to quantitative differences in courtship patterns among competing genotypes. Sexual vigor, variability in vigor within populations, assortative mating, and duration of copulation interact in a complex manner to determine mating success in competitive circumstances. The model has considerable heuristic value in conceptually separating the oftenconfounded effects of sexual isolation and sexual selection (vigor) and allowing their separate estimation from observed matings within and among competing strains. PMID- 29513553 TI - Anterior Cruciate Ligament Transection-Induced Cellular and Extracellular Events in Menisci: Implications for Osteoarthritis. AB - BACKGROUND: The meniscus plays an important role in knee joint diseases such as osteoarthritis (OA). Meniscal injuries can be accompanied by joint catabolic events initiated by inflammation, leading to articular cartilage destruction, but the cellular events responsible for intrinsic meniscal injury and the extracellular matrix changes necessary for meniscal degradation are not well known. PURPOSE: To explore the cellular and matrix-related changes of menisci based on a mouse OA model of anterior cruciate ligament transection (ACLT). STUDY DESIGN: Controlled laboratory study. METHODS: A mouse ACLT OA model was established by transection of anterior cruciate ligaments on the right knee joints of 8-week-old male (n = 34) and female (n = 34) C57 mice. The knee joints were collected at 1, 2, 4, and 8 weeks after ACLT surgery, and the meniscal changes were analyzed by radiography, histology, immunohistochemistry, immunoblot, and quantitative real-time polymerase chain reaction. RESULTS: The deterioration of menisci was more extensive than that of articular cartilage and subchondral bone at 4 weeks after ACLT surgery. The rapid loss of collagen II and Sox9 in chondrocyte-like cells in the white-white zone of menisci was confirmed, and the activation of potential meniscus progenitor cells and chondroblasts was identified based on the increase of CD90, CD105, and Runx2. Further, the intrinsic inflammation in the bone marrow-like zone of menisci was activated by enhancement of dendritic cells (CD11c+), T cells (CD3+), and macrophages (F4/80+) with the increase of the inflammatory factors interleukin 1beta and tumor necrosis factor alpha. Finally, the extracellular matrix events involving changes in chemokines, increases of matrix proteases (matrix metalloproteinases and ADAMTS5), and decreases of lysyl oxidase family were elucidated. CONCLUSION: ACLT induced meniscal changes not only could explain the contribution of the meniscus to the progress of OA but also could provide a cue for initiation of preventive treatments in the early stages of OA. CLINICAL RELEVANCE: This study provides support for better protection of menisci in ACL injury-induced conditions such as OA and indicates that menisci should be considered in the development of clinical pharmacological interventions. PMID- 29513554 TI - The Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS): Normative Data. AB - BACKGROUND: Recent data have shown an increase in youth sports participation at younger ages, which may be linked to greater musculoskeletal injury risk. The Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi FABS) is a validated 8-item instrument designed to quantify the activity of children between 10 and 18 years old. Normative data on pediatric and adolescent activity level are unknown. PURPOSE: To establish normative activity-level data for American youth and to determine if there is a natural decrease in activity level during adolescence. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A cross-sectional investigation was performed among 2002 US children and adolescents equally split by sex and age and representing census-weighted distributions of state of residency, race/ethnicity, and health insurance status. Respondents completed the HSS Pedi-FABS, as well as survey questions on demographics and sports participation. Normative data were reported with descriptive statistics. Linear regression analysis was performed to determine if there was an effect of age on activity level during adolescence. RESULTS: A total of 2002 respondents completed the survey; the mean age of the respondents at the time of survey completion was 14.0 +/- 2.6 years. Mean weekly amount of reported physical activity was 9.3 +/- 8.4 hours. HSS Pedi-FABS scores were normally distributed with a mean of 15.4 +/- 8.5 points (out of 30 possible points). There was a modest but statistically significant decrease in HSS Pedi-FABS activity scores with increasing age ( r = -0.175, P < .001), corresponding to a linear decrease in activity scores by 27% on average from age 10 to 18 years. CONCLUSION: The current study provides baseline normative data for activity level in a census-weighted representative population sample of 2002 American youth through the use of a validated activity score (HSS Pedi-FABS). There was a modest but statistically significant decrease in activity scores with increasing age. These results will aid future research by providing normative, representative population-level activity data and will help to quantify the natural rate of decreased activity during adolescence. PMID- 29513555 TI - Social Selection in Human Populations: Fitness Interaction Among Sibs. AB - A social selection model with one locus and two alleles has been constructed by considering the fitness interaction among sibs. It is shown that the equilibrium gene frequency depends on the magnitude of viability reduction (gamma) and fertility reduction (alpha), the additional fitness reduction resulting from an affected sib (beta), the probability that the heterozygote develops the trait (h), and the potential number of sibs (n). With mutational input from the wild type allele to the deleterious gene at a rate of u per generation, the equilibrium frequency of deleterious genes is given approximately by u/hs for 0 < h < 1 and $$?sqrt{u/s}$$ for h = 0, where s = alpha + gamma + beta(n - 1)(1 - gamma)/2. Thus, the frequency of genetic diseases in a population depends not only on the intrinsic deleterious effect of disease but also on sociocultural reactions to the trait. PMID- 29513556 TI - Minimal Community Structure: An Explanation of Species Abundance Patterns. AB - Recent proposals that the canonical lognormal distribution and the resulting species-area constant, $$z ?simeq 1/4$$ , are artifacts of the general lognormal curve and regression techniques, are shown to be inadequate. An alternative hypothesis is suggested which accounts for these regularities in terms of a hierarchical community structure represented by a sequentially divided niche space. This hierarchical pattern, which can be considered to be a minimal form of community structure, derives from evolutionary and ecological considerations for generating species diversity, and is shown to account for the observed abundance structures of small ensembles as well as large natural communities. Evidence is presented which implies that niche apportionment between species may involve the random division of more than one resource, and an interesting invariance in the pattern of apportionment is observed for assemblages with three species. The possibility that the canonical lognormal distribution is a conceptual artifact resulting from arbitrary systems of classification is considered and shown to be false. Aside from its intuitive appeal, the model presented should be of interest because it offers explanations of two ubiquitous patterns in nature: the canonical lognormal and the resulting species-area constant. PMID- 29513557 TI - Advances in techniques for reducing cholesterol in egg yolk: A review. AB - ABSTRACTS Eggs are highly nutritious food whose high cholesterol content has been always an inconvenience due to concerns about the relationship between dietary cholesterol and atherosclerotic cardiovascular risk. As this remains uncertain, low cholesterol intake is recommended. This review deals with the techniques employed to reduce the cholesterol content in egg yolk once the egg is shelled. There are four main techniques: i) solvent extraction, ii) fractionation by centrifugation, iii) cholesterol chelates or adsorbents and iv) cholesterol biotransformation. Analyse of techniques, descriptions and recent advances are included in this review. Solvent extraction and cholesterol biotransformation allow to reduce up to 94.7% and 93.4%, respectively. However, both methods have not been scaled up due to food safety and economic reasons. Nowadays, fractionation by centrifugation and cholesterol chelates are the only feasible methods with industrial applications, obtaining up to 82% and 99%, respectively. Fractionation method can be considered the best because no substances are added. PMID- 29513558 TI - Recent developments in intelligent packaging for enhancing food quality and safety. AB - The role of packaging cannot be denied in the life cycle of any food product. Intelligent packaging is an emerging technology in the food packaging sector. Although it still needs its full emergence in the market, its importance has been proved for the maintenance of food quality and safety. The present review describes several aspects of intelligent packaging. It first highlights different tools used in intelligent packaging and elucidates the role of these packaging devices for maintaining the quality of different food items in terms of controlling microbial growth and gas concentration, and for providing convenience and easiness to its users in the form of time temperature indication. This review also discusses other intelligent packaging solutions in supply chain management of food products to control theft and counterfeiting conducts and broaden the image of the food companies in terms of branding and marketing. Overall, intelligent packaging can ensure food quality and safety in the food industry, however there are still some concerns over this emerging technology including high cost and legal aspects, and thus future work should be performed to overcome these problems for further promoting its applications in the food industry. Moreover, work should also be carried out to combine several single intelligent packaging devices into a single one, so that most of the benefits from this emerging technology can be achieved. PMID- 29513559 TI - Protection of Recessive and Dominant Traits in a Subdivided Population with General Migration Structure. AB - The problem of migration-selection interaction in a subdivided population affecting a recessive allele is studied. Explicit conditions for protection of a recessive allele are determined, accessible for any migration structure. More specifically, consider allele a recessive to allele A distributed over N demes endowed with fitness parameters wi, 1, 1 for genotypes aa, Aa, and AA operating in deme i, respectively. For an arbitrary migration structure between demes summarized by the backward migration matrix, M = |mij|Ni,j=1 (mij = the proportion per generation of the population in deme i whose parents came from deme j), let $$?underline{?xi}$$ = (xi1,..., xiN) be the unique left eigenvector of M corresponding to eigenvalue 1, whose sum is normalized to unity. The exact necessary and sufficient condition for protection of the recessive allele, a, is that the "weighted average" of the aa-genotype fitness values, namely ?Ni=1 xiiwi, exceed unity. The result applies whether soft or hard selection is assumed. It is further established that, with a dominant or recessive trait, fixation of alleles a and A cannot coexist as stable alternatives. Interpretations and further applications of the conditions are given for some special migration patterns, including the stepping-stone migration mode and the generalized Island model gene flow. PMID- 29513560 TI - Roles of IL-1alpha/beta in regeneration of cardiotoxin-injured muscle and satellite cell function. AB - Skeletal muscle regeneration after injury is a complex process involving interactions between inflammatory microenvironments and satellite cells. Interleukin (IL)-1 is a key mediator of inflammatory responses and exerts pleiotropic impacts on various cell types. Thus, we aimed to investigate the role of IL-1 during skeletal muscle regeneration. We herein show that IL-1alpha/beta double knockout (IL-1KO) mice exhibit delayed muscle regeneration after cardiotoxin (CTX) injection, characterized by delayed infiltrations of immune cells accompanied by suppressed local production of proinflammatory factors including IL-6 and delayed increase of paired box 7 (PAX7)-positive satellite cells postinjury compared with those of wild-type (WT) mice. A series of in vitro experiments using satellite cells obtained from the IL-1KO mice unexpectedly revealed that IL-1KO myoblasts have impairments in terms of both proliferation and differentiation, both of which were reversed by exogenous IL-1beta administration in culture. Intriguingly, the delay in myogenesis was not attributable to the myogenic transcriptional program since MyoD and myogenin were highly upregulated in IL-1KO cells, instead appearing, at least in part, to be due to dysregulation of cellular fusion events, possibly resulting from aberrant actin regulatory systems. We conclude that IL-1 plays a positive role in muscle regeneration by coordinating the initial interactions among inflammatory microenvironments and satellite cells. Our findings also provide compelling evidence that IL-1 is intimately engaged in regulating the fundamental function of myocytes. PMID- 29513561 TI - Targeted afferent renal denervation reduces arterial pressure but not renal inflammation in established DOCA-salt hypertension in the rat. AB - Recent preclinical studies show renal denervation (RDNx) may be an effective treatment for hypertension; however, the mechanism remains unknown. We have recently reported total RDNx (TRDNx) and afferent-selective RDNx (ARDNx) similarly attenuated the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Whereas TRDNx abolished renal inflammation, ARDNx had a minimal effect despite an identical antihypertensive effect. Although this study established that ARDNx attenuates the development of DOCA-salt hypertension, it is unknown whether this mechanism remains operative once hypertension is established. The current study tested the hypothesis that TRDNx and ARDNx would similarly decrease mean arterial pressure (MAP) in the DOCA-salt hypertensive rat, and only TRDNx would mitigate renal inflammation. After 21 days of DOCA-salt treatment, male Sprague-Dawley rats underwent TRDNx ( n = 16), ARDNx ( n = 16), or Sham ( n = 14) treatment and were monitored for 14 days. Compared with baseline, TRDNx and ARDNx decreased MAP similarly (TRDNx -14 +/- 4 and ARDNx -15 +/- 6 mmHg). After analysis of diurnal rhythm, rhythm-adjusted mean and amplitude of night/day cycle were also reduced in TRDNx and ARDNx groups compared with Sham. Notably, no change in renal inflammation, injury, or function was detected with either treatment. We conclude from these findings that: 1) RDNx mitigates established DOCA-salt hypertension; 2) the MAP responses to RDNx are primarily mediated by ablation of afferent renal nerves; and 3) renal nerves do not contribute to the maintenance of renal inflammation in DOCA-salt hypertension. PMID- 29513563 TI - Chronic hypertension in pregnancy: impact of ethnicity and superimposed preeclampsia on placental, endothelial, and renal biomarkers. AB - Black ethnicity is associated with worse pregnancy outcomes in women with chronic hypertension. Preexisting endothelial and renal dysfunction and poor placentation may contribute, but pathophysiological mechanisms underpinning increased risk are poorly understood. This cohort study aimed to investigate the relationship between ethnicity, superimposed preeclampsia, and longitudinal changes in markers of endothelial, renal, and placental dysfunction in women with chronic hypertension. Plasma concentrations of placental growth factor (PlGF), syndecan 1, renin, and aldosterone and urinary angiotensinogen-to-creatinine ratio (AGTCR), protein-to-creatinine ratio (PCR), and albumin-to-creatinine ratio (ACR) were quantified during pregnancy and postpartum in women with chronic hypertension. Comparisons of longitudinal biomarker concentrations were made using log-transformation and random effects logistic regression allowing for gestation. Of 117 women, superimposed preeclampsia was diagnosed in 21% ( n = 25), with 24% ( n = 6) having an additional diagnosis of diabetes. The cohort included 63 (54%) women who self-identified as being of black ethnicity. PlGF concentrations were 67% lower [95% confidence interval (CI) -79 to -48%] and AGTCR, PCR, and ACR were higher over gestation, in women with subsequent superimposed preeclampsia (compared with those without superimposed preeclampsia). PlGF <100 pg/ml at 20-23.9 wk of gestation predicted subsequent birth weight <3rd percentile with 88% sensitivity (95% CI 47-100%) and 83% specificity (95% CI 70-92%). Black women had 43% lower renin (95% CI -58 to -23%) and 41% lower aldosterone (95%CI -45 to -15%) concentrations over gestation. Changes in placental (PlGF) and renal (AGTCR/PCR/ACR) biomarkers predated adverse pregnancy outcome. Ethnic variation in the renin-angiotensin-aldosterone system exists in women with chronic hypertension in pregnancy and may be important in treatment selection. PMID- 29513562 TI - Long-term hypoxia uncouples Ca2+ and eNOS in bradykinin-mediated pulmonary arterial relaxation. AB - Bradykinin-induced activation of the pulmonary endothelium triggers a rise in intracellular Ca2+ that activates nitric oxide (NO)-dependent vasorelaxation. Chronic hypoxia is commonly associated with increased pulmonary vascular tone, which can cause pulmonary hypertension in responsive individuals. In the present study, we tested the hypothesis that long-term high-altitude hypoxia (LTH) diminishes bradykinin-induced Ca2+ signals and inhibits endothelial nitric oxide synthase (eNOS), prostacyclin (PGI2), and large-conductance K+ (BKCa) channels in sheep, which are moderately responsive to LTH, resulting in decreased pulmonary arterial vasorelaxation. Pulmonary arteries were isolated from ewes kept near sea level (720 m) or at high altitude (3,801 m) for >100 days. Vessel force was measured with wire myography and endothelial intracellular Ca2+ with confocal microscopy. eNOS was inhibited with 100 MUM NG-nitro-l-arginine methyl ester (l NAME), PGI2 production was inhibited with 10 uM indomethacin that inhibits cyclooxygenase, and BKCa channels were blocked with 1 mM tetraethylammonium. Bradykinin-induced endothelial Ca2+ signals increased following LTH, but bradykinin relaxation decreased. Furthermore, some vessels contracted in response to bradykinin after LTH. l-NAME sensitivity decreased, suggesting that eNOS dysfunction played a role in uncoupling Ca2+ signals and bradykinin relaxation. The Ca2+ ionophore A-23187 (10 uM) elicited an enhanced Ca2+ response following LTH while relaxation was unchanged although l-NAME sensitivity increased. Additionally, BKCa function decreased during bradykinin relaxation following LTH. Western analysis showed that BKCa alpha-subunit expression was increased by LTH while that for the beta1 subunit was unchanged. Overall, these results suggest that those even moderately responsive to LTH can have impaired endothelial function. PMID- 29513565 TI - Sodium nitrate supplementation alters mitochondrial H2O2 emission but does not improve mitochondrial oxidative metabolism in the heart of healthy rats. AB - Supplementation with dietary inorganic nitrate ([Formula: see text]) is increasingly recognized to confer cardioprotective effects in both healthy and clinical populations. While the mechanism(s) remains ambiguous, in skeletal muscle oral consumption of NaNO3 has been shown to improve mitochondrial efficiency. Whether NaNO3 has similar effects on mitochondria within the heart is unknown. Therefore, we comprehensively investigated the effect of NaNO3 supplementation on in vivo left ventricular (LV) function and mitochondrial bioenergetics. Healthy male Sprague-Dawley rats were supplemented with NaNO3 (1 g/l) in their drinking water for 7 days. Echocardiography and invasive hemodynamics were used to assess LV morphology and function. Blood pressure (BP) was measured by tail-cuff and invasive hemodynamics. Mitochondrial bioenergetics were measured in LV isolated mitochondria and permeabilized muscle fibers by high resolution respirometry and fluorometry. Nitrate decreased ( P < 0.05) BP, LV end diastolic pressure, and maximal LV pressure. Rates of LV relaxation (when normalized to mean arterial pressure) tended ( P = 0.13) to be higher with nitrate supplementation. However, nitrate did not alter LV mitochondrial respiration, coupling efficiency, or oxygen affinity in isolated mitochondria or permeabilized muscle fibers. In contrast, nitrate increased ( P < 0.05) the propensity for mitochondrial H2O2 emission in the absence of changes in cellular redox state and decreased the sensitivity of mitochondria to ADP (apparent Km). These results add to the therapeutic potential of nitrate supplementation in cardiovascular diseases and suggest that nitrate may confer these beneficial effects via mitochondrial redox signaling. PMID- 29513564 TI - Sex differences in mitochondrial respiratory function in human skeletal muscle. AB - Mitochondrial bioenergetic contributions to sex differences in human skeletal muscle metabolism remain poorly defined. The primary aim of this study was to determine whether mitochondrial respiratory kinetics differed between healthy young men and women in permeabilized skeletal muscle fibers. While men and women displayed similar ( P > 0.05) maximal respiration rates and abundance of mitochondrial/adenosine diphosphate (ADP) transport proteins, women had lower ( P < 0.05) mitochondrial ADP sensitivity (+30% apparent Km) and absolute respiration rates at a physiologically relevant ADP concentration (100 MUM). Moreover, although men and women exhibited similar carnitine palmitoyl transferase-I protein content- and palmitoyl-CoA-supported respiration, women displayed greater sensitivity to malonyl-CoA-mediated respiratory inhibition. These data establish baseline sex differences in mitochondrial bioenergetics and provide the foundation for studying mitochondrial function within the context of metabolic perturbations and diseases that affect men and women differently. PMID- 29513566 TI - Reactive oxygen species upregulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells. AB - Unloading-mediated muscle atrophy is associated with increased reactive oxygen species (ROS) production. We previously demonstrated that elevated ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) resulted in the loss of muscle volume (Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T. Mol Cell Biol 29: 4798-4811, 2009). However, the pathological role of ROS production associated with unloading-mediated muscle atrophy still remains unknown. Here, we showed that the ROS-mediated signal transduction caused by microgravity or its simulation contributes to Cbl-b expression. In L6 myotubes, the assessment of redox status revealed that oxidized glutathione was increased under microgravity conditions, and simulated microgravity caused a burst of ROS, implicating ROS as a critical upstream mediator linking to downstream atrophic signaling. ROS generation activated the ERK1/2 early-growth response protein (Egr)1/2-Cbl-b signaling pathway, an established contributing pathway to muscle volume loss. Interestingly, antioxidant treatments such as N-acetylcysteine and TEMPOL, but not catalase, blocked the clinorotation-mediated activation of ERK1/2. The increased ROS induced transcriptional activity of Egr1 and/or Egr2 to stimulate Cbl-b expression through the ERK1/2 pathway in L6 myoblasts, since treatment with Egr1/2 siRNA and an ERK1/2 inhibitor significantly suppressed clinorotation induced Cbl-b and Egr expression, respectively. Promoter and gel mobility shift assays revealed that Cbl-b was upregulated via an Egr consensus oxidative responsive element at -110 to -60 bp of the Cbl-b promoter. Together, this indicates that under microgravity conditions, elevated ROS may be a crucial mechanotransducer in skeletal muscle cells, regulating muscle mass through Cbl-b expression activated by the ERK-Egr signaling pathway. PMID- 29513567 TI - Telomeric noncoding RNA promotes mouse embryonic stem cell self-renewal through inhibition of TCF3 activity. AB - Although long noncoding RNAs (lncRNAs) are emerging as new modulators in the fate decision of pluripotent stem cells, the functions of specific lncRNAs remain unclear. Here, we found that telomeric RNA (TERRA or TelRNA), one type of lncRNAs, is highly expressed in mouse embryonic stem cells (mESCs) but declines significantly upon differentiation. TERRA is induced by the Wnt/beta-catenin signaling pathway and can reproduce its self-renewal-promoting effect when overexpressed. Further studies revealed that T cell factor 3 ( TCF3) is a potential downstream target of TERRA and mediates the effect of TERRA in mESC maintenance. TERRA inhibits TCF3 transcription, while enforced TCF3 expression abrogates the undifferentiated state of mESCs supported by TERRA. Accordingly, the transcripts of the pluripotency genes Esrrb, Tfcp2l1, and Klf2, repressed by TCF3 in mESCs, are increased in TERRA-overexpressing cells. Our study therefore highlights the important role of TERRA in mESC maintenance and also uncovers a mechanism by which TERRA promotes self-renewal. These data will expand our understanding of the pluripotent regulatory network of ESCs. PMID- 29513569 TI - Cre-dependent AAV vectors for highly targeted expression of disease-related proteins and neurodegeneration in the substantia nigra. AB - Recombinant adeno-associated virus (AAV) vectors are a popular genetic approach in neuroscience because they confer such efficient transgene expression in the brain and spinal cord. A number of studies have used AAV to express pathological disease-related proteins in the dopaminergic neurons of the substantia nigra in situ ( e.g., alpha-synuclein to model aspects of Parkinson's disease). The neuropathology and neurodegeneration of Parkinson's disease occur in a circumscribed pattern in the brain, and one of the most important goals of any gene transfer study is accurate, pinpoint targeting. By combining Cre recombinase dependent AAVs in Cre-driver rats in which Cre is expressed only in the tyrosine hydroxylase neurons, we have achieved more highly targeted expression of several disease-relevant neuropathological proteins in the substantia nigra pars compacta than using constitutive expression AAV vectors. Alpha-synuclein, tau, transactive response DNA-binding protein of 43 kDa, or the control fluorescent protein yellow fluorescent protein was individually expressed to induce highly targeted, dopaminergic neuron-specific neurodegeneration models. The refined targeting foreshadows a next-generation disease modeling system for expressing neurodegenerative disease-related proteins in a disease-relevant manner. We foresee specific utilities of this in vivo AAV vector targeting of pathological proteins to a well-defined and well-demarcated cell population.-Grames, M. S., Dayton, R. D., Jackson, K. L., Richard, A. D., Lu, X., Klein, R. L. Cre-dependent AAV vectors for highly targeted expression of disease-related proteins and neurodegeneration in the substantia nigra. PMID- 29513568 TI - Overexpression of hexokinase 2 reduces mitochondrial calcium overload in coronary endothelial cells of type 2 diabetic mice. AB - Coronary microvascular rarefaction, due to endothelial cell (EC) dysfunction, is one of the causes of increased morbidity and mortality in diabetes. Coronary ECs in diabetes are more apoptotic due partly to mitochondrial calcium overload. This study was designed to investigate the role of hexokinase 2 (HK2, an endogenous inhibitor of voltage-dependent anion channel) in coronary endothelial dysfunction in type 2 diabetes. We used mouse coronary ECs (MCECs) isolated from type 2 diabetic mice and human coronary ECs (HCECs) from type 2 diabetic patients to examine protein levels and mitochondrial function. ECs were more apoptotic and capillary density was lower in the left ventricle of diabetic mice than the control. MCECs from diabetic mice exhibited significant increase in mitochondrial Ca2+ concentration ([Ca2+]mito) compared with the control. Among several regulatory proteins for [Ca2+]mito, hexokinase 1 (HK1) and HK2 were significantly lower in MCECs from diabetic mice than control MCECs. We also found that the level of HK2 ubiquitination was higher in MCECs from diabetic mice than in control MCECs. In line with the data from MCECs, HCECs from diabetic patients showed lower HK2 protein levels than HCECs from nondiabetic patients. High glucose treatment, but not high-fat treatment, significantly decreased HK2 protein levels in MCECs. HK2 overexpression in MCECs of diabetic mice not only lowered the level of [Ca2+]mito, but also reduced mitochondrial reactive oxygen species production toward the level seen in control MCECs. These data suggest that HK2 is a potential therapeutic target for coronary microvascular disease in diabetes by restoring mitochondrial function in coronary ECs. PMID- 29513570 TI - Antiviral activity of double-stranded RNA-binding protein PACT against influenza A virus mediated via suppression of viral RNA polymerase. AB - PACT is a double-stranded RNA-binding protein that has been implicated in host influenza A virus (IAV) interaction. PACT facilitates the action of RIG-I in the activation of the type I IFN response, which is suppressed by the viral nonstructural protein NS1. PACT is also known to interact with the IAV RNA polymerase subunit PA. Exactly how PACT exerts its antiviral activity during IAV infection remains to be elucidated. In the current study, we demonstrated the interplay between PACT and IAV polymerase. Induction of IFN-beta by the IAV RNP complex was most robust when both RIG-I and PACT were expressed. PACT-dependent activation of IFN-beta production was suppressed by the IAV polymerase subunits, polymerase acidic protein, polymerase basic protein 1 (PB1), and PB2. PACT associated with PA, PB1, and PB2. Compromising PACT in IAV-infected A549 cells resulted in the augmentation of viral RNA (vRNA) transcription and replication and IFN-beta production. Furthermore, vRNA replication was boosted by knockdown of PACT in both A549 cells and IFN-deficient Vero cells. Thus, the antiviral activity of PACT is mediated primarily via its interaction with and inhibition of IAV polymerase. Taken together, our findings reveal a new facet of the host-IAV interaction in which the interplay between PACT and IAV polymerase affects the outcome of viral infection and antiviral response.-Chan, C.-P., Yuen, C.-K., Cheung, P.-H. H., Fung, S.-Y., Lui, P.-Y., Chen, H., Kok, K.-H., Jin, D.-Y. Antiviral activity of double-stranded RNA-binding protein PACT against influenza A virus mediated via suppression of viral RNA polymerase. PMID- 29513571 TI - Uncoupling effects of estrogen receptor alpha on LKB1/AMPK interaction upon adiponectin exposure in breast cancer. AB - Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-alpha (ERalpha)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERalpha signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERalpha-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERalpha-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERalpha-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERalpha positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERalpha-negative breast cancer, also opportunely combined with antiestrogen therapy. -Mauro, L., Naimo, G. D., Gelsomino, L., Malivindi, R., Bruno, L., Pellegrino, M., Tarallo, R., Memoli, D., Weisz, A., Panno, M. L., Ando, S. Uncoupling effects of estrogen receptor alpha on LKB1/AMPK interaction upon adiponectin exposure in breast cancer. PMID- 29513573 TI - Single-Payer Plan for New York Could Lead the Country. PMID- 29513574 TI - Public Health Advocacy in the Tumultuous Times of the Trump Administration. PMID- 29513575 TI - Investigating Cumulative Marijuana Use and Risk of Cardiovascular Disease in Middle Age With Longitudinal Data. PMID- 29513576 TI - Reis et al. Respond. PMID- 29513577 TI - Quantifying the Epidemic of Prescription Opioid Overdose Deaths. PMID- 29513578 TI - Integrating Structural Determinants Into MPH Training of Health Promotion Professionals. PMID- 29513579 TI - The Invisible Forces That Create the Health of Populations: A Public Health of Consequence, April 2018. PMID- 29513580 TI - Moffit Responds. PMID- 29513581 TI - The EPA: Time to Re-Invent Environmental Protection. PMID- 29513583 TI - Effect of Providing Contraception Free of Charge. PMID- 29513584 TI - "Complete Streets" Policies and Eliminating Pedestrian Fatalities. PMID- 29513586 TI - Why It Is Important to Promote Clinical Independence Among Health Professionals Working in Prisons, Jails, and Other Detention Settings. PMID- 29513585 TI - Woolhandler and Himmelstein Respond. PMID- 29513588 TI - Culturally Competent, Integrated Behavioral Health Service Delivery to Homeless Children. PMID- 29513587 TI - HIV Stigma Among Black Women in the United States: Intersectionality, Support, Resilience. PMID- 29513589 TI - The Incredibly Credible Prevalence of Child Protective Services Contact in New Zealand and the United States. PMID- 29513590 TI - Building a Healthier Nation Together: Reasonable Compromises, Yes, but Appeasement, No. PMID- 29513591 TI - Uprooting Institutionalized Racism as Public Health Practice. PMID- 29513592 TI - Probing Beyond Individual Factors to Understand Influenza and Pneumococcal Vaccine Uptake. PMID- 29513593 TI - Kirkham Responds. PMID- 29513594 TI - Immigration Versus Immigrant: The Cycle of Anti-Immigrant Policies. PMID- 29513595 TI - More Research Needed to Increase Policies for HPV Vaccine Uptake. PMID- 29513596 TI - The Public Health Dialogue. PMID- 29513597 TI - AJPH Global News. PMID- 29513598 TI - Environmental Justice: Progress Derailed. PMID- 29513599 TI - Professional Development and Research to Improve School Practices and LGBTQ Health in US Schools. PMID- 29513601 TI - News From The Nation's Health. PMID- 29513600 TI - Zimmer Responds. PMID- 29513603 TI - Union Rate and Rate of Hardware Removal Following Plate Fixation of Metatarsal Shaft and Neck Fractures. AB - BACKGROUND: There have been very few studies related to the treatment of first, second, third, and fourth (MT) metatarsal shaft and neck fractures. In order to reduce metatarsal fracture malunion, many surgeons have turned from K-wire to plate fixation of these fractures. This study reports the healing rates, final fracture angulation, and need for hardware removal of operatively treated first to fourth MT shaft and neck fractures with plate fixation. METHODS: A retrospective review was performed on all metatarsal fractures at our institution between 2008 and 2014 to identify all first to fourth MT shaft and neck fractures. Medical records and radiographs were reviewed for evidence of union, sagittal, and coronal fracture angulation (degrees), time to full weight bearing, plate size, fracture location (neck vs shaft), and number of screws on each side of the fracture. Multiple linear regression analysis was used to make calculations of statistical significance. RESULTS: Forty-five patients with a total of 75 first to fourth MT fractures treated with plate fixation were included in this study. All fractures went on to union and full weight bearing. The average time to union and time to full weight bearing was 10.9 +/- 2 weeks and 7.5 +/- 1.6 weeks, respectively. The average coronal and sagittal plane angulation was 3.9 and 2.2 degrees, respectively. Fractures located in the neck were found to have higher coronal plane angulation malunion compared with fractures in the shaft ( P = .019). No variable was found to be related to final sagittal plane angulation. No patient had a plate removed, and 26 of 27 of patients did not want to have the plate removed. CONCLUSION: Metatarsal fractures fixed with plates had high rates of union and low final fracture angulation. No patient included in this study underwent hardware removal. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 29513606 TI - Validation of the mini pediatric asthma quality of life questionnaire and identification of risk factors affecting quality of life among Lebanese children. AB - BACKGROUND: Few studies used various scales to assess the QOL in Lebanon in general but none was specific to asthma. Our objective was to assess the asthma related quality of life, using the mini Pediatric Asthma Quality of Life Questionnaire (PAQLQ), in Lebanese asthmatic children, check its validity compared to the original version, and identify clinical and sociodemographic risk factors that might affect these children's QOL. METHODS: This retrospective study included 300 children aged between 7-16 years (51.6% boys and 48.4% girls). To confirm the mini-PAQLQ questionnaire construct validity in the Lebanese population, an exploratory factor analysis was launched for the 13 items of the questionnaire, using the principal component analysis technique. Cronbach's alpha was recorded for reliability analysis. A multivariate analysis linear regression was carried out, taking the QOL score as the dependent variable. RESULTS: The correlation coefficients for factors 1 (symptoms and emotions) and 2 (activities) were similar to that of the original scale. High Cronbach's alphas were found for factor 1 (0.914), factor 2 (0.888), and the full scale (0.921). Uncontrolled asthma, the child's respiratory problems before the age of 2 years, and the presence of pets at home significantly decreased the children's asthma-related quality of life (Beta = -1.541; Beta = -6.846, and Beta = -5.364, respectively). CONCLUSION: We were able to validate the mini-PAQLQ among the Lebanese population. The identification of risk factors, some of which are amenable to intervention, especially uncontrolled asthma, could lead to an improvement in the asthmatic children's QOL. PMID- 29513605 TI - Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior. AB - Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding. PMID- 29513607 TI - Role of the Inferior Alveolar Nerve in Rodent Lower Incisor Stem Cells. AB - In developing teeth, the sequential and reciprocal interactions between epithelial and mesenchymal tissues promote stem/progenitor cell differentiation. However, the origin of the stem/progenitor cells has been the subject of considerable debate. According to recent studies, mesenchymal stem cells originate from periarterial cells and are regulated by neurons in various organs. The present study examined the role of innervation in tooth development and rodent incisor stem/progenitor cell homeostasis. Rodent incisors continuously grow throughout their lives, and the lower incisors are innervated by the inferior alveolar nerve (IAN). In this study, we resected the IAN in adult rats, and the intact contralateral side served as a nonsurgical control. Sham control rats received the same treatment as the resected rats, except for the resection process. The extent of incisor eruption was measured, and both mesenchymal and epithelial stem/progenitor cells were visualized and compared between the IAN resected and sham-operated groups. One week after surgery, the IAN-resected incisors exhibited a chalky consistency, and the eruption rate was decreased. Micro-computed tomography and histological analyses performed 4 wk after surgery revealed osteodentin formation, disorganized ameloblast layers, and reduced enamel thickness in the IAN-resected incisors. Immunohistochemical analysis revealed a reduction in the CD90- and LRIG1-positive mesenchymal cell ratio in the IAN-resected incisors. However, the p40-positive epithelial stem/progenitor cell ratio was comparable between the 2 groups. Thus, mesenchymal stem/progenitor cell homeostasis is more related to IAN innervation than to epithelial stem/progenitor cells. Furthermore, sensory nerve innervation influences subsequent incisor growth and formation. PMID- 29513608 TI - Bayesian sample size determination for a Phase III clinical trial with diluted treatment effect. AB - When Phase III treatment effect is diluted from what was observed from Phase II results, we propose to determine the Bayesian sample size for a Phase III clinical trial based on the normal, uniform, and truncated normal prior distributions of the treatment effects on an interval, which starts from an acceptable treatment effect to the observed treatment effect from Phase II. After incorporating the prior information of the treatment effects, the Bayesian sample size is the number of patients of the Phase III trial for a given Bayesian Predictive Power (BPP) or Bayesian Historical Predictive Power (BHPP). After that, the numerical simulations are carried out to determine the Bayesian sample size for the Phase III clinical trial. In particular, there exists a hook phenomenon for the BHPP when the number of patients of the Phase II trial equals 70 assuming the normal, uniform, or truncated normal treatment effect. Moreover, we add some sensitivity analysis of the Bayesian sample size about the parameters in the simulations. Finally, we determine the Bayesian sample size (number of events or deaths) of the Phase III trial for a fixed power, Bayesian Historical Power (BHP), and BHPP in the axitinib example. PMID- 29513610 TI - Exploring the intersection of executive function and medication adherence in school-age children with asthma. AB - : Asthma is one of the most common chronic diseases of childhood. For children with persistent asthma, asthma control is largely related to controller medication adherence. With increasing calls for children to be involved in their own asthma management, there is a gap in our knowledge about the executive functioning of children with asthma. OBJECTIVE: The purpose of this study was to explore the relationship between executive function, asthma, and medication adherence among school-age children with asthma. METHODS: Thirty-one children ages 7 to 11 years (M = 8.9 +/- 1.51) and one of their parents were enrolled in this study. Parents reported on asthma control while children reported on asthma control, medication beliefs, medication adherence, and completed an executive function battery that assessed inhibition, updating, shifting and planning. RESULTS: Compared to the reference sample, children in this study had significantly lower composite scores in inhibition, t (31) = -3.84, p =. 001, and shifting, t (30) = -3.73, p =. 001. Controlling for age and asthma control, hierarchical regression analyses revealed that shifting accounted for 16% of the variance in child-reported medication adherence. CONCLUSIONS: This study revealed lowered executive functioning scores among school-age children with persistent asthma. Furthermore, it appears executive functioning and controller medication adherence are intertwined and warrant future exploration. PMID- 29513609 TI - Using REDCap for ambulatory assessment: Implementation in a clinical trial for smoking cessation to augment in-person data collection. AB - BACKGROUND: The use of ambulatory assessment to study behavior and physiology in daily life is becoming more common, yet barriers to implementation remain. Limitations in budget, time, and expertise may inhibit development or purchase of dedicated ambulatory assessment software. Research Electronic Data Capture (REDCap) is widely used worldwide, offering a cost-effective and accessible option for implementing research studies. OBJECTIVES: To present a step-by-step guideline on how to implement ambulatory assessment using REDCap and provide preliminary evidence of feasibility. METHODS: Feasibility and acceptability data are presented for randomized participants (N ranged from 19 to 36, depending on analysis) from an ongoing 8-week smoking cessation pharmacological clinical trial (ClinicalTrials.gov Identifier: NCT02737358). Participants (N = 36; 50% female) completed up to three ambulatory assessment surveys per day, depending on the phase of the study. These included self-report and video confirmation of smoking biomarkers and medication adherence. RESULTS: Participants completed 74.8% of morning reports (86.6% for study completers), 73.8% of videos confirming smoking biomarkers, and 70.4% of videos confirming medication adherence. Study completers reported that the REDCap assessments were easy to use, and 78.9% of participants preferred the REDCap assessments to traditional, paper measures. CONCLUSIONS: These data from a pharmacological trial suggest feasibility of remote data collection using REDCap. As REDCap functionality is continually evolving, it is likely that options for collecting ambulatory assessment data via this platform will progressively improve allowing for greater individualization of assessment scheduling for enhancing data collection in clinical trials. PMID- 29513611 TI - Driver Vigilance in Automated Vehicles: Hazard Detection Failures Are a Matter of Time. AB - OBJECTIVE: The primary aim of the current study was to determine whether monitoring the roadway for hazards during automated driving results in a vigilance decrement. BACKGROUND: Although automated vehicles are relatively novel, the nature of human-automation interaction within them has the classic hallmarks of a vigilance task. Drivers must maintain attention for prolonged periods of time to detect and respond to rare and unpredictable events, for example, roadway hazards that automation may be ill equipped to detect. Given the similarity with traditional vigilance tasks, we predicted that drivers of a simulated automated vehicle would demonstrate a vigilance decrement in hazard detection performance. METHOD: Participants "drove" a simulated automated vehicle for 40 minutes. During that time, their task was to monitor the roadway for roadway hazards. RESULTS: As predicted, hazard detection rate declined precipitously, and reaction times slowed as the drive progressed. Further, subjective ratings of workload and task-related stress indicated that sustained monitoring is demanding and distressing and it is a challenge to maintain task engagement. CONCLUSION: Monitoring the roadway for potential hazards during automated driving results in workload, stress, and performance decrements similar to those observed in traditional vigilance tasks. APPLICATION: To the degree that vigilance is required of automated vehicle drivers, performance errors and associated safety risks are likely to occur as a function of time on task. Vigilance should be a focal safety concern in the development of vehicle automation. PMID- 29513612 TI - On sample size requirement for analytical similarity assessment. AB - For approval of biosimilar products, the U.S. Food and Drug Administration (FDA) recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarirty between a proposed biosimilar product and its corresponding innovative (reference) biologic product. The stepwise approach starts with the assessment of analytical similarity of critical quality attributes (CQAs) for structural/physicochemical and functional properties in the manufacturing process of biosimilar products. For Tier 1 CQAs which are most relevant to clinical outcomes, the FDA recommends an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC). While performing the equivalence test, sample size is a critical component of the equivalence test. This article focuses on the discussion of the FDA's proposal: select an appropriate sample size by adjusting EAC margin and variability ([Formula: see text]). The article provides a thorough discussion on the FDA's proposal; sample size requirement under different scenarios are briefly described and a numerical study which compares sample size requirement under various combinations of study parameters is conducted. PMID- 29513613 TI - Time reference in nonfluent and fluent aphasia: a cross-linguistic test of the PAst DIscourse LInking Hypothesis. AB - Recent studies by Bastiaanse and colleagues found that time reference is selectively impaired in people with nonfluent agrammatic aphasia, with reference to the past being more difficult to process than reference to the present or to the future. To account for this dissociation, they formulated the PAst DIscourse LInking Hypothesis (PADILIH), which posits that past reference is more demanding than present/future reference because it involves discourse linking. There is some evidence that this hypothesis can be applied to people with fluent aphasia as well. However, the existing evidence for the PADILIH is contradictory, and most of it has been provided by employing a test that predominantly taps retrieval processes, leaving largely unexplored the underlying ability to encode time reference-related prephonological features. Within a cross-linguistic approach, this study tests the PADILIH by means of a sentence completion task that 'equally' taps encoding and retrieval abilities. This study also investigates if the PADILIH's scope can be extended to fluent aphasia. Greek- and Italian-speaking individuals with aphasia participated in the study. The Greek group consisted of both individuals with nonfluent agrammatic aphasia and individuals with fluent aphasia, who also presented signs of agrammatism. The Italian group consisted of individuals with agrammatic nonfluent aphasia only. The two Greek subgroups performed similarly. Neither language group of participants with aphasia exhibited a pattern of performance consistent with the predictions of the PADILIH. However, a double dissociation observed within the Greek group suggests a hypothesis that may reconcile the present results with the PADILIH. PMID- 29513614 TI - Extremely low frequency variable electromagnetic fields affect cancer and noncancerous cells in vitro differently: Preliminary study. AB - The exposure to extremely low frequency electromagnetic field (ELF-EMF) may result in various changes at the cellular level. To identify the effect of ELF EMF exposure on viability of cells, cancer cells (U87-MG; 143B) and noncancerous cells (BJ; HEK) in exponential growth phase were exposed or sham-exposed to different values of frequency (2, 20, 30, 50 and 60 Hz), different shapes (sinusoidal, square and triangular) and time of exposure (0.5, 1, 2, 3 h) to electromagnetic field. After exposure, viability of cells was detected by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found a different effect of exposition of cancer and noncancerous cells to ELF-EMF on viability of cells. This preliminary study revealed that electro magentic field(EMF) might serve as a potential tool for manipulating viability of cells. PMID- 29513615 TI - Monoclonal Antibodies for Emerging Infectious Diseases - Borrowing from History. PMID- 29513616 TI - Retinal Pigment Epithelium Detachment in Acute Vogt-Koyanagi-Harada Disease: An Unusual Finding at Presentation. AB - PURPOSE: To report the cases of two patients who presented with acute Vogt Koyanagi-Harada (VKH) disease and associated retinal pigment epithelium detachment (PED). METHODS: 2 case reports. Case 1: A 22-year-old male patient complained of acute bilateral decrease in vision. Initial best corrected visual acuity (BCVA) was 20/63, OU. There was 1+ vitreous cells, OU, exudative retinal detachment (ERD) in the right eye (RE), and a macular deep yellow lesion suggestive of PED in the left eye (LE). Case 2: A 40-year-old female patient presented with bilateral vision blurring. BCVA was 20/40 in the RE and 20/32 in the LE. There was 1+ vitreous cells OU, bilateral optic disc swelling and retinal striae. RESULTS: Multimodal imaging showed features of acute VKH disease with associated PED in the two patients. ERD and PED resolved under oral prednisone and cyclosporine in both cases. CONCLUSION: PED may rarely occur in acute VKH disease at presentation. PMID- 29513617 TI - Dynamic transitions between marijuana use and cigarette smoking among US adolescents and emerging adults. AB - BACKGROUND: Marijuana and tobacco are considered two closely related substances. It is of great significance to understand the mutual impact of marijuana and cigarette use when more states in the US have legalized marijuana use. OBJECTIVE: This study aims to investigate the transitions between marijuana and cigarette use among adolescents and emerging adults. METHOD: Guided by the probabilistic discrete events systems (PDES) theory, a five-stage model with 21 transition paths was constructed to quantify dynamic transitions between marijuana and cigarette use. The five stages were NU: Never-user, MU: Current marijuana user, CU: Current cigarette user, MCU: Current marijuana-cigarette user, and FU: Former user. The proposed five-stage PDES model was tested using the 2013 National Survey on Drug Use and Health data (N = 26,665, 50.45% male). Transition probabilities were estimated using the Moore-Penrose generalized inverse matrix method. RESULT: Among the adolescents, 51.14% of the CUs transited to use marijuana (MCU/MU), higher than the proportion of those who first used marijuana and then transferred to cigarettes (MCU/CU) (41.66%). The quitting rates for MUs, CUs and MCUs were 29.38%, 25.93% and 27.76%, respectively. Of the total FUs, 31.90% transited to MUs, 17.06% to CUs, and 17.39% to MCUs. Among the young adults, more people progressed from MUs to CUs. Transition probabilities by single year of age were also estimated. CONCLUSION: This is the first study to quantify marijuana-cigarette transitions. Study findings indicate more cigarette to-marijuana transitions for adolescents and more marijuana-to-cigarette transitions for emerging adults. Future intervention programs should consider this age-related difference in marijuana-cigarette use transitions. PMID- 29513618 TI - Liquid Biopsy in Head and Neck Cancer: Promises and Challenges. AB - Head and neck cancer is the sixth most common cancer worldwide. It remains one of the leading causes of death, and its early detection is crucial. Liquid biopsy has emerged as a promising tool for detecting and monitoring the disease status of patients with early and advanced cancers. Circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomal miRNAs have received enormous attention because of their apparent clinical implications. Analyses of these circulating biomarkers have paved the way for novel therapeutic approaches and precision medicine. A growing number of reports have implicated the use of circulating biomarkers for detection, treatment planning, response monitoring, and prognosis assessment. Although these new biomarkers can provide a wide range of possible clinical applications, no validated circulating biomarkers have yet been integrated into clinical practice for head and neck cancer. In this review, we summarize the current knowledge of circulating biomarkers in this field, focusing on their feasibility, limitations, and key areas of clinical applications. We also highlight recent advances in salivary diagnostics and their potential application in head and neck cancer. PMID- 29513620 TI - Validation of a Pulse Oximetry System for High-Altitude Waterfowl by Examining the Hypoxia Responses of the Andean Goose (Chloephaga melanoptera). AB - Hypoxia at high altitudes constrains O2 supply to support metabolism, thermoregulation in the cold, and exercise. High-altitude natives that somehow overcome this challenge-who live, reproduce, and sometimes perform impressive feats of exercise at high altitudes-are a powerful group in which to study the evolution of physiological systems underlying hypoxia resistance. Here, we sought to determine whether a common pulse oximetry system for rodents (MouseOx Plus) can be used reliably in studies of high-altitude birds by examining the hypoxia responses of the Andean goose. We compared concurrent measurements of heart rate obtained using pulse oximetry versus electrocardiography. We also compared our measurements of peripheral arterial O2 saturation (SaO2) in uncannulated birds with published data collected from blood samples in birds that were surgically implanted arterial cannulae. Responses to acute hypoxia were measured during stepwise reductions in inspired partial pressure of O2. Andean geese exhibited very modest breathing and heart rate responses to hypoxia but were nevertheless able to maintain normal O2 consumption rates during severe hypoxia exposure down to 5 kPa O2. There were some minor quantitative differences between uncannulated and cannulated birds, which suggest that surgery, cannulation, and/or other sources of variability between studies had modest effects on the hypoxic ventilatory response, heart rate, blood hemoglobin, and hematocrit. Nevertheless, measurements of heart rate and SaO2 by pulse oximetry had small standard errors and were generally concordant and well correlated with measurements using other techniques. We conclude that the MouseOx Plus pulse oximetry system can be a valuable tool for studying the cardiorespiratory physiology of waterfowl without the deleterious effects of surgery/cannulation. PMID- 29513621 TI - The 'over-the-top' modified Cutler-Beard procedure for complete upper eyelid defect reconstruction. AB - PURPOSE: To describe the 'Over-the-Top' Modified Cutler Beard Procedure (OTTMCB) for complete upper eyelid defect reconstruction Methods: This is retrospective case note review of four patients that underwent the OTTMCB procedure. This two stage procedure comprises the replacement of the posterior lamella with a free tarsal graft from the contralateral upper eyelid, and the anterior lamella with a lower lid skin flap over the lower eyelid margin which is divided 2-4 weeks later. RESULTS: The procedure was undertaken for four patients with 75-90% upper eyelid defects from tumour excision surgery. One patient had post-operative dehiscence requiring debridement and resuturing and further reconstructive surgery 18 months later to improve the cosmesis and lagophthalmos. The other three patients had good functional and cosmetic outcomes. CONCLUSIONS: The OTTMCB procedure replaces the anterior and posterior lamellae of the upper eyelid with 'like-for-like' tissues. It avoids some of the drawbacks of the original and other variations of the Cutler-Beard procedure and achieves a good cosmetic outcome. PMID- 29513622 TI - Crowdsourcing as a method for collecting data pertaining to the effects of alcohol on perceptions of partner aggression. AB - BACKGROUND: Efforts designed to investigate the effects of recent alcohol use on the perception of intimate partner aggression have been stultified by significant financial and logistical barriers that warrant the development of supplemental research methods that may result in more prolific investigation of the phenomenon. OBJECTIVES: The current study explored the viability of using online crowdsourcing to assess the effects of recent alcohol use on the perception of partner aggression. METHOD: Mechanical Turk was used to recruit a convenience sample of 60 males who were asked to provide information on their own use of partner aggression, their most recent episode of alcohol use, and their perception of the behaviors and characters depicted in a written partner aggression vignette. Data were evaluated using five separate hierarchical multiple regression models predicting participant perception. RESULTS: Analyses revealed that 35% of the sample had used partner aggression in the past year and that 22% of the sample had consumed alcohol in the past day. Nonviolent participants perceived the aggressor and the behavior more negatively than partner violent participants. Some indicators revealed that recent alcohol use was associated with more positive perceptions of partner aggression. CONCLUSION: Expected associations among prior partner aggression, recent alcohol use, and perception of partner aggression vignettes were observed. Crowdsourcing may represent a source for data evaluating the effects of recent alcohol use on perceptions of aggression. Methodological refinement will benefit research and, ultimately, clinical prevention and intervention. PMID- 29513623 TI - Reactivity of larger intracranial arteries using 7 T MRI in young adults. AB - The larger intracranial conduit vessels contribute to the total cerebral vascular resistance, and understanding their vasoreactivity to physiological stimuli is required when attempting to understand regional brain perfusion. Reactivity of the larger cerebral conduit arteries remains understudied due to a need for improved imaging methods to simultaneously assess these vessels in a single stimulus. We characterized reactivity of basal intracranial conduit arteries (basilar, right and left posterior, middle and anterior cerebral arteries) and the right and left internal carotid arteries, to manipulations in end-tidal CO2 (PetCO2). Cross-sectional area changes (%CSA) were evaluated from high-resolution (0.5 mm isotropic) images collected at 7 T using a T1-weighted 3D SPACE pulse sequence, providing high contrast between vessel lumen and surrounding tissue. Cerebrovascular reactivity was calculated as %CSA/DeltaPetCO2 in eight healthy individuals (18-23 years) during normocapnia (41 +/- 4 mmHg), hypercapnia (48 +/- 4 mmHg; breathing 5% CO2, balance oxygen), and hypocapnia (31 +/- 8 mmHg; via hyperventilation). Reactivity to hypercapnia ranged from 0.8%/mmHg in the right internal carotid artery to 2.7%/mmHg in the left anterior cerebral artery. During hypocapnia, vasoconstriction ranged from 0.9%/mmHg in the basilar artery to 2.6%/mmHg in the right posterior cerebral artery. Heterogeneous cerebrovascular reactivity to hypercapnia and hypocapnia was characterized across basal intracranial conduit and internal carotid arteries. PMID- 29513624 TI - Prevalence and risk factors for prehypertension and hypertension among adults in Central China from 2000-2011. AB - BACKGROUND: Hypertension is frequently studied in surveys; however, prehypertension, a new blood pressure status between normotension and hypertension, is rarely reported. METHODS: All data were derived from the China Health and Nutrition Survey (CHNS) and were analysed by logistic regression for correlation. RESULTS: The prehypertension prevalence was 27.4%, with a hypertension rate of 36.9%. The awareness, treatment, and uncontrolled rates among all hypertension participates were 19.8%, 83.6%, and 55.0%, respectively. The epidemic rate of hypertension increased with increasing age (p < 0.001), and prehypertension appeared to have an epidemic peak in the age group of 38-57 years (p < 0.001). In general, the incidence of hypertension in urban participants was higher than in rural subjects (p < 0.001), and prehypertension in urban subjects was lower than that in rural subjects (p < 0.001). According to the results of logistic regression, hypertension and prehypertension were associated with age, gender, location, body mass index (BMI), body fat rate (BFR), waist circumference (WC), education, and the intake of energy-yielding nutrients<0.05). CONCLUSION: The current study reveals a high epidemic rate of hypertension and prehypertension in Central China. These results indicate the urgent need to develop strategies to improve the prevention of hypertension and prehypertension in Central China. PMID- 29513619 TI - Analytical comparability study of recombinant monoclonal antibody therapeutics. AB - Process changes are inevitable in the life cycle of recombinant monoclonal antibody therapeutics. Products made using pre- and post-change processes are required to be comparable as demonstrated by comparability studies to qualify for continuous development and commercial supply. Establishment of comparability is a systematic process of gathering and evaluating data based on scientific understanding and clinical experience of the relationship between product quality attributes and their impact on safety and efficacy. This review summarizes the current understanding of various modifications of recombinant monoclonal antibodies. It further outlines the critical steps in designing and executing successful comparability studies to support process changes at different stages of a product's lifecycle. PMID- 29513625 TI - Leveraging user perspectives for insight into cannabis concentrates. AB - BACKGROUND: The US has seen an increase in the popularity of highly concentrated forms of cannabis (hereafter concentrates) and too little is known about the potential risks associated with their use. OBJECTIVES: The present study aims to better understand the patterns and outcomes of concentrates use through the perspectives of young adult users. METHODS: Participants (N = 234, 27.9% female) aged 18-35 years were recruited using SurveyMonkey Audience(r) and had ingested concentrates at least once in the past 6 months. They were queried on concentrates use patterns (e.g., frequency, medical/recreational) and the effects experienced after using concentrates (e.g., physiological/psychological, strength/duration). RESULTS: A total of 27.8% of participants reported frequent use of concentrates (>=10 days in past month). Those who used for medical purposes or lived in states where use is legal were more likely to use concentrates frequently. While most (64.2%) did not report experiencing potentially serious side effects, some reported a sense of altered reality/confusion (23.3%), rapid heartbeat (11.2%), lung pain (9.9%) and severe paranoia (6.9%). Among those who used concentrates in the past month (N = 168), 72.6% used concentrates with other cannabis forms, 57.7% used along with alcohol, and 22.6% used with other drugs. CONCLUSION: Continued research on concentrates use in the US is needed. Research-informed policies that foster safe and responsible use of concentrates are necessary to protect users, especially those who use concentrates frequently, from potential negative side effects. PMID- 29513626 TI - Diagnostic Value of Positive Findings of Toxoplasma gondii-Specific Immunoglobulin M Serum Antibody in Uveitis Patients to Confirm Ocular Toxoplasmosis. AB - PURPOSE: To assess the value of positive immunoglobulin (Ig) M serum antibody (Ab) findings in uveitis patients. METHODS: We reviewed medical records of patients who had a positive serological test for Toxoplasma gondii-specific IgM Ab. Their clinical data, including history, demographic characteristics, laboratory findings, clinical findings, treatment outcomes, and recurrences, were reviewed retrospectively. RESULTS: Of 2919 uveitis patients who underwent a serological test for suspected ocular toxoplasmosis (OT), 18 presented with positive Ig M results. All 18 patients (100.0% specificity) were clinically diagnosed with OT. None had any retinochoroidal scar at the initial visit, indicating the OT was a recent and primary infection. However, 15 patients (83.3%) had no history suspected to account for the Toxoplasma transmission. CONCLUSIONS: The T. gondii IgM serum Ab is a specific biomarker for diagnosis of primary OT. Epidemiological studies are warranted to investigate the non-classic transmission routes of T. gondii in OT. PMID- 29513628 TI - Correction to: Figueira et al., Primary orbital melanoma: a case series and literature review. PMID- 29513627 TI - The Functional Characterization of Podosphaera xanthii Candidate Effector Genes Reveals Novel Target Functions for Fungal Pathogenicity. AB - Podosphaera xanthii is the main causal agent of powdery mildew disease in cucurbits. In a previous study, we determined that P. xanthii expresses approximately 50 Podosphaera effector candidates (PECs), identified based on the presence of a predicted signal peptide and the absence of functional annotation. In this work, we used host-induced gene silencing (HIGS), employing Agrobacterium tumefaciens as a vector for the delivery of the silencing constructs (ATM-HIGS), to identify genes involved in early plant-pathogen interaction. The analysis of seven selected PEC-encoding genes showed that six of them, PEC007, PEC009, PEC019, PEC032, PEC034, and PEC054, are required for P. xanthii pathogenesis, as revealed by reduced fungal growth and increased production of hydrogen peroxide by host cells. In addition, protein models and protein-ligand predictions allowed us to identify putative functions for these candidates. The biochemical activities of PEC019, PEC032, and PEC054 were elucidated using their corresponding proteins expressed in Escherichia coli. These proteins were confirmed as phospholipid-binding protein, alpha-mannosidase, and cellulose binding protein. Further, BLAST searches showed that these three effectors are widely distributed in phytopathogenic fungi. These results suggest novel targets for fungal effectors, such as host-cell plasma membrane, host-cell glycosylation, and damage-associated molecular pattern-triggered immunity. PMID- 29513629 TI - Death by Suicide among Canadian Medical Students: A National Survey-Based Study. AB - OBJECTIVE: To estimate a rate of death by suicide in the Canadian medical student population and examine the prevalence of institutional response policies for suicide. METHODS: A survey was sent to all 17 Canadian medical undergraduate programs (MDUPs) to collect information on deaths by suicide over the past 10 years. In the case of a reported suicide, basic demographic data was collected. Respondents were asked to indicate whether internal statistics or response policies for suicide existed at their MDUP. RESULTS: Responses were obtained from 16 of 17 (94%) MDUPs. Six suicides (50% female) were reported over the ten-year period from 2006 to 2016. The estimated cause-specific mortality rate was 5.9 8.7/100,000 medical students/year. There were seven (44%) MDUPs that kept statistics on student deaths including suicides and 10 (63%) reported having policies or guidelines regarding what to do in the event of a suicide. CONCLUSIONS: Our estimated suicide rate falls within previously reported rates in medical students. While this may be lower than the national rate for Canadians between the ages of 20-30 years old, any suicide in the medical student community must be an impetus for national dialogue and further study. A strategy is needed to better define the prevalence, risk factors for and impact of medical student suicide in Canada. PMID- 29513630 TI - Quality Review in Psychiatry. AB - This position paper has been substantially revised by the Canadian Psychiatric Association's Professional Standards and Practice Committee and approved for republication by the CPA's Board of Directors on August 31, 2016. The original position paper1 was developed by the Professional Standards and Practice Council and approved by the Board of Directors on April 9, 1994. PMID- 29513632 TI - Photoautotrophic cultivating options of freshwater green microalgal Chlorococcum humicola for biomass and carotenoid production. AB - Photoautotrophic cultivation of Chlorococcum humicola was performed in batch and continuous modes in different cultivating system arrangements to compare biomass and carotenoids' concentration and their productivities. Batch result from stirred tank and airlift photobioreactors indicated the positive effect of increasing light intensity on growth and carotenoid production, whereas the finding from continuous cultivation indicated that carotenoid enhancement preferred high light intensity and nitrogen-deficient environment. The highest biomass (1.31 +/- 0.04 g L-1) and carotenoid (4.59 +/- 0.06 mg L-1) concentration as well as the highest productivities, 0.46 g L-1 d-1 for biomass and 1.61 mg L-1 d-1 for carotenoids, were obtained when maintaining high light intensity of 10 klx, BG-11 medium and 2% (v/v) CO2 simultaneously, while the highest carotenoid content (4.84 mg g-1) was associated with high light intensity and nitrogen deficient environment, which was induced by feed-modified BG-11 growth medium containing nitrate 20 folds lower than the original medium. Finally, the cultivating system arranged into smaller stirred tank photobioreactors in series yielded approximately 2.5 folds increase in both biomass and carotenoid productivities relative to using single airlift photobioreactor with equivalent working volume and similar operating condition. PMID- 29513633 TI - Cancer clinical trials - current and controversial issues in design and analysis. PMID- 29513634 TI - Statistical issues and advances in cancer precision medicine research. PMID- 29513631 TI - Media Guidelines for Reporting on Suicide: 2017 Update of the Canadian Psychiatric Association Policy Paper. AB - This paper has been substantially revised by the Canadian Psychiatric Association's Research Committee and approved for republication by the CPA's Board of Directors on May 3, 2017. The original policy paper1 was developed by the Scientific and Research Affairs Standing Committee and approved by the Board of Directors on November 10, 2008. PMID- 29513636 TI - Home Dental Bleaching Monitored With Microelectronic Sensors to Record the Wearing Times of an Acetate Tray/Bleaching Product. AB - The present case study quantifies the clinical wearing time of an acetate tray/bleaching product during home dental bleaching. The patient was instructed to use a 10% carbamide peroxide gel for 6-8 hours each day for 20 days. The wearing time of the tray was measured by a microsensor from TheraMon microelectronic system (Sales Agency Gschladt, Hargelsberg, Austria) completely embedded in the tray so that the clinician would be informed as to the precise time the tray was placed in the mouth. Evaluation of the daily printout during dental bleaching demonstrated that the patient did not correctly follow the clinician's instructions as to the wearing time of the tray. Recording the wearing time of dental bleaching agents can be beneficial for both dental professional and patient to obtain a more effective treatment according to the patient's needs and expectations. PMID- 29513635 TI - Double-blind Randomized Study to Evaluate the Safety and Efficacy of Over-the counter Tooth-whitening Agents Containing 2.9% Hydrogen Peroxide. AB - OBJECTIVES: In this double-blind randomized study, we evaluated the safety and efficacy of over-the-counter (OTC) bleaching products that included 2.9% hydrogen peroxide (H2O2) with two methods of application: strip and paint-on. METHODS AND MATERIALS: A commonly used product was selected for each type (strip and paint on) of OTC bleaching agent. In total, 75 volunteers were assigned randomly into five groups: two test groups (strip and paint-on), two negative control groups (products without H2O2), and one positive control group (dentist-supervised home bleaching). The tooth shade was evaluated with a spectrophotometer and Vita shade guide at baseline and 2 weeks and 4 weeks after use. To document any adverse reactions, such as hypersensitivity or tissue irritation, all patients were examined and the Gingival Index (GI), Plaque Index (PI), and a visual analog scale (VAS) measuring the cold response were obtained. RESULTS: There were significant differences among the five groups ( p<0.001). The positive control showed the greatest color changes; then, in decreasing order, the strip-type test group, paint-on-type test group, and negative controls. The strip-type bleaching agent was significantly more effective than the paint-on-type agent and the negative control, while it was significantly less effective than the dentist supervised home bleaching. Regardless of the treatment group, the canines showed greater color changes than did the central or lateral incisors. Some cases of gingival irritation and hypersensitivity were observed, but they were mild and reversible. GI, PI, and VAS scores were not significantly changed. CONCLUSIONS: Within the limitations of this study, the results indicated that the strip-type and paint-on-type OTC bleaching agents were significantly less efficacious than was dentist-supervised home bleaching; however, they showed acceptable safety and efficacy. The strip-type was more effective than was the paint-on-type in this study. PMID- 29513637 TI - Self-etching Primers vs Acid Conditioning: Impact on Bond Strength Between Ceramics and Resin Cement. AB - This study tested whether a self-etching surface agent and the conventional hydrofluoric acid (HF) would provide the same bonding capacity between resin cement and feldspathic (Fd) and lithium disilicate (Ld) ceramics. Ceramic blocks were cut with a low-speed diamond saw with water cooling (Isomet 1000, Buehler, Lake Bluff, IL, USA) into 20 blocks of 5 * 7 * 4 mm, which were ground flat in a polishing machine (EcoMet/AutoMet 250, Buehler) under water cooling. The blocks were randomly divided into eight groups (n=5), according to ceramic type (Ld or Fd), surface conditioning (HF + Monobond Plus or Etch and Prime), and aging by thermocycling (TC or absence-baseline). After 24 hours in 37 degrees C distilled water, blocks were embedded into acrylic resin and 1-mm2 cross-section beams composed of ceramic/cement/composite were obtained. The microtensile test was performed in a universal testing machine (DL-1000, EMIC, Sao Jose dos Campos, Brazil; 0.5 mm.min-1, 50 kgf load cell). Bond strength (MPa) was calculated by dividing the load at failure (in N) by the bonded area (mm2). The fractured specimens were examined under stereomicroscopy, and one representative sample of each group was randomly selected before the cementation and was further used for analysis using scanning electron microscopy (SEM) and energy-dispersive x-ray spectroscopy (EDS). The self-etching agent showed the highest bond strength for Fd (24.66+/-4.5) and Ld (24.73+/-6.9) ceramics and a decrease in surface wettability. SEM and EDS showed the presence of similar components in the tested materials with different topographies for both. Therefore, the self-etching primer was able to deliver even higher bonding than HF+silane to a resin cement. PMID- 29513638 TI - Effect of Different Computer-aided Design/Computer-aided Manufacturing (CAD/CAM) Materials and Thicknesses on the Fracture Resistance of Occlusal Veneers. AB - The aim was to evaluate, in vitro, the influence of different computer-aided design/computer-aided manufacturing (CAD/CAM) materials (IPS e.max CAD, Vita Enamic, and Lava Ultimate) and thicknesses (0.6 mm and 1.5 mm) on the fracture resistance of occlusal veneers. Sixty human third molars were prepared to simulate advanced erosion of the occlusal surface, and the teeth were randomly divided into six experimental groups (n=10) according to the material and thickness used to build the veneers. Ten sound teeth formed the control group. The veneers were adhesively luted and submitted to mechanical cyclic loading (1 million cycles at 200-N load). The fracture resistance test was performed in a universal testing machine. The failures were classified as "reparable" and "irreparable." According to two-way analysis of variance and the Tukey test, the interaction (material * thickness) was significant ( p=0.013). The highest fracture resistance was obtained for IPS e.max CAD at a 1.5-mm thickness (4995 N) and was significantly higher compared to the other experimental groups ( p<0.05). The lowest fracture resistance was obtained for Vita Enamic at 0.6 mm (2973 N), although this resistance was not significantly different from those for IPS e.max CAD at 0.6 mm (3067 N), Lava Ultimate at 0.6 mm (3384 N), Vita Enamic at 1.5 mm (3540 N), and Lava Ultimate at 1.5 mm (3584 N) ( p>0.05). The experimental groups did not differ significantly from the sound teeth (3991 N) ( p>0.05). The failures were predominantly repairable. The occlusal veneers of IPS e.max CAD, Vita Enamic, and Lava Ultimate, with thicknesses of 0.6 mm and 1.5 mm, obtained fracture resistances similar to those associated with sound teeth. PMID- 29513639 TI - Application of the Self- Assembling Peptide P11-4 for Prevention of Acidic Erosion. AB - The aim of this study was to use ultrasonography to evaluate the effect of the self-assembling peptide P11-4 on acid erosion prevention. Curodont Repair (CR), which includes peptide P11-4, was used. Rectangular prisms of bovine enamel (4*1*1 mm) were immersed in pure orange juice for a period of 5 minutes six times per day for 28 days. These samples were divided into four groups of six specimens each and treated differently for an additional period of 28 days: 1) baseline group specimens were stored in artificial saliva; 2) CR group specimens were exposed to curodont without acid challenge; 3) NCRA (no curodont+acid challenge) specimens were treated with orange juice without curodont exposure; and 4) CRA (CR+acid challenge) specimens were treated with curodont before treatment with orange juice. The propagation time of longitudinal ultrasonic velocity (UV) was measured. Ultrastructural observation of each tested enamel surface was carried out using field-emission scanning electron microscopy (SEM). The UV data were analyzed using two-way analysis of variance with time and treatment as confounding factors. Post hoc pairwise tests among groups were performed using the Tukey honestly significant difference test. The average UV in intact bovine enamel for the baseline group ranged from 4,483 to 4,549 m/s and did not vary significantly within the test period. The average ultrasonic velocity (UV) in all samples decreased after the initial erosion. The UV in NCRA decreased further over time. Increased UVs were found for CR and CRA. For CR and CRA, there was no significant difference in UV at the end of the experiment from the initial value before erosion. In the results of SEM observation, the CR and CRA groups had similar morphologic features in that etching patterns were not clearly due to precipitation between the enamel rods. From the results of this in vitro study, it might be concluded that applying enamel matrix derivatives and self-assembling peptides on erosive lesions can improve remineralization. PMID- 29513640 TI - Prospective Clinical Study of Zirconia Full-coverage Restorations on Teeth Prepared With Biologically Oriented Preparation Technique on Gingival Health: Results After Two-year Follow-up. AB - OBJECTIVES: To evaluate the clinical behavior of one-piece complete-coverage crowns and fixed partial dentures (FPDs) on teeth with vertical preparation without finish line biologically oriented preparation technique (BOPT). METHODS AND MATERIALS: This prospective study included 52 patients requiring treatment with restorations in the esthetic region: 74 crowns and 27 FPDs. The sample included a total of 149 teeth that were prepared vertically without finish line. The sample was divided into two groups: one-piece crowns and FPDs, all with zirconia cores, feldspathic ceramic veneer, and a 0.5-mm prosthetic finish line of zirconia. All procedures were carried out at the University of Valencia from 2013 to 2014. The following parameters were evaluated over a two-year follow-up: oral hygiene, periodontal state, gingival thickening, gingival margin stability, the presence of complications, and restoration survival rate. Patient satisfaction with treatment was assessed by means of a visual analogue scale (VAS). RESULTS: Two years after treatment, 80.5% of treated teeth remained free of gingival inflammation and bleeding. Mean gingival thickening was 0.41 +/- 0.28 mm for one-piece crowns and 0.38 +/- 0.36 mm for FPDs. Gingival margin stability was 100%, but 2% of the sample presented biological complications. The VAS patient satisfaction scores were eight out of a maximum score of 10. CONCLUSIONS: Two years after treatment, vertical preparation without finish line produces gingival thickening, margin stability, and optimal esthetics. Neither crowns nor FPDs presented any mechanical complications. PMID- 29513641 TI - Effect of Baicalein on Matrix Metalloproteinases and Durability of Resin-Dentin Bonding. AB - OBJECTIVE: In an attempt to increase resin-dentin bonding quality, this study used baicalein as a preconditioner in an etch-and-rinse adhesive to evaluate its effect on matrix metalloproteinases (MMPs) and adhesive durability. METHODS: As a MMP inhibitor and potential collagen cross-linking agent, baicalein was used as a preconditioner in an etch-and-rinse adhesive system. The degree of conversion was evaluated by Fourier-transform infrared spectroscopy. EnzChek gelatinase/collagenase assay kits were then used to detect the MMP inhibitory effect of different concentrations of baicalein (0.1, 0.5, 2.5, and 5.0 MUg/mL) on dentin powders. During in vitro bonding procedures, flat dentin surfaces on sound third molars were preconditioned with 2.5 MUg/mL baicalein after being acid etched; this step was followed by continuation of adhesive processes and build-up of resin composite. After resin-dentin stick preparation, bonding strength, failure mode, and interface nanoleakage were respectively evaluated via microtensile testing, stereomicroscopy, and field emission scanning electron microscopy either immediately or after storage in artificial saliva for three or six months. Data were analyzed by two-way analysis of variance and Tukey test (alpha=0.05). RESULTS: Baicalein at a concentration of 0-5.0 MUg/mL did not influence the conversion of adhesives. However, it inhibited the activities of dentin-bond gelatinase and collagenase, especially at a concentration of 2.5 MUg/mL, while effectively increasing microtensile bonding strength and decreasing nanoleakage in vitro, both immediately and after aging. CONCLUSIONS: Baicalein used as preconditioner in an etch-and-rinse adhesive system has an anti-MMP function and effectively improves resin-dentin bonding durability in vitro, which has potential value in clinical bonding procedures. PMID- 29513642 TI - Effect of Magnification on the Precision of Tooth Preparation in Dentistry. AB - OBJECTIVES: To evaluate the impact of magnification aids on the precision of tooth preparation under simulated clinical conditions. METHODS AND MATERIALS: Two plastic blocks marked with a geometric shape were fixed in a dental phantom head: a circle as the distal surface of tooth 16 (UNS 3) and a y-shaped figure as the occlusal surface of tooth 36 (UNS 19). Sixteen dentists (mean age: 39 years; range: 26-67 years) prepared the geometric shapes from the inside to the boundary line with a cylindrical bur and water-cooling. The boundary line had to be touched but not erased. Chair-side assistance was provided to simulate the clinical situation. Tooth 16 was prepared under indirect vision via a dental mirror. Tooth 36 was prepared under direct vision A) without magnification aids, B) with Galilean loupes, 2.5* and light-emitting diode light, and C) with a microscope, 6.4* and coaxial light. The preparation procedure was performed three times in different sequences of the magnification devices and with a break of at least 1 week between each procedure. The correctly prepared contour and the incorrectly prepared areas were evaluated in relation to the whole circumference of the geometric shapes. RESULTS: For both values the precision was significantly higher when a microscope was used, followed by preparation using loupes; precision was lowest without magnification aids ( p<0.0001). This was true for both indirect and direct vision ( p<0.05). CONCLUSIONS: Magnification devices improved the precision of tooth preparation under simulated clinical conditions. PMID- 29513643 TI - Effectiveness of the Multilayered Caries Model and Visuo-tactile Virtual Reality Simulator for Minimally Invasive Caries Removal: A Randomized Controlled Trial. AB - This work presents the multilayered caries model with a visuo-tactile virtual reality simulator and a randomized controlled trial protocol to determine the effectiveness of the simulator in training for minimally invasive caries removal. A three-dimensional, multilayered caries model was reconstructed from 10 micro computed tomography (CT) images of deeply carious extracted human teeth before and after caries removal. The full grey scale 0-255 yielded a median grey scale value of 0-9, 10-18, 19-25, 26-52, and 53-80 regarding dental pulp, infected carious dentin, affected carious dentin, normal dentin, and normal enamel, respectively. The simulator was connected to two haptic devices for a handpiece and mouth mirror. The visuo-tactile feedback during the operation varied depending on the grey scale. Sixth-year dental students underwent a pretraining assessment of caries removal on extracted teeth. The students were then randomly assigned to train on either the simulator (n=16) or conventional extracted teeth (n=16) for 3 days, after which the assessment was repeated. The posttraining performance of caries removal improved compared with pretraining in both groups (Wilcoxon, p<0.05). The equivalence test for proportional differences (two 1 sided t-tests) with a 0.2 margin confirmed that the participants in both groups had identical posttraining performance scores (95% CI=0.92, 1; p=0.00). In conclusion, training on the micro-CT multilayered caries model with the visuo tactile virtual reality simulator and conventional extracted tooth had equivalent effects on improving performance of minimally invasive caries removal. PMID- 29513644 TI - Advances in toxicological research and risk assessment. PMID- 29513645 TI - Characterization of methane emissions from five cold heavy oil production with sands (CHOPS) facilities. AB - : Cold heavy oil production with sands (CHOPS) is a common oil extraction method in the Canadian provinces of Alberta and Saskatchewan that can result in significant methane emissions due to annular venting. Little is known about the magnitude of these emissions, nor their contributions to the regional methane budget. Here the authors present the results of field measurements of methane emissions from CHOPS wells and compare them with self-reported venting rates. The tracer ratio method was used not only to analyze total site emissions but at one site it was also used to locate primary emission sources and quantify their contributions to the facility-wide emission rate, revealing the annular vent to be a dominant source. Emissions measured from five different CHOPS sites in Alberta showed large discrepancies between the measured and reported rates, with emissions being mainly underreported. These methane emission rates are placed in the context of current reporting procedures and the role that gas-oil ratio (GOR) measurements play in vented volume estimates. In addition to methane, emissions of higher hydrocarbons were also measured; a chemical "fingerprint" associated with CHOPS wells in this region reveals very low emission ratios of ethane, propane, and aromatics versus methane. The results of this study may inform future studies of CHOPS sites and aid in developing policy to mitigate regional methane emissions. IMPLICATIONS: Methane measurements from cold heavy oil production with sand (CHOPS) sites identify annular venting to be a potentially major source of emissions at these facilities. The measured emission rates are generally larger than reported by operators, with uncertainty in the gas-oil ratio (GOR) possibly playing a large role in this discrepancy. These results have potential policy implications for reducing methane emissions in Alberta in order to achieve the Canadian government's goal of reducing methane emissions by 40-45% below 2012 levels within 8 yr. PMID- 29513646 TI - Direct measurement of bipolar cell responses to electrical stimulation in wholemount mouse retina. AB - OBJECTIVE: This in vitro investigation examines the response of retinal bipolar cells to extracellular electrical stimulation. APPROACH: In vitro investigations characterizing the response of retinal neurons to electrical stimulation have primarily focused on retinal ganglion cells because they are the output neurons of the retina and their superficial position in the retina makes them readily accessible to in vitro recording techniques. Thus, the majority of information regarding the response of inner retinal neurons has been inferred from ganglion cell activity. Here we use patch clamp electrophysiology to directly record electrically-evoked activity in bipolar cells within the inner retina of normal Tg(Gng13-EGFP)GI206Gsat and degenerate rd10 Tg(Gng13-EGFP)GI206Gsat mice using a wholemount preparation. MAIN RESULTS: Bipolar cells respond to electrical stimulation with time-locked depolarizing voltage transients. The latency of the response declines with increases in stimulation amplitude. A desensitizing response is observed during repeated stimulation with 25 ms biphasic current pulses delivered at pulse rates greater than 6 pps. A burst of long-latency (200 1000 ms) inhibitory postsynaptic potentials are evoked by the stimulus and the burst exhibits evidence of a lower and upper stimulation threshold. SIGNIFICANCE: These results provide insights into the various types of bipolar cell activity elicited by electrical stimulation and may be useful for future retinal prosthesis stimulation protocols. This investigation uses patch clamp electrophysiology to provide direct analysis of ON-type bipolar cell responses to electrical stimulation in a wholemount retina preparation. It explores the effects of variable stimulus amplitudes, pulse widths, and frequencies in both normal and degenerate retina. The analysis adds to a body of work largely based upon indirect measurements of bipolar cell activity, and the methodology demonstrates an alternative retina preparation technique in which to acquire single-cell activity. PMID- 29513647 TI - Ex vivo validation of a stoichiometric dual energy CT proton stopping power ratio calibration. AB - A major source of uncertainty in proton therapy is the conversion of Hounsfield unit (HU) to proton stopping power ratio relative to water (SPR). In this study, we measured and quantified the accuracy of a stoichiometric dual energy CT (DECT) SPR calibration. We applied a stoichiometric DECT calibration method to derive the SPR using CT images acquired sequentially at [Formula: see text] and [Formula: see text]. The dual energy index was derived based on the HUs of the paired spectral images and used to calculate the effective atomic number (Z eff), relative electron density ([Formula: see text]), and SPRs of phantom and biological materials. Two methods were used to verify the derived SPRs. The first method measured the sample's water equivalent thicknesses to deduce the SPRs using a multi-layer ion chamber (MLIC) device. The second method utilized Gafchromic EBT3 film to directly compare relative ranges between sample and water after proton pencil beam irradiation. Ex vivo validation was performed using five different types of frozen animal tissues with the MLIC and three types of fresh animal tissues using film. In addition, the residual ranges recorded on the film were used to compare with those from the treatment planning system using both DECT and SECT derived SPRs. Bland-Altman analysis indicates that the differences between DECT and SPR measurement of tissue surrogates, frozen and fresh animal tissues has a mean of 0.07% and standard deviation of 0.58% compared to 0.55% and 1.94% respectively for single energy CT (SECT) and SPR measurement. Our ex vivo study indicates that the stoichiometric DECT SPR calibration method has the potential to be more accurate than SECT calibration under ideal conditions although beam hardening effects and other image artifacts may increase this uncertainty. PMID- 29513648 TI - Metabolic Profiling of Amino Acids Associated with Mortality in Patients with Acute Paraquat Poisoning. AB - BACKGROUND Paraquat is a major cause of fatal poisoning after ingestion in many parts of Asia and the Pacific nations. However, optimal prognostic indicators to evaluate patient mortality have not been unequivocally established. Following acute paraquat poisoning, a number of amino acids (AA), are abnormally expressed in metabolic pathways. However, the alterations in AA metabolite levels after paraquat poisoning remain unknown in humans. MATERIAL AND METHODS In the present study, 40 patients were enrolled, of whom 16 survived and 24 died. A metabolomics approach was used to assess changes in AA metabolites in plasma and its potential prognostic value following paraquat poisoning. Mass spectrometry (MS) based on metabolite identification was conducted. RESULTS Twenty-five AA levels in plasma were abnormally expressed in non-survivor patients. Among them, creatinine, indolelactate, and 3-(4-hydroxyphenyl)lactate were found to be highly correlated with paraquat death prediction. It was noted that the intensity levels of these 3 AA metabolites in the non-survivor group were substantially higher than in the survivor group. Furthermore, we examined receiver operating characteristic (ROC) curves for clinical validation. ROC results showed that 3-(4 hydroxyphenyl)lactate had the highest AUC of 0.84, while indolelactate and creatinine had AUCs of 0.75 and 0.83, respectively, suggesting that they can be used to predict the clinical outcome (although this methodology is expensive to implement). CONCLUSIONS Metabolic profiling of AA levels could be a reliable tool to identify effective indicators for the early high precision prognosis of paraquat poisoning. PMID- 29513650 TI - Confocal non-line-of-sight imaging based on the light-cone transform. AB - How to image objects that are hidden from a camera's view is a problem of fundamental importance to many fields of research, with applications in robotic vision, defence, remote sensing, medical imaging and autonomous vehicles. Non line-of-sight (NLOS) imaging at macroscopic scales has been demonstrated by scanning a visible surface with a pulsed laser and a time-resolved detector. Whereas light detection and ranging (LIDAR) systems use such measurements to recover the shape of visible objects from direct reflections, NLOS imaging reconstructs the shape and albedo of hidden objects from multiply scattered light. Despite recent advances, NLOS imaging has remained impractical owing to the prohibitive memory and processing requirements of existing reconstruction algorithms, and the extremely weak signal of multiply scattered light. Here we show that a confocal scanning procedure can address these challenges by facilitating the derivation of the light-cone transform to solve the NLOS reconstruction problem. This method requires much smaller computational and memory resources than previous reconstruction methods do and images hidden objects at unprecedented resolution. Confocal scanning also provides a sizeable increase in signal and range when imaging retroreflective objects. We quantify the resolution bounds of NLOS imaging, demonstrate its potential for real-time tracking and derive efficient algorithms that incorporate image priors and a physically accurate noise model. Additionally, we describe successful outdoor experiments of NLOS imaging under indirect sunlight. PMID- 29513649 TI - Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. AB - New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18 77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved. PMID- 29513651 TI - Gating mechanisms of acid-sensing ion channels. AB - Acid-sensing ion channels (ASICs) are trimeric, proton-gated and sodium-selective members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout vertebrate central and peripheral nervous systems. Gating of ASICs occurs on a millisecond time scale and the mechanism involves three conformational states: high pH resting, low pH open and low pH desensitized. Existing X-ray structures of ASIC1a describe the conformations of the open and desensitized states, but the structure of the high pH resting state and detailed mechanisms of the activation and desensitization of the channel have remained elusive. Here we present structures of the high pH resting state of homotrimeric chicken (Gallus gallus) ASIC1a, determined by X-ray crystallography and single particle cryo-electron microscopy, and present a comprehensive molecular mechanism for proton-dependent gating in ASICs. In the resting state, the position of the thumb domain is further from the three-fold molecular axis, thereby expanding the 'acidic pocket' in comparison to the open and desensitized states. Activation therefore involves 'closure' of the thumb into the acidic pocket, expansion of the lower palm domain and an iris-like opening of the channel gate. Furthermore, we demonstrate how the beta11-beta12 linkers that demarcate the upper and lower palm domains serve as a molecular 'clutch', and undergo a simple rearrangement to permit rapid desensitization. PMID- 29513652 TI - EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma. AB - Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours. PMID- 29513653 TI - Developmental diversification of cortical inhibitory interneurons. AB - Diverse subsets of cortical interneurons have vital roles in higher-order brain functions. To investigate how this diversity is generated, here we used single cell RNA sequencing to profile the transcriptomes of mouse cells collected along a developmental time course. Heterogeneity within mitotic progenitors in the ganglionic eminences is driven by a highly conserved maturation trajectory, alongside eminence-specific transcription factor expression that seeds the emergence of later diversity. Upon becoming postmitotic, progenitors diverge and differentiate into transcriptionally distinct states, including an interneuron precursor state. By integrating datasets across developmental time points, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, and uncovered the embryonic emergence of cardinal interneuron subtypes. Our analysis revealed that the transcription factor Mef2c, which is linked to various neuropsychiatric and neurodevelopmental disorders, delineates early precursors of parvalbumin-expressing neurons, and is essential for their development. These findings shed new light on the molecular diversification of early inhibitory precursors, and identify gene modules that may influence the specification of human interneuron subtypes. PMID- 29513655 TI - Altruism in a volatile world. AB - The evolution of altruism-costly self-sacrifice in the service of others-has puzzled biologists since The Origin of Species. For half a century, attempts to understand altruism have developed around the concept that altruists may help relatives to have extra offspring in order to spread shared genes. This theory known as inclusive fitness-is founded on a simple inequality termed Hamilton's rule. However, explanations of altruism have typically not considered the stochasticity of natural environments, which will not necessarily favour genotypes that produce the greatest average reproductive success. Moreover, empirical data across many taxa reveal associations between altruism and environmental stochasticity, a pattern not predicted by standard interpretations of Hamilton's rule. Here we derive Hamilton's rule with explicit stochasticity, leading to new predictions about the evolution of altruism. We show that altruists can increase the long-term success of their genotype by reducing the temporal variability in the number of offspring produced by their relatives. Consequently, costly altruism can evolve even if it has a net negative effect on the average reproductive success of related recipients. The selective pressure on volatility-suppressing altruism is proportional to the coefficient of variation in population fitness, and is therefore diminished by its own success. Our results formalize the hitherto elusive link between bet-hedging and altruism, and reveal missing fitness effects in the evolution of animal societies. PMID- 29513654 TI - Pursuing sustainable productivity with millions of smallholder farmers. AB - Sustainably feeding a growing population is a grand challenge, and one that is particularly difficult in regions that are dominated by smallholder farming. Despite local successes, mobilizing vast smallholder communities with science- and evidence-based management practices to simultaneously address production and pollution problems has been infeasible. Here we report the outcome of concerted efforts in engaging millions of Chinese smallholder farmers to adopt enhanced management practices for greater yield and environmental performance. First, we conducted field trials across China's major agroecological zones to develop locally applicable recommendations using a comprehensive decision-support program. Engaging farmers to adopt those recommendations involved the collaboration of a core network of 1,152 researchers with numerous extension agents and agribusiness personnel. From 2005 to 2015, about 20.9 million farmers in 452 counties adopted enhanced management practices in fields with a total of 37.7 million cumulative hectares over the years. Average yields (maize, rice and wheat) increased by 10.8-11.5%, generating a net grain output of 33 million tonnes (Mt). At the same time, application of nitrogen decreased by 14.7-18.1%, saving 1.2 Mt of nitrogen fertilizers. The increased grain output and decreased nitrogen fertilizer use were equivalent to US$12.2 billion. Estimated reactive nitrogen losses averaged 4.5-4.7 kg nitrogen per Megagram (Mg) with the intervention compared to 6.0-6.4 kg nitrogen per Mg without. Greenhouse gas emissions were 328 kg, 812 kg and 434 kg CO2 equivalent per Mg of maize, rice and wheat produced, respectively, compared to 422 kg, 941 kg and 549 kg CO2 equivalent per Mg without the intervention. On the basis of a large-scale survey (8.6 million farmer participants) and scenario analyses, we further demonstrate the potential impacts of implementing the enhanced management practices on China's food security and sustainability outlook. PMID- 29513656 TI - Pervasive phosphorus limitation of tree species but not communities in tropical forests. AB - Phosphorus availability is widely assumed to limit primary productivity in tropical forests, but support for this paradigm is equivocal. Although biogeochemical theory predicts that phosphorus limitation should be prevalent on old, strongly weathered soils, experimental manipulations have failed to detect a consistent response to phosphorus addition in species-rich lowland tropical forests. Here we show, by quantifying the growth of 541 tropical tree species across a steep natural phosphorus gradient in Panama, that phosphorus limitation is widespread at the level of individual species and strengthens markedly below a threshold of two parts per million exchangeable soil phosphate. However, this pervasive species-specific phosphorus limitation does not translate into a community-wide response, because some species grow rapidly on infertile soils despite extremely low phosphorus availability. These results redefine our understanding of nutrient limitation in diverse plant communities and have important implications for attempts to predict the response of tropical forests to environmental change. PMID- 29513657 TI - Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. AB - Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5 E11.5, including genome-wide loss of 5-methylcytosine. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro. PMID- 29513658 TI - BRDT is an essential epigenetic regulator for proper chromatin organization, silencing of sex chromosomes and crossover formation in male meiosis. AB - The double bromodomain and extra-terminal domain (BET) proteins are critical epigenetic readers that bind to acetylated histones in chromatin and regulate transcriptional activity and modulate changes in chromatin structure and organization. The testis-specific BET member, BRDT, is essential for the normal progression of spermatogenesis as mutations in the Brdt gene result in complete male sterility. Although BRDT is expressed in both spermatocytes and spermatids, loss of the first bromodomain of BRDT leads to severe defects in spermiogenesis without overtly compromising meiosis. In contrast, complete loss of BRDT blocks the progression of spermatocytes into the first meiotic division, resulting in a complete absence of post-meiotic cells. Although BRDT has been implicated in chromatin remodeling and mRNA processing during spermiogenesis, little is known about its role in meiotic processes. Here we report that BRDT is an essential regulator of chromatin organization and reprograming during prophase I of meiosis. Loss of BRDT function disrupts the epigenetic state of the meiotic sex chromosome inactivation in spermatocytes, affecting the synapsis and silencing of the X and Y chromosomes. We also found that BRDT controls the global chromatin organization and histone modifications of the chromatin attached to the synaptonemal complex. Furthermore, the homeostasis of crossover formation and localization during pachynema was altered, underlining a possible epigenetic mechanism by which crossovers are regulated and differentially established in mammalian male genomes. Our observations reveal novel findings about the function of BRDT in meiosis and provide insight into how epigenetic regulators modulate the progression of male mammalian meiosis and the formation of haploid gametes. PMID- 29513659 TI - Targeted versus non-targeted HIV testing offered via electronic questionnaire in a Swiss emergency department: A randomized controlled study. AB - BACKGROUND: In Switzerland, the national HIV testing recommendations propose targeted testing. Although the emergency department (ED) is mentioned specifically as a site where HIV testing should take place, the testing rate in our ED is 1% of patients seen. The aim of this study was to use electronic tablets to offer testing to ED patients and to examine whether non-targeted screening increased testing rates compared to targeted testing. METHODS: This randomised, cross-over design study took place at Lausanne University Hospital, Switzerland, between August and November 2015. Eligible patients were randomised to a targeted testing or a non-targeted screening arm. Using electronic tablets, targeted arm patients completed a risk factor assessment; patients with risk factors were offered free rapid HIV testing. Non-targeted arm patients received information about HIV and HIV testing on their tablet and were then offered testing. In a second step, patients who declined testing were crossed over to the other strategy. The primary endpoint was the HIV testing rate per arm. RESULTS: Eighty patients were recruited to each study arm. In the targeted arm, 17 patients (of 80, 21%) had at least one risk factor and were offered testing, of whom eight (of 17, 47%) accepted. HIV testing rate in the targeted arm was 10% (8/80) compared to 48% (38/80) in the non-targeted arm (P<0.001). Secondary cross screening, where targeted arm patients without risk factors were offered non targeted screening, increased the testing rate in the targeted arm to 45% (36/80). Among patients offered testing, the acceptance rate did not differ between targeted and non-targeted arms, at 48% and 53%, respectively (P = 0.9). DISCUSSION: In our centre, non-targeted HIV screening resulted in a higher testing rate than targeted testing due to more patients being offered a test. The acceptance rate of testing offered did not differ between targeted and non targeted arms. Electronic tablets were well-received by patients and easy to use. We conclude that non-targeted HIV screening using electronic tablets would increase the HIV testing rate in our ED. TRIAL REGISTRATION: ClinicalTrials.gov NCT03038724. PMID- 29513660 TI - Longitudinal trends in the frequency of medium and fast race winning times in Australian harness racing: Relationships with rules moderating whip use. AB - The use of whips in racing is subject to current debate, not least because the prospect that fatigued horses cannot respond renders the practice futile and inhumane. The racing industries maintain whip use is a form of encouragement and that the rules of racing that govern whip use safeguard horse welfare. The current study examined longitudinal trends in the frequency of medium and fast race winning times in Australian harness racing between September 2007 and August 2016 to explore relationships with a series of changes that moderated whip use. The first change, introduced January 2010, moderated whip action so that horses were struck with less force. Subsequent amendments reversed this change for the final 200m of the race except in one racing jurisdiction. However, those amendments were eventually reversed, restoring the first rule change in all geographic locations. Despite whip use being regulated from January 2010, a long term trend of increased frequency of both fast and medium winning times over 1609m (~1 mile) was noted. Even after adjusting for this trend, all whip handling codes were associated with greater odds of winning times being less than 1:55 minutes compared with the pre-2010 period. A similar finding for times less than 2:00 minutes did not reach statistical significance. Additionally, the periods immediately before and after introducing the most stringent regulations were compared. This revealed that, when introduced in 2010, these regulations were associated with faster winning times. Their re-introduction in 2016, was associated with no significant differences. Despite concerns that tightening of whip regulations might reduce performance, none of our analyses revealed any significant reduction in either fast or medium winning times in races following the tightening of regulations governing the use of the whip. These findings question the putative need for whips to improve racing performance. PMID- 29513663 TI - Correction: Prevalence of Active and Latent Yaws in the Solomon Islands 18 Months after Azithromycin Mass Drug Administration for Trachoma. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004927.]. PMID- 29513661 TI - Deploying digital health data to optimize influenza surveillance at national and local scales. AB - The surveillance of influenza activity is critical to early detection of epidemics and pandemics and the design of disease control strategies. Case reporting through a voluntary network of sentinel physicians is a commonly used method of passive surveillance for monitoring rates of influenza-like illness (ILI) worldwide. Despite its ubiquity, little attention has been given to the processes underlying the observation, collection, and spatial aggregation of sentinel surveillance data, and its subsequent effects on epidemiological understanding. We harnessed the high specificity of diagnosis codes in medical claims from a database that represented 2.5 billion visits from upwards of 120,000 United States healthcare providers each year. Among influenza seasons from 2002-2009 and the 2009 pandemic, we simulated limitations of sentinel surveillance systems such as low coverage and coarse spatial resolution, and performed Bayesian inference to probe the robustness of ecological inference and spatial prediction of disease burden. Our models suggest that a number of socio environmental factors, in addition to local population interactions, state specific health policies, as well as sampling effort may be responsible for the spatial patterns in U.S. sentinel ILI surveillance. In addition, we find that biases related to spatial aggregation were accentuated among areas with more heterogeneous disease risk, and sentinel systems designed with fixed reporting locations across seasons provided robust inference and prediction. With the growing availability of health-associated big data worldwide, our results suggest mechanisms for optimizing digital data streams to complement traditional surveillance in developed settings and enhance surveillance opportunities in developing countries. PMID- 29513662 TI - Arabidopsis ICK/KRP cyclin-dependent kinase inhibitors function to ensure the formation of one megaspore mother cell and one functional megaspore per ovule. AB - In most plants, the female germline starts with the differentiation of one megaspore mother cell (MMC) in each ovule that produces four megaspores through meiosis, one of which survives to become the functional megaspore (FM). The FM further develops into an embryo sac. Little is known regarding the control of MMC formation to one per ovule and the selective survival of the FM. The ICK/KRPs (interactor/inhibitor of cyclin-dependent kinase (CDK)/Kip-related proteins) are plant CDK inhibitors and cell cycle regulators. Here we report that in the ovules of Arabidopsis mutant with all seven ICK/KRP genes inactivated, supernumerary MMCs, FMs and embryo sacs were formed and the two embryo sacs could be fertilized to form two embryos with separate endosperm compartments. Twin seedlings were observed in about 2% seeds. Further, in the mutant ovules the number and position of surviving megaspores from one MMC were variable, indicating that the positional signal for determining the survival of megaspore was affected. Strikingly, ICK4 fusion protein with yellow fluorescence protein was strongly present in the degenerative megaspores but absent in the FM, suggesting an important role of ICKs in the degeneration of non-functional megaspores. The absence of or much weaker phenotypes in lower orders of mutants and complementation of the septuple mutant by ICK4 or ICK7 indicate that multiple ICK/KRPs function redundantly in restricting the formation of more than one MMC and in the selective survival of FM, which are critical to ensure the development of one embryo sac and one embryo per ovule. PMID- 29513664 TI - Robust vehicle detection in different weather conditions: Using MIPM. AB - Intelligent Transportation Systems (ITS) allow us to have high quality traffic information to reduce the risk of potentially critical situations. Conventional image-based traffic detection methods have difficulties acquiring good images due to perspective and background noise, poor lighting and weather conditions. In this paper, we propose a new method to accurately segment and track vehicles. After removing perspective using Modified Inverse Perspective Mapping (MIPM), Hough transform is applied to extract road lines and lanes. Then, Gaussian Mixture Models (GMM) are used to segment moving objects and to tackle car shadow effects, we apply a chromacity-based strategy. Finally, performance is evaluated through three different video benchmarks: own recorded videos in Madrid and Tehran (with different weather conditions at urban and interurban areas); and two well-known public datasets (KITTI and DETRAC). Our results indicate that the proposed algorithms are robust, and more accurate compared to others, especially when facing occlusions, lighting variations and weather conditions. PMID- 29513665 TI - Correction: Effect of Ionic Diffusion on Extracellular Potentials in Neural Tissue. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005193.]. PMID- 29513666 TI - Generation of iPSCs carrying a common LRRK2 risk allele for in vitro modeling of idiopathic Parkinson's disease. AB - Induced pluripotent stem cells (iPSCs) have recapitulated several aspects of Parkinson's disease (PD), but most iPSCs are derived from familial cases, which account for only about 15% of patients. Thus, while the emphasis has justifiably been on using iPSCs to model rare familial cases, models for the most common forms of PD are critically lacking. Here, we report the generation of an iPSC based model of idiopathic PD (iPD) with or without RS1491923, which is a common risk variant in the LRRK2 locus. Consistent with GWA studies, we found large variability in our datasets. However, iPSC-derived neurons carrying the risk allele emerged for displaying subtle disturbances of cellular degradative systems, in line with familial PD models. We also observed that treatment with the LRRK2 inhibitor CZC-25146 slightly reduced a marker of aSYN pathology in all iPD lines. Future iPSC-based studies may need to be structured similarly to large GWA studies in order to obtain relevant statistical power. However, results from this pilot study suggest that iPSC-based modeling represents an attractive way to investigate idiopathic diseases. PMID- 29513667 TI - Zika virus epidemiology in Bolivia: A seroprevalence study in volunteer blood donors. AB - BACKGROUND: Zika virus (ZIKV), was widely reported in Latin America and has been associated with neuropathologies, as microcephaly, but only few seroprevalence studies have been published to date. Our objective was to determine the seroprevalence amongst Bolivian blood donors and estimate the future potential circulation of the virus. METHODOLOGY: A ZIKV seroprevalence study was conducted between December 2016 and April 2017 in 814 asymptomatic Bolivian volunteer blood donors residing in various eco-environments corresponding to contrasting entomological activities. It was based on detection of IgG to ZIKV using NS1 ELISA screening, followed by a seroneutralisation test in case of positive or equivocal ELISA result. CONCLUSIONS/SIGNIFICANCE: Analysis revealed that ZIKV circulation occurred in tropical areas (Beni: 39%; Santa Cruz de la Sierra: 21.5%) but not in highlands (~0% in Cochabamba, La Paz, Tarija). It was modulated by Aedes aegypti activity and the virus spread was not limited by previous immunity to dengue. Cases were geo-localised in a wide range of urban areas in Santa Cruz and Trinidad. No differences in seroprevalence related to gender or age-groups could be identified. It is concluded that ZIKV has been intensely circulating in the Beni region and has still a significant potential for propagating in the area of Santa Cruz. PMID- 29513668 TI - Burnout among medical students during the first years of undergraduate school: Prevalence and associated factors. AB - OBJECTIVE: To evaluate the prevalence and possible factors associated with the development of burnout among medical students in the first years of undergraduate school. METHOD: A cross-sectional study was conducted at the Barretos School of Health Sciences, Dr. Paulo Prata. A total of 330 students in the first four years of medical undergraduate school were invited to participate in responding to the sociodemographic and Maslach Burnout Inventory-Student Survey (MBI-SS) questionnaires. The first-year group consisted of 150 students, followed by the second-, third-, and fourth-year groups, with 60 students each. RESULTS: Data from 265 students who answered at least the sociodemographic questionnaire and the MBI-SS were analyzed (response rate = 80.3%). One (n = 1, 0.3%) potential participant viewed the Informed Consent Form but did not agree to participate in the study. A total of 187 students (187/265, 70.6%) presented high levels of emotional exhaustion, 140 (140/265, 52.8%) had high cynicism, and 129 (129/265, 48.7%) had low academic efficacy. The two-dimensional criterion indicated that 119 (44.9%) students experienced burnout. Based on the three-dimensional criterion, 70 students (26.4%) presented with burnout. The year with the highest frequency of affected students for both criteria was the first year (p = 0.001). Personal attributes were able to explain 11% (DeltaR = 0.11) of the variability of burnout under the two-dimensional criterion and 14.4% (R2 = 0.144) under the three-dimensional criterion. CONCLUSION: This study showed a high prevalence of burnout among medical students in a private school using active teaching methodologies. In the first years of graduation, students' personal attributes (optimism and self-perception of health) and school attributes (motivation and routine of the exhaustive study) were associated with higher levels of burnout. These findings reinforce the need to establish preventive measures focused on the personal attributes of first-year students, providing better performance, motivation, optimism, and empathy in the subsequent stages of the course. PMID- 29513669 TI - Organisational capacity and its relationship to research use in six Australian health policy agencies. AB - There are calls for policymakers to make greater use of research when formulating policies. Therefore, it is important that policy organisations have a range of tools and systems to support their staff in using research in their work. The aim of the present study was to measure the extent to which a range of tools and systems to support research use were available within six Australian agencies with a role in health policy, and examine whether this was related to the extent of engagement with, and use of research in policymaking by their staff. The presence of relevant systems and tools was assessed via a structured interview called ORACLe which is conducted with a senior executive from the agency. To measure research use, four policymakers from each agency undertook a structured interview called SAGE, which assesses and scores the extent to which policymakers engaged with (i.e., searched for, appraised, and generated) research, and used research in the development of a specific policy document. The results showed that all agencies had at least a moderate range of tools and systems in place, in particular policy development processes; resources to access and use research (such as journals, databases, libraries, and access to research experts); processes to generate new research; and mechanisms to establish relationships with researchers. Agencies were less likely, however, to provide research training for staff and leaders, or to have evidence-based processes for evaluating existing policies. For the majority of agencies, the availability of tools and systems was related to the extent to which policymakers engaged with, and used research when developing policy documents. However, some agencies did not display this relationship, suggesting that other factors, namely the organisation's culture towards research use, must also be considered. PMID- 29513670 TI - First insights into the vocal repertoire of infant and juvenile Southern white rhinoceros. AB - Describing vocal repertoires represents an essential step towards gaining an overview about the complexity of acoustic communication in a given species. The analysis of infant vocalisations is essential for understanding the development and usage of species-specific vocalisations, but is often underrepresented, especially in species with long inter-birth intervals such as the white rhinoceros. Thus, this study aimed for the first time to characterise the infant and juvenile vocal repertoire of the Southern white rhinoceros and to relate these findings to the adult vocal repertoire. The behaviour of seven mother reared white rhinoceros calves (two males, five females) and one hand-reared calf (male), ranging from one month to four years, was simultaneously audio and video taped at three zoos. Normally reared infants and juveniles uttered four discriminable call types (Whine, Snort, Threat, and Pant) that were produced in different behavioural contexts. All call types were also uttered by the hand reared calf. Call rates of Whines, but not of the other call types, decreased with age. These findings provide the first evidence that infant and juvenile rhinoceros utter specific call types in distinct contexts, even if they grow up with limited social interaction with conspecifics. By comparing our findings with the current literature on vocalisations of adult white rhinoceros and other solitary rhinoceros species, we discuss to which extent differences in the social lifestyle across species affect acoustic communication in mammals. PMID- 29513671 TI - Implementation of an ergonomics intervention in a Swedish flight baggage handling company-A process evaluation. AB - OBJECTIVE: To conduct a process evaluation of the implementation of an ergonomics training program aimed at increasing the use of loading assist devices in flight baggage handling. METHODS: Feasibility related to the process items recruitment, reach, context, dose delivered (training time and content); dose received (participants' engagement); satisfaction with training; intermediate outcomes (skills, confidence and behaviors); and barriers and facilitators of the training intervention were assessed by qualitative and quantitative methods. RESULTS: Implementation proved successful regarding dose delivered, dose received and satisfaction. Confidence among participants in the training program in using and talking about devices, observed use of devices among colleagues, and internal feedback on work behavior increased significantly (p<0.01). Main facilitators were self-efficacy, motivation, and perceived utility of training among the trainees. Barriers included lack of peer support, opportunities to observe and practice behaviors, and follow-up activities; as well as staff reduction and job insecurity. CONCLUSIONS: In identifying important barriers and facilitators for a successful outcome, this study can help supporting the effectiveness of future interventions. Our results suggest that barriers caused by organizational changes may likely be alleviated by recruiting motivated trainees and securing strong organizational support for the implementation. PMID- 29513672 TI - 'Not all that burns is wood'. A social perspective on fuel exploitation and use during the Indus urban period (2600-1900 BC). AB - Ancient civilisations depended heavily on natural fuel resources for a wide array of activities, and this had an impact on such resources that can be traced in the archaeological record. At its urban apex, the populations of the Indus Civilisation (2600-1900 BC) produced a wide range of objects and crafts, several of which involved highly specialised pyrotechnology. In the wake of increasing aridity and a period of weakened monsoon rainfall that affected South Asia from 2100 BC, these activities potentially put pressure on the natural resource base that may have had to be counterbalanced by differentiation in fuel use. The combined analysis of archaeobotanical and geoarchaeological remains from four Indus urban phase archaeological sites, has enable an assessment of the mechanisms through which people exploited wood, and diversified their fuel resources to adapt to the arid to semi-arid environments in which they lived. The combined use of local wood species with alternative fuels, such as dung and crop processing leftovers, are evidence for resilient socio-ecological practices during the 700 years of Indus urbanism and perhaps beyond. PMID- 29513673 TI - Genomic diversity is similar between Atlantic Forest restorations and natural remnants for the native tree Casearia sylvestris Sw. AB - The primary focus of tropical forest restoration has been the recovery of forest structure and tree taxonomic diversity, with limited attention given to genetic conservation. Populations reintroduced through restoration plantings may have low genetic diversity and be genetically structured due to founder effects and genetic drift, which limit the potential of restoration to recover ecologically resilient plant communities. Here, we studied the genetic diversity, genetic structure and differentiation using single nucleotide polymorphisms (SNP) markers between restored and natural populations of the native tree Casearia sylvestris in the Atlantic Forest of Brazil. We sampled leaves from approximately 24 adult individuals in each of the study sites: two restoration plantations (27 and 62 years old) and two forest remnants. We prepared and sequenced a genotyping-by sequencing library, SNP markers were identified de novo using Stacks pipeline, and genetic parameters and structure analyses were then estimated for populations. The sequencing step was successful for 80 sampled individuals. Neutral genetic diversity was similar among restored and natural populations (AR = 1.72 +/- 0.005; HO = 0.135 +/- 0.005; HE = 0.167 +/- 0.005; FIS = 0.16 +/- 0.022), which were not genetically structured by population subdivision. In spite of this absence of genetic structure by population we found genetic structure within populations but even so there is not spatial genetic structure in any population studied. Less than 1% of the neutral alleles were exclusive to a population. In general, contrary to our expectations, restoration plantations were then effective for conserving tree genetic diversity in human-modified tropical landscapes. Furthermore, we demonstrate that genotyping-by-sequencing can be a useful tool in restoration genetics. PMID- 29513674 TI - Integrating HIV and hypertension management in low-resource settings: Lessons from Malawi. AB - Pragna Patel and colleagues describe the implementation of a hypertension management model for HIV-infected people in Malawi. PMID- 29513675 TI - Doublethink and scale mismatch polarize policies for an invasive tree. AB - Mismatches between invasive species management policies and ecological knowledge can lead to profound societal consequences. For this reason, natural resource agencies have adopted the scientifically-based density-impact invasive species curve to guide invasive species management. We use the density-impact model to evaluate how well management policies for a native invader (Juniperus virginiana) match scientific guidelines. Juniperus virginiana invasion is causing a sub continental regime shift from grasslands to woodlands in central North America, and its impacts span collapses in endemic diversity, heightened wildfire risk, and crashes in grazing land profitability. We (1) use land cover data to identify the stage of Juniperus virginiana invasion for three ecoregions within Nebraska, USA, (2) determine the range of invasion stages at individual land parcel extents within each ecoregion based on the density-impact model, and (3) determine policy alignment and mismatches relative to the density-impact model in order to assess their potential to meet sustainability targets and avoid societal impacts as Juniperus virginiana abundance increases. We found that nearly all policies evidenced doublethink and policy-ecology mismatches, for instance, promoting spread of Juniperus virginiana regardless of invasion stage while simultaneously managing it as a native invader in the same ecoregion. Like other invasive species, theory and literature for this native invader indicate that the consequences of invasion are unlikely to be prevented if policies fail to prioritize management at incipient invasion stages. Theory suggests a more realistic approach would be to align policy with the stage of invasion at local and ecoregion management scales. There is a need for scientists, policy makers, and ecosystem managers to move past ideologies governing native versus non-native invader classification and toward a framework that accounts for the uniqueness of native species invasions, their anthropogenic drivers, and their impacts on ecosystem services. PMID- 29513676 TI - Mechanical endovascular therapy for acute ischemic stroke: An indirect treatment comparison between Solitaire and Penumbra thrombectomy devices. AB - BACKGROUND: Randomized controlled trials (RCTs) have compared mechanical endovascular therapy (MET) in addition to intravenous tissue plasminogen activator (IVtPA) to IVtPA alone for the management of acute ischemic stroke (AIS). Direct comparative studies between individual METs are not available. In lieu of head-to-head randomized control trials, we performed an adjusted indirect treatment comparison (ITC) meta-analysis to assess the comparative efficacy and safety of different METs, Solitaire+IVtPA and Penumbra+IVtPA in AIS patients. METHODS AND FINDINGS: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from January 1, 2005 through April 1, 2017 for RCTs in AIS patients, comparing a single MET+IVtPA to IVtPA alone and reporting shift in ordinal modified Rankin Scale (mRS) score at 90 days. Secondary endpoints included 90 day mortality and symptomatic intracranial hemorrhage (sICH). Endpoints were pooled using traditional random effects meta-analysis methods, producing odds ratios and 95% confidence intervals. Adjusted ITCs using pooled estimates were then performed. Three studies (SWIFT PRIME, EXTEND-IA, THERAPY) were included; two evaluating the Solitaire stent retriever and one the Penumbra system. Traditional meta-analysis demonstrated that each MET+IVtPA resulted in increased odds of improving ordinal mRS score vs. IVtPA alone, but did not alter the odds of death or sICH. Adjusted ITC showed no significant difference between the METs for any outcome. CONCLUSION: No significant difference in efficacy or safety between the Solitaire and Penumbra devices was observed. PMID- 29513677 TI - Deblurring traffic sign images based on exemplars. AB - Motion blur appearing in traffic sign images may lead to poor recognition results, and therefore it is of great significance to study how to deblur the images. In this paper, a novel method for deblurring traffic sign is proposed based on exemplars and several related approaches are also made. First, an exemplar dataset construction method is proposed based on multiple-size partition strategy to lower calculation cost of exemplar matching. Second, a matching criterion based on gradient information and entropy correlation coefficient is also proposed to enhance the matching accuracy. Third, L0.5-norm is introduced as the regularization item to maintain the sparsity of blur kernel. Experiments verify the superiority of the proposed approaches and extensive evaluations against state-of-the-art methods demonstrate the effectiveness of the proposed algorithm. PMID- 29513678 TI - Neurological manifestations in chronic hepatitis C patients receiving care in a reference hospital in sub-Saharan Africa: A cross-sectional study. AB - BACKGROUND: Chronic hepatitis C infection is a major public health concern, with a high burden in Sub-Saharan Africa. There is growing evidence that chronic hepatitis C virus (HCV) infection causes neurological complications. This study aimed at assessing the prevalence and factors associated with neurological manifestations in chronic hepatitis C patients. METHODS: Through a cross sectional design, a semi-structured questionnaire was used to collect data from consecutive chronic HCV infected patients attending the outpatient gastroenterology unit of the Douala General Hospital (DGH). Data collection was by interview, patient record review (including HCV RNA quantification, HCV genotyping and the assessment of liver fibrosis and necroinflammatory activity), clinical examination complemented by 3 tools; Neuropathic pain diagnostic questionnaire, Brief peripheral neuropathy screen and mini mental state examination score. Data were analysed using Statistical package for social sciences version 20 for windows. RESULTS: Of the 121 chronic hepatitis C patients (51.2% males) recruited, 54.5% (95% Confidence interval: 46.3%, 62.8%) had at least one neurological manifestation, with peripheral nervous system manifestations being more common (50.4%). Age >= 55 years (Adjusted Odds Ratio: 4.82, 95%CI: 1.02-18.81, p = 0.02), longer duration of illness (AOR: 1.012, 95%CI: 1.00-1.02, p = 0.01) and high viral load (AOR: 3.40, 95% CI: 1.20-9.64, p = 0.02) were significantly associated with neurological manifestations. Peripheral neuropathy was the most common neurological manifestation (49.6%), presenting mainly as sensory neuropathy (47.9%). Age >= 55 years (AOR: 6.25, 95%CI: 1.33-29.08, p = 0.02) and longer duration of illness (AOR: 1.01, 1.00 1.02, p = 0.01) were significantly associated with peripheral neuropathy. CONCLUSION: Over half of the patients with chronic hepatitis C attending the DGH have a neurological manifestation, mainly presenting as sensory peripheral neuropathy. Routine screening of chronic hepatitis C patients for peripheral neuropathy is therefore necessary, with prime focus on those with older age and longer duration of illness. PMID- 29513679 TI - Transcriptome analysis of nitric oxide-responsive genes in upland cotton (Gossypium hirsutum). AB - Nitric oxide (NO) is an important signaling molecule with diverse physiological functions in plants. It is therefore important to characterize the downstream genes and signal transduction networks modulated by NO. Here, we identified 1,932 differentially expressed genes (DEGs) responding to NO in upland cotton using high throughput tag sequencing. The results of quantitative real-time polymerase chain reaction (qRT-PCR) analysis of 25 DEGs showed good consistency. Gene Ontology (GO) and KEGG pathway were analyzed to gain a better understanding of these DEGs. We identified 157 DEGs belonging to 36 transcription factor (TF) families and 72 DEGs related to eight plant hormones, among which several TF families and hormones were involved in stress responses. Hydrogen peroxide and malondialdehyde (MDA) contents were increased, as well related genes after treatment with sodium nitroprusside (SNP) (an NO donor), suggesting a role for NO in the plant stress response. Finally, we compared of the current and previous data indicating a massive number of NO-responsive genes at the large-scale transcriptome level. This study evaluated the landscape of NO-responsive genes in cotton and identified the involvement of NO in the stress response. Some of the identified DEGs represent good candidates for further functional analysis in cotton. PMID- 29513680 TI - Augmented frontal cortex diacylglycerol levels in Parkinson's disease and Lewy Body Disease. AB - BACKGROUND: Research from our laboratory, and that of other investigators, has demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of subjects with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). We have extended these observations to investigate the frontal cortex of subjects with Parkinson's disease (PD) and Lewy Body Disease (LBD), with and without coexisting pathologic features of AD. METHODS/PRINCIPAL FINDINGS: Utilizing a high-resolution mass spectrometry analytical platform, we clearly demonstrate that DAG levels are significantly increased in the frontal cortex of subjects with PD, LBD with intermediate neocortical AD neuropathology, and in LBD with established neocortical AD neuropathology. In the case of the PD cohort, increases in cortical DAG levels were detected in cases with no neocortical pathology but were greater in subjects with neocortical pathology. These data suggest that DAG changes occur early in the disease processes and are amplified as cortical dysfunction becomes more established. CONCLUSIONS: These findings suggest that altered DAG synthesis/metabolism is a common feature of neurodegenerative diseases, characterized by proteinopathy, that ultimately result in cognitive deficits. With regard to the mechanism responsible for these biochemical alterations, selective decrements in cortical levels of phosphatidylcholines in LBD and PD suggest that augmented degradation and/or decreased synthesis of these structural glycerophospholipids may contribute to increases in the pool size of free DAGs. The observed augmentation of DAG levels may be phospholipase-driven since neuroinflammation is a consistent feature of all disease cohorts. If this conclusion can be validated it would support utilizing DAG levels as a biomarker of the early disease process and the investigation of early intervention with anti-inflammatory agents. PMID- 29513681 TI - Reward abundance interferes with error-based learning in a visuomotor adaptation task. AB - The brain rapidly adapts reaching movements to changing circumstances by using visual feedback about errors. Providing reward in addition to error feedback facilitates the adaptation but the underlying mechanism is unknown. Here, we investigate whether the proportion of trials rewarded (the 'reward abundance') influences how much participants adapt to their errors. We used a 3D multi-target pointing task in which reward alone is insufficient for motor adaptation. Participants (N = 423) performed the pointing task with feedback based on a shifted hand-position. On a proportion of trials we gave them rewarding feedback that their hand hit the target. Half of the participants only received this reward feedback. The other half also received feedback about endpoint errors. In different groups, we varied the proportion of trials that was rewarded. As expected, participants who received feedback about their errors did adapt, but participants who only received reward-feedback did not. Critically, participants who received abundant rewards adapted less to their errors than participants who received less reward. Thus, reward abundance negatively influences how much participants learn from their errors. Probably participants used a mechanism that relied more on the reward feedback when the reward was abundant. Because participants could not adapt to the reward, this interfered with adaptation to errors. PMID- 29513682 TI - Single-session tDCS over the dominant hemisphere affects contralateral spectral EEG power, but does not enhance neurofeedback-guided event-related desynchronization of the non-dominant hemisphere's sensorimotor rhythm. AB - BACKGROUND AND OBJECTIVE: Transcranial direct current stimulation (tDCS) and neurofeedback-guided motor imagery (MI) have attracted considerable interest in neurorehabilitation, given their ability to influence neuroplasticity. As tDCS has been shown to modulate event-related desynchronization (ERD), the neural signature of motor imagery detected for neurofeedback, a combination of the techniques was recently proposed. One limitation of this approach is that the area targeted for stimulation is the same from which the signal for neurofeedback is acquired. As tDCS may interfere with proximal electroencephalographic (EEG) electrodes, in this study our aim was to test whether contralateral tDCS could have interhemispheric effects on the spectral power of the unstimulated hemisphere, possibly mediated by transcallosal connection, and whether such effects could be used to enhance ERD magnitudes. A contralateral stimulation approach would indeed facilitate co-registration, as the stimulation electrode would be far from the recording sites. METHODS: Twenty right-handed healthy volunteers (aged 21 to 32) participated in the study: ten assigned to cathodal, ten to anodal versus sham stimulation. We applied stimulation over the dominant (left) hemisphere, and assessed ERD and spectral power over the non-dominant (right) hemisphere. The effect of tDCS was evaluated over time. Spectral power was assessed in theta, alpha and beta bands, under both rest and MI conditions, while ERD was evaluated in alpha and beta bands. RESULTS: Two main findings emerged: (1) contralateral alpha-ERD was reduced after anodal (p = 0.0147), but not enhanced after cathodal tDCS; (2) both stimulations had remote effects on the spectral power of the contralateral hemisphere, particularly in theta and alpha (significant differences in the topographical t-value maps). CONCLUSION: The absence of contralateral cathodal ERD enhancement suggests that the protocol is not applicable in the context of MI training. Nevertheless, ERD results of anodal and spectral power results of both stimulations complement recent findings on the distant tDCS effects between functionally related areas. PMID- 29513684 TI - Prevalence of clinical trial status discrepancies: A cross-sectional study of 10,492 trials registered on both ClinicalTrials.gov and the European Union Clinical Trials Register. AB - OBJECTIVE: Trial registries are a key source of information for clinicians and researchers. While building OpenTrials, an open database of public trial information, we identified errors and omissions in registries, including discrepancies between descriptions of the same trial in different registries. We set out to ascertain the prevalence of discrepancies in trial completion status using a cohort of trials registered on both the European Union Clinical Trials Register (EUCTR) and ClinicalTrials.gov. STUDY DESIGN AND SETTING: We used matching titles and registry IDs provided by both registries to build a cohort of dual-registered trials. Completion statuses were compared; we calculated descriptive statistics on the prevalence of discrepancies. RESULTS: 11,988 dual registered trials were identified. 1,496 did not provide a comparable completion status, leaving 10,492 trials. 16.2% were discrepant on completion status. The majority of discrepancies (90.5%) were a 'completed' trial on ClinicalTrials.gov inaccurately marked as 'ongoing' on EUCTR. Overall, 33.9% of dual-registered trials described as 'ongoing' on EUCTR were listed as 'completed' on ClinicalTrials.gov. CONCLUSION: Completion status on registries is commonly inaccurate. Previous work on publication bias may underestimate non-reporting. We describe simple steps registry owners and trialists could take to improve accuracy. PMID- 29513683 TI - Individual differences in regulatory mode moderate the effectiveness of a pilot mHealth trial for diabetes management among older veterans. AB - mHealth tools to help people manage chronic illnesses have surged in popularity, but evidence of their effectiveness remains mixed. The aim of this study was to address a gap in the mHealth and health psychology literatures by investigating how individual differences in psychological traits are associated with mHealth effectiveness. Drawing from regulatory mode theory, we tested the role of locomotion and assessment in explaining why mHealth tools are effective for some but not everyone. A 13-week pilot study investigated the effectiveness of an mHealth app in improving health behaviors among older veterans (n = 27) with poorly controlled Type 2 diabetes. We developed a gamified mHealth tool (DiaSocial) aimed at encouraging tracking of glucose control, exercise, nutrition, and medication adherence. Important individual differences in longitudinal trends of adherence, operationalized as points earned for healthy behavior, over the course of the 13-week study period were found. Specifically, low locomotion was associated with unchanging levels of adherence during the course of the study. In contrast, high locomotion was associated with generally stronger adherence although it exhibited a quadratic longitudinal trend. In addition, high assessment was associated with a marginal, positive trend in adherence over time while low assessment was associated with a marginal, negative trend. Next, we examined the relationship between greater adherence and improved clinical outcomes, finding that greater adherence was associated with greater reductions in glycated hemoglobin (HbA1c) levels. Findings from the pilot study suggest that mHealth technologies can help older adults improve their diabetes management, but a "one size fits all" approach may yield suboptimal outcomes. PMID- 29513685 TI - Asymmetric affective forecasting errors and their correlation with subjective well-being. AB - AIMS: Social scientists have postulated that the discrepancy between achievements and expectations affects individuals' subjective well-being. Still, little has been done to qualify and quantify such a psychological effect. Our empirical analysis assesses the consequences of positive and negative affective forecasting errors-the difference between realized and expected subjective well-being-on the subsequent level of subjective well-being. DATA: We use longitudinal data on a representative sample of 13,431 individuals from the German Socio-Economic Panel. In our sample, 52% of individuals are females, average age is 43 years, average years of education is 11.4 and 27% of our sample lives in East Germany. Subjective well-being (measured by self-reported life satisfaction) is assessed on a 0-10 discrete scale and its sample average is equal to 6.75 points. METHODS: We develop a simple theoretical framework to assess the consequences of positive and negative affective forecasting errors-the difference between realized and expected subjective well-being-on the subsequent level of subjective well-being, properly accounting for the endogenous adjustment of expectations to positive and negative affective forecasting errors, and use it to derive testable predictions. Given the theoretical framework, we estimate two panel-data equations, the first depicting the association between positive and negative affective forecasting errors and the successive level of subjective well-being and the second describing the correlation between subjective well-being expectations for the future and hedonic failures and successes. Our models control for individual fixed effects and a large battery of time-varying demographic characteristics, health and socio-economic status. RESULTS AND CONCLUSIONS: While surpassing expectations is uncorrelated with subjective well-being, failing to match expectations is negatively associated with subsequent realizations of subjective well-being. Expectations are positively (negatively) correlated to positive (negative) forecasting errors. We speculate that in the first case the positive adjustment in expectations is strong enough to cancel out the potential positive effects on subjective well-being of beaten expectations, while in the second case it is not, and individuals persistently bear the negative emotional consequences of not achieving expectations. PMID- 29513686 TI - Antibacterial activity and safety of commercial veterinary cationic steroid antibiotics and neutral superoxidized water. AB - Antibiotic resistance of bacteria common to the ocular surface is an evolving problem. Thus, novel treatment options with new modes of action are required. We investigated the antibacterial activity and safety of three commercially available topical veterinary ophthalmic products (cationic steroid antibiotics, products A and B, and a neutral superoxidized water, product C) to determine their potential use as antimicrobial alternatives. The minimum inhibitory concentrations (MIC) of the three products were determined against 17 antibiotic resistant bacterial clinical isolates from the ocular surface. Using a standard cytotoxicity assay, the products at varying concentrations were evaluated with a corneal fibroblast cell line and a macrophage-like cell line to determine their potential toxic effect in vitro. The commercial ophthalmic solutions, ofloxacin 0.3%, tobramycin 0.3% and gentamicin 0.3% were used as positive controls for the MIC and tobramycin 0.3% was used as positive control for the cytotoxicity assays. For the MIC, Product C showed no inhibition of growth for any organisms, while Products A and B showed inhibition of growth similar to slightly less than the positive controls. For the cytotoxicity assays, Product C exhibited minimal toxicity while Products A and B exhibited toxicity similar to the controls. In conclusion, Product C had no antibacterial activity in these assays, while Products A and B had antibacterial profiles similar to slightly less than common topical ophthalmic antibiotics and cytotoxicity profiles similar to common topical ophthalmic antibiotics. To our knowledge, this is the first report on the antibacterial activity and safety of the cationic steroid antibiotics and superoxidized water. PMID- 29513687 TI - Generation of functional cardiomyocytes from rat embryonic and induced pluripotent stem cells using feeder-free expansion and differentiation in suspension culture. AB - The possibility to generate cardiomyocytes from pluripotent stem cells in vitro has enormous significance for basic research, disease modeling, drug development and heart repair. The concept of heart muscle reconstruction has been studied and optimized in the rat model using rat primary cardiovascular cells or xenogeneic pluripotent stem cell derived-cardiomyocytes for years. However, the lack of rat pluripotent stem cells (rPSCs) and their cardiovascular derivatives prevented the establishment of an authentic clinically relevant syngeneic or allogeneic rat heart regeneration model. In this study, we comparatively explored the potential of recently available rat embryonic stem cells (rESCs) and induced pluripotent stem cells (riPSCs) as a source for cardiomyocytes (CMs). We developed feeder cell-free culture conditions facilitating the expansion of undifferentiated rPSCs and initiated cardiac differentiation by embryoid body (EB)-formation in agarose microwell arrays, which substituted the robust but labor-intensive hanging drop (HD) method. Ascorbic acid was identified as an efficient enhancer of cardiac differentiation in both rPSC types by significantly increasing the number of beating EBs (3.6 +/- 1.6-fold for rESCs and 17.6 +/- 3.2-fold for riPSCs). These optimizations resulted in a differentiation efficiency of up to 20% cTnTpos rPSC derived CMs. CMs showed spontaneous contractions, expressed cardiac markers and had typical morphological features. Electrophysiology of riPSC-CMs revealed different cardiac subtypes and physiological responses to cardio-active drugs. In conclusion, we describe rPSCs as a robust source of CMs, which is a prerequisite for detailed preclinical studies of myocardial reconstruction in a physiologically and immunologically relevant small animal model. PMID- 29513688 TI - Relationship between sleep quality and dizziness. AB - OBJECTIVE: Poor sleep quality has a number of significant negative effects on daytime function. However, few studies have examined sleep quality in patients with dizziness. Here, we investigated the potential association between sleep quality and various types of dizziness. SUBJECTS AND METHODS: We examined dizziness and sleep disturbance in 237 patients experiencing dizziness using Korean versions of the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), and Dizziness Handicap Inventory (DHI). All participants were classified as having benign paroxysmal positional vertigo (BPPV), Meniere's disease (MD), vestibular neuritis (VN), vestibular migraine (VM), psychogenic dizziness (PD), or Other. RESULTS: The mean PSQI and ISI scores were highest in the PD group. The rate of sleep disturbance was highest in the Other group when the cut-off score for each questionnaire was set differently, except ISI >= 15. The correlation between DHI and sleep disturbance indices was highest in the VM group. Multivariate regression showed that PSQI score and DHI-E score were significantly related to the PD and Other groups, while the Other group was significantly related to the ISI score. CONCLUSION: The findings of this study strongly suggest that there are associations between sleep quality and some disease subtypes associated with dizziness. Therefore, it is important to consider sleep disturbance in patients with psychogenic dizziness, such as phobic postural vertigo and chronic subjective dizziness, or nonspecific dizziness. PMID- 29513689 TI - Is local trait variation related to total range size of tropical trees? AB - The reasons why the range size of closely related species often varies significantly have intrigued scientists for many years. Among other hypotheses, species with high trait variation were suggested to occupy more diverse environments, have more continuity in their distributions, and consequently have larger range sizes. Here, using 34 tree species of lowlands tropical rainforest in southern Costa Rica, we explored whether inherent trait variability expressed at the local scale in functional traits is related to the species' total geographical range size. We formed 17 congeneric pairs of one narrow endemic and one widespread species, sampled 335 individuals and measured eight functional traits: leaf area, leaf thickness, leaf dry matter content, specific leaf area, leaf nitrogen content, leaf phosphorus content, leaf nitrogen to phosphorus ratio, and wood specific gravity. We tested whether there are significant differences in the locally expressed variation of individual traits or in multidimensional trait variance between the species in congeneric pairs and whether species' range size could hence be predicted from local trait variability. However, we could not find such differences between widely distributed and narrow range species. We discuss the possible reasons for these findings including the fact that higher trait variability of widespread species may result from successive local adaptations during range expansion and may hence often be an effect rather than the cause of larger ranges. PMID- 29513690 TI - Advanced quantitative methods in correlating sarcopenic muscle degeneration with lower extremity function biometrics and comorbidities. AB - Sarcopenic muscular degeneration has been consistently identified as an independent risk factor for mortality in aging populations. Recent investigations have realized the quantitative potential of computed tomography (CT) image analysis to describe skeletal muscle volume and composition; however, the optimum approach to assessing these data remains debated. Current literature reports average Hounsfield unit (HU) values and/or segmented soft tissue cross-sectional areas to investigate muscle quality. However, standardized methods for CT analyses and their utility as a comorbidity index remain undefined, and no existing studies compare these methods to the assessment of entire radiodensitometric distributions. The primary aim of this study was to present a comparison of nonlinear trimodal regression analysis (NTRA) parameters of entire radiodensitometric muscle distributions against extant CT metrics and their correlation with lower extremity function (LEF) biometrics (normal/fast gait speed, timed up-and-go, and isometric leg strength) and biochemical and nutritional parameters, such as total solubilized cholesterol (SCHOL) and body mass index (BMI). Data were obtained from 3,162 subjects, aged 66-96 years, from the population-based AGES-Reykjavik Study. 1-D k-means clustering was employed to discretize each biometric and comorbidity dataset into twelve subpopulations, in accordance with Sturges' Formula for Class Selection. Dataset linear regressions were performed against eleven NTRA distribution parameters and standard CT analyses (fat/muscle cross-sectional area and average HU value). Parameters from NTRA and CT standards were analogously assembled by age and sex. Analysis of specific NTRA parameters with standard CT results showed linear correlation coefficients greater than 0.85, but multiple regression analysis of correlative NTRA parameters yielded a correlation coefficient of 0.99 (P<0.005). These results highlight the specificities of each muscle quality metric to LEF biometrics, SCHOL, and BMI, and particularly highlight the value of the connective tissue regime in this regard. PMID- 29513691 TI - Poor biosecurity could lead to disease outbreaks in animal populations. AB - Human-mediated disease outbreaks due to poor biosecurity practices when processing animals in wild populations have been suspected. We tested whether not changing nitrile gloves between processing wood frog (Lithobates sylvaticus) tadpoles and co-housing individuals increased pathogen transmission and subsequent diseased-induced mortality caused by the emerging pathogen, ranavirus. We found that not changing gloves between processing infected and uninfected tadpoles resulted in transmission of ranavirus and increased the risk of mortality of uninfected tadpoles by 30X. Co-housing tadpoles for only 15 minutes with 10% of individuals infected resulted in ranavirus transmission and 50% mortality of uninfected tadpoles. More extreme mortality was observed when the co housing infection prevalence was >10%. Our results illustrate that human-induced disease outbreaks due to poor biosecurity practices are possible in wild animal populations. PMID- 29513692 TI - Vaccination of lambs against Haemonchus contortus with the recombinant rHc23. Effect of adjuvant and antigen dose. AB - Haemonchus contortus is the most pathogenic gastrointestinal helminth of small ruminants. Natural or experimental repeated infections and several native antigens confer a partially protective immune response but vaccination with subunit antigens has been elusive. Promising results have been obtained with a recombinant form of a somatic antigen (rHc23). In this paper we present the results obtained in vaccination trials in lambs using two dosages of rHc23 and standard adjuvants. Six-months old Manchego females lambs were vaccinated with rHc23 (50 or 200 MUg/dose) adjuvanted with 1mL aluminum hydroxide on days -42, 28 and -14 or with 200 MUg/dose rHc23 and 5 mg Quil A on days -49, -28 and -7. Control lambs were kept receiving only the adjuvants the same days or no treatment. Moreover one group did not receive any treatment or infection. On day 0 vaccinated lambs, untreated animals and those receiving the adjuvant were infected per os with a monospecific single infection of 4000 L3 of H. contortus. Infection was kept for 58 days and follow-up included the determination of serum specific antibody response (ELISA, WB), hematological parameters (eosinophil counts, hematocrit) and fecal egg counts (epg). Absence of hematocrit alterations, reduction of helminth's eggs output and abomasal parasite burden at the end of the experiment were the efficacy criteria of vaccination with the recombinant. Immunization with both adjuvants and antigen dosages elicited strong antibody responses particularly with Quil A. Vaccinated groups showed significant reduction of fecal egg excretion and abomasal helminth burdens. Highest protection of lambs against challenge was achieved with aluminum hydroxide and 200 MUg/dose rHc23 with a reduction of over 70% of the abomasal burden and over 80% of fecal egg output. Results suggest that rHc23 could be a valuable recombinant candidate for vaccination against haemonchosis. No clear relationship was found between antibody levels and protection this pointing towards involvement of both humoral and cellular components in the protective response elicited by rHc23. PMID- 29513693 TI - Health and health risk behaviour of adolescents-Differences according to family structure. Results of the German KiGGS cohort study. AB - OBJECTIVE: This study's aim was to investigate the association between family structure and different health-related outcomes in adolescence (self-rated health, emotional and behavioural problems, health-related quality of life, regular smoking, and heavy episodic drinking). Furthermore, we analysed the extent to which socio-economic status, family cohesion and the pre-transition health status explain family structure-related health disparities. METHODS: We used longitudinal data from the first two waves of the German KiGGS cohort study carried out by the Robert Koch Institute (baseline: 2003-2006, follow-up: 2009 2012). The sample comprised 4,692 respondents aged 11 to 17 years. Using data from both waves, effects of family structure on health status at follow-up were calculated applying linear and logistic regression models. RESULTS: We found that adolescents continuously living with both birth parents were in good health. Adolescents whose parents separated after the baseline survey, reported poorer health and were more likely to smoke. The transition from stepfamily to single parent family was also associated with a higher risk of regular smoking. Lower health-related quality of life as well as higher scores for emotional and behavioural problems occurred in almost all non-nuclear family structures, although not all effects were statistically significant. No significant effects of family structure on heavy episodic drinking were found. While family cohesion mediated the effects of family structure on adolescents' health, the mediating effect of socio-economic status was small. After controlling for pre-transition health, the effects were even lower. CONCLUSIONS: Because the direct effects of family structure on adolescents' health were small and family cohesion was found to be an important mediator in the association between family structure and adolescents' health, prevention programmes and interventions should be directed towards the parent-adolescent relationship rather than just the family structure, in order to minimize the psychosocial stress of adolescents during the period of family transition. PMID- 29513694 TI - Morphological and mechanical properties of flexible resilin joints on damselfly wings (Rhinocypha spp.). AB - Resilin functions as an elastic spring that demonstrates extraordinary extensibility and elasticity. Here we use combined techniques, laser scanning confocal microscopy (LSCM) and scanning electron microscopy (SEM) to illuminate the structure and study the function of wing flexibility in damselflies, focusing on the genus Rhinocypha. Morphological studies using LSCM and SEM revealed that resilin patches and cuticular spikes were widespread along the longitudinal veins on both dorsal and ventral wing surfaces. Nanoindentation was performed by using atomic force microscopy (AFM), where the wing samples were divided into three sections (membrane of the wing, mobile and immobile joints). The resulting topographic images revealed the presence of various sizes of nanostructures for all sample sections. The elasticity range values were: membrane (0.04 to 0.16 GPa), mobile joint (1.1 to 2.0 GPa) and immobile joint (1.8 to 6.0 GPa). The elastomeric and glycine-rich biopolymer, resilin was shown to be an important protein responsible for the elasticity and wing flexibility. PMID- 29513695 TI - Thermal physiology of Amazonian lizards (Reptilia: Squamata). AB - We summarize thermal-biology data of 69 species of Amazonian lizards, including mode of thermoregulation and field-active body temperatures (Tb). We also provide new data on preferred temperatures (Tpref), voluntary and thermal-tolerance ranges, and thermal-performance curves (TPC's) for 27 species from nine sites in the Brazilian Amazonia. We tested for phylogenetic signal and pairwise correlations among thermal traits. We found that species generally categorized as thermoregulators have the highest mean values for all thermal traits, and broader ranges for Tb, critical thermal maximum (CTmax) and optimal (Topt) temperatures. Species generally categorized as thermoconformers have large ranges for Tpref, critical thermal minimum (CTmin), and minimum voluntary (VTmin) temperatures for performance. Despite these differences, our results show that all thermal characteristics overlap between both groups and suggest that Amazonian lizards do not fit into discrete thermoregulatory categories. The traits are all correlated, with the exceptions of (1) Topt, which does not correlate with CTmax, and (2) CTmin, and correlates only with Topt. Weak phylogenetic signals for Tb, Tpref and VTmin indicate that these characters may be shaped by local environmental conditions and influenced by phylogeny. We found that open-habitat species perform well under present environmental conditions, without experiencing detectable thermal stress from high environmental temperatures induced in lab experiments. For forest-dwelling lizards, we expect warming trends in Amazonia to induce thermal stress, as temperatures surpass the thermal tolerances for these species. PMID- 29513697 TI - Some linguistic neutrosophic Hamy mean operators and their application to multi attribute group decision making. AB - Linguistic neutrosophic numbers (LNNs) can easily describe the incomplete and indeterminate information by the truth, indeterminacy, and falsity linguistic variables (LVs), and the Hamy mean (HM) operator is a good tool to deal with multiple attribute group decision making (MAGDM) problems because it can capture the interrelationship among the multi-input arguments. Motivated by these ideas, we develop linguistic neutrosophic HM (LNHM) operator and weighted linguistic neutrosophic HM (WLNHM) operator. Some desirable properties and special cases of two operators are discussed in detail. Furthermore, considering the situation in which the decision makers (DMs) can't give the suitable weight of each attribute directly from various reasons, we propose the concept of entropy for linguistic neutrosophic set (LNS) to obtain the attribute weight vector objectively, and then the method for MAGDM problems with LNNs is proposed, and some examples are used to illustrate the effectiveness and superiority of the proposed method by comparing with the existing methods. PMID- 29513696 TI - Differences in play can illuminate differences in affiliation: A comparative study on chimpanzees and gorillas. AB - Play behaviour reinforces social affiliation in several primate species, including humans. Via a comparative approach, we tested the hypothesis that play dynamics in a group of lowland gorillas (Gorilla gorilla gorilla) are different from those in a group of chimpanzees (Pan troglodytes) as a reflection of their difference in social affiliation and agonistic support. We selected one group of lowland gorillas and one of chimpanzees, hosted at the ZooParc de Beauval (France), managed in a similar way and living in similar enclosures. The same observers video-collected and analysed data on play behaviour in both groups, by applying identical methodological procedures. Data showed that adult play was less frequent in the group of gorillas compare to chimpanzees. Polyadic play, which involves more than two players and is characterised by the most uncertain outcome, was also less frequent in gorillas than chimpanzees. Play sessions were more unbalanced (more unidirectional patterns by one of the player towards the other) in chimpanzees than in gorillas but in the latter play escalated more frequently into serious aggression. Play asymmetry in the gorilla group increased as the number of players increased, which explains why gorillas limited their polyadic playful interactions. In conclusion, our findings on the study groups of apes can be a valuable starting point to expand the study of social play in the great apes to evaluate if inter-individual affiliative relationships really account for the differences in play distribution and dynamics. PMID- 29513698 TI - Clinical and laboratory predictors of influenza infection among individuals with influenza-like illness presenting to an urban Thai hospital over a five-year period. AB - Early diagnosis of influenza infection maximizes the effectiveness of antiviral medicines. Here, we assess the ability for clinical characteristics and rapid influenza tests to predict PCR-confirmed influenza infection in a sentinel, cross sectional study for influenza-like illness (ILI) in Thailand. Participants meeting criteria for acute ILI (fever > 38 degrees C and cough or sore throat) were recruited from inpatient and outpatient departments in Bangkok, Thailand, from 2009-2014. The primary endpoint for the study was the occurrence of virologically-confirmed influenza infection (based upon detection of viral RNA by RT-PCR) among individuals presenting for care with ILI. Nasal and throat swabs were tested by rapid influenza test (QuickVue) and by RT-PCR. Vaccine effectiveness (VE) was calculated using the case test-negative method. Classification and Regression Tree (CART) analysis was used to predict influenza RT-PCR positivity based upon symptoms reported. We enrolled 4572 individuals with ILI; 32.7% had detectable influenza RNA by RT-PCR. Influenza cases were attributable to influenza B (38.6%), A(H1N1)pdm09 (35.1%), and A(H3N2) (26.3%) viruses. VE was highest against influenza A(H1N1)pdm09 virus and among adults. The most important symptoms for predicting influenza PCR-positivity among patients with ILI were cough, runny nose, chills, and body aches. The accuracy of the CART predictive model was 72.8%, with an NPV of 78.1% and a PPV of 59.7%. During epidemic periods, PPV improved to 68.5%. The PPV of the QuickVue assay relative to RT-PCR was 93.0% overall, with peak performance during epidemic periods and in the absence of oseltamivir treatment. Clinical criteria demonstrated poor predictive capability outside of epidemic periods while rapid tests were reasonably accurate and may provide an acceptable alternative to RT PCR testing in resource-limited areas. PMID- 29513699 TI - Why do open-label placebos work? A randomized controlled trial of an open-label placebo induction with and without extended information about the placebo effect in allergic rhinitis. AB - BACKGROUND: Several studies demonstrated that placebo treatment may have a significant impact on many different symptoms. While in the traditional view concealment of the placebo is essential, recent studies report intriguing evidence that placebos may work even without deception. For example, it has been demonstrated that open-label placebos can improve symptoms in allergic rhinitis. However, the mechanisms of how placebos without concealment work remain unknown. TRIAL DESIGN: In order to examine expectancy effects we conducted a randomized controlled trial (N = 46), in which patients with allergic symptoms received either placebos without deception or no pills at all. In half of those patients we induced positive expectations about the placebo effect. After two weeks we tested whether symptoms and quality of life had changed. RESULTS: Results revealed that open-label placebos improved allergic symptoms more than the control group. Inducing positive expectations had no effects on the improvement of allergic symptoms (the primary and more objective outcome), but on mental sum scores of the quality of life questionnaire. CONCLUSIONS: Placebos without deception can improve symptoms in allergic rhinitis. Positive expectations do not contribute to the efficacy of open-label placebos, but seem to have an effect on more global and subjective well-being (mental or emotional quality of life). CLINICAL TRIAL REGISTRATION NUMBER: German Clinical Trials Register, DRKS00012303. PMID- 29513700 TI - Probabilistic models of individual and collective animal behavior. AB - Recent developments in automated tracking allow uninterrupted, high-resolution recording of animal trajectories, sometimes coupled with the identification of stereotyped changes of body pose or other behaviors of interest. Analysis and interpretation of such data represents a challenge: the timing of animal behaviors may be stochastic and modulated by kinematic variables, by the interaction with the environment or with the conspecifics within the animal group, and dependent on internal cognitive or behavioral state of the individual. Existing models for collective motion typically fail to incorporate the discrete, stochastic, and internal-state-dependent aspects of behavior, while models focusing on individual animal behavior typically ignore the spatial aspects of the problem. Here we propose a probabilistic modeling framework to address this gap. Each animal can switch stochastically between different behavioral states, with each state resulting in a possibly different law of motion through space. Switching rates for behavioral transitions can depend in a very general way, which we seek to identify from data, on the effects of the environment as well as the interaction between the animals. We represent the switching dynamics as a Generalized Linear Model and show that: (i) forward simulation of multiple interacting animals is possible using a variant of the Gillespie's Stochastic Simulation Algorithm; (ii) formulated properly, the maximum likelihood inference of switching rate functions is tractably solvable by gradient descent; (iii) model selection can be used to identify factors that modulate behavioral state switching and to appropriately adjust model complexity to data. To illustrate our framework, we apply it to two synthetic models of animal motion and to real zebrafish tracking data. PMID- 29513701 TI - Survival in Southern European patients waitlisted for kidney transplant after graft failure: A competing risk analysis. AB - BACKGROUND: Whether patients waitlisted for a second transplant after failure of a previous kidney graft have higher mortality than transplant-naive waitlisted patients is uncertain. METHODS: We assessed the relationship between a failed transplant and mortality in 3851 adult KT candidates, listed between 1984-2012, using a competing risk analysis in the total population and in a propensity score matched cohort. Mortality was also modeled by inverse probability weighting (IPTW) competing risk regression. RESULTS: At waitlist entry 225 (5.8%) patients had experienced transplant failure. All-cause mortality was higher in the post graft failure group (16% vs. 11%; P = 0.033). Most deaths occurred within three years after listing. Cardiovascular disease was the leading cause of death (25.3%), followed by infections (19.3%). Multivariate competing risk regression showed that prior transplant failure was associated with a 1.5-fold increased risk of mortality (95% confidence interval [CI], 1.01-2.2). After propensity score matching (1:5), the competing risk regression model revealed a subhazard ratio (SHR) of 1.6 (95% CI, 1.01-2.5). A similar mortality risk was observed after the IPTW analysis (SHR, 1.7; 95% CI, 1.1-2.6). CONCLUSIONS: Previous transplant failure is associated with increased mortality among KT candidates after relisting. This information is important in daily clinical practice when assessing relisted patients for a retransplant. PMID- 29513703 TI - Physical simulation and theoretical evolution for ground fissures triggered by underground coal mining. AB - Underground coal mining activities are prone to cause movement and breakage in geological strata and also lead to mining subsidence and even ground fissures. Along the direction working panel advancing, ground fissures may occur in roof in front and/or behind working panel. However, the investigations of previous similarity tests in lab only emphasize on the region behind working panel. By improving strata material property in construction and mounting artificial pressure devices, two physical simulation tests were conducted and successfully investigated the simulated results. Then, the mechanical model of "cantilever beam and elastic foundation beam" was proposed to calculate the stress distribution and the crack initiation angle in overlying strata and it well explains the mechanisms of ground fissures generation and propagation. Results show that, the maximum internal force in roof always occurred in front of working panel. However, because the void space in gob due to excavation is large enough to cause the bend and rotation of roof strata, compare to the triaxially compressed region in front of working panel, the roof always broke off at some positions above gob since the stress concentration resulting from such bend and rotation of strata could easily reach the limit strength of strata rocks. Also, the length of cantilever beam changed dynamically as respect to the panel advancing and the breakage intervals. Thus, the breakage position where the internal force first reached the limit tensile strength is not fixed and there will be two different kinds of relative positions between the crack initiation point and the working panel. The crack initiation direction is always perpendicular to the internal force, and the crack propagation direction is affected by the initiation angle, overburden-separation degree and the position of the hydraulic shields. If there is no overburden-separation or less, the roofs will break off as a composite beam and the propagation direction will be roughly along the central line between the initial broken point and the support position. Otherwise, the roof strata will bend with the support shields moving forward, then the fracture angle will be close to the initiation angle and the fault surface will be stepped. PMID- 29513702 TI - Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy. AB - In Sri Lanka, an endemic of chronic kidney disease of unknown origin (CKDu) is affecting rural communities. The endemic has similarities with Mesoamerican Nephropathy (MeN) in Central America, however it has not yet been clarified if the endemics are related diagnostic entities. We designed this study of kidney biopsies from patients with CKDu in Sri Lanka to compare with MeN morphology. Eleven patients with CKDu were recruited at the General Hospital, Polonnaruwa, using similar inclusion and exclusion criteria as our previous MeN studies. Inclusion criteria were 20-65 years of age and plasma creatinine 100-220 MUmol/L. Exclusion criteria were diabetes mellitus, uncontrolled hypertension and albuminuria >1g/24h. Kidney biopsies, blood and urine samples were collected, and participants answered a questionnaire. Included participants were between 27-61 years of age and had a mean eGFR of 38+/-14 ml/min/1.73m2. Main findings in the biopsies were chronic glomerular and tubulointerstitial damage with glomerulosclerosis (8-75%), glomerular hypertrophy and mild to moderate tubulointerstitial changes. The morphology was more heterogeneous and interstitial inflammation and vascular changes were more common compared to our previous studies of MeN. In two patients the biopsies showed morphological signs of acute pyelonephritis but urine cultures were negative. Electrolyte disturbances with low levels of serum sodium, potassium, and/or magnesium were common. In the urine, only four patients displayed albuminuria, but many patients exhibited elevated alpha-1-microglobulin and magnesium levels. This is the first study reporting detailed biochemical and clinical data together with renal morphology, including electron microscopy, from Sri Lankan patients with CKDu. Our data show that there are many similarities in the biochemical and morphological profile of the CKDu endemics in Central America and Sri Lanka, supporting a common etiology. However, there are differences, such as a more mixed morphology, more interstitial inflammation and vascular changes in Sri Lankan patients. PMID- 29513704 TI - Route optimization as an instrument to improve animal welfare and economics in pre-slaughter logistics. AB - Each year, more than three million animals are transported from farms to abattoirs in Sweden. Animal transport is related to economic and environmental costs and a negative impact on animal welfare. Time and the number of pick-up stops between farms and abattoirs are two key parameters for animal welfare. Both are highly dependent on efficient and qualitative transportation planning, which may be difficult if done manually. We have examined the benefits of using route optimization in cattle transportation planning. To simulate the effects of various planning time windows and transportation time regulations and number of pick-up stops along each route, we have used data that represent one year of cattle transport. Our optimization model is a development of a model used in forestry transport that solves a general pick-up and delivery vehicle routing problem. The objective is to minimize transportation costs. We have shown that the length of the planning time window has a significant impact on the animal transport time, the total driving time and the total distance driven; these parameters that will not only affect animal welfare but also affect the economy and environment in the pre-slaughter logistic chain. In addition, we have shown that changes in animal transportation regulations, such as minimizing the number of allowed pick-up stops on each route or minimizing animal transportation time, will have positive effects on animal welfare measured in transportation hours and number of pick-up stops. However, this leads to an increase in working time and driven distances, leading to higher transportation costs for the transport and negative environmental impact. PMID- 29513705 TI - Domestic cattle (Bos taurus taurus) are motivated to obtain forage and demonstrate contrafreeloading. AB - Domestic cattle (Bos taurus taurus) are adapted to digest high-roughage diets, but in confinement they are commonly fed low-roughage, high-energy diets. This practice may leave cattle with an unfulfilled need to consume forage. A way to quantify motivation is to require animals to work to access a resource. Using this method, we evaluated cattle motivation to obtain forage when fed high- or low-roughage diets during and 30 d before the study. Individual heifers were fed Sudan grass (Sorghum * drummondii) hay (high roughage, n = 6) or a diet with 12% forage (as fed, low roughage, n = 6) in an open feed trough. In a second trough, 200 g/d of Sudan grass hay were fed behind a push gate, to which additional weight was added daily until heifers no longer pushed. We predicted heifers would push heavier weights, show a shorter latency, and spend more time pushing the gate when fed a low- vs. high-roughage diet. Indeed, heifers fed a low-roughage diet pushed the gate immediately after hay delivery (1.7 min) and much sooner than those fed a high-roughage diet (75.7 min). On the day before they no longer pushed the gate, latency for heifers in the low-roughage treatment remained only 3.2 min after hay delivery. The suddenness with which they ceased pushing the next day suggests they were unable to move heavier weights to express their motivation. This may explain why maximum weight pushed and time spent pushing the gate did not differ between treatments. The gate pushing by heifers with unrestricted hay access is the first demonstration by cattle of contrafreeloading: performing work to obtain a resource that is simultaneously available for free. In conclusion, consuming forage is important to cattle and is affected by both their primary diet and an internal motivation to work to obtain feed. PMID- 29513706 TI - A care bundle including antenatal corticosteroids reduces preterm infant mortality in Tanzania a low resource country. AB - BACKGROUND: Preterm neonatal mortality (NM) has remained high and unchanged for many years in Tanzania, a resource-limited country. Major causes of mortality include birth asphyxia, respiratory insufficiency and infections. Antenatal corticosteroids (ACS) have been shown to significantly reduce mortality in developed countries. There is inconsistent use of ACS in Tanzania. OBJECTIVE: To determine whether implementation of a care bundle that includes ACS, maternal antibiotics (MA), neonatal antibiotics (NA) and avoidance of moderate hypothermia (temperature < 36 degrees C) targeting infants of estimated gestational age (EGA) 28 to 34 6/7 weeks would reduce NM (< 7 days) by 35%. METHODS: A Pre (September 2014 to May 2015) and Post (June 2015 to June 2017) Implementation strategy was used and introduced at three University-affiliated and one District Hospital. Dexamethasone, as the ACS, was added to the national formulary in May 2015, facilitating its free use down to the district level. FINDINGS: NM was reduced 26% from 166 to 122/1000 livebirths (P = 0.005) and fresh stillbirths (FSB) 33% from 162/1000 to 111/1000 (p = 0.0002) Pre versus Post Implementation. Medications including combinations increased significantly at all sites (p<0.0001). By logistic regression, combinations of ACS, maternal and NA (odds ratio (OR) 0.33), ACS and NA (OR 0.30) versus no treatment were significantly associated with reduced NM. NM significantly decreased per 250g birthweight increase (OR 0.59), and per one week increase in EGA (OR 0.87). Moderate hypothermia declined pre versus post implementation (p<0.0001) and was two-fold more common in infants who died versus survivors. INTERPRETATION: A low-cost care bundle, ~$6 per patient, was associated with a significant reduction in NM and FSB rates. The former presumably by reducing respiratory morbidity with ACS and minimizing infections with antibiotics. If these findings can be replicated in other resource-limited settings, the potential for further reduction of <5 year mortality rates becomes enormous. PMID- 29513707 TI - Optimum water depth ranges of dominant submersed macrophytes in a natural freshwater lake. AB - Macrophytes show a zonal distribution along the lake littoral zone because of their specific preferred water depths while the optimum growth water depths of dominant submersed macrophytes in natural lakes are not well known. We studied the seasonal biomass and frequency patterns of dominant and companion submersed macrophytes along the water depth gradient in Lake Erhai in 2013. The results showed that the species richness and community biomass showed hump-back shaped patterns along the water depth gradient both in polydominant and monodominant communities. Biomass percentage of Potamogenton maackianus showed a hump-back pattern while biomass percentages of Ceratophyllum demersum and Vallisneria natans appeared U-shaped patterns across the water depth gradient in polydominant communities whereas biomass percentage of V. natans increased with the water depth in monodominant communities. Dominant species demonstrated a broader distribution range of water depth than companion species. Frequency and biomass of companion species declined drastically with the water depth whereas those of dominant species showed non-linear patterns across the water depth gradient. Namely, along the water depth gradient, biomass of P. maackianus and V. natans showed hump-back patterns and biomasses of C. demersum displayed a U-shaped pattern in the polydominant communities but biomass of V. natans demonstrated a hump-back pattern in the monodominant communities; frequency of P. maackianus showed a hump-back pattern and C. demersum and V. natans maintained high frequencies in the two types of communities. We can speculate that in Lake Erhai the optimum growth water depths of P. maackianus and C. demersum in the polydominant communities are 2.5-4.5 m and 1-2 m or 5-6 m, respectively and that of V. natans is 3-5 m in the polydominant communities and 2.5-5 m in the monodominant communities. This is the first report that the optimum water depth ranges in the horizontal direction of three dominant submersed macrophytes in a natural freshwater lake were determined. PMID- 29513709 TI - Delineating modern variation from extinct morphology in the fossil record using shells of the Eastern Box Turtle (Terrapene carolina). AB - Characterization of morphological variation in the shells of extant Eastern Box Turtles, Terrapene carolina, provides a baseline for comparison to fossil populations. It also provides an example of the difficulties inherent to recognizing intraspecific diversity in the fossil record. The degree to which variation in fossils of T. carolina can be accommodated by extant variation in the species has been disagreed upon for over eighty years. Using morphometric analyses of the carapace, I address the relationship between modern and fossil T. carolina in terms of sexual dimorphism, geographic and subspecific variation, and allometric variation. Modern T. carolina display weak male-biased sexual size dimorphism. Sexual shape dimorphism cannot be reliably detected in the fossil record. Rather than a four-part subspecific division, patterns of geographic variation are more consistent with clinal variation between various regions in the species distribution. Allometric patterns are qualitatively similar to those documented in other emydid turtles and explain a significant amount of shape variation. When allometric patterns are accounted for, Holocene specimens are not significantly different from modern specimens. In contrast, several geologically older specimens have significantly different carapace shape with no modern analogue. Those large, fossilized specimens represent extinct variation occupying novel portions of morphospace. This study highlights the need for additional documentation of modern osteological variation that can be used to test hypotheses of intraspecific evolution in the fossil record. PMID- 29513708 TI - Ketamine independently modulated power and phase-coupling of theta oscillations in Sp4 hypomorphic mice. AB - Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate (NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity to ketamine. As accumulating evidence on molecular mechanisms and behavioral phenotypes established Sp4 hypomorphism as a promising animal model, systems-level neural circuit mechanisms of Sp4 hypomorphism, especially network dynamics underlying cognitive functions, remain poorly understood. We attempted to close this gap in knowledge in the present study by recording multi channel epidural electroencephalogram (EEG) from awake behaving wildtype and Sp4 hypomorphic mice. We characterized cortical theta-band power and phase-coupling phenotypes, a known neural circuit substrate underlying cognitive functions, and further studied the effects of a subanesthetic dosage of ketamine on theta abnormalities unique to Sp4 hypomorphism. Sp4 hypomorphic mice had markedly elevated theta power localized frontally and parietally, a more pronounced theta phase progression along the neuraxis, and a stronger frontal-parietal theta coupling. Acute subanesthetic ketamine did not affect theta power in wildtype animals but significantly reduced it in Sp4 hypomorphic mice, nearly completely neutralizing their excessive frontal/parietal theta power. Ketamine did not significantly alter cortical theta phase progression in either wildtype or Sp4 hypomorphic animals, but significantly strengthened cortical theta phase-coupling in wildtype, but not in Sp4 hypomorphic animals. Our results suggested that the resting-state phenotypes of cortical theta oscillations unique to Sp4 hypomorphic mice closely mimicked a schizophrenic endophenotype. Further, ketamine independently modulated Sp4 hypomorphic anomalies in theta power and phase coupling, suggesting separate underlying neural circuit mechanisms. PMID- 29513710 TI - Real-time predictive seasonal influenza model in Catalonia, Spain. AB - Influenza surveillance is critical to monitoring the situation during epidemic seasons and predictive mathematic models may aid the early detection of epidemic patterns. The objective of this study was to design a real-time spatial predictive model of ILI (Influenza Like Illness) incidence rate in Catalonia using one- and two-week forecasts. The available data sources used to select explanatory variables to include in the model were the statutory reporting disease system and the sentinel surveillance system in Catalonia for influenza incidence rates, the official climate service in Catalonia for meteorological data, laboratory data and Google Flu Trend. Time series for every explanatory variable with data from the last 4 seasons (from 2010-2011 to 2013-2014) was created. A pilot test was conducted during the 2014-2015 season to select the explanatory variables to be included in the model and the type of model to be applied. During the 2015-2016 season a real-time model was applied weekly, obtaining the intensity level and predicted incidence rates with 95% confidence levels one and two weeks away for each health region. At the end of the season, the confidence interval success rate (CISR) and intensity level success rate (ILSR) were analysed. For the 2015-2016 season a CISR of 85.3% at one week and 87.1% at two weeks and an ILSR of 82.9% and 82% were observed, respectively. The model described is a useful tool although it is hard to evaluate due to uncertainty. The accuracy of prediction at one and two weeks was above 80% globally, but was lower during the peak epidemic period. In order to improve the predictive power, new explanatory variables should be included. PMID- 29513711 TI - A novel carbon tipped single micro-optrode for combined optogenetics and electrophysiology. AB - Optical microelectrodes (optrodes) are used in neuroscience to transmit light into the brain of a genetically modified animal to evoke and record electrical activity from light-sensitive neurons. Our novel micro-optrode solution integrates a light-transmitting 125 micrometer optical fiber and a 9 micrometer carbon monofilament to form an electrical lead element, which is contained in a borosilicate glass sheathing coaxial arrangement ending with a micrometer-sized carbon tip. This novel unit design is stiff and slender enough to be used for targeting deep brain areas, and may cause less tissue damage compared with previous models. The center-positioned carbon fiber is less prone to light induced artifacts than side-lit metal microelectrodes previously presented. The carbon tip is capable of not only recording electrical signals of neuronal origin but can also provide valuable surface area for electron transfer, which is essential in electrochemical (voltammetry, amperometry) or microbiosensor applications. We present details of design and manufacture as well as operational examples of the newly developed single micro-optrode, which includes assessments of 1) carbon tip length-impedance relationship, 2) light transmission capabilities, 3) photoelectric artifacts in carbon fibers, 4) responses to dopamine using fast-scan cyclic voltammetry in vivo, and 5) optogenetic stimulation and spike or local field potential recording from the rat brain transfected with channelrhodopsin-2. With this work, we demonstrate that our novel carbon tipped single micro-optrode may open up new avenues for use in optogenetic stimulation when needing to be combined with extracellular recording, electrochemical, or microbiosensor measurements performed on a millisecond basis. PMID- 29513712 TI - Impact of universal medical insurance system on the accessibility of medical service supply and affordability of patients in China. AB - BACKGROUND: China's universal medical insurance system (UMIS) is designed to promote social fairness through improving access to medical services and reducing out-of-pocket (OOP) costs for all Chinese. However, it is still not known whether UMIS has a significant impact on the accessibility of medical service supply and the affordability, as well as the seeking-care choice, of patients in China. METHODS: Segmented time-series regression analysis, as a powerful statistical method of interrupted time series design, was used to estimate the changes in the quantity and quality of medical service supply before and after the implementation of UMIS. The rates of catastrophic payments and seeking-care choices for UMIS beneficiaries were selected to measure the affordability and medical service flow of patients after the implementation of UMIS. RESULTS: China's UMIS was established in 2008. After that, the trending increase of the expenditure of the UMIS was higher than that of increase in revenue compared to previous years. Up to 2014, the UMIS had covered 97.5% of the entire population in China. After introduction of the UMIS, there were significant increases in licensed physicians, nurses, and hospital beds per 1000 individuals. In addition, hospital outpatient visits and inpatient visits per year increased compared to the pre-UMIS period. The average fatality rate of inpatients in the overall hospital and general hospital and the average fatality rate due to acute myocardial infarction (AMI) in general hospitals was significantly decreased. In contrast, no significant and prospective changes were observed in rural physicians per 1000 individuals, inpatient visits and inpatient fatality rate in the community centers and township hospitals compared to the pre-UMIS period. After 2008, the rates of catastrophic payments for UMIS inpatients at different income levels were declining at three levels of hospitals. Whichever income level, the rate of catastrophic payments for inpatients of Urban Employee's Basic Medical Insurance was the lowest. For the low-income patients, a single hospitalization at a tertiary hospital can lead to catastrophic payments. It is needless to say what the economic burden could be if patients required multiple hospitalizations within a year. UMIS beneficiaries showed the intention of growth to seek hospitalization services in tertiary hospitals. CONCLUSIONS: Introduction of the UMIS contributed to an increase in available medical services and the use thereof, and a decrease in fatality rate. The affordability of UMIS beneficiaries for medical expenses was successfully ameliorated. The differences in patients' affordability are mainly manifested in different medical insurance schemes and different seeking-care choices. The ability of the poor patients covered by UMIS to resist catastrophic medical payments is still relatively weak. Therefore, the current UMIS should reform the insurance payment model to promote the integration of medical services and the formation of a tiered treatment system. UMIS also should establish supplementary medical insurance packages for the poor. PMID- 29513713 TI - Effects of leaf wetness duration and temperature on infection of Prunus by Xanthomonas arboricola pv. pruni. AB - Xanthomonas arboricola pv. pruni is the causal agent of bacterial spot disease of stone fruits and almond. The bacterium is distributed throughout the major stone fruit-producing areas of the World and is considered a quarantine organism in the European Union according to the Council Directive 2000/29/EC, and by the European and Mediterranean Plant Protection Organization. The effect of leaf wetness duration and temperature on infection of Prunus by X. arboricola pv. pruni was determined in controlled environment experiments. Potted plants of the peach almond hybrid GF-677 were inoculated with bacterial suspensions and exposed to combinations of six leaf wetness durations (from 0 to 24 h) and seven fixed temperatures (from 5 to 35 degrees C) during the infection period. Then, plants were transferred to a biosafety greenhouse, removed from bags, and incubated at optimal conditions for disease development. Although leaf wetness was required for infection of Prunus by X. arboricola pv. pruni, temperature had a greater effect than leaf wetness duration on disease severity. The combined effect of wetness duration and temperature on disease severity was quantified using a modification of the Weibull equation proposed by Duthie. The reduced-form of Duthie's model obtained by nonlinear regression analysis fitted well to data (R = 0.87 and R2adj = 0.85), and all parameters were significantly different from 0. The estimated optimal temperature for infection by X. arboricola pv. pruni was 28.9 degrees C. Wetness periods longer than 10 h at temperatures close to 20 degrees C, or 5 h at temperatures between 25 and 35 degrees C were necessary to cause high disease severity. The predictive capacity of the model was evaluated using an additional set of data obtained from new wetness duration-temperature combinations. In 92% of the events the observed severity agreed with the predicted level of infection risk. The risk chart derived from the reduced form of Duthie's model can be used to estimate the potential risk for infection of Prunus by X. arboricola pv. pruni based on observed or forecasted temperature and wetness duration. PMID- 29513715 TI - Timing of embryonic quiescence determines viability of embryos from the calanoid copepod, Acartia tonsa (Dana). AB - Like 41 other calanoid copepods, Acartia tonsa, are capable of inducing embryonic quiescence when experiencing unfavorable environmental conditions. The ecdysone signaling cascade is known to have a key function in developmental processes like embryogenesis and molting of arthropods, including copepods. We examined the role of ecdysteroid-phosphate phosphatase (EPPase), ecdysone receptor (EcR), beta fushi tarazu transcription factor 1 (betaFTZ-F1), and the ecdysteroid-regulated early gene E74 (E74), which represent different levels of the ecdysone-signaling cascade in our calanoid model organism. Progression of embryogenesis was monitored and hatching success determined to evaluate viability. Embryos that were induced quiescence before the gastrulation stage would stay in gastrulation during the rest of quiescence and exhibited a slower pace of hatching as compared to subitaneous embryos. In contrast, embryos developed further than gastrulation would stay in gastrulation or later stages during quiescence and showed a rapid pace in hatching after quiescence termination. Expression patterns suggested two peaks of the biological active ecdysteroids, 20-hydroxyecdysone (20E). The first peak of 20E was expressed in concert with the beginning of embryogenesis originating from yolk-conjugated ecdysteroids, based on EPPase expression. The second peak is suggested to originate from de novo synthesized 20E around the limb bud stage. During quiescence, the expression patterns of EPPase, EcR, betaFTZ-F1, and E74 were either decreasing or not changing over time. This suggests that the ecdysone-signaling pathway play a key role in the subitaneous development of A. tonsa embryogenesis, but not during quiescence. The observation is of profound ecological and practical relevance for the dynamics of egg banks. PMID- 29513714 TI - Identification of blood biomarkers in glioblastoma by SWATH mass spectrometry and quantitative targeted absolute proteomics. AB - Molecular biomarkers in blood are needed to aid the early diagnosis and clinical assessment of glioblastoma (GBM). Here, in order to identify biomarker candidates in plasma of GBM patients, we performed quantitative comparisons of the plasma proteomes of GBM patients (n = 14) and healthy controls (n = 15) using SWATH mass spectrometry analysis. The results were validated by means of quantitative targeted absolute proteomics analysis. As a result, we identified eight biomarker candidates for GBM (leucine-rich alpha-2-glycoprotein (LRG1), complement component C9 (C9), C-reactive protein (CRP), alpha-1-antichymotrypsin (SERPINA3), apolipoprotein B-100 (APOB), gelsolin (GSN), Ig alpha-1 chain C region (IGHA1), and apolipoprotein A-IV (APOA4)). Among them, LRG1, C9, CRP, GSN, IGHA1, and APOA4 gave values of the area under the receiver operating characteristics curve of greater than 0.80. To investigate the relationships between the biomarker candidates and GBM biology, we examined correlations between plasma concentrations of biomarker candidates and clinical presentation (tumor size, progression-free survival time, or overall survival time) in GBM patients. The plasma concentrations of LRG1, CRP, and C9 showed significant positive correlations with tumor size (R2 = 0.534, 0.495, and 0.452, respectively). PMID- 29513716 TI - A descriptive analysis of depression and pain complaints among patients with cancer in a low income country. AB - BACKGROUND: In high income countries, cancer is one of the leading causes of death, with co-morbid depression contributing to the risk of increased mortality. However, both cancer and depression are neglected conditions in low income countries. The current study assessed the magnitude of depression and the association of pain complaints with depression among patients with cancer in a low income country. METHOD: In this cross-sectional study participants were 390 patients with established diagnosis of cancer, who were recruited consecutively when visiting a tertiary treatment centre in Addis Ababa, Ethiopia. The occurrence of depression was determined using the nine items Patient Health Questionnaire (PHQ-9). Major depressive disorder was confirmed: (1) when five or more of the PHQ-9 symptoms were endorsed as occurring for at least 'more than seven days', with the exception of suicidal ideation item which counted as a positive rating if it had occurred even once in the previous fifteen days. (2) one of the symptoms has to be either depressed mood or loss of interest. Pain complaint was measured by Numeral Rating Scale (NRS) and severity of pain was assessed using Verbal Rating Scale (VRS). RESULTS: The prevalence of major depressive disorder was 16.4% (95%CI: 13.1%, 20.4%), and subthreshold depression was 17.4% (95%CI: 14.0%, 21.5%). Pain complaints occurred in 69.0% (95%CI: 64.3%, 73.4%) of the participants. The odds of having a major depressive symptom was over four times higher among participants who had pain. LIMITATIONS: The study was cross sectional and liable to recall bias. Recruitment was carried out in a tertiary referral hospital, which might lead to the selection of more economically well-off and educated participants limiting generalizability of the study. Moreover, we did not control for cancer types, which may be related to pain and the experience of depression. Some of the somatic symptoms in PHQ9 may also be related to the cancer itself. CONCLUSIONS: This study highlights the clinical significance of both depression and pain complaints in patients with cancer in a low income country. Exploration of the impact of depressive disorders on quality of life and outcome of cancer is an important area for further research in low income countries. PMID- 29513717 TI - An anti-PDGFRbeta aptamer for selective delivery of small therapeutic peptide to cardiac cells. AB - Small therapeutic peptides represent a promising field for the treatment of pathologies such as cardiac diseases. However, the lack of proper target selective carriers hampers their translation towards a potential clinical application. Aptamers are cell-specific carriers that bind with high affinity to their specific target. However, some limitations on their conjugation to small peptides and the functionality of the resulting aptamer-peptide chimera exist. Here, we generated a novel aptamer-peptide chimera through conjugation of the PDGFRbeta-targeting Gint4.T aptamer to MP, a small mimetic peptide that via targeting of the Cavbeta2 subunit of the L-type calcium channel (LTCC) can recover myocardial function in pathological heart conditions associated with defective LTCC function. The conjugation reaction was performed by click chemistry in the presence of N,N,N',N',N"-pentamethyldiethylenetriamine as a Cu (I) stabilizing agent in a DMSO-free aqueous buffer. When administered to cardiac cells, the Gint4.T-MP aptamer-peptide chimera was successfully internalized in cells, allowing the functional targeting of MP to LTCC. This approach represents the first example of the use of an internalizing aptamer for selective delivery of a small therapeutic peptide to cardiac cells. PMID- 29513718 TI - Acral melanoma detection using a convolutional neural network for dermoscopy images. AB - BACKGROUND/PURPOSE: Acral melanoma is the most common type of melanoma in Asians, and usually results in a poor prognosis due to late diagnosis. We applied a convolutional neural network to dermoscopy images of acral melanoma and benign nevi on the hands and feet and evaluated its usefulness for the early diagnosis of these conditions. METHODS: A total of 724 dermoscopy images comprising acral melanoma (350 images from 81 patients) and benign nevi (374 images from 194 patients), and confirmed by histopathological examination, were analyzed in this study. To perform the 2-fold cross validation, we split them into two mutually exclusive subsets: half of the total image dataset was selected for training and the rest for testing, and we calculated the accuracy of diagnosis comparing it with the dermatologist's and non-expert's evaluation. RESULTS: The accuracy (percentage of true positive and true negative from all images) of the convolutional neural network was 83.51% and 80.23%, which was higher than the non expert's evaluation (67.84%, 62.71%) and close to that of the expert (81.08%, 81.64%). Moreover, the convolutional neural network showed area-under-the-curve values like 0.8, 0.84 and Youden's index like 0.6795, 0.6073, which were similar score with the expert. CONCLUSION: Although further data analysis is necessary to improve their accuracy, convolutional neural networks would be helpful to detect acral melanoma from dermoscopy images of the hands and feet. PMID- 29513719 TI - The role of agency in the implementation of Isoniazid Preventive Therapy (IPT): Lessons from oMakoti in uMgungundlovu District, South Africa. AB - INTRODUCTION: In response to revisions in global and national policy in 2011, six month isoniazid preventive therapy (IPT) became freely available as a preventive measure for people living with HIV in the uMgungundlovu District of KwaZulu-Natal province, South Africa. Given a difference in uptake and completion by sex, we sought to explore the reasons why Zulu women were more likely to accept and complete IPT compared to men in an effort to inform future implementation. METHODS: Utilising a community-based participatory research approach and ethnographic methods, we undertook 17 individual and group interviews, and met regularly with grassroots community advisory teams in three Zulu communities located in uMgungundlovu District between March 2012-December 2016. FINDINGS & DISCUSSION: Three categories described women's willingness to initiate IPT: women are caregivers, women are obedient, and appearance is important. The findings suggest that the success of IPT implementation amongst clinic-utilising women of uMgungundlovu is related to the cultural gender norms of uMakoti, isiZulu for "the bride" or "the wife." We invoke the cultural concept of inhlonipho, meaning "to show respect," to discuss how the cultural values of uMakoti may conflict with biomedical expectations of adherence. Such conflict can result in misinterpretations by healthcare providers or patients, and lead some patients to fear the repercussions of asking questions or contemplating discontinuation with the provider, preferring instead to appear obedient. We propose a shift in emphasis from adherence-focussed strategies, characteristic of the current biomedical approach, to practices that promote patient agency in an effort to offer IPT more appropriately. IMPLICATIONS: Building on existing tools, namely the harm reduction model and the use of mini-ethnography, we provide guidance on how to support women to participate as agents in the decision to initiate or continue IPT, decisions which may also impact the health and choices of the family. PMID- 29513720 TI - Functional near-infrared spectroscopy during optic flow with and without fixation. AB - BACKGROUND AND PURPOSE: Individuals with visual vertigo describe symptoms of dizziness, disorientation, and/or impaired balance in environments with conflicting visual and vestibular information or complex visual stimuli. Physical therapists often prescribe habituation exercises using optic flow to treat these symptoms, but there are no evidence-based guidelines for delivering optic flow and it is unclear how the brain processes such stimuli. The purposes of this study were to use functional near-infrared spectroscopy (fNIRS) to explore cerebral activation during optic flow, and determine if visual fixation had a modulating effect on brain activity. METHODS: Fifteen healthy participants (7 males and 8 females; mean age 41 years old) stood in a virtual reality environment and viewed optic flow moving unidirectionally in the yaw plane with and without fixation. Changes in cerebral activation were recorded from the bilateral fronto-temporo-parietal and occipital lobes using fNIRS. RESULTS: Cerebral activation was greater with visual motion than while viewing a stationary scene. Greater cerebral activation in the bilateral fronto-temporo parietal lobes was observed when optic flow was viewed with fixation. DISCUSSION AND CONCLUSIONS: Optic flow activates the bilateral fronto-temporo-parietal regions of the cerebral cortex. This activation is greater while viewing optic flow and a fixation target, providing preliminary evidence supporting the use of a fixation target during habituation exercises. PMID- 29513721 TI - Assessment of the immunogenicity of residual host cell protein impurities of OsrHSA. AB - Human serum albumin (HSA) is the most abundant protein in human plasma and is widely used at high doses for treating various diseases. Recombinant HSA is an alternative approach to plasma-derived HSA, providing increased safety and an unlimited supply. However, the safety of the residual host cell proteins (HCPs) co-purified with Oryza sativa HSA (OsrHSA) remains to be determined. An animal system was used to assess the immunogenicity of OsrHSA and its residual HCPs. Low immunogenicity and immunotoxicity of the residual HCPs at a dose of 25 MUg/kg, equivalent to 25 times the clinical dosage of HSA, were observed. An anti-drug antibody (ADA) analysis revealed that anti-HSA, anti-OsrHSA or anti-HCP antibodies developed with a low frequency in pHSA and OsrHSA treatments, but the titers were as low as 1.0-2.0. Furthermore, the titer and the incidence of the specific antibodies were not significantly different between the pHSA and OsrHSA groups, indicating that OsrHSA presents similar immunogenicity to that of pHSA. More importantly, no cytokines were stimulated after the administration of OsrHSA and the residual HCPs, suggesting that there was no risk of a cytokine storm. These results demonstrated that the residual HCPs from OsrHSA have low immunogenicity, indicating that the rice endosperm is one of the best hosts for plant molecular pharming. PMID- 29513722 TI - Attitudes towards bystander cardiopulmonary resuscitation: Results from a cross sectional general population survey. AB - Survival from out-of-hospital cardiac arrest (OHCA) varies across the developed world. Although not all OHCA are recoverable, the survival rate in Scotland is lower than in comparable countries, with higher average survival rates of 7.9% in England and 9% across Europe. The purpose of this paper is to explore the barriers, facilitators and public attitudes to administering bystander cardiopulmonary resuscitation (CPR) which could inform future policy and initiatives to improve the rate of bystander CPR. Data was collected via a cross sectional general population survey of 1027 adults in Scotland. 52% of respondents had been trained in CPR. Of those who were not trained, two fifths (42%) expressed a willingness to receive CPR training. Fewer than half (49%) felt confident administering CPR, rising to 82% if they were talked through it by a call handler. Multivariate analyses identified that people in social grade C2DE were less likely than those in social grade ABC1 to be CPR trained and less confident to administer CPR if talked through by a call handler. The older a person was, the less likely they were to be CPR trained, show willingness to be CPR trained or be confident to administer bystander CPR with or without instruction from an emergency call handler. These findings are particularly relevant considering that most OHCA happen in the homes of older people. In a developed country such as Scotland with widely available CPR training, only half of the adult population reported feeling confident about administering bystander CPR. Further efforts tailored specifically for people who are older, unemployed and have a lower social grade are required to increase knowledge, confidence and uptake of training in bystander CPR. PMID- 29513723 TI - Serum cystatin C is an independent biomarker associated with the renal resistive index in patients with chronic kidney disease. AB - Cystatin C is a cysteine protease inhibitor that is produced by nearly all human cells. The serum level of cystatin C is a stronger predictor of the renal outcome and the risk of cardiovascular events than the creatinine level. The resistive index (RI) on renal Doppler ultrasonography is a good indicator of vascular resistance as well as the renal outcomes in patients with chronic kidney disease (CKD). However, it is unclear whether serum cystatin C is associated with signs of vascular dysfunction, such as the renal RI. We measured the serum cystatin C levels in 101 CKD patients and investigated the relationships between cystatin C and markers of vascular dysfunction, including the renal RI, ankle-brachial pulse wave velocity (baPWV), intima-media thickness (IMT), and cardiac function. The renal RI was significantly correlated with the serum cystatin C level (p < 0.0001, r = 0.6920). The serum cystatin C level was found to be a significant determinant of the renal RI (p < 0.0001), but not the baPWV, in a multivariate regression analysis. The multivariate odds ratio of the serum cystatin C level for a renal RI of more than 0.66 was statistically significant (2.92, p = 0.0106). The area under the receiver-operating characteristic curve comparing the sensitivity and specificity of cystatin C for predicting an RI of more than 0.66 was 0.882 (cutoff value: 2.04 mg/L). In conclusion, the serum cystatin C level is an independent biomarker associated with the renal RI in patients with CKD. PMID- 29513724 TI - Factors associated with the use of complementary and alternative medicines for prostate cancer by long-term survivors. AB - OBJECTIVE: To assess whether the use of complementary and alternative medicines therapies (CAMs) for prostate cancer and/or its treatment side effects by long term survivors is associated with selected socio-demographic, clinical, health related quality-of-life (HRQOL) and/or psychological factors. DESIGN, SETTING AND PARTICIPANTS: The Prostate Cancer Care and Outcomes Study (PCOS) is a population based cohort study of men with prostate cancer who were aged less than 70 years at diagnosis in New South Wales, Australia. Included in these analyses were men who returned a 10-year follow-up questionnaire, which included questions about CAM use. METHODS: Validated instruments assessed patient's HRQOL and psychological well-being. Poisson regression with robust variance estimation was used to estimate the adjusted relative risks of current CAM use for prostate cancer according to socio-demographic, clinical, HRQOL and psychological factors. RESULTS: 996 of 1634 (61%) living PCOS participants completed the 10-year questionnaire. Of these 996 men, 168 (17%) were using CAMs for prostate cancer and 525 (53%) were using CAMs for any reason (including prostate cancer). Those using CAM for prostate cancer were more likely to be regular or occasional support group participants (vs. no participation RR = 2.02; 95%CI 1.41-2.88), born in another country (vs. Australian born RR = 1.59; 95%CI 1.17-2.16), have received androgen deprivation treatment (ADT) since diagnosis (RR = 1.60; 95%CI 1.12-2.28) or in the past two years (RR = 2.34; 95%CI 1.56-3.52). CAM use was associated with greater fear of recurrence (RR = 1.29; 95%CI 1.12-1.48), cancer specific distress (RR = 1.15; 95%CI 1.01-1.30), cancer-specific hyperarousal (RR = 1.17; 95%CI 1.04-1.31), cancer locus of control (RR = 1.16; 95%CI 1.01-1.34) and less satisfaction with medical treatments (RR = 0.86; 95%CI 0.76-0.97), but not with intrusive thinking, cognitive avoidance, depression, anxiety or any HRQOL domains. CONCLUSIONS: In this study, about one in six long term prostate cancer survivors used CAMs for their prostate cancer with use centred around ADT, country of birth, distress, cancer control, fear of recurrence and active help seeking. PMID- 29513725 TI - Assessment of serum bile acid profiles as biomarkers of liver injury and liver disease in humans. AB - To assess the potential of individual bile acids (IBA) and their profiles as mechanistic biomarkers of liver injury for humans in real world situations, we interrogated samples collected under minimum controlled conditions (ie subjects were not fasted). Total bile acids (TBA) have been considered to be biomarkers of liver injury for decades, and more recently, monitoring of IBA has been proposed for differentiation of variety of etiologies of liver injury. We established a LC MS/MS methodology to analyze nine IBA, generated reference ranges, and examined effects of age, gender, and ethnicity for each IBA. Furthermore, we evaluated the ability of IBA and their profiles to detect hepatic injury in subjects with a broad range of liver impairments. To date, our study utilized the largest total cohort of samples (N = 645) that were divided into 2 groups, healthy or liver impaired, to evaluate IBA as biomarkers. The TBA serum levels in the Asian ethnic group trended higher when compared to other ethnic groups, and the serum concentrations of IBA, such as glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), chenodeoxycholic acid (CDCA), and taurochenoxycholic acid (TCDCA) were significantly increased. To our knowledge, this report is the first to describe ethnic differences in serum concentrations of IBAs. In patients with hepatic impairments, with the exception of deoxycholic acid (DCA), the concentrations of IBAs were significantly elevated when compared with healthy subjects. The conjugated bile acids displayed greater differences between healthy subjects and subjects with hepatic impairments than non-conjugated bile acids. Furthermore, the subjects with hepatic impairments exhibited distinct profiles (signatures) of IBAs that clustered subjects according the nature of their liver impairments. Although additional studies are needed, our data suggested that the analysis of IBA has the potential to become useful for differentiation of various forms of liver injury. PMID- 29513727 TI - Novel vehicle detection system based on stacked DoG kernel and AdaBoost. AB - This paper proposes a novel vehicle detection system that can overcome some limitations of typical vehicle detection systems using AdaBoost-based methods. The performance of the AdaBoost-based vehicle detection system is dependent on its training data. Thus, its performance decreases when the shape of a target differs from its training data, or the pattern of a preceding vehicle is not visible in the image due to the light conditions. A stacked Difference of Gaussian (DoG)-based feature extraction algorithm is proposed to address this issue by recognizing common characteristics, such as the shadow and rear wheels beneath vehicles-of vehicles under various conditions. The common characteristics of vehicles are extracted by applying the stacked DoG shaped kernel obtained from the 3D plot of an image through a convolution method and investigating only certain regions that have a similar patterns. A new vehicle detection system is constructed by combining the novel stacked DoG feature extraction algorithm with the AdaBoost method. Experiments are provided to demonstrate the effectiveness of the proposed vehicle detection system under different conditions. PMID- 29513726 TI - Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life. AB - BACKGROUND: The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life. STUDY DESIGN: Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated. RESULTS: Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age. CONCLUSION: A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD). PMID- 29513728 TI - Identification of a microRNA signature associated with survivability in cervical squamous cell carcinoma. AB - BACKGROUND: The aim of this study is to find the potential miRNA expression signature capable of predicting survival time for cervical squamous cell carcinoma (CSCC) patients. METHODS: The expression of 332 miRNAs was measured in 131 (Training cohort) and 130 (Validation cohort) patients with CSCC in the Cancer Genome Atlas (TCGA) data portal. The miRNA expression signature was identified by Cox Proportion Hazard regression model to the Training data set, and subsequently validated in an independent Validation set. Kaplan-Meier curves and the receiver operating characteristic analyses of 5 years were used to access the overall survival of miRNA signature. MiRNA signature-gene target analysis was performed, followed by the construction of the regulatory network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to explore the function of target genes of miRNA signature. RESULTS: A 2-miRNA expression signature of hsa-mir-642a and hsa-mir-378c associated with survivability was identified in CSCC. Both of them had a significant diagnostic and prognostic value of patients with CSCC. A total of 345 miRNA signature-target pairs were obtained in the miRNA signature-gene target regulatory network, in which 316 genes were targets of has-mir-378c and has-mir-642a. Functional analysis of target genes showed that MAPK signaling pathway, VEGF signaling pathway and endocytosis were the significantly enriched signal pathways that covered most genes. CONCLUSIONS: The 2-miRNA signature adds to the prognostic value of CSCC. In-depth interrogation of the 2-miRNAs will provide important biological insights that finding and developing novel molecularly prediction to improve prognosis for CSCC patients. PMID- 29513729 TI - The incidence of acute pulmonary embolism following syncope in anticoagulant naive patients: A retrospective cohort study. AB - BACKGROUND: A recently published, large prospective study showed unexpectedly high prevalence of acute pulmonary embolism (APE) among patients hospitalized for syncope. In such a case, a high incidence of recurrent pulmonary embolism is expected among patients who were discharged without APE workup. OBJECTIVES: To determine the incidence of symptomatic APE among patients hospitalized for a first episode of syncope and discharged without APE workup or anticoagulation. METHODS: This retrospective cohort study included patients hospitalized at Rambam Health Care Campus between January 2006 and February 2017 with a primary admission diagnosis of syncope, who were not investigated for APE and were not taking anticoagulants. The patients were followed up for up to three years after discharge. The occurrence of venous thromboembolism (VTE) during the follow-up period was documented. RESULTS: The median follow-up duration was 33 months. 1,126 subjects completed a three-year follow-up. During this period, 38 patients (3.38%) developed VTE, 17 (1.51%) of them had APE. The cumulative incidence of VTE and APE was 1.9% (95% CI 1.3%-2.5%) and 0.9% (95% CI 0.4%-1.3%) respectively. Only seven subjects developed APE during the first year of follow-up. The median times from the event of syncope to the development of APE and VTE were 18 and 19 months respectively. CONCLUSIONS: The cumulative incidence of VTE during a three year follow-up period after an episode of syncope is low. In the absence of clinical suspicion, a routine diagnostic workup for APE in patients with syncope cannot be recommended. PMID- 29513730 TI - Isolation and characterization of two novel groups of kanamycin-resistance ColE1 like plasmids in Salmonella enterica serotypes from food animals. AB - While antimicrobial resistance in Salmonella enterica is mainly attributed to large plasmids, small plasmids may also harbor antimicrobial resistance genes. Previously, three major groups of ColE1-like plasmids conferring kanamycin resistance (KanR) in various S. enterica serotypes from diagnostic samples of human or animals were reported. In this study, over 200 KanR S. enterica isolates from slaughter samples, collected in 2010 and 2011 as a part of the animal arm of the National Antimicrobial Resistance Monitoring System, were screened for the presence of ColE1-like plasmids. Twenty-three KanR ColE1-like plasmids were successfully isolated. Restriction fragment mapping revealed five major plasmid groups with subgroups, including two new groups, X (n = 3) and Y/Y2/Y3 (n = 4), in addition to the previously identified groups A (n = 7), B (n = 6), and C/C3 (n = 3). Nearly 75% of the plasmid-carrying isolates were from turkey and included all the isolates carrying X and Y plasmids. All group X plasmids were from serotype Hadar. Serotype Senftenberg carried all the group Y plasmids and one group B plasmid. All Typhimurium isolates (n = 4) carried group A plasmids, while Newport isolates (n = 3) each carried a different plasmid group (A, B, or C). The presence of the selection bias in the NARMS strain collection prevents interpretation of findings at the population level. However, this study demonstrated that KanR ColE1-like plasmids are widely distributed among different S. enterica serotypes in the NARMS isolates and may play a role in dissemination of antimicrobial resistance genes. PMID- 29513731 TI - Separability of active semantic and phonological maintenance in verbal working memory. AB - Models of verbal working memory that incorporate active memory maintenance, long term memory networks, and attention control have been developed. Current studies suggest that semantic representations of words, evoked via long-term memory networks, are actively maintained until they are needed to fulfill a role. In other words, it is possible that some mechanism actively refreshes semantic representations of words, analogous to but independently from articulatory rehearsal which refreshes phonological representations. One valuable piece of evidence is a double dissociation, observed in a dual task paradigm in which manual tapping disrupted a semantic memory task while articulatory suppression disrupted a phonological memory task. However, in that study, the secondary tasks could have competed not only with the maintenance but also with the encoding activities. Additionally, the study items in the phonological memory tasks were words; hence, the discriminability of the memory tasks is doubtful. The present study, therefore, examined a potential double dissociation in situations where the secondary tasks could not compete with encoding, using a modified phonological memory task. Furthermore, this article discusses a potential mechanism for maintaining semantic representations. PMID- 29513732 TI - In ovo CpG DNA delivery increases innate and adaptive immune cells in respiratory, gastrointestinal and immune systems post-hatch correlating with lower infectious laryngotracheitis virus infection. AB - Cytosine-guanosine deoxynucleotides (CpG) DNA can be delivered in ovo at embryo day (ED)18 for the stimulation of toll-like receptor (TLR)21 signaling pathway that ultimately protects chickens against a number of bacterial and viral infections. There is a dearth of information understanding the mechanisms of protection induced by in ovo delivered CpG DNA. The objective of this study was to determine the immune cell changes post-hatch following in ovo delivery of the TLR21 ligand, CpG DNA. In order to quantify changes of percentage of KUL01+, IgM+ B, cluster of differentiation (CD)4+ and CD8alpha+ cells, trachea, lung, duodenum, large intestine, spleen and bursa of Fabricius were collected on day 1 post-hatch. We found increased recruitments of KUL01+ cells, in organs of these body systems post-hatch following in ovo delivery of CpG DNA. Although IgM+ B cells, CD4+ and CD8alpha+ cells were increased in lungs and immune system organs, these cells were not quantifiable from the trachea, duodenum and large intestine immediately following the hatch. Furthermore, when CpG DNA is delivered in ovo and subsequently infected with infectious laryngotracheitis virus (ILTV) post hatch on day 1, CpG DNA reduces morbidity and mortality resulting from ILTV infection. This study provides insights into the mechanisms of host responses elicited following in ovo delivery of CpG DNA in avian species. PMID- 29513733 TI - The Arabidopsis thaliana Mediator subunit MED8 regulates plant immunity to Botrytis Cinerea through interacting with the basic helix-loop-helix (bHLH) transcription factor FAMA. AB - The Mediator complex is at the core of transcriptional regulation and plays a central role in plant immunity. The MEDIATOR25 (MED25) subunit of Arabidopsis thaliana regulates jasmonate-dependent resistance to Botrytis cinerea through interacting with the basic helix-loop-helix (bHLH) transcription factor of jasmonate signaling, MYC2. Another Mediator subunit, MED8, acts independently or together with MED25 in plant immunity. However, unlike MED25, the underlying action mechanisms of MED8 in regulating B. cinerea resistance are still unknown. Here, we demonstrated that MED8 regulated plant immunity to B. cinerea through interacting with another bHLH transcription factor, FAMA, which was previously shown to control the final proliferation/differentiation switch during stomatal development. Our research demonstrates that FAMA is also an essential component of B. cinerea resistance. The fama loss-of-function mutants (fama-1 and fama-2) increased susceptibility to B. cinerea infection and reduced defense-gene expression. On the contrary, transgenic lines constitutively overexpressing FAMA showed opposite B. cinerea responses compared with the fama loss-of-function mutants. FAMA-overexpressed plants displayed enhanced resistance to B. cinerea infection and increased expression levels of defensin genes following B. cinerea treatment. Genetic analysis of MED8 and FAMA suggested that FAMA-regulated pathogen resistance was dependent on MED8. In addition, MED8 and FAMA were both associated with the G-box region in the promoter of ORA59. Our findings indicate that the MED8 subunit of the A. thaliana Mediator regulates plant immunity to B. cinerea through interacting with the transcription factor FAMA, which was discovered to be a key component in B. cinerea resistance. PMID- 29513734 TI - Biochemical properties of thyroid peroxidase (TPO) expressed in human breast and mammary-derived cell lines. AB - Thyroid peroxidase (TPO) is an enzyme and autoantigen expressed in thyroid and breast tissues. Thyroid TPO undergoes a complex maturation process however, nothing is known about post-translational modifications of breast-expressed TPO. In this study, we have investigated the biochemical properties of TPO expressed in normal and cancerous human breast tissues, and the maturation process and antigenicity of TPO present in a panel of human breast tissue-derived cell lines. We found that the molecular weight of breast TPO was slightly lower than that of thyroid TPO due to decreased glycosylation and as suggest results of Western blot also shorter amino acid chain. Breast TPO exhibit enzymatic activity and isoelectric point comparable to that of thyroid TPO. The biochemical properties of TPO expressed in mammary cell lines and normal thyrocytes are similar regarding glycan content, molecular weight and isoelectric point. However, no peroxidase activity and dimer formation was detected in any of these cell lines since the majority of TPO protein was localized in the cytoplasmic compartment, and the TPO expression at the cell surface was too low to detect its enzymatic activity. Lactoperoxidase, a protein highly homologous to TPO expressed also in breast tissues, does not influence the obtained data. TPO expressed in the cell lines was recognized by a broad panel of TPO-specific antibodies. Although some differences in biochemical properties between thyroid and breast TPO were observed, they do not seem to be critical for the overall three-dimensional structure. This conclusion is supported by the fact that TPO expressed in breast tissues and cell lines reacts well with conformation-sensitive antibodies. Taking into account a close resemblance between both proteins, especially high antigenicity, future studies should investigate the potential immunotherapies directed against breast-expressed TPO and its specific epitopes. PMID- 29513735 TI - Automated quantification of Haller's layer in choroid using swept-source optical coherence tomography. AB - OBJECTIVE: To develop an algorithm for automated quantification of Haller's layer in choroid using swept-source optical coherence tomography (OCT). BACKGROUND: So far, to understand the association of various diseases with structural changes of choroid, only gross indicators such as thickness, volume and vascularity index have been examined. However, certain diseases affect specific sublayers of the choroid. Accordingly, a need for targeted quantitation arises. In particular, there is significant interest in understanding Haller's layer, a choroidal sublayer comprising relatively large blood vessels. Unfortunately, its intricate vasculature makes, manual quantitation difficult, tedious, and error-prone. To surmount this difficulty, it is imperative to develop an algorithmic method. METHODOLOGY: The primary contribution of this work consists in developing an approach for detecting the boundary between Haller's and Sattler's layers, the latter comprising medium-sized vessels. The proposed algorithm estimates vessel cross-sections using exponentiation-based binarization, and labels a vessel large if its cross-section exceeds certain statistically determined threshold. Finally, the desired boundary is obtained as a smooth curve joining the innermost points of such large vessels. On 50 OCT B-scans (of 50 healthy eyes), our algorithm was validated both qualitatively and quantitatively, by comparing with intra-observer variability. Extensive statistical analysis was performed using metrics including Dice coefficient (DC), correlation coefficient (CC) and absolute difference (AD). RESULTS: The proposed algorithm achieved a mean DC of 89.48% (SD:5.03%) in close agreement with the intra-observer repeatability of 89.12% (SD:5.68%). Corresponding mean AD and mean CC were of 17.54 MUm (SD:16.45MUm) and 98.10% (SD:1.60%) which too approximate the respective intra-observer repeatability values 19.19 MUm (SD:17.69 MUm) and 98.58% (SD:1.12%). CONCLUSION: High correlation between algorithmic and manual delineations indicates suitability of our algorithm for clinically analyzing choroid in greater finer details, especially, in diseased eyes. PMID- 29513736 TI - A new perspective on the pathogenesis of chronic renal disease in captive cheetahs (Acinonyx jubatus). AB - The sustainability of captive cheetah populations is limited by high mortality due to chronic renal disease. This necropsy study, conducted on 243 captive cheetahs from one institution, investigated the relationships between focal palatine erosions, gastritis, enterocolitis, glomerulosclerosis, chronic renal infarcts, renal cortical and medullary fibrosis, and renal medullary amyloidosis at death. Associations between the individual renal lesions and death due to chronic renal disease and comparisons of lesion prevalence between captive bred and wild born and between normal and king coated cheetahs were also assessed. All lesions were significantly positively correlated with age at death. Renal medullary fibrosis was the only lesion associated with the likelihood of death being due to chronic renal disease, and cheetahs with this lesion were younger, on average, than cheetahs with other renal lesions. Alimentary tract lesions were not associated with amyloidosis. All lesions, except for palatine erosions, were more common in wild born than in captive bred cheetahs; the former were older at death than the latter. Having a king coat had no clear effect on disease prevalence. These results suggest that age and renal medullary fibrosis are the primary factors influencing the pathogenesis of chronic renal disease in captive cheetahs. Apart from amyloidosis, these findings are analogous to those described in chronic renal disease in domestic cats, which is postulated to result primarily from repetitive hypoxic injury of renal tubules, mediated by age and stress. Cheetahs may be particularly susceptible to acute renal tubular injury due to their propensity for stress and their extended life span in captivity, as well as their adaptation for fecundity (rather than longevity) and adrenaline mediated high speed prey chases. The presence of chronic renal disease in subadult cheetahs suggests that prevention, identification and mitigation of stress are critical to the successful prevention of chronic renal disease in captive cheetahs. PMID- 29513737 TI - Attentional lapses are reduced by repeated stimuli having own-name during a monotonous task. AB - The goal of the present study was to examine the effect of listening to self relevant words (i.e., one's own name) on vigilant attention, arousal, and subjective sleepiness during performance of a psychomotor vigilance test (PVT). Twenty-one participants aged 20-26 years (22.2 +/- 1.76) performed a PVT in four experimental conditions: one in which their own full name was pronounced every 20 s in the stimuli epochs, one in which their full name was pronounced in inverted form, one in which beeps were played, and a control condition with no stimuli. Listening to personal names reduced attentional lapses during the PVT (i.e., the number of reaction times no less than 500 ms). The results are a first step in applying the name effect to technologies and devices aimed at maintaining arousal levels and preventing accidents during a monotonous task, such as driving. PMID- 29513738 TI - Accuracy of detection of carboxyhemoglobin and methemoglobin in human and bovine blood with an inexpensive, pocket-size infrared scanner. AB - Detecting life-threatening common dyshemoglobins such as carboxyhemoglobin (COHb, resulting from carbon monoxide poisoning) or methemoglobin (MetHb, caused by exposure to nitrates) typically requires a laboratory CO-oximeter. Because of cost, these spectrophotometer-based instrument are often inaccessible in resource poor settings. The aim of this study was to determine if an inexpensive pocket infrared spectrometer and smartphone (SCiO(r)Pocket Molecular Sensor, Consumer Physics Ltd., Israel) accurately detects COHb and MetHb in single drops of blood. COHb was created by adding carbon monoxide gas to syringes of heparinized blood human or cow blood. In separate syringes, MetHb was produced by addition of sodium nitrite solution. After incubation and mixing, fractional concentrations of COHb or MetHb were measured using a Radiometer ABL-90 Flex(r) CO-oximeter. Fifty microliters of the sample were then placed on a microscope slide, a cover slip applied and scanned with the SCiO spectrometer. The spectrograms were used to create simple linear models predicting [COHb] or [MetHb] based on spectrogram maxima, minima and isobestic wavelengths. Our model predicted clinically significant carbon monoxide poisoning (COHb >=15%) with a sensitivity of 93% and specificity of 88% (regression r2 = 0.63, slope P<0.0001), with a mean bias of 0.11% and an RMS error of 21%. Methemoglobinemia severe enough to cause symptoms (>20% MetHb) was detected with a sensitivity of 100% and specificity of 71% (regression r2 = 0.92, slope P<0.001) mean bias 2.7% and RMS error 21%. Although not as precise as a laboratory CO-oximeter, an inexpensive pocket-sized infrared scanner/smartphone detects >15% COHb or >20% MetHb on a single drop of blood with enough accuracy to be useful as an initial clinical screening. The SCiO and similar relatively low cost spectrometers could be developed as inexpensive diagnostic tools for developing countries. PMID- 29513739 TI - Pathology and bacteria related to digital dermatitis in dairy cattle in all year round grazing system in Brazil. AB - Digital dermatitis (DD) is one of the main causes of lameness in dairy cattle worldwide, and it is frequently reported in high-yielding, free stall dairy herds from regions with a temperate climate. However, DD is also observed with high prevalence in grazing cattle with a low milk yield in tropical regions. To clarify whether these differences have an impact on the etiology of the disease, we studied DD lesions from all year round grazing cattle of mixed breed in Brazil using high-throughput 16S rRNA gene sequencing and fluorescent in situ hybridization. The study included samples from 66 skin lesions and 5 healthy skins collected from five farms. Both techniques showed Treponema spp. to be the most abundant bacteria, present in all but one of the samples with minimal epidermal alterations. We identified eleven different Treponema strains belonging to the six major phylotypes of Treponema which have all previously been identified in DD lesions. Furthermore, we identify Dichelobacter nodosus in DD lesions by gene sequencing and also by fluorescent in situ hybridization in almost half of biopsy specimens in areas with mild epithelial damage and together with Treponema. The present data support the hypothesis that Treponema constitutes the main pathogen responsible for DD, independent of the environment and region where cows are kept, and it further suggests D. nodosus as another potentially important pathogen. PMID- 29513740 TI - COP1, a negative regulator of photomorphogenesis, positively regulates plant disease resistance via double-stranded RNA binding proteins. AB - The E3 ubiquitin ligase COP1 (Constitutive Photomorphogenesis 1) is a well known component of the light-mediated plant development that acts as a repressor of photomorphogenesis. Here we show that COP1 positively regulates defense against turnip crinkle virus (TCV) and avrRPM1 bacteria by contributing to stability of resistance (R) protein HRT and RPM1, respectively. HRT and RPM1 levels and thereby pathogen resistance is significantly reduced in the cop1 mutant background. Notably, the levels of at least two double-stranded RNA binding (DRB) proteins DRB1 and DRB4 are reduced in the cop1 mutant background suggesting that COP1 affects HRT stability via its effect on the DRB proteins. Indeed, a mutation in either drb1 or drb4 resulted in degradation of HRT. In contrast to COP1, a multi-subunit E3 ligase encoded by anaphase-promoting complex (APC) 10 negatively regulates DRB4 and TCV resistance but had no effect on DRB1 levels. We propose that COP1-mediated positive regulation of HRT is dependent on a balance between COP1 and negative regulators that target DRB1 and DRB4. PMID- 29513741 TI - Modulating mimicry: Exploring the roles of inhibitory control and social understanding in 5-year-olds' behavioral mimicry. AB - During adult interactions, behavioral mimicry, the implicit copying of an interaction partner's postures and mannerisms, communicates liking and affiliation. While this social behavior likely develops during early childhood, it is unclear which factors contribute to its emergence. Here, the roles of inhibitory control and social understanding on 5-year-olds' behavioral mimicry were investigated. Following a social manipulation in which one experimenter shared a sticker with the child and the other experimenter kept two stickers for herself, children watched a video in which these experimenters each told a story. During this story session, children in the experimental group (n = 28) observed the experimenters perform face and hand rubbing behaviors whereas the control group (n = 23) did not see these behaviors. Children's inhibitory control was assessed using the day-night task and their social understanding was measured through a parental questionnaire. Surprisingly, group-level analyses revealed that the experimental group performed the behaviors significantly less than the control group (i.e. a negative mimicry effect) for both the sticker-sharer and sticker-keeper. Yet, the hypothesized effects of inhibitory control and social understanding were found. Inhibitory control predicted children's selective mimicry of the sticker-keeper versus sticker-sharer and children's overall mimicry was correlated with social understanding. These results provide the first indications to suggest that factors of social and cognitive development dynamically influence the emergence and specificity of behavioral mimicry during early childhood. PMID- 29513742 TI - Predicting urinary tract infections in the emergency department with machine learning. AB - BACKGROUND: Urinary tract infection (UTI) is a common emergency department (ED) diagnosis with reported high diagnostic error rates. Because a urine culture, part of the gold standard for diagnosis of UTI, is usually not available for 24 48 hours after an ED visit, diagnosis and treatment decisions are based on symptoms, physical findings, and other laboratory results, potentially leading to overutilization, antibiotic resistance, and delayed treatment. Previous research has demonstrated inadequate diagnostic performance for both individual laboratory tests and prediction tools. OBJECTIVE: Our aim, was to train, validate, and compare machine-learning based predictive models for UTI in a large diverse set of ED patients. METHODS: Single-center, multi-site, retrospective cohort analysis of 80,387 adult ED visits with urine culture results and UTI symptoms. We developed models for UTI prediction with six machine learning algorithms using demographic information, vitals, laboratory results, medications, past medical history, chief complaint, and structured historical and physical exam findings. Models were developed with both the full set of 211 variables and a reduced set of 10 variables. UTI predictions were compared between models and to proxies of provider judgment (documentation of UTI diagnosis and antibiotic administration). RESULTS: The machine learning models had an area under the curve ranging from 0.826-0.904, with extreme gradient boosting (XGBoost) the top performing algorithm for both full and reduced models. The XGBoost full and reduced models demonstrated greatly improved specificity when compared to the provider judgment proxy of UTI diagnosis OR antibiotic administration with specificity differences of 33.3 (31.3-34.3) and 29.6 (28.5-30.6), while also demonstrating superior sensitivity when compared to documentation of UTI diagnosis with sensitivity differences of 38.7 (38.1-39.4) and 33.2 (32.5-33.9). In the admission and discharge cohorts using the full XGboost model, approximately 1 in 4 patients (4109/15855) would be re-categorized from a false positive to a true negative and approximately 1 in 11 patients (1372/15855) would be re-categorized from a false negative to a true positive. CONCLUSION: The best performing machine learning algorithm, XGBoost, accurately diagnosed positive urine culture results, and outperformed previously developed models in the literature and several proxies for provider judgment. Future prospective validation is warranted. PMID- 29513743 TI - Retinal guanylyl cyclase activating protein 1 forms a functional dimer. AB - Retinal guanylyl cyclases (RetGCs) in vertebrate photoreceptors are regulated by the guanylyl cyclase activator proteins (GCAP1 and GCAP2). Here, we report EPR double electron-electron resonance (DEER) studies on the most ubiquitous GCAP isoform, GCAP1 and site-directed mutagenesis analysis to determine an atomic resolution structural model of a GCAP1 dimer. Nitroxide spin-label probes were introduced at individual GCAP1 residues: T29C, E57C, E133C, and E154C. The intermolecular distance of each spin-label probe (measured by DEER) defined restraints for calculating the GCAP1 dimeric structure by molecular docking. The DEER-derived structural model of the GCAP1 dimer was similar within the experimental error for both the Mg2+-bound activator and Ca2+-bound inhibitor states (RMSD < 2.0 A). The GCAP1 dimer possesses intermolecular hydrophobic contacts involving the side chain atoms of H19, Y22, F73 and V77. The structural model of the dimer was validated by GCAP1 mutations (H19R, Y22D, F73E, and V77E) at the dimer interface that each abolished protein dimerization. Previous studies have shown that each of these mutants either diminished or completely suppressed the ability of GCAP1 to activate the cyclase. These results suggest that GCAP1 dimerization may affect compartmentalization of GCAP1 in the photoreceptors and/or affect regulation of the cyclase activity. PMID- 29513744 TI - Acute radiation impacts contractility of guinea-pig bladder strips affecting mucosal-detrusor interactions. AB - Radiation-induced bladder toxicity is associated with radiation therapy for pelvic malignancies, arising from unavoidable irradiation of neighbouring normal bladder tissue. This study aimed to investigate the acute impact of ionizing radiation on the contractility of bladder strips and identify the radiation sensitivity of the mucosa vs the detrusor. Guinea-pig bladder strips (intact or mucosa-free) received ex vivo sham or 20Gy irradiation and were studied with in vitro myography, electrical field stimulation and Ca2+-fluorescence imaging. Frequency-dependent, neurogenic contractions in intact strips were reduced by irradiation across the force-frequency graph. The radiation-difference persisted in atropine (1MUM); subsequent addition of PPADs (100MUM) blocked the radiation effect at higher stimulation frequencies and decreased the force-frequency plot. Conversely, neurogenic contractions in mucosa-free strips were radiation insensitive. Radiation did not affect agonist-evoked contractions (1MUM carbachol, 5mM ATP) in intact or mucosa-free strips. Interestingly, agonist evoked contractions were larger in irradiated mucosa-free strips vs irradiated intact strips suggesting that radiation may have unmasked an inhibitory mucosal element. Spontaneous activity was larger in control intact vs mucosa-free preparations; this difference was absent in irradiated strips. Spontaneous Ca2+ transients in smooth muscle cells within tissue preparations were reduced by radiation. Radiation affected neurogenic and agonist-evoked bladder contractions and also reduced Ca2+-signalling events in smooth muscle cells when the mucosal layer was present. Radiation eliminated a positive modulatory effect on spontaneous activity by the mucosa layer. Overall, the findings suggest that radiation impairs contractility via mucosal regulatory mechanisms independent of the development of radiation cystitis. PMID- 29513746 TI - Benthic meiofaunal community response to the cascading effects of herbivory within an algal halo system of the Great Barrier Reef. AB - Benthic fauna play a crucial role in organic matter decomposition and nutrient cycling at the sediment-water boundary in aquatic ecosystems. In terrestrial systems, grazing herbivores have been shown to influence below-ground communities through alterations to plant distribution and composition, however whether similar cascading effects occur in aquatic systems is unknown. Here, we assess the relationship between benthic invertebrates and above-ground fish grazing across the 'grazing halos' of Heron Island lagoon, Australia. Grazing halos, which occur around patch reefs globally, are caused by removal of seagrass or benthic macroalgae by herbivorous fish that results in distinct bands of unvegetated sediments surrounding patch reefs. We found that benthic algal canopy height significantly increased with distance from patch reef, and that algal canopy height was positively correlated with the abundances of only one invertebrate taxon (Nematoda). Both sediment carbon to nitrogen ratios (C:N) and mean sediment particle size (MUm) demonstrated a positive correlation with Nematoda and Arthropoda (predominantly copepod) abundances, respectively. These positive correlations indicate that environmental conditions are a major contributor to benthic invertebrate community distribution, acting on benthic communities in conjunction with the cascading effects of above-ground algal grazing. These results suggest that benthic communities, and the ecosystem functions they perform in this system, may be less responsive to changes in above ground herbivorous processes than those previously studied in terrestrial systems. Understanding how above-ground organisms, and processes, affect their benthic invertebrate counterparts can shed light on how changes in aquatic communities may affect ecosystem function in previously unknown ways. PMID- 29513745 TI - Nicotinic acetylcholine receptor (CHRN) expression and function in cultured human adult fungiform (HBO) taste cells. AB - In rodents, CHRNs are involved in bitter taste transduction of nicotine and ethanol. Currently, it is not clear if CHRNs are expressed in human taste cells and if they play a role in transducing the bitter taste of nicotine and ethanol or in the synthesis and release of neurohumoral peptides. Accordingly, we investigated the expression and functional role of CHRNs in HBO cells. Using molecular techniques, we demonstrate that a subset of HBO cells express CHRNs that also co-express TRPM5, T1R3 or T2R38. Exposing HBO cells to nicotine or ethanol acutely or to nicotine chronically induced a differential increase in the expression of CHRN mRNA and protein in a dose- and time-dependent manner. Acutely exposing HBO cells to a mixture containing nicotine plus ethanol induced a smaller increase in CHRN mRNAs relative to nicotine or ethanol treatment alone. A subset of HBO cells responded to nicotine, acetylcholine and ATP with a transient increase in [Ca2+]i. Nicotine effects on [Ca2+]i were mecamylamine sensitive. Brain-derived neurotrophic factor (BDNF) protein was detected in HBO cells using ELISA. Acute nicotine exposure decreased BDNF in HBO cells and increased BDNF release in the medium. CHRNs were also detected in HEK293 cells by RT-PCR. Unlike HBO cells, CHRNs were localized in most of HEK293 cells and majority of HEK293 cells responded to nicotine and ethanol stimulation with a transient increase in [Ca2+]i. BDNF levels in HEK293 cells were significantly higher than in HBO cells but the nicotine induced release of BDNF in the media was a fraction of the BDNF cellular content. We conclude that CHRNs are expressed in TRPM5 positive HBO cells. CHRN mRNA expression is modulated by exposure to nicotine and ethanol in a dose- and time-dependent manner. Nicotine induces the synthesis and release of BDNF in HBO cells. PMID- 29513747 TI - A model for estimating pathogen variability in shellfish and predicting minimum depuration times. AB - Norovirus is a major cause of viral gastroenteritis, with shellfish consumption being identified as one potential norovirus entry point into the human population. Minimising shellfish norovirus levels is therefore important for both the consumer's protection and the shellfish industry's reputation. One method used to reduce microbiological risks in shellfish is depuration; however, this process also presents additional costs to industry. Providing a mechanism to estimate norovirus levels during depuration would therefore be useful to stakeholders. This paper presents a mathematical model of the depuration process and its impact on norovirus levels found in shellfish. Two fundamental stages of norovirus depuration are considered: (i) the initial distribution of norovirus loads within a shellfish population and (ii) the way in which the initial norovirus loads evolve during depuration. Realistic assumptions are made about the dynamics of norovirus during depuration, and mathematical descriptions of both stages are derived and combined into a single model. Parameters to describe the depuration effect and norovirus load values are derived from existing norovirus data obtained from U.K. harvest sites. However, obtaining population estimates of norovirus variability is time-consuming and expensive; this model addresses the issue by assuming a 'worst case scenario' for variability of pathogens, which is independent of mean pathogen levels. The model is then used to predict minimum depuration times required to achieve norovirus levels which fall within possible risk management levels, as well as predictions of minimum depuration times for other water-borne pathogens found in shellfish. Times for Escherichia coli predicted by the model all fall within the minimum 42 hours required for class B harvest sites, whereas minimum depuration times for norovirus and FRNA+ bacteriophage are substantially longer. Thus this study provides relevant information and tools to assist norovirus risk managers with future control strategies. PMID- 29513748 TI - Dependency-based Siamese long short-term memory network for learning sentence representations. AB - Textual representations play an important role in the field of natural language processing (NLP). The efficiency of NLP tasks, such as text comprehension and information extraction, can be significantly improved with proper textual representations. As neural networks are gradually applied to learn the representation of words and phrases, fairly efficient models of learning short text representations have been developed, such as the continuous bag of words (CBOW) and skip-gram models, and they have been extensively employed in a variety of NLP tasks. Because of the complex structure generated by the longer text lengths, such as sentences, algorithms appropriate for learning short textual representations are not applicable for learning long textual representations. One method of learning long textual representations is the Long Short-Term Memory (LSTM) network, which is suitable for processing sequences. However, the standard LSTM does not adequately address the primary sentence structure (subject, predicate and object), which is an important factor for producing appropriate sentence representations. To resolve this issue, this paper proposes the dependency-based LSTM model (D-LSTM). The D-LSTM divides a sentence representation into two parts: a basic component and a supporting component. The D-LSTM uses a pre-trained dependency parser to obtain the primary sentence information and generate supporting components, and it also uses a standard LSTM model to generate the basic sentence components. A weight factor that can adjust the ratio of the basic and supporting components in a sentence is introduced to generate the sentence representation. Compared with the representation learned by the standard LSTM, the sentence representation learned by the D-LSTM contains a greater amount of useful information. The experimental results show that the D LSTM is superior to the standard LSTM for sentences involving compositional knowledge (SICK) data. PMID- 29513749 TI - Chloroquine augments TRAIL-induced apoptosis and induces G2/M phase arrest in human pancreatic cancer cells. AB - Autophagy contributes to the treatment-resistance of many types of cancers, and chloroquine (CQ) inhibits autophagy. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) kills cancer cells but is minimally cytotoxic to normal cells. However, because the therapeutic efficacy of TRAIL is limited, it is necessary to augment TRAIL-induced anti-tumor effects. In this study, we explored the anti-tumor effects of a combination of CQ and TRAIL on two human pancreatic cancer cell lines: TRAIL-sensitive MiaPaCa-2 cells and Panc-1 cells that are less sensitive to TRAIL. Although both CQ and TRAIL reduced cancer cell viability in a dose-dependent manner, the combination acted synergistically. CQ increased the expression level of type-II LC3B without decreasing the expression of p62, an autophagic substrate, thus indicating inhibition of autophagy. CQ did not increase the levels of death receptors on cancer cells but reduced the expression of anti-apoptotic proteins. A combination of CQ and TRAIL significantly increased cancer cell apoptosis. CQ induced cell-cycle arrest in the G2/M phase. Also, CQ increased the p21 level but reduced that of cyclin B1. A combination of CQ and TRAIL reduced the colony-forming abilities of cancer cells to extents greater than either material alone. In xenograft models, combination CQ and TRAIL therapy significantly suppressed the growth of subcutaneously established MiaPaCa-2 and Panc-1 cells, compared with the untreated or monotherapy groups. Together, the results indicate that CQ in combination with TRAIL may be useful to treat human pancreatic cancer. PMID- 29513750 TI - Hemoglobin transfusion trigger in an internal medicine department - A "real world" six year experience. AB - BACKGROUND: Transfusion guidelines advocate restrictive rather than liberal use of red blood cells (RBC) and are based mostly on randomized trials in intensive care and surgical departments. We aimed to study RBC transfusion practice in the medical patients' population. METHODS: The data in this study were collected from patients over the age of 18 years admitted to an Internal Medicine department between 2009 and 2014 who received at least one unit of packed red blood cells (RBC). In addition, data on demographics, patients' diagnoses, laboratory tests and number of transfused RBC units were extracted from the electronic health records. RESULTS: One thousand three hundred and twenty eight patients were included, having mean age of 75 +/- 14 years. The median hemoglobin (Hb) trigger for RBC transfusion was 8.0 g/dl (IQR 7.3-8.7g/dl), and most patients received either one (43.4%) or two (33.4%) RBC units. There was no significant difference in Hb trigger between males and females (Hb 8.0 g/dl and 7.9 g/dl, respectively, p = 0.098), and a weak correlation with age (r = 0.108 p = 0.001). Patients with cardiovascular and lung diseases had a statistically significant higher Hb trigger compared to patients without those diagnoses, however the median difference between them was 0.5 g/dl or less. CONCLUSIONS: These "real world" data we collected show a Hb trigger compliant with the upper limit of published guidelines and influenced by medical patients' common diagnoses. Prospective trials addressing patients hospitalized in internal medicine departments could further contribute to transfusion decision algorithms. PMID- 29513751 TI - Impacts of diurnal temperature and larval density on aquatic development of Aedes aegypti. AB - The increasing range of Aedes aegypti, vector for Zika, dengue, chikungunya, and other viruses, has brought attention to the need to understand the population and transmission dynamics of this mosquito. It is well understood that environmental factors and breeding site characteristics play a role in organismal development and the potential to transmit pathogens. In this study, we observe the impact of larval density in combination with diurnal temperature on the time to pupation, emergence, and mortality of Aedes aegypti. Experiments were conducted at two diurnal temperature ranges based on 10 years of historical temperatures of Houston, Texas (21-32 degrees C and 26.5-37.5 degrees C). Experiments at constant temperatures (26.5 degrees C, 32 degrees C) were also conducted for comparison. At each temperature setting, five larval densities were observed (0.2, 1, 2, 4, 5 larvae per mL of water). Data collected shows significant differences in time to first pupation, time of first emergence, maximum rate of pupation, time of maximum rate of pupation, maximum rate of emergence, time of maximum rate of emergence, final average proportion of adult emergence, and average proportion of larval mortality. Further, data indicates a significant interactive effect between temperature fluctuation and larval density on these measures. Thus, wild population estimates should account for temperature fluctuations, larval density, and their interaction in low-volume containers. PMID- 29513753 TI - Impacts of climate change on cropping patterns in a tropical, sub-humid watershed. AB - In recent decades, there have been substantial increases in crop production in sub-Saharan Africa (SSA) as a result of higher yields, increased cropping intensity, expansion of irrigated cropping systems, and rainfed cropland expansion. Yet, to date much of the research focus of the impact of climate change on crop production in the coming decades has been on crop yield responses. In this study, we analyse the impact of climate change on the potential for increasing rainfed cropping intensity through sequential cropping and irrigation expansion in central Benin. Our approach combines hydrological modelling and scenario analysis involving two Representative Concentration Pathways (RCPs), two water-use scenarios for the watershed based on the Shared Socioeconomic Pathways (SSPs), and environmental water requirements leading to sustained streamflow. Our analyses show that in Benin, warmer temperatures will severely limit crop production increases achieved through the expansion of sequential cropping. Depending on the climate change scenario, between 50% and 95% of cultivated areas that can currently support sequential cropping or will need to revert to single cropping. The results also show that the irrigation potential of the watershed will be at least halved by mid-century in all scenario combinations. Given the urgent need to increase crop production to meet the demands of a growing population in SSA, our study outlines challenges and the need for planned development that need to be overcome to improve food security in the coming decades. PMID- 29513752 TI - Anti-cancer characteristics and ototoxicity of platinum(II) amine complexes with only one leaving ligand. AB - Unlike cisplatin, which forms bifunctional DNA adducts, monofunctional platinum(II) complexes bind only one strand of DNA and might target cancer without causing auditory side-effects associated with cisplatin treatment. We synthesized the monofunctional triamine-ligated platinum(II) complexes, Pt(diethylenetriamine)Cl, [Pt(dien)Cl]+, and Pt(N,N-diethyldiethylenetriamine)Cl, [Pt(Et2dien)Cl]+, and the monofunctional heterocyclic-ligated platinum(II) complexes, pyriplatin and phenanthriplatin, and compared their 5'-GMP binding rates, cellular compartmental distribution and cellular viability effects. A zebrafish inner ear model was used to determine if the monofunctional complexes and cisplatin caused hearing threshold shifts and reduced auditory hair cell density. The four monofunctional complexes had varied relative GMP binding rates, but similar cytosolic and nuclear compartmental uptake in three cancer cell lines (A549, Caco2, HTB16) and a control cell line (IMR90). Phenanthriplatin had the strongest effect against cellular viability, comparable to cisplatin, followed by [Pt(Et2dien)Cl]+, pyriplatin and [Pt(dien)Cl]+. Phenanthriplatin also produced the highest hearing threshold shifts followed by [Pt(dien)Cl]+, [Pt(Et2dien)Cl]+, cisplatin and pyriplatin. Hair cell counts taken from four regions of the zebrafish saccule showed that cisplatin significantly reduced hair cell density in three regions and phenanthriplatin in only one region, with the other complexes having no significant effect. Utricular hair cell density was not reduced by any of the compounds. Our results suggest that placing greater steric hindrance cis to one side of the platinum coordinating center in monofunctional complexes promotes efficient targeting of the nuclear compartment and guanosine residues, and may be responsible for reducing cancer cell viability. Also, the monofunctional compounds caused hearing threshold shifts with minimal effect on hair cell density, which suggests that they may affect different pathways than cisplatin. PMID- 29513754 TI - Using Bluetooth proximity sensing to determine where office workers spend time at work. AB - BACKGROUND: Most wearable devices that measure movement in workplaces cannot determine the context in which people spend time. This study examined the accuracy of Bluetooth sensing (10-second intervals) via the ActiGraph GT9X Link monitor to determine location in an office setting, using two simple, bespoke algorithms. METHODS: For one work day (mean+/-SD 6.2+/-1.1 hours), 30 office workers (30% men, aged 38+/-11 years) simultaneously wore chest-mounted cameras (video recording) and Bluetooth-enabled monitors (initialised as receivers) on the wrist and thigh. Additional monitors (initialised as beacons) were placed in the entry, kitchen, photocopy room, corridors, and the wearer's office. Firstly, participant presence/absence at each location was predicted from the presence/absence of signals at that location (ignoring all other signals). Secondly, using the information gathered at multiple locations simultaneously, a simple heuristic model was used to predict at which location the participant was present. The Bluetooth-determined location for each algorithm was tested against the camera in terms of F-scores. RESULTS: When considering locations individually, the accuracy obtained was excellent in the office (F-score = 0.98 and 0.97 for thigh and wrist positions) but poor in other locations (F-score = 0.04 to 0.36), stemming primarily from a high false positive rate. The multi location algorithm exhibited high accuracy for the office location (F-score = 0.97 for both wear positions). It also improved the F-scores obtained in the remaining locations, but not always to levels indicating good accuracy (e.g., F score for photocopy room ~0.1 in both wear positions). CONCLUSIONS: The Bluetooth signalling function shows promise for determining where workers spend most of their time (i.e., their office). Placing beacons in multiple locations and using a rule-based decision model improved classification accuracy; however, for workplace locations visited infrequently or with considerable movement, accuracy was below desirable levels. Further development of algorithms is warranted. PMID- 29513755 TI - Mast cells are important regulator of acupoint sensitization via the secretion of tryptase, 5-hydroxytryptamine, and histamine. AB - Mast cells (MCs) play a crucial role in mediating the establishment of networks among the circulatory, nervous and immune system at acupoints. However, the changes which occur in MCs during acupoint sensitization, i.e. the dynamic transformation of an acupoint from a "silenced" to an "activated" status, remain uncharacterized. To investigate the morphological and functional changes of MCs as an aid to understanding the cellular mechanism underlying acupoint sensitization, a rat model of knee osteoarthritis (OA) was induced by an injection of mono-iodoacetate (MIA) on day 0. On day 14, toluidine blue and immunofluorescence staining were used to observe the recruitment and degranulation of MCs and the release of mast cell co-expressed mediators: tryptase, 5-hydroxytryptamine (5-HT) and histamine (HA) at the acupoints Yanglingquan (GB34), Heding (EX-LE2) and Weizhong (BL40). Results showed that the number of MCs as well as the percentages of degranulated and extensively degranulated MCs at the acupoints GB34 and EX-LE2 in the light (A), mild (B), heavy (C) osteoarthritis groups were larger than those in the normal control (N) and normal saline (NS) groups (p < 0.01). Comparisons among the A, B and C groups suggested that the number and the degranulation extent of the MCs at the acupoints GB34 and EX-LE2 were positively correlated with the severity of the disease. Some MCs in the A, B and C group showed the release of 5-HT, HA, and tryptase in degranulation at the acupoints GB34 and EX-LE2. Such changes in MCs were not observed at the acupoint BL40. In conclusion, this study confirmed that acupoint sensitization is associated with the increase in recruitment and degranulation levels of MCs on a acupoint-specific and disease severity-dependent manner. The release of tryptase, 5-HT, and HA during MC degranulation is likely to be one of the cellular mechanisms occurring during acupoint sensitization. PMID- 29513756 TI - Microenvironmental cues enhance mesenchymal stem cell-mediated immunomodulation and regulatory T-cell expansion. AB - Mesenchymal stem cells (MSCs) are known to both have powerful immunosuppressive properties and promote allograft tolerance. Determining the environmental oxygen tension and inflammatory conditions under which MSCs are optimally primed for this immunosuppressive function is essential to their utilization in promoting graft tolerance. Of particular interest is the mechanisms governing the interaction between MSCs and regulatory T cells (Tregs), which is relatively unknown. We performed our experiments utilizing rat bone marrow derived MSCs. We observed that priming MSCs in hypoxia promotes maintenance of stem-like characteristics, with greater expression of typical MSC cell-surface markers, increased proliferation, and maintenance of differentiation potential. Addition of autologous MSCs to CD4+/allogeneic endothelial cell (EC) co-culture increases regulatory T cell (Treg) proliferation, which is further enhanced when MSCs are primed in hypoxia. Furthermore, MSC-mediated Treg expansion does not require direct cell-cell contact. The expression of indolamine 2,3-dioxygenase, a mediator of MSC immunomodulation, increases when MSCs are primed in hypoxia, and inhibition of IDO significantly decreases the expansion of Tregs. Priming with inflammatory cytokines IFNgamma and TNFalpha increases also expression of markers associated with MSC immunomodulatory function, but decreases MSC proliferation. The expression of IDO also increases when MSCs are primed with inflammatory cytokines. However, there is no increase in Treg expansion when MSCs are primed with IFNgamma, suggesting an alternate mechanism for inflammatory-stimulated MSC immunomodulation. Overall, these results suggest that MSCs primed in hypoxia or inflammatory conditions are optimally primed for immunosuppressive function. These results provide a clearer picture of how to enhance MSC immunomodulation for clinical use. PMID- 29513757 TI - Comparison of neuroprotective efficacy of poly-arginine R18 and R18D (D enantiomer) peptides following permanent middle cerebral artery occlusion in the Wistar rat and in vitro toxicity studies. AB - We have previously demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties, with poly-arginine peptide R18 identified as being highly effective at reducing infarct volume following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. Since peptides synthesised using D-isoform amino acids have greater stability than L-isoform peptides due to increased resistance to proteolytic degradation, they represent potentially more effective peptide therapeutics. Therefore we compared the neuroprotective efficacy of R18 and its D-enantiomer R18D following permanent MCAO in the Wistar rat. Furthermore, as increased peptide stability may also increase peptide toxicity, we examined the effects of R18 and R18D on cultured cortical neurons, astrocytes, brain endothelial cells (bEND.3), and embryonic kidney cells (HEK293) following a 10-minute or 24-hour peptide exposure duration. The in vivo studies demonstrated that R18D resulted in a greater reduction in mean infarct volume compared to R18 (33%, p = 0.004 vs 12%, p = 0.27) after intravenous administration at 300 nmol/kg 30 minutes after MCAO. Both R18D and R18 reduced cerebral hemisphere swelling to a comparable degree (27%, p = 0.03 and 30%, p = 0.02), and improved neurological assessment scores (1.5, p = 0.02 and 2, p = 0.058 vs 3 for vehicle). No abnormal histological findings specific to peptide treatments were observed in hematoxylin and eosin stained sections of kidney, liver, spleen, lung and heart. In vitro studies demonstrated that R18 and R18D were most toxic to neurons, followed by astrocytes, HEK293 and bEND.3 cells, but only at high concentrations and/or following 24-hour exposure. These findings further highlight the neuroprotective properties of poly-arginine peptides, and indicate that R18D at the dose examined is more potent than R18 in Wistar rats, and justify continued investigation of the R18 peptide as a novel neuroprotective agent for stroke. PMID- 29513758 TI - A systems pharmacology model for inflammatory bowel disease. AB - MOTIVATION: The literature on complex diseases is abundant but not always quantitative. This is particularly so for Inflammatory Bowel Disease (IBD), where many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. We propose the elaboration and validation of a logic network for IBD able to capture the information available in the literature that will facilitate the identification/validation of therapeutic targets. RESULTS: In this article, we propose a logic model for Inflammatory Bowel Disease (IBD) which consists of 43 nodes and 298 qualitative interactions. The model presented is able to describe the pathogenic mechanisms of the disorder and qualitatively describes the characteristic chronic inflammation. A perturbation analysis performed on the IBD network indicates that the model is robust. Also, as described in clinical trials, a simulation of anti-TNFalpha, anti-IL2 and Granulocyte and Monocyte Apheresis showed a decrease in the Metalloproteinases node (MMPs), which means a decrease in tissue damage. In contrast, as clinical trials have demonstrated, a simulation of anti-IL17 and anti-IFNgamma or IL10 overexpression therapy did not show any major change in MMPs expression, as corresponds to a failed therapy. The model proved to be a promising in silico tool for the evaluation of potential therapeutic targets, the identification of new IBD biomarkers, the integration of IBD polymorphisms to anticipate responders and non-responders and can be reduced and transformed in quantitative model/s. PMID- 29513759 TI - Subtype assignment of CLL based on B-cell subset associated gene signatures from normal bone marrow - A proof of concept study. AB - Diagnostic and prognostic evaluation of chronic lymphocytic leukemia (CLL) involves blood cell counts, immunophenotyping, IgVH mutation status, and cytogenetic analyses. We generated B-cell associated gene-signatures (BAGS) based on six naturally occurring B-cell subsets within normal bone marrow. Our hypothesis is that by segregating CLL according to BAGS, we can identify subtypes with prognostic implications in support of pathogenetic value of BAGS. Microarray based gene-expression samples from eight independent CLL cohorts (1,024 untreated patients) were BAGS-stratified into pre-BI, pre-BII, immature, naive, memory, or plasma cell subtypes; the majority falling within the memory (24.5-45.8%) or naive (14.5-32.3%) categories. For a subset of CLL patients (n = 296), time to treatment (TTT) was shorter amongst early differentiation subtypes (pre-BI/pre BII/immature) compared to late subtypes (memory/plasma cell, HR: 0.53 [0.35 0.78]). Particularly, pre-BII subtype patients had the shortest TTT among all subtypes. Correlates derived for BAGS subtype and IgVH mutation (n = 405) revealed an elevated mutation frequency in late vs. early subtypes (71% vs. 45%, P < .001). Predictions for BAGS subtype resistance towards rituximab and cyclophosphamide varied for rituximab, whereas all subtypes were sensitive to cyclophosphamide. This study supports our hypothesis that BAGS-subtyping may be of tangible prognostic and pathogenetic value for CLL patients. PMID- 29513760 TI - Metformin suppresses retinal angiogenesis and inflammation in vitro and in vivo. AB - The oral anti-diabetic drug metformin has been found to reduce cardiovascular complications independent of glycemic control in diabetic patients. However, its role in diabetic retinal microvascular complications is not clear. This study is to investigate the effects of metformin on retinal vascular endothelium and its possible mechanisms, regarding two major pathogenic features of diabetic retinopathy: angiogenesis and inflammation. In human retinal vascular endothelial cell culture, metformin inhibited various steps of angiogenesis including endothelial cell proliferation, migration, and tube formation in a dose-dependent manner. Its anti-angiogenic activity was confirmed in vivo that metformin significantly reduced spontaneous intraretinal neovascularization in a very-low density lipoprotein receptor knockout mutant mouse (p<0.05). Several inflammatory molecules upregulated by tumor necrosis factor-alpha in human retinal vascular endothelial cells were markedly reduced by metformin, including nuclear factor kappa B p65 (NFkappaB p65), intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8). Further, metformin significantly decreased retinal leukocyte adhesion (p<0.05) in streptozotocin induced diabetic mice. Activation of AMP-activated protein kinase was found to play a partial role in the suppression of ICAM-1 and MCP-1 by metformin, but not in those of NFkappaB p65 and IL-8. Our findings support the notion that metformin has considerable anti-angiogenic and anti-inflammatory effects on retinal vasculature. Metformin could be potentially used for the purpose of treating diabetic retinopathy in addition to blood glucose control in diabetic patients. PMID- 29513761 TI - Peripheral neuropathy in patients with multiple sclerosis. AB - OBJECTIVES: To determine the prevalence and severity of neuropathic pain, sudomotor dysfunction and abnormal vibration perception in patients with MS. METHODS: 73 patients with MS and 32 age-matched healthy controls underwent assessment of expanded disability severity score (EDSS), DN4 to assess neuropathic pain, electrochemical skin conductance (ESC) to assess sudomotor function and vibration perception threshold (VPT). RESULTS: Patients with MS had a higher DN4 score (p < 0.001) with 14% fulfilling the criteria for neuropathic pain elevated VPT (p < 0.001) and lower ESC on the feet (p < 0.001) and hands (p < 0.001) compared to control participants. ESC on the feet (32% of MS patients) and hands (30% of MS patients) were lower, and DN4 (77% of MS patients) and VPT (64% of MS patients) were greater than 2SD of the healthy control values, respectively. EDSS correlated with the number of relapses (r = 0.564, p < 0.001), VPT (r = -0.457, < 0.001) and ESC on the feet (r = -0.268, p = 0.023). CONCLUSIONS: Patients with multiple sclerosis have evidence of sudomotor dysfunction and elevated vibration perception, which were associated with neurological disability from MS. PMID- 29513762 TI - Are university rankings useful to improve research? A systematic review. AB - INTRODUCTION: Concerns about reproducibility and impact of research urge improvement initiatives. Current university ranking systems evaluate and compare universities on measures of academic and research performance. Although often useful for marketing purposes, the value of ranking systems when examining quality and outcomes is unclear. The purpose of this study was to evaluate usefulness of ranking systems and identify opportunities to support research quality and performance improvement. METHODS: A systematic review of university ranking systems was conducted to investigate research performance and academic quality measures. Eligibility requirements included: inclusion of at least 100 doctoral granting institutions, be currently produced on an ongoing basis and include both global and US universities, publish rank calculation methodology in English and independently calculate ranks. Ranking systems must also include some measures of research outcomes. Indicators were abstracted and contrasted with basic quality improvement requirements. Exploration of aggregation methods, validity of research and academic quality indicators, and suitability for quality improvement within ranking systems were also conducted. RESULTS: A total of 24 ranking systems were identified and 13 eligible ranking systems were evaluated. Six of the 13 rankings are 100% focused on research performance. For those reporting weighting, 76% of the total ranks are attributed to research indicators, with 24% attributed to academic or teaching quality. Seven systems rely on reputation surveys and/or faculty and alumni awards. Rankings influence academic choice yet research performance measures are the most weighted indicators. There are no generally accepted academic quality indicators in ranking systems. DISCUSSION: No single ranking system provides a comprehensive evaluation of research and academic quality. Utilizing a combined approach of the Leiden, Thomson Reuters Most Innovative Universities, and the SCImago ranking systems may provide institutions with a more effective feedback for research improvement. Rankings which extensively rely on subjective reputation and "luxury" indicators, such as award winning faculty or alumni who are high ranking executives, are not well suited for academic or research performance improvement initiatives. Future efforts should better explore measurement of the university research performance through comprehensive and standardized indicators. This paper could serve as a general literature citation when one or more of university ranking systems are used in efforts to improve academic prominence and research performance. PMID- 29513763 TI - Computational modeling of opioid-induced synaptic plasticity in hippocampus. AB - According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will suggest how one can prevent this type of pathological LTP. To this purpose, a detailed computational model is presented, which consists of one pyramidal neuron and one interneuron both from CA3, one CA1 pyramidal neuron, and one astrocyte. Based on experimental findings morphine affects the hippocampal neurons in three primary ways: 1) disinhibitory mechanism of interneurons in CA3, 2) enhancement of NMDARs current by MU Opioid Receptor (MUOR) activation and 3) by attenuation of astrocytic glutamate reuptake ability. By utilizing these effects, simulations were implemented. Our results indicate that morphine can induce LTP by all aforementioned possible mechanisms. Based on our simulation results, attenuation of pathologic LTP achieved mainly by stimulation of astrocytic glutamate transporters, down-regulation of the astrocytic metabotropic glutamate receptors (mGlurs) or by applying NMDAR's antagonist. Based on our observations, we suggest that astrocyte has a dominant role in forming addiction-related memories. This finding may help researchers in exploring drug actions for preventing relapse. PMID- 29513764 TI - Immuno-PET imaging of tumor-infiltrating lymphocytes using zirconium-89 radiolabeled anti-CD3 antibody in immune-competent mice bearing syngeneic tumors. AB - The ability to non-invasively monitor tumor-infiltrating T cells in vivo could provide a powerful tool to visualize and quantify tumor immune infiltrates. For non-invasive evaluations in vivo, an anti-CD3 mAb was modified with desferrioxamine (DFO) and radiolabeled with zirconium-89 (Zr-89 or 89Zr). Radiolabeled 89Zr-DFO-anti-CD3 was tested for T cell detection using positron emission tomography (PET) in both healthy mice and mice bearing syngeneic bladder cancer BBN975. In vivo PET/CT and ex vivo biodistribution demonstrated preferential accumulation and visualization of tracer in the spleen, thymus, lymph nodes, and bone marrow. In tumor bearing mice, 89Zr-DFO-anti-CD3 demonstrated an 11.5-fold increase in tumor-to-blood signal compared to isotype control. Immunological profiling demonstrated no significant change to total T cell count, but observed CD4+ T cell depletion and CD8+ T cell expansion to the central and effector memory. This was very encouraging since a high CD8+ to CD4+ T cell ratio has already been associated with better patient prognosis. Ultimately, this anti-CD3 mAb allowed for in vivo imaging of homeostatic T cell distribution, and more specifically tumor-infiltrating T cells. Future applications of this radiolabeled mAb against CD3 could include prediction and monitoring of patient response to immunotherapy. PMID- 29513765 TI - Use of data mining techniques to classify soil CO2 emission induced by crop management in sugarcane field. AB - Soil CO2 emissions are regarded as one of the largest flows of the global carbon cycle and small changes in their magnitude can have a large effect on the CO2 concentration in the atmosphere. Thus, a better understanding of this attribute would enable the identification of promoters and the development of strategies to mitigate the risks of climate change. Therefore, our study aimed at using data mining techniques to predict the soil CO2 emission induced by crop management in sugarcane areas in Brazil. To do so, we used different variable selection methods (correlation, chi-square, wrapper) and classification (Decision tree, Bayesian models, neural networks, support vector machine, bagging with logistic regression), and finally we tested the efficiency of different approaches through the Receiver Operating Characteristic (ROC) curve. The original dataset consisted of 19 variables (18 independent variables and one dependent (or response) variable). The association between cover crop and minimum tillage are effective strategies to promote the mitigation of soil CO2 emissions, in which the average CO2 emissions are 63 kg ha-1 day-1. The variables soil moisture, soil temperature (Ts), rainfall, pH, and organic carbon were most frequently selected for soil CO2 emission classification using different methods for attribute selection. According to the results of the ROC curve, the best approaches for soil CO2 emission classification were the following: (I)-the Multilayer Perceptron classifier with attribute selection through the wrapper method, that presented rate of false positive of 13,50%, true positive of 94,20% area under the curve (AUC) of 89,90% (II)-the Bagging classifier with logistic regression with attribute selection through the Chi-square method, that presented rate of false positive of 13,50%, true positive of 94,20% AUC of 89,90%. However, the (I) approach stands out in relation to (II) for its higher positive class accuracy (high CO2 emission) and lower computational cost. PMID- 29513766 TI - Material security, life history, and moralistic religions: A cross-cultural examination. AB - Researchers have recently proposed that "moralistic" religions-those with moral doctrines, moralistic supernatural punishment, and lower emphasis on ritual emerged as an effect of greater wealth and material security. One interpretation appeals to life history theory, predicting that individuals with "slow life history" strategies will be more attracted to moralistic traditions as a means to judge those with "fast life history" strategies. As we had reservations about the validity of this application of life history theory, we tested these predictions with a data set consisting of 592 individuals from eight diverse societies. Our sample includes individuals from a wide range of traditions, including world religions such as Buddhism, Hinduism and Christianity, but also local traditions rooted in beliefs in animism, ancestor worship, and worship of spirits associated with nature. We first test for the presence of associations between material security, years of formal education, and reproductive success. Consistent with popular life history predictions, we find evidence that material security and education are associated with reduced reproduction. Building on this, we then test whether or not these demographic factors predict the moral concern, punitiveness, attributed knowledge-breadth, and frequency of ritual devotions towards two deities in each society. Here, we find no reliable evidence of a relationship between number of children, material security, or formal education and the individual-level religious beliefs and behaviors. We conclude with a discussion of why life-history theory is an inadequate interpretation for the emergence of factors typifying the moralistic traditions. PMID- 29513769 TI - Cortical Bone Repositioning Technique for Horizontal Alveolar Bone Augmentation: A Case Series. AB - The objective of this study was to present a novel procedure for cortical bone repositioning (CBR) that maintains a secure space under the periosteum by replacement of the lateral cortex via fixation, employing titanium screws. Seven systemically healthy patients presenting with horizontal alveolar bone defects in radiographs and CT images were enrolled for CBR technique for horizontal alveolar bone augmentation. A lateral cortical bone block was cut in the defects and freed from the original bony surface. A screw was inserted into the block, and the block was placed laterally to allow fixation. The block was checked for adequate stability, and the flap was closed after creation of periosteal releasing incisions to ensure tension-free closure. There were no complications, and 16 implants were placed uneventfully. Preoperative bone width in the defect area was 3.28 mm; the postoperative 4-month bone width in the same area was 6.46 mm. The mean implant stability quotient (ISQ) at placement was 68. At the secondary operation for changing to a healing abutment, the mean ISQ was 72. All patients were functionally and esthetically rehabilitated with implant-supported dentures. CBR technique is a simple procedure without the use of any biomaterials or devices. The main advantage of this technique in comparison to autogenous grafts is the lack of donor site issues. This technique has the possibility of inducing the patient's regenerative ability for bone healing. PMID- 29513767 TI - Association of gadolinium-enhanced magnetic resonance imaging with hepatic fibrosis and inflammation in primary sclerosing cholangitis. AB - OBJECTIVE: To evaluate magnetic resonance imaging (MRI) parameters T2 signal, contrast enhancement (CE), and relative liver enhancement (RLE) of extracellular gadolinium-based contrast agent (GBCA)-enhanced MRI as a marker for hepatic fibrosis and inflammation in patients with primary sclerosing cholangitis (PSC). METHODS: 3.0-Tesla MRI scans and liver biopsies of 40 patients (41.2 +/- 17.1 years) were retrospectively reviewed. Biopsies were obtained within a mean time of 54 +/- 55 days to MRI scans and specimens were categorized according to Ishak modified hepatic activity index (mHAI) and Scheuer staging of fibrosis. T2 signal (N = 40), CE alterations (N = 29), and RLE (N = 29) were assessed by two raters. Mixed-effects regression models were applied to estimate the association between histopathology and MRI parameters. RESULTS: No significant association was observed between T2 signal or CE alterations with stages of fibrosis or mHAI grading. Regression models revealed significant positive associations of portal venous phase RLE with mHAI grade >= 7 points [beta = 25.5; 95% CI (2.53; 48.62); p = 0.04] and delayed phase RLE with stages of fibrosis [stage 2: beta = 35.13; 95% CI (11.35; 58.87); p = 0.007; stage 3/4: beta = 69.24; 95% CI (45.77; 92.75); p < 0.001]. The optimal cut-off value of 66.6% delayed phase RLE distinguished fibrosis stages 0-2 from 3-4 with a sensitivity of 0.833 and specificity of 0.972. Inter-rater reliability (IRR) for quantification of RLE was 'excellent' (r = 0.90-0.98). IRR was 'substantial' for detection of T2 signal in the right liver lobe (RL) (Kappa = 0.77) and 'almost perfect' for T2 signal of the left liver lobe (LL) and CE of both lobes (Kappa = 0.87-1.0). CONCLUSION: The simple and reproducible method of RLE quantification on standard extracellular GBCA-enhanced MRI may provide a correlate measure of advanced stages of hepatic fibrosis and potentially also inflammation in PSC patients, if validated in larger cohorts. PMID- 29513770 TI - Marginal Adaptation and Fracture Resistance of Lithium Disilicate Laminate Veneers on Teeth with Different Preparation Depths. AB - The purpose of this study was to evaluate the marginal adaptation and fracture load of ceramic laminate veneers on teeth with different preparation depths. A total of 75 extracted intact human maxillary central incisors were prepared with three different preparation depths (P) and assigned to the following five groups (n = 15): P1 (0.3-mm depth of preparation; preparation entirely in enamel); P2 (0.5-mm depth of preparation; preparation in enamel and dentin complex); P3 (1-mm depth of preparation; preparation entirely in dentin); P4 (no preparation, only surface roughening); and P5 (unrestored, intact teeth as control). A total of 60 lithium disilicate laminate veneers were fabricated. The marginal adaptation of the veneers was evaluated by light microscope and scanning electron microscope after cementation with resin cement. Finally, the veneers were loaded until fracture at a 90-degree angle to the lingual surface of the tooth. Statistical analyses were performed using analysis of variance and Tukey multiple range test. There was a significant difference between the marginal gap value of the distocervical measurement points of P1 and P2 and the distal measurement points of P3 and P4 (P = .33 and P = .017, respectively). The highest fracture resistance values were observed in the P5 group (mean: 389.55 +/- 22 N) and the P2 group (mean: 322.86 +/- 79.38 N), and the lowest values were observed in the P3 group (mean: 219.21 +/- 60.74 N). The marginal adaptation of the laminate veneer restorations was not related to the depth of preparation. Mean fracture resistance of laminate veneers with 0.5-mm preparation depth was greater than that of the 0.3-mm and 1-mm preparation depth laminate veneers and those with no preparation. PMID- 29513768 TI - Socioeconomic patterns of underweight and its association with self-rated health, cognition and quality of life among older adults in India. AB - BACKGROUND: Underweight defined as body mass index (BMI) < 18.5 is associated with negative health and quality of life outcomes including mortality. Yet, little is known about the socioeconomic differentials in underweight and its association with health and well-being among older adults in India. This study examined the socioeconomic differentials in underweight among respondents aged >=50 in India. Consequently, three outcomes of the association of underweight were studied. These are poor self-rated health, cognition and quality of life. METHODS: Cross-sectional data on 6,372 older adults derived from the first wave of the WHO's Study on global AGEing and adult health (SAGE), a nationally representative survey conducted in six states of India during 2007-8, were used. Bivariate and multivariate regression analyses were applied to fulfil the objectives. RESULTS: The overall prevalence of underweight was 38 percent in the study population. Further, socioeconomic status showed a significant and negative association with underweight. The association of underweight with poor self-rated health (OR = 1.60; p < .001), cognition (beta = -0.95; p < .001) and quality of life (beta = -1.90; p < .001) were remained statistically significant after adjusting for age, sex, place of residence, marital status, years of schooling, wealth quintile, sleep problems, chronic diseases, low back pain and state/province. CONCLUSION: The results indicated significant socioeconomic differentials in underweight and its association with poor self-rated health, cognition and quality of life outcomes. Interventions focussing on underweight older adults are important to enhance the overall wellbeing of the growing older population in India. PMID- 29513771 TI - Lip Repositioning with Vestibular Shallowing Technique for Treatment of Excessive Gingival Display with Various Etiologies. AB - Improvement of smile esthetics is a major goal of modern dentistry. Various treatment modalities have been proposed to correct excessive gingival display (EGD), depending on the identified etiologies. This study reports on the clinical and patient-centered outcomes of a novel lip repositioning technique with vestibular shallowing approach in the treatment of three types of EGD with varying etiologies. Periosteal fenestration with cicatrization (scarification) was performed at the mucogingival junction to ensure the stability of esthetic outcomes. Suspensory triangular sutures and extraoral tissue stabilization tapes were used to facilitate the cicatrization process during the healing phase of this novel technique. Postoperative clinical examination revealed 84% reduction in gingival display that remained stable for 13 to 16 months with a high level of patient satisfaction. PMID- 29513772 TI - Histologic and Radiographic Analysis of Nonhealing Extraction Sockets Treated with Bio-Oss Collagen After a 4-Month Healing Period: A Prospective Descriptive Study in Humans. AB - Healing of extraction sockets may sometimes result in formation of fibrous tissue instead of bone, even after 4 months, an occurrence that may hinder implant placement. The aim of this preliminary observational study was to histologically evaluate quality and amount of bone regeneration after treating nonhealing sockets with a bovine-derived xenograft enriched with porcine collagen (Bio-Oss Collagen, Geistlich) without barrier membranes. Biopsy specimens were collected during implant placement, 4 months after grafting. A total of 10 cases were treated and evaluated. In all cases, correct implant placement was possible and no implant failure occurred up to 6 months after loading. The histologic analysis demonstrated new bone formation in all specimens. The percentage of newly formed bone was 29.1% (SD 20.71%; range 5% to 48%). Xenograft particles in direct contact with newly formed bone were visible, and mature lamellar bone was observed in 8 cases. PMID- 29513773 TI - Guided Bone Regeneration in the Treatment of a Lateral Periodontal Cyst: 2-Year Clinical and Radiologic Follow-up. AB - Lateral periodontal cysts (LPCs) are rare odontogenic cysts of developmental origin. A 52-year-old man presented with an asymptomatic gingival swelling located between the mandibular left canine and first premolar, both of which were vital. Radiography showed a well-circumscribed radiolucent area and loss of the lamina dura around the tooth socket in contact with the lesion and of the interproximal buccal bone. The lesion was enucleated. The defect was immediately grafted with a 1:1 mixed autologous and heterologous bone graft covered with a collagen membrane. Histology confirmed the diagnosis of LPC. At 12- and 24-month clinical and radiologic follow-up, complete bone and periodontal healing was found, with no sign of recurrence. PMID- 29513774 TI - Effectiveness of Enamel Matrix Derivative in Conjunction with Particulate Autologous Bone in the Treatment of Noncontained Intrabony Defects: A 2-Year Prospective Case Series. AB - This case series evaluated the healing of deep intrabony defects treated with a combination of enamel matrix derivative and autologous particulate bone harvested from the buccal and lingual/palatal cortical plate with a Piezosurgery device. A total of 15 defects with a predominantly one- or two-wall component were consecutively treated in 15 patients with advanced chronic periodontitis. In all selected sites, the three-wall component was <= 25% of the total defect depth. Clinical and radiographic parameters were recorded at baseline and 12 and 24 months postoperatively. All defects showed favorable clinical and radiographic outcomes at the 24-month follow-up. The probing depth reduction was 4.4 +/- 1.6 mm, and more than 50% of the defects presented clinical attachment level gain of at least 5 mm. The bone fill was 3.1 +/- 1.6 mm. PMID- 29513775 TI - Osseoincorporation of Porous Tantalum Trabecular-Structured Metal: A Histologic and Histomorphometric Study in Humans. AB - Porous tantalum trabecular-structured metal (PTTM) has been applied to titanium orthopedic and dental implants. This study evaluated the healing pattern of bone growth into experimental PTTM cylinders (N = 24; 3.0 * 5.0 mm) implanted in the partially edentulous jaws of 23 healthy volunteers divided into four groups. Six PTTM cylinders per group were explanted, prepared, and analyzed histologically/metrically after 2, 3, 6, and 12 weeks of submerged healing. PTTM implant osseoincorporation resulted from the formation of an osteogenic tissue network that over the course of 12 weeks resulted in vascular bone volume levels in PTTM that are comparable to clinically observed mean trabecular volumes in edentulous posterior jaws. PMID- 29513776 TI - Tissue Remodeling in Immediate Versus Delayed Prosthetic Restoration in Fresh Socket Implants in the Esthetic Zone: Four-Year Follow-up. AB - The aim of this study was to compare midfacial soft tissue assessment and horizontal width changes of fresh socket implants in immediate and delayed prosthetic restorations. Patients requiring extractions in the maxillary esthetic zone were recruited. In one group, 30 implants were placed using an immediate loading approach; in the second group, 30 implants were loaded after a period of 3 months. At the 4-year follow-up, statistically significant differences (P < .001) were found. Immediate implants restored on the day of surgery demonstrated more stable midfacial soft tissue levels and bone volume maintenance than delayed implants. PMID- 29513777 TI - Influence of Polishing System on the Surface Roughness of Flowable and Regular Viscosity Bulk Fill Composites. AB - This study evaluated the influence of polishing protocols on the surface roughness of flowable and regular bulk fill composites. Five bulk fill composites were tested: SureFil SDR Flow (SDR), Tetric EvoFlow Bulk fill (TEF), Filtek Bulk Fill Flowable (FIF), Tetric EvoCeram Bulk Fill (TEC), and Filtek Bulk Fill Posterior (FIP). Two polishing protocols were tested: Sof-Lex and Astropol. Astropol created a smoother surface for FIP (P < .05); however, the polishing protocol did not influence surface roughness on TEC (P > .05). SDR, TEF, and FIF exhibited rougher surfaces when polished. Sof-Lex created rougher surfaces for bulk fill composites. It was concluded that surface roughness was related to material composition rather than the polishing system. PMID- 29513778 TI - Four Stable and Functioning Dental Implants Retrieved for Fracture After 14 and 17 Years from the Same Patient: A Histologic and Histomorphometric Report. AB - The aim of the present study was a histologic and histomorphometric analysis of the peri-implant tissue reactions and of the bone-titanium interface in successfully osseointegrated, clinically stable, and immobile retrieved titanium dental implants after a long loading period. Four successfully osseointegrated and stable implants with a sandblasted surface were retrieved from a patient due to fracture, two after 14 years of loading and two after 17 years. None of these implants has been previously reported. Mature, compact bone with a few marrow spaces was observed around all four implants. At low magnification, a high percentage of bone-implant contact (BIC) was present at the interface of almost all implants. BIC percentage for the four implants was 83%, 66%, 74%, and 65%. In almost all the implants, the space within the threads was almost completely filled by compact bone. Close, tight contact between bone and implant surface was observed in all specimens, and no gaps or fibrous connective tissue was found at the bone-implant interface. All implants appeared to be well integrated in the surrounding mineralized bone, and all showed adequate BIC percentages after a long loading history. PMID- 29513779 TI - First report of Chrysodeixis includens (Walker, [1858]) (Lepidotera: Noctuidae) Injurious to Pineapple (Ananas comosus L.) (Bromeliaceae) in Brazil. PMID- 29513780 TI - ? PMID- 29513781 TI - Acuariidae (Nematoda) in Procellariiformes (Aves) on the southern coast of Rio Grande do Sul, Brazil. AB - Acuariidae nematodes are normally found in the digestive tract of aquatic birds, including Procellariiformes. Were examined Calonectris borealis (n = 4), Diomedea exulans (n = 1), Macronectes giganteus (n = 8), Thalassarche chlororhynchos (n = 5), Thalassarche melanophrys (n = 15), Procellaria aequinoctialis (n = 4), Puffinus gravis (n = 2) and Puffinus puffinus (n = 6), collected on the southern coast of RS, Brazil. A total of 16 birds (35.5%) were parasitized by two species of Acuariidae. Stegophorus diomedeae and Seuratia shipleyi were identified, with prevalences of 26.1% and 21.7%, respectively. Few studies on nematodes in Procellariiformes have been conducted. Here, the acuariids Seuratia shipleyi in Calonectris borealis and Procellaria aequinoctialis and Stegophorus diomedeae in Diomedea exulans, Procellaria aequinoctialis and Thalassarche chlororhynchos were reported for the first time. PMID- 29513782 TI - Neonchocotyle violantei n. sp. (Monogenea, Hexabothriidae) from Pseudobatos lentiginosus (Rhinopristiformes, Rhinobatidae) of Yucatan, Gulf of Mexico. AB - Neonchocotyle violantei n. sp. (Monogenea: Hexabothriidae) infects the gill of the Atlantic guitarfish, Pseudobatos lentiginosus (Rhinopristiformes, Rhinobatidae) from littoral waters of Celestun, Yucatan, Mexico. It is assigned to Neonchocotyle because it has, among other features, an asymmetrical haptor, a seminal receptacle, a smooth ootype, and an egg with two elongate filaments. It differs from Neonchocotyle pastinacae, the only congener, by having a small body (821 long by 315 wide, length to width = 2.6:1), two pairs of microhooks between the haptoral appendix suckers, extracaecal (submarginal) vaginal pores, and 5-9 testes. This is the first record of a species of Neonchocotyle in the Gulf of Mexico, the first monogenean reported from P. lentiginosus in Mexico and the second species of Hexabothriidae reported from Mexico. PMID- 29513783 TI - Introns in Cryptococcus. AB - In Cryptococcus neoformans, nearly all genes are interrupted by small introns. In recent years, genome annotation and genetic analysis have illuminated the major roles these introns play in the biology of this pathogenic yeast. Introns are necessary for gene expression and alternative splicing can regulate gene expression in response to environmental cues. In addition, recent studies have revealed that C. neoformans introns help to prevent transposon dissemination and protect genome integrity. These characteristics of cryptococcal introns are probably not unique to Cryptococcus, and this yeast likely can be considered as a model for intron-related studies in fungi. PMID- 29513786 TI - A rare mediastinal occurrence of neuroblastoma in an adult: case report. AB - CONTEXT: Neuroblastoma is the most common extracranial malignant solid tumor that occurs during childhood. It arises from primitive cells and is seen in the adrenal medulla and sympathetic ganglia of the sympathetic nervous system. CASE REPORT: We present a rare case of a 40-year-old man who was diagnosed with the onset of neuroblastoma arising in the mediastinum. He was treated by means of surgical resection in the superior mediastinum after neoadjuvant chemotherapy. The patient's surgical outcome was satisfactory. CONCLUSION: There are still no standard treatment guidelines for adult neuroblastoma patients. Although they have a poor prognosis, the main treatment option should be complete surgery at an early stage. This situation may become clarified through biological and genetic studies in the future. PMID- 29513784 TI - Advances in Cryptococcus genomics: insights into the evolution of pathogenesis. AB - Cryptococcus species are the causative agents of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals. Initial work on the molecular epidemiology of this fungal pathogen utilized genotyping approaches to describe the genetic diversity and biogeography of two species, Cryptococcus neoformans and Cryptococcus gattii. Whole genome sequencing of representatives of both species resulted in reference assemblies enabling a wide array of downstream studies and genomic resources. With the increasing availability of whole genome sequencing, both species have now had hundreds of individual isolates sequenced, providing fine-scale insight into the evolution and diversification of Cryptococcus and allowing for the first genome-wide association studies to identify genetic variants associated with human virulence. Sequencing has also begun to examine the microevolution of isolates during prolonged infection and to identify variants specific to outbreak lineages, highlighting the potential role of hyper-mutation in evolving within short time scales. We can anticipate that further advances in sequencing technology and sequencing microbial genomes at scale, including metagenomics approaches, will continue to refine our view of how the evolution of Cryptococcus drives its success as a pathogen. PMID- 29513785 TI - The war on cryptococcosis: A Review of the antifungal arsenal. AB - Cryptococcal meningitis is the most common central nervous system infection in the world today. It occurs primarily, but not exclusively, in immunocompromised individuals and despite substantial improvement in management of clinical events like AIDS, the numbers of cases of cryptococcosis remain very high. Unfortunately, despite several antifungal agents available for treatment, morbidity and mortality rates remain high with this fungal infection. In this Review, we will describe the treatments and strategies for success, identify the failures, and provide insights into the future developments / improvements for management. This sugar-coated yeast can play havoc within the human brain. Our goals must be to either prevent or diagnose disease early and treat aggressively with all our clinical tools when disease is detected. PMID- 29513787 TI - Educational inequality in Rio de Janeiro and its impact on multimorbidity: evidence from the Pro-Saude study. A cross-sectional analysis. AB - BACKGROUND: Information about multimorbidity is scarce in developing countries. This study aimed to estimate the association of educational attainment with occurrences of multimorbidity in a population of public employees on university campuses in Rio de Janeiro. DESIGN AND SETTING: We conducted cross-sectional analyses on baseline data (1999-2001) from 3,253 participants in the Pro-Saude study, conducted in Brazil. METHODS: The prevalence of multimorbidity, defined as a self-reported history of medical diagnoses of two or more chronic conditions, was estimated according to sex, age, smoking, obesity and educational level. The association between education and multimorbidity was estimated using odds ratios (OR) and the relative and slope indices of inequality, in order to quantify the degree of educational inequality among individuals with multimorbidity in this population. RESULTS: Greater age, female sex, smoking and obesity had direct associations with multimorbidity; and tobacco exposure and obesity also showed direct relationships with poorer educational level. There was a monotonic inverse linear trend between educational level and the presence of multimorbidity among women, with twice the odds (OR 2.47; 95% confidence interval, CI: 1.42-4.40) between extremities of schooling categories. There was excess multimorbidity of 22% at the lowest extremity of schooling, thus showing that women with worse educational status were more affected by the outcome. No trend and no excess multimorbidity was seen among men. CONCLUSIONS: Educational inequality is an important determinant for development of multimorbidity. Men and women experience its effect differently. Researchers need to consider that sex may be an effect modifier in multimorbidity studies. PMID- 29513788 TI - Advancement in liver laparoscopic resection - development of a new surgical device. AB - Liver resection is the standard treatment for any liver lesion. Laparoscopic liver resection is associated with lower intra-operative blood loss and fewer complications than open resection. Access to the posterior part of the right liver lobe is very uncomfortable and difficult for surgeons due the anatomic position, especially when employing laparoscopic surgery. Based on these experiences, a new laparoscopic device was developed that is capable of bending its long axis and allowing the application of radiofrequency energy in areas that were not technically accessible. The device is equipped with four telescopic needle electrodes that cause tissue coagulation after the delivery of radiofrequency energy. Ex vivo testing was performed in 2012 and 2014 at the University Hospital, Ostrava, on a porcine liver tissue. The main goal of this testing was to verify if the newly proposed electrode layout was suitable for sufficient tissue coagulation and creating a safety zone around lesions. During the ex vivo testing, the material of needle electrodes was improved to achieve the lowest possibility of adhesion. The power supply was adjusted from 20 to 120 W and the ablation time, which varied from 10 to 110 s, was monitored. Subsequently, optimal power delivery and time for coagulation was determined. This experimental study demonstrated the feasibility and safety of the newly developed device. Based on the ex vivo testing, LARA-K1 can create a safety zone of coagulation. For further assessment of the new device, an in vivo study should be performed. PMID- 29513789 TI - Phenolic profile and antioxidant activity from peels and seeds of melon (Cucumis melo L. var. reticulatus) and their antiproliferative effect in cancer cells. AB - Melon (Cucumis melo L.) has high economic value and in recent years, its production has increased; however, part of the fruit is wasted. Usually, inedible parts such as peel and seeds are discarded during processing and consumption. Extracts of melon residues were prepared and their phenolic compounds, antioxidants and antiproliferative activities were evaluated. Total phenolic compounds were found in hydroethanolic, hydromethanolic, and aqueous extracts, especially for melon peel (1.016 mg gallic acid equivalent/100 g). Flavonoids total content found for melon peel aqueous extract was 262 ug of catechin equivalent (CA)/100 g. In all extracts of melon peel significant amounts of gallic acid, catechin, and eugenol were found. For total antioxidant capacity, reported as ascorbic acid equivalent, the hydroethanolic and hydromethanolic extracts in peels and hydromethanolic in seeds were 89, 74, and 83 mg/g, respectively. Different extracts of melon showed iron and copper ions chelating activity at different concentrations, especially melon peel aqueous extract, reaching values of 61% for iron and 84% for copper. The hydroethanolic extract of melon peel presented a significant ability for hydroxyl radicals scavenging (68%). To assess the antiproliferative potential in human cancer cell lines, such as kidney carcinoma, colorectal carcinoma, cervical adenocarcinoma and cervical carcinoma, MTT assay was performed. The proliferation was inhibited by 20-85% at extracts concentrations of 0.1-1.0 mg/mL in all cancer cell lines. The results suggest that melon residues extracts display a high antioxidant activity in in vitro assays and have effective biological activity against the growth of human tumor cells. PMID- 29513790 TI - Urinary semaphorin 3A as an early biomarker to predict contrast-induced acute kidney injury in patients undergoing percutaneous coronary intervention. AB - Contrast-induced acute kidney injury (CI-AKI) is a serious complication of diagnostic coronary angiograph and percutaneous coronary intervention (PCI). However, the exact pathophysiological mechanisms underlying CI-AKI development are largely unknown. The present study examined whether urinary semaphorin 3A levels predict the development of CI-AKI in patients undergoing PCI. This study enrolled 168 patients with stable angina undergoing elective PCI. Serial urine samples, obtained at baseline and 2, 6, 12, 24, 36, and 48 h post-PCI were analyzed by semaphorin 3A and neutrophil gelatinase-associated lipocalin (NGAL) ELISA kit. AKI was defined as an increase in serum creatinine beyond 50% according to the RIFLE classification system. Receiver operator characteristic (ROC) curve analyses identified optimal semaphorin 3A and NGAL values for diagnosing CI-AKI. CI-AKI occurred in 20 of 168 patients. There were no significant differences in the baseline clinical characteristics and angiographic findings between non-AKI patients group and AKI patients group. Both urinary semaphorin 3A and NGAL levels significantly increased at 2 and 6 h post-PCI. ROC analysis showed that the cut-off value of 389.5 pg/mg semaphorin 3A at 2 h post PCI corresponds to 94% sensitivity and 75% specificity and the cut-off value of 94.4 ng/mg NGAL at 2 h post-PCI corresponds to 74% sensitivity and 82% specificity. Logistic regression showed that semaphorin 3A levels at 2 and 6 h post-PCI were the significant predictors of AKI in our cohort. Urinary semaphorin 3A may be a promising early biomarker for predicting CI-AKI in patients undergoing PCI. PMID- 29513792 TI - Polydatin inhibits cell proliferation, invasion and migration, and induces cell apoptosis in hepatocellular carcinoma. AB - Polydatin, a small molecule from Polygonum cuspidatum, has many biological functions, particularly anti-cancer effects. However, the anti-cancer effects of polydatin in hepatocellular carcinoma (HCC) have not been examined yet. In the present study, MTT assay, BrdU assay, transwell invasion assay, and wound healing assay were performed to determine cell proliferation, invasion and migration. Flow cytometry and TUNEL assay were used to measure cell apoptosis. Quantitative real-time PCR and western blotting assays were used to determine mRNA and protein expression levels. Xenograft experiment was performed to determine the in vivo anti-tumor effect of polydatin. Immunostaining was performed to analyze the expression of caspase-3 and Ki-67. Our results showed that polydatin inhibited cell proliferation in a concentration-dependent and time-dependent manner in the HCC cell lines. Polydatin also induced cell apoptosis in a concentration dependent manner possibly via increasing the caspase-3 activity, and up regulating the protein expression of caspase-3, caspase-9, Bax, and down regulating the protein expression of Bcl-2. In addition, polydatin treatment had an inhibitory effect on cell proliferation, invasion and migration in HCC cell lines. Polydatin treatment also suppressed the Wnt/beta-catenin signaling activities in HCC cells. Polydatin treatment significantly reduced tumor growth in nude mice inoculated with HepG2 cells, suppressed the expression of Ki-67, and increased caspase-3 expression and TUNEL activity. Our data indicated the important role of polydatin for the suppression of HCC progression. PMID- 29513791 TI - Inflammatory biomarkers responses after acute whole body vibration in fibromyalgia. AB - The aims of this study were 1) to characterize the intensity of the vibration stimulation in women diagnosed with fibromyalgia (FM) compared to a control group of healthy women (HW) matched by age and anthropometric parameters, and 2) to investigate the effect of a single session of whole body vibration (WBV) on inflammatory responses. Levels of adipokines, soluble tumor necrosis factor receptors (sTNFr1, sTNFr2), and brain-derived neurotrophic factor (BDNF) were determined by enzyme-linked immunosorbent assay. Oxygen consumption (VO2) was estimated by a portable gas analysis system, heart rate (HR) was measured using a HR monitor, and perceived exertion (RPE) was evaluated using the Borg scale of perceived exertion. Acutely mild WBV increased VO2 and HR similarly in both groups. There was an interaction (disease vs vibration) in RPE (P=0.0078), showing a higher RPE in FM compared to HW at rest, which further increased in FM after acute WBV, whereas it remained unchanged in HW. In addition, there was an interaction (disease vs vibration) in plasma levels of adiponectin (P=0.0001), sTNFR1 (P=0.000001), sTNFR2 (P=0.0052), leptin (P=0.0007), resistin (P=0.0166), and BDNF (P=0.0179). In conclusion, a single acute session of mild and short WBV can improve the inflammatory status in patients with FM, reaching values close to those of matched HW at their basal status. The neuroendocrine mechanism seems to be an exercise-induced modulation towards greater adaptation to stress response in these patients. PMID- 29513793 TI - Tea polyphenols induce S phase arrest and apoptosis in gallbladder cancer cells. AB - Gallbladder cancer (GBC) is the most common malignancy in the biliary tract. Without effective treatment, its prognosis is notoriously poor. Tea polyphenols (TPs) have many pharmacological and health benefits, including antioxidant, anti inflammatory, anti-tumor, anti-thrombotic, antibacterial, and vasodilatory properties. However, the anti-cancer effect of TPs in human gallbladder cancer has not yet been determined. Cell viability and colony formation assay were used to investigate the cell growth. Cell cycle and apoptosis were evaluated by flow cytometry analysis. Western blot assay was used to detect the expression of proteins related to cell cycle and apoptosis. Human tumor xenografts were used to examine the effect of TPs on gallbladder cancer cells in vivo. TPs significantly inhibited cell growth of gallbladder cancer cell lines in a dose- and time dependent manner. Cell cycle progression in GBC cells was blocked at the S phase by TPs. TPs also induced mitochondrial-related apoptosis in GBC cells by upregulating Bax, cleaved caspase-3, and cleaved PARP expressions and downregulating Bcl-2, cyclin A, and Cdk2 expressions. The effects of TPs on GBC were further proven in vivo in a mouse xenograft model. Our study is the first to report that TPs inhibit GBC cell growth and these compounds may have potential as novel therapeutic agents for treating gallbladder cancer. PMID- 29513795 TI - Structural heart disease as the cause of syncope. AB - We described the clinical evolution of patients with structural heart disease presenting at the emergency room with syncope. Patients were stratified according to their syncope etiology and available scores for syncope prognostication. Cox proportional hazard models were used to investigate the relationship between etiology of the syncope and event-free survival. Of the 82,678 emergency visits during the study period, 160 (0.16%) patients were there due to syncope, having a previous diagnosis of structural heart disease. During the median follow-up of 33.8+/-13.8 months, mean age at the qualifying syncope event was 68.3 years and 40.6% of patients were male. Syncope was vasovagal in 32%, cardiogenic in 57%, orthostatic hypotension in 6%, and of unknown causes in 5% of patients. The primary composite endpoint death, readmission, and emergency visit in 30 days was 39.4% in vasovagal syncope and 60.6% cardiogenic syncope (P<0.001). Primary endpoint-free survival was lower for patients with cardiogenic syncope (HR=2.97, 95%CI=1.94-4.55; P<0.001). The scores were analyzed for diagnostic performance with area under the curve (AUC) and did not help differentiate patients with an increased risk of adverse events. The differential diagnosis of syncope causes in patients with structural heart disease is important, because vasovagal and postural hypotension have better survival and less probability of emergency room or hospital readmission. The available scores are not reliable tools for prognosis in this specific patient population. PMID- 29513794 TI - The hepatic ectonucleotide pyrophosphatase/phosphodiesterase 1 gene mRNA abundance is reduced by insulin and induced by dexamethasone. AB - Hormones regulate hepatic gene expressions to maintain metabolic homeostasis. Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been thought to interfere with insulin signaling. To determine its potential role in the regulation of metabolism, we analyzed its gene (Enpp1) expression in the liver of rats experiencing fasting and refeeding cycles, and in primary rat hepatocytes and human hepatoma HepG2 cells treated with insulin and dexamethasone using northern blot and real-time PCR techniques. Hepatic Enpp1 expression was induced by fasting and reduced by refeeding in the rat liver. In primary rat hepatocytes and HepG2 hepatoma cells, insulin reduced Enpp1 mRNA abundance, whereas dexamethasone induced it. Dexamethasone disrupted the insulin-reduced Enpp1 expression in primary hepatocytes. This is in contrast to the responses of the expression of the cytosolic form of phosphoenolpyruvate carboxykinase gene to the same hormones, where insulin reduced it significantly in the process. In addition, the dexamethasone-induced Enpp1 gene expression was attenuated in the presence of 8 Br-cAMP. In conclusion, we demonstrated for the first time that hepatic Enpp1 is regulated in the cycle of fasting and refeeding, a process that might be attributed to insulin-reduced Enpp1 expression. This insulin-reduced Enpp1 expression might play a role in the development of complications in diabetic patients. PMID- 29513796 TI - Morphological changes in rat rectus abdominis muscle induced by diabetes and pregnancy. AB - The urethral muscle of diabetic pregnant rats is affected by long-term mild diabetes and short-term severe diabetes, which plays a crucial role in the pathogenesis of pelvic floor disorders. We hypothesized that muscles outside the pelvis are subject to similar changes. The current study aimed at analyzing the effects of long-term mild and short-term severe diabetes on the structure and ultrastructure of fiber muscles and collagen in rats' rectus abdominis (RA) muscle. Therefore, the RA muscle of virgin, pregnant, long-term mild diabetic, short-term severe diabetic, long-term mild diabetic pregnant and short-term severe diabetic pregnant 3-month-old Wistar rats were collected. The structure was analyzed by picrosirius red staining, immunohistochemistry for fast and slow muscle fibers and transmission electron microscopy. We investigated two levels of STZ- induced diabetes: long-term mild diabetes (blood glucose level: 120-200 mg/dL) and short-term severe diabetes (blood glucose level >300 mg/dL). Long-term mild diabetic pregnant and short-term severe diabetic pregnant rats had decreased fast fibers and increased slow fibers, disrupted areas of sarcomere, intermyofibrillar mitochondria and myelin figures in the RA muscle. Both groups enabled us to analyze the specific influence of pregnancy, separately from diabetes. The current study demonstrated that diabetes and pregnancy induced intramuscular transformation and reorganization of RA muscle with a switch of fiber type adjusting their architecture according to intensity and duration of hyperglycemic insult within pregnancy. PMID- 29513797 TI - Treatment with ascorbic acid and alpha-tocopherol modulates oxidative-stress markers in the spinal cord of rats with neuropathic pain. AB - Vitamin E (vit. E) and vitamin C (vit. C) are antioxidants that inhibit nociception. The effect of these vitamins on oxidative-stress markers in the spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve is unknown. This study investigated the effect of intraperitoneal administration of vit. E (15 mg.kg-1.day-1) and vit. C (30 mg.kg-1.day-1), given alone or in combination, on spinal cord oxidative-stress markers in CCI rats. Adult male Wistar rats weighing 200-250 g were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received injections of vitamins or vehicle (saline containing 1% Tween 80) for 3 or 10 days (n=6/each group). The vitamins prevented the reduction in total thiol content and the increase in superoxide-anion generation that were found in vehicle-treated CCI rats. While nitric-oxide metabolites increased in vehicle treated CCI rats 3 days after surgery, these metabolites did not show significant changes in vitamin-treated CCI rats. In all rats, total antioxidant capacity and hydrogen-peroxide levels did not change significantly. Lipid hydroperoxides increased 25% only in vehicle-treated CCI rats. These changes may contribute to vit. C- and vit. E-induced antinociception, because scavenging reactive oxygen species seems to help normalize the spinal cord oxidative status altered by pain. PMID- 29513798 TI - Analgesic effects of Marasmius androsaceus mycelia ethanol extract and possible mechanisms in mice. AB - Marasmius androsaceus is a medicinal fungus mainly used to treat various forms of pain in China. This study investigated the analgesic effects of an ethanol extract of M. androsaceus (MAE) and its potential molecular mechanisms. Oral administration of MAE (50, 200, and 1000 mg/kg) had significant analgesic effects in an acid-induced writhing test, a formalin test, and a hot-plate test, with effectiveness similar to tramadol (the positive control drug). The autonomic activity test showed that MAE had no harmful effects on the central nervous system in mice. MAE resulted in significantly enhanced levels of noradrenalin and 5-hydroxytryptamine in serum but suppressed both of these neurotransmitters in the hypothalamus after 30 s of hot-plate stimulation. Co-administration with nimodipine (10 mg/kg; a Ca2+ channel blocker) strongly enhanced the analgesic effect in the hot-plate test compared to MAE alone. Moreover, MAE down-regulated the expression of calmodulin-dependent protein kinase II (CaMKII) in the hypothalamus after a 30-s thermal stimulus. These results suggested that the analgesic ability of MAE is related to the regulation of metabolism by monoamine neurotransmitters and Ca2+/CaMKII-mediated signaling, which can potentially aid the development of peripheral neuropathic pain treatments obtained from M. androsaceus. PMID- 29513799 TI - Ginsenoside Rg1 inhibits dietary-induced obesity and improves obesity-related glucose metabolic disorders. AB - Obesity and its consequent type 2 diabetes are significant threats to global health. Emerging evidence indicates that ginsenosides from ginseng (Panax ginseng) have anti-diabetic activity. We hypothesized that ginsenosides Rg1 could suppress dietary-induced obesity and improve obesity-related glucose metabolic disorders. Our results showed that ginsenoside Rg1 attenuated dietary-induced body weight gain and fat accumulation in white adipocyte tissue of mice fed a high-fat diet. Furthermore, we found that ginsenosides Rg1 not only decreased fasting glucose concentration and the 2-h postprandial glucose concentration, but also improved insulin resistance and glucose intolerance in those mice. Ginsenoside Rg1 also activated the AMPK pathway in vitro and in vivo and increased plasma membrane translocation of GLUT4 in C2C12 skeletal muscle cells. In conclusion, our observations suggested that ginsenoside Rg1 inhibited dietary induced obesity and improved obesity-related insulin resistance and glucose intolerance by activation of the AMPK pathway. PMID- 29513800 TI - DIAGNOSTIC VALUE OF C-REACTIVE PROTEIN AND THE INFLUENCE OF VISCERAL FAT IN PATIENTS WITH OBESITY AND ACUTE APPENDICITIS. AB - BACKGROUND: The C reactive protein (CRP) is one of the most accurate inflammatory markers in acute appendicitis (AA). Obesity leads to a pro-inflammatory state with increased CRP, which may interfere with the interpretation of this laboratory test in AA. AIM: To assess sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CRP in patients with AA and their correlation to body mass index (BMI) and body fat composition. METHOD: This is a retrospective study based on clinical records and imaging studies of 191 subjects with histopathologically confirmed AA compared to 249 controls who underwent abdominal computed tomography (CT). Clinical and epidemiological data, BMI, and CRP values were extracted from medical records. CT scans were assessed for AA findings and body composition measurements. RESULTS: CRP values increased according to patients' BMI, with varying sensitivity from 79.78% in subjects with normal or lean BMI, 87.87% in overweight, and 93.5% in individuals with obesity. A similar pattern was observed for NPV: an increase with increasing BMI, 69.3% in individuals with normal or lean BMI, 84.3% in overweight, and 91.3% in individuals with obesity. There was a positive correlation between CRP and visceral fat area in patients with AA. CONCLUSIONS: Variations exist for sensitivity, specificity, PPV, and NPV values of CRP in patients with AA, stratified by BMI. An increase in visceral fat area is associated with elevated CRP across the BMI spectrum. PMID- 29513801 TI - ADDUCTOR POLLICIS MUSCLE THICKNESS AND PREDICTION OF POSTOPERATIVE MORTALITY IN PATIENTS WITH STOMACH CANCER. AB - BACKGROUND: Malnutrition is very prevalent in patients with gastric cancer and increases the risk of morbidity and mortality. Adductor pollicis muscle thickness (APMT) appears as an important objective, quick, inexpensive and noninvasive measure to assess the muscle compartment. AIM: To compare APMT and other nutritional assessment methods and to correlate these methods with postoperative mortality. METHODS: Forty-four patients, 29 men and 15 women, mean age of 63+/ 10.2 and ranging from 34-83 years, who underwent nine (20.5%) partial and 34 (77.3%) total gastrectomies due to stomach cancer (stage II to IIIa) were preoperatively assessed by Patient Generated Subjective Global Assessment (PG SGA), anthropometry and laboratorial profile. RESULTS: APMT better predicted death (p<0.001) on both, dominant and non-dominant hand, and well correlated with albumin (p=0.039) and PG-SGA (p=0.007). CONCLUSION: APMT clearly allowed to determine malnutrition and to predict risk of death in patients with gastric cancer. PMID- 29513802 TI - RADIOLOGICAL STUDY OF MEGACOLON IN TRYPANOSOMA CRUZI INFECTED RATS. AB - BACKGROUND: Researches on Chagas disease still use several animals and rats, due to size and susceptibility were preferred by many authors. AIM: To develop an experimental model of megacolon in rats inoculated with the strain Y of Trypanosoma cruzi. METHODS: Thirty male Wistar rats were distributed in three groups inoculated with different inoculants: Group A: 600000, Group B: 1000000 and Group C: 1500000 blood trypomastigotes of T. cruzi. Animals were sedated intramuscularly at zero inoculation time (T0) and 60 days after inoculation (T60), to perform the barium enema in order to evaluate the dilatation of the different segments of colon in a comparative study of the measurements obtained, using a digital caliper. Evidence of infection was performed by blood smear collected from the animal's tail 18 days after inoculation with observation of blood forms. RESULTS: Comparing the intestinal diameter of the inoculated animals with 60,0000 trypomastigotes in the T0 of infection with T60 days after the inoculation, significant dilatation was observed between the proximal, medial and distal segments (p<0.01), indicating the establishment of the megacolon model. In addition, comparing intestinal diameter between the different segments, with in the T0 of infection and the T60 after inoculation, significant alterations were observed (p<0.05). CONCLUSION: The proposed model was possible for in vivo studies of alterations due to infection by T. cruzi and functional alterations of the colon. In addition, the changes manifested in the colon are not directly proportional to the size of the inoculum, but to the time of infection that the animals were submitted, since the animals inoculated with 60,0000 blood forms were the ones which presented the most significant alterations. PMID- 29513803 TI - COMPARATIVE ANALYSIS OF SURGICAL HEMOSTATIC SPONGES IN LIVER INJURY: STUDY IN RATS. AB - BACKGROUND: Obtaining effective hemostasis either in the traumatic or surgical lesions of parenchymal viscera, especially the liver, has always been a challenge. AIM: Comparative study between the use of different hemostatic sponges in hepatic wound and their capacity of integration to cells in a short period. METHODS: Fifteen Wistar rats were divided into three groups. Through laparotomy a standardized wound in hepatic right lobe was made. The animals were treated with three sponges, being gelatin in group I, equine collagen in group II, and oxidized cellulose in group III. The hemostatic capacity was analysed. On the 7o day after surgery samples for histology analysis (H&E and picrosirius) were collected for inflammatory evaluation and collagen quantification (types I and III) with polarized microscopy. RESULTS: All materials used had similar haemostatic effects, with no significant difference in hemostasis time. In the assessment of tissue repair and adhesions provoked, as well as analysis of the inflammatory process, the gelatin sponge presented greater inflammation and adhesions to the contiguous structures to the procedure in relation to the other groups. CONCLUSION: Animals which had their wounds treated with collagen and regenerated cellulose sponges presented better results in relationship to the ones treated with gelatin sponge. PMID- 29513804 TI - DIABETES REMISSION RATE IN DIFFERENT BMI GRADES FOLLOWING ROUX-EN-Y GASTRIC BYPASS. AB - BACKGROUND: Type 2 diabetes mellitus has a high long-term remission rate after laparoscopic Roux-en-Y gastric bypass (LRYGB), but few studies have analyzed patients with BMI<35 kg/m2. AIM: To compare glycemic control after LRYGB between BMI 30-35 kg/m2 (intervention group or IG) and >35 kg/m2 patients (control group or CG) and to evaluate weight loss, comorbidities and surgical morbidity. METHODS: Sixty-six diabetic patients (30 in IG group and 36 in CG group) were submitted to LRYGB. Data collected annually after surgery were analyzed with generalized estimating equations. RESULTS: Average follow-up was 4.3 years. There was no statistical difference between groups using complete remission American Diabetes Association criteria (OR 2.214, 95%CI 0.800-5.637, p=0.13). There was significant difference between groups using partial remission American Diabetes Association criteria (p=0.002), favouring the CG group (OR 6.392, 95%CI 1.922 21.260). The higher BMI group also had lower HbA1c levels (-0.77%, 95%CI -1.26 to -0.29, p=0.002). There were no significant differences in remission of hypertension, dyslipidemia and surgical morbidity, while weight was better controlled in the IG group. CONCLUSION: No differences were found in diabetes complete remission, although greater partial remission and the lower levels of glycated hemoglobin in the BMI >35 kg/m2 group suggest a better response among more obese diabetic patients with LRYGB. In addition, both groups had important metabolic modifications at the expense of low morbidity. PMID- 29513805 TI - PREVALENCE OF JOINT PAIN AND OSTEOARTHRITIS IN OBESE BRAZILIAN POPULATION. AB - BACKGROUND: High body mass index, as well as maintaining this condition for a long period of time, are important risk factors for the development of osteoarthritis. AIM: To determine joint pain and osteoarthritis prevalence in patients referred to bariatric surgery. METHODS: Morbidly obese patients referred to bariatric surgery responded to the visual analogue pain scale (VAS) and the WOMAC questionnaire. X-rays of the hips and knees were evaluated. The primary endpoints were self-reported joint pain and the diagnosis of osteoarthritis by clinical and radiological criteria of the American College of Rheumatology. RESULTS: 141 patients were interviewed (85.1% women) with a mean age of 40 years. The mean body mass index was 46. The lumbar spine and knee joint were the most commonly reported as painful (77.9% and 73.2% respectively). Prevalence of knee osteoarthritis was 63.1% and hip osteoarthritis was 40.8%. Age, mean VAS and WOMAC scores were higher in the osteoarthritic individuals. CONCLUSION: There is prevalence of 90.1% of pain symptoms in morbidly obese patients referred to bariatric surgery. The prevalence of knee osteoarthritis was 63.1% and hip osteoarthritis was 40.8% in this sample. PMID- 29513806 TI - DRAIN AMYLASE ON THE FIRST POSTOPERATIVE DAY OF WHIPPLE SURGERY: WHAT VALUE IS THE BEST PREDICTOR FOR EARLY DRAIN REMOVAL? AB - BACKGROUND: The value of drain amylase on the first postoperative day after pancreatic resections has been described as an efficient predictor of pancreatic fistula. In spite of this, the cut-off point below which the drains can be removed early remains controversial. AIM: Validate the use of the amylase on the 1st postoperative day in the correlation with pancreatic fistula and define the value at which early drain removal is safe. METHOD: Were included patients undergoing Whipple surgery in the period of 2007 to 2016. Group 1 enrolled the ones who did not develop fistula and those who developed biochemical fistula for less than seven days postoperatively and group 2 included patients who developed persistent biochemical fistula between seven and 21 days and those with grade B and C fistula. RESULTS: Sixty-one patients were included, 41 comprised group 1 and 20 group 2. The incidence of abdominal collections, need for reoperation and time of hospitalization were for group 1 and 2, respectively: 17.1%, 17.1% and 9.5 days, and 65%, 40% and 21.1 days. The median of the amylase from the drain at 1st postoperative day was in group 1 and 2, respectively: 175 U/l and 3172.5 U/l (p=0.001). Using a cut-off of 180 to predict the group to which the patient would belong there was obtained sensitivity, specificity, positive predictive value and negative predictive value of 100%, 48.8%, 50% and 100% respectively. CONCLUSION: It was validated the cut-off value of 180 U/l as appropriate to early drain removal. PMID- 29513808 TI - Comparative study of polyglactin 910 and simple catgut in the formation of intraperitoneal adhesions. AB - PURPOSE: To compare polyglactin 910 and simple catgut sutures for the incidence of intraperitoneal adhesions. METHODS: Twenty female Wistar rats were placed into two groups. Group 1 received ischemic sutures and Group 2 received polyglactin 910. Five sutures inductive of adhesions in each rat were made. After 14 days, the rats were euthanized with an assessment of the presence of adhesions, the number of sutures involved and classification according to the Granat et al. scale described by Ozel et al17. RESULTS: In total, 19 of the 20 rats presented adhesions, with nine from Group 1 and ten from Group 2. There was a smaller number of affected sutures in Group 1, while in Group 2 the majority of the sutures formed adhesions (p=0.0197). According to the Granat et al. scale, Group 1 predominately developed fine, filamentous adhesions or thickening in a restricted area. Group 2 mainly presented extensive, thick adhesions with the involvement of the viscera (p=0.0055). CONCLUSION: Polyglactin 910 sutures formed more adhesions that were more extensive and thicker than the simple catgut sutures. PMID- 29513807 TI - PERCUTANEOUS RADIOFREQUENCY ASSISTED LIVER PARTITION WITH PORTAL VEIN EMBOLIZATION FOR STAGED HEPATECTOMY (PRALPPS). AB - BACKGROUND: When a major hepatic resection is necessary, sometimes the future liver remnant is not enough to maintain sufficient liver function and patients are more likely to develop liver failure after surgery. AIM: To test the hypothesis that performing a percutaneous radiofrecuency liver partition plus percutaneous portal vein embolization (PRALPPS) for stage hepatectomy in pigs is feasible. METHODS: Four pigs (Sus scrofa domesticus) both sexes with weights between 25 to 35 kg underwent percutaneous portal vein embolization with coils of the left portal vein. By contrasted CT, the difference between the liver parenchyma corresponding to the embolized zone and the normal one was identified. Immediately, using the fusion of images between ultrasound and CT as a guide, radiofrequency needles were placed percutaneouslyand then ablated until the liver partition was complete. Finally, hepatectomy was completed with a laparoscopic approach. RESULTS: All animals have survived the procedures, with no reported complications. The successful portal embolization process was confirmed both by portography and CT. In the macroscopic analysis of the pieces, the depth of the ablation was analyzed. The hepatic hilum was respected. On the other hand, the correct position of the embolization material on the left portal vein could be also observed. CONCLUSION: "Percutaneous radiofrequency assisted liver partition with portal vein embolization" (PRALLPS) is a feasible procedure. PMID- 29513809 TI - Effects of thymoquinone and curcumin on the regeneration of rat livers subject to 70% hepatectomy. AB - PURPOSE: To investigate thymoquinone, curcumin and a combination of these two drugs were effective or not at the growth of liver. METHODS: Forty female Wistar Albino rats distributed into five groups of eight rats each, control, thymoquinone, curcumin, and thymoquinone/curcumin groups. Pathological specimens were studied using the Ki-67 Proliferation Index(PI); and arginase(Arg), tissue plasminogen activator(tPA), ceruloplasmin(Cer) and nitric oxide(NO) were studied in biochemical analysis. RESULTS: Our results showed that Ki-67 proliferation index was low in Groups 1. The proliferation coefficient was significantly higher in the Group 2 and Group 4 than in the Group 1 and Group 3.(P < 0.001 between Groups 1 and 2, 1 and 4, and 3 and 4). There was no difference between Groups 2 and 4 (P = 1). The results of the biochemical Arg, tPA and Cer test showed statistically between the Group 1 and Group 2. NO showed significant differences Group 1 and 3. CONCLUSIONS: Thymoquinone and curcumin both have known positive effects on the organism. Histological and biochemical tests showed that thymoquinone is more effective than curcumin. PMID- 29513810 TI - Efficacy of phosphocreatine pre-administration on XIAP and Smac in ischemic penumbra of rats with focal cerebral ischemia reperfusion injury. AB - PURPOSE: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). METHODS: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B , and group C . After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. RESULTS: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. CONCLUSIONS: Phosphocreatine pre administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra. PMID- 29513811 TI - Investigation of the antioxidant effects of pheniramine maleate and nebivolol on testicular damage in rats with experimentally induced testis torsion. AB - PURPOSE: To investigate the biochemical, histopathologic, and spermatogenetic changes in the detorsionated testicle after experimental torsion and to study the antioxidant effects of pheniramine maleate and nebivolol. METHODS: Twenty-four Sprague-Dawley male rats were divided into 4 groups: Group 1: Sham; Group 2: Torsion/Detorsion (T/D); Group 3: T/D + Pheniramine maleate (PM); Group 4: T/D + Nebivolol (NB) group. Paroxanase (PON), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stres index (OSI) were measured, and spermatogenetic and histopathologic evaluation was performed in tissue and blood samples. RESULTS: The evaluation of tissue TAS indicated no statistically significant difference in Group 3 compared to Group 2. A statistically significant increase was detected in Group 4 compared to Group 2. Serum PON levels revealed a statistically significant increase in Groups 3 and 4 compared to Groups 1 and 2. The Johnsen testicular biopsy score decreased in Groups 3 and 4, but the decrease was not statistically significant. CONCLUSIONS: Pheniramine maleate and nebivolol have antioxidant effects against ischemia-reperfusion damage. They also support tissue recovery, which is more significantly observed by nebivolol. PMID- 29513812 TI - The effect of pycnogenol on lymphatic nodes and adhesion during in a peritoneal adhesion model in rats. AB - PURPOSE: To investigate the effects of pycnogenol on peritoneal adhesions and additionally to investigate the immunohistochemical effects of free oxygen radicals and reactive lymph nodes detected in the adhesive tissue that was sampled surrounding the cecum on intra-abdominal adhesions. METHODS: Twenty-seven Wistar Albino rats were divided into three groups. In group 1 (sham), laparotomy was performed and stitched up. In group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered 2 cc of saline. In group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Pycnogenol derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum, and the rats were sacrificed. RESULTS: In group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. CONCLUSIONS: No positive outcomes indicating that pycnogenol reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Moreover, a significant increase in lymph node size was detected secondary to inflammation. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, pycnogenol increased the production of free oxygen radicals in the tissue. PMID- 29513813 TI - Effects of the application of the amniotic membrane in the healing process of skin wounds in rats. AB - PURPOSE: To evaluate the efficacy of the application of the human amniotic membrane (HAM) on the inflammatory process, fibroblast proliferation, formation of collagenand reduction of skin wound areas in rats. METHODS: Thirty six rats were submitted to a surgical injury induction and divided into two groups (n = 18): group C (control) and T (treated with the HAM). The macroscopic evolution in the wound area and the histological characteristics of the skin samples were evaluated. RESULTS: The regression of the wound area was greater in group T. The histological analysis revealed a significant reduction (p < 0.05) in the inflammatory infiltrate in group T at all experimental periods compared with that in the control group. Furthermore, the group T presented a significant increase in the proliferation of fibroblasts at 14 and 21 days compared with group C (p < 0.05). Regarding the deposition of mature collagen fibers, there was an increase in the replacement of type III collagen by type I collagen in group T (p < 0.05). CONCLUSION: Treatment with the HAM reduced the healing time as well as the inflammatory responses, increased the proliferation of fibroblasts, and induced a higher concentration of mature collagen fibers. PMID- 29513814 TI - Transforming growth factor beta1 (TGF-beta1) levels in a rat model of induced pleural empyema. AB - PURPOSE: To evaluate the concentration of transforming growth factor beta 1 (TGFB1) levels in a rat pleural effusion obtained by inoculation of intrapleural bacteria or turpentine through thoracentesis. METHODS: Thirty-Nine Wistar rats were divided into three groups: Staphylococcus aureus (SA, n = 17); Streptococcus pneumoniae (SP, n = 12); and turpentine (control, n = 10). Pleural fluid was collected through ultrasound-guided thoracentesis 12 h, 24 h, and 36 h after instillation of bacteria or turpentine. Levels of TGFB1 were measured in pleural fluid. RESULTS: At 12 h, mean TGFB1concentrations were 5.3450 pg/mL in the SA group, 5.3449 pg/mL in the SP group, and 5.3450 pg/mL in controls. At 24 h, they were 4.6700 pg/mL in the SA group, 4.6700 pg/mL in the SP group, and 4.6700 pg/mL in controls. At 36 h, they were 4.6699 pg/mL in the SA group and in control. No difference was observed among the groups in mean TGFB1concentration (p = 0.12); however, a significant intragroup reduction in mean TGFB1 was observed between 12 and 24 h (p < 0.01). CONCLUSION: The transforming growth factor beta 1 concentrations were not useful as a diagnostic tool or an early marker of infected pleural effusion. PMID- 29513815 TI - Effect of a new cross-linked hyaluronan gel on the staple line after sleeve gastrectomy in a rat model. AB - PURPOSE: To evaluate the effect of a new cross-linked hyaluronan (NCHA) gel on healing of the staple line in an experimental sleeve gastrectomy. METHODS: Eighteen rats were randomly divided into three groups. The control group (n = 6) received no medication. In the saline group (n = 6) and NCHA gel group (n = 6), saline and NCHA gel were respectively administered onto the staple line and intraperitoneally into the abdominal cavity after the standard stapling procedure. RESULTS: The fibroblast activity and collagen deposition were significantly higher in the NCHA gel group than in the control group (p = 0.00, p = 0.017) and saline group (p = 0.004, p = 0.015). The tissue hydroxyproline protein level was significantly higher in the NCHA gel group than in the control group (p = 0.041). Adhesion formation was significantly lower in the NCHA gel group than in the control and saline groups (p = 0.015, p = 0.041). CONCLUSIONS: New cross-linked hyaluronan gel could be an effective approach to improve staple line wound healing and prevent potential leakage after sleeve gastrectomy. Moreover, NCHA gel helps to prevent adhesion formation without compromising healing of the staple line. PMID- 29513816 TI - Effects of aquaporin 4 and inward rectifier potassium channel 4.1 on medullospinal edema after methylprednisolone treatment to suppress acute spinal cord injury in rats. AB - PURPOSE: To investigate the effects of aquaporin 4 (AQP4) and inward rectifier potassium channel 4.1 (Kir4.1) on medullospinal edema after treatment with methylprednisolone (MP) to suppress acute spinal cord injury (ASCI) in rats. METHODS: Sprague Dawley rats were randomly divided into control, sham, ASCI, and MP-treated ASCI groups. After the induction of ASCI, we injected 30 mg/kg MP via the tail vein at various time points. The Tarlov scoring method was applied to evaluate neurological symptoms, and the wet-dry weights method was applied to measure the water content of the spinal cord. RESULTS: The motor function score of the ASCI group was significantly lower than that of the sham group, and the spinal water content was significantly increased. In addition, the levels of AQP4 and Kir4.1 were significantly increased, as was their degree of coexpression. Compared with that in the ASCI group, the motor function score and the water content were significantly increased in the MP group; in addition, the expression and coexpression of AQP4 and Kir4.1 were significantly reduced. CONCLUSION: Methylprednisolone inhibited medullospinal edema in rats with acute spinal cord injury, possibly by reducing the coexpression of aquaporin 4 and Kir4.1 in medullospinal tissues. PMID- 29513817 TI - Effect of powdered shells treatment of the snail Megalobulimus lopesi on wounds of diabetic rats. AB - PURPOSE: To analyzed the healing effect of the powdered shell of the Megalobulimus lopesi snail on wounds of diabetic rats, since in non-diabetic rats the powdered shell presented healing potential. METHODS: Seventy-two Wistar rats (Rattus norvegicus albinus) were divided into three groups: Control group (GC.diab), no therapeutic intervention on the wound; Vehicle's Control group, topical via, in diabetic rats (GCvt.diab): Powder Shell Group (PC) applied topically (GPCvt.diab): Experimental group was administered topically shortly after wound dressing and once a day during the experimental period (3, 7, 14 and 21 days) the composition containing the powdered shell of the snail. The following variables related to the healing potential were analyzed: macroscopic one, where the capacity of reduction of the wound area was evaluated; histological analysis in HE, angiogenic activity, morphometric analysis (re epithelization), leukocyte inflammatory infiltrate; leukocyte count and also differentiation in peripheral blood. RESULTS: The topical application in wounds of diabetic rats presented healing activity, accelerating wound closure, stimulating angiogenesis and being pro-inflammatory in the early and anti inflammatory stages in the final times of the healing process. CONCLUSION: The topical administration of the powdered shell on wounds of diabetic patients becomes a therapeutic option of low cost, with ease in the administration and access as well. PMID- 29513818 TI - Erratum. AB - [This corrects the article doi: 10.1590/s0102-865020170120000006]. PMID- 29513819 TI - Lower galactosylation levels of the Lipophosphoglycan from Leishmania (Leishmania) major-like strains affect interaction with Phlebotomus papatasi and Lutzomyia longipalpis. AB - BACKGROUND Leishmania major is an Old World species causing cutaneous leishmaniasis and is transmitted by Phlebotomus papatasi and Phlebotomus duboscqi. In Brazil, two isolates from patients who never left the country were characterised as L. major-like (BH49 and BH121). Using molecular techniques, these isolates were indistinguishable from the L. major reference strain (FV1). OBJECTIVES We evaluated the lipophosphoglycans (LPGs) of the strains and their behaviour in Old and New World sand fly vectors. METHODS LPGs were purified, and repeat units were qualitatively evaluated by immunoblotting. Experimental in vivo infection with L. major-like strains was performed in Lutzomyia longipalpis (New World, permissive vector) and Ph. papatasi (Old World, restrictive or specific vector). FINDINGS The LPGs of both strains were devoid of arabinosylated side chains, whereas the LPG of strain BH49 was more galactosylated than that of strain BH121. All strains with different levels of galactosylation in their LPGs were able to infect both vectors, exhibiting colonisation of the stomodeal valve and metacyclogenesis. The BH121 strain (less galactosylated) exhibited lower infection intensity compared to BH49 and FV1 in both vectors. MAIN CONCLUSIONS Intraspecific variation in the LPG of L. major-like strains occur, and the different galactosylation levels affected interactions with the invertebrate host. PMID- 29513820 TI - Improved reverse transcription-polymerase chain reaction assay for the detection of flaviviruses with semi-nested primers for discrimination between dengue virus serotypes and Zika virus. AB - BACKGROUND The genus Flavivirus includes a variety of medically important viruses, including dengue virus (DENV) and Zika virus (ZIKV), which are most prevalent in Brazil. Because the clinical profile of patients affected by different DENV serotypes or ZIKV may be similar, the development of new methods that facilitate a rapid and accurate diagnosis is crucial. OBJECTIVES The current study aimed to develop an improved reverse transcription-polymerase chain reaction (RT-PCR) protocol for universal detection of flaviviruses by using semi nested primers that discriminate between DENV serotypes and ZIKV. METHODS The bioinformatics workflow adopted for primer design included: (1) alignment of 1,442 flavivirus genome sequences, (2) characterisation of 27 conserved regions, (3) generation of a primer set comprising 77 universal primers, and (4) selection of primer pairs with greatest coverage and specificity. Following primer design, the reaction was validated in vitro. The same approach was applied to the design of primers specific for DENV and ZIKV, using a species-specific sequence database. FINDINGS The new assay amplified an 800-806 nt variable region of the NS5 gene and allowed discrimination of virtually all flavivirus species using reference-sequence comparison. The 800-806 nt fragment was validated as a template for a semi-nested multiplex PCR using five additional primers for the detection of DENV and ZIKV. These primers were designed to generate amplicons of different sizes, allowing differentiation of the four serotypes of DENV, and ZIKV using agarose gel electrophoresis. MAIN CONCLUSIONS The bioinformatics pipeline allowed efficient primer design, making it possible to identify the best targets within the coding region of the NS5 protein. The multiplex system proved effective in differentiation of DENV1-4 and ZIKV on a 2% agarose gel. The possibility of discriminating DENV serotypes and ZIKV in the same reaction provided a faster result consuming less sample. In addition, this simplified approach ensured the reduction of the cost per analysis. PMID- 29513821 TI - Utility of immunoglobulin isotypes against LID-1 and NDO-LID for, particularly IgG1, confirming the diagnosis of multibacillary leprosy. AB - BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers. OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO. METHODS Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis. FINDINGS Our data confirm that serum IgM antibodies against NDO-HSA and IgG antibodies against LID-1, as well as IgG/M antibodies against NDO-LID, are markedly increased in MB patients. For the first time, our data reveal a selective increase in IgG1 and IgG3 antibodies against LID-1 and NDO-LID in MB patients, demonstrating that these antibody isotypes are suitable for differentiation between MB and PB patients. ROC curve analysis indicates an improved capacity for diagnosing MB leprosy patients using the detection of IgG antibodies, particularly the IgG1 isotype, specific to LID-1 and NDO-LID over the performance levels attained with NDO-HSA. CONCLUSIONS Our findings indicate that serological tests based on the detection of antigen-specific IgG1 antibodies are a useful tool to differentiate MB from PB patients, and indicate the enhanced performance of the LID-1 and NDO-LID antigens in the serodiagnosis of leprosy. PMID- 29513822 TI - Dimensions of the World Bank's history as a political, intellectual, and financial actor. PMID- 29513823 TI - Prevalence, associated factors, and limitations related to chronic back problems in adults and elderly in Brazil. AB - The objective was to analyze the epidemiological characteristics of chronic back problems in Brazil and study the association between their prevalence and demographic and socioeconomic factors, lifestyle, and health conditions. The study used micro-data from the Brazilian National Health Survey (PNS), 2013. The epidemiological indicators were: prevalence, time with chronic back problems, life cycle (from young adults to the elderly), limitations in activities of daily living, and mean age at onset of symptoms, according to sex and age bracket. In order to analyze inequality in chronic back problems according to socioeconomic characteristics and risk factors, a multivariate logistic regression model was used, based on life cycle stages, with the presence of chronic back problems as the dependent variable and the following independent variables: sex, schooling, area of residence, race/color, self-rated health, types of chronic diseases, body mass index (BMI), and physical activity. Prevalence of chronic back problems in Brazil was 18.5%, and was higher in women than in men (21.1%; 95%CI: 20.2-21.9). Mean age at onset of chronic back problems was 35 years. There was an association between chronic back problems and lower schooling, poor self-rated health, and presence of the majority of the selected chronic diseases. Area of residence, BMI, age, and race/color were weakly associated or not associated with chronic back problems. Prevalence of chronic back problems stabilized at 50 years of age, but the severity of limitations increased at older ages. As in other countries, high prevalence and the impact on living conditions revealed the need for epidemiological studies on chronic back problems in Brazil. The results suggest that health promotion and the prevention of chronic back problems should be intensified, especially before 50 years of age, considering the on-going population aging in Brazil. PMID- 29513824 TI - Lead and mercury levels in an environmentally exposed population in the Central Brazil. AB - The objective was to assess the level of exposure to lead and mercury in a population in the Pantanal region in Mato Grosso State, Brazil. Blood lead (PbB) (n = 119) and urinary mercury (HgU) (n = 109) in local residents were measured by atomic absorption spectrometry. Comparison of means and correlations between variables used analysis of variance (ANOVA) and linear regression, respectively, with 95% confidence intervals. Mean PbB was 2.82 +/- 1.53ug dL-1. The comparison of PbB stratified by collection site (p <= 0.01), work activity (p <= 0.01), and consumption of locally produced cow's milk (p <= 0.05) showed statistically significant differences. There were also positive associations between PbB and collection site (p <= 0.01), participants' profession (p <= 0.05), local milk (p <= 0.01), and source of drinking water (p <= 0.01). Mean HgU was 1.41 +/- 0.98ug L-1. The levels only showed significant differences for participants' profession (p <= 0.01), and positive associations emerged between HgU and work activity (p <= 0.01) and body mass index (p <= 0.01). The samples showed low lead and mercury levels, similar to those found in other environmentally exposed populations. Despite these low concentrations, current knowledge on the toxicity of these metals shows that health effects can already be felt at levels that were previously considered safe, thus characterizing a health hazard. PMID- 29513825 TI - Association between perceived racial discrimination and hypertension: findings from the ELSA-Brasil study. AB - "Pardos" and blacks in Brazil and blacks in the USA are at greater risk of developing arterial hypertension than whites, and the causes of this inequality are still little understood. Psychosocial and contextual factors, including racial discrimination, are indicated as conditions associated with this inequality. The aim of this study was to identify the association between perceived racial discrimination and hypertension. The study evaluated 14,012 workers from the ELSA-Brazil baseline population. Perceived discrimination was measured by the Lifetime Major Events Scale, adapted to Portuguese. Classification by race/color followed the categories proposed by Brazilian Institute of Geography and Statistics (IBGE). Hypertension was defined by standard criteria. The association between the compound variable - race/racial discrimination - and hypertension was estimated by Poisson regression with robust variance and stratified by the categories of body mass index (BMI) and sex. Choosing white women as the reference group, in the BMI < 25kg/m2 stratum, "pardo" women showed adjusted OR for arterial hypertension of 1.98 (95%CI: 1.17 3.36) and 1.3 (95%CI: 1.13-1.65), respectively, whether or not they experienced racial discrimination. For black women, ORs were 1.9 (95%CI: 1.42-2.62) and 1.72 (95%CI: 1.36-2.18), respectively, for the same categories. Among women with BMI > 25kg/m2 and men in any BMI category, no effect of racial discrimination was identified. Despite the differences in point estimates of prevalence of hypertension between "pardo" women who reported and those who did not report discrimination, our results are insufficient to assert that an association exists between racial discrimination and hypertension. PMID- 29513826 TI - [Food and nutritional security: situation analysis of decentralization in the national public policy]. AB - The aim of this study was to analyze the situation with the decentralization of the Brazilian National System of Food and Nutritional Security (SISAN), created in 2006 under the Brazilian National Food and Nutritional Security Act (LOSAN). Based on the criteria for joining SISAN, as set out in Decree 7,272 of August 25, 2010, the authors analyzed data from the basic information surveys of the Brazilian Institute of Geography and Statistics, 2014 (Estadic e Munic/2014). The results show that decentralization of SISAN is still incipient at the municipal level, although all the states of Brazil have already joined the system. The social assistance sector has played an outstanding role in coordinating SISAN at the state and municipal levels, while in the latter the health sector has also played a relevant role. The analysis of food and nutritional security activities conducted to date, based on the sources of federal, state, and municipal funds, further shows that the federal sphere has still not played a strong inductive role capable of leading the expansion of SISAN. More effective funding mechanisms and the assignment of responsibilities to the states and municipalities are relevant factors for consolidating the system's state-level base and expanding the municipal base in the search for an identity and capillarity for SISAN. PMID- 29513827 TI - Factors that influence human resources for health policy formulation: a multiple case study in Brazil and Portugal. AB - This study aims to analyze whether the process by which policies for human resources for health that aim to improve the geographic distribution of physicians have been informed by scientific evidence in Brazil and Portugal. This was a multiple case study on a decision-making process for human resources for health in Brazil and Portugal. The respective case studies were based on Brazil's More Doctors Program (Programa Mais Medicos - PMM) and Portugal's strategy of hiring foreign physicians through bilateral agreements, to work in the country's National Health Service (SNS). We interviewed 27 key actors in the policy-making process on the following topics: factors that influenced the policy decisions, actors that were expected to win or lose from the policy, and the scientific evidence and available data used in the policy-making, among others. The most evident factors appearing in the interviews as having influenced the PMM were: institutions; external factors (Presidential elections); group interests (e.g. physicians' professional associations), governments (Brazil and Cuba), international organizations, and civil society; and ideas (scientific evidence). The most frequently cited factors in Portugal were: institutions and interests of government (from Portugal and the countries involved in the bilateral agreements), civil society, and groups (physicians' professional associations). Contrary to the case study in Brazil, where the evidence was reported to having played an important role in the policy decisions, in Portugal, scientific evidence was not identified as contributing to the specific policy process. PMID- 29513828 TI - Tuberculosis: renewed challenge in Brazil. PMID- 29513829 TI - Para-kala-azar dermal leishmaniasis in a patient in Brazil: a case report. AB - Visceral leishmaniasis is common in Brazil and is caused by Leishmania (Leishmania) infantum/chagasi. Post-kala-azar dermal leishmaniasis frequently follows visceral leishmaniasis caused by L. donovani, and para-kala-azar dermal leishmaniasis refers to an uncommon presentation wherein it occurs simultaneously along with visceral leishmaniasis. While post-kala-azar dermal leishmaniasis only occurs occasionally in L. infantum/chagasi infections, it frequently occurs in patients with concomitant immunosuppression (HIV co-infection). Here, we describe the first case of para-kala-azar dermal leishmaniasis in Brazil. It is important to raise awareness of post- and para-kala-azar dermal leishmaniasis in L. infantum endemic areas as these patients may contribute to visceral leishmaniasis transmission. PMID- 29513830 TI - American cutaneous leishmaniasis triggered by electrocoagulation. AB - Cutaneous leishmaniasis is usually transmitted by infected phlebotomine sand fly bites that initiate local cutaneous lesions. Few reports in the literature describe other modes of transmission. We report a case of a previously healthy 59 year-old woman who underwent electrocoagulation to remove seborrheic keratosis confirmed by dermatoscopy. Three months later, a skin fragment tested positive for Leishmania culture; the parasite was identified as L. (V.) braziliensis. Trauma may generate inflammatory cascades that favor Leishmania growth and lesion formation in previously infected patients. American cutaneous leishmaniasis is a dynamic disease with unclear pathophysiology because of continually changing environments, demographics, and human behaviors. PMID- 29513831 TI - Fatal septic shock caused by Paracoccidioides brasiliensis phylogenetic species S1 in a young immunocompetent patient: a case report. AB - The authors report the first case of fatal septic shock, a rare clinical presentation of paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis S1. We also provide an immunological evaluation of the patient. Severe clinical signs such as organ dysfunction and digital gangrene occurred in this case. The patient presented a remarkable cell activation profile and diminished percentage of peripheral blood T regulatory cells. A decrease in anti inflammatory IL-1RA plasma level showed the potential for endothelium damage, probably contributing to a vasculitis process. Together with P. lutzii, P. brasiliensis appears to be involved in severe cases of PCM. PMID- 29513833 TI - Phoneutrism inside a protected area in the State of Sao Paulo. PMID- 29513832 TI - Anaphylactic reaction/angioedema associated with jellyfish sting. AB - The most frequent jellyfish in Southern Brazil causes mainly local pain and skin plaques. A 3-year-old female bather presented an erythematous, irregular plaque on the left forearm after contact with a jellyfish and intense facial angioedema with facial flushing. The lungs had vesicular murmur, wheezes, and snorts, and pink and spumous secretion in the airways with intercostal retraction. She was administered subcutaneous adrenaline (0.1mg/kg) and hydrocortisone intravenous (10mg/kg) with total recovery in a few minutes. The manifestations of anaphylactic reactions are distinct from those of envenomations, and prompt and adequate care is fundamental in these situations. PMID- 29513834 TI - Seabather's eruption in Ipanema Beach, Rio de Janeiro, Brazil. PMID- 29513835 TI - Mucosal leishmaniasis: urgent need for more research. PMID- 29513836 TI - Effectiveness of first-wave protease inhibitors in hepatitis C virus genotype 1 infection: a multicenter study in Brazil. AB - INTRODUCTION: In 2013, combination therapy using peginterferon, ribavirin, and boceprevir or telaprevir was introduced to treat hepatitis C virus genotype 1 infection in Brazil. The effectiveness of this therapy in four Brazilian regions was evaluated. METHODS: Clinical and virological data were obtained from patients of public health institutions in five cities, including sustained virological response (SVR) and side effects. Patients with advanced fibrosis (F3/4), moderate fibrosis (F2) for > 3 years, or extra-hepatic manifestations were treated according to Ministry of Health protocol. Treatment effectiveness was verified by using bivariate and multivariate analysis; p-values of < 0.05 were considered significant. RESULTS: Of 275 patients (64.7% men; average age, 57 years old), most (61.8%) were treatment-experienced; 53.9% had subgenotype 1a infection, 85.1% had advanced fibrosis, and 85.5% were treated with telaprevir. SVR was observed in 54.2%. Rapid virological response (RVR) was observed in 54.6% of patients (data available for 251 patients). Overall, 87.5% reported side effects and 42.5% did not complete treatment. Skin rash, severe infection, and death occurred in 17.8%, 2.5%, and death in 1.4% of cases, respectively. SVR was associated with treatment completion, RVR, and anemia. CONCLUSIONS: The effectiveness of hepatitis C virus triple therapy was lower than that reported in phase III clinical trials, possibly owing to the prioritized treatment of patients with advanced liver fibrosis. The high frequency of side effects and treatment interruptions observed supported the decision of the Brazilian authorities to suspend its use when safer and more effective drugs became available in 2015. PMID- 29513837 TI - Tuberculosis: renewed challenge in Brazil. AB - This article reviews tuberculosis control actions performed over the last decade, at a global level. The perspectives for the fulfillment of the goals of the new Global Tuberculosis Elimination Plan are described, where the insertion of social protection (Pillar 2) and research (Pillar 3) will play an innovative and strategic role, especially in high-burden countries, like Brazil. PMID- 29513838 TI - Social conditions and immune response in human immunodeficiency virus seropositive pregnant women: a cross-sectional study in Brazil. AB - INTRODUCTION: The functioning of the immune system during pregnancy is altered in both human immunodeficiency virus (HIV)-infected and uninfected women. Unfavorable socioeconomic conditions have been indicative of higher morbidity and mortality and worsening of the immune system. The aim of this study was to correlate social status with levels of interleukin (IL)-10 (non-inflammatory) and interferon-gamma (IFN-gamma; inflammatory) cytokines. METHODS: A cross-sectional study was conducted with three groups of women: 33 pregnant HIV-infected (G1); 40 non-pregnant, HIV-infected (G2); and 35 pregnant, HIV-uninfected. To measure the social status, a compound indicator called the social status index (SSI), was established using sociodemographic variables (i.e., education level, housing conditions, per capita income, and habitation and sanitary conditions). RESULTS: The HIV-infected women had a higher proportion of unfavorable SSI (73% and 75% of G1 and G2, respectively). There were significantly lower IL-10 levels in the G1 group with both unfavorable and favorable SSI than in the other groups. No significant difference in IFN-gamma levels was observed among groups. However, the G1 group had higher IFN-gamma values among both favorable and unfavorable SSI groups. CONCLUSIONS: Higher rates of unfavorable conditions, including lower education levels, IL-10 levels, and a trend for higher IFN-gamma levels, were identified among HIV-infected women, pregnant and non-pregnant. These factors may interfere in health care and lead to poor outcomes during pregnancy. Therefore, we suggest that health policies could be created to specifically address these factors in this population. PMID- 29513839 TI - Human metapneumovirus in Southern Brazil. AB - INTRODUCTION: Infections caused by respiratory viruses are important problems worldwide, especially in children. Human metapneumovirus (hMPV) is a respiratory pathogen and causes severe infections with nonspecific symptoms. This study reports the hMPV occurrence and dissemination in southern Brazil and compares the frequency of occurrence of this virus and the human respiratory syncytial virus (hRSV) in the epidemiological weeks in a three-year period (2009-2011). METHODS: In total, 545 nasopharyngeal (NP) specimens from individuals with Severe Acute Respiratory Syndrome (SARS) who were negative for other seven respiratory viruses were analyzed for the presence of hMPV. Human metapneumovirus was detected by direct immunofluorescence and real-time reverse transcription polymerase chain reaction. RESULTS: hMPV was detected in 109 patients from the main geographic regions of the southernmost state of Brazil, presenting similar overall prevalence in males (46.8%) and females (53.2%). Among children who were less than six years old, hMPV was detected in 99 samples of all age groups, with a higher frequency in infants who were less than one year old (45.7%) compared to all other age groups until six years. hMPV and hRSV infection occurred in almost the same epidemiological weeks (EWs) of each year, with peaks of incidence between EW 31/37 and EW 26/38 for the years 2009 and 2011, respectively. hMPV was further detected in several cases of SARS and it was the only virus detected in three deaths. CONCLUSIONS: These findings indicate that hMPV is in circulation in southern Brazil and highlight the importance of diagnosing hMPV for influenza like illness in the population. PMID- 29513840 TI - Comparative analysis of Mouse Inoculation Test and Virus Isolation in Cell Culture for rabies diagnosis in animals of Parana, Brazil. AB - INTRODUCTION: Rabies is an acute zoonotic disease, caused by a rhabdovirus that can affect all mammals, and is commonly transmitted by the bite of a rabid animal. The definitive diagnosis is laboratorial, by the Fluorescent Antibody Test (FAT) as a quick test and Mouse Inoculation Test (MIT) as a confirmatory test (gold standard). Studies conducted over the past three decades indicate that MIT and Virus Isolation in Cell Culture (VICC) can provide the same effectiveness, the latter being considered superior in bioethics and animal welfare. The aim of this study was to compare VICC with MIT, in terms of accuracy, biosafety and occupational health, supply and equipment costs, bioethics and animal welfare, in a Brazilian public health lab. METHODS: We utilized 400 samples of animal neurological tissue to compare the performance of VICC against MIT. The variables analyzed were accuracy, biosafety and occupational health, time spent in performing the tests, supply and equipment costs, bioethics and animal welfare evaluation. RESULTS: Both VICC and MIT had almost the same accuracy (99.8%), although VICC presented fewer risks regarding biosafety and mental health of the technicians, and reduced time between inoculation and obtaining the results (approximately 22 days less). In addition, VICC presented lower supply costs (86.5% less), equipment costs (32.6% less), and the advantage of not using animals. CONCLUSIONS: These results confirm that VICC can replace MIT, offering the same accuracy and better features regarding cost, results, biosafety and occupational health, and bioethics and animal welfare. PMID- 29513841 TI - Clonal relationships, antimicrobial susceptibilities, and molecular characterization of extended-spectrum beta-lactamase-producing Escherichia coli isolates from urinary tract infections and fecal samples in Southeast Iran. AB - INTRODUCTION: Multidrug-resistant (MDR) Escherichia coli, a species that is a leading cause of urinary tract infections (UTIs) and is a major global public health concern. This study was designed to detect the differences in antibiotic resistance patterns, the production and type of extended spectrum beta-lactamases (ESBLs), and the clonal relationships among E. coli isolates from UTIs and fecal samples. METHODS: Antibacterial resistance was determined by the disk diffusion method. ESBL, carbapenemase, and AmpC-producing isolates were detected phenotypically. Then, the ESBL genes were sequenced to detect the type. Enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC PCR) was performed on the ESBL-positive isolates. RESULTS: The most common effective antibacterial agents were colistin, imipenem, and amikacin. Among the isolates, 204 (56.6%) were MDR. Of the 163 ESBL-positive isolates, 11 (6.7%) produced AmpC, and the frequencies of beta-lactamase-positive genes were as follows: bla CTX-Mgroup1, 76%; bla TEM1, 74.8%; bla SHV12, 1.2%; and bla OXA1, 12.88%. ERIC PCR showed a diverse pattern, suggesting that clonal spread of E. coli in this area is uncommon, and that most of the infecting strains are endogenous. CONCLUSIONS: The high rates of antibacterial-resistant and MDR isolates are quite important since these strains can act as source of resistant bacteria that can be spread in the community. Controlling antibiotic use, against inappropriate use and abuse, in the community and continuous surveillance of emerging resistance traits are critical to controlling the spread of resistance. PMID- 29513842 TI - Evaluation of in vitro anti-Trypanosoma cruzi activity of medications benznidazole, amiodarone hydrochloride, and their combination. AB - INTRODUCTION: Approximately seven to eight million people worldwide have Chagas disease. In Brazil, benznidazole is the most commonly used active drug against Trypanosoma cruzi; however, its efficacy is limited, and side effects are frequent. Recent studies suggest that amiodarone may be beneficial in the treatment of this disease, by exerting anti-T. cruzi action. This study evaluated changes in T. cruzi cell count in in vitro cultures subjected to different doses of benznidazole, amiodarone, and their combination. METHODS: T. cruzi (Y strain) cultures containing approximately 100,000 cells were treated with either 100mg, 50mg, 25mg, 12.5mg, or 10mg of benznidazole, amiodarone, or their combination. On the 4th day, cell count was compared to the baseline data. RESULTS: On the 4th day, no parasites were observed in any of the treated cultures. CONCLUSIONS: Benznidazole and amiodarone were equally effective in eliminating T. cruzi in culture. The combination of the two drugs was also equally effective, but our data cannot demonstrate synergism, as similar results were obtained when the drugs were tested individually or in combination. It is suggested that this study be repeated with other T. cruzi strains to determine whether similar results can be obtained again. PMID- 29513843 TI - Epidemiological factors associated with Toxoplasma gondii infection in postpartum women treated in the public healthcare system of Goiania, State of Goias, Brazil. AB - INTRODUCTION: Knowledge of the epidemiological profile and risk factors for Toxoplasma gondii infection among postpartum women is a relevant issue, because this protozoan can be vertically transmitted to the developing fetus, which can cause severe and debilitating disease. The aim of this study was to assess the risk factors associated with T. gondii infection in postpartum women in Goiania, GO, Brazil. METHODS: This cross-sectional study comprised 229 postpartum women, among whom 204 were chronically infected (IgG+/IgM-), and 25 were seronegative (IgG-/IgM-; control group). All the patients were asked to complete a form to provide sociodemographic, clinical, dietary, and cultural information. The data were analyzed to compare seropositivity and risk factors based on the odds ratio (OR) thereof. RESULTS: The sociodemographic characteristics associated with the risk for toxoplasmosis were: education <= 8 years [OR: 2.521, confidence interval (CI): 1.01-6.301, p=0.049], and age >= 30 years (OR: 4.090; CI: 1.180-14.112, p=0.023). Clinical and behavioral characteristics related to eating raw and undercooked meat, were not found to be risk factors associated with a positive test for toxoplasmosis. CONCLUSIONS: Our findings concur with the results of other studies conducted in Brazil and abroad, where variables such as low levels of schooling, and advanced age (>= 30 years) are major risk factors for pregnant women to become infected with T. gondii. PMID- 29513844 TI - Is the recent increment in attributable deaths to type-2 diabetes (T2D) associated with the latest chikungunya outbreak in a major epidemic area in Brazil? AB - INTRODUCTION: Chikungunya virus (CHIKV) can negatively influence outcomes in patients with pre-existing conditions. We investigated the association between the recent CHIKV outbreak and increased type 2 diabetes (T2D)-attributable deaths. METHODS: Monthly averages of T2D-attributable deaths between 2001 and 2016 were determined and compared to the equivalent data for 2017 and the recent CHIKV outbreak. RESULTS: CHKV outbreak peaked in April 2017 with 4,394.4 cases/100,000 inhabitants, while T2D-attributable deaths in the same period increased by 35.2%. CONCLUSIONS: T2D-attributable deaths significantly increased compared to the previous data, which overlapped with CHIKV incidence. The pathophysiology of this association warrants further investigations. PMID- 29513845 TI - Development and characterization of a packaging cell line for pseudo-infectious yellow fever virus particle generation. AB - INTRODUCTION: Pseudo-infectious yellow fever viral particles (YFV-PIVs) have been used to study vaccines and viral packaging. Here, we report the development of a packaging cell line, which expresses the YFV prM/E proteins. METHODS: HEK293 cells were transfected with YFV prM/E and C (84 nt) genes to generate HEK293-YFV PrM/E-opt. The cells were evaluated for their ability to express the heterologous proteins and to package the replicon repYFV-17D-LucIRES, generating YFV-PIVs. RESULTS: The expression of prM/E proteins was confirmed, and the cell line trans packaged the replicon for recovery of a reporter for the YFV-PIVs. CONCLUSIONS: HEK293-YFV-prM/E-opt trans-packaging capacity demonstrates its possible biotechnology application. PMID- 29513846 TI - Actinomycosis, a lurking threat: a report of 11 cases and literature review. AB - Actinomycosis remains characteristically uncommon, but is still an important cause of morbidity. Its clinical presentation is usually indolent and chronic as slow growing masses that can evolve into fistulae, and for that reason are frequently underdiagnosed. Actinomyces spp is often disregarded clinically and is classified as a colonizing microorganism. In this review of literature, we concomitantly present 11 cases of actinomycosis with different localizations, diagnosed at a tertiary hospital between 2009 and 2016. We outline the findings of at least one factor of immunosuppression in > 90% of the reported cases. PMID- 29513847 TI - Building Infestation Index for Aedes aegypti and occurrence of dengue fever in the municipality of Foz do Iguacu, Parana, Brazil, from 2001 to 2016. AB - INTRODUCTION: the Building Infestation Index (BII) uses the Rapid Assay of the Larval Index for Aedes aegypti (LIRAa) to express the relationship between positive and surveyed properties. We evaluated LIRAa and the relationship between the BII and climate variables for dengue cases in Foz do Iguacu municipality, Parana. METHODS: Spearman's correlations for mean precipitation, mean temperature, BII, and dengue cases (time lag). RESULTS: positive correlations between BII and cases, and mean temperature and cases at two months. Weak correlation between precipitation and cases at three months. CONCLUSIONS: LIRAa and climate variables correlate with dengue cases. PMID- 29513848 TI - First report of Triatoma sordida Stal, 1859 (Hemiptera, Reduviidae, Triatominae) in the State of Acre and Brazilian Western Amazon. AB - INTRODUCTION: The occurrence of Triatoma sordida in the Brazilian Western Amazon is reported for the first time. METHODS: Triatoma sordida specimens were collected from a Gallus gallus nest in a peridomiciliary area of Senador Guiomard municipality in the state of Acre. RESULTS: The number of triatomine species in Acre increased from six to seven with this first report of T. sordida in the Brazilian Western Amazon. CONCLUSIONS: The occurrence of T. sordida in Acre is of concern since it is among the most captured triatomines in peridomiciliary environments in Brazil, and carries a high potential for vector transmission. PMID- 29513849 TI - Hymenoptera stings in Brazil: a neglected health threat in Amazonas State. AB - INTRODUCTION: Hymenoptera injuries are commonly caused by stinging insects. In Amazonas state, Brazil, there is no information regarding distribution, profile, and systemic manifestations associated with Hymenoptera injuries. METHODS: This study aimed to identify risk factors for systemic manifestation using the Brazilian Notifiable Diseases Surveillance System (2007 to 2015). RESULTS: Half of Hymenoptera injuries were caused by bee stings. Hymenoptera injuries were concentrated in Manaus, and 13.36% of cases displayed systemic signs. Delayed medical assistance (4 to 12 hours) presented four times more risk for systemic manifestations. CONCLUSIONS: Simple clinical observations and history of injury are critical information for prognostic improvement. PMID- 29513850 TI - Matrix-assisted laser desorption ionization-time of flight: a promising alternative method of identifying the major coagulase-negative Staphylococci species. AB - INTRODUCTION.: This study aimed to evaluate different methods for differentiation of species of coagulase-negative staphylococci (CoNS) that caused infections in hospitalized immunocompromised patients. METHODS.: A total of 134 CoNS strains were characterized using four different methods. RESULTS. : The results of matrix assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) analysis were in complete agreement with those of tuf gene sequencing (kappa index = 1.00). The kappa index of Vitek 2(r) Compact analysis was 0.85 (very good) and that of the conventional method was 0.63 (moderate). CONCLUSIONS: . MALDI-TOF MS provided rapid and accurate results for the identification of CoNS (134; 100%). PMID- 29513851 TI - Clonal relation and antimicrobial resistance pattern of extended-spectrum beta lactamase- and AmpC beta-lactamase-producing Enterobacter spp. isolated from different clinical samples in Tehran, Iran. AB - INTRODUCTION: Here, we determined the genes encoding antibiotic resistance enzymes and virulence factors and evaluated the genetic relationship between Enterobacter spp. isolated from different clinical samples. METHODS: A total of 57 clinical isolates of Enterobacter spp. were tested for the production of extended-spectrum beta-lactamases (ESBLs), carbapenemase, and AmpC using phenotypic and genotypic methods. RESULTS: The most common ESBLs and AmpC beta lactamases were bla TEM (63.3%) and bla EBC (57.7%), respectively. The most prevalent virulence gene was rpos (87.7%). The random amplified polymorphic DNA (RAPD) patterns of strains were genetically unrelated. CONCLUSIONS: RAPD polymerase chain reaction analysis revealed high genetic diversity among isolates. PMID- 29513852 TI - Impact of Bacille Calmette-Guerin revaccination on serum IgE levels in a randomized controlled trial. AB - INTRODUCTION: Bacille Calmette-Guerin (BCG) downmodulates allergen-specific IgE levels and prevents other atopic responses in experimental models but fails to protect against respiratory allergies. Human responsiveness to BCG is variable and may interfere with protection. METHODS: Multivariate models were evaluated to test the possible effect of responsiveness (assessed by IFN-gamma production) to BCG revaccination on the modulation of total and allergen-specific serum IgE levels in healthy volunteers participating in a randomized controlled trial. RESULTS: Serum total or Derp-specific IgE levels did not change regardless of the increase in IFN-gamma levels. CONCLUSIONS: BCG responsiveness does not affect protection against atopy. PMID- 29513853 TI - Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles. AB - INTRODUCTION: Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS: Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and beta2-glycoprotein-I (beta2GPI) Val247Leu polymorphism were assessed. RESULTS: Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented beta2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS: Corticosteroid or thalidomide adverse effects and aPL and beta2GPI polymorphisms may cause TBE in patients with MB leprosy. PMID- 29513854 TI - QUESTIONS RELATED TO SCREENING OF EMOTIONAL/BEHAVIORAL PROBLEMS IN PRESCHOOLERS. PMID- 29513856 TI - Measurement of social inequalities in health: concepts and methodological approaches in the Brazilian context. AB - This study aims to describe methodological approaches to measure and monitor health inequalities and to illustrate their applicability. The measures most frequently used in the literature were reviewed. Data on coverage and quality of pre-natal care in Brazil, from the Demographic and Maternal and Child Health Survey (PNDS-2006) and the National Health Survey (PNS-2013) were used to illustrate their applicability. Absolute and relative measures of inequalities were presented, highlighting their complementary character. Despite the progress achieved in the national indicators of pre-natal care, important inequalities were still identified between population subgroups, with no change in the magnitude of the differences throughout the studied period. Brazil has important social inequalities, whose consequences still lead to health inequalities. Their description and monitoring are highly relevant to support polices focused on those vulnerable population groups who have been left behind. PMID- 29513855 TI - INTAKE OF SUGAR-SWEETENED BEVERAGES, MILK AND ITS ASSOCIATION WITH BODY MASS INDEX IN ADOLESCENCE: A SYSTEMATIC REVIEW. AB - OBJECTIVE: To systematize literature references addressing the association of sugar-sweetened beverage (SSB) and milk intake with body mass index (BMI) in adolescents. DATA SOURCE: A search was carried out in PubMed (US National Library of Medicine National Institutes of Health) and BVS (Virtual Library in Health). The descriptors used were: adolescents, young adult, beverages, drinking, obesity, overweight, BMI, and nutritional status. The following filters were applied: age ranging from 10 to 19 years, studies published in Portuguese or English language between 2011-2015. DATA SYNTHESIS: Thirty studies were selected (22 cross-sectional studies, 4 cohort studies, 1 randomized clinical trial, 1 case-control study, and 1 quasi-experimental study). There was association between the intake of these beverages and increase in BMI in 55% of all 20 studies that dealt with sugary drinks. When it came to soft drinks, 100% of studies reported association with increase in BMI. As to milk intake, only one article showed association with increased BMI. Three articles reported milk as a protection factor against increase in BMI; three studies found no association between this intake and BMI. Nineteen studies had representative samples and 20 surveys reported random samples. Among papers using questionnaires, 84% had been validated. CONCLUSIONS: There is no consensus in the literature about the association between SSB or milk intake and BMI in adolescents. PMID- 29513857 TI - Trends in the dental surgeon workforce in Brazil 2007-2014: a time series study using data from the National Registry of Health Services. AB - OBJECTIVE: the objective was to analyze trends in the dental surgeon workforce in Brazil between 2007 and 2014. METHODS: this is a time series study using data from the Brazilian National Register of Health Establishments and the Brazilian National Institute of Geography and Statistics. Prais-Winsten generalized linear regression was used to estimate time trends and to calculate the annual percent change in the dental surgeon workforce over the period. RESULTS: the number of dental surgeons working as general practitioners and as specialists grew on average by 12.7% and 17.3% per annum, respectively; dental surgeon workforce expansion in relation to general practitioners (0.5%) and specialists (11.6%) was lower in the public sector, compared to the private sector (24.5% and 30.3%, respectively). CONCLUSION: the number of dental surgeons in Brazil is high, although they are not equally distributed between both sectors. This may imply barriers to dental care access in Brazil. PMID- 29513858 TI - Consumption of ultra-processed foods and socioeconomic position: a cross sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA Brasil). AB - The objective of the study was to estimate the contribution of ultra-processed foods to total caloric intake and investigate whether it differs according to socioeconomic position. We analyzed baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil 2008-2010; N = 14.378) and data on dietary intake using a food frequency questionnaire, assigning it into three categories: unprocessed or minimally processed foods and processed culinary ingredients, processed foods, and ultra-processed foods. We measured the associations between socioeconomic position (education, per capita household income, and occupational social class) and the percentage of caloric contribution of ultra-processed foods, using generalized linear regression models adjusted for age and sex. Unprocessed or minimally processed foods and processed culinary ingredients contributed to 65.7% of the total caloric intake, followed by ultra-processed foods (22.7%). After adjustments, the percentage of caloric contribution of ultra processed foods was 20% lower among participants with incomplete elementary school when compared to postgraduates. Compared to individuals from upper income classes, the caloric contribution of ultra-processed foods was 10%, 15% and 20% lower among the ones from the three lowest income, respectively. The caloric contribution of ultra-processed foods was also 7%, 12%, 12%, and 17% lower among participants in the lowest occupational social class compared to those from high social classes. Results suggest that the caloric contribution of ultra-processed foods is higher among individuals from high socioeconomic positions with a dose response relationship for the associations. PMID- 29513859 TI - Women in the world of science and scientific publishing. PMID- 29513860 TI - Early-life socioeconomic status and malocclusion in adolescents and young adults in Uruguay. AB - This study aims to estimate orthodontic treatment need among 15-24 year-old individuals in Montevideo, Uruguay, and the association of occlusal traits with demographic, clinical and socioeconomic factors, considering a life course approach. A cross-sectional study using data from the First National Oral Health Survey in Uruguay was conducted. A two-stage cluster procedure was used to select a sample of 278 individuals in Montevideo. Household interviews and oral examinations were performed by six dentists. Dental Aesthetic (DAI) and Decayed Missing and Filled Teeth Indices (DMFT) were used to assess orthodontic treatment need and dental caries, respectively. Early life and current socioeconomic factors were obtained from the interview. Ordinal logistic regression was used to model the DAI index. Prevalence of definite malocclusion was 20.6%, followed by severe (8.2%) and very severe (7.6%). In the adjusted analysis, individuals with untreated dental caries (OR = 1.11; 95%CI: 1.03-1.20) and those who reported a lower socioeconomic level at 6 years of age (OR = 5.52; 95%CI: 1.06-28.62) had a higher chance of being a worse case of malocclusion. Current socioeconomic position was not associated with orthodontic treatment need. Individuals aged 22 24 years (OR = 1.59; 95%CI: 1.05-2.41) had a lower chance than those aged 14-17. This study shows that orthodontic treatment need is relatively high in Uruguayan adolescents and young adults. There is a potential relationship between early life socioeconomic status and the occurrence of malocclusion in adolescents and young adults under a life course approach. PMID- 29513861 TI - [The health system in Venezuela: a patient without medication?] AB - The situation in Venezuela is marked by a profound socioeconomic crisis that raises questions concerning its effects on the health system. The study's aim was to analyze the trends and current situation of the Venezuelan health system, with special emphasis on financing. Based on the World Health Organization's Framework for Action to Strengthen Health Systems, five of the system's six basic components were studied, along with the results in terms of coverage and the population's health. Healthcare financing in Venezuela proved to be primarily private, with a high and growing share of out-of-pocket expenditures, one of the highest in the world. The health sector is also assigned low fiscal priority, with a reduced public budget, vulnerable to fluctuations in oil prices. Meanwhile, health services provision and effective access have been jeopardized in recent years due to the decreased availability of physicians, particularly in some specialties, gaps in provision and medical equipment in health centers, and shortage of medical inputs, medicines, and vaccines, among other factors, affecting the population's health, worsening of several indicators. The economy's structural characteristics and socioeconomic dynamics have impacted the Venezuelan health system, aggravating longstanding problems like the system's fragmentation, segmentation, and "privatization", triggering the emergence of new difficulties like shortage of medicines and lack of accountability, among others. PMID- 29513862 TI - [The daily routine of teens at a Center for Psychosocial Care for Alcohol and Other Drugs in Brazil: realities and challenges]. AB - This study aimed to shed light on the daily reality of adolescents in relation to drugs, at a Center for Psychosocial Care for Alcohol and Other Drugs (CAPSad) and the other contexts in which they circulate, analyzed from their own perspective. The study included eight adolescents 12 to 18 years of age enrolled in the CAPSad in a medium-sized city in the interior of Sao Paulo State, Brazil. Data collection used an identification form for the adolescents and family network and a semi-structured interview. Data analysis used the collective subject discourse (CSD) technique. The results show that adolescents experience a process of social exclusion and disengagement in various spheres of life, and highlights the CAPSad as an important space in their day-to-day life, although limited in its care for these youngsters. The study's contributed by giving a voice to these adolescents, a group frequently excluded from treatment and outreach services for drug users, as well as identifying and shedding light on the drugs and the specificities of their day-to-day lives, from their own perspective both inside and outside the clinic. PMID- 29513863 TI - Referral system in rural Iran: improvement proposals. AB - Because of insufficient communication between primary health care providers and specialists, which leads to inefficiencies and ineffectiveness in rural population health outcomes, to implement a well-functioning referral system is one of the most important tasks for some countries. Using purposive and snowballing sampling methods, we included health experts, policy-makers, family physicians, clinical specialists, and experts from health insurance organizations in this study according to pre-determined criteria. We recorded all interviews, transcribed and analyzed their content using qualitative methods. We extracted 1,522 individual codes initially. We also collected supplementary data through document review. From reviews and summarizations, four main themes, ten subthemes, and 24 issues emerged from the data. The solutions developed were: care system reform, education system reform, payment system reform, and improves in culture-building and public education. Given the executive experience, the full familiarity, the occupational and geographical diversity of participants, the solutions proposed in this study could positively affect the implementation and improvement of the referral system in Iran. The suggested solutions are complementary to each other and have less interchangeability. PMID- 29513864 TI - Contributions of speech-language therapy to the integration of individuals with Down syndrome in the workplace. AB - PURPOSE: To analyze the contributions of speech-language therapy in the integration of young individuals with Down syndrome (DS) into the workplace, with reference to their professionalization. METHODS: A questionnaire was distributed to eight undergraduate students (tutors) who participated in a project with individuals with DS, five mothers of individuals with DS, and five employees from the institution in which the present study was conducted. The questionnaire assessed the communication, memory, behavior, social interaction, autonomy and independence of the participants with DS, called "trainees". The trainees were employed in one of five routine work sectors at the university that conducted the present study. The data collected in this descriptive and cross-sectional study were analyzed quantitatively and qualitatively. The Research Ethics Committee of the affiliated institute approved the project. RESULTS: Mothers and tutors rated the trainees' language skills as "good". However, their ratings differed from those of the participating employees. After the trainees with DS were placed in a work environment, significant changes were observed in their communication and autonomy. There was no improvement in the trainees' independence, but after training noticeable changes were observed in their social behavior and autonomy. CONCLUSION: Speech-language therapy during vocational training led to positive changes in the social behavior of individuals with DS, as evidenced by an increase in their autonomy and communication. PMID- 29513865 TI - Preparation of a Protocol for Instrumental Assessment of Speech (PRAINF) based on psychometric and linguistic criteria. AB - OBJECTIVE: Propose a protocol for instrumental assessment of adult speech considering psychometric and linguistic criteria. METHODS: The choice of words was based on previously defined Brazilian Portuguese linguistic criteria after a search on the "Portal da Lingua Portuguesa" database using the Portuguese Orthographic Vocabulary (VOP). The defined linguistic criteria considered grammatical class, vowel context, number of syllables, stress, and presence of words in the daily life of Brazilian adults. The choice of the images to represent the words considered the criteria of imageability, clearness, and cultural aspects. The words and images were rigorously evaluated by 13 non specialist judges and six specialist judges. After being examined by the judges, the words were tested in adults through instrumental assessment. RESULTS: The protocol was composed of 19 words and images, with prevalence of nouns over adjectives. Each word included one target sound in Onset Medial position, in the context precedent and following the vowel [a], trisyllabic and paroxytone words. The adults that attended the instrumental assessments succeeded in producing the list of words spontaneously. The data obtained through the assessments provided adequate analysis. CONCLUSION: This study provided additional information on psychometric and linguistic criteria in addition to providing a protocol for instrumental assessment of adult speech. PMID- 29513866 TI - Video feedback for families of hearing impaired children. AB - In order to improve speech-language development in children with hearing impairment, in addition to speech-language therapy, the family should be the modifying agent for a satisfactory therapeutic response. Studies that analyze the effectiveness of speech-language pathology (SLP) intervention programs through video feedback are important, given the positive effects of this tool on the modification of behaviors with families of children with disabilities. Therefore, it is believed that video feedback interventions contribute improve the communicative interactions between the families and children assisted by auditory rehabilitation services. The objectives of this study were to investigate the interaction between families and children with hearing loss and analyze the self esteem and satisfaction of families before and after the intervention program. This is a non-randomized, clinical trial with case report in two groups: Experimental (n=5) and Control (n=5). The intervention was supported by family child interaction videos and adapted instruments. Pre- and post-intervention protocols were applied. In the EG, improvement was observed in the interaction between the families and children with hearing loss and in the self-esteem of participants. The EG showed satisfaction with the intervention. We conclude that the SLP intervention program based on video feedback has positive effects on the family/child interaction and on parent self-esteem. Further studies with stricter methodological controls should be conducted to prove the efficacy of video feedback intervention for families of children with hearing loss. PMID- 29513867 TI - Symptoms of dysphagia in children with cleft lip and/or palate pre- and post surgical correction. AB - PURPOSE: Determine the occurrence of dysphagia symptoms in children with cleft lip and/or palate (CLP) pre- and post-surgical correction. METHODS: Quantitative observational cross-sectional study. Existence of clef lip and/or palate without association with other syndromes was the study inclusion and/or exclusion criterion. Parents and/or legal guardians responded to a recall questionnaire on the identification of occurrence of coughing, choking, vomiting, and nasal escape pre- and postoperatively and whether these symptoms disappeared after surgical correction. The study was approved by the Research Ethics Committee of the aforementioned Institution under protocol no. 1573164. RESULTS: The sample comprised 23 children with mean age of 48 months, mostly male and with unilateral trans-foramen incisor clefts. Statistically significant difference was observed between the pre- and post-surgical periods regarding the presence of dysphagia symptoms. CONCLUSION: Surgical treatment of patients with cleft lip and/or palate proved to be a resource to prevent the occurrence of dysphagia symptoms when associated with adequate intervention chronology. PMID- 29513868 TI - Findings of postoperative clinical assessment of swallowing in infants with congenital heart defect. AB - PURPOSE: Describe the findings of postoperative clinical evaluation of swallowing in infants with congenital heart disease (CHD) in a reference hospital in southern Brazil. METHODS: This is a cross-sectional study conducted postoperatively with infants with medical diagnosis of CHD aged 0-6 months in a Pediatric Intensive Care Unit. Exclusion criteria comprised infants with neurological and respiratory impairments, craniofacial malformation, structural alteration in the upper airways, and suspicion or diagnosis of genetic syndromes. Clinical evaluation was performed through partial application of the Assessment of Pediatric Dysphagia protocol. Regarding statistical analysis, the quantitative variables were described by median and interquartile range and the qualitative variables were described by absolute and relative frequencies. Non-parametric tests were used to evaluate the associations. RESULTS: Of the 31 infants in the sample, 23 (74.2%) were classified with some degree of dysphagia. Significant difference was observed in the clinical evaluation performed with bottle-feeding compared with breast-feeding; a larger number of swallowing disorders was also found in bottle-feeding. Statistically significant correlation was observed between duration of orotracheal intubation (OTI) >24 h and presence of dysphagia. CONCLUSION: Postoperative clinical evaluation enabled description of swallowing impairments in infants with CHD regardless of the type of feeding offered, as well as identification of presence of dysphagia in a large number of individuals in the sample and its association with duration of OTI >24 h. PMID- 29513869 TI - Portuguese adaptation of Shulman's test of pragmatic skills. AB - PURPOSE: The purpose of this study was to apply the Test of Pragmatic Skills in Brazilian children with normal development. METHODS: Participants of this study were 60 children 3:00 to 8:11 years old, equally divided between genders. The examiners had prior contact with the group of children and applied the TOPS - a traditional test that proposes four sets of simple activities, with the common material, applicable in a short period of time - according to the procedure proposed by the author. RESULTS: The results showed a large variability in performance, illustrating that the linguistic and pragmatic skills develop according to the age. It was also observed that the subjects performed all the categories of communicative intentions required by Shulman, indicating that it is not the presence or absence of a specific intent that influences the score in this test, but the quality of the answers provided, which evolves with age. CONCLUSION: Thus, we can conclude that the TOPS proved to be an important instrument that allows answers in informal conversation contexts, verifying that the test is effective in assessing the pragmatic skills of typically developing children and can be an important tool to be used in the assessment of communicative intentions in Brazilian children. PMID- 29513870 TI - Skills for the literacy process. AB - PURPOSE: Examine a set of competencies in children beginning the process of literacy and find whether there is positive correlation with their level of writing. METHODS: Study conducted with 70 six-year-old students enrolled in the first year of Elementary School in municipal schools. The children were submitted to the Initial Reading and Writing Competence Assessment Battery (BACLE) and the Diagnostic Probing Protocol for classification of their level of writing. Descriptive statistical analysis and the Spearman coefficient were used for correlation between instruments. RESULTS: The students presented satisfactory performance in the tasks of the BACLE. Regarding the writing hypothesis, most children presented syllabic level with sound value. Significant positive correlation was observed between body scheme/time-space orientation and language skills. CONCLUSION: The group of schoolchildren performed satisfactorily on tests that measure pre-reading and writing skills. The areas of body scheme/time-space orientation and language presented significant correlation with the level of writing hypothesis, indicating that children with higher scores in these areas present better levels of writing. Identification of the necessary competencies for learning of reading and writing can provide teachers and educational audiology professionals with conditions for evaluation and early intervention in certain abilities for the development of reading and writing. PMID- 29513871 TI - Correlation between bulbar functionality and laryngeal penetration and/or laryngotracheal aspiration on motor neuron disease. AB - OBJECTIVE: Describe and correlate bulbar functionality with laryngeal penetration and/or laryngotracheal aspiration for different food consistencies in Motor Neuron Disease (MND). METHODS: Study participants were 18 individuals diagnosed with MND regardless of the type and time of onset of disease. The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised/BR (ALSFRS-R/BR) was applied, and only the bulbar parameter, which includes speech, salivation and swallowing, was analyzed, with scores raging from 0 (disability) to 12 (normal functionality). Swallowing videofluoroscopy was performed using the Penetration Aspiration Scale (PAS) described by Rosenbek et al. (1996). The Pearson correlation test was used for data analysis. RESULTS: According to food consistency, the PAS level ranged from 1 to 5 for puree consistency, 1 to 4 for thickened liquid, and 1 to 3 for liquid, and no laryngotracheal aspiration was observed. Negative correlation between bulbar functionality and laryngeal penetration was observed for all food consistencies (pasty: r=-0.487, p=0.041; thickened liquid: r=-0.442, p=0.076; liquid r=0.460, p=0.073), but statistically significant difference was found only for the puree consistency, that is, individuals with poor bulbar functionality presented higher levels of laryngeal penetration. CONCLUSION: Negative correlation was observed between bulbar functionality and laryngeal penetration in MND. The bulbar parameters of the ALSFRS-R/BR are significant for predicting risk of laryngotracheal aspiration for pasty consistency in MND. PMID- 29513872 TI - Prevalence of communication, swallowing and orofacial myofunctional disorders in children and adolescents at the time of admission at a cancer hospital. AB - PURPOSE: Describe the prevalence of communication, swallowing and orofacial myofunctional disorders in a group of children and adolescents at the time of registration at a cancer hospital. METHODS: A cross-sectional study conducted with children aged >=2 and adolescents, of both genders, admitted to the Pediatric Oncology Section of the Instituto Nacional de Cancer Jose de Alencar Gomes da Silva (INCA) from March 2014 to April 2015 for investigation and/or treatment of solid tumors. A protocol was used to record the sociodemographic and clinical information and findings of the speech-language pathology clinical evaluation, which included aspects of the oral sensorimotor system, swallowing, speech, language, voice, and hearing. RESULTS: Eighty-eight children/adolescents (41.3%) presented some type of speech-language disorder. The most frequent speech language disorders were orofacial myofunctional disorder, dysphonia, and language impairments, whereas the less frequent ones were dysacusis, tongue paralysis, and trismus. Site of the lesion was the clinical variable that presented statistically significant correlation with presence of speech-language disorders. CONCLUSION: High prevalence of speech-language disorders was observed in children and adolescents at the time of admission at a cancer hospital. Occurrence of speech-language disorders was higher in participants with lesions in the central nervous system and in the head and neck region. PMID- 29513873 TI - Erratum. AB - [This corrects the article doi: 10.1590/0074-02760170062]. PMID- 29513874 TI - Type-2 diabetes alters the basal phenotype of human macrophages and diminishes their capacity to respond, internalise, and control Mycobacterium tuberculosis. AB - BACKGROUND: Type 2 diabetes (T2D) is a risk factor for the development of tuberculosis (TB), although the associated mechanisms are not known. OBJECTIVES: To study the association between T2D and the basal phenotype of macrophages, and their immune response to Mycobacterium tuberculosis (Mtb) infection. METHODS: We evaluated the influence of T2D on the response of monocyte-derived macrophages (MDM) to Mtb in patients with T2D (n = 10) compared to healthy subjects (n = 9), before and after infection with Mtb clinical isolates bearing different degrees of virulence. The levels of cell surface markers for activation secreted cytokines and chemokines, bacterial association, and intracellular bacterial growth were evaluated. FINDINGS: The expression levels of HLA-DR, CD80, and CD86 were low while those of of PD-L1 were high in uninfected MDMs derived from patients with diabetes; as a result of Mtb infection, changes were only observed in the expression levels of PD-L1. The levels of cytokines (e.g., IL-6, IL-1beta, IL-10, and IL-12) and chemokines (e.g., MCP-1, MIG, and RANTES) are perturbed in MDMs derived from patients with diabetes, both before infection and in response to Mtb infection. In response to the more virulent Mtb strains, the levels of association and bacterial clearance were diminished in MDMs derived from patients with diabetes. CONCLUSIONS: T2D affects the basal activation state of the macrophages and its capacity to respond and control Mtb infection. PMID- 29513875 TI - Complement system contributes to modulate the infectivity of susceptible TcI strains of Trypanosoma cruzi. AB - BACKGROUND: Trypanosoma cruzi is a protozoan parasite and an etiological agent of Chagas disease. There is a wide variability in the clinical outcome of its infection, ranging from asymptomatic individuals to those with chronic fatal mega syndromes. Both parasite and host factors, as well as their interplay, are thought to be involved in the process. OBJECTIVES: To evaluate the resistance to complement-mediated killing in two T. cruzi TcI strains with differential virulence and the subsequent effect on their infectivity in mammalian cells. METHODS: Tissue-culture derived trypomastigotes of both strains were incubated in guinea pig serum and subjected to flow cytometry in order to determine their viability and complement activations. Trypomastigotes were also incubated on host cells monolayers in the presence of serum, and infectivity was evaluated under different conditions of complement pathway inhibition. Relative expression of the main parasite-specific complement receptors between the two strains was assessed by quantitative real-time polymerase chain reaction. FINDINGS: In this work, we showed that two TcI strains, one with lower virulence (Ninoa) compared to the other (Qro), differ in their resistance to the lytic activity of complement system, hence causing a compromised ability of Ninoa strain to invade mammalian cells. These results correlate with the three-fold lower messenger RNA (mRNA) levels of complement regulatory protein (CRP), trypomastigote-decay acceleration factor (T-DAF), and complement C2 receptor inhibitor trispanning (CRIT) in Ninoa compared to those in Qro. On the other hand, calreticulin (CRT) mRNA and surface protein levels were higher in Ninoa strain and promoted its infectivity when the lectin pathway of the complement system was inhibited. MAIN CONCLUSIONS: This work suggests the complex interplay of CRP, T-DAF, CRIT, and CRT, and the diagnostic value of mRNA levels in the assessment of virulence potential of T. cruzi strains, particularly when dealing with isolates with similar genetic background. PMID- 29513876 TI - Correlation of transforming growth factor-beta1 and tumour necrosis factor levels with left ventricular function in Chagas disease. AB - BACKGROUND: Transforming growth factor beta1 (TGF-beta1) and tumour necrosis factor (TNF) have been implicated in Chagas disease pathophysiology and may correlate with left ventricular (LV) function. OBJECTIVES: We determined whether TGF-beta1 and TNF serum levels correlate with LV systolic and diastolic functions and brain natriuretic peptide (BNP) serum levels in chronic Chagas disease. METHODS: This cross-sectional study included 152 patients with Chagas disease (43% men; 57 +/- 12 years old), classified as 53 patients with indeterminate form and 99 patients with cardiac form (stage A: 24, stage B: 25, stage C: 44, stage D: 6). TGF-beta1, TNF, and BNP were determined by enzyme-linked immunosorbent assay ELISA. Echocardiogram was used to determine left atrial and LV diameters, as well as LV ejection fraction and diastolic function. FINDINGS: TGF-b1 serum levels were lower in stages B, C, and D, while TNF serum levels were higher in stages C and D of the cardiac form. TGF-beta1 presented a weak correlation with LV diastolic function and LV ejection fraction. TNF presented a weak correlation with left atrial and LV diameters and LV ejection fraction. CONCLUSIONS: TNF is increased, while TGF-beta1 is decreased in the cardiac form of chronic Chagas disease. TNF and TGF-beta1 serum levels present a weak correlation with LV systolic and diastolic function in Chagas disease patients. PMID- 29513878 TI - Estrogen and progesterone promote breast cancer cell proliferation by inducing cyclin G1 expression. AB - Breast cancer is the most common cause of cancer among women in most countries (WHO). Ovarian hormone disorder is thought to be associated with breast tumorigenesis. The present study investigated the effects of estrogen and progesterone administration on cell proliferation and underlying mechanisms in breast cancer MCF-7 cells. It was found that a single administration of estradiol (E2) or progesterone increased MCF-7 cell viability in a dose-dependent manner and promoted cell cycle progression by increasing the percentage of cells in the G2/M phase. A combination of E2 and progesterone led to a stronger effect than single treatment. Moreover, cyclin G1 was up-regulated by E2 and/or progesterone in MCF-7 cells. After knockdown of cyclin G1 in MCF-7 cells using a specific shRNA, estradiol- and progesterone-mediated cell viability and clonogenic ability were significantly limited. Additionally, estradiol- and progesterone-promoted cell accumulation in the G2/M phase was reversed after knockdown of cyclin G1. These data indicated that estrogen and progesterone promoted breast cancer cell proliferation by inducing the expression of cyclin G1. Our data indicated that novel therapeutics against cyclin G1 are promising for the treatment of estrogen- and progesterone-mediated breast cancer progression. PMID- 29513877 TI - RNA viruses in trypanosomatid parasites: a historical overview. AB - Viruses of trypanosomatids are now being extensively studied because of their diversity and the roles they play in flagellates' biology. Among the most prominent examples are leishmaniaviruses implicated in pathogenesis of Leishmania parasites. Here, we present a historical overview of this field, starting with early reports of virus-like particles on electron microphotographs, and culminating in detailed molecular descriptions of viruses obtained using modern next generation sequencing-based techniques. Because of their diversity, different life cycle strategies and host specificity, we believe that trypanosomatids are a fertile ground for further explorations to better understand viral evolution, routes of transitions, and molecular mechanisms of adaptation to different hosts. PMID- 29513879 TI - Expression profile of endothelin receptors (ETA and ETB) and microRNAs-155 and 199 in the corpus cavernosum of rats submitted to chronic alcoholism and diabetes mellitus. AB - Recent evidence shows that chronic ethanol consumption increases endothelin (ET) 1 induced sustained contraction of trabecular smooth muscle cells of the corpora cavernosa in corpus cavernosum of rats by a mechanism that involves increased expression of ETA and ETB receptors. Our goal was to evaluate the effects of alcohol and diabetes and their relationship to miRNA-155, miRNA-199 and endothelin receptors in the corpus cavernosum and blood of rats submitted to the experimental model of diabetes mellitus and chronic alcoholism. Forty-eight male Wistar rats were divided into four groups: control (C), alcoholic (A), diabetic (D), and alcoholic-diabetic (AD). Samples of the corpus cavernosum were prepared to study the protein expression of endothelin receptors by immunohistochemistry and expression of miRNAs-155 and -199 in serum and the cavernous tissue. Immunostaining for endothelin receptors was markedly higher in the A, D, and AD groups than in the C group. Moreover, a significant hypoexpression of the miRNA 199 in the corpus cavernosum tissue from the AD group was observed, compared to the C group. When analyzing the microRNA profile in blood, a significant hypoexpression of miRNA-155 in the AD group was observed compared to the C group. The miRNA-199 analysis demonstrated significant hypoexpression in D and AD groups compared to the C group. Our findings in corpus cavernosum showed downregulated miRNA-155 and miRNA-199 levels associated with upregulated protein expression and unaltered mRNA expression of ET receptors suggesting decreased ET receptor turnover, which can contribute to erectile dysfunction in diabetic rats exposed to high alcohol levels. PMID- 29513880 TI - Association between type of feeding at discharge from the hospital and nutritional status of very low birth weight preterm infants. AB - The ideal feeding for premature babies has been the source of extensive debate. The aim of this study was to assess the association between type of feeding at discharge and the nutritional status of very low birth weight infants. This was a retrospective cohort of preterm babies with birth weight <=1500 g, born between January 2006 and December 2013. The infants were divided into 3 groups according to type of feeding at discharge: exclusive breast milk (group 1), mixed feeding (group 2) and exclusive artificial formula (group 3). Frequencies of each group were calculated, as well as mean Z-score differences in weight, length and head circumference. Six hundred and forty-nine newborns were included. The mean weight of groups 1, 2, and 3 was 1338.7, 1104.0, and 1254.7 g, respectively, and their mean gestational age was 31.9, 30, and 31.2 weeks, respectively. The Z-score differences (means+/-SD) for groups 1, 2, and 3 were: -0.84+/-0.68, -1.02+/-0.75, and -0.86+/-0.71 for weight, -0.21+/-1.23, -0.52+/-1.64 and -0.08+/-1.34 for head circumference, and -1.10+/-1.18, -1.54+/-1.37, and -0.97+/-1.21 for length. A significant difference was observed between groups 2 and 3 in the adjusted Z score model for length, with no significant differences in anthropometric measurements for the other comparative analyses. Because of its many advantages, breastfeeding should be stimulated within neonatal units since nutritional status was not influenced by the different types of feeding. PMID- 29513881 TI - Identification of a novel UMOD mutation (c.163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease. AB - Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC->AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause. PMID- 29513882 TI - Low density lipoprotein modified silica nanoparticles loaded with docetaxel and thalidomide for effective chemotherapy of liver cancer. AB - In the present study, we successfully developed a docetaxel (DTX) and thalidomide (TDD) co-delivery system based on low density lipoprotein (LDL) modified silica nanoparticles (LDL/SLN/DTX/TDD). By employing the tumor homing property of LDL and the drug-loading capability of silica nanoparticles, the prepared LDL/SLN/DTX/TDD was expected to locate and specifically deliver the loaded drugs (DTX and TDD) to achieve effective chemotherapy of liver cancer. In vitro analysis revealed that nano-sized LDL/SLN/DTX/TDD with decent drug loading capabilities was able to increase the delivery efficiency by targeting the low density lipoprotein receptors, which were overexpressed on HepG2 human hepatocellular liver carcinoma cell line, which exerted better cytotoxicity than unmodified silica nanoparticles and free drugs. In vivo imaging and anti-cancer assays also confirmed the preferable tumor-homing and synergetic anti-cancer effects of LDL/SLN/DTX/TDD. PMID- 29513884 TI - ERRATUM: Microtensile bond strength of CAD/CAM materials to dentin under different adhesive strategies. Braz Oral Res. 2017;31:e109. AB - [This corrects the article doi: 10.1590/1807-3107bor-2017.vol31.0109]. PMID- 29513883 TI - Lipid core nanoparticles resembling low-density lipoprotein and regression of atherosclerotic lesions: effects of particle size. AB - Particles are usually polydispersed and size is an important feature for lipid based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems. PMID- 29513885 TI - Immediate tooth replantation: root canal filling for delayed initiation of endodontic treatment. AB - The aim of this study is to evaluate the action of paramonochlorophenol associated with Furacin followed by calcium hydroxide (CH) dressing in the control of inflammatory root resorption in cases of immediate tooth replantation with delayed endodontic treatment. A total of 28 incisors of 3 male dogs were extracted and replanted after 15 minutes, and randomly divided into 3 groups: Group I (n = 8) - endodontic treatment was performed before the extraction and replantation; Group II (n = 10) - endodontic treatment was performed 30 days after replantation and the root canal was filled with CH dressing; Group III (n = 10) - endodontic treatment was performed 30 days after replantation and root canals received temporary medication of paramonochlorophenol-Furacin followed by CH dressing. The animals were euthanized 90 days after replantation. The histomorphological events analyzed at the epithelial reattachment site were the intensity and extent of acute and chronic inflammatory processes, periodontal ligament (PDL) organization, the intensity and extent of acute and chronic inflammatory processes in the PDL space, root resorption, bone tissue, and ankylosis. Data were submitted to the Wilcoxon Signed Ranks Test for group comparison (alpha = 5%). In Groups I, II and III the periodontal ligament was regenerated and most of the resorption areas were repaired by newly formed cementum. The depth and extent of root resorption were significantly higher in Group II than in Group III. The use of paramonochlorophenol-furacin followed by CH dressing was more effective in controlling inflammatory root resorption after immediate tooth replantation. PMID- 29513886 TI - Is there a best conventional material for restoring posterior primary teeth? A network meta-analysis. AB - This study aimed to compare the longevity of different conventional restorative materials placed in posterior primary teeth. This systematic review was conducted following the PRISMA statement and registered in PROSPERO (CRD42016035775). A comprehensive electronic search without date or language restrictions was performed in PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Scopus, Turning Research Into Practice (TRIP) and Clinical Trials databases up to January 2017, selecting randomized clinical trials that assessed the longevity of at least two different conventional restorative materials performed in primary molars. Seventeen studies were included in this systematic review. Pairwise and network meta-analyses were performed and relative risks and 95% confidence intervals (CI) calculated. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. Restorations of primary molars with conventional glass ionomer cement showed increased risk of failure than compomer, resin-modified glass ionomer cement, amalgam, and composite resin. Risk of bias was low in most studies (45.38% of all items across studies). Pediatric dentists should avoid conventional glass ionomer cement for restoring primary molars. PMID- 29513887 TI - Bond strength values of fiberglass post to flared root canals reinforced with different materials. AB - The aim of this study was to compare in vitro the bond strength (BS) between fiberglass posts and flared root canals reinforced with different materials. The roots of 48 premolars were endodontically treated. After one week, the root canals were prepared to simulate an oversized root canal, except for the positive control group (PCG), which was cemented with a prefabricated fiber post (PFP) compatible with the root canal size, simulating an ideal adaptation. The other samples (n=8/group) were used to test alternative restorative techniques for filling root canals: negative control group (NCG [PFP with a smaller diameter than of the root canal]), composite resin group - CRG, bulkfill group - BFG, self adhesive cement group - SAG, and glass ionomer group - GIG. The posts were cemented and after 1 week, each root was sectioned transversely into six 1-mm thick discs and the push-out test was done to evaluate the BS. Data were analyzed by two-way repeated measures ANOVA and Tukey's tests (alpha=0.05). The highest BS value was observed for PCG. The NCG and the GIG groups showed the lowest BS values. Root reinforcement with conventional and bulk-fill composite resins showed the highest BS values; however, the bulk-fill resin was the only treatment able to maintain high BS values in all regions of the root canal. The self adhesive cement showed intermediate results between CRG and GIG. Root reinforcement with bulk-fill composite resin is an effective option for flared root canals before cementation of a prefabricated fiber post. PMID- 29513888 TI - Evaluation of long-term bond strength and selected properties of self-adhesive resin cements. AB - This study evaluated the shear bond strength (SBS) of self-adhesive resin cements (SARCs) to dentin and their physical-chemical properties. Five commercial SARCs were evaluated [SmartCem(r)2 - DENTSPLY (SC2); BisCem(r) - Bisco (BC); SeT PP(r) SDI (SeT); Relyx U100(r) - 3M ESPE (U100) and YCEM(r) SA - Yller (YCEM)]. The SARCs were evaluated for SBS to dentin (n = 10) after 24 h, 6 months, and 12 months. The dentin demineralization caused by acidic monomers was observed by SEM, and pH-neutralization of eluate was observed for 24 h. Degree of conversion (DC), rate of polymerization (Rp), flexural strength (FS), and elastic modulus (E) were evaluated. Immediate SBS of SC2, SET, U100, and YCEM were statistically higher than that of BC (p < 0.001). After 12 months, all SARCs showed reduced SBS values and U100 showed values similar to those of SET and YCEM, and higher than those of BC and SC2 (p = 0.001). Demineralization pattern of SARCs was similar. At 24h, all SARCs showed no differences in the pH-value, except BC and U100 (p < 0.001). YCEM showed the highest Rp. U100, YCEM, and SC2 showed statistically higher FS (p<0.001) and E (p < 0.001) when compared with SET and BC. U100 and YCEM showed the best long-term bonding irrespective of the storage period. A significant reduction in SBS was found for all groups after 12 months. SBS was not shown to be correlated with physical-chemical properties, and appeared to be material-dependent. The polymerization profile suggested that an increased time of light activation, longer than that recommended by manufacturers, would be necessary to optimize DC of SARCs. PMID- 29513889 TI - Acute kidney injury and intra-abdominal hypertension in burn patients in intensive care. AB - OBJECTIVE: To evaluate the frequency of intra-abdominal hypertension in major burn patients and its association with the occurrence of acute kidney injury. METHODS: This was a prospective cohort study of a population of burn patients hospitalized in a specialized intensive care unit. A convenience sample was taken of adult patients hospitalized in the period from 1 August 2015 to 31 October 2016. Clinical and burn data were collected, and serial intra-abdominal pressure measurements taken. The significance level used was 5%. RESULTS: A total of 46 patients were analyzed. Of these, 38 patients developed intra-abdominal hypertension (82.6%). The median increase in intra-abdominal pressure was 15.0mmHg (interquartile range: 12.0 to 19.0). Thirty-two patients (69.9%) developed acute kidney injury. The median time to development of acute kidney injury was 3 days (interquartile range: 1 - 7). The individual analysis of risk factors for acute kidney injury indicated an association with intra-abdominal hypertension (p = 0.041), use of glycopeptides (p = 0.001), use of vasopressors (p = 0.001) and use of mechanical ventilation (p = 0.006). Acute kidney injury was demonstrated to have an association with increased 30-day mortality (log rank, p = 0.009). CONCLUSION: Intra-abdominal hypertension occurred in most patients, predominantly in grades I and II. The identified risk factors for the occurrence of acute kidney injury were intra-abdominal hypertension and use of glycopeptides, vasopressors and mechanical ventilation. Acute kidney injury was associated with increased 30-day mortality. PMID- 29513890 TI - Massive hemoptysis successfully treated with extracorporeal membrane oxygenation and endobronchial thrombolysis. AB - Extracorporeal membrane oxygenation has been used to treat refractory hypoxemia in numerous clinical scenarios. The fundamental principles for the management of massive hemoptysis patients include protecting the airway and healthy lung, locating the source of bleeding and controlling the hemorrhage. We report the case of a patient with acute respiratory failure associated with massive hemoptysis secondary to lung laceration during cardiac surgery. The use of extracorporeal membrane oxygenation allowed patient survival. However, due to the great difficulty in managing pulmonary clots after hemoptysis, it was necessary to use an unusual therapy involving endobronchial infusion of a thrombolytic agent as described in rare cases in the literature. PMID- 29513891 TI - Free vascularized fibula grafting in the operative treatment of malignant bone tumors of the upper extremity: A systematic review of outcomes and complications. AB - BACKGROUND AND OBJECTIVES: Vascularized bone grafting after tumor resection can be an important component in the treatment of bony neoplasms of the upper extremity. The purpose of this study was to determine the outcomes of free vascularized fibula grafting (FVFG) in the treatment of upper extremity sarcomas. METHODS: A systematic review of the literature of FVFG used in the treatment of upper extremity sarcomas was performed. RESULTS: A total of 56 studies were included in final analysis. The most common diagnosis was osteosarcoma (35.1%) and the most common recipient site was the humerus (57.3%). FVFG had a median union rate of 93.3%, with the median time to union being 5.0 months. The most common complications were fracture (11.7%), nerve injury (7.5%), infection (5.7%), and hammer toe deformity (3.3%). The reoperation rate was 34.5%. The most commonly reported standardized assessment of clinical outcomes following treatment was the Musculoskeletal Tumor Society Score, which had a median of 80% postoperatively. CONCLUSIONS: FVFG in the treatment of malignant bony neoplasms of the upper extremity has a high rate of union and good overall outcomes; however, postoperative complication rates are high. A greater degree of standardization is needed in the reporting of patient-centered outcomes to facilitate future comparative studies. PMID- 29513892 TI - Does the number of sentinel lymph nodes removed affect the false negative rate for head and neck melanoma? AB - BACKGROUND AND OBJECTIVES: Head and neck (HN) cutaneous melanoma is associated with worse disease-free survival compared to non-HN cutaneous melanoma, possibly due to inadequate staging. We aim to determine if a higher yield of sentinel lymph nodes (SLNs) affected rates of sentinel lymph node biopsy (SLNB) positivity. METHODS: Two Cancer Registries were used to identify patients who underwent SLNB for HN melanoma. A false negative (FN) was defined by nodal recurrence after negative SLNB. RESULTS: Out of 333 patients who underwent SLNB, 20% (n = 69) had a positive SLN with a FN rate of 6.3%. Those with three or more SLNs had a higher rate of SLN positivity (23.8% [17.5-29.9% CI] vs 16.4% [10.7 23.6% CI]), a lower FN rate (16.7% [10.2-21.2% CI] vs 35.3% [27.1-42.9% CI]), and higher sensitivity (83.3% [82.59-84.09% CI] vs 65.7% [64.87-66.53% CI]) compared to those with one or two SLNs. Of patients in Group 1 (one or two SLNs) with a positive SLN who underwent completion lymph node dissection (20/23), 47% (33-61% CI) had one or more positive non-sentinel nodes compared to 29% (16-51%) of patients in Group 2 (three or more SLNs) (42/46). CONCLUSION: In HN melanoma cases in which multiple nodes are identified, removal of all SLNs will more adequately stage patients. PMID- 29513893 TI - Predictors of complications in heat-treated autograft reconstruction after intercalary resection for malignant musculoskeletal tumors of the extremity. AB - BACKGROUND: Biological reconstruction with recycled heat-treated autografts has been an option for a segmental skeletal defect after intercalary resection for malignant musculoskeletal tumors in the extremity. This study was undertaken to evaluate the clinical outcomes in patients treated with this procedure and identify factors affecting the incidence of complications. METHODS: We retrospectively reviewed 24 patients treated with heat-treated autografts after intercalary resection at our institution between 1992 and 2015. RESULTS: The survival rate of the heat-treated autografts was 70.1% at 10 years. Of the 48 host-graft junctions in the 24 patients, nonunion occurred in 18 junctions (38%). In the univariate analysis, location in the upper extremity, intercalary grafts without vascularized fibula autografts (VFG), and junction at the diaphysis significantly increased the rate of nonunion (P = 0.003, P = 0.003, and P = 0.031, respectively). Location in the upper extremity was an independent factor associated with nonunion in the multivariate analysis (P = 0.006). Upper extremity location and intercalary grafts without VFG were also significant factors for bone absorption (P = 0.042 and P < 0.001, respectively). CONCLUSIONS: Our results can provide useful information to devise possibly novel clinical approaches to patients requiring intercalary reconstruction of the extremity. PMID- 29513894 TI - CK7/CK19 index: A potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients. AB - BACKGROUND AND OBJECTIVES: Frequently aberrant expression of cytokeratin 7 (CK7) and cytokeratin 19 (CK19) have been observed in several human cancers. In this retrospective study, we aimed at investigating the prognostic significance of CK7 and CK19 in intrahepatic cholangiocarcinoma (ICC). METHODS: Immunohistochemistry was performed to assess CK7 and CK19 expression on tissue microarrays in training cohort enrolling 214 ICC patients and validation cohort comprising 108 ICC patients. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of both CKs. RESULTS: Both CK7 and CK19 expression were significantly up-regulated in ICC compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis and larger tumor size. Furthermore, high expression of either CK7 or CK19 predicted a significantly dismal postoperative survival. Integrated analysis of CK7 and CK19 expression was identified as a better indicator for survival probability. Notably, the nomogram integrating CK7/CK19 index had a perfect prognostic performance as compared with current staging systems. The results were further confirmed in the validation cohort. CONCLUSIONS: CK7/CK19 index was an independent adverse prognostic factor for ICC patients' survival, and may be helpful to improve postoperative risk stratification and individualized treatment strategies. PMID- 29513895 TI - Are prophylactic antibiotics necessary prior to transarterial chemoembolization for hepatocellular carcinoma in patients with native biliary anatomy? AB - BACKGROUND AND OBJECTIVES: Prophylactic antibiotics are frequently administered for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). In patients without previous biliary instrumentation, infection risk from TACE is low. We hypothesized that there is a negligible rate of infection in these patients without prophylactic antibiotics. METHODS: We reviewed consecutive patients undergoing TACE between 7/1/2013-6/15/2016. All patients had an intact Sphincter of Oddi, received no peri-procedural antibiotics, and had 30+ days follow-up. Level of arterial selection was recorded. Baseline Child-Pugh (CP) and Barcelona Clinic Liver Cancer (BCLC) scores were recorded. The primary outcome measure was the absence of clinical or imaging findings of hepatic abscess within 30 days. RESULTS: A total of 171 patients underwent 235 TACE procedures. CP scores were A (n = 109), B (n = 47), and C (n = 15). BCLC scores were 0 (n = 1), A (n = 108), B (n = 47), and C (n = 15). TACE was performed segmentally (n = 208) or lobar (n = 27). Three patients died of non-infectious causes before 30 days. No hepatic abscesses developed in evaluable patients: 0/232 infusions. CONCLUSIONS: In patients with HCC and an intact Sphincter of Oddi, TACE was performed safely without prophylactic antibiotics. The majority of the patients were BCLC and CP A/B. Additional study of BCLC and CP C patients is warranted. PMID- 29513896 TI - Core Entrustable Professional Activities in Clinical Pharmacology: Pearls for Clinical Practice: Drug-Drug and Food-Drug Interactions. PMID- 29513897 TI - Discursive Research Methodologies and Couple and Family Therapy Research: Reflections. PMID- 29513898 TI - Toward Valuing Research: Reflections Inspired by Special Section Contributors. PMID- 29513899 TI - Abdominal visceral perforation by buried peritoneal dialysis catheters: Cause or coincidence? AB - Delayed visceral organ perforations after PD catheter insertions are extremely rare. We report two patients who presented with asymptomatic visceral perforation from their buried PD catheters. Five months after a laparoscopic buried PD catheter insertion in a 92-year-old man PD was initiated; bile and bowel contents were noted in the PD effluent. He subsequently expired (from pneumonia) to autopsy revealed the PD catheter within the small bowel. Despite this perforation, there was no evidence of peritonitis, inflammation, nor any bowel content within the peritoneal cavity. A second case was observed 2.5 months after an uncomplicated laparoscopic buried PD catheter insertion in a 60-year-old woman. PD was attempted; the patient had an immediate urge to void. MRI revealed the presence of the PD catheter within her bladder. She underwent PD catheter revision the next day with repair of bladder perforation and ultimately successfully initiated PD. Since the perforations did not occur at the time of catheter placement, we believe that the catheter eroded into a viscus, perhaps related to the lack of a fluid at the catheter - viscus interface. The diagnosis of delayed visceral organ perforation following buried PD catheter insertion may be delayed because the catheter is not immediately used. PMID- 29513900 TI - Comments on "When is hemiarthroplasty preferable to intramedullary prophylactic fixation of malignant lesions of the proximal femur?" PMID- 29513901 TI - Do arteriovenous fistulas increase cardiac risk? AB - An effectively functioning arteriovenous fistula is the life line for patients on long-term hemodialysis, and for most an upper limb, native vessel fistula has significant short- and long-term advantages. There are, however, situations where a fistula has deleterious effects, including the relatively uncommon problem of severe heart failure exacerbated in particular by high-flow fistulas. There is also increasing evidence that a fistula can add to the already high burden of cardiovascular risk in patients with advanced kidney disease, including by promoting water and salt retention, and by inducing or worsening left ventricular hypertrophy. While cases periodically arise where a fistula needs to be ligated with some urgency, such as severe heart failure, an increasingly persuasive case can be made for electively ligating fistulas that are not being used. The most common example of this is in stable renal transplant recipients, where the risks of ligation are outweighed by the potential risks of maintaining an unused fistula. Surgically reducing the blood flow in large (usually upper arm) fistulas is also a legitimate maneuver in specific high-risk situations. PMID- 29513903 TI - Comparison between centrifugal partition chromatography and preparative liquid chromatography as first dimensions in off-line two-dimensional separation: Application to the isolation of multi-targeted compounds from Edelweiss plant. AB - Preparative two-dimensional chromatography is gaining interest in the elucidation of complex samples as it allows the recovery of a large number of molecules without the risks inherent to tedious multi-step sample preparation. While the second dimension is often selected to be liquid chromatography, it may be of interest to compare the specificities of two different techniques, namely liquid chromatography and centrifugal partition chromatography, to be used as first dimension. A fair comparison between off-line CPCxLC and prepLCxLC in selective comprehensive mode for preparative purposes is carried out in this study, illustrated by the isolation of five compounds from high-value Edelweiss plant. The method development of each configuration is achieved on laboratory scale instruments. The quality of separation is compared using 2D-contour plots. The prepLCxLC exhibits a large separation space that leads to an overall large peak capacity, which is of great interest for complex samples. But its limited loading capacity involves a large number of 2 D runs increasing the running costs for preparative purposes. On the other hand, CPCxLC provides a low peak capacity due to the poor efficiency provided by CPC. However, this liquid-liquid technique can be finely tuned to generate a high selectivity, decreasing the number of runs necessary to produce a limited number of target solutes. PMID- 29513902 TI - Using Optical Coherence Tomography to Reveal the Hidden History of The Landsdowne Virgin of the Yarnwinder by Leonardo da Vinci and Studio. AB - Optical coherence tomography (OCT) was used for non-invasive examination of a well-known, yet complex, painting from the studio of Leonardo da Vinci in combination with routine imaging in various bands of electromagnetic radiation. In contrast with these techniques, OCT provides depth-resolved information. Three post-processing modalities were explored: cross-sectional views, maps of scattering from given depths, and their 3D models. Some hidden alterations of the painting owing to past restorations were traced: retouching and overpainting with their positioning within varnish layers as well as indications of a former transfer to canvas. PMID- 29513904 TI - When is hemiarthroplasty preferable to intramedullary prophylactic fixation of metastatic disease of the proximal femur? PMID- 29513905 TI - Discursive Research and Clinical Realities, or the Eye of the Beholder. AB - The comparison of four discursive and conversational analysis studies performed on the same couple consultation session, held by Tom Andersen, show a diversity of results. It can be argued the results are so varied that they constitute different realities, often incompatible with each other. This, far from being a shortcoming of these studies, can be seen as the true richness they can offer to the practicing therapist, who can use research to investigate the different perspectives we can adopt in viewing our clinical activity. The comparison of the four studies raises questions about the role of the therapist in such process. Clinical implications of this are also discussed. PMID- 29513907 TI - Hematology RIs for captive and wild Arabian Sand Gazelles (Gazella subgutturosa marica) of the Kingdom of Saudi Arabia. AB - BACKGROUND: The Arabian Sand Gazelle (Gazella subgutturosa marica, Thomas, 1897) has been extirpated throughout the Arabian Peninsula. Captive breeding and reintroduction for conservation purposes require veterinary support and the use of hematology RIs. OBJECTIVES: The purpose of the study was to establish hematological RIs for the Arabian Sand Gazelle. METHODS: Blood from 231 clinically healthy captive and 22 wild (reintroduced) Arabian Sand Gazelles were sampled. The VetScan HM2 analyzer was used to determine the complete cell count (CBC) on the same morning of sample collection. American Society for Veterinary Clinical Pathology (ASVCP) guidelines were followed for statistical analyses. RESULTS: The white blood cell counts (WBC) and hematocrits (HCT) revealed broad RIs, the red blood cell counts (RBC) and hemoglobin (HGB) were characterized by a narrow RI, and the platelet count (PLT) yielded a wide RI due to high variance in the data. The HGB, MCHC, PLT, and platelet distribution width (PDW) were significantly different between the captive males and females. The majority of the variables assessed were significantly different between captive and wild animals. CONCLUSIONS: The large number of samples obtained for this study was considerable given the rare and endangered status of this species, which overall afforded narrow RIs and CIs. The main exception was for the PLT constituents. The significant differences observed between the captive and wild male gazelles show the need to understand the origin of the animals for which hematologic RIs are determined. PMID- 29513908 TI - New flow cytometry-based method for the assessment of the antibacterial effect of immune cells and subcellular particles. AB - Techniques currently used for assessment of bacterial count or growth are time consuming, offer low throughput, or they are complicated or expensive. The aim of the present work was to elaborate a new method that is able to detect the antibacterial effect of cells, subcellular particles, and soluble compounds in a fast, cost, and labor effective way. Our proposed technique is based on flow cytometry (FC) optimized for detection of small particles and on fluorescently labeled bacteria. It allows direct determination of the bacterial count in 3 hours. The effect of various human phagocytes and extracellular vesicles on gram positive and gram-negative bacteria is investigated in parallel with the new, FC based method, with colony counting and with our previous, OD-based method. Comparing the killing effect of wild type and NADPH oxidase-deficient murine neutrophils presents an example of detection of a clinically important deficiency. Strong correlation was obtained between the results of the different techniques, but the reproducibility of the FC-based test was superior to the OD based test. The major advantages of the new technique are: rapidity, low cost, high throughput, and simplicity. PMID- 29513906 TI - Does inflammation affect outcomes in dialysis patients? AB - Chronic, low-grade inflammation is a common comorbid condition in chronic kidney disease (CKD), and particularly in chronic dialysis patients. In this review, we consider the question of whether inflammation affects outcomes in dialysis patients. Levels of proinflammatory cytokines, as well as C-reactive protein, are elevated in chronic dialysis patients. Multiple factors likely contribute to chronic inflammatory activation in kidney disease patients including the uremic milieu, lifestyle and epigenetic influences, infectious and thrombotic events, the dialysis process, and dysbiosis. Increased inflammatory markers in both CKD and chronic dialysis patients are associated with adverse clinical outcomes including all-cause mortality, cardiovascular events, kidney disease progression, protein energy wasting and diminished motor function, cognitive impairment, as well as other adverse consequences including CKD-mineral and bone disorder, anemia, and insulin resistance. Strategies that have been shown to reduce chronic systemic inflammation in CKD and chronic dialysis patients include both pharmacological and nonpharmacological interventions. However, despite evidence that systemic inflammatory markers can be lowered in kidney disease patients treated with various strategies, evidence that this improves clinical outcomes is largely unavailable and represents an important future research direction. Overall, there is strong observational evidence that inflammation is high in chronic dialysis patients and that this is independently associated with numerous adverse clinical outcomes. Targeting inflammation represents a potentially novel and attractive strategy if it can indeed improve adverse outcomes common in this population. PMID- 29513910 TI - A Couple in Love Entangled in Enigmatic Episodes: A Semantic Analysis. AB - The article presents a semantic analysis inspired by the theory of family semantic polarities developed by Ugazio (, ) applying two versions of a coding system, the Family Semantic Grid (FSG), to a couple session with Tom Andersen as a consultant. One version (FSG II) detects the narrated semantic polarities (NSPs) emerging during the session from the transcript, whereas the other (FSG III) identifies the interactive semantic polarities (ISPs) from the video recording. Both the NSPs and the ISPs are classified according to four sets of meaning called the semantic of freedom, goodness, power, and belonging. The analysis puts forward some hypothesis about the pattern that entangles the couple and highlights Andersen's contributions to overcome the problem troubling the couple. PMID- 29513909 TI - Evaluation of the implementation of the Meeting Centres Support Program in Italy, Poland, and the UK; exploration of the effects on people with dementia. AB - OBJECTIVES: MEETINGDEM investigated whether the Dutch Meeting Centres Support Programme (MCSP) could be implemented in Italy, Poland, and the UK with comparable benefits. This paper reports on the impact on people living with dementia attending pilot Meeting Centres in the 3 countries. METHODS: Nine pilot Meeting Centres (MCs) participated (Italy-5, Poland-2, UK-2). Effectiveness of MCSP was compared with Usual Care (UC) on outcomes measuring behavioural and psychological symptoms (NPI), depression (CSDD), and quality of life (DQoL, QOL AD), analysed by ANCOVAs in a 6-month pre-test/post-test controlled trial. RESULTS: Pre/post data were collected for 85 people with dementia and 93 carers (MCSP) and 74 people with dementia /carer dyads' receiving UC. MCSP showed significant positive effects for DQoL [Self-esteem (F = 4.8, P = 0.03); Positive Affect (F = 14.93, P < 0.00); Feelings of Belonging (F = 7.77, P = 0.01)] with medium and large effect sizes. Higher attendance levels correlated with greater neuropsychiatric symptom reduction (rho = 0.24, P = 0.03) and a greater increase in feelings of support (rho = 0.36, P = 0.001). CONCLUSIONS: MCSPs showed significant wellbeing and health benefits compared with UC, building on the evidence of effectiveness from the Netherlands. In addition to the previously reported successful implementation of MCSP in Italy, Poland, and the UK, these findings suggest that further international dissemination of MCSP is recommended. PMID- 29513911 TI - Study of the enantiomeric separation of the anticholinergic drugs on two immobilized polysaccharide-based chiral stationary phases by HPLC and the possible chiral recognition mechanisms. AB - In this work, the enantiomeric separation of ten anticholinergic drugs was first examined on two derivative polysaccharide chiral stationary phases (CSPs), i.e., Chiralpak ID and Chiralpak IA in the normal phase mode. Except for scopolamine hydrobromide, the remaining nine analytes could be completely separated with good resolutions using both columns under the optimized mobile phase conditions. And the enantiomeric discrimination ability of the studied CSPs towards nine analytes was in the order of Chiralpak ID > Chiralpak IA. The influences of organic modifier types, alcohol content, and base/acid additives on the enantiomeric separation were evaluated and optimized. According to the experimental results, the effect of the structures of analytes on enantiomeric separation was discussed. Additionally, the chiral recognition mechanisms were proposed based on the thermodynamic analysis of the experimental data. PMID- 29513912 TI - Meta-Analysis of the Association Between Autobiographical Memory Specificity and Exposure to Trauma. AB - Cognitive models of emotional disorders suggest that reduced autobiographical memory specificity that results from exposure to traumatic events may play an important role in the aetiology and maintenance of these disorders. However, there has yet to be a comprehensive meta-analysis of the association between trauma exposure and memory specificity, and the role of posttraumatic stress symptoms on this association. We searched PsycINFO and MEDLINE databases and extracted data from studies regarding the mean number or proportion of specific memories that participants with and without trauma exposure recalled on the Autobiographical Memory Test. We also extracted data on differences between groups in terms of posttraumatic stress and depressive symptoms, along with data on trauma timing and participants' ages at the time of assessment. The effect size of memory specificity between participants with and without exposure to trauma was large, d = 0.77, and differed significantly from zero, p < .001. In metaregression, trauma timing was a significant predictor of the heterogeneity in trauma-exposure specificity effect sizes, but posttraumatic stress and depressive symptoms were not. Compromised memory specificity represents an important cognitive consequence of trauma exposure that might have an important influence on risk for, and maintenance of, subsequent emotional pathologies. PMID- 29513913 TI - Erratum for "A Pilot Study of Tailored Cognitive-Behavioral Resilience Training for Trauma Survivors With Subthreshold Distress". PMID- 29513914 TI - Aftermath of Terror: A Nationwide Longitudinal Study of Posttraumatic Stress and Worry Across the Decade Following the September 11, 2001 Terrorist Attacks. AB - Research conducted in the early years after the September 11, 2001 (9/11) terrorist attacks in New York, Pennsylvania, and Washington, DC demonstrated adverse psychological outcomes among residents of the United States who were exposed to the attacks both directly and indirectly via the media. However, less is known about the impact of this collective trauma over time. Beginning at the end of December 2006, a longitudinal study of a nationally representative sample of U.S. residents (Cohort 2, N = 1,613) examined the long-term effects of 9/11, with annual assessments administered every year for 3 years. We assessed rates of 9/11-related posttraumatic stress (PTS) annually during the first 2 years of the study; during the second and third years of the study, we assessed fear and worry regarding future terrorism. Rates of PTS among participants were compared with those assessed annually in a nationally representative sample between 2002 and 2004 (Cohort 1); results indicated a relatively stable pattern of 9/11-related PTS symptoms for 6 years following the attacks. Five to six years after 9/11, we found an association between 9/11-related PTS and both direct, B = 8.45, 95% CI [4.32, 12.59] and media-based (live television), B = 1.78, 95% CI [0.90, 2.65] exposure to the attacks. Six to 7 years post-9/11, fear and worry regarding future terrorism were predicted by 9/11-related PTS symptoms that had been reported approximately 5 years after the attacks, B = 0.04, 95% CI [0.03, 0.05]. The psychological legacy of 9/11 was perceptible among many U.S. residents throughout the decade that followed. PMID- 29513915 TI - Negative Cognitions Prior to Trauma Predict Acute Posttraumatic Stress Disorder Symptomatology. AB - Based on emotional processing theory, preexisting negative cognitions may contribute to the development of posttraumatic stress disorder (PTSD) symptoms. The present study prospectively examined the association between preexisting PTSD related cognitions and subsequent acute PTSD symptoms, and the potential mediators of this association. We also compared the effect of preexisting depressive cognitions and preexisting PTSD-related cognitions on PTSD symptoms. In the current study, 810 Taiwanese undergraduates completed a baseline survey (T1), of which 73.1% (n = 592) participated in a second survey two months later (T2). Of those who completed both surveys, 97 experienced a trauma at least one week before T2; this group comprised the final sample. Hierarchical regression showed that preexisting PTSD-related cognitions (beta = .38, p < .001, sr2 = .117), but not preexisting depressive cognitions (beta = .11, p = .315, sr2 = .011), were a significant and substantial predictor of acute PTSD symptoms after we controlled for established pretrauma risk factors (i.e., gender, prior trauma, and prior psychological problems). Multiple mediation analysis revealed that negative appraisal of symptoms (a1 b1 = 0.90, 95% CI [0.16, 2.18], PM = .251) and trauma-related rumination (a3 b3 = 1.23, 95% CI [0.23, 2.86], PM = .341), but not trauma memory disorganization (a2 b2 = 0.65, 95% CI [-0.17, 1.92], PM = .182), significantly mediated between preexisting PTSD-related cognitions and acute PTSD symptoms. Our findings highlight the role of preexisting negative cognitions in acute PTSD symptomatology. The development of PTSD symptoms is likely determined by the interaction of risk factors before and after trauma. PMID- 29513916 TI - Symptoms of Posttraumatic Stress Rather Than Mild Traumatic Brain Injury Best Account for Altered Emotional Responses in Military Veterans. AB - Emotional dysfunction is evident in posttraumatic stress disorder (PTSD), yet it is unclear what aspects of the disorder most directly relate to aberrant emotional responding. Also, the frequent co-occurrence of blast-related mild traumatic brain injuries (mTBIs) among recently deployed U.S. military personnel complicates efforts to understand the basis for emotional disruption. We studied a cross-sectional sample (enriched for PTSD and mTBI) of 123 U.S. veterans of wars in Iraq and Afghanistan. We measured subjective affective evaluations and peripheral psychophysiological responses to images with pleasant, neutral, unpleasant, and combat-related aversive content. When compared with other postdeployment participants, those who had combat-related PTSD rated pleasant image content as less positive (etap2 = .04) and less arousing (etap2 = .06), and exhibited heightened physiological responsivity to combat image content (etap2 = .07). Symptoms of PTSD were associated with elevated skin conductance responses (beta = .28), reduced heart rate deceleration (beta = .44 to .47), and increased corrugator facial muscle electromyography (beta = .47). No effects for blast related mTBI were observed across any affective modulation measures. These findings point to a greater impact of PTSD symptomatology than blast-related mTBI on emotional functioning and highlight the utility of dimensional assessments of psychopathology for understanding the effects of combat-stress conditions on adjustment to civilian life. PMID- 29513917 TI - Erratum for "Intervention Effectiveness Among War-Affected Children: A Cluster Randomized Controlled Trial on Improving Mental Health". PMID- 29513918 TI - Posttraumatic Stress Disorder 23 Years After the 1988 Spitak Earthquake in Armenia. AB - This population-based longitudinal study examined the rates and predictors of posttraumatic stress disorder (PTSD) among 725 differentially exposed survivors of the 1988 Spitak earthquake in Armenia, 23 years after the event. Participants had been previously evaluated in 1991. Evaluations included assessment of current PTSD (based on DSM-5 criteria), and a variety of potential risk and protective factors. For the whole sample, the rate of PTSD attributed to the earthquake decreased from 48.7% in 1991 to 11.6% in 2012 (p < .001). A "dose of exposure" pattern persisted, and 15.7% of participants who were in Spitak (high exposure) and 6.6% of participants who were in Kirovagan (low exposure) during the earthquake met the criteria for PTSD (p = .003). Additionally, in 2012, another 9.9% of participants met PTSD criteria due to post-earthquake traumas, which is a 5-fold increase from pre- to postearthquake (p < . 001). Factors positively associated with PTSD included earthquake-related job loss, exposure to post earthquake traumas, depression at baseline, and chronic illness since the earthquake. Factors inversely associated with PTSD included housing assistance within two years after the earthquake, support of family and/or friends, and to a lesser degree, higher education and high living standard. These variables accounted for 23.1% of the variance in current PTSD severity scores. These findings indicate that PTSD rates subside significantly after a catastrophic disaster, although earthquake-related PTSD persists among a subgroup of exposed individuals. Predictors of PTSD identified in this study provide guidance for planning acute and longer-term postdisaster public mental health recovery programs. PMID- 29513919 TI - Prospective Examination of Early Associations of Iraq War Zone Deployment, Combat Severity, and Posttraumatic Stress Disorder with New Incident Medical Diagnoses. AB - War zone deployment and posttraumatic stress disorder (PTSD) have been associated with morbidity and mortality decades later. Less is known about the associations between these variables and the early emergence of medical disorders in war zone veterans. This prospective study of 862 U.S. Army soldiers (n = 569 deployed; n = 293 nondeployed) examined: (a) associations between Iraq War deployment status (deployed vs. nondeployed) and new medical diagnoses that emerged within six months after return from Iraq among all participants; and (b) associations between combat severity and PTSD symptoms, and new postdeployment medical diagnoses that emerged within 12 months after return from Iraq within deployed participants. New medical diagnoses were abstracted from diagnostic codes associated with clinical outpatient visits recorded within the Department of Defense Standard Ambulatory Data Record database. Combat severity was measured with the Combat Experiences module of the Deployment Risk and Resilience Inventory, and postdeployment posttraumatic stress disorder symptom severity was measured using the PTSD Checklist-Civilian. Neither deployment nor combat severity was associated with new medical diagnoses. However, among deployed soldiers, more severe PTSD symptoms were associated with increased risk for a new medical disorder diagnosis; every 10-point increase in PTSD symptoms increased odds of a new diagnosis by nearly 20% (odds ratio = 1.20). Results suggest that PTSD symptoms are associated with early morbidity in Iraq War veterans. PMID- 29513920 TI - Selective Aerobic Oxidation of 5-Hydroxymethylfurfural to 2,5-Diformylfuran or 2 Formyl-5-furancarboxylic Acid in Water by using MgO?CeO2 Mixed Oxides as Catalysts. AB - Mixed oxides based on MgO?CeO2 were used as efficient catalysts in the aerobic oxidation of 5-hydroxymethylfurfural (5-HMF) to afford, with very high selectivity, either 2,5-diformylfuran (DFF, 99 %) or 2-formyl-5-furancarboxylic acid (FFCA, 90 %), depending on the reaction conditions. 5-Hydroxymethyl-2 furancarboxylic acid (HMFCA, 57-90 %) was formed only at low concentration of 5 HMF (<0.03 m) or in presence of external bases. The conversion of 5-HMF ranged from a few percent to 99 %, according to the reaction conditions. The oxidation was performed in water, with O2 as oxidant, without any additives. The surface characterization of the catalysts gave important information about their acid base properties, which drive the selectivity of the reaction towards DFF. FFCA was formed from DFF at longer reaction times. Catalysts were studied by XPS and XRD before and after catalytic runs to identify the reason why they undergo reversible deactivation. XRD showed that MgO is hydrated to Mg(OH)2 , which, even if not leached out, changes the basic properties of the catalyst that becomes less active after some time. Calcination of the recovered catalyst allows recovery of its initial activity. The catalyst is thus recoverable (>99 %) and reusable. The use of mixed oxides allows tuning of the basicity of the catalysts, avoiding the need for external bases for efficient and selective conversion of 5 HMF and waste formation, resulting in an environmentally friendly, sustainable process. PMID- 29513921 TI - Ultrasonography and Power Doppler Studies in Chikungunya Disease: Comment on the Article by Chang et al. PMID- 29513922 TI - Reply. PMID- 29513923 TI - Reply. PMID- 29513924 TI - Magnetic Resonance Imaging of the Sacroiliac Joints Indicating Sacroiliitis According to the Assessment of SpondyloArthritis international Society Definition in Healthy Individuals, Runners, and Women With Postpartum Back Pain. AB - OBJECTIVE: To compare magnetic resonance images (MRIs) of the sacroiliac (SI) joints of healthy subjects and individuals with known mechanical strain acting upon the SI joints to those of patients with axial spondyloarthritis (SpA) and patients with chronic back pain. METHODS: Three readers who had received standardized training and were blinded with regard to study group randomly scored MRIs of the SI joints of 172 subjects, including 47 healthy individuals without current or past back pain, 47 axial SpA patients from the Spondyloarthritis Caught Early (SPACE) cohort (with a previous MRI confirmed positive for sacroiliitis), 47 controls with chronic back pain (irrespective of MRI results) from the SPACE cohort, 7 women with postpartum back pain, and 24 frequent runners. MRIs were scored according to the Assessment of SpondyloArthritis international Society (ASAS) definition and Spondyloarthritis Research Consortium of Canada (SPARCC) index. RESULTS: Of the 47 healthy volunteers, 11 (23.4%) had an MRI positive for sacroiliitis, compared to 43 (91.5%) of 47 axial SpA patients and 3 (6.4%) of 47 patients with chronic back pain. Three (12.5%) of the 24 runners and 4 (57.1%) of the 7 women with postpartum back pain had a positive MRI. Using a SPARCC cutoff of >=2 for positivity, 12 (25.5%) of 47 healthy volunteers, 46 (97.9%) of 47 positive axial SpA patients, 5 (10.6%) of 47 controls with chronic back pain, 4 (16.7%) of 24 runners, and 4 (57.1%) of 7 women with postpartum back pain had positive MRIs. Deep bone marrow edema (BME) lesions were not found in healthy volunteers, patients with chronic back pain, or runners, but were found in 42 (89.4%) of 47 positive axial SpA patients and in 1 (14.3%) of 7 women with postpartum back pain. CONCLUSION: A substantial proportion of healthy individuals without current or past back pain has an MRI positive for sacroiliitis according to the ASAS definition. Deep (extensive) BME lesions are almost exclusively found in axial SpA patients. PMID- 29513925 TI - What Imaging-Detected Pathologies Are Associated With Shoulder Symptoms and Their Persistence? A Systematic Literature Review. AB - OBJECTIVE: Shoulder symptoms are common, and imaging is being increasingly used to help with management. However, the relationship between imaging and symptoms remains unclear. This review aims to understand the relationship between imaging detected pathologies, symptoms, and their persistence. METHODS: A systematic review using Medline, EMBASE, Cochrane, and grey literature was conducted to April 2017. The cross-sectional and longitudinal relationships between imaging detected abnormalities and symptoms were analyzed and associations qualitatively characterized by a best-evidence synthesis based on study design, covariate adjustment, and the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Modalities included ultrasound, magnetic resonance imaging (MRI), radiographs, positron emission tomography (PET), bone scintigraphy, and computed tomography. RESULTS: A total of 6,569 abstracts was screened and 56 articles were included. In total, 50 studies did not adjust for covariates and 36 analyzed individual pathologies only. The majority of studies showed conflicting results. There was no significant association between most imaging features and symptoms among high-quality, cross-sectional studies. There was low-quality evidence that enhancement of the joint capsule on MRI and increased uptake on PET were associated with symptoms in adhesive capsulitis. Based on high-quality longitudinal studies, enlarging rotator cuff tears were associated with an increased incidence of symptoms. CONCLUSION: There were conflicting results on the association of imaging features with shoulder symptoms and their persistence. The existing evidence was very low in quality, based on the GRADE methodology. Further high-quality studies are required to understand the relationship between imaging and shoulder symptoms and to determine the appropriate role of imaging in care pathways. PMID- 29513926 TI - Blueprint for an intestinal villus: Species-specific assembly required. AB - Efficient absorption of nutrients by the intestine is essential for life. In mammals and birds, convolution of the intestinal surface into finger-like projections called villi is an important adaptation that ensures the massive surface area for nutrient contact that is required to meet metabolic demands. Each villus projection serves as a functional absorptive unit: it is covered by a simple columnar epithelium that is derived from endoderm and contains a mesodermally derived core with supporting vasculature, lacteals, enteric nerves, smooth muscle, fibroblasts, myofibroblasts, and immune cells. In cross section, the consistency of structure in the billions of individual villi of the adult intestine is strikingly beautiful. Villi are generated in fetal life, and work over several decades has revealed that villus morphogenesis requires substantial "crosstalk" between the endodermal and mesodermal tissue components, with soluble signals, cell-cell contacts, and mechanical forces providing specific dialects for sequential conversations that orchestrate villus assembly. A key part of this process is the formation of subepithelial mesenchymal cell clusters that act as signaling hubs, directing overlying epithelial cells to cease proliferation, thereby driving villus emergence and simultaneously determining the location of future stem cell compartments. Interestingly, distinct species-specific differences govern how and when tissue-shaping signals and forces generate mesenchymal clusters and control villus emergence. As the details of villus development become increasingly clear, the emerging picture highlights a sophisticated local self-assembled cascade that underlies the reproducible elaboration of a regularly patterned field of absorptive villus units. This article is categorized under: Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched Comparative Development and Evolution > Organ System Comparisons Between Species Early Embryonic Development > Development to the Basic Body Plan. PMID- 29513928 TI - The Caenorhabditis elegans Proteome Response to Naturally Associated Microbiome Members of the Genus Ochrobactrum. AB - The nematode Caenorhabditis elegans interacts with a variety of bacteria as it feeds on microbes, and a number of these both associate and persist within the worm's intestine. Host-microbe interactions in C. elegans have been analyzed primarily at the transcriptome level with the host response often been monitored after challenge with pathogens. We assessed the proteome of C. elegans after growth on bacteria capable of colonizing its gut, via a comparative analysis of the nematode exposed to two naturally associated Ochrobactrum spp. (MYb71, MYb237) versus C. elegans grown on Escherichia coli OP50. A total of 4677 C. elegans proteins were identified, 3941 quantified. Significant alterations in protein abundances were observed for 122 proteins, 48 higher and 74 lower in abundance. We observed an increase in abundance of proteins potentially regulated via host signaling pathways, in addition to proteins involved in processing of foreign entities (e.g., lipase, proteases, glutathione metabolism). Decreased in abundance were proteins involved in both degradation and biosynthesis of amino acids, and enzymes associated with the degradation of peptidoglycan (lysozymes). The protein level differences between C. elegans grown on native microbiome members compared to the laboratory food bacterium may help to identify molecular processes involved in host-microbe interactions. PMID- 29513927 TI - Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins. AB - Signal transduction cascades governed by kinases and GTPases are a critical component of the command and control of cellular processes, with the precise outcome partly determined by direct protein-protein interactions (PPIs). Here, we use the human ROCO proteins as a model for investigating PPI signaling events taking advantage of the unique dual kinase/GTPase activities and scaffolding properties of these multidomain proteins. PPI networks are reported that encompass the human ROCO proteins, developed using two complementary approaches. First, using the recently developed weighted PPI network analysis (WPPINA) pipeline, a confidence-weighted overview of validated ROCO protein interactors is obtained from peer-reviewed literature. Second, novel ROCO PPIs are assessed experimentally via protein microarray screens. The networks derived from these orthologous approaches are compared to identify common elements within the ROCO protein interactome; functional enrichment analysis of this common core of the network identified stress response and cell projection organization as shared functions within this protein family. Despite the presence of these commonalities, the results suggest that many unique interactors and therefore some specialized cellular roles have evolved for different members of the ROCO proteins. Overall, this multi-approach strategy to increase the resolution of protein interaction networks represents a prototype for the utility of PPI data integration in understanding signaling biology. PMID- 29513929 TI - Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells: A Novel Experimental Model of Rheumatoid Arthritis. AB - OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcgamma receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system. PMID- 29513930 TI - Reply. PMID- 29513931 TI - Brief Report: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis. AB - OBJECTIVE: To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. METHODS: In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to <=7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), >=1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a >=4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. CONCLUSION: AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE. PMID- 29513932 TI - Patient Perceptions of the Raynaud's Condition Score Diary Provide Insight Into Its Performance in Clinical Trials of Raynaud's Phenomenon: Comment on the Article by Denton et al. PMID- 29513933 TI - Gaining Insight Into Posttranslationally Modified HIV Antigens and Their Underlying Characteristics. AB - Mass spectrometry (MS)-based immunopeptidomics has developed as one of the leading methodologies for comprehensive characterization of in vivo presented human leukocyte antigen (HLA)-bound peptides. Unveiling the identity of HLA-bound peptides derived from diseased cells is crucial to gain knowledge on the constitution of efficient disease-specific T cell responses. The HLA-presented peptidome reflects the status of the cellular proteome, hence disease-related aberrations of posttranslational modifications (PTMs) might lead to presentation of peptides harboring PTMs. Therefore, characterization of HLA-bound PTM peptides could shed light on their relevance in immune and disease processes. In this issue, Ramarathinam et al. investigate the presentation of HIV envelope (HIVenv) peptides bound to the HLA-B*57:01 allele. Among these peptides, the authors specifically focused on a kynurenine-modified peptide. To this end, they characterize the possible origin of the kynurenine modification, its effect on HLA binding affinity, stability, conformation within the complex, and its immunogenicity compared to the native counterpart. PMID- 29513934 TI - Allopurinol Dose Escalation and Mortality Among Patients With Gout: A National Propensity-Matched Cohort Study. AB - OBJECTIVE: Observational data suggest that hyperuricemia and gout are associated with increased mortality, while allopurinol use is associated with reduced mortality. In addition, the protective effect of allopurinol may be dose dependent. The aim of the current study was to determine whether allopurinol dose escalation is associated with cause-specific mortality in patients with gout. METHODS: In this 10-year observational, active-comparator study of US Veterans with gout who initiated treatment with allopurinol, propensity score matching, Cox proportional hazards models, and competing risks regression analyses were used to assess differences in cause-specific mortality between patients whose allopurinol dose was escalated (dose escalators) and those whose allopurinol dose was not escalated or was reduced (non-escalators) over a 2-year period. RESULTS: Among the 6,428 dose escalators and 6,428 matched non-escalators, there were 2,867 deaths during the observation period (40.4 deaths per 1,000 person-years). Dose escalators experienced an increase in all-cause mortality (hazard ratio [HR] 1.08, 95% confidence interval [95% CI] 1.01-1.17), with the effect sizes being similar for incidence of cardiovascular-related deaths (HR 1.08, 95% CI 0.97 1.21) and cancer-related deaths (HR 1.06, 95% CI 0.88-1.27), although neither reached statistical significance. Dose escalation to achieve the goal of lowering the serum urate (SU) level to <6.0 mg/dl was infrequent. At 2 years, 10% of dose escalators were receiving a final daily dose of >300 mg and 31% had achieved the SU goal. In a sensitivity analysis limited to dose escalators achieving the SU goal, there was a nonsignificant reduction of 7% in the hazard of cardiovascular related mortality (HR 0.93, 95% CI 0.76-1.14). CONCLUSION: This is the largest study to date to investigate the effects of allopurinol use on mortality and is the first to use a rigorous active-comparator design. Dose escalation was associated with a small (<10%) increase in all-cause mortality, thus showing that a strategy of allopurinol dose escalation, which in current real-life practice is characterized by limited dose increases, is unlikely to improve the survival of patients with gout. PMID- 29513937 TI - Consideration of Antisynthetase Syndrome Features in Classifying Patients as Having Idiopathic Inflammatory Myopathy: Comment on the Article by Lundberg et al. PMID- 29513935 TI - Dysbiotic Subgingival Microbial Communities in Periodontally Healthy Patients With Rheumatoid Arthritis. AB - OBJECTIVE: Studies that demonstrate an association between rheumatoid arthritis (RA) and dysbiotic oral microbiomes are often confounded by the presence of extensive periodontitis in these individuals. This study was undertaken to investigate the role of RA in modulating the periodontal microbiome by comparing periodontally healthy individuals with RA to those without RA. METHODS: Subgingival plaque was collected from periodontally healthy individuals (22 with RA and 19 without RA), and the 16S gene was sequenced on an Illumina MiSeq platform. Bacterial biodiversity and co-occurrence patterns were examined using the QIIME and PhyloToAST pipelines. RESULTS: The subgingival microbiomes differed significantly between patients with RA and controls based on both community membership and the abundance of lineages, with 41.9% of the community differing in abundance and 19% in membership. In contrast to the sparse and predominantly congeneric co-occurrence networks seen in controls, RA patients revealed a highly connected grid containing a large intergeneric hub anchored by known periodontal pathogens. Predictive metagenomic analysis (PICRUSt) demonstrated that arachidonic acid and ester lipid metabolism pathways might partly explain the robustness of this clustering. As expected from a periodontally healthy cohort, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were not significantly different between groups; however, Cryptobacterium curtum, another organism capable of producing large amounts of citrulline, emerged as a robust discriminant of the microbiome in individuals with RA. CONCLUSION: Our data demonstrate that the oral microbiome in RA is enriched for inflammophilic and citrulline-producing organisms, which may play a role in the production of autoantigenic citrullinated peptides in RA. PMID- 29513936 TI - Identification of an Amino Acid Motif in HLA-DRbeta1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Uveitis is a visually debilitating disorder that affects up to 30% of children with the most common forms of juvenile idiopathic arthritis (JIA). The disease mechanisms predisposing only a subgroup of children to uveitis are unknown. This study was undertaken to identify genetic susceptibility loci for uveitis in JIA, using a genome-wide association study in 522 children with JIA. METHODS: Two cohorts of JIA patients with ophthalmologic follow-up data were genotyped. Data were then imputed using a genome-wide imputation reference panel, and an HLA-specific reference panel was used for imputing amino acids and HLA types in the major histocompatibility complex (MHC). After imputation, genome wide and MHC-specific analyses were performed, and a reverse immunology approach was utilized to model antigen presentation at 13 common HLA-DRbeta1 alleles. RESULTS: Presence of the amino acid serine at position 11 (serine 11) in HLA DRbeta1 was associated with an increased risk of uveitis in JIA patients (odds ratio [OR] 2.60, P = 5.43 * 10-10 ) and was specific to girls (Pfemales = 7.61 * 10-10 versus Pmales = 0.18). Serine 11 resides in the YST motif in the peptide binding groove of HLA-DRbeta1; all 3 amino acids in this motif are in perfect linkage disequilibrium and show identical association with disease. Quantitative prediction of binding affinity revealed that HLA-DRbeta1 alleles with the YST motif could be distinguished on the basis of discernable peptide-binding preferences. CONCLUSION: These findings highlight a genetically distinct, sexually dimorphic feature of JIA with uveitis as compared to JIA without uveitis. The association could be indicative of the potential involvement of antigen presentation by HLA-DRbeta1 in the development of uveitis in JIA. The results of this study may advance our progress toward improved treatments for, and possible prevention of, the sight-threatening complications of uveitis in children with JIA. PMID- 29513938 TI - Female Reproductive and Hormonal Factors and Incidence of Primary Total Knee Arthroplasty Due to Osteoarthritis. AB - OBJECTIVE: To examine the associations of female reproductive and hormonal factors with incidence of total knee arthroplasty (TKA) for osteoarthritis (OA), and to determine whether the associations differ according to overweight/obesity status. METHODS: This study included 22,289 women in the Melbourne Collaborative Cohort Study. Data on age at menarche, pregnancy, parity, years of menstruation, oral contraceptive (OC) use, menopausal status, and hormone replacement therapy (HRT) were collected in 1990-1994. Incidence of TKA during 2001-2013 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. All analyses were adjusted for age, body mass index (BMI) at midlife, change in BMI (from early reproductive age to midlife), country of birth, physical activity, smoking, and education level. RESULTS: Over the course of 12.7 years, 1,208 TKAs for OA were identified. Ever being pregnant was associated with increased risk of TKA (hazard ratio [HR] 1.32 [95% confidence interval (95% CI) 1.06-1.63]). Parity was positively associated with risk of TKA (P for trend = 0.003). OC users had increased risk of TKA compared with non-users (for OC use of <5 years, HR 1.25 [95% CI 1.08-1.45]; for OC use of >=5 years, HR 1.17 [95% CI 1.00-1.37]). A 1-year increase in menstruation was associated with a 1% decrease in risk of TKA (HR 0.99 [95% CI 0.97-0.99]). These associations remained significant only in women of normal weight at early reproductive age. Current HRT users had increased risk of TKA compared with non-users (HR 1.37 [95% CI 1.14-1.64]); the association was significant only in non-obese women at midlife. CONCLUSION: Reproductive and hormonal factors were associated with risk of knee OA. These associations remained significant in women of normal weight at early reproductive age and in non-obese women at midlife. Further work is needed to understand the complex effect of these factors on knee OA. PMID- 29513939 TI - Mind the Gap: Women and Acute Myocardial Infarctions-An Integrated Review of Literature. AB - Mortality rates of women suffering from an acute myocardial infarction (AMI) are high, and in young women are on the rise. The goal of this review is to investigate what is known about women's experience of AMI symptoms. By exploring the complexity and intersections evident in the literature though an integrative literature review process, it becomes apparent that the problem involves deeper contextual influences arisingfrom women's situation in society. Keyfindings in this review suggest that not recognizing the risk or symptoms of an AMI can lead to delayed health care seeking behaviours, and warrants the need for further education. Awareness of these findings has implications for women's health outcomes and mortality rates. This review adds value to clinical practice by reifying the potential gaps in knowledge currently available to women and health care providers, and suggests filling these gaps with new more inclusive ways of knowing surrounding this phenomenon. PMID- 29513940 TI - Easing the Economic Burden of Atrial Fibrillation: Making the Case for a Structured Clinical Nurse Specialist-Led Outpatient Clinic. AB - As the life expectancy of Canadians continues to increase, so does the economic burden of chronic conditions within the health care system. One chronic condition that has increased over the past decade is atrialfibrillation (AF). With health care costs forAF estimated at more than $800 million and rising, a new approach is needed to manage AF care to reduce hospitalizations and emergency room visits, while improving patients' quality of life. Multidisciplinary outpatient clinics for heart failure patients have been implemented across Canada over the past decade, and have shown a reduction in hospital admissions and emergency room visits. It is probable that the same benefit could be seen with the implementation of a structured, nurse-led outpatient AF clinic. The purpose of this article is to review the existing literature on AF outpatient management, and establish the best approachfor a clinical nurse specialist-led AF outpatient clinic within the Canadian health care system. PMID- 29513941 TI - Augmentation Index and Pulse Wave Velocity--Agreement of Two Indicators and Relationships to Blood Pressures. AB - AIMS: The purpose of the study was to investigate the agreement between carotid femoral pulse wave velocity (cfPWV) and augmentation index adjusted at heart rate 75 bpm (AI@75) and to examine the relationship of AI@75 and cfPVW to demographic factors and blood pressures (BPs) in Korean Americans. METHODS: This study was a secondary analysis of a previous data setfrom 102 Korean Americans. AI@75 and cfPWV were measured using the SphygmoCor equipment. Age, gender, height, body weight and brachial BPs were included in the analysis. RESULT AND CONCLUSION: cfPWV and AI@7S showed a good agreement. DBP was independently associated with both cfPWV (p=.022) and AI@75 (p<.001). Although PP is considered a surrogate measure of arterial stiffness, it was related to neither cfPWV nor AI@75 in our healthy middle-aged Korean Ameri- cans. Unlike cfPWV, AI@75 should be measured and analyzed carefully considering height since height was independently related to AI@75 (p<.001). PMID- 29513942 TI - PLANTAGO OVATA: A COMPREHENSIVE REVIEW ON CULTIVATION, BIOCHEMICAL, PHARMACEUTICAL AND PHARMACOLOGICAL ASPECTS. AB - The basic aspire of current study was to review different aspects of Plantago ovata together with its cultivation, growth, biochemistry, pharmaceutical and pharmacological attributes. Plantago ovata belongs to family Plantaginaceae. It is an annual herb, indigenous to Mediterranean region especially Southern Europe, North Africa and West Asia. Different electronic databases (Medline, Science Direct, Springer link, Pubmed, Google and Google Scholar) were analyzed for the literature on medicinal properties of Plantago ovata. The literature analysis has revealed that Plantago ovata has been endowed with diverse pharmaceutical and pharmacological activities. It is widely used in numerous medicines owing to its both pharmaceutical properties such as mucilage, superdisintegrant, gelling agent, suspending agent as well as pharmacological actions like anti-diarrheal, anti-constipation, wound healer, hypocholestrolemic and hypoglycemic. Thus, Plantago ovata can be employed in the manufacture of a number of pharmaceutical products as well as a safe and efficacious ethnobotanical remedy in several health problems. PMID- 29513943 TI - A CRITICAL REVIEW ON PHARMACOLOGICAL SIGNIFICANCE OF HYDROGEN SULFIDE (H2S) ON NF kappaB CONCENTRATION AND ICAM-1 EXPRESSION IN RENAL ISCHEMIA REPERFUSION INJURY. AB - Until recently hydrogen sulfide (H2S) was the least appreciated of the three gasotransmitters but now recognized as 3Y gaseous mediator after nitric oxide(NO) and carbon monoxide (CO). H2S regulates a number of physiological processes like vasorelaxation, prevention of inflammation, leukocyte adhesion, anti-prolifera- tive effects, anti-thrombotic effects, resistance to oxidative stress and protection against ischemia reperfusion injury (IRI). However, considerable amount of research is still needed to evaluate the mechanisms involved in the therapeutic effects of H2S in IRI such as its effects on nuclear factor-kappa B (NF-KB) concentration and intercellular adhesion molecule-1 (ICAM-1) expression in renal IRI and ARF (acute renal failure). More than a decade of good repute among researchers, H2S research has certain results that need to be clarified more such as whether H2S is pro-inflammatory or anti-inflammatory agent. Moreover, pathways adopted by H2S in the protein modification and its effects on cell signalling specially its effect on NF-KB in the process of inflamma- tion are not fully elucidated. H2S has delighted researchers and a great deal of information is being generated every year.The main purpose of the review is to provide an update on the development in the research of H2S in renal IRI due to uncertainty of the exact role of H2S on ICAM-1 expression and NF-KB concentration whether it inhibits or activates them. PMID- 29513944 TI - PRINTING TECHNIQUES: RECENT DEVELOPMENTS IN PHARMACEUTICAL TECHNOLOGY. AB - In the last few years there has been a huge progress in a development of printing techniques and their application in pharmaceutical sciences and particularly in the pharmaceutical technology. The variety of printing methods makes it necessary to systemize them, explain the principles of operation, and specify the possibilities of their use in pharmaceutical technology. This paper aims to review the printing techniques used in a drug development process. The growing interest in 2D and 3D printing methods results in continuously increasing number of scientific papers. Introduction of the first printed drug Spritam@ to the market seems to be a milestone of the 3D printing development. Thus, a particular aim of this review is to show the latest achievements of the researchers in the field of the printing medicines. PMID- 29513945 TI - DETERMINATION OF VENLAFAXINE, VILAZODONE AND THEIR MAIN ACTIVE METABOLITES IN HUMAN SERUM BY HPLC-DAD AND HPLC-MS. AB - A high performance liquid chromatography (HPLC) method for simultaneous analysis of venlafaxine and its major metabolite 0-desmethylvenlafaxine and vilazodone and its methabolite M10 have been devel- oped and validated. Chromatography was performed on the Phenyl-Hexyl column with mobile phase containing methanol, acetate buffer at pH 3.5 and diethylamine. The application of stationary phase with 7r-7c moieties and mobile phase containing diethylamine as silanol blocker lets to obtain double protection against silanols and thus very high theoretical plate numbers were obtained. The good separation selectivity, good peaks' symmetry and very high systems efficiency for all investigated compounds were obtained in applied chromatographic system. The method is very efficient and suitable for the analysis of investigated drugs and their metabolites in human serum for patients' pharmacotherapy control. PMID- 29513946 TI - HPLC METHOD FOR SEPARATING ENANTIOMERS OF IMIDAZOLE DERIVATIVES - ANTIFUNGAL COMPOUNDS. AB - The aim of this study was to test separation possibility of enantiomers of nine active substances belonging to imidazole derivatives: bifonazole, butoconazole, econazole, enilconazole, fenticonazole, isoconazole, miconazole, sertaconazole and tioconazole. The study was performed using HPLC method and the CHI- RALCEL OJ column (10 gm; 250 x 4.6 mm), the mobile phase flow rate of 0.8 mL/min and detection at 220 rim. Mobile phases containing hexane and the following modifiers: alcohols (2-propanol, ethanol, methanol) and diethylamine were tested. At first isocratic elution was used but some enantiomers eluted after a long retention time and their peaks were asymmetrical and too wide. Therefore, a gradient elution was developed allow- ing to obtain satisfactory retention times and other parameters of enentioseparation of the compounds. PMID- 29513947 TI - THE ESTROGENS / CHROMIUM INTERACTION IN THE NITRIC OXIDE GENERATION. AB - The interaction of estrogens with environmental toxins in free radicals generation: reactive oxygen species (ROS) or reactive nitrogen species (RNS) which participates in cancerogenesis is not yet recognized. Chromium(VI) is widely present in environment. One of its toxicity pathway is free radicals generation. Estrogens have the ability to scavenge free radicals, but may also act as prooxidants. Both chromium(VI) and estrogens are classified by International Agency for Research on Cancer (IARC) as carcinogens, so synergistic effect seems very dangerous. The interaction of chromium and estrogens in ROS generation are partly described but there are no reports on estrogen/chromium interaction on nitric oxide (NO) generation. The aim of the study was to examine the interaction of chromium(VI) and 17-p-estradiol (E2) on NO level in human blood as well as the role of E2 metabolites: 4-hydroxyestradiol (4-OHE2) and 16a hydroxyestrone (16alpha-OHE1) in these processes. The NO level was estimated with the diagnostic kit (Nitric Oxide Colorimetric Detection Kit from Arbor Assays) in human blood in vitm. The results showed that Cr(VI) in used concentration (0.5; 1.0 and 5.0 gg/mL) decreases significantly NO level in blood, acting antagonistically to E2 and 4-OHE2. Estrogens (E2, 4-OHE2 and 16alpha-OHEI) do not protect against inhibiting effect of Cr(VI) on nitric oxide generation in blood because after combined exposure the decreased production of NO in blood was noted. In conclusion, presented results provide the information about the character of estrogen/Cr(VI) interaction in NO level in human blood. It is important knowledge for cardio protected effect e.g., hormone replacement therapy in environmental or occupational exposure to Cr(VI), chromium supplementation, also important for cancer risk evaluation. PMID- 29513948 TI - EVALUATION OF IN VITRO TIGECYCLINE ACTIVITY AGAINST MULTIDRUG-RESISTANT ACINETOBACTER BAUMANNII CLINICAL ISOLATES FROM POLAND. AB - Acinetobacter baumannii is a major cause of nosocomial infections worldwide. Therapeutic options in management of this bacteria are limited. Tigecycline is considered as an alternative treatment of infections caused by multidrug resistant A. baumannii strains, however this resistance has emerged recently. Another growing problem is a lack of international consensus between U.S. FDA and EUCAST recommendations, regarding tigecycline breakpoints for Acinetobacter spp., and frequently off-label use. The aim of the present study was to assess the in vitm susceptibility to tigecycline and other antimicrobials, routinely used in the treatment of infections, among 155 A. baumannii isolates, collected between 2008-2013 from a hospital in Poland. The most active agent against the tested MDR strains was colistin (99.3% susceptible isolates). Our study has shown a low efficiency of tigecycline, with 74.2% of non-susceptible strains (according to the U.S. FDA guidelines). Tigecycline MIC values ranged from 0.125 to 48 mg/L. The MIC50 and MIC90 were 3 and 8 mg/L, respectively, and 25.8% (40) of the isolates displayed MIC = 2 mg/L. The highest percentage of tigecycline-resistant strains were noted in 2010 (56.3%). Our study revealed remarkably high tigecycline non-susceptibili- ty rates among MDR A. baumannii isolates, therefore this antimicrobial should be administered with caution. PMID- 29513949 TI - IN VITRO EVALUATION OF BIOLOGICAL ACTIVITY OF CINNAMIC, CAFFEIC, FERULIC AND CHLOROGENIC ACIDS WITH USE OF ESCHERICHIA COLI K-12 RECA::GFP BIOSENSOR STRAIN. AB - Cinnamic acid and its derivatives are important and promising compounds in cancer therapy, because of its broad spectrum of anicancer and antioxidative ability, and with high potential for development into new generation drugs. The aim of this study was to compare the cyto- and genotoxic effects of cinnamic acid and its derivatives with the use of4Escherichia coli K-12 recA::gfp microbial biosensor strain with plasmid fusion of recA promoter and gfp gene as reporter. Obtained results indicate that recA::gfpmut2 genetic system was a sensitive biosensor to the most chemicals tested in our experiments. The cinnamic acid and its derivatives modulated the reactivity of wcA promoter in relation to control sample and significantly inhibited bacteria cells growth. In the light of our results only chlorogenic and ferulic acids at higher concentrations demonstrated cyto and genotoxic activity toward to E. coli K-12 mcA::gfp cells. PMID- 29513950 TI - MONITORING OF SYNERGISTIC ENHANCEMENT OF CAFFEIC ACID ON ESCHERICHIA COLI K-12 RECA::GFP STRAIN TREATED WITH DACARBAZINE. AB - Caffeic acid and its derivatives because of its biological activities, including antioxidants, antithrombosis, antihypertensive, antifibrosis, antiviral, and anti tumor properties are good candidates as adjuvants in anticancer therapy. The aim of this study was the examination of cyto- and genotoxic effect of caffeic acid on Escherichia coli K-12 recA::gfp strain treated with dacarbazine. Obtained results indicate that dacarbazine and caffeic acid influenced the reactivity of recA promoter and modulate the level of gfp expression in genetic construct rrcA::gfpmut2 in E. coli K-12. Simultaneuos administration of dacarbazine with caffeic acid caused the stronger inhibition of the bacteria growth than the dacarbazine and caffeic acid separated administration to bacteria cells. The simultaneous effect of the both tested chemicals - dacarbazine and caffeic acid indicated (cytostatic effect) anticancer activity in relation to bacteria cells. It suggests, that combination of known anticancer drug - dacarbazine w ith caffeic acid exerted synergistic cytotoxic and genotoxic effects toward E. coli K 12 cells and indicated the possibility of usefulness of caffeic acid as a natural adjuvant in anticancer therapy. PMID- 29513952 TI - HYBRIDS OF OLEANOLIC ACID WITH NORBORNENE-2,3-DICARBOXIMIDE-N- CARBOXYLIC ACIDS AS POTENTIAL ANTICANCER AGENTS. AB - The synthesis and cytotoxic activity of new oleanolic acid derivatives (8a-c and 9a-c) are presented. The obtained compounds are hybrids of oleanolic acid oximes and carboxylic acids containing short alkyl chains linked with nitrogen atom of norbomene-2,3-dicarboximide moieties via the nitrogen atom. The structures of the obtained new compounds (8a-c and 9a-c) were confinmed by spectral data. The derivatives 8a-c and 9a-c were subjected to the MTT assay in order to evaluate their cytotoxic activity towards HeLa, KB, MCF-7, HepG2 and HDF cell lines in comparison to mother compound (oleanolic acid, 1). Among the tested oximes acylated with carboxylic acids containing norbomene-imide moieties, the derivative 8b, with a propionoxyimino linker, exhibited the most advantageous level of cytotoxicity, with IC50 values from 2.75 pM (for MCF-7 cells) to 4.36 pM (for HDF cells). PMID- 29513951 TI - XYLITOL IMPROVES ANTI-OXIDATIVE DEFENSE SYSTEM IN SERUM, LIVER, HEART, KIDNEY AND PANCREAS OF NORMAL AND TYPE 2 DIABETES MODEL OF RATS. AB - The present study investigated the anti-oxidative effects of xylitol both in vitro and in vivo in normal and type 2 diabetes (T2D) rat model. Free radical scavenging and ferric reducing potentials of different concentrations of xylitol were investigated in vitro. For in vivo study, six weeks old male Sprague-Dawley rats were divided into four groups, namely: Normal Control (NC), Diabetic Control (DBC), Normal Xylitol (NXYL) and Diabetic Xylitol (DXYL). T2D was induced in the DBC and DXYL groups. After the confirmation of diabetes, a 10% xylitol solution was supplied instead of drinking water to NXYL and DXYL, while normal drinking water was supplied to NC and DBC ad libitum. After five weeks intervention period, the animals were sacri- ficed and thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) concentrations as well as superoxide dismutase, catalase glutathione reductase and glutathione peroxidase activities were determined in the liver, heart, kidney, pancreatic tissues and serum samples. Xylitol exhibited significant (p < 0.05) in vitro nitric oxide and hydroxyl radical scavenging and ferric reducing activities. In vivo study revealed significant (p < 0.05) reduction in TBARS concentrations in the xylitol consuming groups compared to their respective controls. Significant (p < 0.05) increase in GSH levels and antioxidant enzyme activities were observed in analyzed tissues and serum of xylitol-fed animals compared to their respective controls. Results of this study indicate that xylitol has strong anti-oxidative potential against T2D-associated oxidative stress. Hence, xylitol can be used as a potential supplement in diabetic foods and food products. PMID- 29513953 TI - SYNTHESIS AND IN VITRO BIOLOGICAL EVALUATION OF NEW TETRACYCLIC PYRIDOTHIENOQUINOLINES AS POTENTIAL ANTIMICROBIAL AGENTS. AB - Synthesis of a series of novel 10-substituted-pyrido[3',2':4,5]thieno[3,2-b] quinoline derivatives 3-15, which contain a planar tetracyclic heteroring system, has been accomplished. The synthetic approaches for the target compounds included, condensation reaction of 10-amino derivatives 2 with triethyl orthoformate to give ethyl N-formimidate derivatives 3, which in turn reacted with different amines to give N-substituted formimidamide derivatives 4a,b. In addition, N-mustard derivative 6 was synthesized via treatment of 2,2'- azanediylbis(ethan-1-ol) derivative 5 with thionyl chloride. Meanwhile, the amino derivative 2 reacted with ethyl chloroacetate to give ethyl aminoacetae derivative 7, then the latter reacted with chlorosulfonyl isocyanate to produce sulfamoyl chloride derivative 8. On the other hand, the ester derivative-7 condensed with hydrazine hydrate to give acetohydrazide derivative 10, which utilized as a key intermediate for the synthesis of new compounds (11-15) conjugated with a variety of bioactive heterocyclic moieties at position-10. Antimicrobial evaluation for all the synthesized compounds, against Gram-positive bacteria; Gram-negative bacteria; and pathogenic fungi strains, showed that the majority of these compounds have potent antibacterial and antifungal activity compared with the standard drugs. PMID- 29513954 TI - SYNTHESIS AND BIOLOGICAL EVALUATION OF SULFONAMIDE DERIVATIVES AS ANTIMICROBIAL AGENTS. AB - The present study investigates, the synthesis of new derivatives of benzenesulfonamide nucleus hybridized with various substituted pyrazole 4, 8 and thiazole ring 6 using 4-amino-N-butylbenzenesulfonamide 1 as the key starting compound. Furthermore, 3,5-diaminopyrazole derivative 10 was allowed to react with different reagents such as an active methylene compounds, ketone dithioacetal, ethoxymethylene malononitrile and cyanoguanidine for a preparation of new benzenesulfonamide derivatives 11-18 conjugated with different substituted hetero-bicyclic ring systems. In vitm-antimicrobial evaluation was performed for most of the newly synthesized compounds using ciprofloxacin and Fluconazole as antibacterial and antifungal standard drugs, respectively The most promising dual antibacterial and antifungal potency was gained by the sulfamoylphenyl butenoic acid derivative 7, followed by the sulfamoylphenyl-2-chloroacetamide 5 and its heterocyclic pyrazolopyrimidine derivative 16. Further development and structural optimization will be carried out to get new more potent and safer antimicrobials. PMID- 29513956 TI - SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL SCREENING OF DIANDRINE A. AB - Synthesis of a proline-rich cyclic hexapeptide - diandrine A [VI] was accomplished by coupling of tetrapeptide unit Boc-Gly-Pro-Trp-Pro-OH with dipeptide unit Tyr-Phe-OMe followed by cyclization of linear peptide unit [V] under alkaline condition. Structure of newly synthesized cyclopolypeptide was elucidated by means of spectral techniques including FTIR, 'H NMR, "C NMR, MS analyses. VI was subjected to pharmacological screening and found to exhibit good antifungal activity against dermatophytes. Further, VI possessed potent antihelmintic activity against earthworms M. konkanensis, P. corthruses and Eudrilus sp. PMID- 29513955 TI - NEW PYRIDINE AND TRIAZOLOPYRIDINE DERIVATIVES: SYNTHESIS, ANTIMICROBIAL AND ANTIOXIDANT EVALUATION. AB - A novel series of pyridine and triazolopyridine derivatives have been synthesized (1-17) and characterized on the basis of their elemental analyses and spectral data. In vitro antibacterial, antifungal and antioxidant evaluation were carried out for most of the new products. Compounds 3, 5b, 6c, 6d and 13 showed promising growth inhibition against Candida albicans and Aspergillus niger comparable to fluconazole as a reference antifungal drug. Furthermore, the derivatives 5d, 6c, 6d and 9 showed higher scavenging activity (99.4, 97.2, 94.8 and 90%) than that of ascorbic acid (86.4%) towards the DPPH radicals. PMID- 29513957 TI - RESEARCH ON EXTRACTION TECHNOLOGY, ANTIBACTERIAL AND ANTIOXIDANT ACTIVITY OF ETHANOL EXTRACT FROM LEAVES OF ABUTILON THEOPHRASTI MEDIC. AB - This paper described the extraction procedure and determination method for the total flavonoids in ethanol extract from the leaves of Abutilon theophrasti Medic., and evaluated antibacterial and antioxidant activity. Maximum extraction yield was achieved using 60% ethanol, 1 : 30 (g/mL) of a ratio of material to solvent, 20 min of extraction time, 40 kHz of ultrasonic frequency, 100 W of ultrasonic power, 600C of extraction temperature and two extraction cycles. Total flavonoids content was 16.79 RE mg/g medicinal materials. The extracts had effective antibacterial activity against 24 test strains from S. aureus and E. coli, MICs ranged from 2.18 to 8.7 mg/mL; it was also revealed that the extracts demonstrated high flavonids content and potent antioxidant activity, achieved by hydroxyl radical, DPPH radical and ABTS radical scavenging. These results indicated thathe extract may be a promising plant demonstrating antibacterial and antioxidant activities. PMID- 29513958 TI - ACETYL CHOLINESTERASE AND BUTYRYL CHOLINESTERASE INhIBITORY ACTIVITIES OF ZALEYA PENTANDRA. AB - The aim of this study was to reveal acetyl cholinesterase (AchE) and butyryl cholinesterase (BchE) inhibitory activities of Zaleya pentandra. The aerial parts of the plant were air, freeze-dried and powdered. The extraction was carried out with methanol at room temperature for 24 h. The extract was concentrated on rotavapor and fractioned by column chromatography. The isolation and purification afforded amorphous solid which was subjected to physical, chemical and spectroscopic techniques i.e., UV, IR, H-NMR, "C-NMR and HREI-MS for the structure elucidation of the isolated compound. The compound was concluded as "Pentandradione" a novel compound. AchE and BchE inhibitory activities were estimated. The result showed that the isolated extract possessed significant activity against butyryl cholinesterase as compared to standard eserine while the extract lacks acetyl cholinesterase inhibitory activity. PMID- 29513959 TI - MICROTOX TEST AS A TOOL TO ASSESS ANTIMICROBIAL PROPERTIES OF HERBAL INFUSIONS USED IN URINARY TRACT INFECTIONS. AB - Herbs can be used preventatively, to aid treatment and to ease the symptoms of urinary tract infections (UTIs). Traditional medicine uses herbal infusions such as: lingonberry leaf (Vitis idaeae folium), birch leaf (Betulaefolium) wild thyme extract (Serpylli herba), dwarf everlast flower (Helichrysi inflorescentia), goldenrod (Virgauneae herba, also called Solidaginis herba), restharrow root (Ononidis radix), agrimony (Agrimoniae herba), rowanberry (Sorbi aucupariae fructus), black elderberry (Sambuci fructus), and juniper berry (Juniperifrictus). This study examined which of the herbal infusions used in treatment and reduction of symptoms of UTIs have the greatest efficacy, and at which concentration levels (5.85 mg/mL; 0.59 mg/mL; 0.29 mg/mL). The results obtained suggest that the Microtox test can be successfully used to assess the healing properties of herbal infusions. The results of the experiments carried out using the Microtox test show that both in preventative medicine, as well as in aiding treatment of UTIs, the biggest benefit is brought by herbal infusions of wild thyme extract and birch leaf (at all concentrations), and also by infusions at higher concentrations (approx. 5.85 mg/mL) of agrimony, dwarf everlast flower, lingonberry leaf, artichoke herb, goldenrod, and juniper berry. PMID- 29513960 TI - EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF MELILOTUS OFFICINALIS L. AGAINST PARACETAMOL AND CARBON TETRACHLORIDE INDUCED HEPATIC INJURY IN MICE. AB - Hepatic diseases are becoming common day by day and pose serious health threats to the life of humans. In order to treat these diseases, the attention of man is diverting towards herbal drugs, which are much safer and cost effective than synthetic drugs. The aim of present study was to investigate hepatoprotective activity of methanolic extract of Melilomus officinalis against paracetamol and carbon tetrachloride induced hepatic damage. Melilotus officinalis at selected oral doses of 50 mg/kg and 100 mg/kg showed significant hepatoprotective effects by decreasing the levels of serum marker enzymes such as total bilirubin, SGOT, SGPT, ALP, albumin and total protein, when compared with standard drug (silymarin) and negative control. Similarly, histopathological studies also supported biochemical estimations. It was concluded that extract of Melilotus officinali has strong hepatoprotective activity against paracetamol and carbon tetrachloride induced hepatotoxicity, which might be due to free radical scavenging mechanisms exhibited by flavonoids and phenolics, thus affirming its traditional therapeutic role in liver injury. PMID- 29513961 TI - NEUROPROTECTIVE EFFECT OF BOSWELLIA SERRATA AND ITS ACTIVE CONSTITUENT ACETYL 11 KETO-beta-BOSWELLIC ACID AGAINST OXYGEN-GLUCOSE-SERUM DEPRIVATION-INDUCED CELL INJURY. AB - Oxidative stress plays a key role in pathophysiology of brain ischemia. This study aimed to test whether B. serrata hydroalcoholic extract (BSE) and its active constituent 3-acetyl-1 1-keto-beta-boswellic acid (AKBA) could protect neurons against ischemic condition induced by oxygen, glucose and serum deprivation (OGSD). First, PC12 neural cells were incubated with BSE (0-400 pg/mL) or AKBA (0-40 pg/mL) for 24 h to find non-cytotoxic concentrations of BSE and AKBA. Then, the cells were pre- (for 2 h) and co-treated with 1.5-6 MUg/mL BSE or 0.5-2.5 pg/mL AKBA, and then exposed to OGSD condition for 6 h. The IC50. values of BSE and AKBA were 95 and 12.2 MUg/mL, respectively. BSE (3 and 6 pg/mL) and AKBA (1 and 2.5 pg/mL) significantly increased viability of ischemic cells, in a concertation-dependent manner. The levels of intracellular oxygen free radicals, lipid peroxidation and oxidative DNA damage were also significantly and concentration-dependently decreased following treatment of ischemic cells with BSE or AKBA. Using HPLC analysis, the mount of AKBA in a sample of BSE was found to be 9.2%. In conclusion, B. sernata and AKBA reduce neuronal cell death induced by OGSD and this neuroprotective effect is mediated via attenuation of oxidative stress. PMID- 29513962 TI - THE USE OF EXTRACTS FROM PASSIFLORA SPP. IN HELPING THE TREATMENT OF ACANTHAMOEBIASIS. AB - Chronic progressive diseases of the central nervous system such as granulomatous amoebic encephalitis, amoebic keratitis, amoebic pneumonitis and also skin infections caused by free-living amoebae (Acanhamoeba spp.) are a significant challenge for pharmacotherapy. This is due to the lack of effective treatment because of encystation, which makes the amoebae highly resistant to anti-amoebic drugs. A very inter- esting and promising source of future drugs in this area are plant materials obtained not only from the habitat but also from plant in vitro culture as an alternative source of biomaterials. Alcoholic extracts from leaves of Passiflora incarnata, P. caerulea, P. alata (Passifloraceae) and from callus cultures were evaluated in vito for amoebicidal activity. Phytochemical analysis showed that all extracts contained phenolic compounds including flavonoids? Biological study revealed that all extracts showed amoebostatic and amoebicidal properties in concentrations from 4 to 12 mg/mL. Extracts of P. alata leaf and callus showed the most effective activities (IC5, 4.01 mg/mL, IC,5 7.29 mg/mL, respectively) after 48 h of exposure, which was correlated with the highest concentration of total phenolics and flavonoids in comparison with other extracts. PMID- 29513963 TI - THE EFFECT OF TOTAL AND PARTIAL NEPHRECTOMY ON THE PHARMACOKINETICS OF INTRAVENOUS PARACETAMOL IN HUMANS. AB - Paracetamol is one of the most common analgesic and antipyretic drugs. Recently intravenous paracetamol has been widely used to treat moderate postoperative pain. Surgery is the main method of treatment of renal cancer. Total or partial nephrectomy can be performed, depending on the size and location of the tumor. Pharmacokinetics of drugs may depend on the type of surgery. The aim of the study was to compare the postinfusion pharmacokinetics of paracetamol in patients after total nephrectomy (TN) and nephron sparing surgery (NSS).The research was carried out on two groups of patients after nephrectomy: total (TN n = 37; mean [SD], age, 60.4 [10.9] years; BMI, 26.5 [3.8] kg/m2; creatinine clearance, Cl, 80.9 [37.1] mL/min) and nephron sparing surgery (NSS n = 17; 57.9 [16.5] years; BMI, 29.5 [5.3] kg/m2; Cl, 97.6 [27.8] mL/min). The patients were treated with paracetamol (PerfalganO Bristol-Myers Squibb) at an intravenous dose of 1.000 mg, which was infused for 15 minutes after surgery. The concentrations of paracetamol in the patients' plasma were determined by the HPLC method with UV detection (X = 261 run). The main pharmacokinetic parameters of paracetamol in the TN vs. NSS group were as follows: C.. 29.08 [17.39] vs. 27.54 [15.70] pg/mL (p = 0.6692); AUC5, 29.24 [13.86] vs. 34.85 [14.28] pg.h/mL (p = 0.2896); AUMC5,,,, 47.58 [26.08] vs. 62.02 [27.64] pg-h/mL (p = 0.1345); to. 2.34 [0.96] vs. 1.93 [0.50] h (p = 0.1415), respectively. In both groups the exposure to paracetamol was comparable. The t1/2 after nephron sparing surgery was shorter than after total nephrectomy. Therefore, these patients may demand more frequent drug administration. In the NSS group the C. of the analgesic was considerably reduced in men. PMID- 29513964 TI - EVALUATION OF ACRYLATES/C10-30 ALKYL ACRYLATE CROSS- POLYMER MIXTURE EFFECTIVENESS ON O/W TYPE EMULSION FORMULATION. AB - Acrylates/C1O-30 alkyl acrylate cross-polymer mixtures were used in order to prepare stable and oil-in-water (o/w) pharmaceutical emulsions of organic oils. The resulting o/w pre-emulsions, prepared with different alkyl acrylate cross polymers were unequally stable. We observed a synergistic effect when a polymer mixture was used and-the resulting pre-emulsions were more stable for significant duration. The observed effect is confirmed by, statistical analysis, the feature is remarkably important when we look for more stable pharmaceutical emulsions formed with less additives. PMID- 29513965 TI - FORMULATION AND STABILITY EVALUATION OF BAUHINIA VARIEGATA EXTRACT TOPICAL EMULSION. AB - This study presents the results for the development of water in oil (W/O) emulsion containing 2 % Bauhinia variegata (BV) extract with good antioxidant potential for cosmetic application. Different ratios of surfactant, oil and water were investigated to optimize the ratio of ingredients. It was found that emulsifier and oil4ratio were important in improving the stability of emulsion. The formulation having 2.5% Abil EM90, 12% liquid paraffin, 83.5% distilled water and 2% BV extract was found to be most stable. Stability of the formulation was further evaluated by characterizing for organoleptic, sedimentation, microscopic and rheological properties at a range of storage conditions for a period of 12 weeks. Experimental findings showed stable formulation behavior with respect to color change, liquefaction and phase separation. Centrifugation test was carried out to predict the long term stability..The rheological parameters were evaluated from Power Law and the flow index value less than 1 suggested non-Newtonian behavior of the W/O emulsion. The mean droplet size of the internal phase of freshly prepared formulation was 4.06 ? 1.99 pm that did not change significantly (p > 0.05) during the storage. The newly developed formulation exhibited promising attributes over long term storage and open opportunities for the topical delivery of natural antioxidants for cosmetic and pharmaceutical objectives. PMID- 29513966 TI - STUDY OF OFLOXACIN ENANTIOMERS DISSOLUTION FROM SELECTED SOLID DOSAGE FORMS USING HIGH PERFORMANCE CAPILLARY ELECTROPHORESIS METHOD. AB - The commercially available coated tablets containing either racemic form of ofloxacin (Tarivid 200 mg, OfloHexal 200 mg and Ofloxacin-Ratiopharm 200 mg) or only levofloxacin S-(-)-isomer (Tavanic 250 mg) were examined. The aim of our study was to establish the kinetics of dissolution rate process of ofloxacin optical isomers (S-(-) and R-(+)-ofloxacin) from solid oral dosage forms using flow-through cell method (USP 4 method). The concentrations of analytes (racemic ofloxacin and its enantiomers) in the samples of tablet extracts as well as in dissolution media (0.1 M/L HCl and phosphate buffer pH 6.8) were determined by validated high performance capillary electrophoresis method. The fraction of the average dose of the individual optical isomers of ofloxacin released from the examined tablets was calculated. In the case of the OfloHexal, Ofloxacin Ratiopharm and Tavanic it was found to be around 100% for both S-(-) and R-(+) ofloxacin in 0.1 M/L HCI after 30 min of dissolution test. The fraction of the average dose for the Tarivid tablets was approximately 50% at the same time. A similar results were observed for the Ofloxacin-Ratiopharm and Tavanic tablets examined in phosphate buffer (average fraction about 100% after 30 min), while in the case of Tarivid and OfloHexal the averige fraction of the dose determined in a buffer pH 6.8 was 14% and 44%, respectively. There were not found any differences in the kinetics of dissolution of the S-(-)-ofloxacin and R-(+) ofloxacin isomers within the same formulation. However, statistically significant differences were found in the dissolution of ofloxacin enantiomers between different preparations. PMID- 29513967 TI - NEW METHODOLOGY FOR DEVELOPMENT OF ORODISPERSIBLE TABLETS USING HIGH-SHEAR GRANULATION PROCESS. AB - Development of orodispersible delivery system of high mechanical properties and low disintegration time is a big challenge. The aim of the current work was to assess and optimize the high shear granulation process as a new methodology for development of orodispersible tablets of high quality attributes using design of experiment approach. A two factor, three levels (32), full factorial design was carried out to investigate the main and interaction effects of independent variables, water amount (XI) and granulation time (X2) on the characteristics of granules and final product, tablet. The produced granules were analyzed for their granule size, density and flowability. Furthermore, the produced tablets were tested for: weight variation, breaking force/ crushing strength, friability, disintegration time and drug dissolution. Regression analysis results of multiple linear models showed a high correlation between the adjusted R-squared and predicted R-squared for all granules and tablets characteristics, the difference is less than 0.2. All dependent responses of granules and tablets were found to be impacted significantly (p < 0.05) by the two independent variables. However, water amount demonstrated the most dominant effect for all granules and tablet characteristics as shown by higher its coefficient estimate for all selected responses. Numerical optimization using desirability function was performed to optimize the variables under study to provide orodispersible system within the USP limit with respect of mechanical properties and disintegration time. It was found that the higher desirability (0.915) could be attained at the low level pf water (180 g) and short granulation time (1.65 min). Eventually, this study provides the formulator with helpful information in selecting the proper level of water and granulation time to provide an orodispersible system of high crushing strength and very low disintegration time, when high shear granulation methodology was used as a method of manufacture. PMID- 29513971 TI - MOTIVATIONS SURROUNDING THE PURSUIT OF A PHARMACY CAREER - THE CASE OF POLISH STUDENTS. AB - The objective was to examine the motivation for studying pharmacy. A self administered questionnaire, developed and validated by the authors, was completed by a sample of 414 Polish pharmaceutical students (Year I - Year 5). The students ranked their motives on a Likert-like scale and their underlying dimensions were identified using exploratory and confirmatory techniques. Several socio demographic variables and future pharmaceutical career plans were-also identified. The reliability and validity of the proposed questionnaire were confinued. Factor analysis revealed three factors determining the choices of the respondents: coincidental, instrumental and autotelic. Two of the top three reasons for studying pharmacy were autotelic. A relatively small percentage of respondents chose a pharmaceutical education due to coincidence. The motivation for choosing a pharmaceutical career remained relatively stable among students of all the study years. The practice point of our survey can be that, basing on Polish case, we,propose the validated self-administered questionnaire that displays acceptable construct validity and internal consistency, and can serve as an example tool to assess the particular motives and expectations of potential students and employees in the pharmaceutical area. PMID- 29513969 TI - EVALUATION OF ANTICOAGULANT EFFECT OF SULFATED POLYSACCHARIDE (SPS) FROM CODIUM DWARKENSE BORGESEN IN kappa-CARRAGEENAN INDUCED HYPERCOAGULABLE STATE IN WISTAR ALBINO RATS. AB - Our aim of the present study was to evaluate the anticoagulant effect of sulfated polysaccharides (SPS) from Codium dwarkense Bergesen in ic-carrageenan induced hypercoagulable state in Wistar albino rats. 48 Wistar albino rats of either sex were randomly divided into 6 groups - disease control, active control, treatment lowmand high dose and preventive low and high dose. K-Carrageenan (3 mg/kg) single dose intravenously was given in rat tail vein at pre-decided time to produce hypercoagulable state. Baseline, 24, 48 and 72 hours duration blood samples were collected for PT, INR, aPTT, platelet count and fibrinogen level, FDP and D-Dimer measurements. At the end of experiment, animals were sacrificed for histopathology analysis of lung, liver and mesentery. Sulfated polysaccharide (SPS) significantly restored altered coagulation parameters (PT, INR, aPTI, platelet count and fibrinogen level) without affecting fibrinolytic parameters (FDP and D-Dimer). Administration of SPS both as a treatment and preventive therapy reduced the number of microthrombi along with less structural damage in histopathology of lung, liver and mesentery. Heparin served as active control and its administration significantly prolonged aPT' and restored PT. This study shows, anticoagulant activity of SPS extracted from Codium dwarkense Bergesen in Wistar albino rats. PMID- 29513973 TI - PHARMACEUTICAL CARE IN OPINION OF POLISH MEDICAL AND PHARMACEUTICAL STUDENTS: AN EXPLORATORY STUDY. AB - Pharmacy students should have a sufficient level of knowledge, skills, and attitude to practice pharmaceutical care effectively in the routine practice in the community pharmacy. Moreover, the strong cooperation between pharmacists and physicians is strongly needed in the process of providing pharmaceutical care. The aim of the study was to investigate the opinions of students of the Faculty of Medicine and Pharmacy from Medical University of Gdansk on pharmaceutical care and cognitive services and aspects of interprofessional collaboration between physicians and pharmacists under the conditions of Polish healthcare system. A crosssectional questionnaire was given at the Faculty of Pharmacy and Faculty of Medicine at the Medical University of Gdansk, Poland. Both, pharmacy and medical students expressed positive attitude towards pharmaceutical care. Medical students declared that pharmacists should be empowered to refill the prescriptions for medicinal products of the Rx category used in chronic diseases and have access to patients' medical records. However, in the opinions of students of the pharmaceutical faculty, physicians did not support the concept of pharmaceutical care. Pharmacy students identified obstacles to effective implementation of pharmaceutical care in community pharmacies, i.e., lack of time or lack of knowledge in the field of soft skills. Both, students from the Faculty of Pharmacy and Faculty of Medicine, Medical University of Gdansk supported the idea of implementation of pharmaceutical care into Polish community pharmacies. Moreover, they recognized the process of evolution of pharmacists' competencies to more clinical role. Therefore, more representative studies are strongly needed to improve the development of pharmaceutical care in Poland. PMID- 29513974 TI - NURSE PRESCRIBING. KNOWLEDGE AND ATTITUDES OF POLISH NURSES IN THE EVE OF EXTENDING THEIR PROFESSIONAL COMPETENCES: CROSS-SECTIONAL STUDY. AB - In Poland, since 1 January 2016 nurses who graduated from the master studies or hold a title of a specialist may ordain and prescribe specific medicines ("independent nurse prescribing" - INP). Nurses, who completed bachelor studies or hold a title of a specialist are allowed to prescribe drugs to continue the patient's treatment as ordered by a physician ("supplementary nurse prescribing" SNP). The aim of this paper was to analyze the knowledge and attitudes of the Polish nurse specialists to their new professional rights in the independent ordaining of some drugs and drug prescribing. Participants were 902 women and 26 men. The age average was 42.4 (min. 26, max. 65, SD = 7.56, median: 43, mode: 40). 300 respondents - secondary medical education, 325 - the bachelor degree, 277 - the master degree. Own, validated questionnaire. Attitudes with answers based on the Likert scale (1-5) assessed by the nonparametric ANOVA Kruskal Wallis test with the post-hoc analysis. The same statistical model was used in the evaluation of potential differences for the total scale of knowledge and attitudes.On average less than half of answers about the knowledge were correct (average of difficulty index was 39%). Nurses believe that the introduction of nurse prescribing will increase the nurse's control of the therapeutic process (mean: 3.22/5). No significant differences between the attitudes of respondents with different education level (p = 0.206; H = 3.160). 55% of nurses supports the introduction of INP. Respondents with the master education significantly more frequently support INP than those with secondary education (p = 0.001; z = 3.685). The knowledge of nurses on the extension of their professional rights is unsatisfactory and requires urgent complementation. The health policy makers should consider an extensive information campaign, especially in the group of nurses with advanced practice who will have prescribing competences. Nurses' attitudes to nurse prescribing are generally positive. Concerns expressed are the same as in the opinions of nurses from countries where the professional rights underwent extension earlier. PMID- 29513970 TI - SOCIO-ECONOMIC CONSTRAINS FACED BY TB PATIENTS THAT LEAD TO NON-COMPLIANCE - A CROSS SECTIONAL STUDY IN SOUTHERN PUNJAB, PAKISTAN. AB - Tuberculosis (TB) is an infectious disease that is communicable from one person to another. Pakistan stands forefront among few unfortunate countries that still have heavy burden of TB infection. Being a developing country, TB patients in Pakistan have to face different socio-economic constraints that upset life of the patients as well as their families. A cross sectional survey was conducted in three selected districts, Lodharan, Bahawalpur and Bahawalnagar during February 2011 to June 2011. From three hundred selected patients 210 Were enrolled in study after receiving written consents. Data were collected though structured questionnaire and verbal-interviews and statistically analyzes by using the univariate analysis. The survey results showed that the low educational status (p < 0.0012, CI 95%), unawareness of disease (88.7%), crowded population (p = 0.0000, CI, 95%), poverty, high treatment cost and distant access to public health facilities were directly related to prevalence of TB. Different disease related constraints including poor attitude of family members, colleagues, society and even health care professionals (p = 0.0000, CI 95%) were also found to be major social factors leading to non-compliance and denial of TB treatment. Socio-economic constraints such as low literacy rate, unemployment, unawareness of disease, high treatment cost, poor attitude of family, society and healthcare professionals were directly related to noncompliance and should be given high priority consideration for achieving better TB management and mitigation. PMID- 29513972 TI - QUALITY OF PHARMACEUTICAL CARE AT THE STAGE OF PATIENTS' NEEDS IDENTIFICATION UNDER CONDITIONS OF COMMUNITY PHARMACIES AS A TRANSBORDER PROBLEM. AB - The results of the study of the real pharmaceutical practice in relation to the patient's needs identification defined that the problem of not always high pharmaceutical care quality at this stage is equally up-to-date for the community pharmacies of Lviv (Ukraine) and Lublin (Poland). It was found that the quantity and amount of questions set by a pharmacist are not related to the conversation duration with a pharmacy visitor, and the communication duration does not have the statistically confirmed dependence on the queue availability, therefore in the context of pharmaceutical care quality, these criteria are of no high importance. Instead, drug-related problems (n = 209) verified by the authors of this article,tthat have been distributed into the groups according to the criterion of the information amount received by a pharmacist studying the needs of the patient (visitor of a pharmacy), were determined as a quantitative indicator of potential pharmaceutical care quality increase. PMID- 29513968 TI - ANGIOEDEMA AFTER ANGIOTENSIN-CONVERTING ENZYME INHIBITORS. AB - Angiotensin-converting enzyme inhibitors (ACEI) are one of the most frequently used drugs in the therapy of cardiovascular diseases. Beneficial therapeutic effects may be accompanied by different adverse reactions including angioedema. Recently published data suggest that ACEI-induced angioedema can be life threatening without emergent intervention, for example due to the respiratory arrest. Monitoring this adverse Jreaction may be especially important for elderly patients who probably receive many different medicines and supplements and thus might be particularly at risk of adverse drug reactions. In the paper we describe two cases of ACEI-induced angioedema in older patients. PMID- 29513975 TI - Estates team looks to tackle skills shortages. AB - Concerned that engineering skills gaps, compounded by difficulties in attracting skilled tradespeople, will leave the Trust's Estates team poorly equipped and insufficiently skilled to meet the challenge of keeping a large acute hospital running efficiently over coming years, the management team within the Estates Maintenance Department at the University Hospital Southampton NHS Foundation Trust has introduced a Workforce Development Programme to tackle existing skills gaps, bring in and retain able and enthusiastic new recruits, and ensure strong succession planning. HEJ editor, Jonathan Baillie, met with the Trust's director of estates, Mark Bagnall, and head of Estates Maintenance, Paul Stafford, to find out more. PMID- 29513976 TI - Testing air permeability in isolation rooms. AB - Blanca Beato-Arribas, the Asset Performance Team leader at BSRIA, the ISO 9001 registered test, instruments, research, and consultancy organisation, describes her recent work testing the design of isolation rooms that allow the room to be optimally used for both infectious and immunocompromised patients. With pressure differentials the determining factor when controlling infection between an isolation suite and the rest of the hospital, she explains that air permeability levels within the suite should be as low as possible. PMID- 29513978 TI - Biometrics can help protect and safeguard. AB - Shaun Oakes, managing director at ievo, a north-east England-based manufacturer of biometric fingerprint readers, argues that growing use of biometrics technology can improve security and afford better protection to premises, valuable items, and people, across an ever-busier NHS. PMID- 29513977 TI - Combining people, processes, and technology. AB - Julia Fishman, managing director and vice-President, Clinical Strategy, at TeleTracking Technologies, discusses the in-use benefits of patient, staff, and asset tracking and flow technologies, arguing that their effective deployment across an NHS under considerable pressure on many fronts can free up more time to care, bring considerable cost and wider efficiencies, and help to address the perennial issue of 'bed blocking'. PMID- 29513979 TI - Ultraclean surgery in today's theatre arena. AB - Steve Stott, managing director of Medical Air, discusses the many benefits of ultraclean ventilation systems in the 21st century operating theatre environment, explaining that the development of ever-more advanced and 'flexibly designed' UCV canopies has enabled them to be installed in a wide range of theatres, extending the variety of surgeries that can be undertaken, while helping to minimise the risk of surgical site infection. PMID- 29513980 TI - Adaptability at the heart of New Papworth Hospital. AB - Steve Squire, head of Sika Major Projects, discusses approaches to integrated specification at the New Papworth Hospital, which is currently under construction at the famous Addenbrooke's Hospital site in Cambridge. He explains that ensuring that the fabric of the building supports an extended service life for the hospital, excellent build quality, and reduced maintenance, have been a high priority, with Sika supplying a number of its products for use in different parts of the structure. PMID- 29513981 TI - Designing cancer centres' many challenges. AB - Catherine Zeliotis, healthcare leader and senior associate at global healthcare architectural practice, Stantec (pictured), discusses the latest thinking in the design of cancer centres, providing best practice examples from Stantec projects throughout the world. PMID- 29513982 TI - Multiple Reaction Products from the Hydrolysis of Chiral and Prochiral Organophosphate Substrates by the Phosphotriesterase from Sphingobium sp. TCM1. AB - The phosphotriesterase from Sphingobium sp. TCM1 ( Sb-PTE) is notable for its ability to hydrolyze organophosphates that are not substrates for other enzymes. In an attempt to determine the catalytic properties of Sb-PTE for hydrolysis of chiral phosphotriesters, we discovered that multiple phosphodiester products are formed from a single substrate. For example, Sb-PTE catalyzes the hydrolysis of the RP-enantiomer of methyl cyclohexyl p-nitrophenyl phosphate with exclusive formation of methyl cyclohexyl phosphate. However, the enzyme catalyzes hydrolysis of the SP-enantiomer of this substrate to an equal mixture of methyl cyclohexyl phosphate and cyclohexyl p-nitrophenyl phosphate products. The ability of this enzyme to catalyze the hydrolysis of a methyl ester at the same rate as the hydrolysis of a p-nitrophenyl ester contained within the same substrate is remarkable. The overall scope of the stereoselective properties of this enzyme is addressed with a library of chiral and prochiral substrates. PMID- 29513983 TI - Molecular Structure of Isocyanic Acid, HNCO, the Imide of Carbon Dioxide. AB - Isocyanic acid, HNCO, the imide of carbon dioxide, was prepared by reaction of stearic acid and potassium cyanate (KOCN) at 60 degrees C in a sealed, thoroughly dried reactor. Interestingly, its crystal structure, solved by X-ray single crystal diffraction at 123(2) K, shows a group-subgroup relation for the NCO- anion to carbon dioxide: (for CO2, cP12, Pa3, a = 5.624(2) A, 150 K, C-O 1.151(2) A; for HNCO, oP16, Pca21, a = 5.6176(9), b = 5.6236(8), c = 5.6231(7) A, 123(2) K). Precise positions of H, N, C, and O were determined by DFT calculations with WIEN2k leading to interatomic distances C-O 1.17, C-N 1.22, N-H 1.03, and -N-H...N 2.14 A, and the interatomic angle N-C-O 171 degrees . PMID- 29513984 TI - Solvent-Dependent Copper-Catalyzed Indolyl C3-Oxygenation and N1-Cyclization Reactions: Selective Synthesis of 3 H-Indol-3-ones and Indolo[1,2- c]quinazolines. AB - A simple and practical procedure for the selective preparation of 3 H-indol-3-one and indolo[1,2- c]quinazoline derivatives through copper-catalyzed aerobic oxygenation and intramolecular cyclization reactions of 2-(2-amidoaryl)-1 H indoles in the presence of acid has been disclosed. Interestingly, the reaction outcomes are exclusively dependent on the reaction medium employed. With DMF as the solvent, the amide moiety of indole substrates could act as an auxiliary to enable the indole's oxygenation reaction with molecular oxygen from air as the oxidant to give 3 H-indol-3-one derivatives in a highly selective manner. On the other hand, when the reactions were performed in 1,4-dioxane, the amide moiety switched to participate in an intramolecular indolyl N1-cyclization to afford indolo[1,2- c]quinazolines as the predominating products. PMID- 29513985 TI - Saturated Vapor-Assisted Growth of Single-Crystalline Organic-Inorganic Hybrid Perovskite Nanowires for High-Performance Photodetectors with Robust Stability. AB - One-dimensional organic-inorganic hybrid perovskite nanowires (NWs) with well defined structures can possess superior optical and electrical properties for optoelectronic applications. However, most of the current perovskite NWs are prepared in the air, making the perovskite NWs vulnerable to moisture and resulting in large amounts of grain boundaries (GBs)/surface defects on NWs. Here, we report the use of an isolated growth environment (organic solvent vapor atmosphere), termed saturated vapor-assisted crystallization method, to fabricate high-quality single-crystalline CH3NH3PbI3 NWs. The NWs have smooth surface with few GBs and surface defects because of the elimination of moisture intrusion in the vapor atmosphere. Significantly, photodetectors based on the as-prepared single-crystalline CH3NH3PbI3 NWs demonstrated an extremely high photoresponsivity up to 460 A/W, an ultrafast response time of ~180 us, a large specific detectivity of 2.6 * 1013 jones, as well as an improved stability in air over 45 days. The device performance is among the best in the CH3NH3PbI3 NW-based devices. Kelvin probe force microscopy investigation further offered an insight into the excellent photoconductive properties of the CH3NH3PbI3 NWs. This work paves the way toward the fabrication of high-performance nano-optoelectronic devices based on the high-quality organic-inorganic hybrid perovskite CH3NH3PbI3 NWs. PMID- 29513986 TI - Origins of the Stokes Shift in PbS Quantum Dots: Impact of Polydispersity, Ligands, and Defects. AB - Understanding the origins of the excessive Stokes shift in the lead chalcogenides family of colloidal quantum dots (CQDs) is of great importance at both the fundamental and applied levels; however, our current understanding is far from satisfactory. Here, utilizing a combination of ab initio computations and UV-vis and photoluminescence measurements, we investigated the contributions to the Stokes shift from polydispersity, ligands, and defects in PbS CQDs. The key results are as follows: (1) The size and energetic disorder of a polydisperse CQD film increase the Stokes shift by 20 to 50 meV compared to that of an isolated CQD; (2) Franck-Condon (FC) shifts increase as the electronegativities of the ligands increase, but the variations are small (<15 meV). (3) Unlike the aforementioned two minor factors, the presence of certain intrinsic defects such as VCl+ (in Cl-passivated CQDs) can cause substantial electron density localization of the band edge states and consequent large FC shifts (100s of meV). This effect arising from defects can explain the excessive Stokes shifts in PbS CQDs and improve our understanding of the optical properties of PbS CQDs. PMID- 29513987 TI - Cholesterol-Modified Caged siRNAs for Photoregulating Exogenous and Endogenous Gene Expression. AB - siRNA has been widely applied in research and drug development due to its sequence-specific gene silencing ability. However, how to spatiotemporally control its function is still one of its challenges. Light, a fast and noninvasive trigger, is a promising tool for spatiotemporal control of gene expression. Here, we designed and synthesized a new series of caged siRNAs modified with single cholesterol at the 5' terminal of antisense strand RNA through a photolabile linker (Chol-PL-siRNAs). We demonstrated that these caged siRNAs were successfully used to photochemically regulate both exogenous ( firefly luciferase and gfp) and endogenous gene expression (mitotic kinesin-5, Eg5) in cells. PMID- 29513988 TI - Thermal Transport in Supported Graphene Nanomesh. AB - Graphene is considered as a promising candidate material to replace silicon for the next-generation nanoelectronics because of its superb carrier mobility. To evaluate its thermal dissipation capability as electronic materials, the thermal transport in monolayer graphene was extensively explored over the past decade. However, the supported chemical vapor deposition (CVD) grown monolayer graphene with submicron structures were seldom studied, which is important for practical nanoelectronics. Here we investigate the thermal transport properties in a series of CVD graphene nanomeshes patterned by a hard-template-assisted etching method. The experimental and numerical results uncovered the phonon backscattering at hole boundary (<100 nm neck width) and its substantial contribution to the thermal conductivity reduction. PMID- 29513989 TI - Unusual Influence of Fluorinated Anions on the Stretching Vibrations of Liquid Water. AB - Infrared (IR) spectroscopy is a commonly used and invaluable tool in the studies of solvation phenomena in aqueous solutions. Concurrently, ab initio molecular dynamics (AIMD) simulations deliver the solvation shell picture at a molecular detail level and allow for a consistent decomposition of the theoretical IR spectrum into underlying spatial correlations. Here, we demonstrate how the novel spectral decomposition techniques can extract important information from the computed IR spectra of aqueous solutions of BF4- and PF6-, interesting weakly coordinating anions that have been known for a long time to alter the IR spectrum of water in an unusual manner. The distance-dependent spectra of both ions are analyzed using the spectral similarity method that provides a quantitative picture of both the spectrum of the solute-affected solvent and the number of solvent molecules thus altered. We find, in accordance with previous experiments, a considerable blue shift of the nuOH stretching band of liquid water by 264 cm-1 for BF4- and 306 cm-1 for PF6-, with the affected numbers being 3.7 and 4.2, respectively. Considering also the additional information on solute-solvent dipolar couplings delivered by radially and spatially resolved IR spectra, the computational IR spectroscopy based on AIMD simulations is shown to be a viable predictive tool with strong interpretative power. PMID- 29513990 TI - Rate Constants for the Reactions of OH Radical with the ( E)/( Z) Isomers of CF3CF?CHCl and CHF2CF?CHCl. AB - The rate constants for the reactions of OH radical with ( E)- and ( Z)-isomers of CF3CF?CHCl and CHF2CF?CHCl have been measured over the temperature range of 250 430 K. Kinetic measurements have been performed using flash and laser photolysis methods combined with laser-induced fluorescence. Arrhenius rate constants have been determined as k(( E)-CF3CF?CHCl) = (1.09 +/- 0.03) * 10-12 . exp[(50 +/- 10)K/ T], k(( Z)-CF3CF?CHCl) = (8.02 +/- 0.19) * 10-13 . exp[-(100 +/- 10)K/ T], k(( E)-CHF2CF?CHCl) = (1.50 +/- 0.03) * 10-12 . exp[(160 +/- 10)K/ T], and k(( Z) CHF2CF?CHCl) = (1.36 +/- 0.03) * 10-12 . exp[(360 +/- 10)K/ T] cm3 molecule-1 s 1. Infrared absorption spectra have also been measured at room temperature. The atmospheric lifetimes of ( E)-CF3CF?CHCl, ( Z)-CF3CF?CHCl, ( E)-CHF2CF?CHCl, and ( Z)-CHF2CF?CHCl have been estimated as 8.9, 20, 4.6, and 2.6 days, respectively, and their global warming potentials and ozone depletion potentials were determined as 0.23, 0.88, 0.060, and 0.016 and 0.00010, 0.00023, 0.000057, and 0.000030, respectively. Additionally, the rate constants for OH radical addition and IR spectra of these compounds were determined computationally. Consistent with experiment, our calculations indicate that the reactivity toward OH radical addition is reduced as ( Z)-CHF2CF?CHCl > ( E)-CHF2CF?CHCl > ( E)-CF3CF?CHCl > ( Z)-CF3CF?CHCl, where the ( E)/( Z) reactivity is reversed for CF3CF?CHCl and CHF2CF?CHCl. The calculations reproduced the observed temperature dependencies of the rate constants for the OH radical reactions, which is slightly positive for ( Z)-CF3CF?CHCl but negative for the other compounds. PMID- 29513992 TI - The Charge-Balancing Role of Calcium and Alkali Ions in Per-Alkaline Aluminosilicate Glasses. AB - The structural arrangement of alkali-modified calcium aluminosilicate glasses has implications for important properties of these glasses in a wide range of industrial applications. The roles of sodium and potassium and their competition with calcium as network modifiers in peralkaline aluminosilicate glasses have been investigated by 27Al and 29Si MAS NMR spectroscopy. The 29Si MAS NMR spectra are simulated using two models for distributing Al in the silicate glass network. One model assumes a hierarchical, quasi-heterogeneous aluminosilicate network, whereas the other is based on differences in relative lattice energies between Si O-Si, Al-O-Al, and Si-O-Al linkages. A systematic divergence between these simulations and the experimental 29Si NMR spectra is observed as a function of the sodium content exceeding that required for stoichiometric charge-balancing of the negatively charged AlO4 tetrahedra. Similar correlations between simulations and experimental 29Si NMR spectra cannot be made for the excess calcium content. Moreover, systematic variations in the 27Al isotropic chemical shifts and the second-order quadrupole effect parameters, derived from the 27Al MAS NMR spectra, are reported as a function of the SiO2 content. These observations strongly suggest that alkali ions preferentially charge-balance AlO43- as compared to alkaline earth (calcium) ions. In contrast, calcium dominates over the alkali ions in the formation of nonbridging oxygens associated with the SiO4 tetrahedra. PMID- 29513991 TI - Selective Binding of Folic Acid and Derivatives by Imprinted Nanoparticle Receptors in Water. AB - Folate receptors are overexpressed on cancer cells and frequently used for targeted delivery. Creation of synthetic receptors to bind folic acid and its analogues in water, however, is challenging because of its complex hydrogen bonding patterns and competition for hydrogen bonds from the solvent. Micellar imprinting within cross-linkable surfactants circumvented these problems because the nonpolar micellar environment strengthened the hydrogen bonds between the amide group in the surfactant and the template molecule. Incorporation of polymerizable thiouronium functional monomers further enhanced the binding through hydrogen-bond-reinforced ion pairs with the glutamate moiety of the template. The resulting imprinted micelles were able to bind folate and their analogues with submicromolar affinity and distinguish small changes in the hydrogen-bonding patterns as well as the number/position of carboxylic acids. The binding constant obtained was 2-3 orders of magnitude higher than those reported for small-molecule synthetic receptors. Our binding study also revealed interesting details in the binding. For example, the relative contributions of different segments of the molecule to the binding followed the order of carboxylates > pyrimidine ring > pyrazine ring. PMID- 29513993 TI - Reaction F + C2H4: Rate Constant and Yields of the Reaction Products as a Function of Temperature over 298-950 K. AB - The kinetics and products of the reaction of F + C2H4 have been studied in a discharge flow reactor combined with an electron impact ionization mass spectrometer at nearly 2 Torr total pressure of helium in the temperature range 298-950 K. The total rate constant of the reaction, k1 = (1.78 +/- 0.30) * 10-10 cm3 molecule-1 s-1, determined under pseudo-first-order conditions, monitoring the kinetics of F atom consumption in excess of C2H4, was found to be temperature independent in the temperature range used. H, C2H3F, and HF were identified as the reaction products. Absolute measurements of the yields of these species allowed to determine the branching ratios, k1b/ k1 = (0.73 +/- 0.07) exp(-(425 +/ 45)/ T) and k1a/ k1 = 1 - (0.73 +/- 0.07) exp(-(425 +/- 45)/ T) and partial rate constants for addition-elimination (H + C2H3F) and H atom abstraction (HF + C2H3) pathways of the title reaction: k1a = (0.80 +/- 0.07) * 10-10exp(189 +/- 37/ T) and k1b = (1.26 +/- 0.13) * 10-10exp(-414 +/- 45/ T) cm3 molecule-1 s-1, respectively, at T = 298-950 K and with 2sigma quoted uncertainties. The overall reaction rate constant can be adequately described by both the temperature independent value and as a sum of k1a and k1b. The kinetic and mechanistic data from the present study are discussed in comparison with previous absolute and relative measurements and theoretical calculations. PMID- 29513994 TI - Evaluation of General and Tailor Made Force Fields via X-ray Thermal Diffuse Scattering Using Molecular Dynamics and Monte Carlo Simulations of Crystalline Aspirin. AB - We have performed a comparison of the experimental thermal diffuse scattering (TDS) from crystalline Aspirin (form I) to that calculated from molecular dynamics (MD) simulations based on a variety of general force fields and a tailor made force field (TMFF). A comparison is also made with Monte Carlo (MC) simulations which use a "harmonic network" approach to describe the intermolecular interactions. These comparisons were based on the hypothesis that TDS could be a useful experimental data in validation of such simulation parameter sets, especially when calculations of dynamical properties (e.g., thermodynamic free energies) from molecular crystals are concerned. Currently such a validation of force field parameters against experimental data is often limited to calculation of specific physical properties, e.g., absolute lattice energies usually at 0 K or heat capacity measurements. TDS harvested from in house or synchrotron experiments comprises highly detailed structural information representative of the dynamical motions of the crystal lattice. Thus, TDS is a well-suited experimental data-driven means of cross validating theoretical approaches targeted at understanding dynamical properties of crystals. We found from the results of our investigation that the TMFF and COMPASS (from the commercial software "Materials Studio") parameter sets gave the best agreement with experiment. From our homologous MC simulation analysis we are able to show that force constants associated with the molecular torsion angles are likely to be a strong contributing factor for the apparent reason why these aforementioned force fields performed better. PMID- 29513995 TI - Interaction between a Nonsteroidal Anti-inflammatory Drug (Ibuprofen) and an Anionic Surfactant (AOT) and Effects of Salt (NaI) and Hydrotrope (4-4-4). AB - Ibuprofen (IBF), 2-(4-isobutylphenyl) propionic acid, is a surface-active, common nonsteroidal anti-inflammatory drug (NSAID), and it possesses a high critical micelle concentration (cmc) compared to that of conventional surfactants. The interactions of this common NSAID with an anionic surfactant, sodium octyl sulfosuccinate, were studied by tensiometric, fluorimetric, and calorimetric measurements to investigate this system as a possible model drug-delivery system for an NSAID like IBF, particularly in a high-dose regime for IBF. The interactions between the drug and the surfactant were modeled using a regular solution theory approach in the presence and absence of a model electrolyte (sodium iodide) and a novel nonaromatic, gemini hydrotrope, tetramethylene-1,4 bis( N, N-dimethyl- N-butylammonium)bromide (4-4-4). Both the simple and the hydrotropic electrolyte were shown to have an effect on the solution properties (aggregation parameters, interfacial properties, and thermodynamics of aggregate formation) of the drug-surfactant mixtures and on the interaction between the drug and the surfactant. Surface charges of all self-assembled systems were estimated from zeta-potential measurements, whereas density functional theory calculations showed the interaction energy comparison among all of the binary and ternary combinations. All of these results were interpreted in terms of how altering the subtle balance of hydrophobic and electrostatic forces can significantly improve the ability of these self-assembled systems to transport drug molecules. PMID- 29513996 TI - Magnetic Bistability in Naphtho-1,3,2-dithiazolyl: Solid State Interconversion of a Thiazyl pi-Radical and Its N-N sigma-Bonded Dimer. AB - Crystals of the heterocyclic radical naphtho-1,3,2-dithiazolyl NDTA display magnetic bistability with a well-defined hysteretic phase transition at Tc? = 128(2) K and Tc? = 188(2) K. The magnetic signature arises from a radical/dimer interconversion involving one of the two independent pi-radicals in the P1 unit cell. Variable temperature X-ray crystallography has established that while all the radicals in HT-NDTA serve as paramagnetic ( S = 1/2) centers, half of the radicals in LT-NDTA form closed-shell N-N sigma-bonded dimers ( S = 0) and half retain their S = 1/2 spin state. The wide window of bistability (60 K) may be attributed to the large structural changes that accompany the phase transition. PMID- 29513997 TI - Dynamic Tunneling Junctions at the Atomic Intersection of Two Twisted Graphene Edges. AB - The investigation of the transport properties of single molecules by flowing tunneling currents across extremely narrow gaps is relevant for challenges as diverse as the development of molecular electronics and sequencing of DNA. The achievement of well-defined electrode architectures remains a technical challenge, especially due to the necessity of high precision fabrication processes and the chemical instability of most bulk metals. Here, we illustrate a continuously adjustable tunneling junction between the edges of two twisted graphene sheets. The unique property of the graphene electrodes is that the sheets are rigidly supported all the way to the atomic edge. By analyzing the tunneling current characteristics, we also demonstrate that the spacing across the gap junction can be controllably adjusted. Finally, we demonstrate the transition from the tunneling regime to contact and the formation of an atomic sized junction between the two edges of graphene. PMID- 29513998 TI - Surface Charge Influence on the Phase Separation and Viscosity of Cellulose Nanocrystals. AB - A series of four cellulose nanocrystal (CNC) suspensions were prepared from bleached softwood kraft pulp using different conditions of sulfuric acid hydrolysis. The CNCs were identical in size (95 nm in length * 5 nm in width) but had different surface charges corresponding to the harshness of the hydrolysis conditions. Consequently, it was possible to isolate the effects of surface charge on the self-assembly and viscosity of the CNC suspensions across surface charges ranging from 0.27%S to 0.89%S. The four suspensions (never-dried, free of added electrolyte) all underwent liquid crystalline phase separation, but the concentration onset for the emergence of the chiral nematic phase shifted to higher values with increasing surface charge. Similarly, suspension viscosity was also influenced by surface charge, with suspensions of lower surface charge CNCs more viscous and tending to gel at lower concentrations. The properties of the suspensions were interpreted in terms of the increase in effective diameter of the nanocrystals due to the surface electrostatic repulsion of the negative sulfate half-esters, as modified by the screening effects of the H+ counterions in the suspensions. The results suggest that there is a threshold surface charge density (~0.3%S) above which effective volume considerations are dominant across the concentration range relevant to liquid crystalline phase formation. Above this threshold value, phase separation occurs at the same effective volume fraction of CNCs (~10 vol %), with a corresponding increase in critical concentration due to the decrease in effective diameter that occurs with increasing surface charge. Below or near this threshold value, the formation of end-to-end aggregates may favor gelation and interfere with ordered phase formation. PMID- 29513999 TI - Multiple Structural Transitions in Langmuir Monolayers of Charged Soft-Shell Nanoparticles. AB - We have investigated the morphologies of Langmuir layers of charged, polymeric hard-core/interlayer/soft-shell nanoparticles spread at the air-water interface. Depending on various mutual interactions, which are correlated to the areal densities of the deposited nanoparticles, we observed ordered patterns of nondense and closed-packed arrangements of core/interlayer/shell (CIS) nanoparticle ordering. At low areal densities, we found an almost regular distribution of the charged CIS nanoparticles on the water surface, which resulted from long-range repulsive electrostatic interactions between them. At higher areal densities, domains of more closely packed and ordered nanoparticles were formed, coexisting with regions of randomly and sparsely distributed nanoparticles. We relate these domains to the interplay of electrostatic repulsion and capillary attraction caused by the dipolar character of like charged particles at the interface, allowing for a characteristic separation distance between nanoparticles of about 3-4 times the nanoparticle diameter. At relatively high areal densities, attractive van der Waals forces were finally capable of making nanoparticles to come in contact with each other, leading to densely packed patches of hexagonally ordered nanoparticles coexisting with regions of rather well-ordered nanoparticles separated by about 1 MUm and regions of randomly and sparsely distributed nanoparticles. Intriguingly, upon re expansion of the area available per nanoparticle, these densely packed patches disappeared, indicating that steric repulsion due to the presence of soft shells as well as long-range electrostatic repulsive forces were strong enough to assure reversibility of the morphological behavior. PMID- 29514000 TI - Enhanced Hydrothermal Stability of gamma-Al2O3 Catalyst Supports with Alkyl Phosphonate Coatings. AB - In this study, monolayers formed from organophosphonic acids were employed to stabilize porous gamma-Al2O3, both as a single component and as a support for Pt nanoparticle catalysts, during exposure to hydrothermal conditions. To provide a baseline, structural changes of uncoated gamma-Al2O3 catalysts under model aqueous phase reforming conditions (liquid water at 200 degrees C and autogenic pressure) were examined over the course of 20 h. These changes were characterized by X-ray diffraction, NMR spectroscopy, N2 physisorption, and IR spectroscopy. It was demonstrated that gamma-alumina was rapidly converted into a hydrated boehmite (AlOOH) phase with significantly decreased surface area. Deposition of alkyl phosphonate groups on gamma-alumina drastically inhibited the formation of boehmite, thereby maintaining its high specific surface area over 20 h of treatment. 27Al MAS NMR spectra demonstrated that hydrothermal stability increased with alkyl tail length despite lower P coverages. Although the inhibition of boehmite formation by the phosphonic acids was attributed primarily to the formation of Al2O3-PO x bonds, it was found that use of longer-chain octadecylphosphonic acids led to the most pronounced effect. Phosphonate coatings on Pt/gamma-Al2O3 improved stability without adversely affecting the rate of a model reaction, catalytic hydrogenation of 1-hexene. PMID- 29514001 TI - Does Microbial Biodegradation of Water-Soluble Components of Oil Reduce the Toxicity to Early Life Stages of Fish? AB - Microbial degradation following oil spills results in metabolites from the original oil. Metabolites are expected to display lower bioaccumulation potential and acute toxicity to marine organisms due to microbial-facilitated incorporation of chemical functional groups and a general decrease in lipophilicity. The toxicity and characterization of metabolites are poorly studied. The purpose of the present work was to evaluate the toxicity of degraded (0-21 days) water soluble oil components. Low-energy water accommodated fraction (LE-WAF) of a weathered crude oil was prepared with nutrient amended seawater at 5 degrees C, kept in the dark, and sampled at 0, 10, 14, and 21 days. Samples were extracted with dichloromethane and toxicity experiments were conducted with reconstituted extracts. Toxicity experiments were conducted for 4 days on developing cod ( Gadus morhua) embryos during a critical period of their heart development. After exposure, embryos were kept in clean seawater and observed until 5 days post hatch. Survival, hatching, morphometric aberrations, and cardiac function was studied. The expected decrease in sublethal toxicity during the biodegradation period was not found, indicating that metabolites formed during biodegradation likely contributed to larvae toxicity. PMID- 29514002 TI - International Trade Drives Global Resource Use: A Structural Decomposition Analysis of Raw Material Consumption from 1990-2010. AB - Globalization led to an immense increase of international trade and the emergence of complex global value chains. At the same time, global resource use and pressures on the environment are increasing steadily. With these two processes in parallel, the question arises whether trade contributes positively to resource efficiency, or to the contrary is further driving resource use? In this article, the socioeconomic driving forces of increasing global raw material consumption (RMC) are investigated to assess the role of changing trade relations, extended supply chains and increasing consumption. We apply a structural decomposition analysis of changes in RMC from 1990 to 2010, utilizing the Eora multi-regional input-output (MRIO) model. We find that changes in international trade patterns significantly contributed to an increase of global RMC. Wealthy developed countries play a major role in driving global RMC growth through changes in their trade structures, as they shifted production processes increasingly to less material-efficient input suppliers. Even the dramatic increase in material consumption in the emerging economies has not diminished the role of industrialized countries as drivers of global RMC growth. PMID- 29514003 TI - PEGylation of Tobramycin Improves Mucus Penetration and Antimicrobial Activity against Pseudomonas aeruginosa Biofilms in Vitro. AB - Pseudomonas aeruginosa is the predominant pathogen in the persistent lung infections of cystic fibrosis (CF) patients among other diseases. One of the mechanisms of resistance of P. aeruginosa infections is the formation and presence of biofilms. Previously, we demonstrated that PEGylated-tobramycin (Tob PEG) had superior antimicrobial activity against P. aeruginosa biofilms compared to tobramycin (Tob). The goal of this study was to optimize the method of PEGylation of Tob and assess its activity in an in vitro CF-like mucus barrier biofilm model. Tob was PEGylated using three separate chemical conjugation methods and analyzed by 1H NMR. A comparison of the Tob-PEG products from the different conjugation methods showed significant differences in the reduction of biofilm proliferation after 24 h of treatment. In the CF-like mucus barrier model, Tob-PEG was significantly better than Tob in reducing P. aeruginosa proliferation after only 5 h of treatment ( p < 0.01). Finally, Tob-PEG caused a reduction in the number of surviving P. aeruginosa biofilm colonies higher than that of Tob ( p < 0.0001). We demonstrate the significantly improved antimicrobial activity of Tob-PEG against P. aeruginosa biofilms compared to Tob using two PEGylation methods. Tob-PEG had better in vitro activity compared to that of Tob against P. aeruginosa biofilms growing in a CF-like mucus barrier model. PMID- 29514004 TI - Synthesis of Cyclohexanones through a Catalytic Cationic Cyclization of Alkynols or Enynes. AB - A novel procedure for the synthesis of cyclohexanones from alkynol or enyne derivatives through a cationic cyclization has been developed. The key points to obtain the six-membered ring derivatives are the use of starting materials containing a terminal alkyne, the use of tetrafluoroboric acid as a promoter of the cationic cyclization, and the appropriate selection of 1,1,1,3,3,3 hexafluoropropan-2-ol (HFIP) as solvent. This strategy can be extended to the biomimetic cationic cyclization of several terpene-derived polyenynes. PMID- 29514005 TI - In Situ, Time-Resolved, and Mechanistic Studies of Metal-Organic Framework Nucleation and Growth. AB - The vast chemical and structural diversity of metal-organic frameworks (MOFs) opens up the exciting possibility of "crystal engineering" MOFs tailored for particular catalytic or separation applications. Yet the process of reaction discovery, optimization, and scale-up of MOF synthesis remains extremely challenging, presenting significant obstacles to the synthetic realization of many otherwise promising MOF structures. Recently, significant new insights into the fundamental processes governing MOF nucleation and growth, as well as the relationship between reaction parameters and synthetic outcome, have been derived using powerful in situ, time-resolved and/or mechanistic studies of MOF crystallization. This Review provides a summary and associated critical analysis of the results of these and other related "direct" studies of MOF nucleation and growth, with a particular emphasis on the recent advances in instrument technologies that have enabled such studies and on the major hypotheses, theories, and models that have been used to explain MOF formation. We conclude with a summary of the major insights that have been gained from the work summarized in this Review, outlining our own perspective on potential fruitful new directions for investigation. PMID- 29514006 TI - Enzyme Degradable Hyperbranched Polyphosphoester Micellar Nanomedicines for NIR Imaging-Guided Chemo-Photothermal Therapy of Drug-Resistant Cancers. AB - Multidrug resistance (MDR) is the major cause for chemotherapy failure, which constitutes a formidable challenge in the field of cancer therapy. The synergistic chemo-photothermal treatment has been reported to be a potential strategy to overcome MDR. In this work, rationally designed enzyme-degradable, hyperbranched polyphosphoester nanomedicines were developed for reversing MDR via the codelivery of doxorubicin and IR-780 (hPPEDOX&IR) as combined chemo photothermal therapy. The amphiphilic hyperbranched polyphosphoesters with phosphate bond as the branching point were synthesized via a simple but robust one-step polycondensation reaction. The self-assembled hPPEDOX&IR exhibited good serum stability, sustained release, preferable tumor accumulation, and enhanced drug influx of doxorubicin in resistant MCF-7/ADR cells. Moreover, the degradation of hPPEDOX&IR was accelerated in the presence of alkaline phosphatase, which was overexpressed in various cancers, resulting in the fast release of encapsulated doxorubicin. The enzyme-degradable polymer generated synergistic chemo-photothermal cytotoxicity against MCF-7/ADR cells and, thus, the efficient ablation of DOX-resistant tumor without regrowth. This delivery system may open a new avenue for codelivery of chemo- and photothermal therapeutics for MDR tumor therapy. PMID- 29514007 TI - Supplementation of grape seed and skin extract to orlistat therapy prevents high fat diet-induced murine spleen lipotoxicity. AB - Spleen is the largest lymphoid organ and obesity is related to an elevated risk of immunity dysfunction. The mechanism whereby fat adversely affects the spleen is poorly understood. This study was designed to assess the effectiveness of grape seed and skin extract (GSSE) and orlistat (Xenical, Xe) on high-fat diet (HFD)-induced spleen lipotoxicity. Obese rats were treated either with GSSE (4 g/kg body weight) or Xe (2 mg/kg body weight) or GSSE+Xe and monitored for weight loss for 3 months. Animals were then sacrificed and their spleen used for the evaluation of lipotoxicity-induced oxidative stress and inflammation as well as the putative protection afforded by GSSE and Xe treatment. HFD induced body weight gain and glycogen accumulation into the spleen; ectopic deposition of cholesterol and triglycerides and an oxidative stress characterized by increased lipoperoxidation and carbonylation; inhibition of antioxidant enzyme activities, such as catalase, glutathione peroxidase, and superoxide dismutase; depletion of zinc and copper; and a concomitant increase in calcium. HFD also increased plasma pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17A, tumour necrosis factor alpha, and C-reactive protein, and decreased plasma IL-10 and adiponectin. Importantly, GSSE counteracted all the deleterious effects of HFD on spleen (i.e., lipotoxicity, oxidative stress, and inflammation) and the best protection was obtained when combining Xe+GSSE. Combining GSSE with Xe prevented against fat induced spleen lipotoxicity, oxidative stress, and inflammation; this combination may be beneficial in other diseases related to the spleen. PMID- 29514008 TI - Tristetraprolin Is Required for Alveolar Bone Homeostasis. AB - Tristetraprolin (TTP) is an RNA-binding protein that targets numerous immunomodulatory mRNA transcripts for degradation. Many TTP targets are key players in the pathogenesis of periodontal bone loss, including tumor necrosis factor-alpha. To better understand the extent that host immune factors play during periodontal bone loss, we assessed alveolar bone levels, inflammation and osteoclast activity in periodontal tissues, and immune response in draining cervical lymph nodes in TTP-deficient and wild-type (WT) mice in an aging study. WT and TTP-deficient (knockout [KO]) mice were used for all studies under specific pathogen-free conditions. Data were collected on mice aged 3, 6, and 9 mo. Microcomputed tomography (uCT) was performed on maxillae where 3-dimensional images were generated and bone loss was assessed. Decalcified sections of specimens were scored for inflammation and stained with tartrate-resistant acid phosphate (TRAP) to visualize osteoclasts. Immunophenotyping was performed on single-cell suspensions isolated from primary and peripheral lymphoid tissues using flow cytometry. Results presented indicate that TTP KO mice had significantly more alveolar bone loss over time compared with WT controls. Bone loss was associated with significant increases in inflammatory cell infiltration and an increased percentage of alveolar bone surfaces apposed with TRAP+ cells. Furthermore, it was found that the draining cervical lymph nodes were significantly enlarged in TTP-deficient animals and contained a distinct pathological immune profile compared with WT controls. Finally, the oral microbiome in the TTP KO mice was significantly different with age from WT cohoused mice. The severe bone loss, inflammation, and increased osteoclast activity observed in these mice support the concept that TTP plays a critical role in the maintenance of alveolar bone homeostasis in the presence of oral commensal flora. This study suggests that TTP is required to inhibit excessive inflammatory host responses that contribute to periodontal bone loss, even in the absence of specific periodontal pathogens. PMID- 29514010 TI - DNA distribution pattern and metabolite profile of wild edible lobster mushroom (Hypomyces lactifluorum/Russula brevipes). AB - Lobster mushroom is a wild edible mushroom with potential commercial value. It is the product resulting of the infection, most commonly of Russula brevipes, by Hypomyces lactifluorum. This study undertook quantitative polymerase chain reaction analysis of tissues sampled at different infection stages to investigate R. brevipes - H. lactifluorum interaction. We followed the colonization of R. brevipes sporocarps by H. lactifluorum that leads to the edible lobster mushrooms. In parallel, metabolomics analysis was performed to detect differences in metabolite profile among non-infected R. brevipes sporocarp and lobster mushroom. The results show that H. lactifluorum DNA is not restricted to the margin but is distributed relatively evenly across the sporocarp of the lobster mushroom. Russula brevipes DNA was also present throughout the sporocarp but was less abundant at the margins and increased inwards. Russula brevipes DNA also declined as the infection progressed. Metabolomics analysis revealed that the flesh of lobster mushroom, which remains identical in appearance to the flesh of the host, undergoes transformation that alters its metabolite profile, most notably of lipids and terpene compounds. These results define a parasitic relationship between the two species that entails a decline of R. brevipes DNA and a modification of its metabolite profile. PMID- 29514014 TI - Reduction of atmospheric fine particle level by restricting the idling vehicles around a sensitive area. AB - : Atmospheric particles are a major problem that could lead to harmful effects on human health, especially in densely populated urban areas. Chiayi is a typical city with very high population and traffic density, as well as being located at the downwind side of several pollution sources. Multiple contributors for PM2.5 (particulate matter with an aerodynamic diameter >=2.5 MUm) and ultrafine particles cause complicated air quality problems. This study focused on the inhibition of local emission sources by restricting the idling vehicles around a school area and evaluating the changes in surrounding atmospheric PM conditions. Two stationary sites were monitored, including a background site on the upwind side of the school and a campus site inside the school, to monitor the exposure level, before and after the idling prohibition. In the base condition, the PM2.5 mass concentrations were found to increase 15% from the background, whereas the nitrate (NO3-) content had a significant increase at the campus site. The anthropogenic metal contents in PM2.5 were higher at the campus site than the background site. Mobile emissions were found to be the most likely contributor to the school hot spot area by chemical mass balance modeling (CMB8.2). On the other hand, the PM2.5 in the school campus fell to only 2% after idling vehicle control, when the mobile source contribution reduced from 42.8% to 36.7%. The mobile monitoring also showed significant reductions in atmospheric PM2.5, PM0.1, polycyclic aromatic hydrocarbons (PAHs), and black carbon (BC) levels by 16.5%, 33.3%, 48.0%, and 11.5%, respectively. Consequently, the restriction of local idling emission was proven to significantly reduce PM and harmful pollutants in the hot spots around the school environment. IMPLICATIONS: The emission of idling vehicles strongly affects the levels of particles and relative pollutants in near ground air around a school area. The PM2.5 mass concentration at a campus site increased from the background site by 15%, whereas NO3- and anthropogenic metals also significantly increased. Meanwhile, the PM2.5 contribution from mobile source in the campus increased 6.6% from the upwind site. An idling prohibition took place and showed impressive results. Reductions of PM2.5, ionic component, and non-natural metal contents were found after the idling prohibition. The mobile monitoring also pointed out a significant improvement with the spatial analysis of PM2.5, PM0.1, PAH, and black carbon concentrations. These findings are very useful to effectively improve the local air quality of a densely city during the rush hour. PMID- 29514015 TI - The ERICA Score: An MR Imaging-based Visual Scoring System for the Assessment of Entorhinal Cortex Atrophy in Alzheimer Disease. AB - Purpose To establish and evaluate a visual score focused on entorhinal cortex atrophy (ERICA), as the entorhinal cortex is one of the first brain structures affected in Alzheimer disease (AD). Materials and Methods In this retrospective study, ERICA was visually evaluated with magnetic resonance imaging (2009-2016). First, a four-point ERICA score was developed by using data in 48 consecutive subjects (20 patients with AD and 28 control subjects). Then, in the main analysis, ERICA and the standard medial temporal lobe atrophy (MTA) scores were determined in an independent cohort of 60 patients suspected of having AD (mean age, 69.4 years; range, 46-86 years) and in 60 age-matched patients with subjective cognitive decline (SCD) (mean age, 72.4 years; range 50-87 years). Score performances were evaluated with kappa statistics, receiver operating characteristic analysis, t tests, and analysis of variance according to the Standards for Reporting of Diagnostic Accuracy Studies. Results Patients with AD had higher MTA scores (mean, 2.13) and ERICA scores (mean, 2.05) than patients with SCD (P < .001). An ERICA score of 2 or greater achieved a higher diagnostic accuracy (91%) than the MTA score (74%), with a sensitivity of 83% versus 57% and a specificity of 98% versus 92% in discriminating dementia caused by AD from SCD (P < .001). The ERICA score was correlated with amyloid beta 42/40 ratio (rho = 0.54, P < .001) and with cerebrospinal fluid tau (rho = 0.35, P = .001) and p-tau (rho = 0.31, P = .004). In multivariable linear regression analysis, ERICA was associated with verbal learning and recall (beta = -.40 and -.41), nonverbal recall (beta = -.28), and cued recall (beta = -.41, P <= .002 for all). Conclusion An ERICA score of 2 or greater indicates probable AD with high diagnostic accuracy. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29514016 TI - Functional Connectivity of the Corticobasal Ganglia-Thalamocortical Network in Parkinson Disease: A Systematic Review and Meta-Analysis with Cross-Validation. AB - Purpose To quantitatively summarize the functional connectivity (FC) feature of the corticobasal ganglia-thalamocortical (CBTC) network in patients with Parkinson disease (PD) by means of a meta-analysis with cross-validation. Materials and Methods For this prospective study, a systematic literature search in the PubMed and EMBASE databases was performed for resting-state functional magnetic resonance (MR) imaging studies of PD published between January 2000 and May 2017. Then, a coordinate-based meta-analysis was conducted by Effect Size Signed Differential Mapping. A cross-validation analysis was performed by using an independent resting-state functional MR imaging data set that contained 25 patients with PD and 19 age-, sex-, and education-matched healthy control participants. Two-sample t test was performed on FC maps between PD and control groups. Results Thirty studies with 854 patients with PD and 831 control participants were included in this meta-analysis. The main meta-analysis found increased FC in the left pre- and postcentral gyrus in patients with PD compared with healthy control participants (z = 2.6; P < .001). The abnormality of the postcentral gyrus was further confirmed by subgroup meta-analyses on medication naive (n = 25; z = 2.2; P < .001) and medication-off (n = 11; z = 1.5; P < .001) experiments, which suggested that the finding was unaffected by medication. The abnormality of the postcentral gyrus was cross-validated by the independent data set (t = 5.0; P < .05), which suggested a high reproducibility and generalizability. Conclusion This meta-analysis emphasizes the left postcentral gyrus as a critical region in PD, which may become a potential target for clinical intervention. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29514018 TI - Reducing the Number of Measurements in Liver Point Shear-Wave Elastography: Factors that Influence the Number and Reliability of Measurements in Assessment of Liver Fibrosis in Clinical Practice. AB - Purpose To identify the minimum number of measurements required for the noninvasive assessment of liver fibrosis by using point shear-wave elastography (pSWE) and determine whether the use of a reliability indicator such as interquartile range [IQR]-to-median ratio will affect diagnostic performance. Materials and Methods Ten liver shear-wave velocity (SWV) measurements by pSWE were obtained in 232 participants. Interclass correlation coefficients (ICC) between the median of the first two through the first nine measurements and all 10 measurements were calculated; the minimum number of measurements with ICC greater than 0.95 versus all 10 measurements was determined. The diagnostic performance of the minimum number of measurements and 10 measurements in identifying significant (Ishak stage, >=3) and severe fibrosis or cirrhosis (Ishak stage, >=5) was compared by using areas under the receiver operating characteristic curve. These were compared between measurements that demonstrated higher or lower reliability (IQR-to-median ratio of <= 30% and IQR-to-median ratio of > 30%, respectively). Results Compared with 10 measurements, a minimum of six SWV measurements was required. The overall area under the curve for diagnosing significant (areas under the receiver operating characteristic curve, 0.828 vs 0.839; P = .487) and severe fibrosis or cirrhosis (0.953 vs 0.969, respectively; P = .145) did not differ according to number of measurements (six vs 10); a median of six measurements resulted in only limited disagreement (nine of 232 [3.9%]) versus histologic evaluation. When using 10 measurements, higher reliability measurements showed a lower percentage of discordance between pSWE and significant fibrosis and severe fibrosis or cirrhosis (22 [14.7%] and three [2.0%] of 150 cases, respectively) compared with lower reliability measurements (26 [31.7%] and eight [9.8%] of 82 cases, respectively). Significant fibrosis was an independent predictor for lower reliability (hazard ratio, 2.22; P < .020). Conclusion A limited number of SWV measurements (median six vs median 10) were required for the assessment of liver fibrosis by using pSWE. The number of measurements had less influence on the diagnostic accuracy compared with lower reliability measurements. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29514019 TI - Physician-Assisted Suicide and Psychiatric Illness. PMID- 29514017 TI - MR Imaging of Rectal Cancer: Radiomics Analysis to Assess Treatment Response after Neoadjuvant Therapy. AB - Purpose To investigate the value of T2-weighted-based radiomics compared with qualitative assessment at T2-weighted imaging and diffusion-weighted (DW) imaging for diagnosis of clinical complete response in patients with rectal cancer after neoadjuvant chemotherapy-radiation therapy (CRT). Materials and Methods This retrospective study included 114 patients with rectal cancer who underwent magnetic resonance (MR) imaging after CRT between March 2012 and February 2016. Median age among women (47 of 114, 41%) was 55.9 years (interquartile range, 45.4 66.7 years) and median age among men (67 of 114, 59%) was 55 years (interquartile range, 48-67 years). Surgical histopathologic analysis was the reference standard for pathologic complete response (pCR). For qualitative assessment, two radiologists reached a consensus. For radiomics, one radiologist segmented the volume of interest on high-spatial-resolution T2-weighted images. A random forest classifier was trained to separate the patients by their outcomes after balancing the number of patients in each response category by using the synthetic minority oversampling technique. Statistical analysis was performed by using the Wilcoxon rank-sum test, McNemar test, and Benjamini-Hochberg method. Results Twenty-one of 114 patients (18%) achieved pCR. The radiomic classifier demonstrated an area under the curve of 0.93 (95% confidence interval [CI]: 0.87, 0.96), sensitivity of 100% (95% CI: 0.84, 1), specificity of 91% (95% CI: 0.84, 0.96), positive predictive value of 72% (95% CI: 0.53, 0.87), and negative predictive value of 100% (95% CI: 0.96, 1). The diagnostic performance of radiomics was significantly higher than was qualitative assessment at T2-weighted imaging or DW imaging alone (P < .02). The specificity and positive predictive values were significantly higher in radiomics than were at combined T2-weighted and DW imaging (P < .0001). Conclusion T2-weighted-based radiomics showed better classification performance compared with qualitative assessment at T2-weighted and DW imaging for diagnosing pCR in patients with locally advanced rectal cancer after CRT. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29514020 TI - Self-Management of an Inferior ST-Segment Elevation Myocardial Infarction. PMID- 29514021 TI - Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. PMID- 29514022 TI - Case 7-2018: A 25-Year-Old Man with New-Onset Seizures. PMID- 29514023 TI - Balancing Safety and Innovation for Cell-Based Regenerative Medicine. PMID- 29514024 TI - Management of Acute Hip Fracture. PMID- 29514025 TI - Letermovir Prophylaxis for Cytomegalovirus. PMID- 29514026 TI - Physician-Assisted Death for Psychiatric Patients - Misguided Public Policy. PMID- 29514027 TI - Acute Angle-Closure Glaucoma. PMID- 29514028 TI - Xanthogranulomatous Pyelonephritis. PMID- 29514029 TI - Tumors and Transformations. PMID- 29514031 TI - Ambient Temperature and Screening for Nasopharyngeal Cancer. PMID- 29514032 TI - A Gain-of-Function Mutation in EPO in Familial Erythrocytosis. AB - Familial erythrocytosis with elevated erythropoietin levels is frequently caused by mutations in genes that regulate oxygen-dependent transcription of the gene encoding erythropoietin ( EPO). We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis. This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1. (Funded by the Gebert Ruf Foundation and others.). PMID- 29514030 TI - Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B. AB - BACKGROUND: Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants' receiving hepatitis B immune globulin. METHODS: In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)-positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)-positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group). RESULTS: From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log10 IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29). CONCLUSIONS: In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .). PMID- 29514033 TI - Necrotizing Soft-Tissue Infections. PMID- 29514034 TI - Primary Sjogren's Syndrome. PMID- 29514035 TI - A Shift in Thinking to Reduce Mother-to-Infant Transmission of Hepatitis B. PMID- 29514036 TI - Hearing Loss in Adults. PMID- 29514037 TI - Effects of Sotagliflozin Added to Insulin in Type 1 Diabetes. PMID- 29514038 TI - Interleukin-4 (IL4) -590C/T (rs2243250) gene polymorphism is not associated with diabetic nephropathy (DN) in Caucasians with type 2 diabetes mellitus (T2DM). AB - Diabetic nephropathy (DN) is a microvascular complication that affects up to 40% of diabetic patients and can lead to end-stage kidney disease. Inflammatory cytokines such as interleukin 1 (IL-1), IL-6, IL-18 and tumor necrosis factor alpha (TNFalpha) have been linked to the development and progression of DN. The aim of our study was to examine the relationship between interleukin-4 (IL4) 590C/T (rs2243250) gene polymorphism and DN in patients with type 2 diabetes mellitus (T2DM). This study is a continuation of our previous research on the association between angiotensinogen (AGT) gene polymorphisms and DN in patients with T2DM. We included 651 unrelated Slovenian (Caucasian) patients who had had T2DM for at least 10 years. The participants were classified into a group of T2DM patients with DN (276 cases) and a group without DN (375 controls). IL4 rs2243250 polymorphism was analyzed using a TaqMan SNP genotyping assay and StepOne Real Time PCR System. The frequencies of rs2243250 TT, CT and CC (wild type) genotypes were 3.2%, 29.4% and 67.4%, respectively in patients with DN, and 2.7%, 34.4% and 62.9%, respectively in controls. Our logistic regression analysis adjusted for gender, age, diabetes duration, and glycated hemoglobin showed no association between rs2243250 and the risk for DN (OR 1.06; CI 0.37-3.05; p = 0.9). IL4 rs2243250 is not associated with DN in our subset of Slovenian patients with T2DM. PMID- 29514039 TI - A Young Patient with Leg Weakness and Hypokalemia-Case Report. AB - A 20-year-old female patient was admitted to hospital because of bilateral leg weakness. Laboratory investigation showed metabolic alkalosis and severe hypokalemia. Differential diagnosis included mineralocorticoid or apparent mineralocorticoid excess diseases, with a high aldosterone-to-renin ratio (ARR) after correcting hypokalemia. After confirmatory tests, imaging studies revealed a unilateral adrenocortical adenoma consistent with Conn's disease. Surgery was curative. PMID- 29514040 TI - A Population-based Study of Peripartum Cardiomyopathy in Southern Israel: Are Bedouin Women a New High-risk Group? AB - OBJECTIVES: Peripartum cardiomyopathy (PPCM) is a serious complication of pregnancy. Studies investigating the risk factors that worsen outcomes have yielded conflicting results. The goals of this study were to describe the clinical and echocardiographic characteristics of PPCM in a single tertiary center and to determine the prognostic factors associated with persistence of left ventricular (LV) dysfunction in these women. STUDY DESIGN: This retrospective cross-sectional population-based cohort study included all patients with PPCM confirmed by echocardiography who delivered at our center from 2004 to 2014. Two groups were compared to determine long-term maternal outcome: (1) those who recovered normal LV function; and (2) those with residual systolic LV dysfunction. RESULTS: There were 148,994 deliveries during the study period. Of these, 89,196 patients were Bedouin and 59,798 were non-Bedouin. Forty-six patients met the PPCM study inclusion criteria. The PPCM prevalence for the total deliveries was 1:3,239. The PPCM prevalence among Bedouin patients was 1:2,787 versus non-Bedouin patients of 1:4,983 (P=0.037). None of the women had pre existing chronic hypertension, and there was no maternal death. Patients who had severe or moderate LV dysfunction at the clinical presentation of PPCM were less likely to regain normal LV function than those with mild dysfunction (81.2% versus 56.7%, P=0.009). Based on initial echocardiogram, a trend toward residual LV dysfunction was noted in patients with a dilated left ventricle as compared to those with a non-dilated left ventricle (18.8% versus 6.7%, P=0.32). A hypokinetic right ventricle was found in 15.2% of the women who suffered from PPCM. CONCLUSION: In our cohort, Bedouin women may be at increased risk for PPCM, and patients with severe LV dysfunction have a lower chance of recovery from PPCM. PMID- 29514041 TI - Recombinant batroxobin-coated nonwoven chitosan as hemostatic dressing for initial hemorrhage control. AB - The choice of hemostat is determined by the situation and the degree of hemorrhage. One common hemostat, the nonwoven dressing, is easy to handled and controls severe bleeding on wider wounds. In this study, chitosan-based nonwoven dressings with recombinant batroxobin (rBat) were used as efficacious hemostatic dressing agents. Hemostatic agents need to absorb blood quickly in the early stages of blood coagulation cascade to rapidly and effectively control of excessive hemorrhages. To date, most studies of hemostatic agents focused on a single material and hemostats composed of multiple materials have not been studied sufficiently. Thus, we made a chitosan dressing coated with rBat and investigated the microstructure, mechanical properties, hemostatic efficacy, and clotting properties of the coated dressing. Our results showed that the rBat had a synergetic effect on chitosan that improved blood coagulation. Furthermore, the dressing had excellent bleeding control in an Sprague-Dawley (SD) rat femoral artery hemorrhage model. In conclusion, hemostasis can be improved by combining a chitosan-based nonwoven dressing with other agents, and rBat-coated chitosan based nonwoven dressings have enormous potential to improve blood coagulation. PMID- 29514042 TI - Cloning, expression, characterization and homology modeling of a novel water forming NADH oxidase from Streptococcus mutans ATCC 25175. AB - A novel nicotinamide adenine dinucleotide (NADH) oxidase from Streptococcus mutans ATCC 25175 (SmNox) was cloned and overexpressed in Escherichia coli BL21 (DE3). Sequence analysis revealed an open reading frame of 1374bp, capable of encoding a polypeptide of 457 amino acid residues. The molecular mass of the purified SmNox was estimated to be ~49.9kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The purified SmNox had the highest specific activity of 281.2U.mg-1 at optimal pH and temperature of 7.0 and 35 degrees C, with a Km of 57.7MUM and a Vmax of 154.3U.mg-1. The good stability at room temperature was observed. Homology modeling and substrate docking were performed to evaluate the catalytic characteristics. The results indicated that Nicotinamide ring of NADH extends vertically toward to re-face of coenzyme (FAD), and the specific conformation of NADH suggested that the charges transfer in SmNox complex could be easier than in its homologous enzyme (LbNox) under alkaline environment. The characterization of the SmNox indicated it has potential in industrial regeneration of coenzyme NAD+ for coupling with dehydrogenases. PMID- 29514043 TI - "It is my business": A Mixed-Methods Analysis of Covert Contraceptive Use among Women in Rakai, Uganda. AB - OBJECTIVES: Covert contraceptive use (CCU) is the use of family planning without a partner's knowledge. This study sought to examine CCU prevalence among women living in Rakai, Uganda, predictors of CCU, and why women resort to CCU. STUDY DESIGN: We used data from women (15-49years) currently using contraceptives (oral contraceptives, Depo Provera, implants, intrauterine devices, and periodic abstinence) during Round 15 (2011-2013) of the Rakai Community Cohort Survey (n=2206). We utilized logistic regressions to analyze the association between self-reported CCU and current contraceptive method, sexual activity, experience of violence, and demographic data. We also used data from in-depth interviews (IDI) on HIV and reproductive health conducted in 2013-2016. RESULTS: CCU prevalence was 26%. In the multivariable model, being previously married (aOR=2.2 [1.7-2.9]), having no formal education (aOR=2.1 [1.1-3.9]), and experiencing physical violence (aOR=1.7 [1.3-2.2]) or having more than 1 sex partner (aOR=1.6 [1.2-2.2]) in the past 12months were CCU predictors. Advancing past primary school decreased the odds of CCU (aOR=0.7 [0.6-0.9]). HIV was positively associated with CCU in the unadjusted model, but not the adjusted. In the IDIs, women primarily resorted to CCU because of discordant fertility desires-coupled with financial insecurity, negative stereotypes towards contraceptives use, deteriorating health, and familial pressure to reproduce. One woman employed CCU because she feared being ostracized from her community. CONCLUSIONS: CCU is common amongst users of contraception and is used to hide family planning from partners and communities. Women that diverge from Uganda's cultural norms had higher odds of CCU. IMPLICATIONS: Clinicians and practitioners should be aware of CCU among their patients and should educate women on the wide variety of contraceptive methods to help them decide if their current covert method is best for their health and safety. PMID- 29514044 TI - Usefulness of in-house real time PCR for HBV DNA quantification in serum and oral fluid samples. AB - For quantification of hepatitis B virus DNA (HBV DNA), commercial assays are used with serum or plasma samples, but oral fluid samples could be an alternative for HBV diagnosis due to ease of collection. This study aims to develop in-house real time PCR using synthetic curve for HBV DNA quantification for serum and oral fluid samples. Samples were collected from 103 individuals (55 HBsAg reactive and HBV DNA reactive by commercial assay and 48 without HBV markers) and submitted to two in-house real time PCR assays for HBV pre-S/S region with different standard curves: qPCR plasmidial and qPCR synthetic. A total of 27 serum samples were HBV DNA positive by qPCR plasmidial and 40 with qPCR synthetic (72% and 85% of concordance, respectively). Quantitative PCR synthetic presented efficiency of 99% and sensitivity of 2log10 copies/mL. Among oral fluid samples, five and ten were detected using qPCR plasmidial and synthetic, respectively. This study demonstrated that qPCR synthetic using serum samples could be used as alternative for HBV DNA quantification due to its sensitivity. In addition, it was possible to quantify HBV DNA in oral fluid samples suggesting the potential of this specimen for molecular diagnosis of HBV. PMID- 29514045 TI - Integrated data analysis identifies potential inducers and pathways during the endothelial differentiation of bone-marrow stromal cells by DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. AB - Bone-Marrow Stromal Cells (BMSCs)-derived vascular endothelial cells (VECs) is regarded as an important therapeutic strategy for spinal cord injury, disc degeneration, cerebral ischemic disease and diabetes. The change in DNA methylation level is essential for stem cell differentiation. However, the DNA methylation related mechanisms underlying the endothelial differentiation of BMSCs are not well understood. In this study, DNA methyltransferase inhibitor, 5 aza-2'-deoxycytidine (5-aza-dC) significantly elevated the endothelial markers expression (CD31/PECAM1, CD105/ENG, eNOS and VE-cadherin), as well as promoted the capacity of angiogenesis on Matrigel. The result of Alexa 488-Ac-LDL uptake assay indicated that the differentiation ratio of BMSCs into VECs was 68.7% in 5 azaz-dC induced differentiation. And then we screened differentiation inducers with altered expression patterns and DNA methylation levels in four important families (VEGF, ANG, FGF and ETS). By integrating these data, five endothelial differentiation inducers (VEGFA, ANGPT2, FGF2, FGF9 and ETS1) which were directly upregulated by 5-aza-dC and five indirect factors (FGF1, FGF3, ETS2, ETV1 and ETV4) were identified. These data suggested that 5-aza-dC is an excellent chemical molecule for BMSCs differentiation into functional VECs and also provided essential clues for DNA methylation related signaling during 5-aza-dC induced endothelial differentiation of BMSCs. PMID- 29514046 TI - Resveratrol stimulates c-Fos gene transcription via activation of ERK1/2 involving multiple genetic elements. AB - The polyphenol resveratrol is found in many plant and fruits and is a constituent of our diet. Resveratrol has been proposed to have chemopreventive and anti inflammatory activities. On the cellular level, resveratrol activates stimulus regulated transcription factors. To identify resveratrol-responsive elements within a natural gene promoter, the molecular pathway leading to c-Fos gene expression by resveratrol was dissected. The c-Fos gene encodes a basic region leucine zipper transcription factor and is a prototype of an immediate-early gene that is regulated by a wide range of signaling molecules. We analyzed chromatin integrated c-Fos promoter-luciferase reporter genes where transcription factor binding sites were destroyed by point mutations or deletion mutagenesis. The results show that mutation of the binding sites for serum response factor (SRF), activator protein-1 (AP-1) and cAMP response element binding protein (CREB) significantly reduced reporter gene transcription following stimulation of the cells with resveratrol. Inactivation of the binding sites for signal transducer and activator of transcription (STAT) or ternary complex factors did not influence resveratrol-regulated c-Fos promoter activity. Thus, the c-Fos promoter contains three resveratrol-responsive elements, the cAMP response element (CRE), and the binding sites for SRF and AP-1. Moreover, we show that the transcriptional activation potential of the c-Fos protein is increased in resveratrol-stimulated cells, indicating that the biological activity of c-Fos is elevated by resveratrol stimulation. Pharmacological and genetic experiments revealed that the protein kinase ERK1/2 is the signal transducer that connects resveratrol treatment with the c-Fos gene. PMID- 29514047 TI - Deletion of NLRX1 increases fatty acid metabolism and prevents diet-induced hepatic steatosis and metabolic syndrome. AB - NOD-like receptor (NLR)X1 (NLRX1) is an ubiquitously expressed inflammasome independent NLR that is uniquely localized in mitochondria with as yet unknown effects on metabolic diseases. Here, we report that NLRX1 is essential in regulating cellular metabolism in non-immune parenchymal hepatocytes by decreasing mitochondrial fatty acid-dependent oxidative phosphorylation (OXPHOS) and promoting glycolysis. NLRX1 loss in mice has a profound impact on the prevention of diet-induced metabolic syndrome parameters, non-alcoholic fatty liver disease (NAFLD) progression, and renal dysfunction. Despite enhanced caloric intake, NLRX1 deletion in mice fed a western diet (WD) results in protection from liver steatosis, hepatic fibrosis, obesity, insulin resistance, glycosuria and kidney dysfunction parameters independent from inflammation. While mitochondrial content was equal, NLRX1 loss in hepatocytes leads to increased fatty acid oxidation and decreased steatosis. In contrast, glycolysis was decreased in NLRX1-deficient cells versus controls. Thus, although first implicated in immune regulation, we show that NLRX1 function extends to the control of hepatocyte energy metabolism via the restriction of mitochondrial fatty acid-dependent OXPHOS and enhancement of glycolysis. As such NLRX1 may be an attractive novel therapeutic target for NAFLD and metabolic syndrome. PMID- 29514048 TI - Endothelial cells cope with hypoxia-induced depletion of ATP via activation of cellular purine turnover and phosphotransfer networks. AB - Intravascular ATP and adenosine have emerged as important regulators of endothelial barrier function, vascular remodeling and neovascularization at various pathological states, including hypoxia, inflammation and oxidative stress. By using human umbilical vein endothelial cells (HUVEC) and bovine vasa vasorum endothelial cells (VVEC) as representatives of macro- and microvessel phenotypes, this study was undertaken to evaluate cellular mechanisms contributing to physiological adaptation of vascular endothelium to hypoxia, with a particular emphasis on ectoenzymatic purine-converting activities and their link to intracellular ATP homeostasis and signaling pathways. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), ecto-5'-nucleotidase/CD73 and ecto-adenylate kinase activities were determined by thin-layer chromatography (TLC) with 3H-labelled nucleotide substrates. Exposure of HUVEC and VVEC to 1% O2 for 4-24 h triggered rather moderate activation of ATP breakdown into adenosine via the CD39-CD73 axis. Additional TLC analysis of salvage pathways revealed the enhanced ability of hypoxic HUVEC to convert cell-incorporated [3H]adenosine into [3H]ADP/ATP. Furthermore, following a period of hypoxia, HUVEC underwent concurrent changes in intracellular signaling manifested in the depletion of putative ATP stores and targeted up-regulation of phospho-p53, p70S6K/mTOR and other tyrosine kinases. The revealed complex implication of both extrinsic and intrinsic mechanisms into a tuned hypoxia-induced control of purine homeostasis and signaling may open up further research for the development of pharmacological treatments to improve endothelial cell function under disease conditions associated with a loss of cellular ATP during oxygen deprivation. PMID- 29514050 TI - Mechanism of aggregation and membrane interactions of mammalian prion protein. AB - The cellular prion protein (PrPC), which is present ubiquitously in all mammalian neurons, is normally found to be linked to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. The conformational conversion of PrPC into misfolded and aggregated forms is associated with transmissible neurodegenerative diseases known as prion diseases. The importance of different misfolded conformations in prion diseases, and the mechanism by which prion aggregates induce neurotoxicity remain poorly understood. Multiple studies have been shown that the toxicity of misfolded prion protein is directly correlated with its ability to interact with and perturb membranes. This review describes the current progress toward understanding prion protein misfolding and aggregation, as well as the interaction of prion protein aggregates with lipid membrane. PMID- 29514049 TI - Comparison of Drug-Eluting Stent with Bare-Metal Stent Implantation in Femoropopliteal Artery Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: This study aimed to perform a systematic review and meta-analysis of current evidence comparing the drug-eluting stent (DES) with the bare-metal stent (BMS) in the treatment of femoropopliteal artery disease (FPAD). METHODS: All relevant articles reporting the results of DES versus BMS implantation in FPAD were systematically searched in MEDLINE, EMBASE, and Cochrane database. Randomized controlled trial (RCT), cohort, and retrospective study were all included. The efficacy end points included late lumen loss (LLL), binary restenosis, primary patency rate, freedom from target lesion revascularization (TLR), and stent fracture. Related data of the follow-up outcomes were extracted and pooled. For each end point, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 9 studies with 776 patients were included in this meta-analysis. There was no statistically significant difference between the DES and BMS groups in terms of LLL at 6 months (standard mean difference = -0.37, P = 0.07); binary restenosis at 6, 12, and 24 months (OR = 0.44, P = 0.20; OR = 0.75, P = 0.74; and OR = 0.62, P = 0.36; respectively); primary patency rate at 6, 12, and 24 months (OR = 1.18, P = 0.73; OR = 1.43, P = 0.70; OR = 1.25, P = 0.68, respectively); freedom from TLR at 12 months (OR = 1.13, P = 0.79); and stent fracture at 6 months (OR = 1.67, P = 0.38). A sensitivity analysis demonstrated that there was a significant benefit in the DES group over the BMS group in binary restenosis at 6 months (OR = 0.22, P = 0.008) after excluding a retrospective study, whereas no significant difference was observed when eliminating any other study. A subgroup analysis did not reveal any significant difference between a subgroup (sirolimus-eluting stent or paclitaxel eluting stent) and the BMS group in FPAD. CONCLUSIONS: According to current evidence, DES was not superior to BMS in the treatment of FPAD. Further larger RCTs are needed to provide more evidence in the comparison between DES and BMS for FPAD. PMID- 29514051 TI - Preparation of poloxamer-based nanofibers for enhanced dissolution of carvedilol. AB - Polymer nanofibers have become increasingly important for improvement of dissolution and bioavailability of poorly soluble drugs, representing a great challenge in pharmaceutical development. Here, we introduced a new concept of using amphiphilic polymers as fundamental excipients in electrospun nanofibers, which would improve drug solubilization and accelerate its release. Hydrophilic poloxamer-based nanofibers were developed as a novel drug delivery system for carvedilol. These nanofibers were electrospun from different liquid carvedilol dispersions, as carvedilol (nano)suspensions or ethanol solution. The electrospun products showed similar morphologies, but different mean fiber diameters (170-450 nm). Carvedilol dissolution rates from nanofibers were faster compared to its dissolution from polymer films. The electrospinning from ethanol solution resulted in the highest dissolution rate, since >90% of the drug was dissolved in the first 5 min. The type of liquid medium significantly affects also the drug crystallinity. Thus, nanofibers produced from ethanol polymer solution showed no detectable crystalline carvedilol, whereas crystalline carvedilol form II or III was detected in the other nanofiber samples investigated. In a prolonged stability study (to 1 year), the potential of nanofibers to preserve the active ingredient in the initial non-crystalline form was demonstrated. Poloxamer-based nanofibers thus represent a promising formulation for immediate release and improved dissolution rates of poorly soluble drugs. PMID- 29514052 TI - Analytical and clinical validation of a dried blood spot assay for the determination of paclitaxel using high-performance liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Paclitaxel (PCT) is a chemotherapeutic drug widely used for the treatment of several types of tumors, and its use is associated with severe adverse events, mainly neurologic and hematopoietic toxicities. The relation between systemic exposure and clinical response to PCT was previously described, making paclitaxel a potential candidate for therapeutic drug monitoring (TDM). The use of dried blood spot (DBS) sampling could allow complex sampling schedules required for TDM of PCT. The aim of this study was to develop and validate an LC MS/MS assay for the quantification of PCT in DBS. METHODS: PCT was extracted from one 8 mm DBS punch with a mixture of methanol and acetonitrile, followed by chromatographic separation in a Kinetex C18 (50 * 4.6 mm, 2.6 MUm) column. Detection was performed in a 5500-QTRAP(r) mass spectrometer, with a run time of 2.3 min. RESULTS: The assay was linear in the range of 2.5 to 400 ng mL-1. Precision (CV%) and accuracy at the concentration levels of 7.5, 40 and 150 ng mL 1 were 1.69-4.9% and 106.25 to 109.92%, respectively. PCT was stable for 21 days at 25 and 45 degrees C. The method was applied to DBS samples obtained from 34 patients under PCT chemotherapy. The use of a simple correction factor, derived from the correlation between PCT concentrations in plasma and DBS in this set of patients, allowed unbiased estimation of PCT plasma concentrations from DBS measurements, with similar clinical decisions using either plasma or DBS measurements. CONCLUSIONS: DBS testing of PCT concentrations represents a promising alternative for the dissemination of PCT dose individualization. PMID- 29514054 TI - The long-lived Octodon degus as a rodent drug discovery model for Alzheimer's and other age-related diseases. AB - Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disease. Despite decades of research, no disease modifying therapy is available and a change of research objectives and/or development of novel research tools may be required. Much AD research has been based on experimental models using animals with a short lifespan that have been extensively genetically manipulated and do not represent the full spectrum of late-onset AD, which make up the majority of cases. The aetiology of AD is heterogeneous and involves multiple factors associated with the late-onset of the disease like disturbances in brain insulin, oxidative stress, neuroinflammation, metabolic syndrome, retinal degeneration and sleep disturbances which are all progressive abnormalities that could account for many molecular, biochemical and histopathological lesions found in brain from patients dying from AD. This review is based on the long-lived rodent Octodon degus (degu) which is a small diurnal rodent native to South America that can spontaneously develop cognitive decline with concomitant phospho tau, beta-amyloid pathology and neuroinflammation in brain. In addition, the degu can also develop several other conditions like type 2 diabetes, macular and retinal degeneration and atherosclerosis, conditions that are often associated with aging and are often comorbid with AD. Long-lived animals like the degu may provide a more realistic model to study late onset AD. PMID- 29514055 TI - Structure-activity relationships of HDAC8 inhibitors: Non-hydroxamates as anticancer agents. AB - Histone deacetylase inhibitors (HDACIs) have a paramount importance in the acetylation process of histone and non-histone proteins that are crucial players in the cellular epigenetic modifications. HDACIs exert effective antiproliferation through DNA repairing, cell cycle arrest, apoptosis induction and alteration of genetic expression. HDAC8 is one of the crucial HDACs, affects the epigenetic gene silencing process and cancer progression. Hence, HDAC8 is one of the key cancer targets among class I HDACs that may be effectively blocked as a benchmark therapy to combat malignancy. In the current review, a special emphasis has been given for the non-hydroxamate type of HDAC8 inhibitors. It may provide some fruitful structural information to design newer better active candidates to fight against target specific malignancies in future. PMID- 29514056 TI - Hydrogen sulfide and autophagy: A double edged sword. AB - Hydrogen sulfide (H2S) has been considered the third gaseous signaling molecule that plays important roles in a wide range of physiological and pathological conditions. However, there has been some controversy on the role of H2S in autophagy. Recent studies indicate that a number of signaling pathways are involved in the pro-autophagy effect of H2S, such as PI3K/Akt/mTOR, AMPK/mTOR, LKB1/STRAD/MO25, and miR-30c signaling pathways. On the other hand, there are many signaling pathways that play important roles in the anti-autophagy effect of H2S, including SR-A, PI3K/SGK1/GSK3beta, PI3K/AKT/mTOR, Nrf2-ROS-AMPK, AMPK/mTOR, and JNK1 signaling pathways. Novel H2S-releasing donors/drugs could be designed and identified in order to increase the therapeutic effects by mediating autophagy in human diseases. In this review, the H2S metabolism in mammals is summarized and the effects of signaling pathways in H2S-mediated autophagy are further discussed. PMID- 29514057 TI - Calcium sensing receptor expression and signalling in cardiovascular physiology and disease. AB - Initially identified in the parathyroidea, the calcium sensing receptor (CaSR) is now recognized as an ubiquitously expressed receptor that exerts specific functions in multiple organs including the cardiovascular system. This review will focus on the role that CaSR plays in vascular and cardiac tissues. In the vasculature, CaSR is expressed in endothelial and smooth muscle cells. CaSR of endothelial cells participates in part to the regulation of local perfusion by linkage of CaSR activation to endothelial hyperpolarization and nitric oxide release. CaSR of smooth muscle cells is involved in the control of proliferation. In the pulmonary vasculature, however, CaSR participates in the onset of pulmonary hypertension, making CaSR antagonism a therapeutic option in this case. In the heart, CaSR is expressed in cardiac fibroblasts and myoyctes, contributing to normal cardiac function and composition of extracellular matrix. More important, activation of CaSR may participate in the cardiac protective effects of ischaemic pre-conditioning. In conclusion, CaSR plays an important physiological role in many regulatory pathways of the cardiovascular system, but due to the complex interaction between various cardiovascular cells and cell specific effects, use of activators or inhibitors of CaSR for treatment of specific disease forms is yet not on the way. PMID- 29514058 TI - Food for Training-Western Diet and Inflammatory Memory. AB - In recent years, trained immunity has emerged as an attractive concept to explain cross-protection against pathogens mediated by the innate immune system. Using a diet-based sterile inflammation model, Christ et al. (2018) have shown in a recent issue of Cell that trained immunity may also play a critical role in responding to diet and endogenous sterile triggers. PMID- 29514059 TI - Dietary Fructose Metabolism By Splanchnic Organs: Size Matters. AB - The initial metabolism of fructose is thought to primarily take place in the liver. Using stable isotope labeling combined with tissue and arterio-venous sampling, Jang et al. (2018) demonstrate that in mice, the small intestine is the primary site of fructose metabolism. This raises important questions about fructose handling in humans. PMID- 29514053 TI - The role of TAM family receptors and ligands in the nervous system: From development to pathobiology. AB - Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K-dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6-/- and TAM mutant mice models. PMID- 29514060 TI - Adipose Dendritic Cells Come Out of Hiding. AB - In this issue of Cell Metabolism, Macdougall et al. (2018) identify two subsets of conventional dendritic cells in visceral adipose tissue and demonstrate that these subsets engage distinct adipocyte-associated signaling pathways to drive their tolerogenic phenotypes in the lean state. PMID- 29514061 TI - High Cholesterol at the Heart of Phagolysosomal Damage. AB - Phagolysosome membrane rupture can trigger a maladaptive immune response that promotes tissue damage. In Science, Cantuti-Castelvetri et al. (2018) report that cholesterol-rich myelin debris overwhelms reverse cholesterol transport in aged phagocytes, leading to cholesterol crystal formation, damaged phagolysosomes, and limited tissue repair. PMID- 29514062 TI - Diet and Cardiovascular Disease: Advances and Challenges in Population-Based Studies. AB - In this Minireview, we provide an epidemiologist's perspective on the debate and recent advances in determining the relationship between diet and cardiovascular health. We conclude that, in order to reduce the global burden of cardiovascular disease, there should be a greater emphasis on improving overall diet quality and food sources of macronutrients, such as dietary fats and carbohydrates. In addition, building a strong evidence base through high-quality intervention and observational studies is crucial for effective policy changes, which can greatly improve the food environment and population health. PMID- 29514063 TI - The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications. AB - Post-translational modification of lysine residues via reversible acylation occurs on proteins from diverse pathways, functions, and organisms. While nuclear protein acylation reflects the competing activities of enzymatic acyltransferases and deacylases, mitochondrial acylation appears to be driven mostly via a non enzymatic mechanism. Three protein deacylases, SIRT3, SIRT4, and SIRT5, reside in the mitochondria and remove these modifications from targeted proteins in an NAD+ dependent manner. Recent proteomic surveys of mitochondrial protein acylation have identified the sites of protein acetylation, succinylation, glutarylation, and malonylation and their regulation by SIRT3 and SIRT5. Here, we review recent advances in this rapidly moving field, their biological significance, and their implications for mitochondrial function, metabolic regulation, and disease pathogenesis. PMID- 29514064 TI - Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. AB - Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan. PMID- 29514066 TI - Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis. AB - Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway. PMID- 29514065 TI - Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point. AB - Every animal species has a signature blood glucose level or glycemic set point. These set points are different, and the normal glycemic levels (normoglycemia) of one species would be life threatening for other species. Mouse normoglycemia can be considered diabetic for humans. The biological determinants of the glycemic set point remain unclear. Here we show that the pancreatic islet imposes its glycemic set point on the organism, making it the bona fide glucostat in the body. Moreover, and in contrast to rodent islets, glucagon input from the alpha cell to the insulin-secreting beta cell is necessary to fine-tune the distinctive human set point. These findings affect transplantation and regenerative approaches to treat diabetes because restoring normoglycemia may require more than replacing only the beta cells. Furthermore, therapeutic strategies using glucagon receptor antagonists as hypoglycemic agents need to be reassessed, as they may reset the overall glucostat in the organism. PMID- 29514067 TI - Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets. AB - Visceral adipose tissue (VAT) has multiple roles in orchestrating whole-body energy homeostasis. In addition, VAT is now considered an immune site harboring an array of innate and adaptive immune cells with a direct role in immune surveillance and host defense. We report that conventional dendritic cells (cDCs) in VAT acquire a tolerogenic phenotype through upregulation of pathways involved in adipocyte differentiation. While activation of the Wnt/beta-catenin pathway in cDC1 DCs induces IL-10 production, upregulation of the PPARgamma pathway in cDC2 DCs directly suppresses their activation. Combined, they promote an anti inflammatory milieu in vivo delaying the onset of obesity-induced chronic inflammation and insulin resistance. Under long-term over-nutrition, changes in adipocyte biology curtail beta-catenin and PPARgamma activation, contributing to VAT inflammation. PMID- 29514068 TI - Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues. AB - The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function. These biomechanical signaling mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes. PMID- 29514069 TI - Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits. AB - Brown adipose tissue (BAT) thermogenesis is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that BAT-specific liver kinase b1 knockout (Lkb1BKO) mice exhibited impaired BAT mitochondrial respiration and thermogenesis but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to defective BAT mitochondrial respiration in Lkb1BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the trade-off between BAT thermogenesis and systemic metabolism at room temperature and thermoneutrality. Collectively, our data demonstrate that ETC proteome imbalance in BAT regulates systemic metabolism independently of thermogenesis. PMID- 29514070 TI - The Pericyte of the Pancreatic Islet Regulates Capillary Diameter and Local Blood Flow. AB - Efficient insulin secretion requires a well-functioning pancreatic islet microvasculature. The dense network of islet capillaries includes the islet pericyte, a cell that has barely been studied. Here we show that islet pericytes help control local blood flow by adjusting islet capillary diameter. Islet pericytes cover 40% of the microvasculature, are contractile, and are innervated by sympathetic axons. Sympathetic adrenergic input increases pericyte activity and reduces capillary diameter and local blood flow. By contrast, activating beta cells by increasing glucose concentration inhibits pericytes, dilates islet capillaries, and increases local blood flow. These effects on pericytes are mediated by endogenous adenosine, which is likely derived from ATP co-released with insulin. Pericyte coverage of islet capillaries drops drastically in type 2 diabetes, suggesting that, under diabetic conditions, islets lose this mechanism to control their own blood supply. This may lead to inadequate insulin release into the circulation, further deteriorating glycemic control. PMID- 29514071 TI - Yeast Mitoribosome Large Subunit Assembly Proceeds by Hierarchical Incorporation of Protein Clusters and Modules on the Inner Membrane. AB - Mitoribosomes are specialized for the synthesis of hydrophobic membrane proteins encoded by mtDNA, all essential for oxidative phosphorylation. Despite their linkage to human mitochondrial diseases and the recent cryoelectron microscopy reconstruction of yeast and mammalian mitoribosomes, how they are assembled remains obscure. Here, we dissected the yeast mitoribosome large subunit (mtLSU) assembly process by systematic genomic deletion of 44 mtLSU proteins (MRPs). Analysis of the strain collection unveiled 37 proteins essential for functional mtLSU assembly, three of which are critical for mtLSU 21S rRNA stability. Hierarchical cluster analysis of mtLSU subassemblies accumulated in mutant strains revealed co-operative assembly of protein sets forming structural clusters and preassembled modules. It also indicated crucial roles for mitochondrion-specific membrane-binding MRPs in anchoring newly transcribed 21S rRNA to the inner membrane, where assembly proceeds. Our results define the yeast mtLSU assembly landscape in vivo and provide a foundation for studies of mitoribosome assembly across evolution. PMID- 29514072 TI - Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. AB - The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+, is elusive. Here, we report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Untargeted metabolite profiling of the liver and metabolic flux analysis of liver-derived cells revealed NAM-mediated improvement in glucose homeostasis in mice on a high fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Targeted NAD metabolome analysis in liver revealed depressed expression of NAM salvage in NAM-treated mice, an effect counteracted by higher expression of de novo NAD biosynthetic enzymes. Although neither hepatic NAD+ nor NADP+ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD fed mice in the absence of survival effects. PMID- 29514074 TI - Non-invasive Measurement of Brown Fat Metabolism Based on Optoacoustic Imaging of Hemoglobin Gradients. AB - Metabolism is a fundamental process of life. However, non-invasive measurement of local tissue metabolism is limited today by a deficiency in adequate tools for in vivo observations. We designed a multi-modular platform that explored the relation between local tissue oxygen consumption, determined by label-free optoacoustic measurements of hemoglobin, and concurrent indirect calorimetry obtained during metabolic activation of brown adipose tissue (BAT). By studying mice and humans, we show how video-rate handheld multi-spectral optoacoustic tomography (MSOT) in the 700-970 nm spectral range enables non-invasive imaging of BAT activation, consistent with positron emission tomography findings. Moreover, we observe BAT composition differences between healthy and diabetic tissues. The study consolidates hemoglobin as a principal label-free biomarker for longitudinal non-invasive imaging of BAT morphology and bioenergetics in situ. We also resolve water and fat components in volunteers, and contrast MSOT readouts with magnetic resonance imaging data. PMID- 29514075 TI - Deciphering Pancreatic Islet beta Cell and alpha Cell Maturation Pathways and Characteristic Features at the Single-Cell Level. PMID- 29514073 TI - Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. AB - Caloric restriction (CR) extends lifespan and delays the onset of age-related disorders in diverse species. Metabolic regulatory pathways have been implicated in the mechanisms of CR, but the molecular details have not been elucidated. Here, we show that CR engages RNA processing of genes associated with a highly integrated reprogramming of hepatic metabolism. We conducted molecular profiling of liver biopsies collected from adult male rhesus monkeys (Macaca mulatta) at baseline and after 2 years on control or CR (30% restricted) diet. Quantitation of over 20,000 molecules from the hepatic transcriptome, proteome, and metabolome indicated that metabolism and RNA processing are major features of the response to CR. Predictive models identified lipid, branched-chain amino acid, and short chain carbon metabolic pathways, with alternate transcript use for over half of the genes in the CR network. We conclude that RNA-based mechanisms are central to the CR response and integral in metabolic reprogramming. PMID- 29514076 TI - Virus-like Immune Defense Protein in Mushrooms. AB - Fungi and plants do not have an adaptive immune system. Innate immunity serves as their sole defense, often based on carbohydrate recognition by lectins. In a twist of nature, as revealed by Sommer et al. (2018) in this issue of Structure, a conserved fungal immunoprotein adopts the shape of a miniature virus. PMID- 29514077 TI - Conserved Functional Dynamics: I Like to Move It, Move It! AB - The catalytic activities of enzymes are typically associated with their unique structures. However, structural dynamics may also play a functional role in enzyme catalysis. In support of this idea, Narayanan et al. (2018) show in this issue of Structure that enzymes are characterized by the presence of evolutionarily conserved dynamic traits. PMID- 29514079 TI - An Augmented Pocketome: Detection and Analysis of Small-Molecule Binding Pockets in Proteins of Known 3D Structure. AB - Protein-ligand interactions form the basis of most cellular events. Identifying ligand binding pockets in proteins will greatly facilitate rationalizing and predicting protein function. Ligand binding sites are unknown for many proteins of known three-dimensional (3D) structure, creating a gap in our understanding of protein structure-function relationships. To bridge this gap, we detect pockets in proteins of known 3D structures, using computational techniques. This augmented pocketome (PocketDB) consists of 249,096 pockets, which is about seven times larger than what is currently known. We deduce possible ligand associations for about 46% of the newly identified pockets. The augmented pocketome, when subjected to clustering based on similarities among pockets, yielded 2,161 site types, which are associated with 1,037 ligand types, together providing fold-site type-ligand-type associations. The PocketDB resource facilitates a structure based function annotation, delineation of the structural basis of ligand recognition, and provides functional clues for domains of unknown functions, allosteric proteins, and druggable pockets. PMID- 29514078 TI - Mechanism of Mg2+-Accompanied Product Release in Sugar Nucleotidyltransferases. AB - The nucleotidyl transfer reaction, catalyzed by sugar nucleotidyltransferases (SNTs), is assisted by two active site Mg2+ ions. While studying this reaction using X-ray crystallography, we captured snapshots of the pyrophosphate (product) as it exits along a pocket. Surprisingly, one of the active site Mg2+ ions remains coordinated to the exiting pyrophosphate. This hints at the participation of Mg2+ in the process of product release, besides its role in catalyzing nucleotidyl transfer. These observations are further supported by enhanced sampling molecular dynamics simulations. Free energy computations suggest that the product release is likely to be rate limiting in SNTs, and the origin of the high free energy barrier for product release could be traced back to the "slow" conformational change of an Arg residue at the exit end of the pocket. These results establish a dual role for Mg2+, and propose a general mechanism of product release during the nucleotidyl transfer by SNTs. PMID- 29514080 TI - From Retina to Stem Cell and Back Again: Memories of a Chromatin Journey. AB - The use of retinal organoids requires efficient differentiation from induced pluripotent stem cells (iPSCs). In this issue of Cell Reports, Wang et al. (2018) examine how the chromatin landscape after iPSC programming predicts their ability to differentiate into retinal tissue. PMID- 29514082 TI - Periostin Limits Tumor Response to VEGFA Inhibition. AB - Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and alphaSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2 like macrophages in human PNETs, and depleting macrophages with a colony stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. PMID- 29514081 TI - ERRgamma Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1alpha/beta-Deficient Muscle. AB - PGC1alpha is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRgamma. To decipher their epistatic relationship, we explored ERRgamma gain of function in muscle-specific PGC1alpha/beta double-knockout (PKO) mice. ERRgamma-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1alpha/beta. Furthermore, in combination with voluntary exercise, ERRgamma gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1alpha/beta regulates both innate and adaptive energy metabolism. PMID- 29514083 TI - PI3K/Akt Cooperates with Oncogenic Notch by Inducing Nitric Oxide-Dependent Inflammation. AB - The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis. PMID- 29514084 TI - Innate Immune Signaling in Drosophila Blocks Insulin Signaling by Uncoupling PI(3,4,5)P3 Production and Akt Activation. AB - In obese adipose tissue, Toll-like receptor signaling in macrophages leads to insulin resistance in adipocytes. Similarly, Toll signaling in the Drosophila larval fat body blocks insulin-dependent growth and nutrient storage. We find that Toll acts cell autonomously to block growth but not PI(3,4,5)P3 production in fat body cells expressing constitutively active PI3K. Fat body Toll signaling blocks whole-animal growth in rictor mutants lacking TORC2 activity, but not in larvae lacking Pdk1. Phosphorylation of Akt on the Pdk1 site, Thr342, is significantly reduced by Toll signaling, and expression of mutant AktT342D rescues cell and animal growth, nutrient storage, and viability in animals with active Toll signaling. Altogether, these data show that innate immune signaling blocks insulin signaling at a more distal level than previously appreciated, and they suggest that manipulations affecting the Pdk1 arm of the pathway may have profound effects on insulin sensitivity in inflamed tissues. PMID- 29514085 TI - DiSNE Movie Visualization and Assessment of Clonal Kinetics Reveal Multiple Trajectories of Dendritic Cell Development. AB - A thorough understanding of cellular development is incumbent on assessing the complexities of fate and kinetics of individual clones within a population. Here, we develop a system for robust periodical assessment of lineage outputs of thousands of transient clones and establishment of bona fide cellular trajectories. We appraise the development of dendritic cells (DCs) in fms-like tyrosine kinase 3 ligand culture from barcode-labeled hematopoietic stem and progenitor cells (HSPCs) by serially measuring barcode signatures and visualize these multidimensional data using developmental interpolated t-distributed stochastic neighborhood embedding (DiSNE) time-lapse movies. We identify multiple cellular trajectories of DC development that are characterized by distinct fate bias and expansion kinetics and determine that these are intrinsically programmed. We demonstrate that conventional DC and plasmacytoid DC trajectories are largely separated already at the HSPC stage. This framework allows systematic evaluation of clonal dynamics and can be applied to other steady-state or perturbed developmental systems. PMID- 29514086 TI - Transcriptional Dysregulation in Postnatal Glutamatergic Progenitors Contributes to Closure of the Cortical Neurogenic Period. AB - Progenitors of cortical glutamatergic neurons (Glu progenitors) are usually thought to switch fate before birth to produce astrocytes. We used fate-mapping approaches to show that a large fraction of Glu progenitors persist in the postnatal forebrain after closure of the cortical neurogenesis period. Postnatal Glu progenitors do not accumulate during embryonal development but are produced by embryonal radial glial cells that persist after birth in the dorsal subventricular zone and continue to give rise to cortical neurons, although with low efficiency. Single-cell RNA sequencing reveals a dysregulation of transcriptional programs, which parallels changes in m6A methylation and correlates with the gradual decline in cortical neurogenesis observed in vivo. Rescuing experiments show that postnatal progenitors are partially permissive to genetic and pharmacological manipulations. Our study provides an in-depth characterization of postnatal Glu progenitors and identifies potential therapeutic targets for promoting brain repair. PMID- 29514087 TI - Glia Modulate a Neuronal Circuit for Locomotion Suppression during Sleep in C. elegans. AB - Glia have been suggested to regulate sleep-like states in vertebrates and invertebrates alike. In the nematode Caenorhabditis elegans, sleep is associated with molting between larval stages. To understand if glia modulate neural circuits driving sleep in C. elegans larvae, we ablated the astrocyte-like CEPsh glia. We found that glia-ablated animals exhibit episodes of immobility preceding sleep, prolonged sleep, molting-independent short-duration locomotory pausing, and delayed development. CEPsh glia ensheath synapses between the sleep associated ALA neuron and its postsynaptic partner AVE, a major locomotion interneuron. While AVE calcium transients normally correlate with head retraction, glia ablation results in prolonged calcium transients that are uncoupled from movement. Strikingly, all these glia ablation defects are suppressed by the ablation of ALA. Our results suggest that glia attenuate sleep promoting inhibitory connections between ALA and AVE, uncovering specific roles for glia in sleep behavior. We propose that similar mechanisms may underlie glial roles in sleep in other animals. PMID- 29514088 TI - CEP128 Localizes to the Subdistal Appendages of the Mother Centriole and Regulates TGF-beta/BMP Signaling at the Primary Cilium. AB - The centrosome is the main microtubule-organizing center in animal cells and comprises a mother and daughter centriole surrounded by pericentriolar material. During formation of primary cilia, the mother centriole transforms into a basal body that templates the ciliary axoneme. Ciliogenesis depends on mother centriole specific distal appendages, whereas the role of subdistal appendages in ciliary function is unclear. Here, we identify CEP128 as a centriole subdistal appendage protein required for regulating ciliary signaling. Loss of CEP128 did not grossly affect centrosomal or ciliary structure but caused impaired transforming growth factor-beta/bone morphogenetic protein (TGF-beta/BMP) signaling in zebrafish and at the primary cilium in cultured mammalian cells. This phenotype is likely the result of defective vesicle trafficking at the cilium as ciliary localization of RAB11 was impaired upon loss of CEP128, and quantitative phosphoproteomics revealed that CEP128 loss affects TGF-beta1-induced phosphorylation of multiple proteins that regulate cilium-associated vesicle trafficking. PMID- 29514089 TI - Phosphorylated EGFR Dimers Are Not Sufficient to Activate Ras. AB - Growth factor binding to EGFR drives conformational changes that promote homodimerization and transphosphorylation, followed by adaptor recruitment, oligomerization, and signaling through Ras. Whether specific receptor conformations and oligomerization states are necessary for efficient activation of Ras is unclear. We therefore evaluated the sufficiency of a phosphorylated EGFR dimer to activate Ras without growth factor by developing a chemical-genetic strategy to crosslink and "trap" full-length EGFR homodimers on cells. Trapped dimers become phosphorylated and recruit adaptor proteins at stoichiometry equivalent to that of EGF-stimulated receptors. Surprisingly, these phosphorylated dimers do not activate Ras, Erk, or Akt. In the absence of EGF, phosphorylated dimers do not further oligomerize or reorganize on cell membranes. These results suggest that a phosphorylated EGFR dimer loaded with core signaling adapters is not sufficient to activate Ras and that EGFR ligands contribute to conformational changes or receptor dynamics necessary for oligomerization and efficient signal propagation through the SOS-Ras-MAPK pathway. PMID- 29514090 TI - Retinal Cell Type DNA Methylation and Histone Modifications Predict Reprogramming Efficiency and Retinogenesis in 3D Organoid Cultures. AB - Diverse cell types can be reprogrammed into pluripotent stem cells by ectopic expression of Oct4 (Pou5f1), Klf4, Sox3, and Myc. Many of these induced pluripotent stem cells (iPSCs) retain memory, in terms of DNA methylation and histone modifications (epigenetic memory), of their cellular origins, and this may bias subsequent differentiation. Neurons are difficult to reprogram, and there has not been a systematic side-by-side characterization of reprogramming efficiency or epigenetic memory across different neuronal subtypes. Here, we compare reprogramming efficiency of five different retinal cell types at two different stages of development. Retinal differentiation from each iPSC line was measured using a quantitative standardized scoring system called STEM-RET and compared to the epigenetic memory. Neurons with the lowest reprogramming efficiency produced iPSC lines with the best retinal differentiation and were more likely to retain epigenetic memory of their cellular origins. In addition, we identified biomarkers of iPSCs that are predictive of retinal differentiation. PMID- 29514091 TI - Long-Range Enhancer Interactions Are Prevalent in Mouse Embryonic Stem Cells and Are Reorganized upon Pluripotent State Transition. AB - Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs). We found that SEs form complex, spatial networks in which individual SEs contact multiple promoters, and a rewiring of promoter-SE interactions occurs between pluripotent states. We also show that long-range promoter-SE interactions are more prevalent in ESCs than in epiblast stem cells (EpiSCs) or Nanog-deficient ESCs. We conclude that SEs form cell-type-specific interaction networks that are partly dependent on core transcription factors, thereby providing insights into the gene regulatory organization of pluripotent cells. PMID- 29514092 TI - Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors. AB - Monocytes and dendritic cells (DCs), mononuclear phagocytes essential for immune responses, develop from hematopoietic stem cells via monocyte-DC progenitors (MDPs). The molecular basis of their development remains unclear. Because promoter-distal enhancers are key to cell fate decisions, we analyzed enhancer landscapes during mononuclear phagocyte development in vivo. Monocyte- and DC specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Although Irf8-/- mononuclear phagocyte progenitors, including MDPs, displayed grossly normal gene expression patterns, their enhancer landscapes resembled that of an upstream progenitor population. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and, therefore, direct future gene expression to achieve mononuclear phagocyte development. PMID- 29514093 TI - IL-23 and IL-1beta Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation. AB - Th17 cells drive autoimmune disease but also control commensal microbes. A common link among antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor (TCR) and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation from human naive T cells, but not effector/memory cells. CD28 suppressed the classical Th17 transcriptional program, while inducing known Th17 regulators, and acted through an Akt-dependent mechanism. Th17 cells differentiated without CD28 were not anergic: they showed robust proliferation and maintained Th17 cytokine production following restimulation. Interleukin (IL)-23 and IL-1beta promoted glucose uptake and increased glycolysis. Although modestly increased compared to CD28 costimulation, glycolysis was necessary to support Th17 differentiation, indicating that cytokine-mediated metabolic shifts were sufficient to obviate the classical requirement for CD28 in Th17 differentiation. Together, these data propose that, in humans, strength of TCR/CD28/Akt activation serves as a rheostat tuning the magnitude of Th17 development driven by IL-23 and IL-1beta. PMID- 29514094 TI - An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages. AB - ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control. PMID- 29514095 TI - alpha Cell Function and Gene Expression Are Compromised in Type 1 Diabetes. AB - Many patients with type 1 diabetes (T1D) have residual beta cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual beta cells and alpha cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant beta cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D alpha cells was markedly reduced, and these cells had alterations in transcription factors constituting alpha and beta cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of alpha-to-beta cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia. PMID- 29514096 TI - Targeting a Sirt5-Positive Subpopulation Overcomes Multidrug Resistance in Wild Type Kras Colorectal Carcinomas. AB - A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate. Succinate binds to and activates a reactive oxygen species-scavenging enzyme, thioredoxin reductase 2 (TrxR2), to confer chemotherapy resistance. In contrast, Sirt5+ cells exhibit an elevated succinate to-aKG ratio that inhibits aKG-dependent dioxygenases to maintain cetuximab resistance. Our findings suggest that Sirt5 inhibitors in combination with chemotherapeutic agents and/or cetuximab may represent a therapeutic strategy for CRC patients harboring wild-type Kras. PMID- 29514097 TI - Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor Dependent Mechanism in Mice. AB - Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing's syndrome, a disorder of excessive GCs, phenocopies several menopause induced metabolic pathologies. Here, we show that the glucocorticoid receptor (GR) drives steatosis in hypogonadal female mice because hepatocyte-specific GR knockout mice are refractory to developing ovariectomy-induced steatosis. Intriguingly, transcriptional profiling revealed that ovariectomy elicits hepatic GC hypersensitivity globally. Hypogonadism-induced GC hypersensitivity results from a loss of systemic but not hepatic estrogen (E2) signaling, given that hepatocyte-specific E2 receptor deletion does not confer GC hypersensitivity. Mechanistically, enhanced chromatin recruitment and ligand-dependent hyperphosphorylation of GR underlie ovariectomy-induced glucocorticoid hypersensitivity. The dysregulated glucocorticoid-mediated signaling present in hypogonadal females is a product of increased follicle-stimulating hormone (FSH) production because FSH treatment in ovary-intact mice recapitulates glucocorticoid hypersensitivity similar to hypogonadal female mice. Our findings uncover a regulatory axis between estradiol, FSH, and hepatic glucocorticoid receptor signaling that, when disrupted, as in menopause, promotes hepatic steatosis. PMID- 29514099 TI - Muscle-Specific Histone H3K36 Dimethyltransferase SET-18 Shortens Lifespan of Caenorhabditis elegans by Repressing daf-16a Expression. AB - Mounting evidence shows that histone methylation, a typical epigenetic mark, is crucial for gene expression regulation during aging. Decreased trimethylation of Lys 36 on histone H3 (H3K36me3) in worms and yeast is reported to shorten lifespan. The function of H3K36me2 in aging remains unclear. In this study, we identified Caenorhabditis elegans SET-18 as a histone H3K36 dimethyltransferase. SET-18 deletion extended lifespan and increased oxidative stress resistance, dependent on daf-16 activity in the insulin/IGF pathway. In set-18 mutants, transcription of daf-16 isoform a (daf-16a) was specifically upregulated. Accordingly, a decrease in H3K36me2 on daf-16a promoter was observed. Muscle specific expression of SET-18 increased in aged worms (day 7 and day 11), attributable to elevation of global H3K36me2 and inhibition of daf-16a expression. Consequently, longevity was shortened. These findings suggested that chromatic repression mediated by tissue-specific H3K36 dimethyltransferase might be detrimental to lifespan and may have implications in human age-related diseases. PMID- 29514098 TI - Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy. AB - Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals. PMID- 29514100 TI - Coupling of Rigor Mortis and Intestinal Necrosis during C. elegans Organismal Death. AB - Organismal death is a process of systemic collapse whose mechanisms are less well understood than those of cell death. We previously reported that death in C. elegans is accompanied by a calcium-propagated wave of intestinal necrosis, marked by a wave of blue autofluorescence (death fluorescence). Here, we describe another feature of organismal death, a wave of body wall muscle contraction, or death contraction (DC). This phenomenon is accompanied by a wave of intramuscular Ca2+ release and, subsequently, of intestinal necrosis. Correlation of directions of the DC and intestinal necrosis waves implies coupling of these death processes. Long-lived insulin/IGF-1-signaling mutants show reduced DC and delayed intestinal necrosis, suggesting possible resistance to organismal death. DC resembles mammalian rigor mortis, a postmortem necrosis-related process in which Ca2+ influx promotes muscle hyper-contraction. In contrast to mammals, DC is an early rather than a late event in C. elegans organismal death. VIDEO ABSTRACT. PMID- 29514101 TI - Accelerated Evolution in Distinctive Species Reveals Candidate Elements for Clinically Relevant Traits, Including Mutation and Cancer Resistance. AB - The identity of most functional elements in the mammalian genome and the phenotypes they impact are unclear. Here, we perform a genome-wide comparative analysis of patterns of accelerated evolution in species with highly distinctive traits to discover candidate functional elements for clinically important phenotypes. We identify accelerated regions (ARs) in the elephant, hibernating bat, orca, dolphin, naked mole rat, and thirteen-lined ground squirrel lineages in mammalian conserved regions, uncovering ~33,000 elements that bind hundreds of different regulatory proteins in humans and mice. ARs in the elephant, the largest land mammal, are uniquely enriched near elephant DNA damage response genes. The genomic hotspot for elephant ARs is the E3 ligase subunit of the Fanconi anemia complex, a master regulator of DNA repair. Additionally, ARs in the six species are associated with specific human clinical phenotypes that have apparent concordance with overt traits in each species. PMID- 29514102 TI - Cooperative CRF and alpha1 Adrenergic Signaling in the VTA Promotes NMDA Plasticity and Drives Social Stress Enhancement of Cocaine Conditioning. AB - Stressful events rapidly trigger activity-dependent synaptic plasticity, driving the formation of aversive memories. However, it remains unclear how stressful experience affects plasticity mechanisms to regulate appetitive learning, such as intake of addictive drugs. Using rats, we show that corticotropin-releasing factor (CRF) and alpha1 adrenergic receptor (alpha1AR) signaling enhance the plasticity of NMDA-receptor-mediated glutamatergic transmission in ventral tegmental area (VTA) dopamine (DA) neurons through distinct effects on inositol 1,4,5-triphosphate (IP3)-dependent Ca2+ signaling. We find that CRF amplifies IP3 Ca2+ signaling induced by stimulation of alpha1ARs, revealing a cooperative mechanism that promotes glutamatergic plasticity. In line with this, acute social defeat stress engages similar cooperative CRF and alpha1AR signaling in the VTA to enhance learning of cocaine-paired cues. These data provide evidence that CRF and alpha1ARs act in concert to regulate IP3-Ca2+ signaling in the VTA and promote learning of drug-associated cues. PMID- 29514104 TI - Large-Scale Phosphoproteomics Reveals Shp-2 Phosphatase-Dependent Regulators of Pdgf Receptor Signaling. AB - Despite its low cellular abundance, phosphotyrosine (pTyr) regulates numerous cell signaling pathways in health and disease. We applied comprehensive phosphoproteomics to unravel differential regulators of receptor tyrosine kinase (RTK)-initiated signaling networks upon activation by Pdgf-betabeta, Fgf-2, or Igf-1 and identified more than 40,000 phosphorylation sites, including many phosphotyrosine sites without additional enrichment. The analysis revealed RTK specific regulation of hundreds of pTyr sites on key signaling molecules. We found the tyrosine phosphatase Shp-2 to be the master regulator of Pdgfr pTyr signaling. Application of a recently introduced allosteric Shp-2 inhibitor revealed global regulation of the Pdgf-dependent tyrosine phosphoproteome, which significantly impaired cell migration. In addition, we present a list of hundreds of Shp-2-dependent targets and putative substrates, including Rasa1 and Cortactin with increased pTyr and Gab1 and Erk1/2 with decreased pTyr. Our study demonstrates that large-scale quantitative phosphoproteomics can precisely dissect tightly regulated kinase-phosphatase signaling networks. PMID- 29514103 TI - Directional Reaching for Water as a Cortex-Dependent Behavioral Framework for Mice. AB - Optogenetic tools and imaging methods for recording and manipulating brain activity have boosted the field of neuroscience in unprecedented ways. However, behavioral paradigms for mice lag behind those of primates, limiting the full potential of such tools. Here, we present an innovative behavioral framework in which head-fixed mice directionally reach for water droplets, similar to the primate "center-out" reaching task. Mice rapidly engaged in the task, performed hundreds of trials, and reached in multiple directions when droplets were presented at different locations. Surprisingly, mice used chemosensation to determine the presence of water droplets. Optogenetic inactivation of the motor cortex halted the initiation and rapidly diverted the trajectory of ongoing movements. Layer 2/3 two-photon imaging revealed robust direction selectivity in most reach-related neurons. Finally, mice performed directional reaching instructed by vibratotactile stimuli, demonstrating the potential of this framework for studying, in addition to motor control, sensory processing, and decision making. PMID- 29514105 TI - Fine-Resolution Mapping of TF Binding and Chromatin Interactions. AB - Transcription factor (TF) binding to DNA is crucial for transcriptional regulation. There are multiple methods for mapping such binding. These methods balance between input requirements, spatial resolution, and compatibility with high-throughput automation. Here, we describe SLIM-ChIP (short-fragment-enriched, low-input, indexed MNase ChIP), which combines enzymatic fragmentation of chromatin and on-bead indexing to address these desiderata. SLIM-ChIP reproduces a high-resolution binding map of yeast Reb1 comparable with existing methods, yet with less input material and full compatibility with high-throughput procedures. We demonstrate the robustness and flexibility of SLIM-ChIP by probing additional factors in yeast and mouse. Finally, we show that SLIM-ChIP provides information on the chromatin landscape surrounding the bound transcription factor. We identify a class of Reb1 sites where the proximal -1 nucleosome tightly interacts with Reb1 and maintains unidirectional transcription. SLIM-ChIP is an attractive solution for mapping DNA binding proteins and charting the surrounding chromatin occupancy landscape at a single-cell level. PMID- 29514106 TI - Phosphaturic mesenchymal tumor without osteomalacia: additional confirmation of the "nonphosphaturic" variant, with emphasis on the roles of FGF23 chromogenic in situ hybridization and FN1-FGFR1 fluorescence in situ hybridization. AB - Phosphaturic mesenchymal tumor (PMT) is a rare, histologically distinctive neoplasm that classically presents with phosphaturia and tumor-induced osteomalacia (TIO; ie, oncogenic osteomalacia). Both the phosphaturia and the TIO are due to paraneoplastic production of FGF23 (a phosphatonin) by the neoplastic cells, which are genetically characterized by rearrangements of FN1 (most often with FGFR1, and less frequently with FGF1). However, rare cases of PMT present without phosphaturia and TIO (ie, the "nonphosphaturic" variant) and are therefore much more challenging to diagnose. Here, we report the first case of a genetically confirmed, nonphosphaturic PMT, in which the correct diagnosis was established through a combination of careful histologic evaluation, FGF23 chromogenic in situ hybridization, and fluorescence in situ hybridization testing for FN1-FGFR1. PMID- 29514107 TI - A case report of atypical Spitz tumor harboring a novel MLPH-ALK gene fusion with discordant ALK immunohistochemistry results. AB - Frequent kinase fusions have been reported in spitzoid neoplasms, approximately 10% of which involve ALK rearrangements. Herein, we report a case of atypical Spitz tumor with a novel MLPH-ALK fusion, which has not been previously reported to contribute to cancer development. The tumor was detected in the right arm of a 40-year-old woman. The novel ALK fusion was identified by a 5'-rapid amplification of cDNA ends-based system optimized for formalin-fixed, paraffin embedded tissue. Initially, ALK expression was detected by immunohistochemistry using 5A4 antibodies for both sensitive and conventional polymer detection methods. However, the anti-ALK1 antibody, which is commonly used for the diagnosis of ALK-positive anaplastic large cell lymphoma, failed to confirm ALK expression. These results indicated that ALK immunohistochemistry results in ALK rearranged atypical Spitz tumor may differ based on the type of primary antibody clone, which can be a potential diagnostic pitfall. PMID- 29514108 TI - Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population. AB - Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization. We further determined FGFR2 protein expression by immunohistochemistry and analyzed the clinicopathologic records of the patients. Eight tumors (6.6%) had FGFR2 translocations, whereas 15 (12.3%) had low-level FGFR2 amplification. Interestingly, the tumors that showed both translocation and low-level amplification frequently were of the mass-forming type. Compared with the ICCs with normal FGFR2s, tumors with amplifications secreted less mucus (P = .017) and typically were accompanied by hepatitis B virus infection (P = .004). Tumors with low-level amplification generally were of lower stage (P = .013) and associated with better overall survival (P = .017). As tumors with FGFR2 amplification exhibit different biology from lesions with a normal gene, low-level amplification of FGFR2 may play an important role in tumor progression and may be a marker for targeted therapy. PMID- 29514109 TI - Propranolol prevents liver cirrhosis by inhibiting hepatic stellate cell activation mediated by the PDGFR/Akt pathway. AB - Propranolol is known to reduce portal pressure by decreasing blood flow to the splanchnic circulation and the liver. However, it is unknown if propranolol improves fibrogenesis and sinusoidal remodeling in the cirrhotic liver. The aim of this study was to investigate the therapeutic effects of propranolol on carbon tetrachloride (CCl4)-induced liver fibrosis in a mouse model and the intrinsic mechanisms underlying those effects. In this study, a hepatic cirrhosis mouse model was induced by CCl4 administration for 6 weeks. Propranolol was simultaneously administered orally in the experimental group. Liver tissue and blood samples were collected for histological and molecular analyses. LX-2 cells induced by platelet-derived growth factor-BB (PDGF-BB) were used to evaluate the anti-fibrogenic effect of propranolol in vitro. The results showed that treatment of mice with CCl4 induced hepatic fibrosis, as evidenced by inflammatory cell infiltration, collagen deposition and abnormal vascular formation in the liver tissue. All these changes were significantly attenuated by propranolol treatment. Furthermore, we also found that propranolol inhibited PDGF-BB-induced hepatic stellate cell migration, fibrogenesis, and PDGFR/Akt phosphorylation. Taken together, propranolol might prevent CCl4-induced liver injury and fibrosis at least partially through inhibiting the PDGF-BB-induced PDGFR/Akt pathway. The anti-fibrogenic effect of propranolol may support its status as a first-line treatment in patients with chronic liver disease. PMID- 29514110 TI - Shaping the use of psychotropic medicines in nursing homes: A qualitative study on organisational culture. AB - Psychotropic medicines have limited efficacy in the management of behavioural and psychological disturbances, yet they are commonly used in nursing homes. Organisational culture is an important consideration influencing use of psychotropic medicines. Schein's theory elucidates that organisational culture is underpinned by basic assumptions, which are the taken for granted beliefs driving organisational members' behaviour and practices. By exploring the basic assumptions of culture we are able to find explanations for why psychotropic medicines are prescribed contrary to standards. A qualitative study guided by Schein's theory was conducted using semi-structured interviews with 40 staff representing a broad range of roles from eight nursing homes. Findings from the study suggest two basic assumptions influenced the use of psychotropic medicines: locus of control and necessity for efficiency or comprehensiveness. Locus of control pertained to whether staff believed they could control decisions when facing negative work experiences. Necessity for efficiency or comprehensiveness concerned how much time and effort was spent on a given task. Participants' arrived at decisions to use psychotropic medicines that were inconsistent with ideal standards when they believed they were helpless to do the right thing by the resident and it was necessary to restrict time on a given task. Basic assumptions tended to provide the rationale for staff to use psychotropic medicines when it was not compatible with standards. Organisational culture is an important factor that should be addressed to optimise psychotropic medicine use. PMID- 29514112 TI - Rift Valley fever vaccines: current and future needs. AB - Rift Valley fever (RVF) is a zoonotic mosquito-borne bunyaviral disease associated with high abortion rates, neonatal deaths, and fetal malformations in ruminants, and mild to severe disease in humans. Outbreaks of RVF cause huge economic losses and public health impacts in endemic countries in Africa and the Arabian Peninsula. A proper vaccination strategy is important for preventing or minimizing outbreaks. Vaccination against RVF is not practiced in many countries, however, due to absence or irregular occurrences of outbreaks, despite serological evidence of RVF viral activity. Nonetheless, effective vaccination strategies, and functional national and international multi-disciplinary networks, remain crucial for ensuring availability of vaccines and supporting execution of vaccination in high risk areas for efficient response to RVF alerts and outbreaks. PMID- 29514111 TI - Effects of exposure to ambient ultrafine particles on respiratory health and systemic inflammation in children. AB - It is known that ultrafine particles (UFP, particles smaller than 0.1 MUm) can penetrate deep into the lungs and potentially have adverse health effects. However, epidemiological data on the health effects of UFP is limited. Therefore, our objective was to test the hypothesis that exposure to UFPs is associated with respiratory health status and systemic inflammation among children aged 8 to 11 years. We conducted a cross-sectional study among 655 children (43.3% male) attending 25 primary (elementary) schools in the Brisbane Metropolitan Area, Australia. Ultrafine particle number concentration (PNC) was measured at each school and modelled at homes using Land Use Regression to derive exposure estimates. Health outcomes were respiratory symptoms and diagnoses, measured by parent-completed questionnaire, spirometric lung function, exhaled nitric oxide (FeNO), and serum C reactive protein (CRP). Exposure-response models, adjusted for potential personal and environmental confounders measured at the individual, home and school level, were fitted using Bayesian methods. PNC was not independently associated with respiratory symptoms, asthma diagnosis or spirometric lung function. However, PNC was positively associated with an increase in CRP (1.188-fold change per 1000 UFP cm-3 day/day (95% credible interval 1.077 to 1.299)) and an increase in FeNO among atopic participants (1.054 fold change per 1000 UFP cm-3 day/day (95% CrI 1.005 to 1.106)). UFPs do not affect respiratory health outcomes in children but do have systemic effects, detected here in the form of a positive association with a biomarker for systemic inflammation. This is consistent with the known propensity of UFPs to penetrate deep into the lung and circulatory system. PMID- 29514113 TI - Mitochondria dysfunctions under Fe and S deficiency: is citric acid involved in the regulation of adaptive responses? AB - Within the last years, extensive information has been accumulated on the reciprocal influence between S and Fe nutrition at both physiological and molecular level in several plant species, but the mechanisms regulating S and Fe sensing and signaling are not fully understood. Fe and S interact for the building of Fe-S clusters, and mitochondria is one of the cellular compartments where Fe-S cluster assembly takes place. Therefore, it would be expected that mitochondria might play a central role in the regulation of Fe and S interaction. The Fe deficiency-induced alteration in the synthesis of mitochondria-derived carboxylic acids, such as citric acid, and the evidence that such molecules have already been identified as important players of metabolite signaling in several organisms, further support this hypothesis. Tomato plants were grown under single or combined Fe and S deficiency with the aim of verifying whether mitochondria activities played a role in Fe/S interaction. Both Fe and S deficiencies determined similar alteration of respiratory chain activity: a general decrease of Fe-S containing complexes as well as an increase of alternative NAD(P)H activities was observed in both Fe and S deficient-plants. However, the content of Krebs cycle-related organic acids in roots was substantially different in response to treatments, being the accumulation of citric acid always increased, while the others (i.e. succinic, malic, fumaric acids) always decreased. Interestingly, citric acid levels significantly correlated with the expression of some Fe and S deficiency induced genes. Our results contribute to existing knowledge on the complexity of the S/Fe interaction, suggesting a model in which endogenous alteration of citric acid content in plant tissues might act as signal molecule for the regulation of some nuclear-encoded and nutrient-responsive genes and also provide a basis for further study of the mechanism underlying S and Fe sensing and signalling. PMID- 29514114 TI - Long-term effectiveness and safety of stereotactic gamma knife surgery as a primary sole treatment in the management of glomus jagulare tumor. AB - OBJECTIVE: This study aims to report and confirm long-term effectiveness and safety of stereotactic Gamma Knife Surgery as a primary sole treatment in the management of 40 glomus jagulare tumors patients. PATIENTS AND METHODS: Retrospective analysis of clinical and radiological outcomes of 40 GJTs consecutive patients treated with GKS as primary sole treatment at International Medical Center (IMC), Cairo-Egypt from the beginning of 2005 till the end of 2014,with mean follow-up period of 84 months (range 36-156 months), mean tumor volume was 6.5 cc, and mean peripheral radiation dose of 15 Gy, to mean isodose curve of 38%. RESULTS: The most common neurological deficit at initial evaluation was bulbar symptoms in 24 patients, followed by pulsatile tinnitus in 22, deterioration of hearing in 20 patients. The overall clinical control achieved in 92.5% of patients, while actuarial tumor size control rate post- GKS was 97.5% at 3 years, 97% at 5 years and 92% at 10 years of follow-up period. CONCLUSIONS: Gamma knife surgery could be used effectively and safely as a primary sole treatment tool in the management of glomus jugulare tumors. PMID- 29514115 TI - Attachment, caregiving in couple relationships, and prosocial behavior in the wider world. AB - According to attachment theory, a sense of attachment security (confidence that others will be available and supportive when needed) facilitates the functioning of the caregiving behavioral system and the empathic provision of care to suffering others. In this article we review what has been learned during the last decade about attachment-related individual differences in caregiving within couple relationships and prosocial behavior in the wider world. We begin with a brief account of attachment theory and the dynamic interplay of the attachment and caregiving behavioral systems. We then review findings from correlational and experimental studies showing that attachment security has positive influences on noticing and reacting favorably to the suffering of romantic partners and strangers. PMID- 29514116 TI - Altered anatomical connections of associative and limbic cortico-basal-ganglia circuits in obsessive-compulsive disorder. AB - BACKGROUND: Current neurocognitive models suppose dysfunctions of associative and limbic cortico-basal ganglia circuits to be at the core of obsessive-compulsive disorder (OCD). As little is known about the state of underlying anatomical connections, we investigated whether these connections were reduced and/or not properly organised in OCD patients compared to control. METHODS: Diffusion magnetic resonance images were obtained in 37 OCD patients with predominant checking symptoms and 37 matched healthy controls. We developed indices to characterise the quantity (spatial extent and density) and the organisation (topography and segregation) of 24 anatomical connections between associative and limbic cortical (anterior cingulate, dorsolateral prefrontal, orbitofrontal cortices and the frontal pole), and subcortical (caudate nucleus, putamen and thalamus) areas in each hemisphere. RESULTS: Associative and limbic cortico-basal ganglia connections were reduced in OCD patients compared to controls: 19/24 connections had a reduced subcortical spatial extent, 9/24 had a reduced density. Moreover, while the general topography was conserved, the different cortical projection fields in the striatum and thalamus were hyper-segregated in OCD patients compared to controls. CONCLUSION: These quantitative and qualitative differences of anatomical connections go beyond the current model of a reduced cortical control of automatic behaviour stored in the basal ganglia. The hyper segregation in OCD could also impair the integration of cortical information in the thalamus and striatum and distort the subsequent behavioural selection process. This provides new working hypotheses for functional and behavioural studies on OCD. PMID- 29514117 TI - Measuring costs of community mental health care in Italy: A prevalence-based study. AB - BACKGROUND: Information on individual mental healthcare costs and utilization patterns in Italy is scant. We analysed the use and the annual costs of community mental health services (MHS) in an Italian local health authority (LHA). Our aims are to compare the characteristics of patients in the top decile of costs with those of the remaining 90%, and to investigate the demographic and clinical determinants of costs. METHODS: This retrospective study is based on administrative data of adult patients with at least one contact with MHS in 2013. Costs of services were estimated using a microcosting method. We defined as high cost (HC) those patients whose community mental health services costs place them in the top decile of the cost distribution. The predictors of costs were investigated using multiple linear regression. RESULTS: The overall costs borne for 7601 patients were 17 million ?, with HC accounting for 87% of costs and 73% of services. Compared with the rest of the patients, HC were younger, more likely to be male, to have a diagnosis of psychosis, and longer and more intensive MHS utilization. In multiple linear regression, younger age, longer duration of contact with MHS, psychosis, bipolar disorder, personality disorder, depression, dementia and Italian citizenship accounted for 20.7% of cost variance. CONCLUSION: Direct mental health costs are concentrated among a small fraction of patients who receive intensive socio-rehabilitation in community services. One limitation includes the unavailability of hospital costs. Our methodology is replicable and useful for national and cross-national benchmarking. PMID- 29514118 TI - Long-term effect of prenatal exposure to malnutrition on risk of schizophrenia in adulthood: Evidence from the Chinese famine of 1959-1961. AB - BACKGROUND: Schizophrenia is a common major mental disorder and prenatal nutritional deficiency may increase its risk. We aimed to investigate long-term impact of prenatal exposure to malnutrition on risk of schizophrenia in adulthood using the Chinese famine of 1959-1961 as a natural experiment. METHODS: We obtained data from the Second National Sample Survey on Disability implemented in 31 provinces in 2006, and restricted our analysis to 387,093 individuals born from 1956 to 1965. Schizophrenia was ascertained by psychiatrists based on the International Statistical Classification of Diseases, Tenth Revision. Famine severity was defined as cohort size shrinkage index. The famine effect on adult schizophrenia was estimated by difference-in-difference models, established by examining the variations of famine exposure across birth cohorts. RESULTS: Compared with the reference cohort of 1965, famine cohorts (1959-1962) had significantly higher odds (OR: 1.84; 95% CI: 1.13, 3.00; P = 0.014) of schizophrenia in the rural population. After adjusting for multiple covariates, this association remained significant (OR: 1.82; 95% CI: 1.11, 2.98; P = 0.018). We did not observe statistically significant differences in odds of schizophrenia among famine cohorts compared with the reference cohort in the urban population. CONCLUSIONS: Prenatal malnutrition exposure has a detrimental impact on risk of schizophrenia in adulthood in the rural population. Further studies were needed to investigate corresponding mechanisms on this topic. PMID- 29514119 TI - The educational impact of shocks in utero: Evidence from Rwanda. AB - Research on the impact of violence and conflict on education typically focuses on exposure among a cohort of school-aged children. In line with the fetal origins hypothesis, this paper studies the long-run effect of exposure to adverse maternal health shocks while still in the womb. Exploiting the sudden and discrete nature of the Rwandan genocide and an identification strategy based on temporal and spatial variation, we find that the cohort in utero during the genocide reported on average 0.3 fewer years of schooling in the 2012 Rwanda. Population and Housing Census and was 8% points less likely to finish primary school relative to the cohort in utero just a couple of months later. PMID- 29514120 TI - Tuberculosis mastitis presenting as bilateral breast masses. AB - Tuberculosis mastitis can be a challenging diagnosis, often presenting with clinical and imaging findings that are suspicious for malignancy. We present a case of a 49-year-old female with a breast mass initially diagnosed as idiopathic granulomatous mastitis. Failure to respond to standard treatments, development of new breast masses, and discovery of a concurrent ulcerating thigh rash with similar histologic findings as the breast masses prompted further investigation, which ultimately lead to the diagnosis of tuberculosis mastitis. There was rapid resolution of both breast and skin symptoms after initiation of empiric drug therapy. PMID- 29514121 TI - Interpersonal beliefs related to suicide and facial emotion processing in psychotic disorders. AB - Deficits in social cognition are present in psychotic disorders; moreover, maladaptive interpersonal beliefs have been posited to underlie risk of suicidal ideation and behavior. However, the association between social cognition and negative appraisals as potential risk factors for suicidal ideation and behavior in psychotic disorders has not been assessed. In a pilot study, we assessed accuracy and error biases in facial emotion recognition (Penn ER-40), maladaptive interpersonal beliefs as measured by the Interpersonal Needs Questionnaire (INQ), and current suicide ideation and history of past attempts in a sample of 101 outpatients with psychotic disorders (75 schizophrenia/schizoaffective; 26 bipolar disorder). INQ scores were positively associated with history of suicide attempts and current ideation. INQ scores were inversely related with emotion recognition accuracy yet positively correlated with bias toward perceiving anger in neutral expressions. The association between biases pertaining to anger and INQ scores persisted after adjusting for global cognitive ability and were more evident in schizophrenia than in bipolar disorder. The present findings suggest that maladaptive beliefs are associated with a tendency to misperceive neutral stimuli as threatening and are associated with suicidal ideation and behavior. Although better cognitive ability is associated with higher rates of suicide attempts in psychotic disorders, biases in misinterpreting anger in others may be a specific deficit related to formation of maladaptive beliefs about others, which, in turn, are associated with history of suicide attempts. PMID- 29514123 TI - Perspective taking: motivation and impediment to shared reality. AB - Taking another person's perspective requires acknowledging that there is another viewpoint, which can challenge the concept of shared reality. At the same time, taking someone else's perspective can also preserve shared reality, by helping to explain how aspects of the world may be perceived differently by two different individuals. Thus, establishing or maintaining shared reality may be a primary motivator for perspective taking in everyday life. However, depending on the content (e.g., self-perceptions, assumptions about other people, cherished beliefs) used in constructing another perspective and comparing it with one's own, perspective taking may in some cases instead highlight differences between how people view the world, thus hindering a sense of shared reality. PMID- 29514122 TI - Assessment of determinants and quality of life of university students with social phobias in a coastal city of south India. AB - BACKGROUND: Social phobia is a common psychiatric disorder, and its onset happens usually around late adolescence period. Therefore, early diagnosis and its management is essential in any educational setting. OBJECTIVES: To identify university students with social phobia, to find out its determinants and to observe its impact on their quality of life. METHODS: The data was collected using a self-administered questionnaire. Social Phobia Inventory Questionnaire and Quality of Life Enjoyment and Satisfaction Questionnaire were used. RESULTS: The mean age of the 450 student participants was 20.6 +/- 1.6 years. Majority [312(69.3%)] were males and majority [305(67.8%)] were native of urban areas. Of the total, 169(37.6%) were found to have social phobia. Among them, 114(67.5%) had mild, 47(27.8%) had moderate and 8(4.7%) had severe social phobia. Family history of anxiety disorders (P = 0.006), embarrassment with own socio-economic status (P = 0.001) and past history of failure in academic examinations (P < 0.001) were significantly associated with the presence of social phobia among the participants. Preference of interaction using social media instead of face to face communication with people (P = 0.013), and by texting rather than calling the person (P = 0.002) were seen significantly more among those with social phobia. The mean quality of life scores was found to be deteriorating significantly with increasing intensity of social phobia among students (P < 0.001). CONCLUSION: Social phobia was seen among more than one-third of the participants. Counselling centers are therefore required to address this problem at universities. This will also help to improve the quality of life and the socializing skills of those affected. PMID- 29514124 TI - Chromatographic retention behaviour, modelling and optimization of a UHPLC-UV separation of the regioisomers of the Novel Psychoactive Substance (NPS) methoxphenidine (MXP). AB - A detailed investigation into the chromatographic retention behaviour and separation of the three regioisomers of the Novel Psychoactive Substance (NPS) methoxphenidine (i.e. 2-, 3- and 4-MXP isomers) has revealed the ionization state of the analyte and stationary phase, to be the controlling factor in dictating which retention mechanism is in operation. At low pH, poor separation and retention was observed. In contrast, at intermediate pH, enhanced retention and separation of the three MXP isomers was obtained; it appeared that there was a synergistic effect between the electrostatic and hydrophobic mechanisms. At high pH, the MXP isomers were retained by hydrophobic retention. Accurate retention time predictions (<0.5%) were achievable using non-linear retention models (3 * 3). This allowed the optimization of the gradient separation of the MXP isomers using a two-dimensional gradient and temperature design space. Prediction errors for peak width and resolution were, in most cases, lower than 5%. The use of linear models (2 * 2) still afforded retention time and resolution accuracies of <2.3 and 11% respectively. A rapid and highly sensitive LC-MS friendly method (i.e. Rsmin > 5 within 4 min) was predicted and verified. The developed methodology should be highly suitable for the rapid, specific and sensitive detection and control of MXP regioisomers. PMID- 29514125 TI - First identification of Cryptosporidium parvum subtype IIaA20G1R1 in water buffalos (Bubalus bubalis). AB - Cryptosporidium can infect a wide variety of vertebrate animals, including mammals, birds, amphibians, reptiles, and fish. There are few molecular characterizations of Cryptosporidium isolated from water buffalo. Thus, the present study investigated the occurrence and molecular characterization of Cryptosporidium spp. in water buffalos by nested-PCR. Non-diarrheic feces were obtained from 122 water buffalo calves. All samples were tested by nested-PCR based on the 18S rRNA gene, after which positive samples were analyzed by RFLP and genetic sequencing. Sixteen fecal (13.1%) samples were positive, and RFLP showed that fifteen presented patterns consistent with C. ryanae and one with C. parvum. Sequencing of the gp60 gene from the C. parvum positive sample indicated the subtype IIaA20G1R1. This is the first identification of the IIaA20G1R1 subtype in water buffalos. PMID- 29514126 TI - Co-hydrothermal treatment of fallen leaves with iron sludge to prepare magnetic iron product and solid fuel. AB - The hydrothermal carbonization (HTC) was performed on Metasequoia Leaves (ML) in the presence of iron sludge, both of which were generated as solid residuals. The relations between sludge, char's properties and operating conditions were systemically investigated. Iron sludge primarily catalyzed the efficient formation of char with higher heating value (HHV) becoming 1.15-1.65 times of ML (18.21 MJ/kg) and was meanwhile reduced to magnetite. The hydrated Fe ions in octahedron crystals acted as nucleophiles facilitating the dehydration and decarboxylation reactions. The increased HHV is found strong temperature dependent while prolonging the residence time is more preferable for low organic acids generation. Thermogravimetric analysis confirmed the iron sludge enhanced conversion of volatile to fixed carbon. The as-prepared solid char showed better stability after catalytic HTC treatment, having ignition temperature increased from 253 to 426 degrees C as compared to the char prepared without iron sludge addition. PMID- 29514127 TI - Anaerobic co-digestion of high-strength organic wastes pretreated by thermal hydrolysis. AB - Thermal hydrolysis (TH) pretreatment was investigated for the anaerobic digestion (AD) of a mixture of high-strength organic wastes (i.e., dewatered human feces, dewatered sewage sludge, and food wastewater) at laboratory scale to simulate a full-scale plant and evaluate its feasibility. The reactors maintained efficient and stable performance at a hydraulic retention time of 20 days, which may be not sufficient for the mesophilic AD of high-suspended-solid wastes, despite the temporal variations in organic load. The addition of FeCl3 was effective in controlling H2S and resulted in significant changes in the microbial community structure, particularly the methanogens. The temporary interruption in feeding or temperature control led to immediate performance deterioration, but it recovered rapidly when normal operations were resumed. The overall results suggest that the AD process coupled with TH pretreatment can provide an efficient, robust, and resilient system to manage high-suspended-solid wastes, supporting the feasibility of its full-scale implementation. PMID- 29514128 TI - Synthesis and antinociceptive evaluation of bioisosteres and hybrids of naproxen, ibuprofen and paracetamol. AB - The aim of this work was to design, synthesize and characterize the potential anti-nociceptive and anti-inflammatory activities of a new series of bioisosteres and hybrids from known non-steroidal anti-inflammatory drugs (NSAIDs). The compounds 4-(acetylamino)phenyl (2S)-2-(6-methoxy-2-naphthyl)propanoate (GUF-1) and 4-(acetylamino)phenyl 2-(R,S)-(4-isobutylphenyl)propanoate (GUF-2) were synthesized as hybrids (also known as heterodimers); whereas those named 2-(R,S) (4-isobutylphenyl)-N-1H-tetrazol-5-ylpropanamide (GUF-3), (2S)-2-(6-methoxy-2 naphthyl)-N-1H-tetrazol-5-ylpropanamide (GUF-4), [2-(R,S)-N-hydroxy-2-[4-(2 methylpropyl)phenyl]propanamide] (GUF-5), and (2S)-N-hydroxy-2-(6-methoxy-2 naphthyl)propanamide (GUF-6) were synthesized as bioisosteres of the NSAIDs paracetamol, ibuprofen, and naproxen, respectively. All these compounds were characterized by spectroscopic and spectrometric analysis. Antinociceptive activity of GUF-1 to GUF-6 was evaluated using the formalin test in rats. Pharmacological responses of GUF-1, GUF-2 (hybrids), and GUF-5 (bioisostere) demonstrated significant antinociceptive effects; thus these compounds were assayed in an inflammation test like carrageenan-induced paw oedema in rats. Complete molecular docking of cyclooxygenase and the GUF-1 and GUF-2 hybrids showed high docking scores, compared to the reference drugs. Our data demonstrate that compounds GUF-1, GUF-2, and GUF-5 possesses antinociceptive and antiinflammatory activities resembling and improving those known for the traditional NSAIDs, paracetamol, naproxen and ibuprofen. PMID- 29514129 TI - Comparative study of effects of assemblages AII and BIV of Giardia duodenalis on mucosa and microbiota of the small intestine in mice. AB - AIMS: Giardiasis is one of the major causes of diarrhea worldwide and its symptoms vary in intensity, which can be attributed to different parasite assemblages. The goal of the present study was to compare the effects of infection caused by assemblages AII and BIV ofGiardia duodenalis on the response of the small intestine, microbiota, and behavioral parameters in mice. MAIN METHODS: Swiss mice were infected with assemblages AII and BIV of G. duodenalis for 15 days. Leucometry, pain, intestinal microbiota and histological parameters of the duodenum and jejunum were evaluated in the experimental groups. KEY FINDINGS: Both assemblages modified the composition of the intestinal microbiota. Infection with assemblage AII promoted leukocytosis, reflected by increasing number of polymorphonuclear cells, intraepithelial lymphocytes and pain-related behavior, indicating that this was the more aggressive assemblage with regard to its effects on the intestinal mucosa and duodenum. SIGNIFICANCE: The specific assemblage of the parasite is an important parameter that affects symptomatology in the host. PMID- 29514130 TI - Effects of polysaccharide from Portulaca oleracea L. on voltage-gated Na+ channel of INS-1 cells. AB - Our previous work showed that polysaccharide isolated from Portulaca oleracea L. (POP) has an insulinotropic effect. The voltage-gated Na+ channel (VGSC) in the excitement phase plays an important role. This work aims to study the effect of POP on the voltage-gated Na+ channel current (INa) and its channel dynamic characteristics in insulin-secreting beta-cell line (INS-1) cells of rat. Our results revealed that POP can inhibit the amplitude of INa and improve cell survival in a concentration-dependent manner. POP concentration of 0.5 mg mL-1 reduced the amplitude of INa, suppressed the INa of steady-state activation, shifted the steady-state inactivation curves of INa to negative potentials, prolonged the time course of INa recovery from inactivation, and enhanced the activity-dependent attenuation of INa. Furthermore, 0.5 mg mL-1 POP or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited INa and also improved insulin synthesis and cell survival. Collectively, these results revealed that POP protects INS-1 cells and enhances the insulin synthesis in INS-1 cells, and the mechanism through the partial inhibition on INa channel is strongly recommended. PMID- 29514131 TI - Potential of resveratrol in mitigating metabolic disturbances induced by ethanol. AB - Alcohol abuse is associated with numerous health problems, including metabolic disturbances and liver damage. Therefore, different compounds are continuously being tested to evaluate their potential effectiveness in reducing these harmful changes. Animal studies clearly show that resveratrol is capable of ameliorating some consequences of ethanol ingestion. Resveratrol is a naturally occurring diphenolic compound having pleiotropic, health-promoting properties. Its beneficial action have been also demonstrated in animal models with ethanol induced metabolic disturbances and liver injury. In ethanol treated animals, resveratrol effectively reduced liver lipid accumulation. Moreover, this compound diminished necrosis of hepatocytes, and also reduced liver fibrosis. The hepatoprotective action of resveratrol is largely associated with its ant-oxidant and anti-inflammatory properties, and also covers changes in activities of some enzymes. It is known that this compound upregulates the adiponectin-SIRT1-AMPK signaling pathway in the liver. Resveratrol was also found to positively affect blood lipids in animals exposed to ethanol. Moreover, administration of resveratrol to animals with ethanol-induced hypoinsulinemia and insulin resistance was shown to alleviate these disturbances. These outcomes clearly indicate that resveratrol holds great potential to reduce some consequences of ethanol ingestion. However, human studies are required to fully assess its therapeutic value. PMID- 29514132 TI - Hormone actions controlling sex-specific life-extension. PMID- 29514133 TI - SIRT2 in age-related neurodegenerative disorders. PMID- 29514134 TI - Methylomic survival predictors, frailty, and mortality. AB - Survival predictors are of potential use for informing on biological age and targeting prevention of aging-related morbidity. We assessed associations of 2 novel methylomic survival indicators, a methylation-based mortality risk score (MRscore) and the epigenetic clock-derived age acceleration (AA), with a well known survival predictor, frailty index (FI), and compared the 3 indicators in mortality prediction. In a large population-based cohort with 14-year follow-up, we found both MRscore and AA to be independently associated with FI, but the association was much stronger for MRscore than for AA. Although all 3 indicators were individually associated with all-cause mortality, robust associations only persisted for MRscore and FI when simultaneously including the 3 indicators in regression models, with hazard ratios (95% CI) of 1.91 (1.63-2.22), 1.37 (1.25 1.51), and 1.05 (0.90-1.22), respectively, per standard deviation increase of MRscore, FI, and AA. Prediction error curves, Harrell's C-statistics, and time dependent AUCs all showed higher predictive accuracy for MRscore than for FI and AA. These findings were validated in independent samples. Our study demonstrates the ability of the MRscore to strongly enhance survival prediction beyond established markers of biological age, such as FI and AA, and it thus bears potential of a surrogate endpoint for clinical research and intervention. PMID- 29514135 TI - CD40L promotes development of acute aortic dissection via induction of inflammation and impairment of endothelial cell function. AB - Acute aortic dissection is one of the most lethal cardiovascular disease. The major histopathological feature of AAD is medial degradation, especially breakdown of elastin and collagen. However, the underlying mechanism remains a mystery. Platelets expressed CD40 Ligand (CD40L) is recently recognised as a key effector of cardiovascular disease development through its pro-inflammatory effect. To clarify the role of CD40L in AAD, we examined level of CD40L in human blood serum samples and found that it is significantly higher in AAD patients compared with healthy subjects (26.8+/-5.52 ng/mL versus 13.4+/-4.00 ng/mL). To further investigate if CD40L is involve in the development of AAD, we applied beta-aminopropionitrile (BAPN) induced mouse model of AAD. Consistent with the human data, circulating CD40L in AAD mice much higher than normal mice (148.40+/ 75.96 pg/mL versus 44.09+/-19.65 pg/mL). Meanwhile, multiple pro-inflammatory chemokines significantly increased in AAD mice. Importantly, the CD40L-/- mice treated with BAPN did not develop these phenotypes. Lastly, we confirmed that endothelial cells migration was significantly inhibited by CD40L, suggesting impaired recovery from intimal injury. In summary, we found that CD40L promoted AAD development through its pro-inflammatory effects and inhibition of endothelial cell function. PMID- 29514136 TI - Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in Drosophila. AB - Stem cell dysfunction is closely linked to tissue and organismal aging and age related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11, Rad50, Nbs1, ATM, ATR, Chk1, and Chk2, which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult fly's survival. Our data indicated a distinct effect of DDR depletion in stem or niche cells on tissue resident stem cell proliferation. Our findings provide evidence of the essential role of DDR in protecting EC against ISC aging, thus providing a better understanding of the molecular mechanisms of stem cell/niche aging. PMID- 29514137 TI - Efficacy of On-Demand Therapy Using 20-mg Vonoprazan for Mild Reflux Esophagitis. AB - BACKGROUND: The study aimed to evaluate the efficacy of on-demand therapy using 20-mg vonoprazan for mild reflux esophagitis (RE). METHODS: On-demand therapy by taking one 20-mg tablet of vonoprazan only when reflux symptoms occurred was performed for 24 weeks using 30 patients with mild RE who were receiving maintenance therapy with proton pomp inhibitors (PPIs). The presence or absence of RE, degree of overall satisfaction with the treatment, score of symptoms, and fasting gastrin level before breakfast were examined before and after on-demand therapy. The number of tablets taken during the 24-week period was also noted. RESULTS: One of the 30 patients dropped out of on-demand therapy 1 week after its initiation. Remission was maintained in 25 (86.2%) of the 29 patients (all 10 [100%] Los Angeles classification grade A patients and 15 (78.9%) of the 19 grade B patients). However, 4 grade B patients exhibited grade B relapse. There were no differences in the degree of overall satisfaction, score of symptoms or the gastrin level between PPI and on-demand therapies. The number of vonoprazan tablets taken during the observation period was 33 tablets (median)/24 weeks. CONCLUSION: On-demand therapy using 20-mg vonoprazan tablets is an effective alternative maintenance therapy for mild RE. PMID- 29514138 TI - Effects of Gene Variants Controlling Vitamin D Metabolism and Serum Levels on Hepatic Steatosis. AB - BACKGROUND/AIMS: Common genetic variations in vitamin D metabolism are associated with liver stiffness. Whether these genes are implicated in hepatic steatosis remains unclear. Here we aimed to analyse the association of common vitamin D pathway gene variants with liver steatosis. METHODS: Liver steatosis was assessed non-invasively in 241 patients with chronic liver conditions by controlled attenuation parameter (CAP). The following polymorphisms were genotyped using TaqMan assays: group-specific component (GC) rs7041, 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657, -vitamin D receptor (VDR) rs7974353. Chemiluminescence immunoassay determined serum 25 hydroxyvitamin D (25(OH) D) concentrations. RESULTS: Vitamin D deficiency (defined by 25(OH)D concentrations <20 ng/mL) occurred in 66% of patients. Median CAP was 296 (100-400) dB/m. Patients with advanced steatosis (CAP >=280 dB/m) had significantly (p = 0.033) lower 25(OH)D levels as compared to patients with CAP <280 dB/m. Moreover, the rare allele [T] in GC rs7041 was significantly (p = 0.018) associated with higher 25(OH)D levels in patients with CAP <280 dB/m. However, GC, DHCR7, CYP2R1, and VDR polymorphisms were not related to liver steatosis and obesity traits. CONCLUSIONS: Higher CAP values are associated with low serum 25(OH)D concentrations but not with common vitamin D pathway gene variants. PMID- 29514139 TI - Real-World Scenario Improvements in Serum Phosphorus Levels and Pill Burden in Peritoneal Dialysis Patients Treated with Sucroferric Oxyhydroxide. AB - BACKGROUND: A database analysis was conducted to assess the effectiveness of sucroferric oxyhydroxide (SO) on lowering serum phosphorus and phosphate binder (PB) pill burden among adult peritoneal dialysis (PD) patients prescribed SO as part of routine care. METHODS: Adult PD patients (n = 258) prescribed SO through a renal pharmacy service were analyzed. Baseline was 3 months before SO prescription. SO-treated follow-up was for 6 months or until either a new PB was prescribed, SO was not refilled, PD modality changed, or patient was discharged. In-range serum phosphorus was defined as <=5.5 mg/dL. RESULTS: At baseline, mean serum phosphorus was 6.59 mg/dL with 10 prescribed PB pills/day. The proportion of patients achieving in-range serum phosphorus increased by 72% from baseline to month 6. Prescribed PB pills/day decreased by 57% (10 at baseline to 4.3 at SO follow-up, p < 0.0001). The mean length of SO follow-up was 5.1 months; SO follow up ended for 38, 27, and 50 patients at months 4, 5, and 6, respectively, due to no further PB fills, and for 10, 11, and 4 patients at months 4, 5, and 6, respectively, due to another PB prescribed. In patients with baseline serum phosphorus >5.5 mg/dL who achieved in-range serum phosphorus during SO follow-up for >=1 quarter, a notable improvement in serum phosphorus (6.54 to 5.10 mg/dL, p < 0.0001) was observed, and there was a 53% reduction in PB pill burden (9.9 to 4.7, p < 0.0001). CONCLUSION: Among PD patients prescribed SO as part of routine care, improvements in serum phosphorus control and >50% reduction in PB pills/day were observed. PMID- 29514140 TI - Accordance of Online Health Information on Prostate Cancer with the European Association of Urology Guidelines. AB - BACKGROUND: The internet is an emerging source of information for prostate cancer (PCa) patients. Since little is known about the quality of information on PCa provided online, we investigated its accordance to the latest European Association of Urology (EAU) guidelines. METHODS: A total of 89 German web pages were included for analysis. A quality model classifying the provider of information and its expertise was introduced. Correctness of provided information was systematically compared to the EAU guidelines. RESULTS: Information was provided by medical experts (41%), media (11%), and pharmaceutical companies (6%). Certificates were found in 23% with a significantly higher rate if provided by medical experts (p = 0.003). The minority of web pages showed information in accordance with the EAU guidelines regarding screening (63%), diagnosis (32%), classification (39%), therapy (36%), complications (8%), and follow-up (27%). Web pages by medical experts as well as websites with any kind of certification showed a significantly higher guideline conformity regarding diagnosis (p = 0.027, p = 0.002), therapy (p = 0.010, p = 0.011), follow-up (p = 0.005, p < 0.001), and availability of references (p = 0.017, p = 0.003). CONCLUSIONS: The present study reveals that online health information on PCa lacks concordance to current guidelines. Certified websites or websites provided by medical experts showed a significantly higher quality and accordance with guidelines. PMID- 29514141 TI - Endoscopic and Immunohistochemical Characteristics of Gastric Cancer with versus without Helicobacter Pylori Eradication. AB - BACKGROUND/AIMS: The rate of gastric cancer (GC) after Helicobacter pylori eradication has gradually increased; therefore, we investigate the clinicopathological features of GC following eradication in comparison with those of GC with H. pylori infection. METHODS: This study included 50 subjects with GC after eradication (GCE) and 151 patients with GC with H. pylori infection (GCI). Clinicopathological factors were assessed. The manifestation of GC was further evaluated using immunohistochemical analysis and in situ hybridization. RESULTS: Macroscopic analysis revealed a significantly higher ratio of depressed type /elevated type in the GCE compared with the GCI (30/19 vs. 61/77, p = 0.041). The gastric phenotype was more common in the GCE compared with the GCI, and the proportion of CDX2-positive cases was lower in the GCE (8 out of 18; 44.4%) compared with the GCI (18 out of 19; 94.7%; p = 0.00082). Ki-67 labeling index was significantly lower in the GCE (32.03 +/- 22.15) compared with the GCI (79.20 +/- 14.87, p < 0.0001). No patient in the GCE showed evidence of Epstein-Barr virus infection. CONCLUSION: The clinicopathological characteristics of GC following H. pylori eradication differ from those of GC in patients with H. pylori infection in terms of morphology, mucin phenotype, and proliferation rate. PMID- 29514142 TI - Hand-Sewn versus Stapled Closure of Loop Ileostomy: A Meta-Analysis. AB - BACKGROUND: Individual trials comparing hand-sewn with stapled closure of loop ileostomy show different outcomes due to lack of statistical power. A systematic review, with a pooled analysis of results, might provide a more definitive answer. This review aimed to compare hand-sewn with stapled anastomotic technique for closure of a loop ileostomy and looked at the effect of bowel resection on the complication rates. METHODOLOGY: Relevant studies were identified from MEDLINE, EMBASE and the Cochrane database. All randomised clinical trials, prospective and retrospective studies comparing hand-sewn with stapled closure of loop ileostomy were included. RESULTS: Of the 4,917 patients in 15 identified studies, 3,406 had hand-sewn and 1,511 stapled anastomosis. There was no difference in the rate of anastomotic leak between the hand-sewn (2.93%, 55/1,877) and the stapled group (2.08%, 25/1,202) (OR 0.81, 95% CI 0.43-1.54, p = 0.52, I2 = 33%). The rate of small-bowel obstruction was higher in the hand-sewn group (7.03%, 231/3,284) compared to the stapled group (5.58%, 73/1,308; OR 0.69, 95% CI 0.51-0.92, p = 0.01, I2 = 0%). There was no difference in the incidence of anastomotic leak and small-bowel obstruction in the hand-sewn anastomosis between patients with or without bowel resection. CONCLUSIONS: There was no significant difference in the rate of anastomotic leakage between the hand-sewn and stapled techniques. The rate of small-bowel obstruction was higher in the hand-sewn group. Performance of bowel resection does not significantly increase the incidence of anastomotic leak or small-bowel obstruction. PMID- 29514143 TI - Long-Term Follow-Up after Paediatric Kidney Transplantation and Influence Factors on Graft Survival: A Single-Centre Experience of 16 years. AB - INTRODUCTION: To evaluate graft- and patient survival after paediatric kidney transplantation and detecting influence factors, which affect the post-transplant time. MATERIALS AND METHODS: We analysed long-term survival rates and complications after paediatric kidney transplantation and searched for predictive parameters for graft function. RESULTS: In 132 patients, 143 kidney transplantations were performed. Graft failure occurred in 25%. Chronic rejections were the leading cause of graft loss (42.9%). Graft survival rates were 92.2% after 1 year, 85.5% after 5 years, 71.1% after 10 years and 62.1% after 15 years. The following parameters strongly influenced graft survival: number of transplants (p = 0.014), year of transplant (p < 0.0001 for 1997-2005), Epo-therapy post-transplant (p = 0.001), hypotension donor (p = 0.027), cold ischemia time (p = 0.023), anastomosis time >50 min (p = 0.008), delayed graft function (p = 0.003) and deceased donation (p = 0.039). The percentage of patients who died was 5.6%. Overall patient survival rates were 99.3% after 1 year, 95.2% after 5 years, 94.2% after 10 years and 90.7% after 15 years. Various types of infections (42.9%) were the main causes of death. CONCLUSIONS: The main causes of death after kidney transplantations in paediatric recipients are malignancy and infections. To avoid vascular complications especially in young recipients (<9 years), the cold ischemia time should be as short as possible. PMID- 29514144 TI - Health-Related Quality of Life after Radical Cystectomy for Bladder Cancer in Elderly Patients with Ileal Orthotopic Neobladder or Ileal Conduit: Results from a Multicentre Cross-Sectional Study Using Validated Questionnaires. AB - OBJECTIVE: To evaluate health-related quality of life (HR-QoL) outcomes in elderly patients with different type of urinary diversion (UD), ileal conduit (IC) and ileal orthotopic neobladder (IONB), after radical cystectomy (RC) for bladder cancer, by using validated self-reported cancer-specific instruments. PATIENTS AND METHODS: We retrospectively reviewed 77 patients who received an IC or an IONB after RC. HR-QoL was assessed with specific and validated disease questionnaires, administered at last follow-up. RESULT: At univariate analysis, at a mean follow-up of 60.91 +/- 5.63 months, IONB results were favourable with regard to the following HR-QoL aspects: nausea and vomiting (p = 0.045), pain (p = 0.049), appetite loss (p = 0.03), constipation (p = 0.000), financial impact (p = 0.012) and cognitive functioning (p = 0.000). This last functional aspect was significantly worse in female patients (p = 0.029). Emotional functioning was significantly better in patients without long-term complications (p = 0.016). At multivariate analysis, male gender and IONB were independent predictors of better cognitive functioning, while long-term complications negatively affected emotional functioning. CONCLUSIONS: Obtained results suggest that an IONB can also be suitable for elderly patients compared with an IC with few and selected advantages in favour of the former UD. Preoperative patient's selection, counselling, education and active participation in the decision-making process lead to a more suitable choice of treatment. PMID- 29514145 TI - Preoperative Midregional Pro-Adrenomedullin and High-Sensitivity Troponin T Predict Perioperative Cardiovascular Events in Noncardiac Surgery. AB - OBJECTIVE: We evaluated the utility of preoperative midregional (MR) pro adrenomedullin (proADM) and cardiac troponin T (TnT) for improved detection of patients at high risk for perioperative cardiac events and mortality after major noncardiac surgery. SUBJECTS AND METHODS: This prospective, single-center, observational study enrolled 79 patients undergoing major noncardiac surgery. After initial clinical assessment (clinical history, physical examination, echocardiogram, blood tests, and chest X-ray), MR-proADM and high-sensitivity TnT (hsTnT) were measured within 48 h prior to surgery by immunoluminometric and electrochemiluminescence immunoassay. Patients were followed by the consulting physician until discharge or up to 14 days in the hospital after surgery. Perioperative cardiac events included myocardial infarction and development or aggravation of congestive heart failure. Data were compared between patients who developed target events and event-free patients. RESULTS: Within 14 days of monitoring, 14 patients (17.72%) developed target events: 9 (11.39%) died and 5 (6.33%) developed cardiovascular events. The average age of the patients was 71.29 +/- 6.62 years (range: 55-87). Sex, age, and hsTnT did not significantly differ between groups. MR- proADM concentration was higher in deceased patients (p = 0.01). The upper quartile of MR-proADM was associated with a fatal outcome (66.7 vs. 20.0%, p < 0.01) and with cardiovascular events (64.3 vs. 16.9%, p < 0.01). MR-proADM above the cutoff value (>=0.85) was associated with a fatal outcome (88.9 vs. 20.0%, p < 0.01) and cardiovascular events (71.4 vs. 28.6%, p < 0.01); this association was not observed for hsTnT. CONCLUSION: Preoperative measurement of MR-proADM provides useful information for perioperative cardiac events in high-risk patients scheduled for noncardiac surgery. PMID- 29514146 TI - Multiparametric Evaluation Predicts Different Mid-Term Outcomes in Crohn's Disease. AB - AIM: To evaluate if a single and/or combined (clinical, endoscopic and radiological) assessment could predict clinical outcomes in Crohn's disease (CD). METHODS: We prospectively evaluated 57 CD cases who underwent both a colonoscopy and a CT-enterography (CTE). Harvey-Bradshaw Index (HBi), SES-CD (and/or Rutgeerts score) and the radiological disease activity were defined to stratify patients according to clinical, endoscopic and radiological disease activity respectively. Hospitalizations, surgery, therapeutic changes and deaths were evaluated up to 36 months (time 1) for 53 patients. RESULTS: CTE and endoscopy agreed in stratifying disease activity in 47% of cases (k = -0.05; p = 0.694), CTE and HBi in 35% (k = 0.09; p = 0.08), endoscopy and HBi in 39% (k = 0.13; p = 0.03). Taken together, CTE, endoscopy and HBi agreed only in 18% of cases (k = 0.01; p = 0.41). Among the 11 cases with mucosal healing, only 3 (27%) showed transmural healing. Patients with endoscopic activity needed significantly more changes of therapy compared to patients with endoscopic remission (p = 0.02). Patients with higher transmural or clinical activity at baseline required significantly more hospitalizations (p < 0.01). Hospitalization rate decreases with an increase in the number of parameters indicating remissions at baseline (p = 0.04). CONCLUSIONS: Clinical, endoscopic and radiological assessments offer complementary information and could predict different mid-term outcomes in CD. PMID- 29514148 TI - The Relationship between Carotid and Femoral Artery Intima-Media Thickness and Histopathologic Grade of Atherosclerosis in Patients with Chronic Kidney Disease. AB - BACKGROUND/AIMS: Variability in the grade of atherosclerosis among patients with chronic kidney disease (CKD) could affect the ultrasound measurements of intima media thickness (IMT). We sought to investigate IMTs of carotid (cIMT) and femoral (fIMT) arteries in CKD patients and assess the degree of their correlation with histopathological atherosclerosis. METHODS: Eighty-nine out of 99 enrolled subjects completed this study. The subjects were divided into 3 groups: 34 patients with CKD (Case group), 31 with coronary artery disease undergoing coronary artery bypass graft (CABG, positive control group), and 24 healthy kidney donors (negative control group). For histopathological assessment of atherosclerosis, arterial tissue samples were obtained from the patients in each study group. The cIMT and fIMTs were measured by ultrasonography. RESULTS: Histopathological atherosclerosis was present in 82.3, 100, and 20.8% of CKD, CABG, and donor groups respectively (p < 0.001). CKD patients had higher values of cIMT and fIMT than the donor group (p = 0.01 and 0.004, respectively). cIMT was positively correlated with the grade of atherosclerosis in the CKD group only (p < 0.001), while fIMT was correlated with the grade of atherosclerosis in both CKD and donor groups (p < 0.001 and p = 0.009 respectively). In CKD patients, cIMT >0.65 mm and femoral values >0.57 mm predicted the presence of histopathological atherosclerosis with sensitivities of 96 and 92% respectively. CONCLUSION: Higher values of cIMT and fIMT in CKD patients are associated with higher rates and degrees of histopathological atherosclerosis. Additionally, when compared to fIMT, cIMT has a higher sensitivity for detecting atherosclerosis in CKD patients. PMID- 29514149 TI - Aged Black-and-Gold Howler Monkey Female (Alouatta caraya): A Sign of Reproductive Senescence? AB - Reproductive senescence patterns have been scarcely studied in Neotropical primates. The few studies available on the hormonal profiles of aging female monkeys indicate that the decline of ovarian function in nonhuman primates may resemble the hormonal events associated with the perimenopause in women. In this study, we explore a reproductive hormone profile of an aged black-and-gold howler monkey female (Alouatta caraya) from a wild population in northeastern Argentina and compare this profile with that of a cycling female in the same population. As part of a larger study, we recorded sociosexual behaviors in adult and subadult females belonging to two groups, and we collected urine (n = 877) to determine the sex hormone profile of each female. These samples were analyzed using enzyme immunoassays for estrone conjugates and pregnanediol-3-glucuronide (PdG). We found differences in mean values of PdG between the younger (cycling) and the older female. These hormone values were lower in the older female, and she did not show any signs of cyclicity for either reproductive hormone. Our results show that the aging female in this wild population shows signs of ovarian senescence, indicated by low, acyclic levels of progesterone metabolites. PMID- 29514147 TI - Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia. AB - Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (alpha-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms alpha-tocopherol and gamma tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions. PMID- 29514151 TI - Differential Response of Dopamine Mediated by beta-Adrenergic Receptors in Human Keratinocytes and Macrophages: Potential Implication in Wound Healing. AB - OBJECTIVE: Dopamine is an immunomodulatory neurotransmitter. In the skin, keratinocytes and macrophages produce proinflammatory cytokines and metalloproteinases (MMPs) which participate in wound healing. These cells have a catecholaminergic system that modulates skin pathophysiologic processes. We have demonstrated that dopamine modulates cytokine production in keratinocytes via dopaminergic and adrenergic receptors (ARs). The aim of this study was to evaluate the effect of dopamine and its interaction with beta-ARs in human HaCaT keratinocytes and THP-1 macrophages. We evaluated the production of inflammatory mediators implicated in wound healing. METHODS: Cells were stimulated with dopamine in the absence or presence of the beta-adrenergic antagonist propranolol. Wound closure, MMP activity, and the production of IL-8, IL-1beta, and IkappaB/NFkappaB pathway activation were determined in stimulated cells. RESULTS: Dopamine did not affect the wound closure in human keratinocytes, but diminished the propranolol stimulatory effect, thus delaying cell migration. Similarly, dopamine significantly decreased MMP-9 activity and the propranolol induced MMP activity. Dopamine significantly increased the p65-NFkappaB subunit levels in the nuclear extracts, which were reduced in the presence of propranolol in keratinocytes. On the other hand, dopamine significantly increased MMP-9 activity in THP-1 macrophages, but did not modify the propranolol-increased enzymatic activity. Dopamine significantly increased IL-8 production in human macrophages, an effect that was partially reduced by propranolol. Dopamine did not modify the p65-NFkappaB levels in the nuclear extracts in THP-1 macrophages. CONCLUSION: We suggest that the effect of dopamine via beta-ARs depends on the physiological condition and the cell type involved, thus contributing to either improve or interfere with the healing process. PMID- 29514150 TI - High Serum Thyrotropin Concentrations within the Reference Range: A Predictor of Malignancy in Nodular Thyroid Disease. AB - OBJECTIVE: This study assessed whether or not a simple biochemical parameter, serum thyrotropin (TSH), within the reference range can predict the likelihood of thyroid malignancy in subjects undergoing fine-needle aspiration biopsy (FNAB) for thyroid nodules. SUBJECTS AND METHODS: This cross-sectional study evaluated 236 patients without overt thyroid dysfunction who were not on levothyroxine therapy. They underwent FNAB of the thyroid nodules at the Clementino Fraga Filho University Hospital between 2011 and 2012. The reference range and serum TSH quartiles were determined according to age-specific values for serum TSH and then compared between the cases with benign thyroid nodular disease and differentiated thyroid carcinoma (DTC) based on surgical pathology reports. RESULTS: Of the 236 patients, 201 (85.1%) underwent a surgical procedure (thyroidectomy) and 89/236 (44.3%) had DTC. The mean TSH concentrations were 2.09 +/- 1.15 mU/L in benign patients versus 2.73 +/- 1.33 mU/L in cases of DTC (p < 0.01). As TSH increased from quartiles 1 to 4, the frequency of a malignant diagnosis also increased progressively from 22% in quartile 1 to 65% in the last quartile (p <= 0.001). CONCLUSION: Thyrotropin levels were positively associated with the diagnosis of DTC in thyroid nodules. PMID- 29514153 TI - The Scientific Illusion of Victor Burq (1822-1884). AB - Victor Burq (1822-1884) is closely associated with a therapy named "burquism" by Jean-Martin Charcot, which was used in treating hysteria, especially hysteric anesthesia and paralysis, by applying metals, mainly copper, to affected zones. In 1876, Charcot, Luys, and Dumontpallier, commissioned by the Societe de Biologie, issued 2 opinions validating the results obtained by Burq during the 25 years he dedicated to his research. From that point forward, the careers of these 3 famous physicians were lastingly reoriented toward the practice of hypnosis. This neo-mesmeric resurgence at the end of the nineteenth century can be considered the cause of an epistemological change that gave rise to "psychological medicine." During the repeated cholera epidemics in the mid nineteenth century, Burq recommended preventive and corrective ingestion of copper, after observing that smelter workers were unaffected by the disease. The mechanisms of copper's anti-bacterial action have since been elucidated and legitimize Burq's anti-cholera campaign. Burq also advocated the ingestion of copper sulphate to treat diabetes. Current-day findings on intestinal microbiota and how these organisms influence blood sugar regulation support Burq's claims, considered far-fetched for many years. PMID- 29514152 TI - Investigation of Exposure Factors for Various Breast Composition and Thicknesses in Digital Screening Mammography Related to Breast Dose. AB - OBJECTIVE: To investigate the effect of exposure factors used in digital screening mammography on image quality of different breast compositions. MATERIAL AND METHODS: A digital mammography unit, with tungsten (W) as target, rhodium (Rh) and silver (Ag) as filters, and amorphous selenium detectors, was used to image Computerized Imaging Reference Systems (CIRS) Model 12A phantoms of thickness 4, 5, and 6 cm. Images of each phantom were obtained using target filter combinations of W/Rh and W/Ag, at 28, 30, and 32 kVp. Images were evaluated by 5 senior technologists with experience in mammography. Image scores were assigned, for each type of feature present in the phantom. Statistical analysis was performed using nonparametric tests to compare sets of image scores at p = 0.05. RESULTS: A small but statistically significant improvement was detected in the visibility of microcalcifications (8.8 +/- 0.2; p = 0.031) for the W/Rh combination but this did not show any differences in the visibility of masses or fibers. The entrance skin dose (ESD) and mean glandular dose (MGD) were lower for the W/Ag (ESD = 1.30-3.70; MGD = 0.44-0.93 mGy) combination compared to W/Rh (ESD = 1.66-5.40; MGD = 0.52-1.12 mGy). The Mann-Whitney test revealed that 30-kV exposure with the W/Rh combination showed a significantly better visibility of specks in the 30/70 phantom compared to other exposures. CONCLUSION: The use of an Rh filter showed a better image quality for all phantoms. 28 and 30 kVp with the W/Rh combination provided a slightly better image quality, and the MGD is less than 1.2 mGy. PMID- 29514154 TI - Bladder Dysfunction in Children with Neurofibromatosis Type I: Report of Four Cases and Review of the Literature. AB - AIM: Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder. Malignant transformation into malignant peripheral nerve sheath tumors (MPNST) can occur. However, urinary tract involvement is rare. We report 4 cases of NF1 with bladder dysfunction. METHODS: A retrospective single center analysis of 4 patients was conducted over a 17-year period, focusing on urinary tract involvement. RESULTS: NF1 was diagnosed at a median of 16.5 months (4-36) and urinary involvement occurred at a median of 5.25 years (4-9) after diagnosis. Bladder dysfunction was due to spinal cord compression in 2 cases, bladder invasion in 1 case, and cerebral lesions in 1 case. Malignant transformation of neurofibromas into MPNST occurred in 2 patients. Mechanisms of urinary involvement in NF1 are diverse and no pre-established protocol of management and follow-up exists. CONCLUSION: Although rare, dysfunction of the bladder can arise in NF1 and innovative strategies then need to be considered. This is best achieved with the help of a multidisciplinary team and a national reference center when available. PMID- 29514155 TI - Re: Do JJ Stents Increase the Effectiveness of Extracorporeal Shock Wave Lithotripsy for Pediatric Renal Stones? PMID- 29514156 TI - Cinacalcet for Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Cinacalcet could decrease serum calcium, phosphate, and parathyroid hormone (PTH) in previous meta-analyses. However, the effect of cinacalcet on the new biomarkers such as fibroblast growth factor-23 (FGF-23), bone markers, and vascular calcification are still unestablished. We conducted a meta-analysis to examine the effects of cinacalcet on all laboratory and clinical spectrums of chronic kidney disease-mineral bone disorders (CKD-MBD). METHODS: A systematic literature search was conducted in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov to identify randomized controlled trials (RCTs) comparing the effect of cinacalcet relative to standard treatment on CKD-MBD surrogate markers and clinical outcomes. Random-effect models were used to compute the weighted mean difference for continuous variables and the risk ratio for binary variables. RESULTS: Twenty-four RCTs (10,031 dialysis patients) were identified. Besides lowering effects on calcium, phosphate, and PTH, cinacalcet significantly reduced bone resorptive marker (tartrate-resistant acid phosphatase 5b) but unaltered bone formation markers (bone alkaline phosphatase and osteocalcin). Cinacalcet also resulted in significant higher risk of hypocalcemia, nausea, vomiting, and diarrhea. Cinacalcet significantly lowered serum FGF-23 level, although unaltered all-cause mortalities. CONCLUSIONS: Use of cinacalcet in dialysis patients improves several CKD-MBD-related surrogate markers. However, the benefit on all-cause mortalities was not demonstrated. PMID- 29514157 TI - Cognitive Reserve Hypothesis in Frontotemporal Dementia: Evidence from a Brain SPECT Study in a Series of Greek Frontotemporal Dementia Patients. AB - BACKGROUND AND OBJECTIVE: Cognitive reserve (CR) mediates the clinical expression of brain pathology in Alzheimer's disease, while there are much less relevant data in frontotemporal dementia (FTD). In the present study we examined whether CR, measured using the Cognitive Reserve Index (CRI), correlated with regional cerebral blood flow (rCBF) in Greek FTD patients. METHODS: Eighty FTD patients, i.e., 47 with behavioral variant FTD (bvFTD) and 33 with primary progressive aphasia (PPA), were enrolled into this study. CR was assessed using the CRI questionnaire, which provides a total score (CRI) and 3 subscores, i.e., CRI education, CRI-working activity, and CRI-leisure time. The FTD-Clinical Dementia Rating Scale was used to assess the severity of dementia and a brain SPECT study was performed to measure rCBF. Finally, multiple regression analyses were conducted to explore correlations between CR indices and frontotemporal rCBF. RESULTS: In both the bvFTD and the PPA groups, higher scores in the CRI, CRI education, and CRI-leisure time correlated with lower rCBF in the bilateral frontal and left temporal cortex, respectively, controlling for age, sex, time since symptom onset, and disease severity. CONCLUSION: In the present study, lifetime participation in leisure time activities was found to mitigate the burden of disease in bvFTD and PPA patients. Moreover, FTD patients with a higher educational attainment were able to cope better with greater brain damage. Determination of the most suitable activities to build an adequate level of CR is crucial for dementia prevention. PMID- 29514158 TI - Economy of Standards: European Association of Urology Guideline Changes Influence Treatment Costs in Stage I Testicular Cancer Patients. AB - OBJECTIVE: The study aimed to calculate direct medical costs (DMC) during the first year of diagnosis and to evaluate the impact of guideline changes on treatment costs in clinical stage (CS) I testicular germ cell tumor (TGCT) patients in a German healthcare system. MATERIALS AND METHODS: Healthcare expenditures as DMC during the first year of diagnosis for 307 TGCT patients in CS I treated at our institution from 1987 to 2013 were calculated from the statutory health insurance perspective using patient level data. Three periods were defined referring to the first European Association of Urology (EAU) guideline in 2001 as well as to subsequent major guideline changes in 2005 and 2010. Data source for cost calculations were the German Diagnosis Related Groups system for inpatient stays (version 2014) and the German system for reimbursement of outpatient care (EBM - Einheitlicher Bewertungsmabetastab, edition 2014). RESULTS: During our 25 years of study period, mean DMC in the first year after diagnosis for the entire cohort of TGCT patients in CS I almost halved from EUR 13.000 to EUR 6.900 (p < 0.001). From 1987 to 2001, DMC for CS I seminomatous germ cell tumor (SGCT) patients were EUR 13.790 +/- 4.700. From 2002 to 2010, mean costs were EUR 10.900 +/- 5.990, and from 2011 to 2013, mean costs were EUR 5.190 +/- 3.700. For CS I non-seminomatous germ cell tumor (NSGCT) patients, from 1987 to 2001, mean DMC were EUR 11.650 +/- 5.690. From 2002 to 2010, mean costs were EUR 11.230 +/- 5.990, and from 2011 to 2013, mean costs were EUR 11.170 +/- 7.390. Follow-up examinations became less frequent over time, which caused a significant cost reduction for NSGCT (p = 0.042) while costs remained stable for SGCT. When adding costs of relapse treatment, active surveillance (AS) was the most cost-effective adjuvant treatment option in CS I NSGCT whereas one course carboplatin or AS caused similar expenditures in SGCT patients. CONCLUSION: The introduction of the EAU guidelines in 2001 caused a decrease in DMC in CS I seminoma patients. This cost reduction mainly took place due to the declining importance of radiation therapy. No substantial changes were seen in patients with CS I NSGCT. Costs for follow-up care also diminished, but to a lesser degree. Even when considering expenditures for relapse treatment, AS remained cost-effective in CS I TCGT patients. Our data show that evidence-based medicine in TGCT can reduce DMC in the first year after diagnosis. PMID- 29514159 TI - Ten-Year Survival of End-Stage Renal Disease Patients Treated with High Efficiency Online Hemodiafiltration: A Cohort Study of a Center in South East Asia. AB - BACKGROUND: Recently, in the first hemodiafiltration (HDF) experience report from South East Asia (SEA), we reported a 3-year prospective study demonstrating the various short-term benefits of high-efficiency online HDF (OL-HDF) over high-flux hemodialysis (HD). Very few long-term survival reports of high-efficiency OL-HDF are available and the data are heterogeneous and incomplete. OBJECTIVES: The present historical cohort study was conducted to determine the long-term survival and outcome of high-efficiency OL-HDF-treated patients. METHODS: Sixty-six high efficiency OL-HDF treated patients at a center in SEA were included in the study. The prescription included blood and dialysis fluid flow rates of 400 and 800 mL/min, respectively. The post- or pre-dilution substitution fluid of 100 or 200 mL/min, respectively, was prescribed. RESULTS: Of 66 HDF patients, whose age was 57.4 +/- 14.0 years, there were 38 (58%) females. The majority of comorbidity was diabetes (36%). There were 33 (50%) incident HDF cases that were prescribed OL HDF at the dialysis initiation and 33 (50%) prevalent HDF cases that were switched from HD to OL-HDF. The 1-, 3-, 5-, and 10-year survival rate were 95.1, 83.4, 77.7, and 61.8% respectively. The mean survival time was 8.99 +/- 0.64 years. There were 15 transplantations and 15 deaths during this study periods. The 2 major causes of death were cardiovascular (33.3%) and infectious diseases (20%). Serum ferritin was the only parameter that correlated with mortality (HR 1.004, p = 0.005). There was comparable survival between incident and prevalent HDF cases. The survival after transplantation of a sub-group of patients who received kidney transplantation (KT) was not different from that of the overall HDF patients (p = 0.93). CONCLUSIONS: High-efficiency OL-HDF could provide an excellent long-term survival nearly comparable to the KT sub-group. PMID- 29514160 TI - Efficacy and Safety of Hyaluronic Acid Gel for the Prevention of Intrauterine Adhesion: A Meta-Analysis of Randomized Clinical Trials. AB - BACKGROUND: The aim of this study is to assess the clinical effectiveness and safety of hyaluronic acid gel for the prevention of postoperative intrauterine adhesions (IUAs). METHODS: PubMed, Cochrane Library, Embase and ClinicalTrials.gov databases were searched for randomized controlled trials. RESULTS: Six RCTs with a total of 564 patients met the inclusion criteria. The meta-analysis showed that, compared to no other treatment method, hyaluronic acid gel significantly reduced the rate of any IUA (risk ratio [RR] 0.68; 95% CI 0.53 0.86; p = 0.03; I2 = 64%) and adhesion score (standard mean difference = -2.90; 95% CI -4.61 to -1.49; p < 0.00001; I2 = 98%) following intraperitoneal or intrauterine surgery. Treatment lowered the rate of IUAs classified as moderate (RR 0.26; 95% CI 0.13-0.52; p = 0.13; I2 = 0%), but not those deemed mild (RR 0.86; 95% CI 0.62-1.21; p = 0.39; I2 = 3%) or severe (RR 0.33; 95% CI 0.03-3.09; p = 0.33; I2 = 0). Compliance with hyaluronic acid gel treatment was low. CONCLUSION: Hyaluronic acid gel can prevent IUAs, particularly those with moderate severity and a lower adhesion score. PMID- 29514161 TI - Implementation of the Neonatal Sepsis Calculator in an Australian Tertiary Perinatal Centre. AB - BACKGROUND: Early-onset sepsis (EOS) is a potentially fatal condition that affects about 0.3-0.8/1,000 infants born at >=35 weeks' gestation in developed countries. Current EOS management algorithms result in 8-15% of infants receiving antibiotics for suspected sepsis. The Neonatal Sepsis Calculator provides evidence-based estimates of individual sepsis risk, but data on its clinical application is limited. OBJECTIVES: To evaluate the feasibility, safety, and effect on the newborn infants that were investigated and that received antibiotic treatment for suspected EOS following the introduction of the Neonatal Sepsis Calculator. METHODS: This was a prospective, observational, single-centre cohort study comparing the rates of newborn infants born at >=35 weeks' gestation requiring evaluation and/or treatment for suspected EOS in a large tertiary perinatal centre before versus after the prospective introduction of the Neonatal Sepsis Calculator (Epoch 1: October 2014 to January 2015 vs. Epoch 2: July to December 2016). RESULTS: There were 1,732 and 2,502 eligible infants born during Epochs 1 and 2, respectively. Of these, 425 (24.2%) and 530 (21.2%), respectively, were admitted to the neonatal unit. The proportion of infants investigated for sepsis decreased from 15.2 to 11.1%, and that of infants treated with antibiotics from 12.0 to 7.6%. One case of EOS occurred during each Epoch. CONCLUSIONS: The implementation of the Neonatal Sepsis Calculator was feasible and safe in our unit. Application of this clinical decision support tool may reduce the number of infants undergoing investigations and empirical treatment for suspected EOS. PMID- 29514162 TI - Design, Rationale, Methodology, and Aims of a Greek Prospective Idiopathic Pulmonary Fibrosis Registry: Investigating Idiopathic Pulmonary Fibrosis in Greece (INDULGE IPF). AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown origin. Despite the fact that the guidelines on the diagnosis and management of the disease were updated in 2015, incorporating novel agents recently introduced in the therapeutic approach of IPF, there is a lack of data on the epidemiology, disease status, and treatment in clinical practice. Contemporary data provided by national registries in IPF provide valuable information to guide clinical management of the disease in the real world setting, adjusted to the local needs. OBJECTIVE: Investigating Idiopathic Pulmonary Fibrosis in Greece (INDULGE IPF) is a Greek observational registry aiming at gaining further knowledge on the characteristics, management, progression, and outcomes of patients with IPF treated under real-world, clinical practice conditions in Greece. METHODS: Approximately 300 patients will be enrolled consecutively in seven reference centers, constituting the largest IPF registry ever established in Greece. CONCLUSION: This registry is expected to provide data on the characteristics of IPF patients in Greece and the entire clinical management during the course of the disease. PMID- 29514163 TI - Prophylactic Effect of Dexamethasone on Regorafenib-Related Fatigue and/or Malaise: A Randomized, Placebo-Controlled, Double-Blind Clinical Study in Patients with Unresectable Metastatic Colorectal Cancer (KSCC1402/HGCSG1402). AB - BACKGROUND: Regorafenib is an oral multikinase inhibitor with a proven survival benefit for metastatic colorectal cancer patients. The KSCC1402/HGCSG1402 study investigated the prophylactic effect of oral dexamethasone (DEX) on regorafenib related fatigue and/or malaise. PATIENTS AND METHODS: Patients who progressed after standard chemotherapy were randomized 1: 1 to a DEX group (2 mg/day; days 1 28) with regorafenib or a placebo group with regorafenib. The primary endpoint was the incidence of fatigue and/or malaise, based on version 4.0 of the National Cancer Institute's CTCAE (Common Terminology Criteria for Adverse Events). One of the secondary endpoints was the in-cidence of fatigue and/or malaise based on the CTCAE assessed by patient-reported outcome (PRO). RESULTS: The incidence of any grade of fatigue and/or malaise assessed by the investigators was 58.8% in the DEX group and 61.1% in the placebo group (p = 0.8101), and that assessed by PRO was 47.2 and 58.3%, respectively (p = 0.3450). The incidence of grade >=2 fatigue and/or malaise, as assessed by the investigators, was 19.4% for the DEX group and 38.9% for the placebo group (p = 0.0695), and that assessed by PRO was 27.8 and 52.8%, respectively (p = 0.0306). CONCLUSION: Our results suggest that prophylactic oral DEX is clinically effective in improving regorafenib-related fatigue and/or malaise. PMID- 29514164 TI - Methanolic Extract of Leathery Murdah, Terminalia coriacea (Roxb.) Wight and Arn. Leaves Exhibits Anti-Inflammatory Activity in Acute and Chronic Models. AB - OBJECTIVE: The aim of the present study was to evaluate anti-inflammatory activity of methanolic extract of Terminalia coriacea. MATERIALS AND METHODS: A methanolic extract of T. coriacea leaves was studied in albino Wistar rats with carrageenan-induced paw edema, an acute model, and cotton pellet-induced granuloma, a chronic model, at 3 oral test doses (125, 250, and 500 mg/kg). Aspirin 100 mg/kg was used as a positive control. Paw volume and wet and dry weights of cotton pellets were determined. The data were analyzed by one-way ANOVA followed by Dunnett's multiple comparison test. RESULTS: The test extract at doses of 125 and 250 mg/kg decreased paw volume and wet and dry weights of cotton pellets. The highest test dose (500 mg/kg) displayed a response comparable to that of the standard drug (p < 0.01) on paw volume. The extract produced similar (p < 0.05) decrease in wet weight of the cotton pellet at 125 and 250 mg/kg, whereas the effect of 500 mg/kg of the extract was comparable to that of aspirin 100 mg/kg (p < 0.01). The extract of T. coriacea at 500 mg/kg induced the most significant (p < 0.01) effect on wet weight of granulomatous tissue. CONCLUSION: The methanolic extract of T. coriacea leaves successfully decreased paw edema as well as dry and wet weights of granulomatous tissue in both acute and chronic inflammatory models thus confirming the anti- edematogenic, antitransudative, and antiproliferative properties of T. coriacea. PMID- 29514165 TI - High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial - Background, Aims, and Study Protocol. AB - BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. OBJECTIVES: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. METHODS: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates >=36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. RESULTS AND CONCLUSIONS: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE. PMID- 29514166 TI - The Influence of Leaf Consumption on Time Allocation in Black Howler Monkeys (Alouatta pigra). AB - The analysis of factors that determine variation in time budgets is important to understand the interactions between environment, behaviour and fitness. We tested the hypothesis that changes in the dietary patterns of black howler monkeys (Alouatta pigra) caused by a decrease in the availability of preferred foods are a main determinant of variation in time budgets. We predicted that individuals would trade off travel time for resting time (i.e., minimize energy expenditure) as the diet included more leaves. We conducted our study in the Mexican state of Campeche between 2005 and 2008, where we studied the behaviour of 28 adult males and 32 adult females belonging to 14 different groups for a total of 3,747.2 focal sampling hours. Study groups lived in forest fragments with variation in habitat quality. Individuals showed different rest:travel trade-offs in response to leaf consumption according to the quality of the forest fragments they lived in. Individuals that lived in high-quality fragments increased resting time under more folivorous regimes, whereas those living in low-quality fragments increased travel time. Our results suggest that howler monkeys living in low-quality fragments spend more time foraging to compensate for the low quality of the available resources. PMID- 29514167 TI - Long-Term Influence of C1-C2 Pedicle Screw Fixation on Occipitoatlantal Angle and Subaxial Cervical Spine in the Pediatric Population. AB - OBJECTIVE: The goal of this study was to evaluate the impact of C1-C2 pedicle screw fixation on the occipitoatlantal angle and subaxial cervical spine for a pediatric population, and the clinical efficacy and adjacent-segment degeneration after C1-C2 pedicle screw fixation with a minimum of 2 years of follow-up. METHODS: Twenty-two pediatric patients with atlantoaxial dislocation who were enrolled in this study underwent atlantoaxial pedicle screw fixation. The correlation between C0-C1, C2-C7, and C1-C2 pre- and postoperative sagittal angles was assessed using plain radiographs, and adjacent-segment degeneration (ASD) and JOA scores (Japanese Orthopaedic Association scores) were evaluated after atlantoaxial pedicle screw fixation. RESULTS: The C1-C2 angle increased from 16.1 +/- 13.37 to 28.1 +/- 5.1 degrees (p < 0.01). The pre- and postoperative C1-C2 angles were negatively correlated with the pre- and postoperative C0-C1 and C2-C7 angles, respectively. In accordance with the optimal atlantoaxial fusion angle (25-30 degrees ) obtained from the literature, postoperative JOA scores were greater in the groups with angles of more than 30 degrees and less than 25 degrees , although the difference in ASD was not statistically significant. Postoperative JOA scores were not relevant to the postoperative C1-C2 angle; however, there was a positive correlation between JOA improvement rate and the change of the C1-C2 angle postoperatively. CONCLUSION: Atlantoaxial pedicle screw fixation can be used easily to reduce atlantoaxial dislocation in the pediatric population; however, outside the range of the optimal atlantoaxial fusion angle it can change the occipitoatlantal angle and subaxial alignment, which induces ASD and influences the clinical efficacy. It is necessary to achieve an optimal atlantoaxial angle when using atlantoaxial pedicle screw fixation. PMID- 29514168 TI - Place of Residence and Cognitive Function among the Adult Population in India. AB - BACKGROUND: The place of residence has been linked to cognitive function among adults in developed countries. This study examined how urban and rural residence was associated with cognitive function among adults in India. METHODS: The World Health Organization Study on Global AGEing and Adult Health data was used to examine cognition among 6,244 community-residing adults age 50+ in 6 states in India. Residential status was categorized as urban, rural, urban-to-urban, rural to-urban, rural-to-rural, and urban-to-rural. Cognition was assessed by immediate and delayed recall tests, digit span test, and verbal fluency test. Multilevel models were used to account for state-level differences and adjusted for individual-level sociodemographic, psychosocial, and health-related factors. RESULTS: Urban residents and urban-to-urban migrants had the highest levels of cognition, whereas rural residents and those who migrated to (or within) rural areas had the lowest cognition. The differences largely persisted after adjustment for multiple covariates; however, rural-to-urban migrants had no difference in cognition from urban residents once socioeconomic factors were taken into account. CONCLUSION: Cognition among adults in India differed significantly according to their current and past place of residence. Socioeconomic factors played an important role in the cognitive function of adults in urban areas. PMID- 29514169 TI - Acetazolamide Reduces Retinal Inner Nuclear Layer Thickness in Microcystic Macular Edema Secondary to Optic Neuropathy. AB - Optic neuropathy (ON) is commonly complicated by microcystic macular edema (MME), that is, small vertical cystoid spaces in the inner nuclear layer (INL) of the macula. We performed a retrospective consecutive case series of 14 eyes from 11 patients with ON and MME that were treated with oral acetazolamide, acting on cellular water transport. Contralateral eyes without MME were used as controls. Segmentation of images obtained with OCT was used to determine changes of individual retinal layer thickness during treatment. Retinal INL thickness consistently decreased in all eyes after 2-3 weeks of treatment. Recurrence of MME was observed after treatment cessation. No significant change of retinal thickness was found in contralateral unaffected eyes. Visual function did not change with treatment. Acetazolamide significantly improved the MME in eyes with ON. However, visual function did not. Acetazolamide is a treatment option for MME associated with ON but without an impact on the visual function. PMID- 29514170 TI - Association of Fatigue Intensification with Cognitive Impairment during Radiation Therapy for Prostate Cancer. AB - PURPOSE: Cancer-related fatigue is a common complaint during cancer treatment and is often associated with cognitive impairment. This study examined cognitive deficits that were associated with fatigue symptoms during external-beam radiation therapy (EBRT) in men with localized prostate cancer. METHODS: A total of 36 participants were enrolled and followed up at baseline, 24 h, 7 days, 14 days after EBRT initiation, at midpoint, and at completion of EBRT. Fatigue was measured by self-report using the Functional Assessment of Cancer Therapy - Fatigue (FACT-F), and cognitive impairment by the Computer Assessment of Mild Cognitive Impairment (CAMCI(r)). RESULTS: Subjects with increased fatigue during EBRT reported a significant decline in cognitive function and had difficulties with CAMCI(r)'s route finding and item recall tasks during EBRT. Increased fatigue during EBRT was associated with perceived cognitive difficulties in executive function and recognition memory, but not with attention or verbal memory. CONCLUSIONS: Our results suggest that there might be specific cognitive domains that are associated with increased fatigue during EBRT. These findings will provide important information for targeting specific cognitive domains using pharmacotherapy or behavioral interventions. CAMCI(r) is a valuable tool for psycho social providers to detect subtle cognitive impairment in fatigued cancer patients in a clinical setting. PMID- 29514171 TI - Optical coherence tomography-verified morphological correlates of high-intensity coronary plaques on non-contrast T1-weighted magnetic resonance imaging in patients with stable coronary artery disease. AB - Aims: Coronary high-intensity plaques (HIPs) with a high plaque-to-myocardial signal intensity ratio (PMR) on non-contrast T1-weighted imaging in patients with stable coronary artery disease (CAD) are associated with future coronary events. To characterize the morphological substrate of HIP, we performed a correlative optical coherence tomography (OCT) study. Methods and results: We examined 137 lesions in 105 patients with stable angina pectoris or silent myocardial ischaemia scheduled for percutaneous coronary intervention (PCI) using a 3 T magnetic resonance scanner. Pre-interventional OCT was performed for PCI target lesions. HIP was defined as PMR >= 1.4. Of the 137 lesions, 34% were HIP and 66% were non-HIP. The prevalence of lipid-rich plaque (96% vs. 70%, P < 0.001), macrophage accumulation (65% vs. 46%, P = 0.046), cholesterol crystals (46% vs. 22%, P = 0.006), and healed plaque rupture (multiple layers of different optical densities overlaying a large lipid accumulation, 72% vs. 18%, P < 0.001) was significantly higher in the HIP group than the non-HIP group; no significant differences were observed for the presence of thin cap fibroatheroma, intracoronary thrombus, and plaque rupture between the two groups. Multivariable stepwise logistic regression analysis showed that HIP was significantly associated with the presence of healed plaque rupture [odds ratio (OR) 9.32; 95% confidence interval (95% CI) 4.05-22.71; P < 0.001] and lipid-rich plaque (OR 4.38; 95% CI 1.08-29.77; P = 0.038). Conclusions: The significant association between HIP- and OCT-derived healed plaque rupture and large lipid core provides new insights into the characteristics of high-risk plaques, even in clinically stable CAD. PMID- 29514172 TI - Myeloid-derived suppressor cells suppress CD4+ T cell activity and prevent the development of type 2 diabetes. AB - CD4+ T cells play an important role in the progression of type 2 diabetes mellitus (T2DM). It is known that T cell responses can be suppressed by myeloid derived suppressor cells (MDSCs). In this study, we aimed to explore the potential role of MDSCs in the progression of T2DM, and to examine whether the underlying mechanism was associated with CD4+ T cells. Peripheral blood samples were obtained from T2DM patients and healthy controls, as well as C57BL6J db/db mice and control heterozygous (db/-) mice. The frequency of MDSCs and CD4+ T cells was analyzed using flow cytometry. Serum levels of the cytokines interleukin (IL)-4, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were quantified using ELISA kits. Cell proliferation was assessed using carboxyfluorescein succinimidyl ester (CFSE) labeling. In addition, the severity of insulitis was assessed using H&E staining of the pancreata. The data showed an increased frequency of CD11b+/CD33+ MDSCs and CD4+ T cells in the peripheral blood of T2DM patients. In addition, there were decreased IL-4 level and increased TNF-alpha and IFN-gamma levels in the serum from T2DM patients. In db/db mice, an increased frequency of CD11b+/Gr-1+ MDSCs and CD4+ T cells was found in splenocytes, as well as in the peripheral blood. MDSCs inhibited the proliferation and modulated the cytokine secretion of CD4+ T cells in vitro and delayed the development of diabetes in NOD/SCID mice. In conclusion, MDSCs suppress CD4+ T cell activity and prevent the development of T2DM. PMID- 29514173 TI - Curative therapy of a hepatitis C infection due to an infected heart donor: 5 year outcomes after heart transplantation. AB - Heart transplantation is the gold standard therapy for patients diagnosed with end-stage heart failure. Despite the shortage of appropriate donor organs, the transplantation of hepatitis C-infected hearts is disputed. Previous research has shown that long-term results are controversial, and the risk of severe clinical infection should not be underestimated. PMID- 29514174 TI - Mitral valve infective endocarditis: putting the puzzle pieces together. PMID- 29514176 TI - FasParser2: a graphical platform for batch manipulation of tremendous amount of sequence data. AB - Summary: FasParser is a graphical platform for manipulating sequences and alignments in a batch mode. It is particularly useful for biologists handling large datasets of sequences, even without an experience in programming. Here, I present an updated version 'FasParser2', featuring numerous improvements with sets of novel functions that can facilitate sequence manipulation. Its main additional features include (i) re-designed graphical interface which greatly improves its capability for batch processing, (ii) a trimming function to strip poorly-aligned regions in multiple sequence alignments, (iii) a series of functions that can identify as well as remove 'bad' sequence (either too short or too divergent sequences), (iv) an Editor tool for viewing and editing of biological sequences and (v) interfaces (with other programs) for detection of positive selection as well as primer design. Availability and implementation: The compiled Windows binary is freely available at https://github.com/Sun Yanbo/FasParser/releases. PMID- 29514175 TI - Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus Coinfected Patients With Low Isoniazid and Rifampicin Concentrations. AB - Background: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. Methods: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. Results: We enrolled 268 HIV infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37-.77; P = .001) or by the end of follow-up (0.61; .44-.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure. Conclusion: Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission. Clinical Trials Registration: NCT01782950. PMID- 29514178 TI - The Medical Council on Alcohol's 50th Anniversary Witness Seminar. PMID- 29514177 TI - Surgical treatment for intravenous-cardiac leiomyomatosis. AB - OBJECTIVES: There are few published studies on the rare disorder of intravenous cardiac leiomyomatosis (IVCL). This study aimed to propose an individualized strategy for surgical treatment of IVCL. METHODS: In this retrospective study, we reviewed 50 patients who had undergone IVCL removal from November 2002 to October 2017 in our hospital. IVCL was classified as Type A-E according to the extent and size, with Type E being the most severe. Clinical manifestations, surgical features and follow-up data were analysed. RESULTS: Of the 50 patients in this series, 8 had Type A IVCL, 8 Type B, 29 Type C, 2 Type D and 3 Type E IVCL. One stage removal of IVCL was performed via laparotomy without cardiopulmonary bypass (CPB) in the 8 patients with Type A, 1-stage tumour resection via sternolaparotomy under deep hypothermic arrest in 7 of the 8 patients with Type B and IVCL removal via sternolaparotomy under CPB, with 27 also under deep hypothermic arrest, in all 29 patients with Type C. Sixteen of the patients with Type C IVCL underwent staged procedures, 13 a 1-stage procedure and 21 required hepatic mobilization. All patients with Type C or E cases underwent 1-stage tumour removal via sternolaparotomy under deep hypothermic arrest. All 50 patients survived surgery. IVCL was confirmed postoperatively by histology. Ten patients had residual tumours; 9 of which did not progress. No deaths occurred during 47.8 +/- 38.4 (range 1-177) months of follow-up. CONCLUSIONS: The only known curative treatment for IVCL is surgery. Herein, we present an individualized strategy for selecting surgical treatment. PMID- 29514179 TI - AltHapAlignR: improved accuracy of RNA-seq analyses through the use of alternative haplotypes. AB - Motivation: Reliance on mapping to a single reference haplotype currently limits accurate estimation of allele or haplotype-specific expression using RNA sequencing, notably in highly polymorphic regions such as the major histocompatibility complex. Results: We present AltHapAlignR, a method incorporating alternate reference haplotypes to generate gene- and haplotype level estimates of transcript abundance for any genomic region where such information is available. We validate using simulated and experimental data to quantify input allelic ratios for major histocompatibility complex haplotypes, demonstrating significantly improved correlation with ground truth estimates of gene counts compared to standard single reference mapping. We apply AltHapAlignR to RNA-seq data from 462 individuals, showing how significant underestimation of expression of the majority of classical human leukocyte antigen genes using conventional mapping can be corrected using AltHapAlignR to allow more accurate quantification of gene expression for individual alleles and haplotypes. Availability and implementation: Source code freely available at https://github.com/jknightlab/AltHapAlignR. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29514180 TI - Individualizing Tuberculosis (TB) Treatment: Are TB Programs in High Burden Settings Ready for Prime Time Therapeutic Drug Monitoring? PMID- 29514181 TI - PWMScan: a fast tool for scanning entire genomes with a position-specific weight matrix. AB - Summary: Transcription factors regulate gene expression by binding to specific short DNA sequences of 5-20 bp to regulate the rate of transcription of genetic information from DNA to messenger RNA. We present PWMScan, a fast web-based tool to scan server-resident genomes for matches to a user-supplied PWM or transcription factor binding site model from a public database. Availability and implementation: The web server and source code are available at http://ccg.vital it.ch/pwmscan and https://sourceforge.net/projects/pwmscan, respectively. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29514182 TI - To be or not to be central-does this really matter? PMID- 29514184 TI - The quality of warfarin therapy and CHA2DS2-VASc score associate with the incidence of myocardial infarction and cardiovascular outcome in patients with atrial fibrillation: data from the nationwide FinWAF Registry. AB - Aims: The impact of the quality of warfarin therapy on cardiovascular outcomes excluding stroke is largely unknown. The aims of this study were to evaluate the association between the warfarin control and the incidence and outcome of myocardial infarction (MI) and to validate the predictive value of the CHA2DS2 VASc score for MI in atrial fibrillation (AF) patients taking warfarin. Methods and results: The nationwide FinWAF Registry consists of 54 568 AF patients (mean age 73.31 +/- 10.7 years, 52% men) taking warfarin. The quality of warfarin therapy was assessed continuously by calculating the time in therapeutic range within a 60-day window using the Rosendaal method (TTR60). Adjusted Cox proportional hazards models were prepared for the incidence of MI and cardiovascular mortality in six different TTR60 categories. During the 3.2 +/- 1.6 years of follow-up, the annual incidence of MI (95% confidence interval) was 3.3% (3.0-3.5%), 2.9% (2.6-3.3%), 2.4% (2.1-2.7%), 1.9% (1.7-2.2%), 1.7% (1.5 2.0%), and 1.2% (1.1-1.3%) among patients with TTR60 <40%, 40-50%, 50-60%, 60 70%, 70-80%, and >80%, respectively. Well-managed warfarin therapy (TTR60 > 80%) was associated also with a lower cardiovascular mortality, whereas a high CHA2DS2 VASc score correlated with poor outcome. Conclusion: Cardiovascular outcome was superior among AF patients with good warfarin control and in those with a low CHA2DS2-VASc score. The inverse association between the TTR60 and incidence of MI and cardiovascular mortality indicate that in AF patients the quality of warfarin therapy is critical not only for prevention of stroke but also with regard to cardiovascular outcome. PMID- 29514183 TI - An early European experience with transapical off-pump mitral valve repair with NeoChord implantation. AB - OBJECTIVES: Transapical off-pump NeoChord repair is a novel minimally invasive surgical procedure to treat degenerative mitral valve regurgitation. The aim was to evaluate 1-year clinical results of the NeoChord procedure in a consecutive cohort of patients. METHODS: Between February 2013 and July 2016, 213 patients were enrolled in the NeoChord Independent International Registry. All patients presented severe mitral regurgitation due to flail/prolapse of 1 or both leaflets, and they all completed postoperative echocardiographic assessment up to 1 year. We identified the primary end point as composed of procedural success, freedom from mortality, stroke, reintervention, recurrence of severe mitral regurgitation, rehospitalization and decrease of at least 1 New York Heart Association functional class at 1-year follow-up. We also compared outcomes according to the anatomical classification (Type A: isolated central posterior leaflet disease; Type B: posterior multisegment disease; Type C: anterior, bileaflet, paracommissural disease with/without leaflet/annular calcifications). RESULTS: The median age was 68 years (interquartile range 56-77), and the median EuroSCORE II was 1.05% (interquartile range 0.67-1.76). The number of Type A, B and C patients was 82 (38.5%), 98 (46%) and 33 (15.5%), respectively. Procedural success was achieved in 206 (96.7%) patients. At 1-year follow-up, overall survival was 98 +/- 1%. Composite end point was achieved in 84 +/- 2.5% for the overall population and 94 +/- 2.6%, 82.6 +/- 3.8% and 63.6 +/- 8.4% in Type A, Type B and Type C patients, respectively (P < 0.0001). CONCLUSIONS: These results demonstrate that the NeoChord procedure is safe, effective and reproducible. Clinical and echocardiographic efficacy is maintained up to 1 year with significant differences among the anatomical groups. Specific anatomical selection criteria are necessary to achieve stable results. PMID- 29514185 TI - Mid-term survival outcome of single-port video-assisted thoracoscopic anatomical lung resection: a two-centre experience. AB - OBJECTIVES: Single-port video-assisted thoracoscopic surgery (SPVATS) anatomical resection has been shown to be a feasible technique for lung cancer patients. Whether SPVATS has equivalent or better oncological outcomes for lung cancer patients remains controversial. The purpose of this study was to evaluate the perioperative and mid-term survival outcomes of SPVATS in 2 different medical centres. METHODS: We retrospectively reviewed patients who underwent SPVATS anatomical resections between January 2014 and February 2017 in Coruna University Hospital's Minimally Invasive Thoracic Surgery Unit (Spain) and Chang Gung Memorial Hospital (Taiwan). Survival outcomes were assessed by pathological stage according to the American Joint Committee on Cancer (AJCC) 7th and 8th classifications. RESULTS: In total, 307 patients were enrolled in this study. Mean drainage days and postoperative hospital stay were 3.90 +/- 2.98 and 5.03 +/ 3.34 days. The overall 30-day mortality, 90-day morbidity and mortality rate were 0.7%, 20.1% and 0.7%, respectively. The 2-year disease-free survival and 2 year overall survival of the cohort were 80.6% and 93.4% for 1A, 68.8% and 84.6% for 1B, 51.0% and 66.7% for 2A, 21.6% and 61.1% for 2B, 47.6% and 58.5% for 3A, respectively, following the AJCC 7th classification. By the AJCC 8th classification, these were 92.3% and 100% for 1A1, 73.7% and 91.4% for 1A2, 75.2% and 93.4% for 1A3, 62.1% and 85.9% for 1B, 55.6% and 72.7% for 2A, 47.1% and 64.2% for 2B and 42.1% and 60.3% for 3A. CONCLUSIONS: Our preliminary results revealed that SPVATS anatomical resection achieves acceptable 2-year survival outcomes for early-stage lung cancer and is consistent with AJCC 8th staging system 2-year survival data. For advanced stage non-small-cell lung cancer patients, further evaluation is warranted. PMID- 29514186 TI - CC-401 Promotes beta-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition. AB - Pharmacologic expansion of endogenous beta cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control beta-cell growth we screened ~2400 bioactive compounds for rat beta-cell replication modulating activity. Numerous hit compounds impaired or promoted rat beta-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) beta-cell replication via dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat beta cells, which were broadly growth responsive to compound treatment, human beta-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3beta (GSK-3beta) or activin A receptor type II-like kinase/transforming growth factor-beta (ALK5/TGF-beta) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human beta-cell-replication induction. However, inhibition of NFAT activity had limited effect on CC-401 induced beta-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A dependent phosphorylation/stabilization of the beta-cell-replication inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control beta-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control beta-cell growth. PMID- 29514187 TI - Development and Validation of the Nursing Home Minimum Data Set 3.0 Mortality Risk Score (MRS3). AB - Purpose: To develop a score to predict mortality using the Minimum Data Set 3.0 (MDS 3.0) that can be readily calculated from items collected during nursing home (NH) residents' admission assessments. Participants: We developed a training cohort of Medicare beneficiaries newly admitted to U.S. NHs during 2012 (N=1,426,815) and a testing cohort from 2013 (N=1,160,964). Methods: Data came from the MDS 3.0 assessments linked to the Medicare Beneficiary Summary File. Using the training dataset, we developed a composite MDS 3.0 Mortality Risk Score (MRS3) consisting of 17 clinical items and patients' age groups based on their relation to 30-day mortality. We assessed the calibration and discrimination of the MRS3 in predicting 30-day and 60-day mortality and compared its performance to the Charlson Comorbidity Index and the clinician's assessment of 6-month prognosis measured at admission. Results: The 30-day and 60-day mortality rate for the testing population was 2.8% and 5.6%, respectively. Results from logistic regression models suggest that the MRS3 performed well in predicting death within 30 and 60 days (C-Statistics of 0.744 (95%CL = 0.741, 0.747) and 0.709 (95%CL=0.706, 0.711), respectively). The MRS3 was a superior predictor of mortality compared to the Charlson Comorbidity Index (C-statistics of 0.611 (95%CL=0.607, 0.615) and 0.608 (95%CL=0.605, 0.610)) and the clinicians' assessments of patients' 6-month prognoses (C-statistics of 0.543 (95%CL=0.542, 0.545) and 0.528 (95%CL=0.527, 0.529). Conclusions: The MRS3 is a good predictor of mortality and can be useful in guiding decision-making, informing plans of care, and adjusting for patients' risk of mortality. PMID- 29514188 TI - Xanthomonas oryzae pv. oryzae type III effector PthXo3JXOV suppresses innate immunity, induces susceptibility and binds to multiple targets in rice. AB - Transcription activator-like (TAL) effectors encoded by tal genes were recognized as a key virulence strategy used by Xanthomonas oryzae pv. oryzae (Xoo) to cause bacterial leaf blight of rice. TAL effector PthXo3 is a major virulence factor identified in a Philippine Xoo strain PXO61, and it can induce the expression of susceptibility gene OsSWEET14 by binding to the effector-binding element (EBE) in the promoter region. In this study, pthXo3 homologous genes were also identified and isolated from Xoo Chinese strain OS198 and Japanese strain JXOV, which were named as pthXo3OS198 and pthXo3JXOV, respectively. When pthXo3JXOV was delivered into PXO99A, the resulting strain PXO99A/pthXo3JXOV significantly increased virulence in 18 out of 23 rice varieties tested, with the most prominent increase in lesion length and bacteria propagation in rice IRBB13. PthXo3JXOV suppresses the plant's innate immunity by inhibiting hypersensitive response (HR) and callose deposition. The Agrobacterium tumefaciens-mediated transient expression assays showed that, besides OsSWEET14, PthXo3JXOV also interacts with other targets by binding to the EBEs in their promoter regions. Our results suggest that PthXo3JXOV may interact with multiple targets to execute its virulence functions. PMID- 29514189 TI - Demography of Rusty Grain Beetle in Stored Bulk Wheat: Part I, Population Dynamics at Different Temperatures and Grain Bulk Sizes. AB - Population dynamics of rusty grain beetle, Cryptolestes ferrugineus (Stephens; Coleoptera: Cucujidae), was studied using different sizes of grain bulks (patches) at various temperatures. The temperatures were 21, 25, 30, 35 degrees C, T-decrease (30 degrees C in the first 4 wk and then decreased 1 degrees C /wk), and T-increase (21 degrees C in the first 2 wk and then increased 1 degrees C /wk). Number of adults and offspring and infested wheat kernels were counted every 4 wk up to 24 wk (31 wk for the T-decrease). The grain bulk patches used were: small (50 ml inner volume, 0.03 kg wheat), medium (2.6 liters inner volume, 2 kg wheat), and large (18 liters inner volume, 14 kg wheat). All of the correlation coefficients between the insect numbers and kernel infestation percentage were >=0.63. Two types of the population dynamic curves were observed: insect number or density continually increased with time during the entire experiment, or there was a rise then a fall in insect number or density over time, giving a peak number or density. The peak insect density was approximately 400 to 500 adults/kg of wheat for all patches at 30 degrees C or lower. At 35 degrees C, the peak densities of live adults were 3,956 +/- 630, 2,094 +/- 34, and 1,003 +/- 70 adults/kg of wheat in small, medium, and large patches, respectively. Patch size influenced insect population dynamics at 35 degrees C. Insect number inside large patch was more dependent on the previous insect number than that inside small patches. PMID- 29514190 TI - A socioecological measurement of homophobia for all countries and its public health impact. AB - Background: Measuring homophobia at country level is important to guide public health policy as reductions in stigma are associated with improved health outcomes among gay men and other men who have sex with men. Methods: We developed a Homophobic Climate Index incorporating institutional and social components of homophobia. Institutional homophobia was based on the level of enforcement of laws that criminalise, protect or recognise same-sex relations. Social homophobia was based on the level of acceptance and justifiability of homosexuality. We estimated the Index for 158 countries and assessed its robustness and validity. Results: Western Europe is the most inclusive region, followed by Latin America. Africa and the Middle East are home to the most homophobic countries with two exceptions: South Africa and Cabo Verde. We found that a 1% decrease in the level of homophobia is associated with a 10% increase in the gross domestic product per capita. Countries whose citizens face gender inequality, human rights abuses, low health expenditures and low life satisfaction are the ones with a higher homophobic climate. Moreover, a 10% increase in the level of homophobia at country level is associated with a 1.7-year loss in life expectancy for males. A higher level of homophobia is associated with increased AIDS-related death among HIV-positive men. Conclusion: The socioecological approach of this index demonstrates the negative social, economic and health consequences of homophobia in low- and middle-income countries. It provides sound evidence for public health policy in favour of the inclusion of sexual minorities. PMID- 29514191 TI - Reply: Towards personalized therapy for multiple sclerosis: limitations of observational data. PMID- 29514192 TI - Are we underestimating the value of minimally invasive extracorporeal circuits in blood conservation? PMID- 29514193 TI - Posterior papillary muscle rupture after transapical transcatheter aortic valve implantation. AB - Transapical transcatheter aortic valve implantation is a well-established alternative in patients at a high risk for conventional aortic valve replacement. We performed transapical transcatheter aortic valve implantation on an 83-year old woman with symptomatic severe aortic stenosis. Intraoperative transoesophageal echocardiography (TOE) after transcatheter aortic valve implantation showed mild mitral regurgitation without intracardiac structural injury. In the intensive care unit, the patient gradually had haemodynamic instability; TOE revealed severe mitral regurgitation with A2 and A3 prolapse due to rupture of the posterior papillary muscle. To repair the mitral regurgitation, mitral valve replacement was performed. Preoperative TOE revealed posterior displacement of the left ventricle due to right ventricular dilatation. Computed tomography showed the insertion angle of the guidewire from the left ventricular apex to the aortic valve as 95.6 degrees and a relatively sharp angle of guidewire through the aortic valve. In such a case, it is necessary to carefully perform the catheter procedures to prevent intracardiac structure injury; posterior papillary muscle is particularly crucial. PMID- 29514194 TI - Chromium resistance genetic element flanked by XerC/XerD recombination sites and its distribution in environmental and clinical Acinetobacter strains. AB - A novel mobile genetic element has been identified in small plasmids isolated from permafrost strains of Acinetobacter lwoffii. This element, designated the chrAB dif module, contains the chromium resistance genes chrA and chrB, functionally active both in the original host strains and after transfer into Acinetobacter baylyi. The 3011 bp chrAB dif module is flanked by XerC/XerD recombination sites highly homologous to those of the site-specific recombination system dif/Xer. Analysis of public databases revealed almost identical variants of the chrAB dif module in different plasmids in strains of various Acinetobacter species predominantly inhabiting the environment (A. lwoffii, Acinetobacter indicus, Acinetobacter idrijaensis, Acinetobacter shindleri and Acinetobacter nosocomialis). Together with previously described Acinetobacter antibiotic resistance elements, the chrAB dif module defines a new group of mobile elements that rely on the dif/Xer system for their mobility. Our observations suggest an ancient origin of the mobile elements flanked by dif sites and their participation in the mobilization of plasmid genes bearing adaptive functions. PMID- 29514195 TI - Early Sign Language Experience Goes Along with an Increased Cross-modal Gain for Affective Prosodic Recognition in Congenitally Deaf CI Users. AB - It is yet unclear whether congenitally deaf cochlear implant (CD CI) users' visual and multisensory emotion perception is influenced by their history in sign language acquisition. We hypothesized that early-signing CD CI users, relative to late-signing CD CI users and hearing, non-signing controls, show better facial expression recognition and rely more on the facial cues of audio-visual emotional stimuli. Two groups of young adult CD CI users-early signers (ES CI users; n = 11) and late signers (LS CI users; n = 10)-and a group of hearing, non-signing, age-matched controls (n = 12) performed an emotion recognition task with auditory, visual, and cross-modal emotionally congruent and incongruent speech stimuli. On different trials, participants categorized either the facial or the vocal expressions. The ES CI users more accurately recognized affective prosody than the LS CI users in the presence of congruent facial information. Furthermore, the ES CI users, but not the LS CI users, gained more than the controls from congruent visual stimuli when recognizing affective prosody. Both CI groups performed overall worse than the controls in recognizing affective prosody. These results suggest that early sign language experience affects multisensory emotion perception in CD CI users. PMID- 29514196 TI - Plant Cuttings: news in Botany. PMID- 29514197 TI - Variation in length of hospital stay after lung cancer surgery in the Netherlands. AB - OBJECTIVES: Length of stay (LOS) in the hospital after lung cancer surgery is influenced by patient characteristics, tumour characteristics, surgical technique and perioperative care. Our objective was to determine whether there were variation in LOS between hospitals that could not be accounted for by these known parameters. Residual variation in LOS would suggest important differences in perioperative care protocols and discharge criteria. METHODS: This study analysed data from the Netherlands National Cancer Registry (NNCR) on 10 195 anatomical lung resections for primary lung cancer from 2010 to 2015. Multivariable analysis was performed for multiple factors, using hierarchical linear regression analysis of the mean LOS. Information on comorbidity and socio-economic status was not available. Association between LOS and postoperative mortality was evaluated in multivariable logistic regression. RESULTS: The median LOS was 7 days (interquartile range 5-10 days), and the mean LOS was 8.3 days. LOS was negatively affected by larger resections, open surgery and advancing age. Histology and tumour stage had little influence. Overall, 30-day and 90-day mortality were 2.1% and 3.8%, respectively; 1.7% and 3.3% (not significant) in the group of hospitals with shorter LOS. After case-mix correction, residual between-hospital variation in the mean LOS was observed, ranging from 1.5 days shorter to almost 2.5 days longer. CONCLUSIONS: A clinically relevant between hospital variation in LOS after lung cancer surgery is observed in the Netherlands. Although residual confounding by comorbidity or socio-economic status cannot be excluded, this variation is deemed to be largely due to differences in perioperative care protocols. Evaluation of best practices can help to improve perioperative care for lung surgery patients and optimize LOS. PMID- 29514198 TI - The pipe model theory half a century on: a review. PMID- 29514199 TI - Exploring the Identities of Hearing Parents who Chose Cochlear Implantation for their Children with Hearing Loss. AB - We aimed to determine the types of identities hearing parents construct when telling online stories about their children with hearing loss (HL) who use cochlear implants (CIs). To do so, we employed a qualitative design and sampled 20 different blogs United States origins and written by parents of children who use CIs. We then used thematic narrative analysis (Braun & Clarke, 2006; Riessman, C. K. (2008). Narrative methods for the human sciences. Thousand Oaks, CA: Sage Publications.) to uncover recurring themes from these parents' blogs. The themes then allowed us to assign identities to the parents. Four identities emerged in the parents' stories: (1) advocates, (2) resilient parents, (3) obedient worriers, and (4) matter-of-fact narrators. Identifying and understanding these parent identities is a first step toward improving theoretical and clinical insights into parents' perspectives and experiences following their children's diagnosis of HL. Such insights could ultimately improve audiologists' abilities to help families seek out, implement, and follow through with family-centered hearing healthcare. PMID- 29514200 TI - Tastant-Evoked Arc Expression in the Nucleus of the Solitary Tract and Nodose/Petrosal Ganglion of the Mouse Is Specific for Bitter Compounds. AB - Despite long and intense research, some fundamental questions regarding representation of taste information in the brain still remain unanswered. This might in part be due to shortcomings of the established methods that limit the researcher either to thorough characterization of few elements or to analyze the response of the entirety of neurons to only one stimulus. To overcome these restrictions, we evaluate the use of the immediate early gene Arc as a neuronal activity marker in the early neural structures of the taste pathway, the nodose/petrosal ganglion (NPG) and the nucleus of the solitary tract (NTS). Responses of NPG and NTS neurons were limited to substances that taste bitter to humans and are avoided by mice. Arc-expressing cells were concentrated in the rostromedial part of the dorsal NTS suggesting a role in gustatory processing. The use of Arc as a neuronal activity marker has several advantages, primarily the possibility to analyze the response of large numbers of neurons while using more than one stimulus makes Arc an interesting new tool for research in the early stages of taste processing. PMID- 29514201 TI - Smooth muscle cell and arterial aging: basic and clinical aspects. AB - Arterial aging engages a plethora of key signalling pathways that act in concert to induce vascular smooth muscle cell (VSMC) phenotypic changes leading to vascular degeneration and extracellular matrix degradation responsible for alterations of the mechanical properties of the vascular wall. This review highlights proof-of-concept examples of components of the extracellular matrix, VSMC receptors which connect extracellular and intracellular structures, and signalling pathways regulating changes in mechanotransduction and vascular homeostasis in aging. Furthermore, it provides a new framework for understanding how VSMC stiffness and adhesion to extracellular matrix contribute to arterial stiffness and how interactions with endothelial cells, platelets, and immune cells can regulate vascular aging. The identification of the key players of VSMC changes operating in large and small-sized arteries in response to increased mechanical load may be useful to better elucidate the causes and consequences of vascular aging and associated progression of hypertension, arteriosclerosis, and atherosclerosis. PMID- 29514203 TI - Mothers of Deaf Children in the 21st Century. Dynamic Positioning Between the Medical and Cultural-Linguistic Discourses. PMID- 29514204 TI - Demography of Rusty Grain Beetle in Stored Bulk Wheat: Part II. Mathematical Modeling to Characterize and Predict Population Dynamics. AB - Data collected in Part I of this study were further analyzed by using mathematical modeling methods. Out of the nine unstructured population models tested, no model could fit the insect numbers under all of the tested conditions. This analysis showed that Cryptolestes ferrugineus (Stephens) (Coleoptera: Laemophloeidae) inside small patches (50 ml volume) had different characterization of population dynamics from that inside large patches (18 liter volume) and had different population demography when the insect number at the previous time was different. The key factor analysis showed that the first two main factors influencing the population dynamics were the temperature and the previous insect numbers. The total numbers of insects increased with the increase of sum of degree days. However, the degree day model developed based on the constant temperatures could not predict insect numbers under fluctuating temperatures. A newly developed model, which used the result of the unstructured population models, key factor analysis, and the degree day model, could explain about 66% of the insect numbers under fluctuating temperature conditions. PMID- 29514205 TI - Histopathological evaluation of aortic dissection: a comparison of congenital versus acquired aortic wall weakness. AB - OBJECTIVES: The aim of this study was to identify pathological changes of aortic dissection based on histopathological evaluation of aortic wall weakness by comparing patients with and without congenital abnormalities. METHODS: We reviewed records of patients who underwent repair for dissection-related aortic disease between 2008 and 2015. Fifty patients (20 men and 30 women; mean age 66.9 +/- 14.0 years) who underwent surgery with subsequent histopathological examination of the aortic wall were divided into 2 groups. Group 1 had congenital abnormalities, including Marfan syndrome and bicuspid aortic valve (n = 5), and Group 2 had no congenital abnormalities (n = 45). We compared the histopathological characteristics of the aortic wall in these patients. RESULTS: There were significant differences in age and body surface area between the 2 groups. Although 80% of Group 1 patients developed dissection at the middle of the media, all Group 2 patients developed dissection at the outer one-third of the media, which is along the pathway of the vasa vasorum of the aortic wall. Both groups showed the same extent of degeneration of the vasa vasorum. Group 1 showed a severe score of mucoid extracellular matrix accumulation in the aortic media. CONCLUSIONS: Although it may be multifactorial, congenital maldevelopment of the media tends to result in dissection of the centre of the media, and acquired aortic wall weakness is concentrated in the outer third of the media. Degeneration of the vasa vasorum may be an important emerging substrate for developing aortic dissection. PMID- 29514202 TI - Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. AB - Vascular calcification is associated with a significant increase in all-cause mortality and atherosclerotic plaque rupture. Calcification has been determined to be an active process driven in part by vascular smooth muscle cell (VSMC) transdifferentiation within the vascular wall. Historically, VSMC phenotype switching has been viewed as binary, with the cells able to adopt a physiological contractile phenotype or an alternate 'synthetic' phenotype in response to injury. More recent work, including lineage tracing has however revealed that VSMCs are able to adopt a number of phenotypes, including calcific (osteogenic, chondrocytic, and osteoclastic), adipogenic, and macrophagic phenotypes. Whilst the mechanisms that drive VSMC differentiation are still being elucidated it is becoming clear that medial calcification may differ in several ways from the intimal calcification seen in atherosclerotic lesions, including risk factors and specific drivers for VSMC phenotype changes and calcification. This article aims to compare and contrast the role of VSMCs in driving calcification in both atherosclerosis and in the vessel media focusing on the major drivers of calcification, including aging, uraemia, mechanical stress, oxidative stress, and inflammation. The review also discusses novel findings that have also brought attention to specific pro- and anti-calcifying proteins, extracellular vesicles, mitochondrial dysfunction, and a uraemic milieu as major determinants of vascular calcification. PMID- 29514206 TI - Corrigendum to: Cardiac screening in Nepal. PMID- 29514208 TI - Fitness cost of mcr-1-mediated polymyxin resistance in Klebsiella pneumoniae. AB - Objectives: The discovery of mobile colistin resistance mcr-1, a plasmid-borne polymyxin resistance gene, highlights the potential for widespread resistance to the last-line polymyxins. In the present study, we investigated the impact of mcr 1 acquisition on polymyxin resistance and biological fitness in Klebsiella pneumoniae. Methods: K. pneumoniae B5055 was used as the parental strain for the construction of strains carrying vector only (pBBR1MCS-5) and mcr-1 recombinant plasmids (pmcr-1). Plasmid stability was determined by serial passaging for 10 consecutive days in antibiotic-free LB broth, followed by patching on gentamicin containing and antibiotic-free LB agar plates. Lipid A was analysed using LC-MS. The biological fitness was examined using an in vitro competition assay analysed with flow cytometry. The in vivo fitness cost of mcr-1 was evaluated in a neutropenic mouse thigh infection model. Results: Increased polymyxin resistance was observed following acquisition of mcr-1 in K. pneumoniae B5055. The modification of lipid A with phosphoethanolamine following mcr-1 addition was demonstrated by lipid A profiling. The plasmid stability assay revealed the instability of the plasmid after acquiring mcr-1. Reduced in vitro biological fitness and in vivo growth were observed with the mcr-1-carrying K. pneumoniae strain. Conclusions: Although mcr-1 confers a moderate level of polymyxin resistance, it is associated with a significant biological fitness cost in K. pneumoniae. This indicates that mcr-1-mediated resistance in K. pneumoniae could be attenuated by limiting the usage of polymyxins. PMID- 29514207 TI - Pneumocystis Cytochrome b Mutants Associated With Atovaquone Prophylaxis Failure as the Cause of Pneumocystis Infection Outbreak Among Heart Transplant Recipients. AB - Background: Although trimethoprim-sulfamethoxazole is the more efficient drug for prophylactic and curative treatment of pneumocystosis, atovaquone is considered a second-line prophylactic treatment in immunocompromised patients. Variations in atovaquone absorption and mutant fungi selection after atovaquone exposure have been associated with atovaquone prophylactic failure. We report here a Pneumocystis jirovecii cytochrome b (cyt b) mutation (A144V) associated with such prophylactic failure during a pneumocystosis outbreak among heart transplant recipients. Methods: Analyses of clinical data, serum drug dosage, and molecular modeling of the P. jirovecii Rieske-cyt b complex were performed to investigate these prophylactic failures. Results: The cyt b A144V mutation was detected in all infected, heart transplant recipient patients exposed to atovaquone prophylaxis but in none of 11 other immunocompromised, infected control patients not treated with atovaquone. Serum atovaquone concentrations associated with these prophylactic failures were similar than those found in noninfected exposed control patients under a similar prophylactic regimen. Computational modeling of the P. jirovecii Rieske-cyt b complex and in silico mutagenesis indicated that the cyt b A144V mutation might alter the volume of the atovaquone-binding pocket, which could decrease atovaquone binding. Conclusions: These data suggest that the cyt b A144V mutation confers diminished sensitivity to atovaquone, resulting in spread of Pneumocystis pneumonia among heart transplant recipients submitted to atovaquone prophylaxis. Potential selection and interhuman transmission of resistant P. jirovecii strain during atovaquone prophylactic treatment has to be considered and could limit its extended large-scale use in immucompromised patients. PMID- 29514209 TI - Gene of the transcriptional activator MET4 is involved in regulation of glutathione biosynthesis in the methylotrophic yeast Ogataea (Hansenula) polymorpha. AB - Glutathione is the most abundant cellular thiol and the low molecular weight peptide present in cells. The methylotrophic yeast Ogataea (Hansenula) polymorpha is considered as a promising cell factory for the synthesis of glutathione. In this study, a competitive O. polymorpha glutathione producer was constructed by overexpression of the GSH2 gene, encoding gamma-glutamylcysteine synthetase, the first enzyme involved in glutathione biosynthesis, and the MET4 gene coding for central regulator of sulfur metabolism. Overexpression of MET4 gene in the background of overexpressed GSH2 gene resulted in 5-fold increased glutathione production during shake flask cultivation as compared to the wild-type strain, reaching 2167 mg L-1. During bioreactor cultivation, glutathione accumulation by obtained recombinant strain was 5-fold increased relative to that by the parental strain with overexpressed only GSH2 gene, on the first 25 h of batch cultivation in mineral medium. Obtained results suggest involvement of Met4 transcriptional activator in regulation of GSH synthesis in the methylotrophic yeast O. polymorpha. PMID- 29514210 TI - New Insights into the Methylation Status of Virulent Diuraphis noxia (Hemiptera: Aphididae) Biotypes. AB - Epigenetic modifications provide a means for aphid biotype development that a lack of genetic variation, owing to an anholocyclic reproduction lifecycle, fails to do. Here we present data on the DNA methylation status in four South African Russian wheat aphids (RWA), Diuraphis noxia (Kurdjomov) (Hemiptera: Aphididae) biotypes expressing different levels of virulence against its host, Triticum aestivum L. (Poales: Poaceae, Triticeae). The DNA methylation status of these biotypes was determined through the use of methylation-sensitive amplification polymorphism analysis, restriction site-specific fluorescence labeling-a novel technique, and measuring relative global DNA methylation and hydroxymethylation. The least virulent RWA biotype, SA1, was methylated, while biotypes displaying intermediate virulence, SA2 and SA3, exhibited intermediate levels of hemimethylation. The genome of the most virulent RWA biotype, SAM, seems to be hypomethylated, which is likely attained through the process of demethylation. PMID- 29514212 TI - A history of why fathers' RNA matters. AB - Having been debated for many years, the presence and role of spermatozoal RNAs is resolving, and their contribution to development is now appreciated. Data from different species continue show that sperm contain a complex suite of coding and noncoding RNAs that play a role in an individual's life course. Mature sperm RNAs provide a retrospective of spermatogenesis, with their presence and abundance reflecting sperm maturation, fertility potential, and the paternal contribution to the developmental path the offspring may follow.Sperm RNAs delivered upon fertilization provide some of the initial contacts with the oocyte, directly confront the maternal with the paternal contribution as a prelude to genome consolidation. Following syngamy, early embryo development may in part be modulated by paternal RNAs that can include epidydimal passengers. This provides a direct path to relay an experience and then initiate a paternal response to the environment to the oocyte and beyond. Their epigenetic impact is likely felt prior to embryonic genome activation when the population of sperm delivered transcripts markedly changes. Here, we review the insights gained from sperm RNAs over the years, the subtypes, and the caveats of the RNAs described. We discuss the role of sperm RNAs in fertilization and embryo development, and their possible mechanism(s) influencing offspring phenotype. Approaches to meet the future challenges as the study of sperm RNAs continues, include, elucidating the potential mechanisms underlying how paternal allostatic load, the constant adaptation of health to external conditions, may be relayed by sperm RNAs to affect future generations. PMID- 29514211 TI - CTX-M ESBL-producing Enterobacteriaceae: estimated prevalence in adults in England in 2014. AB - Background: ESBL-producing Enterobacteriaceae (ESBLPE) are increasing in prevalence worldwide and are more difficult to treat than non-ESBLPE. Their prevalence in the UK general population is unknown, as the only previous UK ESBLPE faecal colonization study involved patients with diarrhoea. Objectives: To estimate the prevalence of CTX-M ESBLPE faecal colonization in the general adult population of England in 2014, and investigate risk factors. Methods: A stratified random sample of 58 337 registered patients from 16 general practices within four areas of England were invited to participate by returning faeces specimens and self-completed questionnaires. Specimens were tested for ESBLPE and carbapenemase-producing Enterobacteriaceae (CPE). Results: 2430 individuals participated (4% of those invited). The estimated prevalence of colonization with CTX-M ESBLPE in England was 7.3% (95% CI 5.6%-9.4%) (Shropshire 774 participants, 4.9% colonization; Southampton City 740 participants, 9.2%; Newham 612 participants, 12.7%; Heart of Birmingham 234 individuals, 16.0%) and was particularly high in: those born in Afghanistan (10 participants, 60.0% colonization, 95% CI 29.7%-84.2%); those born on the Indian subcontinent (India, Pakistan, Bangladesh or Sri Lanka) (259 participants, 25.0% colonization, 95% CI 18.5%-32.9%); travellers to South Asia (India, Pakistan, Bangladesh, Sri Lanka or Nepal) in the last year (140 participants, 38.5% colonization, 95% CI 27.8% 50.5%); and healthcare domestics (8 participants, unweighted 37.5% colonization, 95% CI 8.5%-75.5%). Risk factors identified included: being born in the Indian subcontinent (aOR 5.4, 95% CI 3.0-9.7); travel to South Asia (aOR 2.9, 95% CI 1.8 4.8) or to Africa, China, South or Central America, South East or Pacific Asia or Afghanistan (aOR 2.6, 95% CI 1.7-4.1) in the last year; and working as a healthcare domestic (aOR 6.2, 95% CI 1.3-31). None of the 48 participants who took co-amoxiclav in the last year was colonized with CTX-M ESBLPE. blaCTX-M-15 accounted for 66% of CTX-M ESBLPE positives. 0.1% (two participants) were colonized with CPE. Conclusions: CTX-M ESBLPE are established in the general population in England and prevalence is particularly high in people from certain countries of birth or with recent travel. We recommend that these findings be taken into account in guidance on the empirical management of patients presenting with a likely Enterobacteriaceae infection. PMID- 29514213 TI - The Chemical Sensitivity and Electrical Activity of Individual Olfactory Sensory Neurons to a Range of Sex Pheromones and Food Odors in the Goldfish. AB - Although it is well established that the olfactory epithelium of teleost fish detects at least 6 classes of biologically relevant odorants using 5 types of olfactory sensory neurons (OSNs), little is understood about the specificity of individual OSNs and thus how they encode identity of natural odors. In this study, we used in vivo extracellular single-unit recording to examine the odor responsiveness and physiological characteristics of 109 individual OSNs in mature male goldfish to a broad range of biological odorants including feeding stimuli (amino acids, polyamines, nucleotides), sex pheromones (sex steroids, prostaglandins [PGs]), and a putative social cue (bile acids). Sixty-one OSNs were chemosensitive, with over half of these (36) responding to amino acids, 7 to polyamines, 7 to nucleotides, 5 to bile acids, 9 to PGs, and 7 to sex steroids. Approximately a quarter of the amino acid-sensitive units also responded to polyamines or nucleotides. Three of 6 amino acid-sensitive units responded to more than 1 amino acid compound, and 5 sex pheromone-sensitive units detected just 1 sex pheromone. While pheromone-sensitive OSNs also responded to the adenylyl cyclase activator, forskolin, amino acid-sensitive OSNs responded to either forskolin or a phospholipase C activator, imipramine. Most OSNs responded to odorants and activators with excitation. Our results suggest that pheromone information is encoded by OSNs specifically tuned to single sex pheromones and employ adenylyl cyclase, suggestive of a labeled-line organization, while food information is encoded by a combination of OSNs that use both adenylyl cyclase and phospholipase C and are often less specifically tuned. PMID- 29514214 TI - Assessing the degree of residual confounding: a cohort study on the association between disability pension and mortality. AB - Background: Previous studies showed that disability pensioners have a higher risk of premature death than others, but residual confounding has been suggested. The aim was to assess the degree of residual confounding of the association between disability pension (DP) and risk of premature death. Methods: Prospective cohort study of everyone aged 19-64 years, living in Sweden 31 December 2004 (n = 5 406 469), followed up through 2010. Mortality hazard rates over time were estimated for three groups; incident disability pensioners during 2005 from start of DP (February-December 2005), prevalent disability pensioners (January 2005 or since before), and individuals not on DP in January 2005, after standardizing populations to characteristics of the incident disability pensioners, stratified by previous hospitalization or not. If DP has no immediate effect on mortality, incident disability pensioners and those not on DP should initially have similar hazard rates, thereby, allowing assessment of the degree of residual confounding. Results: For those not previously hospitalized, the mortality hazard rate on the first DP day was: 3.07 (95% CI 2.21, 4.36), 2.09 (1.78, 2.48) and 0.78 (0.73, 0.84) per thousand person-years for incident, prevalent, and non DP, respectively. Among previously hospitalized these figures were: 21.67 (17.73, 26.24), 17.00 (15.76, 18.51) and 18.88 (18.14, 19.64) respectively. Hazard ratios were 1.15 (0.94, 1.40) in the strata with and 3.94 (2.78, 5.57) in the strata without, previous hospitalization comparing incident DP with non-DP. Conclusions: Substantial residual confounding was found in the association between DP and premature death among those not previously hospitalized. PMID- 29514215 TI - Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation. AB - Defects in the MFSD8 gene encoding the lysosomal membrane protein CLN7 lead to CLN7 disease, a neurodegenerative lysosomal storage disorder belonging to the group of neuronal ceroid lipofuscinoses. Here, we have performed a SILAC-based quantitative analysis of the lysosomal proteome using Cln7-deficient mouse embryonic fibroblasts (MEFs) from a Cln7 knockout (ko) mouse model. From 3335 different proteins identified, we detected 56 soluble lysosomal proteins and 29 highly abundant lysosomal membrane proteins. Quantification revealed that the amounts of 12 different soluble lysosomal proteins were significantly reduced in Cln7 ko MEFs compared with wild-type controls. One of the most significantly depleted lysosomal proteins was Cln5 protein that underlies another distinct neuronal ceroid lipofuscinosis disorder. Expression analyses showed that the mRNA expression, biosynthesis, intracellular sorting and proteolytic processing of Cln5 were not affected, whereas the depletion of mature Cln5 protein was due to increased proteolytic degradation by cysteine proteases in Cln7 ko lysosomes. Considering the similar phenotypes of CLN5 and CLN7 patients, our data suggest that depletion of CLN5 may play an important part in the pathogenesis of CLN7 disease. In addition, we found a defect in the ability of Cln7 ko MEFs to adapt to starvation conditions as shown by impaired mammalian target of rapamycin complex 1 reactivation, reduced autolysosome tubulation and increased perinuclear accumulation of autolysosomes compared with controls. In summary, depletion of multiple soluble lysosomal proteins suggest a critical role of CLN7 for lysosomal function, which may contribute to the pathogenesis and progression of CLN7 disease. PMID- 29514216 TI - Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time. AB - Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naive MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set. PMID- 29514218 TI - Towards personalized therapy for multiple sclerosis: limitations of observational data. PMID- 29514217 TI - Downsized cryopreserved and standard-sized allografts for right ventricular outflow tract reconstruction in children: long-term single-institutional experience. AB - OBJECTIVES: The objective of this study was to determine long-term results with bicuspidalized allografts compared to non-bicuspidalized allografts in children under 2 years undergoing primary correction of the right ventricular outflow tract. METHODS: Thirty-five consecutive bicuspidalized allografts were compared to 45 consecutive non-bicuspidalized allografts implanted during the same period. Valve-related events were analysed with Kaplan-Meier and Cox-regression techniques. Mixed-effects modelling was used to analyse serial echocardiographic measurements of pulmonary gradient. In addition, a systematic review with meta analysis of the published literature concerning implantation of bicuspidalized allografts was performed. RESULTS: Perioperative characteristics and in-hospital mortality [bicuspidalized 5 (14.3%), non-bicuspidalized 6 (13.3%)] were comparable (P = 0.902). Bicuspidalized allografts were smaller (14.7 vs 16.5 mm, P = 0.023) and always (100%) of pulmonary origin compared to 26 (57.8%) of the standard-sized allografts. There were no differences in late mortality between the bicuspidalized and non-bicuspidalized group (6.7% vs 7.7%, P = 0.798) or freedom from allograft replacement at 10 years (82 +/- 10% and 71 +/- 8%, for bicuspidalized and non-bicuspidalized allografts, respectively). Evolution of peak pulmonary gradient (P = 0.273) was comparable between bicuspidalized and non bicuspidalized allografts. Meta-analysis showed a pooled early and late mortality for bicuspidalized allograft patients of 10.72% [95% confidence interval (CI) 6.13-18.75] and 1.6% per year (95% CI 0.99-2.79), respectively. Pooled estimated late reintervention and replacement rates were 5.94% per year (95% CI 3.42-10.30) and 3.78% per year (95% CI 2.69-5.32), respectively. CONCLUSIONS: Bicuspidalization seems to be a viable alternative to combat limited supply of small-sized allografts with acceptable survival and reintervention rates comparable to non-bicuspidalized allografts. PMID- 29514219 TI - Language and Psychosocial Functioning among Deaf Learners with and without Cochlear Implants. PMID- 29514220 TI - Long non-coding RNA CASC2 inhibits tumorigenesis via the miR-181a/PLXNC1 axis in melanoma. AB - Melanoma is the most malignant and aggressive form of skin carcinoma originating in the pigment-producing melanocytes. In this study, to further investigate the molecular mechanisms of the development and progression of melanoma, we explored the impacts of long non-coding RNA (lncRNA) CASC2 on melanoma cell functions. Microarray analysis was carried out to identify the expression of lncRNA CASC2 in melanoma cells. MiR-181a was predicted as a sponging target of CASC2 by miRcode, while the 3'-UTR of Plexin C1 (PLXNC1) was a potential target of miR-181a according to the TargetScan database. The correlation among CASC2, miR-181a, and PLXNC1 was verified by dual luciferase reporter assay and qRT-PCR. After manipulation of CASC2, miR-181a and PLXNC1 expression with transfection in A375 and M14 cells, cell viability, apoptosis, and invasive ability were evaluated using CCK-8, flow cytometry and Transwell assays, respectively. A low expression of CASC2 was detected in melanoma tissues and cells. Dual luciferase reporting assay confirmed that miR-181a targeted the 3'-UTR of PLXNC1. Furthermore, CASC2 could efficiently sponge miR-181a, thereby facilitating the expression of PLXNC1. Up-regulation of CASC2 suppressed the cell proliferation and invasion, but induced the apoptosis of melanoma cells. Our results demonstrated that lncRNA CASC2 can promote PLXNC1 expression by sponging miR-181a, thereby inhibiting the proliferation and invasion of melanoma cells, indicating that lncRNA CASC2 functions via the miR-181a/PLXNC1 axis in melanoma. PMID- 29514221 TI - The 'morning dip' in antimicrobial appropriateness: circumstances determining appropriateness of antimicrobial prescribing. AB - Objectives: Quality of care has been shown to vary depending on the time of day or day of the week and depending on caregivers' gender and experience. We aimed to study how these factors influence quality of antimicrobial prescribing. Methods: Prospective point-prevalence surveys were performed to determine the association between the above-mentioned prescription factors and antimicrobial appropriateness. Surveys included cases of patients admitted to a tertiary care hospital with a prescribed systemic antimicrobial drug and its prescribers. The main outcome was appropriateness of antimicrobial prescriptions. A post hoc qualitative survey among hospital physicians asked physicians to reflect on the results. Results: The study included 351 antimicrobial prescriptions by 150 physicians prescribed for 276 patients. Appropriateness of antimicrobial prescribing in the morning was significantly lower compared with the afternoon and evening/night [43% versus 68% versus 70%, crude OR afternoon versus morning = 3.00 (95% CI = 1.60-5.48), crude OR evening/night versus morning = 3.40 (95% CI = 1.64-6.69)]. First-year residents performed significantly worse than their more experienced colleagues [51% versus 69%, crude OR = 2.09 (95% CI = 1.26-3.38)]. Infectious disease expert consultation improved appropriateness [54% versus 81%, crude OR = 3.71 (95% CI = 2.05-6.23)]. No significant effects for gender or office hours versus non-office hours were found. Post hoc survey results suggest creating room to improve prescribing circumstances during mornings and for inexperienced physicians. Conclusions: Antimicrobial prescribing was less appropriate in the mornings and when prescribed by inexperienced physicians. Appropriateness may be increased by improving prescribing circumstances. PMID- 29514222 TI - Short-term mechanical circulatory support for severe primary graft dysfunction following orthotopic heart transplant. AB - OBJECTIVES: Primary graft dysfunction (PGD) is a devastating complication and the most common cause of early death following a heart transplant. The goal of this study was to report our experience of using mechanical circulatory support to manage severe PGD. METHODS: Following 208 heart transplants performed between January 2007 and May 2017, 14 (6.7%) patients presented with severe PGD. We provided haemodynamic support using the following approaches: a venoarterial extracorporeal membrane oxygenation device, left ventricular assist device, right ventricular assist device and biventricular assist device. Primary complications included severe PGD, which resulted in hospital deaths and late survival. The mean follow-up was 3.7 +/- 2.7 years. RESULTS: Fourteen (6.7%) heart transplant recipients presented with severe PGD. Seven patients received a venoarterial extracorporeal membrane oxygenation device; 1 patient received a left ventricular assist device; 4 patients received a right ventricular assist device; and 2 patients received a biventricular assist device. Mean device support and explantation times were 4.7 +/- 2 and 6.3 +/- 2 days, respectively. Weaning with cardiac recovery was successful in 57.1% of the patients. The hospital mortality rate was 50%. Postoperative causes of morbidity included renal failure that necessitated dialysis in 28.5%, surgical re-exploration due to postoperative bleeding in 57.1%, pneumonia in 28.5%, sepsis in 14.2%, sternal wound infection in 14.2% and mediastinitis in 7.1% of the patients, respectively. There were no deaths following hospital discharge or later follow-up appointments. CONCLUSIONS: Mechanical support devices such as venoarterial extracorporeal membrane oxygenation specifically offer a reliable therapeutic approach. Recognizing the relatively high number of deaths in-hospital, patients who have cardiac recovery and a successful hospital discharge can expect a favourable late outcome. PMID- 29514223 TI - Improving the value of public RNA-seq expression data by phenotype prediction. AB - Publicly available genomic data are a valuable resource for studying normal human variation and disease, but these data are often not well labeled or annotated. The lack of phenotype information for public genomic data severely limits their utility for addressing targeted biological questions. We develop an in silico phenotyping approach for predicting critical missing annotation directly from genomic measurements using well-annotated genomic and phenotypic data produced by consortia like TCGA and GTEx as training data. We apply in silico phenotyping to a set of 70 000 RNA-seq samples we recently processed on a common pipeline as part of the recount2 project. We use gene expression data to build and evaluate predictors for both biological phenotypes (sex, tissue, sample source) and experimental conditions (sequencing strategy). We demonstrate how these predictions can be used to study cross-sample properties of public genomic data, select genomic projects with specific characteristics, and perform downstream analyses using predicted phenotypes. The methods to perform phenotype prediction are available in the phenopredict R package and the predictions for recount2 are available from the recount R package. With data and phenotype information available for 70,000 human samples, expression data is available for use on a scale that was not previously feasible. PMID- 29514224 TI - Enhanced recovery after surgery pathway for patients undergoing cardiac surgery: a randomized clinical trial. AB - OBJECTIVES: Enhanced recovery after surgery (ERAS) pathways have not been reported in cardiac surgery. The aim of this study was to evaluate the clinical effectiveness and safety profile of ERAS pathways compared with routine care for patients undergoing cardiac valvular surgery. METHODS: A randomized clinical trial was conducted between July 2015 and November 2016. A total of 226 patients who underwent elective valvular surgery were randomly assigned to the ERAS pathway or routine care (control) group. The ERAS protocol consisted of an evidence-based systematic optimization approach for managing perioperative patients. The control group received routine care. The primary end-point was readiness for hospital discharge. The secondary outcomes were duration of intensive care unit (ICU) stay, length of postoperative vasoactive drug support, duration of mechanical ventilation, time to first bowel movement, removal of surgical drain, overall medical costs and complication rate. RESULTS: Postoperative time to readiness for discharge was significantly shorter in the ERAS group (6.0 (2.0~14.0) days) than the control group (7.0 (4.0~16.0) days, P = 0.01), and the duration of ICU stay and duration of mechanical ventilation were significantly shorter in the ERAS group (20.9 (13.5~69.3) h, 7.2 (0.0~22.3) h, respectively) than the control group (22.0 (13.4~212.3) h, P = 0.001; 8.8 (3.7~44.9) h, respectively; P < 0.0001). The overall treatment cost of the ERAS group (69202 (52089~123823) CNY) was significantly lower than that of the control group (77058 (51390~144290) CNY, P = 0.002). CONCLUSIONS: ERAS pathways reduce the length of ICU and hospital stay, postoperative complications and cost for patients undergoing cardiac surgery. Clinical trial registration: ClinicalTrials.gov: NCT02479581. PMID- 29514225 TI - Consumer perceptions of specific design characteristics for front-of-package nutrition labels. AB - An increasing number of countries are developing front-of-package (FOP) labels; however, there is limited evidence examining the impact of specific design characteristics for these labels. The current study investigated consumer perceptions of several FOP label design characteristics, including potential differences among sociodemographic sub-groups. Two hundred and thirty-four participants aged 16 years or older completed nine label rating tasks on a laptop at a local shopping mall in Canada. The rating tasks asked participants to rate five primary design characteristics (border, background presence, background colour, 'caution' symbol and government attribution) on their noticeability, readability, believability and likelihood of changing their beverage choice. FOP labels with a border, solid background and contrasting colours increased noticeability. A solid background increased readability, while a contrasting background colour reduced it. Both a 'caution' symbol and a government attribution increased the believability of the labels and the perceived likelihood of influencing beverage choice. The effect of the design characteristics was generally similar across sociodemographic groups, with modest differences in five of the nine outcomes. Label design characteristics, such as the use of a border, colour and symbols can enhance the salience of FOP nutrition labels and may increase the likelihood that FOP labels are used by consumers. PMID- 29514226 TI - Geometric changes in the aortic valve annulus during the cardiac cycle: impact on aortic valve repair. AB - OBJECTIVES: The growing experience in aortic valve (AV) repair showed that annular stabilization is a crucial component to achieve stable long-term results after AV repair. Dynamic changes in the AV annulus during the cardiac cycle may have an impact on annuloplasty design. METHODS: We retrospectively analysed full cardiac cycle multislice computed tomography data from 58 consecutive patients (mean age 75.9 +/- 6.5 years, 36% men) with normally functioning tricuspid AVs (normal AV subgroup). The following computed tomography parameters were measured during systole and diastole: maximum, minimum and mean AV annulus diameter, AV annular area and AV annular perimeter. The AV annular eccentricity index was calculated (%) [(max AV annulus * 100/min AV annulus) - 100] in systole and diastole. Subsequently, multislice computed tomography data from 20 patients with severe aortic regurgitation were analysed [aortic valve regurgitation (AR) subgroup]. RESULTS: In the normal AV subgroup, there was a significant decrease in the mean AV annulus diameter from systole to diastole (i.e. 24.6 +/- 2.5 mm vs 23.9 +/- 2.4 mm, respectively; P < 0.001), which occurred predominantly in the short annular axis (i.e. 21.2 +/- 2.4 mm in systole vs 19.9 +/- 2.3 mm in diastole; P < 0.001). The mean AV annular area decreased significantly in diastole (i.e. 467.5 +/- 94.5 mm2 in systole vs 444.8 +/- 86.1 mm2 in diastole; P = 0.012). The annular eccentricity index increased significantly in diastole (33.0 +/- 12.2% in systole vs 41.4 +/- 13.5% in diastole; P < 0.001). Furthermore, we found an inverse linear correlation between the mean AV annulus diameter and the annular eccentricity index (r = -0.40, P = 0.034). The diastolic annular eccentricity index was significantly reduced in the AR subgroup (i.e. 41.4 +/- 13.5% in the normal AV subgroup vs 33.7 +/- 14.8% in the AR cohort; P = 0.035). CONCLUSIONS: The normal AV annulus undergoes important geometric deformation during the cardiac cycle that is significantly reduced in diastole in the AR scenario. A novel AV annuloplasty system should ideally adapt for this marked diastolic annular eccentricity and thereby allow for dynamic aortic root changes during the cardiac cycle. PMID- 29514227 TI - Enzymatic synthesis of cyclic dinucleotide analogs by a promiscuous cyclic-AMP GMP synthetase and analysis of cyclic dinucleotide responsive riboswitches. AB - Cyclic dinucleotides are second messenger molecules produced by both prokaryotes and eukaryotes in response to external stimuli. In bacteria, these molecules bind to RNA riboswitches and several protein receptors ultimately leading to phenotypic changes such as biofilm formation, ion transport and secretion of virulence factors. Some cyclic dinucleotide analogs bind differentially to biological receptors and can therefore be used to better understand cyclic dinucleotide mechanisms in vitro and in vivo. However, production of some of these analogs involves lengthy, multistep syntheses. Here, we describe a new, simple method for enzymatic synthesis of several 3', 5' linked cyclic dinucleotide analogs of c-di-GMP, c-di-AMP and c-AMP-GMP using the cyclic-AMP-GMP synthetase, DncV. The enzymatic reaction efficiently produced most cyclic dinucleotide analogs, such as 2'-amino sugar substitutions and phosphorothioate backbone modifications, for all three types of cyclic dinucleotides without the use of protecting groups or organic solvents. We used these novel analogs to explore differences in phosphate backbone and 2'-hydroxyl recognition between GEMM-I and GEMM-Ib riboswitches. PMID- 29514228 TI - Reading Comprehension and Phonics Research: Review of Correlational Analyses with Deaf and Hard-of-Hearing Students. AB - This manuscript reviews 28 studies of reading research on deaf and hard-of hearing (DHH) students published since 2000 that used correlational analyses. The examination focused on assessment issues affecting measurement and analysis of relationships between early phonological or orthographic skills and reading comprehension. Mixed outcomes complicate efforts to determine evidence-based practices, and to develop an accurate model of reading. Across the 28 studies, DHH participants represented a wide age range with potential floor and ceiling effects that reduce score variability for valid correlations. Many studies assessed readers beyond the optimal ages during which early skills develop and are most useful for reading. Reading skills also were assessed using a diverse array of measures and skill definitions. Particularly for reading comprehension, word-level and text-level abilities appear to be different constructs. Suggestions include more consistent skill definitions and differential timing for early- versus later-developing skill assessments to ensure more robust correlational relationships. PMID- 29514230 TI - Unemployment and work disability due to common mental disorders among young adults: selection or causation? AB - Background: Unemployment in early adulthood is associated with higher rate of disability due to common mental disorders (CMDs). We investigated to what extent the association between unemployment and sub-sequent long-term sickness absence due to CMDs is direct or whether it is dependent on accumulation of mental health problems and socioeconomic disadvantage. Methods: In this longitudinal study, a population-based 60% sample of Finnish young adults born between 1983 and 1985 (N = 116 878) was followed up for the incidence of CMDs from 2006 to 2010. Sociodemographic and health-related covariates were identified using several nationwide registers. Hazard ratios (HRs) with 95% confidence intervals (CIs), and survival and cumulative hazard functions for CMD were calculated. A matching procedure was applied to account for the systematic differences in the distribution of the baseline characteristics. Results: A total of 1416 (2.4%) of men and 2539 (4.4%) of women were granted a long-term sickness allowance for CMD during the follow-up. After matching, HR (95% CI) of CMD for men decreased from 2.38 (2.12-2.68) to 1.31 (1.03-1.67) and for women from 1.97 (1.79-2.18) to 1.39 (1.18-1.65). Approximately half of the effect of the unemployment on CMDs was explained by the background variables. Conclusion: Using a causal approach, our study suggests that unemployment is consistently associated with an increased risk of work disability due to CMDs. Considering the young unemployed as a risk group may help in targeting interventions promoting mental health and improving educational and employment opportunities. PMID- 29514229 TI - Host range of antibiotic resistance genes in wastewater treatment plant influent and effluent. AB - Wastewater treatment plants (WWTPs) collect wastewater from various sources for a multi-step treatment process. By mixing a large variety of bacteria and promoting their proximity, WWTPs constitute potential hotspots for the emergence of antibiotic resistant bacteria. Concerns have been expressed regarding the potential of WWTPs to spread antibiotic resistance genes (ARGs) from environmental reservoirs to human pathogens. We utilized epicPCR (Emulsion, Paired Isolation and Concatenation PCR) to detect the bacterial hosts of ARGs in two WWTPs. We identified the host distribution of four resistance-associated genes (tetM, int1, qacEDelta1and blaOXA-58) in influent and effluent. The bacterial hosts of these resistance genes varied between the WWTP influent and effluent, with a generally decreasing host range in the effluent. Through 16S rRNA gene sequencing, it was determined that the resistance gene carrying bacteria include both abundant and rare taxa. Our results suggest that the studied WWTPs mostly succeed in decreasing the host range of the resistance genes during the treatment process. Still, there were instances where effluent contained resistance genes in bacterial groups not carrying these genes in the influent. By permitting exhaustive profiling of resistance-associated gene hosts in WWTP bacterial communities, the application of epicPCR provides a new level of precision to our resistance gene risk estimates. PMID- 29514231 TI - The Persistent Challenge of Advanced HIV Disease and AIDS in the Era of Antiretroviral Therapy. PMID- 29514232 TI - Managing Advanced HIV Disease in a Public Health Approach. AB - In 2017, the World Health Organization (WHO) published guidelines for the management of advanced human immunodeficiency virus (HIV) disease within a public health approach. Recent data suggest that more than a third of people starting antiretroviral therapy (ART) do so with advanced HIV disease, and an increasing number of patients re-present to care at an advanced stage of HIV disease following a period of disengagement from care. These guidelines recommend a standardized package of care for adults, adolescents, and children, based on the leading causes of morbidity and mortality: tuberculosis, severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. A package of targeted interventions to reduce mortality and morbidity was recommended, based on results of 2 recent randomized trials that both showed a mortality reduction associated with delivery of a simplified intervention package. Taking these results and existing recommendations into consideration, WHO recommends that a package of care be offered to those presenting with advanced HIV disease; depending on age and CD4 cell count, the package may include opportunistic infection screening and prophylaxis, including fluconazole preemptive therapy for those who are cryptococcal antigen positive and without evidence of meningitis. Rapid ART initiation and intensified adherence interventions should also be proposed to everyone presenting with advanced HIV disease. PMID- 29514233 TI - The Continuing Burden of Advanced HIV Disease Over 10 Years of Increasing Antiretroviral Therapy Coverage in South Africa. AB - Background: Antiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)-related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa. Methods: Annual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/uL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care. Results: Patients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/uL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/uL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/uL in 2016 were men, compared to approximately one-third of all patients on ART in the same year. Conclusions: Ongoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response. PMID- 29514234 TI - Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial. AB - Background: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity. Methods: Participants started ART with a CD4 count <100 cells/uL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non-mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown. Results: Median pre-ART CD4 count was 37 cells/uL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2). Conclusions: Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease. Clinical Trials Registration: ISRCTN43622374. PMID- 29514236 TI - CD4 Cell Count Threshold for Cryptococcal Antigen Screening of HIV-Infected Individuals: A Systematic Review and Meta-analysis. AB - Background: Current guidelines recommend screening all people living with human immunodeficiency virus (PLHIV) who have a CD4 count <=100 cells/uL for cryptococcal antigen (CrAg) to identify those patients who could benefit from preemptive fluconazole treatment prior to the onset of meningitis. We conducted a systematic review to assess the prevalence of CrAg positivity at different CD4 cell counts. Methods: We searched 4 databases and abstracts from 3 conferences up to 1 September 2017 for studies reporting prevalence of CrAg positivity according to CD4 cell count strata. Prevalence estimates were pooled using random effects models. Results: Sixty studies met our inclusion criteria. The pooled prevalence of cryptococcal antigenemia was 6.5% (95% confidence interval [CI], 5.7%-7.3%; 54 studies) among patients with CD4 count <=100 cells/uL and 2.0% (95% CI, 1.2% 2.7%; 21 studies) among patients with CD4 count 101-200 cells/uL. Twenty-one studies provided sufficient information to compare CrAg prevalence per strata; overall, 18.6% (95% CI, 15.4%-22.2%) of the CrAg-positive cases identified at <=200 cells/uL (n = 11823) were identified among individuals with a CD4 count 101 200 cells/uL. CrAg prevalence was higher among inpatients (9.8% [95% CI, 4.0% 15.5%]) compared with outpatients (6.3% [95% CI, 5.3%-7.4%]). Conclusions: The findings of this review support current recommendations to screen all PLHIV who have a CD4 count <=100 cells/uL for CrAg and suggest that screening may be considered at CD4 cell count <=200 cells/uL. PMID- 29514237 TI - Priorities for Decreasing Morbidity and Mortality in Children With Advanced HIV Disease. AB - Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed. PMID- 29514238 TI - Persistent High Burden of Advanced HIV Disease Among Patients Seeking Care in South Africa's National HIV Program: Data From a Nationwide Laboratory Cohort. AB - Background: The South African national HIV program has increased antiretroviral therapy (ART) coverage over the last decade, supported by policy changes allowing for earlier ART initiation. However, many patients still enter care with advanced (<200 cells/MUL) and very advanced (<100 cells/MUL) HIV disease. We assessed disease progression at entry to care using nationwide laboratory data. Methods: We constructed a national HIV cohort using laboratory records containing HIV RNA loads and CD4 counts from 2004 to 2016 to determine entry into care. We estimated numbers and proportions of adults with the first CD4 count <100 cells/ MUL or 100 199 cells/MUL. We calculated relative risks of presenting with advanced disease associated with male sex. Results: 8.04 million first CD4 results were identified. From 2005 to 2011, the proportion of patients entering into care with CD4 count <200 cells/MUL declined from 46.8% to 35.6%. From 2011 onward, the proportion of patients entering ART with advanced HIV disease has remained relatively unchanged. In 2016, we estimated that of 654 868 patients entering care, 32.9% had advanced HIV disease, and 16.8% had very advanced HIV disease. Men were almost twice as likely as women (23.1% vs 12.6% ) to enter care with very advanced HIV disease. Conclusions: The proportion of patients presenting with advanced HIV disease in South Africa remains consistently high despite ART scale-up, representing a large and avoidable burden of morbidity. Early HIV diagnosis, rapid linkage to ART and approaches to attract men into early ART initiation should be prioritized. PMID- 29514239 TI - High Proportions of Patients With Advanced HIV Are Antiretroviral Therapy Experienced: Hospitalization Outcomes From 2 Sub-Saharan African Sites. AB - Background: Human immunodeficiency virus (HIV) remains an important cause of hospitalization and death in low- and middle- income countries. Yet morbidity and in-hospital mortality patterns remain poorly characterized, with prior antiretroviral therapy (ART) exposure and treatment failure status largely unknown. Methods: We studied HIV-infected inpatients aged >=13 years from cohorts in Kenya and the Democratic Republic of Congo (DRC), assessing clinical and demographic characteristics and hospitalization outcomes. Kenyan inpatients were prospectively enrolled during hospitalization; identical retrospective data were extracted for Congolese patients meeting the study criteria using routine medical information. Results: Among 338 HIV-infected patients in Kenya and 411 in DRC, 83.7% (95% confidence interval [CI], 79.4%-87.3%) and 97.3% (95% CI, 95.2% 98.5%), were admitted with advanced disease (defined as CD4 <200 cells/uL or World Health Organization stage 3/4 illness). Among inpatients with advanced HIV, 35.4% and 21.7% were ART-naive at admission. Patients under care had a median time of 44.1 (interquartile range [IQR], 18.4-90.5) months and 55.9 (IQR, 28.1 99.6) months on treatment; 17.2% (95% CI, 13.5%-21.6%) and 29.6% (95% CI, 25.4% 34.3%) died, 25.9% (95% CI, 16.0%-39.0%) and 22.5% (95% CI, 15.8%-31.0%) of these within 48 hours. Conclusions: Across 2 diverse clinical contexts in sub-Saharan Africa, advanced HIV inpatients were frequently admitted with low CD4 counts, often failing first-line ART. Earlier identification of treatment failure and rapid switching to second-line ART are needed. PMID- 29514235 TI - Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial. AB - Background: Severely immunocompromised human immunodeficiency virus (HIV) infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods: The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children >=5 years of age with CD4 counts <100 cells/uL initiating ART in Uganda, Zimbabwe, Malawi, and Kenya. Baseline predictors of mortality through 48 weeks were identified using Cox regression with backwards elimination (exit P > .1). Results: Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/uL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/uL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/uL), but low symptom burden and maintained fat mass. The remaining groups had 4%-6% mortality. Conclusions: Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up. Clinical Trials Registration: ISRCTN43622374. PMID- 29514241 TI - Designing Surveillance of Healthcare-Associated Infections in the Era of Automation and Reporting Mandates. AB - Surveillance and feedback of infection rates to clinicians and other stakeholders is a cornerstone of healthcare-associated infection (HAI) prevention programs. In addition, HAIs are increasingly included in public reporting and payment mandates. Conventional manual surveillance methods are resource intensive and lack standardization. Developments in information technology have propelled a movement toward the use of standardized and semiautomated methods.When developing automated surveillance systems, several strategies can be chosen with regard to the degree of automation and standardization and the definitions used. Yet, the advantages of highly standardized surveillance may come at the price of decreased clinical relevance and limited preventability. The choice among (automated) surveillance approaches, therefore, should be guided by the intended aim and scale of surveillance (eg, research, in-hospital quality improvement, national surveillance, or pay-for-performance mandates), as this choice dictates subsequent methods, important performance characteristics, and suitability of the data generated for the different applications. PMID- 29514240 TI - Cellular uptake mediated by epidermal growth factor receptor facilitates the intracellular activity of phosphorothioate-modified antisense oligonucleotides. AB - Chemically modified antisense oligonucleotides (ASOs) with phosphorothioate (PS) linkages have been extensively studied as research and therapeutic agents. PS ASOs can enter the cell and trigger cleavage of complementary RNA by RNase H1 even in the absence of transfection reagent. A number of cell surface proteins have been identified that bind PS-ASOs and mediate their cellular uptake; however, the mechanisms that lead to productive internalization of PS-ASOs are not well understood. Here, we characterized the interaction between PS-ASOs and epidermal growth factor receptor (EGFR). We found that PS-ASOs trafficked together with EGF and EGFR into clathrin-coated pit structures. Their co localization was also observed at early endosomes and inside enlarged late endosomes. Reduction of EGFR decreased PS-ASO activity without affecting EGF mediated signaling pathways and overexpression of EGFR increased PS-ASO activity in cells. Furthermore, reduction of EGFR delays PS-ASO trafficking from early to late endosomes. Thus, EGFR binds to PS-ASOs at the cell surface and mediates essential steps for active (productive) cellular uptake of PS-ASOs through its cargo-dependent trafficking processes which migrate PS-ASOs from early to late endosomes. This EGFR-mediated process can also serve as an additional model to better understand the mechanism of intracellular uptake and endosomal release of PS-ASOs. PMID- 29514244 TI - A Systematic Review of Services to DHH Children in Rural and Remote Regions. AB - Children in regional, rural and remote areas have less access to services than those living in urban areas. Practitioners serving children with a hearing loss have attempted to address this gap, however there are few studies investigating service access and experiences of non-metropolitan families and professionals. This systematic review evaluates the literature on service provision to children with a hearing loss living in regional, rural and remote areas of Australia. A search of five databases, the gray literature and a prominent author located 37 relevant documents. The journal articles were rated for quality and the findings of all documents were themed. The evidence from this review indicates that children with a hearing loss living in regional, rural and remote Australia experience reduced quality and frequency of service. Further investigation is needed to identify the accessibility and suitability of services for children with a hearing loss in non-metropolitan areas. PMID- 29514245 TI - Evaluation of Pyrethroid Insecticides and Insect Growth Regulators Applied to Different Surfaces for Control of Trogoderma granarium (Coleoptera: Dermestidae) the Khapra Beetle. AB - The khapra beetle, Trogoderma granarium Everts (Coleoptera: Dermestidae), is a serious pest of stored products and is the only stored product insect pest that triggers a quarantine response when it is found in the United States. The larvae of T. granarium feed on a wide range of dry food products of plant and animal origin, including cereals, dried fish, and museum specimens. In this study, we evaluated the residual efficacy of two pyrethroid insecticides, deltamethrin and cyfluthrin, applied on concrete, wood, painted wood, vinyl flooring tile, and metal surfaces using small and large T. granarium larvae. Residual efficacy of two insect growth regulators (IGRs), methoprene and pyriproxyfen was also evaluated on concrete, metal, and wood surfaces. In both studies, larvae were exposed with provision of a food source on the treated surfaces and residual assays were conducted at 0 months (1 d), 1, 2, and 3 months post treatment. In general, both of the pyrethroids provided a high level of control of T. granarium larvae, though small larvae were much more susceptible than large larvae. The IGRs were comparatively less effective, with more larval survival and adult emergence of exposed larvae compared with the pyrethroids. Residues of the pyrethroids and IGRs were most persistent on the metal surface. Results can be used to help to control and eradicate infestations of T. granarium when they are detected in the United States. PMID- 29514246 TI - Contribution of discretionary food and drink consumption to socio-economic inequalities in children's weight: prospective study of Australian children. AB - Background: In high-income countries, children with a lower socio-economic position (SEP) are more likely to gain excess weight compared with children with a higher SEP. The extent to which children's consumption of discretionary food and drinks contributes to the development of these inequalities over childhood has not been examined. Methods: The study sample comprised 3190 children from the nationally representative Longitudinal Study of Australian Children. Linear and logistic regression models were fitted in accordance with the product of coefficients mediation method to determine the contribution of cumulative consumption of sweet drinks, discretionary hot foods, savoury snacks and sweet snacks from the first year of life, over a period of 10 years, on the relationship between SEP and children's body mass index (BMI) z-score at age 10 11 years. Results: At age 10-11, mean BMI z-score was 0.17 in the highest SEP tertile, 0.33 in the middle and 0.47 in the lowest tertile. Corresponding values for overweight and obesity prevalence were 16.6%, 25.7% and 32.7%, respectively. Eleven per cent [95% confidence interval (CI) 4.77%, 19.84%] of the observed difference in BMI z-score at age 10-11 years was mediated by socio-economic differences in consumption of sweet drinks and discretionary hot foods including pies and hot chips throughout childhood. Conclusions: Findings indicate that consumption of sweet drinks and discretionary hot food, from the first year of life, is likely to contribute to the development of inequalities in excess weight among children. Poor dietary intake is a key risk factor for excess weight gain among children and a reduction in discretionary food and drinks is likely to contribute to the dual goal of improving overall weight and reducing socio economic inequalities in weight gain across childhood. To maximally reduce inequalities in weight gain across childhood, additional determinants must also be identified and targeted. PMID- 29514247 TI - Absorption of foliar-applied Zn fertilizers by trichomes in soybean and tomato. AB - The present study investigated the role of trichomes in absorption of foliar applied zinc fertilizers in soybean and tomato. Using synchrotron-based X-ray fluorescence microscopy for in situ analyses of hydrated leaves, we found that upon foliar application of ZnSO4, Zn accumulated within 15 min in some non glandular trichomes in soybean, but not in tomato. However, analyses of cross sections of soybean leaves did not show any marked accumulation of Zn in tissues surrounding trichomes. Furthermore, when near-isogenic lines of soybean differing 10-fold in trichome density were used to compare Zn absorption, it was found that foliar Zn absorption was not related to trichome density. Therefore, it is suggested that trichomes are not part of the primary pathway through which foliar applied Zn moves across the leaf surface in soybean and tomato. However, this does not preclude trichomes being important in other plant species, as they are known to be highly diverse. We also compared the absorption of Zn when supplied as either ZnSO4, nano-ZnO, or bulk-ZnO, and found that absorption from ZnSO4 was about 10-fold higher than from nano- and bulk-ZnO, suggesting that it was mainly absorbed as soluble Zn. This study improves our understanding of the absorption of foliar-applied nutrients. PMID- 29514248 TI - Characteristics and optimised fermentation of a novel magnetotactic bacterium, Magnetospirillum sp. ME-1. AB - Magnetotactic bacteria (MTB) can biosynthesise magnetosomes, which have great potential for commercial applications. A new MTB strain, Magnetospirillum sp. ME 1, was isolated and cultivated from freshwater sediments of East Lake (Wuhan, China) using the limiting dilution method. ME-1 had a chain of 17 +/- 4 magnetosomes in the form of cubooctahedral crystals with a shape factor of 0.89. ME-1 was closest to Magnetospirillum sp. XM-1 according to 16S rRNA gene sequence similarity. Compared with XM-1, ME-1 possessed an additional copy of mamPA and a larger mamO in magnetosome-specific genes. ME-1 had an intact citric acid cycle, and complete pathway models of ammonium assimilation and dissimilatory nitrate reduction. Potential carbon and nitrogen sources in these pathways were confirmed to be used in ME-1. Adipate was determined to be used in the fermentation medium as a new kind of dicarboxylic acid. The optimised fermentation medium was determined by orthogonal tests. The large-scale production of magnetosomes was achieved and the magnetosome yield (wet weight) reached 120 mg L-1 by fed-batch cultivation of ME-1 at 49 h in a 10-L fermenter with the optimised fermentation medium. This study may provide insights into the isolation and cultivation of other new MTB strains and the production of magnetosomes. PMID- 29514249 TI - Preventing Hypoglycemia in Type 2 Diabetes. PMID- 29514251 TI - Review of policies to increase fruit and vegetable consumption and physical activity in 49 low- and middle-income countries. AB - Background: Inadequate physical activity (PA) and consumption of fruits and vegetables (FV) are known risk factors for non-communicable diseases (NCDs). Consequently, the World Health Organization (WHO) encourages the development of policies to increase PA and FV consumption. We reviewed available policies between 2004 and 2013 to increase FV consumption and PA from a convenience sample of 49 LMICs. Method: Information on national policies were obtained from government ministries involved with the formulation of nutrition and PA policies, WHO databases and from PubMed and Scopus. Results: Of the 49 countries, 57% had policies to increase FV consumption, and 76% had policies to promote PA. Policy reviews indicated strategies that focus on schools, communities, the general public, the environment, the economy, mass media and WHO recommendations. Of the 28 countries with FV policies, 18% had formulated policies that met the WHO recommendations for daily intake of FV. Likewise, of the 37 countries with PA policies, 24% had policies that promoted the WHO recommendations for daily PA. Conclusion: Greater progress has been made in developing policies to increase PA compared to policies to increase FV consumption in low- and middle-income countries. However, most countries are still lagging behind in developing policies to meet the WHO recommendations. PMID- 29514252 TI - First-in-man: successful interventional closure of severe paravalvular leakage after surgical rapid deployment aortic valve replacement. PMID- 29514250 TI - Pseudomonas aeruginosa MutL promotes large chromosomal deletions through non homologous end joining to prevent bacteriophage predation. AB - Pseudomonas aeruginosa is an opportunistic pathogen with a relatively large genome, and has been shown to routinely lose genomic fragments during environmental selection. However, the underlying molecular mechanisms that promote chromosomal deletion are still poorly understood. In a recent study, we showed that by deleting a large chromosomal fragment containing two closely situated genes, hmgA and galU, P. aeruginosa was able to form 'brown mutants', bacteriophage (phage) resistant mutants with a brown color phenotype. In this study, we show that the brown mutants occur at a frequency of 227 +/- 87 * 10-8 and contain a deletion ranging from ~200 to ~620 kb. By screening P. aeruginosa transposon mutants, we identified mutL gene whose mutation constrained the emergence of phage-resistant brown mutants. Moreover, the P. aeruginosa MutL (PaMutL) nicking activity can result in DNA double strand break (DSB), which is then repaired by non-homologous end joining (NHEJ), leading to chromosomal deletions. Thus, we reported a noncanonical function of PaMutL that promotes chromosomal deletions through NHEJ to prevent phage predation. PMID- 29514253 TI - Biodiversity of biological soil crusts from the Polar Regions revealed by metabarcoding. AB - Biological soil crusts (BSCs) are amalgamations of autotrophic, heterotrophic and saprotrophic organisms. In the Polar Regions, these unique communities occupy essential ecological functions such as primary production, nitrogen fixation and ecosystem engineering. Here, we present the first molecular survey of BSCs from the Arctic and Antarctica focused on both eukaryotes and prokaryotes as well as passive and active biodiversity. Considering sequence abundance, Bryophyta is among the most abundant taxa in all analyzed BSCs suggesting that they were in a late successional stage. In terms of algal and cyanobacterial biodiversity, the genera Chloromonas, Coccomyxa, Elliptochloris and Nostoc were identified in all samples regardless of origin confirming their ubiquitous distribution. For the first time, we found the chrysophyte Spumella to be common in polar BSCs as it was present in all analyzed samples. Co-occurrence analysis revealed the presence of sulfur metabolizing microbes indicating that BSCs also play an important role for the sulfur cycle. In general, phototrophs were most abundant within the BSCs but there was also a diverse community of heterotrophs and saprotrophs. Our results show that BSCs are unique microecosystems in polar environments with an unexpectedly high biodiversity. PMID- 29514255 TI - Reply to El-Essawi and Harringer. PMID- 29514254 TI - Increased Risk of HIV Acquisition Among Women Throughout Pregnancy and During the Postpartum Period: A Prospective Per-Coital-Act Analysis Among Women With HIV Infected Partners. AB - Background: Understanding the absolute and relative risk of human immunodeficiency virus type 1 (HIV) acquisition during pregnancy and the postpartum period can inform HIV prevention strategies for women. Methods: We used a complementary log-log model and data from 2751 HIV-serodiscordant couples to compare the probability of HIV acquisition among women per sex act during early pregnancy, late pregnancy, the postpartum period, and the nonpregnant period. Results: At total of 686 pregnancies were identified, and 82 incident HIV infections occurred. After adjustment for condom use, age, preexposure prophylaxis (PrEP) use, and HIV viral load, the per-act probability of HIV acquisition was higher in late pregnancy (adjusted relative risk [aRR], 2.82; P = .01) and the postpartum period (aRR, 3.97; P = .01) as compared to that during nonpregnant period. For a 25-year-old woman not taking PrEP, the HIV acquisition probability per condomless sex act with an HIV-infected male partner with a viral load of 10 000 copies/mL was 0.0011 (95% confidence interval [CI] 0.005-0.0019), 0.0022 (95% CI, 0.0004-0.0093), 0.0030 (95% CI, 0.0007-0.0108), and 0.0042 (95% CI, 0.0007-0.0177) during the nonpregnant period, early pregnancy, late pregnancy, and the postpartum period, respectively. Conclusion: The HIV acquisition probability per condomless sex act steadily increased during pregnancy and was highest during the postpartum period, suggesting that biological changes during pregnancy and the postpartum period increase HIV susceptibility among women. PMID- 29514256 TI - Phase 1 study of ombrabulin in combination with docetaxel and cisplatin in Japanese patients with advanced solid tumors. AB - Background: The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models. Methods: In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated. Results: Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2). Conclusion: A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level. Clinical trial registration ID: ClinicalTrials.gov number, NCT01095302. PMID- 29514257 TI - CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration. AB - Aims: Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Methods and results: Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Conclusions: Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases. PMID- 29514258 TI - Aortopexy for the treatment of tracheobronchomalacia in 100 children: a 10-year single-centre experience. AB - OBJECTIVES: Our study describes and analyses the results from aortopexy for the treatment of airway malacia in children. METHODS: Demographic data, characteristics and preoperative, operative and outcome details, including the need for reintervention, were collected for children undergoing aortopexy between 2006 and 2016. RESULTS: One hundred patients [median age 8.2 months, interquartile range (IQR) 3.3-26.0 months] underwent aortopexy. Sixty-four (64%) patients had tracheomalacia (TM) only, 24 (24%) patients had TM extending into their bronchus (tracheobronchomalacia) and 11 (11%) patients had bronchomalacia. Forty-one (41%) children had gastro-oesophageal reflux disease, of which 17 (41%) children underwent a Nissen fundoplication. Twenty-eight (28%) children underwent a tracheo-oesophageal fistula repair prior to aortopexy (median 5.7 months, IQR 2.9-17.6 months). The median duration of follow-up was 5.3 years (IQR 2.9-7.5 years). Thirty-five (35%) patients were on mechanical ventilatory support before aortopexy. Twenty-seven (77%) patients could be safely weaned from ventilator support during the same admission after aortopexy (median 2 days, IQR 0-3 days). Fourteen patients required reintervention. Overall mortality was 16%. Multivariable analysis revealed preoperative ventilation (P = 0.004) and bronchial involvement (P = 0.004) to be adverse predictors of survival. Only bronchial involvement was a predictor for reintervention (P = 0.012). CONCLUSIONS: Aortopexy appears to be an effective procedure in the treatment of children with severe airway malacia. Bronchial involvement is associated with adverse outcome, and other procedures could be more suitable. For the treatment of severe airway malacia with isolated airway compression, we currently recommend aortopexy to be considered. PMID- 29514259 TI - A group of nuclear factor Y transcription factors are sub-functionalized during endosperm development in monocots. AB - Nuclear factor Y (NF-Y) is a heterotrimeric transcription factor that consists of three subunits, NF-YA, NF-YB, and NF-YC. Gene functions of NF-Ys during endosperm development are not well understood. In this study, we identified eight rice NF-Y encoding genes, namely OsNF-YA8, OsNF-YB1,9, and OsNF-YC8,9,10,11,12, that are predominantly expressed in the endosperm. Interestingly, the close homologs of these OsNF-Ys are present only in monocot species and are also preferentially expressed in the endosperm, suggesting that they have roles in the regulation of endosperm development. A systemic analysis of interactions between rice endosperm preferential NF-Ys in yeast revealed that OsNF-YBs and OsNF-YCs could interact with each other. We also found that the endosperm-preferential OsNF-YBs and OsNF YCs could interact with some ethylene response factors (ERFs) of rice. Unlike OsNF-YC8,9,10, the members of OsNF-YB1,9 or OsNF-YC 11,12 showed no transcriptional activation when present alone. However, they displayed functional activity while in dimer form. In addition, OsNF-YB1-knockout lines showed significant changes in seed morphology, further confirming its role in endosperm development. Our findings provide evidence that a group of phylogenetically conserved NF-Ys is probably differentiated in monocots to regulate endosperm development. PMID- 29514261 TI - The Immatures of Culicoides trilineatus (Diptera: Ceratopogonidae) Potential Vector of the Bluetongue Virus. AB - The fourth instar larva and pupa of Culicoides trilineatus Fox (Diptera, Ceratopogonidae), a species considered as potential vector of the bluetongue virus in Central and South America, are described, illustrated, and photomicrographed for the first time by using binocular, phase-contrast, and scanning electron microscopy. The immatures were collected by using a siphon bottle in tree holes in Salta Province, Argentina, transported to the laboratory, and there reared to the adult's emergence. They are compared with the immatures of Culicoides debilipalpis Lutz (Diptera, Ceratopogonidae), another Neotropical species that develops in tree holes. Details on larval biology and habitat are given. PMID- 29514260 TI - In cell mutational interference mapping experiment (in cell MIME) identifies the 5' polyadenylation signal as a dual regulator of HIV-1 genomic RNA production and packaging. AB - Non-coding RNA regulatory elements are important for viral replication, making them promising targets for therapeutic intervention. However, regulatory RNA is challenging to detect and characterise using classical structure-function assays. Here, we present in cell Mutational Interference Mapping Experiment (in cell MIME) as a way to define RNA regulatory landscapes at single nucleotide resolution under native conditions. In cell MIME is based on (i) random mutation of an RNA target, (ii) expression of mutated RNA in cells, (iii) physical separation of RNA into functional and non-functional populations, and (iv) high throughput sequencing to identify mutations affecting function. We used in cell MIME to define RNA elements within the 5' region of the HIV-1 genomic RNA (gRNA) that are important for viral replication in cells. We identified three distinct RNA motifs controlling intracellular gRNA production, and two distinct motifs required for gRNA packaging into virions. Our analysis reveals the 73AAUAAA78 polyadenylation motif within the 5' PolyA domain as a dual regulator of gRNA production and gRNA packaging, and demonstrates that a functional polyadenylation signal is required for viral packaging even though it negatively affects gRNA production. PMID- 29514262 TI - ESHRE/ESGE female genital tract anomalies classification system-the potential impact of discarding arcuate uterus on clinical practice. AB - STUDY QUESTION: What would be a potential impact of implementing the new ESHRE/European Society of Gynaecological Endoscopy (ESGE) female genital anomalies classification system on the management of women with previous diagnosis of arcuate uteri based on the modified American Society for Reproductive Medicine (ASRM) criteria? SUMMARY ANSWER: A significant number of women with previous diagnosis of arcuate uteri are reclassified as having partial septate uteri according to the new ESHRE/ESGE classification system which may increase the number of remedial surgical procedures. WHAT IS KNOWN ALREADY: The ESHRE/ESGE classification system has defined measurement techniques, reference points and specific cut-offs to facilitate the differentiation between normal and septate uteri. These criteria have been arbitrarily defined and they rely on the measurement of uterine wall thickness and depth of distortion of uterine fundus. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study. We searched our ultrasound clinic database from January 2011 to December 2014 to identify all women diagnosed with arcuate uterus on three-dimensional ultrasound according to the modified ASRM criteria. PARTICIPANTS/MATERIALS, SETTING, METHODS: For each woman, the ultrasound images were stored in our clinical database and they were re-examined according to ESHRE/ESGE specifications. The presence and location of all acquired uterine anomalies, such as fibroids or adenomyosis was noted. We applied the two diagnostic approaches as specified by the ESHRE/ESGE classification: the main option (MO) and the alternative option (AO). We used the Kappa statistic to quantify the agreement between the two approaches. We also compared the number of previous miscarriages in women with normal and partial septate uteri according to the ESHRE/ESGE classification. Non-parametric Mann Whitney and Kruskal-Wallis tests were used for the analyses and receiver operating characteristic curves were constructed to assess the predictive values of the calculated uterine distortion indices for the detection of women at risk of suffering multiple pregnancy losses. MAIN RESULTS AND THE ROLE OF CHANCE: We included 270 women diagnosed with arcuate uterus in the study. In all, 77 women (28.5%, 95% confidence interval (CI) 23.1-33.9) had evidence of fibroids or adenomyosis. These abnormalities precluded the application of either proposed ESHRE/ESGE techniques to assess uterine morphology in 25 women (9.3%, 95% CI 5.8 12.7). When using the MO, 138/237 (58.2%, 95% CI 51.9-64.3) women were diagnosed with partial septate uterus compared to 61/230 (26.5%, 95% CI 21.2-32.6) women when using the AO. In 222 women in whom we were able to apply both MO and AO, there was agreement in the diagnosis of septate uterus between the two techniques in 146/222 cases (65.8%, 95% CI 59.3-71.7; Kappa 0.42, 95%CI 0.35-0.5). There was no statistical difference in the proportion of women with history of previous multiple miscarriages between those diagnosed with normal or partial septate uteri using either MO (6.2%, 95% CI 2.9-12.9 vs. 9.5%, 95% CI 5.6-15.6; P = 0.47) or AO (7.2%, 95% CI 4.2-12.1 vs. 11.7%, 95% CI 5.8-22.2; P = 0.29). LIMITATIONS, REASONS FOR CAUTION: This study was retrospective in nature and the definition of arcuate uterus used in the study is not universally accepted. The reproductive history data were collected retrospectively and therefore may be prone to bias. WIDER IMPLICATIONS OF THE FINDINGS: There are methodological weaknesses in the new ESHRE/ESGE classification system which would need to be addressed in future revisions. There was no significant difference in the past reproductive outcomes between women diagnosed with normal and anomalous uteri and the clinicians should exercise caution when offering surgical correction to women diagnosed with partial septate uteri using the new ESHRE/ESGE classification. STUDY FUNDING/COMPETING INTEREST(S): No study funding was received and no competing interests are present. TRIAL REGISTRATION NUMBER: N/A. PMID- 29514263 TI - Food As Medicine: Diet, Diabetes Management, and the Patient in Twentieth Century Britain. AB - In classic accounts of the development of modern medicine in Europe and North America, the sick person is often portrayed as having a history of disappearance with the rise of the objectified body of the modern patient. To this account, sociologists and historians of medicine have added another for the period after 1950, in which the patient as subjective person "reappears" in medical discourse. However, despite histories of practice and identity revising narratives of disappearance, the patient's reappearance has largely escaped further assessment. Using an analysis of dietary management in twentieth-century British diabetes care, this article challenges accounts of this reappearance in three ways. Firstly, it argues that discursive interest in the social and psychological aspects of care emerged earlier than suggested. Secondly, it grounds such interest in reconfigured institutional arrangements that were initially designed to rationalize care and improve efficiency. Finally, it argues that patients regularly exceeded the efforts of even an expanded management regime to normalize and regulate life. Food planning, preparation, and consumption continued to sit at the nexus of competing demands that mediated medical efforts to cultivate governable selves and bodies. PMID- 29514264 TI - Multigenerational effects of a reduced balanced protein diet during the rearing and laying period of broiler breeders. 2. Zootechnical performance of the F1 broiler offspring. AB - Several studies in mammals focused on the maternal programming of the metabolism by epigenetic mechanisms, while currently, the consequences of a maternal dietary treatment on the offspring performance of farm animals are of particular interest for commercial purpose. In the present study, we investigated if the zootechnical performance of the progeny was altered by a maternal dietary treatment, being a lower dietary crude protein (CP) of the grandparent and/or parent generation. The multigenerational effects of a reduced maternal CP content were investigated by reducing the dietary CP level by 25% in rearing and laying diets of pure line A breeders. The F0 generation breeders were fed either control (C) or reduced balanced protein (RP) diets. The F1 breeder generation was constructed by dividing the F0 female progeny again over a C or RP diet, resulting in 4 dietary treatments in the F1 generation: C/C, C/RP, RP/C, and RP/RP (letters indicating the diets in, respectively, F0 and F1 generations). The offspring performance was evaluated by a zootechnical and nitrogen retention trial on C and low-protein (LP) broiler diets. For the C broiler diet, the C/RP and RP/RP offspring were characterized by a higher BW from d 35 until d 42 compared to the C/C progeny, whereas the RP/C offspring had an intermediate BW that did not differ from the other groups. A tendency (P = 0.067) towards a better nitrogen retention was observed for the offspring of breeders that received the RP diets in F0 and/or F1 generation compared to the C/C progeny. For the LP broiler diet, the C/RP (P = 0.021) and RP/C (P = 0.001) offspring had a higher BW compared to the C/C progeny during the entire grow-out period. In addition, the C/RP offspring were characterized by a lower FCR from d 28 onwards (P = 0.021). In conclusion, dietary treatments imposed on mother hens can have direct effects on the next generation, as well as indirect effects on multiple generations. PMID- 29514265 TI - Effects of stocking density and string provision on welfare-related measures in commercial broiler chickens in windowed houses. AB - Lower stocking densities (SD) are sometimes used in windowed houses for broilers as part of systems designed to produce high-welfare products. However, there is little scientific information on the effects of SD on welfare-related measures in broilers in windowed houses, and on whether these effects are influenced by environmental enrichment. Commercial windowed broiler chicken houses were assigned to 4 target SD (30, 32, 34, and 36 kg/m2) and 2 levels of access to string [+S (one piece per 1,000 birds/house), -S] in a 4 * 2 factorial arrangement. Treatments were applied in one of 4 houses on each of 2 farms, and replicated over 10 production cycles. Levels of lying behavior, apparent fear related behavior, and gait score were observed in wk 3 to 5. The incidence and severity of dermatitis lesions were assessed at d 30 and at slaughter. Environmental and production performance parameters also were measured. No significant treatment effects were obtained for levels of lying or fear-related behavior, final body weight, presence of dermatitis lesions at slaughter, or percentage of downgraded carcasses. There were no significant treatment effects on measures of gait, but the percentage of birds with a gait score of >=2 tended to increase at higher SD. The severity of dermatitis lesions at d 30 increased with increasing SD, and was significantly greater at densities of 34 and 36 kg/m2 than of 30 kg/m2. Litter moisture content was not significantly affected by treatment, which may have reflected a numerical decline in water consumption with increasing SD. Results suggest that increasing SD is a risk factor for more severe dermatitis; however, increasing density from 30 to 32 kg/m2 did not significantly affect this variable. In addition, the proportion of lame birds, levels of lying behavior, and performance were not significantly affected by increasing SD. Providing suspended string at typical commercial levels did not have beneficial effects on welfare-related measures, and further research should perhaps investigate effects of greater levels of provision. PMID- 29514266 TI - SCH79797 improves outcomes in experimental bacterial pneumonia by boosting neutrophil killing and direct antibiotic activity. AB - Objectives: The role of protease-activated receptor 1 (PAR1) in the pathogenesis of pneumonia and sepsis is ambiguous given the existing literature. As PAR1 is classically activated by the coagulation-based protease thrombin and leads to vascular leakage, our hypothesis was that PAR1 blockade with SCH79797 would be therapeutically beneficial in an experimental model of murine Gram-negative pneumonia. Methods: In this study, we administered SCH79797 via the intrapulmonary route 6 h after the establishment of Escherichia coli pneumonia and observed a significant improvement in survival, lung injury, bacterial clearance and inflammation. We focused on neutrophils as a potential target of the PAR1 antagonist, since they are the predominant inflammatory cell type in the infected lung. Results: Neutrophils appear to express PAR1 at low levels and the PAR1 antagonist SCH79797 enhanced neutrophil killing. Part of this effect may be explained by alterations in the generation of reactive oxygen species (ROS). SCH79797 also led to robust neutrophil extracellular trap (NET) generation and cathelicidin-related antimicrobial peptide (CRAMP) release by neutrophils. Surprisingly, SCH79797 also had a potent, direct antibiotic effect with disruption of the E. coli cell membrane. However, the newer-generation PAR1 antagonist, vorapaxar (SCH530348), had no appreciable effect on neutrophil activity or direct bacterial killing, which suggests the effects seen with SCH79797 may be PAR1 independent. Conclusions: In summary, we observed that intrapulmonary treatment with SCH79797 has significant therapeutic effects in a model of E. coli pneumonia that appear to be due, in part, to both neutrophil stimulating and direct antibacterial effects of SCH79797. PMID- 29514268 TI - Effects of primary care antimicrobial stewardship outreach on antibiotic use by general practice staff: pragmatic randomized controlled trial of the TARGET antibiotics workshop. AB - Objectives: To determine whether local trainer-led TARGET antibiotic interactive workshops improve antibiotic dispensing in general practice. Methods: Using a McNulty-Zelen-design randomized controlled trial within three regions of England, 152 general practices were stratified by clinical commissioning group, antibiotic dispensing rate and practice patient list size, then randomly allocated to intervention (offered TARGET workshop that incorporated a presentation, reflection on antibiotic data, promotion of patient and general practice (GP) staff resources, clinical scenarios and action planning, 73 practices) or control (usual practice, 79 practices). The primary outcome measure was total oral antibiotic items dispensed/1000 patients for the year after the workshop (or pseudo-workshop date for controls), adjusted for the previous year's dispensing. Results: Thirty-six (51%) intervention practices (166 GPs, 51 nurses and 101 other staff) accepted a TARGET workshop invitation. In the ITT analysis total antibiotic dispensing was 2.7% lower in intervention practices (95% CI -5.5% to 1%, P = 0.06) compared with controls. Dispensing in intervention practices was 4.4% lower for amoxicillin/ampicillin (95% CI 0.6%-8%, P = 0.02); 5.6% lower for trimethoprim (95% CI 0.7%-10.2%, P = 0.03); and a non-significant 7.1% higher for nitrofurantoin (95% CI -0.03 to 15%, P = 0.06). The Complier Average Causal Effect (CACE) analysis, which estimates impact in those that comply with assigned intervention, indicated 6.1% (95% CI 0.2%-11.7%, P = 0.04) lower total antibiotic dispensing in intervention practices and 11% (95% CI 1.6%-19.5%, P = 0.02) lower trimethoprim dispensing. Conclusions: This study within usual service provision found that TARGET antibiotic workshops can help improve antibiotic use, and therefore should be considered as part of any national antimicrobial stewardship initiatives. Additional local facilitation will be needed to encourage all general practices to participate. PMID- 29514269 TI - Effects of Pediococcus acidilactici, mannan-oligosaccharide, butyric acid and their combination on growth performance and intestinal health in young broiler chickens challenged with Salmonella Typhimurium. AB - This study compared the efficacy of Pediococcus acidilactici, mannan oligosaccharide, butyric acid, and their combination on growth performance and intestinal health in broiler chickens challenged with S. Typhimurium. Ross 308 male broilers (n = 420) were randomly assigned to one of the 6 treatments, resulting in 5 replicate pens of 14 chicks per treatment. The treatments included a negative control [(NC), no additive, not challenged]; positive control [(PC), no additive, but challenged with S. Typhimurium at d 3 posthatch], and 4 groups whereby birds were challenged with S. Typhimurium at d 3 posthatch and fed diets supplemented with either probiotic [0.1 g/kg Pediococcus acidilactici (PA)], prebiotic [2 g/kg mannan-oligosaccharides (MOS)], organic acid [0.5 g/kg butyric acid (BA)], or a combination of the 3 additives (MA). The S. Typhimurium challenge decreased feed intake, body weight gain and increased feed conversion ratio and reduced jejunum villus height (VH) and VH to crypt depth (CD) ratio (P < 0.05). Birds on the MA treatment exhibited similar performance to birds on the NC treatment (P > 0.05) and had a lower population of Salmonella in the ceca compared with birds on the PC treatment, at d 14 and 21 post-challenge (P < 0.05). The lowest heterophil to lymphocyte ratio was observed in birds on the MA and NC treatments (P < 0.05). Birds fed diets supplemented with MA or PA had greater VH and VH: CD ratio than birds on the PC treatment at d 7, 14 and 21 d post-challenge (P < 0.05). Suppressed amylase and protease activity was observed as a result of the S. Typhimurium challenge; the enzyme levels were restored in birds fed the additive-supplemented diets, when compared to the birds on the PC treatment, particularly at d 21 post-challenge (P < 0.05). These results indicate that dietary supplementation with a combination of PA, BA, and MOS in broiler chickens could be used as an effective tool for controlling S. Typhimurium and promoting growth performance. PMID- 29514267 TI - The yeast Ty1 retrotransposon requires components of the nuclear pore complex for transcription and genomic integration. AB - Nuclear pore complexes (NPCs) orchestrate cargo between the cytoplasm and nucleus and regulate chromatin organization. NPC proteins, or nucleoporins (Nups), are required for human immunodeficiency virus type 1 (HIV-1) gene expression and genomic integration of viral DNA. We utilize the Ty1 retrotransposon of Saccharomyces cerevisiae (S. cerevisiae) to study retroviral integration because retrotransposons are the progenitors of retroviruses and have conserved integrase (IN) enzymes. Ty1-IN targets Ty1 elements into the genome upstream of RNA polymerase (Pol) III transcribed genes such as transfer RNA (tRNA) genes. Evidence that S. cerevisiae tRNA genes are recruited to NPCs prompted our investigation of a functional role for the NPC in Ty1 targeting into the genome. We find that Ty1 mobility is reduced in multiple Nup mutants that cannot be accounted for by defects in Ty1 gene expression, cDNA production or Ty1-IN nuclear entry. Instead, we find that Ty1 insertion upstream of tRNA genes is impaired. We also identify Nup mutants with wild type Ty1 mobility but impaired Ty1 targeting. The NPC nuclear basket, which interacts with chromatin, is required for both Ty1 expression and nucleosome targeting. Deletion of components of the NPC nuclear basket causes mis-targeting of Ty1 elements to the ends of chromosomes. PMID- 29514270 TI - Cytotoxic and mutagenic properties of alkyl phosphotriester lesions in Escherichia coli cells. AB - Exposure to many endogenous and exogenous agents can give rise to DNA alkylation, which constitutes a major type of DNA damage. Among the DNA alkylation products, alkyl phosphotriesters have relatively high frequencies of occurrence and are resistant to repair in mammalian tissues. However, little is known about how these lesions affect the efficiency and fidelity of DNA replication in cells or how the replicative bypass of these lesions is modulated by translesion synthesis DNA polymerases. In this study, we synthesized oligodeoxyribonucleotides containing four pairs (Sp and Rp) of alkyl phosphotriester lesions at a defined site, and examined how these lesions are recognized by DNA replication machinery in Escherichia coli cells. We found that the Sp diastereomer of the alkyl phosphotriester lesions could be efficiently bypassed, whereas the Rp counterparts moderately blocked DNA replication. Moreover, the Sp-methyl phosphotriester induced TT->GT and TT->GC mutations at the flanking TT dinucleotide site, and the induction of these mutations required Ada protein, which is known to remove efficiently the methyl group from the Sp-methyl phosphotriester. Together, our study provided a comprehensive understanding about the recognition of alkyl phosphotriester lesions by DNA replication machinery in cells, and revealed for the first time the Ada-dependent induction of mutations at the Sp-methyl phosphotriester site. PMID- 29514272 TI - The Effect of Music Therapy Entrainment on Physiologic Measures of Infants in the Cardiac Intensive Care Unit: Single Case Withdrawal Pilot Study. AB - Background: Although evidence suggests music therapy lowers the heart rate of ill adults undergoing painful procedures and premature infants in the NICU, the effect of music therapy interventions on physiologic response in infants with congenital heart disease (CHD) being cared for in the cardiac intensive care unit (CICU) has not been explored. Objective: The purpose of this study was to explore the effect of the music therapy entrainment on physiologic responses of infants with CHD in the CICU. Methods: Five infants in the CICU received music therapy entrainment 3-5 times per week for up to 3 weeks. Sessions took place both prior to and after the infant's surgical cardiac repair. Heart rate, respiratory rate, blood pressure, and oxygen saturations were recorded every 15 seconds for 20 minutes prior to the intervention (baseline), during the 20-minute music therapy entrainment (intervention), and for 20 minutes after the intervention (return to baseline). Comparisons of baseline to intervention measures were based on means, standard deviations, and derivatives of the signal. Results: Four of 5 infants experienced a decrease in average heart and respiratory rates as well as improvement in the derivative of the heart rate signal. Greater improvements were found when infants were located in the open bay and were receiving sedatives or narcotics. Conclusions: Our findings provide initial evidence that music therapy entrainment may be a valuable intervention to support improved physiologic stability in infants with CHD. PMID- 29514273 TI - Microsurgical Resection of Cavernous Sinus Meningioma: 2-Dimensional Operative Video. PMID- 29514271 TI - Structural insights into the unique mechanism of transcription activation by Caulobacter crescentus GcrA. AB - Canonical bacterial transcription activators bind to non-transcribed promoter elements to increase transcription of their target genes. Here we report crystal structures of binary complexes comprising domains of Caulobacter crescentus GcrA, a noncanonical bacterial transcription factor, that support a novel mechanism for transcription activation through the preferential binding of methylated cis regulatory elements and the promotion of open complex formation through an interaction with region 2 of the principal sigma factor, sigma70. We present crystal structures of the C-terminal, sigma factor-interacting domain (GcrA-SID) in complex with domain 2 of sigma70 (sigma702), and the N-terminal, DNA-binding domain (GcrA-DBD) in complex with methylated double-stranded DNA (dsDNA). The structures reveal interactions essential for transcription activation and DNA recognition by GcrA. These structures, along with mutational analyses, support a mechanism of transcription activation in which GcrA associates with RNA polymerase (RNAP) prior to promoter binding through GcrA-SID, arming RNAP with a flexible GcrA-DBD. The RNAP-GcrA complex then binds and activates target promoters harboring a methylated GcrA binding site either upstream or downstream of the transcription start site. PMID- 29514274 TI - Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. AB - The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new definition of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibiotic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publications and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accordance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakeholders (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is critically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments. Broth microdilution methods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infection by GNB should be improved. This guidance, with infection control to arrest increases in MDR, should be used to improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicrobial pharmacy and paramedical staff where they can be adapted for local use. PMID- 29514275 TI - Lonafarnib synergizes with azoles against Aspergillus spp. and Exophiala spp. PMID- 29514277 TI - Microsurgical Management of a Blister Anterior Cerebral Artery Aneurysm: 3 Dimensional Operative Video. PMID- 29514276 TI - Forsythia suspensa extract protects broilers against breast muscle oxidative injury induced by corticosterone mimicked pre-slaughter acute stress. AB - Broilers were used to determine the protective effects of Forsythia suspensa extract (FSE) against breast muscle oxidative injury induced by corticosterone (CS) mimicking pre-slaughter acute stress. A total of 144 male Arbor Acre broilers was randomly allotted to one of 4 treatments in a 2 * 2 factorial arrangement that included FSE supplementation (0 or 100 mg/kg) and subcutaneous injection of CS (0 or 4 mg/kg) at 3 h before slaughter. Corticosterone increased live BW loss, and the adverse effect was attenuated by FSE in broilers subjected to CS (P < 0.05). Serum levels of CS, uric acid, and glucose were increased, and postmortem breast muscle pH values at 45 min and 24 h were decreased for CS challenged broilers (P < 0.05). Corticosterone increased lightness and yellowness values and decreased redness of breast muscle (P < 0.05), and FSE decreased yellowness and increased redness of breast muscle (P < 0.05). Drip loss was increased by CS for birds supplemented without FSE (P < 0.05) and decreased by FSE for birds under CS challenge (P < 0.05). Corticosterone increased monounsaturated fatty acid (FA) and decreased polyunsaturated FA in breast muscle (P < 0.05), and saturated FA was decreased and polyunsaturated FA was increased by FSE (P < 0.05). Malondialdehyde and carbonyl contents in breast muscle were increased by CS and decreased by FSE (P < 0.05). Inhibition of 1,1-diphenyl-2 picryl-hydrazyl was decreased by CS and increased by FSE (P < 0.05). The activities of total-antioxidant capacity, glutathione peroxidase, and superoxide dismutase in breast muscle were lower in birds subjected to CS (P < 0.05) and were greater in birds supplemented with FSE (P < 0.05). Collectively, live BW loss and breast muscle oxidative injury were increased by CS in broilers, and these stress-related adverse effects could be attenuated by FSE supplementation via enhanced scavenging ability of free radicals and antioxidant capacity. Therefore, FSE could protect broilers against breast muscle oxidative injury when acute stress happens. PMID- 29514278 TI - Ascending aorta, aortic arch and supra-aortic vessels rupture in blunt thoracic trauma. AB - Surgical strategy and long-term outcomes of patients with rupture of the ascending aorta, aortic arch and supra-aortic vessels following blunt thoracic trauma have been rarely reported. We reviewed our institutional experience between 1995 and 2016. We identified 2 patients with an innominate artery ruptures, 2 with an aortic arch ruptures and 1 with an ascending aorta rupture; all were induced by the posterior displacement of the anterior chest wall. All patients underwent open surgical repair. Cardiopulmonary bypass with antegrade cerebral perfusion was required in 2 cases. All patients were alive at the end of the follow-up (median 18 months; from 3 to 180 months) including 1 patient with cortical blindness. PMID- 29514279 TI - An inventory of supranational antimicrobial resistance surveillance networks involving low- and middle-income countries since 2000. AB - Low- and middle-income countries (LMICs) shoulder the bulk of the global burden of infectious diseases and drug resistance. We searched for supranational networks performing antimicrobial resistance (AMR) surveillance in LMICs and assessed their organization, methodology, impacts and challenges. Since 2000, 72 supranational networks for AMR surveillance in bacteria, fungi, HIV, TB and malaria have been created that have involved LMICs, of which 34 are ongoing. The median (range) duration of the networks was 6 years (1-70) and the number of LMICs included was 8 (1-67). Networks were categorized as WHO/governmental (n = 26), academic (n = 24) or pharma initiated (n = 22). Funding sources varied, with 30 networks receiving public or WHO funding, 25 corporate, 13 trust or foundation, and 4 funded from more than one source. The leading global programmes for drug resistance surveillance in TB, malaria and HIV gather data in LMICs through periodic active surveillance efforts or combined active and passive approaches. The biggest challenges faced by these networks has been achieving high coverage across LMICs and complying with the recommended frequency of reporting. Obtaining high quality, representative surveillance data in LMICs is challenging. Antibiotic resistance surveillance requires a level of laboratory infrastructure and training that is not widely available in LMICs. The nascent Global Antimicrobial Resistance Surveillance System (GLASS) aims to build up passive surveillance in all member states. Past experience suggests complementary active approaches may be needed in many LMICs if representative, clinically relevant, meaningful data are to be obtained. Maintaining an up-to-date registry of networks would promote a more coordinated approach to surveillance. PMID- 29514280 TI - Secondary BH4 deficiency links protein homeostasis to regulation of phenylalanine metabolism. AB - Metabolic control of phenylalanine concentrations in body fluids is essential for cognitive development and executive function. The hepatic phenylalanine hydroxylating system is regulated by the ratio of l-phenylalanine, which is substrate of phenylalanine hydroxylase (PAH), to the PAH cofactor tetrahydrobiopterin (BH4). Physiologically, phenylalanine availability is governed by nutrient intake, whereas liver BH4 is kept at constant level. In phenylketonuria, PAH deficiency leads to elevated blood phenylalanine and is often caused by PAH protein misfolding with loss of function. Here, we report secondary hepatic BH4 deficiency in Pah-deficient mice. Alterations in de novo synthesis and turnover of BH4 were ruled out as molecular causes. We demonstrate that kinetically instable and aggregation-prone variant Pah proteins trap BH4, shifting the pool of free BH4 towards bound BH4. Interference of PAH protein misfolding with metabolite-based control of l-phenylalanine turnover suggests a mechanistic link between perturbation of protein homeostasis and disturbed regulation of metabolic pathways. PMID- 29514281 TI - Willingness to care for blood-borne virus-infected patients in Thailand. AB - Background: Although stigma and discrimination by nurses against patients infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) have been reported, potential determinants of nurses' willingness to care for these patients have not been well studied in Thailand. Aims: To identify factors associated with Thai nurses' willingness to care for patients infected with HIV or HCV. Methods: Multivariable logistic regression analysis of data from a questionnaire completed by nurses at a large hospital in Bangkok, Thailand. Results: Of 626 nurses, 546 (87%) nurses participated. Eleven per cent (59) and 6% (34) had previously experienced HIV- or HCV-infected blood contamination incidents, respectively. Forty-four per cent (240) and 38% (208) reported unwillingness to care for HIV- or HCV-infected patients, respectively. Willingness to care was less common [adjusted odds ratios 0.51 (0.34-0.74) for HIV and 0.62 (0.42-0.89) for HCV] in nurses aged >= 40 years and in those who feared HCV [0.63 (0.37-0.99)], but not HIV [0.84 (0.5-1.26)] transmission. Nurses who had confidence in protecting themselves against infection with HIV [1.84 (1.52-2.04)] and HCV [1.87 (1.45-2.18)], and accepting attitudes towards HIV infected co-workers [1.39 (1.08-1.66)] but not HCV-infected co-workers [1.16 (0.83-1.5)], were more willing to care for HIV- and HCV-infected patients. Conclusions: Around 4 in 10 Thai nurses in our sample were unwilling to care for HIV- or HCV-infected patients. Minimizing the risk of nosocomial transmission and improving the public perception of infected individuals may help improve nurses' willingness to care for such patients, in Thailand or elsewhere. PMID- 29514283 TI - District team problem solving as an approach to district health programme planning: a review, and survey of its status in selected districts in Indonesia. AB - District team problem solving (DTPS) was developed by WHO in the 1980s to explicitly engage local stakeholders in decentralized planning and, in later iterations, budgeting of health services. It became WHO's global flagship approach to district-level health priority-setting and planning. DTPS entails multisectoral stakeholders (the team) using local data to prioritize and fund services, and should enhance capacity in management of decentralized healthcare. From the late 1990s, DTPS evolved through several phases in Indonesia. Multiple donors supported its use for planning maternal and child health (MCH) services, with substantive national government input, despite no formal assessment of its sustained uptake or benefits. In the context of new interest to promote DTPS for MCH in Indonesia, we assessed its status there in 2013-14, focussing on its implementation status and on associated MCH data collection (PWS-KIA). We used mixed methods to capture local challenges to and opportunities for DTPS in seven sub-national locations in 6 of Indonesia's 31 provinces. DTPS remained active only in the two locations whose local government ever allocated funds to the process; in the others, it stopped once the initial non-government funding ceased. An official decree establishing DTPS and team membership was only issued in four locations, and it was not evident that the intended multisectoral representation was achieved in any site. Trained DTPS facilitators remained available in only four locations. In all districts, interviewees described PWS KIA as potentially serving a revived DTPS, but insufficiently robust to underwrite local advocacy for investment in MCH. Although efforts to introduce DTPS as a uniform approach to district MCH planning in Indonesia have not been sustained, strong commitment to evidence-based planning remains. Decentralized health planning processes require quality data, local government buy-in and associated funding, and should link explicitly to broader administrative planning processes and budget cycles. PMID- 29514284 TI - Microsurgical Clipping of an Ophthalmic Artery Aneurysm With a Limited Intradural Anterior Clinoidectomy: 3-Dimensional Operative Video. PMID- 29514282 TI - A Critical Role of Mitochondria in BDNF-Associated Synaptic Plasticity After One Week Vortioxetine Treatment. AB - Background: Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain derived neurotrophic factor signaling. Methods: Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Results: Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Conclusion: Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine's modulation of serotonin receptors. PMID- 29514285 TI - Pediatric Pontine Cavernous Malformations: The Presigmoid, Posterior Petrosal Approach. AB - BACKGROUND: Brainstem cavernous malformations (cavernomas) in children have a high risk of hemorrhage and neurological deterioration. This risk is magnified if the child has a genetic predisposition for cavernoma formation. The surgical management is challenging and carries a significant risk of morbidity. OBJECTIVE: To describe the feasibility of a posterior petrosal approach to brainstem cavernomas in a pediatric population. METHODS: A single institution operative experience with this technique was reviewed; 2 cases were identified and are technically described here with supportive figures and illustrations, as well as a focused literature review. RESULTS: Two pediatric cases with multiple symptomatic hemorrhages from large expanding pontine cavernomas were identified. Both cavernomas were resected through a presigmoid posterior petrosal approach. While this approach is well described in the adult literature for ventral brainstem lesions, its description for the treatment of pontine cavernomas in the pediatric populations is scarce. CONCLUSION: This study demonstrates the utility and feasibility of the posterior petrosal approach in two pediatric patients at different points in cranial base development. PMID- 29514286 TI - Gene expression and activity of methionine converting enzymes in broiler chickens fed methionine isomers or precursors. AB - Common dietary supplemental methionine (Met) sources include DL-methionine (DL Met) and the Met precursor DL-2-hydroxy-4-(methylthio) butanoic acid (DL-HMTBA). For bio-utilization, D-Met and DL-HMTBA are converted into L-Met through oxidation and transamination. The objective of this study was to determine the effect of different dietary supplemental Met sources on gene expression and enzyme activity of Met oxidases in male broiler chickens. Liver, muscle, duodenum, jejunum, and ileum were collected at days 10 (d 10), 21 (d 21), and 26 (d 26) post-hatch from male broiler chickens that were fed a basal diet deficient in sulfur amino acids (SAA) (control), or the control diet supplemented with DL Met, L-Met, or DL-HMTBA to meet SAA requirements. The mRNA abundance of D-Met oxidase, L-HMTBA oxidase, and D-HMTBA oxidase was measured by real-time PCR, and oxidase activities were measured using colorimetric assays (n = 5). Liver expressed more D- and L-HMTBA oxidase mRNA, while breast muscle and liver expressed more D-Met oxidase mRNA than other tissues. In the liver, DL-HMTBA and L-Met supplementation were associated with greater mRNA abundance of L-HMTBA oxidase compared to the control diet-fed group at d 10 but not d 21 or d 26. DL HMTBA supplementation, however, was not associated with changes in the mRNA abundance of D-HMTBA oxidase. The Met-deficient diet at d 26 was associated with greater hepatic abundance of DAO mRNA, which is responsible for oxidation of amino acids. Oxidase activities were similar among the Met deficient and Met supplemented groups. In conclusion, dietary Met supplementation influenced the transcriptional regulation and activity of Met oxidases in a tissue and age specific manner. Met oxidases may thus act as a determining factor in the bioefficacy of different dietary supplemental Met sources. PMID- 29514287 TI - Mannose-binding lectin genotypes and outcome in end-stage renal disease: a prospective cohort study. AB - Background: Patients with end-stage renal disease (ESRD) have high morbidity and mortality rates, with cardiovascular diseases and infections being the major causes of death. Mannose-binding lectin (MBL) has been suggested to play a protective role in this regard. The aim of this study was to investigate a possible clinical association of MBL genotypes (MBL2) with outcome among patients on dialysis or with a functioning graft. Methods: A total of 98 patients with ESRD accepted for living-donor renal transplantation or on the waiting list for transplantation were included and prospectively followed for an average of 9 years (range 7.5-9.9). Medical records were evaluated regarding transplantation status, diabetes mellitus, vascular parameters and infections for all the patients. Cox regression models and logistic regression analysis were used for statistical analyses. The cohort was divided into two groups according to the MBL2 genotype (normal A/A versus variant A/O or O/O). Results: We found no evidence for an association between the MBL2 genotype and all-cause mortality, cardiovascular events or bacterial infections (pneumonia, urinary tract infection, fistula infection or other infections). Conclusion: In this cohort, the MBL2 genotype did not seem to be associated with any long-term clinical effects in ESRD patients on dialysis or with a functioning graft. PMID- 29514288 TI - Application of the red fluorescent protein mCherry in mycelial labeling and organelle tracing in the dermatophyte Trichophyton mentagrophytes. AB - Trichophyton mentagrophytes is a fungus that causes skin disease in humans and other animals worldwide. Studies on molecular biology and fluorescent labeling of the fungus are limited. Here, we applied mCherry for the first time in T. mentagrophytes to label the fungus and its organelles. We constructed four expression vectors of mCherry or mCherry fusions containing a variety of resistance markers and promoters, which were then integrated, together with two previous mCherry expression vectors, in T. mentagrophytes via Agrobacterium tumefaciens-mediated transformation (AtMT). The resulting transformants emitted bright red fluorescence. We used the histone protein H2B and the peroxisome targeting signal 1 (PTS1) peptide to target the nucleus and peroxisomes, respectively, in T. mentagrophytes. In the transformants expressing mCherry-fused H2B, the fluorescence was distinctly localized to the nuclei in hyphae, spores and the fungal cells in infected animal tissue. In the T. mentagrophytes transformants where the peroxisome was targeted, the mCherry was present as small dots (0.2-1 MUm diameter) throughout the spores and the hyphae. We also constructed a T. mentagrophytes AtMT library containing more than 1000 hygromycin resistant transformants that were genetically stable. Our results provide useful tools for further investigations on molecular pathogenesis of T. mentagrophytes. PMID- 29514289 TI - Spotlight on... Kathleen Scott. PMID- 29514290 TI - The FBH family of bHLH transcription factors controls ACC synthase expression in sugarcane. AB - Ethylene is a phytohormone involved in the regulation of several aspects of plant development and in responses to biotic and abiotic stress. The effects of exogenous application of ethylene to sugarcane plants are well characterized as growth inhibition of immature internodes and stimulation of sucrose accumulation. However, the molecular network underlying the control of ethylene biosynthesis in sugarcane remains largely unknown. The chemical reaction catalyzed by 1 aminocyclopropane-1-carboxylic acid synthase (ACS) is an important rate-limiting step that regulates ethylene production in plants. In this work, using a yeast one-hybrid approach, we identified three basic helix-loop-helix (bHLH) transcription factors, homologs of Arabidopsis FBH (FLOWERING BHLH), that bind to the promoter of ScACS2 (Sugarcane ACS2), a sugarcane type 3 ACS isozyme gene. Protein-protein interaction assays showed that sugarcane FBH1 (ScFBH1), ScFBH2, and ScFBH3 form homo- and heterodimers in the nucleus. Gene expression analysis revealed that ScFBHs and ScACS2 transcripts are more abundant in maturing internodes during afternoon and night. In addition, Arabidopsis functional analysis demonstrated that FBH controls ethylene production by regulating transcript levels of ACS7, a homolog of ScACS2. These results indicate that ScFBHs transcriptionally regulate ethylene biosynthesis in maturing internodes of sugarcane. PMID- 29514291 TI - Evaluation of different Campylobacter jejuni isolates to colonize the intestinal tract of commercial turkey poults and selective media for enumeration. AB - Consumption of contaminated poultry products is the main source of human campylobacteriosis, for which Campylobacter jejuni is responsible for 90% of human cases. Although chickens are believed to be a main source of human exposure to C. jejuni, turkeys also contribute to cases of human infection. Little is known about the kinetics of C. jejuni intestinal colonization in turkeys, or best selective media for their recovery. Enumeration of C. jejuni from intestinal samples can be challenging because most selective Campylobacter media support the growth of non-Campylobacter organisms. In this study, we sought to compare a) C. jejuni isolates that persistently colonize different compartments of the poult intestinal tract, and b) selective media to enumerate C. jejuni from turkey intestinal samples. Three-week-old poults were orally colonized with C. jejuni isolates NCTC 11168 or NADC 20827 (isolated from a turkey flock). Mock-colonized poults were orally gavaged with uninoculated media. Poults were euthanized at d 3, 7, and 21 post colonization and direct plated on different selective Campylobacter media [Campy Line agar with sulfamethoxazole (CLA-S), CHROMagar Campylobacter (CAC) and Campy Cefex] for enumeration. Isolates NCTC 11168 and NADC 20827 poorly colonized the distal ileum. Both isolates colonized the colon, but the number of NADC 20827 significantly decreased at d 21. Isolates NCTC 11168 and NADC 20827 persistently colonized the cecum for up to 21 days. There was no significant difference in the Campylobacter amount recovered on CLA-S and CAC. Campy Cefex failed to prevent growth of background microbes to enumerate C. jejuni from turkey samples. Two independent PCR assays (multiplex PCR and qPCR) confirmed that colonies grown on CLA-S or CAC were C. jejuni. Data from this study demonstrated that isolates NCTC 11168 and NADC 20827 persistently colonized the cecum, and CLA-S or CAC were successful to enumerate Campylobacter from intestinal samples. These findings will be useful to evaluate the host response by C. jejuni in turkeys, and test pre-harvest strategies to reduce its colonization and promote food safety. PMID- 29514292 TI - Phytochrome B regulates resource allocation in Brassica rapa. AB - Crop biomass and yield are tightly linked to how the light signaling network translates information about the environment into allocation of resources, including photosynthates. Once activated, the phytochrome (phy) class of photoreceptors signal and re-deploy carbon resources to alter growth, plant architecture, and reproductive timing. Most of the previous characterization of the light-modulated growth program has been performed in the reference plant Arabidopsis thaliana. Here, we use Brassica rapa as a crop model to test for conservation of the phytochrome-carbon network. In response to elevated levels of CO2, B. rapa seedlings showed increases in hypocotyl length, shoot and root fresh weight, and the number of lateral roots. All of these responses were dependent on nitrogen and polar auxin transport. In addition, we identified putative B. rapa orthologs of PhyB and isolated two nonsense alleles. BrphyB mutants had significantly decreased or absent CO2-stimulated growth responses. Mutant seedlings also showed misregulation of auxin-dependent genes and genes involved in chloroplast development. Adult mutant plants had reduced chlorophyll levels, photosynthetic rate, stomatal index, and seed yield. These findings support a recently proposed holistic role for phytochromes in regulating resource allocation, biomass production, and metabolic state in the developing plant. PMID- 29514294 TI - Microsurgical Clipping of Partially Thrombosed Wide-Necked Saccular Aneurysm From a Dysplastic M1 Segment in a Pediatric Patient: 3-Dimensional Operative Video. PMID- 29514293 TI - Effects of dietary protein sources and nisin on rumen fermentation, nutrient digestion, plasma metabolites, nitrogen utilization, and growth performance in growing lambs. AB - This study investigated the effects of dietary protein sources and nisin on rumen fermentation, nutrient digestion, plasma metabolites, N utilization, and growth performance in growing lambs. Thirty-two male Hu lambs (23 +/- 2 kg initial BW) were assigned to four dietary treatments in a randomized block design with a 2 * 2 factorial arrangement. Two protein sources, soybean meal (SBM) and dried distillers grains with solubles (DDGS), and two levels of nisin, 0 and 30.5 mg of nisin/kg of feed, were used to formulate four isonitrogenous and isoenergetic diets. No interaction (P >= 0.16) of protein * nisin was found except on apparent digestibility of DM, OM, NDF, and ADF (P <= 0.02). Lambs receiving DDGS had lower (P <= 0.04) concentrations of ruminal acetate and butyrate, but propionate concentrations did not differ (P = 0.39), compared with those fed SBM, leading to a trend for reduced total VFA concentration (P = 0.07). Ruminal NH3-N and total branched-chain VFA concentrations were lower (P <= 0.01) in the lambs fed DDGS than in those fed SBM. The DDGS-fed lambs had less (P < 0.01) CP, but greater (P < 0.01) ether extract apparent digestibility than those fed SBM. For plasma metabolites, only blood urea N and albumin concentrations were lower in the DDGS fed lambs (P < 0.01) than in those fed SBM. Nitrogen excretion pathway was altered when DDGS replaced SBM, with fecal N excretion (% of N intake) being greater (P < 0.01), while urinary N excretion (% of N intake) tending to be less (P = 0.06) from the DDGS-fed lambs than those fed SBM. Protein sources affected growth performance in an age/time-dependent manner. From weeks 1 to 4, DDGS resulted in less (P = 0.03) DMI and ADG than SBM. From weeks 5 to 8, DDGS did not affect (P >= 0.23) DMI or ADG but resulted in a greater (P = 0.04) G:F than SBM. Final BW did not differ (P = 0.58) duo to protein source. Providing nisin had no impact on DMI (P = 0.44), ADG (P = 0.84), or G:F (P = 0.73). Nisin addition only affected plasma uric acid concentration (P = 0.04). It was concluded that DDGS could substitute for SBM as a nitrogen source to growing Hu lambs to reduce N excretion via urine without adverse effects on animal performance, but nisin supplementation probably had no additional benefits. PMID- 29514295 TI - Effects of adding methionine in low-protein diet and subsequently fed low-energy diet on productive performance, blood chemical profile, and lipid metabolism related gene expression of broiler chickens. AB - This study was conducted to evaluate the effects of supplementing methionine (Met) in a low-protein (Low-CP) diet during d 11 to 24 and subsequently feeding with a low-metabolizable energy diet (Low-ME; -75 kcal/kg) or a normal ME diet during d 25 to 42 on the productive performance, blood chemical profile, and lipid metabolism-related gene expression of broiler chickens. The 1,600 broiler chicks were divided into 5 groups as follows: 1) Normal CP, then Normal ME; 2) Low-CP, then Normal ME; 3) Low-CP, then Low-ME; 4) Low-CP+Met, then Normal ME; and 5) Low-CP+Met, then Low-ME. During d 11 to 24, the growth performance of the control group was better than those of the other groups (P < 0.01). In Low-CP diets, the addition of Met resulted in an improvement in the growth performance, breast meat yield, protein conversion ratio, plasma total protein, and albumin (P < 0.01). Moreover, the supplementation significantly increased the plasma triglyceride content (P < 0.01). Feeding Low-CP or Low-CP+Met diets increased the abdominal fat content compared to the control group (P < 0.01). Feeding the Low CP+Met, then Normal ME (d 25 to 42) resulted in compensation in the feed conversion ratio (FCR), protein conversion ratio, and energy conversion ratio equal to or better than the control group (P < 0.01). The body weights of birds fed Low-CP diets were still inferior to the control group (P < 0.01), except in the Low-CP+Met group followed by the normal ME diet. Feeding with the Low-ME diet tended to decrease the expression of the carnitine palmitoyl transferase I gene in the liver (P = 0.08). In conclusion, supplementing Met in the Low-CP diet during the grower period and subsequently feeding with a control diet improved the feed and protein conversion ratios, reduced fat accumulation, and reduced the production cost of broiler chickens with regard to fat deposition compared to the control diet. PMID- 29514296 TI - The effect of drying method temperature, collection method, and marker type on apparent ileal amino acid digestibility in 21-day-old broilers fed corn-soybean meal-barley based diet. AB - For accurate estimation of nutrient digestibility, an ideal drying and sampling method is required to preserve the quality of the digesta. A standard corn soybean meal (corn-SBM) broiler starter diet was fed from d 0 to 10 before birds were placed on the experimental diets until d 21. One hundred and sixty-eight male Cobb 500 broiler chicks were used to evaluate the effect of two drying methods (freeze-dryer vs. forced air-oven) and two drying temperatures (40 vs. 55 degrees C) (Exp 1), while ninety-six chicks were used to evaluate the effect of flushing and squeezing as well as marker types (titanium vs. chromium) on apparent ileal DM, N, Ca, P, and AA digestibility (Exp 2). There were seven (Exp 1) or eight (Exp 2) replicate cages per treatment with 6 birds/cage. Digesta from the distal two thirds of the ileum was obtained from birds following euthanasia on d 21 by squeezing (Exp 1) and squeezing or flushing (Exp 2). Samples collected were stored in the freezer at -20 degrees C until they were either freeze-dried (FD) or oven-dried (OD) at 40 or 55 degrees C. There were no interactions between the drying methods and drying temperatures (Exp 1) on apparent ileal DM, N, and AA digestibility. Met had the highest (92.3%) while Cys had the lowest (73.8%) digestibility value. In Exp 2, no interaction between sampling methods and marker types was observed. The effect of sampling methods was not significant except for Arg and Met where squeezing resulted in higher (P < 0.05) digestibility values. Furthermore, apparent ileal His, Ile, Cys, Ser, and Tyr digestibility tended to be higher (P < 0.1) in squeezed digesta compared to the flushed digesta. Results from these studies showed that OD ileal digesta at 40 or 55 degrees C had no negative effect on apparent ileal AA digestibility. Likewise, marker type did not influence apparent ileal AA digestibility values. PMID- 29514297 TI - Endoscopic Resection of a Paraclinoid Meningioma Extending Into the Optic Canal: 2-Dimensional Operative Video. PMID- 29514298 TI - Accelerating genetic gains in legumes for the development of prosperous smallholder agriculture: integrating genomics, phenotyping, systems modelling and agronomy. AB - Grain legumes form an important component of the human diet, provide feed for livestock, and replenish soil fertility through biological nitrogen fixation. Globally, the demand for food legumes is increasing as they complement cereals in protein requirements and possess a high percentage of digestible protein. Climate change has enhanced the frequency and intensity of drought stress, posing serious production constraints, especially in rainfed regions where most legumes are produced. Genetic improvement of legumes, like other crops, is mostly based on pedigree and performance-based selection over the past half century. To achieve faster genetic gains in legumes in rainfed conditions, this review proposes the integration of modern genomics approaches, high throughput phenomics, and simulation modelling in support of crop improvement that leads to improved varieties that perform with appropriate agronomy. Selection intensity, generation interval, and improved operational efficiencies in breeding are expected to further enhance the genetic gain in experimental plots. Improved seed access to farmers, combined with appropriate agronomic packages in farmers' fields, will deliver higher genetic gains. Enhanced genetic gains, including not only productivity but also nutritional and market traits, will increase the profitability of farming and the availability of affordable nutritious food especially in developing countries. PMID- 29514299 TI - Global challenges in kidney diseases. PMID- 29514300 TI - Comparative Oviposition Site Selection in Containers by Aedes aegypti and Aedes albopictus (Diptera: Culicidae) from Florida. AB - Invasive container mosquito species Aedes aegypti (L.) and Ae. albopictus (Skuse) frequently co-occur in nature where they are typically segregated spatially by distinctive macrohabitat preferences that may select for different oviposition strategies. In a standard cage environment, we compared oviposition site selection by individual gravid females of these species exposed to variable numbers of water-holding cups and the presence or absence of a rugose wettable container lining. Offered plastic cups with and without lining, both species laid a significantly higher percentage of eggs in cups with lining (95.3% for Ae. aegypti, 88.4% for Ae. albopictus), than in cups without (4.7% for Ae. aegypti, 11.6% for Ae. albopictus). Linear regressions of container availability versus the number of lined cups colonized were similar for Ae. aegypti and Ae. albopictus. Rates of oviposition on the water surface differed by species for both cup types, with Ae. albopictus laying a higher percentage of eggs on the water surface in cups without lining (28.1% for Ae. aegypti, 51.3% for Ae. albopictus), than in cups with (5.3% for Ae. aegypti, 2.5% for Ae. albopictus). The more varied oviposition strategies of Ae. albopictus are interpreted in the context of its broader macrohabitat use and inferior egg desiccation resistance. PMID- 29514302 TI - Ultra-rapid auxin metabolite profiling for high-throughput mutant screening in Arabidopsis. AB - Auxin (indole-3-acetic acid, IAA) plays fundamental roles as a signalling molecule during numerous plant growth and development processes. The formation of local auxin gradients and auxin maxima/minima, which is very important for these processes, is regulated by auxin metabolism (biosynthesis, degradation, and conjugation) as well as transport. When studying auxin metabolism pathways it is crucial to combine data obtained from genetic investigations with the identification and quantification of individual metabolites. Thus, to facilitate efforts to elucidate auxin metabolism and its roles in plants, we have developed a high-throughput method for simultaneously quantifying IAA and its key metabolites in minute samples (<10 mg FW) of Arabidopsis thaliana tissues by in tip micro solid-phase extraction and fast LC-tandem MS. As a proof of concept, we applied the method to a collection of Arabidopsis mutant lines and identified lines with altered IAA metabolite profiles using multivariate data analysis. Finally, we explored the correlation between IAA metabolite profiles and IAA related phenotypes. The developed rapid analysis of large numbers of samples (>100 samples d-1) is a valuable tool to screen for novel regulators of auxin metabolism and homeostasis among large collections of genotypes. PMID- 29514301 TI - Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients. AB - Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001). Conclusions: Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes. PMID- 29514304 TI - Brain Connectivity and Cognitive Flexibility in Nonirradiated Adult Survivors of Childhood Leukemia. AB - Background: This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Methods: Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1 weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearman's rank and Pearson's correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Results: Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Conclusions: Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility. PMID- 29514303 TI - Altered brain perfusion patterns in wakefulness and slow-wave sleep in sleepwalkers. AB - Study Objectives: The present study assessed brain perfusion patterns with single photon emission computed tomography (SPECT) during sleepwalkers' post-sleep deprivation slow-wave sleep (SWS) and resting-state wakefulness. Methods: Following a 24 hr period of sleep deprivation, 10 sleepwalkers and 10 sex- and age-matched controls were scanned with a high-resolution SPECT scanner. Participants were injected with 99mTc-ethylene cysteinate dimer after 2 min of stable SWS within their first sleep cycle as well as during resting-state wakefulness, both after a subsequent 24 hr period of sleep deprivation. Results: When compared with controls' brain perfusion patterns during both SWS and resting state wakefulness, sleepwalkers showed reduced regional cerebral perfusion in several bilateral frontal regions, including the superior frontal, middle frontal, and medial frontal gyri. Moreover, reduced regional cerebral perfusion was also found in sleepwalkers' left postcentral gyrus, insula, and superior temporal gyrus during SWS compared with controls. During resting-state wakefulness compared with controls, reduced cerebral perfusion was also found in parietal and temporal regions of sleepwalkers' left hemisphere, whereas the right parahippocampal gyrus showed increased regional cerebral perfusion. Conclusions: Our results reveal patterns of reduced regional cerebral perfusion in sleepwalkers' frontal and parietal areas when compared with controls, regions previously associated with SWS generation and episode occurrence. Additionally, reduced perfusion in the dorsolateral prefrontal cortex and insula during recovery SWS is consistent with the clinical features of somnambulistic episodes, including impaired awareness and reduced pain perception. Altered regional cerebral perfusion patterns during sleepwalkers' resting-state wakefulness may be related to daytime functional anomalies in this population. PMID- 29514305 TI - Was Luigi Cornaro a Dietary Expert? AB - Luigi Cornaro (d. 1566) was a Venetian nobleman whose book De Vita Sobria (On the Temperate Life) was an instant success and has proved to be one of the most long lasting and influential works of practical medical advice, counseling readers how to live long and healthily. Yet Cornaro was not a physician and his account raises a series of questions about the nature and location of medical expertise. Who can have that expertise? Can you, and should you, be your own physician, and, if so, on what grounds? I situate Cornaro's claims to expertise within a historically specific culture of medical dietetics in which personal experience counted for much. How did certain dietary practices "agree with" individuals? How did personal experience figure in constituting expertise? Was a healthy regime compatible with ordinary civic life and, if not, did it matter? What was the role of precise quantitative measure in prescribing the regime making for health and longevity? I address these questions with respect to Cornaro's historical setting and also in relation to pervasive commentary on his text over the centuries that followed. PMID- 29514306 TI - Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study. AB - Background: The low efficacy of rotavirus vaccines in clinical trials performed in low-resource settings may be partially explained by acquired immunity from natural exposure, especially in settings with high disease incidence. Methods: In a clinical trial of monovalent rotavirus vaccine in Bangladesh, we compared the original per-protocol efficacy estimate to efficacy derived from a recurrent events survival model in which children were considered naturally exposed and potentially immune after their first rotavirus diarrhea (RVD) episode. We then simulated trial cohorts to estimate the expected impact of prior exposure on efficacy estimates for varying rotavirus incidence rates and vaccine efficacies. Results: Accounting for natural immunity increased the per-protocol vaccine efficacy estimate against severe RVD from 63.1% (95% confidence interval [CI], 33.0%-79.7%) to 70.2% (95% CI, 44.5%-84.0%) in the postvaccination period, and original year 2 efficacy was underestimated by 14%. The simulations demonstrated that this expected impact increases linearly with RVD incidence, will be greatest for vaccine efficacies near 50%, and can reach 20% in settings with high incidence and low efficacy. Conclusions: High rotavirus incidence leads to predictably lower vaccine efficacy estimates due to the acquisition of natural immunity in unvaccinated children, and this phenomenon should be considered when comparing efficacy estimates across settings. Clinical Trials Registration: NCT01375647. PMID- 29514307 TI - Inferring Phylogenetic Networks Using PhyloNet. AB - PhyloNet was released in 2008 as a software package for representing and analyzing phylogenetic networks. At the time of its release, the main functionalities in PhyloNet consisted of measures for comparing network topologies and a single heuristic for reconciling gene trees with a species tree. Since then, PhyloNet has grown significantly. The software package now includes a wide array of methods for inferring phylogenetic networks from data sets of unlinked loci while accounting for both reticulation (e.g., hybridization) and incomplete lineage sorting. In particular, PhyloNet now allows for maximum parsimony, maximum likelihood, and Bayesian inference of phylogenetic networks from gene tree estimates. Furthermore, Bayesian inference directly from sequence data (sequence alignments or biallelic markers) is implemented. Maximum parsimony is based on an extension of the "minimizing deep coalescences" criterion to phylogenetic networks, whereas maximum likelihood and Bayesian inference are based on the multispecies network coalescent. All methods allow for multiple individuals per species. As computing the likelihood of a phylogenetic network is computationally hard, PhyloNet allows for evaluation and inference of networks using a pseudolikelihood measure. PhyloNet summarizes the results of the various analyzes and generates phylogenetic networks in the extended Newick format that is readily viewable by existing visualization software. PMID- 29514308 TI - Genetic Diversity of Cryptosporidium hominis in a Bangladeshi Community as Revealed by Whole-Genome Sequencing. AB - We studied the genetic diversity of Cryptosporidium hominis infections in slum dwelling infants from Dhaka over a 2-year period. Cryptosporidium hominis infections were common during the monsoon, and were genetically diverse as measured by gp60 genotyping and whole-genome resequencing. Recombination in the parasite was evidenced by the decay of linkage disequilibrium in the genome over <300 bp. Regions of the genome with high levels of polymorphism were also identified. Yet to be determined is if genomic diversity is responsible in part for the high rate of reinfection, seasonality, and varied clinical presentations of cryptosporidiosis in this population. PMID- 29514309 TI - Influence of ultrasound probe treatment time and protease type on functional and physicochemical characteristics of egg white protein hydrolysates. AB - The objective of this study was to discover the relationship between the ultrasound probe treatment (UPT) on egg white proteins (EWPs) before EWPs hydrolysis by different proteases, and the functional properties of the obtained hydrolysates. To fulfill this goal, the protein solubility, foaming, and emulsifying properties were studied as a function of the UPT time and then related to the surface characteristics and structural properties. The changes in the hydrolysates microstructures and macromolecular conformation, induced by the UPT, were followed using scanning electron microscope analyzis (SEM) and Fourier transforms infrared spectroscopy (FTIR). The results showed that UPT influenced (P < 0.05) the proteolysis of egg white proteins for all examined treatment times. Alcalase hydrolysates (AHs) and papain hydrolysates (PHs) were found to have a higher solubility, as a consequence of their relatively higher foaming, and emulsifying properties compared to the untreated hydrolysates. The changes in surface hydrophobicity, sulfhydryl content and surface charge of AHs and PHs indicated unfolding of EWPs affected by ultrasound. SEM analyzis showed that UPT destroyed the microstructures of AHs and PHs, while FTIR spectra indicated remarkable changes in the macromolecular conformation of AHs and PHs after UPT. This study revealed that by combining ultrasound pre-hydrolysis treatment under controlled conditions with thoughtful proteases selection, hydrolysates with improved functional properties could be produced, enhancing utilization of EWPs in food products. PMID- 29514311 TI - Anterior Clinoidectomy and Microsurgical Clipping of a Giant Thrombotic Recurrent Ophthalmic Artery Aneurysm Previously Wrapped and Stent Coiled: 2-Dimensional Operative Video. PMID- 29514310 TI - ASAS-SSR Triennial Reproduction Symposium: The use of natural cycle's follicular dynamic to improve oocyte quality in dairy cows and heifers. AB - The selection of the best dairy heifers is mainly driven by the genetic value of their parents. The phenotype analysis of cows and of the daughters of bulls has been used to identify the best genetic value for decades before being replaced by genomic selection of individuals that are not yet parents. Because it is possible to predict the future value of an individual by its genetic makeup, it becomes feasible to do it as early as the blastocyst stage and to decide which should be transferred or not. Because we know the genotype of an animal at birth, or even before, it is becoming desirable to reproduce this animal as soon as possible to reduce generation interval and improve selection speed. Nature provides constraints that can be overcome: a single oocyte per cycle and age at puberty. Indeed, it is now possible to super-stimulate the ovary at any age and to start collecting oocytes at 6 mo by trans-vaginal ultrasonography. The challenge becomes the production of good eggs and embryos capable of implanting and developing into healthy calves. Our understanding of ovarian follicular physiology has been instrumental in designing stimulation protocols that may be adjusted to any physiological context including age, and even the individual animal, to obtain a good response. Therefore, the combination of procedures developed in cows to optimize oocyte quality, for example, FSH coasting, in association with in vitro fertilization and optimal culture conditions can now result in the production of several female embryos twice a month from animals 6 to12 mo of age. The transcriptomic and epigenetic analyses of embryos produced from the same females at different ages were compared and few differences were noted in particular in relation to embryo metabolism. These embryos are as good as the ones obtained from adult animals and can be produced with sexed sperm of bulls 12 mo of age. This combination of these technical optimizations with blastocyst genotyping allows the selection of a second generation within a year. PMID- 29514312 TI - Microsurgical Management of a Previously Coiled Giant Middle Cerebral Artery Aneurysm: 3-Dimensional Operative Video. PMID- 29514314 TI - How does sleep affect the perception of facial emotion? PMID- 29514313 TI - Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution. AB - To expand our capacity to discover venom sequences from the genomes of venomous organisms, we applied targeted sequencing techniques to selectively recover venom gene superfamilies and nontoxin loci from the genomes of 32 cone snail species (family, Conidae), a diverse group of marine gastropods that capture their prey using a cocktail of neurotoxic peptides (conotoxins). We were able to successfully recover conotoxin gene superfamilies across all species with high confidence (> 100* coverage) and used these data to provide new insights into conotoxin evolution. First, we found that conotoxin gene superfamilies are composed of one to six exons and are typically short in length (mean = ~85 bp). Second, we expanded our understanding of the following genetic features of conotoxin evolution: 1) positive selection, where exons coding the mature toxin region were often three times more divergent than their adjacent noncoding regions, 2) expression regulation, with comparisons to transcriptome data showing that cone snails only express a fraction of the genes available in their genome (24-63%), and 3) extensive gene turnover, where Conidae species varied from 120 to 859 conotoxin gene copies. Finally, using comparative phylogenetic methods, we found that while diet specificity did not predict patterns of conotoxin evolution, dietary breadth was positively correlated with total conotoxin gene diversity. Overall, the targeted sequencing technique demonstrated here has the potential to radically increase the pace at which venom gene families are sequenced and studied, reshaping our ability to understand the impact of genetic changes on ecologically relevant phenotypes and subsequent diversification. PMID- 29514315 TI - Chemical Neurolysis of the Genicular Nerves for Chronic Knee Pain: Reviving an Old Dog and an Old Trick. PMID- 29514316 TI - A Conceptual Matrix of the Temporal and Spatial Dimensions of Socioeconomic Status and Their Relationship with Health. PMID- 29514317 TI - Reinforcement Enhancing Effects of Nicotine via Patch and Nasal Spray. AB - Introduction: Confirming preclinical findings, nicotine in humans (via smoking) enhances reinforcement from non-drug rewards. Recent demonstration of similar effects with nicotine via e-cigarettes suggests they may also occur when using nicotine replacement therapies (NRT). Methods: Effects of nicotine via NRT patch or nasal spray were assessed on responding reinforced by music, video, or monetary rewards, or for no reward (control). Non-treatment seeking smokers (N=31) participated in three virtually identical experimental sessions, each following overnight abstinence (CO<=10 ppm). In a fully within-subjects design using a double-dummy procedure, these sessions involved: 1) nicotine patch (Nicoderm 14 mg) plus placebo spray, 2) placebo patch plus nicotine spray (Nicotrol, 2 x 1 mg /trial), or 3) placebo patch plus placebo spray. Session order was counter-balanced. Results: Relative to placebo, reinforced responding due to nicotine via spray or patch was greater for video reward (both p<.01) but not for music reward (both p>.10). Similar results for NRT spray and patch confirms preclinical findings indicating no difference between fast and slow nicotine delivery, respectively, on reinforcement enhancing effects. Withdrawal relief was unrelated to these effects of nicotine via NRT on non-drug reinforcement. Conclusions: Nicotine from NRT has some reinforcement enhancing effects in humans, possibly in a manner consistent with nicotine via e-cigarettes but not tobacco smoking. Our findings could suggest differential dose-dependency of available rewards to enhanced reinforcement by nicotine. Such effects may help contribute to the efficacy of NRT for aiding smoking cessation, but more research focusing on dose-dependency of these nicotine actions is needed. Implications: Acute nicotine from smoking enhances reinforced responding for non-drug sensory rewards. Yet, non-smoked nicotine, including from NRT medications of patch and nasal spray, may act more selectively across rewards, perhaps due to lower dosing exposure. Our results suggest that nicotine via NRT enhances responding for visual (video) reward, but not from auditory (music) reward, just as in prior results using e-cigarettes. Withdrawal relief from NRT was unrelated to reinforced responding, consistent with positive (and not negative) reinforcement from this nicotine. Further research evaluating the dose-response effects of nicotine may clarify differences in enhanced reinforcement depending on the type of available reward. PMID- 29514318 TI - Superficial Temporal Artery to Middle Cerebral Artery Bypass in a 1-Year-Old Moyamoya Patient: 2-Dimensional Operative Video. PMID- 29514320 TI - Posterior Inferior Cerebellar Artery Pseudoaneurysm Clip Ligation With Reimplantation Into the Vertebral Artery: 3-Dimensional Operative Video. PMID- 29514319 TI - Cerebral Hyperperfusion Syndrome by the Numbers: Transient Focal Neurological Deficit, Imaging-Proven Focal Hyperperfusion, and High Graft Flow Rate Following Superficial Temporal Artery-Middle Cerebral Artery bypass in a Patient With Symptomatic Carotid Occlusion-Case Report. AB - BACKGROUND AND IMPORTANCE: Cerebral hyperperfusion syndrome (CHS) is a well-known complication of superficial temporal artery (STA) to middle cerebral artery (MCA) bypass for ischemic cerebrovascular disease. While this argues against "low flow" in the bypass construct, flow rates in the graft have not been previously quantified in the setting of CHS. CLINICAL PRESENTATION: A 58-yr-old man presented with recurrent left hemispheric ischemic strokes and fluctuating right hemiparesis and aphasia. Vascular imaging revealed left cervical internal carotid artery occlusion and perfusion imaging confirmed left hemispheric hypoperfusion. After failing to respond to maximal medical therapy, the patient underwent single barrel STA-MCA bypass. Postoperatively, his symptoms resolved and blood pressure (BP) was strictly controlled within normal range. However, 2 d later, he developed severe expressive aphasia. CTA demonstrated a patent bypass graft and SPECT showed focal hyperperfusion in Broca's speech area. Seizure activity was ruled out. A high graft flow rate of 52 mL/min was documented by quantitative magnetic resonance angiography (MRA). Thus, the diagnosis of CHS was made and managed with strict BP control. The patient exhibited complete recovery of speech over a period of days and was discharged home. Repeat SPECT at 4 mo showed resolution of hyperperfusion and quantitative MRA demonstrated reduction of graft flow rate to 34 mL/min. CONCLUSION: This is the first case of perfusion imaging proven CHS after STA-MCA bypass, where high graft flow rates are objectively documented. Our observations constitute irrefutable evidence challenging the classic belief that the STA-MCA bypass is a low-flow construct. PMID- 29514321 TI - Analysis of Surgical Freedom Variation Across the Basilar Artery Bifurcation: Towards a Deeper Insight Into Approach Selection for Basilar Apex Aneurysms. AB - BACKGROUND: The orbitozygomatic approach is generally advocated over the pterional approach for basilar apex aneurysms. However, the impact of the extensions of the pterional approach on the obtained maneuverability over multiple vascular targets (relevant to basilar apex surgery) has not been studied before. OBJECTIVE: To analyze the patterns of surgical freedom change across the basilar bifurcation between the pterional, orbitopterional, and orbitozygomatic approaches. METHODS: Surgical freedom was assessed for 3 vascular targets important in basilar apex aneurysm surgery (ipsilateral and contralateral P1-P2 junctions, and basilar apex), and compared between the pterional, orbitopterional, and orbitozygomatic approaches in 10 cadaveric specimens. RESULTS: Transitioning from the pterional to orbitopterional approach, the surgical freedom increased significantly at all 3 targets (P < .05). However, the gain in surgical freedom declined progressively from the most superficial target (60% for ipsilateral P1-P2 junction) to the deepest target (35% for contralateral P1-P2 junction). Conversely, transitioning from the orbitopterional to the orbitozygomatic approach, the gain in surgical freedom was minimal for the ipsilateral P1-P2 and basilar apex (<4%), but increased dramatically to 19% at the contralateral P1-P2 junction. CONCLUSION: The orbitopterional approach provides a remarkable increase in surgical maneuverability compared to the pterional approach for the basilar apex target and the relevant adjacent arterial targets. However, compared to the orbitopterional, the orbitozygomatic approach adds little maneuverability except for the deepest target (ie, contralateral P1 P2 junction). Therefore, the orbitozygomatic approach may be most efficacious with larger basilar apex aneurysms limiting the control over of the contralateral P1 PCA. PMID- 29514323 TI - Israeli general practitioners' dissatisfaction with their own primary healthcare. AB - Background: Many physicians treat themselves despite established guidelines against such practice. Aims: To examine whether general practitioners (GPs) are satisfied with their personal primary care and how this could be improved. Methods: We sent a questionnaire to GPs in Israel. We examined the gap between preference to use formal medical care and use in practice, satisfaction with physicians' primary healthcare, self-prescribing and ways to improve physician access to care. Results: There were 203 respondents (response rate 203/985; 21%). Sixty-one per cent reported not having a GP. Older respondents were less likely to have their own GP. Thirty-seven per cent of physicians reported receiving less formal medical care than they desired. This gap was higher in those reporting self-prescription of benzodiazepines and anti-depressants (P < 0.05) and was significantly associated with dissatisfaction with primary healthcare. Odds for being satisfied with personal care was reduced by more than 85% in GPs who reported receiving less formal medical care than they desired (odds ratio 0.146; 95% confidence interval 0.064-0.333). Conclusions: Our findings inform the profile of physician self-treatment and the dissatisfaction associated with it. Dissatisfaction was associated with a gap between desired and actual care rather than with having or not having a personal GP. There was no consensus regarding what would assist physicians to access GPs. PMID- 29514324 TI - Tobacco Smoking and Brain Endogenous Opioid Release: More than Nicotine Alone. AB - Introduction: The effects of smoking denicotinized (denic) and average nicotine (avnic) tobacco cigarettes were studied on brain mu opioid receptor binding by positron emission tomography with 11C carfentanil. The results indicated the importance of physiological and psychological effects induced by denic smoking. Methods: Regional mu opioid binding potential (non-displaceable binding potential, BPND) was measured in 20 adult male overnight abstinent chronic tobacco smokers. The denic sessions were conducted about 8:00 AM followed by avnic sessions about 2 hours later. Venous plasma nicotine levels and scores of craving to smoke were assessed before and after each smoking session. Fagerstrom scores of nicotine dependence were determined. Pearson's and Spearman's correlation tests were used to examine associations between BPND and other smoking parameters. Results: Surprisingly the very low plasma nicotine peak levels after denic smoking (mean+/-SD: 3.3+/-1.8 ng/ml) were significantly correlated with BPND after denic and avnic smoking. Equally surprising no association was found between nicotine levels after avnic smoking and BPND. Delta craving scores and Fagerstrom scores were correlated with both BPND after denic and avnic in several brain regions. Conclusions: Very small amounts of nicotine, psychological and behavioral effects of denic smoking appear to have important actions on the endogenous mu opioid system. Implications: Associations between very low venous plasma nicotine levels after denic smoking and regional brain mu opioid receptor availability are a surprising "placebo" effect. Delta craving and Fagerstrom scores were correlated with BPND in several brain regions including amygdala, hippocampus, insula, nucleus accumbens, putamen and ventral striatum. This study is limited by modest Power (mean 1-beta=0.6) for all correlation analyses. PMID- 29514325 TI - The role of reactive oxygen species in the integration of temperature and light signals. AB - The remarkable plasticity of the biochemical machinery in plants allows the integration of a multitude of stimuli, enabling acclimation to a wide range of growth conditions. The integration of information on light and temperature enables plants to sense seasonal changes and adjust growth, defense, and transition to flowering according to the prevailing conditions. By now, the role of reactive oxygen species (ROS) as important signaling molecules has been established. Here, we review recent data on ROS as important components in the integration of light and temperature signaling by crosstalk with the circadian clock and calcium signaling. Furthermore, we highlight that different environmental conditions critically affect the interpretation of stress stimuli, and consequently defense mechanisms and stress outcome. For example, day length plays an important role in whether enhanced ROS production under stress conditions is directed towards activation of redox poising mechanisms or triggering programmed cell death (PCD). Furthermore, a mild increase in temperature can cause down-regulation of immunity and render plants more sensitive to biotrophic pathogens. Taken together, the evidence presented here demonstrates the complexity of signaling pathways and outline the importance of their correct interpretation in context with the given environmental conditions. PMID- 29514326 TI - Cellulose Synthase Mutants Distinctively Affect Cell Growth and Cell Wall Integrity for Plant Biomass Production in Arabidopsis. AB - Cellulose is the most characteristic component of plant cell walls, and plays a central role in plant mechanical strength and morphogenesis. Despite the fact that cellulose synthase (CesA) mutants exhibit a reduction in cellulose level, much remains unknown about their impacts on cell growth (elongation and division) and cell wall integrity that fundamentally determine plant growth. Here, we examined three major types of AtCesA mutants (rsw1, an AtCesA1 mutant; prc1-1 and cesa6, AtCesA6-null mutants; and IRX3, an AtCesA7 mutant) and transgenic mutants that overexpressed AtCesA genes in the background of AtCesA6-null mutants. We found that AtCesA6-null mutants showed a reduced cell elongation of young seedlings with little impact on cell division, which consequently affected cell wall integrity and biomass yield of mature plants. In comparison, rsw1 seedlings exhibited a strong defect in both cell elongation and division at restrictive temperature, whereas the IRX3 mutant showed normal seedling growth. Analyses of transgenic mutants indicated that primary wall AtCesA2, AtCesA3, AtCesA5 and AtCesA9 genes played a partial role in restoration of seedling growth. However, co-overexpression of AtCesA2 and AtCesA5 in AtCesA6-null mutants could greatly enhance cell division and fully restore wall integrity, leading to a significant increase in secondary wall thickness and biomass production in mature plants. Hence, this study has demonstrated distinct functions of AtCesA genes in plant cell growth and cell wall deposition for biomass production, which helps to expalin our recent finding that only three AtCesA6-like genes, rather than other AtCesA genes of the AtCesA family, could greatly enhance biomass production in transgenic Arabidopsis plants. PMID- 29514327 TI - How Do Physical Therapists in the United Kingdom Manage Patients With Hip Osteoarthritis? Results of a Cross-Sectional Survey. AB - Background: Hip osteoarthritis (OA) is common, painful, and disabling. Physical therapists have an important role in managing patients with hip OA; however, little is known about their current management approach and whether it aligns with clinical guideline recommendations. Objective: The objective of this study is to describe United Kingdom (UK) physical therapists' current management of patients with hip OA and to determine whether it aligns with clinical guidelines. Design: The design is a cross-section questionnaire. Methods: A questionnaire was mailed to 3126 physical therapists in the UK that explored physical therapists' self-reported management of a patient with hip OA using a case vignette and clinical management questions. Results: The response rate was 52.7% (n = 1646). In total, 1148 (69.7%) physical therapists had treated a patient with hip OA in the last 6 months and were included in the analyses. A treatment package was commonly provided incorporating advice, exercise (strength training 95.9%; general physical activity 85.4%), and other nonpharmacological modalities, predominantly manual therapy (69.6%), and gait retraining (66.4%). There were some differences in reported management between physical therapists based in the National Health Service (NHS) and non-NHS-based physical therapists, including fewer treatment sessions being provided by NHS-based therapists. Limitations: Limitations include the potential for nonresponder bias and, in clinical practice, physical therapists may manage patients with hip OA differently. Conclusion: UK-based physical therapists commonly provide a package of care for patients with hip OA that is broadly in line with current clinical guidelines, including advice, exercise, and other nonpharmacological treatments. There were some differences in clinical practice between NHS and non-NHS-based physical therapists, but whether these differences impact on clinical outcomes remains unknown. PMID- 29514322 TI - Capturing the 'ome': the expanding molecular toolbox for RNA and DNA library construction. AB - All sequencing experiments and most functional genomics screens rely on the generation of libraries to comprehensively capture pools of targeted sequences. In the past decade especially, driven by the progress in the field of massively parallel sequencing, numerous studies have comprehensively assessed the impact of particular manipulations on library complexity and quality, and characterized the activities and specificities of several key enzymes used in library construction. Fortunately, careful protocol design and reagent choice can substantially mitigate many of these biases, and enable reliable representation of sequences in libraries. This review aims to guide the reader through the vast expanse of literature on the subject to promote informed library generation, independent of the application. PMID- 29514329 TI - Validation of the Subjective Global Nutrition Assessment (SGNA) and Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP) to Identify Malnutrition in Hospitalized Malaysian Children. AB - Background: Early detection of malnutrition in hospitalized children helps reduce length of hospital stay and morbidity. A validated nutrition tool is essential to correctly identify children at risk of malnutrition or who are already malnourished. This study compared the use of the Subjective Global Nutrition Assessment (SGNA, nutrition assessment tool) and Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP, nutrition screening tool) with objective nutritional parameters to identify malnutrition in hospitalized children. Methods: A cross-sectional study was carried out in two general paediatric wards in a public hospital. SGNA and STAMP were performed on 82 children (52 boys and 30 girls) of age 1-7 years. The scores from both methods were compared against Academy of Nutrition and Dietetics/American Society of Parental and Enteral Nutrition Consensus Statement for identification of paediatric malnutrition. The objective measurements include anthropometry (weight, height and mid-arm circumference), dietary intake and biochemical markers (C-reactive protein, total lymphocytes and serum albumin). Kappa agreement between methods, sensitivity, specificity and cross-classification were computed. Results: SGNA and STAMP identified 45% and 79% of the children to be at risk of malnutrition, respectively. Using a compendium of objective parameters, 46% of the children were confirmed to be malnourished. The agreement between SGNA and objective measurements (k = 0.337) was stronger than between STAMP and objective measurements (k = 0.052) in evaluating the nutritional status of hospitalized children. SGNA also has a 4-fold higher specificity (70.45%) than STAMP (18.18%) in detecting children who are malnourished. Conclusion: SGNA is a valid nutrition assessment tool in diagnosing malnutrition status among hospitalized children in Malaysia. The discrepancy in specificity values between the two methods explains the distinguished roles between SGNA and STAMP. The use of STAMP will have to be followed up with a more valid tool such as SGNA to verify the actual nutrition status of the paediatric population. PMID- 29514328 TI - Effects of dietary protein level and age at photo stimulation on reproduction traits of broiler breeders and progeny performance. AB - A study with a 2 * 2 factorial arrangement was conducted to determine the effects of 2 dietary crude protein levels, high (CPh) or low (CPl), supplemented with free amino acids (AA), and 2 ages at photo stimulation (PS)-early (21 wk; PSe) or late (23 wk; PSl)-on reproduction traits of broiler breeders and progeny performance. Diets were isocaloric, and calculated CP content of the CPl diets was 15 g/kg lower than the CPh diets during all phases. A total of 480 female and 64 male Ross 308 breeders of 20 wk of age were used. Total egg production was similar between CPl and CPh birds during phase 1 and 2 but was reduced by 2.8 eggs for CPl birds during phase 3. For the overall laying period, CPl birds tended (P = 0.075) to produce 4.7 fewer total eggs. Hatchability of set eggs was similar between CPl and CPh birds during phases 1 and 2 but tended (P = 0.064) to be lower for CPl birds in phase 3. PSe birds showed an advanced age at sexual maturity and age at peak production of 4.6 and 5.3 d, respectively, resulting in 2.5 more total eggs during phase 1. During phase 1, PSe birds showed an almost 5% increased fertility. Chick production in phase 1 was higher for PSe birds resulting in a tendency (P = 0.071) to higher overall chick production of almost 8 chicks. Progeny from early PS breeders showed an overall significant lower feed conversion ratio (FCR). It was concluded that egg and chick production during phases 1 and 2 were not affected by dietary CP level, but egg and chick production was reduced for CPl birds during phase 3. On the other hand, PSe birds showed an increased number of chicks. It is possible to decrease CP level of breeder diets with comparable reproduction from 22 to 46 wk; however, this is questionable for phase 3. For maximal chick production, early PS is recommended. PMID- 29514330 TI - Effects of Consumer Antimicrobials Benzalkonium Chloride, Benzethonium Chloride, and Chloroxylenol on Colonic Inflammation and Colitis-Associated Colon Tumorigenesis in Mice. AB - Benzalkonium chloride (BAC), benzethonium chloride (BET), and chloroxylenol (PCMX) are antimicrobial ingredients used in many consumer products and are frequently detected in the environment. In 2016, the U.S. Food and Drug Administration removed 19 antimicrobial ingredients from consumer antiseptic wash products, but deferred rulemaking for BAC, BET, and PCMX to allow additional time to develop new safety and efficacy data for these 3 antimicrobials. Therefore, it is important and timely to better understand the effects of these 3 compounds on human health. Here, we report that exposure to low doses of these antimicrobial compounds, in particular BAC, increases dextran sodium sulfate (DSS)-induced colonic inflammation and azoxymethane/DSS-induced colon tumorigenesis in mice. In addition, we find that exposure to BAC increases activation of Toll-like receptor 4 signaling in the systemic circulation, by disrupting intestinal barrier function and thus enhancing circulating levels of bacterial products. Together, our results suggest that these widely used antimicrobial compounds could exaggerate disease development of inflammatory bowel disease and associated colon cancer. Further studies are urgently needed to better characterize the impacts of these compounds on gut diseases. PMID- 29514332 TI - Availability, Quality, and Relevance of Toxicogenomics Data for Human Health Risk Assessment: A Scoping Review of the Literature on Trihalomethanes. AB - Human health risk assessment (HHRA) must be adapted to the challenges of the 21st century, and the use of toxicogenomics data in HHRA is among the changes that regulatory agencies worldwide are trying to implement. However, the use of toxicogenomics data in HHRA is still limited. The purpose of this study was to explore the availability, quality, and relevance to HHRA of toxicogenomics publications as potential barriers to their use in HHRA. We conducted a scoping review of available toxicogenomics literature, using trihalomethanes as a case study. Four bibliographic databases (including the Comparative Toxicogenomics Database) were assessed. An evaluation table was developed to characterize quality and relevance of studies included on the basis of criteria proposed in the literature. Studies were selected and analyzed by 2 independent reviewers. Only 9 studies, published between 1997 and 2015, were included in the analysis. Based on the selected criteria, critical methodological details were often missing; in fact, only 3 out of 9 studies were considered to be of adequate quality for HHRA. No studies met >3 (out of 7) criteria of relevance to HHRA (eg, adequate number of doses and sample size). This first scoping review of toxicogenomics publications on trihalomethanes shows that low availability, quality, and relevance to HHRA of toxicogenomics publications presents potential barriers to their use in HHRA. Improved reporting of methodological details and study design is needed in the future so that toxicogenomics studies can be appropriately assessed regarding their quality and value for HHRA. PMID- 29514331 TI - Prosody production networks are modulated by sensory cues and social context. AB - The neurobiology of emotional prosody production is not well investigated. In particular, the effects of cues and social context are not known. The present study sought to differentiate cued from free emotion generation and the effect of social feedback from a human listener. Online speech filtering enabled fMRI during prosodic communication in 30 participants. Emotional vocalizations were a) free, b) auditorily cued, c) visually cued, or d) with interactive feedback. In addition to distributed language networks, cued emotions increased activity in auditory and - in case of visual stimuli - visual cortex. Responses were larger in pSTG at the right hemisphere and the ventral striatum when participants were listened to and received feedback from the experimenter. Sensory, language, and reward networks contributed to prosody production and were modulated by cues and social context. The right pSTG is a central hub for communication in social interactions - in particular for interpersonal evaluation of vocal emotions. PMID- 29514333 TI - Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose. AB - Objective: Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design: Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting: Ambulatory. Subjects: Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Methods: Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results: Cold pressor responses (seconds): baseline: control 34 +/- 6 vs buprenorphine 17 +/- 2 (P = 0.009); morphine infusion-end: control 52 +/- 11(P = 0.04), buprenorphine 17 +/- 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 +/- 6 vs buprenorphine 53 +/- 5 (P = 0.13); infusion-end: control 74 +/- 5 (P = 0.007), buprenorphine 53 +/- 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 +/- 1, buprenorphine 136 +/- 10. Conclusions: Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed. PMID- 29514334 TI - A Study on the Leptospirosis Outbreak Among US Marine Trainees in Okinawa, Japan. AB - Introduction: The US Marines operate the Jungle Warfare Training Center (JWTC) in Northern Okinawa, where leptospirosis is endemic. The JWTC endurance course involves prolonged fresh and stagnant water exposures in a simulated jungle warfare environment. Since a leptospirosis outbreak in 1987, JWTC has required prophylactic use of doxycycline at 200 mg weekly during exposure to the endurance course. This policy is based on a 1982 study in a similar environment in Panama. In August and September of 2014, an outbreak of leptospirosis occurred among 81 Marines training at JWTC. We analyzed data from the largest reported outbreak of leptospirosis among US military members. Materials and Methods: Two hundred and thirty nine US Marines who completed the endurance course were interviewed by trained personnel regarding their exposures and use of prophylactic medication utilizing a standardized questionnaire. All available personnel who went through the course during the outbreak period were interviewed regardless of whether or not they became ill. The Armed Forces Health Surveillance Branch's case definition was used to identify cases. Results: Eighty-one cases in 239 personnel were identified (attack rate = 33.9%). Exposures linked to being a case were swallowing water in the stagnant pond (attack rate ratio [ARR] = 2.3, 95% confidence interval [CI] = 1.4-3.7), cuts on the body (ARR = 1.5, 95% CI = 1.01 2.11), and insect bites (ARR = 2.0, 95% CI = 1.2-3.4). Exposures not linked to being a case were taking doxycycline before the exposure (ARR = 3.2, 95% CI = 0.5 22.2), taking doxycycline after the exposure (ARR = 0.9, 95% CI = 0.6-1.3), and swallowing water in the natural stream (ARR = 1.3, 95% CI = 0.9-1.9). Conclusions: Attack rate data indicate that whether or not personnel took pre- or post-exposure doxycycline made no difference statistically. Increased internal exposure (via swallowing water or through broken skin) increased risk of symptomatic disease. This new study combined with a growing body of literature should prompt researchers to re-examine recommendations for those with significant water exposure in areas with high leptospirosis levels. PMID- 29514335 TI - Opioid Use Patterns Among Active Duty Service Members and Civilians: 2006-2014. AB - Introduction: Between 2001 and 2009, opioid analgesic prescriptions in the Military Health System quadrupled to 3.8 million. The sheer quantity of opioid analgesics available sets the stage for issues related to misuse, abuse, and diversion. To address this issue, the Department of Defense implemented several directives and clinical guidelines to improve access to appropriate pain care and safe opioid prescribing. Unfortunately, little has been done to characterize changing patterns of opioid use in active duty service members (ADSM), so little is known about how combat operations and military health care policy may have influenced this significant problem. We examined changes in opioid use for ADSM between 2006 and 2014, compared trends with the civilian population, and explored the potential role of military-specific factors in changes in opioid use in the Military Health System. Materials and Methods: After obtaining Institutional Review Board approval, administrative prescription records (Pharmacy Data Transaction Records) for non-deployed ADSM were used to determine the number of opioid prescriptions dispensed each year and the proportion of ADSM who received at least one prescription per month between 2006 and 2014. Based on the observation and the literature, we identified December 2011 as the demarcation point (the optimal point to identify the downturn in opioid use) and used it to compare opioid use trends before and after. We used an autoregressive forecast model to verify changes in opioid use patterns before and after 2011. Several interrupted time series models examined whether military system-level factors were associated with changes in opioid use. Results: Between 2006 and 2014, 1,516,979 ADSM filled 7,119,945 opioid prescriptions, either in military treatment facilities or purchased through TRICARE. Both active duty and civilian populations showed signs of decreasing use after 2011, but this change was much more pronounced among ADSM. The forecast model showed a significant difference after 2011 between the projected and actual proportion of ADSM filling an opioid prescription, confirming 2011 as a point of divergence in opioid use. Interrupted time series models showed that the deflection point was associated with significant decreases. A significant increase of 0.261% in opioid prescriptions was seen for every 1,000 wounded in action service members in a given month. Troops returning from Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn did not appear to influence the rates of use. Even after accounting for returning troops from Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn and wounded in action counts, the deflection point was associated with a lower proportion of ADSM who filled an opioid prescription, leading to a decrease of 1.61% by the end of the observation period (December 2014). Conclusion: After December 2011, opioid use patterns significantly decreased in both civilian and ADSM populations, but more so in the military population. Many factors, such as numbers of those wounded in action and the structural organization of the Military Health System, may have caused the decline, although more than likely the decrease was influenced by many factors inside and outside of the military, including policy directives and cultural changes. PMID- 29514336 TI - Imaging of Combat-Related Thoracic Trauma - Review of Penetrating Trauma. AB - Introduction: Combat-related thoracic trauma is a significant contributor to morbidity and mortality of the casualties from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). Penetrating, blunt, and blast injuries were the most common mechanisms of trauma. Imaging plays a key role in the management of combat-related thoracic trauma casualties. This review discusses the imaging manifestations of thoracic injuries from penetrating trauma, emphasizing epidemiology and diagnostic clues seen during OEF and OIF. Materials and Methods: The assessment of radiologic findings in patients who suffer from combat-related thoracic trauma is the basis of this review article. The imaging modalities for this study include multi-detector computed tomography and chest radiography. Results: High-velocity penetrating projectile injuries appear as hemorrhage and re-expansion pulmonary edema from the temporary cavity and a linear, blood-filled track from the permanent cavity. In cases where the projectile passes totally through the body, entrance wounds at the skin surface and tracks through the subcutaneous tissues may be the only indications of penetrating trauma. When assessing vascular injury, special attention should be paid to the right hilum in contrast-enhanced multi-detector computed tomography, as contrast is concentrated in the superior vena cava and superior cavoatrial junction may obscure small fragments. Additionally, CT angiography may show vessel disruption or extravasation of contrast distal to normal vessel location in addition to intraluminal filling defects and pseudo-aneurysms. Tension pneumopericardium may rarely complicate penetrating or blunt chest trauma. On imaging, distension of the pericardial sack by pneumopericardium and compression of the heart support the diagnosis of tension. On multi-detector computed tomography in the acute trauma setting, fluid in the pleural space should be considered hemothorax, particularly when Hounsfield units are above 35. Acutely, extravasated blood will have similar attenuation to the thoracic vasculature, whereas clotted blood will have higher values of 50-90 Hounsfield units. Conclusion: Combat-related thoracic trauma continues to be a significant contributor to the morbidity and mortality of those injured during OEF and OIF. This review of the imaging manifestations of penetrating thoracic injury during OEF and OIF focuses on key diagnostic findings for clinicians caring for combat casualties. The distinct injury pattern and atypical imaging manifestations of penetrating trauma are important to recognize early due to the acuity of this patient population and the influence of accurate diagnosis on clinical management. PMID- 29514337 TI - The Association Between Sickle Cell Trait in U.S. Service Members with Deployment, Length of Service, and Mortality, 1992-2012. AB - Introduction: Sickle cell trait (SCT) affects an estimated 5.02% of non-Hispanic blacks, 1.08% of Hispanics, and 0.1% of Whites in the U.S. military. Policies for SCT screening and occupational restrictions vary by service. Population-based studies of SCT with quantification of military-relevant outcomes are lacking. Methods: The study design was a retrospective cohort of 15,081 SCT-positive versus 60,320 SCT-negative U.S. active duty personnel enlisted from 1992 to 2012 and followed through 2013. Military-relevant outcome included number and days of deployment, length of service, and cause of death. Results: SCT-positive versus SCT-negative service members experienced more deployments (p < 0.01) and longer number of days deployed for all services, especially the Army (p < 0.001). The median length of service was longer for SCT-positive service members stratified by service and by gender (p < 0.05). The adjusted risk of length of service greater than 5 yr by SCT status was 1.37 (95% confidence interval 1.31-1.43) with greater than a three-fold higher risk in the Navy and Air Force compared with the Army. Crude mortality rate was not significantly different by SCT status, although deaths due to suicide, self-directed violence, and other non-specific causes were more common in SCT-positive service members. Conclusion: We found that SCT-positive service members deployed more frequently, for greater lengths of time, and remained in service longer. No significant difference in crude mortality ratio was discovered. Additional research on military-relevant outcomes and a cost-effectiveness analysis of SCT screening practices are needed to inform evidence-based SCT enlistment policies. PMID- 29514338 TI - U.S. Service Member Deployment in Response to the Ebola Crisis: The Psychological Perspective. AB - Introduction: In the fall of 2014, the United States and other nations responded to the worst outbreak of the Ebola virus disease in history. As part of this effort, U.S. service members deployed to West Africa to support a spectrum of activities that did not involve direct patient care. Although previous studies identified the psychological impact of responding to an outbreak, these studies were limited to retrospective data, small sample sizes, and medical personnel. The goals of the present study were to (a) document the mental health and well being of troops deploying in response to an infectious disease outbreak; (b) identify their stressors, attitudes toward deployment, and health risk concerns; and (c) understand the role of combat experience in adjusting to these types of missions. Materials and Methods: Study participants at both pre- and during deployment were active duty U.S. soldiers in a combat aviation battalion from a large U.S. military installation. U.S. soldiers were surveyed (n = 251) 3 wk before deploying to Liberia (October 2014) and surveyed again during their deployment (February 2015; n = 173). Participants were primarily male (86.1%), junior ranking (56.0%), and just over half had previous combat deployment experience (51.2%). Surveys were anonymous and not linked to one another over time. Results: Overall rates of mental health problems were low (2.4% at pre deployment and 5.8% during deployment), whereas sleep problems were reported by 4.9% at pre-deployment and 12% during deployment. At pre-deployment, top stressors focused on health threats; fewer stressors were reported during deployment. Soldiers were relatively less concerned about contracting Ebola than other more prevalent diseases. Soldiers with combat experience reported more somatic and sleep problems at pre-deployment than those without previous combat experience. There were no significant differences during deployment between those with and without previous combat experience. Conclusion: Overall, a small proportion of respondents reported significant rates of mental health problems. In contrast, sleep problems were reported by 12% during deployment. In terms of attitudes toward the mission, the vast majority reported that they knew what to do to protect themselves from disease and that they understood the potential risk involved. The study also confirmed previous findings that soldiers with previous combat experience had more somatic symptoms at pre-deployment than those without, although this distinction appeared limited to the pre-deployment phase. Results can be used to address anxiety by personnel during pre-deployment and to inform leadership preparing personnel to deploy in response to future infectious disease outbreaks. PMID- 29514339 TI - False-Positive Monospot in a Returning Traveler with Dengue Fever. AB - The heterophile antibody (Monospot), initial test of choice for Epstein-Barr virus (EBV)-associated infectious mononucleosis, is both sensitive (70-92%) and specific (96-100%). False positives have been demonstrated in cases of viral hepatitis, human immunodeficiency virus, leukemia, lymphoma, pancreatic cancer, systemic lupus erythematosus, and rubella. We present a case of a 46-yr-old male who developed fever, chills, headaches, myalgia, fatigue, and photophobia 1 d after returning from the Philippines. He demonstrated a mild transaminitis and significant thrombocytopenia (12,000 cells/MUL). His initial evaluation revealed a positive heterophile antibody test. Without a classic EBV presentation, a fever in returning traveler evaluation was instituted resulting in a positive dengue test by direct fluorescence IgM (8.82 IU) and IgG (7.13 IU), respectively. Both his EBV DNA polymerase chain reaction and IgM by viral capsid antigen were negative. Dengue, an RNA flavivirus, and the dengue antibody have demonstrated cross-reactivity with other flaviviruses including Japanese encephalitis virus, yellow fever virus, West Nile virus, and St. Louis encephalitis. However, EBV is a double-helix DNA herpesvirus and structurally very different. To our knowledge, this is the first reported case of cross-reactivity between dengue and EBV that describes a potential false positive for the heterophile antibody test. PMID- 29514340 TI - A Comparison of Veterans with Post-traumatic Stress Disorder, with Mild Traumatic Brain Injury and with Both Disorders: Understanding Multimorbidity. AB - Introduction: Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common military service-related conditions diagnosed both singly and together in veterans returning from recent military conflicts overseas. The impact of these disorders in real-world Veterans Health Administration practice has not been studied extensively, and few studies have examined the association of these disorders both by themselves and together with sociodemographic characteristics, psychiatric and medical comorbidities, health service utilization, and psychotropic medication fills. This study aims to add to the broader study of multimorbidity and the impact it has on patient care. Materials and Methods: This study used a national Veterans Health Administration sample (N = 164,884) to compare characteristics of veterans diagnosed with mTBI, PTSD, and with both disorders. Relative rates of diagnosis with psychiatric and medical disorders, utilization of medical and psychiatric services, and prescription rates of psychotropic medication fills were examined to determine the impact that the disorders had on these rates, both in isolation and together. Results: With few exceptions, diagnosis with PTSD, both alone and in the presence of mTBI, was associated with greater risk of comorbid psychiatric diagnosis, higher service utilization, and greater psychotropic medication fills. Notable correlates specific to mTBI included headache, seizure disorder, paraplegia, and cerebrovascular accident. Conclusion: PTSD thus plays the dominant role in the development of psychiatric difficulties and service use independently of mTBI. The recognition of the central importance of psychiatric difficulties in the functional outcomes of individuals who have experienced an mTBI suggests a need to assure access of veterans to psychiatric treatment services. PMID- 29514341 TI - Spontaneous Lung Herniation Through the Chest Wall. AB - A 71-yr-old male with a medical history significant for chronic obstructive pulmonary disease presented to emergency department for worsening cough, right sided pleuritic chest pain, and dyspnea. This was the patient's third visit to the emergency department in 4 d. The patient was initially treated for chronic obstructive pulmonary disease exacerbation and subsequently evaluated for congestive heart failure. He was ultimately diagnosed with a spontaneous herniation of the lung parenchyma through the chest wall. The patient was transferred to an outside host nation facility for definitive treatment and repair of the chest wall defect. Refractory cough and dyspnea failing to respond to typical treatments should warrant an expanded differential to include the rare etiology of atraumatic spontaneous lung herniation. PMID- 29514342 TI - A Case of Non-simultaneous Bilateral Partial Triceps Tendon Repair. AB - A partial triceps tendon tear is an uncommon injury. Even rarer is a bilateral partial triceps tendon tear in which there has been one documented case. This case report illustrates a 37-yr-old African-American male who sustained non simultaneous bilateral partial triceps tendon avulsions. He sustained a traumatic right partial triceps tendon avulsion after a fall onto an outstretched right arm that required operative repair after failure of conservative treatment. Five months later, he sustained a similar injury after falling on an outstretched left arm that was repaired 9 d later. His post-operative courses were uncomplicated. He returned to full duty at his 6 mo and remained symptom free at 12 mo. The case demonstrates that operative treatment of partial triceps tendon avulsions using bone tunnels yields good outcomes in high-demand patients who have failed conservative treatment and who have had an operative repair of the contralateral extremity. PMID- 29514343 TI - Imaging of Combat-Related Thoracic Trauma - Blunt Trauma and Blast Lung Injury. AB - Introduction: Combat-related thoracic trauma (CRTT) is a significant contributor to morbidity and mortality of the casualties from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). Penetrating, blunt, and blast injuries are the most common mechanisms of trauma to the chest. Imaging plays a key role in the battlefield management of CRTT casualties. This work discusses the imaging manifestations of thoracic injuries from blunt trauma and blast injury, emphasizing epidemiology and diagnostic clues seen during OEF and OIF. Materials and Methods: The assessment of radiologic findings in patients who suffer from combat-related blunt thoracic trauma and blast injury is the basis of this work. The imaging modalities for this work include multi-detector computed tomography (MDCT) and chest radiography. Results: Multiple imaging modalities are available to imagers on or near the battlefront, including radiography, fluoroscopy, and MDCT. MDCT with multi-planar reconstructions is the most sensitive imaging modality available in combat hospitals for the evaluation of CRTT. In modern combat, blunt and blast injuries account for a significant portion of CRTT. Individual body armor converts penetrating trauma to blunt trauma, leading to pulmonary contusion that accounted for 50.2% of thoracic injuries during OIF and OEF. Flail chest, a subset of blunt chest injury, is caused by significant blunt force to the chest and occurs four times as frequently in combat casualties when compared with the civilian population. Imaging features of CRTT have significant diagnostic and prognostic value. Pulmonary contusions on chest radiography appear as patchy consolidations in the acute setting with ill-defined and non-segmental borders. MDCT of the chest is a superior imaging modality in diagnosing and evaluating pulmonary contusion. Contusions on MDCT appear as crescentic ground glass opacities (opacities through which lung interstitium and vasculature are still visible) and areas of consolidation that often do not respect the anatomic boundaries of the affected lobes. Additionally, small pulmonary contusions may exhibit sub-pleural sparing and may distinguish contusion from pneumonia or other lung pathology. Although pulmonary laceration is typically the result of penetrating trauma, laceration may also be caused by displaced rib fractures or significant shearing forces on the lung without penetrating injury. Because of elastic recoil of the normal pulmonary parenchyma surrounding the injury, pulmonary lacerations may present as late as 48-72 h after injury. Pulmonary lacerations may appear similar to pulmonary contusions on chest radiography initially and will require MDCT for definitive diagnosis. Blast injury is a defining injury of modern combat. Blast lung injury is initially diagnosed with chest radiography, where the pattern of lung opacities has previously been described by clinicians as "batwing" or "butterfly" because of its central appearance in the lung. "Peribronchovascular" may be a more accurate description of primary blast lung based on its appearance on MDCT. This pattern may differentiate primary blast lung injury from other causes of thoracic trauma. Conclusion: CRTT continues to be a significant contributor to the morbidity and mortality of those injured during OEF and OIF. The distinct injury patterns and atypical imaging manifestations of blunt trauma and blast lung injury are important to recognize early because of the acuity of this patient population and the influence of accurate diagnosis on clinical management. PMID- 29514344 TI - Does Mobile Care ('mCare') Improve Quality of Life and Treatment Satisfaction Among Service Members Rehabilitating in the Community? Results from a 36-Wk, Randomized Controlled Trial. AB - Introduction: Research has shown that mobile phones can help with management of numerous health problems. As an adjunct to care management provided to injured service members rehabilitating in their communities, particularly those with mild traumatic brain injury (mTBI), post-traumatic stress (PTS), and/or behavioral health problems, the Army developed a mobile phone application called "mCare." This study examined whether service members who received mCare had higher well being, were more satisfied with their care, and viewed mCare as a valuable part of their care management as compared with their counterparts who received standard care management alone, and whether those with mTBI, PTS, and/or behavioral health problems benefited differently from mCare. Materials and Methods: In-processing service members at four community-based warrior transition units were recruited for participation in a 36-wk, randomized, controlled trial and allocated to receive standard care management plus mCare (n = 95) or standard care management alone (n = 87). Participants in the mCare group received daily questionnaires, tips, and appointment reminders. All participants were asked to complete the General Well-being Schedule (GWS) at baseline, 12, 24, and 36 wk, and the Case Management Quality Questionnaire (CMQQ) at 12, 24, and 36 wk. All participants and care managers were approached to complete interviews about the usability/likeability of mCare or standard care management. The analyses tested for group differences in completion of the intervention, graphed means for the GWS and CMQQ by group/subgroup, and statistically compared the longitudinal trends in these outcomes using mixed models in which group, time, and group*time were included as regression variables. The analyses also tallied interview responses and identified thematic quotes. The study protocol was reviewed and approved by the Walter Reed National Military Medical Center's Institutional Review Board. Results: Estimated rate of change in GWS scores was -2.2 (standard error = 1.0; t = -2.1; p = 0.0382). Estimated rate of change in CMQQ scores was 0.8 (standard error = 0.5; t = -1.52; p = 0.1299). Neither change was meaningful. Rates of change in the GWS and CMQQ scores did not differ by group or by behavioral health, mTBI, and PTS subgroups within the groups. The interviews found that 83% of mCare participants liked the communication with their care managers versus 73% of standard care management participants. Participants in both the mCare group and the care managers said that they liked the application's appointment tracking and reminders. Care managers thought mCare was particularly useful for people with mTBI, PTS, and cognitive problems. Conclusion: mCare did not result in differences in general well-being and satisfaction with care management among service members rehabilitating in their communities, some with mTBI, PTS, and/or behavioral health problems. But participants and care managers who used mCare said that they found it useful. Study limitations included the diversity of clinical issues of the participants, greater missing data among mCare participants, and the high baseline quality of care management in the settings observed. The fact that patients and care managers liked mCare, apart from no changes in outcomes, is important because health care is increasingly adopting mobile solutions. PMID- 29514345 TI - Military Trauma and Surgical Procedures in Conflict Area: A Review for the Utilization of Forward Surgical Team. AB - Introduction: Forward surgical teams (FSTs) have been used as highly mobile surgical facilities that provide "damage control" medical support in modern wars. FST regiments differ greatly in different armed services and nations. We systemically reviewed the utilization of FSTs around the world with an emphasis on the medical conditions and workloads encountered by FSTs in modern wars. Materials and Methods: We searched for terms related to FSTs, such as "Forward Surgical Team" and "Field Surgical Team," in the PubMed, EMBASE, Web of Science, and MEDLINE databases and collected any articles that provided numerical data on the organization of medical personnel combat casualty characteristics, including the casualty composition, injury types and locations, and mechanisms of injury, and surgical procedures performed. Technical articles, case reports of specific types of injury or disease, and literature reviews of previous experiences and logistical theories were discarded. Results: We identified 24 articles involving 29 FSTs that were included in the analysis. The FSTs were typically composed of 8 20 medical personnel and had limited medical capacity. Battle-related injuries constituted approximately two-thirds of all injury types treated by the FSTs. The extremities, torso, and head and neck were the three most frequently injured sites and accounted for approximately 51.1%, 16.6%, and 13.2% of all wounds, respectively. The three most frequent injury mechanisms were fragments or explosive injuries (44.8%), gunshot wounds (28.1%), and motor vehicle accidents/road traffic accidents (9.1%). Soft tissue surgeries (41.0%) and orthopedic operations (31.6%) were the two procedures that were most frequently performed by the FSTs. The average numbers of surgical procedures performed by small FSTs (1.27/unit.day) and full FSTs (1.28/unit.day) seemed to be comparable. Conclusion: Modern conflict may require more flexible small FSTs, especially during the initial phases of war. More orthopedic surgeons should be included in FSTs, and orthopedic skill training should be intensified before deployment. The utilization of FSTs and level III facilities must be evaluated within the context of the battlefield conditions, medical care requirements, and evacuation efficiency. PMID- 29514346 TI - Report of Autonomic Symptoms in a Clinical Sample of Veterans with Gulf War Illness. AB - Introduction: Previous studies suggest that autonomic dysfunction may be an underlying factor in Gulf War Illness. This study examined self-reported symptoms of autonomic dysfunction and their relationship with physical functioning among veterans with Gulf War Illness. Materials and Methods: We abstracted medical records of Gulf War Veterans clinically evaluated at the New Jersey War Related Illness and Injury Study Center between 2010 and 2016. The outcome measure was the Veteran version of the Short Form Health Survey (VR-36) physical functioning scale. Autonomic function was assessed using a composite variable constructed from the chart abstraction to mimic the Composite Autonomic Symptom Scale (COMPASS-31). Results: Seventy-six veterans were included in the final analysis. The autonomic symptom burden score was 45 (+/-14). Increased autonomic symptom burden, greater mental health burden (PTSD/depression), and greater body mass index were individually associated with poorer physical functioning. A general linear regression containing these variables revealed that patients with both PTSD and depression (b = -15.2, p = 0.03) or either PTSD or depression (b = 22.7, p < 0.01) had lower physical functioning than those without; the other variables became not significant (body mass index: p = 0.07; autonomic function: p = 0.89). Conclusion: The average autonomic function score indicated significant burden in Gulf War Veterans, consistent with published research. We did not detect an independent association between autonomic symptom burden and physical functioning, likely due to the non-specific nature of the measure used to capture autonomic symptoms or the stronger association between mental health conditions and physical functioning. Future work utilizing valid and standardized instruments to clinically evaluate autonomic function is warranted. PMID- 29514347 TI - Assessment of Deployment-Related Exposures on Risk of Incident Mental Health Diagnoses Among Air Force Medical Service Personnel: Nested Case-Control Study. AB - Background: Recent military conflicts in Iraq (Operation Iraqi Freedom), Afghanistan (Operation Enduring Freedom), and elsewhere have been associated with psychological impacts among military personnel. However, relatively little is known about the relationship between those conflicts and psychological health of military health care professionals. Previous work has shown certain demographic factors associated with diagnosed mental health conditions after deployment. However, unique exposures in the deployed environment may be present that are also associated. Understanding the relationship between the demographic factors, exposures, and post-deployment mental health (PDMH) conditions has not been investigated. The purpose of this study was to determine the association between occupational and/or environmental exposures and incident PDMH conditions in a defined population of United States Air Force health care personnel returning from the deployed environment (i.e., deployment-related exposures). Methods: A nested case-control study compared cohort members with (N = 4,114) and without (N = 14,073) a PDMH condition in terms of deployment-related occupational and/or environmental exposures. PDMH conditions were identified using the electronic health record and exposures were determined using post-deployment health assessments. Demographic-adjusted multivariable logistic regression models were used to compute odds ratios (ORs). Results: The final regression model comprised five exposure and 12 demographic variables. Reported exposures were not strongly associated with incident PDMH conditions (OR ranged from 1.22 to 1.38) and were lower than some demographic factors. Demographic characteristics with relatively large effect sizes (ORs less than 0.5 or greater than 1.5) included the protective factors of Air Force Guardsman (OR: 0.45), reservists (OR: 0.34), and surgeons (OR: 0.32), as well as the risk factor of nurses (OR: 1.51). All model parameters had a p-value less than 0.0001 and the area under the receiver operating characteristic curve was 0.668. Conclusions: Given the low area under the receiver operating characteristic, the final statistical model had only marginal performance in its ability to correctly identify cases. Thus, other factors should be studied to identify additional predictors for PDMH conditions. PMID- 29514348 TI - Causes of Oral-Maxillofacial Injury of U.S. Military Personnel in Iraq and Afghanistan, 2001-2014. AB - Background: Few studies have examined the causes or mechanisms of oral maxillofacial (OMF) injury among deployed military populations. This study reports causes of OMF injuries to U.S. Department of Defense personnel deployed to Afghanistan in Operation Enduring Freedom (OEF) or to Iraq in Operation Iraqi Freedom (OIF) and Operation New Dawn (OND). This study provides follow-on analysis of a previous report of OMF injury rates among U.S. military personnel in Iraq and Afghanistan from 2001 to 2014. Methods: The populations studied were military personnel deployed to Afghanistan in OEF or Iraq in OIF and OND, who sought care at a level III military treatment facility for one or more OMF injuries. Injuries were identified in the Department of Defense Trauma Registry using diagnosis codes associated with OMF battle and non-battle injuries. Causes associated with these injuries were identified by evaluation of the data field "dominant injury mechanism." All OMF injuries incurred from October 19, 2001, to June 30, 2014, were included. Findings/Results: Approximately 89% of all OMF battle injuries in both OIF/OND and OEF were due to explosives or explosive devices. The three leading causes of OMF non-battle injuries for both OIF/OND and OEF were motor vehicle crashes/accidents (MVCs), falls, and "other blunt" trauma. MVCs as well as other blunt trauma accounted for a greater percentage of OMF non battle injuries in OIF/OND than in OEF (p < 0.01). OMF non-battle injuries due to falls were more likely to occur in OEF (p = 0.05). Helicopter/plane crashes were responsible for a significantly higher percentage of OMF non-battle injuries in OEF compared with OIF/OND (p < 0.01). Discussion/Impact/Recommendations: Across both theaters of war, Iraq and Afghanistan, the main causes of OMF battle and non battle injuries were consistent. Battle injuries were primarily due to explosives or explosive devices and the three main causes of non-battle injuries were MVCs, falls, and other blunt trauma. However, the distribution of causes differed by war theater. Future studies should focus on potential reasons for cause distribution disparities in MVCs and helicopter/plane crashes as they can only be partially explained by topography and infrastructure differences between Iraq and Afghanistan. Further surveillance is needed to understand the scope of OMF injuries in military-armed conflicts and operations. PMID- 29514349 TI - Recovery from Mild Traumatic Brain Injury Following Uncomplicated Mounted and Dismounted Blast: A Natural History Approach. AB - Objective: The purpose of this study is to utilize a natural history approach to describe and understand symptom recovery in personnel diagnosed with a blast related mild traumatic brain injury (mTBI) resulting from an improvised explosive device blast. Participants and Design: The population included military personnel who experienced a blast mTBI while mounted (vehicle; n = 176) or dismounted (on foot; n = 37) (N = 213). Patients had no co-morbid psychiatric or muscle-skeletal issues and were treated within 72 h of injury. Prevalence and duration of self reported symptoms were separately analyzed by injury context (mounted vs dismounted). Results: Headache was prominently reported in both mounted (85%) and dismounted (75%) populations. The mean time from injury to return to full duty was between 7.8 d (mounted) and 8.5 d (dismounted). The dismounted population reported visual changes that lasted 0.74 d longer. Conclusion: Our analysis implicates that headache is a common and acutely persistent symptom in mTBI regardless of injury context. Additionally, patients in mounted vs dismounted injury did not report significant differences in symptom prevalence. Although knowing the injury context (i.e., dismounted vs mounted) may be beneficial for providers to understand symptom presentations and deliver accurate anticipatory guidance for patients with blast-related mTBI, no significant differences were observed in this population. This may be due to the population characteristic as the trajectory of recovery may vary for patients who were not able to return to full duty within 30 d or required higher levels of care. PMID- 29514350 TI - Depression in Female Veterans Returning from Deployment: The Role of Social Factors. AB - Objective: Women are serving in the armed forces and deployed to areas of conflict in increasing numbers. Problems such as depressive symptoms and risks related to combat exposure can have negative effects on adjustment following service; understanding the relationship between these problems may contribute to strategies providers can use to facilitate healthy adjustment after deployment. The purpose of this study is to examine social factors as they relate to mental health adjustment, namely depressive symptoms among female veterans who served in Iraq and Afghanistan as part of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn (OND). We hypothesized that combat exposure would predict higher levels of depressive symptoms and that social support would moderate the relationship between combat exposure and depression. Methods: In a cross-sectional design, 128 female Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn veterans completed an online survey about combat experience, social support, depression, demographic characteristics, and behavioral health symptom history. We conducted multiple regression analyses to examine linear and moderating relationships. Results: There was no significant relationship between combat exposure and depression; social support did not significantly moderate the relationship between combat exposure and depression. However, higher levels of social support and financial comfort were significantly related to lower levels of depression. Conclusion: This study highlights the role of social factors, specifically social support and perceived financial status, as potential barriers to healthy emotional readjustment following deployment. These findings suggest that it may be beneficial for mental health providers to screen female veterans and refer them to appropriate services to reduce financial stressors and strengthen their use of social support. More research should continue to examine more fully the impact of combat exposure on female service members' mental health and work to isolate the factors most strongly related to depression. PMID- 29514351 TI - Phosphite-Mediated Suppression of Anthocyanin Accumulation Regulated by Mitochondrial ATP Synthesis and Sugars in Arabidopsis. AB - Despite the essential role of phosphate (Pi) in plant growth and development, how plants sense and signal the change of Pi supply to adjust its uptake and utilization is not yet well understood. Pi itself has been proposed to be a signaling molecule that regulates Pi starvation responses (PSRs) because phosphite (Phi), a non-metabolized Pi analog, suppresses several PSRs. In this study, we identified a phosphite-insensitive1 (phi1) mutant which retained anthocyanin, a visible PSR, in Phi-containing but Pi-deficient medium. phi1 mutants were impaired in the gene encoding an FAd subunit of mitochondrial F1Fo ATP synthase and showed a reduced mitochondrial ATP level in roots, growth hypersensitivity to oligomycin and an increased mitochondrial membrane potential, suggesting that this gene has a crucial role in mitochondrial ATP synthesis. phi1 mutants accumulated a high level of sugars in shoots, which may account for the increased accumulation of anthocyanin and starch in Phi-containing conditions. Gene expression analysis showed that a subset of genes involved in carbohydrate metabolism in phi1 was misregulated in response to Phi. The majority of genes were repressed by Pi starvation and, unlike wild-type plants, their repression in phi1 was not affected by the addition of Phi. Our findings show that defective mitochondrial ATP synthesis results in sugar accumulation, leading to alteration of Phi-mediated suppression of PSRs. This study reinforces the role of sugars, and also reveals a cross-talk among ATP, sugars and Pi/Phi molecules in mediating PSRs. PMID- 29514352 TI - The Reliability of Electronic Health Record Data Used for Obstetrical Research. AB - BACKGROUND: Hospital electronic health record (EHR) data are increasingly being called upon for research purposes, yet only recently has it been tested to examine its reliability. Studies that have examined reliability of EHR data for research purposes have varied widely in methods used and field of inquiry, with little reporting of the reliability of perinatal and obstetric variables in the current literature. OBJECTIVE: To assess the reliability of data extracted from a commercially available inpatient EHR as compared with manually abstracted data for common attributes used in obstetrical research. METHODS: Data extracted through automated EHR reports for 3,250 women who delivered a live infant at a large hospital in the Pacific Northwest were compared with manual chart abstraction for the following perinatal measures: delivery method, labor induction, labor augmentation, cervical ripening, vertex presentation, and postpartum hemorrhage. RESULTS: Almost perfect agreement was observed for all four modes of delivery (vacuum assisted: kappa = 0.92; 95% confidence interval [CI] = 0.88-0.95, forceps assisted: kappa = 0.90; 95%CI = 0.76-1.00, cesarean delivery: kappa = 0.91; 95%CI = 0.90-0.93, and spontaneous vaginal delivery: kappa = 0.91; 95%CI = 0.90-0.93). Cervical ripening demonstrated substantial agreement (kappa = 0.77; 95%CI = 0.73-0.80); labor induction (kappa = 0.65; 95%CI = 0.62-0.68) and augmentation (kappa = 0.54; 95%CI = 0.49-0.58) demonstrated moderate agreement between the two data sources. Vertex presentation (kappa = 0.35; 95%CI = 0.31-0.40) and post-partum hemorrhage (kappa = 0.21; 95%CI = 0.13 0.28) demonstrated fair agreement. CONCLUSION: Our study demonstrates variability in the reliability of obstetrical data collected and reported through the EHR. While delivery method was satisfactorily reliable in our sample, other examined perinatal measures were less so when compared with manual chart abstraction. The use of multiple modalities for assessing reliability presents a more consistent and rigorous approach for assessing reliability of data from EHR systems and underscores the importance of requiring validation of automated EHR data for research purposes. PMID- 29514353 TI - The Value of Monitoring Clinical Decision Support Interventions. AB - BACKGROUND: Well-functioning clinical decision support (CDS) can facilitate provider workflow, improve patient care, promote better outcomes, and reduce costs. However, poorly functioning CDS may lead to alert fatigue, cause providers to ignore important CDS interventions, and increase provider dissatisfaction. OBJECTIVE: The purpose of this article is to describe one institution's experience in implementing a program to create and maintain properly functioning CDS by systematically monitoring CDS firing rates and patterns. METHODS: Four types of CDS monitoring activities were implemented as part of the CDS lifecycle. One type of monitoring occurs prior to releasing active CDS, while the other types occur at different points after CDS activation. RESULTS: Two hundred and forty-eight CDS interventions were monitored over a 2-year period. The rate of detecting a malfunction or significant opportunity for improvement was 37% during preactivation and 18% during immediate postactivation monitoring. Monitoring also informed the process of responding to user feedback about alerts. Finally, an automated alert detection tool identified 128 instances of alert pattern change over the same period. A subset of cases was evaluated by knowledge engineers to identify true and false positives, the results of which were used to optimize the tool's pattern detection algorithms. CONCLUSION: CDS monitoring can identify malfunctions and/or significant improvement opportunities even after careful design and robust testing. CDS monitoring provides information when responding to user feedback. Ongoing, continuous, and automated monitoring can detect malfunctions in real time, before users report problems. Therefore, CDS monitoring should be part of any systematic program of implementing and maintaining CDS. PMID- 29514354 TI - Cumulative risks of stent migration and gastrointestinal bleeding in patients with lumen-apposing metal stents. AB - BACKGROUND: Delayed gastrointestinal (GI) bleeding and stent migration are known adverse events which may occur following placement of lumen-apposing metal stents (LAMSs). METHODS: All consecutive patients who underwent LAMS placement between May 2011 and June 2017 at a single tertiary medical center were included. Demographics and procedural details were prospectively collected. Post-procedure follow-up and outcome measures were retrospectively collected. The cumulative risks of migration and LAMS-related GI bleeding were estimated using the life table method. Risk predictors were assessed using Cox proportional hazards models. RESULTS: We analyzed 250 patients (64.8 % men; median age 71.6 [interquartile range (IQR) 57.9 - 83.6]). Median follow-up was 78.5 days (IQR 31 246.5 days). Thirty-four stent migrations (13.6 %) occurred (5 symptomatic). On multivariable analysis, associations with migration included nasocystic drains (hazard ratio [HR] 6.5, 95 % confidence interval [CI] 2.2 - 19.3), pancreatic fluid collections (PFCs; HR 4.2, 95 %CI 1.8 - 10.1), and double-pigtail stents (HR 2.4, 95 %CI 1.2 - 4.9). Migration risk at 12 months was 25.5 % (95 %CI 17.9 % - 35.7 %) and was higher for PFCs 48.9 % (33.4 % - 66.9 %) than other indications 8.4 % (4.9 % - 17.5 %; P < 0.001). LAMSs placed for longer durations (i. e. enteral anastomoses, biliary and gallbladder drainage) presented an 8.4 % cumulative risk at 2 years. There were 13 LAMS-related GI hemorrhages (5.2 %), two of them fatal, presenting a median of 3 days (IQR 1 - 9 days) after deployment. The cumulative risk of bleeding at 12 months was 6.9 % (3.6 % - 12.7 %). CONCLUSIONS: LAMS migration occurs in 1 out of 7 cases and is most common when treating PFCs. Bleeding related to LAMS placement occurs much less commonly but can be life-threatening. PMID- 29514355 TI - [Service Use of an Early Intervention Centre, Clinical and Sociodemographic Characteristics of Young Adults with Early Psychosis with and without Migration Background]. AB - BACKGROUND: The present study evaluated service use of our newly established Early Intervention and Treatment Centre (FRITZ) in Berlin for young adults with first or early psychosis with and without migration background. METHODS: We conducted a retrospective chart review of in-patients with early psychosis who were admitted to FRITZ between May 2014 and May 2015. We investigated the proportion of patients with migration background, sociodemographic and clinical characteristics of patients. RESULTS: Corresponding to the proportion of migrants in the catchment area, 35 % of our service users from the catchment area (n = 60) had a migration background. Migrants had a better social adaption, but showed lower insight into illness, less substance induced psychoses and less inpatient admissions. The majority of all patients were admitted to FRITZ via the emergency department. CONCLUSIONS: The findings indicate that FRITZ was almost equally well received by patients with and without migration background. Patients with migration background showed distinct sociodemographic and clinical characteristics that could be relevant for treatment. Implications for future clinical practice are discussed. PMID- 29514356 TI - [Human and Influenza - an Overview]. AB - Influenza is an acute viral disease with involvement of the respiratory tract. It can be life-threatening. New types of influenza viruses can spread globally and cause influenza pandemics with exalted case numbers. The knowledge about epidemiology, preventive hygiene and vaccination, diagnostic, therapy and clinics are essential for the general practitioner as well as the specialist. This article gives an overview with focus on seasonal influenza in adults. In addition, molecular pathological characteristics of influenza viruses are explained and current problems in influenza management are named. The course consists of 10 multiple-choice questions to consolidate the acquired knowledge. PMID- 29514357 TI - ? PMID- 29514358 TI - ? PMID- 29514359 TI - Lithium: A Global Perspective. PMID- 29514360 TI - Efficacy, Tolerability, and Safety of Blonanserin in Schizophrenia: An Updated and Extended Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: We conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) comparing blonanserin with other antipsychotics (amisulpride, aripiprazole, haloperidol, paliperidone, and risperidone). METHODS: Weighted mean difference (WMD), risk ratio, and number needed to harm (NNH) with 95% confidence intervals (95% CIs) were calculated using random-effects model. RESULTS: Ten RCTs (n=1521) were included in this study. Blonanserin was superior to aripiprazole in improvement of Positive and Negative Syndrome Scale total scores (WMD=-10.62, 95% CI=-17.67 to -3.560, p=0.003). Blonanserin was associated with a higher incidence of all-cause discontinuation (RR=1.373, 95% CI=1.088-1.734, p=0.008, NNH=11), akathisia, extrapyramidal disorder, and agitation/excitement and a lower risk of hyperprolactinemia compared with risperidone + paliperidone. DISCUSSION: The current meta-analytic study did not update the comparison of blonanserin vs. haloperidol because there were no new RCTs. Our results suggest that the efficacy of blonanserin for schizophrenia is comparable with that of other antipsychotics, and blonanserin seems to be well tolerated. PMID- 29514361 TI - Erratum to: The Learning Curve Associated with Robotic Total Knee Arthroplasty. PMID- 29514362 TI - Impact of Intravenous Acetaminophen on Lengths of Stay and Discharge Status after Total Knee Arthroplasty. AB - Postoperative pain remains difficult to control after total knee arthroplasty (TKA). While various modalities have been used, they have been associated with several side effects. For example, opioids have many side effects including: sedation, dizziness, nausea, vomiting, constipation, respiratory depression, and can lead to dependency. Recently, intravenous (IV) acetaminophen has been introduced as a method to manage postoperative pain. Therefore, the purpose of this study was to compare the postoperative outcomes of TKA patients who received oral acetaminophen versus IV acetaminophen. Specifically, this study evaluated: (1) the hospital lengths of stay (LOS) and (2) discharge dispositions. The Premier Database was used to review patients who underwent TKA from 2012 to 2015. A total of 134,216 TKA patients received oral acetaminophen, whereas 56,475 TKA patients received IV acetaminophen postoperatively. LOS were calculated as the number of days from the date of hospital admission to the date of discharge, and the discharge disposition was categorized as to home or to a skilled nursing facility (SNF). Compared with the oral group, the IV acetaminophen group had a 0.14 days shorter LOS (95% confidence interval [CI], -0.15 to -0.13; p < 0.001) and 22% higher chance of being discharged home (odds ratio [OR] = 1.22; 95% CI, 1.19-1.25; p < 0.001). Also, compared with the oral group, the IV group had a 13% lower chance of being discharged to a SNF (OR = 0.87; 95% CI, 0.85-0.90; p < 0.001). This study demonstrated that TKA patients who received IV acetaminophen were associated with a significantly shorter hospital LOS as well as being discharged home and fewer patients had to go to SNF. This may lead to a reduction in the total cost of health care, while, at the same time, decreasing the resource use in patients who undergo TKA. PMID- 29514363 TI - Comparison of Techniques for Preimplantation Treatment of Osteochondral Allograft Bone. AB - Articular defects are a major problem with few effective treatment options. Osteochondral allograft (OCA) transplantation can be an effective treatment; however, lack of OCA bone integration can cause failure. This controlled laboratory study was designed to compare clinically applicable methods for marrow element removal and enhanced delivery of bone marrow aspirate concentrate (BMC) to OCA bone. We hypothesized that compressed carbon dioxide (CO2) treatment of OCA bone would result in significantly better marrow element removal, significantly more retention and distribution of viable osteoprogenitor cells, and significantly higher osteoinductive protein elution from OCAs compared with other preimplantation treatments. Fresh humeral heads (n = 24) were harvested and stored for 14 days, then randomly assigned to treatment based on marrow element removal and bone treatment: (standard of care [SOC]) (n = 4) - SOC high-pulse saline lavage, no BMC; (BMC) (n = 5) - saline lavage then canine BMC; (Drill + BMC) (n = 5) - 1.1 mm drill-hole immediately subchondral then saline lavage then BMC injection through drill hole; (Carb + BMC) (n = 5) - saline lavage then CO2 then BMC; or (Saline-Carb + BMC) (n = 5) - saline lavage and CO2 together then BMC. Treated OCAs were cultured for 14 days. On day 3, media were collected, centrifuged to isolate cells, and replaced. Cells were cultured for 11 days for colony forming unit (CFU) determination. OCA media were collected on days 7 and 14 of culture for analysis. On day 14, each graft was assessed for viable cell retention and distribution, and bone marrow element removal. BMC had significantly higher (p = 0.001) viable cell distribution compared with the SOC, Drill + BMC, Carb + BMC, and Saline-Carb + BMC groups. BMC and Drill + BMC had significantly higher (p < 0.05) CFUs than SOC, Carb + BMC, and Saline-Carb + BMC. Drill + BMC and Carb + BMC had the highest media concentrations of the osteoinductive biomarkers. The Carb + BMC and Saline-Carb + BMC groups were associated with significantly superior marrow element removal (p < 0.02) compared with the SOC, Drill + BMC, and BMC groups. Saline irrigation plus saturation with autogenous BMC appears to be the most advantageous preimplantation treatment for OCA transplantation. PMID- 29514364 TI - Patellofemoral Imbalance in a Balanced Total Knee Arthroplasty: How Does it Occur? AB - Despite the overall successful outcomes following primary total knee arthroplasty (TKA) and the concept that a well-balanced TKA yields a more successful result, concerns still remain in the reported literature regarding the patellofemoral joint. Diminished outcomes have been associated with poorly balanced or placed patella implants. The effect of different techniques to achieve flexion-extension balance and the use of posterior stabilized (PS) versus cruciate retaining (CR) implant designs on patellofemoral balancing has not been previously studied. The purpose of this study is to utilize a validated computational analysis software to simulate the effects of varying implant positions and sizes of femoral components. The patellofemoral retinaculum (PFR) load was significantly affected by some conditions, while others did not reach significance. The proximal-distal implant position with knee flexion angle (p < 0.001), the implant size (p < 0.001), and the implant bearing type (CR/PS) (p < 0.05) were significant. For the proximal-distal implant position and knee flexion angle, a more proximal implant position (elevating the joint line) increased the PFR load from 15 to 30 degrees , and a more proximal implant position reduced retinaculum load from 60 to 135 degrees . However, at 45 degrees , implant position does not affect retinaculum load. Achieving the appropriate balance between the dynamic nature of both the tibiofemoral and the patellofemoral interaction in TKA has proven to be complex and challenging to manage. Balancing of a TKA is essential to the proper functioning and overall longevity of the implant. These results demonstrate that patellofemoral balance is affected by implant size and position during flexion extension gap balancing. PMID- 29514365 TI - One-Stage Arthroscopic Reduction Combined with Multiligament Reconstruction or Repair for Irreducible Posterolateral Knee Dislocation: A Retrospective Case Series with Minimum 2-Year Follow-Up. AB - The purpose of this study was to evaluate the clinical outcomes after arthroscopic management of irreducible posterolateral knee dislocation. Twenty one patients with irreducible posterolateral knee dislocation were treated in our institution from January 2009 to May 2014. Inclusion criteria were as follows: (1) patients who underwent one-stage arthroscopic reduction combined with multiligament reconstruction or repair and (2) patients with a minimum 2-year follow-up. Knee stability was assessed using physical examination and side-to side differences (SSD) determined with a KT-1000 arthrometer and Telos stress device. Other assessments included the International Knee Documentation Committee (IKDC) subjective score, Lysholm score, Tegner score, and patient satisfaction rate. Thirteen of the 21 patients (8 males and 5 females) met our inclusion criteria and were included in this analysis. The mean age was 37.8 years (range, 27-56 years). The mean time from injury to surgery was 1.84 days (range, 1-3 days). The mean follow-up period was 32.6 months (range, 24-46 months). At the final follow-up, with the exception of one patient who had an abnormal valgus stress test, all patients achieved normal or nearly normal Lachman test, pivot shift test, posterior drawer test, and varus and valgus stress tests. The mean SSD of total anterior-posterior translation and isolated anterior translation determined with a KT-1000 arthrometer were 2.15 +/- 1.57 mm (range, 0-6 mm) and 1.61 +/- 0.86 mm (range, 1-4 mm), respectively. The mean SSD of anterior translation, posterior translation, and medial and lateral joint gapping determined with a Telos stress device were 2.23 +/- 0.92 mm (range, 1-4 mm), 3.23 +/- 1.16 mm (range, 2-5 mm), 1.77 +/- 1.87 mm (range, 0-7 mm), and 0.46 +/- 0.52 mm (range, 0-2 mm), respectively. The IKDC subjective score, Lysholm score, and Tegner score improved significantly postoperatively (p = 0.001) with a satisfaction rate of 84.6%. One-stage arthroscopic reduction combined with multiligament reconstruction or repair was an effective, reliable treatment for irreducible posterolateral knee dislocation. This is a case series with level of evidence as IV. PMID- 29514366 TI - The Relationship between Soft-Tissue Balance and Intraoperative Kinematics of Guided Motion Total Knee Arthroplasty. AB - A new design of the so-called "guided-motion" total knee arthroplasty (TKA) is expected to produce normal-like kinematics. The implant behaves strictly as a mechanically constraint-guided motion system. However, no previous reports have demonstrated the most appropriate surgical technique or soft-tissue balance that would reproduce ideal kinematics. The purpose of this study was to clarify the relationship between soft-tissue balance and the intraoperative kinematics of guided-motion TKA. In this study, intraoperative kinematics of 95 patients whose TKA was performed with a guided-motion prosthesis (Journey II BCS Smith and Nephew) were measured using the computed tomography (CT)-free navigation system. All procedures were performed via the same soft-tissue balancing technique, which focused on the medial compartment because guided-motion TKA must acquire medial stability to induce medial pivot motion. We measured the extension and flexion osteotomy gaps using a force-controlled compartment-specific ligament tensioner with a distraction force of 80 N for each compartment and divided patients into three groups based on the relationship between extension and flexion joint osteotomy gaps of the medial compartment: group1- loose flexion gap, group 2 equal joint gap, and group 3-tight flexion gap. We compared the preoperative demographic characteristics, implant alignment, and intraoperative kinematics among the three groups. There was no difference between the preoperative demographic characteristics and postoperative implant alignment in the three groups. The relative tibial internal rotational angles in groups 1 and 2 were significantly larger than that in group 3 at 60 degrees , 90 degrees , and maximum flexion (p < 0.05). The appropriate soft-tissue balance of the medial compartment for guided-motion TKA was an equal joint osteotomy gap or a larger flexion than extension gap. A tight flexion gap should be avoided. PMID- 29514367 TI - Unicompartmental Knee Arthroplasty: The Past, Current Controversies, and Future Perspectives. AB - Unicompartmental knee arthroplasty (UKA) is a bone conserving and ligament sparing procedure that reliably restores normal knee kinematics and function for arthritis limited either to the medial or the lateral compartment of the knee. Although there is enough evidence to demonstrate that the UKA offers good medium to long-term success given the correct patient selection, prosthesis design, and implantation technique, there are several reports to suggest inferior survival rates in comparison with the total knee arthroplasty (TKA). Furthermore, it is a specialized procedure which works well in the hands of the experienced operator and therefore different authors' tend to draw different conclusions based on the same evidence, and as a result, there is great variability in the usage of the UKA. The aim of this current concept's review is to present to the readers the history of the UKA especially with reference to implant design, discuss current controversies, and outline the future perspectives of this novel procedure. PMID- 29514368 TI - Multiple Low Doses of Intravenous Corticosteroids to Improve Early Rehabilitation in Total Knee Arthroplasty: A Randomized Clinical Trial. AB - Low doses of corticosteroids have been proved to be effective in decreasing the inflammatory cytokines and relieving the pain. However, the optimal dosage of corticosteroids in total knee arthroplasty (TKA) is undetermined. A total of 103 patients were randomly divided into three groups. Group A containing 32 patients received normal saline. Group B including 36 patients used two doses of 100 mg hydrocortisone, given 2 hours before and 8 hours after surgery. Group C involving 35 patients received four doses of 100 mg hydrocortisone, 8 hours apart.The level of interleukin 6 (IL-6) and C-reactive protein (CRP) were lower in group C than those in group A when detected at 12, 24, and 48 hours after operation and even lower than that in group B at 24 and 48 hours (p < 0.05, all). The visual analog scale (VAS) pain scores were significantly reduced by using two doses of hydrocortisone at the first 12 hours compared with group A (p > 0.05), but it did not show statistic difference 24 hours later (p > 0.05). For comparison, patients with multiple doses achieved continuously better outcomes on pain management than the blank control group within postoperative 36 hours at rest and at 24 hours with activity. In addition, patients using multiple doses of hydrocortisone achieved fewer occurrences of nausea and vomiting, fever, and sleeplessness, better knee function recovery, better patient satisfaction, and shorter length of hospital stays (p < 0.05, all).Multiple dose of hydrocortisone was benefit to the pain management and early rehabilitation in TKA and may be recommended to the clinical practice. PMID- 29514369 TI - What are the Short-Term Outcomes in Multiple Sclerosis Patients after Total Knee Arthroplasty? AB - Due to the paucity of evidence, this study was conducted to evaluate: (1) unique characteristics of multiple sclerosis (MS) patients and (2) short-term clinical outcomes, of primary total knee arthroplasty (TKA) in patients with MS (MS-TKA) compared with matched non-MS patients. MS patients who underwent TKA were identified using the Nationwide Inpatient Sample (NIS) database. The study sample consisted of 10,884 patients with MS and 56,45,227 control cohort. Various patient factors were compared. To control for potential confounders, with the use of propensity scores, MS-TKA patients were matched (1:3) to non-MS-TKA patients and regression analyses were performed to compare perioperative complications, length of stay (LOS), and discharge dispositions. Patients with MS were younger, more likely to be females, on corticosteroids, and more likely to have muscle spasms and gait abnormalities. Annual frequency of TKAs in MS patients increased from 1.16/1,000 TKAs in 2002 to 2.48/1,000 TKAs in 2013 (p < 0.001). Compared with the matched cohort, MS patients had significantly greater odds for any medical complication (odds ratio [OR] = 1.26; 95% confidence interval [CI], 1.11 1.44), longer mean LOS (mean difference: 0.15; 95% CI, 0.09-0.22), and had a greater chance of being discharged to a care facility (OR = 2.17; 95% CI, 1.96 2.40). In this study, we identified specific characteristics of patients with MS who had TKA and analyzed and compared their short-term TKA outcomes to non-MS patients. It was demonstrated that more patients with MS are undergoing TKA, and these patients were at a higher risk of perioperative complications, had longer LOS, and were more likely to be discharged to a sub-acute or inpatient facility. Orthopaedic surgeons should be cognizant of the increased risks and provide proper counseling to MS patients who are candidates for TKA. PMID- 29514370 TI - Contemporary Surgical Trends in the Management of Symptomatic Meniscal Tears among United States Military Servicemembers from 2010 to 2015. AB - : The purpose of this investigation is to report on trends over time in the treatment of meniscal pathology among military orthopaedic surgeons, as well as to evaluate the impact of patient demographics and concomitant procedure on the type of meniscal procedure performed. We performed a retrospective analysis of all active-duty United States military servicemembers who underwent a meniscal procedure from 2010 to 2015 within the Military Health System. Patient demographics and surgical variables were extracted from the electronic medical record. Treatments were categorized by location and by type of intervention (i.e., repair or debridement). Chi-square and linear regression analyses were performed to identify temporal trends in meniscal procedures and factors that were correlated with the type of meniscal procedure performed. Out of 29,571 meniscal procedures analyzed, partial meniscectomy was performed in 81.3% (n = 24,343) of cases, meniscal repair in 20.3% (n = 6,073), and meniscus allograft transplantation (MAT) in 0.7% (n = 206). The rates of debridement, repair, and concomitant surgeries did not demonstrate any significant temporal trends, whereas MAT demonstrated a significant decrease in overall utilization. Nearly two-thirds of all meniscal procedures were performed in the medial compartment. MAT occurred equally between the medial and lateral compartments. Lateral meniscal lesions demonstrated significantly higher rates of debridement. With each year of advancing age, there was a 3.7% increasing likelihood of meniscectomy and 6.5% decreasing likelihood of repair. Females were more likely to undergo meniscal repair than males. Patients in the military population were more likely to undergo meniscal repair compared with previously reported rates in the civilian population. In this physically active cohort of nearly 30,000 military patients, 1 in 5 meniscal tears were treated with meniscal repair. Meniscal repairs were performed at a higher rate for all age groups compared with previously reported rates in the civilian population. Further research is required to elucidate the causative factors behind these differences and the effect on postoperative outcomes. LEVEL OF EVIDENCE: IV, cross-sectional study. PMID- 29514371 TI - Patient-Specific Instrument Can Improve Functional and Radiographic Results during Learning Curve for Oxford Unicompartmental Knee Arthroplasty. AB - The true value of use of patient-specific instrumentation (PSI) systems by inexperienced surgeons during their learning curve to improve the clinical and radiographic outcome of unicompartmental knee arthroplasty (UKA) has not been previously studied. Fifty patients with a mean age of 64.3 years undergoing surgery for Oxford UKA were prospectively divided into two groups. Twenty-five patients were operated on by a surgeon with no prior experience in UKA using a PSI system and the other 25 patients by an experienced surgeon using a conventional procedure. Patients were scored using joint range of motion (ROM), the Knee Society Score (KSS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the 12-item Short-Form (SF-12) before and 3 months and 2 years after surgery. Impact of use of PSI was measured by comparing clinical and radiographic outcome, complications, and implant survival. No evidence of poorer clinical outcome was seen in any subscale of KSS, KOOS, and SF-12 for inexperienced surgeons using PSI (p = 0.45, p = 0.32, and p = 0.61, respectively). No difference was found between the two procedures in precision of radiographic alignment of components (p = 0.53). No complication occurred in any group. PSI may improve precision of component alignment during the learning curve of surgeons, thus achieving functional results similar to those of more experienced surgeons using a conventional procedure. PMID- 29514372 TI - Posterior Condyle Offset and Maximum Knee Flexion Following a Cruciate Retaining Total Knee Arthroplasty. AB - Inconsistent data has been reported on the effect of the femoral posterior condyle offset (PCO) on the maximal knee flexion after total knee arthroplasty (TKA). This study investigated the relationship between the postoperative changes of the PCO and the changes of maximal knee flexion after a cruciate retaining (CR) TKA. Nine patients with medial osteoarthritis (OA) in one knee were investigated. Before operation, each index knee was magnetic resonance imaging (MRI) scanned for construction of a three-dimensional (3D) knee model. The patient then performed a maximal weight-bearing (WB) flexion and the index knee flexion was measured using a dual fluoroscopy technique. At an average of 8 months after a CR TKA, all patients performed the same WB knee flexion. The postoperative changes of the PCO, the posterior cruciate ligament (PCL) elongation, and the posterior tibial slope (PTS) were determined. The postoperative changes of maximal knee flexion were determined by comparing with the preoperative maximal flexion angles of the knee. The correlations of the postoperative changes of PCO and PTS with the postoperative changes of the maximal flexion angle and PCL elongation of the knee were analyzed. The preoperative PCO (28.5 +/- 4.5 mm) was significantly smaller than the postoperative PCO (31.1 +/- 5.1 mm) (p < 0.05). The increasing of PCO after surgery is correlated with the decreasing of maximal knee flexion angle (r = 0.74) and the increasing of PCL elongation (r = 0.64) after the TKA. The PTS was not found to change significantly after the TKA and was not significantly correlated to the maximal knee flexion angle and PCL elongation. The postoperative increases of the PCO were shown to cause overstretching of the PCL and poor flexion angle of the knee after the CR TKA. Restoration of PCO could help optimize the maximal flexion of the knee after the TKA with consideration about PCL tension. PMID- 29514373 TI - Long-Term Clinical Results of Double Bundle Reconstruction of the Medial Patellofemoral Ligament for Patellar Instability. AB - Medial patellofemoral ligament (MPFL) reconstruction is a satisfactory technique for patellar instability, and the anatomical double bundle variant is recommended for better clinical results. However, long-term outcomes are still uncharacterized. This study aimed to assess the effectiveness of double bundle reconstruction of the MPFL for patellar instability by means of established scores. A total of 68 patients with chronic patellar instability who underwent surgery from May 2005 to February 2010 were included prospectively. Anatomical double reconstruction of the MPFL with the semitendinosus tendon was conducted. Tegner Activity Scale (TAS), Kujala score, Lysholm knee score, and objective physical examination were assessed during follow-up. Median follow-up time for the patients was 8 (range, 6-10) years. Eight patients were lost to follow-up after 2 years. Preoperative mean TAS was 2.85 +/- 0.78, increased to 4.91 +/- 0.84 at 6 months and 7.26 +/- 0.78 at 2 years postoperatively, and was 7.82 +/- 0.89 at last follow-up. At last follow-up, pain free at rest was achieved in all patients; and 8 patients had knee pain in activities of daily living. Mean Kujala score was 57.53 +/- 8.59 preoperatively, and increased to 61.22 +/- 6.46, 89.51 +/- 3.90, and 88.92 +/- 3.84 at 6 months, 2 years postoperatively, and at last follow-up, respectively. Lysholm scores were also increased from preoperative values of 43.53 +/- 10.20 to 58.22 +/- 6.80, 89.37 +/- 4.38, and 89.67 +/- 4.13 at 6 months, 2 years postoperatively, and at last follow-up, respectively. Range of motion was 121.44 +/- 12.69, 129.71 +/- 6.39, 130.93 +/- 5.67, and 130.78 +/- 5.80 at preoperative point, 6 months, 2 years postoperatively, and at last follow up, respectively. Long-term clinical results of double bundle reconstruction of the MPFL for patellar instability were encouraging. PMID- 29514374 TI - Tibial Spine Fractures in Children: Evaluation, Management, and Future Directions. AB - Fractures of the tibial spine are estimated to occur in 3 per 100,000 children annually, but account for 2 to 5% of pediatric knee injuries with effusion. Although these fractures were historically associated with bicycle accidents, the surge of organized youth sports in recent decades has brought renewed attention to this injury. While minimally displaced fractures can be treated nonoperatively, several techniques have been described for fixation of displaced or comminuted fractures. Sequelae of this injury can include arthrofibrosis, knee instability, and nonunion. Future collaborative endeavors will aim to further identify risk factors for these complications to optimize the treatment of tibial spine fractures in children. PMID- 29514375 TI - Venous Thromboembolism Prophylaxis after Total Knee Arthroplasty. AB - Venous thromboembolic disease (VTED) is a major cause of morbidity and mortality after total knee arthroplasty (TKA). Current VTED prophylaxis protocols consist of early mobilization, mechanical compression devices, and pharmacologic agents. Venous phasic flow-regulated below-knee devices are generally favored, but the optimal duration and method of mechanical prophylaxis is unknown. Risk stratification models have been developed to guide pharmacologic prophylaxis. For patients with standard VTED risk profile, aspirin has become increasingly popular. Recent studies have validated the efficacy, relatively low bleeding risks, and cost-effectiveness of aspirin in the patients with standard risk profile. Current evidence suggests that the newer oral anticoagulants, including the factor Xa and the direct thrombin inhibitors, are effective for the reduction of postoperative VTED but may be associated with increased bleeding and wound complication rates. PMID- 29514376 TI - Contemporary Perioperative Analgesia in Total Knee Arthroplasty: Multimodal Protocols, Regional Anesthesia, and Peripheral Nerve Blockade. AB - Perioperative care of the total knee arthroplasty (TKA) patient has evolved considerably over the past decade. Among the changes driving this evolution toward shorter hospitalization and accelerated rehabilitation have been regional anesthesia, peripheral nerve blockade, and multimodal analgesia protocols. These complementary techniques are increasingly supported by scientific evidence, though considerable uncertainty persists regarding the optimal combination of strategies. Continued refinement of technique and critical evaluation is trending toward greater characterization of the comparative effectiveness of myriad options. Contemporary interdisciplinary arthroplasty care teams have the opportunity to individualize the TKA patient's perioperative pain control to optimize not only the clinical outcome but also patient satisfaction. PMID- 29514377 TI - Proximal Tibial Fractures in the Pediatric Population. AB - Injuries about the proximal tibia are quite common in children. Understanding the mechanisms of injury and treatment strategies is imperative for practitioners caring for these patients. Similarly, appreciating the anatomy of the proximal tibia and the adjacent neurovascular structures can assist a practitioner in recognizing the potential associated risks following fracture. Patients with injuries about the proximal tibia require long-term follow-up, and knowledge of the natural history of these fractures is imperative. PMID- 29514378 TI - Muscular Strength is Independently Associated with Cystatin C: The KORA-Age Study. AB - The purpose of this study was to investigate if there is a link between muscular strength (MS) and markers of chronic kidney disease (CKD) among older adults. The cross-sectional analysis based on 1041 men and women, aged 65-94 years, who participated in the KORA-Age study. Participants underwent an interview and extensive examinations including anthropometric measurements, diseases and drug intake registration, determination of health-related behaviors, collection of blood samples for measurements of cystatin C and maximal muscle strength evaluation. One-Way ANOVA revealed significant differences in both mean cystatin C (1.16+/-0.37 vs. 1.03+/-0.29 vs. 0.93+/-0.24 mg/L, p<0.001) and mean eGFRcysC (63.61+/-18.61 vs. 72.14+/-18.92 vs. 79.87+/-18.19 ml/min/1.73 m2, p<0.05) across thirds of maximal muscular strength (from lowest to highest). MS in the lowest third was significantly associated with increased odds of having elevated cystatin C (OR: 1.70, 95% CI: 1.01-2.85, p=0.043) after controlling for age, gender, fat mass, fat-free mass, alcohol intake, smoking status, number of regularly used medications, multimorbidity status, hs-CRP, telomere length and levels of physical activity. Lower levels of MS are independently associated with higher concentrations of cystatin C and lower eGFRcysC in older individuals. Increasing the levels of muscular strength may be useful to prevent the age related CKD disease of older adults. PMID- 29514379 TI - [In Vitro Study of Subablative Er : YAG Laser and Diode Laser Therapy vs. Thermal Cautery in Microbial Keratitis]. AB - BACKGROUND: In microbial keratitis, thermal cautery leads to thermal necrosis associated with germ reduction. Subablative heating of the cornea using an Er : YAG laser or diode laser is an alternative option. Thermal effects and reproducibility of both procedures were investigated. MATERIAL AND METHODS: Thermal effects were monitored with an infrared imaging system. Temperature of stromal tissue of enucleated porcine eyes was measured. Effects of thermal injury were rated by microscopic photography and histopathologic examination. Reduction of living bacteria was visualized by laser scanning microscopy and fluorescent stain on stromal tissue models containing E. coli bacteria. RESULTS: Corneal samples showed thermal damage depths of 110 - 250 um after thermal cautery at contact times of 1 - 3 s. Superficial temperature ranged from 70 to 80 degrees C. Thickness of thermal necrosis after laser irradiation was between 50 and 270 um. Temperature ranged from 60 to 120 degrees C. Laser scanning microscopy of a stromal tissue model, comprising Escherichia coli bacteria in soft agar, showed a mortification of bacteria over 40% up to 100 um depth after treatment for 25 s. Treatment with diode laser showed an even better effect: more than 60% of bacteria were dead up to 250 um depth and more than 50% up to 450 um depth in the stromal tissue model. CONCLUSIONS: All procedures are able to induce high temperatures in tissue to achieve effective germ reduction in corneal stroma. Effect and reproducibility of the thermal cautery procedure depends on the surgeon's experience. Energy dose and thermal effect can be calculated for the Er : YAG and diode laser procedure to affect the infected stromal layer selectively. PMID- 29514380 TI - [Evaluation of Changes in Corneal Biomechanics in Patients with Systemic Sclerosis]. AB - INTRODUCTION: Our study compares the biomechanical properties of the cornea in patients with long-term pre-existing (for at least 10 years) systemic sclerosis (SSc) with those of healthy suspects. MATERIAL/METHODS: The examination was performed in 14 systemic SSc patients and 38 healthy volunteers. Non-invasive assessment of corneal biomechanical parameters, including central corneal thickness (CCT), corneal hysteresis (CH) and corneal resistance factor (CRF), was performed in one randomised study eye in accordance with a standardised protocol. Intraocular pressure (IOP) values were analysed using different measuring techniques, including Goldmann applanation tonometry (GAT), dynamic contour tonometry (DCT) and Ocular Response Analyzer(r) (ORA)-based non-contact tonometry (NCT), GAT-correlated IOP (IOPgat) and CCT-compensated-IOP (IOPcc). RESULTS: When measured with DCT and ORA-based NCT, IOP levels were significantly lower in SSc patients than in the control group (DCT IOP: p = 0.048, NCT IOPgat: p = 0.002, NCT IOPcc: p < 0.001). CCT was also significantly reduced in the SSc (p = 0.001). There were no statistically significant differences between the groups in CH and CRF. The difference between the corrected values (CHcorr - CRFcorr) was negative in the two groups. This was slightly lower for the SSc patients (delta = - 0.83) than for the control group (delta = - 0.66). For SSc patients, there were highly significant negative correlations between CH and CRF and between CHcorr and CRFcorr. In contrast, in the control group there was a non-significant positive correlation between age and biomechanical properties. CONCLUSION: In the course of the disease SSc leads to various alterations in connective tissue, which can also involve corneal tissue. CCT becomes significantly thinner and simultaneously partially loses elastic properties and gains viscosity. This accounts for reduced IOP values with dynamic contour tonometry as well as with ORA-tonometry (Goldmann correlated IOP, CCT-compensated IOP). This distinct pre-existing significant negative correlation between age and CH and CRF values in patients with SSc could be due to slight regression of the viscous components and diminution of corneal damping capacity. PMID- 29514381 TI - [What is a Cataract, and When Should its Removal be Indicated? An Opinion]. AB - Not every cataract needs phacoemulsification. One problem is the terminological differentiation between "physiological loss of transparency due to ageing" and "cataract". In case of a "real cataract" the autonomous patient must be informed "in any direction". The time of phacoemulsification is determined by the patient and not by the ophthalmologist. PMID- 29514382 TI - Presentation of Original Research at the European Congress of Radiology 2010: Frequency of Publication in Medline-Indexed Journals Within 5 Years After Presentation. AB - OBJECTIVES: To determine the rate at which original studies presented orally at the European Congress of Radiology (ECR) 2010 were published in Medline-indexed journals and to identify factors predictive of publication. METHODS: A total of 869 abstracts were included in the study. A Medline search of articles published between March 2010 and February 2015 was conducted to identify articles written by the first, second, and/or last authors of all abstracts published in the Scientific Program of ECR 2010. The publication year, journal, country of origin, subspecialty and nature of the research (i. e., human, animal or technical) were recorded. RESULTS: Between March 2010 and February 2015 a total of 450 abstracts (publication rate, 51.8 %) were subsequently published in 125 Medline-indexed journals, chiefly in European Radiology (11.1 %). 443/450 (98.4 %) articles were published in English language. The subspecialties of molecular imaging and cardiac imaging had the highest publication rates (75.0 % and 62.0 %, respectively), while computer application studies had the lowest (27.6 %). The nature of research, origin of the abstract and subspecialty significantly influenced the subsequent publication rate. CONCLUSION: More than half of the original studies presented orally at ECR 2010 were subsequently published in Medline-indexed journals. More articles were published in the journal European Radiology than in any other identified journal. KEY POINTS: . ECR 2010 had a high subsequent publication rate. . Most subsequently published articles were published in radiology journals. . Nearly all articles were published in the English language. CITATION FORMAT: . Dollinger M, Zeman F, Muller-Wille R et al. Presentation of Original Research at the European Congress of Radiology 2010: Frequency of Publication in Medline-Indexed Journals Within 5 Years After Presentation. Fortschr Rontgenstr 2017; 190: 327 - 333. PMID- 29514383 TI - Quantitative and Qualitative Assessment of Pulmonary Emphysema with T2-Weighted PROPELLER MRI in a High-Risk Population Compared to Low-Dose CT. AB - PURPOSE: To determine the suitability of T2-weighted PROPELLER MRI for the assessment of pulmonary emphysema. MATERIALS AND METHODS: 60 participants in a lung cancer screening program (30 subjects with pulmonary emphysema, and 30 control subjects without emphysema) were included for this retrospective study. All subjects were examined with low-dose CT (LDCT) and MRI within the screening program. The use of a T2-weighted PROPELLER sequence for the assessment of emphysema was analyzed and correlated with the results of LDCT. The presence and the extent of pulmonary emphysema were first assessed qualitatively using a three point score, and then quantitatively with a semi-automated software program to obtain emphysema indices. RESULTS: All 30 cases with pulmonary emphysema were accurately detected by MRI. There were 3 cases with emphysema according to MRI without emphysematous changes on LDCT (false-positive results). The qualitative scores as well as the emphysema indices were significantly higher in the emphysema group compared to the control group for MRI and LDCT (p < 0.001). Both the scores and the indices correlated significantly between MRI and LDCT (qualitative score of severity: r = 0.912/p < 0.001 in the emphysema group and r = 0.668/p < 0.001 in the control group; emphysema index: r = 0.960/p < 0.001 in the emphysema group and r = 0.746/p < 0.001 in the control group). CONCLUSION: The presence and the extent of pulmonary emphysema may be assessed qualitatively and quantitatively by T2-weighted PROPELLER MRI with very good correlation to LDCT. KEY POINTS: . T2-weighted PROPELLER MRI may be suitable for the assessment of pulmonary emphysema.. . There was significant correlation between MRI and LDCT regarding qualitative scores and quantitative emphysema indices in our study with correlation coefficients for different subgroups ranging from r = 0.668 to r = 0.960.. . T2-weighted PROPELLER MRI may have the potential to be used for follow up examinations in patients with severe emphysema to avoid radiation exposure of repeated CTs.. CITATION FORMAT: . Meier-Schroers M, Sprinkart AM, Becker M et al. Quantitative and Qualitative Assessment of Pulmonary Emphysema with T2-Weighted PROPELLER MRI in a High-Risk Population Compared to Low-Dose CT. Fortschr Rontgenstr 2018; 190: 733 - 739. PMID- 29514384 TI - Externally Acquired Radiological Image Data and Reporting for the Clinical Routine, Conference and Boards - Legal Aspects of the Second Opinion in Germany. AB - BACKGROUND: Because of an increasing number of boards and conferences, the number of second opinion readings of externally acquired image data is growing dramatically. In this review article we intend to give medical and legal recommendations for the documentation and interpretation of externally acquired radiological data for second opinions and board presentations based on German jurisdiction. METHOD: Using the FAQ format as a dialog between radiologists and medical legal experts, we answer the most crucial questions regarding correct documentation and interpretation for externally acquired radiological image data based on an up-to-date literature search. RESULTS: Based on the unity of radiological image data and the corresponding written report according to the radiation protection law, the primary report should be present when composing a second opinion. If the primary external report is not present, this should be mentioned as a limitation. All radiological second opinions should be documented in written form. This is especially important in cases of discrepant findings. Legally, the attending physician is responsible for selecting the radiological opinion. The radiologist should not rely on the written primary report without personal reevaluation. Legally, it would be considered radiological malpractice if the external image data and previous image data are not evaluated personally. CONCLUSION: From a legal point of view, there are explicit recommendations regarding thorough documentation of a second opinion as an independent medical service in all cases. KEY POINTS: . The written external report should be present when composing a second opinion report or case presentation.. . Second opinions or external case interpretations should be documented in written form.. . It is considered malpractice to completely rely on the external written report for a second opinion.. . In discrepant radiological findings the treating physician is responsible for choosing the correct radiological interpretation.. CITATION FORMAT: . Schreyer AG, Rosenberg B, Steinhauser RT. Externally Acquired Radiological Image Data and Reporting for the Clinical Routine, Conference and Boards - Legal Aspects of the Second Opinion in Germany. Fortschr Rontgenstr 2018; 190: 610 - 615. PMID- 29514385 TI - Analysis of presurgical uterine artery embolization (PUAE) for very large uterus myomatosus; patient's desire to preserve the uterus; case series and literature review. AB - PURPOSE: Purpose of this paper to present results of a group of 21 consecutive patients who underwent uterine artery embolization (UAE) immediately before myomectomy. Surgical myomectomy can lead to a substantial blood loss in case of large or multiple tumors due to the hypervascularization of the tumors. This may lead to multiple blood transfusion or hysterectomy. In cases were the preservation of the uterus is demanded, pre-operative embolization could reduce the risk of substantial bleeding. MATERIALS AND METHODS: Between January 2011 and March 2016, 21 patients underwent UAE 24 hours before myomectomy. All patients were asked by questionnaire about post-surgical follow-up, complications, the length of the scar, satisfaction and improvement of symptoms. Data of the operation and embolization were retrospectively assessed. RESULTS: UAE could be performed in all patients without complications. Mean diameter of the largest myoma was 12.7 +/- 3.2 cm, primary preservation of the uterus succeeded in all cases. In none of the cases a perioperative blood transfusion was necessary. One patient underwent hysterectomy in another hospital after primary successful resection, one patient received transfusion of 2 bags of red blood cell concentrate during her stay in hospital.11 of 21 patients responded to the questionnaire. 10 of 11 had subjective symptom improvement. Mean inability to work was 31 days, the mean self-measured length was 12 cm. 9 of 11 patients would recommend the procedure, one patient was in the second trimester of pregnancy. CONCLUSION: Preoperative uterine artery embolization facilitates a safe and uterus-preserving myomectomy in patients with very large or multiple fibroids. KEY POINTS: . Uterus-preserving myomectomy can be used in cases of large uteri or with multiple fibroids with low amount of blood loss.. . The combination of preoperative embolization and subsequent myomectomy may be a therapeutic option in cases of infertility due to a fibroid-induced uterine deformation.. . Good interdisciplinary cooperation is essential for sustainable results in this complex group of patients.. CITATION FORMAT: . Schnapauff D, Russ M, Kroncke T et al. Analysis of presurgical uterine artery embolization (PUAE) for very large uterus myomatosus; patient's desire to preserve the uterus; case series and literature review. Fortschr Rontgenstr 2018; 190: 616 - 622. PMID- 29514386 TI - ? PMID- 29514387 TI - ? PMID- 29514388 TI - iRoot FM exerts an antibacterial effect on Porphyromonas endodontalis and improves the properties of stem cells from the apical papilla. AB - AIM: To investigate the antibacterial activity of a novel intracanal medicament, iRoot FM, against Porphyromonas endodontalis and its effects on the proliferation and osteo-/odontogenic differentiation of stem cells from apical papilla (SCAP). METHODOLOGY: The agar diffusion test was used to compare the antimicrobial efficacy of iRoot FM with two traditional intracanal medicaments, calcium hydroxide [Ca(OH)2 ] and triple antibiotic paste (TAP). The CCK-8 assay was used to assess the proliferation rate of SCAP when exposed to the three intracanal medicaments. The expression levels of ALP and DMP-1 and the capacity to form mineralized nodules were used to evaluate the osteo-/odontogenic differentiation of SCAP, as assessed by real-time PCR, Western blotting and alizarin red S staining. Data were statistically analysed with one-way analysis of variance (anova), and comparisons between each of two groups were analysed by the least significance difference method. P values less than 0.05 were considered statistically significant. RESULTS: The zone of inhibition against P. endodontalis produced by iRoot FM was 20.74 +/- 4.35 mm, whilst the zones of inhibition of Ca(OH)2 and TAP were 24.89 +/- 3.84 mm and 34.51 +/- 1.20 mm. The antibacterial capacity of iRoot FM was similar to that of Ca(OH)2 (P > 0.05). SCAP, cultured in conditioned medium with iRoot FM, was associated with greater proliferation and osteo-/odontogenic differentiation capacity than those cultured in conditioned medium with Ca(OH)2 and TAP (P < 0.05). Moreover, iRoot FM had no negative effects on the proliferation rate of SCAP. CONCLUSIONS: iRoot FM exhibited excellent antibacterial activity against P. endodontalis and could improve the proliferation and differentiation of SCAP. The findings provide evidence that iRoot FM has potential as an intracanal medicament for endodontic procedures in immature permanent teeth. PMID- 29514390 TI - Direct acting antivirals for patients without advanced liver disease: All for treatment and treatment for all? PMID- 29514389 TI - Host and viral factors associated with serum hepatitis B virus RNA levels among patients in need for treatment. AB - : Hepatitis B virus (HBV) RNA in serum is a novel biomarker for intrahepatic HBV replication and treatment response. For its proper use, it is essential to identify factors influencing serum HBV RNA level. Using a rapid amplification of complimentary DNA (cDNA) ends (RACE) PCR technique (lower limit of detection [LLD], 800 copies/mL [c/mL]), serum HBV RNA levels were measured in samples of 488 untreated individuals with chronic HBV infection who were eligible to treatment according to currently used recommendations. We explored the association of serum levels of HBV RNA with patient- and virus-associated factors. HBV genotype distribution was 21/10/20/46/3% for A/B/C/D/other. Mean HBV RNA serum level was 5.9 (1.6) log10 c/mL (hepatitis B e antigen [HBeAg]-positive chronic hepatitis B [CHB], 6.5 [1.2] log c/mL; HBeAg-negative CHB, 4.1 [1.2] log c/mL; P < 0.001). By multivariable linear regression, factors associated with lower HBV RNA level were HBeAg negativity (beta = -0.69; P < 0.001), HBV genotypes A (beta = -0.13; P = 0.002), B (beta = -0.07; P = 0.049), and C (beta = -0.61; P < 0.001) in comparison to D, and presence of HBV basal core promoter mutation either alone (beta = -0.14; P = 0.001) or in combination with precore mutation (beta = -0.22; P < 0.001). Higher serum alanine aminotransferase (ALT) was associated with higher HBV RNA (beta = 0.23; P < 0.001). HBV RNA correlated strongly with HBV DNA (HBeAg-pos, r = 0.72; P < 0.001; HBeAg-neg, r = 0.78; P < 0.001) and moderately with quantitative hepatitis B surface antigen (qHBsAg; HBeAg-pos, r = 0.54; P < 0.001; HBeAg-neg, r = 0.19; P = 0.04) and quantitative hepatitis B surface antigen (qHBeAg; r = 0.41; P < 0.001). CONCLUSION: In this multiethnic cohort of 488 untreated individuals with CHB, factors associated with serum HBV RNA level were HBeAg status, serum ALT, HBV genotype, and presence of basal core promotor mutations. For the future use of serum HBV RNA as a clinical marker, it seems mandatory to take these factors into consideration. (Hepatology 2018). PMID- 29514391 TI - Use of glucose biosensors to measure extracellular glucose exudation by intertidal microphytobenthos in southern Tasmania. AB - Micro glucose biosensors were used to measure net extracellular glucose produced by natural microphytobenthos and three diatom cultures (Amphora coffeaeformis, Navicula menisculus, Nitzschia longissima) from southern Tasmania, Australia. They were exposed to a light gradient in either nutrient-replete or nutrient limiting conditions. Glucose exudation in the natural communities increased with increased light but the response in the cultures was variable. Similarly, nutrient-replete conditions elicited lower rates of glucose exudation in the natural communities but produced variable species-specific responses in the cultures. Increased glucose exudation mostly correlated with a reduction in maximum quantum yield (Fv /Fm ). The same trend was observed in the natural communities for relative maximum electron transfer rates (rETRmax ) but responses in the cultures were again variable and species-specific. Responses of the three species to increased light and nutrient deficiency were variable, although glucose exudation, Fv /Fm and rETRmax was mostly lower in the nutrient-limited media. In a second set of experiments species/communities were treated with/without antibiotics. In the dark, glucose concentrations in treatments with antibiotics remained unchanged, while in those with bacteria, it fell rapidly. In the sediment communities, glucose consumption in the dark was ~25% the rate of exudation at the highest light level. In culture, exudation rates were up to 100% greater than those with active bacteria. Rates of glucose consumption in the dark in the antibiotic-treated samples were negligible and up to 104 times lower than those with active bacteria. These results demonstrate the important role extracellular glucose exudation has on maintaining an active microbial loop. PMID- 29514392 TI - Hypothalamic endoplasmic reticulum stress as a key mediator of obesity-induced leptin resistance. AB - Obesity is an epidemic disease that is increasing worldwide and is a major risk factor for many metabolic diseases. However, effective agents for the prevention or treatment of obesity remain limited. Therefore, it is urgent to clarify the pathophysiological mechanisms underlying the development and progression of obesity and exploit potential agents to cure and prevent this disease. According to a recent study series, obesity is associated with the development of endoplasmic reticulum stress and the activation of its stress responses (unfolded protein response) in metabolically active tissues, which contribute to the development of obesity-related insulin and leptin resistance, inflammation and energy imbalance. Hypothalamic endoplasmic reticulum stress is the central mechanism underlying the development of obesity-associated leptin resistance and disruption of energy homeostasis; thus, targeting endoplasmic reticulum stress offers a promising therapeutic strategy for improving leptin sensitivity, increasing energy expenditure and ultimately combating obesity. In this review, we highlight the relationship between and mechanism underlying hypothalamic endoplasmic reticulum stress and obesity-associated leptin resistance and energy imbalance and provide new insight regarding strategies for the treatment of obesity. PMID- 29514394 TI - Reply. PMID- 29514393 TI - Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients. AB - BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients. METHODS: Six cases of PJP occurred in HTx recipients within 10 months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates. RESULTS: At the time of PJP-related hospitalization, patients' mean age was 49 +/- standard deviation 4 years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2 years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases. CONCLUSIONS: We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6 months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks. PMID- 29514395 TI - Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions. AB - OBJECTIVE: To investigate the detection rate of 16p11.2 recurrent microdeletions in fetuses with abnormal ultrasound findings and determine the common abnormal ultrasound findings in fetuses carrying the deletion. METHODS: This study reviewed 2262 consecutive fetuses with abnormal ultrasound findings who underwent prenatal chromosomal microarray analysis between October 2014 and December 2016. Cases carrying the 16p11.2 recurrent microdeletion were further genetically analyzed, and their clinical features were reviewed. RESULTS: The 16p11.2 recurrent microdeletion was identified in 12 fetuses, who had skeletal malformations (5/12), cardiovascular malformations (4/12), or isolated ultrasound markers (3/12). Approximately 0.5% (12/2262) of the fetuses with abnormal ultrasound findings harbored the deletion. The 5 fetuses with skeletal malformations displayed vertebral defects, particularly in the hemivertebra and butterfly vertebra. The detection rate of the 16p11.2 recurrent microdeletion was statistically significant (P < .05) among fetuses with skeletal malformations (3.6%, 5/140), fetuses with cardiovascular malformations (1.1%, 4/367), and fetuses with isolated ultrasound markers (0.4%, 3/702). CONCLUSION: The most frequent ultrasound findings in fetuses with 16p11.2 recurrent microdeletions are skeletal malformations (particularly vertebral malformations), followed by cardiovascular malformations, and isolated ultrasound markers. PMID- 29514396 TI - Thoracic epidural analgesia in donor hepatectomy: An analysis. PMID- 29514397 TI - Influence of auditory attention on sentence recognition captured by the neural phase. AB - The aim of this study was to investigate whether attentional influences on speech recognition are reflected in the neural phase entrained by an external modulator. Sentences were presented in 7 Hz sinusoidally modulated noise while the neural response to that modulation frequency was monitored by electroencephalogram (EEG) recordings in 21 participants. We implemented a selective attention paradigm including three different attention conditions while keeping physical stimulus parameters constant. The participants' task was either to repeat the sentence as accurately as possible (speech recognition task), to count the number of decrements implemented in modulated noise (decrement detection task), or to do both (dual task), while the EEG was recorded. Behavioural analysis revealed reduced performance in the dual task condition for decrement detection, possibly reflecting limited cognitive resources. EEG analysis revealed no significant differences in power for the 7 Hz modulation frequency, but an attention dependent phase difference between tasks. Further phase analysis revealed a significant difference 500 ms after sentence onset between trials with correct and incorrect responses for speech recognition, indicating that speech recognition performance and the neural phase are linked via selective attention mechanisms, at least shortly after sentence onset. However, the neural phase effects identified were small and await further investigation. PMID- 29514398 TI - Relatives' involvement in the care of patients in acute medical wards in two different countries-An ethnographic study. AB - AIMS AND OBJECTIVES: To explore the nature of relatives' involvement in the care of patients in acute medical settings in Australia and Saudi Arabia and to explore the perceptions, attitudes and experiences of nurses. BACKGROUND: There is little known about how relatives respond to being involved in patient care and the impact this has on the quality of care. Equally, little is known about how nurses enable such involvement. Previous studies have focused on settings such as critical care and paediatrics where relatives' involvement as advocates is mostly acknowledged and accepted. DESIGN: The study used a qualitative ethnographic approach based on an interpretive paradigm. METHODS: Data collection was carried out in medical settings in two major hospitals: one in Australia and another in Saudi Arabia. Data were collected by observations and interviews over a 6-month period, with 3 months spent in each setting. RESULTS: In both fields, relatives and nurses faced ongoing ambiguity about the role relatives should play in the hospital environment. Nurses were challenged by the unpredictability of relatives' participation in patient care. The nurses' fear of taking responsibility and uncertainty about the relatives' role led them to take varied and individualised approaches to the involvement of relatives in patient care. Relatives were unclear about how to behave in the role; what the needs of patients were; and whether they were contributing positively to care and this resulted in frustration. CONCLUSION: The results show that ambiguity regarding the role of relatives led to problems in patient care such as safety concerns and conflict with nurses. RELEVANCE TO CLINICAL PRACTICE: This study identified the need for patients' relatives and nursing staff to more actively engage in negotiating and managing their respective roles in acute medical areas. This could be supported by the development and use of a set of principles or guidelines for nurses, relatives and patients regarding relatives' involvement in hospital care settings to reduce ambiguity for all involved. PMID- 29514399 TI - Relationships between socio-clinico-demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest Old Survey on Total Health (TOOTH). AB - BACKGROUND: Despite a steady increase in life expectancy, a few studies have investigated cross-sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio-clinico-demographic factors in the oldest-old exclusively. OBJECTIVES: The aims of this study were to examine socio-clinico-demographic characteristics associated with global cognition and its changes in the oldest-old. METHODS: We reanalyzed a dataset of cognitively preserved community-dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6-year longitudinal observational study. This study consisted of (1) baseline cross-sectional analyses examining correlates of global cognition (n = 248) among socio-clinico-demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3-year follow-up (n = 195). The Mini-Mental State Examination was used as a screening test to assess global cognition. RESULTS: At baseline, higher weights were related to higher cognitive function in the oldest-old. The baseline predictors of global cognitive decline in 3-year follow-up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order. CONCLUSIONS: The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest-old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population. PMID- 29514400 TI - Salpingopharyngeal fistula as a treatment for guttural pouch mycosis in seven horses. AB - BACKGROUND: Guttural pouch mycosis (GPM) is a cause of nasal discharge, dysphagia and fatal haemorrhage in the horse. OBJECTIVES: To report the complications and success of salpingopharyngeal fistulation in horses with GPM. We hypothesised that creating a direct static opening into the guttural pouch from the pharynx would cause a regression of fungal plaques due to a change in the guttural pouch environment and that this treatment would result in resolution of infection prior to secondary complications. STUDY DESIGN: Retrospective case series. METHODS: The medical records of all horses diagnosed with GPM that were presented to New Bolton Center between the years 2006 and 2017 were examined retrospectively. Seven cases of guttural pouch mycosis treated with salpingopharyngostomy without other surgical intervention were included. Information collected included signalment, presenting complaint, which pouch was affected, size and location of the plaques, laryngeal and pharyngeal function, concurrent medical therapy, location of the fistula, surgical time, time to resolution of clinical signs, time to full resolution of the mycotic plaque, and patency of the salpingopharyngostomy site. RESULTS: Nasal discharge resolved in 10-30 days post operatively in all cases where nasal discharge was present. The mycotic plaques showed complete resolution at time points ranging from 1 to 6 months post operatively. No case developed epistaxis or neurological deficits post operatively that were not present at presentation. MAIN LIMITATIONS: There were differing adjunctive treatments between cases. This technique is not appropriate for horses that have had epistaxis or are currently bleeding. CONCLUSIONS: Salpingopharyngostomy can minimise cost of treatment, be performed on an outpatient basis and provide better exposure of the infected area with few complications. This case series documents seven cases treated with this method that resolved the infection without any further complications of the mycosis. PMID- 29514401 TI - Radiotherapy for anal squamous cell carcinoma: must the upper pelvic nodes and the inguinal nodes be treated? AB - BACKGROUND: Loco-regional failure is the predominant cause of death in anal squamous cell carcinoma. We assessed patterns of loco-regional recurrence to determine the impact of radiotherapy (RT) volumes on patient outcome. METHODS: Retrospective clinical study, including patients treated curatively with RT or chemo-radiotherapy between 1994 and 2007. RT fields/volumes were reviewed and compared with patterns of failure. Patients were classified as having whole pelvic radiotherapy (WPRT) if RT extended to L5/S1 or lower pelvic radiotherapy (LPRT) if it extended to the lower sacroiliac joints or below. Patients with negative inguinal nodes either underwent prophylactic inguinal radiotherapy (PIRT) or had inguinal observation (IO). Patterns of failure were compared. RESULTS: Twenty-seven patients (53%) had WPRT and 24 (47%) had LPRT. Forty-two patients had negative inguinal nodes: 29 (69%) had PIRT and 13 (31%) had IO. Median follow-up was 5.8 years. Twelve regional failures occurred in eight patients: three pelvic, one inguinal and four pelvic and inguinal. All patients with regional failure died of disease. Pelvic nodal failure was 7.7% in N0 and 33% in N1-3 patients (P = 0.012). There was no difference in pelvic regional failure between WPRT and LPRT (11% versus 16%, P = 0.64). There was only one possible regional failure above LPRT in this group (4%). Inguinal failure was 0% in the PIRT group compared with 23% in IO group (P = 0.009). CONCLUSION: There was no difference in pelvic regional failure between WPRT and LPRT. LPRT is likely to be safe in N0 patients. Inguinal nodes should be treated in all patients. PMID- 29514402 TI - How fundamental aspects of nursing care are defined in the literature: A scoping review. AB - AIMS AND OBJECTIVES: To investigate how fundamental aspects of nursing care have been defined in the literature from 2010-2016. BACKGROUND: A 2010 narrative review of nursing texts identified little consensus on what constitutes the fundamental aspects of nursing care. Since then there has been a proliferation of policies, strategic frameworks and research teams dedicated to investigating such care. It is unclear whether this increased activity has led to greater conceptual clarity. DESIGN: Scoping review using the Joanna Briggs Institute methodology. METHODS: A search of published and grey literature was undertaken using CINAHL, Scopus, PubMed and ProQuest. Documents providing a definition for fundamental aspects of nursing care were included for review. Definitions were identified and mapped. RESULTS: Forty-nine documents were included. Two ways of constructing the discourse around fundamental aspects of nursing care were identified: compassionate care (n = 25) and fundamentals of care (n = 24). The literature on compassionate care focused primarily on the moral attributes of nurses and their ability to establish meaningful connections with patients. The literature on fundamentals of care was split between describing such care as a list of nursing activities and describing it as a complex, multidimensional construct. CONCLUSIONS: There appears to be a lack of consensus around how fundamental aspects of nursing care are defined. Compassionate care and fundamentals of care have commonalities in terms of emphasising the nurse-patient relationship; however, only the literature on fundamentals of care addresses patients' physical care needs. Despite their commonalities, it seems the two bodies of work are being developed largely independent of one another. RELEVANCE TO CLINICAL PRACTICE: This scoping review identified areas of convergence and divergence around fundamental aspects of nursing care. An agreed definition for such care is needed to enable the development of a robust evidence base to underpin the coherent and consistent development of nursing practice. PMID- 29514403 TI - Mechanical circulatory support for acute right ventricular failure in the setting of pulmonary embolism. AB - BACKGROUND: Right ventricular (RV) failure due to pulmonary embolism (PE) increases morbidity and mortality and contributes to prolonged hospital length of stay and higher costs of care. RV mechanical circulatory support (MCS) including Impella RP devices have been increasingly used in hemodynamically compromised PE patients who are refractory to intravascular volume expansion and inotropic therapy. However, effectiveness and safety of Impella RP, in hemodynamically unstable PE patients is unknown. METHODS: We included consecutive patients who presented to Detroit Medical Center between November 3, 2015 and October 2, 2017 with acute PE and had evidence of hemodynamic compromise indicating Impella RP. RESULTS: Total of five cases were identified. All patients met the shock definition due to massive or submassive PE and therefore received Impella RP on admission. Cardiac index was improved from mean of 1.69/min/m2, (0.88-2.15 L/min/m2 ), to 2.5 L/min/m2 (range 1.88-3.4), after 24 h of treatment. Similarly, mean heart rate reduced to 92 beats per minute (79-105), and mean systolic blood pressure increased to 140 mmHg (115-179). No significant changes were found in renal function, hemoglobin and platelets level during device use. One patient experienced hemoglobin drop from 13.7 to 7.3 g/dL but did not require blood transfusion. All patients survived to discharge. CONCLUSION: In patients with PE and RV shock, Impella RP device resulted in immediate hemodynamic benefit with reversal of shock and favorable survival to discharge. PMID- 29514404 TI - A prospective cohort study of early-pregnancy risk factors for gestational diabetes in polycystic ovarian syndrome. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is a strong risk factor for gestational diabetes (GDM). However, the association between features of PCOS during early pregnancy and the risk of GDM is not clearly characterized. In this prospective cohort study, we seek to identify early-pregnancy risk factors for GDM in PCOS women. METHODS: Between 2011 and 2013, 248 women with PCOS were followed from their first prenatal visit to delivery. Multiple early-pregnancy metabolic factors were evaluated for their association with the risk of GDM. RESULTS: Among 248 subjects, 75 (30.2%) developed GDM. Single factor analysis identified a number of metabolic risk factors for GDM, including higher body mass index, fasting plasma glucose (FPG) and insulin resistance; abnormal cholesterol; elevated blood pressure and free androgen index; lower level of sex-hormone binding globulin (SHBG); and less gestational weight gain. Multivariate analysis showed that FPG, non-high-density lipoprotein-cholesterol and SHBG are independent predictive factors for GDM. CONCLUSIONS: Our study established strong association of multiple early-pregnancy risk factors with development of GDM in PCOS women. These risk factors are predominantly related to the regulation of glucose, lipid, and androgen metabolism. Among these factors, FPG, non-high density lipoprotein-cholesterol, and SHBG, predict incident GDM. PMID- 29514405 TI - Association between pathologic grade and multiphase computed tomography enhancement in pancreatic neuroendocrine neoplasm. AB - BACKGROUND AND AIM: Pancreatic neuroendocrine neoplasms (PanNENs) are rare diseases but gradually increasing in prevalence with different prognosis. Multiphase contrast-enhanced computed tomography (CT) is known as widely used imaging modality for the diagnosis of pancreatic tumors. We aimed to investigate whether CT enhancement pattern is associated with the pathologic tumor grade and can predict that of PanNEN. METHODS: Ninety PanNEN patients who underwent multiphase enhanced CT before pathologic diagnosis were retrospectively reviewed. CT enhancement values at each phase were measured, and its relation with pathologic grade was assessed. RESULTS: Ninety PanNENs included 62 G1 (68.9%), 21 G2 (23.3%), and 7 G3 (7.8%). The enhancement values of the early arterial phase were significantly different among three groups (G1 119.4 HU, G2 94.7 HU, and G3 64.8 HU; G1 vs G2, P = 0.043; G1 vs G3, P = 0.001; and G2 vs G3, P = 0.027). In the late arterial phase, there was a difference between grade 1/2 and 3 but no significant difference between grade 1 and grade 2 (G1 164.3 HU, G2 142.9 HU, and G3 94.1 HU; G1 vs G2, P = 0.804; G1 vs G3, P = 0.016; and G2 vs G3, P = 0.022). The enhancement value of the portal phase did not differ significantly among the three groups. Diagnostic ability of the early arterial enhancement value for the differentiation of the G1 (cutoff 109.5 HU, sensitivity 73.3%, and specificity 62.5%) was comparable with that of the tumor size (cutoff 20.5 mm, sensitivity 68.9%, and specificity 66.7%). CONCLUSIONS: Computed tomography enhancement value at early arterial phase and its changing pattern can be a useful predictor for the differentiation of pathologic grade of PanNENs. PMID- 29514407 TI - Tropomyosin-directed tuning of myosin motor function: Insights from mutagenesis. PMID- 29514406 TI - Liver transplantation for intrahepatic cholangiocarcinoma. AB - Although hepatocellular carcinoma (HCC) has become a common indication for liver transplantation (LT), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) are historically contraindicated due to their aggressive behavior. On the basis of recent experiences, some groups have proposed a clinical trial investigating the role of LT for patients with early cholangiocarcinoma (CCA), defined as a single lesion <= 2 cm. The purpose of this study is to assess the clinicopathologic features and outcomes following LT for patients who were initially diagnosed with HCC and subsequently found to have either ICC or cHCC-CCA on explant. Patients with the diagnosis of primary liver cancer (PLC) after LT from a single center were retrospectively reviewed. Outcomes for patients with early CCA were compared with patients with HCC within Milan criteria (MC). Out of 618 patients transplanted with PLC, 44 patients were found to have CCA on explant. On the basis of preoperative imaging, 12 patients met criteria for early CCA and were compared with 319 patients who had HCC within MC. The 1- and 5-year overall survival for early CCA versus HCC was 63.6% versus 90.0% and 63.6% versus 70.3% (log-rank, P = 0.25), respectively. Overall recurrence was 33.3% for early CCA versus 11% for HCC. On explant the patients with CCA were more likely understaged with higher tumor grade and vascular invasion. In conclusion, patients with CCA present a diagnostic challenge, which often leads to the finding of more aggressive lesions on explant after LT, higher recurrence rates, and worse post-LT survival. Careful consideration of this diagnostic conundrum needs to be made before a clinical trial is undertaken. Liver Transplantation 24 634-644 2018 AASLD. PMID- 29514408 TI - Neuroanatomical characterization of imidazoline I2 receptor agonist-induced antinociception. AB - Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I2 receptor (I2 R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I2 R-associated behaviors are unknown. I2 Rs are enriched in the arcuate nucleus, dorsal raphe (DR), interpeduncular nucleus, lateral mammillary body, medial habenula, nucleus accumbens (NAc) and paraventricular nucleus; thus, this study investigated the antinociceptive and hypothermic effects of microinjections of the I2 R agonist 2 (2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI). In rats, intra-DR microinjections produced antinociception in complete Freund's adjuvant- and chronic constriction injury-induced pain models. Intra-NAc microinjections produced antinociception and increased noxious stimulus-associated side time in a place escape/avoidance paradigm. Intra-NAc pretreatment with the I2 R antagonist idazoxan but not the D1 receptor antagonist SCH23390 or the D2 receptor antagonist raclopride attenuated intra-NAc 2-BFI-induced antinociception. Intra NAc idazoxan did not attenuate systemically administered 2-BFI-induced antinociception. Microinjections into the other regions did not produce antinociception, and in none of the regions produced hypothermia. These data suggest that I2 R activation in some but not all I2 R-enriched brain regions is sufficient to produce antinociception and supports the theory that different I2 R associated effects are mediated via distinct receptor populations, which may in turn be distributed differentially throughout the CNS. PMID- 29514409 TI - Diagnostic and clinical role of serum proteinase 3 antineutrophil cytoplasmic antibodies in inflammatory bowel disease. AB - BACKGROUND AND AIM: Proteinase 3 antineutrophil cytoplasmic antibodies (PR3 ANCAs) are well-known serological markers for granulomatosis with polyangiitis, but their role as serological markers for inflammatory bowel disease remains uncertain. The present study aimed to evaluate the diagnostic and clinical role of PR3-ANCAs as markers for inflammatory bowel disease. METHODS: Using a new methodology with chemiluminescence enzyme immunoassay, serum PR3-ANCA titers were assessed in 102 patients with ulcerative colitis (UC), 67 patients with Crohn's disease (CD), 44 controls with other intestinal diseases, and 66 healthy controls. Associations with clinical data were investigated. The diagnostic role of PR3-ANCAs was evaluated by receiver operating characteristic analysis. RESULTS: Proteinase 3 antineutrophil cytoplasmic antibody titers were significantly higher in patients with UC than in those with CD patients, patients with intestinal diseases (intestinal controls), and healthy controls (all P < 0.001). Receiver operating characteristic analysis demonstrated an area under the curve of 0.85 (95% confidence interval: 0.83-0.87) and showed that the manufacturer's cutoff value (3.5 U/mL) had a sensitivity of 39.2% and specificity of 96.6% for UC. There was a significant difference between PR3-ANCA-positive and PR3-ANCA-negative patients with regard to disease duration (P < 0.05) and disease severity (P < 0.01). CONCLUSIONS: Proteinase 3 antineutrophil cytoplasmic antibodies were significantly more prevalent in patients with UC than in those with CD and controls. Our results suggested the role of PR3-ANCAs as serological markers for aiding in diagnosing UC and evaluating disease severity. Further prospective studies are needed across multiple populations of patients and ethnic groups. PMID- 29514411 TI - Embryonal tumor with multilayered rosettes: Diagnosis on intra-operative squash smear. AB - We describe a rare example of infratentorial primitive neuroectodermal tumor categorized as embryonal tumor with multilayered rosettes diagnosed on intra operative squash smear and frozen section and discuss its key diagnostic features, pitfalls and differentials. Correct interpretation at the time of frozen section is crucial as it helps in deciding the further course of surgery. To the best of our knowledge, this is the first such report in the literature. PMID- 29514410 TI - Trends in analgesic consumption in France over the last 10 years and comparison of patterns across Europe. AB - AIMS: The aims of the present study were to describe the consumption trends of three groups of analgesics (non-opioids, and mild and strong opioids) between 2006 and 2015 in France, and compare this pattern of use with six European countries in 2015. METHODS: Annual drugs sales were extracted from the French national authority's consumption database, and from the IMS Multinational Integrated Data Analysis System and national databases for European countries. RESULTS: The use of mild opioids in France was found to have decreased by 53% over the past 10 years, owing to the declining use of dextropropoxyphene combinations, along with an increase in the use of non-opioids and strong opioids (from 72 to 93, and 2 to 2.8 defined daily doses/1000 inhabitants/day, respectively). Paracetamol, the most consumed analgesic, increased over this period, particularly for the adult high dose (+140%). The use of tramadol and codeine combinations also increased, by 62% and 42%, respectively. Morphine remained the most used strong opioid, although there were also large increases in the consumption of oxycodone (+613%) and fentanyl (+263% and +72% for transmucosal and transdermal forms, respectively). A comparison of the patterns of use in Europe in 2015 showed a higher consumption of mild and strong opioids in the UK. France ranked first and third place, respectively, for paracetamol and mild opioid consumption, whereas its use of strong opioids was among the lowest. CONCLUSIONS: Paracetamol consumption is clearly highest in France, whereas its use of strong opioids is among the lowest in Europe, although its consumption of oxycodone has increased significantly. Further studies are required specifically to monitor these drugs. PMID- 29514412 TI - Proton pump inhibitors not associated with hypomagnesemia, regardless of dose or concomitant diuretic use. AB - BACKGROUND AND AIM: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications worldwide, with dramatic efficacy for upper gastrointestinal acid-related disorders. In recent years, however, the safety of long-term PPI use has been questioned. One issue based on scant and conflicting literature is the possibility of PPI-related hypomagnesemia. Our purpose was to assess for any clinically significant alteration in serum magnesium levels in large groups of patients taking different PPIs in varying doses, with or without diuretics. METHODS: This was a retrospective review of patient records at time of hospitalization, from February 2012 to December 2014. Two thousand four hundred patients were randomly selected from a pool of 12 058 magnesium levels performed at or within 24 h of hospital admission. Patients were categorized in six groups based on outpatient PPI and/or diuretic use. The main outcome studied was hypomagnesemia, defined as serum magnesium level < 1.6 mg/dL. RESULTS: Mean magnesium levels were normal in PPI users (1.84 +/- 0.29 mg/dL [normal 1.6 to 2.5 mg/dL]) and PPI nonusers (1.85 +/- 0.30 mg/dL), P = 0.40, and there was no statistical difference in the prevalence of hypomagnesemia (14.7% vs 15.1%, P = 0.77). In separate groups, there were also no significant differences in serum magnesium levels between those taking PPIs of varying doses, with or without concomitant diuretics, and those not taking PPIs or diuretics. CONCLUSION: Regardless of PPI dosage or concomitant diuretics prescribed, magnesium levels were unaffected. Routine screening of serum magnesium in PPI patients appears unnecessary. PMID- 29514414 TI - Summary and recommendations from the International Atomic Energy Agency Technical Meeting on the Development of Stable Isotope Reference Products (21-25 November 2016). PMID- 29514413 TI - Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine. AB - The alarming increase in heroin overdoses in the USA is a reminder of the need for efficacious and novel treatments for opiate addiction. This may reflect the relatively poor understanding of the neural basis of heroin, as compared to cocaine, seeking behaviour. While cocaine reinforcement depends on the mesolimbic system, well-established cocaine seeking is dependent on dorsolateral striatum (aDLS) dopamine-dependent mechanisms which are disrupted by N-acetylcysteine, through normalisation of corticostriatal glutamate homeostasis. However, it is unknown whether a functional recruitment of aDLS dopamine-dependent control over instrumental responding also occurs for heroin seeking, even though heroin reinforcement does not depend on the mesolimbic dopamine system. Lister Hooded rats acquired heroin self-administration and were subsequently trained to seek heroin daily over prolonged periods of time under the control of drug-paired cues, as measured under a second-order schedule of reinforcement. At different stages of training, that is, early on and when heroin seeking behaviour was well established, we measured the sensitivity of drug-seeking responses to either bilateral aDLS infusions of the dopamine receptor antagonist alpha-flupenthixol (5, 10 and 15 MUg/side) or systemic administration of N-acetylcysteine (30, 60 and 90 mg/kg). The results demonstrate that control over heroin seeking behaviour devolves to aDLS dopamine-dependent mechanisms after extended training. Further aDLS-dependent well-established, cue-controlled heroin seeking was disrupted by N acetylcysteine. Comparison with previous data on cocaine suggests that the development of drug seeking habits and the alteration of corticostriatal glutamate homeostasis, which is restored by N-acetylcysteine, are quantitatively similar between heroin and cocaine. PMID- 29514415 TI - Spheroid formation and stemness preservation of human periodontal ligament cells on chitosan films. AB - OBJECTIVE: The therapeutic potential of periodontal ligament cells for periodontal regeneration gradually decreases when cultured as a monolayer in vitro. Three-dimensional cell culture models provide an alternative to traditional monolayer cell culture. This study aimed to comparatively evaluate the influence of spheroid culture on periodontal ligament cells. MATERIALS AND METHODS: Chitosan films were used to culture three-dimensional periodontal ligament cell spheroids. The proliferation, self-renewal, and osteogenic capacity of periodontal ligament cells derived from spheroids were evaluated and compared with cells cultured on a monolayer. RESULTS: Viable spheroids of periodontal ligament cells were formed on chitosan films. Compared to monolayer cell culture, periodontal ligament cells exhibited decreased proliferation upon spheroid formation. In contrast, their expression of genes related to self-renewal was significantly higher comparison with cells cultured in a monolayer. Moreover, the formation of periodontal ligament cell spheroids increased their colony-forming unit ability and osteogenic differentiation capacity. CONCLUSION: The results demonstrate the successful use of chitosan films for the culture of periodontal ligament cell spheroids. Compared to cells cultured in monolayer, periodontal ligament cells in spheroids did not proliferate, but exhibited higher self renewal gene expression, colony-forming unit and osteogenic capacity. PMID- 29514416 TI - Working memory alpha-beta band oscillatory signatures in adolescents and young adults. AB - The timing of neural activity is an intriguing way of exposing behaviorally relevant neural activity, as neural populations exploit transient windows of synchronized activations to exchange dynamic communications in the service of various cognitive operations. The link between neural synchrony and working memory (WM) has been supported at the theoretical and empirical level. However, findings have also shown that WM encoding is also related to significant alpha beta desynchronization. These findings have been primarily recorded during subsequent memory effect paradigms that compare correct with incorrect encoding trials. The dissociable contribution imparted by various processes to WM performance suggests that incorrect performance may not be directly translatable to unsuccessful encoding. Here, we address the relationship between alpha-beta desynchronization and encoding through the use of an alternative paradigm design by contrasting frontal and parietal human scalp electroencephalography activity during the encoding interval of a delayed matching-to-sample task with that recorded during a control task. The additional use of non-verbal/semantic visual stimulation and recruitment of typically developing adolescent subjects has led us to the conclusion that encoding-relevant alpha-beta decrements can be replicated via a non-verbal/semantic delayed matching-to-sample task and these are also evident in typically developing adolescents, in addition to adults, as has been previously demonstrated. The identification of encoding-related alpha beta decrements in adolescent subjects performing such WM tasks may open new avenues to explore whether such a rhythmic signature may explain WM and electrophysiological deficits that emerge in various adolescent neuropsychiatric disorders such as attention deficit hyperactivity disorder. PMID- 29514417 TI - Dopaminergic neuromodulation of high gamma stimulus phase-locking in gerbil primary auditory cortex mediated by D1/D5-receptors. AB - Cortical release of the neurotransmitter dopamine has been implied in adapting cortical processing with respect to various functions including coding of stimulus salience, expectancy, error prediction, behavioral relevance and learning. Dopamine agonists have been shown to modulate recurrent cortico thalamic feedback, and should therefore also affect synchronization and amplitude of thalamo-cortical oscillations. In this study, we have used multitaper spectral and time-frequency analysis of stimulus-evoked and spontaneous current source density patterns in primary auditory cortex of Mongolian gerbils to characterize dopaminergic neuromodulation of the oscillatory structure of current sources and sinks. We systemically applied D1/D5-receptor agonist SKF-38393 followed by competitive D1/D5-receptor antagonist SCH-23390. Our results reveal an increase in stimulus phase-locking in the high gamma-band (88-97 Hz) by SKF-38393, specifically in layers III/IV at the best frequency, which occurred at 20 ms after tone onset, and was reversed by SCH-23390. However, changes in induced oscillatory power after SKF-38393 treatment occurred stimulus-independently in the background activity in different layers than phase-locking effects and were not reversed by SCH-23390. These effects might either reflect longer-lasting changes in neural background noise, non-specific changes due to ketamine anesthesia, or an interaction of both. Without concomitant stimulus-induced power increase, increased stimulus phase-locking in layers III/IV indicates enhanced phase-resetting of neural oscillations by the stimulus after D1/D5-receptor activation. The frequency characteristics, together with the demonstrated stimulus specificity and layer specificity, suggest that changes in phase resetting originate from dopaminergic neuromodulation of thalamo-cortical interactions. Enhanced phase-resetting might be a key step in the recruitment of cortical activity modes interpreting sensory input. PMID- 29514418 TI - Role of hepatitis B surface antigen in hepatitis B virus relapse after entecavir or tenofovir prophylaxis in patients undergoing cancer chemotherapy. AB - BACKGROUND AND AIM: This study investigated whether hepatitis B surface antigen (HBsAg) could predict hepatitis B virus (HBV) relapse after cessation of entecavir or tenofovir disoproxil fumarate (TDF) prophylaxis for chronic hepatitis B cancer patients who are undergoing chemotherapy. METHODS: The study enrolled 122 hepatitis B e-antigen-negative cancer patients who underwent chemotherapy with entecavir or TDF for antiviral prophylaxis and posttreatment follow-up for at least 6 months. RESULTS: Of the 122 patients, 52 and 18 experienced virological and clinical relapse, which had 3-year cumulative incidences of 46.6% and 18.6%, respectively. Multivariate analysis showed that end-of-treatment HBsAg levels and baseline HBV-DNA >= 2000 IU/mL were independent predictors of virological relapse. The best HBsAg cutoff value was 500 IU/mL. An end-of-treatment HBsAg of 500 IU/mL was useful for predicting virological relapse in patients with baseline HBV-DNA < 2000 IU/mL (3-year rate: 21.3% vs 46.4%, P = 0.038, in patients with HBsAg < 500 and >= 500 IU/mL, respectively), but not in patients with baseline HBV-DNA >= 2000 IU/mL. Of the 52 patients who experienced virological relapse, 13 experienced transient virological relapse. Patients with baseline HBV-DNA level < 2000 IU/mL experienced a higher rate of transient virological relapse (42.1% vs 15.2%, P = 0.031). Three patients experienced hepatic decompensation upon alanine aminotransferase flares, and no patient died after timely retreatment. Ten patients experienced posttreatment HBsAg loss, and the 3-year HBsAg loss rate was 30.7% in patients with end-of-treatment HBsAg < 100 IU/mL. CONCLUSIONS: The baseline HBV-DNA and end-of-treatment HBsAg levels could predict virological relapse after withdrawal of entecavir and TDF prophylaxis for chemotherapy. PMID- 29514419 TI - Spontaneous eye blink rate and dopamine synthesis capacity: preliminary evidence for an absence of positive correlation. AB - Dopamine is central to a number of cognitive functions and brain disorders. Given the cost of neurochemical imaging in humans, behavioural proxy measures of dopamine have gained in popularity in the past decade, such as spontaneous eye blink rate (sEBR). Increased sEBR is commonly associated with increased dopamine function based on pharmacological evidence and patient studies. Yet, this hypothesis has not been validated using in vivo measures of dopamine function in humans. To fill this gap, we measured sEBR and striatal dopamine synthesis capacity using [18 F]DOPA PET in 20 participants (nine healthy individuals and 11 pathological gamblers). Our results, based on frequentist and Bayesian statistics, as well as region-of-interest and voxel-wise analyses, argue against a positive relationship between sEBR and striatal dopamine synthesis capacity. They show that, if anything, the evidence is in favour of a negative relationship. These results, which complement findings from a recent study that failed to observe a relationship between sEBR and dopamine D2 receptor availability, suggest that caution and nuance are warranted when interpreting sEBR in terms of a proxy measure of striatal dopamine. PMID- 29514420 TI - The effect of different post-harvest treatments on the quality of borage (Borago officinalis) petals. AB - BACKGROUND: Borage is an edible flower with a very limited shelf-life (approx. 1 day). After harvest, flowers dry and shrink rapidly and become darker. Extending the shelf life of borage will make it more appealing for commercialization and it will enable borage growers to expand their market. The aim of the present work is to evaluate the effect of three post-harvest technologies. METHODS: Freeze drying, hot air convective drying and alginate edible coating were applied to borage petals, and the visual appearance, water activity (aw) and weight loss was evaluated. RESULTS: Hot air-dried samples had an unsatisfactory visual appearance. Freeze dried flowers were less shrunken and dried while showing the lowest aw (0.25 ±0.01). Alginate coated flowers had a good visual ap- pearance, like fresh flowers, which was maintained during refrigerated storage (for 5 days), four days longer than those which were uncoated. Nevertheless, the flowers became fragile and it was difficult to handle them without causing damage. CONCLUSIONS: Freeze drying may be applied to produce dried borage flowers for infusions, while alginate coat- ing is a promising treatment to increase shelf-life subject to further development. PMID- 29514421 TI - Cytotoxic activity of stigmasteryl esters and products of their thermo-oxidative degradation against drug sensitive and drug resistant human acute lymphoblastic leukemia cells. AB - BACKGROUND: Phytosterols are mainly known as a cholesterol-lowering factor, although they form oxidation products during food storage and processing. Moreover, phytosterol oxidation products (POP) can be ab- sorbed and found in human serum, so there is the need to investigate their impact on different kinds of cells. METHODS: Esters of fatty acids (oleic, linoleic and linolenic) with stigmasterol were synthetized and heated at 180°C, for 1–12 hours. The cytotoxic effect on the leukemic cells of unheated stigmasteryl esters and the mixture of compounds after heating was determined using MTT assays. POP were identified using GC-MS. The total number of POP was analysed by SPE fractionation and GC-FID separation. Dimers, trimers and oligomers in non-polar fraction were determined by gel permeation chromatography with refractive index detection. RESULTS: After heating, stigmasterol oxidation products were formed (up to 1.1 mg/g ester). The heating increased the potency of the compounds to reduce cell population and form POPs and oligomers in a time-dependent manner. CONCLUSIONS: The cytotoxicity depends on the kind of ester, dose and time. The strongest cytotoxic effect was found after 72 hours of cell treatment. Among the three stigmasteryl esters tested the most cytotoxic effect was caused by stigmasteryl linoleate. PMID- 29514422 TI - Physico-chemical and thermal properties of chicken myofibrillar protein concentrate (CMPC) mixed with barley bran flour during frozen storage. AB - BACKGROUND: Possible new additives for surimi-like products made from chicken meat, which could improve its functional properties during frozen storage, are the subject of much research. The use of dietary fibre in surimi-like products made from chicken meat has not been extensively studied. The objective of this study was to determine the effectiveness of barley bran flour in stabilizing chicken myofibrillar proteins during frozen storage and maintaining its functionality. METHODS: Surimi-like material (chicken myofibrillar protein concentrate – CMPC) from mechanically deboned chicken meat was mixed with barley bran flour (0–6%) and stored in a freezer for 30, 60, 90 and 180 days. Instrumental color measurements (L*, a*, and b* values) were taken using a Hunter-Lab Mini ScanXE. Texture profile analysis (TPA) tests were performed using a TA.XT2i SMS Stable Micro Systems Texture Analyzer) equipped with an aluminium cylindrical probe P/75. Differential scanning calorim- etry (DSC) was used for the determination of denaturation temperatures and enthalpies. RESULTS: Denaturation enthalpies of CMPC increased when the mass fraction of barley bran was increased (w = 0–6%). Instrumental color parameters (L*, a* and b*) of CMPC gels were significantly (p < 0.05) af- fected by the addition of barley bran. Texture profile analysis (TPA) parameters – hardness and chewiness – increased significantly (p < 0.05) with the addition of barley bran (w = 0–6%). Cohesiveness and springiness were also significantly (p < 0.05) affected by the addition of barley bran (w = 0–6%) during frozen storage. CONCLUSIONS: The increase in denaturation enthalpies and some instrumental textural and color parameters, indicate possible interactions of chicken myofibrillar proteins with barley bran. PMID- 29514423 TI - Identification and study of the behavior of S. aureus and S. epidermidis in fresh and frozen strawberries. AB - BACKGROUND: Methicillin-Resistant Staphylococcus aureus (MRSA), which is resistant to many antibiotics, creates a serious problem for human health if present in food. This study aimed to assess the quality of commercially-available fresh and frozen strawberries and to compare the behavior of staphylococci in these fruits as affected by the temperature of freezing. METHODS: The research material included different species of fresh strawberries and strawberries frozen with the fluidization method to –40°C and packaged in an industrial environment. These were checked for the presence of Staphylococcus aureus resistant to methicillin (MRSA). The strawberries were purchased at food markets in the Tricity and were divided into two groups (A and B). Group A was analyzed without washing, group B was washed in sterile, distilled water for 15 minutes. The strawberries were placed in sterile PE/PA bags. Then 1 mL of Staphylococcus aureus Rosenbach ATCC 25923 and Staphylococcus epi- dermidis ATCC 12228 of known inoculum were added to each bag (except the control samples). The samples were mixed thoroughly and then hermetically sealed. The samples were then frozen and stored in the freezer at a temperature of –18 ±2°C for 2 months. In the material being tested Staphylococcus aureus was cultured in selective Baird-Parker RPF Agar. Incubation was carried out at a temperature of 37°C for 48 hours in sterile conditions. After 48 hours of incubation, characteristic colonies were transferred onto the reaction field of the PROLEXTM STAPH XTRA LATEX KIT. RESULTS: The results obtained show that 1/3 of the samples of commercial strawberries analyzed were colo- nized by methicillin-resistant Staphylococcus aureus (MRSA). The process of fruit washing was observed to reduce the number of samples containing MRSA from 11.7 to 8.3%. There was no significant difference in the size of the S. aureus ATCC 25923 population after freezing the strawberries at –18°C, depending on the particular washing process for these fruits. The analysis of strawberries frozen with the fluidization method at –40°C showed a minimum contamination degree with S. aureus after the period of storage. CONCLUSIONS: Studies have shown that MRSA are present in 15.4% of strawberries obtained from the field. Storing strawberries frozen at –18ºC causes a reduction in the number of S. aureus by 0.16 log10CFU/g and S. epidermidis by 0.47 log10CFU/g when they were subjected to rinsing after harvesting. Effective inhibition of MRSA in strawberries is obtained when fluidization technology is applied at –40ºC. PMID- 29514424 TI - The use of nano-sized eggshell powder for calcium fortification of cow?s and buffalo?s milk yogurts. AB - BACKGROUND: Calcium is an essential element for the growth, activity, and maintenance of the human body. Eggshells are a waste product which has received growing interest as a cheap and effective source of dietary calcium. Yogurt is a food which can be fortified with functional additives, including calcium. The aim of this study was to produce yogurt with a high calcium content by fortification with nano-sized eggshell powder (nano-ESP). METHODS: Nano-sized ESP was prepared from pre-boiled and dried eggshell, using a ball mill. Yogurt was prepared from cow’s milk supplemented with 3% skimmed milk powder, and from buffalo’s milk fortified with 0.1, 0.2 and 0.3% and 0.1, 0.3 and 0.5% nano ESP respectively. RESULTS: Electron microscopic transmission showed that the powder consisted of nano-sized crystalline struc- tures (~10 nm). Laser scattering showed that particles followed a normal distribution pattern with z average of 590.5 nm, and had negative zeta-potential of –9.33 ±4.2 mV. Results regarding changes in yogurt composi- tion, acid development, calcium distribution, biochemical changes, textural parameters and sensory attributes have been presented and discussed. CONCLUSIONS: The addition of up to 0.3% nano ESP made cow and buffalo high-calcium yogurts with an acceptable composition and quality. High-calcium yogurt may offer better health benefits, such as combating osteoporosis. PMID- 29514425 TI - The comparison of the physicochemical parameters and antioxidant activity of homemade and commercial pomegranate juices. AB - BACKGROUND: The pomegranate (Punica granatum L.) has gained a reputation as a fruit with many health- promoting properties. It is considered to help prevent or treat various disease risk factors including high blood pressure, high cholesterol, oxidative stress, hyperglycemia and inflammatory activities. It has been demonstrated that certain components of pomegranates, such as polyphenols, have potential antioxidant, anti-inflammatory and anticarcinogenic effects. METHODS: Five commercially available (CA) and three homemade (HM) pomegranate (Puni- ca granatum L.) juices were evaluated for their physicochemical properties including titratable acidity (TA), pH and total soluble solids (TSS), as well as antioxidant properties such as anthocyanin content, ascorbic acid content (AA), antioxidant activity (DPPH), total phenolic compounds (TPC) and ferric reducing antioxidant power (FRAP). Moreover, the concentrations of 18 different elements (Ca, K, Mg, P, S, Na, Cr, Cu, Fe, Mn, Mo, Sr, Zn, Al, Cd, Ni, Pb, Hg) were determined using the ICP-OES method, with prior wet mineralization. RESULTS: TA was significantly lower (P < 0.05) in homemade than in commercial juices (0.380 and 1.318% citric acid respectively). The TPC and FRAP parameters were about 50% higher in commercial than in homemade juices. Polyphenols were strongly correlated with antioxidant activity measured by FRAP and DPPH tests (r = 0.958 and 0.886 respectively), and a significant correlation for anthocyanins and vitamin C (r = 0.849) was observed. The most common mineral in each tested juice was potassium (132.69–3151.87 mg/dm3) and a high level of magnesium (23.42–123.63 mg/dm3) was found. CONCLUSIONS: Obtaining juices from whole fruits (peel and arils), as in commercial production, enhanced the content of polyphenol compounds and the antioxidant activity of the juice. However, a better mineral compo- sition was observed in homemade juices. PMID- 29514426 TI - Lactobacillus spp. belonging to the Casei group display a variety of adhesins. AB - BACKGROUND: n. Adhesion of bacteria from the genus Lactobacillus to the gastrointestinal epithelium is, to a considerable degree, dependent on the interactions between adhesins found on the surface of bacterial cells and elements found within the epithelium. A significant role in these interactions is played by bacterial pro teins exposed to the cell wall surface, which are capable of binding to molecules of substances comprising the extracellular matrix of the intestinal epithelium. METHODS: In order to analyze the extracellular proteome of intestinal bacteria in terms of the presence of cell adhesion molecules, a total of twenty strains from the Lactobacillus spp. group Casei were tested. The analyses were conducted using SDS PAGE, 2-D electrophoresis, Western blot and mass spectrometry. An experiment was also conducted to assess the adhesion capacity of the tested strains to cervical epithelial cells (HeLa). RESULTS: The tested strains varied in their adhesion efficiency to HeLa cells, ranging from 0.5% to 29%. Us- ing electrophoretic methods a total of 54 extracellular protein fractions were distinguished in these strains, additionally identifying potential adhesion molecules (e.g. a surface antigen of the NLP/P60 family and a small heat shock protein/chaperonin). CONCLUSIONS: The identification of these proteins in the extracellular proteome of Latobacillus spp. isolates may suggest that they serve currently unknown functions on the cell surface, including those connected with the interactions between bacteria and the intestinal epithelium. Such analyses may provide insight into new factors promoting probiotic adhesion to various types of epithelial cells. PMID- 29514427 TI - The impact of lifestyle factors on age-related differences in hair trace element content in pregnant women in the third trimester. AB - BACKGROUND: Trace elements play a significant role in the regulation of human reproduction, while advanced age may have a significant impact on trace element metabolism. The objective of the present study was to assess the impact of lifestyle factors on age-related differences in hair trace element content in pregnant women in the third trimester. METHODS: A total of 124 pregnant women aged 20–29 (n = 72) and 30–39 (n = 52) were ex- amined. Scalp hair trace element content was assessed using inductively coupled plasma mass spectrometry at NexION 300D (Perkin Elmer, USA) after microwave digestion. RESULTS: The results showed that the elder pregnant women had 36% (p = 0.009), 14% (p = 0.045), and 45% (p = 0.044) lower hair Zn, V, and Cd content, and 16% (p = 0.044) higher hair B levels – in comparison to the respective younger group values. Multiple regression analysis demonstrated that the age of the women had a significant influence on hair V and Zn levels. B content was also significantly influenced by age at first intercourse, smoking status, and specific dietary habits. None of the lifestyle factors were associated with hair Cd content in pregnant women. Hair V levels were also affected by following a special diet. Interestingly, alcohol intake did not have a significant impact on hair trace element content. CONCLUSIONS: These data indicate that lifestyle factors have a significant influence on age-related changes in hair trace elements during pregnancy that may impact the outcome of pregnancy. PMID- 29514428 TI - Effects of unextruded and extruded cranberry pomace on selected metabolic parameters in high-fat diet fed rats. AB - BACKGROUND: The effects of un-extruded (UCP) and extruded cranberry pomace (ECP) on fecal fat excretion, liver index, lipid and carbohydrate metabolism, and inhibition of oxidative stress due to a high-fat diet (HFD) in rats were studied. METHODS: The Wistar rats for 8 weeks received one of the four diets: (1) control (modified the American Institute of Nutrition: AIN based diet containing 7% fat), (2) HFD (AIN based diet containing 30% fat), (3) HFD with 3% un-extruded (UCP) and (4) HFD with 3% (ECP). RESULTS: Both UCP and ECP significantly improved the plasma antioxidant capacity and decreased lipid per- oxidation in rats fed a HFD. However, only the addition of 3% UCP into the HFD significantly increased the fecal lipid excretion and considerably decreased serum triglycerides level in rats. CONCLUSIONS: Further investigation is needed to determine the role of an individual components present in UCP and ECP in the improvement of metabolic conditions observed in the current study. PMID- 29514429 TI - Fatty acid profile and oxidation tests of fat extracted from yogurt using rose hip seed oil. AB - BACKGROUND: Yogurt is a dairy product with a high nutritional value. However, like all milk products, it contains milk fat and is rich in saturated fatty acids. It would be desirable to enrich dairy products in poly- unsaturated fatty acids to increase dietary intake amongst consumers and improve their health. Also, some LAB bacteria are able to produce CLA and CLnA isomers from linoleic and linolenic acids. The aim of this study was to investigate the chemical properties and fatty acid profile of yogurt with the addition of 3.5% of rose hip seed oil. METHODS: Yogurt was made from skimmed milk and yogurt starter culture YC-180 Ch. Hansen (Denmark), with the addition of 3.5% of rose hip seed oil. The peroxide value, acid value, iodine value, TBA rate and fatty acid profile were determined in fat extracted from the yogurt after 1 and 14 days of storage and in fresh rose hip seed oil. The fatty acid profile was determined using gas chromatographic methods with mass spectrometric detectors. RESULTS: Fat extracted from the yogurts had lower levels of peroxides than the fresh oil. It was more acidic and the iodine value was higher than in the fresh oil. Rose hip seed oil enriched the product with polyunsaturated fatty acids. After 14 days of storage, linoleic and linolenic acid levels had increased. Moreover, the content of myristic and palmitic acids had decreased. CONCLUSIONS: The rose hip seed oil added to the yogurt was less susceptible to oxidation. The content of un- saturated fatty acids in the yogurt increased with the addition of the oil, making yogurt with rose hip seed oil an excellent source of Ω-3 and Ω 6 fatty acids. Conjugated linoleic (CLA) and linolenic (CLnA) acids were not detected. However, yogurt manufactured with appropriate adjunct cultures and with the correct oil addition could be a natural source of CLA and CLnA in the human diet. PMID- 29514430 TI - Experiences of and barriers to transition-related healthcare among Korean transgender adults: focus on gender identity disorder diagnosis, hormone therapy, and sex reassignment surgery. AB - OBJECTIVES: Transgender people may encounter barriers to transition-related healthcare services. This study aimed to investigate the experiences of transition-related healthcare and barriers to those procedures among transgender adults in Korea. METHODS: In 2017, we conducted a nationwide cross-sectional survey of 278 transgender adults, which named Rainbow Connection Project II, in Korea. We assessed the prevalence of transition-related healthcare, including gender identity disorder (GID) diagnosis, hormone therapy, and sex reassignment surgery. To understand the barriers to those procedures, we also asked participants for their reasons for not receiving each procedure. Further, this study examined their experiences of and the reasons for using non-prescribed hormone medications. RESULTS: Of transgender people participated in the survey, 91.0% (n=253/278) were diagnosed with GID, 88.0% (n=243/276) received hormone therapy, and 42.4% (n=115/271) have had any kind of sex reassignment surgery. Cost was the most common barrier to transition-related healthcare among Korean transgender adults. Other common barriers were identified as follows: negative experiences in healthcare settings, lack of specialized healthcare professionals and facilities, and social stigma against transgender people. Among those who had taken hormone medications, 25.1% (n=61/243) reported that they had ever purchased them without a prescription. CONCLUSIONS: Our findings suggest that barriers to transition-related healthcare exist in Korea and constrain transgender individuals' safe access to the needed healthcare. Institutional interventions are strongly recommended to improve access to transition-related healthcare. These interventions include provision of programs to train Korean healthcare professionals and expansion of national health insurance to include these procedures. PMID- 29514431 TI - Isoquinoline alkaloids supplementation on performance and carcass traits of feedlot bulls. AB - OBJECTIVE: Isoquinoline Alkaloids, derived from one plant (Macleaya cordata) can be an alternative when it is desired to increase performance in feedlot cattle. However, results on these nutritional additives in high energy diets in ruminants are still incipient in literature. In this context, the objective of this study was to evaluate performance and carcass traits of feedlot bulls supplemented with sanguinarine, the main alkaloid presents in Macleaya cordata in high energy density diets. METHODS: Thirty-two crossbred Angus-Nelore bulls with mean initial body weight of 365+/-10 kg and mean initial age of 11+/-3 months were used. The experiment lasted 119 days, with 14 days of adaptation and 105 experimental days. Experimental diet consisted of 85% whole corn grains and 15% protein-vitamin mineral nucleus and supplied ad libitum. Treatments consisted of a control diet (CON) and a diet with sanguinarine supplementation (SAN) at a dosage of 4 g of product sufficient to provide 6 mg of sanguinarine/d. Experimental design was completely randomized. RESULTS: Dry matter intake, average daily gain and feed conversion were similar (p>0.05) between treatments. However, SAN group animals had higher carcass yield (p = 0.045) and were more efficient in the transformation of dry matter consumed in carcass gain (p = 0.046) than CON. In addition, haptoglobin, increased throughout feedlot duration meaning high challenge for the animals due to the diet, but this behavior was similar (p>0.05) between treatments. CONCLUSION: Sanguinarine produced positive results in relation to carcass yield and could be used as an additive for bulls fed diets receiving high energy density diet. PMID- 29514432 TI - Effects of feeding level on nutrient digestibility and enteric methane production in growing goats (Capra hircus hircus) and Sika deer (Cervus nippon hortulorum). AB - Objective: Two experiments were conducted to determine the effects of feeding level on nutrient digestibility and enteric methane (CH4) emissions in growing goats and Sika deer. METHODS: Three growing male goats (initial body weight [BW] of 22.4+/-0.9 kg) and three growing male deer (initial BW of 20.2+/-4.8 kg) were each allotted to a respiration-metabolism chamber for an adaptation period of 7 d and a data collection period of 3 d. An experimental diet was offered to each animal at one of three feeding levels (1.5%, 2.0%, and 2.5% of BW) in a 3*3 Latin square design. The chambers were used for measuring enteric CH4 emission. RESULTS: Nutrient digestibility decreased linearly in goats as feeding level increased, whereas Sika deer digestibility was not affected by feeding level. The enteric production of CH4 expressed as g/kg dry matter intake (DMI), g/kg organic matter intake, and % of gross energy intake decreased linearly with increased feeding level in goats; however, that of Sika deer was not affected by feeding level. Six equations were estimated for predicting the enteric CH4 emission from goats and Sika deer. For goat, equation 1 was found to be of the highest accuracy: CH4 (g/d) = 6.2 (+/-14.1)+10.2 (+/-7.01)*DMI (kg/d)+0.0048 (+/ 0.0275)*dry matter digestibility (DMD, g/kg)-0.0070 (+/-0.0187)*neutral detergent fiber digestibility (NDFD; g/kg). For Sika deer, equation 4 was found to be of the highest accuracy: CH4 (g/d) = -13.0 (+/-30.8)+29.4 (+/-3.93)*DMI (kg/d)+0.046 (0.094)*DMD (g/kg)-0.0363 (+/-0.0636)*NDFD (g/kg). CONCLUSION: Increasing the feeding level increased CH4 production in both goats and Sika deer, and predictive models of enteric CH4 production by goats and Sika deer were estimated. PMID- 29514433 TI - Liver metabolic perturbations of heat-stressed lactating dairy cows. AB - Objective: The objective of the present study was to elucidate the mechanism underlying liver metabolic perturbations in dairy cows exposed to heat stress (HS). METHODS: Liquid chromatography massabl spectrometry was used to analyze metabolic differences in livers of 20 dairy cows, with and without exposure to HS. RESULTS: The results revealed 33 potential metabolite candidate biomarkers for the detection of HS in dairy cows. Fifteen of these metabolites (glucose, lactate, pyruvate, acetoacetate, beta-hydroxybutyrate, fumaric acid, citric acid, choline, glycine, proline, isoleucine, leucine, urea, creatinine, and orotic acid) were previously found to be potential biomarkers of HS in plasma or milk, discriminating dairy cows with and without HS. CONCLUSION: All the potential diagnostic biomarkers were involved in glycolysis, amino acid, ketone, tricarboxylic acid, or nucleotide metabolism, indicating that HS mainly affected energy and nucleotide metabolism in lactating dairy cows. PMID- 29514434 TI - Correlation analyses of CpG island methylation of cluster of differentiation 4 protein with gene expression and T lymphocyte subpopulation traits. AB - Objective: Cluster of differentiation 4 protein (CD4) gene is an important immune related gene which plays a significant role in T cell development and host resistance during viral infection. METHODS: In order to unravel the relationship of CpG island methylation level of CD4 gene with its gene expression and T lymphocyte subpopulation traits, we used one typical Chinese indigenous breed (Dapulian, DP) and one commercial breed (Landrace), then predicted the CpG island of CD4 gene, determined the methylation status of CpG sites by bisulfite sequencing polymerase chain reaction (BSP), and carried out the correlation analyses of methylation frequencies of CpG sites with mRNA expression and T lymphocyte subpopulation traits. RESULTS: There was one CpG island predicted in the upstream -2 kb region and exon one of porcine CD4 gene, which located 333 bp upstream from the start site of gene and contained nine CpG sites. The correlation analysis results indicated that the methylation frequency of CpG_2 significantly correlated with CD4 mRNA expression in the DP and Landrace combined population, though it did not reach significance level in DP and Landrace separately. Additionally, 15 potential binding transcription factors (TFs) were predicted within the CpG island, and one of them (Jumonji) contained CpG_2 site, suggesting that it may influence the CD4 gene expression through the potential binding TFs. We also found methylation frequency of CpG_2 negatively correlated with T lymphocyte subpopulation traits CD4+CD8-CD3-, CD4-CD8+CD3- and CD4+/CD8+, and positively correlated with CD4-CD8+CD3+ and CD4+CD8+CD3+ (for all correlation, p<0.01) in DP and Landrace combined population. Thus, the CpG_2 was a critical methylation site for porcine CD4 gene expression and T lymphocyte subpopulation traits. CONCLUSION: We speculated that increased methylation frequency of CpG_2 may lead to the decreased expression of CD4, which may have some kind of influence on T lymphocyte subpopulation traits and the immunity of DP population. PMID- 29514435 TI - Effects of different dietary ratio of physically effective neutral detergent fiber and metabolizable glucose on rumen fermentation, blood metabolites and growth performance of 8 to 10-month-old heifers. AB - Objective: The present study was undertaken to determine an optimal balance between the amount of physically effective neutral detergent fiber (peNDF) to metabolizable glucose (MG) on rumen fermentation, blood metabolites and growth performance of 8 to 10-month-old heifers. METHODS: A total of 15 healthy Holstein heifers weighing an average of 256 kg (8 month of age) were randomly assigned to three groups of five. Treatment diets consisted of the following three peNDF8.0/MG levels: 1.46 (Treatment A), 1.74 (Treatment B), and 2.08 (Treatment C). RESULTS: The results showed that the ratio of peNDF8.0/MG affected rumen fermentation, blood metabolites and growth performance of heifers. The average daily gain of heifers tended to decrease as the ratio of peNDF8.0/MG increased (p = 0.07). The concentrations of blood urea nitrogen, triglyceride, and cholesterol increased significantly (p<0.05), while the high-density lipoprotein concentration decreased (p<0.05). After feeding 2 h and 4 h, insulin concentration in Treatment A was greater than Treatment C (p<0.05). Propionate concentration had decreasing trend (p = 0.07); acetate to propionate ratio and non-glucogenic to glucogenic volatile fatty acid (NGR) increased significantly (p<0.05). In addition, the digestibility of dry matter, crude protein, neutral detergent fiber, and acid detergent fiber decreased significantly (p<0.05). CONCLUSION: The present investigation indicated that dietary peNDF8.0/MG ratio can affect the growth and development, blood metabolites, rumen fermentation and apparent digestibility of heifers, and the optimal dietary peNDF8.0/MG ratio for 8 to 10-month-old heifers in the present study was 1.46. PMID- 29514436 TI - Effect of cumin essential oil usage on fermentation quality, aerobic stability and in vitro digetibility of alfalfa silage. AB - Objective: This study was carried out to determine the effects of cumin essential oil on the silage fermentation, aerobic stability and in vitro digestibility of alfalfa silages. METHODS: Alfalfa was harvested at early bloom (5th cutting) stage in October and wilted for about 3 hours. The research was carried out at three groups which were the control group where no additive control was done (CON), cumin essential oil (CMN3) with 300 mg/kg and CMN5 with 500 mg/kg cumin essential oil addition. Alfalfa was ensiled in plastic bags. The packages were stored at 8 degrees C+/-2 degrees C under laboratory conditions. All groups were sampled for physical, chemical and microbiological analysis 120th day after ensiling. At the end of the ensiling period, all silages were subjected to an aerobic stability test for 7 days. In addition, enzimatic solubility of organic matter (ESOM), metabolizable energy (ME), and relative feed value (RFV) of these silages were determined. RESULTS: pH level decreased in the cumin groups compared to CON (p<0.05), thus inhibiting proteolytic enzymes from breaking down proteins into ammonia. In addition, it increased ESOM amount, and concordantly provided an increase of ME contents. Similarly, dry matter intake and RFV ratio increased. After opening the silage, it kept its aerobic stability for three days. CONCLUSION: Cumin essential oil improved fermentation, and affected chemical and microbiological characteristics of silages. Especially the addition of 300 mg/kg cumin provided cell wall fractionation through stimulating the activities of enzymes responsible. It also increased the number and activity of lactic acid bacteria (LAB) through providing a development of LAB. PMID- 29514437 TI - Effect of golden needle mushroom (Flammulina velutipes) stem waste on laying performance, calcium utilization, immune response and serum immunity at early phase of production. AB - OBJECTIVE: This experiment was conducted to evaluate the effects of golden needle mushroom (Flammulina velutipes) stem waste (FVW), on organic eggs production, calcium utilization, antibody response, serum immunoglobulin, and serum cytokine concentration at early phase of production in laying hens. METHODS: A total 210, 19 weeks old aged ISA Brown layers were randomly assigned into 5 equal treatment groups, with 7 replications of 6 hens each. Dietary treatment included a standard basal diet as control; antibiotic (0.05% flavomycin); 2% FVW; 4% FVW; and 6% FVW. The experimental duration was 10 weeks. RESULTS: There was no significant differences (p>0.05) on hen day egg production, egg weight, egg mass, feed intake, and feed conversion ratio (FCR) among experimental groups. Unmarketable eggs were significantly lower (p<0.05) both in 4% FVW and 6% FVW fed groups than control group. The calcium retention and calcium in egg shell deposition were significantly higher (p<0.05) in FVW inclusion groups than control and antibiotic groups. Antibody titers against Newcastle diseases were significantly higher (p<0.05) in 6% FVW fed group (except combined with 4% FVW at day 147) and infectious bronchitis were significantly higher (p< 0.05) in FVW fed groups (except 2% FVW and 4% FVW at day 161) than control and antibiotic groups. Serum immunoglobulin sIgA was significantly higher (p<0.05) in all levels of FVW and IgG was significantly higher (p<0.05) in 4% FVW than control and antibiotic groups. Serum cytokine concentration interleukin-2 (IL-2) was significantly higher (p<0.05) in 6% FVW; IL-6 and tumor necrotic factor-alpha were significantly higher (p<0.05) both in 4% FVW and 6% FVW than control and antibiotic groups; IL-4 was significantly higher (p<0.05) in antibiotic, 2% FVW and 4% FVW fed groups than control. CONCLUSION: F. velutipes mushroom waste can be used as a novel substitute for antibiotic for organic egg production and sound health status in laying hens. PMID- 29514438 TI - Characterization of Tifton 85 bermudagrass haylage with different layers of polyethylene film and storage time. AB - Objective: The objective was to characterize the fermentative and microbiological profile of Tifton 85 bermudagrass haylage with different layers of polyethylene film and storage time. METHODS: The experimental design consisted of a randomized block design with four and six wrapping layers (100 and 150 microns in total. respectively) allocated in the main plots, through repeated measures analysis (30, 60, and 90 days of storage) with four replicates. RESULTS: The storage time and number of wrapping layers did not show changes in the population of Clostridium and lactic acid bacteria. A decrease was observed in the enterobacteria population with an increase in the storage period in the two wrapping layers studied. Upon opening of the haylage at 30 days, the population of Bacillus was lower in haylages made with six layers of wrapping (3.63 log colony forming units/g). No growth of Listeria sp. or Salmonella sp. was observed during the experimental period. The fungal genera with a greater occurrence were Penicillium sp. and Fusarium sp. The following mycotoxins were not detected: ochratoxin A, fumonisins, and zearalenone. Relative to the organic butyric, propionic, and acetic acids, the haylages presented a low concentration of lactic acid; this may have prevented a drop in the pH, which was high when the silos were opened (5.4). The levels of ammoniacal nitrogen and soluble carbohydrates presented no variation among the number of wrapping layers, with an overall average of 35.55 and 38.04 g/kg. CONCLUSION: Tifton 85 bermudagrass haylage wrapped with four and six layers presented adequate fermentation and microbiological characteristics in the evaluated periods. PMID- 29514439 TI - Genetic parameters for marbling and body score in Anglonubian goats using Bayesian inference via threshold and linear models. AB - OBJECTIVE: The aim of this study was to estimate (co) variance components and genetic parameters for categorical carcass traits using Bayesian inference via mixed linear and threshold animal models in Anglonubian goats. METHODS: Data were obtained from Anglonubian goats reared in the Brazilian Mid-North region. The traits in study were body condition score, marbling in the rib eye, ribeye area, fat thickness of the sternum, hip height, leg perimeter, and body weight. The numerator relationship matrix contained information from 793 animals. The single- and two-trait analyses were performed to estimate (co) variance components and genetic parameters via linear and threshold animal models. For estimation of genetic parameters, chains with 2 and 4 million cycles were tested. An 1,000,000 cycle initial burn-in was considered with values taken every 250 cycles, in a total of 4,000 samples. Convergence was monitored by Geweke criteria and Monte Carlo error chain. RESULTS: Threshold model best fits categorical data since it is more efficient to detect genetic variability. In two-trait analysis the contribution of the increase in information and the correlations between traits contributed to increase the estimated values for (co) variance components and heritability, in comparison to single-trait analysis. Heritability estimates for the study traits were from low to moderate magnitude. CONCLUSION: Direct selection of the continuous distribution of traits such as thickness sternal fat and hip height allows obtaining the indirect selection for marbling of ribeye. PMID- 29514440 TI - Cashmere growth control in Liaoning cashmere goat by ovarian carcinoma immunoreactive antigen-like protein 2 and decorin genes. AB - OBJECTIVE: The study investigated the biological functions and mechanisms for controlling cashmere growth of Liaoning cashmere goat by ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) and decorin (DCN) genes. METHODS: cDNA library of Liaoning cashmere goat was constructed in early stages. OCIAD2 and DCN genes related to cashmere growth were identified by homology analysis comparison. The expression location of OCIAD2 and DCN genes in primary and secondary hair follicles (SF) was performed using in situ hybridization. The expression of OCIAD2 and DCN genes in primary and SF was performed using real time polymerase chain reaction (PCR). RESULTS: In situ hybridization revealed that OCIAD2 and DCN were expressed in the inner root sheath of Liaoning cashmere goat hair follicles. Real-time quantitative PCR showed that these genes were highly expressed in SF during anagen, while these genes were highly expressed in primary hair follicle in catagen phase. Melatonin (MT) inhibited the expression of OCIAD2 and promoted the expression of DCN. Insulin-like growth factors-1 (IGF 1) inhibited the expression of OCIAD2 and DCN, while fibroblast growth factors 5 (FGF5) promoted the expression of these genes. MT and IGF-1 promoted OCIAD2 synergistically, while MT and FGF5 inhibited the genes simultaneously. MT+IGF 1/MT+FGF5 inhibited DCN gene. RNAi technology showed that OCIAD2 expression was promoted, while that of DCN was inhibited. CONCLUSION: Activation of bone morphogenetic protein (BMP) signaling pathway up-regulated OCIAD2 expression and stimulated SF to control cell proliferation. DCN gene affected hair follicle morphogenesis and periodic changes by promoting transforming growth factor-beta (TGF-beta) and BMP signaling pathways. OCIAD2 and DCN genes have opposite effects on TGF-beta signaling pathway and inhibit each other to affect the hair growth. PMID- 29514441 TI - Anthocyanin and proanthocyanidin contents, antioxidant activity, and in situ degradability of black and red rice grains. AB - Objective: An experiment was conducted to assess the antioxidant contents and activities of colored rice grains and to evaluate their nutritive characteristics in terms of chemical composition and in situ ruminal degradation. METHODS: Ten cultivars of colored rice grains (Oryza sativa L.) collected from several areas of Japan were studied, and control rice without pigment, maize, barley, and wheat grains were used as control grains. Their chemical compositions, pigment, polyphenol contents, total antioxidant capacity (TAC), and degradation characteristics were determined. RESULTS: The starch contents of the colored rice grains were in the range of 73.5% to 79.6%, similar to that of the control rice grain. The black and red rice grains contained anthocyanin (maximum: 5,045.6 MUg/g) and proanthocyanidin (maximum: 3,060.6 MUg/g) at high concentrations as their principal pigments, respectively. There were significantly (p<0.05) positive relationships among the pigment contents, polyphenol content, and TAC values in the colored and control rice grains, indicating that the increase in pigment contents also contributed to the increased polyphenol content and TAC values in the colored rice grains. The dry matter and starch degradation characteristics, as represented by c (fractional degradation rate of slowly degradable fraction) and by the effective degradability, of the colored rice grains and the control rice grain were ranked as follows among commonly used grains: wheat>barley >=rice>maize. The colored rice grains also included the most digestible starch, since their potential degradable fraction and actual degradability at 48 h incubation were almost 100%. CONCLUSION: Colored rice grains have high potential to be used as antioxidant sources in addition to starch sources in ruminants. PMID- 29514442 TI - Effects of nandrolone decanoate on expression of steroidogenic enzymes in the rat testis. AB - OBJECTIVE: Nandrolone decanoate (ND) is an anabolic-androgenic steroid frequently used for clinical treatment. However, the inappropriate use of ND results in the reduction of serum testosterone level and sperm production. The suppressive effect of ND on testosterone production has not been investigated in detail. The present study was designed to examine the effect of ND on the expression of steroidogenic enzymes in the rat testis. METHODS: Male Sprague Dawley rats at 50 days of age were subcutaneously administrated with either 2 or 10 mg of ND/kg body weight/week for 2 or 12 weeks. The changes of transcript and protein levels of steroidogenic enzymes in the testis were determined by real-time polymerase chain reaction and western blotting analyses, respectively. Moreover, immunohistochemical analysis was employed to determine the changes of immunostaining intensity of these enzymes. The steroidogenic enzymes investigated were steroidogenic acute regulatory protein, cytochrome P450 side chain cleavage enzyme, 17alpha-hydroxylase, 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 aromatase. RESULTS: The treatment of ND resulted in depletion of Leydig cells and sloughing of germ cells in the testis. The ND treatment caused significant expressional decreases of steroidogenic enzymes at transcript and protein levels, and the destructive effects of ND on the testis were more apparent with a higher dose and a longer period of the treatment. Evident reduction of immunostaining intensity present in Leydig cells was clearly detected by the ND treatment. CONCLUSION: The exposure to ND in young male results not only in histological changes of the testis but also in aberrant gene expression of testicular steroidogenic enzymes, consequently leading into the reduction of testosterone production in the testis and thus likely disruption of spermatogenesis. PMID- 29514443 TI - Comparative study of some analytical methods to quantify lignin concentration in tropical grasses. AB - Objective: Lignin plays a relevant role in the inhibition of cell wall (CW) structural carbohydrate degradation. Thus, obtaining accurate estimates of the lignin content in tropical plants is important in order to properly characterize the mechanism of lignin action on cell wall degradation. Comparing conflicting results between the different methods available for commercial use will bring insight on the subject. This way, providing data to better understand the relationship between lignin concentration and implications with tropical forage degradation. Methods: Five grass species, Brachiaria brizantha cv Marandu, Brachiaria brizantha cv Xaraes (MG-5), Panicum maximum cv Mombaca, Pennisetum purpureum cv Cameroon and Pennisetum purpureum cv Napier, were harvested at five maturity stages. Acid detergent lignin (ADL), Klason lignin (KL), acetyl bromide lignin (ABL) and permanganate lignin (PerL) were measured on all species. Lignin concentration was correlated with in vitro degradability. Results: Highly significant effects for maturity, lignin method and their interaction on lignin content were observed. The ADL, KL and ABL methods had similar negative correlations with degradability. The PerL method failed to reliably estimate the degradability of tropical grasses, possibly due to interference of other substances potentially soluble in the KMnO4 solution. Conclusion: ADL and KL methods use strong acid (H2SO4) and require determination of ash and N content in the lignin residues, therefore, increasing time and cost of analysis. The ABL method has no need for such corrections and is a fast and a convenient method for determination of total lignin content in plants, thus, it may be a good option for routine laboratory analysis. PMID- 29514444 TI - Effects of feeding different proportions of silver leaf desmodium (Desmodium uncinatum) with banana (Musa paradisiaca) leaf on nutrient utilization in Horro sheep fed a basal diet of natural grass hay. AB - OBJECTIVE: The objective was to evaluate feed intake, digestibility, body weight change and carcass characteristics of sheep fed a basal diet of hay supplemented with banana leaves and silver leaf desmodium. METHODS: Thirty yearling lambs with an average initial body weight of 15.85+/-1.6 kg were grouped into six blocks of five rams in each block. The treatments were: hay alone (T1), hay+ 100% banana leaf (T2), hay+67% banana leaf+33% desmodium leaf (T3), hay+33% banana leaf+67% desmodium leaf (T4), andhay+100% desmodium leaf (T5). Three hundred grams of treatment diets were offered daily on as fed basis. The feeding and digestibility trials lasted for 84 and 7 days, respectively, followed by carcass evaluation. RESULTS: The total dry matter (DM) intake for T3, T4, and T5 were greater (p<0.05) than those fed T1 and T2 diets. The lowest (p<0.05) organic matter (OM) intake was recorded in rams reared on T1 diet. The total crude protein (CP) intake was in the following order: T5> T4>T3>T2>T1. Ram lambs receiving supplementary diets had higher (p<0.05) DM, OM, CP, neutral detergent fiber and acid detergent fiber digestibility compared with the control diet. The empty body weight and slaughter weight was highest (p<0.05) in rams receiving T3, T4, and T5 diets. The average daily gain and feed conversion efficiency was highest (p< 0.05) in rams receiving the supplementary diets. The dressing percentage on the basis of hot carcass weight linearly increased with increasing levels of desmodium. Rams reared on supplementary diet had higher (p<0.05) rib eye area compared with the control diet. CONCLUSION: In conclusion, when banana leaf is used as a supplement to poor quality grass, better body weight gain was obtained when fed in combination with desmodium. PMID- 29514445 TI - The Effect of Intermittent Watering on Performance, Blood Metabolites, and Nutrient Digestibility in Baluchi Lambs. AB - Objective: This study was conducted to evaluate the effect of intermittent watering on Baluchi lambs, regarding their performance, blood metabolites, and nutrient digestibility. Methods: Twenty male Baluchi lambs, 120 +/- 5 days of age and 29 +/-2.2 kg body weight were randomly assigned to four watering treatments: (T1) free access to water during the day, (T2) watered ad libitum twice a day, (T3) watered ad libitum once a day, (T4) watered ad libitum once every two days. The experiment lasted 42 days. Results: water restriction led to reduction in weight gain, DMI, water consumption, Water/DMI (p<0.05). Rectal temperature and respiration rate non influenced (p>0.05). aldosterone, cortisol, insulin hormone affected by treatments (p<0.05). Serum glucose, creatinine, total protein and globulin not affected (p> 0.05). while observed significant difference among T3 with other treatment in BUN (p<0.05). significant differences were observed in serum cholesterol and triglyceride between T4 and other groups (p< 0.05). There was a significant difference between T4 and T1 and T2 in albumin serum (p< 0.05). RBC WBC non influenced by water restriction (p< 0.05). However, PCV, MCV, MCH, MCHC and hemoglobin influenced by treatments (p< 0.05). sodium and chloride of serum was significantly higher in T4, and there were significant differences among the treatments (p< 0.05). But there were no differences among the treatments (p> 0.05), with regard to calcium, phosphorus, magnesium, potassium. Digestibility of ADF, NDF, CP and OM was different among T3, T4 and other treatments (p< 0.05), while no differences were found in EE digestibility among treatments (p> 0.05). There was a significant difference between T4 and other groups and between T4 and T1 regarding fecal output and urine exertion respectively. Conclusion: This results implies that Baluchi lambs can tolerate water restriction up to once a day for at least 28 days without harmful effects. PMID- 29514446 TI - Net energy content of rice bran, corn germ meal, corn gluten feed, peanut meal, and sunflower meal in growing pigs. AB - OBJECTIVE: The objective of this experiment was to determine the net energy (NE) content of full-fat rice bran (FFRB), corn germ meal (CGM), corn gluten feed (CGF), solvent-extracted peanut meal (PNM), and dehulled sunflower meal (SFM) fed to growing pigs using indirect calorimetry or published prediction equations. METHODS: Twelve growing barrows with an average initial body weight (BW) of 32.4+/-3.3 kg were allotted to a replicated 3*6 Youden square design with 3 successive periods and 6 diets. During each period, pigs were individually housed in metabolism crates for 16 d, which included 7 days for adaptation. On d 8, the pigs were transferred to the respiration chambers and fed one of the 6 diets at 2.0 MJ metabolizable energy (ME)/kg BW0.6/d. Total feces and urine were collected and daily heat production was measured from d 9 to d 13. On d 14 and d15, pigs were fed at their maintenance energy requirement level. On the last day pigs were fasted and fasting heat production was measured. RESULTS: The NE of FFRB, CGM, CGF, PNM, and SFM measured by indirect calorimetry method was 12.33, 8.75, 7.51, 10.79, and 6.49 MJ/kg dry matter (DM), respectively. The NE/ME ratios ranged from 67.2% (SFM) to 78.5% (CGF). The NE values for the 5 ingredients calculated according to the prediction equations were 12.22, 8.55, 6.79, 10.51, and 6.17 MJ/kg DM, respectively. CONCLUSION: The NE values were the highest for FFRB and PNM and the lowest in the corn co-products and SFM. The average NE of the 5 ingredients measured by indirect calorimetry method in the current study was greater than values predicted from NE prediction equations (0.32 MJ/kg DM). PMID- 29514447 TI - Genome wide association study of fatty acid composition in Duroc swine. AB - Objective: Genome wide association study was conducted to identify and validate candidate genes associated with fatty acid composition of pork. METHODS: A total of 480 purebreed Duroc pigs were genotyped using IlluminaPorcine60k bead chips while the association test was implemented following genome-wide rapid association using Mixed Model and Regression-Genomic Control (GRAMMAR-GC) approach. RESULTS: A total of 25, 29, and 16 single nucleotide polymorphisms (SNPs) were significantly associated with stearic (18:0), oleic (18:1) and saturated fatty acids (SFA), respectively. Genome wide significant variants were located on the same region of swine chromosome 14 (SSC14) that spanned from 120 to 124 Mb. Top SNP ALGA008191 was located at 5 kb near the stearoyl-CoA desaturase (SCD) gene. This gene is directly involved in desaturation of stearic acid into oleic acid. General relationship of significant SNPs showed high linkage disequilibrium thus genome-wide signals was attributed to SCD gene. However, understanding the role of other genes like elongation of very long chain fatty acids-3 (ELOVL3) located on this chromosomal segment might help in further understanding of metabolism and biosynthesis of fatty acids. CONCLUSION: Overall, this study provides evidence that validates SCD gene as strong candidate gene associated with fatty acid composition in Duroc pigs. Moreover, this study confirms significant SNPs near ELOVL3 gene. PMID- 29514448 TI - Reproductive fecundity of Iraqi Awassi ewes immunized against synthetic inhibin alpha subunit or steroid-free bovine follicular fluid. AB - Objective: The present study was conducted to investigate the impacts of active and passive immunization against synthetic inhibin and steroid-free bovine follicular fluid, respectively, on reproductive fecundity out of breeding season in Iraqi Awassi ewes. METHODS: Follicular fluid was aspired from mature bovine follicles, treated with activated charcoal, and used for immunization of male rabbits for obtaining steroid free bovine follicular fluid (SFBFF) antiserum. Forty non-pregnant Awassi ewes were allocated into 4 groups (n = 10 each). At day 38 of experiment, ewes were treated with intra-vaginal MPA sponge (60 mg for 12 days). At days 0, 28, and 50, ewes were treated with 4, 2, and 2 mL of normal saline (control; C-ve), 400, 200, and 200 MUg of ovalbumin (C+ve), 400, 200 and 200 MUg of inhibin (SI group), respectively, and 4 mL of normal saline at day 0, and 4 and 2 mL of SFBFF antiserum at days 28 and 50, respectively, (AI group). After mating with Awassi rams, pregnancy and embryo number were diagnosed, at day 38 of pregnancy, using ultrasonography. Blood samples were collected at days 30, 60, 90, and 120 of pregnancy, for assessment of estradiol-17beta (E2) and progesterone (P4) levels. After parturition, numbers of delivered lambs were recorded. RESULTS: The results revealed significant increase of P4 and significant decrease of E2 levels in SI and AI pregnant ewes than controls at days 30, 60, 90, and 120. Newborn number increased significantly in SI and AI treated than control ewes. CONCLUSION: Active or passive immunization against endogenous inhibin could augment reproductive fecundity out of breeding season in Iraqi Awassi ewes. PMID- 29514449 TI - miR-375 down-regulation of the rearranged L-myc fusion and hypoxia-induced gene domain protein 1A genes and effects on Sertoli cell proliferation. AB - Objective: This study aimed to screen and identify the target genes of miR-375 in pig Sertoli (ST) cells and to elucidate the effect of miR-375 on the proliferation of ST cells. METHODS: In this study, bioinformatics software was used to predict and verify miR-375 target genes. Quantitative polymerase chain reaction (PCR) was used to detect the relationship between miR-375 and its target genes in ST cells. Enzyme-linked immunosorbent assay (ELISA) of rearranged L-myc fusion (RLF) and hypoxia-induced gene domain protein 1A (HIGD1A) was performed on porcine ST cells, which were transfected with a miR-375 mimics and inhibitor to verify the results. Dual luciferase reporter gene assays were performed to assess the interactions among miR-375, RLF, and HIGD1A. The effect of miR-375 on the proliferation of ST cells was analyzed by CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS). RESULTS: Five possible target genes of miR-375, including RLF, HIGD1A, colorectal cancer associated 2, POU class 3 homeobox 1, and WW domain binding protein 1 like, were found. The results of quantitative PCR suggested that mRNA expression of RLF and HIGD1A had a negative correlation with miR-375, indicating that RLF and HIGD1A are likely the target genes of miR-375. The ELISA results revealed that RLF and HIGD1A were negatively correlated with the miR-375 protein level. The luminescence results for the miR-375 group co transfected with wild-type RLF and HIGD1A vector were significantly lower than those of the miR-375 group co-transfected with the blank vector or mutant RLF and HIGD1A vectors. The present findings suggest that RLF and HIGD1A are target genes of miR-375 and that miR-375 inhibits ST cell proliferation according to MTS analysis. CONCLUSION: It was speculated that miR-375 affects cell proliferation through its target genes, which play an important role in the development of testicular tissue. PMID- 29514450 TI - In silico approaches to identify the functional and structural effects of non synonymous SNPs in selective sweeps of the Berkshire pig genome. AB - Objective: Non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in Berkshire selective sweep regions and then were investigated to discover genetic nsSNP mechanisms that were potentially associated with Berkshire domestication and meat quality. We further used bioinformatics tools to predict damaging amino-acid substitutions in Berkshire-related nsSNPs. METHODS: nsSNPs were examined in whole genome resequencing data of 110 pigs, including 14 Berkshire pigs, generated using the Illumina Hiseq2000 platform to identify variations that might affect meat quality in Berkshire pigs. RESULTS: Total 65,550 nsSNPs were identified in the mapped regions; among these, 319 were found in Berkshire selective-sweep regions reported in a previous study. Genes encompassing these nsSNPs were involved in lipid metabolism, intramuscular fatty acid deposition, and muscle development. The effects of amino acid change by nsSNPs on protein functions were predicted using sorting intolerant from tolerant and polymorphism phenotyping V2 to reveal their potential roles in biological processes that may correlate with the unique Berkshire meat-quality traits. CONCLUSION: Our nsSNP findings confirmed the history of Berkshire pigs and illustrated the effects of domestication on generic-variation patterns. Our novel findings, which are generally consistent with those of previous studies, facilitated a better understanding of Berkshire domestication. In summary, we extensively investigated the relationship between genomic composition and phenotypic traits by scanning for nsSNPs in large-scale whole-genome sequencing data. PMID- 29514451 TI - Effect of Cultivar and Cultivation Year on the Metabolite Profile of Onion Bulbs ( Allium cepa L.). AB - This study investigated the variation of metabolite profiles of onion bulbs ( Allium cepa L.) depending on genetic and environmental factors. Nine onion cultivars ("Corrado", "Cupido", "Forum", "Hytech", "Picador", "Redlight", "Snowpack", "Stardust", "Sturon") with different scale color and dry matter content were grown in a two-year field trial. Using a recently established metabolite profiling approach based on liquid chromatography-coupled electrospray ionization quadrupole time-of-flight mass spectrometry, 106 polar and semipolar metabolites which belong to compound classes determining nutritional, sensory, and technological quality of onion bulbs such as saccharides, flavonoids, S substitued cysteine conjugates, amino acids, and derived gamma-glutamyl peptides were relatively quantitated in parallel. Statistical analyses of the obtained data indicated that depending on the compound class genetic and environmental factors differently contributed to variation of metabolite levels. For saccharides and flavonoids the genetic factor was the major source of variation, whereas for cysteine sulfoxides, amino acids, and peptides both genetic and environmental factors had a significant impact on corresponding metabolite levels. PMID- 29514452 TI - Heliobacteria Reveal Fermentation As a Key Pathway for Mercury Reduction in Anoxic Environments. AB - The accumulation of mercury (Hg) in rice, a dietary staple for over half of the world's population, is rapidly becoming a global food safety issue. Rice paddies support the anaerobic production of toxic methylmercury that accumulates in plant tissue, however the microbial controls of Hg cycling in anoxic environments remain poorly understood. In this study, we reveal a novel reductive Hg metabolism in a representative of the family Heliobacteria ( Heliobacterium modesticaldum Ice1) that we confirm in model chemotrophic anaerobes. Heliobacteria served as our initial model because they are a family of spore forming fermentative photoheterotrophs commonly isolated from terrestrial environments. We observed that H. modesticaldum reduced up to 75% of HgII under phototrophic or fermentative conditions. Fermentative HgII reduction relied on the ability of cells to oxidize pyruvate whereas phototrophic HgII reduction could be supported even in the absence of a carbon source. Inhibiting pyruvate fermentation eliminated HgII reduction in all chemotrophic strains tested, whereas phototrophic cells remained unaffected. Here we propose a non mer-operon dependent mechanism for Hg0 production in anoxic environments devoid of light where external electron acceptors are limited. These mechanistic details provide the foundation for novel bioremediation strategies to limit the negative impacts of Hg pollution. PMID- 29514453 TI - Fuzhuan Brick Tea Polysaccharides Attenuate Metabolic Syndrome in High-Fat Diet Induced Mice in Association with Modulation in the Gut Microbiota. AB - An increasing amount of evidence suggests that the gut microbiota composition and structure contribute to the pathophysiology of metabolic syndrome (MS), which has been put forward as a new target in the treatment of diet-induced MS. In this work, we aimed to investigate effects of Fuzhuan brick tea polysaccharides (FBTPS) on MS and gut microbiota dysbiosis in high-fat diet (HFD) fed mice and to further investigate whether its attenuation of MS is related to the modulation of gut microbiota. The results showed that FBTPS intervention could significantly attenuate metabolic syndrome in HFD-induced mice. Based on results of sequencing, FBTPS treatment could increase the phylogenetic diversity of HFD-induced microbiota. FBTPS intervention could significantly restore the HFD-induced increases in relative abundances of Erysipelotrichaceae, Coriobacteriaceae, and Streptococcaceae. Spearman's correlation analysis showed that 44 key OTUs were negatively or positively associated with MS. Our results suggested that FBTPS could serve as a novel candidate for prevention of MS in association with the modulation of gut microbiota. PMID- 29514454 TI - Flexible or Robust Amorphous Photonic Crystals from Network-Forming Block Copolymers for Sensing Solvent Vapors. AB - Large-area and flexible amorphous photonic crystals (APCs) featuring interconnected network microstructures are fabricated using high-molecular-weight polystyrene- block-poly(methyl methacrylate) (PS-PMMA) block copolymers. Kinetically controlled microphase separation combining with synergistic weak incompatibility gives rise to short-range-order network microstructures, exhibiting noniridescent optical properties. Solubility-dependent solvatochromism with distinct responses to various organic solvent vapors is observed in the network-forming APC film. By taking advantage of photodegradation of the PMMA block, nanoporous network-forming films were prepared for subsequent template synthesis of robust SiO2- and TiO2-based APC films through sol-gel reaction. Consequently, refractive index contrast of the APC film was able to be manipulated, resulting in intensely enhanced reflectivity and increased response rate for detecting solvent vapor. With the integration of self-assembly and photolithography approaches, flexible and robust network-forming APC films with well-defined photopatterned textures are carried out. This can provide a novel means for the design of photopatterned organic or inorganic APC films for sensing solvent vapors. PMID- 29514455 TI - Structural Modification of (-)-Epigallocatechin Gallate (EGCG) Shows Significant Enhancement in Mitochondrial Biogenesis. AB - (-)-Epigallocatechin-3-gallate (EGCG) is known as a mitochondria-targeted molecule that can prevent mitochondrial deterioration and induce mitochondrial biogenesis by modulating key regulators of mitochondrial metabolism. In this study, we tackled whether derivatization of EGCG could result in enhancement of its effects on mitochondrial biogenesis. EGCG, EGCG peracetate (AcEGCG), and its 4"- O-alkyl substituted congeners prepared by previously reported procedures were biologically evaluated. Interestingly, EGCG and AcEGCG were only marginally effective in inducing mitochondrial biogenesis, while AcEGCG congeners with an alkyl group at the 4"- O position showed significantly increased biological activity compared to their parent compound. Among these series, 3f with a methyl branched carbonate chain at the 4"- O position of the AcEGCG scaffold showed the most enhancement in inducing mitochondrial biogenesis. Hepa1-6 cells treated with 3f exhibited increases in both mitochondrial mass (1.5 times) and relative mtDNA content to nDNA (1.5 times). As a mitochondrial biogenesis enhancer, 3f also increased expression levels of regulators for mitochondrial function, including PGC-1alpha (4.0 fold), p-AMPK (2.5 fold), SIRT1 (4.2 fold), ERRalpha (1.8 fold), NRF-1 (1.6 fold), NRF-2 (1.7 fold), and mtTFA (1.6 folds). Investigation of oxidative phosphorylation by mitochondria in the presence of 3f revealed that 3f increased the NAD+/NADH ratio, the amount of cytochrome c, ATP synthesis, and oxygen consumption in Hepa1-6 cells by 2.2, 1.4, 1.5, and 2.1 fold, respectively. Taken together, these results warrant an extensive structure-activity relationship study for EGCG derivatives to develop novel mitochondrial biogenesis enhancers. PMID- 29514456 TI - Seabird Tissues As Efficient Biomonitoring Tools for Hg Isotopic Investigations: Implications of Using Blood and Feathers from Chicks and Adults. AB - Blood and feathers are the two most targeted avian tissues for environmental biomonitoring studies, with mercury (Hg) concentration in blood and body feathers reflecting short and long-term Hg exposure, respectively. In this work, we investigated how Hg isotopic composition (e.g., delta202Hg and Delta199Hg) of blood and feathers from either seabird chicks (skuas, n = 40) or adults (penguins, n = 62) can accurately provide information on exposure to Hg in marine ecosystems. Our results indicate a strong correlation between blood and feather Hg isotopic values for skua chicks, with similar delta202Hg and Delta199Hg values in the two tissues (mean difference: -0.01 +/- 0.25 0/00 and -0.05 +/- 0.12 0/00, respectively). Since blood and body feathers of chicks integrate the same temporal window of Hg exposure, this suggests that delta202Hg and Delta199Hg values can be directly compared without any correction factors within and between avian groups. Conversely, penguin adults show higher delta202Hg and Delta199Hg values in feathers than in blood (mean differences: 0.28 +/- 0.190/00 and 0.25 +/ 0.130/00), most likely due to tissue-specific Hg temporal integration. Since feathers integrate long-term (i.e., the intermoult period) Hg accumulation, whereas blood reflects short-term (i.e., seasonal) Hg exposure in adult birds, the two tissues provide complementary information on trophic ecology at different time scales. PMID- 29514457 TI - Hierarchically Porous Carbons Derived from Biomasses with Excellent Microwave Absorption Performance. AB - A variety of biomass-based carbon materials with two-level porous structure have been successfully prepared by one-step carbonization process. The first level of microscale pores templates from the inherent porous tissues, while the second one of nanopores is produced by the in situ etching by the embedded alkaline metal elements. The superimposed effect of nano and microscale pores endows the hierarchically porous carbons (HPCs) with excellent microwave absorption (MA) performance. Among them, the spinach-derived HPC exhibits a maximum reflection loss of -62.2 dB and a broad effective absorption bandwidth of 7.3 GHz. Particularly, this excellent MA performance can be reproduced using the biomass materials belonging to different families, harvested seasons, and origins, indicating a green and sustainable process. These encouraging findings shed the insights on the preparation of biomass-derived microwave absorbents with promising practical applications. PMID- 29514458 TI - Modular Synthesis of 3,6-Disubstituted-1,2,4-triazines via the Cyclodehydration of beta-Keto- N-acylsulfonamides with Hydrazine Salts. AB - A straightforward method for preparing 3,6-disubstituted-1,2,4-triazines through a redox-efficient cyclodehydration of beta-keto- N-acylsulfonamides with hydrazine salts is described. Two approaches for synthesizing the requisite beta keto- N-acylsulfonamides are presented, which allow for the late stage incorporation of either the C3 or C6 substituent in a flexible manner from acid chlorides or alpha-bromoketones, respectively. The scope of this methodology includes primary and secondary sp3-linked substituents at both the C3 and C6 positions, and the mild reaction conditions tolerate a variety of sensitive functionalities. PMID- 29514459 TI - Primer in Genetics and Genomics, Article 7-Multifactorial Concepts: Gene-Gene Interactions. AB - Most common disorders affecting human health are not attributable to simple Mendelian (single-gene) inheritance patterns. Rather, the risk of developing a complex disease is often the result of interactions across genes, whereby one gene modifies the phenotype of another gene. These types of interactions can occur between two or more genes and are referred to as epistasis. There are five major types of epistatic interactions, but in human genetics, additive epistasis is most often discussed and includes both positive and negative subtypes. Detecting epistatic interactions can be quite difficult because seemingly unrelated genes can interact with and influence each other. As a result of this complexity, statistical geneticists are constantly developing new methods to enhance detection, but there are disadvantages to each proposed method. In this article, we explore the concept of epistasis, discuss different types of epistatic interactions, and provide a brief introduction to statistical methods researchers use to uncover sets of epistatic interactions. Then, we consider Alzheimer's disease as an exemplar for a disease with epistatic effects. Finally, we provide helpful resources, where nurses can learn more about epistasis in order to incorporate these methods into their own program of research. PMID- 29514461 TI - Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia. AB - Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems. PMID- 29514460 TI - Altered DNA Methylation Patterns Associated With Clinically Relevant Increases in PTSD Symptoms and PTSD Symptom Profiles in Military Personnel. AB - Military personnel experience posttraumatic stress disorder (PTSD), which is associated with differential DNA methylation across the whole genome. However, the relationship between these DNA methylation patterns and clinically relevant increases in PTSD severity is not yet clearly understood. The purpose of this study was to identify differences in DNA methylation associated with PTSD symptoms and investigate DNA methylation changes related to increases in the severity of PTSD in military personnel. In this pilot study, a cross-sectional comparison was made between military personnel with PTSD (n = 8) and combat matched controls without PTSD (n = 6). Symptom measures were obtained, and genome wide DNA methylation was measured using methylated DNA immunoprecipitation (MeDIP seq) from whole blood samples at baseline and 3 months later. A longitudinal comparison measured DNA methylation changes in military personnel with clinically relevant increases in PTSD symptoms between time points (PTSD onset) and compared methylation patterns to controls with no clinical changes in PTSD. In military personnel with elevated PTSD symptoms 3 months following baseline, 119 genes exhibited reduced methylation and 8 genes exhibited increased methylation. Genes with reduced methylation in the PTSD-onset group relate to the canonical pathways of netrin signaling, Wnt/Ca+ pathway, and axonal guidance signaling. These gene pathways relate to neurological disorders, and the current findings suggest that these epigenetic changes potentially relate to PTSD symptomology. This study provides some novel insights into the role of epigenetic changes in PTSD symptoms and the progression of PTSD symptoms in military personnel. PMID- 29514462 TI - Meropenem/Vaborbactam, the First Carbapenem/beta-Lactamase Inhibitor Combination. AB - OBJECTIVE: To review the pharmacology, spectrum of activity, pharmacokinetics, pharmacodynamics, safety, efficacy, administration, and considerations for clinical use of meropenem/vaborbactam (M/V). DATA SOURCES: A literature search using PubMed and clinicaltrials.gov (June 2013 to December 2017) was conducted using the search terms meropenem, vaborbactam, RPX7009, biapenem, RPX2003, and carbavance. References from relevant articles and conference abstracts were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical, phase I studies, and phase III studies written in the English language were evaluated. DATA SYNTHESIS: M/V is a novel carbapenem/beta-lactamase inhibitor antimicrobial with in vitro activity against nearly 99% of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. M/V is approved for the treatment of adults with complicated urinary tract infections (cUTIs), including pyelonephritis. In a phase III cUTI trial (TANGO I), 98.4% of patients treated with M/V experienced overall clinical success compared with 94% of patients treated with piperacillin/tazobactam (95% CI = 0.7 to 9.1). When compared with best available therapy for carbapenem resistant Enterobacteriaceae (CRE) infections in TANGO II, patients receiving M/V were more likely to achieve clinical cure at both the end of therapy (64.3% vs 33.3%, P = 0.04) as well as at the test of cure (57.1% vs 26.7%, P = 0.04). The most common adverse effects associated with M/V were headache, infusion-site reactions, and diarrhea. CONCLUSION: M/V has a valuable role in the treatment of CRE and should be used judiciously to preserve its use for resistant infections. PMID- 29514463 TI - Prescription Adaptation Services: A Regulatory and Practice Perspective. AB - "Prescription adaptation services" refers to the ability of a pharmacist to autonomously "adapt" an existing prescription when the action is intended to optimize the therapeutic outcome. Adaptation services typically fall into 2 categories: (1) renewals and (2) changes. Renewals ensure continuity of care for patients and may be emergency renewals (typically 72 hours) or continuation-of therapy renewals (typically 90 or more days). Changes include therapeutic substitutions or changes to quantity, formulation, route of administration, dose/interval, and completing missing information. With an appropriate framework in place, adaptation services can safely optimize medication therapy outcomes while promoting efficiencies. PMID- 29514464 TI - A Prescription for Prescribing: Ensuring Continued Pharmacist Preparedness. AB - The scope of practice for pharmacists in the United States increasingly includes elements of prescribing under collaborative practice agreements and statewide protocols. However, as a result of continued health care access concerns, we believe that pharmacists will be called on to serve as independent prescribers in the future. For this anticipated practice expansion to become a successful reality, the assurance of pharmacist preparedness and continuous professional development through profession-wide standards will be imperative. PMID- 29514465 TI - Association Between Malnutrition and Depression Among Community-Dwelling Older Chinese Adults. AB - Malnutrition and depression are of important concern among older adults. We investigated the association between malnutrition and depression among community dwelling older Chinese adults and how both affect health care costs. Data from 4916 older adults (age >=60 years) collected as part of 2013-Wave II China Health and Retirement Longitudinal Study (CHARLS) survey were analyzed. Measures of body mass index and weight loss were used as indicators of malnutrition. Malnourished subjects were 31% more likely to be depressed than their non-malnourished counterparts (odds ratio = 1.311, P < .1). Health care-related cost was Y591.8 higher for malnourished older adult per year compared to a non-malnourished counterpart ( P < .1), thus confirming that incidence of depression coupled with malnutrition significantly increases health care-related costs. These results highlight the importance of malnutrition and depression screening and treatment for older Chinese community-dwelling adults, and the importance of community based nutrition-specific programs that could address the needs of the affected populations. PMID- 29514466 TI - Postthrombotic Syndrome in Patients Treated With Rivaroxaban or Warfarin for Venous Thromboembolism. AB - Postthrombotic syndrome (PTS) is a frequent complication of venous thromboembolism (VTE). Using MarketScan claims data from January 2012 to June 2015, we identified adults with a primary diagnosis code for VTE during a hospitalization/emergency department visit, >=6 months of insurance coverage prior to the index event and newly started on rivaroxaban or warfarin within 30 days of the index VTE. Patients with <4-month follow-up postindex event or a claim for any anticoagulant during 6-month baseline period were excluded. Differences in baseline characteristics between rivaroxaban and warfarin users were adjusted for using inverse probability of treatment weights based on propensity scores. Patients were followed for the development of PTS starting 3 months after the index VTE. Cox regression was performed and reported as hazard ratios with 95% confidence intervals (CIs). In total, 10 463 rivaroxaban and 26 494 warfarin users were followed for a mean of 16 +/- 9 (range, 4-39) months. Duration of anticoagulation was similar between cohorts (median = 6 months). Rivaroxaban was associated with a 23% (95% CI: 16-30) reduced hazard of PTS versus warfarin. Rivaroxaban was associated with a significant risk reduction in symptoms of PTS compared to warfarin in patients with VTE treated in routine practice. PMID- 29514467 TI - Optimal Antithrombin Activity Threshold for Initiating Antithrombin Supplementation in Patients With Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study. AB - Low-dose antithrombin supplementation therapy (1500 IU/d for 3 days) improves outcomes in patients with sepsis-induced disseminated intravascular coagulation (DIC). This retrospective study evaluated the optimal antithrombin activity threshold to initiate supplementation, and the effects of supplementation therapy in 1033 patients with sepsis-induced DIC whose antithrombin activity levels were measured upon admission to 42 intensive care units across Japan. Of the 509 patients who had received antithrombin supplementation therapy, in-hospital mortality was significantly reduced only in patients with very low antithrombin activity (<=43%; bottom quartile; adjusted hazard ratio: 0.603; 95% confidence interval: 0.368-0.988; P = .045). Similar associations were not observed in patients with low, moderate, or normal antithrombin activity levels. Supplementation therapy did not correlate with the incidence of bleeding requiring transfusion. The adjusted hazard ratios for in-hospital mortality increased gradually with antithrombin activity only when initial activity levels were very low to normal but plateaued thereafter. We conclude that antithrombin supplementation therapy in patients with sepsis-induced DIC and very low antithrombin activity may improve survival without increasing the risk of bleeding. PMID- 29514469 TI - The Relationship Between Neutrophil-Lymphocyte Ratio and In-Stent Restenosis. PMID- 29514473 TI - A qualitative systematic review of published work on disclosure and help-seeking for domestic violence and abuse among women from ethnic minority populations in the UK. AB - INTRODUCTION: Domestic violence and abuse has been recognised as an international public health problem. However, the pervasiveness of the problem is unknown due in part to underreporting, especially among women from ethnic minority populations. In relation to this group, this review seeks to explore: (1) the barriers to disclosure; (2) the facilitators of help-seeking; and (3) self perceived impacts of domestic violence. DESIGN: We systematically identified published qualitative studies conducted among women from ethnic minority populations in the UK. Data analysis was completed using thematic analysis approach. RESULT: 562 papers were identified and eight papers from four studies conducted among women from ethnic minority populations in the UK met the inclusion criteria and were reviewed. Barriers to disclosure include: Immigration status, community influences, problems with language and interpretation, and unsupportive attitudes of staff within mainstream services. Facilitators of help seeking were: escalation of abuse and safety of children. Self-perceived impact of abuse includes: shame, denial, loss of identity and lack of choice. CONCLUSION: There is an on-going need for staff from domestic violence services to be aware of the complexities within which women from ethnic minority populations experience domestic violence and abuse. PMID- 29514481 TI - Palliative Care Patients' Quality of Dying and Circumstances of Death-Comparison of Informal Caregivers' and Health-Care Professionals' Estimates. AB - BACKGROUND: Patient-reported outcomes are usually considered to be the gold standard assessment. However, for the assessment of quality of dying and death, ratings of informal caregivers (ICGs) or health-care professionals (HCPs) must be considered for ethical and methodological reasons. This article aims to present results of ICGs' and HCPs' estimates of the questionnaire, quality of dying and death (QoDD) on patients who died in PCUs and to compare the level of agreement of both ratings/raters. METHODS: The parent validation study to this analysis assessed the ICG and HCP versions of the QoDD. Descriptive statistics are presented for each item in both versions. T tests for the estimation of differences between ICG and HCP were performed. Case-related absolute differences between estimates were analyzed regarding the extent of agreement and deviation. RESULTS: Two hundred fifteen matched ICG and HCP ratings were analyzed. The ratings in all 6 QoDD dimensions were high; single items scored low. Mean absolute difference between both ratings was 0.33 (standard deviation [SD]: 3.08; median 0.05) on a 0 to 10 numerical rating scale and ranges between -8.24 (higher rating of ICGs compared to HCPs) and 9.33 (higher rating of HCPs compared to ICGs). CONCLUSIONS: The findings appear to show a high satisfaction with quality of dying and death as rated by ICGs and HCPs, but we suspect this might be indicative of a methodological challenge, that is, a ceiling effect in both assessments. Single low scoring items may provide important clues for improvement in end-of-life care. Although descriptive data show comparable mean values and standard deviations, the actual congruence of ratings is low. In summary, replacing one rating by another cannot be recommended. PMID- 29514480 TI - The Use of Simulation to Teach Nursing Students and Clinicians Palliative Care and End-of-Life Communication: A Systematic Review. AB - OBJECTIVES: To present the findings of a systematic review on the use of simulation-based learning experiences (SBLEs) to teach communication skills to nursing students and clinicians who provide palliative and end-of-life care to patients and their families. BACKGROUND: Palliative care communication skills are fundamental to providing holistic patient care. Since nurses have the greatest amount of direct exposure to patients, building such communication competencies is essential. However, exposure to patients and families receiving palliative and end-of-life care is often limited, resulting in few opportunities to learn these skills in the clinical setting. Simulation-based learning experiences can be used to supplement didactic teaching and clinical experiences to build the requisite communication skills. METHODS: Searches of CINAHL, MEDLINE, PsychINFO, ERIC, and Web of Science electronic databases and Grey Literature returned 442 unique records. Thirty articles met the established criteria, including the SBLE must contain a nursing role. RESULTS: Simulation-based learning experience are being used to teach palliative and end-of-life communication skills to nursing students and clinicians. Lack of standardization, poor evaluation methods, and limited exposure to the entire interprofessional team makes it difficult to identify and disseminate validated best practices. CONCLUSION: While the need for further research is acknowledged, we recommend this evidence be augmented by training programs that utilize SBLEs through (1) applying standards, (2) clearly specifying goals and objectives, (3) integrating externally validated scenarios, and (4) employing rigorous evaluation methods and measures that link the SBLE to the training objectives and desired clinician practice behaviors and patient outcomes. PMID- 29514482 TI - Decision-Making on a Deadline: Tracheostomy, Nutrition, and Autonomy. PMID- 29514485 TI - Special Issue: Chemometrics. PMID- 29514486 TI - A Pilot Study of a Mindfulness-Based Art Therapy Intervention in Outpatients With Cancer. AB - BACKGROUND: Patients with cancer frequently experience physical and psychological distress that can worsen their quality of life. OBJECTIVES: We assessed the outcomes of an 8-week mindfulness-based art therapy (MBAT) intervention, Walkabout: Looking In, Looking Out, on symptoms, sleep quality, health-related quality of life, sense of coherence (SOC), and spirituality in outpatients with cancer. METHODS: A 1-group, pre-post intervention design with repeated measures at baseline, week 4, and week 8. RESULTS: Despite a small pilot sample (n = 18), we found large effect sizes and statistically significant improvements from week 1 to week 8 in depression, the comprehensibility subscale of the SOC, and each subscale of spirituality, that is, peace, meaning, and faith. There were no significant changes in physical functioning, pain, sleep, tiredness, drowsiness, nausea, and appetite. CONCLUSIONS: The MBAT intervention, Walkabout, seems to meet key palliative care goals including improvement in emotional well-being, comprehensibility, and meaning making among outpatients with cancer. PMID- 29514487 TI - Comparative Analysis of the Views of Oncologic Subspecialists and Palliative/Supportive Care Physicians Regarding Advanced Care Planning and End-of Life Care. AB - BACKGROUND: Early palliative/supportive care (PSC) consultation and advance care planning (ACP) improve outcomes for patients with incurable cancer. However, PSC is underutilized in the United States. OBJECTIVE: To examine philosophical differences among PSC, radiation oncology (RO), and medical oncology (MO) physicians in order to understand barriers to early PSC referral. DESIGN: An electronic survey collected views of a nationwide cohort of health-care professionals regarding ACP and end-of-life care. Setting/Participants/Measurements: A subgroup analysis compared the responses from all 51 PSC, 178 RO, and 81 MO physician participants (12% response rate), using Pearson chi2 and Mann-Whitney U tests for categorical and ordinal data, respectively. RESULTS: More statistically significant differences were observed between RO-PSC (12 questions) and MO-PSC (12 questions) than RO-MO (4 questions). Both RO and MO were more likely than PSC physicians to believe doctors adequately care for emotional ( P < .001) and physical ( P < .001) needs of patients with an incurable illness. Both RO and MO were also less likely to believe that PSC physicians were helpful at addressing these needs ( P = .002 and <.001, respectively) or that patients' awareness of their life expectancy leads to better medical ( P = .007 and .002, respectively) and personal ( P = .001 for each) decisions. Palliative/supportive care physicians felt that doctors are generally less successful at explaining/clarifying advanced life-sustaining treatments than RO ( P < .001) or MO ( P = .004). MO favored later initiation of ACP than either RO ( P = .006) or PSC physicians ( P = .004). CONCLUSIONS: Differences in perception of appropriate end-of-life care exist between oncologists and PSC physicians, suggesting a need for improved education and communication between these groups. PMID- 29514488 TI - Palliative Care Matters: Lessons From the Loss of a Facility Dog. AB - Animal-assisted intervention is gaining attention as a stress reduction modality. Quantitative data demonstrate its effectiveness, as a recent study published in AJHPM supported that a Veterans Affairs (VA) hospital facility dog paired with a palliative care psychologist had a measurable impact on salivary cortisol levels and heart rate in hospitalized veterans. There remains an important role for qualitative insights. The Denver VA palliative care team learned a range of lessons from the sudden loss of their facility dog, many of which relate directly to palliative care. The importance of communication, adjusting to changing teams, and the need for consultation and support based in shared goals and values all became evident in the course of the facility dog's illness. After her death, lessons shifted to grief and loss and how providers, patients, and a community care for each other. People's connection to the facility dog ultimately proved to be a critical factor in helping them connect with one another. PMID- 29514489 TI - Please Ask Gently: Using Culturally Targeted Communication Strategies to Initiate End-of-Life Care Discussions With Older Chinese Americans. AB - BACKGROUND: Health-care providers (HCPs) find facilitating end-of-life (EOL) care discussions challenging, especially with patients whose ethnicities differ from their own. Currently, there is little guidance on how to initiate and facilitate such discussions with older Chinese Americans (>=55 years) and their families. OBJECTIVE: To explore communication strategies for HCPs to initiate EOL care discussions with older Chinese Americans in the San Francisco Bay Area. DESIGN: This qualitative (focused) ethnographic study included field observations and individual semistructured interviews with 14 community-dwelling older Chinese Americans who lived independently at home, 9 adult children, and 7 HCPs. Responses were analyzed using open coding, memos, and comparison across participants. RESULTS: The study participants emphasized the importance of assessing readiness for early EOL care discussions. All recommended using indirect communication approaches to determine older Chinese Americans' readiness. Indirect communication can be culturally targeted and applied at both system-wide (ie, health-care system) and individual (ie, HCP) levels. To institutionalize the practice, health-care facilities should implement EOL care discussion inquiries as part of routine during check-in or intake questionnaires. In individual practice, using depersonalized communication strategies to initiate the discussion was recommended to determine older Chinese Americans' readiness. CONCLUSION: Assessing readiness should be an essential and necessary action for early EOL care discussions. Culturally targeted assessment of older Chinese Americans includes using indirect communication approaches to initiate an EOL care discussion to determine their readiness. In addition to health-care system integration, providers should implement and evaluate proposed EOL discussion initiation prompts with their older Chinese American patients. PMID- 29514504 TI - Synthesis of citrophilus mealybug sex pheromone using chrysanthemol extracted from Pyrethrum (Tanacetum cinerariifolium). AB - A commercial pyrethrum extract was used as a source of chrysanthemol for the synthesis of the citrophilus mealybug (Pseudococcus calceolariae) sex pheromone. The chrysanthemic acid esters (pyrethrins I) were isolated and subsequently reduced to obtain chrysanthemol, which was used for ester pheromone synthesis. Field tests showed that the pheromone synthesized using plant-derived chrysanthemol was as attractive to male P. calceolariae as the pheromone obtained using a commercial isomeric chrysanthemol mixture. PMID- 29514503 TI - Toward an Intergenerational Model for Tobacco-Focused CBPR: Integrating Youth Perspectives via Photovoice. AB - The growing prominence of community-based participatory research (CBPR) presents as an opportunity to improve tobacco-related intervention efforts. CBPR collaborations for tobacco/health, however, typically engage only adults, thus affording only a partial understanding of community context as related to tobacco. This is problematic given evidence around age of tobacco use initiation and the influence of local tobacco environments on youth. The CEASE and Resist youth photovoice project was developed as part of the Communities Engaged and Advocating for a Smoke-free Environment (CEASE) CBPR collaboration in Southwest Baltimore. With the broader CEASE initiative focused on adult smoking cessation, CEASE and Resist had three aims: (1) elucidate how youth from a high-tobacco burden community perceive/interact with their local tobacco environment, (2) train youth as active change agents for tobacco-related community health, and (3) improve intergenerational understandings of tobacco use/impacts within the community. Fourteen youth were recruited from three schools and trained in participatory research and photography ethics/guiding principles. Youth met at regular intervals to discuss and narrate their photos. This article provides an overview of what their work revealed/achieved and discusses how including participatory youth research within traditionally adult-focused work can facilitate intergenerational CBPR for sustainable local action on tobacco and community health. PMID- 29514505 TI - QSAR classification and regression models for beta-secretase inhibitors using relative distance matrices. AB - The development of robust QSAR models to predict the activity of molecules of beta-secretase inhibitors is an area of interest due to the increase of Alzheimer's disease in patients in the global population. In this paper, we present a proposal based on the use of relative distance matrices as input data to the QSAR algorithms. These matrices store measurements of distances between the structural characteristics of pairs of molecules and between the molecules and a structural pattern extracted from the whole data set, thus efficiently representing a correlation between structural changes and activity. For the building of the classification and regression models support vector machine, tree complex and Gaussian process algorithms have been used; and for the validation of the models cross-validation, bootstrapping and y-randomizing techniques have been applied. The results obtained are close to 100% in accuracy and area under receiver operating characteristic values in classification, and close to 1.0 for r2 and 0.1 for root mean square error in regression in training and in external validation, proving the 'goodness' of the proposal. PMID- 29514507 TI - Lilly Calls into Question the Validity of Published Insulin Concentration Results. PMID- 29514506 TI - Neighbourhood Material and Social Deprivation and Exposure to Antidepressant Drug Treatment: A Cohort Study Using Administrative Data. AB - OBJECTIVE: To assess whether neighbourhood deprivation is associated with exposure to an antidepressant drug treatment (ADT) and its quality among individuals diagnosed with unipolar depression and insured by the Quebec public drug plan. METHOD: We conducted an administrative database cohort study of adults covered by the Quebec public drug plan who were diagnosed with a new episode of unipolar depression. We assessed material and social deprivation using an area based index. We considered exposure to an ADT as having >=1 claim for an ADT within the 365 days following depression diagnosis. Among those exposed to ADT, ADT quality was assessed with 3 indicators: first-line recommended ADT, persistence with the ADT, and compliance with the ADT. Generalized linear models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (95% CI). RESULTS: Of 100,432 individuals with unipolar depression, 65,436 (65%) were exposed to an ADT in the year following the diagnosis. Individuals living in the most materially deprived areas were slightly more likely to be exposed to an ADT than those living in the least deprived areas (aPR, 1.04; 95% CI, 1.03 to 1.06). The likelihoods of being exposed to a first line ADT, persisting for the minimum recommended duration and complying with the ADT were independent of the deprivation levels. CONCLUSIONS: Neighbourhood deprivation was not associated with ADT quality among individuals insured by the Quebec public drug plan. It might be partly attributable to the public drug plan whose goal is to provide equitable access to prescription drugs regardless of income. PMID- 29514508 TI - Time-Averaged Self-Monitored Blood Glucose Values Estimate Hemoglobin A1c Outcomes in Patients With Type 1 Diabetes. PMID- 29514509 TI - Digital Diabetes Self-Management: A Trilateral Serial. AB - The way diabetes patients cope with their disease in day-to-day routines is decisive for the development or the prevention of medical complications. Smartphones have created the ubiquitous environment to support health care with mobile applications (mHealth). This article comments on the publication by Offringa et al in JDST, which is one of few studies that tries to isolate the effects of a diabetes app. At the same time, it is a good example to discuss general aspects of mHealth in diabetes care. Treatment context, eHealth literacy, interoperability, and efficiency will determine the success of diabetes apps. The development has not yet reached its end. A triple quality feedback loop linking persons with diabetes, health care providers, and mHealth providers is suggested. PMID- 29514510 TI - Inaction over retractions of identified fraudulent publications: ongoing weakness in the system of scientific self-correction. AB - Published articles may be retracted when their findings are no longer considered reliable due to honest error, publication misconduct, or research misconduct. This article focuses on the case of a single serial violator of research and publication ethics in anesthesiology and critical care, which is widely publicized. A chain of events led to detection of misconduct that had substantial impact on the evidence base for the safety of hydroxyethyl starch, an intravenous artificial colloid solution, which is reflected in current guidelines on fluid management and volume resuscitation. As citations to retracted works continue to be a cause for concern, this article reviews the retraction status of this author's published articles to determine whether sufficient action has been taken to retract his body of work. Results show that retraction practices are not uniform and that guidelines for retraction are still not being fully implemented, resulting in retractions of insufficient quantity and quality. As retractions continue to emerge for the author's publications, with ten more since 2011, and as they are generally increasing, these data on retractions not only provide findings of misconduct, but also allow us to make inferences about ongoing weaknesses in the system of scientific literature. PMID- 29514511 TI - Can a phone call make a difference? Breastfeeding self-efficacy and nurse responses to mother's calls for help. AB - Telephone support is a format that presents an opportunity to sustain breastfeeding at a time when mothers identify themselves as at risk of cessation. The interactive mechanisms by which support is provided have not, however, been well investigated. We aimed to identify characteristics of calls that support breastfeeding self-efficacy. Thematic analysis of 149 calls from mothers seeking help for breastfeeding made to a 24-hour parenting helpline over a four week period, in Brisbane, Australia. Call-takers were 12 qualified and experienced maternal and child health nurses. Calls classified according to changes in breastfeeding self-efficacy across the call were thematically analysed to identify distinguishing interactional characteristics. Key interactional characteristics that served to build self-efficacy were privileging the mother, teamwork and credible affirmation while those that failed to build self-efficacy were laissez-faire affirmation and pragmatic problem-solving responses. Nurse responses that undermined caller self-efficacy conceptualized breastfeeding as a problem. Telephone helplines have potential to enhance mothers' confidence and sustain breastfeeding when there is a call for help, this study highlights that the style of interaction is critical. The findings identify the need for specific training to increase awareness of interactional styles and delivery of advice through telehealth formats. PMID- 29514513 TI - Synergies of urushiol and its pechmann derivative compatible with paclitaxel anti HepG2 activity. AB - The paper investigated the synergistic inhibitory effects of 1 (triene urushiol), 2 (monoene urushiol), 3 (urushiol pechmann derivative) and paclitaxel on proliferation of human hepatocellular carcinoma cell line HepG2. The inhibitory rate of cell proliferation was detected by MTT assay after HepG2 cells were separately treated with compounds 1, 2 and 3 combined with paclitaxel at different concentrations for 72 h. The joint index analysis was used to examine whether those compatible drugs had synergistic effect. The results showed that compounds 1, 2 and 3 had significant inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner, and their half inhibitory concentrations IC50 were 29.3, 55.5 and 27.1 MUM respectively. The synergistic effect of compounds 1, 2 and 3 combined with paclitaxel significantly inhibited the proliferation of HepG2 cells in vitro. PMID- 29514512 TI - Ethnic Differences in Mental Health Status and Service Utilization: A Population Based Study in Ontario, Canada. AB - BACKGROUND: The purpose of this study was to compare the prevalence of self reported mental health factors, mental health service use, and unmet needs across the 4 largest ethnic groups in Ontario, Canada: white, South Asian, Chinese, and black groups. METHODS: The study population was derived from the Canadian Community Health Survey, using a cross-sectional sample of 254,951 white, South Asian, Chinese, and black residents living in Ontario, Canada, between 2001 and 2014. Age- and sex-standardized prevalence estimates for mental health factors, mental health service use, and unmet needs were calculated for each of the 4 ethnic groups overall and by sociodemographic characteristics. RESULTS: We found that self-reported physician-diagnosed mood and anxiety disorders and mental health service use were generally lower among South Asian, Chinese, and black respondents compared to white respondents. Chinese individuals reported the weakest sense of belonging to their local community and the poorest self-rated mental health and were nearly as likely to report suicidal thoughts in the past year as white respondents. Among those self-reporting fair or poor mental health, less than half sought help from a mental health professional, ranging from only 19.8% in the Chinese group to 50.8% in the white group. CONCLUSIONS: The prevalence of mental health factors and mental health service use varied widely across ethnic groups. Efforts are needed to better understand and address cultural and system-level barriers surrounding high unmet needs and to identify ethnically tailored and culturally appropriate clinical supports and practices to ensure equitable and timely mental health care. PMID- 29514514 TI - Characteristics of Correctly Identified Pediatric Obesity and Overweight Status and Management in an Academic General Pediatric Clinic. AB - This study identified and characterized the rates of documentation and guideline based management of overweight and obese children within an academic pediatric clinic through a retrospective electronic medical record review of 7422 well child visits in 2016. Diagnosis and treatment were analyzed by patient's weight diagnosis, sex, age, and provider training level. The percentages of correctly identified severely obese (90.2%), obese (77.0%), and overweight (42.0%) children were much higher than in previous retrospective chart reviews; however, less than 30% of children were referred for more intensive weight management to a dietitian or pediatric obesity weight management program. Increased provider training level was associated with a lower adherence to pediatric obesity guidelines. Strategic modifications to electronic medical records that automatically offer body mass index-associated weight diagnoses with a link to treatment pathways and resources are needed to facilitate improved compliance with current pediatric obesity guidelines in the primary care setting. PMID- 29514515 TI - Previously undescribed benzoxepins with bioactivities against inducible pro inflammatory cyclooxygenase and lipoxygenase from Rhizophora annamalayana Kathir. AB - Two unprecedented benzoxepins were obtained from the ethyl acetate fraction of the leaves of Rhizophora annamalayana Kathir, and characterized as 4-(11 (hydroxymethyl)-10-methylpentan-2-yl)-4, 5-dihydrobenzo[c]oxepin-1(3H)-one (1) and (E)-methyl-14-hydroxy-4-(11-(5-hydroxy-1-oxo-3,4,5-tetrahydrobenzo[c]oxepin-4 yl)ethyl)-10-methylhept-11-enoate (2). The benzoxepin 2 exhibited greater 1, 1 diphenyl-2-picrylhydrazyl and 2, 2'-azino-bis-3 ethylbenzothiozoline-6-sulfonic acid diammonium radical scavenging assays (IC50 0.68 and 0.84 mg/mL, respectively) than those recorded with 1 (IC50 0.70 and 0.89 mg/mL, respectively). The tetrahydrobenzo[c]oxepin analogue (2) exhibited significantly great cyclooxygenase-2 and 5-lipoxygenase inhibitory properties (IC50 0.87 and 0.94 mg/mL, respectively), while compared with its dihydrobenzo[c]oxepin-1(3H) one isoform (1) (IC50 1.16 and 1.64 mg/mL, respectively). The dihydrobenzo[c]oxepin-1(3H)-one isoform (2) exhibited significantly greater selectivity index (~2) than synthetic ibuprofen (0.44) (p < 0.05), which attributed the higher anti-inflammatory selectivity of the former against inducible pro-inflammatory cyclooxygenase-2 than its constitutive isoform (cyclooxygenase-1). No significant difference in 5-lipoxygenase (5-LOX) inhibitory activities were apparent between compound 2 (IC50 0.94 mg/mL) and synthetic ibuprofen (IC50 0.93 mg/mL). PMID- 29514516 TI - Differences in BMI between Mexican and Colombian patients receiving antipsychotics: results from the International Study of Latinos on Antipsychotics (ISLA). AB - OBJECTIVE: The objective of this study is to examine the association of country of residence with body mass index (BMI) between Mexican and Colombian patients exposed to antipsychotics. We hypothesize that there will be a significant association between country of residence and BMI and that Mexican patients will have higher BMI than their Colombian counterparts. DESIGN: The International Study of Latinos on Antipsychotics (ISLA) is a multisite, international, cross sectional study of adult Latino patients exposed to antipsychotics in two Latin American Countries (i.e. Mexico and Colombia). Data were collected from a total of 205 patients (149 from Mexico and 56 from Colombia). The sites in Mexico included outpatient clinics in Mexicali, Monterrey and Tijuana. In Colombia, data were collected from outpatient clinics in Bogota. For this study we included patients attending outpatient psychiatric community clinics that received at least one antipsychotic (new and old generation) for the last 3 months. A linear regression model was used to determine the association of country of residence with BMI for participants exposed to an antipsychotic. RESULTS: After controlling for demographics, behaviors, biological and comorbid psychiatric variables, there was a significant difference between Colombia vs. Mexico in the BMI of patients exposed to antipsychotics (beta = 4.9; p < 0.05). CONCLUSION: Our hypotheses were supported. These results suggest that differences in BMI in patients exposed to antipsychotics in Mexico and Colombia may reflect differences in prevalence of overweight/obesity at the population level in the respective countries, and highlights the involvement of other risk factors, which may include genetics. PMID- 29514517 TI - A systematic review of the diagnostic utility of simple tests of change after trial removal of cerebrospinal fluid in adults with normal pressure hydrocephalus. AB - OBJECTIVE: To synthesize the evidence regarding the diagnostic value of simple ancillary tests post cerebrospinal fluid drainage in normal pressure hydrocephalus. DATA SOURCES: MEDLINE, CINAHL, PsycINFO, Scopus, Web of Science, and Cochrane library databases; last searched on 12 September 2017. REVIEW METHODS: This review was performed applying the steps of the PRISMA statement. The QUADAS 2 tool was used to assess the risk of bias. Prospective and retrospective trials were systematically reviewed, and data on diagnostic accuracy were extracted. Meta-analysis (where possible) was performed. Hierarchical summary receiver operating characteristic package was used to calculate pooled estimates of included diagnostic studies. RESULTS: Seventeen trials (with 812 subjects in total) were identified for inclusion in the meta analyses for the 18-meter walk test, video-recorded gait performance, cognitive test, and Timed Up and Go Test. The summary estimates of sensitivity and specificity for the 18-meter walk test was 0.83 (95% CI 0.57 to 0.99) and 0.67 (95% CI 0.33 to 0.95), video-recorded gait performance was 0.85 (95% CI 0.47 to 0.99) and 0.68 (95% CI 0.33 to 0.96), cognitive test was 0.82 (95% CI 0.41-0.99) and 0.75 (95% CI 0.39-0.99), and Timed Up and Go Test was 0.89 (95% CI 0.79-0.95) and 0.63 (95% CI 0.24-0.90), respectively. CONCLUSION: This review highlights the diagnostic value of the 18-meter walk test, video-recorded gait performance, cognitive test, and Timed Up and Go Test in predicting shunt outcomes among adults with normal pressure hydrocephalus. PMID- 29514518 TI - Responsiveness of Noninvasive Continuous Cardiac Output Monitoring During the Valsalva Maneuver. AB - To describe the baseline hemodynamic variables and response time of hemodynamic changes associated with the Valsalva maneuver using noninvasive continuous cardiac output monitoring (Nexfin). Hemodynamic monitoring provides an integral component of advanced clinical care and the ability to monitor response to treatment interventions. The emergence of noninvasive hemodynamic monitoring provides clinicians with an opportunity to monitor and assess patients rapidly with ease of implementation. However, the responsiveness of this method in tracking dynamic changes that occur has not been fully elucidated. A prospective observational study was conducted involving 44 healthy volunteers (age = 38 +/-12 years). Participants performed a Valsalva maneuvers to illicit dynamic changes in blood pressure, cardiac output, cardiac index, systemic vascular resistance index (SVRI), and stroke volume. Changes in these hemodynamic parameters were monitored while performing repeated standardized Valsalva maneuvers. Baseline hemodynamic values were obtained in all 44 participants, and showed an interaction with age, accompanying a significant decline in cardiac index ( r = -.66, p < .05) and stroke volume ( r = -.68, p < .05), and an increase in SVRI ( r = .67, p < .05) with increasing age. The Valsalva maneuver, performed in 20 participants, resulted in a change of 10% from baseline blood pressure and cardiac index, which was detected within 4.53 s ( SD = 4.36) and 3.31 s ( SD = 2.21), respectively. Noninvasive continuous cardiac monitoring demonstrated the ability to rapidly detect logical and predictable hemodynamic changes. These observations suggest that such Nexfin technology may have useful clinical applications. PMID- 29514519 TI - Exploiting mAb structure characteristics for a directed QbD implementation in early process development. AB - In today's biopharmaceutical industries, the lead time to develop and produce a new monoclonal antibody takes years before it can be launched commercially. The reasons lie in the complexity of the monoclonal antibodies and the need for high product quality to ensure clinical safety which has a significant impact on the process development time. Frameworks such as quality by design are becoming widely used by the pharmaceutical industries as they introduce a systematic approach for building quality into the product. However, full implementation of quality by design has still not been achieved due to attrition mainly from limited risk assessment of product properties as well as the large number of process factors affecting product quality that needs to be investigated during the process development. This has introduced a need for better methods and tools that can be used for early risk assessment and predictions of critical product properties and process factors to enhance process development and reduce costs. In this review, we investigate how the quantitative structure-activity relationships framework can be applied to an existing process development framework such as quality by design in order to increase product understanding based on the protein structure of monoclonal antibodies. Compared to quality by design, where the effect of process parameters on the drug product are explored, quantitative structure-activity relationships gives a reversed perspective which investigates how the protein structure can affect the performance in different unit operations. This provides valuable information that can be used during the early process development of new drug products where limited process understanding is available. Thus, quantitative structure-activity relationships methodology is explored and explained in detail and we investigate the means of directly linking the structural properties of monoclonal antibodies to process data. The resulting information as a decision tool can help to enhance the risk assessment to better aid process development and thereby overcome some of the limitations and challenges present in QbD implementation today. PMID- 29514520 TI - Addendum. PMID- 29514521 TI - User surveys support designing a prosthetic wrist that incorporates the Dart Thrower's Motion. AB - AIM: Prosthetic devices are not meeting the needs of people with upper limb amputations. Due to controlsidelimitations, prosthetic wrists cannot yet be fully articulated. This study sought to determine which wrist motions users felt were most important for completing activities of daily living. We specifically invstigated whether adding a combinationof flexion and deviation known as the Dart Thrower's Motion to a prosthetic wrist would help improve functionality. METHODS: Fifteen participants with a trans-radial amputation, aged 25-64 years, who use a prosthesis completed an online survey and answered interview questions to determine which types of tasks pose particular challenges. Participants were asked what kinds of improvements they would like to see in a new prosthesis. A subset of five participants were interviewed in-depth to provide further information about difficulties they face using their device. RESULTS: The survey showed that participants had difficulty performing activities of daily living that involve a combination of wrist flexion and deviation known as the "Dart Throwers Motion". Interview responses confirmed that users have difficulty performing these tasks, especially those that require tools. Additionally, users said that they were more interested in having flexion and deviation than rotation in a prosthetic wrist. CONCLUSION: This research indicates that including the Dart Thrower's Motion in future designs of prosthetic wrists would improve these devices and people with upper limb amputations would be excited to see this improvement in their devices. Implications for Rehabilitation * Over one third of people with upper limb amputations do not use a prosthesis because prosthetic devices do not meet their needs.* The number of motions possible in state of the art prosthetic devices is limited by the small number of control sites available.* The Dart Thrower?s Motion is a wrist motion used for many activities of daily living but unavailable in commercial prosthetics leading many prosthetics users to have difficulty with these tasks.* Prosthetic use, and therefore quality of life, could be improved by including the Dart Thrower's Motion in a prosthesis. PMID- 29514522 TI - DNA barcoding evaluation and implications for phylogenetic relationships in ladybird beetles (Coleoptera: Coccinellidae). AB - Ladybird beetles (Coleoptera: Coccinellidae), with broad morphological diversity, wide geographic distribution and substantial agricultural significance, are a challenging group for taxonomists and phylogenetics. As a promising tool to identify and discover new species, DNA barcoding might offer significant potential for identification, taxonomy and phylogeny of ladybird beetles. In the present study, a total of 1364 COI (cytochrome C oxidase subunit I) sequences representing 128 species from 52 genera of ladybird beetles were screened for barcoding evaluation and phylogenetic analysis. Our results from the barcoding analysis revealed that COI displays a similar level of species identification efficiency (nearly 90%) either based on Kimura two-parameter (K2P) distances calculation or on simplified neighbour-joining (NJ) tree construction. The phylogenetic relationships within the family Coccinellidae was analyzed by Bayesian-inference (BI) method. The phylogenetic results confirmed the monophyly of the subfamilies Microweisinae and Coccinellinae sensu Slipinski (2007), and suggested that the subfamilies Coccidulinae, Chilocorinae and Scymninae are paraphyletic. However, the phylogenetic relationships among different subfamilies are not clearly defined and thus remain to be thoroughly studied. Overall, our study confirmed the usefulness of DNA barcoding for coccinellid species identification and phylogenetic inference. PMID- 29514523 TI - The prevalence and severity of disease-related disabilities and their impact on quality of life in neuromuscular diseases. AB - PURPOSE: People with neuromuscular disease experience lower quality of life levels than people from the general population. We examined the prevalence and severity of a broad range of neuromuscular disease-related disabilities and their impact on health-related quality of life. MATERIALS AND METHODS: A cross sectional postal survey study was conducted among patients diagnosed with neuromuscular disease. Patients completed the Neuromuscular Disease Impact Profile, a disease-related disability impact questionnaire, and two generic health-related quality of life questionnaires: the medical outcome study Short Form Questionnaire and the World Health Organization Quality of Life-bref. The impact of disabilities on quality of life was estimated using multiple regression analyses. RESULTS: Six hundred sixty two patients (68% response rate) completed the questionnaires. There were no differences in quality of life between diagnosis-based subgroups. 'Impairments in muscle functions' had the highest prevalence and severity scores in the total sample and diagnosis-based subgroups. Neuromuscular disease-related disabilities showed strong and independent associations with all aspects of health-related quality of life. 'Impairments in mental functions and pain' was the most important predictor of health-related quality of life followed by 'restrictions in participation in life situations'. CONCLUSIONS: Although 'impairment in muscle functions' is the most prevalent and severe disability, the 'impairments in mental functions and pain' have a strong association with health-related quality of life in patients with a neuromuscular disease. Implications for rehabilitation Disease-related disabilities have a strong and independent associations with all aspects of health-related quality of life. Although health-related domains of quality of life are affected by the neuromuscular disease, the general quality of life is quite good. The most prevalent and severe disability in total group and diagnosis-based subgroups is 'impairments in muscle functions'. The most significant predictor in health related quality of life is 'impairments in mental functions and pain'. PMID- 29514524 TI - Randomised comparison of silicone gel and onion extract gel for post-surgical scars. AB - To compare the efficacy of silicone gel and onion extract gel on new surgical wounds, we performed a randomised controlled trial evaluating the appearance of the laparoscopic surgical scars of 60 subjects after 12 weeks of two times daily application of either silicone gel or onion extract gel. Objective scar assessment by the Vancouver Scar Scale (VSS) and the Image Panel Scale (IPS) and subjective scar assessment by the Body Image Scale (BIS) and Cosmetic Scale (CS) were performed after 12 weeks of treatment. Safety was also evaluated by gathering adverse events related to application of the gel. After 12 weeks of applying the assigned gel, there were no differences between the two groups in VSS (p = .779), IPS (p = .621), BIS (p = .924), or CS (p = .843). Subject compliance and safety with the assigned gel was similar between the two study groups. Our conclusion was that silicone gel and onion extract gel had similar compliance, side effects and efficacy in making surgical scars less distinct. Impact Statement What is already known on this subject: There are commercially available, topical scar emollients for prevention of surgical scarring. Despite their popularity, data demonstrating the efficacy of these scar emollients are lacking. What do the results of this study add: After 12 weeks of applying the assigned topical scar emollients, there were no differences between the two groups in terms of cosmesis and satisfaction. What are the implications of these findings for clinical practice and/or further research: Silicone gel and onion extract gel had similar compliance, side effects and efficacy in making surgical scars less distinct. PMID- 29514525 TI - Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague-Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days. AB - Poly- and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF3(CF2)8COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague-Dawley rats were exposed to 0-2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B6C3F1/N mice were exposed once/week to 0-5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26-89%) was observed following exposure to >=0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig + and NK + cells were decreased (17.6 27%). At >= 1.25 mg PFDA/kg/week the numbers of splenic CD3+, CD4+, CD8+, and Mac3+ cells were decreased (10.5-39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24-39%) at >=0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral- and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice. PMID- 29514526 TI - Intrauterine balloon tamponade and bilateral hydronephrosis: do they really have a cause-effect relationship? PMID- 29514527 TI - Highly elevated human epididymis protein 4 (HE4) following endometrioma rupture: a case report. PMID- 29514528 TI - Patient value: its nature, measurement, and role in real world evidence studies and outcomes-based reimbursement. AB - The assessment of "patient value" is fundamental to clinical trials, real world evidence studies, and outcomes-based reimbursement schemes. Measures of health related quality-of-life (HRQoL) are widely used in health research. Such measures are effective in determining the presence or absence of symptoms and functional ability. However, HRQoL measures were not intended, nor designed, to determine the value to patients of alternative health states. Functions have no intrinsic value-they are a means to fulfil human needs. However, needs can be met in a variety of ways, for example by adopting different functions or by the provision of social services. It is possible to analyze all functions in terms of the needs they satisfy. A needs model has been applied in health research since the 1990s. It is concerned with the extent to which human needs are fulfilled in the presence of disease and its treatment. It is argued that this is the major concern of the patient. Needs-based measures are patient-centric and produce a valid unidimensional index of outcome. Consequently, they provide a direct means of measuring patient value. This approach provides the possibility of evaluating health services in terms of the value they provide to consumers and payers. It also has a role to play in real-world evidence studies and outcomes-based reimbursement. It is recommended that greater attention is given in future to the development of patient-reported outcome measures that provide direct assessments of patient value. PMID- 29514529 TI - How to improve health literacy to reduce short- and long-term consequences of maternal obesity? AB - AIM: To demonstrate the global challenge of maternal obesity and to propose models to increase awareness and health literacy. METHODS: The regional perinatal data base and the international literature were reviewed to demonstrate the rising rates of maternal overweight and obesity causing major public health problems in low and high-resourced countries. A preliminary systematic review analyzing interventions in maternal obesity and a fact box based on a recent Cochrane review on dietary interventions were performed. RESULTS: Between 2000 and 2015, the regional rates of maternal overweight and obesity have significantly increased, and the rate of morbid maternal obesity has even doubled. Pregnant women were insufficiently informed about the health risks and international recommendations for weight gain associated with pre-pregnancy body mass index. Scientific publications and guidelines of professional boards have not yet interrupted the vicious cycle of transgenerational transfer of associated health risks for the offspring. For the first time we propose a fact box to translate the results from a Cochrane review about dietary interventions into a transparent information for health care providers and patients which could help to improve awareness. CONCLUSIONS: Improving health literacy and translating clinical science into models which are understandable by policy makers, health care providers and parents is a challenge mainly if health risks are modifiable during gestation and could prevent the increasing burden of obesity for future societies. PMID- 29514530 TI - Accuracy of the fetal cerebroplacental ratio for the detection of intrapartum compromise in nonsmall fetuses. AB - OBJECTIVE: To study the accuracy of the cerebroplacental ratio (CPR) for the detection of intrapartum fetal compromise (IFC) in fetuses growing over the 10th centile. METHODS: This was a prospective study of 569 nonsmall fetuses attending the day hospital unit of a tertiary hospital that underwent an ultrasound examination at 36-40 weeks, and were delivered within 4 weeks of examination. IFC was defined as a composite of abnormal intrapartum fetal heart rate or intrapartum fetal scalp pH <7.20 requiring cesarean section, neonatal umbilical cord pH <7.20, 5 min Apgar score <7 and postpartum admission to neonatal or pediatric intensive care units. The accuracy of CPR for the prediction of IFC was calculated alone and in combination with other perinatal parameters using univariate and multivariate logistic regression models, which alternatively included the onset of labor to evaluate the influence of induction of labor (IOL) on IFC, and a brief composite adverse outcome of two parameters to prove the strength of the approach. RESULTS: The incidence of IFC was 17.9%. CPR sensitivity was 30.4% for a false positive rate (FFR) of 10 and 14.7% for an FPP of 5% (AUC = 0.62, p < .001). The multivariate analysis showed that only fetal gender and parity increased the predictive accuracy of CPR alone, although the improvement was poor (AUC = 0.67, p < .001). No differences were observed using any of the alternative models. Finally, IOL had no influence on IFC. CONCLUSIONS: Despite their apparent normality, a proportion of fetuses growing over the 10th centile suffer IFC. Some of them are suitable for detection by means of CPR. PMID- 29514531 TI - Measurement of the fetal occiput-spine angle during the first stage of labor as predictor of the progress and outcome of labor. AB - BACKGROUND: Fetal head attitude has a substantial impact on labor progress and outcome. Fetal head deflexion is basically diagnosed by digital vaginal examination during labor. OBJECTIVES: To assess the effect of the fetal occiput spine angle (OSA) measured through transabdominal ultrasound during the first stage of labor on the progress and outcome of labor. MATERIAL AND METHODS: A prospective cohort study conducted on 400 women with term uncomplicated singleton pregnancy with occipitoanterior position during active labor. The angle between two tangential lines to occipital bone and the vertebral body of the first cervical spine was measured during active labor. Follow up till delivery was done. The primary outcome parameter was the labor duration. Secondary outcomes included the mode of delivery, occurrence of maternal and fetal complications. RESULTS: There was a significant longer duration of both first and second stage of labor among women with OSA <126 degrees when compared to those with OSA >=126 degrees (6.8 +/- 2.1 and1.89 +/- 0.85 versus 4.16 +/- 1.63 and 0.92 +/- 0.43, respectively). Women with OSA <126 degrees had higher incidence of CS (46.3 versus 5.7%), perineal tears (10.4 versus 5.1%), vaginal tears (22.4 versus 6.3%), need for oxytocin augmentation (47.8 versus 21.3%) when compared to those with OSA >=126. OSA at cutoff value of 126 degrees had a sensitivity, specificity, and accuracy of 8264.6 and 78.4% and 93.79 and 92% in prediction of mode of delivery and overall complications, respectively. CONCLUSIONS: There was a significantly longer duration of both first and second stages of labor with higher rates of CS and maternal and fetal complications in women with OSA <126. PMID- 29514532 TI - A case of severe neonatal asphyxia due to umbilical artery thrombosis. PMID- 29514534 TI - Child Neurology: A Fragile Future. PMID- 29514533 TI - Maternal and neonatal outcomes of placenta increta and percreta from a multicenter study in China. AB - OBJECTIVE: The objective of this study is to identify the maternal and neonatal outcomes in women with placenta increta or placenta percreta in China. MATERIALS AND METHODS: We retrospectively analyzed 2219 cases from 20 tertiary care centers in China between January 2011 and December 2015. All cases were diagnosed of placenta increta or placenta percreta, based on either intraoperative findings or histopathological findings. RESULTS: The incidence of placenta increta and placenta percreta progressively increased from 0.18% in 2011 to 0.78% in 2015. Compared with the placenta increta, placenta percreta was strongly related to serious adverse outcomes: postpartum hemorrhage (65.9% versus 38.6%, p = .003), blood transfusion (86.2% versus 46.5%, p < .001), hysterectomy (43.3% versus 11.2%, p < .001), preterm birth (65.7% versus 49.9%, p < .001), and the need for neonatal intensive care unit (NICU) admission (54.5% versus 36.7%, p < .001). CONCLUSION: The incidence of placenta increta and placenta percreta is likely to increase in China. The depth of placenta implantation is associated with the severity of outcomes. Placenta percreta tends to have worse maternal and neonatal outcomes. PMID- 29514535 TI - Isolated vasculitis of the urinary bladder: a note on diagnosis and prognosis. PMID- 29514536 TI - Neither barriers nor refugia explain genetic structure in a major biogeographic break: phylogeography of praying mantises in the Brazilian Atlantic Forest. AB - The Atlantic Forest is one of the world's top biodiversity hotspots, but the diversification processes of its biota are still poorly known, with competing models attributing dominant roles to either Quaternary climatic changes or geographic barriers. Many studies identify the Doce river as a major phylogeographic break, but the reasons for this phenomenon are highly debated. Here we test the predictions of the refugial and barrier models for a common species of praying mantis, Miobantia fuscata, focusing in the areas immediately south and north of the Doce river. Our analyses show high intraspecific genetic diversity, deep coalescence times and no evidence for recent population expansion. Phylogeographic structure is inconsistent with a refugial hypothesis. Significant gene flow between northern and southern populations also conflicts with a strong role for geographic barriers. This study highlights the need for considering invertebrate taxa to infer recent landscape changes, and points towards a more complex picture of genetic diversification in the Atlantic Forest. PMID- 29514537 TI - Are symptoms after a colorectal segmental resection in deep endometriosis really improved? The point of view of women before and after surgery. AB - INTRODUCTION: Bowel endometriosis can cause debilitating symptoms. Surgical colorectal resection is often required for symptomatic relief. Aim of our study was to evaluate quality of life over a one-year follow-up period in patients submitted to a colorectal resection for the treatment of deep endometriosis. Change in intestinal and extra-intestinal symptoms, and reproductive outcome were also evaluated. METHODS: A prospective observational study was conducted on a cohort of 20 women affected by intestinal endometriosis and submitted to a laparoscopic colorectal resection. The subjects completed a questionnaire about quality of life (SF-36), and they scored in a 100-point rank questionnaire gynecological, urinary and gastrointestinal symptoms, pre-operatively and one- year postoperatively. RESULTS: Significant improvements were observed in all domains of the SF-36 throughout the study period. Dysmenorrhea, dyspareunia and not menstrual pelvic pain showed a significant decrease 1 year after surgery. There was also a decrease in abdominal pain, rectal bleeding and constipation but not of nausea, abdominal pain, defecation pain, tenesmus, diarrhea, mucorrhea. Also some urinary symptoms did not improve. CONCLUSIONS: The radical surgical approach has a positive impact on quality of life, although it does not improve all the symptoms complained before surgery. Clear pre-surgical counseling and careful patient selection is suggested. PMID- 29514539 TI - The use of transrectal ultrasound-guided biopsy following the introduction of prostate-specific antigen testing in Denmark: a population-based analysis. AB - OBJECTIVE: Incidence rates of prostate cancer in Denmark resemble those of countries that endorse prostate-specific antigen (PSA) screening. So far, no studies have described the consequences of PSA testing on diagnostic activity on a population level. The aim of this study was to describe the frequency of systematic transrectal ultrasound-guided biopsy (TRUS-gb) activity, including rebiopsy rates, in Denmark between 1995 and 2011. MATERIALS AND METHODS: All men who underwent TRUS-gb during the period were identified in the Danish Prostate Cancer Registry. In total, 83,041 biopsy sets from 64,430 individuals were identified. The diagnostic rate and the frequency of rebiopsy were analyzed. Age, histology and PSA were compared at the time of biopsy. RESULTS: The number of TRUS-gb per 100,000 men per year increased 4.6-fold. The mean number of TRUS-gb procedures per individual increased from 1.08 in 1995 to 1.46 in 2011 (p = .0001), and the proportion of men with negative initial biopsy sets who underwent rebiopsy increased from 22% in 1995 to 41% in 2004, later decreasing to 31% in 2009. CONCLUSIONS: The diagnostic activity in Denmark and the rebiopsy rates in men with initial negative TRUS-gb have increased substantially, and guidelines for the management of men with a negative initial biopsy are highly warranted. PMID- 29514540 TI - Planning for outdoor play: Government and family decision-making. AB - BACKGROUND: Despite indisputable developmental benefits of outdoor play, children with disabilities can experience play inequity. Play decisions are multifactorial; influenced by children's skills and their familial and community environments. Government agencies have responsibilities for equity and inclusion of people with disabilities; including in play. AIM: This multiple-perspective case study aimed to understand outdoor play decision-making for children with disabilities from the perspectives and interactions of: local government and families of primary school-aged children with disabilities. MATERIAL AND METHOD: Five mothers, four local government employees, and two not-for-profit organization representatives participated in semi-structured interviews. Inductive and iterative analyzes involved first understanding perspectives of individuals, then stakeholders (local government and families), and finally similarities and differences through cross-case analysis. FINDINGS: Local government focused more on physical access, than social inclusion. Local government met only minimal requirements and had little engagement with families. This resulted in poor understanding and action around family needs and preferences when designing public outdoor play spaces. CONCLUSION AND SIGNIFICANCE: To increase meaningful choice and participation in outdoor play, government understanding of family values and agency around engagement with local government needs to improve. Supporting familial collective capabilities requires understanding interactions between individuals, play, disability, and outdoor play environments. PMID- 29514541 TI - Assessing Acid-Base Status in Circulatory Failure: Relationship Between Arterial and Peripheral Venous Blood Gas Measurements in Hypovolemic Shock. AB - BACKGROUND AND OBJECTIVES: In severe circulatory failure agreement between arterial and mixed venous or central venous values is poor; venous values are more reflective of tissue acid-base imbalance. No prior study has examined the relationship between peripheral venous blood gas (VBG) values and arterial blood gas (ABG) values in hemodynamic compromise. The objective of this study was to examine the correlation between hemodynamic parameters, specifically systolic blood pressure (SBP) and the arterial-peripheral venous (A-PV) difference for all commonly used acid-base parameters (pH, Pco2, and bicarbonate). DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Data were obtained prospectively from adult patients with trauma. When an ABG was obtained for clinical purposes, a VBG was drawn as soon as possible. Patients were excluded if the ABG and VBG were drawn >10 minutes apart. RESULTS: The correlations between A-PV pH, A-PV Pco2, and A-PV bicarbonate and SBP were not statistically significant ( P = .55, .17, and .09, respectively). Although patients with hypotension had a lower mean arterial and peripheral venous pH and bicarbonate compared to hemodynamically stable patients, mean A-PV differences for pH and Pco2 were not statistically different ( P = .24 and .16, respectively) between hypotensive and normotensive groups. CONCLUSIONS: In hypovolemic shock, the peripheral VBG does not demonstrate a higher CO2 concentration and lower pH compared to arterial blood. Therefore, the peripheral VBG is not a surrogate for the tissue acid-base status in hypovolemic shock, likely due to peripheral vasoconstriction and central shunting of blood to essential organs. This contrasts with the selective venous respiratory acidosis previously demonstrated in central venous and mixed venous measurements in circulatory failure, which is more reflective of acid-base imbalance at the tissue level than arterial blood. Further work needs to be done to better define the relationship between ABG and both central and peripheral VBG values in various types of shock. PMID- 29514542 TI - Development of a Transgender and Gender Nonconforming Language Self-Efficacy Scale for Social Service Providers Working With Older Adults. AB - There is consensus that providers who work with transgender and gender nonconforming (TGNC) older adults should use the language preferred by the older adult; however, assessment tools to document professional training efforts are lacking. This study presents data on a new TGNC Language Self-Efficacy Scale, using responses collected from employees and volunteers of area agencies on aging (AAA) across the United States ( N = 155). Exploratory factor analysis supports a two-factor model: Interactions and Information subscales significantly correlated with knowledge of TGNC terminology, genderism and transphobia, gender role beliefs, beliefs about gender and gender identity, and attitudes toward lesbians and gay men. Future directions include additional measurement development work and replication of these findings outside of AAAs. PMID- 29514543 TI - Distal biceps tendon repair using both an anchor and a bone tunnel via one and a second stab incision: A retrospective study. AB - Our aim was to evaluate the outcome of our surgical technique for the repair of complete distal biceps tendon rupture in nonprofessional athletes. We examined the effect of our surgical technique in restoring the functionality of 11 injured limbs by correlating the total functional outcome of the repaired limb with their contralateral side. PMID- 29514544 TI - A Pilot Study of the !Vivir Mi Vida! Lifestyle Intervention for Rural-Dwelling, Late-Midlife Latinos: Study Design and Protocol. AB - Older, rural-dwelling Latinos face multiple health disparities. We describe the protocol of a pilot study of a community health worker-occupational therapist-led lifestyle program, !Vivir Mi Vida! ( !VMV!), designed for delivery in primary care and adapted for late-midlife, Latino rural-living patients. Using mixed methods, we collected feasibility, acceptability, and preliminary efficacy data on !VMV!. Forty 50- to 64-year-old Latinos participated in a 16-week lifestyle intervention led by a community health worker-occupational therapist team. We conducted pre- and post-intervention assessments to evaluate the efficacy of !VMV! in improving psychosocial and clinical health outcomes. Focus groups and interviews were held post-intervention with participants and key stakeholders to assess feasibility and acceptability. This is the first trial designed to evaluate a lifestyle intervention that includes collaboration between occupational therapists and community health workers within primary care. The detailed description of methodology promotes research transparency and reproducibility of a community health worker-occupational therapist-led lifestyle intervention. PMID- 29514545 TI - The Doctor-Patient Relationship and Information-Seeking Behavior: Four Orientations to Cancer Communication. AB - BACKGROUND: In cancer communication, patients and physicians often understand a patient's experience and situation differently. This can negatively impact health outcomes and the physician-patient relationship. AIM: To explore how cancer patients' interpretations of the physician's role as information giver affect the communication relationship with the physician and their information-seeking behavior regarding different aspects of their cancer care. DESIGN: Participants completed a semistructured qualitative interview addressing their treatment experience and communication with their physician. Interviews were coded and analyzed using inductive thematic analysis. SETTING/PARTICIPANTS: Ten patients with cancer treated at a regional cancer center in central Illinois participated in the study. Cancer stages I to IV and 4 cancer types were represented. RESULTS: Participants' orientations to the relationship with their physician (and their information-seeking behavior) were classified into 4 general categories: (1) "questioners" have a general mistrust toward their physicians and the information doctors are giving; (2) "the undecided" focuses on physician "fit," often requiring time to step away in order to make decisions and process information; (3) "cross-checkers" are concerned with content of their treatment protocol, often double-checking the treatment plan; and (4) "the experience-oriented" feel a gap between their experience and their physician's experience (and perspective), often seeking information from other survivors. All categories described a perceived lack of adequate exchange of information and the need to seek information outside of the physician-patient relationship to compensate. CONCLUSION: Participants exhibited different information-seeking behaviors based on how they interpreted the role of their physician as information giver. This affected what kind of information they sought and how they understood the information received, which in turn affected understanding of their broader experience and care. PMID- 29514546 TI - Efficacy and safety of peripherally inserted central venous catheters in acute cardiac care management. AB - PURPOSE: Patients admitted to cardiac intensive care unit need administration of drugs intravenously often in concomitance of therapeutic techniques such as non invasive ventilation, continuous renal replacement therapy and intra-aortic balloon counterpulsation. Therefore, the insertion of central venous catheters provides a reliable access for delivering medications, laboratory testing and hemodynamic monitoring, but it is associated with the risk of important complications. In our study, we tested the efficacy and safety of peripherally inserted central catheters to manage cardiac intensive care. METHODS: All patients admitted to cardiac intensive care unit with indication for elective central venous access were checked by venous arm ultrasound for peripherally inserted central catheter's implantation. Peripherally inserted central catheters were inserted by ultrasound-guided puncture. After 7 days from the catheter's placement and at the removal, vascular ultrasound examination was performed searching signs of upper extremity deep venous thrombosis. In case of sepsis, blood cultures peripherally from the catheter and direct culture of the tip of the catheter were done to establish a catheter-related blood stream infection. RESULTS: In our cardiac intensive care unit, 137 peripherally inserted central catheters were placed: 80.3% of patients eligible for a peripherally inserted central catheter were implanted. The rate of symptomatic catheter-related peripheral venous thrombosis was 1.4%. Catheter-related blood stream infection was diagnosed in one patient (0.7%; 5.7 * 1000 peripherally inserted central catheter days). All peripherally inserted central catheters were inserted successfully without other major complications. CONCLUSIONS: In patients admitted to cardiac intensive care unit, peripherally inserted central catheters' insertion was feasible in a high percentage of patients and was associated with low infective complications and clinical thrombosis rate. PMID- 29514547 TI - Managing professional knowledge boundaries during ECHO telementoring consultations in two Veterans Affairs specialty care liver clinics: A theme oriented discourse analysis. AB - Introduction Consultations are the traditional method of communication between generalist and specialist providers managing patients with specialty care needs. Traditional written consultations have limitations, including inadequate clinical information and inappropriate, or unclear consultation questions. Teleconsultations minimize these limitations through real-time communication between generalist and specialist providers to actively manage professional knowledge boundaries about specialty care problems. Methods We video-recorded 37 teleconsultation sessions, resulting in 115 consultations between generalist and specialty care providers participating in Veterans Affairs (VA) Extension for Community Healthcare Outcomes (ECHO) liver clinics. Data were collected at two US sites across nine months to observe consultation communication among 33 primary care generalists and three liver specialists. Video recordings were transcribed verbatim and analysed using theme-oriented discourse analysis to characterize consultation question content and format. Results Generalists' consultation question content addressed a range of topics, including treatment, diagnosis, interpreting results, patient communication, screening and surveillance, and care coordination. Some generalists relied on descriptive narratives rather than a specific question to convey complex patient cases. Consultation question format showed nearly even division between targeting general medical knowledge and specialty care knowledge domains, including specialty care, medical, organizational, and experiential knowledge. Discussion Timely access to specialists through teleconsultation has the potential to transform specialty care delivery. This article examines provider-to-provider interactions to understand how the communication process contributes to knowledge management during teleconsultations. Video studies of health information technology use provide a rich opportunity for analysing real-time communication that may help improve cross-specialty collaboration and the coordinated management of patients with specialty care needs. PMID- 29514548 TI - Robotic pancreatic surgery: old concerns, new perspectives. AB - BACKGROUND: Described for the first time in 2003, the robotic pancreatic surgery shows interesting results. The evaluation of post-operative outcomes is necessary once we describe an innovative surgical approach. METHODS: We have performed a retrospective analysis of a prospectively maintained database on robotic pancreatic surgery including malignant and benign indications for surgery. RESULTS: A total of 50 consecutive patients underwent robotic pancreatic surgery (26 pancreatico duodenectomy and 24 distal pancreatectomy) between January 2012 and July 2015 in a single centre. The overall operative time was 425 (390-620) min. In a subgroup of highly selected malignant tumours, we were able to achieve 88% of R0 resection with robotic approach. A number of lymphnodes rose significantly with growing experience (p = .025). The overall major complication rate (15%), as well as pancreatic fistula rate (16%) were acceptable. The two year overall survival for the whole group was 65%. CONCLUSION: The robotic pancreatic surgery in a highly selected group of patients seems safe and feasible. The cost-effectiveness and long-term oncologic outcomes need further investigations. PMID- 29514549 TI - Prenatal smoking and postpartum depression: a meta-analysis. AB - OBJECTIVES: Postpartum depression (PPD) is a common emotional distress among many women in diversified cultures. The aim of this study was to examine the relationship between prenatal smoking and PPD. METHODS: We systematically searched PubMed, ISI Web of Science, EMBASE, Elsevier ScienceDirect, OVID and Springer databases up to 15 March 2017. The pooled odds ratio (OR) of PPD was compared between prenatal smoking women and the ones who did not smoke during pregnancy. The fixed effect model or random effect models were chosen according to heterogeneity between studies. RESULTS: A total of 13 studies with 1,476,922 women were included in the meta-analysis. The average incidence of PPD was 3.0% (1717/57,997) in women with smoke exposure and 1.3% (6571/488,225) in women without smoke exposure. The pooled OR was 2.325 (95% CI 1.925-2.808; Z = 8.76, p < .0001) by random-effect model. The funnel plot was symmetrical, and either the Begg's test (Z = 0.92, p=.360) or the Egger's test (t = 0.04, p = .9700) suggested no publication bias among included studies. Sensitivity analysis indicated that the result was robust. CONCLUSION: Our meta-analysis indicated that prenatal smoking was associated with postpartum depression. PMID- 29514550 TI - Racial Differences in Children's Trauma Symptoms Following Complex Trauma Exposure. AB - Complex trauma exposure has been defined as multiple or chronic interpersonal trauma that begins early in life, which leads to widespread dysregulation. Previous studies have reported that minorities may be at greater risk for trauma exposure and symptoms; yet, racial differences have not been investigated in the context of complex trauma. The aim of the present study was to determine if there are racial disparities in children's trauma exposure and outcomes among 167 child survivors of complex trauma (3-18 years, M = 9.90, SD = 3.92; 61.67% female; 62.2% Black). Black children endorsed a greater number of trauma types and were more likely to have experienced community violence and have been placed in child protective custody than White children. Caregivers of White children endorsed higher levels of select internalizing symptoms and social concerns whereas Black children reported higher levels of sexual concerns than White children. White children who experience complex trauma may be at higher risk for some trauma related difficulties. Alternatively, caregivers of White children may perceive them to have, or be more willing to acknowledge, higher levels of symptoms than Black children. Future work is needed to further investigate the role of race in disclosure of trauma exposure and related symptoms. PMID- 29514551 TI - A Methodological Study of Order Effects in Reporting Relational Aggression Experiences. AB - Unlike the overt nature of physical aggression, which lends itself to simpler and more direct methods of investigation, the often-masked nature of relational aggression has led to difficulties and debate regarding the most effective tools of study. Given concerns with the accuracy of third-party relational aggression reports, especially as individuals age, self-report measures may be particularly useful when assessing experiences with relational aggression. However, it is important to recognize validity concerns-in particular, the potential effects of item order presentation-associated with self-report of relational aggression perpetration and victimization. To investigate this issue, surveys were administered and completed by 179 young adults randomly assigned to one of four survey conditions reflecting manipulation of item order. Survey conditions included presentation of (a) perpetration items only, (b) victimization items only, (c) perpetration items followed by victimization items, and (d) victimization items followed by perpetration items. Results revealed that participants reported perpetrating relational aggression significantly more often when asked only about perpetration or when asked about perpetration before victimization, compared with participants who were asked about victimization before perpetration. Item order manipulation did not result in significant differences in self-reported victimization experiences. Results of this study indicate a need for greater consideration of item order when conducting research using self-report data and the importance of additional investigation into which form of item presentation elicits the most accurate self-report information. PMID- 29514552 TI - [Nursing home placement of people with dementia: a secondary analysis of qualitative data and literature review on perspectives of informal caregivers and healthcare professionals]. AB - Background: Nursing home placement of people with dementia can become necessary when informal care is no longer sufficient. Informal carers experience the transition period as an additional burden. Aim: Experiences and views of informal carers and healthcare professionals regarding the transition from people with dementia to a nursing home are investigated to improve the support for informal carers. Method: This secondary analysis included data from all five focus groups with n = 30 informal carers and healthcare professionals conducted as part of the "RightTimePlaceCare" project. To supplement the material which resulted from a single interview question, a literature analysis with the same focus was conducted. Results: The merged results indicated that informal carers needed professional support early on at home until after the nursing home placement. Concerns regarding nursing homes, financial aspects and family related issues were important aspects in the decision making. Healthcare professionals recommended provision of early guidance regarding those matters and making own experiences with nursing homes. Healthcare professionals should serve as mediators during the transition process and improve the collaboration between service providers. Conclusions: Empowering families to make informed choices could be facilitated by offering advice at home about their options for formal support services, financial support, and housing solutions. Healthcare professionals should support caregivers to make a decision, coordinate the placement and to cope with the new situation. PMID- 29514554 TI - Grief, Tragic Death, and Multiple Loss in the Lives of Irish Traveller Community Health Workers. AB - Recent data on the inequities in mortality, health, and access to health services experienced by the Traveller community in Ireland show higher rates of death by suicide and other sudden causes among members of this marginalized minority group than in the general population. Psychological literature on bereavement suggests that traumatic deaths and multiple deaths within a close network may be more likely to lead to complicated grief reactions. The aim of this study is to add to our understanding of the effects of the differential mortality rate by exploring how grief is experienced within the Traveller community in the context of bereavement from multiple deaths or sudden deaths (including suicide). Data from three semistructured focus group interviews with a total of 10 Traveller Community Health Worker participants (nine female and one male) were analyzed using Interpretative Phenomenological Analysis. Two master themes organized the salient phenomenological aspects of the grief experience: Living with Tragic Loss and Communicating Tragic Loss. A picture emerged of individual and community level loss that is extensive, profound, and enduring. The sequelae of deaths by suicide include difficulties in coping, a search for meaning, and a pervasive sense of fear. Silence, the embodied act of giving voice to tragic loss, and strategies for managing disclosure of tragic deaths with children were all strong themes which emerged from the analysis. This study uses interpretative phenomenological analysis to generate a vivid picture of the lived psychological experience of grief as it is experienced by members of a minority group with above average rates of sudden and early deaths. This contributes to understanding the burden of health inequality in an underresearched population. Findings in relation to challenges in communicating with children about tragic deaths can be integrated into bereavement support resources. PMID- 29514553 TI - Caregiver Burden, Care Recipient Depressive Symptomology, and Social Exchange: Does Race Matter? AB - Informal caregivers play a vital role in supporting seriously ill patients. However, informal caregiving is burdensome and can lead to negative health outcomes for the caregiver and the care recipient. The study's aim was to evaluate relationships among caregiver burden, care recipient depressive symptomology, and race. Guided by the social exchange perspective, we examined cross-sectional dyadic data from the National Long-Term Care Survey (N = 1279). Using ordinal logistic regression, we found that higher caregiver-reported objective burden was associated with higher care recipient depressive symptoms ( P < .05), an association that was stronger for blacks. Interestingly, despite significant levels of objective burden, there was an association between lower depressive symptoms in black care recipients when there was an exchange of the social good "helpful company" with a caregiver. These findings illustrate the importance of supporting reciprocal exchange as a promising component of maintaining balanced caregiver-care recipient relationships among black older adults and their informal caregivers. PMID- 29514555 TI - High Degree of Satisfaction With the Support Given by Multidisciplinary Palliative Home Care Teams in the County of Stockholm. AB - OBJECTIVE: At the initiative of Stockholm County Council, a survey was performed by an independent investigator to evaluate satisfaction among patients and their families with the advanced palliative home care teams in the county of Stockholm. The survey was performed in 2010 and compiled in 2011. The aim was to evaluate the impressions of patients and their families of the support given by the palliative home care teams in the Stockholm area and to evaluate the management of symptom control, availability, continuity, confidence, and quality of communication. METHODS: A questionnaire was sent to 1424 patients and 329 family members to evaluate the views of the users of the home care service. RESULTS: The response rate was 78% among both patients and their families or other caregivers. The proportion of positive and very positive responses among those who needed the specific help of the team was as follows: information about the service 86%, availability around the clock 96%, influence and feeling of shared responsibility 88%, and possibility of family members to have supportive discussions 95%. Eighty three percent of patients experienced total pain relief and 99% total or partial relief. The corresponding figures for anxiety were 77% and 97% and for other symptom reliefs 79% and 98%, respectively. These figures were comparable to a smaller survey in 2014 and were high compared to the results from other medical services using similar questionnaires. Significance of the Results: A high quality of care is possible to achieve within palliative home care services. PMID- 29514556 TI - Tuberculous sacroiliitis in a patient with systemic lupus erythematosus: a case report and literature review. AB - Systemic lupus erythematosus (SLE) patients are at higher risk of developing opportunistic infections such as tuberculosis (TB), especially extrapulmonary forms like osteoarticular TB, compared to the general population. However, tuberculous sacroiliitis has been scarcely reported in these patients. We present a 34-year-old woman with SLE who developed articular tuberculosis simultaneously affecting the right sacroiliac joint and the left knee. The patient was successfully treated with antituberculosis therapy for nine months. In this case, in addition to the immunological abnormalities of lupus, the long-term glucocorticoid therapy at high dosages was the main risk factor for the development of osteoarticular tuberculosis. PMID- 29514557 TI - Incremental health care services and expenditures associated with depression among individuals with cutaneous lupus erythematosus (CLE). AB - Objectives The objective of this paper is to describe the annual direct medical expenditures for cutaneous lupus erythematosus (CLE) patients, and to estimate the incremental health care expenditures and utilization associated with depression among adults with CLE, while controlling for covariates. Methods Using the 2014 Medical Expenditure Panel Survey (MEPS), we compared CLE patients with and without depression to determine differences in: (a) health care utilization inpatient, outpatient, office-based and emergency room (ER) visits, and prescriptions filled; and (b) expenditures-total costs, inpatient, outpatient, office-based, ER, and prescription medication costs, and other costs using demography-adjusted and comorbidity-adjusted multivariate models (age, gender, race/ethnicity, marital status, education, perception of health status, poverty category, smoking status, and Charlson Comorbidity Index). Results The total direct medical expenditure associated with CLE is estimated at approximately $29.7 billion in 2014 US dollars. After adjusting for covariates, adults with CLE and depression had more hospital discharges (utilization ratio (UR) = 1.13, 95% confidence interval (CI) (1.00-1.28)), ER visits (UR = 1.17, 95% CI (1.09-1.37)), and prescribed medicines (UR = 2.15, 95% CI (1.51-3.05)) than those without depression. Adults with CLE and depression had significantly higher average annual total expenditure that those without depression ($19,854 vs. $9735). Conclusions High health care expenditures are significant for patients with CLE, especially among those with depression. Prescription drugs, inpatient visits, and ER visits contributed most to the total expenditures in CLE patients with depression. Early diagnosis and treatment of depression in CLE patients may reduce total health care expenditures and utilization in this population. PMID- 29514558 TI - Perioperative Surgical Home Reduces Rapid Response Calls to a Postoperative Surgical Ward: How Anesthesiologists Are Improving the Inpatient Safety Net. AB - BACKGROUND: The Perioperative Surgical Home (PSH) is an anesthesiologist-led, coordinated care model that may improve patient experience and safety. We hypothesized that PSH will decrease activation of the rapid response system for surgical inpatients. METHODS: This retrospective study was performed at an academic Veterans Affairs hospital with a PSH. Data from both medical and surgical cohorts admitted to a single ward were analyzed for the Pre-PSH (July 2006 to October 2010) and Post-PSH (November 2011 to May 2015) epochs. The primary outcome was incidence of rapid response team (RRT) activations per 1000 bed-days. RESULTS: Surgical patients had 5.8 RRT activations per 1000 bed-days Pre-PSH versus 3.7/1000 bed-days Post-PSH ( P = .006). There was no difference in RRT activations per 1000 bed-days for medical patients before and after PSH implementation. Pre-PSH was an independent predictor of mortality in the multivariable model (odds ratio = 1.7; P = .010). CONCLUSION: PSH is associated with decreased RRT activations among surgical inpatients only. PMID- 29514559 TI - Reversed Depth in Anticorrelated Random-Dot Stereograms and the Central Peripheral Difference in Visual Inference. AB - In a random-dot stereogram, the percept of object surfaces in a three-dimensional scene is generated by images presented to left and right eyes that comprise interocularly corresponding random black and white dots. The spatial disparities between the corresponding dots determine the depths of object surfaces. If the dots are anticorrelated, such that a black dot in one monocular image corresponds to a white dot in the other, disparity-tuned neurons in the primary visual cortex (V1) respond as if their preferred disparities become nonpreferred and vice versa, thereby reversing the disparity signs reported to higher visual areas. Typically, when viewing anticorrelated random-dot stereograms presented in the central visual field, humans have great difficulty perceiving the reversed depth or indeed any coherent depth at all. We report that the reversed depth is more easily perceived in the peripheral visual field, supporting a recently proposed central-peripheral dichotomy in the way that feedback from higher to lower visual cortical areas implements visual inference. PMID- 29514560 TI - Essentiality and function of WalK/WalR two-component system: the past, present, and future of research. AB - The WalK/WalR two-component system (TCS), originally identified in Bacillus subtilis, is very highly conserved in gram-positive bacteria, including several important pathogens. The WalK/WalR TCS appears to be involved in the growth of most bacterial species encoding it. Previous studies have indicated conserved functions of this system, defining this signal transduction pathway as a crucial regulatory system for cell wall metabolism. Because of such effects on essential functions, this system is considered a potential target for anti-infective therapeutics. In this review, we discuss the role of WalK/WalR TCS in different bacterial cells, focusing on the function of the genes in its regulon as well as the variations in walRK operon structure, its auxiliary proteins, and the composition of its regulon. We also discuss recent experimental data addressing its essential function and the potential type of signal being sensed by B. subtilis. This review also focuses on the potential future research. PMID- 29514561 TI - Anatomical site distribution and genotypes of Chlamydia trachomatis infecting asymptomatic men who have sex with men in northeast Thailand. AB - Chlamydia trachomatis is a common agent of sexually transmitted infection, especially in asymptomatic extra-genital sites among men who have sex with men (MSM). This study aims to investigate anatomical site distribution and genotypes of C. trachomatis from asymptomatic MSM in northeast Thailand. Specimens were collected using swabs from anorectal, oropharyngeal, and urethral sites in 346 asymptomatic MSM. C. trachomatis infection was determined by real-time polymerase chain reaction and genotyping was based on sequences of the ompA gene. The results showed that infection by C. trachomatis was most common at the urethral site (29.1%, 101/346) followed by oropharyngeal (17.6%, 61/346) and anorectal site (17.0%, 59/346). In addition, C. trachomatis infection was significantly associated with absence of condom use (odds ratio = 1.909, 95%CI = 1.054-3.457, P = 0.033) at the urethral site. Overall 49.4% (171/346) of individuals were infected in at least one site. Infection at only the anorectum, oropharynx, or urethra was seen in 9.0, 9.3, and 18.5% of participants, respectively. Concurrent infections at anorectum/oropharynx, anorectum/urethra, oropharynx/urethra, and all three sites were 2.0, 4.3, 4.6, and 1.7%, respectively. Genotype D predominated at the anorectal and urethral sites among asymptomatic MSM in northeast Thailand. Concurrent infection in two or three anatomical sites occurred. C. trachomatis screening at all three sites in asymptomatic MSM is important and should be considered for proper treatment and prevention of transmission. PMID- 29514562 TI - Evaluation of antioxidant and anti-inflammatory efficacy of caffeine in rat model of neurotoxicity. AB - OBJECTIVE: The present study aims to investigate the neuroprotective effect of caffeine against aluminum chloride (AlCl3)-induced neurotoxicity in rats. METHODS: Twenty-one male albino rats were divided into 3 groups: control, AlCl3 intoxicated group that received daily oral administration of AlCl3 (100 mg/kg for 30 days) and protected group injected daily with caffeine (20 mg/kg intraperitoneally) one hour before oral administration of AlCl3 for 30 days. Levels of lipid peroxidation, reduced glutathione, and nitric oxide and the activities of acetylcholinesterase (AchE) and Na+/K+-ATPase were measured spectrophotometrically. Tumor necrosis factor-alpha (TNF-alpha) was evaluated by ELISA kit. RESULTS: The data revealed evidence of oxidative and nitrosative stress in the cerebral cortex, hippocampus, and striatum of AlCl3-intoxicated rats. This was indicated from the increased levels of lipid peroxidation and nitric oxide together with the decreased level of reduced glutathione. Moreover, the daily AlCl3 administration increased AchE and Na+/K+-ATPase activities and the level of TNF-alpha in the selected brain regions. Protection with caffeine ameliorated the oxidative stress induced by AlCl3 in the cerebral cortex, hippocampus, and striatum. In addition, caffeine restored the elevated level of TNF-alpha in the hippocampus and striatum. This was accompanied by an improvement in the activities of AchE and Na+/K+-ATPase in the studied brain regions. DISCUSSION AND CONCLUSIONS: The present findings clearly indicate that caffeine provides a significant neuroprotection against AlCl3-induced neurotoxicity mediated by its antioxidant, anti-inflammatory, and anticholinesterase properties. PMID- 29514563 TI - Metal composition of ambient PM2.5 influences the pulmonary function of schoolchildren: A case study of school located nearby of an electric arc furnace factory. AB - The present study combined air sampling with pulmonary function tests (PFTs) to determine both the extent of air pollution proximal to an electric arc furnace (EAF) and its impact on human health. The mass concentrations of particulate matter with aerodynamic diameters less than 2.5 um (PM2.5) in exposure areas were not significantly higher than the samples taken at a control area. However, the concentrations of five metal elements, Cd, Cr, Cu, Ni, and Zn in PM2.5 were significantly higher in the exposure area than that of the control area. PFTs showed that the average forced vital capacity (FVC) of boys was decreased with decreasing distance from the EAF factory. With normalization of pulmonary function by age, height, and weight, we found that the FVC became more negative with a decrease in distance from the EAF. Lastly, regression analysis was performed to analyze the impact of the concentrations of the five metals in PM2.5 on the performance of pulmonary function. The results showed that the metals can be ranked from the highest to the lowest in terms of impact on the FVC of boys as follows: Cr, Cd, Ni, Cu, and Zn. This finding is consistent with the ranking of metal toxicity reported in the literature for a rat lung epithelial cell line. The results of this study showed that only measuring PM2.5 mass concentrations may not provide a full explanation of its toxicity and health effects. The chemical composition of the PM2.5 can be an important factor that determined the health impact of PM2.5. PMID- 29514564 TI - Reproducibility of the index of orthognathic functional treatment need scores derived from plaster study casts and their three-dimensional digital equivalents: a pilot study. AB - OBJECTIVE: To determine the reproducibility of Index of Orthognathic Functional Treatment Need (IOFTN) scores derived from plaster casts and their three dimensional (3D) digital equivalents. DESIGN: Pilot study, prospective analytical. SETTING: UK hospital orthodontic department. PARTICIPANTS: Thirty casts and their digital equivalents, representing the pre-treatment malocclusions of patients requiring orthodontic-orthognathic surgical treatment, were scored by four clinicians using IOFTN. METHODS: Casts were scanned using a 3Shape digital scanner and 3D models produced using OrthoAnalyzerTM (3Shape Ltd, Copenhagen, Denmark). Examiners independently determined the IOFTN scores for the casts and digital models, to test their inter- and intra-operator reliability using weighted Kappa scores. RESULTS: Intra-operator agreement with IOFTN major categories (1-5: treatment need) was very good for plaster casts (0.83-0.98) and good-very good for digital models (0.78-0.83). Inter-operator agreement was moderate-very good for casts (0.58-0.82) and good-very good for digital models (0.65-0.92). Intra-operator agreement with IOFTN sub-categories (1-14: feature of malocclusion) was good-very good for casts (0.70-0.97) and digital models (0.80 0.94). Inter-operator agreement was moderate-good for casts (0.53-0.77); and moderate-very good for the digital models (0.58-0.90). CONCLUSIONS: Digital models are an acceptable alternative to plaster casts for examining the malocclusion of patients requiring combined orthodontic-orthognathic surgical treatment and determining treatment need. PMID- 29514565 TI - Venous stent patency may be affected by collateral vein lumen size. AB - Purpose Deep venous thrombosis causes blood flow deviation. It is hypothesized that with stent placement, developed collateral veins become redundant. This article evaluates the relation between the surface area of the collaterals and stent patency. Methods The azygos and hemiazygos veins were identified and the largest surface area was measured at thoracic level. Patency rates of stented tracts were evaluated and related to collateral vein lumen size. Results The vena cava occlusion and the azygos and hemiazygos vein surface area measurements were positive and statistically significant related (OR 1.01, 95% CI 1.003-1.019, p = 0.004) respectively (and OR 1.007, 95% CI 1.001-1.013, p = 0.004). An azygos surface area measurement of 23 (p<0.001) and hemiazygos surface area measurement of 40 (p = 0.008) was shown as cut-off point related to higher occlusion rates. Conclusions The surface area of major venous collateral pathways seems to be related to stent occlusion in deep venous interventions. PMID- 29514566 TI - Altered velocity gradient in lower limb chronic venous disease. AB - Background In physiology, velocity of the deep venous compartment is higher than the one in the saphenous compartment which is higher than the one in the tributaries. Considering that velocity variation is associated with changes in the pressure gradient, aim of the present study is to assess changes in venous kinetics in case of superficial chronic venous disease, so to provide further clues in venous drainage direction determination. Methods Venous ultrasound scanning was performed on 40 lower limbs of 28 chronic venous disease patients (C2-6Ep,As,Pr). Velocities were measured in three different venous segments: great saphenous vein at 2 cm above the origin of the incompetent tributary (Group A). great saphenous vein at 2 cm below the origin of tributary (Group-B). tributary at 2 cm from its origin from the great saphenous vein (Group-C.) Results Diastolic time average velocity was higher in group-C (-21.3 +/- 8.5 cm/s) than in group-A (-15.7 +/- 5.2 cm/s; p = .0001) and group-B (-11.1 +/- 2.9 cm/s; p = .0001), thus indicating an inversion of the physiological velocity gradient in chronic venous disease patients. Discussion Chronic venous disease presents a subverted velocity gradient. These data introduce objective hemodynamics data, paving the way for further investigation in venous drainage direction determination. PMID- 29514567 TI - Design and evaluation of the psychometric properties of a self-questionnaire on patient adherence to wearing elastic compression stockings. AB - Background Patients' adherence to elastic compression stockings is difficult to evaluate, and therefore we create a short self-questionnaire and validate its psychometric properties. Methods We reduce the questions with Varimed rotation analysis, evaluate its internal consistency using Cronbach's alpha test and its external validity by comparison to electronic thermic captors. Receiver operating characteristic (ROC) analysis was used to determine a threshold and determine its sensitivity and specificity. Results The initial questionnaire was reduced from 22 to 5 questions rated from 0 to 4. The internal consistency and its external validity are good, and the ROC analysis shows that values > 3 correspond to poor compliance with a sensitivity of 88.1% and a specificity of 63.1%. Conclusion The adherence score is valid for the detection of patients poorly compliant to the wearing of elastic compression. Its small number of questions makes it a suitable for a screening in everyday practice. PMID- 29514568 TI - Evaluation of a Diabetes Prevention Program Lifestyle Intervention in Older Adults: A Randomized Controlled Study in Three Senior/Community Centers of Varying Socioeconomic Status. AB - Purpose The purpose of this study is to evaluate the feasibility and effectiveness of an adapted Diabetes Prevention Program (DPP) lifestyle program, DPP Group Lifestyle Balance (GLB), delivered in 3 economically diverse senior/community centers. Methods The DPP-GLB was implemented in 3 senior/community centers in Allegheny County, PA. A 6-month delayed control intervention design was used. Participants were randomized to begin the DPP-GLB immediately (immediate) or after a 6-month delay (delayed). Adults (n = 134; mean age = 62.8 years) with BMI >=24 kg/m2 and prediabetes and/or the metabolic syndrome took part. Weight, physical activity (PA), and diabetes and cardiovascular disease (CVD) risk factors were assessed at 6, 12, and 18 months from baseline. Results At 6 months, the immediate group demonstrated greater mean weight loss than the delayed control group as well as significantly greater improvements in PA, A1C, fasting insulin, and waist circumference. In pre-post analyses, both randomized groups showed similar success that was maintained at 18 months. Conclusions The DPP-GLB delivered in economically diverse community centers was effective in this group of older adults. These findings support provision of coverage for prevention programs in older adults at risk for diabetes/CVD, which is important considering the large number of individuals who will be Medicare eligible in the near future. PMID- 29514570 TI - Executive Summary of Key Concepts. PMID- 29514569 TI - Exploring the Concept of Healing Spaces. AB - Evidence-based design (EBD) research has demonstrated the power of environmental design to support improved patient, family, and staff outcomes and to minimize or avoid harm in healthcare settings. While healthcare has primarily focused on fixing the body, there is a growing recognition that our healthcare system could do more by promoting overall wellness, and this requires expanding the focus to healing. This article explores how we can extend what we know from EBD about health impacts of spatial design to the more elusive goal of healing. By breaking the concept of healing into antecedent components (emotional, psychological, social, behavioral, and functional), this review of the literature presents the existing evidence to identify how healthcare spaces can foster healing. The environmental variables found to directly affect or facilitate one or more dimension of healing were organized into six groups of variables-homelike environment, access to views and nature, light, noise control, barrier-free environment, and room layout. While there is limited scientific research confirming design solutions for creating healing spaces, the literature search revealed relationships that provide a basis for a draft definition. Healing spaces evoke a sense of cohesion of the mind, body, and spirit. They support healing intention and foster healing relationships. PMID- 29514572 TI - Anthropometric reference curves for term neonates born at 3400 meters above sea level. AB - OBJECTIVE: To describe the 3rd, 10th, 50th, 90th, and 97th percentile of weight, length, ponderal index (PI), head circumference (HC), and head circumference for birthweight index (HCBWI). METHODS: Descriptive, retrospective, and transverse study performed in the Adolfo Guevara Velazco National Hospital (AGVNH) at 3400 m above sea level between January 2005 and December 2010. The main inclusion criteria were singleton pregnancy, term gestational age, and absence of fetal structural anomalies. RESULTS: Of a total of 10,903 newborns evaluated, 7635 met inclusion criteria. Using the findings from the above population, polynomial models were constructed for the 3rd, 10th, 50th, 90th, and 97th percentiles of weight, length, HC, PI, and HCBWI. CONCLUSIONS: Reference curves were developed for the 3rd, 10th, 50th, 90th, and 97th percentile for weight, height, head circumference (HC), ponderal index (PI), and HCBWI for term newborns according to sex born at 3400 m above sea level. PMID- 29514573 TI - The missing lynx of Eurasia at its Southern edge: a connection to the critically endangered Balkan lynx. AB - The populations of Eurasian lynx in Anatolia are as fragmented as the European populations. Although the origins of and the connections between the European lynx populations have been elucidated, there have been no genetic studies on the lynx populations in Turkey. The lack of genetic and evolutionary information about lynx in Anatolia, which is considered to be a biodiversity hotspot, makes it difficult to track the migration routes during the Quaternary. In this study, we present the genetic characteristics of two isolated lynx populations in Southwest Taurus Mountains and the Turkish Caucasus as well as two individuals from Erzincan area. DNA purified from the ecological scat samples collected from Ciglikara Nature Reserve in Elmali-Antalya and Allahuekber Mountains in Sarikamis Kars, as well as two roadkill samples from Erzincan, has been analysed for phylogenetic markers such as the mitochondrial DNA control region and cytochrome b. The DNA sequences were compared with haplotypes previously detected in populations from Europe and the Caucasus in order to determine the evolutionary relationships of the populations. This study compares the current genetic structure of some of the Turkish lynx populations to the other lynx genetic data, mostly carried out with museum samples around the world. Three haplotypes were found in three different regions of Anatolia. The Northeast and Southwest populations harbour genetically distinct haplotypes, the latter one, a new haplotype: H13-TR is the only phylogenetic connection to the critically endangered Balkan lynx yet to be described. PMID- 29514574 TI - Effects of an ethical empowerment program on critical care nurses' ethical decision-making. AB - BACKGROUND: Nurses require empowerment if they are to make ethical decisions. Ethical empowerment has always been one of the main concerns in nurse training programs. Research aim: The present study was conducted to determine the effect of an ethical empowerment program on critical care nurses' ethical decision making. RESEARCH DESIGN: This is a clinical trial study with two groups and pre and post design. Participants and research context: In this study, 60 nurses working in Intensive Care Unit were selected through random sampling and then divided into a control and an experimental group after filling out the Moral Sensitivity Questionnaire. Both groups completed the questionnaire again immediately and 2 months after the ethical empowerment workshop had been held for the experimental group. The collected data were analyzed in SPSS-16 using descriptive and inferential statistics. Ethical considerations: The goals of the study were explained to the participants and then a written informed consent was received from them. FINDINGS: The results showed no significant differences between the two groups in terms of their ethical sensitivity scores at the beginning of the study; however, immediately and 2 months after the intervention, the mean score increased significantly in the experimental group. Moreover, the scores obtained 2 months after the workshop increased compared to the pre intervention scores but showed a drop compared to the scores reported immediately after the workshop. DISCUSSION: The ethical empowerment program, given to the critical care nurses in this study, improved their ethical sensitivity in making decisions significantly over time. Despite the extensive methods, available for teaching nursing ethics, the ethical empowerment program, adopted in this study, had long-lasting effects in terms of ameliorating the process of ethical decision making in clinical situations. CONCLUSION: The ethical empowerment of nurses requires the adoption and application of proper methods and patterns of complying with nursing ethics. PMID- 29514575 TI - A qualitative description of service providers' experiences of ethical issues in HIV care. AB - BACKGROUND: Managing HIV treatment is a complex multi-dimensional task because of a combination of factors such as stigma and discrimination of some populations who frequently get infected with HIV. In addition, patient-provider encounters have become increasingly multicultural, making effective communication and provision of ethically sound care a challenge. PURPOSE: This article explores ethical issues that health service providers in the United States and Botswana encountered in their interaction with patients in HIV care. RESEARCH DESIGN: A descriptive qualitative design was used to collect data from health service providers and patients using focused group discussions. This article is based on responses from health service providers only. Participants and context: This article is based on 11 focused group discussions with a total sample of 71 service providers in seven US sites and one Botswana site. Ethical considerations: Ethical review boards at all the study sites reviewed the study protocol and approved it. Ethical review boards of the study's coordinating centers, Rutgers University and the University of California at San Francisco, also approved it. The study participants provided a written informed consent to participate. FINDINGS: HIV service providers encountered ethical challenges in all the four Beauchamp and Childress' biomedical ethics of respect for patients' autonomy, beneficence, justice, and nonmaleficence. DISCUSSION: The finding that HIV service providers encounter ethical challenges in their interaction with patients is supported by prior studies. The ethical challenges are particularly prominent in multicultural care and resource-constrained care environments. CONCLUSION: Provision of HIV care is fraught with ethical challenges that tend to pose different issues depending on a given care environment. It is important that strong partnerships are developed among key stakeholders in HIV care. In addition, health service providers need to be provided with resources so they can provide quality and ethically sound care. PMID- 29514576 TI - Nanostructured formulations and drug delivery systems. PMID- 29514579 TI - Perspectives on Neuroscience and Behavior. PMID- 29514581 TI - Strangulation of giant rectal prolapse. AB - Introduction Rectal prolapse is the complete protrusion of the rectum through the anal canal, incarceration rarely complicates rectal prolapse. Even more rarely, it becomes strangulated and gangrenous, necessitating emergency surgery. Case presentation We present the first reported case of strangulated acute rectal prolapse as the first manifestation of rectal prolapse. The patient was a 26-year old man who presented with a 20*6 cm semi-spherical mass extra-anally. Rectosigmoidectomy with sacral rectopexy was performed, resecting 20 cm of the incarcerated rectum and sigmoid colon. The postoperative course was uneventful with a good final result after colostomy closure and continuity restoration. Conclusion The successful treatment of this patient illustrates the value of surgery in this difficult and unusual case scenario of rectal incarceration. PMID- 29514582 TI - A case of an acute cutaneous drug reaction with hydroxychloroquine. AB - Hydroxychloroquine is considered a relatively benign drug and is regularly used by rheumatologists and dermatologists. We highlight the severe adverse drug reaction potential of this commonly prescribed medication. We report the case of a 63-year-old male, who presented with widespread skin eruption following initiation of hydroxychloroquine two weeks earlier for an inflammatory arthritis. He had typical clinical, biochemical and histological features of the now recognised formal 'diagnosis' of severe cutaneous adverse drug reaction. The culprit drug was stopped and he responded to oral and topical steroids as well as supportive measures. Severe reactions to hydroxychloroquine are uncommon; however, as in this case, drug hypersensitivity reactions often manifest in skin. In a drug normally considered to be safe, these potential cutaneous side effects should be highlighted in information given to patients prior to commencement. PMID- 29514583 TI - A prospective observational study of emergency department presentations following novel psychoactive substance use. AB - Background and aims Novel psychoactive substances are compounds intended to mimic the effects of illicit drugs. They provide a unique challenge to healthcare, as complications of their use and their impact on services are relatively unknown. This study aims to determine nature of presentations, patient demographics and impact on healthcare. Methods Novel psychoactive substances users who presented to a large urban emergency department over 4 weeks were prospectively identified and followed for 1 year. Patients over 13 years old were eligible for inclusion. Information regarding patient demographics and presentations was collected. Results During the study period, 53 patients (39 male), mean age 32.6 +/- 8.9 (+/ standard deviation), presented 148 times with complaints relating to novel psychoactive substances use. Study population characteristics included history of illicit drug use (83.0%), intravenous drug use (64.2%), psychiatric diagnosis or symptoms (56.6%), methadone prescription (52.8%) and having no fixed abode (37.7%). Injection was the most common method of use (72.3%), Burst the most commonly named agent (19.6%) and behavioural change the most common presenting complaint (31.1%). Patients collectively spent 10,620 h in hospital over 1 year. Conclusion This study highlights differences between the young population targeted by government campaigns regarding novel psychoactive substances use and the presenting population to hospital, and the associated burden on the National Health Service. PMID- 29514584 TI - Unstable angina in the era of high-sensitivity troponin testing: a genuine entity and a cautionary tale. AB - High-sensitivity cardiac troponin assays have emerged as a powerful tool in the management of patients presenting acutely to hospital with suspected cardiac chest pain. Recent guidelines emphasize the reassurance offered by low troponin concentrations early after admission. We describe a patient with known coronary artery disease, who presented with a classical history of recurrent myocardial ischaemia. High-sensitivity cardiac Troponin-I concentrations remained in the low normal sex-specific reference range, despite serial testing on the day of admission, and despite recurrent pain with dynamic ECG changes. Urgent coronary angiography confirmed severe multi-vessel disease. He required an intra-aortic balloon pump within 24 h due to clinical instability, and had urgent coronary artery bypass surgery a few days later. This case confirms that "unstable angina" remains a genuine entity. It highlights the hazards of over-reliance on any single test and serves as a reminder of the importance of integrating tests with clinical assessment. PMID- 29514585 TI - Current standards for assessing pregnancy status before surgery are subjective and should be replaced with definitive, objective evidence. AB - We report a case of a young woman admitted electively for laparoscopic Nissen fundoplication, and again three days post-operatively as an emergency with profuse vomiting and abdominal pain. She underwent diagnostic laparoscopy, and a small gastric perforation was found at the site of the fundoplication and this was suture-repaired. On both admissions, she was "screened" for pregnancy as per current guidelines. On the second admission, following a CT scan, she was found to have a gravid uterus with a foetus of 16-18 weeks' gestation. In the opinion of the authors, this case highlights that current National Institute for Health and Care Excellence guidelines may be insufficient and could lead to unnecessary harm either to mother or foetus pre-, peri- or post-operatively. PMID- 29514586 TI - An Integrative Review of Bullying and Lateral Violence Among Nurses in Magnet(r) Organizations. AB - Over the past several years, researchers have postulated that Magnet(r) organizations improve collegiality and potentially could mitigate workplace bullying and lateral violence (BLV). In order to synthesize and evaluate the existing literature on BLV in the Magnet(r) setting, an integrative review was conducted. The final analysis consisted of 11 articles (8 quantitative and 3 qualitative studies) and revealed that researchers still use a variety of terms to define and measure BLV. Several of the studies used blended samples of both Magnet(r) and non-Magnet nurses, making it difficult to evaluate for response differences. The existing studies suggest that BLV continues to exist and remain a large issue even in the Magnet(r) setting (Hickson, 2013; Latham, Ringl, & Hogan, 2013). Future studies should examine the prevalence of BLV in both Magnet(r) and non-Magnet organizations and also explore the organizational factors that reduce its occurrence. PMID- 29514588 TI - Emotion regulation in social anxiety: a systematic investigation and meta analysis using self-report, subjective, and event-related potentials measures. AB - Recent models of social anxiety disorder emphasise the role of emotion dysregulation; however, the nature of the proposed impairment needs clarification. In a replication and extension framework, four studies (N = 193) examined whether individuals with social anxiety (HSAs) are impaired in using cognitive reappraisal and expressive suppression. Self-reports and lab-based tasks of suppression and reappraisal were utilised among individuals with high and low levels of social anxiety. A meta-analysis of these studies indicated that, compared to controls, HSAs reported less frequent and effective use of reappraisal and more frequent and effective use of suppression. Counter to most models and our hypotheses, HSAs were more successful than controls in lab-based reappraisal of shame-arousing pictures as measured by subjective ratings, but not by event-related potentials. HSAs were less successful than controls in lab-based suppression of shame-arousing pictures as measured by subjective ratings, but not by event-related potentials. The results held even when participants were under social stress (impromptu speech anticipation). Overall, subjective reports of HSAs reveal strong deficits in emotion regulation whereas lab-based measures provided less conclusive evidence of such deficits. These results suggest that individuals with social anxiety experience difficulties implementing their reappraisal abilities in daily life. PMID- 29514589 TI - Comparison of urea recirculation and thermodilution for monitoring of vascular access in patients undergoing hemodialysis. AB - : Introduction It is important to monitor vascular access in patients with stage 5 chronic kidney disease receiving hemodialysis. Access recirculation can help to detect a need for intervention. OBJECTIVES: To compare urea recirculation with recirculation by thermodilution using blood temperature monitoring to predict a need for intervention of vascular access over a 6-month period. METHODS: We analyzed urea recirculation and blood temperature monitoring simultaneously in 61 patients undergoing hemodialysis. During the 6-month follow-up, we recorded all cases of angioplasty or surgery (thrombectomy or reanastomosis). In line with previous studies, we considered a value to be positive when urea recirculation was >10% and blood temperature monitoring >15%. Receiver operating characteristic curves were constructed. RESULTS: Mean urea recirculation was 9.5% +/- 6.6% and mean blood temperature monitoring 12.9% +/- 4.3% (p = 0.001). Urea recirculation >10% had a sensitivity of 80% and specificity of 78%. Blood temperature monitoring >15% had a sensitivity of 33% and specificity of 85%. During follow up, 25% of patients developed need for intervention of vascular access. We found an association between vascular access dysfunction and urea recirculation. The Kaplan-Meier analysis confirmed an association between urea recirculation and risk of vascular access dysfunction (log rank = 17.2; p = 0.001). We were unable to confirm this association with blood temperature monitoring (log rank = 0.879; p = 0.656). CONCLUSION: Urea recirculation is better predictor of vascular access dysfunction than thermodilution. PMID- 29514590 TI - Effects of exposure to an intensive HIV-prevention programme on behavioural changes among female sex workers in Nairobi, Kenya. AB - While Kenya has had a long-standing national HIV-prevention programme, evidence on the level of exposure to its interventions and related effects on behavioural changes among female sex workers (FSWs) is limited. Using cross-sectional behavioural data collected in 2013 from 1 357 FSWs aged 18 years and above in Nairobi, Kenya, this study explores the relationship between FSW programme exposure levels and behavioural outcomes including condom use, sexually transmitted infection (STI)-treatment, and empowerment measures like disclosure of self-identity and violence reporting. We categorised programme exposure levels as none, moderate and intensive. Multivariate logistic regression was used for analysis. Overall, 35% of the FSWs were not exposed to any HIV prevention programme, whereas about 24% had moderate and 41% had intensive exposure. FSWs having intensive programme exposure had a higher likelihood of using condoms consistently with occasional clients (AOR: 1.57; 95% CI: 1.08-2.31) and seeking treatment for STIs (AOR: 3.37; 95% CI: 1.63-7.02) compared to FSWs with no or moderate exposure. Intensive programme exposure was also associated with higher self-disclosure of sex-work identity (AOR: 1.63; 95% CI: 1.19-2.24), reporting of violence to police (AOR: 2.45; 95% CI: 1.03-5.84), and negotiation of condom use at last sex when the client was under the influence of alcohol (AOR: 1.63; 95% CI: 0.94-2.82). Although HIV prevention programmes in Kenya have been underway for over a decade, programme efforts were largely focused on saturating the coverage (intervention breadth). Strategies should now focus on ensuring improved quality of contacts through intensified programme exposure (intervention depth) to enhance gains in behavioural change among FSWs and preventing the burden of HIV infection among them. PMID- 29514592 TI - Effects of isoflavones on behavior, estradiol, glutamate, and GABA levels in intact middle-aged female rats. AB - OBJECTIVES: Estrogen and phytoestrogens, mainly isoflavones (SIF) treatment has been suggested to improve mood, behavior, and cognitive function in postmenopausal women. However, there is a lack of information on the mechanism of such treatment on the central nervous system. We used rats to investigate the effects of long-term treatment with commercial isoflavones on behavior, hormones, and brain neurotransmitter levels. METHODS: Intact female middle-aged (12 months) rats received 50, 100, and 200 mg/kg/day of commercial isoflavones extract by gavage for 90 days. After treatment, locomotor activity, anxiety-like behavior, spatial memory, estradiol, and neurotransmitter levels were measured. RESULTS: Isoflavones treatment decreased total body weight gain in rats received 100 (P < 0.05) and 200 mg/kg (P < 0.05). There were no differences in locomotor activity or anxiety-like behavior; however, isoflavone treatment improved spatial memory (P < 0.05). Estradiol concentration was increased (P < 0.05) in groups SIF 100 and SIF 200. Glutamate (P < 0.01) and gamma-aminobutyric acid (GABA) were increased in the prefrontal cortex (PFC) of rats receiving the highest doses and in the hypothalamus in rats that received SIF200 (P < 0.05). DISCUSSION: These findings showed that long-term treatment with commercial isoflavones decreased total body weight gain and facilitated spatial memory performance in rats and this may be involved with the increase in estradiol levels as well as the increase in GABA and glutamate levels in PFC. Furthermore, isoflavones treatment may attenuate age-related cognitive impairment and may therefore be an effective tool to combat this undesirable feature of the natural aging process. PMID- 29514591 TI - Standards for recanalisation of chronic venous outflow obstructions. AB - Postthrombotic syndrome (PTS) is the most common complication after iliofemoral deep vein thrombosis. It reduces quality of life and increases deep vein thrombosis (DVT)-related costs. The clinical symptoms and severity of PTS may vary; the most common symptoms include edema, pain (venous claudication), hyperpigmentation, lipodermatosclerosis, and ulceration. PTS is based on the principle of outflow obstruction, which may be caused by venous hypertension and may lead to valvular damage and venous reflux or insufficiency. Recent technical developments and new stent techniques now allow recanalisation of even complex venous outflow obstructions within the iliac vein and the inferior vena cava. This manuscript gives an overview on the latest standards for venous recanalisation. PMID- 29514594 TI - Perception of quality health care delivery under capitation payment: a cross sectional survey of health insurance subscribers and providers in Ghana. AB - BACKGROUND: Ghana introduced capitation payment method in 2012 but was faced with resistance for its perceived poor quality of care. This paper assesses National Health Insurance Scheme subscribers and care providers' perception of quality of care under the capitation payment method. METHODS: This is a cross-sectional survey of subscribers and care providers perception of quality of care in three administrative regions of Ghana using a 5-point Likert scale for the assessment based on a set of quality of care measures. We performed descriptive analysis to determine average perception of quality of care scores for each of the measures used. Bivariate and multivariate analyses were also performed to examine relationships between respondent's characteristics and their perception of quality of care. RESULTS: In general, subscribers expressed positive perception about the quality of care though subscribers in Ashanti were less positive compared to those in the Central region. A chi-square analysis, however, showed significant differences in subscribers' perception of quality of care by occupation (p = 0.002), region (p = 0.007) length of NHIS membership (p = 0.006), and age (p = 0.014). Multivariate logistic regression analysis also showed that different factors, other than region of residence, were significantly associated with perceived good quality of care. Analysis of health care providers' responses also showed significant differences in their perception of quality of care by region (p = 0.001). Multivariate logistic model showed that health care providers in the Volta region (OR = 0.14, 95% CI: 0.03-0.58) were significantly less likely to perceive quality of care as good compared to those in the Ashanti region. CONCLUSION: Subscribers and care providers across the three regions have relatively good perception of the quality of health care in general though subscribers in Ashanti were less positive than those in the Central region. It is, therefore, plausible that capitation payment may have influenced the relatively low perception of quality of care in the Ashanti region. PMID- 29514593 TI - Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history. AB - BACKGROUND: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. METHODS: The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. RESULTS: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. CONCLUSIONS: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation. PMID- 29514595 TI - An educational intervention to improve hand hygiene compliance in Vietnam. AB - BACKGROUND: Hand hygiene compliance is the basis of infection control programs. In developing countries models to improve hand hygiene compliance to reduce healthcare acquired infections are required. The aim of this study was to determine hand hygiene compliance following an educational program in an obstetric and gynecological hospital in Vietnam. METHODS: Health care workers from neonatal intensive care, delivery suite and a surgical ward from Hung Vuong Hospital, Ho Chi Minh City, Vietnam undertook a 4-h educational program targeting hand hygiene. Compliance was monitored monthly for six months following the intervention. Hand hygiene knowledge was assessed at baseline and after six months of the study. RESULTS: There were 7124 opportunities over 370 hand hygiene recording sessions with 1531 opportunities at baseline and 1620 at 6 months following the intervention. Hand hygiene compliance increased significantly from baseline across all sites (43.6% [95% Confidence interval CI: 41.1-46.1] to 63% [95% CI: 60.6-65.3]; p < 0.0001). Health care worker hand hygiene compliance increased significantly after intervention (p < 0.0001). There were significant improvements in knowledge scores from baseline to 2 months post educational intervention with mean difference standard deviations (SD): 1.5 (2.5); p < 0.001). CONCLUSIONS: A simple educational model was implemented in a Vietnamese hospital that revealed good hand hygiene compliance for an extended period of time. Hand hygiene knowledge increased during the intervention. This hand hygiene model could be used in developing countries were resources are limited. PMID- 29514596 TI - Development and evaluation of a blended educational programme for general practitioners' trainers to stimulate proactive HIV testing. AB - BACKGROUND: In the Netherlands, a substantial proportion of newly diagnosed HIV patients present late for care, therefore, we investigated the effectiveness of a blended educational programme for trainers of GPs designed to stimulate proactive HIV testing. METHODS: GP trainers at the Academic Medical Center in Amsterdam were invited to participate in a two days training programme incorporating evidence-based practice guidelines and multiple teaching strategies, including interactive lectures, discussion groups, e-learning and quality improvement targets. The GP trainers completed questionnaires before and after the programme to evaluate the effect of the programme. We also used six-monthly cumulative laboratory data from 2010 to 2015 to compare the participating GPs' HIV tests to the general trend in testing among non-participating GPs. RESULTS: 150 GP trainers attended the first session, and 74 completed the questionnaires for both sessions. GPs median score on achieving their quality improvement targets was high and the quality of the programme highly appreciated. Between 2010 and 2013, the mean annual number of laboratory-documented HIV tests decreased by 9.1% in the 624 GPs in the control group, and by 13.0% for 11 GPs in the intervention group. After the programme, the annual decreases were 2.3% and 1.8%, respectively. Before the programme, the GPs in the intervention group had 50% more laboratory-documented HIV tests than GPs in the control group. After the programme, GPs in the intervention group had twice as many laboratory-documented HIV tests as the controls. CONCLUSIONS: We provided a detailed description of a programme based on educational and clinical evidence. We could not retrieve laboratory-documented HIV testing data for the majority of GPs in both the intervention and control groups. Therefore, the limited results should be interpreted with caution as our findings may not be representative of all participants. The blended educational programme appears to have stabilized - at a higher level - the initially stronger downward trend in testing for 11 GPs undergoing the intervention, indicating that the programme may have had an impact on their HIV testing behaviour. PMID- 29514597 TI - Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review. AB - BACKGROUND: Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. METHODS: We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. RESULTS: For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. CONCLUSIONS: Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses. PMID- 29514598 TI - Mapping transmission foci to eliminate malaria in the People's Republic of China, 2010-2015: a retrospective analysis. AB - BACKGROUND: China has initiated the National Malaria Elimination Action Plan, which aims to eliminate malaria by 2020. However, the transmission of malaria occurs sporadically or in distinct foci, which greatly hampers progress toward elimination in China and other countries. The object of this study was to foci categorization and evaluates whether the response met the requirements issued by the nation or WHO. METHODS: Residual transmissions were investigated and located with fine spatial resolution mapping from parasitological confirmed malaria cases by use of routine national surveillance data. The "1-3-7" timeframes were monitored for each focus between 2012 and 2015. Each focus was identified, and the application of appropriate measures was evaluated. RESULTS: A total of 5996 indigenous cases were recorded between 2010 and 2015; during this period, the number of cases declined by 99.1% (2010, n = 4262; 2015, n = 39). Most indigenous cases (92.5%) were reported in Anhui (n = 2326), Yunnan (n = 1373), Henan (n = 930), Hubei (n = 459), and Guizhou (n = 458). The temporal distribution showed that the indigenous malaria cases were clustered during the period of May to August. A total of 320 foci were carefully investigated and analyzed: 24 were active foci; 72, residual non-active foci; and 224 cleared-up foci. For the foci response evaluation, all the active foci were investigated within 7 days, while 80.2% of the residual non-active foci were responded within 7 days. In addition, reactive case detection (RACD) was carried out with 92.9% of the active foci and vector investigation carried out with 75%. For residual non-active foci, RACD was carried out with 83.2% and vector investigation with 78.2% of the foci. CONCLUSIONS: This study used nationwide data to categorize foci in China and evaluate the response of these areas during the control and elimination phases. Our approach stratifies future control responses by identifying those locations where the elimination of endemic transmission is needed, such as in the counties at the China-Myanmar border and in Tibet. In addition, this study will help local CDC staff to reassess their needs and responses against different types of foci during the elimination and post-elimination phases. PMID- 29514599 TI - Social factors and quality of life aspects on frailty syndrome in community dwelling older adults: the VERISAUDE study. AB - BACKGROUND: Frailty is a multidimensional clinical geriatric syndrome that may be reversed in its early stages. Most studies have paid attention to its physical or phenotypic boundaries, however, little is known about the social aspects surrounding this geriatric syndrome. The study examined the relationship between socio-demographic factors, social resources, quality of life and frailty in older adults. METHODS: This cross-sectional study included a representative sample (n = 749) of adults aged >=65 years enrolled in forty-three senior centers located in North-West Spain. Socio-demographic data, social resources by the Older Americans Resources and Services Scale, quality of life by the World Health Organization's Quality of Life measure-brief version (WHOQOL-BREF), and frailty status diagnosed by the Frailty phenotype were measured. RESULTS: Female gender, age older than 75 years, single marital status, a poor quality of life, and low scores in the physical health domain of the WHOQOL-BREF were the main determinants of being non robust. Together, these variables explained 24.4% of the variance. Age between 80 and 89 years, and a poor quality of life were the main determinants for non robust men, whilst the physical health domain of the WHOQOL-BREF was the single main determinant for women. CONCLUSIONS: Our study found evidence that physical frailty is associated with social determinants and several quality of life domains. More research on this understudied topic is needed to avoid healthcare expenditures and improve the quality of life of non-robust elders. PMID- 29514600 TI - Low incidence of multidrug-resistant bacteria and nosocomial infection due to a preventive multimodal nosocomial infection control: a 10-year single centre prospective cohort study in neurocritical care. AB - BACKGROUND: Nosocomial infection (NI) control is an important issue in neurocritical care due to secondary brain damage and the increased morbidity and mortality of primary acute neurocritical care patients. The primary aim of this study was to determine incidence of nosocomial infections and multidrug-resistant bacteria and seek predictors of nosocomial infections in a preventive multimodal nosocomial infection protocol in the neurointensive care unit (NICU). The secondary aim focused on their impact on stay, mortality and cost in the NICU. METHODS: A10-year, single-centre prospective observational cohort study was conducted on 3464 acute brain disease patients. There were 198 (5.7%) patients with nosocomial infection (wound 2.1%, respiratory 1.8%, urinary 1.0%, bloodstream 0.7% and other 0.1%); 67 (1.9%) with Extended spectrum beta-lactamase (ESBL); 52 (1.5%) with Methicillin-resistant Staphylococcus aureus (MRSA), nobody with Vancomycin-resistant enterococcus (VRE). The protocol included hygienic, epidemiological status and antibiotic policy. Univariate and multivarite logistic regression analysis was used for identifying predictors of nosocomial infection. RESULTS: From 198 NI patients, 153 had onset of NI during their NICU stay (4.4%; wound 1.0%, respiratory 1.7%, urinary 0.9%, bloodstream 0.6%, other 0.1%); ESBL in 31 (0.9%) patients, MRSA in 30 (0.9%) patients. Antibiotics in prophylaxis was given to 63.0% patients (59.2 % for operations), in therapy to 9.7% patients. Predictors of NI in multivariate logistic regression analysis were airways (OR 2.69, 95% CI 1.81-3.99, p<0.001), urine catheters (OR 2.77, 95% CI 1.00-7.70, p=0.050), NICU stay (OR 1.14, 95% CI 1.12-1.16, p<0.001), transfusions (OR 1.79, 95% CI 1.07-2.97, p=0.025) antibiotic prophylaxis (OR 0.50, 95% CI 0.34-0.74, p<0.001), wound complications (OR 2.30, 95% CI 1.33-3.97, p=0.003). NI patients had longer stay (p<0.001), higher mortality (p<0.001) and higher TISS sums (p<0.001) in the NICU. CONCLUSIONS: The presented preventive multimodal nosocomial infection control management was efficient; it gave low rates of nosocomial infections (4.2%) and multidrug-resistant bacteria (ESBL 0.9%, MRSA 0.9% and no VRE). Strong predictors for onset of nosocomial infection were accesses such as airways and urine catheters, NICU stay, antibiotic prophylaxis, wound complications and transfusion. This study confirmed nosocomial infection is associated with worse outcome, higher cost and longer NICU stay. PMID- 29514601 TI - Prediction of sensitivity to gefitinib/erlotinib for EGFR mutations in NSCLC based on structural interaction fingerprints and multilinear principal component analysis. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) with activating EGFR mutations, especially exon 19 deletions and the L858R point mutation, is particularly responsive to gefitinib and erlotinib. However, the sensitivity varies for less common and rare EGFR mutations. There are various explanations for the low sensitivity of EGFR exon 20 insertions and the exon 20 T790 M point mutation to gefitinib/erlotinib. However, few studies discuss, from a structural perspective, why less common mutations, like G719X and L861Q, have moderate sensitivity to gefitinib/erlotinib. RESULTS: To decode the drug sensitivity/selectivity of EGFR mutants, it is important to analyze the interaction between EGFR mutants and EGFR inhibitors. In this paper, the 30 most common EGFR mutants were selected and the technique of protein-ligand interaction fingerprint (IFP) was applied to analyze and compare the binding modes of EGFR mutant-gefitinib/erlotinib complexes. Molecular dynamics simulations were employed to obtain the dynamic trajectory and a matrix of IFPs for each EGFR mutant-inhibitor complex. Multilinear Principal Component Analysis (MPCA) was applied for dimensionality reduction and feature selection. The selected features were further analyzed for use as a drug sensitivity predictor. The results showed that the accuracy of prediction of drug sensitivity was very high for both gefitinib and erlotinib. Targeted Projection Pursuit (TPP) was used to show that the data points can be easily separated based on their sensitivities to gefetinib/erlotinib. CONCLUSIONS: We can conclude that the IFP features of EGFR mutant-TKI complexes and the MPCA-based tensor object feature extraction are useful to predict the drug sensitivity of EGFR mutants. The findings provide new insights for studying and predicting drug resistance/sensitivity of EGFR mutations in NSCLC and can be beneficial to the design of future targeted therapies and innovative drug discovery. PMID- 29514602 TI - Incidence and mortality rates of varicella among end stage renal disease (ESRD) patients in Singapore General Hospital, a 12-year review. AB - BACKGROUND: End stage renal disease (ESRD)/ end stage renal failure (ESRF) is on the rise globally and especially in Singapore. Varicella or chickenpox is not uncommon among adults especially ESRD/ESRF patients. It has been reported to cause complications and even death among immunocompetent adults. METHODS: A retrospective data collection on patients with varicella infection and ESRD in Singapore General Hospital (SGH) from the year 2005 to 2016 was performed. Continuous data and categorical data were summarized as median (range) and count (%) respectively. The association of health care utilization (total length of hospital stay, readmission related to varicella, intensive care unit admission) and mortality with complication due to varicella were tested using chi-square and Mann-Whitney test for categorical and continuous outcomes respectively. RESULTS: Sixty-six patients with ESRD developed varicella during the study period (2005 2016). The case incidence rates for varicella among ESRD ranges from 97 to 267 per 100,000 populations with ESRD yearly. There were 9 deaths (13.6%). Mortality was higher among the ESRD patients with one or more varicella complications compared to patients without complications ((25% vs 7.1%, 95% CI for difference: 1.1%, 36.9%, p = .063). Likewise, utilisation of intensive or high dependency units were higher among patients with complications compared to those without (20.8% vs 2.4%, 95% CI for difference: 1.6%, 35.3%, p = .012). Length of stay was twice as long in the group with complications compared to patients without (median (IQR) days: 14 (8, 21) vs 7 (5, 14), p = .065), although it did not reach statistical significance. CONCLUSIONS: Varicella is associated with high morbidity and significant mortality rate in ESRD patients. Varicella vaccination is recommended for seronegative ESRD patients. PMID- 29514603 TI - GABAB receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways. AB - BACKGROUND: High-grade chondrosarcoma, which has a high incidence of local recurrence and pulmonary metastasis despite surgical resection, is associated with poor prognosis. Therefore, new and effective adjuvant therapies are urgently required for this disease. Gamma-aminobutyric acid (GABA), which acts as a neurotrophic factor during nervous system development, is related to the proliferation and migration of certain cancer cells. The GABAergic system, which is composed of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), and GABA receptors, has an important function in nerve growth and development of neural crest. Therefore, the GABAergic system may play important functional roles in the proliferation of chondrosarcoma cells, which are derived from neural crest cells. We examined the anti-tumor effects of the GABAergic system on a chondrosarcoma cell line. METHODS: We evaluated the underlying mechanisms of the anti-tumor effects of the GABAergic system, such as the involvement of different signaling pathways, apoptosis, and cell cycle arrest, in the high-grade chondrosarcoma cell line OUMS-27. In addition, we performed whole cell patch-clamp recordings for Ca2+ currents and evaluated the changes in intracellular Ca2+ concentration via Ca2+ channels, which are related to the GABAB receptor in high-grade chondrosarcoma cells. RESULTS: The GABAB receptor antagonist CGP had anti-tumor effects on high-grade chondrosarcoma cells in a dose-dependent manner. The activities of caspase 3 and caspase 9 were significantly elevated in CGP-treated cells compared to in untreated cells. The activity of caspase 8 did not differ significantly between untreated cells and CGP-treated cells. However, caspase 8 tended to be up-regulated in CGP-treated cells. The GABAB receptor antagonist exhibited anti-tumor effects at the G1/S cell cycle checkpoint and induced apoptosis via dual inhibition of the PI3/Akt/mTOR and MAPK signaling pathways. Furthermore, the changes in intracellular Ca2+ via GABAB receptor-related Ca2+ channels inhibited the proliferation of high-grade chondrosarcoma cells by inducing and modulating apoptotic pathways. CONCLUSIONS: The GABAB receptor antagonist may improve the prognosis of high-grade chondrosarcoma by exerting anti-tumor effects via different signaling pathways, apoptosis, cell cycle arrest, and Ca2+ channels in high-grade chondrosarcoma cells. PMID- 29514604 TI - Efficacy of serum procalcitonin to predict spontaneous preterm birth in women with threatened preterm labour: a prospective observational study. AB - BACKGROUND: A hypothesis of preterm parturition is that the pathogenesis of spontaneous preterm birth (sPTB) may be associated with an inflammatory process. Based on this theory, we have hypothesized that an inflammatory biomarker, procalcitonin (PCT), may be a good predictive marker of sPTB at the admission for threatened preterm labour (TPL). The present study was aimed to investigate the association between serum PCT and sPTB in women with TPL and to evaluate whether PCT levels may predict sPTB in women with TPL within 7 or 14 days. METHODS: In a prospective observational laboratory-based study, women with singleton pregnancies, TPL between 24 and 36 weeks and intact membranes, were enrolled between January 2014 and June 2016. Participants received routine medical management of TPL (tocolysis with atosiban, antenatal corticosteroids, and biological tests at admission (C-reactive protein, white blood cell count, and PCT measured on electrochemiluminescence immunoassay)). The primary endpoint was sPTB before 37 weeks of gestation. The value of serum PCT levels to predict sPTB within 7 or 14 days were evaluated using receiver-operating curves (ROC) analysis. RESULTS: A total of 124 women were included in our study. PCT levels did not statistically differ between women with sPTB (n = 30, 24.2%) and controls (n = 94) (median in ng/mL [interquartile range]: 0.043 [0.02-0.07] compared to 0.042 [0.02-0.13], respectively; P = 0.56). PCT levels did not also statistically differ between women with sPTB within 7 days (n = 7, 5.6%) or 14 days (n = 12, 9.7%) after testing and controls. Moreover, subgroup analysis revealed no difference among PCT levels at admission between 24 and 28 weeks, between 28 and 32 weeks and over 32 weeks, and controls. On the basis of the receiver-operating characteristic curve, the highest sensitivity and specificity corresponded to a PCT concentration of 0.038 ng/mL, with poor predictive values for sPTB within 7 or 14 days. CONCLUSION: Serum PCT was not relevant to predict sPTB within 7 or 14 days in women admitted with TPL between 24 and 36 weeks, and thus it is not a suitable biological marker to confirm the hypothesis of an inflammatory process associated with preterm parturition. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT01977079 ), Registered 24 October 2013. PMID- 29514605 TI - Predictive value of spot versus 24-hour measures of proteinuria for death, end stage kidney disease or chronic kidney disease progression. AB - BACKGROUND: Proteinuria is well recognised as a marker of chronic kidney disease (CKD), as a risk factor for progression of CKD among those with known CKD, and as a risk factor for cardiovascular events and death among both the general and CKD populations. Which measure of proteinuria is most predictive of renal events remains uncertain. METHODS: We conducted a prospective study with 144 proteinuric CKD and kidney transplant recipients attending an outpatient clinic of a tertiary care hospital in Australia. We concurrently collected morning spot urine protein to-creatinine ratio (UPCR), albumin-to-creatinine ratio (UACR) and 24-h urinary protein excretion (24-UPE) from each participant at baseline. The primary outcome was a composite of death, ESKD or > 30% decline in eGFR over 5-years. Secondary outcomes were each component of the composite outcome. For each proteinuria measure, we performed a Cox Proportional Hazards model and calculated the Harrell's C-statistic and Akaike's Information Criterion (AIC). RESULTS: After a mean follow-up of 5 years (range 4.4-6), 85 (59%) patients met the primary composite outcome including 23 deaths (16%). The multivariable analysis showed strong evidence of an association between each log-transformed proteinuria measurement and the primary composite outcome. [Log-UPCR 1.31 (95% CI 1.18-1.63), log-UACR 1.27 (1.11-1.45) and log-24-UPE 1.43 (1.20-1.71)]. The C-Statistic were similar for all three measures of proteinuria [UPCR: 0.74 (95% CI: 0.69-0.80), UACR: 0.75 (0.69-0.81), 24-UPE: 0.75 (0.69-0.81)] as were the models' AIC (671, 668 and 665 respectively). For secondary outcomes, no proteinuria measure was significantly associated with death alone ([log-UPCR = 1.18 (0.96-1.84), log-UACR = 1.19 (1.00-1.55), log-24-UPE = 1.19 (0.83-1.71)], whilst UACR and 24-UPE demonstrated marginally better association with ESKD and > 30% decline in eGFR respectively. [For ESKD, adj log-UACR HR = 1.33 (1.07-1.66). For > 30% decline in eGFR, log-24-UPE adj HR = 1.54 (1.13-2.09)]. CONCLUSION: In patients with stable, non-nephrotic CKD, all three measures of proteinuria were similarly predictive of hard clinical endpoints, defined as a composite of death, ESKD and > 30% decline in eGFR. However, which measure best predicted the outcomes individually is less certain. PMID- 29514606 TI - Scar site metastasis of renal cell carcinoma diagnosed on-site cytology: a case report. AB - BACKGROUND: Renal cell carcinomas (RCCs) have a propensity for widespread metastases and a wide range of survival rates. They can spread into adjacent organs by direct extension and can invade local or distant sites by lymphatic, hematogenous or lympho-hematogeneous pathways. Scar site metastasis is very rare. CASE PRESENTATION: We report a rare case of scar site RCC metastasis in a patient who underwent left radical nephrectomy 10 months ago. CONCLUSION: FNAC is a simple and easy technique that can help in the definitive diagnosis of subcutaneous lesions. A correct early stage diagnosis of metastatic RCC can considerably improve the survival rates. PMID- 29514607 TI - Initiation of traditional birth attendants and their traditional and spiritual practices during pregnancy and childbirth in Ghana. AB - BACKGROUND: Prior to the advent of modern obstetric services, traditional birth attendants (TBAs) have rendered services to pregnant women and women in labour for a long time. Although it is anticipated that women in contemporary societies will give birth in hospitals and clinics, some women still patronize the services of TBAs. The study therefore sought to gain an in-depth understanding of the initiation of TBAs and their traditional and spiritual practices employed during pregnancy and childbirth in Ghana. METHODS: The design was an exploratory qualitative one using in-depth individual interviews. Data saturation was reached with 16 participants who were all of Christian faith. Interviews were conducted with a semi-structured interview guide, audiotaped and transcribed verbatim. Content analysis was employed to generate findings. RESULTS: The findings showed that TBAs were initiated through apprenticeship from family members who were TBAs and other non-family TBAs as well as through dreams and revelations. They practice using both spiritual and physical methods and their work was founded on spiritual directions, use of spiritual artefacts, herbs and physical examination. TBAs delay cutting of the cord and disposal of the placenta was associated with beliefs which indicated that when not properly disposed, it will have negative consequences on the child during adulthood. CONCLUSION: Although, TBAs like maternal health professionals operate to improve maternal health care, some of their spiritual practices and beliefs may pose threats to their clients. Nonetheless, with appropriate initiation and training, they can become useful. PMID- 29514608 TI - Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations. AB - BACKGROUND: Angiogenesis is a process of formation of new blood vessels and is an important criteria demonstrated by cancer cells. Over a period of time, these cancer cells infect the other parts of the healthy body by a process called progression. The objective of the present article is to identify a drug molecule that inhibits angiogenesis and progression. METHODS: In this pursuit, ligand based pharmacophore virtual screening was employed, generating a pharmacophore model, Hypo1 consisting of four features. Furthermore, this Hypo1 was validated recruiting, Fischer's randomization, test set method and decoy set method. Later, Hypo1 was allowed to screen databases such as Maybridge, Chembridge, Asinex and NCI and were further filtered by ADMET filters and Lipinski's Rule of Five. A total of 699 molecules that passed the above criteria, were challenged against 4AG8, an angiogenic drug target employing GOLD v5.2.2. RESULTS: The results rendered by molecular docking, DFT and the MD simulations showed only one molecule (Hit) obeyed the back-to-front approach. This molecule displayed a dock score of 89.77, involving the amino acids, Glu885 and Cys919, Asp1046, respectively and additionally formed several important hydrophobic interactions. Furthermore, the identified lead molecule showed interactions with key residues when challenged with CDK2 protein, 1URW. CONCLUSION: The lead candidate showed several interactions with the crucial residues of both the targets. Furthermore, we speculate that the residues Cys919 and Leu83 are important in the development of dual inhibitor. Therefore, the identified lead molecule can act as a potential inhibitor for angiogenesis and progression. PMID- 29514609 TI - Public health impact and cost effectiveness of routine childhood vaccination for hepatitis a in Jordan: a dynamic model approach. AB - BACKGROUND: As the socioeconomic conditions in Jordan have improved over recent decades the disease and economic burden of Hepatitis A has increased. The purpose of this study is to assess the potential health and economic impact of a two-dose hepatitis A vaccine program covering one-year old children in Jordan. METHODS: We adapted an age-structured population model of hepatitis A transmission dynamics to project the epidemiologic and economic impact of vaccinating one-year old children for 50 years in Jordan. The epidemiologic model was calibrated using local data on hepatitis A in Jordan. These data included seroprevalence and incidence data from the Jordan Ministry of Health as well as hospitalization data from King Abdullah University Hospital in Irbid, Jordan. We assumed 90% of all children would be vaccinated with the two-dose regimen by two years of age. The economic evaluation adopted a societal perspective and measured benefits using the quality-adjusted life-year (QALY). RESULTS: The modeled vaccination program reduced the incidence of hepatitis A in Jordan by 99%, 50 years after its introduction. The model projected 4.26 million avoided hepatitis A infections, 1.42 million outpatient visits, 22,475 hospitalizations, 508 fulminant cases, 95 liver transplants, and 76 deaths over a 50 year time horizon. In addition, we found, over a 50 year time horizon, the vaccination program would gain 37,502 QALYs and save over $42.6 million in total costs. The vaccination program became cost-saving within 6 years of its introduction and was highly cost-effective during the first 5 years. CONCLUSION: A vaccination program covering one-year old children is projected to be a cost-saving intervention that will significantly reduce the public health and economic burden of hepatitis A in Jordan. PMID- 29514610 TI - Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers. AB - BACKGROUND: CD73 is one of the critical component in the formation of immunosuppressive microenvironment in cancers. We aimed to provide an overview of the current status of CD73 expression and its relationship with clinicopathlogical features and prognosis in different cancers. METHODS: PubMed, Web of Science, EMBASE and Cochrane library were searched to identify the relevant studies. CD73 expression level in distinct cancers and its relationship with clinicopathlogical characteristics and prognosis were investigated using online database. Meta-analyses were conducted using RevMan v5.0 and STATA v12.0. RESULTS: Fourteen publications with 2951 cases were included. The incidence of high CD73 expression was 0.50 (95% CI: 0.36-0.63). Data from Oncomine validated that median CD73 expression level in tumor tissues was markedly higher than that in normal tissues in most kinds of cancers except cecum adenocarcinoma and ovarian cancer (P < 0.05). High CD73 expression was significantly correlated with shorter overall survival (OS) in various cancers (high risk [HR] = 1.48; P < 0.05). Subgroup analysis using online database demonstrated that high CD73 expression was significantly correlated with poor OS in breast (HR = 1.23; P < 0.05) and ovarian cancer (HR = 1.14; P < 0.05), but favorable OS in lung (HR = 0.80; P < 0.05) and gastric cancer (HR = 0.71; P < 0.05). High CD73 expression was dramatically associated with lymph node metastases (OR = 2.61; P = 0.05). CONCLUSION: High CD73 expression was significantly associated with lymph node metastases and a promising prognostic factor in different types of cancers. PMID- 29514611 TI - Prospective study of bilateral mix-and-match implantation of diffractive multifocal intraocular lenses in Koreans. AB - BACKGROUND: To evaluate monocular and binocular visual outcomes for near, intermediate, and far distance in patients implanted with diffractive multifocal intraocular lenses (IOLs) with different add power contralaterally. METHODS: This is a prospective contralateral study. Two diffractive multifocal IOLs with different added power were implanted bilaterally in twenty patients. TECNIS(r) ZKB00 (+ 2.75 D) was implanted in a dominant eye, and TECNIS(r) ZLB00 (+ 3.25 D) was implanted in a non-dominant eye. Uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), and manifest refraction (MR) values were measured at 1 month and 3 months postoperatively. At the 3-month follow-up, defocus curve, contrast sensitivity, and reading performance were evaluated. Quality of vision, overall satisfaction, and spectacle independence were evaluated by questionnaire. RESULTS: Postoperative binocular UDVA, visual acuity at 80 cm, 60 cm, 50 cm, 43 cm, 33 cm were - 0.08 +/- 0.10, 0.12 +/- 0.14, 0.09 +/- 0.09, 0.07 +/- 0.11, 0.14 +/- 0.09, 0.25 +/- 0.11 logMAR. The binocular defocus curve showed an extended range of good visual acuity with sharp vision being observed from 0 D to - 2.50 D defocus (logMAR<=0.1). Reading performance was significantly improved compared to baseline. All patients were spectacle-free at distance, and 94.74% of the patients did not require glasses for near and intermediate vision. CONCLUSIONS: Mix-and-match implantation of diffractive multifocal IOLs with different add power provides an excellent wide range of vision, as well as high levels of visual quality and patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02556944, https://clinicaltrials.gov/show/NCT02556944. PMID- 29514612 TI - Belimumab and low-doses of mycophenolate mofetil as induction therapy of class IV lupus nephritis: case series and literature review. AB - BACKGROUND: The treatment of Lupus Nephritis (LN) is an unmet need in the management of patients with Systemic Lupus Erythematosus (SLE). CASE PRESENTATION : We report two cases of women affected by Lupus Nephritis (LN) ISN/RNP Class IV with serological active disease, high disease activity and marked fatigue. In both cases, Mycophenolate mofetil (MMF), as induction therapy, was poorly tolerated because of gastrointestinal toxicity. Belimumab, together with low doses of MMF, was effective as induction treatment leading to early achievement of complete renal response in these two selected cases of LN. CONCLUSIONS: We also report a literature review concerning the efficacy and safety of Belimumab in Lupus Nephritis. Further studies are needed to evaluate the use of Belimumab to manage the renal involvement in patients with Systemic Lupus Erythematosus, waiting for the results of ongoing randomized clinical trials. PMID- 29514613 TI - Pragmatism in practice: lessons learned during screening and enrollment for a randomised controlled trial in rural northern Ethiopia. AB - BACKGROUND: We use the example of the Gojjam Lymphoedema Best Practice Trial (GoLBeT), a pragmatic trial in a remote rural setting in northern Ethiopia, to extract lessons relevant to other investigators balancing the demands of practicality and community acceptability with internal and external validity in clinical trials. METHODS: We explain in detail the preparation for the trial, its setting in northern Ethiopia, the identification and selection of patients (inclusion and exclusion criterion, identifying and screening of patients at home, enrollment of patients at the health centres and health posts), and randomisation. RESULTS: We describe the challenges met, together with strategies employed to overcome them. CONCLUSIONS: Examples given in the previous section are contextualised and general principles extracted where possible. We conclude that it is possible to conduct a trial that balances approaches that support internal validity (e.g. careful design of proformas, accurate case identification, control over data quality and high retention rates) with those that favour generalisability (e.g. 'real world' setting and low rates of exclusion). Strategies, such as Rapid Ethical Assessment, that increase researchers' understanding of the study setting and inclusion of hard-to-reach participants are likely to have resource and time implications, but are vital in achieving an appropriate balance. TRIAL REGISTRATION: ISRCTN67805210, registered 24/01/2013. PMID- 29514614 TI - Novel hemostatic biomolecules based on elastin-like polypeptides and the self assembling peptide RADA-16. AB - BACKGROUND: Safe and effective hemostatic materials are important for reducing mortality resulting from excessive hemorrhage. In this work, new biomaterials with hemostatic effects were created by fusing the gene coding for RADA-16, a self-assembling peptide with the sequence RADARADARADARADA, to the 3'-end of the open reading frame (ORF) encoding elastin-like polypeptides through gene recombination. RESULTS: The fusion proteins, termed 36R, 60R and 96R, were solubly over-expressed in Escherichia coli BL21 (DE3) based on genetic manipulation of the high-efficiency prokaryotic expression vector pET28a (+) and bacterial transformation. Western Blot analysis showed that the over-expressed proteins were the target fusion proteins. The target proteins 36R with 94.72% purity, 60R with 96.91% purity and 96R with 96.37% purity were prepared using an inverse phase transition cycle at 65 degrees C followed by His-tag affinity chromatography. The proliferation results of the mouse fibroblast cell line L929 and hippocampus neuron cell line HT22 indicated that the fusion proteins did not cause obvious cell toxicity. The lyophilized spongy film of the purified 36R, 60R and 96R could stop the hemorrhage of a 2 * 2 mm bleeding wound in the mouse liver after 27.21 +/- 1.92 s, 18.65 +/- 1.97 s and 15.85 +/- 1.21 s, respectively. The hemostasis time was 21.23 +/- 1.84 s for rat-tail collagen and 14.44 +/- 1.33 s for RADA-16 lyophilized on gauze. The hemostatic time of three treated groups were all significantly superior to that of the negative control without any hemostasis treatment, which spontaneously stopped bleeding after 37.64 +/- 1.34 s. Statistical analysis showed that the spongy film with purified 96R exhibited an exciting hemostatic effect that was superior to rat-tail collagen and close to that of RADA-16 lyophilized on gauze. CONCLUSIONS: These results revealed that the fusion proteins achieved by gene recombination technology could serve as a promising hemostatic material. PMID- 29514615 TI - Above chaos, quest, and restitution: narrative experiences of African immigrant youth's settlement in Canada. AB - BACKGROUND: African Immigrant and refugee youth represent an increasing group of newcomers in Canada. Upon their immigration, youth experience challenges that have the potential to lead to poor health, yet little is known about their settlement journey. Accordingly, this qualitative study examines the settlement journey of African immigrant and refugee youth with a focus on how their experiences were shaped by the social determinants of health. METHODS: We conducted a total of 70 interviews with 52 immigrant and refugee youth (ages 13 29 years) who had arrived in Canada in the preceding six years. Qualitative data was analyzed using Frank's dialogical narrative analysis approach (Frank AW, Practicing Dialogical Narrative Analysis. In: Varieties of Narrative Analysis, 2016). RESULTS: Youth experienced different settlement journeys that are described in the three narrative typologies of chaos, quest, and restitution. The chaos narrative of a long road ahead revealed the themes of 'facing challenges' and 'still the outsider.' The quest narrative of not there yet was represented by the themes of 'stepping out of your comfort zone' and 'being relentless.' The theme of 'supportive environments' depicted the restitution narrative of dreams become a reality. Youth highlighted the impact of social determinants of health in their settlement. CONCLUSION: Youth experienced different settlement journeys that were mired in chaos and challenges. However, youth were more likely to experience restitution when they received social support and found a sense of belonging. In future, policies and programs that seek to improve immigrant and refugee youth's settlement experiences need to be multifaceted, offer more support and promote a sense of belonging. PMID- 29514616 TI - Self-care of chronic musculoskeletal pain - experiences and attitudes of patients and health care providers. AB - BACKGROUND: Self-care is often the first choice for people with chronic musculoskeletal pain. Self-care includes the use of non-prescription medications with no doctor's supervision, as well as the use of other modern and traditional treatment methods with no consultation of the health care provider. Self-care may have positive effects on the successful outcome of a multidisciplinary approach to treatment. The aim of this study was to investigate the experiences and attitudes of patients and health care providers to the self-care of chronic musculoskeletal pain. METHODS: Qualitative Phenomenological study, where the data were collected by the method of an audio-taped interview in 15 patients at the outpatient clinic for pain management and in 20 health care providers involved in the treatment of those patients. The interviews were transcribed verbatim and analyzed by principles of Interpretative Thematic Analysis. RESULTS: Topics identified in patients: a) positive aspects of self-care, b) a need for pain self care, c) social aspects of pain self-care. Topics identified in health care providers: a) aspects of self-care, b) a need for self-care c) risks of self care. Most of patients have positive attitude to self-care and this is the first step to pain management and to care for itself. The most frequent factors influencing decision about the self-care are heavy pain, unavailability of the doctor, long awaiting time for the therapy, or ineffectiveness of methods of conventional medicine. The health care providers believe that self-care of chronic musculoskeletal pain may be a patient's contribution to clinical treatment. However, good awareness of methods used is important in this context, to avoid adverse effects of self-care. CONCLUSION: Patients understand the self care of musculoskeletal pain as an individually adjusted treatment and believe in its effectiveness. Health care providers support self-care as an adjunction to clinical management only, and think that self-care of musculoskeletal pain acts as a placebo, with a short-lived effect on chronic musculoskeletal pain. PMID- 29514617 TI - Could pelvic parameters determine optimal postoperative thoracic kyphosis in Lenke type 1 AIS patients? AB - BACKGROUND: A proper restoration of sagittal alignment is essential in AIS patients, but few studies provided a formula to predict an optimal surgical thoracic kyphosis (TK) gain in adolescent idiopathic scoliosis (AIS) patients. A formula was recently proposed (LL = (PI+TK)/2 + 10) to predict the optimal lumbar lordosis (LL) in adult spinal deformity patients, which has not been validated in adolescents. The aim of this study is to establish a formula with TK and pelvic parameters in normal adolescents and predict an optimal TK with this formula pre- and post-operatively in Lenke 1 AIS patients. METHODS: A total of 60 asymptomatic adolescents were used to validate the proposed formula. The subject was considered to match with the formula, if the difference between the virtual TK and the theoretical TK was less than 10 degrees . Then regression analysis was performed to establish a new formula to predict TK in adolescents. The predictive efficiency of the new formula was also validated in 40 Lenke 1 AIS patients. RESULTS: Of the 60 asymptomatic adolescents, only 26 (43.33%) asymptomatic adolescents matched with the adjusted formula: TK = 2 * (LL-10)-PI. The paired t test revealed a significantly different theoretical TK (tTK) compared to the virtual TK (41.23 +/- 18.29 degrees vs. 24.80 +/- 8.75 degrees , P < 0.001). Multiple linear regression showed that TK had a relationship with LL, SS and age (R2 = 0.331): TK = - 0.785 * LL-0.843 * SS + 0.858 * age + 3.754. There were 27 (67.50%), 32 (80.00%) and 35 (87.50%) Lenke 1 AIS patients matched this formula preoperatively, postoperatively and at the last follow-up. CONCLUSION: Our results revealed that the predictive formula for sagittal alignment for adults was not applicable in adolescents. This study established a new predictive formula for TK based on asymptomatic adolescents. In Lenke 1 AIS patients, post op TK in 87.5% of patients matched the predictive value, indicating that the new formula can be considered as a reference when making a surgery strategy. PMID- 29514618 TI - Early-career researchers' views on ethical dimensions of patient engagement in research. AB - BACKGROUND: Increasing attention and efforts are being put towards engaging patients in health research, and some have even argued that patient engagement in research (PER) is an ethical imperative. Yet there is relatively little empirical data on ethical issues associated with PER. METHODS: A three-round Delphi survey was conducted with a panel of early-career researchers (ECRs) involved in PER. One of the objectives was to examine the ethical dimensions of PER as well as ECRs' self-perceived level of preparedness to conduct PER ethically. The study was conducted among awardees of the Quebec SPOR-SUPPORT Unit in Canada, who represent the next generation of researchers involved in PER. Many themes were addressed throughout the study, such as definition, values, patients' roles, expected characteristics of patients, and anticipated challenges (including ethical issues). Open-ended questions were used, and all quantitative data were collected through statements using 7-point Likert scales. RESULTS: Between April and November 2016, 25 ECRs were invited to participate; 18 completed both the first and second rounds, and 16 completed the third round. Panelists consisted of nine women and seven men with various backgrounds (general practitioners and postgraduate students). The majority were between 25 and 44 years old. Panelists' responses showed PER raises important ethical issues: 1) professionalization of patients involved in research (with risks of patients becoming less representative); 2) adequate remuneration of patients; 3) fair recognition of patients' experiential knowledge; and 4) tokenism (engaging patients only for symbolic appeal). While the panelists felt moderately prepared to confront these ethical issues, they reported being uncomfortable applying for an ethics certificate for a PER project. CONCLUSION: If PER is an ethical imperative, it is vital to establish clear ethical standards and to train and support the PER community to identify and resolve ethical issues. Despite their overall readiness to conduct PER, panelists did not feel adequately prepared to address many of these issues. It is not easy for ECRs to reconcile ethical desiderata and logistical imperatives. Additional research should focus on supporting the responsible conduct of PER, which, if not done, can undermine the credibility and feasibility of the entire PER enterprise. PMID- 29514619 TI - Drug use prevention: factors associated with program implementation in Brazilian urban schools. AB - BACKGROUND: A school is a learning environment that contributes to the construction of personal values, beliefs, habits and lifestyles, provide convenient settings for the implementation of drug use prevention programs targeting adolescents, who are the population group at highest risk of initiating drug use. The objective of the present study was to investigate the prevalence of factors associated with implementing drug use prevention programs in Brazilian public and private middle and high urban schools. METHODS: The present population based cross-sectional survey was conducted with a probability sample of 1151 school administrators stratified by the 5 Brazilian administrative divisions, in 2014. A close-ended, self-reported online questionnaire was used. Logistic regression analysis was used to identify factors associated with implementing drug use prevention programs in schools. RESULTS: A total of 51.1% of the schools had adopted drug use prevention programs. The factors associated with program implementation were as follows: belonging to the public school network; having a library; development of activities targeting sexuality; development of "Health at School Program" activities; offering extracurricular activities; and having an administrator that participated in training courses on drugs. CONCLUSIONS: The adoption of drug use prevention practices in Brazilian schools may be expanded with greater orchestration of schools through specialized training of administrators and teachers, expansion of the School Health Program and concomitant development of the schools' structural and curricular attributes. PMID- 29514620 TI - Palliative care in the home: a scoping review of study quality, primary outcomes, and thematic component analysis. AB - BACKGROUND: The aim of palliative care is to improve the quality of life of patients and families through the prevention and relief of suffering. Frequently, patients may choose to receive palliative care in the home. The objective of this paper is to summarize the quality and primary outcomes measured within the palliative care in the home literature. This will synthesize the current state of the literature and inform future work. METHODS: A scoping review was completed using PRISMA guidelines. PubMed, Embase, CINAHL, Web of Science, Cochrane Library, EconLit, PsycINFO, Centre for Reviews and Dissemination, Database of Abstracts of Reviews of Effects, and National Health Service Economic Evaluation Database were searched from inception to August 2016. Inclusion criteria included: 1) care was provided in the "home of the patient" as defined by the study, 2) outcomes were reported, and 3) reported original data. Thematic component analysis was completed to categorize interventions. RESULTS: Fifty three studies formed the final data set. The literature varied extensively. Five themes were identified: accessibility of healthcare, caregiver support, individualized patient centered care, multidisciplinary care provision, and quality improvement. Primary outcomes were resource use, symptom burden, quality of life, satisfaction, caregiver distress, place of death, cost analysis, or described experiences. The majority of studies were of moderate or unclear quality. CONCLUSIONS: There is robust literature of varying quality, assessing different components of palliative care in the home interventions, and measuring different outcomes. To be meaningful to patients, these interventions need to be consistently evaluated with outcomes that matter to patients. Future research could focus on reaching a consensus for outcomes to evaluate palliative care in the home interventions. PMID- 29514621 TI - A predictive model of thyroid malignancy using clinical, biochemical and sonographic parameters for patients in a multi-center setting. AB - BACKGROUND: Thyroid nodules are highly prevalent, but a robust, feasible method for malignancy differentiation has not yet been well documented. This study aimed to establish a practical model for thyroid nodule discrimination. METHODS: Records for 2984 patients who underwent thyroidectomy were analyzed. Clinical, laboratory, and US variables were assessed retrospectively. Multivariate logistic regression analysis was performed and a mathematical model was established for malignancy prediction. RESULTS: The results showed that the malignant group was younger and had smaller nodules than the benign group (43.5 +/- 11.6 vs. 48.5 +/- 11.5 y, p < 0.001; 1.96 +/- 1.16 vs. 2.75 +/- 1.70 cm, p < 0.001, respectively). The serum thyrotropin (TSH) level (median = 1.63 mIU/L, IQR (0.89-2.66) vs. 1.19 (0.59-2.10), p < 0.001) was higher in the malignant group than in the benign group. Patients with malignancies tested positive for anti-thyroglobulin antibody (TGAb) and anti-thyroid peroxidase antibody (TPOAb) more frequently than those with benign nodules (TGAb, 30.3% vs. 15.0%, p < 0.001; TPOAb, 25.6% vs. 18.0%, p = 0.028). The prevalence of ultrasound (US) features (irregular shape, ill defined margin, solid structure, hypoechogenicity, microcalcifications, macrocalcifications and central intranodular flow) was significantly higher in the malignant group. Multivariate logistic regression analysis confirmed that age (OR = 0.963, 95% CI = 0.934-0.993, p = 0.017), TGAb (OR = 4.435, 95% CI = 1.902 10.345, p = 0.001), hypoechogenicity (OR = 2.830, 95% CI = 1.113-7.195, p = 0.029), microcalcifications (OR = 4.624, 95% CI = 2.008-10.646, p < 0.001), and central intranodular flow (OR = 2.155, 95% CI = 1.011-4.594, p < 0.05) were independent predictors of thyroid malignancy. A predictive model including four variables (age, TGAb, hypoechogenicity and microcalcification) showed an optimal discriminatory accuracy (area under the curve, AUC) of 0.808 (95% CI = 0.761 0.855). The best cut-off value for prediction was 0.52, achieving sensitivity and specificity of 84.6% and 76.3%, respectively. CONCLUSION: A predictive model of malignancy that combines clinical, laboratory and sonographic characteristics would aid clinicians in avoiding unnecessary procedures and making better clinical decisions. PMID- 29514622 TI - Quantitative MRI comparison of multifidus muscle degeneration in thoracolumbar fractures treated with open and minimally invasive approach. AB - BACKGROUND: Minimally invasive pedicle screw fixation has less approach-related morbidity than open screw placement and is allegedly less traumatizing on paravertebral muscles, as there is no requirement to mobilize and retract the adjacent muscle portion. The approach-related long-term effects to the morphology of the paravertebral muscles are unknown. The purpose of this study was to compare the long-term amount of fatty degeneration of the multifidus muscle in patients treated with a classical open or a minimally invasive approach. METHODS: Fourteen Patients meeting inclusion criteria were selected. In all patients a singular fracture of the thoracolumbar spine with a two-level posterior instrumentation was treated, either using an open approach or a minimally invasive approach. All patients underwent quantitative MRI spectroscopy for quantification of the fatty degeneration in the multifidus muscle as a long-term proof for muscle loss after minimum 4-year follow-up. Clinical outcome was assessed using Oswestry Low Back Pain Disability Questionnaire, SF-36 and VA scale for pain. RESULTS: The minimally invasive approach group failed to show less muscle degeneration in comparison to the open group. Total amount of fatty degeneration was 14.22% in the MIS group and 12.60% in the open group (p = 0.64). In accordance to MRI quantitative results there was no difference in the clinical outcome after a mean follow up of 5.9 years (+/-1.8). CONCLUSION: As short-term advantages of minimal invasive screw placement have been widely demonstrated, no advantage of the MIS, displaying a significant difference in the amount of fatty degeneration and resulting in a better clinical outcome could be found. Besides the well-known short-term advantage of minimally invasive pedicle screw placement, a long-term advantage, such as less muscle degeneration and thus superior clinical results, compared to the open approach could not be shown. PMID- 29514623 TI - Association of urinary sodium excretion with blood pressure and risk factors associated with hypertension among Cameroonian pygmies and bantus: a cross sectional study. AB - BACKGROUND: High salt intake increases blood pressure (BP) and hypertension risk. This study aimed to examine association of urinary sodium excretion with BP and hypertension correlates among Cameroonian pygmies under hunter-gatherer subsistence mode and Bantus, living in urban area under unhealthy behavioral habits. METHODS: In this cross-sectional cluster sampling study, we randomly enrolled rural pygmies living in Lolodorf and urban Bantus living in Douala. The World Health Organization steps questionnaire was used to collect socio demographic and lifestyle data. Height, weight, BP and single overnight spot urine samples were obtained in all participants. BP was measured in triplicate. Urinary sodium and potassium excretion was determined by flame photometry. Data were recorded and analyzed using SPSS 16.0. RESULTS: We included 150 Pygmies and 150 Bantus aged 38 +/- 12 years and 33 +/- 11 years, respectively (p < 0.0001). Compare to Bantus, pygmy's height and weight were respectively: 1.54 +/- 0.09 m vs 1.72 +/- 0.12 m; and 54.4 +/- 9.2 kg vs 77.2 +/- 14.8 kg, all p < 0.0001. Age standardized prevalence of hypertension was 3.3% among Pygmies and 28% among Bantus (p < 0.0001). Age-adjusted systolic and diastolic BP were lower in Pygmies than in Bantus (107 +/- 12 vs 119 +/- 17 mmHg and 71 +/- 11 vs 78 +/- 13 mmHg respectively, all P < 0.0001). BP increased with age but to a lesser extent in Pygmies (all p < 0.01). Urinary sodium excretion was lower in Pygmies than in Bantus (46.9 +/- 32.4 vs 121.5 +/- 61.0 mmol/l, p < 0.0001). Systolic and diastolic BP were positively associated with urinary sodium excretion in Bantus (all p < 0.05). In the two groups, urinary potassium excretion was similar, and was not related to blood pressure. In the total study group and in Bantus taken separately, urinary sodium excretion was higher in hypertensive than in normotensive subjects. Multivariable logistic regression showed that urinary sodium excretion, Bantu status and age emerged as independent determinants of hypertension in the whole study group (OR (95%CI): 1.012 (1.005-1.018); 11.408 (3.599-36.165); 1.095 (1.057-1.135) respectively, p < 0.0001). CONCLUSION: Hunter-gatherer pygmies exhibit low level of urinary sodium excretion related to low rate of hypertension and slower BP increase with age. Salt intake was a major driver of hypertension in our study population. Our findings highlight the need of efforts to implement nationwide prevention programs promoting risk factor screening and healthier lifestyles including reduction of dietary salt intake in Cameroonian. PMID- 29514624 TI - Lack of genetic susceptibility in takotsubo cardiomyopathy: a case-control study. AB - BACKGROUND: Takotsubo cardiomyopathy (TCM), also known as "broken heart syndrome", is a type of heart failure characterized by transient ventricular dysfunction in the absence of obstructive coronary lesions. Although associated with increased levels of catecholamines, pathophysiological mechanisms are unknown. Relapses and family heritability indicate a genetic predisposition. Several small studies have investigated associations between three different loci; the beta1-adrenic receptor (ADRB1), G-protein-coupled receptor kinase 5 (GRK5), Bcl-associated athanogene 3 (BAG3) and TCM but no consensus has been reached. METHODS: Participants were recruited using the Swedish Coronary Angiography and Angioplasty Register (SCAAR). TCM patients without coronary artery disease (CAD)(n = 258) were identified and age- and sex-matched subjects with (n = 164) and without (n = 243) CAD were selected as controls. DNA was isolated from saliva and genotyped for candidate single nucleotide polymorphisms in the ADRB1, GRK5 and BAG3 genes. Allele frequencies and Odds Ratios (OR) with 95% Confidence Intervals (CI) for the investigated polymorphisms were compared, respectively calculated for TCM patients and controls. RESULTS: There were no differences in allele frequencies between TCM patients and controls. OR (CI) for TCM patients having at least one minor allele using controls as reference were 1.07 (0.75-1.55) for ADRB1, 0.45 (0.11-1.85) for GRK5 and 1.27 (0.74-2.19) for BAG3. CONCLUSION: By genotyping a large takotsubo cohort, we demonstrate a lack of association between candidate SNPs in the ADRB1, GRK5 and BAG3 genes, earlier suggested to contribute to TCM. Our result indicates a need to expand the search for new genetic candidates contributing to TCM. PMID- 29514625 TI - Palliative care in the emergency department: an educational investigation and intervention. AB - BACKGROUND: To investigate the value of a novel simulation-based palliative care educational intervention within an emergency medicine (EM) residency curriculum. METHODS: A palliative care scenario was designed and implemented in the simulation program at an urban academic emergency department (ED) with a 3-year EM residency program. EM residents attended one of eight high-fidelity simulation sessions, in groups of 5-6. A standardized participant portrayed the patient's family member. One resident from each session managed the scenario while the others observed. A 45-min debriefing session and small group discussion followed the scenario, facilitated by an EM simulation faculty member and a resident investigator. Best practices in palliative care were highlighted along with focused learner performance feedback. Participants completed an anonymous pre/post education intervention survey. RESULTS: Forty of 42 EM residents (95%) participated in the study. Confidence in implementing palliative care skills and perceived importance of palliative care improved after this educational intervention. Specifically, residents 1) felt EM physicians had an important role in palliative care, 2) had increased confidence in the ability to determine patient decision-making capacity, 3) had improved confidence in initiating palliative discussions/treatment, 4) believed palliative education was important in residency, and 5) felt simulation was an effective means to learn palliative care. Differences noted between PGY1 and PGY 3 training levels in survey responses disappeared post-intervention. Residents noted being most comfortable with delivering bad news and symptom management and least comfortable with disease prognostication. Residents reported time constraints and implementation logistics in the ED as the most challenging factors for palliative care initiation. CONCLUSION: Our case-based simulation intervention was associated with an increase in both the perceived importance of ED palliative care and self reported confidence in implementing palliative care skills. Time constraints and implementation logistics were rated as the most challenging factors for palliative care initiation in the ED. PMID- 29514626 TI - An information-theoretic approach to the modeling and analysis of whole-genome bisulfite sequencing data. AB - BACKGROUND: DNA methylation is a stable form of epigenetic memory used by cells to control gene expression. Whole genome bisulfite sequencing (WGBS) has emerged as a gold-standard experimental technique for studying DNA methylation by producing high resolution genome-wide methylation profiles. Statistical modeling and analysis is employed to computationally extract and quantify information from these profiles in an effort to identify regions of the genome that demonstrate crucial or aberrant epigenetic behavior. However, the performance of most currently available methods for methylation analysis is hampered by their inability to directly account for statistical dependencies between neighboring methylation sites, thus ignoring significant information available in WGBS reads. RESULTS: We present a powerful information-theoretic approach for genome-wide modeling and analysis of WGBS data based on the 1D Ising model of statistical physics. This approach takes into account correlations in methylation by utilizing a joint probability model that encapsulates all information available in WGBS methylation reads and produces accurate results even when applied on single WGBS samples with low coverage. Using the Shannon entropy, our approach provides a rigorous quantification of methylation stochasticity in individual WGBS samples genome-wide. Furthermore, it utilizes the Jensen-Shannon distance to evaluate differences in methylation distributions between a test and a reference sample. Differential performance assessment using simulated and real human lung normal/cancer data demonstrate a clear superiority of our approach over DSS, a recently proposed method for WGBS data analysis. Critically, these results demonstrate that marginal methods become statistically invalid when correlations are present in the data. CONCLUSIONS: This contribution demonstrates clear benefits and the necessity of modeling joint probability distributions of methylation using the 1D Ising model of statistical physics and of quantifying methylation stochasticity using concepts from information theory. By employing this methodology, substantial improvement of DNA methylation analysis can be achieved by effectively taking into account the massive amount of statistical information available in WGBS data, which is largely ignored by existing methods. PMID- 29514627 TI - A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis congenita in a Chinese Han family. AB - BACKGROUND: Dyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. Cells from patients with DC exhibit short telomere. The genetic basis of the majority of DC cases remains unknown. METHODS: A 2 generational Chinese Han family with DC was studied using targeted capture and next-generation sequencing to identify the underlying DC related mutations. RESULTS: In this study, we identified a unique homozygous WD repeat containing antisense to TP53 (WRAP53) Arg298Trp mutation in the proband with DC and heterozygous WRAP53 Arg298Trp mutations in his asymptomatic, consanguineous parents and his sister, indicating an autosomal recessive inheritance mode. The proband with the homozygous WRAP53 Arg298Trp mutation had short telomere, classic clinical symptoms, and no response to danazol, glucocorticoid or cyclosporin A. CONCLUSIONS: Thus, we reported for the first time that a unique homozygous WRAP53 mutation site underlies the development of DC. PMID- 29514628 TI - Toxicity of Crepis lacera in grazing ruminants. AB - BACKGROUND: Crepis lacera is a plant from the Asteraceae family that is common in the Mediterranean region. Farmers believe that this plant may be deadly to small ruminants in areas of southern Italy. However, scientific evidence is lacking, and no proof exists that C. lacera is toxic to ruminants. Necropsies conducted on four sheep revealed lesions in their livers and kidneys. RESULTS: In the current study, we described sheep poisoning and isolated secondary metabolites from Crepis lacera to assess the metabolites' biological activity both in vitro and in vivo. Phytochemical study of the aerial portions of Crepis lacera led to the isolation of five sesquiterpene lactones and two phenolic compounds. Cellular viability was evaluated in cell cultures of the bovine kidney cell line Madin Darby Bovine Kidney (MDBK) after incubation with phytochemicals. Our results showed that three sesquiterpene lactones, 8-epidesacylcynaropicrin-3-O-beta glucopyranoside (2), 8-epigrosheimin (3), and 8-beta-hydroxydehydrozaluzanin C (4), were cytotoxic after 48 h of incubation. In addition, in the in vivo study, animals that received 1 mg/kg body weight (bw) of Crepis lacera extract and were then sacrificed after 48 h showed significant lesions in their liver, lungs and kidneys. These lesions were also found in rats that received 2 mg/kg bw of the same extract and sacrificed after 24 and 48 h. CONCLUSIONS: These results validate the hypothesis that C. lacera is potentially dangerous when ingested in large quantities by grazing small domestic ruminants. Further studies are necessary to clarify the molecular mechanisms of Crepis spp. toxicity in animals. PMID- 29514629 TI - The determinants of individual health care expenditures in prison: evidence from Switzerland. AB - BACKGROUND: Prison health systems are subject to increasing pressures given the specific health needs of a growing and aging prison population. Identifying the drivers of medical spending among incarcerated individuals is therefore key for health care governance in prisons. This study assesses the determinants of individual health care expenditures within the prisons of the canton of Vaud, a large region of Switzerland. METHODS: We use a unique dataset linking demographic and prison stay characteristics as well as objective measures of morbidity to detailed medical invoice data. We adopt a multivariate regression approach to model total, somatic and psychiatric outpatient health care expenditures. RESULTS: We find that chronic infectious, musculoskeletal and skin diseases are strong predictors of total and somatic costs. Schizophrenia, neurotic and personality disorders as well as the abuse of illicit drugs and pharmaceuticals drive total and psychiatric costs. Furthermore, cumulating psychiatric and somatic comorbidities has an incremental effect on costs. CONCLUSION: By identifying the characteristics associated with health care expenditures in prison, this study constitutes a key step towards a more efficient use of medical resources in prison. PMID- 29514630 TI - Polyphenols of Salix aegyptiaca modulate the activities of drug metabolizing and antioxidant enzymes, and level of lipid peroxidation. AB - BACKGROUND: Salix aegyptiaca is known for its medicinal properties mainly due to the presence of salicylate compounds. However, it also contains other beneficial phytochemicals such as gallic acid, quercetin, rutin and vanillin. The aim of the study was to examine the redox potential, antioxidant and anti-inflammatory activity of these phytochemicals along with acetylsalicylic acid. METHODS: The redox potential and antioxidant activity of gallic acid, quercetin, rutin, vanillin and acetylsalicylic acid were determined by oxidation-reduction potential electrode method and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, respectively. In ex vivo studies, antioxidant activity of these phytochemicals was determined by lipid peroxidation and carbonyl content assay in the liver of mice. Anti-inflammatory activity was determined by protein denaturation method. Six-week old C57BL/6 mice treated with gallic acid (100 mg/kg body weight) and acetylsalicylic acid (25 and 50 mg/kg body weight) to investigate their in vivo modulatory effects on the specific activities of drug metabolizing phase I and phase II enzymes, antioxidant enzymes and level of lipid peroxidation in liver. RESULTS: The order of ability to donate electron and antioxidant activity was found to be: gallic acid > quercetin > rutin > vanillin > acetylsalicylic acid. In ex vivo studies, the similar pattern and magnitude of inhibitory effects of these phytochemicals against peroxidative damage in microsomes and protein carbonyl in cytosolic fraction were observed. In in vivo studies, gallic acid and acetylsalicylic acid alone or in combination, enhanced the specific activities of drug metabolizing phase I and phase II enzymes as well as antioxidant enzymes and also inhibited lipid peroxidation in liver. CONCLUSIONS: These findings show a close link between the electron donation and antioxidation potential of these phytochemicals, and in turn their biological activity. Gallic acid, quercetin, rutin and vanillin were found to be better electron donors and antioxidants and therefore, might be mainly responsible for the antioxidant properties of S. aegyptiaca, while acetylsalicylic acid provided its maximum anti-inflammatory activity. PMID- 29514631 TI - How can healthcare organizations implement patient-centered care? Examining a large-scale cultural transformation. AB - BACKGROUND: Healthcare organizations increasingly are focused on providing care which is patient-centered rather than disease-focused. Yet little is known about how best to transform the culture of care in these organizations. We sought to understand key organizational factors for implementing patient-centered care cultural transformation through an examination of efforts in the US Department of Veterans Affairs. METHODS: We conducted multi-day site visits at four US Department of Veterans Affairs medical centers designated as leaders in providing patient-centered care. We conducted qualitative semi-structured interviews with 108 employees (22 senior leaders, 42 middle managers, 37 front-line providers and 7 staff). Transcripts of audio recordings were analyzed using a priori codes based on the Consolidated Framework for Implementation Research. We used constant comparison analysis to synthesize codes into meaningful domains. RESULTS: Sites described actions taken to foster patient-centered care in seven domains: 1) leadership; 2) patient and family engagement; 3) staff engagement; 4) focus on innovations; 5) alignment of staff roles and priorities; 6) organizational structures and processes; 7) environment of care. Within each domain, we identified multi-faceted strategies for implementing change. These included efforts by all levels of organizational leaders who modeled patient-centered care in their interactions and fostered willingness to try novel approaches to care amongst staff. Alignment and integration of patient centered care within the organization, particularly surrounding roles, priorities and bureaucratic rules, remained major challenges. CONCLUSIONS: Transforming healthcare systems to focus on patient-centered care and better serve the "whole" patient is a complex endeavor. Efforts to transform healthcare culture require robust, multi-pronged efforts at all levels of the organization; leadership is only the beginning. Challenges remain for incorporating patient-centered approaches in the context of competing priorities and regulations. Through actions within each of the domains, organizations may begin to truly transform to patient-driven care. PMID- 29514632 TI - Effects of a new medical insurance payment system for hospice patients in palliative care programs in Korea. AB - BACKGROUND: This study investigates the effects of a new medical insurance payment system for hospice patients in palliative care programs and analyzes length of survival (LoS) determinants. METHOD: At the Pusan National University Hospital hospice center, between January 2015 and April 2016, 276 patients were hospitalized with several diagnosed types of terminal stage cancer. This study separated patients into two groups, "old" and "new," by admission date, considering the new system has been applied from July 15, 2015. The study subsequently compared LoS, total cost, and out-of-pocket expenses for the two groups. RESULTS: Overall, 142 patients applied to the new medical insurance payment system group, while the old medical insurance payment system included 134 patients. The results do not show a significantly negative difference in LoS for the new system group (p = 0.054). Total cost is higher within the new group (p < 0.001); however, the new system registers lower patient out-of-pocket expenses (p < 0.001). CONCLUSION: The novelty of this study is proving that the new medical insurance payment system is not inferior to the classic one in terms of LoS. The total cost of the new system increased due to a multidisciplinary approach toward palliative care. However, out-of-pocket expenses for patients overall decreased, easing their financial burden. PMID- 29514633 TI - A latent growth curve model to estimate electronic screen use patterns amongst adolescents aged 10 to 17 years. AB - BACKGROUND: High quality, longitudinal data describing young people's screen use across a number of distinct forms of screen activity is missing from the literature. This study tracked multiple screen use activities (passive screen use, gaming, social networking, web searching) amongst 10- to 17-year-old adolescents across 24 months. METHODS: This study tracked the screen use of 1948 Australian students in Grade 5 (n = 636), Grade 7 (n = 672), and Grade 9 (n = 640) for 24 months. At approximately six-month intervals, students reported their total screen time as well as time spent on social networking, passive screen use, gaming, and web use. Patterns of screen use were determined using latent growth curve modelling. RESULTS: In the Grades 7 and 9 cohorts, girls generally reported more screen use than boys (by approximately one hour a day), though all cohorts of boys reported more gaming. The different forms of screen use were remarkably stable, though specific cohorts showed change for certain forms of screen activity. CONCLUSION: These results highlight the diverse nature of adolescent screen use and emphasise the need to consider both grade and sex in future research and policy. PMID- 29514635 TI - Patient data and patient rights: Swiss healthcare stakeholders' ethical awareness regarding large patient data sets - a qualitative study. AB - BACKGROUND: There is a growing interest in aggregating more biomedical and patient data into large health data sets for research and public benefits. However, collecting and processing patient data raises new ethical issues regarding patient's rights, social justice and trust in public institutions. The aim of this empirical study is to gain an in-depth understanding of the awareness of possible ethical risks and corresponding obligations among those who are involved in projects using patient data, i.e. healthcare professionals, regulators and policy makers. METHODS: We used a qualitative design to examine Swiss healthcare stakeholders' experiences and perceptions of ethical challenges with regard to patient data in real-life settings where clinical registries are sponsored, created and/or used. A semi-structured interview was carried out with 22 participants (11 physicians, 7 policy-makers, 4 ethical committee members) between July 2014 and January 2015. The interviews were audio-recorded, transcribed, coded and analysed using a thematic method derived from Grounded Theory. RESULTS: All interviewees were concerned as a matter of priority with the needs of legal and operating norms for the collection and use of data, whereas less interest was shown in issues regarding patient agency, the need for reciprocity, and shared governance in the management and use of clinical registries' patient data. This observed asymmetry highlights a possible tension between public and research interests on the one hand, and the recognition of patients' rights and citizens' involvement on the other. CONCLUSIONS: The advocation of further health-related data sharing on the grounds of research and public interest, without due regard for the perspective of patients and donors, could run the risk of fostering distrust towards healthcare data collections. Ultimately, this could diminish the expected social benefits. However, rather than setting patient rights against public interest, new ethical approaches could strengthen both concurrently. On a normative level, this study thus provides material from which to develop further ethical reflection towards a more cooperative approach involving patients and citizens in the governance of their health-related big data. PMID- 29514636 TI - Outcome of elderly emergency department patients hospitalised on weekends - a retrospective cohort study. AB - BACKGROUND: Studies investigating different medical conditions and settings have demonstrated mixed results regarding the weekend effect. However, data on the outcome of elderly patients hospitalised on weekends is scarce. The objective was to compare in-hospital and two-day mortality rates between elderly emergency department (ED) patients (>=65 years) admitted on weekends versus weekdays. METHODS: A retrospective cohort study of emergency department visits of internal medicine patients >=65 years presenting to the emergency department between 01 and 09-2010 and 31-08-2012 was conducted. The weekend was defined as the period from midnight on Friday to midnight on Sunday. RESULTS: Data on 3697 emergency department visits by elderly internal medicine patients (mean age 78.6 years old) were included. In total, 2743 emergency department visits (74.2%) resulted in hospitalisation, of which 22.9% occurred on weekends. Comorbidity and urgency levels were higher in patients admitted on weekends. In-hospital mortality was 11.4% for patients admitted on weekends compared with 8.9% on weekdays (OR 1.3, 95%CI 0.99-1.8). Two-day mortality was 3.2% in patients hospitalised on weekends versus 1.9% on weekdays (OR 1.7, 95%CI 0.99-2.9). Multivariable adjustment for age, comorbidity and triage level demonstrated comparable in-hospital and two-day mortality for weekend and week admission (ORadj 1.2, 95%CI 0.9-1.7 and ORadj 1.5, 95%CI 0.8-2.6, resp.). CONCLUSION: A small weekend effect was observed in elderly internal medicine patients, which was not statistically significant. This effect was partly explained by a higher comorbidity and urgency level in elderly patients hospitalised on weekends than during weekdays. Emergency care for the elderly is not compromised by adjusted logistics during the weekend. PMID- 29514634 TI - Multi-tissue transcriptomic study reveals the main role of liver in the chicken adaptive response to a switch in dietary energy source through the transcriptional regulation of lipogenesis. AB - BACKGROUND: Because the cost of cereals is unstable and represents a large part of production charges for meat-type chicken, there is an urge to formulate alternative diets from more cost-effective feedstuff. We have recently shown that meat-type chicken source is prone to adapt to dietary starch substitution with fat and fiber. The aim of this study was to better understand the molecular mechanisms of this adaptation to changes in dietary energy sources through the fine characterization of transcriptomic changes occurring in three major metabolic tissues - liver, adipose tissue and muscle - as well as in circulating blood cells. RESULTS: We revealed the fine-tuned regulation of many hepatic genes encoding key enzymes driving glycogenesis and de novo fatty acid synthesis pathways and of some genes participating in oxidation. Among the genes expressed upon consumption of a high-fat, high-fiber diet, we highlighted CPT1A, which encodes a key enzyme in the regulation of fatty acid oxidation. Conversely, the repression of lipogenic genes by the high-fat diet was clearly associated with the down-regulation of SREBF1 transcripts but was not associated with the transcript regulation of MLXIPL and NR1H3, which are both transcription factors. This result suggests a pivotal role for SREBF1 in lipogenesis regulation in response to a decrease in dietary starch and an increase in dietary PUFA. Other prospective regulators of de novo hepatic lipogenesis were suggested, such as PPARD, JUN, TADA2A and KAT2B, the last two genes belonging to the lysine acetyl transferase (KAT) complex family regulating histone and non-histone protein acetylation. Hepatic glycogenic genes were also down-regulated in chickens fed a high-fat, high-fiber diet compared to those in chickens fed a starch-based diet. No significant dietary-associated variations in gene expression profiles was observed in the other studied tissues, suggesting that the liver mainly contributed to the adaptation of birds to changes in energy source and nutrients in their diets, at least at the transcriptional level. Moreover, we showed that PUFA deposition observed in the different tissues may not rely on transcriptional changes. CONCLUSION: We showed the major role of the liver, at the gene expression level, in the adaptive response of chicken to dietary starch substitution with fat and fiber. PMID- 29514637 TI - Time utilization and perceived psychosocial work environment among staff in Swedish primary care settings. AB - BACKGROUND: Over the past decades, reorganizations and structural changes in Swedish primary care have affected time utilization among health care professionals. Consequently, increases in administrative tasks have substantially reduced the time available for face-to-face consultations. This study examined how work-time was utilized and the association between work time utilization and the perceived psychosocial work environment in Swedish primary care settings. METHODS: This descriptive, multicentre, cross-sectional study was performed in 2014-2015. Data collection began with questionnaire. In the first section, respondents were asked to estimate how their workload was distributed between patients (direct and indirect patient work) and other work tasks. The questionnaire also comprised the Copenhagen Psychosocial Questionnaire, which assessed the psychosocial work environment. Next a time study was conducted where the participants reported their work-time based on three main categories: direct patient-related work, indirect patient-related work, and other work tasks. Each main category had a number of subcategories. The participants recorded the time spent (minutes) on each work task per hour, every day, for two separate weeks. Eleven primary care centres located in southeast Sweden participated. All professionals were asked to participate (n = 441), including registered nurses, primary care physicians, care administrators, nurse assistants, and allied professionals. Response rates were 75% and 79% for the questionnaires and the time study, respectively. RESULTS: All health professionals allocated between 30.9% - 37.2% of their work-time to each main category: direct patient work, indirect patient work, and other work. All professionals estimated a higher proportion of time spent in direct patient work than they reported in the time study. Physicians scored highest on the psychosocial scales of quantitative demands, stress, and role conflicts. Among allied professionals, the proportion of work-time spent on administrative tasks was associated with more role conflicts. Younger staff perceived more adverse working conditions than older staff. CONCLUSIONS: This study indicated that Swedish primary care staff spent a limited proportion of their work time directly with patients. PCPs seemed to perceive their work environment in negative terms to a greater extent than other staff members. This study showed that work task allocations influenced the perceived psychosocial work environment. PMID- 29514638 TI - Integrated analysis of DNA-methylation and gene expression using high-dimensional penalized regression: a cohort study on bone mineral density in postmenopausal women. AB - BACKGROUND: Using high-dimensional penalized regression we studied genome-wide DNA-methylation in bone biopsies of 80 postmenopausal women in relation to their bone mineral density (BMD). The women showed BMD varying from severely osteoporotic to normal. Global gene expression data from the same individuals was available, and since DNA-methylation often affects gene expression, the overall aim of this paper was to include both of these omics data sets into an integrated analysis. METHODS: The classical penalized regression uses one penalty, but we incorporated individual penalties for each of the DNA-methylation sites. These individual penalties were guided by the strength of association between DNA methylations and gene transcript levels. DNA-methylations that were highly associated to one or more transcripts got lower penalties and were therefore favored compared to DNA-methylations showing less association to expression. Because of the complex pathways and interactions among genes, we investigated both the association between DNA-methylations and their corresponding cis gene, as well as the association between DNA-methylations and trans-located genes. Two integrating penalized methods were used: first, an adaptive group-regularized ridge regression, and secondly, variable selection was performed through a modified version of the weighted lasso. RESULTS: When information from gene expressions was integrated, predictive performance was considerably improved, in terms of predictive mean square error, compared to classical penalized regression without data integration. We found a 14.7% improvement in the ridge regression case and a 17% improvement for the lasso case. Our version of the weighted lasso with data integration found a list of 22 interesting methylation sites. Several corresponded to genes that are known to be important in bone formation. Using BMD as response and these 22 methylation sites as covariates, least square regression analyses resulted in R2=0.726, comparable to an average R2=0.438 for 10000 randomly selected groups of DNA-methylations with group size 22. CONCLUSIONS: Two recent types of penalized regression methods were adapted to integrate DNA methylation and their association to gene expression in the analysis of bone mineral density. In both cases predictions clearly benefit from including the additional information on gene expressions. PMID- 29514640 TI - Intracerebral hemorrhage after external ventricular drain placement: an evaluation of risk factors for post-procedural hemorrhagic complications. AB - BACKGROUND: The objective of this study was to evaluate and identify the risk factors for developing a new or enlarged intracranial hemorrhage (ICH) after the placement of an external ventricular drain. METHODS: A single center, nested case control study of individuals who received an external ventricular drain from June 1, 2011 to June 30, 2014 was conducted at a large academic medical center. A bivariate analysis was conducted to compare those individuals who experienced a post-procedural intracranial hemorrhage to those who did not experience a new bleed. The variables identified as having a p-value less than 0.15 in the bivariate analysis were then evaluated using a multivariate logistic regression model. RESULTS: Twenty-seven of the eighty-one study participants experienced a new or enlarged intracranial hemorrhage after the placement of an external ventricular drain. Of these twenty-seven patients, 6 individuals received an antiplatelet within ninety-six hours of external ventricular drain placement (p = 0.024). The multivariate logistic regression model identified antiplatelet use within 96 h of external ventricular drain insertion as an independent risk factor for post-EVD ICH (OR 13.1; 95% CI 1.95-88.6; p = 0.008). CONCLUSION: Compared to those study participants who did not receive an antiplatelet within 96 h of external ventricular drain placement, those participants who did receive an antiplatelet were 13.1 times more likely to exhibit a new or enlarged intracranial hemorrhage. PMID- 29514639 TI - Aligning policy objectives and payment design in palliative care. AB - BACKGROUND: Payment models for palliative care vary across nations, with few adopting contemporary payments designs that apply to other parts of the health system. AIM: To propose optimal payment arrangements for palliative care. APPROACH: Review of relevant literature on funding mechanisms in health care generally and palliative care in particular. RESULTS: Payment models for palliative care should move toward activity-based funding using an agreed classification, be uncapped funding with performance monitoring, and make explicit use of performance metrics and reporting. CONCLUSIONS: If palliative care is to become a universally accessible service, new approaches to funding, based on the experience of funding reforms in other parts of the health system, need to be adopted. PMID- 29514641 TI - Association between COX2 -765G/C polymorphism and periodontitis in Chinese population: a meta-analysis. AB - BACKGROUND: Studies had attempted to clarify the relation between COX2 -765G/C gene polymorphisms and periodontitis risk, but there has been no definite consensus to date. A meta-analysis was performed to further explore the relationship of COX2 -765G/C polymorphism on periodontitis risk among Chinese population. METHODS: The databases of PubMed, Springer Link, Ovid, Chinese Wanfang Databases, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biology Medicine were searched up to January 2017. The overall result and subgroup analysis results were combined using fixed-effect or random-effect based on the heterogeneity. RESULTS: Finally, 7 case-control publications including 1399 periodontitis cases and 1663 controls were identified according to the inclusion criteria. In the total analyses, COX2 -765G/C polymorphism had nonsignificant association on periodontitis risk in all models. The subgroup analyses suggested a significantly increased risk of periodontitis in studies with population-based controls and a significantly decreased risk in studies with hospital-based controls. CONCLUSIONS: This meta-analysis indicated that COX2 765G/C polymorphism had significantly affect on periodontitis risk among Chinese individuals, which should be confirmed by other ethnic groups. PMID- 29514642 TI - Enhancing communication skills for telehealth: development and implementation of a Teach-Back intervention for a national maternal and child health helpline in Australia. AB - BACKGROUND: Telehealth professionals require advanced communication skills, in part to compensate for lack of visual cues. Teach-Back is a best practice communication technique that has been recommended but not previously evaluated for consumer telehealth. We aimed to implement Teach-Back at a national maternal and child health telephone helpline. We describe the intervention and report telenurse experiences learning to use Teach-Back. METHODS: We identified barriers (time, knowledge, skills, beliefs) and enablers (self-reflection) to using Teach Back, and developed a novel training program to address these, guided by the Theoretical Domains Framework. We engaged maternal and child health telenurses to participate in a "communication skills" study. The intervention had two key components: guided self-reflection and a Teach-Back skills workshop. For the duration of the 7-week study nurses completed brief online surveys following each call, reflecting on both the effectiveness of their communication and perceived caller understanding. At the end of each shift they reflected on what worked well. Teach-Back knowledge, skills, and beliefs were addressed in a 2-h workshop using videos, discussion, and role play. We explored nurses' experiences of the intervention in focus groups and interviews; and analysed transcripts and comments from the self-reflection surveys using the Framework method. This study forms part of a larger evaluation conducted in 2016. RESULTS: In total 16 nurses participated: 15 were trained in Teach-Back, and 13 participated in focus groups or interviews. All engaged with both self-reflection and Teach-Back, although to differing extents. Those who reported acquiring Teach-Back skills easily limited themselves to one or two Teach-Back phrases. Nurses reported that actively self reflecting (including on what they did well) was useful both for developing Teach Back skills and analysing effectiveness of the techniques. Most wanted more opportunity to learn how their colleagues manage Teach-Back in different situations, and more visual reminders to use Teach-Back. CONCLUSIONS: Our theory informed intervention successfully enabled nurses to use Teach-Back. Guided self reflection is a low-resource method aligned with nurse professional identity that can facilitate Teach-Back skills learning, and could also be applied to other advanced communication skills for telehealth. Listening to multiple workplace specific examples of Teach-Back is recommended for future training. TRIAL REGISTRATION: ACTRN12616000623493 Registered 15 May 2016. Retrospectively registered. PMID- 29514643 TI - Unusual presentation of a hepatocellular carcinoma as a potential late side effect of radiotherapy in a patient treated for Wilms tumor in childhood. AB - BACKGROUND: The development of a second primary tumor is a potential late side effect of radiotherapy. Particularly, an increased risk of secondary cancers, mostly of digestive or breast origin, has been observed in patients treated with high-dose radiotherapy for Wilms tumor (WT) in childhood. However, hepatocellular carcinoma (HCC) has been very rarely described as a potentially radiotherapy induced tumor. We describe the case of a patient with an aggressive HCC 50 years after the treatment of a WT. CASE PRESENTATION: A 49-year old man, treated at the age of 6 weeks for a right WT by a right nephrectomy and adjuvant radiotherapy, presented with a right abdominal mass. Imaging demonstrated a 100-mm tumor invading the inferior segment of the right liver, the right colon and the right psoas muscle. The patient had no previous history of liver disease, nor of alcohol consumption, and hepatitis serologies were negatives. Biopsy demonstrated a poorly differentiated tumor of unknown origin. A panel of tumor markers was negative. Explorative surgery has been performed allowing en bloc R0 tumor resection, including resection of segments VI and VII of the liver, right hemicolectomy and resection of the anterior sheet of the right psoas muscle. Pathological examination revealed a poorly differentiated HCC. No signs of cirrhosis or chronic liver disease were observed in the non-tumor liver. Twenty weeks after surgery, the patient developed a multifocal tumor recurrence that was treated with intra-arterial 90Yttrium radioembolization. CONCLUSION: In this case, the absence of risk factors for HCC, such as cirrhosis, viral hepatitis and chronic liver disease, highly suggests the development of HCC to be related to previous high-dose radiation therapy given for a right WT to a field involving the inferior part of the liver. This observation shows radiotherapy to/near the liver, particularly in childhood, to be a potential risk factor for HCC, stressing the need for a long-term specific follow-up in patients irradiated in childhood. PMID- 29514644 TI - Association between apolipoprotein B genetic polymorphism and the risk of calcific aortic stenosis in Chinese subjects, in Xinjiang, China. AB - BACKGROUND: Limited information is available when it comes to the impact of genetic on Calcific Aortic Stenosis (CAS). Apolipoprotein B (apoB) is a key component in lipid metabolism and plays an important role in the dynamic equilibrium of cholesterol. We performed a case-control study to explore the association of apoB genetic polymorphisms with CAS in Chinese subjects, in Xinjiang, China. METHODS: We designed a case-control study including 314 CAS patients and 652 age- and sex-matched control subjects. Using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method, we genotyped two SNPs (rs6725189 and rs693) of apoB gene in all subjects. RESULTS: We found that the rs693 T allele was associated with a significantly elevated CAS risk [TT/CT vs. CC: adjusted odds ratio (AOR) = 1.58, 95% confidence interval (CI) = 1.82 2.10, P = 0.002] and the rs6725189 T allele was also associated with a significantly elevated CAS risk (GT vs. GG: AOR = 1.82, 95% CI = 1.14-2.92, P = 0.013). Furthermore, we also found that the TC levels were significantly higher in rs693 TT/CT genotypes than that in CC genotypes (P < 0.05). CONCLUSIONS: Both rs693 and rs6725189 of the apoB gene are associated with CAS in Chinese subjects, in Xinjiang, China. PMID- 29514646 TI - Correction to: Outcomes of notifications to health practitioner boards: a retrospective cohort study. AB - The original article [1] contains a major error whereby all rates in Table 2 are mistakenly presented as 50% of their true values; this error was caused by a miscalculation in annualising the original values that represented the rates. PMID- 29514645 TI - Development and validation of a new knowledge, attitude, belief and practice questionnaire on leptospirosis in Malaysia. AB - BACKGROUND: In Malaysia, leptospirosis is considered an endemic disease, with sporadic outbreaks following rainy or flood seasons. The objective of this study was to develop and validate a new knowledge, attitude, belief and practice (KABP) questionnaire on leptospirosis for use in urban and rural populations in Malaysia. METHODS: The questionnaire comprised development and validation stages. The development phase encompassed a literature review, expert panel review, focus group testing, and evaluation. The validation phase consisted of exploratory and confirmatory parts to verify the psychometric properties of the questionnaire. A total of 214 and 759 participants were recruited from two Malaysian states, Kelantan and Selangor respectively, for the validation phase. The participants comprised urban and rural communities with a high reported incidence of leptospirosis. The knowledge section of the validation phase utilized item response theory (IRT) analysis. The attitude and belief sections utilized exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). RESULTS: The development phase resulted in a questionnaire that included four main sections: knowledge, attitude, belief, and practice. In the exploratory phase, as shown by the IRT analysis of knowledge about leptospirosis, the difficulty and discrimination values of the items were acceptable, with the exception of two items. Based on the EFA, the psychometric properties of the attitude, belief, and practice sections were poor. Thus, these sections were revised, and no further factor analysis of the practice section was conducted. In the confirmatory stage, the difficulty and discrimination values of the items in the knowledge section remained within the acceptable range. The CFA of the attitude section resulted in a good-fitting two-factor model. The CFA of the belief section retained low number of items, although the analysis resulted in a good fit in the final three-factor model. CONCLUSIONS: Based on the IRT analysis and factor analytic evidence, the knowledge and attitude sections of the KABP questionnaire on leptospirosis were psychometrically valid. However, the psychometric properties of the belief section were unsatisfactory, despite being revised after the initial validation study. Further development of this section is warranted in future studies. PMID- 29514647 TI - Immune response and protective effect against chronic Toxoplasma gondii infection induced by vaccination with a DNA vaccine encoding profilin. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite that can infect almost all warm-blooded animals. T. gondii profilin (TgPF) plays a crucial role in parasite motility and host cell invasion, and has shown promise against toxoplasmosis. DNA vaccine was considered to elicit effective humoral and cell mediated immunity against T. gondii infection. The objective of the present study was to evaluate the immunogenicity of TgPF in mice using a DNA vaccination strategy. METHODS: A DNA vaccine (pVAX-PF) encoding TgPF gene was constructed and then was intramuscularly injected into mice with and without a plasmid encoding IL-15 (pVAX-IL-15). The immune responses in immunized Kunming mice including lymphocyte proliferation, levels of cytokines, antibody titers and T lymphocyte subclasses were analyzed. The protective efficacy against chronic T. gondii infection was observed at 4 weeks post-infection with the cyst-forming PRU strain of T. gondii (Genotype II). RESULTS: EitherpVAX-PF with or without pVAX-IL-15 could elicit higher level of IgG and IgG2a antibodies and produce strong cellular immune responses in the immunized mice. The brain cyst numbers in mice immunized with pVAX-PF + pVAX-IL-15 (1843 +/- 215.7) and pVAX-PF (1897 +/- 337.8) were reduced 40.82% and 39.08%, respectively, compared to that in mice received nothing (3114 +/- 168.8), and the differences were statistically significant (P < 0.0001). However, the T. gondii cyst numbers in mice immunized with pVAX-PF + pVAX-IL-15 were not statistically significantly different compared to that in mice immunized with pVAX-PF alone [t(10) = 0.33, P > 0.05]. CONCLUSIONS: The present study indicated that TgPF could be a promising vaccine candidate against chronic toxoplasmosis, which can be further used to develop multi-epitope vaccine formulations in food-producing animals against T. gondii infection. PMID- 29514648 TI - Long-term smoking alters abundance of over half of the proteome in bronchoalveolar lavage cell in smokers with normal spirometry, with effects on molecular pathways associated with COPD. AB - BACKGROUND: Smoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). METHODS: To identify dysregulation of specific proteins and pathways in bronchoalveolar lavage (BAL) cells associated with smoking, isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun proteomics analyses were performed on BAL cells from healthy never-smokers and smokers with normal lung function from the Karolinska COSMIC cohort. Multivariate statistical modeling, multivariate correlations with clinical data, and pathway enrichment analysis were performed. RESULTS: Smoking exerted a significant impact on the BAL cell proteome, with more than 500 proteins representing 15 molecular pathways altered due to smoking. The majority of these alterations occurred in a gender independent manner. The phagosomal- and leukocyte trans endothelial migration (LTM) pathways significantly correlated with FEV1/FVC as well as the percentage of CD8+ T-cells and CD8+CD69+ T-cells in smokers. The correlations to clinical parameters in healthy never-smokers were minor. CONCLUSION: The significant correlations of proteins in the phagosome- and LTM pathways with activated cytotoxic T-cells (CD69+) and the level of airway obstruction (FEV1/FVC) in smokers, both hallmarks of COPD, suggests that these two pathways may play a role in the molecular events preceding the development of COPD in susceptible smokers. Both pathways were found to be further dysregulated in COPD patients from the same cohort, thereby providing further support to this hypothesis. Given that not all smokers develop COPD in spite of decades of smoking, it is also plausible that some of the molecular pathways associated with response to smoking exert protective mechanisms to smoking-related pathologies in resilient individuals. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02627872 ; Retrospectively registered on December 9, 2015. PMID- 29514649 TI - Study protocol: a hybrid effectiveness-implementation trial of Moral Reconation Therapy in the US Veterans Health Administration. AB - BACKGROUND: Moral Reconation Therapy (MRT) is a cognitive-behavioral intervention aimed at reducing risk for criminal recidivism by restructuring antisocial attitudes and cognitions (i.e., "criminogenic thinking"). MRT has empirical support for reducing risk for criminal recidivism among civilian offenders. Recently, a version of MRT was developed for military veterans; however, no randomized controlled trials (RCT) have been conducted with the veteran-specific protocol, and the effectiveness and implementation potential of MRT outside of correctional settings has not been established. METHODS: Using a Hybrid Type 1 RCT design, this study will test the effectiveness of MRT to reduce risk for criminal recidivism and improve health-related outcomes among justice-involved veterans entering mental health residential treatment at three US Veterans Health Administration (VHA) Medical Centers. Upon admission to the treatment program, justice-involved veterans will complete a baseline assessment, be randomized to usual care (UC) or UC + MRT, and be followed 6 and 12 months post-baseline. A process evaluation will also be conducted to identify barriers and facilitators to implementation of MRT in residential treatment. DISCUSSION: The primary aim of this study is to evaluate the effectiveness of MRT with justice-involved veterans. If MRT proves effective in this trial, the findings can provide large healthcare systems that serve veterans with an evidence-based intervention for addressing criminogenic thinking among justice-involved adults, as well as guidance on how to facilitate future implementation of MRT in non-correctional settings. TRIAL REGISTRATION: This trial is funded by the VA Health Services Research & Development Program (IIR 14-081) and is registered with ClinicalTrials.gov (ID: NCT02524171 ). PMID- 29514650 TI - Prevalence of bovine tuberculosis in cattle, goats, and camels of traditional livestock raising communities in Eritrea. AB - BACKGROUND: The aim of the current study was to assess the prevalence of bovine tuberculosis (BTB) in cattle, goats, and camels, and its zoonotic potential within the traditional livestock raising communities in four regions of Eritrea. The Single Intradermal Comparative Tuberculin Test (SICTT) as indicator of M. bovis infection was conducted on 1077 cattle, 876 goats, and 195 camels. To elucidate possible risk factors for BTB transmission between animals and its potential zoonotic implication, questionnaire based face-to-face interviews were conducted in households of which 232 raised cattle, 128 goats, and 29 camels. RESULTS: The results of the SCITT were interpreted using the OIE standard (> 4 mm cut-off) for positive responses. In cattle, individual animal (n = 1077) and herd (n = 413) prevalences were 1.2% (n = 13) [Confidence Interval (CI) 95% CI, 1.0 1.3%] and 3.2% (n = 13) (95% CI, 3.0-3.4%), respectively. In goats (n = 876), none of the animals was positive. In camels, individual animal (n = 195) and herd (n = 70), BTB prevalences were 1.5% (n = 3) (95% CI,1.4-1.6%) and 2.9(n = 2) (95% CI, 0.9-4.6%), respectively. Overall, male animals were more at risk (OR = 2.6; 95% CI:1.0-8.7) when compared to females. Sharing of water points, introduction of new animals into herds and migration of animals over large distances were common events that may contribute to intra and inter-species transmission of BTB. Consumption of raw milk, lack of BTB transmission awareness, and low levels of education were common in the farming communities. CONCLUSION: The current study highlighted a low prevalence of M. bovis in cattle, goats and camels in extensive traditional livestock in Eritrea. Despite this, the spatial distribution of affected animals across most of the sampled regions and consumption of unpasteurized milk warrants surveillance, cautious and timely control measures for the disease. PMID- 29514651 TI - Burden of early, advanced and metastatic breast cancer in The Netherlands. AB - BACKGROUND: The aim of this study was to estimate the total economic and health related burden of breast cancer in the Netherlands. METHODS: Data on incidence, prevalence, mortality and survival were extracted from the Dutch National Cancer Registry and were used to calculate the economic and health related burden of breast cancer for overall, DCIS (stage 0), early- (stage I), locally advanced- (stage II-III) and metastatic- (stage IV) breast cancer by age groups and by year (if applicable). RESULTS: The overall incidence of breast cancer increased from 103.4 up to 153.2 per 100,000 women between 1990 and 2014. The increase was driven by DCIS and early breast cancer as the incidence of locally advanced and metastatic breast cancer remained stable. Between 1990 and 2014, ten-year overall survival rates increased from 87% to 93% for early breast cancer, 41% to 62% for locally advanced- and from 6% to 9% for metastatic disease. Annually, breast cancer in the Netherlands is responsible for approximately 3100 deaths, 26,000 life years lost, 65,000 Disability Adjusted Life Years (DALYs) and an economic burden of ?1.27 billion. CONCLUSIONS: This study provides a comprehensive assessment of the burden of breast cancer and subsequent trends over time in the Netherlands. PMID- 29514653 TI - Correction to: Mixed-method tutoring support improves learning outcomes of veterinary students in basic subjects. AB - The original article [1] contains an error whereby Fig. 2a and b are mistakenly swapped with each other, and thus do not correspond to their correct respective sub-headings in the caption. PMID- 29514652 TI - The relationship between nut intake and risk of colorectal cancer: a case control study. AB - BACKGROUND: Nut consumption is known to reduce the risk of obesity, diabetes mellitus, and cardiovascular disease. However, in previous studies, portion sizes and categories of nut consumption have varied, and few studies have assessed the association between colorectal cancer risk and nut consumption. In this study, we investigated the relationship between nut consumption and colorectal cancer risk. METHODS: A case-control study was conducted among 923 colorectal cancer patients and 1846 controls recruited from the National Cancer Center in Korea. Information on dietary intake was collected using a semi-quantitative food frequency questionnaire with 106 items, including peanuts, pine nuts, and almonds (as 1 food item). Nut consumption was categorized as none, < 1 serving per week, 1-3 servings per week, and >=3 servings per week. A binary logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) for the association between nut consumption and colorectal cancer risk, and a polytomous logistic regression model was used for sub-site analyses. RESULTS: High nut consumption was strongly associated with reduced risk of colorectal cancer among women (adjusted ORs: 0.30, 95%CI: 0.15-0.60 for the >=3 servings per week group vs. none). A similar inverse association was observed for men (adjusted ORs: 0.28, 95% CI: 0.17-0.47). In sub-site analyses, adjusted ORs (95% CIs) comparing the >=3 servings per week group vs none were 0.25 (0.09-0.70) for proximal colon cancer, 0.39 (0.19-0.80) for distal colon cancer, and 0.23 (0.12 0.46) for rectal cancer among men. An inverse association was also found among women for distal colon cancer (OR: 0.13, 95% CI: 0.04-0.48) and rectal cancer (OR: 0.40, 95% CI: 0.17-0.95). CONCLUSIONS: We found a statistically significant association between high frequency of nut consumption and reduced risk of colorectal cancer. This association was observed for all sub-sites of the colon and rectum among both men and women, with the exception of proximal colon cancer for women. PMID- 29514654 TI - Clinical significance and prognostic value of receptor conversion in hormone receptor positive breast cancers after neoadjuvant chemotherapy. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) is widely used in advanced breast cancer patients. However, there is little known about conversion frequency of estrogen receptor (ER) and/or progesterone receptor (PR) status for hormone receptor positive-breast cancer patients after NAC and their correlation with prognosis. METHODS: In this study, 231 breast cancer patients with residual disease after NAC were enrolled and divided into receptor stable group (having no conversion in both ER and PR status pre- and post-NAC) and any receptor conversion group (having any conversion in either ER or PR status). Univariate and multivariate survival analyses were used to compare survival differences between the two groups. RESULTS: Fifty-five patients (23.8%) had ER and/or PR conversion after NAC. Younger patients (<= 50 years) were more likely to have receptor conversion (P = 0.014). For 213 patients (92.2%) who received adjuvant endocrinotherapy after surgery, the 5-year disease free survival (DFS) estimates for patients in the any receptor conversion group (55.2%) was worse than patients in the receptor stable group (73.7%, Log-rank test, P = 0.015). While the 5-year overall survival estimates for patients with or without receptor conversion were not statistically different (86.0 vs. 82.4%, Log-rank test, P = 0.587). In multivariate Cox proportional hazard analyses, patients with any receptor conversion had worse DFS (hazard ratio, 1.995; 95% confidence interval, 1.130 3.521, P = 0.031). CONCLUSIONS: It is necessary to recommend patients to test biomarkers in residual disease and pay more attention to patients who have any receptor conversion. These patients may need more individual therapy after surgery. PMID- 29514655 TI - Respiratory morbidity through the first decade of life in a national cohort of children born extremely preterm. AB - BACKGROUND: Advances in perinatal care have markedly increased the prospects of survival for infants born extremely preterm (EP). The aim of this study was to investigate hospitalisation rates and respiratory morbidity from five to 11 years of age in a prospective national cohort of EP children born in the surfactant era. METHODS: This was a national prospective cohort study of all children born in Norway during 1999 and 2000 with gestational age (GA) < 28 weeks or birth weight < 1000 grams, and of individually matched term-born controls recruited for a regional subsample. Data on hospital admissions, respiratory symptoms, and use of asthma medication was obtained by parental questionnaires at 11 years of age. RESULTS: Questionnaires were returned for 232/372 (62%) EP-born and 57/61 (93%) regional term-born controls. Throughout the study period, 67 (29%) EP-born and seven (13%) term-born controls were admitted to hospital (odds ratio (OR) 2.90, 95% confidence interval (CI): 1.25, 6.72). Admissions were mainly due to surgical procedures, with only 12% due to respiratory causes, and were not influenced by neonatal bronchopulmonary dysplasia (BPD) or low GA(<= 25 weeks). Respiratory symptoms, asthma and use of asthma medication tended to be more common for EP born, significantly so for medication use and wheeze on exercise. Neonatal BPD was a risk factor for medication use, but not for current wheeze. In multivariate regression models, home oxygen after discharge (OR 4.84, 95% CI: 1.38, 17.06) and parental asthma (OR 4.38, 95% CI: 1.69, 11.38) predicted current asthma, but neither BPD nor low GA were associated with respiratory symptoms at 11 years of age. CONCLUSIONS: Hospitalisation rates five to 11 years after EP birth were low, but twice those of term-born controls, and unrelated to neonatal BPD and low GA. Respiratory causes were rare. Respiratory complaints were more common in children born EP, but the burden of symptoms had declined since early childhood. PMID- 29514657 TI - Effects of child characteristics and dental history on dental fear: cross sectional study. AB - BACKGROUND: Dental fear (DF) is a challenging problem in dentistry. It is multifactorial in origin and many contributing factors have been identified. The aim of the study was to assess dental fear among 12-15 years old Arabic speaking children in Jeddah, Saudi Arabia and its relation to demographic variables, previous dental experience, and child behaviour. METHODS: In this cross-sectional study, a total of 1522 boys and girls from middle schools in Jeddah, Saudi Arabia participated in this study during the period of 2014 to 2016. The Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) was used to assess DF. A parental questionnaire was used to record the children's previous dental experience. Children were examined for caries and the children's behaviour was assessed during dental examination using Frankl Behaviour Rating Scale. The associations between different variables and the CFSS-DS scores were analysed using t-tests, ANOVA, and multiple linear regression analysis. RESULTS: The response rate of the questionnaires was 78.6%. The mean CFSS-DS score was 25.99 +/- 9.3 out of a maximum of 75. Bivariate analysis showed that younger children, girls, and public school students were significantly more fearful than older children, boys, and private school children, respectively (P < 0.001). Children who showed poor behaviour during dental examination were significantly more fearful than those with good behaviour (P < 0.001). Regression analysis showed that children who had significantly higher scores of dental fear were the children who did not visit the dentist in the past year due to dental fear; who never visited the dentist or those who only visited the dentist on pain; who were reported by parents as crying, screaming, or resistant during their previous dental visit; and those who were described to be in pain during previous dental treatment. Dental caries showed no significant association with DF. CONCLUSIONS: This study confirms that DF is low among 12-15 years old Arabic speaking children in Jeddah, Saudi Arabia. DF is associated with age, gender, school type, irregular patterns of dental visits, painful experiences during previous dental visits and negative behaviours during dental examinations. PMID- 29514658 TI - Meta-analysis of association between TCF7L2 polymorphism rs7903146 and type 2 diabetes mellitus. AB - BACKGROUND: Large scale association studies have found a significant association between type 2 diabetes mellitus (T2DM) and transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146. However, the quality of data varies greatly, as the studies report inconsistent results in different populations. Hence, we perform this meta-analysis to give a more convincing result. METHODS: The articles, published from January 1st, 2000 to April 1st, 2017, were identified by searching in PubMed and Google Scholar. A total of 56628 participants (34232 cases and 22396 controls) were included in the meta-analysis. A total of 28 studies were divided into 4 subgroups: Caucasian (10 studies), East Asian (5 studies), South Asian (5 studies) and Others (8 studies). All the data analyses were analyzed by the R package meta. RESULTS: The significant association was observed by using the dominant model (OR = 1.41, CI = 1.36 - 1.47, p < 0.0001), recessive model (OR = 1.58, CI = 1.48 - 1.69, p < 0.0001), additive model(CT vs CC) (OR = 1.34, CI = 1.28-1.39, p < 0.0001), additive model(TT vs CC) (OR = 1.81, CI = 1.69-1.94, p < 0.0001)and allele model (OR = 1.35, CI = 1.31-1.39, p < 0.0001). CONCLUSION: The meta-analysis suggested that rs7903146 was significantly associated with T2DM in Caucasian, East Asian, South Asian and other ethnicities. PMID- 29514659 TI - One in three adolescent schoolgirls in urban northwest Ethiopia is stunted. AB - BACKGROUND: Poor nutritional status of adolescent girls has a negative effect on the next generation as undernourished adolescents enter pregnancy with poor nutrient reserve. However, there is scarcity of evidence showing the burden of stunting among adolescent girls in Ethiopia. Therefore, the objective of this study aimed to assess prevalence of stunting and associated factors among school adolescent girls in Gondar City Administration, northwest Ethiopia. METHODS: Cross-sectional study was conducted from March to April, 2017. A multi-stage sampling technique was used to select812 school adolescent girls. World Health Organization Anthro-plus software was used to analyze anthropometric data into Height for Age Z-score. A multivariable logistic regression analysis was employed to identify the factors associated with stunting. Adjusted Odds Ratio (AOR) with 95% confidence interval was used to show the strength of association, while a P value< 0.05 of was used to declare the significance of association. RESULTS: The overall prevalence of stunting among adolescent girls was 33.1% (95% CI: 29.9, 36.5). Middle age of adolescence (AOR = 0.22, 95% CI: 0.15, 0.34), unsatisfactory media exposure (AOR = 1.69, 95% CI: 1.01, 2.84) and poor mother's education (AOR = 2.84, 95% CI: 1.07, 7.94) were significantly associated with stunting. CONCLUSIONS: One-third of adolescent girls are stunted in Gondar City which suggests the serious public health importance of the problem. Enhancing mother's education and media exposure are critical to address the high burden of stunting. PMID- 29514656 TI - Targeting Hif1a rescues cone degeneration and prevents subretinal neovascularization in a model of chronic hypoxia. AB - BACKGROUND: Degeneration of cone photoreceptors leads to loss of vision in patients suffering from age-related macular degeneration (AMD) and other cone dystrophies. Evidence, such as choroidal ischemia and decreased choroidal blood flow, implicates reduced tissue oxygenation in AMD pathology and suggests a role of the cellular response to hypoxia in disease onset and progression. Such a chronic hypoxic situation may promote several cellular responses including stabilization of hypoxia-inducible factors (HIFs). METHODS: To investigate the consequence of a chronic activation of the molecular response to hypoxia in cones, von Hippel Lindau protein (VHL) was specifically ablated in cones of the all-cone R91W;Nrl -/- mouse. Retinal function and morphology was evaluated by ERG and light microscopy, while differential gene expression was tested by real-time PCR. Retinal vasculature was analyzed by immunostainings and fluorescein angiography. Two-way ANOVA with Sidak's multiple comparison test was performed for statistical analysis. RESULTS: Cone-specific ablation of Vhl resulted in stabilization and activation of hypoxia-inducible factor 1A (HIF1A) which led to increased expression of genes associated with hypoxia and retinal stress. Our data demonstrate severe cone degeneration and pathologic vessel growth, features that are central to AMD pathology. Subretinal neovascularization was accompanied by vascular leakage and infiltration of microglia cells. Interestingly, we observed increased expression of tissue inhibitor of metalloproteinase 3 (Timp3) during the aging process, a gene associated with AMD and Bruch's membrane integrity. Additional deletion of Hif1a protected cone cells, prevented pathological vessel growth and preserved vision. CONCLUSIONS: Our data provide evidence for a HIF1A-mediated mechanism leading to pathological vessel growth and cone degeneration in response to a chronic hypoxia-like situation. Consequently, our results identify HIF1A as a potential therapeutic target to rescue hypoxia related vision loss in patients. PMID- 29514660 TI - Does Chinese calligraphy therapy reduce neuropsychiatric symptoms: a systematic review and meta-analysis. AB - BACKGROUND: There are currently no systematic reviews or meta-analyses of Chinese calligraphy therapy (CCT) to reduce neuropsychiatric symptoms. The aim of this systematic review and meta-analysis was to explore the efficacy of CCT for people with neuropsychiatric symptoms. METHODS: We searched Chinese and English databases, including the Cochrane Central Register of Controlled Trials and Wanfang Data for relevant articles published between the earliest year available and December 2016. The search was limited to randomized controlled trials and controlled clinical studies and the associated keywords were "handwriting," "Chinese calligraphy," "Chinese calligraphy therapy," "Calligraphy exercise," and "Calligraphy training." The 21 articles that met these criteria were used in the analysis. The Joanna Briggs Institute critical appraisal checklist was used to assess methodological quality. RESULTS: CCT significantly reduced psychosis (10 studies, 965 subjects, standardized mean difference [SMD] = - 0.17, 95% confidence intervals [CI] [- 0.30, - 0.40], Z = 2.60, p < 0.01), anxiety symptoms (9 studies, 579 subjects, SMD = - 0.78, 95% CI [- 0.95, - 0.61], Z = 8.98, p < 0.001), and depressive symptoms (7 studies, 456 subjects, SMD = - 0.69, 95% CI [- 0.88, - 0.50], Z = 7.11, p < 0.001). CCT also significantly improved cognitive function (2 studies, 55 subjects, MD = 2.17, 95% CI [- 0.03, 4.38], Z = 1.93, p = 0.05) and neurofeedback (3 studies, 148 subjects, SMD = - 1.09, 95% CI [- 1.44, - 0.73], Z = 6.01, p < 0.001). The therapy also significantly reduced the positive psychopathological expression of schizophrenia symptoms (4 studies, 287 subjects, SMD = - 0.35, 95% CI [- 0.59, - 0.12], Z = 2.96, p = 0.003) and reduced the negative symptoms of schizophrenia (4 studies, 276 subjects, SMD = - 1.39, 95% CI [- 1.65, - 1.12], Z = 10.23, p < 0.001). CONCLUSIONS: CCT exerts a curative effect on neuropsychiatric symptoms, but the evidence remains insufficient. A large number of RCTs are needed to facilitate additional systematic reviews of evidence for CCT. PMID- 29514661 TI - Physiological and molecular effects of interleukin-18 administration on the mouse kidney. AB - BACKGROUND: The cytokine interleukin-18 was originally identified as an interferon-gamma-inducing proinflammatory factor; however, there is increasing evidence to suggest that it has non-immunological effects on physiological functions. We previously investigated the potential pathophysiological relationship between interleukin-18 and dyslipidemia, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and suggested interleukin-18 as a possible novel treatment for not only these diseases but also for cancer immunotherapy. Before clinical application, the effects of interleukin-18 on the kidney need to be determined. In the current study, we examined the kidney of interleukin-18 knockout (Il18-/-) mice and the effects of interleukin-18 on the kidney following intravenous administration of recombinant interleukin-18. METHODS: Il18-/- male mice were generated on the C57Bl/6 background and littermate C57Bl/6 Il18+/+ male mice were used as controls. To assess kidney damage, serum creatinine and blood urea nitrogen levels were measured and histopathological analysis was performed. For molecular analysis, microarray and quantitative reverse transcription PCR was performed using mice 6 and 12 weeks old. To evaluate the short- and long-term effects of interleukin-18 on the kidney, recombinant interleukin-18 was administered for 2 and 12 weeks, respectively. RESULTS: Compared with Il18+/+ mice, Il18-/- mice developed kidney failure in their youth-6 weeks of age, but the condition was observed to improve as the mice aged, even though dyslipidemia, arteriosclerosis, and higher insulin resistance occurred. Analyses of potential molecular mechanisms involved in the onset of early kidney failure in Il18-/- mice identified a number of associated genes, such as Itgam, Nov, and Ppard. Intravenous administration of recombinant interleukin-18 over both the short and long term showed no effects on the kidney despite significant improvement in metabolic diseases. CONCLUSIONS: Short- and long-term administration of interleukin-18 appeared to have no adverse effects on the kidney in these mice, suggesting that administration may be a safe and novel treatment for metabolic diseases and cancer. PMID- 29514662 TI - Antidepressant use and risk of adverse outcomes in people aged 20-64 years: cohort study using a primary care database. AB - BACKGROUND: Antidepressants are one of the most commonly prescribed medications in young and middle-aged adults, but there is relatively little information on their safety across a range of adverse outcomes in this age group. This study aimed to assess associations between antidepressant treatment and several adverse outcomes in people aged 20-64 years diagnosed with depression. METHODS: We conducted a cohort study in 238,963 patients aged 20-64 years registered with practices across the UK contributing to the QResearch primary care database. Only patients with a first diagnosis of depression were included. Outcomes were falls, fractures, upper gastrointestinal bleed, road traffic accidents, adverse drug reactions and all-cause mortality recorded during follow-up. Cox proportional hazards models were used to estimate hazard ratios associated with antidepressant exposure adjusting for potential confounding variables. RESULTS: During 5 years of follow-up, 4651 patients had experienced a fall, 4796 had fractures, 1066 had upper gastrointestinal bleeds, 3690 had road traffic accidents, 1058 had experienced adverse drug reactions, and 3181 patients died. Fracture rates were significantly increased for selective serotonin reuptake inhibitors (adjusted hazard ratio 1.30, 95% CI 1.21-1.39) and other antidepressants (1.28, 1.11-1.48) compared with periods when antidepressants were not used. All antidepressant drug classes were associated with significantly increased rates of falls. Rates of adverse drug reactions were significantly higher for tricyclic and related antidepressants (1.54, 1.25-1.88) and other antidepressants (1.61, 1.22-2.12) compared with selective serotonin reuptake inhibitors. Trazodone was associated with a significantly increased risk of upper gastrointestinal bleed. All-cause mortality rates were significantly higher for tricyclic and related antidepressants (1.39, 1.22-1.59) and other antidepressants (1.26, 1.08-1.47) than for selective serotonin reuptake inhibitors over 5 years but not 1 year, and were significantly reduced after 85 or more days of treatment with selective serotonin reuptake inhibitors. Mirtazapine was associated with significantly increased mortality rates over 1 and 5 years of follow-up. CONCLUSIONS: Selective serotonin reuptake inhibitors had higher rates of fracture than tricyclic and related antidepressants but lower mortality and adverse drug reaction rates than the other antidepressant drug classes. The association between mirtazapine and increased mortality merits further investigation. These risks should be carefully considered and balanced against potential benefits for individual patients when the decision to prescribe an antidepressant is made. PMID- 29514664 TI - Planning and preparing for public health threats at airports. AB - The ever-increasing speed and scope of human mobility by international air travel has led to a global transport network for infectious diseases with the potential to introduce pathogens into non-endemic areas, and to facilitate rapid spread of novel or mutated zoonotic agents.Robust national emergency preparedness is vital to mitigate the transmission of infectious diseases agents domestically and to prevent onward spread to other countries. Given the complex range of stakeholders who respond to an infectious disease threat being transmitted through air travel, it is important that protocols be tested and practised extensively in advance of a real emergency. Simulation exercises include the identification of possible scenarios based on the probability of hazards and the vulnerability of populations as a basis for planning, and provide a useful measure of preparedness efforts and capabilities.In October 2016, a live simulation exercise was conducted at a major airport in Ireland incorporating a public health threat for the first time, with the notification of a possible case of MERS-CoV aboard an aircraft plus an undercarriage fire. Strengths of the response to the communicable disease threat included appropriate public health risk assessment, case management, passenger information gathering, notification to relevant parties, and communication to passengers and multiple agencies.Lessons learned include:o Exercise planning should not be overly ambitious. In testing too many facets of emergency response, the public health response could be deprioritised.o The practical implementation of communication protocols in a real-time exercise of this scope proved challenging. These protocols should continue to be checked and tested by desk-top exercises to ensure that all staff concerned are familiar with them, especially in the context of staff turn-over.o The roles and responsibilities of the various agencies must be clear to avoid role confusion.o Equipment and infrastructure capacities must be considered and in place in advance of an actual incident or test, for example whether or not cell phone signals require boosting during a major event.Importantly, exercises bring together individuals representing organisations with different roles and perspectives allowing identification of capabilities and limitations, and problem solving about how to address the gaps and overlaps in a low-threat collaborative setting. PMID- 29514663 TI - Proteomic profiling of lung immune cells reveals dysregulation of phagocytotic pathways in female-dominated molecular COPD phenotype. AB - BACKGROUND: Smoking is the main risk factor for chronic obstructive pulmonary disease (COPD). Women with COPD who smoke experienced a higher risk of hospitalization and worse decline of lung function. Yet the mechanisms of these gender-related differences in clinical presentations in COPD remain unknown. The aim of our study is to identify proteins and molecular pathways associated with COPD pathogenesis, with emphasis on elucidating molecular gender difference. METHOD: We employed shotgun isobaric tags for relative and absolute quantitation (iTRAQ) proteome analyses of bronchoalveolar lavage (BAL) cells from smokers with normal lung function (n = 25) and early stage COPD patients (n = 18). Multivariate modeling, pathway enrichment analysis, and correlation with clinical characteristics were performed to identify specific proteins and pathways of interest. RESULTS: More pronounced alterations both at the protein- and pathway- levels were observed in female COPD patients, involving dysregulation of the FcgammaR-mediated phagocytosis-lysosomal axis and increase in oxidative stress. Alterations in pathways of the phagocytosis-lysosomal axis associated with a female-dominated COPD phenotype correlated well with specific clinical features: FcgammaR-mediated phagocytosis correlated with FEV1/FVC, the lysosomal pathway correlated with CT < -950 Hounsfield Units (HU), and regulation of actin cytoskeleton correlated with FEV1 and FEV1/FVC in female COPD patients. Alterations observed in the corresponding male cohort were minor. CONCLUSION: The identified molecular pathways suggest dysregulation of several phagocytosis related pathways in BAL cells in female COPD patients, with correlation to both the level of obstruction (FEV1/FVC) and disease severity (FEV1) as well as emphysema (CT < -950 HU) in women. TRIAL REGISTRATION: No.: NCT02627872 , retrospectively registered on December 9, 2015. PMID- 29514665 TI - The English National Cohort Study of Flooding and Health: the change in the prevalence of psychological morbidity at year two. AB - BACKGROUND: The longer term impact of flooding on health is poorly understood. In 2015, following widespread flooding in the UK during winter 2013/14, Public Health England launched the English National Study of Flooding and Health. The study identified a higher prevalence of probable psychological morbidity one year after exposure to flooding. We now report findings after two years. METHODS: In year two (2016), a self-assessment questionnaire including flooding-related exposures and validated instruments to screen for probable anxiety, depression and post-traumatic stress disorder (PTSD) was sent to all participants who consented to further follow-up. Participants exposure status was categorised according to responses in year one; we assessed for exposure to new episodes of flooding and continuing flood-related problems in respondents homes. We calculated the prevalence and odds ratio for each outcome by exposure group relative to unaffected participants, adjusting for confounders. We used the McNemar test to assess change in outcomes between year one and year two. RESULTS: In year two, 1064 (70%) people responded. The prevalence of probable psychological morbidity remained elevated amongst flooded participants [n = 339] (depression 10.6%, anxiety 13.6%, PTSD 24.5%) and disrupted participants [n = 512] (depression 4.1%, anxiety 6.4%, PTSD 8.9%), although these rates were reduced compared to year one. A greater reduction in anxiety 7.6% (95% confidence interval [CI] 4.6-9.9) was seen than depression 3.8% (95% CI 1.5-6.1) and PTSD: 6.6% (95% CI 3.9-9.2). Exposure to flooding was associated with a higher odds of anxiety (adjusted odds ratio [aOR] 5.2 95%, 95% CI 1.7-16.3) and depression (aOR 8.7, 95% CI 1.9-39.8) but not PTSD. Exposure to disruption caused by flooding was not significantly associated with probable psychological morbidity. Persistent damage in the home as a consequence of the original flooding event was reported by 119 participants (14%). The odds of probable psychological morbidity amongst flooded participants who reported persistent damage, compared with those who were unaffected, were significantly higher than the same comparison amongst flooded participants who did not report persistent damage. CONCLUSIONS: This study shows a continuance of probable psychological morbidity at least two years following exposure to flooding. Commissioners and providers of health and social care services should be aware that the increased need in populations may be prolonged. Efforts to resolve persistent damage to homes may reduce the risk of probable psychological morbidity. PMID- 29514666 TI - Analysis of factors delaying the surgical treatment of patients with neurological deficits in the course of spinal metastatic disease. AB - BACKGROUND: Thoracic spine cancer metastases is frequently the cause of neurological deficits. Despite the availability of diagnostics, delays in treatment are still quite common. The aim of this work is to analyze the reasons for delayed diagnostics and treatment, in patients with neurological deficits in the course of metastatic spine disease. METHODS: In our study patients medical data was analyzed from 2013 to 2015. The analysis covered the following aspects: symptoms of metastases, time of neurological deficits occurrence, where and when initial diagnostics were performed, time from diagnosis to proper surgical treatment in an oncological centre. In total, 411 patients were consulted and 287 were operated on. Of 112 patients with neurological deficits, 64 underwent surgeries. Women represented the majority of the patients. The most common primary neoplasms were breast cancer and myeloma. RESULTS: In 75% of the patients neurological symptoms occurred prior to admission to a hospital. The average time between the onset of neurological symptoms and medical consultation was 4 days. The patients were diagnosed mainly at neurologic, orthopedic and emergency departments. The mean time between undergoing radiological examinations and receiving the examinations results was 2.4 days for CT and 2.8 days for MRI. The average time between a patients' admission from the department where they were initially diagnosed, to the orthopedic oncology ward was 4.5 days. CONCLUSIONS: The most common cause of the delayed treatment of patients with neurological deficits, in the course of metastatic spine disease, is a combination of the lack of knowledge among patients and healthcare personnel regarding the necessity of early diagnosis. PMID- 29514668 TI - Integrated cost-benefit analysis of tsetse control and herd productivity to inform control programs for animal African trypanosomiasis. AB - BACKGROUND: Animal African trypanosomiasis (AAT) and its tsetse vector are responsible for annual losses estimated in billions of US dollars ($). Recent years have seen the implementation of a series of multinational interventions. However, actors of AAT control face complex resource allocation decisions due to the geographical range of AAT, diversity of ecological and livestock systems, and range of control methods available. METHODS: The study presented here integrates an existing tsetse abundance model with a bio-economic herd model that captures local production characteristics as well as heterogeneities in AAT incidence and breed. These models were used to predict the impact of tsetse elimination on the net value of cattle production in the districts of Mambwe, in Zambia, and Faro et Deo in Cameroon. The net value of cattle production under the current situation was used as a baseline, and compared with alternative publicly funded control programmes. In Zambia, the current baseline is AAT control implemented privately by cattle owners (Scenario Z0). In Cameroon, the baseline (Scenario C0) is a small-scale publicly funded tsetse control programme and privately funded control at farm level. The model was run for 10 years, using a discount rate of 5%. RESULTS: Compared to Scenario C0, benefit-cost ratios (BCR) of 4.5 (4.4-4.7) for Scenario C1 (tsetse suppression using insecticide treatment of cattle (ITC) and traps + maintenance with ITC barrier), and 3.8 (3.6-4.0) for Scenario C2 (tsetse suppression using ITC and traps + maintenance with barrier of targets), were estimated in Cameroon. For Zambia, the benefit-cost ratio calculated for Scenarios Z1 (targets, ITC barrier), Z2 (targets, barrier traps), Z3 (aerial spraying, ITC barrier), and Z4 (aerial spraying, barrier traps) were 2.3 (1.8 - 2.7), 2.0 (1.6-2.4), 2.8 (2.3-3.3) and 2.5 (2.0-2.9), respectively. Sensitivity analysis showed that the profitability of the projects is relatively resistant to variations in the costs of the interventions and their technical efficiency. CONCLUSIONS: It is envisioned that the methodologies presented here will be useful for the evaluation and design of existing and future control programmes, ensuring they have tangible benefits in the communities they are targeting. PMID- 29514667 TI - Bacillus subtilis spore with surface display of paramyosin from Clonorchis sinensis potentializes a promising oral vaccine candidate. AB - BACKGROUND: Clonorchiasis caused by Clonorchis sinensis has become increasingly prevalent in recent years. Effective prevention strategies are urgently needed to control this food-borne infectious disease. Previous studies indicated that paramyosin of C. sinensis (CsPmy) is a potential vaccine candidate. METHODS: We constructed a recombinant plasmid of PEB03-CotC-CsPmy, transformed it into Bacillus subtilis WB600 strain (B.s-CotC-CsPmy), and confirmed CsPmy expression on the spore surface by SDS-PAGE, Western blotting and immunofluorescence assay. The immune response and protective efficacy of the recombinant spore were investigated in BALB/c mice after intragastrical or intraperitoneal immunization. Additionally, biochemical enzyme activities in sera, the intestinal histopathology and gut microflora of spore-treated mice were investigated. RESULTS: CsPmy was successfully expressed on the spore surface and the fusion protein on the spore surface with thermostability. Specific IgG in sera and intestinal mucus were increased after intraperitoneal and intragastrical immunization. The sIgA level in intestinal mucus, feces and bile of B.s-CotC CsPmy orally treated mice were also significantly raised. Furthermore, numerous IgA-secreting cells were detected in intestinal mucosa of intragastrically immunized mice. No inflammatory injury was observed in the intestinal tissues and there was no significant difference in levels of enzyme-indicated liver function among the groups. Additionally, the diversity and abundance of gut microbiota were not changed after oral immunization. Intragastric and intraperitoneal immunization of B.s-CotC-CsPmy spores in mice resulted in egg reduction rates of 48.3 and 51.2% after challenge infection, respectively. Liver fibrosis degree in B.s-CotC-CsPmy spores treated groups was also significantly reduced. CONCLUSIONS: CsPmy expressed on the spore surface maintained its immunogenicity. Both intragastrical and intraperitoneal immunization with B.s-CotC-CsPmy spores induced systemic and local mucosal immune response in mice. Although both intragastric and intraperitoneal immunization elicited a similar protective effect, intragastric immunization induced stronger mucosal immune response without side effects to the liver, intestine and gut microbiota, compared with intraperitoneal immunization. Oral immunization with B. subtilis spore expressing CsPmy on the surface was a promising, safe and needle-free vaccination strategy against clonorchiasis. PMID- 29514669 TI - Online-based interventions for sexual health among individuals with cancer: a systematic review. AB - BACKGROUND: Online interventions have the advantages of being widely available, accessible, comfortable, cost effective, and they can provide tailored information and support. Despite these benefits, the effects of specifically devised online intervention programs for cancer patients' sexual problems are somewhat unclear. The aim of this review is to describe online-based interventions and to assess their effects on sexual health among cancer survivors and/or their partners. METHODS: We investigated the effects of online sexual interventions among individuals with cancer or their partners. Among these, we considered 4 eligible articles. RESULTS: Despite the diversity of contents of the interventions, the identified modes of delivery among most of the interventions were as follows: education, interactive methods, cognitive behavior therapy, tailored information, and self-monitoring. Methods of monitoring the interventions, including the utilization of the web site and post-treatment program rating, were reported. All the online intervention programs incorporated a focus on physical, psychological, cognitive, and social aspects of sexual health. Significant effects on patient sexual function and interest and the psychological aspect of sexual problems were reported. CONCLUSION: This study provides evidence that online-based interventions would be effective in improving the psycho-sexual problems of cancer survivors and their partners. PMID- 29514670 TI - Antihypertensive drugs use and the risk of prostate cancer: a meta-analysis of 21 observational studies. AB - BACKGROUND: Due to the lack of strong evidence to identify the relationship between antihypertensive drugs use and the risk of prostate cancer, it was needed to do a systematic review to go into the subject. METHODS: We systematically searched PubMed, Web of Science and Embase to identify studies published, through May 2015. Two evaluators independently reviewed and selected articles involving the subject. We used the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies. All extracted results to evaluate the relationship between antihypertensive drugs usage and prostate cancer risk were pool-analysed using Stata 12.0 software. RESULTS: A total of 12 cohort and 9 case-control studies were ultimately included in our review. Most of the studies were evaluated to be of high quality. There was no significant relationship between angiotensin converting enzyme inhibitors (ACEI) usage and the risk of prostate cancer (RR 1.07, 95% CI 0.96-1.20), according to the total pool-analysed. Use of angiotensin receptor blocker (ARB) was not associated with the risk of prostate cancer (RR 1.09, 95% CI 0.97-1.21), while use of CCB may well increase prostate cancer risk based on the total pool-analysed (RR 1.08, 95% CI 1-1.16). Moreover, subgroup analysis suggested that use of CCB clearly increased prostate cancer risk (RR 1.10, 95% CI 1.04-1.16) in terms of case-control studies. There was also no significant relationship between use of diuretic (RR 1.09, 95% CI 0.95-1.25) or antiadrenergic agents (RR 1.22, 95% CI 0.76-1.96) and prostate cancer risk. CONCLUSIONS: There is no significant relationship between the use of antihypertensive drugs (ACEI, ARB, beta-blockers and diuretics) and prostate cancer risk, but CCB may well increase prostate cancer risk, according to existing observational studies. PMID- 29514671 TI - Temporomandibular disorders and psychosocial status in osteogenesis imperfecta - a cross-sectional study. AB - BACKGROUND: Osteogenesis Imperfecta (OI) is characterized by a number of deviations in the orofacial region. The aims of the present study were to investigate the occurrence of temporomandibular disorders, to evaluate the psychosocial status, and to assess the dental occlusion in a population of adult OI patients. METHODS: Participants (n = 75) were classified with mild OI, type I (n = 56), or moderate-severe OI, type III and IV (n = 19). OI patients were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders (axis I and II). RESULTS: Temporomandibular disorders and functional limitations in the orofacial region were rare and did not differ between patients with mild and moderate-severe OI (P > 0.050). No significant differences between Graded Chronic Pain Scale grades 0, 1, and 2 were found in mild OI vs. moderate severe OI (P > 0.160). Few patients (16%) had signs of depression, but close to half (48%) had signs of somatization. Patients with moderate-severe OI had a lower mean number of teeth compared to patients with mild OI (P < 0.050). In general, malocclusions were prevalent, and mandibular overjet and posterior cross bite were found more often in moderate-severe OI compared with mild (P < 0.050). CONCLUSIONS: Patients with moderate-severe OI had more malocclusions than patients with mild OI. The psychosocial status of OI patients was remarkably healthy considering the severity of this disabling systemic disorder. The bodily pain complaints frequently reported in OI patients were not largely reflected in the orofacial area as painful temporomandibular disorders. PMID- 29514672 TI - The origins of breast cancer associated with mammographic density: a testable biological hypothesis. AB - BACKGROUND: Our purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases. METHODS: We used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population. RESULTS: Extensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population. CONCLUSIONS: These findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions. PMID- 29514673 TI - Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts. AB - BACKGROUND: Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. METHODS: In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 MUL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 MUl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. 18F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). RESULTS: A T/B >= 3.59 on pre-treatment 18F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B >= 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. CONCLUSIONS: Tumor tissue hypoxia as measured with 18F FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation. PMID- 29514674 TI - Need for normalization: the non-standard reference standard for microvascular invasion diagnosis in hepatocellular carcinoma. AB - BACKGROUND: Preoperative microvascular invasion (MVI) assessment in hepatocellular carcinoma (HCC) is one of the current research focuses, with studies reporting controversial results regarding MVI-associated risk factors. As a possible source of bias, reported MVI rate (percentage of MVI-positive patients) varies a lot among studies. Pathological examination should have been the golden criteria of MVI diagnosis, but no standard and generally adopted pathological examination protocol exists. METHODS AND RESULTS: It is highly possible that underestimated pathological diagnosis of MVI exists. We present two likely examples to stress the problem and indicate the root of the problem partially being an unreliable pathological examination. Results of studies basing on unreliable reference standard can be less convincing and even misleading, which is the most basic and fundamental problem in this research field. CONCLUSION: There is an urgent need to settle the disputes regarding pathological sampling, microscopy, and reporting, in order to promote future academic exchange and consensus development on MVI assessment. Several concerns about pathological MVI assessment should be focused on in the future research as we put up in the review. PMID- 29514675 TI - Detection of differentially expressed genes involved in osteoarthritis pathology. AB - BACKGROUND: Osteoarthritis (OA) is the most common chronic disorder of joints; however, the key genes and transcription factors (TFs) associated with OA are still unclear. Through bioinformatics tools, the study aimed to understand the mechanism of genes associated with the development of OA. METHODS: Four gene expression profiling datasets were used to identify differentially expressed genes (DEGs) between OA and healthy control samples by a meta-analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed with Multifaceted Analysis Tool for Human Transcriptome (MATHT). Subsequently, a protein-protein interaction (PPI) network was constructed for these DEGs. Significant network modules were identified using ReactomeFIViz, and the pathway of each module was enriched using MATHT. In addition, TFs in the DEGs were identified. RESULTS: In total, 690 DEGs were identified between OA and healthy control samples, including 449 upregulated and 241 downregulated DEGs. Additionally, 622 nodes and 2752 interactions constituted the PPI network, including 401 upregulated and 221 downregulated DEGs. Among them, FOS, TWIST1, POU2F1, SMARCA4, and CREBBP were also identified as TFs. RT-PCR results showed that the expression levels of Fos, Twist1, Pou2f1, Smarca4, and Crebbp decreased in mice with OA. In addition, FOS, TWIST1, SMARCA4, and CREBBP were involved in the positive regulation of transcription from the RNA polymerase II promoter. CONCLUSIONS: TWIST1, POU2F1, SMARCA4, and CREBBP may play an important role in OA pathology. PMID- 29514676 TI - The effects of home-based primary care on Medicare costs at Spectrum Health/Priority Health (Grand Rapids, MI, USA) from 2012-present: a matched cohort study. AB - BACKGROUND: In the United States, home-based primary care (HBPC) is increasingly proposed as a means of enabling frail elders to remain at home for as long as possible, while still receiving needed medical care. However, there are relatively few studies of either the medical outcome effects or cost benefits of HBPC. In this paper, we examine medical cost and mortality outcomes for enrollees in the HBPC program offered by Spectrum Health/Priority Health (SH/PH), a not-for profit integrated health care/health insurance system located in Grand Rapids, MI, USA. METHODS: We perform a concurrent matched cohort study. SH/PH HBPC enrollees during 2012-2014 are matched for prior costs, age, sex and comorbidities against controls selected from unenrolled insurance plan members. Twelve and twenty four-month medical costs are compared between HBPC participants and matched controls, overall and conditional on mortality status. Mortality rates of HBPC participants are studied on their own and in comparison to controls. RESULTS: At 12 and 24 months, in comparison to matched controls HBPC participants show higher ($2933) and lower ($8620) costs respectively. Relative costs and savings of HBPC participants are a function of short term increased costs upon entry into the program (enrollees who survive the first year cost $5866 more than controls); substantial savings at end-of-life (approximately $37,037 in savings relative to controls are realized); and the overall mortality of HBPC participants (mean residual lifespan is 37.75 months from the time of enrollment). We project the present value of lifetime medical cost savings due to enrollment in the HBPC program to be at least $14,336. CONCLUSIONS: The SH/PC HBPC program reduces healthcare costs while enabling frail elders to remain at home. Reduction in costs is obtained at end-of-life and is offset with a smaller initial increase in costs upon enrollment. PMID- 29514677 TI - Effectiveness of a combination of cognitive behavioral therapy and task-oriented balance training in reducing the fear of falling in patients with chronic stroke: study protocol for a randomized controlled trial. AB - BACKGROUND: The consequences of falls are devastating for patients with stroke. Balance problems and fear of falling are two major challenges, and recent systematic reviews have revealed that habitual physical exercise training alone cannot reduce the occurrence of falls in stroke survivors. However, recent trials with community-dwelling healthy older adults yielded the promising result that interventions with a cognitive behavioral therapy (CBT) component can simultaneously promote balance and reduce the fear of falling. Therefore, the aim of the proposed clinical trial is to evaluate the effectiveness of a combination of CBT and task-oriented balance training (TOBT) in promoting subjective balance confidence, and thereby reducing fear-avoidance behavior, improving balance ability, reducing fall risk, and promoting independent living, community reintegration, and health-related quality of life of patients with stroke. METHODS: The study will constitute a placebo-controlled single-blind parallel group randomized controlled trial in which patients are assessed immediately, at 3 months, and at 12 months. The selected participants will be randomly allocated into one of two parallel groups (the experimental group and the control group) with a 1:1 ratio. Both groups will receive 45 min of TOBT twice per week for 8 weeks. In addition, the experimental group will receive a 45-min CBT-based group intervention, and the control group will receive 45 min of general health education (GHE) twice per week for 8 weeks. The primary outcome measure is subjective balance confidence. The secondary outcome measures are fear-avoidance behavior, balance ability, fall risk, level of activities of daily living, community reintegration, and health-related quality of life. DISCUSSION: The proposed clinical trial will compare the effectiveness of CBT combined with TOBT and GHE combined with TOBT in promoting subjective balance confidence among chronic stroke patients. We hope our results will provide evidence of a safe, cost-effective, and readily transferrable therapeutic approach to clinical practice that reduces fear-avoidance behavior, improves balance ability, reduces fall risk, promotes independence and community reintegration, and enhances health related quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02937532 . Registered on 17 October 2016. PMID- 29514678 TI - Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model. AB - BACKGROUND: In multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial. METHODS: Using an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG35-55-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves. RESULTS: All forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes. CONCLUSIONS: A prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful. PMID- 29514679 TI - Quality assurance target for community-based breast cancer screening in China: a model simulation. AB - BACKGROUND: We aimed to clarify the feasibility of a community-based screening strategy for breast cancer in Tianjin, China; to identify the factors that most significantly influenced its feasibility; and to identify the reference range for quality control. METHODS: A state-transition Markov model simulated a hypothetical cohort of 100,000 healthy women, the start aged was set at 35 years and the time horizon was set to 50 years. The primary outcome for the model was the incremental cost-utility ratio (ICUR), defined as the program's cost per quality-adjusted life year (QALY) gained. Three screening strategies providing by community health service for women aged 35 to 69 years was compared regarding to different intervals. RESULT: The probability of the ICUR being below 20 272USD (i.e., triple the annual gross domestic product [3 GDPs]) per QALY saved was 100% for annual screening strategy and screening every three years. Only when the attendance rate was > 50%, the probability for annual screening would be cost effective > 95%. The probability for the annual screening strategy being cost effective could reach to 95% for a willingness-to-pay (WTP) of 2 GDPs when the compliance rate for transfer was > 80%. When 10% stage I tumors were detected by screening, the probability of the annual screening strategy being cost effective would be up to 95% for a WTP > 3 GDPs. CONCLUSION: Annual community-based breast cancer screening was cost effective for a WTP of 3 GDP based on the incidence of breast cancer in Tianjin, China. Measures are needed to ensure performance indicators to a desirable level for the cost-effectiveness of breast cancer screening. PMID- 29514680 TI - Environmental suitability for Lutzomyia (Nyssomyia) whitmani (Diptera: Psychodidae: Phlebotominae) and the occurrence of American cutaneous leishmaniasis in Brazil. AB - BACKGROUND: Leishmaniasis represents an important public health problem in Brazil. The continuous process of urbanization and expansion of human activities in forest areas impacts natural habitats, modifying the ecology of some species of Leishmania, as well as its vectors and reservoirs and, consequently, changes the epidemiological pattern that contributes to the expansion of American cutaneous leishmaniasis in Brazil. Here, we discuss Lutzomyia (Nyssomyia) whitmani, the main vector of ACL, transmitting two dermotropic Leishmania species including Leishmania (Viannia) braziliensis and Leishmania (V.) shawi. METHODS: We used the maximum entropy niche modelling approach (MaxEnt) to evaluate the environmental suitability of L. (N.) whitmani and the transmission of ACL in Brazil, in addition to designing models for a future scenario of climate change. MaxEnt was used under the "auto-features" mode and the default settings, with 100 fold repetition (bootstrap). The logistic output was used with higher values in the habitat suitability map, representing more favourable conditions for the occurrence of L. (N.) whitmani and human cases of ACL. RESULTS: Two models were developed: the Lutzomyia (N.) whitmani model (LWM) and the American cutaneous leishmaniasis model (ACLM). LWM identified the species "preferential habitat" included regions with moderate annual precipitation (AP) between 1000-1600 mm, intermediate vegetation density (NDVI) values, mean temperature of the coldest quarter (MTCQ), between 15-21 degrees C, and annual mean temperature (AMT), between 19-24 degrees C. ACLM indicates that ACL is strongly associated with areas of intermediate density vegetation, areas with AP between 800-1200 mm, MTCQ above 16 degrees C and AMT below 23 degrees C. CONCLUSIONS: The models generated for L. (N.) whitmani and ACL indicated a satisfactory predictive capacity. Future projections of LWM indicate an expansion of climatic suitability for L. (N.) whitmani for the northern and southern regions of Brazil. Future projections of ACL indicate the ongoing process of disease expansion in the face of the predicted climatic changes and reinforce the broad geographical expanse of this disease in Brazil. The models were able to identify that a continuous process of environmental degradation favours the establishment of L. (N.) whitmani and the occurrence of ACL by a strong association of the vector(s) and ACL to areas of intermediate vegetation cover density. PMID- 29514681 TI - Teamwork in primary palliative care: general practitioners' and specialised oncology nurses' complementary competencies. AB - BACKGROUND: Generalists such as general practitioners and district nurses have been the main actors in community palliative care in Norway. Specialised oncology nurses with postgraduate palliative training are increasingly becoming involved. There is little research on their contribution. This study explores how general practitioners (GPs) and oncology nurses (ONs) experience their collaboration in primary palliative care. METHODS: A qualitative focus group and interview study in rural Northern Norway, involving 52 health professionals. Five uni professional focus group discussions were followed by five interprofessional discussions and six individual interviews. Transcripts were analysed thematically. RESULTS: The ideal cooperation between GPs and ONs was as a "meeting of experts" with complementary competencies. GPs drew on their generalist backgrounds, including their often long-term relationship with and knowledge of the patient. The ONs contributed longitudinal clinical observations and used their specialised knowledge to make treatment suggestions. While ONs were often experienced and many had developed a form of pattern recognition, they needed GPs' competencies for complex clinical judgements. However, ONs sometimes lacked timely advice from GPs, and could feel left alone with sick patients. To avoid this, some ONs bypassed GPs and contacted palliative specialists directly. While traditional professional hierarchies were not a barrier, we found that organization, funding and remuneration were significant barriers to cooperation. GPs often did not have time to meet with ONs to discuss shared patients. We also found that ONs and GPs had different strategies for learning. While ONs belonged to a networking nursing collective aiming for continuous quality improvement, GPs learned mostly from their individual experience of caring for patients. CONCLUSIONS: The complementary competences and autonomous roles of a specialised nurse and a general practitioner represented a good match for primary palliative care. When planning high-quality teamwork in primary care, organizational barriers to cooperation and different cultures for learning need consideration. PMID- 29514682 TI - A feasibility study for NOn-Traditional providers to support the management of Elderly People with Anxiety and Depression: The NOTEPAD study Protocol. AB - BACKGROUND: Anxiety and depression are common among older people, with up to 20% reporting such symptoms, and the prevalence increases with co-morbid chronic physical health problems. Access to treatment for anxiety and depression in this population is poor due to a combination of factors at the level of patient, practitioner and healthcare system. There is evidence to suggest that older people with anxiety and/or depression may benefit both from one-to-one interventions and group social or educational activities, which reduce loneliness, are participatory and offer some activity. Non-traditional providers (support workers) working within third-sector (voluntary) organisations are a valuable source of expertise within the community but are under-utilised by primary care practitioners. Such a resource could increase access to care, and be less stigmatising and more acceptable for older people. METHODS: The study is in three phases and this paper describes the protocol for phase III, which will evaluate the feasibility of recruiting general practices and patients into the study, and determine whether support workers can deliver the intervention to older people with sufficient fidelity and whether this approach is acceptable to patients, general practitioners and the third-sector providers. Phase III of the NOTEPAD study is a randomised controlled trial (RCT) that is individually randomised. It recruited participants from approximately six general practices in the UK. In total, 100 participants aged 65 years and over who score 10 or more on PHQ9 or GAD7 for anxiety or depression will be recruited and randomised to the intervention or usual general practice care. A mixed methods approach will be used and follow-up will be conducted 12 weeks post-randomisation. DISCUSSION: This study will inform the design and methods of a future full-scale RCT. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN16318986 . Registered 10 November 2016. The ISRCTN registration is in line with the World Health Organization Trial Registration Data Set. The present paper represents the original version of the protocol. Any changes to the protocol will be communicated to ISRCTN. PMID- 29514683 TI - A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/beta-catenin pathways for treatment of AML with high PRL-3 phosphatase. AB - BACKGROUND: Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor. METHODS: In this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism. RESULTS: The list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/beta-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/beta-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG 001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/beta-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells. CONCLUSIONS: In summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/beta-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation. PMID- 29514684 TI - Dentists' perception, knowledge, and clinical management of molar-incisor hypomineralisation in Kuwait: a cross-sectional study. AB - BACKGROUND: Molar-incisor Hypomineralisation (MIH) is considered as a global dental problem. There is little knowledge of general dental practitioners (GDPs) and dental specialists (DSs) about this condition in different parts of the world, particularly in Gulf Cooperation Council (GCC) countries. Hence, this study has been carried out to assess the knowledge of GDPS and DSs in Kuwait about MIH condition, its clinical presentation and management. Findings would help national school oral health program (SOHP) to promote good oral healthcare. METHODS: A structured questionnaire was distributed to 310 attendees of the 18th Kuwait Dental Association Scientific Conference, Kuwait. Data concerning demographic variables, prevalence, diagnosis, severity, training demands and clinical management of MIH were collected. RESULTS: A response rate of 71.3% (221/310) was reported. 94% of respondents noticed MIH in their practice. Yellow/brown demarcation has been observed as a common clinical presentation (> 50%). Almost 10-20% of MIH prevalence has been reported by the participants. Resin composite was the dental material often used in treating MIH teeth (~ 65%), and fewer than half would use it for treating moderately affected molars. Most respondents would use preformed metal crowns for severe MIH (63%). Dental journals were the information source for DSs; whereas, the internet was the information source for GDPs. Child's behaviour was the main reported barrier for treatment of MIH affected children. Many GDPs felt unconfident when diagnosing MIH compared to dental specialists. Respondents supported the need to investigate MIH prevalence and to receive a clinical training. CONCLUSIONS: Molar incisor hypomineralisation is a recognised dental condition by practitioners in Kuwait. Yellow/brown demarcated opacities were the most reported clinical presentation, and the composite resin was the most preferred dental material for restoring MIH teeth. Most GDPs and dental specialists would use preformed metal crowns for severely affected molars. GDPs reported low levels of confidence in MIH diagnosis which necessitates conducting continuing education courses to provide high- quality dental care for children with MIH. PMID- 29514685 TI - Sex as predictor for achieved health outcomes and received care in ischemic stroke and intracerebral hemorrhage: a register-based study. AB - BACKGROUND: Differences in stroke care and health outcomes between men and women are debated. The objective of this study was to explore the relationship between patients' sex and post-stroke health outcomes and received care in a Swedish setting. METHODS: Patients with a registered diagnosis of acute intracerebral hemorrhage (ICH) or ischemic stroke (IS) within regional administrative systems (ICD-10 codes I61* or I63*) and the Swedish Stroke Register during 2010-2011 were included and followed for 1 year. Data linkage to multiple other data sources on individual level was performed. Adjustments were performed for age, socioeconomic factors, living arrangements, ADL dependency, and stroke severity in multivariate regression analyses of health outcomes and received care. Health outcomes (e.g., survival, functioning, satisfaction) and received care measures (regional and municipal resources and processes) were studied. RESULTS: Study population: 13,775 women and 13,916 men. After case-mix adjustments for the above factors, we found women to have higher 1-year survival rates after both IS (ORfemale = 1.17, p < 0.001) and ICH (ORfemale = 1.65, p < 0.001). Initial inpatient stay at hospital was, however, shorter for women (betafemale, IS = - 0.05, p < 0.001; betafemale, ICH = - 0.08, p < 0.005). For IS, good function (mRS <= 2) was more common in men (ORfemale = 0.86, p < 0.001) who also received more inpatient care during the first year (betafemale = - 0.05, p < 0.001). CONCLUSIONS: A lower proportion of women had good functioning, a difference that remained in IS after adjustments for age, socioeconomic factors, living arrangements, ADL dependency, and stroke severity. The amount of received hospital care was lower for women after adjustments. Whether shorter hospital stay results in lower function or is a consequence of lower function cannot be elucidated. One-year survival was higher in men when no adjustments were made but lower after adjustments. This likely reflects that women were older at time of stroke, had more severe strokes, and more disability pre-stroke-factors that make a direct comparison between the sexes intricate. PMID- 29514686 TI - Inhibition of cell-adhesion protein DPYSL3 promotes metastasis of lung cancer. AB - BACKGROUND: Our previous screening study suggested that the cell-adhesions protein Dihydropyrimidinase-like 3 (DPYSL3) was a candidate metastatic lung cancer related molecule. This study aimed to analyze the correlation between DPYSL3 and metastatic lung cancer. METHODS: Stable DPYSL3 knockdown Lewis lung carcinoma (LLC) cells were constructed with a retroviral system. Cell migration and invasion assays were performed to determine the role of DPYSL3 in LLC cells' migration and invasion changes. A metastatic lung tumor model in which the stable DPYSL3 knockdown LLC cells were injected through tail vein was used to analyze the role of DPYSL3 in tumor metastasis in vivo. The correlation between DPYSL3 expression and the survival time of lung cancer patients were analyzed in KMPLOT database. RESULTS: Knockdown of DPYSL3 promoted the migratory and invasive of LLC cells compared to the control group. Meanwhile, the motility of LLC cells was also increased with the inhibition of DPYSL3. The TGFbeta-induced EMT increased when DPYSL3 was inhibited. The expression of EMT markers, TWIST1 and N-cadherin, significantly increased to almost two times with the knockdown of DPYSL3. Furthermore, inhibition of DPYSL3 promoted the progression of metastatic xenograft in C57BL/6 mice. The expression level of DPYSL3 decreased in lung cancer patients with distant metastasis. CONCLUSIONS: Knockdown of DPYSL3 promoted the metastatic ability of LLC cells in vitro and in vivo. PMID- 29514687 TI - A synthesis of the patho-physiology of Mycobacterium avium subspecies paratuberculosis infection in sheep to inform mathematical modelling of ovine paratuberculosis. AB - This literature review of exposure to Mycobacterium avium subsp. paratuberculosis (MAP) in sheep enabled a synthesis of the patho-physiology of ovine paratuberculosis (PTB). These results could be used to inform subsequent modelling of ovine PTB. We reviewed studies of both experimental and natural exposure. They were generally comparable. Possible outcomes following exposure were latent infection, i.e. mere colonization without lesions; active infection, with inflammatory histopathology in the intestinal tissues resulting in mild disease and low faecal shedding; and affection, with severe intestinal pathology, reduced production, clinical signs and high faecal shedding. Latent infection was an uninformative outcome for modelling. By contrast, histological lesions and their grade appeared to be a good marker of active infection and progression stages to clinical disease. The two possible pathways following infection are non progression leading to recovery and progression to clinical disease, causing death. These pathways are mediated by different immune mechanisms. This synthesis suggested that host-related characteristics such as age at exposure and breed, combined with pathogen-related factors such as MAP dose, strain and inoculum type for experimental infection, have a strong influence on the outcome of exposure. The material reviewed consisted of disparate studies often with low numbers of sheep and study-level confounders. Hence comparisons between and across studies was difficult and this precluded quantitative model parameter estimation. Nevertheless, it allowed a robust synthesis of the current understanding of patho physiology of ovine PTB, which can inform mathematical modelling of this disease. PMID- 29514688 TI - Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer. AB - The plasmalogens are a class of glycerophospholipids which contain a vinyl-ether and an ester bond at the sn-1 and sn-2 positions, respectively, in the glycerol backbone. They constitute 10 mol% of the total mass of phospholipids in humans, mainly as membrane structure components. Plasmalogens are important for the organization and stability of lipid raft microdomains and cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Although the clinical significance of plasmalogens is linked to peroxisomal disorders, the pathophysiological roles and their possible metabolic pathways are not fully understood since they present unique structural attributes for the different tissue types. Studies suggest that changes in plasmalogen metabolism may contribute to the development of various types of cancer. Here, we review the molecular characteristics of plasmalogens in order to significantly increase our understanding of the plasmalogen molecule and its involvement in gastrointestinal cancers as well as other types of cancers. PMID- 29514689 TI - Patient-identified information and communication needs in the context of major trauma. AB - BACKGROUND: Navigating complex health care systems during the multiple phases of recovery following major trauma entails many challenges for injured patients. Patients' experiences communicating with health professionals are of particular importance in this context. The aim of this study was to explore seriously injured patients' perceptions of communication with and information provided by health professionals in their first 3-years following injury. METHODS: A qualitative study designed was used, nested within a population-based longitudinal cohort study. Semi-structured telephone interviews were undertaken with 65 major trauma patients, aged 17 years and older at the time of injury, identified through purposive sampling from the Victorian State Trauma Registry. A detailed thematic analysis was undertaken using a framework approach. RESULTS: Many seriously injured patients faced barriers to communication with health professionals in the hospital, rehabilitation and in the community settings. Key themes related to limited contact with health professionals, insufficient information provision, and challenges with information coordination. Communication difficulties were particularly apparent when many health professionals were involved in patient care, or when patients transitioned from hospital to rehabilitation or to the community. Difficulties in patient-health professional engagement compromised communication and exchange of information particularly at transitions of care, e.g., discharge from hospital. Conversely, positive attributes displayed by health professionals such as active discussion, clear language, listening and an empathetic manner, all facilitated effective communication. Most patients preferred communication consistent with patient centred approaches, and the use of multiple modes to communicate information. CONCLUSIONS: The communication and information needs of seriously injured patients were inconsistently met over the course of their recovery continuum. To assist patients along their recovery trajectories, patient-centred communication approaches and considerations for environmental and patients' health literacy are recommended. Additionally, assistance with information coordination and comprehensive multimodal information provision should be available for injured patients. PMID- 29514690 TI - Effect of physical exercise on spontaneous physical activity energy expenditure and energy intake in overweight adults (the EFECT study): a study protocol for a randomized controlled trial. AB - BACKGROUND: Physical exercise interventions have been extensively advocated for the treatment of obesity; however, clinical trials evaluating the effectiveness of exercise interventions on weight control show controversial results. Compensatory mechanisms through a decrease in energy expenditure and/or an increase in caloric consumption is a possible explanation. Several physiological mechanisms involved in the energy balance could explain compensatory mechanisms, but the influences of physical exercise on these adjustments are still unclear. Therefore, the present trial aims to evaluate the effects of exercise on non exercise physical activity energy expenditure, energy intake and appetite sensations among active overweight/obese adults, as well as, to investigate hormonal changes associated with physical exercise. METHODS: This study is a randomized controlled trial with parallel, three-group experimental arms. Eighty one overweight/obese adults will be randomly allocated (1:1:1 ratio) to a vigorous exercise group, moderate exercise group or control group. The trial will be conducted at a military institution and the intervention groups will be submitted to exercise sessions in the evening, three times a week for 65 min, during a 2-week period. The primary outcome will be total spontaneous physical activity energy expenditure during a 2-week period. Secondary outcomes will be caloric intake, appetite sensations and laboratorial biomarkers. Intention-to treat analysis will be performed using linear mixed-effects models to evaluate the effect of treatment-by-time interaction on primary and secondary outcomes. Data analysis will be performed using SAS 9.3 and statistical significance will be set at p < 0.05. DISCUSSION: The results of the present study will help to understand the effect of physical exercise training on subsequent non-exercise physical activity, appetite and energy intake as well as understand the physiological mechanisms underlying a possible compensatory phenomenon, supporting the development of more effective interventions for prevention and treatment of obesity. TRIAL REGISTRATION: Physical Exercise and Energy Balance trial registry, trial registration number: NCT 03138187 . Registered on 30 April 2017. PMID- 29514692 TI - The ethnoprimatology of the Maijuna of the Peruvian Amazon and implications for primate conservation. AB - BACKGROUND: In Amazonia, primates are not only an important food source but they also hold significant cultural and symbolic value for many indigenous groups. We document the relationship between primates and community members of the Maijuna indigenous community of Sucusari in the Peruvian Amazon and describe how ethnoprimatological studies provide a better understanding of the significance of primates in people's lives. Additionally, we explore how ethnoprimatological studies can help inform and enhance primate conservation initiatives. METHODS: Semi-structured interviews were conducted with 50 residents of the community of Sucusari to assess the classification, cultural significance and traditional uses, beliefs, ceremonies and stories of primates within the Sucusari River basin. RESULTS: Primates play an important role in the lives of individuals in the Sucusari community. They are distinguished by their arboreal lifestyle, and among the 11 species reported in the area, seven (Lagothrix lagotricha, Alouatta seniculus, Pithecia monachus, Callicebus spp., Saimiri sciureus, Leontocebus nigricollis) are highly recognized and culturally salient. Primates are used as food, medicine, pets, domestic tools and in the production of handicrafts. They are primarily hunted for local consumption, with larger primates such as L. lagotricha being preferred. Lagothrix lagotricha was also the most commonly reported pet species and the only observed pet primate in the community during surveys. Maijuna traditional beliefs include ancestral dietary taboos for A. seniculus, which are referred to as sorcerer monkeys, but this taboo is no longer fully adhered to. Maijuna traditional stories associated with primates describe the origin of primates found in Sucusari. CONCLUSION: Primates are embedded in the intricate sociocultural system of the community of Sucusari. Better understanding the relationship between primates and people can help to focus conservation efforts on primate species of particularly high sociocultural importance as well as ecological value, such as L. lagotricha. We highly recommend the inclusion of ethnoprimatological studies into primate conservation initiatives to accomplish more effective conservation planning, ultimately integrating the goals of biodiversity conservation with the cultural and economic needs of indigenous and local communities. PMID- 29514691 TI - Systems biology as an emerging paradigm in transfusion medicine. AB - Blood transfusions are an important part of modern medicine, delivering approximately 85 million blood units to patients annually. Recently, the field of transfusion medicine has started to benefit from the "omic" data revolution and corresponding systems biology analytics. The red blood cell is the simplest human cell, making it an accessible starting point for the application of systems biology approaches.In this review, we discuss how the use of systems biology has led to significant contributions in transfusion medicine, including the identification of three distinct metabolic states that define the baseline decay process of red blood cells during storage. We then describe how a series of perturbations to the standard storage conditions characterized the underlying metabolic phenotypes. Finally, we show how the analysis of high-dimensional data led to the identification of predictive biomarkers.The transfusion medicine community is in the early stages of a paradigm shift, moving away from the measurement of a handful of chosen variables to embracing systems biology and a cell-scale point of view. PMID- 29514693 TI - Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trial. AB - BACKGROUND: Kidneys from deceased donors are being used to meet the growing need for grafts. However, delayed graft function (DGF) and acute rejection incidences are high, leading to adverse effects on graft outcomes. Optimal induction intervention should include both renal structure injury repair and immune response suppression. Mesenchymal stem cells (MSCs) with potent anti inflammatory, regenerative, and immune-modulatory properties are considered a candidate to prevent DGF and acute rejection in renal transplantation. Thus, this prospective multicenter paired study aimed to assess the clinical value of allogeneic MSCs as induction therapy to prevent both DGF and acute rejection in deceased donor renal transplantation. METHODS: Forty-two renal allograft recipients were recruited and divided into trial and control groups. The trial group (21 cases) received 2 * 106/kg human umbilical-cord-derived MSCs (UC-MSCs) via the peripheral vein before renal transplantation, and 5 * 106 cells via the renal artery during the surgical procedure. All recipients received standard induction therapy. Incidences of DGF and biopsy-proven acute rejection were recorded postoperatively and severe postoperative complications were assessed. Graft and recipient survivals were also evaluated. RESULTS: Treatment with UC MSCs achieved comparable graft and recipient survivals with non-MSC treatment (P = 0.97 and 0.15, respectively). No increase in postoperative complications, including DGF and acute rejection, were observed (incidence of DGF: 9.5% in the MSC group versus 33.3% in the non-MSC group, P = 0.13; Incidence of acute rejection: 14.3% versus 4.8%, P = 0.61). Equal postoperative estimated glomerular filtration rates were found between the two groups (P = 0.88). All patients tolerated the MSCs infusion without adverse clinical effects. Additionally, a multiprobe fluorescence in situ hybridization assay revealed that UC-MSCs administered via the renal artery were absent from the recipient's biopsy sample. CONCLUSIONS: Umbilical-cord-derived MSCs can be used as clinically feasible and safe induction therapy. Adequate timing and frequency of UC-MSCs administration may have a significant effect on graft and recipient outcomes. Trial registration NCT02490020 . Registered on June 29 2015. PMID- 29514694 TI - Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients. AB - BACKGROUND: Multiple sclerosis (MS) is characterized by increased activation of peripheral blood mononuclear cells (PBMCs), linked to perturbations in the phosphorylation of signaling proteins. METHODS: We developed a phosphoflow cytometry protocol to assess the levels of 11 phosphorylated nuclear proteins at baseline conditions and after cell activation in distinct PBMC populations from 41 treatment-naive relapsing-remitting (RR) MS subjects and 37 healthy controls, and in a second cohort of 9 untreated RRMS patients and 10 secondary progressive (SP) MS patients. Levels of HLA-ABC, HLA-E, and HLA-DR were also assessed. Phosphorylation levels of selected proteins were also assessed in mouse splenocytes isolated from myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE). RESULTS: Modest differences were observed at baseline between patients and controls, with general lower phosphorylation levels in cells from affected individuals. Conversely, a dramatic increase in phosphorylated p38MAPK and STAT proteins was observed across all cell types in MS patients compared to controls after in vitro activation. A similar phosphorylation profile was observed in mouse lymphocytes primed in vivo with MOG. Furthermore, levels of all p-STAT proteins were found directly correlated with HLA expression in monocytes. Levels of phosphorylated proteins did not differ between relapsing-remitting and secondary progressive MS patients either in baseline conditions or after stimulation. Lastly, phosphorylation levels appear to be independent of the genotype. CONCLUSION: The response to IFN-alpha through STAT proteins signaling is strongly dysregulated in MS patients irrespective of disease stage. These findings suggest that the aberrant activation of this pathway could lead to changes in the expression of HLA molecules in antigen presenting cells, which are known to play important roles in the regulation of the immune response in health and disease. PMID- 29514695 TI - Glycemic variability in continuous glucose monitoring is inversely associated with baroreflex sensitivity in type 2 diabetes: a preliminary report. AB - BACKGROUND: It is presently unclear whether glycemic variability (GV) is associated with baroreflex sensitivity (BRS), which is an early indicator of cardiovascular autonomic neuropathy. The present study is the first to examine the relationships between BRS and GV measured using continuous glucose monitoring (CGM). METHODS: This was a multicenter, prospective, open-label clinical trial. A total of 102 patients with type 2 diabetes were consecutively recruited for this study. GV was assessed by measuring the standard deviation (SD), glucose coefficient of variation (CV), and the mean amplitude of glycemic excursions (MAGE) during CGM. The BRS was analyzed from electrocardiogram and blood pressure recordings using the sequence method on the first day of hospitalization. RESULTS: A total of 94 patients (mean diabetes duration 9.7 +/- 9.6 years, mean HbA1c 61.0 +/- 16.8 mmol/mol [7.7 +/- 1.5%]) were analyzed. In the univariate analysis, CGM-SD (r = - 0.375, p = 0.000), CGM-CV (r = - 0.386, p = 0.000), and MAGE (r = - 0.395, p = 0.000) were inversely related to BRS. In addition to GV, the level of BRS correlated with the coefficient of variation in the R-R intervals (CVR-R) (r = 0.520, p = 0.000), heart rate (HR) (r = - 0.310, p = 0.002), cardio-ankle vascular index (CAVI) (r = - 0.326, p = 0.001), age (r = - 0.519, p = 0.000), and estimated glomerular filtration rate (eGFR) (r = 0.276, p = 0.007). Multiple regression analysis showed that CGM-CV and MAGE were significantly related to a decrease in BRS. These findings remained after adjusting the BRS for age, sex, hypertension, dyslipidemia, HR, eGFR, CAVI, and CGM-mean glucose. Additionally, BRS was divided according to quartiles of the duration of diabetes (Q1-4). BRS decreased after a 2-year duration of diabetes independently of age and sex. CONCLUSIONS: GV was inversely related to BRS independently of blood glucose levels in type 2 diabetic patients. Measurement of BRS may have the potential to predict CV events in consideration of GV. Trial registration UMIN Clinical Trials Registry UMIN000025964, 28/02/2017. PMID- 29514696 TI - Integrating genome-wide DNA methylation and mRNA expression profiles identified different molecular features between Kashin-Beck disease and primary osteoarthritis. AB - BACKGROUND: Kashin-Beck disease (KBD) is an endemic osteochondropathy of unknown etiology. Osteoarthritis (OA) is a form of degenerative joint disease sharing similar clinical manifestations and pathological changes to articular cartilage with KBD. METHODS: A genome-wide DNA methylation profile of articular cartilage from five KBD patients and five OA patients was first performed using the Illumina Infinium HumanMethylation450 BeadChip. Together with a previous gene expression profiling dataset comparing KBD cartilage with OA cartilage, an integrative pathway enrichment analysis of the genome-wide DNA methylation and the mRNA expression profiles conducted in articular cartilage was performed by InCroMAP software. RESULTS: We identified 241 common genes altered in both the DNA methylation profile and the mRNA expression profile of articular cartilage of KBD versus OA, including CHST13 (NM_152889, fold-change = 0.5979, P methy = 0.0430), TGFBR1 (NM_004612, fold-change = 2.077, P methy = 0.0430), TGFBR2 (NM_001024847, fold-change = 1.543, P methy = 0.037), TGFBR3 (NM_001276, fold change = 0.4515, P methy = 6.04 * 10-4), and ADAM12 (NM_021641, fold-change = 1.9768, P methy = 0.0178). Integrative pathway enrichment analysis identified 19 significant KEGG pathways, including mTOR signaling (P = 0.0301), glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate (P = 0.0391), glycosaminoglycan biosynthesis-keratan sulfate (P = 0.0278), and PI3K-Akt signaling (P = 0.0243). CONCLUSION: This study identified different molecular features between Kashin-Beck disease and primary osteoarthritis and provided novel clues for clarifying the pathogenetic differences between KBD and OA. PMID- 29514697 TI - Cardiac output Optimisation following Liver Transplant (COLT) trial: study protocol for a feasibility randomised controlled trial. AB - BACKGROUND: Patients with liver cirrhosis undergoing liver transplantation have a hyperdynamic circulation which persists into the early postoperative period making accurate assessment of fluid requirements challenging. Goal-directed fluid therapy (GDFT) has been shown to reduce morbidity and mortality in a number of surgery settings. The impact of GDFT in patients undergoing liver transplantation is unknown. A feasibility trial was designed to determine patient and clinician support for recruitment into a randomised controlled trial of GDFT following liver transplantation, adherence to a GDFT protocol, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate the efficacy of GDFT in patients undergoing liver transplantation. METHODS: The Cardiac output Optimisation following Liver Transplant (COLT) trial is designed as a prospective, single-centre, randomised controlled study to assess the feasibility and safety of GDFT in liver transplantation for patients with cirrhosis. Consenting adults (aged between 18 and 80 years) with biopsy-proven liver cirrhosis who have been selected to undergo a first liver transplantation will be included in the trial and randomised into GDFT or standard care starting immediately after surgery and continuing for the first 12 h thereafter. Both groups will have cardiac output and stroke volume monitored using the FloTrac (EV1000) device. The intervention will consist of a protocolised GDFT approach to patient management, using stroke volume optimisation. The control group will receive standard care, without stroke volume and cardiac output measurement. After 12 h the patient's fluid management will revert to standard of care. The primary endpoint of this study is feasibility. Secondary endpoints will include a safety assessment of the intervention, graft and patient survival, liver function, postoperative complications graded by Clavien-Dindo criteria, length of intensive care and hospital stay and quality of life across the intervention and control groups. DISCUSSION: There is a growing body of evidence that the use of perioperative GDFT in surgical patients can improve outcomes; however, signals of harm have also been detected. Patients with liver cirrhosis undergoing liver transplantation have markedly different cardiovascular physiology than general surgical patients. If GDFT is proven to be feasible and safe in this patient group, then a multicentre trial to demonstrate efficacy and cost-effectiveness will be required. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Registry, ID: ISRCTN10329248. Registered on 4 April 2016. PMID- 29514698 TI - Correlates of social behavior change communication on care-seeking behaviors for children with fever: an analysis of malaria household survey data from Liberia. AB - BACKGROUND: In 2010, malaria was responsible for an estimated 41% of deaths among children under the age of five years in Liberia. The same year, the Rebuilding Basic Health Services Project launched "Healthy Baby, Happy Mother," a social and behavior change communication campaign. The campaign encouraged caregivers to take children under the age of five years to a health facility as soon as children developed fever. This study investigated correlates of two case management outcomes: care-seeking for children under five with fever during the past two weeks and administration of an artemisinin-based combination therapy (ACT) the same or next day as fever onset. METHODS: Data from a 2014 cross sectional household survey from four counties was used to investigate correlates of two case management outcomes. Using multilevel analysis, the association between these outcomes and a caregiver's recall of the campaign, her sociodemographic characteristics, and unmeasured characteristics of the community she lived in was investigated. RESULTS: Caregivers living in Grand Kru County were less likely (OR = 0.21, 95% CI 0.073, 0.632) to take a child to a health facility than those in Bong County. Caregiver recall of the campaign was positively associated with the odds that a child received an ACT promptly (OR 3.62, 95% CI 1.398-9.372), but not with the odds of a caregiver taking a child in their care to a health facility. While unmeasured community-level factors accounted for 19.0% of the variation in the odds that a caregiver's child was brought to a health facility, they did not play a role in the odds of prompt ACT treatment. CONCLUSIONS: Recalling the "Healthy Mother, Happy Baby" campaign was positively associated with the odds that children received ACT promptly, even in the absence of other malaria prevention and treatment messaging. While caregiver exposure was not associated with care-seeking during the two weeks before interview, prompt care-seeking likely preceded prompt receipt of ACT since most ACT came from health facilities. Unmeasured community-level factors, such as distance from the health facility, may play a role in determining the odds that a caregiver takes a child to a health facility. PMID- 29514699 TI - Go Play Outside! Effects of a risk-reframing tool on mothers' tolerance for, and parenting practices associated with, children's risky play: study protocol for a randomized controlled trial. AB - BACKGROUND: Children's risky play is associated with a variety of positive developmental, physical and mental health outcomes, including greater physical activity, self-confidence and risk-management skills. Children's opportunities for risky play have eroded over time, limited by parents' fears and beliefs about risk, particularly among mothers. We developed a digital tool and in-person Risk reframing (RR) workshop to reframe parents' perceptions of risk and change parenting behaviours. The purpose of this paper is to describe our RR intervention, rationale and protocol for a randomised controlled trial to examine whether it leads to increases in mothers' tolerance of risk in play and goal attainment relating to promoting their child's opportunities for risky play. METHODS: We use a randomised controlled trial design and will recruit a total of 501 mothers of children aged 6-12 years. The RR digital tool is designed for a one-time visit and includes three chapters of self-reflection and experiential learning tasks. The RR in-person tool is a 2-h facilitated workshop in which participants are guided through discussion of the same tasks contained within the digital tool. The control condition consists of reading the Position Statement on Active Outdoor Play. Primary outcome is increased tolerance of risk in play, as measured by the Tolerance of Risk in Play Scale. Secondary outcome is self reported attainment of a behaviour-change goal that participants set for themselves. We will test the hypothesis that there will be differences between the experimental and control conditions with respect to tolerance of risk in play using mixed-effects models. We will test the hypothesis that there will be differences between the experimental and control conditions with respect to goal attainment using logistic regression. DISCUSSION: The results of this trial will have important implications for facilitating the widespread change in parents' risk perception that is necessary for promoting broad societal understanding of the importance of children's risky play. In addition, the findings may provide relevant information for the design of behaviour-change tools to increase parental tolerance of risk. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03374683 . Retrospectively registered on 15 December 2017. PMID- 29514700 TI - Impact of a genetic counseling requirement prior to genetic testing. AB - BACKGROUND: Genetic counseling by a Genetic Counselor (GC) is a requirement prior to genetic testing for cancer susceptibility genes (GC-mandate policy) for some insurers. This study evaluated the impact of this policy from the patient perspective. METHODS: Surveys were sent to individuals for whom their insurer ordered genetic testing for the cancer susceptibility genes BCRA1 and BRCA2 over a 1 year time period that spanned the introduction of a GC-mandate policy. Responses were assessed by time period (before/after policy introduction) and genetic test completion. RESULTS: The surveys were completed by 1247/4950 (25.7%) eligible individuals. After policy introduction, there was no change in the proportion of respondents who completed genetic testing (p = 0.13) or had a mutation (p = 0.55). Overall decisional conflict (uncertainty or feeling uninformed) around genetic testing did not change after policy introduction (p = 0.16), but was significantly higher among respondents who did not complete genetic testing (p < 0.01). Although a larger proportion of respondents saw a GC after policy introduction (p < 0.01), fewer did so to better understand their test results (p < 0.01). The proportion of respondents who did not see a GC due to insurance issues/requirements and time restraints was higher among those tested after policy introduction or who did not complete genetic testing (p < 0.01). In multivariate analysis, respondents with a household income of $25,000 or greater were 3-times more likely to complete testing. CONCLUSIONS: A GC mandate policy did not improve decisional conflict or increase the number of deleterious mutations identified and low-income respondents were less likely to complete testing. On the contrary, insurance requirements and time constraints may be preventing individuals at risk from receiving appropriate testing. PMID- 29514701 TI - Knowledge and perspectives of female genital cutting among the local religious leaders in Erbil governorate, Iraqi Kurdistan region. AB - BACKGROUND: Religious leaders are one of the key actors in the issue of female genital cutting (FGC) due to the influential position they have in the community and the frequent association of FGC with the religion. This study aimed to assess the knowledge and perspectives of the local religious leaders in Erbil governorate, Iraqi Kurdistan Region about different aspects of FGC. METHODS: In depth interviews were conducted with a sample of 29 local religious leaders. A semi-structured questionnaire was used that included questions about their knowledge, understanding, and perspectives on different aspects of FGC such as the reasons for practicing it, their contact and communication with the community regarding the practice and perspectives about banning the practice by law. RESULTS: Participants believed that FGC is useful for reducing or regulating the sexual desire of women to prevent adultery and engagement in pre and extramarital sexual relations and to enhance hygiene of women. They indicated that there is no any risk in doing FGC if there is no excessive cut. Most participants indicated that FGC is attributed to the religion and some considered it a tradition mixed with the religion. People rarely ask the advice of the religious leaders regarding FGC, but they frequently complain about the effects of the practice. Participants did not support having a law to ban FGC either because they thought it would be against the religion's advice on FGC or it will not work. CONCLUSIONS: The local religious leaders lack adequate knowledge about different aspects of FGC particularly the health consequences. There are different and disputing viewpoints about the reasons for practicing FGC, and there is poor support for having a law banning the practice. There is an essential need for enhancing the knowledge of the local religious leaders regarding FGC and its adverse effects on the women's health. PMID- 29514702 TI - Correction to: skeletal muscle mechanics: questions, problems and possible solutions. AB - In Fig. 3a of the original manuscript [1], the passive force at the beginning of the force-time history (approximately from 0 to 1 s) of each of the black and orange traces was interchanged in the coloring process. This was an error in the artwork preparation, not the original data. The corrected figure is shown below. PMID- 29514703 TI - Pharmacological activation of TAZ enhances osteogenic differentiation and bone formation of adipose-derived stem cells. AB - BACKGROUND: Adipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. The transcriptional coactivator with PDZ-binding motif (TAZ) has been demonstrated to modulate osteogenic and adipogenic differentiation of mesenchymal stem cells. However, its roles during ADSC differentiation and therapeutic potentials for bone regeneration have as yet not been well established. METHODS: TAZ expression was measured during osteogenic differentiation of ADSCs in vitro. Both loss-of-function and gain-of-function approaches by TAZ knockdown or enforced overexpression were utilized to determine its functions during osteogenic differentiation of ADSCs. TM-25659, a chemical activator of TAZ, was used to determine whether pharmacological activation of TAZ in ADSCs enhanced osteogenic differentiation in vitro and bone formation in animal models. The molecular mechanisms underlying TAZ in promoting osteogenesis of ADSCs were also explored. RESULTS: Increased TAZ expression was observed during osteogenic differentiation of human ADSCs. TAZ knockdown resulted in compromised osteogenic differentiation and enhanced adipogenic differentiation of ADSCs. In contrast, enforced TAZ overexpression yielded increased osteogenic differentiation and bone regeneration in vivo, and impaired adipogenic differentiation of ADSCs. Pharmacological activation of TAZ by its chemical activator TM-25659 facilitated osteogenic differentiation of ADSCs. Noticeably, transient treatment of ADSCs with TM-25659 or intraperitoneal injection of TM-25659 significantly enhanced bone regeneration of ADSCs loaded with porous beta-TCP in vivo. Mechanistically, TM-25659 exposure significantly promoted TAZ phosphorylation and nuclear translocation, and potentiated the assembly of the TAZ-Runx2 complex. Subsequently, the TAZ-Runx2 complex was further recruited to the promoter of osteocalcin and in turn enhanced its transcription. CONCLUSIONS: Our findings indicate that TAZ is a key mediator that promotes ADSC commitment to the osteoblast lineage. Pharmacological activation of TAZ in ADSCs might become a feasible and promising approach to enhance bone regeneration and repair. PMID- 29514704 TI - Decreased STEC shedding by cattle following passive and active vaccination based on recombinant Escherichia coli Shiga toxoids. AB - The principal virulence factor of Shiga toxin (Stx)-producing Escherichia coli (STEC), the eponymous Stx, modulates cellular immune responses in cattle, the primary STEC reservoir. We examined whether immunization with genetically inactivated recombinant Shiga toxoids (rStx1MUT/rStx2MUT) influences STEC shedding in a calf cohort. A group of 24 calves was passively (colostrum from immunized cows) and actively (intra-muscularly at 5th and 8th week) vaccinated. Twenty-four calves served as unvaccinated controls (fed with low anti-Stx colostrum, placebo injected). Each group was divided according to the vitamin E concentration they received by milk replacer (moderate and high supplemented). The effective transfer of Stx-neutralizing antibodies from dams to calves via colostrum was confirmed by Vero cell assay. Serum antibody titers in calves differed significantly between the vaccinated and the control group until the 16th week of life. Using the expression of activation marker CD25 on CD4+CD45RO+ cells and CD8alphahiCD45RO+ cells as flow cytometry based read-out, cells from vaccinated animals responded more pronounced than those of control calves to lysates of STEC and E. coli strains isolated from the farm as well as to rStx2MUT in the 16th week. Summarized for the entire observation period, less fecal samples from vaccinated calves were stx1 and/or stx2 positive than samples from control animals when calves were fed a moderate amount of vitamin E. This study provides first evidence, that transfer to and induction in young calves of Stx neutralizing antibodies by Shiga toxoid vaccination offers the opportunity to reduce the incidence of stx-positive fecal samples in a calf cohort. PMID- 29514705 TI - Auricular acupressure for insomnia in hemodialysis patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Patients on maintenance hemodialysis (MHD) frequently complain of insomnia. Poor sleep quality impairs their quality of life and adversely affects long-term outcome. Previously we applied auricular acupressure therapy (AAT) for MHD patients with insomnia and yielded favorable results. AAT probably improves sleep quality by stimulating the vagus nerve and inhibiting sympathetic overactivity. However, the efficacy of AAT for insomnia in this population is still lacking. The proposed randomized controlled trial (RCT) will evaluate the efficacy and safety of AAT for improvement of sleep quality in MHD patients with insomnia. METHODS/DESIGN: The proposed study is a multi-center, double-blind (participants and assessors), parallel-group RCT. A total of 112 participants with insomnia will be recruited from six hemodialysis centers in Guangzhou, China, and randomly allocated in a 1:1 ratio to receive auricular acupressure on either active points (AA group) or control points (points irrelevant to insomnia management, SAA group). The treatment will last for 8 weeks prior to a follow-up period of 12 weeks. Evaluation by blinded assessors at baseline, at 8 weeks (end of treatment) as well as at 4-week, 8-week and 12-week follow-ups (after intervention) will include Pittsburgh Sleep Quality Index (PSQI) scores and average weekly dose of hypnotics. The primary endpoint is clinical response rate (percentage of participants who reach a reduction of PSQI global score >= 3 in each group) at 8 weeks from baseline. Secondary endpoints include the changes in PSQI scores over time from baseline, as well as the changes in weekly dose of hypnotics. DISCUSSION: This paper describes the rationale and design of a double blind RCT that aims to determine the efficacy and safety of AAT for insomnia of hemodialysis patients. If successful, this project will provide evidence of the efficacy and safety of AAT for insomnia of hemodialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov , Identifier: NCT03015766 . Registered on 22 December 2016. PMID- 29514706 TI - The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial. AB - BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance. METHODS/DESIGN: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression. DISCUSSION: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM. TRIAL REGISTRATION: ISRCTN, ISRCTN10038996 . Registered on 15 December 2016. PMID- 29514707 TI - Low heart rate variability relates to the progression of gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is one of the most common malignant gastrointestinal tumors with the high morbidity and mortality, affecting the quality of human life. This study aimed to identify the role of heart rate variability (HRV) in patients with GC. METHODS: From January 2010 to June 2014, 383 consecutive patients diagnosed with GC were enrolled in this study. Clinical and pathological information from each patient were retrospectively recorded. HRV, including standard deviation of normal-to-normal RR intervals (SDNN) and root mean square of successive differences (RMSSD), were measured by electrocardiography. RESULTS: The results showed that the SDNN and RMSSD in GC patients were 19.02 +/- 13.58 ms and 21.64 +/- 17.57 ms, respectively. HRV decreased with advanced clinical stage (P < 0.0001). HRV correlated with tumor size, tumor infiltration, lymph node metastasis and distant metastasis (P < 0.001); however, no correlation with tumor site and metastasis severity was found (P > 0.05). C-reactive protein (CRP) was higher in the low HRV group than that in high HRV group (P = 0.008). CONCLUSIONS: GC patients showed a lower HRV that was correlated with tumor stage. HRV decreased with tumor progression, which may be related to a mechanism involving vagal nerve excitement inhibiting the inflammatory reaction. PMID- 29514708 TI - Fully quantitative pixel-wise analysis of cardiovascular magnetic resonance perfusion improves discrimination of dark rim artifact from perfusion defects associated with epicardial coronary stenosis. AB - BACKGROUND: Dark rim artifacts in first-pass cardiovascular magnetic resonance (CMR) perfusion images can mimic perfusion defects and affect diagnostic accuracy for coronary artery disease (CAD). We evaluated whether quantitative myocardial blood flow (MBF) can differentiate dark rim artifacts from true perfusion defects in CMR perfusion. METHODS: Regadenoson perfusion CMR was performed at 1.5 T in 76 patients. Significant CAD was defined by quantitative invasive coronary angiography (QCA) >= 50% diameter stenosis. Non-significant CAD (NonCAD) was defined as stenosis by QCA < 50% diameter stenosis or computed tomographic coronary angiography (CTA) < 30% in all major epicardial arteries. Dark rim artifacts had study specific and guideline-based definitions for comparison purposes. MBF was quantified at the pixel-level and sector-level. RESULTS: In a NonCAD subgroup with dark rim artifacts, stress MBF was lower in the subendocardial than midmyocardial and epicardial layers (2.17 +/- 0.61 vs. 3.06 +/- 0.75 vs. 3.24 +/- 0.80 mL/min/g, both p < 0.001) and was also 30% lower than in remote regions (2.17 +/- 0.61 vs. 2.83 +/- 0.67 mL/min/g, p < 0.001). However, subendocardial stress MBF in dark rim artifacts was 37-56% higher than in true perfusion defects (2.17 +/- 0.61 vs. 0.95 +/- 0.43 mL/min/g, p < 0.001). Absolute stress MBF differentiated CAD from NonCAD with an accuracy ranging from 86 to 89% (all p < 0.001) using pixel-level analyses. Similar results were seen at a sector level. CONCLUSION: Quantitative stress MBF is lower in dark rim artifacts than remote myocardium but significantly higher than in true perfusion defects. If confirmed in larger series, this approach may aid the interpretation of clinical stress perfusion exams. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00027170 ; first posted 11/28/2001; updated 11/27/2017. PMID- 29514709 TI - Proteomic study revealed antipsychotics-induced nuclear protein regulations in B35 cells are similar to the regulations in C6 cells and rat cortex. AB - BACKGROUND: Based on accumulating evidence, the regulation of protein expression by antipsychotic drugs (APDs) might be closely related to the control of psychotic symptoms when these drugs are used to treat mental disorders. The low quantity of nuclear proteins in the cell hinders their detection because signal for rare proteins are masked in most proteomic detection systems. METHODS: Nuclear proteins fractionated from APD-treated B35 cells were labeled with iTRAQ and detected by LC/MS/MS to investigate APD-induced alterations in nuclear protein expression. Western blot, immunofluorescent cell staining, and immunohistochemical staining were applied to validate the findings. RESULTS: The expression of ADP/ATP translocase 2, heat shock cognate 71 kDa protein, histone H1.2, histone H3.3, histone H4, non-POU domain-containing octamer-binding protein, nucleolin, nucleophosmin, prelamin-A/C, plectin-1, vimentin, and 40S ribosomal protein S3a was regulated by APDs in B35 cells, according to our proteomic data. According to the results of the gene ontology analysis, all these proteins played important roles in biological processes or in molecular functions in cells. Western blot results showing APD-induced alterations in nuclear protein expression in B35 cells were consistent with the LC/MS/MS results. Heat shock cognate 71 kDa protein and vimentin expression in C6 cells were not affected by the three APDs. As shown in the immunofluorescent cell staining, all the three APDs altered protein expression to similar extents. We also examined whether the expression of these proteins was affected by APDs in the prefrontal cortex of rats administered sub-chronic and chronic APD treatments by western blotting and immunohistochemical staining. CONCLUSIONS: The findings of the proteomic analysis of APD-treated B35 cells were recapitulated in the APD-treated rat cortex. The expression of some proteins was altered by APDs in rat prefrontal cortex in a time-dependent manner. PMID- 29514710 TI - Added value of diffusion-weighted imaging in hepatic tumors and its impact on patient management. AB - BACKGROUND: To investigate the added diagnostic value of diffusion-weighted imaging (DWI) of the liver and its impact on therapy decisions in patients with hepatic malignancy. METHODS: Interdisciplinary gastrointestinal tumorboard cases concerning patients with hepatic malignancies discussed between 11/2015 and 06/2016 were included in this retrospective, single-center study. Two radiologists independently reviewed the respective liver MR-examination first without, then with DWI. The readers were blinded regarding number, position and size of hepatic malignancies. Cases in which DWI revealed additional findings concerning the hepatic tumor status as compared to conventional sequences alone were presented to experienced members of the interdisciplinary tumor board. In this retrospective setting changes in treatment decisions based on these additional findings in the DWI sequences were recorded. RESULTS: A total of 87 patients were included. DWI revealed additional findings in 12 patients (13,8%). These new findings had a direct effect on the therapy in 8 patients (9,2%): In 6 patients (6,9%) the surgical/interventional treatment was adapted (n = 5: extended resection, n = 1: with transarterial chemoembolization of a single hepatocellular carcinoma only detectable in DWI); 2 patients (2,3%) received systemic therapy (n = 1: neo-adjuvant, n = 1: palliative) based on the additional findings in DWI. In 4 patients (4.6%) additional DWI findings did not affect the therapeutic decision. CONCLUSIONS: DWI is a relevant diagnostic tool in oncologic imaging of the liver. By providing further information regarding tumor load in hepatic malignancies it can lead to a significant change in treatment. PMID- 29514711 TI - Improving interpretation of publically reported statistics on health and healthcare: the Figure Interpretation Assessment Tool (FIAT-Health). AB - BACKGROUND: Policy-makers, managers, scientists, patients and the general public are confronted daily with figures on health and healthcare through public reporting in newspapers, webpages and press releases. However, information on the key characteristics of these figures necessary for their correct interpretation is often not adequately communicated, which can lead to misinterpretation and misinformed decision-making. The objective of this research was to map the key characteristics relevant to the interpretation of figures on health and healthcare, and to develop a Figure Interpretation Assessment Tool-Health (FIAT Health) through which figures on health and healthcare can be systematically assessed, allowing for a better interpretation of these figures. METHODS: The abovementioned key characteristics of figures on health and healthcare were identified through systematic expert consultations in the Netherlands on four topic categories of figures, namely morbidity, healthcare expenditure, healthcare outcomes and lifestyle. The identified characteristics were used as a frame for the development of the FIAT-Health. Development of the tool and its content was supported and validated through regular review by a sounding board of potential users. RESULTS: Identified characteristics relevant for the interpretation of figures in the four categories relate to the figures' origin, credibility, expression, subject matter, population and geographical focus, time period, and underlying data collection methods. The characteristics were translated into a set of 13 dichotomous and 4-point Likert scale questions constituting the FIAT Health, and two final assessment statements. Users of the FIAT-Health were provided with a summary overview of their answers to support a final assessment of the correctness of a figure and the appropriateness of its reporting. CONCLUSIONS: FIAT-Health can support policy-makers, managers, scientists, patients and the general public to systematically assess the quality of publicly reported figures on health and healthcare. It also has the potential to support the producers of health and healthcare data in clearly communicating their data to different audiences. Future research should focus on the further validation of the tool in practice. PMID- 29514712 TI - Sirukumab in rheumatoid arthritis refractory to sulfasalazine or methotrexate: a randomized phase 3 safety and efficacy study in Japanese patients. AB - BACKGROUND: Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. METHODS: In this phase 3, double blind study, 122 patients (age >= 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. CONCLUSIONS: Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine. TRIAL REGISTRATION: NCT01689532 . Registered 18 September 2012. PMID- 29514713 TI - A need for NAD+ in muscle development, homeostasis, and aging. AB - Skeletal muscle enables posture, breathing, and locomotion. Skeletal muscle also impacts systemic processes such as metabolism, thermoregulation, and immunity. Skeletal muscle is energetically expensive and is a major consumer of glucose and fatty acids. Metabolism of fatty acids and glucose requires NAD+ function as a hydrogen/electron transfer molecule. Therefore, NAD+ plays a vital role in energy production. In addition, NAD+ also functions as a cosubstrate for post translational modifications such as deacetylation and ADP-ribosylation. Therefore, NAD+ levels influence a myriad of cellular processes including mitochondrial biogenesis, transcription, and organization of the extracellular matrix. Clearly, NAD+ is a major player in skeletal muscle development, regeneration, aging, and disease. The vast majority of studies indicate that lower NAD+ levels are deleterious for muscle health and higher NAD+ levels augment muscle health. However, the downstream mechanisms of NAD+ function throughout different cellular compartments are not well understood. The purpose of this review is to highlight recent studies investigating NAD+ function in muscle development, homeostasis, disease, and regeneration. Emerging research areas include elucidating roles for NAD+ in muscle lysosome function and calcium mobilization, mechanisms controlling fluctuations in NAD+ levels during muscle development and regeneration, and interactions between targets of NAD+ signaling (especially mitochondria and the extracellular matrix). This knowledge should facilitate identification of more precise pharmacological and activity-based interventions to raise NAD+ levels in skeletal muscle, thereby promoting human health and function in normal and disease states. PMID- 29514714 TI - Comparing the effects of China's three basic health insurance schemes on the equity of health-related quality of life: using the method of coarsened exact matching. AB - BACKGROUND: China has three basic health insurance schemes: Urban Employee Basic Medical Insurance (UEBMI), Urban Resident Basic Medical Insurance (URBMI) and New Rural Cooperative Medical Scheme (NRCMS). This study aimed to compare the equity of health-related quality of life (HRQoL) of residents under any two of the schemes. METHODS: Using data from the 5th National Health Services Survey of Shaanxi Province, China, coarsened exact matching method was employed to control confounding factors. We included a matched sample of 6802 respondents between UEBMI and URBMI, 34,169 respondents between UEBMI and NRCMS, and 36,928 respondents between URBMI and NRCMS. HRQoL was measured by EQ-5D-3L based on the Chinese-specific value set. Concentration index was adopted to assess health inequality and was decomposed into its contributing factors to explain health inequality. RESULTS: After matching, the horizontal inequity indexes were 0.0036 and 0.0045 in UEBMI and URBMI, 0.0035 and 0.0058 in UEBMI and NRCMS, and 0.0053 and 0.0052 in URBMI and NRCMS respectively, which were mainly explained by age, educational and economic statuses. The findings demonstrated the pro-rich health inequity was much higher for the rural scheme than that for the urban ones. CONCLUSION: This study highlights the need to consolidate all three schemes by administrating uniformly, merging funds pooling and benefit packages. Based on the contributing factors, strategies aim to facilitate health conditions of the elderly, narrow economic gap, and reduce educational inequity, are essential. This study will provide evidence-based strategies on consolidating the fragmented health schemes towards reducing health inequity in both China and other developing countries. PMID- 29514715 TI - Pachydermoperiostosis in a patient with chronic hepatitis B virus infection referred as acromegaly: a case report. AB - BACKGROUND: Primary hypertrophic osteoarthropathy also known as pachydermoperiostosis is a rare genetic disorder that has often been confused with acromegaly because of similar clinical features. Vascular endothelial growth factors which have been implicated in the clinical features of pachydermoperiostosis, have also been shown to be present in chronic hepatitis and implicated in the malignant transformation of hepatitis B infection to hepatocellular carcinoma. To the best of our knowledge there is one reported case of pachydermoperiostosis with chronic hepatitis B infection. We do not imply a causal relationship between pachydermoperiostosis and hepatitis B infection because pachydermoperiostosis is a genetic disorder; however, the question is raised whether hypertrophic osteoarthropathy is one of the many extrahepatic manifestations of chronic hepatitis B infection. CASE PRESENTATION: A 21-year-old African (Ghanaian) man with chronic hepatitis B infection was referred to our Endocrine unit as having acromegaly with changing facial features, enlarging hands and feet, and large knee joint effusions which affected activities of daily living. He was finally diagnosed as having pachydermoperiostosis when acromegaly, rheumatological disorders, as well as cardiopulmonary disorders were ruled out. He improved with arthrocentesis, a tapering regime of steroids, non-steroidal anti-inflammatory drugs, and proton pump inhibitors. CONCLUSIONS: The possible role of hepatitis B in hypertrophic osteoarthropathy, that is, secondary hypertrophic osteoarthropathy, needs to be explored; however, with digital clubbing in his father our patient is likely to have pachydermoperiostosis. PMID- 29514716 TI - The Entamoeba histolytica TBP and TRF1 transcription factors are GAAC-box binding proteins, which display differential gene expression under different stress stimuli and during the interaction with mammalian cells. AB - BACKGROUND: Entamoeba histolytica is the protozoan parasite responsible for human amebiasis. It causes up to 100,000 deaths worldwide each year. This parasite has two closely related basal transcription factors, the TATA-box binding protein (EhTBP) and the TBP-related factor 1 (EhTRF1). TBP binds to the canonical TATTTAAA-box, as well as to different TATA variants. TRF1 also binds to the TATTTAAA-box. However, their binding capacity to diverse core promoter elements, including the GAAC-element, and their role in gene regulation in this parasite remains unknown. METHODS: EMSA experiments were performed to determine the binding capacity of recombinant TBP and TRF1 to TATA variants, GAAC and GAAC-like boxes. For the functional analysis under different stress stimuli (e.g. growth curve, serum depletion, heat-shock, and UV-irradiation) and during the interaction with mammalian cells (erythrocytes, MDCK cell monolayers, and hepatocytes of hamsters), RT-qPCR, and gene knockdown were performed. RESULTS: Both transcription factors bound to the different TATA variants tested, as well as to the GAAC-boxes, suggesting that they are GAAC-box-binding proteins. The K D values determined for TBP and TRF1 for the different TATA variants and GAAC-box were in the range of 10-12 M to 10-11 M. During the death phase of growth or in serum depletion, Ehtbp mRNA levels significantly increased, whereas the mRNA level of Ehtrf1 did not change under these conditions. Ehtrf1 gene expression was negatively regulated by UV-irradiation and heat-shock stress, with no changes in Ehtbp gene expression. Moreover, Ehtrf1 gene also showed a negative regulation during erythrophagocytosis, liver abscess formation, and a transient expression level increase at the initial phase of MDCK cell destruction. Finally, the Ehtbp gene knockdown displayed a drastic decrease in the efficiency of erythrophagocytosis in G3 trophozoites. CONCLUSIONS: To our knowledge, this study reveals that these basal transcription factors are able to bind multiple core promoter elements. However, their immediate change in gene expression level in response to different stimuli, as well as during the interaction with mammalian cells, and the diminishing of erythrophagocytosis by silencing the Ehtbp gene indicate the different physiological roles of these transcription factors in E. histolytica. PMID- 29514717 TI - Including all voices in international data-sharing governance. AB - BACKGROUND: Governments, funding bodies, institutions, and publishers have developed a number of strategies to encourage researchers to facilitate access to datasets. The rationale behind this approach is that this will bring a number of benefits and enable advances in healthcare and medicine by allowing the maximum returns from the investment in research, as well as reducing waste and promoting transparency. As this approach gains momentum, these data-sharing practices have implications for many kinds of research as they become standard practice across the world. MAIN TEXT: The governance frameworks that have been developed to support biomedical research are not well equipped to deal with the complexities of international data sharing. This system is nationally based and is dependent upon expert committees for oversight and compliance, which has often led to piece meal decision-making. This system tends to perpetuate inequalities by obscuring the contributions and the important role of different data providers along the data stream, whether they be low- or middle-income country researchers, patients, research participants, groups, or communities. As research and data-sharing activities are largely publicly funded, there is a strong moral argument for including the people who provide the data in decision-making and to develop governance systems for their continued participation. CONCLUSIONS: We recommend that governance of science becomes more transparent, representative, and responsive to the voices of many constituencies by conducting public consultations about data-sharing addressing issues of access and use; including all data providers in decision-making about the use and sharing of data along the whole of the data stream; and using digital technologies to encourage accessibility, transparency, and accountability. We anticipate that this approach could enhance the legitimacy of the research process, generate insights that may otherwise be overlooked or ignored, and help to bring valuable perspectives into the decision-making around international data sharing. PMID- 29514718 TI - Brief electrical stimulation and synkinesis after facial nerve crush injury: a randomized prospective animal study. AB - BACKGROUND: Recent studies have examined the effects of brief electrical stimulation (BES) on nerve regeneration, with some suggesting that BES accelerates facial nerve recovery. However, the facial nerve outcome measurement in these studies has not been precise or accurate. Furthermore, no previous studies have been able to demonstrate the effect of BES on synkinesis. The objective of this study is to examine the effect of brief electrical stimulation (BES) on facial nerve function and synkinesis in a rat model. METHODS: Four groups of six rats underwent a facial nerve injury procedure. Group 1 and 2 underwent a crush injury at the main trunk of the nerve, with group 2 additionally receiving BES for 1 h. Group 3 and 4 underwent a transection injury at the main trunk, with group 4 additionally receiving BES for 1 h. A laser curtain model was used to measure amplitude of whisking at 2, 4, and 6 weeks. Fluorogold and fluororuby neurotracers were additionally injected into each facial nerve to measure synkinesis. Buccal and marginal mandibular branches of the facial nerve were each injected with different neurotracers at 3 months following injury. Based on facial nucleus motoneuron labelling of untreated rats, comparison was made to post-treatment animals to deduce whether synkinesis had taken place. All animals underwent trans-cardiac perfusion with subsequent neural tissue sectioning. RESULTS: At week two, the amplitude observed for group 1 and 2 was 14.4 and 24.0 degrees, respectively (p = 0.0004). Group 4 also demonstrated improved whisking compared to group 3. Fluorescent neuroimaging labelling appear to confirm improved pathway specific regeneration with BES following facial nerve injury. CONCLUSIONS: This is the first study to use an implantable stimulator for serial BES following a crush injury in a validated animal model. Results suggest performing BES after facial nerve injury is associated with accelerated facial nerve function and improved facial nerve specific pathway regeneration in a rat model. PMID- 29514719 TI - Protecting Healthcare Personnel in Outpatient Settings: The Influence of Mandatory Versus Nonmandatory Influenza Vaccination Policies on Workplace Absenteeism During Multiple Respiratory Virus Seasons. AB - OBJECTIVE To determine the effect of mandatory and nonmandatory influenza vaccination policies on vaccination rates and symptomatic absenteeism among healthcare personnel (HCP). DESIGN Retrospective observational cohort study. SETTING This study took place at 3 university medical centers with mandatory influenza vaccination policies and 4 Veterans Affairs (VA) healthcare systems with nonmandatory influenza vaccination policies. PARTICIPANTS The study included 2,304 outpatient HCP at mandatory vaccination sites and 1,759 outpatient HCP at nonmandatory vaccination sites. METHODS To determine the incidence and duration of absenteeism in outpatient settings, HCP participating in the Respiratory Protection Effectiveness Clinical Trial at both mandatory and nonmandatory vaccination sites over 3 viral respiratory illness (VRI) seasons (2012-2015) reported their influenza vaccination status and symptomatic days absent from work weekly throughout a 12-week period during the peak VRI season each year. The adjusted effects of vaccination and other modulating factors on absenteeism rates were estimated using multivariable regression models. RESULTS The proportion of participants who received influenza vaccination was lower each year at nonmandatory than at mandatory vaccination sites (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.07-0.11). Among HCP who reported at least 1 sick day, vaccinated HCP had lower symptomatic days absent compared to unvaccinated HCP (OR for 2012-2013 and 2013-2014, 0.82; 95% CI, 0.72-0.93; OR for 2014-2015, 0.81; 95% CI, 0.69-0.95). CONCLUSIONS These data suggest that mandatory HCP influenza vaccination policies increase influenza vaccination rates and that HCP symptomatic absenteeism diminishes as rates of influenza vaccination increase. These findings should be considered in formulating HCP influenza vaccination policies. Infect Control Hosp Epidemiol 2018;39:452-461. PMID- 29514720 TI - The Association between Cardiopulmonary Resuscitation in Out-of-Hospital Settings and Chest Injuries: A Retrospective Observational Study. AB - OBJECTIVES: The aim of this study was to assess the risk of cardiopulmonary resuscitation (CPR) performed in out-of-hospital settings for chest injuries in patients with out-of-hospital cardiac arrest (OHCA). METHODS: This retrospective, observational study was conducted in an emergency critical care medical center in Japan. Non-traumatic OHCA patients transferred to the hospital from April 2013 through August 2016 were analyzed. The outcome was defined by chest injuries related to CPR, which is composite of rib fractures, sternal fractures, and pneumothoraces. A multivariate logistic regression analysis was performed to assess the independent risk factors for chest injuries related to CPR. The threshold of out-of-hospital CPR duration that increased risk of chest injuries was also assessed. RESULTS: A total of 472 patients were identified, of whom 233 patients sustained chest injuries. The multivariate logistic regression model showed that the independent risk factors for chest injuries were age and out-of hospital CPR duration (age: AOR=1.06 [95% CI, 1.04 to 1.07]; out-of-hospital CPR duration: AOR=1.03 [95% CI, 1.01 to 1.05]). In-hospital CPR duration was not an independent risk factor for chest injuries. When the duration of out-of-hospital CPR extended over 15 minutes, the likelihood of chest injuries increased; however, this association was not statistically significant. CONCLUSIONS: Long duration of out-of-hospital CPR was an independent risk factor for chest injuries, possibly due to the difficulty of maintaining adequate quality of CPR. Further investigations to assess the efficacy of alternative CPR devices are expected in cases requiring long transportation times. Takayama W , Koguchi H , Endo A , Otomo Y . The association between cardiopulmonary resuscitation in out of-hospital settings and chest injuries: a retrospective observational study. Prehosp Disaster Med. 2018;33(2):171-175. PMID- 29514721 TI - Decaffeinated coffee improves insulin sensitivity in healthy men. AB - Epidemiological studies have found coffee consumption is associated with a lower risk for type 2 diabetes mellitus, but the underlying mechanisms remain unclear. Thus, the aim of this randomised, cross-over single-blind study was to investigate the effects of regular coffee, regular coffee with sugar and decaffeinated coffee consumption on glucose metabolism and incretin hormones. Seventeen healthy men participated in five trials each, during which they consumed coffee (decaffeinated, regular (containing caffeine) or regular with sugar) or water (with or without sugar). After 1 h of each intervention, they received an oral glucose tolerance test with one intravenous dose of [1 13C]glucose. The Oral Dose Intravenous Label Experiment was applied and glucose and insulin levels were interpreted using a stable isotope two-compartment minimal model. A mixed-model procedure (PROC MIXED), with subject as random effect and time as repeated measure, was used to compare the effects of the beverages on glucose metabolism and incretin parameters (glucose-dependent insulinotropic peptide (GIP)) and glucagon-like peptide-1 (GLP-1)). Insulin sensitivity was higher with decaffeinated coffee than with water (P<0.05). Regular coffee with sugar did not significantly affect glucose, insulin, C peptide and incretin hormones, compared with water with sugar. Glucose, insulin, C-peptide, GLP-1 and GIP levels were not statistically different after regular and decaffeinated coffee compared with water. Our findings demonstrated that the consumption of decaffeinated coffee improves insulin sensitivity without changing incretin hormones levels. There was no short-term adverse effect on glucose homoeostasis, after an oral glucose challenge, attributable to the consumption of regular coffee with sugar. PMID- 29514722 TI - Dementia, post-traumatic stress disorder and major depressive disorder: a review of the mental health risk factors for dementia in the military veteran population. AB - BACKGROUND: Dementia is currently incurable, irreversible and a major cause of disability for the world's older population. The association between mental health difficulties, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), and dementia has a long history within the civilian population. Despite the increased importance of this link within the military veteran population, who suffer a greater propensity of mental health difficulties and consist largely of over 65s, attention is only recently being paid to the salience of such an association for this group. This paper aims to explore the relationship between PTSD and MDD with dementia within the military veteran population. METHOD: A systematic review was conducted on articles from 1990 to July 2016 on MEDLINE, EMBASE, EBSCO and Web of Science electronic databases with an update conducted in February 2017. RESULTS: Six empirical studies were identified from the review, the majority of which originated from the USA. Five of the studies asserted that veterans with a diagnosis of either PTSD or MDD are at a significantly greater risk of developing dementia than 'healthy' controls. The final study, conducted in Australia, found only a small, but non-significant, correlation between earlier MDD and future dementia, but no concurrent correlation. CONCLUSIONS: While causality cannot be determined, it is likely that PTSD and depressive disorders are related to an increased risk of dementia in military veterans. Potential pathological explanations and risk factors are reviewed and the clinical and neuroscience implications of these findings are explored. PMID- 29514723 TI - How foraging works: uncertainty magnifies food-seeking motivation. AB - Food uncertainty has the effect of invigorating food-related responses. Psychologists have noted that mammals and birds respond more to a conditioned stimulus that unreliably predicts food delivery, and ecologists have shown that animals (especially small passerines) consume and/or hoard more food and can get fatter when access to that resource is unpredictable. Are these phenomena related? We think they are. Psychologists have proposed several mechanistic interpretations, while ecologists have suggested a functional interpretation: the effect of unpredictability on fat reserves and hoarding behavior is an evolutionary strategy acting against the risk of starvation when food is in short supply. Both perspectives are complementary, and we argue that the psychology of incentive motivational processes can shed some light on the causal mechanisms leading animals to seek and consume more food under uncertainty in the wild. Our theoretical approach is in agreement with neuroscientific data relating to the role of dopamine, a neurotransmitter strongly involved in incentive motivation, and its plausibility has received some explanatory and predictive value with respect to Pavlovian phenomena. Overall, we argue that the occasional and unavoidable absence of food rewards has motivational effects (called incentive hope) that facilitate foraging effort. It is shown that this hypothesis is computationally tenable, leading foragers in an unpredictable environment to consume more food items and to have higher long-term energy storage than foragers in a predictable environment. PMID- 29514724 TI - Oestrogen, progesterone and stem cells: the discordant trio in endometriosis? AB - Oestrogen-progesterone signalling is highly versatile and critical for the maintenance of healthy endometrium in humans. The genomic and nongenomic signalling cascades initiated by these hormones in differentiated cells of endometrium have been the primary focus of research since 1920s. However, last decade of research has shown a significant role of stem cells in the maintenance of a healthy endometrium and the modulatory effects of hormones on these cells. Endometriosis, the growth of endometrium outside the uterus, is very common in infertile patients and the elusiveness in understanding of disease pathology causes hindrance in selection of treatment approaches to enhance fertility. In endometriosis, the stem cells are dysfunctional as it can confer progesterone resistance to their progenies resulting in disharmony of hormonal orchestration of endometrial homeostasis. The bidirectional communication between stem cell signalling pathways and oestrogen-progesterone signalling is found to be disrupted in endometriosis though it is not clear which precedes the other. In this paper, we review the intricate connection between hormones, stem cells and the cross-talks in their signalling cascades in normal endometrium and discuss how this is deregulated in endometriosis. Re-examination of the oestrogen progesterone dependency of endometrium with a focus on stem cells is imperative to delineate infertility associated with endometriosis and thereby aid in designing better treatment modalities. PMID- 29514725 TI - "All of a sudden, a lot less still makes it worthwhile to be alive:" Palliative care patients' views on life. AB - OBJECTIVE: We aimed to elucidate the views on life as narrated by patients in palliative care (PC) to find out what patients deem to be essential in their life, whether something has changed concerning their view of life in light of the disease, and whether interviewees would like to give others something to take with them. METHOD: Data were collected from narrative audio and video interviews with 18 inpatients in a specialized PC unit. Interviews were recorded and transcribed verbatim and analyzed using qualitative content analysis applying MAXQDA software. CDs and DVDs with recorded interviews were provided to patients. Result Eighteen interviews were analyzed: 11 audio and 7 video recordings. The age range was 41-80 years. Patients reported on changes in their views on life. Despite it being a complex and painful process, patients still gave examples of benefits experienced during their illness trajectory. Patients identified resources and coping strategies such as meaningful contacts with close others and mindfulness. Shifts have occurred in terms of taking more time for themselves, enjoying the moment, being more calm, and spending more time with family and friends. What patients wanted to pass on to others was to pay attention to the needs of both the self and the others, shape your life individually, confront yourself early with issues of death and dying, and care for your fellow human beings. Patients and relatives valued the opportunity to keep their interview as a CD/DVD. Significance of results Results support the idea that many people facing terminal illness continue to focus on living and remain within their biographies and the contexts of their lives, even if their functional status declines. Patients and relatives appreciated that interviews were provided as kind of a legacy. Yet, more robust research is needed to decide whether such interviews yield any therapeutic effect. PMID- 29514726 TI - Sporadic and recurrent non-suicidal self-injury before age 14 and incident onset of psychiatric disorders by 17 years: prospective cohort study. AB - BACKGROUND: Non-suicidal self-injury (NSSI) is highly prevalent in adolescents and may be a behavioural marker for emergent mental illnesses. Aims To determine whether sporadic or recurrent NSSI up to the age of 14 years predicted increased risk of new onset of psychiatric disorder in the subsequent 3 years, independent of psychiatric symptoms and social risk factors. METHOD: In total, 945 individuals aged 14 years with no past/present history of mental illness completed a clinical interview and completed a questionnaire about NSSI at the ages of 14 and 17 years. RESULTS: Recurrent NSSI at baseline predicted total disorders, depression and eating disorders. Sporadic baseline NSSI predicted new onset of anxiety disorders only. CONCLUSIONS: NSSI (especially recurrent NSSI) in the early-adolescent years is a behavioural marker of newly emerging mental illnesses. Professionals should treat both recurrent and sporadic NSSI as important risk factors, and prevention strategies could be targeted at this vulnerable group. Declaration of interest None. PMID- 29514727 TI - A New Triage Support Tool in Case of Explosion. AB - Deafness frequently observed in explosion victims, currently following terrorist attack, is a barrier to communication between victims and first responders. This may result in a delay in the initial triage and evacuation. In such situations, Paris Fire Brigade (Paris, France) proposes the use of assistance cards to help conscious, but deafened patients at the site of an attack where there may be numerous victims. Yavari-Sartakhti O , Briche F , Jost D , Michaud N , Bignand M , Tourtier JP . A new triage support tool in case of explosion. Prehosp Disaster Med. 2018;33(2):213-214. PMID- 29514728 TI - Health care burden and treatment patterns in commercially insured children with chronic idiopathic/spontaneous urticaria: A real-world study in the United States. AB - BACKGROUND: Chronic idiopathic urticaria (CIU)/spontaneous urticaria (CSU) is defined by the presence of wheals, angioedema, or both for >=6 weeks, with or without an identifiable trigger. Real-world health care data among children with CIU/CSU remain scarce. OBJECTIVES: To describe treatment patterns, health care resource utilization (HRU), and costs in pediatric patients with CIU/CSU (<12 years old) and to compare these with pediatric patients without CIU/CSU. METHODS: A commercial administrative claims data base (September 2013 to June 2016) was used. The CIU/CSU cohort included pediatric patients with either two or more claims for a diagnosis of urticaria >=6 weeks apart or one or more claims for a diagnosis of urticaria and one or more claims for a diagnosis of angioedema >=6 weeks apart (index was defined as the first claim). The control cohort comprised pediatric patients without urticaria or angioedema (index randomly assigned). Patients with <6 months of eligibility before and after the index date were excluded. HRU and costs were compared between the cohorts during the observation period after propensity score matching. RESULTS: A total of 6109 pediatric patients with CIU/CSU were selected, and 6107 were 1:1 matched with controls. The patients with CIU/CSU who had a mean +/- standard deviation age of 4.58 +/- 3.36 years, and 47.9% were girls. CIU/CSU-related medication use increased after diagnosis (e.g., baseline versus 6-month follow-up, 2.2 versus 8.0% for nonsedating prescription H1 antihistamines; 7.4 versus 17.4% for oral corticosteroids). Relative to the controls, the patients with CIU/CSU had higher rates of HRU (incidence rate ratios of 1.71, 2.39, and 2.07 for inpatient, emergency department, and outpatient visits, respectively; all p < 0.01), and higher all-cause per patient per year costs (mean cost differences of $2090, $1606, and $483 for total, medical, and pharmacy costs, respectively; all p < 0.01). CONCLUSION: This study highlighted unmet needs in pediatric patients with CIU/CSU who had increased medication (e.g., oral corticosteroids) and HRU burden after a diagnosis for CIU/CSU, and higher rates of HRU and costs relative to those without CIU/CSU. PMID- 29514730 TI - Ultrasonography of an Oral Cavity Onchocercidae Nodule. PMID- 29514731 TI - Parasite-Vector Interaction of Chagas Disease: A Mini-Review. AB - Trypanosoma cruzi is a protozoan of great importance to public health: it has infected millions of people in the world and is the etiologic agent of Chagas disease, which can cause cardiac and gastrointestinal disorders in patients and may even lead to death. The main vector of transmission of this parasite is triatomine bugs, which have a habit of defecating while feeding on blood and passing the parasite to their own hosts through their feces. Although it has been argued that T. cruzi is not pathogenic for this vector, other studies indicate that the success of the infection depends on several molecules and factors, including the insect's intestinal microbiota, which may experience changes as a result of infection that include decreased fitness. Moreover, the effects of infection depend on the insect species, the parasite strain, and environmental conditions involved. However, the parasite-vector interaction is still underexplored. A deeper understanding of this relationship is an important tool for discovering new approaches to T. cruzi transmission and Chagas disease. PMID- 29514732 TI - ERRATUM. AB - The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP 1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI. PMID- 29514733 TI - New objective measurements of semen wave motion are associated with fertility in sheep. AB - In sheep, wave motion in semen is currently used by AI centres to select ejaculates for insemination. Despite its low cost, convenience and established ability to predict fertility, the subjectivity of this assessment is a limiting factor for its applicability. The aims of the present study were to establish an objective method for the analysis of wave motion and to assess the associations of objective parameters with fertility after cervical insemination. Collective sperm motion in undiluted semen was observed by phase contrast microscopy at low magnification in a 100-um deep glass chamber. Images of moving dark waves over a grey background were recorded and analysed by the optic flow method, producing several velocity-related parameters. Turbulence was assessed from the motion of fluorescent polystyrene beads. Among objective parameters, optical flow entropy and the average speed of beads were both able to discriminate ejaculates suitable for insemination. Two synthetic variables of optic flow and bead motion and a global objective variable were computed from linear combinations of individual parameters and compared with the subjective motion score for their predictive value. These were as efficient as the wave motion score for assessing fertility and can be proposed for the assessment of ram semen in routine AI procedures. PMID- 29514734 TI - CASA-Mot in mammals: an update. AB - Sperm motility is one of the most widely used parameters of sperm quality. Computer-aided sperm motility analysis (CASA-Mot) systems were developed to reduce the subjectivity of sperm motility assessment, and have had broad scientific and practical acceptance. In this review, the sources of variation and current applications of this technology and its relationships with other sperm quality tests are described in detail. Despite remarkable advances in the technique, there is still great need for standardisation in many species, and the numerous factors that affect the results make it difficult to provide universally accepted criteria for classifying semen samples based on sperm motility characteristics. The main fields for CASA-Mot include the study of male fertility and pathologies, evaluation of the effects of physical and chemical agents, improvement of epidemiological survey studies, more precise calculation of seminal doses for farm animals, realisation of basic studies about sperm function, improvement of sperm technologies such as cryopreservation and quality control analysis. Numerous relationships have been established between CASA-Mot and other sperm quality tests, although most of these parameters are complementary. Future CASA-Mot systems will probably be able to integrate several sperm quality parameters with motility. PMID- 29514735 TI - Making the most of sperm activation responses: experiments with boar spermatozoa and bicarbonate. AB - Attempting to extract useful and reliable information about semen quality and its fertility potential remains a difficult exercise, partly because the sperm heterogeneity within samples often renders simple statistical analyses rather meaningless. In fact, a mean and standard deviation may reflect neither the very fast swimming activities of the most active cells nor the slow and sluggish activities of others. Herein we propose that the information value within semen samples can be maximised if current knowledge about sperm activation mechanisms is exploited before undertaking the measurements. We explain, using boar semen as an example, that estimating and defining relative sperm subpopulation sizes, after activation by bicarbonate, provides a means of quantifying sperm quality. Although such estimates may indeed be related to in vivo fertility, the general approach also suggests potential new avenues that could be exploited for the elaboration of novel in vitro tests for the characterisation of toxic environmental chemicals and, indeed, to reduce the number of animals used in such testing programs. PMID- 29514736 TI - Corrigendum to "Monitoring training load and fatigue in soccer players with physiological markers" [Physiol. Behav. 181 (2017) 86-94]. PMID- 29514737 TI - Trends in the incidence of serous fallopian tube, ovarian, and peritoneal cancer in the US. AB - OBJECTIVE: To identify the trends in incidence of serous fallopian tube, ovarian, and peritoneal epithelial cancers in the United States. METHODS: Data was obtained from United States Cancer Statistics (USCS) from 2001 to 2014. All incidences are per 100,000 women. Analyses were performed using SEER*Stat and Joinpoint regression programs. RESULTS: Of the 146,470 patients with serous cancers, 9381 (6.4%) were fallopian tube, 121,418 (82.9%) were ovarian, and 15,671 (10.7%) were primary peritoneal. The study period was divided from 2001 to 2005, 2006-2010, and 2011-2014, and there was an increase in fallopian tube incidence from 0.19 to 0.35 to 0.63, with a corresponding decrease in ovarian incidence from 5.31 to 5.08 to 4.86. There was no significant change in peritoneal cancers from 0.64 to 0.69 to 0.62. The age-specific peak incidence of fallopian tube cancer was younger at age 70-74, compared to ovarian and peritoneal cancer at age 75-79. Further, the incidence of serous fallopian tube cancer was highest in Whites at 0.42, compared to Blacks at 0.24, Hispanics at 0.27, and Asians at 0.28. CONCLUSION: From 2001 to 2014, the diagnosis of serous fallopian tube cancer increased fourfold with a corresponding decrease in ovarian cancer. The peak incidence of tubal cancer was 70-74years with an increased incidence in Whites. PMID- 29514738 TI - Treatment and outcome of elderly patients with advanced stage ovarian cancer: A nationwide analysis. AB - OBJECTIVE: To provide an overview of treatment strategies for elderly patients with advanced stage epithelial ovarian cancer (EOC) in daily practice, evaluate changes over time and relate this to surgical mortality and survival. METHODS: All women diagnosed with advanced stage (FIGO IIB and higher) EOC between 2002 and 2013 were selected from the Netherlands Cancer Registry (n=10,440) and stratified by age, stage and period of diagnosis. Elderly patients were defined as aged >=70years. Time trends in treatment patterns and postoperative mortality were described by age category and tested using multivariable logistic regression. Relative survival was calculated. RESULTS: With advancing age, less patients received ((neo-)adjuvant) treatment. Over time, elderly patients were less often treated (OR 2002-2004 versus 2011-2013: 0.73; 95%CI:0.58-0.92). But if treated, more often standard treatment was provided and 30-day postoperative mortality decreased from 4.5% to 1.9% between 2005 and 2007 and 2011-2013. In all age categories treatment shifted from primary surgery towards primary chemotherapy, in patients aged 70-79years combination therapy increased (+5%) between 2002 and 2004 and 2011-2013. Five-year relative survival for patients diagnosed in 2008-2010 aged <70years was 34% compared to 18% for elderly patients. CONCLUSION: Large treatment differences exist between younger and elderly patients. Over time, selection of elderly patients eligible for curative surgical treatment may have improved. More elderly patients were treated with neoadjuvant chemotherapy while less patients underwent surgery and simultaneously postoperative mortality decreased. However, the large and increasing number of elderly patients without treatment and the large survival gap suggests opportunities for further improvements in the care for elderly EOC patients. PMID- 29514739 TI - [Propensity score: Interests, use and limitations. A practical guide for clinicians]. AB - Propensity scores have been proposed in the early 1980s, and are increasingly used in epidemiology since the 2000s. They are is used to minimize the selection bias in observational studies, leading to a comparability between the exposure groups close to that observed in randomized trials. However, they have important limitations. Besides, new statistical techniques to improve the propensity score performances are more and more complex, while the build and the use of propensity score require a strict methodology to avoid bias, imprecision and non reproducibility. This overview, designed for clinicians, is aimed at describing the advantages, techniques of use and limitations of propensity scores. A reading grid is provided in order to help interpreting studies using propensity scores. PMID- 29514740 TI - Optimal timing for elective resection of asymptomatic congenital pulmonary airway malformations. AB - PURPOSE: We sought to determine optimal timing for CPAM resection within the first year of life. METHODS: We queried the National Surgical Quality Improvement Program pediatric database from 2012 to 2015 for elective CPAM resections on patients less than 1year of age. Patients were divided by age in months: 1-3 (n=57), 4-6 (n=135), and 6-12 (n=214). Patient operative variables and 30-day postoperative outcomes were compared. RESULTS: A total of 406 patients were included with no differences in demographics or comorbidities. Median operative time increased with each older age category (115min, 152min, 163min, respectively; p<0.01). Thoracoscopic approach was less utilized in 1-3months (40.4%) compared to the older two age categories (65.9% and 69.6%, respectively; p<0.01). There were no differences by age in major complications, conversion to open, or readmissions. On multivariate analysis, ASA class>=3 (p<0.01) and prolonged operative time (p<0.01) were associated with a major complication. Furthermore, operations on patients aged 6-12months were associated with increased operative time (p<0.01) regardless of operative approach. CONCLUSION: Elective CPAM resections are equally safe in patients 1-12months of age. Earlier resection including both open and thoracoscopic resection is associated with decreased operative time. LEVEL OF EVIDENCE: IIc, Outcomes Research. PMID- 29514741 TI - Hepatopulmonary Syndrome and Portopulmonary Hypertension in Children: Recent Advances in Diagnosis and Management. PMID- 29514742 TI - Potential Impact on Development: More Evidence for Risk-Appropriate Neonatal Care. PMID- 29514743 TI - A case-mix classification system for explaining healthcare costs using administrative data in Italy. AB - BACKGROUND: The Italian National Health Service (NHS) provides universal coverage to all citizens, granting primary and hospital care with a copayment system for outpatient and drug services. Financing of Local Health Trusts (LHTs) is based on a capitation system adjusted only for age, gender and area of residence. We applied a risk-adjustment system (Johns Hopkins Adjusted Clinical Groups System, ACG(r) System) in order to explain health care costs using routinely collected administrative data in the Veneto Region (North-eastern Italy). METHODS: All residents in the Veneto Region were included in the study. The ACG system was applied to classify the regional population based on the following information sources for the year 2015: Hospital Discharges, Emergency Room visits, Chronic disease registry for copayment exemptions, ambulatory visits, medications, the Home care database, and drug prescriptions. Simple linear regressions were used to contrast an age-gender model to models incorporating more comprehensive risk measures aimed at predicting health care costs. RESULTS: A simple age-gender model explained only 8% of the variance of 2015 total costs. Adding diagnoses related variables provided a 23% increase, while pharmacy based variables provided an additional 17% increase in explained variance. The adjusted R-squared of the comprehensive model was 6 times that of the simple age-gender model. CONCLUSIONS: ACG System provides substantial improvement in predicting health care costs when compared to simple age-gender adjustments. Aging itself is not the main determinant of the increase of health care costs, which is better explained by the accumulation of chronic conditions and the resulting multimorbidity. PMID- 29514745 TI - Computerized interpretation of electrocardiograms: Taking stock and implementing new knowledge. PMID- 29514744 TI - Association between blood eosinophil count with asthma hospital readmissions. AB - INTRODUCTION: The presence of eosinophils in asthma inflammation is a relevant factor in the pathophysiology of the disease, however the relationship between the blood eosinophil count (BEC) with asthma severity and prognosis is still under debate. The aim of this work is to analyze the relationship between the BEC levels and hospital readmissions in patients with asthma. MATERIAL AND METHODS: A review was retrospectively carried out on all admissions of patients over 18 years old due to exacerbation of asthma occurring in our hospital between the years 2000 and 2010. The personal characteristics and the asthma personal history of each patient were recorded. The BEC was determined from the first blood sample taken from the patient after their arrival at the hospital. Hospital early, late and frequent readmissions were analyzed using 4 cut-off points; less than 150 eosinophils/MUL vs >=150/MUL, less than 200 vs 200 /MUL, less than 300 vs >=300/MUL, and less than 400 vs >=400/MUL. RESULTS: We have included 1316 patients, 70% of whom are women, as well as a mean age of 60 years, and a mean FEV1 of 73.5% of the reference value. The mean eosinophil blood count was 201.7 cells/MUL. A BEC >=300 cells/MUL showed a reduction of risk of late readmission of 42%, a BEC >=400 cells/MUL showed a reduction in late readmission risk of 41% and decrease in frequent late readmission of 63%. CONCLUSIONS: Our study appears to support that an elevated BEC is associated with a lower incidence of asthma hospital readmissions. PMID- 29514746 TI - Multidisciplinary unit for the surgical management of geriatric patient. PMID- 29514747 TI - Scalp blocks for brain tumor craniotomies: A retrospective survival analysis of a propensity match cohort of patients. AB - To test the association between the use of scalp blocks for malignant brain tumor craniotomy and survival. This is a retrospective study conducted in a tertiary academic center. Demographic, intraoperative and survival data from 808 adult patients with malignant brain tumors was included in the analysis. Patients were divided in those who received an Intraoperative use of scalp block or not. The progression free survival (PFS) and overall survival (OS) rates were compared in patients who had and had not scalp blocks. Kaplan-Meier method was used for time to-event analysis including recurrence free survival and overall survival. Multivariate analyses before and after propensity score matching were conducted to test the association between different covariates including scalp blocks with PFS and OS. Five hundred and ninety (73%) of the patients had a scalp block. Before PSM, patients with a scalp block were more likely to have an ASA physical status of 3-4, recurrent tumors and receive adjuvant radiation. Patients with scalp block showed no significant reduction in intraoperative opioids. After adjusting for significant covariates, the administration of a scalp block was not associated with an increase in PFS (HR, 95%CI = 0.98, 0.8-1.2, p = 0.892) or OS (HR, 95%CI = 1.02, 0.82-1.26, p = 0.847) survival. This retrospective study suggests that the use of scalp blocks during brain tumor surgery is not associated with patients' longer survival. PMID- 29514748 TI - Systematic review and directors survey of quality indicators for the cardiovascular intensive care unit. AB - BACKGROUND: Quality indicators (QIs) are increasingly used in cardiovascular care as measures of performance but there is currently no consensus on indicators for the cardiovascular intensive care unit (CICU). METHODS: We searched Medline, CINAHL, EMBASE, and COCHRANE databases from inception until October 2016 and websites for organizations involved in quality measurement for QIs relevant to cardiovascular disease in an intensive or critical care setting. We surveyed 14 expert cardiac intensivist-administrators (7 European; 7 North American) on the importance and relevance of each indicator as a measure of CICU care quality using a scale of 1 (=lowest) to 10 (=highest). Indicators with a mean score >=8/10 for both importance and relevance were included in the final set. RESULTS: Overall, 108 QIs (70 process, 18 structural, 18 outcome, 1 patient engagement, and 1 covering multiple domains) were identified in 30 articles representing 23 agencies, organizations, and societies. Disease-specific QIs included myocardial infarction (n = 37), heart failure (n = 31), atrial fibrillation (n = 11), and cardiac rehabilitation (n = 1); general QIs represented about one-quarter (n = 28) of all measures. Fifteen QIs were selected for the final QI set: 7 process, 2 structural, and 6 outcome measures, including 6 general and 9 disease-specific measures. Outcome measures chosen to evaluate general CICU performance included overall CICU mortality, length of stay, and readmission rate. CONCLUSIONS: Numerous QIs relevant to the CICU have been recommended by a variety of organizations. The indicators chosen by the cardiac intensivist-administrators could serve as a basis for future efforts to develop a standardized set of quality measures for the CICU. PMID- 29514749 TI - The low prevalence of pulmonary embolism in patients with syncope: What should clinicians do? PMID- 29514750 TI - Let's talk about sex: Development and evaluation of a sexual history and counseling curriculum for internal medicine interns. AB - OBJECTIVE: We developed a curriculum to increase internal medicine interns' proficiency in sexual history taking and sexually transmitted illness (STI) counseling. METHODS: The 4-h curriculum included didactics and interactive components, and was evaluated with matched pre- and post-surveys. RESULTS: Twenty one interns completed the curriculum. Mean knowledge score improved from 59% to 76% from pre- to post-curriculum (P = 0.004). Median comfort score (Likert scale 1-5) with obtaining a sexual history improved from 3.8 [IQR 3.0, 4.0] to 3.8 [IQR 3.6, 4.6] and 3.8 [IQR 3.6, 4.0] to 4.1 [IQR 3.9, 4.8] for male (P = 0.05) and female patients (P = 0.007), respectively. Median frequency score for obtaining a sexual history improved from 2.9 [IQR 2.7, 3.0] to 3.1 [IQR 2.8, 3.4] and 3.2 [IQR 2.8, 3.7] to 3.4 [IQR 3.2, 4.0] for male (P = 0.16) and female patients (P = 0.008), respectively. Pre- and post- curriculum, interns reported significantly higher comfort and frequency in obtaining sexual histories from female vs. male patients. Post- curriculum, interns reported significantly higher comfort with positive STI counseling. PRACTICE IMPLICATIONS: Our curriculum improved interns' knowledge and comfort in sexual history taking and STI counseling. Future interventions should address sex disparities in sexual history taking. PMID- 29514751 TI - Comment: On ignoring the literature and relevant tests in evaluating effectively maintained inequality. PMID- 29514752 TI - Acceptance of homosexuality through education? Investigating the role of education, family background and individual characteristics in the United Kingdom. AB - Higher educated people tend to be more accepting of homosexuality than lower educated people. This has inspired claims that education leads to a higher acceptance of homosexuality. Alternatively, the association between education and acceptance of homosexuality could be confounded by (un)observed family background and stable individual characteristics. This study investigated the association between education and acceptance of homosexuality and the role of potential confounders in a unique longitudinal sample of British siblings. Multilevel and fixed effects analyses show that both perspectives apply. A large part of the association between education and acceptance of homosexuality could be attributed to family background and observed individual characteristics (one third), as well as unobserved individual characteristics (an additional third), but the positive association remains. Findings are discussed in light of existing explanations regarding the effect of education on the acceptance of homosexuality. PMID- 29514753 TI - Obesity and gender as status beliefs. AB - For over 30 years, researchers have examined social influence using status characteristics theory (Berger and Conner, 1974). While research has investigated beauty and attractiveness as status characteristics (e.g., Webster and Driskell, 1983), there is a dearth of research that examines whether obesity has status value using status characteristics theory. The current paper reviews the literature on, demonstrating how they are related to status characteristics. Next, this paper demonstrates how the effects of both gender and obesity can be explained by considering them as status characteristics, which have the potential to create subsequent status beliefs and stigma. Finally, this study reports empirical findings that support obesity as a status characteristic. We find an effect for obesity on ratings of diffuse status, and effects for both obesity and gender on ratings of influence. PMID- 29514754 TI - Understanding Americans' abortion attitudes: The role of the local religious context. AB - Although abortion became legal over 40 years ago, Americans remain staunchly divided over its acceptability. Personal religious beliefs and behaviors have emerged as some of the most important factors shaping disapproval. Despite religion's importance, very little attention has been given to how the local religious context may shape views and abortion access. Using data from the General Social Survey (N = 6922) that has geographical identifiers, we examine the role of the local religious context for shaping attitudes and the presence of a county abortion clinic. We find that as the level of county religious engagement rises, religious and secular residents alike develop more conservative attitudes. Conversely, as the county Catholic rate increases, moderate and liberal Protestants become more prochoice. While the county conservative Protestant rate has no influence on residents' attitudes, it is the only religious contextual measure that shapes the likelihood that a county has an abortion clinic. PMID- 29514756 TI - Ontological insecurity and subjective feelings of unsafety: Analysing socially constructed fears in Italy. AB - Perception of insecurity arises as a complex social phenomenon affected by factors that go beyond actual crime rates. Previous contributions to the field of fear of crime studies have shown, for instance, that the perception of social and physical disorder may generate insecurity among residents even in contexts where crime is comparatively low. Meanwhile, sociological approaches have led to a conceptualization of insecurity as an umbrella sentiment grounded in a wider feeling of unease. Building further on this assumption, data gathered in a large scale survey in Italy (n = 15,428) were analysed by implementing exploratory and confirmatory factor analysis with the objective of assessing the validity of a model of "ontological insecurity". The results of our analysis support a conceptualization of insecurity where socially constructed anxieties (due to health and financial precariousness), as well as ethnic, sexual and religious based stigmatization, play a prominent role in determining an individual's feeling of insecurity. PMID- 29514755 TI - Fear of violence during armed conflict: Social roles and responsibilities as determinants of fear. AB - This article investigates the prevalence and determinants of fear as a consequence of living through armed conflict. We use survey data from Nepal during the armed conflict (1996-2006) to examine how trauma, sex and gender, age, marriage, and household size affect fear of violence. We also disaggregate types of worry, and find substantial variance on whether respondents were more concerned about livelihood consequences of conflict than physical danger. We supplement quantitative analyses with discussion of in-depth interviews from the study area on these same topics. Overall, our results highlight the enduring impact of gender roles in Nepal and that conflict might disproportionately affect those who are already vulnerable and have greater social responsibilities. This article provides a unique comparison between fear of violence during armed conflict in a low-income country to the fear of crime literature based in high income countries. PMID- 29514758 TI - In the shadow of production: Coal waste accumulation and environmental inequality formation in Eastern Kentucky. AB - This article advances an environmental-sociological and quantitative spatial analytic approach to the study of environmental inequality formation in coal country. We use spatial error regression models in a case study of 2000 census block group proximity to hazardous coal waste impoundments amidst shifting coal production trajectories and impoundment disaster contexts in the declining Eastern Kentucky coalfields. Proximity to abandoned and sealed mines, coal production density, and the "buffering effect" of rural-agricultural context are the most powerful predictors of impoundment proximity in the period encapsulating the boom years of coal production and culminating in 2000. Amidst continued coal industry decline and the post-2000 Martin County impoundment disaster context, proximity to older impoundments, including the failed Martin County impoundment, proximity to abandoned and sealed mines, and poverty levels by 2000 are the most powerful predictors of proximity to impoundments sited from 2001 to 2006. Findings have important environmental justice research and policy implications. PMID- 29514757 TI - Things are looking up: Physical beauty, social mobility, and optimistic dispositions. AB - Physical attractiveness tends to inspire friendlier reactions and more positive evaluations from others, so that the beautiful are likelier to succeed across many kinds of endeavors. Does this history of success lead to a more optimistic, hopeful attitude? Evidence from the 2016 General Social Survey and the 1972 National Election Study suggests that it often does: those whom interviewers rate as better-looking tend to report higher expectations that life will turn out well for them, and show signs of greater upward social mobility. Since optimism is itself an important contributor to success in many social endeavors, these findings suggest an understudied mechanism by which beauty leads to better life outcomes, as well as a means by which social interactions may shape personal dispositions. PMID- 29514759 TI - Understanding the density of nonprofit organizations across Los Angeles neighborhoods: Does concentrated disadvantage and violent crime matter? AB - Although some urban sociology perspectives suggest how certain sociodeomgraphic characteristics influence nonprofit development, there is a dearth of empirical research to assess neighborhood differences in nonprofit organizations. The goal of the current study is to build upon the extant literature by examining how both concentrated disadvantage and violent crime impact nonprofit density across neighborhoods. Using data from Los Angeles census tracts from 2010 to 2012, I test for linear and nonlinear influences that these two neighborhood factors might exert on nonprofit density. Poisson regression models show that concentrated disadvantage has a nonlinear (U-shaped) effect on all forms of nonprofit density, whereas violent crime has a linear and deleterious effect on all forms of nonprofit density. These results provide important new insights for urban sociology and policy; most importantly, the extent to which neighborhoods with ongoing social problems can later respond to such problems via access to nonprofit organizations. PMID- 29514760 TI - Response: Issues surrounding Effectively Maintained Inequality and educational transitions. PMID- 29514761 TI - Adolescent caretaking of younger siblings. AB - Sibling interactions play important roles in socialization; however, little is known about sibling caretaking in contemporary families. This study examined the prevalence of adolescents providing care for younger siblings and the quality of care as associated with a broad spectrum of individual, microsystem, and macrosystem factors. Relying on nationally representative time diary data from the American Time Use Survey, we found that factors at multiple levels (individual, microsystem, and macrosystem) were associated with sibling caretaking. Gendered patterns in caretaking emerged. The caretaker's sex and the ages and sexes of younger siblings correlated with the incidence and quality of sibling care. Boys more often cared for younger brothers, and girls more often cared for younger sisters. In addition, boys more often played with younger siblings while girls more often provided physical care and talked with younger siblings, mirroring gendered patterns seen in parents. PMID- 29514762 TI - Socioeconomic variation in the association of marriage with depressive symptoms. AB - Although the health-relevant resources that marriage is argued to provide vary by socioeconomic status (SES), little research has examined whether the association of marriage with psychological well-being varies by SES. Focusing on depressive symptoms as an outcome and using a two-stage Heckit procedure with multilevel modeling, results from analyses of four waves of data (n = 4340 person-waves) from the American Changing Lives Survey (ACL) shows that differences in depressive symptoms between never-married and married adults varies by adjusted household income. Depressive symptoms are highest among the never married, and differences from the married greatest, at the lowest levels of income. As income increases these differences are eliminated. The conditioning effect of income is partially mediated by financial security, self-efficacy, and social support from friends and relatives. The implications of these findings for U.S. marriage promotion policies are discussed. PMID- 29514763 TI - Social capital and self-rated health: Clarifying the role of trust. AB - While research on social capital and health typically focuses on generalized trust (trust in abstract others), questions about the conceptualization and measurement of generalized trust remain, including whether trust should even be considered a part of social capital. We present a new approach to studying trust in the context of health and argue that consideration of the mechanisms through which social capital influences health highlights the central theoretical role of particularized trust (trust in known others). Furthermore, we argue that the effects of trust and social networks on health are dependent on one another. Analyzing data from Waves 5 and 6 of the World Values Survey (WVS), we find that, net of control variables, particularized trust is more strongly associated with self-rated health than is generalized trust. In addition, we find that the predicted effects of particularized and generalized trust on self-rated health are conditioned by membership in voluntary associations and vice versa. PMID- 29514764 TI - Per- and polyfluoroalkyl substance (PFAS) exposure assessment in a community exposed to contaminated drinking water, New Hampshire, 2015. AB - BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in manufacturing that resist environmental degradation, can leach into drinking water, and bioaccumulate in tissues. Some studies have shown associations with negative health outcomes. In May 2014, a New Hampshire public drinking water supply was found to be contaminated with PFAS from a former U.S. Air Force base. OBJECTIVES: We established a serum testing program to assess PFAS exposure in the affected community. METHODS: Serum samples and demographic and exposure information were collected from consenting eligible participants. Samples were tested for PFAS at three analytical laboratories. Geometric means and 95% confidence intervals were calculated and analyzed by age and exposure variables. RESULTS: A total of 1578 individuals provided samples for PFAS testing; >94% were found to have perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) detectable in serum. Geometric mean serum concentrations of PFOS, PFOA, and PFHxS were 8.6 MUg/L (95% CI:8.3-8.9), 3.1 MUg/L (95% CI: 3.0-3.2), and 4.1 MUg/L (95% CI: 3.9-4.3), respectively, which were statistically higher than the general U.S. POPULATION: Significant associations were observed between PFAS serum concentrations and age, time spent in the affected community, childcare attendance, and water consumption. CONCLUSIONS: PFOS, PFOA, and PFHxS were found in significantly higher levels in the affected population, consistent with PFAS drinking water contamination. Given increased recognition of PFAS contamination in the U.S, a coordinated national response is needed to improve access to biomonitoring and understand health impacts. PMID- 29514765 TI - Plasma fetuin-B concentrations are associated with insulin resistance and first phase glucose-stimulated insulin secretion in individuals with different degrees of glucose tolerance. AB - AIMS: To assess circulating fetuin-B concentrations in subjects with different degrees of glucose tolerance and to analyze the association of fetuin-B concentrations with insulin resistance and the first phase of glucose-stimulated insulin secretion. METHODS: Plasma fetuin-B concentrations were analyzed in 149 subjects with normal glucose tolerance (NGT, n=54), impaired glucose regulation (preDM, n=42) and newly diagnosed type-2 diabetes mellitus (nT2DM, n=53). Intravenous glucose tolerance tests (IVGTTs) and biochemical parameters were also assessed in all participants. RESULTS: Plasma fetuin-B concentrations were significantly higher in nT2DM patients compared with NGT and preDM subjects (both P<0.001) and positively correlated with FPG, 2hPG, HOMA-IR, HbA1c, hsCRP, FINS and TG (P<0.05), but negatively correlated with AIR, AUC, GDI and fasting Belfiore index (P<0.01). After adjusting for age and gender, all correlations remained statistically significant (P<0.05). Multivariate logistic regression analysis revealed that plasma fetuin-B concentrations were significantly correlated with nT2DM after controlling for age, gender, BMI, WHR, blood pressure and lipid profiles. CONCLUSION: Patients with nT2DM have significantly higher concentrations of plasma fetuin-B compared with NGT subjects and plasma fetuin-B is strongly associated with glucose and lipid metabolism, chronic inflammation and first-phase glucose-stimulated insulin secretion and insulin resistance. PMID- 29514766 TI - Erratum to "DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine"[DNA Repair, 62 (2018) 1-7]. PMID- 29514767 TI - [Diagnostic strategies for endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - In this chapter we have examined the possibilities of screening endometriosis, both in the general population as well as in the target population. We then proposed decision trees, for primary and secondary care. Currently, there is not enough data in the literature to develop or organize a screening test for endometriosis. Screening for endometriosis is not recommended in the general population (level A). There is also no evidence to support systematic screening in a population with genetic risk factors (endometriosis in a relative), or with other clinical risk factors (increased menstrual volume, short cycles, early menarche) (level A). However, it is possible to propose a decision tree for the management of chronic pelvic pain symptoms (dysmenorrhea, dyspareunia, non menstrual pelvic pain). The search for symptoms suggestive of endometriosis (intense dysmenorrhea [visual analogue scale >7/10, frequent abstention, resistance to level 1 analgesics], infertility) should be systematic. The search for localizing symptoms of deep endometriosis (deep dyspareunia, cyclic defecation pain, cyclic urinary signs) enables to orient the patient to second line evaluation. We propose a decision tree for second and third line evaluations, according to the suspicion and/or the discovery of deep lesions with specific locations, or the suspicion of superficial lesions. PMID- 29514768 TI - Outcome age-based prediction of successful cognitive aging by total cholesterol. AB - INTRODUCTION: Some associations of high total cholesterol with dementia risk diminish as the outcome age-age at cognitive assessment-increases. METHODS: The Framingham Heart Study provided 1897 participants with intact cognition at entry. Cox regression analysis for incident marked cognitive decline included "time dependent" coefficients, with associations between total cholesterol and covariates changing by outcome age. Decline within age categories of 75-84 and 85 94 years was also examined. RESULTS: Significant associations of rising total cholesterol linear slope, low entry age, low education, and statin nonuse with risk diminished significantly by outcome age. At 85-94 years, falling linear slope was significant. DISCUSSION: The protected survival model posits a minority subpopulation with protection against mortality and cognitive decline associated with total cholesterol risk factors. It predicts the observed diminished or reversed cholesterol associations with increasing age. Protection is particularly likely for successful cognitive aging-intact cognition at very old age-despite increased risk from cholesterol. PMID- 29514769 TI - Genetic portrait of 27 Y-STR loci in the Tibetan ethnic population of the Qinghai province of China. PMID- 29514770 TI - Primary Langerhans Cell Histiocytosis of the Extrahepatic Bile Duct Occurring in an Adult Patient AB - Background: Langerhans cell histiocytosis is characterized by an abnormal proliferation of neoplastic Langerhans cells. Langerhans cell histiocytosis commonly affects the pediatric population, whereas presentation in adults remains a rare event. The presentation of Langerhans cell histiocytosis is highly variable, but the involvement of skin, bone, and lung is very common. Langerhans cell histiocytosis presenting as a bile duct mass is rare and usually occurs as part of a multiorgan system disease. Case Report: We present a case of Langerhans cell histiocytosis confined to the extrahepatic bile duct in a 62-year-old female patient with sclerosing cholangitis. The mass was composed of mononuclear cells with cleaved nuclei that were positive for CD68, S100, and CD1a as assessed by immunohistochemistry. Conclusion: This is the first report of Langerhans cell histiocytosis limited to the extrahepatic bile duct in an adult patient. We discuss the clinical manifestations and the challenges encountered in the diagnosis and treatment of this rare entity. PMID- 29514771 TI - Development of eHOME, a Mobile Instrument for Reporting, Monitoring, and Consulting Drug-Related Problems in Home Care: Human-Centered Design Study. AB - BACKGROUND: Home care patients often use many medications and are prone to drug related problems (DRPs). For the management of problems related to drug use, home care could add to the multidisciplinary expertise of general practitioners (GPs) and pharmacists. The home care observation of medication-related problems by home care employees (HOME)-instrument is paper-based and assists home care workers in reporting potential DRPs. To facilitate the multiprofessional consultation, a digital report of DRPs from the HOME-instrument and digital monitoring and consulting of DRPs between home care and general practices and pharmacies is desired. OBJECTIVE: The objective of this study was to develop an electronic HOME system (eHOME), a mobile version of the HOME-instrument that includes a monitoring and a consulting system for primary care. METHODS: The development phase of the Medical Research Council (MRC) framework was followed in which an iterative human-centered design (HCD) approach was applied. The approach involved a Delphi round for the context of use and user requirements analysis of the digital HOME-instrument and the monitoring and consulting system followed by 2 series of pilots for testing the usability and redesign. RESULTS: By using an iterative design approach and by involving home care workers, GPs, and pharmacists throughout the process as informants, design partners, and testers, important aspects that were crucial for system realization and user acceptance were revealed. Through the report webpage interface, which includes the adjusted content of the HOME-instrument and added home care practice-based problems, home care workers can digitally report observed DRPs. Furthermore, it was found that the monitoring and consulting webpage interfaces enable digital consultation between home care and general practices and pharmacies. The webpages were considered convenient, clear, easy, and usable. CONCLUSIONS: By employing an HCD approach, the eHOME-instrument was found to be an easy-to-use system. The systematic approach promises a valuable contribution for the future development of digital mobile systems of paper-based tools. PMID- 29514772 TI - Evaluation of a Mobile Phone-Based Intervention to Increase Parents' Knowledge About the Measles-Mumps-Rubella Vaccination and Their Psychological Empowerment: Mixed-Method Approach. AB - BACKGROUND: There is mixed evidence on the effectiveness of vaccination-related interventions. A major limitation of most intervention studies is that they do not apply randomized controlled trials (RCTs), the method that, over the last 2 decades, has increasingly been considered as the only method to provide proof of the effectiveness of an intervention and, consequently, as the most important instrument in deciding whether to adopt an intervention or not. This study, however, holds that methods other than RCTs also can produce meaningful results. OBJECTIVE: The aim of this study was to evaluate 2 mobile phone-based interventions aimed at increasing parents' knowledge of the measles-mumps-rubella (MMR) vaccination (through elements of gamification) and their psychological empowerment (through the use of narratives), respectively. The 2 interventions were part of an RCT. METHODS: We conducted 2 studies with the RCT participants: a Web-based survey aimed at assessing their rating of the tool regarding a number of qualities such as usability and usefulness (N=140), and qualitative telephonic interviews to explore participants' experiences with the app (N=60). RESULTS: The results of the survey showed that participants receiving the knowledge intervention (alone or together with the empowerment intervention) liked the app significantly better compared with the group that only received the empowerment intervention (F2,137=15.335; P<.001). Parents who were exposed to the empowerment intervention complained that they did not receive useful information but were only invited to make an informed, autonomous MMR vaccination decision. CONCLUSIONS: The results suggest that efforts to empower patients should always be accompanied by the provision of factual information. Using a narrative format that promotes parents' identification can be an appropriate strategy, but it should be employed together with the presentation of more points of views and notions regarding, for instance, the risks and benefits of the vaccination at the same time. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number 30768813; http://www.isrctn.com/ ISRCTN30768813 (Archived by WebCite at http://www.webcitation.org/6xOQSJ3w8). PMID- 29514774 TI - Self-Reflected Well-Being via a Smartphone App in Clinical Medical Students: Feasibility Study. AB - BACKGROUND: Well-being in medical students has become an area of concern, with a number of studies reporting high rates of clinical depression, anxiety, burnout, and suicidal ideation in this population. OBJECTIVE: The aim of this study was to increase awareness of well-being in medical students by using a smartphone app. The primary objective of this study was to determine the validity and feasibility of the Particip8 app for student self-reflected well-being data collection. METHODS: Undergraduate medical students of the Dunedin School of Medicine were recruited into the study. They were asked to self-reflect daily on their well being and to note what experiences they had encountered during that day. Qualitative data were also collected both before and after the study in the form of focus groups and "free-text" email surveys. All participants consented for the data collected to be anonymously reported to the medical faculty. RESULTS: A total of 29 participants (69%, 20/29 female; 31%, 9/29 male; aged 21-30 years) were enrolled, with overall median compliance of 71% at the study day level. The self-reflected well-being scores were associated with both positive and negative experiences described by the participants, with most negative experiences associated with around 20% lower well-being scores for that day; the largest effect being "receiving feedback that was not constructive or helpful," and the most positive experiences associated with around 20% higher scores for that day. CONCLUSIONS: The study of daily data collection via the Particip8 app was found to be feasible, and the self-reflected well-being scores showed validity against participant's reflections of experiences during that day. PMID- 29514773 TI - Effect of Mobile Phone Text Message Reminders on Routine Immunization Uptake in Pakistan: Randomized Controlled Trial. AB - BACKGROUND: Improved routine immunization (RI) coverage is recommended as the priority public health strategy to decrease vaccine-preventable diseases and eradicate polio in Pakistan and worldwide. OBJECTIVE: The objective of this study was to ascertain whether customized, automated, one-way text messaging (short message service, SMS) reminders delivered to caregivers via mobile phones when a child is due for an RI visit can improve vaccination uptake and timelines in Pakistan. METHODS: This was a randomized controlled trial, conducted in an urban squatter settlement area of Karachi, Pakistan. Infants less than 2 weeks of age with at least one family member who had a valid mobile phone connection and was comfortable receiving and reading SMS text messages were included. Participants were randomized to the intervention (standard care + one-way SMS reminder) or control (standard care) groups. The primary outcome was to compare the proportion of children immunized up to date at 18 weeks of age. Vaccine given at 6, 10, and 14 weeks schedule includes DPT-Hep-B-Hib vaccine (ie, diphtheria, pertussis, and tetanus; hepatitis B; and Haemophilus influenza type b) and oral poliovirus vaccine (OPV). Data were analyzed using chi-square tests of independence and tested for both per protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: Out of those approached, 84.3% (300/356) of the participants were eligible for enrollment and 94.1% (318/338) of the participants had a working mobile phone. Only children in the PP analyses, who received an SMS reminder for vaccine uptake at 6 weeks visit, showed a statistically significant difference (96.0%, 86/90 vs 86.4%, 102/118; P=.03).The immunization coverage was consistently higher in the intervention group according to ITT analyses at the 6 weeks scheduled visit (76.0% vs 71.3%, P=.36). The 10 weeks scheduled visit (58.7% vs 52.7%, P=.30) and the 14 weeks scheduled visit (31.3% vs 26.0%, P=.31), however, were not statistically significant. CONCLUSIONS: Automated simple one-way SMS reminders in local languages might be feasible for improving routine vaccination coverage. Whether one-way SMS reminders alone can have a strong impact on parental attitudes and behavior for improvement of RI coverage and timeliness needs to be further evaluated by better-powered studies and by comparing different types and content of text messages in low-and middle-income countries (LMICs). TRIAL REGISTRATION: ClinicalTrials.gov NCT01859546; https://clinicaltrials.gov/ct2/show/NCT01859546 (Archived by WebCite at http://www.webcitation.org/6xFr57AOc). PMID- 29514775 TI - Scope, Breadth, and Differences in Online Physician Ratings Related to Geography, Specialty, and Year: Observational Retrospective Study. AB - BACKGROUND: Physician ratings websites have emerged as a novel forum for consumers to comment on their health care experiences. Little is known about such ratings in Canada. OBJECTIVE: We investigated the scope and trends for specialty, geographic region, and time for online physician ratings in Canada using a national data source from the country's leading physician-rating website. METHODS: This observational retrospective study used online ratings data from Canadian physicians (January 2005-September 2013; N=640,603). For specialty, province, and year of rating, we assessed whether physicians were likely to be rated favorably by using the proportion of ratings greater than the overall median rating. RESULTS: In total, 57,412 unique physicians had 640,603 individual ratings. Overall, ratings were positive (mean 3.9, SD 1.3). On average, each physician had 11.2 (SD 10.1) ratings. By comparing specialties with Canadian Institute of Health Information physician population numbers over our study period, we inferred that certain specialties (obstetrics and gynecology, family practice, surgery, and dermatology) were more commonly rated, whereas others (pathology, radiology, genetics, and anesthesia) were less represented. Ratings varied by specialty; cardiac surgery, nephrology, genetics, and radiology were more likely to be rated in the top 50th percentile, whereas addiction medicine, dermatology, neurology, and psychiatry were more often rated in the lower 50th percentile of ratings. Regarding geographic practice location, ratings were more likely to be favorable for physicians practicing in eastern provinces compared with western and central Canada. Regarding year, the absolute number of ratings peaked in 2007 before stabilizing and decreasing by 2013. Moreover, ratings were most likely to be positive in 2007 and again in 2013. CONCLUSIONS: Physician rating websites are a relatively novel source of provider-level patient satisfaction and are a valuable source of the patient experience. It is important to understand the breadth and scope of such ratings, particularly regarding specialty, geographic practice location, and changes over time. PMID- 29514776 TI - Web-Based Activity Within a Sexual Health Economy: Observational Study. AB - BACKGROUND: Regular testing for sexually transmitted infections (STIs) is important to maintain sexual health. Self-sampling kits ordered online and delivered in the post may increase access, convenience, and cost-effectiveness. Sexual health economies may target limited resources more effectively by signposting users toward Web-based or face-to-face services according to clinical need. OBJECTIVE: The aim of this paper was to investigate the impact of two interventions on testing activity across a whole sexual health economy: (1) the introduction of open access Web-based STI testing services and (2) a clinic policy of triage and signpost online where users without symptoms who attended clinics for STI testing were supported to access the Web-based service instead. METHODS: Data on attendances at all specialist public sexual health providers in an inner-London area were collated into a single database. Each record included information on user demographics, service type accessed, and clinical activity provided, including test results. Clinical activity was categorized as a simple STI test (could be done in a clinic or online), a complex visit (requiring face to-face consultation), or other. RESULTS: Introduction of Web-based services increased total testing activity across the whole sexual health economy by 18.47% (from 36,373 to 43,091 in the same 6-month period-2014-2015 and 2015-2016), suggesting unmet need for testing in the area. Triage and signposting shifted activity out of the clinic onto the Web-based service, with simple STI testing in the clinic decreasing from 16.90% (920/5443) to 12.25% (511/4172) of total activity, P<.001, and complex activity in the clinic increasing from 69.15% (3764/5443) to 74.86% (3123/4172) of total activity, P<.001. This intervention created a new population of online users with different demographic and clinical profiles from those who use Web-based services spontaneously. Some triage and signposted users (29.62%, 375/1266) did not complete the Web-based testing process, suggesting the potential for missed diagnoses. CONCLUSIONS: This evaluation shows that users can effectively be transitioned from face-to-face to Web-based services and that this introduces a new population to Web-based service use and changes the focus of clinic-based activity. Further development is underway to optimize the triage and signposting process to support test completion. PMID- 29514777 TI - Building Yolnu Skills, Knowledge, and Priorities into Early Childhood Assessment and Support: Protocol for a Qualitative Study. AB - BACKGROUND: Yolngu or Yolnu are a group of indigenous Australian people inhabiting north-eastern Arnhem Land in the Northern Territory of Australia. Recent government policy addressing disparities in outcomes between Indigenous and other children in Australia has resulted in the rapid introduction of early childhood interventions in remote Aboriginal communities. This is despite minimal research into their appropriateness or effectiveness for these contexts. OBJECTIVE: This research aims to privilege Aboriginal early childhood knowledge, priorities and practices and to strengthen the evidence base for culturally responsive and relevant assessment processes and support that distinguishes "difference" from "deficit" to facilitate optimal child development. METHODS: This collaborative qualitative research employs video ethnography, participant observation and in-depth interviews, involving Aboriginal families and researchers in design, implementation, interpretation and dissemination using a locally developed, culturally responsive research approach. Longitudinal case studies are being conducted with 6 families over 5 years and emerging findings are being explored with a further 50 families and key community informants. Data from all sources are analyzed inductively using a collaborative and iterative process. The study findings, grounded in an in-depth understanding of the cultural context of the study but with relevance to policy and practice more widely, are informing the development of a Web-based educational resource and targeted knowledge exchange activities. RESULTS: This paper focuses only on the research approach used in this project. The findings will be reported in detail in future publications. In response to community concerns about lack of recognition of Aboriginal early childhood strengths, priorities and knowledge, this collaborative community-driven project strengthens the evidence base for developing culturally responsive and relevant early childhood services and assessment processes to support optimal child development. The study findings are guiding the development of a Web-based educational resource for staff working with Aboriginal communities and families in the field of early child development. This website will also function as a community-developed tool for strengthening and maintaining Aboriginal knowledge and practice related to child development and child rearing. It will be widely accessible to community members through a range of platforms (eg, mobile phones and tablets) and will provide a model for other cultural contexts. CONCLUSIONS: This project will facilitate wider recognition and reflection of cultural knowledge and practice in early childhood programs and policies and will support strengthening and maintenance of cultural knowledge. The culturally responsive and highly collaborative approach to community-based research on which this project is based will also inform future research through sharing knowledge about the research process as well as research findings. PMID- 29514778 TI - Research is needed to understand the causes of male infertility and develop treatments. PMID- 29514779 TI - Health department made no plans for future training of 1500 extra medical students, BMJ finds. PMID- 29514780 TI - Sixty seconds on . . . WhatsApp. PMID- 29514781 TI - Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. AB - OBJECTIVE: To evaluate the association between pre-diagnostic circulating vitamin D concentration and the subsequent risk of overall and site specific cancer in a large cohort study. DESIGN: Nested case-cohort study within the Japan Public Health Center-based Prospective Study cohort. SETTING: Nine public health centre areas across Japan. PARTICIPANTS: 3301 incident cases of cancer and 4044 randomly selected subcohort participants. EXPOSURE: Plasma concentration of 25 hydroxyvitamin D measured by enzyme immunoassay. Participants were divided into quarters based on the sex and season specific distribution of 25-hydroxyvitamin D among subcohorts. Weighted Cox proportional hazard models were used to calculate the multivariable adjusted hazard ratios for overall and site specific cancer across categories of 25-hydroxyvitamin D concentration, with the lowest quarter as the reference. MAIN OUTCOME MEASURE: Incidence of overall or site specific cancer. RESULTS: Plasma 25-hydroxyvitamin D concentration was inversely associated with the risk of total cancer, with multivariable adjusted hazard ratios for the second to fourth quarters compared with the lowest quarter of 0.81 (95% confidence interval 0.70 to 0.94), 0.75 (0.65 to 0.87), and 0.78 (0.67 to 0.91), respectively (P for trend=0.001). Among the findings for cancers at specific sites, an inverse association was found for liver cancer, with corresponding hazard ratios of 0.70 (0.44 to 1.13), 0.65 (0.40 to 1.06), and 0.45 (0.26 to 0.79) (P for trend=0.006). A sensitivity analysis showed that alternately removing cases of cancer at one specific site from total cancer cases did not substantially change the overall hazard ratios. CONCLUSIONS: In this large prospective study, higher vitamin D concentration was associated with lower risk of total cancer. These findings support the hypothesis that vitamin D has protective effects against cancers at many sites. PMID- 29514783 TI - High prevalence of MYD88 and CD79B mutations in intravascular large B-cell lymphoma. PMID- 29514784 TI - Patient Commentary: I was pregnant, in pain, and desperate when I chose acupuncture. PMID- 29514785 TI - Should doctors recommend acupuncture for pain? PMID- 29514782 TI - The MYC oncogene is a global regulator of the immune response. AB - The MYC proto-oncogene is a gene product that coordinates the transcriptional regulation of a multitude of genes that are essential to cellular programs required for normal as well as neoplastic cellular growth and proliferation, including cell cycle, self-renewal, survival, cell growth, metabolism, protein and ribosomal biogenesis, and differentiation. Here, we propose that MYC regulates these programs in a manner that is coordinated with a global influence on the host immune response. MYC had been presumed to contribute to tumorigenesis through tumor cell-intrinsic influences. More recently, MYC expression in tumor cells has been shown to regulate the tumor microenvironment through effects on both innate and adaptive immune effector cells and immune regulatory cytokines. Then, MYC was shown to regulate the expression of the immune checkpoint gene products CD47 and programmed death-ligand 1. Similarly, other oncogenes, which are known to modulate MYC, have been shown to regulate immune checkpoints. Hence, MYC may generally prevent highly proliferative cells from eliciting an immune response. MYC-driven neoplastic cells have coopted this mechanism to bypass immune detection. Thus, MYC inactivation can restore the immune response against a tumor. MYC-induced tumors may be particularly sensitive to immuno-oncology therapeutic interventions. PMID- 29514786 TI - Action on substance misuse in older people is "imperative," says college. PMID- 29514788 TI - Patient safety would be undermined if manslaughter review hampers reflective practice, NHS chief executive says. PMID- 29514787 TI - Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study. AB - OBJECTIVE: To determine the differences between recommendations by the National Comprehensive Cancer Network (NCNN) guidelines and Food and Drug Administration approvals of anticancer drugs, and the evidence cited by the NCCN to justify recommendations where differences exist. DESIGN: Retrospective observational study. SETTING: National Comprehensive Cancer Network and FDA. PARTICIPANTS: 47 new molecular entities approved by the FDA between 2011 and 2015. MAIN OUTCOME MEASURES: Comparison of all FDA approved indications (new and supplemental) with all NCCN recommendations as of 25 March 2016. When the NCCN made recommendations beyond the FDA's approvals, the recommendation was classified and the cited evidence noted. RESULTS: 47 drugs initially approved by the FDA between 2011 and 2015 for adult hematologic or solid cancers were examined. These 47 drugs were authorized for 69 FDA approved indications, whereas the NCCN recommended these drugs for 113 indications, of which 69 (62%) overlapped with the 69 FDA approved indications and 44 (39%) were additional recommendations. The average number of recommendations beyond the FDA approved indications was 0.92. 23% (n=10) of the additional recommendations were based on evidence from randomized controlled trials, and 16% (n=7) were based on evidence from phase III studies. During 21 months of follow-up, the FDA granted approval to 14% (n=6) of the additional recommendations. CONCLUSION: The NCCN frequently recommends beyond the FDA approved indications even for newer, branded drugs. The strength of the evidence cited by the NCCN supporting such recommendations is weak. Our findings raise concern that the NCCN justifies the coverage of costly, toxic cancer drugs based on weak evidence. PMID- 29514789 TI - Objective testing is cost effective. PMID- 29514791 TI - Hero's return. PMID- 29514792 TI - Sellu is cleared of medical misconduct. PMID- 29514793 TI - Confronting unprofessional behaviour in medicine. PMID- 29514794 TI - Saleyha Ahsan: Trust me, I'm an activist. PMID- 29514790 TI - Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm. AB - Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the Sipa1-/- MPN mouse model, we find that Sipa1 deletion causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to the initiation of the MPN. Importantly, the altered Sipa1-/- BM niche is required for the development of MDS/MPN following transplantation of normal hematopoietic cells. RNA sequencing reveals an enhanced inflammatory cytokine signaling and dysregulated Dicer1, Kitl, Angptl1, Cxcl12, and Thpo in the Sipa1-/- BM cellular niches. Our data suggest that Sipa1 expression in the BM niche is critical for maintaining BM niche homeostasis. Moreover, Sipa1 loss-induced BM niche alterations likely enable evolution of clonal hematopoiesis to the hematological malignancies. Therefore, restoring Sipa1 expression or modulating the altered signaling pathways involved might offer therapeutic potential for MPN. PMID- 29514795 TI - Developing guidelines is expensive. PMID- 29514797 TI - CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells. AB - CD16A is a potent cytotoxicity receptor on human natural killer (NK) cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2- and IL15-driven NK cell proliferation and expansion. This effect involved the upregulation of CD25 (IL2Ralpha) and CD132 (gammac) on NK cells, resulting in increased sensitivity to low-dose IL2 or to IL15. CD16A engagement initially induced NK cell cytotoxicity. The lower NK cell reactivity observed 1 day after CD16A engagement could be recovered by reculture in IL2 or IL15. After reculture in IL2 or IL15, these CD16A-experienced NK cells exerted more vigorous IFNgamma production upon restimulation with tumor cells or cytokines. Importantly, after reculture, CD16A-experienced NK cells also exerted increased cytotoxicity toward different tumor targets, mainly through the activating NK cell receptor NKG2D. Our findings uncover a role for CD16A engagement in priming NK cell responses to restimulation by cytokines and tumor cells, indicative of a memory-like functionality. Our study suggests that combination of AFM13 with IL2 or IL15 may boost NK cell antitumor activity in patients by expanding tumor-reactive NK cells and enhancing NK cell reactivity, even upon repeated tumor encounters. Cancer Immunol Res; 6(5); 517-27. (c)2018 AACR. PMID- 29514796 TI - Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGFbetaRIII-p38MAPK-pS249/T252RB Pathway. AB - Bone metastasis from prostate cancer can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTCs are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 prostate cancer cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single-cell level revealed that conditioned medium from differentiated, but not undifferentiated, osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to prostate cancer cells. Gene array analyses identified GDF10 and TGFbeta2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating prostate cancer tumor cells differ in their dormancy response. TGFbeta2 and GDF10 induced dormancy through TGFbetaRIII to activate phospho-p38MAPK, which phosphorylates retinoblastoma (RB) at the novel N-terminal S249/T252 sites to block prostate cancer cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 prostate cancer cell lines abolished tumor cell dormancy both in vitro and in vivo Lower TGFbetaRIII expression in patients with prostate cancer correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTCs are induced into a dormant state through TGFbetaRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone.Significance: These findings provide mechanistic insights into the dormancy of metastatic prostate cancer in the bone and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. Cancer Res; 78(11); 2911-24. (c)2018 AACR. PMID- 29514798 TI - Comparative Effects of Cholecalciferol and Calcitriol on Circulating Markers of CKD Mineral Bone Disorder: A Randomized Clinical Trial. PMID- 29514799 TI - Long-Term Outcomes of Childhood Left Ventricular Non-Compaction Cardiomyopathy: Results from a National Population-Based Study. AB - Background -Long-term outcomes for childhood left ventricular non-compaction (LVNC) are uncertain. We examined late outcomes for children with LVNC enrolled in a national population-based study. Methods -The National Australian Childhood Cardiomyopathy Study includes all children in Australia with primary cardiomyopathy diagnosed <10 years of age between 1987 and 1996. Outcomes for LVNC subjects with a dilated phenotype (LVNC-D) were compared to those with dilated cardiomyopathy (DCM). Propensity-score analysis was used for risk factor adjustment. Results -There were 29 subjects with LVNC (9.2% of all cardiomyopathy subjects) with a mean annual incidence of newly diagnosed cases of 0.11 per 100,000 at-risk persons. Congestive heart failure was the initial symptom in 24 (83%) of 29 subjects, and 27 (93%) had a dilated phenotype (LVNC-D). The median age at diagnosis was 0.3 (interquartile interval 0.08 - 1.3) years of age. The median (interquartile interval) duration of follow-up was 6.8 (0.7-14.1) years for all subjects and 24.7 (23.3 - 27.7) years for surviving subjects. Freedom from death or transplantation was 48% (95% CI 30 - 65%) at 10 years after diagnosis and 45% (95% CI 27-63%) at 15 years. By competing risk analysis, 21% of LVNC subjects were alive with normal LV systolic function and 31% were alive with abnormal function at 15 years. Propensity-score matching between LVNC-D and DCM subjects suggested a lower freedom from death/transplantation at 15 years after diagnosis in the LVNC-D subjects (LVNC-D: 46% (95% CI 26-66%) vs. DCM: 70% (95% CI 42-97%), p=0.08). Using propensity-score inverse probability of treatment weighted Cox regression, we found evidence that LVNC-D was associated with a greater risk of death or transplantation (HR 2.3, 95% CI 1.4-3.8, p=0.0012). Conclusions -Symptomatic children with LVNC usually present in early infancy with a predominant dilated phenotype. Long-term outcomes are worse than for matched children with DCM. PMID- 29514800 TI - Association between salt substitutes/enhancers and changes in sodium levels in fast-food restaurants: a cross-sectional analysis. AB - BACKGROUND: Restaurant foods have high sodium levels, and efforts have been made to promote reductions. The objective of this study was to understand if salt substitutes and enhancers are associated with changes in sodium levels in fast food restaurants. METHODS: A longitudinal database (MENU-FLIP) containing nutrition information for Canadian chain restaurants with 20 or more locations nationally was created in 2010 and updated in 2013 and 2016. In 2016, when available, ingredient lists were collected from restaurant websites and searched for the presence of salt substitutes/enhancers. Changes in sodium levels (per serving) and the prevalence of salt substitutes/enhancers in 222 foods from 12 of the leading fast-food restaurant chains were compared across 3 time points. RESULTS: Sixty-nine percent of foods contained a salt substitute/enhancer. Substitutes/enhancers were found in every restaurant chain (n = 12) for which ingredient data were available. The most common substitutes/enhancers were yeast extracts (in 30% of foods), calcium chloride (28%), monosodium glutamate (14%) and potassium chloride (12%). Sodium levels in foods that contained substitutes/enhancers decreased significantly more (190 +/- 42 mg/serving) over the study period than those in foods that did not contain a substitute/enhancer (40 +/- 17 mg/serving, p < 0.001). INTERPRETATION: Salt substitutes and enhancers are prevalent in restaurant foods and are one means by which restaurants may be lowering sodium levels in their foods. At this time, the potential consequences of these findings, if any, are uncertain. PMID- 29514801 TI - Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12-week blinded randomised controlled trial. AB - OBJECTIVES: Guidelines recommend intra-articular glucocorticoid injection in patients with painful hip osteoarthritis. However, intra-articular hip injection is an invasive procedure. The efficacy of systemic glucocorticoid treatment for pain reduction in hip osteoarthritis is unknown. This randomised, double-blind, trial assessed effectiveness in hip pain reduction of an intramuscular glucocorticoid injection compared with a placebo injection in patients with hip osteoarthritis. METHODS: Patients with painful hip osteoarthritis were randomised to either 40 mg triamcinolone acetate or placebo with an intramuscular injection into the gluteus muscle. The primary outcomes were severity of hip pain at rest, during walking (0-10) and WOMAC pain at 2-week postinjection. We used linear mixed models for repeated measurements at 2, 4, 6 and 12 weeks for the intention to-treat data analysis. RESULTS: Of the 107 patients randomised, 106 could be analysed (52 in the glucocorticoid group, 54 in the placebo group). At 2-week follow-up, compared with placebo injection, the intramuscular glucocorticoid injection showed a significant and clinically relevant difference in hip pain reduction at rest (difference -1.3, 95% CI -2.3 to -0.3). This effect persisted for the entire 12-week follow-up. For hip pain during walking, the effect was present at 4-week, 6-week and 12-week follow-ups, and for WOMAC pain the effect was present at 6-week and 12-week follow-up. CONCLUSIONS: An intramuscular glucocorticoid injection showed effectiveness in patients with hip osteoarthritis on one of the three primary outcomes at 2-week postinjection. All primary outcomes showed effectiveness from 4 to 6 weeks, up to a 12-week follow-up. TRIAL REGISTRATION NUMBER: NTR2966. PMID- 29514803 TI - Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study. AB - OBJECTIVE: To demonstrate clinical equivalence of adalimumab biosimilar candidate BI 695501 with Humira. METHODS: Patients with active rheumatoid arthritis on stable methotrexate were randomised to BI 695501 or Humira in a double-blind, parallel-group, equivalence study. At week 24, patients were rerandomised to continue BI 695501 or Humira, or switch from Humira to BI 695501. The coprimary endpoints were the percentage of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at weeks 12 and 24. Further efficacy and safety endpoints and immunogenicity were assessed up to week 58. RESULTS: 645 patients were randomised. At week 12, 67.0% and 61.1% (90% CI -0.9 to 12.7) of patients receiving BI 695501 (n=324) and Humira (n=321), respectively, achieved ACR20; at week 24 the corresponding values were 69.0% and 64.5% (95% CI -3.4 to 12.5). These differences were within prespecified margins (week 12: 90% CI (-12% to 15%); week 24: 95% CI (-15% to 15%)), demonstrating therapeutic bioequivalence. 593 patients were rerandomised at week 24. Up to week 48, mean change from baseline in Disease Activity Score 28-erythrocyte sedimentation rate and ACR20/ACR50/ACR70 response rates were similar across the switched (n=147), continuous BI 695501 (n=298) and continuous Humira (n=148) groups. Similar immunogenicity (antidrug antibodies (ADAs), ADA titres and neutralising antibodies) was seen between BI 695501 and Humira (to week 24) and across rerandomised groups (to week 48). Safety and tolerability profiles were similar between groups. CONCLUSIONS: BI 695501 demonstrated similar efficacy, safety and immunogenicity to Humira; switch from Humira to BI 695501 had no impact on efficacy, safety and immunogenicity. TRIAL REGISTRATION NUMBER: NCT02137226, Results. PMID- 29514802 TI - Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis. AB - OBJECTIVES: Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. METHODS: Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). RESULTS: We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5*10-5) and RA (OR 2.8 (1.4 to 5.6), P=3.8*10-3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5*10-7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5*10-5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. CONCLUSIONS: The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases. PMID- 29514804 TI - Patient and Caregiver Determinants of Patient Quality of Life and Caregiver Strain in Left Ventricular Assist Device Therapy. AB - BACKGROUND: Although current guidelines emphasize the importance of social support to the success of left ventricular assist device (LVAD) therapy, few studies examine the influence of the caregiver on patient outcomes or quantify the impact of LVAD caregiving on caregiver outcomes. The purpose of this analysis was to identify patient and caregiver determinants of patient quality of life (QOL) and caregiver strain in response to LVAD therapy. METHODS AND RESULTS: Data on patients receiving LVAD therapy and their caregivers (n=50 dyads) were prospectively collected pre-implantation and 1, 3, and 6 months post implantation. Growth curve modeling was used to describe change in patient QOL (Kansas City Cardiomyopathy Questionnaire) and caregiver strain (Multidimensional Caregiver Strain Index). Patient QOL improved most in the first month (beta=23.22+/-3.76, P<0.001), followed by gradual gains over 6 months (beta=1.90+/-0.64, P<0.01). Caregivers experienced worsening of strain in the first month (beta=4.30+/-1.42, P<0.01), followed by gradual resolution to pre implantation levels by 6 months (beta=-0.71+/-0.23, P<0.01). Worse pre implantation patient symptoms were associated with greater improvement in patient QOL (beta=0.53+/-0.19, P<0.01) but worsening caregiver strain (beta=0.15+/-0.07, P=0.04). Better relationship quality was associated with greater improvement in patient QOL (beta=14.39+/-5.85, P=0.01) and less pre-implantation caregiver strain (beta=-9.31+/-2.28, P<0.001). Nonspousal caregivers experienced less pre implantation strain (beta=-8.60+/-3.10, P=0.01), and patients with nonspousal caregivers had less improvement in QOL (beta=-3.70+/-1.62, P=0.02). CONCLUSIONS: A combination of patient and caregiver characteristics predicts patient and caregiver response to LVAD therapy. Including caregiver factors in future studies may be helpful in developing interventions that improve patient and caregiver outcomes, together. PMID- 29514805 TI - Predicting Long Term Outcome in Patients Treated With Continuous Flow Left Ventricular Assist Device: The Penn-Columbia Risk Score. AB - BACKGROUND: Predicting which patients are unlikely to benefit from continuous flow left ventricular assist device (LVAD) treatment is crucial for the identification of appropriate patients. Previously developed scoring systems are limited to past eras of device or restricted to specific devices. Our objective was to create a risk model for patients treated with continuous flow LVAD based on the preimplant variables. METHODS AND RESULTS: We performed a retrospective analysis of all patients implanted with a continuous flow LVAD between 2006 and 2014 at the University of Pennsylvania and included a total of 210 patients (male 78%; mean age, 56+/-15; mean follow-up, 465+/-486 days). From all plausible preoperative covariates, we performed univariate Cox regression analysis for covariates affecting the odds of 1-year survival following implantation (P<0.2). These variables were included in a multivariable model and dropped if significance rose above P=0.2. From this base model, we performed step-wise forward and backward selection for other covariates that improved power by minimizing Akaike Information Criteria while maximizing the Harrell Concordance Index. We then used Kaplan-Meier curves, the log-rank test, and Cox proportional hazard models to assess internal validity of the scoring system and its ability to stratify survival. A final optimized model was identified based on clinical and echocardiographic parameters preceding LVAD implantation. One-year mortality was significantly higher in patients with higher risk scores (hazard ratio, 1.38; P=0.004). This hazard ratio represents the multiplied risk of death for every increase of 1 point in the risk score. The risk score was validated in a separate patient cohort of 260 patients at Columbia University, which confirmed the prognostic utility of this risk score (P=0.0237). CONCLUSION: We present a novel risk score and its validation for prediction of long-term survival in patients with current types of continuous flow LVAD support. PMID- 29514806 TI - Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure. AB - BACKGROUND: Delivering therapeutic materials, like stem cells or gene vectors, to the myocardium is difficult in the setting of ischemic heart failure because of decreased coronary flow and impaired microvascular perfusion (MP). The aim of this study was to determine if mechanical left ventricular (LV) unloading with the Impella increases coronary flow and MP in a subacute myocardial infarction. METHODS AND RESULTS: Anterior transmural myocardial infarction (infarct size, 26.0+/-3.4%) was induced in Yorkshire pigs. At 2 weeks after myocardial infarction, 6 animals underwent mechanical LV unloading by Impella, whereas 4 animals underwent pharmacological LV unloading using sodium nitroprusside for 2 hours. LV unloading with Impella significantly reduced end-diastolic volume ( 16+/-11mL, P=0.02) and end-diastolic pressure (EDP; -32+/-23 mm Hg, P=0.03), resulting in a significant decrease in LV end-diastolic wall stress (EDWS) (infarct: 71.6+/-14.7 to 43.3+/-10.8 kdynes/cm2 [P=0.02]; remote: 66.6+/-20.9 to 40.6+/-13.3 kdynes/cm2 [P=0.02]). Coronary flow increased immediately and remained elevated after 2 hours in Impella-treated pigs. Compared with the baseline, MP measured by fluorescent microspheres significantly increased within the infarct zone (109+/-81%, P=0.003), but not in the remote zone. Although sodium nitroprusside effectively reduced LV-EDWS, 2 (50%) of sodium nitroprusside treated pigs developed profound systemic hypotension. A significant correlation was observed between the infarct MP and EDWS (r2=0.43, P=0.03), suggesting an important role of EDWS in regulating MP during LV unloading in the infarcted myocardium. CONCLUSIONS: LV unloading using an Impella decreased EDWS and increased infarct MP without hemodynamic decompensation. Mechanical LV unloading is a novel and efficient approach to increase infarct MP in patients with subacute myocardial infarction. PMID- 29514807 TI - Sex Differences in Timeliness of Reperfusion in Young Patients With ST-Segment Elevation Myocardial Infarction by Initial Electrocardiographic Characteristics. AB - BACKGROUND: Young women with ST-segment-elevation myocardial infarction experience reperfusion delays more frequently than men. Our aim was to determine the electrocardiographic correlates of delay in reperfusion in young patients with ST-segment-elevation myocardial infarction. METHODS AND RESULTS: We examined sex differences in initial electrocardiographic characteristics among 1359 patients with ST-segment-elevation myocardial infarction in a prospective, observational, cohort study (2008-2012) of 3501 patients with acute myocardial infarction, 18 to 55 years of age, as part of the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study at 103 US and 24 Spanish hospitals enrolling in a 2:1 ratio for women/men. We created a multivariable logistic regression model to assess the relationship between reperfusion delay (door-to-balloon time >90 or >120 minutes for transfer or door-to-needle time >30 minutes) and electrocardiographic characteristics, adjusting for sex, sociodemographic characteristics, and clinical characteristics at presentation. In our study (834 women and 525 men), women were more likely to exceed reperfusion time guidelines than men (42.4% versus 31.5%; P<0.01). In multivariable analyses, female sex persisted as an important factor in exceeding reperfusion guidelines after adjusting for electrocardiographic characteristics (odds ratio, 1.57; 95% CI, 1.15-2.15). Positive voltage criteria for left ventricular hypertrophy and absence of a prehospital ECG were positive predictors of reperfusion delay; and ST elevation in lateral leads was an inverse predictor of reperfusion delay. CONCLUSIONS: Sex disparities in timeliness to reperfusion in young patients with ST-segment-elevation myocardial infarction persisted, despite adjusting for initial electrocardiographic characteristics. Left ventricular hypertrophy by voltage criteria and absence of prehospital ECG are strongly positively correlated and ST elevation in lateral leads is negatively correlated with reperfusion delay. PMID- 29514808 TI - Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS-BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment. AB - BACKGROUND: The Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio (INR), Elderly, Drugs or alcohol use (HAS BLED) score has strong predictive validity for major bleeding complications, but limited validation has been conducted in venous thromboembolism (VTE). This study evaluates the HAS-BLED score in a large cohort of VTE patients. METHODS AND RESULTS: A retrospective cohort of adults >=18 years with primary diagnosis of VTE between January 1, 2010 and November 31, 2013 were identified in an insurance claims database. Patients were tracked until death, any bleed event, or end of study period. HAS-BLED score and components were evaluated via proportional hazard models. Cumulative incidence functions were reported at 30, 60, 90, and 180 days. N=132 280 patients with a VTE were identified, with 73.8% having HAS BLED scores of 0 to 2, 3.6% score >=4, and 4789 bleeding events (3.6% all patients). A 1-point HAS-BLED score increase was associated with 20% to 30% bleeding rate increase overall, but in a cancer cohort only the increase from 3- to 4-points was significant for all bleeds (csHR=1.41, 95% CI: 1.17-1.69; sdHR=1.40, 95% CI: 1.17-1.69) and major bleeds (csHR=1.66, 95% CI: 1.26-2.20; sdHR=1.66, 95% CI: 1.25-2.19). Adding cancer to the model as an independent covariate provided the strongest association among all covariates, with csHR=2.25 (95% CI: 1.98-2.56) and sdHR=2.11 (95% CI: 1.85-2.41) in the model for major bleeds. CONCLUSIONS: The HAS-BLED score has good predictive validity for bleeding risks in patients with VTE. The addition of cancer as an independent bleeding risk factor merits consideration, possibly as part of the "B" criterion ("bleeding tendency or predisposition"). PMID- 29514809 TI - Association of Atrial Fibrillation With Cognitive Decline and Dementia Over 20 Years: The ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study). AB - BACKGROUND: Previous studies have reported that atrial fibrillation (AF) is associated with cognitive decline and dementia. These studies, however, had limited follow-up, were based mostly on white and highly selected populations, and did not account for attrition. We evaluated the association of incident AF with 20-year change in cognitive performance (accounting for attrition) and incident dementia in the ARIC (Atherosclerosis Risk in Communities) Study. METHODS AND RESULTS: We analyzed data from 12 515 participants (mean age, 56.9 [SD, 5.7] years in 1990-1992; 56% women and 24% black) from 1990 to 1992 through 2011 to 2013. Incident AF was ascertained from study ECGs and hospital discharge codes. Cognitive tests were performed in 1990 to 1992, 1996 to 1998, and 2011 to 2013. Incident dementia was clinician adjudicated. We used generalized estimating equations and Cox proportional hazards models to assess the association of time dependent AF with change in Z scores of cognitive tests and incident dementia, respectively. During 20 years, 2106 participants developed AF and 1157 participants developed dementia. After accounting for cardiovascular risk factors, including ischemic stroke, the average decline over 20 years in global cognitive Z score was 0.115 (95% confidence interval, 0.014-0.215) greater in participants with AF than in those without AF. Further adjustment for attrition by multiple imputation by chained equations strengthened the association. In addition, incident AF was associated with an increased risk of dementia (hazard ratio, 1.23; 95% confidence interval, 1.04-1.45), after adjusting for cardiovascular risk factors, including ischemic stroke. CONCLUSIONS: AF is associated with greater cognitive decline and increased risk of dementia, independent of ischemic stroke. Because cognitive decline is a precursor to dementia, our findings prompt further investigation to identify specific treatments for AF that will delay the trajectory of cognitive decline and, thus, prevent dementia in patients with AF. PMID- 29514811 TI - Clinicians' gaze behaviour in simulated paediatric emergencies. AB - AIM: Differences in the gaze behaviour of experts and novices are described in aviation and surgery. This study sought to describe the gaze behaviour of clinicians from different training backgrounds during a simulated paediatric emergency. METHODS: Clinicians from four clinical areas undertook a simulated emergency. Participants wore SMI (SensoMotoric Instruments) eye tracking glasses. We measured the fixation count and dwell time on predefined areas of interest and the time taken to key clinical interventions. RESULTS: Paediatric intensive care unit (PICU) consultants performed best and focused longer on the chest and airway. Paediatric consultants and trainees spent longer looking at the defibrillator and algorithm (51 180 ms and 50 551 ms, respectively) than the PICU and paediatric emergency medicine consultants. CONCLUSIONS: This study is the first to describe differences in the gaze behaviour between experts and novices in a resuscitation. They mirror those described in aviation and surgery. Further research is needed to evaluate the potential use of eye tracking as an educational tool. PMID- 29514810 TI - Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells. AB - BACKGROUND: Platelet-derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet-derived growth factor BB-treated PASMCs found a significantly downregulated microRNA, miR-1281, but it has not been associated with any cellular function, and we investigated the possibility. METHODS AND RESULTS: Real-time quantitative reverse transcription-polymerase chain reaction assay proved that downregulation of miR-1281 was a conserved phenomenon in human and rat PASMCs. Overexpression and inhibition of miR-1281 in PASMCs promoted and suppressed, respectively, the cell proliferation and migration. Bioinformatic prediction and 3'-untranslated region reporter assay identified histone deacetylase 4 to be a direct target of miR-1281. Supporting this, proliferation and migration assay demonstrated the cellular function of histone deacetylase 4 is inversely correlated with that of miR-1281. Mechanistically, it is found that platelet-derived growth factor BB activates the phosphatidylinositol 3-kinase pathway, which then induces the expression of DNA methyltransferase 1, leading to enhanced methylation of a flanking CpG island and repressed miR-1281 expression. Finally, a reduced miR-1281 level was consistently identified in hypoxic PASMCs in vitro, in pulmonary arteries of rats with monocrotaline-induced pulmonary arterial hypertension, and in serum of patients with coronary heart disease-pulmonary arterial hypertension. These data suggest that there may be a diagnostic and therapeutic use for miR-1281. CONCLUSIONS: Herein, we report a novel regulatory axis, phosphatidylinositol 3-kinase-DNA methyltransferase 1-miR-1281-histone deacetylase 4, integrating multiple epigenetic regulators that participate in platelet-derived growth factor BB stimulated PASMC proliferation and migration and pulmonary vascular remodeling. PMID- 29514812 TI - Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status. AB - OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines. INTERVENTIONS: Blood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations. MAIN OUTCOME MEASURE: The measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time -concentration curve (AUC0-8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables. RESULTS: For INH, the difference in drug exposures in children <3 years (Cmax 3.18 ug/mL and AUC0-8 hours15.76 ug/mL hour) and children >3 years (Cmax3.05 ug/mL and AUC0-8 hours 14.37 ug/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 ug/mL; AUC0-8 hours14.81 ug/mL hour) were also comparable with their normal counterparts (Cmax3.09 ug/mL, P=0.99; AUC0-8 hours 14.69 ug/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 ug/mL, AUC0-8 hours 155.45 ug/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 ug/mL, P=0.03; AUC 202.63 ug/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 ug/mL, AUC0-8 hours167.64 ug/mL hour) when compared with normal counterparts (Cmax 37.60 ug/mL, P=0.02; AUC0-8 hours 208.77 ug/mL hour, P=0.01). CONCLUSIONS: The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children. PMID- 29514813 TI - Evaluation of 'TRY': an algorithm for neonatal continuous positive airways pressure in low-income settings. AB - BACKGROUND: Non-invasive respiratory support using bubble continuous positive airway pressure (bCPAP) is useful in treating babies with respiratory distress syndrome. Despite its proven clinical and cost-effectiveness, implementation is hampered by the inappropriate administration of bCPAP in low-resource settings. A clinical algorithm-'TRY' (based on Tone: good; Respiratory distress; Yes, heart rate above 100 beats/min)-has been developed to correctly identify which newborns would benefit most from bCPAP in a teaching hospital in Malawi. OBJECTIVE: To evaluate the reliability, sensitivity and specificity of TRY when employed by nurses in a Malawian district hospital. METHODS: Nursing staff in a Malawian district hospital baby unit were asked, over a 2-month period, to complete TRY assessments for every newly admitted baby with the following inclusion criteria: clinical evidence of respiratory distress and/or birth weight less than 1.3 kg. A visiting paediatrician, blinded to nurses' assessments, concurrently assessed each baby, providing both a TRY assessment and a clinical decision regarding the need for CPAP administration. Inter-rater reliability was calculated comparing nursing and paediatrician TRY assessment outcomes. Sensitivity and specificity were estimated comparing nurse TRY assessments against the paediatrician's clinical decision. RESULTS: Two hundred and eighty-seven infants were admitted during the study period; 145 (51%) of these met the inclusion criteria, and of these 57 (39%) received joint assessments. The inter-rater reliability was high (kappa 0.822). Sensitivity and specificity were 92% and 96%, respectively. CONCLUSIONS: District hospital nurses, using the TRY-CPAP algorithm, reliably identified babies that might benefit from bCPAP and thus improved its effective implementation. PMID- 29514814 TI - Approaching quality improvement at scale: a learning health system approach in Kenya. PMID- 29514816 TI - Infographic: The 'weekend warrior' physical activity pattern and mortality. PMID- 29514815 TI - Predicting inflammatory bowel disease in children with abdominal pain and diarrhoea: calgranulin-C versus calprotectin stool tests. AB - OBJECTIVE: Calgranulin-C (S100A12) is a new faecal marker of inflammation that is potentially more specific for inflammatory bowel disease (IBD) than calprotectin, since it is only released by activated granulocytes. We compared calgranulin-C and calprotectin to see which of the two tests best predicted IBD in children with chronic abdominal pain and diarrhoea. DESIGN: Delayed-type cross-sectional diagnostic study. SETTING AND PATIENTS: Previously undiagnosed patients aged 6-17 years, who were seen in paediatric clinics in the Netherlands and Belgium, sent in a stool sample for analysis. Patients with a high likelihood of IBD underwent upper and lower endoscopy (ie, preferred reference test), while those with a low likelihood were followed for 6 months for latent IBD to become visible (ie, alternative reference test). We used Bayesian modelling to correct for differential verification bias. MAIN OUTCOME MEASURES: Primary outcome was the specificity for IBD using predefined test thresholds (calgranulin-C: 0.75 ug/g, calprotectin: 50 ug/g). Secondary outcome was the test accuracy with thresholds based on receiver operating characteristics (ROC) analysis. RESULTS: IBD was diagnosed in 93 of 337 patients. Calgranulin-C had significantly better specificity than calprotectin when predefined thresholds were used (97% (95% credible interval (CI) 94% to 99%) vs 71% (95% CI 63% to 79%), respectively). When ROC-based thresholds were used (calgranulin-C: 0.75 ug/g, calprotectin: 400 ug/g), both tests performed equally well (specificity: 97% (95% CI 94% to 99%) vs 98% (95% CI 95% to 100%)). CONCLUSIONS: Both calgranulin-C and calprotectin have excellent test characteristics to predict IBD and justify endoscopy. TRIAL REGISTRATION NUMBER: NCT02197780. PMID- 29514817 TI - Prevention programmes including Nordic exercises to prevent hamstring injuries in football players (PEDro synthesis). PMID- 29514818 TI - Should we continue to consider serum cholesterol as an exogenous poisoning? PMID- 29514820 TI - Response to: 'Optimising the efficacy of gait retraining'. PMID- 29514819 TI - Diagnosis, treatment and prevention of ankle sprains: update of an evidence-based clinical guideline. AB - This guideline aimed to advance current understandings regarding the diagnosis, prevention and therapeutic interventions for ankle sprains by updating the existing guideline and incorporate new research. A secondary objective was to provide an update related to the cost-effectiveness of diagnostic procedures, therapeutic interventions and prevention strategies. It was posited that subsequent interaction of clinicians with this guideline could help reduce health impairments and patient burden associated with this prevalent musculoskeletal injury. The previous guideline provided evidence that the severity of ligament damage can be assessed most reliably by delayed physical examination (4-5 days post trauma). After correct diagnosis, it can be stated that even though a short time of immobilisation may be helpful in relieving pain and swelling, the patient with an acute lateral ankle ligament rupture benefits most from use of tape or a brace in combination with an exercise programme.New in this update: Participation in certain sports is associated with a heightened risk of sustaining a lateral ankle sprain. Care should be taken with non-steroidal anti-inflammatory drugs (NSAIDs) usage after an ankle sprain. They may be used to reduce pain and swelling, but usage is not without complications and NSAIDs may suppress the natural healing process. Concerning treatment, supervised exercise-based programmes preferred over passive modalities as it stimulates the recovery of functional joint stability. Surgery should be reserved for cases that do not respond to thorough and comprehensive exercise-based treatment. For the prevention of recurrent lateral ankle sprains, ankle braces should be considered as an efficacious option. PMID- 29514821 TI - It's time we paved a healthier path of least resistance. PMID- 29514822 TI - "What's my risk of sustaining an ACL injury while playing sports?" A systematic review with meta-analysis. AB - OBJECTIVE: To estimate the incidence proportion (IP) and incidence rate (IR) for ACL injury in athletes. DESIGN: Systematic review with meta-analysis DATA SOURCES: The PubMed, CINAHL and SPORTDiscus electronic databases were searched from inception to 20 January 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they reported total number of participants/population by sex, total number of ACL injuries by sex and total person-time by sex. RESULTS: Fifty-eight studies were included. The IP and IR of ACL injury in female athletes were 3.5% (1 out of every 29 athletes) and 1.5/10 000 athlete-exposures over a period of 1 season-25 years. The IP and IR of ACL injury in male athletes were 2.0% (1 out of every 50 athletes) and 0.9/10 000 athlete-exposures over a period of 1-25 years. Female athletes had a higher relative risk (RR) for ACL injury compared with males (RR=1.5; 95% CI 1.2 to 1.9; P<0.01) and a higher incidence rate ratio (IRR) of ACL injury compared with males over 1 season-25 years (IRR=1.7; 95% CI 1.4 to 2.2; P<0.010). When accounting for participation level, the disparity in the IR between female and male athletes was highest for amateur athletes compared with intermediate and elite athletes (IRR=2.1; 95% CI 1.3 to 3.4; P<0.01; I2=82%). Amateur female athletes remained at higher risk of ACL injury than did with amateur male athletes. In studies where follow-up length was <1 year, female athletes had a higher IR of ACL injury than did to males (IRR=1.7; 95% CI 1.3 to 2.2; P<0.01). Where follow-up was 1 year and beyond, there was no sex difference in the IR of ACL injury (IRR=2.1; 95% CI 0.9 to 4.8; P=0.06; I2=65%). SUMMARY/CONCLUSIONS: One in 29 female athletes and 1 in 50 male athletes ruptured their ACL in a window that spanned from 1season to 25 years. The IR of ACL injury among female athletes in a season was 1.7 times higher than the IR of ACL injury among male athletes and the IP of ACL injury among female athletes was 1.5 times higher than the IP of ACL injury among male athletes. The reported sex disparity in ACL injury rates is independent of participation level and length of follow-up. PMID- 29514823 TI - GLA:D to have a high-value option for patients with knee and hip arthritis across four continents: Good Life with osteoArthritis from Denmark. PMID- 29514824 TI - Avoid routinely prescribing medicines for non-specific low back pain. PMID- 29514825 TI - Establishment and long-term maintenance of primary intestinal epithelial cells cultured from the rainbow trout, Oncorhynchus mykiss. AB - A novel method for the establishment and long-term maintenance of ex vivo cultures from intestinal regions of the rainbow trout, Oncorhynchus mykiss (Walbaum), is reported. Adherence of cells was observed within hours, epithelial island formation recorded at 48 h and rapid proliferation with confluence achieved between 9-14 days. In addition to metabolic characterisation, basic morphology of growing cells was characterised using histology, immunofluorescence, transmission electron microscopy (TEM) and transepithelial electrical resistance (TEER). Regional differences in intestinal ethoxyresorufin O-deethylase (EROD) and 7-ethoxycoumarin-O-deethylation (ECOD) activities in these primary grown enterocytes were compared following exposure to model inducers [i.e. alpha-NF, beta-NF, B(a)P] which demonstrated significant differences. Regional differences in dietary uptake and metabolism of contaminants can therefore be studied in this in vitro system to increase our understanding of fundamental processes, while concurrently providing a means to reduce the number of fish required for biological studies in line with the principles of the 3Rs (Reduce, Refine and Replace).This article has an associated First Person interview with the first author of the paper. PMID- 29514826 TI - N-Methylation of BI 187004 by Thiol S-Methyltransferase. AB - BI 187004, an 11beta-hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite [N-methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O-methyltransferase (rhCOMT), histamine N-methyltransferase (rhHNMT), nicotinamide N methyltransferase (rhNNMT), glycine N-methyltransferase (rhGNMT), and thiopurine S-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro alpha-methylbenzylamine (DCMB), an inhibitor of thiol S-methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N-methylation biotransformation and an HNMT-mediated regioselective N-methylation. PMID- 29514829 TI - Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity. AB - Cisplatin is a cytostatic drug used for treatment of solid organ tumors. The main adverse effect is organic cation transporter 2 (OCT2)-mediated nephrotoxicity, observed in 30% of patients. The contribution of other renal drug transporters is elusive. Here, cisplatin-induced toxicity was evaluated in human-derived conditionally immortalized proximal tubule epithelial cells (ciPTEC) expressing renal drug transporters, including OCT2 and organic anion transporters 1 (OAT1) or 3 (OAT3). Parent ciPTEC demonstrated OCT2-dependent cisplatin toxicity (TC50 34 +/- 1 MUM after 24-hour exposure), as determined by cell viability. Overexpression of OAT1 and OAT3 resulted in reduced sensitivity to cisplatin (TC50 45 +/- 6 and 64 +/- 11 MUM after 24-hour exposure, respectively). This effect was independent of OAT-mediated transport, as the OAT substrates probenecid and diclofenac did not influence cytotoxicity. Decreased cisplatin sensitivity in OAT-expressing cells was associated directly with a trend toward reduced intracellular cisplatin accumulation, explained by reduced OCT2 gene expression and activity. This was evaluated by Vmax of the OCT2-model substrate ASP+ (23.5 +/- 0.1, 13.1 +/- 0.3, and 21.6 +/- 0.6 minutes-1 in ciPTEC-parent, ciPTEC-OAT1, and ciPTEC-OAT3, respectively). Although gene expression of cisplatin efflux transporter multidrug and toxin extrusion 1 (MATE1) was 16.2 +/- 0.3-fold upregulated in ciPTEC-OAT1 and 6.1 +/- 0.7-fold in ciPTEC-OAT3, toxicity was unaffected by the MATE substrate pyrimethamine, suggesting that MATE1 does not play a role in the current experimental set-up. In conclusion, OAT expression results in reduced cisplatin sensitivity in renal proximal tubule cells, explained by reduced OCT2-mediated uptake capacity. In vitro drug-induced toxicity studies should consider models that express both OCT and OAT drug transporters. PMID- 29514827 TI - Beyond Competitive Inhibition: Regulation of ABC Transporters by Kinases and Protein-Protein Interactions as Potential Mechanisms of Drug-Drug Interactions. AB - ATP-binding cassette (ABC) transporters are transmembrane efflux transporters mediating the extrusion of an array of substrates ranging from amino acids and lipids to xenobiotics, and many therapeutic compounds, including anticancer drugs. The ABC transporters are also recognized as important contributors to pharmacokinetics, especially in drug-drug interactions and adverse drug effects. Drugs and xenobiotics, as well as pathologic conditions, can influence the transcription of ABC transporters, or modify their activity or intracellular localization. Kinases can affect the aforementioned processes for ABC transporters as do protein interactions. In this review, we focus on the ABC transporters ABCB1, ABCB11, ABCC1, ABCC4, and ABCG2 and illustrate how kinases and protein-protein interactions affect these transporters. The clinical relevance of these factors is currently unknown; however, these examples suggest that our understanding of drug-drug interactions will benefit from further knowledge of how kinases and protein-protein interactions affect ABC transporters. PMID- 29514828 TI - Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting. AB - This article is a report on a symposium entitled "Physiological Regulation of Drug Metabolism and Transport" sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2017 meeting in Chicago, IL. The contributions of physiologic and pathophysiological regulation of drug-metabolizing enzymes and transporters to interindividual variability in drug metabolism are increasingly recognized but in many cases are not well understood. The presentations herein discuss the phenomenology, consequences, and mechanism of such regulation. CYP2D6 transgenic mice were used to provide insights into the mechanism of regulation of this enzyme in pregnancy, via hepatocyte nuclear factor 4alpha, small heterodimer partner, and retinoids. Regulation of intestinal and hepatic drug-processing enzymes by the intestinal microbiota via tryptophan and its metabolites was investigated. The potential impact of parasitic infections on human drug metabolism and clearance was assessed in mice infected with Schistosoma mansoni or Plasmodium chabaudi chabaudi AS, both of which produced widespread and profound effects on murine hepatic drug-metabolizing enzymes. Finally, the induction of Abcc drug efflux transporters by fasting was investigated. This was demonstrated to occur via a cAMP, protein kinase A/nuclear factor-E2-related factor 2/Sirtuin 1 pathway via antioxidant response elements on the Abcc genes. PMID- 29514830 TI - Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes. AB - RATIONALE: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). OBJECTIVE: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. METHODS AND RESULTS: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. CONCLUSIONS: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality. PMID- 29514832 TI - Rare case of metaplastic breast cancer in a man. AB - Metaplastic breast cancer (MBC) in men is an extremely rare entity. MBC is typically very aggressive with a poor prognosis. In men, it has only been reported three times in the literature. We report a 47-year-old man who presented with right-sided breast erythema and nipple inversion. Mammogram revealed a 2.4 cm spiculated mass. Initial pathology was inconclusive; however, right-sided simple mastectomy showed invasive metaplastic carcinoma with adenosquamous histology. He received adjuvant chemotherapy with 4 cycles of dose dense Adriamycin and cyclophosphamide followed by 12 weeks of paclitaxel and chest wall radiation. Although oestrogen receptor status was 1%, tamoxifen was not given due to recent diagnosis of pulmonary embolism. Two years after treatment, he is currently living with no signs of recurrence. This case will serve as a useful addition to the current literature discussing successful diagnosis, treatment and prognosis of a man with MBC. PMID- 29514833 TI - Possible anti-VGKC autoimmune limbic encephalitis associated with SIADH. AB - An 80-year-old woman presented with a 5-week history of increasing confusion. Examination was remarkable only for deficits in short-term memory and paranoid thoughts. Blood tests revealed hyponatraemia, and further biochemical testing was consistent with syndrome of inappropriate antidiuretic hormone (SIADH). After an exhaustive diagnostic workup for causes of SIADH, the only abnormal finding was a mildly raised antivoltage-gated potassium channel (VGKC) titre of 185 pmol/L (0 69) consistent with possible anti-VGKC autoimmune limbic encephalitis. However, other diagnostic features were absent. She is currently undergoing outpatient investigation for other causes of memory loss. PMID- 29514831 TI - Cardiac Kir2.1 and NaV1.5 Channels Traffic Together to the Sarcolemma to Control Excitability. AB - RATIONALE: In cardiomyocytes, NaV1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. OBJECTIVE: The objective of this study was to test whether NaV1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. METHODS AND RESULTS: In patch-clamp experiments, coexpression of trafficking-deficient mutants Kir2.1Delta314-315 or Kir2.1R44A/R46A with wild-type (WT) NaV1.5WT in heterologous cells reduced inward sodium current compared with NaV1.5WT alone or coexpressed with Kir2.1WT. In cell surface biotinylation experiments, expression of Kir2.1Delta314-315 reduced NaV1.5 channel surface expression. Glycosylation analysis suggested that NaV1.5WT and Kir2.1WT channels associate early in their biosynthetic pathway, and fluorescence recovery after photobleaching experiments demonstrated that coexpression with Kir2.1 increased cytoplasmic mobility of NaV1.5WT, and vice versa, whereas coexpression with Kir2.1Delta314-315 reduced mobility of both channels. Viral gene transfer of Kir2.1Delta314-315 in adult rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current and inward sodium current, maximum diastolic potential and action potential depolarization rate, and increased action potential duration. On immunostaining, the AP1 (adaptor protein complex 1) colocalized with NaV1.5WT and Kir2.1WT within areas corresponding to t-tubules and intercalated discs. Like Kir2.1WT, NaV1.5WT coimmunoprecipitated with AP1. Site-directed mutagenesis revealed that NaV1.5WT channels interact with AP1 through the NaV1.5Y1810 residue, suggesting that, like for Kir2.1WT, AP1 can mark NaV1.5 channels for incorporation into clathrin-coated vesicles at the trans-Golgi. Silencing the AP1 Upsilon-adaptin subunit in human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current, inward sodium current, and maximum diastolic potential and impaired rate-dependent action potential duration adaptation. CONCLUSIONS: The NaV1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of NaV1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases. PMID- 29514834 TI - Acute epiglottitis with intramural oesophageal dissection. PMID- 29514835 TI - Pulmonary metastasis from endometrial carcinoma. PMID- 29514836 TI - Uncommon cause of dysphagia: paraneoplastic achalasia. AB - Achalasia secondary to underlying neoplasm is a rare entity. Early recognition of secondary achalasia is important as its treatment involves management of underlying malignancy, while treatment of primary achalasia mainly involves lowering the lower oesophageal sphincter pressure with pneumatic dilatation or Heller's myotomy. We discuss an interesting case of achalasia secondary to non Hodgkin's lymphoma. PMID- 29514837 TI - An uncommon chronic osteochondral defect in the lateral tibial plateau detected after a separate injury. AB - Osteochondral defects (OCD) are rare conditions that usually present in young adolescents. The causes include trauma, inflammation, ischaemia, genetics and changes at secondary ossification centres. The case report presents a 27-year-old man with chronic intermittent left knee pain for about 3 years. He typically develops the symptom after prolonged standing or when rising from a prolonged seated position. An initial MRI scan in 2014 did not identify and report an OCD that was present in his left lateral tibial plateau. It was only after an accidental tibial fracture injury this year that the defect was incidentally detected on a scan. OCD can be staged based on MRI and/or arthroscopic findings. The treatment can be either non-operative or operative, but this largely depends on the age of the patient, the severity of symptoms and the staging of the defect. PMID- 29514838 TI - Infant with a skin lesion and respiratory distress. PMID- 29514839 TI - Identification and Validation of Stromal Immunotype Predict Survival and Benefit from Adjuvant Chemotherapy in Patients with Muscle-Invasive Bladder Cancer. AB - Purpose: This study aims to construct the stromal immunotype, which could improve the prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC).Experimental Design: A total of 118 patients with MIBC from Shanghai Cancer Center, 140 patients with MIBC from Zhongshan Hospital, and 287 patients with MIBC from TCGA cohort were included in the study. Immune cell infiltration was evaluated by IHC staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotypes based on the LASSO Cox regression model.Results: Using the LASSO model, we classified patients with MIBC into stromal immunotype A subgroup (CTLhighNKhighTreglowMacrophagelowMClow) and stromal immunotype B subgroup (CTLlowNKlowTreghighMacrophagehighMChigh). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (OS, 76.0% vs. 44.0%; P < 0.001) and 5-year disease-free survival (DFS, 62.8% vs. 48.3%; P < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either OS or DFS was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients, but further analysis revealed that OS and disease-free was significantly improved by ACT in pT3+pT4 patients (P = 0.016 and P = 0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) expression.Conclusions: The stromal immunotypes could effectively predict survival and recurrence of MIBC. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT. Clin Cancer Res; 24(13); 3069-78. (c)2018 AACR. PMID- 29514840 TI - The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis. AB - Purpose: Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature PAX3-FOXO1 (P3F) fusion gene. Five-year survival for aRMS is <50%, with no improvement in over 4 decades. Although the transcriptional coactivator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis.Experimental Design: After determining from publicly available datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss of function on aRMS oncogenic phenotypes in vitro and tumorigenesis in vivo Finally, we performed pharmacologic studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity.Results: TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression. In vitro, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G2-M phase of the cell cycle. In vivo, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine.Conclusions: TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS. Clin Cancer Res; 24(11); 2616-30. (c)2018 AACR. PMID- 29514842 TI - Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model. AB - Purpose: Currently, <50% of high-risk pediatric solid tumors like neuroblastoma can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature.Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles. Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance nanoparticle retention. We treated neuroblastomas with SN38-TOA nanoparticles and compared the efficacy with the parent prodrug CPT-11 using a mouse xenograft model.Results: Nanoparticle treatment induced prolonged event-free survival (EFS) in most mice, compared with CPT-11. This was shown for both SH-SY5Y and IMR-32 neuroblastoma xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared with conventional CPT-11 delivery. Interestingly, when recurrent CPT-11-treated tumors were re-treated with SN38-TOA nanoparticles, the tumors transformed from undifferentiated neuroblastomas to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology.Conclusions: Nanoparticle delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in nanoparticles during circulation should decrease toxicity. We propose that nanoparticle-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors. Clin Cancer Res; 24(11); 2585-93. (c)2018 AACR. PMID- 29514841 TI - Genome-wide Discovery and Identification of a Novel miRNA Signature for Recurrence Prediction in Stage II and III Colorectal Cancer. AB - Purpose: The current tumor-node-metastasis (TNM) staging system is inadequate at identifying patients with high-risk colorectal cancer. Using a systematic and comprehensive biomarker discovery and validation approach, we aimed to identify an miRNA recurrence classifier (MRC) that can improve upon the current TNM staging as well as is superior to currently offered molecular assays.Experimental Design: Three independent genome-wide miRNA expression profiling datasets were used for biomarker discovery (N = 158) and in silico validation (N = 109 and N = 40) to identify an miRNA signature for predicting tumor recurrence in patients with colorectal cancer. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh frozen (N = 127, cohort 1) and formalin-fixed paraffin-embedded (FFPE; N = 165, cohort 2 and N = 139, cohort 3) specimens.Results: We identified an 8-miRNA signature that significantly predicted recurrence-free interval (RFI) in the discovery (P = 0.002) and two independent publicly available datasets (P = 0.00006 and P = 0.002). The RT-PCR-based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in patients with stage II and III colorectal cancer [cohort 1: hazard ratio (HR), 3.44 (1.56-7.45), P = 0.001; cohort 2: HR, 6.15 (3.33-11.35), P = 0.001; and cohort 3: HR, 4.23 (2.26-7.92), P = 0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence and achieved superior predictive accuracy over the currently available molecular assays. The RT-PCR based MRC risk score = (-0.1218 * miR-744) + (-3.7142 * miR-429) + (-2.2051 * miR 362) + (3.0564 * miR-200b) + (2.4997 * miR-191) + (-0.0065 * miR-30c2) + (2.2224 * miR-30b) + (-1.1162 * miR-33a).Conclusions: This novel MRC is superior to currently used clinicopathologic features, as well as National Comprehensive Cancer Network (NCCN) criteria, and works regardless of adjuvant chemotherapy status in identifying patients with high-risk stage II and III colorectal cancer. This can be readily deployed in clinical practice with FFPE specimens for decision-making pending further model testing and validation. Clin Cancer Res; 24(16); 3867-77. (c)2018 AACRSee related commentary by Rodriguez et al., p. 3787. PMID- 29514843 TI - The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome. AB - Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival.Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219; validation cohort, n = 418; 77% and 79% estrogen receptor alpha (ERalpha) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P = 0.015) and validation (HR, 0.50; P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERalpha-positive tumors and AR positivity >=78% had the best survival in both cohorts (P < 0.0001). Among the combined ERalpha-positive cases, those with comparable or higher levels of AR (AR:ERalpha-positivity ratio >0.87) had the best outcomes (P < 0.0001).Conclusions: This study defines an optimal AR cut point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer. Clin Cancer Res; 24(10); 2328-41. (c)2018 AACR. PMID- 29514844 TI - COX-2/PGE2 Axis Regulates HIF2alpha Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment. AB - Purpose: Hypoxia-inducible factor-2alpha (HIF2alpha) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2alpha activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2alpha activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2alpha on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2alpha level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2alpha and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2alpha activity by promoting HIF2alpha nuclear translocation via MAPK pathway. The activation of HIF2alpha then led to the enhanced activation of VEGF, cyclin D1, and TGFalpha/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2alpha expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFalpha/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. (c)2018 AACR. PMID- 29514845 TI - PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8+ T-Cell-Driven Antitumor Immunity. AB - Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti CD27 monoclonal antibodies (mAb).Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow cytometry analysis were used to delineate mechanisms underpinning the observed synergy.Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFNgamma, TNFalpha, granzyme B, and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL2 and Myc. However, division of labor was also apparent such that anti-PD 1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for antitumor immunity. Finally, we show that a clinically relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD L1 blockade for protection against lymphoma in human-CD27 transgenic mice.Conclusions: Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8+ T-cell activation. Clin Cancer Res; 24(10); 2383-94. (c)2018 AACR. PMID- 29514847 TI - Can child restraint product information developed using consumer testing sustain correct use 6 months after child restraint purchase? Study protocol for a cluster randomised controlled trial. AB - BACKGROUND: With long-standing and widespread high rates of errors in child restraint use, there is a need to identify effective methods to address this problem. Information supplied with products at the point of sale may be a potentially efficient delivery point for such a countermeasure. The aim of this study is to establish whether product materials developed using a consumer-driven approach reduce errors in restraint use among purchasers of new child restraint systems. METHODS: A cluster randomised controlled trial (cRCT) will be conducted. Retail stores (n=22) in the greater Sydney area will be randomised into intervention sites (n=11) and control sites (n=11), stratified by geographical and socioeconomic indicators. Participants (n=836) will enter the study on purchase of a restraint. Outcome measures are errors in installation of the restraint as observed by a trained researcher during a 6-month follow-up home assessment, and adjustment checks made by the parent when the child is placed into the restraint (observed using naturalistic methods). Process evaluation measures will also be collected during the home visit. An intention-to-treat approach will be used for all analyses. Correct use and adjustment checks made by the parent will be compared between control and intervention groups using a logistic regression model. The number of installation errors between groups will be compared using Poisson regression. DISCUSSION: This cRCT will determine the effectiveness of targeted, consumer-driven information on actual error rates in use of restraints. More broadly, it may provide a best practice model for developing safety product information. TRIAL REGISTRATION NUMBER: ACTRN12617001252303p; Pre-results. PMID- 29514846 TI - Kinesin 6 Regulation in Drosophila Female Meiosis by the Non-conserved N- and C- Terminal Domains. AB - Bipolar spindle assembly occurs in the absence of centrosomes in the oocytes of most organisms. In the absence of centrosomes in Drosophila oocytes, we have proposed that the kinesin 6 Subito, a MKLP-2 homolog, is required for establishing spindle bipolarity and chromosome biorientation by assembling a robust central spindle during prometaphase I. Although the functions of the conserved motor domains of kinesins is well studied, less is known about the contribution of the poorly conserved N- and C- terminal domains to motor function. In this study, we have investigated the contribution of these domains to kinesin 6 functions in meiosis and early embryonic development. We found that the N-terminal domain has antagonistic elements that regulate localization of the motor to microtubules. Other parts of the N- and C-terminal domains are not required for microtubule localization but are required for motor function. Some of these elements of Subito are more important for either mitosis or meiosis, as revealed by separation-of-function mutants. One of the functions for both the N- and C-terminals domains is to restrict the CPC to the central spindle in a ring around the chromosomes. We also provide evidence that CDK1 phosphorylation of Subito regulates its activity associated with homolog bi-orientation. These results suggest the N- and C-terminal domains of Subito, while not required for localization to the central spindle microtubules, have important roles regulating Subito, by interacting with other spindle proteins and promoting activities such as bipolar spindle formation and homologous chromosome bi-orientation during meiosis. PMID- 29514848 TI - Interprofessional learning interventions: championing a lost cause? PMID- 29514849 TI - Morphine is not superior to ibuprofen for managing children's pain following minor orthopedic surgery. PMID- 29514850 TI - Regulation of RNA polymerase II processivity by Spt5 is restricted to a narrow window during elongation. AB - Spt5 is a highly conserved RNA polymerase II (Pol II)-associated pausing and elongation factor. However, its impact on global elongation and Pol II processivity in mammalian cells has not been clarified. Here, we show that depleting Spt5 in mouse embryonic fibroblasts (MEFs) does not cause global elongation defects or decreased elongation rates. Instead, in Spt5-depleted cells, a fraction of Pol II molecules are dislodged during elongation, thus decreasing the number of Pol II complexes that complete the transcription cycle. Most strikingly, this decrease is restricted to a narrow window between 15 and 20 kb from the promoter, a distance which coincides with the stage where accelerating Pol II attains maximum elongation speed. Consequently, long genes show a greater dependency on Spt5 for optimal elongation efficiency and overall gene expression than short genes. We propose that an important role of Spt5 in mammalian elongation is to promote the processivity of those Pol II complexes that are transitioning toward maximum elongation speed 15-20 kb from the promoter. PMID- 29514851 TI - Transmembrane redox control and proteolysis of PdeC, a novel type of c-di-GMP phosphodiesterase. AB - The nucleotide second messenger c-di-GMP nearly ubiquitously promotes bacterial biofilm formation, with enzymes that synthesize and degrade c-di-GMP being controlled by diverse N-terminal sensor domains. Here, we describe a novel class of widely occurring c-di-GMP phosphodiesterases (PDE) that feature a periplasmic "CSS domain" with two highly conserved cysteines that is flanked by two transmembrane regions (TM1 and TM2) and followed by a cytoplasmic EAL domain with PDE activity. Using PdeC, one of the five CSS domain PDEs of Escherichia coli K 12, we show that DsbA/DsbB-promoted disulfide bond formation in the CSS domain reduces PDE activity. By contrast, the free thiol form is enzymatically highly active, with the TM2 region promoting dimerization. Moreover, this form is processed by periplasmic proteases DegP and DegQ, yielding a highly active TM2 + EAL fragment that is slowly removed by further proteolysis. Similar redox control and proteolysis was also observed for a second CSS domain PDE, PdeB. At the physiological level, CSS domain PDEs modulate production and supracellular architecture of extracellular matrix polymers in the deeper layers of mature E. coli biofilms. PMID- 29514852 TI - Focused Training for the Handover of Critical Patient Information During Simulated Pediatric Emergencies. AB - OBJECTIVES: Miscommunication has been implicated as a leading cause of medical errors, and standardized handover programs have been associated with improved patient outcomes. However, the role of structured handovers in pediatric emergencies remains unclear. We sought to determine if training with an airway, breathing, circulation, situation, background, assessment, recommendation handover tool could improve the transmission of essential patient information during multidisciplinary simulations of critically ill children. METHODS: We conducted a prospective, randomized, intervention study with first-year pediatric residents at a quaternary academic children's hospital. Baseline and second handovers were recorded for residents in the intervention group (n = 12) and residents in the control group (n = 8) during multidisciplinary simulations throughout the academic year. The intervention group received handover education after baseline handover observation and a cognitive aid before second handover observation. Audio-recorded handovers were scored by using a Delphi-developed assessment tool by a blinded rater. RESULTS: There was no difference in baseline handover scores between groups (P = .69), but second handover scores were significantly higher in the intervention group (median 12.5 [interquartile range 12-13] versus median 7.5 [interquartile range 6-8] in the control group; P < .01). Trained residents were more likely to include a reason for the call (P < .01), focused history (P = .02), and summative assessment (P = .03). Neither timing of the second observation in the academic year nor duration between first and second observation were associated with the second handover scores (both P > .5). CONCLUSIONS: Structured handover training and provision of a cognitive aid may improve the inclusion of essential patient information in the handover of simulated critically ill children. PMID- 29514853 TI - Understanding Parental Preferences for Participants in Medical Decision-making for Their Hospitalized Children. AB - OBJECTIVES: Family-centered care promotes parental engagement in medical decision making for hospitalized children. Little is understood about parental preferences and factors influencing the desire to involve extended family in decision-making. We explored parent and family member interest in participation in medical decision-making. METHODS: Parents of hospitalized children <=7 years old admitted to the inpatient service were interviewed regarding preferences for self-, other parent, and extended family involvement in decision-making. Scores were calculated for each potential participant on a scale of 1 to 5 (5 indicating that parents strongly agreed with participation). Associations of decision-making preferences with parental age, education, language, and health; the involvement of a child with chronic illness; and the level of clinical acuity were assessed with chi2 tests, Wilcoxon rank tests, and the Spearman correlation. RESULTS: There were 116 participants. Parents' median level of interest in participation in decision-making was as follows: self (4.3; interquartile range [IQR]: 4-4.6); other parent (3.6; IQR: 2.7-4), and family (2.0; IQR: 1.7-2.7). Parents with better physical health (P < .001) and those in a relationship with the other parent (P < .001) were more likely to desire involvement of the other parent in medical decision-making. This was also true for those who faced higher acuity scenarios. Parents <35 years old (P < .01) and those who were interviewed in Spanish (P = .03) were more likely to desire participation of extended family members. CONCLUSIONS: Parents of hospitalized children want to participate in medical decision-making. Desire for the involvement of other family members is complex; therefore, discussions regarding parental preferences are necessary. PMID- 29514854 TI - "Selective" Class C G Protein-Coupled Receptor Modulators Are Neutral or Biased mGlu5 Allosteric Ligands. AB - Numerous positive and negative allosteric modulators (PAMs and NAMs) of class C G protein-coupled receptors (GPCRs) have been developed as valuable preclinical pharmacologic tools and therapeutic agents. Although many class C GPCR allosteric modulators have undergone subtype selectivity screening, most assay paradigms have failed to perform rigorous pharmacologic assessment. Using mGlu5 as a representative class C GPCR, we tested the hypothesis that allosteric modulator selectivity was based on cooperativity rather than affinity. Specifically, we aimed to identify ligands that bound to mGlu5 but exhibited neutral cooperativity with mGlu5 agonists. We additionally evaluated the potential for these ligands to exhibit biased pharmacology. Radioligand binding, intracellular calcium (iCa2+) mobilization, and inositol monophosphate (IP1) accumulation assays were undertaken in human embryonic kidney cells expressing low levels of rat mGlu5 (HEK293A-mGlu5-low) for diverse allosteric chemotypes. Numerous "non-mGlu5" class C GPCR allosteric modulators incompletely displaced allosteric mGlu5 radioligand [3H]methoxy-PEPy binding, consistent with a negative allosteric interaction. Affinity estimates for CPCCOEt (mGlu1 ligand), PHCCC (mGlu4 ligand), GS39783 (GABAB ligand), AZ12216052 (mGlu8 ligand), and CGP7930 (GABAB ligand) at mGlu5 were within 10-fold of their target receptor. Most class C GPCR allosteric modulators had neutral cooperativity with both orthosteric and allosteric mGlu5 agonists in functional assays; however, NPS2143 (calcium-sensing receptor (CaSR) NAM), cinacalcet (CaSR PAM), CGP7930, and AZ12216052 were partial mGlu5 agonists for IP1 accumulation, but not iCa2+ mobilization. By using mGlu5 as a model class C GPCR, we find that for many class C GPCR allosteric modulators, subtype selectivity is driven by cooperativity and misinterpreted owing to unappreciated bias. PMID- 29514855 TI - The Novel C-terminal Truncated 90-kDa Isoform of Topoisomerase IIalpha (TOP2alpha/90) Is a Determinant of Etoposide Resistance in K562 Leukemia Cells via Heterodimerization with the TOP2alpha/170 Isoform. AB - DNA topoisomerase IIalpha (170 kDa, TOP2alpha/170) is essential in proliferating cells by resolving DNA topological entanglements during chromosome condensation, replication, and segregation. We previously characterized a C-terminally truncated isoform (TOP2alpha/90), detectable in human leukemia K562 cells but more abundantly expressed in a clonal subline, K/VP.5, with acquired resistance to the anticancer agent etoposide. TOP2alpha/90 (786 aa) is the translation product of a TOP2alpha mRNA that retains a processed intron 19. TOP2alpha/90 lacks the active-site tyrosine-805 required to generate double-strand DNA breaks as well as nuclear localization signals present in the TOP2alpha/170 isoform (1531 aa). Here, we found that TOP2alpha/90, like TOP2alpha/170, was detectable in the nucleus and cytoplasm of K562 and K/VP.5 cells. Coimmunoprecipitation of endogenous TOP2alpha/90 and TOP2alpha/170 demonstrated heterodimerization of these isoforms. Forced expression of TOP2alpha/90 in K562 cells suppressed, whereas siRNA-mediated knockdown of TOP2alpha/90 in K/VP.5 cells enhanced, etoposide-mediated DNA strand breaks compared with similarly treated cells transfected with empty vector or control siRNAs, respectively. In addition, forced expression of TOP2alpha/90 in K562 cells inhibited etoposide cytotoxicity assessed by clonogenic assays. qPCR and immunoassays demonstrated TOP2alpha/90 mRNA and protein expression in normal human tissues/cells and in leukemia cells from patients. Together, results strongly suggest that TOP2alpha/90 expression decreases drug-induced TOP2alpha-DNA covalent complexes and is a determinant of chemoresistance through a dominant-negative effect related to heterodimerization with TOP2alpha/170. Alternative processing of TOP2alpha pre-mRNA, and subsequent synthesis of TOP2alpha/90, may be an important mechanism regulating the formation and/or stability of cytotoxic TOP2alpha/170-DNA covalent complexes in response to TOP2alpha-targeting agents. PMID- 29514856 TI - Mitotic spindle assembly and gamma-tubulin localisation depend on the integral nuclear membrane protein Samp1. AB - We have investigated a possible role for the inner nuclear membrane protein Samp1 (also known as TMEM201) in the mitotic machinery. Live-cell imaging showed that Samp1a-YFP (Samp1a is the short isoform of Samp1) distributed as filamentous structures in the mitotic spindle, partially colocalising with beta-tubulin. Samp1 depletion resulted in an increased frequency of cells with signs of chromosomal mis-segregation and prolonged metaphase, indicating problems with spindle assembly and/or chromosomal alignment. Consistent with this, mitotic spindles in Samp1-depleted cells contained significantly lower levels of beta tubulin and gamma-tubulin, phenotypes that were rescued by overexpression of Samp1a-YFP. We found that Samp1 can bind directly to gamma-tubulin and that Samp1 co-precipitated with gamma-tubulin and the HAUS6 subunit of the Augmin complex in live cells. The levels of HAUS6, in the mitotic spindle also decreased after Samp1 depletion. We show that Samp1 is involved in the recruitment of HAUS6 and gamma-tubulin to the mitotic spindle. Samp1 is the first inner nuclear membrane protein shown to have a function in mitotic spindle assembly. PMID- 29514857 TI - Rab7 knockout unveils regulated autolysosome maturation induced by glutamine starvation. AB - Macroautophagy (simply called autophagy hereafter) is an intracellular degradation mechanism that is activated by nutrient starvation. Although it is well known that starvation induces autophagosome formation in an mTORC1-dependent manner, whether starvation also regulates autophagosome or autolysosome maturation was unclear. In the present study, we succeeded in demonstrating that starvation activates autolysosome maturation in mammalian cells. We found that knockout (KO) of Rab7 (herein referring to the Rab7a isoform) caused an accumulation of a massive number of LC3-positive autolysosomes under nutrient rich conditions, indicating that Rab7 is dispensable for autophagosome-lysosome fusion. Intriguingly, the autolysosomes that had accumulated in Rab7-KO cells matured and disappeared after starvation for a brief period (~10 min), and we identified glutamine as an essential nutrient for autolysosome maturation. In contrast, forced inactivation of mTORC1 through treatment with its inhibitor Torin2 failed to induce autolysosome maturation, suggesting that the process is controlled by an mTORC1-independent mechanism. Since starvation-induced autolysosome maturation was also observed in wild-type cells, the nutrient starvation-induced maturation of autolysosomes is likely to be a generalized mechanism in the same manner as starvation-induced autophagosome formation. Such multistep regulatory mechanisms would enable efficient autophagic flux during starvation. PMID- 29514859 TI - Large and middle hepatitis B surface antigen: the lower the better? PMID- 29514858 TI - E3 Ubiquitin Ligases: Key Regulators of Hormone Signaling in Plants. AB - Ubiquitin-mediated control of protein stability is central to most aspects of plant hormone signaling. Attachment of ubiquitin to target proteins occurs via an enzymatic cascade with the final step being catalyzed by a family of enzymes known as E3 ubiquitin ligases, which have been classified based on their protein domains and structures. Although E3 ubiquitin ligases are conserved among eukaryotes, in plants they are well-known to fulfill unique roles as central regulators of phytohormone signaling, including hormone perception and regulation of hormone biosynthesis. This review will highlight up-to-date findings that have refined well-known E3 ligase-substrate interactions and defined novel E3 ligase substrates that mediate numerous hormone signaling pathways. Additionally, examples of how particular E3 ligases may mediate hormone crosstalk will be discussed as an emerging theme. Looking forward, promising experimental approaches and methods that will provide deeper mechanistic insight into the roles of E3 ubiquitin ligases in plants will be considered. PMID- 29514860 TI - Genetic Variance Partitioning and Genome-Wide Prediction with Allele Dosage Information in Autotetraploid Potato. AB - As one of the world's most important food crops, the potato (Solanum tuberosum L.) has spurred innovation in autotetraploid genetics, including in the use of SNP arrays to determine allele dosage at thousands of markers. By combining genotype and pedigree information with phenotype data for economically important traits, the objectives of this study were to (1) partition the genetic variance into additive vs. nonadditive components, and (2) determine the accuracy of genome-wide prediction. Between 2012 and 2017, a training population of 571 clones was evaluated for total yield, specific gravity, and chip fry color. Genomic covariance matrices for additive (G), digenic dominant (D), and additive * additive epistatic (G#G) effects were calculated using 3895 markers, and the numerator relationship matrix (A) was calculated from a 13-generation pedigree. Based on model fit and prediction accuracy, mixed model analysis with G was superior to A for yield and fry color but not specific gravity. The amount of additive genetic variance captured by markers was 20% of the total genetic variance for specific gravity, compared to 45% for yield and fry color. Within the training population, including nonadditive effects improved accuracy and/or bias for all three traits when predicting total genotypic value. When six F1 populations were used for validation, prediction accuracy ranged from 0.06 to 0.63 and was consistently lower (0.13 on average) without allele dosage information. We conclude that genome-wide prediction is feasible in potato and that it will improve selection for breeding value given the substantial amount of nonadditive genetic variance in elite germplasm. PMID- 29514861 TI - Genomic Prediction from Multiple-Trait Bayesian Regression Methods Using Mixture Priors. AB - Bayesian multiple-regression methods incorporating different mixture priors for marker effects are used widely in genomic prediction. Improvement in prediction accuracies from using those methods, such as BayesB, BayesC, and BayesCpi, have been shown in single-trait analyses with both simulated and real data. These methods have been extended to multi-trait analyses, but only under the restrictive assumption that a locus simultaneously affects all the traits or none of them. This assumption is not biologically meaningful, especially in multi trait analyses involving many traits. In this paper, we develop and implement a more general multi-trait BayesC[Formula: see text] and BayesB methods allowing a broader range of mixture priors. Our methods allow a locus to affect any combination of traits, e.g., in a 5-trait analysis, the "restrictive" model only allows two situations, whereas ours allow all 32 situations. Further, we compare our methods to single-trait methods and the "restrictive" multi-trait formulation using real and simulated data. In the real data analysis, higher prediction accuracies were observed from both our new broad-based multi-trait methods and the "restrictive" formulation. The broad-based and restrictive multi-trait methods showed similar prediction accuracies. In the simulated data analysis, higher prediction accuracies to the "restrictive" method were observed from our general multi-trait methods for intermediate training population size. The software tool JWAS offers open-source routines to perform these analyses. PMID- 29514863 TI - Comment on "Why are NGOs sceptical of genome editing?" PMID- 29514862 TI - PAWS1 controls Wnt signalling through association with casein kinase 1alpha. AB - The BMP and Wnt signalling pathways determine axis specification during embryonic development. Our previous work has shown that PAWS1 (also known as FAM83G) interacts with SMAD1 and modulates BMP signalling. Here, surprisingly, we show that overexpression of PAWS1 in Xenopus embryos activates Wnt signalling and causes complete axis duplication. Consistent with these observations in Xenopus, Wnt signalling is diminished in U2OS osteosarcoma cells lacking PAWS1, while BMP signalling is unaffected. We show that PAWS1 interacts and co-localises with the alpha isoform of casein kinase 1 (CK1), and that PAWS1 mutations incapable of binding CK1 fail both to activate Wnt signalling and to elicit axis duplication in Xenopus embryos. PMID- 29514864 TI - Reply to Tagliabue. PMID- 29514866 TI - Intramyocardial block in patients with atrioventricular block. AB - Atrioventricular (AV) block has been extensively studied. However, conduction inside the myocardium in patients with AV block has not been reported. In this study, we aimed to demonstrate the presence of intramyocardial block in patients with AV block. Five consecutive patients with spontaneous high-grade AV block and Torsades de pointes (TdP) were prospectively studied with standard United States Catheter Instruments (USCI) endocardial temporary catheter located at the right ventricle (RV) apex. The morphology of endocardial potentials observed in the basic QRS complexes as well as during episodes of TdP was studied. The electrogram (EGM) of the basic rhythm showed a sharp deflection of high amplitude preceded and/or followed by a smooth potential of low amplitude interpreted as far-field potentials in all patients. The sharp potential can be observed at the beginning, in the middle or at the end of the smooth potential. All these potentials were reproduced from beat to beat and were falling inside the QRS complex of the surface ECG. Therefore, these aspects are zones of electrically depressed or silent myocardium larger than the interelectrode distance of 12 mm. This situation is in agreement with recent genetic factors. In this study, we demonstrated for the first time that patients with spontaneous AV block also have trouble in ventricular activation located on the AV conduction system and inside the myocardium. It is then possible to speculate that the presence of diffuse non conducting myocardium explains why most TdPs do not degenerate into ventricular fibrillation (VF) and generally stop spontaneously. PMID- 29514867 TI - Fifteen-minute consultation: the child with a non-blanching rash. PMID- 29514865 TI - Calcium-induced release of calcium in muscle: 50 years of work and the emerging consensus. AB - Ryanodine-sensitive intracellular Ca2+ channels (RyRs) open upon binding Ca2+ at cytosolic-facing sites. This results in concerted, self-reinforcing opening of RyRs clustered in specialized regions on the membranes of Ca2+ storage organelles (endoplasmic reticulum and sarcoplasmic reticulum), a process that produces Ca2+ induced Ca2+ release (CICR). The process is optimized to achieve large but brief and localized increases in cytosolic Ca2+ concentration, a feature now believed to be critical for encoding the multiplicity of signals conveyed by this ion. In this paper, I trace the path of research that led to a consensus on the physiological significance of CICR in skeletal muscle, beginning with its discovery. I focus on the approaches that were developed to quantify the contribution of CICR to the Ca2+ increase that results in contraction, as opposed to the flux activated directly by membrane depolarization (depolarization-induced Ca2+ release [DICR]). Although the emerging consensus is that CICR plays an important role alongside DICR in most taxa, its contribution in most mammalian muscles appears to be limited to embryogenesis. Finally, I survey the relevance of CICR, confirmed or plausible, to pathogenesis as well as the multiple questions about activation of release channels that remain unanswered after 50 years. PMID- 29514868 TI - Identifying RNA splicing factors using IFT genes in Chlamydomonas reinhardtii. AB - Intraflagellar transport moves proteins in and out of flagella/cilia and it is essential for the assembly of these organelles. Using whole-genome sequencing, we identified splice site mutations in two IFT genes, IFT81 (fla9) and IFT121 (ift121-2), which lead to flagellar assembly defects in the unicellular green alga Chlamydomonas reinhardtii The splicing defects in these ift mutants are partially corrected by mutations in two conserved spliceosome proteins, DGR14 and FRA10. We identified a dgr14 deletion mutant, which suppresses the 3' splice site mutation in IFT81, and a frameshift mutant of FRA10, which suppresses the 5' splice site mutation in IFT121 Surprisingly, we found dgr14-1 and fra10 mutations suppress both splice site mutations. We suggest these two proteins are involved in facilitating splice site recognition/interaction; in their absence some splice site mutations are tolerated. Nonsense mutations in SMG1, which is involved in nonsense-mediated decay, lead to accumulation of aberrant transcripts and partial restoration of flagellar assembly in the ift mutants. The high density of introns and the conservation of noncore splicing factors, together with the ease of scoring the ift mutant phenotype, make Chlamydomonas an attractive organism to identify new proteins involved in splicing through suppressor screening. PMID- 29514870 TI - Reviewers in 2017. PMID- 29514871 TI - Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption. AB - Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, N-acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions. PMID- 29514869 TI - Assembly and regulation of gamma-tubulin complexes. AB - Microtubules are major constituents of the cytoskeleton in all eukaryotic cells. They are essential for chromosome segregation during cell division, for directional intracellular transport and for building specialized cellular structures such as cilia or flagella. Their assembly has to be controlled spatially and temporally. For this, the cell uses multiprotein complexes containing gamma-tubulin. gamma-Tubulin has been found in two different types of complexes, gamma-tubulin small complexes and gamma-tubulin ring complexes. Binding to adaptors and activator proteins transforms these complexes into structural templates that drive the nucleation of new microtubules in a highly controlled manner. This review discusses recent advances on the mechanisms of assembly, recruitment and activation of gamma-tubulin complexes at microtubule organizing centres. PMID- 29514872 TI - Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly. AB - BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11 deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred. METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect. RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects. PMID- 29514873 TI - Multiplex genomewide association analysis of breast milk fatty acid composition extends the phenotypic association and potential selection of FADS1 variants to arachidonic acid, a critical infant micronutrient. AB - BACKGROUND: Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition. METHODS: We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE. RESULTS: After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the FADS1/2/3 region were also associated with breast milk FA composition (experiment-wise significance threshold 4.2*10-9). Hypothesis-neutral comparison of the 33 fractions showed that the most significant genetic association at the FADS1/2/3 locus was with fraction of arachidonic acid (AA) at SNP rs174556, with a very large per major allele effect size of 17% higher breast milk AA level. There was no evidence of independent association at FADS1/2/3 with any other FA or SNP after conditioning on AA and rs174556. We also found novel significant experiment-wise SNP associations with: polyunsaturated fatty acid (PUFA) 6/PUFA3 ratio (sorting nexin 29), eicosenoic (intergenic) and capric (component of oligomeric Golgi complex 3) acids; and six additional loci at genomewide significance (<5*10-8). CONCLUSIONS: AA is the primary FA in breast milk influenced by genetic variation at the FADS1/2/3 locus, extending the potential phenotypes under genetic selection to include breast milk composition, thereby possibly affecting infant growth or cognition. Breast milk FA composition is influenced by maternal genetics in addition to diet and body composition. PMID- 29514874 TI - Aquatic acidification: a mechanism underpinning maintained oxygen transport and performance in fish experiencing elevated carbon dioxide conditions. AB - Aquatic acidification, caused by elevating levels of atmospheric carbon dioxide (CO2), is increasing in both freshwater and marine ecosystems worldwide. However, few studies have examined how acidification will affect oxygen (O2) transport and, therefore, performance in fishes. Although data are generally lacking, the majority of fishes investigated in this meta-analysis exhibited no effect of elevated CO2 at the level of O2 uptake, suggesting that they are able to maintain metabolic performance during a period of acidosis. Notably, the mechanisms that fish employ to maintain performance and O2 uptake have yet to be verified. Here, we summarize current data related to one recently proposed mechanism underpinning the maintenance of O2 uptake during exposure to aquatic acidification, and reveal knowledge gaps that could be targeted for future research. Most studies have examined O2 uptake rates while fishes were resting and did not calculate aerobic scope, even though aerobic scope can aid in predicting changes to whole-animal metabolic performance. Furthermore, research is lacking on different age classes, freshwater species and elasmobranchs, all of which might be impacted by future acidification conditions. Finally, this Review further seeks to emphasize the importance of developing collaborative efforts between molecular, physiological and ecological approaches in order to provide more comprehensive predictions as to how future fish populations will be affected by climate change. PMID- 29514875 TI - Early career researchers: an interview with Yossi Yovel. AB - Yossi Yovel is an Assistant Professor at Tel-Aviv University, Israel, where he studies bat echolocation. He received his joint honours Bachelor's degree in Biology and Physics before moving to complete his PhD with Hans-Ulrich Schnitzler at University of Tubingen, Germany, in 2008. He then completed postdocs at the Weizmann Institute, Israel, and University of Chicago, USA. PMID- 29514876 TI - Adipogenesis in fish. AB - White adipose tissue (AT) is the main lipid storage depot in vertebrates. Initially considered to be a simple lipid store, AT has recently been recognized as playing a role as an endocrine organ that is implicated in processes such as energy homeostasis and as a rich source of stem cells. Interest in adipogenesis has increased not only because of the prevalence of obesity, metabolic syndrome and type 2 diabetes in humans, but also in aquaculture because of the excessive fat deposition experienced in some cultured fish species, which may compromise both their welfare and their final product quality. Adipocyte development is well conserved among vertebrates, and this conservation has facilitated the rapid characterization of several adipogenesis models in fish. This Review presents the main findings of adipogenesis research based in primary cultures of the preadipocytes of farmed fish species. Zebrafish has emerged as an excellent model for studying the early stages of adipocyte fish development in vivo Nevertheless, larger fish species are more suitable for the isolation of preadipocytes from visceral AT and for studies in which preadipocytes are differentiated in vitro to form mature adipocytes. Differentiated adipocytes contain lipid droplets and express adipocyte marker genes such as those encoding the peroxisome proliferator activated receptor gamma (ppargamma), CCAAT-enhancer-binding protein alpha (c/ebpalpha), lipoprotein lipase (lpl), fatty acid synthase (fas), fatty acid binding protein 11 (fabp11), fatty acid transporter protein1 (fatp1), adiponectin and leptin. Differentiated adipocytes also have elevated glycerol 3-phosphate (G3P) dehydrogenase (GPDH) activity. To better understand fish adipocyte development and regulation, different adipokines, fatty acids, growth factors and PPAR agonists have been studied, providing relevant insights into which factors affect these processes and counterbalance AT dysregulation. PMID- 29514877 TI - The many roles of fats in overwintering insects. AB - Temperate, polar and alpine insects generally do not feed over winter and hence must manage their energy stores to fuel their metabolism over winter and to meet the energetic demands of development and reproduction in the spring. In this Review, we give an overview of the accumulation, use and conservation of fat reserves in overwintering insects and discuss the ways insects modify fats to facilitate their selective consumption or conservation. Many insects are in diapause and have depressed metabolic rates over winter; together with low temperatures, this means that lipid stores are likely to be consumed predominantly in the autumn and spring, when temperatures are higher but insects remain dormant. Although there is ample evidence for a shift towards less saturated lipids in overwintering insects, switches between the use of carbohydrate and lipid stores during winter have not been well-explored. Insects usually accumulate cryoprotectants over winter, and the resulting increase in haemolymph viscosity is likely to reduce lipid transport. For freeze-tolerant insects (which withstand internal ice), we speculate that impaired oxygen delivery limits lipid oxidation when frozen. Acetylated triacylglycerols remain liquid at low temperatures and interact with water molecules, providing intriguing possibilities for a role in cryoprotection. Similarly, antifreeze glycolipids may play an important role in structuring water and ice during overwintering. We also touch on the uncertain role of non-esterified fatty acids in insect overwintering. In conclusion, lipids are an important component of insect overwintering energetics, but there remain many uncertainties ripe for detailed exploration. PMID- 29514878 TI - Nature's fat-burning machine: brown adipose tissue in a hibernating mammal. AB - Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals that rapidly produces heat via nonshivering thermogenesis. Small mammalian hibernators have evolved the greatest capacity for BAT because they use it to rewarm from hypothermic torpor numerous times throughout the hibernation season. Although hibernator BAT physiology has been investigated for decades, recent efforts have been directed toward understanding the molecular underpinnings of BAT regulation and function using a variety of methods, from mitochondrial functional assays to 'omics' approaches. As a result, the inner-workings of hibernator BAT are now being illuminated. In this Review, we discuss recent research progress that has identified players and pathways involved in brown adipocyte differentiation and maturation, as well as those involved in metabolic regulation. The unique phenotype of hibernation, and its reliance on BAT to generate heat to arouse mammals from torpor, has uncovered new molecular mechanisms and potential strategies for biomedical applications. PMID- 29514879 TI - Heterogeneity of adipose tissue in development and metabolic function. AB - Adipose tissue is a central metabolic organ. Unlike other organs, adipose tissue is compartmentalized into individual depots and distributed throughout the body. These different adipose depots show major functional differences and risk associations for developing metabolic syndrome. Recent advances in lineage tracing demonstrate that individual adipose depots are composed of adipocytes that are derived from distinct precursor populations, giving rise to different populations of energy-storing white adipocytes. Moreover, distinct lineages of energy-dissipating brown and beige adipocytes exist in discrete depots or within white adipose tissue depots. In this Review, we discuss developmental and functional heterogeneity, as well as sexual dimorphism, between and within individual adipose tissue depots. We highlight current data relating to the differences between subcutaneous and visceral white adipose tissue in the development of metabolic dysfunction, with special emphasis on adipose tissue expansion and remodeling of the extracellular matrix. Moreover, we provide a detailed overview of adipose tissue development as well as the consensus and controversies relating to adult adipocyte precursor populations. PMID- 29514880 TI - Drosophila as a model to study obesity and metabolic disease. AB - Excess adipose fat accumulation, or obesity, is a growing problem worldwide in terms of both the rate of incidence and the severity of obesity-associated metabolic disease. Adipose tissue evolved in animals as a specialized dynamic lipid storage depot: adipose cells synthesize fat (a process called lipogenesis) when energy is plentiful and mobilize stored fat (a process called lipolysis) when energy is needed. When a disruption of lipid homeostasis favors increased fat synthesis and storage with little turnover owing to genetic predisposition, overnutrition or sedentary living, complications such as diabetes and cardiovascular disease are more likely to arise. The vinegar fly Drosophila melanogaster (Diptera: Drosophilidae) is used as a model to better understand the mechanisms governing fat metabolism and distribution. Flies offer a wealth of paradigms with which to study the regulation and physiological effects of fat accumulation. Obese flies accumulate triacylglycerols in the fat body, an organ similar to mammalian adipose tissue, which specializes in lipid storage and catabolism. Discoveries in Drosophila have ranged from endocrine hormones that control obesity to subcellular mechanisms that regulate lipogenesis and lipolysis, many of which are evolutionarily conserved. Furthermore, obese flies exhibit pathophysiological complications, including hyperglycemia, reduced longevity and cardiovascular function - similar to those observed in obese humans. Here, we review some of the salient features of the fly that enable researchers to study the contributions of feeding, absorption, distribution and the metabolism of lipids to systemic physiology. PMID- 29514881 TI - Fructose-containing caloric sweeteners as a cause of obesity and metabolic disorders. AB - Compared with other carbohydrates, fructose-containing caloric sweeteners (sucrose, high-fructose corn syrup, pure fructose and fructose-glucose mixtures) are characterized by: a sweet taste generally associated with a positive hedonic tone; specific intestinal fructose transporters, i.e. GLUT5; a two-step fructose metabolism, consisting of the conversion of fructose carbones into ubiquitous energy substrates in splanchnic organs where fructolytic enzymes are expressed, and secondary delivery of these substrates to extrasplanchnic tissues. Fructose is a dispensable nutrient, yet its energy can be stored very efficiently owing to a rapid induction of intestinal fructose transporters and of splanchnic fructolytic and lipogenic enzymes by dietary fructose-containing caloric sweeteners. In addition, compared with fat or other dietary carbohydrates, fructose may be favored as an energy store because it uses different intestinal absorption mechanisms and different inter-organ trafficking pathways. These specific features make fructose an advantageous energy substrate in wild animals, mainly when consumed before periods of scarcity or high energy turnover such as migrations. These properties of fructose storage are also advantageous to humans who are involved in strenuous sport activities. In subjects with low physical activity, however, these same features of fructose metabolism may have the harmful effect of favoring energy overconsumption. Furthermore, a continuous exposure to high fructose intake associated with a low energy turnover leads to a chronic overproduction of intrahepatic trioses-phosphate production, which is secondarily responsible for the development of hepatic insulin resistance, intrahepatic fat accumulation, and increased blood triglyceride concentrations. In the long term, these effects may contribute to the development of metabolic and cardiovascular diseases. PMID- 29514882 TI - Genomic imprinting, growth and maternal-fetal interactions. AB - In the 1980s, mouse nuclear transplantation experiments revealed that both male and female parental genomes are required for successful development to term ( McGrath and Solter, 1983; Surani and Barton, 1983). This non-equivalence of parental genomes is because imprinted genes are predominantly expressed from only one parental chromosome. Uniparental inheritance of these genomic regions causes paediatric growth disorders such as Beckwith-Wiedemann and Silver-Russell syndromes (reviewed in Peters, 2014). More than 100 imprinted genes have now been discovered and the functions of many of these genes have been assessed in murine models. The first such genes described were the fetal growth factor insulin-like growth factor 2 (Igf2) and its inhibitor Igf2 receptor (Igf2r) ( DeChiara et al., 1991; Lau et al., 1994; Wang et al., 1994). Since then, it has emerged that most imprinted genes modulate fetal growth and resource acquisition in a variety of ways. First, imprinted genes are required for the development of a functional placenta, the organ that mediates the exchange of nutrients between mother and fetus. Second, these genes act in an embryo-autonomous manner to affect the growth rate and organogenesis. Finally, imprinted genes can signal the nutritional status between mother and fetus, and can modulate levels of maternal care. Importantly, many imprinted genes have been shown to affect postnatal growth and energy homeostasis. Given that abnormal birthweight correlates with adverse adult metabolic health, including obesity and cardiovascular disease, it is crucial to understand how the modulation of this dosage-sensitive, epigenetically regulated class of genes can contribute to fetal and postnatal growth, with implications for lifelong health and disease. PMID- 29514883 TI - Adipose morphology and metabolic disease. AB - Adipose morphology is defined as the number and size distribution of adipocytes (fat cells) within adipose tissue. Adipose tissue with fewer but larger adipocytes is said to have a 'hypertrophic' morphology, whereas adipose with many adipocytes of a smaller size is said to have a 'hyperplastic' morphology. Hypertrophic adipose morphology is positively associated with insulin resistance, diabetes and cardiovascular disease. By contrast, hyperplastic morphology is associated with improved metabolic parameters. These phenotypic associations suggest that adipose morphology influences risk of cardiometabolic disease. Intriguingly, monozygotic twin studies have determined that adipose morphology is in part determined genetically. Therefore, identifying the genetic regulation of adipose morphology may help us to predict, prevent and ameliorate insulin resistance and associated metabolic diseases. Here, we review the current literature regarding adipose morphology in relation to: (1) metabolic and medical implications; (2) the methods used to assess adipose morphology; and (3) transcriptional differences between morphologies. We further highlight three mechanisms that have been hypothesized to promote adipocyte hypertrophy and thus to regulate adipose morphology. PMID- 29514884 TI - Non-adrenergic control of lipolysis and thermogenesis in adipose tissues. AB - The enormous plasticity of adipose tissues, to rapidly adapt to altered physiological states of energy demand, is under neuronal and endocrine control. In energy balance, lipolysis of triacylglycerols and re-esterification of free fatty acids are opposing processes operating in parallel at identical rates, thus allowing a more dynamic transition from anabolism to catabolism, and vice versa. In response to alterations in the state of energy balance, one of the two processes predominates, enabling the efficient mobilization or storage of energy in a negative or positive energy balance, respectively. The release of noradrenaline from the sympathetic nervous system activates lipolysis in a depot specific manner by initiating the canonical adrenergic receptor-Gs-protein adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A pathway, targeting proteins of the lipolytic machinery associated with the interface of the lipid droplets. In brown and brite adipocytes, lipolysis stimulated by this signaling pathway is a prerequisite for the activation of non-shivering thermogenesis. Free fatty acids released by lipolysis are direct activators of uncoupling protein 1-mediated leak respiration. Thus, pro- and anti-lipolytic mediators are bona fide modulators of thermogenesis in brown and brite adipocytes. In this Review, we discuss adrenergic and non-adrenergic mechanisms controlling lipolysis and thermogenesis and provide a comprehensive overview of pro- and anti-lipolytic mediators. PMID- 29514885 TI - Obese super athletes: fat-fueled migration in birds and bats. AB - Migratory birds are physiologically specialized to accumulate massive fat stores (up to 50-60% of body mass), and to transport and oxidize fatty acids at very high rates to sustain flight for many hours or days. Target gene, protein and enzyme analyses and recent -omic studies of bird flight muscles confirm that high capacities for fatty acid uptake, cytosolic transport, and oxidation are consistent features that make fat-fueled migration possible. Augmented circulatory transport by lipoproteins is suggested by field data but has not been experimentally verified. Migratory bats have high aerobic capacity and fatty acid oxidation potential; however, endurance flight fueled by adipose-stored fat has not been demonstrated. Patterns of fattening and expression of muscle fatty acid transporters are inconsistent, and bats may partially fuel migratory flight with ingested nutrients. Changes in energy intake, digestive capacity, liver lipid metabolism and body temperature regulation may contribute to migratory fattening. Although control of appetite is similar in birds and mammals, neuroendocrine mechanisms regulating seasonal changes in fuel store set-points in migrants remain poorly understood. Triacylglycerol of birds and bats contains mostly 16 and 18 carbon fatty acids with variable amounts of 18:2n-6 and 18:3n-3 depending on diet. Unsaturation of fat converges near 70% during migration, and unsaturated fatty acids are preferentially mobilized and oxidized, making them good fuel. Twenty and 22 carbon n-3 and n-6 polyunsaturated fatty acids (PUFA) may affect membrane function and peroxisome proliferator-activated receptor signaling. However, evidence for dietary PUFA as doping agents in migratory birds is equivocal and requires further study. PMID- 29514886 TI - The effect of diet and exercise on lipid droplet dynamics in human muscle tissue. AB - The majority of fat in the human body is stored as triacylglycerols in white adipose tissue. In the obese state, adipose tissue mass expands and excess lipids are stored in non-adipose tissues, such as skeletal muscle. Lipids are stored in skeletal muscle in the form of small lipid droplets. Although originally viewed as dull organelles that simply store lipids as a consequence of lipid overflow from adipose tissue, lipid droplets are now recognized as key components in the cell that exert a variety of relevant functions in multiple tissues (including muscle). Here, we review the effect of diet and exercise interventions on myocellular lipid droplets and their putative role in insulin sensitivity from a human perspective. We also provide an overview of lipid droplet biology and identify gaps for future research. PMID- 29514887 TI - The evolution of body fatness: trading off disease and predation risk. AB - Human obesity has a large genetic component, yet has many serious negative consequences. How this state of affairs has evolved has generated wide debate. The thrifty gene hypothesis was the first attempt to explain obesity as a consequence of adaptive responses to an ancient environment that in modern society become disadvantageous. The idea is that genes (or more precisely, alleles) predisposing to obesity may have been selected for by repeated exposure to famines. However, this idea has many flaws: for instance, selection of the supposed magnitude over the duration of human evolution would fix any thrifty alleles (famines kill the old and young, not the obese) and there is no evidence that hunter-gatherer populations become obese between famines. An alternative idea (called thrifty late) is that selection in famines has only happened since the agricultural revolution. However, this is inconsistent with the absence of strong signatures of selection at single nucleotide polymorphisms linked to obesity. In parallel to discussions about the origin of obesity, there has been much debate regarding the regulation of body weight. There are three basic models: the set-point, settling point and dual-intervention point models. Selection might act against low and high levels of adiposity because food unpredictability and the risk of starvation selects against low adiposity whereas the risk of predation selects against high adiposity. Although evidence for the latter is quite strong, evidence for the former is relatively weak. The release from predation ~2-million years ago is suggested to have led to the upper intervention point drifting in evolutionary time, leading to the modern distribution of obesity: the drifty gene hypothesis. Recent critiques of the dual intervention point/drifty gene idea are flawed and inconsistent with known aspects of energy balance physiology. Here, I present a new formulation of the dual-intervention point model. This model includes the novel suggestion that food unpredictability and starvation are insignificant factors driving fat storage, and that the main force driving up fat storage is the risk of disease and the need to survive periods of pathogen-induced anorexia. This model shows why two independent intervention points are more likely to evolve than a single set point. The molecular basis of the lower intervention point is likely based around the leptin pathway signalling. Determining the molecular basis of the upper intervention point is a crucial key target for future obesity research. A potential definitive test to separate the different models is also described. PMID- 29514888 TI - Insights into brown adipose tissue evolution and function from non-model organisms. AB - Brown adipose tissue (BAT) enables adaptive thermoregulation through heat production that is catalyzed by mitochondrial uncoupling protein 1 (UCP1). BAT is frequently studied in rodent model organisms, and recently in adult humans to treat metabolic diseases. However, complementary studies of many non-model species, which have diversified to many more ecological niches, may significantly broaden our understanding of BAT regulation and its physiological roles. This Review highlights the research on non-model organisms, which was instrumental to the discovery of BAT function, and the unique evolutionary history of BAT/UCP1 in mammalian thermogenesis. The comparative biology of BAT provides a powerful integrative approach that could identify conserved and specialized functional changes in BAT and UCP1 by considering species diversity, ecology and evolution, and by fusing multiple scientific disciplines such as physiology and biochemistry. Thus, resolving the complete picture of BAT biology may fail if comparative studies of non-model organisms are neglected. PMID- 29514889 TI - The many, exciting sequels to the story of fat. PMID- 29514890 TI - Function and evolution of specialized endogenous lipids in toothed whales. AB - The Odontocetes (toothed whales) possess two types of specialized fat and, therefore, represent an interesting group when considering the evolution and function of adipose tissue. All whales have a layer of superficial blubber, which insulates and streamlines, provides buoyancy and acts as an energy reserve. Some toothed whales deposit large amounts of wax esters, rather than triacylglycerols, in blubber, which is unusual. Waxes have very different physical and physiological properties, which may impact blubber function. The cranial acoustic fat depots serve to focus sound during echolocation and hearing. The acoustic fats have unique morphologies; however, they are even more specialized biochemically because they are composed of a mix of endogenous waxes and triacylglycerols with unusual branched elements (derived from amino acids) that are not present in other mammals. Both waxes and branched elements alter how sound travels through a fat body; they are arranged in a 3D topographical pattern to focus sound. Furthermore, the specific branched-chain acid/alcohol synthesis mechanisms and products vary phylogenetically (e.g. dolphins synthesize lipids from leucine whereas beaked whales use valine). I propose that these specialized lipids evolved first in the head: wax synthesis first emerged to serve an acoustic function in toothed whales, with branched-chain synthesis adding additional acoustic focusing power, and some species secondarily retained wax synthesis pathways for blubber. Further research is necessary to elucidate specific molecular mechanisms controlling the synthesis and deposition of wax esters and branched-chain fatty acids, as well as their spatial deposition within tissues and within adipocytes. PMID- 29514891 TI - Are we what we eat? Changes to the feed fatty acid composition of farmed salmon and its effects through the food chain. AB - 'Are we what we eat?' Yes and no. Although dietary fat affects body fat, there are many modifying mechanisms. In Atlantic salmon, there is a high level of retention of the n-3 fatty acid (FA) docosahexaenoic acid (DHA, 22:6n-3) relative to the dietary content, whereas saturated FAs never seem to increase above a specified level, which is probably an adaptation to low and fluctuating body temperature. Net production of eicosapentaenoic acid (EPA, 20:5n-3) and especially DHA occurs in salmon when dietary levels are low; however, this synthesis is not sufficient to maintain EPA and DHA at similar tissue levels to those of a traditional fish oil-fed farmed salmon. The commercial diets of farmed salmon have changed over the past 15 years towards a more plant-based diet owing to the limited availability of the marine ingredients fish meal and fish oil, resulting in decreased EPA and DHA and increased n-6 FAs. Salmon is part of the human diet, leading to the question 'Are we what the salmon eats?' Dietary intervention studies using salmon have shown positive effects on FA profiles and health biomarkers in humans; however, most of these studies used salmon that were fed high levels of marine ingredients. Only a few human intervention studies and mouse trials have explored the effects of the changing feed composition of farmed salmon. In conclusion, when evaluating feed ingredients for farmed fish, effects throughout the food chain on fish health, fillet composition and human health need to be considered. PMID- 29514892 TI - Adiposity and fat metabolism during combined fasting and lactation in elephant seals. AB - Animals that fast depend on mobilizing lipid stores to power metabolism. Northern elephant seals (Mirounga angustirostris) incorporate extended fasting into several life-history stages: development, molting, breeding and lactation. The physiological processes enabling fasting and lactation are important in the context of the ecology and life history of elephant seals. The rare combination of fasting and lactation depends on the efficient mobilization of lipid from adipose stores and its direction into milk production. The mother elephant seal must ration her finite body stores to power maintenance metabolism, as well as to produce large quantities of lipid and protein-rich milk. Lipid from body stores must first be mobilized; the action of lipolytic enzymes and hormones stimulate the release of fatty acids into the bloodstream. Biochemical processes affect the release of specific fatty acids in a predictable manner, and the pattern of release from lipid stores is closely reflected in the fatty acid content of the milk lipid. The content of the milk may have substantial developmental, thermoregulatory and metabolic consequences for the pup. The lactation and developmental patterns found in elephant seals are similar in some respects to those of other mammals; however, even within the limited number of mammals that simultaneously fast and lactate, there are important differences in the mechanisms that regulate lipid mobilization and milk lipid content. Although ungulates and humans do not fast during lactation, there are interesting comparisons to these groups regarding lipid mobilization and milk lipid content patterns. PMID- 29514893 TI - Exercise-induced adaptations to white and brown adipose tissue. AB - The beneficial effects of exercise on skeletal muscle and the cardiovascular system have long been known. Recent studies have focused on investigating the effects of exercise on adipose tissue and the effects that these exercise-induced adaptations have on overall metabolic health. Examination of exercise-induced adaptations in both white adipose tissue (WAT) and brown adipose tissue (BAT) has revealed marked differences in each tissue with exercise. In WAT, there are changes to both subcutaneous WAT (scWAT) and visceral WAT (vWAT), including decreased adipocyte size and lipid content, increased expression of metabolic genes, altered secretion of adipokines and increased mitochondrial activity. Adaptations specific to scWAT include lipidomic remodeling of phospholipids and, in rodents, the beiging of scWAT. The changes to BAT are less clear: studies evaluating the effect of exercise on the BAT of humans and rodents have revealed contradictory data, making this an important area of current investigation. In this Review, we discuss the exercise-induced changes to WAT and BAT that have been reported by different studies and highlight the current questions in this field. PMID- 29514895 TI - Correction to: Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction. PMID- 29514896 TI - Semen quality in patients with pituitary disease and adult-onset hypogonadotropic hypogonadism. AB - OBJECTIVE: Gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) are released from the pituitary gland and stimulate Leydig cells to produce testosterone and initiates spermatogenesis. Little is known about how and when the deterioration of semen quality occurs in patients with adult-onset gonadotropin insufficiency. DESIGN AND METHODS: A retrospective study comprising 20 testosterone-deficient men (median age, 29 years) with acquired pituitary disease who delivered semen for cryopreservation before initiation of testosterone therapy. Semen variables and hormone concentrations were compared to those of young healthy men (n = 340). RESULTS: Thirteen of 20 patients (65%) and 82% of controls had total sperm counts above 39 million and progressive motile spermatozoa above 32% (P = 0.05). For the individual semen variables, there were no significant differences in semen volume (median (intraquartile range) 3.0 (1.3 6.8) vs 3.2 (2.3-4.3) mL, P = 0.47), sperm concentration 41 (11-71) vs 43 (22-73) mill/mL (P = 0.56) or total sperm counts (P = 0.66). One patient had azoospermia. Patients vs controls had lower serum testosterone 5.4 (2.2-7.6) vs 19.7 (15.5 24.5) nmol/L (P = 0.001), calculated free testosterone (cfT) 145 (56-183) vs 464 (359-574) pmol/L (P < 0.001), LH 1.5 (1.1-2.1) vs 3.1 (2.3-4.0) U/L (P = 0.002) and inhibin b (P < 0.001). Levels of FSH were similar (P = 0.63). Testosterone/LH ratio and cfT/LH ratio were reduced in patients (both P < 0.001). CONCLUSIONS: Despite Leydig cell insufficiency in patients with acquired pituitary insufficiency, the majority presented with normal semen quality based on the determination of the number of progressively motile spermatozoa. In addition, the data suggest reduced LH bioactivity in patients with pituitary insufficiency. PMID- 29514897 TI - Sex differences in risk factors for subclinical hypothyroidism. AB - OBJECTIVE: To investigate the prevalence of subclinical hypothyroidism (SCH) in Korean adults and identify the risk factors for the occurrence of SCH by sex. DESIGN AND METHODS: This study used data from the Sixth Korea National Health and Nutrition Examination Survey (KNHANES VI), a cross-sectional, nationally representative survey, which comprises a health interview survey, a health examination survey and a nutrition survey. To examine SCH, the reference range of thyroid-stimulating hormone (TSH) was defined using both the range provided by the test kit manufacturer (SCH-M) and a population-based range (SCH-P). We investigated the prevalence of SCH and its risk factors by sex using both reference ranges. RESULTS: The prevalence of SCH in Koreans according to SCH-M (0.35-5.5 uIU/mL) was 5.6%, and 3.3% with SCH-P (0.62-6.68 uIU/mL). For men, smoking significantly reduced the incidence of SCH, positive anti-thyroid peroxidase antibody (TPOAb) significantly increased the risk of SCH, and in an adjusted model, the risk of SCH in all quartiles increased as the urine iodine creatinine ratio (UICR) quartile increased. For women, positive TPOAb was confirmed as a risk factor for SCH, as was the highest UICR quartile. Furthermore, the odds ratio for SCH in urban vs rural residence was 1.78. CONCLUSIONS: The prevalence rates of SCH were similar to those reported in the literature and previously known risk factors were confirmed using both TSH reference ranges. The notable findings from this study are that the increased risk of SCH with increased iodine intake was more marked in men than in women and that residential area may be a risk factor for SCH in women. PMID- 29514898 TI - Health status, quality of life and medical care in adult women with Turner syndrome. AB - BACKGROUND: Previous studies have shown that only a minority of patients with Turner syndrome (TS) have adequate medical care after transfer to adult care. AIM OF THIS STUDY: To assess the status of medical follow-up and quality of life (QoL) in adult women diagnosed with TS and followed up until transfer. To compare the subjective and objective view of the medical care quality and initiate improvements based on patients' experiences and current recommendations. METHODS: 39 adult women with TS out of 64 patients contacted were seen for a clinical and laboratory check, cardiac ultrasound, standardized and structured questionnaires (SF-36v2 and Beck depression inventory). RESULTS: 7/39 of the patients were not being followed medically at all. Only 2/39 consulted all the specialists recommended. Comorbidities were newly diagnosed in 27/39 patients; of these, 11 related to the cardiovascular system. Patients in our cohort scored as high as the mean reference population for SF-36v2 in both mental and physical compartments. Obese participants had lower scores in the physical function section, whereas higher education was related to higher physical QoL scores. Adult height slightly correlated positively with physical health. CONCLUSION: Medical follow-up was inadequate in our study cohort of adults with TS. Even though their medical follow-up was insufficient, these women felt adequately treated, leaving them vulnerable for premature illness. Initiatives in health autonomy and a structured transfer process as well as closer collaborations within specialities are urgently needed. PMID- 29514899 TI - Role of Microvesicles in the Spread of Herpes Simplex Virus 1 in Oligodendrocytic Cells. AB - Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establishes latent infections in the neurons of sensory ganglia. In some cases, the virus spreads into the central nervous system, causing encephalitis or meningitis. Cells infected with several different types of viruses may secrete microvesicles (MVs) containing viral proteins and RNAs. In some instances, extracellular microvesicles harboring infectious virus have been found. Here we describe the features of shedding microvesicles released by the human oligodendroglial HOG cell line infected with HSV-1 and their participation in the viral cycle. Using transmission electron microscopy, we detected for the first time microvesicles containing HSV-1 virions. Interestingly, the Chinese hamster ovary (CHO) cell line, which is resistant to infection by free HSV-1 virions, was susceptible to HSV-1 infection after being exposed to virus containing microvesicles. Therefore, our results indicate for the first time that MVs released by infected cells contain virions, are endocytosed by naive cells, and lead to a productive infection. Furthermore, infection of CHO cells was not completely neutralized when virus-containing microvesicles were preincubated with neutralizing anti-HSV-1 antibodies. The lack of complete neutralization and the ability of MVs to infect nectin-1/HVEM-negative CHO-K1 cells suggest a novel way for HSV-1 to spread to and enter target cells. Taken together, our results suggest that HSV-1 could spread through microvesicles to expand its tropism and that microvesicles could shield the virus from neutralizing antibodies as a possible mechanism to escape the host immune response.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establishes latent infections in neurons. Extracellular vesicles are a heterogeneous group of membrane vesicles secreted by most cell types. Microvesicles, which are extracellular vesicles which derive from the shedding of the plasma membrane, isolated from the supernatant of HSV-1-infected HOG cells were analyzed to find out whether they were involved in the viral cycle. The importance of our investigation lies in the detection, for the first time, of microvesicles containing HSV-1 virions. In addition, virus-containing microvesicles were endocytosed into CHO-K1 cells and were able to actively infect these otherwise nonpermissive cells. Finally, the infection of CHO cells with these virus-containing microvesicles was not completely neutralized by anti-HSV-1 antibodies, suggesting that these extracellular vesicles might shield the virus from neutralizing antibodies as a possible mechanism of immune evasion. PMID- 29514900 TI - Human T Lymphocytes Are Permissive for Dengue Virus Replication. AB - Dengue virus (DV) infection can cause either a self-limiting flu-like disease or a threatening hemorrhage that may evolve to shock and death. A variety of cell types, such as dendritic cells, monocytes, and B cells, can be infected by DV. However, despite the role of T lymphocytes in the control of DV replication, there remains a paucity of information on possible DV-T cell interactions during the disease course. In the present study, we have demonstrated that primary human naive CD4+ and CD8+ T cells are permissive for DV infection. Importantly, both T cell subtypes support viral replication and secrete viable virus particles. DV infection triggers the activation of both CD4+ and CD8+ T lymphocytes, but preactivation of T cells reduces the susceptibility of T cells to DV infection. Interestingly, the cytotoxicity-inducing protein granzyme A is highly secreted by human CD4+ but not CD8+ T cells after exposure to DV in vitro Additionally, using annexin V and polycaspase assays, we have demonstrated that T lymphocytes, in contrast to monocytes, are resistant to DV-induced apoptosis. Strikingly, both CD4+ and CD8+ T cells were found to be infected with DV in acutely infected dengue patients. Together, these results show that T cells are permissive for DV infection in vitro and in vivo, suggesting that this cell population may be a viral reservoir during the acute phase of the disease.IMPORTANCE Infection by dengue virus (DV) causes a flu-like disease that can evolve to severe hemorrhaging and death. T lymphocytes are important cells that regulate antibody secretion by B cells and trigger the death of infected cells. However, little is known about the direct interaction between DV and T lymphocytes. Here, we show that T lymphocytes from healthy donors are susceptible to infection by DV, leading to cell activation. Additionally, T cells seem to be resistant to DV induced apoptosis, suggesting a potential role as a viral reservoir in humans. Finally, we show that both CD4+ and CD8+ T lymphocytes from acutely infected DV patients are infected by DV. Our results raise new questions about DV pathogenesis and vaccine development. PMID- 29514901 TI - Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on MERS-CoV Spike to avoid neutralization escape. AB - Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or healthcare-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell-cloning strategy, we have identified and characterized multiple neutralizing mAbs specifically binding to the receptor binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific mAbs tended to have greater neutralizing potency than non-RBD S1-specific mAbs. Six RBD-specific and five S1-specific mAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined co-crystal structures for two mAbs targeting RBD from different angles and show they can only bind RBD in the "out" position. We then showed that selected RBD-specific, non-RBD S1, and S2-specific mAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD mAbs delayed the emergence of escape mutations in a cell-based virus-escape assay. These studies identify mAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization, and for developing more effective interventions to prevent or treat MERS-CoV infections.IMPORTANCE: MERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using structurally-defined probes for the MERS-CoV Spike (S) glycoprotein, the target for neutralizing antibodies, single B cells were sorted from a convalescent human and immunized non-human primates (NHPs). mAbs produced from paired immunoglobulin gene sequences were mapped to multiple epitopes within and outside the receptor-binding domain (RBD) and protected against lethal MERS infection in a murine model following passive immunization. Importantly, combining mAbs targeting distinct epitopes prevented viral neutralization escape from RBD-directed mAbs. These data suggest that antibody responses to multiple domains on CoV Spike may improve immunity and will guide future vaccine and therapeutic development efforts. PMID- 29514902 TI - Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection. AB - The mouse model of West Nile virus (WNV), which is a leading cause of mosquito borne encephalitis worldwide, has provided fundamental insights into the host and viral factors that regulate viral pathogenesis and infection outcome. In particular, CD8+ T cells are critical for controlling WNV replication and promoting protection against infection. Here, we present the characterization of a T cell receptor (TCR)-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein (here referred to as transgenic WNV-I mice). Using an adoptive-transfer model, we found that WNV-I CD8+ T cells behave similarly to endogenous CD8+ T cell responses, with an expansion phase in the periphery beginning around day 7 postinfection (p.i.) followed by a contraction phase through day 15 p.i. Through the use of in vivo intravascular immune cell staining, we determined the kinetics, expansion, and differentiation into effector and memory subsets of WNV-I CD8+ T cells within the spleen and brain. We found that red-pulp WNV-I CD8+ T cells were more effector-like than white-pulp WNV-I CD8+ T cells, which displayed increased differentiation into memory precursor cells. Within the central nervous system (CNS), we found that WNV-I CD8+ T cells were polyfunctional (gamma interferon [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]), displayed tissue-resident characteristics (CD69+ and CD103+), persisted in the brain through day 15 p.i., and reduced the viral burden within the brain. The use of these TCR-transgenic WNV-I mice provides a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection.IMPORTANCE West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. There are currently no approved therapeutics or vaccines for use in humans to treat or prevent WNV infection. CD8+ T cells are critical for controlling WNV replication and protecting against infection. Here, we present a comprehensive characterization of a novel TCR transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein. In this study, we determine the kinetics, proliferation, differentiation into effector and memory subsets, homing, and clearance of WNV in the CNS. Our findings provide a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection. PMID- 29514903 TI - Caspase-Dependent Suppression of Type I Interferon Signaling Promotes Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. AB - An important component of lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is the ability of the virus to evade the innate immune response, specifically type I interferon (IFN) responses that are triggered by recognition of viral nucleic acids. Inhibition of type I IFN responses by the virus promotes viral replication. Here, we report that KSHV uses a caspase dependent mechanism to block type I IFN, in particular IFN-beta, responses during lytic infection. Inhibition of caspases during KSHV reactivation resulted in increased TBK1/IKKepsilon-dependent phosphorylation of IRF3 as well as elevated levels of IFN-beta transcription and secretion. The increased secretion of IFN beta upon caspase inhibition reduced viral gene expression, viral DNA replication, and virus production. Blocking IFN-beta production or signaling restored viral replication. Overall, our results show that caspase-mediated regulation of pathogen sensing machinery is an important mechanism exploited by KSHV to evade innate immune responses.IMPORTANCE KSHV is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining tumor that is one of the most common causes of cancer death in sub-Saharan Africa. In this study, we examined the role of a set of cellular proteases, called caspases, in the regulation of immune responses during KSHV infection. We demonstrate that caspases prevent the induction and secretion of the antiviral factor IFN-beta during replicative KSHV infection. The reduced IFN-beta production allows for high viral gene expression and viral replication. Therefore, caspases are important for maintaining KSHV replication. Overall, our results suggest that KSHV utilizes caspases to evade innate immune responses, and that inhibiting caspases could boost the innate immune response to this pathogen and potentially be a new antiviral strategy. PMID- 29514904 TI - Experimental Analysis of Mimivirus Translation Initiation Factor 4a Reveals Its Importance in Viral Protein Translation during Infection of Acanthamoeba polyphaga. AB - The Acanthamoeba polyphaga mimivirus is the first giant virus ever described, with a 1.2-Mb genome which encodes 979 proteins, including central components of the translation apparatus. One of these proteins, R458, was predicted to initiate translation, although its specific role remains unknown. We silenced the R458 gene using small interfering RNA (siRNA) and compared levels of viral fitness and protein expression in silenced versus wild-type mimivirus. Silencing decreased the growth rate, but viral particle production at the end of the viral cycle was unaffected. A comparative proteomic approach using two-dimensional difference-in gel electrophoresis (2D-DIGE) revealed deregulation of the expression of 32 proteins in silenced mimivirus, which were defined as up- or downregulated. Besides revealing proteins with unknown functions, silencing R458 also revealed deregulation in proteins associated with viral particle structures, transcriptional machinery, oxidative pathways, modification of proteins/lipids, and DNA topology/repair. Most of these proteins belong to genes transcribed at the end of the viral cycle. Overall, our data suggest that the R458 protein regulates the expression of mimivirus proteins and, thus, that mimivirus translational proteins may not be strictly redundant in relation to those from the amoeba host. As is the case for eukaryotic initiation factor 4a (eIF4a), the R458 protein is the prototypical member of the ATP-dependent DEAD box RNA helicase mechanism. We suggest that the R458 protein is required to unwind the secondary structures at the 5' ends of mRNAs and to bind the mRNA to the ribosome, making it possible to scan for the start codon. These data are the first experimental evidence of mimivirus translation-related genes, predicted to initiate protein biosynthesis.IMPORTANCE The presence in the genome of a mimivirus of genes coding for many translational processes, with the exception of ribosome constituents, has been the subject of debate since its discovery in 2003. In this work, we focused on the R458 mimivirus gene, predicted to initiate protein biosynthesis. After silencing was performed, we observed that it has no major effect on mimivirus multiplication but that it affects protein expression and fitness. This suggests that it is effectively used by mimivirus during its developmental cycle. Until large-scale genetic manipulation of giant viruses becomes possible, the silencing strategy used here on mimivirus translation related factors will open the way to understanding the functions of these translational genes. PMID- 29514905 TI - Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection. AB - Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L * T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease.IMPORTANCE Acute viral infections are thought to be cleared by the host with few lasting consequences. However, there may be much broader and long-lasting effects of viruses on immune homeostasis. Infection with reovirus, a common, nonpathogenic virus, triggers inflammation against innocuous food antigens, implicating this virus in the development of celiac disease, an autoimmune intestinal disorder triggered by exposure to dietary gluten. Using two reovirus strains that differ in the capacity to abrogate oral tolerance, we found that strain-specific differences in the capacity to replicate in the intestine inversely correlate with the capacity to induce apoptotic death of intestinal epithelial cells, providing a host-mediated process to restrict intestinal infection. This work contributes new knowledge about virus-host interactions in the intestine and establishes a foundation for future studies to define mechanisms by which viruses break oral tolerance in celiac disease. PMID- 29514906 TI - A DNA Vaccine Expressing Consensus Hemagglutinin-Esterase Fusion Protein Protected Guinea Pigs from Infection by Two Lineages of Influenza D Virus. AB - Two lineages of influenza D virus (IDV) have been found to infect cattle and promote bovine respiratory disease complex, one of the most commonly diagnosed causes of morbidity and mortality within the cattle industry. Furthermore, IDV can infect other economically important domestic livestock, including pigs, and has the potential to infect humans, which necessitates the need for an efficacious vaccine. In this study, we designed a DNA vaccine expressing consensus hemagglutinin-esterase fusion (HEF) protein (FluD-Vax) and tested its protective efficacy against two lineages of IDV (D/OK and D/660) in guinea pigs. Animals that received FluD-Vax (n = 12) developed appreciable titers of neutralizing antibodies against IDV lineage representatives, D/OK and D/660. Importantly, vaccinated animals were protected against intranasal challenge with IDV [3 * 105 50% tissue culture infective dose(s) (TCID50)] D/OK (n = 6) or D/600 (n = 6), based on the absence of viral RNA in necropsied tissues (5 and 7 days postchallenge) using quantitative reverse transcription-PCR and in situ hybridization. In contrast, animals that received a sham DNA vaccine (n = 12) had no detectable neutralizing antibodies against IDV, and viral RNA was readily detectable in respiratory tract tissues after intranasal challenge (3 * 105 TCID50) with IDV D/OK (n = 6) or D/660 (n = 6). Using a TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay, we found that IDV D/OK and D/600 infections induced apoptosis in epithelial cells lining alveoli and bronchioles, as well as nonepithelial cells in lung tissues. Our results demonstrate for the first time that the consensus IDV HEF DNA vaccine can elicit complete protection against infection from two lineages of IDV in the guinea pig model.IMPORTANCE Influenza D virus (IDV) infection has been associated with bovine respiratory disease complex, one of the most devastating diseases of the cattle population. Moreover, with broad host range and high environmental stability, IDV has the potential to further gain virulence or even infect humans. An efficacious vaccine is needed to prevent infection and stop potential cross species transmission. In this study, we designed a DNA vaccine encoding the consensus hemagglutinin-esterase fusion (HEF) protein of two lineages of IDV (D/OK and D/660) and tested its efficacy in a guinea pig model. Our results showed that the consensus DNA vaccine elicited high-titer neutralizing antibodies and achieved sterilizing protection against two lineage-representative IDV intranasal infections. To our knowledge, this is the first study showing that a DNA vaccine expressing consensus HEF is efficacious in preventing different lineages of IDV infections. PMID- 29514907 TI - Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins. AB - Zaire and Sudan ebolavirus species cause a severe disease in humans and nonhuman primates (NHPs) characterized by a high mortality rate. There are no licensed therapies or vaccines against Ebola virus disease (EVD), and the recent 2013 to 2016 outbreak in West Africa highlighted the need for EVD-specific medical countermeasures. Here, we generated and characterized head-to-head the immunogenicity and efficacy of five vaccine candidates against Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing either the virus glycoprotein (GP) or GP together with the virus protein 40 (VP40) forming virus-like particles (VLPs). In a human monocytic cell line, the different MVA vectors (termed MVA EBOVs and MVA-SUDVs) triggered robust innate immune responses, with production of beta interferon (IFN-beta), proinflammatory cytokines, and chemokines. Additionally, several innate immune cells, such as dendritic cells, neutrophils, and natural killer cells, were differentially recruited in the peritoneal cavity of mice inoculated with MVA-EBOVs. After immunization of mice with a homologous prime/boost protocol (MVA/MVA), total IgG antibodies against GP or VP40 from Zaire and Sudan ebolavirus were differentially induced by these vectors, which were mainly of the IgG1 and IgG3 isotypes. Remarkably, an MVA-EBOV construct coexpressing GP and VP40 protected chimeric mice challenged with EBOV to a greater extent than a vector expressing GP alone. These results support the consideration of MVA-EBOVs and MVA-SUDVs expressing GP and VP40 and producing VLPs as best-in-class potential vaccine candidates against EBOV and SUDV.IMPORTANCE EBOV and SUDV cause a severe hemorrhagic fever affecting humans and NHPs. Since their discovery in 1976, they have caused several sporadic epidemics, with the recent outbreak in West Africa from 2013 to 2016 being the largest and most severe, with more than 11,000 deaths being reported. Although some vaccines are in advanced clinical phases, less expensive, safer, and more effective licensed vaccines are desirable. We generated and characterized head-to head the immunogenicity and efficacy of five novel vaccines against EBOV and SUDV based on the poxvirus MVA expressing GP or GP and VP40. The expression of GP and VP40 leads to the formation of VLPs. These MVA-EBOV and MVA-SUDV recombinants triggered robust innate and humoral immune responses in mice. Furthermore, MVA EBOV recombinants expressing GP and VP40 induced high protection against EBOV in a mouse challenge model. Thus, MVA expressing GP and VP40 and producing VLPs is a promising vaccine candidate against EBOV and SUDV. PMID- 29514908 TI - Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation. AB - Porcine circovirus type 2 (PCV2) capsid protein (Cap) is a unique structure protein that plays pivotal roles in the process of viral replication and pathogenesis. Herein, we characterized a putative porcine Makorin RING finger protein 1 (pMKRN1) variant, an N-terminal-truncated variant of putative full-size porcine MKRN1 which has a unique expression pattern resulting from the porcine mkrn1 gene and which interacts with PCV2 Cap. A domain mapping assay showed that the C terminus of pMKRN1 and fragments (amino acids 108 to 198) of Cap are required for this interaction. PCV2 transiently upregulated pMKRN1 in PK-15 cells, but persistent viral infection downregulated pMKRN1 in major pathological tissues of PCV2-infected piglets. Overexpression of pMKRN1 significantly inhibited the generation of progeny PCV2 via ubiquitination and degradation of Cap, whereas knockout of pMKRN1 blocked Cap degradation and promoted progeny virus replication. pMKRN1 specifically targeted PCV2 Cap lysine residues 164, 179, and 191 to induce polyubiquitination and subsequent degradation. Mutation of either of the three lysine residues in the Cap protein or mutation of the histidine at residue 243 within the RING finger domain of pMKRN1 abrogated the E3 ligase activity of pMKRN1, rendering cells incapable of inducing Cap ubiquitination and degradation. Consistent with this finding, a Cap ubiquitination-deficient PCV2 strain showed enhanced virus replication and produced severe histological lesions in the lung and lymph node tissues compared with wild-type PCV2. Taken together, the results presented here suggest that PCV2 downregulates the pMKRN1 variant to avoid pMKRN1-mediated Cap ubiquitination and degradation, thus promoting viral replication and pathogenesis in its targeted tissues.IMPORTANCE Porcine circovirus type 2 is the pathogen to which pigs are the most susceptible, causing immense economic losses in the global swine industry, but whether host cells have developed some strategies to prevent viral replication is still unclear. Here, we found that porcine MKRN1 (pMKRN1) was upregulated in the early stage of PCV2 infection and mediated the polyubiquitination and degradation of Cap protein to block PCV2 replication, yet persistent PCV2 infection downregulated pMKRN1 levels to avoid degradation, promoting viral replication and pathogenesis in its targeted tissues. These data present new insight into the molecular mechanisms underlying the antiviral effects of pMKRN1 E3 ligase during PCV2 infection and also suggest potential new control measures for PCV2 outbreaks. PMID- 29514910 TI - Depletion of the insulator protein CTCF results in HSV-1 reactivation in vivo. AB - Herpes Simplex Virus 1 (HSV-1) establishes a lifelong latent infection in host peripheral neurons including the neurons of the trigeminal ganglia (TG). HSV-1 can reactivate from neurons to cause recurrent infection. During latency, the insulator protein CTCF occupies DNA binding sites on the HSV-1 genome and these sites have been previously characterized as functional enhancer-blocking insulators. Previously, CTCF was found to be dissociated from wild type virus post-reactivation but not in mutants that do not reactivate, indicating that CTCF eviction may also be an important component of reactivation. To further elucidate the role of CTCF in reactivation of HSV-1, we used recombinant adeno-associated virus (rAAV) vectors to deliver an siRNA targeting CTCF to peripheral neurons latent with HSV-1 in rabbit TG. Our data show that CTCF depletion resulted in long-term and persistent shedding of infectious virus in the cornea and increased ICP0 expression in the ganglia, indicating that CTCF depletion facilitates HSV-1 reactivation.IMPORTANCE Increasing evidence has shown that the insulator protein CTCF regulates gene expression of DNA viruses, including the gammaherpesviruses. While CTCF occupation and insulator function control gene expression in DNA viruses, CTCF eviction has been correlated to increased lytic gene expression and the dissolution of transcriptional domains. Our previous data have shown that in the alphaherpesvirus HSV-1, CTCF was found to be dissociated from the HSV-1 genome post-reactivation, further indicating a global role for CTCF eviction in the transition from latency to reactivation in HSV-1 genomes. Using an rAAV8, we targeted HSV-1 infected peripheral neurons for CTCF depletion to show that CTCF depletion precedes the shedding of infectious virus and increased lytic gene expression in vivo, providing the first evidence that CTCF depletion facilitates HSV-1 reactivation. PMID- 29514909 TI - HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System. AB - The primate lentiviral accessory protein Nef downregulates CD4 and major histocompatibility complex class I (MHC-I) from the cell surface via independent endosomal trafficking pathways to promote viral pathogenesis. In addition, Nef antagonizes a novel restriction factor, SERINC5 (Ser5), to increase viral infectivity. To explore the molecular mechanism of Ser5 antagonism by Nef, we determined how Nef affects Ser5 expression and intracellular trafficking in comparison to CD4 and MHC-I. We confirm that Nef excludes Ser5 from human immunodeficiency virus type 1 (HIV-1) virions by downregulating its cell surface expression via similar functional motifs required for CD4 downregulation. We find that Nef decreases both Ser5 and CD4 expression at steady-state levels, which are rescued by NH4Cl or bafilomycin A1 treatment. Nef binding to Ser5 was detected in living cells using a bimolecular fluorescence complementation assay, where Nef membrane association is required for interaction. In addition, Nef triggers rapid Ser5 internalization via receptor-mediated endocytosis and relocalizes Ser5 to Rab5+ early, Rab7+ late, and Rab11+ recycling endosomes. Manipulation of AP-2, Rab5, Rab7, and Rab11 expression levels affects the Nef-dependent Ser5 and CD4 downregulation. Moreover, although Nef does not promote Ser5 polyubiquitination, Ser5 downregulation relies on the ubiquitination pathway, and both K48- and K63 specific ubiquitin linkages are required for the downregulation. Finally, Nef promotes Ser5 colocalization with LAMP1, which is enhanced by bafilomycin A1 treatment, suggesting that Ser5 is targeted to lysosomes for destruction. We conclude that Nef uses a similar mechanism to downregulate Ser5 and CD4, which sorts Ser5 into a point-of-no-return degradative pathway to counteract its restriction.IMPORTANCE Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) express an accessory protein called Nef to promote viral pathogenesis. Nef drives immune escape in vivo through downregulation of CD4 and MHC-I from the host cell surface. Recently, Nef was reported to counteract a novel host restriction factor, Ser5, to increase viral infectivity. Nef downregulates cell surface Ser5, thus preventing its incorporation into virus particles, resulting in disruption of its antiviral activity. Here, we report mechanistic studies of Nef-mediated Ser5 downregulation in comparison to CD4 and MHC-I. We demonstrate that Nef binds directly to Ser5 in living cells and that Nef-Ser5 interaction requires Nef association with the plasma membrane. Subsequently, Nef internalizes Ser5 from the plasma membrane via receptor mediated endocytosis, and targets ubiquitinated Ser5 to endosomes and lysosomes for destruction. Collectively, these results provide new insights into our ongoing understanding of the Nef-Ser5 arms race in HIV-1 infection. PMID- 29514911 TI - A Stem-Loop Structure in Potato Leafroll Virus Open Reading Frame 5 (ORF5) Is Essential for Readthrough Translation of the Coat Protein ORF Stop Codon 700 Bases Upstream. AB - Translational readthrough of the stop codon of the capsid protein (CP) open reading frame (ORF) is used by members of the Luteoviridae to produce their minor capsid protein as a readthrough protein (RTP). The elements regulating RTP expression are not well understood, but they involve long-distance interactions between RNA domains. Using high-resolution mass spectrometry, glutamine and tyrosine were identified as the primary amino acids inserted at the stop codon of Potato leafroll virus (PLRV) CP ORF. We characterized the contributions of a cytidine-rich domain immediately downstream and a branched stem-loop structure 600 to 700 nucleotides downstream of the CP stop codon. Mutations predicted to disrupt and restore the base of the distal stem-loop structure prevented and restored stop codon readthrough. Motifs in the downstream readthrough element (DRTE) are predicted to base pair to a site within 27 nucleotides (nt) of the CP ORF stop codon. Consistent with a requirement for this base pairing, the DRTE of Cereal yellow dwarf virus was not compatible with the stop codon-proximal element of PLRV in facilitating readthrough. Moreover, deletion of the complementary tract of bases from the stop codon-proximal region or the DRTE of PLRV prevented readthrough. In contrast, the distance and sequence composition between the two domains was flexible. Mutants deficient in RTP translation moved long distances in plants, but fewer infection foci developed in systemically infected leaves. Selective 2'-hydroxyl acylation and primer extension (SHAPE) probing to determine the secondary structure of the mutant DRTEs revealed that the functional mutants were more likely to have bases accessible for long-distance base pairing than the nonfunctional mutants. This study reveals a heretofore unknown combination of RNA structure and sequence that reduces stop codon efficiency, allowing translation of a key viral protein.IMPORTANCE Programmed stop codon readthrough is used by many animal and plant viruses to produce key viral proteins. Moreover, such "leaky" stop codons are used in host mRNAs or can arise from mutations that cause genetic disease. Thus, it is important to understand the mechanism(s) of stop codon readthrough. Here, we shed light on the mechanism of readthrough of the stop codon of the coat protein ORFs of viruses in the Luteoviridae by identifying the amino acids inserted at the stop codon and RNA structures that facilitate this "leakiness" of the stop codon. Members of the Luteoviridae encode a C terminal extension to the capsid protein known as the readthrough protein (RTP). We characterized two RNA domains in Potato leafroll virus (PLRV), located 600 to 700 nucleotides apart, that are essential for efficient RTP translation. We further determined that the PLRV readthrough process involves both local structures and long-range RNA-RNA interactions. Genetic manipulation of the RNA structure altered the ability of PLRV to translate RTP and systemically infect the plant. This demonstrates that plant virus RNA contains multiple layers of information beyond the primary sequence and extends our understanding of stop codon readthrough. Strategic targets that can be exploited to disrupt the virus life cycle and reduce its ability to move within and between plant hosts were revealed. PMID- 29514912 TI - Adenovirus Vector Vaccination Impacts NK Cell Rheostat Function following Lymphocytic Choriomeningitis Virus Infection. AB - Natural killer (NK) cells respond rapidly as a first line of defense against infectious pathogens. In addition, NK cells may provide a "rheostat" function and have been shown to reduce the magnitude of antigen-specific T cell responses following infection to avoid immunopathology. However, it remains unknown whether NK cells similarly modulate vaccine-elicited T cell responses following virus challenge. We used the lymphocytic choriomeningitis virus (LCMV) clone 13 infection model to address whether NK cells regulate T cell responses in adenovirus vector-vaccinated mice following challenge. As expected, NK cell depletion in unvaccinated mice resulted in increased virus-specific CD4+ and CD8+ T cell responses and immunopathology following LCMV challenge. In contrast, NK cell depletion had minimal to no impact on antigen-specific T cell responses in mice that were vaccinated with an adenovirus serotype 5 (Ad5)-GP vector prior to LCMV challenge. Moreover, NK cell depletion in vaccinated mice prior to challenge did not result in immunopathology and did not compromise protective efficacy. These data suggest that adenovirus vaccine-elicited T cells may be less sensitive to NK cell rheostat regulation than T cells primed by LCMV infection.IMPORTANCE Recent data have shown that NK cell depletion leads to enhanced virus-elicited T cell responses that can result in severe immunopathology following LCMV infection in mice. In this study, we observed that NK cells exerted minimal to no impact on vaccine-elicited T cells following LCMV challenge, suggesting that adenovirus vaccine-elicited T cells may be less subject to NK cell regulation. These data contribute to our understanding of NK cell regulatory functions and T cell-based vaccines. PMID- 29514913 TI - Contribution of NK Cell Education to both Direct and Anti-HIV-1 Antibody Dependent NK Cell Functions. AB - Antibody Fc-dependent functions are linked to prevention and control of HIV-1 infection. Basic NK cell biology is likely key to understanding the contributions that anti-HIV-1 antibody-dependent NK cell activation and cytolysis make to HIV-1 susceptibility and disease progression. The importance of NK cell education through inhibitory receptors specific for self-HLA-I in determining the potency of anti-HIV-1 antibody-mediated NK cell activation and cytolysis is controversial. To address this issue more definitively, we utilized HLA-I genotyping, flow cytometry staining panels, and cytolysis assays to assess the functionality of educated and noneducated peripheral blood NK cells. We now demonstrate that educated NK cells are superior in terms of their capacity to become activated and/or mediate cytolysis following anti-HIV-1 antibody-dependent stimulation. The profiles of activation observed were similar to those observed upon direct stimulation of NK cells with target cells devoid of HLA-I. Noneducated NK cells make significantly lower contributions to total NK cell activation than would be expected from their frequency within the total NK cell population (i.e., they are hypofunctional), and educated NK cells make contributions similar to or higher than their frequency in the total NK cell population. Finally, NK cells educated through at least one killer immunoglobulin like receptor and NKG2A exhibited the most significant difference between actual and expected contributions to the total NK cell response, based on their frequency within the total NK cell population, suggesting that summation of NK cell education through inhibitory receptors determines overall NK cell functionality. These observations have potential implications for understanding HIV-1 vaccine efficacy and disease progression.IMPORTANCE NK cells are major mediators of anti-HIV-1 antibody-dependent functions, including cytokine production and cytolysis. The mechanisms controlling the capacity of individual NK cells to mediate antibody-dependent functions remain poorly defined. We now show that NK cell education determines the capacity of NK cells to exhibit anti HIV-1 antibody-dependent activation and mediate antibody-dependent cellular cytotoxicity. These observations suggest that the process of NK cell education could be of importance for understanding HIV-1 pathogenesis and designing immune based prophylactics or therapeutics. PMID- 29514914 TI - Reduced cell-associated DNA and improved viral control in macaques following passive transfer of a single anti-V2 monoclonal antibody and repeated SHIV challenges. AB - A high level of V1V2-specific IgG antibodies in vaccinees' sera was the only independent variable that correlated with a reduced risk of HIV acquisition in the RV144 clinical trial. In contrast, IgG avidity, antibody neutralization, and antibody-dependent cellular cytotoxicity each failed as independent correlates of infection. Extended analyses of RV144 samples demonstrated antiviral activity of V1V2-specific vaccine-induced antibodies. V2-specific antibodies have also been associated with protection from SIV, and the V2i-specific subset of human monoclonal antibodies (mAbs), while poor neutralizers, mediate Fc-dependent antiviral functions in vitro The objective of this study was to determine the protective efficacy of a V2i-specific human mAb 830A against mucosal SHIV challenge. V2i mAb binding sites overlap the integrin binding site in the V2 region and are similar to the epitopes bound by antibodies associated with reduced HIV infection rate in RV144. Because the IgG3 subclass was a correlate of reduced infection rate in RV144, we compared passive protection by both IgG1 and IgG3 subclasses of V2i mAb 830A. This experiment represents the first in vivo test of the hypothesis emanating from RV144 and SIV studies that V2i Abs can reduce infection risk. The results show that passive transfer with a single V2i mAb, IgG1 830A, reduced plasma and PBMC virus levels and decreased viral DNA in lymphoid tissues compared to controls, but too few animals remained uninfected to achieve significance in reducing infection risk. Based on these findings, we conclude that V2i antibodies can impede viral seeding following mucosal challenge, resulting in improved viral control.IMPORTANCE Since the results of the HIV RV144 clinical trial were reported, there has been significant interest in understanding how protection was mediated. Antibodies directed to a subregion of the Envelope protein called V1V2 were directly correlated with reduced risk, and surprisingly low virus neutralization was observed. To determine whether these antibodies alone could mediate protection, we used a human monoclonal antibody directed to V2 with properties similar to those elicited in the vaccine trial for passive infusions in rhesus macaques and challenge with SHIV. The single V2 antibody at the dose given did not significantly reduce the number of infections, but there was a significant reduction in seeding of virus to the lymph nodes and a decrease in plasma viremia in the HIV antibody-infused macaques compared with the control antibody-infused animals. This finding shows that V2 antibodies mediate antiviral activities in vivo that could contribute to a protective HIV vaccine. PMID- 29514915 TI - Identification of H209 as Essential for pH 8-Triggered Receptor-Independent Syncytium Formation by S Protein of Mouse Hepatitis Virus A59. AB - The spike glycoprotein (S) of murine coronavirus mouse hepatitis virus (MHV) strain A59 uses murine carcinoembryonic antigen-related cell adhesion molecule 1a as its receptor for cell entry, but S protein can also be triggered in the absence of receptor by pH 8.0 alone at 37 degrees C. The mechanism by which conformational changes of this S glycoprotein can be triggered by pH 8.0 has not yet been determined. Here, we show that MHV-A59 S protein is triggered by pH 8.0 at 37 degrees C to induce receptor-independent syncytium (RIS) formation on 293T cells, and that the conformational changes in S proteins triggered by pH 8.0 are very similar to those triggered by receptor binding. We systemically mutated each of 15 histidine residues in S protein and found that H209 is essential for pH 8.0 triggered RIS formation, while H179, H441, H643, and H759 also play important roles in this process. Replacement of H209 with Ala had no effect on receptor binding, but in murine 17Cl.1 cells mutant H209A MHV-A59 showed delayed growth kinetics and was readily outcompeted by wild-type virus when mixed together, indicating that the H209A mutation caused a defect in virus fitness. Finally, the H209A mutation significantly increased the thermostability of S protein in its prefusion conformation, which may raise the energy barrier for conformational change of S protein required for membrane fusion and lead to a decrease in virus fitness in cell culture. Thus, MHV-A59 may have evolved to lower the stability of its S protein in order to increase virus fitness.IMPORTANCE Enveloped viruses enter cells through fusion of viral and cellular membranes, and the process is mediated by interactions between viral envelope proteins and their host receptors. In the prefusion conformation, viral envelope proteins are metastable, and activation to the fusion conformation is tightly regulated, since premature activation would lead to loss of viral infectivity. The stability of viral envelope proteins greatly influences their activation and virus fitness. Here, we report that, similar to the A82V mutation in Ebola glycoprotein, in the S glycoprotein of murine coronavirus MHV-A59, the histidine residue at position of 209 significantly affects the thermal stability of the S protein, determines whether S protein can be activated at 37 degrees C by either pH 8.0 alone or by receptor binding, and affects viral fitness in cell culture. Thus, the spike glycoprotein of MHV-A59 has evolved to retain histidine at position 209 to optimize virus fitness. PMID- 29514916 TI - CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. AB - Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss. CDK2-deficient mice displayed enhanced resistance to cisplatin toxicity in cochlear explants and to cisplatin- and noise-induced hearing loss in vivo. Mechanistically, we showed that kenpaullone directly inhibits CDK2 kinase activity and reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing cell survival. Our experiments have revealed the proapoptotic function of CDK2 in postmitotic cochlear cells and have identified promising therapeutics for preventing hearing loss. PMID- 29514917 TI - Bcl11b, a novel GATA3-interacting protein, suppresses Th1 while limiting Th2 cell differentiation. AB - GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells. PMID- 29514918 TI - CLAMP/Spef1 regulates planar cell polarity signaling and asymmetric microtubule accumulation in the Xenopus ciliated epithelia. AB - Most epithelial cells polarize along the axis of the tissue, a feature known as planar cell polarity (PCP). The initiation of PCP requires cell-cell signaling via the noncanonical Wnt/PCP pathway. Additionally, changes in the cytoskeleton both facilitate and reflect this polarity. We have identified CLAMP/Spef1 as a novel regulator of PCP signaling. In addition to decorating microtubules (MTs) and the ciliary rootlet, a pool of CLAMP localizes at the apical cell cortex. Depletion of CLAMP leads to the loss of PCP protein asymmetry, defects in cilia polarity, and defects in the angle of cell division. Additionally, depletion of CLAMP leads to a loss of the atypical cadherin-like molecule Celrs2, suggesting that CLAMP facilitates the stabilization of junctional interactions responsible for proper PCP protein localization. Depletion of CLAMP also affects the polarized organization of MTs. We hypothesize that CLAMP facilitates the establishment of cell polarity and promotes the asymmetric accumulation of MTs downstream of the establishment of proper PCP. PMID- 29514919 TI - The Rab11-binding protein RELCH/KIAA1468 controls intracellular cholesterol distribution. AB - Cholesterol, which is endocytosed to the late endosome (LE)/lysosome, is delivered to other organelles through vesicular and nonvesicular transport mechanisms. In this study, we discuss a novel mechanism of cholesterol transport from recycling endosomes (REs) to the trans-Golgi network (TGN) through RELCH/KIAA1468, which is newly identified in this study as a Rab11-GTP- and OSBP binding protein. After treating cells with 25-hydroxycholesterol to induce OSBP relocation from the cytoplasm to the TGN, REs accumulated around the TGN area, but this accumulation was diminished in RELCH- or OSBP-depleted cells. Cholesterol content in the TGN was decreased in Rab11-, RELCH-, and OSBP-depleted cells and increased in the LE/lysosome. According to in vitro reconstitution experiments, RELCH tethers Rab11-bound RE-like and OSBP-bound TGN-like liposomes and promotes OSBP-dependent cholesterol transfer from RE-like to TGN-like liposomes. These data suggest that RELCH promotes nonvesicular cholesterol transport from REs to the TGN through membrane tethering. PMID- 29514920 TI - Cell size-dependent regulation of Wee1 localization by Cdr2 cortical nodes. AB - Cell size control requires mechanisms that link cell growth with Cdk1 activity. In fission yeast, the protein kinase Cdr2 forms cortical nodes that include the Cdk1 inhibitor Wee1 along with the Wee1-inhibitory kinase Cdr1. We investigated how nodes inhibit Wee1 during cell growth. Biochemical fractionation revealed that Cdr2 nodes were megadalton structures enriched for activated Cdr2, which increases in level during interphase growth. In live-cell total internal reflection fluorescence microscopy videos, Cdr2 and Cdr1 remained constant at nodes over time, but Wee1 localized to nodes in short bursts. Recruitment of Wee1 to nodes required Cdr2 kinase activity and the noncatalytic N terminus of Wee1. Bursts of Wee1 localization to nodes increased 20-fold as cells doubled in size throughout G2. Size-dependent signaling was caused in part by the Cdr2 inhibitor Pom1, which suppressed Wee1 node bursts in small cells. Thus, increasing Cdr2 activity during cell growth promotes Wee1 localization to nodes, where inhibitory phosphorylation of Wee1 by Cdr1 and Cdr2 kinases promotes mitotic entry. PMID- 29514921 TI - Intimate partner violence against low-income women in Mexico City and associations with work-related disruptions: a latent class analysis using cross sectional data. AB - BACKGROUND: Disrupting women's employment is a strategy that abusive partners could use to prevent women from maintaining economic independence and stability. Yet, few studies have investigated disruptions in employment among victims of intimate partner violence (IPV) in low-income and middle-income countries. Moreover, even fewer have sought to identify which female victims of IPV are most vulnerable to such disruptions. METHODS: Using baseline data from 947 women in Mexico City enrolled in a randomised controlled trial, multilevel latent class analysis (LCA) was used to classify women based on their reported IPV experiences. Furthermore, multilevel logistic regression analyses were performed on a subsample of women reporting current work (n=572) to investigate associations between LCA membership and IPV-related employment disruptions. RESULTS: Overall, 40.6% of women who were working at the time of the survey reported some form of work-related disruption due to IPV. LCA identified four distinct classes of IPV experiences: Low Physical and Sexual Violence (39.1%); High Sexual and Low Physical Violence class (9.6%); High Physical and Low Sexual Violence and Injuries (36.5%); High Physical and Sexual Violence and Injuries (14.8%). Compared with women in the Low Physical and Sexual Violence class, women in the High Physical and Sexual Violence and Injuries class and women in the High Physical and Low Sexual Violence and Injuries class were at greater risk of work disruption (adjusted relative risk (ARR) 2.44, 95% CI 1.80 to 3.29; ARR 2.05, 95% CI 1.56 to 2.70, respectively). No other statistically significant associations emerged. CONCLUSION: IPV, and specific patterns of IPV experiences, must be considered both in work settings and, more broadly, by economic development programmes. TRIAL REGISTRATION NUMBER: NCT01661504. PMID- 29514922 TI - Relative deprivation and disordered gambling in youths. AB - BACKGROUND: Previous research has found that area-level income inequality and individual-level relative deprivation both contribute to disordered gambling in adults. However, the socioeconomic factors that contribute to disordered gambling in youths and protective factors in their social environment have not been fully explored. This study examined the association between relative deprivation and youth disordered gambling and the potential moderating role of social support in this association. METHODS: We used data on family material assets and self reported symptoms of disordered gambling symptoms in 19 321 participants of the 2013/2014 Italian Health Behaviour in School-aged Children study. Relative deprivation was measured using the Yitzhaki index and classmates as a social reference group. Its association with disordered gambling was tested using multilevel negative binomial regression analyses. We also tested moderated effects of relative deprivation on disordered gambling by four sources of social support: families, peers, teachers and classmates. RESULTS: Relative deprivation related to a fourfold increase in the rate of disordered gambling symptoms (incidence rate ratio=4.18) after differences in absolute family wealth and other variables were statistically controlled. Symptoms were also more prevalent in males, first-generation immigrants and less supported youth. Peer support moderated the association between relative deprivation and symptoms, suggesting that high deprivation and low peer support have interactive links to disordered gambling. CONCLUSION: Relative deprivation among classmates relate to youth symptoms of disordered gambling. Youth who live in economically unequal settings and perceive a lack of social support may be at greatest risk. PMID- 29514923 TI - Has the UK Healthy Start voucher scheme been associated with an increased fruit and vegetable intake among target families? Analysis of Health Survey for England data, 2001-2014. AB - BACKGROUND: Healthy Start (HS) is a UK government programme, introduced in 2006, providing vouchers to pregnant women or families with children aged <4 who are in receipt of certain benefits. Vouchers can be exchanged for fruit and vegetables (F&V), milk or infant formula. We sought to identify any association between HS and F&V intake. METHODS: We analysed repeated cross-sectional data from the Health Survey for England. Study participants were classified into one of four groups: one HS-eligible group and three control groups, meeting only the income or demographic or no eligibility criterion. Outcome measures were mean F&V intake and the proportions of participants consuming >=3 and >=1 portion/day. Outcomes were compared across the four groups over four time periods: 2001-2003, 2004 2006, 2007-2009 and 2010-2014. Regression analyses examined whether F&V intake among HS-eligible participants had a significantly different rate of change from those in the control groups. RESULTS: The change in mean F&V consumption over time was similar in HS-eligible adults and children to that of the control groups. Likewise, the change in odds of consuming >=3 or >=1 portion of F&V/day over time was similar among HS-eligible participants and control groups. CONCLUSION: This study found that during the period 2001-2003 to 2010-2014, F&V consumption among adults and children in households deemed eligible for HS changed similarly to that of other adults and children. Potential explanations include that vouchers may have been spent on milk or infant formula, or that vouchers helped protect F&V consumption in low-income households. PMID- 29514925 TI - Obesity and its association with sociodemographic factors, health behaviours and health status among Aboriginal and non-Aboriginal adults in New South Wales, Australia. AB - BACKGROUND: High body mass index (BMI) is the second leading contributor to Australia's burden of disease and is particularly prevalent among Aboriginal peoples. This paper aims to provide insight into factors relating to obesity among Aboriginal adults and Aboriginal-non-Aboriginal differences. METHODS: Cross sectional analysis of data from the 45 and Up Study, comparing obesity (BMI >=30 kg/m2) prevalence and risk factors among 1515 Aboriginal and 213 301 non Aboriginal adults in New South Wales. Age-sex-adjusted prevalence ratios (PRs) for obesity by sociodemographic factors, health behaviours and health status were estimated (multivariable log-binomial regression) for Aboriginal and non Aboriginal participants separately. We quantified the extent to which key factors (physical activity, screen time, education, remoteness, area-level disadvantage) accounted for any excess Aboriginal obesity prevalence. RESULTS: Obesity prevalence was 39% among Aboriginal and 22% among non-Aboriginal participants (PR=1.65, 95% CI 1.55 to 1.76). Risk factors for obesity were generally similar for Aboriginal and non-Aboriginal participants and included individual-level and area-level disadvantage, physical inactivity, and poor physical and mental health, with steeper gradients observed among non-Aboriginal participants for some factors (Pinteraction <0.05). Many risk factors were more common among Aboriginal versus non-Aboriginal participants; key factors accounted for >40% of the excess Aboriginal obesity prevalence. CONCLUSION: A substantial proportion of the excess obesity prevalence among Aboriginal versus non-Aboriginal participants was explained by physical activity, screen time, education, remoteness and area level disadvantage. Socioeconomic and health behaviour factors are potential targets for promoting healthy BMI, but these must be considered within the context of upstream social and cultural factors. Adults with health needs and disability require particular attention. PMID- 29514924 TI - Secular change in the association between urbanisation and abdominal adiposity in China (1993-2011). AB - BACKGROUND: Little attention has been paid to how the association between urbanisation and abdominal adiposity changes over the course of economic development in low-income and middle-income countries. METHODS: Data came from the China Health and Nutrition Survey waves 1993-2011 (seven waves). A mixed linear model was used to investigate the association between community-level urbanisation with waist-to-height ratio (WHtR; an indicator of abdominal adiposity). We incorporated interaction terms between urbanisation and study waves to understand how the association changed over time. The analyses were stratified by age (children vs adults). RESULTS: Adult WHtR was positively associated with urbanisation in earlier waves but became inversely associated over time. More specifically, a 1 SD increase in the urbanisation index was associated with higher WHtR by 0.002 and 0.005 in waves 1993 and 1997, while it was associated with lower WHtR by 0.001 in 2011. Among child participants, the increase in WHtR over time was predominantly observed in more urbanised communities. CONCLUSION: Our study suggests a shift in adult abdominal adiposity from more urbanised communities to less urbanised communities over a time of rapid economic development in China. Children living in more urbanised communities had higher increase in abdominal obesity with urbanisation over time relative to children living in less urbanised communities. PMID- 29514926 TI - Community-based stroke system of care improves patient outcomes in Chinese rural areas. AB - BACKGROUND: Building effective and efficient stroke care systems is a key step in improving prevention, treatment and rehabilitation of stroke. The aim of this study was to evaluate the effectiveness of this stroke system of care on stroke management during a 2-year follow-up. METHODS: A stroke system of care was developed from November 2009 to November 2010 in three townships in Ganyu County. Additional three matched townships were invited as controls. We first investigated the stroke incidence of these populations. Subsequently, this stroke system of care and an educational campaign in the three intervention townships were implemented and the effectiveness of the system was evaluated in the next 2 years. RESULTS: At postintervention, more patients in the intervention communities obtained stroke knowledge and then the proportion of patients with stroke who were admitted within 3 hours of onset markedly increased in 2012 (12.0% vs 8.1%, p=0.044) and in 2013 (15.2% vs 9.7%, p=0.008) compared with those in the control communities. In the intervention communities, this proportion of patients with acute ischaemic stroke who received thrombolytic treatment was markedly raised from 2.1% in 2012 to 3.0% in 2013. More importantly, the fatality rate substantially decreased in 2013 in the intervention communities compared with that in the control communities (6.1% vs 9.7%, p=0.032). Similarly, the disability rate significantly decreased in 2013 (45.3% vs 51.5%, p=0.045). CONCLUSIONS: The community-based stroke system of care was effective and practical for optimising stroke treatments and improving patient outcomes. TRIAL REGISTRATION NUMBER: ChiCTR-RCH-13003408, Post-results. PMID- 29514927 TI - A VCP inhibitor substrate trapping approach (VISTA) enables proteomic profiling of endogenous ERAD substrates. AB - Endoplasmic reticulum (ER)-associated degradation (ERAD) mediates the proteasomal clearance of proteins from the early secretory pathway. In this process, ubiquitinated substrates are extracted from membrane-embedded dislocation complexes by the AAA ATPase VCP and targeted to the cytosolic 26S proteasome. In addition to its well-established role in the degradation of misfolded proteins, ERAD also regulates the abundance of key proteins such as enzymes involved in cholesterol synthesis. However, due to the lack of generalizable methods, our understanding of the scope of proteins targeted by ERAD remains limited. To overcome this obstacle, we developed a VCP inhibitor substrate trapping approach (VISTA) to identify endogenous ERAD substrates. VISTA exploits the small-molecule VCP inhibitor CB5083 to trap ERAD substrates in a membrane-associated, ubiquitinated form. This strategy, coupled with quantitative ubiquitin proteomics, identified previously validated (e.g., ApoB100, Insig2, and DHCR7) and novel (e.g., SCD1 and RNF5) ERAD substrates in cultured human hepatocellular carcinoma cells. Moreover, our results indicate that RNF5 autoubiquitination on multiple lysine residues targets it for ubiquitin and VCP--dependent clearance. Thus, VISTA provides a generalizable discovery method that expands the available toolbox of strategies to elucidate the ERAD substrate landscape. PMID- 29514928 TI - The I1 dynein-associated tether and tether head complex is a conserved regulator of ciliary motility. AB - Motile cilia are essential for propelling cells and moving fluids across tissues. The activity of axonemal dynein motors must be precisely coordinated to generate ciliary motility, but their regulatory mechanisms are not well understood. The tether and tether head (T/TH) complex was hypothesized to provide mechanical feedback during ciliary beating because it links the motor domains of the regulatory I1 dynein to the ciliary doublet microtubule. Combining genetic and biochemical approaches with cryoelectron tomography, we identified FAP44 and FAP43 (plus the algae-specific, FAP43-redundant FAP244) as T/TH components. WT mutant comparisons revealed that the heterodimeric T/TH complex is required for the positional stability of the I1 dynein motor domains, stable anchoring of CK1 kinase, and proper phosphorylation of the regulatory IC138-subunit. T/TH also interacts with inner dynein arm d and radial spoke 3, another important motility regulator. The T/TH complex is a conserved regulator of I1 dynein and plays an important role in the signaling pathway that is critical for normal ciliary motility. PMID- 29514929 TI - Fluorescence fluctuation spectroscopy reveals differential SUN protein oligomerization in living cells. AB - Linker-of-nucleoskeleton-and-cytoskeleton (LINC) complexes are conserved molecular bridges within the nuclear envelope that mediate mechanical force transmission into the nucleoplasm. The core of a LINC complex is formed by a transluminal interaction between the outer and inner nuclear membrane KASH and SUN proteins, respectively. Mammals encode six KASH proteins and five SUN proteins. Recently, KASH proteins were shown to bind to the domain interfaces of trimeric SUN2 proteins in vitro. However, neither the existence of SUN2 trimers in living cells nor the extent to which other SUN proteins conform to this assembly state have been tested experimentally. Here we extend the application of fluorescence fluctuation spectroscopy to quantify SUN protein oligomerization in the nuclear envelopes of living cells. Using this approach, we demonstrate for the first time that SUN2 trimerizes in vivo and we demonstrate that the in vivo oligomerization of SUN1 is not limited to a trimer. In addition, we provide evidence to support the existence of potential regulators of SUN protein oligomerization in the nuclear envelope. The differential SUN protein oligomerization illustrated here suggests that SUN proteins may have evolved to form different assembly states in order to participate in diverse mechanotransduction events. PMID- 29514930 TI - Inositol polyphosphate multikinase regulation of Trypanosoma brucei life stage development. AB - Many cellular processes change during the Trypanosoma brucei life cycle as this parasite alternates between the mammalian host and tsetse fly vector. We show that the inositol phosphate pathway helps regulate these developmental changes. Knockdown of inositol polyphosphate multikinase (IPMK), which phosphorylates Ins(1,4,5)P3 and Ins(1,3,4,5)P4, resulted in changes in bloodstream forms that are characteristic of insect stage procyclic forms. These changes include expression of the procyclic surface coat, up-regulation of RNA-binding proteins that we show to regulate stage-specific transcripts, and activation of oxidative phosphorylation with increased ATP production in bloodstream forms. These changes were accompanied by development of procyclic morphology, which also occurred by the expression of a catalytically inactive IPMK, implying that regulation of these processes entails IPMK activity. Proteins involved in signaling, protein synthesis and turnover, and metabolism were affinity-enriched with the IPMK substrate or product. Developmental changes associated with IPMK knockdown or catalytic inactivation reflected processes that are enriched with inositol phosphates, and chemical and genetic perturbation of these processes affected T. brucei development. Hence, IPMK helps regulate T. brucei development, perhaps by affecting inositol phosphate interactions with proteins of the regulatory network that controls energy metabolism and development. PMID- 29514931 TI - Voltage-gated potassium channel blocker 4-aminopyridine induces glioma cell apoptosis by reducing expression of microRNA-10b-5p. AB - Accumulating evidence has demonstrated that voltage-gated potassium channels (Kv channels) were associated with regulating cell proliferation and apoptosis in tumor cells. Our previous study proved that the Kv channel blocker 4 aminopyridine (4-AP) could inhibit cell proliferation and induce apoptosis in glioma. However, the precise mechanisms were not clear yet. MicroRNAs (miRNAs) are small noncoding RNAs that act as key mediators in the progression of tumor, so the aim of this study was to investigate the role of miRNAs in the apoptosis promoting effect of 4-AP in glioma cells. Using a microRNA array, we found that 4 AP altered the miRNA expression in glioma cells, and the down-regulation of miR 10b-5p induced by 4-AP was verified by real-time PCR. Transfection of miR-10b-5p mimic significantly inhibited 4-AP-induced caspases activation and apoptosis. Moreover, we verified that apoptosis-related molecule Apaf-1 was the direct target of miR-10b-5p. Furthermore, miR-10b-5p mimic significantly inhibited 4-AP induced up-regulation of Apaf-1 and its downstream apoptosis-related proteins, such as cleaved caspase-3. In conclusion, Kv channel blocker 4-AP may exert its anti-tumor effect by down-regulating the expression of miR-10b-5p and then raised expression of Apaf-1 and its downstream apoptosis-related proteins. Current data provide evidence that miRNAs play important roles in Kv channels-mediated cell proliferation and apoptosis. PMID- 29514932 TI - A newly characterized vacuolar serine carboxypeptidase, Atg42/Ybr139w, is required for normal vacuole function and the terminal steps of autophagy in the yeast Saccharomyces cerevisiae. AB - Macroautophagy (hereafter autophagy) is a cellular recycling pathway essential for cell survival during nutrient deprivation that culminates in the degradation of cargo within the vacuole in yeast and the lysosome in mammals, followed by efflux of the resultant macromolecules back into the cytosol. The yeast vacuole is home to many different hydrolytic proteins and while few have established roles in autophagy, the involvement of others remains unclear. The vacuolar serine carboxypeptidase Y (Prc1) has not been previously shown to have a role in vacuolar zymogen activation and has not been directly implicated in the terminal degradation steps of autophagy. Through a combination of molecular genetic, cell biological, and biochemical approaches, we have shown that Prc1 has a functional homologue, Ybr139w, and that cells deficient in both Prc1 and Ybr139w have defects in autophagy-dependent protein synthesis, vacuolar zymogen activation, and autophagic body breakdown. Thus, we have demonstrated that Ybr139w and Prc1 have important roles in proteolytic processing in the vacuole and the terminal steps of autophagy. PMID- 29514933 TI - The yeast arrestin-related protein Bul1 is a novel actor of glucose-induced endocytosis. AB - Yeast cells have a remarkable ability to adapt to nutritional changes in their environment. During adaptation, nutrient-signaling pathways drive the selective endocytosis of nutrient transporters present at the cell surface. A current challenge is to understand the mechanistic basis of this regulation. Transporter endocytosis is triggered by their ubiquitylation, which involves the ubiquitin ligase Rsp5 and its adaptors of the arrestin-related family (ART). This step is highly regulated by nutrient availability. For instance, the monocarboxylate transporter Jen1 is ubiquitylated, endocytosed, and degraded upon exposure to glucose. The ART protein Rod1 is required for this overall process; yet Rod1 rather controls Jen1 trafficking later in the endocytic pathway and is almost dispensable for Jen1 internalization. Thus, how glucose triggers Jen1 internalization remains unclear. We report that another ART named Bul1, but not its paralogue Bul2, contributes to Jen1 internalization. Bul1 responds to glucose availability, and preferentially acts at the plasma membrane for Jen1 internalization. Thus, multiple ARTs can act sequentially along the endocytic pathway to control transporter homeostasis. Moreover, Bul1 is in charge of Jen1 endocytosis after cycloheximide treatment, suggesting that the functional redundancy of ARTs may be explained by their ability to interact with multiple cargoes in various conditions. PMID- 29514934 TI - Potential Point-of-Care Testing for Dengue Virus in the Field. AB - The four serotypes of dengue virus (DENV) cause one of the most important and rapidly emerging mosquito-borne viral diseases in humans. Of the currently available diagnostic tests for dengue, the reverse transcription-PCR (RT-PCR) assay is the most sensitive and specific, and so it is commonly used as the gold standard. However, the requirement of a sophisticated and expensive thermal cycler makes it very difficult to use as a point-of-care diagnostic test in resource-limited regions where dengue is endemic. Tsai et al. (J Clin Microbiol 56:e01865-17, 2018, https://doi.org/10.1128/JCM.01865-17) report the analytical and clinical performances of a reverse transcription-insulated isothermal PCR (RT iiPCR) assay with a portable nucleic acid analyzer for rapid detection of the four DENV serotypes; its reproducibility and complete agreement on clinical samples with the multiplex RT-PCR assay developed by the Centers for Disease Control and Prevention suggest that the dengue RT-iiPCR is a potential point-of care test. Compared with other DENV RNA detection methods, the unique isothermal PCR design of RT-iiPCR, together with further improvements, would represent a promising new type of field-deployable diagnostic test for dengue. PMID- 29514935 TI - Rapid Molecular Detection of Gastrointestinal Pathogens and Its Role in Antimicrobial Stewardship. AB - We aimed to detect the etiological agents of acute diarrhea by a molecular gastrointestinal pathogen test (MGPT) and to assess the impact of MGPT on antimicrobial stewardship programs (ASP). This is a prospective observational study and was conducted between 1 January 2015 and 30 June 2017. We included consequent patients who had acute diarrhea. At the end of 2015, we implemented ASP in acute diarrhea cases and compared the outcomes in the pre-ASP and post-ASP periods. An FDA-cleared multiplexed gastrointestinal PCR panel system, the BioFire FilmArray (Idaho Technology, Salt Lake City, UT), which detects 20 pathogens in stool, was used. In 499 out of 699 patients (71%), at least one pathogen was detected. Among 314 adults with positive MGPT, 101 (32%) enteropathogenic Escherichia coli (EPEC), 71 (23%) enteroaggregative E. coli (EAEC), 68 (22%) enterotoxigenic E. coli (ETEC), 55 (18%) Shiga toxin-producing E. coli (STEC) (17%) Norovirus, 48 (15%) Campylobacter, 21 (7%) Salmonella, and 20 (6%) Clostridium difficile strains were detected. Among 185 children, 55 (30%) EPEC, 37 (20%) C. difficile, 32 (17%) Norovirus, 29 (16%) EAEC, 22 (12%) STEC, 21 (11%) ETEC, 21 (11%) Campylobacter, 20 (11%) Salmonella, and 16 (5%) Rotavirus strains were detected. Inappropriate antibiotic use decreased in the post-ASP period compared with the pre-ASP period among inpatients (42.9% and 25.8%, respectively; P = 0.023). Using MGPT in clinical practice significantly decreased the unnecessary use of antibiotics. Detection of high rates of C. difficile in children and Salmonella spp., as well as relatively high rates of Campylobacter spp., which were hard to isolate by routine stool culture, were remarkable. PMID- 29514936 TI - Multi- and Extensively Drug Resistant Mycobacterium tuberculosis in South Africa: a Molecular Analysis of Historical Isolates. AB - Modern advances in genomics provide an opportunity to reinterpret historical bacterial culture collections. In this study, genotypic antibiotic resistance profiles of Mycobacterium tuberculosis isolates from a historical 20-year-old multidrug-resistant tuberculosis (MDR-TB) culture collection in South Africa are described. DNA samples extracted from the phenotypically MDR-TB isolates (n = 240) were assayed by Hain line probe assay (LPA) for the confirmation of MDR-TB and by Illumina Miseq whole-genome sequencing (WGS) for the characterization of mutations in eight genes (rpoB, katG, inhA, rpsL, pncA, embB, gyrA, and rrs) that are known to code for resistance to commonly used anti-TB agents. LPA identified 71.3% of the TB isolates as MDR-TB, 18.3% as rifampin (RIF) monoresistant, 2% as isoniazid (INH) monoresistant, and 8.3% as susceptible to both RIF and INH (RIF+INH). In a subset of 42 randomly selected isolates designated as RIF+INH resistant by Lowenstein-Jensen (LJ) culture in 1993, LPA and WGS results confirmed MDR-TB. In all five INH-monoresistant isolates by LPA and in all but one (the wild type) of the 34 successfully sequenced RIF-monoresistant isolates, WGS revealed matching mutations. Only 26% of isolates designated as susceptible by LPA, however, were found to be wild type by WGS. Novel mutations were found in the rpoB (Thr480Ala, Gln253Arg, Val249Met, Val251Tyr, Val251Phe), katG (Trp477STOP, Gln88STOP, Trp198STOP, Trp412STOP), embB (Thr11Xaa, Gln59Pro), and pncA (Thr100Ile, Thr159Ala, Ala134Arg, Val163Ala, Thr153Ile, DelGpos7, Phe106Ser) genes. Three MDR-TB isolates showed mutations in both the gyrA and rrs genes, suggesting that extensively drug-resistant tuberculosis existed in South Africa well before its formal recognition in 2006. PMID- 29514937 TI - An Improved Medium for Colistin Susceptibility Testing. AB - The plasmid-located colistin resistance gene mcr-1 confers low-level resistance to colistin, a last-line antibiotic against multidrug-resistant Gram-negative bacteria. Current CLSI-EUCAST recommendations require the use of a broth microdilution (BMD) method with cation-adjusted Mueller-Hinton (CA-MH) medium for colistin susceptibility testing, but approximately 15% of all MCR-1 producers are classified as sensitive in that broth. Here we report on an improved calcium enhanced Mueller-Hinton (CE-MH) medium that permits simple and reliable determination of mcr-1-containing Enterobacteriaceae Colistin susceptibility testing was performed for 50 mcr-1-containing Escherichia coli and Klebsiella pneumoniae isolates, 7 intrinsically polymyxin-resistant species, K. pneumoniae and E. coli isolates with acquired resistance to polymyxins due to mgrB and pmrB mutations, respectively, and 32 mcr-1-negative, colistin-susceptible isolates of Acinetobacter baumannii, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, and Salmonella enterica serovar Typhimurium. A comparison of the colistin MICs determined in CA-MH medium and those obtained in CE-MH medium was performed using both the BMD and strip-based susceptibility test formats. We validated the data using an isogenic IncX4 plasmid lacking mcr-1 Use of the CE-MH broth provides clear separation between resistant and susceptible isolates in both BMD and gradient diffusion assays; this is true for both mcr-1-containing Enterobacteriaceae isolates and those exhibiting either intrinsic or acquired colistin resistance. CE-MH medium is simple to prepare and overcomes current problems associated with BMD and strip-based colistin susceptibility testing, and use of the medium is easy to implement in routine diagnostic laboratories, even in resource-poor settings. PMID- 29514938 TI - Comprehensive Molecular Approach for Characterization of Hepatitis E Virus Genotype 3 Variants. AB - Autochthonous hepatitis E virus genotype 3 (HEV-3) infections in industrialized countries are more frequent than previously assumed. HEV-3 is zoonotic and the causal pathogen of chronic hepatitis E. According to the latest classification of the family Hepeviridae, 10 designated HEV-3 subtypes (HEV-3a to HEV-3j) and 7 unassigned HEV-3 subtypes are proposed. In order to identify and characterize the HEV-3 variants in circulation, we developed a molecular approach combining a sensitive HEV-specific real-time reverse transcription-PCR (RT-PCR) targeting the overlapping region of HEV ORF2 and ORF3 (the ORF2/3 region) and two newly designed consensus nested RT-PCRs targeting the HEV ORF1 and ORF2 genes, respectively. Since complete genome sequences are required for new HEV-3 subtype assignment, we implemented a straightforward approach for full-length HEV-3 genome amplification. Twenty-nine human serum samples and six human feces samples from chronic hepatitis E patients were selected for evaluation of the system. Viral loads ranged from 1 * 104 to 1.9 * 1010 copies/ml of serum and from 1.8 * 104 to 1 * 1012 copies/g of feces. Sequence and phylogenetic analyses of partial ORF1 and ORF2 sequences showed that HEV strains had considerable genetic diversity and clustered into the HEV-3c (29/35), HEV-3e (2/35), HEV-3f (2/35), and unassigned HEV-3 (2/35) subtypes. Moreover, from these strains, three full length HEV-3 genome sequences were generated and characterized. DE/15-0030 represents a typical HEV-3c strain (95.7% nucleotide identity to wbGER27), while DE/15-0031 and SW/16-0282 have <89.2% homology to known HEV-3 strains and are phylogenetically divergent, indicating novel HEV-3 subtypes. In summary, our approach will significantly facilitate the detection, quantification, and determination of HEV-3 strains and will thus help to improve molecular diagnostics and our knowledge of HEV diversity and evolution. PMID- 29514939 TI - Improved Discrimination of Bacillus anthracis from Closely Related Species in the Bacillus cereus Sensu Lato Group Based on Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. AB - Discrimination of highly pathogenic bacteria, such as Bacillus anthracis, from closely related species based on molecular biological methods is challenging. We applied matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to a collection of B. anthracis strains and close relatives in order to significantly improve the statistical confidence of identification results for this group of bacteria. Protein mass spectra of 189 verified and diverse Bacillus strains of the Bacillus cereus sensu lato group were generated using MALDI-TOF MS and subsequently analyzed with supervised and unsupervised statistical methods, such as shrinkage discriminant analysis (SDA) and principal-component analysis (PCA). We aimed at identifying specific biomarkers in the protein spectra of B. anthracis not present in closely related Bacillus species. We could identify 7, 10, 18, and 14 B. anthracis-specific biomarker candidates that were absent in B. cereus, B. mycoides, B. thuringiensis, and B. weihenstephanensis strains, respectively. Main spectra (MSP) of a defined collection of Bacillus strains were compiled using the Bruker Biotyper software and added to an in-house reference library. Reevaluation of this library with 15 hitherto untested strains of B. anthracis and B. cereus yielded improved score values. The B. anthracis strains were identified with score values between 2.33 and 2.55 using the in-house database, while the same strains were identified with scores between 1.94 and 2.37 using the commercial database, and no false-positive identifications occurred using the in-house database. PMID- 29514941 TI - Correction. PMID- 29514940 TI - Visible DNA Microarray System as an Adjunctive Molecular Test in Identification of Pathogenic Fungi Directly from a Blood Culture Bottle. AB - A DNA microarray platform, based on the nucleotide sequences of the internal transcribed spacer regions (ITS1 and ITS2) of the rRNA gene, was developed to identify 32 fungal pathogens at the species level. The probe sequences were spotted onto polycarbonate slides with a mini-microarray printer, and after the hybridization, the results were visible with the naked eye. The performance of the microarray platform was evaluated against the commercial automated systems (Vitek 2 and BD Phoenix systems) and DNA sequencing (gold standard). A total of 461 blood culture bottles were tested: 127 positive for fungi, 302 positive for bacteria, and 32 that were negative. Once the microorganisms were identified by automated systems, fungal DNA was extracted directly from the blood culture bottles. The DNA products were tested using the microarray platform, and DNA sequencing was performed. The results of the microarray and DNA sequencing were concordant in 96.7% of cases, and the results from the automated systems and DNA sequencing were concordant in 98.4%. Of all the nucleotide sequences contained in the microarray platform, the microarray failed to identify four fungal isolates (one Candida parapsilosis, two Candida tropicalis, and one Cryptococcus neoformans). Of note, the microarray detected Candida krusei DNA in two blood cultures from the same patient, whereas the automated system was only positive for Enterococcus faecium Our microarray system provided reliable and fast fungal identification compared to that from DNA sequencing and the automated systems. The simplicity of reading the results by the naked eye made this DNA platform a suitable method for fungal molecular diagnosis. PMID- 29514942 TI - RecQ Helicases Function in Development, DNA Repair, and Gene Targeting in Physcomitrella patens. AB - RecQ DNA helicases are genome surveillance proteins found in all kingdoms of life. They are characterized best in humans, as mutations in RecQ genes lead to developmental abnormalities and diseases. To better understand RecQ functions in plants we concentrated on Arabidopsis thaliana and Physcomitrella patens, the model species predominantly used for studies on DNA repair and gene targeting. Phylogenetic analysis of the six P. patens RecQ genes revealed their orthologs in humans and plants. Because Arabidopsis and P. patens differ in their RecQ4 and RecQ6 genes, reporter and deletion moss mutants were generated and gene functions studied in reciprocal cross-species and cross-kingdom approaches. Both proteins can be found in meristematic moss tissues, although at low levels and with distinct expression patterns. PpRecQ4 is involved in embryogenesis and in subsequent development as demonstrated by sterility of DeltaPpRecQ4 mutants and by morphological aberrations. Additionally, DeltaPpRecQ4 displays an increased sensitivity to DNA damages and an increased rate of gene targeting. Therefore, we conclude that PpRecQ4 acts as a repressor of recombination. In contrast, PpRecQ6 is not obviously important for moss development or DNA repair but does function as a potent enhancer of gene targeting. PMID- 29514944 TI - Sun exposure over the life course and associations with multiple sclerosis. AB - OBJECTIVE: To examine sun exposure and multiple sclerosis (MS) over the life course (ages 5-15 and 16-20 years, every 10 years thereafter). METHODS: Cases with MS (n = 151) and age-matched controls (n = 235) from the Nurses' Health Study cohorts completed summer, winter, and lifetime sun exposure history questionnaires. Cumulative ambient ultraviolet (UV)-B (based on latitude, altitude, cloud cover) exposure before MS onset was expressed as tertiles. Seasonal sun exposure was defined as low vs high hours per week (summer [<=9 vs >10 h/wk]; winter [<=3 vs >4 h/wk]). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated via conditional logistic regression with adjustment for body mass index, ancestry, smoking, and vitamin D supplementation. RESULTS: Most participants were white (98%); the mean age at MS onset was 39.5 years. Living in high (vs low) UV-B areas before MS onset was associated with a 45% lower MS risk (adjusted RR 0.55, 95% CI 0.42-0.73). Similar reduced risks (51%-52%) for medium or high exposure were observed at ages 5 to 15 years and at 5 to 15 years before MS onset (adjusted p < 0.05). At age 5 to 15 years, living in a high (vs low) UV-B area and having high (vs low) summer sun exposure were associated with a lower MS risk (RR 0.45, 95% CI 0.21-0.96). CONCLUSION: Living in high ambient UV-B areas during childhood and the years leading up to MS onset was associated with a lower MS risk. High summer sun exposure in high ambient UV B areas was also associated with a reduced risk. PMID- 29514943 TI - A Newly Identified Flower-Specific Splice Variant of AUXIN RESPONSE FACTOR8 Regulates Stamen Elongation and Endothecium Lignification in Arabidopsis. AB - In addition to the full-length transcript ARF8.1, a splice variant (ARF8.2) of the auxin response factor gene ARF8 has been reported. Here, we identified an intron-retaining variant of ARF8.2, ARF8.4, whose translated product is imported into the nucleus and has tissue-specific localization in Arabidopsis thaliana By inducibly expressing each variant in arf8-7 flowers, we show that ARF8.4 fully complements the short-stamen phenotype of the mutant and restores the expression of AUX/IAA19, encoding a key regulator of stamen elongation. By contrast, the expression of ARF8.2 and ARF8.1 had minor or no effects on arf8-7 stamen elongation and AUX/IAA19 expression. Coexpression of ARF8.2 and ARF8.4 in both the wild type and arf8-7 caused premature anther dehiscence: We show that ARF8.2 is responsible for increased expression of the jasmonic acid biosynthetic gene DAD1 and that ARF8.4 is responsible for premature endothecium lignification due to precocious expression of transcription factor gene MYB26 Finally, we show that ARF8.4 binds to specific auxin-related sequences in both the AUX/IAA19 and MYB26 promoters and activates their transcription more efficiently than ARF8.2. Our data suggest that ARF8.4 is a tissue-specific functional splice variant that controls filament elongation and endothecium lignification by directly regulating key genes involved in these processes. PMID- 29514945 TI - Central vein sign in multiple sclerosis: Ready for front and center? PMID- 29514946 TI - Progressive neurodegeneration following spinal cord injury: Implications for clinical trials. AB - OBJECTIVE: To quantify atrophy, demyelination, and iron accumulation over 2 years following acute spinal cord injury and to identify MRI predictors of clinical outcomes and determine their suitability as surrogate markers of therapeutic intervention. METHODS: We assessed 156 quantitative MRI datasets from 15 patients with spinal cord injury and 18 controls at baseline and 2, 6, 12, and 24 months after injury. Clinical recovery (including neuropathic pain) was assessed at each time point. Between-group differences in linear and nonlinear trajectories of volume, myelin, and iron change were estimated. Structural changes by 6 months were used to predict clinical outcomes at 2 years. RESULTS: The majority of patients showed clinical improvement with recovery stabilizing at 2 years. Cord atrophy decelerated, while cortical white and gray matter atrophy progressed over 2 years. Myelin content in the spinal cord and cortex decreased progressively over time, while cerebellar loss decreases decelerated. As atrophy progressed in the thalamus, sustained iron accumulation was evident. Smaller cord and cranial corticospinal tract atrophy, and myelin changes within the sensorimotor cortices, by 6 months predicted recovery in lower extremity motor score at 2 years. Whereas greater cord atrophy and microstructural changes in the cerebellum, anterior cingulate cortex, and secondary sensory cortex by 6 months predicted worse sensory impairment and greater neuropathic pain intensity at 2 years. CONCLUSION: These results draw attention to trauma-induced neuroplastic processes and highlight the intimate relationships among neurodegenerative processes in the cord and brain. These measurable changes are sufficiently large, systematic, and predictive to render them viable outcome measures for clinical trials. PMID- 29514947 TI - Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum. AB - OBJECTIVE: To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort. METHODS: CSF NfL and p/t tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD FUS). RESULTS: NfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau). CONCLUSION: NfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders. PMID- 29514948 TI - Value of the central vein sign at 3T to differentiate MS from seropositive NMOSD. AB - OBJECTIVE: To assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). METHODS: Eighteen aquaporin-4-antibody-positive patients with NMOSD, 18 patients with relapsing-remitting MS, and 25 healthy controls underwent 3T MRI. The presence of a central vein in white matter lesions on susceptibility-weighted imaging, defined as a thin hypointense line or a small dot, was recorded. RESULTS: The proportion of lesions with the CVS was higher in MS than NMOSD (80% vs 32%, p < 0.001). A greater proportion of lesions with the CVS predicted the diagnosis of MS, rather than NMOSD (odds ratio 1.10, 95% confidence interval [CI] 1.04 to 1.16, p = 0.001), suggesting that each percent unit increase in the proportion of lesions with the CVS in an individual patient was associated with a 10% increase in the risk of the same patient having MS. If more than 54% of the lesions on any given scan show the CVS, then the patient can be given a diagnosis of MS with an accuracy of 94% (95% CIs 81.34, 99.32, p < 0.001, sensitivity/specificity 90%/100%). CONCLUSION: The clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD, previously suggested using 7T scanners, is now extended to clinical 3T scanners, thereby making a step towards the use of CVS in clinical practice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD. PMID- 29514949 TI - The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection. AB - The transition of effector T cells or memory precursors into distinct long-lived memory T cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and effector cell differentiation, it is not clear if clonal contraction and memory development is passive or active. Using respiratory virus infection, we found that CD8 T cells that cannot express the TNF family molecule lymphotoxin-like, exhibits inducible expression, competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT) are unimpaired in their initial response and clonally expand to form effector cell pools. Thereafter, LIGHT-deficient CD8 T cells undergo strikingly enhanced clonal contraction with resultant compromised accumulation of both circulating and tissue-resident memory cells. LIGHT expression at the peak of the effector response regulates the balance of several pro- and antiapoptotic genes, including Akt, and has a preferential impact on the development of the peripheral memory population. These results underscore the importance of LIGHT activity in programming memory CD8 T cell development, and suggest that CD8 effector T cells can dictate their own fate into becoming memory cells by expressing LIGHT. PMID- 29514951 TI - Discovery and Analysis of Invertebrate IgVJ-C2 Structure from Amphioxus Provides Insight into the Evolution of the Ig Superfamily. AB - The emergence of adaptive immunity in jawed vertebrates depended on the appearance of variable immune receptors, BCRs and TCRs, which exhibit variable-J constant (VJ-C)-type Ig superfamily folds. Hitherto, however, the structures of IgV-J-IgC-type molecules had never been characterized in invertebrates, leaving the origin of BCR/TCR-type molecules unknown. Using x-ray crystallography, the structure of a VJ-C2 molecule, named AmpIgVJ-C2, was determined in amphioxus (Branchiostoma floridae). The first domain shows typical V folding, including the hydrophobic core, CDR analogs, and eight conserved residues. The second domain is a C2-type Ig superfamily domain, as defined by its short length and the absence of beta-strand D- and C1-typical motifs. AmpIgVJ-C2 molecules form homodimers, using "three-layer packing dimerization," as described for TCRs and BCRs. The AmpIgVJ-C2 V domain harbors a diglycine motif in beta-strand G and forms a beta bulge structure participating in V-V intermolecular interaction. By immunohistochemistry, AmpIgVJ-C2 molecules were primarily found in mucosal tissues, whereas PCR and sequence analysis indicated considerable genetic variation at the single-gene level; these findings would be consistent with an immune function and a basic ability to adapt to binding different immune targets. Our results show a BCR/TCR-ancestral like molecule in amphioxus and help us to understand the evolution of the adaptive immune system. PMID- 29514950 TI - miR-130a and miR-212 Disrupt the Intestinal Epithelial Barrier through Modulation of PPARgamma and Occludin Expression in Chronic Simian Immunodeficiency Virus Infected Rhesus Macaques. AB - Intestinal epithelial barrier dysfunction is a well-known sequela of HIV/SIV infection that persists despite antiretroviral therapy. Although inflammation is a triggering factor, the underlying molecular mechanisms remain unknown. Emerging evidence suggests that epithelial barrier function is epigenetically regulated by inflammation-induced microRNAs (miRNAs). Accordingly, we profiled and characterized miRNA/mRNA expression exclusively in colonic epithelium and identified 46 differentially expressed miRNAs (20 upregulated and 26 downregulated) in chronically SIV-infected rhesus macaques (Macaca mulatta). We bioinformatically crossed the predicted miRNA targets to transcriptomic data and characterized miR-130a and miR-212 as both were predicted to interact with critical epithelial barrier-associated genes. Next, we characterized peroxisome proliferator-activated receptor gamma (PPARgamma) and occludin (OCLN), predicted targets of miR-130a and miR-212, respectively, as their downregulation has been strongly linked to epithelial barrier disruption and dysbiosis. Immunofluorescence, luciferase reporter, and overexpression studies confirmed the ability of miR-130a and miR-212 to decrease protein expression of PPARgamma and OCLN, respectively, and reduce transepithelial electrical resistance. Because Delta-9-tetrahydrocannabinol exerted protective effects in the intestine in our previous studies, we successfully used it to reverse miR-130a- and miR-212 mediated reduction in transepithelial electrical resistance. Finally, ex vivo Delta-9-tetrahydrocannabinol treatment of colon tissue from chronically SIV infected rhesus macaques significantly increased PPARgamma expression. Our findings suggest that dysregulated miR-130a and miR-212 expression in colonic epithelium during chronic HIV/SIV infection can facilitate epithelial barrier disruption by downregulating OCLN and PPARgamma expression. Most importantly, our results highlight the beneficial effects of cannabinoids on epithelial barrier function in not just HIV/SIV but potentially other chronic intestinal inflammatory diseases. PMID- 29514952 TI - Teleost Basophils Have IgM-Dependent and Dual Ig-Independent Degranulation Systems. AB - Recently, mammalian basophils have been highlighted as having roles in allergy and antiparasitic immunity; however, there is little information about the functions and evolutionary origin of basophils, because they are the least abundant leukocyte in most vertebrates. In this study, we characterized the teleost basophils that are abundant in the peripheral blood of fugu (Takifugu rubripes). Fugu basophils have two distinct granules: reddish-purple and dark violet ones. Teleost fish do not have IgG and IgE, but we found that fugu IgM bound on the surface of the basophils, and the cross-linked IgM induced degranulation of both types of granules. This indicates that teleost basophils can be activated in an Ab-dependent manner. Furthermore, papain induced the degranulation of the reddish-purple granules, which contain histamine, and the released granules stimulated the migration of various leukocytes. In contrast, chitin elicited the degranulation of the dark violet granules, which resulted in CD4+ T cell-specific migration. Thus, fugu basophils control immune responses via two distinct Ab-independent mechanisms. In addition, fugu basophils endocytosed soluble Ag and expressed MHC class II and B7-H1/DC. These findings suggested that fugu basophils can interact with T cells as APCs. Thus, the Ab-dependent basophil activation predates the emergence of IgG and IgE, and fish basophils exhibit different dynamics and features of degranulation to distinct stimuli compared with mammalian basophils. Some features of teleost basophils are more similar to those of mammalian mast cells than to those of mammalian basophils. PMID- 29514954 TI - Assembling the mitochondrial ATP synthase. PMID- 29514953 TI - Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation. AB - A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a-/ Rag1-/- mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Rorgammat+ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorgammat alleviated the spontaneous colonic inflammation in Gpr109a-/-Rag1-/- mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL 23 production, ILC3, and colonic inflammation in Gpr109a-/-Rag1-/- mice. The ceca of Gpr109a-/-Rag1-/- mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1-/- mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23 mediated immunopathologies. PMID- 29514955 TI - beta-Arrestin1 mediates hMENA expression and ovarian cancer metastasis. PMID- 29514956 TI - Breeding plant broad-spectrum resistance without yield penalties. PMID- 29514958 TI - Experimental evolution heals the scars of genome-scale recoding. PMID- 29514957 TI - Defaunation shadow on mutualistic interactions. PMID- 29514959 TI - Crystal structure of bacterial succinate:quinone oxidoreductase flavoprotein SdhA in complex with its assembly factor SdhE. AB - Succinate:quinone oxidoreductase (SQR) functions in energy metabolism, coupling the tricarboxylic acid cycle and electron transport chain in bacteria and mitochondria. The biogenesis of flavinylated SdhA, the catalytic subunit of SQR, is assisted by a highly conserved assembly factor termed SdhE in bacteria via an unknown mechanism. By using X-ray crystallography, we have solved the structure of Escherichia coli SdhE in complex with SdhA to 2.15-A resolution. Our structure shows that SdhE makes a direct interaction with the flavin adenine dinucleotide linked residue His45 in SdhA and maintains the capping domain of SdhA in an "open" conformation. This displaces the catalytic residues of the succinate dehydrogenase active site by as much as 9.0 A compared with SdhA in the assembled SQR complex. These data suggest that bacterial SdhE proteins, and their mitochondrial homologs, are assembly chaperones that constrain the conformation of SdhA to facilitate efficient flavinylation while regulating succinate dehydrogenase activity for productive biogenesis of SQR. PMID- 29514961 TI - Managing the global land resource. AB - With a growing population with changing demands, competition for the global land resource is increasing. We need to feed a projected population of 9-10 billion by 2050, rising to approximately 12 billion by 2100. At the same time, we need to reduce the climate impact of agriculture, forestry and other land use, and we almost certainly need to deliver land-based greenhouse gas removal for additional climate change mitigation. In addition, we need to deliver progress towards meeting the United Nations Sustainable Development Goals, all without compromising the many ecosystem services provided by land and without exceeding planetary boundaries. Managing the land to tackle these pressing issues is a major global challenge. In this perspective paper, I provide a very broad overview of the main challenges, and explore co-benefits, trade-offs and possible solutions. PMID- 29514960 TI - Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation. AB - Rapid antibody production in response to invading pathogens requires the dramatic expansion of pathogen-derived antigen-specific B lymphocyte populations. Whether B cell population dynamics are based on stochastic competition between competing cell fates, as in the development of competence by the bacterium Bacillus subtilis, or on deterministic cell fate decisions that execute a predictable program, as during the development of the worm Caenorhabditis elegans, remains unclear. Here, we developed long-term live-cell microscopy of B cell population expansion and multiscale mechanistic computational modeling to characterize the role of molecular noise in determining phenotype heterogeneity. We show that the cell lineage trees underlying B cell population dynamics are mediated by a largely predictable decision-making process where the heterogeneity of cell proliferation and death decisions at any given timepoint largely derives from nongenetic heterogeneity in the founder cells. This means that contrary to previous models, only a minority of genetically identical founder cells contribute the majority to the population response. We computationally predict and experimentally confirm nongenetic molecular determinants that are predictive of founder cells' proliferative capacity. While founder cell heterogeneity may arise from different exposure histories, we show that it may also be due to the gradual accumulation of small amounts of intrinsic noise during the lineage differentiation process of hematopoietic stem cells to mature B cells. Our finding of the largely deterministic nature of B lymphocyte responses may provide opportunities for diagnostic and therapeutic development. PMID- 29514962 TI - Repeated imitation makes human vocalizations more word-like. AB - People have long pondered the evolution of language and the origin of words. Here, we investigate how conventional spoken words might emerge from imitations of environmental sounds. Does the repeated imitation of an environmental sound gradually give rise to more word-like forms? In what ways do these forms resemble the original sounds that motivated them (i.e. exhibit iconicity)? Participants played a version of the children's game 'Telephone'. The first generation of participants imitated recognizable environmental sounds (e.g. glass breaking, water splashing). Subsequent generations imitated the previous generation of imitations for a maximum of eight generations. The results showed that the imitations became more stable and word-like, and later imitations were easier to learn as category labels. At the same time, even after eight generations, both spoken imitations and their written transcriptions could be matched above chance to the category of environmental sound that motivated them. These results show how repeated imitation can create progressively more word-like forms while continuing to retain a resemblance to the original sound that motivated them, and speak to the possible role of human vocal imitation in explaining the origins of at least some spoken words. PMID- 29514963 TI - Relatedness decreases and reciprocity increases cooperation in Norway rats. AB - Kin selection and reciprocity are two mechanisms underlying the evolution of cooperation, but the relative importance of kinship and reciprocity for decisions to cooperate are yet unclear for most cases of cooperation. Here, we experimentally tested the relative importance of relatedness and received cooperation for decisions to help a conspecific in wild-type Norway rats (Rattus norvegicus). Test rats provided more food to non-kin than to siblings, and they generally donated more food to previously helpful social partners than to those that had refused help. The rats thus applied reciprocal cooperation rules irrespective of relatedness, highlighting the importance of reciprocal help for cooperative interactions among both related and unrelated conspecifics. PMID- 29514965 TI - Reviewers in 2017. PMID- 29514964 TI - Maternal modulation of paternal effects on offspring development. AB - The paternal transmission of environmentally induced phenotypes across generations has been reported to occur following a number of qualitatively different exposures and appear to be driven, at least in part, by epigenetic factors that are inherited via the sperm. However, previous studies of paternal germline transmission have not addressed the role of mothers in the propagation of paternal effects to offspring. We hypothesized that paternal exposure to nutritional restriction would impact male mate quality and subsequent maternal reproductive investment with consequences for the transmission of paternal germline effects. In the current report, using embryo transfer in mice, we demonstrate that sperm factors in adult food restricted males can influence growth rate, hypothalamic gene expression and behaviour in female offspring. However, under natural mating conditions females mated with food restricted males show increased pre- and postnatal care, and phenotypic outcomes observed during embryo transfer conditions are absent or reversed. We demonstrate that these compensatory changes in maternal investment are associated with a reduced mate preference for food restricted males and elevated gene expression within the maternal hypothalamus. Therefore, paternal experience can influence offspring development via germline inheritance, but mothers can serve as a modulating factor in determining the impact of paternal influences on offspring development. PMID- 29514966 TI - Inferring forest fate from demographic data: from vital rates to population dynamic models. AB - As population-level patterns of interest in forests emerge from individual vital rates, modelling forest dynamics requires making the link between the scales at which data are collected (individual stems) and the scales at which questions are asked (e.g. populations and communities). Structured population models (e.g. integral projection models (IPMs)) are useful tools for linking vital rates to population dynamics. However, the application of such models to forest trees remains challenging owing to features of tree life cycles, such as slow growth, long lifespan and lack of data on crucial ontogenic stages. We developed a survival model that accounts for size-dependent mortality and a growth model that characterizes individual heterogeneity. We integrated vital rate models into two types of population model; an analytically tractable form of IPM and an individual-based model (IBM) that is applied with stochastic simulations. We calculated longevities, passage times to, and occupancy time in, different life cycle stages, important metrics for understanding how demographic rates translate into patterns of forest turnover and carbon residence times. Here, we illustrate the methods for three tropical forest species with varying life-forms. Population dynamics from IPMs and IBMs matched a 34 year time series of data (albeit a snapshot of the life cycle for canopy trees) and highlight differences in life history strategies between species. Specifically, the greater variation in growth rates within the two canopy species suggests an ability to respond to available resources, which in turn manifests as faster passage times and greater occupancy times in larger size classes. The framework presented here offers a novel and accessible approach to modelling the population dynamics of forest trees. PMID- 29514967 TI - Morphologically cryptic Amazonian bird species pairs exhibit strong postzygotic reproductive isolation. AB - We possess limited understanding of how speciation unfolds in the most species rich region of the planet-the Amazon basin. Hybrid zones provide valuable information on the evolution of reproductive isolation, but few studies of Amazonian vertebrate hybrid zones have rigorously examined the genome-wide underpinnings of reproductive isolation. We used genome-wide genetic datasets to show that two deeply diverged, but morphologically cryptic sister species of forest understorey birds show little evidence for prezygotic reproductive isolation, but substantial postzygotic isolation. Patterns of heterozygosity and hybrid index revealed that hybrid classes with heavily recombined genomes are rare and closely match simulations with high levels of selection against hybrids. Genomic and geographical clines exhibit a remarkable similarity across loci in cline centres, and have exceptionally narrow cline widths, suggesting that postzygotic isolation is driven by genetic incompatibilities at many loci, rather than a few loci of strong effect. We propose Amazonian understorey forest birds speciate slowly via gradual accumulation of postzygotic genetic incompatibilities, with prezygotic barriers playing a less important role. Our results suggest old, cryptic Amazonian taxa classified as subspecies could have substantial postzygotic isolation deserving species recognition and that species richness is likely to be substantially underestimated in Amazonia. PMID- 29514968 TI - How new concepts become universal scientific approaches: insights from citation network analysis of agent-based complex systems science. AB - Progress in understanding and managing complex systems comprised of decision making agents, such as cells, organisms, ecosystems or societies, is-like many scientific endeavours-limited by disciplinary boundaries. These boundaries, however, are moving and can actively be made porous or even disappear. To study this process, I advanced an original bibliometric approach based on network analysis to track and understand the development of the model-based science of agent-based complex systems (ACS). I analysed research citations between the two communities devoted to ACS research, namely agent-based (ABM) and individual based modelling (IBM). Both terms refer to the same approach, yet the former is preferred in engineering and social sciences, while the latter prevails in natural sciences. This situation provided a unique case study for grasping how a new concept evolves distinctly across scientific domains and how to foster convergence into a universal scientific approach. The present analysis based on novel hetero-citation metrics revealed the historical development of ABM and IBM, confirmed their past disjointedness, and detected their progressive merger. The separation between these synonymous disciplines had silently opposed the free flow of knowledge among ACS practitioners and thereby hindered the transfer of methodological advances and the emergence of general systems theories. A surprisingly small number of key publications sparked the ongoing fusion between ABM and IBM research. Beside reviews raising awareness of broad-spectrum issues, generic protocols for model formulation and boundary-transcending inference strategies were critical means of science integration. Accessible broad-spectrum software similarly contributed to this change. From the modelling viewpoint, the discovery of the unification of ABM and IBM demonstrates that a wide variety of systems substantiate the premise of ACS research that microscale behaviours of agents and system-level dynamics are inseparably bound. PMID- 29514970 TI - Ecological opportunity and predator-prey interactions: linking eco-evolutionary processes and diversification in adaptive radiations. AB - Much of life's diversity has arisen through ecological opportunity and adaptive radiations, but the mechanistic underpinning of such diversification is not fully understood. Competition and predation can affect adaptive radiations, but contrasting theoretical and empirical results show that they can both promote and interrupt diversification. A mechanistic understanding of the link between microevolutionary processes and macroevolutionary patterns is thus needed, especially in trophic communities. Here, we use a trait-based eco-evolutionary model to investigate the mechanisms linking competition, predation and adaptive radiations. By combining available micro-evolutionary theory and simulations of adaptive radiations we show that intraspecific competition is crucial for diversification as it induces disruptive selection, in particular in early phases of radiation. The diversification rate is however decreased in later phases owing to interspecific competition as niche availability, and population sizes are decreased. We provide new insight into how predation tends to have a negative effect on prey diversification through decreased population sizes, decreased disruptive selection and through the exclusion of prey from parts of niche space. The seemingly disparate effects of competition and predation on adaptive radiations, listed in the literature, may thus be acting and interacting in the same adaptive radiation at different relative strength as the radiation progresses. PMID- 29514969 TI - Cleaner wrasse indirectly affect the cognitive performance of a damselfish through ectoparasite removal. AB - Cleaning organisms play a fundamental ecological role by removing ectoparasites and infected tissue from client surfaces. We used the well-studied cleaning mutualisms involving the cleaner wrasse, Labroides dimidiatus, to test how client cognition is affected by ectoparasites and whether these effects are mitigated by cleaners. Ambon damselfish (Pomacentrus amboinensis) collected from experimental reef patches without cleaner wrasse performed worse in a visual discrimination test than conspecifics from patches with cleaners. Endoparasite abundance also negatively influenced success in this test. Visual discrimination performance was also impaired in damselfish experimentally infected with gnathiid (Crustacea: Isopoda) ectoparasites. Neither cleaner absence nor gnathiid infection affected performance in spatial recognition or reversal learning tests. Injection with immune-stimulating lipopolysaccharide did not affect visual discrimination performance relative to saline-injected controls, suggesting that cognitive impairments are not due to an innate immune response. Our results highlight the complex, indirect role of cleaning organisms in promoting the health of their clients via ectoparasite removal and emphasize the negative impact of parasites on host's cognitive abilities. PMID- 29514971 TI - Temperature and competition interact to structure Himalayan bird communities. AB - Longstanding theory predicts that competitive interactions set species' range limits in relatively aseasonal, species-rich regions, while temperature limits distributions in more seasonal, species-poor areas. More recent theory holds that species evolve narrow physiological tolerances in aseasonal regions, with temperature being an important determining factor in such zones. We tested how abiotic (temperature) and biotic (competition) factors set range limits and structure bird communities along strong, opposing, temperature-seasonality and species-richness gradients in the Himalayas, in two regions separated by 1500 km. By examining the degree to which seasonal elevational migration conserves year round thermal niches across species, we show that species in the relatively aseasonal and speciose east are more constrained by temperature compared with species in the highly seasonal west. We further show that seasonality has a profound effect on the strength of competition between congeneric species. Competition appears to be stronger in winter, a period of resource scarcity in the Himalayas, in both the east and the west, with similarly sized eastern species more likely to segregate in thermal niche space in winter. Our results indicate that rather than acting in isolation, abiotic and biotic factors mediate each other to structure ecological communities. PMID- 29514972 TI - The enemy of my enemy is my friend: native pine marten recovery reverses the decline of the red squirrel by suppressing grey squirrel populations. AB - Shared enemies may instigate or modify competitive interactions between species. The dis-equilibrium caused by non-native species introductions has revealed that the outcome of such indirect interactions can often be dramatic. However, studies of enemy-mediated competition mostly consider the impact of a single enemy, despite species being embedded in complex networks of interactions. Here, we demonstrate that native red and invasive grey squirrels in Britain, two terrestrial species linked by resource and disease-mediated apparent competition, are also now linked by a second enemy-mediated relationship involving a shared native predator recovering from historical persecution, the European pine marten. Through combining spatial capture-recapture techniques to estimate pine marten density, and squirrel site-occupancy data, we find that the impact of exposure to predation is highly asymmetrical, with non-native grey squirrel occupancy strongly negatively affected by exposure to pine martens. By contrast, exposure to pine marten predation has an indirect positive effect on red squirrel populations. Pine marten predation thus reverses the well-documented outcome of resource and apparent competition between red and grey squirrels. PMID- 29514974 TI - Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. AB - OBJECTIVES: Neonatal abstinence syndrome (NAS) after an infant's in-utero exposure to opioids has increased dramatically in incidence. No treatment standards exist, leading to substantial variations in practice, degree of opioid exposure, and hospital length of stay. METHODS: The Ohio Perinatal Quality Collaborative conducted an extensive multi-modal quality improvement initiative with the goal to (1) standardize identification, nonpharmacologic and pharmacologic treatment in level-2 and 3 NICUs in Ohio, (2) reduce the use of and length of treatment with opioids, and (3) reduce hospital length of stay in pharmacologically treated newborns with NAS. RESULTS: Fifty-two of 54 (96%) Ohio NICUs participated in the collaborative. Compliance with the nonpharmacologic bundle improved from 37% to 59%, and the pharmacologic bundle improved from 59% to 68%. Forty-eight percent of the 3266 opioid-exposed infants received pharmacologic treatment of symptoms of NAS, and this rate did not change significantly across the time period. Regardless of the opioid used to pharmacologically treat infants with NAS, the length of treatment decreased from 13.4 to 12.0 days, and length of stay decreased from 18.3 to 17 days. CONCLUSIONS: Standardized approaches to the identification and nonpharmacologic and pharmacologic care were associated with a reduced length of opioid exposure and hospital stay in a large statewide collaborative. Other states and institutions treating opioid-exposed infants may benefit from the adoption of these practices. PMID- 29514973 TI - Characterizing the phylogenetic specialism-generalism spectrum of mammal parasites. AB - The distribution of parasites across mammalian hosts is complex and represents a differential ability or opportunity to infect different host species. Here, we take a macroecological approach to investigate factors influencing why some parasites show a tendency to infect species widely distributed in the host phylogeny (phylogenetic generalism) while others infect only closely related hosts. Using a database on over 1400 parasite species that have been documented to infect up to 69 terrestrial mammal host species, we characterize the phylogenetic generalism of parasites using standard effect sizes for three metrics: mean pairwise phylogenetic distance (PD), maximum PD and phylogenetic aggregation. We identify a trend towards phylogenetic specialism, though statistically host relatedness is most often equivalent to that expected from a random sample of host species. Bacteria and arthropod parasites are typically the most generalist, viruses and helminths exhibit intermediate generalism, and protozoa are on average the most specialist. While viruses and helminths have similar mean pairwise PD on average, the viruses exhibit higher variation as a group. Close-contact transmission is the transmission mode most associated with specialism. Most parasites exhibiting phylogenetic aggregation (associating with discrete groups of species dispersed across the host phylogeny) are helminths and viruses. PMID- 29514975 TI - Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review. AB - CONTEXT: Hormonal interventions are being increasingly used to treat young people with gender dysphoria, but their effects in this population have not been systematically reviewed before. OBJECTIVE: To review evidence for the physical, psychosocial, and cognitive effects of gonadotropin-releasing hormone analogs (GnRHa), gender-affirming hormones, antiandrogens, and progestins on transgender adolescents. DATA SOURCES: We searched Medline, Embase, and PubMed databases from January 1, 1946, to June 10, 2017. STUDY SELECTION: We selected primary studies in which researchers examined the hormonal treatment of transgender adolescents and assessed their psychosocial, cognitive, and/or physical effects. DATA EXTRACTION: Two authors independently screened studies for inclusion and extracted data from eligible articles using a standardized recording form. RESULTS: Thirteen studies met our inclusion criteria, in which researchers examined GnRHas (n = 9), estrogen (n = 3), testosterone (n = 5), antiandrogen (cyproterone acetate) (n = 1), and progestin (lynestrenol) (n = 1). Most treatments successfully achieved their intended physical effects, with GnRHas and cyproterone acetate suppressing sex hormones and estrogen or testosterone causing feminization or masculinization of secondary sex characteristics. GnRHa treatment was associated with improvement across multiple measures of psychological functioning but not gender dysphoria itself, whereas the psychosocial effects of gender-affirming hormones in transgender youth have not yet been adequately assessed. LIMITATIONS: There are few studies in this field and they have all been observational. CONCLUSIONS: Low-quality evidence suggests that hormonal treatments for transgender adolescents can achieve their intended physical effects, but evidence regarding their psychosocial and cognitive impact are generally lacking. Future research to address these knowledge gaps and improve understanding of the long-term effects of these treatments is required. PMID- 29514976 TI - Functional roles of the DNA-binding HMGB domain in the histone chaperone FACT in nucleosome reorganization. AB - The essential histone chaperone FACT (facilitates chromatin transcription) promotes both nucleosome assembly and disassembly. FACT is a heterodimer of Spt16 with either SSRP1 or Pob3, differing primarily by the presence of a high-mobility group B (HMGB) DNA-binding domain furnished only by SSRP1. Yeast FACT lacks the intrinsic HMGB domain found in SSRP1-based homologs such as human FACT, but yeast FACT activity is supported by Nhp6, which is a freestanding, single HMGB-domain protein. The importance of histone binding by FACT domains has been established, but the roles of DNA-binding activity remain poorly understood. Here, we examined these roles by fusing single or multiple HMGB modules to Pob3 to mimic SSRP1 or to test the effects of extended DNA-binding capacity. Human FACT and a yeast mimic both required Nhp6 to support nucleosome reorganization in vitro, indicating that a single intrinsic DNA-binding HMGB module is insufficient for full FACT activity. Three fused HMGB modules supported activity without Nhp6 assistance, but this FACT variant did not efficiently release from nucleosomes and was toxic in vivo Notably, intrinsic DNA-binding HMGB modules reduced the DNA accessibility and histone H2A-H2B dimer loss normally associated with nucleosome reorganization. We propose that DNA bending by HMGB domains promotes nucleosome destabilization and reorganization by exposing FACT's histone-binding sites, but DNA bending also produces DNA curvature needed to accommodate nucleosome assembly. Intrinsic DNA-bending activity therefore favors nucleosome assembly by FACT over nucleosome reorganization, but excessive activity impairs FACT release, suggesting a quality control checkpoint during nucleosome assembly. PMID- 29514977 TI - The HUS box is required for allosteric regulation of the Sec7 Arf-GEF. AB - The Golgi complex is the central membrane and protein-sorting station in eukaryotic cells. Activation of Arf (ADP-ribosylation factor) GTPases is essential for vesicle formation via recruitment of cargo adaptors and coat proteins necessary for Golgi trafficking. Arf activation is spatially and temporally regulated by distinct guanine nucleotide exchange factors (GEFs) at different Golgi compartments. The yeast Arf-GEF Sec7 is a conserved and essential activator of Arf1 at the trans-Golgi network. Sec7 contains a highly conserved regulatory region, the homology upstream of Sec7 (HUS) box, with an unknown mechanistic role. In this study we explore how the HUS box, which is N-terminal to the catalytic domain, acts together with C-terminal regulatory domains in the allosteric activation of Sec7. We report that mutation of the HUS box disrupts positive feedback and allosteric activation of Sec7 by the GTPase Ypt31, a yeast Rab11 homolog. Taken together, our results support a model in which the inter- and intramolecular interactions of the HUS box and the C terminus are necessary for the allosteric activation of Sec7. PMID- 29514979 TI - Introduction to the Thematic Minireview Series: Brain glycogen metabolism. AB - The synthesis of glycogen allows for efficient intracellular storage of glucose molecules in a soluble form that can be rapidly released to enter glycolysis in response to energy demand. Intensive studies of glucose and glycogen metabolism, predominantly in skeletal muscle and liver, have produced innumerable insights into the mechanisms of hormone action, resulting in the award of several Nobel Prizes over the last one hundred years. Glycogen is actually present in all cells and tissues, albeit at much lower levels than found in muscle or liver. However, metabolic and physiological roles of glycogen in other tissues are poorly understood. This series of Minireviews summarizes what is known about the enzymes involved in brain glycogen metabolism and studies that have linked glycogen metabolism to multiple brain functions involving metabolic communication between astrocytes and neurons. Recent studies unexpectedly linking some forms of epilepsy to mutations in two poorly understood proteins involved in glycogen metabolism are also reviewed. PMID- 29514978 TI - Spatiotemporal compartmentalization of hepatic NADH and NADPH metabolism. AB - Compartmentalization is a fundamental design principle of eukaryotic metabolism. Here, we review the compartmentalization of NAD+/NADH and NADP+/NADPH with a focus on the liver, an organ that experiences the extremes of biochemical physiology each day. Historical studies of the liver, using classical biochemical fractionation and measurements of redox-coupled metabolites, have given rise to the prevailing view that mitochondrial NAD(H) pools tend to be oxidized and important for energy homeostasis, whereas cytosolic NADP(H) pools tend to be highly reduced for reductive biosynthesis. Despite this textbook view, many questions still remain as to the relative size of these subcellular pools and their redox ratios in different physiological states, and to what extent such redox ratios are simply indicators versus drivers of metabolism. By performing a bioinformatic survey, we find that the liver expresses 352 known or predicted enzymes composing the hepatic NAD(P)ome, i.e. the union of all predicted enzymes producing or consuming NADP(H) or NAD(H) or using them as a redox co-factor. Notably, less than half are predicted to be localized within the cytosol or mitochondria, and a very large fraction of these genes exhibit gene expression patterns that vary during the time of day or in response to fasting or feeding. A future challenge lies in applying emerging new genetic tools to measure and manipulate in vivo hepatic NADP(H) and NAD(H) with subcellular and temporal resolution. Insights from such fundamental studies will be crucial in deciphering the pathogenesis of very common diseases known to involve alterations in hepatic NAD(P)H, such as diabetes and fatty liver disease. PMID- 29514980 TI - Pyruvate kinase M2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma. AB - Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory element-binding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation. PMID- 29514983 TI - Nucleosome-Dependent Pathways That Control Mitotic Progression. AB - The majority of eukaryotic chromosomal DNA exists in the form of nucleosomes, where ~147 bp DNA wraps around histone hetero-octamers, composed of histone H3, H4, H2A, and H2B. Despite their obvious importance in DNA compaction and accessibility, studying their specific roles, such as regulation of mitotic progression, in a physiological environment is associated with critical caveats because of their major contributions in transcriptional control. Through establishing a method to deplete endogenous histones H3 and H4 from frog egg extracts and complementing their functions using recombinant nucleosome arrays, we are now able to analyze their roles in mitotic progression without affecting overall transcriptomic profiles. Here we summarize advancements learned from this system, illustrating that microtubule and nuclear envelope assembly can be regulated by two major nucleosome-bound protein complexes, RCC1-Ran and the chromosomal passenger complex (CPC) containing the mitotic protein kinase Aurora B. We also discuss roles of the CPC on the proteomic composition of mitotic chromatin. The CPC promotes dissociation of a variety of nucleosome remodelers and DNA repair pathway proteins, suggesting its role in suppressing DNA processing activities on mitotic chromosomes. We speculate that this suppression particularly on chromosomes under microtubule tension may be important to preserve genome integrity. PMID- 29514981 TI - Structural basis for the regulatory interaction of the methylglyoxal synthase MgsA with the carbon flux regulator Crh in Bacillus subtilis. AB - Utilization of energy-rich carbon sources such as glucose is fundamental to the evolutionary success of bacteria. Glucose can be catabolized via glycolysis for feeding the intermediary metabolism. The methylglyoxal synthase MgsA produces methylglyoxal from the glycolytic intermediate dihydroxyacetone phosphate. Methylglyoxal is toxic, requiring stringent regulation of MgsA activity. In the Gram-positive bacterium Bacillus subtilis, an interaction with the phosphoprotein Crh controls MgsA activity. In the absence of preferred carbon sources, Crh is present in the nonphosphorylated state and binds to and thereby inhibits MgsA. To better understand the mechanism of regulation of MgsA, here we performed biochemical and structural analyses of B. subtilis MgsA and of its interaction with Crh. Our results indicated that MgsA forms a hexamer (i.e. a trimer of dimers) in the crystal structure, whereas it seems to exist in an equilibrium between a dimer and hexamer in solution. In the hexamer, two alternative dimers could be distinguished, but only one appeared to prevail in solution. Further analysis strongly suggested that the hexamer is the biologically active form. In vitro cross-linking studies revealed that Crh interacts with the N-terminal helices of MgsA and that the Crh-MgsA binding inactivates MgsA by distorting and thereby blocking its active site. In summary, our results indicate that dimeric and hexameric MgsA species exist in an equilibrium in solution, that the hexameric species is the active form, and that binding to Crh deforms and blocks the active site in MgsA. PMID- 29514982 TI - Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease. AB - DNA interstrand cross-links (ICLs) block the progress of the replication and transcription machineries and can weaken chromosomal stability, resulting in various diseases. FANCD2-FANCI-associated nuclease (FAN1) is a conserved structure-specific nuclease that unhooks DNA ICLs independently of the Fanconi anemia pathway. Recent structural studies have proposed two different mechanistic features for ICL unhooking by human FAN1: a specific basic pocket that recognizes the terminal phosphate of a 1-nucleotide (nt) 5' flap or FAN1 dimerization. Herein, we show that despite lacking these features, Pseudomonas aeruginosa FAN1 (PaFAN1) cleaves substrates at ~3-nt intervals and resolves ICLs. Crystal structures of PaFAN1 bound to various DNA substrates revealed that its conserved basic Arg/Lys patch comprising Arg-228 and Lys-260 recognizes phosphate groups near the 5' terminus of a DNA substrate with a 1-nt flap or a nick. Substitution of Lys-260 did not affect PaFAN1's initial endonuclease activity but significantly decreased its subsequent exonuclease activity and ICL unhooking. The Arg/Lys patch also interacted with phosphates at a 3-nt gap, and this interaction could drive movement of the scissile phosphates into the PaFAN1 active site. In human FAN1, the ICL-resolving activity was not affected by individual disruption of the Arg/Lys patch or basic pocket. However, simultaneous substitution of both FAN1 regions significantly reduced its ICL-resolving activity, suggesting that these two basic regions play a complementary role in ICL repair. On the basis of these findings, we propose a conserved role for two basic regions in FAN1 to guide ICL unhooking and to maintain genomic stability. PMID- 29514984 TI - Synergistic adhesion mechanisms of spider capture silk. AB - It is well known that capture silk, the main sticky component of the orb web of a spider, plays an important role in the spider's ability to capture prey via adhesion. However, the detailed mechanism with which the spider achieves its unparalleled high-adhesion performance remains elusive. In this work, we combine experiments and theoretical analysis to investigate the adhesion mechanisms of spider silk. In addition to the widely recognized adhesion effect of the sticky glue, we reveal a synergistic enhancement mechanism due to the elasticity of silk fibres. A balance between silk stiffness, strength and glue stickiness is crucial to endow the silk with superior adhesion, as well as outstanding energy absorption capacity and structural robustness. The revealed mechanisms deepen our understanding of the working principles of spider silk and suggest guidelines for biomimetic designs of spider-inspired adhesion and capture devices. PMID- 29514985 TI - Combat biofouling with microscopic ridge-like surface morphology: a bioinspired study. AB - Biofouling refers to the unfavourable attachment and accumulation of marine sessile organisms (e.g. barnacles, mussels and tubeworms) on the solid surfaces immerged in ocean. The enormous economic loss caused by biofouling in combination with the severe environmental impacts induced by the current antifouling approaches entails the development of novel antifouling strategies with least environmental impact. Inspired by the superior antifouling performance of the leaves of mangrove tree Sonneratia apetala, here we propose to combat biofouling by using a surface with microscopic ridge-like morphology. Settlement tests with tubeworm larvae on polymeric replicas of S. apetala leaves confirm that the microscopic ridge-like surface morphology can effectively prevent biofouling. A contact mechanics-based model is then established to quantify the dependence of tubeworm settlement on the structural features of the microscopic ridge-like morphology, giving rise to theoretical guidelines to optimize the morphology for better antifouling performance. Under the direction of the obtained guidelines, a synthetic surface with microscopic ridge-like morphology is developed, exhibiting antifouling performance comparable to that of the S. apetala replica. Our results not only reveal the underlying mechanism accounting for the superior antifouling property of the S. apetala leaves, but also provide applicable guidance for the development of synthetic antifouling surfaces. PMID- 29514986 TI - Switches induced by quorum sensing in a model of enzyme-loaded microparticles. AB - Quorum sensing refers to the ability of bacteria and other single-celled organisms to respond to changes in cell density or number with population-wide changes in behaviour. Here, simulations were performed to investigate quorum sensing in groups of diffusively coupled enzyme microparticles using a well characterized autocatalytic reaction which raises the pH of the medium: hydrolysis of urea by urease. The enzyme urease is found in both plants and microorganisms, and has been widely exploited in engineering processes. We demonstrate how increases in group size can be used to achieve a sigmoidal switch in pH at high enzyme loading, oscillations in pH at intermediate enzyme loading and a bistable, hysteretic switch at low enzyme loading. Thus, quorum sensing can be exploited to obtain different types of response in the same system, depending on the enzyme concentration. The implications for microorganisms in colonies are discussed, and the results could help in the design of synthetic quorum sensing for biotechnology applications such as drug delivery. PMID- 29514987 TI - Gyroscopic stabilization minimizes drag on Ruellia ciliatiflora seeds. AB - Fruits of Ruellia ciliatiflora (Acanthaceae) explosively launch small (2.5 mm diameter * 0.46 mm thick), disc-shaped seeds at velocities over 15 m s-1, reaching distances of up to 7 m. Through high-speed video analysis, we observe that seeds fly with extraordinary backspin of up to 1660 Hz. By modelling the seeds as spinning discs, we show that flying with backspin is stable against gyroscopic precession. This stable backspin orientation minimizes the frontal area during flight, decreasing drag force on the seeds and thus increasing dispersal distance. From high-speed video of the seeds' flight, we experimentally determine drag forces that are 40% less than those calculated for a sphere of the same volume and density. This reduces the energy costs for seed dispersal by up to a factor of five. PMID- 29514989 TI - Reviewers in 2017. PMID- 29514988 TI - Elucidation of the hierarchical structure of natural eumelanins. AB - Eumelanin is one of the most ubiquitous pigments in living organisms and plays an important role in coloration and UV protection. Because eumelanin is highly cross linked and insoluble in solvents, the chemical structure is still not completely known. In this study, we used atomic force microscopy, X-ray photoelectron spectroscopy and solid-state nuclear magnetic resonance (NMR) to compare intact eumelanosomes (pigment granules mostly made of eumelanin) from four phylogentically distant species: cuttlefish (Sepia officinalis) inks, black fish crow (Corvus ossifragus) feathers, iridescent wild turkey (Melleagris gallopavo) feathers and black human hair. We found that eumelanosomes from all four species are composed of subunit nanoparticles with a length of 10-60 nm, consistent with earlier observations in eumelanosomes from the sepia ink and human hair. The solid-state NMR results indicate the presence of quinone methide tautomers in all four eumelanins. We also found clear differences in the UV absorbance, the ratio of 5,6-dihydroxyindole-2-carboxylic acid/5,6-dihydroxyindole and protonated aryl carbon ratios in sepia eumelanin relative to the other three. This comparison of natural eumelanin across a phylogenetically broad group of organisms provides insights into the change in the eumelanin structure over the evolutionary history and enables the production of synthetic eumelanin with properties that are similar to natural eumelanin. PMID- 29514991 TI - Predatory dipteran larva contributes to nutrient sequestration in a carnivorous pitcher plant. AB - The fluids of Nepenthes pitcher plants are habitats to many specialized animals known as inquilines, which facilitate the conversion of prey protein into pitcher absorbable nitrogen forms such as ammonium. Xenoplatyura beaveri (Diptera: Mycetophilidae) is a predatory dipteran inquiline that inhabits the pitchers of Nepenthes ampullaria Larvae of X. beaveri construct sticky webs over the fluid surface of N. ampullaria to ensnare emerging adult dipteran inquilines. However, the interaction between X. beaveri and its host has never been examined before, and it is not known if X. beaveri can contribute to nutrient sequestration in N. ampullaria. Xenoplatyura beaveri individuals were reared in artificial pitchers in the laboratory on a diet of emergent Tripteroides tenax mosquitoes, and the ammonium concentration of the pitcher fluids was measured over time. Fluid ammonium concentration in tubes containing X. beaveri was significantly greater than those of the controls. Furthermore, fluid ammonium concentrations increased greatly after X. beaveri larvae metamorphosed, although the cause of this increase could not be identified. Our results show that a terrestrial, inquiline predator can contribute significantly to nutrient sequestration in the phytotelma it inhabits, and suggest that this interaction has a net mutualistic outcome for both species. PMID- 29514990 TI - Limited by the roof of the world: mountain radiations of Apollo swallowtails controlled by diversity-dependence processes. AB - Mountainous areas contain a substantial part of the world species richness, but the evolutionary origins and diversification of this biodiversity remain elusive. Diversification may result from differences in clade age (longer time to diversify), net diversification rates (faster speciation rate) or carrying capacities (number of niches). The likelihood of these macroevolutionary scenarios was assessed for six clades of Apollo swallowtails (Parnassius) that diversified mainly in the Himalayan-Tibetan region. The analyses suggest that neither the clade age nor the speciation rate could explain the mountain butterfly diversification. Instead diversity-dependence models were strongly supported for each group. Models further estimated clades' carrying capacities, which approximate to the current number of species, indicating that diversity equilibrium has been reached (or close to being reached). The results suggest that diversification of mountain butterflies was controlled by ecological limits, which governed the number of niches, and provide macroevolutionary justification for regarding mountains as islands. PMID- 29514992 TI - Trade-off between fertility and predation risk drives a geometric sequence in the pattern of group sizes in baboons. AB - Group-living offers both benefits (protection against predators, access to resources) and costs (increased ecological competition, the impact of group size on fertility). Here, we use cluster analysis to detect natural patternings in a comprehensive sample of baboon groups, and identify a geometric sequence with peaks at approximately 20, 40, 80 and 160. We suggest (i) that these form a set of demographic oscillators that set habitat-specific limits to group size and (ii) that the oscillator arises from a trade-off between female fertility and predation risk. PMID- 29514993 TI - Age-based soldier polyethism: old termite soldiers take more risks than young soldiers. AB - Who should take on risky tasks in an age-heterogeneous society? Life-history theory predicts that, in social insects, riskier tasks should be undertaken by sterile individuals with a shorter life expectancy. The loss of individuals with shorter life expectancy is less costly for colony reproductive success than the loss of individuals with longer life expectancy. Termite colonies have a sterile soldier caste, specialized defenders engaged in the most risky tasks. Here we show that termite soldiers exhibit age-dependent polyethism, as old soldiers are engaged in front-line defence more than young soldiers. Our nest defence experiment showed that old soldiers went to the front line and blocked the nest opening against approaching predatory ants more often than young soldiers. We also found that young soldiers were more biased toward choosing central nest defence as royal guards than old soldiers. These results demonstrate that termite soldiers have age-based task allocation, by which ageing predisposes soldiers to switch to more dangerous tasks. This age-dependent soldier task allocation increases the life expectancy of soldiers, allowing them to promote their lifetime contribution to colony reproductive success. PMID- 29514994 TI - Reviewers in 2017. PMID- 29514995 TI - Characteristics of and risk factors for death in elderly patients with acute kidney injury: a multicentre retrospective study in China. AB - PURPOSE OF THE STUDY: The incidence of acute kidney injury (AKI) with a poor prognosis in the elderly has been increasing each year. This study aimed to investigate the clinical characteristics of and risk factors for death from AKI in the elderly and help improve prognosis. STUDY DESIGN: This study was a retrospective cohort study based on data from adult patients (>=18 years old) admitted to 15 hospitals in China between 1 January 2009 and 31 December 2011. The characteristics of AKI in the elderly were compared with those in younger patients. RESULTS: In elderly patients with AKI, rates of hypertension, cardiovascular disease and multiple organ dysfunction syndrome (MODS) were higher than in younger patients (44.2% vs 31.2%, 16.1% vs 4.6% and 20.9% vs 16.9%, respectively), the length of ICU stay was longer (3.8 days vs 2.7 days, P=0.019) and renal biopsy (1.0% vs 7.13%, P<0.001) and dialysis (9.6% vs 19.2%, P<0.001) were performed less. Hospital-acquired (HA) AKI was more common than community acquired (CA) AKI (60.3% vs 39.7%), while the most common cause of AKI was pre renal (53.5%). Multiple logistic regression analysis showed that age (OR 1.041, 95% CI 1.023 to 1.059), cardiovascular disease (OR 1.980, 95% CI 1.402 to 2.797), cancer (OR 2.302, 95% CI 1.654 to 3.203), MODS (OR 3.023, 95% CI 1.627 to 5.620) and mechanical ventilation (OR 2.408, 95% CI 1.187 to 4.887) were significant risk factors for death. CONCLUSIONS: HA-AKI and pre-renal AKI were more common in the elderly. Age, cardiovascular disease, cancer, MODS and mechanical ventilation were independent risk factors for death in the elderly with AKI. PMID- 29514996 TI - Rule of 100: a litmus test for informationless diagnostic tests. PMID- 29514997 TI - Combating low birth weight due to malaria infection in pregnancy. AB - Decreased l-arginine and nitric oxide bioavailability in pregnant women with malaria contributes to low birth weight, suggesting that l-arginine supplementation could be a potential treatment (McDonald et al). PMID- 29514998 TI - T follicular helper-like cells contribute to skin fibrosis. AB - Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (TH) and T follicular helper (TFH) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS+ T cells and their contribution to inflammation and fibrosis in SSc are still unknown. We show that CD4+ ICOS-expressing T cells with a TFH-like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS+ TFH-like cells were found to be increased in the skin of graft versus-host disease (GVHD)-SSc mice and contributed to dermal fibrosis via an interleukin-21- and matrix metalloproteinase 12-dependent mechanism. Administration of an anti-ICOS antibody to GVHD-SSc mice prevented the expansion of ICOS+ TFH-like cells and inhibited inflammation and dermal fibrosis. Interleukin-21 neutralization in GVHD-SSc mice blocked disease pathogenesis by reducing skin fibrosis. These results identify ICOS+ TFH-like profibrotic cells as key drivers of fibrosis in a GVHD-SSc model and suggest that inhibition of these cells could offer therapeutic benefit for SSc. PMID- 29514999 TI - Malaria in pregnancy alters l-arginine bioavailability and placental vascular development. AB - Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. l Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. We hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that l-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, we show that MIP was associated with lower concentrations of l-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, l-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance l-arginine bioavailability as strategies to improve birth outcomes. PMID- 29515000 TI - Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia. AB - Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3alpha/beta inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent beta-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of beta-catenin are associated with many cancers. Knockdown of GSK3alpha or GSK3beta individually does not increase beta catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp133->Glu196 "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog selective GSK3 inhibitors. These GSK3alpha- and GSK3beta-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3alpha was identified as a therapeutic target using genetic approaches. The GSK3alpha-selective compound BRD0705 inhibits kinase function and does not stabilize beta-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3alpha inhibition, offering a promising therapeutic approach in AML. PMID- 29515001 TI - Smartphone-based blood pressure monitoring via the oscillometric finger-pressing method. AB - High blood pressure (BP) is a major cardiovascular risk factor that is treatable, yet hypertension awareness and control rates are low. Ubiquitous BP monitoring technology could improve hypertension management, but existing devices require an inflatable cuff and are not compatible with such anytime, anywhere measurement of BP. We extended the oscillometric principle, which is used by most automatic cuff devices, to develop a cuff-less BP monitoring device using a smartphone. As the user presses her/his finger against the smartphone, the external pressure of the underlying artery is steadily increased while the phone measures the applied pressure and resulting variable-amplitude blood volume oscillations. A smartphone application provides visual feedback to guide the amount of pressure applied over time via the finger pressing and computes systolic and diastolic BP from the measurements. We prospectively tested the smartphone-based device for real-time BP monitoring in human subjects to evaluate usability (n = 30) and accuracy against a standard automatic cuff-based device (n = 32). We likewise tested a finger cuff device, which uses the volume-clamp method of BP detection. About 90% of the users learned the finger actuation required by the smartphone-based device after one or two practice trials. The device yielded bias and precision errors of 3.3 and 8.8 mmHg for systolic BP and -5.6 and 7.7 mmHg for diastolic BP over a 40 to 50 mmHg range of BP. These errors were comparable to the finger cuff device. Cuff-less and calibration-free monitoring of systolic and diastolic BP may be feasible via a smartphone. PMID- 29515003 TI - Type 2 diabetes mellitus severity correlates with risk of hip fracture in patients with osteoporosis. AB - BACKGROUND: Osteoporosis is a major public health problem because of its associated fractures and the resulting complications. The objective of this study was to identify the association between the severity of type 2 diabetes mellitus (T2DM) and the risk of hip fracture in osteoporotic patients. METHODS: The patients who received a diagnosis of osteoporosis between 2006 and 2010, with an adequate follow-up between 2006 and 2015, were enrolled in this study. Among patients with T2DM, the severity of the disease was evaluated using the Diabetes Complication Severity Index (DCSI). Logistic regression models were used to calculate the odds ratios and to predict the risk of hip fracture in diabetic osteoporotic patients. RESULTS: A total of 1188 patients were enrolled in the final study, 87 patients had hip fractures in the follow-up period between 2006 and 2015. Among the diabetic patients, each level of the continuous DCSI was associated with a 1.56-fold greater risk of hip fracture. In further stratification, patients with a DCSI > 3 had a significantly higher risk of hip fracture in comparison with those with a DCSI <= 1. The categorical DCSI (DCSI > 3), HbA1c level on the diagnosis of T2DM and duration of diabetes, facilitate predicting the risk of hip fracture. CONCLUSION: The severity of T2DM reflects the risk of hip fracture in osteoporotic patients. Physicians should pay attention to osteoporotic patients presenting with a high HbA1c level on diagnosis of T2DM and a higher DCSI because of their vulnerability to hip fracture. PMID- 29515002 TI - A PET imaging approach for determining EGFR mutation status for improved lung cancer patient management. AB - Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. We report a positron emission tomography (PET) tracer, N-(3-chloro-4 fluorophenyl)-7-(2-(2-(2-(2-18F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6 methoxyquinazolin-4-amine (18F-MPG), with high specificity to activating EGFR mutant kinase. We evaluate the feasibility of using 18F-MPG PET for noninvasive imaging and quantification of EGFR-activating mutation status in preclinical models of NSCLC and in patients with primary and metastatic NSCLC tumors. 18F-MPG PET in NSCLC animal models showed a significant correlation (R2 = 0.9050) between 18F-MPG uptake and activating EGFR mutation status. In clinical studies with NSCLC patients (n = 75), the concordance between the detection of EGFR activation by 18F-MPG PET/computed tomography (CT) and tissue biopsy reached 84.29%. There was a greater response to EGFR-TKIs (81.58% versus 6.06%) and longer median progression-free survival (348 days versus 183 days) in NSCLC patients when 18F MPG PET/CT SUVmax (maximum standard uptake value) was >=2.23 versus <2.23. Our study demonstrates that 18F-MPG PET/CT is a powerful method for precise quantification of EGFR-activating mutation status in NSCLC patients, and it is a promising strategy for noninvasively identifying patients sensitive to EGFR-TKIs and for monitoring the efficacy of EGFR-TKI therapy. PMID- 29515004 TI - Hospital standardised mortality ratio: A reliable indicator of quality of care? AB - BACKGROUND: This study investigates (1) whether the hospital standardised mortality ratio (HSMR) model underestimates or overestimates disease severity and (2) the completeness of the data collected by administrators to calculate HSMR in a cohort of deceased patients with the diagnosis of pneumonia. METHODS: In this retrospective cohort study Pneumonia Severity Index (PSI) and Abbreviated Mortality in Emergency Department Sepsis (abbMEDS) scores and associated mortality probabilities were obtained from 32 deceased pneumonia patients over the year 2014 in the VU University Medical Centre. These were compared with mortality probabilities of the Central Bureau for Statistics (CBS) calculated for every patient using the HSMR model. Clinical charts were examined to extract relevant comorbidities to determine the reliability of data sent to the national registration of hospital care. RESULTS: Risk categories determined by using the PSI and the abbMEDS were significantly higher compared with the risk categories according to HSMR (p = 0.001, respectively p = 0.000). The mean difference between the number of comorbidities in our registration and the coders' registration was 1.97 (p = 0.00). The mean difference was 0.97 (p = 0.000) for the number of comorbidities of influence on the Charlson Comorbidity Index (CCI) and 1.25 (p = 0.001) for the calculated CCI. CONCLUSION: The results of this study suggest that the mortality probabilities as calculated by the CBS are an underestimation of the risk of dying for each patient. Our study also showed that the registration of data sent to the CBS underestimated the actual comorbidities of the patient, and could possibly influence the HSMR. PMID- 29515005 TI - Residents' readiness for out-of-hours service: a Dutch national survey. AB - BACKGROUND: Residents play a crucial role in out-of-hours service. Their perceived readiness for out-of-hours service, however, remains underexposed. This national exploratory study assesses whether or not Dutch residents feel sufficiently prepared to provide out-of-hours service at the time of their first shift, and aims to identify factors influencing perceived readiness. METHODS: An online questionnaire focussing on residents' working conditions was accessible from 21 September to 10 November 2015. Questions targeting perceived readiness for out-of-hours service were presented to all responding medical residents actively involved in out-of-hours service. Residents who felt sufficiently prepared were compared with residents who did not, exploring both individual characteristics and environmental factors. RESULTS: A total of 960 residents (mean age 32.5 years +/-; 3.5, 72.4% female) from over 30 different medical specialties were included. Thirty-six percent of responding residents felt insufficiently prepared to provide out-of-hours service at the time of their first shift. Current junior status (p = 0.020), prolonged clinical experience prior to the first shift (p < 0.001), targeted training (p < 0.001), assessment of relevant skills and competencies (p < 0.001), and formal consequences following negative assessment (p = 0.001) were positively associated with perceived readiness. CONCLUSION: One-third of responding residents felt insufficiently prepared for their first out-of-hours shift. Our results emphasise the need for sufficient time to gain clinical experience as a new graduate, and underline the positive contribution of targeted training and assessment of skills and competencies relevant to out-of-hours service. PMID- 29515006 TI - Nonsteroidal anti-inflammatory drug hypersensitivity: not always an allergy! AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of hypersensitivity reactions. Several distinct clinical syndromes are described regarding NSAID hypersensitivity. Such a reaction is generally caused by a non immunological mechanism. In susceptible patients, COX-1 inhibition leads to an imbalance in lipid mediators such as leukotrienes and prostaglandins. It is essential to distinguish multiple nonspecific NSAID hypersensitivity from single NSAID hypersensitivity, since the management of these respective syndromes is essentially different. This review provides an overview on all the aspects of NSAID hypersensitivity reactions, from pathophysiology to clinical symptoms, leading practical recommendations. PMID- 29515008 TI - Distrusting confidence. PMID- 29515007 TI - Clinical value of serum lactate measurement in diagnosing acute mesenteric ischaemia. AB - Acute mesenteric ischaemia (AMI) is a life-threatening disease with a mortality rate around 60%. This high mortality rate is largely caused by diagnostic delay, which means there is a pressing need for a reliable biomarker. In clinical practice, serum lactate measurement is often used for the diagnosis of AMI. To assess the diagnostic value of serum lactate, we performed a literature search. Lactate has two different isomers. The well-known L-lactate, produced by anaerobic glycolysis, and the more unknown D-lactate which is only produced by intestinal bacteria. In this review, we present and evaluate the current literature on the diagnostic value of the measurement of both lactate isomers. Furthermore, we suggest another biomarker which might have the potential to serve as a useful diagnostic test in the future. PMID- 29515009 TI - Pancreatitis as the presenting symptom of abdominal sarcoidosis. AB - We present a 60-year-old woman with non-pulmonary sarcoidosis manifesting as acute pancreatitis, possibly due to hypercalcaemia. Pancreatitis in sarcoidosis is rare, particularly as a presenting symptom. This case demonstrates that sarcoidosis should be included in the differential diagnosis of pancreatitis with hypercalcaemia, even without pulmonary signs of sarcoidosis. PMID- 29515010 TI - An unusual causative pathogen of sepsis after a cat bite: Anaerobiospirillum succiniciproducens. AB - A 40-year-old woman with a history of liver cirrhosis presented with septic shock caused by an Anaerobiospirillum succiniciproducens bacteraemia after a cat bite. A. succiniciproducens sepsis can develop after a cat or dog bite, especially in immunocompromised hosts, or might occur after translocation from the gut flora. It is a potentially lethal infection. PMID- 29515011 TI - A special twist in the suspicion of cancer. PMID- 29515012 TI - Answer to Photo Quiz: A special twist in the suspicion of cancer. PMID- 29515013 TI - An unusual cause of chronic abdominal symptoms. PMID- 29515014 TI - Answer to Photo Quiz: An unusual cause of chronic abdominal symptoms. PMID- 29515016 TI - Answer to Photo Quiz: Occupational lung disease on a farm. PMID- 29515015 TI - Occupational lung disease on a farm. PMID- 29515018 TI - Answer to Photo Quiz: Traumatic tracheal intubation: An uncommon cause of acute airway obstruction. PMID- 29515017 TI - Traumatic tracheal intubation: An uncommon cause of acute airway obstruction. PMID- 29515019 TI - Introduction of a deformable x-ray CT polymer gel dosimetry system. AB - This study introduces the first 3D deformable dosimetry system based on x-ray computed tomography (CT) polymer gel dosimetry and establishes the setup reproducibility, deformation characteristics and dose response of the system. A N isopropylacrylamide (NIPAM)-based gel formulation optimized for x-ray CT gel dosimetry was used, with a latex balloon serving as the deformable container and low-density polyethylene and polyvinyl alcohol providing additional oxygen barrier. Deformable gels were irradiated with a 6 MV calibration pattern to determine dosimetric response and a dosimetrically uniform plan to determine the spatial uniformity of the response. Wax beads were added to each gel as fiducial markers to track the deformation and setup of the gel dosimeters. From positions of the beads on CT images the setup reproducibility and the limits and reproducibility of gel deformation were determined. Comparison of gel measurements with Monte Carlo dose calculations found excellent dosimetric accuracy, comparable to that of an established non-deformable dosimetry system, with a mean dose discrepancy of 1.5% in the low-dose gradient region and a gamma pass rate of 97.9% using a 3%/3 mm criterion. The deformable dosimeter also showed good overall spatial dose uniformity throughout the dosimeter with some discrepancies within 20 mm of the edge of the container. Tracking of the beads within the dosimeter found that sub-millimetre setup accuracy is achievable with this system. The dosimeter was able to deform and relax when externally compressed by up to 30 mm without sustaining any permanent damage. Internal deformations in 3D produced average marker movements of up to 12 mm along the direction of compression. These deformations were also shown to be reproducible over 100 consecutive deformations. This work has established several important characteristics of a new deformable dosimetry system which shows promise for future clinical applications, including the validation of deformable dose accumulation algorithms. PMID- 29515020 TI - High-purity production of ultrathin boron nitride nanosheets via shock chilling and their enhanced mechanical performance and transparency in nanocomposite hydrogels. AB - A simple, highly efficient, and eco-friendly method is prepared to divide bulk boron nitride (BN) into boron nitride nanosheets (BNNSs). Due to the anisotropy of the hexagonal BN expansion coefficient, bulk BN is exfoliated utilizing the rapid and tremendous change in temperature, the extreme gasification of water, and ice thermal expansion pressure under freeze drying. The thickness of most of the BNNSs was less than ~3 nm with a yield of 12-16 wt%. The as-obtained BNNS/polyacrylamide (PAAm) composite hydrogels exhibited outstanding mechanical properties. The tensile strength is fives times the bulk of the BN/PAAm composite hydrogels and the elongations are more than nine-fold the bulk of the BN/PAAm composite hydrogels. The BNNS/PAAm nanocomposite hydrogels also exhibited excellent elastic recovery, and the hysteresis of the BNNS nanocomposite hydrogels was negligible even after 30 cycles with a maximum tensile strain (epsilon max) of 700%. This work provides new insight into the fabrication of BN/polymer nanocomposites utilizing the excellent mechanical properties and transparency of BN. The results confirm that a few layers of BNNSs can also efficiently and directly improve the mechanical properties of composite polymer due to its stronger surface free energy and better wettability. PMID- 29515021 TI - Thyroid metastases from renal cell carcinoma. Report of a case and review of the literature. AB - Metastases to thyroid gland are a rare occurrence in surgical practice. The most frequent primitive tumor is renal cell carcinoma. We report a case of thyroid metastasis from renal cell carcinoma in a 70-year-old man who underwent left nephrectomy ten years earlier, presented with a diagnosis of multinodular goiter, associated with thyroiditis and right laterocervical lymphadenopathy. A total and the surgical excision of laterocervical lymph node were performed. The results, according to the histological examination, were metastases from renal cell carcinoma, involving both the thyroid gland and the lymph node. Therefore, since the delay of presentation and the difficulties of diagnosis, we recommend log term follow-up of the head and neck region, for those patients with renal cell carcinoma diagnosis. PMID- 29515022 TI - Inhibition of the methyltranferase EZH2 improves aortic performance in experimental thoracic aortic aneurysm. AB - Loss-of-function mutations in genes encoding contractile proteins have been observed in thoracic aortic aneurysms (TAA). To gain insight into the contribution of contractile protein deficiency in the pathogenesis of TAA, we examined human aneurysm samples. We found multiple contractile gene products deficient in TAA samples, and in particular, expression of SM22alpha was inversely correlated with aneurysm size. SM22alpha-deficient mice demonstrated pregnancy-induced aortic dissection, and SM22alpha deficiency worsened aortic aneurysm in Fbn1C1039G/+ (Marfan) mice, validating this gene product as a TAA effector. We found that repression of SM22alpha was enforced by increased activity of the methyltransferase EZH2. TGF-beta effectors such as SMAD3 were excluded from binding SM22alpha-encoding chromatin (TAGLN) in TAA samples, while treatment with the EZH2 inhibitor GSK343 improved cytoskeletal architecture and restored SM22alpha expression. Finally, inhibition of EZH2 improved aortic performance in Fbn1C1039G/+ mice, in association with restoration of contractile protein expression (including SM22alpha). Together, these data inform our understanding of contractile protein deficiency in TAA and support the pursuit of chromatin modifying factors as therapeutic targets in aortic disease. PMID- 29515023 TI - LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity. AB - Excess lipid accumulation is an early signature of nonalcoholic fatty liver disease (NAFLD). Although liver receptor homolog 1 (LRH-1) (encoded by NR5A2) is suppressed in human NAFLD, evidence linking this phospholipid-bound nuclear receptor to hepatic lipid metabolism is lacking. Here, we report an essential role for LRH-1 in hepatic lipid storage and phospholipid composition based on an acute hepatic KO of LRH-1 in adult mice (LRH-1AAV8-Cre mice). Indeed, LRH-1 deficient hepatocytes exhibited large cytosolic lipid droplets and increased triglycerides (TGs). LRH-1-deficient mice fed high-fat diet displayed macrovesicular steatosis, liver injury, and glucose intolerance, all of which were reversed or improved by expressing wild-type human LRH-1. While hepatic lipid synthesis decreased and lipid export remained unchanged in mutants, elevated circulating free fatty acid helped explain the lipid imbalance in LRH 1AAV8-Cre mice. Lipidomic and genomic analyses revealed that loss of LRH-1 disrupts hepatic phospholipid composition, leading to lowered arachidonoyl (AA) phospholipids due to repression of Elovl5 and Fads2, two critical genes in AA biosynthesis. Our findings reveal a role for the phospholipid sensor LRH-1 in maintaining adequate pools of hepatic AA phospholipids, further supporting the idea that phospholipid diversity is an important contributor to healthy hepatic lipid storage. PMID- 29515024 TI - Identification of periplakin as a major regulator of lung injury and repair in mice. AB - Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury. Deletion of the Ppl gene in mice improved survival and reduced lung fibrosis development after bleomycin-induced injury. Notably, Ppl deletion promoted an antiinflammatory alveolar environment linked to profound changes in type 2 alveolar epithelial cells, including overexpression of antiinflammatory cytokines, decreased expression of profibrotic mediators, and altered cell signaling with a reduced response to TGF-beta1. These results identify periplakin as a previously unidentified regulator of the response to injury in the lung. PMID- 29515025 TI - Nlrp3-dependent IL-1beta inhibits CD103+ dendritic cell differentiation in the gut. AB - Inflammatory bowel disease (IBD) is associated with enhanced levels of the IL-1 family cytokines IL-1beta and IL-18, which are activated by the Nlrp3 inflammasome. Here, we investigated the role of inflammasome-driven cytokine release on T cell polarization and DC differentiation in steady state and T cell transfer colitis. In vitro and in vivo data showed that IL-1beta induces Th17 polarization and increases GM-CSF production by T cells. Reduced IL-1beta levels in Nlrp3-/- mice correlated with enhanced FLT3L levels and increased frequency of tolerogenic CD103+ DC. In the T cell transfer colitis model, Nlrp3 deficiency resulted in lower IL-1beta levels, reduced Th17 immunity, and less severe colitis. Unaltered IL-18 levels in both mouse strains pointed toward Nlrp3 independent processing. Importantly, cohousing revealed that the gut microbiome had no impact on the observed Nlrp3-/- phenotype. This study demonstrates that NLRP3 acts as a molecular switch of intestinal homeostasis by shifting local immune cells toward an inflammatory phenotype via IL-1beta. PMID- 29515026 TI - Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD. AB - Autosomal dominant polycystic kidney disease (ADPKD) can be caused by mutations in the PKD1 or PKD2 genes. The PKD1 gene product is a Wnt cell-surface receptor. We previously showed that a lack of the PKD2 gene product, PC2, increases beta catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether beta catenin signaling plays a role in polycystic kidney disease phenotypes or if a Wnt inhibitor can halt cyst formation in ADPKD disease models. Here, using genetic and pharmacologic approaches, we demonstrated that the elevated beta catenin signaling caused by PC2 deficiency contributes significantly to disease phenotypes in a mouse ortholog of human ADPKD. Pharmacologically inhibiting beta catenin stability or the production of mature Wnt protein, or genetically reducing the expression of Ctnnb1 (which encodes beta-catenin), suppressed the formation of renal cysts, improved renal function, and extended survival in ADPKD mice. Our study clearly demonstrates the importance of beta-catenin signaling in disease phenotypes associated with Pkd2 mutation. It also describes the effects of two Wnt inhibitors, XAV939 and LGK974, on various Wnt signaling targets as a potential therapeutic modality for ADPKD, for which there is currently no effective therapy. PMID- 29515027 TI - Interferon-gamma converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1. AB - Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM, but while IFN-gamma-activated ECs (gamma-ECs) show increased ability to stimulate alloreactive T cells, IFN-gamma-activated PCs (gamma-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, gamma-PCs, ECs, and gamma-ECs reveal induction of indoleamine 2,3 dioxygenase 1 (IDO1) in gamma-PCs to significantly higher levels than in gamma ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces gamma-PC-mediated immunoregulatory effects. Furthermore, human PCs express IDO1 in a skin allograft rejection humanized mouse model and in human renal allografts with acute T cell-mediated rejection. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-gamma-induced IDO1-mediated tryptophan depletion. PMID- 29515028 TI - Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus. AB - B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients. PMID- 29515030 TI - NRG1-Fc improves metabolic health via dual hepatic and central action. AB - Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake. PMID- 29515029 TI - Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site. AB - Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs-specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades. PMID- 29515031 TI - Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. AB - Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy. PMID- 29515032 TI - Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus host disease. AB - Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ-specific approaches to block immunopathology while avoiding global immune suppression. PMID- 29515033 TI - Calnexin is necessary for T cell transmigration into the central nervous system. AB - In multiple sclerosis (MS), a demyelinating inflammatory disease of the CNS, and its animal model (experimental autoimmune encephalomyelitis; EAE), circulating immune cells gain access to the CNS across the blood-brain barrier to cause inflammation, myelin destruction, and neuronal damage. Here, we discovered that calnexin, an ER chaperone, is highly abundant in human brain endothelial cells of MS patients. Conversely, mice lacking calnexin exhibited resistance to EAE induction, no evidence of immune cell infiltration into the CNS, and no induction of inflammation markers within the CNS. Furthermore, calnexin deficiency in mice did not alter the development or function of the immune system. Instead, the loss of calnexin led to a defect in brain endothelial cell function that resulted in reduced T cell trafficking across the blood-brain barrier. These findings identify calnexin in brain endothelial cells as a potentially novel target for developing strategies aimed at managing or preventing the pathogenic cascade that drives neuroinflammation and destruction of the myelin sheath in MS. PMID- 29515034 TI - Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice. AB - Insulin resistance is associated with increased incidence and enhanced progression of cancers. However, little is known about strategies that can effectively ameliorate insulin resistance and consequently halt cancer progression. Herein, we propose that the transcription factor Nrf2 (also known as Nfe2l2) may be such a target, given its central role in disease prevention. To this end, we developed a mouse that overexpresses the Notch intracellular domain in adipocytes (AdNICD), leading to lipodystrophy-induced severe insulin resistance and subsequent development of sarcomas, as a model reflecting that Notch signaling is deregulated in cancers and shows positive associations with insulin resistance and fatty liver disease in humans. Nrf2 pathway activation was achieved by knocking down Keap1, a repressor of Nrf2, in the AdNICD background. Constitutively enhanced Nrf2 signaling in this setting led to prevention of hepatic steatosis, dyslipidemia, and insulin resistance by repressing hepatic lipogenic pathways and restoration of the hepatic fatty acid profile to control levels. This protective effect of Nrf2 against diabetes extended to significant reduction and delay in sarcoma incidence and latency. Our study highlights that the Nrf2 pathway, which has been induced by small molecules in clinical trials, is a potential therapeutic target against insulin resistance and subsequent risk of cancer. PMID- 29515035 TI - Exosomal microRNA predicts and protects against severe bronchopulmonary dysplasia in extremely premature infants. AB - Premature infants are at high risk for developing bronchopulmonary dysplasia (BPD), characterized by chronic inflammation and inhibition of lung development, which we have recently identified as being modulated by microRNAs (miRNAs) and alterations in the airway microbiome. Exosomes and exosomal miRNAs may regulate cell differentiation and tissue and organ development. We discovered that tracheal aspirates from infants with severe BPD had increased numbers of, but smaller, exosomes compared with term controls. Similarly, bronchoalveolar lavage fluid from hyperoxia-exposed mice (an animal model of BPD) and supernatants from hyperoxia-exposed human bronchial epithelial cells (in vitro model of BPD) had increased exosomes compared with air controls. Next, in a prospective cohort study of tracheal aspirates obtained at birth from extremely preterm infants, utilizing independent discovery and validation cohorts, we identified unbiased exosomal miRNA signatures predictive of severe BPD. The strongest signal of reduced miR-876-3p in BPD-susceptible compared with BPD-resistant infants was confirmed in the animal model and in vitro models of BPD. In addition, based on our recent discovery of increased Proteobacteria in the airway microbiome being associated with BPD, we developed potentially novel in vivo and in vitro models for BPD combining Proteobacterial LPS and hyperoxia exposure. Addition of LPS led to a larger reduction in exosomal miR 876-3p in both hyperoxia and normoxia compared with hyperoxia alone, thus indicating a potential mechanism by which alterations in microbiota can suppress miR 876-3p. Gain of function of miR 876-3p improved the alveolar architecture in the in vivo BPD model, demonstrating a causal link between miR 876-3p and BPD. In summary, we provide evidence for the strong predictive biomarker potential of miR 876-3p in severe BPD. We also provide insights on the pathogenesis of neonatal lung disease, as modulated by hyperoxia and microbial product-induced changes in exosomal miRNA 876-3p, which could be targeted for future therapeutic development. PMID- 29515036 TI - Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis. AB - BACKGROUND: Cirrhosis is associated with gut microbial changes, but current 16S rDNA techniques sequence both dead and live bacteria. We aimed to determine the rRNA content compared with DNA from the same stool sample to evaluate cirrhosis progression and predict hospitalizations. METHODS: Cirrhotics and controls provided stool for RNA and DNA analysis. Comparisons were made between cirrhotics/controls and within cirrhosis (compensated/decompensated, infected/uninfected, renal dysfunction/not, rifaximin use/not) with respect to DNA and RNA bacterial content using linear discriminant analysis. A separate group was treated with omeprazole for 14 days with longitudinal microbiota evaluation. Patients were followed for 90 days for hospitalizations. Multivariable models for hospitalizations with clinical data with and without DNA and RNA microbial data were created. RESULTS: Twenty-six controls and 154 cirrhotics (54 infected, 62 decompensated, 20 renal dysfunction, 18 rifaximin) were included. RNA and DNA analysis showed differing potentially pathogenic taxa but similar autochthonous taxa composition. Thirty subjects underwent the omeprazole study, which demonstrated differences between RNA and DNA changes. Thirty-six patients were hospitalized within 90 days. In the RNA model, MELD score and Enterococcus were independently predictive of hospitalizations, while in the DNA model MELD was predictive and Roseburia protective. In both models, adding microbiota significantly added to the MELD score in predicting hospitalizations. CONCLUSION: DNA and RNA analysis of the same stool sample demonstrated differing microbiota composition, which independently predicts the hospitalization risk in cirrhosis. RNA and DNA content of gut microbiota in cirrhosis are modulated differentially with disease severity, infections, and omeprazole use. TRIAL REGISTRATION: NCT01458990. FUNDING: VA Merit I0CX001076. PMID- 29515037 TI - Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. AB - BACKGROUND: A defining pathophysiologic feature of sepsis is profound apoptosis induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common gamma-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia. Twenty seven patients at academic sites in France and the United States received CYT107 or placebo for 4 weeks. Primary aims were to determine the safety of CYT107 in sepsis and its ability to reverse lymphopenia. RESULTS: CYT107 was well tolerated without evidence of inducing cytokine storm or worsening inflammation or organ dysfunction. CYT107 caused a 3- to 4-fold increase in absolute lymphocyte counts and in circulating CD4+ and CD8+ T cells that persisted for weeks after drug administration. CYT107 also increased T cell proliferation and activation. CONCLUSIONS: This is the first trial of an immunoadjuvant therapy targeting defects in adaptive immunity in patients with sepsis. CYT107 reversed the marked loss of CD4+ and CD8+ immune effector cells, a hallmark of sepsis and a likely key mechanism in its morbidity and mortality. CYT107 represents a potential new way forward in the treatment of patients with sepsis by restoring adaptive immunity. Such immune-based therapy should be broadly protective against diverse pathogens including multidrug resistant bacteria that preferentially target patients with impaired immunity. TRIAL REGISTRATION: Trials registered at clinicaltrials.gov: NCT02640807 and NCT02797431. FUNDING: Revimmune, NIH National Institute of General Medical Sciences GM44118. PMID- 29515038 TI - Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection. AB - Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair. PMID- 29515039 TI - Physiological mechanisms of sustained fumagillin-induced weight loss. AB - Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feeding. Here, we show that feeding of rats on a high-fat diet supplemented with fumagillin (HF/FG) suppresses the aggressive feeding observed in pair-fed controls (HF/PF) and alters expression of circadian genes relative to the HF/PF group. Multiple indices of reduced energy expenditure are observed in HF/FG but not HF/PF rats. HF/FG rats also exhibit changes in gut hormones linked to food intake, increased energy harvest by gut microbiota, and caloric spilling in the urine. Studies in gnotobiotic mice reveal that effects of fumagillin on energy expenditure but not feeding behavior may be mediated by the gut microbiota. In sum, fumagillin engages weight loss-inducing behavioral and physiologic circuits distinct from those activated by simple caloric restriction. PMID- 29515040 TI - A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes. AB - Autoimmune-mediated destruction of pancreatic islet beta cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted. Subjects were followed for 10 years to determine time of seroconversion. Any cohort effect and the time of seroconversion were corrected to uncover genes differentially expressed (DE) in seroconverting children. Gene expression signatures associated with seroconversion were evident during the first year of life, with 67 DE genes identified in seroconverting children relative to those remaining antibody negative. These genes contribute to T cell-, DC-, and B cell-related immune responses. Near-birth expression of ADCY9, PTCH1, MEX3B, IL15RA, ZNF714, TENM1, and PLEKHA5, along with HLA risk score predicted seroconversion (AUC 0.85). The ubiquitin-proteasome pathway linked DE genes and T1D susceptibility genes. Therefore, a gene expression signature in infancy predicts risk of seroconversion. Ubiquitination may play a mechanistic role in diabetes progression. PMID- 29515042 TI - CD8+ T cells in beige adipogenesis and energy homeostasis. AB - Although accumulation of lymphocytes in the white adipose tissue (WAT) in obesity is linked to insulin resistance, it remains unclear whether lymphocytes also participate in the regulation of energy homeostasis in the WAT. Here, we demonstrate enhanced energy dissipation in Rag1-/- mice, increased catecholaminergic input to subcutaneous WAT, and significant beige adipogenesis. Adoptive transfer experiments demonstrated that CD8+ T cell deficiency accounts for the enhanced beige adipogenesis in Rag1-/- mice. Consistently, we identified that CD8-/- mice also presented with enhanced beige adipogenesis. The inhibitory effect of CD8+ T cells on beige adipogenesis was reversed by blockade of IFN gamma. All together, our findings identify an effect of CD8+ T cells in regulating energy dissipation in lean WAT, mediated by IFN-gamma modulation of the abundance of resident immune cells and of local catecholaminergic activity. Our results provide a plausible explanation for the clinical signs of metabolic dysfunction in diseases characterized by altered CD8+ T cell abundance and suggest targeting of CD8+ T cells as a promising therapeutic approach for obesity and other diseases with altered energy homeostasis. PMID- 29515044 TI - Evaluation of mold-enclosed shear bond strength between zirconia core and porcelain veneer. AB - This study aimed to evaluate the mold-enclosed shear bond strength (ME-SBS) of zirconia to veneering porcelain with different surface treatments. Colored or uncolored zirconia coupons were either highly polished or airborne-particle abraded. The specimens were divided into groups with/without application of liner. Veneering porcelain was fired into an alumina ring mold on the zirconia coupons. The assembled specimens were subjected to the ME-SBS test. The mean ME SBS for groups ranged from 7-10 MPa with no significant difference (p>0.05). A three-way ANOVA showed that coloring and surface roughening of the zirconia specimen had no significant influence on the ME-SBS value, but liner application exhibited a significant effect with a minor decrease in the MESBS (p=0.049). Surface treatments (coloring, airborne-particle abrasion, and liner application) were found to not cause a significant increase to the zirconia-porcelain bond strength. The application of zirconia liner had a slight negative influence on the ME-SBS results. PMID- 29515041 TI - Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries. AB - The emergence of community-associated methicillin-resistant Staphylococcus aureus during the past decade along with an impending shortage of effective antistaphylococcal antibiotics have fueled impressive advances in our understanding of how S. aureus overcomes the host environment to establish infection. Backed by recent technologic advances, studies have uncovered elaborate metabolic, nutritional, and virulence strategies deployed by S. aureus to survive the restrictive and hostile environment imposed by the host, leading to a plethora of promising antimicrobial approaches that have potential to remedy the antibiotic resistance crisis. In this Review, we highlight some of the critical and recently elucidated bacterial strategies that are potentially amenable to intervention, discuss their relevance to human diseases, and address the translational challenges posed by current animal models. PMID- 29515043 TI - Early pathogenesis of the foot-and-mouth disease virus O/JPN/2010 in experimentally infected pigs. AB - We examined the histological distribution of the lesions and the viral antigen associated with the virus and virus RNA in multisystemic organs in the early stages of foot-and-mouth disease virus (FMDV) O/JPN/2010 infection in pigs. Characteristic lesions commonly observed in pigs with FMD arise following inoculation with 106 tissue culture infectious dose (TCID)50/ml of FMDV O/JPN/2010 in pigs at 3 days post inoculation (dpi) by a natural infectious route. However, none of the six pigs inoculated with 103 TCID50/ml of FMDV O/JPN/2010 showed any evidence of infection up to 6 dpi. Immunohistochemical detection for the FMDV antigen and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) showed that FMDV predominantly infected prickle cells in the stratum spinosum in the tongue, coronet and bulb of the heel, and caused these infected cells to undergo cell death by apoptosis. However, there was no evidence that FMDV O/JPN/2010 infected epithelial/epidermal basal cells in the basal layer. Epithelial lesions with viral antigen in the tongue were distributed in the dorsal surface but not in the papillae, corpus linguae or inferior surface of the tongue. Non-suppurative myocarditis and epithelial lesions in the esophagus with FMDV antigen were observed in all three pigs examined at 3 dpi. PMID- 29515045 TI - Evaluation of the flexural mechanical properties of various thermoplastic denture base polymers. AB - This study evaluated the flexural mechanical properties of various thermoplastic denture base polymers (six polyamides, four acrylic resins, polyester, polypropylene, and polycarbonate) by three different testing conditions; specimens were tested in water bath at 37 degrees C (Wet/Water, by ISO 20795-1), or in ambient air (Wet/Air) after being immersed in distilled water for 50 h, or after desiccation for 7 days (Dry/Air). The mean ultimate flexural strength (UFS) and flexural modulus (FM) for most products ranged from 27 to 61 MPa and from 611 to 1,783 MPa respectively, which failed to meet the minimum requirements of the international standard, except for polycarbonate (89 and 2,245 MPa). The mean UFS and FM values were ranked Dry/Air>Wet/Air>Wet/Water (p<0.05). In conclusion, the flexural mechanical properties of denture base polymers varied with the products and were significantly affected by the testing medium (air or water) and specimen conditions (wet or dry). PMID- 29515046 TI - Current Status of Rotational Atherectomy in the Drug-Eluting Stent Era. PMID- 29515047 TI - Exploring Deep Into the Coronary Microcirculation of Patients With Microvascular Angina. PMID- 29515048 TI - Progression of Functional Tricuspid Regurgitation With Aortic Valve Stenosis After Intervention. PMID- 29515049 TI - Human Amniotic Fluid Stem Cells: Therapeutic Potential for Perinatal Patients with Intractable Neurological Disease. AB - Mesenchymal stem cells (MSCs) have generated great interest in the fields of regenerative medicine and immunotherapy because of their unique biological properties. Among MSCs, amniotic fluid stem cells (AFS) have a number of characteristics that make them attractive candidates for tissue engineering and cell replacement strategies, particularly for perinatal medicine. If various neonatal conditions, including birth asphyxia, preterm birth, and congenital abnormalities, which result in long-lasting severe impairments, could be predicted during pregnancy, it would allow collection of small samples of amniotic fluid cells by amniocentesis. In vitro culture of these autologous AFS during pregnancy would make them available for use soon after birth. Hypoxic ischemic encephalopathy (HIE) and myelomeningocele (MMC) are neonatal conditions that cause permanent neurological disability, for which the treatment options are extremely limited. Experiments using animal models of HIE and MMC and human clinical trials have demonstrated that MSCs, including AFS, have beneficial effects on the central nervous system through paracrine influences, indicating that autologous AFS treatment may be applicable for intractable neurological diseases, including HIE and MMC, during the perinatal period. In this review, we focus on recent research related to the therapeutic potential of AFS for perinatal neurological diseases such as HIE and MMC. PMID- 29515050 TI - Assessing Impact of High-Dose Pitavastatin on Carotid Artery Elasticity with Speckle-Tracking Strain Imaging. AB - AIM: Speckle-tracking imaging has been introduced for the precise assessment of vessel mechanics. However, there are no data on the role of this imaging tool in assessing the changes in vasculature with statin therapy, which is known to enhance vascular elasticity. METHODS: This study was a prospective study including 48 statin-naive patients (age, 58.2+/-8.4 years; 29.2% male) with hypercholesterolemia. Circumferential carotid artery strain (CAS) and stiffness index (beta2) were measured using speckle-tracking imaging before and after 3 months of high-dose pitavastatin treatment (4 mg daily). For the comparison, we measured conventional carotid elasticity parameters and intima-media thickness using B-mode ultrasound at the same time points. RESULTS: Compared with baseline, there was significant improvement in circumferential CAS (2.98%+/-1.18% to 3.40%+/-1.43%, p=0.008) and beta2 (0.19+/-0.07 to 0.17+/-0.08, p=0.047) after statin therapy. Contrariwise, there were no significant changes in all conventional carotid elasticity metrics and intima-media thickness. When stratifying patients into two subgroups by 10 year atherosclerotic cardiovascular disease (ASCVD) risk, speckle-tracking-derived circumferential CAS and beta2 improved significantly only in patients with ASCVD risk >= 7.5%. CONCLUSIONS: Short-term treatment with high-dose pitavastatin improved carotid artery elasticity measured by speckle-tracking method, but not conventional parameters by B-mode ultrasound. Speckle-tracking-based measurements may allow the early noninvasive assessment of statin effects on vascular function in hypercholesterolemic patients. PMID- 29515051 TI - Circulating Oxidized Low-Density Lipoprotein Levels Independently Predict 10-Year Progression of Subclinical Carotid Atherosclerosis: A Community-Based Cohort Study. AB - AIMS: To investigate the association between circulating oxidized low-density lipoprotein (ox-LDL) levels and progression of subclinical atherosclerosis and to examine whether this link is independent of other low-density lipoprotein (LDL) related parameters. METHODS: Totally, 804 subjects who were free of cardiovascular disease at baseline completed risk factor surveys and carotid ultrasound measurements in 2002 and 2012. Modified Poisson regression was performed to examine the association between baseline serum ox-LDL levels and the 10-year risk of progression of carotid atherosclerosis which was defined as the development of at least one new plaque in a previously plaque-free carotid segment at re-examination. RESULTS: The mean age of the subjects was 58.6+/-7.7 years at baseline and 43.3% were men. A total of 504 (62.7%) subjects had carotid plaque progression at re-examination. Subjects in the intermediate and highest tertiles of ox-LDL had a significantly higher adjusted risk of atherosclerosis progression than those in the lowest tertile [relative risk (95% confidence interval) 1.17 (1.01-1.34) for the intermediate tertile and 1.23 (1.07-1.42) for the highest tertile]. This association was independent of baseline levels of LDL C, total LDL particle number, and small LDL particle number. CONCLUSION: This study demonstrates that serum ox-LDL levels predict 10-year progression of subclinical atherosclerosis. Moreover, this effect is independent of the cholesterol content, the number, and the size of LDL particles. PMID- 29515052 TI - Semi-synthesis of Twelve Known 20Z/E Pseudo-Ginsenosides and Their Comparative Study of Antioxidative Activity in Free Radical Induced Hemolysis of Rabbit Erythrocytes. AB - Twelve pseudo-ginsenosides were synthesized under a mild condition, via a simple three-step called acetylation, elimination-addition and saponification. The inhibitory effects of these twelve pseudo-ginsenosides were screened on the hemolysis of rabbit erythrocytes caused by 2,2'-azobis (2-amidinopropane hydrochloride) (AAPH). It was found that the IC50 values followed the sequence of (20Z) pseudo-protopanaxatriol (pseudo-PPT)<(20Z) pseudo-protopanaxadiol (pseudo PPD)<(20Z) pseudo-Rh2<(20E) pseudo-PPT<(20E) pseudo-PPD<(20E) pseudo-Rh2<(20Z) pseudo-Rg2<(20E) pseudo-Rg20.05) were observed. Moreover, the results of the colony forming unit-fibroblast assay and sphere formation assay demonstrated that the SCB-MSCs had increased self-renewal potential. SCB-MSCs expressed higher levels of the stemness markers Nanog, OCT4, and Sox-2 compared to in BMS-MSCs (P<0.05). Furthermore, the results of both the CCK-8-based assay and CFSE dilution assay showed that SCB-MSCs exhibited enhanced proliferative capacity. In addition, SCB-MSCs exhibited higher phosphorylation of extracellular signal related kinase/mitogen-activated protein kinase signaling, which is closely related to MSC proliferation. In conclusion, we identified SCB-MSCs as a novel stem cell population that met the requirements of MSCs; the unique properties of SCB-MSC are important for the potential treatment of tissue damage resulting from disease and trauma. PMID- 29515060 TI - Isolation and characterization of buffalo (bubalus bubalis) amniotic mesenchymal stem cells derived from amnion from the first trimester pregnancy. AB - Amniotic mesenchymal stem cells (AMSCs) from livestock are valuable resources for animal reproduction and veterinary therapeutic. The purpose of this study is to explore a suitable way to isolate and culture the buffalo AMSCs (bAMSCs), and to identify their biological characteristics. Digestion with a combination of trypsin-EDTA and collagenase type I could obtain pure bAMSCs more effectively than trypsin-EDTA or collagenase type I alone. bAMSCs could proliferate steadily in vitro culture and exhibited fibroblastic-like morphology in vortex-shaped colony. bAMSCs were positive for MSC-specific markers CD44, CD90, CD105, CD73, beta-integrin (CD29) and CD166, and pluripotent markers OCT4, SOX2, NANOG, REX-1, SSEA-1, SSEA-4 and TRA-1-81, but negative for hematopoietic markers CD34, CD45 and epithelial cells specific marker Cytokeratin 18. In addition, bAMSCs were capable of differentiating into adipogenic, osteogenic, chondrogenic and neural lineages, with expression of FABP4, Ost, ACAN, COL2A1, Nestin and beta III tubulin. Glycogen synthase kinase 3 inhibitor: kenpaullone promoted bAMSCs to differentiate into neural lineage. This study provides an effective protocol to obtain and characterize bAMSCs, which have proven useful as a cell resource for buffalo cell reprogramming studies and transgenic animal production. PMID- 29515061 TI - Successful treatment of refractory demodicosis and transient papules with a single dose of fluralaner in a dog with uncontrolled severe endocrine disease. AB - A 12-year-old female Shih-Tzu with hyperadrenocorticism and hypothyroidism developed concurrent refractory generalized demodicosis that did not respond to doramectin treatment. Although amitraz treatment was effective, the dog developed severe diabetes, which resulted in the cessation of amitraz and trilostane. Attempts to control the diabetes were unsuccessful, and its hyperadrenocorticism was left untreated, leading to the recurrence of demodicosis. However, demodicosis went into complete remission with a single dose of fluralaner. Transient erythematous papules appeared on the trunk three days after the administration of fluralaner, but no other adverse reactions were noted. We demonstrated that fluralaner is a potent treatment for demodicosis, and skin eruptions are possible after the first dose of the drug. PMID- 29515063 TI - ? PMID- 29515064 TI - [Clinical characteristics of vascular adverse events and significance of peripheral artery disease as a risk factor in chronic myeloid leukemia patients treated with nilotinib]. AB - Vascular adverse events (VAEs) in chronic myeloid leukemia (CML) patients treated with nilotinib (NIL) has become a; however, studies on strategies to prevent VAEs remain limited. Therefore, the present study investigated VAEs in 19 CML patients treated with NIL at our hospital. The median age of the patients was 65 years and median follow-up period was 55 months after the initiation of NIL. VAEs occurred in 8 patients (peripheral artery disease (PAD), n=6; cerebral infarction (CI), n=3; coronary artery disease (CAD), n=4). The median elapsed time from the initiation of NIL to VAEs was 42 months. The 4-year cumulative incidence of VAEs was 23.5%. Majority of the patients with VAEs were smokers (P=0.074). All the six patients with PAD were diagnosed on the basis of the ankle-brachial index (ABI<0.9) in the asymptomatic phase; 4 of these patients had other VAEs (CI, n=1; CAD, n=2; CI and CAD, n=1). However, antecedent asymptomatic PAD was diagnosed even before CAD was diagnosed in two patients. Nevertheless, in cardiology, extensive studies have indicated that asymptomatic PAD is a risk factor for the development of cardiovascular events. In conclusion, for the effective management of CML patients treated with NIL, a routine screening with ABI to diagnose asymptomatic PAD may be beneficial in preventing severe VAEs. PMID- 29515062 TI - Verification of the causal relationship between subchronic exposures to dinotefuran and depression-related phenotype in juvenile mice. AB - It has been suggested that an increase in the use of pesticides affects neurodevelopment, but there has been no animal experiment showing a causal relation between neonicotinoid pesticides (NNs) and depression. We examined whether dinotefuran (DIN), the most widely used NN in Japan, induces depression. Male mice were administered DIN between 3 and 8 weeks of age, referring to the no observed-effect level (NOEL). The mice were then subjected to a tail suspension test (TST) and a forced swimming test (FST). After these tests, their brains were dissected for immunohistochemical analyses of serotonin (5-HT). Antidepressant activity in TST and no decrease in 5-HT-positive cells were observed. The subchronic exposure to DIN alone in juvenile male mice may not cause depression like indication. PMID- 29515065 TI - [Efficacy and safety of biosimilar filgrastim for autologous peripheral blood stem cell harvest and transplantation: a single-institutional retrospective analysis]. AB - Three biosimilar filgrastim products are currently available in Japan. Among these, the safety and efficacy of two imported drugs for autologous peripheral blood stem cell harvest (autoPBSCH) and autologous peripheral blood stem cell transplantation (autoPBSCT) have been studied widely; however, evidence of the safety and efficacy of domestically manufactured filgrastim is limited. Therefore, we compared the efficacy and safety of domestic biosimilar filgrastim (BF1, n=23) with those of originator filgrastim (OF, n=21) for autoPBSCH and autoPBSCT. Before autoPBSCH, the same median total dose of 3.3 mg filgrastim was administered to patients in the BF1 and OF groups. Median numbers of CD34 positive cells harvested did not significantly differ between BF1 (4.32*106/kg) and OF (4.75*106/kg) groups. After autoPBSCT, the median total doses of BF1 and OF used for neutrophil recovery were 2.7 and 3.3 mg, respectively. There were no significant inter-group differences in the time to bone marrow recovery, total transfusion units, hospitalization duration, overall survival at 1 year, or adverse events. Compared with OF, the cost of BF1 was considerably lower by 229,529 yen per transplantation case. Thus, the efficacy and safety of BF1 were comparable to those of OF, making BF1 an effective and economical alternative to OF. PMID- 29515066 TI - [Japan Marrow Donor Program and its coordinating process: current situations]. AB - We evaluated 18,487 patients and 223,842 cases of donor coordination among patients enrolled in the Japan Marrow Donor Program (JMDP) from January 2004 to December 2013. For patients who underwent stem cell transplantation from a JMDP donor [unrelated bone marrow transplantation (UBMT)], the median number of coordination and days from registration to transplantation were 11 and 146, respectively. Among enrolled patients, 40% did not undergo UBMT. With the increased estimated number of human leukocyte antigen 6/6-matched donors, the probability of undergoing UBMT was higher, and in those who underwent UBMT, the duration of coordination was shorter. Regarding the reasons for the termination of coordination, those attributable to the donors varied depending on the age and sex of the donors. Male donors in their 20s had lower and higher termination rates because of health conditions and inconvenience, respectively, compared with donors of different age and female sex. Among donors who experienced coordination more than once, the donation rate was higher if the precedent coordination ended because of reasons attributable to the patient compared with the donation rate because of other reasons. Using the results of our study, strategies to achieve a more efficient and rapid coordination process are warranted. PMID- 29515067 TI - [Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance mimicking POEMS syndrome]. AB - A 40-year-old female presented with a skin rash, hepatosplenomegaly, hypothyroidism, IgG-lambda monoclonal gammopathy, slightly elevated serum VEGF levels, and >1-year history of weakness in the posterior cervical muscles. Based on these symptoms and her clinical course, she was suspected of having POEMS syndrome. However, because there was no sign of peripheral neuropathy (PN), the criteria for the diagnosis of POEMS syndrome were not met. Consequently, she continued follow-up and was under close observation as an outpatient. She complained of slowly progressive dyspnea that was identified as type 2 respiratory failure requiring non-invasive positive pressure ventilation. She received systemic chemotherapy, including thalidomide and dexamethasone, as the respiratory failure was predominantly a result of POEMS-associated PN. Although the skin eruptions improved upon treatment, respiratory failure gradually worsened, and she required mechanical ventilation. The patient was suspected of having sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS), because of resistant to chemotherapy and second opinion suggestion. A thigh muscle biopsy revealed the presence of nemaline rods and led to the definitive diagnosis of SLONM-MGUS. Unfortunately, she was unable to receive autologous stem cell transplantation, and finally died because of progressive respiratory failure. SLONM-MGUS is an extremely rare disease but should be considered as a critical, monoclonal-protein related condition. PMID- 29515068 TI - [Pediatric acute lymphoblastic leukemia presenting with bone and joint pain]. AB - We report on three cases of pediatric acute lymphoblastic leukemia presenting with bone pain and arthralgia as initial symptoms. At the first visit, their primary signs were recurrent bone pain and arthralgia, without significant peripheral blood abnormalities. It took 2-4 months to confirm the diagnosis from the onset of arthralgia due to this atypical presentation of the disease. Definitive diagnosis was obtained by bone marrow examination, and in all cases, complete remission was achieved by chemotherapy. As a feature of imaging, MRI exhibited diffuse bone marrow signal changes in T1-weighted images, and FDG-PET showed extensive abnormal bone marrow uptakes. In cases 2 and 3, it was difficult to diagnose by bone marrow aspiration from the iliac bone, but definitive diagnosis was obtained by bone marrow aspiration from the tibia, in which FDG-PET showed increased uptake. FDG-PET was therefore considered useful for the selection of bone marrow aspiration sites. In cases presenting with recurrent migratory bone pain and arthralgia, we need to consider performing bone marrow aspiration and imaging, such as MRI and FDG-PET, for early diagnosis and treatment of leukemia. PMID- 29515069 TI - [Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment]. AB - A 37-year-old woman was diagnosed with chronic phase chronic myeloid leukemia. Nilotinib treatment was initiated; however, it had to be discontinued due to an allergic reaction one month later, and dasatinib treatment was provided. Although favorable response was obtained, she started complaining of shortness of breath 7 months after initiating dasatinib treatment. Chest X-ray and echocardiography indicated pulmonary congestion and hypertension. Further, she was diagnosed with mixed connective tissue disease (MCTD) based on Raynaud phenomenon, swollen fingers, sclerodactyly, pancytopenia, hypocomplementemia, and positive anti-U1 RNP antibody. Consequently, dasatinib treatment was discontinued, and she was administered prednisolone (1 mg/kg/day), which was effective and successfully tapered with concomitant administration of cyclophosphamide. This is the first case of MCTD that developed during dasatinib treatment. However, because the present case was a young woman, the development of MCTD could probably be attributed to autoimmune diatheses or it may be a coincidence. However, the possibility of patients receiving dasatinib treatment developing autoimmune diseases needs to be assessed. PMID- 29515070 TI - [Atypical hemolytic uremic syndrome with C3 p.I1157T missense mutation successfully treated with eculizumab]. AB - A 23-year-old man from Mie Prefecture, Japan, with past and family history of hematuria was diagnosed with influenza A and admitted to our hospital on the following day because of hemoglobinuria. He was diagnosed with thrombotic microangiopathy and was suspected of having atypical hemolytic uremic syndrome (aHUS). C3 p.I1157T missense mutation, which we had previously reported in eight aHUS patients from six families in Mie Prefecture, was identified. The laboratory findings and symptoms of our patient promptly improved after administering eculizumab. Little information is available on abnormalities of the complement system in aHUS or on mutation-specific outcomes of eculizumab therapy. Eculizumab was effective for treating our aHUS patient with C3 p.I1157T missense mutation. PMID- 29515071 TI - [Atypical hemolytic uremic syndrome in an elderly patient successfully treated with eculizumab]. AB - Herein, we present an elderly onset case of aHUS successfully treated with eculizumab. An 80-year-old woman with severe anemia, thrombocytopenia, and acute renal dysfunction was admitted to our hospital. A laboratory test revealed steep elevation in the LDH level, and the peripheral blood smear showed erythrocyte fragmentations. Accordingly, we diagnosed thrombotic microangiopathy, and treatment with plasma exchange was immediately initiated. In addition, she required hemodialysis because of rapid impairment of the renal function. After excluding Shiga toxin-producing Escherichia coli infection and malignancy and confirming her ADMTS13 activity above 10%, we diagnosed aHUS, according to the Japanese diagnostic criteria for aHUS. Next, we initiated treatment with eculizumab. Her hematological findings improved 23 days after the starting of eculizumab. In addition, her renal function gradually recovered, and hemodialysis was discontinued. The genetic test for several complement regulatory genes tested negative. The onset of aHUS is reported in children or young adults and is rarely reported in elderly. However, our case suggests the importance of precisely diagnosing aHUS and initiating early administration of eculizumab for improving the outcome even in elderly patients. PMID- 29515072 TI - [Long-term administration of brentuximab vedotin in a patient with primary cutaneous anaplastic large cell lymphoma with peripheral blood involvement with leukemic change]. AB - We report a case of long-term administration of brentuximab vedotin (BV) for primary cutaneous anaplastic large cell lymphoma (pc-ALCL) with leukemic change. A 67-year-old man with lymphadenopathy was admitted to our hospital. Six years ago, he was diagnosed with pc-ALCL at another hospital, and complete remission was achieved with radiation therapy. We performed a biopsy of his lymph node and diagnosed the recurrence of pc-ALCL with leukemic change. Initially, CHOP and GCD regimens were ineffective; however, partial remission was achieved following BV therapy. Thus far, he has received 42 courses of BV; he has responded well to the treatment and no serious side effects have been observed. PMID- 29515074 TI - [Overview]. PMID- 29515073 TI - [Essential thrombocythemia complicated by intracranial thrombohemorrhagic events]. AB - Although the life expectancy if patients with essential thrombocythemia (ET) is considered to be almost similar to that of the general population, advanced age, leukocytosis, and a previous history of thrombosis are poor prognostic factors, and it is important to prevent thrombohemorrhagic events, leukemic transformation, and secondary malignancies. We report an 85-year-old ET patient with a history of asymptomatic lacunar infarction, who developed symptomatic cerebral infarction and even chronic subdural hematoma. It is necessary to follow patients who have asymptomatic cerebral infarction or chronic ischemic change and to examine the necessity of brain imaging and treatment intervention at the time of diagnosis. PMID- 29515075 TI - [Mesenchymal stem cell therapy in hematopoietic stem cell transplantation]. AB - Mesenchymal stem cells (MSCs) have received considerable attention in allogeneic hematopoietic cell transplantation because of their abilities to modulate immune responses and promote hematopoiesis. Because MSCs are capable of producing several cytokines and growth factors, they have been widely used in the treatment of graft-versus-host disease (GVHD). A number of clinical trials have demonstrated the safety and efficacy of MSC therapy for acute GVHD. Moreover, in Japan, allogeneic bone marrow-derived MSC product, TEMCELL(r), was approved as a regenerative medicine for acute GVHD. Besides, MSCs can also produce bone marrow stroma and promote hematopoiesis, the co-transplantation of hematopoietic stem cells and MSCs have been efficiently performed in cord blood transplantation and HLA-mismatched transplantation to enhance engraftment and prevent GVHD. In this review, we provide an overview of clinical trials using MSCs in allogeneic hematopoietic cell transplantation and discuss the possibilities and optimization of MSC therapy. PMID- 29515076 TI - [Immunotherapy for refractory viral infections]. AB - Various antiviral agents have been developed, which are sometimes associated with toxicity, development of virus-resistant strain, and high cost. Virus-specific T cell (VST) therapy provides an alternative curative therapy that can be effective for a prolonged time without eliciting drug resistance. VSTs can be directly separated using several types of capture devices and can be obtained by stimulating peripheral blood mononuclear cells with viral antigens (virus, protein, or peptide) loaded on antigen-presenting cells (APC). APC can be transduced with virus-antigen coding plasmid or pulsed with overlapping peptides. VST therapy has been studied in drug non-responsive viral infections after hematopoietic cell transplantation (HCT). Several previous studies have demonstrated the efficacy of VST therapy without significant severe GVHD. In addition, VSTs from a third-party donor have been prepared and administered for post-HCT viral infection. Although target viruses of VSTs include herpes virus species and polyomavirus species, a wide variety of pathogens, such as papillomavirus, intracellular bacteria, and fungi, can be treated by pathogen specific T-cells. Perhaps, these specific T-cells could be used for opportunistic infections in other immunocompromised hosts in the near future. PMID- 29515077 TI - [Cancer immunotherapy using gene-engineered T cells]. AB - Cancer immunotherapies using gene-engineered T cells comprise adoptive transfer of T-cell receptor (TCR) and chimeric antigen receptor (CAR) gene-transduced T cells. Although CD19-targeting CAR-T cell therapy is the most progressed, wherein B-cell malignancy is treated efficiently, it also induces cytokine release syndrome and neurotoxicity, which frequently leads to serious adverse events. Of note, TCR-T cell therapy has been primarily used to target melanoma, resulting in 30%-50% of tumor responses. In clinical trials that target NY-ESO-1-expressing synovial sarcoma, a high efficacy of 50%-60% has been obtained. To date, no specific clinical efficacy has been reported for epithelial tumors. Serious on target adverse effects in normal tissues have been reported when using affinity enhanced TCR of mutated or mouse-derived ones. Furthermore, there are potential risks in using high-affinity TCRs and in targeting tumor antigens that may also be expressed in normal tissues. PMID- 29515078 TI - [Immune cell therapy using iPS cells]. AB - Adoptive cell therapy using tumor-infiltrating T cells has shown durable responses in patients with melanoma, and immunotherapy using genetically engineered T cells (TCR-T or CAR-T) is rapidly emerging as a promising treatment, especially for hematological malignancies. However, the progress is limited because of the lack of readily available good-quality human T cells. Although the efficacy of adoptive cell therapy correlates with the quality of infusing T cells, most antigen-specific T cells in patients with cancer have been exhausted. To overcome this, we have reprogrammed donor (or original) T cells to iPS cells (T-iPS) and differentiated these into rejuvenated antigen-specific cells (T-iPS T). Moreover, iPS cells provide an unlimited source of genetically engineered T cells such as TCR/CAR-T or PD-1 knockout T cells. The iPS cells' potential for immune cell therapy is infinite. PMID- 29515079 TI - ? PMID- 29515080 TI - ? PMID- 29515081 TI - A Devised Option of Neonatal Palliation for Compromised Tetralogy of Fallot with Absent Pulmonary Valve Syndrome. AB - Neonatal primary repair of tetralogy of Fallot (TOF) with absent pulmonary valve (APV) syndrome is associated with high mortality rates. Our plan involves a staged repair that avoids one-stage intracardiac repair (ICR), with a first palliation that closes the main pulmonary orifice using an expanded polytetrafluoroethylene (ePTFE) patch, pulmonary arterioplication, and an adjustable Blalock-Taussig (BT) shunt. This strategy was used for a neonatal case with TOF/APV syndrome with hypoplastic left ventricle (LV). There was evidence of subsequent progressive increase in the LV size, and bronchial compression was relieved and an ICR was performed successfully at 9 months of age. PMID- 29515082 TI - Thymectomy during Myasthenic Crisis under Artificial Respiration. AB - A 34-year-old man was diagnosed with thymoma, which was evaluated preoperatively as stage II or III, with myasthenia gravis (MG). The size of the tumor was 70 * 44 * 80 mm. No invasion to neighboring organs was observed. Prednisolone was prescribed for stabilization of MG. However, a myasthenic crisis (MC) occurred, and intensive care, including emergent endobronchial intubation followed by artificial ventilation, pulse steroid therapy, high-dose intravenous immunoglobulin, and tacrolimus hydrate, was initiated. A chest computed tomography on day 6 revealed tumor reduction to 50 * 30 * 60 mm. An extended total thymectomy by median sternotomy was performed, and artificial ventilation was continued after that. Scheduled artificial ventilation and steroid therapy together can, therefore, enable complete resection of thymoma in patients undergoing treatment for MC. While ventilation helps avert a respiratory failure, the steroid therapy temporarily reduces the tumor size, making resection easier. PMID- 29515083 TI - Heart Valve Surgery in Patients with Patent Coronary Artery Bypass Grafts. PMID- 29515084 TI - A Comparison of Black-blood T2 Mapping Sequences for Carotid Vessel Wall Imaging at 3T: An Assessment of Accuracy and Repeatability. AB - PURPOSE: This study is to compare the accuracy of four different black-blood T2 mapping sequences in carotid vessel wall. METHODS: Four different black-blood T2 mapping sequences were developed and tested through phantom experiments and 17 healthy volunteers. The four sequences were: 1) double inversion-recovery (DIR) prepared 2D multi-echo spin-echo (MESE); 2) DIR-prepared 2D multi-echo fast spin echo (MEFSE); 3) improved motion-sensitized driven-equilibrium (iMSDE) prepared 3D FSE and 4) iMSDE prepared 3D fast spoiled gradient echo (FSPGR). The concordance correlation coefficient and Bland-Altman statistics were used to compare the sequences with a gold-standard 2D MESE, without blood suppression in phantom studies. The volunteers were scanned twice to test the repeatability. Mean and standard deviation of vessel wall T2, signal-to-noise (SNR), the coefficient of variance and interclass coefficient (ICC) of the two scans were compared. RESULTS: The phantom study demonstrated that T2 measurements had high concordance with respect to the gold-standard (all r values >0.9). In the volunteer study, the DIR 2D MEFSE had significantly higher T2 values than the other three sequences (P < 0.01). There was no difference in T2 measurements obtained using the other three sequences (P > 0.05). iMSDE 3D FSE had the highest SNR (P < 0.05) compared with the other three sequences. The 2D DIR MESE has the highest repeatability (ICC: 0.96, [95% CI: 0.88-0.99]). CONCLUSION: Although accurate T2 measurements can be achieved in phantom by the four sequences, in vivo vessel wall T2 quantification shows significant differences. The in vivo images can be influenced by multiple factors including black-blood preparation and acquisition method. Therefore, a careful choice of acquisition methods and analysis of the confounding factors are required for accurate in vivo carotid vessel wall T2 measurements. From the settings in this study, the iMSDE prepared 3D FSE is preferred for the future volunteer/patient scans. PMID- 29515085 TI - Improved 3D-real Inversion Recovery: A Robust Imaging Technique for Endolymphatic Hydrops after Intravenous Administration of Gadolinium. PMID- 29515086 TI - MR Imaging of Secondary Massive Ovarian Edema Caused by Ovarian Metastasis from Appendiceal Adenocarcinoma. PMID- 29515087 TI - Non-contrast-enhanced T1 Mapping of Dilated Cardiomyopathy: Comparison between Native T1 Values and Late Gadolinium Enhancement. AB - PURPOSE: We sought to use non-contrast-enhanced T1 mapping to determine the native T1 values required to identify myocardial fibrosis in patients with dilated cardiomyopathy (DCM). METHODS: A total of 25 patients with DCM and 15 healthy controls were enrolled. All subjects underwent T1 mapping using modified look-locker inversion recovery, and the patients underwent late gadolinium enhancement (LGE) imaging. Basal and mid-ventricular levels were divided into eight segments and the T1 value was measured in each segment. The T1 values of septal segments with LGE were compared with those of the septal segments without LGE, the minimum T1 value of each patient, and the T1 values of the normal septal myocardium. RESULTS: Late gadolinium-enhancement was present in 12 septal segments (24.0%) from 10 patients (40.0%). T1 values were significantly higher in septal segments with LGE than in those without (1373.7 vs. 1288.0 ms; P = 0.035) or in normal septal myocardium (1209.1 ms; P < 0.01). A receiver operating characteristic analysis revealed the appropriate cutoff value of 1349.4 ms for identifying LGE with a sensitivity of 75% and specificity of 92.1%. When the minimum T1 value + 1.2 standard deviation (SD) was used as the threshold, the sensitivity was 75% and specificity was 89.5%. CONCLUSION: Non-contrast-enhanced T1 mapping can be used for assessment of myocardial fibrosis associated with DCM by using the appropriate threshold. PMID- 29515090 TI - King cobra peptide OH-CATH30 as a potential candidate drug through clinic drug resistant isolates. AB - Cationic antimicrobial peptides (AMPs) are considered as important candidate therapeutic agents, which exert potent microbicidal properties against bacteria, fungi and some viruses. Based on our previous findings king cobra cathelicidin (OH-CATH) is a 34-amino acid peptide that exerts strong antibacterial and weak hemolytic activity. The aim of this research is to evaluate the efficacy of both OH-CATH30 and its analog D-OH-CATH30 against clinical isolates comparing with routinely utilized antibiotics in vitro. In this study, 584 clinical isolates were tested (spanning 2013-2016) and the efficacy of the candidate peptides and antibiotics were determined by a broth microdilution method according to the CLSI guidelines. Among the 584 clinical isolates, 85% were susceptible to OH-CATH30 and its analogs. Both L- and D-OH-CATH30 showed higher efficacy against (toward) Gram-positive bacteria and stronger antibacterial activity against nearly all Gram-negative bacteria tested compare with antibiotics. The highest bactericidal activity was detected against Acinetobacter spp., including multi-drug-resistant Acinetobacter baumannii (MRAB) and methicillin-resistant Staphylococcus aureus (MRSA). The overall efficacy of OH-CATH30 and its analogs was higher than that of the 9 routinely used antibiotics. OH-CATH30 is a promising candidate drug for the treatment of a wide variety of bacterial infections which are resistant to many routinely used antimicrobial agents. PMID- 29515088 TI - In vivo genome editing thrives with diversified CRISPR technologies. AB - Prokaryotic type II adaptive immune systems have been developed into the versatile CRISPR technology, which has been widely applied in site-specific genome editing and has revolutionized biomedical research due to its superior efficiency and flexibility. Recent studies have greatly diversified CRISPR technologies by coupling it with various DNA repair mechanisms and targeting strategies. These new advances have significantly expanded the generation of genetically modified animal models, either by including species in which targeted genetic modification could not be achieved previously, or through introducing complex genetic modifications that take multiple steps and cost years to achieve using traditional methods. Herein, we review the recent developments and applications of CRISPR-based technology in generating various animal models, and discuss the everlasting impact of this new progress on biomedical research. PMID- 29515091 TI - Biogeography of the Shimba Hills ecosystem herpetofauna in Kenya. AB - The Shimba Hills ecosystem along the south coast of Kenya is a key East African biodiversity hotspot. Historically, it is biogeographically assignable to the East African coastal biome. We examined the current Shimba Hills herpetofauna and their zoogeographical affinities to the coastal forests and nearby Eastern Arc Mountains biodiversity hotspots. The key studied sites included the Shimba Hills National Reserve, forest reserves, Kaya forests, and adjacent private land. Data on herpetofaunal richness were obtained from recent field surveys, literature, and specimens held at the National Museums of Kenya, Herpetology Section Collection, Nairobi. The Makadara, Mwele, and Longo-Mwagandi forests within the Shimba Hills National Reserve hosted the highest number of unique and rare species. Generally, the forest reserves and Kaya forests were important refuges for forest-associated species. On private land, Mukurumudzi Dam riparian areas were the best amphibian habitat and were host to three IUCN (Red List) Endangered EN amphibian species, namely, Boulengerula changamwensis, Hyperolius rubrovermiculatus, and Afrixalus sylvaticus, as well as one snake species Elapsoidea nigra. Using herpetofauna as zoogeographic indicators, the Shimba Hills were determined to be at a crossroads between the coastal forests (13 endemic species) and the Eastern Arc Mountains (seven endemic species). Most of the Eastern Arc Mountains endemic species were from recent records, and thus more are likely to be found in the future. This 'hybrid' species richness pattern is attributable to the hilly topography of the Shimba Hills and their proximity to the Indian Ocean. This has contributed to the Shimba Hills being the richest herpetofauna area in Kenya, with a total of 89 and 36 reptile and amphibian species, respectively. Because of its unique zoogeography, the Shimba Hills ecosystem is undoubtedly a key biodiversity area for conservation investment. PMID- 29515092 TI - Discovery of Japalura chapaensis Bourret, 1937 (Reptilia: Squamata: Agamidae) from Southeast Yunnan Province, China. AB - Due to a paucity of surveys in northern Indochina and lack of international collaborations among neighboring countries, recognized distributional ranges for many amphibian and reptile species end at the political borders for some countries, despite seemingly continuous suitable habitat spanning the region. Combining both morphological and genetic data, we report the first discovery of Japalura chapaensis, a rare agamid lizard believed previously to be endemic to northern Vietnam only, along the border region of southeastern Yunnan Province, China. To facilitate future research on the genus Japalura sensu lato in Indochina, we provide detailed descriptions of additional specimens of this rare species, including the first description of coloration in life and an expanded diagnosis, and discuss the species boundary of J. chapaensis with respect to its congeners. PMID- 29515089 TI - Kidney disease models: tools to identify mechanisms and potential therapeutic targets. AB - Acute kidney injury (AKI) and chronic kidney disease (CKD) are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models (mainly genetically modified mouse models). Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored. PMID- 29515093 TI - Stereotypy and variability of social calls among clustering female big-footed myotis (Myotis macrodactylus). AB - Echolocating bats have developed advanced auditory perception systems, predominantly using acoustic signaling to communicate with each other. They can emit a diverse range of social calls in complex behavioral contexts. This study examined the vocal repertoire of five pregnant big-footed myotis bats (Myotis macrodactylus). In the process of clustering, the last individual to return to the colony (LI) emitted social calls that correlated with behavior, as recorded on a PC-based digital recorder. These last individuals could emit 10 simple monosyllabic and 27 complex multisyllabic types of calls, constituting four types of syllables. The social calls were composed of highly stereotyped syllables, hierarchically organized by a common set of syllables. However, intra-specific variation was also found in the number of syllables, syllable order and patterns of syllable repetition across call renditions. Data were obtained to characterize the significant individual differences that existed in the maximum frequency and duration of calls. Time taken to return to the roost was negatively associated with the diversity of social calls. Our findings indicate that variability in social calls may be an effective strategy taken by individuals during reintegration into clusters of female M. macrodactylus. PMID- 29515094 TI - AutoSeqMan: batch assembly of contigs for Sanger sequences. AB - With the wide application of DNA sequencing technology, DNA sequences are still increasingly generated through the Sanger sequencing platform. SeqMan (in the LaserGene package) is an excellent program with an easy-to-use graphical user interface (GUI) employed to assemble Sanger sequences into contigs. However, with increasing data size, larger sample sets and more sequenced loci make contig assemble complicated due to the considerable number of manual operations required to run SeqMan. Here, we present the 'autoSeqMan' software program, which can automatedly assemble contigs using SeqMan scripting language. There are two main modules available, namely, 'Classification' and 'Assembly'. Classification first undertakes preprocessing work, whereas Assembly generates a SeqMan script to consecutively assemble contigs for the classified files. Through comparison with manual operation, we showed that autoSeqMan saved substantial time in the preprocessing and assembly of Sanger sequences. We hope this tool will be useful for those with large sample sets to analyze, but with little programming experience. It is freely available at https://github.com/ Sun-Yanbo/autoSeqMan. PMID- 29515095 TI - Complete mitochondrial genome of the Thai Red Junglefowl (Gallus gallus) and phylogenetic analysis. AB - In this study, we sequenced the complete mitochondrial genome (mitogenome) of the Thai Red Junglefowl (RJF; Gallus gallus) using the next-generation sequencing (NGS) platform of the Ion Torrent PGM. Samples were taken from Mae Wang District, Chiang Mai Province, northern Thailand. Our data showed the complete mitogenome to be 16 785 bp in length, composed by 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and one control region. The genome nucleotide composition was 30.3% A, 23.7% T, 32.5% C, and 13.5% G, resulting in a high percentage of A+T (50.4%). Phylogenetic analysis revealed that the mitogenome belonged to haplogroup X, whereas those of all domestic chickens belong to haplogroups A to G. This newly released mitogenome sequence will advance further evolutionary and population genetics study of the RJF and domestic chicken. The availability of the G. gallus mitogenome will also contribute to further conservation genetics research of a unique species, listed as 'data deficient' in Thailand. PMID- 29515096 TI - Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies. AB - BACKGROUND Human lung cancer is still the leading cause of cancer-related mortality around the world, although a variety of new therapies have been used in the treatment of this disease. Antibody-drug conjugate (ADC) has revolutionized the field of cancer therapy in recent decades. Unlike traditional chemotherapy that damages the healthy cells, ADC first utilizes monoclonal antibodies to bind tumor-specific antigen targets and then deliver a highly potent cytotoxic agent to kill tumor cells. Thus, ADC can benefit cancer patients because this drug has less severe adverse effects. MATERIAL AND METHODS One type of ADC for non-small cell lung cancer (NSCLC) was designed in this study: Erbitux-vc-PAB-MMAE. It is a mouse/human chimeric monoclonal antibody, Erbitux, conjugating to the tubulin inhibitor auristatin. The efficacy of ADC was investigated through in vitro and in vivo studies. RESULTS Our in vitro study demonstrated that Erbitux-vc-PAB-MMAE could effectively inhibit proliferation of human lung cancer A549 cells, and arrested cell cycle at G2/M phase. In a mouse xenograft model, the results indicated that Erbitux-vc-PAB-MMAE could be exactly delivered to tumor tissues, and effectively inhibited tumor growth via promoting apoptosis of cancer cells. CONCLUSIONS The antibody portion of an ADC drug (Erbitux) was used as a vector to bring the effector molecule (tubulin inhibitor MMAE) to the targeted tumor tissue. This antibody-drug conjugate can exert a strong anti-tumor effect. PMID- 29515097 TI - Multiple Lymphomatous Polyposis of the Intestine with Ileocecal Intussusception Due to Mantle Cell Lymphoma: A Case Report of a 34-Year-Old Man. AB - BACKGROUND Multiple lymphomatous polyposis of the gastrointestinal tract can be associated with the B-cell lymphoma variant, mantle cell lymphoma, with most cases having been described in patients who are more than 50 years-of-age. A rare case of multiple lymphomatous polyposis due to mantle cell lymphoma is reported in a 34-year-old man. CASE REPORT A 34-year-old man presented with paroxysmal abdominal pain followed by spontaneous remission, which had been previously diagnosed as gastritis. An episode of ileocecal intussusception occurred, which was confirmed on imaging studies. The diagnosis of multiple lymphomatous polyposis due to mantle cell lymphoma was confirmed following ileocecal resection and histopathology. The patient refused to receive chemotherapy following surgery. Currently, at two-year follow-up, no further abnormality has been found. A review of the literature has shown the importance of endoscopic evaluation in the diagnosis of lymphomatous polyposis. CONCLUSIONS Multiple lymphomatous polyposis due to mantle cell lymphoma has rarely been described in young patients under the age of 50 years. Gastrointestinal endoscopic examination is important for the early diagnosis of multiple lymphomatous polyposis. PMID- 29515098 TI - LncRNA HCP5 promotes follicular thyroid carcinoma progression via miRNAs sponge. AB - Long non-coding RNAs (lncRNAs), which are important functional regulators in cancer, have received increased attention in recent years. In this study, next generation sequencing technology was used to identify aberrantly expressed lncRNAs in follicular thyroid carcinoma (FTC). The long non-coding RNA-HLA complex P5 (HCP5) was found to be overexpressed in FTC. The results of the qPCR analysis were consistent with the sequencing results. In addition, functional experiments showed that overexpression of HCP5 can promote the proliferation, migration, invasiveness and angiogenic ability of FTC cells. Furthermore, according to the sequencing results, HCP5 and alpha-2, 6-sialyltransferase 2 (ST6GAL2) were co-expressed in FTC. We hypothesised that ST6GAL2 may be regulated by HCP5, which would in turn mediate the activity of FTC cells. Through qPCR, immunostaining analyses and functional experiments, we determined that the expression of HCP5 was elevated and was correlated with the levels of ST6GAL2 in FTC tissues and cells. Mechanistic experiments showed that HCP5 functions as a competing endogenous RNA (ceRNA) and acts as a sponge for miR-22-3p, miR-186-5p and miR-216a-5p, which activates ST6GAL2. In summary, our study revealed that HCP5 is a tumour regulator in the development of FTC and that it may contribute to improvement of FTC diagnosis and therapy. PMID- 29515099 TI - Improving genetic prediction by leveraging genetic correlations among human diseases and traits. AB - Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. PMID- 29515100 TI - A multi-omic analysis reveals the role of fumarate in regulating the virulence of enterohemorrhagic Escherichia coli. AB - The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) is responsible for outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) worldwide. Several molecular mechanisms have been described for the pathogenicity of EHEC; however, the role of bacterial metabolism in the virulence of EHEC during infection in vivo remains unclear. Here we show that aerobic metabolism plays an important role in the regulation of EHEC virulence in Caenorhabditis elegans. Our functional genomic analyses showed that disruption of the genes encoding the succinate dehydrogenase complex (Sdh) of EHEC, including the sdhA gene, attenuated its toxicity toward C. elegans animals. Sdh converts succinate to fumarate and links the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) simultaneously. Succinate accumulation and fumarate depletion in the EHEC sdhA mutant cells were also demonstrated to be concomitant by metabolomic analyses. Moreover, fumarate replenishment to the sdhA mutant significantly increased its virulence toward C. elegans. These results suggest that the TCA cycle, ETC, and alteration in metabolome all account for the attenuated toxicity of the sdhA mutant, and Sdh catabolite fumarate in particular plays a critical role in the regulation of EHEC virulence. In addition, we identified the tryptophanase (TnaA) as a downstream virulence determinant of SdhA using a label free proteomic method. We demonstrated that expression of tnaA is regulated by fumarate in EHEC. Taken together, our multi-omic analyses demonstrate that sdhA is required for the virulence of EHEC, and aerobic metabolism plays important roles in the pathogenicity of EHEC infection in C. elegans. Moreover, our study highlights the potential targeting of SdhA, if druggable, as alternative preventive or therapeutic strategies by which to combat EHEC infection. PMID- 29515101 TI - Synergistic actions of FGF2 and bone marrow transplantation mitigate radiation induced intestinal injury. AB - Unwanted radiological or nuclear exposure remains a public health risk for which effective therapeutic countermeasures are lacking. Here, we evaluated the efficacy of fibroblast growth factor-2 (FGF2) in treating radiation-induced gastrointestinal syndrome (RIGS) incurred by lethal whole-body irradiation (WBI) when administered in conjunction with bone marrow transplantation (BMT). In vitro experiments indicated FGF2 treatment increased proliferation, reduced apoptosis, and upregulated AKT-GSK3beta/beta-catenin signaling in irradiated IEC-6 cells. We next established and analyzed mice cohorts consisting of sham irradiation (Group Sh); 12 Gy WBI (Group A); WBI with BMT (Group B); WBI with FGF2 treatment (Group F); and WBI with BMT and FGF2 treatment (Group BF). At 2 weeks post-irradiation, Group BF showed a dramatic increase in survival over all other groups. Intestinal epithelium of Group BF, but not Group B or F, showed augmented proliferation, decreased apoptosis, and preserved crypt numbers and morphology. Furthermore, Group BF maintained intestinal barrier function with minimal inflammatory disturbances in a manner comparable to Group Sh. In accordance, transcriptomic analyses showed significant upregulation of intestinal barrier and stem cell markers in Group BF relative to Groups A and B. Taken together, parenteral FGF2 synergizes with BMT to confer potent mitigation against RIGS. PMID- 29515103 TI - Candida blankii: an emergent opportunistic yeast with reduced susceptibility to antifungals. PMID- 29515102 TI - Early-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila. AB - Environmental stresses experienced during development exert many long-term effects upon health and disease. For example, chemical oxidants or genetic perturbations that induce low levels of reactive oxygen species can extend lifespan in several species. In some cases, the beneficial effects of low-dose oxidants are attributed to adaptive protective mechanisms such as mitohormesis, which involve long-term increases in the expression of stress response genes. Here we show in Drosophila that transient exposure to low concentrations of oxidants during development leads to an extension of adult lifespan. Surprisingly, this depends upon oxidants acting in an antibiotic-like manner to selectively deplete the microbiome of Acetobacter proteobacteria. We demonstrate that the presence of Acetobacter species, such as A. aceti, in the indigenous microbiota increases age-related gut dysfunction and shortens lifespan. This study demonstrates that low-dose oxidant exposure during early life can extend lifespan via microbiome remodelling rather than mitohormesis. PMID- 29515104 TI - Detailed analysis of clonal evolution and cytogenetic evolution patterns in patients with myelodysplastic syndromes (MDS) and related myeloid disorders. AB - Clonal cytogenetic evolution (CE) (i.e., acquisition of new chromosomal aberrations over time) is relevant for the progression of myelodysplastic syndromes (MDS). We performed detailed analysis of CE in 729 patients with MDS and related disorders. Patients with CE showed shorter survival (median OS 18.0 versus 53.9 months; P < 0.01), higher leukemic transformation rate (48.0% versus 21.4%; P < 0.01) and shorter intervals to leukemic transformation (P < 0.01). Two main CE patterns were detected: early versus late CE (median onset 5.3 versus 21.9 months; P < 0.01) with worse survival outcomes for early CE. In the case of CE, del (7q)/-7 (P = 0.020) and del (17p) (P = 0.002) were especially unfavorable. Extending the evolution patterns from Tricot et al. (1985) forming five subgroups, prognosis was best (median OS not reached) in patients with "transient clones/changing clone size", whereas those with "CE at diagnosis" showed very poor outcomes (P < 0.01 for comparison of all). Detailed sequential cytogenetic analysis during follow-up improves prognostication in MDS patients and acknowledges the dynamic biology of the disease. Evidence, time-point, and patterns of cytogenetic clonal evolution should be included into future prognostic scoring systems for MDS. PMID- 29515105 TI - Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression. AB - Cancer stem cells (CSCs) niche in the tumor microenvironment is responsible for cancer recurrence and therapy failure. To better understand its molecular and biological involvement in hepatocellular carcinoma (HCC) progression, one can design more effective therapies and tailored then to individual patients. While sorafenib is currently the only approved drug for first-line treatment of advanced stage HCC, its role in modulating the CSC niche is estimated to be small. By contrast, transforming growth factor (TGF)-beta pathway seems to influence the CSC and thus may impact hallmarks of HCC, such as liver fibrosis, cirrhosis, and tumor progression. Therefore, blocking this pathway may offer an appealing and druggable target. In our study, we have used galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-beta receptor I (TGFbetaI/ALK5) activation, currently under clinical investigation in HCC patients. Because the drug resistance is mainly mediated by CSCs, we tested the effects of galunisertib on stemness phenotype in HCC cells to determine whether TGF-beta signaling modulates CSC niche and drug resistance. Galunisertib modulated the expression of stemness-related genes only in the invasive (HLE and HLF) HCC cells inducing a decreased expression of CD44 and THY1. Furthermore, galunisertib also reduced the stemness-related functions of invasive HCC cells decreasing the formation of colonies, liver spheroids and invasive growth ability. Interestingly, CD44 loss of function mimicked the galunisertib effects on HCC stemness-related functions. Galunisertib treatment also reduced the expression of stemness-related genes in ex vivo human HCC specimens. Our observations are the first evidence that galunisertib effectiveness overcomes stemness-derived aggressiveness via decreased expression CD44 and THY1. PMID- 29515106 TI - A dual-function epidermal growth factor receptor pathway substrate 8 (Eps8) derived peptide exhibits a potent cytotoxic T lymphocyte-activating effect and a specific inhibitory activity. AB - The identification and characterization of tumor-associated antigens (TAAs) that generate specific cytotoxic T lymphocytes (CTLs) are vital to the development of cancer immunotherapy. The epidermal growth factor receptor (EGFR) pathway substrate 8 gene (Eps8) is involved in regulating cancer progression and might be an ideal antigen. In this study, we searched for novel human leukocyte antigen (HLA)-A*2402-restricted epitopes derived from the Eps8 protein via the HLA binding prediction algorithm. Among four candidates, peptides 327 (EFLDCFQKF), 534 (KYAKSKYDF) and 755 (LFSLNKDEL) induced peptide-specific CTLs to secrete higher levels of interferon-gamma (IFN-gamma) and showed enhanced cytotoxic activity against malignant cancer cells. Our results demonstrated that peptide specific CTLs showed effective antitumor responses, including upregulation of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), granzyme B and perforin. Treatment with peptide-sensitized peripheral blood mononuclear cells (PBMCs) significantly reduced the tumor growth in vivo compared with the non peptide-sensitized PBMC treatment. Importantly, our results indicated that peptide 327 may interfere with EGFR signaling by mechanistically disrupting Eps8/EGFR complex formation. We extended this observation that peptide 327 also suppressed the viability of cancer cells, blocked EGFR signal pathway and reduced the expression of downstream targets. Notably, conjugation of peptide 327 to the TAT sequence (TAT-327) resulted in potent antitumor activity and selective insertion into cancer cell membranes, where it adopted a punctate distribution. Furthermore, peptide 327 and TAT-327 displayed anticancer properties in xenograft models. Our results indicated that 327, 534 and 755 were novel HLA-A*2402 restricted epitopes from Eps8. By inhibiting the Eps8/EGFR interaction, peptide 327 and TAT-327 may serve as novel peptide inhibitors, which could provide an innovative approach for treating various cancers. PMID- 29515107 TI - PARK2 inhibits osteosarcoma cell growth through the JAK2/STAT3/VEGF signaling pathway. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor mainly occurring in children and adolescents. In past decades, studies revealed that PARK2 was a vital tumor suppressor gene in many malignant solid tumors. However, the role of PARK2 in OS remains largely unclear. Therefore, we assessed PARK2 expression in OS tissue and adjacent non-tumor tissues by immunohistochemical (IHC) analysis, and evaluated PARK2 mRNA expression in OS cell lines by real-time PCR analysis. The HOS and U2OS cell lines were employed to establish a PARK2 overexpression model. Using this model, we investigated the potential role of PARK2 in OS and explored the underlying molecular mechanisms. Our study showed PARK2 was downregulated in OS tissue and cell lines, which was significantly associated with higher tumor stage (P < 0.05). Overexpression of PARK2 arrested the cell cycle, inhibited cell proliferation, migration, and invasion, induced cell apoptosis, and reduced tube formation in vitro. Moreover, overexpression of PARK2 significantly suppressed tumor growth and angiogenesis in vivo. Additionally, PARK2 negatively regulated OS development through the JAK2/STAT3/VEGF pathway. Our findings demonstrate that PARK2 is a tumor suppressor gene that may negatively affect OS growth and angiogenesis via partly inhibiting the JAK2/STAT3/VEGF signaling pathway. PMID- 29515108 TI - The convergent roles of NF-kappaB and ER stress in sunitinib-mediated expression of pro-tumorigenic cytokines and refractory phenotype in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common form of kidney cancer. While cure remains exceptionally infrequent in RCC patients with systemic or recurrent disease, current targeted molecular strategies, including multi-targeted tyrosine kinase inhibitors (TKIs), notably changed the treatment paradigm of advanced renal cancer. Yet, complete and durable responses have been noted in only a few cases. Our studies reveal that sunitinib triggers two resistance-promoting signaling pathways in RCC cells, which emanate from the endoplasmic reticulum (ER) stress response: a PERK-driven ER stress response that induces expression of the pro-tumorigenic cytokines IL-6, IL-8, and TNF-alpha, and a TRAF2-mediated NF kappaB survival program that protects tumor cells against cell death. PERK blockade completely prevents sunitinib-induced expression of IL-6, IL-8 and TNF alpha, whereas NF-kappaB inhibition reinstates sensitivity of RCC cells to sunitinib both in vitro and in vivo. Taken together, our findings indicate that ER stress response may contribute to sunitinib resistance in RCC patients. PMID- 29515109 TI - NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer. AB - Nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA (lncRNA), is a core structural component of paraspeckles and is essential for paraspeckle formation. NEAT1 comprises two different isoforms: NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb). Recently, NEAT1 has been shown to have oncogenic roles and to facilitate tumorigenesis in various human cancers. However, the function of NEAT1 in papillary thyroid cancer (PTC) is not well understood. The relative expression levels of NEAT1_2, ATPase family AAA domain-containing protein 2 (ATAD2), and microRNA-106b-5p (miR-106b-5p) were assessed via quantitative real time reverse transcription polymerase chain reaction (qRT-PCR). Four PTC cell lines were used to detect the relative expression of NEAT1_2. The effects of NEAT1_2 on PTC cells were studied by RNA interference approaches in vitro. The effects of NEAT1_2 on downstream proteins were detected by western blotting. The underlying mechanism was clarified by a rescue experiment, and three dual luciferase reporter assays. NEAT1_2 expression was markedly increased in PTC tissues and the PTC cell lines (K1 and TPC1). The relative expression level of NEAT1_2 was positively associated with TNM stage and tumor size. NEAT1_2 knockdown led to a significant inhibition of growth and metastasis, and induced apoptosis in PTC cells. Knockdown of NEAT1_2 significantly inhibited malignant biological behavior by downregulating the oncogene ATAD2. In addition, NEAT1_2 could act as a competing endogenous RNA to regulate the expression of ATAD2 through downregulating miR-106b-5p. Taken together, our results indicated that NEAT1_2 is overexpressed in PTC. NEAT1_2 could function as a competing endogenous RNA to regulate ATAD2 expression by sponging miR-106b-5p in PTC. Targeting NEAT1_2 could be a promising therapeutic strategy for patients with PTC. PMID- 29515110 TI - Raddeanin A suppresses breast cancer-associated osteolysis through inhibiting osteoclasts and breast cancer cells. AB - Bone metastasis is a severe complication of advanced breast cancer, resulting in osteolysis and increased mortality in patients. Raddeanin A (RA), isolated from traditional Chinese herbs, is an oleanane-type triterpenoid saponin with anticancer potential. In this study, we investigated the effects of RA in breast cancer-induced osteolysis and elucidated the possible mechanisms involved in this process. We first verified that RA could suppress osteoclast formation and bone resorption in vitro. Next, we confirmed that RA suppressed Ti-particle-induced osteolysis in a mouse calvarial model, possibly through inhibition of the SRC/AKT signaling pathway. A breast cancer-induced osteolysis mouse model further revealed the positive protective effects of RA by micro-computed tomography and histology. Finally, we demonstrated that RA inhibited invasion and AKT/mammalian target of rapamycin signaling and induced apoptosis in MDA-MB-231 cells. These results indicate that RA is an effective inhibitor of breast cancer-induced osteolysis. PMID- 29515111 TI - CRLF1 promotes malignant phenotypes of papillary thyroid carcinoma by activating the MAPK/ERK and PI3K/AKT pathways. AB - Papillary thyroid carcinoma (PTC) is the one of the most common types of endocrine cancer and has a heterogeneous prognosis. Tumors from patients with poor prognosis may differentially express specific genes. Therefore, an analysis of The Cancer Genome Atlas (TCGA) database was performed and revealed that cytokine receptor-like factor 1 (CRLF1) may be a potential novel target for PTC treatment. The objective of the current study was to explore the expression of CRLF1 in PTC and to investigate the main functions and mechanisms of CRLF1 in PTC. PTC tissues exhibited higher CRLF1 expression at both the mRNA and protein levels than it did with normal thyroid tissues. High CRLF1 levels were associated with aggressive clinicopathological features and poor disease-free survival rates. By using loss-of-function and gain-of-function assays, we found that CRLF1 not only increased cell migration and invasion in vitro but also promoted tumor growth both in vitro and in vivo. In addition, CRLF1 induced epithelial mesenchymal transitions. Overexpression of CRLF1 activated the ERK1/2 and AKT pathways. The oncogenic effects induced by CRLF1 were suppressed by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor MK-2206. These results suggest that CRLF1 enhances cell proliferation and metastasis in PTC and thus may therefore be a potential therapeutic target for PTC. PMID- 29515112 TI - Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases. AB - Exosomes are nano-vesicles secreted by tumor cells. Exosomes can transfer complex biological information and induce a diverse signaling response in a wide array of pathological conditions, such as hypoxia. Hypoxia is associated with aggressive phenotypes and poor outcomes in nasopharyngeal carcinoma (NPC) patients. Here, we analyzed the role of exosomes from hypoxic NPC cells in enhancing the metastases of normoxic cells in a hypoxia-induced factor-1alpha (HIF-1alpha)-dependent manner. HIF-1alpha rapidly accumulates and trans-activates hundreds of genes, such as matrix metalloproteinases (MMPs). We found that MMP-13 was over-expressed in exosomes and cells under hypoxic conditions. HIF-1alpha depletion in hypoxic CNE2 cells led to decreased MMP-13 levels in exosomes and significantly reduced cell migration and invasion. Moreover, exosomal MMP-13 significantly up-regulated Vimentin expression while decreasing E-cadherin levels in CNE2 cells in vitro and in vivo. Furthermore, MMP-13 levels were closely associated with HIF-1alpha expression (r = 0.679, P < 0.001), lymph node metastasis, clinical stage (all P < 0.05) and poor prognosis in NPC patients (P < 0.01). In conclusion, our findings suggest that the hypoxic exosomes were loaded with MMP-13, which could enhance migration and invasiveness and induce microenvironment changes to promote NPC aggressiveness. PMID- 29515113 TI - Suppressing IL-36-driven inflammation using peptide pseudosubstrates for neutrophil proteases. AB - Sterile inflammation is initiated by molecules released from necrotic cells, called damage-associated molecular patterns (DAMPs). Members of the extended IL-1 cytokine family are important DAMPs, are typically only released through necrosis, and require limited proteolytic processing for activation. The IL-1 family cytokines, IL-36alpha, IL-36beta, and IL-36gamma, are expressed as inactive precursors and have been implicated as key initiators of psoriatic-type skin inflammation. We have recently found that IL-36 family cytokines are proteolytically processed and activated by the neutrophil granule-derived proteases, elastase, and cathepsin G. Inhibitors of IL-36 processing may therefore have utility as anti-inflammatory agents through suppressing activation of the latter cytokines. We have identified peptide-based pseudosubstrates for cathepsin G and elastase, based on optimal substrate cleavage motifs, which can antagonize activation of all three IL-36 family cytokines by the latter proteases. Human psoriatic skin plaques displayed elevated IL-36beta processing activity that could be antagonized by peptide pseudosubstrates specific for cathepsin G. Thus, antagonists of neutrophil-derived proteases may have therapeutic potential for blocking activation of IL-36 family cytokines in inflammatory conditions such as psoriasis. PMID- 29515114 TI - Momelotinib therapy for myelofibrosis: a 7-year follow-up. AB - One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2-7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1-3.2) or SRSF2 (HR 2.4, 95% CI 1.3-4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3-16.9), very high risk karyotype (HR 7.9, 95% CI 1.9-32.1), and circulating blasts >=2% (HR 3.9, 95% CI 1.4-11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB. PMID- 29515115 TI - Two-electron spin correlations in precision placed donors in silicon. AB - Substitutional donor atoms in silicon are promising qubits for quantum computation with extremely long relaxation and dephasing times demonstrated. One of the critical challenges of scaling these systems is determining inter-donor distances to achieve controllable wavefunction overlap while at the same time performing high fidelity spin readout on each qubit. Here we achieve such a device by means of scanning tunnelling microscopy lithography. We measure anti correlated spin states between two donor-based spin qubits in silicon separated by 16 +/- 1 nm. By utilising an asymmetric system with two phosphorus donors at one qubit site and one on the other (2P-1P), we demonstrate that the exchange interaction can be turned on and off via electrical control of two in-plane phosphorus doped detuning gates. We determine the tunnel coupling between the 2P 1P system to be 200 MHz and provide a roadmap for the observation of two-electron coherent exchange oscillations. PMID- 29515116 TI - Ultra-thin enzymatic liquid membrane for CO2 separation and capture. AB - The limited flux and selectivities of current carbon dioxide membranes and the high costs associated with conventional absorption-based CO2 sequestration call for alternative CO2 separation approaches. Here we describe an enzymatically active, ultra-thin, biomimetic membrane enabling CO2 capture and separation under ambient pressure and temperature conditions. The membrane comprises a ~18-nm thick close-packed array of 8 nm diameter hydrophilic pores that stabilize water by capillary condensation and precisely accommodate the metalloenzyme carbonic anhydrase (CA). CA catalyzes the rapid interconversion of CO2 and water into carbonic acid. By minimizing diffusional constraints, stabilizing and concentrating CA within the nanopore array to a concentration 10* greater than achievable in solution, our enzymatic liquid membrane separates CO2 at room temperature and atmospheric pressure at a rate of 2600 GPU with CO2/N2 and CO2/H2 selectivities as high as 788 and 1500, respectively, the highest combined flux and selectivity yet reported for ambient condition operation. PMID- 29515117 TI - Ice-volume-forced erosion of the Chinese Loess Plateau global Quaternary stratotype site. AB - The International Commission on Stratigraphy (ICS) utilises benchmark chronostratigraphies to divide geologic time. The reliability of these records is fundamental to understand past global change. Here we use the most detailed luminescence dating age model yet published to show that the ICS chronology for the Quaternary terrestrial type section at Jingbian, desert marginal Chinese Loess Plateau, is inaccurate. There are large hiatuses and depositional changes expressed across a dynamic gully landform at the site, which demonstrates rapid environmental shifts at the East Asian desert margin. We propose a new independent age model and reconstruct monsoon climate and desert expansion/contraction for the last ~250 ka. Our record demonstrates the dominant influence of ice volume on desert expansion, dust dynamics and sediment preservation, and further shows that East Asian Summer Monsoon (EASM) variation closely matches that of ice volume, but lags insolation by ~5 ka. These observations show that the EASM at the monsoon margin does not respond directly to precessional forcing. PMID- 29515118 TI - Batch production of 6-inch uniform monolayer molybdenum disulfide catalyzed by sodium in glass. AB - Monolayer transition metal dichalcogenides (TMDs) have become essential two dimensional materials for their perspectives in engineering next-generation electronics. For related applications, the controlled growth of large-area uniform monolayer TMDs is crucial, while it remains challenging. Herein, we report the direct synthesis of 6-inch uniform monolayer molybdenum disulfide on the solid soda-lime glass, through a designed face-to-face metal-precursor supply route in a facile chemical vapor deposition process. We find that the highly uniform monolayer film, with the composite domains possessing an edge length larger than 400 um, can be achieved within a quite short time of 8 min. This highly efficient growth is proven to be facilitated by sodium catalysts that are homogenously distributed in glass, according to our experimental facts and density functional theory calculations. This work provides insights into the batch production of highly uniform TMD films on the functional glass substrate with the advantages of low cost, easily transferrable, and compatible with direct applications. PMID- 29515119 TI - Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis. AB - Cancer aberrant N- and O-linked protein glycosylation, frequently resulting from an augmented flux through the Hexosamine Biosynthetic Pathway (HBP), play different roles in tumor progression. However, the low specificity and toxicity of the existing HBP inhibitors prevented their use for cancer treatment. Here we report the preclinical evaluation of FR054, a novel inhibitor of the HBP enzyme PGM3, with a remarkable anti-breast cancer effect. In fact, FR054 induces in different breast cancer cells a dramatic decrease in cell proliferation and survival. In particular, in a model of Triple Negative Breast Cancer (TNBC) cells, MDA-MB-231, we show that these effects are correlated to FR054-dependent reduction of both N- and O-glycosylation level that cause also a strong reduction of cancer cell adhesion and migration. Moreover we show that impaired survival of cancer cells upon FR054 treatment is associated with the activation of the Unfolded Protein Response (UPR) and accumulation of intracellular ROS. Finally, we show that FR054 suppresses cancer growth in MDA-MB-231 xenograft mice, supporting the advantage of targeting HBP for therapeutic purpose and encouraging further investigation about the use of this small molecule as a promising compound for breast cancer therapy. PMID- 29515121 TI - Publisher Correction: Influences of organic carbon speciation on hyporheic corridor biogeochemistry and microbial ecology. AB - The original version of this Article contained an error in Fig. 6e, in which the text in the legend was omitted. This has been corrected in both the PDF and HTML versions of the article. PMID- 29515120 TI - Itch/beta-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis. AB - Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/beta-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis. PMID- 29515122 TI - Pan-class I PI3-kinase inhibitor BKM120 induces MEK1/2-dependent mitotic catastrophe in non-Hodgkin lymphoma leading to apoptosis or polyploidy determined by Bax/Bak and p53. AB - Constitutive signaling of PI3K/Akt/mTOR plays a prominent role in malignant transformation and progression of B-cell non-Hodgkin lymphomas (B-NHL) underscoring the need for PI3K targeted therapies. The pan-class I PI3-kinase inhibitor BKM120 has shown preclinical activity in distinct malignancies and is currently tested in clinical trials. Intratumor heterogeneity is an intrinsic property of cancers that contributes to drug resistance and tumor recurrence. Here, we demonstrate that inhibition of PI3-kinases by BKM120 attenuates growth and survival of B-NHL cell lines by inducing mitotic arrest with subsequent induction of intrinsic apoptosis. BKM120-mediated downregulation of Cyclin A and activation of the CDK1/Cyclin B1 complex facilitates mitotic entry. In addition, concomitant BKM120-mediated upregulation of Cyclin B1 expression attenuates completion of mitosis, which results in mitotic catastrophe and apoptotic cell death. In Bax and Bak deficient B-NHL, which are resistant to BKM120-induced apoptosis, BKM120-induced mitotic catastrophe results in polyploidy. Upon re expression of wt p53 in these p53 mutated cells, BKM120-induced polyploidy is strongly reduced demonstrating that the genetic status of the cells determines the outcome of a BKM120-mediated pathway inhibition. Mitotic catastrophe and unfavorable induction of polyploidy can be prevented in this setting by additional inhibition of MEK1/2 signaling. Combining MEK1/2 inhibitors with BKM120 enhances the anti-tumor effects of BKM120, prevents prognostic unfavorable polyploidy and might be a potential strategy for the treatment of B-NHL. PMID- 29515123 TI - Enumeration, functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma. AB - Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients. Newly diagnosed MM patient MAIT cells had reduced IFNgamma production and CD27 expression, suggesting an exhausted phenotype, although IFNgamma-producing capacity is restored in relapsed/refractory patient samples. Moreover, immunomodulatory drugs Lenalidomide and Pomalidomide, indirectly inhibited MAIT cell activation. We further show that cell lines can be pulsed with vitamin-B derivative Ags and that these can be presented via MR1 to MAIT cells in vitro, to induce cytotoxic activity comparable to that of natural killer (NK) cells. Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies. PMID- 29515124 TI - Publisher Correction: Beyond a phenomenological description of magnetostriction. AB - "The technical support from SLAC Accelerator Directorate, Technology Innovation Directorate, LCLS laser division and Test Facility Division is gratefully acknowledged. We thank S.P. Weathersby, R.K. Jobe, D. McCormick, A. Mitra, S. Carron and J. Corbett for their invaluable help and technical assistance. Research at SLAC was supported through the SIMES Institute which like the LCLS and SSRL user facilities is funded by the Office of Basic Energy Sciences of the U.S. Department of Energy under Contract No. DE-AC02-76SF00515. The UED work was performed at SLAC MeV-UED, which is supported in part by the DOE BES SUF Division Accelerator & Detector R&D program, the LCLS Facility, and SLAC under contract Nos. DE-AC02-05-CH11231 and DE-AC02-76SF00515. Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515."and"Work at BNL was supported by DOE BES Materials Science and Engineering Division under Contract No: DE-AC02-98CH10886. J.C. would like to acknowledge the support from National Science Foundation Grant No. 1207252. E.E.F. would like to acknowledge support from the U.S. Department of Energy (DOE), Office of Basic Energy Sciences (BES) under Award No. DE SC0003678."This has been corrected in both the PDF and HTML versions of the Article. PMID- 29515125 TI - Aerosol effects on cloud water amounts were successfully simulated by a global cloud-system resolving model. AB - Aerosols affect climate by modifying cloud properties through their role as cloud condensation nuclei or ice nuclei, called aerosol-cloud interactions. In most global climate models (GCMs), the aerosol-cloud interactions are represented by empirical parameterisations, in which the mass of cloud liquid water (LWP) is assumed to increase monotonically with increasing aerosol loading. Recent satellite observations, however, have yielded contradictory results: LWP can decrease with increasing aerosol loading. This difference implies that GCMs overestimate the aerosol effect, but the reasons for the difference are not obvious. Here, we reproduce satellite-observed LWP responses using a global simulation with explicit representations of cloud microphysics, instead of the parameterisations. Our analyses reveal that the decrease in LWP originates from the response of evaporation and condensation processes to aerosol perturbations, which are not represented in GCMs. The explicit representation of cloud microphysics in global scale modelling reduces the uncertainty of climate prediction. PMID- 29515126 TI - A conserved interaction of the dynein light intermediate chain with dynein dynactin effectors necessary for processivity. AB - Cytoplasmic dynein is the major minus-end-directed microtubule-based motor in cells. Dynein processivity and cargo selectivity depend on cargo-specific effectors that, while generally unrelated, share the ability to interact with dynein and dynactin to form processive dynein-dynactin-effector complexes. How this is achieved is poorly understood. Here, we identify a conserved region of the dynein Light Intermediate Chain 1 (LIC1) that mediates interactions with unrelated dynein-dynactin effectors. Quantitative binding studies map these interactions to a conserved helix within LIC1 and to N-terminal fragments of Hook1, Hook3, BICD2, and Spindly. A structure of the LIC1 helix bound to the N terminal Hook domain reveals a conformational change that creates a hydrophobic cleft for binding of the LIC1 helix. The LIC1 helix competitively inhibits processive dynein-dynactin-effector motility in vitro, whereas structure-inspired mutations in this helix impair lysosomal positioning in cells. The results reveal a conserved mechanism of effector interaction with dynein-dynactin necessary for processive motility. PMID- 29515127 TI - Topological hybrid silicon microlasers. AB - Topological physics provides a robust framework for strategically controlling wave confinement and propagation dynamics. However, current implementations have been restricted to the limited design parameter space defined by passive topological structures. Active systems provide a more general framework where different fundamental symmetry paradigms, such as those arising from non Hermiticity and nonlinear interaction, can generate a new landscape for topological physics and its applications. Here, we bridge this gap and present an experimental investigation of an active topological photonic system, demonstrating a topological hybrid silicon microlaser array respecting the charge conjugation symmetry. The created new symmetry features favour the lasing of a protected zero mode, where robust single-mode laser action in the desired state prevails even with intentionally introduced perturbations. The demonstrated microlaser is hybrid implemented on a silicon-on-insulator substrate, and is thereby readily suitable for integrated silicon photonics with applications in optical communication and computing. PMID- 29515128 TI - The CD14 (-159 C/T) SNP is associated with sCD14 levels and allergic asthma, but not with CD14 expression on monocytes. AB - LPS-ligation to CD14/TLR-4 on monocytes/macrophages triggers the production of IL 12-family cytokines. IL12/18 promote TH1-differentiation, counteracting the TH2 driven asthma. Therefore, CD14 modulation could alter the TH2-differentiation and should be taken into account when studying asthma. To analyse the alteration in CD14 levels and its association with CD14 (-159 C/T) SNP (rs2569190) in Caucasian adults with stable allergic asthma, we performed a cross-sectional study (277 healthy subjects vs. 277 patients) where clinical parameters, CD14 values and the CD14 (-159 C/T) SNP were studied. Apart from typical biomarkers, we found an increment of neuron-specific enolase (NSE) in allergic asthma, probably linked to monocyte activity. Indeed, we evidenced increased monocyte numbers, but lower CD14 expression and normalised sCD14 values in patients. Moreover, we noticed an association of the T allele (P = 0.0162) and TT genotype (P = 0.0196) of the CD14 SNP with a decreased risk of allergic asthma and augmented sCD14 levels. In conclusion, monocyte CD14 expression and normalized sCD14 values were reduced in stable state asthmatics, and this could be related to the presence of an expanded CD14low monocyte subset. This study also demonstrates that the CD14 (-159 C/T) polymorphism is a risk factor for moderate-severe allergic asthma in adult Caucasians. PMID- 29515130 TI - Author Correction: Cancer-associated fibroblasts induce metalloprotease independent cancer cell invasion of the basement membrane. AB - In the original version of this Article, financial support and contributions in manuscript preparation were not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following:'M.P. and P.O. would like to thank Prof. Roderick Y.H. Lim for advice during manuscript preparation and for providing the laboratory and microscopy infrastructure.... [We also thank] the NanoteraProject, awarded to the PATLiSciII Consortium (M.P and P.O)...'. PMID- 29515129 TI - Nitrogen fixation sustained productivity in the wake of the Palaeoproterozoic Great Oxygenation Event. AB - The marine nitrogen cycle is dominated by redox-controlled biogeochemical processes and, therefore, is likely to have been revolutionised in response to Earth-surface oxygenation. The details, timing, and trajectory of nitrogen cycle evolution, however, remain elusive. Here we couple nitrogen and carbon isotope records from multiple drillcores through the Rooihoogte-Timeball Hill Formations from across the Carletonville area of the Kaapvaal Craton where the Great Oxygenation Event (GOE) and its aftermath are recorded. Our data reveal that aerobic nitrogen cycling, featuring metabolisms involving nitrogen oxyanions, was well established prior to the GOE and that ammonium may have dominated the dissolved nitrogen inventory. Pronounced signals of diazotrophy imply a stepwise evolution, with a temporary intermediate stage where both ammonium and nitrate may have been scarce. We suggest that the emergence of the modern nitrogen cycle, with metabolic processes that approximate their contemporary balance, was retarded by low environmental oxygen availability. PMID- 29515131 TI - Machine Learning-based Individual Assessment of Cortical Atrophy Pattern in Alzheimer's Disease Spectrum: Development of the Classifier and Longitudinal Evaluation. AB - To develop a new method for measuring Alzheimer's disease (AD)-specific similarity of cortical atrophy patterns at the individual-level, we employed an individual-level machine learning algorithm. A total of 869 cognitively normal (CN) individuals and 473 patients with probable AD dementia who underwent high resolution 3T brain MRI were included. We propose a machine learning-based method for measuring the similarity of an individual subject's cortical atrophy pattern with that of a representative AD patient cohort. In addition, we validated this similarity measure in two longitudinal cohorts consisting of 79 patients with amnestic-mild cognitive impairment (aMCI) and 27 patients with probable AD dementia. Surface-based morphometry classifier for discriminating AD from CN showed sensitivity and specificity values of 87.1% and 93.3%, respectively. In the longitudinal validation study, aMCI-converts had higher atrophy similarity at both baseline (p < 0.001) and first year visits (p < 0.001) relative to non converters. Similarly, AD patients with faster decline had higher atrophy similarity than slower decliners at baseline (p = 0.042), first year (p = 0.028), and third year visits (p = 0.027). The AD-specific atrophy similarity measure is a novel approach for the prediction of dementia risk and for the evaluation of AD trajectories on an individual subject level. PMID- 29515132 TI - Habitat degradation alters trophic pathways but not food chain length on shallow Caribbean coral reefs. AB - Habitat degradation can affect trophic ecology by differentially affecting specialist and generalist species, and the number and type of interspecific relationships. However, the effects of habitat degradation on the trophic ecology of coral reefs have received limited attention. We compared the trophic structure and food chain length between two shallow Caribbean coral reefs similar in size and close to each other: one dominated by live coral and the other by macroalgae (i.e., degraded). We subjected samples of basal carbon sources (particulate organic matter and algae) and the same 48 species of consumers (invertebrates and fishes) from both reefs to stable isotope analyses, and determined the trophic position of consumers and relative importance of various carbon sources for herbivores, omnivores, and carnivores. We found that both reefs had similar food chain length and trophic structure, but different trophic pathways. On the coral dominated reef, turf algae and epiphytes were the most important carbon source for all consumer categories, whereas on the degraded reef, particulate organic matter was a major carbon source for carnivores. Our results suggest that the trophic structure of the communities associated with these reefs is robust enough to adjust to conditions of degradation. PMID- 29515133 TI - Author Correction: Glacigenic sedimentation pulses triggered post-glacial gas hydrate dissociation. AB - The original version of this Article contained an error in the second sentence of the Abstract, which incorrectly read 'They are stable under high pressure and low, but react sensitively to environmental changes.' The correct version adds 'temperature' after 'low'. This has been corrected in both the PDF and HTML versions of the Article. PMID- 29515134 TI - Celecoxib alleviates nonalcoholic fatty liver disease by restoring autophagic flux. AB - Nonalcoholic fatty liver disease (NAFLD) is a kind of liver lipid synthesis and degradation imbalance related with metabolic syndrome. Celecoxib shows the function of ameliorating NAFLD, but the underlying mechanisms remain unknown. Here, we discuss the possible mechanisms of celecoxib alleviating NAFLD by restoring autophagic flux. Lipids were accumulated in L02 cells treated with palmitate as well as SD rats fed with high-fat diet. Western blot showed that LC3 II/I was higher and p62 was lower on the early stage of steatosis while on the late stage both of them were higher, indicating that autophagic flux was activated on the early stage of steatosis, but blocked on the late stage. Rapamycin alleviated steatosis with activating autophagic flux while chloroquine aggravated steatosis with inhibiting autophagic flux. COX-2 siRNA and celecoxib were used to inhibit COX-2. Western blot and RFP-GFP-LC3 double fluorescence system indicated that celecoxib could ameliorate steatosis and restore autophagic flux in L02 cells treated with palmitate as well as SD rats fed with high-fat diet. In conclusion, celecoxib partially restores autophagic flux via downregulation of COX-2 and alleviates steatosis in vitro and in vivo. PMID- 29515135 TI - Genome-wide transcriptome analysis identifies alternative splicing regulatory network and key splicing factors in mouse and human psoriasis. AB - Psoriasis is a chronic inflammatory disease that affects the skin, nails, and joints. For understanding the mechanism of psoriasis, though, alternative splicing analysis has received relatively little attention in the field. Here, we developed and applied several computational analysis methods to study psoriasis. Using psoriasis mouse and human datasets, our differential alternative splicing analyses detected hundreds of differential alternative splicing changes. Our analysis of conservation revealed many exon-skipping events conserved between mice and humans. In addition, our splicing signature comparison analysis using the psoriasis datasets and our curated splicing factor perturbation RNA-Seq database, SFMetaDB, identified nine candidate splicing factors that may be important in regulating splicing in the psoriasis mouse model dataset. Three of the nine splicing factors were confirmed upon analyzing the human data. Our computational methods have generated predictions for the potential role of splicing in psoriasis. Future experiments on the novel candidates predicted by our computational analysis are expected to provide a better understanding of the molecular mechanism of psoriasis and to pave the way for new therapeutic treatments. PMID- 29515136 TI - Long-term regeneration and remodeling of the pig esophagus after circumferential resection using a retrievable synthetic scaffold carrying autologous cells. AB - Treatment of esophageal disease can necessitate resection and reconstruction of the esophagus. Current reconstruction approaches are limited to utilization of an autologous conduit such as stomach, small bowel, or colon. A tissue engineered construct providing an alternative for esophageal replacement in circumferential, full thickness resection would have significant clinical applications. In the current study, we demonstrate that regeneration of esophageal tissue is feasible and reproducible in a large animal model using synthetic polyurethane electro spun grafts seeded with autologous adipose-derived mesenchymal stem cells (aMSCs) and a disposable bioreactor. The scaffolds were not incorporated into the regrown esophageal tissue and were retrieved endoscopically. Animals underwent adipose tissue biopsy to harvest and expand autologous aMSCs for seeding on electro-spun polyurethane conduits in a bioreactor. Anesthetized pigs underwent full thickness circumferential resection of the mid-lower thoracic esophagus followed by implantation of the cell seeded scaffold. Results from these animals showed gradual structural regrowth of endogenous esophageal tissue, including squamous esophageal mucosa, submucosa, and smooth muscle layers with blood vessel formation. Scaffolds carrying autologous adipose-derived mesenchymal stem cells may provide an alternative to the use of a gastro-intestinal conduit for some patients following resection of the esophagus. PMID- 29515137 TI - Association between maternal interpregnancy interval after live birth or pregnancy termination and birth weight: a quantile regression analysis. AB - We used quantile regression (QR) to assess if the length of the interpregnancy interval (IPI) after live birth and pregnancy termination is associated with weight in subsequent birth. The analysis included 9663 and 3400 women with IPI after live birth and pregnancy termination, respectively. For the women after live birth, an IPI < 12 months had negative effects at the 5th and 10th quantiles of the birth weight (BW) distribution. When the BW was beyond the 90th quantile, the BWs of newborns whose mothers with longer IPI (36-59 months) were higher than the reference group (18~23 months). For women after pregnancy termination in the 10th quantile, it was observed that those pregnant women with IPIs between 36 and 47 months had a negative effect (150 g) on BW compared with the reference group. This finding revealed that mothers with IPI < 12 months resulted in a decrease of 85 g at 75th quantile. The impact of IPI > 119 months in the upper quantile (95th) had an increase of 330 g in BW. Our results demonstrated that both short (<12 months) and long (>36 months) IPIs are independently associated with higher risks of low birth weight (LBW) and macrosomia. PMID- 29515138 TI - Evolution of joint cooperation under phenotypic variations. AB - Effects of phenotypic variation on the species-environment systems and the evolution of cooperation under prescribed phenotypic diversity have been well addressed respectively. Interspecies interactions in the context of evolvable phenotypic diversity remain largely unconsidered. We address the evolutionary dynamics by considering evolvable phenotypic variations under group interactions. Each individual carries a capacitor of phenotypes and pays a cost proportional to its volume. A random phenotype from the capacitor is expressed and the population is thus divided into subpopulations. Group interactions happen in each of these subpopulations, respectively. Competition is global. Results show that phenotypic diversity coevolves with cooperation under a wide range of conditions and that tradeoff between expanding capacitor and rising cost leads to an optimal level of phenotypic diversity best promoting cooperation. We also find that evolved high levels of phenotypic diversity can occasionally collapse due to the invasion of defector mutants, suggesting that cooperation and phenotypic diversity can mutually reinforce each other. PMID- 29515140 TI - Polarity-inverted lateral overgrowth and selective wet-etching and regrowth (PILOSWER) of GaN. AB - On an SiO2-patterned c-plane sapphire substrate, GaN domains were grown with their polarity controlled in accordance with the pattern. While N-polar GaN was grown on hexagonally arranged circular openings, Ga-polar GaN was laterally overgrown on mask regions due to polarity inversion occurring at the boundary of the circular openings. After etching of N-polar GaN on the circular openings by H3PO4, this template was coated with 40-nm Si by sputtering and was slightly etched by KOH. After slight etching, a thin layer of Si left on the circular openings of sapphire,but not on GaN, was oxidized during thermal annealing and served as a dielectric mask during subsequent regrowth. Thus, the subsequent growth of GaN was made only on the existing Ga-polar GaN domains, not on the circular openings of the sapphire substrate. Transmission electron microscopy analysis revealed no sign of threading dislocations in this film. This approach may help fabricating an unholed and merged GaN film physically attached to but epitaxially separated from the SiO2-patterned sapphire. PMID- 29515139 TI - DNA damage induces a SAMHD1-mediated block to the infection of macrophages by HIV 1. AB - Monocyte-derived macrophages (MDMs) are an important target for HIV-1 despite SAMHD1, a myeloid restriction factor for which HIV-1 lacks a counteracting accessory protein. The antiviral activity of SAMHD1 is modulated by phosphorylation of T592 by cyclin-dependent kinases (CDK). We show that treatment of MDMs with neocarzinostatin, a compound that introduces double strand breaks (DBS) in genomic DNA, results in the decrease of phosphorylated SAMHD1, activating its antiviral activity and blocking HIV-1 infection. The effect was specific for DSB as DNA damage induced by UV light irradiation did not affect SAMHD1 phosphorylation and did not block infection. The block to infection was at reverse transcription and was counteracted by Vpx, demonstrating that it was caused by SAMHD1. Neocarzinostatin treatment also activated an innate immune response that induced interferon-stimulated genes but this was not involved in the block to HIV-1 infection, as it was not relieved by an interferon-blocking antibody. In response to Neocarzinostatin-induced DNA damage, the level of the CDK inhibitor p21cip1 increased which could account for the decrease of phosphorylated SAMHD1. The results show that the susceptibility of MDMs to HIV-1 infection can be affected by stimuli that alter the phosphorylation state of SAMHD1, one of which is the DNA damage response. PMID- 29515141 TI - Author Correction: Phosphate-Solubilizing Bacteria Nullify the Antagonistic Effect of Soil Calcification on Bioavailability of Phosphorus in Alkaline Soils. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29515142 TI - Probe-caught spontaneous and deliberate mind wandering in relation to self reported inattentive, hyperactive and impulsive traits in adults. AB - Research has revealed a positive relationship between types of mind wandering and ADHD at clinical and subclinical levels. However, this work did not consider the relationship between mind wandering and the core symptoms of ADHD: inattention, hyperactivity and impulsivity. Given that the DMS-V attributes mind wandering to inattention only, and that only inattention is thought to result from impairment to the executive function linked to mind wandering, the present research sought to examine this relationship in 80 undiagnosed adults. Using both standard and easy versions of the Sustained Attention to Response Task (SART) we measured both spontaneous and deliberate mind wandering. We found that spontaneous mind wandering was related to self-reported inattentive traits when the task was cognitively more challenging (standard SART). However, hyperactive and impulsive traits were related to spontaneous mind wandering independent of task difficulty. The results suggest inattentive traits are not uniquely related to mind wandering; indeed, adults with hyperactive/impulsive traits were more likely to experience mind wandering, suggesting that mind wandering might not be useful diagnostic criteria for inattention. PMID- 29515143 TI - A combined method for DNA analysis and radiocarbon dating from a single sample. AB - Current protocols for ancient DNA and radiocarbon analysis of ancient bones and teeth call for multiple destructive samplings of a given specimen, thereby increasing the extent of undesirable damage to precious archaeological material. Here we present a method that makes it possible to obtain both ancient DNA sequences and radiocarbon dates from the same sample material. This is achieved by releasing DNA from the bone matrix through incubation with either EDTA or phosphate buffer prior to complete demineralization and collagen extraction utilizing the acid-base-acid-gelatinization and ultrafiltration procedure established in most radiocarbon dating laboratories. Using a set of 12 bones of different ages and preservation conditions we demonstrate that on average 89% of the DNA can be released from sample powder with minimal, or 38% without any, detectable collagen loss. We also detect no skews in radiocarbon dates compared to untreated samples. Given the different material demands for radiocarbon dating (500 mg of bone/dentine) and DNA analysis (10-100 mg), combined DNA and collagen extraction not only streamlines the sampling process but also drastically increases the amount of DNA that can be recovered from limited sample material. PMID- 29515144 TI - Sex differentials in relationships between functional fitness and cognitive performance in older adults: a canonical correlation analysis. AB - This study aimed to explore the sex differentials in correlations between functional fitness (FF) and cognitive impairment (CI) in older adults without dementia. A community-based cross-sectional study was conducted using 2096 adults more than 65 years of age. The Senior Fitness test and Mini-mental State Examination (MMSE) were used to measure FF and cognitive performance. Canonical correlation analysis (CCA) was performed to evaluate the relationships between FF and MMSE. Our results confirmed the relationships between FF and CI, furthermore FF and MMSE were significantly different between men and women (P < 0.05). CCA results showed overall FF was positively correlated with overall MMSE in both men (canonical coefficient = 0.37, P < 0.0001) and women (first canonical coefficient = 0.42, P < 0.0001; second canonical coefficient = 0.17, P = 0.004). Among men, 30s-arm curl and language were most highly correlated with FF and MMSE, respectively. Whereas among women, 30s-arm curl and eight-foot up-and-go were most highly correlated with FF, and orientation and recall were most highly correlated with MMSE. In conclusion, there was a sex difference in the relationships between FF and MMSE, which facilitated generating insight into cognitive performance improvement from the perspective of FF enhancement by sex. Prospective studies are needed to explore the causality between FF and cognitive performance. PMID- 29515145 TI - Grain density and its impact on grain filling characteristic of rice: mechanistic testing of the concept in genetically related cultivars. AB - Physiological factors controlling assimilate partitioning was compared in relation to panicle architecture of lax- (Upahar) and compact-panicle (Mahalaxmi) rice cultivars. Grain number and ethylene production at anthesis are low, but filling rate is high in the former compared to high grain number and ethylene production and poor filling trait of the latter. Similar to Mahalaxmi, its progenitors Pankaj and Mahshuri, had attributes of high grain number and grain density, but grain filling was higher and ethylene evolution was lower. Disturbed genetic coherence owing to imbalance of gene groups brought in the cross combinations of Mahshuri and Pankaj could be responsible for high ethylene production leading to semi sterility of Mahalaxmi as the hormone slackened endosperm starch bio-synthesis enzyme activities. Mahalaxmi inherited grain compactness trait of its progenitors, but not the physiological attribute for reduced ethylene production, which impacted grain filling. Upahar, the progeny genotype of Mahalaxmi and IR62 cross, inherited the dominant allele for low ethylene production and good grain filling traits from the high yielding IR62. In conclusion grain filling in compact-panicle rice becomes poor subject to expression of recessive allele for high ethylene production, but the allele is amenable for suppression by corresponding dominant allele in a genetic breeding. PMID- 29515146 TI - Multidimensional impulsivity as a mediator of early life stress and alcohol dependence. AB - Early life stress (ELS) leads to increased susceptibility to serious psychiatric problems such as alcohol dependence, but the mechanisms through which ELS affects alcohol dependence are unclear. We investigated the mediating role of multi dimensional impulsivity in the associations between ELS and alcohol dependence. 330 male patients with alcohol dependence (mean age = 48.39) completed self rating scales of ELS and several self-report measures of impulsivity as well as balloon analogue risk task (BART). After classifying different dimensions of impulsivity using factor analysis, structural equation modeling was conducted to test the mediation effects of impulsivity between ELS and alcohol dependence severity and social onset of hazardous drinking. Among the participants, 64.8%, 42.1% and 47.9% reported at least one episode of childhood maltreatment, sexual abuse and parental conflict, respectively. Response impulsivity-sensation seeking, reflection impulsivity and aggression partially mediated the association between ELS and severity of alcohol dependence (CFI = 0.902 and RMSEA = 0.079). Reflection impulsivity dimension partially mediated the association between ELS and social onset of hazardous drinking (CFI = 0.939, RMSEA = 0.091). These finding imply that stabilizing vulnerabilities such as reflection impulsivity via intervention programs that target young individuals with ELS may be helpful in delaying the onset of hazardous drinking and prevent alcohol dependence. PMID- 29515147 TI - Variation in avian egg shape and nest structure is explained by climatic conditions. AB - Why are avian eggs ovoid, while the eggs of most other vertebrates are symmetrical? The interaction between an egg and its environment likely drives selection that will shape eggs across evolutionary time. For example, eggs incubated in hot, arid regions face acute exposure to harsh climatic conditions relative to those in temperate zones, and this exposure will differ across nest types, with eggs in open nests being more exposed to direct solar radiation than those in enclosed nests. We examined the idea that the geographical distribution of both egg shapes and nest types should reflect selective pressures of key environmental parameters, such as ambient temperature and the drying capacity of air. We took a comparative approach, using 310 passerine species from Australia, many of which are found in some of the most extreme climates on earth. We found that, across the continent, egg elongation decreases and the proportion of species with domed nests with roofs increases in hotter and drier areas with sparse plant canopies. Eggs are most spherical in open nests in the hottest environments, and most elongate in domed nests in wetter, shadier environments. Our findings suggest that climatic conditions played a key role in the evolution of passerine egg shape. PMID- 29515148 TI - Publisher Correction: Spindle associated membrane protein 1 (Samp1) is required for the differentiation of muscle cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29515149 TI - Fast and efficient wireless power transfer via transitionless quantum driving. AB - Shortcut to adiabaticity (STA) techniques have the potential to drive a system beyond the adiabatic limits. Here, we present a robust and efficient method for wireless power transfer (WPT) between two coils based on the so-called transitionless quantum driving (TQD) algorithm. We show that it is possible to transfer power between the coils significantly fast compared to its adiabatic counterpart. The scheme is fairly robust against the variations in the coupling strength and the coupling distance between the coils. Also, the scheme is found to be reasonably immune to intrinsic losses in the coils. PMID- 29515150 TI - Detection of the Malaria causing Plasmodium Parasite in Saliva from Infected Patients using Topoisomerase I Activity as a Biomarker. AB - Malaria is among the major threats to global health with the main burden of disease being in rural areas of developing countries where accurate diagnosis based on non-invasive samples is in high demand. We here present a novel molecular assay for detection of malaria parasites based on technology that may be adapted for low-resource settings. Moreover, we demonstrate the exploitation of this assay for detection of malaria in saliva. The setup relies on pump-free microfluidics enabled extraction combined with a DNA sensor substrate that is converted to a single-stranded DNA circle specifically by topoisomerase I expressed by the malaria causing Plasmodium parasite. Subsequent rolling circle amplification of the generated DNA circle in the presence of biotin conjugated deoxynucleotides resulted in long tandem repeat products that was visualized colorimetrically upon binding of horse radish peroxidase (HRP) and addition of 3,3',5,5'-Tetramethylbenzidine that was converted to a blue colored product by HRP. The assay was directly quantitative, specific for Plasmodium parasites, and allowed detection of Plasmodium infection in a single drop of saliva from 35 out of 35 infected individuals tested. The results could be determined directly by the naked eye and documented by quantifying the color intensity using a standard paper scanner. PMID- 29515152 TI - Probing the Phylogenomics and Putative Pathogenicity Genes of Pythium insidiosum by Oomycete Genome Analyses. AB - Pythium insidiosum is a human-pathogenic oomycete. Many patients infected with it lose organs or die. Toward the goal of developing improved treatment options, we want to understand how Py. insidiosum has evolved to become a successful human pathogen. Our approach here involved the use of comparative genomic and other analyses to identify genes with possible functions in the pathogenicity of Py. insidiosum. We generated an Oomycete Gene Table and used it to explore the genome contents and phylogenomic relationships of Py. insidiosum and 19 other oomycetes. Initial sequence analyses showed that Py. insidiosum is closely related to Pythium species that are not pathogenic to humans. Our analyses also indicated that the organism harbours secreted and adhesin-like proteins, which are absent from related species. Putative virulence proteins were identified by comparison to a set of known virulence genes. Among them is the urease Ure1, which is absent from humans and thus a potential diagnostic and therapeutic target. We used mass spectrometric data to successfully validate the expression of 30% of 14,962 predicted proteins and identify 15 body temperature (37 degrees C)-dependent proteins of Py. insidiosum. This work begins to unravel the determinants of pathogenicity of Py. insidiosum. PMID- 29515151 TI - Inter-niche and inter-individual variation in gut microbial community assessment using stool, rectal swab, and mucosal samples. AB - The purpose of this study is to evaluate similarities and differences in gut bacterial measurements and stability in the microbial communities of three different types of samples that could be used to assess different niches of the gut microbiome: rectal swab, stool, and normal rectal mucosa samples. In swab stool comparisons, there were substantial taxa differences with some taxa varying largely by sample type (e.g. Thermaceae), inter-individual subject variation (e.g. Desulfovibrionaceae), or by both sample type and participant (e.g. Enterobacteriaceae). Comparing all three sample types with whole-genome metagenome shotgun sequencing, swab samples were much closer to stool samples than mucosa samples although all KEGG functional Level 1 and Level 2 pathways were significantly different across all sample types (e.g. transcription and environmental adaptation). However, the individual signature of participants was also observed and was largely stable between two time points. Thus, we found that while the distribution of some taxa was associated with these different sampling techniques, other taxa largely reflected individual differences in the microbial community that were insensitive to sampling technique. There is substantial variability in the assessment of the gut microbial community according to the type of sample. PMID- 29515153 TI - Down-regulation of GADD45A enhances chemosensitivity in melanoma. AB - Melanoma is a malignant skin cancer with considerable drug resistance. Increased expression of DNA repair genes have been reported in melanoma, and this contributes to chemotherapy resistance. GADD45A is involved in DNA repair, cell cycle arrest and apoptosis in response to physiologic or environmental stresses. In this study, we investigated the role of GADD45A in chemotherapy response. Firstly, the mRNA expression of profiled DNA repair genes in cisplatin-treated melanoma cells was detected by RT2 profilerTM PCR array. We found the expression of GADD45A upregulated in a dose- and time- dependent manner. In addition, suppression of GADD45A sensitized melanoma cells to cisplatin and enhanced cisplatin-induced DNA damage. Flow cytometry revealed that downregulating GADD45A released cells from cisplatin-induced G2/M arrest and increased apoptosis. By using a MEK inhibitor, GADD45A was shown to be regulated by MAPK-ERK pathway following cisplatin treatment. Thus, the induction of GADD45A might play important roles in chemotherapy response in human melanoma cancer and could serve as a novel molecular target for melanoma therapy. PMID- 29515154 TI - Proximate mechanisms affecting seasonal differences in migration speed of avian species. AB - Faster migration in spring than in autumn seems to be a common pattern in birds. This has been ultimately explained by seasonally different selection pressures. Variation in migration speed is proximately caused by adjusting travel speed (distance covered during flight) and/or stopover duration (times when birds rest and refuel). Yet, it remains unclear whether individual seasonal differences in migration speed match the common pattern and what the precise role of the proximate, behavioural mechanisms for adjusting migration speed is. By reviewing 64 studies of 401 tracks, I show that in waders, gulls, swifts, and songbirds speeds were significantly higher in spring, while the opposite was the case in waterfowl and owls. Thus, the ultimate mechanisms selecting for a faster migration in spring might not consistently act across bird groups. Breeding latitude, migration strategy, migration distance, flight style, body mass, and sex did not explain seasonal differences in speed. The ratio between spring and autumn total stopover duration of 257 bird tracks significantly negatively affected the seasonal migration speed ratio of the same individuals in a comparative analysis accounting for shared ancestry. Seasonal variation in stopover duration appears thus to be the main biological mechanism regulating seasonal differences in migration speed. PMID- 29515155 TI - Mechanistic insights of Li+ diffusion within doped LiFePO4 from Muon Spectroscopy. AB - The Li+ ion diffusion characteristics of V- and Nb-doped LiFePO4 were examined with respect to undoped LiFePO4 using muon spectroscopy (uSR) as a local probe. As little difference in diffusion coefficient between the pure and doped samples was observed, offering DLi values in the range 1.8-2.3 * 10-10 cm2 s-1, this implied the improvement in electrochemical performance observed within doped LiFePO4 was not a result of increased local Li+ diffusion. This unexpected observation was made possible with the uSR technique, which can measure Li+ self diffusion within LiFePO4, and therefore negated the effect of the LiFePO4 two phase delithiation mechanism, which has previously prevented accurate Li+ diffusion comparison between the doped and undoped materials. Therefore, the authors suggest that uSR is an excellent technique for analysing materials on a local scale to elucidate the effects of dopants on solid-state diffusion behaviour. PMID- 29515156 TI - Capillary flow homogenization during functional activation revealed by optical coherence tomography angiography based capillary velocimetry. AB - Elaborate modeling study suggests an important role of capillary transit time heterogeneity (CTTH) reduction in brain oxygenation during functional hyperemia. Here, we use optical coherence tomography angiography (OCTA) capillary velocimetry to probe blood flow dynamics in cerebral capillary beds and validate the change in CTTH during functional activation in an in vivo rodent model. Through evaluating flow dynamics and consequent transit time parameters from thousands of capillary vessels within three-dimensional (3-D) tissue volume upon hindpaw electrical stimulation, we observe reductions in both capillary mean transit time (MTT) (9.8% +/- 2.2) and CTTH (5.9% +/- 1.4) in the hindlimb somatosensory cortex (HLS1). Additionally, capillary flow pattern modification is observed with a significant difference (p < 0.05) between the HLS1 and non activated cortex regions. These quantitative findings reveal a localized microcirculatory adjustment during functional activation, consistent with previous studies, and support the critical contribution of capillary flow homogenization to brain oxygenation. The OCTA velocimetry is a useful tool to image microcirculatory dynamics in vivo using animal models, enabling a more comprehensive understanding as to hemodynamic-metabolic coupling. PMID- 29515157 TI - Results of the national organised colorectal cancer screening program with FIT in Paris. AB - In France, colorectal cancer (CRC) benefits from a nationwide screening program. The faecal immunochemical test (FIT) is being used since April 2015. The test is recommended in asymptomatic patients followed by a colonoscopy if positive for identification and treatment of colorectal lesions. We investigate the CRC national organised screening program using FIT in Paris. We performed a retrospective observational study, collecting data from the screening program in Paris using the ADECA75 database. Rates of participation, numbers of positive FIT, detection rates and positive predictive values (PPV) for advanced adenomas (AA) and/or CRC were determined. Between 01/01/2016 and 30/06/2017, 620.227 Parisians were eligible and 409.340 were invited to participate to the program. A total of 88.796 participants (23%) performed the test with 3.839 positive tests (4.3%). In the positive test population, 2.706 out of 3.839 individuals (70.5%) performed the required colonoscopy with available reports. Histology reports were only available for 2.401 participants (88,7%). Regarding lesions, 733 (30,5%) and 205 patients (8.5%) had AA and CRC, respectively. Over 18 months of screening with FIT in Paris, the PPV is in line with expected results while the participation rate is below European recommendations. PMID- 29515159 TI - Prolonged life of human acute hippocampal slices from temporal lobe epilepsy surgery. AB - Resected hippocampal tissue from patients with drug-resistant epilepsy presents a unique possibility to test novel treatment strategies directly in target tissue. The post-resection time for testing and analysis however is normally limited. Acute tissue slices allow for electrophysiological recordings typically up to 12 hours. To enable longer time to test novel treatment strategies such as, e.g., gene-therapy, we developed a method for keeping acute human brain slices viable over a longer period. Our protocol keeps neurons viable well up to 48 hours. Using a dual-flow chamber, which allows for microscopic visualisation of individual neurons with a submerged objective for whole-cell patch-clamp recordings, we report stable electrophysiological properties, such as action potential amplitude and threshold during this time. We also demonstrate that epileptiform activity, monitored by individual dentate granule whole-cell recordings, can be consistently induced in these slices, underlying the usefulness of this methodology for testing and/or validating novel treatment strategies for epilepsy. PMID- 29515161 TI - Author Correction: Grape seed proanthocyanidins prevent irradiation-induced differentiation of human lung fibroblasts by ameliorating mitochondrial dysfunction. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29515160 TI - Genomics-Based Identification of Microorganisms in Human Ocular Body Fluid. AB - Advances in genomics have the potential to revolutionize clinical diagnostics. Here, we examine the microbiome of vitreous (intraocular body fluid) from patients who developed endophthalmitis following cataract surgery or intravitreal injection. Endophthalmitis is an inflammation of the intraocular cavity and can lead to a permanent loss of vision. As controls, we included vitreous from endophthalmitis-negative patients, balanced salt solution used during vitrectomy and DNA extraction blanks. We compared two DNA isolation procedures and found that an ultraclean production of reagents appeared to reduce background DNA in these low microbial biomass samples. We created a curated microbial genome database (>5700 genomes) and designed a metagenomics workflow with filtering steps to reduce DNA sequences originating from: (i) human hosts, (ii) ambiguousness/contaminants in public microbial reference genomes and (iii) the environment. Our metagenomic read classification revealed in nearly all cases the same microorganism that was determined in cultivation- and mass spectrometry based analyses. For some patients, we identified the sequence type of the microorganism and antibiotic resistance genes through analyses of whole genome sequence (WGS) assemblies of isolates and metagenomic assemblies. Together, we conclude that genomics-based analyses of human ocular body fluid specimens can provide actionable information relevant to infectious disease management. PMID- 29515162 TI - Surface energy of strained amorphous solids. AB - Surface stress and surface energy are fundamental quantities which characterize the interface between two materials. Although these quantities are identical for interfaces involving only fluids, the Shuttleworth effect demonstrates that this is not the case for most interfaces involving solids, since their surface energies change with strain. Crystalline materials are known to have strain dependent surface energies, but in amorphous materials, such as polymeric glasses and elastomers, the strain dependence is debated due to a dearth of direct measurements. Here, we utilize contact angle measurements on strained glassy and elastomeric solids to address this matter. We show conclusively that interfaces involving polymeric glasses exhibit strain-dependent surface energies, and give strong evidence for the absence of such a dependence for incompressible elastomers. The results provide fundamental insight into our understanding of the interfaces of amorphous solids and their interaction with contacting liquids. PMID- 29515163 TI - Induced nano-scale self-formed metal-oxide interlayer in amorphous silicon tin oxide thin film transistors. AB - Amorphous Silicon-Tin-Oxide thin film transistors (a-STO TFTs) with Mo source/drain electrodes were fabricated. The introduction of a ~8 nm MoOx interlayer between Mo electrodes and a-STO improved the electron injection in a STO TFT. Mo adjacent to the a-STO semiconductor mainly gets oxygen atoms from the oxygen-rich surface of a-STO film to form MoOx interlayer. The self-formed MoOx interlayer acting as an efficient interface modification layer could conduce to the stepwise internal transport barrier formation while blocking Mo atoms diffuse into a-STO layer, which would contribute to the formation of ohmic contact between Mo and a-STO film. It can effectively improve device performance, reduce cost and save energy for the realization of large-area display with high resolution in future. PMID- 29515158 TI - Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states. AB - Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer's disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, 'shape connections' between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus. PMID- 29515164 TI - Activation of Notch-1 in oral epithelial cells by P. gingivalis triggers the expression of the antimicrobial protein PLA2-IIA. AB - P. gingivalis (Pg) is an oral pathogen with the ability to induce oral dysbiosis and periodontal disease. Nevertheless, the mechanisms by which mucosal responses to the oral microbiota in the presence of specific pathogens such as Pg could abrogate the host-microbe symbiotic relationship leading to periodontitis remain unclear. Herein, we identified the Notch-1/PLA2-IIA axis as a new molecular pathway through which Pg could be specifically modulating oral epithelial antimicrobial and inflammatory responses. Pg activated Notch-1, and inhibition or silencing of Notch-1 completely abrogated Pg-induced PLA2-IIA in oral epithelial cells (OECs). Activation of Notch-1 and PLA2-IIA production were associated with Pg-produced gingipains. Other oral Gram-positive and Gram-negative species failed to induce similar responses. Pg enhanced OEC antimicrobial activity through PLA2 IIA. Increased Notch-1 activation correlated with higher PLA2-IIA gingival expression and changes in the abundance of specific oral bacteria phyla during periodontal disease. Oral bacterial species exhibited differential antimicrobial susceptibility to PLA2-IIA. These findings support previous evidence suggesting an important role for epithelial Notch-1 activation and PLA2-IIA production during health and disease at mucosal surfaces, and provide new mechanistic information concerning the regulation of epithelial antimicrobial and pro inflammatory responses modulated by oral pathogenic bacteria associated with periodontal disease. PMID- 29515165 TI - Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation. AB - Immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. Our previous studies showed that activation of nuclear factor kappa B (NF-kappaB) regulates cytokine/growth factor secretion by MSCs. This study aimed to elucidate the role of Rap1 (repressor/activator protein), a novel modulator involved in the NF-kappaB pathway, in regulating the immunomodulatory potency of MSCs in acute allograft rejection of heart transplantation. The immunosuppressive potency of wild-type MSCs (WT-MSCs) or Rap1-deficient MSCs (Rap1-/--MSCs) was examined in mice with acute allograft rejection following heart transplantation. With a combination of immunosuppressant rapamycin at a dose of 1 mg/kg/d, WT-MSCs notably prolonged the survival of the transplanted heart compared with Rap1-/--MSCs. Rap1-/--MSCs displayed a marked insensitivity to inhibit the mixed lymphocyte reaction (MLR) due to impaired cytokine production and a significantly reduced activity of NF-kappaB signaling in vitro. Finally, transplantation of encapsulated WT-MSCs greatly prolonged the survival of the heart allograft compared with encapsulated Rap1-/--MSCs. Our results indicate that Rap1 is essential to maintain the immunomodulatory function of MSCs. Deletion of Rap1 results in impaired immunomodulatory function of MSCs. PMID- 29515166 TI - Phosphorylation of glutaminase by PKCepsilon is essential for its enzymatic activity and critically contributes to tumorigenesis. AB - Glutamine metabolism plays an important role in cancer development and progression. Glutaminase C (GAC), the first enzyme in glutaminolysis, has emerged as an important target for cancer therapy and many studies have focused on the mechanism of enhanced GAC expression in cancer cells. However, little is known about the post-translational modification of GAC. Here, we report that phosphorylation is a crucial post-translational modification of GAC, which is responsible for the higher glutaminase activity in lung tumor tissues and cancer cells. We identify the key Ser314 phosphorylation site on GAC that is regulated by the NF-kappaB-PKCepsilon axis. Blocking Ser314 phosphorylation by the S314A mutation in lung cancer cells inhibits the glutaminase activity, triggers genetic reprogramming, and alleviates tumor malignancy. Furthermore, we find that a high level of GAC phosphorylation correlates with poor survival rate of lung cancer patients. These findings highlight a previously unappreciated mechanism for activation of GAC by phosphorylation and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation. PMID- 29515167 TI - Accuracy of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Mycobacteria: a systematic review and meta analysis. AB - Mycobacterium species are a significant cause of morbidity and mortality worldwide. The present study was carried out to systematically evaluate the accuracy of Matrix-assisted laser desorption ionization-time of flight mass spectroscopy (MALDI-TOF MS) for the identification of clinical pathogenic mycobacteria. After a rigid selection process, 19 articles involving 2,593 mycobacteria isolates were included. The pooled result agreed with the reference method identification for 85% of the isolates to genus level, with 71% (95% CI of 69% to 72%) correct to the species level. The MALDI-TOF MS correctly identified 92% of the M.tuberculosis isolates (95% CI of 0.87 to 0.96), and 68% of M. bovisisolates (95% CI of 27% to 100%) to the species level. Mycobacterium tuberculosis complex in solid media with reference strains using augmented database showing more accurate identification. The identifying accuracy rate of bioMerieuxVitek MS was slight higher than Bruker MALDI Biotyper (75% vs 72%). However, opposite results were obtained in identifications of M. fortuitum, M. kansasii, M. marinum, and M. terrae with these two systems. In summary, our results demonstrate that application of MALDI-TOF MS in clinical pathogenic mycobacteria identification is less satisfactory to date. Increasing need for improvement is important especially at species level. PMID- 29515168 TI - Unexpectedly high piezoelectricity of Sm-doped lead zirconate titanate in the Curie point region. AB - Large piezoelectric coefficients in polycrystalline lead zirconate titanate (PZT) are traditionally achieved through compositional design using a combination of chemical substitution with a donor dopant and adjustment of the zirconium to titanium compositional ratio to meet the morphotropic phase boundary (MPB). In this work, a different route to large piezoelectricity is demonstrated. Results reveal unexpectedly high piezoelectric coefficients at elevated temperatures and compositions far from the MPB. At temperatures near the Curie point, doping with 2 at% Sm results in exceptionally large piezoelectric coefficients of up to 915 pm/V. This value is approximately twice those of other donor dopants (e.g., 477 pm/V for Nb and 435 pm/V for La). Structural changes during the phase transitions of Sm-doped PZT show a pseudo-cubic phase forming ~50 degrees C below the Curie temperature. Possible origins of these effects are discussed and the high piezoelectricity is posited to be due to extrinsic effects. The enhancement of the mechanism at elevated temperatures is attributed to the coexistence of tetragonal and pseudo-cubic phases, which enables strain accommodation during electromechanical deformation and interphase boundary motion. This work provides insight into possible routes for designing high performance piezoelectrics which are alternatives to traditional methods relying on MPB compositions. PMID- 29515169 TI - Soil pH mediates the balance between stochastic and deterministic assembly of bacteria. AB - Little is known about the factors affecting the relative influences of stochastic and deterministic processes that govern the assembly of microbial communities in successional soils. Here, we conducted a meta-analysis of bacterial communities using six different successional soil datasets distributed across different regions. Different relationships between pH and successional age across these datasets allowed us to separate the influences of successional age (i.e., time) from soil pH. We found that extreme acidic or alkaline pH conditions lead to assembly of phylogenetically more clustered bacterial communities through deterministic processes, whereas pH conditions close to neutral lead to phylogenetically less clustered bacterial communities with more stochasticity. We suggest that the influence of pH, rather than successional age, is the main driving force in producing trends in phylogenetic assembly of bacteria, and that pH also influences the relative balance of stochastic and deterministic processes along successional soils. Given that pH had a much stronger association with community assembly than did successional age, we evaluated whether the inferred influence of pH was maintained when studying globally distributed samples collected without regard for successional age. This dataset confirmed the strong influence of pH, suggesting that the influence of soil pH on community assembly processes occurs globally. Extreme pH conditions likely exert more stringent limits on survival and fitness, imposing strong selective pressures through ecological and evolutionary time. Taken together, these findings suggest that the degree to which stochastic vs. deterministic processes shape soil bacterial community assembly is a consequence of soil pH rather than successional age. PMID- 29515171 TI - Author Correction: Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29515170 TI - Comparative genomics sheds light on niche differentiation and the evolutionary history of comammox Nitrospira. AB - The description of comammox Nitrospira spp., performing complete ammonia-to nitrate oxidation, and their co-occurrence with canonical beta-proteobacterial ammonia oxidizing bacteria (beta-AOB) in the environment, calls into question the metabolic potential of comammox Nitrospira and the evolutionary history of their ammonia oxidation pathway. We report four new comammox Nitrospira genomes, constituting two novel species, and the first comparative genomic analysis on comammox Nitrospira. Unlike canonical Nitrospira, comammox Nitrospira genomes lack genes for assimilatory nitrite reduction, suggesting that they have lost the potential to use external nitrite nitrogen sources. By contrast, compared to canonical Nitrospira, comammox Nitrospira harbor a higher diversity of urea transporters and copper homeostasis genes and lack cyanate hydratase genes. Additionally, the two comammox clades differ in their ammonium uptake systems. Contrary to beta-AOB, comammox Nitrospira genomes have single copies of the two central ammonia oxidation pathway operons. Similar to ammonia oxidizing archaea and some oligotrophic AOB strains, they lack genes involved in nitric oxide reduction. Furthermore, comammox Nitrospira genomes encode genes that might allow efficient growth at low oxygen concentrations. Regarding the evolutionary history of comammox Nitrospira, our analyses indicate that several genes belonging to the ammonia oxidation pathway could have been laterally transferred from beta-AOB to comammox Nitrospira. We postulate that the absence of comammox genes in other sublineage II Nitrospira genomes is the result of subsequent loss. PMID- 29515172 TI - N-Acetyl-Aspartate in the dorsolateral prefrontal cortex in men with schizophrenia and auditory verbal hallucinations: A 1.5 T Magnetic Resonance Spectroscopy Study. AB - Auditory verbal hallucinations (AVH) in patients with schizophrenia are linked to abnormalities within a large cerebral network including frontal and temporal regions. Whilst abnormalities of frontal speech production and temporal speech perception regions have been extensively studied, alterations of the dorsolateral prefrontal cortex (DLPFC), a region critically involved in the pathophysiology of schizophrenia, have rarely been studied in relation to AVH. Using 1.5 T proton magnetic resonance spectroscopy, this study examined the relationship between right and left DLPFCs N-AcetylAspartate (NAA) levels and the severity of AVH in patients with schizophrenia. Twenty-seven male patients with schizophrenia were enrolled in this study, 15 presented daily treatment-resistant AVH (AVH+) and 12 reported no AVH (no-AVH). AVH+ patients displayed higher NAA levels in the right DLPFC than no-AVH patients (p = 0.033). In AVH+ patients, NAA levels were higher in the right DLPFC than in the left (p = 0.024). No difference between the right and left DLPFC was observed in no-AVH patients. There was a positive correlation between NAA levels in the right DLPFC and the severity of AVH (r = 0.404, p = 0.037). Despite limited by magnetic field strength, these results suggest that AVH may be associated with increased NAA levels in the right DLPFC in schizophrenia. PMID- 29515173 TI - Author Correction: Sporadic nesting reveals long distance colonisation in the philopatric loggerhead sea turtle (Caretta caretta). AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29515174 TI - On the insulator-to-metal transition in titanium-implanted silicon. AB - Hyperdoped silicon with deep level impurities has attracted much research interest due to its promising optical and electrical properties. In this work, single crystalline silicon supersaturated with titanium is fabricated by ion implantation followed by both pulsed laser melting and flash lamp annealing. The decrease of sheet resistance with increasing Ti concentration is attributed to a surface morphology effect due to the formation of cellular breakdown at the surface and the percolation conduction at high Ti concentration is responsible for the metallic-like conductivity. The insulator-to-metal transition does not happen. However, the doping effect of Ti incorporation at low concentration is not excluded, which might be responsible for the sub-bandgap optical absorption reported in literature. PMID- 29515175 TI - Effect of antibiotics and NSAIDs on cyclooxygenase-2 in the enamel mineralization. AB - The objective of this study was to determine whether the use of the most commonly prescribed antibiotics and non-steroidal anti-inflammatory drugs in childhood could disturb enamel mineralization. Forty-two Swiss mice were divided into seven groups: controls; amoxicillin; amoxicillin/clavulanate; erythromycin; acetaminophen; ibuprofen and celecoxib, to inhibit cyclooxygenase 2 (COX2). SEM EDX analysis was conducted on all cusps of the third molars. Calcium (Ca), phosphorus (P), aluminum, potassium, sodium, magnesium and chlorine were quantified. The stoichiometric Ca/P molar ratios were calculated. Immunohistochemical quantification of COX2 in incisors was carried out by image analysis using COX2-specific immunostaining. Groups treated with antibiotics showed no significant differences in the content of the chemical elements. Only acetaminophen and celecoxib showed a significant decrease in Ca and P compared with the control samples. Ca/P ratios showed no difference. Groups treated with amoxicillin, amoxicillin/clavulanate, erythromycin and acetaminophen showed significantly lower amounts of immunoreactive COX2 at the enamel organ maturation stage of the mouse incisors. Our results suggest that COX2 is involved in the maturation stage of the enamel organ and that its inhibition would appear to alter amelogenesis, producing hypomineralization. PMID- 29515176 TI - Measurement-device-independent quantum key distribution via quantum blockade. AB - Efficiency in measurement-device-independent quantum key distribution(MDI-QKD) can be improved not only by the protocol, but also single-photon sources. We study the behavior of MDI-QKD with statistical fluctuation using quantum blockade source. Numerical simulation for a type of 4-intensity protocol shows that, after parameter optimization, this source can improve the final key rate by 100 times compared with traditional weak coherent state sources. PMID- 29515177 TI - Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit. AB - AMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression. PMID- 29515179 TI - Impact of the pulse contrast ratio on molybdenum Kalpha generation by ultrahigh intensity femtosecond laser solid interaction. AB - We present an extended experimental study of the absolute yield of Kalpha x-ray source (17.48 keV) produced by interaction of an ultrahigh intensity femtosecond laser with solid Mo target for temporal contrast ratios in the range of 1.7 * 107 3.3 * 109 and on three decades of intensity 1016-1019 W/cm2. We demonstrate that for intensity I >= 2 * 1018 W/cm2 Kalpha x-ray emission is independent of the value of contrast ratio. In addition, no saturation of the Kalpha photon number is measured and a value of ~2 * 1010 photons/sr/s is obtained at 10 Hz and I ~1019 W/cm2. Furthermore, Kalpha energy conversion efficiency reaches the same high plateau equal to ~2 * 10-4 at I = 1019 W/cm2 for all the studied contrast ratios. This original result suggests that relativistic J * B heating becomes dominant in these operating conditions which is supposed to be insensitive to the electron density gradient scale length L/lambda. Finally, an additional experimental study performed by changing the angle of incidence of the laser beam onto the solid target highlights a clear signature of the interplay between collisionless absorption mechanisms depending on the contrast ratio and intensity. PMID- 29515178 TI - Brettanomyces bruxellensis population survey reveals a diploid-triploid complex structured according to substrate of isolation and geographical distribution. AB - Brettanomyces bruxellensis is a unicellular fungus of increasing industrial and scientific interest over the past 15 years. Previous studies revealed high genotypic diversity amongst B. bruxellensis strains as well as strain-dependent phenotypic characteristics. Genomic assemblies revealed that some strains harbour triploid genomes and based upon prior genotyping it was inferred that a triploid population was widely dispersed across Australian wine regions. We performed an intraspecific diversity genotypic survey of 1488 B. bruxellensis isolates from 29 countries, 5 continents and 9 different fermentation niches. Using microsatellite analysis in combination with different statistical approaches, we demonstrate that the studied population is structured according to ploidy level, substrate of isolation and geographical origin of the strains, underlying the relative importance of each factor. We found that geographical origin has a different contribution to the population structure according to the substrate of origin, suggesting an anthropic influence on the spatial biodiversity of this microorganism of industrial interest. The observed clustering was correlated to variable stress response, as strains from different groups displayed variation in tolerance to the wine preservative sulfur dioxide (SO2). The potential contribution of the triploid state for adaptation to industrial fermentations and dissemination of the species B. bruxellensis is discussed. PMID- 29515180 TI - Ionic liquid gating control of RKKY interaction in FeCoB/Ru/FeCoB and (Pt/Co)2/Ru/(Co/Pt)2 multilayers. AB - To overcome the fundamental challenge of the weak natural response of antiferromagnetic materials under a magnetic field, voltage manipulation of antiferromagnetic interaction is developed to realize ultrafast, high-density, and power efficient antiferromagnetic spintronics. Here, we report a low voltage modulation of Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction via ionic liquid gating in synthetic antiferromagnetic multilayers of FeCoB/Ru/FeCoB and (Pt/Co)2/Ru/(Co/Pt)2. At room temperature, the distinct voltage control of transition between antiferromagnetic and ferromagnetic ordering is realized and up to 80% of perpendicular magnetic moments manage to switch with a small-applied voltage bias of 2.5 V. We related this ionic liquid gating-induced RKKY interaction modification to the disturbance of itinerant electrons inside synthetic antiferromagnetic heterostructure and the corresponding change of its Fermi level. Voltage tuning of RKKY interaction may enable the next generation of switchable spintronics between antiferromagnetic and ferromagnetic modes with both fundamental and practical perspectives. PMID- 29515181 TI - ZnFeAl-layered double hydroxides/TiO2 composites as photoanodes for photocathodic protection of 304 stainless steel. AB - A series of ZnFeAl-layered double hydroxides/TiO2 (ZnFeAl-LDHs/TiO2) composites are synthesized by a combined anodization and hydrothermal method. The structure, surface morphology, photo absorption and photocathodic protection properties of these samples are characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), ultraviolet-visible diffuse reflectance spectroscopy (UV-vis DRS) and electrochemical tests. The unique structure of the ZnFeAl-LDHs reduces the charge carriers recombination, and the visible photoresponse property increase the light harvesting. The XPS study reveals that the electrons in the ZnFeAl-LDHs travel to TiO2, and the ZnFeAl-LDHs/TiO2 composites generate and transfer more electrons to 304 stainless steel (304SS), and exhibits a better photocathodic protection performance than pure TiO2. In addition, after intermittent visible-light illumination for four days, the photoanode still exhibits good stability and durability. PMID- 29515182 TI - Low incubation temperature during early development negatively affects survival and related innate immune processes in zebrafish larvae exposed to lipopolysaccharide. AB - In many fish species, the immune system is significantly constrained by water temperature. In spite of its critical importance in protecting the host against pathogens, little is known about the influence of embryonic incubation temperature on the innate immunity of fish larvae. Zebrafish (Danio rerio) embryos were incubated at 24, 28 or 32 degrees C until first feeding. Larvae originating from each of these three temperature regimes were further distributed into three challenge temperatures and exposed to lipopolysaccharide (LPS) in a full factorial design (3 incubation * 3 challenge temperatures). At 24 h post LPS challenge, mortality of larvae incubated at 24 degrees C was 1.2 to 2.6-fold higher than those kept at 28 or 32 degrees C, regardless of the challenge temperature. LPS challenge at 24 degrees C stimulated similar immune-related processes but at different levels in larvae incubated at 24 or 32 degrees C, concomitantly with the down-regulation of some chemokine and lysozyme transcripts in the former group. Larvae incubated at 24 degrees C and LPS-challenged at 32 degrees C exhibited a limited immune response with up-regulation of hypoxia and oxidative stress processes. Annexin A2a, S100 calcium binding protein A10b and lymphocyte antigen-6, epidermis were identified as promising candidates for LPS recognition and signal transduction. PMID- 29515185 TI - Immunometabolism: Hyperactive macrophages link heart and joint disease. PMID- 29515183 TI - Emergence of Different Recombinant Porcine Reproductive and Respiratory Syndrome Viruses, China. AB - Epidemiological investigations were conducted on recently emerging porcine reproductive and respiratory syndrome virus (PRRSV) strains in Shandong province in 2014-2015. The proportion of the NADC30 strain identified by ORF7 sequence alignment has been gradually increasing. Three emerging PRRSV strains were successfully isolated, and the complete genomic sequences were determined. Our results indicate the importance of recombinant strains in Shandong province, China. There was a varied degree of recombination of two or three strains (classical, HP-PRRSV and/or NADC30). Moreover, the recombination strains affected the pathogenicity of newly emerged strains. PMID- 29515186 TI - Systemic sclerosis: Autologous HSCT is efficacious, but can we make it safer? PMID- 29515187 TI - Experimental arthritis: TNF chronicity modifies synovial cell death. PMID- 29515188 TI - Cell biology of the neuron: Untangling the ubiquitin-proteasome system. PMID- 29515189 TI - Neurodevelopmental disorders: A targeted rescue. PMID- 29515184 TI - Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations. AB - Recently, a new form of autosomal recessive early-onset parkinsonism (PARK20), due to mutations in the gene encoding the phosphoinositide phosphatase, Synaptojanin 1 (Synj1), has been reported. Several genes responsible for hereditary forms of Parkinson's disease are implicated in distinct steps of the endolysosomal pathway. However, the nature and the degree of endocytic membrane trafficking impairment in early-onset parkinsonism remains elusive. Here, we show that depletion of Synj1 causes drastic alterations of early endosomes, which become enlarged and more numerous, while it does not affect the morphology of late endosomes both in non-neuronal and neuronal cells. Moreover, Synj1 loss impairs the recycling of transferrin, while it does not alter the trafficking of the epidermal growth factor receptor. The ectopic expression of Synj1 restores the functions of early endosomes, and rescues these trafficking defects in depleted cells. Importantly, the same alterations of early endosomal compartments and trafficking defects occur in fibroblasts of PARK20 patients. Our data indicate that Synj1 plays a crucial role in regulating the homeostasis and functions of early endosomal compartments in different cell types, and highlight defective cellular pathways in PARK20. In addition, they strengthen the link between endosomal trafficking and Parkinson's disease. PMID- 29515190 TI - Gene expression: Key codes. PMID- 29515191 TI - Sleep: Ever-decreasing ripples. PMID- 29515193 TI - Spatial processing: Directional dilemmas. PMID- 29515194 TI - Neuronal plasticity: Upscale, downscale. PMID- 29515195 TI - Coffee and caffeine consumption in women affected by hypertension. PMID- 29515196 TI - Species replacement dominates megabenthos beta diversity in a remote seamount setting. AB - Seamounts are proposed to be hotspots of deep-sea biodiversity, a pattern potentially arising from increased productivity in a heterogeneous landscape leading to either high species co-existence or species turnover (beta diversity). However, studies on individual seamounts remain rare, hindering our understanding of the underlying causes of local changes in beta diversity. Here, we investigated processes behind beta diversity using ROV video, coupled with oceanographic and quantitative terrain parameters, over a depth gradient in Annan Seamount, Equatorial Atlantic. By applying recently developed beta diversity analyses, we identified ecologically unique sites and distinguished between two beta diversity processes: species replacement and changes in species richness. The total beta diversity was high with an index of 0.92 out of 1 and was dominated by species replacement (68%). Species replacement was affected by depth related variables, including temperature and water mass in addition to the aspect and local elevation of the seabed. In contrast, changes in species richness component were affected only by the water mass. Water mass, along with substrate also affected differences in species abundance. This study identified, for the first time on seamount megabenthos, the different beta diversity components and drivers, which can contribute towards understanding and protecting regional deep sea biodiversity. PMID- 29515192 TI - Lactate in the brain: from metabolic end-product to signalling molecule. AB - Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system. PMID- 29515197 TI - Mycobacterium ahvazicum sp. nov., the nineteenth species of the Mycobacterium simiae complex. AB - Four slowly growing mycobacteria isolates were isolated from the respiratory tract and soft tissue biopsies collected in four unrelated patients in Iran. Conventional phenotypic tests indicated that these four isolates were identical to Mycobacterium lentiflavum while 16S rRNA gene sequencing yielded a unique sequence separated from that of M. lentiflavum. One representative strain AFP 003T was characterized as comprising a 6,121,237-bp chromosome (66.24% guanosine cytosine content) encoding for 5,758 protein-coding genes, 50 tRNA and one complete rRNA operon. A total of 2,876 proteins were found to be associated with the mobilome, including 195 phage proteins. A total of 1,235 proteins were found to be associated with virulence and 96 with toxin/antitoxin systems. The genome of AFP-003T has the genetic potential to produce secondary metabolites, with 39 genes found to be associated with polyketide synthases and non-ribosomal peptide syntases and 11 genes encoding for bacteriocins. Two regions encoding putative prophages and three OriC regions separated by the dnaA gene were predicted. Strain AFP-003T genome exhibits 86% average nucleotide identity with Mycobacterium genavense genome. Genetic and genomic data indicate that strain AFP 003T is representative of a novel Mycobacterium species that we named Mycobacterium ahvazicum, the nineteenth species of the expanding Mycobacterium simiae complex. PMID- 29515198 TI - Angular dependence of vortex instability in a layered superconductor: the case study of Fe(Se,Te) material. AB - Anisotropy effects on flux pinning and flux flow are strongly effective in cuprate as well as iron-based superconductors due to their intrinsically layered crystallographic structure. However Fe(Se,Te) thin films grown on CaF2 substrate result less anisotropic with respect to all the other iron based superconductors. We present the first study on the angular dependence of the flux flow instability, which occurs in the flux flow regime as a current driven transition to the normal state at the instability point (I*, V*) in the current-voltage characteristics. The voltage jumps are systematically investigated as a function of the temperature, the external magnetic field, and the angle between the field and the Fe(Se,Te) film. The scaling procedure based on the anisotropic Ginzburg Landau approach is successfully applied to the observed angular dependence of the critical voltage V*. Anyway, we find out that Fe(Se,Te) represents the case study of a layered material characterized by a weak anisotropy of its static superconducting properties, but with an increased anisotropy in its vortex dynamics due to the predominant perpendicular component of the external applied magnetic field. Indeed, I* shows less sensitivity to angle variations, thus being promising for high field applications. PMID- 29515199 TI - Damage to epitaxial GaN layer on Al2O3 by 290-MeV 238U32+ ions irradiation. AB - Micro-structural characteristics and electrical properties of an n-type GaN epilayer on Al2O3 irradiated by 290-MeV 238U32+ ions to various fluences were investigated using atomic force microscopy (AFM), scanning electron microscopy (SEM), high-resolution X-ray diffraction (HRXRD), and Raman scattering spectroscopy. AFM images show that the nano-hillocks generated, and the diameter and density of the nano-hillocks, increase obviously with increasing ion fluence, accompanied by an increase in surface roughness. SEM images display that the Al, O, and C elements appear on the GaN surface, along with a spiral-like, layered volcanic-cone structure formed at the highest-fluence irradiation. HRXRD reveals that the dislocation density increases, as the lattices gradually expand, and that Ga2O3 was produced with increasing ion fluence. Raman scattering spectra show that no N and Ga vacancies were produced, the free-carrier concentration decreases, while its mobility first increases and then exhibits a significant reduction with increasing ion fluence. PMID- 29515200 TI - Mechanism of the Escherichia coli MltE lytic transglycosylase, the cell-wall penetrating enzyme for Type VI secretion system assembly. AB - Lytic transglycosylases (LTs) catalyze the non-hydrolytic cleavage of the bacterial cell wall by an intramolecular transacetalization reaction. This reaction is critically and broadly important in modifications of the bacterial cell wall in the course of its biosynthesis, recycling, manifestation of virulence, insertion of structural entities such as the flagellum and the pili, among others. The first QM/MM analysis of the mechanism of reaction of an LT, that for the Escherichia coli MltE, is undertaken. The study reveals a conformational itinerary consistent with an oxocarbenium-like transition state, characterized by a pivotal role for the active-site glutamic acid in proton transfer. Notably, an oxazolinium intermediate, as a potential intermediate, is absent. Rather, substrate-assisted catalysis is observed through a favorable dipole provided by the N-acetyl carbonyl group of MurNAc saccharide. This interaction stabilizes the incipient positive charge development in the transition state. This mechanism coincides with near-synchronous acetal cleavage and acetal formation. PMID- 29515201 TI - Biological Age is a predictor of mortality in Ischemic Stroke. AB - Age and stroke severity are the main mortality predictors after ischemic stroke. However, chronological age and biological age are not exactly concordant. Age related changes in DNA methylation in multiple CpG sites across the genome can be used to estimate biological age, which is influenced by lifestyle, environmental factors, and genetic variation. We analyzed the impact of biological age on 3 month mortality in ischemic stroke. We assessed 594 patients with acute ischemic stroke in a cohort from Hospital del Mar (Barcelona) and validated the results in an independent cohort. Demographic and clinical data, including chronological age, vascular risk factors, initial stroke severity (NIHSS score), recanalization treatment, and previous modified Rankin scale were registered. Biological age was estimated with an algorithm based on DNA methylation in 71 CpGs. Biological age was predictive of 3-month mortality (p = 0.041; OR = 1.05, 95% CI 1.00-1.10), independently of NIHSS score, chronological age, TOAST, vascular risk factors, and blood cell composition. Stratified by TOAST classification, biological age was associated with mortality only in large-artery atherosclerosis etiology (p = 0.004; OR = 1.14, 95% CI 1.04-1.25). As estimated by DNA methylation, biological age is an independent predictor of 3-month mortality in ischemic stroke regardless of chronological age, NIHSS, previous modified Rankin scale, and vascular risk factors. PMID- 29515202 TI - Detailed ecological associations of triatomines revealed by metabarcoding and next-generation sequencing: implications for triatomine behavior and Trypanosoma cruzi transmission cycles. AB - Trypanosoma cruzi is the agent of Chagas disease, transmitted by hematophagous triatomine vectors. Establishing transmission cycles is key to understand the epidemiology of the disease, but integrative assessments of ecological interactions shaping parasite transmission are still limited. Current approaches also lack sensitivity to assess the full extent of this ecological diversity. Here we developed a metabarcoding approach based on next-generation sequencing to identify triatomine gut microbiome, vertebrate feeding hosts, and parasite diversity and their potential interactions. We detected a dynamic microbiome in Triatoma dimidiata, including 23 bacterial orders, which differed according to blood sources. Fourteen vertebrate species served as blood sources, corresponding to domestic, synantropic and sylvatic species, although four (human, dog, cow and mice) accounted for over 50% of blood sources. Importantly, bugs fed on multiple hosts, with up to 11 hosts identified per bug, indicating very frequent host switching. A high clonal diversity of T. cruzi was detected, with up to 20 haplotypes per bug. This analysis provided much greater sensitivity to detect multiple blood meals and multiclonal infections with T. cruzi, which should be taken into account to develop transmission networks, and characterize the risk for human infection, eventually leading to a better control of disease transmission. PMID- 29515203 TI - Natural polyphenols as sirtuin 6 modulators. AB - Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 uM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3-10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation. PMID- 29515204 TI - Conduit stability effects on intensity and steadiness of explosive eruptions. AB - Conduit geometry affects magma ascent dynamics and, consequently, the style and evolution of volcanic eruptions. However, despite geological evidences support the occurrence of conduit widening during most volcanic eruptions, the factors controlling conduit enlargement are still unclear, and the effects of syn eruptive variations of conduit geometry have not been investigated in depth yet. Based on numerical modeling and the application of appropriate stability criteria, we found out a strong relationship between magma rheology and conduit stability, with significant effects on eruptive dynamics. Indeed, in order to be stable, conduits feeding dacitic/rhyolitic eruptions need larger diameters respect to their phonolitic/trachytic counterparts, resulting in the higher eruption rates commonly observed in dacitic/rhyolitic explosive events. Thus, in addition to magma source conditions and viscosity-dependent efficiency for outgassing, we suggest that typical eruption rates for different magma types are also controlled by conduit stability. Results are consistent with a compilation of volcanological data and selected case studies. As stability conditions are not uniform along the conduit, widening is expected to vary in depth, and three axisymmetric geometries with depth-dependent radii were investigated. They are able to produce major modifications in eruptive parameters, suggesting that eruptive dynamics is influenced by syn-eruptive changes in conduit geometry. PMID- 29515205 TI - Biogeographic patterns of aerobic anoxygenic phototrophic bacteria reveal an ecological consistency of phylogenetic clades in different oceanic biomes. AB - In marine environments, aerobic anoxygenic phototrophic (AAP) bacterial assemblages vary in space and along environmental gradients but the factors shaping their diversity and distribution at different taxonomic levels remain poorly identified. Using sets of sequences encoding the M sub-unit of the photosynthetic apparatus from different oceanic regions, we prioritized the processes underlying AAP bacterial biogeographical patterns. The present analysis offers novel insights into the ecological distribution of marine AAP bacteria and highlights that physiological constraints play a key role in structuring AAP bacterial assemblages at a global scale. Salinity especially seems to favor lineage-specific adaptations. Moreover, by inferring the evolutionary history of habitat transitions, a substantial congruence between habitat and evolutionary relatedness was highlighted. The identification of ecological cohesive clades for AAP bacteria suggests that prediction of AAP bacterial assemblages is possible from marine habitat properties. PMID- 29515206 TI - In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase. AB - Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 uM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 uM), with the best candidate, 54, demonstrating an IC50 of 5.6 uM against the RdRp and a CC50 of 62.8 uM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral. PMID- 29515207 TI - Maternal and offspring intelligence in relation to BMI across childhood and adolescence. AB - OBJECTIVE: The present study tested the association between both mothers' and offspring's intelligence and offspring's body mass index (BMI) in youth. METHOD: Participants were members of the National Longitudinal Survey of Youth 1979 (NLSY 79) Children and Young Adults cohort (n = 11,512) and their biological mothers who were members of the NLSY-79 (n = 4932). Offspring's IQ was measured with the Peabody Individual Achievement Test (PIAT). Mothers' IQ was measured with the Armed Forces Qualification Test (AFQT). A series of regression analyses tested the association between IQ and offspring's BMI by age group, while adjusting for pre-pregnancy BMI and family SES. The analyses were stratified by sex and ethnicity (non-Black and non-Hispanic, Black, and Hispanic). RESULTS: The following associations were observed in the fully adjusted analyses. For the non Blacks and non-Hispanics, a SD increment in mothers' IQ was negatively associated with daughters' BMI across all age-groups, ranging from beta = -0.12 (95% CI 0.22 to -0.02, p = 0.021) in late childhood, to beta = -0.17 (95% C.I. -0.27 to 0.07, p = 0001), in early adolescence and a SD increment in boys' IQ was positively associated with their BMI in early adolescence beta = 0.09 (95% CI 0.01-0.18, p = 0.031). For Blacks, there was a non-linear relationship between mothers' IQ and daughters' BMI across childhood and between girls' IQ and BMI across adolescence. There was a positive association between mothers' IQ and sons' BMI in early adolescence (beta = 0.17, 95% CI 0.02-0.32, p = 0.030). For Hispanic boys, there was a positive IQ-BMI association in late childhood (beta = 0.19, 95% CI 0.05-0.33, p = 0.008) and early adolescence (beta = 0.17, 95% CI 0.04-0.31, p = 0.014). CONCLUSION: Mothers' IQ and offspring's IQ were associated with offspring's BMI. The relationships varied in direction and strength across ethnicity, age group and sex. Obesity interventions may benefit from acknowledging the heterogeneous influence that intelligence has on childhood BMI. PMID- 29515208 TI - Exendin-4 modifies adipogenesis of human adipose-derived stromal cells isolated from omentum through multiple mechanisms. AB - BACKGROUND: Abdominal obesity is considered a major factor in the development of metabolic disorders. Glucagon-like peptide-1 (GLP-1) has been reported to have positive effects on improving body metabolism and to reducing insulin resistance. However, it remains less clear whether GLP-1 plays a role in the adipogenesis process of visceral fat. METHODS: Here, we analyzed the in vitro actions and probable mechanisms of Exendin-4, a GLP-1 receptor agonist, on human adipose derived stromal cells (hADSCs) isolated from omentum. RESULTS: Our results demonstrated that Exendin-4 improved cell viability via promoting proliferation and inhibiting apoptosis in hADSCs isolated from omentum. Mechanistically, the activation of MAPK/ ERK1/2, Akt/GSK-3beta, and PKA/CREB pathways and downstream consequences induced are involved in the proliferative and anti-apoptotic roles of Exendin-4. More intriguingly, Exendin-4 could promote the differentiation of omental hADSCs. Underlying mechanisms of the differentiation of hADSCs are associated with the upregulation of the expression of pro-adipogenic genes and downregulation of the expression of anti-adipogenic genes. CONCLUSION: Our data demonstrate that Exendin-4 modifies adipogenesis of hADSCs isolated from omentum through multiple mechanisms, these effects could contribute to the protective actions of GLP-1 receptor agonist body metabolism and insulin sensitivity. PMID- 29515209 TI - The effect of prenatal maternal cigarette smoking on children's BMI z-score with SGA as a mediator. AB - BACKGROUND: The goal of this study was to assess the effect of prenatal maternal cigarette smoking on children's BMI z-score trajectories, and to evaluate whether small-for-gestational-age (SGA) acts as a potential mediator between prenatal maternal cigarette smoking and child's BMI z-score at 4 years of age. METHODS: Group-based trajectory modeling (GBTM) methods were employed to describe and classify developmental BMI z-score trajectories (the outcome of interest) in children from 9 months to 4 years of age (n = 5221) in the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) study (2001-2005). Further analysis examined whether the identified BMI z-score trajectories varied with the exposure, prenatal maternal cigarette smoking. Mediation analyses were utilized to examine whether being SGA (binary measure) acted as a potential mediator in the relationship between prenatal maternal cigarette smoking and BMI z-score among 4-year-old children. RESULTS: Using GBTM, two BMI z-score trajectory groups were identified: normal BMI z-score (57.8%); and high BMI z-score (42.2%). Children of mothers who smoked cigarettes during pregnancy were 2.1 times (RR 95% CI: 1.1-4.0, P value = 0.023) more at risk of being in the high BMI z-score trajectory group. Prenatal cigarette smoking was positively related to SGA at birth, but SGA was inversely related to BMI z-score at 4 years. The direct effect (0.19, 95% CI: 0.18, 0.19; P value < 0.001) of maternal cigarette smoking status during pregnancy on BMI z-score among 4-year-old children was stronger and in the opposite direction of the indirect effect (-0.04, 95% CI: -0.04, -0.04; P value < 0.001) mediated through SGA. CONCLUSIONS: In this study, prenatal maternal cigarette smoking was positively associated with the high BMI z-score group, as well with SGA. The effects of prenatal smoking on BMI z-score at 4 years appears to act through pathways other than SGA. PMID- 29515210 TI - Association between body mass index and laboratory-confirmed influenza in middle aged and older adults: a prospective cohort study. AB - BACKGROUND: Studies conducted during the 2009 influenza A (H1N1) pandemic found that obesity increases the risk of severe influenza including hospitalization and death. In this study, we examined the relationship of BMI with having laboratory confirmed seasonal influenza and influenza-related respiratory hospitalization. METHODS: We linked a cohort of 246,494 adults aged >=45 years with data on BMI to subsequent laboratory-confirmed influenza notifications and cause-specific hospitalizations from 2006 to 2015. Cox-proportional hazard models were used to estimate the risk of incident laboratory-confirmed influenza and influenza related respiratory hospitalizations according to BMI, adjusting for age, sex and other covariates. RESULTS: After 1,840,408 person-years of follow-up, 1891 participants had laboratory-confirmed influenza notifications (crude rate 10.3/10,000 person-years) of whom 623 were hospitalized for a respiratory illness. Compared to those with healthy BMI (22.5 to <25.0 kg/m2), influenza incidence was respectively 27% (adjusted HR [aHR]: 1.27, 95% CI: 1.10-1.46) and 69% (aHR: 1.69, 1.24-2.29) greater among obese (BMI: 30 to <40 kg/m2) and very obese adults (40 to <50 kg/m2). The equivalent aHRs for hospitalization were 1.57 (95% CI: 1.22-2.01) and 4.81 (95% CI: 3.23-7.17). For every 5-unit BMI increase above 22.5 kg/m2, there was a 15% (aHR: 1.15, 95% CI: 1.09-1.22) increase in risk of having a diagnosis of influenza and 42% increase in hospitalization (aHR: 1.42, 95% CI: 1.30-1.60). These trends did not differ between the pandemic year (2009) and other years. CONCLUSIONS: Our results suggest that obese adults have a similar risk of hospitalization for seasonal influenza as adults with cardiovascular disease and diabetes, and should therefore be equally prioritized for funded interventions such as targeted immunization programs. PMID- 29515211 TI - Telehealth for people with spinal cord injury: a narrative review. AB - STUDY DESIGN: Narrative review. OBJECTIVES: To find and discuss what has been published about the use of telehealth, on people with spinal cord injury (teleSCI). SETTING: International. METHOD: Cochrane Library, Ovid Medline, EMBASE and CINAHL, from 1996 till June 2017 have been searched. Searches in PsycINFO, from 1996 till September 2017, were included afterwards. Extracted data include studies in English language, containing information about spinal cord injury and disorders, and telehealth. Literature reviews, systematic reviews, and studies containing other types of neurological disorders, were excluded. Studies were grouped based on how and to whom telehealth was offered. RESULTS: Twenty nine studies were included in the review. They were categorized according to the way teleSCI was provided, and to what modality was used. Some studies utilized more than one modality. TeleSCI seems to be favorable concerning treatment and follow up, as well as favorable socioeconomically and environmentally. The studies spanned across several aims and outcomes. There was also heterogeneity in number of participants, the differences in modalities, and in the level of evidence. Thus it was challenging to compare studies and make future recommendations. CONCLUSIONS: TeleSCI can be used for examination and guiding purposes. Further research is warranted to evaluate optimal utilization, methodology and efficacy. SPONSORSHIP: The first author has received funding from the Norwegian Extra Foundation. PMID- 29515212 TI - Positive airway pressure therapy for sleep-disordered breathing confers short term benefits to patients with spinal cord injury despite widely ranging patterns of use. AB - STUDY DESIGN: Prospective, cohort study. OBJECTIVES: To evaluate the effectiveness of bi-level positive airway pressure (PAP) therapy and the patterns of use for sleep-disordered breathing (SDB) in individuals with spinal cord injury (SCI). SETTING: Academic tertiary care center, USA. METHODS: Overall, 91 adults with C1-T6 SCI for >=3 months were recruited and 74 remained in the study to be evaluated for SDB and follow-up. Individuals with SDB but no nocturnal hypercapnia (NH) were prescribed auto-titrating PAP. Those with NH were prescribed PAP with volume-assured pressure support. Device downloads and overnight transcutaneous capnography were performed at 3, 6, and 12 months to quantify PAP use and effectiveness. Participants kept daily event logs, and quality of life (QOL) questionnaires were performed after 3, 6, and 12 months. RESULTS: Overall, 45% of 91 participants completed the study. There was great diversity among SCI patients in PAP utilization; after 3 months, 37.8% of participants used PAP for >=70% nights and >=240 min per night, whereas 42.2% seldom used PAP and 20% used PAP sporadically or for short periods. PAP therapy was effective in improving OSA in 89% and nocturnal hypercapnia in 77%. Higher PAP pressures predicted higher levels of device use. There were marked reductions in symptoms of autonomic dysreflexia (AD) and orthostatic hypotension as well as some improved indices of QOL. CONCLUSIONS: Despite widely diverse patterns of use, PAP therapy may have short-term benefits with regard to QOL and reducing episodes of dizziness and autonomic dysreflexia. PMID- 29515213 TI - Impact of orthotic therapy for improving activities of daily living in individuals with spinal cord injury: a retrospective cohort study. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the impact of leg orthotic therapy for improving activities of daily living after spinal cord injury. SETTING: Participating acute care and rehabilitation hospitals across Japan. METHODS: We retrospectively identified individuals with spinal cord injury admitted to eight participating hospitals in 2015-2016 from the Japan Rehabilitation Database. Data for 293 individuals were analyzed. Propensity score analysis by inverse probability weighting (IPW) was applied to adjust for potential bias and create two comparable groups. Outcomes were compared between the leg orthotic group and the non-leg orthotic group, using IPW. The primary outcome was motor Functional Independence Measure(r) (FIM) effectiveness score and the secondary outcome was motor FIM score at discharge. FIM was measured on hospital admission and discharge. RESULTS: Leg orthoses were prescribed for 26% of the 293 individuals. Those prescribed leg orthoses had significantly higher motor FIM effectiveness scores than those who were not, before and after IPW (motor FIM effectiveness: 0.54 vs. 0.35, p < 0.01 and 0.45 vs. 0.36, p = 0.02). Discharge motor FIM was significantly higher in individuals who were prescribed leg orthoses than in those who were not, before and after IPW (discharge motor FIM: 64.5 vs. 52.2, p < 0.01 and 58.9 vs. 53.5, p = 0.02). CONCLUSIONS: Leg orthoses may improve activities of daily living in individuals with spinal cord injury after the acute phase. PMID- 29515214 TI - Complications of non-continent cutaneous urinary diversion in adults with spinal cord injury: a retrospective study. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To report the long-term complications of non-continent cutaneous urinary diversion (NCCUD) in adult patients with spinal cord injury (SCI). SETTING: Hospital in Paris, France. METHODS: A retrospective single center study included all adult patients with SCI who underwent an ileal conduit between 1997 and 2014. Early complications were reported according to Clavien-Dindo classification. Long-term complications and reoperation rates were recorded, as well as stoma management and autonomy improvement related to urinary function. RESULTS: One hundred and two patients were included. The surgical indications included failure of intermittent catheterization (n = 43), urethral fistulae due to skin ulcers (n = 50), renal failure (n = 8), recurrent urinary tract infections (n = 9), lithiasis (n = 3), and bladder tumors (n = 2). There were 67 early postoperative complications for 44 patients (43%) leading to an additional surgery in 15 cases: 30 grade I-II, 30 grade III, 6 grade IV, and 1 grade V. A total of 37 late complications were reported for 36 patients (35%): 17 ureteral anastomosis stenosis, 3 stoma hernia, 3 pyocystis (3/15 patients), 7 pyelonephritis, 2 renal failures, 2 ureteral lithiasis, 1 uterine prolapse, 1 incisional hernia, and 1 tumor recurrence. Renal function remained unchanged (p = 0.53). Autonomy related to urinary function was improved in 88% of patients. The correct fitting of the stoma was possible for 81% of the patients. CONCLUSIONS: Despite a perioperative morbidity rate of 43% and a late complication rate of 35%, as a last resort procedure, NCCUD is an end stage solution in patients with SCI to preserve renal function and achieve autonomy. PMID- 29515215 TI - Publisher Correction: Medial preoptic circuit induces hunting-like actions to target objects and prey. AB - In the version of this article initially published, a sentence in the fifth paragraph of the Results read, "Immunohistochemistry revealed that VGLUT2+ MPA neurons rarely expressed CaMKIIalpha, which is a putative marker for subcortical glutamatergic neurons." It should have read, "Immunohistochemistry revealed that CaMKIIalpha+ MPA neurons rarely expressed VGLUT2, which is a putative marker for subcortical glutamatergic neurons." The error has been corrected in the HTML and PDF versions of the article. In the supplementary information originally posted online, the wrong version of Supplementary Fig. 1 was posted and some of the supplementary videos were interchanged. In the corrected Supplementary Fig. 1, the top right subpanel was added and the original Supplementary Fig. 1a was divided into 1a and 1b, with subsequent panels incremented accordingly. The legend was changed from "a. Schematic illustrating electrical lesioning of the rat anterior hypothalamus. Electrical lesion areas (gray) in five representative brain sections are depicted. Scale bar, 1 mm" to "a. Repetitive electrical stimulations of the anterior hypothalamus using bipolar electrodes (Left) caused a lesion at the hypothalamic area (middle, marked by asterisk) successfully in 7 rats (Right, overlapped images of brain sections located from the bregma -0.24 mm). Scale bar, 1 mm. b. Electrical lesion areas (gray) in five representative brain sections from anterior to posterior are depicted." The errors have been corrected online. PMID- 29515216 TI - How do paper and electronic records compare for completeness? A three centre study. AB - OBJECTIVES: Medical records are legal documentation of patients' care hence must be accurate and complete for both medical and legal purposes. Electronic patient record (EPR) systems aim to improve the accuracy of documentation, provide better organisation and access of data. This study compares the completeness of traditional note records and EPR in glaucoma patients. METHODS: Using criteria from the April 2009 National Institute for Health and Care Excellence (NICE) guidelines completeness of data entry was compared between EPR and paper notes in three units. Moorfields Eye Hospital (City Road) uses the Openeyes EPR. Bedford Hospital (Moorfields Eye Centre) and Western Eye Hospital use the Medisoft EPR. The standard was set at 100% compliance for predetermined parameters. RESULTS: One hundred seventy paper notes and 270 electronic records were analysed. With the exception of central corneal thickness (p = 0.31), all other key parameters were more consistently recorded in the paper records than in the EPR. Intraocular pressure (p = 0.004), anterior chamber configuration and depth assessments using gonioscopy (p < 0.001), fundus examination (p = 0.015), past medical history (p < 0.001), medication including glaucoma medication (p < 0.001) and drug allergies (p < 0.001). CONCLUSIONS: Our results show that paper records are significantly more complete than EPR. This is the case for two different EPRs and three separate sites. We propose additional training to aid data-collection; improving the design of EPRs by investigating factors such as layout and use of forced choice fields. PMID- 29515218 TI - In response to: Teofili L, et al. Foetal haemoglobin, blood transfusion, and retinopathy of prematurity. PMID- 29515217 TI - B-cell leukemia/lymphoma 10 promotes angiogenesis in an experimental corneal neovascularization model. AB - PURPOSE: Corneal neovascularization (CrNV) arises from many causes including corneal inflammatory, infectious, or traumatic insult, and frequently leads to impaired vision. This study seeks to determine the role of B-cell leukemia/lymphoma 10 (BCL-10) in the development of experimental CrNV. METHODS: Corneas from BCL-10 knockout (KO) mice and wild-type (WT) mice were burned by sodium hydroxide (NaOH) to create the CrNV model and neovascular formation in the corneas was assessed 2 weeks later. Intracorneal macrophage accumulation and the expression of angiogenic factors were quantified by flow cytometric analysis (FCM) and real-time PCR, respectively. RESULTS: The amount of CrNV was determined 2 weeks after alkali burn. Compared to WT mice, the amount of CrNV in BCL-10 KO mice was significantly decreased. FCM revealed that F4/80-positive macrophages were markedly decreased in BCL-10 KO mice compared with WT mice. Reverse transcription PCR showed that the mRNA expression levels of intracorneal vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (bFGF) and monocyte chemotactic protein 1 were reduced in BCL-10 KO mice compared with WT mice. CONCLUSION: BCL-10 KO mice exhibited reduced alkali-induced CrNV by suppressing intracorneal macrophage infiltration, which subsequently led to decreased VEGF-A and bFGF expression, suggesting that BCL-10 may become a potential clinical intervening target of CrNV. PMID- 29515219 TI - Author Correction: Influence of soil moisture on codenitrification fluxes from a urea-affected pasture soil. AB - A correction has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29515220 TI - Causes and risk factors for singleton stillbirth in Japan: Analysis of a nationwide perinatal database, 2013-2014. AB - Over 80% of perinatal mortality in Japan is due to stillbirths after 22 weeks of gestation, with one in 300 families experiencing fetal loss every year. This study aimed to assess causes and risk factors for singleton stillbirth in Japan. A retrospective cross-sectional study was conducted using the Japan Society of Obstetrics and Gynecology Perinatal Database from January 2013 to December 2014. A total of 379,211 births including 2,133 stillbirths were analyzed. Causes of death were classified into eight categories. A multi-level Poisson regression model was used to assess the relationship between stillbirth and key covariates. Causes of death were unknown in 25-40% of stillbirths across gestational age. Placental abnormality accounted for the largest proportion of known causes, followed by umbilical cord abnormality. Stillbirth risk was increased among small for-gestational-age infants (adjusted relative risk [ARR]: 3.78, 95% confidence interval [CI]: 3.31-4.32) and nulliparous women (ARR: 1.19, 95% CI: 1.05-1.35). Maternal underweight, pregnancy-induced hypertension and oligohydramnios showed a protective effect. Our finding suggests that stillbirths occurring among women with known complications are likely already being prevented. Further reduction in stillbirths must target small-sized fetuses and nulliparous women. Improved recording of the causal pathways of stillbirths is also needed. PMID- 29515223 TI - Letter to the editor: Treatment of patent ductus arteriosus in premature infants. PMID- 29515221 TI - Electroconvulsive therapy (ECT) during pregnancy: quantifying and assessing the electric field strength inside the foetal brain. AB - Electroconvulsive therapy (ECT) is an effective treatment option for severe mental illness during pregnancy. However, there is little knowledge about the amount of electric field produced inside the foetus, which is important to understand the effects of ECT on the foetal excitable tissues. Thus, in this paper, the electric field strength inside the foetus was computed and compared to the basic restriction of the International Commission for Non-Ionizing Radiation Protection (ICNIRP). A computational human phantom representing a 30-weeks pregnant female, four types of electrode placements and a range of stimulus pulse width (0.25 ms-2 ms) and frequency (10 Hz-140 Hz) were used to compute the electric field inside the foetus. A linear relationship between the maximum electric field inside the foetal brain and the electrode current was derived. The results suggest that, considering the maximum current output, pulse width, and frequency range of constant-current ECT devices, the electric field produced inside the foetal brain is most likely below the ICNIRP basic restriction. This is based on the practical scenario of a 30-weeks foetus with a bottom-up and head down foetal position and the mother taller than 1.62 m. PMID- 29515222 TI - Image-Guided Focused-Ultrasound CNS Molecular Delivery: An Implementation via Dynamic Contrast-Enhanced Magnetic-Resonance Imaging. AB - Focused ultrasound (FUS) exposure with microbubbles can transiently open the blood-brain barrier (BBB) to deliver therapeutic molecules into CNS tissues. However, delivered molecular distribution/concentration at the target need to be controlled. Dynamic Contrast-Enhanced Magnetic-Resonance Imaging (DCE-MRI) is a well-established protocol for monitoring the pharmacokinetic/pharmacodynamic behavior of FUS-BBB opening. This study investigates the feasibility of using DCE MRI to estimate molecular CNS penetration under various exposure conditions and molecule sizes. In the 1st stage, a relationship among the imaging index Ktrans, exposure level and molecular size was calibrated and established. In the 2nd stage, various exposure levels and distinct molecules were applied to evaluate the estimated molecular concentration discrepancy with the quantified ones. High correlation (r2 = 0.9684) between Ktrans and transcranial mechanical index (MI) implies Ktrans can serve as an in vivo imaging index to mirror FUS-BBB opening scale. When testing various molecules with the size ranging 1-149 kDa, an overall correlation of r2 = 0.9915 between quantified and predicted concentrations was reached, suggesting the established model can provide reasonably accurate estimation. Our work demonstrates the feasibility of estimating molecular penetration through FUS-BBB opening via DCE-MRI and may facilitate development of FUS-induced BBB opening in brain drug delivery. PMID- 29515224 TI - Blood potassium and urine aldosterone after doxapram therapy for preterm infants. AB - OBJECTIVE: We often encounter infants who developed hypokalaemia following low dose doxapram for apnea of prematurity (AOP). AIMS: To determine changes in blood potassium (K+) levels after doxapram administration. STUDY DESIGN: We studied infants born before 30 weeks gestation. Doxapram (0.1-0.3 mg/kg/h) in addition to methylxanthines was used to treat AOP refractory to methylxanthines. RESULTS: Twenty-five infants received doxapram were studied. Fifty-two percent developed hypokalemia (<3.0 mEq/L) during doxapram administration. Time after starting doxapram to nadir blood K+ (<3.0 mEq/L) level was 11 days. Blood K+ levels normalized after 5 days of stopping doxapram administration. Data at 10 days before and after and at the time of doxapram administration were, respectively: lowest blood K+ level: 3.9, 3.0, and 3.6 mEq/L; urine aldosterone: 90, 206, and 146 pg/MUg creatinine. Blood pH, blood pressure and urine volume were similar. CONCLUSIONS: Doxapram-induced hypokalemia may be due to an inappropriate increase in aldosterone levels. PMID- 29515226 TI - Finding the right treatment for neonatal abstinence syndrome: is this the right time? AB - Neonatal abstinence syndrome (NAS) is a constellation of withdrawal symptoms in infants born to mothers with chronic opioid use during pregnancy. A proportion of infants will need pharmacotherapy in addition to non-pharmacological interventions. In this article, we reviewed a clinical trial comparing the use of sublingual buprenorphine to oral morphine (the most widely used pharmacotherapy for NAS) in term infants. The primary end point was the duration of treatment, and secondary end points were the length of hospital stay, the proportion of infants who needed supplemental phenobarbital, and safety. PMID- 29515225 TI - Retrospective review of neurodevelopmental outcomes in infants treated for neonatal abstinence syndrome. AB - OBJECTIVE: Little is known about developmental outcomes in neonatal abstinence syndrome (NAS). We hypothesized that children treated for NAS would score lower than the normative sample on the Bayley Scales of Infant Development, 3rd edition. STUDY DESIGN: We performed a retrospective cohort study of 87 infants treated for NAS and evaluated at 2 years of age. RESULTS: Children treated for NAS scored significantly lower than the norm (mean 100) on all 3 subscales (cognitive mean 96.5, language mean 93.8, motor mean 94.0, all p < 0.03). Children who lived with foster/adoptive families at follow up had higher cognitive scores (median 100 vs. 95, p = 0.03) than those who lived with biological relatives, and were less likely to have motor scores <85 (p = 0.02). Eight percent of children required treatment for strabismus. CONCLUSIONS: Children treated for NAS are at risk for lower developmental scores and higher rates of strabismus at age 2 than the general population. PMID- 29515227 TI - Structured inpatient evaluation of neonatal cardiac ectopy. AB - OBJECTIVE(S): In well-appearing newborns with suspected cardiac ectopy, we sought to evaluate our practice and test whether initial electrocardiogram (ECG) findings were associated with neonatal arrhythmias (NA). STUDY DESIGN: We identified well-appearing, non-anomalous infants >34 weeks' gestation with suspected ectopy over 3.5 years. NA was defined as >=10% premature atrial contractions (PAC), >=5 beats of atrial tachycardia, >=2% premature ventricular contractions (PVCs), or >=3 beats of ventricular tachycardia. The unadjusted associations between initial ECG findings and NA are reported. RESULT: Among 126 infants with ECGs and Holters performed, NA was observed in 38 patients (30%) and was similar whether PACs were present or not on the initial ECG (33% vs. no PACs: 29%, p = 0.6). However, NAs were identified more frequently based on the presence of PVCs on the initial ECG (83% vs. 25%, p < 0.01). CONCLUSION: NAs were prevalent and both their etiologies and impact on infants warrant future study. PMID- 29515228 TI - Structure and biosynthesis of mayamycin B, a new polyketide with antibacterial activity from Streptomyces sp. 120454. AB - Mayamycin B, a new antibacterial type II polyketide, together with its known congener mayamycin A, were isolated from Streptomyces sp. 120454. The structure of new compound was elucidated by extensive spectroscopic analysis and comparison with literature data. Sequencing and bioinformatics analysis revealed the biosynthetic gene cluster for mayamycins A and B. PMID- 29515229 TI - Computational study on formation of 15-membered azalactone by double reductive amination using molecular mechanics and density functional theory calculations. AB - Formation of 15-membered azalactone by double reductive amination was analyzed using molecular mechanics and density functional theory calculations for simplified model compounds. As a result, the following aspects were clarified. When methylamine attacks a linear bis-aldehyde in the first step, there are possibilities that two regioisomers are formed. However, one of them exhibited remarkably stable energy level compared with the other. The stable isomer indicated a short distance between a methylamine moiety and an unreacted aldehyde. This short distance, about 2.3 A, could be explained by hydrogen bonding, which implied relatively easy cyclization in the second step. Moreover, this cyclization process was supposed to be exothermic according to comparison of energy levels before and after cyclization. PMID- 29515230 TI - Pyrizomicin A and B: structure and bioactivity of new thiazolyl pyridines from Lechevalieria aerocolonigenes K10-0216. AB - Two new antibiotics, designated pyrizomicin A and B, were isolated from the cultured broth of a rare actinomycete strain, Lechevalieria aerocolonigenes K10 0216, by silica gel and HPLC purification. The chemical structures of pyrizomicin A and B were elucidated as new thiazolyl pyridine compounds by nuclear magnetic resonance and mass spectrometry. Pyrizomicin A and B both showed antimicrobial activity. PMID- 29515231 TI - Streptosporangium minutum sp. nov., isolated from garden soil exposed to microwave radiation. AB - The actinobacterium, strain M26T, was isolated from garden soil that was pre treated with microwave radiation. The soil sample was collected in Roodepoort, Gauteng Province, South Africa as part of an antibiotic-screening programme. The isolate produced branched vegetative mycelium with sporangiophores bearing small sporangia ranging from 3 to 6 MUm in diameter. Rapid genus identification revealed that the isolate belongs to the genus Streptosporangium. To confirm this result, the strain was subjected to polyphasic taxonomic characterisation. Chemotaxonomic characteristics were as follows: meso-DAP in the peptidoglycan, the whole-cell hydrolysate yielded madurose, predominant menaquinones were MK9 (21%), MK9(H2) (40%), MK9(H4) (31%) and MK9(H6) (3%); the polar lipid profile included an aminolipid, phosphoglycolipids, phosphatidylethanolamine, and phosphatidylmonomethylethanolamine. In addition, the fatty acid profile showed the presence of C16:0 (12.8%), C17:1omega8c (14.2%), and 10-methyl-C17:0 (15.8%). Furthermore, 16S rRNA gene sequence phylogenetic analysis showed that the strain is closely related to members of the genus Streptosporangium, which supports its classification within the family Streptosporangiaceae. Strain M26T exhibited antibiosis against a range of pathogenic bacteria, including, but not limited to Acinetobacter baumannii ATCC 19606T, Enterobacter cloacae subsp. cloacae ATCC BAA 1143, Enterococcus faecalis ATCC 51299 (vancomycin resistant), Escherichia coli ATCC 25922, Listeria monocytogenes ATCC 19111, Mycobacterium tuberculosis H37RvT, Pseudomonas aeruginosa ATCC 27853, Salmonella enterica subsp. arizonae ATCC 13314T, and the methicillin-resistant Staphylococcus aureus subsp. aureus ATCC 33591 (MRSA). The name Streptosporangium minutum is proposed with the type strain M26T (=LMG 28850T =NRRL B-65295T). PMID- 29515232 TI - TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma. AB - The tumor microenvironment promotes epigenetic changes in tumor cells associated with tumor aggressiveness. Here we report that in primary tumor cells, increased interleukin-6 (IL-6) expression brought on by DNA demethylation of its promoter by ten-eleven translocation 2 (TET2) promotes lung metastasis in osteosarcoma (OS). Xenograft experiments show increased IL-6 expression and decreased methylation of its promoter in OS cells after implantation relative to before implantation. In addition, changes in IL-6 methylation and expression seen in OS cells at the primary site were maintained at the metastatic site. TET2 knockdown in OS cells suppressed upregulation of IL-6 and demethylation of its promoter in xenograft tumors and decreased tumor metastasis. We also present evidence showing that tumor cell-derived IL-6 facilitates glycolytic metabolism in tumor cells by activating the MEK/ERK1/2/hypoxia-inducible transcription factor-1alpha (HIF 1alpha) pathway and increases lung colonization by OS cells by upregulating expression of intercellular adhesion molecule-1 (ICAM-1), enhancing tumor metastasis. Blocking IL-6 signaling with a humanized monoclonal antibody against the IL-6 receptor reduced lung metastasis and prolonged survival of xenografted mice. These findings suggest that TET2-dependent IL-6 induction enables acquisition of aggressive phenotypes in OS cells via the tumor microenvironment and that blocking IL-6 signaling could be serve as a potential therapy to antagonize metastasis. PMID- 29515233 TI - Depression promotes prostate cancer invasion and metastasis via a sympathetic cAMP-FAK signaling pathway. AB - Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking beta2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer. PMID- 29515235 TI - Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role. AB - Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (<6 months duration) emerged as one important predictor of early myeloma-related mortality associated with a significant increase in the risk of death related to myeloma progression. The identification of these patients at high risk of early death is relevant for innovative trials aiming to maintain the depth of first response, since many of them will not receive subsequent lines of therapy. PMID- 29515234 TI - PARP10 suppresses tumor metastasis through regulation of Aurora A activity. AB - ADP-ribosylation, including poly-ADP-ribosylation (PARylation) and mono-ADP ribosylation (MARylation), is a multifunctional post-translational modification catalyzed by intracellular ADP-ribosyltransferases (ARTDs or PARPs). Although PARylation has been investigated most thoroughly, the function of MARylation is currently largely undefined. Here, we provide evidences that deficiency of PARP10, a mono-ADP-ribosyltransferase, markedly increased the migration and invasion of tumor cells through regulation of epithelial-mesenchymal transition (EMT), and PARP10 inhibited tumor metastasis in vivo, which was dependent on its enzyme activity. Mechanistically, we found that PARP10 interacted with and mono ADP-ribosylated Aurora A, and inhibited its kinase activity, thereby regulating its downstream signaling. Moreover, the expression level of PARP10 was downregulated in intrahepatic metastatic hepatocellular carcinoma (HCC) compared with its corresponding primary HCC and adjacent non-tumorous tissues. Taken together, our results indicated that PARP10 has an important role in tumor metastasis suppression via negatively regulation of Aurora A activity. PMID- 29515236 TI - Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. AB - Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence. PMID- 29515237 TI - Managing myeloproliferative neoplasms evidence based on the ELN treatment recommendations 2018. PMID- 29515239 TI - The associations of serum n-6 polyunsaturated fatty acids with serum C-reactive protein in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. AB - BACKGROUND/OBJECTIVES: There are concerns that high intake of n-6 polyunsaturated fatty acids (PUFA) may promote inflammation, because the end-product of n-6 PUFA metabolism, arachidonic acid, is a precursor for pro-inflammatory eicosanoids. Our aim was to investigate cross-sectional associations of the serum n-6 PUFAs, objective biomarkers for exposure, with serum high-sensitivity C-reactive protein (CRP), a key inflammation marker. SUBJECTS/METHODS: The study included 1287 generally healthy men aged 42-60 years from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study, examined in 1984-1989. ANCOVA and logistic regression were used for analyses. RESULTS: In the multivariable-adjusted analyses, both serum total n-6 PUFA and linoleic acid, the predominant n-6 PUFA, were associated with lower CRP. The mean CRP concentrations in quartiles of linoleic acid were 1.86, 1.51, 1.53, and 1.37 mg/L (P-trend = 0.001). The odds ratio for elevated CRP (>3 mg/L) in the highest vs. the lowest quartile was 0.47 (95% confidence interval (CI) 0.25-0.87, P-trend = 0.01). Arachidonic acid or the mainly endogenously produced n-6 PUFAs, gamma-linolenic acid and dihomo-gamma linolenic acid, were not associated with higher CRP, either. Age, body mass index, or serum long-chain n-3 PUFA concentration did not modify the associations (P-interactions > 0.14). CONCLUSIONS: Serum n-6 PUFAs were not associated with increased inflammation in men. In contrast, the main n-6 PUFA linoleic acid had a strong inverse association with the key inflammation marker, CRP. PMID- 29515238 TI - Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. AB - This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting. PMID- 29515241 TI - The rarity of concomitant genetic alterations in lung cancer. PMID- 29515240 TI - T-bet promotes potent antitumor activity of CD4+ CAR T cells. AB - Chimeric antigen receptor (CAR) therapy has shown promise against B cell malignancies in the clinic. However, limited success in patients with solid tumors has prompted the development of new CAR strategies. In this study, a B7H6 specific CAR was combined with different variants of T-bet, a transcription factor that acts as the master regulator to induce a Th1 phenotype in CD4+ T cells, to create more effective CAR T cells. Skewing CD4+ CAR T cells into a Th1 improved CAR T cell functional activity while promoting a robust proinflammatory response against B7H6-expressing tumors. The expression of T-bet with the B7H6 specific CAR in CD4+ T cells conferred higher expression of the CAR, elevated secretion of Th1 and proinflammatory cytokines, and improved cellular cytotoxicity against B7H6-expressing tumor cells. In vivo, CD4+ T cells co expressing a B7H6-specific CAR and T-bet improved the survival of RMA-B7H6 lymphoma-bearing mice. Thus, CD4+ CAR T cells with increased T-bet expression have the potential to modify the tumor microenvironment and the immune response to better treat solid and hematologic cancers. PMID- 29515243 TI - Reply to Lambros et al. PMID- 29515244 TI - Publisher Correction: Resistance to nonribosomal peptide antibiotics mediated by D-stereospecific peptidases. AB - In the version of this article originally published, the links and files for the Supplementary Information, including Supplementary Tables 1-5, Supplementary Figures 1-25, Supplementary Note, Supplementary Datasets 1-4 and the Life Sciences Reporting Summary, were missing in the HTML. The error has been corrected in the HTML version of this article. PMID- 29515245 TI - Impact of T-cell depletion on outcome of patients undergoing allogeneic hematopoietic cell transplantation for myelodysplastic syndrome. PMID- 29515246 TI - Association between recipient TNF rs361525 and acute GVHD: results from analysis of BMT CTN-0201 samples. PMID- 29515247 TI - Matched unrelated donor transplantation in glycogen storage disease type 1b patient corrects severe neutropenia and recurrent infections. PMID- 29515248 TI - Severe pembrolizumab-associated neutropenia after CD34+ selected allogeneic hematopoietic-cell transplantation for multiple myeloma. PMID- 29515249 TI - Severity, course, and predictors of sleep disruption following hematopoietic cell transplantation: a secondary data analysis from the BMT CTN 0902 trial. AB - Sleep disruption has received little attention in hematopoietic cell transplantation (HCT). The goal of this study was to describe severity, course, and predictors of sleep disruption following HCT. A secondary data analysis was conducted of the Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) 0902 study. Participants completed a modified version of the Pittsburgh Sleep Quality Index prior to transplant and 100 and 180 days posttransplant. Growth mixture models were used to characterize subgroups of patients based on baseline sleep disruption and change over time. A total of 570 patients (mean age 55 years, 42% female) were included in the current analyses. Patients could be grouped into four distinct classes based on sleep disruption: (1) clinically significant sleep disruption at baseline that did not improve over time (20%); (2) clinically significant sleep disruption at baseline that improved over time (22%); (3) sleep disruption that did not reach clinical significance at baseline and did not improve over time (45%); and (4) no sleep disruption at baseline or over time (13%). These data provide a more comprehensive understanding of sleep disruption that can be used to develop interventions to improve sleep in HCT recipients. PMID- 29515250 TI - Prognostic significance of microRNA-99a in acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation. AB - Overexpression of microRNA-99a (miR-99a) have been associated with adverse prognosis in acute myeloid leukemia (AML). Nevertheless, whether it also predicts poor outcome in post-allogeneic hematopoietic stem cell transplantation (allo HSCT) AML patients remains unclear. To further elucidate the prognostic value of miR-99a, 74 AML patients with miR-99a expression report who underwent allo-HSCT from The Cancer Genome Atlas database were identified and grouped into either miR 99ahigh or miR-99alow based on their miR-99a expression levels relative to the median. Two groups had similar clinical and molecular characteristics except that miR-99ahigh group had fewer patients of the French-American-British M4 subtype (P = 0.018) and more frequent CEBPA mutations (P = 0.005). Univariate analysis indicated that high miR-99a expression was unfavorable for both event-free survival (EFS) and overall survival (OS; P = 0.029; P = 0.012, respectively). Multivariate analysis suggested that high miR-99a expression was an independent risk factor for both EFS and OS in AML patients who underwent allo-HSCT [hazard ratio (HR) 1.909, 95% confidence interval (CI) 1.043-3.494, P = 0.036 and HR 2.179, 95% CI 1.192-3.982, P = 0.011, respectively]. Our results further proved that high miR-99a expression could predict worse outcome in AML patients, even in those who underwent intensive post-remission therapy such as allo-HCST. PMID- 29515251 TI - Prevalence of self-reported sleep dysfunction before allogeneic hematopoietic cell transplantation. PMID- 29515252 TI - Variability of nutritional practices in peritransplant period after allogeneic hematopoietic stem cell transplantation: a survey by the Complications and Quality of Life Working Party of the EBMT. AB - Recommendations on screening and nutritional support for patients undergoing hematopoietic stem cell transplantation (HSCT) have been presented by international nutritional societies, but nutritional practices remain poorly standardized. Following the general policy of the European Society for Blood and Marrow Transplantation (EBMT) to standardize transplantation procedures, the Complications and Quality of Life Working Party and Nursing Research Group carried out a survey among all EBMT centers about their current nutritional practices. The aim of this study was to better understand current practices, differences from available guidelines, and possible barriers for recommended nutritional therapy. Responses from 90 centers (19%) from 23 countries were received. We observed a marked variability in nutritional care between EBMT centers and a substantial lack of standardized operating procedures in screening patients for malnutrition and management of gastrointestinal GVHD. Furthermore, our study confirmed neutropenic diet as standard of care in most centers as well a preference for parenteral nutritional support over enteral. On the basis of these findings, future EBMT efforts will focus on better implementation of international nutritional guidelines into clinical practice. PMID- 29515253 TI - Clinical-scale manufacturing of gammadelta T cells for protection against infection and disease recurrence following haploidentical peripheral blood stem cell transplantation and cyclophosphamide gvhd prophylaxis. PMID- 29515254 TI - Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells. AB - HACE1 is an E3 ubiquitin ligase described as a tumour suppressor because HACE1 knockout mice develop multi-organ, late-onset cancers and because HACE1 expression is lost in several neoplasms, such as Wilms' tumours and colorectal cancer. However, a search of public databases indicated that HACE1 expression is maintained in melanomas. We demonstrated that HACE1 promoted melanoma cell migration and adhesion in vitro and was required for mouse lung colonisation by melanoma cells in vivo. Transcriptomic analysis of HACE1-depleted melanoma cells revealed an inhibition of ITGAV and ITGB1 as well changes in other genes involved in cell migration. We revealed that HACE1 promoted the K27 ubiquitination of fibronectin and regulated its secretion. Secreted fibronectin regulated ITGAV and ITGB1 expression, as well as melanoma cell adhesion and migration. Our findings disclose a novel molecular cascade involved in the regulation of fibronectin secretion, integrin expression and melanoma cell adhesion. By controlling this cascade, HACE1 displays pro-tumoural properties and is an important regulator of melanoma cell invasive properties. PMID- 29515256 TI - Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer. AB - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC 3(v2) trial, randomised to either postoperative gemcitabine or 5 fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91 3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6 15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine. PMID- 29515257 TI - Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy. AB - BACKGROUND: Cancers are heterogeneous and contain various types of irregular structures that can go undetected when examining them with standard two dimensional microscopes. Studies of intricate networks of vasculature systems, e.g., the tumour lymphatic microvessels, benefit largely from three-dimensional imaging data analysis. METHODS: The new DIPCO (Diagnosing Immunolabeled Paraffin Embedded Cleared Organs) imaging platform uses three-dimensional light-sheet microscopy and whole-mount immunolabelling of cleared samples to study proteins and micro-anatomies deep inside of tumours. RESULTS: Here, we uncovered the whole three-dimensional lymphatic microvasculature of formalin-fixed paraffin-embedded (FFPE) tumours from a cohort of 30 patients with bladder cancer. Our results revealed more heterogeneous spatial deviations in more advanced bladder tumours. We also showed that three-dimensional imaging could determine tumour stage and identify vascular or lymphatic system invasion with higher accuracy than standard two-dimensional histological diagnostic methods. There was no association between sample storage times and outcomes, demonstrating that the DIPCO pipeline could be successfully applied on old FFPE samples. CONCLUSIONS: Studying tumour samples with three-dimensional imaging could help us understand the pathological nature of cancers and provide essential information that might improve the accuracy of cancer staging. PMID- 29515259 TI - Mercury flux from salt marsh sediments: Insights from a comparison between 224Ra/228Th disequilibrium and core incubation methods. AB - In aquatic environments, sediments are the main location of mercury methylation. Thus, accurate quantification of methylmercury (MeHg) fluxes at the sediment water interface is vital to understanding the biogeochemical cycling of mercury, especially the toxic MeHg species, and their bioaccumulation. Traditional approaches, such as core incubations, are difficult to maintain at in-situ conditions during assays, leading to over/underestimation of benthic fluxes. Alternatively, the 224Ra/228Th disequilibrium method for tracing the transfer of dissolved substances across the sediment-water interface, has proven to be a reliable approach for quantifying benthic fluxes. In this study, the 224Ra/228Th disequilibrium and core incubation methods were compared to examine the benthic fluxes of both 224Ra and MeHg in salt marsh sediments of Barn Island, Connecticut, USA from May to August, 2016. The two methods were comparable for 224Ra but contradictory for MeHg. The radiotracer approach indicated that sediments were always the dominant source of both total mercury (THg) and MeHg. The core incubation method for MeHg produced similar results in May and August, but an opposite pattern in June and July, which suggested sediments were a sink of MeHg, contrary to the evidence of significant MeHg gradients between overlying water and porewater at the sediment-water interface. The potential reasons for such differences are discussed. Overall, we conclude that the 224Ra/228Th disequilibrium approach is preferred for estimating the benthic flux of MeHg and that sediment is indeed an important MeHg source in this marshland, and likely in other shallow coastal waters. PMID- 29515258 TI - AKR1C enzymes sustain therapy resistance in paediatric T-ALL. AB - BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors. METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches. RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment. CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy. PMID- 29515255 TI - A kinome-wide RNAi screen identifies ALK as a target to sensitize neuroblastoma cells for HDAC8-inhibitor treatment. AB - The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3 6 uM PCI-34051 or 10 uM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05 uM (ALK amplified) to 0.8 uM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n = 88) and the German Neuroblastoma Trial cohort (n = 649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma. PMID- 29515260 TI - Comparisons of Computed Mobile Phone Induced SAR in the SAM Phantom to That in Anatomically Correct Models of the Human Head. AB - The specific absorption rates (SAR) determined computationally in the specific anthropomorphic mannequin (SAM) and anatomically correct models of the human head when exposed to a mobile phone model are compared as part of a study organized by IEEE Standards Coordinating Committee 34, SubCommittee 2, and Working Group 2, and carried out by an international task force comprising 14 government, academic, and industrial research institutions. The detailed study protocol defined the computational head and mobile phone models. The participants used different finite-difference time-domain software and independently positioned the mobile phone and head models in accordance with the protocol. The results show that when the pinna SAR is calculated separately from the head SAR, SAM produced a higher SAR in the head than the anatomically correct head models. Also the larger (adult) head produced a statistically significant higher peak SAR for both the 1- and 10-g averages than did the smaller (child) head for all conditions of frequency and position. PMID- 29515262 TI - MESSAGE FROM THE PRESIDENT ELECT. PMID- 29515261 TI - MESSAGE FROM THE PRESIDENT. PMID- 29515263 TI - MESSAGE FROM THE GENERAL SECRETARY. PMID- 29515264 TI - WELCOME MESSAGE. PMID- 29515266 TI - AWARDS. PMID- 29515265 TI - "The journey of Psychiatry...". PMID- 29515267 TI - Individual Rights versus Societal Protection - Interface between Law and Psychiatry. PMID- 29515268 TI - Improvements in Depression and Mental Health After Acceptance and Commitment Therapy are Related to Changes in Defusion and Values-Based Action. AB - Acceptance and commitment therapy (ACT) has been found to be effective for various mental health disorders but the processes through which it affects change remain unclear. Much process research in the area is on physical rather than mental health, and focuses on the broad concept of psychological flexibility with little research on specific mechanisms identified in theory such as fusion and values. This study explored whether there was a relationship between two of the main ACT processes (cognitive defusion and values) and levels of depression and distress. Thirty-three participants completed questionnaires at the start and end of their treatment measuring general mental health and distress, depression, levels of cognitive fusion and how much they were living in line with their values and how important their values were to them. Results showed reductions in levels of fusion and increases in values-based action were significantly related to reductions in distress and depression. There was no correlation between changes in values importance and changes in distress or depression. This study therefore suggests decreased defusion and increased values-based action is an important mechanism in the efficacy of ACT in those with depression and mental health problems. The study is however limited by a small sample size and future research with a sample large enough for mediation analysis would be beneficial. PMID- 29515269 TI - Eoalosa janvieri gen. et sp. nov., a new clupeid fish (Teleostei, Clupeiformes) from the Eocene of Monte Bolca, Italy. AB - Fishes of the family Clupeidae are extremely abundant in the Eocene fossiliferous limestone of Monte Bolca representing the most common group from this celebrated locality. A new clupeid from the Pesciara site, Eoalosa janvieri gen. et sp. nov., is described. The new taxon exhibits a unique combination of characters supporting its recognition as a new genus and species of clupeid fish that is tentatively placed in the subfamily Alosinae. The description of this new taxon improves our knowledge of the diversity of clupeoid fishes in the Eocene of Monte Bolca. PMID- 29515271 TI - Partition of Neutral Molecules and Ions from Water to o-Nitrophenyl Octyl Ether and of Neutral Molecules from the Gas Phase to o-Nitrophenyl Octyl Ether. AB - We have set out an equation for partition of 87 neutral molecules from water to o nitrophenyl octyl ether, NPOE, an equation for partition of the 87 neutral molecules and 21 ionic species from water to NPOE, and an equation for partition of 87 neutral molecules from the gas phase to NPOE. Comparison with equations for partition into other solvents shows that, as regards partition of neutral (nonelectrolyte) compounds, NPOE would be a good model for 1,2-dichloroethane and for nitrobenzene. In terms of partition of ions and ionic species, NPOE is quite similar to 1,2-dichloroethane and not far away from other aprotic solvents such as nitrobenzene. PMID- 29515272 TI - Disagreement in Parental Reports of Father Involvement. AB - Despite agreement on the value of father involvement in children's lives, research has been limited due to the exclusion of fathers in studies, questionable validity of mothers' reports on father involvement, and simple measures of fathering behavior. Our study extends previous research by comparing reports of father involvement using robust, multidimensional father involvement measures. Data from 113 fathers and 126 mothers reporting on 221 children were used to assess father involvement. Results indicate that fathers reported significantly higher levels of involvement than mothers reported. Findings from hierarchical linear models suggest that race/ethnicity and mothers' reports of positive relationship quality were associated with smaller discrepancies in reports of father involvement, whereas nonmarried partnerships, older children, father residence, and biological status predicted larger discrepancies. Our study demonstrates the importance of obtaining father involvement reports directly from fathers and why father involvement should be assessed as a multidimensional construct to examine fathering behavior. PMID- 29515273 TI - Cosmetovigilance in India: Need of the day. PMID- 29515274 TI - Incorporating problem based learning into medical curriculum: An experience from a medical college in Mangalore. AB - BACKGROUND: The Medical Council of India (MCI) has envisioned a change in the undergraduate medical curriculum by encouraging integrated teaching and Problem Based Learning (PBL). METHODS: In this cross-sectional study 110 medical teachers of Kasturba Medical College, Mangalore were assessed regarding their perception on PBL. Independent t-test was applied to find out the difference in the mean perception scores regarding PBL among the teachers in pre/para-clinical and clinical departments and P < 0.05 was considered statistically significant. RESULTS: PBL as a teaching method was preferred by 65.2% medical teachers. The teachers from clinical departments (Mean 4.1, SD 0.8) perceived PBL sessions to be more effective than the traditional methods than those from the pre-clinical and para clinical departments (Mean 3.7, SD 3.7) and this difference was found to be statistically significant. (P =0.028). CONCLUSION: PBL can complement integrated teaching and motivates students towards self-learning, and apply the learnt concepts of basic specialties to clinical problem solving. PMID- 29515275 TI - Telmisartan and esculetin combination ameliorates type 2 diabetic cardiomyopathy by reversal of H3, H2A, and H2B histone modifications. AB - OBJECTIVES: Although cardioprotective effects of telmisartan are well explored, its effects on epigenetic alterations associated with type 2 diabetic (T2D) cardiomyopathy remain unmapped. Thus, the present study was designed to evaluate the potential of esculetin and telmisartan combination to reverse histone posttranslational modifications (PTMs) in curbing T2D cardiomyopathy. MATERIALS AND METHODS: T2D was induced by high-fat diet feeding along with low dose of streptozotocin (35 mg/kg, I.P) in male Wistar rats. T2D rats were treated with either telmisartan (10 mg/kg/day, P.O) or esculetin (50 mg/kg/day doses, P.O) or their combination for 2 weeks. Biochemical estimations, vascular reactivity, immunohistochemistry, and western blotting experiments were performed to evaluate the effects of the treatment in T2D cardiomyopathy. RESULTS: Esculetin and telmisartan combination alleviated the pathological features of T2D cardiomyopathy including metabolic perturbations, morphometric alterations, altered vascular reactivity, increased Keap1 and fibronectin expression more effectively than their respective monotherapy. This is the first report showing that telmisartan attenuates increased level of histone PTMs such as H3K9me2, H3K9Ac, H2AK119Ub, and H2BK120Ub in heart of T2D rats. The combination regimen showed a more significant reduction in augmented histone PTMs associated with T2D cardiomyopathy than their independent treatments. CONCLUSIONS: The present study demonstrates that esculetin and telmisartan combination can be an advanced pharmacological approach to ameliorate T2D cardiomyopathy which could be partially attributed to its ability to reverse the epigenetic alterations. PMID- 29515276 TI - Effect of aluminum chloride on blood glucose level and lipid profile in normal, diabetic and treated diabetic rats. AB - OBJECTIVES: The objectives of the study were to assess evaluate the effects of aluminum chloride (AlCl3) on blood glucose and lipid levels in normal, diabetic, and glibenclamide-treated diabetic rats. MATERIALS AND METHODS: Forty-two male Wistar rats were divided into seven groups of six each. Group I was normal control, Groups II and III were given AlCl350 and 100 mg/kg, and Group IV to VII were administered with streptozotocin (STZ) (60 mg/kg) intraperitoneally. Group IV was diabetic control, Group V in addition was given AlCl350 mg/kg, Group VI glibenclamide (10 mg/kg), and Group VII glibenclamide and AlCl3(50 mg/kg) per oral daily for 28 days. Blood glucose and lipid levels were estimated at base line, after diabetes was set in and on the last day of study. Histopathological changes in pancreas, liver, and kidney were studied. RESULTS: No significant change was observed in blood glucose and lipid levels in Group I. Group II and III showed a dose-dependent significant increase in blood glucose was observed. Group V had a reduction in blood glucose but not to the nondiabetic level. Group VI had significant reduction in blood sugar. In Group VII, treated with glibenclamide and AlCl3, there was no significant change in blood glucose reduction compared to Group VI. Lipid levels were reduced in groups treated with AlCl3 and glibenclamide and not in other groups. Gross tissue damage was seen in pancreas in STZ group and in liver and kidney in AlCl3 groups. CONCLUSION: AlCl3 administration in Wistar rats caused in significant hyperglycemia in normal rats, hypoglycemia in diabetic rats, and did not influenced hypoglycemic effect of glibenclamide and in addition, resulted in reduction in lipid levels. PMID- 29515277 TI - Sitagliptin-Moringa oleifera coadministration did not delay the progression nor ameliorated functional and morphological anomalies in alloxan-induced diabetic nephropathy. AB - OBJECTIVE: Sitagliptin (ST) and Moringa oleifera (MO) Lam (Moringaceae) are used concomitantly by diabetic patients, with no study ascertaining for potential favorable or otherwise renal implications. We investigated the effect of coadministration of ST and MO leaf extract on functional and morphological biomarkers of alloxan-induced diabetic nephropathy (DN). MATERIALS AND METHODS: Diabetes was induced with a single dose of 150 mg/kg of alloxan intraperitoneally. Seven groups of eight rats per group were used, with Groups I, II, and VII as normal (NS), diabetic control (DC), and postprandial controls. Groups III, IV, V, and VI were diabetic rats on ST, MO, ST and MO (SM), for 42 days with 2 weeks delayed treatment in a postprandial hyperglycemic group (PPSM), respectively. Serum urea, albumin, electrolyte levels, lipid profile, and kidney tropism were determined in addition to histological examinations. RESULTS: There was a significant increase (P < 0.05) in kidney tropism comparing all drug treated groups and DC to normal rats. Significant increases in serum urea were observed (P = 0.02) in DC, MO-treated, and SM-treated rats compared to normal rats and also in serum triglyceride (P < 0.05) in MO-treated and SM-treated rats compared to controls and other drug-treated groups. A mild reduction in severity of pathologic lesions was observed (glomerulosclerosis Grade 1) in SM-treated rats compared to a marked necrosis in DC (Grade 3). CONCLUSION: The coadministration of ST-MO did not delay the progression of functional anomalies and renal injury nor ameliorated the lesions associated with chronic DN in Wistar rats. PMID- 29515278 TI - Comparison of online reporting systems and their compatibility check with respective adverse drug reaction reporting forms. AB - AIM: Different forms and online tools are available in different countries for spontaneous reporting, one of the most widely used methods of pharmacovigilance. Capturing sufficient information and adequate compatibility of online systems with respective reporting form is highly desirable for appropriate reporting of adverse drug reactions (ADRs). This study was aimed to compare three major online reporting systems (US, UK, and WHO) of the world and also to check their compatibility with the respective ADR reporting form. MATERIALS AND METHODS: A total of 89 data elements to provide relevant information were found out from above three online reporting systems. All three online systems were compared regarding magnitude of information captured by each of them and scoring was done by providing a score of "1" to each element. Compatibility of ADR reporting forms of India (Red form), US (Form 3500), and UK (Yellow card form) was assessed by comparing the information gathered by them with that can be entered into their respective online reporting systems, namely, "VigiFlow," "US online reporting," and "Yellow card online reporting." Each unmatching item was given a score of " 1". RESULTS: VigiFlow scored "74" points, whereas online reporting systems of the US and UK scored "56" and "49," respectively, regarding magnitude of the information gathered by them. Compatibility score was found to be "0," "-9," and "-26" in case of ADR reporting systems of US, UK, and India, respectively. CONCLUSION: Our study reveals that "VigiFlow" is capable of capturing the maximum amount of information but "Form 3500" and "Online reporting system of US" are maximally compatible to each other among ADR reporting systems of all three countries. PMID- 29515279 TI - Comparison of Clinical Effectiveness and Safety of Newer Nonsteroidal Anti inflammatory Drugs in Patients of Osteoarthritis of Knee Joint: A Randomized, Prospective, Open-label Parallel-group Study. AB - OBJECTIVE: Osteoarthritis (OA) is a chronic progressive degenerative disease of weight-bearing joints and the leading cause of disability in elderly. Current medical management of OA is mostly palliative with nonsteroidal anti-inflammatory drugs (NSAIDs) being the mainstay of therapy. Reports of gastrointestinal adverse effects with traditional NSAIDs and cardiovascular adverse effects associated with selective cyclooxygenase-2 (COX-2) inhibitors have prompted the hunt for a better NSAID with no or minimal adverse effects. This study compares the clinical effectiveness and safety of newer NSAIDS etodolac and lornoxicam to diclofenac which has been a standard therapy in patients of OA of knee joint. MATERIALS AND METHODS: It was a randomized, prospective, open-label, parallel-group study conducted in 90 patients of OA of knee joint diagnosed according to the American College of Rheumatology criteria. After obtaining the informed consent, they were randomized in three groups of 30 patients each who received tablet etodolac 400 mg b.i.d, tablet lornoxicam 8 mg b.i.d, and tablet diclofenac sodium 50 mg t.i.d, respectively. The duration of the study was 12 weeks. Data were tabulated and analyzed using analysis of variance (ANOVA) test, and level of significance was determined by its P value. RESULTS: After 12 weeks of treatment, pain intensity and functional indices in terms of visual analog scale and Western Ontario and McMaster Universities Osteoarthritis score were significantly better (P < 0.05) in lornoxicam group as compared to etodolac or diclofenac group along with lesser rate of adverse effects. CONCLUSION: It was concluded that lornoxicam was more effective and better tolerated NSAID than etodolac and diclofenac in treatment of knee joint OA. PMID- 29515280 TI - Pediatric pharmacovigilance in an institute of national importance: Journey has just begun. AB - OBJECTIVE: The objective of this study is to determine the nature and severity of adverse drug reactions (ADRs) in pediatric patients. MATERIALS AND METHODS: In this retrospective cohort study, we extracted the data from all the available pediatric ADR forms submitted to ADR monitoring center (AMC) from May 2014 to December 2016. The data including nature, frequency, causality (World Health Organization [WHO] causality scale), and the severity (Hartwig and Siegel scale for severity) of ADR were extracted. We also assessed the preventability of the event on modified Schumock and Thornton scale of ADR preventability. RESULTS: There were a total of 20 pediatric ADRs reported during this period. Nearly two thirds of the ADRs occurred in patients who were receiving multiple drugs (polytherapy). Antimicrobial agents were the most commonly implicated drugs. The most common ADRs were skin rash (maculopapular, erythematous, and urticaria, itching, etc.). The severity and preventability scales indicated that most reactions (18/20) were moderate in nature and all were preventable. Four reactions were "certainly" and ten ADRs were "probably" related to the suspected drug as determined by the WHO causality assessment. CONCLUSION: Frequency of ADR increased with number of medications patient was receiving. Health-care providers (HCPs) involved in the care of children must be aware of this fact and should use additional drugs when absolutely necessary. They should be involved in pharmacovigilance program by exchanging and updating each other through sharing constructive information, communication, and education concerning the appropriate use of drugs in children. Pediatric pharmacovigilance is the need of the hour and should be given utmost importance for monitoring the safety of drugs in children. Motivating HCPs for voluntary reporting of ADRs for preventing the morbidity and mortality in this vulnerable population could be of immense importance. PMID- 29515281 TI - Fatal dapsone hypersensitivity syndrome with hypothyroidism and steroid-induced diabetes mellitus. AB - Dapsone has been part of the World Health Organization multidrug therapy for the treatment of leprosy. While it has been efficacious in the management of leprosy, there are many patients who develop adverse drug reactions to the drug including life-threatening reactions such as dapsone hypersensitivity syndrome (DHS). We report a case of a patient who was prescribed dapsone as part of multidrug therapy for leprosy following which she developed DHS. Her condition worsened after tapering the oral steroids given to manage the DHS, and she was detected to have hypothyroidism. She developed diabetes mellitus and succumbed to septic shock. PMID- 29515282 TI - Magnesium valproate-induced pedal edema on chronic therapy: A rare adverse drug reaction. AB - Valproate-related pedal edema is usually regarded as a problem occurring after long-term administration of valproate. Valproate has been a drug of choice for the treatment of generalized or partial seizures as monotherapy or adjunctive therapy, bipolar disorder, for the prophylaxis of migraine headache in adults. This case report described patient-acquiring bilateral pedal edema after long term use of magnesium valproate. Discontinuing valproate resulted in rapid improvement of the condition. This adverse reaction to the best of our knowledge is first reported a case of bilateral pedal edema cause by magnesium valproate in low dose. The dose of magnesium valproate was 1200 mg/day. No previous case as reported with the same dose. PMID- 29515283 TI - Are your capsules vegetarian or nonvegetarian: An ethical and scientific justification. AB - Capsules are important component of day to day health management. But recently an issue came up whether the capsule you are using is of vegetarian or non vegetarian origin. Capsule shell can be divided into vegetarian and non vegetarian origin on the basis of their origin. Gelatin capsule shell are typically of animal origin and HPMC or starch based shells are of vegetarian origin. CDSCO received one proposal to replace all non veg capsule with capsule of vegetarian origin. CDSCO has invited comments from different stakeholders regarding this. So, in this editorial, we are addressing different issues lying behind veg and non-veg capsules and scientific justification of the same. PMID- 29515284 TI - The effect of hypofractionated radiation and magnetic nanoparticle hyperthermia on tumor immunogenicity and overall treatment response. AB - It is now known that many tumors develop molecular signals (immune checkpoint modulators) that inhibit an effective tumor immune response. New information also suggest that even well-known cancer treatment modalities such as radiation and hyperthermia generate potentially beneficial immune responses that have been blocked or mitigated by such immune checkpoints, or similar molecules. The cancer therapy challenge is to; a) identify these treatment-based immune signals (proteins, antigens, etc.); b) the treatment doses or regimens that produce them; and c) the mechanisms that block or have the potential to promote them. The goal of this preliminary study, using the B6 mouse - B16 tumor model, clinically relevant radiation doses and fractionation schemes (including those used clinically in hypofractionated radiation therapy), magnetic nanoparticle hyperthermia (mNPH) and sophisticated protein, immune and tumor growth analysis techniques and modulators, is to determine the effect of specific radiation or hyperthermia alone and combined on overall treatment efficacy and immunologic response mechanisms. Preliminary analysis suggests that radiation dose (10 Gy vs. 2 Gy) significantly alters the mechanism of cell death (apoptosis vs. mitosis vs. necrosis) and the resulting immunogenicity. Our hypothesis and data suggest this difference is protein/antigen and immune recognition-based. Similarly, our evidence suggest that radiation doses larger than the conventional 2 Gy dose and specific hyperthermia doses and techniques (including mNP hyperthermia treatment) can be immunologically different, and potentially superior to, the radiation and heat therapy regimens that are typically used in research and clinical practice. PMID- 29515285 TI - Factors controlling the photochemical degradation of methylmercury in coastal and oceanic waters. AB - Many studies have recognized abiotic photochemical degradation as an important sink of methylmercury (CH3Hg) in sunlit surface waters, but the rate-controlling factors remain poorly understood. The overall objective of this study was to improve our understanding of the relative importance of photochemical reactions in the degradation of CH3Hg in surface waters across a variety of marine ecosystems by extending the range of water types studied. Experiments were conducted using surface water collected from coastal sites in Delaware, New Jersey, Connecticut, and Maine, as well as offshore sites on the New England continental shelf break, the equatorial Pacific, and the Arctic Ocean. Filtered water amended with additional CH3Hg at environmentally relevant concentrations was allowed to equilibrate with natural ligands before being exposed to natural sunlight. Water quality parameters - salinity, dissolved organic carbon, and nitrate - were measured, and specific UV absorbance was calculated as a proxy for dissolved aromatic carbon content. Degradation rate constants (0.87-1.67 day-1) varied by a factor of two across all water types tested despite varying characteristics, and did not correlate with initial CH3Hg concentrations or other environmental parameters. The rate constants in terms of cumulative photon flux values were comparable to, but at the high end of, the range of values reported in other studies. Further experiments investigating the controlling parameters of the reaction observed little effect of nitrate and chloride, and potential for bromide involvement. The HydroLight radiative transfer model was used to compute solar irradiance with depth in three representative water bodies - coastal wetland, estuary, and open ocean - allowing for the determination of water column integrated rates. Methylmercury loss per year due to photodegradation was also modeled across a range of latitudes from the Arctic to the Equator in the three model water types, resulting in an estimated global demethylation rate of 25.3 Mmol yr-1. The loss of CH3Hg was greatest in the open ocean due to increased penetration of all wavelengths, especially the UV portion of the spectrum which has a greater ability to degrade CH3Hg. Overall, this study provides additional insights and information to better constrain the importance of photochemical degradation in the cycling of CH3Hg in marine surface waters and its transport from coastal waters to the open ocean. PMID- 29515286 TI - UH3-based ferromagnets: new look at an old material. AB - UH3 is the first discovered material with ferromagnetism based purely on the 5f electronic states, known for more than half century. Although the U metal is Pauli paramagnet, the reduced 5f-5f overlap in compounds allows for moment formation and ordering, typically if the U-U spacing exceeds the Hill limit, i.e. about 340 pm. The stable form of UH3, known as beta-UH3, has rather high TC ~ 170 K. Such high value is rather unusual, considering dU-U = 331 pm. Properties of metastable alpha-UH3 with dU-U = 360 pm could be never well established. Using the fact that alpha-UH3 is in fact bcc U with interstitials filled by H, we attempted to synthesize alpha-UH3 starting from the gamma-U alloys, with the bcc structure retained to room temperature by doping combined with ultrafast cooling. While up to 15% Zr a contamination by beta-UH3 was obtained, 20% Zr yielded single phase alpha-UH3. The TC value remains high and very similar to beta-UH3. One can see an increase up to 187 K for 15% Zr, followed by a weak decrease. Magnetic moments remain close to 1 MUB/U atom. An insight is provided by ab initio calculations, revealing a a charge transfer towards H-1s states, depopulating the U-6d and 7s states, leaving almost pure 5f character around the Fermi level. The 5f magnetism exhibits a high coercivity (MU0Hc up to 5.5 T) and large spontaneous volume magnetostriction of 3.2*10-3. Even higher increase of TC, reaching up to 203 K, can be achieved in analogous Mo stabilized hydrides, which yield an amorphous structure. The compounds represent, together with known hydrides of U6Fe and U6Co, a new group of robust 5f ferromagnets with small dU-U but high TC. Although common hydrides are fine powders, some of the new hydrides described as (UH3)(1-x)T x (T = Zr or Mo) remain monolithic, which allows to study transport and thermodynamic properties. PMID- 29515287 TI - In situ/Operando studies of electrocatalysts using hard X-ray spectroscopy. AB - This review focuses on the use of X-ray absorption and emission spectroscopy techniques using hard X-rays to study electrocatalysts under in situ/operando conditions. We describe the importance and the versatility of methods in the study of electrodes in contact with the electrolytes, when being cycled through the catalytic potentials during the progress of the oxygen-evolution, oxygen reduction and hydrogen evolution reactions. The catalytic oxygen evolution reaction is illustrated with examples using Co, Ni and Mn oxides, and Mo and Co sulfides are used as an example for the hydrogen evolution reaction. A bimetallic, bifunctional oxygen evolving and oxygen reducing Ni/Mn oxide is also presented. The various advantages and constraints in the use of these techniques and the future outlook are discussed. PMID- 29515289 TI - An Automated Solution of the Low-Thrust Interplanetary Trajectory Problem. AB - Preliminary design of low-thrust interplanetary missions is a highly complex process. The mission designer must choose discrete parameters such as the number of flybys, the bodies at which those flybys are performed, and in some cases the final destination. In addition, a time-history of control variables must be chosen that defines the trajectory. There are often many thousands, if not millions, of possible trajectories to be evaluated, which can be a very expensive process in terms of the number of human analyst hours required. An automated approach is therefore very desirable. This work presents such an approach by posing the mission design problem as a hybrid optimal control problem. The method is demonstrated on hypothetical missions to Mercury, the main asteroid belt, and Pluto. PMID- 29515288 TI - Biocatalytic hydrogen-borrowing cascades. AB - The exquisite chemoselectivity and the intrinsic compatibility of enzymes have been widely exploited during the past decade for the development of multi-step biocatalytic reactions in one-pot. In this context, hydrogen-borrowing cascades permit to maximise the atom-efficiency through the internal recycling of redox equivalents, which avoids the use of additional oxidants or reductants. Here, we describe the state-of-the-art in the field of biocatalytic hydrogen-borrowing cascades and provide a future perspective for a wider implementation in organic synthesis. PMID- 29515290 TI - Dopant Distribution in Atomic Layer Deposited ZnO:Al Films Visualized by Transmission Electron Microscopy and Atom Probe Tomography. AB - The maximum conductivity achievable in Al-doped ZnO thin films prepared by atomic layer deposition (ALD) is limited by the low doping efficiency of Al. To better understand the limiting factors for the doping efficiency, the three-dimensional distribution of Al atoms in the ZnO host material matrix has been examined on the atomic scale using a combination of high-resolution transmission electron microscopy (TEM) and atom probe tomography (APT). Although the Al distribution in ZnO films prepared by so-called "ALD supercycles" is often presented as atomically flat delta-doped layers, in reality a broadening of the Al-dopant layers is observed with a full-width-half-maximum of ~2 nm. In addition, an enrichment of the Al at grain boundaries is observed. The low doping efficiency for local Al densities > ~1 nm-3 can be ascribed to the Al solubility limit in ZnO and to the suppression of the ionization of Al dopants from adjacent Al donors. PMID- 29515291 TI - Automated microbeam observation environment for biological analysis-Custom portable environmental control applied to a vertical microbeam system. AB - Vertical Microbeams (VMB) are used to irradiate individual cells with low MeV energy ions. The irradiation of cells using VMBs requires cells to be removed from an incubator; this can cause physiological changes to cells because of the lower CO2 concentration, temperature and relative humidity outside of the incubator. Consequently, for experiments where cells require irradiation and observation for extended time periods, it is important to provide a controlled environment. The highly customised nature of the microscopes used on VMB systems means that there are no commercially available environmentally controlled microscope systems for VMB systems. The Automated Microbeam Observation Environment for Biological Analysis (AMOEBA) is a highly flexible modular environmental control system used to create incubator conditions on the end of a VMB. The AMOEBA takes advantage of the recent "maker" movement to create an open source control system that can be easily configured by the user to fit their control needs even beyond VMB applications. When applied to the task of controlling cell medium temperature, CO2 concentration and relative humidity on VMBs it creates a stable environment that allows cells to multiply on the end of a VMB over a period of 36 h, providing a low-cost (costing less than $2700 to build), customisable alternative to commercial time-lapse microscopy systems. AMOEBA adds the potential of VMBs to explore the long-term effects of radiation on single cells opening up new research areas for VMBs. PMID- 29515293 TI - Clinical Considerations When Treating Adults Who Are Parents. AB - When providing mental health services to adults, we are often treating individuals who, among their other roles, are also parents. The goal of this article was to provide practitioners with the state of the science about both the impact of parental psychopathology on children and the role that children's well being has in parental psychopathology. We discuss the benefits of integrated care for adult clients who are parents, as well as the barriers to providing integrated care for both parents and children in psychotherapy, and provide recommendations for practice. With this information, practitioners will gain greater awareness of their opportunities to treat adults in their parenting roles as well as to contribute to prevention of mental disorders in children. PMID- 29515295 TI - Role of Preoperative Duplex Ultrasonography to Predict Functional Maturation of Wrist Radiocephalic Arteriovenous Fistula: A Study on Indian Population. AB - Radiocephalic arteriovenous fistula (RCAVF) is the first choice for native arteriovenous fistula (AVF). Preoperative vessel assessment with ultrasonography (USG) has been reported to enhance the outcome of native AVF, but data regarding its predictive value for functional maturation of RCAVF are scanty. We aimed to determine the role of preoperative duplex USG (DUS) for prediction of functional maturity of radiocephalic fistula in the wrist. The data from 173 patients were analyzed prospectively. The estimated duplex variable included size, patency, and continuity of cephalic vein and size, peak systolic velocity, and wall calcifications in radial artery at the wrist. The subjects underwent RCAVF creation and were reviewed 6-8 weeks post procedure for adequacy of maturation. Doppler variables between successful and failed maturation groups were compared. Successful functional fistula maturation was noted in 138 (80.9%) patients. Values of radial artery diameter, cephalic vein diameter, and peak systolic velocity were >2 mm, 2.2 mm, and 32.8 cm/s, respectively, for successful maturation of RCAVF in more than 90% of cases. Vascular calcifications were detected preoperatively in 15 diabetic patients and 9 (60%) of them had fistula failure. Preoperative DUS can provide a good prediction on functional maturation of RCAVF. Vascular calcifications were associated with high risk of maturation failure in diabetics. PMID- 29515294 TI - Kidney-Paired Donation to Increase Living Donor Kidney Transplantation in India: Guidelines of Indian Society of Organ Transplantation - 2017. PMID- 29515292 TI - Molecular Responses of Human Retinal Cells to Infection with Dengue Virus. AB - Recent clinical reports indicate that infection with dengue virus (DENV) commonly has ocular manifestations. The most serious threat to vision is dengue retinopathy, including retinal vasculopathy and macular edema. Mechanisms of retinopathy are unstudied, but observations in patients implicate retinal pigment epithelial cells and retinal endothelial cells. Human retinal cells were inoculated with DENV-2 and monitored for up to 72 hours. Epithelial and endothelial cells supported DENV replication and release, but epithelial cells alone demonstrated clear cytopathic effect, and infection was more productive in those cells. Infection induced type I interferon responses from both cells, but this was stronger in epithelial cells. Endothelial cells increased expression of adhesion molecules, with sustained overexpression of vascular adhesion molecule 1. Transcellular impedance decreased for epithelial monolayers, but not endothelial monolayers, coinciding with cytopathic effect. This reduction was accompanied by disorganization of intracellular filamentous-actin and decreased expression of junctional molecules, zonula occludens 1, and catenin-beta1. Changes in endothelial expression of adhesion molecules are consistent with the retinal vasculopathy seen in patients infected with DENV; decreases in epithelial junctional protein expression, paralleling loss of integrity of the epithelium, provide a molecular basis for DENV-associated macular edema. These molecular processes present potential therapeutic targets for vision-threatening dengue retinopathy. PMID- 29515296 TI - Clinicopathological Spectrum of Glomerular Diseases in Adolescents: A Single center Experience over 4 Years. AB - The spectrum of biopsy-proven glomerular disease was studied from a single center in Northwestern India, among adolescents aged 13-19 years. From January 2009 to December 2012, a total of 177 patients with biopsy-proven glomerular disease were studied. The same pathologist reported all the biopsy specimens after subjecting to light, immunofluorescence, and electron microscopy. The clinical profile and laboratory findings of the patients were correlated with the histopathological spectrum of glomerular diseases. Males formed 71.19% (n = 126) and the remaining 28.81% (n = 51) were females. Lupus nephritis had a strong female predominance, whereas minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) had a male predominance. Nephrotic syndrome was the indication for biopsy in 65% of the cases. Rapidly progressive renal failure and acute nephritis were the next common indications accounting for 14% and 7%, respectively. FSGS was the most common glomerular disease in adolescents (n = 45, 25.4%). The next common were MCD and lupus nephritis each contributing 21.6% and 10.7%, respectively. Primary glomerular diseases accounted for 84.75% (n = 150) of the total. The remaining 15.25% (n = 27) were attributed to secondary glomerular diseases, of which lupus nephritis was the most common, i.e., in 70.4% patients (n = 19). FSGS was the most common histology in adolescent nephrotic participants (37%). MCD was the next common, found in 31% of nephrotic patients. Electron microscopy changed the diagnosis made by light microscopy and immunofluorescence in 5.6% cases only, and it confirmed the diagnosis in another 21.6%. Kidney biopsy in adolescents is a safe procedure. The spectrum of glomerular diseases in adolescents is different from that seen in adults and smaller children. PMID- 29515297 TI - Albuminuria and Reduced Estimated Glomerular Filtration Rate among First-degree Relatives of Patients with Chronic Kidney Disease in Lagos, Southwest Nigeria. AB - Screening of individuals at increased risk of developing chronic kidney disease (CKD) has been advocated by several guidelines. Among individuals at increased risk are first-degree relatives (FDRs) of patients with CKD. There is a paucity of data on the prevalence and risk of CKD in FDRs of patients with CKD in sub Saharan African population. This study aimed to screen FDRs of patients with CKD for albuminuria and reduced estimated glomerular filtration rate (eGFR). A cross sectional survey of 230 FDRs of patients with CKD and 230 individuals without family history of CKD was conducted. Urinary albumin: creatinine ratio (ACR) was determined from an early morning spot urine. Glomerular filtration rate was estimated from serum creatinine. Reduced eGFR was defined as eGFR <60 ml/min/1.73 m2 and albuminuria defined as ACR >=30 mg/g. A higher prevalence of albuminuria was found in the FDRs compared to the controls (37.0% vs. 22.2%; P < 0.01). Reduced eGFR was more prevalent among the FDRs compared with the controls (5.7% vs. 1.7%, P < 0.03). Hypertension (odds ratio [OR], 2.9) and reduced eGFR (OR, 9.1) were independent predictors of albuminuria while increasing age (OR, 6.7) and proteinuria (OR, 10.7) predicted reduced eGFR in FDRs. The odds of developing renal dysfunction were increased 2-fold in the FDRs of patients with CKD, OR 2.3, 95% confidence interval, 1.29-3.17. We concluded that albuminuria and reduced eGFR are more prevalent among the FDRs of patient with CKD and they are twice as likely to develop kidney dysfunction as healthy controls. PMID- 29515298 TI - A Study of Clinical Presentation and Correlative Histopathological Patterns in Renal Parenchymal Disease. AB - Suspicion and subsequent detection of renal disease is by an assessment of the urinalysis and renal function in the clinical context. Our attempt in this study is to correlate initial presenting features of urinalysis and renal function to the final histopathological diagnosis. A retrospective analysis of 1059 native kidney biopsies performed from January 2002 to June 2015 at Amrita Institute of Medical Sciences was conducted. Correlative patterns between urinalysis, renal function, and final histopathological diagnosis were studied. Five hundred and eleven (48%) patients had nephrotic syndrome. Out of these, 193 (38%) had pure: nephrotic syndrome, 181 (35.8%) had associated microhematuria, 110 (21.7%) had microhematuria and renal failure, and 27 (5.3%) had only associated renal failure. Minimal change disease (MCD) (30%), membranous nephropathy (30%), and IgA nephropathy (29%) were the major diseases in the respective groups. Five hundred and five (47.6%) patients had subnephrotic proteinuria. Out of these, 29 (5.6%) had only subnephrotic proteinuria, 134 (27%) had additional microhematuria, 300 (59%) had subnephrotic proteinuria, microhematuria, and renal failure, and 42 (8%) had subnephrotic proteinuria with renal failure. Lupus Nephritis (45% and 40%) and IgA Nephropathy (32% and 21%) were the major disorders in the subgroups respectively. Forty-two patients (3.7%) were biopsied for isolated renal failure with bland urinary sediment. Cast nephropathy and acute interstitial nephritis were the major diseases. Out of 89 patients with diabetes who were biopsied, 15 (16.8%) had diabetic nephropathy, 45 (50.5%) had no diabetic nephropathy, and 29 (32.5%) had diabetic nephropathy along with a non diabetic renal disease. Postinfectious glomerulonephritis was the major glomerular disease. IgA nephropathy (22.2%) and membranous nephropathy (15.5%) were the major diseases in patients with diabetes with no diabetic nephropathy. In our population, MCD and membranous nephropathy formed the majority of diseases in biopsied nephrotic syndrome. Added microhematuria did not seem to decrease the incidence of either disease on the whole. We found a significant number of patients with membranous nephropathy with nephrotic syndrome, microhematuria, and additional renal failure. IgA nephropathy formed a majority of cases with nephrotic syndrome, microhematuria, and renal failure. The presence of renal failure regardless of other abnormalities in urinalysis showed a trend toward IgA nephropathy. Membranous nephropathy may have a more varied presentation than was originally thought and IgA nephropathy presenting as nephrotic syndrome may not be uncommon. MCD is the major subgroup of diseases in the pediatric population and presents both as nephrotic syndrome as well as nephrotic syndrome with microhematuria. Thus, urinalysis and renal failure may be a valuable tool in assessing renal disease. PMID- 29515299 TI - Mycophenolate versus Cyclophosphamide for Lupus Nephritis. AB - Systemic lupus erythematosus is common in our country, and renal involvement is an important cause of chronic kidney disease. This study was aimed at comparing the three regimens, i.e., cyclophosphamide-based regimes (low dose and high dose) and mycophenolate mofetil (MMF)-based regime and determining if cyclophosphamide (CPM)-based regime can be an effective, safe, and cheap alternative to MMF-based regime in a resource-limited setting. Out of 144 patients, females constituted 89%. Nephrotic nephritic presentation was the most common. Rapidly progressive renal failure was seen in in 42 (29.1%) patients. Class IV was the most common 66 (45.8%) histological class. Crescentic glomerulonephritis was seen in 18 (12.5%). Overall remission (complete + partial) at 6 months was seen in 71.4% in National Institute of Health regime, 65% in European lupus nephritis trial protocol and 72.9% in MMF regime. End-stage renal disease and switching to other therapies were comparable among the three groups. Although infections were more with CPM, the difference was not statistically significant. CPM-based therapies were associated with a significantly lower cost. PMID- 29515300 TI - Factors Affecting Insulin Resistance and Its Relation to Vitamin D Status and Clinical Nutritional Parameters in Dialysis Patients: A Single-center Indian Study. AB - The aim of this study was to measure insulin resistance (IR) in dialysis patients and its relation to Vitamin D status and nutritional parameters. We included patients on maintenance dialysis, both hemodialysis and peritoneal dialysis (HD and PD). IR was measured by homeostatic model assessment (HOMA)-IR index defined as fasting serum insulin (MUU/L) * fasting blood sugar (mmol/L)/22.5. Baseline Vitamin D levels were measured by chemiluminescence immunoassay (CLIA) method. HOMA-IR index correlated with nutritional parameters such as 7-point subjective global assessment (SGA) and anthropometric measures, for example, body fat percentage, lean body weight (LBW), mid-arm circumference (MAC), and mid-arm muscle circumference (MAMC). A total of 55 patients were studied, of them 74.55% were male with mean age of the study population being 37.44 +/- 14.96 years. The prevalence values of Vitamin D deficiency <30 ngm/ml, <20 ngm/ml, and <10 ngm/ml levels were 96.36%, 70.91%, and 23.64%, respectively. Mean HOMA-IR index was 3.14 +/- 3.86. The correlation of HOMA-IR with Vitamin D was negative (r = -0.140, 95% confidence interval [CI] = -0.397-0.138 and P = 0.309); however, in subgroup analysis, patients with Vitamin D level <20 ng/ml had significantly high IR compared to those with Vitamin D >20 ng/ml, i.e., 3.74 +/- 4.37 and 1.67 +/- 1.47, respectively (P = 0.018). The other measured parameter which had a significant positive correlation with IR was serum uric acid (r = 0.303, 95% CI = 0.021-0.534, and P = 0.025). In nutritional assessment, body mass index, MAC, and MAMC had statistically significant positive correlation with HOMA-IR index (P <= 0.001, 0.004, and 0.004, respectively) unlike SGA (P = 0.480). The mode of dialysis did not have a significant effect on IR (HD vs. PD, P = 0.227). The majority of the patients on maintenance dialysis are Vitamin D deficient. Low Vitamin D level, especially <20 ng/ml, muscle mass, and high serum uric acid level are likely to have more IR in dialysis-dependent patients. PMID- 29515301 TI - Efficacy and Safety of Cyclosporine versus Tacrolimus in Steroid and Cyclophosphamide Resistant Nephrotic Syndrome: A Prospective Study. AB - Calcineurin inhibitors (CNIs) are the preferred drugs for treatment of childhood steroid-resistant nephrotic syndrome (SRNS) who are also resistant to cyclophosphamide (CYC). Although few studies have shown a benefit of one over the other, efficacy and safety of either CNIs (tacrolimus [TAC] or cyclosporine [CSA]) in this special population remained to be assessed in long-term studies. Forty-five children with SRNS who were also resistant to CYC (CYC-SRNS) from January 2006 to June 2011, were included in the study. Patients were treated with CNI either TAC or CSA based on 1:1 allocations and were prospectively observed. Patients who were nonresponsive to CNIs had been treated with mycophenolate mofetil. Outcomes were measured in terms of remission of NS, adverse effects of drugs, and progression of disease. After 6 months of treatment, 16/23 (69.5%) patients on CSA achieved remission and 18/22 (81.8%) on TAC achieved remission (P = 0.3). The side effects hypertrichosis, and gum hyperplasia were significantly less in TAC group as compared to CSA group (P < 0.001). The 1-, 2-, 3-, 4-, and 5 year estimated renal survival (doubling of serum creatinine as event) in CSA group was 96%, 91%, 85%, 54%, and 33% and in TAC group was 96%, 95%, 90%, 89%, and 79%, respectively (P = 0.02). Although TAC and CSA are equally efficacious, TAC has significantly less side effects. The long-term outcome of renal function was significantly better in patients who were treated with TAC as compared to CSA. PMID- 29515302 TI - Neutrophil Gelatinase-associated Lipocalin: As a Predictor of Early Diabetic Nephropathy in Type 2 Diabetes Mellitus. AB - This study was carried out to look for diagnostic and prognostic role of neutrophil gelatinase-associated lipocalin (NGAL) in early diabetic nephropathy (DN) in type 2 diabetes individuals. NGAL was measured in both urinary and serum sample of 144 type 2 diabetes individuals stratified into three categories based on urinary albumin-creatinine ratio and 54 control populations with estimated glomerular filtration rate >60 mL/min/1.73 m2 and serum creatinine <1.2 mg/dl. The serum NGAL (sNGAL), urine NGAL (uNGAL), and uNGAL/urine creatinine were significantly higher in diabetic individuals than in the control populations with significant difference in between the groups (P < 0.05). Difference of above values between control value and normoalbuminuria was also statistically significant (P < 0.05). Again, sNGAL and uNGAL correlate positively with albuminuria (P < 0.05). Tubular injury may precede glomerular injury in diabetic individuals, and NGAL can be used as a biomarker to diagnose DN even earlier to incipient nephropathy. Both sNGAL and uNGAL can predict albuminuria and be used as a noninvasive tool for diagnosis, staging, and progression of DN. PMID- 29515303 TI - Dense Deposit Disease Involving C3 and C4d Deposits. AB - Dense deposit disease (DDD), earlier called Type II membranoproliferative glomerulonephritis is distinct disease having frequent relapses reaching end stage kidney disease by 10-year in up to 50%-60% of cases and high recurrence rate in the allograft. The term DDD is derived from its distinctive ribbon-like osmiophilic deposits in the lamina densa of glomerular basement membrane by electron microscopy. Pathogenetically, alternate pathway dysfunction leads to this disease, which is diagnosed by ultrastructure. Herein, we describe our observation of C4d positivity in an adolescent boy with DDD. PMID- 29515304 TI - Type I Cryoglobulinemic Nephritis in a Patient of Monoclonal Gammopathy of Renal Significance. AB - Monoclonal gammopathy of renal significance is a recently described entity in which a small B-cell clone not meeting the criteria for the diagnosis of multiple myeloma produces renal disease usually through deposition of a secreted monoclonal immunoglobulin. Here, we describe a case of Type I cryoglobulinemic glomerulonephritis diagnosed on a kidney biopsy and caused by a monoclonal IgM produced by a small bone marrow clone. The patient made a complete renal recovery after chemotherapy to suppress the clone. PMID- 29515305 TI - Rare Cause of Hyperkalemia in the Newborn Period: Report of Two Cases of Pseudohypoaldosteronism Type 1. AB - Pseudohypoaldosteronism (PHA) Type 1 is characterized by mineralocorticoid resistance, manifesting as neonatal salt wasting, hypotension, hyperkalemia, hyponatremia, and metabolic acidosis in spite of elevated aldosterone levels and plasma renin activity. It is important to differentiate children with systemic PHA from renal PHA, as these children are likely to decompensate even with mild symptoms. Here, we report two neonates with PHA that presented to us with multiorgan involvement. PMID- 29515306 TI - Eculizumab Dosing in Infants. AB - Eculizumab is the therapy of choice for patients with atypical hemolytic uremic syndrome (aHUS). Dosing recommendations stem from two trials: one retrospective trial (19 children and 5 infants) and one prospective trial (22 patients and 5 infants). This case report highlights the need for more precise dosing recommendations in children, particularly in infants, and for smaller vials of the medication to facilitate more precise dosing. Such changes would ensure that adverse events are minimized and that the children with aHUS who are treated with eculizumab experience an optimal clinical response. PMID- 29515307 TI - Nail-Patella Syndrome: A Rare Cause of Nephrotic Syndrome in Pregnancy. AB - Nail-Patella syndrome (NPS) is an inherited disease with characteristic nail, limb, and renal anomalies. While almost all patients manifest classical skeletal and nail abnormalities, renal involvement is seen in only 40% of patients. Asymptomatic proteinuria is the most common renal presentation. Although a substantial number of patients can progress to nephrotic range proteinuria, development of end-stage kidney disease is rare. Pathological abnormalities are appreciable only by electron microscopy. Our patient who had not been diagnosed with NPS previously presented with new-onset proteinuria during the second trimester of her first pregnancy. The characteristic physical and radiological features confirmed the diagnosis of NPS. Her clinical course was complicated by nephrotic syndrome with fetal loss at 22 weeks and postpartum renal vein thrombosis. Nephrotic state improved after termination of pregnancy. She was managed with angiotensin receptor blocker and anticoagulation. At the end of 2 years of follow-up, she has normal glomerular filtration rate with minimal proteinuria. PMID- 29515308 TI - IgG4 Disease Diagnosed on Computed Tomography-magnetic Resonance Imaging. PMID- 29515309 TI - The Role of Renal Angiography in Hepatitis B-related Polyarteritis Nodosa. PMID- 29515310 TI - First Case of Renal Transplantation Involving a Donor with Bombay Phenotype Blood Group. PMID- 29515311 TI - Cystinuria in a 13-month-old Girl with Absence of Mutations in the SLC3A1 and SLC7A9 Genes. PMID- 29515312 TI - Erratum: Successful Renal Transplantation Across HLA Barrier: Report from India. AB - [This corrects the article on p. 210 in vol. 27, PMID: 28553042.]. PMID- 29515313 TI - Insights into maize genome editing via CRISPR/Cas9. AB - Maize is an important crop for billions of people as food, feed, and industrial raw material. It is a prime driver of the global agricultural economy as well as the livelihoods of millions of farmers. Genetic interventions, such as breeding, hybridization and transgenesis have led to increased productivity of this crop in the last 100 years. The technique of genome editing is the latest advancement in genetics. Genome editing can be used for targeted deletions, additions, and corrections in the genome, all aimed at genetic enhancement of crops. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated protein 9 (CRISPR/Cas9) system is a recent genome editing technique that is considered simple, precise, robust and the most revolutionary. This review summarizes the current state of the art and predicts future directions in the use of the CRISPR/Cas9 tool in maize crop improvement. PMID- 29515314 TI - Identification and comparative analysis of microRNAs from tomato varieties showing contrasting response to ToLCV infections. AB - Increasing incidence of viral infections in crop plants adversely affects their growth and yield. Tomato (Solanum lycopersicum) is considered to be a favorite host for viruses with over 50 species of begomoviruses naturally infecting this crop. Tomato leaf curl virus (ToLCV) is among the most widespread and devastating begomoviruses affecting tomato production. microRNAs (miRs) have been established as key regulators of gene expression and plant development. The miR pathways are disturbed during infection by viruses. Thus, comprehension of regulatory miR networks is crucial in understanding the effect of viral pathogenicity. To identify key miRs involved in ToLCV infection, a high throughput approach involving next generation sequencing was employed. Healthy and infected leaf tissues of two tomato varieties, differing in their susceptibility to ToLCV infection were analyzed. NGS data analysis followed by computational predictions, led to identification of 91 known miRs, 15 novel homologs and 53 novel miRs covering two different varieties of tomato, susceptible (Pusa Ruby) and tolerant (LA1777) to ToLCV infection. The cleaved targets of these miRs were identified using online available degradome libraries from leaf, flower and fruit of tomato and showed their involvement in various biological pathways through KEGG Orthology. With detailed comparative profiling of expression pattern of these miRs, we could associate the specific miRs with the resistant and infected genotypes. This study depicted that in depth analysis of miR expression patterns and their functions will help in identification of molecules that can be used for manipulation of gene expression to increase crop production and developing resistance against diseases. PMID- 29515315 TI - Molecular characterization of 'Clover proliferation' phytoplasma subgroup-D (16SrVI-D) associated with vegetables crops in India. AB - Nine vegetable plants species exhibiting phytoplasma suspected symptoms of white/purple leaf, little leaf, flat stem, witches' broom, phyllody and leaf yellowing were observed in experimental fields at Indian Agricultural Research Institute, New Delhi from December 2015 to July 2016. Total DNA extracted from the three healthy and three symptomatic leaves of all the nine vegetables were subjected to PCR assays using phytoplasma specific primers P1/P7 followed by R16F2n/R16R2 and 3Far/3Rev to amplify the 16S rDNA fragments. No amplifications of DNA were observed in first round PCR assays with primer pair P1/P7 from any of the symptomatic samples. However, phytoplasma DNA specific fragments of ~ 1.3 kb were amplified from Apium graveolens L. (two isolates), Brassica oleracea vr. capitata L. (one isolate) and Solanum melongena L. (one isolate) by using 3Far/3Rev primer pair and 1.2 kb fragment was amplified from Lactuca sativa L. (one isolate) by using R16F2n/R16R2 primer pair. No DNA amplification was seen in other symptomatic vegetable samples of tomato, carrot, cucurbit, bitter gourd and Amaranthus species utilizing either P1/P7 primer pair followed by 3Far/3Rev or R16F2n/R16R2 primer pairs. Out of three leafhopper species collected from the symptomatic vegetable fields, only Hishimonus phycitis was found positive for association of phytoplasma. No DNA amplifications were observed in healthy plant samples and insects collected from non-symptomatic fields. Comparative sequence comparison analyses of 16S rDNA of positive found vegetable phytoplasma strains revealed 100% sequence identities among each other and with phytoplasma strains of 'clover proliferation' (16SrVI) group. Phytoplasma sequences, virtual RFLPs and phylogenetic analyses of 16S rDNA sequence comparison confirmed the identification of 16SrVI subgroup D strain of phytoplasmas in four vegetables and one leafhopper (HP) species. Further virtual RFLP analysis of 16S rDNA sequence of the vegetables phytoplasma strains confirmed their taxonomic classification with strains of 'clover proliferation' subgroup D. Since, H. phycitis feeding on symptomatic vegetable species in the study was also tested positive for the 16SrVI phytoplasma subgroup-D as of vegetables; it may act as potent natural reservoir of 16SrVI-D subgroup of phytoplasmas infecting vegetable and other important agricultural crops. PMID- 29515316 TI - Identification of genes from the ICE-CBF-COR pathway under cold stress in Aegilops-Triticum composite group and the evolution analysis with those from Triticeae. AB - Adverse environmental conditions limit various aspects of plant growth, productivity, and ecological distribution. To get more insights into the signaling pathways under low temperature, we identified 10 C-repeat binding factors (CBFs), 9 inducer of CBF expression (ICEs) and 10 cold-responsive (CORs) genes from Aegilops-Triticum composite group under cold stress. Conserved amino acids analysis revealed that all CBF, ICE, COR contained specific and typical functional domains. Phylogenetic analysis of CBF proteins from Triticeae showed that these CBF homologs were divided into 11 groups. CBFs from Triticum were found in every group, which shows that these CBFs generated prior to the divergence of the subfamilies of Triticeae. The evolutionary relationship among the ICE and COR proteins in Poaceae were divided into four groups with high multispecies specificity, respectively. Moreover, expression analysis revealed that mRNA accumulation was altered by cold treatment and the genes of three types involved in the ICE-CBF-COR signaling pathway were induced by cold stress. Together, the results make CBF, ICE, COR genes family in Triticeae more abundant, and provide a starting point for future studies on transcriptional regulatory network for improvement of chilling tolerance in crop. PMID- 29515317 TI - Salicylic acid promotes plant growth and salt-related gene expression in Dianthus superbus L. (Caryophyllaceae) grown under different salt stress conditions. AB - Salt stress is a critical factor that affects the growth and development of plants. Salicylic acid (SA) is an important signal molecule that mitigates the negative effects of salt stress on plants. To elucidate salt tolerance in large pink Dianthus superbus L. (Caryophyllaceae) and the regulatory mechanism of exogenous SA on D. superbus under different salt stresses, we conducted a pot experiment to evaluate leaf biomass, leaf anatomy, soluble protein and sugar content, and the relative expression of salt-induced genes in D. superbus under 0.3, 0.6, and 0.9% NaCl conditions with and without 0.5 mM SA. The result showed that exposure of D. superbus to salt stress lead to a decrease in leaf growth, soluble protein and sugar content, and mesophyll thickness, together with an increase in the expression of MYB and P5CS genes. Foliar application of SA effectively increased leaf biomass, soluble protein and sugar content, and upregulated the expression of MYB and P5CS in the D. superbus, which facilitated in the acclimation of D. superbus to moderate salt stress. However, when the plants were grown under severe salt stress (0.9% NaCl), no significant difference in plant physiological responses and relevant gene expression between plants with and without SA was observed. The findings of this study suggest that exogenous SA can effectively counteract the adverse effects of moderate salt stress on D. superbus growth and development. PMID- 29515318 TI - Seed priming with sorghum extracts and benzyl aminopurine improves the tolerance against salt stress in wheat (Triticum aestivum L.). AB - Salt stress impedes the productivity of wheat (Triticum aestivum L.) in many parts of the world. This study evaluated the potential role of benzyl aminopurine (BAP) and sorghum water extract (SWE) in improving the wheat performance under saline conditions. Seeds were primed with BAP (5 mg L-1), SWE (5% v/v), BAP + SWE, and distilled water (hydropriming). Soil filled pots maintained at the soil salinity levels of 4 and 10 dS m-1 were used for the sowing of primed and non primed seeds. Salt stress suppressed the wheat growth; seed priming treatments significantly improved the wheat growth under optimal and suboptimal conditions. Total phenolics, total soluble sugars and proteins, alpha-amylase activity, chlorophyll contents, and tissue potassium ion (K+) contents were increased by seed priming under salt stress; while, tissue sodium ion (Na+) contents were decreased. Seed priming with SWE + BAP was the most effective in this regard. Under salt stress, the tissue Na+ contents were reduced by 5.78, 28.3, 32.2, 36.7% by hydropriming, seed priming with SWE, seed priming with BAP, and seed priming with SWE + BAP, respectively over the non-primed control. Effectiveness of seed priming techniques followed the order SWE + BAP > BAP > SWE > Hydropriming. In conclusion, seed priming with SWE + BAP may be opted to improve the tolerance against salt stress in wheat. PMID- 29515319 TI - CO2 enrichment affects eco-physiological growth of maize and alfalfa under different water stress regimes in the UAE. AB - Water stress has been reported to alter morphology and physiology of plants affecting chlorophyll content, stomatal size and density. In this study, drought stress mitigating effects of CO2 enrichment was assessed in greenhouse conditions in the hot climate of UAE. Commercially purchased maize (Zea mays L.) and alfalfa (Medicago sativa L.) were seeded in three different custom-built cage structures, inside a greenhouse. One cage was kept at 1000 ppm CO2, the second at 700 ppm CO2, and the third at ambient greenhouse CO2 environment (i.e. 435 ppm). Three water stress treatments HWS (200 ml per week), MWS (400 ml per week), and CWS (600 ml per week) were given to each cage so that five maize pots and five alfalfa pots in each cage received same water stress treatments. In maize, total chlorophyll content was similar or higher in water stress treatments compared to control for all CO2 concentrations. Stomatal lengths were higher in enriched CO2 environments under water stress. At 700 ppm CO2, stomatal widths decreased as water stress increased from MWS to HWS. At both enriched CO2 environments, stomatal densities decreased compared to ambient CO2 environment. In alfalfa, there was no significant increase in total chlorophyll content under enriched CO2 environments, even though a slight increase was noticed. PMID- 29515320 TI - A calcium-stimulated serine peptidase from a true-branching cyanobacterium, Westiellopsis ramosa sp. nov. AB - Unbranched heterocytous cyanobacteria produce a number of serine peptidases. We have characterized several peptidases in the cell-free extracts of a true branched N2-fixing cyanobacterium, Westiellopsis ramosa sp. nov. Upon substrate gel zymography of intact filaments and heterocytes, five peptidase bands were resolved, whereas in vegetative cells, a single band was discernible. No band was detected in [Formula: see text]-grown cultures suggesting that the peptidases were present under diazotrophic conditions with much of them confined to heterocytes. Using salt precipitation and chromatography, a caseinolytic peptidase, called Wrp49, was purified which also demonstrated fibrinolytic activity. In SDS-PAGE, the purified peptidase was resolved into 17 and 27 kDa fragments. The enzyme in its native state exhibited Mr ~ 49 kDa, and digested gelatin in a substrate gel at a corresponding position. The enzyme showed amidolytic activity on a plasmin specific substrate, D-Val-Leu-Lys p nitroanilide. Moreover, a trypsin specific substrate, N-benzoyl-DL-Arg p nitroanilide was hydrolyzed at an apparent Km = 0.195 mM and Vmax = 5 * 10-7 M s 1. The enzyme was stable in a wide pH and temperature range. While Ca2+ stimulated the activity; phenylmethane sulfonyl fluoride, leupeptin, EDTA and chelants were inhibitory. The activity of the EDTA-inactivated enzyme was completely restored upon adding Ca2+, suggesting that both compounds competed with each other in modulating the enzyme activity. The enzyme showed similarities with a Ca2+ stimulated subtilisin-like serine peptidase of Anabaena variabilis ATCC 29413, but also presented several unique features of metallopeptidases, such as the chelant's response. Moreover, the N-terminal sequence (MTVENLARTGVGPGWR) did not match with any of the known peptidases. PMID- 29515321 TI - Effect of elicitation and precursor feeding on accumulation of 20-hydroxyecdysone in Achyranthes aspera Linn. cell suspension cultures. AB - 20-Hydroxyecdysone is one of the most common ecdysteroids in plants with potential therapeutic applications. In this study, cell suspension cultures of Achyranthes aspera were raised in shake flasks to investigate the production of 20-hydroxyecdysone. The quantification and characterization of 20-hydroxyecdysone in the cultures were done by High performance liquid chromatography (HPLC) and Liquid Chromatography-quadrupole time-of- flight mass spectrometry (LC-Q-TOF) analyses. For raising the suspension, calli initiated from in vitro grown leaf explants were cultured in liquid Murashige and Skoog (MS) medium augmented with combinations of 2, 4-dichlorophenoxyacetic acid (1 mg L-1) and alpha naphthaleneacetic acid (1 mg L-1). Maximum growth index of the cell suspension was 9.9, which was achieved during 20th day of culture (final phase of exponential growth). At this stage, the biomass accumulated was 1.09 +/- 0.09 g dry weight (DW) and the 20-hydroxyecdysone concentration was 0.24 mg g-1 DW. Eliciting the cultures with 0.6 mM Methyl jasmonate for 6 days; enhanced the production of 20-hydroxyecdysone production to 0.35 mg g-1 DW. By augmenting the cultures with the precursors namely cholesterol (10 mg L-1) and 7 dehydrocholesterol (10 mg L-1), production of 20-hydroxyecdysone was boosted to 0.31 mg g-1 DW and 0.28 mg g-1 DW respectively. PMID- 29515322 TI - Fusarium oxysporum cell elicitor enhances betalain content in the cell suspension culture of Celosia cristata. AB - We started a cell suspension culture from magenta coloured calli of cockscomb to study the effect of biotic and abiotic elicitors on the biosynthesis of betalain pigments. The cultures were grown in a flask containing 30 ml MS media fortified with 13.5 MUM 2,4-D and 0.44 MUM BAP. These cultures were elicited during its log phase of growth using fungal elicitors (prepared from mycelia of Fusarium oxysporum), yeast extract, copper sulphate and cobalt chloride. The elicitation reduced the cell count, cell viability and percent pigmented cell in the suspension culture. Similarly, it also resulted in reduced betalain content by all the elicitors except 0.125 * 10-3% fungal elicitor. Rather, fungal elicitor at this concentration significantly enhanced the amaranthin, betanin, betalamic acid and betaxanthin content in the culture. Besides this, copper sulphate doubled the pigment contribution (ratio of particular pigment content to total pigment content) of betaxanthin at all the concentrations. Therefore, we conclude that fungal elicitor can further be investigated to enhance the content of betalain pigments in suspension culture at a larger scale. PMID- 29515323 TI - Morphological analyses and variation in carbohydrate content during the maturation of somatic embryos of Carica papaya. AB - Efficient protocols for somatic embryogenesis of papaya (Carica papaya L.) have great potential for selecting elite hybrid genotypes. Addition of polyethylene glycol (PEG), a nonplasmolyzing osmotic agent, to a maturation medium increases the production of somatic embryos in C. papaya. To study the effects of PEG on somatic embryogenesis of C. papaya, we analyzed somatic embryo development and carbohydrate profile changes during maturation treatments with PEG (6%) or without PEG (control). PEG treatment (6%) increased the number of normal mature somatic embryos followed by somatic plantlet production. In both control and PEG treatments, pro-embryogenic differentiation to the cotyledonary stage was observed and was significantly higher with PEG treatment. Histomorphological analysis of embryonic cultures with PEG revealed meristematic centers containing small isodiametric cells with dense cytoplasm and evident nuclei. Concomitant with the increase in the differentiation of somatic embryos in PEG cultures, there was an increase in the endogenous content of sucrose and starch, which appears to be related to a rising demand for energy, a key point in the conversion of C. papaya somatic embryos. The endogenous carbohydrate profile may be a valuable parameter for developing optimized protocols for the maturation of somatic embryos in papaya. PMID- 29515324 TI - In vitro propagation of Cymbidium goeringii Reichenbach fil. through direct adventitious shoot regeneration. AB - The influence of 2,4-dichlorophenoxyacetic acid (2,4-D), benzyladenine (BA), and thidiazuron (TDZ) on direct rhizome induction and shoot formation from rhizome explants of Cymbidium goeringii was explored. Rhizome segments obtained from in vitro seed cultures of C. goeringii were placed on Murashige and Skoog (MS) medium incorporated with 5, 10, 20, or 40 uM 2,4-D and 1, 2, 4, or 8 uM BA or TDZ alone or in combination with 20 uM 2,4-D. The explants developed only rhizomes on MS medium with or without 2,4-D. The highest percent of rhizome formation (100%) was obtained on MS medium incorporated with 20 MUM of 2,4-D. The morphology and number of rhizomes varied with the level of 2,4-D in the medium. Direct adventitious shoot formation was achieved on medium incorporated with BA or TDZ. The adventitious shoots produced per explant significantly increased with the supplementation of 2,4-D to cytokinin-containing medium. The highest mean of 21.8 +/- 1.8 shoot buds per rhizome segment was obtained in medium fortified with 20 MUM 2,4-D and 2 MUM TDZ. The greatest percent of root induction (100%) and the mean of 5.3 +/- 1.1 roots per shoot were achieved on 1/2 MS medium incorporated with 2 MUM of alpha-naphthaleneacetic acid. About 97% of the in vitro-produced plantlets acclimatized in the greenhouse. An efficient in vitro propagation protocol was thus developed for C. goeringii using rhizome explants. PMID- 29515325 TI - Riboswitch regulation in cyanobacteria is independent of their habitat adaptations. AB - Cyanobacteria are one of the ancient bacterial species occupying a variety of habitats with diverse metabolic preferences. RNA regulators like riboswitches play significant role in controlling the gene expression in prokaryotes. The taxonomic distribution of riboswitches suggests that they might be one of the oldest mechanisms of gene control system. In this paper, we analyzed the distribution of different riboswitch families in various cyanobacterial genomes. It was observed that only four riboswitch classes were abundant in cyanobacteria, B12-element (Cob)/AdoCbl/AdoCbl-variant riboswitch being the most abundant. The analysis suggests that riboswitch mode of regulation is present in cyanobacterial species irrespective of their habitat types. A large number of unidentified genes regulated by riboswitches listed in this analysis indicate the wide range of targets for these riboswitch families. The analysis revealed a large number of genes regulated by riboswitches which may assist in elaborating the diversity among the cyanobacterial species. PMID- 29515326 TI - Identification and characterization of long noncoding RNA in Paulownia tomentosa treated with methyl methane sulfonate. AB - Paulownia is a tree native to China, with important ecological and economic value. Long noncoding RNAs (lncRNAs) are known to play important roles in eukaryotic gene regulation. However, no lncRNAs have been reported in Paulownia so far. We performed RNA sequencing of two Paulownia tomentosa lncRNA libraries constructed from the terminal buds of normal untreated seedlings and 60 mg L-1 MMS-treated seedlings, and obtained a total of 2531 putative lncRNAs. The average length of the lncRNA transcripts was much less than the average length of the mRNA transcripts in the P. tomentosa libraries. A few of the Paulownia lncRNAs were conserved among ten species tested. We identified seven lncRNAs as precursors of 13 known miRNAs, 15 lncRNAs may act as target mimics of 19 miRNAs, and 351 unique noncoding sequences belonging to 133 conserved lncRNA families. In addition, we identified 220 lncRNAs responsive to methyl methane sulfonate (MMS), including seven phytohormone-related lncRNAs and one lncRNAs involved in base excision repair. This is the first time that lncRNAs have been explored in Paulownia. The lncRNA data may also provide new insights into the MMS-response in P. tomentosa. PMID- 29515328 TI - Seed pretreatment with magnetic field alters the storage proteins and lipid profiles in harvested soybean seeds. AB - The increase in crop productivity is an urgent need of the time to reduce scarcity of food in underdeveloped countries. Several biological, chemical and physical methods have been applied to promote crop yield. Application of magnetic field (MF) is an emerging physical method used to increase plant growth and yield. The reports on MF pretreatment-induced nutritional changes in harvested seeds are scarce. We previously identified the optimal frequency of MF to improve plant growth and yield as 1500 nT at 10.0 Hz. This study was aimed to investigate the effect of MF treatment on storage proteins and fatty acids in harvested soybean seeds. The results showed that MF triggered globulin production and suppressed prolamin production. However, lipid content in seeds increased, because MF exposure caused an elevation of several fatty acids including caprylic acid, palmitic acid, heptadecanoic acid, linoleic acid, lignoceric acid and eicosapentaenoic acid. This is the first report to reveal the seed pretreated MF on nutritional values of harvested seeds. This study suggests that MF treatment improves seed quality by regulating the metabolism of storage proteins and fatty acids. PMID- 29515327 TI - Antioxidant potential in Stevia rebaudiana callus in response to polyethylene glycol, paclobutrazol and gibberellin treatments. AB - The study on Stevia callus has the potential to advance the knowledge of antioxidant mechanisms involved in unorganized cells response to drought stress. The effects of polyethylene glycol (PEG; 0 and 4% w/v) in combination with paclobutrazol (PBZ; 0 and 2 mg l-1) and gibberellin (GA; 0 and 2 mg l-1) were studied on Stevia rebaudiana callus. PEG treatment led to an oxidative stress, as indicated by increased H2O2 content whose accumulation was prevented with PBZ and GA treatments. All treatments of PEG, PBZ and GA increased the total antioxidant capacity, with the highest antioxidant power in PBZ and GA treatments without PEG. The activity of superoxide dismutase, catalase and ascorbate peroxidase significantly increased in PEG treatment alone or in combination with PBZ and GA. All treatments of PEG, PBZ and GA significantly increased proteins, amino acids and proline contents, with the highest increase in presence of PBZ in medium culture. In contrary to proline, the activity of pyrroline-5-carboxylate synthetase and proline dehydrogenase did not change in response to any of the treatments. Collectively, our results demonstrated that PBZ and GA increased reactive oxygen species scavenging and osmolytes in PEG-treated calli more than PEG treatment alone to alleviate negative effects of PEG on Stevia calli. These findings will enable us to design effective genetic engineering strategies in callus culture to generate some somaclonal variation that may be useful in enhancing drought resistance in Stevia. PMID- 29515329 TI - Femoral stem size mismatch in women undergoing total hip arthroplasty. AB - Background: Total hip arthroplasty (THA) is a highly successful surgery with a high prevalence in women. Women have been noted to have smaller proximal femoral anatomy and decreased bone strength compared to males. The goal of our study was to define the size discrepancy in femoral stem implants between men and women using a metaphyseal fitting single taper stem. Methods: We retrospectively reviewed the THA's performed by a single surgeon over the previous two years. Data was extracted from operative reports regarding stem size, neck length and offset, and conversion to a different type of stem. This data was reviewed with confidence intervals and a t-test was performed for independent samples with a p < 0.05 being determined significant. Results: We analyzed the data from 276 THA's performed (129 in men, and 147 in women). Women were noted to be associated with smaller stem sizes compared to men (37.67% in women, 6.11% in men), with 7.48% of women requiring conversion to a different type of implant. There was a significant difference in mean stem size (9.21 in men, 6.70 in women, p < 0.0001). Women also required reduced neck options significantly more often than men (38.97% in women, 9.29% in men, p < 0.0001). Conclusion: Review of femoral stem sizes reveals that current femoral stem sizing may not appropriately account for women and alternative stem options should be available if using a metaphyseal fitting single tapered stems. Future consideration should be given to more anatomic female sized femoral stems or alternative options should be available. PMID- 29515330 TI - Taxing Meat: Taking Responsibility for One's Contribution to Antibiotic Resistance. AB - Antibiotic use in animal farming is one of the main drivers of antibiotic resistance both in animals and in humans. In this paper we propose that one feasible and fair way to address this problem is to tax animal products obtained with the use of antibiotics. We argue that such tax is supported both by (a) deontological arguments, which are based on the duty individuals have to compensate society for the antibiotic resistance to which they are contributing through consumption of animal products obtained with the use of antibiotics; and (b) a cost-benefit analysis of taxing such animal products and of using revenue from the tax to fund alternatives to use of antibiotics in animal farming. Finally, we argue that such a tax would be fair because individuals who consume animal products obtained with the use of antibiotics can be held morally responsible, i.e. blameworthy, for their contribution to antibiotic resistance, in spite of the fact that each individual contribution is imperceptible. PMID- 29515331 TI - Prescription opioid use, illicit drug use, and sexually transmitted infections among participants from a community engagement program in North Central Florida. AB - Introduction: The purpose of this analysis was to determine the intersection between prescription opioid use, illicit drug use and STIs amongst Alachua County participants. Methods: Cross-sectional data come from 2,194 Alachua County community members interviewed by Community Health Workers (CHWs) from HealthStreet, a community engagement program of the University of Florida. Demographic characteristics, health risk factors and health conditions were obtained. Results: Among participants, 9.3% reported ever having an STI, 40% reported lifetime use of prescription opioids, and 53% reported ever using an illicit drug. Persons who reported using an illicit drug or an illicit drug plus prescription were 2.89 and 4.12 times as likely to report one or more STIs respectively, compared to those who never used these drugs. Prescription opioid use alone was not statistically related to STIs though female gender (AOR 3.75), lower education (AOR 1.45) and food insecurity (AOR 1.52) were. Discussion: Those who report a history illicit drug use with or without prescription opioid use are at increased risk for STIs and could benefit from prevention programs. Those with factors that are proxies for other disparities (lower education, food insecurity) are especially important targets for intervention among women. PMID- 29515332 TI - Evaluation of SD BIOLINE H. pylori Ag rapid test against double ELISA with SD H. pylori Ag ELISA and EZ-STEP H. pylori Ag ELISA tests. AB - Background: Helicobacter pylori antibody titters fall very slowly even after successful treatment. Therefore, tests detecting H. pylori antibody lack specificity and sensitivity. On the other hand, H. pylori stool antigen tests are reported as an alternative assay because of their reliability and simplicity. However, the comparative performance of H. pylori stool antigen tests for detecting the presence of the bacterium in clinical specimens in the study area is not assessed. Therefore, in this study we evaluated the performance of SD BIOLINE H. pylori Ag rapid test with reference to the commercially available EZ- STEP ELISA and SD BIOLINE H. pylori Ag ELISA tests. Methods: Stool samples were collected to analyse the diagnostic performance of SD BIOLINE H. pylori Ag rapid test kit using SD H. pylori Ag ELISA kit and EZ- STEP ELISA tests as a gold standard. Serum samples were also collected from each patient to test for the presence of H. pylori antibodies using dBest H. pylori Test Disk. Sensitivity, specificity, predictive values and kappa value are assessed. P values < 0.05 were taken statistically significant. Results: Stool and serum samples were collected from 201 dyspeptic patients and analysed. The sensitivity, specificity, positive and negative predictive values of the SD BIOLINE H. pylori Ag rapid test were: 95.6% (95% CI, 88.8-98.8), 92.5% (95%CI, 89-94.1%), 86.7% (95% CI, 80.5-89.6), and 97.6% (95% CI, 993.9-99.3) respectively. Conclusion: The performance of SD BIOLINE H. pylori Ag rapid test was better than the currently available antibody test in study area. Therefore, the SD BIOLINE Ag rapid stool test could replace and be used to diagnose active H. pylori infection before the commencement of therapy among dyspeptic patients. PMID- 29515333 TI - The fate of proteins in outer space. AB - It is well established that any properly conducted biophysical studies of proteins must take appropriate account of solvent. For water-soluble proteins it has been an article of faith that water is largely responsible for stabilizing the fold, a notion that has recently come under increasing scrutiny. Further, there are some instances when proteins are studied experimentally in the absence of solvent, as in matrix-assisted laser desorption/ionization or electrospray mass spectrometry, for example, or in organic solvents for protein engineering purposes. Apart from these considerations, there is considerable speculation as to whether there is life on planets other than Earth, where conditions including the presence of water (both in liquid or vapor form and indeed ice), temperature and pressure may be vastly different from those prevailing on Earth. Mars, for example, has only 0.6% of Earth's mean atmospheric pressure which presents profound problems to protein structures, as this paper and a large corpus of experimental work demonstrate. Similar objections will most likely apply in the case of most exoplanets and other bodies such as comets whose chemistry and climate are still largely unknown. This poses the question, how do proteins survive in these different environments? In order to cast some light on these issues we have conducted a series of molecular dynamics simulations on protein dehydration under a variety of conditions. We find that, while proteins undergoing dehydration can retain their integrity for a short duration they ultimately become disordered, and we further show that the disordering can be retarded if superficial water is kept in place on the surface. These findings are compared with other published results on protein solvation in an astrobiological and astrochemical setting. Inter alia, our results suggest that there are limits as to what to expect in terms of the existence of possible extraterrestrial forms as well to what can be achieved in experimental investigations on living systems despatched from Earth. This finding may appear to undermine currently held hopes that life will be found on nearby planets, but it is important to be aware that the presence of ice and water are by themselves not sufficient; there has to be an atmosphere which includes water vapor at a sufficiently high partial pressure for proteins to be active. A possible scenario in which there has been a history of adequate water vapor pressure which allowed organisms to prepare for a future dessicated state by forming suitable protective capsules cannot of course be ruled out. PMID- 29515334 TI - Epidermal growth factor-mediated Rab25 pathway regulates integrin beta1 trafficking in colon cancer. AB - Background: Integrins play a critical role in carcinogenesis. Integrin beta1 localization is regulated by the guanosine-5'-triphosphate hydrolase Rab25 and integrin beta1 levels are elevated in the serum of colon cancer patients; thus, the present study examined the effects of epidermal growth factor (EGF) and Rab25 on integrin beta1 localization in colon cancer cells. Methods: HCT116 human colon cancer cells were treated with increasing concentrations of EGF, and cell proliferation and protein expression were monitored by MTT and western blot analyses, respectively. Cell fractionation was performed to determine integrin beta1 localization in the membrane and cytosol. Integrin beta1 extracellular shedding was monitored by enzyme-linked immunosorbent assays (ELISAs) with culture supernatants from stimulated cells. HCT116 cells were transfected with Rab25-specific siRNA to determine the significance of Rab25 in integrin beta1 trafficking in the presence of EGF. Results: Total integrin beta1 expression increased in response to EGF and subsequently decreased at 24 h post-stimulation. A similar decrease was observed in purified membrane fractions, whereas no changes were observed in cytosolic levels. ELISAs using media from stimulated cell cultures demonstrated increased integrin beta1 levels corresponding to the decrease observed in membrane fractions, suggesting that EGF induces integrin receptor shedding. EGF stimulation in Rab25-knockdown cells resulted in integrin beta1 accumulation in the membrane, suggesting that Rab25 promotes integrin endocytosis. Conclusions: Integrin beta1 is shed from colon cancer cells in response to EGF stimulation in a Rab25-dependent manner. These results further the present understanding of the role of integrin beta1 in colon cancer progression. PMID- 29515336 TI - Neutrophil to lymphocyte ratio in patients with vitiligo. AB - Introduction: There are a few studies showing an increased risk of insulin resistance, metabolic syndrome, and oxidative stress in patients with vitiligo. Aim: To investigate whether systemic inflammation is increased in vitiligo patients in a case-control study design. Material and methods: Nonsegmental vitiligo patients who had been followed at the outpatient dermatology clinic of a university-affiliated teaching hospital, and healthy controls were enrolled in the study. Patients who were receiving systemic treatments and having a systemic disease such as diabetes mellitus and thyroiditis were excluded. Demographic features were recorded and peripheral blood samples were taken from all participants to study serum whole blood count, creatinine, and C-reactive protein (CRP). Results: Fifty patients with localized vitiligo, 43 patients with generalized vitiligo, and 50 healthy volunteers were enrolled in the study. Neutrophil to lymphocyte ratio and serum CRP levels were significantly higher in patients who have generalized vitiligo than those with localized vitiligo and healthy controls. However, there was no significant difference regarding neutrophil to lymphocyte ratio (NLR) and CRP between localized vitiligo and control groups. Conclusions: Patients with generalized vitiligo seem to have increased systemic inflammation compared with localized vitiligo and control subjects in our cohort. To the best of our knowledge, this is the first study in the literature showing increased NLR values in generalized vitiligo patients. Further studies with cardiovascular disease markers are required to elicit this association better. PMID- 29515337 TI - 5th Belarusian-Polish Conference: Dermatology and Allergology Without Borders. Grodno, 3-5 May 2017. PMID- 29515335 TI - Differential mRNA expression of the main apoptotic proteins in normal and malignant cells and its relation to in vitro resistance. AB - Background: Apoptosis plays an important role in the development and homeostasis of multicellular organisms and its deregulation may result in many serious diseases, including cancer. Now it is clear that some oncogenic mutations disrupt apoptosis, leading to tumour initiation, progression or metastasis. Here, expression of apoptotic genes in context of drug resistance was investigated. Methods: We examined total of 102 samples from leukemic patients (n = 60) and patients with solid tumours (n = 42). We used RT-PCR to determine the levels of mRNA expression and the in vitro chemoresistance of leukemic cells was evaluated using the MTT assay. Results: We found statistically significant increase in mRNA expression of all investigated proteins (p53, BAX, Bcl-2 and Bcl-XL) between the leukemia samples and leukocytes from healthy volunteers. We did not find any significant difference in mRNA levels among the solid tumour samples. Notably, we showed a significant positive correlation in both leukemic and solid tumour patient groups between p53 and BAX mRNA. We found that the highest values for the Bcl-2/BAX ratio were in solid tumours in comparison to leukemic cells or normal leukocytes. Moreover, we assessed the impact of p53 and BAX mRNA levels on the sensitivity of the leukemic cells to selected cytostatics. Conclusions: Elevated levels of p53 and BAX mRNA may indicate cellular response to possible changes in genomic DNA integrity associated with malignant transformation. We suggest that the BAX gene is regulated by the p53 protein but the initiation of apoptosis through the transcription activation of BAX is blocked by the high levels of Bcl 2. Given that the apoptosis resistance mechanisms are different among oncological patients as well as stages of identical malignancy cases, personalized and specific combination therapy is proposed to be more effective in clinical application. PMID- 29515338 TI - ERCP-Related Duodenal Perforation Presenting as Pneumoscrotum. AB - Duodenal perforation is a rare but life-threatening complication of endoscopic retrograde cholangiopancreatography (ERCP). Duodenal perforation can cause air leak into the extraperitoneal space. In rare instances, the air in the extraperitoneal space could dissect along the fascial planes of the abdomen to reach scrotum, leading to pneumoscrotum. We present the case of a 35-year-old male patient who developed scrotal pain and swelling following ERCP. He was found to have extensive pneumoscrotum, pneumoretroperitoneum, pneumomediastinum, and subcutaneous emphysema. The patient was diagnosed with retroperitoneal duodenal perforation. He was managed conservatively with close monitoring and supportive care. PMID- 29515339 TI - Coexisting Granular Cell Tumor and Tubular Adenoma of the Ileocecal Valve. AB - Granular cell tumors (GCTs) have been described as neoplasms of Schwann cell origin. They are often benign and notably uncommon in the gastrointestinal tract. Recently, their incidence has become more common, likely as a result of increased colonoscopy screenings. Very few data exist regarding their potential for malignancy, but malignant GCTs have been reported. Here, we report the case of a young female patient who was diagnosed with an atypical GCT on the ileocecal valve with an overlying tubular adenoma which was found incidentally on colonoscopy. This represents the first known report of a GCT with atypical features on the ileocecal valve, as well as a rare case of overlying adenomatous changes. Due to the paucity of cases, there is no clear modus operandi for their management. Furthermore, it is not clear whether surgical or endoscopic interventions or simple observation may be most appropriate. Further studies are needed to evaluate the potential for malignancy of this tumor, as well as its management. PMID- 29515340 TI - Severe Hepatic and Pulmonary Involvement in Rendu-Osler-Weber Syndrome. AB - We report the case of a young woman with hereditary hemorrhagic telangiectasia (HHT) with severe liver involvement and pulmonary shunting. The medical imaging in this patient illustrates the severe shunting that can occur in these patients who often are asymptomatic. By showing this case, we want to highlight the role of liver transplantation in HHT with hepatic involvement. PMID- 29515341 TI - Spontaneous Rupture of Hepatocellular Carcinoma in a Young Patient with Fatal Outcome. AB - Spontaneous rupture of hepatocellular carcinoma (HCC) is a potentially life threatening complication. Diagnosis may be difficult, particularly in the absence of known liver cirrhosis or tumor. A 20-year-old male patient presented with progressive abdominal pain and shock. His past medical history was uneventful. Anemia, acute renal failure, and abnormal liver function test were demonstrated. Mild hepatomegaly, perihepatic and flank fluid, and multiple hypodense liver lesions suggestive of intrahepatic metastases or multifocal HCC were revealed by computed tomography. Two actively bleeding liver tumors and multiple tumors in a noncirrhotic liver were found. Hemostatic suture and perihepatic packing were performed. The patient remained in critical condition, with a fatal outcome 48 h later. Histopathologic analysis reported HCC and absence of cirrhotic changes. HCC spontaneous rupture incidence is reported between 2.3 and 26%. Median age is 65 years. No liver cirrhosis is found in one-third of patients, with a median age of 51 years. Sudden onset of abdominal pain and shock is observed in the majority of cases. An accurate preoperative diagnosis improves to 75% with ultrasound and computed tomography. Besides hemodynamic stabilization, there is no general agreement on the best treatment option. Transarterial embolization, surgical perihepatic packing, suture plication, and hepatic artery ligation are useful methods of hemostasis in unstable patients. Mortality has been reported from 16.5 to 100%. The histopathologic finding of HCC in a noncirrhotic liver represents a less frequent presentation. A case of spontaneous rupture of HCC carcinoma and a noncirrhotic liver in a young patient is herein reported. PMID- 29515342 TI - A Diminutive T1 Cancer 4 mm in Size Resected by Cold Snare Polypectomy. AB - Cold snare polypectomy (CSP) should be performed for benign lesions, though an accurate diagnosis is sometimes difficult with only white light observation. Irregular findings by narrow-band imaging (NBI) are useful for differentiating malignant lesions from benign lesions, and cases with this finding are not expected for CSP. We present a diminutive T1 cancer resected by CSP as a reflection case. A 68-year-old man underwent colonoscopy for surveillance after polypectomy. A reddish polyp 4 mm in size was detected at the rectum. White light observation showed no depression, but a slight, heterogeneous color change. NBI magnification showed irregular vessel and surface patterns. The polyp was diagnosed as intramucosal cancer. Even though cancerous lesions are regularly resected by endoscopic mucosal resection (EMR), this polyp was resected by CSP in daycare surgery because the patient requested not to be treated by EMR but by CSP, which needed an admission to our institution. The surgeon thought the polyp could be completely resected by CSP. It was thoroughly resected, and a histological examination showed submucosal cancer with a positive vertical margin. Additional surgical resection was not accepted by the patient, since he had received total gastrectomy for gastric cancer and a right hemicolectomy for colonic cancer in the past 7 years. He underwent follow-up colonoscopy 2 months after the CSP. Although there were no recurrent endoscopic findings, endoscopic submucosal dissection was performed to the scar area. The histological examination showed no residual tumor. In conclusion, CSP should only be adopted for benign cases, as cancerous lesions have a possibility for invading the submucosa, like in our case. PMID- 29515343 TI - Endoscopic versus Laparoscopic Full-Thickness Biopsy in the Pathological Evaluation of the Enteric Nervous System. AB - A full-thickness biopsy of the bowel wall is required to evaluate the enteric nervous system. A patient with aggravating gastrointestinal symptoms underwent a laparoscopic full-thickness biopsy of the ileum and, 1 year later, an endoscopic full-thickness biopsy of the sigmoid colon. Both samples showed enteric neuropathy characterized by vacuolated and enlarged neurons. The length of the myenteric plexus was greater in the endoscopic (23 mm) compared to the laparoscopic (11 mm) biopsy, with fewer tissue artefacts in the laparoscopic approach. Clinical deterioration was paralleled by enteric neuropathy with an increase in the percentage of vacuolated and enlarged enteric neurons from 24 to 35%. PMID- 29515344 TI - Sevelamer-Induced Gastrointestinal Injury Presenting as Gastroenteritis. AB - End-stage renal disease (ESRD) is a common disease encountered in clinical practice and is associated with increasing metabolic derangements through disease progression. Phosphate retention is one of the most common derangements and is associated with increased mortality. Hyperphosphatemia becomes increasingly prevalent as glomerular filtration rate decreases. Non-calcium phosphate-binding resins and dietary phosphate restriction are the mainstays for managing hyperphosphatemia in patients with ESRD. Sevelamer carbonate is the most frequently used non-calcium phosphate binder in the US due to ease of administration and an excellent safety profile. However, there is increasing recognition of gastrointestinal injury associated with medication use. Here we report a case of an 81-year-old male with biopsy-proven gastrointestinal mucosal injury secondary to sevelamer carbonate administration. PMID- 29515345 TI - Adult Presentation of Noncirrhotic Portal Hypertension and Ascites following Treatment for Wilms' Tumor in Childhood. AB - A 37-year-old male, who at the age of 8 years had been treated for right-sided Wilms' tumor with nephrectomy, radiotherapy, and chemotherapy, presented with noncirrhotic portal hypertension (NCPH), grade 2 esophageal varices, and ascites. A CT scan demonstrated hypoplasia of liver segments 2 and 3. A liver biopsy showed portal tract fibrosis without cirrhosis, with histological features of NCPH. Liver vein catheterization showed a normal portal pressure gradient of 5 mm Hg while spleen to hepatic vein pressure was 29 mm Hg. NCPH after therapy for Wilms' tumor is described in children within the first few years after treatment. This is the first case report in which the patient first presented symptoms as an adult, many years after cancer treatment. PMID- 29515346 TI - Ileum Histoplasmosis Mimicking Intestinal Tuberculosis and Crohn's Disease. AB - Gastrointestinal histoplasmosis (GIH) without pulmonary and bone marrow involvement is very rare worldwide. It can be misdiagnosed as intestinal tuberculosis or Crohn's disease. There are just few case reports of GIH in patients with a positive HIV antibody test. Here, we report a patient who presented to our hospital with repeated intestinal obstruction. The suspicious diagnosis was intestinal tuberculosis or Crohn's disease due to unspecific clinical manifestations and radiologic images. Our patient's HIV antibody test was negative. She had no medical prescriptions. Therefore, our differential diagnosis needed to include ileum histoplasmosis besides intestinal lymphoma, intestinal tuberculosis, and Crohn's disease. Finally, the patient was diagnosed with ileum histoplasmosis due to surgical resection. It is important to be aware of potential infectious diseases, such as ileum histoplasmosis, when making a differential diagnosis. Moreover, surgical resection might be the final approach for small-intestine stricture with fibrosis. PMID- 29515347 TI - A Bile Duct Stone Formation around a Fish Bone as a Nidus after Pancreatoduodenectomy. AB - We report a rare case of bile duct stone formation around an ingested fish bone as a nidus after pancreatoduodenectomy. A 78-year-old woman was admitted to our department for fever and epigastric pain. Abdominal computed tomography revealed an elongated bile duct stone containing a linearly shaped foreign body of bone density. Enteroscopic lithotomy was performed using single balloon enteroscopy to safely remove the stone and foreign body from the bile duct. The foreign body was determined to be a fish bone by pathological examination and component analysis. PMID- 29515348 TI - Multivariate Classification of Major Depressive Disorder Using the Effective Connectivity and Functional Connectivity. AB - Major depressive disorder (MDD) is a mental disorder characterized by at least 2 weeks of low mood, which is present across most situations. Diagnosis of MDD using rest-state functional magnetic resonance imaging (fMRI) data faces many challenges due to the high dimensionality, small samples, noisy and individual variability. To our best knowledge, no studies aim at classification with effective connectivity and functional connectivity measures between MDD patients and healthy controls. In this study, we performed a data-driving classification analysis using the whole brain connectivity measures which included the functional connectivity from two brain templates and effective connectivity measures created by the default mode network (DMN), dorsal attention network (DAN), frontal-parietal network (FPN), and silence network (SN). Effective connectivity measures were extracted using spectral Dynamic Causal Modeling (spDCM) and transformed into a vectorial feature space. Linear Support Vector Machine (linear SVM), non-linear SVM, k-Nearest Neighbor (KNN), and Logistic Regression (LR) were used as the classifiers to identify the differences between MDD patients and healthy controls. Our results showed that the highest accuracy achieved 91.67% (p < 0.0001) when using 19 effective connections and 89.36% when using 6,650 functional connections. The functional connections with high discriminative power were mainly located within or across the whole brain resting state networks while the discriminative effective connections located in several specific regions, such as posterior cingulate cortex (PCC), ventromedial prefrontal cortex (vmPFC), dorsal cingulate cortex (dACC), and inferior parietal lobes (IPL). To further compare the discriminative power of functional connections and effective connections, a classification analysis only using the functional connections from those four networks was conducted and the highest accuracy achieved 78.33% (p < 0.0001). Our study demonstrated that the effective connectivity measures might play a more important role than functional connectivity in exploring the alterations between patients and health controls and afford a better mechanistic interpretability. Moreover, our results showed a diagnostic potential of the effective connectivity for the diagnosis of MDD patients with high accuracies allowing for earlier prevention or intervention. PMID- 29515349 TI - A Configurable Event-Driven Convolutional Node with Rate Saturation Mechanism for Modular ConvNet Systems Implementation. AB - Convolutional Neural Networks (ConvNets) are a particular type of neural network often used for many applications like image recognition, video analysis or natural language processing. They are inspired by the human brain, following a specific organization of the connectivity pattern between layers of neurons known as receptive field. These networks have been traditionally implemented in software, but they are becoming more computationally expensive as they scale up, having limitations for real-time processing of high-speed stimuli. On the other hand, hardware implementations show difficulties to be used for different applications, due to their reduced flexibility. In this paper, we propose a fully configurable event-driven convolutional node with rate saturation mechanism that can be used to implement arbitrary ConvNets on FPGAs. This node includes a convolutional processing unit and a routing element which allows to build large 2D arrays where any multilayer structure can be implemented. The rate saturation mechanism emulates the refractory behavior in biological neurons, guaranteeing a minimum separation in time between consecutive events. A 4-layer ConvNet with 22 convolutional nodes trained for poker card symbol recognition has been implemented in a Spartan6 FPGA. This network has been tested with a stimulus where 40 poker cards were observed by a Dynamic Vision Sensor (DVS) in 1 s time. Different slow-down factors were applied to characterize the behavior of the system for high speed processing. For slow stimulus play-back, a 96% recognition rate is obtained with a power consumption of 0.85 mW. At maximum play-back speed, a traffic control mechanism downsamples the input stimulus, obtaining a recognition rate above 63% when less than 20% of the input events are processed, demonstrating the robustness of the network. PMID- 29515350 TI - A Pilot Study of Peripheral Muscle Magnetic Stimulation as Add-on Treatment to Repetitive Transcranial Magnetic Stimulation in Chronic Tinnitus. AB - : While brain stimulation techniques have been examined as treatment options for chronic tinnitus for many years, they have recently been extended to multimodal treatment approaches. As chronic tinnitus is often accompanied by comorbid muscular tension in the neck and back, we performed a one-arm pilot study to explore the feasibility of a new multimodal treatment approach. In detail, repetitive peripheral magnetic stimulation (rPMS) of the back was performed before and after each session of repetitive transcranial magnetic stimulation (rTMS) of the brain. Data of 41 patients were analyzed, all of which were treated with ten sessions of rTMS of the left prefrontal and left temporoparietal cortex followed by rPMS of the neck and back muscles. Tinnitus severity was measured using the tinnitus questionnaire (TQ). Neck pain was assessed using the neck pain and disability scale (NPAD). The new treatment approach was feasible and well accepted by the majority of patients. However, the overall patient group did not improve significantly in either of the questionnaires. If patients were divided in different subgroups depending on whether they were suffering from neck pain or somatosensory tinnitus, explorative post-hoc tests suggested differential effects: patients with both neck pain and somatosensory tinnitus had better outcomes than patients without those conditions or with neck pain only. This was true for both the TQ and the NPAD. This effect was of transient nature though: the TQ score went back to its baseline level after a follow-up period of 12 weeks. Based on our results we recommend that in studies that investigate tinnitus treatments targeting somatosensory afferents patients should be stratified according to somatic co-morbidities and somatosensory influence on the tinnitus percept. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT02306447. PMID- 29515351 TI - Interhemispheric Transfer Time Asymmetry of Visual Information Depends on Eye Dominance: An Electrophysiological Study. AB - The interhemispheric transfer of information is a fundamental process in the human brain. When a visual stimulus appears eccentrically in one visual hemifield, it will first activate the contralateral hemisphere but also the ipsilateral one with a slight delay due to the interhemispheric transfer. This interhemispheric transfer of visual information is believed to be faster from the right to the left hemisphere in right-handers. Such an asymmetry is considered as a relevant fact in the context of the lateralization of the human brain. We show here using current source density (CSD) analyses of visually evoked potential (VEP) that, in right-handers and, to a lesser extent in left-handers, this asymmetry is in fact dependent on the sighting eye dominance, the tendency we have to prefer one eye for monocular tasks. Indeed, in right-handers, a faster interhemispheric transfer of visual information from the right to left hemisphere was observed only in participants with a right dominant eye (DE). Right-handers with a left DE showed the opposite pattern, with a faster transfer from the left to the right hemisphere. In left-handers, albeit a smaller number of participants has been tested and hence confirmation is required, only those with a right DE showed an asymmetrical interhemispheric transfer with a faster transfer from the right to the left hemisphere. As a whole these results demonstrate that eye dominance is a fundamental determinant of asymmetries in interhemispheric transfer of visual information and suggest that it is an important factor of brain lateralization. PMID- 29515352 TI - The Role of Insulin/IGF-1/PI3K/Akt/GSK3beta Signaling in Parkinson's Disease Dementia. AB - Dementia, a condition that frequently afflicts patients in advanced stages of Parkinson's disease (PD), results in decreased quality of life and survival time. Nevertheless, the pathological mechanisms underlying Parkinson's disease dementia (PDD) are not completely understood. The symptoms characteristic of PDD may be the result of functional and structural deficiencies. The present study implicates the accumulation of Lewy bodies in the cortex and limbic system as a potent trigger in the development of PDD. In addition, significant Alzheimer-type pathologies, including amyloid-beta (Abeta) plaques and NFTs, are observed in almost half of PDD patients. Interestingly, links between PDD pathogenesis and the mechanisms underlying the development of insulin resistance have begun to emerge. Furthermore, previous studies have demonstrated that insulin treatment reduces amyloid plaques in Alzheimer's disease (AD), and normalizes the production and functionality of dopamine and ameliorates motor impairments in 6 OHDA-induced rat PD models. GSK3beta, a downstream substrate of PI3K/Akt signaling following induction by insulin and IGF-1, exerts an influence on AD and PD physiopathology. The genetic overexpression of GSK3beta in cortex and hippocampus results in signs of neurodegeneration and spatial learning deficits in in vivo models (Lucas et al., 2001), whereas its inhibition results in improvements in cognitive impairment in these rodents, including AD and PD. Accordingly, insulin- or IGF-1-activated PI3K/Akt/GSK3beta signaling may be involved in PDD pathogenesis, at least in the pathology of PD-type + AD-type. PMID- 29515353 TI - Intra-accumbens Raclopride Administration Prevents Behavioral Changes Induced by Intermittent Access to Sucrose Solution. AB - Overeating is one of the most relevant clinical features in Binge Eating Disorder and in some obesity patients. According to several studies, alterations in the mesolimbic dopaminergic transmission produced by non-homeostatic feeding behavior may be associated with changes in the reward system similar to those produced by drugs of abuse. Although it is known that binge-eating is related with changes in dopaminergic transmission mediated by D2 receptors in the nucleus accumbens shell (NAcS), it has not been determined whether these receptors may be a potential target for the treatment of eating pathology with binge-eating. Accordingly, the aim of the present study was to evaluate whether sugar binging induced by intermittent access to a sucrose solution produced changes in the structure of feeding behavior and whether blocking D2 receptors prevented these changes. We used the intermittent access model to a 10% sucrose solution (2 h/day for 4 weeks) to induce sugar binging in Sprague Dawley female rats. Experimental subjects consumed in a 2-h period more than 50% of the caloric intake consumed by the subjects with ad-lib access to the sweetened solution without any increase in body weight or fat accumulation. Furthermore, we evaluated whether sugar binging was associated to the estrous cycle and we did not find differences in caloric intake (estrous vs. diestrus). Subsequently, we characterized the structure of feeding behavior (microstructural analysis) and the motivation for palatable food (breakpoints) of the subjects with sugar binging and found that feeding episodes had short latencies, high frequencies, as well as short durations and inter episode intervals. The intermittent access model did not increase breakpoints, as occurred in subjects with ad-lib access to the sucrose. Finally, we evaluated the effects of D2 receptor blockade in the NAcS, and found that raclopride (18 nM) prevented the observed changes in the frequency and duration of episodes induced by intermittent access to the sucrose solution. Our results suggest that alterations in behavioral patterns associated with binge-eating behavior depend in part on the dopaminergic transmission in the NAcS and that the antagonism of D2 receptors may be a therapeutic tool for feeding pathology with binge-eating. PMID- 29515355 TI - Freedom of Thought and Mental Integrity: The Moral Requirements for Any Neural Prosthesis. AB - There are many kinds of neural prostheses available or being researched today. In most cases they are intended to cure or improve the condition of patients affected by some cerebral deficiency. In other cases, their goal is to provide new means to maintain or improve an individual's normal performance. In all these circumstances, one of the possible risks is that of violating the privacy of brain contents (which partly coincide with mental contents) or of depriving individuals of full control over their thoughts (mental states), as the latter are at least partly detectable by new prosthetic technologies. Given the (ethical) premise that the absolute privacy and integrity of the most relevant part of one's brain data is (one of) the most valuable and inviolable human right(s), I argue that a (technical) principle should guide the design and regulation of new neural prostheses. The premise is justified by the fact that whatever the coercion, the threat or the violence undergone, the person can generally preserve a "private repository" of thought in which to defend her convictions and identity, her dignity, and autonomy. Without it, the person may end up in a state of complete subjection to other individuals. The following functional principle is that neural prostheses should be technically designed and built so as to prevent such outcomes. They should: (a) incorporate systems that can find and signal the unauthorized detection, alteration, and diffusion of brain data and brain functioning; (b) be able to stop any unauthorized detection, alteration, and diffusion of brain data. This should not only regard individual devices, but act as a general (technical) operating principle shared by all interconnected systems that deal with decoding brain activity and brain functioning. PMID- 29515354 TI - Mechanisms of alpha-Synuclein Induced Synaptopathy in Parkinson's Disease. AB - Parkinson's disease (PD) is characterized by intracellular inclusions of aggregated and misfolded alpha-Synuclein (alpha-Syn), and the loss of dopaminergic (DA) neurons in the brain. The resulting motor abnormalities mark the progression of PD, while non-motor symptoms can already be identified during early, prodromal stages of disease. Recent studies provide evidence that during this early prodromal phase, synaptic and axonal abnormalities occur before the degenerative loss of neuronal cell bodies. These early phenotypes can be attributed to synaptic accumulation of toxic alpha-Syn. Under physiological conditions, alpha-Syn functions in its native conformation as a soluble monomer. However, PD patient brains are characterized by intracellular inclusions of insoluble fibrils. Yet, oligomers and protofibrils of alpha-Syn have been identified to be the most toxic species, with their accumulation at presynaptic terminals affecting several steps of neurotransmitter release. First, high levels of alpha-Syn alter the size of synaptic vesicle pools and impair their trafficking. Second, alpha-Syn overexpression can either misregulate or redistribute proteins of the presynaptic SNARE complex. This leads to deficient tethering, docking, priming and fusion of synaptic vesicles at the active zone (AZ). Third, alpha-Syn inclusions are found within the presynaptic AZ, accompanied by a decrease in AZ protein levels. Furthermore, alpha-Syn overexpression reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. These presynaptic alterations mediated by accumulation of alpha-Syn, together impair neurotransmitter exocytosis and neuronal communication. Although alpha-Syn is expressed throughout the brain and enriched at presynaptic terminals, DA neurons are the most vulnerable in PD, likely because alpha-Syn directly regulates dopamine levels. Indeed, evidence suggests that alpha-Syn is a negative modulator of dopamine by inhibiting enzymes responsible for its synthesis. In addition, alpha-Syn is able to interact with and reduce the activity of VMAT2 and DAT. The resulting dysregulation of dopamine levels directly contributes to the formation of toxic alpha-Syn oligomers. Together these data suggest a vicious cycle of accumulating alpha-Syn and deregulated dopamine that triggers synaptic dysfunction and impaired neuronal communication, ultimately causing synaptopathy and progressive neurodegeneration in Parkinson's disease. PMID- 29515358 TI - Modeling Protein Aggregation and the Heat Shock Response in ALS iPSC-Derived Motor Neurons. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by the selective loss of the upper and lower motor neurons. Only 10% of all cases are caused by a mutation in one of the two dozen different identified genes, while the remaining 90% are likely caused by a combination of as yet unidentified genetic and environmental factors. Mutations in C9orf72, SOD1, or TDP-43 are the most common causes of familial ALS, together responsible for at least 60% of these cases. Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62. These inclusions are normally prevented and cleared by heat shock proteins (Hsps), suggesting that ALS motor neurons have an impaired ability to induce the heat shock response (HSR). Accordingly, there is evidence of decreased induction of Hsps in ALS mouse models and in human post-mortem samples compared to unaffected controls. However, the role of Hsps in protein accumulation in human motor neurons has not been fully elucidated. Here, we generated motor neuron cultures from human induced pluripotent stem cell (iPSC) lines carrying mutations in SOD1, TDP-43, or C9orf72. In this study, we provide evidence that despite a lack of overt motor neuron loss, there is an accumulation of insoluble, aggregation-prone proteins in iPSC-derived motor neuron cultures but that content and levels vary with genetic background. Additionally, although iPSC-derived motor neurons are generally capable of inducing the HSR when exposed to a heat stress, protein aggregation itself is not sufficient to induce the HSR or stress granule formation. We therefore conclude that ALS iPSC-derived motor neurons recapitulate key early pathological features of the disease and fail to endogenously upregulate the HSR in response to increased protein burden. PMID- 29515357 TI - Epitranscriptomics: A New Regulatory Mechanism of Brain Development and Function. AB - Epigenetic modifications of DNA and chromatin are long known to control stem cell differentiation and organ function but the role of similar modifications at the level or regulatory RNAs is just beginning to emerge. Over 160 RNA modifications have been identified but their abundance, distribution and functional significance are not known. The few available maps of RNA modifications indicated their dynamic regulation during somatic stem cell differentiation, brain development and function in adulthood suggesting a hitherto unsuspected layer of regulation both at the level of RNA metabolism and post-transcriptional control of gene expression. The advent of programmable, RNA-specific CRISPR-Cas editing platforms together with the identification of RNA modifying enzymes now offers the opportunity to investigate the functional role of these elusive epitranscriptome changes. Here, we discuss recent insights in studying the most abundant modifications in functional mRNAs and lncRNAs, N6-methyladenosine and 5 (hydroxy-)methylcytosine, and their role in regulating somatic stem cell differentiation with particular attention to neural stem cells during mammalian corticogenesis. An outlook on novel CRISPR-Cas based systems that allow stem cell reprogramming by epitranscriptome-editing will also be discussed. PMID- 29515359 TI - The Birth of the Eye Vesicle: When Fate Decision Equals Morphogenesis. AB - As the embryonic ectoderm is induced to form the neural plate, cells inside this epithelium acquire restricted identities that will dictate their behavior and progressive differentiation. The first behavior adopted by most neural plate cells is called neurulation, a morphogenetic movement shaping the neuroepithelium into a tube. One cell population is not adopting this movement: the eye field. Giving eye identity to a defined population inside the neural plate is therefore a key neural fate decision. While all other neural population undergo neurulation similarly, converging toward the midline, the eye field moves outwards, away from the rest of the forming neural tube, to form vesicles. Thus, while delay in acquisition of most other fates would not have significant morphogenetic consequences, defect in the establishment of the eye field would dramatically impact the formation of the eye. Yet, very little is understood of the molecular and cellular mechanisms driving them. Here, we summarize what is known across vertebrate species and propose a model highlighting what is required to form the essential vesicles that initiate the vertebrate eyes. PMID- 29515361 TI - ER Dynamics and Derangement in Neurological Diseases. AB - The endoplasmic reticulum (ER) is a morphologically dynamic organelle containing different membrane subdomains with distinct cellular functions. Numerous observations have revealed that ER stress response induced by disturbed ER homeostasis is linked to various neurological/neurodegenerative disorders. In contrast, recent findings unveil that ER structural derangements are linked to the progression of several neurological diseases. The derangements involve two distinct, and likely opposing pathways. One is dysfunction of ER dynamics machinery, leading to disruption of ER network organization. Another one is facilitation of pre-existing machinery, leading to generation of markedly-ordered de novo membranous structure. Restoring the ER network can be the effective way toward the cure of ER-deranged neurological disorders. PMID- 29515360 TI - Metabolic Disturbances in the Striatum and Substantia Nigra in the Onset and Progression of MPTP-Induced Parkinsonism Model. AB - Metabolic confusion has been linked to the pathogenesis of Parkinson's disease (PD), while the dynamic changes associated with the onset and progression of PD remain unclear. Herein, dynamic changes in metabolites were detected from the initiation to the development of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -induced Parkinsonism model to elucidate its potential metabolic mechanism. Ex vivo1H nuclear magnetic resonance (NMR) spectroscopy was used to measure metabolite changes in the striatum and substantia nigra (SN) of mice at 1, 7, and 21 days after injection of MPTP. Metabolomic analysis revealed a clear separation of the overall metabolites between PD and control mice at different time points. Glutamate (Glu) in the striatum was significantly elevated at induction PD day 1 mice, which persisted to day 21. N-acetylaspartate (NAA) increased in the striatum of induction PD mice on days 1 and 7, but no significant difference was found in striatum on day 21. Myo-Inositol (mI) and taurine (Tau) were also disturbed in the striatum in induction PD day 1 mice. Additionally, key enzymes in the glutamate-glutamine cycle were significantly increased in PD mice. These findings suggest that neuron loss and motor function impairment in induction PD mice may be linked to overactive glutamate-glutamine cycle and altered membrane metabolism. PMID- 29515356 TI - Steroid Transport, Local Synthesis, and Signaling within the Brain: Roles in Neurogenesis, Neuroprotection, and Sexual Behaviors. AB - Sex steroid hormones are synthesized from cholesterol and exert pleiotropic effects notably in the central nervous system. Pioneering studies from Baulieu and colleagues have suggested that steroids are also locally-synthesized in the brain. Such steroids, called neurosteroids, can rapidly modulate neuronal excitability and functions, brain plasticity, and behavior. Accumulating data obtained on a wide variety of species demonstrate that neurosteroidogenesis is an evolutionary conserved feature across fish, birds, and mammals. In this review, we will first document neurosteroidogenesis and steroid signaling for estrogens, progestagens, and androgens in the brain of teleost fish, birds, and mammals. We will next consider the effects of sex steroids in homeostatic and regenerative neurogenesis, in neuroprotection, and in sexual behaviors. In a last part, we will discuss the transport of steroids and lipoproteins from the periphery within the brain (and vice-versa) and document their effects on the blood-brain barrier (BBB) permeability and on neuroprotection. We will emphasize the potential interaction between lipoproteins and sex steroids, addressing the beneficial effects of steroids and lipoproteins, particularly HDL-cholesterol, against the breakdown of the BBB reported to occur during brain ischemic stroke. We will consequently highlight the potential anti-inflammatory, anti-oxidant, and neuroprotective properties of sex steroid and lipoproteins, these latest improving cholesterol and steroid ester transport within the brain after insults. PMID- 29515363 TI - Fast Recognition of BCI-Inefficient Users Using Physiological Features from EEG Signals: A Screening Study of Stroke Patients. AB - Motor imagery (MI) based brain-computer interface (BCI) has been developed as an alternative therapy for stroke rehabilitation. However, experimental evidence demonstrates that a significant portion (10-50%) of subjects are BCI-inefficient users (accuracy less than 70%). Thus, predicting BCI performance prior to clinical BCI usage would facilitate the selection of suitable end-users and improve the efficiency of stroke rehabilitation. In the current study, we proposed two physiological variables, i.e., laterality index (LI) and cortical activation strength (CAS), to predict MI-BCI performance. Twenty-four stroke patients and 10 healthy subjects were recruited for this study. Each subject was required to perform two blocks of left- and right-hand MI tasks. Linear regression analyses were performed between the BCI accuracies and two physiological predictors. Here, the predictors were calculated from the electroencephalography (EEG) signals during paretic hand MI tasks (5 trials; approximately 1 min). LI values exhibited a statistically significant correlation with two-class BCI (left vs. right) performance (r = -0.732, p < 0.001), and CAS values exhibited a statistically significant correlation with brain-switch BCI (task vs. idle) performance (r = 0.641, p < 0.001). Furthermore, the BCI inefficient users were successfully recognized with a sensitivity of 88.2% and a specificity of 85.7% in the two-class BCI. The brain-switch BCI achieved a sensitivity of 100.0% and a specificity of 87.5% in the discrimination of BCI inefficient users. These results demonstrated that the proposed BCI predictors were promising to promote the BCI usage in stroke rehabilitation and contribute to a better understanding of the BCI-inefficiency phenomenon in stroke patients. PMID- 29515362 TI - On the Viability of Diffusion MRI-Based Microstructural Biomarkers in Ischemic Stroke. AB - Recent tract-based analyses provided evidence for the exploitability of 3D-SHORE microstructural descriptors derived from diffusion MRI (dMRI) in revealing white matter (WM) plasticity. In this work, we focused on the main open issues left: (1) the comparative analysis with respect to classical tensor-derived indices, i.e., Fractional Anisotropy (FA) and Mean Diffusivity (MD); and (2) the ability to detect plasticity processes in gray matter (GM). Although signal modeling in GM is still largely unexplored, we investigated their sensibility to stroke induced microstructural modifications occurring in the contralateral hemisphere. A more complete picture could provide hints for investigating the interplay of GM and WM modulations. Ten stroke patients and ten age/gender-matched healthy controls were enrolled in the study and underwent diffusion spectrum imaging (DSI). Acquisitions at three and two time points (tp) were performed on patients and controls, respectively. For all subjects and acquisitions, FA and MD were computed along with 3D-SHORE-based indices [Generalized Fractional Anisotropy (GFA), Propagator Anisotropy (PA), Return To the Axis Probability (RTAP), Return To the Plane Probability (RTPP), and Mean Square Displacement (MSD)]. Tract-based analysis involving the cortical, subcortical and transcallosal motor networks and region-based analysis in GM were successively performed, focusing on the contralateral hemisphere to the stroke. Reproducibility of all the indices on both WM and GM was quantitatively proved on controls. For tract-based, longitudinal group analyses revealed the highest significant differences across the subcortical and transcallosal networks for all the indices. The optimal regression model for predicting the clinical motor outcome at tp3 included GFA, PA, RTPP, and MSD in the subcortical network in combination with the main clinical information at baseline. Region-based analysis in the contralateral GM highlighted the ability of anisotropy indices in discriminating between groups mainly at tp1, while diffusivity indices appeared to be altered at tp2. 3D-SHORE indices proved to be suitable in probing plasticity in both WM and GM, further confirming their viability as a novel family of biomarkers in ischemic stroke in WM and revealing their potential exploitability in GM. Their combination with tensor-derived indices can provide more detailed insights of the different tissue modulations related to stroke pathology. PMID- 29515365 TI - Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice. AB - Mutations in the transcription factor methyl-CpG-binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome (RTT). Besides many other neurological problems, RTT patients show irregular breathing with recurrent apneas or breath-holdings. MeCP2-deficient mice, which recapitulate this breathing phenotype, show a dysregulated, persistent expression of G-protein coupled serotonin receptor 5-ht5b (Htr5b) in the brainstem. To investigate whether the persistence of 5-ht5b expression is contributing to the respiratory phenotype, we crossbred MeCP2-deficient mice with 5-ht5b-deficient mice to generate double knockout mice (Mecp2-/y ;Htr5b-/-). To compare respiration between wild type (WT), Mecp2-/y and Mecp2-/y ;Htr5b-/- mice, we used unrestrained whole-body plethysmography. While the breathing of MeCP2-deficient male mice (Mecp2-/y ) at postnatal day 40 is characterized by a slow breathing rate and the occurrence of prolonged respiratory pauses, we found that in MeCP2 deficient mice, which also lacked the 5-ht5b receptor, the breathing rate and the number of pauses were indistinguishable from WT mice. To test for a potential mechanism, we also analyzed if the known coupling of 5-ht5b receptors to Gi proteins is altering second messenger signaling. Tissue cAMP levels in the medulla of Mecp2-/y mice were decreased as compared to WT mice. In contrast, cAMP levels in Mecp2-/y ;Htr5b-/- mice were indistinguishable from WT mice. Taken together, our data points towards a role of 5-ht5b receptors within the complex breathing phenotype of MeCP2-deficient mice. PMID- 29515364 TI - Junctional E-cadherin/p120-catenin Is Correlated with the Absence of Supporting Cells to Hair Cells Conversion in Postnatal Mice Cochleae. AB - Notch inhibition is known to generate supernumerary hair cells (HCs) at the expense of supporting cells (SCs) in the mammalian inner ear. However, inhibition of Notch activity becomes progressively less effective at inducing SC-to-HC conversion in the postnatal cochlea and balance organs as the animal ages. It has been suggested that the SC-to-HC conversion capacity is inversely correlated with E-cadherin accumulation in postnatal mammalian utricles. However, whether E cadherin localization is linked to the SC-to-HC conversion capacity in the mammalian inner ear is poorly understood. In the present study, we treated cochleae from postnatal day 0 (P0) with the Notch signaling inhibitor DAPT and observed apparent SC-to-HC conversion along with E-cadherin/p120ctn disruption in the sensory region. In addition, the SC-to-HC conversion capacity and E cadherin/p120ctn disorganization were robust in the apex but decreased toward the base. We further demonstrated that the ability to regenerate HCs and the disruption of E-cadherin/p120ctn concomitantly decreased with age and ceased at P7, even after extended DAPT treatments. This timing is consistent with E cadherin/p120ctn accumulation in the postnatal cochleae. These results suggest that the decreasing capacity of SCs to transdifferentiate into HCs correlates with E-cadherin/p120ctn localization in the postnatal cochleae, which might account for the absence of SC-to-HC conversion in the mammalian cochlea. PMID- 29515366 TI - The Activating Transcription Factor 3 (Atf3) Homozygous Knockout Mice Exhibit Enhanced Conditioned Fear and Down Regulation of Hippocampal GELSOLIN. AB - The genetic and molecular basis underlying fear memory formation is a key theme in anxiety disorder research. Because activating transcription factor 3 (ATF3) is induced under stress conditions and is highly expressed in the hippocampus, we hypothesize that ATF3 plays a role in fear memory formation. We used fear conditioning and various other paradigms to test Atf3 knockout mice and study the role of ATF3 in processing fear memory. The results demonstrated that the lack of ATF3 specifically enhanced the expression of fear memory, which was indicated by a higher incidence of the freeze response after fear conditioning, whereas the occurrence of spatial memory including Morris Water Maze and radial arm maze remained unchanged. The enhanced freezing behavior and normal spatial memory of the Atf3 knockout mice resembles the fear response and numbing symptoms often exhibited by patients affected with posttraumatic stress disorder. Additionally, we determined that after fear conditioning, dendritic spine density was increased, and expression of Gelsolin, the gene encoding a severing protein for actin polymerization, was down-regulated in the bilateral hippocampi of the Atf3 knockout mice. Taken together, our results suggest that ATF3 may suppress fear memory formation in mice directly or indirectly through mechanisms involving modulation of actin polymerization. PMID- 29515367 TI - Cohesive Regulation of Neural Progenitor Development by microRNA miR-26, Its Host Gene Ctdsp and Target Gene Emx2 in the Mouse Embryonic Cerebral Cortex. AB - Proper proliferation and differentiation of neural progenitors (NPs) in the developing cerebral cortex are critical for normal brain formation and function. Emerging evidence has shown the importance of microRNAs (miRNAs) in regulating cortical development and the etiology of neurological disorders. Here we show that miR-26 is co-expressed with its host gene Ctdsp in the mouse embryonic cortex. We demonstrate that similar to its host gene Ctdsp2, miR-26 positively regulates proliferation of NPs through controlling the cell-cycle progression, by using miR-26 overexpression and sponge approaches. On the contrary, miR-26 target gene Emx2 limits expansion of cortical NPs, and promotes transcription of miR-26 host gene Ctdsp. Our study suggests that miR-26, its target Emx2 and its host gene Ctdsp cohesively regulate proliferation of NPs during the mouse cortical development. PMID- 29515369 TI - Mapping of Human FOXP2 Enhancers Reveals Complex Regulation. AB - Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators - FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders. PMID- 29515368 TI - CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice. AB - Alcohol exposure can affect brain development, leading to long-lasting behavioral problems, including cognitive impairment, which together is defined as fetal alcohol spectrum disorder (FASD). However, the fundamental mechanisms through which this occurs are largely unknown. In this study, we report that the exposure of postnatal day 7 (P7) mice to ethanol activates caspase-3 via cannabinoid receptor type-1 (CB1R) in neonatal mice and causes a reduction in methylated DNA binding protein (MeCP2) levels. The developmental expression of MeCP2 in mice is closely correlated with synaptogenesis and neuronal maturation. It was shown that ethanol treatment of P7 mice enhanced Mecp2 mRNA levels but reduced protein levels. The genetic deletion of CB1R prevented, and administration of a CB1R antagonist before ethanol treatment of P7 mice inhibited caspase-3 activation. Additionally, it reversed the loss of MeCP2 protein, cAMP response element binding protein (CREB) activation, and activity-regulated cytoskeleton-associated protein (Arc) expression. The inhibition of caspase-3 activity prior to ethanol administration prevented ethanol-induced loss of MeCP2, CREB activation, epigenetic regulation of Arc expression, long-term potentiation (LTP), spatial memory deficits and activity-dependent impairment of several signaling molecules, including MeCP2, in adult mice. Collectively, these results reveal that the ethanol-induced CB1R-mediated activation of caspase-3 degrades the MeCP2 protein in the P7 mouse brain and causes long-lasting neurobehavioral deficits in adult mice. This CB1R-mediated instability of MeCP2 during active synaptic maturation may disrupt synaptic circuit maturation and lead to neurobehavioral abnormalities, as observed in this animal model of FASD. PMID- 29515371 TI - Control of the Nucleotide Cycle in Photoreceptor Cell Extracts by Retinal Degeneration Protein 3. AB - Retinal degeneration protein 3 (RD3) is crucial for photoreceptor cell survival and linked to Leber Congenital Amaurosis type 12 (LCA12), a hereditary retinal disease in humans. RD3 inhibits photoreceptor guanylate cyclases GC-E and GC-F and is involved in transport of GCs from the inner to the outer segments. Otherwise, its role in photoreceptor physiology is poorly understood. Here, we describe a new function of RD3. Purified RD3 evoked an increase in guanylate kinase activity, an enzyme that is involved in the nucleotide cycle in photoreceptors. We demonstrate a direct interaction between guanylate kinase and RD3 using back-scattering interferometry and show by immunohistochemistry of mouse retina sections that RD3 and guanylate kinase co-localize in photoreceptor inner segments and to a lesser extent in the outer plexiform layer. Our findings point toward a more complex function of RD3 in photoreceptors. The RD3 - guanylate kinase interaction may also play a role in other cellular systems, while the GC - RD3 interaction is exclusive to photoreceptors. PMID- 29515370 TI - Revisit the Candidacy of Brain Cell Types as the Cell(s) of Origin for Human High Grade Glioma. AB - High-grade glioma, particularly, glioblastoma, is the most aggressive cancer of the central nervous system (CNS) in adults. Due to its heterogeneous nature, glioblastoma almost inevitably relapses after surgical resection and radio /chemotherapy, and is thus highly lethal and associated with a dismal prognosis. Identifying the cell of origin has been considered an important aspect in understanding tumor heterogeneity, thereby holding great promise in designing novel therapeutic strategies for glioblastoma. Taking advantage of genetic lineage-tracing techniques, performed mainly on genetically engineered mouse models (GEMMs), multiple cell types in the CNS have been suggested as potential cells of origin for glioblastoma, among which adult neural stem cells (NSCs) and oligodendrocyte precursor cells (OPCs) are the major candidates. However, it remains highly debated whether these cell types are equally capable of transforming in patients, given that in the human brain, some cell types divide so slowly, therefore may never have a chance to transform. With the recent advances in studying adult NSCs and OPCs, particularly from the perspective of comparative biology, we now realize that notable differences exist among mammalian species. These differences have critical impacts on shaping our understanding of the cell of origin of glioma in humans. In this perspective, we update the current progress in this field and clarify some misconceptions with inputs from important findings about the biology of adult NSCs and OPCs. We propose to re-evaluate the cellular origin candidacy of these cells, with an emphasis on comparative studies between animal models and humans. PMID- 29515372 TI - Glial Tissue Mechanics and Mechanosensing by Glial Cells. AB - Understanding the mechanical behavior of human brain is critical to interpret the role of physical stimuli in both normal and pathological processes that occur in CNS tissue, such as development, inflammation, neurodegeneration, aging, and most common brain tumors. Despite clear evidence that mechanical cues influence both normal and transformed brain tissue activity as well as normal and transformed brain cell behavior, little is known about the links between mechanical signals and their biochemical and medical consequences. A multi-level approach from whole organ rheology to single cell mechanics is needed to understand the physical aspects of human brain function and its pathologies. This review summarizes the latest achievements in the field. PMID- 29515373 TI - Activation of Astrocytes and Microglial Cells and CCL2/CCR2 Upregulation in the Dorsolateral and Ventrolateral Nuclei of Periaqueductal Gray and Rostral Ventromedial Medulla Following Different Types of Sciatic Nerve Injury. AB - Peripheral nerve injuries (PNIs) may result in cellular and molecular changes in supraspinal structures possibly involved in neuropathic pain (NPP) maintenance. Activated glial cells in specific supraspinal subregions may affect the facilitatory role of descending pathways. Sterile chronic compression injury (sCCI) and complete sciatic nerve transection (CSNT) in rats were used as NPP models to study the activation of glial cells in the subregions of periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Molecular markers for activated astrocytes (glial fibrillary acidic protein, GFAP) and microglial cells (OX42) were assessed by quantitative immunohistochemistry and western blotting. The cellular distribution of CCL2/CCR2 was monitored using immunofluorescence. sCCI induced both mechanical and thermal hypersensitivity from day 1 up to 3 weeks post-injury. Unilateral sCCI or CSNT for 3 weeks induced significant activation of astrocytes bilaterally in both dorsolateral (dlPAG) and ventrolateral PAG (vlPAG) compared to naive or sham-operated rats. More extensive astrocyte activation by CSNT compared to sCCI was induced bilaterally in dlPAG and ipsilaterally in vlPAG. Significantly more extensive activation of astrocytes was also found in RVM after CSNT than sCCI. The CD11b immunopositive region, indicating activated microglial cells, was remarkably larger in dlPAG and vlPAG of both sides from sCCI- and CSNT-operated rats compared to naive or sham operated controls. No significant differences in microglial activation were detected in dlPAG or vlPAG after CSNT compared to sCCI. Both nerve injury models induced no significant differences in microglial activation in the RVM. Neurons and activated GFAP+ astrocytes displayed CCL2-immunoreaction, while activated OX42+ microglial cells were CCR2-immunopositive in both PAG and RVM after sCCI and CSNT. Overall, while CSNT induced robust astrogliosis in both PAG and RVM, microglial cell activation was similar in the supraspinal structures in both injury nerve models. Activated astrocytes in PAG and RVM may sustain facilitation of the descending system maintaining NPP, while microglial activation may be associated with a reaction to long-lasting peripheral injury. Microglial activation via CCR2 may be due to neuronal and astrocytal release of CCL2 in PAG and RVM following injury. PMID- 29515374 TI - TRPV6, TRPM6 and TRPM7 Do Not Contribute to Hair-Cell Mechanotransduction. AB - Hair cells of the inner ear transduce mechanical stimuli like sound or head movements into electrical signals, which are propagated to the central nervous system. The hair-cell mechanotransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6 and TRPM7, were necessary for transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in transduction. Using a cysteine substitution knock-in mouse line and methanethiosulfonate (MTS) reagents selective for this allele, we found that inhibition of TRPV6 had no effect on transduction in mouse cochlear hair cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic cells, which suggested they might be part of the transduction complex. Cochlear hair cell transduction was not affected by manipulations of Mg2+, however, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in transduction, we showed that deletion of either or both of their genes selectively in hair cells had no effect on auditory function. We suggest that TRPV6, TRPM6 and TRPM7 are unlikely to be the pore-forming subunit of the hair-cell transduction channel. PMID- 29515375 TI - Cell Behaviors during Closure of the Choroid Fissure in the Developing Eye. AB - Coloboma is a defect in the morphogenesis of the eye that is a consequence of failure of choroid fissure fusion. It is among the most common congenital defects in humans and can significantly impact vision. However, very little is known about the cellular mechanisms that regulate choroid fissure closure. Using high resolution confocal imaging of the zebrafish optic cup, we find that apico-basal polarity is re-modeled in cells lining the fissure in proximal to distal and inner to outer gradients during fusion. This process is accompanied by cell proliferation, displacement of vasculature, and contact between cells lining the choroid fissure and periocular mesenchyme (POM). To investigate the role of POM cells in closure of the fissure, we transplanted optic vesicles onto the yolk, allowing them to develop in a situation where they are depleted of POM. The choroid fissure forms normally in ectopic eyes but fusion fails in this condition, despite timely apposition of the nasal and temporal lips of the retina. This study resolves some of the cell behaviors underlying choroid fissure fusion and supports a role for POM in choroid fissure fusion. PMID- 29515376 TI - Cerebral Artery Diameter in Inbred Mice Varies as a Function of Strain. AB - Many strains of mice are utilized in mouse models of cerebrovascular diseases. Variations in vascular anatomy between these strains has been documented and may influence the phenotype in stroke models. To address inter-strain variations in the circle of Willis anatomy, the diameters of internal carotid, posterior communicating, anterior cerebral, and middle cerebral arteries in 144 mice from 32 inbred strains were measured. Arterial diameters were analyzed as a function of animal weight, age, and strain. Variations in the structure of the circle of Willis across strains were observed and noted. While right-sided anterior cerebral arteries were significantly greater in diameter than their left-sided counterparts across most strains, variations in arterial diameter are strain specific. Adult mouse weight was not found to be associated with arterial diameter across strains, suggesting that cerebral artery size is associated with strain independently of weight. This study demonstrates strain dependent variations in the murine circle of Willis, which should be taken into consideration when studying mouse models of cerebrovascular diseases. PMID- 29515377 TI - Whisker and Nose Tactile Sense Guide Rat Behavior in a Skilled Reaching Task. AB - Skilled reaching is a complex movement in which a forelimb is extended to grasp food for eating. Video-recordings analysis of control rats enables us to distinguish several components of skilled reaching: Orient, approaching the front wall of the reaching box and poking the nose into the slot to locate the food pellet; Transport, advancing the forelimb through the slot to reach-grasp the pellet; and Withdrawal of the grasped food to eat. Although food location and skilled reaching is guided by olfaction, the importance of whisker/nose tactile sense in rats suggests that this too could play a role in reaching behavior. To test this hypothesis, we studied skilled reaching in rats trained in a single pellet reaching task before and after bilateral whisker trimming and bilateral infraorbital nerve (ION) severing. During the task, bilaterally trimmed rats showed impaired Orient with respect to controls. Specifically, they detected the presence of the wall by hitting it with their nose (rather than their whiskers), and then located the slot through repetitive nose touches. The number of nose touches preceding poking was significantly higher in comparison to controls. On the other hand, macrovibrissae trimming resulted in no change in reaching/grasping or withdrawal components of skilled reaching. Bilaterally ION severed rats, displayed a marked change in the structure of their skilled reaching. With respect to controls, in ION-severed rats: (a) approaches to the front wall were significantly reduced at 3-5 and 6-8 days; (b) nose pokes were significantly reduced at 3-5 days, and the slot was only located after many repetitive nose touches; (c) the reaching-grasping-retracting movement never appeared at 3-5 days; (d) explorative paw movements, equal to zero in controls, reached significance at 9-11 days; and (e) the restored reaching-grasping retracting sequence was globally slower than in controls, but the success rate was the same. These findings strongly indicate that whisker trimming affected Orient, but not the reaching-grasping movement, while ION severing impaired both Orient (persistently) and reaching-grasping-retracting (transiently, for 1-2 weeks) components of skilled reaching in rats. PMID- 29515379 TI - The Human Anger Face Likely Carries a Dual-Signaling Function. PMID- 29515378 TI - Impaired Object Recognition but Normal Social Behavior and Ultrasonic Communication in Cofilin1 Mutant Mice. AB - Autism spectrum disorder (ASD), schizophrenia (SCZ) and intellectual disability (ID) show a remarkable overlap in symptoms, including impairments in cognition, social behavior and communication. Human genetic studies revealed an enrichment of mutations in actin-related genes for these disorders, and some of the strongest candidate genes control actin dynamics. These findings led to the hypotheses: (i) that ASD, SCZ and ID share common disease mechanisms; and (ii) that, at least in a subgroup of affected individuals, defects in the actin cytoskeleton cause or contribute to their pathologies. Cofilin1 emerged as a key regulator of actin dynamics and we previously demonstrated its critical role for synaptic plasticity and associative learning. Notably, recent studies revealed an over-activation of cofilin1 in mutant mice displaying ASD- or SCZ-like behavioral phenotypes, suggesting that dysregulated cofilin1-dependent actin dynamics contribute to their behavioral abnormalities, such as deficits in social behavior. These findings let us hypothesize: (i) that, apart from cognitive impairments, cofilin1 mutants display additional behavioral deficits with relevance to ASD or SCZ; and (ii) that our cofilin1 mutants represent a valuable tool to study the underlying disease mechanisms. To test our hypotheses, we compared social behavior and ultrasonic communication of juvenile mutants to control littermates, and we did not obtain evidence for impaired direct reciprocal social interaction, social approach or social memory. Moreover, concomitant emission of ultrasonic vocalizations was not affected and time-locked to social activity, supporting the notion that ultrasonic vocalizations serve a pro-social communicative function as social contact calls maintaining social proximity. Finally, cofilin1 mutants did not display abnormal repetitive behaviors. Instead, they performed weaker in novel object recognition, thereby demonstrating that cofilin1 is relevant not only for associative learning, but also for "non-matching-to-sample" learning. Here we report the absence of an ASD- or a SCZ-like phenotype in cofilin1 mutants, and we conclude that cofilin1 is relevant specifically for non-social cognition. PMID- 29515380 TI - Prestigious Science Journals Struggle to Reach Even Average Reliability. AB - In which journal a scientist publishes is considered one of the most crucial factors determining their career. The underlying common assumption is that only the best scientists manage to publish in a highly selective tier of the most prestigious journals. However, data from several lines of evidence suggest that the methodological quality of scientific experiments does not increase with increasing rank of the journal. On the contrary, an accumulating body of evidence suggests the inverse: methodological quality and, consequently, reliability of published research works in several fields may be decreasing with increasing journal rank. The data supporting these conclusions circumvent confounding factors such as increased readership and scrutiny for these journals, focusing instead on quantifiable indicators of methodological soundness in the published literature, relying on, in part, semi-automated data extraction from often thousands of publications at a time. With the accumulating evidence over the last decade grew the realization that the very existence of scholarly journals, due to their inherent hierarchy, constitutes one of the major threats to publicly funded science: hiring, promoting and funding scientists who publish unreliable science eventually erodes public trust in science. PMID- 29515381 TI - Distinguishing Anesthetized from Awake State in Patients: A New Approach Using One Second Segments of Raw EEG. AB - Objective: The objective of this study was to test whether properties of 1-s segments of spontaneous scalp EEG activity can be used to automatically distinguish the awake state from the anesthetized state in patients undergoing general propofol anesthesia. Methods: Twenty five channel EEG was recorded from 10 patients undergoing general intravenous propofol anesthesia with remifentanil during anterior cervical discectomy and fusion. From this, we extracted properties of the EEG by applying the Directed Transfer Function (DTF) directly to every 1-s segment of the raw EEG signal. The extracted properties were used to develop a data-driven classification algorithm to categorize patients as "anesthetized" or "awake" for every 1-s segment of raw EEG. Results: The properties of the EEG signal were significantly different in the awake and anesthetized states for at least 8 of the 25 channels (p < 0.05, Bonferroni corrected Wilcoxon rank-sum tests). Using these differences, our algorithms achieved classification accuracies of 95.9%. Conclusion: Properties of the DTF calculated from 1-s segments of raw EEG can be used to reliably classify whether the patients undergoing general anesthesia with propofol and remifentanil were awake or anesthetized. Significance: This method may be useful for developing automatic real-time monitors of anesthesia. PMID- 29515382 TI - Spatial Arrangement and Set Size Influence the Coding of Non-symbolic Quantities in the Intraparietal Sulcus. AB - Performance in visual quantification tasks shows two characteristic patterns as a function of set size. A precise subitizing process for small sets (up to four) was contrasted with an approximate estimation process for larger sets. The spatial arrangement of elements in a set also influences visual quantification performance, with frequently perceived arrangements (e.g., dice patterns) being faster enumerated than random arrangements. Neuropsychological and imaging studies identified the intraparietal sulcus (IPS), as key brain area for quantification, both within and above the subitizing range. However, it is not yet clear if and how set size and spatial arrangement of elements in a set modulate IPS activity during quantification. In an fMRI study, participants enumerated briefly presented dot patterns with random, canonical or dice arrangement within and above the subitizing range. We evaluated how activity amplitude and pattern in the IPS were influenced by size and spatial arrangement of a set. We found a discontinuity in the amplitude of IPS response between subitizing and estimation range, with steep activity increase for sets exceeding four elements. In the estimation range, random dot arrangements elicited stronger IPS response than canonical arrangements which in turn elicited stronger response than dice arrangements. Furthermore, IPS activity patterns differed systematically between arrangements. We found a signature in the IPS response for a transition between subitizing and estimation processes during quantification. Differences in amplitude and pattern of IPS activity for different spatial arrangements indicated a more precise representation of non-symbolic numerical magnitude for dice and canonical than for random arrangements. These findings challenge the idea of an abstract coding of numerosity in the IPS even within a single notation. PMID- 29515383 TI - Functional Dissociation of Latency-Variable, Stimulus- and Response-Locked Target P3 Sub-components in Task-Switching. AB - Cognitive control warrants efficient task performance in dynamic and changing environments through adjustments in executive attention, stimulus and response selection. The well-known P300 component of the human event-related potential (ERP) has long been proposed to index "context-updating"-critical for cognitive control-in simple target detection tasks. However, task switching ERP studies have revealed both target P3 (300-350 ms) and later sustained P3-like potentials (400-1,200 ms) to first targets ensuing transition cues, although it remains unclear whether these target P3-like potentials also reflect context updating operations. To address this question, we applied novel single-trial EEG analyses residue iteration decomposition (RIDE)-in order to disentangle target P3 sub components in a sample of 22 young adults while they either repeated or switched (updated) task rules. The rationale was to revise the context updating hypothesis of P300 elicitation in the light of new evidence suggesting that "the context" consists of not only the sensory units of stimulation, but also associated motor units, and intermediate low- and high-order sensorimotor units, all of which may need to be dynamically updated on a trial by trial basis. The results showed functionally distinct target P3-like potentials in stimulus-locked, response locked, and intermediate RIDE component clusters overlying parietal and frontal regions, implying multiple functionally distinct, though temporarily overlapping context updating operations. These findings support a reformulated version of the context updating hypothesis, and reveal a rich family of distinct target P3-like sub-components during the reactive control of target detection in task-switching, plausibly indexing the complex and dynamic workings of frontoparietal cortical networks subserving cognitive control. PMID- 29515384 TI - The Lateral Prefrontal Cortex and Selection/Inhibition in ADHD. AB - A previous paper from our lab (Shalom, 2009) presented evidence that the medial part of the prefrontal cortex is involved in the integration of raw, unintegrated information into coherent, wholistic mental representations such as perceptual objects, episodic memories, emotional states, and motor actions. It has used this analysis to classify some challenges encountered by people with Autism Spectrum Disorders, linking different types of difficulties in integration with different subareas of the medial prefrontal cortex. The current paper performs a similar analysis for the corresponding subareas of the lateral prefrontal cortex. It presents evidence that the lateral part of the prefrontal cortex is involved in the selection/inhibition of perceptual, memory, emotion, and motor aspects of processing. It then uses this analysis to classify challenges encountered by people with ADHD, linking different types of difficulties in selection/inhibition to different subareas of the lateral prefrontal cortex. PMID- 29515385 TI - Disturbed Experience of Time in Depression-Evidence from Content Analysis. AB - Disturbances in the experience of time have been a commonly reported feature of depressive disorders since the beginning of modern psychiatry and psychological research. However, qualitative research approaches to investigate the phenomenon are rarely used. We employed content analysis to investigate disturbances of time experience in Major Depressive Disorder. Our analysis from 25 participants showed that individuals with Major Depressive Disorder subjectively seem to have lost the ability to influence or change the present, resulting in an impersonal and blocked future. The present is rendered meaningless, the past unchangeably negative, and the passage of time turned into a dragging, inexorable, and viscous continuance. The overall,-possibly intersubjective-concept of time experience, remains largely intact, causing or adding to depressive mood and suffering. We elaborate on how these findings reflect previous theories on the experience of time in depression. This study might encourage future inquiries into both the phenomenal and neuroscientific foundation of time experience under psychopathological conditions. PMID- 29515386 TI - Low-Latency Line Tracking Using Event-Based Dynamic Vision Sensors. AB - In order to safely navigate and orient in their local surroundings autonomous systems need to rapidly extract and persistently track visual features from the environment. While there are many algorithms tackling those tasks for traditional frame-based cameras, these have to deal with the fact that conventional cameras sample their environment with a fixed frequency. Most prominently, the same features have to be found in consecutive frames and corresponding features then need to be matched using elaborate techniques as any information between the two frames is lost. We introduce a novel method to detect and track line structures in data streams of event-based silicon retinae [also known as dynamic vision sensors (DVS)]. In contrast to conventional cameras, these biologically inspired sensors generate a quasicontinuous stream of vision information analogous to the information stream created by the ganglion cells in mammal retinae. All pixels of DVS operate asynchronously without a periodic sampling rate and emit a so-called DVS address event as soon as they perceive a luminance change exceeding an adjustable threshold. We use the high temporal resolution achieved by the DVS to track features continuously through time instead of only at fixed points in time. The focus of this work lies on tracking lines in a mostly static environment which is observed by a moving camera, a typical setting in mobile robotics. Since DVS events are mostly generated at object boundaries and edges which in man-made environments often form lines they were chosen as feature to track. Our method is based on detecting planes of DVS address events in x-y-t-space and tracing these planes through time. It is robust against noise and runs in real time on a standard computer, hence it is suitable for low latency robotics. The efficacy and performance are evaluated on real-world data sets which show artificial structures in an office-building using event data for tracking and frame data for ground-truth estimation from a DAVIS240C sensor. PMID- 29515387 TI - A Case of Erythema Multiforme Major Developed after Sequential Use of Two Immune Checkpoint Inhibitors, Nivolumab and Ipilimumab, for Advanced Melanoma: Possible Implication of Synergistic and/or Complementary Immunomodulatory Effects. AB - Immune checkpoint inhibitors, such as ipilimumab and nivolumab, reverse the imbalance of antitumor self-tolerance and enhance T-cell responses. Currently, ipilimumab and nivolumab have a reported therapeutic impact on unresectable or metastatic melanomas; however, they also induce immune-related adverse events (irAEs). Ipilimumab-induced cutaneous irAEs are mostly low grade and manageable, although all-grade rash may occur in approximately 45% of all patients. We here report the case of a young woman with erythema multiforme major, which developed after sequential use of these 2 immune checkpoint inhibitors for advanced melanoma of the scalp. Initially, she received 12 cycles of nivolumab monotherapy followed by ipilimumab. A week later, multiple erythematous papulo-erythemas appeared on almost her entire body, with high-grade fever, mucosal involvements, and dyspnea. Immunohistochemistry using the lesioned skin revealed lymphocytic infiltration predominantly positive for CD8, contrasting with those for CD4 and Foxp3. Ipilimumab was stopped but she continued to receive empirical antibiotics; additionally, she was treated with intravenous steroid pulse therapy and immunoglobulin, followed by oral prednisolone. Her symptoms subsided rapidly, allowing a restart of nivolumab monotherapy alone. In our case, the long-standing preceding nivolumab monotherapy may synergistically and/or complementary have contributed to - in combination with the later administration of ipilimumab - recover antigen-responsive T-cell immunity, which is similar to the concept of immune reconstitution inflammatory syndrome, resulting in the establishment of an underlying immunopathology of erythema multiforme and life-threatening airway obstruction. PMID- 29515388 TI - Acute Erythroderma in a Patient Receiving TNF-alpha-Blocking Therapy for Hidradenitis Suppurativa. AB - Tumor necrosis factor-alpha (TNF-alpha) normally binds to TNF-alpha receptors, leading to the inflammatory response of autoimmune diseases. Adalimumab is a TNF inhibiting, anti-inflammatory, biological medication which binds to TNF-alpha, thus reducing this inflammatory response. The use of TNF-alpha-inhibiting medication, such as adalimumab, being the first FDA-approved treatment for hidradenitis suppurativa, has drastically changed the management of dermatological diseases. One rarely reported manifestation that occurs as a side effect associated with the use of TNF-alpha-blocking agents is erythroderma. This study, for the first time, reports the case of a patient suffering from hidradenitis suppurativa with concomitant psoriasis, who developed a severe and acute erythrodermic rash after the start of adalimumab therapy. PMID- 29515389 TI - Sarcomatoid Tumor following Radium Treatment. AB - Haemangiomas are benign skin lesions that usually regress spontaneously, but radiotherapy has previously been used to assist the regression and healing of the lesions. Radium and X-rays were used as a treatment for benign skin lesions such as haemangioma until the carcinogenic effect of ionising radiation in humans was described. We report a patient diagnosed with a sarcomatoid carcinoma. Her past history was of particular interest since she had received radium treatment for a haemangioma at the same location more than 70 years before. PMID- 29515390 TI - Non-Melanoma Skin Cancers at Sites of Previous Frostbite: Case Report and Review. AB - The association between ultraviolet radiation exposure and skin cancer is well established. Limited studies have reported an association between frostbite and the development of non-melanoma skin cancer but evidence for a proven link is insufficient and possible carcinogenic mechanisms have not been fully explored. In this report, 3 cases of non-melanoma skin cancer (1 case of basal cell carcinoma and 2 cases of squamous cell carcinoma of the skin) which developed at a site of previous frostbite caused by exposure to extremely cold temperatures in Astana, the capital city of Kazakhstan, are described. PMID- 29515391 TI - Giant Congenital Melanocytic Nevi: An Update and Emerging Therapies. AB - Giant congenital melanocytic nevi (GCMN) are a rare occurrence. Gain-of-function mutation in the NRAS gene is found to be associated with GCMN, causing abnormal proliferation of embryonic melanoblasts. The two major complications associated with GCMN are malignant melanoma and neurocutaneous melanosis. Treatment of GCMN has conventionally been surgical. However, the role of NRAS inhibitors and inactivation of nevus tissue by high hydrostatic pressure are being explored. We present a case of a 1-day-old neonate born with GCMN, along with a review of the literature. PMID- 29515392 TI - Large-Cell Transformed Mycosis Fungoides Coexisting with Mycosis Fungoides Bullosa: A Case Report and Review of the Literature. AB - Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. Both large-cell transformed mycosis fungoides and mycosis fungoides bullosa are rare presentations and predict unfavorable prognosis. We report the case of a 61-year old woman who presented with generalized erythematous scaly annular plaques, and histopathology confirmed the diagnosis of mycosis fungoides. She was treated with various conventional therapies but only achieved partial response and always relapsed after discontinuation of treatment. Her last treatment was combined chemotherapy (CHOP regimen) followed by romidepsin. However, 1 month after the last cycle of romidepsin, she developed multiple ulcerative masses and nodules. Skin biopsy was compatible with CD30+ large cell transformation, and she was treated with a new combination of chemotherapy (ifosfamide, carboplatin, etoposide). One day after receiving chemotherapy, multiple tense bullae on normal appearing skin and mycosis fungoid plaques erupted. A histological study demonstrated subepidermal blistering with epidermotropism of atypical lymphocytes. Direct immunofluorescence study was negative. The results confirmed the diagnosis of mycosis fungoides bullosa. We present the first reported case of large-cell transformed mycosis fungoides coexisting with mycosis fungoides bullosa. PMID- 29515393 TI - Incidental Treatment of a Subclinical Chronic Tension-Type Headache by Cosmetic Use of Botulinum Toxin A: A Case Report. AB - Background: Headache is a common disorder of the nervous system; chronic headache in particular may affect quality of life negatively. The pathophysiology is multifactorial and not completely elucidated. Studies have demonstrated the beneficial effects of botulinum toxin A on chronic migraine headaches, but failed to show the same effect on chronic tension-type headaches. Methods: We present the case of a 32-year-old woman who after receiving cosmetic injections with botulinum toxin A for fine lines of the forehead experienced relief of subclinical tension-type headaches. Conclusions: Although the effect of botulinum toxin A on chronic tension-type headaches is limited, several studies demonstrate its pain-modulating effects, and as such it is worth paying attention to this potential beneficial effect when performing cosmetic injections with botulinum toxin A. PMID- 29515394 TI - Successful Resection of G719X-Positive Pleomorphic Carcinoma after Afatinib Treatment. AB - We report a case of pleomorphic carcinoma with exon 18 mutation (G719X) of the epidermal growth factor receptor (EGFR), which showed good response to afatinib and resulted in successful resection. To our knowledge, this is the first report on the use of afatinib for pleomorphic carcinoma followed by the surgical resection. The patient was a 59-year-old woman, who visited our hospital because chest computed tomography showed a 28 * 28-mm nodule in the left upper lobe. Bronchoscopy was performed and the histological findings of transbronchial biopsy revealed adenosquamous carcinoma positive for G719X mutation in exon 18 of the EGFR. Since fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography revealed a positive accumulation in the bilateral hilar and mediastinal lymph nodes, the disease was diagnosed as cT1bN3M0, stage IIIB. After 3 months of afatinib therapy, FDG accumulation in primary tumor was almost gone. However, FDG accumulation in lymph nodes remained unchanged. Video-assisted thoracic surgery was planned for further diagnostic information and left upper lobectomy with mediastinal lymph node dissection was performed. The resected tumor included adenocarcinoma, squamous cell carcinoma, and spindle cell components, without lymph node metastasis. Thus, the disease was diagnosed as pleomorphic carcinoma (pT2aN0M0, stage IB). All components in the resected specimen had the same G719X mutation in exon 18 of the EGFR. The patient has shown no signs of recurrence at 1 year after the operation. The present case indicates the possibility of minor EGFR mutations in pleomorphic carcinoma and successful outcome by the use of afatinib and surgical resection. PMID- 29515395 TI - Synchronous Primary Renal Cell Carcinoma and Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. AB - Synchronous primary cancers involving the pancreas and kidney are extremely rare and poorly documented. We report the first case of this association treated with chemotherapy and tyrosine kinase inhibitor. A 70-year-old woman presented with a 2-month history of epigastric pain with weight loss of 12 kg. Two weeks previously, she had presented with jaundice and pelvic pain. A computed tomography (CT) scan of the body revealed the presence of an irregular mass in the body of the pancreas, encasing the celiac trunk, with dilatation of the biliary tract. CT also revealed a heterogeneously right renal mass with bone metastasis in the left acetabular cup and the left iliac wing. A biliary metallic prosthesis was performed with a pancreatic mass biopsy. Histology revealed a moderately differentiated pancreatic ductal adenocarcinoma. Another biopsy was performed in the right iliac wing. Pathological examination with immunohistochemistry confirmed the diagnosis of bone metastasis from clear cell renal cell carcinoma. The patient was treated with a combination of gemcitabine, sunitinib, and denosumab. She had a stabilization disease and a prolonged progression-free survival of 9 months. Side effects were manageable and included grade 2 fatigue and grade 2 hypertension. The patient died at 13 months from diagnosis after disease progression. This report suggests that the appropriate treatment for this association in metastatic or unresectable disease is chemotherapy for pancreatic cancer and tyrosine kinase inhibitor for kidney cancer. We also review the appropriate literature concerning that association. PMID- 29515396 TI - Metastatic Urothelial Carcinoma with Glandular Differentiation That Confirmed the Response by Autopsy Specimen to Second-Line mFOLFOX6 (Fluorouracil, Oxaliplatin, and Leucovorin) plus Bevacizumab Chemotherapy. AB - The prognostic significance of glandular differentiation in urothelial carcinoma (UC) is controversial, and thus far there is no established treatment strategy against metastasis of glandular component. We describe here a case of metastatic UC with glandular differentiation that had histological disappearance of adenocarcinoma components at autopsy after sequential chemotherapy with S-1 and cisplatin (CDDP) and with mFOLFOX6 (fluorouracil, oxaliplatin, and leucovorin) plus bevacizumab (mFOLFOX6+Bev). A 62-year-old Asian male was diagnosed with invasive UC with glandular differentiation (T2N0M0) by radical cystectomy and ileal conduit, and careful follow-up observation was made. Eight years after radical operation, peritoneal metastases occurred, and a biopsy specimen using colon fiber revealed high-grade adenocarcinomas with an immunohistochemical profile that included positivity for cytokeratin 7 (CK7) and negativity for cytokeratin 20 (CK20) and uroplakin, which was identical to the radical cystectomy specimen. Thus, he received combination chemotherapy consisting of S-1 and CDDP; however, the peritoneal metastasis worsened after 2 cycles. Therefore, second-line mFOLFOX6+Bev chemotherapy was performed for a total of 5 courses. In spite of this, the patient died, and the final diagnosis by autopsy was multiple metastases of infiltrating pure UC to the lung, bone, and peritoneum. Interestingly, there were no pathological findings of adenocarcinoma, and the immunohistochemical profile of the metastatic lesions was identical to that of the previous specimens from the bladder and colon. This suggests that sequential chemotherapy of S-1 and CDDP and second-line mFOLFOX6+Bev might be a feasible option in metastatic UC with glandular differentiation. PMID- 29515398 TI - Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. AB - Background: Pembrolizumab is a humanized monoclonal antibody which serves to enhance the antitumor immune response by targeting programmed cell death 1 receptor. The use of pembrolizumab plus carboplatin/pemetrexed combination therapy results in improvement in overall survival and progression-free survival rates for non-small cell lung cancer (NSCLC) patients as compared to chemotherapy alone. However, numerous immune-mediated toxicities of pembrolizumab have been reported. Case Presentation: We report the case of a 74-year-old male patient diagnosed with stage IIIA programmed death-ligand 1-positive non-small cell lung adenocarcinoma treated with 4 cycles of carboplatin/pemetrexed plus pembrolizumab combination therapy followed by 2 cycles of pembrolizumab treatment. Follow-up PET-CT scanning showed a very good response at the level of the tumor but new onset activity in bilateral hilar and mediastinal lymph nodes. Biopsy of these lymph nodes revealed a benign pathology with noncaseating granulomas consistent with immune-mediated sarcoidosis. Conclusion: The pathogenesis of immunotherapy induced sarcoidosis is not yet known but has been reported in different cancers and using different checkpoint inhibitors. To our knowledge, this case is the first in the literature displaying pulmonary sarcoidosis in a patient with NSCLC 4 months after having initiated chemotherapy plus pembrolizumab combination therapy. PMID- 29515397 TI - A Case of Lung Adenocarcinoma with Marked Improvement of Pulmonary Lymphangitic Carcinomatosis by Adding Bevacizumab to Cisplatin and Pemetrexed. AB - A 40-year-old man with a diagnosis of lung adenocarcinoma (cT4N3M1c, stage IVB) experienced worsening of lymphangitic carcinomatosis in the right lung and right pleural effusion after receiving 1 cycle of first-line chemotherapy consisting of cisplatin and pemetrexed. Bevacizumab was thus added from the second cycle of the cisplatin-pemetrexed regimen, leading to a marked improvement in pulmonary lymphangitic carcinomatosis and a decrease in pleural effusion. Subsequently, maintenance therapy consisting of pemetrexed and bevacizumab was continued, successfully leading to long-term progression-free survival. Generally, pulmonary lymphangitic carcinomatosis shows poor prognosis because of poor response to chemotherapy. However, recent studies have been elucidating the role of the vascular endothelial growth factor A (VEGF-A)/VEGF receptor-2 pathway in pulmonary lymphangitic carcinomatosis. Therefore, bevacizumab is expected to be beneficial in the treatment of this pathological condition. PMID- 29515399 TI - Multiple Tumor Induction after Treatment of Temporal Arteritis with Prednisone. AB - A 74-year-old female was diagnosed with the autoimmune inflammatory disease temporal arteritis and treated with high and low doses of prednisone over a period of 6 years. During that time, she developed cancers of the lung and colon as well as a soft tumor mass on lumbar vertebrate L3. She also experienced a series of debilitating and disabling symptoms while on prednisone treatment. A temporal analysis of the association of prednisone therapy and immune markers to the successive appearance of the malignant tumors strongly suggests that in the absence of a functioning natural immune and surveillance system by treatment with the immune knockout drug prednisone, spontaneous, multiple independent mutations occurred in several sites in the organ systems of this patient. Over a period of time, these developed into malignant cancers, including a lung nodule which became cancerous 256 days later, as well as the cancers of the colon and a soft tumor mass on lumbar vertebrate L3. PMID- 29515400 TI - Lactic Acidosis in Prostate Cancer: Consider the Warburg Effect. AB - Lactic acidosis is a commonly observed clinical condition that is associated with a poor prognosis, especially in malignancies. We describe a case of an 81-year old patient who presented with symptoms of tachypnea and general discomfort. Arterial blood gas analysis showed a high anion gap acidosis with a lactate level of 9.5 mmol/L with respiratory compensation. CT scanning showed no signs of pulmonary embolism or other causes of impaired tissue oxygenation. Despite treatment with sodium bicarbonate, the patient developed an adrenalin-resistant cardiac arrest, most likely caused by the acidosis. Autopsy revealed Gleason score 5 + 5 metastatic prostate cancer as the most probable cause of the lactic acidosis. Next-generation sequencing indicated a nonsense mutation in the TP53 gene (887delA) and an activating mutation in the PIK3CA gene (1634A>G) as candidate molecular drivers. This case demonstrates the prevalence and clinical relevance of metabolic reprogramming, frequently referred to as "the Warburg effect," in patients with prostate cancer. PMID- 29515401 TI - Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. AB - Simultaneous or sequential, planned administration of ipilimumab could significantly enhance the antitumor effects of nivolumab in advanced melanoma patients. On the other hand, the efficacy of ipilimumab for nivolumab-resistant advanced melanoma is extremely poor. Therefore, additional supportive therapy for anti-PD-1 antibody therapy-resistant advanced melanoma has been widely investigated. In this report, we describe a case of multiple in-transit melanomas developing in a nivolumab-resistant patient successfully treated with ipilimumab in combination with imiquimod. Our present case suggested a possible therapy for nivolumab-resistant multiple in-transit melanomas using ipilimumab in combination with topical imiquimod. PMID- 29515402 TI - Vesicoenteric Fistula Arising from an Adenocarcinoma of Ectopic Pancreatic Tissue in a Meckel Diverticulum. AB - We report a case of a vesicoenteric fistula arising from an adenocarcinoma of ectopic pancreatic tissue in a Meckel diverticulum in a 58-year-old man. The patient suffered from refractory micturition pain and increased urinary frequency. Computerized tomography with a contrast agent showed a ring-shaped enhanced mass near the dome of the urinary bladder. Magnetic resonance imaging showed a cystic mass close to the urinary bladder with partly irregular wall and fistula formation to the urinary bladder. Surgical findings showed a Meckel diverticulum in the ileum, which formed a fistula with the urinary bladder, and Meckel diverticulectomy and partial cystectomy were performed. Histological findings revealed a vesicoenteric fistula arising from a papillary adenocarcinoma of ectopic pancreatic tissue in a Meckel diverticulum. The patient has survived without recurrence for more than 4 years since surgery. PMID- 29515403 TI - A Patient with Advanced Gastric Cancer Who Achieved a Long-Term Prognosis by Early Diagnosis of Sister Mary Joseph's Nodule. AB - The patient was a 66-year-old woman. An induration of approximately 15 mm in size that accompanied redness was palpable in the umbilical fossa. She did not respond to 1-month antibiotic treatment provided by the previous physician. For this reason, a biopsy of the site was performed with the possibility of neoplastic disease in mind, resulting in the detection of adenocarcinoma. Subsequent detailed whole-body examination revealed advanced gastric cancer and peritoneal dissemination, and the induration in the umbilical fossa was diagnosed as a direct infiltration from the peritoneal dissemination. Metastasis or infiltration of malignant tumor to the umbilicus is called Sister Mary Joseph's nodule (SMJN), and considered as a sign of poor prognosis. However, this case was successfully treated and achieved a long-term prognosis by the early diagnosis of SMJN. In routine clinical practice, it is considered necessary to examine patients carefully, as not to overlook SMJN. PMID- 29515404 TI - Successful Treatment of Refractory Squamous Cell Cancer of the Head and Neck with Nivolumab and Ipilimumab. AB - Treatment options for patients with platinum-refractory, recurrent, metastatic head and neck squamous cell carcinoma (HNSCC) are limited, and prognosis is poor. Nivolumab (Opdivo) has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with recurrent or metastatic HNSCC who have disease progression on or after platinum-based therapy. Recently, in patients with metastatic malignant melanoma a significant improvement of outcome and response was achieved with the combination of ipilimumab (CTLA4 antibody) and the programmed death (PD)-1 inhibitor nivolumab compared with monotherapy. Based on these results, the combination of nivolumab and ipilimumab has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma. So far, there have been no data concerning the combination of nivolumab and ipilimumab in squamous cell head and neck cancer. We here present the case of a 46-year-old male with refractory squamous cell head and neck cancer, who was successfully treated with the PD-1 inhibitor nivolumab in combination with the anti-CTLA4 antibody ipilimumab. PMID- 29515405 TI - Metastatic Intimal Sarcoma of the Pulmonary Artery Sensitive to Carboplatin Vinorelbine Chemotherapy: Case Report and Literature Review. AB - Pulmonary artery intimal sarcoma (PAIS) is a very rare tumour with a very poor prognosis. In advanced stages, chemotherapy and radiotherapy are poorly efficient, and no standard chemotherapy guideline is currently available. Here, we report on a 37-year-old woman with PAIS initially treated with surgical resection who developed metastatic relapse refractory to anthracycline-based chemotherapy, then trabectedin, then pazopanib. The patient was then given carboplatin-vinorelbine chemotherapy. The treatment was well tolerated, and, rapidly, a CT scan showed an objective response that lasted 8 months despite the 4th therapeutic line. We review the literature and show that our case is the second one that provides evidence of the efficacy of platinum-vinorelbine regimens in this aggressive tumour. PMID- 29515406 TI - Successful Treatment of Erythrodermic Mycosis Fungoides with Mogamulizumab Followed by Etoposide Monotherapy. AB - Mogamulizumab induces cytotoxicity against CCR4+ lymphoma cells by antibody dependent cell-mediated cytotoxicity in advanced cutaneous T-cell lymphoma patients. Since the efficacy of mogamulizumab in mycosis fungoides (28.6%) is lower than that in Sezary syndrome (47.1%), reagents that enhance the antitumor immune response induced by mogamulizumab are needed to further optimize its use for the treatment of erythrodermic mycosis fungoides. In this report, we present a case of erythrodermic mycosis fungoides successfully treated with mogamulizumab followed by etoposide monotherapy. PMID- 29515407 TI - Tiny Obturator Node Metastasis from Prostate Cancer Not Shown by FDG-PET/CT, CT, or MRI Detected by 11C-Choline PET/CT. AB - We report a 65-year-old male with histopathologically proven prostate cancer and multiple pelvic node metastases using a robotic-assisted radical prostatectomy procedure plus extended pelvic lymph node dissection. Positron emission tomography (PET) scan findings demonstrated a moderate accumulation of 11C choline in a metastatic left obturator node sized 8 * 8 mm, though only a faint uptake of fluorodeoxyglucose (FDG) was noted. 11C-choline PET/computed tomography (CT) may be useful for the diagnosis of a tiny metastatic lymph node not demonstrated by CT, magnetic resonance imaging, or FDG-PET/CT and to determine the need for an extended pelvic lymph node dissection. PMID- 29515408 TI - Metastatic Small Cell Carcinoma of the Breast from Cancer of the Uterine Cervix: A Case Report. AB - We report here on a case of 51-year-old woman with metastatic small cell carcinoma of the breast that came from her cancer of the uterine cervix. She underwent radical hysterectomy with bilateral salpingo-oophorectomy due to small cell carcinoma of the uterine cervix, and adjuvant radiotherapy was administered to the pelvis. Breast metastasis with a palpable mass then occurred 3 months after the primary surgery. Simple mastectomy and adjuvant chemotherapy were performed. She initially showed a good response to the therapy, yet she ultimately died of multiple metastases with a fulminating disease course. This is an extremely rare case, and only 1 similar case has been reported earlier, so we report on this case along with a review of the relevant literature. PMID- 29515409 TI - Beneficial Treatment Management with Trifluridine/Tipiracil in a Patient with Metastatic Colorectal Cancer and Pronounced Hematological Event History during Previous Treatments. AB - Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival in patients with metastatic colorectal cancer (mCRC). The most common treatment related event (grade >=3) was hematological toxicity. We here report long-term disease-stabilizing FTD/TPI treatment of an mCRC patient (KRAS wild-type, ECOG performance status 1 at baseline and at the end of FTD/TPI therapy) with multifocal synchronous metastases and a longstanding history of extensive hematological events during previous treatments. Finally, this 62-year-old male patient was treated for 10 months with FTD/TPI by consecutive alteration of treatment parameters: (i) initial daily dose reduction to 80 mg (72% of the recommended dose), (ii) 20 days dose delay, (iii) a second and later third dose reduction to 70 mg and 60 mg (about 64% and 55%, respectively, of the recommended dose), and (iv) 30 ug per day of granulocyte colony-stimulating factor administration first for 3 days, and later for 5 days, for each treatment cycle. PMID- 29515410 TI - Successful Salvage Chemotherapy with Streptozocin in a Patient with Mediastinal Atypical Carcinoid Tumor Who Had Relapsed after Various Prior Therapies. AB - Pulmonary neuroendocrine tumors are rare, and there have been very few reports regarding optimal chemotherapeutic regimens. Two molecular targeted agents, everolimus and sunitinib, have recently been shown to provide an additional treatment benefit for pulmonary neuroendocrine tumors. However, little information is available regarding the usefulness of streptozocin chemotherapy. Here, we encountered a case of relapsed and refractory mediastinal atypical carcinoid tumor associated with multiple endocrine neoplasia type 1 for various cytotoxic and molecular targeted agents. The patient showed a good response to streptozocin monotherapy. We describe the case and review streptozocin chemotherapy in patients with pulmonary neuroendocrine tumors. PMID- 29515411 TI - Rosai-Dorfman Disease Complicated by Autoimmune Hemolytic Anemia in a Child: A Case Report and Review of the Literature. AB - Rosai-Dorfman disease is a rare histiocytic proliferative disorder that commonly presents with a massive lymphadenopathy and a variety of constitutional symptoms. Severe hemolytic anemia is an infrequent complication of this disease. Although the etiology of the condition is unknown, infectious agents including viruses have been implicated. We describe a 2-year-old female child who presented with fever, pallor, and generalized lymphadenopathy complicated by the development of autoimmune hemolytic anemia. A review of the literature of this condition is also provided. PMID- 29515412 TI - Acute Lymphoblastic Leukemia Presenting as Fanconi Syndrome. AB - Acute lymphoblastic leukemia (ALL) presenting as Fanconi syndrome (FS) is extremely rare. Here, we report a case of ALL presenting as bilateral nephromegaly following FS. A 2-year-old girl was unexpectedly diagnosed with bilateral nephromegaly. After 2 weeks, she developed general fatigue, thirst, and polyuria. Laboratory examinations revealed renal tubular acidosis, hypokalemia, hypophosphatemia, and aminoaciduria, and FS was diagnosed. Replacement of bicarbonate and potassium did not improve her condition. Two weeks after the onset of FS, leukemic cells appeared on a peripheral blood smear, and the patient was diagnosed with precursor B-cell ALL presenting as nephromegaly and FS. Chemotherapy brought about a prompt resolution of acidosis and electrolyte abnormalities, without renal dysfunction. The patient remains well 4 years after the onset of the disease. Although extremely rare, FS should be recognized as one of the emerging renal complications of ALL. PMID- 29515413 TI - CSF-ctDNA SMSEQ Analysis to Tailor the Treatment of a Patient with Brain Metastases: A Case Report. AB - Brain metastases are the most common neurological complications of adult cancers, accounting for more than half of brain tumors. The incidence of brain metastases may be increasing due to improved detection of small lesions by advanced imaging technologies. Given the fast evolution of targeted and immunotherapy regimens, it is essential to serially assess brain malignancies during the disease course for disease monitoring and tailoring of the therapeutic management. For such serial and repetitive assessment, cerebrospinal fluid (CSF) could be the biological fluid of choice to supplement cytology examination for the presence or absence of CNS malignancy, as well as provide extensive information on tumor mutational profile for personalization of treatment. The case described here emphasizes the importance of CSF-ctDNA analysis with the CellMax SMSEQ technology that led to treatment adjustment resulting in clinical remission of the patient. PMID- 29515414 TI - A Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi Tyrosine Kinase Inhibitor Lenvatinib. AB - Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor alpha, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib. PMID- 29515415 TI - Long-Lasting Response to Trabectedin in a Patient with Metastatic Uterine Leiomyosarcoma: A Case Report. AB - Background: Uterine leiomyosarcoma (uLMS) is a rare tumor that accounts for 1% of all uterine malignancies. In spite of adequate surgical resection of uLMS, even in the early stage, patients remain at high risk for local and distant recurrence. Therefore, the treatment of advanced uLMS represents a considerable challenge. Methods: We report the case of a 47-year-old woman who presented with uLMS with abnormal vaginal bleeding. Results: The patient underwent a total hysterectomy and bilateral adnexectomy, which was followed by 1 year progression free survival without adjuvant therapy. Thereafter, new lung metastases and local progression at the vaginal stump were observed. Chemotherapy with ifosfamide and doxorubicin was administered. However, after 4 cycles, a CT scan revealed disease progression in the lung metastases. Subsequently, the patient was treated with trabectedin at a dose of 1.5 mg/m2 for 6 cycles resulting in complete remission of the lung metastases as well as partial remission of the mass in the vaginal stump after 9 cycles of trabectedin. The patient is currently on maintenance therapy with trabectedin and has no recurrence. Conclusion: Trabectedin seems to be an efficient option for patients with uLMS as demonstrated by a long-lasting response in a pretreated patient with an acceptable safety profile with no signs of cumulative toxicity. PMID- 29515416 TI - Surgical Treatment following Chemo-Targeted Therapy with Bevacizumab for Lung Metastasis from Colorectal Carcinoma: Analysis of Safety and Histological Therapeutic Effects in Patients Treated at a Single Institution. AB - Background: Recently, therapeutic strategies for a metastasectomy from colorectal carcinoma after chemo-targeted therapy with bevacizumab have been presented, with which some uncommon but serious adverse events have been reported. However, only few reports have investigated the safety of lung resection after such therapy or the histological effects. We retrospectively analyzed the both of them at our institute. Methods: Of 69 colorectal carcinoma patients who underwent pulmonary metastasectomy procedures from 2009 to 2014, we investigated 11 who also received chemo-targeted therapy prior to surgery. Results: In addition to bevacizumab, 5 fluorouracil (FU)/leucovorin + oxaliplatin or capecitabine was given in 6 cases and 5 FU/leucovorin + irinotecan in 5 cases. The mean period from the end of chemo-targeted therapy to surgery was 2.7 +/- 0.9 months. The response to therapy shown in imaging findings was progressive disease in 6, stable disease in 3, and partial response in 2 (response rate, 18.2%). The operation modes were wedge resection (n = 8, 72.3%), segmentectomy (n = 2, 1 in bilateral lobes, 1 in the right lobe, 18.2%), and lobectomy (n = 1, left lower lobectomy, 9.1%). All patients safely underwent a complete resection. As for postsurgical complications, chylothorax occurred in 1 case and prolonged pulmonary air leakage in 1 case. The histological effects of chemo-targeted therapy were slight. There was no relationship between histological findings with imaging findings obtained prior to the operation (p = 0.63). The 5-year disease-free survival rate after metastasectomy was 10.9%. Conclusions: Pulmonary metastasectomy after chemo targeted therapy for colorectal carcinoma patients obtained acceptable results. In addition, there was no correlation between imaging and histopathologic results following chemo-targeted therapy. PMID- 29515417 TI - Microsurgical Treatment of Intraventricular Cavernoma with Prior Planning Neuroendoscopy. AB - Microsurgery remains the gold standard treatment for intraventricular lesions, but it is not without limitations. The cerebral ventricles approach is considered a challenge for neurosurgeons because of their deep location and their intimate association with critical areas of the brain. It has been shown that direct endoscopic view is superior to magnetic resonance imaging (MRI) in identifying intraventricular structures and lesions. Also, during neuroendoscopy, there is no cerebrospinal fluid leak causing brain collapse as seen in microsurgery. Different surgical strategies should be shared and may improve and facilitate intraventricular lesions resection. Herein, a case of a successful microsurgical cavernoma resection with prior ventriculoscopy is described. A 28-year-old woman was admitted with intense holocranial headache. A mild stiff neck was observed. MRI showed a 3-cm lesion with heterogeneous signal intensity and no contrast enhancement suggestive of cavernoma. Initially, a ventriculoscopy was done to inspect the lesion and the surrounding ventricular structures. After that, a conversion technique from endoscopy to microsurgery was performed. The initial corticectomy was extended and the endoscope pathway was followed into the ventricular cavity. Then, the cavernoma was completely removed by microsurgical technique. No complications were observed. Control MRI showed total tumour removal. The patient remained asymptomatic with no recurrence after 1 year. This case illustrates a successful prior endoscopic approach followed by microsurgery as an alternative to a direct microsurgical approach for intraventricular cavernoma. A previous direct endoscopic view of the lesion and its relation with intraventricular structures may ensure a safe and complete resection by microsurgery. PMID- 29515418 TI - A Case of Traumatic Brain Injury Presenting with Musical Hallucinations. AB - A 67-year-old woman was hospitalized for rehabilitation from the after effects of a traumatic brain injury. In addition to memory impairment, attention disorder, and executive dysfunction, she experienced musical hallucinations. Brain magnetic resonance imaging revealed cerebral contusion in the bilateral temporal lobes and the left frontal lobe. Case reports of musical hallucinations caused by traumatic brain injury are extremely rare. PMID- 29515419 TI - Infliximab-Associated Chronic Inflammatory Central Nervous System Disease and Peroneal Nerve Injury in a Psoriatic Patient Refractory to Treatment: Case Report with 10-Year Follow-Up. AB - The tumor necrosis factor-alpha (TNF-alpha) antagonists infliximab, adalimumab, and etanercept have been approved for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, and psoriatic arthritis. Manifestations of demyelinating disease have been reported for patients receiving TNF-alpha antagonists. We describe a rare manifestation of a chronic inflammatory process affecting both the central and peripheral nervous system in a patient who received infliximab for the treatment of psoriasis and psoriatic arthritis. Infliximab therapy was discontinued and symptoms improved under high-dose intravenous glucocorticoid pulse therapy. PMID- 29515420 TI - Elderly-Onset Neuromyelitis Optica Spectrum Disorder with Pre-Existing Prednisone Allergy. AB - We present a case of an 82-year-old man with new-onset neuromyelitis optica (NMO) spectrum disorder, the treatment of which was complicated by a severe pre existing prednisone allergy. His age caused much initial doubt about his diagnosis, and his corticosteroid allergy altered our management as we attempted to minimize risk to the patient. Our patient was a healthy 82-year-old, right handed man who presented with sensory loss of the bilateral lower extremities and progressive, painless vision loss. MRI showed bilateral pre-chiasmatic optic nerve and optic chiasm enhancement, along with enhancement within the thoracic spinal cord from T3 to T7. Serum NMO-IgG was positive with a titer >1: 100,000. Due to concern of allergic reaction, our patient initially refused high-dose Solu Medrol and opted to try plasma exchange alone, but due to worsening of his symptoms we attempted to use dexamethasone as it had a theoretically lower risk of adverse reaction with a known prednisone allergy. There are several cases of elderly-onset NMO in the literature but this is the only case we could find of NMO accompanied by a rare severe allergy to prednisone. This case demonstrates the relative safety of dexamethasone as an alternative to methylprednisolone for acute management of NMO spectrum disorder, though efficacy has not been established in major trials. Cross-reactivity between various systemic corticosteroids is not as well established as topical corticosteroids, so it is difficult to assess the probability of a reaction between prednisone and methylprednisolone. PMID- 29515421 TI - Central-Variant Posterior Reversible Encephalopathy Syndrome with Albuminocytologic Dissociation. AB - Posterior reversible encephalopathy syndrome (PRES) is a disorder of reversible vasogenic brain edema which mainly involves the parieto-occipital lobes in various clinical settings. The main mechanism is known to be cerebral autoregulation failure and endothelial dysfunction leading to the disruption of the blood-brain barrier. We report the case of a 47-year-old woman with PRES which involved the brain stem and thalami, sparing the cerebral hemispheres. She was admitted to the emergency room because of acute-onset confusion. Her initial blood pressure was 270/220 mm Hg. Routine blood lab tests showed pleocytosis, hyperglycemia, and azotemia. Brain magnetic resonance imaging (MRI) showed a lesion of vasogenic edema involving nearly the whole area of pons, the left side of the midbrain, and the bilateral medial thalami. Cerebrospinal fluid (CSF) examination revealed an increased level of protein with normal white blood cell count. With conservative care, the patient markedly recovered 3 days after symptom onset, and a follow-up MRI confirmed complete resolution of the vasogenic edema. This case suggests that PRES can rarely involve the "central zone" only, sparing the cerebral hemispheres, which may be confused with other neurological diseases. Besides, the CSF albuminocytologic dissociation may suggest the disruption of the blood-brain barrier in patients with PRES. PMID- 29515422 TI - Convulsive Seizures as Presenting Symptom of Metronidazole-Induced Encephalopathy: A Case Report. AB - Introduction: Encephalopathy and convulsive seizures are rare manifestations of metronidazole toxicity. The incidence is unknown, but the condition has most frequently been reported in patients in their fifth to sixth decades. Usually, this condition is regarded as reversible, but permanent deficits and even death have been reported. Case Report: A 66-year-old female patient undergoing metronidazole treatment for pleural empyema was admitted to our institution after her second episode of seizure. Over the course of 1 week after admittance, the patient developed several convulsive seizures along with progressive cerebellar dysfunction and cognitive impairment. MRI revealed bilateral, symmetrical hyperintense signal changes in the pons and dentate nuclei. EEG, ECG, lumbar puncture, and blood samples were normal. The patient improved already 2-3 days after discontinuation of metronidazole and was discharged fully recovered after 17 days. Follow-up clinical assessment and MRI were unremarkable. Conclusion: Metronidazole-induced encephalopathy is a rare condition, and due to a general lack of awareness the diagnosis is often delayed. This condition should be considered in metronidazole-treated patients presenting with unprovoked seizures, myoclonus, cerebellar signs, and encephalopathy. Characteristic MRI lesions may support the clinical suspicion. PMID- 29515423 TI - Clinical and Genetic Analysis of an Asian Indian Family with Charcot-Marie-Tooth Disease Type 4C. AB - Charcot-Marie-Tooth disease type 4C, an autosomal recessive genetic neuropathy, is caused by mutations in the SH3TC2 (SH3 domain and tetratricopeptide repeats 2) gene. Interestingly, although mutations in this gene have been observed in European gypsies, a population that originated in India, there are few publications describing Indian patients. We report our analysis of a 50-year-old woman of Asian Indian descent with onset of progressive distal weakness and sensory loss in childhood. A clinical examination revealed the presence of a neuropathy with pes cavus without spinal abnormalities. Electrophysiological testing confirmed a sensorimotor length-dependent neuropathy with demyelinating features. A genetic analysis revealed she carries 2 novel mutations, c.2488G>T variant (rs879254317) and c.731+5G>A variant (rs879254316), in the SH3TC2 gene. Further genetic testing demonstrated that her son is a carrier of the c.731+5G>A mutation. Our analysis confirms that this patient is a compound heterozygote inheriting these mutations, which are in trans, in an autosomal recessive pattern. Her son developed an episode of sciatic neuropathy with complete resolution. We hypothesize that in his case, haploinsufficiency caused by c.731+5G>A mutation may have predisposed him to the development of this focal neuropathy. PMID- 29515424 TI - Intracranial Leptomeningeal Carcinomatosis: A Diagnostic Study with 18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Leptomeningeal carcinomatosis (LC) diagnosis is based on cerebrospinal fluid (CSF) cytological analysis and contrast-enhanced magnetic resonance imaging (MRI); however, low sensitivity was evidenced in some cases delaying prompt and adequate treatments. Brain 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was also employed in doubtful cases. We retrospectively described 4 suspected LC cases with uncertain or undetectable MRI and initially negative CSF cytology. Whole-body (WB) and brain 18F-FDG PET/computed tomography (CT) were used, the latter showing intracranial tracer uptakes suspected for LC in 3/4 cases. In 2 of these 3 cases, WB scan also evidenced spinal cord lesion and pulmonary tumor, respectively, while both procedures were true negative in the fourth case. CSF cytology became positive after repeated exams in the 3 PET/CT positive cases. In 1 of these 3 patients, it was also confirmed at MRI, while it stayed negative in the remaining PET/CT-negative case with uncertain MRI. 18F-FDG PET/CT could be a useful supportive diagnostic tool in doubtful intracranial and spinal LC. PMID- 29515425 TI - Dystonic Seizures and Intense Hyperperfusion of the Basal Ganglia in a Patient with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. AB - This report describes a rare case presenting with dystonic seizures due to anti-N methyl-D-aspartate (NMDA) receptor encephalitis. The patient was an 18-year-old woman with repeated right-dominant dystonic seizures even under sedation. Single photon emission computed tomography (SPECT) showed intense hyperperfusion of the caudate nuclei, putamen, globus pallidus, thalamus, and insula on the left side, suggesting encephalitis. Antibodies against NMDA receptors were detected in the sera and cerebrospinal fluids. Immune-mediated treatments were administered. Three months later, the dystonic seizures disappeared. We diagnosed her with anti NMDA receptor encephalitis. SPECT suggested that the main region of encephalitis was the basal ganglia. Therefore, we propose that the patient's dystonic seizures may originate from the insula and be generated by intense hyperactivity of the basal ganglia. PMID- 29515426 TI - A Rare Case of Glossopharyngeal Neuralgia due to Neurovascular Conflict. AB - In the context of painful cranial neuropathies, a very rare cause is represented by the irritation of the glossopharyngeal nerve due to various aetiologic factors. Here, we present a case of neuralgia of the ninth right cranial nerve due to a compression of its nerve root upon the kinking of the homolateral vertebral artery, resulting in a disabling clinical overview for the patient. Our objective was to focus the reader's attention on the clinical manifestation, which alone could lead to an immediate diagnosis. The imaging and laboratory studies proved to be fundamental in diagnosing the causes, yet the knowledge of the symptoms and the signs of this rare clinical entity can prevent misdiagnosis, mismanagement and consequent economic expenditure as occurred in the case described here. PMID- 29515427 TI - Lateral Medullary Ischemic Infarct Caused by Posterior Inferior Cerebellar Artery Aneurysm. AB - Posterior inferior cerebellar artery (PICA) aneurysms are rare. The most common complication of intracranial aneurysms is rupture causing subarachnoid hemorrhage. Ischemic infarct, although more common in giant thrombosed aneurysms, is a very rare manifestation of small intracranial aneurysms. Here we describe a patient who presented with lateral medullary acute infarction associated with an ipsilateral, small (4 * 3.5 mm), unruptured and non-thrombosed PICA aneurysm. PMID- 29515428 TI - Lessons Learned from Implantation of Morcher 50D and 96S Artificial Iris Diaphragms. AB - Purpose: To discuss problems associated with the implantation of two Morcher iris diaphragm models. Methods: We describe the history, intraoperative complications, and postoperative complications of 5 patients with specific Morcher iris implants. Results: We implanted Morcher 50D devices in 1 patient and Morcher 96S devices in 4 patients. Complications included postoperative rotation, device mis sizing, difficult intraoperative rotation, zonular dehiscence, and intraoperative hemorrhage. Conclusion: Artificial iris implantation has a steep learning curve. With widespread availability on the horizon in the United States, the sharing of surgical experiences is key to achieving the best outcomes for patients. PMID- 29515429 TI - Chronic Orbital Inflammation Associated to Hydroxyapatite Implants in Anophthalmic Sockets. AB - Purpose: We report 6 patients who received a hydroxyapatite (HA) orbital implant in the socket and developed chronic orbital inflammation unresponsive to conventional medical therapy. Case Reports: We assisted 6 cases (4 males, 2 females) who received an HA orbital implant in the socket between 2015 and 2016 at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, and developed chronic orbital inflammation with chronic discharge, redness, and pain (onset from weeks to over 2 decades after surgery). Computed tomography evaluation indicated inflammation in the orbital tissues, and histological examination showed a foreign body granulomatous reaction mainly localized around and blanching the HA implant. The condition was unresponsive to usual medical treatment and was resolved immediately after implant removal. Conclusions: Chronic inflammation can occur decades after placement of an HA implant in the orbit and can be successfully treated with implant removal. PMID- 29515431 TI - Intralenticular Ozurdex(r) - One Year Later. AB - Reported here is a case of intralenticular sustained-release dexamethasone implant (Ozurdex(r), Allergan, Irvine, CA, USA) present for 1 year with effective treatment of refractory diabetic macular edema without rapid cataract formation. The crystalline lens remained stable for 12 months on exam despite the presence of the steroid-secreting foreign body. The diabetic macular edema resolved on exam and on optical coherence tomography. After 1 year, cataract extraction was uneventfully performed by phacoemulsification for a mild decline in visual acuity. Macular edema remains resolved 2 months following cataract removal. This is the longest reported period of observation of intralenticular Ozurdex in the literature. Ozurdex remains effective despite intralenticular location, and it can have minimal effects on cataract progression. PMID- 29515430 TI - Bitot's Spots following Bariatric Surgery: An Ocular Manifestation of a Systemic Disease. AB - Background: To present a case of ocular complications from vitamin A deficiency following bariatric surgery. Case Report: A 41-year-old woman presented with symptoms of dryness and diminished night vision. Examination revealed corneal punctate staining, keratinization of the conjunctiva, and multiple mid-peripheral white lesions at the level of the retinal pigment epithelium. Given the patient's history of bariatric surgery, anemia, and vitamin D deficiency, further investigation into micronutrient levels was performed and indicated a severe vitamin A deficiency. Oral vitamin A supplementation resulted in the complete resolution of her symptoms within two months. Conclusions: Nutritional deficiencies following bariatric surgery are common and can be disruptive to normal systemic health and visual function. Given that the number of patients pursuing bariatric surgery for weight loss management has increased over the past 50 years, eye care professionals should be aware of the ophthalmic manifestations associated with micronutrient deficiency. PMID- 29515432 TI - Full-Thickness Macular Hole Formation in the Postoperative Period After Initial Vitrectomy for Rhegmatogenous Retinal Detachment. AB - Background and Objective: To evaluate full-thickness macular hole (MH) formation in the postoperative period after initial vitrectomy for rhegmatogenous retinal detachment (rRD). Materials and Methods: We retrospectively reviewed the medical records of 4 consecutive eyes that required additional vitrectomy for full thickness MH between April 2013 and March 2016 after undergoing an initial vitrectomy for rRD. Results: Epiretinal membrane (ERM) was identified by preoperative optical coherence tomography or intraoperative dye staining in each case. Photocoagulation of retinal breaks prior to initial vitrectomy was performed in Cases 1, 2, and 3 (4-16 days), with yttrium-aluminum-garnet capsulotomy after cataract extraction also performed prior to the retinal break formation in Case 3. At the initial vitrectomy, there was a superior retinal break which crossed the equator in Case 2, and an intentional hole was created in Cases 1 and 4. The mean interval from the initial vitrectomy until MH formation was 27.5 +/- 15.8 months. As with Case 2, the intervals in Cases 1 and 4, in which an intentional hole was created, were clearly shorter than in those in Case 3. Finally, MH closure was achieved after an additional vitrectomy (removal of the internal limiting membrane with ERM and gas tamponade) and best-corrected visual acuity improved in each case. Conclusion: ERM was identified in the cases examined in our study. The presence of an intentional hole might shorten the interval of MH formation after vitrectomy for rRD. PMID- 29515434 TI - Resting State BOLD Variability in Alzheimer's Disease: A Marker of Cognitive Decline or Cerebrovascular Status? AB - Background: Alzheimer's disease (AD) is a neurodegenerative disorder that may benefit from early diagnosis and intervention. Therefore, there is a need to identify early biomarkers of AD using non-invasive techniques such as functional magnetic resonance imaging (fMRI). Recently, novel approaches to the analysis of resting-state fMRI data have been developed that focus on the moment-to-moment variability in the blood oxygen level dependent (BOLD) signal. The objective of the current study was to investigate BOLD variability as a novel early biomarker of AD and its associated psychophysiological correlates. Method: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 2 database from 19 participants with AD and 19 similarly aged controls. For each participant, a map of BOLD signal variability (SDBOLD) was computed as the standard deviation of the BOLD timeseries at each voxel. Group comparisons were performed to examine global differences in resting state SDBOLD in AD versus healthy controls. Correlations were then examined between participant SDBOLD maps and (1) ADNI-derived composite scores of memory and executive function and (2) neuroimaging markers of cerebrovascular status. Results: Between-group comparisons revealed significant (p < 0.05) increases in SDBOLD in patients with AD relative to healthy controls in right-lateralized frontal regions. Lower memory scores and higher WMH burden were associated with greater SDBOLD in the healthy control group (p < 0.1), but not individuals with AD. Conclusion: The current study provides proof of concept of a novel resting state fMRI analysis technique that is non-invasive, easily accessible, and clinically compatible. To further explore the potential of SDBOLD as a biomarker of AD, additional studies in larger, longitudinal samples are needed to better understand the changes in SDBOLD that characterize earlier stages of disease progression and their underlying psychophysiological correlates. PMID- 29515433 TI - Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D2 Dopamine Receptor. AB - The dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or beta-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs. the other through a mechanism known as functional selectivity or biased signaling. Our laboratory has previously described a G protein signaling-biased agonist, MLS1547, for the D2R using a variety of in vitro functional assays. To further evaluate the biased signaling activity of this compound, we investigated its ability to promote D2R internalization, a process known to be mediated by beta-arrestin. Using multiple cellular systems and techniques, we found that MLS1547 promotes little D2R internalization, which is consistent with its inability to recruit beta-arrestin. Importantly, we validated these results in primary striatal neurons where the D2R is most highly expressed suggesting that MLS1547 will exhibit biased signaling activity in vivo. In an effort to optimize and further explore structure-activity relationships (SAR) for this scaffold, we conducted an iterative chemistry campaign to synthesize and characterize novel analogs of MLS1547. The resulting analysis confirmed previously described SAR requirements for G protein-biased agonist activity and, importantly, elucidated new structural features that are critical for agonist efficacy and signaling bias of the MLS1547 scaffold. One of the most important determinants for G protein biased signaling is the interaction of a hydrophobic moiety of the compound with a defined pocket formed by residues within transmembrane five and extracellular loop two of the D2R. These results shed new light on the mechanism of biased signaling of the D2R and may lead to improved functionally-selective molecules. PMID- 29515435 TI - Depressive Symptom Dimensions and Their Association with Hippocampal and Entorhinal Cortex Volumes in Community Dwelling Older Adults. AB - Objective: Research has shown that depression is a risk factor for Alzheimer's disease (AD) and subsequent cognitive decline. This is compounded by evidence showing an association between depression and reduced hippocampal volumes; a primary structure implicated in the pathogenesis of the disease. Less is known about the relationship between depression and other AD vulnerable regions such as the entorhinal cortex. Given the heterogeneity of depressive symptom presentation, we examined whether symptom dimensions were associated with hippocampal and entorhinal cortex volumes in community dwelling older adults. Methods: Eighty-one community dwelling adults completed the Beck Depression Inventory - second edition and underwent structural neuroimaging. Measures of hippocampal and entorhinal cortex volumes were obtained using FreeSurfer software. Linear regression models included regions of interest as dependent variables, with depressive symptom dimensions, as independent variables, controlling for total intracranial volumes, age, education, and gender. Results: Somatic symptoms were negatively associated with total, right, and left hippocampal volumes. Affective symptoms were negatively associated with total entorhinal cortex volumes, with a marginal main effect on left entorhinal cortex volumes. Conclusion: Our findings provide support for examining depressive symptoms and their association with AD vulnerable regions along subdimensions of affective, cognitive, and somatic symptoms to better understand profiles of symptoms most associated with these regions. Conceptualizing depressive symptoms in this way may also better inform treatment approaches in terms of targeting types of symptoms that may be more closely linked to poorer brain and cognitive health outcomes. PMID- 29515436 TI - Association between Age and Changes in Heart Rate Variability after Hemodialysis in Patients with Diabetes. AB - Background: Heart rate variability (HRV) represents changes in the time between successive heart beats, and it has been used to assess the autonomic nervous system. Previous studies have reported autonomic dysfunction in diabetic patients undergoing hemodialysis (HD), however, no studies have evaluated the effects of age on changes in HRV in these patients. The aim of this study was to examine the effects of age on changes in HRV in diabetic HD patients. Methods: We enrolled 84 diabetic patients receiving maintenance HD. HRV was measured before and after HD to assess changes in HRV (DeltaHRV). The patients were divided into two groups based on their age (65 years< or >=65 years). Results: Compared to the patients aged <65 years, those aged >=65 years had a higher high frequency (HF) % (p = 0.032) before HD. The patients aged <65 years had a significant increase in very low frequency, low frequency (LF), and HF after HD. The patients aged >=65 years had a significant increase in LF, but a significant decrease in HF% after HD. There was a significant interaction between age and change of HF% (p = 0.023) after HD. After multivariate adjustments for clinical, biochemical data and medications, systolic blood pressure, total cholesterol, hemoglobin, and hemoglobin were associated with DeltaLF, whereas cerebrovascular disease, systolic blood pressure, and fasting glucose were associated with DeltaHF% in patients aged >=65 years. Conclusion: Our study demonstrated significant changes in HRV after HD in diabetic patients. In the patients aged >=65 years, LF was increased, whereas HF% was decreased significantly after HD. Among the HRV parameters, age had an interaction with the change of HF%. PMID- 29515438 TI - Effects of Transcranial Direct Current Stimulation Block Remifentanil-Induced Hyperalgesia: A Randomized, Double-Blind Clinical Trial. AB - Background: Remifentanil-induced hyperalgesia (r-IH) involves an imbalance in the inhibitory and excitatory systems. As the transcranial Direct Current Stimulation (tDCS) modulates the thalamocortical synapses in a top-down manner, we hypothesized that the active (a)-t-DCS would be more effective than sham(s)-tDCS to prevent r-IH. We used an experimental paradigm to induce temporal summation of pain utilizing a repetitive cold test (rCOLDT) assessed by the Numerical Pain Score (NPS 0-10) and we evaluated the function of the descending pain modulatory system (DPMS) by the change on the NPS (0-10) during the conditioned pain modulation (CPM)-task (primary outcomes). We tested whether a-tDCS would be more effective than s-tDCS to improve pain perception assessed by the heat pain threshold (HPT) and the reaction time during the ice-water pain test (IPT) (secondary outcomes). Methods: This double-blinded, factorial randomized trial included 48 healthy males, ages ranging 19-40 years. They were randomized into four equal groups: a-tDCS/saline, s-tDCS/saline, a-tDCS/remifentanil and s tDCS/remifentanil. tDCS was applied over the primary motor cortex, during 20 min at 2 mA, which was introduced 10 min after starting remifentanil infusion at 0.06 MUg?kg-1?min-1 or saline. Results: An ANCOVA mixed model revealed that during the rCOLDT, there was a significant main effect on the NPS scores (F = 3.81; P = 0.01). The s-tDCS/remifentanil group presented larger pain scores during rCOLDT, [mean (SD) 5.49 (1.04)] and a-tDCS/remifentanil group had relative lower pain scores [4.15 (1.62)]; showing its blocking effect on r-IH. a-tDCS/saline and s tDCS/saline groups showed lowest pain scores during rCOLDT, [3.11 (1.2)] and [3.15 (1.62)], respectively. The effect of sedation induced by remifentanil during the rCOLDT was not significant (F = 0.76; P = 0.38). Remifentanil groups showed positive scores in the NPS (0-10) during the CPM-task, that is, it produced a disengagement of the DPMS. Also, s-tDCS/Remifentanil compared to a tDCS showed lower HPT and larger reaction-time during the IPT. Conclusion: These findings suggest that effects of a-tDCS prevent the summation response induced by r-IH during rCOLDT and the a-tDCS blocked the disengagement of DPMS. Thereby, tDCS could be considered as a new approach to contra-regulate paradoxical mechanisms involved in the r-IH. Clinical trials identification: NCT02432677. URL:https://clinicaltrials.gov/. PMID- 29515437 TI - Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice. AB - Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone (1), 3,3',4',5',5,6,7,8 octamethoxyflavone (exoticin) (2), 6,7,4',5'-dimethylenedioxy-3,5,3' trimethoxyflavone (3), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified from N. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1, 3, and 4 (12.5-25 mg/kg b.w.) exhibited dose dependent and significant (p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+ channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1, 3, and 4 (12.5 mg/kg b.w.) demonstrated significant (p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAA receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1-4) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents. PMID- 29515439 TI - Clinical Interpretations of Patient Experience in a Trial of Psilocybin-Assisted Psychotherapy for Alcohol Use Disorder. AB - After a hiatus of some 40 years, clinical research has resumed on the use of classic hallucinogens to treat addiction. Following completion of a small open label feasibility study, we are currently conducting a double-blind placebo controlled clinical trial of psilocybin-assisted treatment of alcohol use disorder. Although treatment effects cannot be analyzed until the study is complete, descriptive case studies provide a useful window into the therapeutic process of psychedelic-assisted treatment of addiction. Here we describe treatment trajectories of three participants in the ongoing trial to illustrate the range of experiences and persisting effects of psilocybin treatment. Although it is difficult to generalize from a few cases, several qualitative conclusions can be drawn from the data presented here. Although participants often find it difficult to describe much of their psilocybin experience, pivotal moments tend to be individualized, extremely vivid, and memorable. Often, the qualitative content extends beyond the clinical problem that is being addressed. The participants discussed in this paper experienced acute and lasting alterations in their perceptions of self, in the quality of their baseline consciousness, and in their relationship with alcohol and drinking. In these cases, experiences of catharsis, forgiveness, self-compassion, and love were at least as salient as classic mystical content. Finally, feelings of increased "spaciousness" or mindfulness, and increased control over choices and behavior were reported following the drug administration sessions. Ultimately, psilocybin-assisted treatment appears to elicit experiences that are extremely variable, yet seem to meet the particular needs of the individual. PMID- 29515440 TI - Resveratrol-Potential Antibacterial Agent against Foodborne Pathogens. AB - Bacterial foodborne pathogens are a significant health burden and the recent emergence of pathogenic resistant strains due to the excessive use of antibiotics makes it more difficult to effectively treat infections as a result of contaminated food. Awareness of this impending health crisis has spurred the search for alternative antimicrobials with natural plant antimicrobials being among the more promising candidates as these substances have good acceptability and likely low toxicity levels as they have long been used in traditional medicines. Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring stilbenoid which has been gaining considerable attention in medical field due to its diverse biological activities - it has been reported to exhibit antioxidant, cardioprotective, anti-diabetic, anticancer, and antiaging properties. Given that resveratrol is phytoalexin, with increased synthesis in response to infection by phytopathogens, there has been interest in exploring its antimicrobial activity. This review aims to provide an overview of the published data on the antibacterial activity of resveratrol against foodborne pathogens, its mechanisms of action as well as its possible applications in food packing and processing; in addition we also summarize the current data on its potential synergism with known antibacterials and future research and applications. PMID- 29515441 TI - Autophagy Flux Contributes to Regulation of Components of Eclipta prostrata L. on Cigarette Smoking-Induced Injury of Bronchial Epithelial Cells. AB - Excessive autophagy plays a crucial role in cigarette smoking extract (CSE) induced inflammation response and oxidative damage of respiratory epithelial cells. The components from Eclipta prostrata L. (CCE) have been shown to be beneficial for CSE-induced epithelial cells injury. However, whether its protection on CSE-stress injury is related to its regulation on autophagy remains still unclear. In this study, CCE, containing mainly wedelolactone of 45.88% and demethylwedelolactone of 23.74%, could improve significantly 10%CSE-induced cell viability of normal human bronchial epithelial (NHBE) cells using CCK-8 kit. We revealed that CCE could remarkably increase autophagic factors Beclin-1, Atg5, ATF4 proteins expression levels and the transformation of LC3-I to LC3-II. Additionally, CCE up-regulated significantly p-p16 and p-p21 phosphorylation levels whereas down-regulated p-p53 in NHBE cells. The changes of typical autolysosom and representative autophagosome in the presence of CCE or/and autophagy inhibitor chloroquine (CQ) were also observed by transmission electron microscopy. These data demonstrated that CCE reduced CSE-induced autophagy flux activation in NHBE cells. The blockade of CCE on autophagy flux contributes to its protection against CSE-induced NHBE cells damage, and CCE is promising to be combination therapeutic molecules to excessive autophagic damage in respiratory diseases. PMID- 29515442 TI - Ginkgolide C Alleviates Myocardial Ischemia/Reperfusion-Induced Inflammatory Injury via Inhibition of CD40-NF-kappaB Pathway. AB - Increasing evidence shows that inflammation plays a vital role in the occurrence and development of ischemia/reperfusion (I/R). Suppression of excessive inflammation can ameliorate impaired cardiac function, which shows therapeutic potential for clinical treatment of myocardial ischemia/reperfusion (MI/R) diseases. In this study, we investigated whether Ginkgolide C (GC), a potent anti inflammatory flavone, extenuated MI/R injury through inhibition of inflammation. In vivo, rats with the occlusion of the left anterior descending (LAD) coronary artery were applied to mimic MI/R injury. In vitro, primary cultured neonatal ventricular myocytes exposed to hypoxia/reoxygenation (H/R) were applied to further discuss the anti-H/R injury property of GC. The results revealed that GC significantly improved the symptoms of MI/R injury, as evidenced by reducing infarct size, preventing myofibrillar degeneration and reversing the mitochondria dysfunction. Moreover, histological analysis and Myeloperoxidase (MPO) activity measurement showed that GC remarkably suppressed Polymorphonuclears (PMNs) infiltration and ameliorated the histopathological damage. Furthermore, GC pretreatment was shown to improve H/R-induced ventricular myocytes viability and enhance tolerance of inflammatory insult, as evidenced by suppressing expression of CD40, translocation of NF-kappaB p65 subunit, phosphorylation of IkappaB alpha, as well as the activity of IKK-beta. In addition, downstream inflammatory cytokines modulated by NF-kappaB signaling were effectively down-regulated both in vivo and in vitro, as determined by immunohistochemistry and ELISA. In conclusion, these results indicate that GC possesses a beneficial effect against MI/R injury via inflammation inhibition that may involve suppression of CD40-NF kappaB signal pathway and downstream inflammatory cytokines expression, which may offer an alternative medication for MI/R diseases. PMID- 29515444 TI - Sulfur-Containing Monoterpenoids as Potential Antithrombotic Drugs: Research in the Molecular Mechanism of Coagulation Activity Using Pinanyl Sulfoxide as an Example. AB - In this article we present the synthesis of enantiomerically pure sulfoxide and study the influence of this compound on hemostasis. Detailed NMR studies and molecular dynamics simulations using sodium dodecyl sulfate (SDS) membrane models indicated that the bicyclic fragment of sulfoxide was embedded into the SDS micelle whereas the -SO(CH2)2OH fragment remained on the surface of the micelle and was in contact with the solvent. We also found that the pro-coagulative activity of sulfoxide was due to its ability to inhibit platelet activation and inhibited the catalytic activity of phospholipid surface which was involved in formation of coagulation clotting factor complexes. PMID- 29515445 TI - DACHPt-Loaded Nanoparticles Self-assembled from Biodegradable Dendritic Copolymer Polyglutamic Acid-b-D-alpha-Tocopheryl Polyethylene Glycol 1000 Succinate for Multidrug Resistant Lung Cancer Therapy. AB - The clinical applications of platinum-based antitumor agents are still largely limited by severe side effects as well as multidrug resistance (MDR). To solve these problems, we developed an 1,2-diaminocyclohexane-platinum(II) (DACHPt) loaded nanoparticle (NP-TPGS-Pt) by self-assembly of poly(amidoamine) polyglutamic acid-b-D-alpha-tocopheryl polyethylene glycol 1000 succinate (PAM PGlu-b-TPGS) and DACHPt. NP-TPGS-Pt showed robust stability and pH-responsive DACHPt release profile in vitro similar to the PEG-containing nanoparticle (NP PEG-Pt). Meanwhile, in contrast with NP-PEG-Pt, NP-TPGS-Pt exhibited efficient nanoparticle-based cellular uptake by the Pt-resistant A549/DDP human lung cancer cells and caused much more cytotoxicity than free Oxaliplatin and NP-PEG-Pt. Finally, this NP-TPGS-Pt was proved to perform outstanding inhibition of Pt resistant tumor growth, much superior than free Oxaliplatin and NP-PEG-Pt. Thus, this NP-TPGS-Pt provides a novel powerful nanomedicine platform for combatting multidrug resistant cancer. PMID- 29515443 TI - Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders. AB - Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA). Noteworthy, GUO and GUA, seem to play opposite roles in the modulation of cognitive functions, such as learning and memory. Indeed GUO, despite exerting neuroprotective, anti-apoptotic and neurotrophic effects, causes a decay of cognitive activities, whereas GUA administration in rats results in working memory improvement (prevented by L-NAME pre-treatment). This study was designed to investigate, in a model of SH-SY5Y neuroblastoma cell line, the signal transduction pathway activated by extracellular GUA. Altogether, our results showed that: (i) in addition to an enhanced phosphorylation of ASK1, p38 and JNK, likely linked to a non-massive and transient ROS production, the PKB/NO/sGC/cGMP/PKG/ERK cascade seems to be the main signaling pathway elicited by extracellular GUA; (ii) the activation of this pathway occurs in a pertussis toxin sensitive manner, thus suggesting the involvement of a putative G protein coupled receptor; (iii) the GUA-induced NO production, strongly reduced by cell pre-treatment with L-NAME, is negatively modulated by the EPAC-cAMP-CaMKII pathway, which causes the over-expression of GDA that, in turn, reduces the levels of GUA. These molecular mechanisms activated by GUA may be useful to support our previous observation showing that GUA improves learning and memory functions through the stimulation of NO signaling pathway, and underscore the therapeutic potential of oral administration of guanine for treating memory related disorders. PMID- 29515446 TI - Is Excessive Polypharmacy a Transient or Persistent Phenomenon? A Nationwide Cohort Study in Taiwan. AB - Objectives: Target populations with persistent polypharmacy should be identified prior to implementing strategies against inappropriate medication use, yet limited information regarding such populations is available. The main objectives were to explore the trends of excessive polypharmacy, whether transient or persistent, at the individual level. The secondary objectives were to identify the factors associated with persistently excessive polypharmacy and to estimate the probabilities for repeatedly excessive polypharmacy. Methods: Retrospective cohort analyses of excessive polypharmacy, defined as prescription of >= 10 medicines at an ambulatory visit, from 2001 to 2013 were conducted using a nationally representative claims database in Taiwan. Survival analyses with log rank test of adult patients with first-time excessive polypharmacy were conducted to predict the probabilities, stratified by age and sex, of having repeatedly excessive polypharmacy. Results: During the study period, excessive polypharmacy occurred in 5.4% of patients for the first time. Among them, 63.9% had repeatedly excessive polypharmacy and the probabilities were higher in men and old people. Men versus women, and old versus middle-aged and young people had shorter median excessive polypharmacy-free times (9.4 vs. 5.5 months, 5.3 vs. 10.1 and 35.0 months, both p < 0.001). Overall, the probabilities of having no repeatedly excessive polypharmacy within 3 months, 6 months, and 1 year were 59.9, 53.6, and 48.1%, respectively. Conclusion: Although male and old patients were more likely to have persistently excessive polypharmacy, most cases of excessive polypharmacy were transient or did not re-appear in the short run. Systemic deprescribing measures should be tailored to at-risk groups. PMID- 29515447 TI - Peripheral Etanercept Administration Normalizes Behavior, Hippocampal Neurogenesis, and Hippocampal Reelin and GABAA Receptor Expression in a Preclinical Model of Depression. AB - Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT) injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-alpha inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes. To test this hypothesis, we examined the effect of repeated CORT injections and concurrent injections of etanercept on measures of object-location and object-in-place memory, forced-swim test behavior, hippocampal neurogenesis, and reelin and GABA beta2/3 immunohistochemistry. CORT increased immobility behavior in the forced swim test and impaired both object-location and object-in-place memory, and these effects were reversed by etanercept. CORT also decreased both the number and complexity of adult-generated neurons, but etanercept restored these measures back to control levels. Finally, CORT decreased the number of reelin and GABA beta2/3-ir cells within the subgranular zone of the dentate gyrus, and etanercept restored these to control levels. These novel results demonstrate that peripheral etanercept has antidepressant effects that are accompanied by a restoration of cognitive function, hippocampal neurogenesis, and GABAergic plasticity, and suggest that a normalization of reelin expression in the dentate gyrus could be a key component underlying these novel antidepressant effects. PMID- 29515448 TI - Autoradiography of 3H-pirenzepine and 3H-AFDX-384 in Mouse Brain Regions: Possible Insights into M1, M2, and M4 Muscarinic Receptors Distribution. AB - : Autoradiography helps to determine the distribution and density of muscarinic receptor (MR) binding sites in the brain. However, it relies on the selectivity of radioligands toward their target. 3H-Pirenzepine is commonly believed to label predominantly M1MR, 3H-AFDX-384 is considered as M2MR selective ligand. Here we performed series of autoradiographies with 3H-AFDX-384 (2 nM), and 3H-pirenzepine (5 nM) in WT, M1KO, M2KO, and M4KO mice to address the ligand selectivity. Labeling with 3H-pirenzepine using M1KO, M2KO, and M4KO brain sections showed the high selectivity toward M1MR. Selectivity of 3H-AFDX-384 toward M2MR varies among brain regions and depends on individual MR subtype proportion. All binding sites in the medulla oblongata and pons, correspond to M2MR. In caudate putamen, nucleus accumbens and olfactory tubercle, 77.7, 74.2, and 74.6% of 3H-AFDX-384 binding sites, respectively, are represented by M4MR and M2MR constitute only a minor portion. In cortex and hippocampus, 3H-AFDX-384 labels almost similar amounts of M2MR and M4MR alongside significant amounts of non-M2/non-M4MR. In cortex, the proportion of 3H-AFDX-384 binding sites attributable to M2MR can be increased by blocking M4MR with MT3 toxin without affecting non-M4MR. PD102807, which is considered as a highly selective M4MR antagonist failed to improve the discrimination of M2MR. Autoradiography with 3H-QNB showed genotype specific loss of binding sites. IN CONCLUSION: while 3H-pirenzepine showed the high selectivity toward M1MR, 3H-AFDX-384 binding sites represent different populations of MR subtypes in a brain-region-specific manner. This finding has to be taken into account when interpreting the binding data. PMID- 29515449 TI - The Psychedelic Debriefing in Alcohol Dependence Treatment: Illustrating Key Change Phenomena through Qualitative Content Analysis of Clinical Sessions. AB - Research on the clinical applications of psychedelic-assisted psychotherapy has demonstrated promising early results for treatment of alcohol dependence. Detailed description of the content and methods of psychedelic-assisted psychotherapy, as it is conducted in clinical settings, is scarce. Methods: An open-label pilot (proof-of-concept) study of psilocybin-assisted treatment of alcohol dependence (NCT01534494) was conducted to generate data for a phase 2 RCT (NCT02061293) of a similar treatment in a larger population. The present paper presents a qualitative content analysis of the 17 debriefing sessions conducted in the pilot study, which occurred the day after corresponding psilocybin medication sessions. Results: Participants articulated a series of key phenomena related to change in drinking outcomes and acute subjective effects of psilocybin. Discussion: The data illuminate change processes in patients' own words during clinical sessions, shedding light on potential therapeutic mechanisms of change and how participants express effects of psilocybin. This study is unique in analyzing actual clinical sessions, as opposed to interviews of patients conducted separately from treatment. PMID- 29515450 TI - Chymase Inhibitor as a Novel Therapeutic Agent for Non-alcoholic Steatohepatitis. AB - Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-beta, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented chymase has been observed in the liver. In histological analysis, chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis. Chymase inhibitor also attenuated the augmentation of angiotensin II, matrix metalloproteinase-9, and transforming growth factor-beta observed in the liver of NASH. Oxidative stress, inflammatory markers, and collagen were attenuated by chymase inhibition. Moreover, chymase inhibitor showed a mitigating effect on established NASH, and survival rates were significantly increased by treatment with chymase inhibitor. In this review, we propose that chymase inhibitor has potential as a novel therapy for NASH. PMID- 29515452 TI - AdipoCount: A New Software for Automatic Adipocyte Counting. AB - Obesity has spread worldwide and become a common health problem in modern society. One typical feature of obesity is the excessive accumulation of fat in adipocytes, which occurs through the following two physiological phenomena: hyperplasia (increase in quantity) and hypertrophy (increase in size) of adipocytes. In clinical and scientific research, the accurate quantification of the number and diameter of adipocytes is necessary for assessing obesity. In this study, we present a new automatic adipocyte counting system, AdipoCount, which is based on image processing algorithms. Comparing with other existing adipocyte counting tools, AdipoCount is more accurate and supports further manual correction. AdipoCount counts adipose cells by the following three-step process: (1) It detects the image edges, which are used to segment the membrane of adipose cells; (2) It uses a watershed-based algorithm to re-segment the missing dyed membrane; and (3) It applies a domain connectivity analysis to count the cells. The outputs of this system are the labels and the statistical data of all adipose cells in the image. The AdipoCount software is freely available for academic use at: http://www.csbio.sjtu.edu.cn/bioinf/AdipoCount/. PMID- 29515451 TI - Physical Exercise-Induced Cardiovascular and Thermoregulatory Adjustments Are Impaired in Rats Subjected to Cutaneous Artery Denervation. AB - This study aimed to investigate the chronic effects of caudal artery denervation on morphometric parameters of the tail vascular smooth muscle and on physical exercise-induced thermoregulatory and cardiovascular adjustments in rats. Male Wistar rats were subjected to caudal artery denervation or the sham procedure. Approximately 26-28 days after these procedures, their thermoregulatory and cardiovascular parameters were evaluated at rest and during or following a fatiguing treadmill run. At the end of the experiments, the rats were euthanized, and samples of their tails were removed to evaluate morphometric parameters of the vascular smooth muscle surrounding the caudal artery. Denervated rats showed morphological adaptations, including increased arterial wall thickness and wall to-lumen ratios. In resting rats and following the fatiguing exercise, caudal artery denervation barely affected the thermoregulatory and cardiovascular parameters evaluated. By contrast, caudal artery denervation attenuated the increase in tail skin temperature, decreased the spontaneous baroreflex sensitivity, and exacerbated the increases in mean arterial pressure in exercising rats. The increased wall-to-lumen ratio of denervated rats correlated negatively with the maximum tail skin temperature attained or cutaneous heat loss sensitivity but correlated positively with the maximum diastolic blood pressure attained during exercise. In conclusion, cutaneous denervation induces vascular remodeling characterized by morphological adaptations of the tail vascular smooth muscle. This vascular remodeling likely underlies the impaired tail heat loss and blood pressure adjustments in denervated rats subjected to physical exercise. Therefore, we have highlighted the importance of cutaneous vascular innervation integrity in thermal and cardiovascular control in stress-challenged rats. In this sense, our findings advance the understanding of thermoregulatory and cardiovascular system reactions after a sustained cutaneous vascular innervation injury, which is essential for the treatment of some diseases, such as Parkinson's disease and type 1 and type 2 diabetes mellitus. PMID- 29515453 TI - GRMDA: Graph Regression for MiRNA-Disease Association Prediction. AB - Nowadays, as more and more associations between microRNAs (miRNAs) and diseases have been discovered, miRNA has gradually become a hot topic in the biological field. Because of the high consumption of time and money on carrying out biological experiments, computational method which can help scientists choose the most likely associations between miRNAs and diseases for further experimental studies is desperately needed. In this study, we proposed a method of Graph Regression for MiRNA-Disease Association prediction (GRMDA) which combines known miRNA-disease associations, miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity. We used Gaussian interaction profile kernel similarity to supplement the shortage of miRNA functional similarity and disease semantic similarity. Furthermore, the graph regression was synchronously performed in three latent spaces, including association space, miRNA similarity space, and disease similarity space, by using two matrix factorization approaches called Singular Value Decomposition and Partial Least-Squares to extract important related attributes and filter the noise. In the leave-one-out cross validation and five-fold cross validation, GRMDA obtained the AUCs of 0.8272 and 0.8080 +/- 0.0024, respectively. Thus, its performance is better than some previous models. In the case study of Lymphoma using the recorded miRNA-disease associations in HMDD V2.0 database, 88% of top 50 predicted miRNAs were verified by experimental literatures. In order to test the performance of GRMDA on new diseases with no known related miRNAs, we took Breast Neoplasms as an example by regarding all the known related miRNAs as unknown ones. We found that 100% of top 50 predicted miRNAs were verified. Moreover, 84% of top 50 predicted miRNAs in case study for Esophageal Neoplasms based on HMDD V1.0 were verified to have known associations. In conclusion, GRMDA is an effective and practical method for miRNA-disease association prediction. PMID- 29515454 TI - In Vivo Recording of Neural and Behavioral Correlates of Anesthesia Induction, Reversal, and Euthanasia in Cephalopod Molluscs. AB - Cephalopod molluscs are among the most behaviorally and neurologically complex invertebrates. As they are now included in research animal welfare regulations in many countries, humane and effective anesthesia is required during invasive procedures. However, currently there is no evidence that agents believed to act as anesthetics produce effects beyond immobility. In this study we demonstrate, for the first time, that two of the most commonly used agents in cephalopod general anesthesia, magnesium chloride and ethanol, are capable of producing strong and reversible blockade of afferent and efferent neural signal; thus they are genuine anesthetics, rather than simply sedating agents that render animals immobile but not insensible. Additionally, we demonstrate that injected magnesium chloride and lidocaine are effective local anesthetic agents. This represents a considerable advance for cephalopod welfare. Using a reversible, minimally invasive recording procedure, we measured activity in the pallial nerve of cuttlefish (Sepia bandensis) and octopus (Abdopus aculeatus, Octopus bocki), during induction and reversal for five putative general anesthetic and two local anesthetic agents. We describe the temporal relationship between loss of behavioral responses (immobility), loss of efferent neural signal (loss of "consciousness") and loss of afferent neural signal (anesthesia) for general anesthesia, and loss of afferent signal for local anesthesia. Both ethanol and magnesium chloride were effective as bath-applied general anesthetics, causing immobility, complete loss of behavioral responsiveness and complete loss of afferent and efferent neural signal. Cold seawater, diethyl ether, and MS-222 (tricaine) were ineffective. Subcutaneous injection of either lidocaine or magnesium chloride blocked behavioral and neural responses to pinch in the injected area, and we conclude that both are effective local anesthetic agents for cephalopods. Lastly, we demonstrate that a standard euthanasia protocol immersion in isotonic magnesium chloride followed by surgical decerebration produced no behavioral response and no neural activity during surgical euthanasia. Based on these data, we conclude that both magnesium chloride and ethanol can function as general anesthetic agents, and lidocaine and magnesium chloride can function as local anesthetic agents for cephalopod molluscs. PMID- 29515455 TI - The Effects of beta-Alanine Supplementation on Muscle pH and the Power-Duration Relationship during High-Intensity Exercise. AB - Purpose: To investigate the influence of beta-alanine (BA) supplementation on muscle carnosine content, muscle pH and the power-duration relationship (i.e., critical power and W'). Methods: In a double-blind, randomized, placebo controlled study, 20 recreationally-active males (22 +/- 3 y, V degrees O2peak 3.73 +/- 0.44 L.min-1) ingested either BA (6.4 g/d for 28 d) or placebo (PL) (6.4 g/d) for 28 d. Subjects completed an incremental test and two 3-min all-out tests separated by 1-min on a cycle ergometer pre- and post-supplementation. Muscle pH was assessed using 31P-magnetic resonance spectroscopy (MRS) during incremental (INC KEE) and intermittent knee-extension exercise (INT KEE). Muscle carnosine content was determined using 1H-MRS. Results: There were no differences in the change in muscle carnosine content from pre- to post-intervention (PL: 1 +/- 16% vs. BA: -4 +/- 25%) or in muscle pH during INC KEE or INT KEE (P > 0.05) between PL and BA, but blood pH (PL: -0.06 +/- 0.10 vs. BA: 0.09 +/- 0.13) during the incremental test was elevated post-supplementation in the BA group only (P < 0.05). The changes from pre- to post-supplementation in critical power (PL: -8 +/ 18 W vs. BA: -6 +/- 17 W) and W' (PL: 1.8 +/- 3.3 kJ vs. BA: 1.5 +/- 1.7 kJ) were not different between groups. No relationships were detected between muscle carnosine content and indices of exercise performance. Conclusions: BA supplementation had no significant effect on muscle carnosine content and no influence on intramuscular pH during incremental or high-intensity intermittent knee-extension exercise. The small increase in blood pH following BA supplementation was not sufficient to significantly alter the power-duration relationship or exercise performance. PMID- 29515456 TI - Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? AB - Neutrophils are the most abundant leukocytes in the circulation, and have been regarded as first line of defense in the innate arm of the immune system. They capture and destroy invading microorganisms, through phagocytosis and intracellular degradation, release of granules, and formation of neutrophil extracellular traps after detecting pathogens. Neutrophils also participate as mediators of inflammation. The classical view for these leukocytes is that neutrophils constitute a homogenous population of terminally differentiated cells with a unique function. However, evidence accumulated in recent years, has revealed that neutrophils present a large phenotypic heterogeneity and functional versatility, which place neutrophils as important modulators of both inflammation and immune responses. Indeed, the roles played by neutrophils in homeostatic conditions as well as in pathological inflammation and immune processes are the focus of a renovated interest in neutrophil biology. In this review, I present the concept of neutrophil phenotypic and functional heterogeneity and describe several neutrophil subpopulations reported to date. I also discuss the role these subpopulations seem to play in homeostasis and disease. PMID- 29515459 TI - Kv7(KCNQ)-K+-Channels Influence Total Peripheral Resistance in Female but Not Male Rats, and Hamper Catecholamine Release in Hypertensive Rats of Both Sexes. AB - K+-channels of the Kv7/KCNQ-family hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells (VSMC). Kv7 may therefore play a role in blood pressure (BP) homeostasis, and prevent a high total peripheral vascular resistance (TPR), a hallmark of hypertensive disease. The present study analyzed if Kv7 channels influence catecholamine release and TPR in normotensive (WKY) and spontaneously hypertensive rats (SHR), and if they may contribute to the antihypertensive protection seen in young, female SHR. Tyramine-stimulated norepinephrine release evokes an adrenergic cardiovascular response, and also allows modulation of release to be reflected in the overflow to plasma. The experiment itself activated some secretion of epinephrine. The results show: (1) XE-991 (Kv7.1-7.4-inhibitor), but not chromanol 293B (Kv7.1 inhibitor), increased tyramine-stimulated norepinephrine overflow and epinephrine secretion in both sexes in SHR, but not WKY. (2) Surprisingly, the Kv7-openers retigabine (Kv7.2-7.5) and ICA-27243 (Kv7.2-7.3-preferring) increased catecholamine release in female SHR. (3) The rise in TPR following tyramine stimulated norepinephrine release was increased by XE-991 but not chromanol in the female WKY only. (4) Retigabine and ICA-27243 reduced the TPR-response to tyramine in the female SHR only. These results suggested: (1) Up-regulation of Kv7.2-7.3 function in sympathetic neurons and chromaffin cells hampered catecholamine release in SHR of both sexes. (2) The increase catecholamine release observed after channel openers in the female SHR may possibly involve reduced transmission in cholinergic neurons which hamper catecholamine release. These two mechanisms may serve to counter-act the hyperadrenergic state in SHR. (3) Kv7.4, most likely in the vasculature, opposed the tension-response to norepinephrine in the female WKY. (4) Vascular Kv7.4-7.5 could be stimulated and then opposed norepinephrine-induced vasoconstriction in the female SHR. (5) Vascular Kv7 channels did not counter-act norepinephrine induced vasoconstriction in male rats, possibly due to different Kv7 channel regulation. Kv7 channels may represent a novel target for antihypertensive therapy. PMID- 29515457 TI - Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications. AB - It is now increasingly appreciated that inflammation is not limited to the control of pathogens by the host, but rather that sterile inflammation which occurs in the absence of viral or bacterial pathogens, accompanies numerous disease states, none more so than the complications that arise as a result of hyperglycaemia. Individuals with type 1 or type 2 diabetes mellitus (T1D, T2D) are at increased risk of developing cardiac and vascular complications. Glucose and blood pressure lowering therapies have not stopped the advance of these morbidities that often lead to fatal heart attacks and/or stroke. A unifying mechanism of hyperglycemia-induced cellular damage was initially proposed to link elevated blood glucose levels with oxidative stress and the dysregulation of metabolic pathways. Pre-clinical evidence has, in most cases, supported this notion. However, therapeutic strategies to lessen oxidative stress in clinical trials has not proved efficacious, most likely due to indiscriminate targeting by antioxidants such as vitamins. Recent evidence now suggests that oxidative stress is a major driver of inflammation and vice versa, with the latest findings suggesting not only a key role for inflammatory pathways underpinning metabolic and haemodynamic dysfunction in diabetes, but furthermore that these perturbations are driven by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This review will address these latest findings with an aim of highlighting the interconnectivity between oxidative stress, NLRP3 activation and inflammation as it pertains to cardiac and vascular injury sustained by diabetes. Current therapeutic strategies to lessen both oxidative stress and inflammation will be emphasized. This will be placed in the context of improving the burden of these diabetic complications. PMID- 29515458 TI - Exercise, Arterial Crosstalk-Modulation, and Inflammation in an Aging Population: The ExAMIN AGE Study. AB - Background: Age is a key determinant for the development of cardiovascular disease and higher age coincides with an increased prevalence of obesity and physical inactivity. The study examines the influence of physical activity on aging processes of physiological systems focusing on the mechanisms of vascular aging. Methods/Design: The study consists of two parts. The cross-sectional approach aims at examining the association of physical fitness and cardiovascular risk with large and small artery function in healthy older active (HOA, n = 40) and sedentary (HOS, n = 40) persons as well as older sedentary individuals with increased cardiovascular risk (OSR, n = 80) aged 50-80 years. In the interventional approach, the OSR group is randomized into a 12-week walking-based high intensity interval training (HIIT) group or a control condition, aiming at examining the effects of HIIT on arterial function in diseased older adults. Active lifestyle is defined as >9 metabolic equivalent of task (MET) per week and sedentary as <=3 MET/week. Inclusion criteria for OSR are overweight or obesity (body mass index >=30 kg/m2) plus at least one additional cardiovascular risk factor. The primary outcome is arterial stiffness as determined by aortic pulse wave velocity (PWV). The secondary outcomes are retinal arterial and venous diameters. Further cardiovascular assessments include peripheral PWV, central haemodynamics, retinal endothelial function, carotid intima media thickness, cardiac strain and diastolic function as well as autonomic function and inflammation. Physical fitness is measured by a treadmill-based spiroergometry to determine peak oxygen uptake. Discussion: The aim of the study is to demonstrate the importance of and need for specific physical activity programs for seniors to achieve healthier aging as a long-term goal. Vascular function defines disease- and age-related end organ damage and represents the potential to contain health at older age. This research will identify cardiovascular biomarkers that best resemble underlying cardiovascular risk in age and disease. The integrated approach will help define new recommendations for treatment guidance of exercise therapy in an aging population. ClinicalTrials. gov: NCT02796976; registered 02 June 2016 (retrospectively registered). PMID- 29515460 TI - Behavioral, Morphological, and Gene Expression Changes Induced by 60Co-gamma Ray Irradiation in Bactrocera tau (Walker). AB - The sterile insect technique (SIT) may reduce pest populations by allowing sufficient amount of irradiation-induced sterile males to mate with wild females whilst maintaining mating ability comparable to wild males. Although the SIT methods are well understood, the optimal sterilizing dose and processing development stage for application vary among species. To ensure effective pest control programs, effects of irradiation on physiology, behavior, and gene function in the target species should be defined, however, little is known about irradiation effects in Bactrocera tau. Here, the effects of irradiation on rates of fecundity, egg hatch, eclosion, mating competitiveness, flight capability, morphology of reproductive organs, and yolk protein (YP) gene expression were studied. The results showed that rates of female fecundity and egg hatch decreased significantly (51 +/- 19 to 0.06 +/- 0.06 and 98.90 +/- 1.01 to 0, respectively) when pupae were treated with >150 Gy irradiation. Flight capability and mating competitiveness were not significantly influenced at doses <250 Gy. Ovaries and fallopian tubes became smaller after irradiation, but there was no change in testes size. Finally, we found that expression of the YP gene was up regulated by irradiation at 30 and 45 days post-emergence, but the mechanisms were unclear. Our study provides information on the determination of the optimal irradiation sterilizing dose in B. tau, and the effects of irradiation on physiology, morphology and gene expression that will facilitate an understanding of sub-lethal impacts of the SIT and expand its use to the control of other species. PMID- 29515461 TI - Bone Marrow-Derived Mononuclear Cell Therapy in Papain-Induced Experimental Pulmonary Emphysema. AB - Murine papain-induced emphysema is a model that reproduces many of the features found in patients. Bone marrow-derived mononuclear cells (BMMC) have already been used to repair the alveolar epithelium in respiratory diseases, but not in the papain model. Thus, we hypothesized that BMMC could prevent the pathophysiological processes in papain-induced experimental emphysema. Female BALB/c mice received intratracheal instillation of 50 MUL of saline (S groups) or papain (P groups, 10 IU/50 MUl of saline) on days 1 and 7 of the experimental protocol. On the 14th day, 2 * 106 BMMC of male BALB/c mice (SC21 and PC21) or saline (SS21 and PS21) were injected by the jugular vein. Analyses were done on days 14 (S14 and P14) and 21 (SS21, PS21, SC21, and PC21) of the protocol. qPCR evaluated the presence of the Y chromosome in the lungs of BMMC recipient animals. Functional residual capacity (FRC), alveolar diameter, cellularity, elastic fiber content, concentrations of TNF-alpha, IL-1beta, IL-6, MIP-2, KC, IFN-gamma, apoptosis, mRNA expression of the dual oxidase (DUOX1 and DUOX2), production of H2O2 and DUOX activity were evaluated in lung tissue. We did not detect the Y chromosome in recipients' lungs. FRC, alveolar diameter, polymorphonuclear cells (PMN) and levels of KC, MIP-2, and IFN-gamma increased in P14 and PS21 groups; the changes in the latter were reverted by BMMC. TNF-alpha, IL-1beta e IL-6 were similar in all groups. The amount of elastic fibers was smaller in P14 and PS21 than in other groups, and BMMC did not increase it in PC21 mice. PS21 animals showed increased DUOX activity and mRNA expression for DUOX1 and 2. Cell therapy reverted the activity of DUOX and mRNA expression of DUOX1. BMMC reduced mRNA expression of DUOX2. Apoptosis index was elevated in PS21 mice, which was reduced by cell therapy in PC21. Static compliance, viscoelastic component of elastance and pressure to overcome viscoelasticity were increased in P14 and PS21 groups. These changes and the high resistive pressure found on day 21 were reverted by BMMC. In conclusion, BMMC showed potent anti inflammatory, antiapoptotic, antioxidant, and restorative roles in papain triggered pulmonary emphysema. PMID- 29515462 TI - AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue. AB - Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), which is specialized in dissipating energy through thermogenesis, potently counteracts obesity. White adipocytes can be converted to thermogenic "brown-like" cells (beige cells; WAT browning) under various stimuli, such as cold exposure. AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates energy metabolism in multiple tissues. However, the role of AMPK in adipose tissue function, especially in the WAT browning process, is not fully understood. To illuminate the effect of adipocyte AMPK on energy metabolism, we generated Adiponectin-Cre-driven adipose tissue specific AMPK alpha1/alpha2 KO mice (AKO). These AKO mice were cold intolerant and their inguinal WAT displayed impaired mitochondrial integrity and biogenesis, and reduced expression of thermogenic markers upon cold exposure. High-fat-diet (HFD)-fed AKO mice exhibited increased adiposity and exacerbated hepatic steatosis and fibrosis and impaired glucose tolerance and insulin sensitivity. Meanwhile, energy expenditure and oxygen consumption were markedly decreased in the AKO mice both in basal conditions and after stimulation with a beta3 adrenergic receptor agonist, CL 316,243. In contrast, we found that in HFD-fed obese mouse model, chronic AMPK activation by A-769662 protected against obesity and related metabolic dysfunction. A-769662 alleviated HFD-induced glucose intolerance and reduced body weight gain and WAT expansion. Notably, A-769662 increased energy expenditure and cold tolerance in HFD-fed mice. A-769662 treatment also induced the browning process in the inguinal fat depot of HFD-fed mice. Likewise, A-769662 enhanced thermogenesis in differentiated inguinal stromal vascular fraction (SVF) cells via AMPK signaling pathway. In summary, a lack of adipocyte AMPKalpha induced thermogenic impairment and obesity in response to cold and nutrient-overload, respectively, whereas chronic AMPK activation by A-769662 promoted WAT browning in inguinal WAT and protected against HFD-induced obesity and related metabolic dysfunction. These findings reveal a vital role for adipocyte AMPK in regulating the browning process in inguinal WAT and in maintaining energy homeostasis, which suggests that the targeted activation of adipocyte AMPK may be a promising strategy for anti obesity therapy. PMID- 29515463 TI - Pulmonary Circulation Transvascular Fluid Fluxes Do Not Change during General Anesthesia in Dogs. AB - General anesthesia (GA) can cause abnormal lung fluid redistribution. Pulmonary circulation transvascular fluid fluxes (JVA ) are attributed to changes in hydrostatic forces and erythrocyte volume (EV) regulation. Despite the very low hydraulic conductance of pulmonary microvasculature it is possible that GA may affect hydrostatic forces through changes in pulmonary vascular resistance (PVR), and EV through alteration of erythrocyte transmembrane ion fluxes ( ionJVA ). Furosemide (Fur) was also used because of its potential to affect pulmonary hydrostatic forces and ionJVA . A hypothesis was tested that JVA , with or without furosemide treatment, will not change with time during GA. Twenty dogs that underwent castration/ovariectomy were randomly assigned to Fur (n = 10) (4 mg/kg IV) or placebo treated group (Con, n = 10). Baseline arterial (BL) and mixed venous blood were sampled during GA just before treatment with Fur or placebo and then at 15, 30 and 45 min post-treatment. Cardiac output (Q) and pulmonary artery pressure (PAP) were measured. JVA and ionJVA were calculated from changes in plasma protein, hemoglobin, hematocrit, plasma and whole blood ions, and Q. Variables were analyzed using random intercept mixed model (P < 0.05). Data are expressed as means +/- SE. Furosemide caused a significant volume depletion as evident from changes in plasma protein and hematocrit (P < 0.001). However; Q, PAP, and JVA were not affected by time or Fur, whereas erythrocyte fluid flux was affected by Fur (P = 0.03). Furosemide also affected erythrocyte transmembrane K+ and Cl-, and transvascular Cl- metabolism (P <= 0.05). No other erythrocyte transmembrane or transvascular ion fluxes were affected by time of GA or Fur. Our hypothesis was verified as JVA was not affected by GA or ion metabolism changes due to Fur treatment. Furosemide and 45 min of GA did not cause significant hydrostatic changes based on Q and PAP. Inhibition of Na+/K+/2Cl- cotransport caused by Fur treatment, which can alter EV regulation and JVA , was offset by the Jacobs Stewart cycle. The results of this study indicate that the Jacobs Stewart cycle/erythrocyte Cl- metabolism can also act as a safety factor for the stability of lung fluid redistribution preserving optimal diffusion distance across the blood gas barrier. PMID- 29515464 TI - Localization and Expression of Nuclear Factor of Activated T-Cells 5 in Myoblasts Exposed to Pro-inflammatory Cytokines or Hyperosmolar Stress and in Biopsies from Myositis Patients. AB - Aims: Regeneration in skeletal muscle relies on regulated myoblast migration and differentiation, in which the transcription factor nuclear factor of activated T cells 5 (NFAT5) participates. Impaired muscle regeneration and chronic inflammation are prevalent in myositis. Little is known about the impact of inflammation on NFAT5 localization and expression in this group of diseases. The goal of this study was to investigate NFAT5 physiology in unaffected myoblasts exposed to cytokine or hyperosmolar stress and in myositis. Methods: NFAT5 intracellular localization and expression were studied in vitro using a cell culture model of myositis. Myoblasts were exposed to DMEM solutions enriched with pro-inflammatory cytokines IFN-gamma with IL-1beta or hyperosmolar DMEM obtained by NaCl supplementation. NFAT5 localization was visualized using immunohistochemistry (IHC) and Western blotting (WB) in fractionated cell lysates. NFAT5 expression was assessed by WB and RT-qPCR. In vivo localization and expression of NFAT5 were studied in muscle biopsies of patients diagnosed with polymyositis (n = 6), dermatomyositis (n = 10), inclusion body myositis (n = 11) and were compared to NFAT5 localization and expression in non-myopathic controls (n = 13). Muscle biopsies were studied by means of quantitative IHC and WB of total protein extracts. Results: In unaffected myoblasts, hyperosmolar stress ensues in NFAT5 nuclear translocation and increased NFAT5 mRNA and protein expression. In contrast, pro-inflammatory cytokines did not lead to NFAT5 nuclear translocation nor increased expression. Cytokines IL-1beta with IFN-gamma induced colocalization of NFAT5 with histone deacetylase 6 (HDAC6), involved in cell motility. In muscle biopsies from dermatomyositis and polymyositis patients, NFAT5 colocalized with HDAC6, while in IBM, this was often absent. Conclusions: Our data suggest impaired NFAT5 localization and expression in unaffected myoblasts in response to inflammation. This disturbed myogenic NFAT5 physiology could possibly explain deleterious effects on muscle regeneration in myositis. PMID- 29515466 TI - Editorial: Memory Systems of the Addicted Brain: The Underestimated Role of Cognitive Biases in Addiction and Its Treatment. PMID- 29515465 TI - Threat Response System: Parallel Brain Processes in Pain vis-a-vis Fear and Anxiety. AB - Pain is essential for avoidance of tissue damage and for promotion of healing. Notwithstanding the survival value, pain brings about emotional suffering reflected in fear and anxiety, which in turn augment pain thus giving rise to a self-sustaining feedforward loop. Given such reciprocal relationships, the present article uses neuroscientific conceptualizations of fear and anxiety as a theoretical framework for hitherto insufficiently understood pathophysiological mechanisms underlying chronic pain. To that end, searches of PubMed-indexed journals were performed using the following Medical Subject Headings' terms: pain and nociception plus amygdala, anxiety, cognitive, fear, sensory, and unconscious. Recursive sets of scientific and clinical evidence extracted from this literature review were summarized within the following key areas: (1) parallelism between acute pain and fear and between chronic pain and anxiety; (2) all are related to the evasion of sensory-perceived threats and are subserved by subcortical circuits mediating automatic threat-induced physiologic responses and defensive actions in conjunction with higher order corticolimbic networks (e.g., thalamocortical, thalamo-striato-cortical and amygdalo-cortical) generating conscious representations and valuation-based adaptive behaviors; (3) some instances of chronic pain and anxiety conditions are driven by the failure to diminish or block respective nociceptive information or unconscious treats from reaching conscious awareness; and (4) the neural correlates of pain-related conscious states and cognitions may become autonomous (i.e., dissociated) from the subcortical activity/function leading to the eventual chronicity. Identifying relative contributions of the diverse neuroanatomical sources, thus, offers prospects for the development of novel preventive, diagnostic, and therapeutic strategies in chronic pain patients. PMID- 29515468 TI - eHealth in Treatment of Offenders in Forensic Mental Health: A Review of the Current State. AB - Background: Treatment of offenders in forensic mental health is complex. Often, these in- or outpatients have low treatment motivation, suffer from multiple disorders, and have poor literacy skills. eHealth may be able to improve treatment outcomes because of its potential to increase motivation and engagement, and it can overcome the predominant one-size-fits-all approach by being tailored to individual patients. Objective: To examine its potential, this systematic review studies the way that eHealth has been used and studied in forensic mental health and identifies accompanying advantages and disadvantages for both patients and treatment, including effectiveness. Methods: A systematic search in Scopus, PsycINFO, and Web of Science was performed up until December 2017. Studies were included if they focused on technological interventions to improve the treatment of forensic psychiatric patients. Results: The search resulted in 50 studies in which eHealth was used for treatment purposes. Multiple types of studies and technologies were identified, such as virtual reality, web based interventions, and videoconferencing. The results confirmed the benefits of technology, for example, the acquisition of unique information about offenders, effectiveness, and tailoring to specific characteristics, but indicated that these are not fully taken advantage of. Discussion: To overcome the barriers and obtain the benefits, eHealth has to have a good fit with patients and the forensic psychiatric context. It has to be seamlessly integrated in existing care and should not be added as an isolated element. To bridge the gap between the current situation and eHealth's potential, further research on development, implementation, and evaluation should be conducted. PMID- 29515467 TI - Early Intervention and a Direction of Novel Therapeutics for the Improvement of Functional Outcomes in Schizophrenia: A Selective Review. AB - Background: A recent review reported that the median proportion of patients recovering from schizophrenia was 13.5% and that this did not change over time. Various factors including the duration of untreated psychosis, cognitive impairment, negative symptoms, and morphological changes in the brain influence the functional outcome of schizophrenia. The authors herein reviewed morphological changes in the brain of schizophrenia patients, effects of early intervention, and a direction of developing novel therapeutics to achieve significant improvement of the functional outcome. Methods: A selective review of the literature including studies from our department was performed. Results: Longitudinal structural neuroimaging studies on schizophrenia revealed that volume reductions in the peri-Sylvian regions (e.g., superior temporal gyrus and insula), which are related to positive psychotic symptoms, progress around the onset (critical stage) of schizophrenia, but become stable in the chronic stage. On the other hand, morphological changes in the fronto-thalamic regions and lateral ventricle, which are related to negative symptoms, neurocognitive dysfunction, and the functional outcome, progress during both the critical and chronic stages. These changes in the peri-Sylvian and fronto-thalamic regions may provide a pathophysiological basis for Crow's two-syndrome classification. Accumulated evidence from early intervention trials suggests that the transition risk from an at-risk mental state (ARMS) to psychosis is approximately 30%. Differences in the cognitive performance, event-related potentials (e.g., mismatch negativity), and brain morphology have been reported between ARMS subjects who later developed psychosis and those who did not. Whether early intervention for ARMS significantly improves the long-term recovery rate of schizophrenia patients remains unknown. With respect to the development of novel therapeutics, animal models of schizophrenia based on the N-methyl-d-aspartate receptor hypofunction hypothesis successfully mimicked behavioral changes associated with cognitive impairments characteristic of the disease. Furthermore, these animal models elicited histological changes in the brain similar to those observed in schizophrenia patients, i.e., decreased numbers of parvalbumin positive interneurons and dendritic spines of pyramidal neurons in the frontal cortex. Some antioxidant compounds were found to ameliorate these behavioral and histological abnormalities. Conclusion: Early intervention coupled with novel therapeutics may offer a promising approach for substantial improvement of the functional outcome of schizophrenia patients. PMID- 29515470 TI - Assessing the Role of Experimental Evidence for Interface Judgment: Licensing of Negative Polarity Items, Scalar Readings, and Focus. AB - This paper reviews a series of experimental studies that address what we call "interface judgment," which is the complex judgment involving integration from multiple levels of grammatical representation such as the syntax-semantics and prosody-semantics interface. We first discuss the results from the ERP literature connected to NPI licensing in different languages, paying particular attention to the N400 and the P600 as neural correlates of this specific phenomenon and focusing on the study by Xiang et al. (2016). The results of this study show evidence that there are two distinct NPI licensing mechanisms, i.e., licensing and rescuing, in line with Giannakidou (1998, 2006). Then we discuss an acceptability judgment task on Greek NPIs which supports the negativity as a scale hypothesis (Zwarts, 1995, 1996; Giannakidou, 1998). For the semantics prosody interface judgment, we discuss two types of findings on two different phenomena and languages: (i) the study by Giannakidou and Yoon (2016) on scalar and non-scalar NPIs in Greek and Korean, which serves as the foundation for Chatzikonstantinou's (2016) study of production data showing distinct prosodic properties in emphatic (scalar) and non-emphatic (non-scalar) Greek NPIs; (ii) a (production and perception) study by Etxeberria and Irurtzun (2015) on the prosodic disambiguation of the scalar/non-scalar readings of sentences containing the focus particle "ere" in Basque. The main conclusion of the paper is that experimental methods of the kind discussed in the paper are useful in establishing physical, quantitative correlates of interface judgment. PMID- 29515469 TI - Enhanced Network Efficiency of Functional Brain Networks in Primary Insomnia Patients. AB - Accumulating evidence from neuroimaging studies suggests that primary insomnia (PI) affects interregional neural coordination of multiple interacting functional brain networks. However, a complete understanding of the whole-brain network organization from a system-level perspective in PI is still lacking. To this end, we investigated in topological organization changes in brain functional networks in PI. 36 PI patients and 38 age-, sex-, and education-matched healthy controls were recruited. All participants underwent a series of neuropsychological assessments and resting-state functional magnetic resonance imaging scans. Individual whole-brain functional network were constructed and analyzed using graph theory-based network approaches. There were no significant differences with respect to age, sex, or education between groups (P > 0.05). Graph-based analyses revealed that participants with PI had a significantly higher total number of edges (P = 0.022), global efficiency (P = 0.014), and normalized global efficiency (P = 0.002), and a significantly lower normalized local efficiency (P = 0.042) compared with controls. Locally, several prefrontal and parietal regions, the superior temporal gyrus, and the thalamus exhibited higher nodal efficiency in participants with PI (P < 0.05, false discovery rate corrected). In addition, most of these regions showed increased functional connectivity in PI patients (P < 0.05, corrected). Finally, altered network efficiency was correlated with neuropsychological variables of the Epworth Sleepiness Scale and Insomnia Severity Index in patients with PI. PI is associated with abnormal organization of large-scale functional brain networks, which may account for memory and emotional dysfunction in people with PI. These findings provide novel implications for neural substrates associated with PI. PMID- 29515471 TI - Trends in the Study of Motivation in Schizophrenia: A Bibliometric Analysis of Six Decades of Research (1956-2017). AB - Motivation in schizophrenia has been a key research aim for several decades. Motivation is a very complex process underlying negative symptoms that has been assessed and identified using very different instruments and terminologies. This study provides a comprehensive overview of the growing literature production and highlights an extensive set of variables to better understand the study of motivation. Electronic databases were searched in order to compile relevant studies of motivation in individuals with schizophrenia. The initial search identified 3,248 potentially interesting records, and of these, 161 articles published between 1956 and 2017 were finally included. Information such as year of publication, journal, country, and number of authors was codified. Variables related to sample characteristics, methodological aspects, and motivational terms were also extracted. The results revealed a significant growth trend in literature production, especially since the 2000s, with reward as the main term studied. In addition, questionnaires were identified as the preferred instrument to assess motivation in patients with schizophrenia. Other aspects such as country of publication, authors, journals of publication, and co-citation network analysis were also examined. The discussion offers recommendations for future research. PMID- 29515472 TI - Developmental Trajectories of Hand Movements in Typical Infants and Those at Risk of Developmental Disorders: An Observational Study of Kinematics during the First Year of Life. AB - Highlights The kinematics of hand movements (spatial use, curvature, acceleration, and velocity) of infants with their mothers in an interactive setting are significantly associated with age in cohorts of typical and at-risk infantsdiffer significantly at 5-6 months of age, depending on the context: relating either with an object or a person.Environmental and developmental factors shape the developmental trajectories of hand movements in different cohorts: environment for infants with VIMs; stage of development for premature infants and those with West syndrome; and both factors for infants with orality disorders.The curvature of hand movements specifically reflects atypical development in infants with West syndrome when developmental age is considered. We aimed to discriminate between typical and atypical developmental trajectory patterns of at-risk infants in an interactive setting in this observational and longitudinal study, with the assumption that hand movements (HM) reflect preverbal communication and its disorders. We examined the developmental trajectories of HM in five cohorts of at-risk infants and one control cohort, followed from ages 2 to 10 months: 25 West syndrome (WS), 13 preterm birth (PB), 16 orality disorder (OD), 14 with visually impaired mothers (VIM), 7 early hospitalization (EH), and 19 typically developing infants (TD). Video-recorded data were collected in three different structured interactive contexts. Descriptors of the hand motion were used to examine the extent to which HM were associated with age and cohort. We obtained four principal results: (i) the kinematics of HM (spatial use, curvature, acceleration, and velocity) were significantly associated with age in all cohorts; (ii) HM significantly differed at 5-6 months of age in TD infants, depending on the context; (iii) environmental and developmental factors shaped the developmental trajectories of HM in different cohorts: environment for VIM, development for PB and WS, and both factors for OD and; (iv) the curvatures of HM showed atypical development in WS infants when developmental age was considered. These findings support the importance of using kinematics of HM to identify very early developmental disorders in an interactive context and would allow early prevention and intervention for at-risk infants. PMID- 29515473 TI - The Persistence of the Self over Time in Mild Cognitive Impairment and Alzheimer's Disease. AB - Diachronic unity is the belief that, despite changes, we are the same person across the lifespan. We propose that diachronic unity is supported by the experience of remembering the self over time during episodic recall (i.e., phenomenological continuity). However, we also predict that diachronic unity is also possible when episodic memory is impaired, as long as the ability to construct life narratives from semantic memory (i.e., semantic continuity) is intact. To examine this prediction, we investigated diachronic unity in Alzheimer's Disease (AD) and amnestic mild cognitive impairment (aMCI), two conditions characterised by disrupted phenomenological continuity. If semantic continuity is also altered in these conditions, there should be an associated deterioration in diachronic unity. Participants with AD, aMCI, and healthy controls (HC) completed a self-persistence interview measuring diachronic unity (beliefs about self-persistence, explanations for stability/change). Semantic continuity was assessed with a life-story interview measuring autobiographical reasoning (self-event connections), and coherence (temporal/thematic/causal) of narratives. Our results highlight a complex relationship between semantic continuity and diachronic unity and revealed a divergence between two aspects of diachronic unity: AD/aMCI groups did not differ from HC in continuity beliefs, but AD explanations for self-persistence were less sophisticated. Semantic continuity was most impaired in AD: their narratives had fewer self-event connections (vs. HCs) and lower temporal/thematic coherence (vs. HC/aMCI), while both AD/aMCI groups had lower causal coherence. Paradoxically AD participants who scored higher on measures of beliefs in the persistence of the core self, provided less sophisticated explanations for their self-persistence and were less able to explore persistence in their life narratives. These findings support the importance of semantic continuity to diachronic unity, but suggest a more nuanced and multifaceted relationship than originally proposed in our model. In AD, diminished life narratives that retain features of cultural life scripts are sufficient for strong subjective beliefs of self-persistence, but not for sophisticated explanations about persistence. Better semantic continuity, with the ability to weave high-quality life narratives, may scaffold the capacity to understand and explain one's diachronic unity, but this produces less surety about self-persistence. PMID- 29515474 TI - Cross-Modality Information Transfer: A Hypothesis about the Relationship among Prehistoric Cave Paintings, Symbolic Thinking, and the Emergence of Language. AB - Early modern humans developed mental capabilities that were immeasurably greater than those of non-human primates. We see this in the rapid innovation in tool making, the development of complex language, and the creation of sophisticated art forms, none of which we find in our closest relatives. While we can readily observe the results of this high-order cognitive capacity, it is difficult to see how it could have developed. We take up the topic of cave art and archeoacoustics, particularly the discovery that cave art is often closely connected to the acoustic properties of the cave chambers in which it is found. Apparently, early modern humans were able to detect the way sound reverberated in these chambers, and they painted artwork on surfaces that were acoustic "hot spots," i.e., suitable for generating echoes. We argue that cave art is a form of cross-modality information transfer, in which acoustic signals are transformed into symbolic visual representations. This form of information transfer across modalities is an instance of how the symbolic mind of early modern humans was taking shape into concrete, externalized language. We also suggest that the earliest rock art found in Africa may constitute one of the first fossilized proxies for the expression of full-fledged human linguistic behavior. PMID- 29515475 TI - Three-Year-Olds' Understanding of Desire Reports Is Robust to Conflict. AB - In this paper, we present two experiments with 3-year-olds, exploring their interpretation of sentences about desires. A mature concept of desire entails that desires may conflict with reality and that different people may have conflicting desires. While previous literature is suggestive, it remains unclear whether young children understand that (a) agents can have counterfactual desires about current states of affairs and (b) agents can have desires that conflict with one's own desires or the desires of others. In this article, we test preschoolers' interpretation of want sentences, in order to better understand their ability to represent conflicting desires, and to interpret sentences reporting these desires. In the first experiment, we use a truth-value judgment task (TVJT) to assess 3-year-olds' understanding of want sentences when the subject of the sentence has a desire that conflicts with reality. In the second experiment, we use a game task to induce desires in the child that conflict with the desires of a competitor, and assess their understanding of sentences describing these desires. In both experiments, we find that 3-year-olds successfully interpret want sentences, suggesting that their ability to represent conflicting desires is adult-like at this age. Given that 3-year-olds generally display difficulty attributing beliefs to others that conflict with reality or with the child's own beliefs, these findings may further cast some doubt on the view that children's persistent difficulty with belief (think) is caused by these kinds of conflicts. PMID- 29515476 TI - The Moderating Effect of Self-Reported State and Trait Anxiety on the Late Positive Potential to Emotional Faces in 6-11-Year-Old Children. AB - Introduction: The emergence of anxiety during childhood is accompanied by the development of attentional biases to threat. However, the neural mechanisms underlying these biases are poorly understood. In addition, previous research has not examined whether state and trait anxiety are independently associated with threat-related biases. Methods: We compared ERP waveforms during the processing of emotional faces in a population sample of 58 6-11-year-olds who completed self reported measures of trait and state anxiety and depression. Results: The results showed that the P1 was larger to angry than neutral faces in the left hemisphere, though early components (P1, N170) were not strongly associated with child anxiety or depression. In contrast, Late Positive Potential (LPP) amplitudes to angry (vs. neutral) faces were significantly and positively associated with symptoms of anxiety/depression. In addition, the difference between LPPs for angry (vs. neutral) faces was independently associated with state and trait anxiety symptoms. Discussion: The results showed that neural responses to facial emotion in children with elevated symptoms of anxiety and depression were most evident at later processing stages characterized as evaluative and effortful. The findings support cognitive models of threat perception in anxiety and indicate that trait elements of anxiety and more transitory fluctuations in anxious affect are important in understanding individual variation in the neural response to threat in late childhood. PMID- 29515478 TI - Creative Persuasion: A Study on Adversarial Behaviors and Strategies in Phishing Attacks. AB - Success of phishing attacks depend on effective exploitation of human weaknesses. This research explores a largely ignored, but crucial aspect of phishing: the adversarial behavior. We aim at understanding human behaviors and strategies that adversaries use, and how these may determine the end-user response to phishing emails. We accomplish this through a novel experiment paradigm involving two phases. In the adversarial phase, 105 participants played the role of a phishing adversary who were incentivized to produce multiple phishing emails that would evade detection and persuade end-users to respond. In the end-user phase, 340 participants performed an email management task, where they examined and classified phishing emails generated by participants in phase-one along with benign emails. Participants in the adversary role, self-reported the strategies they employed in each email they created, and responded to a test of individual creativity. Data from both phases of the study was combined and analyzed, to measure the effect of adversarial behaviors on end-user response to phishing emails. We found that participants who persistently used specific attack strategies (e.g., sending notifications, use of authoritative tone, or expressing shared interest) in all their attempts were overall more successful, compared to others who explored different strategies in each attempt. We also found that strategies largely determined whether an end-user was more likely to respond to an email immediately, or delete it. Individual creativity was not a reliable predictor of adversarial performance, but it was a predictor of an adversary's ability to evade detection. In summary, the phishing example provided initially, the strategies used, and the participants' persistence with some of the strategies led to higher performance in persuading end-users to respond to phishing emails. These insights may be used to inform tools and training procedures to detect phishing strategies in emails. PMID- 29515477 TI - Here Today, Gone Tomorrow? Changes in 4-Month-Olds' Physiologic and Behavioral Responses Do Not Indicate Memory for a Social Stressor. AB - Although much is known about early memory development, only a few studies have explored infants' memory of social stress. While these few studies suggest that infants can remember stressful interactions, limitations seen in both methodology and statistical analyses give pause. In the current study, 4-month-olds and their mothers participated in both stressful and non-stressful interactions over 2 days. On Day 1, memory group infants participated in the double Face-to-Face Still-Face (FFSF) paradigm and control group infants participated in typical play. Both groups experienced the double FFSF paradigm on Day 2. Memory group infants exhibited the standard SF response but no differences in infant cortisol on Day 1. Both infant groups exhibited the standard SF response on Day 2. However, infants in the memory group, who saw the FFSF paradigm for the second time, did not demonstrate changes in cortisol or behavior indicative of memory across the 2 days. There was also no relationship between changes in cortisol and behavior for both days. The findings question the use of salivary cortisol as a measure of social stress and suggest that, although 4-month-olds reacted to the Still-Face social stressor immediately, they did not remember the following day. PMID- 29515479 TI - The Multifactor Measure of Performance: Its Development, Norming, and Validation. AB - This article describes the development as well as the initial norming and validation of the Multifactor Measure of PerformanceTM (MMPTM), which is a psychometric instrument that is designed to study, assess and enhance key predictors of human performance to help individuals perform at a higher level. It was created by the author, for the purpose of going beyond existing conceptual and psychometric models that often focus on relatively few factors that are purported to assess performance at school, in the workplace and elsewhere. The relative sparsity of multifactorial pre-employment assessment instruments exemplifies, for the author, one of the important reasons for developing the MMPTM, which attempts to comprehensively evaluate a wider array of factors that are thought to contribute to performance. In that this situation creates a need in the area of test-construction that should be addressed, the author sought to develop a multifactorial assessment and development instrument that could concomitantly evaluate a combination of physical, cognitive, intra-personal, inter-personal, and motivational factors that significantly contribute to performance. The specific aim of this article is to show why, how and if this could be done as well as to present and discuss the potential importance of the results obtained to date. The findings presented here will hopefully add to what is known about human performance and thus contribute to the professional literature, in addition to contribute to the continued development of the MMPTM. The impetus for developing the MMPTM is first explained below, followed by a detailed description of the process involved and the findings obtained; and their potential application is then discussed as well as the possible limitations of the present research and the need for future studies to address them. PMID- 29515480 TI - Hypernatural Monitoring: A Social Rehearsal Account of Smartphone Addiction. AB - We present a deflationary account of smartphone addiction by situating this purportedly antisocial phenomenon within the fundamentally social dispositions of our species. While we agree with contemporary critics that the hyper connectedness and unpredictable rewards of mobile technology can modulate negative affect, we propose to place the locus of addiction on an evolutionarily older mechanism: the human need to monitor and be monitored by others. Drawing from key findings in evolutionary anthropology and the cognitive science of religion, we articulate a hypernatural monitoring model of smartphone addiction grounded in a general social rehearsal theory of human cognition. Building on recent predictive-processing views of perception and addiction in cognitive neuroscience, we describe the role of social reward anticipation and prediction errors in mediating dysfunctional smartphone use. We conclude with insights from contemplative philosophies and harm-reduction models on finding the right rituals for honoring social connections and setting intentional protocols for the consumption of social information. PMID- 29515482 TI - The Structure of Character Strengths: Variable- and Person-Centered Approaches. AB - This article examines the structure of character strengths (Peterson and Seligman, 2004) following both variable-centered and person-centered approaches. We used the International Personality Item Pool-Values in Action (IPIP-VIA) questionnaire. The IPIP-VIA measures 24 character strengths and consists of 213 direct and reversed items. The present study was conducted in a heterogeneous group of N = 908 Poles (aged 18-78, M = 28.58). It was part of a validation project of a Polish version of the IPIP-VIA questionnaire. The variable-centered approach was used to examine the structure of character strengths on both the scale and item levels. The scale-level results indicated a four-factor structure that can be interpreted based on four of the five personality traits from the Big Five theory (excluding neuroticism). The item-level analysis suggested a slightly different and limited set of character strengths (17 not 24). After conducting a second-order analysis, a four-factor structure emerged, and three of the factors could be interpreted as being consistent with the scale-level factors. Three character strength profiles were found using the person-centered approach. Two of them were consistent with alpha and beta personality metatraits. The structure of character strengths can be described by using categories from the Five Factor Model of personality and metatraits. They form factors similar to some personality traits and occur in similar constellations as metatraits. The main contributions of this paper are: (1) the validation of IPIP-VIA conducted in variable-centered approach in a new research group (Poles) using a different measurement instrument; (2) introducing the person-centered approach to the study of the structure of character strengths. PMID- 29515481 TI - Extraversion Is a Mediator of Gelotophobia: A Study of Autism Spectrum Disorder and the Big Five. AB - Previous research has shown that individuals with autism are frequently mocked in their childhood and are consequently more anxious about being ridiculed. Research has also shown that autistic individuals have a higher level of gelotophobia (fear of being laughed at) compared to typically developed individuals. However, recent studies have also found that gelotophobia is strongly related to personality, which suggests that personality is a factor that helps to create a higher level of gelotophobia in autistic individuals. To investigate whether this is the case, we recruited 279 Taiwanese high school students, 123 with autism spectrum disorder (ASD) and 156 typically developed students as a control group. Self-reporting questionnaires were used to gather data on the Big Five personality traits and on the gelotophobia-related traits of gelotophobia, gelotophilia, and katagelasticism. The results were analyzed and the two groups were compared for differences in gelotophobia and personality. The ASD group was found to have a higher level of gelotophobia than the typically developed group, but lower levels of gelotophilia and katagelasticism. Additionally, the ASD group was found to have lower levels of extraversion and agreeableness than the typically developed group, but no significant difference was found between the two groups in terms of conscientiousness, openness, and emotional stability. We then investigated the possible correlations between gelotophobia-related traits and the Big Five, and consequently the mediation effect of the Big Five on gelotophobia. The results show, firstly, that extraversion rather than ASD is a direct factor in gelotophobia. Secondly, the level of gelotophilia was partly influenced by autism but also to a certain extent by the level of extraversion. Lastly, the results indicate that autism and the level of agreeableness are in conflict when predicting the level of katagelasticism. PMID- 29515483 TI - Testing an Attachment-Based Parenting Intervention-VIPP-FC/A in Adoptive Families with Post-institutionalized Children: Do Maternal Sensitivity and Genetic Markers Count? AB - This study investigated the effectiveness of a newly integrated version of an intervention targeting adoptive mothers' positive parenting for promoting children's emotional availability, by testing the moderating role of both two maternal genetic polymorphisms (i.e., 5HTTLPR and DRD4-VNTR) and emotional availability-EA on intervention outcomes. Mothers with their children (N = 80; Mage = 42.73 years, SD = 3.79; Mage = 33.18 months, SD = 16.83 months) participated in a RCT testing the Video-Feedback Intervention to Promote Positive Parenting and Sensitive Discipline-VIPP-FC/A effectiveness. Mixed effects regression models showed a significant improvement in mother-child EA for the VIPP-intervention vs. the dummy intervention condition, with a moderating role of maternal EA on children's outcomes. No significant moderating effect was found for the two genetic polymorphisms inquired. Children's and mother's outcomes obtained are discussed. PMID- 29515484 TI - The Joint Effects of Spatial Cueing and Transcranial Direct Current Stimulation on Visual Acuity. AB - The present study examined the mutual influence of cortical neuroenhancement and allocation of spatial attention on perception. Specifically, it explored the effects of transcranial Direct Current Stimulation (tDCS) on visual acuity measured with a Landolt gap task and attentional precues. The exogenous cues were used to draw attention either to the location of the target or away from it, generating significant performance benefits and costs. Anodal tDCS applied to posterior occipital area for 15 min improved performance during stimulation, reflecting heightened visual acuity. Reaction times were lower, and accuracy was higher in the tDCS group, compared to a sham control group. Additionally, in post stimulation trials tDCS significantly interacted with the effect of precuing. Reaction times were lower in valid cued trials (benefit) and higher in invalid trials (cost) compared to neutrally cued trials, the effect which was pronounced stronger in tDCS group than in sham control group. The increase of cost and benefit effects in the tDCS group was of a similar magnitude, suggesting that anodal tDCS influenced the overall process of attention orienting. The observed interaction between the stimulation of the visual cortex and precueing indicates a magnification of attention modulation. PMID- 29515485 TI - Personality Traits of Profoundly Hearing Impaired Adolescents with Cochlear Implants - A Comparison with Normal Hearing Peers. AB - The aim of this study was to compare the personality traits of adolescents with cochlear implants (CIs) to a reference group (normal-hearing peers). In the past, the personality development of hearing impaired adolescents was severely compromised. Improved speech perception with CI significantly increased their perspectives. In addition, differences between the reference group and CI users were investigated on personality traits according to level of speech perception skills (high/low) and level of language comprehension (adequate/poor). A cohort of 59 adolescents was assessed 10 years after CI implantation. Personality traits were measured using the standardized Dutch Personality Questionnaire, which consists of 5 scales: Inadequacy, Social Inadequacy, Recalcitrance (RE), Perseverance, and Dominance. Speech perception and language comprehension were tested with standardized tests. The distributions of personality scores, in the clinical or non-clinical range, for the CI group were compared to the reference group using the Chi-Square test for Goodness of Fit. Adolescents with CI showed normal or favorable distributions on all personality scales except for the RE scale. There was a significant influence of speech perception and language comprehension on this scale. Consequently, adolescents with CI who demonstrated high speech perception and adequate language comprehension scores showed similar distribution patterns as the reference group on all personality scales. In conclusion; personality traits that reflect social relations, self-conscience, and school- and task orientation in adolescents with CI are similar to those in normal-hearing peers. This holds, despite variations in speech perception ability and language comprehension levels, for the CI group. On the RE scale, the adolescents with CI with low speech perception and poor language comprehension scores are more likely to score in the clinical deviant range and are at risk. PMID- 29515486 TI - Separability of Lexical and Morphological Knowledge: Evidence from Language Minority Children. AB - Lexical and morphological knowledge of school-aged children are correlated with each other, and are often difficult to distinguish. One reason for this might be that many tasks currently used to assess morphological knowledge require children to inflect or derive real words in the language, thus recruiting their vocabulary knowledge. The current study investigated the possible separability of lexical and morphological knowledge using two complementary approaches. First, we examined the correlations between vocabulary and four morphological tasks tapping different aspects of morphological processing and awareness, and using either real-word or pseudo-word stimuli. Thus, we tested the hypothesis that different morphological tasks recruit lexical knowledge to various degrees. Second, we compared the Hebrew vocabulary and morphological knowledge of 5th grade language minority speaking children to that of their native speaking peers. This comparison allows us to ask whether reduced exposure to the societal language might differentially influence vocabulary and morphological knowledge. The results demonstrate that indeed different morphological tasks rely on lexical knowledge to varying degrees. In addition, language minority students had significantly lower performance in vocabulary and in morphological tasks that recruited vocabulary knowledge to a greater extent. In contrast, both groups performed similarly in abstract morphological tasks with a lower vocabulary load. These results demonstrate that lexical and morphological knowledge may rely on partially separable learning mechanisms, and highlight the importance of distinguishing between these two linguistic components. PMID- 29515487 TI - Robust, Causal, and Incremental Approaches to Investigating Linguistic Adaptation. AB - This paper discusses the maximum robustness approach for studying cases of adaptation in language. We live in an age where we have more data on more languages than ever before, and more data to link it with from other domains. This should make it easier to test hypotheses involving adaptation, and also to spot new patterns that might be explained by adaptation. However, there is not much discussion of the overall approach to research in this area. There are outstanding questions about how to formalize theories, what the criteria are for directing research and how to integrate results from different methods into a clear assessment of a hypothesis. This paper addresses some of those issues by suggesting an approach which is causal, incremental and robust. It illustrates the approach with reference to a recent claim that dry environments select against the use of precise contrasts in pitch. Study 1 replicates a previous analysis of the link between humidity and lexical tone with an alternative dataset and finds that it is not robust. Study 2 performs an analysis with a continuous measure of tone and finds no significant correlation. Study 3 addresses a more recent analysis of the link between humidity and vowel use and finds that it is robust, though the effect size is small and the robustness of the measurement of vowel use is low. Methodological robustness of the general theory is addressed by suggesting additional approaches including iterated learning, a historical case study, corpus studies, and studying individual speech. PMID- 29515488 TI - Well-Being and Functioning at Work Following Thefts and Robberies: A Comparative Study. AB - Thefts and robberies may be traumatizing experiences for employees. The aim of this study is to explore to what extent experiencing robberies and/or thefts at work affect workers' mental health, coping-self-efficacy, social support seeking, workload and job satisfaction. Drawing on Conservation of Resources theory, this research contributes to our understanding of the psychological sequelae of robbery and theft for employees working in small businesses. The few studies on the effects of robberies and thefts in the past have predominantly focused on bank employees. A sample of Italian tobacconists and jewelers completed an anonymous self-report questionnaire examining the experience of robbery and/or theft, social support seeking (Coping Orientation to Problem Experienced scale, COPE-IV), psycho-somatic well-being (General Health Questionnaire, GHQ-12), job satisfaction (a single item). Victims of thefts and/or robberies reported their PTSD symptoms (Impact of Event- Revised 6, IES-R-6) and trauma-related coping self-efficacy (Coping Self-Efficacy scale, CSE-7), based on the last event (N = 319). Descriptive analyses, ANOVA, ANCOVA and multiple regressions analyses have been carried out. The results indicated that victims of thefts and robberies experienced greater workload, higher psycho-physical complaints and greater tendency to seek social support in comparison with their non-affected counterparts. They additionally experienced more post-traumatic symptomatology and perceived lower coping self-efficacy, when compared to those who experienced thefts "only." Multiple regression analyses revealed that CSE was positively related to job satisfaction, although the presence of psycho-physical symptoms was the main predictor of job satisfaction among both non-affected and affected employees. PTSD was not an independent predictor of job satisfaction. In sum, robberies and/or thefts exposure undermines differently workers' well-being. PMID- 29515490 TI - Analyzing Global Components in Developmental Dyscalculia and Dyslexia. AB - The study examined whether developmental deficits in reading and numerical skills could be expressed in terms of global factors by reference to the rate and amount (RAM) and difference engine (DEM) models. From a sample of 325 fifth grade children, we identified 5 children with dyslexia, 16 with dyscalculia, 7 with a "mixed pattern," and 49 control children. Children were asked to read aloud words presented individually that varied for frequency and length and to respond (either vocally or manually) to a series of simple number tasks (addition, subtraction, number reading, and number comparisons). Reaction times were measured. Results indicated that the deficit of children with dyscalculia and children with a mixed pattern on numerical tasks could be explained by a single global factor, similarly to the reading deficit shown by children with dyslexia. As predicted by the DEM, increases in task difficulty were accompanied by a corresponding increase in inter-individual variability for both the reading and numerical tasks. These relationships were constant across the four groups of children but differed in terms of slope and intercept on the x-axis, indicating that two different general rules underlie performance in reading and numerical skills. The study shows for the first time that, as previously shown for reading, also numerical performance can be explained with reference to a global factor. The advantage of this approach is that it takes into account the over-additivity effect, i.e., the presence of larger group differences in the case of more difficult conditions over and above the characteristics of the experimental conditions. It is concluded that reference to models such as the RAM and DEM can be useful in delineating the characteristics of the dyscalculic deficit as well as in the description of co-morbid disturbances, as in the case of dyslexia and dyscalculia. PMID- 29515491 TI - Consistent Partial Least Squares Path Modeling via Regularization. AB - Partial least squares (PLS) path modeling is a component-based structural equation modeling that has been adopted in social and psychological research due to its data-analytic capability and flexibility. A recent methodological advance is consistent PLS (PLSc), designed to produce consistent estimates of path coefficients in structural models involving common factors. In practice, however, PLSc may frequently encounter multicollinearity in part because it takes a strategy of estimating path coefficients based on consistent correlations among independent latent variables. PLSc has yet no remedy for this multicollinearity problem, which can cause loss of statistical power and accuracy in parameter estimation. Thus, a ridge type of regularization is incorporated into PLSc, creating a new technique called regularized PLSc. A comprehensive simulation study is conducted to evaluate the performance of regularized PLSc as compared to its non-regularized counterpart in terms of power and accuracy. The results show that our regularized PLSc is recommended for use when serious multicollinearity is present. PMID- 29515492 TI - Preservice Preschool Teachers' Responses to Bullying Scenarios: The Roles of Years of Study and Empathy. AB - The present study is aim to examine whether preservice preschool teachers' respond differently to physical, verbal and relational bullying, and how their years of study and trait empathy related their responses. There were 242 preservice teachers in the present study. Empathy was measured with the self report Interpersonal Reactive Index; the Bullying Attitude Questionnaire was used to assess their perceptions of incident seriousness, their sympathy toward the victim of the bullying, and their possibility to intervene in the situation. The results revealed that the participants responded most to physical bullying and least to relational bullying. Interestingly, responses to relational bullying tended to decrease during the university period. The empathy dimensions played different roles in the participants' responses to bullying, while cognitive empathy have little relationship with the participants' responses to bullying, emotional empathy played a more complex role in the participants' responses to bullying: empathic concerns moderated the relationship between years of study and responses to bullying, and personal distress negatively predicted the participants' responses to all types of bullying. The implications for bullying intervention and the suggestion for teacher education are discussed. PMID- 29515493 TI - Referential Choices in a Collaborative Storytelling Task: Discourse Stages and Referential Complexity Matter. AB - During a narrative discourse, accessibility of the referents is rarely fixed once and for all. Rather, each referent varies in accessibility as the discourse unfolds, depending on the presence and prominence of the other referents. This leads the speaker to use various referential expressions to refer to the main protagonists of the story at different moments in the narrative. This study relies on a new, collaborative storytelling in sequence task designed to assess how speakers adjust their referential choices when they refer to different characters at specific discourse stages corresponding to the introduction, maintaining, or shift of the character in focus, in increasingly complex referential contexts. Referential complexity of the stories was manipulated through variations in the number of characters (1 vs. 2) and, for stories in which there were two characters, in their ambiguity in gender (different vs. same gender). Data were coded for the type of reference markers as well as the type of reference content (i.e., the extent of the information provided in the referential expression). Results showed that, beyond the expected effects of discourse stages on reference markers (more indefinite markers at the introduction stage, more pronouns at the maintaining stage, and more definite markers at the shift stage), the number of characters and their ambiguity in gender also modulated speakers' referential choices at specific discourse stages, For the maintaining stage, an effect of the number of characters was observed for the use of pronouns and of definite markers, with more pronouns when there was a single character, sometimes replaced by definite expressions when two characters were present in the story. For the shift stage, an effect of gender ambiguity was specifically noted for the reference content with more specific information provided in the referential expression when there was referential ambiguity. Reference content is an aspect of referential marking that is rarely addressed in a narrative context, yet it revealed a quite flexible referential behavior by the speakers. PMID- 29515489 TI - Cognitive Impairment in Parkinson's Disease Is Reflected with Gradual Decrease of EEG Delta Responses during Auditory Discrimination. AB - Parkinson's disease (PD) is a neurodegenerative disease that is characterized by loss of dopaminergic neurons in the substantia nigra. Mild Cognitive impairment (MCI) and dementia may come along with the disease. New indicators are necessary for detecting patients that are likely to develop dementia. Electroencephalogram (EEG) Delta responses are one of the essential electrophysiological indicators that could show the cognitive decline. Many research in literature showed an increase of delta responses with the increased cognitive load. Furthermore, delta responses were decreased in MCI and Alzheimer disease in comparison to healthy controls during cognitive paradigms. There was no previous study that analyzed the delta responses in PD patients with cognitive deficits. The present study aims to fulfill this important gap. 32 patients with Parkinson's disease (12 of them were without any cognitive deficits, 10 of them were PD with MCI, and 10 of them were PD with dementia) and 16 healthy subjects were included in the study. Auditory simple stimuli and Auditory Oddball Paradigms were applied. The maximum amplitudes of each subject's delta response (0.5-3.5 Hz) in 0-600 ms were measured for each electrode and for each stimulation. There was a significant stimulation * group effect [F(df = 6,88) = 3,21; p < 0.015; [Formula: see text] = 0.180], which showed that the difference between groups was specific to the stimulation. Patients with Parkinson's disease (including PD without cognitive deficit, PD with MCI, and PD with dementia) had reduced delta responses than healthy controls upon presentation of target stimulation (p < 0.05, for all comparisons). On the other hand, this was not the case for non-target and simple auditory stimulation. Furthermore, delta responses gradually decrease according to the cognitive impairment in patients with PD. Conclusion: The results of the present study showed that cognitive decline in PD could be represented with decreased event related delta responses during cognitive stimulations. Furthermore, the present study once more strengthens the hypothesis that decrease of delta oscillatory responses could be the candidate of a general electrophysiological indicator for cognitive impairment. PMID- 29515494 TI - Cross-Modal Perception of Noise-in-Music: Audiences Generate Spiky Shapes in Response to Auditory Roughness in a Novel Electroacoustic Concert Setting. AB - Noise has become integral to electroacoustic music aesthetics. In this paper, we define noise as sound that is high in auditory roughness, and examine its effect on cross-modal mapping between sound and visual shape in participants. In order to preserve the ecological validity of contemporary music aesthetics, we developed Rama, a novel interface, for presenting experimentally controlled blocks of electronically generated sounds that varied systematically in roughness, and actively collected data from audience interaction. These sounds were then embedded as musical drones within the overall sound design of a multimedia performance with live musicians, Audience members listened to these sounds, and collectively voted to create the shape of a visual graphic, presented as part of the audio-visual performance. The results of the concert setting were replicated in a controlled laboratory environment to corroborate the findings. Results show a consistent effect of auditory roughness on shape design, with rougher sounds corresponding to spikier shapes. We discuss the implications, as well as evaluate the audience interface. PMID- 29515496 TI - Confirmatory Factor Analysis of the French Version of the Savoring Beliefs Inventory. AB - The Savoring Beliefs Inventory (SBI) is a measure designed to assess attitudes toward savoring positive experience within three temporal orientations: the past (reminiscence), the present moment (present enjoyment), and the future (anticipation). The aim of this study was to validate the structure of the SBI French version. The scale was tested with 335 French-speaking participants. Two models were estimated: a one-factor model representing a general construct of savoring and a three-factor model differentiating between anticipation, present enjoyment, and reminiscence. Several indicators of model fit were used: the root mean square error of approximation (RMSEA), the comparison fit index (CFI), the Tucker-Lewis fit index (TLI), and the standardized root mean residual (SRMR). A chi-square difference test was used to compare the two models. The model fit of the three-factor model assessed by the SRMR showed to be excellent, while it could be considered as satisfactory according to the CFI and TLI coefficients. RMSEA, however, was slightly less adequate. The model fit for the one-factor model seemed less adequate than the three-factor solution. Further, the chi square difference test revealed that the three-factor model had significantly better fit than the one-factor model. Finally, the reliability of the four scores (anticipating pleasure, present moment pleasure, reminiscing pleasure, and total score) was very good. These results show that the French version of the SBI is a valid and valuable scale to measure attitudes regarding the ability to savor positive experience, whether it be in anticipation, reminiscence, or the present moment. PMID- 29515495 TI - The Interaction between Interoceptive and Action States within a Framework of Predictive Coding. AB - The notion of predictive coding assumes that perception is an iterative process between prior knowledge and sensory feedback. To date, this perspective has been primarily applied to exteroceptive perception as well as action and its associated phenomenological experiences such as agency. More recently, this predictive, inferential framework has been theoretically extended to interoception. This idea postulates that subjective feeling states are generated by top-down inferences made about internal and external causes of interoceptive afferents. While the processing of motor signals for action control and the emergence of selfhood have been studied extensively, the contributions of interoceptive input and especially the potential interaction of motor and interoceptive signals remain largely unaddressed. Here, we argue for a specific functional relation between motor and interoceptive awareness. Specifically, we implicate interoceptive predictions in the generation of subjective motor-related feeling states. Furthermore, we propose a distinction between reflexive and pre reflexive modes of agentic action control and suggest that interoceptive input may affect each differently. Finally, we advocate the necessity of continuous interoceptive input for conscious forms of agentic action control. We conclude by discussing further research contributions that would allow for a fuller understanding of the interaction between agency and interoceptive awareness. PMID- 29515498 TI - Feelings-As-Embodied Information: Studying the Role of Feelings As Images in Emotional Disorders. PMID- 29515497 TI - Social Support Modulates Neural Responses to Unfairness in the Ultimatum Game. AB - The current functional MRI study aimed to investigate how responders' fairness considerations and related decision-making processes were affected by social support in the ultimatum game (UG). During scanning, responders either played the standard UG with proposers (control condition) or played the modified UG in which three unknown observers showed social support for responders by acknowledging proposers' norm violation. Results revealed that participants reported higher unfairness feelings and rejection rates of unfair offers in the social support condition relative to the control condition. At the neural level, compared to the control condition, perception of social support from others induced greater activations of anterior cingulate gyrus and right anterior insula when receiving unfair (vs. fair) offers. The medial prefrontal cortex and right anterior insula were more active when the unfair offers were rejected (vs. accepted) in the social support condition than the control condition. These results highlighted the modulation effect of social support on responders' fairness considerations and related decision-making processes. PMID- 29515499 TI - Unusual Configurations of Personality Traits Indicate Multiple Patterns of Their Coalescence. AB - It is widely accepted that the Five Factor Model (FFM) is a satisfactory description of the pattern of covariations among personality traits, which supposedly fits, more or less adequately, every individual. As an amendment to the FFM, we propose that the customary five-factor structure is only a near universal, because it does not fit all individuals but only a large majority of them. Evidences reveal a small minority of participants who have an unusual configuration of personality traits, which is clearly recognizable, both in self- and observer-ratings. We identified three types of atypical configurations of personality traits, characterized mainly by a scatter of subscale scores within each of the FFM factors. How different configurations of personality traits are formed, persist, and function needs further investigation. PMID- 29515500 TI - "The Early Specialised Bird Catches the Worm!" - A Specialised Sampling Model in the Development of Football Talents. AB - Characteristics of learning activities in early sport participation play a key role in the development of the sporting talent. Therefore, pathways of specialisation or diversification/sampling are as well debated as the implementation of practice- or play-oriented activities. The related issues are currently perceived as a two-dimensional construct of domain specificity and performance orientation. In this context, it has been shown that early specialisation, with experiences in practice and play, has led to Swiss junior national team football players reaching higher success levels as adults. This study aimed to examine whether a similar approach improves chances of even being selected for junior national teams from a broader sample. Hence, 294 youth players answered retrospective questionnaires on their early sport participation when entering the Swiss football talent development programme. Using the person oriented Linking of Clusters after removal of a Residue (LICUR) method, volumes of in-club practice, free play and activities besides football until 12 years of age were analysed along with age at initial club participation. According to the results, clusters of Football enthusiasts (p = 0.01) with the most free play and above average in-club practice and Club players (p = 0.02) with the most in-club practice and average free play had a greater chance of reaching junior national team level. Thus, high levels of domain-specific activities seem to increase the chances of junior national team participation. Furthermore, the most successful constellation (Football enthusiasts) may illustrate the relevance of domain specific diversity, induced by several types of practice and play. In line with previous studies, specialising in football and sampling different experiences within this specific domain seems to be the most promising pathway. Therefore, we argue that the optimal model for the development of football talents is a specialised sampling model. PMID- 29515501 TI - Topic Modeling Reveals Distinct Interests within an Online Conspiracy Forum. AB - Conspiracy theories play a troubling role in political discourse. Online forums provide a valuable window into everyday conspiracy theorizing, and can give a clue to the motivations and interests of those who post in such forums. Yet this online activity can be difficult to quantify and study. We describe a unique approach to studying online conspiracy theorists which used non-negative matrix factorization to create a topic model of authors' contributions to the main conspiracy forum on Reddit.com. This subreddit provides a large corpus of comments which spans many years and numerous authors. We show that within the forum, there are multiple sub-populations distinguishable by their loadings on different topics in the model. Further, we argue, these differences are interpretable as differences in background beliefs and motivations. The diversity of the distinct subgroups places constraints on theories of what generates conspiracy theorizing. We argue that traditional "monological" believers are only the tip of an iceberg of commenters. Neither simple irrationality nor common preoccupations can account for the observed diversity. Instead, we suggest, those who endorse conspiracies seem to be primarily brought together by epistemological concerns, and that these central concerns link an otherwise heterogenous group of individuals. PMID- 29515502 TI - The Mental Representation of Polysemy across Word Classes. AB - Experimental studies on polysemy have come to contradictory conclusions on whether words with multiple senses are stored as separate or shared mental representations. The present study examined the semantic relatedness and semantic similarity of literal and non-literal (metonymic and metaphorical) senses of three word classes: nouns, verbs, and adjectives. Two methods were used: a psycholinguistic experiment and a distributional analysis of corpus data. In the experiment, participants were presented with 6-12 short phrases containing a polysemous word in literal, metonymic, or metaphorical senses and were asked to classify them so that phrases with the same perceived sense were grouped together. To investigate the impact of professional background on their decisions, participants were controlled for linguistic vs. non-linguistic education. For nouns and verbs, all participants preferred to group together phrases with literal and metonymic senses, but not any other pairs of senses. For adjectives, two pairs of senses were often grouped together: literal with metonymic, and metonymic with metaphorical. Participants with a linguistic background were more accurate than participants with non-linguistic backgrounds, although both groups shared principal patterns of sense classification. For the distributional analysis of corpus data, we used a semantic vector approach to quantify the similarity of phrases with literal, metonymic, and metaphorical senses in the corpora. We found that phrases with literal and metonymic senses had the highest degree of similarity for the three word classes, and that metonymic and metaphorical senses of adjectives had the highest degree of similarity among all word classes. These findings are in line with the experimental results. Overall, the results suggest that the mental representation of a polysemous word depends on its word class. In nouns and verbs, literal and metonymic senses are stored together, while metaphorical senses are stored separately; in adjectives, metonymic senses significantly overlap with both literal and metaphorical senses. PMID- 29515503 TI - The Influence of the Tri-reference Points on Fairness and Satisfaction Perception. AB - We examined the influence of three reference points (minimum requirements [MR], the status quo [SQ], and goal [G]) proposed by the tri-reference point (TRP) theory on fairness and satisfaction perceptions of pay in three laboratory experiments. To test the effects, we manipulated these three reference points both implicitly (Experiment 1) and explicitly (Experiments 2 and 3). We also provided the information of the salary offered to a peer person that was lower than, equal to, or higher than the salary offer to the participant. As hypothesized, the results demonstrated the important role of these reference points in judging the fairness of and satisfaction with pay when they were explicitly set (an interaction between reference points and social comparison in Experiments 2 and 3, but not in Experiment 1). Participants altered their judgments when the salary was in different regions. When the salary was below MR, participants perceived very low fairness and satisfaction, even when the offer was equal to/exceeded others. When the salary was above G, participants perceived much higher fairness and satisfaction, even with disadvantageous inequality. Participants were more impacted when they were explicitly instructed of the reference points (Experiments 2 and 3) than when they were not (Experiment 1). Moreover, MR appeared to be the most important, followed by G. A Salary below MR was judged as very unacceptable, with very low fairness and satisfaction ratings. PMID- 29515504 TI - Helpful and Hindering Factors in Psychodrama Field Training: A Longitudinal Mixed Methods Study of Student Development. AB - Although the literature indicates that students in mental health professions start to form their professional identity and competence in graduate school, there are few studies on the in-training experience of creative arts therapies students. This mixed methods study examined how five first-year students in a psychodrama master's degree program in Israel experienced their field training, with the aim of identifying the factors likely to promote or hinder the development of their professional identity and sense of professional ability. Longitudinal data were collected weekly throughout the 20-week field training experience. The students reported qualitatively on helpful and hindering factors and were assessed quantitatively on questionnaires measuring professional identity, perceived demands-abilities fit, client involvement, and therapy session evaluations. A thematic analysis of the students' reports indicated that a clear and defined setting and structure, observing the instructor as a role model, actively leading parts of the session, and observing fellow students were all helpful factors. The hindering factors included role confusion, issues related to coping with client resistance and disciplinary problems, as well as school end-of-year activities that disrupted the continuity of therapy. The quantitative results indicated that students' professional identity did not significantly change over the year, whereas a U-shaped curve trajectory characterized the changes in demands-abilities fit and other measures. Students began their field training with an overstated sense of ability that soon declined and later increased. These findings provide indications of which helping and hindering factors should be maximized and minimized, to enhance students' field training. PMID- 29515505 TI - Psychometric Properties of the Positivity Scale among Chinese Adults and Early Adolescents. AB - We conducted two studies to explore the psychometric properties of the Positivity Scale (P Scale) among Chinese adults and early adolescents, using a sample of 552 adults (Study 1) and a sample of 888 early adolescents (i.e., middle school students) (Study 2). First, item analyses and factor analyses were conducted to investigate the one-factor structure of the P Scale. Second, internal consistency reliability, test-retest reliability, and external evidences of validity were evaluated to examine its reliability and validity. Last, we used multi-group confirmatory factor analysis to test measurement invariance across gender. The two studies both provided evidence for its reliability and validity among Chinese adults and early adolescents. For the test of measurement invariance across gender, full scalar invariance was established among early adolescents; partial scalar invariance was supported among adults. Taken together, the results provided preliminary support in the Chinese context for the P Scale as a valid measure to assess the general disposition toward viewing life and experiences in a positive manner. The potential applications for future research and professional practice are discussed. PMID- 29515506 TI - Sociolinguistic Typology and Sign Languages. AB - This paper examines the possible relationship between proposed social determinants of morphological 'complexity' and how this contributes to linguistic diversity, specifically via the typological nature of the sign languages of deaf communities. We sketch how the notion of morphological complexity, as defined by Trudgill (2011), applies to sign languages. Using these criteria, sign languages appear to be languages with low to moderate levels of morphological complexity. This may partly reflect the influence of key social characteristics of communities on the typological nature of languages. Although many deaf communities are relatively small and may involve dense social networks (both social characteristics that Trudgill claimed may lend themselves to morphological 'complexification'), the picture is complicated by the highly variable nature of the sign language acquisition for most deaf people, and the ongoing contact between native signers, hearing non-native signers, and those deaf individuals who only acquire sign languages in later childhood and early adulthood. These are all factors that may work against the emergence of morphological complexification. The relationship between linguistic typology and these key social factors may lead to a better understanding of the nature of sign language grammar. This perspective stands in contrast to other work where sign languages are sometimes presented as having complex morphology despite being young languages (e.g., Aronoff et al., 2005); in some descriptions, the social determinants of morphological complexity have not received much attention, nor has the notion of complexity itself been specifically explored. PMID- 29515507 TI - Effects of an Inquiry-Based Short Intervention on State Test Anxiety in Comparison to Alternative Coping Strategies. AB - Background and Objectives: Test anxiety can have undesirable consequences for learning and academic achievement. The control-value theory of achievement emotions assumes that test anxiety is experienced if a student appraises an achievement situation as important (value appraisal), but feels that the situation and its outcome are not fully under his or her control (control appraisal). Accordingly, modification of cognitive appraisals is assumed to reduce test anxiety. One method aiming at the modification of appraisals is inquiry-based stress reduction. In the present study (N = 162), we assessed the effects of an inquiry-based short intervention on test anxiety. Design: Short term longitudinal, randomized control trial. Methods: Focusing on an individual worry thought, 53 university students received an inquiry-based short intervention. Control participants reflected on their worry thought (n = 55) or were distracted (n = 52). Thought related test anxiety was assessed before, immediately after, and 2 days after the experimental treatment. Results: After the intervention as well as 2 days later, individuals who had received the inquiry-based intervention demonstrated significantly lower test anxiety than participants from the pooled control groups. Further analyses showed that the inquiry-based short intervention was more effective than reflecting on a worry thought but had no advantage over distraction. Conclusions: Our findings provide first experimental evidence for the effectiveness of an inquiry-based short intervention in reducing students' test anxiety. PMID- 29515508 TI - The Dynamic Features of Lip Corners in Genuine and Posed Smiles. AB - The smile is a frequently expressed facial expression that typically conveys a positive emotional state and friendly intent. However, human beings have also learned how to fake smiles, typically by controlling the mouth to provide a genuine-looking expression. This is often accompanied by inaccuracies that can allow others to determine that the smile is false. Mouth movement is one of the most striking features of the smile, yet our understanding of its dynamic elements is still limited. The present study analyzes the dynamic features of lip corners, and considers how they differ between genuine and posed smiles. Employing computer vision techniques, we investigated elements such as the duration, intensity, speed, symmetry of the lip corners, and certain irregularities in genuine and posed smiles obtained from the UvA-NEMO Smile Database. After utilizing the facial analysis tool OpenFace, we further propose a new approach to segmenting the onset, apex, and offset phases of smiles, as well as a means of measuring irregularities and symmetry in facial expressions. We extracted these features according to 2D and 3D coordinates, and conducted an analysis. The results reveal that genuine smiles have higher values for onset, offset, apex, and total durations, as well as offset displacement, and a variable we termed Irregularity-b (the SD of the apex phase) than do posed smiles. Conversely, values tended to be lower for onset and offset Speeds, and Irregularity-a (the rate of peaks), Symmetry-a (the correlation between left and right facial movements), and Symmetry-d (differences in onset frame numbers between the left and right faces). The findings from the present study have been compared to those of previous research, and certain speculations are made. PMID- 29515509 TI - "The Less I Think About It, the Better I Feel": A Thematic Analysis of the Subjective Experience of Malignant Mesothelioma Patients and Their Caregivers. AB - Aim: A cancer diagnosis-and in particular a Malignant Mesothelioma (MM) one breaks the somatopsychic balance of the individual, compromising the quality of residual life and giving rise to many negative emotions difficult to integrate and to elaborate (such as depression, fears, anxieties, hopelessness, guilt, shame, and rage). Several national and international guidelines acknowledged the importance of evaluating psychological and socio-relational features in MM patients and their caregiver. However, only few studies have investigated the subjective experience of MM patients and even less research has focused on the caregivers' experience. Thus, the aim of the present study is to investigate the lived experience of both MM patients and their caregivers, providing an in-depth comprehension of the psychological sequelae of the disease. Materials and Methods: Within a psychoanalytically-informed conceptual framework, open-ended interviews were conducted with 10 MM patients and 9 caregivers. Thematic analysis was employed: interviews were audio-recorded, transcribed verbatim, and coded in order to identify the main recurring themes across the narratives. Results: We detected four different themes: (1) bodily symptoms and embodied emotions; (2) living in or near a National Priority Contaminated Site (NCPS); (3) "nothing is like it was" (that is, the impact of the diagnosis on everyday life, the changes it causes in the family relationships, the things that are still possible to do, the mourning process); (4) "what will become of us?" (that is, worries about the impact of the diagnosis on the beloved ones, death and legacy). Discussion: MM patients and caregivers seem to be stuck in a concrete mental functioning focused on symptoms and they find it difficult to openly think and talk about the affective and emotional consequences of the diagnosis. Alongside this, they express the need to find new and less conflictual ways to stay together and talk to each other during the period of active treatments for the illness (i.e., chemotherapy, radiotherapy, etc) and the end-of-life. The results of this study have important implications for the clinical management of MM and can help develop multi-professional specialist interventions addressed to both patients and caregivers. PMID- 29515510 TI - Commentary: Heads-up limit hold'em poker is solved. PMID- 29515511 TI - Group Facial Width-to-Height Ratio Predicts Intergroup Negotiation Outcomes. AB - Past studies have found that the facial width-to-height ratio (FWHR) is associated with a range of traits and behaviors that are possibly important to dyadic negotiations. However, it is unknown whether the FWHR would have an impact on intergroup negotiations, which happen frequently and often have higher stakes in the real world. To examine this question, in the current study, we randomly assigned 1,337 Chinese business executives into 288 groups and they completed a multi-issue negotiation exercise against each other. Results showed that groups with larger maximum individual FWHRs achieved objectively better negotiation outcomes. We conclude that groups containing individuals with relatively large FWHRs can claim more value in negotiations between groups. PMID- 29515512 TI - Stimulation Induced Electrographic Seizures in Deep Brain Stimulation of the Anterior Nucleus of the Thalamus Do Not Preclude a Subsequent Favorable Treatment Response. AB - Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a method of neuromodulation used for refractory focal epilepsy. We report a patient suffering from drug-resistant epilepsy who developed novel visual symptoms and atypical seizures with the onset of ANT-DBS therapy. Rechallenge under video electroencephalography recording confirmed that lowering the stimulation voltage alleviated these symptoms. Subsequent stimulation with the initial voltage value did not cause the recurrence of either the visual symptoms or the new seizure type, and appeared to alleviate the patient's seizures in long-term follow-up. We therefore hypothesize that the occurrence of stimulation induced seizures at the onset of DBS therapy should not be considered as a failure in the DBS therapy, and the possibility of a subsequent favorable response to the treatment still exists. PMID- 29515513 TI - Immersive Low-Cost Virtual Reality Treatment for Phantom Limb Pain: Evidence from Two Cases. AB - Up to 90% of amputees experience sensations in their phantom limb, often including strong, persistent phantom limb pain (PLP). Standard treatments do not provide relief for the majority of people who experience PLP, but virtual reality (VR) has shown promise. This study provides additional evidence that game-like training with low-cost immersive VR activities can reduce PLP in lower-limb amputees. The user of our system views a real-time rendering of two intact legs in a head-mounted display while playing a set of custom games. The movements of both virtual extremities are controlled by measurements from inertial sensors mounted on the intact and residual limbs. Two individuals with unilateral transtibial amputation underwent multiple sessions of the VR treatment over several weeks. Both participants experienced a significant reduction of pain immediately after each VR session, and their pre-session pain levels also decreased greatly over the course of the study. Although preliminary, these data support the idea that VR interventions like ours may be an effective low-cost treatment of PLP in lower-limb amputees. PMID- 29515514 TI - Progressive Abduction Loading Therapy with Horizontal-Plane Viscous Resistance Targeting Weakness and Flexion Synergy to Treat Upper Limb Function in Chronic Hemiparetic Stroke: A Randomized Clinical Trial. AB - Background: Progressive abduction loading therapy has emerged as a promising exercise therapy in stroke rehabilitation to systematically target the loss of independent joint control (flexion synergy) in individuals with chronic moderate/severe upper-extremity impairment. Preclinical investigations have identified abduction loading during reaching exercise as a key therapeutic factor to improve reaching function. An augmentative approach may be to additionally target weakness by incorporating resistance training to increase constitutive joint torques of reaching with the goal of improving reaching function by "overpowering" flexion synergy. The objective was, therefore, to determine the therapeutic effects of horizontal-plane viscous resistance in combination with progressive abduction loading therapy. Methods: 32 individuals with chronic hemiparetic stroke were randomly allocated to two groups. The two groups had equivalent baseline characteristics on all demographic and outcome metrics including age (59 +/- 11 years), time poststroke (10.1 +/- 7.6 years), and motor impairment (Fugl-Meyer, 26.7 +/- 6.5 out of 66). Both groups received therapy three times/week for 8 weeks while the experimental group included additional horizontal-plane viscous resistance. Quantitative standardized progression of the intervention was achieved using a robotic device. The primary outcomes of reaching distance and velocity under maximum abduction loading and secondary outcomes of isometric strength and a clinical battery were measured at pre-, post , and 3 months following therapy. Results: There was no difference between groups on any outcome measure. However, for combined groups, there was a significant increase in reaching distance (13.2%, effect size; d = 0.56) and velocity (13.6%, effect size; d = 0.27) at posttesting that persisted for 3 months and also a significant increase in abduction, elbow extension, and external rotation strength at posttesting that did not persist 3 months. Similarly, the clinical battery demonstrated a significant improvement in participant-reported measures of "physical problems" and "overall recovery" across all participants. Conclusion: The strengthening approach of incorporating horizontal-plane viscous resistance did not enhance the reaching function improvements observed in both groups. Data do not support the postulation that one can be trained to "overpower" the flexion synergy with resistance training targeting constitutive joint torques of reaching. Instead, flexion synergy must be targeted with progressive abduction loading to improve reaching function. Trial Registration: ClinicalTrials.gov, NCT01548781. PMID- 29515515 TI - Chronic Hypopituitarism Associated with Increased Postconcussive Symptoms Is Prevalent after Blast-Induced Mild Traumatic Brain Injury. AB - The most frequent injury sustained by US service members deployed to Iraq or Afghanistan is mild traumatic brain injuries (mTBI), or concussion, by far most often caused by blast waves from improvised explosive devices or other explosive ordnance. TBI from all causes gives rise to chronic neuroendocrine disorders with an estimated prevalence of 25-50%. The current study expands upon our earlier finding that chronic pituitary gland dysfunction occurs with a similarly high frequency after blast-related concussions. We measured circulating hormone levels and accessed demographic and testing data from two groups of male veterans with hazardous duty experience in Iraq or Afghanistan. Veterans in the mTBI group had experienced one or more blast-related concussion. Members of the deployment control (DC) group encountered similar deployment conditions but had no history of blast-related mTBI. 12 of 39 (31%) of the mTBI participants and 3 of 20 (15%) veterans in the DC group screened positive for one or more neuroendocrine disorders. Positive screens for growth hormone deficiency occurred most often. Analysis of responses on self-report questionnaires revealed main effects of both mTBI and hypopituitarism on postconcussive and posttraumatic stress disorder (PTSD) symptoms. Symptoms associated with pituitary dysfunction overlap considerably with those of PTSD. They include cognitive deficiencies, mood and anxiety disorders, sleep problems, diminished quality of life, deleterious changes in metabolism and body composition, and increased cardiovascular mortality. When such symptoms are due to hypopituitarism, they may be alleviated by hormone replacement. These findings suggest consideration of routine post deployment neuroendocrine screening of service members and veterans who have experienced blast-related mTBI and are reporting postconcussive symptoms. PMID- 29515517 TI - Cushing's Syndrome and Hypothalamic-Pituitary-Adrenal Axis Hyperactivity in Chronic Central Serous Chorioretinopathy. AB - Objective: Central serous chorioretinopathy (CSC), a specific form of macular degeneration, has been reported as presenting manifestation of Cushing's syndrome. Furthermore, CSC has been associated with both exogenous hypercortisolism and endogenous Cushing's syndrome. It is important to know whether CSC patients should be screened for Cushing's syndrome. Although hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in CSC has been suggested, no detailed evaluation of the HPA axis has been performed in a large cohort of CSC patients. This study aimed to investigate whether Cushing's syndrome prevalence is increased among chronic CSC (cCSC) patients and whether detailed endocrinological phenotyping indicates hyperactivity of the HPA axis. Design: Cross-sectional study. Patients: 86 cCSC patients and 24 controls. Measurements: Prevalence of Cushing's syndrome, HPA axis activity. Results: None of the cCSC patients met the clinical or biochemical criteria of Cushing's syndrome. However, compared to controls, HPA axis activity was increased in cCSC patients, reflected by higher 24 h urinary free cortisol, and accompanying higher waist circumference and diastolic blood pressure, whereas circadian cortisol rhythm and feedback were not different. Chronic CSC patients did not report more stress or stress-related problems on questionnaires. Conclusion: No case of Cushing's syndrome was revealed in a large cohort of cCSC patients. Therefore, we advise against screening for Cushing's syndrome in CSC patients, unless additional clinical features are present. However, our results indicate that cCSC is associated with hyperactivity of the HPA axis, albeit not accompanied with perception of more psychosocial stress. PMID- 29515516 TI - Cystic Fibrosis-Related Diabetes. AB - Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD), which affects 40-50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR) also has important roles in the release of insulin and glucagon and in the protection of beta cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups. PMID- 29515518 TI - Nordic Walking Training Causes a Decrease in Blood Cholesterol in Elderly Women Supplemented with Vitamin D. AB - Objective: Different studies have demonstrated that regular exercise can induce changes in the lipid profile, but results remain inconclusive. Available data suggest that correction of vitamin D deficiency can improve the lipid profile. In this study, we have hypothesized that Nordic Walking training will improve lipid profile in elderly women supplemented with vitamin D. Methods: A total of 109 elderly women (68 +/- 5.12 years old) took part in the study. First group [experimental group (EG): 35 women] underwent 12 weeks of Nordic Walking (NW) training combined with vitamin D supplementation (4,000 IU/day), second group [supplementation group (SG): 48 women] was only supplemented with vitamin D (4,000 IU/day), and third group [control group (CG): 31 women] was not subject to any interventions. Blood analysis of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and 25-OH-D3 was performed at baseline and after the 12 weeks of NW training. Additionally, a battery of field tests specifically developed for older adults was used to assess the components of functional fitness. The same blood analysis was repeated for the EG 6 months after the main experiment. Results: After 12 weeks of NW training and vitamin D supplementation, in the EG a decrease in TC, LDL-C, and TG was observed. In the SG, no changes in the lipid profile were observed, whereas in the CG an increase in the HDL-C level was noticed. Positive physical fitness changes were only observed in the EG. Conclusion: Our obtained data confirmed baseline assumption that regular exercise induces positive alternations in lipid profile in elderly women supported by supplementation of vitamin D. PMID- 29515519 TI - Molecular Modeling of Structures and Interaction of Human Corticotropin-Releasing Factor (CRF) Binding Protein and CRF Type-2 Receptor. AB - The corticotropin-releasing factor (CRF) system is a key mediator of the stress response and addictive behavior. The CRF system includes four peptides: The CRF system includes four peptides: CRF, urocortins I-III, CRF binding protein (CRF BP) that binds CRF with high affinity, and two class B G-protein coupled receptors CRF1R and CRF2R. CRF-BP is a secreted protein without significant sequence homology to CRF receptors or to any other known class of protein. Recently, it has been described a potentiation role of CRF-BP over CRF signaling through CRF2R in addictive-related neuronal plasticity and behavior. In addition, it has been described that CRF-BP is capable to physically interact specifically with the alpha isoform of CRF2R and acts like an escort protein increasing the amount of the receptor in the plasma membrane. At present, there are no available structures for CRF-BP or for full-length CRFR. Knowing and studying the structure of these proteins could be beneficial in order to characterize the CRF BP/CRF2alphaR interaction. In this work, we report the modeling of CRF-BP and of full-length CRF2alphaR and CRF2betaR based on the recently solved crystal structures of the transmembrane domains of the human glucagon receptor and human CRF1R, in addition with the resolved N-terminal extracellular domain of CRFRs. These models were further studied using molecular dynamics simulations and protein-protein docking. The results predicted a higher possibility of interaction of CRF-BP with CRF2alphaR than CRF2betaR and yielded the possible residues conforming the interacting interface. Thus, the present study provides a framework for further investigation of the CRF-BP/CRF2alphaR interaction. PMID- 29515520 TI - A Short-Day Photoperiod Delays the Timing of Puberty in Female Mice via Changes in the Kisspeptin System. AB - The reproduction of seasonal breeders is modulated by exposure to light in an interval of 24 h defined as photoperiod. The interruption of reproductive functions in seasonally breeding rodents is accompanied by the suppression of the Kiss1 gene expression, which is known to be essential for reproduction. In non seasonal male rodents, such as rats and mice, short-day photoperiod (SP) conditions or exogenous melatonin treatment also have anti-gonadotropic effects; however, whether photoperiod is able to modulate the puberty onset or Kiss1 gene expression in mice is unknown. In the present study, we investigated whether photoperiodism influences the sexual maturation of female mice via changes in the kisspeptin system. We observed that SP condition delayed the timing of puberty in female mice, decreased the hypothalamic expression of genes related to the reproductive axis and reduced the number of Kiss1-expressing neurons in the rostral hypothalamus. However, SP also reduced the body weight gain during development and affected the expression of neuropeptides involved in the energy balance regulation. When body weight was recovered via a reduction in litter size, the timing of puberty in mice born and raised in SP was advanced and the effects in hypothalamic mRNA expression were reverted. These results suggest that the SP delays the timing of puberty in female mice via changes in the kisspeptin system, although the effects on hypothalamic-pituitary-gonadal axis are likely secondary to changes in body weight gain. PMID- 29515521 TI - GnRH-(1-5) Inhibits TGF-beta Signaling to Regulate the Migration of Immortalized Gonadotropin-Releasing Hormone Neurons. AB - Gonadotropin-releasing hormone (GnRH) neurons originate outside the central nervous system (CNS) in the nasal placode where their migration to the basal forebrain is dependent on the integration of multiple signaling cues during development. The proper migration and establishment of the GnRH neuronal population within the CNS are critical for normal pubertal onset and reproductive function. The endopeptidase EP24.15 is expressed along the migratory path of GnRH neurons and cleaves the full-length GnRH to generate the metabolite GnRH-(1-5). Using the GN11 cell model, which is considered a pre-migratory GnRH neuronal cell line, we demonstrated that GnRH-(1-5) inhibits cellular migration in a wound closure assay by binding the orphan G protein-coupled receptor 173 (GPR173). In our current experiments, we sought to utilize an in vitro migration assay that better reflects the external environment that migrating GnRH neurons are exposed to during development. Therefore, we used a transwell assay where the inserts were coated with or without a matrigel, a gelatinous mixture containing extracellular matrix (ECM) proteins, to mimic the extracellular environment. Interestingly, GnRH-(1-5) inhibited the ability of GN11 cells to migrate only through ECM mimetic and was dependent on GPR173. Furthermore, we found that GN11 cells secrete TGF-beta1, 2, and 3 but only TGF-beta1 release and signaling were inhibited by GnRH-(1-5). To identify potential mechanisms involved in the proteolytic activation of TGF-beta, we measured a panel of genes implicated in ECM remodeling. We found that GnRH-(1-5) consistently increased tissue inhibitors of metalloproteinase 1 expression, which is an inhibitor of proteinase activity, leading to a decrease in bioactive TGF-beta and subsequent signaling. These results suggest that GnRH-(1-5) activating GPR173 may modulate the response of migrating GnRH neurons to external cues present in the ECM environment via an autocrine-dependent mechanism involving TGF-beta. PMID- 29515522 TI - Targeting Fibroblast Growth Factor 23 Signaling with Antibodies and Inhibitors, Is There a Rationale? AB - Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone mainly produced by bone. FGF23 reduces serum phosphate by suppressing intestinal phosphate absorption through reducing 1,25-dihydroxyvitamin D and proximal tubular phosphate reabsorption. Excessive actions of FG23 result in several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia. While neutral phosphate and active vitamin D are standard therapies for child patients with XLH, these medications have several limitations both in their effects and adverse events. Several approaches that inhibit FGF23 actions including anti-FGF23 antibodies and inhibitors of FGF signaling have been shown to improve phenotypes of model mice for FG23-related hypophosphatemic diseases. In addition, clinical trials indicated that a humanized anti-FGF23 antibody increased serum phosphate and improved quality of life in patients with XLH. Furthermore, circulatory FGF23 is high in patients with chronic kidney disease (CKD). Many epidemiological studies indicated the association between high FGF23 levels and various adverse events especially in patients with CKD. However, it is not known whether the inhibition of FGF23 activities in patients with CKD is beneficial for these patients. In this review, recent findings concerning the modulation of FGF23 activities are discussed. PMID- 29515523 TI - IGF Binding Protein-5 Induces Cell Senescence. AB - Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5) with the induction of the tumor suppressor p53 is upregulated during cellular senescence. This mechanism mediates interleukin-6/gp130-induced premature senescence in human fibroblasts, irradiation-induced premature senescence in human endothelial cells (ECs), and replicative senescence in human ECs independent of insulin-like growth factor I (IGF-I) and IGF-II. Additionally, a link between IGFBP-5, hyper-coagulation, and inflammation, which occur with age, has been implicated. Thus, IGFBP-5 seems to play decisive roles in controlling cell senescence and cell inflammation. In this review, we describe the accumulating evidence for this role of IGFBP-5 including our new finding. PMID- 29515524 TI - Environmental Metagenomic Assemblies Reveal Seven New Highly Divergent Chlamydial Lineages and Hallmarks of a Conserved Intracellular Lifestyle. AB - The Chlamydiae phylum exclusively encompasses bacteria sharing a similar obligate intracellular life cycle. Existing 16S rDNA data support a high diversity within the phylum, however genomic data remain scarce owing to the difficulty in isolating strains using culture systems with eukaryotic cells. Yet, Chlamydiae genome data extracted from large scale metagenomic studies might help fill this gap. This work compares 33 cultured and 27 environmental, uncultured chlamydial genomes, in order to clarify the phylogenetic relatedness of the new chlamydial clades and to investigate the genetic diversity of the Chlamydiae phylum. The analysis of published chlamydial genomes from metagenomics bins and single cell sequencing allowed the identification of seven new deeply branching chlamydial clades sharing genetic hallmarks of parasitic Chlamydiae. Comparative genomics suggests important biological differences between those clades, including loss of many proteins involved in cell division in the genus Similichlamydia, and loss of respiratory chain and tricarboxylic acid cycle in several species. Comparative analyses of chlamydial genomes with two proteobacterial orders, the Rhizobiales and the Rickettsiales showed that genomes of different Rhizobiales families are much more similar than genomes of different Rickettsiales families. On the other hand, the chlamydial 16S rRNAs exhibit a higher sequence conservation than their Rickettsiales counterparts, while chlamydial proteins exhibit increased sequence divergence. Studying the diversity and genome plasticity of the entire Chlamydiae phylum is of major interest to better understand the emergence and evolution of this ubiquitous and ancient clade of obligate intracellular bacteria. PMID- 29515525 TI - Morphology and Phylogeny of a New Species of Anaerobic Ciliate, Trimyema finlayi n. sp., with Endosymbiotic Methanogens. AB - Many anaerobic ciliated protozoa contain organelles of mitochondrial ancestry called hydrogenosomes. These organelles generate molecular hydrogen that is consumed by methanogenic Archaea, living in endosymbiosis within many of these ciliates. Here we describe a new species of anaerobic ciliate, Trimyema finlayi n. sp., by using silver impregnation and microscopy to conduct a detailed morphometric analysis. Comparisons with previously published morphological data for this species, as well as the closely related species, Trimyema compressum, demonstrated that despite them being similar, both the mean cell size and the mean number of somatic kineties are lower for T. finlayi than for T. compressum, which suggests that they are distinct species. This was also supported by analysis of the 18S rRNA genes from these ciliates, the sequences of which are 97.5% identical (6 substitutions, 1479 compared bases), and in phylogenetic analyses these sequences grouped with other 18S rRNA genes sequenced from previous isolates of the same respective species. Together these data provide strong evidence that T. finlayi is a novel species of Trimyema, within the class Plagiopylea. Various microscopic techniques demonstrated that T. finlayi n. sp. contains polymorphic endosymbiotic methanogens, and analysis of the endosymbionts' 16S rRNA gene showed that they belong to the genus Methanocorpusculum, which was confirmed using fluorescence in situ hybridization with specific probes. Despite the degree of similarity and close relationship between these ciliates, T. compressum contains endosymbiotic methanogens from a different genus, Methanobrevibacter. In phylogenetic analyses of 16S rRNA genes, the Methanocorpusculum endosymbiont of T. finlayi n. sp. grouped with sequences from Methanomicrobia, including the endosymbiont of an earlier isolate of the same species, 'Trimyema sp.,' which was sampled approximately 22 years earlier, at a distant (~400 km) geographical location. Identification of the same endosymbiont species in the two separate isolates of T. finlayi n. sp. provides evidence for spatial and temporal stability of the Methanocorpusculum-T. finlayi n. sp. endosymbiosis. T. finlayi n. sp. and T. compressum provide an example of two closely related anaerobic ciliates that have endosymbionts from different methanogen genera, suggesting that the endosymbionts have not co-speciated with their hosts. PMID- 29515526 TI - Metagenomic Functional Potential Predicts Degradation Rates of a Model Organophosphorus Xenobiotic in Pesticide Contaminated Soils. AB - Chemical contamination of natural and agricultural habitats is an increasing global problem and a major threat to sustainability and human health. Organophosphorus (OP) compounds are one major class of contaminant and can undergo microbial degradation, however, no studies have applied system-wide ecogenomic tools to investigate OP degradation or use metagenomics to understand the underlying mechanisms of biodegradation in situ and predict degradation potential. Thus, there is a lack of knowledge regarding the functional genes and genomic potential underpinning degradation and community responses to contamination. Here we address this knowledge gap by performing shotgun sequencing of community DNA from agricultural soils with a history of pesticide usage and profiling shifts in functional genes and microbial taxa abundance. Our results showed two distinct groups of soils defined by differing functional and taxonomic profiles. Degradation assays suggested that these groups corresponded to the organophosphorus degradation potential of soils, with the fastest degrading community being defined by increases in transport and nutrient cycling pathways and enzymes potentially involved in phosphorus metabolism. This was against a backdrop of taxonomic community shifts potentially related to contamination adaptation and reflecting the legacy of exposure. Overall our results highlight the value of using holistic system-wide metagenomic approaches as a tool to predict microbial degradation in the context of the ecology of contaminated habitats. PMID- 29515527 TI - Gut Microbiota: An Integral Moderator in Health and Disease. AB - The gut microbiota, as the main member in gut microecology, is an essential mediator in health and disease. The gut microbiota interacts with various organs and systems in the body, including brain, lung, liver, bone, cardiovascular system, and others. Microbiota-derived metabolites such as the short chain fatty acid (SCFA) butyrate are primary signals, which link the gut microbiota and physiology. Recently, the gut microbiota has been identified as the origin of a number of diseases by influencing the related cell signaling pathways such as WNT/beta-catenin pathway in colorectal cancer and T cell receptor signaling in the central nervous system. Moreover, several microRNAs participate in signaling networks through the intervention of the gut microbiota. The interaction between the gut microbiota and miRNAs plays a crucial role in vascular dysfunction and hepatocellular carcinoma (HCC). In this review, we will report and discuss recent findings about the crosstalk between the gut microbiota and physical organs and how the gut microbiota and miRNAs regulate each other while influencing the host via genes, proteins, or metabolites. PMID- 29515528 TI - Examining the Reticulocyte Preference of Two Plasmodium berghei Strains during Blood-Stage Malaria Infection. AB - The blood-stage of the Plasmodium parasite is one of the key phases within its life cycle that influences disease progression during a malaria infection. The efficiency of the parasite in infecting red blood cells (RBC) determines parasite load and parasite-induced hemolysis that is responsible for the development of anemia and potentially drives severe disease progression. However, the molecular factors defining the infectivity of Plasmodium parasites have not been completely identified so far. Using the Plasmodium berghei mouse model for malaria, we characterized and compared the blood-stage infection dynamics of PbANKA WT and a mutant parasite strain lacking a novel Plasmodium antigen, PbmaLS_05, that is well conserved in both human and animal Plasmodium parasite strains. Infection of mice with parasites lacking PbmaLS_05 leads to lower parasitemia levels and less severe disease progression in contrast to mice infected with the wildtype PbANKA strain. To specifically determine the effect of deleting PbmaLS_05 on parasite infectivity we developed a mathematical model describing erythropoiesis and malarial infection of RBC. By applying our model to experimental data studying infection dynamics under normal and drug-induced altered erythropoietic conditions, we found that both PbANKA and PbmaLS_05 (-) parasite strains differed in their infectivity potential during the early intra-erythrocytic stage of infection. Parasites lacking PbmaLS_05 showed a decreased ability to infect RBC, and immature reticulocytes in particular that are usually a preferential target of the parasite. These altered infectivity characteristics limit parasite burden and affect disease progression. Our integrative analysis combining mathematical models and experimental data suggests that deletion of PbmaLS_05 affects productive infection of reticulocytes, which makes this antigen a useful target to analyze the actual processes relating RBC preferences to the development of severe disease outcomes in malaria. PMID- 29515529 TI - Commentary: A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome. PMID- 29515531 TI - NSG2 (ORF19.273) Encoding Protein Controls Sensitivity of Candida albicans to Azoles through Regulating the Synthesis of C14-Methylated Sterols. AB - Antifungal azole drugs inhibit the synthesis of ergosterol and cause the accumulation of sterols containing a 14alpha-methyl group, which is related to the properties of cell membrane. Due to the frequent recurrence of fungal infections and clinical long-term prophylaxis, azole resistance is increasing rapidly. In our research, Nsg2p, encoded by the ORF19.273 in Candida albicans, is found to be involved in the inhibition of 14alpha-methylated sterols and resistance to azoles. Under the action of fluconazole, nsg2Delta/Delta mutants are seriously damaged in the integrity and functions of cell membranes with a decrease of ergosterol ratio and an increase of both obtusifoliol and 14alpha methylfecosterol ratio. The balance between ergosterol and 14alpha-methyl sterols mediated by NSG2 plays an important role in C. albicans responding to azoles in vitro as well as in vivo. These phenotypes are completely different from those of Nsg2p in Saccharomyces cerevisiae, which is proved to increase the stability of HMG-CoA and resistance to lovastatin. Based on the evidence above, it is indicated that the decrease of 14alpha-methylated sterols is an azole-resistant mechanism in C. albicans, which may provide new strategies for overcoming the problems of azole resistance. PMID- 29515530 TI - Antibacterial Effect of Copaifera duckei Dwyer Oleoresin and Its Main Diterpenes against Oral Pathogens and Their Cytotoxic Effect. AB - This study evaluates the antibacterial activity of the Copaifera duckei Dwyer oleoresin and two isolated compounds [eperu-8(20)-15,18-dioic acid and polyalthic acid] against bacteria involved in primary endodontic infections and dental caries and assesses the cytotoxic effect of these substances against a normal cell line. MIC and MBC assays pointed out the most promising metabolites for further studies on bactericidal kinetics, antibiofilm activity, and synergistic antibacterial action. The oleoresin and polyalthic acid but not eperu-8(20)-15,18 dioic provided encouraging MIC and MBC results at concentrations lower than 100 MUg mL-1. The oleoresin and polyalthic acid activities depended on the evaluated strain. A bactericidal effect on Lactobacillus casei (ATCC 11578 and clinical isolate) emerged before 8 h of incubation. For all the tested bacteria, the oleoresin and polyalthic acid inhibited biofilm formation by at least 50%. The oleoresin and polyalthic acid gave the best activity against Actinomyces naeslundii (ATCC 19039) and L. casei (ATCC 11578), respectively. The synergistic assays combining the oleoresin or polyalthic acid with chlorhexidine did not afford interesting results. We examined the cytotoxicity of C. duckei oleoresin, eperu-8(20)-15,18-dioic acid, and polyalthic acid against Chinese hamster lung fibroblasts. The oleoresin and polyalthic acid were cytotoxic at concentrations above 78.1 MUg mL-1, whereas eperu-8(20)-15,18-dioic displayed cytotoxicity at concentrations above 312.5 MUg mL-1. In conclusion, the oleoresin and polyalthic acid are potential sources of antibacterial agents against bacteria involved in primary endodontic infections and dental caries in both the sessile and the planktonic modes at concentrations that do not cause cytotoxicity. PMID- 29515532 TI - Transmission and Toxigenic Potential of Vibrio cholerae in Hilsha Fish (Tenualosa ilisha) for Human Consumption in Bangladesh. AB - Fish have been considered natural reservoirs of Vibrio cholerae, the deadly diarrheal pathogen. However, little is known about the role of fish in the transmission of V. cholerae from the Bay of Bengal to the households of rural and urban Bangladesh. This study analyzes the incidence and pathogenic potential of V. cholerae in Hilsha (Tenualosa ilisha), a commonly caught and consumed fish that exhibits a life cycle in both freshwater and marine environments in Bangladesh. During the period from October 2014 to October 2015, samples from the gills, recta, intestines, and scale swabs of a total of 48 fish were analyzed. The fish were collected both at local markets in the capital city Dhaka and directly from fishermen at the river. PCR analysis by targeting V. cholerae species-specific ompW gene revealed that 39 of 48 (81%) fish were positive in at least one of the sample types. Real-time PCR analysis demonstrated that the cholera-causing ctxA gene was detected in 20% (8 of 39) of V. cholerae-positive fish. A total of 158 V. cholerae isolates were obtained which were categorized into 35 genotypic groups. Altogether, 25 O1 and 133 non-O1/O139 strains were isolated, which were negative for the cholera toxin gene. Other pathogenic genes such as stn/sto, hlyA, chxA, SXT, rtxC, and HA-P were detected. The type three secretion system gene cluster (TTSS) was present in 18% (24 of 133) of non O1/O139 isolates. The antibiotic susceptibility test revealed that the isolates conferred high resistance to sulfamethoxazole-trimethoprim and kanamycin. Both O1 and non-O1/O139 strains were able to accumulate fluid in rabbit ileal loops and caused distinctive cell death in HeLa cell. Multilocus sequence typing (MLST) showed clonal diversity among fish isolates with pandemic clones. Our data suggest a high prevalence of V. cholerae in Hilsha fish, which indicates that this fish could serve as a potential vehicle for V. cholerae transmission. Moreover, the indigenous V. cholerae strains isolated from Hilsha fish possess considerable virulence potential despite being quite diverse from current epidemic strains. This represents the first study of the population structure of V. cholerae associated with fish in Bangladesh. PMID- 29515533 TI - Vibrio tapetis Displays an Original Type IV Secretion System in Strains Pathogenic for Bivalve Molluscs. AB - The Brown Ring Disease (BRD) caused high mortality rates since 1986 in the Manila clam Venerupis philippinarum introduced and cultured in Western Europe from the 1970s. The causative agent of BRD is a Gram-Negative bacterium, Vibrio tapetis, which is also pathogenic to fish. Here we report the first assembly of the complete genome of V. tapetis CECT4600T, together with the genome sequences of 16 additional strains isolated across a broad host and geographic range. Our extensive genome dataset allowed us to describe the pathogen pan- and core genomes and to identify putative virulence factors. The V. tapetis core genome consists of 3,352 genes, including multiple potential virulence factors represented by haemolysins, transcriptional regulators, Type I restriction modification system, GGDEF domain proteins, several conjugative plasmids, and a Type IV secretion system. Future research on the coevolutionary arms race between V. tapetis virulence factors and host resistance mechanisms will improve our understanding of how pathogenicity develops in this emerging pathogen. PMID- 29515534 TI - Assessment of Bona Fide sRNAs in Staphylococcus aureus. AB - Bacterial regulatory RNAs have been extensively studied for over a decade, and are progressively being integrated into the complex genetic regulatory network. Transcriptomic arrays, recent deep-sequencing data and bioinformatics suggest that bacterial genomes produce hundreds of regulatory RNAs. However, while some have been authenticated, the existence of the others varies according to strains and growth conditions, and their detection fluctuates with the methodologies used for data acquisition and interpretation. For example, several small RNA (sRNA) candidates are now known to be parts of UTR transcripts. Accurate annotation of regulatory RNAs is a complex task essential for molecular and functional studies. We defined bona fide sRNAs as those that (i) likely act in trans and (ii) are not expressed from the opposite strand of a coding gene. Using published data and our own RNA-seq data, we reviewed hundreds of Staphylococcus aureus putative regulatory RNAs using the DETR'PROK computational pipeline and visual inspection of expression data, addressing the question of which transcriptional signals correspond to sRNAs. We conclude that the model strain HG003, a NCTC8325 derivative commonly used for S. aureus genetic regulation studies, has only about 50 bona fide sRNAs, indicating that these RNAs are less numerous than commonly stated. Among them, about half are associated to the S. aureus sp. core genome and a quarter are possibly expressed in other Staphylococci. We hypothesize on their features and regulation using bioinformatic approaches. PMID- 29515535 TI - Phosphate Favors the Biosynthesis of CdS Quantum Dots in Acidithiobacillus thiooxidans ATCC 19703 by Improving Metal Uptake and Tolerance. AB - Recently, we reported the production of Cadmium sulfide (CdS) fluorescent semiconductor nanoparticles (quantum dots, QDs) by acidophilic bacteria of the Acidithiobacillus genus. Here, we report that the addition of inorganic phosphate to Acidithiobacillus thiooxidans ATCC 19703 cultures favors the biosynthesis of CdS QDs at acidic conditions (pH 3.5). The effect of pH, phosphate and cadmium concentrations on QDs biosynthesis was studied by using Response Surface Methodology (RSM), a multivariate technique for analytical optimization scarcely used in microbiological studies to date. To address how phosphate affects intracellular biosynthesis of CdS QDs, the effect of inorganic phosphate on bacterial cadmium-uptake was evaluated. By measuring intracellular levels of cadmium we determined that phosphate influences the capacity of cells to incorporate this metal. A relation between cadmium tolerance and phosphate concentrations was also determined, suggesting that phosphate participates in the adaptation of bacteria to toxic levels of this metal. In addition, QDs biosynthesis was also favored by the degradation of intracellular polyphosphates. Altogether, our results indicate that phosphate contributes to A. thiooxidans CdS QDs biosynthesis by influencing cadmium uptake and cadmium tolerance. These QDs may also be acting as a nucleation point for QDs formation at acidic pH. This is the first study reporting the effect of phosphates on QDs biosynthesis and describes a new cadmium-response pathway present in A. thiooxidans and most probably in other bacterial species. PMID- 29515536 TI - Ex Situ Culturing Experiments Revealed Psychrophilic Hydrogentrophic Methanogenesis Being the Potential Dominant Methane-Producing Pathway in Subglacial Sediment in Larsemann Hills, Antarctic. AB - It was recognized only recently that subglacial ecosystems support considerable methanogenic activity, thus significantly contributing the global methane production. However, only limited knowledge is available on the physiological characteristics of this kind of methanogenic community because of the technical constraints associated with sampling and cultivation under corresponding environmental conditions. To elucidate methanogenesis beneath the glacial margin in East Antarctic Ice Sheet, we took an integrated approach that included cultivation of microbes associated with the sediment samples in the lab and analysis of mcrA gene therein. After 7 months of incubation, the highest rate of methanogenesis [398 (pmol/day)/gram] was observed at 1 degrees C on a supply of H2. The rates of methanogenesis were lower on acetate or unamended substrate than on H2. The rates on these two substrates increased when the temperature was raised. Methanomicrobiales predominated before and after prolonged incubation, regardless whether H2, acetate, or unamended substrate were the energy source. Therefore, it was inferred that psychrophilic hydrogenotrophic methanogenesis was the primary methane-producing pathway in the subglacial ecosystem we sampled. These findings highlight the effects of temperature and substrate on potential methanogenesis in the subglacial sediment of this area, and may help us for a better estimation on the Antarctica methane production in a changing climate. PMID- 29515538 TI - Novel Variant of New Delhi Metallo-beta-lactamase, NDM-20, in Escherichia coli. AB - The spread of carbapenem-resistant Enterobacteriaceae (CRE) mediated by New Delhi metallo-beta-lactamase (NDM) poses a serious challenge to clinicians and has become a major public health concern. NDM has been evolving into variants that possess different hydrolysis activity toward antibiotics, so as to affect treatment strategy. In addition, very few studies on NDM variants have focused on animal-derived bacterial isolates. Our study reports a novel NDM variant, NDM-20, in an isolate of Escherichia coli CCD1 recovered from the food animal swine in China. The isolate that was assigned to ST1114, exhibited high level resistance to all beta-lactams tested, including aztreonam and carbapenems. The gene of blaNDM-20 was located on an IncX3-type plasmid, surrounded by multiple insertion sequences. Sequencing analysis demonstrated that blaNDM-20 contained three point mutations at positions 262 (G->T), 460 (A->C), and 809 (G->A), compared with blaNDM-1, and just one point mutation at position 809 (G->A), relative to blaNDM 5. Functional analysis revealed that the blaNDM-20 transformant, DH5alpha+pHSG398/NDM-20, exhibited a higher resistance to ertapenem than that of blaNDM-1 transformant DH5alpha+pHSG398/NDM-1. Kinetic parameter analysis showed that NDM-20 had increased enzymatic activity against some penicillins and cephalosporins but decreased carbapenemase activity relative to NDM-5. The identification of NDM-20 further confirms the evolution and prevalence of NDM variants in bacteria of food-animal origin. PMID- 29515537 TI - Intra-species Genomic and Physiological Variability Impact Stress Resistance in Strains of Probiotic Potential. AB - Large-scale microbiome studies have established that most of the diversity contained in the gastrointestinal tract is represented at the strain level; however, exhaustive genomic and physiological characterization of human isolates is still lacking. With increased use of probiotics as interventions for gastrointestinal disorders, genomic and functional characterization of novel microorganisms becomes essential. In this study, we explored the impact of strain level genomic variability on bacterial physiology of two novel human Lactobacillus rhamnosus strains (AMC143 and AMC010) of probiotic potential in relation to stress resistance. The strains showed differences with known probiotic strains (L. rhamnosus GG, Lc705, and HN001) at the genomic level, including nucleotide polymorphisms, mutations in non-coding regulatory regions, and rearrangements of genomic architecture. Transcriptomics analysis revealed that gene expression profiles differed between strains when exposed to simulated gastrointestinal stresses, suggesting the presence of unique regulatory systems in each strain. In vitro physiological assays to test resistance to conditions mimicking the gut environment (acid, alkali, and bile stress) showed that growth of L. rhamnosus AMC143 was inhibited upon exposure to alkaline pH, while AMC010 and control strain LGG were unaffected. AMC143 also showed a significant survival advantage compared to the other strains upon bile exposure. Reverse transcription qPCR targeting the bile salt hydrolase gene (bsh) revealed that AMC143 expressed bsh poorly (a consequence of a deletion in the bsh promoter and truncation of bsh gene in AMC143), while AMC010 had significantly higher expression levels than AMC143 or LGG. Insertional inactivation of the bsh gene in AMC010 suggested that bsh could be detrimental to bacterial survival during bile stress. Together, these findings show that coupling of classical microbiology with functional genomics methods for the characterization of bacterial strains is critical for the development of novel probiotics, as variability between strains can dramatically alter bacterial physiology and functionality. PMID- 29515539 TI - Identification of Key Residues for Enzymatic Carboxylate Reduction. AB - Carboxylate reductases (CARs, E.C. 1.2.1.30) generate aldehydes from their corresponding carboxylic acid with high selectivity. Little is known about the structure of CARs and their catalytically important amino acid residues. The identification of key residues for carboxylate reduction provides a starting point to gain deeper understanding of enzymatic carboxylate reduction. A multiple sequence alignment of CARs with confirmed activity recently identified in our lab and from the literature revealed a fingerprint of conserved amino acids. We studied the function of conserved residues by multiple sequence alignments and mutational replacements of these residues. In this study, single-site alanine variants of Neurospora crassa CAR were investigated to determine the contribution of conserved residues to the function, expressability or stability of the enzyme. The effect of amino acid replacements was investigated by analyzing enzymatic activity of the variants in vivo and in vitro. Supported by molecular modeling, we interpreted that five of these residues are essential for catalytic activity, or substrate and co-substrate binding. We identified amino acid residues having significant impact on CAR activity. Replacement of His 237, Glu 433, Ser 595, Tyr 844, and Lys 848 by Ala abolish CAR activity, indicating their key role in acid reduction. These results may assist in the functional annotation of CAR coding genes in genomic databases. While some other conserved residues decreased activity or had no significant impact, four residues increased the specific activity of NcCAR variants when replaced by alanine. Finally, we showed that NcCAR wild-type and mutants efficiently reduce aliphatic acids. PMID- 29515540 TI - Recovering Genomics Clusters of Secondary Metabolites from Lakes Using Genome Resolved Metagenomics. AB - Metagenomic approaches became increasingly popular in the past decades due to decreasing costs of DNA sequencing and bioinformatics development. So far, however, the recovery of long genes coding for secondary metabolites still represents a big challenge. Often, the quality of metagenome assemblies is poor, especially in environments with a high microbial diversity where sequence coverage is low and complexity of natural communities high. Recently, new and improved algorithms for binning environmental reads and contigs have been developed to overcome such limitations. Some of these algorithms use a similarity detection approach to classify the obtained reads into taxonomical units and to assemble draft genomes. This approach, however, is quite limited since it can classify exclusively sequences similar to those available (and well classified) in the databases. In this work, we used draft genomes from Lake Stechlin, north eastern Germany, recovered by MetaBat, an efficient binning tool that integrates empirical probabilistic distances of genome abundance, and tetranucleotide frequency for accurate metagenome binning. These genomes were screened for secondary metabolism genes, such as polyketide synthases (PKS) and non-ribosomal peptide synthases (NRPS), using the Anti-SMASH and NAPDOS workflows. With this approach we were able to identify 243 secondary metabolite clusters from 121 genomes recovered from our lake samples. A total of 18 NRPS, 19 PKS, and 3 hybrid PKS/NRPS clusters were found. In addition, it was possible to predict the partial structure of several secondary metabolite clusters allowing for taxonomical classifications and phylogenetic inferences. Our approach revealed a high potential to recover and study secondary metabolites genes from any aquatic ecosystem. PMID- 29515541 TI - Quorum Sensing-Regulated Phenol-Soluble Modulins Limit Persister Cell Populations in Staphylococcus aureus. AB - Incomplete killing of bacterial pathogens by antibiotics is an underlying cause of treatment failure and accompanying complications. Among those avoiding chemotherapy are persisters being individual cells in a population that for extended periods of time survive high antibiotic concentrations proposedly by being in a quiescent state refractory to antibiotic killing. While investigating the human pathogen Staphylococcus aureus and the influence of growth phase on persister formation, we noted that spent supernatants of stationary phase cultures of S. aureus or S. epidermidis, but not of distantly related bacteria, significantly reduced the persister cell frequency upon ciprofloxacin challenge when added to exponentially growing and stationary phase S. aureus cells. Curiously, the persister reducing activity of S. aureus supernatants was also effective against persisters formed by either S. carnosus or Listeria monocytogenes. The persister reducing component, which resisted heat but not proteases and was produced in the late growth phase in an agr quorum-sensing dependent manner, was identified to be the phenol-soluble modulin (PSM) toxins. S. aureus express several PSMs, each with distinct cytolytic and antimicrobial properties; however, the persister reducing activity was specifically linked to synthesis of the PSMalpha family. Correspondingly, a high-persister phenotype of a PSMalpha mutant was observed upon fluoroquinolone or aminoglycoside challenge, demonstrating that the persister reducing activity of PSMs can be endogenously synthesized or extrinsically added. Given that PSMs have been associated with lytic activity against bacterial membranes we propose that PSM toxins increase the susceptibility of persister cells to killing by intracellularly acting antibiotics and that chronic and re-occurring infections with quorum sensing, agr negative mutants may be difficult to treat with antibiotics because of persister cells formed in the absence of PSM toxins. PMID- 29515542 TI - Analysis of CRISPR-Cas System in Streptococcus thermophilus and Its Application. AB - CRISPR-Cas (Clustered regularly interspaced short palindromic repeats-CRISPR associated proteins) loci, which provide a specific immunity against exogenous elements, are hypervariable among distinct prokaryotes. Based on previous researches, this review focuses on concluding systematical genome editing protocols in Streptococcus thermophilus. Firstly, its protocols and optimized conditions in gene editing are introduced. What's more, classification and diversity analyses of S. thermophilus CRISPR-Cas benefit the further understanding of evolution relationship among Streptococcus. Ability of its foreign segment integration and spacer source analyses also indicate a new direction of phage resistance. Above all, all of these point out its potential to be regarded as another model system other than type II CRISPR-Cas in Streptococcus pyogenes. PMID- 29515543 TI - Evolution of Phototrophy in the Chloroflexi Phylum Driven by Horizontal Gene Transfer. AB - The evolutionary mechanisms behind the extant distribution of photosynthesis is a point of substantial contention. Hypotheses range from the presence of phototrophy in the last universal common ancestor and massive gene loss in most lineages, to a later origin in Cyanobacteria followed by extensive horizontal gene transfer into the extant phototrophic clades, with intermediate scenarios that incorporate aspects of both end-members. Here, we report draft genomes of 11 Chloroflexi: the phototrophic Chloroflexia isolate Kouleothrix aurantiaca as well as 10 genome bins recovered from metagenomic sequencing of microbial mats found in Japanese hot springs. Two of these metagenome bins encode photrophic reaction centers and several of these bins form a metabolically diverse, monophyletic clade sister to the Anaerolineae class that we term Candidatus Thermofonsia. Comparisons of organismal (based on conserved ribosomal) and phototrophy (reaction center and bacteriochlorophyll synthesis) protein phylogenies throughout the Chloroflexi demonstrate that two new lineages acquired phototrophy independently via horizontal gene transfer (HGT) from different ancestral donors within the classically phototrophic Chloroflexia class. These results illustrate a complex history of phototrophy within this group, with metabolic innovation tied to HGT. These observations do not support simple hypotheses for the evolution of photosynthesis that require massive character loss from many clades; rather, HGT appears to be the defining mechanic for the distribution of phototrophy in many of the extant clades in which it appears. PMID- 29515545 TI - Functional Analysis of a Putative Type III Secretion System in Stress Adaption by Mesorhizobium alhagi CCNWXJ12-2T. AB - Mesorhizobium alhagi CCNWXJ12-2T, isolated from root nodules of the desert plant Alhagi sparsifolia, contains two type III secretion systems (T3SSs). T3SSs are specialized machinery with wide distribution in bacteria that inject effector proteins into target cells. Our previous study showed that the expression of M. alhagi T3SS1 is upregulated in high-salt conditions. Here, phylogenetic analysis of T3SS1 using the core protein RhcU suggested that T3SS1 belongs to the alpha Rhc II subgroup of the Rhc T3SS family. To elaborate the function of M. alhagi CCNWXJ12-2T T3SS1 in stress adaption, two T3SS1 mutants (DeltarhcQ and DeltaMA29250) were constructed and analyzed. beta-galactosidase transcriptional fusion assays showed that activity of the promoter of T3SS1 was induced by salts. Mutant DeltarhcQ was more sensitive to NaCl and LiCl than the wild-type, but DeltaMA29250 was not. Both mutants were more sensitive to KCl than the wild-type. The intracellular Na+ concentration in DeltarhcQ in high-NaCl conditions (0.4 M) increased by 37% compared to that of the wild-type strain, while the Na+ concentration in DeltaMA29250 increased by 13%. The K+ concentration in both mutants increased by 16% compared to the wild-type in high-KCl conditions (0.3 M). Strain DeltarhcQ showed decreased survival compared to the wild-type after treatment with H2O2, while the survival rate of DeltaMA29250 was almost the same as that of the wild-type. Antioxidant enzyme activities in DeltarhcQ were lower than those in the wild-type strain, but this was not the case for DeltaMA29250. Our data elucidate the beneficial effects of T3SS1 in the adaption of M. alhagi CCNWXJ12-2T to stress. PMID- 29515544 TI - Staphylococcus aureus Membrane-Derived Vesicles Promote Bacterial Virulence and Confer Protective Immunity in Murine Infection Models. AB - Staphylococcus aureus produces membrane-derived vesicles (MVs), which share functional properties to outer membrane vesicles. Atomic force microscopy revealed that S. aureus-derived MVs are associated with the bacterial surface or released into the surrounding environment depending on bacterial growth conditions. By using a comparative proteomic approach, a total of 131 and 617 proteins were identified in MVs isolated from S. aureus grown in Luria-Bertani and brain-heart infusion broth, respectively. Purified S. aureus MVs derived from the bacteria grown in either media induced comparable levels of cytotoxicity and neutrophil-activation. Administration of exogenous MVs increased the resistance of S. aureus to killing by whole blood or purified human neutrophils ex vivo and increased S. aureus survival in vivo. Finally, immunization of mice with S. aureus-derived MVs induced production of IgM, total IgG, IgG1, IgG2a, and IgG2b resulting in protection against subcutaneous and systemic S. aureus infection. Collectively, our results suggest S. aureus MVs can influence bacterial-host interactions during systemic infections and provide protective immunity in murine models of infection. PMID- 29515546 TI - Insight into the Molecular Mechanism of the Transcriptional Regulation of amtB Operon in Streptomyces coelicolor. AB - In Streptomyces coelicolor, amtB transcription is promptly regulated by the global nitrogen regulator GlnR. Although the GlnR binding cis-element has been characterized in amtB promoter, consisting of three GlnR boxes of a3-b3, a1-b1, and a2-b2, its role in GlnR-mediated transcriptional regulation remains unclear. Here, we showed that GlnR had different binding affinity against each pair of GlnR binding sites in amtB promoter (i.e., a3-b3, a1-b1, and a2-b2 sites), and GlnR was able to bind a3-b3 and a1-b1, respectively, but not a2-b2 alone. Consistently, a2 was not a typical GlnR binding site and further experiments showed that a2 was non-essential for GlnR-mediated binding in vitro and transcriptional regulation in vivo. To uncover the physiological role of the three GlnR boxes, we then mutated the wild-type amtB promoter to a typical GlnR binding motif containing two GlnR boxes (a3-b3-a2-b2), and found although the transcription of the mutated promoter could still be activated by GlnR, its increasing rate was less than that of the wild-type. Based on these findings, one could conclude that the three GlnR boxes assisted GlnR in more promptly activating amtB transcription in response to nitrogen limitation, facilitating bacterial growth under nitrogen stresses. PMID- 29515547 TI - Human Endogenous Retroviruses and Their Putative Role in the Development of Autoimmune Disorders Such as Multiple Sclerosis. AB - Human endogenous retroviruses (HERVs) are remnants of retroviral germ line infections of human ancestors and make up ~8% of the human genome. Under physiological conditions, these elements are frequently inactive or non functional due to deactivating mutations and epigenetic control. However, they can be reactivated under certain pathological conditions and produce viral transcripts and proteins. Several disorders, like multiple sclerosis or amyotrophic lateral sclerosis are associated with increased HERV expression. Although their detailed contribution to individual diseases has yet to be elucidated, an increasing number of studies in vitro and in vivo suggest HERVs as potent modulators of the immune system. They are able to affect the transcription of other immune-related genes, interact with pattern recognition receptors, and influence the positive and negative selection of developing thymocytes. Interestingly, HERV envelope proteins can both stimulate and suppress immune responses based on different mechanisms. In the light of HERV proteins becoming an emerging drug target for autoimmune-related disorders and cancer, we will provide an overview on recent findings of the complex interactions between HERVs and the human immune system with a focus on autoimmunity. PMID- 29515548 TI - Diversity of the Bacterial Microbiome in the Roots of Four Saccharum Species: S. spontaneum, S. robustum, S. barberi, and S. officinarum. AB - Endophytic bacteria are nearly ubiquitously present in the internal tissues of plants, and some endophytes can promote plant growth. In this study, we sampled the roots of four ancestral species of sugarcane (two genotypes per species) and two sugarcane cultivars, and used 16S rRNA and nifH gene sequencing to characterize the root endophytic bacterial communities and diazotroph diversity. A total of 7,198 operational taxonomic units (OTUs) were detected for the endophytic bacteria community. The endophytic bacterial communities exhibited significantly different alpha- and beta-diversities. From the 202 detected families in the sugarcane roots, a core microbiome containing 13 families was identified. The nifH gene was successfully detected in 9 of 30 samples from the four sugarcane species assayed, and 1,734 OTUs were merged for endophytic diazotrophs. In the tested samples, 43 families of endophytic diazotrophs were detected, and six families showed differences across samples. Among the 20 most abundant detected genera, 10 have been reported to be involved in nitrogen fixation in sugarcane. These findings demonstrate the diversity of the microbial communities in different sugarcane germplasms and shed light on the mechanism of biological nitrogen fixation in sugarcane. PMID- 29515549 TI - The Small RNA RyhB Is a Regulator of Cytochrome Expression in Shewanella oneidensis. AB - Shewanella oneidensis produces an extensive electron transfer network that results in metabolic flexibility. A large number of c-type cytochromes are expressed by S. oneidensis and these function as the fundamental electron transport chain proteins. Although several S. oneidensis cytochromes have been well-characterized, little is known about how their expression is regulated. In this study, we investigate the role of the ferric uptake regulator (Fur) and the sRNA RyhB in regulation. Our results demonstrate that loss of Fur leads to diminished growth and an apparent decrease in heme-containing proteins. Remarkably, deleting the Fur-repressed ryhB gene almost completely reverses these physiological changes, indicating that the phenotypes resulting from loss of Fur are (at least partially) dependent on RyhB. RNA sequencing identified a number of possible RyhB repressed genes. A large fraction of these encode c-type cytochromes, among them two of the most abundant periplasmic cytochromes CctA (also known as STC) and ScyA. We show that RyhB destabilizes the mRNA of four of its target genes, cctA, scyA, omp35, and nrfA and this requires the presence of the RNA chaperone Hfq. Iron limitation decreases the expression of the RyhB target genes cctA and scyA and this regulation relies on the presence of both Fur and RyhB. Overall, this study suggests that controlling cytochrome expression is of importance to maintain iron homeostasis and that sRNAs molecules are important players in the regulation of fundamental processes in S. oneidensis MR-1. PMID- 29515550 TI - Comparison of Meconium DNA Extraction Methods for Use in Microbiome Studies. AB - The establishment of human gut microbiota commences initially in utero. Meconium the first fecal material passed after birth-can be used to study fetal gut contents; however, processing meconium samples for microbiome studies presents significant technical challenges. Meconium hosts a low biomass microbiome, is tar like in texture and contains high concentrations of PCR inhibitors. This study aimed to evaluate four different DNA extraction methods to elucidate the most effective method for bacterial DNA recovery and sequencing analysis from first pass meconium. Samples from five infants were collected and processed using the following extraction kits: (1) Qiagen QIAamp DNA Stool Mini (QS); (2) Qiagen QIAamp DNA Microbiome (QM); (3) MoBio PowerSoil (PS); (4) MoBio MagAttract PowerMicrobiome (PM). Additionally, Kit PM was employed with a double inhibitor removal treatment (IRT) step (PM2). Bacterial DNA recovery was assessed by qPCR. Any PCR inhibition in samples was measured by spiking DNA eluates with 0.1 ng of pure Streptococcus agalactiae (GBS) DNA followed by qPCR quantitation. Kit PM yielded the highest average total DNA yield (79.3 ng per gram of meconium). Samples extracted with kit PS had the highest detectable levels of 16S rRNA gene by qPCR. The ability of each kit to overcome PCR inhibition varied, with qPCR on GBS-spiked DNA from kits QS, QM, PS, and PM recovering 87.1, 91.0, 88.8, and 37.9% GBS DNA, respectively. Double IRT improved the performance of kit PM, increasing GBS recovery to 56.5%. However, once DNA yield was normalized to the level recovered with the other kits 100% of GBS DNA was detected, suggesting that levels of PCR inhibitors are related to DNA yield from kit PM. Ion Torrent 16S rRNA gene sequencing revealed a high level of inter-kit variation in meconium microbiome structure. In particular, kit QM showed a bias toward extracting Firmicute DNA, while the other kits extracted primarily Proteobacterial DNA. Choice of extraction kit greatly impacts on the ability to extract and detect bacterial DNA in meconium and on the microbiome community structure generated from these samples. PMID- 29515551 TI - An Experimental Insight into Extracellular Phosphatases - Differential Induction of Cell-Specific Activity in Green Algae Cultured under Various Phosphorus Conditions. AB - Extracellular phosphatase activity (PA) has been used as an overall indicator of P depletion in lake phytoplankton. However, detailed insights into the mechanisms of PA regulation are still limited, especially in the case of acid phosphatases. The novel substrate ELF97 phosphate allows for tagging PA on single cells in an epifluorescence microscope. This fluorescence-labeled enzyme activity (FLEA) assay enables for autecological studies in natural phytoplankton and algal cultures. We combined the FLEA assay with image analysis to measure cell-specific acid PA in two closely related species of the genus Coccomyxa (Trebouxiophyceae, Chlorophyta) isolated from two acidic lakes with distinct P availability. The strains were cultured in a mineral medium supplied with organic (beta-glycerol phosphate) or inorganic (orthophosphate) P at three concentrations. Both strains responded to experimental conditions in a similar way, suggesting that acid extracellular phosphatases were regulated irrespectively of the origin and history of the strains. We found an increase in cell-specific PA at low P concentration and the cultures grown with organic P produced significantly higher (ca. 10-fold) PA than those cultured with the same concentrations of inorganic P. The cell-specific PA measured in the cultures grown with the lowest organic P concentration roughly corresponded to those of the original Coccomyxa population from an acidic lake with impaired P availability. The ability of Coccomyxa strains to produce extracellular phosphatases, together with tolerance for both low pH and metals can be one of the factors enabling the dominance of the genus in extreme conditions of acidic lakes. The analysis of frequency distribution of the single-cell PA documented that simple visual counting of 'active' (labeled) and 'non-active' (non-labeled) cells can lead to biased conclusions regarding algal P status because the actual PA of the 'active' cells can vary from negligible to very high values. The FLEA assay using image cytometry offers a strong tool in plankton ecology for exploring P metabolism. PMID- 29515552 TI - The Cyanobacterium Cylindrospermopsis raciborskii (CYRF-01) Responds to Environmental Stresses with Increased Vesiculation Detected at Single-Cell Resolution. AB - Secretion of membrane-limited vesicles, collectively termed extracellular vesicles (EVs), is an important biological process of both eukaryotic and prokaryotic cells. This process has been observed in bacteria, but remains to be better characterized at high resolution in cyanobacteria. In the present work, we address the release of EVs by Cylindrospermopsis raciborskii (CYRF-01), a filamentous bloom-forming cyanobacterium, exposed to environmental stressors. First, non-axenic cultures of C. raciborskii (CYRF-01) were exposed to ultraviolet radiation (UVA + UVB) over a 6 h period, which is known to induce structural damage to this species. Second, C. raciborskii was co-cultured in interaction with another cyanobacterium species, Microcystis aeruginosa (MIRF 01), over a 24 h period. After the incubation times, cell density and viability were analyzed, and samples were processed for transmission electron microscopy (TEM). Our ultrastructural analyses revealed that C. raciborskii constitutively releases EVs from the outer membrane during its normal growth and amplifies such ability in response to environmental stressors. Both situations induced significant formation of outer membrane vesicles (OMVs) by C. raciborskii compared to control cells. Quantitative TEM revealed an increase of 48% (UV) and 60% (interaction) in the OMV numbers compared to control groups. Considering all groups, the OMVs ranged in size from 20 to 300 nm in diameter, with most OMVs showing diameters between 20 and 140 nm. Additionally, we detected that OMV formation is accompanied by phosphatidylserine exposure, a molecular event also observed in EV-secreting eukaryotic cells. Altogether, we identified for the first time that C. raciborskii has the competence to secrete OMVs and that under different stress situations the genesis of these vesicles is increased. The amplified ability of cyanobacteria to release OMVs may be associated with adaptive responses to changes in environmental conditions and interspecies cell communication. PMID- 29515553 TI - Identification of New Factors Modulating Adhesion Abilities of the Pioneer Commensal Bacterium Streptococcus salivarius. AB - Biofilm formation is crucial for bacterial community development and host colonization by Streptococcus salivarius, a pioneer colonizer and commensal bacterium of the human gastrointestinal tract. This ability to form biofilms depends on bacterial adhesion to host surfaces, and on the intercellular aggregation contributing to biofilm cohesiveness. Many S. salivarius isolates auto-aggregate, an adhesion process mediated by cell surface proteins. To gain an insight into the genetic factors of S. salivarius that dictate host adhesion and biofilm formation, we developed a screening method, based on the differential sedimentation of bacteria in semi-liquid conditions according to their auto aggregation capacity, which allowed us to identify twelve mutations affecting this auto-aggregation phenotype. Mutations targeted genes encoding (i) extracellular components, including the CshA surface-exposed protein, the extracellular BglB glucan-binding protein, the GtfE, GtfG and GtfH glycosyltransferases and enzymes responsible for synthesis of cell wall polysaccharides (CwpB, CwpK), (ii) proteins responsible for the extracellular localization of proteins, such as structural components of the accessory SecA2Y2 system (Asp1, Asp2, SecA2) and the SrtA sortase, and (iii) the LiaR transcriptional response regulator. These mutations also influenced biofilm architecture, revealing that similar cell-to-cell interactions govern assembly of auto-aggregates and biofilm formation. We found that BglB, CshA, GtfH and LiaR were specifically associated with bacterial auto-aggregation, whereas Asp1, Asp2, CwpB, CwpK, GtfE, GtfG, SecA2 and SrtA also contributed to adhesion to host cells and host-derived components, or to interactions with the human pathogen Fusobacterium nucleatum. Our study demonstrates that our screening method could also be used to identify genes implicated in the bacterial interactions of pathogens or probiotics, for which aggregation is either a virulence trait or an advantageous feature, respectively. PMID- 29515554 TI - Adaptive Response and Tolerance to Acetic Acid in Saccharomyces cerevisiae and Zygosaccharomyces bailii: A Physiological Genomics Perspective. AB - Acetic acid is an important microbial growth inhibitor in the food industry; it is used as a preservative in foods and beverages and is produced during normal yeast metabolism in biotechnological processes. Acetic acid is also a major inhibitory compound present in lignocellulosic hydrolysates affecting the use of this promising carbon source for sustainable bioprocesses. Although the molecular mechanisms underlying Saccharomyces cerevisiae response and adaptation to acetic acid have been studied for years, only recently they have been examined in more detail in Zygosaccharomyces bailii. However, due to its remarkable tolerance to acetic acid and other weak acids this yeast species is a major threat in the spoilage of acidic foods and beverages and considered as an interesting alternative cell factory in Biotechnology. This review paper emphasizes genome wide strategies that are providing global insights into the molecular targets, signaling pathways and mechanisms behind S. cerevisiae and Z. bailii tolerance to acetic acid, and extends this information to other weak acids whenever relevant. Such comprehensive perspective and the knowledge gathered in these two yeast species allowed the identification of candidate molecular targets, either for the design of effective strategies to overcome yeast spoilage in acidic foods and beverages, or for the rational genome engineering to construct more robust industrial strains. Examples of successful applications are provided. PMID- 29515555 TI - Cytokine Biomarkers Associated with Human Extra-Pulmonary Tuberculosis Clinical Strains and Symptoms. AB - Background: The primary site of infection for Mycobacterium tuberculosis (Mtb) is the alveolar macrophages. However, Mtb can disseminate into other organs and causes extrapulmonary tuberculosis (EPTB). The diagnosis of EPTB is challenging due to relatively inaccessible infectious sites that may be paucibacillary and with clinical symptoms varying by site that are similar to those seen in other diseases. Hence, we sought to identify the expression patterns of a variety of cytokines that may be specific to EPTB from in vitro infections and in the plasma of TB patients. Methods: To define those cytokine secretions associated with EPTB, human THP-1 derived macrophages were first infected with Mtb clinical isolates from pulmonary and EPTB. Infected macrophages supernatants were harvested at different time points and cytokines known to play key roles in TB immune responses including TNF-alpha, IL-6, IL-10, IFN-gamma, and VEGF-A were measured by ELISA. Those cytokines that were in vitro associated to EPTB were also measured in the plasma from patients with PTB, EPTB, non-EPTB-confirmed-like symptoms and healthy controls. Results: While all of the studied cytokine secretions varied after in vitro infection, higher levels of TNF-alpha and VEGF secretions were observed in vitro in the infected macrophages respectively in the PTB and EPTB infecting clinical isolates. Similar trends were observed from the plasma of patients where patients with PTB showed significantly higher level of TNF-alpha compared to EPTB and healthy control groups. The patients with EPTB showed higher plasma level of VEGF compared to those patients with the non-EPTB (p < 0.01) and to healthy controls group (p < 0.0001). Using Receiver Operating Curves (ROC), we showed that TNF-alpha and VEGF concentrations could distinguish EPTB from non-confirmed EPTB with high sensitivity and specificity. Conclusion: Pulmonary and extrapulmonary Mtb clinical isolates showed different cytokine induction pattern in human macrophages that is also found in the plasma level of the EPTB patients. Further investigations are needed to define cytokine secretions that can lead to the definition of bio-signatures to differentiate EPTB from other pathologies with confusing symptoms that hampered the diagnosis of TB. PMID- 29515556 TI - Involvement of BcYak1 in the Regulation of Vegetative Differentiation and Adaptation to Oxidative Stress of Botrytis cinerea. AB - Yak1, a member of the dual-specificity tyrosine phosphorylation-regulated protein kinases, plays an important role in diverse cellular processes in fungi. However, to date, the role of BcYak1 in Botrytis cinerea, the causal agent of gray mold diseases in various plant species, remains uncharacterized. Our previous study identified one lysine acetylation site (Lys252) in BcYak1, which is the first report of such a site in Yak1. In this study, the function of BcYak1 and its lysine acetylation site were investigated using gene disruption and site-directed mutagenesis. The gene deletion mutant DeltaBcYak1 not only exhibits much lower pathogenicity, conidiation and sclerotium formation, but was also much more sensitive to H2O2 and the ergosterol biosynthesis inhibitor (EBI) triadimefon. The Lys252 site-directed mutagenesis mutant strain DeltaBcYak1-K252Q (mimicking the acetylation of the site), however, only showed lower sclerotium formation and higher sensitivity to H2O2. These results indicate that BcYAK1 is involved in the vegetative differentiation, adaptation to oxidative stress and triadimefon, and virulence of B. cinerea. PMID- 29515557 TI - Distribution and Genetic Variability of Fusarium oxysporum Associated with Tomato Diseases in Algeria and a Biocontrol Strategy with Indigenous Trichoderma spp. AB - Fifty fungal isolates were sampled from diseased tomato plants as result of a survey conducted in seven tomato crop areas in Algeria from 2012 to 2015. Morphological criteria and PCR-based identification, using the primers PF02 and PF03, assigned 29 out of 50 isolates to Fusarium oxysporum (Fo). The banding patterns amplified for genes SIX1, SIX3 and SIX4 served to identify races 2 and 3 of Fo f. sp. lycopersici (FOL), and Fo f. sp. radicis lycopersici (FORL) among the Algerian isolates. All FOL isolates showed pathogenicity on the susceptible tomato cv. "Super Marmande," while nine of out 10 Algerian FORL isolates were pathogenic on tomato cv. "Rio Grande." Inter simple sequence repeat (ISSR) fingerprints showed high genetic diversity among Algerian Fo isolates. Seventeen Algerian Trichoderma isolates were also obtained and assigned to the species T. asperellum (12 isolates), T. harzianum (four isolates) and T. ghanense (one isolate) based on ITS and tef1alpha gene sequences. Different in vitro tests identified the antagonistic potential of native Trichoderma isolates against FORL and FOL. Greenhouse biocontrol assays performed on "SM" tomato plants with T. ghanense T8 and T. asperellum T9 and T17, and three Fo isolates showed that isolate T8 performed well against FORL and FOL. This finding was based on an incidence reduction of crown and root rot and Fusarium wilt diseases by 53.1 and 48.3%, respectively. PMID- 29515558 TI - HTLV Deregulation of the NF-kappaB Pathway: An Update on Tax and Antisense Proteins Role. AB - Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia (ATL), an aggressive CD4+/CD25+ T-cell malignancy and of a severe neurodegenerative disease, HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The chronic activation or deregulation of the canonical and non-canonical nuclear factor kappa B (NF-kappaB) pathways play a crucial role in tumorigenesis. The HTLV-1 Tax-1 oncoprotein is a potent activator of the NF kappaB transcription factors and the NF-kappaB response is required for promoting the development of HTLV-1 transformed cell lines. The homologous retrovirus HTLV 2, which also expresses a Tax-2 transforming protein, is not associated with ATL. In this review, we provide an updated synopsis of the role of Tax-1 in the deregulation of the NF-kappaB pathway, highlighting the differences with the homologous Tax-2. Special emphasis is directed toward the understanding of the molecular mechanisms involved in NF-kappaB activation resulting from Tax interaction with host factors affecting several cellular processes, such as cell cycle, apoptosis, senescence, cell proliferation, autophagy, and post translational modifications. We also discuss the current knowledge on the role of the antisense viral protein HBZ in down-regulating the NF-kappaB activation induced by Tax, and its implication in cellular senescence. In addition, we review the recent studies on the mechanism of HBZ-mediated inhibition of NF kappaB activity as compared to that exerted by the HTLV-2 antisense protein, APH 2. Finally, we discuss recent advances aimed at understanding the role exerted in the development of ATL by the perturbation of NF-kappaB pathway by viral regulatory proteins. PMID- 29515559 TI - Enterovirus A71 Proteins: Structure and Function. AB - Enterovirus A71 (EV-A71) infection has grown to become a serious threat to global public health. It is one of the major causes of hand, foot, and mouth disease (HFMD) in infants and young children. EV-A71 can also infect the central nervous system (CNS) and induce diverse neurological complications, such as brainstem encephalitis, aseptic meningitis, and acute flaccid paralysis, or even death. Viral proteins play a crucial role in EV-A71 infection. Many recent studies have discussed the structure and function of EV-A71 proteins, and the findings reported will definitely aid the development of vaccines and therapeutic approaches. This article reviews the progress in the research on the structure and function of EV-A71 proteins. Available literature can provide a basis for studying the pathogenesis of EV-A71 infection in detail. PMID- 29515560 TI - Investigation of Endogenous Retrovirus Sequences in the Neighborhood of Genes Up regulated in a Neuroblastoma Model after Treatment with Hypoxia-Mimetic Cobalt Chloride. AB - Human endogenous retroviruses (ERVs) have been found to be associated with different diseases, e.g., multiple sclerosis (MS). Most human ERVs integrated in our genome are not competent to replicate and these sequences are presumably silent. However, transcription of human ERVs can be reactivated, e.g., by hypoxia. Interestingly, MS has been linked to hypoxia since decades. As some patterns of demyelination are similar to white matter ischemia, hypoxic damage is discussed. Therefore, we are interested in the association between hypoxia and ERVs. As a model, we used human SH-SY5Y neuroblastoma cells after treatment with the hypoxia-mimetic cobalt chloride and analyzed differences in the gene expression profiles in comparison to untreated cells. The vicinity of up regulated genes was scanned for endogenous retrovirus-derived sequences. Five genes were found to be strongly up-regulated in SH-SY5Y cells after treatment with cobalt chloride: clusterin, glutathione peroxidase 3, insulin-like growth factor 2, solute carrier family 7 member 11, and neural precursor cell expressed developmentally down-regulated protein 9. In the vicinity of these genes we identified large (>1,000 bp) open reading frames (ORFs). Most of these ORFs showed only low similarities to proteins from retro-transcribing viruses. However, we found very high similarity between retrovirus envelope sequences and a sequence in the vicinity of neural precursor cell expressed developmentally down-regulated protein 9. This sequence encodes the human endogenous retrovirus group FRD member 1, the encoded protein product is called syncytin 2. Transfection of syncytin 2 into the well-characterized Ewing sarcoma cell line A673 was not able to modulate the low immunostimulatory activity of this cell line. Future research is needed to determine whether the identified genes and the human endogenous retrovirus group FRD member 1 might play a role in the etiology of MS. PMID- 29515561 TI - Characterization of the Adaptive Amoxicillin Resistance of Lactobacillus casei Zhang by Proteomic Analysis. AB - Amoxicillin is one of the most commonly prescribed antibiotics for bacterial infections and gastrointestinal disorders. To investigate the adaptation of Lactobacillus (L.) casei Zhang to amoxicillin stress, an iTRAQ-based comparative proteomic analysis was performed to compare the protein profiles between the parental L. casei Zhang and its amoxicillin-resistant descendent strains. Our results revealed a significant increase in the relative expression of 38 proteins (>2.0-folds, P < 0.05), while the relative expression of 34 proteins significantly decreased (<-2.0-folds, P < 0.05). The amoxicillin-resistant descendent strain exhibited marked alterations in carbohydrate and amino acid metabolism. Moreover, certain components involving in membrane metabolism were activated. The differences in the proteomic profiles between the two strains might explain the enhanced stress resistance of the adapted bacteria. PMID- 29515562 TI - High Prevalence of Intra-Familial Co-colonization by Extended-Spectrum Cephalosporin Resistant Enterobacteriaceae in Preschool Children and Their Parents in Dutch Households. AB - Extended-spectrum cephalosporin-resistant (ESCR) Enterobacteriaceae pose a serious infection control challenge for public health. The emergence of the ESCR phenotype is mostly facilitated by plasmid-mediated horizontal extended-spectrum beta-lactamases (ESBLs) and AmpC gene transfer within Enterobacteriaceae. Current data regarding the plasmid contribution to this emergence within the Dutch human population is limited. Hence, the aim of this study was to gain insight into the role of plasmids in the dissemination of ESBL/AmpC genes inside Dutch households with preschool children and precisely delineate co-colonization. In 87 ESCREnterobacteriaceae from fecal samples of parents and preschool children within 66 Dutch households, genomic localization, plasmid type and insertion sequences linked to ESBL/AmpC genes were determined. Chromosomal location of ESBL/AmpC genes was confirmed when needed. An epidemiologically relevant subset of the isolates based on household co-carriage was assessed by Multilocus Sequence Typing and Pulsed-Field Gel Electrophoresis for genetic relatedness. The narrow-host range I1alpha and F plasmids were the major facilitators of ESBL/AmpC gene dissemination. Interestingly, we documented a relatively high occurrence of chromosomal integration of typically plasmid-encoded ESBL/AmpC-genes. A high diversity of non-epidemic Escherichia coli sequence types (STs) was revealed; the predominant STs belonged to the pandemic lineages of extraintestinal pathogenic E. coli ST131 and ST69. Intra-familiar co-carriage by identical ESCREnterobacteriaceae was documented in 7 households compared to 14 based on sole gene typing, as previously reported. Co-carriage was more frequent than expected based on pure chance, suggesting clonal transmission between children and parents within the household. PMID- 29515564 TI - Corrigendum: Tobacco Rotated with Rapeseed for Soil-Borne Phytophthora Pathogen Biocontrol: Mediated by Rapeseed Root Exudates. AB - [This corrects the article on p. 894 in vol. 7, PMID: 27379037.]. PMID- 29515563 TI - The SCO4117 ECF Sigma Factor Pleiotropically Controls Secondary Metabolism and Morphogenesis in Streptomyces coelicolor. AB - Extracytoplasmic function (ECF) sigma factors are a major type of bacterial signal-transducers whose biological functions remain poorly characterized in streptomycetes. In this work we studied SCO4117, a conserved ECF sigma factor from the ECF52 family overexpressed during substrate and aerial mycelium stages. The ECF52 sigma factors harbor, in addition to the ECF sigma factor domain, a zinc finger domain, a transmembrane region, a proline-rich C-terminal extension, and a carbohydrate-binding domain. This class of ECF sigma factors is exclusive to Actinobacteria. We demonstrate that SCO4117 is an activator of secondary metabolism, aerial mycelium differentiation, and sporulation, in all the culture media (sucrose-free R5A, GYM, MM, and SFM) analyzed. Aerial mycelium formation and sporulation are delayed in a SCO4117 knockout strain. Actinorhodin production is delayed and calcium-dependent antibiotic production is diminished, in the DeltaSCO4117 mutant. By contast, undecylprodigiosin production do not show significant variations. The expression of genes encoding secondary metabolism pathways (deoxysugar synthases, actinorhodin biosynthetic genes) and genes involved in differentiation (rdl, chp, nepA, ssgB) was dramatically reduced (up to 300-fold) in the SCO4117 knockout. A putative motif bound, with the consensus "CSGYN-17bps-SRHA" sequence, was identified in the promoter region of 29 genes showing affected transcription in the SCO4117 mutant, including one of the SCO4117 promoters. SCO4117 is a conserved gene with complex regulation at the transcriptional and post-translational levels and the first member of the ECF52 family characterized. PMID- 29515566 TI - The Metabolic Sensor GPR43 Receptor Plays a Role in the Control of Klebsiella pneumoniae Infection in the Lung. AB - Pneumonia is one of the leading causes of death and mortality worldwide. The inflammatory responses that follow respiratory infections are protective leading to pathogen clearance but can also be deleterious if unregulated. The microbiota is known to be an important protective barrier against infections, mediating both direct inhibitory effects against the potential pathogen and also regulating the immune responses contributing to a proper clearance of the pathogen and return to homeostasis. GPR43 is one receptor for acetate, a microbiota metabolite shown to induce and to regulate important immune functions. Here, we addressed the role of GPR43 signaling during pulmonary bacterial infections. We have shown for the first time that the absence of GPR43 leads to increased susceptibility to Klebsiella pneumoniae infection, which was associated to both uncontrolled proliferation of bacteria and to increased inflammatory response. Mechanistically, we showed that GPR43 expression especially in neutrophils and alveolar macrophages is important for bacterial phagocytosis and killing. In addition, treatment with the GPR43 ligand, acetate, is protective during bacterial lung infection. This was associated to reduction in the number of bacteria in the airways and to the control of the inflammatory responses. Altogether, GPR43 plays an important role in the "gut-lung axis" as a sensor of the host gut microbiota activity through acetate binding promoting a proper immune response in the lungs. PMID- 29515565 TI - A20/Tumor Necrosis Factor alpha-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models. AB - Immune cell activation is a stringently regulated process, as exaggerated innate and adaptive immune responses can lead to autoinflammatory and autoimmune diseases. Perhaps the best-characterized molecular pathway promoting cell activation is the nuclear factor-kappaB (NF-kappaB) signaling pathway. Stimulation of this pathway leads to transcription of numerous pro-inflammatory and cell-survival genes. Several mechanisms tightly control NF-kappaB activity, including the key regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor alpha-induced protein 3 (TNFAIP3). Single nucleotide polymorphisms (SNPs) in the vicinity of the TNFAIP3 gene are associated with a spectrum of chronic systemic inflammatory diseases, indicative of its clinical relevance. Mice harboring targeted cell-specific deletions of the Tnfaip3 gene in innate immune cells such as macrophages spontaneously develop autoinflammatory disease. When immune cells involved in the adaptive immune response, such as dendritic cells or B-cells, are targeted for A20/TNFAIP3 deletion, mice develop spontaneous inflammation that resembles human autoimmune disease. Therefore, more knowledge on A20/TNFAIP3 function in cells of the immune system is beneficial in our understanding of autoinflammation and autoimmunity. Using the aforementioned mouse models, novel A20/TNFAIP3 functions have recently been described including control of necroptosis and inflammasome activity. In this review, we discuss the function of the A20/TNFAIP3 enzyme and its critical role in various innate and adaptive immune cells. Finally, we discuss the latest findings on TNFAIP3 SNPs in human autoinflammatory and autoimmune diseases and address that genotyping of TNFAIP3 SNPs may guide treatment decisions. PMID- 29515567 TI - Interorgan Molecular Communication Strategies of "Local" and "Systemic" Innate Immune Responses in Mosquito Anopheles stephensi. AB - Mosquitoes that transmit many deadly infectious diseases also need to keep fighting against many microbial infections. Constitutive expression of multiple antimicrobial peptides (AMPs) in almost all body tissues is believed to facilitate the effective management of these local infections. When any infection breaches the local barrier, AMPs are induced rapidly in non-target tissues such as hemocytes (HCs) and establish their co-ordination with systemic immune effectors to clear off the body infection. But how interorgan immune communication is managed during local and systemic infections remain largely unknown. To understand this interorgan molecular relationship, we identified, extensively profiled and compared the expression of AMPs in three important mosquito tissues viz. midgut, fat body (FB), and HCs. dsRNA-mediated AMPs silencing suggests that mosquito tissues are able to manage an optimal expression of AMPs at the physiological level. We also examined the possible contribution of two important immune regulator genes relish (REL) and nitric oxide synthase, controlling AMPs expression in these tissues during local or systemic infections. We show that each tissue has a unique ability to respond to local/systemic challenges, but HCs are more specialized to recognize and discriminate-specific antigens than gut and FB. Our investigation also revealed that both REL and NO participate in the overall management of the interorgan immune responses, but at the same time each tissue also has its own ability to maintain the interorgan flow of signals. In our knowledge, this is the first large-scale study examining the interorgan immune relationship in the mosquito. PMID- 29515568 TI - The Role of Astrocytes in Multiple Sclerosis. AB - The role traditionally assigned to astrocytes in the pathogenesis of multiple sclerosis (MS) lesions has been the formation of the glial scar once inflammation has subsided. Astrocytes are now recognized to be early and highly active players during lesion formation and key for providing peripheral immune cells access to the central nervous system. Here, we review the role of astrocytes in the formation and evolution of MS lesions, including the recently described functional polarization of astrocytes, discuss prototypical pathways for astrocyte activation, and summarize mechanisms by which MS treatments affect astrocyte function. PMID- 29515569 TI - Computational Strategies for Dissecting the High-Dimensional Complexity of Adaptive Immune Repertoires. AB - The adaptive immune system recognizes antigens via an immense array of antigen binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics. PMID- 29515570 TI - Factors Affecting the Immunity to Respiratory Syncytial Virus: From Epigenetics to Microbiome. AB - Respiratory syncytial virus (RSV) is a common pathogen that infects virtually all children by 2 years of age and is the leading cause of hospitalization of infants worldwide. While most children experience mild symptoms, some children progress to severe lower respiratory tract infection. Those children with severe disease have a much higher risk of developing childhood wheezing later in life. Many risk factors are known to result in exacerbated disease, including premature birth and early age of RSV infection, when the immune system is relatively immature. The development of the immune system before and after birth may be altered by several extrinsic and intrinsic factors that could lead to severe disease predisposition in children who do not exhibit any currently known risk factors. Recently, the role of the microbiome and the resulting metabolite profile has been an area of intense study in the development of lung disease, including viral infection and asthma. This review explores both known risk factors that can lead to severe RSV induced disease as well as emerging topics in the development of immunity to RSV and the long-term consequences of severe infection. PMID- 29515571 TI - Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance. AB - Antigen-specific immune tolerance has been a long-standing goal for immunotherapy for the treatment of autoimmune diseases and allergies and for the prevention of allograft rejection and anti-drug antibodies directed against biologic therapies. Nanoparticles have emerged as powerful tools to initiate and modulate immune responses due to their inherent capacity to target antigen-presenting cells (APCs) and deliver coordinated signals that can elicit an antigen-specific immune response. A wide range of strategies have been described to create tolerogenic nanoparticles (tNPs) that fall into three broad categories. One strategy includes tNPs that provide antigen alone to harness natural tolerogenic processes and environments, such as presentation of antigen in the absence of costimulatory signals, oral tolerance, the tolerogenic environment of the liver, and apoptotic cell death. A second strategy includes tNPs that carry antigen and simultaneously target tolerogenic receptors, such as pro-tolerogenic cytokine receptors, aryl hydrocarbon receptor, FAS receptor, and the CD22 inhibitory receptor. A third strategy includes tNPs that carry a payload of tolerogenic pharmacological agents that can "lock" APCs into a developmental or metabolic state that favors tolerogenic presentation of antigens. These diverse strategies have led to the development of tNPs that are capable of inducing antigen-specific immunological tolerance, not just immunosuppression, in animal models. These novel tNP technologies herald a promising approach to specifically prevent and treat unwanted immune reactions in humans. The first tNP, SEL-212, a biodegradable synthetic vaccine particle encapsulating rapamycin, has reached the clinic and is currently in Phase 2 clinical trials. PMID- 29515573 TI - AmpliSeq Screening of Genes Encoding the C-Type Lectin Receptors and Their Signaling Components Reveals a Common Variant in MASP1 Associated with Pulmonary Tuberculosis in an Indian Population. AB - Tuberculosis (TB) is a multifactorial disease governed by bacterial, host and environmental factors. On the host side, growing evidence shows the crucial role that genetic variants play in the susceptibility to Mycobacterium tuberculosis (Mtb) infection. Such polymorphisms have been described in genes encoding for different cytokines and pattern recognition receptors (PRR), including numerous Toll-like receptors (TLRs). In recent years, several members of the C-type lectin receptors (CTLRs) have been identified as key PRRs in TB pathogenesis. Nevertheless, studies to date have only addressed particular genetic polymorphisms in these receptors or their related pathways in relation with TB. In the present study, we screened the main CTLR gene clusters as well as CTLR pathway-related genes for genetic variation associated with pulmonary tuberculosis (PTB). This case-control study comprised 144 newly diagnosed pulmonary TB patients and 181 healthy controls recruited at the Bhagwan Mahavir Medical Research Center (BMMRC), Hyderabad, India. A two-stage study was employed in which an explorative AmpliSeq-based screening was followed by a validation phase using iPLEX MassARRAY. Our results revealed one SNP (rs3774275) in MASP1 significantly associated with PTB in our population (joint analysis p = 0.0028). Furthermore, serum levels of MASP1 were significantly elevated in TB patients when compared to healthy controls. Moreover, in the present study we could observe an impact of increased MASP1 levels on the lectin pathway complement activity in vitro. In conclusion, our results demonstrate a significant association of MASP1 polymorphism rs3774275 and MASP1 serum levels with the development of pulmonary TB. The present work contributes to our understanding of host-Mtb interaction and reinforces the critical significance of mannose-binding lectin and the lectin-complement pathway in Mtb pathogenesis. Moreover, it proposes a MASP1 polymorphism as a potential genetic marker for TB resistance. PMID- 29515572 TI - Chimeric Antigen Receptor T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. AB - Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects. PMID- 29515574 TI - Human Intestinal Epithelial Cells Release Antiviral Factors That Inhibit HIV Infection of Macrophages. AB - As a rich source of CD4+ T cells and macrophages, the gastrointestinal (GI) tract is a major target site for HIV infection. The interplay between GI-resident macrophages and intestinal epithelial cells (IECs) constitutes an important element of GI innate immunity against pathogens. In this study, we investigated whether human IECs have the ability to produce antiviral factors that can inhibit HIV infection of macrophages. We demonstrated that IECs possess functional toll like receptor 3 (TLR3), the activation of which resulted in induction of key interferon (IFN) regulatory factors (IRF3 and IRF7), IFN-beta, IFN-lambda, and CC chemokines (MIP-1alpha, MIP-1beta, RANTES), the ligands of HIV entry co-receptor CCR5. In addition, TLR3-activated IECs release exosomes that contained the anti HIV factors, including IFN-stimulated genes (ISGs: ISG15, ISG56, MxB, OAS-1, GBP5, and Viperin) and HIV restriction miRNAs (miRNA-17, miRNA-20, miRNA-28, miRNA-29 family members, and miRNA-125b). Importantly, treatment of macrophages with supernatant (SN) from the activated IEC cultures inhibited HIV replication. Further studies showed that IEC SN could also induce the expression of antiviral ISGs and cellular HIV restriction factors (Tetherin and APOBEC3G/3F) in HIV infected macrophages. These findings indicated that IECs might act as an important element in GI innate immunity against HIV infection/replication. PMID- 29515575 TI - High-Throughput Sequencing of the Expressed Torafugu (Takifugu rubripes) Antibody Sequences Distinguishes IgM and IgT Repertoires and Reveals Evidence of Convergent Evolution. AB - B-cell antigen receptor (BCR) or antibody diversity arises from somatic recombination of immunoglobulin (Ig) gene segments and is concentrated within the Ig heavy (H) chain complementarity-determining region 3 (CDR-H3). We performed high-throughput sequencing of the expressed antibody heavy-chain repertoire from adult torafugu. We found that torafugu use between 70 and 82% of all possible V (variable), D (diversity), and J (joining) gene segment combinations and that they share a similar frequency distribution of these VDJ combinations. The CDR-H3 sequence repertoire observed in individuals is biased with the preferential use of a small number of VDJ, dominated by sequences containing inserted nucleotides. We uncovered the common CDR-H3 amino-acid (aa) sequences shared by individuals. Common CDR-H3 sequences feature highly convergent nucleic-acid recombination compared with private ones. Finally, we observed differences in repertoires between IgM and IgT, including the unequal usage frequencies of V gene segment and the biased number of nucleotide insertion/deletion at VDJ junction regions that leads to distinct distributions of CDR-H3 lengths. PMID- 29515576 TI - Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions. AB - Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression. PMID- 29515577 TI - Immunization Strategies Producing a Humoral IgG Immune Response against Devil Facial Tumor Disease in the Majority of Tasmanian Devils Destined for Wild Release. AB - Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government's Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials (N = 19 and N = 33), these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIXTM, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIXTM, polyICLC (Hiltonol(r)) and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of devils in these anti-DFTD immunization trials was remarkable, especially as DFTD is hallmarked by its immune evasion mechanisms. Microsatellite analyzes of MHC revealed that some MHC-I microsatellites correlated to stronger immune responses. These trials signify the first step in the long-term objective of releasing devils with immunity to DFTD into the wild. PMID- 29515578 TI - Mechanisms for Cell-to-Cell Transmission of HIV-1. AB - While HIV-1 infection of target cells with cell-free viral particles has been largely documented, intercellular transmission through direct cell-to-cell contact may be a predominant mode of propagation in host. To spread, HIV-1 infects cells of the immune system and takes advantage of their specific particularities and functions. Subversion of intercellular communication allows to improve HIV-1 replication through a multiplicity of intercellular structures and membrane protrusions, like tunneling nanotubes, filopodia, or lamellipodia like structures involved in the formation of the virological synapse. Other features of immune cells, like the immunological synapse or the phagocytosis of infected cells are hijacked by HIV-1 and used as gateways to infect target cells. Finally, HIV-1 reuses its fusogenic capacity to provoke fusion between infected donor cells and target cells, and to form infected syncytia with high capacity of viral production and improved capacities of motility or survival. All these modes of cell-to-cell transfer are now considered as viral mechanisms to escape immune system and antiretroviral therapies, and could be involved in the establishment of persistent virus reservoirs in different host tissues. PMID- 29515579 TI - Calcineurin B in CD4+ T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway. AB - Calcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4+ T cells (Cnb1CD4 mice) to delineate the role of the Cn-NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4 mice developed severe, spontaneous colitis characterized at the molecular level by an increased T helper-1-cell response but an unaltered regulatory T-cell compartment. Antibiotic treatment ameliorated the intestinal inflammation observed in Cnb1CD4 mice, suggesting that the microbiota contributes to the onset of colitis. CD4+ T cells isolated from Cnb1CD4 mice produced high levels of IFNgamma due to increased activation of the JAK2/STAT4 pathway induced by IL-12. Our data highlight that Cn signaling in CD4+ T cells is critical for intestinal immune homeostasis in part by inhibiting IL-12 responsiveness of CD4+ T cells. PMID- 29515581 TI - Autophagy Mediates Interleukin-1beta Secretion in Human Neutrophils. AB - Interleukin-1beta (IL-1beta), a major pro-inflammatory cytokine, is a leaderless cytosolic protein whose secretion does not follow the classical endoplasmic reticulum-to-Golgi pathway, and for which a canonical mechanism of secretion remains to be established. Neutrophils are essential players against bacterial and fungi infections. These cells are rapidly and massively recruited from the circulation into infected tissues and, beyond of displaying an impressive arsenal of toxic weapons effective to kill pathogens, are also an important source of IL 1beta in infectious conditions. Here, we analyzed if an unconventional secretory autophagy mechanism is involved in the exportation of IL-1beta by these cells. Our findings indicated that inhibition of autophagy with 3-methyladenine and Wortmannin markedly reduced IL-1beta secretion induced by LPS + ATP, as did the disruption of the autophagic flux with Bafilomycin A1 and E64d. These compounds did not noticeable affect neutrophil viability ruling out that the effects on IL 1beta secretion were due to cell death. Furthermore, VPS34IN-1, a specific autophagy inhibitor, was still able to reduce IL-1beta secretion when added after it was synthesized. Moreover, siRNA-mediated knockdown of ATG5 markedly reduced IL-1beta secretion in neutrophil-differentiated PLB985 cells. Upon LPS + ATP stimulation, IL-1beta was incorporated to an autophagic compartment, as was revealed by its colocalization with LC3B by confocal microscopy. Overlapping of IL-1beta-LC3B in a vesicular compartment peaked before IL-1beta increased in culture supernatants. On the other hand, stimulation of autophagy by cell starvation augmented the colocalization of IL-1beta and LC3B and then promoted neutrophil IL-1beta secretion. In addition, specific ELISAs indicated that although both IL-1beta and pro-IL-1beta are released to culture supernatants upon neutrophil stimulation, autophagy only promotes IL-1beta secretion. Furthermore, the serine proteases inhibitor AEBSF reduced IL-1beta secretion. Moreover, IL 1beta could be also found colocalizing with elastase, suggesting both some vesicles containing IL-1beta intersect azurophil granules content and that serine proteases also regulate IL-1beta secretion. Altogether, our findings indicate that an unconventional autophagy-mediated secretory pathway mediates IL-1beta secretion in human neutrophils. PMID- 29515582 TI - CD4+ T Cell Help Is Mandatory for Naive and Memory Donor-Specific Antibody Responses: Impact of Therapeutic Immunosuppression. AB - Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients' spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal. PMID- 29515583 TI - K63-Linked Polyubiquitination on TRAF6 Regulates LPS-Mediated MAPK Activation, Cytokine Production, and Bacterial Clearance in Toll-Like Receptor 7/8 Primed Murine Macrophages. AB - Post viral infection bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. Despite much efforts put into the discovery of mechanisms of post viral-bacterial infections and their complications in recent years, the molecular mechanisms underlying the increased susceptibility to bacterial infection remain poorly understood. In this study, we focused on the pathways regulating immune responses in murine macrophages and modeled post viral-bacterial infections through pretreatment of bone marrow-derived macrophages (BMDMs) with a toll-like receptor (TLR) 7/8 ligand (R848) and subsequent challenge with TLR2/4 agonists to mimic bacterial infection. We found R848-primed BMDMs upon subsequent exposure to TLR2/4 ligands respond with enhanced inflammatory cytokine production, especially IL-6 and TNF-alpha. The enhanced cytokine production in R848-primed BMDMs in response to TLR2/4 was due to increased TGF-beta-activated kinase (TAK) 1 phosphorylation with subsequent activation of ERK and p38 MAPKs. Furthermore, we identified that R848 priming leads to increased K63-linked polyubiquitination on TRAF6. K63-linked polyubiquitination on TRAF6 is a signal leading to enhanced activation of downstream pathways including TAK1. Importantly, R848-primed BMDMs infected with live bacteria exhibited decreased bacterial clearance. Small molecule enhancer of rapamycin 3, an ubiquitin ligase inhibitor reversed the K63 linked polyubiquitination on TRAF6 in R848-primed BMDMs and subsequently decreased TAK1 and MAPK phosphorylation, and cytokine production as well as reversed the decreased bacterial clearance capacity of BMDMs. Our study may provide a novel molecular target to alleviate post viral-bacterial infections. PMID- 29515584 TI - Regulatory T-Cells Mediate IFN-alpha-Induced Resistance against Antigen-Induced Arthritis. AB - Objective: CD4+FoxP3+CD25+ regulatory T-cells (Tregs) are important for preventing tissue destruction. Here, we investigate the role of Tregs for protection against experimental arthritis by IFN-alpha. Methods: Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP+/- mice [allowing selective depletion of Tregs by diphtheria toxin (DT)] and CD4-Cre+/- IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-alpha or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine. Tregs were depleted in DT-treated Foxp3DTReGFP+/- mice and enumerated by FoxP3 staining. Suppressive capacity of FACS-sorted CD25+highCD4+ Tregs was tested in vivo by adoptive transfer and ex vivo in cocultures with antigen-stimulated CFSE stained T-responder (CD25-CD4+) cells. IDO was inhibited by 1-methyl tryptophan. Results: Both control mice and mice devoid of IFNAR-signaling in T helper cells were protected from arthritis by IFN-alpha. Depletion of Tregs in the arthritis phase, but not at immunization, abolished the protective effect of IFN-alpha and kynurenine against arthritis. IFN-alpha increased the number of Tregs in ex vivo cultures upon antigen recall stimulation but not in naive cells. IFN-alpha also increased the suppressive capacity of Tregs against mBSA-induced T-responder cell proliferation ex vivo and against arthritis when adoptively transferred. The increased suppressive activity against proliferation conferred by IFN-alpha was clearly reduced by in vivo inhibition of IDO at immunization, which also abolished the protective effect of IFN-alpha against arthritis. Conclusion: By activating IDO during antigen sensitization, IFN-alpha activates Tregs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN alpha suppresses inflammation. PMID- 29515585 TI - Influence of Intestinal Indigenous Microbiota on Intrafamilial Infection by Helicobacter pylori in Japan. AB - Helicobacter pylori is a causative pathogen of chronic gastritis, gastric ulcer disease, and gastric cancer. Humans are known to be a natural host for H. pylori and tend to acquire the pathogen before the age of 5 years. The infection may then persist lifelong if eradication therapy is not applied. One of the modes of transmission of H. pylori is between family members, and therefore, the presence of infected family members is an important risk factor in children. However, other environmental factors have not been fully analyzed. The present study was performed to clarify whether and to what extent intestinal microbiota affect H. pylori intrafamilial infection. The fecal specimens from H. pylori-infected infants and H. pylori-infected and non-infected family members were collected in cohort studies conducted by Sasayama City, Hyogo Prefecture from 2010 to 2013. In total, 18 fecal DNA from 5 families were analyzed. Samples were amplified using 16S rRNA universal primers, and the amplicons were sequenced using the Ion PGM system. Principal-coordinate analysis demonstrated that there was no difference in intestinal microbiota between H. pylori-positive and H. pylori-negative groups. In intrafamilial comparison tests, the Manhattan distance of intestinal microbiota between the H. pylori-infected infant proband and H. pylori-negative mother was nearest in the family with low intestinal microbial diversity. However, in the family with the highest intestinal microbial diversity, the nearest Manhattan distance was shown between the H. pylori-infected infant proband and H. pylori-infected mother. The results in this study showed that the composition of the intestinal microbiota was very similar between members of the same family, and as such, colonization with organisms highly similar to the infected parent(s) may be a risk factor for H. pylori infection in children. PMID- 29515580 TI - How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive. AB - Experimental evidence indicates that mesenchymal stromal cells (MSCs) may regulate tumor microenvironment (TME). It is conceivable that the interaction with MSC can influence neoplastic cell functional behavior, remodeling TME and generating a tumor cell niche that supports tissue neovascularization, tumor invasion and metastasization. In addition, MSC can release transforming growth factor-beta that is involved in the epithelial-mesenchymal transition of carcinoma cells; this transition is essential to give rise to aggressive tumor cells and favor cancer progression. Also, MSC can both affect the anti-tumor immune response and limit drug availability surrounding tumor cells, thus creating a sort of barrier. This mechanism, in principle, should limit tumor expansion but, on the contrary, often leads to the impairment of the immune system-mediated recognition of tumor cells. Furthermore, the cross-talk between MSC and anti-tumor lymphocytes of the innate and adaptive arms of the immune system strongly drives TME to become immunosuppressive. Indeed, MSC can trigger the generation of several types of regulatory cells which block immune response and eventually impair the elimination of tumor cells. Based on these considerations, it should be possible to favor the anti-tumor immune response acting on TME. First, we will review the molecular mechanisms involved in MSC mediated regulation of immune response. Second, we will focus on the experimental data supporting that it is possible to convert TME from immunosuppressive to immunostimulant, specifically targeting MSC. PMID- 29515587 TI - T Cell Phenotype and T Cell Receptor Repertoire in Patients with Major Depressive Disorder. AB - While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case-control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/- cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vbeta repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR beta chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder. PMID- 29515586 TI - The Neutrophil's Choice: Phagocytose vs Make Neutrophil Extracellular Traps. AB - Neutrophils recognize particulate substrates of microbial or endogenous origin and react by sequestering the cargo via phagocytosis or by releasing neutrophil extracellular traps (NETs) outside the cell, thus modifying and alerting the environment and bystander leukocytes. The signals that determine the choice between phagocytosis and the generation of NETs are still poorly characterized. Neutrophils that had phagocytosed bulky particulate substrates, such as apoptotic cells and activated platelets, appear to be "poised" in an unresponsive state. Environmental conditions, the metabolic, adhesive and activation state of the phagocyte, and the size of and signals associated with the tethered phagocytic cargo influence the choice of the neutrophils, prompting either phagocytic clearance or the generation of NETs. The choice is dichotomic and apparently irreversible. Defects in phagocytosis may foster the intravascular generation of NETs, thus promoting vascular inflammation and morbidities associated with diseases characterized by defective phagocytic clearance, such as systemic lupus erythematosus. There is a strong potential for novel treatments based on new knowledge of the events determining the inflammatory and pro-thrombotic function of inflammatory leukocytes. PMID- 29515588 TI - Endothelial to Mesenchymal Transition Represents a Key Link in the Interaction between Inflammation and Endothelial Dysfunction. AB - Endothelial cells that line the inner walls of blood vessels are in direct contact with blood and display remarkable heterogeneity in their response to exogenous stimuli. These ECs have unique location-dependent properties determined by the corresponding vascular beds and play an important role in regulating the homeostasis of the vascular system. Evidence suggests that vascular endothelial cells exposed to various environments undergo dynamic phenotypic switching, a key biological program in the context of endothelial heterogeneity, but that might result in EC dysfunction and, in turn, cause a variety of human diseases. Emerging studies show the importance of endothelial to mesenchymal transition (EndMT) in endothelial dysfunction during inflammation. EndMT is a complex biological process in which ECs lose their endothelial characteristics, acquire mesenchymal phenotypes, and express mesenchymal cell markers, such as alpha smooth muscle actin and fibroblast-specific protein 1. EndMT is induced by inflammatory responses, leading to pathological states, including tissue fibrosis, pulmonary arterial hypertension, and atherosclerosis, via dysfunction of the vascular system. Although the mechanisms associated with inflammation induced EndMT have been identified, unraveling the specific role of this phenotypic switching in vascular dysfunction remains a challenge. Here, we review the current understanding on the interactions between inflammatory processes, EndMT, and endothelial dysfunction, with a focus on the mechanisms that regulate essential signaling pathways. Identification of such mechanisms will guide future research and could provide novel therapeutic targets for the treatment of vascular diseases. PMID- 29515590 TI - Editorial: HIV-Induced Damage of B Cells and Production of HIV Neutralizing Antibodies. PMID- 29515589 TI - Improved Immune Responses in Young and Aged Mice with Adjuvanted Vaccines against H1N1 Influenza Infection. AB - Elderly people are at high risk for influenza-related morbidity and mortality due to progressive immunosenescence. While toll-like receptor (TLR) agonist containing adjuvants, and other adjuvants, have been shown to enhance influenza vaccine-induced protective responses, the mechanisms underlying how these adjuvanted vaccines could benefit the elderly remain elusive. Here, we show that a split H1N1 influenza vaccine (sH1N1) combined with a TLR4 agonist, glucopyranosyl lipid adjuvant formulated in a stable oil-in-water emulsion (GLA SE), boosts IgG2c:IgG1 ratios, enhances hemagglutination inhibition (HAI) titers, and increases protection in aged mice. We find that all adjuvanted sH1N1 vaccines tested were able to protect both young and aged mice from lethal A/H1N1/California/4/2009 virus challenge after two immunizations compared to vaccine alone. We show that GLA-SE combined with sH1N1, however, also provides enhanced protection from morbidity in aged mice given one immunization (based on change in weight percentage). While the GLA-SE-adjuvanted sH1N1 vaccine promotes the generation of cytokine-producing T helper 1 cells, germinal center B cells, and long-lived bone marrow plasma cells in young mice, these responses were muted in aged mice. Differential in vitro responses, dependent on age, were also observed from mouse-derived bone marrow-derived dendritic cells and lung homogenates following stimulation with adjuvants, including GLA-SE. Besides enhanced HAI titers, additional protective factors elicited with sH1N1 + GLA-SE in young mice were observed, including (a) rapid reduction of viral titers in the lung, (b) prevention of excessive lung inflammation, and (c) homeostatic maintenance of alveolar macrophages (AMs) following H1N1 infection. Collectively, our results provide insight into mechanisms of adjuvant-mediated immune protection in the young and elderly. PMID- 29515592 TI - Coevolution of the Toll-Like Receptor 4 Complex with Calgranulins and Lipopolysaccharide. AB - Toll-like receptor 4 (TLR4) induces inflammation in response to both pathogen- and host-derived molecules. Lipopolysaccharide (LPS) recognition by TLR4 has been shown to occur across the amniotes, but endogenous signaling through TLR4 has not been validated outside of placental mammals. To determine whether endogenous danger signaling is also shared across amniotes, we studied the evolution of TLR4 activation by the calgranulin proteins (S100A8, S100A9, and S100A12), a clade of host molecules that potently activate TLR4 in placental mammals. We performed phylogenetic and syntenic analysis and found MRP-126-a gene in birds and reptiles is likely orthologous to the mammalian calgranulins. We then used an ex vivo TLR4 activation assay to establish that calgranulin pro-inflammatory activity is not specific to placental mammals, but is also exhibited by representative marsupial and sauropsid species. This activity is strongly dependent on the cofactors CD14 and MD-2 for all species studied, suggesting a conserved mode of activation across the amniotes. Ortholog complementation experiments between the calgranulins, TLR4, CD14, and MD-2 revealed extensive lineage specific coevolution and multi-way interactions between components that are necessary for the activation of NF-kappaB signaling by calgranulins and LPS. Our work demonstrates that calgranulin activation of TLR4 evolved at least ~320 million years ago and has been conserved in the amniote innate immune system. PMID- 29515594 TI - Mammalian Target of Rapamycin Inhibition in Trypanosoma cruzi-Infected Macrophages Leads to an Intracellular Profile That Is Detrimental for Infection. AB - The causative agent of Chagas' disease, Trypanosoma cruzi, affects approximately 10 million people living mainly in Latin America, with macrophages being one of the first cellular actors confronting the invasion during T. cruzi infection and their function depending on their proper activation and polarization into distinct M1 and M2 subtypes. Macrophage polarization is thought to be regulated not only by cytokines and growth factors but also by environmental signals. The metabolic checkpoint kinase mammalian target of rapamycin (mTOR)-mediated sensing of environmental and metabolic cues influences macrophage polarization in a complex and as of yet incompletely understood manner. Here, we studied the role of the mTOR pathway in macrophages during T. cruzi infection. We demonstrated that the parasite activated mTOR, which was beneficial for its replication since inhibition of mTOR in macrophages by different inhibitors decreased parasite replication. Moreover, in rapamycin pretreated and infected macrophages, we observed a decreased arginase activity and expression, reduced IL-10 and increased interleukin-12 production, compared to control infected macrophages treated with DMSO. Surprisingly, we also found a reduced iNOS activity and expression in these macrophages. Therefore, we investigated possible alternative mechanisms involved in controlling parasite replication in rapamycin pretreated and infected macrophages. Although, cytoplasmic ROS and the enzyme indoleamine 2, 3-dioxygenase (IDO) were not involved, we observed a significant increase in IL 6, TNF-alpha, and IL-1beta production. Taking into account that IL-1beta is produced by activation of the cytoplasmic receptor NLRP3, which is one of the main components of the inflammasome, we evaluated NLRP3 expression during mTOR inhibition and T. cruzi infection. We observed that rapamycin-pretreated and infected macrophages showed a significant increase in NLRP3 expression and produced higher levels of mitochondrial ROS (mtROS) compared with control cells. Moreover, inhibition of mtROS production partially reversed the effect of rapamycin on parasite replication, with there being a significant increase in parasite load in rapamycin pretreated and infected macrophages from NLRP3 KO mice compared to wild-type control cells. Our findings strongly suggest that mTOR inhibition during T. cruzi infection induces NLRP3 inflammasome activation and mtROS production, resulting in an inflammatory-like macrophage profile that controls T. cruzi replication. PMID- 29515593 TI - Signals Controlling Lytic Granule Polarization at the Cytotoxic Immune Synapse. AB - Cytotoxic immunity relies on specialized effector T cells, the cytotoxic T cells, which are endowed with specialized cytolytic machinery that permits them to induce death of their targets. Upon recognition of a target cell, cytotoxic T cells form a lytic immune synapse and by docking the microtubule-organizing center at the synaptic membrane get prepared to deliver a lethal hit of enzymes contained in lytic granules. New insights suggest that the directionality of lytic granule trafficking along the microtubules represents a fine means to tune the functional outcome of the encounter between a T cell and its target. Thus, mechanisms regulating the directionality of granule transport may have a major impact in settings characterized by evasion from the cytotoxic response, such as chronic infection and cancer. Here, we review our current knowledge on the signaling pathways implicated in the polarized trafficking at the immune synapse of cytotoxic T cells, complementing it with information on the regulation of this process in natural killer cells. Furthermore, we highlight some of the parameters which we consider critical in studying the polarized trafficking of lytic granules, including the use of freshly isolated cytotoxic T cells, and discuss some of the major open questions. PMID- 29515595 TI - Targeted Delivery of Toxoplasma gondii Antigens to Dendritic Cells Promote Immunogenicity and Protective Efficiency against Toxoplasmosis. AB - Toxoplasmosis is a major public health problem and the development of a human vaccine is of high priority. Efficient vaccination against Toxoplasma gondii requires both a mucosal and systemic Th1 immune response. Moreover, dendritic cells play a critical role in orchestrating the innate immune functions and driving specific adaptive immunity to T. gondii. In this study, we explore an original vaccination strategy that combines administration via mucosal and systemic routes of fusion proteins able to target the major T. gondii surface antigen SAG1 to DCs using an antibody fragment single-chain fragment variable (scFv) directed against DEC205 endocytic receptor. Our results show that SAG1 targeting to DCs by scFv via intranasal and subcutaneous administration improved protection against chronic T. gondii infection. A marked reduction in brain parasite burden is observed when compared with the intranasal or the subcutaneous route alone. DC targeting improved both local and systemic humoral and cellular immune responses and potentiated more specifically the Th1 response profile by more efficient production of IFN-gamma, interleukin-2, IgG2a, and nasal IgA. This study provides evidence of the potential of DC targeting for the development of new vaccines against a range of Apicomplexa parasites. PMID- 29515591 TI - The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders. AB - During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated. PMID- 29515596 TI - Genomic Sequencing of Japanese Plum (Prunus salicina Lindl.) Mutants Provides a New Model for Rosaceae Fruit Ripening Studies. AB - It has recently been described that the Japanese plum "Santa Rosa" bud sport series contains variations in ripening pattern: climacteric, suppressed climacteric and non-climacteric types. This provides an interesting model to study the role of ethylene and other key mechanisms governing fruit ripening, softening and senescence. The aim of the current study was to investigate such differences at the genomic level, using this series of plum bud sports, with special reference to genes involved in ethylene biosynthesis, signal transduction, and sugar metabolism. Genomic DNA, isolated from leaf samples of six Japanese plum cultivars ("Santa Rosa", "July Santa Rosa", "Late Santa Rosa", "Sweet Miriam", "Roysum", and "Casselman"), was used to construct paired-end standard Illumina libraries. Sequences were aligned to the Prunus persica genome, and genomic variations (SNPs, INDELS, and CNV's) were investigated. Results determined 12 potential candidate genes with significant copy number variation (CNV), being associated with ethylene perception and signal transduction components. Additionally, the Maximum Likelihood (ML) phylogenetic tree showed two sorbitol dehydrogenase genes grouping into a distinct clade, indicating that this natural group is well-defined and presents high sequence identity among its members. In contrast, the ethylene group, which includes ACO1, ACS1, ACS4, ACS5, CTR1, ERF1, ERF3, and ethylene-receptor genes, was widely distributed and clustered into 10 different groups. Thus, ACS, ERF, and sorbitol dehydrogenase proteins potentially share a common ancestor for different plant genomes, while the expansion rate may be related to ancestral expansion rather than species specific events. Based on the distribution of the clades, we suggest that gene function diversification for the ripening pathway occurred prior to family extension. We herein report all the frameshift mutations in genes involved in sugar transport and ethylene biosynthesis detected as well as the gene CNV implicated in ripening differences. PMID- 29515597 TI - Genotyping by Sequencing and Genome-Environment Associations in Wild Common Bean Predict Widespread Divergent Adaptation to Drought. AB - Drought will reduce global crop production by >10% in 2050 substantially worsening global malnutrition. Breeding for resistance to drought will require accessing crop genetic diversity found in the wild accessions from the driest high stress ecosystems. Genome-environment associations (GEA) in crop wild relatives reveal natural adaptation, and therefore can be used to identify adaptive variation. We explored this approach in the food crop Phaseolus vulgaris L., characterizing 86 geo-referenced wild accessions using genotyping by sequencing (GBS) to discover single nucleotide polymorphisms (SNPs). The wild beans represented Mesoamerica, Guatemala, Colombia, Ecuador/Northern Peru and Andean groupings. We found high polymorphism with a total of 22,845 SNPs across the 86 accessions that confirmed genetic relationships for the groups. As a second objective, we quantified allelic associations with a bioclimatic-based drought index using 10 different statistical models that accounted for population structure. Based on the optimum model, 115 SNPs in 90 regions, widespread in all 11 common bean chromosomes, were associated with the bioclimatic-based drought index. A gene coding for an ankyrin repeat-containing protein and a phototropic responsive NPH3 gene were identified as potential candidates. Genomic windows of 1 Mb containing associated SNPs had more positive Tajima's D scores than windows without associated markers. This indicates that adaptation to drought, as estimated by bioclimatic variables, has been under natural divergent selection, suggesting that drought tolerance may be favorable under dry conditions but harmful in humid conditions. Our work exemplifies that genomic signatures of adaptation are useful for germplasm characterization, potentially enhancing future marker-assisted selection and crop improvement. PMID- 29515598 TI - Mapping of HKT1;5 Gene in Barley Using GWAS Approach and Its Implication in Salt Tolerance Mechanism. AB - Sodium (Na+) accumulation in the cytosol will result in ion homeostasis imbalance and toxicity of transpiring leaves. Studies of salinity tolerance in the diploid wheat ancestor Triticum monococcum showed that HKT1;5-like gene was a major gene in the QTL for salt tolerance, named Nax2. In the present study, we were interested in investigating the molecular mechanisms underpinning the role of the HKT1;5 gene in salt tolerance in barley (Hordeum vulgare). A USDA mini-core collection of 2,671 barley lines, part of a field trial was screened for salinity tolerance, and a Genome Wide Association Study (GWAS) was performed. Our results showed important SNPs that are correlated with salt tolerance that mapped to a region where HKT1;5 ion transporter located on chromosome four. Furthermore, sodium (Na+) and potassium (K+) content analysis revealed that tolerant lines accumulate more sodium in roots and leaf sheaths, than in the sensitive ones. In contrast, sodium concentration was reduced in leaf blades of the tolerant lines under salt stress. In the absence of NaCl, the concentration of Na+ and K+ were the same in the roots, leaf sheaths and leaf blades between the tolerant and the sensitive lines. In order to study the molecular mechanism behind that, alleles of the HKT1;5 gene from five tolerant and five sensitive barley lines were cloned and sequenced. Sequence analysis did not show the presence of any polymorphism that distinguishes between the tolerant and sensitive alleles. Our real-time RT PCR experiments, showed that the expression of HKT1;5 gene in roots of the tolerant line was significantly induced after challenging the plants with salt stress. In contrast, in leaf sheaths the expression was decreased after salt treatment. In sensitive lines, there was no difference in the expression of HKT1;5 gene in leaf sheath under control and saline conditions, while a slight increase in the expression was observed in roots after salt treatment. These results provide stronger evidence that HKT1;5 gene in barley play a key role in withdrawing Na+ from the xylem and therefore reducing its transport to leaves. Given all that, these data support the hypothesis that HKT1;5 gene is responsible for Na+ unloading to the xylem and controlling its distribution in the shoots, which provide new insight into the understanding of this QTL for salinity tolerance in barley. PMID- 29515600 TI - Organ Homologies and Perianth Evolution in the Dasymaschalon Alliance (Annonaceae): Inner Petal Loss and Its Functional Consequences. AB - The Dasymaschalon alliance within the early divergent angiosperm family Annonaceae comprises c. 180 species in four genera (Dasymaschalon, Desmos, Friesodielsia, and Monanthotaxis). The alliance offers an excellent opportunity for investigating perianth evolution and functional adaptations because of the presence of different numbers of petal whorls and contrasting floral chamber morphologies. The absence of the inner petal whorl in Dasymaschalon renders it distinctive in the family: previous studies have suggested that its three outermost stamens might be homologous with the inner petals of the sister genus, Friesodielsia, reflecting a homeotic shift of floral organ identify from inner petals to stamens. To investigate this hypothesis and general perianth evolution in the alliance, we (i) compared the floral vascularization of selected Dasymaschalon and Friesodielsia species using paraffin serial sectioning, and (ii) mapped selected perianth characters of inferred functional significance onto a molecular phylogenetic framework of the Dasymaschalon alliance (46 accessions; five cpDNA, and two nrDNA markers). The results indicate that the vasculature of the outermost stamen whorl of Dasymaschalon does not fuse with the perianth cortical vascular system, but instead splits from the basal traces of the free stamen bundles, contradicting previous inferences of homology with the inner corolla whorl of other Annonaceae. The loss of the inner petal whorl in Dasymaschalon is less likely to be due to a homeotic mutation, and instead possibly involved either the loss of genes that are responsible for determining inner petals or else the expression failure of these genes. Optimizations of perianth characters indicate that the absence of the inner petal whorl and the connivence of outer petals during anthesis are synapomorphic for Dasymaschalon. Circadian trapping of pollinators is inferred either to be derived in the stem lineage of the Dasymaschalon-Friesodielsia clade, or else to have evolved in parallel in the Dasymaschalon and Friesodielsia lineages. Subsequent changes in the remaining petals of Dasymaschalon flowers (which do not fully separate during anthesis) are likely to have enabled perpetuation of the circadian trapping mechanism, lessening the adverse impacts of inner petal loss. PMID- 29515599 TI - Analysis of Yellow Striped Mutants of Zea mays Reveals Novel Loci Contributing to Iron Deficiency Chlorosis. AB - The micronutrient iron (Fe) is essential for photosynthesis, respiration, and many other processes, but it is only sparingly soluble in aqueous solution, making adequate acquisition by plants a serious challenge. Fe is a limiting factor for plant growth on approximately 30% of the world's arable lands. Moreover, Fe deficiency in humans is a global health issue, affecting 1.62 billion people, or about 25% of the world's population. It is imperative that we gain a better understanding of the mechanisms that plants use to regulate iron homeostasis, since these will be important targets for future biofortification and crop improvement strategies. Grasses and non-grasses have evolved independent mechanisms for primary iron uptake from the soil. The grasses, which include most of the world's staple grains, have evolved a distinct 'chelation' mechanism to acquire iron from the soil. Strong iron chelators called phytosiderophores (PSs) are synthesized by grasses and secreted into the rhizosphere where they bind and solubilize Fe(III). The Fe(III)-PS complex is then taken up into root cells via transporters specific for the Fe(III)-PS complex. In this study, 31 novel, uncharacterized striped maize mutants available through the Maize Genetics Cooperation Stock Center (MGCSC) were analyzed to determine whether their mutant phenotypes are caused by decreased iron. Many of these proved to be either pale yellow or white striped mutants. Complementation tests were performed by crossing the MGCSC mutants to ys1 and ys3 reference mutants. This allowed assignment of 10 ys1 alleles and 4 ys3 alleles among the novel mutants. In addition, four ys* mutant lines were identified that are not allelic to either ys1 or ys3. Three of these were characterized as being non-allelic to each other and as having low iron in leaves. These represent new genes involved in iron acquisition by maize, and future cloning of these genes may reveal novel aspects of the grass iron acquisition mechanism. PMID- 29515601 TI - Physiological and Molecular Processes Associated with Long Duration of ABA Treatment. AB - Plants need to respond to various environmental stresses such as abiotic stress for proper development and growth. The responses to abiotic stress can be biochemically demanding, resulting in a trade-off that negatively affects plant growth and development. Thus, plant stress responses must be fine-tuned depending on the stress severity and duration. Abscisic acid, a phytohormone, plays a key role in responses to abiotic stress. Here, we investigated time-dependent physiological and molecular responses to long-term ABA treatment in Arabidopsis as an approach to gain insight into the plant responses to long-term abiotic stress. Upon ABA treatment, the amount of cellular ABA increased to higher levels, reaching to a peak at 24 h after treatment (HAT), and then gradually decreased with time whereas ABA-GE was maintained at lower levels until 24 HAT and then abruptly increased to higher levels at 48 HAT followed by a gradual decline at later time points. Many genes involved in dehydration stress responses, ABA metabolism, chloroplast biogenesis, and chlorophyll degradation were strongly expressed at early time points with a peak at 24 or 48 HAT followed by gradual decreases in induction fold or even suppression at later time points. At the physiological level, long-term ABA treatment caused leaf yellowing, reduced chlorophyll levels, and inhibited chloroplast division in addition to the growth suppression whereas short-term ABA treatment did not affect chlorophyll levels. Our results indicate that the duration of ABA treatment is a crucial factor in determining the mode of ABA-mediated signaling and plant responses: active mobilization of cellular resources at early time points and suppressive responses at later time points. PMID- 29515602 TI - Development of Biofortified Maize Hybrids through Marker-Assisted Stacking of beta-Carotene Hydroxylase, Lycopene-epsilon-Cyclase and Opaque2 Genes. AB - Traditional yellow maize though contains high kernel carotenoids, the concentration of provitamin A (proA) is quite low (<2 MUg/g), compared to recommended level (15 MUg/g). It also possesses poor endosperm protein quality due to low concentration of lysine and tryptophan. Natural variant of crtRB1 (beta-carotene hydroxylase) and lcyE (lycopene-epsilon-cyclase) cause significant enhancement of proA concentration, while recessive allele, opaque2 (o2) enhances the level of these amino acids. Development of biofortified maize enriched in proA, lysine and tryptophan thus holds significance in alleviation of micronutrient malnutrition. In the present study, marker-assisted stacking of crtRB1, lcyE and o2 was undertaken in the genetic background of four maize hybrids (HQPM1, HQPM4, HQPM5, and HQPM7) popularly grown in India. HP704-22 and HP704-23 were used as donors, while four elite QPM parents viz., HKI161, HKI163, HKI193-1, and HKI193-2 were used as recipients. CrtRB1 showed severe segregation distortion, while lcyE segregated as per the expectation. Recovery of recurrent parent genome (RPG) among selected backcross progenies ranged from 89 to 93%. Introgressed progenies possessed high concentration of proA (7.38-13.59 MUg/g), compared to 1.65-2.04 MUg/g in the recurrent parents. The reconstituted hybrids showed an average of 4.5-fold increase in proA with a range of 9.25-12.88 MUg/g, compared to original hybrids (2.14-2.48 MUg/g). Similar plant-, ear-, and grain- characteristics of improved versions of both inbreds and hybrids were observed when evaluated with their respective original versions. Mean lysine (0.334%) and tryptophan (0.080%) of the improved hybrids were at par with the original versions (lysine: 0.340%, tryptophan: 0.083%). Improved hybrids also possessed similar grain yield potential (6,301-8,545 kg/ha) with their original versions (6,135-8,479 kg/ha) evaluated at two locations. This is the first study of staking crtRB1-, lcyE-, and o2-, favorable alleles in single genetic background. The improved inbreds can be effectively used as potential donor for independent and/or simultaneous introgression of crtRB1, lcyE, and o2 in the future breeding programme. These biofortified maize hybrids, rich in proA, lysine and tryptophan will hold great promise for nutritional security. PMID- 29515603 TI - SKL1 Is Essential for Chloroplast Development in Arabidopsis. AB - The Arabidopsis shikimate kinase-like 1 (skl1-8) mutant is characterized by a pigment-defective phenotype. Although the related phenotypical defect mainly has been attributed to the blocking of chloroplast development, the molecular functions of SKL1 remain largely unknown. In this study, we combined multiple approaches to investigate the potential functions of SKL1. Results showed that the skl1-8 mutant exhibited an albino phenotype and had dramatically reduced chlorophyll content as a consequence of a single nuclear recessive gene mutation. Chemical complementation analysis indicated that SKL1 does not function as SK enzyme in the shikimate pathway. In addition, by chlorophyll fluorescence parameters and immunoblot analysis, the levels of photosynthetic proteins are substantially reduced. Moreover, by transcriptome analysis, specific groups of nuclear genes involved in photosynthesis, such as light-harvesting complex, pigment metabolism, carbon metabolism, and chloroplast gene expression, were down regulated, whereas several defense and oxidative stress responsive genes were up regulated in the skl1-8 mutant compared with the wide type. Furthermore, we found the expression of genes related to auxin transport and response was repressed in the skl1-8 mutant, probable suggesting that SKL1 is involved in auxin-related pathways during chloroplast development. Together, these results provide a useful reference for characterization of SKL1 function during chloroplast biogenesis and development. PMID- 29515604 TI - Heterologous Expression of Secreted Bacterial BPP and HAP Phytases in Plants Stimulates Arabidopsis thaliana Growth on Phytate. AB - Phytases are specialized phosphatases capable of releasing inorganic phosphate from myo-inositol hexakisphosphate (phytate), which is highly abundant in many soils. As inorganic phosphorus reserves decrease over time in many agricultural soils, genetic manipulation of plants to enable secretion of potent phytases into the rhizosphere has been proposed as a promising approach to improve plant phosphorus nutrition. Several families of biotechnologically important phytases have been discovered and characterized, but little data are available on which phytase families can offer the most benefits toward improving plant phosphorus intake. We have developed transgenic Arabidopsis thaliana plants expressing bacterial phytases PaPhyC (HAP family of phytases) and 168phyA (BPP family) under the control of root-specific inducible promoter Pht1;2. The effects of each phytase expression on growth, morphology and inorganic phosphorus accumulation in plants grown on phytate hydroponically or in perlite as the only source of phosphorus were investigated. The most enzymatic activity for both phytases was detected in cell wall-bound fractions of roots, indicating that these enzymes were efficiently secreted. Expression of both bacterial phytases in roots improved plant growth on phytate and resulted in larger rosette leaf area and diameter, higher phosphorus content and increased shoot dry weight, implying that these plants were indeed capable of utilizing phytate as the source of phosphorus for growth and development. When grown on phytate the HAP-type phytase outperformed its BPP-type counterpart for plant biomass production, though this effect was only observed in hydroponic conditions and not in perlite. Furthermore, we found no evidence of adverse side effects of microbial phytase expression in A. thaliana on plant physiology and seed germination. Our data highlight important functional differences between these members of bacterial phytase families and indicate that future crop biotechnologies involving such enzymes will require a very careful evaluation of phytase source and activity. Overall, our data suggest feasibility of using bacterial phytases to improve plant growth in conditions of phosphorus deficiency and demonstrate that inducible expression of recombinant enzymes should be investigated further as a viable approach to plant biotechnology. PMID- 29515605 TI - Resilient Leaf Physiological Response of European Beech (Fagus sylvatica L.) to Summer Drought and Drought Release. AB - Drought is a major environmental constraint to trees, causing severe stress and thus adversely affecting their functional integrity. European beech (Fagus sylvatica L.) is a key species in mesic forests that is commonly expected to suffer in a future climate with more intense and frequent droughts. Here, we assessed the seasonal response of leaf physiological characteristics of beech saplings to drought and drought release to investigate their potential to recover from the imposed stress and overcome previous limitations. Saplings were transplanted to model ecosystems and exposed to a simulated summer drought. Pre dawn water potentials (psipd), stomatal conductance (gS), intercellular CO2 concentration (ci), net-photosynthesis (AN), PSII chlorophyll fluorescence (PItot), non-structural carbohydrate concentrations (NSC; soluble sugars, starch) and carbon isotope signatures were measured in leaves throughout the growing season. Pre-dawn water potentials (psipd), gS, ci, AN, and PItot decreased as drought progressed, and the concentration of soluble sugars increased at the expense of starch. Carbon isotopes in soluble sugars (delta13CS) showed a distinct increase under drought, suggesting, together with decreased ci, stomatal limitation of AN. Drought effects on psipd, ci, and NSC disappeared shortly after re-watering, while full recovery of gS, AN, and PItot was delayed by 1 week. The fast recovery of NSC was reflected by a rapid decay of the drought signal in delta13C values, indicating a rapid turnover of assimilates and a reactivation of carbon metabolism. After recovery, the previously drought-exposed saplings showed a stimulation of AN and a trend toward elevated starch concentrations, which counteracted the previous drought limitations. Overall, our results suggest that the internal water relations of beech saplings and the physiological activity of leaves are restored rapidly after drought release. In the case of AN, stimulation after drought may partially compensate for limitations on photosynthetic activity during drought. Our observations suggest high resilience of beech to drought, contradicting the general belief that beech is particularly sensitive to environmental stressors. PMID- 29515606 TI - Investigating Drought Tolerance in Chickpea Using Genome-Wide Association Mapping and Genomic Selection Based on Whole-Genome Resequencing Data. AB - Drought tolerance is a complex trait that involves numerous genes. Identifying key causal genes or linked molecular markers can facilitate the fast development of drought tolerant varieties. Using a whole-genome resequencing approach, we sequenced 132 chickpea varieties and advanced breeding lines and found more than 144,000 single nucleotide polymorphisms (SNPs). We measured 13 yield and yield related traits in three drought-prone environments of Western Australia. The genotypic effects were significant for all traits, and many traits showed highly significant correlations, ranging from 0.83 between grain yield and biomass to 0.67 between seed weight and seed emergence rate. To identify candidate genes, the SNP and trait data were incorporated into the SUPER genome-wide association study (GWAS) model, a modified version of the linear mixed model. We found that several SNPs from auxin-related genes, including auxin efflux carrier protein (PIN3), p-glycoprotein, and nodulin MtN21/EamA-like transporter, were significantly associated with yield and yield-related traits under drought-prone environments. We identified four genetic regions containing SNPs significantly associated with several different traits, which was an indication of pleiotropic effects. We also investigated the possibility of incorporating the GWAS results into a genomic selection (GS) model, which is another approach to deal with complex traits. Compared to using all SNPs, application of the GS model using subsets of SNPs significantly associated with the traits under investigation increased the prediction accuracies of three yield and yield-related traits by more than twofold. This has important implication for implementing GS in plant breeding programs. PMID- 29515607 TI - Response of Submerged Macrophyte Communities to External and Internal Restoration Measures in North Temperate Shallow Lakes. AB - Submerged macrophytes play a key role in north temperate shallow lakes by stabilizing clear-water conditions. Eutrophication has resulted in macrophyte loss and shifts to turbid conditions in many lakes. Considerable efforts have been devoted to shallow lake restoration in many countries, but long-term success depends on a stable recovery of submerged macrophytes. However, recovery patterns vary widely and remain to be fully understood. We hypothesize that reduced external nutrient loading leads to an intermediate recovery state with clear spring and turbid summer conditions similar to the pattern described for eutrophication. In contrast, lake internal restoration measures can result in transient clear-water conditions both in spring and summer and reversals to turbid conditions. Furthermore, we hypothesize that these contrasting restoration measures result in different macrophyte species composition, with added implications for seasonal dynamics due to differences in plant traits. To test these hypotheses, we analyzed data on water quality and submerged macrophytes from 49 north temperate shallow lakes that were in a turbid state and subjected to restoration measures. To study the dynamics of macrophytes during nutrient load reduction, we adapted the ecosystem model PCLake. Our survey and model simulations revealed the existence of an intermediate recovery state upon reduced external nutrient loading, characterized by spring clear-water phases and turbid summers, whereas internal lake restoration measures often resulted in clear-water conditions in spring and summer with returns to turbid conditions after some years. External and internal lake restoration measures resulted in different macrophyte communities. The intermediate recovery state following reduced nutrient loading is characterized by a few macrophyte species (mainly pondweeds) that can resist wave action allowing survival in shallow areas, germinate early in spring, have energy-rich vegetative propagules facilitating rapid initial growth and that can complete their life cycle by early summer. Later in the growing season these plants are, according to our simulations, outcompeted by periphyton, leading to late-summer phytoplankton blooms. Internal lake restoration measures often coincide with a rapid but transient colonization by hornworts, waterweeds or charophytes. Stable clear-water conditions and a diverse macrophyte flora only occurred decades after external nutrient load reduction or when measures were combined. PMID- 29515608 TI - Associations between Macrophyte Life Forms and Environmental and Morphometric Factors in a Large Sub-tropical Floodplain. AB - Macrophyte assemblages are composed of species with different life forms and various ecological functions. Our aim was to investigate the potential environmental determinants of changes in the biomass of individual life forms and of the composition of the macrophyte assemblage in terms of life forms diversity. We sampled 23 waterbodies at low and high water levels in the Middle Parana River floodplain. Macrophyte biomass samples were collected and classified in terms of life forms. We performed a redundancy analysis using the biomass of the various life forms to assess the importance of environmental variables to the composition of macrophyte life forms. Linear regressions were applied to investigate the environmental determinants of the biomasses of individual life forms. The degree of connectivity and the combination of depth, hydrology and nitrate were the main determinants of the composition in terms of life forms. The biomass of each individual life form was explained by different combinations of environmental variables, but the connectivity was the most important one. Our study shows that groups of species with similar life forms respond to environmental factors in particular ways, which might alter the biomass composition of life forms. Given that the ecosystem functioning depends on the functional characteristics of local communities, our findings about the relation between environmental changes and the community composition in terms of life forms (or functional composition) can be a helpful tool for predicting changes on ecosystem processes (such as nutrient cycling) against possible future scenarios. PMID- 29515609 TI - Long-Term Vegetation Dynamics in a Megadiverse Hotspot: The Ice-Age Record of a Pre-montane Forest of Central Ecuador. AB - Tropical ecosystems play a key role in many aspects of Earth system dynamics currently of global concern, including carbon sequestration and biodiversity. To accurately understand complex tropical systems it is necessary to parameterise key ecological aspects, such as rates of change (RoC), species turnover, dynamism, resilience, or stability. To obtain a long-term (>50 years) perspective on these ecological aspects we must turn to the fossil record. However, compared to temperate zones, collecting continuous sedimentary archives in the lowland tropics is often difficult due to the active landscape processes, with potentially frequent volcanic, tectonic, and/or fluvial events confounding sediment deposition, preservation, and recovery. Consequently, the nature, and drivers, of vegetation dynamics during the last glacial are barely known from many non-montane tropical landscapes. One of the first lowland Amazonian locations from which palaeoecological data were obtained was an outcrop near Mera (Ecuador). Mera was discovered, and analysed, by Paul Colinvaux in the 1980s, but his interpretation of the data as indicative of a forested glacial period were criticised based on the ecology and age control. Here we present new palaeoecological data from a lake located less than 10 km away from Mera. Sediment cores raised from Laguna Pindo (1250 masl; 1 degrees 27'S, 78 degrees 05'W) have been shown to span the late last glacial period [50-13 cal kyr BP (calibrated kiloyears before present)]. The palaeoecological information obtained from Laguna Pindo indicate that the region was characterised by a relatively stable plant community, formed by taxa nowadays common at both mid and high elevations. Miconia was the dominant taxon until around 30 cal kyr BP, when it was replaced by Hedyosmum, Asteraceae and Ilex among other taxa. Heat intolerant taxa including Podocarpus, Alnus, and Myrica peaked around the onset of the Last Glacial Maximum (c. 21 cal kyr BP). The results obtained from Laguna Pindo support Colinvaux's hypothesis that glacial cooling resulted in a reshuffling of taxa in the region but did not lead to a loss of the forest structure. Wide tolerances of the plant species occurring to glacial temperature range and cloud formation have been suggested to explain Pindo forest stability. This scenario is radically different than the present situation, so vulnerability of the tropical pre-montane forest is highlighted to be increased in the next decades. PMID- 29515610 TI - Physical and Chemical Barriers in Root Tissues Contribute to Quantitative Resistance to Fusarium oxysporum f. sp. pisi in Pea. AB - Fusarium wilt caused by Fusarium oxysporum f. sp. pisi (Fop) is one of the most destructive diseases of pea worldwide. Control of this disease is difficult and it is mainly based on the use of resistant cultivars. While monogenic resistance has been successfully used in the field, it is at risk of breakdown by the constant evolution of the pathogen. New sources of quantitative resistance have been recently identified from a wild relative Pisum spp. collection. Here, we characterize histologically the resistance mechanisms occurring in these sources of quantitative resistance. Detailed comparison, of the reaction at cellular level, of eight pea accessions with differential responses to Fop race 2, showed that resistant accessions established several barriers at the epidermis, exodermis, cortex, endodermis and vascular stele efficiently impeding fungal progression. The main components of these different barriers were carbohydrates and phenolic compounds including lignin. We found that these barriers were mainly based on three defense mechanisms including cell wall strengthening, formation of papilla-like structures at penetration sites and accumulation of different substances within and between cells. These defense reactions varied in intensity and localization between resistant accessions. Our results also clarify some steps of the infection process of F. oxysporum in plant and support the important role of cell wall-degrading enzymes in F. oxysporum pathogenicity. PMID- 29515611 TI - Synchrotron Time-Lapse Imaging of Lignocellulosic Biomass Hydrolysis: Tracking Enzyme Localization by Protein Autofluorescence and Biochemical Modification of Cell Walls by Microfluidic Infrared Microspectroscopy. AB - Tracking enzyme localization and following the local biochemical modification of the substrate should help explain the recalcitrance of lignocellulosic plant cell walls to enzymatic degradation. Time-lapse studies using conventional imaging require enzyme labeling and following the biochemical modifications of biopolymers found in plant cell walls, which cannot be easily achieved. In the present work, synchrotron facilities have been used to image the enzymatic degradation of lignocellulosic biomass without labeling the enzyme or the cell walls. Multichannel autofluorescence imaging of the protein and phenolic compounds after excitation at 275 nm highlighted the presence or absence of enzymes on cell walls and made it possible to track them during the reaction. Image analysis was used to quantify the fluorescence intensity variations. Consistent variations in the enzyme concentration were found locally for cell cavities and their surrounding cell walls. Microfluidic FT-IR microspectroscopy allowed for time-lapse tracking of local changes in the polysaccharides in cell walls during degradation. Hemicellulose degradation was found to occur prior to cellulose degradation using a Celluclast(r) preparation. Combining the fluorescence and FT-IR information yielded the conclusion that enzymes did not bind to lignified cell walls, which were consequently not degraded. Fluorescence multiscale imaging and FT-IR microspectroscopy showed an unexpected variability both in the initial biochemical composition and the degradation pattern, highlighting micro-domains in the cell wall of a given cell. Fluorescence intensity quantification showed that the enzymes were not evenly distributed, and their amount increased progressively on degradable cell walls. During degradation, adjacent cells were separated and the cell wall fragmented until complete degradation. PMID- 29515612 TI - An Initiative for the Study and Use of Genetic Diversity of Domesticated Plants and Their Wild Relatives. AB - Domestication has been influenced by formal plant breeding since the onset of intensive agriculture and the Green Revolution. Despite providing food security for some regions, intensive agriculture has had substantial detrimental consequences for the environment and does not fulfill smallholder's needs under most developing countries conditions. Therefore, it is necessary to look for alternative plant production techniques, effective for each environmental, socio cultural, and economic conditions. This is particularly relevant for countries that are megadiverse and major centers of plant domestication and diversification. In this white paper, a Mexico-centered initiative is proposed, with two main objectives: (1) to study, understand, conserve, and sustainably use the genetic diversity of domesticated plants and their wild relatives, as well as the ongoing evolutionary processes that generate and maintain it; and (2) to strengthen food and forestry production in a socially fair and environmentally friendly way. To fulfill these objectives, the initiative focuses on the source of variability available for domestication (genetic diversity and functional genomics), the context in which domestication acts (breeding and production) and one of its main challenges (environmental change). Research on these components can be framed to target and connect both the theoretical understanding of the evolutionary processes, the practical aspects of conservation, and food and forestry production. The target, main challenges, problems to be faced and key research questions are presented for each component, followed by a roadmap for the consolidation of this proposal as a national initiative. PMID- 29515613 TI - Trichoderma-Inoculated Miscanthus Straw Can Replace Peat in Strawberry Cultivation, with Beneficial Effects on Disease Control. AB - Peat based growing media are not ecologically sustainable and often fail to support biological control. Miscanthus straw was (1) tested to partially replace peat; and (2) pre-colonized with a Trichoderma strain to increase the biological control capacity of the growing media. In two strawberry pot trials (denoted as experiment I & II), extruded and non-extruded miscanthus straw, with or without pre-colonization with T. harzianum T22, was used to partially (20% v/v) replace peat. We tested the performance of each mixture by monitoring strawberry plant development, nutrient content in the leaves and growing media, sensitivity of the fruit to the fungal pathogen Botrytis cinerea, rhizosphere community and strawberry defense responses. N immobilization by miscanthus straw reduced strawberry growth and yield in experiment II but not in I. The pre-colonization of the straw with Trichoderma increased the post-harvest disease suppressiveness against B. cinerea and changed the rhizosphere fungal microbiome in both experiments. In addition, defense-related genes were induced in experiment II. The use of miscanthus straw in growing media will reduce the demand for peat and close resource loops. Successful pre-colonization of this straw with biological control fungi will optimize crop cultivation, requiring fewer pesticide applications, which will benefit the environment and human health. PMID- 29515614 TI - Activation of the Transducers of Unfolded Protein Response in Plants. AB - Maintenance of homeostasis of the endoplasmic reticulum (ER) ensures the balance between loading of nascent proteins and their secretion. Certain developmental conditions or environmental stressors affect protein folding causing ER stress. The resultant ER stress is mitigated by upregulating a set of stress-responsive genes in the nucleus modulating the mechanism of the unfolded protein response (UPR). In plants, the UPR is mediated by two major pathways; by the proteolytic processing of bZIP17/28 and by the IRE1-mediated splicing of bZIP60 mRNA. Recent studies have shown the involvement of plant-specific NAC transcription factors in UPR regulation. The molecular mechanisms activating plant-UPR transducers are only recently being unveiled. This review focuses on important structural features involved in the activation of the UPR transducers like bZIP17/28/60, IRE1, BAG7, and NAC017/062/089/103. Also, we discuss the activation of the UPR pathways, including BAG7-bZIP28 and IRE1-bZIP60, in detail, together with the NAC TFs, which adds a new paradigm to the plant UPR. PMID- 29515616 TI - Recruiting Conventional Tree Architecture Models into State-of-the-Art LiDAR Mapping for Investigating Tree Growth Habits in Structure. AB - Mensuration of tree growth habits is of considerable importance for understanding forest ecosystem processes and forest biophysical responses to climate changes. However, the complexity of tree crown morphology that is typically formed after many years of growth tends to render it a non-trivial task, even for the state-of the-art 3D forest mapping technology-light detection and ranging (LiDAR). Fortunately, botanists have deduced the large structural diversity of tree forms into only a limited number of tree architecture models, which can present a priori knowledge about tree structure, growth, and other attributes for different species. This study attempted to recruit Halle architecture models (HAMs) into LiDAR mapping to investigate tree growth habits in structure. First, following the HAM-characterized tree structure organization rules, we run the kernel procedure of tree species classification based on the LiDAR-collected point clouds using a support vector machine classifier in the leave-one-out-for-cross validation mode. Then, the HAM corresponding to each of the classified tree species was identified based on expert knowledge, assisted by the comparison of the LiDAR-derived feature parameters. Next, the tree growth habits in structure for each of the tree species were derived from the determined HAM. In the case of four tree species growing in the boreal environment, the tests indicated that the classification accuracy reached 85.0%, and their growth habits could be derived by qualitative and quantitative means. Overall, the strategy of recruiting conventional HAMs into LiDAR mapping for investigating tree growth habits in structure was validated, thereby paving a new way for efficiently reflecting tree growth habits and projecting forest structure dynamics. PMID- 29515617 TI - Agroclimatology and Wheat Production: Coping with Climate Change. AB - Cereal production around the world is critical to the food supply for the human population. Crop productivity is primarily determined by a combination of temperature and precipitation because temperatures have to be in the range for plant growth and precipitation has to supply crop water requirements for a given environment. The question is often asked about the changes in productivity and what we can expect in the future and we evaluated the causes for variation in historical annual statewide wheat grain yields in Oklahoma, Kansas, and North Dakota across the Great Plains of United States. Wheat (Triticum aestivum L.) is adapted to this area and we focused on production in these states from 1950 to 2016. This analysis used a framework for annual yields using yield gaps between attainable and actual yields and found the primary cause of the variation among years were attributable to inadequate precipitation during the grain-filling period. In Oklahoma, wheat yields were reduced when April and May precipitation was limited (r2 = 0.70), while in Kansas, May precipitation was the dominant factor (r2 = 0.78), and in North Dakota June-July precipitation was the factor explaining yield variation (r2 = 0.65). Temperature varied among seasons and at the statewide level did not explain a significant portion of the yield variation. The pattern of increased variation in precipitation will cause further variation in wheat production across the Great Plains. Reducing yield variation among years will require adaptation practices that increase water availability to the crop coupled with the positive impact derived from other management practices, e.g., cultivars, fertilizer management, etc. PMID- 29515615 TI - HorTILLUS-A Rich and Renewable Source of Induced Mutations for Forward/Reverse Genetics and Pre-breeding Programs in Barley (Hordeum vulgare L.). AB - TILLING (Targeting Induced Local Lesions IN Genomes) is a strategy used for functional analysis of genes that combines the classical mutagenesis and a rapid, high-throughput identification of mutations within a gene of interest. TILLING has been initially developed as a discovery platform for functional genomics, but soon it has become a valuable tool in development of desired alleles for crop breeding, alternative to transgenic approach. Here we present the HorTILLUS ( Hordeum-TILLING-University of Silesia) population created for spring barley cultivar "Sebastian" after double-treatment of seeds with two chemical mutagens: sodium azide (NaN3) and N-methyl-N-nitrosourea (MNU). The population comprises more than 9,600 M2 plants from which DNA was isolated, seeds harvested, vacuum packed, and deposited in seed bank. M3 progeny of 3,481 M2 individuals was grown in the field and phenotyped. The screening for mutations was performed for 32 genes related to different aspects of plant growth and development. For each gene fragment, 3,072-6,912 M2 plants were used for mutation identification using LI COR sequencer. In total, 382 mutations were found in 182.2 Mb screened. The average mutation density in the HorTILLUS, estimated as 1 mutation per 477 kb, is among the highest mutation densities reported for barley. The majority of mutations were G/C to A/T transitions, however about 8% transversions were also detected. Sixty-one percent of mutations found in coding regions were missense, 37.5% silent and 1.1% nonsense. In each gene, the missense mutations with a potential effect on protein function were identified. The HorTILLUS platform is the largest of the TILLING populations reported for barley and best characterized. The population proved to be a useful tool, both in functional genomic studies and in forward selection of barley mutants with required phenotypic changes. We are constantly renewing the HorTILLUS population, which makes it a permanent source of new mutations. We offer the usage of this valuable resource to the interested barley researchers on cooperative basis. PMID- 29515618 TI - Verbal or Visual Memory Score and Regional Cerebral Blood Flow in Alzheimer Disease. AB - Objective: Among many cognitive function deficits, memory impairment is an initial and cardinal symptom in Alzheimer disease (AD). In most cases, verbal and visual memory scores correlate highly, but in some cases the deficit of verbal or visual memory is very different from that of the other memory. In this study, we examined the neural substrates of verbal and visual memory in patients with AD. Methods: One hundred eighty-eight consecutive patients with AD were recruited from outpatient units. Verbal and visual memory scores were evaluated using the Wechsler Memory Scale - revised. The patients underwent brain SPECT with 99mTc ethylcysteinate dimer. Results: After removing the effects of age, sex, education, and Mini-Mental State Examination scores, correlation analysis showed a significant correlation of verbal memory scores to regional cerebral blood flow (rCBF) in the bilateral cingulate gyrus and left precuneus. Similarly, a significant correlation of visual memory scores to rCBF was found in the right precuneus and right cingulate gyrus. Conclusion: The posterior medial cortices (PMC) are very important areas in episodic memory among patients with mild AD. Verbal memory is more closely related to the both sides of the PMC, while visual memory is more closely related to the right PMC. PMID- 29515619 TI - Assessment of Dementia in Individuals with Dual Sensory Loss: Application of a Tactile Test Battery. AB - Background/Aims: Individuals with dual sensory loss (DSL) are more likely to experience cognitive decline with age than individuals without sensory loss. Other studies have pointed to the challenges in assessing cognitive abilities in individuals with DSL, as most existing instruments rely on use of vision and hearing. The aim of this study was to develop and evaluate a Tactile Test Battery (TTB) for cognitive assessment in individuals with DSL. Method: Twenty elderly individuals with DSL, 20 with diagnosed dementia, and 20 without dementia or DSL (controls) completed the following tactile tests developed for the present study: Spatial learning, Spatial recall, Tactile form board, Clock reading, and Naming. The participants with dementia and controls also completed the Mini-Mental State Examination (MMSE). Results: Overall, participants with dementia performed significantly worse on the tactile tests than participants with DSL and control participants. No significant differences on the tactile tests were found between participants with DSL and controls. The TTB and MMSE scores correlated significantly. Conclusion: The findings from this study of applying tactile tests for cognitive examination in individuals with DSL are promising. They indicate that symptoms of dementia can be differentiated from symptoms related to DSL. PMID- 29515620 TI - Impairment of the Missing Fundamental Phenomenon in Individuals with Alzheimer's Disease: A Neuropsychological and Voxel-Based Morphometric Study. AB - Background/Aims: The missing fundamental phenomenon (MFP) is a universal pitch perception illusion that occurs in animals and humans. In this study, we aimed to determine whether the MFP is impaired in patients with Alzheimer's disease (AD) using an auditory pitch perception experiment. We further examined anatomical correlates of the MFP in patients with AD by measuring gray matter volume (GMV) on magnetic resonance images via voxel-based morphometric analysis. Methods: We prospectively enrolled 29 patients with AD and 20 healthy older adults. Auditory stimuli included 12 melodies of Japanese nursery songs that were expected to be familiar to participants. We constructed the melodies using pure and missing fundamental tones (MFTs). Results: Patients with AD exhibited significantly poorer performance on the MFT task than healthy controls. MFT scores were positively correlated with GMV in the bilateral insula and temporal poles, left inferior frontal gyrus, right entorhinal cortex, and right cerebellum. Conclusions: These results suggest that impairments in the MFP represent a manifestation of the degeneration of auditory-related brain regions in AD. Further studies are required to more fully elucidate the neural mechanisms underlying auditory impairments in patients with AD and related dementia disorders. PMID- 29515621 TI - Delirium, Frailty, and Fast-Track Surgery in Oncogeriatrics: Is There a Link? AB - Background/Aims: Postoperative delirium (POD) is more frequent in elderly patients undergoing major cancer surgery. The interplay between individual clinical vulnerability and a series of perioperative factors seems to play a relevant role. Surgery is the first-line treatment option for cancer, and fast track surgery (FTS) has been documented to decrease postoperative complications. The study sought to assess, after comprehensive geriatric assessment (CGA) and frailty stratification (Rockwood 40 items index), which perioperative parameters were predictive of POD development in elderly patients undergoing FTS for colorectal cancer. Methods: A total of 107 consecutive subjects admitted for elective colorectal FTS were enrolled. All patients underwent CGA, frailly stratification, Timed up & go (TUG) test, 4AT test for delirium screening, anesthesiologists physical status classification, and Dindo-Clavien classification. Results: The incidence of POD was 12.3%. Patients' prevalent clinical phenotype was pre-frail. The multivariate analysis indicated physical performance (TUG in seconds) as the most significant predictor of POD for each second of increase. Conclusions: Only few procedure-specific studies have examined the impact of FTS for colorectal cancer on POD. This is the first study to investigate the risk factors for POD, in a vulnerable octogenarian oncogeriatric population submitted to FTS surgery and frailty stratification. PMID- 29515622 TI - High Incidence of Sporadic Creutzfeldt-Jakob Disease in Slovenia in 2015: A Case Series. AB - Background: Creutzfeldt-Jakob disease (CJD) is a rare fatal neurodegenerative disorder presenting with rapid cognitive decline and additional signs. The clinical characteristics of an increasing number of sporadic CJD (sCJD) patients admitted to the Ljubljana University Medical Centre are presented as well as the incidence of sCJD in Slovenia in 2015 compared to previous years. Methods: We investigated patients presenting with rapidly progressive dementia and at least one additional sign. The diagnosis was made based on clinical diagnostic criteria and an autopsy was performed in all cases. Data on definite sCJD cases in Slovenia since 1999 were obtained and its incidence was calculated. Results: Eight patients with definite sCJD died in 2015 in Slovenia (incidence: 3.89 cases per million). The long-term incidence 1999 was 1.67 per million. Conclusions: The incidence of sCJD was considerably higher in 2015. It reflects fluctuations in sporadic cases of this rare disease. The rising trend might indicate a previous underestimation and better recognition of the disease. PMID- 29515623 TI - Growth of Malignant Non-CNS Tumors Alters Brain Metabolome. AB - Cancer survivors experience numerous treatment side effects that negatively affect their quality of life. Cognitive side effects are especially insidious, as they affect memory, cognition, and learning. Neurocognitive deficits occur prior to cancer treatment, arising even before cancer diagnosis, and we refer to them as "tumor brain." Metabolomics is a new area of research that focuses on metabolome profiles and provides important mechanistic insights into various human diseases, including cancer, neurodegenerative diseases, and aging. Many neurological diseases and conditions affect metabolic processes in the brain. However, the tumor brain metabolome has never been analyzed. In our study we used direct flow injection/mass spectrometry (DI-MS) analysis to establish the effects of the growth of lung cancer, pancreatic cancer, and sarcoma on the brain metabolome of TumorGraftTM mice. We found that the growth of malignant non-CNS tumors impacted metabolic processes in the brain, affecting protein biosynthesis, and amino acid and sphingolipid metabolism. The observed metabolic changes were similar to those reported for neurodegenerative diseases and brain aging, and may have potential mechanistic value for future analysis of the tumor brain phenomenon. PMID- 29515624 TI - Population Genetic Analysis of Theileria annulata from Six Geographical Regions in China, Determined on the Basis of Micro- and Mini-satellite Markers. AB - Theileria annulata, a tick-borne apicomplexan protozoan, causes a lymphoproliferative disease of cattle with high prevalence in tropical and sub tropical regions. Understanding the genetic diversity and structure of local populations will provide more fundamental knowledge for the population genetics and epidemics of protozoa. In this study, 78 samples of T. annulata collected from cattle/yaks representing 6 different geographic populations in China were genotyped using eight micro- and mini-satellite markers. High genetic variation within population, moderate genetic differentiation, and high level of diversity co-occurring with significant linkage disequilibrium were observed, which indicates there is gene flow between these populations in spite of the existence of reproductive and geographical barriers among populations. Furthermore, some degree of genetic differentiation was also found between samples from China and Oman. These findings provide a first glimpse of the genetic diversity of the T. annulata populations in China, and might contribute to the knowledge of distribution, dynamics, and epidemiology of T. annulata populations and optimize the management strategies for control. PMID- 29515625 TI - Transferring Exome Sequencing Data from Clinical Laboratories to Healthcare Providers: Lessons Learned at a Pediatric Hospital. AB - The adoption rate of genome sequencing for clinical diagnostics has been steadily increasing leading to the possibility of improvement in diagnostic yields. Although laboratories generate a summary clinical report, sharing raw genomic data with healthcare providers is equally important, both for secondary research studies as well as for a deeper analysis of the data itself, as seen by the efforts from organizations such as American College of Medical Genetics and Genomics and Global Alliance for Genomics and Health. Here, we aim to describe the existing protocol of genomic data sharing between a certified clinical laboratory and a healthcare provider and highlight some of the lessons learned. This study tracked and subsequently evaluated the data transfer workflow for 19 patients, all of whom consented to be part of this research study and visited the genetics clinic at a tertiary pediatric hospital between April 2016 to December 2016. Two of the most noticeable elements observed through this study are the manual validation steps and the discrepancies in patient identifiers used by a clinical lab vs. healthcare provider. Both of these add complexity to the transfer process as well as make it more susceptible to errors. The results from this study highlight some of the critical changes that need to be made in order to improve genomic data sharing workflows between healthcare providers and clinical sequencing laboratories. PMID- 29515626 TI - A mechanistic model of heat transfer for gas-liquid flow in vertical wellbore annuli. AB - The most prominent aspect of multiphase flow is the variation in the physical distribution of the phases in the flow conduit known as the flow pattern. Several different flow patterns can exist under different flow conditions which have significant effects on liquid holdup, pressure gradient and heat transfer. Gas liquid two-phase flow in an annulus can be found in a variety of practical situations. In high rate oil and gas production, it may be beneficial to flow fluids vertically through the annulus configuration between well tubing and casing. The flow patterns in annuli are different from pipe flow. There are both casing and tubing liquid films in slug flow and annular flow in the annulus. Multiphase heat transfer depends on the hydrodynamic behavior of the flow. There are very limited research results that can be found in the open literature for multiphase heat transfer in wellbore annuli. A mechanistic model of multiphase heat transfer is developed for different flow patterns of upward gas-liquid flow in vertical annuli. The required local flow parameters are predicted by use of the hydraulic model of steady-state multiphase flow in wellbore annuli recently developed by Yin et al. The modified heat-transfer model for single gas or liquid flow is verified by comparison with Manabe's experimental results. For different flow patterns, it is compared with modified unified Zhang et al. model based on representative diameters. PMID- 29515627 TI - Kidney Stone Disease: An Update on Current Concepts. AB - Kidney stone disease is a crystal concretion formed usually within the kidneys. It is an increasing urological disorder of human health, affecting about 12% of the world population. It has been associated with an increased risk of end-stage renal failure. The etiology of kidney stone is multifactorial. The most common type of kidney stone is calcium oxalate formed at Randall's plaque on the renal papillary surfaces. The mechanism of stone formation is a complex process which results from several physicochemical events including supersaturation, nucleation, growth, aggregation, and retention of urinary stone constituents within tubular cells. These steps are modulated by an imbalance between factors that promote or inhibit urinary crystallization. It is also noted that cellular injury promotes retention of particles on renal papillary surfaces. The exposure of renal epithelial cells to oxalate causes a signaling cascade which leads to apoptosis by p38 mitogen-activated protein kinase pathways. Currently, there is no satisfactory drug to cure and/or prevent kidney stone recurrences. Thus, further understanding of the pathophysiology of kidney stone formation is a research area to manage urolithiasis using new drugs. Therefore, this review has intended to provide a compiled up-to-date information on kidney stone etiology, pathogenesis, and prevention approaches. PMID- 29515629 TI - The Relationship Between Cytokeratins 7 and 20 Expression, and Prognostic Factors in Colon Adenocarcinoma: An Immunohistochemical Study. AB - Background & Objective: The role of synchronized expression pattern of cytokeratin (CK) 7 and CK20 in the prognosis of colon adenocarcinoma is unclear. The current study aimed at determining the relationship between the expression of cytokeratins 7 and 20 and prognostic factors in colon adenocarcinoma. Methods: In the current cross sectional Study, 52 archival samples of colon adenocarcinoma with different histopathologic differentiation were examined immunohistochemically to analyze the expression of Ck7 and Ck20. The relationship between cytokeratin expression and prognostic factors, such as histopathologic differentiation, lymph node involvement, and depth of invasion, were assessed. Results: CK7-/CK20+ was the most prevalent pattern in the current study. The difference among histopathologic grade, lymph node involvement, and depth of invasion in different CK7/CK20 expression patterns was insignificant (P=0.26, P=0.46, and P=0.22, respectively). Conclusion: No relationship was observed between CK7/CK20 expression and prognostic factors in colon adenocarcinoma, in the current study. PMID- 29515628 TI - Pediatric Germ Cell Tumors: A Developmental Perspective. AB - Germ cell tumors (GCTs) arising in infants, children, and adolescents present a set of special challenges. GCTs make up about 3% of malignancies in children aged 0-18 and nearly 15% of cancers in adolescents. Epidemiologic and molecular evidence suggests that GCTs in young children likely represent a distinct biologic group as compared to GCTs of older adolescents and adults. Despite this difference, pediatric GCTs are typically treated with cisplatin-based multiagent regimens similar to those used in adults. There is evidence that children are particularly vulnerable to late effects of conventional therapy, including ototoxicity, pulmonary abnormalities, and secondary malignancies, motivating the search for molecular targets for novel therapies. Evidence is accumulating that the genes and mechanisms controlling normal germ cell development are particularly relevant to the understanding of germ cell tumorigenesis. Perturbations in the epigenetic program of germ cell differentiation, with resulting effects on the regulation of pluripotency, may contribute to the marked histologic variability of GCTs. Perturbations in the KIT receptor signaling pathway have been identified via next-generation sequencing studies and in genome wide association studies of testicular cancer susceptibility. Here, we review these and other biological insights that may fuel further translational and clinical research in childhood GCTs. PMID- 29515631 TI - Correlation Between Subclinical Hypothyroidism and Dyslipidemia. AB - Background & Objective: Thyroid hormones have an important role in the regulation of lipid metabolism. Subclinical hypothyroidism (SCH), defined as a mild increase in thyroid-stimulating hormone (TSH) and normal level of thyroxine (T4), could be associated with altered lipid profile. The current study aimed at assessing the association between SCH and changes in lipid profile. Methods: Data of 53 patients with SCH and 53 euthyroid cases were collected from Besat Hospital in Hamadan, Iran, in 2013. The age range of the cases was 18 to 60 years, and the groups were matched in terms of gender, age, and body mass index (BMI). SCH was defined as a TSH value of 4.2 to 10 mU/L, and normal T4 as 0.8 to 2.8 ng/dL. Control cases had a normal TSH ranging from 0.5 to 4.2 mU/L. The total serum cholesterol (TCHOL), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels in both groups were examined and the results were recorded. Results: Participants with SCH had significantly higher LDL and lower HDL levels than the control group regardless of age group and gender (P-value <0.001), but there was no difference in TG and TCHOL levels (P-value <0.05). The prevalence of dyslipidemia and SCH was only significant in females (P-value =0.009). Totally, there was significant correlation between the prevalence of dyslipidemia and SCH regardless of gender (P-value =0.04). Conclusion: SCH is associated with dyslipidemia, and biochemical screening for thyroid dysfunction is recommended in all patients with dyslipidemia. PMID- 29515630 TI - Clinical Manifestations and Diagnosis of Nonalcoholic Fatty Liver Disease. AB - Background & Objective: Nonalcoholic fatty liver diseases (NAFLD) is the major cause of hepatocellular carcinoma and increases the risk of mortality. Understanding the trends of its clinical and biochemical changes is essential to identify patients with NAFLD that are at the greatest risk of nonalcoholic steatohepatitis (NASH) and cirrhosis in Iran. Methods: Patients with NAFLD confirmed by ultrasonography were enrolled into the current study. They had negative serologic markers of viral or autoimmune hepatitis, no findings in favor of metabolic liver disease, and had not received medications that affect liver, such as silymarin and Ursobil. Biochemical and clinical symptoms and histological variables were evaluated for each patient. Descriptive statistics were used to compute all variables. Results: A total of 206 patients, including 109 male and 97 female, with the mean age of 41.2 years were enrolled. The number of patients without obesity and diabetes were 34 (16.4%) and 48 (23.1%), respectively. Sleep disorder, delayed sleep, daytime sleepiness, and late dinner were noticeably common in patients with NAFLD. Furthermore, anxiety, thirst sensation, bloating, warming sensation, defecation disturbances, and upper abdominal pain were common among patients with NAFLD. Conclusion: NAFLD is a heterogeneous disorder with vast clinical presentations. It seems that anxiety and gastrointestinal problem are common among such patients. Moreover, inadvertent sleep could have a considerable effect on developing NAFLD. Patients with diabetes have more severe NAFLD, based on clinical and histological findings. PMID- 29515632 TI - Platelet Septic Transfusion Reactions in Patients With Hemato-Oncological Diseases. AB - Background & Objective: Bacterial, contamination of blood components are a significant risk for transfusion reactions. Inherently, platelet concentrates (PCs) are vulnerable to bacterial contamination, due to the storage condition of processed PCs at room temperature, which provide very suitable conditions for the proliferation of microorganisms.The current study aimed at investigating the transfusion associated septic reaction rate in patients with hemato-oncological diseases in Imam Khomeini Hospital, Tehran, Iran, and identifying the contaminating bacteria. Methods: A total of 3056 adult patients of the Cancer Center of Imam Khomeini Hospital in Tehran transfused with PCs were studied based on the clinical symptoms of septic transfusion reaction from June 1, 2010 to May 31, 2011. Patient presented with the criteria of reaction and the residual components were evaluated for bacterial contamination by Bac T/Alert system. Results: Patients with leukemia or lymphoma transfused with random-donor PCs were evaluated the signs and symptoms of transfusion reaction occurred only in 12 (%0.4) cases. Automated cultivation found 3 positive blood cultures. Among these a male recipient was categorized as possible septic transfusion reaction and Citrobacterfreundii was isolated from blood sample. Conclusion: Appropriate clinical utilization of PCs transfusion, and ongoing vigilance to recognize, investigate, promptly treat, and report all suspicious transfusion reactions are necessary to manage the transfusion complication including transfusion transmitted infections (TTI). PMID- 29515633 TI - Possible Interrelationship of Inflammatory Cells in Dry Type Cutaneous Leishmaniasis. AB - Background & Objective: There is a complicated interaction between leishmaniasis and the host immune cells, and also between the host immune cells. These interactions have fundamental effects on the outcome of the disease.The current study aimed at characterizing the number, distribution, co-localization, and interrelation of 4 types of inflammatory cells in different clinical forms of dry type cutaneous leishmaniasis (CL). Methods: Thirty-nine cases of CL were studied. The cases were classified clinically as 14 cases of acute leishmaniasis with indurated papules, nodules, and plaques with central crust formation < 2 years, 7 cases of chronic type with non-healing lesions > 2 years, and 12 cases of lupoid leishmaniasis with characteristic papules around previous scars of CL > 2 years. Paraffin-embedded blocks were stained with hematoxylin and eosin (H&E) and also stained immunohistochemically for CD4, CD8, CD68, and CD1a. Results: In acute CL, there was a significant correlation between CD68+ macrophages and CD1a+ epidermal dendritic cells (DCs); the population of CD68+ macrophages and CD1a+ epidermal DCs increased in parallel.In lupoid CL, there was a significant correlation between CD1a+ epidermal DCs, and CD1a+ dermal DCs and population of CD1a+ epidermal DCs; the number of CD1a+ dermal DCs increased in parallel. Conclusions: The result of the current study could be used as a baseline to design and study the new targeted therapy of synergistic effects of macrophages and DCs to phagocytizing leishmania bodies; and/or suggestion planning of individualizing setup of vaccine by autologous interaction of macrophages and DC in CL. PMID- 29515635 TI - Effect of Silibinin on Maspin and ERalpha Gene Expression in MCF-7 Human Breast Cancer Cell Line. AB - Background and objective: According to reports, a serine protease inhibitor (Maspin) suppresses metastasis, invasion and angiogenesis in breast and prostate cancers. Silibinin is a natural polyphenolic flavonoid with anti-cancer activity. We assessed the effects of silibinin on cell viability, maspin and ERalpha gene expression in MCF-7 cell line. Methods: The human MCF-7 breast cancer cell line was cultured in Dulbecco's Modified Eagle's Medium (DMEM) and treated with different concentrations of silibinin (100-600 MUg/mL) for 24, 48 and 72 hours. The cytotoxic effect of silibinin on MCF-7 viability was determined using Methyl Thiazolyl-Tetrazolium (MTT) assay by IC50 determination. The fold changes of Maspin and ERalpha expression were determined by reverse-transcription real-time Polymerase Chain Reaction (PCR). All experiments on the cells were performed in triplicates. Results: The maximum inhibitory effect of silibinin on cell viability was observed at 600 MUg/mL after 72-hour incubation (p = 0.001). Incubation of the cells with silibinin for 48 and 72 hours significantly decreased IC50 values to 250 and 207 MUg/mL (p = 0.005 and p= 0.006), respectively. The expression of maspin and ERalpha in the treated cells compared to controls was significantly decreased following treatment with different concentrations of silibinin during a 24-hour period. Conclusions: Silibinin reduces both maspin and ERalpha gene expression in MCF-7 cell line. The therapeutic effect of silibinin on the treatment of breast cancer may be mediated by the reduction of ERalpha expression. For verifying this hypothesis and the possible therapeutic implication of silibinin on breast cancer, further studies in this direction are necessary. PMID- 29515634 TI - Chromogenic in situ Hybridization Compared with Real time Quantitative Polymerase Chain Reaction to Evaluate HER2/neu Status in Breast Cancer. AB - Background and objective: The assessment of human epidermal growth factor receptor 2 (HER2) status has become of great importance in the diagnosis of breast cancer. The aim of this study was to investigate the diagnostic value of quantitative Polymerase Chain Reaction (qPCR) and Chromogenic In Situ Hybridization (CISH) to assess HER2 status of biopsy specimens. Methods: To elucidate the status of HER2 gene amplification, biopsies of breast carcinoma from 120 patients with 2+ IHC status were analyzed by qPCR and CISH. Results: The results of the two experiments were compared, and it was depicted that the concordance rate between CISH and qPCR assays was 88.1%.The quantification of HER2 gene with CISH and qPCR showed that there was a significant correlation (p value= 0.0001 and r= 0.808). Conclusion: The results of this research support the idea that qPCR is a precise and reproducible technique, which can be employed as a supplementary method to evaluate HER2 status. PMID- 29515636 TI - The Prevalence of Human Papilloma Virus in Squamous Cell Carcinoma of Oral Tongue. AB - Background and objective: Oral tongue Squamous Cell carcinoma (SCC) commonly involves males between the sixth to eighth decades of life. Major risk factors are tobacco usage and alcohol consumption. The increasing number of patients developing oral tongue cancer without these well-known risk factors suggests that a viral infection, such as Human Papillomavirus (HPV), may be responsible for this increase, by acting as an oncogenic agent. This study investigated the prevalence of HPV infection and its clinicopathologic significance in oral tongue SCCs. Methods: Tissue blocks from a total of 50 cases (patients with oral tongue SCC) and 50 controls (palatine tonsillar tissues with benign diagnosis) were selected. DNA was extracted from tumoral and non-tumoral tissue blocks. Detection of common HPV DNA by nested Polymerase Chain Reaction (PCR), and high-risk genotypes, HPV 16 and HPV 18, by conventional PCR, was achieved and the results correlated with clinicopathological parameters. Results: Of the 50 patients (18 males and 32 females with a mean age of 57.36+/-12.18 years, and age range of 27 to 86 years), 7 (14%) had HPV positive results. None of the control group subjects had HPV DNA positive results (P-value of 0.012). The HPV genotype 16/18 was not detected in positive cases. No statistically significant association was found between HPV status and gender, age, tumor grade, tumor stage or lymph node involvement. Conclusion: Although there was a significantly higher prevalence of HPV in oral tongue SCC, its association with carcinogenesis in this area requires further studies. PMID- 29515637 TI - Evaluation of Nuclear Morphometry and Ki-67 Index in Clear Cell Renal Cell Carcinomas: a Five-Year Study. AB - Background and objective: Clear Cell Renal Cell Carcinoma (CCRCC) is the most common adult renal neoplasm. Staging and grading of RCC are important predictors of survival. Fuhrman nuclear grading is widely used for CCRCC, the subjective nature of which has prompted more objective methods to evaluate nuclear features. Furthermore, Ki-67, a reliable marker of cellular proliferation may provide another variable for assessment of the biological behavior of RCC. The aim of this research was to study nuclear morphometry and Fuhrman nuclear grading of clear cell RCC, and to assess their relationship with the Ki-67 index. Methods: Hematoxylin and eosin slides of forty cases of CCRCC were retrieved and studied for pathologic variables, including Fuhrman nuclear grade, pathological tumor and node stage. Nuclear morphometric analysis was performed using computer-assisted image analysis. The relationship between Fuhrman nuclear grading, pathologic stage, tumor size, nuclear morphometry and proliferative index were analyzed. Results: According to Fuhrman grading, four (10%) cases were grade I, 23 (57.5%) were grade II, 12 (30%) were grade III, and one (2.5%) was grade IV. Moderate to high correlation was seen between Fuhrman nuclear grade and mean nuclear area, perimeter, diameter, length, nuclear roundness factor and Ki -67, with a P value of < 0.05. Conclusion: The CCRCC is an extremely heterogenous disease and clinical outcome is unpredictable despite several validated prognostic factors. The widely used Fuhrman nuclear grading is subjective, while nuclear morphometry, using computer assisted image analysis, can ensure more objective assessment. The Ki-67 index could provide reliable information and compliment the other prognostic parameters. PMID- 29515638 TI - The HER-2 as a Target Gene of Curcumin to Protect Hepatocytes Against the Arsenic induced Carcinoma in Mice. AB - Background & objective: The HER-2 gene is an important on co protein overexpressed in many types of cancers. The current study hypothesized that curcumin downregulates HER-2 and inhibits the signal transduction pathway of PI3K/Akt, MAPK, and activation of NFkappaB, which could be useful to treat overexpressed-HER-2 hepatocellular carcinoma (HCC). Methods: In the current study, 40 male NMRI (Naval Medical Research Institute) mice were divided into 4 groups of 10 as follow: Group1 (control group) only received 5 mL/kg corn oil, group 2 (poisoned group) received 30 mg/L arsenic (As2O3) dissolved in water, group3 (curcumin treated), and group 4 (curcumin and arsenic treated) received 10 to 20mg/5mL/kg for 60 days. Once experimental period was completed, liver samples were collected. The analysis of the gene expression was performed by real-time polymerase chain reaction (PCR) technique. Results: Gene expression analysis showed that curcumin had significantly downregulated the activity of HER-2, in poisoned mice. Conclusion: According to the current study results, it could be concluded that curcumin has the inhibitory potential toward HER-2-overexpressed HCC. PMID- 29515639 TI - Conserved OprF as a Selective Immunogen against Pseudomonas aeruginosa. AB - Background & Objectives: Due to the importance of Pseudomonas aeruginosa in severe inpatient infections and high mortality, the need for an efficient vaccine against these bacteria is increasing. In this regard, the general outer membrane porin of the most problematic microorganism P. aeruginosa, outer membrane protein F (OprF), is a good vaccine candidate. Methods: The databank of NCBI was used to retrieve protein sequences recorded for OprF in P. aeruginosa.The current study aimed at investigating the conservation of the OprF in 150 reference sequences, clinical, and environmental strains of P. aeruginosa from different countries via bioinformatic tools.T-COFFEE and PRALINE software were used for alignment. Results: Of these, 134 strains were isolated from clinical specimens and other strains from environmental samples. Evaluation of alignment by the mentioned software clearly showed that this protein was conserved. Antigenicity and grand average of hydropathicity were favorable. Conclusion: Conservation of OprF in all pathogenic and environmental strains of P. aeruginosa indicated that it can be considered as a good immunogen; however, the protectivity of OprF should be validated experimentally. PMID- 29515640 TI - Endothelin-1 Expression in Prostate Needle Biopsy Specimens Correlated With Aggressiveness of Prostatic Cancer. AB - Background & Objective: As the prostate adenocarcinoma is one of the most common malignant tumors in males, looking for a marker to effectively predict aggressiveness and metastatic potential in an apparently localized cancer in initial needle biopsy specimens can help the clinicians to make more appropriate decision for treatment, planning, and choosing appropriate targeted therapy. The present study assessed the value of Endothelin-1 expression to predict prognosis of prostatic cancer. Methods: In a cross sectional study, 83 patients who underwent radical prostatectomy in Hasheminejad Kidney Center in 2008 through 2012 were assigned to two groups including 43 with and 40 without extra-prostatic extension (EPE). Endothelin-1 staining was performed on Paraffin Embedded blocks of preoperative needle biopsies. Results: The expression of Endothelin-1 increased in 72% of patients in the group with EPE (P<0.001). The group with Endothelin-1 positivity showed higher serum level of prostate specific antigen (PSA) (p = 0.039). Endothelin-1 expression was positive in 67% of patients with perineurial invasion (P<0.001). Adjusting the baseline variables of PSA and PN in a multivariable logistic regression model, the Endothelin-1 positivity could effectively predict EPE in patients with prostatic cancer (OR: 5.46, p = 0.010). Conclusion: Correlation of Endothelin-1 expression in needle biopsy specimens in expected with extra-prostatic extension of tumor in radical prostatectomy specimens, perineurial invasion and serum PSA level at the time of diagnosis. PMID- 29515641 TI - Testicular Biopsy in Males With Infertility: A Longitudinal Study. AB - Background & objective: Regarding the importance of histologic examination of testicular biopsy for clinical planning of infertility, the current study was conducted to compare 2 separate histologic examination of testicular biopsy. Also, some cases with known fertility outcome were followed and their histological patterns were also compared with those of the outcome. Methods: The current study was conducted on testicular biopsies of 924 males evaluated for infertility from 1990 to 2013, retrieved from the archive of pathology department of Shahid Beheshti Hospital, Babol, Northern Iran. All slides were reviewed by a pathologist unaware of the original results. Data including age, histological pattern of spermatogenesis (pure and mixed), smoking, and the history of ejaculatory duct obstruction were retrieved from the pathology archive. In some cases, the outcome was also compared with that of the histological pattern. All analyses were executed using SPSS version 22 statistical software. To analyze the data, t test, Chi-square test, one-way ANOVA, and the least significant difference (LSD) test were used. Results and Conclusion: Out of the 924 testicular biopsies, 34 (3.7%) cases had different reports from original reading. LSD analysis indicated Sertoli cell only syndrome (SCO) as the most common histological pattern. There was a significant difference between the mean age of cases with SCO and that of the ones with hypospermatogenesis (HYPO) (P =0.03). Obstruction was higher in pure pattern (P=0.04). The pregnancy rate was higher in the wives of males with obstructive infertility than the ones with non obstructive infertility. SCO was the most common histological pattern of testicular biopsy during 23 years. Pure patterns were more than mixed patterns, and the mean age was lower in mixed patterns. Also, pure patterns were the most common findings in the cases with obstructive infertility. PMID- 29515642 TI - Sero-prevalence of Helicobacter pylori Infection in Neyshabur, Iran, During 2010 2015. AB - Backgrounds & Objective: The Helicobacter pylori prevalence has continuously decreased during recent years in Iran. The current study aimed at determining H. pylori prevalence in Neyshabur city, Northeast Iran, during 2010-2015. Methods: The current epidemiologic survey was conducted in Neyshabur from 2010 to 2015 to determine the prevalence of H. pylori infection. A total of 11596 participants (3681 male with the mean age of 31.7+/-6.2 years and 7915 female with mean age of 68.3+/-4.7 years) were included. The enzyme-linked immunosorbent assay kits for the detection of H. pylori and Stat Fax 3200(r) Microplate Reader (USA) with a sensitivity of 95% and specificity of 98% were used. Titers above 12 units were considered positive for IgG, IgA, and IgM (negative <8, equivocal 8 to 12, and positive >12 U). The Chi-square t test and F test were used to analyze data. Results and Conclusion: The overall IgA, IgG, and IgM seropositive samples among the study participants were 852 (7.2%), 9000 (72.8%), and 1256 (5.2%), respectively. The IgA seropositivity was significantly high among the age group above 51 years, compared with the other age groups. Moreover, the IgG and IgM seropositivity were significantly high among the age groups 41 to 50 and 31 to 40 years respectively, compared with the other age groups. There was no significant difference between male and female cases regarding IgA and IgG seropositive samples, but IgM level was significantly higher among females, compared with that of the male cases. Furthermore, there was no significant alteration in IgA, IgG, and IgM seropositivity during 2010-2014 in Neyshabur. The prevalence of H. pylori in Neyshabur was high in the healthy population. Furthermore, the H. pylori prevalence did not change from 2010 to 2014 in the studied city. Effective approaches to improve health, educational, and socioeconomic status should be implemented to minimize and control H. pylori infection. PMID- 29515643 TI - Physical Activity, Exercise and Sport Programs as Effective Therapeutic Tools in Psychosocial Rehabilitation. AB - People with severe psychosocial disabilities have a 20-years shorter lifespan due to chronic somatic comorbidities and the long-term consequences of the side effects of antipsychotic drugs. They often are sedentary and show lower levels of physical activity, factors which can contribute to their shorter lifespan, because of the greater cardiovascular risk. An increasing amount of evidence, including clinical trials, pointed out that sport, physical activity and structured exercise programs improve physical and psychological wellbeing of people with psychosocial disabilities, playing also an important role against their social isolation and self-stigma. The NICE and APA guidelines include exercise and physical activity for the management of depressive symptoms. Safe and effective programs require multidisciplinary teams that should always include mental health professionals, able to recognize the psychosocial needs, the impact of symptomatology, the role of secondary effects of psychotropic medication, the effect of previous exercise history, the lack of motivation, the inexperience with effort intensity and the frustration of people with psychosocial disabilities. PMID- 29515644 TI - Effects of Aerobic Exercise on Anxiety Symptoms and Cortical Activity in Patients with Panic Disorder: A Pilot Study. AB - Background: The effects of the aerobic exercise on anxiety symptoms in patients with Panic Disorder (PD) remain unclear. Thus, the investigation of possible changes in EEG frontal asymmetry could contribute to understand the relationship among exercise, brain and anxiety. Objective: To investigate the acute effects of aerobic exercise on the symptoms of anxiety and the chronic effects of aerobic exercise on severity and symptoms related to PD, besides the changes in EEG frontal asymmetry. Methods: Ten PD patients were divided into two groups, Exercise Group (EG; n=5) and Control Group (CG; n=5), in a randomized allocation. At baseline and post-intervention, they submitted the psychological evaluation through Panic Disorder Severity Scale (PDSS), Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), EEG frontal asymmetry, and maximal oxygen consumption (VO2max). On the second visit, the patients of EG being submitted to the aerobic exercise (treadmill, 25 minutes, and 50-55% of heart rate reserve) and the CG remained seated for the same period of time. Both groups submitted a psychological evaluation with Subjective Units of Distress Scale (SUDS) at baseline, immediately after (Post-0), and after 10 minutes of the rest pause (Post-10). The patients performed 12 sessions of aerobic exercise with 48-72 hours of interval between sessions. Results: In EG, SUDS increased immediately after exercise practice and showed chronic decrease in BAI and BDI-II as well as increased in VO2max (Post-intervention). Conclusion: Aerobic exercise can promote increase in anxiety acutely and regular aerobic exercise promotes reduction in anxiety levels. PMID- 29515646 TI - Risk factors for unsafe behaviors toward grenades among rural populations affected by explosive devices in Colombia. AB - Background: Following decades of armed conflict, Colombia remains highly affected by explosive device (ED) contamination, especially in rural areas. Many victims are injured by EDs despite knowing their dangers. Determining risk factors for unsafe behaviors toward EDs, including grenades, is critical for preventing injuries. Methods: In 2012, CDC assisted Colombian partners in conducting a multi stage knowledge, attitudes, and practices survey in rural ED-affected areas. Within each of 40 clusters, 28 households were selected, and participants aged 10 years or older were asked about behaviors toward EDs. Participants reported actual behaviors toward past EDs encountered and theoretical behaviors toward EDs not encountered. Behaviors were a priori classified as unsafe or safe. This analysis focuses on behaviors toward the most commonly encountered device, grenades. Results: Of 928 adult and 562 child participants, 488 (52.5%) adults and 249 (43.9%) children encountered ED, while 121 (13.7%) adults and 148 (26.9%) children received mine risk education (MRE). Among the 430 (46.7%) adults who encountered grenades, 113 (25.7%) reported unsafe behaviors; multivariable analysis showed that unsafe behavior was associated with working outdoors (adjusted odds ratio [aOR]: 1.7, 95% confidence interval [CI]: 1.1-2.7). Among the 429 (46.5%) adults who did not encounter ED, 61 (14.6%) described unsafe theoretical behaviors toward grenades; multivariable analysis showed that unsafe behavior was associated with older age (aOR: 1.02, 95% confidence limit [CL]: 1.00-1.05) and black or Afro-Colombian identity (aOR: 2.5, 95% CI 1.3-5.1). Among the 181 (32.0%) children who encountered grenades, 41 (23.8%) reported unsafe behaviors, while among the 311 (55.9%) children who did not encounter ED, 30 (10.2%) reported unsafe behavior. In both groups of children, multivariable analysis showed that unsafe behavior was associated with lower mean score on knowledge of ED, with aOR: 0.7, 95% CL: 0.6-0.9, and aOR: 0.8, 95% CL: 0.6-0.98, respectively. Conclusions: Participants reported frequent ED exposure but low receipt of MRE. Our findings should guide MRE improvement in ED-affected areas by strengthening the connection between ED knowledge and avoiding unsafe behavior, with a particular focus on people working outdoors. MRE should promote knowledge of ED risks but should also recognize socioeconomic factors that lead to engaging in unsafe behaviors. PMID- 29515645 TI - Evaluation of capillary leakage after vasopressin resuscitation in a hemorrhagic shock model. AB - Background: Hemorrhagic shock (HS) is a major threat to patients with trauma and spontaneous bleeding. The aim of the study was to investigate early effects of vasopressin on metabolic and hemodynamic parameters and endothelium permeability by measuring capillary leakage compared to those of other resuscitation strategies in a HS model. Methods: Forty-five Sprague-Dawley rats were randomized into five groups: S group (n = 5), sham-operated rats without shock or resuscitation; HS group (n = 10), HS and no resuscitation; RL group (n = 10), HS and resuscitation with Ringer's lactate (RL); RLB group (n = 10), HS and resuscitation with two-third shed blood plus RL; and vasopressin group (n = 10), HS and resuscitation with RL, followed by continuous infusion of 0.04 U/kg/min vasopressin. The effects of resuscitation on hemodynamic parameters [mean arterial pressure (MAP), superior mesenteric artery blood flow (MBF), and mesenteric vascular resistances (MVR)], arterial blood gases, bicarbonate, base deficit, and lactate levels as well as on capillary leakage in the lung, ileum, and kidney were investigated. Capillary leakage was evaluated with Evans blue dye extravasation. Results: In the vasopressin group, the MAP was higher than in the RL and RLB groups (p < 0.001), while MBF was decreased (p < 0.001). MVR were increased only in the vasopressin group (p < 0.001). Capillary leakage was increased in the lungs of the animals in the vasopressin group compared to that in the lungs of animals in the RLB group (p < 0.05); this increase was associated with the lowest partial pressure of oxygen (p < 0.05). Conversely, decreased capillary leakage was observed with vasopressin in the ileum (p < 0.05). Increased capillary leakage was observed in the kidney in the RLB and vasopressin groups (p < 0.05). Lastly, vasopressin use was associated with higher base deficit and lactate levels when compared to the RL and RLB groups (p < 0.001). Conclusion: Although vasopressin was proposed as a vasoactive drug for provisional hemodynamic optimization in the early phase of HS resuscitation, the overall findings of this experimental study focus on the possible critical side effects of vasopressin on metabolic parameters and endothelium permeability. PMID- 29515647 TI - Treatment expectancy, working alliance, and outcome of Trauma-Focused Cognitive Behavioral Therapy with children and adolescents. AB - Background: It has been shown that positive treatment expectancy (TE) and good working alliance increase psychotherapeutic success in adult patients, either directly or mediated by other common treatment factors like collaboration. However, the effects of TE in psychotherapy with children, adolescents and their caregivers are mostly unknown. Due to characteristics of the disorder such as avoidant behavior, common factors may be especially important in evidence-based treatment of posttraumatic stress symptoms (PTSS), e.g. for the initiation of exposure based techniques. Methods: TE, collaboration, working alliance and PTSS were assessed in 65 children and adolescents (age M = 12.5; SD = 2.9) and their caregivers. Patients' and caregivers' TE were assessed before initiation of Trauma-Focused Cognitive Behavioral Therapy (TF-CBT). Patients' and caregivers' working alliance, as well as patients' collaboration were assessed at mid treatment, patients' PTSS at pre- and post-treatment. Path analysis tested both direct and indirect effects (by collaboration and working alliance) of pre treatment TE on post-treatment PTSS, and on PTSS difference scores. Results: Patients' or caregivers' TE did not directly predict PTSS after TF-CBT. Post treatment PTSS was not predicted by patients' or caregivers' TE via patients' collaboration or patients' or caregivers' working alliance. Caregivers' working alliance with therapists significantly contributed to the reduction of PTSS in children and adolescents (post-treatment PTSS: beta = - 0.553; p < 0.001; PTSS difference score: beta = 0.335; p = 0.031). Conclusions: TE seems less important than caregivers' working alliance in TF-CBT for decreasing PTSS. Future studies should assess TE and working alliance repeatedly during treatment and from different perspectives to understand their effects on outcome. The inclusion of a supportive caregiver and the formation of a good relationship between therapists and caregivers can be regarded as essential for treatment success in children and adolescents with PTSS. PMID- 29515648 TI - Analysis of the Impact of Configuration of the Stabilisation System for Femoral Diaphyseal Fractures on the State of Stresses and Displacements. AB - Introduction: The treatment of femoral diaphyseal fractures by intramedullary nailing has become a common procedure in orthopaedic surgery. The purpose of this numerical simulation was to present how the changes in configuration of the stabilisation system can affect the stress and displacement state in the bone tissue and implanted device. Material and Methods: The numerical comparison of the stabilisation variants for the type 32-A2 femoral diaphyseal fracture (according to the AO classification) performed by using the Charfix2 (ChM(r)) anatomical nail locked in a number of chosen ways. The displacement and the stress distributions both in the bone and implant were obtained and analysed by computational simulation. Results: In all models, there was the same characteristic distribution, which shows there were minimal rotational movements of the bone around the anatomical axis. In all cases, stress concentrations were generated in the nail material in the area of the fracture gap. Conclusions: The obtained results indicate that there is a visible advantage to one-plane distal stabilisation in the reduction of stresses regardless of the type of proximal stabilisation. The results of calculations indicate that the use of proximal stabilisation with a neck screw reduces the possibility of damage to the implant. PMID- 29515649 TI - Human Hand Motion Analysis during Different Eating Activities. AB - The focus of this research is to analyse both human hand motion and force, during eating, with respect to differing food characteristics and cutlery (including a fork and a spoon). A glove consisting of bend and force sensors has been used to capture the motion and contact force exerted by fingers during different eating activities. The Pearson correlation coefficient has been used to show that a significant linear relationship exists between the bending motion of the fingers and the forces exerted during eating. Analysis of variance (ANOVA) and independent samples t-tests are performed to establish whether the motion and force exerted by the fingers while eating is influenced by the different food characteristics and cutlery. The middle finger motion showed the least positive correlation with index fingertip and thumb-tip force, irrespective of the food characteristics and cutlery used. The ANOVA and t-test results revealed that bending motion of the index finger and thumb varies with respect to differing food characteristics and the type of cutlery used (fork/spoon), whereas the bending motion of the middle finger remains unaffected. Additionally, the contact forces exerted by the thumb tip and index fingertip remain unaffected with respect to differing food types and cutlery used. PMID- 29515650 TI - Computer-Assisted Optimization of the Acetabular Rotation in Periacetabular Osteotomy Using Patient's Anatomy-Specific Finite Element Analysis. AB - Periacetabular osteotomy (PAO) is a complex surgical procedure to restore acetabular coverage in the dysplastic hip, and the amount of acetabular rotation during PAO plays a key role. Using computational simulations, this study assessed the optimal direction and amount of the acetabular rotation in three dimensions for a patient undergoing PAO. Anatomy-specific finite element (FE) models of the hip were constructed based on clinical CT images. The calculated acetabular rotation during PAO were 9.7 degrees , 18 degrees , and 4.3 degrees in sagittal, coronal, and transverse planes, respectively. Based on the actual acetabular rotations, twelve postoperative FE models were generated. An optimal position was found by gradually varying the amount of the acetabular rotations in each anatomical plane. The coronal plane was found to be the principal rotational plane, which showed the strongest effects on joint contact pressure compared to other planes. It is suggested that rotation in the coronal plane of the osteotomized acetabulum is one of the primary surgical parameters to achieve the optimal clinical outcome for a given patient. PMID- 29515651 TI - Innovative Design and Performance Evaluation of Bionic Imprinting Toothed Wheel. AB - A highly efficient soil-burrowing dung beetle possesses an intricate outer contour curve on its foreleg end-tooth. This study was carried out based on evidence that this special outer contour curve has the potential of reducing soil penetration resistance and could enhance soil-burrowing efficiency. A toothed wheel is a typical agricultural implement for soil imprinting, to increase its working efficiency; the approach of the bionic geometrical structure was utilized to optimize the innovative shape of imprinting toothed wheel. Characteristics in the dung beetle's foreleg end-tooth were extracted and studied by the edge detection technique. Then, this special outer contour curve was modeled by a nine order polynomial function and used for the innovative design of imprinting the tooth's cutting edge. Both the conventional and bionic teeth were manufactured, and traction tests in a soil bin were conducted. Taking required draft force and volume of imprinted microbasin as the evaluating indexes, operating efficiency and quality of different toothed wheels were compared and investigated. Results indicate that compared with the conventional toothed wheel, a bionic toothed wheel possesses a better forward resistance reduction property against soil and, meanwhile, can enhance the quality of soil imprinting by increasing the volume of the created micro-basin. PMID- 29515652 TI - Palliative hysterectomy for vaginal bleeding from breast cancer metastatic to the uterus. AB - Breast cancer is the most prevalent cancer in the United States. With an increasing rate of survivorship and extended life span for patients with metastatic disease, the demand for palliative care is increasing. Although uncommon, metastases to gynaecologic organs have been reported and are often present with post-menopausal bleeding. Post-menopausal bleeding can become clinically significant and have a detrimental effect on quality of life. We report the case of a 70-year-old woman with symptomatic vaginal bleeding caused by breast cancer metastatic to her uterus, cervix, fallopian tubes and ovaries. She was successfully treated with minimally invasive hysterectomy, resolving her vaginal bleeding and anemia and allowing her to resume chemotherapy. PMID- 29515653 TI - MGMT promoter methylation in Peruvian patients with glioblastoma. AB - Purpose: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases. Patients and methods: We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008-2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue. MGMT-promoter methylation status and the expression level of MGMT gene were evaluated by methylation-specific PCR and real-time PCR, respectively. Results: Unmethylated, methylated and partially methylated statuses were found in 54%, 20% and 26% of paraffin-embedded samples, respectively. Methylation status was confirmed in the Virgen de la Salud Hospital and frozen samples. There was an association between the status of MGMT-promoter methylation and the level of gene expression (p = 0.001). Methylation was associated with increased progression-free survival (p = 0.002) and overall survival (OS) (p < 0.001). Conclusion: MGMT-promoter methylation frequency in Peruvian glioblastoma is similar to that reported in other populations and the detection test has been standardised. PMID- 29515655 TI - Cauda equina syndrome secondary to leptomeningeal metastases from recurrent primary peritoneal carcinoma. AB - The patient is a 42-year-old woman with metastatic primary peritoneal carcinoma and known brain metastases, who subsequently developed cauda equina syndrome after presenting with ataxia, lower extremity weakness, and bowel and bladder incontinence secondary to leptomeningeal metastasis after treatment with neoadjuvant chemotherapy, surgical debulking, and adjuvant chemotherapy. Metastases to the central nervous system (CNS) and leptomeninges are rare events in epithelial ovarian and primary peritoneal carcinomas as these tumours do not have a predilection for the CNS. Cauda equina syndrome is often characterised by gait disturbances, bowel and bladder dysfunction, saddle anaesthesia, and lower extremity muscle weakness. In patients with known metastatic gynaecologic carcinomas presenting with nonspecific neurologic symptoms, cauda equina syndrome should remain high in the differential diagnosis. PMID- 29515654 TI - Aspirin: 120 years of innovation. A report from the 2017 Scientific Conference of the International Aspirin Foundation, 14 September 2017, Charite, Berlin. AB - Acetylsalicylic acid was first synthesised by Dr FeIix Hoffman on 10th August 1897 and Aspirin was born. It quickly became the best-known pain killer in the world and in the 120 years since this event, aspirin has continued to attract interest, innovation and excitement. Set within the walls of the preserved ruins of Rudolf Virchow's lecture hall at Charite, within Berlin's Museum of Medical History, the International Aspirin Foundation's 28th Scientific Conference served to facilitate international, multi-disease, multidisciplinary discussion about the current understanding of aspirin's mechanisms of action and its utility in modern medicine as well as ideas for future research into its multifaceted applications to enhance global health. In addition to the delegates in Berlin, 300 medical doctors at the 19th Annual Scientific Congress of the Chinese Society of Cardiology were able to join the cardiology sessions from Taiyuan, Shangxi province via a live streaming link to and from China. This led to useful discussion and allowed a truly international perspective to the meeting. PMID- 29515656 TI - Rediscovery in science-a second eureka moment? A case in the neovascularization in cancer. AB - Rediscoveries are not uncommon. However, sometimes they can be more significant than confirmatory or extensions of existing findings, although many authors today refer to them as discoveries in their own right. This has led to papers repeatedly rehearsing the expression "we show here for the first time...". When a finding has opened up a whole new field of research, this is more in line with a true discovery. When particular attention is drawn to such an event by editorials in widely read journals, such as Nature, its importance is bolstered. But if it turns out to be a rediscovery, the implications are considerable and the problem has to be brought to the attention not only of those in the same field of research, but to a wider audience to put the record straight. Consequently, acknowledgment of those who made the original discovery needs to be equally well publicised. A short discussion is presented of ways we might reduce the many claims of "new" discoveries that seem to be of considerable significance but are in fact rediscoveries. PMID- 29515657 TI - Towards ending viral hepatitis as a public health threat: translating new momentum into concrete results in South-East Asia. PMID- 29515658 TI - Chlortetracycline and florfenicol induce expression of genes associated with pathogenicity in multidrug-resistant Salmonella enterica serovar Typhimurium. AB - Background: Multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Typhimurium) is a serious public health threat as infections caused by these strains are more difficult and expensive to treat. Livestock serve as a reservoir for MDR Salmonella, and the antibiotics chlortetracycline and florfenicol are frequently administrated to food-producing animals to treat and prevent various diseases. Therefore, we evaluated the response of MDR S. Typhimurium after exposure to these two antibiotics. Results: We exposed four MDR S. Typhimurium isolates to sub-inhibitory concentrations of chlortetracycline (16 and 32 ug/ml) or florfenicol (16 ug/ml) for 30 min during early-log phase. Differentially expressed genes following antibiotic treatment were identified using RNA-seq, and genes associated with attachment and those located within the Salmonella pathogenicity islands were significantly up-regulated following exposure to either antibiotic. The effect of antibiotic exposure on cellular invasion and motility was also assessed. Swimming and swarming motility were decreased due to antibiotic exposure. However, we observed chlortetracycline enhanced cellular invasion in two strains and florfenicol enhanced invasion in a third isolate. Conclusions: Chlortetracycline and florfenicol exposure during early-log growth altered the expression of nearly half of the genes in the S. Typhimurium genome, including a large number of genes associated with virulence and pathogenesis; this transcriptional alteration was not due to the SOS response. The results suggest that exposure to either of these two antibiotics may lead to the expression of virulence genes that are typically only transcribed in vivo, as well as only during late-log or stationary phase in vitro. PMID- 29515660 TI - Breathe: continuing education in respiratory medicine. AB - The March issue of Breathe focuses on ERS activities to further education in respiratory medicine http://ow.ly/CLoR30hWJZy. PMID- 29515661 TI - Myths and maxims in paediatric respiratory medicine. AB - Introducing a new series of articles focusing on myths and maxims related to conditions clinicians in paediatric respiratory medicine encounter on a regular basis ?http://ow.ly/sUid30hWIs2. PMID- 29515662 TI - Summer schools of adult and paediatric respiratory medicine: course report. AB - Participants in the 2017 ERS summer schools of adult and paediatric respiratory medicine describe their experiences http://ow.ly/i4y930hzLU0. PMID- 29515663 TI - The ERS-industry fellowship: a tale of two experiences. AB - Recipients of the ERS Fellowship in Industry discuss their experiences http://ow.ly/1gcE30hMe89. PMID- 29515664 TI - Update of the ERS international Adult Respiratory Medicine syllabus for postgraduate training. AB - First published in 2006, the first European core syllabus in Adult Respiratory Medicine was developed with the intention of harmonising education and training throughout Europe. Internationally recognised by the European Union of Medical Specialists and identified as the first document of its kind in respiratory medicine, it has provided a comprehensive guide for both local and national institutions in the development of adult respiratory training programmes. Like all fields in education, respiratory medicine is an ever-changing area and as such, respective syllabi, curricula and training programmes must adapt and diversify in line with the evolution of core medical concepts. Given the proven importance of the Adult Respiratory Medicine syllabus from both a national and international standpoint, it is of equal importance that said syllabus remains abreast of emerging trends so as to sustain the synchronisation of respiratory medicine in Europe. In order to develop an updated programme, a comprehensive review process of the current syllabus is a necessary endeavour and a step that the European Respiratory Society (ERS) has undertaken through the process of a needs assessment. PMID- 29515665 TI - What do patients know? Education from the European Lung Foundation perspective. AB - : The European Lung Foundation (ELF) is an organisation whose mission is to bring together the public and patients with respiratory professionals to improve lung health. A core part of all its activities focus on education: the education of patients on their condition, including how to prevent, treat and manage it; the education of healthcare professionals on how to improve work with patients and awareness about the issues that are important to patients; and education of the public and policy makers of the importance of lung health at a European level. ELF was founded and works in a unique partnership with the European Respiratory Society (ERS). This article has been written by the recent past Chairs and the new Chairs of three ELF committees (Council (D. Smyth and I. Saraiva), Professional Advisory Committee (K. Lisspers and G. Hardavella) and Patient Advisory Committee (J. Fuertes and K. Hill)) in order to reflect on ELF's journey in this regard over recent years. In particular, it seems a good moment to assess the success and impact of the first patient Chair of ELF, Dan Smyth, and reflect on what this has meant for ELF's educational activities, and what the future now looks like. Educational aims: To understand the importance of educated patients (patients that are knowledgeable on their condition and how healthcare processes work).To understand the importance of guiding patients to quality reliable sources of information and education.To establish ways to ensure that healthcare professionals are prepared to work with educated patients.To outline the initiatives that ELF has driven forward in the field of education.To see the value in patients advocating at the European level for raising standards of education for patients and physicians. PMID- 29515666 TI - Contemporary challenges for specialist nursing in interstitial lung disease. AB - : The role of clinical nurse specialists (CNSs) in interstitial lung disease (ILD) is evolving in response to clinical guidelines and the growth of clinical research. The role is well established in the UK, although more ILD posts are needed to ensure supply meets clinical demand. This phenomenon is also happening across Europe. An appreciation of the similarities and differences between CNS and advanced nurse practitioners is important given the challenges in defining, developing and supporting this nursing specialisation. Globally, different models exist. In some countries charitable organisations take a leading role in supporting patients. Many European centres look to the National Institute for Health and Care Excellence guidelines and quality standards as a template to develop and evaluate the role of the ILD CNS. We present a UK perspective in the context of a government subsidised healthcare system to promote professional discussion and debate regarding the future of nursing practice in the ILD specialty. Key points: ILDs are often complex and associated with significant mortality, morbidity and co-morbid conditions that require a technical healthcare skill setThere is worldwide shortage of nurses, low retention rates and retirement of many skilled nursesCollaboration across the ILD interdisciplinary community is needed to safeguard the future of our professions and high-quality patient careThe ILD interdisciplinary and nurse network has identified key priorities to help secure the future of the ILD clinical and academic nurse specialism. Educational aims: To explain the similarities and differences between clinical nurse specialists (CNSs) and advanced nurse practitioners (ANPs) in the context of ILD specialismTo review contemporary nursing specialism in the UK's government subsidised healthcare systemTo stimulate discussion and debate across the European/international respiratory community regarding the clinical and academic development of the ILD CNSTo identify key priorities that will support collaboration across the ILD interdisciplinary workforce in clinical practice and research. PMID- 29515667 TI - A 50-year-old male with fever, cough, dyspnoea, chest pain, weight loss and night sweats. AB - Can you diagnose this case of a 50-year-old male with a 10-week history of high fever, mucopurulent cough, dyspnoea, right-sided chest pain, weight loss and night sweats ?http://ow.ly/QFEM30h26GE. PMID- 29515669 TI - New kids on the block in the ECMC and opportunities ?for early career members in 2018. AB - Opportunities for early career members to get involved in ERS activities in 2018 ?http://ow.ly/rmyd30hDBCN. PMID- 29515668 TI - An unusual presentation of a more common disease entity. AB - Beware unusual presentations of more common disease entities, as in this interactive case report http://ow.ly/qj7f30eVFsp. PMID- 29515671 TI - Radiology corner. PMID- 29515670 TI - Novel therapies for severe asthma in children and adults. AB - The heterogeneous nature of asthma requires personalised treatments. Monoclonal antibody treatments showed good efficacy, and should be considered when symptoms are poorly controlled despite good inhaler technique, compliance and controlled comorbidities. http://ow.ly/UWpg30hImQh. PMID- 29515673 TI - Confidences de Salon: Daiana Stolz. AB - ERS Education Council Chair, Daiana Stolz, gives an insight into her life http://ow.ly/NsOX30hSjSo. PMID- 29515672 TI - Assembly 3: Basic and Translational Sciences. AB - Meet @ERStalk Assembly 3: Basic and Translational Sciences http://ow.ly/66E830hFi7U. PMID- 29515674 TI - Bronchiectasis. AB - Bronchiectasis is a long-term lung condition. If you have bronchiectasis, your airways (tubes connecting your windpipe to the lowest part of the lungs) are wider than normal. This leads to mucus (or sputum) building up and making you more at risk of getting lung infections. PMID- 29515675 TI - Hydrogen-Borrowing Alcohol Bioamination with Coimmobilized Dehydrogenases. AB - The amination of alcohols is an important transformation in chemistry. The redox neutral (i.e., hydrogen-borrowing) asymmetric amination of alcohols is enabled by the combination of an alcohol dehydrogenase (ADH) with an amine dehydrogenase (AmDH). In this work, we enhanced the efficiency of hydrogen-borrowing biocatalytic amination by co-immobilizing both dehydrogenases on controlled porosity glass FeIII ion-affinity beads. The recyclability of the dual-enzyme system was demonstrated (5 cycles) with total turnover numbers of >4000 and >1000 for ADH and AmDH, respectively. A set of (S)-configured alcohol substrates was aminated with up to 95% conversion and >99%ee (R). Preparative-scale amination of (S)-phenylpropan-2-ol resulted in 90% conversion and 80% yield of the product in 24 h. PMID- 29515676 TI - DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. AB - Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients. Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data. Results: Among the 137 patients that later relapsed, patients with a CIMP- profile (n = 42) at initial diagnosis had an inferior overall survival (pOS5years 33%) compared to CIMP+ patients (n = 95, pOS5years 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors. Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL. PMID- 29515677 TI - Pharmacological inhibition of EZH2 disrupts the female germline epigenome. AB - Background: Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results: In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Surprisingly, once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Conclusion: Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring. PMID- 29515679 TI - Role of Diet in Influencing Rheumatoid Arthritis Disease Activity. AB - Background: Patients with Rheumatoid Arthritis (RA) frequently ask their doctors about which diets to follow, and even in the absence of advice from their physicians, many patients are undertaking various dietary interventions. Discussion: However, the role of dietary modifications in RA is not well understood. Several studies have tried to address these gaps in our understanding. Intestinal microbial modifications are being studied for the prevention and management of RA. Some benefits of vegan diet may be explained by antioxidant constituents, lactobacilli and fibre, and by potential changes in intestinal flora. Similarly, Mediterranean diet shows anti-inflammatory effects due to protective properties of omega-3 polyunsaturated fatty acids and vitamins, but also by influencing the gut microbiome. Gluten-free and elemental diets have been associated with some benefits in RA though the existing evidence is limited. Long-term intake of fish and other sources of long-chain polyunsaturated fatty acids are protective for development of RA. The benefits of fasting, anti-oxidant supplementation, flavanoids, and probiotics in RA are not clear. Vitamin D has been shown to influence autoimmunity and specifically decrease RA disease activity. The role of supplements such as fish oils and vitamin D should be explored in future trials to gain new insights in disease pathogenesis and develop RA-specific dietary recommendations. Conclusion: Specifically more research is needed to explore the association of diet and the gut microbiome and how this can influence RA disease activity. PMID- 29515678 TI - Pharmacognostical Sources of Popular Medicine To Treat Alzheimer's Disease. AB - Background: A large number of classical and recently discovered plants are indicated in preventing and/or treating Alzheimer's disease (AD). Objective: Name of plants with their anti-AD effects are important for their further use and investigation. Method: A short overview of AD is given; anti-Alzheimer plants are given in a Table. Results: Various medicinal plants are listed here as sources of popular medicines to be used in cases when patients are afraid of developing and/or suffer from AD. Some of these plants have been used for centuries. The major sources in the literature, over one hundred of references are given for plants that show beneficial effect on the progress of AD. Conclusion: Plant extracts are widely used addition to the synthetic drugs approved by various administrative authorities to stop/slow down the progress of symptoms of AD. PMID- 29515680 TI - Transosseous Suture Fixation of True 4-part Valgus Impacted Fractures of the Proximal Humerus: Clinical and Radiological Outcome in 49 Patients. AB - Background: The valgus-impacted (VI) 4-part fractures are a subset of fractures of the proximal humerus with a unique anatomic configuration characterized by a relatively lower incidence of avascular necrosis after operative intervention. Objectives: The present study reports the midterm clinical and radiological results of a large series of consecutive patients with 4-part VI fractures treated with a minimal invasive technique of internal fixation. Methods: Over a ten-year period (2004-2014), we treated 56 patients with a true 4-part valgus impacted fracture of the proximal part of the humerus. Four patients were lost to follow-up and three died, leaving 49 patients (33 female, 16 males, average age 60,1 years) available for the study. Fracture fixation was achieved through the lateral transdeltoid approach with transosseous suturing of the tuberosities to each other, to the metaphysis and to the articular part of the humeral head avoiding gross disimpaction of the humeral head from the valgus position. Functional outcome assessment was performed using the parameters of the Constant Murley score within a mean follow up period of 43,8 months (range, 24 to 115 months). Results: All fractures were united within the first 3 months except one that showed late displacement and finally nonunion. The median Constant score was 81,7 points and the functional score in comparison with the unaffected shoulder was 86.2%. There were three patients with total Avascular Necrosis (AVN) of the head revised to hemiarthroplasty. The nonunion case was revised to reverse shoulder arthroplasty 12 months after surgery. In five cases, absorption of the greater tuberosity was noted in the last radiographic control without any serious consequences to the shoulder function. Conclusion: Advantages of this minimally invasive technique can be summarized as shorter operative time, no use of hardware, minimal soft tissue damage, low incidence of avascular necrosis, stable osteosynthesis with "tension band effect" and adequate rotator cuff repair allowing for early joint motion. PMID- 29515681 TI - Visual Acuity Improvement in Continuous vs Divided Occlusion in Anisometropic Amblyopia. AB - Purpose: To compare visual acuity improvement between continuous and split part time occlusion for the treatment of moderate and severe anisometropic amblyopia. Methods: Randomised clinical trials in 6 - 13 y.o children with moderate and severe anisometropic amblyopia. Each patient was consecutively selected with continuous or split part-time occlusion. Best corrected visual acuity's improvement was followed up to six weeks and statistical data were analyzed using chi square and unpaired t-test. Results: Best corrected visual acuity's improvement was comparable between continuous and split part-time occlusion (0.20+/-0.27 vs 0.21+/-0.25; p = 0.79). Conclusion: Split part-time occlusion may be considered as an alternative treatment for moderate and severe anisometropic amblyopia treatment. PMID- 29515682 TI - A Review of Trend of Nursing Theories related Caregivers in Korea. AB - Background: The prevalence of chronic diseases has been rapidly increased due to population aging. As the duration of care needs increase, the caregivers' socioeconomic burdens have also increased. Objective: This review examines the attributes of caregiving experience and quality of life of caregivers in Korea with a focus on the application of nursing theory. Method: We reviewed studies on caregivers' caring for adult patients published till 2016 in 4 bio-medical research portal websites or data bases. A total of 1,939 studies were identified through the keyword search. One hundred forty five studies were selected by a process; of which, 17 studies were theory-applied. Selected studies were analyzed in accordance with the structured analysis format. Results: Quantitative studies accounted for 76.6%, while 22.1% were qualitative studies and 1.3% were triangulation studies. Caregiver-related studies increased after 2000. Most frequently, the caregivers were spouses (28.4%), and most frequently, care was provided to a recipient affected by stroke (22.5%). The 17 theory-based studies described 20 theories (70% psychology theories, 30% nursing theories). The most frequent nursing theory was the theory of stress, appraisal and coping. Conclusion: This study sought to better understand caregiving through the analysis of Korean studies on the caregiving experience and caregivers' QOL and this finding helped presenting empirical data for nursing by identifying the nursing theories applied to the caregiving experience and caregivers' QOL. The results suggest that the need for further expansion of nursing theories and their greater utilization in the studies of caregiving. PMID- 29515684 TI - Individualised patient profile: clinical utility of Flammer syndrome phenotype and general lessons for predictive, preventive and personalised medicine. AB - This case report introduces a female patient, who since her teenager age evidently suffers from Flammer syndrome (FS) as the clearly defined sub-optimal health condition. Further, the patient has experienced collateral pathological conditions which primarily might be linked to the family (genetic) predisposition, but the development of which could be synergistically promoted by the FS-phenotype. The facts are thoroughly analysed and consequent hypotheses are presented, which are indicative for highly desirable predictive diagnostics and targeted preventive measures to be created based on the accurate interpretation of the individualised patient profile. The authors emphasise the great clinical relevance of the FS and field-related research. PMID- 29515683 TI - Pregnancy-associated breast cancer: the risky status quo and new concepts of predictive medicine. AB - The paper is motivated by severe concerns regarding currently applied care of the pregnancy-associated breast cancer (PABC) characterised by particularly poor outcomes of the disease. Psychological and ethical aspects play a crucial role in PABC: the highest priority not to damage the foetus significantly complicates any treatment generally, and it is quite usual that patients disclaim undergoing any breast cancer treatment during pregnancy. Although, due to global demographic trends, PABC is far from appearing rarely now, severe societal and economic consequences of the disease are still neglected by currently applied reactive medical approach. These actualities require creating new strategies which should be better adapted to the needs of the society at large by advancing the PABC care based on predictive diagnostic approaches specifically in premenopausal women, innovative screening programmes focused on young female populations, targeted prevention in high-risk groups, and optimised treatment concepts. The article summarises the facts and provides recommendations to advance the field-related research and medical services specifically dedicated to the PABC care. PMID- 29515686 TI - Heart rate variability: the comparison between high tension and normal tension glaucoma. AB - Relevance: Vascular factors may be involved in the development of both high tension glaucoma (HTG) and normal tension (NTG) glaucoma; however, they may be not exactly the same. Autonomic dysfunction characterized by heart rate variability (HRV) is one of the possible reasons of decrease in mean ocular perfusion pressure (MOPP). Purpose: To compare the shift of the HRV parameters in NTG and HTG patients after a cold provocation test (CPT). Methods: MOPP, 24-hour blood pressure and HRV were studied in 30 NTG, 30 HTG patients, and 28 healthy subjects. The cardiovascular fitness assessment was made before and after the CPT. The direction and magnitude of the average group shifts of the HRV parameters after CPT were assessed using the method of comparing regression lines in order to reveal the difference between the groups. Results: MOPP and minimum daily diastolic blood pressure were decreased in HTG and NTG patients compared to healthy subjects. There was no difference in MOPP between HTG and NTG before the CPT. However, all HRV parameters reflected the predominance of sympathetic innervation in glaucoma patients compared to healthy subjects (P < 0.05).Before the CPT, the standard deviation of NN intervals (SDNN) of HRV was lower in HTG compared to NTG, 27.2 +/- 4.1 ms and 35.33 +/- 2.43 ms (P = 0.02), respectively. After the CPT, SDNN decreased in NTG by 1.7 ms and increased in HTG and healthy subjects by 5.0 ms and 7.09 ms, respectively (P < 0.05). The analysis of relative shift of other HRV parameters after the CPT also revealed a significant difference between NTG and HTG in regard to the predominance of sympathetic innervation in NTG compared to HTG. Conclusion: Patients with NTG have more pronounced disturbance of autonomic nervous system than HTG patients, which is manifested with the activation of sympathetic nervous system in response to CPT. This finding refers to the NTG pathogenesis and suggests the use of HRV assessment in glaucoma diagnosis and monitoring. PMID- 29515687 TI - Clinical and laboratory evaluation of microstructural changes in the physical, mechanical and chemical properties of dental filling materials under the influence of an electromagnetic field. AB - Restorative filling materials used for dental caries prevention and treatment consist of various components including monomers or oligomers, which play a significant role in forming the main structure of these materials, as well as in characterising their physical, mechanical and chemical properties. The necessity for the development and improvement of structural characteristics of polymeric dental filling materials intended for caries prevention and their life duration increase served as the initiating factor of our research. According to the research purpose and challenges, we studied the changes in the physical, mechanical and chemical properties of composite filling materials with and without electromagnetic field influence. The investigations in vivo include the study of microstructural features of polymeric filling materials by scanning electron microscopy (SEM) and the investigations in vitro include the study of sealed and extracted human teeth chips by using X-ray spectral analysis. We also evaluated the changes in the strength characteristics of dental filling materials with and without electromagnetic field influence. The analysis of the obtained data indicates the presence of structural changes in polymeric dental filling materials, including the material microstructure condensation confirmed by the SEM results, an increase in the strength and adhesion characteristics and certain regularities of the chemical elemental composition concentration change in the area of hard tooth tissue and dental filling material. These scientific data will provide tooth caries prevention and promote the increase of treatment quality. PMID- 29515685 TI - Optical coherence tomography in neuromyelitis optica spectrum disorders: potential advantages for individualized monitoring of progression and therapy. AB - Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing inflammatory disorders of the central nervous system (CNS). Optic neuritis (ON) is the first NMOSD-related clinical event in 55% of the patients, which causes damage to the optic nerve and leads to visual impairment. Retinal optical coherence tomography (OCT) has emerged as a promising method for diagnosis of NMOSD and potential individual monitoring of disease course and severity. OCT not only detects damage to the afferent visual system caused by ON but potentially also NMOSD-specific intraretinal pathology, i.e. astrocytopathy. This article summarizes retinal involvement in NMOSD and reviews OCT methods that could be used now and in the future, for differential diagnosis, for monitoring of disease course, and in clinical trials. PMID- 29515688 TI - High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model. AB - Background: Liver fibrosis (LF) is a chronic disease, associated with many collateral diseases including reproductive dysfunction. Although the normal liver has a large regenerative capacity the complications of LF could be severe and irreversible. Hormone and sex-related issues of LF development and interactions with male reproductive have not been finally studied. The aim was to study the reproductive function of male rats in experimental CCl4-induced liver fibrosis rat model, and the capability for restoration of both the liver and male reproduction system. Materials: Studies were conducted on 20 3-month old Wistar male rats. The experimental animals were injected with freshly prepared 50% olive oil solution of carbohydrate tetrachloride (CCl4). On the 8th week after injection we noted the manifestations of liver fibrosis. The rats were left to self-healing of the liver for 8 weeks. All male rats underwent ultrasound and biopsy of the liver and testes on the 8th and 16th weeks. The male rats were mated with healthy females before CCl4 injection, after modeling LF on the 8th week, and after self-healing of the liver. Pregnancy was monitored on ultrasound. Results: On the 8th week of experiment we observed ultrasound manifestation of advanced liver fibrosis, including hepatosplenomegaly, portal hypertension. Ultrasound exam of the rat testes showed testicular degeneration, hydrocele, fibrosis, scarring, petrifications, size reduction, and restriction of testicular descent; testes size decreased from 1.24 +/- 0.62 ml to 0.61 +/- 0.13, p < 0.01. Liver histology showed granular dystrophy of hepatocytes, necrotic areas, lipid inclusions in parenchyma. Rats with liver fibrosis demonstrated severe injury of the reproductive system and altering of fertility: the offspring of male rats with advanced LF was 4.71 +/- 0.53 born alive vs 9.55 +/- 0.47 born from mating with healthy males, p < 0.001. Eight weeks after last CCl4 injection, we revealed signs of liver regeneration, significant recovery of its structure. The ALT and AST levels significantly decreased and reached background measurements. As a result of the second interbreeding after liver self-healing no significant difference was found vs previous mating. Conclusion: Carbohydrate tetrachloride induces injury of liver parenchyma evoking fast and severe liver fibrosis, and is associated with irreversible structural and functional changes in testes, reducing fertility, decreasing potential pregnancy rate, and affecting its development. Liver showed high potential to regenerate, however the self restoring after liver fibrosis was not accompanied with recovery of the reproductive system. PMID- 29515690 TI - Implementation of personalized medicine in Central-Eastern Europe: pitfalls and potentials based on citizen's attitude. AB - Objective: Next-generation sequencing is increasingly utilized worldwide as a research and diagnostic tool and is anticipated to be implemented into everyday clinical practice. Since Central-Eastern European attitude toward genetic testing, especially broad genetic testing, is not well known, we performed a survey on this issue among Hungarian participants. Methods: A self-administered questionnaire was distributed among patients and patient relatives at our neurogenetic outpatient clinic. Members of the general population were also recruited via public media. We used chi-square testing and binary logistic regression to examine factors influencing attitude. Results: We identified a mixed attitude toward genetic testing. Access to physician consultation positively influenced attitude. A higher self-determined genetic familiarity score associated with higher perceived genetic influence score, which in turn associated with greater willingness to participate in genetic testing. Medical professionals constituted a skeptical group. Conclusions: We think that given the controversies and complexities of the next-generation sequencing field, the optimal clinical translation of NGS data should be performed in institutions which have the unique capability to provide interprofessional health education, transformative biomedical research, and crucial patient care. With optimization of the clinical translational process, improvement of genetic literacy may increase patient engagement and empowerment. Relevance of the article for predictive preventive and personalized medicine: The paper highlights that in countries with relatively low-genetic literacy, a special strategy is needed to enhance the implementation of personalized medicine. PMID- 29515691 TI - Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma. AB - Background: Immunotherapies that target immune-checkpoint molecules such PD-1 have helped to achieve durable responses in melanoma treatment. However, 25% of melanoma patients who showed objective responses to PD-1 blockade develop resistance and suffer from disease progression and ultimately death, which necessitates the identification of related resistance mechanisms.IL-34 is a cytokine that controls the biology of myeloid cell lineage through binding to CSF 1R. IL-34 is importantly involved in the pathogenesis of various diseases. In cancer, the expression of IL-34 has been suggested to associate with tumor growth, metastasis, angiogenesis, and therapeutic resistance such as in lung cancers and malignant pleural mesotheliomas. In this study, we evaluate the possible involvement of IL-34 in immunotherapeutic resistance. Case presentation: Melanoma resection species were obtained from a patient who developed a refractory melanoma against immunotherapy with Nivolumab, and stained with anti IL-34, anti-melanoma antigens and anti-CD163 antibody. Staining of these markers was compared between primary or metastatic refractory melanoma tissues. Immunohistochemistry staining of melanoma tissues showed an enhanced expression of IL-34 in metastatic refractory melanoma compared to primary melanoma tissues, which correlates with increased frequencies of CD163+ macrophages. Conclusion: We introduce for the first time a clinical case of a patient with metastatic refractory melanoma that acquired resistance to anti-PD-1 immunotherapy, showing an enhanced expression of IL-34 in refractory melanoma tissues. PMID- 29515693 TI - Endovenous Treatment for Acute Massive Pulmonary Thromboembolism. AB - Treatment for venous thromboembolic conditions differs significantly depending on whether the condition is acute or chronic. Endovenous treatment is now available for treating the most severe cases of acute massive pulmonary thromboembolism, and the goal is rapid central clot removal to relieve life-threatening pulmonary circulation. Endovenous catheter interventions include catheter-directed thrombolysis and catheter-assisted thrombus removal. The latter is divided into aspiration thrombectomy, fragmentation, and rheolytic thrombectomy. Data from cohort studies indicate that the clinical outcome and safety after open surgical treatment and endovenous treatment may be comparable. This paper reviews the current approaches to endovenous treatment for acute massive pulmonary thromboembolism, and presents our study of hybrid treatment using a combination of local fibrinolysis, mechanical fragmentation, and clot aspiration. PMID- 29515692 TI - Cardiovascular Disease in Patients with End-Stage Renal Disease on Hemodialysis. AB - Cardiovascular disease is a major concern for patients with end-stage renal disease (ESRD), especially those on hemodialysis. ESRD patients with coronary artery disease often do not have symptoms or present with atypical symptoms. Coronary lesions in ESRD patients are characterized by increased media thickness, infiltration and activation of macrophages, and marked calcification. Several studies showed worsened clinical outcomes after coronary revascularization, which were dependent on the severity of renal dysfunction. ESRD patients on hemodialysis have the most severe renal dysfunction; thus, the clinical outcomes are worse in these patients than in those with other types of renal dysfunction. Medications for primary or secondary cardiovascular prevention are also insufficient in ESRD patients. Efficacy of drug-eluting stents is inferior in ESRD patients, compared to the excellent outcomes observed in patients with normal renal function. Unsatisfactory outcomes with trials targeting cardiovascular disease in patients with ESRD emphasize a large potential to improve outcomes. Thus, optimal strategies for diagnosis, prevention, and management of cardiovascular disease should be modified in ESRD patients. PMID- 29515694 TI - Early and Mid-Term Outcomes Following TEVAR for Chronic Type B Aortic Dissection. AB - We examined the outcomes of aortic remodeling for chronic type B aortic dissection (cTBD) after thoracic endovascular aneurysm repair (TEVAR). Objective & Methods: Thirty-eight patients underwent TEVAR for cTBD at our institution. We classified cTBD patients into the early cTBD group (16 cases, 2 weeks-4 months from onset) and late cTBD group (22 cases, >4 months from onset). Results: There were no cases of paraplegia, stroke, and hospital death in both groups. There was no worsening of complicated cases. We achieved false lumen thrombosis in cases with a double-barreled thoracic aorta. The early cTBD group had more complete shrinkage cases (60%) than the late cTBD group (11%). Conclusion: We obtained favorable mid-term outcomes after TEVAR for cTBD patients. Early cTBD patients obtained good aortic remodeling with TEVAR. (This is a translation of Jpn J Vasc Surg 2016; 25: 233-239.). PMID- 29515689 TI - The crucial role of multiomic approach in cancer research and clinically relevant outcomes. AB - Cancer with heavily economic and social burden is the hot point in the field of medical research. Some remarkable achievements have been made; however, the exact mechanisms of tumor initiation and development remain unclear. Cancer is a complex, whole-body disease that involves multiple abnormalities in the levels of DNA, RNA, protein, metabolite and medical imaging. Biological omics including genomics, transcriptomics, proteomics, metabolomics and radiomics aims to systematically understand carcinogenesis in different biological levels, which is driving the shift of cancer research paradigm from single parameter model to multi-parameter systematical model. The rapid development of various omics technologies is driving one to conveniently get multi-omics data, which accelerates predictive, preventive and personalized medicine (PPPM) practice allowing prediction of response with substantially increased accuracy, stratification of particular patients and eventual personalization of medicine. This review article describes the methodology, advances, and clinically relevant outcomes of different "omics" technologies in cancer research, and especially emphasizes the importance and scientific merit of integrating multi-omics in cancer research and clinically relevant outcomes. PMID- 29515695 TI - Evaluation and Coil Embolization of the Aortic Side Branches for Prevention of Type II Endoleak after Endovascular Repair of Abdominal Aortic Aneurysm. AB - Objectives: Aneurysm shrinkage after EVAR is the strong factor of favorable outcomes after endovascular abdominal aortic aneurysm repair (EVAR), and type II endoleaks is the risk factor of no aneurysm shrinkage or aneurysm enlargement in the long term. In this study, we evaluate the aortic side branches relate to early postoperative type II endoleak, and performed coil embolization for those vessels for prevention of type II endoleak. Methods: Patency and diameter of aortic side branches including inferior mesenteric artery (IMA) and lumbar artery (LA) were evaluated in 56 consecutive patients with abdominal aortic aneurysm who were scheduled for EVAR. Coil embolization with Interlock was performed in 24 patients during EVAR for all patent IMA and LA with maximal diameter more than 2.0 mm. Computed tomography was performed one week after EVAR for evaluation of endoleak. Results: In patients with IMA more than 2.5 mm in diameter, the frequency of type II endoleak was approximately 90% regardless of the number of patent LA. In case with patent IMA less than 2.5 mm or with 2 or more patent LA larger than 2.0 mm, the frequency of type II endoleak was 46 to 67%. Coil embolization for IMA was successfully performed in 15/16 patients (94%). Coil embolization of LA was performed for patent LA larger than 2.0 mm and 29 out of 45 LA (64%) were successfully occluded. There was no perioperative complication associated with coil embolization. The frequency of type II endoleak was significantly lower in patients with coil embolization than those without coil embolization (4.2% vs 58.9%, p<0.0001). Conclusion: Patent IMA and LA in diameter larger than 2.0 mm were associated with type II endoleak one week after EVAR, and coil embolization with Interlock during EVAR is safe and effective procedure to prevent type II endoleak. (This is a translation of Jpn J Vasc Surg 2016; 25: 321 328.). PMID- 29515696 TI - Outcomes of Extended Endovascular Aortic Repair for Aorto-Iliac Aneurysm with Internal Iliac Artery Occlusion. AB - Objective: Patients of aorto-iliac aneurysms who undergo endovascular aortic repair (EVAR) require internal iliac artery (IIA) occlusion with coil embolization and its coverage with the stent graft to prevent type II endoleak after extending the endograft into the external iliac artery. However, it has become well recognized that IIA occlusion cause buttock claudication and other various sequelae due to pelvic ischemia. We retrospectively analyzed IIA occlusion outcomes. Methods: From October 2008 to February 2015, 71 patients with aorto-iliac aneurysms underwent IIA occlusion prior to EVAR. The relationship between pelvic circulation and symptom of pelvic ischemia was studied. Results: Buttock claudication occurred in 17 patients (22.9%) of all. Eight patients (14.8%) in unilateral IIA occlusion group (54 patients) and nine patients (52.9%) in bilateral IIA group (17 patients) had sequelae of claudication. The sacrifice of the communication of superior gluteal artery (SGA) and inferior gluteal artery (IGA) led to buttock claudication in 18 (64.3%) of 28 limbs. Instead, only 4 of 60 limbs had buttock claudication, when we preserved the communication between SGA and IGA. In all patients, staged treatment of aorto-iliac aneurysms with IIA occlusion and EVAR were done successfully without pelvic ischemic complications except for buttock claudication, and postoperative CT scanning showed no endoleakage. Conclusion: IIA occlusion prior to EVAR is recognized as a safe and reasonable strategy. It is emphasized that preservation of the communication of SGA and IGA is important to prevent buttock claudication. (This is a translation of Jpn J Vasc Surg 2016; 25: 240-245.). PMID- 29515697 TI - Asymptomatic Isolated Calf Deep Vein Thrombosis: Does It Worsen after Varicose Vein Surgery? AB - In our varicose vein center, on a trial basis, among the patients with asymptomatic calf deep vein thrombosis (CDVT) we carefully selected the patients for varicose vein surgery using the requirements as follows; 1) the patients had varicose veins with incompetent saphenous veins, 2) sequential examination including DUS confirmed stability and clinical insignificance of asymptomatic CDVT, 3) the patients do not have any risk factors for DVT such as a coagulation profile disorder (antithrombin deficiency, protein C deficiency, protein S deficiency, or antiphospholipid syndrome) or malignancies, 4) surgery is possible under local anesthesia alone, and 5) the patients can understand the concept of asymptomatic CDVT and undergo the surgery on their own will and informed consent. The patients who fulfilled these conditions underwent the varicose vein surgery. Twenty-eight patients with 30 limbs with varicose veins had asymptomatic CDVT, found by preoperative duplex ultrasonography (DUS). Among CDVT, 91% of CDVT existed in the soleal veins. After the diagnosis of the asymptomatic CDVT, serial DUS was performed and showed no changes in the status of the thrombus. Then varicose vein surgery (high ligation of the saphenous junctions either with or without stripping of the saphenous veins) was performed. After the surgery, the CDVT was re-evaluated by DUS. In 27 limbs, CDVT did not show any changes in the status of the thrombus, and in 3 limbs the CDVT was partially resolved. These data suggest that, at least, as far as the patients fulfilled these conditions, varicose vein surgery did not worsen the asymptomatic CDVT. (This is a translation of Jpn J Phlebol 2016; 27: 405-412.). PMID- 29515698 TI - Management of Pulmonary Thromboembolism Based on Severity and Vulnerability to Thrombolysis. AB - Background: The incidence of pulmonary thromboembolism has been considered rare in Japan. However, its occurrence has been increasing because of westernized lifestyle and diet, increased diagnostic technique, and recognition of this disease. Method: Between January 2003 and September 2014, 179 patients were treated for pulmonary thromboembolism. We classified these patients into 3 groups; Massive (n=35), Sub-massive (n=29) and Nonmassive (n=115) and retrospectively reviewed the treatment options and the outcome. Results: Percutaneous cardiopulmonary support (PCPS) was applied for patients with hemodynamic instability and IVC filter was inserted if there was proximal DVT. In non-massive group (n=115), 95.7% of the patient underwent anticoagulant therapy and 47.0% of the patients received IVC filter. In submassive group (n=29), 48.3% of the patient received thrombolytic therapy and 93.1% of the patient underwent IVC filter insertion. Surgical pulmonary embolectomy was performed in 3 patients who had high risk of thrombolytic therapy in submassive group. There was no death in this group. In massive group, 4 patients who had cardiogenic shock died in acute phase. PCPS was applied in 5 patients, pulmonary embolectomy was performed in 13 patients, thrombolytic therapy was performed in 4 patients and 13 patients underwent anticoagulant therapy alone. There were 7 deaths (20.0%) in this group. Conclusions: In submassive group, treatment should be decided depending on the bleeding risk. In massive group, pulmonary embolectomy was effective. (This is a translation of Jpn J Phlebol 2016; 27: 53-59.). PMID- 29515699 TI - Predictive Factors for Post-Ischemic Compartment Syndrome in Non-Traumatic Acute Limb Ischemia in a Lower Extremity. AB - Objective: Compartment syndrome (CS) is serious complication following revascularization of acute limb ischemia (ALI). However, predictive factors associated with CS remain unclear. This study aimed to identify these predictive factors. Materials and Methods: Twenty-two patients who presented with non traumatic ALI between November 2013 and October 2015 were enrolled and monitored for CS in this prospective cohort study. Predictive factors were compared between the CS and non-CS groups. Results: There were 5 patients in the CS group and 17 patients in the non-CS group. Four predictive factors were associated with CS: (1) inadequate backflow (80% and 12% in the CS and non-CS groups, respectively; P=.001); (2) serum creatine kinase (CK) level (20,683 U/L and 911 U/L in the CS and non-CS groups, respectively; P<.001); (3) positive fluid balance after admission (4,324 mL and 1,223 mL in the CS and non-CS groups, respectively; P<.001); and (4) Rutherford category IIB (100% and 18% in the CS and non-CS groups, respectively; P=.0002). Conclusion: Inadequate backflow, high serum CK level, positive fluid balance, and advanced-stage ALI were associated with CS. This information may be useful in identification of high-risk patients for CS prevention and in early detection of CS following the revascularization procedure. PMID- 29515700 TI - Use of Negative Pressure Wound Therapy for Lower Limb Bypass Incisions. AB - Objective: The use of negative pressure wound therapy (NPWT) for post-surgical cardiothoracic, orthopedic, plastic, and obstetric and gynecologic procedures has been described. However, there are no data regarding its use for lower limb bypass incisions. We aimed to investigate the outcomes of NPWT in preventing surgical site infection (SSI) in patients with lower limb arterial bypass incisions. Materials and Methods: We retrospectively used data of 42 patients who underwent lower limb arterial bypass with reversed great saphenous vein between March 2014 and June 2016 and compared conventional wound therapy and NPWT with regard to preventing SSI. Results: Twenty-eight (67%) patients underwent conventional wound therapy and 14 (33%) underwent NPWT. There were no statistical differences regarding patient characteristics and mean SSI risk scores between the two patient groups (13.7% for conventional wound therapy vs. 13.4% for NPWT; P=0.831). In the conventional group, nine instances of SSI (32%) and three (11%) of these required subsequent surgical wound debridement, whereas in the NPWT group, there was no SSI incidence (P=0.019). Secondary outcomes such as the length of hospital stay, 30-day readmission rate, and need for secondary vascular procedures were not statistically different between the two groups. Conclusion: The use of NPWT for lower limb arterial bypass incisions is superior to that of conventional wound therapy because it may prevent SSIs. PMID- 29515702 TI - Mid-Term Report on the Safety and Effectiveness of Endovenous Radiofrequency Ablation for Varicose Veins. AB - Objective: Endovenous radiofrequency ablation (RFA), a relatively new technique for treating great saphenous varicose veins, is less invasive compared with stripping surgery. This study examined the mid-term safety and effectiveness of RFA for varicose veins. Materials and Methods: We enrolled 104 patients (147 limbs) who underwent RFA for varicose veins of the lower extremities (females, 67; 64.4%). The mean age was 68.9+/-9.2 years (39-85 years). In 121 limbs (82.3%), there were great saphenous veins. All patients were observed as outpatients for 12 months after the procedure. RFA was performed using ClosureFastTM catheters with tumescent local anesthesia. Results: There was 99.4% occlusion of the treated veins, and partial recanalization was observed in one limb. Endovenous heat-induced thrombosis (EHIT) was identified in five limbs (3.4%). All EHITs were class 1 according to the Kabnick classification, and they disappeared within 1 month of the intervention without antithrombotic therapy. No other major complications were observed. Mean venous clinical severity scores improved from 5.31 at the baseline to 1.10, 0.39, 0.14, and 0.06 at 1, 3, 6, and 12 months, respectively. Conclusion: RFA is a safe and effective strategy for varicose veins of the lower extremities. PMID- 29515701 TI - Cryopreserved Human Allografts for the Reconstruction of Aortic and Peripheral Prosthetic Graft Infection. AB - Background: This study aimed to present cases with cryopreserved human allografts (CHAs) for vascular reconstruction in both aortic and peripheral infected prosthetic grafts. Materials and Methods: This is a single center, observational descriptive study with retrospective analysis. In all cases, the infected prosthetic graft material was completely removed. At discharge, patients were administered anticoagulants. Follow-up examinations included clinical visits, echo-color-Doppler ultrasounds, or computed tomography angiography within 30 days and at 3, 6, and 12 months after the treatment, and then twice per year. Results: We treated 21 patients (90% men, n=19) with the mean age of 71+/-12 years and mean interval between the initial operation and replacement with CHA of 30 months [range, 1-216; interquartile range (IQR), 2-36]. In-hospital mortality was 14% (n=3); no CHA-related complication led to death. Limb salvage was 100%. No patient was lost at the median follow-up of 14 months (range, 2-61; IQR, 6-39). No rupture, aneurysmal degeneration, or re-infection occurred. Estimated freedom from CHA-related adverse events (95% confidence interval, 43-63) was 95% at 3 years. Conclusion: In our experience, CHAs are a viable option for prosthetic graft infections and provide satisfactory clinical results and favorable stability because of a very low rate of CHA-related adverse events during follow up. PMID- 29515703 TI - Management of Arterial Injury in Children with Supracondylar Fracture of the Humerus and a Pulseless Hand. AB - Objective: To share our experience regarding the management of arterial injuries in children with pulseless hand secondary to supracondylar fracture of the humerus (SFH). Patients and Methods: All consecutive children with pulseless hands after SFH who were being treated in the vascular surgery units of the Combined Military Hospital, Lahore and Peshawar between September 2011 and September 2016 were included. The type of fracture, mode and pattern of injury, time from injury to definitive treatment, operative treatment, and complications were recorded. Results: There were 55 [82% (n=45) male and 18% (n=10) female] patients with pulseless hand and SFH [Gartland type III: 18% (n=10) and IV: 82% (n=45)]. The hand was cold in 38.1% (n=21) patients and warm in 61.8% (n=34). The most common mode of injury was accidental fall [45% (n=25)], and the mean time from injury to presentation was 4+/-2.5 hours (mean+/-standard deviation). Overall, 71% (n=39) patients underwent vascular reconstruction: autologous interposition venous grafting was performed in 49% (n=19) and segmental resection and primary anastomosis in 25% (n=10) of the cases. There were no cases with amputation, fasciotomy, re-exploration, or long-term ischemic sequel. Conclusion: Immediate vascular exploration is the treatment of choice for cold, pulseless hand. A similar approach should be adopted for warm, pulseless hand if there is no immediate return of pulse. PMID- 29515704 TI - Assessment of the Safety and Efficacy of Edoxaban for the Treatment of Venous Thromboembolism Secondary to Active Malignancy. AB - Objective: To assess the safety and efficacy of edoxaban for the treatment of venous thromboembolism (VTE) secondary to active malignancy. Materials and Methods: We enrolled 48 patients with newly diagnosed VTE secondary to active malignancy that was treated with oral edoxaban for 1 year between September 2014 and August 2015. We retrospectively examined the presence or absence of recurrent symptomatic VTE, VTE-related mortality, and bleeding events. Results: No recurrent symptomatic VTE or VTE-related deaths were recorded, enabling efficient assessment. Treatment safety was determined based on the reports of bleeding. Bleeding was reported in two patients, with serious bleeding in one of them. Conclusion: Edoxaban is safe and effective for the treatment of VTE secondary to active malignancy. PMID- 29515705 TI - Natural History and Chronological Growth Rate of Renal Artery Aneurysms. AB - Objective: Renal artery aneurysm (RAA) is an uncommon disease, the natural course of which is still not well known. The objective of this study is to define factors that affect the growth rate of RAAs. Materials and Methods: We retrospectively reviewed 32 aneurysms in 26 patients at our institute between January 2010 and March 2016. Basal demographics, comorbidities, reason for diagnosis, and details of the aneurysms and interventions were recorded. The chronological changes in the diameter of the RAA using multiplanar reconstructions of computed tomography images were measured and analyzed. Results: The baseline mean diameter was 20.1+/-8.4 mm (range: 9.9-41). The mean follow-up period was 3.13+/-2.1 y (range: 0.5-7.1). The median growth rate was 0.35 mm/y (interquartile range: 0.05, 0.62). The growth rate was slower when the initial diameter was <20 mm than when it was >20 mm (p=0.036). Also, whole completed calcification was a significant factor for slower growth (p=0.016). We performed ex-vivo surgery in two cases and coil packing with stenting in one. No ruptures occurred during the study period. Conclusion: Our results suggest that cases with an RAA diameter <20 mm do not require intervention. The interval period can be longer in whole-completed calcification types. PMID- 29515706 TI - Pretreatment with the Free Radical Scavenger Edaravone Mitigates Kidney Glycogen Depletion and Neutrophil Infiltration after Leg Ischemia in a Rat Model: A Pilot Study. AB - Objective: We have previously shown that pretreatment with the free radical scavenger edaravone (Radicut(r), Mitsubishi Tanabe Pharma Co., Japan) mitigated skeletal muscle damage due to ischemia reperfusion. In this study, we sought to validate its use in an experimental model of myonephropathic-metabolic syndrome (MNMS). Methods: Either edaravone (3.0 mg/kg; edaravone group; n=4) or saline (saline group; n=6) was intraperitoneally injected into male Lewis rats (508+/-31 g). Normal kidneys were harvested as control (n=3). MNMS was induced by bilaterally clamping the common femoral arteries for 5 h and declamping 5 h later. Kidney damage was evaluated by quantifying Periodic Acid Schiff (PAS) positive area (glycogen storage) and esterase-positive cells (neutrophil infiltration). Results: The PAS-positive area in the saline group was significantly lower than that in the normal group (36.9+/-2.6 vs. 66.9+/-1.2%, P<0.01); the PAS-positive area in the edaravone group remained comparable to that in the normal group (52.9+/-0.9%, P<0.01). Esterase-positive cells in the saline group were significantly higher than in normal kidneys (62.4+/-5.6 vs. 17.5+/-2.4 cells/mm2, P<0.01), while they were significantly reduced in the edaravone group (32.8+/-5.7 cells/mm2, P<0.01). Conclusion: Edaravone pretreatment mitigates MNMS induced kidney damage by reducing both glycogen depletion and neutrophil infiltration. PMID- 29515707 TI - Infrarenal Abdominal Aortic Pseudoaneurysm: Is It a Real Emergency? AB - Abdominal aortic pseudoaneurysm is a rare but life-threatening condition that occurs due to penetrating or blunt trauma. Clinical manifestations are variable, and the time interval from the initial trauma to diagnosis is variable. A prompt diagnosis and an aggressive management approach are required to avoid catastrophic complications. Possible treatment options are open surgical repair, endovascular repair, pseudoanerysmal sac thrombosis induction through direct thrombin injection, and coil embolization. Here, we present the case of a 75-year old man affected by an infrarenal abdominal aortic pseudoaneurysm presenting with abdominal and lumbar pain for 3 days, who was successfully treated with an endograft. PMID- 29515708 TI - An Endovascular Strategy for Occlusion or Stenosis with Severe Calcification in the Non-Stenting Zone, creatinG Lumens And SlitS with Crosser in Unique Technique (GLASS CUT): A Case Report. AB - In treating non-stenting zones (NSZs), such as the common femoral artery (CFA) and popliteal artery (PA), the best method to treat severely calcified NSZ lesions remains controversial. Here we describe a new method for the treatment of severely calcified PA and CFA lesions using the Crosser(r) system (CS). After the first wire passed the lesion, the CS was passed through the other wire to create new cracks and lumens (NCAL) in both cases. After creating NCAL around the lumen of the first wire, a large scoring balloon was inflated to crush the severe calcification like a "GLASS CUT" with a glass knife. PMID- 29515709 TI - Visualization of Recanalized Coronary Occlusion with Dissection by Optical Frequency Domain Imaging. AB - A 43-year-old asymptomatic male patient with a positive stress myocardial perfusion imaging result was admitted to our institution. Although no organic lesion was detected by 64-row coronary computed tomography angiography (CCTA), invasive coronary angiography revealed a unique anatomy with a long lesion in the middle of the left anterior descending artery. Optical frequency domain imaging (OFDI) demonstrated the details of the recanalized occlusion with coronary dissection. OFDI provides in vivo coronary images with high spatial resolution and better three-dimensional reconstructions and supports invasive coronary angiography to elucidate infinitesimal and complicated intraluminal morphology that might be missed by CCTA alone. PMID- 29515710 TI - A Simple Reproducible Method to Treat Acute or Subacute Arterial Obstruction When the Thrombus Is Adherent to the Arterial Wall. AB - We report three consecutive patients with limb ischemia, where symptoms appeared several days to weeks prior to presentation. In all cases, initial over-the-wire thrombectomy failed due to adherence of the thrombus to the arterial wall. We adopted a new approach of stretching the whole obstructed segment by a series of ballooning using a percutaneous transluminal angioplasty (PTA) catheter. A subsequent thrombectomy was successful in all three cases. No further intervention, such as stenting or bypass surgery, was required. The adhering thrombus was dissected by stretching the arterial wall at the site of obstruction. PMID- 29515711 TI - Successful Percutaneous Retrieval of IVC Filter with Wide Retroperitoneal Penetration Presenting with Gastrointestinal Bleeding. AB - Symptomatic penetration of the retroperitoneal structures by inferior vena cava (IVC) filter is a rare clinical entity. Vast majority of these patients require laparotomy and open retrieval of the filter. We report a case of a filter penetrating into the duodenum within two months of implantation resulting in gastrointestinal bleeding. The patient was successfully managed with percutaneous retrieval of the filter, blood transfusion and serial abdominal examination thus avoiding laparotomy. PMID- 29515712 TI - Jetstream XC Device for Treatment of Long Viabahn Stents Occlusions in the Superficial Femoral Artery: A Report of Two Cases. AB - Repeated restenotic events are common in superficial femoral artery and as of late, Viabahn stent grafts have been FDA (U.S. Food & Drug Administration) approved. Viabahn have been particularly attractive given that they provided a physical barrier for the development of neointimal hyperplasia. This particular feature however, also underscores one of the main limitations of the therapy; providing a physical barrier of collateral circulation and predisposing to acute limb ischemia. Viabahn endograft thrombosis is characterized by stent edge stenosis and endograft thrombosis. Here we present 2 cases of Viabahn graft thrombosis successfully treated with the Jetstream atherectomy device, a rotational cutter with aspiration capacity. PMID- 29515713 TI - Bilateral External Iliac Artery Dissection in a Middle-Aged Male Athlete. AB - We present the case of a bilateral external iliac artery (EIA) dissection in a 44 year-old male athlete. The patient was referred to our department for right lower abdominal pain without claudication during single squatting. His athletic history included participation in approximately five athletic events per year. Contrast enhanced computed tomography (CT) revealed bilateral EIA dissection and right renal infarction. Following medical treatment for his hypertension and considering his medical history, a bilateral EIA replacement with 8-mm Dacron straight grafts was performed on the 24th day after hospital admission. Postoperative contrast-enhanced CT revealed good bilateral graft patency and perfusion following surgery. PMID- 29515714 TI - 8th Asian PAD Workshop. PMID- 29515716 TI - CONTENTS OF VOLUME 10, 2017. PMID- 29515718 TI - Experiences of nurses on the critical shortage of medical equipment at a rural district hospital in South Africa: a qualitative study. AB - Introduction: Medical equipment is an essential health intervention tool used by nurses for prevention, diagnosis and treatment of disease and for rehabilitation of patients. However, access to functioning medical equipment is a challenge in low- and middle-income countries. The World Health Organization estimated that 50 to 80 percent of medical equipment in developing countries is not working, creating a barrier to the ability of the health system to deliver health services to patients. This study explored and described the lived experiences of nurses working at a district hospital with a critical shortage of medical equipment. Methods: A qualitative, exploratory, phenomenological and descriptive study design was used. A purposive sampling was used to select participants and due to saturation of data 14 nurses participated in the study. Research ethics were observed. Data was collected through semi-structured interviews using an interview guide. Interviews were audio-taped and field notes were taken. Voice recordings were transcribed verbatim and Tesch's open coding method was used for data analysis. Findings were confirmed by an independent coder. Results: Critical shortage of medical equipment at the hospital occurred in the form of unavailability of equipment, low quality and poor maintenance of the few that were available. Shortage impacted negatively on nursing care, nursing profession and the hospital. Conclusion: Nurses should be provided with functional medical equipment in order to provide quality nursing care. Management, leadership and governance structures should be strengthened to ensure that procurement and maintenance plans for medical equipment are developed and implemented. PMID- 29515717 TI - A UNIFIED FRAMEWORK FOR VARIANCE COMPONENT ESTIMATION WITH SUMMARY STATISTICS IN GENOME-WIDE ASSOCIATION STUDIES. AB - Linear mixed models (LMMs) are among the most commonly used tools for genetic association studies. However, the standard method for estimating variance components in LMMs-the restricted maximum likelihood estimation method (REML) suffers from several important drawbacks: REML requires individual-level genotypes and phenotypes from all samples in the study, is computationally slow, and produces downward-biased estimates in case control studies. To remedy these drawbacks, we present an alternative framework for variance component estimation, which we refer to as MQS. MQS is based on the method of moments (MoM) and the minimal norm quadratic unbiased estimation (MINQUE) criterion, and brings two seemingly unrelated methods-the renowned Haseman-Elston (HE) regression and the recent LD score regression (LDSC)-into the same unified statistical framework. With this new framework, we provide an alternative but mathematically equivalent form of HE that allows for the use of summary statistics. We provide an exact estimation form of LDSC to yield unbiased and statistically more efficient estimates. A key feature of our method is its ability to pair marginal z-scores computed using all samples with SNP correlation information computed using a small random subset of individuals (or individuals from a proper reference panel), while capable of producing estimates that can be almost as accurate as if both quantities are computed using the full data. As a result, our method produces unbiased and statistically efficient estimates, and makes use of summary statistics, while it is computationally efficient for large data sets. Using simulations and applications to 37 phenotypes from 8 real data sets, we illustrate the benefits of our method for estimating and partitioning SNP heritability in population studies as well as for heritability estimation in family studies. Our method is implemented in the GEMMA software package, freely available at www.xzlab.org/software.html. PMID- 29515719 TI - Factors associated with cholera in Kenya, 2008-2013. AB - Introduction: Kenya experienced widespread cholera outbreaks in 1997-1999 and 2007-2010. The re-emergence of cholera in Kenya in 2015 indicates that cholera remains a public health threat. Understanding past outbreaks is important for preventing future outbreaks. This study investigated the relationship between cholera occurrence in Kenya and various environmental and demographic factors related to water, sanitation, socio-economic status, education, urbanization and availability of health facilities during the time period 2008-2013. Methods: The primary outcome analyzed was the number of cholera cases at the district level, obtained from the Kenya Ministry of Health's national cholera surveillance records. Values of independent variables were obtained from the 2009 Kenya Population and Housing Census and other national surveys. The data were analyzed using a zero-inflated negative binomial regression model. Results: Multivariate analysis indicated that the risk of cholera was associated with open defecation, use of unimproved water sources, poverty headcount ratio and the number of health facilities per 100,000 population (p < 0.05). No statistically significant association was found between cholera occurrence and education, percentage of population living in urban areas or population density. Conclusion: The Sustainable Development Goals and Kenya's blueprint for development, Kenya Vision 2030, call for access to sanitation facilities and clean water for all by 2030. Kenya has made important economic strides in recent years but continues to be affected by diseases like cholera that are associated with low socio-economic status. Further expansion of access to sanitation facilities and clean water is necessary for preventing cholera in Kenya. PMID- 29515720 TI - [Bean's syndrome in children: about two cases]. AB - Diffuse angiomatosis or Bean's syndrome is a rare disease characterized by venous malformations mainly involving the skin and the digestive tract which can result in hemorrhage of variable severity. This study reports the case of two children aged 5 and 9 and a half years respectively with diffuse angiomatosis who had been treated in the Department of Emergency Paediatric Surgery over the years. The diagnosis was based on rectal bleeding and/or melenas causing severe anemia requiring regular transfusions in both patients as well as skin angiomas occurrence at the level of the limbs. Radiological evaluation showed the presence of multiple lesions at the level of the jejunum and ileum consistent with small intestinal angiomatosis in the child aged 9 and a half years. It didn't show abdominal lesions in the child aged 5 years. The two patients were admitted to the operating block. Angiomas were surgically individualized. Some of them were actively bleeding. Enterotomy was performed. Postoperative sequelae was marked by the stop of the bleedings. This study aims to update the current understanding of this rare pathology as well as the benefit of surgical treatment in controlling the complications caused by this pathology and in reducing the frequency of transfusions. PMID- 29515721 TI - [Initial manifestation and atypical site for metastatic synovial sarcoma in an immunocompetent adult patient: about a case and literature review]. AB - Synovial sarcoma (SS) is a rare tumor. It is characterized by various sites of occurrence but rarely involves the chest. The tumor may be wrongly diagnosed as benign due to its slow growth. Less than 10% of patients present with metastatic cancer. Endobronchial metastases are exceptional. Immunohistochemical examination and cytogenetic analysis allow to distinguish it from other mesenchymal tumors. The presence of SYT-SSX fusion transcript allows the diagnosis. Surgery is used for localized tumors that can be treated with radiation therapy while chemiotherapy is used for metastatic tumors. The average rate of locoregional or metastatic recurrence two years after SS is 50%. We report the case of a 28-year old patient with metastatic SS characterized by its uncommon metastatic site. He presented with endobronchial metastasis revealing his disease, that had evolved for more than 2 years. The SS is life-threatening due to its slow and insidious growth. Prognosis is guarded. This study aimed to emphasize this atypical site for metastatic synovial sarcoma as well as to insist on the role of early diagnosis and treatment. PMID- 29515722 TI - [Xanthelasmoid mastocytosis: a rare form of cutaneous mastocytosis]. AB - Mastocytosis is a rare disease characterized by the abnormal accumulation of mast cells in the skin and possibly in other organs. It can occur in a variety of forms; xanthelasmoid mastocytosis(XM) is a very rare form classified as papulo nodular. Clinically, it appears as buff-yellow soft papules or nodules of variable size. Triggerings are those of classic mastocytosis. Darier's sign is often absent. Histology shows dense infiltrate of mast cells in the deep dermis. This clinical form can be singled out because of the persistence of lesions beyond puberty without the additional risk of systemic involvement. We here report the case of a 18-month old female infant, with no previous medical history. Maculopapular, intensely pruritic, ovalaires, brownish lesions with a buff-yellow centre, with elastic consistency and different sizes first occurred at the age of 8 months. The initial interview of parents revealed that the infant had had episode of flush especially caused by warmth. Darrier's sign was negative. Skin biopsy showed dermal infiltrate of mast cells, allowing to retain the diagnosis of xanthelasmoid mastocytosis. Complementary examinations as well as trypsin dosage were normal. Treatment was based on the exclusion of drugs and of factors participating in mast cells degranulation and antihistamines. PMID- 29515723 TI - [Celiac disease in adult patients revealed by polyserositis: about a case]. AB - Celiac disease (CD) is an autoimmune disease affecting multiple organs. It often presents as gastrointestinal manifestations associated with malabsorption. However, serosa involvement uncommonly reveals this enteropathy, making the diagnosis difficult. We here report the case of JA, aged 63 years, admitted to hospital to detect the cause of malabsorption syndrome associated with polyserositis signs including pleurisy, pericarditis, ascites and hydrocephalus. The diagnosis of CD was based on endoscopic signs without serology tests. Patient's evolution was partially favorable, due to lack of compliance with a gluten-free diet. Our study reports the first case of CD revealed by polyserositis. CD should be suspected in patients with malabsorption syndrome, in the absence of evocative signs. PMID- 29515724 TI - A case report of a giant appendiceal mucocele and literature review. AB - A 43-year-old female presented at the accident and emergency department of Princess Marina Hospital, Gaborone, Botswana. She reported a deep dull aching pain of two years duration in the right iliac fossa that has been progressively becoming worse. Ultrasound revealed a large sausage like cystic mass extending from the pelvis up to the medial aspect of the ascending colon. CT scan showed a large sausage like cystic mass extending from the pelvis up to the hepatic flexure of the colon with the cecum displaced. No metastatic features were seen. We made an impression of appendiceal mucocele. A semi-elective laparotomy was scheduled. Intraoperative findings: a giant intact cystic distended appendix with involved base, displacing the cecum cranially. A right hemicolectomy was performed. The histopathological results revealed a low-grade appendicular mucinous neoplasm with no lymph node involvement. The surgical margins were free. The patient recovered uneventfully. PMID- 29515725 TI - [Soft tissue melanoma: a clinical case]. AB - Soft tissue melanoma was first described by Enzinger in 1965 under the name of clear cell sarcoma. In 1983, Chung and Enzinger renamed it soft tissue melanoma due to its immunohistochemical similarities with melanoma. We here report the case of a 22-year old young man with this rare type of melanoma, presenting with molluscoid lesion on his ankle without any clinical sign of malignancy. Histology examination confirmed the diagnosis of soft tissue melanoma. PMID- 29515726 TI - Comparison of two doses of hypobaric bupivacaine in unilateral spinal anesthesia for hip fracture surgery: 5 mg versus 7.5 mg. AB - Introduction: Hip fracture is a frequent and severe disease. Its prognosis depends on the perioperative hemodynamic stability which can be preserved by the unilateral spinal anesthesia especially with low doses of local anesthetics. This study aims to compare the efficacy and hemodynamic stability of two doses of hypobaric bupivacaine (7.5 mg vs 5 mg) in unilateral spinal anesthesia. Methods: In this prospective, randomized, double-blind study, 108 patients scheduled for hip fracture surgery under unilateral spinal anesthesia were enrolled to receive either 5 mg (group 1) or 7.5 mg (group 2) of hypobaric bupivacaine. Spinal anesthesia was performed in lateral position. Patients' socio-demographic characteristics, hemodynamic profile, sensory and motor blocks parameters were recorded. Results: Both groups were comparable regarding to demographic data. Two cases of failure occurred in group 1 and one case in group 2 corresponding to a comparable efficiency rates (96.29% and 98.14% respectively; p = 0.5). A higher mean onset and lower mean regression times of sensory block were significantly noted in group 1 (7.79+/-3.76 min vs 5.75+/-2.35 min, p < 0.001 and 91.29+/-31.55 min vs 112.77+/-18.77 min, p <0.001 respectively). Incidence of bilateralization (29.62% vs 87.03%, p < 0.001), incidence of hypotensive episodes (59.25% vs 92.59%, p < 0.001) and vascular loading (1481.48+/-411.65 ml vs 2111.11+/-596.10 ml, p < 0.001) were significantly higher in group 2. Conclusion: The dosage of 5mg of hypobaric bupivacaine in unilateral spinal anesthesia is as effective as the dosage of 7.5 mg with lower bilateralization incidence and better hemodynamic stability. PMID- 29515727 TI - Prevalence and determinants of diarrhoea among infants in selected primary health centres in Kaduna north local government area, Nigeria. AB - Introduction: Despite efforts toward the prevention and management of diarrhoea, associated mortality among infants has remained high in Northern Nigeria. This study was designed to determine the prevalence and identify determinants of diarrhoea among infants in Kaduna North Local Government Area (KNLGA), Nigeria. Methods: In a cross-sectional survey 630 mothers of infants attending three primary health care centers were interviewed. Data was collected on socio-demo graphic characteristics, infant care practices, infant diarrhoea history and mothers knowledge of causes, symptoms and management of diarrhea. Data were analyzed using descriptive statistics, Chi-square, and logistic regression tests at 5% level of significance. Results: Mothers' mean age was 27+/-5.5 years and 46.1% had secondary education. Infants' mean age was 22.4+/- 12.8 weeks and 50% were females. Prevalence of diarrhoea in the two weeks preceding the study was 21.1%. Only 11.7% of mothers had poor knowledge of diarrhoea. About 76.3% of mothers always washed their hands with soap after cleaning infants' perineum. Majority of infants (84.6%) completed age appropriate immunization while 31.6% were exclusively breastfed. Infants whose mothers sometimes (OR=2.32; 95% CI: 1.4 3.87) or never washed (OR=2.64; 95% CI: 1.19-5.82) their hands with soap after cleaning the infants perineumand those with incomplete age appropriate immunization (OR=1.87, 95% CI: 1.2-2.896) were more likely to have diarrhoea. Conclusion: Promotion of hygiene and nutrition education for mothers particularly on proper infant feeding practices, hand washing practices and complete immunization of infants is needed to address the diarrhea determinants. PMID- 29515728 TI - Rare hereditary cause of chronic pancreatitis in a young male: SPINK1 mutation. AB - Hereditary chronic pancreatitis associated with a mutation in the serine protease inhibitor, Kazal Type-1 (SPINK-1 gene) is extremely rare. The SPINK1 mutation results in trypsinogen activation which predisposes to chronic pancreatitis predominately when combined with CFTR gene mutations. It presents as either chronic or recurrent acute pancreatitis. Symptom control and management of complications is important. Active surveillance with cross-sectional imaging for pancreatic malignancy in individuals with hereditary pancreatitis is advocated due to individuals being high risk. We present an unusual case of a young male who initially presented with renal colic and was incidentally diagnosed with severe chronic pancreatitis on abdominal imaging, with genetic testing confirming a homozygous SPINK1 mutation. PMID- 29515729 TI - [Bullous pemphigoid and Parkinson's disease: about a case]. AB - Bullous pemphigoid (BP) is an organ-specific autoimmune disease which can be associated with many pathologies including degenerative neurological diseases such as Parkinson's and Alzheimer's disease. Studies have suggested the possibility of cross-immune responses through "epitope spreading". Bullous dermatosis has been reported to be secondary to neurological disease, at intervals ranging from a few months to a maximum of a few years. Then is it an unusual association or a causation? It has been suggested that drug consumption, decubitus lesions, traumatic events as well as reduced immunity can be triggers for BP in patients with neurological disease. We report the case of a 93-year old patient with a 10-year history of advanced Parkinson's disease, hospitalized for the treatment of a common bullous pemphigoid confirmed by histology and immunohistochemistry. The patient was treated with oral corticosteroids. After a week of treatment, the patient died due to septic shock. Neurological disorders represent a real risk factor for BP. BP could be considered as a marker for neurological disorder. These associations are of broad interest, because they can play a role in the etiopathogenesis of BP and contribute to a complete understanding of the causes of these neurodegenerative diseases. PMID- 29515730 TI - Full median sternotomy approach for treatment of upper thoracic vertebral tuberculosis in a developing country: case report and short literature review. AB - Direct anterior approach to the cervicothoracic spine (C7-T4) poses a technical challenge in neurosurgery, due to the presence of important neurovascular structures anterior to the cervicothoracic junction (CTJ). Median Sternotomy approach is a surgical option that allows for direct anterior exposure of the lower cervical and upper thoracic vertebrae. We report the first case from Ghana, West Africa of a young man who developed post-tuberculosis osteomyelitis of upper thoracic (T1-2) vertebrae with cord compression after spinal tuberculosis in childhood. He underwent a full median Sternotomy for Anterior Decompression and Fusion of C7-T2 with autologous iliac crest bone graft. We detail our operative procedure and review the relevant literature. PMID- 29515731 TI - [Pseudotumor cerebri revealing sarcoidosis]. AB - Sarcoidosis is a multivisceral granulomatosis of unknown aetiology which may have various clinical and radiological manifestations. Cerebral sarcoidosis, although rare, can appears as a misleading pseudotumor. We report the case of a young Tunisian adult hospitalized for intracranial hypertension associated with pseudotumoral lesion on radiology, which was revealed to be systemic sarcoidosis. PMID- 29515732 TI - [Gallbladder agenesis: about three cases]. AB - Gallbladder agenesis is a rare congenital anomaly. This study aimed to highlight the epidemiological aspects of this condition as well as the peculiarities of its diagnostic and therapeutic management through three case reports. Two adults were admitted to Hospital with hepatic colics and dyspepsia. Ultrasound showed multilithiasic scleroatrophic vesicle. In one of the two patients, CT scan results showed a stone at the level of scleroatrophic vesicle. These two patients were wrongly operated for vesicular lithiasis by using conventional method. The absence of gallbladder was detected during surgery. In order to confirm post operative diagnosis, the first patient underwent biliary MRI. The other patient was lost to follow-up. The third patient was a 13-year old child hospitalized with acute pancreatitis. Vesicular agenesis was suspected based on its scannographic aspect and then confirmed using biliary MRI. This patient didn't underwent surgery. PMID- 29515733 TI - [Pleural and lung metastasis from degenerated multiple adenofibromas: about a case]. AB - Multiple adenofibromas or adenofibromatosis is characterized by the presence of at least 3 mono- or bilateral adenofibromas increasing significantly in size, causing trophic disorders. We report the case of a 46-year old female patient who had been followed up since she was 30 years old for bilateral adenofibromatosis that required 4 surgical procedures. Patient's medical data were collected in the Department of Respiratory Diseases at the Ibn Rochd University Hospital Center, Casablanca. Basing on preoperative assessment before bilateral mastectomy, the patient underwent chest X-ray that showed opaque right hemithorax exerting compression on the mediastinum. Clinical examination showed effusion syndrome in the right hemithorax and left supraclavicular cervical adenopathy. Pleural puncture biopsy confirmed the presence of poorly differentiated invasive carcinoma in the pleura, supporting breast origin. Bronchoscopy after pleural puncture objectified infiltration of the whole bronchial tree; biopsies confirmed the anatomopathological results. The recommended treatment strategy was based on multidrug chemotherapy. Patient's evolution was marked by the occurrence of hepatic metastases. This study shows that adenofibromas require regular monitoring given the risk of trasformation to breast cancer, which is a frequent cause of pleuropulmonary metastases. PMID- 29515734 TI - [Post-traumatic scleromalacia]. AB - We here report the case of a 18-year old patient who was referred for evaluation of pigmented subconjunctival tumor of the left eye mimicking uveal melanoma. The patient reported that the lesion had evolved rapidly during the previous months. Eye exam showed prominent dark brown lesion adjacent to the limbus between 3 and 9 hours, measuring 10 mm x 6 mm (A). Ultrasonographic biomicroscopy revealed cystic structure communicating with the vitreous cavity, suggesting the diagnosis of uveal hernia rather of melanoma. During a more thorough interview, the patient reported that he had undergone transfixing keratoplasty for cloudy patch secondary to blunt trauma from stone's throw dating back 10 years. We assumed that the scleral wall had been damaged, leading to the development of scleromalacia with uveal hernia. The patient had recently had an acute episode of vomiting which could have lead to an increase in lesion size. The patient was followed up for several weeks, during which the lesion was stable. The patient underwent surgery with successful uveal tissue reintegration and sclera closure (B). PMID- 29515735 TI - An unusual localisation of a superficial angiomyxoma. PMID- 29515736 TI - Estimation of seroprevalence of HIV, hepatitis B and C virus and syphilis among blood donors in the hospital of Aioun, Mauritania. AB - Introduction: To estimating the seroprevalence of HIV, hepatitis B, hepatitis C and syphilis among blood donors in the Aioun hospital. Methods: This is a retrospective study from 1 January 2010 to 31 December 2015. Results: On the five year study period, 1,123 donors were collected. Of these, 182 were HIV-positive, an overall prevalence of 16.2% with predominance in male with a sex ratio Man/Woman of 5.2. The average age of donors was 32.7 +/- 10 years (range 17-73 years). The most represented that age group 21-30 years (40.5%). The seroprevalence found were 1.2% for HIV, 11.8% for HBV, HCV 0.2% and 3% for syphilis. Co-infection was found in 0.7% of which 0.5% of dual HIV HBV/Syphilis and 0.2% in HBV/HIV. Conclusion: The transmission of infectious agents related to transfusion represents the greatest threat to transfusion safety of the recipient. Therefore, a rigorous selection and screening of blood donors are highly recommended to ensure blood safety for the recipient. PMID- 29515737 TI - [Lipoblastoma detected in older children: an unusual case and literature review]. AB - Lipoblastoma is a relatively rare benign tumor. It derives from embryonic white fat cells. It almost exclusively affects children less than 3 years of age. We report a case of lipoblastoma of the left thigh detected in an older child (11 years) and a literature review. Diagnosis was based on histology while surgical treatment was based on total resection of the mass. The postoperative course was simple with a follow-up period of 9 months. PMID- 29515738 TI - Factors leading to dyspepsia in renal transplant recipients. AB - Introduction: Renal transplantation is the definitive treatment for end stage renal disease. Patients subjected to transplantation require lifelong immunosuppression and are prone to several gastrointestinal disorders. Dyspepsia is a common disorder in these patients. The objective of this study was to determine factors leading to dyspepsia in renal (kidney) transplant recipients. Methods: It was a cross sectional study conducted at department of hepatogastroenterology and transplant sciences, SIUT Karachi, from 1-6-15 to 1-12 15 for six months. All renal transplanted patients having dyspeptic symptoms for more than 6 weeks. EGD was performed, biopsy specimens obtained from antrum and duodenum, these were sent for histopathological examination. Frequency and percentages were obtained for categorical variables, mean +/- SD was calculated for continuous variables. Chi square test was used for categorical variable and student t-test for continuous variables. Results: Ninety patients were included in the study out of which 64 (71.1%) were males, mean age was 35.82 +/- 10.04 years (range: 18-65 years). Gastritis (non H.pylori associated) in 78 (78.6%), duodenitis in 35 (38.9%) and H. pylori infection in 29 (32.2%), renal transplant recipients. Most of the patients belonged to Sindhi ethnicity, 27 (30%), followed by Punjabi. Hypertension was the most common co-morbid condition in our patients found in 29 (32.2%), while most of them don't have any co morbid condition. Duodenitis was found to be associated with tacrolimus use (p = 0.037). Conclusion: Gastritis is the most common factor accountable for this symptoms, followed by duodenitis and H. Pylori. Patients taking tacrolimus as immunosuppressant are more prone to develop duodenitis. PMID- 29515739 TI - Patterns and presentations of colorectal cancer at Komfo-Anokye teaching hospital Kumasi, Ghana. AB - Introduction: Colorectal cancer is a major cause of morbidity and mortality globally and its incidence is increasing in developing countries. This study determined the incidence, clinical features and the histopathological patterns of colorectal cancer at Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana. Methods: A retrospective review of all colorectal cancer cases over a six year period from (2009-2015) presented to the Surgical and Oncological Department of KATH. Patients' records were retrieved and information on their demographics, clinical and pathological presentations recorded. Results: In all, 221 cases of colorectal cancer were identified over the study period. The mean age was 54 +/- 16.8 and ranged from 16 to 90 years. Sixteen (7.24%) had family history of cancer and the prevalence of comorbidities was (24.89%). The commonest clinical symptoms presented were weight loss (44.80%), bleeding per rectum (39.82%) and abdominal pain (38.91%) Majority of the patients presented with rectal cancers (48.87%). Microscopically, adenocarcinoma (68.33%) was the most common histopathological type. According to Tumour Node Metastasis (TNM) staging of cancer, majority of the patients 89(40.27%) were identified as being in late stage (TNM Stage III). The overall crude annual incidence was 4.62 per 100000 populations. The age specific standardized incidence rate was 7.93 per 100,000 population. Conclusion: This study has clearly showed a high incidence in colorectal cancer at KATH, with similar trends in clinico-pathological patterns comparable to that of most African countries. These include predominance of rectal cancers, high incidence among younger people and delayed presentation of the disease at advanced stage. PMID- 29515741 TI - [Meningococcal infections associated with febrile purpura among children hospitalized in a Moroccan Hospital: incidence and associated clinical factors]. AB - Introduction: Febrile purpura (FP) is suggestive of meningococcal disease, requiring almost always further investigations and a treatment based on broad spectrum antibiotics. This study aimed to determine the incidence of meningococcal infections as well as their associated clinical signs in children with febrile purpura hospitalized in the emergency department. Methods: We conducted a descriptive, retrospective study in the pediatric emergency department at the Children's Hospital of Casablanca over a period of 3 years. The hospitalized children with FP who had undergone bloodculture, whether or not associated with lumbar puncture, were included in the study. Statistical analysis was performed using SPSS v.16 software. Results: We enrolled 96 children, 49 boys and 47 girls. The average age was 53.3 +/- 40.5 months. Mean body temperature was 38.9 degrees C. Meningococcal infection was diagnosed in 35/96 children. The diagnosis of meningococcemia was retained in 22 children, associated with meningitis in four patients. Symptoms and physical signs significantly associated with meningococcal infection included lethargy (p = 0.04), convulsions (p = 0.01) and purpura occurring outside the skin area drained by the superior vena cava (p = 0.01). Conclusion: FP occurring outside the skin area drained by the superior vena cava or associated with convulsions is srongly related to meningococcal infection, whose incidence seems to be high among Moroccan children. PMID- 29515740 TI - Factors influencing uptake of intermittent preventive treatment of malaria in pregnancy using sulphadoxine pyrimethamine in Sunyani Municipality, Ghana. AB - Introduction: Malaria continues to pose a public health challenge in Ghana particularly in pregnant women. Ghana adopted intermittent preventive treatment of malaria in pregnancy policy using sulphadoxine pyrimethamine. Despite its implementation, its coverage still remains low. This study sought to investigate factors that influence the uptake of intermittent preventive treatment of malaria in pregnancy in the Sunyani Municipality. Methods: This was a cross sectional study which employed a quantitative method. The study was conducted in five selected facilities in the Sunyani Municipality within the period of January to June 2015. Structured questionnaires were administered to 400 pregnant women randomly sampled from antenatal clinics of selected health facilities. Descriptive, bivariate and multivariate analysis of quantitative data was done using Stata12. Results: A total of 400 pregnant women at 36 weeks or more gestational age were studied. The study revealed that 98.5% of the pregnant women received at least one (1) dose of sulphadoxine pyrimethamine during the current pregnancy with 71% receiving optimal (at least 3 doses) doses of sulphadoxine pyrimethamine for intermittent preventive treatment of malaria in pregnancy at the time of study. The study revealed that women who attended ANC >=4 times (Adjusted OR = 4.7, 95% CI 1.31-17.2), knowledge of malaria in pregnancy (Adjusted OR = 2.2, 95% CI 1.03-4.62) and knowledge of intermittent preventive treatment for malaria in pregnancy (Adjusted OR = 1.8, 95% CI 1.15-2.96) were found to be positively associated with the uptake of optimal doses of sulphadoxine pyrimethamine. Conclusion: This study has demonstrated that having a good knowledge of malaria in pregnancy and intermittent preventive treatment of malaria in pregnancy can significantly influence the uptake of optimal doses of sulphadoxine pyrimethamine. Encouraging women to attend antenatal care regularly (at least four visits) could also increase the optimal uptake of sulphadoxine pyrimethamine. PMID- 29515742 TI - [Morgagnian cataract]. AB - Cataract is a total or partial clouding of the lens of the eye. It can be congenital or acquired. Cataract associated with the aging process (senile) is the most common type. Common symptoms include visual impairment which varies based on the type and the density of lens opacity. Cataracts etiology is varied and treatment is based on surgery. In patients with morgagnian cataract cortex liquefies and lens core hardens and becomes cloudy. We here report the case of a 51-year old patient with no notable medical history presenting with progressive decreased visual acuity in the left eye with no pain or redness of the eye associated. Ophthalmologic examination showed visual acuity (the individual can see hand movement), clear cornea, normal anterior chamber depth, an intraocular pressure of 15 mmgh and morgagnian cataract. The patient underwent phacoemulsification cataract surgery with implantation within the capsular bag. Post-operative suites were simple. PMID- 29515743 TI - ? AB - Introduction: This study aimed to evaluate the daily consumption of milk products in a population of Moroccan children and to determine the factors influencing this consumption. Methods: We conducted a prospective study from 1 October 2013 to 31 April 2014. Children aged between 2 and 16 years were included in the study. The participants were recruited in the city of Fez. Data were collected using a frequency questionnaire. Enrolled parents and children were interviewed on their consumption of milk products and on sociodemographic factors. Children underwent anthropometric examination. The association between variables in milk products consumption was analyzed using univariate and multivariate analysis with logistic regression model. Results: Food survey involved 286 children: 151 girls (52.8%) and 131 boys (45.8%). Children aged 2 to 3 years accounted for 26.4%, those aged 4 to 7 years accounted for 28.9%, those aged 7 to 9 years accounted for 18.3% and adolescents aged 10 to 16 years accounted for 26.4%. Children consumed on average 2.5+/-1 milk products per day. 57.8% of children aged 2 to 3 years, 53.6% of children aged 4 to 6 years, 40% of children aged 7 to 9 years and 41.2% of children aged 10 to 16 years consumed at least 3 milk products per day. The factors associated with the consumption of at least three milk products per day in univariate analysis were an illiterate maternal education level p < 0.001 OR= 0.1 and an elementary maternal education level p = 0.002 OR = 0.1, a medium familial socio-economic status p < 0.001 OR = 3, age p = 0.01 OR = 0.9 and a normal body mass index p = 0.01 OR = 2.5 and > 90 degrees percentiles p < 0.001 OR= 6. There was a positive correlation between a body mass index > 90 degrees percentiles p= 0.01 OR = 3.9 and the quantity of consumed milk products while there was a negative correlation between a body mass index > 90 degrees percentiles p = 0.01 OR = 3.9 and a low maternal schooling: illiterate p = 0.008 OR= 0.1 elementary p = 0.009 OR = 0.1. Conclusion: The consumption of milk and of other milk products was inappropriate in particular among children aged 7 to 9 years and adolescents aged 10 to 16 years. Low maternal schooling and a body mass index higher than 90 degrees percentiles were factors independently associated with the consumption of less than 3 milk products per day. The awareness of parents and children about the role of the milk and its derivatives in children diet is essential. PMID- 29515744 TI - ? AB - The delivery of a macrosomic infant is a relatively common situation. It can put mother and fetus at high risk. The main maternal complications are the increase in cesarean rates, postpartum hemorrhage and cervicovaginal traumatic lacerations. The main fetal complication is shoulder dystocia increasing the risk of brachial plexus. The objective was to identify risk factors and maternal-fetal complications associated with fetal macrosomia. Comparative retrospective study conducted at Kairouan University Hospital maternity unit in 2010. We compared a group of 820 cases of macrosomic infants to a control group of 800 cases of infants born in the same period of time. During the study period we collected clinical data of 820 macrosomic cases on a total of 7.495 deliveries, corresponding to a total incidence of 10.94%. Several factors predisposing to fetal macrosomia were highlighted: Maternal age> 35 years was present in 28.5% of cases; Maternal obesity was found in 45% of cases; A personal history of macrosomia was noted in 28,8% of cases; Prolonged pregnancies > 41 weeks of amenorrhoea was noted in 35.6% of cases; Multiparity was found in 47% of cases. Maternal complications were essentially postpartum hemorrhage: 71 cases and genital traumas: 24 cases. Perinatal complications were dominated by shoulder dystocia: 27 cases (3.3%). Traumatic postpartum complications were found in 11.6%. PMID- 29515746 TI - [Unusual macrocystic lymphatic malformation in an adult patient]. AB - Macrocystic lymphatic malformations (MLMs) constitute a circumscribed variation in deep lymphangiomas. They are characterized by a rare occurrence in adults, by their rapid expansion and by their frequent occurrence at the level of the cervicofacial region (75%) and axillary region (20%). They rarely occur in lower limbs. The diagnosis of MLMs is primarily based on clinical examination. Ultrasound has a valuable role in positive diagnosis and sometimes in differential diagnosis. MRI has a role in the diagnosis and the assessment of tumor extent, thus making a valuable contribution to surgery. Therapeutically, MLMs are mainly treated by sclerotherapy; surgery is rarely indicated. We report the case of 26-year old man with a one-year history of huge painless and rapidly evolving subcutaneous swelling in the right thigh. Clinical examination showed circumferential compressible non-beating infiltrated mass, surmounted by vegetative and ulcerated lesions. The remainder of the clinical examination showed the presence of inguinal ipsilateral lymphadenopathy, with mobility limitation of the right knee. Angio-MRI objectified diffuse heterogeneous gadolinium-enhancing cutaneous, subcutaneous thickening of the right thigh with perimuscolar aponeurotic involvement. Lymphoscintigraphy showed asymmetry of the accumultion of radiopharmaceutical kinetics that was reduced in the right lower limb in favor of an overload of the lymphatic system at rest. Given the clinico radiological data, the diagnosis of MLM was retained. Given the seat of the lymphangioma and its extent, after consultation with the surgeons there was no indication for surgery. Immobilization with a removable bandage was indicated for our patient. PMID- 29515745 TI - [Occult hepatitis B reactivation in a patient with homozygous sickle cell disease: clinical case and literature review]. AB - Occult Hepatitis B corresponds to the presence of hepatitis B virus deoxyribonucleic acid (HBV-DNA) in serum and/or in liver of a patient despite HBsAg negativity. Clinically, it is usually asymptomatic. Its reactivation is rare and commonly occurs in immunosuppressed individuals. We report the case of a 21-year old patient from Senegal, with homozygous sickle cell disease, presenting with cholestatic jaundice. Laboratory tests showed reactivation of occult Hepatitis B. This study emphasizes the need to systematically investigate the presence of occult Hepatitis B in patients with sickle cell disease suffering from acute liver disease. PMID- 29515747 TI - Assessment of three medical and research laboratories using WHO AFRO_SLIPTA Quality Standards in Southwestern Uganda: a long way to go. AB - Introduction: While the laboratory represents more than 70% of clinical diagnosis and patient management, access to reliable and quality laboratory diagnostics in sub-Saharan Africa remains a challenge. To gain knowledge and suggest evidence based interventions towards laboratory improvement in Southwestern Uganda, we assessed the baseline laboratory quality standards in three medical and research laboratories in Southwestern Uganda. Methods: We conducted a cross sectional survey from October, 2013 to April, 2014. Selected laboratories, including one private research, one private for profit and one public laboratory, were assessed using the WHO AFRO_SLIPTA checklist and baseline scores were determined. Results: The three laboratories assessed met basic facility requirements, had trained personnel, and safety measures in place. Sample reception was properly designed and executed with a well designated chain of custody. All laboratories had sufficient equipment for the nature of work they were involved in. However, we found that standard operating procedures were incomplete in all three laboratories, lack of quality audit schemes by two laboratories and only one laboratory enrolled into external quality assurance schemes. The SLIPTA scores were one star for the research laboratory and no star for both the public and private-for-profit laboratories. Conclusion: While most of the laboratory systems were in place, the low scores obtained by the assessed laboratories reflect the need for improvement to reach standards of quality assured diagnostics in the region. Therefore, routine mentorship and regional supportive supervision are necessary to increase the quality of laboratory services. PMID- 29515748 TI - A rare case of important and recurrent abnormal uterine bleeding in a post partum woman caused by cavernous hemangioma: a case report and review of literature. AB - The cavernous hemangioma is a rare benign vascular tumor. About 50 cases of this disease were found in the literature over the last century and only 9 cases of cavernous hemangioma on the pregnant uterus were published it comes into cavernous or capillary form. The symptomatology is not unequivocal and when it occurs during pregnancy or postpartum, it causes life-threatening cataclysmic hemorrhage. Antenatal diagnosis is difficult and requires a multidisciplinary approach with pathologists, radiologists and gynecologists to avoid these complications or unnecessary hysterectomies. The diagnosis is histological. Hysterectomy is possible after failure of conservative treatment means. We report a rare case, a novel mixed cavernous hemangioma of the body associated with a capillary hemangioma of the cervix in a patient of 28 years 5th visors with recurrent genital bleeding in the postpartum period leading to a hysterectomy. PMID- 29515749 TI - Low humoral responses to human cytomegalovirus is associated with immunological treatment failure among HIV infected patients on highly active antiretroviral therapy. AB - Human cytomegalovirus (HCMV) is one of the opportunistic infections associated with significant morbidity and mortality among HIV/AIDS patients especially before introduction of antiretroviral therapy (ART). Little is known regarding the humoral immune response against HCMV in relation to CD4 counts among HIV infected individuals. A total of 90 achieved sera from HIV infected patients attending Bugando Medical centre care and treatment centre (CTC) aged 18 years and above were retrieved and analyzed. Sociodemographic data were collected using structured data collection tool. Detection of specific HCMV antibodies was done using Indirect Enzyme Linked Immunosorbent Assay (ELISA). Data were analyzed by using STATA version 11. A total of 90 HIV infected patients were enrolled in the study whereby 36(40%) had immunological treatment failure. The mean age of the study participants was 39+/-12.3 years. The Prevalence of specific HCMV IgG antibodies was 84(93.3%, 95% CI: 88-98.5) while the prevalence of specific HCMV IgM antibodies was 2(2.3% 95% CI: 0.8-5.4). The median CD4 counts at 6 months and 12 months on HAART were significantly high in treatment success group. At 12 months of HAART as CD4 counts increases the HCMV IgG index value was also found to increase significantly, p=0.04. Significant proportion of HIV infected individuals was infected with HCMV. Higher median HCMV IgG titers were observed among patients with immunological treatment success. There is a need to investigate humoral immune responses in HIV infected individuals in relation to CD4 counts against various infectious diseases in developing countries where most of these infections are endemic. PMID- 29515750 TI - [Ankylosing spondylitis associated with Still's disease: should it be considered a pathophysiologic link or a simple association?] AB - Ankylosing spondylitis is a chronic inflammatory rheumatism; it is part of the group of spondyloarthrites. General signs such as fever and weight loss are of little importance. Adult Still's disease is a rare systemic condition, a diagnosis of exclusion commonly characterized by high hectic fever, rash, arthritis and various systemic manifestations. Few cases of ankylosing spondylitis associated with adult Still's disease have been described in the literature. We here report the case of a 31-year old patient followed up for ankylosing spondylitis presenting with fever which had lasted for a long time and clinico-biological signs compatible with adult Still's disease. A possible pathophysiologic link between the two diseases may be suggested, even if their simultaneous occurrence has been rarely reported in the literature. PMID- 29515751 TI - Topical Ivermectin: Data Supporting Dual Modes of Action in Rosacea. AB - Until recently, the potential modes of action of topical ivermectin in rosacea have been speculated but not studied. Short-term studies (12 week), long-term studies (up to 52 weeks), and case report series have now been completed, and topical ivermectin (IVM), formulated as a 1% cream that is applied once daily, has been shown to be effective, well-tolerated, and safe for the treatment of rosacea. This article reviews outcomes from studies that support dual modes of action, including both anti-inflammatory and anti-parasitic effects. PMID- 29515752 TI - PET Imaging of Cardiac Hypoxia: Hitting Hypoxia Where It Hurts. AB - Purpose of Review: In this review, we outline the potential for hypoxia imaging as a diagnostic and prognostic tool in cardiology. We describe the lead hypoxia PET radiotracers currently in development and propose a rationale for how they should most appropriately be screened and validated. Recent Findings: While the majority of hypoxia imaging agents has been developed for oncology, the requirements for hypoxia imaging in cardiology are different. Recent work suggests that the bis(thiosemicarbazone) family of compounds may be capable of detecting the subtle degrees of hypoxia associated with cardiovascular syndromes, and that they have the potential to be "tuned" to provide different tracers for different applications. Summary: New tracers currently in development show significant promise for imaging evolving cardiovascular disease. Fundamental to their exploitation is their careful, considered validation and characterization so that the information they provide delivers the greatest prognostic insight achievable. PMID- 29515753 TI - Effect of the diet type and temperature on the C. elegans transcriptome. AB - The transcriptomes of model organisms have been defined under specific laboratory growth conditions. The standard protocol for Caenorhabditis elegans growth and maintenance is 20 degrees C on an Escherichia coli diet. Temperatures ranging from 15 degrees C to 25 degrees C or feeding with other species of bacteria are considered physiological conditions, but the effect of these conditions on the worm transcriptome has not been well characterized. Here, we compare the global gene expression profile for the reference Caenorhabditis elegans strain (N2) grown at 15 degrees C, 20 degrees C, and 25 degrees C on two different diets, Escherichia coli and Bacillus subtilis. When C. elegans were fed E. coli and the growth temperature was increased, we observed an enhancement of defense response pathways and down-regulation of genes associated with metabolic functions. However, when C. elegans were fed B. subtilis and the growth temperature was increased, the nematodes exhibited a decrease in defense response pathways and an enhancement of expression of genes associated with metabolic functions. Our results show that C. elegans undergo significant metabolic and defense response changes when the maintenance temperature fluctuates within the physiological range and that the degree of pathogenicity of the bacterial diet can further alter the worm transcriptome. PMID- 29515754 TI - Age-related changes in expression and signaling of TAM receptor inflammatory regulators in monocytes. AB - The multifactorial immune deterioration in aging--termed "inflamm-aging"--is comprised of a state of low-grade, chronic inflammation and complex dysregulation of responses to immune stimulation. The TAM family (Tyro 3, Axl, and Mer) of receptor tyrosine kinases are negative regulators of Toll like receptor-mediated immune responses that broadly inhibit cytokine receptor cascades to inhibit inflammation. Here we demonstrate elevated expression of TAM receptors in monocytes of older adults, and an age-dependent difference in signaling mediator AKT resulting in dysregulated responses to signaling though Mer. Our results may be especially significant in tissue, where levels of Mer are highest, and may present avenues for modulation of chronic tissue inflammation noted in aging. PMID- 29515755 TI - CGEF-1 regulates mTORC1 signaling during adult longevity and stress response in C. elegans. AB - The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this study, we demonstrate that CGEF-1, the C. elegans homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in C. elegans. cgef-1 mutants display prolonged lifespan and enhanced stress resistance. The transcription factors DAF-16/FoxO and SKN-1/Nrf are required for increased longevity and stress tolerance, and induce protective gene expression in cgef-1 mutants. Genetic evidence indicates that cgef-1 functions in the same pathway with rheb-1, the mTOR kinase let-363, and daf-15/Raptor. When cgef-1 is inactivated, phosphorylation of 4E-BP, a central mTORC1 substrate for protein translation is reduced in C. elegans. Moreover, autophagy is increased upon cgef 1 and mTORC1 inhibition. In addition, we show that in human cells Dbl associates with Rheb and stimulates mTORC1 downstream targets for protein synthesis suggesting that the function of CGEF-1/Dbl in the mTORC1 signaling pathway is evolutionarily conserved. These findings have important implications for mTOR functions and signaling mechanisms in aging and age-related diseases. PMID- 29515756 TI - Overexpression of Cu-Zn SOD in Brucella abortus suppresses bacterial intracellular replication via down-regulation of Sar1 activity. AB - Brucella Cu-Zn superoxide dismutase (Cu-Zn SOD) is a periplasmic protein, and immunization of mice with recombinant Cu-Zn SOD protein confers protection against Brucella abortus infection. However, the role of Cu-Zn SOD during the process of Brucella infection remains unknown. Here, we report that Cu-Zn SOD is secreted into culture medium and is translocated into host cells independent of type IV secretion systems (T4SS). Furthermore, co-immunoprecipitation and immunofluorescence studies reveal that Brucella abortus Cu-Zn SOD interacts with the small GTPase Sar1. Overexpression of Cu-Zn SOD in Brucella abortus inhibits bacterial intracellular growth by abolishing Sar1 activity in a manner independent of reactive oxygen species (ROS) production. PMID- 29515757 TI - SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents. AB - While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied human pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of gammaH2AX confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data from The Cancer Genome Atlas, we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) were associated with extended patient survival specifically when treated with platinum containing regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens. PMID- 29515758 TI - Expression of TDRD9 in a subset of lung carcinomas by CpG island hypomethylation protects from DNA damage. AB - Tudor domain containing protein 9 (TDRD9) is a RNA helicase normally expressed in the germline, where it is involved in the biosynthesis of PIWI-interacting RNAs (piRNAs). Here, we show that TDRD9 is highly expressed in a subset of non-small cell lung carcinomas and derived cell lines by hypomethylation of its CpG island. Furthermore, TDRD9 expression is associated with poor prognosis in lung adenocarcinoma. We find that downregulation of TDRD9 expression in TDRD9-positive cell lines causes a decrease in cell proliferation, S-phase cell cycle arrest, and apoptosis. Transcriptomic analysis demonstrated that TDRD9 knockdown causes upregulation of cell cycle and DNA repair genes. We also observed that TDRD9 knockdown triggers activation of the catalytic subunit of the DNA dependent protein kinase (DNA-PKcs) and phosphorylation of H2A.X, which are indicative of an increase of DNA double strand breaks. TDRD9-silenced cells also presented aberrant mitosis and abnormal-shaped nuclei indicating defects in chromosomal segregation. Finally, TDRD9 silencing caused hypersensitivity to the replication stress inducer aphidicolin, while overexpression of the protein increased resistance to the drug, suggesting that TDRD9 protects from replicative stress to TDRD9-positive tumor cells. Thus, our results place TDRD9 as a marker for prognosis and as a potential therapeutic target in a subset of lung carcinomas. PMID- 29515759 TI - NFAT-mediated defects in erythropoiesis cause anemia in Il2-/- mice. AB - The role of NFAT family transcription factors in erythropoiesis is so far unknown, although their involvement has been suggested previously. We have shown recently that Il2-/- mice develop severe anemia due to defects in KLF1 activity during BM erythropoiesis. Although, KLF1 activity is indispensable for erythropoiesis, the molecular details of Klf1 expression have not yet been elucidated. Here we show that an enhanced NFATc1 activity induced by increased integrin-cAMP signaling plays a critical role in the dysregulation of Klf1 expression and thereby cause anemia in Il2-/- mice. Interestingly, enhanced NFATc1 activity augmented apoptosis of immature erythrocytes in Il2-/- mice. On the other hand, ablation of NFATc1 activity enhanced differentiation of Ter119+ cells in BM. Restoring IL-2 signaling in Il2-/- mice reversed the increase in cAMP-NFAT signaling and facilitated normal erythropoiesis. Altogether, our study identified an NFAT-mediated negative signaling axis, manipulation of which could facilitate erythropoiesis and prevent anemia development. PMID- 29515760 TI - Molecular characterization of breast cancer cell response to metabolic drugs. AB - Metabolic reprogramming is a hallmark of cancer. It has been described that breast cancer subtypes present metabolism differences and this fact enables the possibility of using metabolic inhibitors as targeted drugs in specific scenarios. In this study, breast cancer cell lines were treated with metformin and rapamycin, showing a heterogeneous response to treatment and leading to cell cycle disruption. The genetic causes and molecular effects of this differential response were characterized by means of SNP genotyping and mass spectrometry based proteomics. Protein expression was analyzed using probabilistic graphical models, showing that treatments elicit various responses in some biological processes such as transcription. Moreover, flux balance analysis using protein expression values showed that predicted growth rates were comparable with cell viability measurements and suggesting an increase in reactive oxygen species response enzymes due to metformin treatment. In addition, a method to assess flux differences in whole pathways was proposed. Our results show that these diverse approaches provide complementary information and allow us to suggest hypotheses about the response to drugs that target metabolism and their mechanisms of action. PMID- 29515761 TI - Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression. AB - NRG1 fusions were recently reported as a new molecular feature of Invasive Mucinous Adenocarcinoma (IMA) of the lung. The NRG1 chimeric ligand acts as a strong inductor of phosphorylation and tyrosine kinase activity of the ErbB2/ErbB3 heterodimer, thus enhancing the PI3K-AKT/MAPK pathways. The NRG1 fusions were widely investigated in Asian IMA cohorts, whereas just anecdotal information are available about the occurrence of NRG1 fusions in IMA Caucasian population. Here we firstly explored a large Caucasian cohort of 51 IMAs and 34 non-IMA cases for the occurrence of NRG1 rearrangements by fluorescent in situ hybridization (FISH) and RNA target sequencing. FISH results were correlated to the immunohistochemical expression of phosphorylated-ErbB3 (pErbB3) receptor and the mutational status of KRAS, EGFR and ALK genes. The NRG1 rearrangements were detected in 31% IMAs and 3% non-IMAs and the CD74-NRG1 fusion transcript variant was characterized in 4 NRG1-positive IMAs. Moreover, pErbB3 expression was found to be strictly associated to the mucinous pattern (p = 0.012, Chi-square test) and all IMA cases showing aberrant expression of pErbB3 demonstrated NRG1 rearrangements. No significant correlation between NRG1 rearrangements and EGFR, KRAS or ALK mutations respectively, was observed. We report for the first time that NRG1 fusions are driver alterations clearly associated with mucinous lung adenocarcinoma subtype of Caucasian patients and not exclusive of Asiatic population. pErbB3 immunostaining may represent a strong predictor of NRG1 fusions, pointing out the detection of pErbB3 by IHC as a rapid and effective pre screening method to select the NRG1-positive patients. PMID- 29515762 TI - TMIGD1 acts as a tumor suppressor through regulation of p21Cip1/p27Kip1 in renal cancer. AB - Renal cell carcinoma (RCC) is a high-risk metastasizing tumor with a poor prognosis and poorly understood mechanism. In this study, we demonstrate that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) is a novel tumor suppressor that is highly expressed in normal renal tubular epithelial cells, but it is downregulated in human renal cancer. We have identified CCAAT/enhancer binding proteinbeta (C/EBPbeta, also called LAP) as a key transcriptional regulator of TMIGD1, whose loss of expression is responsible for downregulation of TMIGD1 in RCC. Transcriptionally active C/EBPbeta/LAP physically interacted with and increased TMIGD1 promoter activity and expression of TMIGD1. Re introduction of TMIGD1 into renal tumor cells significantly inhibited tumor growth and metastatic behaviors such as morphogenic branching and cell migration. Restoring TMIGD1 expression in renal tumor cells stimulated phosphorylation of p38MAK, induced expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in regulation of the cell cycle. The present study identifies TMIGD1 as a novel candidate tumor suppressor gene and provides important insight into pathobiology of RCC that could lead to a better diagnosis and possible novel therapy for RCC. PMID- 29515763 TI - Anticancer activity of biogenerated silver nanoparticles: an integrated proteomic investigation. AB - Silver nanoparticles (AgNPs), embedded into a specific polysaccharide (EPS), were biogenerated by Klebsiella oxytoca DSM 29614 under aerobic (AgNPs-EPSaer) and anaerobic conditions (AgNPs-EPSanaer). Both AgNPs-EPS matrices were tested by MTT assay for cytotoxic activity against human breast (SKBR3 and 8701-BC) and colon (HT-29, HCT 116 and Caco-2) cancer cell lines, revealing AgNPs-EPSaer as the most active, in terms of IC50, with a more pronounced efficacy against breast cancer cell lines. Therefore, colony forming capability, morphological changes, generation of reactive oxygen species (ROS), induction of apoptosis and autophagy, inhibition of migratory and invasive capabilities and proteomic changes were investigated using SKBR3 breast cancer cells with the aim to elucidate AgNPs-EPSaer mode of action. In particular, AgNPs-EPSaer induced a significant decrease of cell motility and MMP-2 and MMP-9 activity and a significant increase of ROS generation, which, in turn, supported cell death mainly through autophagy and in a minor extend through apoptosis. Consistently, TEM micrographs and the determination of total silver in subcellular fractions indicated that the Ag+ accumulated preferentially in mitochondria and in smaller concentrations in nucleus, where interact with DNA. Interestingly, these evidences were confirmed by a differential proteomic analysis that highlighted important pathways involved in AgNPs-EPSaer toxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment triggering cell death trough apoptosis and/or autophagy activation. PMID- 29515764 TI - Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML. PMID- 29515765 TI - Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. AB - The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (>= 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3-7.5, p = 0.011) and number of mutations (>= 3) (HR 2.5, CI 1.3-4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an independent prognostic factor in MDS and that mutation data can add value to clinical prognostic models. PMID- 29515766 TI - Cell banking for regulatory T cell-based therapy: strategies to overcome the impact of cryopreservation on the Treg viability and phenotype. AB - The first clinical trials with adoptive Treg therapy have shown safety and potential efficacy. Feasibility of such therapy could be improved if cells are cryopreserved and stored until optimal timing for infusion. Herein, we report the evaluation of two cell-banking strategies for Treg therapy: 1) cryopreservation of CD4+ cells for subsequent Treg isolation/expansion and 2) cryopreservation of ex-vivo expanded Tregs (CD4+CD25hiCD127lo/- cells). First, we checked how cryopreservation affects cell viability and Treg markers expression. Then, we performed Treg isolation/expansion with the final products release testing. We observed substantial decrease in cell number recovery after thawing and overnight culture. This observation might be explained by the high percentage of necrotic and apoptotic cells found just after thawing. Furthermore, we noticed fluctuations in percentage of CD4+CD25hiCD127- and CD4+FoxP3+ cells obtained from cryopreserved CD4+ as well as Treg cells. However, after re-stimulation Tregs expanded well, presented a stable phenotype and fulfilled the release criteria at the end of expansions. Cryopreservation of CD4+ cells for subsequent Treg isolation/expansion and cryopreservation of expanded Tregs with re-stimulation and expansion after thawing, are promising solutions to overcome detrimental effects of cryopreservation. Both of these cell-banking strategies for Treg therapy can be applied when designing new clinical trials. PMID- 29515768 TI - CXCR2 is a negative regulator of p21 in p53-dependent and independent manner via Akt-mediated Mdm2 in ovarian cancer. AB - Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation. CXCR2 decreased p53 protein, a regulator of p21, and downregulated p21 promoter activity only in p53WT cells. The p53 responsive element (RE) of p21 promoter played a critical role in this CXCR2-mediated p21 downregulation. Moreover, CXCR2-positive cells activated more Akt than CXCR2-negative cells followed by enhanced murine double minute (Mdm2). Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells. Cell cycle analysis revealed that CXCR2 decreased p21 gene in p53-null cells. Interestingly, romidepsin (histone deacetylase inhibitor)-induced p21 upregulation did not involve the p53 RE in the p21 promoter in p53-null cells. Romidepsin decreased the protein levels of Akt1 and Mdm2, leading to induction of p21 in p53-null cells. CXCR2 reduced romidepsin-induced p21 upregulation by activating Akt-induced Mdm2. Taken together, CXCR2 enhances cell proliferation by suppressing p21 through Akt-Mdm2 signaling in p53-dependent and independent manner. PMID- 29515769 TI - Evaluation of tenascin-C by tenatumomab in T-cell non-Hodgkin lymphomas identifies a new target for radioimmunotherapy. AB - The clinical outcome of T-cell non-Hodgkin lymphoma (NHL) is poor and innovative treatments are needed. Tenascin-C is a large extracellular glycoprotein not expressed under physiological conditions, but overexpressed in cancer. Aim of the study was to evaluate tenascin-C expression within pathologic tissue of T-cell NHL and determine its clinical significance. We used an immunohistochemistry approach using the anti-tenascin-C monoclonal antibody Tenatumomab in 75 systemic T-cell NHL (including 72 mature and 3 precursor T-cell NHL), and 25 primary cutaneous T-cell NHL. Data were analyzed in terms of staining intensity, proportion of involved areas and histologic pattern, and results were correlated with clinical characteristics and outcome. Ninety-three percent of the cases were tenascin-C positive and 59% of systemic diseases were characterized by a predominant involvement (>50%). Stromal expression was detected in all the cases while vascular and vascular plus cytoplasmic expression was present in 49% and 23%. The constant overexpression of the tenascin-C gene was observed in two independent publicly available T-cell NHL gene expression datasets. In conclusions, tenascin-C represents an attractive target that sets the rationale to investigate the therapeutic activity of radiolabeled Tenatumomab in T-cell NHL. PMID- 29515767 TI - Efficacy of histology-agnostic and molecularly-driven HER2 inhibitors for refractory cancers. AB - A targeted therapy is recommended in case of ERBB2 alteration for breast and gastric carcinomas, but miscellaneous other tumor types are ERBB2-altered at low prevalence. Broadening the administration of HER2 inhibitors across tumor types and genomic alterations could benefit to patients with refractory metastatic tumors. Targeted next-generation-sequencing (tNGS) and comparative genomic hybridization array (CGH) have been performed on fresh tumor biopsies of patients included in the MOSCATO-01 and ongoing MOSCATO-02 trials to administrate HER2 inhibitors in case of ERBB2 pathogenic mutation of amplification. Between December 2011 and January 2017 a molecular analysis was performed for 934 patients (759 CGH and 912 tNGS). A novel ERBB2 alteration has been found in 4.7% (n = 44/934), including 1.5% (n = 14/912) ERBB2 mutations, and 4% (n = 30/759) ERBB2 amplifications. A matched HER2 inhibitor was administrated to 70% (31/44) of patients and consisted in trastuzumab plus chemotherapy for 90% of them (28/31). On the 31 evaluable patients, 1 complete response (CR), 10 partial response (PR) and 2 stable disease (SD) >24 weeks were observed accounting for a clinical benefit rate (CBR) of 42% (n = 13/31, 95% CI 25-61%). Besides breast and oesogastric carcinomas, 19 patients affected by 8 different tumor types had a CBR of 25% for ERBB2 mutations (n = 2/8, 95% CI 3%-65%, with 2 PR) and 64% for ERBB2 amplifications (n = 7/11, 95% CI 31%-89%; with 1 CR, 4 PR, 2 SD). ERBB2 genomic alterations were diffuse across metastatic tumor types and signs of efficacy emerged for HER2 targeted treatments, especially in case of ERBB2 amplifications or a p.S310Y ERBB2 mutation. PMID- 29515770 TI - Ruxolitinib significantly enhances in vitro apoptosis in Hodgkin lymphoma and primary mediastinal B-cell lymphoma and survival in a lymphoma xenograft murine model. AB - Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) share similar molecular features by gene expression profiling. Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity, suggesting aberrant activity of JAK2 and STAT pathways. This signaling pathway alteration may in part play an important role in the pathogenesis and/or chemoradiotherapy resistance in HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor, with activity against myeloproliferative neoplasms (MPNs) including those harboring the JAK2V617F mutation. We investigated the in vitro and in vivo efficacy of ruxolitinib and changes in downstream signaling pathways in HL and PMBL. We demonstrated that ruxolitinib significantly inhibited STAT signaling in both HL and PMBL with constitutively active JAK2 signaling. We also observed that ruxolitinib significantly induced in vitro anti-proliferative effects (p < 0.05) and increased programmed cell death (p < 0.05) against both HL and PMBL cells. Importantly, ruxolitinib significantly inhibited tumor progression by bioluminescence (p < 0.05) and significantly improved survival in HL (p = 0.0001) and PMBL (p < 0.0001) xenograft NSG mice. Taken altogether, these studies suggest that ruxolitinib may be a potential adjuvant targeted agent in the therapeutic approach in patients with high risk HL and PMBL. PMID- 29515772 TI - The c-Raf modulator RRD-251 enhances nuclear c-Raf/GSK-3/VDR axis signaling and augments 1,25-dihydroxyvitamin D3-induced differentiation of HL-60 myeloblastic leukemia cells. AB - Differentiation therapy is used in cancer treatment. Epidemiologic studies showed that higher vitamin D levels are associated with reduced cancer risks. However, the therapeutic doses needed for differentiation are accompanied by hypercalcemia and intolerable pathological sequelae. In the present work we evaluated if RRD 251, a small-molecule, can enhance vitamin D3-induced differentiation of leukemic cells, in the hope of decreasing the needed vitamin D3-dose. We demonstrate that RRD-251 enhances vitamin D3-induced differentiation of leukemic cells, the enrichment of the c-Raf kinase in the nucleus, the binding of nuclear c-Raf to GSK-3, increased phosphorylation of GSK-3 ser 21/9 inhibitory sites, and the binding of GSK-3 to VDR, where GSK-3 inhibition is known to enhance transcriptional activation by VDR. Enhancement of D3-induced p-GSK-3 ser 21/9 by RRD-251 was associated with enhanced Akt-GSK-3 binding, Akt being a known GSK-3 inhibitor, and diminished Erk1/2 binding. Diminishing Erk interaction with GSK-3 was associated with enhanced interaction with Vav1, a known driver of myeloid differentiation. This is redolent of an ATRA/c-Raf/GSK-3/RARalpha axis we previously reported, although the phosphorylation effects to enhance transcriptional activation on RARalpha vs VDR diverge. Taken together this indicates potential therapeutic significance for a c-Raf/GSK-3/VDR or RARalpha axis for leukemic myelo-monocytic differentiation. PMID- 29515773 TI - Interleukin 17 and peripheral IL-17-expressing T cells are negatively correlated with the overall survival of head and neck cancer patients. AB - The presence and clinical significance of interleukin (IL)-17 and IL-17 expressing cells have recently been studied in several types of cancer, but their correlation to tumor development remains controversial. Additionally, the contribution of peripheral IL-17-expressing cells to head and neck cancer (HNC) progression is still poorly understood. We collected peripheral blood from healthy donors and HNC patients to isolate PBMCs. The percentages of IL-17 expressing cells and the production of inflammatory cytokines in PBMCs were measured to determine their association with clinical outcomes and overall survival in HNC. We evaluated the effect and potential mechanism of IL-17 on human oral squamous carcinomas in vitro using exogenous IL-17 stimulation. In comparison to healthy donors, the PBMCs of HNC patients have a significant accumulation of IL-17-expressing T cells and their frequencies were positively correlated with the disease stage. A significantly higher production of PBMC IL 17, TGF-beta and IL-21 and plasma VEGF-A were found in HNC patients. Importantly, the 5-years overall survival of HNC patients with a higher percentage of IL-17 expressing cells is significantly decreased. Furthermore, the addition of IL-17 appeared to promote human oral squamous carcinoma cell proliferation via the production of IL-6 and VEGF-A. Our findings suggest that IL-17 has the potential to mediate pro-tumor immunity in the HNC tumor microenvironment. Enhanced IL-17 expressing cells, including Th17 and Tc17 cells, in the peripheral blood could be a significant predictor of a poor prognosis for HNC patients. PMID- 29515774 TI - Unbiased compound-protein interface mapping and prediction of chemoresistance loci through forward genetics in haploid stem cells. AB - Forward genetic screens in haploid mammalian cells have recently emerged as powerful tools for the discovery and investigation of recessive traits. Use of the haploid system provides unique genetic tractability and resolution. Upon positive selection, these screens typically employ analysis of loss-of-function (LOF) alleles and are thus limited to non-essential genes. Many relevant compounds, including anti-cancer therapeutics, however, target essential genes, precluding positive selection of LOF alleles. Here, we asked whether the use of random and saturating chemical mutagenesis might enable screens that identify essential biological targets of toxic compounds. We compare and contrast chemical mutagenesis with insertional mutagenesis. Selecting mutagenized cells with thapsigargin, an inhibitor of the essential Ca2+ pump SERCA2, insertional mutagenesis retrieved cell clones overexpressing SERCA2. With chemical mutagenesis, we identify six single amino acid substitutions in the known SERCA2 thapsigargin binding interface that confer drug resistance. In a second screen, we used the anti-cancer drug MG132/bortezomib (Velcade), which inhibits proteasome activity. Using chemical mutagenesis, we found 7 point mutations in the essential subunit Psmb5 that map to the bortezomib binding surface. Importantly, 4 of these had previously been identified in human tumors with acquired bortezomib resistance. Insertional mutagenesis did not identify Psmb5 in this screen, demonstrating the unique ability of chemical mutagenesis to identify relevant point mutations in essential genes. Thus, chemical mutagenesis in haploid embryonic stem cells can define the interaction of toxic small molecules with essential proteins at amino acid resolution, fully mapping small molecule protein binding interfaces. PMID- 29515771 TI - Proteomic analyses identify prognostic biomarkers for pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Here we show that shotgun and targeted protein sequencing can be used to identify potential prognostic biomarkers in formalin-fixed paraffin-embedded specimens from 9 patients with PDAC with "short" survival (<12 months) and 10 patients with "long" survival (>45 months) undergoing surgical resection. A total of 24 and 147 proteins were significantly upregulated [fold change >=2 or <=0.5 and P<0.05; or different detection frequencies (>=5 samples)] in patients with "short" survival (including GLUT1) and "long" survival (including C9orf64, FAM96A, CDH1 and CDH17), respectively. STRING analysis of these proteins indicated a tight protein protein interaction network centered on TP53. Ingenuity pathway analysis linked proteins representing "activated stroma factors" and "basal tumor factors" to poor prognosis of PDAC. It also highlighted TCF1 and CTNNB1 as possible upstream regulators. Further parallel reaction monitoring verified that seven proteins were upregulated in patients with "short" survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with "long" survival, including EPCAM, LGALS4, VIL1, CLCA1 and TPPP3. Thus, we verified 25 protein biomarker candidates for PDAC prognosis at the tissue level. Furthermore, an activated stroma status and protein-protein interactions with TP53 might be linked to poor prognosis of PDAC. PMID- 29515775 TI - Prominent role of RAB39A-RXRB axis in cancer development and stemness. AB - In this study, we found that RAB39A, a member of the RAS oncogene family, was selectively expressed in cancer cells of different histotypes, by analyzing gene expression in human osteosarcoma cells and the cancer stem cells (CSCs) and by comparing them with normal cells through global transcriptomics and principal component analyses. We further validated RAB39A as a therapeutic target, by silencing its expression. The silencing impaired cancer stemness and spherogenic ability in vitro, as well as tumorigenesis in vivo. RNA-seq analyses in the silenced spheres suggested that RAB39A is associated downstream with RXRB and KLF4. Notably, RXRB expression was inhibited in RAB39A-silenced CSCs. Induced overexpression of RXRB in RAB39A-silenced cells restored spherogenic ability and tumorigenesis, confirming RXRB as a major effector of RAB39A. Quantitative RT-PCR analysis of ~400 human cancer tissues showed that RAB39A was highly expressed in sarcomas and in malignancies of lymphoid, adrenal and testicular tissues. Our data provide the rationale for targeting of the RAB39A-RXRB axis as a therapy for aggressive cancers. PMID- 29515776 TI - Neovascular PSMA expression is a common feature in malignant neoplasms of the thyroid. AB - Aim: PSMA (prostate-specific membrane antigen) is physiologically expressed in normal prostate tissue and over expressed in prostate cancer cells, therefore constituting a potential target for antibody-based radioligand therapy. Very recent imaging findings reported PSMA-PET/CT uptake in various thyroid lesions. We were therefore encouraged to systematically analyse PSMA expression in different benign and malignant thyroid lesions. Methods: Immunohistochemistry was used to detect PSMA expression in 101 thyroid lesions, while neovasculature was identified by CD34 immunostaining. Results: PSMA expression in the neovasculature was significantly more frequent in malignant tumors (36/63; 57.1%) compared to benign diseases (5/38; 13.2%; p = 0.0001). In addition, PSMA expression levels in the neovasculature of poorly and undifferentiated thyroid cancers were significantly higher compared to differentiated thyroid tumors (p = 0.021). However, one case with a strong expression in follicular adenoma was identified. Conclusions: We conclude that neovascular PSMA expression is common in thyroid cancer but may also rarely be found in benign thyroid diseases, such as follicular adenoma. High expression in the tumor-associated neovasculature is predominantly found in poorly differentiated and undifferentiated (anaplastic) thyroid cancer. This knowledge is highly relevant when interpreting PSMA/PET-CT scans from patients with prostate cancer. In addition, our findings might provide a rationale for further evaluation of PSMA-targeted anti-neovascular or radioligand therapy in metastatic dedifferentiated thyroid cancer. PMID- 29515777 TI - RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. AB - Purpose: Medullary Thyroid Cancer (MTC) whose pathogenesis is strictly related to RET proto-oncogene alterations, has been shown to have a heterogenic RET mutation profile in subpopulations of MTC. The aim of our study was to investigate the RET somatic mutation profile in primary MTC and in the corresponding metastatic tissues in a series of advanced metastatic cases. Results: This study demonstrated that in about 20% of cases a different RET mutation profile can be found when comparing primary tumor and its corresponding metastases. Furthermore in 8% of tumors, RET intratumor heterogeneity was observed We also showed that in some cases an imbalance of RET copy number was present. We confirmed a high prevalence (90%) of RET somatic mutations in advanced tumors. Materials and Methods: Fifty-six MTC patients (50 somatic and 6 hereditary cases) have been included in the study and a total of 209 specimens have been analysed by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) has been used to investigate amplification/deletion of RET alleles. Conclusions: In conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity. PMID- 29515778 TI - Targeting intracellular B2 receptors using novel cell-penetrating antagonists to arrest growth and induce apoptosis in human triple-negative breast cancer. AB - G protein-coupled receptors (GPCRs) are integral cell-surface proteins having a central role in tumor growth and metastasis. However, several GPCRs retain an atypical intracellular/nuclear location in various types of cancer. The pathological significance of this is currently unknown. Here we extend this observation by showing that the bradykinin B2R (BK-B2R) is nuclearly expressed in the human triple-negative breast cancer (TNBC) cell line MDA-MB-231 and in human clinical specimens of TNBC. We posited that these "nuclearized" receptors could be involved in oncogenic signaling linked to aberrant growth and survival maintenance of TNBC. We used cell-penetrating BK-B2R antagonists, including FR173657 and novel transducible, cell-permeable forms of the peptide B2R antagonist HOE 140 (NG68, NG134) to demonstrate their superior efficacy over impermeable ones (HOE 140), in blocking proliferation and promoting apoptosis of MDA-MB-231 cells. Some showed an even greater antineoplastic activity over conventional chemotherapeutic drugs in vitro. The cell-permeable B2R antagonists had less to no anticancer effects on B2R shRNA-knockdown or non-B2R expressing (COS-1) cells, indicating specificity in their action. Possible mechanisms of their anticancer effects may involve activation of p38kinase/p27Kip1 pathways. Together, our data support the existence of a possible intracrine signaling pathway via internal/nuclear B2R, critical for the growth of TNBC cells, and identify new chemical entities that enable to target the corresponding intracellular GPCRs. PMID- 29515779 TI - Reversible LSD1 inhibition with HCI-2509 induces the p53 gene expression signature and disrupts the MYCN signature in high-risk neuroblastoma cells. AB - Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets. HCI-2509 results in increased histone methyl marks and p53 levels along with cell cycle arrest in the G2/M phase and inhibition of colony formation of NGP cells. Our findings indicate that LSD1 inhibition with HCI-2509 has a multi-target effect in neuroblastoma cell lines, mediated in part via p53. MYCN-amplified neuroblastoma cells have a targeted benefit as HCI-2509 downregulates the MYCN upregulated gene set. PMID- 29515780 TI - Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. AB - Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01-induced NASH. PMID- 29515781 TI - CXCR4: A new player in vestibular schwannoma pathogenesis. AB - Background: CXCR4 is a chemokine receptor that recruits blood stem cells and increases tumor cell growth and invasiveness. We examined CXCR4 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and correlated the levels with the patients' clinical characteristics. The aim was to determine whether CXCR4 can be used as a prognostic marker and as a target for systemic therapy. Results: Overall, CXCR4 mRNA levels were 4.6-fold higher in VS versus control; the levels were 4.9-fold higher in NF2 patients and 4.2-fold higher in sporadic VS patients. IHC and WB showed heterogeneous protein expression, and CXCR4 was expressed mainly in S100-positive Schwann cells. There was no correlation between the CXCR4 protein levels and tumor extension. However, there was a trend towards correlation between higher expression levels and greater hearing loss. Materials and Methods: CXCR4 mRNA and protein levels were determined in VS samples (n = 60); of these, 30 samples were from patients with NF2. Healthy nerves from autopsies served as controls. CXCR4 mRNA levels were measured by PCR, and protein levels were measured by immunohistochemistry (IHC) and Western blotting (WB). Tumor extension and hearing loss were categorized according to the Hannover Classification as clinical parameters. Conclusions: CXCR4 mRNA was overexpressed in VS relative to healthy vestibular nerves, and there was a trend towards higher CXCR4 expression levels being correlated with greater functional impairment. Thus, CXCR4 may be a prognostic marker of VS, and CXCR4 inhibition has potential as a systemic approach for the treatment of VS. PMID- 29515782 TI - Urokinase-derived peptide UP-7 suppresses tumor angiogenesis and metastasis through inhibition of FAK activation. AB - The recombinant kringle domain of urokinase (UK1) has been shown to inhibit angiogenesis and brain tumor growth in vivo. To avoid limitations in application due to mass production of recombinant protein, we attempted to develop a novel peptide inhibitor from UK1 sequence consisting of 83 amino acids that contains alpha-helices, loops and beta-sheets. We dissected UK1 sequence to seven peptides based on structure and amino acid characteristics, and examined the anti angiogenic activities for the constructed peptides. Among the tested peptides, UP 7 most potently inhibited the proliferation and migration of endothelial cells (ECs) in vitro, and also potently inhibited in vivo angiogenesis in the mouse matrigel plug assay. Such anti-angiogenic activities were not exerted by the scrambled peptide. At molecular level, UP-7 inhibited growth factor-induced phosphorylation of FAK and ERK1/2. It also suppressed formation of stress fibers and focal adhesions and also inhibited the attachment and spreading of ECs onto immobilized fibronectin. In a lung cancer animal model xenografted with non-UP-7 sensitive NCI-H460 cells, systemic treatment of UP-7 effectively suppressed tumor growth through inhibition of angiogenesis. Interestingly, breast cancer cells such as LM-MDA-MB-231 cells were moderately sensitive to UP-7 in proliferation differently from other cancer cells. UP-7 also inhibited migration, invasion and FAK phosphorylation of LM-MDA-MB-231 cells. Accordingly, UP-7 potently inhibited lung metastatic growth of LM-MDA-MB-231 cells in an experimental metastasis model. Taken together, these results suggest that novel peptide UP-7 can be effectively used for treatment of breast cancer metastatic growth through inhibition of angiogenesis and invasion. PMID- 29515783 TI - HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway. AB - Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5 FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both in vitro and in vivo. Further experiments indicate that HMGA2 directly binds to the promoter of Dvl2 and induces its transcription, which leads to increased activation of the Wnt/beta-catenin pathway. Taken together, our data suggest that HMGA2 enhances the chemoresistance to 5-FU in CRC via activating the Dvl2/Wnt pathway. Therefore, HMGA2 may serve as a predictive biomarker and a potential therapeutic target in CRC. PMID- 29515784 TI - Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting beta2 and beta5 subunits. AB - Proteasome inhibitors (PI), mainly targeting the beta5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the beta5 and beta2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (beta5 subunit) and trypsin-like (beta2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog 1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the beta5 and beta2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of beta2 and beta5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome beta2 and beta5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM. PMID- 29515785 TI - Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in intensity modulated radiation therapy for nasopharyngeal carcinoma. AB - Background: Inflammatory response markers plays an important role in tumor progression. The aim of this analysis was to evaluate whether the neutrophil-to lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) could predict the prognosis of nasopharyngeal carcinoma(NPC). Materials and Methods: 247 patients who underwent Intensity Modulated Radiation Therapy( IMRT )were enrolled from January 2012 and December 2012. NLR, and PLR were calculated from peripheral blood cell counts taken at pre-treatment. Optimal cutoff values of NLR and PLR were determined on the basis of receiver operating characteristic curve analysis. Overall survival (OS), progression-free survival(PFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival ( LRFS) rates were compared according to NLR and PLR level respectively. Multivariate analysis was performed to assess the prognostic value of NLR and PLR. Results: The 5-year estimated OS, PFS, LRFS and DFS were 87.2, 77.8, 96.9, and 86.2%, respectively. Our results shows that the NLR was significantly associated with T-stage (P < 0.05), N-stage (P < 0.05) and tumor stage(P < 0.05). PLR was significantly associated with T-stage (P < 0.05) and tumor stage(P < 0.05). NLR was an independent prognostic indicator for OS (HR: 3.259, P = 0.004), PFS (HR:7.093, P < 0.001), DMFS (HR: 6.576, P = 0.003), except for PLR. In subgroup analysis, adjuvant chemotherapy had no significantly improved survival for patients with high NLR. Conclusions: NLR is a strong prognostic factor for NPC patients. NLR might not be a useful indicator for selection of treatment strategies for loco regionally advanced NPC. PMID- 29515786 TI - Evaluation of tumor hypoxia prior to radiotherapy in intermediate-risk prostate cancer using 18F-fluoromisonidazole PET/CT: a pilot study. AB - Purpose: Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance. Predicting which patients might be bad candidates for radiotherapy may help better personalize treatment decisions in intermediate-risk prostate cancer patients. We assessed spatial distribution of 18F-Misonidazole (FMISO) PET/CT uptake in the prostate prior to radiotherapy treatment. Materials and Methods: Intermediate-risk prostate cancer patients about to receive high dose (>74 Gy) radiotherapy to the prostate without hormonal treatment were prospectively recruited between 9/2012 and 10/2014. Prior to radiotherapy, all patients underwent a FMISO PET/CT as well as a MRI and 18F-choline-PET. 18F choline and FMISO-positive volumes were semi-automatically determined using the fuzzy locally adaptive Bayesian (FLAB) method. In FMISO-positive patients, a dynamic analysis of early tumor uptake was performed. Group differences were assessed using the Wilcoxon signed rank test. Parameters were correlated using Spearman rank correlation. Results: Of 27 patients (median age 76) recruited to the study, 7 and 9 patients were considered positive at 2.5h and 3.5h FMISO PET/CT respectively. Median SUVmax and SUVmax tumor to muscle (T/M) ratio were respectively 3.4 and 3.6 at 2.5h, and 3.2 and 4.4 at 3.5h. The median FMISO positive volume was 1.1 ml. Conclusions: This is the first study regarding hypoxia imaging using FMISO in prostate cancer showing that a small FMISO positive volume was detected in one third of intermediate-risk prostate cancer patients. PMID- 29515787 TI - Effect of traumatic brain injury on nicotine-induced modulation of dopamine release in the striatum and nucleus accumbens shell. AB - Background: Traumatic brain injury is associated with substantial alterations in reward processing, but underlying mechanisms are controversial. Objective: A better understanding of alterations in dopamine (DA) release patterns from the dorsal striatum and nucleus accumbens shell (NAc) may provide insights into posttraumatic reward pathology. Materials and Methods: The patterns of DA release with or without exposure to nicotine in brain slices with striatum and NAc, isolated from Sprague-Dawley rats with 6 psi fluid percussion (FPI) or sham injury were analysis by using fast-scan cyclic voltammetry. Tonic and phasic DA releases were assessed using single pulse and 10 pulses at 25 Hz, respectively. DA release relative to stimulation intensity, frequency, number of pulses, and paired-pulse facilitation was evaluated to determine release probability and response to bursting. Results: There was a profound suppression in tonic DA release after nicotine desensitization after FPI, and the input/output curve for the DA release based on stimulation intensity was shifted to the right. FPI was associated with a significant decrease in frequency-dependent DA release augmentation, DA release induced by high frequency stimulation trains, and DA release in response to paired-pulse facilitation. The effect of nicotine desensitization was similar in FPI and sham-injured animals, although significantly smaller after FPI. Nicotine desensitization-induced differences between phasic and tonic release concentrations that contrasted with the reward related signals then became less prominent in NAc after FPI. Conclusions: TBI blunts DA release from mesolimbic reward centers, and more intense stimuli are required to produce context-dependent DA release sufficient to have a physiological effect. Implications: The nicotine desensitization-related suppression in tonic DA release was profound with right-ward shift of the input/output curve for DA release after FPI. FPI was associated with a significant decrease in frequency-dependent DA release augmentation, DA release induced by high frequency stimulation trains, and DA release in response to paired-pulse facilitation. Nicotine desensitization-induced differences between phasic and tonic release concentrations that contrasted with the reward-related signals then became less prominent in NAc after FPI. TBI thus blunts DA release from mesolimbic reward centers, and more intense stimuli are required to produce context-dependent DA release sufficient to have a physiological effect. PMID- 29515788 TI - CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells. AB - A number of studies report that epithelial to mesenchymal transition (EMT) supports the generation and maintenance of cancer stem cells (CSCs), which show tumor seeding ability and drug resistance; however, the molecular mechanisms underlying induction of EMT-associated tumor malignancy remain unclear. The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatin-resistance, which resulted in EMT induction. CD44s induced an EMT phenotype in cisplatin resistant cells by up-regulating ZEB1, a transcriptional repressor of E-cadherin. More importantly, CD44s up-regulated ZEB1 by suppressing microRNA-200c, which is a non-coding RNA that directly represses the ZEB1 gene. These results demonstrate the importance of the association between platinum resistance and CD44s during EMT induction in oral cancer cells. PMID- 29515789 TI - Mutational landscape of radiation-associated angiosarcoma of the breast. AB - Purpose: Radiation-associated breast angiosarcomas are a rare complication of radiation therapy for breast carcinoma. With relatively little is known about the genetic abnormalities present in these secondary tumors, we examined genomic variation in biospecimens from radiation-associated breast angiosarcomas. Experimental Design: Patients were identified that had a previous breast cancer diagnosis, received radiation therapy, and developed angiosarcoma in the ipsilateral breast as the earlier cancer. Tumor regions were isolated from archival blocks using subsequent laser capture microdissection. Next generation sequencing was performed using a targeted panel of 160 cancer-related genes. Genomic variants were identified for mutation and trinucleotide-based mutational signature analysis. Results: 44 variants in 34 genes were found in more than two thirds of the cases; this included 12 variants identified as potentially deleterious. Of particular note, the BRCA1 DNA damage response pathway was highly enriched with genetic variation. In a comparison to local recurrences, 14 variants in 11 genes were present in both the primary and recurrent lesions including variants in genes associated with the DNA damage response machinery. Furthermore, the mutational signature analysis shows that a previously defined IR signature is present in almost all of the current samples characterized by predominantly C->T substitutions. Conclusions: While radiation-associated breast angiosarcomas are relatively uncommon, their prognosis is very poor. These data demonstrate a mutational pattern associated with genes involved in DNA repair. While important in revealing the biology behind these tumors, it may also suggest new treatment strategies that will prove successful. PMID- 29515790 TI - Impact of glutathione peroxidase 4 on cell proliferation, angiogenesis and cytokine production in hepatocellular carcinoma. AB - Insufficient supplementation with the micronutrient selenium and persistent hepatic inflammation predispose to hepatocellular carcinoma (HCC). Inflammation associated reactive oxygen species attack membrane lipids and form lipid hydroperoxides able to propagate oxidative hepatic damage. Selenium-containing enzyme glutathione peroxidase 4 (GPx4) antagonizes this damage by reducing lipid hydroperoxides to respective hydroxides. However, the role of GPx4 in HCC remains elusive. We generated two human HCC cell lines with stable overexpression of GPx4, performed xenotransplantation into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) host mice and characterized the tumors formed. The experimental data were verified using gene expression data from two independent HCC patient cohorts. GPx4 overexpression protected from oxidative stress and reduced intracellular free radical level. GPx4-overexpressing cells displayed impaired tumor growth, reduced proliferation, altered angiogenesis and decreased expression of clinically relevant cytokine interleukin-8 and C-reactive protein. Moreover, GPx4 overexpression impaired migration of endothelial cells in vitro, and enhanced expression of thrombospondin 1, an endogenous inhibitor of angiogenesis. In patients, GPx4 expression in tumors positively correlated with survival and was linked to pathways which regulate cell proliferation, motility, tissue remodelling, immune response and M1 macrophage polarization. The patient data largely confirmed experimental findings especially in a subclass of poor prognosis tumors with high proliferation. GPx4 suppresses formation and progression of HCC by inhibition of angiogenesis and tumor cell proliferation as well as by immune-mediated mechanisms. Modification of GPx4 expression may represent a novel tool for HCC prevention or treatment. PMID- 29515791 TI - Adverse effects of paternal chemotherapy exposure on the progeny brain: intergenerational chemobrain. AB - Recent advances in cancer treatments have led to significant increases in cure rates. Most cancer patients are treated with various cytotoxic chemotherapy regimens. These treatment modalities are mutagenic and genotoxic and cause a wide array of late-occurring health problems, and even exert a deleterious influence on future offspring. The adverse effects from exposed parents on offspring are referred to as transgenerational effects, and currently little is known about chemotherapy-induced transgenerational effects. Furthermore, transgenerational effects have not been studied in the brains of progeny of exposed parents. In this study, we analyzed the existence and molecular nature of transgenerational effects in the brains of progeny of animals exposed to three common chemotherapy agents: cyclophosphamide (CPP), procarbazine (PCB) and mitomycin C (MMC). For the first time, our results show that paternal exposure to chemotherapy drugs causes transgenerational changes in the brain of unexposed progeny. Although no DNA damage was observed in terms of gammaH2AX levels, some alterations were found in levels of PCNA, protein involved in DNA repair, replication and profileration. Furthermore, there were changes in proliferation and apoptosis proteins BCL2 and AKT1, the proteins associated with DNA methylation, DNMT1 and MeCP2. Some altered expression trends were noted in proteins involved in myelin biogenesis, MBP and MYT1L. Moreover, global transcriptome profiling revealed changes in over 200 genes in the whole brains of progeny of animals exposed to CPP, and the changes in the levels of FOXP2 and ELK1proteins were confirmed by western blot analysis. These findings suggest that paternal chemotherapy significantly affects offspring brain development and may affect brain functioning. This research provides a key roadmap for future investigations of the novel phenomenon of transgenerational effects of chemotherapy in the brain of progeny of exposed parents. PMID- 29515792 TI - Clinicopathological significance of CHFR promoter methylation in gastric cancer: a meta-analysis. AB - The mitotic checkpoint gene (CHFR) (Checkpoint with Forkhead-associated and Ring finger domains is a G2 phase/mitosis checkpoint and tumor-suppressor gene. Recent studies have reported the relationship of CHFR promoter methylation with clinicopathological significance of gastric cancer. However, the results remain unclear due to small size of sample. We pooled 15 studies including 827 gastric cancer patients and conducted a meta-analysis to investigate the clinicopathological significance of CHFR promoter methylation in gastric cancer. Our data revealed that the frequency of CHFR promoter methylation was higher in gastric cancer than in normal gastric tissue, Odd Ratio (OR) was 10.12 with 95% CI 5.17-19.79, p < 0.00001. Additionally, the rate of CHFR promoter methylation was significantly increased in high grade of gastric cancer compared to low grade, OR was 1.64 with 95% CI 1.00-2.68, p = 0.05. CHFR methylation was significantly associated with the positive lymph node metastasis, OR was 1.56 with 95% CI 1.05-2.32, p = 0.03. We concluded that CHFR could serve as a biomarker for diagnosis of gastric cancer, and a drug target for development of gene therapy in gastric cancer. CHFR promoter methylation is associated with tumor poor differentiation and lymph node metastasis. PMID- 29515793 TI - Factors associated with postoperative renal sinus invasion and perinephric fat invasion in renal cell cancer: treatment planning implications. AB - In patients with renal cell carcinoma (RCC), postoperative upstaging including perinephric fat invasion (PNI) and renal sinus invasion (RSI) leads to unfavorable oncological outcomes. Determining the preoperative risk factors for postoperative upstaging could be beneficial for treatment planning. In this study, 267 RCC patients who underwent radical nephrectomy were studied retrospectively. The RSI incidence was significantly greater than that of PNI. Kaplan-Meier analysis revealed that patients with RSI, PNI, and RSI plus PNI had poorer disease-free-survival than those with neither RSI nor PNI. Univariate and multivariate logistic regression analyses indicated that a tumor extension into the sinus, an irregular tumor-sinus border, and an irregular tumor shape in CT/MRI imaging were independent risk factors for RSI. And a tumor larger than 5 cm, an irregular tumor-perinephric fat border, and a tumor necrosis were independent risk factors for PNI. Subgrouping of patients into low-, moderate-, and high-risk groups according to these factors, revealed a direct association between the risk factors and PNI/RSI incidence. In conclusion, in patients with RCC, preoperative risk factors associated with postoperative upstaging could be assessed by imaging data obtained using CT or MRI. Preoperative Risk group classification would be clinically useful for patient counseling and treatment planning. PMID- 29515794 TI - Appropriate magnetic resonance imaging techniques for gross tumor volume delineation in external beam radiation therapy of locally advanced cervical cancer. AB - Background: Accurate delineation of the gross tumor volumes (GTV) is a prerequisite for precise radiotherapy planning and delivery. Different MRI sequences have different advantages and limitations in their ability to discriminate primary cervical tumor from normal tissue. The purpose of this work is to determine appropriate MRI techniques for GTV delineation for external-beam radiation therapy of locally advanced cervical cancer (LACC). Materials and Methods: GTVs were delineated on the MRI, CT, and PET images acquired for 23 LACC patients in treatment positions to obtain GTVs on CT (GTV-CT), on various MRI sequences including T1 (GTV-T1), T2 (GTV-T2), T1 with fat suppression and contrast (GTV-T1F+), DWI-ADC (GTV-ADC) and on PET were generated using the threshold of 40% of maximum SUV (GTV-SUV40%) as well as SUV of 2.5 (GTV-SUV2.5). MRI, CT and PET were registered for comparison. The GTVs defined by MRI were compared using the overlap ratio (OR) and relative volume ratio (RVR). The union of GTV-T2 and GTV-ADC was generated to represent the MRI-based GTV (GTV-MRI). Results: The differences between GTV-T2 and other MRI GTVs are significant (P < 0.05). The average ORs for GTV-T1, GTV-T1F+, and GTV-ADC related to GTV-T2 were 86.3%, 81.6%, and 61.6% with the corresponding average RVRs 113.8%, 112.3% and 77.2%, respectively. There is no significant difference between GTV-T1 and GTV T1F+. GTV-ADC was generally smaller than GTV-T2, however, encompassed suspicious regions that are uncovered in GTV-T2 (up to 16% of GTV-T2) because of different imaging mechanisms. There was significant difference between GTV-MRI, GTV-SUV2.5, GTV-SUV40%, and GTV-CT. On average, GTV-MRI is 18.4% smaller than GTV-CT. Conclusions: MRI provides improved visualization of disease over CT or PET for cervical cancer. The GTV from the union of GTV-T2 and GTV-ADC provides a reasonable GTV including tumor region defined anatomically and functionally with MRI and substantially reduces the conventional GTV defined on CT. PMID- 29515795 TI - A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer. AB - Background: Indoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. Adenovirus p53 (Ad.p53) is used to generate DC vaccines against p53. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted. Materials and Methods: The phase-1 study combined 7 indoximod dose levels with < 6 Ad.p53-DC vaccinations every 2 weeks. Primary endpoints were maximum-tolerated dose in phase 1 and objective response in phase 2. Flow cytometry measured immune responses. Results: Thirty-nine patients were treated. In combination with Ad.p53 DC vaccine, the maximum-tolerated dose of indoximod was 1600 mg twice daily. Attributable toxicities were grade 1-2. Best response was stable disease in 4 patients. Immunologic responses were detected in 7 out of 23 evaluable patients. Median progression-free survival was 13.3 weeks (95% confidence interval, 12.97 21.85) and median overall survival was 20.71 weeks (95% confidence interval, 25.75-46.15). Nine out of 22 patients (40%) benefitted from chemotherapy after vaccination. Median overall survival in chemotherapy responders was 69.4 weeks (30.1-122.1). Conclusions: Indoximod 1600 mg twice daily with Ad.p53-DC was well tolerated. There may have been a chemosensitization effect. Future trials should explore combining this treatment with chemotherapy. PMID- 29515796 TI - Prognostic significance of the red blood cell distribution width that maintain at high level following completion of first line therapy in mutiple myeloma patients. AB - To investigate the prognostic value of the red blood cell distribution width(RDW) recovery from low levels at diagnosis after completion of first line therapy in mutiple myeloma (MM)patients,we enrolled 78 consecutive patients with MM and followed up from 2005 to 2016 in our hospital. The RDW was measured following completion of first-line therapy.The log-rank test, univariate analysis, and Cox regression analysis were used to evaluate the relationship between RDW and survival. We found that patients with an RDW >= 15.5% at diagnosis, as well as at completion of first-line therapy, had significantly lower progression-free survival (PFS) and overall survival(OS) rates than those with an RDW < 15.5%(P < 0.05).Patients with RDW that maintained more than 15.5% upon completion of therapy showed a shorter OS (P < 0.05) and PFS (P < 0.05) compared with patients with an RDW that decreased to a lower level.The multivariate analysis showed that RDW >= 15.5% after the completion of first-line therapy were an independent prognostic marker of poorer OS (P = 0.044) and PFS (P = 0.034). Therefore,we demonstrated that RDW at diagnosis, as well as at completion of first-line therapy is an independent predictor for mutiple myeloma patients.RDW maintained at high level, irrespective of whether RDW decreased to the cutoff value predicted an unfavorable prognosis in patients with MM. PMID- 29515797 TI - 18F-fluorothymidine PET for predicting survival in patients with resectable pancreatic cancer. AB - Purpose: The aim of this study was to correlate preoperative 3'-deoxy-3'-[18F] fluorothymidine (FLT) uptake with the clinical outcome and survival in these patients after surgery. Materials and Methods: We performed a prospective analysis in 27 patients with adenocarcinoma of the pancreas (15 males, 12 females, mean age: 62 +/- 13 years, range: 34 - 86 years). FLT PET (45 min p.i., 300 MBq FLT; ECAT HR+) images were acquired according to standard protocols. FLT uptake was quantified using standardised uptake values (SUV). Mean follow-up was 35 months (range 24-49). FLT uptake was correlated with survival using Martingale residual analysis. Results: Twenty-two patients died during follow-up. Mean overall survival was 18.8 months (SD: 12.7 months, 95% CI: 7.7, 26.5). FLT PET showed a mean SUV of 2.5 (range: 1.1 - 6.5). Martingale residual analysis revealed significant correlation between survival and FLT uptake (p = 0.045). The corresponding estimated hazard ratio per one-point increment of SUVmean was 1.298 (95% CI: 1.001, 1.685; p < 0.05). Conclusions: FLT PET allows risk stratification for death in patients with resectable pancreatic cancer prior to surgery. PMID- 29515798 TI - Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. AB - Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea. Ongoing experimental and clinical studies have illuminated great potential of berberine in regulation of glucose and lipid homeostasis, cancer growth and inflammation. Furthermore, the lipid lowering effect of berberine is comparable to those conventional lipid drugs but with low toxicity. Therefore, it is right time to transform beneficial effects of berberine into therapeutic practice. Metformin and berberine share many features in actions despite different structure and both could be excellent drugs in treating T2DM, obesity, cardiac diseases, tumour, as well as inflammation. Since these disorders are often connected and comprise common pathogenic factors that could be targeted by the two drugs, understanding their actions can give us rationale for expansion of their clinical uses. PMID- 29515799 TI - Newly developed anti-angiogenic therapy in non-small cell lung cancer. AB - Angiogenesis and its role in the growth and development of non-small cell lung cancer (NSCLC) metastases has become an increasing clinical problem. Vascular endothelial growth factor (VEGF) plays a key role in advanced NSCLC. To some extent, anti-angiogenic therapies acquired some efficacy in combination with chemotherapy, target therapy and immunotherapy. However, the reliable clinical benefit obtained with these drugs is still questionable and often quantitatively limited. In this review, the authors highlight the data obtained from first-line, second-line, epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) target therapy and immunotherapy in NSCLC patients who are treated with anti angiogenic molecules in advanced NSCLC. The purpose of this study is to help us truly understand how to best use angiogenesis therapy in advanced NSCLC. PMID- 29515800 TI - The novel strategies for next-generation cancer treatment: miRNA combined with chemotherapeutic agents for the treatment of cancer. AB - Medical practitioners are recommending combination therapy in cancer for its various advantages. Combination therapy increases the efficacy of treatment due to its synergistic effects in cancer treatment. In this post-genomic era, microRNAs (miRNAs) are receiving attention for their role in human disease and disease therapy. In this review, we discuss the combination of miRNAs and chemotherapeutic agents for cancer treatment. Moreover, we attempted to portray the role of miRNAs in cancer therapy; outline combination therapy, especially chemo-combination therapy, and discuss the basis for miRNA-based chemo combination therapies and chemo-combination therapy with miRNA for cancer treatment. PMID- 29515801 TI - Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression. AB - Background: Response to targeting and non-targeting agents is variable and molecular information remains poorly described in patients with recurrent sonic hedgehog-driven medulloblastoma (SHH-MB). Materials and Methods: Clinical and PET/CT findings during treatment with successive hedgehog antagonists and temozolomide monotherapies are described in a heavily pre-treated patient with recurrent extraneural metastases from PTCH1 mutated/ wild type smoothened (SMO) CNS SHH-MB. Molecular tests were prospectively performed in tissue from two extraneural sites at progression. Results: Sustained clinical/metabolic response was obtained to vismodegib. At progression, itraconazole was ineffective, but salvage temozolomide treatment results in a response similar to vismodegib. At further progression, acquired SMO and PIK3CA mutations were identified in bone (G477L and H1047A, respectively) and epidural (L412P and H1065L, respectively) metastases. No response was observed with subsequent sonidegib treatment. Conclusions: This is the first clinical report of recurrent extraneural PTCH1 mutated SHH-MB exhibiting: 1) a sustained response to vismodegib and temozolomide, and 2) inter-metastatic molecular heterogeneity and acquired SMO G477L, SMO-L412P, and PIK3CA-H1065L mutations at progression, highlighting the need for a multitarget treatment approach. PMID- 29515802 TI - On-demand intermittent beclomethasone is effective for mild asthma in Brazil. AB - Background: Daily inhaled corticosteroids are widely recommended for mild persistent asthma. This study aimed to assess the efficacy of the intermittent use of beclomethasone as an alternative treatment for mild persistent asthma. Methods: In this 16-week trial, children aged 6-18 years were evaluated. Subjects in the continuous treatment arm of the study received 500 MUg/day of beclomethasone, whereas the intermittent ones were given 1000 MUg/day (250 MUg every 6 h) in combination with albuterol for 7 days upon exacerbations or worsening of symptoms. Primary outcome (i.e., treatment failure) was the occurrence of any asthma exacerbation requiring prednisone, and co-secondary outcomes were the mean/median differences for both, (1) the pre-bronchodilator FEV1 (% predicted) and (2) asthma control test (ACT/cACT) scores, from randomization to the last follow-up visit, and beclomethasone and albuterol consumption. Results: Ninety-four subjects from each treatment arm were included. They were comparable regarding all baseline characteristics; prednisone was used by 10 (10.6%) and 7 (7.4%) patients, respectively (95% CI - 6.1 to 12.6%, for the difference; p = 0.47). Statistical analysis showed no statistically significant differences with respect to both FEV1 (p = 0.39) and ACT/cACT scores (p = 0.38). As assessed through canister weighting, children used from 0.5 to 0.7 and from 1.6 to 1.8 puffs per day of beclomethasone in the intermittent and continuous regimens, respectively. Regarding albuterol, received 0.3-0.4 (intermittent) and 0.1-0.2 (continuous) inhalations per day. There were no relevant clinical or functional differences between the two treatment regimens. Conclusion: Clinicians might consider intermittent inhaled steroid therapy as a therapeutic regimen for mild persistent asthma.Trial registration The Portuguese and English versions of the study protocol were submitted, approved, and registered in the Brazilian Network Platform for Clinical Trials (http://www.ensaiosclinicos.gov.br) under the primary identifier number "RBR-3gbyhk". This platform is part of the Primary Registries in the World Health Organization Registry Network, where the trial is registered under the following Universal Trial Number: 1111-1149-4774. PMID- 29515803 TI - Overweight/obesity among adults in North-Western Ethiopia: a community-based cross sectional study. AB - Background: Nowadays adulthood overweight/obesity is an emerging public health problem in developing countries. There is no information on magnitude and contributing factors of adulthood overweight/obesity in Ethiopia, particularly in North West region of the country. Thus, the aim of this study was to assess magnitude and contributing factors of adulthood overweight/obesity in North West region of Ethiopia. Methods: A community-based cross-sectional study was conducted from September1, 2015 to November 30, 2015 in northwest region of Ethiopia particularly Bahir-Dar city and its rural districts. A total of 1484 adult participants were recruited in the study. Stratified multistage followed by systematic random sampling technique was employed to select participants. Overweight/obesity was determined using center for diseases control cutoff points. A multivariable binary logistic regression model was fitted to identify factors associated with overweight/obesity. Adjusted Odds Ratio (AOR) with the corresponding 95% Confidence Interval (CI) was calculated to show the strength of association. Results: A total of 1405 adults were participated in the study with a response rate of 94.7%. This study indicated that 11.3 (95% CI: 9.6, 13.1) adults were overweight and obese of which about 9.3% and 2% of adults were overweight and obese, respectively. The higher odds of being Overweight/Obese were noted among urban residents, females and older age. However performing mild to moderate physical activity [AOR = 0.608, 95% CI: 0.37, 0.99] and consumption of fruit and vegetable [AOR = 0.51, 95% CI: 0.34, 0.77] were found to be protective against overweight/obesity. Conclusion: Though, it was a problem of developed countries adulthood overweight /obesity is emerged as a public health problem among adults in Ethiopia particularly in the study area, northwest region. Hence, preventive interventions focusing on urban residents, females through encouraging Physical activity, fruit and vegetable consumption is essential to prevent emergence of adulthood overweight/obesity. PMID- 29515804 TI - The future is female. Is that a problem for sea turtle conservation? PMID- 29515805 TI - Elevated temperatures are associated with stress in rooftop-nesting Common Nighthawk (Chordeiles minor) chicks. AB - Grasslands and riparian forests in southeastern South Dakota have been greatly reduced since historical times, primarily due to conversion to row-crop agriculture. Common Nighthawk (Chordeiles minor) nesting habitat includes grasslands, open woodlands and urban rooftops, but nesting sites in southeastern South Dakota are confined to rooftops, as natural nesting habitat is limited. Nighthawks nesting on exposed rooftop habitats may encounter thermal conditions that increase operative temperatures relative to vegetated land cover types. Mean humidity has increased and mean wind speed and cloud cover have decreased during the nighthawk breeding season from 1948 to 2016 in southeastern South Dakota. These changes might contribute to increasing operative temperatures at exposed rooftop nest sites and this could influence chick condition. We studied nest micro-climate and the plasma stress response for 24 rooftop-nesting nighthawk chicks from 17 nests during 2015 and 2016. High humidity prior to blood collection reduced both baseline and stress-induced plasma corticosterone (CORT). In contrast, high maximum temperatures during the day before sampling increased stress-induced CORT. The magnitude of the chick stress response was significantly negatively related to maximum wind speed for the week prior to CORT measurement. Other weather and micro-climate variables were not significant effectors of CORT metrics. Most chicks had low baseline CORT and were able to mount a stress response, but a subset of chicks (n = 4) showed elevated baseline CORT and a negative association between the magnitude of stress response and ambient temperature. For this subset, mean ambient temperature for the day before sampling was significantly higher (2.3 degrees C) than for chicks with typical baseline CORT levels. These data suggest that regional climate change trends could affect the ability of nighthawk chicks to mount a stress response, which, in turn, might influence the susceptibility of nighthawk chicks to climate change in the Northern Prairie region. PMID- 29515809 TI - Eye-tracking-aided digital system for strabismus diagnosis. AB - Strabismus is one of the most common vision disorders in preschool children. It can cause amblyopia and even permanent vision loss. In addition to a vision problem, strabismus brings to both children and adults serious negative impacts in their daily life, education, employment etc. Timely diagnosis of strabismus is thus crucial. However, traditional diagnosis methods conducted by ophthalmologists rely significantly on their experiences, making the diagnosis results subjective. It is also inconvenient for those methods being used for strabismus examination in large communities such as schools. In light of that, in this Letter, the authors develop an objective, digital and automatic system based on eye-tracking technique for diagnosing strabismus. The system exploits eye tracking technique to acquire a person's eye gaze data while he or she is looking at some targets. A group of features are proposed to characterise the gaze data. The person's strabismus condition can be diagnosed according to the features. A strabismus gaze dataset is built using the system. Experimental results on the dataset demonstrate the effectiveness of the proposed system for strabismus diagnosis. PMID- 29515810 TI - Cardiorespiratory system monitoring using a developed acoustic sensor. AB - This Letter proposes a wireless acoustic sensor for monitoring heartbeat and respiration rate based on phonocardiogram (PCG). The developed sensor comprises a processor, a transceiver which operates at industrial, scientific and medical band and the frequency of 2.54 GHz as well as two capacitor microphones which one for recording the heartbeat and another one for respiration rate. To evaluate the precision of the presented sensor in estimating heartbeat and respiration rate, the sensor is tested on the different volunteers and the obtained results are compared with a gold standard as a reference. The results reveal that root-mean square error are determined <2.27 beats/min and 0.92 breaths/min for the heartbeat and respiration rate in turn. While the standard deviation of the error is obtained <1.26 and 0.63 for heartbeat and respiration rate, respectively. Also, the sensor estimate sounds of [Formula: see text] to [Formula: see text] obtained PCG signal with sensitivity and specificity 98.1% and 98.3% in turn that make 3% improvement than previous works. The results prove that the sensor can be appropriate candidate for recognising abnormal condition in the cardiorespiratory system. PMID- 29515811 TI - Relevance of two manual tumour volume estimation methods for diffuse low-grade gliomas. AB - Management of diffuse low-grade glioma (DLGG) relies extensively on tumour volume estimation from MRI datasets. Two methods are currently clinically used to define this volume: the commonly used three-diameters solution and the more rarely used software-based volume reconstruction from the manual segmentations approach. The authors conducted an initial study of inter-practitioners' variability of software-based manual segmentations on DLGGs MRI datasets. A panel of 13 experts from various specialties and years of experience delineated 12 DLGGs' MRI scans. A statistical analysis on the segmented tumour volumes and pixels indicated that the individual practitioner, the years of experience and the specialty seem to have no significant impact on the segmentation of DLGGs. This is an interesting result as it had not yet been demonstrated and as it encourages cross disciplinary collaboration. Their second study was with the three-diameters method, investigating its impact and that of the software-based volume reconstruction from manual segmentations method on tumour volume. They relied on the same dataset and on a participant from the first study. They compared the average of tumour volumes acquired by software reconstruction from manual segmentations method with tumour volumes obtained with the three-diameters method. The authors found that there is no statistically significant difference between the volumes estimated with the two approaches. These results correspond to non-operated and easily delineable DLGGs and are particularly interesting for time-consuming CUBE MRIs. Nonetheless, the three-diameters method has limitations in estimating tumour volumes for resected DLGGs, for which case the software based manual segmentation method becomes more appropriate. PMID- 29515808 TI - Seizure prophylaxis in the neuroscience intensive care unit. AB - Background: Seizures are a considerable complication in critically ill patients. Their incidence is significantly high in neurosciences intensive care unit patients. Seizure prophylaxis with anti-epileptic drugs is a common practice in neurosciences intensive care unit. However, its utility in patients without clinical seizure, with an underlying neurological injury, is somewhat controversial. Body: In this article, we have reviewed the evidence for seizure prophylaxis in commonly encountered neurological conditions in neurosciences intensive care unit and discussed the possible prognostic role of continuous electroencephalography monitoring in detecting early seizures in critically ill patients. Conclusion: Based on the current evidence and guidelines, we have proposed a presumptive protocol for seizure prophylaxis in neurosciences intensive care unit. Patients with severe traumatic brain injury and possible subarachnoid hemorrhage seem to benefit with a short course of anti-epileptic drug. In patients with other neurological illnesses, the use of continuous electroencephalography would make sense rather than indiscriminately administering anti-epileptic drug. PMID- 29515812 TI - Cascade and parallel combination (CPC) of adaptive filters for estimating heart rate during intensive physical exercise from photoplethysmographic signal. AB - Photoplethysmographic (PPG) signal is getting popularity for monitoring heart rate in wearable devices because of simplicity of construction and low cost of the sensor. The task becomes very difficult due to the presence of various motion artefacts. In this study, an algorithm based on cascade and parallel combination (CPC) of adaptive filters is proposed in order to reduce the effect of motion artefacts. First, preliminary noise reduction is performed by averaging two channel PPG signals. Next in order to reduce the effect of motion artefacts, a cascaded filter structure consisting of three cascaded adaptive filter blocks is developed where three-channel accelerometer signals are used as references to motion artefacts. To further reduce the affect of noise, a scheme based on convex combination of two such cascaded adaptive noise cancelers is introduced, where two widely used adaptive filters namely recursive least squares and least mean squares filters are employed. Heart rates are estimated from the noise reduced PPG signal in spectral domain. Finally, an efficient heart rate tracking algorithm is designed based on the nature of the heart rate variability. The performance of the proposed CPC method is tested on a widely used public database. It is found that the proposed method offers very low estimation error and a smooth heart rate tracking with simple algorithmic approach. PMID- 29515813 TI - Cloud-based adaptive exon prediction for DNA analysis. AB - Cloud computing offers significant research and economic benefits to healthcare organisations. Cloud services provide a safe place for storing and managing large amounts of such sensitive data. Under conventional flow of gene information, gene sequence laboratories send out raw and inferred information via Internet to several sequence libraries. DNA sequencing storage costs will be minimised by use of cloud service. In this study, the authors put forward a novel genomic informatics system using Amazon Cloud Services, where genomic sequence information is stored and accessed for processing. True identification of exon regions in a DNA sequence is a key task in bioinformatics, which helps in disease identification and design drugs. Three base periodicity property of exons forms the basis of all exon identification techniques. Adaptive signal processing techniques found to be promising in comparison with several other methods. Several adaptive exon predictors (AEPs) are developed using variable normalised least mean square and its maximum normalised variants to reduce computational complexity. Finally, performance evaluation of various AEPs is done based on measures such as sensitivity, specificity and precision using various standard genomic datasets taken from National Center for Biotechnology Information genomic sequence database. PMID- 29515814 TI - Mean curvature and texture constrained composite weighted random walk algorithm for optic disc segmentation towards glaucoma screening. AB - Accurate optic disc (OD) segmentation is an important step in obtaining cup-to disc ratio-based glaucoma screening using fundus imaging. It is a challenging task because of the subtle OD boundary, blood vessel occlusion and intensity inhomogeneity. In this Letter, the authors propose an improved version of the random walk algorithm for OD segmentation to tackle such challenges. The algorithm incorporates the mean curvature and Gabor texture energy features to define the new composite weight function to compute the edge weights. Unlike the deformable model-based OD segmentation techniques, the proposed algorithm remains unaffected by curve initialisation and local energy minima problem. The effectiveness of the proposed method is verified with DRIVE, DIARETDB1, DRISHTI GS and MESSIDOR database images using the performance measures such as mean absolute distance, overlapping ratio, dice coefficient, sensitivity, specificity and precision. The obtained OD segmentation results and quantitative performance measures show robustness and superiority of the proposed algorithm in handling the complex challenges in OD segmentation. PMID- 29515815 TI - Blood leakage detection during dialysis therapy based on fog computing with array photocell sensors and heteroassociative memory model. AB - Blood leakage and blood loss are serious life-threatening complications occurring during dialysis therapy. These events have been of concerns to both healthcare givers and patients. More than 40% of adult blood volume can be lost in just a few minutes, resulting in morbidities and mortality. The authors intend to propose the design of a warning tool for the detection of blood leakage/blood loss during dialysis therapy based on fog computing with an array of photocell sensors and heteroassociative memory (HAM) model. Photocell sensors are arranged in an array on a flexible substrate to detect blood leakage via the resistance changes with illumination in the visible spectrum of 500-700 nm. The HAM model is implemented to design a virtual alarm unit using electricity changes in an embedded system. The proposed warning tool can indicate the risk level in both end-sensing units and remote monitor devices via a wireless network and fog/cloud computing. The animal experimental results (pig blood) will demonstrate the feasibility. PMID- 29515816 TI - The challenge of safe driving among elderly drivers. AB - The challenge of ageing has two key aspects with regard to driving: mobility and safety. It is necessary for elderly adults to preserve independent mobility and activity; however, physical frailty and cognitive limitations have negative effects on their safety. Therefore, the issue of driving, and more specifically, the fostering of safe driving of old people, is crucial, especially due the increasing number of elderly people holding a driving license. The purpose of this Letter is to point out the complexity of elderly driving and to suggest countermeasures by acknowledging that obtaining the correct balance between safety and mobility of older drivers is a complicated and sensitive task. To address this issue, the authors suggest accommodating their driving behaviour and patterns, in light of the deteriorating driving skills, by integrating social and policy procedures and use of emerging technologies. Policy steps to support elderly drivers and their loved ones by gradually controlling driving of elderly population when this becomes risky to them may serve as a desired countermeasure according to a proved tool such as technology. Utilisation of advanced technologies can help to monitor travel and driver behaviour and ability to make the necessary alterations, based on elderly driving skills. PMID- 29515817 TI - Synergistic effect of natural chickpea leaf exudates acids in heterocyclization: a greener protocol for benzopyran synthesis. AB - Without using any toxic or hazardous reagent, ligand, acid, transition metal catalyst, additives/promoters and organic solvent, green Knoevenagel condensation and tandem Knoevenagel-Michael reactions have been successfully carried out by using chickpea leaf exudates as a naturally sourced Bronsted acid type bio catalyst. The reaction proceeds in neat chickpea leaf exudates at room temperature in aqueous conditions in very short reaction times, and therefore, it is an evergreen and environmentally sound alternative to the existing protocols for benzopyran synthesis. In comparison to the conventional methods, this synthetic pathway complies with several key requirements of green chemistry principles such as the utilization of biodegradable catalyst obtained from renewable feedstock, auxiliary aqueous conditions, along with waste prevention. The same protocol was also extended to the synthesis of 2H-xanthene-1,8-diones by condensation of aromatic aldehydes with dimedone achieving excellent yields. Thus, the reported protocol offers an attractive option because of its ecological safety, environmental acceptance, sustainability, low-cost straightforward work up procedure and with excellent values of green chemistry metrics as compared with other reported methods. PMID- 29515818 TI - Male-mediated species recognition among African weakly electric fishes. AB - Effective communication among sympatric species is often instrumental for behavioural isolation, where the failure to successfully discriminate between potential mates could lead to less fit hybrid offspring. Discrimination between con- and heterospecifics tends to occur more often in the sex that invests more in offspring production, i.e. females, but males may also mediate reproductive isolation. In this study, we show that among two Campylomormyrus African weakly electric fish species, males preferentially associate with conspecific females during choice tests using live fish as stimuli, i.e. when all sensory modalities potentially used for communication were present. We then conducted playback experiments to determine whether the species-specific electric organ discharge (EOD) used for electrocommunication serves as the cue for this conspecific association preference. Interestingly, only C. compressirostris males associated significantly more with the conspecific EOD waveform when playback stimuli were provided, while no such association preference was observed in C. tamandua males. Given our results, the EOD appears to serve, in part, as a male-mediated pre zygotic isolation mechanism among sympatric species. However, the failure of C. tamandua males to discriminate between con- and heterospecific playback discharges suggests that multiple modalities may be necessary for species recognition in some African weakly electric fish species. PMID- 29515819 TI - Swimming mechanics and propulsive efficiency in the chambered nautilus. AB - The chambered nautilus (Nautilus pompilius) encounters severe environmental hypoxia during diurnal vertical movements in the ocean. The metabolic cost of locomotion (Cmet) and swimming performance depend on how efficiently momentum is imparted to the water and how long on-board oxygen stores last. While propulsive efficiency is generally thought to be relatively low in jet propelled animals, the low Cmet in Nautilus indicates that this is not the case. We measured the wake structure in Nautilus during jet propulsion swimming, to determine their propulsive efficiency. Animals swam with either an anterior-first or posterior first orientation. With increasing swimming speed, whole cycle propulsive efficiency increased during posterior-first swimming but decreased during anterior-first swimming, reaching a maximum of 0.76. The highest propulsive efficiencies were achieved by using an asymmetrical contractile cycle in which the fluid ejection phase was relatively longer than the refilling phase, reducing the volume flow rate of the ejected fluid. Our results demonstrate that a relatively high whole cycle propulsive efficiency underlies the low Cmet in Nautilus, representing a strategy to reduce the metabolic demands in an animal that spends a significant part of its daily life in a hypoxic environment. PMID- 29515820 TI - Scientific risk communication about controversial issues influences public perceptions of scientists' political orientations and credibility. AB - Many scientists communicate with the public about risks associated with scientific issues, but such communication may have unintended consequences for how the public views the political orientations and the credibility of the communicating scientist. We explore this possibility using an experiment with a nationally representative sample of Americans in the fall of 2015. We find that risk communication on controversial scientific issues sometimes influences perceptions of the political orientations and credibility of the communicating scientist when the scientist addresses the risks of issues associated with conservative or liberal groups. This relationship is moderated by participant political ideology, with liberals adjusting their perceptions of the scientists' political beliefs more substantially when the scientist addressed the risks of marijuana use when compared with other issues. Conservatives' political perceptions were less impacted by the issue context of the scientific risk communication but indirectly influenced credibility perceptions. Our results support a contextual model of audience interpretation of scientific risk communication. Scientists should be cognizant that audience members may make inferences about the communicating scientist's political orientations and credibility when they engage in risk communication efforts about controversial issues. PMID- 29515821 TI - A density functional theory study of the role of functionalized graphene particles as effective additives in power cable insulation. AB - The role of a series of functionalized graphene additives in power cable insulation in suppressing the growth of electrical treeing and preventing the degradation of the polymer matrix has been investigated by density functional theory calculations. Bader charge analysis indicates that pristine, doped or defect graphene could effectively capture hot electrons to block their attack on cross-linked polyethylene (XLPE) because of the pi-pi conjugated unsaturated structures. Further exploration of the electronic properties in the interfacial region between the additives and XLPE shows that N-doped single-vacancy graphene, graphene oxide and B-, N-, Si- or P-doped graphene oxide have relatively strong physical interaction with XLPE to restrict its mobility and rather weak chemical activity to prevent the cleavage of the C-H or C-C bond, suggesting that they are all potential candidates as effective additives. The understanding of the features of functionalized graphene additives in trapping electrons and interfacial interaction will assist in the screening of promising additives as voltage stabilizers in power cables. PMID- 29515822 TI - Is countershading camouflage robust to lighting change due to weather? AB - Countershading is a pattern of coloration thought to have evolved in order to implement camouflage. By adopting a pattern of coloration that makes the surface facing towards the sun darker and the surface facing away from the sun lighter, the overall amount of light reflected off an animal can be made more uniformly bright. Countershading could hence contribute to visual camouflage by increasing background matching or reducing cues to shape. However, the usefulness of countershading is constrained by a particular pattern delivering 'optimal' camouflage only for very specific lighting conditions. In this study, we test the robustness of countershading camouflage to lighting change due to weather, using human participants as a 'generic' predator. In a simulated three-dimensional environment, we constructed an array of simple leaf-shaped items and a single ellipsoidal target 'prey'. We set these items in two light environments: strongly directional 'sunny' and more diffuse 'cloudy'. The target object was given the optimal pattern of countershading for one of these two environment types or displayed a uniform pattern. By measuring detection time and accuracy, we explored whether and how target detection depended on the match between the pattern of coloration on the target object and scene lighting. Detection times were longest when the countershading was appropriate to the illumination; incorrectly camouflaged targets were detected with a similar pattern of speed and accuracy to uniformly coloured targets. We conclude that structural changes in light environment, such as caused by differences in weather, do change the effectiveness of countershading camouflage. PMID- 29515823 TI - Adaptive phenotypic variation among clonal ant workers. AB - Phenotypic variations are observed in most organisms, but their significance is not always known. The phenotypic variations observed in social insects are exceptions. Genetically based response threshold variances have been identified among workers and are thought to play several important adaptive roles in social life, e.g. allocating tasks among workers according to demand, promoting the sustainability of the colony and forming the basis of rationality in collective decision-making. Several parthenogenetic ants produce clonal workers and new queens by asexual reproduction. It is not clearly known whether such genetically equivalent workers show phenotypic variations. Here, we demonstrate that clonal workers of the parthenogenetic ant Strumigenys membranifera show large threshold variances among clonal workers. A multi-locus genetic marker confirmed that colony members are genetic clones, but they showed variations in their sucrose response thresholds. We examined the changing pattern of the thresholds over time generating hypotheses regarding the mechanism underlying the observed phenotypic variations. The results support the hypothesis that epigenetic modifications that occur after eclosion into the adult form are the cause of the phenotypic variations in this asexual species. PMID- 29515824 TI - Controlled iris radiance in a diurnal fish looking at prey. AB - Active sensing using light, or active photolocation, is only known from deep sea and nocturnal fish with chemiluminescent 'search' lights. Bright irides in diurnal fish species have recently been proposed as a potential analogue. Here, we contribute to this discussion by testing whether iris radiance is actively modulated. The focus is on behaviourally controlled iris reflections, called 'ocular sparks'. The triplefin Tripterygion delaisi can alternate between red and blue ocular sparks, allowing us to test the prediction that spark frequency and hue depend on background hue and prey presence. In a first experiment, we found that blue ocular sparks were significantly more often 'on' against red backgrounds, and red ocular sparks against blue backgrounds, particularly when copepods were present. A second experiment tested whether hungry fish showed more ocular sparks, which was not the case. However, background hue once more resulted in a significant differential use of ocular sparks. We conclude that iris radiance through ocular sparks in T. delaisi is not a side effect of eye movement, but adaptively modulated in response to the context under which prey are detected. We discuss the possible alternative functions of ocular sparks, including an as yet speculative role in active photolocation. PMID- 29515825 TI - A simple route to a novel acid-sensitive 20(S)-O-linked camptothecin norcantharidin acid ester derivative. AB - A facile synthetic method was developed for a novel acid-sensitive camptothecin norcantharidin acid ester derivative I. The total yield can reach 71%. This method provides several advantages, including high yield and simple working procedure for the synthesis of analogues. The new synthetic compound I has been shown to exhibit better solubility and similar activity against tumour cell lines. PMID- 29515826 TI - Photophysical studies on curcumin-sophorolipid nanostructures: applications in quorum quenching and imaging. AB - Sophorolipid biosurfactants are biodegradable, less toxic and FDA approved. The purified acidic form of sophorolipid is stimuli-responsive with self-assembling properties and used for solubilizing hydrophobic drugs. This study encapsulated curcumin (CU) with acidic sophorolipid (ASL) micelles and analysed using photophysical studies like UV-visible spectroscopy, photoluminescence (PL) spectroscopy and time-correlated single photon counting (TCSPC). TEM images have revealed ellipsoid micelles of approximately 100 nm size and were confirmed by dynamic light scattering. The bacterial fluorescence uptake studies showed the uptake of formed CUASL nanostructures into both Gram-positive and Gram-negative bacteria. They also showed quorum quenching activity against Pseudomonas aeruginosa. The results have demonstrated this system has potential theranostic applications. PMID- 29515827 TI - Investigating structure-property relationships of biomineralized calcium phosphate compounds as fluorescent quenching-recovery platform. AB - The structure-property relationship between biomineralized calcium phosphate compounds upon a fluorescent quenching-recovery platform and their distinct crystalline structure and surficial functional groups are investigated. A fluorescence-based sensing platform is shown to be viable for the sensing of 8 hydroxy-2-deoxy-guanosine in simulated systems. PMID- 29515829 TI - Complexity of possibly gapped histogram and analysis of histogram. AB - We demonstrate that gaps and distributional patterns embedded within real-valued measurements are inseparable biological and mechanistic information contents of the system. Such patterns are discovered through data-driven possibly gapped histogram, which further leads to the geometry-based analysis of histogram (ANOHT). Constructing a possibly gapped histogram is a complex problem of statistical mechanics due to the ensemble of candidate histograms being captured by a two-layer Ising model. This construction is also a distinctive problem of Information Theory from the perspective of data compression via uniformity. By defining a Hamiltonian (or energy) as a sum of total coding lengths of boundaries and total decoding errors within bins, this issue of computing the minimum energy macroscopic states is surprisingly resolved by applying the hierarchical clustering algorithm. Thus, a possibly gapped histogram corresponds to a macro state. And then the first phase of ANOHT is developed for simultaneous comparison of multiple treatments, while the second phase of ANOHT is developed based on classical empirical process theory for a tree-geometry that can check the authenticity of branches of the treatment tree. The well-known Iris data are used to illustrate our technical developments. Also, a large baseball pitching dataset and a heavily right-censored divorce data are analysed to showcase the existential gaps and utilities of ANOHT. PMID- 29515830 TI - Removal of cadmium from aqueous solutions using industrial coal fly ash-nZVI. AB - Batch experiments were conducted to test the effects of various solution properties, such as pH, temperature, initial concentration and anoxic and aerobic atmosphere, on Cd removal by nanoscale zerovalent iron (nZVI) supported on industrial coal fly ash. Cd (II) could be removed by adsorption on fly ash-nZVI in a very short time (5 min) with high removal rates (greater than 99.9%) over a wide range of concentration (5-100 mg l-1). Cd (II) was physically adsorbed on the surface of fly ash-nZVI. The preparation of fly ash-nZVI can incorporate the use of waste media, making the overall adsorbent more removal efficient and low cost. PMID- 29515828 TI - Gene expression differs in susceptible and resistant amphibians exposed to Batrachochytrium dendrobatidis. AB - Chytridiomycosis, the disease caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), has devastated global amphibian biodiversity. Nevertheless, some hosts avoid disease after Bd exposure even as others experience near complete extirpation. It remains unclear whether the amphibian adaptive immune system plays a role in Bd defence. Here, we describe gene expression in two host species-one susceptible to chytridiomycosis and one resistant-following exposure to two Bd isolates that differ in virulence. Susceptible wood frogs (Rana sylvatica) had high infection loads and mortality when exposed to the more virulent Bd isolate but lower infection loads and no fatal disease when exposed to the less virulent isolate. Resistant American bullfrogs (R. catesbeiana) had high survival across treatments and rapidly cleared Bd infection or avoided infection entirely. We found widespread upregulation of adaptive immune genes and downregulation of important metabolic and cellular maintenance components in wood frogs after Bd exposure, whereas American bullfrogs showed little gene expression change and no evidence of an adaptive immune response. Wood frog responses suggest that adaptive immune defences may be ineffective against virulent Bd isolates that can cause rapid physiological dysfunction. By contrast, American bullfrogs exhibited robust resistance to Bd that is likely attributable, at least in part, to their continued upkeep of metabolic and skin integrity pathways as well as greater antimicrobial peptide expression compared to wood frogs, regardless of exposure. Greater understanding of these defences will ultimately help conservationists manage chytridiomycosis. PMID- 29515831 TI - A down-shifting Eu3+-doped Y2WO6/TiO2 photoelectrode for improved light harvesting in dye-sensitized solar cells. AB - Y1.86Eu0.14WO6 phosphors were prepared using a solid-state reaction method. Their optical properties were analysed, and they was mixed with TiO2, sintered, and used as a photoelectrode (PE) in dye-sensitized solar cells (DSSCs). The as prepared photoelectrode was characterized by photoluminescence spectroscopy, diffuse reflectance, electrochemical impedance spectroscopy (EIS) and X-ray diffraction. The photoelectric conversion efficiency of the DSSC with TiO2:Y1.86Eu0.14WO6 (100:2.5) was 25.8% higher than that of a DSCC using pure TiO2 as PE. This high efficiency is due to the ability of the luminescent material to convert ultraviolet radiation from the sun to visible radiation, thus improving the solar light harvesting of the DSSC. PMID- 29515833 TI - Fabrication and electromagnetic performance of talc/NiTiO3 composite. AB - In this study, the electromagnetic (EM) performance of talc/NiTiO3 composite was evaluated. The morphology of talc displayed a lamella structure; there were many nanoparticles of NiTiO3 coated on the talc lamella. Thermal destruction occurred, which increased the surface area from 2.51 m2 g-1 to 79.09 m2 g-1 at the calcined stage at 650 degrees C. The presence of NiTiO3 increased dielectric loss and magnetic loss of talc. The calculation of EM wave absorption of talc/NiTiO3 obtained a maximum reflection loss of -11.94 dB at the thickness of 6.85 mm; the optimum thickness for microwave absorption is 6.3-7.3 mm. This study revealed a new approach for fabricating an EM absorber and broadening applications of both talc and NiTiO3 in EM absorption. PMID- 29515832 TI - Identification of allosteric disulfides from labile bonds in X-ray structures. AB - Protein disulfide bonds link pairs of cysteine sulfur atoms and are either structural or functional motifs. The allosteric disulfides control the function of the protein in which they reside when cleaved or formed. Here, we identify potential allosteric disulfides in all Protein Data Bank X-ray structures from bonds that are present in some molecules of a protein crystal but absent in others, or present in some structures of a protein but absent in others. We reasoned that the labile nature of these disulfides signifies a propensity for cleavage and so possible allosteric regulation of the protein in which the bond resides. A total of 511 labile disulfide bonds were identified. The labile disulfides are more stressed than the average bond, being characterized by high average torsional strain and stretching of the sulfur-sulfur bond and neighbouring bond angles. This pre-stress likely underpins their susceptibility to cleavage. The coagulation, complement and oxygen-sensing hypoxia inducible factor-1 pathways, which are known or have been suggested to be regulated by allosteric disulfides, are enriched in proteins containing labile disulfides. The identification of labile disulfide bonds will facilitate the study of this post translational modification. PMID- 29515834 TI - Body odour disgust sensitivity predicts authoritarian attitudes. AB - Authoritarianism has resurfaced as a research topic in political psychology, as it appears relevant to explain current political trends. Authoritarian attitudes have been consistently linked to feelings of disgust, an emotion that is thought to have evolved to protect the organism from contamination. We hypothesized that body odour disgust sensitivity (BODS) might be associated with authoritarianism, as chemo-signalling is a primitive system for regulating interpersonal contact and disease avoidance, which are key features also in authoritarianism. We used well-validated scales for measuring BODS, authoritarianism and related constructs. Across two studies, we found that BODS is positively related to authoritarianism. In a third study, we showed a positive association between BODS scores and support for Donald Trump, who, at the time of data collection, was a presidential candidate with an agenda described as resonating with authoritarian attitudes. Authoritarianism fully explained the positive association between BODS and support for Donald Trump. Our findings highlight body odour disgust as a new and promising domain in political psychology research. Authoritarianism and BODS might be part of the same disease avoidance framework, and our results contribute to the growing evidence that contemporary social attitudes might be rooted in basic sensory functions. PMID- 29515835 TI - Experimental and numerical investigations on spray characteristics of fatty acid methyl esters. AB - A comparative experimental and numerical study is conducted to establish the significance of the use of single-component over multi-component representatives of biodiesel, diesel and their blend for predicting spray tip penetration. Methyl oleate and methyl laurate are used as single-component representative fuels for biodiesel. The pure components n-heptane, n-dodecane and n-tetradecane are used as single-component representative fuels for diesel. Methyl laurate is found to represent biodiesel of coconut, whereas methyl oleate is found to represent biodiesel having high percentage of long-chain fatty acid esters. The spray tip penetration of methyl oleate is found to be in good agreement with the measured spray tip penetration of karanja biodiesel. The spray tip penetration prediction of n-heptane fuel is closely following diesel spray tip penetration along with that of n-tetradecane and n-dodecane. The study suggests that the knowledge of the single-component representatives of biodiesel, diesel and their blend is sufficient to predict the spray tip penetration of the corresponding biodiesel, diesel and their blend under non-evaporating environment. PMID- 29515836 TI - Mate limitation and sex ratio evolution. AB - Sex ratio evolution has been one of the most successful areas of evolutionary theory. Pioneered by Dusing and Fisher under panmixia, and later extended by Hamilton to cover local mate competition (LMC), these models often assume, either implicitly or explicitly, that all females are fertilized. Here, we examine the effects of relaxing this assumption, under both panmictic and LMC models with diploid genetics. We revisit the question of the mathematical relationship between sex ratio and probability of fertilization, and use these results to model sex ratio evolution under risk of incomplete fertilization. We find that (i) under panmixia, mate limitation has no effect on the evolutionarily stable strategy (ESS) sex allocation; (ii) under LMC, mate limitation can make sex allocation less female-biased than under complete fertilization; (iii) contrary to what is occasionally stated, a significant fraction of daughters can remain unfertilized at the ESS in LMC with mate limitation; (iv) with a commonly used mating function, the fraction of unfertilized daughters can be quite large, and (v) with more realistic fertilization functions, the deviation becomes smaller. The models are presented in three equivalent forms: individual selection, kin selection and group selection. This serves as an example of the equivalence of the methods, while each approach has their own advantages. We discuss possible extensions of the model to haplodiploidy. PMID- 29515837 TI - Topological, chemical and electro-optical characteristics of riboflavin-doped artificial and natural DNA thin films. AB - DNA is considered as a useful building bio-material, and it serves as an efficient template to align functionalized nanomaterials. Riboflavin (RF)-doped synthetic double-crossover DNA (DX-DNA) lattices and natural salmon DNA (SDNA) thin films were constructed using substrate-assisted growth and drop-casting methods, respectively, and their topological, chemical and electro-optical characteristics were evaluated. The critical doping concentrations of RF ([RF]C, approx. 5 mM) at given concentrations of DX-DNA and SDNA were obtained by observing the phase transition (from crystalline to amorphous structures) of DX DNA and precipitation of SDNA in solution above [RF]C. [RF]C are verified by analysing the atomic force microscopy images for DX-DNA and current, absorbance and photoluminescence (PL) for SDNA. We study the physical characteristics of RF embedded SDNA thin films, using the Fourier transform infrared spectrum to understand the interaction between the RF and DNA molecules, current to evaluate the conductance, absorption to understand the RF binding to the DNA and PL to analyse the energy transfer between the RF and DNA. The current and UV absorption band of SDNA thin films decrease up to [RF]C followed by an increase above [RF]C. By contrast, the PL intensity illustrates the reverse trend, as compared to the current and UV absorption behaviour as a function of the varying [RF]. Owing to the intense PL characteristic of RF, the DNA lattices and thin films with RF might offer immense potential to develop efficient bio-sensors and useful bio photonic devices. PMID- 29515838 TI - Effects of eco-friendly carbohydrate-based superabsorbent polymers on seed germination and seedling growth of maize. AB - Desertification is the degradation of land in arid and semi-arid areas. Nowadays, lack of water and desertification are extreme problems for plant survival and growth in the arid and semi-arid areas of the world. It becomes increasingly important as to how to let the plant absorb moisture more effectively for keeping growth strong. We synthesized superabsorbent polymers (SAPs) with carbohydrate and characterized them by Fourier transform infrared spectra analyses, scanning electron microscopy and thermogravimetric/differential thermal analyses. Then, a completely randomized experiment was conducted to assess the effect of carbohydrate-based SAPs on seed germination and seedling growth of maize in an artificial climate chest. The results showed that adding an appropriate amount of SAPs could improve root length, shoot length, total biomass, germination potential and germination rate. It indicates that this SAP is not toxic to plants and can promote seed germination, and at the same time provides a possibility of replacing other substrates. PMID- 29515839 TI - An adaptable but threatened big cat: density, diet and prey selection of the Indochinese leopard (Panthera pardus delacouri) in eastern Cambodia. AB - We studied the Indochinese leopard (Panthera pardus delacouri) in eastern Cambodia, in one of the few potentially remaining viable populations in Southeast Asia. The aims were to determine the: (i) current leopard density in Srepok Wildlife Sanctuary (SWS) and (ii) diet, prey selection and predation impact of leopard in SWS. The density, estimated using spatially explicit capture-recapture models, was 1.0 leopard/100 km2, 72% lower than an estimate from 2009 at the same site, and one of the lowest densities ever reported in Asia. Dietary analysis of 73 DNA confirmed scats showed leopard consumed 13 prey species, although ungulates comprised 87% of the biomass consumed (BC). The overall main prey (42% BC) was banteng (Bos javanicus), making this the only known leopard population whose main prey had adult weight greater than 500 kg. Consumption of wild pig (Sus scrofa) was also one of the highest ever reported (22% BC), indicating leopard consistently predated on ungulates with some of the largest adult weights in SWS. There were important differences in diet and prey selection between sexes, as males consumed mostly banteng (62% BC) in proportion to availability, but few muntjac (Muntiacus vaginalis; 7% BC), whereas females selectively consumed muntjac (56% BC) and avoided banteng (less than 1% BC). Predation impact was low (0.5-3.2% of populations) for the three ungulate species consumed. We conclude that the Indochinese leopard is an important apex predator in SWS, but this unique population is declining at an alarming rate and will soon be eradicated unless effective protection is provided. PMID- 29515840 TI - Modification of wheat gluten for improvement of binding capacity with keratin in hair. AB - In this study, enzymatic hydrolysis and cationization with epoxypropyldodecyldimethylammonium chloride of wheat protein, an economic protein complex containing great amount of disulfide bonds, were conducted to improve properties such as solubility and disassociation behaviour for recovery of damaged hair when used in shampoo. The optimal conditions for enzymatic hydrolysis were pH 8.2, 55 degrees C with Alcalase for 60 min. After the selected hydrolysis, the degree of hydrolysis, nitrogen solubility index, foaming capacity index, foam stability index, emulsifying activity index and emulsion stability index of hydrolysate with 58.71% of short-chain peptides (less than 1000 Da) were 8.81%, 39.07%, 225%, 56.67%, 9.62 m2 g-1 and 49.08, respectively. The cationization was followed to raise the isoelectric point of wheat protein hydrolysate from 7.0 to 10.0, which could facilitate the quaternized protein hydrolysate to adhere to the surface of hair at the range of pH 5-6 of hair care products to form more disulfide bonds. The results show that a shampoo with quaternized wheat proteins hydrolysate possesses excellent properties in recovering damaged hair, making the surface of hair smooth and compact. PMID- 29515841 TI - Optimization of methylene blue removal by stable emulsified liquid membrane using Plackett-Burman and Box-Behnken designs of experiments. AB - The stability of an emulsified liquid membrane composed of Span80 as a surfactant, D2EHPA as an extractant and sulfuric acid as an internal phase was first studied according to different diluents and many operating parameters using the Plackett-Burman design of experiments. Then the removal of methylene blue from an aqueous solution has been carried out using this emulsified liquid membrane at its stability conditions. The effects of operating parameters were analysed from the Box-Behnken design of experiments. The optimization of the extraction has been realized applying the response surface methodology and the results showed that the dye extraction yielding 98.72% was achieved at optimized conditions. PMID- 29515842 TI - The narrow gap between norms and cooperative behaviour in a reindeer herding community. AB - Cooperation evolves on social networks and is shaped, in part, by norms: beliefs and expectations about the behaviour of others or of oneself. Networks of cooperative social partners and associated norms are vital for pastoralists, such as Saami reindeer herders in northern Norway. However, little is known quantitatively about how norms structure pastoralists' social networks or shape cooperation. Saami herders reported their social networks and participated in field experiments, allowing us to gauge the overlap between reported and emergent cooperation. We show that individuals' perceptions of reciprocal cooperation within their social networks exceeded actual reciprocity, although both occurred frequently and were concentrated within herding groups. Herders with more extensive cooperation networks received more rewards in an economic game. Although herders overestimated reciprocal helping, cooperation in this community was still extensive, suggesting that perceived norms potentially allow network structures promoting cooperation to emerge and be maintained. PMID- 29515843 TI - A method for estimating Hill function-based dynamic models of gene regulatory networks. AB - Gene regulatory networks (GRNs) are quite large and complex. To better understand and analyse GRNs, mathematical models are being employed. Different types of models, such as logical, continuous and stochastic models, can be used to describe GRNs. In this paper, we present a new approach to identify continuous models, because they are more suitable for large number of genes and quantitative analysis. One of the most promising techniques for identifying continuous models of GRNs is based on Hill functions and the generalized profiling method (GPM). The advantage of this approach is low computational cost and insensitivity to initial conditions. In the GPM, a constrained nonlinear optimization problem has to be solved that is usually underdetermined. In this paper, we propose a new optimization approach in which we reformulate the optimization problem such that constraints are embedded implicitly in the cost function. Moreover, we propose to split the unknown parameter in two sets based on the structure of Hill functions. These two sets are estimated separately to resolve the issue of the underdetermined problem. As a case study, we apply the proposed technique on the SOS response in Escherichia coli and compare the results with the existing literature. PMID- 29515844 TI - Amadori-glycated phosphatidylethanolamine enhances the physical stability and selective targeting ability of liposomes. AB - Liposomes consisting of 100% phosphatidylcholine exhibit poor membrane fusion, cellular uptake and selective targeting capacities. To overcome these limitations, we used Amadori-glycated phosphatidylethanolamine, which is universally present in animals and commonly consumed in foods. We found that liposomes containing Amadori-glycated phosphatidylethanolamine exhibited significantly reduced negative membrane potential and demonstrated high cellular uptake. PMID- 29515845 TI - Counterfactual quantum erasure: spooky action without entanglement. AB - We combine the eyebrow-raising quantum phenomena of erasure and counterfactuality for the first time, proposing a simple yet unusual quantum eraser: A distant Bob can decide to erase which-path information from Alice's photon, dramatically restoring interference-without previously shared entanglement, and without Alice's photon ever leaving her laboratory. PMID- 29515846 TI - On the feasibility of the computational modelling of the endoluminal vacuum assisted closure of an oesophageal anastomotic leakage. AB - Endoluminal vacuum-assisted closure (E-VAC) is a promising therapy to treat anastomotic leakages of the oesophagus and bowel which are associated with high morbidity and mortality rates. An open-pore polyurethane foam is introduced into the leakage cavity and connected to a device that applies a suction pressure to accelerate the closure of the defect. Computational analysis of this healing process can advance our understanding of the biomechanical mechanisms at play. To this aim, we use a dual-stage finite-element analysis in which (i) the structural problem addresses the cavity reduction caused by the suction and (ii) a new constitutive formulation models tissue healing via permanent deformations coupled to a stiffness increase. The numerical implementation in an in-house code is described and a qualitative example illustrates the basic characteristics of the model. The computational model successfully reproduces the generic closure of an anastomotic leakage cavity, supporting the hypothesis that suction pressure promotes healing by means of the aforementioned mechanisms. However, the current framework needs to be enriched with empirical data to help advance device designs and treatment guidelines. Nonetheless, this conceptual study confirms that computational analysis can reproduce E-VAC of anastomotic leakages and establishes the bases for better understanding the mechanobiology of anastomotic defect healing. PMID- 29515847 TI - Songbird dynamics under the sea: acoustic interactions between humpback whales suggest song mediates male interactions. AB - The function of song has been well studied in numerous taxa and plays a role in mediating both intersexual and intrasexual interactions. Humpback whales are among few mammals who sing, but the role of sexual selection on song in this species is poorly understood. While one predominant hypothesis is that song mediates male-male interactions, the mechanism by which this may occur has never been explored. We applied metrics typically used to assess songbird interactions to examine song sequences and movement patterns of humpback whale singers. We found that males altered their song presentation in the presence of other singers; focal males increased the rate at which they switched between phrase types (p = 0.005), and tended to increase the overall evenness of their song presentation (p = 0.06) after a second male began singing. Two-singer dyads overlapped their song sequences significantly more than expected by chance. Spatial analyses revealed that change in distance between singers was related to whether both males kept singing (p = 0.012), with close approaches leading to song cessation. Overall, acoustic interactions resemble known mechanisms of mediating intrasexual interactions in songbirds. Future work should focus on more precisely resolving how changes in song presentation may be used in competition between singing males. PMID- 29515848 TI - Coupled electro-thermal field in a high current electrolysis cell or liquid metal batteries. AB - Coupled electro-thermal field exists widely in chemical batteries and electrolysis industry. In this study, a three-dimensional numerical model, which is based on the finite-element software ANSYS, has been built to simulate the electro-thermal field in a magnesium electrolysis cell. The adjustment of the relative position of the anode and cathode can change the energy consumption of the magnesium electrolysis process significantly. Besides, the current intensity has a nonlinear effect on heat balance, and the effects of heat transfer coefficients, electrolysis and air temperature on the heat balance have been released to maintain the thermal stability in a magnesium electrolysis cell. The relationship between structure as well as process parameters and electro-thermal field has been obtained and the simulation results can provide experience for the scale-up design in liquid metal batteries. PMID- 29515849 TI - Porous metallosilicates for heterogeneous, liquid-phase catalysis: perspectives and pertaining challenges. AB - Porous silicates containing dilute amounts of tri-, tetra- and penta-valent metal sites, such as TS-1, Sn-beta and Fe-ZSM-5, have recently emerged as state of the art catalysts for a variety of sustainable chemical transformations. In contrast with their aluminosilicate cousins, which are widely employed throughout the refinery industry for gas-phase catalytic transformations, such metallosilicates have exhibited unprecedented levels of performance for a variety of liquid-phase catalytic processes, including the conversion of biomass to chemicals, and sustainable oxidation technologies with H2O2. However, despite their unique levels of performance for these new types of chemical transformations, increased utilization of these promising materials is complicated by several factors. For example, their utilization in a liquid, and often polar, medium hinders process intensification (scale-up, catalyst deactivation). Moreover, such materials do not generally exhibit the active-site homogeneity of conventional aluminosilicates, and they typically possess a wide variety of active-site ensembles, only some of which may be directly involved in the catalytic chemistry of interest. Consequently, mechanistic understanding of these catalysts remains relatively low, and competitive reactions are commonly observed. Accordingly, unified approaches towards developing more active, selective and stable porous metallosilicates have not yet been achieved. Drawing on some of the most recent literature in the field, the purpose of this mini review is both to highlight the breakthroughs made with regard to the use of porous metallosilicates as heterogeneous catalysts for liquid-phase processing, and to highlight the pertaining challenges that we, and others, aim to overcome during the forthcoming years. PMID- 29515850 TI - External immunity in ant societies: sociality and colony size do not predict investment in antimicrobials. AB - Social insects live in dense groups with a high probability of disease transmission and have therefore faced strong pressures to develop defences against pathogens. For this reason, social insects have been hypothesized to invest in antimicrobial secretions as a mechanism of external immunity to prevent the spread of disease. However, empirical studies linking the evolution of sociality with increased investment in antimicrobials have been relatively few. Here we quantify the strength of antimicrobial secretions among 20 ant species that cover a broad spectrum of ant diversity and colony sizes. We extracted external compounds from ant workers to test whether they inhibited the growth of the bacterium Staphylococcus epidermidis. Because all ant species are highly social, we predicted that all species would exhibit some antimicrobial activity and that species that form the largest colonies would exhibit the strongest antimicrobial response. Our comparative approach revealed that strong surface antimicrobials are common to particular ant clades, but 40% of species exhibited no antimicrobial activity at all. We also found no correlation between antimicrobial activity and colony size. Rather than relying on antimicrobial secretions as external immunity to control pathogen spread, many ant species have probably developed alternative strategies to defend against disease pressure. PMID- 29515851 TI - Using phosphine ligands with a biological role to modulate reactivity in novel platinum complexes. AB - Three platinum complexes with cis and trans configuration cis-[Pt(TCEP)2Cl2], cis [Pt(tmTCEP)2Cl2] and trans-[Pt(TCEP)2Cl2], where TCEP is tris(2 carboxyethyl)phosphine, have been synthesized and fully characterized by usual techniques including single-crystal X-ray diffraction for trans-[Pt(TCEP)2Cl2] and cis-[Pt(tmTCEP)2Cl2]. Here, we also report on an esterification process of TCEP, which takes place in the presence of alcohols, leading to a platinum complex coordinated to an ester tmTCEP (2-methoxycarbonylethyl phosphine) ligand. The stability in solution of the three compounds and their interaction with biological models such as DNA (pBR322 and calf thymus DNA) and proteins (lysozyme and RNase) have also been studied. PMID- 29515853 TI - Degradation of clofibric acid in UV/chlorine disinfection process: kinetics, reactive species contribution and pathways. AB - As a potential endocrine disruptor, clofibric acid (CA) was investigated in this study for its degradation kinetics and pathways in UV/chlorine process. The results showed that CA in both UV photolysis and UV/chlorine processes could be degraded via pseudo-first-order kinetics, while it almost could not be degraded in the dark chlorination process. The observed rate constant (kobs) in UV photolysis was 0.0078 min-1, and increased to 0.0107 min-1 combining with 0.1 mM chlorine. The kobs increased to 0.0447 min-1 with further increasing the chlorine dosage from 0.1 to 1.0 mM, and reached a plateau at higher dosage (greater than 1.0 mM). The higher kobs was obtained at acid solution rather than basic solution. Moreover, the calculated contributions of radical species to kobs indicated that the HO* contributed significantly to CA degradation in acidic conditions, while the reactive chlorine species and UV direct photolysis dominated in neutral and basic solution. The degradation of CA was slightly inhibited in the presence of [Formula: see text] (1 ~ 50 mM), barely affected by the presence of Cl- (1 ~ 200 mM) and greatly suppressed by humic acid (0 ~ 5 mg l 1). Thirteen main degradation intermediates and three degradation pathways of CA were identified during UV/chlorine process. PMID- 29515852 TI - Evidence for parallel activation of the pre-supplementary motor area and inferior frontal cortex during response inhibition: a combined MEG and TMS study. AB - This pre-registered experiment sought to uncover the temporal relationship between the inferior frontal cortex (IFC) and the pre-supplementary motor area (pre-SMA) during stopping of an ongoing action. Both regions have previously been highlighted as being central to cognitive control of actions, particularly response inhibition. Here we tested which area is activated first during the stopping process using magnetoencephalography, before assessing the relative chronometry of each region using functionally localized transcranial magnetic stimulation. Both lines of evidence pointed towards simultaneous activity across both regions, suggesting that parallel, mutually interdependent processing may form the cortical basis of stopping. Additional exploratory analysis, however, provided weak evidence in support of previous suggestions that the pre-SMA may provide an ongoing drive of activity to the IFC. PMID- 29515854 TI - Orientation-dependent structural and photocatalytic properties of LaCoO3 epitaxial nano-thin films. AB - LaCoO3 epitaxial films were grown on (100), (110) and (111) oriented LaAlO3 substrates by the polymer-assisted deposition method. Crystal structure measurement and cross-section observation indicate that all the LaCoO3 films are epitaxially grown in accordance with the orientation of LaAlO3 substrates, with biaxial compressive strain in the ab plane. Owing to the different strain directions of CoO6 octahedron, the mean Co-O bond length increases by different amounts in (100), (110) and (111) oriented films compared with that of bulk LaCoO3, and the (100) oriented LaCoO3 has the largest increase. Photocatalytic degradation of methyl orange indicates that the order of photocatalytic activity of the three oriented films is (100) > (111) > (110). Combined with analysis of electronic nature and band structure for LaCoO3 films, it is found that the change of the photocatalytic activity is closely related to the crystal field splitting energy of Co3+ and Co-O binding energy. The increase in the mean Co-O bond length will decrease the crystal field splitting energy of Co3+ and Co-O binding energy and further reduce the value of band gap energy, thus improving the photocatalytic activity. This may also provide a clue for expanding the visible-light-induced photocatalytic application of LaCoO3. PMID- 29515855 TI - Esterification of phenyl acetic acid with p-cresol using metal cation exchanged montmorillonite nanoclay catalysts. AB - The liquid phase esterification of phenyl acetic acid with p-cresol over different metal cation exchanged montmorillonite nanoclays yields p-cresyl phenyl acetate. Different metal cation exchanged montmorillonite nanoclays (M n+ = Al3+, Zn2+, Mn2+, Fe3+, Cu2+) were prepared and the catalytic activity was studied. The esterification reaction was conducted by varying molar ratio of the reactants, reaction time and catalyst amount on the yield of the ester. Among the different metal cation exchanged catalysts used, Al3+-montmorillonite nanoclay was found to be more active. The characterization of the material used was studied under different techniques, namely X-ray diffraction, scanning electron microscopy and thermogravimetric analysis. The product obtained, p-cresyl phenyl acetate, was identified by thin-layer chromotography and confirmed by Fourier transform infrared, 1H NMR and 13C NMR. The regeneration activity of used catalyst was also investigated up to fourth generation. PMID- 29515856 TI - Multiscale analysis of enantioselectivity in enzyme-catalysed 'lethal synthesis' using projector-based embedding. AB - The action of fluoroacetate as a broad-spectrum mammalian pesticide depends on the 'lethal synthesis' of fluorocitrate by citrate synthase, through a subtle enantioselective enolization of fluoroacetyl-coenzyme A. In this work, we demonstrate how a projection-based embedding method can be applied to calculate coupled cluster (CCSD(T)) reaction profiles from quantum mechanics/molecular mechanics optimized pathways for this enzyme reaction. Comparison of pro-R and pro-S proton abstraction in citrate synthase at the CCSD(T)-in-DFT//MM level yields the correct enantioselectivity. We thus demonstrate the potential of projection-based embedding for determining stereoselectivity in enzymatic systems. We further show that the method is simple to apply, eliminates variability due to the choice of density functional theory functional and allows the efficient calculation of CCSD(T) quality enzyme reaction barriers. PMID- 29515857 TI - Interdependence theory of tissue failure: bulk and boundary effects. AB - The mortality rate of many complex multicellular organisms increases with age, which suggests that net ageing damage is accumulative, despite remodelling processes. But how exactly do these little mishaps in the cellular level accumulate and spread to become a systemic catastrophe? To address this question we present experiments with synthetic tissues, an analytical model consistent with experiments, and a number of implications that follow the analytical model. Our theoretical framework describes how shape, curvature and density influences the propagation of failure in a tissue subjected to oxidative damage. We propose that ageing is an emergent property governed by interaction between cells, and that intercellular processes play a role that is at least as important as intracellular ones. PMID- 29515858 TI - Distance-dependent aposematism and camouflage in the cinnabar moth caterpillar (Tyria jacobaeae, Erebidae). AB - Defended prey often use distinctive, conspicuous, colours to advertise their unprofitability to potential predators (aposematism). These warning signals are frequently made up of salient, high contrast, stripes which have been hypothesized to increase the speed and accuracy of predator avoidance learning. Limitations in predator visual acuity, however, mean that these patterns cannot be resolved when viewed from a distance, and adjacent patches of colour will blend together (pattern blending). We investigated how saliency changes at different viewing distances in the toxic and brightly coloured cinnabar moth caterpillar (Tyria jacobaeae). We found that although the caterpillars' orange and-black stripes are highly salient at close range, when viewed from a distance the colours blend together to match closely those of the background. Cinnabar caterpillars therefore produce a distance-dependent signal combining salient aposematism with targeted background matching camouflage, without necessarily compromising the size or saturation of their aposematic signal. PMID- 29515859 TI - Isotopic niche reflects stress-induced variability in physiological status. AB - The isotopic niche has become an established concept in trophic ecology. However, the assumptions behind this approach have rarely been evaluated. Evidence is accumulating that physiological stress can affect both magnitude and inter individual variability of the isotopic signature in consumers via alterations in metabolic pathways. We hypothesized that stress factors (inadequate nutrition, parasite infestations, and exposure to toxic substances or varying oxygen conditions) might lead to suboptimal physiological performance and altered stable isotope signatures. The latter can be misinterpreted as alterations in isotopic niche. This hypothesis was tested by inducing physiological stress in the deposit feeding amphipod Monoporeia affinis exposed to either different feeding regimes or contaminated sediments. In the amphipods, we measured body condition indices or reproductive output to assess growth status and delta13C and delta15N values to derive isotope niche metrics. As hypothesized, greater isotopic niche estimates were derived for the stressed animals compared to the control groups. Moreover, the delta15N values were influenced by body size, reproductive status and parasite infestations, while delta13C values were influenced by body size, oxygen conditions and survival. Using regression analysis with isotope composition and growth variables as predictors, we were able to discriminate between the amphipods exposed to nutritionally or chemically stressful conditions and those in the control groups. Thus, interpretation of isotopic niche can be confounded by natural or anthropogenic stressors that may induce an apparent change in isotopic niche. These findings stress the importance of including measures of growth and health status when evaluating stable isotope data in food web studies. PMID- 29515861 TI - Comparative chemical analysis of volatile compounds of Echinops ilicifolius using hydrodistillation and headspace solid-phase microextraction and the antibacterial activities of its essential oil. AB - The volatile compounds from various parts of Echinops ilicifolius (Compositae) such as flowers, leaves and roots obtained by hydrodistillation (HD) and headspace solid-phase microextraction (HS-SPME) methods were subsequently analysed by GC and GC/MS and compared. Thirty-seven and 20 components of the flower of E. ilicifolius were characterized, representing 99.7% and 100.0% of the total compositions using the HD and HS-SPME methods, respectively. The major constituents of the hydrodistilled oil were identified as linalool (58.6%), geraniol (17.4%), n-dodecane (10.9%) and nerol (5.4%), whereas HS-SPME extract was rich in n-octane (34.0%), n-decane (25.1%), p-cymene (11.1%), gamma-terpinene (5.3%) and 1,8-cineole (5.1%). n-Hexadecanoic acid (32.3%), linalool (16.4%) and geraniol (8.3%) were the main components among 43 constituents identified in hydrodistilled extract of the leaf, representing 99.5% of the total components detected, whereas 16 compounds representing 99.9% of the HS-SPME method were identified, among which n-decane (32.6%), p-cymene (14.0%), n-octane (10.3%), limonene (9.2%), gamma-terpinene (9.1%), 1,8-cineole (7.9%) and alpha-pinene (5.9%) were the major ones. Among 23 components comprising 91.2% of the total hydrodistilled oil detected, n-decane (23.1%), n-dodecane (14.5%), silphiperfol 4,7(14)-diene (11.1%), selin-11-en-4-a-ol (9.5%), n-hexadecanoic acid (7.8%) and n-tetradecane (5.3%) were the main constituents in the root of E. ilicifolius, whereas 1,8-cineole (29.0%), n-decane (12.6%), n-octane (12.6%), camphor (12.0%), p-cymene (9.6%) and gamma-terpinene (5.9%) were the main components among the 20 constituents characterized in HS-SPME extract, representing 99.9% of the total components detected. The antibacterial activity of the flower, leaf and root oils of E. ilicifolius against six Gram-positive and Gram-negative bacteria was determined using the MIC method. The growth inhibitory zone (mm) was also measured. PMID- 29515860 TI - Bifunctional fluorescent probes for detection of amyloid aggregates and reactive oxygen species. AB - Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H2O2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H2O2. We characterized the optical properties of these probes using both bulk fluorescence measurements and single aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of alpha-synuclein and pathophysiological H2O2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease. PMID- 29515862 TI - Evaluation of sampling frequency, window size and sensor position for classification of sheep behaviour. AB - Automated behavioural classification and identification through sensors has the potential to improve health and welfare of the animals. Position of a sensor, sampling frequency and window size of segmented signal data has a major impact on classification accuracy in activity recognition and energy needs for the sensor, yet, there are no studies in precision livestock farming that have evaluated the effect of all these factors simultaneously. The aim of this study was to evaluate the effects of position (ear and collar), sampling frequency (8, 16 and 32 Hz) of a triaxial accelerometer and gyroscope sensor and window size (3, 5 and 7 s) on the classification of important behaviours in sheep such as lying, standing and walking. Behaviours were classified using a random forest approach with 44 feature characteristics. The best performance for walking, standing and lying classification in sheep (accuracy 95%, F-score 91%-97%) was obtained using combination of 32 Hz, 7 s and 32 Hz, 5 s for both ear and collar sensors, although, results obtained with 16 Hz and 7 s window were comparable with accuracy of 91%-93% and F-score 88%-95%. Energy efficiency was best at a 7 s window. This suggests that sampling at 16 Hz with 7 s window will offer benefits in a real-time behavioural monitoring system for sheep due to reduced energy needs. PMID- 29515863 TI - Fluorescent component and complexation mechanism of extracellular polymeric substances during dye wastewater biotreatment by anaerobic granular sludge. AB - In this study, methylene blue (MB) wastewater was biotreated by anaerobic granular sludge (AnGS), and the fluorescent components of extracellular polymeric substances (EPS) and complexation mechanism were evaluated. Based on the experimental data, the sorption of MB by both live and inactivated AnGS followed the pseudo-second-order model, and the adsorption isotherm conformed well to the Langmuir model. It was shown that the difference in the sorption of live and inactivated AnGS was not significant, indicating that the sorption is mainly a physical-chemical process and metabolically mediated diffusion is negligible. The interaction between EPS and MB was proved by three-dimensional excitation emission matrix (3D-EEM) and synchronous fluorescence spectra. 3D-EEM indicated that protein (PN)-like substances were the main peaks of EPS, and gradually quenched with increase of MB concentrations. According to synchronous fluorescence spectra, the main fluorescence quenching was caused by PN-like and humic-like fractions, and belonged to the static type of quenching. FTIR spectra demonstrated that hydroxyl and amino groups played a major role in MB sorption. PMID- 29515865 TI - Electrical, dielectric properties and study of AC electrical conduction mechanism of Li0.9?0.1NiV0.5P0.5O4. AB - In this paper, we report the measurements of impedance spectroscopy for a new olivine-type lithium deficiency Li0.9?0.1NiV0.5P0.5O4 compound. It was synthesized by the conventional solid-state technique. All the X-ray diffraction peaks of the compound are indexed, and it is found that the sample is well crystallized in orthorhombic olivine structure belonging to the space group Pnma. Conductivity and dielectric analyses of the sample are carried out at different temperatures and frequencies using the complex impedance spectroscopy technique. The electrical conductivity of Li0.9?0.1NiV0.5P0.5O4 is higher than that of parent compound LiNiV0.5P0.5O4. Temperature dependence of the DC conductivity and modulus was found to obey the Arrhenius law. The obtained values of activation energy are different which confirms that transport in the title compound is not due to a simple hopping mechanism. To determine the conduction mechanism, the AC conductivity and its frequency exponent have been analysed in this work by a theoretical model based on quantum mechanical tunnelling: the non-overlapping small polaron tunnelling model. PMID- 29515864 TI - Effects of rogue ryanodine receptors on Ca2+ sparks in cardiac myocytes. AB - Ca2+ sparks and Ca2+ quarks, arising from clustered and rogue ryanodine receptors (RyRs), are significant Ca2+ release events from the junctional sarcoplasmic reticulum (JSR). Based on the anomalous subdiffusion of Ca2+ in the cytoplasm, a mathematical model was developed to investigate the effects of rogue RyRs on Ca2+ sparks in cardiac myocytes. Ca2+ quarks and sparks from the stochastic opening of rogue and clustered RyRs are numerically reproduced and agree with experimental measurements. It is found that the stochastic opening Ca2+ release units (CRUs) of clustered RyRs are regulated by free Ca2+ concentration in the JSR lumen (i.e. [Ca2+]lumen). The frequency of spontaneous Ca2+ sparks is remarkably increased by the rogue RyRs opening at high [Ca2+]lumen, but not at low [Ca2+]lumen. Hence, the opening of rogue RyRs contributes to the formation of Ca2+ sparks at high [Ca2+]lumen. The interplay of Ca2+ sparks and Ca2+ quarks has been discussed in detail. This work is of significance to provide insight into understanding Ca2+ release mechanisms in cardiac myocytes. PMID- 29515866 TI - Group social rank is associated with performance on a spatial learning task. AB - Dominant individuals differ from subordinates in their performances on cognitive tasks across a suite of taxa. Previous studies often only consider dyadic relationships, rather than the more ecologically relevant social hierarchies or networks, hence failing to account for how dyadic relationships may be adjusted within larger social groups. We used a novel statistical method: randomized Elo ratings, to infer the social hierarchy of 18 male pheasants, Phasianus colchicus, while in a captive, mixed-sex group with a linear hierarchy. We assayed individual learning performance of these males on a binary spatial discrimination task to investigate whether inter-individual variation in performance is associated with group social rank. Task performance improved with increasing trial number and was positively related to social rank, with higher ranking males showing greater levels of success. Motivation to participate in the task was not related to social rank or task performance, thus indicating that these rank related differences are not a consequence of differences in motivation to complete the task. Our results provide important information about how variation in cognitive performance relates to an individual's social rank within a group. Whether the social environment causes differences in learning performance or instead, inherent differences in learning ability predetermine rank remains to be tested. PMID- 29515867 TI - Shared periodic performer movements coordinate interactions in duo improvisations. AB - Human interaction involves the exchange of temporally coordinated, multimodal cues. Our work focused on interaction in the visual domain, using music performance as a case for analysis due to its temporally diverse and hierarchical structures. We made use of two improvising duo datasets-(i) performances of a jazz standard with a regular pulse and (ii) non-pulsed, free improvizations-to investigate whether human judgements of moments of interaction between co performers are influenced by body movement coordination at multiple timescales. Bouts of interaction in the performances were manually annotated by experts and the performers' movements were quantified using computer vision techniques. The annotated interaction bouts were then predicted using several quantitative movement and audio features. Over 80% of the interaction bouts were successfully predicted by a broadband measure of the energy of the cross-wavelet transform of the co-performers' movements in non-pulsed duos. A more complex model, with multiple predictors that captured more specific, interacting features of the movements, was needed to explain a significant amount of variance in the pulsed duos. The methods developed here have key implications for future work on measuring visual coordination in musical ensemble performances, and can be easily adapted to other musical contexts, ensemble types and traditions. PMID- 29515868 TI - Kinship underlies costly cooperation in Mosuo villages. AB - The relative importance of social evolution theories such as kin selection, direct reciprocity and need-based transfers in explaining real-world cooperation is the source of much debate. Previous field studies of cooperation in human communities have revealed variability in the extent to which each of these theories explains human sociality in different contexts. We conducted multivariate social network analyses predicting costly cooperation-labouring on another household's farm-in 128 082 dyads of Mosuo farming households in southwest China. Through information-theoretic model selection, we tested the roles played by genealogical relatedness, affinal relationships (including reproductive partners), reciprocity, relative need, wealth, household size, spatial proximity and gift-giving in an economic game. The best-fitting model included all factors, along with interactions between relatedness and (i) reciprocity, (ii) need, (iii) the presence of own children in another household and (iv) proximity. Our results show how a real-world form of cooperation was driven by kinship. Households tended to help kin in need (but not needy non-kin) and travel further to help spatially distant relatives. Households were more likely to establish reciprocal relationships with distant relatives and non-kin but closer kin cooperated regardless of reciprocity. These patterns of kin-driven cooperation show the importance of inclusive fitness in understanding human social behaviour. PMID- 29515869 TI - Natural variation in female reproductive hormones does not affect contrast sensitivity. AB - Evidence suggests that females experience adaptive shifts in facial preferences across the menstrual cycle. However, recent discussions and meta-analyses suggest that these findings are equivocal. A previously unexplored question is the extent to which shifts in female preferences are modulated by hormone-dependent changes occurring in low-level vision, such as visual sensitivity. This mechanistic approach has been a novel method for investigating the extent to which complex perceptual phenomena are driven by low-level versus higher-level perceptual processes. We investigated whether the contrast sensitivity function-an early dimension of vision-is also influenced by variation in female reproductive hormones. Visual contrast thresholds were measured for 1, 4 and 16 cycles/degree gratings during the ovulatory, luteal and menstrual phases of the menstrual cycle in naturally cycling women, and women using oral contraceptives. Male participants were tested at similar time intervals. Results showed that visual contrast sensitivity does not differ according to sex, or use of oral contraception, nor does it vary relative to hormonal shifts across the menstrual cycle. These findings suggest that shifts in female preferences are not driven by changes in visual sensitivity, and are therefore likely attributable to changes in higher-level perception or cognition. PMID- 29515870 TI - Integrating viscoelastic mass spring dampers into position-based dynamics to simulate soft tissue deformation in real time. AB - We propose a novel method to simulate soft tissue deformation for virtual surgery applications. The method considers the mechanical properties of soft tissue, such as its viscoelasticity, nonlinearity and incompressibility; its speed, stability and accuracy also meet the requirements for a surgery simulator. Modifying the traditional equation for mass spring dampers (MSD) introduces nonlinearity and viscoelasticity into the calculation of elastic force. Then, the elastic force is used in the constraint projection step for naturally reducing constraint potential. The node position is enforced by the combined spring force and constraint conservative force through Newton's second law. We conduct a comparison study of conventional MSD and position-based dynamics for our new integrating method. Our approach enables stable, fast and large step simulation by freely controlling visual effects based on nonlinearity, viscoelasticity and incompressibility. We implement a laparoscopic cholecystectomy simulator to demonstrate the practicality of our method, in which liver and gallbladder deformation can be simulated in real time. Our method is an appropriate choice for the development of real-time virtual surgery applications. PMID- 29515871 TI - An optimized approach for local de novo assembly of overlapping paired-end RAD reads from multiple individuals. AB - Restriction site-associated DNA (RAD) sequencing is revolutionizing studies in ecological, evolutionary and conservation genomics. However, the assembly of paired-end RAD reads with random-sheared ends is still challenging, especially for non-model species with high genetic variance. Here, we present an efficient optimized approach with a pipeline software, RADassembler, which makes full use of paired-end RAD reads with random-sheared ends from multiple individuals to assemble RAD contigs. RADassembler integrates the algorithms for choosing the optimal number of mismatches within and across individuals at the clustering stage, and then uses a two-step assembly approach at the assembly stage. RADassembler also uses data reduction and parallelization strategies to promote efficiency. Compared to other tools, both the assembly results based on simulation and real RAD datasets demonstrated that RADassembler could always assemble the appropriate number of contigs with high qualities, and more read pairs were properly mapped to the assembled contigs. This approach provides an optimal tool for dealing with the complexity in the assembly of paired-end RAD reads with random-sheared ends for non-model species in ecological, evolutionary and conservation studies. RADassembler is available at https://github.com/lyl8086/RADscripts. PMID- 29515872 TI - Synthesis of adenosine analogues with indole moiety as human adenosine A3 receptor ligands. AB - Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G-protein-coupled receptor superfamily. The human A3AR (hA3AR) subtype is implicated in several cytoprotective functions. Therefore, hA3AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anti-cancer and cardioprotective agents. Here, we prepared novel adenosine derivatives with indole moiety as hA3AR ligands. According to the biological assay, we found that 2-substituents 11 were critical structural determinants for A3AR ligands (Ki = 111 nM). The observed structure affinity relationships of this class of ligands were also exhaustively rationalized using the molecular modelling approach. This allows the investigation on the binding mode of the potential compound in the ligand-binding pocket of the human A3 receptor. The results demonstrated that 11 can interact with the ASN250, GLN167, PHE168 and VAL178 through hydrogen bonding, which are shown to be important for ligand-receptor interaction. PMID- 29515873 TI - Implementing Parrondo's paradox with two-coin quantum walks. AB - Parrondo's paradox is ubiquitous in games, ratchets and random walks. The apparent paradox, devised by J. M. R. Parrondo, that two losing games A and B can produce a winning outcome has been adapted in many physical and biological systems to explain their working. However, proposals on demonstrating Parrondo's paradox using quantum walks failed for a large number of steps. In this work, we show that instead of a single coin if we consider a two-coin initial state which may or may not be entangled, we can observe a genuine Parrondo's paradox with quantum walks. Furthermore, we focus on reasons for this and pin down the asymmetry in initial two-coin state or asymmetry in shift operator, either of which is necessary for observing a genuine Parrondo's paradox. We extend our work to a three-coin initial state too with similar results. The implications of our work for observing quantum ratchet-like behaviour using quantum walks are also discussed. PMID- 29515874 TI - Discovery of benzothiazolylquinoline conjugates as novel human A3 receptor antagonists: biological evaluations and molecular docking studies. AB - Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the hA3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound 6a showed best potency and selectivity at hA3 among other adenosine receptors. PMID- 29515876 TI - Online incidental statistical learning of audiovisual word sequences in adults: a registered report. AB - Statistical learning has been proposed as a key mechanism in language learning. Our main goal was to examine whether adults are capable of simultaneously extracting statistical dependencies in a task where stimuli include a range of structures amenable to statistical learning within a single paradigm. We devised an online statistical learning task using real word auditory-picture sequences that vary in two dimensions: (i) predictability and (ii) adjacency of dependent elements. This task was followed by an offline recall task to probe learning of each sequence type. We registered three hypotheses with specific predictions. First, adults would extract regular patterns from continuous stream (effect of grammaticality). Second, within grammatical conditions, they would show differential speeding up for each condition as a factor of statistical complexity of the condition and exposure. Third, our novel approach to measure online statistical learning would be reliable in showing individual differences in statistical learning ability. Further, we explored the relation between statistical learning and a measure of verbal short-term memory (STM). Forty-two participants were tested and retested after an interval of at least 3 days on our novel statistical learning task. We analysed the reaction time data using a novel regression discontinuity approach. Consistent with prediction, participants showed a grammaticality effect, agreeing with the predicted order of difficulty for learning different statistical structures. Furthermore, a learning index from the task showed acceptable test-retest reliability (r = 0.67). However, STM did not correlate with statistical learning. We discuss the findings noting the benefits of online measures in tracking the learning process. PMID- 29515875 TI - Preparation of novel polyamine-type chelating resin with hyperbranched structures and its adsorption performance. AB - This paper explored the method of combining atom transfer radical polymerization (ATRP) technology and hyperbranched polymer principle to prepare the high capacity chelating resin. First, surface-initiated atom transfer radical polymerization (SI-ATRP) method was used to graft glycidyl methacrylate (GMA) on chloromethylated cross-linked styrene-divinylbenzene resin, and then the novel polyamine chelating resin with a kind of hyperbranched structure was prepared through the amination reaction between amino group of (2-aminoethyl) triamine and epoxy group in GMA. This resin had a selective effect on As(V) and Cr(VI) at a relatively low pH and can be used for the disposal of waste water containing As(V) and Cr(VI). It had a relatively strong adsorption effect on Cu(II), Pb(II), Cd(II) and Cr(III) and can be used for the disposal of heavy metal ion waste water. The finding was that, the adsorption capacity of resin on the studied heavy metal ions was higher than that of the chelating resin synthesized by traditional technology and also higher than that of the resin modified by ATRP technology and bifunctional chelator, indicating that the combination of ATRP and hyperbranched polymer concept is an effective method to prepare chelating resin with high capacity. PMID- 29515877 TI - On gamesmen and fair men: explaining fairness in non-cooperative bargaining games. AB - Experiments on bargaining games have repeatedly shown that subjects fail to use backward induction, and that they only rarely make demands in accordance with the subgame perfect equilibrium. In a recent paper, we proposed an alternative model, termed 'economic harmony' in which we modified the individual's utility by defining it as a function of the ratio between the actual and aspired pay-offs. We also abandoned the notion of equilibrium, in favour of a new notion of 'harmony', defined as the intersection of strategies, at which all players are equally satisfied. We showed that the proposed model yields excellent predictions of offers in the ultimatum game, and requests in the sequential common pool resource dilemma game. Strikingly, the predicted demand in the ultimatum game is equal to the famous Golden Ratio (approx. 0.62 of the entire pie). The same prediction was recently derived independently by Schuster (Schuster 2017. Sci. Rep.7, 5642). In this paper, we extend the solution to bargaining games with alternating offers. We show that the derived solution predicts the opening demands reported in several experiments, on games with equal and unequal discount factors and game horizons. Our solution also predicts several unexplained findings, including the puzzling 'disadvantageous counter-offers', and the insensitivity of opening demands to variations in the players' discount factors, and game horizon. Strikingly, we find that the predicted opening demand in the alternating offers game is also equal to the Golden Ratio. PMID- 29515879 TI - Isospectrals of non-uniform Rayleigh beams with respect to their uniform counterparts. AB - In this paper, we look for non-uniform Rayleigh beams isospectral to a given uniform Rayleigh beam. Isospectral systems are those that have the same spectral properties, i.e. the same free vibration natural frequencies for a given boundary condition. A transformation is proposed that converts the fourth-order governing differential equation of non-uniform Rayleigh beam into a uniform Rayleigh beam. If the coefficients of the transformed equation match with those of the uniform beam equation, then the non-uniform beam is isospectral to the given uniform beam. The boundary-condition configuration should be preserved under this transformation. We present the constraints under which the boundary configurations will remain unchanged. Frequency equivalence of the non-uniform beams and the uniform beam is confirmed by the finite-element method. For the considered cases, examples of beams having a rectangular cross section are presented to show the application of our analysis. PMID- 29515878 TI - Aspirin locally disrupts the liquid-ordered phase. AB - Local structure and dynamics of lipid membranes play an important role in membrane function. The diffusion of small molecules, the curvature of lipids around a protein and the existence of cholesterol-rich lipid domains (rafts) are examples for the membrane to serve as a functional interface. The collective fluctuations of lipid tails, in particular, are relevant for diffusion of membrane constituents and small molecules in and across membranes, and for structure and formation of membrane domains. We studied the effect of aspirin (acetylsalicylic acid, ASA) on local structure and dynamics of membranes composed of dimyristoylphosphocholine (DMPC) and cholesterol. Aspirin is a common analgesic, but is also used in the treatment of cholesterol. Using coherent inelastic neutron scattering experiments and molecular dynamics (MD) simulations, we present evidence that ASA binds to liquid-ordered, raft-like domains and disturbs domain organization and dampens collective fluctuations. By hydrogen bonding to lipid molecules, ASA forms 'superfluid' complexes with lipid molecules that can organize laterally in superlattices and suppress cholesterol's ordering effect. PMID- 29515880 TI - Differential gene expression is not required for facultative sex allocation: a transcriptome analysis of brain tissue in the parasitoid wasp Nasonia vitripennis. AB - Whole-transcriptome technologies have been widely used in behavioural genetics to identify genes associated with the performance of a behaviour and provide clues to its mechanistic basis. Here, we consider the genetic basis of sex allocation behaviour in the parasitoid wasp Nasonia vitripennis. Female Nasonia facultatively vary their offspring sex ratio in line with Hamilton's theory of local mate competition (LMC). A single female or 'foundress' laying eggs on a patch will lay just enough sons to fertilize her daughters. As the number of 'foundresses' laying eggs on a patch increases (and LMC declines), females produce increasingly male-biased sex ratios. Phenotypic studies have revealed the cues females use to estimate the level of LMC their sons will experience, but our understanding of the genetics underlying sex allocation is limited. Here, we exposed females to three foundress number conditions, i.e. three LMC conditions, and allowed them to oviposit. mRNA was extracted from only the heads of these females to target the brain tissue. The subsequent RNA-seq experiment confirmed that differential gene expression is not associated with the response to sex allocation cues and that we must instead turn to the underlying neuroscience to reveal the underpinnings of this impressive behavioural plasticity. PMID- 29515881 TI - Fluorescence and photophysical properties of xylene isomers in water: with experimental and theoretical approaches. AB - A thorough analysis of the photophysical properties involved in electronic transitions in excitation-emission spectra of xylene isomers has been carried out using the time-dependent density functional theory (PBEPBE/6-31 + G(d,p)) method. For the first time a structural and spectroscopic investigation to distinguish isomers of xylene, a widespread priority pollutant, was conducted experimentally and theoretically. The fluorescence properties of xylene isomers (sole and mixture (binary and ternary)) in water were studied. The fluorescence peak intensities of xylenes were linearly correlated to concentration, in the order of p-xylene > o-xylene > m-xylene at an excitation/emission wavelength (ex/em) of 260 nm/285 nm for o-, m-xylene and ex/em 265 nm/290 nm for p-xylene at the same concentration. The theoretical excitation/emission wavelengths were at ex/em 247 nm/267 nm, 248 nm/269 nm and 251 nm/307 nm for o-, m- and p-xylene, respectively. The vertical excitation and emission state energies of p-xylene (ex/em 4.94 eV/4.03 eV) were lower and the internal conversion energy difference (0.90 eV) was higher than those of m-xylene (ex/em 5.00 eV/4.60 eV) (0.4 eV) and o-xylene (ex/em 5.02 eV/4.64 eV) (0.377 eV). The order of theoretical emission and oscillator strength (0.0187 > 0.0175 > 0.0339) for p-xylene > o-xylene > m-xylene was observed to be in agreement with the experimental fluorescence intensities. These findings provide a novel fast method to distinguish isomers based on their photophysical properties. PMID- 29515882 TI - How maternal investment varies with environmental factors and the age and physiological state of wild tsetse Glossina pallidipes and Glossina morsitans morsitans. AB - Theory suggests females should optimize resource allocation across reproductive bouts to maximize lifetime reproduction, balancing current and future reproductive efforts according to physiological state and projected survival and reproduction. Tests of these ideas focus on long-lived vertebrates: few measure age-related reproductive output in iteroparous invertebrates, or partition reserves between those allocated to offspring versus mothers. We investigated how maternal age, and environmental and physiological factors influence reproductive investment in wild tsetse, Glossina pallidipes Austen and G. morsitans morsitans Westwood. Tsetse provide a tractable system to measure reproductive allocation. Females exhibit high maternal investment, producing single, large offspring that rely exclusively on maternal reserves. We find that mothers in better physiological condition and experiencing cooler temperatures produce larger offspring. Pupal size increases significantly but weakly with age. In both species, females with less fat invest proportionately more in offspring. Post partum fat decreases in flies with badly frayed wings: poor flight capability may limit their feeding efficiency, or they may sacrifice more reserves as a terminal investment. Our results support evidence that offspring size increases with maternal size, investment depends on the environment, and females with lower chances of future reproduction invest more into current offspring. We discuss the implications of maternal effects for predicting vector population responses to environmental change. PMID- 29515883 TI - Study on the optimization of the deposition rate of planetary GaN-MOCVD films based on CFD simulation and the corresponding surface model. AB - Metal-organic chemical vapour deposition (MOCVD) is a key technique for fabricating GaN thin film structures for light-emitting and semiconductor laser diodes. Film uniformity is an important index to measure equipment performance and chip processes. This paper introduces a method to improve the quality of thin films by optimizing the rotation speed of different substrates of a model consisting of a planetary with seven 6-inch wafers for the planetary GaN-MOCVD. A numerical solution to the transient state at low pressure is obtained using computational fluid dynamics. To evaluate the role of the different zone speeds on the growth uniformity, single factor analysis is introduced. The results show that the growth rate and uniformity are strongly related to the rotational speed. Next, a response surface model was constructed by using the variables and the corresponding simulation results. The optimized combination of the matching of different speeds is also proposed as a useful reference for applications in industry, obtained by a response surface model and genetic algorithm with a balance between the growth rate and the growth uniformity. This method can save time, and the optimization can obtain the most uniform and highest thin film quality. PMID- 29515884 TI - Hovering hummingbird wing aerodynamics during the annual cycle. II. Implications of wing feather moult. AB - Birds usually moult their feathers in a particular sequence which may incur aerodynamic, physiological and behavioural implications. Among birds, hummingbirds are unique species in their sustained hovering flight. Because hummingbirds frequently hover-feed, they must maintain sufficiently high flight capacities even when moulting their flight feathers. A hummingbird wing consists of 10 primary flight feathers whose absence during moult may strongly affect wing performance. Using dynamic similarity rules, we compared time-accurate aerodynamic loads and flow field measurements over several wing geometries that follow the natural feather moult sequence of Calypte anna, a common hummingbird species in western North America. Our results suggest a drop of more than 20% in lift production during the early stages of the moult sequence in which mid-wing flight feathers are moulted. We also found that the wing's ability to generate lift strongly depended on the morphological integrity of the outer primaries and leading-edge. These findings may explain the evolution of wing morphology and moult attributes. Specifically, the high overlap between adjacent wing feathers, especially at the wing tip, and the slow sequential replacement of the wing feathers result in a relatively small reduction in wing surface area during moult with limited aerodynamic implications. We present power and efficiency analyses for hover flight during moult under several plausible scenarios, suggesting that body mass reduction could be a compensatory mechanism that preserves the energetic costs of hover flight. PMID- 29515885 TI - Photothermal fabrication of microscale patterned DNA hydrogels. AB - This paper introduces a method for fabricating microscale DNA hydrogels using irradiation with patterned light. Optical fabrication allows for the flexible and tunable formation of DNA hydrogels without changing the environmental conditions. Our scheme is based on local heat generation via the photothermal effect, which is induced by light irradiation on a quenching species. We demonstrate experimentally that, depending on the power and irradiation time, light irradiation enables the creation of local microscale DNA hydrogels, while the shapes of the DNA hydrogels are controlled by the irradiation patterns. PMID- 29515886 TI - Multimodal integration and stimulus categorization in putative mushroom body output neurons of the honeybee. AB - Flowers attract pollinating insects like honeybees by sophisticated compositions of olfactory and visual cues. Using honeybees as a model to study olfactory visual integration at the neuronal level, we focused on mushroom body (MB) output neurons (MBON). From a neuronal circuit perspective, MBONs represent a prominent level of sensory-modality convergence in the insect brain. We established an experimental design allowing electrophysiological characterization of olfactory, visual, as well as olfactory-visual induced activation of individual MBONs. Despite the obvious convergence of olfactory and visual pathways in the MB, we found numerous unimodal MBONs. However, a substantial proportion of MBONs (32%) responded to both modalities and thus integrated olfactory-visual information across MB input layers. In these neurons, representation of the olfactory-visual compound was significantly increased compared with that of single components, suggesting an additive, but nonlinear integration. Population analyses of olfactory-visual MBONs revealed three categories: (i) olfactory, (ii) visual and (iii) olfactory-visual compound stimuli. Interestingly, no significant differentiation was apparent regarding different stimulus qualities within these categories. We conclude that encoding of stimulus quality within a modality is largely completed at the level of MB input, and information at the MB output is integrated across modalities to efficiently categorize sensory information for downstream behavioural decision processing. PMID- 29515887 TI - Study on room temperature gas-sensing performance of CuO film-decorated ordered porous ZnO composite by In2O3 sensitization. AB - For the first time, ordered mesoporous ZnO nanoparticles have been synthesized by a template method. The electroplating after chemical plating method was creatively used to form copper film on the surface of the prepared ZnO, and then a CuO film-decorated ordered porous ZnO composite (CuO/ZnO) was obtained by a high-temperature oxidation method. In2O3 was loaded into the prepared CuO film ZnO by an ultrasonic-assisted method to sensitize the room temperature gas sensing performance of the prepared CuO/ZnO materials. The doped In2O3 could effectively improve the gas-sensing properties of the prepared materials to nitrogen oxides (NO x ) at room temperature. The 1% In2O3 doped CuO/ZnO sample (1 wt% In2O3-CuO/ZnO) showed the best gas-sensing properties whose response to 100 ppm NO x reached 82%, and the detectable minimum concentration reached 1 ppm at room temperature. The prepared materials had a good selectivity, better response, very low detection limit, and high sensitivity to NO x gas at room temperature, which would have a great development space in the gas sensor field and a great research value. PMID- 29515888 TI - Early development of vocal interaction rules in a duetting songbird. AB - Exchange of vocal signals is an important aspect of animal communication. Although birdsong is the premier model for understanding vocal development, the development of vocal interaction rules in birds and possible parallels to humans have been little studied. Many tropical songbirds engage in complex vocal interactions in the form of duets between mated pairs. In some species, duets show precise temporal coordination and follow rules (duet codes) governing which song type one bird uses to reply to each of the song types of its mate. We determined whether these duetting rules are acquired during early development in canebrake wrens. Results show that juveniles acquire a duet code by singing with a mated pair of adults and that juveniles gradually increase their fidelity to the code over time. Additionally, we found that juveniles exhibit poorer temporal coordination than adults and improve their coordination as time progresses. Human turn-taking, an analogous rule to temporal coordination, is learned during early development. We report that the ontogeny of vocal interaction rules in songbirds is analogous to that of human conversation rules. PMID- 29515889 TI - MnO2-graphene nanosheets wrapped mesoporous carbon/sulfur composite for lithium sulfur batteries. AB - MnO2-graphene nanosheets wrapped mesoporous carbon/sulfur (MGN@MC/S) composite is successfully synthesized derived from metal-organic frameworks and investigated as cathode for lithium-ion batteries. Used as cathode, MGN@MC/S composite possesses electronic conductivity network for redox electron transfer and strong chemical bonding to lithium polysulfides, which enables low capacity loss to be achieved. MGN@MC/S cathodes exhibit high reversible capacity of 1475 mA h g-1 at 0.1 C and an ultra-low capacity fading of 0.042% per cycle at 1 C over 450 cycles. PMID- 29515890 TI - Therapeutic target discovery using Boolean network attractors: improvements of kali. AB - In a previous article, an algorithm for identifying therapeutic targets in Boolean networks modelling pathological mechanisms was introduced. In the present article, the improvements made on this algorithm, named kali, are described. These improvements are (i) the possibility to work on asynchronous Boolean networks, (ii) a finer assessment of therapeutic targets and (iii) the possibility to use multivalued logic. kali assumes that the attractors of a dynamical system, such as a Boolean network, are associated with the phenotypes of the modelled biological system. Given a logic-based model of pathological mechanisms, kali searches for therapeutic targets able to reduce the reachability of the attractors associated with pathological phenotypes, thus reducing their likeliness. kali is illustrated on an example network and used on a biological case study. The case study is a published logic-based model of bladder tumorigenesis from which kali returns consistent results. However, like any computational tool, kali can predict but cannot replace human expertise: it is a supporting tool for coping with the complexity of biological systems in the field of drug discovery. PMID- 29515891 TI - Direct amidation of non-activated phenylacetic acid and benzylamine derivatives catalysed by NiCl2. AB - This paper describes an eco-friendly and efficient direct amidation of benzylamine and phenylacetic acid derivatives in the presence of 10 mol% NiCl2 as catalyst without any drying agent. For the different phenylacetic acid and benzylamine derivatives, the direct catalysed amidation gave moderate-to excellent yields in toluene. The steric and electronic effects of substituent groups on the phenyl ring of acid were crucial to the yields of the direct amidation. The catalyst NiCl2 can be recycled three times without loss of activity. PMID- 29515892 TI - Molecular evidence for the first records of facultative parthenogenesis in elapid snakes. AB - Parthenogenesis is a form of asexual reproduction by which embryos develop from unfertilized eggs. Parthenogenesis occurs in reptiles; however, it is not yet known to occur in the widespread elapid snakes (Elapidae), which include well known taxa such as cobras, mambas, taipans and sea snakes. Here, we describe the production of viable parthenogens in two species of Australo-Papuan elapids with divergent reproductive modes: the oviparous coastal/Papuan taipan (Oxyuranus scutellatus) and the viviparous southern death adder (Acanthophis antarcticus). Analyses of nuclear SNP data excluded paternity for putative fathers and convincingly demonstrated asexual reproduction, thus representing the first evidence of facultative parthenogenesis in Elapidae. Our finding has broad implications for understanding the evolution of reproductive diversity in snakes, as well as managing the conservation of genetic diversity in wild and captive populations. PMID- 29515893 TI - Letting the 'cat' out of the bag: pouch young development of the extinct Tasmanian tiger revealed by X-ray computed tomography. AB - The Tasmanian tiger or thylacine (Thylacinus cynocephalus) was an iconic Australian marsupial predator that was hunted to extinction in the early 1900s. Despite sharing striking similarities with canids, they failed to evolve many of the specialized anatomical features that characterize carnivorous placental mammals. These evolutionary limitations are thought to arise from functional constraints associated with the marsupial mode of reproduction, in which otherwise highly altricial young use their well-developed forelimbs to climb to the pouch and mouth to suckle. Here we present the first three-dimensional digital developmental series of the thylacine throughout its pouch life using X ray computed tomography on all known ethanol-preserved specimens. Based on detailed skeletal measurements, we refine the species growth curve to improve age estimates for the individuals. Comparison of allometric growth trends in the appendicular skeleton (fore- and hindlimbs) with that of other placental and marsupial mammals revealed that despite their unique adult morphologies, thylacines retained a generalized early marsupial ontogeny. Our approach also revealed mislabelled specimens that possessed large epipubic bones (vestigial in thylacine) and differing vertebral numbers. All of our generated CT models are publicly available, preserving their developmental morphology and providing a novel digital resource for future studies of this unique marsupial. PMID- 29515894 TI - Forming three-dimensional closed shapes from two-dimensional soft ribbons by controlled buckling. AB - Conventional manufacturing techniques-moulding, machining and casting-exist to produce three-dimensional (3D) shapes. However, these industrial processes are typically geared for mass production and are not directly applicable to residential settings, where inexpensive and versatile tools are desirable. Moreover, those techniques are, in general, not adequate to process soft elastic materials. Here, we introduce a new concept of forming 3D closed hollow shapes from two-dimensional (2D) elastic ribbons by controlled buckling. We numerically and experimentally characterize how the profile and thickness of the ribbon determine its buckled shape. We find a 2D master profile with which various elliptical 3D shapes can be formed. More complex natural and artificial hollow shapes, such as strawberry, hourglass and wheel, can also be achieved via strategic design and pattern engraving on the ribbons. The nonlinear response of the post-buckling regime is rationalized through finite-element analysis, which shows good quantitative agreement with experiments. This robust fabrication should complement conventional techniques and provide a rich arena for future studies on the mechanics and new applications of elastic hollow structures. PMID- 29515895 TI - A biomolecular proportional integral controller based on feedback regulations of protein level and activity. AB - Homeostasis is the capacity of living organisms to keep internal conditions regulated at a constant level, despite environmental fluctuations. Integral feedback control is known to play a key role in this behaviour. Here, I show that a feedback system involving transcriptional and post-translational regulations of the same executor protein acts as a proportional integral (PI) controller, leading to enhanced transient performances in comparison with a classical integral loop. Such a biomolecular controller-which I call a level and activity PI controller (LA-PI)-is involved in the regulation of ammonium uptake by Escherichia coli through the transporter AmtB. The P II molecules, which reflect the nitrogen status of the cell, inhibit both the production of AmtB and its activity (via the NtrB-NtrC system and the formation of a complex with GlnK, respectively). Other examples of LA-PI controller include copper and zinc transporters, and the redox regulation in photosynthesis. This scheme has thus emerged through evolution in many biological systems, surely because of the benefits it offers in terms of performances (rapid and perfect adaptation) and economy (protein production according to needs). PMID- 29515896 TI - Effects of complexity and seasonality on backward bifurcation in vector-host models. AB - We study implications of complexity and seasonality in vector-host epidemiological models exhibiting backward bifurcation. Vector-host diseases represent complex infection systems that can vary in the transmission processes and population stages involved in disease progression. Seasonal fluctuations in external forcing factors can also interact in a complex way with internal host factors to govern the transmission dynamics. In backward bifurcation, the insufficiency of R0 < 1 for predicting the stability of the disease-free equilibrium (DFE) state arises due to existence of bistability (coexisting DFE and endemic equilibria) for a range of R0 values below one. Here we report that this region of bistability decreases with increasing complexity of vector-borne disease transmission as well as with increasing seasonality strength. The decreases in the bistability region are accompanied by a reduced force of infection acting on primary hosts. As a consequence, we show counterintuitively that a more complex vector-borne disease may be easier to control in settings of high seasonality. PMID- 29515897 TI - A novel and highly efficient esterification process using triphenylphosphine oxide with oxalyl chloride. AB - Triphenylphosphine oxide (TPPO) and oxalyl chloride ((COCl)2) are used as novel and high-efficiency coupling reagents for the esterification of alcohols with carboxylic acids via the TPPO/(COCl)2 system at room temperature for 1 h. The reaction represents the first TPPO-promoted esterification under mild and neutral conditions with excellent yields. Furthermore, we proposed a plausible mechanism with the help of 31P NMR spectroscopy. PMID- 29515898 TI - Quasi-two-layer morphodynamic model for bedload-dominated problems: bed slope induced morphological diffusion. AB - We derive a two-layer depth-averaged model of sediment transport and morphological evolution for application to bedload-dominated problems. The near bed transport region is represented by the lower (bedload) layer which has an arbitrarily constant, vanishing thickness (of approx. 10 times the sediment particle diameter), and whose average sediment concentration is free to vary. Sediment is allowed to enter the upper layer, and hence the total load may also be simulated, provided that concentrations of suspended sediment remain low. The model conforms with established theories of bedload, and is validated satisfactorily against empirical expressions for sediment transport rates and the morphodynamic experiment of a migrating mining pit by Lee et al. (1993 J. Hydraul. Eng.119, 64-80 (doi:10.1061/(ASCE)0733-9429(1993)119:1(64))). Investigation into the effect of a local bed gradient on bedload leads to derivation of an analytical, physically meaningful expression for morphological diffusion induced by a non-zero local bed slope. Incorporation of the proposed morphological diffusion into a conventional morphodynamic model (defined as a coupling between the shallow water equations, Exner equation and an empirical formula for bedload) improves model predictions when applied to the evolution of a mining pit, without the need either to resort to special numerical treatment of the equations or to use additional tuning parameters. PMID- 29515899 TI - Social structure of the harem-forming promiscuous fruit bat, Cynopterus sphinx, is the harem truly important? AB - Bats are social animals and display a diverse variety of mating and social systems, with most species exhibiting some form of polygyny. Their social organization is fluid and individuals frequently switch partners and roosting sites. While harem-like social organization is observed in multiple tropical species, its importance is contested in many of them. In this study, we investigated the role of harems in the social organization of the old world fruit bat Cynopterus sphinx. Based on regular behavioural observations over a period of 20 months and genetic data from microsatellite markers, we observed that the social organization is flexible, individuals regularly shift between roosts and the social organization resembles a fission-fusion society. Behavioural and genetic analyses suggest that the harems are not strict units of social structure, and the colony does not show signatures of subdivision with harems as behavioural units. We also observed that there was no correlation between individuals with high association index and pairwise relatedness. Our findings indicate that similar to the mating system, the social organization of C. sphinx can also be categorized as a fission-fusion society, and hence the term 'harem' is a misnomer. We conclude that the social system of C. sphinx is flexible, with multi-male multi-female organization, and individuals tend to be loyal to a given area rather than a roost. PMID- 29515900 TI - Evaluating the personality structure of semi-captive Asian elephants living in their natural habitat. AB - Data on personality for long-lived, highly social wild mammals with high cognitive abilities are rare. We investigated the personality structure of Asian elephants (Elephas maximus) by using a large sample of semi-captive timber elephants in Myanmar. Data were collected during 2014-2017 using questionnaires, for which elephant riders (mahouts) rated 28 behavioural adjectives of elephants. Repeated questionnaires were obtained for each elephant from several raters whenever possible, resulting in 690 ratings of 150 female and 107 male elephants. We started by performing a confirmatory factor analysis to compare the fit of our data to a previously published captive elephant personality structure. Owing to a poor fit of this model to our data, we proceeded by performing explanatory factor analysis to determine the personality structure in our study population. This model suggested that personality in these elephants was manifested as three factors that we labelled as Attentiveness, Sociability and Aggressiveness. This structure did not differ between the sexes. These results provide the basis for future research on the link between personality and reproductive success in this endangered species and more generally, help to resolve the selective pressures on personalities in long-lived, highly social species. PMID- 29515901 TI - The comparative evidence for urban species sorting by anthropogenic noise. AB - Anthropogenic noise is more intense at lower sound frequencies, which could decrease urban tolerance of animals with low-frequency vocalizations. Four large comparative studies tested whether anthropogenic noise filters bird species according to the sound frequencies they use and produced discrepant results. We reanalysed data from these studies to explain their different results. Urban tolerance of bird species (defined here as often occurring and breeding in cities) is very weakly related to urban preference or relative abundance (defined based on changes in population density from urban to nearby rural environments). Data on urban preference/abundance are potentially accurate for individual cities but differ among cities for the same species, whereas existing data on urban tolerance are coarser but provide a more global synthesis. Cross-species comparisons find a positive association between the sound frequency of song and urban tolerance, but not urban preference/abundance. We found that showing an association between song frequency and urban tolerance requires controlling for additional species traits that influence urban living. On the contrary, controlling for other species traits is not required to show a positive association between song frequency and use of noisy relative to quiet areas within the same type of environment. Together, comparative evidence indicates that masking by urban noise is part of a larger set of factors influencing urban living: all else being equal, species with high-frequency sounds are more likely to tolerate cities than species with low-frequency sounds, but they are not more likely to prefer, or to be more abundant in, urban than non-urban habitats. PMID- 29515902 TI - Magnetic field inhomogeneities due to CO2 incubator shelves: a source of experimental confounding and variability? AB - A thorough assessment of the static magnetic field (SMF) inside a CO2 incubator allowed us to identify non-negligible inhomogeneities close to the floor, ceiling, walls and the door. Given that incubator's shelves are made of a non magnetic stainless steel alloy, we did not expect any important effect of them on the SMF. Surprisingly, we did find relatively strong distortion of the SMF due to shelves. Indeed, our high-resolution maps of the SMF revealed that distortion is such that field intensities differing by a factor of up to 36 were measured on the surface of the shelf at locations only few millimetres apart from each other. Furthermore, the most intense of these fields was around five times greater than the ones found inside the incubator (without the metallic shelves in), while the lowest one was around 10 times lower, reaching the so-called hypomagnetic field range. Our findings, together with a survey of the literature on biological effects of hypomagnetic fields, soundly support the idea that SMF inhomogeneities inside incubators, especially due to shelves' holes, are a potential source of confounding and variability in experiments with cell cultures kept in an incubator. PMID- 29515903 TI - Mixing and diffusion in a two-type population. AB - The outbreak of epidemics, the rise of religious radicalization or the motivational influence of fellow students in classrooms are some of the issues that can be described as diffusion processes in heterogeneous groups. Understanding the role that interaction patterns between groups (e.g. homophily or segregation) play in the diffusion of certain traits or behaviours is a major challenge for contemporary societies. Here, we study the impact on diffusion processes of mixing (or, alternatively, segregating) two groups that present different sensitivities or propensities to contagion. We find non-monotonic effects of mixing and inefficient segregation levels, i.e. situations where a change in the mixing level can benefit both groups, e.g. where an increase in the mixing level can reduce the expected contagion levels in both groups. These findings can have fundamental consequences for the design of inclusion policies. PMID- 29515904 TI - Numerical simulation of the free surface and water inflow of a slope, considering the nonlinear flow properties of gravel layers: a case study. AB - Groundwater is an important factor of slope stability, and 90% of slope failures are related to the influence of groundwater. In the past, free surface calculations and the prediction of water inflow were based on Darcy's law. However, Darcy's law for steady fluid flow is a special case of non-Darcy flow, and many types of non-Darcy flows occur in practical engineering applications. In this paper, based on the experimental results of laboratory water seepage tests, the seepage state of each soil layer in the open-pit slope of the Yanshan Iron Mine, China, were determined, and the seepage parameters were obtained. The seepage behaviour in the silt layer, fine sand layer, silty clay layer and gravelly clay layer followed the traditional Darcy law, while the gravel layers showed clear nonlinear characteristics. The permeability increases exponentially and the non-Darcy coefficient decreases exponentially with an increase in porosity, and the relation among the permeability, the porosity and the non-Darcy coefficient is investigated. A coupled mathematical model is established for two flow fields, on the basis of Darcy flow in the low-permeability layers and Forchheimer flow in the high-permeability layers. In addition, the effect of the seepage in the slope on the transition from Darcy flow to Forchheimer flow was considered. Then, a numerical simulation was conducted by using finite-element software (FELAC 2.2). The results indicate that the free surface calculated by the Darcy-Forchheimer model is in good agreement with the in situ measurements; however, there is an evident deviation of the simulation results from the measured data when the Darcy model is used. Through a parameter sensitivity analysis of the gravel layers, it can be found that the height of the overflow point and the water inflow calculated by the Darcy-Forchheimer model are consistently less than those of the Darcy model, and the discrepancy between these two models increases as the permeability increases. The necessity of adopting the Darcy-Forchheimer model was explained. The Darcy-Forchheimer model would be applicable in slope engineering applications with highly permeable rock. PMID- 29515905 TI - The emergence of consensus: a primer. AB - The origin of population-scale coordination has puzzled philosophers and scientists for centuries. Recently, game theory, evolutionary approaches and complex systems science have provided quantitative insights on the mechanisms of social consensus. However, the literature is vast and widely scattered across fields, making it hard for the single researcher to navigate it. This short review aims to provide a compact overview of the main dimensions over which the debate has unfolded and to discuss some representative examples. It focuses on those situations in which consensus emerges 'spontaneously' in the absence of centralized institutions and covers topics that include the macroscopic consequences of the different microscopic rules of behavioural contagion, the role of social networks and the mechanisms that prevent the formation of a consensus or alter it after it has emerged. Special attention is devoted to the recent wave of experiments on the emergence of consensus in social systems. PMID- 29515906 TI - Repeatable aversion across threat types is linked with life-history traits but is dependent on how aversion is measured. AB - Personality research suggests that individual differences in risk aversion may be explained by links with life-history variation. However, few empirical studies examine whether repeatable differences in risk avoidance behaviour covary with life-history traits among individuals in natural populations, or how these links vary depending on the context and the way risk aversion is measured. We measured two different risk avoidance behaviours (latency to enter the nest and inspection time) in wild great tits (Parus major) in two different contexts-response to a novel object and to a predator cue placed at the nest-box during incubation---and related these behaviours to female reproductive success and condition. Females responded equally strongly to both stimuli, and although both behaviours were repeatable, they did not correlate. Latency to enter was negatively related to body condition and the number of offspring fledged. By contrast, inspection time was directly explained by whether incubating females had been flushed from the nest before the trial began. Thus, our inferences on the relationship between risk aversion and fitness depend on how risk aversion was measured. Our results highlight the limitations of drawing conclusions about the relevance of single measures of a personality trait such as risk aversion. PMID- 29515907 TI - Information theory, predictability and the emergence of complex life. AB - Despite the obvious advantage of simple life forms capable of fast replication, different levels of cognitive complexity have been achieved by living systems in terms of their potential to cope with environmental uncertainty. Against the inevitable cost associated with detecting environmental cues and responding to them in adaptive ways, we conjecture that the potential for predicting the environment can overcome the expenses associated with maintaining costly, complex structures. We present a minimal formal model grounded in information theory and selection, in which successive generations of agents are mapped into transmitters and receivers of a coded message. Our agents are guessing machines and their capacity to deal with environments of different complexity defines the conditions to sustain more complex agents. PMID- 29515908 TI - Penetrative trace fossils from the late Ediacaran of Mongolia: early onset of the agronomic revolution. AB - The Cambrian radiation of complex animals includes a dramatic increase in the depth and intensity of bioturbation in seafloor sediment known as the 'agronomic revolution'. This bioturbation transition was coupled with a shift in dominant trace fossil style from horizontal surficial traces in the late Precambrian to vertically penetrative trace fossils in the Cambrian. Here we show the existence of the first vertically penetrative trace fossils from the latest Ediacaran: dense occurrences of the U-shaped trace fossil Arenicolites from late Precambrian marine carbonates of Western Mongolia. Their Ediacaran age is established through stable carbon isotope chemostratigraphy and their occurrence stratigraphically below the first appearance of the trace fossil Treptichnus pedum. These Arenicolites are large in diameter, penetrate down to at least 4 cm into the sediment, and were presumably formed by the activity of bilaterian animals. They are preserved commonly as paired circular openings on bedding planes with maximum diameters ranging up to almost 1 cm, and as U- and J-shaped tubes in vertical sections of beds. Discovery of these complex penetrative trace fossils demonstrates that the agronomic revolution started earlier than previously considered. PMID- 29515909 TI - Implications of asymptomatic carriers for infectious disease transmission and control. AB - For infectious pathogens such as Staphylococcus aureus and Streptococcus pneumoniae, some hosts may carry the pathogen and transmit it to others, yet display no symptoms themselves. These asymptomatic carriers contribute to the spread of disease but go largely undetected and can therefore undermine efforts to control transmission. Understanding the natural history of carriage and its relationship to disease is important for the design of effective interventions to control transmission. Mathematical models of infectious diseases are frequently used to inform decisions about control and should therefore accurately capture the role played by asymptomatic carriers. In practice, incorporating asymptomatic carriers into models is challenging due to the sparsity of direct evidence. This absence of data leads to uncertainty in estimates of model parameters and, more fundamentally, in the selection of an appropriate model structure. To assess the implications of this uncertainty, we systematically reviewed published models of carriage and propose a new model of disease transmission with asymptomatic carriage. Analysis of our model shows how different assumptions about the role of asymptomatic carriers can lead to different conclusions about the transmission and control of disease. Critically, selecting an inappropriate model structure, even when parameters are correctly estimated, may lead to over- or under estimates of intervention effectiveness. Our results provide a more complete understanding of the role of asymptomatic carriers in transmission and highlight the importance of accurately incorporating carriers into models used to make decisions about disease control. PMID- 29515910 TI - Multiple benefits of alloparental care in a fluctuating environment. AB - Although cooperatively breeding vertebrates occur disproportionately in unpredictable environments, the underlying mechanism shaping this biogeographic pattern remains unclear. Cooperative breeding may buffer against harsh conditions (hard life hypothesis), or additionally allow for sustained breeding under benign conditions (temporal variability hypothesis). To distinguish between the hard life and temporal variability hypotheses, we investigated whether the number of alloparents at a nest increased reproductive success or load-lightening in superb starlings (Lamprotornis superbus), and whether these two types of benefits varied in harsh and benign years. We found that mothers experienced both types of benefits consistent with the temporal variability hypothesis, as larger contingents of alloparents increased the number of young fledged while simultaneously allowing mothers to reduce their provisioning rates under both harsh and benign rainfall conditions. By contrast, fathers experienced load lightening only under benign rainfall conditions, suggesting that cooperative breeding may serve to take advantage of unpredictable benign breeding seasons when they do occur. Cooperative breeding in unpredictable environments may thus promote flexibility in offspring care behaviour, which could mitigate variability in the cost of raising young. Our results highlight the importance of considering how offspring care decisions vary among breeding roles and across fluctuating environmental conditions. PMID- 29515911 TI - Trypanosoma amblyommi sp. nov. (Protozoa: Kinetoplastida) isolated from Amblyomma brasiliense (Acari: Ixodidae) ticks in Rio de Janeiro, Brazil. AB - Parasites of the genus Trypanosoma are microorganisms that display wide morphological, biological and genetic variability. Here we present the first description of an isolate of the genus Trypanosoma naturally infecting the tick Amblyomma brasiliense. The ticks were collected from a specimen of Tayassu pecari (Queixada, white-lipped peccary) from the Itatiaia National Park, Itatiaia, Rio de Janeiro, Brazil. The isolate was characterised by molecular, morphometric and biological analyses. A Trypanosoma culture was isolated from crushed nymphal and adult ticks, propagated in the tick cell line IDE8 and maintained in L15B culture medium, incubated at 32 degrees C. The isolate grew well in L15B medium at 30 degrees C, 32 degrees C and 34 degrees C but not at lower or higher temperatures. The culture remained stable in axenic L15B medium at 30 degrees C. Cryopreserved cultures retained viability after cryopreservation in liquid nitrogen. Growth in axenic medium and developmental forms of the trypanosomes were analysed. Analysis of the 18S rDNA region confirmed the authenticity of this new species and the nucleotide sequence was deposited in Genbank. The species was named Trypanosoma amblyommi sp. nov. strain C1RJ. Characteristics related to pathogenicity, involvement with vertebrate hosts, epidemiology, developmental cycle and transmission mechanisms are still unknown. Therefore, further studies are necessary to understand aspects of the biological cycle of Trypanosoma amblyommi sp. nov. PMID- 29515912 TI - Review article: Novel technologies in the treatment and monitoring of advanced and relapsed epithelial ovarian cancer. AB - Epithelial Ovarian cancer (EOC) is the fifth most common cause of cancer death in females in the UK. It has long been recognized to be a set of heterogeneous diseases, with high grade serous being the most common subtype. The majority of patients with EOC present at an advanced stage (FIGO III-IV), and have the largest risk for disease recurrence from which a high percentage will develop resistance to chemotherapy. Despite continual advances in diagnostics, imaging, surgery and treatment of EOC, there has been little variation in the survival rates for patients with EOC. In this review we will introduce novel bioengineering advances in modelling the lymphatic system and real-time tissue monitoring to improve the clinical and therapeutic outcome for patients with EOC. We discuss the advent of the non-invasive "liquid biopsy" in the surveillance of patients undergoing treatment and follow-up. Finally, we present new bioengineering advances for palliative care of patients to lessen symptoms of patients with ascites and improve quality of life. PMID- 29515913 TI - Current strategies and successes in engaging women in vector control: a systematic review. AB - Introduction: Vector-borne diseases (VBDs) cause significant mortality and morbidity in low-income and middle-income countries and present a risk to high income countries. Vector control programmes may confront social and cultural norms that impede their execution. Anecdotal evidence suggests that incorporating women in the design, delivery and adoption of health interventions increases acceptance and compliance. A better understanding of programmes that have attempted to increase women's involvement in vector control could help shape best practices. The objective of this systematic review was to assess and critically summarise evidence regarding the effectiveness of women participating in vector control. Methods: Seven databases were searched from inception to 21 December 2015. Two investigators independently reviewed all titles and abstracts for relevant articles. Grey literature was searched by assessing websites that focus on international development and vector control. Results: In total, 23 articles representing 17 unique studies were included in this review. Studies discussed the involvement of women in the control of vectors for malaria (n=10), dengue (n=8), human African trypanosomiasis (n=3), schistosomiasis (n=1) and a combination (malaria and schistosomiasis, n=1). Seven programmes were found in the grey literature or through personal communications. Available literature indicates that women can be successfully engaged in vector control programmes and, when given the opportunity, they can create and sustain businesses that aim to decrease the burden of VBDs in their communities. Conclusion: This systematic review demonstrated that women can be successfully engaged in vector control programmes at the community level. However, rigorous comparative effectiveness studies need to be conducted. PMID- 29515914 TI - Making sense of child, early and forced marriage among Syrian refugee girls: a mixed methods study in Lebanon. AB - Introduction: The Syrian conflict has resulted in over 2.3 million child refugees in the Middle East and the prevalence of early marriage has reportedly increased among displaced Syrian families. This study explores the underlying factors contributing to child marriage among Syrian refugees in Lebanon with the goal of informing community-based strategies to address the issue. Methods: In July August 2016, trained interviewers collected self-interpreted stories in Lebanon using Cognitive Edge's SenseMaker, a mixed-method data collection tool. Participants included married and unmarried Syrian girls, Syrian parents as well as married and unmarried men. Each participant shared a story about the experiences of Syrian girls and then interpreted the story by plotting their perspectives on a variety of questions. Patterns in the responses were analysed in SPSS and the accompanying qualitative narratives were reviewed to facilitate interpretation of the quantitative results. Results: 1422 self-interpreted stories from 1346 unique participants were collected with 40% of shared stories focused on (n=332) or mentioning (n=245) child marriage. Quantitative data summarised the different perspectives of female and male participants. Syrian girls and mothers were more likely to share stories about protection/security and/or education and were more likely to report that girls were overprotected. Male participants were more likely to share stories about financial security as well as sexual exploitation of girls and more often reported that girls were not protected enough. Despite these gendered perspectives, many of the shared narratives highlighted similar themes of financial hardship, lack of educational opportunities and safety concerns around sexual and gender-based violence (SGBV). Conclusions: A complex myriad of factors contribute to early marriage including poverty, lack of educational opportunities and concerns about SGBV. Sexual exploitation under the guise of marriage is a reality for some Syrian girls. Gender-specific strategies to address child marriage might be more effective in reducing this harmful practice. PMID- 29515915 TI - Do less populous countries receive more development assistance for health per capita? Longitudinal evidence for 143 countries, 1990-2014. AB - Background: Per capita allocation of overall development assistance has been shown to be biased towards countries with lower population size, meaning funders tend to provide proportionally less development assistance to countries with large populations. Individuals that happen to be part of large populations therefore tend to receive less assistance. However, no study has investigated whether this is also true regarding development assistance for health. We examined whether this so-called 'small-country bias' exists in the health aid sector. Methods: We analysed the effect of a country's population size on the receipt of development assistance for health per capita (in 2015 US$) among 143 countries over the period 1990-2014. Explanatory variables shown to be associated with receipt of development assistance for health were included: gross domestic product per capita, burden of disease, under-5 mortality rate, maternal mortality ratio, vaccination coverage (diphtheria, tetanus and pertussis) and fertility rate. We used the within-between regression analysis, popularised by Mundluck, as well as a number of robustness tests, including ordinary least squares, random effects and fixed-effects regressions. Results: Our results suggest there exists significant negative effect of population size on the amount of development assistance for health per capita countries received. According to the within between estimator, a 1% larger population size is associated with a 0.4% lower per capita development assistance for health between countries (-0.37, 95% CI 0.45 to -0.28), and 2.3% lower per capita development assistance for health within countries (-2.29, 95% CI -3.86 to -0.72). Conclusions: Our findings support the hypothesis that small-country bias exists within international health aid, as has been previously documented for aid in general. In a rapidly changing landscape of global health and development, the inclusion of population size in allocation decisions should be challenged on the basis of equitable access to healthcare and health aid effectiveness. PMID- 29515916 TI - Removing user fees to improve access to caesarean delivery: a quasi-experimental evaluation in western Africa. AB - Introduction: Mali and Benin introduced a user fee exemption policy focused on caesarean sections in 2005 and 2009, respectively. The objective of this study is to assess the impact of this policy on service utilisation and neonatal outcomes. We focus specifically on whether the policy differentially impacts women by education level, zone of residence and wealth quintile of the household. Methods: We use a difference-in-differences approach using two other western African countries with no fee exemption policies as the comparison group (Cameroon and Nigeria). Data were extracted from Demographic and Health Surveys over four periods between the early 1990s and the early 2000s. We assess the impact of the policy on three outcomes: caesarean delivery, facility-based delivery and neonatal mortality. Results: We analyse 99 800 childbirths. The free caesarean policy had a positive impact on caesarean section rates (adjusted OR=1.36 (95% CI 1.11 to 1.66; P<=0.01), particularly in non-educated women (adjusted OR=2.71; 95% CI 1.70 to 4.32; P<=0.001), those living in rural areas (adjusted OR=2.02; 95% CI 1.48 to 2.76; P<=0.001) and women in the middle-class wealth index (adjusted OR=3.88; 95% CI 1.77 to 4.72; P<=0.001). The policy contributes to the increase in the proportion of facility-based delivery (adjusted OR=1.68; 95% CI 1.48 to 1.89; P<=0.001) and may also contribute to the decrease of neonatal mortality (adjusted OR=0.70; 95% CI 0.58 to 0.85; P<=0.001). Conclusion: This study is the first to evaluate the impact of a user fee exemption policy focused on caesarean sections on maternal and child health outcomes with robust methods. It provides evidence that eliminating fees for caesareans benefits both women and neonates in sub-Saharan countries. PMID- 29515917 TI - Simulating the impact of excise taxation for disease prevention in low-income and middle-income countries: an application to South Africa. AB - Introduction: Excise taxes are policy tools that have been applied internationally with some success to reduce consumption of products adversely impacting population health including tobacco, alcohol and increasingly junk foods and sugary beverages. As in other low-income and middle-income countries, South Africa faces a growing burden of lifestyle diseases; accordingly we simulate the impact of multiple excise tax interventions in this setting. Methods: We construct a mathematical model to simulate the health and revenue effects of increased excise taxes, which is adaptable to a variety of settings given its limited data requirements. Applying the model to South Africa, we simulate the impact of increased tax rates on tobacco and beer and of the introduction of a tax on sugar-sweetened beverages (SSB). Drawing on surveys of product usage and risk factor prevalence, the model uses a potential impact fraction to simulate the health effects of tax interventions. Results: Adopting an excise rate of 60% on tobacco would result in a gain of 858 923 life-years (95% uncertainty interval (UI) 480 188 to 1 310 329), while adopting an excise rate of 25% on beer would result in a gain of 568 063 life-years (95% UI 412 110 to 775 560) and the adoption of a 20% tax on SSBs would result in a gain of 688 719 life-years (95% UI 321 788 to 1 079 653). Conclusion: More aggressive excise tax policies on tobacco, beer and SSBs in South Africa could result in meaningful improvements in population health and raised revenue. PMID- 29515918 TI - Violence against children in South Africa: the cost of inaction to society and the economy. AB - Despite the extent and magnitude of violence against children in South Africa, political and financial investments to prevent violence against children remain low. A recent costing study investigating the social burden and economic impact of violence against children in South Africa found notable reductions to mental and physical health outcomes in the population if children were prevented from experiencing violence, neglect and witnessing family violence. The results showed, among others, that drug abuse in the entire population could be reduced by up to 14% if sexual violence against children could be prevented, self-harm could be reduced by 23% in the population if children did not experience physical violence, anxiety could be reduced by 10% if children were not emotionally abused, alcohol abuse could be reduced by 14% in women if they did not experience neglect as children, and lastly, interpersonal violence in the population could be reduced by 16% if children did not witness family violence. The study further estimated that the cost of inaction in 2015 amounted to nearly 5% of the country's gross domestic product. These findings show that preventing children from experiencing and witnessing violence can help to strengthen the health of a nation by ensuring children reach their full potential and drive the country's economy and growth. The paper further discusses ways in which preventing and ending violence against children may be prioritised in South Africa through, for instance, intersectoral collaboration and improving routine monitoring data, such as through the sustainable development goals. PMID- 29515919 TI - How to and how not to develop a theory of change to evaluate a complex intervention: reflections on an experience in the Democratic Republic of Congo. AB - Theories of change (ToCs) describe how interventions can bring about long-term outcomes through a logical sequence of intermediate outcomes and have been used to design and measure the impact of public health programmes in several countries. In recognition of their capacity to provide a framework for monitoring and evaluation, they are being increasingly employed in the development sector. The construction of a ToC typically occurs through a consultative process, requiring stakeholders to reflect on how their programmes can bring about change. ToCs help make explicit any underlying assumptions, acknowledge the role of context and provide evidence to justify the chain of causal pathways. However, while much literature exists on how to develop a ToC with respect to interventions in theory, there is comparatively little reflection on applying it in practice to complex interventions in the health sector. This paper describes the initial process of developing a ToC to inform the design of an evaluation of a complex intervention aiming to improve government payments to health workers in the Democratic Republic of Congo. Lessons learnt include: the need for the ToC to understand how the intervention produces effects on the wider system and having broad stakeholder engagement at the outset to maximise chances of the intervention's success and ensure ownership. Power relationships between stakeholders may also affect the ToC discourse but can be minimised by having an independent facilitator. We hope these insights are of use to other global public health practitioners using this approach to evaluate complex interventions. PMID- 29515921 TI - Acute Primary Adrenal Insufficiency after Hip Replacement in a Patient with Acute Intermittent Porphyria. AB - Adrenal insufficiency is a potentially life-threatening condition when it occurs acutely, as in adrenal hemorrhage. Generally it is not reversible and requires chronic replacement therapy. Acute intermittent porphyria (AIP) is a rare genetic disease characterized by alterations in heme biosynthesis that result in accumulation of precursors in tissues. A crisis can be triggered by many conditions such as surgery and infections. Symptoms are similar to those of acute hypoadrenalism. Moreover, both conditions are characterized by hyponatremia. We describe the case of a postmenopausal woman known to be affected by AIP who developed after surgery a primary adrenal insufficiency associated with adrenal enlargement; the latter completely reverted in six months. PMID- 29515922 TI - A Case of Cushing's Syndrome due to Ectopic Adrenocorticotropic Hormone Secretion from Esthesioneuroblastoma with Long Term Follow-Up after Resection. AB - We present a case of a 52-year-old male who developed Cushing's Syndrome due to ectopic adrenocorticotrophic hormone (ACTH) secretion from a large esthesioneuroblastoma (ENB) of the nasal sinuses. The patient initially presented with polyuria, polydipsia, weakness, and confusion. Computed tomography scan of the head and magnetic resonance imaging showed a 7 cm skull base mass centered in the right cribriform plate without sella involvement. Work-up revealed ACTH dependent hypercortisolemia, which did not suppress appropriately after high-dose dexamethasone. Subsequent imaging of the chest, abdomen, and pelvis did not reveal other possible ectopic sources of ACTH secretion besides the ENB. His hospital course was complicated by severe hypokalemia and hyperglycemia before successful surgical resection of the tumor, the biopsy of which showed ENB. Postoperatively, his ACTH level dropped below the limit of detection. In the ensuing 4 months, he underwent adjuvant chemoradiation with carboplatin and docetaxel with good response and resolution of hypokalemia and hyperglycemia, with no sign of recurrence as of 30 months postoperatively. His endogenous cortisol production is rising but has not completely recovered. PMID- 29515923 TI - Internal Spreading of Papillary Thyroid Carcinoma: A Case Report and Systemic Review. AB - An 18-year-old female diagnosed finally as PTC with intrathyroid spread was reported, and the diagnosis and surgical treatment of internal spreading of PTC were discussed. One lump was found on the thyroid isthmus by physical examination and B ultrasound, and multiple nodular shadows were found by CT. This patient finally underwent total thyroidectomy with bilateral central node dissection due to multifocal papillary thyroid carcinoma except PTC in the isthmus found in right lobe by intraoperative frozen section. The pathological section showed a major thyroid carcinoma in thyroid isthmus with scattered micropapillary carcinoma around it in the whole thyroid gland. The small lesions are distributed around central lesion in a radial form and the number of small lesions decreases with increased distance from central lesion. PTC with internal spread should be distinguished from multifocal PTC and poorly differentiated PTC in pathology. Thyroid cancerous node had a large diameter; it was likely to have internal spread. Combined imaging before surgery should be valued to diagnose PTC with internal spread. Preoperative CT and intraoperative frozen section are helpful for surgical volume selection of PTC with internal spread. PMID- 29515924 TI - Iatrogenic T-Cell Lymphoma with Associated Hemophagocytic Lymphohistiocyotsis in a Patient with Long-Standing Rheumatoid Arthritis. AB - Patients with rheumatoid arthritis are at increased risk of hematological malignancies, especially when exposed to immunosuppressive therapy. The mechanisms of lymphomagenesis remain poorly understood but factors implicated include high disease activity, exposure to antitumoral necrosis factor medications, and Epstein-Barr virus infection. Lymphoid malignancies of T-cell origin are uncommon in patients with rheumatoid arthirits. Clinical presentation with associated hemophagocytic lymphohistiocyotsis is rare and confers a poor prognosis. This case report illustrates a case of a patient with long-standing rheumatoid arthritis and an iatrogenic peripheral T-cell lymphoma with secondary hemophagocytic lymphohistiocytosis who achieved a complete response after intensive chemotherapy. PMID- 29515925 TI - Tumor-Like Reaction to Polypropylene Mesh from a Mid-Urethral Sling Material Resembling Giant Cell Tumor of Vagina. AB - Background: Polypropylene material is widely used in gynecological surgery. There are few reports regarding its carcinogenic potential. There is lack of evidence supporting tumor formation directly attributed to the use of polypropylene material. Case: This patient is a 49-year-old woman with a history of stress urinary incontinence which required a MiniArc(r) Sling who presented with a hard, tender, immobile mass on the anterior vaginal wall. Pathological analysis of the mass revealed a tumor-like reaction to the polypropylene material that resembled a giant cell tumor of soft tissue. Conclusion: The use of polypropylene in surgery is ubiquitous across disciplines; thus consideration for a tumor-like reaction to the material should exist for patients who present with a mass near the surgical site. PMID- 29515926 TI - The Effect of Nasal Functions on the Integrity of Grafts after Myringoplasty. AB - Objective: We aimed to evaluate the effects of nasal functions for the integrity of grafts after myringoplasty. Methods: In our study 78 patients who underwent myringoplasty operation between 2011-2013 were included. Group I was defined as the group with an intact tympanic membrane following surgery. Group II was defined as the group with a tympanic membrane perforation following surgery. Group I consisted of 44 and Group II consisted of 34 patients. Subjective and objective measurements of nasal functions, Eustachian tube function (ETF), and allergic status were performed using nasal obstruction symptom evaluation (NOSE) scale, visual analog scale (VAS), and the score for allergic rhinitis (SFAR) questionnaires and acoustic rhinometry and saccharin test. It was investigated whether there was any difference between these two groups in terms of these parameters. Results: There was statistically no significant difference between groups according to the age, sex and the presence of tubal dysfunction and allergic rhinitis (p>0.05). In the group of intact tympanic membranes, the likelihood of right ear being the operated one was significantly higher compared to the group of myringoplasty failures (p=0.037). The VAS and NOSE scales did not show any significant difference between groups in terms of successful outcome of myringoplasty (p>0.05). The nasal congestion index (NCI) and the mucociliary clearance (MCC) did not show any significant difference between groups in terms of successful outcome of myringoplasty (p>0.05). Conclusion: This study has shown that nasal functions measured by objective and subjective methods had no effects on the success of myringoplasty. PMID- 29515927 TI - Comparison of Audiological Findings in Patients with Vestibular Migraine and Migraine. AB - Objective: The aim of this study was to investigate and compare the auditory findings in vestibular migraine (VM) and migraine patients without a history of vertigo. Methods: This study was conducted on 44 patients diagnosed with definite VM and 31 patients diagnosed with migraine who were followed and treated between January 2011 and February 2015. Also, 52 healthy subjects were included in this study as a control group. All participants underwent a detailed otorhinolaryngological examination followed by audiological evaluation, including pure tone audiometry, speech reception threshold, speech recognition score, and acoustic immitancemetry. Results: In the VM group, there were 16 patients (36.4%) with tinnitus, while in the other groups we did not observe any patients with tinnitus. The rate of tinnitus in the VM group was significantly higher in comparison to other groups (p<0.05). None of the groups had any patients with permanent or fluctuating sensorineural hearing loss. Conclusion: We conclude that patients with VM should be closely and longitudinally followed up for the early detection of other otological symptoms and possible occurrence of sensorineural hearing loss in the long term. PMID- 29515928 TI - Paranasal Sinus Anatomic Variations Accompanying Maxillary Sinus Retention Cysts: A Radiological Analysis. AB - Objective: The risk factors for the development of retention cysts of the maxillary sinuses (RCMs) are not clear, although RCMs are common findings on radiographic images. This study was conducted to evaluate the correlation between RCMs and other nasal-paranasal anomalies and to demonstrate the possible effects of these anomalies on the development of RCMs. Methods: In the study, paranasal sinus computerized tomography (PNsCT) images from 5166 patients were retrospectively reviewed. Correlations between RCMs and osteomeatal complex obstruction, accessory ostium presence, abnormalities of the middle turbinate, and nasal septal deviation were analyzed in the PNsCT images. The paranasal sinus anomalies on the side of the RCMs were compared to the contralateral side. Results: A total of 1880 RCMs were detected in 1429 (27.6%) of 5166 patients. At least one nasal-paranasal sinus anomaly was associated with 88.7% of the RCMs. In the descending order, accessory ostium presence, accessory ostium, middle turbinate anomalies, and nasal septal deviation are pathologies that accompany RCMs. When unilateral RCMs were compared with the normal side, significant correlations were observed between RCMs and osteomeatal complex obstruction, accessory ostium, and middle turbinate anomalies (p=0.001, p=0.016, and p=0.03, respectively). RCMs were commonly found on the same side as osteomeatal complex obstruction (p=0.001), middle turbinate anomalies (p=0.001), and accessory ostium (p=0.052). Conclusions: In this study, the coexistence of osteomeatal complex obstruction, accessory ostium, middle turbinate anomalies, and nasal septum deviation with RCMs was analyzed by investigating PNsCT findings in 5166 patients. The results show that RCMs are associated with pathologies that increase paranasal inflammation, such as osteomeatal complex obstruction, and are good markers for nasal-paranasal sinus anomalies. The presence of incidental RCMs should be a warning sign of nasal-paranasal sinus anomalies. PMID- 29515929 TI - Citation Analysis of Turkish Otorhinolaryngology Publications and Comparison with Five Countries. AB - Objective: In this cross-sectional study, it was aimed to analyse quantitatively citations of articles written by Turkish authors in the publications of Turkish otorhinolaryngologists. For comparison, the same investigation was performed for publications from five countries from different regions of the world. Methods: References of publications belonging to the 2015 issues of four selected Turkey based Otorhinolaryngology (ORL) journals were reviewed. The number and properties of references of articles published by Turkish authors in ORL journals belonging to the Science Citation Index (SCI) were investigated. Finally, a similar investigation was performed for ORL journals published in the five selected countries. Results: In the 2015 issues of the ORL Forum Electronic Journal of Otorhinolaryngology and Head and Neck Surgery, The Turkish Journal of Ear Nose and Throat, Journal of Otorhinolaryngology and Head Neck Surgery, and the Turkish Archives of Otorhinolaryngology; the number of references was 2708 and the number of references in which the first author was Turkish was 460; 149 of these were from Turkish journals. During the same period, 85 publications in which the first author was Turkish were found in the ORL journals belonging to SCI. In these publications, 271 of 2252 references belonged to Turkish authors and 18 of them were included in Turkey-based journals. When the references of articles published in five ORL journals of the National ORL Societies in Brazil, India, Iran, Italy, and Japan were investigated, the most national citations were observed in publications in Brazil, Italy, and Japan. Conclusion: In this cross-sectional study, citations from Turkey and other countries of the world were quantitatively evaluated in publications made by Turkish authors in the Turkey-based and SCI ORL journals. To our knowledge, our study is the first that is based on this subject. Increasing the number of similar studies might provide important contributions to Turkish ORL publishing. PMID- 29515930 TI - Auricular Lobuloplasty. AB - Objective: To evaluate surgical outcomes of auricular lobuloplasy. Methods: In total, 13 patients (10 females and 3 males; average age, 32.3+/-8.48 years; range 21-44 years) who underwent auricular lobuloplasty were included in this study. Demographic characteristics, cause of surgery, presence of complications, and patient satisfaction were evaluated. Results: The mean follow-up was 16.5+/-9.6 months with the shortest and the longest follow-up being 6 and 34 months, respectively. Surgeries were performed under local anesthesia in 10 cases (76.9%) and under general anesthesia in three cases (23.1%). Lobuloplasty were performed in eight cases (61.5%) with a diagnosis of partial lobule cleft, four cases (30.7%) with a diagnosis of elongated lobule, and one case (7.8%) with a diagnosis of congenital earlobe cleft. There were no postoperative complications and revision surgery was not necessary for any of the patients. Conclusion: Multiple surgical techniques exist for repairing earlobe deformities. Auricular lobuloplasty is a surgical procedure that has several advantages including safety, ease of use, and effectiveness. PMID- 29515931 TI - Sublingual Lymph Node Metastasis in Early-Stage Floor of the Mouth Carcinoma. AB - Metastasis to the sublingual lymph nodes is very rare in oral cavity cancers. We present an early-stage floor of the mouth (FOM) cancer case with metastasis to the sublingual lymph node. Even though the rate of metastatic sublingual lymph nodes is low, the uncommon presence of sublingual lymph node metastasis in an early-stage FOM cancer case raises the question of routine FOM dissection. Further anatomic and pathologic studies addressing the rate and pattern of sublingual lymph node metastasis are warranted. PMID- 29515932 TI - Successful Treatment of a Case with Cervical Lymphatic Malformation: Repeated Bleomycin Sclerotherapy. AB - Lymphatic malformations (LM) are benign congenital malformations of the lymphatic system. They are frequently seen in the neck and sometimes can be life threatening due to compression to the airway. Treatment modalities are widespread including surgical excision, radiotherapy, laser therapy, and application of intralesional sclerosing agents. We report the successful treatment of cervical LM in a 3-year-old boy who presented with a sudden onset of a large cystic mass in the posterior cervical triangle and was treated with repeated injections of intralesional bleomycin. PMID- 29515933 TI - Laryngeal Verruca Vulgaris Presenting with Dysphonia: A Case Report. AB - Verruca vulgaris is a common skin lesion that is associated with human papilloma virus and is observed on the surface of skin. Verruca vulgaris is rarely seen in mucosal membranes. Atypical locations may be confused with verrucous carcinoma. The incidence of laryngeal verruca vulgaris has not yet been reported in the literature. Differential diagnoses in histopathological examinations include keratosis, squamous papilloma, verrucous hyperplasia, and verrucous carcinoma. Distinguishing disease from verrucous carcinoma is particularly important because the treatment approach can be altered. In this report, we present a rare case of laryngeal verruca vulgaris that was diagnosed on the basis of histopathological features. PMID- 29515934 TI - High-Grade Basal Cell Adenocarcinoma Arising from the Parotid Gland: A Case Report and Review of the Literature. AB - Basal cell adenocarcinomas are exceptionally rare and were first included in the histopathological classification of salivary gland tumors by the World Health Organization in 1991. These tumors are generally described as a low-grade malignancy with rare regional or distant metastasis. However, 48 basal cell adenocarcinoma cases arising from the major salivary glands have been described as high-grade malignancy in the English literature. Surgical excision and possible postoperative radiotherapy is the treatment of choice. Close follow up is mandatory for early detection of possible local recurrence. A 66-year-old female with high-grade basal cell adenocarcinoma of the parotid gland was presented in this study. Total parotidectomy with protection of the facial nerve integrity and postoperative radiotherapy were performed. At the most recent follow-up examination, 24 months after the surgery, the patient had no complaints and there was no sign of disease recurrence. PMID- 29515935 TI - 3D-printed vascular networks direct therapeutic angiogenesis in ischaemia. AB - Arterial bypass grafts remain the gold standard for the treatment of end-stage ischaemic disease. Yet patients unable to tolerate the cardiovascular stress of arterial surgery or those with unreconstructable disease would benefit from grafts that are able to induce therapeutic angiogenesis. Here, we introduce an approach whereby implantation of 3D-printed grafts containing endothelial-cell lined lumens induces spontaneous, geometrically guided generation of collateral circulation in ischaemic settings. In rodent models of hind-limb ischaemia and myocardial infarction, we demonstrate that the vascular patches rescue perfusion of distal tissues, preventing capillary loss, muscle atrophy and loss of function. Inhibiting anastomoses between the construct and the host's local capillary beds, or implanting constructs with unpatterned endothelial cells, abrogates reperfusion. Our 3D-printed grafts constitute an efficient and scalable approach to engineer vascular patches able to guide rapid therapeutic angiogenesis and perfusion for the treatment of ischaemic diseases. PMID- 29515937 TI - Chronodes: Interactive Multifocus Exploration of Event Sequences. AB - The advent of mobile health (mHealth) technologies challenges the capabilities of current visualizations, interactive tools, and algorithms. We present Chronodes, an interactive system that unifies data mining and human-centric visualization techniques to support explorative analysis of longitudinal mHealth data. Chronodes extracts and visualizes frequent event sequences that reveal chronological patterns across multiple participant timelines of mHealth data. It then combines novel interaction and visualization techniques to enable multifocus event sequence analysis, which allows health researchers to interactively define, explore, and compare groups of participant behaviors using event sequence combinations. Through summarizing insights gained from a pilot study with 20 behavioral and biomedical health experts, we discuss Chronodes's efficacy and potential impact in the mHealth domain. Ultimately, we outline important open challenges in mHealth, and offer recommendations and design guidelines for future research. PMID- 29515938 TI - Suppressed without a Cause: A Case of Idiopathic Immune Deficiency. AB - We report a case of a 45-year-old male who presented with a headache, fever, vomiting, somnolence, and difficulty walking for 10 days. His cerebrospinal fluid studies revealed cryptococcal meningitis. Chest and abdominal computed tomography (CT) scans showed splenomegaly along with mediastinal, retroperitoneal and inguinal lymphadenopathy. CD4 count turned out to be 208 MUL-1. Human immunodeficiency virus (HIV) testing, serum protein electrophoresis, serum light chains and quantitative immunoglobulins were non-diagnostic and CD4 lymphopenia was attributed to acute infection. However, a persistent CD4 lymphopenia was seen in subsequent outpatient testing, which prompted a detailed workup for secondary causes of immunodeficiency. Repeated lymph node biopsies with analytic cytometric immunophenotypic analysis were normal, as was the bone marrow biopsy with detailed immunophenotypic and cytogenetic studies. The patient was hence being treated as a case of idiopathic CD4 lymphocytopenia. PMID- 29515936 TI - Polymeric scaffolds for three-dimensional culture of nerve cells: a model of peripheral nerve regeneration. AB - Understanding peripheral nerve repair requires the evaluation of 3D structures that serve as platforms for 3D cell culture. Multiple platforms for 3D cell culture have been developed, mimicking peripheral nerve growth and function, in order to study tissue repair or diseases. To recreate an appropriate 3D environment for peripheral nerve cells, key factors are to be considered including: selection of cells, polymeric biomaterials to be used, and fabrication techniques to shape and form the 3D scaffolds for cellular culture. This review focuses on polymeric 3D platforms used for the development of 3D peripheral nerve cell cultures. PMID- 29515939 TI - Evolution of Technique in Endoscopic Transsphenoidal Surgery for Pituitary Adenoma: A Single Institution Experience from 220 Procedures. AB - Introduction Endoscopic transsphenoidal surgery (ETSS) for pituitary adenoma (PA) has been a recent shift from the traditional microscopic technique. Although some literature demonstrated superiority of ETSS over the microscopic method and some evaluated mono- vs. binostril access within the ETSS, none had explored the potential influence of dedicated instrument, as this procedure had evolved, on patients' outcomes when compared to traditional microscopic tools. Objective To investigate our own clinical and radiographic outcomes of ETSS for PA with its technical evolution over time as well as a significance of, having vs. lacking, the special endoscopic tools. Methods Included patients underwent ETSS for PA performed by the first author (AH). Prospectively recorded patients' data concerning pre-, intra- and postoperative clinical and radiographic assessments were subject to analysis. The three groups of differently evolving ETSS techniques, beginning with mononostril (MN) to binostril ETSS with standard microsurgical instruments (BN1) and, lastly, binostril ETSS with specially designed endoscopic tools (BN2), were examined for their impact on the intra- and, short- and long-term, postoperative results. Also, the survival after ETSS for PA, as defined by the need for reintervention in each technical group, was appraised. Results From January 2006 to 2012, there were 47, 101 and 72 ETSS, from 183 patients, in the MN, BN1 and BN2 cohorts, respectively. Significant preoperative findings were greater proportion of patients with prior surgery (p=0.01) and tumors with parasellar extension (p=0.02) in the binostril (BN1&2) than the MN group. Substantially shorter operative time and less amount of blood loss were evident as our technique had evolved (p<0.001). Despite higher incidence, and more advanced grades, of cerebrospinal fluid leakage in the binostril groups (p < 0.001), the requirement for post-ETSS surgical repair was less than the mononostril cohort (p=0.04). At six-month follow-up (n=214), quantitative radiographic outcome analysis was markedly superior in BN2. Consequently, long-term result was better in this latest technical group. Important negative risk factors, from multivariate Cox regression analysis, were prior surgery, Knosp grade, and firm tumor while BN1, BN2 and percentages of anteroposterior dimension PA removal had positive effect on longer survival. Conclusion The evolution of technique for ETSS for PA from MN to BN2 has shown its efficacy by improving intra- and postoperative outcomes in our study cohorts. Based on our results, not only that a neurosurgeon, wishing to start performing ETSS, should enroll in a formal fellowship training but he/she should also utilize advanced endoscopic tools, as we have proved its superior results in dealing with PA. PMID- 29515940 TI - Pure Squamous Cell Carcinoma of the Gallbladder Masquerading as a Hepatic Mass. AB - Gallbladder (GB) carcinomas are adenocarcinomas (AC) in the majority of cases. Adenosquamous carcinoma (ASC) and pure squamous cell carcinoma (SCC) of the gallbladder are rarely encountered and comprise 1-3% of gallbladder cancer cases. Pure squamous cell carcinoma of the gallbladder is rarer with less than 1% of the incidence. Most of the published literature is based on case reports and case series. The survival rates of ASC and SCC of the gallbladder are significantly lower (mean of five months) compared to the AC of the gallbladder (mean survival of 11.4 months). Most of these lesions are advanced at presentation, rendering them unresectable and resulting in a poor prognosis. However, if the lesions are diagnosed at an early stage, they could potentially be resectable. We report one such rare case of pure SCC GB presenting as a hepatic mass. The patient subsequently underwent resection of the gallbladder and liver mass with complete recovery and is currently planned for chemotherapy and radiation treatment. PMID- 29515942 TI - Implementation of a Comprehensive Curriculum in Personal Finance for Medical Fellows. AB - INTRODUCTION: Many residents and fellows complete graduate medical education having received minimal unbiased financial planning guidance. This places them at risk of making ill-informed financial decisions, which may lead to significant harm to them and their families. Therefore, we sought to provide fellows with comprehensive unbiased financial education and empower them to make timely, constructive financial decisions. METHODS: A self-selected cohort of cardiovascular disease, pulmonary and critical care, and infectious disease fellows (n = 18) at a single institution attended a live, eight-hour interactive course on personal finance. The course consisted of four two-hour sessions delivered over four weeks, facilitated by an unbiased business school faculty member with expertise in personal finance. Prior to the course, all participants completed a demographic survey. After course completion, participants were offered an exit survey evaluating the course, which also asked respondents for any tangible financial decisions made as a result of the course learning. Results: Participants included 12 women and six men, with a mean age of 33 and varying amounts of debt and financial assets. Twelve respondents completed the exit survey, and all "Strongly Agreed" that courses on financial literacy are important for trainees. In addition, 11 reported that the course helped them make important financial decisions, providing 21 examples. CONCLUSIONS: Fellows derive a significant benefit from objective financial literacy education. Graduate medical education programs should offer comprehensive financial literacy education to all graduating trainees, and that education should be provided by an unbiased expert who has no incentive to sell financial products and services. PMID- 29515943 TI - Applicability of Laparoscopic Nephrectomy in the Treatment of Multicystic Dysplastic Kidney: Sorting Out Surgical Indication. AB - Introduction We evaluated the applicability of laparoscopic nephrectomy in the treatment of multicystic dysplastic kidney (MCDK) in children, including procedures performed by resident physicians or trainees in surgical urology. Methods We retrospectively evaluated the medical records of 20 children with MCDK who underwent laparoscopic nephrectomy over a six-year period. Data collected included gender, laterality of the affected kidney, age at the time of surgery, the largest diameter of the multicystic kidney and associated urological diagnoses, surgical, and postoperative data. All surgical procedures were performed transperitoneally. Results The mean age at the time of surgery was 46 months with a slight predominance of girls. The right side was the more affected side, and the average diameter of the affected kidney at the time of surgical excision was 5.8 cm. Other changes in the urinary tract were found in five children. The mean operative time was 133 minutes. On pathological examination, on average, the pieces measured 4.8 cm and weighed 18.1 g. There were no operative complications. The average length of hospital stay was 37.35 hours. Conclusion Laparoscopic nephrectomy was confirmed as an applicable treatment for MCDK. The technique was easy to perform, safe and efficient, even when performed by trainees in pediatric urology. PMID- 29515941 TI - On the Inclusion of Short-distance Bystander Effects into a Logistic Tumor Control Probability Model. AB - Currently, interactions between voxels are neglected in the tumor control probability (TCP) models used in biologically-driven intensity-modulated radiotherapy treatment planning. However, experimental data suggests that this may not always be justified when bystander effects are important. We propose a model inspired by the Ising model, a short-range interaction model, to investigate if and when it is important to include voxel to voxel interactions in biologically-driven treatment planning. This Ising-like model for TCP is derived by first showing that the logistic model of tumor control is mathematically equivalent to a non-interacting Ising model. Using this correspondence, the parameters of the logistic model are mapped to the parameters of an Ising-like model and bystander interactions are introduced as a short-range interaction as is the case for the Ising model. As an example, we apply the model to study the effect of bystander interactions in the case of radiation therapy for prostate cancer. The model shows that it is adequate to neglect bystander interactions for dose distributions that completely cover the treatment target and yield TCP estimates that lie in the shoulder of the dose response curve. However, for dose distributions that yield TCP estimates that lie on the steep part of the dose response curve or for inhomogeneous dose distributions having significant hot and/or cold regions, bystander effects may be important. Furthermore, the proposed model highlights a previously unexplored and potentially fruitful connection between the fields of statistical mechanics and tumor control probability/normal tissue complication probability modeling. PMID- 29515944 TI - pH Dependence of the Number of Discrete Conformers of Carbonic Anhydrase 2, as Evaluated from Collision Cross-Section Using Ion Mobility Coupled with Electrospray Ionization. AB - Ion mobility experiments coupled with electrospray ionization (ESI) were conducted to evaluate the folding states of bovine carbonic anhydrase 2 (CA2) under three different pH conditions. Collision cross-section (CCS) of the CA2 ions generated by ESI revealed the presence of six discrete conformers in the gas phase under the conditions employed in this study. The CCS of the most extended conformer was three times larger than that of the most compact one. The charge state distribution of the CA2 ions was indicative of three conformers being present. Although there was consistency in conformer assignment conducted by CCS and charge state distribution, the CCS measurement was shown to be more effective because the information obtained provided more detailed knowledge of the conformation of the protein. PMID- 29515945 TI - iQuant2: Software for Rapid and Quantitative Imaging Using Laser Ablation-ICP Mass Spectrometry. AB - We report on the development of a software program named iQuant2 which creates visual images from two-dimensional signal intensity data obtained by a laser ablation-ICP-mass spectrometry (LA-ICPMS) technique. Time-resolved signal intensity profiles can be converted to position resolved signal intensity data based on the rastering rate (MUm s-1) of the laser ablation. Background signal intensities obtained without laser ablation (gas blank) are used as the background, and all of the blank-subtracted intensity data can be used for the imaging analysis. With this software, deformation of the created image can be corrected visually on a PC screen. The line profile analysis between the user selected points can be observed using the iQuant2 software. To accomplish this, data points on the profile line were automatically calculated based on the interpolation between the analysis points. The resulting imaging data can be exported and stored as JPEG, BMP or PNG formats for further processing. Moreover, a semi-quantitative analysis can be made based on the coupling of the external correction of the RSF (relative sensitivity factor) using NIST SRM610 with normalization of the corrected signal intensity data being 100%. The calculated abundance data for major elements are in reasonable agreement with the values obtained by electron probe micro analyzer (EPMA). With the software developed in this study, both the rapid imaging and semi-quantitative determinations can be made. PMID- 29515947 TI - Design of polar self-assembling lactic acid derivatives possessing submicrometre helical pitch. AB - Several new lactic acid derivatives containing the keto linkage group far from the chiral part and short alkyl chains have been synthesized and characterised by polarising optical microscopy, differential scanning calorimetry, as well as electro-optic and dielectric spectroscopy. The materials possess a self assembling behaviour on the nanoscale level as they form polar smectic liquid crystalline mesophases, namely the orthogonal paraelectric SmA* and the tilted ferroelectric SmC* phases, in a broad temperature range down to room temperature. A short helical pitch (~120-320 nm), relatively high spontaneous polarisation (~150 nC/cm2) and reasonable tilt angle values have been determined within the temperature range of the tilted ferroelectric SmC* phase. The obtained results make the new materials useful for the advanced mixture design and for further utilisation in electro-optic devices based on the deformed helix ferroelectric effect. PMID- 29515946 TI - Nanoparticle delivery to metastatic breast cancer cells by nanoengineered mesenchymal stem cells. AB - We created a 3D cell co-culture model by combining nanoengineered mesenchymal stem cells (MSCs) with the metastatic breast cancer cell line MDA-MD-231 and primary breast cancer cell line MCF7 to explore the transfer of quantum dots (QDs) to cancer cells. First, the optimal conditions for high-content QD loading in MSCs were established. Then, QD uptake in breast cancer cells was assessed after 24 h in a 3D co-culture with nanoengineered MSCs. We found that incubation of MSCs with QDs in a serum-free medium provided the best accumulation results. It was found that 24 h post-labelling QDs were eliminated from MSCs. Our results demonstrate that breast cancer cells efficiently uptake QDs that are released from nanoengineered MSCs in a 3D co-culture. Moreover, the uptake is considerably enhanced in metastatic MDA-MB-231 cells compared with MCF7 primary breast cancer cells. Our findings suggest that nanoengineered MSCs could serve as a vehicle for targeted drug delivery to metastatic cancer. PMID- 29515948 TI - Periodic structures on liquid-phase smectic A, nematic and isotropic free surfaces. AB - The free boundary of smectic A (SmA), nematic and isotropic liquid phases were studied using a polarized optical microscope, an interferometric surface structure analyzer (ISSA), an atomic force microscope (AFM) and a scanning near field optical microscope (SNOM). Images of the SmA phase free surface obtained by the polarized microscope and ISSA are in good correlation and show a well-known focal domain structure. The new periodic stripe structure was observed by scanning near-field optical microscopy on the surface of the smectic A, nematic and isotropic phases. The properties of this periodic structure are similar to the charged liquid helium surface and can be explained by nonlinear electrostatic instabilities previously described. PMID- 29515949 TI - Sugarcane juice derived carbon dot-graphitic carbon nitride composites for bisphenol A degradation under sunlight irradiation. AB - Carbon dots (CDs) and graphitic carbon nitride (g-C3N4) composites (CD/g-C3N4) were successfully synthesized by a hydrothermal method using urea and sugarcane juice as starting materials. The chemical composition, morphological structure and optical properties of the composites and CDs were characterized using various spectroscopic techniques as well as transmission electron microscopy. X-ray photoelectron spectroscopy (XPS) results revealed new signals for carbonyl and carboxyl groups originating from the CDs in CD/g-C3N4 composites while X-ray diffraction (XRD) results showed distortion of the host matrix after incorporating CDs into g-C3N4. Both analyses signified the interaction between g C3N4 and CDs. The photoluminescence (PL) analysis indicated that the presence of too many CDs will create trap states at the CD/g-C3N4 interface, decelerating the electron (e-) transport. However, the CD/g-C3N4(0.5) composite with the highest coverage of CDs still achieved the best bisphenol A (BPA) degradation rate at 3.87 times higher than that of g-C3N4. Hence, the charge separation efficiency should not be one of the main factors responsible for the enhancement of the photocatalytic activity of CD/g-C3N4. Instead, the light absorption capability was the dominant factor since the photoreactivity correlated well with the ultraviolet-visible diffuse reflectance spectra (UV-vis DRS) results. Although the CDs did not display upconversion photoluminescence (UCPL) properties, the pi conjugated CDs served as a photosensitizer (like organic dyes) to sensitize g C3N4 and injected electrons to the conduction band (CB) of g-C3N4, resulting in the extended absorption spectrum from the visible to the near-infrared (NIR) region. This extended spectral absorption allows for the generation of more electrons for the enhancement of BPA degradation. It was determined that the reactive radical species responsible for the photocatalytic activity were the superoxide anion radical (O2*-) and holes (h+) after performing multiple scavenging tests. PMID- 29515950 TI - Photocatalytic and adsorption properties of TiO2-pillared montmorillonite obtained by hydrothermally activated intercalation of titanium polyhydroxo complexes. AB - We report on a new approach for the synthesis of TiO2-pillared montmorillonite, where the pillars exhibit a high degree of crystallinity (nanocrystals) representing a mixture of anatase and rutile phases. The structures exhibit improved adsorption and photocatalytic activity as a result of hydrothermally activated intercalation of titanium polyhydroxo complexes (i.e., TiCl4 hydrolysis products) in a solution with a concentration close to the sol formation limit. The materials, produced at various annealing temperatures from the intercalated samples, were characterized by infrared spectroscopy, differential scanning calorimetry (DSC)/thermogravimetric analysis (TGA), X-ray diffraction, dynamic light scattering (DLS) measurements, and liquefied nitrogen adsorption/desorption. The photocatalytic activity of the TiO2-pillared materials was studied using the degradation of anionic (methyl orange, MO) and cationic (rhodamine B, RhB) dyes in water under UV irradiation. The combined effect of adsorption and photocatalysis resulted in removal of 100% MO and 97.5% RhB (with an initial concentration of 40 mg/L and a photocatalyst-sorbent concentration of 1 g/L) in about 100 minutes. The produced TiO2-pillared montmorillonite showed increased photocatalytic activity as compared to the commercially available photocatalyst Degussa P25. PMID- 29515951 TI - Temperature-tunable lasing from dye-doped chiral microdroplets encapsulated in a thin polymeric film. AB - In the last decade, much interest has grown around the possibility to use liquid crystal droplets as optical microcavities and lasers. In particular, 3D laser emission from dye-doped cholesteric liquid crystals confined inside microdroplets paves the way for many applications in the field of sensors or tunable photonics. Several techniques can be used to obtain small microresonators as, for example, dispersing a liquid crystal inside an immiscible isotropic fluid to create an emulsion. Recently, the possibility to obtain a thin free-standing film starting from an emulsion having a mixture of water and polyvinyl alcohol as isotropic matrix has been reported. After the water evaporation, a polymeric film in which the microdroplets are encapsulated has been obtained. Bragg-type laser emission has been recorded from the emulsion as well as from the thin film. Here, we report on the possibility to tune the laser emission as a function of temperature. Using a chiral dopant with temperature dependent solubility, the emitted laser wavelength can be tuned in a range of 40 nm by a temperature variation of 18 degrees C. The proposed device can have applications in the field of sensors and for the development of anti-counterfeiting labels. PMID- 29515953 TI - Dynamic behavior of nematic liquid crystal mixtures with quantum dots in electric fields. AB - The dynamic behavior of a mixture consisting of liquid crystalline 4-cyano-4' pentylbiphenyl (5CB) and CdSe/ZnS quantum dots in electric fields was theoretically studied. The model was based on elastic continuum theory considering the interaction of the nematic molecules with the surrounding molecules, with the quantum dots and with the electric field. Experimental data obtained by dynamic measurements on a sample containing 0.89% (mass fraction) of CdSe/ZnS quantum dots revealed a decrease of the relaxation time compared to pure 5CB. PMID- 29515952 TI - Electron interaction with copper(II) carboxylate compounds. AB - In the present study we have performed electron collision experiments with copper carboxylate complexes: [Cu2(t-BuNH2)2(u-O2CC2F5)4], [Cu2(s-BuNH2)2(u-O2CC2F5)4], [Cu2(EtNH2)2(u-O2CC2F5)4], and [Cu2(u-O2CC2F5)4]. Mass spectrometry was used to identify the fragmentation pattern of the coordination compounds produced in crossed electron - molecular beam experiments and to measure the dependence of ion yields of positive and negative ions on the electron energy. The dissociation pattern of positive ions contains a sequential loss of both the carboxylate ligands and/or the amine ligands from the complexes. Moreover, the fragmentation of the ligands themselves is visible in the mass spectrum below m/z 140. For the studied complexes the metallated ions containing both ligands, e.g., Cu2(O2CC2F5)(RNH2)+, Cu2(O2CC2F5)3(RNH2)2+ confirm the evaporation of whole complex molecules. A significant production of Cu+ ion was observed only for [Cu2(u-O2CC2F5)4], a weak yield was detected for [Cu2(EtNH2)2(u-O2CC2F5)4] as well. The dissociative electron attachment processes leading to formation of negative ions are similar for all investigated molecules as the highest unoccupied molecular orbital of the studied complexes has Cu-N and Cu-O antibonding character. For all complexes, formation of the Cu2(O2CC2F5)4-* anion is observed together with mononuclear DEA fragments Cu(O2CC2F5)3-, Cu(O2CC2F5)2- and Cu(O2CC2F5)-*. All dominant DEA fragments of these complexes are formed through single particle resonant processes close to 0 eV. PMID- 29515954 TI - Blister formation during graphite surface oxidation by Hummers' method. AB - Graphite oxide has a complex structure that can be modified in many ways to obtain materials for a wide range of applications. It is known that the graphite precursor has an important role in the synthesis of graphite oxide. In the present study, the basal-plane surface of highly annealed pyrolythic graphite (HAPG) was oxidized by Hummers' method and investigated by Raman spectroscopy and atomic force microscopy. HAPG was used as a graphite precursor because its surface after cleavage contains well-ordered millimeter-sized regions. The treatment resulted in graphite intercalation by sulfuric acid and blister formation all over the surface. Surprisingly, the destruction of the sp2-lattice was not detected in the ordered regions. We suggest that the reagent diffusion under the basal plane surface occurred through the cleavage steps and dislocations with the Burgers vector parallel to the c-axis in graphite. PMID- 29515955 TI - Engineering of oriented carbon nanotubes in composite materials. AB - The orientation and arrangement engineering of carbon nanotubes (CNTs) in composite structures is considered a challenging issue. In this regard, two groups of in situ and ex situ techniques have been developed. In the first, the arrangement is achieved during CNT growth, while in the latter, the CNTs are initially grown in random orientation and the arrangement is then achieved during the device integration process. As the ex situ techniques are free from growth restrictions and more flexible in terms of controlling the alignment and sorting of the CNTs, they are considered by some as the preferred technique for engineering of oriented CNTs. This review focuses on recent progress in the improvement of the orientation and alignment of CNTs in composite materials. Moreover, the advantages and disadvantages of the processes are discussed as well as their future outlook. PMID- 29515956 TI - Facile synthesis of ZnFe2O4 photocatalysts for decolourization of organic dyes under solar irradiation. AB - ZnFe2O4 was fabricated by a simple solution-combustion method. The structural, optical and electronic properties are investigated by XRD, TEM, FESEM, UV-vis DRS, PL, FTIR and photocurrent measurements. The photocatalytic activity of the prepared material is studied with regard to the degradation of rhodamine B (Rh B) and Congo red under solar irradiation. The kinetic study showed that the material exhibits zeroth and first order reaction kinetics for the degradation of Rh B and Congo red, respectively. The photocatalytic behaviour of ZnFe2O4 was systematically studied as a function of the activation temperature. ZnFe2O4 prepared at 500 degrees C showed the highest activity in degrading Rh B and Congo red. The highest activity of ZnFe2O4-500 degrees C correlates well with the lowest PL intensity, highest photocurrent and lowest particle size. PMID- 29515957 TI - Influence of the preparation method on the photocatalytic activity of Nd-modified TiO2. AB - Nd-modified TiO2 photocatalysts have been obtained via hydrothermal (HT) and sol hydrothermal (SHT) methods. The as-prepared samples were characterized by X-ray diffraction (XRD), BET surface area measurements, scanning electron microscopy (SEM), diffuse reflectance spectroscopy (DRS), luminescence spectroscopy and X ray photoelectron spectroscopy (XPS). The photocatalytic activity of the synthesized samples was evaluated by the degradation of phenol in aqueous solution under irradiation with UV-vis (lambda > 350 nm) and vis (lambda > 420 nm) light, as well as by the degradation of gaseous toluene under irradiation with vis (lambdamax = 415 nm) light. It was found that Nd-modified TiO2 is an efficient photocatalyst for the degradation of phenol and toluene under visible light. XPS analysis revealed that the photocatalyst prepared via HT method contains a three-times higher amount of hydroxy groups at the surface layer and a two-times higher amount of surface defects than that obtained by the SHT method. The photocatalytic efficiency of phenol and toluene degradation under vis irradiation in the presence of 0.25% Nd-TiO2(HT) reached 0.62 and 3.36 MUmol.dm 1.min-1, respectively. Photocatalytic activity tests in the presence of Nd-TiO2 and scavenger confirm that superoxide radicals were responsible for the visible light-induced degradation of the model pollutant in aqueous solution. PMID- 29515958 TI - High-contrast and reversible scattering switching via hybrid metal-dielectric metasurfaces. AB - Novel types of optical hybrid metasurfaces consist of metallic and dielectric elements are designed and proposed for controlling the interference between magnetic and electric modes of the system, in a reversible manner. By employing the thermo-optical effect of silicon and gold nanoantennas we demonstrate an active control on the excitation and interference between electric and magnetic modes, and subsequently, the Kerker condition, as a directive radiation pattern with zero backscattering, via temperature control as a versatile tool. This control allows precise tuning optical properties of the system and stimulating switchable sharp spectral Fano-like resonance. Furthermore, it is shown that by adjusting the intermediate distance between metallic and dielectric elements, opposite scattering directionalities are achievable in an arbitrary wavelength. Interestingly, this effect is shown to have a direct influence on nonlinear properties, too, where 10-fold enhancement in the intensity of third harmonic light can be obtained for this system, via heating. This hybrid metasurface can find a wide range of applications in slow light, nonlinear optics and bio chemical sensing. PMID- 29515959 TI - Kinetics of solvent supported tubule formation of Lotus (Nelumbo nucifera) wax on highly oriented pyrolytic graphite (HOPG) investigated by atomic force microscopy. AB - The time dependence of the formation of lotus wax tubules after recrystallization from various chloroform-based solutions on an HOPG surface at room temperature was studied by atomic force microscopy (magnetic AC mode) taking series of consecutive images of the formation process. The growth of the tubules oriented in an upright fashion follows a sequential rodlet->ring->tubule behavior. The influence of a number of factors, e.g., different wax concentration in chloroform, the additional presence of water, or salts [(NH4)2SO4, NH4NO3] or a mixture of salt/water in the solution on the growth rate and orientation of the tubules is also investigated. Different wax concentrations were found to have no effect on the growth rate or the orientation of tubules in none of the solutions. The presence of water, however, considerably increased the growth rate of tubule formation, while the presence of salt was again found to have no effect on growth rate or orientation of tubules. PMID- 29515960 TI - Optimal fractal tree-like microchannel networks with slip for laminar-flow modified Murray's law. AB - The fractal tree-like branched network is an effective channel design structure to reduce the hydraulic resistance as compared with the conventional parallel channel network. In order for a laminar flow to achieve minimum hydraulic resistance, it is believed that the optimal fractal tree-like channel network obeys the well-accepted Murray's law of betam = N-1/3 (betam is the optimal diameter ratio between the daughter channel and the parent channel and N is the branching number at every level), which is obtained under the assumption of no slip conditions at the channel wall-liquid interface. However, at the microscale, the no-slip condition is not always reasonable; the slip condition should indeed be considered at some solid-liquid interfaces for the optimal design of the fractal tree-like channel network. The present work reinvestigates Murray's law for laminar flow in a fractal tree-like microchannel network considering slip condition. It is found that the slip increases the complexity of the optimal design of the fractal tree-like microchannel network to achieve the minimum hydraulic resistance. The optimal diameter ratio to achieve minimum hydraulic resistance is not only dependent on the branching number, as stated by Murray's law, but also dependent on the slip length, the level number, the length ratio between the daughter channel and the parent channel, and the diameter of the channel. The optimal diameter ratio decreases with the increasing slip length, the increasing level number and the increasing length ratio between the daughter channel and the parent channel, and decreases with decreasing channel diameter. These complicated relations were found to become relaxed and simplified to Murray's law when the ratio between the slip length and the diameter of the channel is small enough. PMID- 29515961 TI - Lyapunov estimation for high-speed demodulation in multifrequency atomic force microscopy. AB - An important issue in the emerging field of multifrequency atomic force microscopy (MF-AFM) is the accurate and fast demodulation of the cantilever-tip deflection signal. As this signal consists of multiple frequency components and noise processes, a lock-in amplifier is typically employed for its narrowband response. However, this demodulator suffers inherent bandwidth limitations as high-frequency mixing products must be filtered out and several must be operated in parallel. Many MF-AFM methods require amplitude and phase demodulation at multiple frequencies of interest, enabling both z-axis feedback and phase contrast imaging to be achieved. This article proposes a model-based multifrequency Lyapunov filter implemented on a field-programmable gate array (FPGA) for high-speed MF-AFM demodulation. System descriptions and simulations are verified by experimental results demonstrating high tracking bandwidths, strong off-mode rejection and minor sensitivity to cross-coupling effects. Additionally, a five-frequency system operating at 3.5 MHz is implemented for higher harmonic amplitude and phase imaging up to 1 MHz. PMID- 29515962 TI - Colloidal solution of silver nanoparticles for label-free colorimetric sensing of ammonia in aqueous solutions. AB - Silver nanoparticles were synthesized in the presence of saccharides and ammonia (NH3) in the concentration range from 10-2 to 103 ppm to develop an optical sensor for NH3 in aqueous solutions. Ammonia affects the features of the nanoparticles obtained in a concentration-dependent manner as determined by UV vis absorption analysis and TEM observations. Structural and morphological analysis provides the basis for the production of a colorimetric label-free sensor for ammonia. Overall, surface plasmon resonance increases when ammonia concentration rises, although the functional trend is not the same over the entire investigated ammonia concentration range. Three different ranges have been identified: very low ammonia concentrations from 0.01 to 0.2 ppm, high ammonia concentrations from 20 to 350 ppm and, most importantly, the intermediate or physiological range of ammonia from 0.5 to 10 ppm. PMID- 29515963 TI - Differential expression of leaf proteins in four cultivars of peanut (Arachis hypogaea L.) under water stress. AB - Drought is a major constraint to the productivity of many crops affecting various physiological and biochemical processes. Seventy percent of the peanuts are grown in semiarid tropics that are frequently prone to drought stress. So, we analyzed its effect in 4 cultivars of peanut, with different degrees of drought tolerance, under 10 and 20 days of water stress using two-dimensional gel electrophoresis and mass spectrometry. A total of 189 differentially expressed protein spots were identified in the leaf proteome of all the 4 cultivars using PD Quest Basic software; 74 in ICGV 91114, 41 in ICGS 76, 44 in J 11 and 30 in JL 24. Of these, 30 protein spots were subjected to in-gel trypsin digestion followed by MALDI-TOF that are functionally categorized into 5 groups: molecular chaperones, signal transducers, photosynthetic proteins, defense proteins and detoxification proteins. Of these, 12 proteins were sequenced. Late embryogenesis abundant protein, calcium ion binding protein, sucrose synthase isoform-1, 17.3 kDa heat shock protein and structural maintenance of chromosome proteins were overexpressed only in the 15 and 20 days stressed plants of ICGV 91114 cultivar while cytosolic ascorbate peroxidase was expressed with varying levels in the 10 and 20 days stressed plants of all the 4 cultivars. Signaling protein like 14-3-3 and defense proteins like alpha-methyl-mannoside-specific lectin and mannose/glucose-binding lectins were differentially expressed in the 4 cultivars. Photosynthetic protein like Rubisco was down-regulated in the stressed plants of all 4 cultivars while Photosystem-I reaction center subunit-II of chloroplast precursor protein was overexpressed in only 20 days stressed plants of ICGV 91114, ICGS 76 and J11 cultivars. These differentially expressed proteins could potentially be used as protein markers for screening the peanut germplasm and further crop improvement. PMID- 29515964 TI - Bio-ethanol production from waste biomass of Pogonatherum crinitum phytoremediator: an eco-friendly strategy for renewable energy. AB - In this study, we have described three steps to produce ethanol from Pogonatherum crinitum, which was derived after the treatment of textile wastewater. (a) Production of biomass: biomass samples collected from a hydroponic P. crinitum phytoreactor treating dye textile effluents and augmented with Ca-alginate immobilized growth-promoting bacterium, Bacillus pumilus strain PgJ (consortium phytoreactor), and waste sorghum husks were collected and dried. Compositional analysis of biomass (consortium phytoreactor) showed that the concentration of cellulose, hemicelluloses and lignin was 42, 30 and 17%, respectively, whereas the biomass samples without the growth-promoting bacterium (normal phytoreactor) was slightly lower, 40, 29 and 16%, respectively. (b) Hydrolysate (sugar) production: a crude sample of the fungus, Phanerochaete chrysosporium containing hydrolytic enzymes such as endoglucanase (53.25 U/ml), exoglucanase (8.38 U/ml), glucoamylase (115.04 U/ml), xylanase (83.88 U/ml), LiP (0.972 U/ml) and MnP (0.459 U/ml) was obtained, and added to consortium, normal and control phytoreactor derived biomass supplemented with Tween-20 (0.2% v/v). The hydrolysate of biomass from consortium phytoreactor produced maximum reducing sugar (0.93 g/l) than hydrolysates of normal phytoreactor biomass (0.82 g/l) and control phytoreactor biomass (0.79 g/l). FTIR and XRD analysis confirmed structural changes in treated biomass. (c) Ethanol production: the bioethanol produced from enzymatic hydrolysates of waste biomass of consortium and normal phytoreactor using Saccharomyces cerevisiae (KCTC 7296) was 42.2 and 39.4 g/l, respectively, while control phytoreactor biomass hydrolysate showed only 25.5 g/l. Thus, the amalgamation of phytoremediation and bioethanol production can be the truly environment-friendly way to eliminate the problem of textile dye along with bioenergy generation. PMID- 29515966 TI - Erratum to: Delayed Closure of Giant Omphaloceles in West Africa: Report of Five Cases. AB - [This corrects the article DOI: 10.1055/s-0037-1599796.]. PMID- 29515967 TI - Acute Stent Migration into the Right Ventricle in a Patient with Iliac Vein Stenting. AB - Endovascular stent placement for chronic postthrombotic iliofemoral venous obstructive lesions is an effective therapeutic option and might be complicated by stent migration. We report a case of a venous stent that was lost from the iliac vein into the right ventricle rescued by emergent open-heart surgery. PMID- 29515965 TI - Genome-wide identification of glutathione peroxidase (GPX) gene family and their response to abiotic stress in cucumber. AB - Plant glutathione peroxidases (GPXs) are non-heme thiol peroxidases that play vital roles in maintaining H2O2 homeostasis and regulating plant response to abiotic stress. Here, we performed a comparative genomic analysis of the GPX gene family in cucumber (Cucumis sativus). As a result, a total of 6 CsGPX genes were identified, which were unevenly located in four out of the seven chromosomes in cucumber genome. Based on the phylogenetic analysis, the GPX genes of cucumber, Arabidopsis and rice could be classified into five groups. Analysis of the distribution of conserved domains of GPX proteins showed that all these proteins contain three highly conserved motifs, as well as other conserved sequences and residues. Gene structure analysis revealed a conserved exon-intron organization pattern of these genes. Through analyzing the promoter regions of CsGPX genes, many hormone-, stress-, and development-responsive cis-elements were identified. Moreover, we also investigated their expression patterns in different tissues and developmental stages as well as in response to abiotic stress and x acid (ABA) treatments. The qRT-PCR results showed that the transcripts of CsGPX genes varied largely under abiotic stress and ABA treatments at different time points. These results demonstrate that cucumber GPX gene family may function in tissue development and plant stress responses. PMID- 29515968 TI - Striatal abnormalities in trichotillomania: a multi-site MRI analysis. AB - Trichotillomania (hair-pulling disorder) is characterized by the repetitive pulling out of one's own hair, and is classified as an Obsessive-Compulsive Related Disorder. Abnormalities of the ventral and dorsal striatum have been implicated in disease models of trichotillomania, based on translational research, but direct evidence is lacking. The aim of this study was to elucidate subcortical morphometric abnormalities, including localized curvature changes, in trichotillomania. De-identified MRI scans were pooled by contacting authors of previous peer-reviewed studies that examined brain structure in adult patients with trichotillomania, following an extensive literature search. Group differences on subcortical volumes of interest were explored (t-tests) and localized differences in subcortical structure morphology were quantified using permutation testing. The pooled sample comprised N=68 individuals with trichotillomania and N=41 healthy controls. Groups were well-matched in terms of age, gender, and educational levels. Significant volumetric reductions were found in trichotillomania patients versus controls in right amygdala and left putamen. Localized shape deformities were found in bilateral nucleus accumbens, bilateral amygdala, right caudate and right putamen. Structural abnormalities of subcortical regions involved in affect regulation, inhibitory control, and habit generation, play a key role in the pathophysiology of trichotillomania. Trichotillomania may constitute a useful model through which to better understand other compulsive symptoms. These findings may account for why certain medications appear effective for trichotillomania, namely those modulating subcortical dopamine and glutamatergic function. Future work should study the state versus trait nature of these changes, and the impact of treatment. PMID- 29515969 TI - Rethinking immigration policy theory beyond 'Western liberal democracies'. AB - How do political systems shape immigration policy-making? Explicitly or implicitly, comparative politics and migration policy theories suggest a 'regime effect' that links specific dynamics of immigration policy to liberal democracy. The literature's dominant focus on so-called 'Western liberal democracies', however, has left the 'regime effect' largely untested and research on variations and similarities in immigration policymaking across political systems strikingly undertheorized. This paper challenges the theoretical usefulness of essentialist, dichotomous categories such as Western/non-Western or democratic/autocratic and calls for a more nuanced theorizing of immigration policy-making. It proposes a two-dimensional classification of immigration policy theories, distinguishing between 'issue-specific' theories that capture immigration policy processes regardless of the political system in place and 'regime-specific' theories whose insights are tied to the characteristics of a political system. The paper also advances the 'illiberal paradox' hypothesis to explain why illiberal, autocratic states may enact liberal immigration policies. This theoretical expansion beyond the 'Western' and 'liberal' bubble is illustrated by an analysis of immigration policy-making in 21st century Morocco and Tunisia. Showing how domestic and international institutions, interests, and ideas shape immigration policy-making in Morocco's monarchy and Tunisia's democratic transition, the paper investigates the broader role of political systems in immigration politics and herewith seeks to contribute to a more general and global theorization of immigration policies. PMID- 29515970 TI - Establishing and Maintaining an Extensive Library of Patient-Derived Xenograft Models. AB - Patient-derived xenograft (PDX) models have recently emerged as a highly desirable platform in oncology and are expected to substantially broaden the way in vivo studies are designed and executed and to reshape drug discovery programs. However, acquisition of patient-derived samples, and propagation, annotation and distribution of PDXs are complex processes that require a high degree of coordination among clinic, surgery and laboratory personnel, and are fraught with challenges that are administrative, procedural and technical. Here, we examine in detail the major aspects of this complex process and relate our experience in establishing a PDX Core Laboratory within a large academic institution. PMID- 29515971 TI - The Expression and Prognostic Impact of Immune Cytolytic Activity-Related Markers in Human Malignancies: A Comprehensive Meta-analysis. AB - Background: Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies. Still, it is not completely understood how different tumors induce and adapt to immune responses. Methods: Here, we calculated the CYT across different cancer types and focused on differences between primary and metastatic tumors. Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types. We correlated the cytolytic levels in each cancer type with the corresponding patient group's overall survival, the expression of several immune-checkpoint molecules, as well as with the load of tumor-infiltrating lymphocytes (TILs), and tumor-associated neutrophils (TANs) in these tumors. Results: We found diverse levels of CYT across different cancer types, with highest levels in kidney, lung, and cervical cancers, and lowest levels in glioma, adrenocortical carcinoma (ACC), and uveal melanoma. GZMA protein was either lowly expressed or absent in at least half of these tumors; whereas PRF1 protein was not detected in almost any of the different tumor types, analyzing tissue microarrays from 20 different tumor types. CYT was significantly higher in metastatic skin melanoma and correlated significantly to the TIL load. In TCGA ACC, skin melanoma, and bladder cancer, CYT was associated with an improved patient outcome and high levels of both GZMA and PRF1 synergistically affected patient survival in these cancers. In bladder, breast, colon, esophageal, kidney, ovarian, pancreatic, testicular, and thyroid cancers, high CYT was accompanied by upregulation of at least one immune-checkpoint molecule, indicating that similar to melanoma and prostate cancer, immune responses in cytolytic-high tumors elicit immune suppression in the tumor microenvironment. Conclusion: Overall, our data highlight the existence of diverse levels of CYT across different cancer types and suggest that along with the existence of complicated associations among various tumor-infiltrated immune cells, it is capable to promote or inhibit the establishment of a permissive tumor microenvironment, depending on the cancer type. High levels of immunosuppression seem to exist in several tumor types. PMID- 29515972 TI - Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature. AB - The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation. PMID- 29515973 TI - Cohort Profile: The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE). AB - : The cohort was set up in order to analyze late effects in long-term testicular cancer survivors (TCS) and to contribute to the design of future follow-up programs addressing and potentially preventing late effects. Data for this cross sectional study were collected between January 1, 2014, and December 31, 2016, among living Danish TCS and 60% agreed to participate in the cohort (N = 2,572). Mean time since testicular cancer (TC) diagnosis was 18 years (range 7-33) and mean age of participants was 53 years (range 25-95). Data consist of results of a questionnaire with patient reported outcomes which covers a broad range of items on late-effects. The study also included data obtained through linkages to Danish registries, a biobank, and clinical data from hospital files and pathology reports originating from the Danish Testicular Cancer Database (DaTeCa). The treatment during the observation period has been nearly the same for all stages of TC and is in agreement with today's standard treatment, this allows for interesting analysis with a wide timespan. We have extensive data on non responders and are able to validate our study findings. Data from a Danish reference population (N = 162,283) allow us to compare our findings with a Danish background population. The cohort can easily be extended to access more outcomes, or include new TCS. A limitation of the present study is the cross-sectional design and despite the large sample size, The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE) lacks statistical power to study very rare late effects. Since it was voluntary to participate in the study we have some selection bias, for instance, we lack responders who were not in a paired relationship, but we would still argue that this cohort of TCSs is representative for TCSs in Denmark. Collaboration and data access: Researches interested in collaboration with the DaTeCa-LATE study group please contact Professor Gedske Daugaard kirsten.gedske.daugaard@regionh.dk. PMID- 29515974 TI - Oropharyngeal Microbiota in Frail Older Patients Unaffected by Time in Hospital. AB - Respiratory tract infections are the commonest nosocomial infections, and occur predominantly in frailer, older patients with multiple comorbidities. The oropharyngeal microbiota is the major reservoir of infection. This study explored the relative contributions of time in hospital and patient demographics to the community structure of the oropharyngeal microbiota in older patients with lower limb fracture. We collected 167 throat swabs from 53 patients (mean age 83) over 14 days after hospitalization, and analyzed these using 16S rRNA gene sequencing. We calculated frailty/comorbidity indices, undertook dental examinations and collected data on respiratory tract infections. We analyzed microbial community composition using correspondence (CA) and canonical correspondence analysis. Ten patients were treated for respiratory tract infection. Microbial community structure was related to frailty, number of teeth and comorbidity on admission, with comorbidity exerting the largest effect. Time in hospital neither significantly changed alpha (t = -0.910, p = 0.365) nor beta diversity (CA1 t = 0.022, p = 0.982; CA2 t = -0.513, p = 0.609) of microbial communities in patient samples. Incidence of respiratory pathogens were not associated with time in hospital (t = -0.207, p = 0.837), nor with alpha diversity of the oral microbiota (t = -1.599, p = 0.113). Patient characteristics at admission, rather than time in hospital, influenced the community structure of the oral microbiota. PMID- 29515976 TI - Fas-ligand and caspase-3 positivity in three cases of histiocytic sarcoma: a different etiopathogenic pathway? AB - Histiocytic sarcoma (HS) is a rare malignant neoplasia of hematopoietic origin and unknown etiology. We studied three patients with histiocytic sarcoma reviewing the morphological and immunohistochemical aspects. We evaluated in particular, if apoptosis may be unbalanced in this disease. All cases have morphological and immunohistochemical features consistent with the diagnosis of histiocytic sarcoma. The markers CD163, CD68, vimentin, lysozyme, and S-100 were positive in all cases. Similarly, the three samples were positive for Fas-ligand and Caspase-3. It is well-known that neoplasms may induce increased levels of Fas ligand with the blockade of the apoptosis process. In the context of HS, the increased Fas-ligand expression represents a new area for research. Indeed, it is linked to proinflammatory stimulus and, maybe with the association of an infection. PMID- 29515977 TI - Occurrence of mesothelial/monocytic incidental cardiac excrescences in material from open-heart procedures: case reports and literature review. AB - Mesothelial/monocytic incidental cardiac excrescences (MICE) are unusual findings during the histological analysis of material from the pericardium, mediastinum, or other tissues collected in open-heart surgery. Despite their somewhat worrisome histological appearance, they show a benign clinical course, and further treatment is virtually never necessary. Hence, the importance of recognizing the entity relays in its differential diagnosis, as an unaware medical pathologist may misinterpret it for a malignant neoplasm. Other mesothelial and histiocytic proliferative lesions, sharing very close histological morphology and immunohistochemistry features with MICE, have been described in sites other than the heart or the mediastinum. This similarity has led to the proposal of the common denomination "histiocytosis with raisinoid nuclei." We report three cases from the pathology archives of the Heart Institute of Sao Paulo University (Incor/HC-FMUSP), diagnosed as "mesothelial/monocytic incidental cardiac excrescence," with immunohistochemical documentation, and provide a literature review of this entity. PMID- 29515978 TI - Virtual autopsy: Machine Learning and AI provide new opportunities for investigating minimal tumor burden and therapy resistance by cancer patients. PMID- 29515975 TI - Triclosan Enhances the Clearing of Pathogenic Intracellular Salmonella or Candida albicans but Disturbs the Intestinal Microbiota through mTOR-Independent Autophagy. AB - Triclosan (TCS) is a broad-spectrum antimicrobial agent, whose well-known antibacterial mechanism is inhibiting lipid synthesis. Autophagy, an innate immune response, is an intracellular process that delivers the cargo including pathogens to lysosomes for degradation. In this study, we first demonstrated that TCS induced autophagy in a dose-dependent manner in non-phagocytic cells (HeLa) and in macrophages (Raw264.7) and in vivo. The western blot results also revealed that TCS induced autophagy via the AMPK/ULK1 and JNK/ERK/p38 pathways independent of mTOR. The immunofluorescence results indicated that TCS up-regulated the expression of the ubiquitin receptors NDP52 and p62 and strengthened the co localization of these receptors with Salmonella enterica Typhimurium (S. typhimurium) or Candida albicans (C. albicans) in infected MPhi cells. In addition, sub-lethal concentrations of TCS enhanced the clearing of the pathogens S. typhimurium or C. albicans in infected MPhi and in corresponding mouse infection models in vivo. Specifically, we found that a sub-inhibitory concentration of TCS induced autophagy, leading to an imbalance of the intestinal microflora in mice through the analysis of 16s rRNA Sequencing. Together, these results demonstrated that TCS induced autophagy, which enhanced the killing against pathogenic S. typhimurium or C. albicans within mammal cells but broke the balance of the intestinal microflora. PMID- 29515979 TI - Thymic teratoma presenting as non-immune hydrops fetalis. AB - Teratomas are one of the most frequent tumors in the pediatric population. They occur anywhere along the midline of the body, following the course of the embryonic germ cell ridge. In the mediastinal location, they exert space occupying effects, leading to a myriad of complications, including non-immune hydrops fetalis. We describe a fatal case of an immature thymic teratoma in a neonate presenting with hydrops fetalis. This case emphasizes the importance of early diagnosis and surgical intervention in such cases. PMID- 29515980 TI - Huge recurrent gastric neuroendocrine tumor: a second-line chemotherapeutic dilemma. AB - Chemotherapy is considered "state of the art" for the treatment of poorly differentiated neuroendocrine neoplasms. Unfortunately, there is no standard effective post-first-line treatment for relapsing high-grade gastroenteropancreatic neuroendocrine neoplasms. We report the case of a patient with a gastric neuroendocrine carcinoma stage IV, with massive gastrointestinal bleeding at diagnosis. After the first line of platin-based chemotherapy a major tumoral response was documented, but the patient relapsed after 4 months. A second line of chemotherapy treatment was given, with the FOLFOX regimen, and the patient has been free of progression for almost 2 years. There is no second-line standard treatment accepted for this type of carcinoma, but 5-fluorouracil combined with oxaliplatin showed interesting antitumor activity. PMID- 29515981 TI - Gastric lethal hemorrhage due to Dieulafoy's disease. AB - Gastric Dieulafoy's lesion (DL) is a potentially fatal entity that causes upper digestive hemorrhage as a consequence of the erosion of an abnormal large-caliber artery in the submucosa of the gastrointestinal tract. We report the case of a 59 year-old female patient admitted to the emergency facility due to melena without any active sign of bleeding during the esophagogastroduodenoscopy. Unexpectedly, she progressed presenting a massive hematemesis followed by an irreversible cardiorespiratory arrest. The aim of this study is to draw attention to DL as a possible cause of massive and fatal digestive hemorrhage, and to describe the anatomical autopsy findings. PMID- 29515982 TI - Stance of pathology residents on declining number of autopsies. PMID- 29515983 TI - Suspicious scars: physical child abuse vs Ehlers-Danlos syndrome. AB - Child abuse is a sensitive topic among many medical practitioners and the diagnosis of this entity requires awareness about conditions which can mimic physical child abuse. Here, the authors present a case of a 13-year-old school non-attendee who was referred due to multiple scars, over areas prone to accidental as well as non-accidental injury, who underwent medicolegal examination due to suspicion of physical child abuse. On further inquiry, it was discovered that she had easy bruising and poor wound healing. A diagnosis of Ehlers-Danlos syndrome was established and physical child abuse was excluded. This case emphasizes the importance of identifying conditions which may confound the diagnosis of physical child abuse. This is of utmost importance in avoiding adverse legal and psycho-social implications on the child, family and society. PMID- 29515984 TI - Gingival complex odontoma: a rare case report with a review of the literature. AB - Odontomas are odontogenic tumors composed of a mixture of dental tissues. They are very common hamartomas of the jaws. However, their peripheral or gingival counterparts are extremely uncommon. The objective of this article is to report a rare case of gingival complex odontoma in an 11-year-old patient, and also to review all published cases of this type of lesion. PMID- 29515985 TI - Traumatic injury to the internal carotid artery by the hyoid bone: a rare cause of ischemic stroke. AB - Central nervous system (CNS) ischemic events, besides being a common and devastating disease, are accompanied by severe disability and other morbidities. The cause of such events is not always that simple to diagnose, and among the young, a broad spectrum of possibilities should be considered. We present the case of a young man who presented two episodes of CNS ischemia with a 1 year gap between them, which occurred in the same situation while he was walking and carrying a heavy backpack. The second event first presented as a transient ischemic attack followed by a stroke the day after. The diagnostic work-up showed an indentation of the greater cornu of the hyoid bone over the internal carotid artery, which injured the media and intimal layers. At the arterial injury site, a micro thrombus was found, which explained the source of the embolic event to the CNS. The patient was operated on, and the procedure included the resection of the posterior horn of the hyoid bone, the resection of the injured segment of the internal carotid artery followed by carotid-carotid bypass with the great saphenous vein. The postoperative period and the recovery were uneventful as was the 5-month follow-up. We call attention to this unusual cause of stroke and present other cases reported in the literature. PMID- 29515986 TI - Aorto-Right Ventricular Tunnel in Transposition of the Great Arteries. AB - Aorto-ventricular tunnel is an extremely rare congenital heart defect, consisting of failure of attachment of an aortic leaflet along the semilunar hinge. In all published reports the leaflet involved was either the right coronary leaflet, most frequently, or the left coronary leaflet, in most of the cases opening toward the left ventricle, with only one-eighth of the reported cases communicating with the right ventricle. Treatment of the aorto-ventricular tunnel has been anecdotally reported by interventional closure with a device and more frequently with surgical approach, either as an isolated malformation or as associated lesions. To the best of our knowledge, the presence of an aorto ventricular tunnel of the non-adjacent aortic leaflet in transposition of the great arteries has never been reported. We have observed an aorto-ventricular tunnel involving the non-adjacent leaflet of the aortic root, which after arterial switch became the pulmonary root. The patient presented 18 years after the arterial switch with progressive dilatation of the right ventricle due to severe degree of pulmonary valve regurgitation, confirmed by echocardiography and cardiac MRI. Indication for surgery was given with the plan for a pulmonary valve implantation. Because of the intra-operative finding of disconnection of the anterior leaflet of the pulmonary valve (former aortic valve) along the semilunar hinge, the surgical plan was modified and the anterior leaflet was attached to the valve annulus, with subsequent plasty in correspondence with the right and left commissurae to reduce the size of the dilated annulus to normal diameter. The post-operative course was uneventful, with extubation after few hours and discharge 4 days after surgery, with echocardiography showing trivial degree of pulmonary valve regurgitation. The patient remains in good conditions 6 months after surgery. PMID- 29515987 TI - Clinical and Pathological Correlation in Pediatric Invasive Pulmonary Aspergillosis. AB - Introduction: Invasive' pulmonary aspergillosis (IPA) has been one of the major causes of mortality in immunocompromised patients. The gold standard method for a diagnosis of IPA is histopathological examination of the lung tissue; however, post-procedural bleeding limits the feasibility of lung biopsy. The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and The National Institute of Allergy and Infectious Disease Mycoses Study Group (EORTC/MSG) defined IPA. The objective of this study was to validate the EORTC/MSG 2008 definition of IPA, compared with histopathology in the pediatric population. Methods: Histopathological examinations of lung tissues of children aged 1 month-18 years with respiratory tract infection at the time of obtaining biopsy were retrieved. Retrospective chart reviews for clinical characteristics were performed. IPA diagnosis was classified according to the EORTC/MSG 2008 definition. Results: During the 10-year period, there were 256 lung tissues, of which 58 specimens were suspected to have pulmonary infection. Fourteen patients (24%) were noted to have IPA. Seven patients (50%) with proven IPA were classified as probable, while the remaining 50% were classified as possible, and none were classified as no IPA, by using EORTC/MSG 2008 definition. Other 44 specimens demonstrated 14 (32%), 14 (32%), and 16 (36%) were classified as probable, possible, and no IPA, respectively. When comparing probable or possible IPA with no IPA, we found that the EORTC/MSG 2008 definition had 100% sensitivity, 36% specificity, 33% positive predictive value, and 100% negative predictive value in diagnosis of IPA. Conclusion: Our study illustrated that the EORTC/MSG 2008 definition provided an excellent sensitivity but low specificity for diagnosing IPA. PMID- 29515988 TI - Educating the Public Health Workforce: A Scoping Review. AB - The aim of this scoping review was to identify and characterize the recent literature pertaining to the education of the public health workforce worldwide. The importance of preparing a public health workforce with sufficient capacity and appropriate capabilities has been recognized by major organizations around the world (1). Champions for public health note that a suitably educated workforce is essential to the delivery of public health services, including emergency response to biological, manmade, and natural disasters, within countries and across the globe. No single repository offers a comprehensive compilation of who is teaching public health, to whom, and for what end. Moreover, no international consensus prevails on what higher education should entail or what pedagogy is optimal for providing the necessary education. Although health agencies, public or private, might project workforce needs, the higher level of education remains the sole responsibility of higher education institutions. The long-term goal of this study is to describe approaches to the education of the public health workforce around the world by identifying the peer reviewed literature, published primarily by academicians involved in educating those who will perform public health functions. This paper reports on the first phase of the study: identifying and categorizing papers published in peer reviewed literature between 2000 and 2015. PMID- 29515989 TI - Variation in Research Designs Used to Test the Effectiveness of Dissemination and Implementation Strategies: A Review. AB - Background: The need for optimal study designs in dissemination and implementation (D&I) research is increasingly recognized. Despite the wide range of study designs available for D&I research, we lack understanding of the types of designs and methodologies that are routinely used in the field. This review assesses the designs and methodologies in recently proposed D&I studies and provides resources to guide design decisions. Methods: We reviewed 404 study protocols published in the journal Implementation Science from 2/2006 to 9/2017. Eligible studies tested the efficacy or effectiveness of D&I strategies (i.e., not effectiveness of the underlying clinical or public health intervention); had a comparison by group and/or time; and used >=1 quantitative measure. Several design elements were extracted: design category (e.g., randomized); design type [e.g., cluster randomized controlled trial (RCT)]; data type (e.g., quantitative); D&I theoretical framework; levels of treatment assignment, intervention, and measurement; and country in which the research was conducted. Each protocol was double-coded, and discrepancies were resolved through discussion. Results: Of the 404 protocols reviewed, 212 (52%) studies tested one or more implementation strategy across 208 manuscripts, therefore meeting inclusion criteria. Of the included studies, 77% utilized randomized designs, primarily cluster RCTs. The use of alternative designs (e.g., stepped wedge) increased over time. Fewer studies were quasi-experimental (17%) or observational (6%). Many study design categories (e.g., controlled pre-post, matched pair cluster design) were represented by only one or two studies. Most articles proposed quantitative and qualitative methods (61%), with the remaining 39% proposing only quantitative. Half of protocols (52%) reported using a theoretical framework to guide the study. The four most frequently reported frameworks were Consolidated Framework for Implementing Research and RE-AIM (n = 16 each), followed by Promoting Action on Research Implementation in Health Services and Theoretical Domains Framework (n = 12 each). Conclusion: While several novel designs for D&I research have been proposed (e.g., stepped wedge, adaptive designs), the majority of the studies in our sample employed RCT designs. Alternative study designs are increasing in use but may be underutilized for a variety of reasons, including preference of funders or lack of awareness of these designs. Promisingly, the prevalent use of quantitative and qualitative methods together reflects methodological innovation in newer D&I research. PMID- 29515990 TI - Self-Harm Thoughts Postpartum as a Marker for Long-Term Morbidity. AB - Introduction: Postpartum depression predisposes to maternal affective and somatic disorders. It is important to identify which women are at an increased risk of subsequent morbidity and would benefit from an intensified follow-up. Self-harm thoughts (SHTs), with or without other depressive symptomatology, might have prognostic value for maternal health beyond the postpartum period. Aim: This study is to investigate the somatic and psychiatric morbidity of postpartum women with SHTs, with or without other depressive symptoms, over a 7-year follow-up period. Materials and methods: The subjects for this study are derived from a population-based Swedish cohort of women who gave birth at Uppsala University Hospital (May 2006-June 2007) and who answered the Edinburgh Postnatal Depression Scale (EPDS) at 5 days, 6 weeks, and 6 months postpartum. Three groups were included: women reporting SHTs (SHT group, n = 107) on item 10 of the EPDS; women reporting depressive symptoms, i.e., EPDS >= 12 at 6 weeks and/or 6 months postpartum, without SHTs (DEP group, n = 94); and randomly selected controls screening negatively for postpartum depression (CTL group, n = 104). The number of diagnostic codes for somatic and psychiatric morbidity according to the International Statistical Classification of Diseases and Related Health Problems system, and the number of medical interventions were retrieved from medical records over 7 years following childbirth and were used as the outcome measures, together with any prescription of antidepressants and sick leave during the follow-up. Results: The SHT group had the highest psychiatric morbidity of all groups and more somatic morbidity than controls. Affective disorders were more common in the SHT and the DEP groups compared with controls, as well as antidepressant prescriptions and sick leave. One-fifth of women with SHTs did not screen positive for depressive symptoms; nevertheless, they had more somatic and psychiatric morbidity than the control group. Conclusion: Women reporting thoughts of self-harm in the postpartum period are at an increased risk of somatic and psychiatric morbidity during a follow-up of 7 years after delivery, and this increased risk may not be fully attributed to depressive symptoms. Results underline the importance of screening for self-harm symptoms postpartum and point to a need for individualized follow-up. PMID- 29515991 TI - Vaccination Perceptions of College Students: With and without Vaccination Waiver. AB - Introduction: The resurgence of vaccine preventable diseases occurs more often among intentionally unvaccinated individuals, placing at direct risk young adults not caught up on vaccinations. The objectives of this study were to characterize the sociodemographic characteristics of young adults with and without vaccination waivers and identify their perceived benefits, barriers, and influencers of vaccination. Methods: Young adults (n = 964) from a Midwestern rural university responded to a survey (fall 2015-spring 2016) designed to identify their perception toward vaccination. Instrument consistency was measured using the Cronbach alpha-scores. The Chi-square test was used to test any sociodemographic differences and Mann-Whitney U-tests results for differences between exempt and non-exempt students. Analysis occurred in spring 2017. Results: A little over one third of young adults with a vaccination waiver were not up to date on their vaccinations, and think that vaccinations can cause autism. The biggest identifiable benefit was effective control against disease. The surveyed young adults ranked the out of pocket cost associated with vaccination as the most important barrier and safe and easy to use vaccines as the most important influencer of vaccination. Conclusion: Young adults who have had a vaccination waiver appear to not be up to date on their vaccinations. Vaccine administration programs, such as university campus clinics, would benefit from addressing perceptions unique to young adults with and without a vaccine waiver. This would subsequently better provide young adults a second shot for getting appropriately caught up on vaccinations. PMID- 29515992 TI - Food Insecurity Is Associated with Low Adherence to the Mediterranean Diet and Adverse Health Conditions in Portuguese Adults. AB - Background: Food insecurity is a limited or uncertain access to the adequate food and is a significant public health problem. We aimed to assess determinants of food insecurity and the corresponding health impact in Portugal, a southern European country that faced a severe economic crisis. Methods: Data were derived from the Epidemiology of Chronic Diseases Cohort Study (EpiDoC), a population based cohort of 10,661 individuals that were representative of the Portuguese adult population and followed since 2011. A cross-sectional analysis of the third wave of evaluation (EpiDoC 3) was performed between 2015 and 2016. Food insecurity was assessed with the household food insecurity psychometric scale. Socioeconomic, demographic, lifestyle, adherence to Mediterranean diet (MD), self reported non-communicable disease, health-related quality of life (HRQoL) (EQ-5D 3L), physical function (HAQ score), and health resource consumption information was also collected. Results: The estimated proportion of food insecurity was 19.3% among a total of 5,653 participants. Food insecure households had low adherence to the MD (OR = 0.44; 95% IC 0.31-0.62). In addition, diabetes (OR = 1.69; 95% IC 1.20-2.40), rheumatic disease (OR = 1.67; 95% IC 1.07-2.60), and depression symptoms (OR = 1.50; 95% IC 1.09-2.06) were independently associated with food insecurity. On average, food insecure households had a lower HRQoL (OR = 0.18; 95% IC 0.11-0.31) and a higher disability (OR = 2.59; 95% IC 2.04-3.29). A significantly higher proportion of food insecure households reported being hospitalized (OR = 1.57; 95% IC 1.18-2.07) and had more public hospital medical appointments (OR = 1.48; 95% IC 1.12-1.94) in the previous 12 months. Conclusion: We found that food insecurity is highly prevalent in Portugal. Food insecurity was associated with low adherence to the MD, non-communicable chronic diseases, lower quality of life, and higher health resource consumption. Therefore, this study provides valuable insight into the relationship between food security and the diet and health of the population during an economic crisis. PMID- 29515994 TI - Catalytic Fast Pyrolysis of Biomass Impregnated with Potassium Phosphate in a Hydrogen Atmosphere for the Production of Phenol and Activated Carbon. AB - A new technique was proposed to co-produce phenol and activated carbon (AC) from catalytic fast pyrolysis of biomass impregnated with K3PO4 in a hydrogen atmosphere, followed by activation of the pyrolytic solid residues. Lab-scale catalytic fast pyrolysis experiments were performed to quantitatively determine the pyrolytic product distribution, as well as to investigate the effects of several factors on the phenol production, including pyrolysis atmosphere, catalyst type, biomass type, catalytic pyrolysis temperature, and catalyst impregnation content. In addition, the pyrolytic solid residues were activated to prepare ACs with high specific surface areas. The results indicated that phenol could be obtained due to the synergistic effects of K3PO4 and hydrogen atmosphere, with the yield and selectivity reaching 5.3 wt% and 17.8% from catalytic fast pyrolysis of poplar wood with 8 wt% K3PO4 at 550 degrees C in a hydrogen atmosphere. This technique was adaptable to different woody materials for phenol production. Moreover, gas product generated from the pyrolysis process was feasible to be recycled to provide the hydrogen atmosphere, instead of extra hydrogen supply. In addition, the pyrolytic solid residue was suitable for AC preparation, using CO2 activation method, the specific surface area was as high as 1,605 m2/g. PMID- 29515993 TI - In Silico Prediction of Chemical Toxicity for Drug Design Using Machine Learning Methods and Structural Alerts. AB - During drug development, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization. The emphasis of this article was put on the recent progress of predictive models built for various toxicities. Available databases and web servers were also provided. Though the methods and models are very helpful for drug design, there are still some challenges and limitations to be improved for drug safety assessment in the future. PMID- 29515995 TI - Measurement and Finite Element Model Validation of Immature Porcine Brain-Skull Displacement during Rapid Sagittal Head Rotations. AB - Computational models are valuable tools for studying tissue-level mechanisms of traumatic brain injury, but to produce more accurate estimates of tissue deformation, these models must be validated against experimental data. In this study, we present in situ measurements of brain-skull displacement in the neonatal piglet head (n = 3) at the sagittal midline during six rapid non-impact rotations (two rotations per specimen) with peak angular velocities averaging 51.7 +/- 1.4 rad/s. Marks on the sagittally cut brain and skull/rigid potting surfaces were tracked, and peak values of relative brain-skull displacement were extracted and found to be significantly less than values extracted from a previous axial plane model. In a finite element model of the sagittally transected neonatal porcine head, the brain-skull boundary condition was matched to the measured physical experiment data. Despite smaller sagittal plane displacements at the brain-skull boundary, the corresponding finite element boundary condition optimized for sagittal plane rotations is far less stiff than its axial counterpart, likely due to the prominent role of the boundary geometry in restricting interface movement. Finally, bridging veins were included in the finite element model. Varying the bridging vein mechanical behavior over a previously reported range had no influence on the brain-skull boundary displacements. This direction-specific sagittal plane boundary condition can be employed in finite element models of rapid sagittal head rotations. PMID- 29515997 TI - Hepatitis B Virus Blood Screening: Need for Reappraisal of Blood Safety Measures? AB - Over the past decades, the risk of HBV transfusion-transmission has been steadily reduced through the recruitment of volunteer donors, the selection of donors based on risk-behavior evaluation, the development of increasingly more sensitive hepatitis B antigen (HBsAg) assays, the use of hepatitis B core antibody (anti HBc) screening in some low-endemic countries, and the recent implementation of HBV nucleic acid testing (NAT). Despite this accumulation of blood safety measures, the desirable zero risk goal has yet to be achieved. The residual risk of HBV transfusion-transmission appears associated with the preseroconversion window period and occult HBV infection characterized by the absence of detectable HBsAg and extremely low levels of HBV DNA. Infected donations tested false negative with serology and/or NAT still persist and derived blood components were shown to transmit the virus, although rarely. Questions regarding the apparent redundancy of some safety measures prompted debates on how to reduce the cost of HBV blood screening. In particular, accumulating data strongly suggests that HBsAg testing may add little, if any HBV risk reduction value when HBV NAT and anti-HBc screening also apply. Absence or minimal acceptable infectious risk needs to be assessed before considering discontinuing HBsAg. Nevertheless, HBsAg remains essential in high-endemic settings where anti-HBc testing cannot be implemented without compromising blood availability. HBV screening strategy should be decided according to local epidemiology, estimate of the infectious risk, and resources. PMID- 29515996 TI - Exosome-Based Cell-Cell Communication in the Tumor Microenvironment. AB - Tumors are not isolated entities, but complex systemic networks involving cell cell communication between transformed and non-transformed cells. The milieu created by tumor-associated cells may either support or halt tumor progression. In addition to cell-cell contact, cells communicate through secreted factors via a highly complex system involving characteristics such as ligand concentration, receptor expression and integration of diverse signaling pathways. Of these, extracellular vesicles, such as exosomes, are emerging as novel cell-cell communication mediators in physiological and pathological scenarios. Exosomes, membrane vesicles of endocytic origin released by all cells (both healthy and diseased), ranging in size from 30 to 150 nm, transport all the main biomolecules, including lipids, proteins, DNAs, messenger RNAs and microRNA, and perform intercellular transfer of components, locally and systemically. By acting not only in tumor cells, but also in tumor-associated cells such as fibroblasts, endothelium, leukocytes and progenitor cells, tumor- and non-tumor cells-derived exosomes have emerged as new players in tumor growth and invasion, tumor associated angiogenesis, tissue inflammation and immunologic remodeling. In addition, due to their property of carrying molecules from their cell of origin to the peripheral circulation, exosomes have been increasingly studied as sources of tumor biomarkers in liquid biopsies. Here we review the current literature on the participation of exosomes in the communication between tumor and tumor associated cells, highlighting the role of this process in the setup of tumor microenvironments that modulate tumor initiation and metastasis. PMID- 29515998 TI - Quantitative Ex Vivo MRI Changes due to Progressive Formalin Fixation in Whole Human Brain Specimens: Longitudinal Characterization of Diffusion, Relaxometry, and Myelin Water Fraction Measurements at 3T. AB - Purpose: Postmortem MRI can be used to reveal important pathologies and establish radiology-pathology correlations. However, quantitative MRI values are altered by tissue fixation. Therefore, the purpose of this study was to investigate time dependent effects of formalin fixation on MRI relaxometry (T1 and T2), diffusion tensor imaging (fractional anisotropy, FA; and mean diffusivity, MD), and myelin water fraction (MWF) measurements throughout intact human brain specimens. Methods: Two whole, neurologically-healthy human brains were immersed in 10% formalin solution and scanned at 13 time points between 0 and 1,032 h. Whole brain maps of longitudinal (T1) and transverse (T2) relaxation times, FA, MD, and MWF were generated at each time point to illustrate spatiotemporal changes, and region-of-interest analyses were then performed in eight brain structures to quantify temporal changes with progressive fixation. Results: Although neither of the diffusion measures (FA nor MD) showed significant changes as a function of formalin fixation time, both T1 and T2-relaxation times significantly decreased, and MWF estimates significantly increased with progressive fixation until (and likely beyond) our final measurements were taken at 1,032 h. Conclusion: These results suggest that T1-relaxation, T2-relaxation and MWF estimates must be performed quite early in the fixation process to avoid formalin-induced changes compared to in vivo values; and furthermore, that different ex vivo scans within an experiment must be acquired at consistent (albeit still early) fixation intervals to avoid fixative-related differences between samples. Conversely, ex vivo diffusion measures (FA and MD) appear to depend more on other factors (e.g., pulse sequence optimization, sample temperature, etc.). PMID- 29516000 TI - Comorbidities in Anti-Cyclic Citrullinated Peptide Positive At-Risk Individuals Do Not Differ from Those Patients with Early Inflammatory Arthritis. AB - Objectives: To compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of inflammatory arthritis (IA) to those in patients with early IA. Methods: Baseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n = 296). The second cohort [the Inflammatory Arthritis CONtinuum study (IACON)] recruited patients with early IA (n = 725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status, and body mass index. Results: Patients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid-lowering agent, ischemic heart disease, cerebrovascular disease, lung disease, and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p = 0.037). Conclusion: There was no significant difference in comorbidities among people with CCP antibodies but without IA, compared to those of patients with established IA. PMID- 29516001 TI - Feasibility of Systematic Respiratory-Gated Acquisition in Unselected Patients Referred for 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Objective: Respiratory motion in 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) induces blurred images, leading to errors in location and quantification for lung and abdominal lesions. Various methods have been developed to correct for these artifacts, and most of current PET/CT scanners are equipped with a respiratory gating system. However, they are not routinely performed because their use is time-consuming. The aim of this study is to assess the feasibility and quantitative impact of a systematic respiratory-gated acquisition in unselected patients referred for FDG PET/CT, without increasing acquisition time. Methods: Patients referred for a FDG PET/CT examination to the nuclear medicine department of Brest University Hospital were consecutively enrolled, during a 3-month period. Cases presenting lung or liver uptakes were analyzed. Two sets of images were reconstructed from data recorded during a unique acquisition with a continuous table speed of 1 mm/s of the used Biograph mCT Flow PET/CT scanner: standard free-breathing images, and respiratory gated images. Lesion location and quantitative parameters were recorded and compared. Results: From October 1 2015 to December 31 2015, 847 patients were referred for FDG PET/CT, 741 underwent a respiratory-gated acquisition. Out of them, 213 (29%) had one or more lung or liver uptake but 82 (38%) had no usable respiratory-gated signal. Accordingly, 131 (62%) patients with 183 lung or liver uptakes were analyzed. Considering the 183 lesions, 140 and 43 were located in the lungs and the liver, respectively. The median (IQR) difference between respiratory-gated images and non-gated images was 18% (4-32) for SUVmax, increasing to 30% (14-57) in lower lobes for lung lesions, and -18% (-40 to -4) for MTV (p < 0.05). Technologists' active personal dosimetry and mean total examinations duration were not statistically different between periods with and without respiratory gating. Conclusion: This study showed that a systematic respiratory-gated acquisition without increasing acquisition time is feasible in a daily routine and results in a significant impact on PET quantification. However, clinical impact on patient management remains to be determined. PMID- 29516002 TI - Treatment Outcomes of Tuberculosis at Asella Teaching Hospital, Ethiopia: Ten Years' Retrospective Aggregated Data. AB - Background: Directly Observed Treatment Short-course (DOTS) has been one of the major strategies to combat the epidemic of tuberculosis (TB) globally. This study aimed to evaluate TB treatment outcomes between September 2004 and July 2014 under the DOTS program at one of the largest public hospitals in Ethiopia. Methods: A retrospective data of TB patients registered at Asella Teaching Hospital between September 2004 and July 2014 were obtained from hospital registry. Treatment outcomes and types of TB cases were categorized according to the national TB control program guideline. Binomial and multinomial logistic regression models were used to analyze the association between treatment outcomes and potential predictor variables. Results: A total of 1,755 TB patients' records were included in the study. Of these, 945 (53.8%) were male, 480 (27.4%) smear positive TB, 287 (16.4%) HIV positive, and 1,549 (88.3%) new cases. Among 480 smear-positive pulmonary TB cases, 377 (78.5%) patients were cured, 21 (4.40) completed the treatment, 35 (7.3%) transferred out, 19 (4.0%) died, 24 (5.0%) defaulted, and 4 (0.8%) failure. Overall, 398 (82.9%) smear-positive pulmonary TB patients were successfully treated. For smear-negative TB (n = 641) and extrapulmonary TB cases (n = 634), 1,036 (81.3%) completed the treatment and demonstrated favorable response. Taking all TB types into account, 1,434 (81.7%) were considered as successfully treated. In the multivariate binary logistic model, patients in older age group (AOR = 0.386, 95% CI: 0.250-0.596) and retreatment cases (AOR = 0.422, 95% CI: 0.226-0.790) were less likely to be successfully treated compared to younger and new cases, respectively. In multinomial logistic regression, age increment by 1 year increased the risk of death and default of TB patients by 0.05 (adjusted beta = 0.05; 95% CI: 0.03, 0.06) and 0.02 (adjusted beta = 0.02; 95% CI: 0.01, 0.04). The odds of TB patients who died during treatment were higher among HIV-infected TB patients (adjusted beta = 2.65; 95% CI: 1.28, 5.50). Conclusion: The treatment success rate of TB patients was low as compared to the national target. TB control needs to be strengthened for the enhancement of treatment outcome. PMID- 29516003 TI - The Effects of Diet on the Proportion of Intramuscular Fat in Human Muscle: A Systematic Review and Meta-analysis. AB - Background: There is an increasing trend in the consumption of poor-quality diets worldwide, contributing to the increase of non-communicable diseases. Diet directly influences physiological composition and subsequently physical health. Studies have shown that dietary macronutrient and energy content can influence the proportion of intramuscular fat (IMF), which mediates various metabolic and endocrine dysfunction. The purpose of this systematic review was to identify evidence in the literature assessing the association between different dietary interventions on the proportion of IMF in humans. Methods: Three medical databases were investigated (Medline, EMBASE, and Cochrane) to identify studies assessing changes in IMF after dietary interventions. The primary outcome measure was the change in IMF proportions after a dietary intervention. The effects of high-fat, high-carbohydrate, low-calorie, and starvation diets were assessed qualitatively. A meta-analysis assessing the effect of high-fat diets was conducted. Follow-up sensitivity and subgroup analyses were also conducted. Results: One thousand eight hundred and sixty-six articles were identified for review. Of these articles, 13 were eligible for inclusion after a full screening. High-fat diets increased IMF proportions, standardized mean difference = 1.24 (95% confidence interval, 0.43-2.05) and a significant overall effect size (P = 0.003). Diets with an increased proportion of carbohydrates decreased IMF proportions; however, increasing caloric intake with carbohydrates increased IMF. Starvation diets increased IMF stores, and hypocaloric diets did not result in any IMF proportion changes. Conclusion: This systematic review suggests that high fat diets and diets with caloric intake increased above the amount required to maintain BMI with carbohydrates, and short-term starvation diets are associated with increases in IMF content. Further studies are needed to assess the effects of macronutrient combinations on IMF and the influence of diet-induced IMF alterations on health outcomes. In addition, IMF poses a possibly effective clinical marker of health. PMID- 29516004 TI - Reference Values for Physical Stress Echocardiography in Asymptomatic Patients after Mitral Valve Repair. AB - Background: Clinical decision-making in symptomatic patients after mitral valve (MV) repair remains challenging as echocardiographic reference values are lacking. In native MV disease intervention is recommended for mean transmitral pressure gradient (TPG) >15 mmHg or systolic pulmonary artery pressure (SPAP) >60 mmHg at peak exercise. Insight into standard stress echo parameters after MV repair may therefore aid to clinical decision-making during follow-up. Hypothesis: Stress echocardiography derived parameters in asymptomatic patients after successful MV repair differ from current guidelines for native valves. Material and methods: In 25 patients (NYHA I) after MV repair stress echocardiography was performed on a semi-supine bicycle. Doppler flow records and MV related hemodynamics at rest and peak were obtained. Linear regression analysis was performed for mean TPG and SPAP at peak, using predetermined variables and confounders. Results: Mean TPG at rest (3.2 +/- 1.4 mmHg) significantly increased at peak (15.0 +/- 3.4 mmHg) but was always <25 mmHg. Mean SPAP at rest (21.4 +/- 3.8 mmHg) significantly increased at peak (41.8 +/- 8.9 mmHg) but was never >57 mmHg. Only the indexed MV ring diameter was inversely correlated to mean TPG at peak in a multivariable model. Conclusion: In contrast to current recommendations in native MV disease, our data indicate that the standard value for mean TPG during stress echocardiography in asymptomatic patients after successful MV repair was above the guideline threshold of 15 mmHg in >50%, but always <25 mmHg. For SPAP, patients never reached the guideline cutoff (60 mmHg). Long-term follow-up data are needed to provide insight in clinical consequences. Baseline stress echocardiography may indicate individual reference values to compare with during follow-up. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT02371863?term=chamuleau+AND+Mitral&rank=1. PMID- 29515999 TI - Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease. AB - Activation of the innate immune system through pattern-recognition receptor (PRR) signaling plays a pivotal role in the early induction of host defense following exposure to pathogens. Loss of intestinal innate immune regulation leading aberrant immune responses has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The precise role of PRRs in gut inflammation is not well understood, but considering their role as bacterial sensors and their genetic association with IBD, they likely contribute to dysregulated immune responses to the commensal microbiota. The purpose of this review is to evaluate the emerging functions of PRRs including their functional cross-talk, how they respond to mitochondrial damage, induce mitophagy or autophagy, and influence adaptive immune responses by interacting with the antigen presentation machinery. The review also summarizes some of the recent attempts to harness these pathways for therapeutic approaches in intestinal inflammation. PMID- 29516006 TI - Myositis, Ganglioneuritis, and Myocarditis with Distinct Perifascicular Muscle Atrophy in a 2-Year-Old Male Boxer. AB - A 2-year-old male, intact Boxer was referred for chronic diarrhea, hyporexia, labored breathing, weakness and elevated creatine kinase, and alanine aminotransferase activities. Initial examination and diagnostics revealed a peripheral nervous system neurolocalization, atrial premature complexes, and generalized megaesophagus. Progressive worsening of the dog's condition was noted after 36 h; the dog developed aspiration pneumonia, was febrile and oxygen dependent. The owners elected humane euthanasia. Immediately postmortem biopsies of the left cranial tibial and triceps muscles and the left peroneal nerve were obtained. Postmortem histology revealed concurrent myositis, myocarditis, endocarditis, and ganglioneuritis. Mixed mononuclear cell infiltrations and a distinct perifascicular pattern of muscle fiber atrophy was present in both muscles. This is a novel case of diffuse inflammatory myopathy with a distinct perifascicular pattern of atrophy in addition to endocarditis, myocarditis, and epicarditis. PMID- 29516005 TI - Contemporary Strategies in the Management of Civilian Abdominal Vascular Trauma. AB - The evaluation and management of patients with abdominal vascular trauma or injury requires immediate and effective decision-making in these unfavorable circumstances. The majority of these patients arrive at trauma centers in profound shock, secondary to massive blood loss, which is often unrelenting. Moreover, ischemia, compartment syndrome, thrombosis, and embolization may also be life threatening and require immediate intervention. To minimize the risk of these potentially lethal complications, early understanding of the disease process and emergent therapeutic intervention are necessary. In the literature, the management of acute traumatic vascular injuries is restricted to traditional open surgical techniques. However, in penetrating injuries surgeons often face a potentially contaminated field, which renders the placement of prosthetic grafts inappropriate. Currently, however, there are sparse data on the management of vascular trauma with endovascular techniques. The role of endovascular technique in penetrating abdominal vascular trauma, which is almost always associated with severe active bleeding, is limited. It is worth mentioning that hybrid operating rooms with angiographic radiology capabilities offer more opportunities for the management of this kind of injuries by either temporary control of the devastating bleeding using endovascular balloon tamponade or with embolization and stenting. On the other hand, blunt abdominal injuries are less dangerous and they could be treated at most times by endovascular means. Since surgeons continue to encounter abdominal vascular trauma, open and endovascular techniques will evolve constantly giving us encouraging messages for the near future. PMID- 29516007 TI - Manipulation of Plant Growth Regulators on Phytochemical Constituents and DNA Protection Potential of the Medicinal Plant Arnebia benthamii. AB - Arnebia benthamii of the family Boraginaceae is a critically endangered nonendemic plant of the Kashmir Himalayas and is used to treat a number of human diseases. The current study was based on developing an in vitro micropropagation protocol vis-a-vis induction of various secondary metabolites under in vitro conditions for the possible biological activity. A tissue culture protocol was developed for A. benthamii for the first time in the Himalayan region using varied combinations and proper media formulations, including various adjuvants: Murashige and Skoog (MS) media, growth hormones, sugars, agar, and so forth. The influence of different media combinations was estimated, and the MS + thidiazuron (TDZ) + indole 3-acetic acid (IAA) combination favors a higher regeneration potential. The higher amounts of chemical constituents were also recorded on the same treatment. The in vitro plant samples also showed a noteworthy effect of scavenging of hydroxyl radicals vis-a-vis protection from oxidative DNA damage. The in vitro raised plants are good candidates for the development of antioxidant molecules. PMID- 29516008 TI - From 4D Medical Images (CT, MRI, and Ultrasound) to 4D Structured Mesh Models of the Left Ventricular Endocardium for Patient-Specific Simulations. AB - With cardiovascular disease (CVD) remaining the primary cause of death worldwide, early detection of CVDs becomes essential. The intracardiac flow is an important component of ventricular function, motion kinetics, wash-out of ventricular chambers, and ventricular energetics. Coupling between Computational Fluid Dynamics (CFD) simulations and medical images can play a fundamental role in terms of patient-specific diagnostic tools. From a technical perspective, CFD simulations with moving boundaries could easily lead to negative volumes errors and the sudden failure of the simulation. The generation of high-quality 4D meshes (3D in space + time) with 1-to-1 vertex becomes essential to perform a CFD simulation with moving boundaries. In this context, we developed a semiautomatic morphing tool able to create 4D high-quality structured meshes starting from a segmented 4D dataset. To prove the versatility and efficiency, the method was tested on three different 4D datasets (Ultrasound, MRI, and CT) by evaluating the quality and accuracy of the resulting 4D meshes. Furthermore, an estimation of some physiological quantities is accomplished for the 4D CT reconstruction. Future research will aim at extending the region of interest, further automation of the meshing algorithm, and generating structured hexahedral mesh models both for the blood and myocardial volume. PMID- 29516009 TI - Melatonin Modulation of Sirtuin-1 Attenuates Liver Injury in a Hypercholesterolemic Mouse Model. AB - Hypercholesterolemia increases and exacerbates stress signals leading also to liver damage (LD) and failure. Sirtuin1 (SIRT1) is involved in lifespan extension and it plays an essential role in hepatic lipid metabolism. However, its involvement in liver hypercholesterolemic damage is not yet completely defined. This in vivo study evaluated the role of SIRT1 in the hypercholesterolemic related LD and, then, investigated how oral supplementation of melatonin, pleiotropic indoleamine, may be protective. Control mice and apolipoprotein E deficient mice (ApoE-/-) of 6 and 15 weeks of age were treated or not treated with melatonin at the dose of 10 mg/kg/day for 9 weeks. In this study, we evaluated serum biochemical markers, liver SIRT1 expression, and oxidative stress markers. We observed that hypercholesterolemia increased significantly serum cholesterol and triglycerides, reduced significantly liver SIRT1, and, in turn, induced hepatic oxidative stress in untreated ApoE-/- mice with respect to control mice. Interestingly, melatonin treatment improved serum biochemical markers and hepatic morphological impairment and inhibited oxidative stress through its antioxidant properties and also by SIRT1 upregulation. In summary, melatonin oral supplementation may represent a new protective approach to block hypercholesterolemic liver alterations involving also a SIRT1-dependent mechanism. PMID- 29516011 TI - Meta-Analysis of miRNAs and Their Involvement as Biomarkers in Oral Cancers. AB - Oral Squamous Cell Carcinoma (OSCC) is one of the most common cancers worldwide. Recent studies have highlighted the role of miRNA in disease pathology, indicating its potential use as an early diagnostic marker. Dysregulated expression of miRNAs is known to affect cell growth, and these may function as tumor suppressors or oncogenes in various cancers. The main objective of this study was to characterize the extracellular miRNAs involved in oral cancer (OC) that can potentially be used as biomarkers of OC. A total of 318 miRNAs involved in oral carcinoma were shortlisted. Differentially expressed genes (DEGs) of oral carcinoma from reported experiments were identified. Common genes between lists of DEGs of OC of each miRNA were identified. These common genes are the targets of specific miRNA, which may be used as biomarkers of OC. A list of significant biomarkers for cancer was generated like CDH2 and CDK7, and functional enrichment analysis identified the role of miRNAs in major pathways like cell adhesion molecules pathway affected by cancer. We observed that at least 25 genes like ABCF3, ALDH2, CD163L1, and so forth are regulated by a maximum number of miRNAs; thereby, they can be used as biomarkers of OC. PMID- 29516010 TI - Systematic Analysis of RNA Regulatory Network in Rat Brain after Ischemic Stroke. AB - Although extensive studies have identified large number of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in ischemic stroke, the RNA regulation network response to focal ischemia remains poorly understood. In this study, we simultaneously interrogate the expression profiles of lncRNAs, miRNAs, and mRNAs changes during focal ischemia induced by transient middle cerebral artery occlusion. A set of 1924 novel lncRNAs were identified and may involve brain injury and DNA repair as revealed by coexpression network analysis. Furthermore, many short interspersed elements (SINE) mediated lncRNA:mRNA duplexes were identified, implying that lncRNAs mediate Staufen1-mediated mRNA decay (SMD) which may play a role during focal ischemia. Moreover, based on the competitive endogenous RNA (ceRNA) hypothesis, a stroke regulatory ceRNA network which reveals functional lncRNA:miRNA:mRNA interactions was revealed in ischemic stroke. In brief, this work reports a large number of novel lncRNAs responding to focal ischemia and constructs a systematic RNA regulation network which highlighted the role of ncRNAs in ischemic stroke. PMID- 29516012 TI - Circulating Serum Level of Visfatin in Patients with Endometrial Cancer. AB - Obesity is a well-known factor that leads to many diseases including endometrial cancer. The adipose tissue is a heterogeneous organ of internal secretion. Visfatin is a newly discovered protein produced by fat tissues. The purpose of this work was to evaluate serum level concentrations of visfatin in patients with endometrial cancer based on clinical progression and histopathological tumor differentiation. The diagnostic capabilities of visfatin protein in high differentiation (FIGO III and IV) from a lower (FIGO I and II) clinical stage and prognostic degree of cell differentiation (G1 versus G2, G2 versus G3) on the basis of the analysis of the area under the ROC curve are as follows: 0.87, 0.81, and 0.86. Significantly higher concentrations of visfatin have been observed in patients with invasion of the blood vessels (p = 0.02) and lymph node metastases (p = 0.01) in reference to the depth of infiltration of the endometrium (p = 0.004), as well as the size of the tumor (p = 0.003). Visfatin serum concentrations did not differ due to the invasion of the lymphatic vessels only. Visfatin seems to be a good marker of endometrial cancer progress. High visfatin serum level predicts poor prognosis in endometrial cancer patients. PMID- 29516013 TI - Update of ALDH as a Potential Biomarker and Therapeutic Target for AML. AB - Studies employing mouse transplantation have illustrated the role of aldehyde dehydrogenase (ALDH) defining hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs). Besides being a molecular marker, ALDH mediates drug resistance in AML, which induces poor prognosis of the patients. In AML patients, either CD34+ALDHbr population or CD34+CD38-ALDHint population was found to denote LSCs and minimal residual disease (MRD). A bunch of reagents targeting ALDH directly or indirectly have been evaluated. ATRA, disulfiram, and dimethyl ampal thiolester (DIMATE) are all shown to be potential candidates to open new perspective for AML treatment. However, inconsistent results have been shown for markers of LSCs, which makes it even more difficult to differentiate LSCs and HSCs. In this review, we elevated the role of ALDH to be a potential marker to define and distinguish HSCs and LSCs and its importance in prognosis and target therapy in AML patients. In addition to immunophenotypical markers, ALDH is also functionally active in defining and distinguishing HSCs and LSCs and offers intracellular protections against cytotoxic drugs. Targeting ALDH may be a potential strategy to improve AML treatment. Additional studies concerning specific targeting ALDH and mechanisms of its roles in LSCs are warranted. PMID- 29516016 TI - Portal Cavernoma Mimicking Pancreatic Malignancy. AB - Portal cavernoma colangiopathy (PCC) is an uncommon cause of portal hypertension, and it is an important differential diagnosis of pancreatic malignancy given the expanded network of collateral vessels. On imaging studies, portal cavernoma can be seen as a hypoechoic mass, possibly associated with distal common bile duct obstruction. Most cases occur in non-cirrhotic patients. During the symptomatic phase, these patients carry a high-risk of complications related to sustained biliary obstruction. We report a unique patient with obstructive jaundice and a presumed pancreatic mass that proved to be a portal cavernoma complicated by PCC in the setting of nodular regenerative hyperplasia of the liver. PMID- 29516015 TI - Improvement of Endovascular Stroke Treatment: A 24-Hour Neuroradiological On-Site Service Is Not Enough. AB - Background and Purpose: With the advent of endovascular stroke treatment (EST) with mechanical thrombectomy, stroke treatment has also become more challenging. Purpose of this study was to investigate whether a fulltime neuroradiological on site service and workflow optimization with a structured documentation of the interdisciplinary stroke workflow resulted in improved procedural times. Material and Methods: Procedural times of 322 consecutive patients, who received EST (1) before (n = 96) and (2) after (n = 126) establishing a 24-hour neuroradiological on-site service as well as (3) after implementation of a structured interdisciplinary workflow documentation ("Stroke Check") (n = 100), were analysed. Results: A fulltime neuroradiological on-site service resulted in a nonsignificant improvement of procedural times during out-of-hours admissions (p >= 0.204). Working hours and out-of-hours procedural times improved significantly, if additional workflow optimization was realized (p <= 0.026). Conclusions: A 24-hour interventional on-site service is a major prerequisite to adequately provide modern reperfusion therapies in patients with acute ischemic stroke. However, simple measures like standardized and focused documentation that affect the entire interdisciplinary pre- and intrahospital stroke rescue chain seem to be important. PMID- 29516014 TI - Eryptosis: An Erythrocyte's Suicidal Type of Cell Death. AB - Erythrocytes play an important role in oxygen and carbon dioxide transport. Although erythrocytes possess no nucleus or mitochondria, they fulfil several metabolic activities namely, the Embden-Meyerhof pathway, as well as the hexose monophosphate shunt. Metabolic processes within the erythrocyte contribute to the morphology/shape of the cell and important constituents are being kept in an active, reduced form. Erythrocytes undergo a form of suicidal cell death called eryptosis. Eryptosis results from a wide variety of contributors including hyperosmolarity, oxidative stress, and exposure to xenobiotics. Eryptosis occurs before the erythrocyte has had a chance to be naturally removed from the circulation after its 120-day lifespan and is characterised by the presence of membrane blebbing, cell shrinkage, and phosphatidylserine exposure that correspond to nucleated cell apoptotic characteristics. After eryptosis is triggered there is an increase in cytosolic calcium (Ca2+) ion levels. This increase causes activation of Ca2+-sensitive potassium (K+) channels which leads to a decrease in intracellular potassium chloride (KCl) and shrinkage of the erythrocyte. Ceramide, produced by sphingomyelinase from the cell membrane's sphingomyelin, contributes to the occurrence of eryptosis. Eryptosis ensures healthy erythrocyte quantity in circulation whereas excessive eryptosis may set an environment for the clinical presence of pathophysiological conditions including anaemia. PMID- 29516017 TI - Ischemic Renal Injury Complicating Intragastric Balloon Insertion. AB - A 25-year-old obese woman experienced ischemic renal injury as a complication of intragastric balloon (IGB) insertion for weight reduction. Although IGB is associated with a low risk of renal injury in the form of acute renal failure, this presentation has never been reported. The patient responded well to treatment, with complete clinical and radiologic resolution after balloon removal. She did not have an apparent cause of renal ischemia other than a significant compression of the renal vessels by the balloon as seen on imaging. PMID- 29516018 TI - Emerging Role of Vedolizumab in Managing Refractory Immune Checkpoint Inhibitor Induced Enteritis. AB - We report a 62-year-old white woman with metastatic choroidal melanoma who developed immune checkpoint inhibitor (ICI)-induced enteritis and grade 3 diarrhea refractory to steroids and infliximab. Her diarrhea quickly resolved after infusion of vedolizumab, and the patient was able to taper down steroids. Vedolizumab's mechanism of action and its gut specificity have the potential to reverse immune-induced enterocolitis without neutralizing or reversing the therapeutic benefit of ICI on the malignancy. PMID- 29516019 TI - Fishbone Migration in the Intrahepatic Bile Duct after Pancreaticoduodenectomy. PMID- 29516020 TI - Small Bowel Obstruction Due to Migration of a Transrectally Inserted Foreign Body. PMID- 29516021 TI - Hypertension Among Persons Living With HIV in Medical Care in the United States Medical Monitoring Project, 2013-2014. AB - Hypertension is a leading modifiable risk factor for cardiovascular disease (CVD), and persons living with HIV are at increased risk for both hypertension and CVD. Therefore, using data from a nationally representative sample of patients living with HIV, we assessed missed opportunities for the optimal management of hypertension. PMID- 29516022 TI - Time Course of C-Reactive Protein and Procalcitonin Levels During the Treatment of Acute Bacterial Skin Infections. AB - In a pilot study of 22 patients with an acute bacterial skin infection, serum levels of C-reactive protein and procalcitonin tended to be elevated at presentation and declined within 3-5 days of treatment. Further study of a biomarker-guided treatment strategy to reduce antibiotic overuse in skin infections is warranted. PMID- 29516023 TI - Palivizumab Prophylaxis for Respiratory Syncytial Virus: Examining the Evidence Around Value. AB - Respiratory syncytial virus (RSV) infection is the most common cause of lower respiratory tract infection and the leading cause of hospitalization among young children, incurring high annual costs among US children under the age of 5 years. Palivizumab has been found to be effective in reducing hospitalization and preventing serious lower respiratory tract infections in high-risk infants. This paper presents a systematic review of the cost-effectiveness studies of palivizumab and describes the main highlights of a round table discussion with clinical, payer, economic, research method, and other experts. The objectives of the discussion were to (1) review the current state of clinical, epidemiology, and economic data related to severe RSV disease; (2) review new cost effectiveness estimates of RSV immunoprophylaxis in US preterm infants, including a review of the field's areas of agreement and disagreement; and (3) identify needs for further research. PMID- 29516024 TI - Immunomonitoring of MSC-Treated GvHD Patients Reveals Only Moderate Potential for Response Prediction but Indicates Treatment Safety. AB - Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients. CD4+ T helper (Th) cell levels remained particularly low throughout the follow-up period. The relative proportion of Th1 cells decreased, while regulatory T cells remained unaltered, and only very few Th2 and Th17 cells could be detected. Serum concentrations of regenerating islet-derived protein 3-alpha, cytokeratin-18 fragments (CK18F), and elafin were significantly elevated in patient samples compared with healthy controls, but only CK18F showed any potential in the prediction of patients' response to MSCs. No obvious markers for MSC therapy response were revealed in this study, but the results suggest that allogeneic MSCs do not provoke overt T cell-mediated immune responses at least in immunosuppressed aGvHD patients. The results advocate for the safety of MSC therapy and bring new insights in MSC immunomodulation mechanisms. PMID- 29516025 TI - In vivo Imaging of Tumor and Immune Cell Interactions in the Lung. AB - Immunotherapy has demonstrated great therapeutic potential by activating the immune system to fight cancer. However, little is known about the specific dynamics of interactions that occur between tumor and immune cells. In this protocol we describe a novel method to visualize the interaction of tumor and immune cells in the lung of live mice, which can be applied to other organs. In this protocol fluorescent-labeled tumor cells are transferred to recipient mice expressing fluorescently tagged immune cells. Tumor-immune cell interactions in the lung are then imaged by confocal or two photon microscopy. Analysis of tumor interactions with immune cells using this protocol should aid in a better understanding of the importance of these interactions and their role in developing immunotherapies. PMID- 29516026 TI - FACS-based Isolation of Neural and Glioma Stem Cell Populations from Fresh Human Tissues Utilizing EGF Ligand. AB - Direct isolation of human neural and glioma stem cells from fresh tissues permits their biological study without prior culture and may capture novel aspects of their molecular phenotype in their native state. Recently, we demonstrated the ability to prospectively isolate stem cell populations from fresh human germinal matrix and glioblastoma samples, exploiting the ability of cells to bind the Epidermal Growth Factor (EGF) ligand in fluorescence-activated cell sorting (FACS). We demonstrated that FACS-isolated EGF-bound neural and glioblastoma populations encompass the sphere-forming colonies in vitro, and are capable of both self-renewal and multilineage differentiation. Here we describe in detail the purification methodology of EGF-bound (i.e., EGFR+) human neural and glioma cells with stem cell properties from fresh postmortem and surgical tissues. The ability to prospectively isolate stem cell populations using native ligand binding ability opens new doors for understanding both normal and tumor cell biology in uncultured conditions, and is applicable for various downstream molecular sequencing studies at both population and single-cell resolution. PMID- 29516027 TI - Measuring Nucleosome Assembly Activity in vitro with the Nucleosome Assembly and Quantification (NAQ) Assay. AB - Nucleosomes organize the eukaryotic genome into chromatin. In cells, nucleosome assembly relies on the activity of histone chaperones, proteins with high binding affinity to histones. At least a subset of histone chaperones promotes histone deposition in vivo. However, it has been challenging to characterize this activity, due to the lack of quantitative assays. Here we developed a quantitative nucleosome assembly (NAQ) assay to measure the amount of nucleosome formation in vitro. This assay relies on a Micrococcal nuclease (MNase) digestion step that yields DNA fragments protected by the deposited histone proteins. A subsequent run on the Bioanalyzer machine allows the accurate quantification of the fragments (length and amount), relative to a loading control. This allows us to measure nucleosome formation by following the signature DNA length of ~150 bp. This assay finally enables the characterization of the nucleosome assembly activity of different histone chaperones, a step forward in the understanding of the functional roles of these proteins in vivo. PMID- 29516028 TI - Comparison of Measures of E-cigarette Advertising Exposure and Receptivity. AB - Objectives: We tested how various measures of e-cigarette advertising exposure and receptivity are related to each other and compare to each other in their associations with e-cigarette use susceptibility and behavior. Methods: Cross sectional data were collected from young adult college students (N = 470; Mage = 20.9, SD = 2.1; 65% women). Measures of e-cigarette advertising exposure/receptivity compared included a cued recall measure, measures of marketing receptivity, perceived ad exposure, liking of e-cigarette ads, and frequency of convenience store visit, which is considered a measure of point-of sale ad exposure. Results: The cued-recall measure was associated with e cigarette use experimentation but not current e-cigarette use. Marketing receptivity was associated with current e-cigarette use but not e-cigarette use experimentation. Liking of e-cigarette ads was the only measure associated with e cigarette use susceptibility. Frequency of convenience store visit was associated with current e-cigarette use but not e-cigarette use experimentation or susceptibility. Conclusion: Inclusion of multiple measures of marketing exposure and receptivity is recommended for regulatory research concerning e-cigarette marketing. Marketing receptivity and cued recall measures are strong correlates of current and ever e-cigarette use, respectively. PMID- 29516030 TI - Data on novel C fibers@MoSe2 nanoplates core-shell composite for highly efficient solar-driven photocatalytically degrading environmental pollutants. AB - The data presented in this article are related to a research article entitled 'Highly efficient solar-driven photocatalytic degradation on environmental pollutants over a novel C fibers@MoSe2 nanoplates core-shell composite' (Wang et al., 2018) [1]. In this article, we report original data on the synthesis processes optimization of the proposed composite together with its formation mechanism. The report includes the composition, microstructure and morphology of the corresponding samples, and the photocatalytic activity and stability of the optimal composite. Compared with commercially available MoSe2 powder, the reaction rate constant of the optimal composite catalyst for the degradation of methylene blue (MB) and rhodamine B (RhB) under simulated sunlight irradiation (SSI) could be increased in a factor of about 14 and 8, respectively. The data are presented in this format to allow the comparison with those from other researchers in this field, and understanding the synthesis and photocatalysis mechanism of similar catalysts. PMID- 29516029 TI - Use Behaviors, Dependence, and Nicotine Exposure Associated with Ad Libitum Cigar Smoking. AB - Objectives: To examine factors important to cigar smoking and subsequent nicotine exposure, we evaluated the impact of cigar type, cigarette smoking history, and inhalation behaviors on nicotine dependence, smoking topography, and biomarkers of exposure in current exclusive cigar smokers. Methods: Adult, exclusive cigar smokers (N = 77) were recruited based on cigar type, cigarette smoking history, and self-reported inhalation behaviors. Participants smoked their own brand product ad libitum for up to one hour; dependence symptoms, smoking topography, and biomarkers of exposure were assessed. Results: Cigar smokers showed low levels of dependence. Cigar smoking alleviated withdrawal and craving symptoms, increased plasma nicotine concentration, and increased exhaled CO. Multiple regression analyses indicate that inhalation behaviors were associated with increased dependence and greater reductions in withdrawal symptoms upon cigar smoking. Large cigar smokers smoked longer and smoked more tobacco than small cigar and cigarillo smokers. Furthermore, large cigar smokers and self-reported inhalers were exposed to more nicotine than small cigar smokers and non-inhalers. Conclusions: Our study suggests that cigar type and smoking behaviors affect dependence and nicotine exposure upon cigar smoking. These findings provide additional insight into the substantial risks associated with cigar smoking. PMID- 29516031 TI - Survey datasets on women participation in green jobs in the construction industry. AB - The unique qualities of women can make them bearers of solutions towards achieving sustainability and dealing with the dangers attributed to climate change. The attitudinal study utilized a questionnaire instrument to obtain perception of female construction professionals. By using a well-structured questionnaire, data was obtained on women participating in green jobs in the construction Industry. Descriptive statistics is performed on the collected data and presented in tables and mean scores (MS). In addition, inferential statistics of categorical regression was performed on the data to determine the level of influence (beta factor) the identified barriers had on the level of participation in green jobs. Barriers and the socio-economic benefits which can guide policies and actions on attracting, retaining and exploring the capabilities of women in green jobs can be obtained from the survey data when analyzed. PMID- 29516032 TI - Data on a new beta titanium alloy system reinforced with superlattice intermetallic precipitates. AB - The data presented in this article are related to the research article entitled "a new beta titanium alloy system reinforced with superlattice intermetallic precipitates" (Knowles et al., 2018) [1]. This includes data from the as-cast alloy obtained using scanning electron microscopy (SEM) and x-ray diffraction (XRD) as well as SEM data in the solution heat treated condition. Transmission electron microscopy (TEM) selected area diffraction patterns (SADPs) are included from the alloy in the solution heat treated condition, as well as the aged condition that contained < 100 nm B2 TiFe precipitates [1], the latter of which was found to exhibit double diffraction owing to the precipitate and matrix channels being of a similar width to the foil thickness (Williams and Carter, 2009) [2]. Further details are provided on the macroscopic compression testing of small scale cylinders. Of the micropillar deformation experiment performed in [1], SEM micrographs of focused ion beam (FIB) prepared 2 um micropillars are presented alongside those obtained at the end of the in-situ SEM deformation as well as videos of the in-situ deformation. Further, a table is included that lists the Schmidt factors of all the possible slip systems given the crystal orientations and loading axis of the deformed micropillars in the solution heat treated and aged conditions. PMID- 29516033 TI - Antioxidant activities of traditional plants in Sri Lanka by DPPH free radical scavenging assay. AB - This article describes free radical-scavenging activities of extracts of several plants harvested in Sri Lanka through the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. These plants have traditionally been used in the indigenous systems of medicine in Sri Lanka, such as Ayurveda, as described below. (English name, "local name in Sri Lanka," (scientific name)). bougainvillea plant, "bouganvilla," (Bougainvillea grabla), purple fruited pea eggplant,"welthibbatu," (Solanum trilobatum) [1], country borage plant, "kapparawalliya," (Plectranthus amboinicus) [2], malabar nut plant, "adhatoda," (Justicia adhatoda) [3], long pepper plant,"thippili," (Piper longum) [4], holy basil plant, "maduruthala," (Ocimum tenuiflorum) [5], air plant, "akkapana," (Kalanchoe pinnata) [6], plumed cockscomb plant, "kiri-henda," (Celosia argentea) [7], neem plant,"kohomba," (Azadirachta indica) [8], balipoovu plant, "polpala," (Aerva lanata) [9], balloon vine plant, "wel penera," (Cardiospermum halicacabum) [10], emblic myrobalan plant, "nelli," (Phyllanthus emblica) [11], indian copperleaf plant, "kuppameniya," (Acalypha indica) [12], spreading hogweed plant, "pita sudu sarana," (Boerhavia diffusa) [13], curry leaf plant, "karapincha," (Murraya koenigii) [14], indian pennywort plant, "gotukola," (Centera asiatica) [15], jewish plum plant, "ambarella,"(Spondias dulcis) [16]. PMID- 29516034 TI - QSAR ligand dataset for modelling mutagenicity, genotoxicity, and rodent carcinogenicity. AB - Five datasets were constructed from ligand and bioassay result data from the literature. These datasets include bioassay results from the Ames mutagenicity assay, Greenscreen GADD-45a-GFP assay, Syrian Hamster Embryo (SHE) assay, and 2 year rat carcinogenicity assay results. These datasets provide information about chemical mutagenicity, genotoxicity and carcinogenicity. PMID- 29516035 TI - Association analysis between hyperuricemia and long term mortality after acute coronary syndrome in three subgroups of patients. AB - These data are linked to the research article, entitled Hyperuricemia as a prognostic factor after acute coronary syndrome published in Atherosclerosis. Data from patients admitted for acute coronary syndrome between 2008 and 2013 were collected during the hospitalization, and a follow-up until endpoint or end of study was carried out. Multivariate analysis of variables associated with long term mortality after acute coronary syndrome in patients stratified by the presence of diabetes, hypertension or kidney failure is provided in this article. PMID- 29516036 TI - Inhibition of a Descending Prefrontal Circuit Prevents Ketamine-Induced Stress Resilience in Females. AB - Stress is a potent etiological factor in the onset of major depressive disorder and posttraumatic stress disorder (PTSD). Therefore, significant efforts have been made to identify factors that produce resilience to the outcomes of a later stressor, in hopes of preventing untoward clinical outcomes. The NMDA receptor antagonist ketamine has recently emerged as a prophylactic capable of preventing neurochemical and behavioral outcomes of a future stressor. Despite promising results of preclinical studies performed in male rats, the effects of proactive ketamine in female rats remains unknown. This is alarming given that stress related disorders affect females at nearly twice the rate of males. Here we explore the prophylactic effects of ketamine on stress-induced anxiety-like behavior and the neural circuit-level processes that mediate these effects in female rats. Ketamine given one week prior to an uncontrollable stressor (inescapable tailshock; IS) reduced typical stress-induced activation of the serotonergic (5-HT) dorsal raphe nucleus (DRN) and eliminated DRN-dependent juvenile social exploration (JSE) deficits 24 h after the stressor. Proactive ketamine altered prelimbic cortex (PL) neural ensembles so that a later experience with IS now activated these cells, which it ordinarily would not. Ketamine acutely activated a PL to DRN (PL-DRN) circuit and inhibition of this circuit with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) at the time of IS one week later prevented stress prophylaxis, suggesting that persistent changes in PL-DRN circuit activity are responsible, at least in part, for mediating long-term effects associated with ketamine. PMID- 29516037 TI - Endoscopic Ultrasound-Guided Fine Needle Aspiration Accurately Diagnoses Smaller Pancreatic Neuroendocrine Tumors Compared To Computer Tomography-Guided Fine Needle Aspiration. AB - Introduction: The role of EUS-guided FNA as a highly sensitive modality in the diagnosis of pancreatic adenocarcinoma is well documented. However, there is little published data on the role of EUS-FNA in diagnosing pancreatic neuroendocrine tumors (NETs). Objective: The aim of this study is to compare the sensitivity of EUS-FNA to that of CT-FNA for diagnosing pancreatic NETs. Methods: This is a single institution retrospective analysis of the operating characteristics of EUS-FNA and CT-FNA in detecting pancreatic NETs. Only patients with a final diagnosis of pancreatic NET were selected for this study. Procedure related data, including tumor size and location, and presence of a cytotechnologist were recorded. The results of each FNA were compared to the final clinico-pathological diagnosis to calculate sensitivity. Results: Twenty eight patients undergoing FNA (19 by EUS, 9 by CT) were analyzed. NETs diagnosed by EUS-FNA were smaller compared with CT-FNA (2.7 +/- 0.9cm vs. 6.5 +/- 2.1cm, p = 0.009) and were more often found in the pancreatic head (47.4% vs. 11.1%, p = 0.035). There were no significant differences in sensitivity between EUS-FNA and CT-FNA specimens (73.7% vs. 88.9%, p = 0.33). Conclusion: EUS-guided FNA is as sensitive as CT-guided FNA in diagnosing pancreatic NETs, but its main advantage is in the diagnosis of smaller pancreatic NETs in the head of the pancreas. It may also be the preferred approach in the diagnosis of multifocal pancreatic NETs in the setting of MEN I Syndrome. PMID- 29516038 TI - Increasing undergraduate nursing students' cultural competence: an evaluation study. AB - Background: Cultural competence has become increasingly important for Chinese health professionals because of internationalization and the opening up of China to overseas visitors and business as well as a growing awareness of the needs of minority groups within China. This study aimed to evaluate a workshop designed to improve cultural competence among Chinese undergraduate nursing students. Methods: A one-group pretest and posttest design was applied. The intervention was a one-day workshop based on transformative learning theory using a variety of teaching strategies. Forty undergraduate nursing students from a university in Wuhan, China selected by convenient sampling received the intervention. Data were collected before the intervention (T1), immediately after the intervention (T2), and 1 month (T3) and 3 months (T4) following the intervention through the Chinese version of Cultural Competence Inventory for Nurses (CCIN). A researcher-designed evaluation form including open-ended questions was also used. Results: Participants' scores by CCIN increased significantly in the total score (p < .001) as well as the components of cultural awareness (p = .003), cultural knowledge (p < .001), cultural understanding (p = .007) and cultural skills (p < .001), but not in cultural respect. This improvement maintained at T3 and T4. Overall, participants were satisfied with the workshop, and the qualitative results supported the effects of this intervention. Conclusions: The one-day workshop was effective in improving nursing students' cultural competence. Replication or further refinement of this workshop is recommended for future research among additional nursing students with diverse backgrounds. PMID- 29516040 TI - The current state of refractive surgery. PMID- 29516039 TI - Non-structural misalignments of body posture in the sagittal plane. AB - Background: The physiological sagittal spinal curvature represents a typical feature of good body posture in the sagittal plane. The cervical and the lumbar spine are curved anteriorly (lordosis), while the thoracic segment is curved posteriorly (kyphosis). The pelvis is inclined anteriorly, and the lower limbs' joints remain in a neutral position. However, there are many deviations from the optimal body alignment.The aim of this paper is to present the most common types of non-structural misalignments of the body posture in the sagittal plane. Main body of the abstract: The most common types of non-structural misalignments of body posture in the sagittal plane are as follows: (1) lordotic, (2) kyphotic, (3) flat-back, and (4) sway-back postures. Each one may influence both the skeletal and the muscular system leading to the functional disturbance and an increased strain of the supporting structures. Usually, the disturbances localized within the muscles are analyzed in respect to their shortening or lengthening. However, according to suggestions presented in the literature, when the muscles responsible for maintaining good body posture (the so-called stabilizers) are not being stimulated to resist against gravity for an extended period of time, e.g., during prolonged sitting, their stabilizing function is disturbed by the hypoactivity reaction resulting in muscular weakness. The deficit of the locomotor system stability triggers a compensatory mechanism-the stabilizing function is overtaken by the so-called mobilizing muscles. However, as a side effect, such compensation leads to the increased activity of mobilizers (hyperactivity) and decreased flexibility, which may finally lead to the pathological chain of reaction within the musculoskeletal system. Conclusions: There exist four principal types of non-structural body posture misalignments in the sagittal plane: lordotic posture, kyphotic posture, flat-back posture, and sway-back posture. Each of them can disturb the physiological loading of the musculoskeletal system in a specific way, which may lead to a functional disorder.When planning postural corrective exercises, not only the analysis of muscles in respect to their shortening and lengthening but also their hypoactivity and hyperactivity should be considered. PMID- 29516041 TI - Stem cells treatment in the ocular surface regeneration. AB - The article presents the modern treatment with stem cells in the reconstruction of ocular surface. The turnover of the stem cells, the location in the limbus areas, the importance of limbal stem cells presence, the clinical appearance of stem cell deficiency, investigations method for this illness and the management of stem cell deficiency (artificial lacrimal tear drops, mini scleral contact lenses and the surgical treatment with allografts and autografts of stem cells) were taken into account. PMID- 29516042 TI - The role of clear lens extraction in angle closure glaucoma. AB - Clear lens extraction can be considered a therapeutic option in angle closure glaucoma (ACG). Even if it does not represent the first choice of treatment, it can be taken into consideration when the topical treatment does not control the intraocular pressure (IOP) and iridotomy does not have a positive effect on the angle closure, especially in appositional angle closure when biometry or ultrabiomicroscopy (UBM) show lens involvement. In angle closure glaucoma, clear lens extraction represents an etiological treatment that takes into account the role of the lens in the pathogenesis of the disease. If we ignore it and we choose a filtrating surgery as therapeutic option we can end up with complications such as prolonged athalamia, corneal damage and lens opacification that will eventually require cataract surgery, but performed late and with higher risks. Before performing a filtrating surgery in ACG, we should take an UBM. We also need to choose the best moment to perform surgery, after topical treatment and iridotomy have been tested, but before trabecular damage appears. PMID- 29516044 TI - Endothelial cells loss to the hyperopic pacients during phacoemulsification. AB - Introduction: The phacoemulsification cataract surgery is the most frequently performed surgery and it generally improves vision in over 90% of the patients. Hyperopic patients are a challenge during phacoemulsification especially because of their short eyeball and shallow anterior chamber. A shallow anterior chamber is associated with overall reduction of the safe zone, which may lead to difficulty in creating the corneal incisions, harder capsulorhexis performing, or endothelial complications. Purpose: The aim of the study was to present the endothelial cells loss after the phacoemulsification procedure in the hyperopic patients. Material and Methods: A number of 1775 patients operated in the Ophthalmology Department of the Clinical Hospital Sibiu from January 11, 2011 to December 20, 2013 have been included in our study; 595 cases with emmetropia and the rest of the 1180 patients had the following refraction errors: 216 - myopia and 964 - hypermetropia. From the total cases of the hypermetropia, we selected 72 patients to measure the endothelial cells density and the corneal thickness by using specular microscopy, one day before and 7-14 days after surgery. Results and discussions: The preexisting hypermetropia might modify the intraoperative and postoperative cataract surgery evolution. Endothelial cell loss is potentially higher from surgical trauma so that the endothelium must be protected with viscoelastics. The loss of endothelial cells in hyperopic eyes occurred with an average of 267 cell/ mm2 and the thickness of the cornea increased by 13 um. Conclusion: The phacoemulsification surgery in the presence of hypermetropia requires more attention. The biometry and the specular microscopy are very important tasks for the preoperative assessment, surgery, and postoperative care. The protection of the corneal endothelium with viscoelastics leads to an insignificant modification of the endothelial cells in hyperopic patients compared to an anterior study of the patients with all ametropies. PMID- 29516045 TI - Anatomical results and complications after silicone oil removal. AB - : The aim of the report was to evaluate anatomical results and intra and postoperative complications after silicone oil (SIO) removal. Methods: Retrospective, interventional study evaluating consecutive cases with ambulatory SIO removal after vitrectomy for complex retinal detachments. The anatomical result was the main followed parameter. Intra and postoperative complications and also intraocular pressure changes were evaluated. Cases were followed-up for at least 12 months. Results: A total of 98 consecutive cases were reviewed. The main duration of oil endotamponade was 5.46 months (3-16 months). In 15 cases (15.30%) signs of SIO emulsification were noted at the time of removal. A stable anatomical result after SIO removal was obtained in 94 out of 98 cases (95.91%). Retinal detachment recurrence appeared in first month postoperatively (1 case) and between the 3rd and 4th month postoperatively (3 cases). Main indications for 5000cs SIO endotamponade during ambulatory 23G vitrectomy were represented by proliferative vitreoretinopathy (PVR) (78 cases - 79.59%), proliferative diabetic retinopathy (17 cases - 17.34%) and giant retinal tears (3 cases - 3.06%). 29 eyes (29.59%) were pseudophakic at primary surgery. However, most phakic eyes showed cataract appearance and progression during SIO endotamponade and also after SIO removal. Intraocular pressure significantly decreased after SIO removal with the occurrence of various choroidal detachments in 8 cases (8.16%), resolving spontaneously within the first week postoperatively. Conclusions: In our experience, the retinal detachment recurrence rate after SIO removal was 4.08%. This promising anatomical result confirms the need for an accurate primary surgery and also for a safe moment of SIO removal according to the severity of primary pathology. PMID- 29516043 TI - Retinal changes in diabetic patients without diabetic retinopathy. AB - Purpose: The purpose of this study was to measure retinal vessel caliber and to examine early changes in macular thickness using optical coherence tomography (OCT). We evaluated to what extend vascular caliber and macular thickness differed between patients with type 2 diabetes mellitus without diabetic retinopathy compared with healthy individuals. Methods: 26 diabetic patients without diabetic retinopathy and 26 normal participants without any retinal and optic nerve diseases underwent ophthalmic examination, fundus photography, and OCT imaging. Temporal inferior retinal vessel diameters were measured using OCT. Also, we measured macular thickness in nine ETDRS subfields using Cirrus OCT. Results: The mean age in the diabetic group was 61.5 years and in the control group, 55.5 years. Wider retinal arterioles and venules were found in patients with diabetes compared with healthy subjects (120 um versus 96 um, p<0.005 and 137 um versus 120.5 um, p value <0.001, respectively). In patients with type 2 diabetes mellitus, central macular thickness was significantly thinner than that of control eyes (243.5 um versus 269.9 um, p value <0.001). Conclusions: Our results support the hypothesis that the association between vascular damage and structural changes of the neuroretina is an early indicator of retinal impairment in patients with diabetes without diabetic retinopathy. PMID- 29516046 TI - Posterior Capsule Opacification and Nd-YAG rates evaluation in a large series of pseudophakic cases. AB - Purpose: To evaluate the influence of Intraocular Lens (IOL) material and design on Posterior Capsule Opacification (PCO) and Neodymium-YAG (Nd-YAG) rates in eyes implanted with different Posterior Chamber Intraocular Lenses (PC IOLs) designs at the end of uncomplicated cataract surgeries. Setting: Oculus Eye Clinic, Bucharest, Romania. Design: Retrospective, observational study. Methods: This study comprised 4805 eyes operated for cataract in 2012 and 2013 with a post operative average follow up of 40 +/- 6,15 months (27-54 months). The PCO and Nd YAG rates were recorded and compared among different IOL materials and designs and among different pathology groups. Results: From 4805 IOLs implanted, 2560 (53,27%) were hydrophilic and 2245 (45,73%) hydrophobic, 2937 (61%) were aspherical and 1868 (39%) spherical. We found statistical significant differences in the PCO and Nd-YAG rates between hydrophilic (18% and 14% respectively) and hydrophobic lenses (4% and 2% respectively) (p<0.0001). There were also statistically significant differences in the sub-group of hydrophilic aspheric IOLs, finding lower PCO and Nd:YAG rates with the C-loop haptics configuration (12,6% and 3,3% respectively) compared with the broad optic/ haptic junction (29,75% and 24,73% respectively) (p<0.001). No statistically significant differences on PCO and Nd:YAG rates were found for the different associated pathologies (p>0.05). Conclusions: Hydrophilic lenses showed statistically higher PCO and Nd:YAG rates than hydrophobic lenses. In contrast, the optic asphericity and the associated pathologies had no influence on the PCO and Nd:YAG rates. IOL design and material seem to be the main characteristics influencing PCO and Nd YAG rates. Abbreviations: LECs = lens epithelial cells. PMID- 29516047 TI - Uncommon form of normal-tension glaucoma. AB - Aim: To present diagnostic particularities, assessment of prognosis, and the need for treatment in a case of normal-tension glaucoma. Methods: - presentation of clinical changes and investigations supporting the diagnosis; - careful anamnesis that disclosed new elements, useful for the evaluation of the case. Results: after a two-year follow-up period, we can ascertain that the optic atrophy is non progressive. Conclusions: the assessment of risk factors and a rigorous anamnesis were significant for the establishment of prognosis and need for treatment. PMID- 29516048 TI - The importance of ganglion cell complex investigation in myopic patients. AB - Glaucoma is an optic neuropathy that affects the ganglion cell complex in all its components: cell bodies, dendrites, and axons, the dendritic arbor being the first one damaged. This is the reason why the thickness of the ganglion cell and internal plexiform layers can be taken into account as an early predictor of the glaucomatous changes, along with the retinal nerve fiber layer (RNFL) thickness. However, due to disc tilting and peripapillary atrophy, the RNFL evaluation may be prone to errors in myopic patients. We presented the cases of two myopic patients, who, after a routine examination, were identified as glaucoma suspects. The Optical Coherence Tomography (OCT) scan revealed a nerve fiber loss which was not confirmed by the ganglion cell complex scan. Thereafter we manually adjusted the optic disc margins according to the patients' myopic changes and this time the retinal nerve fiber layer was also normal. We observed that the ganglion cell complex evaluation led to fewer errors than the retinal nerve fiber layer evaluation, particularly in front of a myopic patient. Nevertheless, various investigations should be considered in the attempt to issue a diagnosis of glaucoma. PMID- 29516049 TI - Optic Pit Maculopathy. AB - This paper discusses a 32-year-old woman's case who presented a chronic decrease of visual acuity. In this case, the treatment was complex and consisted of a 25 GA vitrectomy, MLI peeling, covering the defect at the optic nerve papilla with that patch, gas endotamponade (C3F8). Abbreviations: MLI = internal limiting membrane; ODP-M = optic disc pit maculopathy. PMID- 29516050 TI - Multifocal Choroiditis and Panuveitis - difficulties in diagnosis and treatment. AB - We present the case of a 49-year-old patient who was treated with Aripriprazole in context of Paranoid Schizophrenia. The patient had a history of numerous Panuveitis recurrences for the left eye, which led to a marked decrease of the vision VA-NLP and was diagnosed with Multifocal Choroiditis and Panuveitis for the right eye. The examination revealed VA of 20/ 200 for right eye, keratic precipitates, and vitritis. Fundus aspect of the right eye showed multiple discrete, ovoid, yellowish-grey lesions at the posterior pole and periphery, optic disc oedema was present. The Human leukocyte antigen typing of group A, ancillary investigation (OCT, Angiofluorography, B-mode ultrasonography) and fundus examination confirmed the diagnosis of Multifocal Choroiditis and Panuveitis but we did not exclude antipsychotic-related chorioretinopathy or a Birdshot-like Syndrome. PMID- 29516051 TI - Endothelial keratoplasty for Fuchs dystrophy. AB - We report the case of a 69-year-old female with Fuchs endothelial dystrophy and posterior chamber in-the-bag intraocular lens, whom we treated with DMEK surgical technique. We encountered difficulties both during obtaining the endothelium from the young donor and during the intraocular unrolling and its application on the stroma. We evaluated both preoperative and postoperative the following parameters: visual acuity, slit lamp, and optical coherence tomography appearance of the cornea, corneal thickness, intraocular pressure, endothelial cell density. In all postoperative assessments, the endothelium was attached to the host's stroma, with small peripheral, inferior folding area. Short-term results were favorable with a clear cornea and significant improvement in visual acuity obtained in the first 3 months of postoperative follow-up. Abbreviation: BCVA = best-corrected visual acuity, RE = right eye, LE = left eye, OCT = optical coherence tomography, DMEK = Descemet membrane endothelial keratoplasty. PMID- 29516052 TI - Eales disease in a young adult man Case report. AB - Purpose: To report the case of a 39-year-old man with bilateral Eales disease. Methods: The clinical, angiographic, and ultrasonographic evaluations of the patient were thoroughly and specifically carried out. Results: The treatment consisted of pars plana vitrectomy and endolaser treatment at the time of surgery to the left eye and laser scatter retinal photocoagulation to the right eye. Postoperatively, the visual acuity improved at 20/ 20 to the left eye. Conclusions: Eales disease is a clinical diagnosis of exclusion as many other retinal disorders can mimic it, especially conditions of retinal inflammation or neovascularization. The condition, with a characteristic clinical picture, fluorescein angiographic finding, and natural course, is considered a specific disease entity, easily distinguished from other vasculitides and retinopathies. PMID- 29516053 TI - Case report: bilateral optic nerve head drusen and glaucoma. AB - Optic nerve head drusen is an incidental finding in current ophthalmological practice. Although patients rarely display symptoms, structural, and functional defects, there are exceptional cases when clinical appearance can make it difficult to diagnose underlying or coexisting conditions, such as glaucoma. The following case report demonstrates how overlapping optic nerve pathologies can interfere in clinical judgement and therapeutic decision making in a young male patient, with relevant family history for both glaucoma and bilateral optic nerve head drusen. PMID- 29516054 TI - Beyond Trisomy 21: Phenotypic Variability in People with Down Syndrome Explained by Further Chromosome Mis-segregation and Mosaic Aneuploidy. AB - Phenotypic variability is a fundamental feature of the human population and is particularly evident among people with Down syndrome and/or Alzheimer's disease. Herein, we review current theories of the potential origins of this phenotypic variability and propose a novel mechanism based on our finding that the Alzheimer's disease-associated Abeta peptide, encoded on chromosome 21, disrupts the mitotic spindle, induces abnormal chromosome segregation, and produces mosaic populations of aneuploid cells in all tissues of people with Alzheimer's disease and in mouse and cell models thereof. Thus, individuals exposed to increased levels of the Abeta peptide should accumulate mosaic populations of aneuploid cells, with different chromosomes affected in different tissues and in different individuals. Specifically, people with Down syndrome, who express elevated levels of Abeta peptide throughout their lifetimes, would be predicted to accumulate additional types of aneuploidy, beyond trisomy 21 and including changes in their trisomy 21 status, in mosaic cell populations. Such mosaic aneuploidy would introduce a novel form of genetic variability that could potentially underlie much of the observed phenotypic variability among people with Down syndrome, and possibly also among people with Alzheimer's disease. This mosaic aneuploidy theory of phenotypic variability in Down syndrome is supported by several observations, makes several testable predictions, and identifies a potential approach to reducing the frequency of some of the most debilitating features of Down syndrome, including Alzheimer's disease. PMID- 29516055 TI - The Emerging Business Models and Value Proposition of Mobile Health Clinics. AB - Mobile health clinics are increasingly used to deliver healthcare to urban and rural populations. An estimated 2000 vehicles in the United States are now delivering between 5 and 6 million visits annually; however, despite this growth, mobile health clinics represent an underutilized resource that could transform the way healthcare is delivered, especially in underserved areas. Preliminary research has shown that mobile health clinics have the potential to reduce costs and improve health outcomes. Their value lies primarily in their mobility, their ability to be flexibly deployed and customized to fit the evolving needs of populations and health systems, and their ability to link clinical and community settings. Few studies have identified how mobile health clinics can be sustainably utilized. We discuss the value proposition of mobile health clinics and propose 3 potential business models for them-adoption by accountable care organizations, payers, and employers. PMID- 29516056 TI - Endoscopic and minimally-invasive ear surgery: A path to better outcomes. AB - The development of endoscopic ear surgery techniques promises to change the way we approach ear surgery. In this review paper, we explore the current evidence, seek to determine the advantages of endoscopic ear surgery, and see if these advantages are both measureable and meaningful. The wide field of view of the endoscope allows the surgeon to better visualize the various recesses of the middle ear cleft. Endoscopes make it possible to address the target pathology transcanal, while minimizing dissection or normal tissue done purely for exposure, leading to the evolution of minimally-invasive ear surgery and reducing morbidity. When used in chronic ear surgery, endoscopy appears to have the potential to significantly reduce cholesteatoma recidivism rates. Using endoscopes as an adjunct can increase the surgeon's confidence in total cholesteatoma removal. By doing so, endoscopes reduce the need to reopen the mastoid during second-look surgery, help preserve the canal wall, or even change post-cholesteatoma follow-up protocols by channeling more patients away from a planned second-look. PMID- 29516057 TI - Results of pediatric endoscopic and endoscopically assisted tympanoplasty. AB - Objectives: To evaluate the success of pediatric endoscopic and endoscopically assisted transcanal cartilage inlay tympanoplasty. Methods: Retrospective review of single surgeon experience. Results: During a 3 year period, 30 children underwent 31 endoscopic or endoscopically assisted transcanal tympanoplasties by the senior surgeon using tragal cartilage/perichondrial inlay grafts. There were 22 boys and 8 girls, ranging in age from 3.5 to 17 years (median 6 years). All tragal cartilage grafts (31/31; 100%) survived. Twenty-seven surgeries (27/31; 82%) resulted in an intact drum (17/31; 55%) or a microperforation (10/31; 32%). In four cases (4/31; 13%) significant perforations formed in previously unaffected portions of the drum. Conclusion: Transcanal endoscopic cartilage inlay tympanoplasty offers a practical, minimally invasive approach to tympanoplasty for children of any age. It avoids postauricular or endaural incisions, tympanomeatal flap elevation, and canalplasty. Graft survival is uniform. Microperforation at the graft margins remained in 1/3 of children. Technical modifications may lead to higher rates of tympanic closure. PMID- 29516058 TI - Use of porcine small intestinal submucosa for pediatric endoscopic tympanic membrane repair. AB - Tympanic membrane perforationsoccur frequently in children, and can result in hearing loss, otorrhea, pain, and cholesteatoma. Due to the narrower ear canal in children, a postauricular incision is often needed to access the tympanic membrane for surgical repair. Endoscopic approaches are increasingly being used for tympanic membrane repair, reducing the need for postauricular incisions. As the need for a postauricular incision decreases, the demand for non-autologous grafting material has increased. Acellular porcine small intestinal submucosa (SIS) has been described in the literature as an alternative to commonly used autologous grafts, and is well suited for use with transcanal endoscopic ear surgery as a minimally invasive approach. This paper describes techniques for use of SIS in endoscopic tympanic membrane repair in children. PMID- 29516059 TI - Audiological results of endoscopic surgical repair of the long process of incus. AB - Objective: The purpose of this study is to evaluate our experience with endoscopic repair of ossicular discontinuity at the incudostapedial joint, with or without an intact stapes suprastructure, and present our hearing results. We classify results based on the causative pathology, the type of ossiculoplasty, and type of lesion. We demonstrate the ability to endoscopically place a total ossicular replacement prosthesis (TORP), measuring 4.25 mm, between the stapes footplate and the incus remnant to reestablish ossicular continuity. Methods: This was a retrospective case series conducted in tertiary referral center (Hopital de la Timone) Marseille, France. 25 patients underwent incudostapedial rebridging ossiculoplasty between 2009 and 2013. Fifteen cases of chronic otitis media and 10 otosclerosis revisions were included in the study. Three different materials were used in ossiculoplasty, hydroxyapatite cement, incus remnant, and partial/total ossicular replacement prostheses. Audiometric results were evaluated before and after ossiculoplasty. Twelve month follow-up data is provided. Results: The mean postoperative air-bone gap was 15 dB (5-25 dB). Hearing results were better inotosclerosis revisions. Hydroxyapatite cement produced an air-bone gap of 5 dB, TORP placed under the incus produced a 12 dB gap, and TORP placed under the malleus resulted in a 12 dB gap and one deaf ear. In cases of chronic otitis media, the residual air-bone gap was 17 dB with PORP, 12 dB with TORP, and 20 dB with incus transposition. Conclusion: The hydroxyapatite cement is effective in the reconstruction of ossicular discontinuity but the high price limits its utilization. TORP placed under the incus is a reliable and stable method of ossicular reconstruction that is cost effective and offers satisfactory hearing results in selected patients. PMID- 29516060 TI - Endoscopic transcanal modified canal-wall-down mastoidectomy for cholesteatoma. AB - Attic cholesteatoma with antral extension in tight sclerotic mastoid cavities is a common presentation that creates difficult decision-making intraoperatively. Drilling through a sclerotic and small mastoid cavity, keeping the canal wall intactis often difficult and increases the risk of serious injury. Consequently, a canal-wall-down mastoidectomy is often performed. The endoscopic transcanal modified canal-wall-down mastoidectomy approach allows the benefits of an open cavity for cholesteatoma resection and the benefits of a closed cavity for better long-term care and a more normal ear canal and middle ear reconstruction. PMID- 29516061 TI - Endoscopic excision of a tympanic paraganglioma: Training the next generation of ear surgeons. AB - Tympanic paragangliomas are uncommon vascular tumors of neural crest origin. Classically these lesions have been surgically managed via a transcanal or transmastoid approach using binocular microscopy. We describe a case in which a tympanic paraganglioma was removed via a transcanal approach, using the endoscope exclusively. Endoscopic ear surgery enhances visualization, helping to ensure complete tumor removal, while reducing unnecessary dissection and its associated morbidity. For small middle ear neoplasms, a purely endoscopic approach is feasible, with excellent results. Resident education in ear surgery has also been enhanced by the use of endoscopes. The wide field of view provided by the endoscope helps trainees understand the intricate three-dimensional anatomy of the middle ear cleft. PMID- 29516062 TI - Qualitative analysis of the Dix-Hallpike maneuver in multi-canal BPPV using a biomechanical model: Introduction of an expanded Dix-Hallpike maneuver for enhanced diagnosis of multi-canal BPPV. AB - Introduction/Objective: Multiple canal BPPV can be a diagnostic challenge to the clinician. This is due in part to the complex anatomy of the labyrinth but also to complex and often simultaneous ocular responses that result from stimulation of multiple canals during traditional diagnostic testing. Our objective was to analyze the Dix-Hallpike maneuver used in the diagnosis of BPPV to look for patterns of simultaneous canal response and to develop a diagnostic maneuver that will allow separation of canal responses in multiple canal BPPV. Methods: A previously created and published 3D biomechanical model of the human labyrinths for the study of BPPV was used to analyze and compare the position and movement of otoliths in the Dix-Hallpike maneuver as well as in a proposed expanded version of the traditional Dix-Hallpike maneuver. Results: The traditional Dix Hallpike maneuver with the head hanging may promote movement of otoliths in 5 of the six semicircular canals. The Dix-Hallpike maneuver with the head lowered only to the horizontal position allows for otoconia in only the lowermost posterior canal to fall to the most gravity dependent position. This position allows for minimal or no movement of otoconia in the contralateral posterior canal, or in either superior canal. Turning the head ninety degrees to the opposite side while still in the horizontal position will provoke otolith movement in only the contralateral posterior canal. The superior canals can then be examined for free otolith debris by extending the neck to a head-hanging position. These positions may be assumed directly from one to the next in the lying position. There seems to be no advantage to sitting up between positions. Conclusion: The Dix-Hallpike maneuver may cause simultaneous movement of otoliths present in multiple canals and create an obstacle to accurate diagnosis in multi-canal BPPV. An expanded Dix Hallpike maneuver is described which adds intermediate steps with the head positioned to the right and left in the horizontal position before head-hanging. This expanded maneuver has helped to isolate affected semi-circular canals for individual assessment in multiple canal BPPV. PMID- 29516063 TI - Clinical-radiological correlation and role of computed tomography staging in chronic rhinosinusitis. AB - Objective: This study aimed to determine whether there is a clinical-radiological correlation in chronic rhinosinusitis (CRS), to compare operative findings with those of computed tomography (CT) imaging, and to determine the importance of a CT score and staging in management of CRS. Methods: This study is a prospective study. Adult patients meeting diagnostic criteria for CRS were prospectively studied using the Lund-Mackay (LM) symptom score and sinus CT scan. The symptom scores were correlated with CT stage according to the Kennedy and LM staging systems. Similarly, the intraoperative findings were correlated with the Kennedy staging system. The spectrum of anatomical variations in our study population was compared with the findings of symptomatic patients in various other studies. Results: Thirty-four adult patients (13 females, 21 males, mean age: 33 years) met our inclusion criteria. Most of the patients presented with nasal obstruction, headache, and hyposmia. Nasal polyposis was the most common finding in CT scans, with many cases of retention cysts reported as polyps. In total, 50% of patients had a deviated septum. Concha bullosa was the most common finding among the various anatomical variations encroaching the ostiomeatal complex (OMC). In 60%-70% of cases, the CT scan grading correlated with operative findings. LM symptoms scores showed a poor correlation with both LM CT scores and the Kennedy stage. Conclusions: Although CT provided detailed information on sinus involvement; its relation with symptom severity is not reliable. The Kennedy CT staging system correlated better with CRS symptoms. Thus, use of Kennedy staging could be useful to endoscopic sinus surgeons as it provides an insight into the pathophysiology, can guide treatment, and facilitate prognosis prediction in CRS. PMID- 29516064 TI - Surgical management of the tonsillectomy and adenoidectomy patient. PMID- 29516065 TI - Photo-responsive photonic crystals for broad wavelength shifts. AB - A facile method to realize photo-responsive inverse opal photonic crystal polymer (IOPP) films with an adjustable broad-wavelength-range photonic band gap (PBG) was demonstrated in this communication. When immersing the IOPP film in malachite green carbinol base (MGCB) solution, under light irradiation, the MGCB released hydroxide ions. In this way, optical signals were converted to chemical signals. As a result, the pH sensitive IOPP film expanded and the PBG changed. The band gap movement of the IOPP films with different monomer to cross-linker ratios was studied in this work. PMID- 29516066 TI - Mechanistic insights into two-photon-driven photocatalysis in organic synthesis. AB - A mechanism based on the sequential absorption of two photons by the components of a redox couple has been recently proposed for catalysis of the energetically demanding reduction of aryl halides. Here, we analyze the suggested photochemical mechanism of this reaction, which employs perylenediimide (PDI) as a photocatalyst, on the basis of spectroscopic, electrochemical and electron paramagnetic resonance data. Our results indicate that the photoexcited PDI radical anion (*PDI-) cannot play the role of a photosensitizer in the aforementioned process. Instead, the reduction of 4'-bromoacetophenone likely involves *PDI- decomposition products. The extremely short lifetime of the photoexcited transient species, as *PDI-, is a major general limitation for photocatalytic schemes based on sequential two-photon excitation. In order to better understand the potential of such schemes, we discuss them in the context of the Z-scheme in natural photosynthesis. PMID- 29516067 TI - Enhanced oxygen reduction of multi-Fe3O4@carbon core-shell electrocatalysts through a nanoparticle/polymer co-assembly strategy. AB - This paper reports a facile synthesis of multi-Fe3O4@carbon (mFe3O4@C) core-shell nanoparticles (NPs) using co-assembly of Fe3O4 NPs and polystyrene-b poly(ethylene oxide) (PS-b-PEO) as a template. Slow solvent exchange leads to multiple tiny hydrophobic Fe3O4 NPs entrapped within PS-b-PEO micelles. After polydopamine coating and subsequent carbonization, a carbon shell encapsulating multiple Fe3O4 cores is obtained. The significant features of mFe3O4@C lie in the more active Fe3O4 sites and available free space within the carbon shell. As a result, the oxygen reduction performance of the resultant mFe3O4@C shows a higher onset potential than that of single Fe3O4@C. Meanwhile, mFe3O4@C exhibits a larger limiting current density (5.2 mA cm-2 at 1.0 V), long-time stability, and methanol tolerance compared to commercial Pt/C. The generality of the micellar immobilized NPs as a template is expected to boost the fabrication of various core-shell NPs for practical applications. PMID- 29516068 TI - Synthesis of multilayered structure of nano-dimensional silica glass/reduced graphene oxide for advanced electrochemical applications. AB - During the past few years, intensive research has been carried out to design new functional materials for superior electrochemical applications. Due to low storage capacity and low charge transport, silica based glasses have not yet been investigated for their supercapacitive behavior. Therefore, in the present study, a multilayered structure of silica-based nanoglass and reduced graphene oxide has been designed to remarkably enhance the specific capacitance by exploiting the porosity, large surface area, sufficient dangling bonds in the nanoglass and high electrical conductivity of rGO. The charge transport in the composite structure is also investigated to understand the electrochemical properties. It is found that Simmons tunneling or direct tunneling is the dominant mechanism of charge conduction between the graphene layers via the potential barrier of silica nanoglass phase. We believe that this study will open up a new area in the design of glass-based two-dimensional nanocomposites for superior supercapacitor applications. PMID- 29516073 TI - Structural evolution and stability of non-crosslinked fiber networks with inter fiber adhesion. AB - Adhesion plays an important role in the mechanics of nanoscale fibers such as various biological filaments, carbon nanotubes and artificial polymeric nanofibers. In this work we study assemblies of non-crosslinked filaments and characterize their adhesion-driven structural evolution and their final stable structure. The key parameters of the problem are the network density, the fiber length, the bending stiffness of fibers and the strength of adhesion. The system of fibers self-organizes in one of three types of structures: locked networks, in which fibers remain in the as-deposited state, cellular networks, in which fibers form bundles and these organize into a larger scale network, and disintegrated networks, in which the network of bundles becomes disconnected. We determine the parametric space corresponding to each of these structures. Further, we identify a triangular structure of bundles, similar to the Plateau triangle occurring in foams, which stabilizes the network of bundles and study in detail the stabilization mechanism. The analysis provides design guidelines and a physical picture of the stability and structure of random fiber networks with adhesion. PMID- 29516074 TI - Photo-switchable patterning of gold nanoparticles along 3D DNA nanotubes. AB - We have developed a reversible photoswitching platform based on 3D DNA nanotubes by integrating photoisomerizable azobenzene molecules along the edges. This would allow the reversible conformational changes of the nanotubes between linear and bent features and the switchable patterning of gold nanoparticles in response to UV/Vis irradiation. This work provides a new strategy to create reversibly reconfigurable transformative nanomaterials for potential applications in the fields of renewable energy, sensing, nanorobotics and nanomedicine. PMID- 29516078 TI - Death by Gun Violence-Guns Are Not the Problem. PMID- 29516079 TI - Mendelian Randomization Concerns. PMID- 29516081 TI - Psychophysical Boundary for Categorization of Voiced-Voiceless Stop Consonants in Native Japanese Speakers. AB - Purpose: The purpose of this study was to investigate the psychophysical boundary used for categorization of voiced-voiceless stop consonants in native Japanese speakers. Method: Twelve native Japanese speakers participated in the experiment. The stimuli were synthetic stop consonant-vowel stimuli varying in voice onset time (VOT) with manipulation of the amplitude of the initial noise portion and the first formant (F1) frequency of the periodic portion. There were 3 tasks, namely, speech identification to either /d/ or /t/, detection of the noise portion, and simultaneity judgment of onsets of the noise and periodic portions. Results: The VOT boundaries of /d/-/t/ were close to the shortest VOT values that allowed for detection of the noise portion but not to those for perceived nonsimultaneity of the noise and periodic portions. The slopes of noise detection functions along VOT were as sharp as those of voiced-voiceless identification functions. In addition, the effects of manipulating the amplitude of the noise portion and the F1 frequency of the periodic portion on the detection of the noise portion were similar to those on voiced-voiceless identification. Conclusion: The psychophysical boundary of perception of the initial noise portion masked by the following periodic portion may be used for voiced-voiceless categorization by Japanese speakers. PMID- 29516080 TI - Validating 4 Staging Systems for Cutaneous Squamous Cell Carcinoma Using Population-Based Data: A Nested Case-Control Study. AB - Importance: Cutaneous squamous cell carcinoma (cSCC) has metastatic potential, but the prognostic value of current staging systems in nonselected patients is uncertain. Objective: To assess the effect of risk factors for metastasis and to evaluate validity and usefulness of 4 staging systems for cSCC using population based data. Design, Setting, and Participants: This was a nationwide, population based, nested case-control study. The Cancer Registry of Norway, which receives compulsory data on all cancers in the Norwegian population of approximately 5.2 million inhabitants. All patients diagnosed as having a primary invasive cSCC in the period 2000 to 2004 (n = 6721) were identified. Of these, 112 patients were diagnosed with metastasis within 5 years. As control patients, 112 patients with cSCC without metastases, matched for sex and age at diagnosis, were identified by random. Clinical data and biopsy specimens of primary cSCC were collected for all 224 patients. The biopsies were reexamined histologically by an experienced pathologist using well-established criteria for cSCC, yielding 103 patients with metastasis (cases) and 81 cSCC without metastasis (controls). Main Outcomes and Measures: The ability of 4 cSCC staging systems (ie, the American Joint Committee on Cancer, 7th edition [AJCC 7] staging system, the staging system used by Breuninger et al, the Brigham and Women's Hospital [BWH] staging system, and the AJCC, 8th edition [AJCC 8] staging systems) to identify patients who developed metastasis with 5 years of follow-up. External validation was performed by logistic regression, discrimination (sensitivity, specificity, proportion correctly classified, concordance index), and calibration (R2, Hosmer-Lemeshow test, plots) statistics. Results: Of 6721 patients; 3674 (54.7%) were men and 3047 (45.3%) were women, with a mean age at diagnosis of 78 years. Of the 103 patients with cSCC diagnosed with metastasis within 5 years, 60 [58.3%] were men, and mean [SD] age 72.7 [13.5] years. Of the 81 patients with cSCC without metastasis, 51 [63.0%] were men, and mean [SD] age 74.6 [11.7] 15 years. The staging systems distinguished poorly to moderately between patients who developed metastasis and those who did not. The ability to cluster patients with similar outcomes within the same staging category was low, particularly when using the AJCC 7 system. Using the AJCC 7 system, the risk of metastasis for T2 patients was 3-fold, compared with T1 patients (OR, 2.96; 95% CI, 1.43-6.15). In the system used by Breuninger et al, high-risk categories for diameter and tumor thickness and the BWH system's T2b category collected relatively homogeneous groups. In the systems used by Breuninger et al and Brigham-Women's Hospital, risk of metastasis was significantly elevated with increasing stage or risk category. Using the system by Breuninger et al, the risk of metastasis was less than 3-fold for tumors in the high-risk category of the combined variable (OR, 2.72; 95% CI, 1.29-5.74). The BWH system gave ORs for metastasis at 4.6 (95% CI, 2.23-9.49) and 21.31 (95% CI, 6.07-74.88) for the T2a and T2b categories, respectively. Conclusions and Relevance: Using population-based data, 4 current staging systems for cSCC were unsatisfactory in identifying nonselected cSCC patients at high risk for metastasis. The system used by Breuninger gave the best results. PMID- 29516083 TI - Value of Adding Predictive Clinical Decision Tools to Spine Surgery. PMID- 29516082 TI - The Problem of Burnout Among Surgeons. PMID- 29516085 TI - Death by Gun Violence-Guns Are Not the Problem-Reply. PMID- 29516086 TI - Notice of Retraction and Replacement. Karalunas et al. Subtyping attention deficit/hyperactivity disorder using temperament dimensions: toward biologically based nosologic criteria. JAMA Psychiatry. 2014;71(9):1015-1024. PMID- 29516084 TI - Postmenopausal Women With a "Normal" BMI Might Be Overweight or Even Obese. PMID- 29516087 TI - Race/Ethnicity and Age Distribution of Breast Cancer Diagnosis in the United States. PMID- 29516088 TI - Mendelian Randomization Concerns-Reply. PMID- 29516090 TI - A Large Abdominal Mass in a Young Man. PMID- 29516089 TI - Scarring in Patients With PIK3CA-Related Overgrowth Syndromes. AB - Importance: Patients with somatic overgrowth commonly require surgical intervention to preserve function and improve cosmesis. To our knowledge no observation of scarring outcomes in this population has been published to date. Objective: To observe the frequency of abnormal scarring in patients with somatic overgrowth and sequencing-verified mutations in the PIK3CA gene. Design, Setting, and Participants: This retrospective study evaluated scarring outcomes in patients with PIK3CA-related overgrowth. Samples of affected tissue were sequenced between July 2015 and October 2016. Medical records from multiple large academic tertiary care centers were reviewed for surgical history and scar descriptions, and clinical photographs were assessed by 2 surgeons (J.N.J. and D.M.K.) to confirm abnormal scarring. Analysis of medical records and photographs was performed between April 2017 and June 2017 by a multidisciplinary team from dermatology, plastic surgery, orthopedic surgery, radiology, and genetics departments. All patients considered for the study were diagnosed with somatic overgrowth and previously had affected tissue sent for next-generation sequencing. Those with pathogenic PIK3CA variants and 1 or more prior surgical procedures were reviewed. Main Outcomes and Measures: Presence of excessive scarring in patients with PIK3CA overgrowth. Results: A total of 57 patients with segmental overgrowth syndromes were sequenced. Of the 57 patients, 25 (44%) had pathogenic or likely pathogenic variants in PIK3CA. Of those with pathogenic PIK3CA variants, 6 (24%) had past surgical procedures, all with preoperative and postoperative photographs. Of 6 patients with PIK3CA-related overgrowth and a history of 1 or more surgical procedure, 4 (67%) developed excessive scarring. The cohort with abnormal scarring comprised 3 females and 1 male, with a median age of 8.5 years. All abnormal scarring occurred in affected overgrowth tissue. Three of the 4 patients developed the excessive scarring after debulking procedures for overgrowth and/or vascular malformations of the upper or lower extremity. Conclusions and Relevance: Excessive scarring occurred frequently in patients with PIK3CA-related overgrowth syndromes. The risk of abnormal scarring should therefore be discussed preoperatively. Given the activating nature of these PIK3CA variants, we suggest that the excessive scarring may be owing in part to up-regulation of the PI3K-Akt-mTOR pathway. Additional studies are needed to assess scarring outcomes in patients with other types of overgrowth. PMID- 29516091 TI - Facial Neutrophilic Dermatosis Mimicking Iododerma and Associated With Inflammatory Bowel Disease. PMID- 29516093 TI - Health-Related Quality of Life in Patients With Frontal Fibrosing Alopecia. PMID- 29516092 TI - Multivariate Associations Among Behavioral, Clinical, and Multimodal Imaging Phenotypes in Patients With Psychosis. AB - Importance: Alterations in multiple neuroimaging phenotypes have been reported in psychotic disorders. However, neuroimaging measures can be influenced by factors that are not directly related to psychosis and may confound the interpretation of case-control differences. Therefore, a detailed characterization of the contribution of these factors to neuroimaging phenotypes in psychosis is warranted. Objective: To quantify the association between neuroimaging measures and behavioral, health, and demographic variables in psychosis using an integrated multivariate approach. Design, Setting, and Participants: This imaging study was conducted at a university research hospital from June 26, 2014, to March 9, 2017. High-resolution multimodal magnetic resonance imaging data were obtained from 100 patients with schizophrenia, 40 patients with bipolar disorder, and 50 healthy volunteers; computed were cortical thickness, subcortical volumes, white matter fractional anisotropy, task-related brain activation (during working memory and emotional recognition), and resting-state functional connectivity. Ascertained in all participants were nonimaging measures pertaining to clinical features, cognition, substance use, psychological trauma, physical activity, and body mass index. The association between imaging and nonimaging measures was modeled using sparse canonical correlation analysis with robust reliability testing. Main Outcomes and Measures: Multivariate patterns of the association between nonimaging and neuroimaging measures in patients with psychosis and healthy volunteers. Results: The analyses were performed in 92 patients with schizophrenia (23 female [25.0%]; mean [SD] age, 27.0 [7.6] years), 37 patients with bipolar disorder (12 female [32.4%]; mean [SD] age, 27.5 [8.1] years), and 48 healthy volunteers (20 female [41.7%]; mean [SD] age, 29.8 [8.5] years). The imaging and nonimaging data sets showed significant covariation (r = 0.63, P < .001), which was independent of diagnosis. Among the nonimaging variables examined, age (r = -0.53), IQ (r = 0.36), and body mass index (r = -0.25) were associated with multiple imaging phenotypes; cannabis use (r = 0.23) and other substance use (r = 0.33) were associated with subcortical volumes, and alcohol use was associated with white matter integrity (r = -0.15). Within the multivariate models, positive symptoms retained associations with the global neuroimaging (r = -0.13), the cortical thickness (r = -0.22), and the task related activation variates (r = -0.18); negative symptoms were mostly associated with measures of subcortical volume (r = 0.23), and depression/anxiety was associated with measures of white matter integrity (r = 0.12). Conclusions and Relevance: Multivariate analyses provide a more accurate characterization of the association between brain alterations and psychosis because they enable the modeling of other key factors that influence neuroimaging phenotypes. PMID- 29516094 TI - Association of Schizophrenia With the Risk of Breast Cancer Incidence: A Meta analysis. AB - Importance: Patients with schizophrenia are considered to have many risk factors for the development of cancer. However, the incidence of breast cancer in women with schizophrenia compared with the general population remains uncertain. Objective: To perform an updated meta-analysis to evaluate the association between schizophrenia and the risk of breast cancer. Data Sources: A systematic search of the PubMed and EMBASE databases was conducted using the search terms schizophrenia, schizophrenic, psychosis, combined with breast and cancer, tumor, neoplasm, or carcinoma. The final literature search was performed on August 15, 2017. Study Selection: Cohort studies reporting the standardized incidence ratio (SIR) for the risk of breast cancer in women with schizophrenia compared with the general population. Data Extraction and Synthesis: The meta-analysis adhered to Meta-analysis of Observational Studies in Epidemiology and the Cochrane Handbook for Systematic Reviews of Interventions. Data extraction was performed independently. A random-effects model was used to pool the results, and a recently proposed prediction interval was calculated to describe the heterogeneity. Main Outcomes and Measures: The SIR for the risk of breast cancer in women with schizophrenia compared with the general population or those without schizophrenia. Results: Twelve cohorts including 125 760 women were included in this meta-analysis. The results of the meta-analysis showed that schizophrenia was associated with a significantly increased risk of breast cancer incidence in women (SIR, 1.31; 95% CI, 1.14-1.50; P < .001), with significant heterogeneity (P < .001; I2 = 89%). Substantial between-study variance was also suggested by the wide prediction interval (0.81-2.10), which indicated that it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population. The subgroup analysis results showed that the association was not significantly affected by whether breast cancer cases were excluded at baseline or the sample size of the included studies. Conclusions and Relevance: The incidence of breast cancer in women with schizophrenia is higher than that of the general female population. However, significant heterogeneity exists among the included studies. Women with schizophrenia deserve intensive prevention and treatment of breast cancer. PMID- 29516095 TI - A Model for Sustained Collaboration to Address the Unmet Global Burden of Bladder Exstrophy-Epispadias Complex and Penopubic Epispadias: The International Bladder Exstrophy Consortium. AB - Importance: International collaboration to alleviate the massive burden of surgical disease is recognized by World Health Organization as an urgent need, yet the surgical mission model to treat reconstructive surgical challenges is often constrained in ensuring adequate patient follow-up, optimal outcomes, and sustainability. Objective: To determine whether a collaboration predicated on long-term commitment by surgeons returning to the same institution annually combined with an experienced host surgical team and infrastructure to ensure sustained patient follow-up could provide surgical care with acceptable outcomes to treat bladder exstrophy-epispadias complex (BE) and penopubic epispadias (PE). Design, Setting, and Participants: In this prospective, observational study, long term collaboration was created and based at a public hospital in Ahmedabad, India, between January 2009 and January 2015. The entire postoperative cohort was recalled in January 2016 for comprehensive examination, measurement of continence outcomes, and assessment of surgical complications. Seventy-six percent of patients (n = 57) who underwent complete primary repair of exstrophy during the study interval returned for annual follow-up in 2016 and formed the study cohort: 23 patients with primary BE, 19 patients with redo BE, and 11 patients with PE repair. Main Outcomes and Measures: Demographics, operative techniques, and perioperative complications were recorded. A postoperative protocol outlining procedures to ensure monitoring of study participants was followed including removal of ureteral stents, urethral catheter, external fixators, imaging, and patient discharge. Results: Of the 57 patients, 4 were excluded because they underwent ureterosigmoidostomy. Median age at time of surgery was 3 years (primary BE), 7 years (redo BE), and 10 years (PE), with median follow-up of 3 years, 5 years and 3 years, respectively; boys made up more than 70% of each cohort (n = 17 for primary BE, n = 15 for redo BE, and n = 9 for PE). All BE and 3 PE repairs (27%) were completed with concurrent anterior pubic osteotomies. Seventeen of 53 patients (32%) experienced complications. Only 1 patient with BE (4%) had a bladder dehiscence and was repaired the following year. Conclusions and Relevance: A unique surgical mission model consisting of an international collaborative focused on treating the complex diagnoses of BE and PE offers outcomes comparable with those in high-income countries, demonstrating a significant patient retention rate and an opportunity to rigorously study outcomes over an accelerated interval owing to the high burden of disease in India. Postoperative care following a systematized algorithm and rigorous follow up is mandatory to ensure safety and optimal outcomes. PMID- 29516097 TI - Correction of a Table Column Heading. PMID- 29516096 TI - Development and Validation of a Prediction Model for Pain and Functional Outcomes After Lumbar Spine Surgery. AB - Importance: Functional impairment and pain are common indications for the initiation of lumbar spine surgery, but information about expected improvement in these patient-reported outcome (PRO) domains is not readily available to most patients and clinicians considering this type of surgery. Objective: To assess population-level PRO response after lumbar spine surgery, and develop/validate a prediction tool for PRO improvement. Design, Setting, and Participants: This statewide multicenter cohort was based at 15 Washington state hospitals representing approximately 75% of the state's spine fusion procedures. The Spine Surgical Care and Outcomes Assessment Program and the survey center at the Comparative Effectiveness Translational Network prospectively collected clinical and PRO data from adult candidates for lumbar surgery, preoperatively and postoperatively, between 2012 and 2016. Prediction models were derived for PRO improvement 1 year after lumbar fusion surgeries on a random sample of 85% of the data and were validated in the remaining 15%. Surgical candidates from 2012 through 2015 were included; follow-up surveying continued until December 31, 2016, and data analysis was completed from July 2016 to April 2017. Main Outcomes and Measures: Functional improvement, defined as a reduction in Oswestry Disability Index score of 15 points or more; and back pain and leg pain improvement, defined a reduction in Numeric Rating Scale score of 2 points or more. Results: A total of 1965 adult lumbar surgical candidates (mean [SD] age, 61.3 [12.5] years; 944 [59.6%] female) completed baseline surveys before surgery and at least 1 postoperative follow-up survey within 3 years. Of these, 1583 (80.6%) underwent elective lumbar fusion procedures; 1223 (77.3%) had stenosis, and 1033 (65.3%) had spondylolisthesis. Twelve-month follow-up participation rates for each outcome were between 66% and 70%. Improvements were reported in function, back pain, and leg pain at 12 months by 306 of 528 surgical patients (58.0%), 616 of 899 patients (68.5%), and 355 of 464 patients (76.5%), respectively, whose baseline scores indicated moderate to severe symptoms. Among nonoperative patients, 35 (43.8%), 47 (53.4%), and 53 (63.9%) reported improvements in function, back pain, and leg pain, respectively. Demographic and clinical characteristics included in the final prediction models were age, sex, race, insurance status, American Society of Anesthesiologists score, smoking status, diagnoses, prior surgery, prescription opioid use, asthma, and baseline PRO scores. The models had good predictive performance in the validation cohort (concordance statistic, 0.66-0.79) and were incorporated into a patient-facing, web-based interactive tool (https://becertain.shinyapps.io/lumbar_fusion_calculator). Conclusions and Relevance: The PRO response prediction tool, informed by population-level data, explained most of the variability in pain reduction and functional improvement after surgery. Giving patients accurate information about their likelihood of outcomes may be a helpful component in surgery decision making. PMID- 29516099 TI - Reevaluating Mohs Surgery Appropriate Use Criteria for Primary Superficial Basal Cell Carcinoma. PMID- 29516098 TI - Association of Fibroblast Growth Factor 23 With Risk of Incident Coronary Heart Disease in Community-Living Adults. AB - Importance: Higher circulating fibroblast growth factor 23 (FGF23) concentrations are associated with cardiovascular disease events linked to heart failure, but associations of FGF23 with coronary heart disease (CHD) have been less consistent. Objective: To determine the association of plasma FGF23 concentrations with incident CHD and whether this association differs by race, sex, or chronic kidney disease status. Design, Setting, and Participants: We examined the association of FGF23 concentrations with incident CHD risk within the Reasons for Geographic and Racial Differences in Stroke study, a prospective cohort of black and white adults 45 years and older enrolled between January 2003 and October 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured FGF23 concentrations in 829 participants who developed incident CHD and in 812 participants randomly selected from the Reasons for Geographic and Racial Differences in Stroke study cohort (cohort random sample). To account for the stratified sampling design, the cohort random sample was weighted back to the original cohort overall (n = 22 127). Cox proportional hazards models were used to examine the association of FGF23 concentration with incident CHD, adjusting for CHD risk factors and kidney function. In prespecified analyses, we examined whether race, sex, or chronic kidney disease modified the association of FGF23 concentration with incident CHD. Exposures: Plasma C terminal FGF23 concentrations. Main Outcomes and Measures: Investigator adjudicated incident CHD events. Results: Of the 22 127 participants in the weighted cohort random sample, 13 059 (58.9%) were female and 9435 (42.6%) were black, and the mean age was 64.3 (95% CI, 63.7-64.9) years. Greater age, lower estimated glomerular filtration rate, higher urine albumin to creatinine ratio, and female sex were associated with higher FGF23 concentration at baseline. In multivariable models adjusted for established CHD risk factors and kidney function, higher FGF23 concentrations were associated with greater risk of CHD (hazard ratio [HR] comparing fourth with first quartile, 2.15; 95% CI, 1.35 3.42). The magnitude and strength of these associations differed by sex. However, these differences were no longer observed when adjusting for hormone therapy in women (men: HR comparing fourth with first quartile, 2.40; 95% CI, 1.30-4.42; women: HR comparing fourth with first quartile, 2.34; 95% CI, 1.04-5.27) or when using sex-specific FGF23 quartiles (men: HR comparing fourth with first quartile, 2.65; 95% CI, 1.43-4.90; women: HR comparing fourth with first quartile, 2.26; 95% CI, 1.02-5.03). Conclusions and Relevance: Higher FGF23 concentrations were associated with greater risk of CHD. Heterogeneity in the association by sex may be caused by differences in the distribution of plasma FGF23 concentrations or the use of hormone therapy in men vs women. PMID- 29516100 TI - Mass Customization for Population Health. PMID- 29516101 TI - Mass Customization, Ubiquitous Information, and Improvements to Health Outcomes in the United States. PMID- 29516102 TI - Measurements of 24-Hour Urinary Sodium and Potassium Excretion: Importance and Implications. PMID- 29516104 TI - Estimated 24-Hour Urinary Sodium and Potassium Excretion in US Adults. AB - Importance: In 2010, the Institute of Medicine (now the National Academy of Medicine) recommended collecting 24-hour urine to estimate US sodium intake because previous studies indicated 90% of sodium consumed was excreted in urine. Objective: To estimate mean population sodium intake and describe urinary potassium excretion among US adults. Design, Setting, and Participants: In a nationally representative cross-sectional survey of the US noninstitutionalized population, 827 of 1103 (75%) randomly selected, nonpregnant participants aged 20 to 69 years in the examination component of the National Health and Nutrition Examination Survey (NHANES) collected at least one 24-hour urine specimen in 2014. The overall survey response rate for the 24-hour urine collection was approximately 50% (75% [24-hour urine component response rate] * 66% [examination component response rate]). Exposures: 24-hour collection of urine. Main Outcomes and Measures: Mean 24-hour urinary sodium and potassium excretion. Weighted national estimates of demographic and health characteristics and mean electrolyte excretion accounting for the complex survey design, selection probabilities, and nonresponse. Results: The study sample (n = 827) represented a population of whom 48.8% were men; 63.7% were non-Hispanic white, 15.8% Hispanic, 11.9% non-Hispanic black, and 5.6% non-Hispanic Asian; 43.5% had hypertension (according to 2017 hypertension guidelines); and 10.0% reported a diagnosis of diabetes. Overall mean 24-hour urinary sodium excretion was 3608 mg (95% CI, 3414-3803). The overall median was 3320 mg (interquartile range, 2308-4524). In secondary analyses by sex, mean sodium excretion was 4205 mg (95% CI, 3959-4452) in men (n = 421) and 3039 mg (95% CI, 2844-3234) in women (n = 406). By age group, mean sodium excretion was 3699 mg (95% CI, 3449-3949) in adults aged 20 to 44 years (n = 432) and 3507 mg (95% CI, 3266-3748) in adults aged 45 to 69 years (n = 395). Overall mean 24-hour urinary potassium excretion was 2155 mg (95% CI, 2030-2280); by sex, 2399 mg (95% CI, 2253-2545) in men and 1922 mg (95% CI, 1757-2086) in women; and by age, 1986 mg (95% CI, 1878-2094) in adults aged 20 to 44 years and 2343 mg (95% CI, 2151-2534) in adults aged 45 to 69 years. Conclusions and Relevance: In cross-sectional data from a 2014 sample of US adults, estimated mean sodium intake was 3608 mg per day. The findings provide a benchmark for future studies. PMID- 29516106 TI - [Der Orthopade-towards an English-speaking journal?] PMID- 29516105 TI - CT colonography: over two decades from discovery to practice. AB - Since the introduction of CT colonography (CTC) in the mid-1990s, there have been continuous advancements in the examination technique and advanced visualization software for interpretation. This review will cover the origins of CTC as a natural extension of abdominal CT imaging, and discuss the evolution of CTC through the subsequent clinical phases of feasibility, validation, and implementation. PMID- 29516107 TI - [Reversed total shoulder arthroplasty in rotator cuff defect arthropathy]. AB - BACKGROUND: In a progredient rotator cuff tear with tendon retraction, fatty infiltration and atrophy of rotator cuff muscles the humerus cannot be centered and stabilized sufficiently in the glenohumeral joint. This leads to rotator cuff defect arthropathy as an eccentric osteoarthritis with acetabularization and wear of the acromion, as well as of the glenoid. INDICATION: A painful pseudoparalysis of the shoulder indicates the implantation of a reversed total shoulder arthroplasty (rTSA) to reduce pain and restore active motion. The rTSA improves the motoric function of the deltoid muscle by medialization and caudalization of the center of rotation via an optimized lever arm and is also indicated in cranio caudally centered osteoarthritis with static posterior humeral decentration due to a bi-concavely eroded glenoid. THERAPY: Currently, humeral anatomical resection with an inclination of 135 degrees and a humeral retrotorsion of 20-40 degrees , in rTSA in contrast to 155 degrees inclination, has been shown to lead to better glenohumeral motion without loss of stability. Additionally, a reduced glenohumeral offset should be restored by especially bony lateral augmentation of the glenoid. In a pre-operatively positive lag sign for external rotation caused by a rupture of the infraspinatus/teres minor tendon, a lateral latissimus/teres major muscle tendon transfer in rTSA can optimize active external rotation. The tendon of the subscapularis muscle should be re-fixated in the deltopectoral approach for rTSA whenever possible for better anterior stability of the glenohumeral joint. Larger diameters of the glenospheres have been shown to have more stability and better motion. Humeral metaphyseal metal liners with corresponding polyethylene glenospheres can avoid osteolysis of the inferior scapular neck caused by polyethylene debris due to impingement of the humeral liner at the scapular neck. PMID- 29516108 TI - [Shoulder prosthesis replacement options : New implants, treatment algorithms and clinical results]. AB - BACKGROUND: Bony defect situations are a common problem in revision arthroplasty of the shoulder and are the cause of the complexity of the procedure. Aseptic and septic loosening as well as difficult implant removal can result in humeral and/or glenoid bone loss. PLANNING: A careful preoperative imaging is needed to estimate the extent of the bony defect and to enable precise planning of the bone reconstruction and the required implants. However, the size of the defect needs to be re-evaluated intraoperatively after removal of the implant components and any larger defects have to be addressed appropriately. PROSTHESIS DESIGN: While in the glenoid autologous bone grafts and, to a lesser extent, allogenic bone grafts are preferred, metallic augmented implants have recently become available to fill the glenoid bone defect. However, humeral defects are normally addressed with longer revision stems, possibly with allograft augmentation. The soft tissue loss in proximal humeral defects can be addressed with fixation techniques to improve function and reduce the risk of dislocation. Modern modular prosthesis designs allow prosthesis conversion while leaving bony, tightly integrated component parts on the glenoid or shaft. This review describes the preoperative diagnostic steps as well as techniques for revision surgery of the shoulder in the case of bone loss. PMID- 29516109 TI - Properties of Artificial Phospholipid Membranes Containing Lauryl Gallate or Cholesterol. AB - Lauryl gallate (LG) is an antioxidant agent. However, it exhibits poor solubility in water. Its interactions with the membrane result in structure evolution thus affecting the membrane functionality. In this paper the Brewster angle microscope coupled with the Langmuir trough was applied to determine the morphology, phase behaviour, thickness and miscibility of ternary Langmuir monolayers with equal mole fractions of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC); 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC) and an increasing mole fraction of LG. The results were discussed as regards analogous systems where cholesterol (Chol) was the third component. Moreover, the phosphatidylcholine-lauryl gallate (PC-LG) interactions were monitored by the attenuated total reflectance Fourier transform infrared spectroscopy and time-of-flight secondary ion mass spectrometry. Besides lipid composition, the addition of LG was found to be a significant factor to modulate the model membrane properties. The LG molecules adjust themselves to the PC monolayer structure. The hydrophobic fragment is dipped into the membrane interior while the hydroxyl groups of phenolic gallate moiety associate with the polar groups of PC mainly through hydrogen bonding inducing the compacting effect. LG is found to be deeply submerged within DOPC, closer to the double bonds, and its insertion practically does not affect the DPPC/DOPC membrane fluidity. This is crucial for getting more profound insight into the role of LG in stabilizing the non-raft domains, mostly exposed to oxidation in which LG can co-localize and serve its antioxidant function. PMID- 29516110 TI - Catalysis of Ground State cis[Formula: see text] trans Isomerization of Bacteriorhodopsin's Retinal Chromophore by a Hydrogen-Bond Network. AB - For the photocycle of the membrane protein bacteriorhodopsin to proceed efficiently, the thermal 13-cis to all-trans back-isomerization of the retinal chromophore must return the protein to its resting state on a time-scale of milliseconds. Here, we report on quantum mechanical/molecular mechanical energy calculations examining the structural and energetic determinants of the retinal cis-trans isomerization in the protein environment. The results suggest that a hydrogen-bonded network consisting of the retinal Schiff base, active site amino acid residues, and water molecules can stabilize the twisted retinal, thus reducing the intrinsic energy cost of the cis-trans thermal isomerization barrier. PMID- 29516111 TI - Diagnosis of isolated extensor carpi radialis longus (ECRL) tendon avulsion fracture using ultrasound: a paradigm shift. AB - Isolated avulsion fracture of the extensor carpi radialis longus (ECRL) tendon is a rare and poorly understood injury. We present a unique case of a 45-year-old male who fell on his flexed right hand. He presented with a subtle but extremely painful mass on the dorsum of his wrist. Ultrasound (U/S) imaging of the mass revealed an avulsed bone fragment attached to the ECRL tendon, confirming the clinical suspicion of an ECRL avulsion injury. Computed tomography and magnetic resonance imaging are well-documented imaging modalities to detect tendon avulsions. As demonstrated by this case report, U/S is an excellent diagnostic tool for ECRL rupture, a cost-effective alternative that provides real-time dynamic examination of hand injuries. To our knowledge, this is the first case of ECRL avulsion diagnosed by U/S. The purpose of this case report is to educate the reader on detection and diagnosis of ECRL tendon avulsion using U/S, a time efficient and cost-effective imaging modality that is infrequently used for this purpose. PMID- 29516112 TI - Primary hydatid cyst in the posterior thigh, and its percutaneous treatment. AB - Hydatid cyst (echinococcosis) is an endemic parasitic disease, usually encountered in those dealing with agriculture and livestock. The most frequently affected organs are the liver and the lungs. The disease is very rarely encountered in soft tissues. Diagnosing a soft-tissue hydatid cyst may be challenging unless the mass possesses the characteristic features of a hydatid cyst. Soft-tissue hydatid cysts may be treated percutaneously, just like those encountered in the liver. In this case report, we present the radiological findings and modified percutaneous aspiration-injection-reaspiration (PAIR) treatment of a hydatid cyst located in the posterior aspect of the thigh. PMID- 29516113 TI - Treatment of Unruptured, Saccular, Anterior Choroidal Artery Aneurysms with Flow Diversion : A Single Centre Experience. AB - BACKGROUND: The region of the brain supplied by the anterior choroidal artery (AChoA) is exquisitely eloquent. Aneurysms arising at or close to the origin of the vessel are not uncommon and damage or occlusion to the vessel can result in devastating consequences. The optimal treatment strategy is yet to be determined. OBJECTIVE: We sought to determine the efficacy of flow diversion for the treatment of unruptured AChoA aneurysms. METHOD: A retrospective review of our prospectively maintained database was performed to identify all patients with unruptured aneurysms of the AChoA between March 2009 and May 2017. The fundus size, number and type of flow-diverting stent (FD), complications and follow-up data were recorded. RESULTS: We identified 30 patients (60% female), average age 52.8 +/- 10.8 years (range 27-73), with 30 aneurysms. The aneurysms were generally small with a mean fundus diameter of 3.4 mm (range 1-7 mm). Early angiographic follow-up data were available for all patients at which point 15 aneurysms were completely occluded (50%). Delayed angiographic follow-up was available in 24 patients and occlusion was seen in 21 patients (87.5%). Of the patients one developed transient ischemic symptoms after interruption of the antiplatelet medication and another patient had a small embolic infarct with transient symptoms in the periprocedural period. CONCLUSION: Flow diversion can be used to successfully treat aneurysms of the AChoA. The treatment carries a high rate of technical and radiological success with a good safety profile. PMID- 29516115 TI - Advances in Sequencing and Resequencing in Crop Plants. AB - DNA sequencing technologies have changed the face of biological research over the last 20 years. From reference genomes to population level resequencing studies, these technologies have made significant contributions to our understanding of plant biology and evolution. As the technologies have increased in power, the breadth and complexity of the questions that can be asked has increased. Along with this, the challenges of managing unprecedented quantities of sequence data are mounting. This chapter describes a few aspects of the journey so far and looks forward to what may lie ahead. Graphical Abstract. PMID- 29516114 TI - [Acute emergencies in oncology]. AB - The spectrum of dermato-oncological emergencies is multifaceted. They are particularly observed in cases with malignant melanoma due to the large number of patients and prolonged survival rates that are associated with new therapies for advanced disease. Dermato-oncological patients present to the hospital with symptoms like nausea and emesis, unexpected neurological deficits, various gastrointestinal problems, and even acute abdomen, acute breathlessness, or hemoptysis. Furthermore, emergencies can be caused by hematological problems like anemia and leukopenia. In addition to standardized care for medical emergencies, there are many other problems caused by metastases and/or therapeutic side effects that need interdisciplinary skills to optimize procedures and deliberate on surgical interventions, radiotherapy, and medical therapeutic choices with regard to the overall situation of the patient. The article deals with a spectrum of acute organ-specific emergencies, including recommendations for medical treatment and considerations for therapeutic decisions. Recommendations for supportive care in patients who are severely ill are summarized. In addition to stage-adapted pain therapy, supportive measures such as nutritional supplementation, the use of dronabinol in cases of loss of appetite, and antipruritic therapies are outlined. This article provides a succinct summary of the most frequently observed dermato-oncological emergencies with references to the respective detailed literature of associated medical societies and guidelines. PMID- 29516116 TI - TILLING: The Next Generation. AB - Gene space: the final frontier in plant functional genomics. These are the voyages of TILLING, the reverse-genetics strategy that sought to boldly go where no-one had gone before by combining high-density chemical mutagenesis with high throughput mutation discovery. Its 18-year mission has been to explore new technologies such as next generation sequencing and to seek out new strategies like in silico databases of catalogued EMS-induced mutations from entire mutant plant populations. This chapter is a clip show highlighting key milestones in the development of TILLING. Use of different technologies for the discovery of induced mutations, establishment of TILLING in different plant species, what has been learned about the effect of chemical mutagens on the plant genome, development of exome capture sequencing in wheat, and a look to the future of reverse-genetics with targeted genome editing are discussed. Graphical Abstract. PMID- 29516117 TI - Post-discharge rise in BNP and rehospitalization for heart failure. AB - BACKGROUND: The B-type natriuretic peptide (BNP) level on discharge of patients hospitalized with decompensated heart failure (HF) is widely considered as the "baseline" value, and treatment should be targeted to maintain this level. The prognostic value of an increase in BNP level from discharge to the 1-month follow up in predicting rehospitalization has not been previously explored. METHODS: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial data were utilized to determine whether an increase in BNP level from discharge to the 1-month follow-up is associated with a higher risk of rehospitalization. The study endpoints were all-cause rehospitalization up to 6 months following randomization. RESULTS: Among 44 patients (mean age, 56 years, 71% men) who had their BNP levels checked on discharge and at the 1-month follow-up, the average BNP level on discharge of the whole cohort was 467 pg/ml, which increased to 919 pg/ml at 1 month (p = 0.001). The median and interquartile range of the magnitude of rise in BNP level from discharge to 1-month follow-up was higher in rehospitalized compared with non-rehospitalized patients (329 [11, 956] vs. 44 [-90, 316] pg/ml, p = 0.039, in both groups, respectively). Receiver operator characteristic curves showed that the magnitude of the rise in BNP from discharge to the 1-month follow-up had an area under the curve of 0.686 (p = 0.0255) in predicting all-cause rehospitalization. Rehospitalized and non rehospitalized patients had similar degree of clinical congestion and comparable BNP level on hospital discharge. CONCLUSION: The magnitude of the rise in BNP level from discharge to the 1-month follow-up is a useful prognostic factor that predicts rehospitalization in patients with HF. PMID- 29516118 TI - Association of rs5888 SNP in SCARB1 gene with coronary artery disease : Study of a Han Chinese population. AB - BACKGROUND: The scavenger receptor class B type I (SCARB1) gene plays an important role in high-density lipoprotein cholesterol (HDL-C) metabolism and may be involved in the pathogenesis of coronary artery disease (CAD). The rs5888 (C/T) single-nucleotide polymorphism (SNP) in the SCARB1 gene is functional, and we therefore examined the association between rs5888 and CAD. METHODS: The rs5888 genotypes were analyzed in 287 Chinese patients with CAD and 367 controls via the high-resolution melting curve (HRM) method. Allele frequency and genotype distribution were compared. The levels of plasma triglyceride (TG), total cholesterol (TC), HDL-C, and low-density lipoprotein-cholesterol (LDL-C) were also compared between the groups with different genotypes. RESULTS: The proportion of subjects with TT and CT genotypes in the control group was significantly higher than that in the CAD group (50.95% vs. 32.75%, p < 0.001). The frequency of individuals with T alleles in the control group was significantly higher than that in the CAD group (28.75% vs. 17.25%, p < 0.001). In the combined population (CAD and control groups), the HDL-C concentration in individuals with the TT genotype was significantly higher than in those with the CT genotype (1.81 +/- 1.29 vs. 1.42 +/- 0.56, p = 0.026) or in those with the CC genotype (1.81 +/- 1.29 vs. 1.42 +/- 0.72, p = 0.021). CONCLUSION: The results of this study suggest that the rs5888 SNP in the SCARB1 gene is associated with CAD; furthermore, the TT genotype is associated with a higher HDL-C concentration. PMID- 29516119 TI - Non-invasive arterial pressure monitoring revisited. PMID- 29516120 TI - Lung volumes and transpulmonary pressure are decreased with expiratory effort and restored with passive breathing in ARDS: a reapplication of the traditional Campbell diagram. PMID- 29516121 TI - Is there a disconnect between what we do and what we should do? A survey of intensive care physicians and nurses in California. PMID- 29516122 TI - Medial meniscal and chondral pathology at the time of revision anterior cruciate ligament reconstruction results in inferior mid-term patient-reported outcomes. AB - PURPOSE: Anterior cruciate ligament (ACL) injuries are frequently not isolated injuries and damage to the menisci and articular cartilage surfaces is common. The concomitant presence of meniscal and chondral damage has the potential to influence patient outcomes following ACL reconstruction surgery and especially following revision ACL reconstruction where these findings are more common. However, study results regarding the mid-term outcome have been inconsistent. The purpose of this study was to compare mid-term patient-reported outcomes and return to sport in patients with and without meniscal and chondral pathology at the time of revision ACL reconstruction surgery. METHODS: A cohort of 180 patients (131 males, 49 female) with a mean age of 25.3 (SD 7.8) years participated at an average follow-up time of 4.6 (SD 1.3) years after revision ACL reconstruction surgery. All patients completed the IKDC Subjective, Marx Activity, KOOS-Quality of Life (QOL) and Single Numerical Assessment (SANE) scores. In addition, patients were asked to indicate the highest level of sport to which they had returned following their revision surgery. Any further injuries to either knee were also documented. Patients were grouped according to whether or not they had medial or lateral meniscal pathology at the time of revision surgery; and whether or not they had > 50% depth chondral damage (ICRS 3 or 4). All outcomes were compared between these groupings. RESULTS: Patients with medial meniscal pathology had significantly lower Marx, KOOS-QOL and SANE scores than patients without. There were no differences in any outcome score between patients with and without lateral meniscal pathology. Patients with ICRS 3 or 4 chondral pathology had significantly lower scores on all patient-reported outcomes as well as a lower rate of return to the same level of pre-injury sport. CONCLUSION: The presence of more severe chondral damage at the time of revision ACL reconstruction has a negative impact on functional outcomes, activity levels and return to sport rates. In addition, the presence of medial meniscal pathology was associated with significantly lower functional and quality of life scores than patients without pathology. These findings provide important clinically relevant data on the outcomes following revision ACL reconstruction with concomitant chondral and meniscal injury. LEVEL OF EVIDENCE: III. PMID- 29516123 TI - Completion repair exhibits increased healing characteristics compared with in situ repair of partial thickness bursal rotator cuff tears. AB - PURPOSE: Little information is available regarding the healing capacity of in situ and completion repair for the treatment of partial thickness rotator cuff tears. The purpose of the study was to analyze the healing characteristics of both techniques. METHODS: Twenty-four adult Sprague-Dawley rats were operated. Partial thickness bursal side tears were created bilaterally at the supraspinatus tendons. Additional 6 rats were used as the sham group. The right shoulders were repaired in situ, and the left shoulders were repaired using the tear completion technique on the 10th day after detachment surgery. Rats were sacrificed on the 10th and 30th days after repair surgery. Type I collagen, the TNF-alpha concentrations, the number and diameter of fibroblasts, and neovascularization were examined at two different time points. RESULTS: The collagen concentration (ng/mg total protein) was significantly increased in both groups at T1 and decreased in the in situ group, whereas completion repair continued to increase at T2 (P < 0.05). The mean fibroblast diameter in the completion repair group continued to increase at both time points (P < 0.05). Neovascularization was significantly increased with tear completion compared with in situ repair (P < 0.05) at T1. No significant (n.s.) differences regarding the TNF-alpha concentration (pg/mg total protein) were noted for both surgical techniques at T2 (P > 0.05). CONCLUSION: Despite the concerns of detaching the intact tendon, the completion repair technique exhibited increased healing characteristics compared with the in situ technique. The reason for this finding might be the refreshing effect of debridement at the chronic degenerated tendon that could improve the healing response. PMID- 29516124 TI - In-group biases and oculomotor responses: beyond simple approach motivation. AB - An in-group bias describes an individual's bias towards a group that they belong to. Previous studies suggest that in-group bias facilitates approach motor responses, but disrupts avoidance ones. Such motor biases are shown to be more robust when the out-group is threatening. We investigated whether, under controlled visual familiarity and complexity, in-group biases still promote pro saccade and hinder anti-saccades oculomotor responses. Participants first learned to associate an in-group or out-group label with an arbitrary shape. They were then instructed to listen to the group-relevant auditory cue (name of own and a rival university) followed by one of the shapes. Half of the participants were instructed to look towards the visual target if it matched the preceding group relevant auditory cue and to look away from it if it did not match. The other half of the participants received reversed instructions. This design allowed us to orthogonally manipulate the effect of in-group bias and cognitive control demand on oculomotor responses. Both pro- and anti-saccades were faster and more accurate following the in-group auditory cue. Independently, pro-saccades were performed better than anti-saccades, and match judgements were faster and more accurate than non-match judgements. Our findings indicate that under higher cognitive control demands individuals' oculomotor responses improved following the motivationally salient cue (in-group). Our findings have important implications for learning and cognitive control in a social context. As we included rival groups, our results might to some extent reflect the effects of out-group threat. Future studies could extend our findings using non-threatening out-groups instead. PMID- 29516125 TI - Medical speciality, medication or skills: key factors of prehospital joint reduction. A prospective, multicenter cohort study. AB - PURPOSE: Joint dislocations occur frequently in prehospital settings. The medical specialities of emergency physicians are heterogeneous. Decision making and the success rates of reduction attempt can vary greatly. The aim of this prospective multicentre study was to identify the factors most crucial for achieving successful prehospital reduction. METHODS: Study was conducted from 05/2012 05/2015 investigating cases of shoulder, patella and ankle joint dislocations in 16 emergency physician rescue stations. Parameters included: affected joint, type and use of medication, incidence and circumstances of reduction or reduction attempt and medical specialty as well as subjective skill status. RESULTS: In total 118 patients could be included. Mean age was 40.1 +/- 21.3 years. Medical specialties were: n = 61 (51.7%) anaesthesiologists (A), n = 41 (34.5%) surgeons (S), and n = 16 (13.5%) internal medicine/others (I/O). Reduction attempt was performed in n = 97 (82.2%). With taking into account the complexity of the reduction (S) had significantly the highest success rates followed by (A) and (I/O). Regarding the applied medication there was neither a significant correlation between pain (p = 0.161) nor success of reduction (p = 0.09). A higher number of attempts does not improve the success rate (p <= 0.001), the pain level was no predictor for success of reduction attempt (p = 0.88). CONCLUSION: A successful reduction is determined by the trias of affected joint, skill level and medical specialty of the physician. In each case this trias should be considered by the physician in charge and he must evaluate limitations and circumstances. PMID- 29516126 TI - A De Novo Novel Nonsense Mutation of GATA4 is Responsible for a Patient with Atrial Septal Defect. PMID- 29516127 TI - Transthoracic Echocardiographic Assessment of Coronary Flow in the Diagnosis of Right Ventricular-Dependent Coronary Circulation in Pulmonary Atresia with Intact Ventricular Septum. AB - Right ventricular-dependent coronary circulation (RVDCC) is associated with pulmonary atresia with intact ventricular septum and is defined by two or more epicardial coronary arteries with atresia or severe stenosis resulting in the dependency of coronary supply by retrograde flow. The hypothesis of this study is that coronary Doppler flow patterns on echocardiography can be used to distinguish patients with RVDCC. Between 2007 and 2016, we reviewed 16 patients with pulmonary atresia or critical pulmonary stenosis. Patients were divided into two groups, those with RVDCC (determined by angiography or pathology evaluation) and those without. Echocardiographic evaluation of the coronary arteries included 2-dimensional measurements and pulse wave Doppler flow pattern in 3 epicardial coronary arteries. Velocity-time integral (VTI) and maximal velocity (Vmax) were measured and compared between the two groups. Three coronary flow patterns were demonstrated: (1) all antegrade flow, (2) antegrade to retrograde VTI flow ratio > 1, and (3) antegrade to retrograde VTI flow ratio <= 1. Of the 7 patients with RVDCC, 6 (86%) had evidence of flow pattern 3 in >= 2 of the 3 coronary arteries in contrast to 0 (0%) of the non-RVDCC patients (p = 0.001). Higher retrograde Vmax was associated with RVDCC (p < 0.001) and coronary artery dilatation with Z score >= + 3 was also associated with RVDCC (p = 0.02). Echocardiographic evaluation of the coronaries can be useful in identifying RVDCC. More retrograde flow in at least two coronary arteries is strongly suggestive of RVDCC. Dilatation of the coronary arteries is also supportive evidence. PMID- 29516128 TI - Is increased peripheral ligamentous laxity in term pregnant women associated with obstetric anal sphincter injury? AB - INTRODUCTION AND HYPOTHESIS: Increased ligamentous laxity is associated with pelvic floor distension in pregnant women. This considered, it may also be related to the risk of obstetric anal sphincter injury (OASI). Our objective was to assess the association among increased ligamentous laxity, perineal tear severity, and OASI occurrence. METHODS: This is a prospective study. We assessed ligamentous laxity between the 36th week of pregnancy and the onset of labor, by measuring the passive extension of the nondominant index finger for a 0.26 N.m torque applied to the second metacarpophalangeal joint (MCP laxity). We collected perineal tear occurrence and classification (Royal College of Obstetricians and Gynecologists). We investigated the MCP laxity distribution according to the stage of perineal tears, and then we looked for a predictive level of MCP laxity for OASI. RESULTS: A total of 272 of the 300 pregnant women included had a vaginal delivery and were considered for the analysis. Mean age was 29 years, mean body mass index was 24.5 kg/m2 and 39.2% of women were nulliparous. We reported 12 cases of OASI. MCP laxity significantly increased with the stage of perineal tears from 58 degrees in stage 0 to 69 degrees and 66 degrees for stages 3a and 3b respectively. An MCP laxity higher than 64 degrees was associated with OASI with sensitivity of 75%, specificity of 56%, and an area under the curve of 0.65. CONCLUSION: Increased ligamentous laxity seems associated with OASI occurrence, which is the opposite of the initial hypothesis. This suggests that the stiffest tissues might be at a lower risk of injury. PMID- 29516129 TI - Prevalence of Chronic Hypoparathyroidism in a Mediterranean Region as Estimated by the Analysis of Anonymous Healthcare Database. AB - Epidemiological data on prevalence and incidence of chronic hypoparathyroidism are still scarce. This study aimed to establish prevalence of chronic hypoparathyroidism and incidence of surgical hypoparathyroidism using the analysis of electronic anonymous public health care database. Data referred to a 5-year period (2009-2013, Region of Tuscany, Italy, as a sample representative of the whole Mediterranean/European population, estimated mean population: 3,750,000 inhabitants) were retrieved by the analysis of pharmaceutical distribution dataset, containing data related to drugs reimbursed by public health system, hospital discharge and procedures codes, and ICD9 exemption codes for chronic diseases. The application of a specific algorithm was applied to indirectly identify people with chronic hypoparathyroidism as assuming chronic therapy with active vitamin D metabolites (AVDM). The number of people taking AVDM for a period equal to or longer than 6 months till the end of the study period, with ICD9 exemption code for hypoparathyroidism, and with a disease-related discharge code were identified. Within this restricted group, patients with chronic kidney disease and osteoporosis were excluded. The indirect estimate of chronic hypoparathyroidism in a European Mediterranean subpopulation by means of the analysis of chronic therapy with AVDM was 27/100,000 inhabitants (female:male ratio = 2.2:1), with a mean age of 63.5 +/- 16.7 years. The risk of developing hypoparathyroidism after neck surgery was 1.5%. While the epidemiological approaches based on disease code and hospital discharge code greatly underestimates the prevalence of hypoparathyroidism, the indirect estimate of this disease through the analysis of prescriptions of AVDM in a European region is in line with the results of studies performed in other regions of the world. PMID- 29516130 TI - Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies. AB - PURPOSE: Radioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation. METHODS: This was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records. RESULTS: Most radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1-45.9) versus 30.9 months (19.6-46.8); p = 0.243); stage B: 18.4 months (11.2-19.4) versus 22.8 months (10.9-34.2); p = 0.815; and stage C: 8.8 months (7.1-10.8) versus 10.8 months (7.7-12.6); p = 0.976. CONCLUSIONS: Radioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment. PMID- 29516131 TI - 18F-Fluorocholine PET/CT in the assessment of primary hyperparathyroidism compared with 99mTc-MIBI or 99mTc-tetrofosmin SPECT/CT: a prospective dual-centre study in 100 patients. AB - PURPOSE: In this prospective study we compared the accuracy of 18F-fluorocholine PET/CT with that of 99mTc-MIBI or99mTc-tetrofosmin SPECT/CT in the preoperative detection of parathyroid adenoma in patients with primary hyperparathyroidism. We also assessed the value of semiquantitative parameters in differentiating between parathyroid hyperplasia and adenoma. METHODS: Both 18F-fluorocholine PET/CT and 99mTc-MIBI/tetrofosmin SPECT/CT were performed in 100 consecutive patients with biochemical evidence of primary hyperparathyroidism. At least one abnormal focus on either 18F-fluorocholine or 99mTc-MIBI/tetrofosmin corresponding to a parathyroid gland or ectopic parathyroid tissue was considered as a positive finding. In 76 patients with positive findings on at least one imaging modality, surgical exploration was performed within 6 months, and the results were related to histopathological findings and clinical and laboratory findings at 3-6 months as the standard of truth. In 24 patients, no surgery was performed: in 18 patients with positive imaging findings surgery was refused or considered risky, and in 6 patients imaging was negative. Therefore, data from 82 patients (76 undergoing surgery, 6 without surgery) in whom the standard of truth criteria were met, were used in the final analysis. RESULTS: All patients showed biochemical evidence of primary hyperparathyroidism with a mean serum calcium level of 2.78 +/- 0.34 mmol/l and parathormone (PTH) level of 196.5 +/- 236.4 pg/ml. The study results in 76 patients with verified histopathology and 3 patients with negative imaging findings were analysed. Three of six patients with negative imaging showed normalized serum PTH and calcium levels on laboratory follow-up at 3 and 6 months, and the results were considered true negative. In a patient-based analysis, the detection rate with 18F-fluorocholine PET/CT was 93% (76/82), but was only 61% (50/82) with 99mTc-MIBI/tetrofosmin SPECT/CT. In a lesion-based analysis, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy of 18F-fluorocholine PET/CT in the detection of parathyroid adenoma were 93.7%, 96.0%, 90.2%, 97.4% and 95.3%, respectively, and of 99mTc-MIBI/tetrofosmin SPECT/CT were 60.8%, 98.5%, 94.1%, 86.3% and 87.7%, respectively. Although 18F-fluorocholine PET-positive adenomatous lesions showed higher SUVmax values than the hyperplastic glands (6.80 +/- 3.78 vs. 4.53 +/- 0.40) in the semiquantitative analysis, the difference was not significant (p = 0.236). The mean size (measured as the length of the greatest dimension) and weight of adenomas were 15.9 +/- 7.6 mm (median 15 mm, range 1-40 mm) and 1.71 +/- 1.86 g (median 1 g, range: 0.25-9 g), respectively. Among the analysed parameters including serum calcium and PTH and the size and weight of parathyroid adenomas, size was significantly different between patients with negative 99mTc-MIBI/tetrofosmin SPECT/CT and those with positive 99mTc-MIBI/tetrofosmin SPECT/CT (mean size 13.4 +/- 7.6 mm vs. 16.9 +/- 7.4 mm, respectively; p = 0.042). CONCLUSION: In this prospective study, 18F fluorocholine PET/CT showed promise as a functional imaging modality, being clearly superior to 99mTc-MIBI/tetrofosmin SPECT/CT, especially in the detection and localization of small parathyroid adenomas in patients with primary hyperparathyroidism. SUVmax was higher in parathyroid adenomas than in hyperplasia. However, further evaluation of this modality is needed. PMID- 29516133 TI - Combined untargeted and targeted fingerprinting by comprehensive two-dimensional gas chromatography: revealing fructose-induced changes in mice urinary metabolic signatures. AB - This study exploits the information potential of comprehensive two-dimensional gas chromatography configured with a parallel dual secondary column-dual detection by mass spectrometry and flame ionization (GC*2GC-MS/FID) to study changes in urinary metabolic signatures of mice subjected to high-fructose diets. Samples are taken from mice fed with normal or fructose-enriched diets provided either in aqueous solution or in solid form and analyzed at three stages of the dietary intervention (1, 6, and 12 weeks). Automated Untargeted and Targeted fingerprinting for 2D data elaboration is adopted for the most inclusive data mining of GC*GC patterns. The UT fingerprinting strategy performs a fully automated peak-region features fingerprinting and combines results from pre targeted compounds and unknowns across the sample-set. The most informative metabolites, with statistically relevant differences between sample groups, are obtained by unsupervised multivariate analysis (MVA) and cross-validated by multi factor analysis (MFA) with external standard quantitation by GC-MS. Results indicate coherent clustering of mice urine signatures according to dietary manipulation. Notably, the metabolite fingerprints of mice fed with liquid fructose exhibited greater derangement in fructose, glucose, citric, pyruvic, malic, malonic, gluconic, cis-aconitic, succinic and 2-keto glutaric acids, glycine acyl derivatives (N-carboxy glycine, N-butyrylglycine, N isovaleroylglycine, N-phenylacetylglycine), and hippuric acid. Untargeted fingerprinting indicates some analytes which were not a priori pre-targeted which provide additional insights: N-acetyl glucosamine, N-acetyl glutamine, malonyl glycine, methyl malonyl glycine, and glutaric acid. Visual features fingerprinting is used to track individual variations during experiments, thereby extending the panorama of possible data elaboration tools. Graphical abstract ?. PMID- 29516132 TI - Cell-specific production, secretion, and function of apolipoprotein E. AB - Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is secreted from many cells throughout the body. ApoE is best known for its role in lipoprotein metabolism. Recent studies underline the association of circulating lipoprotein-associated apoE levels and the development for cardiovascular disease (CVD). Besides its well-established role in pathology of CVD, it is also implicated in neurodegenerative diseases and recent new data on adipose-produced apoE point to a novel metabolic role for apoE in obesity. The regulation of apoE production and secretion is remarkably cell and tissue specific. Here, we summarize recent insights into the differential regulation apoE production and secretion by hepatocytes, monocytes/macrophages, adipocytes, and the central nervous system and relevant variations in apoE biochemistry and function. PMID- 29516134 TI - Analysis of unauthorized Sudan dyes in food by high-performance thin-layer chromatography. AB - Food authenticity and food safety are of high importance to organizations as well as to the food industry to ensure an accurate labeling of food products. Respective analytical methods should provide a fast screening and a reliable cost efficient quantitation. HPTLC was pointed out as key analytical technique in this field. A new HPTLC method applying caffeine-impregnated silica gel plates was developed for eight most frequently found fat-soluble azo dyes unauthorizedly added to spices, spice mixtures, pastes, sauces, and palm oils. A simple post chromatographic UV irradiation provided an effective sample cleanup, which took 4 min for up to 46 samples in parallel. The method was trimmed to enable 23 simultaneous separations within 20 min for quantitation or 46 separations within 5 min for screening. Linear (4-40 ng/band) or polynomial (10-200 ng/band) calibrations of the eight azo dyes revealed high correlation coefficients and low standard deviations. Limits of detection and quantification were determined to be 2-3 and 6-9 ng/zone, respectively. After an easy sample extraction, recoveries of 70-120% were obtained from chili, paprika, and curcuma powder as well as from chili sauce, curry paste, and palm oil spiked at low (mainly 25-50 mg/kg) and high levels (150-300 mg/kg). For unequivocal identification, the compound in a suspect zone was eluted via a column into the mass spectrometer. This resulted in the hyphenation HPTLC-vis-HPLC-DAD-ESI-MS. Graphical abstract Simplified clean-up by UV irradiation for Sudan dye analysis in food by HPTLC-vis-HPLC-DAD-ESI-MS. PMID- 29516135 TI - Bioinformatics and peptidomics approaches to the discovery and analysis of food derived bioactive peptides. AB - There are emerging advancements in the strategies used for the discovery and development of food-derived bioactive peptides because of their multiple food and health applications. Bioinformatics and peptidomics are two computational and analytical techniques that have the potential to speed up the development of bioactive peptides from bench to market. Structure-activity relationships observed in peptides form the basis for bioinformatics and in silico prediction of bioactive sequences encrypted in food proteins. Peptidomics, on the other hand, relies on "hyphenated" (liquid chromatography-mass spectrometry-based) techniques for the detection, profiling, and quantitation of peptides. Together, bioinformatics and peptidomics approaches provide a low-cost and effective means of predicting, profiling, and screening bioactive protein hydrolysates and peptides from food. This article discuses the basis, strengths, and limitations of bioinformatics and peptidomics approaches currently used for the discovery and analysis of food-derived bioactive peptides. PMID- 29516136 TI - Fluorescent aptasensor for detection of four tetracycline veterinary drugs in milk based on catalytic hairpin assembly reaction and displacement of G quadruplex. AB - Based on a novel signal amplification strategy by catalytic hairpin assembly and displacement of G-quadruplex DNA, an enzyme-free, non-label fluorescent aptasensing approach was established for sensitive detection of four tetracycline veterinary drugs in milk. The network consisted of a pair of partially complementary DNA hairpins (HP1 and HP2). The DNA aptamer of four tetracycline veterinary drugs was located at the sticky end of the HP1. The ring region of HP1 rich in G and C could form a stable G-quadruplex structure, which could emit specific fluorescence signal after binding with the fluorescent dye and N methylmesoporphyrin IX (NMM). When presented in the system, the target analytes would be repeatedly used to trigger a recycling procedure between the hairpins, generating numerous HP1-HP2 duplex complexes and displacing G-quadruplex DNA. Thus, the sensitive detection of target analytes was achieved in a wide linear range (0-1000 MUg/L) with the detection limit of 4.6 MUg/L. Moreover, this proposed method showed high discrimination efficiency towards target analytes against other common mismatched veterinary drugs, and could be successfully applied to the analysis of milk samples. Graphical abstract Schematic of target analyte detection based on catalytic hairpin assembly reaction and displacement of G-quadruplex. PMID- 29516137 TI - Elucidation of non-intentionally added substances migrating from polyester polyurethane lacquers using automated LC-HRMS data processing. AB - An untargeted strategy aiming at identifying non-intentionally added substances (NIAS) migrating from coatings was developed. This innovative approach was applied to two polyester-polyurethane lacquers, for which suppliers previously provided the identity of the monomers involved. Lacquers were extracted with acetonitrile and analyzed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Data, acquired in the full scan mode, were processed using an open-source R-environment (xcms and CAMERA packages) to list the detected features and deconvolute them in groups related to individual compounds. The most intense groups, accounting for more than 85% of cumulated feature intensities, were then investigated. A homemade database, populated with predicted polyester oligomer combinations from a relevant selection of diols and diacids, enabled highlighting the presence of 14 and 17 cyclic predicted polyester oligomers in the two lacquers, including three mutual combinations explained by common known monomers. Combination hypotheses were strengthened by chromatographic considerations and by the investigation of fragmentation patterns. Regarding unpredicted migrating substances, four monomers were hypothesised to explain several polyester or caprolactam oligomer series. Finally, considering both predicted and tentatively elucidated unpredicted oligomers, it was possible to assign hypotheses to features representing up to 82% and 90% of the cumulated intensities in the two lacquers, plus 9% and 3% (respectively) originating from the procedural blank. Graphical abstract Elucidation of non-intentionally added substances. PMID- 29516138 TI - Evaluation of the Persistence and Leaching Behaviour of Thiram Fungicide in Soil, Water and Oil Palm Leaves. AB - The residual levels and persistence of thiram in the soil, water and oil palm seedling leaves were investigated under field conditions. The experimental plots were carried out on a clay loam soil and applied with three treatments namely; manufacturer's recommended dosage (25.6 g a.i. plot-1), manufacturer's double recommended dosage (51.2 g a.i. plot-1), and control (water) were applied. Thiram residues were detected in the soil from day 0 to day 3 in the range of 0.22-27.04 mg kg-1. Low concentrations of thiram were observed in the water and leave samples in the range of 0.27-2.52 mg L-1 and 1.34-12.28 mg kg-1, respectively. Results have shown that thiram has a rapid degradation and has less persistence due to climatic factors. These findings suggest that thiram is safe when applied at manufacturer's recommended dosage on oil palm seedlings due to low residual levels observed in soil and water bodies. PMID- 29516139 TI - Carbonaceous Species of PM2.5 in Megacity Delhi, India During 2012-2016. AB - Organic carbon (OC) and elemental carbon (EC) in PM2.5 were estimated to study the seasonal and inter-annual variability of atmospheric total carbonaceous aerosols (TCA) at an urban site of megacity Delhi, India for 5 years from January, 2012 to December, 2016. The annual average (+/- standard deviation) concentrations of PM2.5, OC, EC and TCA were 128 +/- 81, 16.6 +/- 12.2, 8.4 +/- 5.8 and 34.5 +/- 25.2 ug m-3, respectively. During the study, significant seasonal variations in mass concentrations of PM2.5, OC, EC and TCA were observed with maxima in winter and minima in monsoon seasons. Significant correlations between OC and EC, and OC/EC ratio suggested that vehicular emissions, fossil fuel combustion and biomass burning could be major sources of carbonaceous aerosols of PM2.5 at the sampling site of Delhi, India. PMID- 29516140 TI - Cadmium Immobilization Potential of Rice Straw-Derived Biochar, Zeolite and Rock Phosphate: Extraction Techniques and Adsorption Mechanism. AB - Heavy metal contamination in agricultural soils has become a serious environmental concern due to their generally high mobility and toxic effects on plants and food security. An incubation study was conducted to assess the effectiveness of biochar (BC), zeolite (ZE) and rock phosphate (RP) stabilizers on the immobilization of cadmium (Cd) in contaminated soils. Various extraction techniques were carried out: a sequential extraction procedure, the European Community Bureau of Reference (BCR), the toxicity characteristics leaching procedure (TCLP) and extraction with ammonium nitrate. In addition, Cd adsorption by these materials was observed using Langmuir and Freundlich isotherms. The results showed that with an increase in soil pH the exchangeable fraction of Cd in soil was significantly reduced by 28%-29.4%, 9%-13% and 4%-14% for BC, ZE, and RP, respectively. According to the Langmuir adsorption isotherm, BC-amended soil showed a higher adsorption capacity (Qm) of Cd from 8.38 to 19.85 mg g-1. Overall, BC offered better results when compared to other amendments. PMID- 29516141 TI - 4-Hydroxybenzoic acid-a versatile platform intermediate for value-added compounds. AB - 4-Hydroxybenzoic acid (4-HBA) has recently emerged as a promising intermediate for several value-added bioproducts with potential biotechnological applications in food, cosmetics, pharmacy, fungicides, etc. Over the past years, a variety of biosynthetic techniques have been developed for producing the 4-HBA and 4-HBA based products. At this juncture, synthetic biology and metabolic engineering approaches enabled the biosynthesis of 4-HBA to address the increasing demand for high-value bioproducts. This review summarizes the biosynthesis of a variety of industrially pertinent compounds such as resveratrol, muconic acid, gastrodin, xiamenmycin, and vanillyl alcohol using 4-HBA as the starting feedstock. Moreover, potential research activities with a close-up look at the future perspectives to produce new compounds using 4-HBA have also been discussed. PMID- 29516142 TI - Enhanced productivity of gamma-amino butyric acid by cascade modifications of a whole-cell biocatalyst. AB - We previously developed a gamma-amino butyric acid (GABA)-producing strain of Escherichia coli, leading to production of 614.15 g/L GABA at 45 degrees C from L-glutamic acid (L-Glu) with a productivity of 40.94 g/L/h by three successive whole-cell conversion cycles. However, the increase in pH caused by the accumulation of GABA resulted in inactivation of the biocatalyst and consequently led to relatively lower productivity. In this study, by overcoming the major problem associated with the increase in pH during the production process, a more efficient biocatalyst was obtained through cascade modifications of the previously reported E. coli strain. First, we introduced four amino acid mutations to the codon-optimized GadB protein from Lactococcus lactis to shift its decarboxylation activity toward a neutral pH, resulting in 306.65 g/L of GABA with 99.14 mol% conversion yield and 69.8% increase in GABA productivity. Second, we promoted transportation of L-Glu and GABA by removing the genomic region encoding the C-plug of GadC (a glutamate/GABA antiporter) to allow its transport path to remain open at a neutral pH, which improved the GABA productivity by 16.8% with 99.3 mol% conversion of 3 M L-Glu. Third, we enhanced the expression of soluble GadB by introducing the GroESL molecular chaperones, leading to 20.2% improvement in GABA productivity, with 307.40 g/L of GABA and a 61.48 g/L/h productivity obtained in one cycle. Finally, we inhibited the degradation of GABA by inactivation of gadA and gadB from the E. coli genome, which resulted in almost no GABA degradation after 40 h. After the cascade system modifications, the engineered recombinant E. coli strain achieved a 44.04 g/L/h productivity with a 99.6 mol% conversion of 3 M L-Glu in a 5-L bioreactor, about twofold increase in productivity compared to the starting strain. This increase represents the highest GABA productivity by whole-cell bioconversion using L-Glu as a substrate in one cycle observed to date, even better than the productivity obtained from the three successive conversion cycles. PMID- 29516143 TI - Microbial degradation of sulfamethoxazole in the environment. AB - Sulfamethoxazole (SMX) is one of the most widely applied sulfonamide antibiotics in the world, which is becoming a ubiquitous pollutant in the environment. In this mini-review, the microbial degradation of SMX was briefly reviewed. The performance of the conventional wastewater treatment plants in removing SMX was provided. The microorganisms capable of degrading SMX, including mixed cultures and pure cultures, were presented. The effects of environmental conditions such as temperature, pH, initial SMX concentration, and additional carbon sources on the biodegradation of SMX were discussed. The metabolic pathways of SMX degradation were summarized. Finally, the suggestions were made for further studies. PMID- 29516144 TI - Intestinal bacterial signatures of white feces syndrome in shrimp. AB - Increasing evidence suggests that the intestinal microbiota is closely correlated with the host's health status. Thus, a serious disturbance that disrupts the stability of the intestinal microecosystem could cause host disease. Shrimps are one of the most important products among fishery trading commodities. However, digestive system diseases, such as white feces syndrome (WFS), frequently occur in shrimp culture and have led to enormous economic losses across the world. The WFS occurrences are unclear. Here, we compared intestinal bacterial communities of WFS shrimp and healthy shrimp. Intestinal bacterial communities of WFS shrimp exhibited less diversity but were more heterogeneous than those of healthy shrimp. The intestinal bacterial communities were significantly different between WFS shrimp and healthy shrimp; compared with healthy shrimp, in WFS shrimp, Candidatus Bacilloplasma and Phascolarctobacterium were overrepresented, whereas Paracoccus and Lactococcus were underrepresented. PICRUSt functional predictions indicated that the relative abundances of genes involved in energy metabolism and genetic information processing were significantly greater in WFS shrimp. Collectively, we found that the composition and predicted functions of the intestinal bacterial community were markedly shifted by WFS. Significant increases in Candidatus Bacilloplasma and Phascolarctobacterium and decreases in Paracoccus and Lactococcus may contribute to WFS in shrimp. PMID- 29516145 TI - The second conserved motif in bacterial laccase regulates catalysis and robustness. AB - Laccase (EC1.10.3.2), an oxidase that binds multiple copper ions, is heterogeneous in different species, implying diversity in its function. Nevertheless, the four copper-binding motifs are conserved in most laccases, especially bacterial forms. In order to exploit laccase more widely and more effectively in industrial processes, we investigated the regulatory effects, if any, of the second conserved copper-binding motif in the bacterial laccases CAR2 and CAHH1. The data suggested that three critical amino acid residues His155, His157, and Thr/Ala158 in this motif strongly regulated laccase's catalysis, substrate range, and robustness. Indeed, these residues were essential for laccase's catalytic activity. The data also suggested that laccase's catalytic efficiency and activity are not completely consistent with its stability, and that the enzyme might have evolved naturally to its favor stability. This study provides important insights into the second conserved copper-binding motif and defines some of the previously undefined amino acid residues in this conserved motif and their significances. PMID- 29516146 TI - New oenological practice to promote non-Saccharomyces species of interest: saturating grape juice with carbon dioxide. AB - Non-Saccharomyces yeast species, naturally found in grape must, may impact wine quality positively or negatively. In this study, a mixture of five non Saccharomyces species (Torulaspora delbrueckii, Metschnikowia spp., Starmerella bacillaris (formerly called Candida zemplinina), Hanseniaspora uvarum, Pichia kluyveri), mimicking the composition of the natural non-Saccharomyces community found in grape must, was used for alcoholic fermentation. The impact of CO2 saturation of the grape juice was studied first on this mixture alone, and then in the presence of Saccharomyces cerevisiae. Two isogenic strains of this species were used: the first with a short and the second a long fermentation lag phase. This study demonstrated that saturating grape juice with CO2 had interesting potential as an oenological technique, inhibiting undesirable species (S. bacillaris and H. uvarum) and stimulating non-Saccharomyces of interest (T. delbrueckii and P. kluyveri). This stimulating effect was particularly marked when CO2 saturation was associated with the presence of S. cerevisiae with long fermentation lag phase. The direct consequence of this association was an enhancement of 3-SH levels in the resulting wine. PMID- 29516147 TI - Four second-sphere residues of Thermus thermophilus SG0.5JP17-16 laccase tune the catalysis by hydrogen-bonding networks. AB - The multicopper oxidases catalyze 1-electron oxidation of four substrate molecules and concomitantly 4-electron reduction of dioxygen to water. The substrate loses the electrons at the type 1 copper (T1 Cu) site of the enzyme, while the dioxygen is reduced to water at the trinuclear copper center. A highly conserved Glu residue, which is at the dioxygen-entering channel, shuttles the proton to break the O-O bond of dioxygen. At the water-leaving channel, an Asp residue was found to be important in the protonation mechanism. In this study, laccase from Thermus thermophilus SG0.5JP17-16 (lacTT) was investigated to address how four second-sphere residues E356, E456, D106, and D423 affect the activity of the enzyme. Kinetic data indicate that catalytic activities of the enzyme are altered by site-directed mutagenesis on four second-sphere residues. The structural model of lacTT was generated by homology modeling. Structural and spectral data indicate that the E356 residue is situated at the substrate-binding site, responsible for the binding of the substrate and the geometry of the T1 Cu site by hydrogen-bonding networks; the E456 residue, located at the dioxygen entering channel, plays a critical role in stabilizing the structure of all active copper centers and shuttling the proton to the trinuclear copper cluster (TNC) for the reductive reaction of dioxygen; the D106 and D423 residues are at the water-leaving channel, and they are important for the essential geometry of the TNC and the release of the water molecules. Altogether, this study contributes to the further understanding of the basic mechanism involving the oxidation of the substrate, electron transfer, and the reduction of dioxygen in lacTT. PMID- 29516148 TI - Integrating molecular and ecological approaches to identify potential polymicrobial pathogens over a shrimp disease progression. AB - It is now recognized that some gut diseases attribute to polymicrobial pathogens infections. Thus, traditional isolation of single pathogen from disease subjects could bias the identification of causal agents. To fill this gap, using Illumina sequencing of the bacterial 16S rRNA gene, we explored the dynamics of gut bacterial communities over a shrimp disease progression. The results showed significant differences in the gut bacterial communities between healthy and diseased shrimp. Potential pathogens were inferred by a local pathogens database, of which two OTUs (affiliated with Vibrio tubiashii and Vibrio harveyi) exhibited significantly higher abundances in diseased shrimp as compared to healthy subjects. The two OTUs cumulatively contributed 64.5% dissimilarity in the gut microbiotas between shrimp health status. Notably, the random Forest model depicted that profiles of the two OTUs contributed 78.5% predicted accuracy of shrimp health status. Removal of the two OTUs from co-occurrence networks led to network fragmentation, suggesting their gatekeeper features. For these evidences, the two OTUs were inferred as candidate pathogens. Three virulence genes (bca, tlpA, and fdeC) that were coded by the two candidate pathogens were inferred by a virulence factor database, which were enriched significantly (P < 0.05 in the three cases, as validated by qPCR) in diseased shrimp as compared to healthy ones. The two candidate pathogens were repressed by Flavobacteriaceae, Garvieae, and Photobacrerium species in healthy shrimp, while these interactions shifted into synergy in disease cohorts. Collectively, our findings offer a frame to identify potential polymicrobial pathogen infections from an ecological perspective. PMID- 29516149 TI - Effect of dilution rate on productivity of continuous bacteriophage production in cellstat. AB - Ability to efficiently propagate high quantities of bacteriophages (phages) is of great importance considering higher phage production needs in the future. Continuous production of phages could represent an interesting option. In our study, we tried to elucidate the effect of dilution rate on productivity of continuous production of phages in cellstat. As a model system, a well-studied phage T4 and Escherichia coli K-12 as a host were used. Experiments where physiology of bacteria was changing with dilution rate of cellstat and where bacterial physiology was kept constant were performed. For both setups there exists an optimal dilution rate when maximal productivity is achieved. Experimentally obtained values of phage concentration and corresponding productivity were compared with mathematical model predictions, and good agreement was obtained for both types of experiments. Analysis of mathematical model coefficients revealed that latent period and burst size to dilution rate coefficient mostly affect optimum dilution rate and productivity. Due to high sensitivity, it is important to evaluate phage growth parameters carefully, to run cellstat under optimal productivity. PMID- 29516151 TI - [Nutrition, microbiome and multiple sclerosis : Current knowledge from basic research and clinical practice]. AB - Epidemiological data indicate a disproportional increase in the incidence of multiple sclerosis (MS) over the last decades, particularly in industrialized countries. Although this increase is also associated with altered diagnostic criteria and improved sensitivity of imaging procedures, current data suggest that particularly alterations in our way of life play an important role. In recent years the importance of the gut and intestinal microbiome for some neurological diseases and in particular for MS was recognized. Because nutritional habits have a substantial influence on the composition of the microbiome and our nutrition has changed considerably in the last decades, nutritional components can play an important role in the pathogenesis of MS. In this further education article we summarize the currently available evidence on the role of the gut and on the effects of dietary components on the microbiome in the pathogenesis of MS. PMID- 29516153 TI - [Cardiology 2018 : From basic science to high efficiency medicine]. PMID- 29516152 TI - Carboplatin (every 21 days) and divided-dose paclitaxel (days 1, 11): rationale and tolerance in chemotherapy naive women with high-grade epithelial cancers of Mullerian origin. AB - PURPOSE: We report here on the tolerance of a carboplatin-'divided dose' paclitaxel (given on days 1 and 11) regimen in chemotherapy-naive patients with resected and staged endometrial epithelial neoplasms deemed at high-risk of recurrence or early stage epithelial high-grade serous tubo-ovarian adenocarcinomas after risk-reducing surgery. More recently, we applied this regimen as neoadjuvant chemotherapy for advanced ovarian cancer presentations. METHODS: A retrospective chart review of patients receiving this day 1, 11 paclitaxel regimens in combination with carboplatin at AUC 6 every 3 weeks since 2004 was carried out by the second author with subsequent updates by the first and third authors. Tolerance over the first three cycles was analyzed. RESULTS: A total of 27 women were treated with at least three cycles of this paclitaxel 'divided dose' schedule combined with carboplatin: 6 had endometrial adenocarcinoma, 9 had early stage ovarian cancer, and 12 received it as part of neoadjuvant therapy prior to undergoing cytoreductive surgery. Only 14 of 27 patients required dose reductions to complete the first three cycles of treatment. CONCLUSIONS: A median of three cycles of divided dose paclitaxel (D1, D11) concurrent with carboplatin dosed every 3 weeks was found to be safe and feasible as adjuvant to surgery in early endometrial and ovarian cancers or as neoadjuvant treatment in chemotherapy-naive women with ovarian cancer. PMID- 29516154 TI - The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy. AB - Immunotherapy of non-small cell lung cancer (NSCLC), by immune checkpoint inhibitors, has profoundly improved the clinical management of advanced disease. However, only a fraction of patients respond and no effective predictive factors have been defined. Here, we discuss the prospects for identification of such predictors of response to immunotherapy, by fostering an in-depth analysis of the immune landscape of NSCLC. The emerging picture, from several recent studies, is that the immune contexture of NSCLC lesions is a complex and heterogeneous feature, as documented by analysis for frequency, phenotype and spatial distribution of innate and adaptive immune cells, and by characterization of functional status of inhibitory receptor+ T cells. The complexity of the immune landscape of NSCLC stems from the interaction of several factors, including tumor histology, molecular subtype, main oncogenic drivers, nonsynonymous mutational load, tumor aneuploidy, clonal heterogeneity and tumor evolution, as well as the process of epithelial-mesenchymal transition. All these factors contribute to shape NSCLC immune profiles that have clear prognostic significance. An integrated analysis of the immune and molecular profile of the neoplastic lesions may allow to define the potential predictive role of the immune landscape for response to immunotherapy. PMID- 29516155 TI - Rituximab as a therapeutic option for patients with advanced melanoma. AB - Treatment of metastatic melanoma remains challenging, despite a variety of new and promising immunotherapeutic and targeted approaches to therapy. New treatment options are still needed to improve long-term tumour control. We present a case series of seven patients with metastatic melanoma who were treated individually with the anti-CD20 antibody rituximab between July 2014 and July 2015. Two of the patients were treated in an adjuvant setting. All patients had already received a variety of treatments. During an induction phase, the administration of four cycles of weekly rituximab 375 mg/m2 body surface area was planned. After imaging, patients with stable disease continued therapy with rituximab 375 mg/m2 body surface area every 4 weeks up to a maximum of 24 weeks. Two patients experienced grade 2 infusion reactions during the first infusion. Otherwise, treatment was well tolerated and there were no grade 3 or 4 side effects. Staging after the induction phase showed stable disease in five patients, and two patients had progressive disease. Median progression-free survival was 6.3 months (95% CI 4.97-7.53), median overall survival was 14.7 months (95% CI 4.52-24.94), and one patient was still alive in December 2016. In conclusion, rituximab might be a therapeutic option for metastatic melanoma. However, further studies on rituximab among larger patient cohorts are warranted. Evaluation of therapy in an adjuvant setting or in combination with other systemic treatment might, therefore, be of particular interest. PMID- 29516156 TI - Integrating and analyzing medical and environmental data using ETL and Business Intelligence tools. AB - Processing data that originates from different sources (such as environmental and medical data) can prove to be a difficult task, due to the heterogeneity of variables, storage systems, and file formats that can be used. Moreover, once the amount of data reaches a certain threshold, conventional mining methods (based on spreadsheets or statistical software) become cumbersome or even impossible to apply. Data Extract, Transform, and Load (ETL) solutions provide a framework to normalize and integrate heterogeneous data into a local data store. Additionally, the application of Online Analytical Processing (OLAP), a set of Business Intelligence (BI) methodologies and practices for multidimensional data analysis, can be an invaluable tool for its examination and mining. In this article, we describe a solution based on an ETL + OLAP tandem used for the on-the-fly analysis of tens of millions of individual medical, meteorological, and air quality observations from 16 provinces in Spain provided by 20 different national and regional entities in a diverse array for file types and formats, with the intention of evaluating the effect of several environmental variables on human health in future studies. Our work shows how a sizable amount of data, spread across a wide range of file formats and structures, and originating from a number of different sources belonging to various business domains, can be integrated in a single system that researchers can use for global data analysis and mining. PMID- 29516157 TI - Phenological changes of the most commonly sampled ground beetle (Coleoptera: Carabidae) species in the UK environmental change network. AB - Despite the important roles ground beetles (Coleoptera: Carabidae) play in ecosystems, the highly valued ecosystem services they provide, and ample descriptive documentation of their phenology, the relative impact of various environmental factors on carabid phenology is not well studied. Using the long term pitfall trap capture data from 12 terrestrial Environmental Change Network (ECN) sites from the UK, we examined how changing climate influenced the phenology of common carabids, and the role particular climate components had on phenological parameters. Of the 28 species included in the analyses, 19 showed earlier start of their activity. This advance was particularly pronounced in the spring, supporting the view that early phenophases have a greater tendency to change and these changes are more directly controlled by temperature than later ones. Autumn activity extended only a few cases, suggesting a photoperiod-driven start of hibernation. No association was found between life-history traits and the ability of species to change their phenology. Air temperatures between April and June were the most important factors determining the start of activity of each species, whilst late season precipitation hastened the cessation of activity. The balance between the advantages and disadvantages of changing phenology on various levels is likely to depend on the species and even on local environmental criteria. The substantially changing phenology of Carabidae may influence their function in ecosystems and the ecosystem services they provide. PMID- 29516158 TI - [Update on upper eyelid blepharoplasty]. AB - BACKGROUND: Upper eyelid blepharoplasty is among the most frequent oculoplastic surgical procedures. It is often performed as one of the first esthetic surgical interventions by surgeons of various disciplines. While there is a high probability of happy and satisfied patients postoperatively, there are important potential surgical complications that should be prevented. This requires a careful preoperative, perioperative and postoperative approach. OBJECTIVE: This synopsis presents the basic considerations concerning upper eyelid blepharoplasty to serve as practical surgical guidelines. MATERIAL AND METHODS: This is a compendium of important preoperative, perioperative and postoperative contemplations derived from the medical literature, expert opinions and the authors' personal experiences. RESULTS: Careful examination and documentation of eyelid and periorbital findings are required in order to identify additional pathologies to dermatochalasis and plan the surgical approach accordingly. There is a trend in the literature and in expert opinions away from large tissue resection and towards volume preserving and volume reconstructing surgical techniques. Correct placement of the skin fold as well as maintaining lid symmetry are crucial points in order to achieve a natural appearance and patient satisfaction. CONCLUSION: Careful and realistic patient information, state of the art surgery including cautious tissue resection and correct symmetrical formation of the skin fold as well as postoperative assistance and availability increase the likelihood of satisfied patients after blepharoplasty. PMID- 29516159 TI - [Retinopathy of prematurity : Current developments in therapy and epidemiology]. PMID- 29516160 TI - [Capsule rupture and vitrectomy during phacoemulsification]. AB - BACKGROUND: Rupture of the posterior capsule can occur as one of the complications during phacoemulsification. OBJECTIVE: The aim of this study was to determine whether the risk of capsule rupture depends on the surgeon's concentration or experience, time of day and season, the side to be operated on and anatomy of the eye as well as the frequency with which it can be expected. MATERIAL AND METHODS: The patient collective was derived from patients who underwent cataract surgery by phacoemulsification between 2004 and 2014. All surgeries were performed by the same surgeon and constituted no primarily combined operations. Thereby, it was determined how many capsule ruptures occurred, with and without vitrectomy. RESULTS: There were so significant differences between the left or right eye, weekday or month. During the various surgical steps of cataract surgery, the occurrence of capsule rupture was only significantly more frequent at the time of capsule polishing. CONCLUSION: Compared to the results of other studies, the risk of complications was lower in the operation collective investigated in this study. PMID- 29516161 TI - Diagnostic characteristics of anterior cutaneous nerve entrapment syndrome in childhood. AB - : Some children suffering from chronic abdominal pain may have an abdominal wall entity such as anterior cutaneous nerve entrapment syndrome. This syndrome is largely suspected on a combination of findings at history and physical examination. The aim is to obtain clues in history and physical examinations in a selected population of children with anterior cutaneous nerve entrapment syndrome. We analyzed all children with abdominal pain visiting our hospital between January 2013 and January 2015. A total of 71 cases were identified (median age 15 years, range 8-17, 77% female). Pain was severe (median 8, range 6 9), stabbing/burning (84%), superficial (88%), aggravated by physical activity (91%), and always in one abdominal area (97%). Hypo-/hyperesthesia (87%) or a positive pinch test (89%) was often found at the skin overlying the painful spot. Increased pain was reported by 97% when the abdominal muscles were tensed (Carnett test). A single anterior rectus sheath block is successful in almost all patients (97%). CONCLUSION: A combination of typical findings in history and physical examination allows for diagnosing childhood ACNES. What is Known: * Anterior cutaneous nerve entrapment syndrome (ACNES) is often overlooked in chronic abdominal pain. * Pediatric literature on diagnostic work up for ACNES is poor. What is New: * Two third reported treatment delay due to misdiagnosis as functional abdominal pain. * Medical history and physical examination revealed neuropathic pain characteristic in up to 90% of the cases. PMID- 29516162 TI - Replacement options for the B2 glenoid in osteoarthritis of the shoulder: a biomechanical study. AB - BACKGROUND: Glenoid replacement in cases of severe glenoid retroversion (RV) or eccentric wear is challenging. The aim of this study was to evaluate different treatment methods under standardized conditions to assist surgeons in the decision-making process. METHODS: Three treatment options for severe glenoid RV (15 degrees ) were compared: (1) no RV correction; (2) complete RV correction; (3) no RV correction and implantation of a posterior augmented glenoid (PAG). A highly standardized implantation protocol using artificial glenoid bones (five per group) was chosen, and a physiologic shoulder movement was applied in a biomechanical setting. Micromotions (MM) between glenoid components and bone were quantified using an optical 3D measuring system. RESULTS: In the uncorrected retroversion group, three instances of subluxation of the prosthetic head occurred between 2000 and 4000 cycles. At 2000 cycles, significantly more MM were observed in the uncorrected RV group than in the corrected RV group (p < 0.0001) or to the augmented group (p < 0.0001). At 10|000 cycles, more MM were observed in the posterior augmented group than in the corrected RV group (p < 0.0001). CONCLUSION: If sufficient bone stock is available, retroversion correction should be favored. Posterior augmented glenoids seem to be a suitable treatment option if complete correction of the retroversion is not possible without compromising the glenoid vault. Without correction of the retroversion, high failure rates were observed. PMID- 29516163 TI - Histological activity score on baseline liver biopsy can predict non-response to steroids in patients with severe alcoholic hepatitis. AB - Baseline clinical and biochemical parameters fail to predict non-response to steroids in severe alcoholic hepatitis patients. Liver biopsy features have not been adequately assessed for predicting response to steroid therapy in severe alcoholic hepatitis. We aimed to identify histological parameters, which can predict steroid response in severe alcoholic hepatitis (SAH). We analyzed histological data of 107 SAH patients (71 in a derivative and 36 in a validation cohort) who presented within 4 weeks after inset of jaundice and were prospectively treated with steroids (40 mg/day). Histopathological parameters were semi-quantitatively scored in the pre-therapy biopsies in the derivative cohort, and a histological scoring system of SAH was developed which differentiated between steroid responders (Lille score < 0.45 at day 7) and non responders. Seventeen of the 71 (24%) patients in the derivation cohort and 9 of 36 (25%) in the validation cohort were non-responders to steroids. In the derivation cohort, in comparison to responders, non-responders had higher severity of ballooning degeneration (BD) (mean 3.87 +/- 0.91 versus 2.92 +/- 1.33; p = 0.013) and density of Mallory-Denk bodies (MD) (mean 2.27 +/- 0.79 versus. 1.69 +/- 0.97; p = 0.028) on liver histology. A score derived using BD and MD (range 0-8) had high sensitivity (81%), specificity (64%), and negative predictive value (91%) in identifying patients who did not respond to steroids. The AUROC for a combined MD and BD score of > 5 for predicting steroid non response was 0.731. Baseline histological parameters in SAH, ballooning degeneration, and Mallory-Denk bodies can reliably identify non-response to corticosteroids and help to stratify patients prior to introduction of therapy. PMID- 29516164 TI - Cathepsin K expression in clear cell "sugar" tumor (PEComa) of the lung. AB - Clear cell "sugar" tumor is a rare benign neoplasm arising in the lung, considered as a part of the PEComa family. As PEComas of other sites, this tumor expresses melanocytic markers such as HMB45 and Melan-A. Despite cathepsin K, MITF and CD68 staining are known to be positive in a large number of PEComas and TFE3 rearrangement has been reported in a subset of PEComas, no data is available regarding the expression of these markers and the occurrence of TFE3 and TFEB rearrangement in clear cell "sugar" tumor of the lung. We have investigated the immunolabeling of cathepsin K, MITF, and CD68 in five cases of clear cell "sugar" tumor. Moreover, we have also sought the presence of TFE3 and TFEB rearrangement by fluorescence in situ hybridization (FISH) assay. In all tumors, strong immunoreactivity of cathepsin K and CD68 (PG-M1 and KP1 clone) was demonstrated, whereas none of them labeled for MITF staining and showed TFE3 or TFEB rearrangement. These findings widen the immunohistochemical profile of clear cell "sugar" tumor providing useful new markers for challenging cases. The expression of lysosomal markers, such as cathepsin K and CD68, strengthens the hypothesis that this tumor is part of the PEComa family. PMID- 29516166 TI - Have we forgotten imaging prior to and after kidney transplantation? AB - KEY POINTS: * The number of publications on imaging and kidney transplantation is low. * These publications are poorly cited, as compared with other fields of imaging. * Conversely, there is a clinical need for evidence-based recommendations. * Innovative advances for the use of imaging and kidney transplantation are essential. * An increased focus and adequate research funding are highly anticipated by clinicians. PMID- 29516167 TI - Efficient and low-cost alternative of lipase concentration aiming at the application in the treatment of waste cooking oils. AB - In this study, we evaluated the concentration of lipases from Aspergillus niger using efficient and low-cost methods aiming at application in the treatment of waste cooking oils. The change in ionic strength of the medium by the addition of salt and precipitation with ethanol increased the specific activity from 2.90 to 28.50 U/mg, resulting in a purification factor of 9.82-fold. The use of acetone resulted in a specific activity of 33.63 U/mg, resulting in a purification factor of 11.60-fold. After that, the concentrated lipase was used in the hydrolysis of waste cooking oil and 753.07 and 421.60 umol/mL of free fatty acids were obtained for the enzyme precipitated with ethanol and acetone, respectively. The hydrolysis of waste cooking oil catalyzed by homemade purified lipase in ultrasonic media can be considered a pretreatment of oil by converting a significant amount of triglycerides into free fatty acids. PMID- 29516168 TI - Patterns of bisphosphonate treatment among patients with multiple myeloma treated at oncology clinics across the USA: observations from real-world data. AB - PURPOSE: Current guidelines recommend that intravenous bisphosphonates be initiated in all patients with multiple myeloma for management of bone disease. The objective of this study was to describe real-world bisphosphonate treatment patterns. METHODS: This was a retrospective observational study using oncology electronic health record (EHR) data contained in Amgen's Oncology Services Comprehensive Electronic Records (OSCER) database, generated by Flatiron Health (New York, NY), representing over 1.5 million US oncology patients. Patients were newly diagnosed with multiple myeloma between January 1, 2009 and April 30, 2016. Timing of bisphosphonate administration, frequency, schedule, changes in dosing schedule, and discontinuations were calculated. Bisphosphonate treatment relative to renal function and anti-multiple myeloma therapy regimens were also assessed. RESULTS: A total of 11,112 patients were enrolled in the study with a median follow-up of 687 days. Sixty-three percent received >= 1 bisphosphonate administration, primarily every 4 weeks (67.7%). Mean time from diagnosis to bisphosphonate administration was 106 days (median, 29). Most patients (58.2%) initiated treatment in first year after diagnosis and about half (51.9%) either discontinued or changed dosing. Patients with poorer renal function by estimated glomerular filtration rate (eGFR) stage at baseline were less likely to receive bisphosphonates (eGFR stage 5 vs 1: 24 vs 72%) and more likely to have delayed initiation of bisphosphonate treatment from diagnosis (eGFR stage 5 vs 1: median 70 vs 25 days). CONCLUSIONS: Real-world data from US oncology practices indicate that many patients with multiple myeloma may not receive optimal therapy for bone disease, particularly those with renal impairment. PMID- 29516165 TI - Kinetics, mechanism, and inhibition of monoamine oxidase. AB - Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism, and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modelling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation. However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine, and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration. PMID- 29516169 TI - Caregiver burden and its related factors in advanced Parkinson's disease: data from the PREDICT study. AB - INTRODUCTION: Caring for a person with Parkinson's disease (PD) is associated with an increased risk of psychiatric morbidity and persistent distress. The objective of this study was to describe the burden and the related factors of caregivers of advanced PD (APD) patients either treated with continuous dopaminergic delivery systems or standard therapy. METHODS: This cross-sectional, epidemiologic study conducted in 13 Italian sites enrolled PD patients treated with continuous dopaminergic delivering systems [either levodopa/carbidopa intestinal gel (LCIG) infusion or continuous subcutaneous apomorphine infusion (CSAI)] or continuation of standard of care (SOC) with a caregiver. Patient quality of life (QoL) and caregiver burden were assessed using the Parkinson's Disease Questionnaire (PDQ-8) and Zarit Burden Inventory (ZBI), respectively. RESULTS: 126 patients (mean age 69.3 +/- 8 years) and their caregivers (mean age 57.9 +/- 12.9) were enrolled. Most caregivers were spouses. Fifty-three patients were treated with LCIG, 19 with CSAI, and 54 with SOC. Mean ZBI scores were 29.6 +/- 14.4 for LCIG, 35.8 +/- 20.2 for CSAI, and 31.4 +/- 16.0 for SOC. Caregivers of LCIG, CSAI, and SOC patients showed no burden or mild/moderate burden in 74, 53, and 63% of the cases, respectively. Mean PDQ-8 scores were 11.25 +/- 5.67, 11.26 +/- 5.55, and 14.22 +/- 6.51 in LCIG, CSAI, and SOC patients. Neurologists considered patients "very much or much improved" in 89, 58, and 13% of the LCIG, CSAI, and SOC groups using the Clinical Global Impression-Global Improvement Scale. Predictors significantly associated with caregiver burden were patients and caregivers' judgment of QoL and caregivers' need to change work. CONCLUSIONS: Caregiver burden showed a tendency to be lower when patients are treated with LCIG than with CSAI or SOC. PMID- 29516171 TI - Tomato Ve resistance locus; defense or growth. AB - MAIN CONCLUSION: Verticillium colonization does induce a cascade of defense/stress proteins but the Ve1 gene also promotes enhanced root growth, which appears to allow the plant to outgrow the pathogen and avoid symptoms associated with an exaggerated defense response. In tomato, the Ve1 gene provides resistance to the vascular pathogen, Verticillium dahliae, race 1; ve1 plants are susceptible. However, the physiological basis of the resistance is unknown. While developing alternative lines of mutant Ve1 gene transformants to address this question a striking difference was observed in transformation frequency resulting from the inefficient rooting of plantlets from ve1 callus relative to Ve1 callus. Subsequent experiments with resistant and susceptible near-isolines of the cultivar Craigella, as well as Ve1 transformants, showed that in both artificial medium and soil, root growth was significantly enhanced in the resistant cultivar. Parallel studies of Verticillium colonization indicated a significantly lower overall concentration in the resistant plant characteristic of the resistant phenotype, but an almost equal total fungal biomass in both resistant and susceptible roots. Proteomic analyses of the roots of Verticillium-infected plants revealed elevated levels of defense/stress proteins, which correlated with the fungal concentration rather than resistance. Hormone analyses demonstrated a higher cis-ABA level in the resistant isoline consistent with enhanced root growth. Taken together these studies indicate a similar fungal biomass in the roots of both isolines where the Ve1 gene also promotes root production. In the case of the Craigella/Vd1 pathosystem, this appears to allow the host to resist better by outgrowing the pathogen with less wilt rather than reliance only on partial immunity. PMID- 29516170 TI - Can cardiovascular magnetic resonance prompt early cardiovascular/rheumatic treatment in autoimmune rheumatic diseases? Current practice and future perspectives. AB - Life expectancy in autoimmune rheumatic diseases (ARDs) remains lower compared to the general population, due to various comoborbidities. Cardiovascular disease (CVD) represents the main contributor to premature mortality. Conventional and biologic disease-modifying antirheumatic drugs (DMARDs) have considerably improved long-term outcomes in ARDs not only by suppressing systemic inflammation but also by lowering CVD burden. Regarding atherosclerotic disease prevention, EULAR has recommended tight disease control accompanied by regular assessment of traditional CVD risk factors and lifestyle changes. However, this approach, although rational and evidence-based, does not account for important issues such as myocardial inflammation and the long asymptomatic period that usually proceeds clinical manifestations of CVD disease in ARDs before or after the diagnosis of systemic disease. Cardiovascular magnetic resonance (CMR) can offer reliable, reproducible and operator independent information regarding myocardial inflammation, ischemia and fibrosis. Some studies suggest a role for CMR in the risk stratification of ARDs and demonstrate that oedema/fibrosis visualisation with CMR may have the potential to inform cardiac and rheumatic treatment modification in ARDs with or without abnormal routine cardiac evaluation. In this review, we discuss how CMR findings could influence anti-rheumatic treatment decisions targeting optimal control of both systemic and myocardial inflammation irrespective of clinical manifestations of cardiac disease. CMR can provide a different approach that is very promising for risk stratification and treatment modification; however, further studies are needed before the inclusion of CMR in the routine evaluation and treatment of patients with ARDs. PMID- 29516172 TI - Reliability of Untrained and Experienced Raters on FEES: Rating Overall Residue is a Simple Task. AB - The purpose of this study was to investigate the reliability of residue ratings on Fiberoptic Endoscopic Evaluation of Swallowing (FEES). We also examined rating differences based on experience to determine if years of experience influenced residue ratings. A group of 44 raters watched 81 FEES videos representing a wide range of residue severities for thin liquid, applesauce, and cracker boluses. Raters were untrained on the rating scales and simply rated their overall impression of residue amount on a visual analog scale (VAS) and a five-point ordinal scale in a randomized fashion across two sessions. Intra-class correlation coefficients, kappa coefficients, and ANOVAs were used to analyze agreement and differences in ratings. Residue ratings on both the VAS and ordinal scales had acceptable inter- and intra-rater reliability. Inter-rater agreement was acceptable (ICC > 0.7) for all comparisons. Intra-rater agreement was excellent on the VAS scale (rc = 0.9) and good on the ordinal scale (k = 0.78). There was no significant difference between expert ratings and other raters based on years of experience for cracker ratings (p = 0.2119) and applesauce ratings (p = 0.2899), but there was a significant difference between clinicians on thin liquid ratings (p = 0.0005). Without any specific training, raters demonstrated high reliability when rating the overall amount of residue on FEES. Years of experience with FEES did not influence residue ratings, suggesting that expert ratings of overall residue amount are not unique or specialized. Rating the overall amount of residue on FEES appears to be a simple visual-perceptual task for puree and cracker boluses. PMID- 29516173 TI - Effort-reward imbalance in police work: associations with the cortisol awakening response. AB - PURPOSE: We hypothesized that effort-reward imbalance (ERI) is associated with an atypical cortisol response. ERI has been associated with higher job stress. Stress triggers cortisol secretion via the hypothalamic-pituitary-adrenal (HPA) axis, and significant deviation from a typical cortisol pattern can indicate HPA axis dysfunction. METHODS: 176 police officers participated from the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) Study. ERI was the exposure variable. Outcome variables were saliva-based peak and mean cortisol values, total area under the curve ground (AUCG) and baseline (AUCI); linear regression line fitted to log-transformed cortisol. Regression analyses were used to examine linear trend between ERI and cortisol parameters. Repeated measures analysis examined whether the pattern of cortisol over time differed between low ERI (< median) and high ERI (>= median). RESULTS: Mean age was 46 years (SD = 6.6). After adjustment for potential confounders, there was a significant inverse association between ERI and peak cortisol (beta = - 0.20, p = 0.009), average cortisol (beta = - 0.23, p = 0.003), and total area under the curve (beta = - 0.21, p = 0.009). ERI was not significantly associated with AUCI (beta = - 0.11, p = 0.214); slope of the regression line fitted to the cortisol profile (beta = - 0.009, p = 0.908). Repeated measures analyses showed that the cortisol pattern did not vary significantly between high and low ERI using the median as a cut point (interaction p value = 0.790). CONCLUSIONS: ERI was inversely associated with the magnitude of awakening cortisol over time, indicating HPA axis dysregulation and potential future health outcomes. PMID- 29516175 TI - Evaluation of dural venous sinuses and confluence of sinuses via MRI venography: anatomy, anatomic variations, and the classification of variations. AB - PURPOSE: We aimed to determine the anatomical variations more comprehensively particularly at the level of superior sagittal sinus (SSS), confluence of sinuses (CS), transverse sinuses (TS), straight sinuses (SS) and occipital sinuses (OS) with the help of the images obtained via MRI venography, and to contribute to the classification efforts. METHODS: In our retrospective study, we evaluated 211 patients who admitted to our hospital with various complaints and cerebral MRI venography has been performed. All investigations were performed by using 1.5-T MRIscanner (Achiva, Philips) with a VEN-3D -PCA MR venous angiography technique. Section thickness was 0.8 mm and axial plane was used. Other parameters were as follows: 17/7.1 (TR/TE), flip angle, 10.00, FOV, 220-mm, and matrix 244x140. RESULTS: We divided our cases into 3 types but we increased the number of subgroups. Type I was divided into 4 subgroups (Type IA, IB, IC, ID), Type II into 9 (Type IIA1, IIA2, IIB1, IIB2, IIC, IID1, IID2, IIE1, IIE2) and Type III into 2 (Type IIIA, IIIB). Type I constitutes a 26.06% of whole cases, and Type II 59.71%, Type III 14.21%. In our cases R-TS wasn't revealed in 10 cases (4.73%) whereas in 37 cases (17.53%) it was hypoplastic. L-TSwasn't shown in 26 cases (12.32%) and in 85 cases (49.09%) it was hypoplastic. R-Sig S wasn't revealed in 7 (3,31%) and was hypoplastic in 34 (16.11%) whereas L-Sig S wasn't present in 2 (0.94%) and hypoplastic in 72 (34.12%). Among these cases 14 had bilateral hypoplastic TS (6.63%). In cases with hypoplastic TS or Sig S, as an alternative pathway 30 patients had OS (14.21%). Two of these patients had double OS. CONCLUSION: Our wish is to contribute to the efforts of clarifying and classifying the intracranial venous structures and their anatomical variations. We hope our study enlightens a path in this field for future studies. PMID- 29516174 TI - Symbiotic cornucopia of the monophagous planthopper Ommatidiotus dissimilis (Fallen, 1806) (Hemiptera: Fulgoromorpha: Caliscelidae). AB - In contrast to Cicadomorpha, in which numerous symbiotic bacteria have been identified and characterized, the symbionts of fulgoromorphans are poorly known. Here, we present the results of histological, ultrastructural, and molecular analyses of the symbiotic system of the planthopper Ommatidiotus dissimilis. Amplification, cloning, and sequencing of bacterial 16S RNA genes have revealed that O. dissimilis is host to five types of bacteria. Apart from bacteria Sulcia and Vidania, which are regarded as ancestral symbionts of Fulgoromorpha, three additional types of bacteria belonging to the genera Sodalis, Wolbachia, and Rickettsia have been detected. Histological and ultrastructural investigations have shown that bacteria Sulcia, Vidania, and Sodalis house separate bacteriocytes, whereas bacteria Wolbachia and Rickettsia are dispersed within various insect tissue. Additionally, bacteria belonging to the genus Vidania occupy the bacteriome localized in the lumen of the hindgut. Both molecular and microscopic analyses have revealed that all the symbionts are transovarially transmitted between generations. PMID- 29516176 TI - Removal of Polyacrylamide Gel (Aquamid(r)) from the Lip as a Solution for Late Onset Complications: Our 8-Year Experience. AB - BACKGROUND: The polyacrylamide hydrogel Aquamid(r) has been used as a permanent filler to enhance facial soft tissue volume and correct wrinkles since 2001. Various long-term studies have proved the safety of the product. Nonetheless, if complications such as migration occur, they can be difficult to treat. METHODS: Eleven patients suffering from late-onset complications after taking Aquamid(r) injections in the lips underwent product removal and subsequent labial reconstruction between 2009 and 2017. The reconstruction was performed using a modified bikini reduction technique combined, in eight cases, with immediate autologous fat grafting. RESULTS: In all the patients, general fibrosis and a diffused distribution of the product within all three layers of the lips resulted in the need for labial reconstruction. Migration, as far as in the mucosa and perioral skin, accounted for macroscopically visible yellowish accumulations. In ten out of eleven cases, an individually modified bikini reduction technique, with or without any combination of autologous fat grafting, led to an esthetically satisfying result. One patient developed a severe upper lip necrosis. CONCLUSION: Contradictory to several previous studies attesting to the lack of migration after Aquamid(r) application to the lips, capsule formation around the product is impaired, allowing for migration even years after the injection. Product aspiration is not possible in these cases, thus necessitating complex lip reconstruction. Bikini reduction and fat grafting are valuable tools for labial reconstruction. Product residuals within the mucosa have to be accepted. Special care has to be taken while treating smokers. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29516177 TI - Transient Blockade of Endothelin-1 Mitigates Amiodarone-Induced Pulmonary Fibrosis. AB - INTRODUCTION: A number of studies indicate that endothelin-1 (ET-1) may act as an inflammatory cell "gatekeeper," by regulating the influx of neutrophils following pulmonary injury. To further examine the role of ET-1 in modulating lung inflammation, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of amiodarone (AM) or 24 h afterwards. METHODS: In both cases, the extent of lung injury and repair was determined by (1) histopathological changes; (2) neutrophil content in bronchoalveolar lavage fluid (BALF); (3) lung collagen content; (4) tumor necrosis factor receptor 1 expression by BALF macrophages; (5) BALF levels of (a) transforming growth factor beta-1, (b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and (c) platelet-derived growth factor BB; (6) alveolar septal cell apoptosis. RESULTS: For each parameter, pretreatment with HJP272 resulted in a significant reduction compared to AM alone, whereas post-treatment was either ineffective or produced only a marginally significant change, suggesting that the course of lung inflammation and repair is programmed at a very early stage. CONCLUSIONS: This finding may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, they may be useful as an adjunct to therapeutic regimens involving drugs that have fibrogenic potential. PMID- 29516178 TI - The effect of lateral crural overlay surgical technique on elasticity of nasal ala. AB - INTRODUCTION: The nasal tip refinement is the most difficult stages of rhinoplasty surgery; whereas, the most important part in terms of beauty and performance is the projection refinement. Lateral crural overlay (LCO) is a common technique in rhinoplasty used to reduce nasal tip projection and increase nasal tip rotation. Given the important role of lower lateral cartilage (LLC) in the non-collapse of nasal external valve and air passage, it is necessary to evaluate the changes in nasal elasticity caused by surgery. MATERIALS AND METHOD: The design of this quasi experimental study was self-control (before-after). Tip plasty was performed on twenty-four samples (12 cases of rhinoplasty) using LCO technique. To examine the elasticity, the strain index of each ala was measured by a mechanical device, invented by the author, before and after the operation. RESULTS: Out of 24 samples 12 were female and 12 were male. The mean strain index of nasal ala before and after the surgery was 0.24 +/- 0.046 and 0.19 +/- 0.040 respectively (P < 0.001). The mean strain index of nasal ala before and after surgery for female was 0.27 +/- 0.046 and 0.20 +/- 0.050 respectively (P = 0.004). For male, it was 0.20 +/- 0.018 before and 0.18 +/- 0.020 after the surgery. (P < 0.001). CONCLUSION: Using LCO surgical technique for nasal tip refinement can lead to nasal elasticity increase regardless of gender; although, LLC is cut during implementing this technique. PMID- 29516179 TI - Authors' response to Commentary on "European status on temporal bone training: a questionnaire study". PMID- 29516180 TI - Improvement of Cupriavidus taiwanensis Nodulation and Plant Growth Promoting Abilities by the Expression of an Exogenous ACC Deaminase Gene. AB - Several rhizobial strains possess the ability to modulate leguminous plants ethylene levels by producing the enzyme 1-aminocyclopropane-1-carboxylate (ACC) deaminase. While the effect of ACC deaminase has been studied in several rhizobia belonging to the Alphaproteobacteria class, not much is understood about its impact in the nodulation abilities of rhizobia belonging to the Betaproteobacteria class, which are common symbionts of Mimosa species. In this work, we report the impact of ACC deaminase production by the Betaproteobacterium, Cupriavidus taiwanensis STM894, and its role in the nodulation of Mimosa pudica. C. taiwanensis STM894 was studied following its transformation with the plasmid pRKACC, containing an ACC deaminase gene. The expression of the exogenous ACC deaminase led to increased nodulation and M. pudica growth promotion by C. taiwanensis STM894. These results indicate that ACC deaminase plays an important role in modulating ethylene levels that inhibit the nodulation process induced by both rhizobia belonging to the Alpha and Betaproteobacteria class. PMID- 29516182 TI - Barriers to Drug Distribution into the Perinatal and Postnatal Brain. AB - Drug bioavailability to the developing brain is a major concern in the treatment of neonates and infants as well as pregnant and breast-feeding women. Central adverse drug reactions can have dramatic consequences for brain development, leading to major neurological impairment. Factors setting the cerebral bioavailability of drugs include protein-unbound drug concentration in plasma, local cerebral blood flow, permeability across blood-brain interfaces, binding to neural cells, volume of cerebral fluid compartments, and cerebrospinal fluid secretion rate. Most of these factors change during development, which will affect cerebral drug concentrations. Regarding the impact of blood-brain interfaces, the blood-brain barrier located at the cerebral endothelium and the blood-cerebrospinal fluid barrier located at the choroid plexus epithelium both display a tight phenotype early on in embryos. However, the developmental regulation of some multispecific efflux transporters that also limit the entry of numerous drugs into the brain through barrier cells is expected to favor drug penetration in the neonatal brain. Finally, drug cerebral bioavailability is likely to be affected following perinatal injuries that alter blood-brain interface properties. A thorough investigation of these mechanisms is mandatory for a better risk assessment of drug treatments in pregnant or breast-feeding women, and in neonate and pediatric patients. PMID- 29516185 TI - Effect of grain boundary complexions on the deformation behavior of Ni bicrystal during bending creep. AB - The dependence of creep deformation behavior of nickel bicrystal specimens on grain boundary (GB) complexion was investigated by performing a simulated bending creep test using molecular dynamics methods. Strain burst phenomena were observed during the low temperature [500 K, i.e., <0.3 * melting point of nickel (Tm)] bending creep process. Atomic strain and dislocation analyses showed that the time of occurrence of strain burst depends on how easily GB migration happens in bicrystal specimens. Specimens with kite monolayer segregation GB complexion were found to be stable at low temperature (500 K), whereas specimens with split-kite GB complexion were stable at a comparatively higher temperature (900 K). In case of further elevated creep temperatures, e.g., 1100 K and 1300 K, split-kite GB complexion becomes unstable and leads to early failure of the specimen at those temperatures. Additionally, it was observed that split-kite bilayer segregation and normal kite GB complexions exhibit localized increases in elastic modulus during bending creep process, occurring at temperatures of 1100 K and 1300 K, respectively, due to the formation of interpenetrating icosahedral clusters. Graphical abstract Representative creep curves during bending creep deformation of various grain boundary complexions at 900 K. PMID- 29516184 TI - Cold active pectinase, amylase and protease production by yeast isolates obtained from environmental samples. AB - The present study was performed to screen for psychrophilic yeasts that are able to secrete cold active enzymes. Yeast isolates were obtained from environmental samples from northern Turkey and examined for enzyme production at low temperatures. The isolates which were capable of cold active enzyme production on plates were identified by molecular identification techniques. It has been found that the isolates belonged to three genera of yeasts, i.e., Rhodosporidiobolus, Cystofilobasidium and Yamadazyma. The isolates were then fermented in different media at 15 degrees C and the pectinase, amylase and protease activities were determined in the range of 0.76-1.73, 0.5-1.57 and 2.11-10.53 U/mL, respectively. Maximum enzyme activities were found in Yamadazyma isolates for all three enzymes. To the best of our knowledge, cold active pectinase, amylase and protease production by Yamadazyma spp. were investigated for the first time in the present study. Besides, this is the first report which indicates cold active amylase production by Cystofilobasidium capitatum and pectinase production by Rhodosporidiobolus colostri. Yeast isolates obtained in this study may have potential for industrial cold active enzyme production. PMID- 29516183 TI - Bleeding Lesion of the Small Bowel: an Extensive Update Leaving No Stone Unturned. AB - PURPOSE OF REVIEW: Gastrointestinal bleeding originating from the small bowel (SB) poses a challenge to the treating gastroenterologist. Once diagnosed, management is not a walk in the park either. This review intends to summarize the current state-of-the-art evidence in a complete way with special attention for vascular and ulcerative lesions, to provide the reader with a clinical guide and flow chart towards SB bleeding. RECENT FINDINGS: Absence of SB bleeding lesions on CE does not directly yield better prognosis; although having a lower rebleeding rate the first 2 years, rebleeding in the long term is high. Push enteroscopy can play an early role in patients with SB bleeding if suspicion of angioectasia is high, since these lesions tend to be located in the proximal SB. Endoscopic management of angioectasia is, however, difficult and shows poor results. Capsule endoscopy (CE) or device-assisted enteroscopy (DAE) remain the diagnostic mainstay in SB bleeding, choosing one over the other based upon patient characteristics and expected lesions. PMID- 29516187 TI - Anti-GD2 Immunoliposomes for Targeted Delivery of the Survivin Inhibitor Sepantronium Bromide (YM155) to Neuroblastoma Tumor Cells. AB - PURPOSE: Sepantronium bromide (YM155) is a hydrophilic quaternary compound that cannot be administered orally due to its low oral bioavailability; it is furthermore rapidly eliminated via the kidneys. The current study aims at improving the pharmacokinetic profile of YM155 by its formulation in immunoliposomes that can achieve its enhanced delivery into tumor tissue and facilitate uptake in neuroblastoma cancer cells. METHODS: PEGylated YM155 loaded liposomes composed of DPPC, cholesterol and DSPE-PEG2000 were prepared via passive film-hydration and extrusion method. Targeted (i.e. immuno-)liposomes were prepared by surface functionalization with SATA modified monoclonal anti disialoganglioside (GD2) antibodies. Liposomes were characterized based on their size, charge, antibody coupling and YM155 encapsulation efficiency, and stability. Flow cytometry analysis and confocal microscopy were performed on IMR32 and KCNR neuroblastoma cell lines. The efficacy of developed formulations were assessed by in-vitro toxicity assays. A pilot pharmacokinetic analysis was performed to assess plasma circulation and tumor accumulation profiles of the developed liposomal formulations. RESULTS: YM155 loaded immunoliposomes had a size of 170 nm and zeta potential of -10 mV, with an antibody coupling efficiency of 60% andYM155 encapsulation efficiency of14%. Targeted and control liposomal formulations were found to have similar YM155 release rates in a release medium containing 50% serum. An in-vitro toxicity study on KCNR cells showed less toxicity for immunoliposomes as compared to free YM155. In-vivo pharmacokinetic evaluation of YM155 liposomes showed prolonged blood circulation and significantly increased half-lives of liposomal YM155 in tumor tissue, as compared to a bolus injection of free YM155. CONCLUSIONS: YM155 loaded immunoliposomes were successfully formulated and characterized, and initial in vivo results show their potential for improving the circulation time and tumor accumulation of YM155. PMID- 29516188 TI - Consistency of electronic measurements of endodontic working length when using multiple devices from the same manufacturer-an in vitro study. AB - OBJECTIVES: To assess the consistency of electronic determination of endodontic working length obtained from four identical electronic root canal length measurement devices (ERCLMD) from five different types of ERCLMD each under various in vitro conditions. MATERIALS AND METHODS: Eight extracted teeth, seven single-rooted teeth, and one molar were accessed. Root length was measured and instruments were inserted and fixed with the tip placed beyond and short of the apical constriction, in roots with an artificial perforation or an open apex. Devices tested were Root ZX (Morita, Kyoto, Japan), Dentaport ZX (Morita), Apex ID (SybronEndo, Glendora, USA), ProPex II (Dentsply Maillefer, Victoria, Australia), and Raypex 6 (VDW-Antaeos, Munich, Germany). Teeth were irrigated with different solutions (NaOCl, EDTA, CHX). ERCLMDs were connected and measurements were recorded. Consistency was classified by the scores 0-4. Comparisons were carried out using the Kruskal-Wallis test (alpha = 0.05). For multiple testing, the level of significance was adjusted and analysis was performed using the Mann-Whitney U test. RESULTS: Among the five types of ERCLMD, Apex ID and Raypex 6 showed the highest consistency. There was no statistically significant difference between the settings and conditions. Raypex 6 showed the highest consistency for measurements in case of a perforation. CONCLUSION: Different devices from one type of ERCLMD show a high consistency. Nevertheless, general statements on the accuracy of one type of ERCLMD taken from studies investigating only one device per type should be drawn with caution. CLINICAL RELEVANCE: The study refers to the reliability and repeatability of determination of endodontic working length by using ERCLMDs. PMID- 29516186 TI - Remote Patient Monitoring in IBD: Current State and Future Directions. AB - PURPOSE OF REVIEW: Mobile apps are now increasingly used in conjunction with telemedicine and wearable devices to support remote patient monitoring (RPM). The goal of this paper is to review the available evidence and assess the scope of RPM integration into standard practices for care and management of chronic disease in general and, more specifically, inflammatory bowel disease (IBD). RECENT FINDINGS: RPM has been associated with improvements in health outcomes and indicators across a broad range of chronic diseases. However, there is limited data on the effectiveness of RPM in IBD care. From the emerging literature and body of research, we found promising results about the feasibility of integrating RPM in IBD care and RPM's capacity to support IBD improvement in key process and outcome metrics. Concerns regarding privacy and provider acceptability have limited the mass integration of RPM to date. However, with the healthcare industry's move toward value-based population care and the advent of novel payment models for RPM reimbursement, the adoption of RPM into standard IBD care practices will likely increase as the technology continues to improve and become a mainstream tool for healthcare delivery in the near future. PMID- 29516189 TI - DFT study of geometrical and vibrational features of a 3',5'-deoxydisugar monophosphate (dDSMP) DNA model in the presence of counterions and solvent. AB - The B3LYP/6-31++G* theoretical level was used to study the influence of various hexahydrated monovalent (Li+, Na+, K+) and divalent (Mg2+) metal counterions in interaction with the charged PO2- group, on the geometrical and vibrational characteristics of the DNA fragments of 3',5'-dDSMP, represented by four conformers (g+g+, g+t, g-g- and g-t). All complexes were optimized through two solvation models [the explicit model (6H2O) and the hybrid model (6H2O/Continuum)]. The results obtained established that, in the hybrid model, counterions (Li+, Na+, K+, Mg2+) always remain in the bisector plane of the O1-P O2 angle. When these counterions are explicitly hydrated, the smallest counterions (Li+, Na+) deviate from the bisector plane, while the largest counterions (K+ and Mg2+) always remain in the same plane. On the other hand, the present calculations reveal that the g+g+ conformer is the most stable in the presence of monovalent counterions, while conformers g+t and g-t are the most stable in the presence of the divalent counterion Mg2+. Finally, the hybrid solvation model seems to be in better agreement with the available crystallographic and spectroscopic (Raman) experiments than the explicit model. Indeed, the six conformational torsions of the C4'-C3'-O3'-PO-2-O5'-C5'-C4' segment of all complexes of the g-g- conformer in 6H2O/Continuum remain similar to the available experimental data of A- and B-DNA forms. The calculated wavenumbers of the g+g+ conformer in the presence of the monovalent counterion and of g-t conformer in presence of the divalent counterion in the hybrid model are in good agreement with the Raman experimental data of A- and B-DNA forms. In addition, the maximum deviation between the calculated wavenumbers in the 6H2O/Continuum for the g+g+ conformer and experimental value measured in an aqueous solution of the DMP-Na+ complex, is <1.07% for the PO2- (asymmetric and symmetric) stretching modes and <2.03% for the O5'-C5' and O3'-C3' stretching modes. Graphical abstract dDSMP-(OO)- Mg2+/6W/Continuum. PMID- 29516190 TI - A Clinical Guide to Combination Lipid-Lowering Therapy. AB - PURPOSE OF REVIEW: We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction. RECENT FINDINGS: Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies. A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies. PMID- 29516191 TI - Application of the index WQI-CCME with data aggregation per monitoring campaign and per section of the river: case study-Joanes River, Brazil. AB - This work applied the Water Quality Index developed by the Canadian Council of Ministers of the Environment (WQI-CCME), to communicate the water quality per section of the Joanes River basin, State of Bahia, Brazil. WQI-CCME is a statistical procedure that originally requires the execution of at least four monitoring campaigns per monitoring location and the measurement of at least four parameters. This paper presents a new aggregation method to calculate the WQI CCME because, to apply the original method in Joanes River, a huge loss of information would occur, by the fact that, the number of analyzed parameters varied between the monitoring campaigns developed by the Government Monitoring Program. This work modified the original aggregation method replacing it by a data aggregation for a single monitoring campaign, in a minimum of four monitoring locations per section of the river and a minimum of four parameters per monitoring location. Comparison between the calculation of WQI-CCME for river sections, with the index, WQI-CETESB, developed by the Brazilian Environmental Sanitation and Technology Company-CETESB, proved the applicability of the new aggregation method. The WQI-CETESB has it bases on the WQI from the National Sanitation Foundation and uses nine fixed parameters. As WQI-CCME uses the totality of the analyzed parameters without restrictions, it is more flexible, and the results seem more adequate to indicate the real river water quality. However, the WQI-CCME has a more stringent water quality scale in comparison with the WQI-CETESB, resulting in inferior water quality information. In conclusion, the WQI-CCME with a new aggregation method is adequate for communicating the water quality at a given time, per section of a river, respecting the minimum number of four analyses and four monitoring points. As a result, without a need to wait for other campaigns, it reduces the cost of a monitoring program and the period to communicate the water quality. The adequacy of the WQI-CCME was similar to the finding of others. PMID- 29516192 TI - Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). AB - To test whether remote ischaemic conditioning (RIC) as adjuvant to standard of care (SOC) would prevent progression towards heart failure (HF) after ST elevation myocardial infarction (STEMI). Single-centre parallel 1:1 randomized trial (computerized block-randomization, concealed allocation) to assess superiority of RIC (3 cycles of intermittent 5 min lower limb ischaemia) over SOC in consecutive STEMI patients (NCT02313961, clinical trials.gov). From 258 patients randomized to RIC or SOC, 9 and 4% were excluded because of unconfirmed diagnosis and previously unrecognized exclusion criteria, respectively. Combined primary outcome of cardiac mortality and hospitalization for HF was reduced in RIC compared with SOC (n = 231 and 217, respectively; HR = 0.35, 95% CI 0.15 0.78) as well as each outcome in isolation. No difference was found in serum troponin I levels between groups. Median and maximum follow-up time were 2.1 and 3.7 years, respectively. In-hospital HF (RR = 0.68, 95% CI 0.47-0.98), need for diuretics (RR = 0.68, 95% CI 0.48-0.97) and inotropes and/or intra-aortic balloon pump (RR = 0.17, 95% CI 0.04-0.76) were decreased in RIC. On planned 12 months follow-up echocardiography (n = 193 and 173 in RIC and SOC, respectively) ejection fraction (EF) recovery was enhanced in patients presenting with impaired left ventricular (LV) function (10% absolute difference in median EF compared with SOC; P < 0.001). In addition to previously reported improved myocardial salvage index and reduced infarct size RIC was shown beneficial in a combined hard clinical endpoint of cardiac mortality and hospitalization for HF. Improved EF recovery was also documented in patients with impaired LV function. PMID- 29516194 TI - Towards a better understanding of the many facets of attention deficit/hyperactivity disorder. PMID- 29516193 TI - Soil heavy metal pollution and risk assessment associated with the Zn-Pb mining region in Yunnan, Southwest China. AB - The environmental assessment and identification of sources of heavy metals in Zn Pb ore deposits are important steps for the effective prevention of subsequent contamination and for the development of corrective measures. The concentrations of eight heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in soils from 40 sampling points around the Jinding Zn-Pb mine in Yunnan, China, were analyzed. An environmental quality assessment of the obtained data was performed using five different contamination and pollution indexes. Statistical analyses were performed to identify the relations among the heavy metals and the pH in soils and possible sources of pollution. The concentrations of As, Cd, Pb, and Zn were extremely high, and 23, 95, 25, and 35% of the samples, respectively, exceeded the heavy metal limits set in the Chinese Environmental Quality Standard for Soils (GB15618-1995, grade III). According to the contamination and pollution indexes, environmental risks in the area are high or extremely high. The highest risk is represented by Cd contamination, the median concentration of which exceeds the GB15618-1995 limit. Based on the combination of statistical analyses and geostatistical mapping, we identified three groups of heavy metals that originate from different sources. The main sources of As, Cd, Pb, Zn, and Cu are mining activities, airborne particulates from smelters, and the weathering of tailings. The main sources of Hg are dust fallout and gaseous emissions from smelters and tailing dams. Cr and Ni originate from lithogenic sources. PMID- 29516195 TI - Unraveling genetic factors involved in intelligence, educational attainment and socioeconomic standing: what are the implications for childhood mental health care professionals? PMID- 29516196 TI - Imbalances in intraoperative opioid administration can affect the study outcomes. PMID- 29516197 TI - Results of the treatment of first carpometacarpal joint osteoarthritis: trapeziectomy alone versus trapeziectomy associated with suspensionplasty. AB - BACKGROUNDS: The goal of this study was to compare trapeziectomy alone to trapeziectomy associated with a technique of suspensionplasty using the abductor pollicis longus with a minimum of 6 years of follow-up in the treatment of osteoarthritis of the first carpometacarpal joint. METHODS: Our series included 46 trapeziectomies in 35 patients, aged 69 years in average, among which 27 were women. In 27 cases group I, a trapeziectomy alone was performed, and in 19 cases group II, a trapeziectomy associated with an abductor pollicis longus suspensionplasty was performed. RESULTS: At the last follow-up, the difference between pre- and postoperative Quick DASH was - 36.104 in average in group I and 38.877 in average in group II p = 0.7717. The difference between pre- and postoperative pain was - 3.926 in average in group I and - 4.368 in average in group II p = 0.35. The difference of pre- and postoperative thumb opposition was 0.630 in group I and 0.421 in group II p = 0.3033. The average difference of pre- and postoperative key pinch was 0.389 in group I and 0.842 in group II p = 0.3303. No complication was reported. CONCLUSIONS: Our results suggest that it is unnecessary to perform a ligamentoplasty when a trapeziectomy is indicated. PMID- 29516198 TI - Evolution of Photoluminescence, Raman, and Structure of CH3NH3PbI3 Perovskite Microwires Under Humidity Exposure. AB - Self-assembled organic-inorganic CH3NH3PbI3 perovskite microwires (MWs) upon humidity exposure along several weeks were investigated by photoluminescence (PL) spectroscopy, Raman spectroscopy, and X-ray diffraction (XRD). We show that, in addition to the common perovskite decomposition into PbI2 and the formation of a hydrated phase, humidity induced a gradual PL redshift at the initial weeks that is stabilized for longer exposure (~ 21 nm over the degradation process) and an intensity enhancement. Original perovskite Raman band and XRD reflections slightly shifted upon humidity, indicating defects formation and structure distortion of the MWs crystal lattice. By correlating the PL, Raman, and XRD results, it is believed that the redshift of the MWs PL emission was originated from the structural disorder caused by the incorporation of H2O molecules in the crystal lattice and radiative recombination through moisture-induced subgap trap states. Our study provides insights into the optical and structural response of organic-inorganic perovskite materials upon humidity exposure. PMID- 29516199 TI - Keratoconus-like tomographic changes in a case of recurrent interstitial keratitis. AB - BACKGROUND: The purpose of this report was to describe a single case of recurrent interstitial keratitis in a young patient leading to keratoconus-like corneal changes. RESULTS: Over the 2 years follow-up, the patient developed clinical signs of keratoconus with Vogt's striae, Fleischer Ring and paracentral stromal thinning in the affected eye only. The tomographic measurements revealed a rapid reduction of corneal thickness from 581 to 303 MUm and an irregular steepening of the pathological cornea. True net corneal power increased from 42.8 to 48.8 dioptres (D) and maximal power of the anterior surface from 44.9 to 66.9 D. Best corrected visual acuity (BCVA) decreased from 20/20 to 20/200. A penetrating excimer laser keratoplasty was performed to restore vision and corneal stability. CONCLUSION: Keratoconus-like changes can occur in young patients with recurrent interstitial keratitis and request corneal transplantation. PMID- 29516201 TI - Expert's comment concerning Grand Rounds case entitled "Correction of dropped head deformity through combined anterior and posterior osteotomies to restore horizontal gaze and improve sagittal alignment" by W.H. Bronson et al. [Eur Spine J (2017): doi:10.1007/s00586-017-5184-6]. PMID- 29516200 TI - How Can We Improve Disease Education in People with Gout? AB - PURPOSE OF REVIEW: Gout management is currently suboptimal despite excellent available therapy. Gout patient education has been shown to enhance medication adherence and self-management, but needs improvement. We explored the literature on gout patient education including gaps in gout patient knowledge; use of written materials; in-person individual and group sessions; education via nurses, pharmacists, or multi-disciplinary groups; and use of phone, web-based, mobile health app, and text messaging educational efforts. RECENT FINDINGS: Nurse-led interventions have shown significant improvement in reaching urate goals. Pharmacist-led programs have likewise succeeded, but to a lesser degree. A multi disciplinary approach has shown feasibility. Needs-assessments, patient questionnaires, and psychosocial evaluations can enhance targeted education. An interactive and patient-centered approach can enhance gout educational interventions. Optimal programs will assess for and address educational needs related to knowledge gaps, health literacy, race, gender, socio-economic status, and level of social support. PMID- 29516202 TI - Synthesis and characterization of novel iminobenzoates with terminal pyrazine moieties. AB - Apart from its numerous biological activities like antidiabetic, anti inflammatory, antimicrobial, pyrazine moiety plays an important role in luminescent materials. Its role in luminescent materials is due to its highly electron deficient nature specially when it is in the centre along the mainstay of extended pi-conjugated systems. Similarly, new liquid crystalline compounds are being made constantly where the central benzoaromatic moiety is being replaced with the heterocycles including pyrazine due to their more variable nature. Pyrazine derivatives can also be used in supramolecular assemblies due to their efficient hydrogen bonding, protonation and complexation properties. Keeping in view the enormous applications of pyrazine derivatives we planned to synthesize new extended iminobenzoates with pyrazine moieties at the terminal positions. The planned iminobenzoates with terminal pyrazine moieties were prepared following standard procedures. The pyrazine-2-carbohydrazide (1) and 5 methylpyrazine-2-carbohydrazide (2) were prepared by refluxing their methyl esters with hydrazine hydrate in methanol. The esters (3a-3f) were synthesized by reacting 4-hydroxybenzaldehyde with differently substituted acid halides in tetrahydrofuran in the presence of triethyl amine. The target compounds that is, iminobenzoates with the pyrazine moieties at terminal positions (4a-4l), were obtained in good to excellent yields by the reaction of the hydrazides with the esters at reflux. The synthesized compounds were fully characterized using different spectroanalytical techniques including FT-IR, NMR, Mass, elemental analysis and single crystal X-ray diffraction analysis. The paper describes the synthesis of novel iminobenzoates following easy methods while utilizing commercially available starting materials. The synthesized iminobenzoates may possibly be converted to compounds with luminescent and liquid crystalline properties after making suitable changes to the pyrazine moieties. Properly substituted pyrazines on both sides, capable of further suitable extensions, may result in compounds with such properties. PMID- 29516203 TI - Hybrid Epicardial-Endocardial Approach to Atrial Fibrillation Ablation. AB - WHO SHOULD UNDERGO HYBRID AF ABLATION?: Patients with symptomatic persistent or long-standing persistent atrial fibrillation refractory to pharmacological or routine catheter ablation can be considered for hybrid epicardial-endocardial AF ablation. Although it seems clear that patient selection should be important when considering hybrid AF ablation for optimal results, unfortunately, available data on the outcomes of hybrid epicardial-endocardial ablation is limited. Hybrid ablation is rarely compared to stand-alone catheter ablation, the surgical approach (access site, lesion set, ablation tool) is inconsistent, and the patient population studied is often suitable for a catheter ablation approach (paroxysmal AF, minimal structural heart disease). We believe that the hybrid approach should be considered in patients who either have had unsuccessful catheter ablations or have significant structural heart disease evident by enlarged left atrial size or atrial fibrosis. These are the patients who warrant the added risk of a hybrid approach and who stand to benefit from a more extensive ablation including isolation of the posterior wall of the left atrium. Multi-center studies with a uniform hybrid ablation approach and comparison with a stand-alone catheter ablation approach are needed to help clarify the role of hybrid AF ablation. PMID- 29516205 TI - Factors influencing medical students' choice of emergency medicine as a career specialty-a descriptive study of Saudi medical students. AB - BACKGROUND: Choosing a medical specialty is a poorly understood process. Although studies conducted around the world have attempted to identify the factors that affect medical students' choice of specialty, data is scarce on the factors that influence the choice of specialty of Saudi Arabian medical students, in particular those planning a career in emergency medicine (EM). In this study, we investigated whether Saudi medical students choosing EM are influenced by different factors to those choosing other specialties. METHODS: A cross-sectional survey was conducted at King Saud bin Abdulaziz University for Health Sciences (KSAUHS), Riyadh, Saudi Arabia. The questionnaire distributed among all undergraduate and postgraduate medical students of both sexes in the second and third phases (57% were males and 43% were females). RESULTS: A total of 436 students answered the questionnaire, a response rate of 53.4%. EM group was most influenced by hospital orientation and lifestyle and least influenced by social orientation and prestige provided by their specialty. Unlike controllable lifestyle (CL) group and primary care (PC) group, EM reported lesser influence of social orientation on their career choice. When compared with students primarily interested in the surgical subspecialties (SS), EM group were less likely to report prestige as an important influence. Moreover, students interested in SS reported a leaser influence of medical lifestyle in comparison to EM group. When compared with CL group, EM group reported more interest in medical lifestyle. CONCLUSIONS: We found that students primarily interested in EM had different values and career expectations to other specialty groups. The trends in specialty choice should be appraised to meet future needs. PMID- 29516204 TI - Seeing the World as it is: Mimicking Veridical Motion Perception in Schizophrenia Using Non-invasive Brain Stimulation in Healthy Participants. AB - Schizophrenia (Sz) is a mental health disorder characterized by severe cognitive, emotional, social, and perceptual deficits. Visual deficits are found in tasks relying on the magnocellular/dorsal stream. In our first experiment we established deficits in global motion processing in Sz patients compared to healthy controls. We used a novel task in which background optic flow produces a distortion of the apparent trajectory of a moving stimulus, leading control participants to provide biased estimates of the true motion trajectory under conditions of global stimulation. Sz patients were significantly less affected by the global background motion, and reported trajectories that were more veridically accurate than those of controls. In order to study the mechanism of this effect, we performed a second experiment where we applied transcranial electrical stimulation over area MT+ to selectively modify global motion processing of optic flow displays in healthy participants. Cathodal and high frequency random noise stimulation had opposite effects on trajectory perception in optic flow. The brain stimulation over a control site and in a control task revealed that the effect of stimulation was specific for global motion processing in area MT+. These findings both support prior studies of impaired early visual processing in Sz and provide novel approaches for measurement and manipulation of the underlying circuits. PMID- 29516206 TI - Effect of Anagliptin and Sitagliptin in Type 2 Diabetic Patients with Dyslipidemia and Cardiovascular Risk: What Is the Real REASON Behind It? PMID- 29516207 TI - Model-Based Adaptive Optimal Design (MBAOD) Improves Combination Dose Finding Designs: an Example in Oncology. AB - Design of phase 1 combination therapy trials is complex compared to single therapy trials. In this work, model-based adaptive optimal design (MBAOD) was exemplified and evaluated for a combination of paclitaxel and a hypothetical new compound in a phase 1 study to determine the best dosing regimen for a phase 2 trial. Neutropenia was assumed as the main toxicity and the dose optimization process targeted a 33% probability of grade 4 neutropenia and maximal efficacy (based on preclinical studies) by changing the dose amount of both drugs and the dosing schedule for the new drug. Different starting conditions (e.g., initial dose), search paths (e.g., maximal change in dose intensity per step), and stopping criteria (e.g., "3 + 3 rule") were explored. The MBAOD approach was successfully implemented allowing the possibility of flexible designs with the modification of doses and dosing schedule throughout the trial. The 3 + 3 rule was shown to be highly conservative (selection of a dosing regimen with at least 90% of the possible maximal efficacy in less than 21% of the cases) but also safer (selection of a toxic design in less than 2% of the cases). Without the 3 + 3 rule, better performance was observed (>67% of selected designs were associated with at least 90% of possible maximal efficacy) while the proportion of DLTs per trial was similar. Overall, MBAOD is a promising tool in the context of dose finding studies of combination treatments and was showed to be flexible enough to be associated with requirements imposed by clinical protocols. PMID- 29516208 TI - Time-dependent change in relapse sites of renal cell carcinoma after curative surgery. AB - We investigated time-dependent changes in the relapse features of renal cell carcinoma (RCC) after curative surgery. Between 1985 and 2015, 1398 patients with RCC (1226 clear cell RCC, 89 papillary RCC, and 53 chromophobe RCC) underwent curative surgery at Yokohama City University Hospital and its affiliated hospitals. We retrospectively reviewed the clinicopathologic factors of patients with relapse after surgery. Median follow-up was 56.3 months. Recurrence occurred in 245 patients (217 clear cell RCC, 12 papillary RCC, and 3 chromophobe RCC). Papillary RCC and chromophobe RCC had no recurrence beyond 5 years after surgery, but 20 cases of clear cell carcinoma had recurrence beyond 10 years after surgery. The typical recurrence sites of clear cell RCC were lung (46.6%), bone (17.9%), liver (7.6%), and lymph nodes (6.5%). The proportion of recurrences at these typical sites was 83.9% for recurrences within 5 years, 76.3% between 5 and 10 years, and 40.0% beyond 10 years. In contrast, the proportion of retroperitoneal organ recurrence, including contralateral kidney, pancreas, and adrenal glands, increased with increasing time after surgery. Interestingly, the hazard ratio of typical site relapse decreased whereas that of retroperitoneal organ relapse increased in a time-dependent manner. In summary, clear cell RCC showed potential to relapse beyond 10 years after surgery. Recurrence at typical sites decreased whereas retroperitoneal organ recurrence increased in a time dependent manner. Clinicians should check for recurrence at various sites beyond 10 years, especially in clear cell RCC. PMID- 29516209 TI - Extended publication guidelines for the reporting of clinical research in Clinical and Experimental Metastasis. PMID- 29516210 TI - Exciting new article categories introduced not Clinical and Experimental Metastasis: submit your article now! PMID- 29516211 TI - Quantitative assessment of fluorescence intensity of ICG in sentinel nodes in early gastric cancer. AB - BACKGROUND: The sentinel node (SN) detection by dual tracer method using indocyanine green (ICG) and a radioisotope (RI) has been recommended for early gastric cancer. However, institutions are limited due to radioactivity in the RI method. The greatest advantage of the RI method is that it objectively assesses RI uptake as a numerical value. The aim of the present study was to verify the usefulness of ICG fluorescence intensity in SN. METHODS: Seventeen patients with early gastric cancer were enrolled in this study. RI uptake by each lymph node was measured using Navigator GPS and fluorescence nodes were identified using the hyper eye medical system (HEMS). Fluorescence intensity in fluorescence nodes was evaluated using ICG intensity imaging software (Mizuho, Japan) of the HEMS. RESULTS: The total number of dissected lymph nodes was 227, with an average of 13.3 per patient. The numbers of HN, FN-S, and FN-B were 64, 77, and 34. RI uptake was significantly greater by FN-S than by non-FN-S (P = 0.0016). The median fluorescence intensity value was higher in HN than in non-HN (P < 0.001). A correlation was observed between RI uptake and fluorescence intensity. Dissecting FNs with fluorescence intensity levels of 1-6 resulted in 92.1% dissection of HNs. CONCLUSION: It is possible that the evaluation of fluorescence intensity is useful for selected SNs instead of RI tracer. If fluorescence intensity is measurable in surgery, an infrared fluorescence method using ICG may be useful and safe for the detection of SN in early gastric cancer. PMID- 29516212 TI - Electronic Assessment of Physical Decline in Geriatric Cancer Patients. AB - PURPOSE OF REVIEW: The purpose of this review is to explore state-of-the-art remote monitoring and emerging new sensing technologies for in-home physical assessment and their application/potential in cancer care. In addition, we discuss the main functional and non-functional requirements and research challenges of employing such technologies in real-world settings. RECENT FINDINGS: With rapid growth in aging population, effective and efficient patient care has become an important topic. Advances in remote monitoring and in its forefront in-home physical assessment technologies play a fundamental role in reducing the cost and improving the quality of care by complementing the traditional in-clinic healthcare. However, there is a gap in medical research community regarding the applicability and potential outcomes of such systems. While some studies reported positive outcomes using remote assessment technologies, such as web/smart phone-based self-reports and wearable sensors, the cancer research community is still lacking far behind. Thorough investigation of more advanced technologies in cancer care is warranted. PMID- 29516213 TI - Plasmodium parasites in reptiles from the Colombia Orinoco-Amazon basin: a re description of Plasmodium kentropyxi Lainson R, Landau I, Paperna I, 2001 and Plasmodium carmelinoi Lainson R, Franco CM, da Matta R, 2010. AB - Colombia is a megadiverse country with about 600 species of reptiles; however, there are few studies on species of hemoparasites found in this taxonomic group. Here, we document the presence of Plasmodium spp. in four species of reptiles from the northern part of the Orinoco-Amazon region in Colombia. Individuals analyzed in this study were captured in localities between 200 and 500 m altitude, in the department of Guaviare. Each sample was screened for haemosporidian parasites by using morphology and a nested polymerase chain reaction (PCR) protocol that targets the mitochondrial cytochrome b (cytb) gene. Four morphotypes of the genus Plasmodium were found; two of these species are re described using morphological and molecular data (cytb). For the other two morphotypes, it was not possible to assign a described species. Among those, Plasmodium screened one species was only detected by microscopy. Considering the potential species diversity, it is possible that commonly used primers may not detect all species, reinforcing the importance of using microscopy in haematozoa surveys. There was no correspondence between the morphological traits associated with the subgenera and the phylogenetic relationships that we found in our analyses. Additionally, we found an expansion in the geographical distribution of these two species, and a new host for P. kentropyxi, demonstrating that studies of tropical herpetofauna and their parasites deserve more attention. PMID- 29516215 TI - Molecular detection and characterization of Theileria spp. infecting cattle in Sennar State, Sudan. AB - Tropical theileriosis is a serious animal disease transmitted by tick vectors. The agents of theileriosis are obligate intracellular parasites that cause mild to severe disease in the mammalian host. Tropical theileriosis has been recognized as a burden to the development of the dairy industry in Sudan and causes major economic losses. However, knowledge about the distribution of Theileria spp. in Sudan and the extent of sequence variation within the 18S rRNA gene is currently unknown. The aim of this study was to determine the diversity of Theileria spp. using 18S rRNA-based PCR to detect parasites in cattle followed by cloning and sequencing. We observed an overall prevalence rate of 63% hemoparasite infection in cattle from Sennar state. A subset of samples was used for cloning and sequencing of the 18S rRNA gene. Nineteen of 44 animals were co infected with more than one species of Theilera. Phylogenetic analysis revealed three Theileria spp. that were predominant in cattle including pathogenic T. annulata and apathogenic T. velifera and T. mutans. The present study provides information regarding the prevalence of theileriosis in Sudan and will help to design strategies to control it. Additionally, more study is needed to determine tick vector competence and degree of coinfection with multiple Theileria spp. in Sudan. This represents the first molecular phylogeny report to identify Theileria spp. in cattle from Sudan. PMID- 29516216 TI - Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update. AB - Over the last two decades, molecular-targeted agents have become mainstream treatment for many types of malignancies and have improved the overall survival of patients. However, most patients eventually develop resistance to these targeted therapies. Recently, immunotherapies such as immune checkpoint inhibitors have revolutionized the treatment paradigm for many types of malignancies. Immune checkpoint inhibitors have been approved for treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, bladder cancer and gastric cancer. However, oncologists have been faced with immune-related adverse events caused by immune checkpoint inhibitors; these are generally mild but can be fatal in some cases. Because immune checkpoint inhibitors have distinct toxicity profiles from those of chemotherapy or targeted therapy, many oncologists are not familiar with the principles for optimal management of immune-related adverse events, which require early recognition and appropriate treatment without delay. To achieve this, oncologists must educate patients and health-care workers, develop checklists of appropriate tests for immune-related adverse events and collaborate closely with organ specialists. Clinical questions that remain include whether immune checkpoint inhibitors should be administered to patients with autoimmune disease and whether patients for whom immune-related adverse events lead to delays in immunotherapy should be retreated. In addition, the predicted use of combination immunotherapies in the near future means that oncologists will face a higher incidence and severity of immune-related adverse events. This review provides an overview of the optimal management of immune-related adverse events attributed to immune checkpoint inhibitors. PMID- 29516217 TI - Molecular basis of dopamine replacement therapy and its side effects in Parkinson's disease. AB - There is currently no cure for Parkinson's disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson's disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed. PMID- 29516214 TI - Proteomic profile approach of effect of putrescine depletion over Trichomonas vaginalis. AB - Infection with Trichomonas vaginalis produces a malodorous seropurulent vaginal discharge due to several chemicals, including polyamines. The presence of 1,4 diamino-2-butanone (DAB) reduces the amount of intracellular putrescine by 90%, preventing the cotransport of exogenous spermine. DAB-treated parasites present morphological changes, which are restored by adding exogenous putrescine into the culture medium. However, the effect of polyamines over the trichomonad proteomic profile is unknown. In this study, we used a proteomic approach to analyze the polyamine-depletion and restoration effect by exogenous putrescine on T. vaginalis proteome. In the presence of inhibitor DAB, we obtained 369 spots in polyamine-depleted condition and observed 499 spots in the normal culture media. With DAB treatment, the intensity of 43 spots was increased but was found to be reduced in 39 spots, as compared to normal conditions. Interestingly, in DAB treated parasites restored with a medium with added exogenous putrescine, 472 spots were found, of which 33 were upregulated and 63 were downregulated in protein intensity. Some of these downregulated proteins in DAB-treated parasites are involved in several cellular pathways such as glycolysis, glycolytic fermentation, arginine dihydrolase pathway, redox homeostasis, host cell binding mediated by carbohydrate, chaperone function, and cytoskeletal remodeling. Interestingly, the intensity of some of the proteins was restored by adding exogenous putrescine. In conclusion, the presence of DAB altered the proteomic profile of T. vaginalis, resulting in a decrease in the intensity of 130 proteins and an increase in the intensity of 43 proteins that was restored by the addition of putrescine. PMID- 29516218 TI - Neural crest stem cells protect spinal cord neurons from excitotoxic damage and inhibit glial activation by secretion of brain-derived neurotrophic factor. AB - The acute phase of spinal cord injury is characterized by excitotoxic and inflammatory events that mediate extensive neuronal loss in the gray matter. Neural crest stem cells (NCSCs) can exert neuroprotective and anti-inflammatory effects that may be mediated by soluble factors. We therefore hypothesize that transplantation of NCSCs to acutely injured spinal cord slice cultures (SCSCs) can prevent neuronal loss after excitotoxic injury. NCSCs were applied onto SCSCs previously subjected to N-methyl-D-aspartate (NMDA)-induced injury. Immunohistochemistry and TUNEL staining were used to quantitatively study cell populations and apoptosis. Concentrations of neurotrophic factors were measured by ELISA. Migration and differentiation properties of NCSCs on SCSCs, laminin, or hyaluronic acid hydrogel were separately studied. NCSCs counteracted the loss of NeuN-positive neurons that was otherwise observed after NMDA-induced excitotoxicity, partly by inhibiting neuronal apoptosis. They also reduced activation of both microglial cells and astrocytes. The concentration of brain derived neurotrophic factor (BDNF) was increased in supernatants from SCSCs cultured with NCSCs compared to SCSCs alone and BDNF alone mimicked the effects of NCSC application on SCSCs. NCSCs migrated superficially across the surface of SCSCs and showed no signs of neuronal or glial differentiation but preserved their expression of SOX2 and Krox20. In conclusion, NCSCs exert neuroprotective, anti-apoptotic and glia-inhibitory effects on excitotoxically injured spinal cord tissue, some of these effects mediated by secretion of BDNF. However, the investigated NCSCs seem not to undergo neuronal or glial differentiation in the short term since markers indicative of an undifferentiated state were expressed during the entire observation period. PMID- 29516219 TI - Finite element analysis of dental implants with validation: to what extent can we expect the model to predict biological phenomena? A literature review and proposal for classification of a validation process. AB - A literature review of finite element analysis (FEA) studies of dental implants with their model validation process was performed to establish the criteria for evaluating validation methods with respect to their similarity to biological behavior. An electronic literature search of PubMed was conducted up to January 2017 using the Medical Subject Headings "dental implants" and "finite element analysis." After accessing the full texts, the context of each article was searched using the words "valid" and "validation" and articles in which these words appeared were read to determine whether they met the inclusion criteria for the review. Of 601 articles published from 1997 to 2016, 48 that met the eligibility criteria were selected. The articles were categorized according to their validation method as follows: in vivo experiments in humans (n = 1) and other animals (n = 3), model experiments (n = 32), others' clinical data and past literature (n = 9), and other software (n = 2). Validation techniques with a high level of sufficiency and efficiency are still rare in FEA studies of dental implants. High-level validation, especially using in vivo experiments tied to an accurate finite element method, needs to become an established part of FEA studies. The recognition of a validation process should be considered when judging the practicality of an FEA study. PMID- 29516221 TI - Diet quality, dietary patterns and short sleep duration: a cross-sectional population-based study. AB - OBJECTIVE: To examine the cross-sectional association between habitual diet quality, dietary patterns and sleep duration. METHODS: A cross-sectional study of 838 men and 1065 women participating in a large, population-based cohort study, the Geelong Osteoporosis Study. A diet quality score (DQS) was derived from answers to a food-frequency questionnaire, and a factor analysis identified habitual dietary patterns. Self-reported sleep duration was dichotomized into 'short sleep duration' (< 7 h/night) and 'adequate sleep duration' (>= 7 h/night). Sleep duration was also grouped into predetermined cut-off ranges (< 5, 5.01-6, 6.01-7, 7.01-8, 8.01-9, 9.01-10 and >= 10.01 h /night) to explore the relationship between sleep duration, DQS and dietary patterns. RESULTS: 363 (34.0%) women and 339 (36.1%) men were identified with short sleep duration. After adjustments for age, socioeconomic status, education, physical activity and body mass index, each standard deviation increase in the factor score for traditional dietary pattern was associated with a 13% reduced odds for short sleep duration in men. In women, each standard deviation increase in DQS score was associated with a 21% reduced odds for short sleep duration. In women, adequate sleep was related to higher modern dietary pattern scores when compared both with excessive sleep duration (> 9 h) and shorter sleep duration (< 7 h). CONCLUSION: Diet quality score was associated with adequate sleep duration (>= 7 h) and reduced odds for short sleep duration (< 7 h) in Australian women. PMID- 29516222 TI - Burden and trend of diet-related non-communicable diseases in Australia and comparison with 34 OECD countries, 1990-2015: findings from the Global Burden of Disease Study 2015. AB - BACKGROUND: Diet is a major determining factor for many non-communicable chronic diseases (NCDs). However, evidence on diet-related NCD burden remains limited. We assessed the trends in diet-related NCDs in Australia from 1990 to 2015 and compared the results with other countries of the Organization for Economic Co operation and Development (OECD). METHODS: We used data and methods from the Global Burden of Disease (GBD) 2015 study to estimate the NCD mortality and disability-adjusted life years (DALYs) attributable to 14 dietary risk factors in Australia and 34 OECD nations. Countries were further ranked from the lowest (first) to highest (35th) burden using an age-standardized population attributable fraction (PAF). RESULTS: In 2015, the estimated number of deaths attributable to dietary risks was 29,414 deaths [95% uncertainty interval (UI) 24,697 - 34,058 or 19.7% of NCD deaths] and 443,385 DALYs (95% UI 377,680-511,388 or 9.5% of NCD DALYs) in Australia. Young (25-49 years) and middle-age (50-69 years) male adults had a higher PAF of diet-related NCD deaths and DALYs than their female counterparts. Diets low in fruits, vegetables, nuts and seeds and whole grains, but high in sodium, were the major contributors to both NCD deaths and DALYs. Overall, 42.3% of cardiovascular deaths were attributable to dietary risk factors. The age-standardized PAF of diet-related NCD mortality and DALYs decreased over the study period by 28.2% (from 27.0% in 1990 to 19.4% in 2015) and 41.0% (from 14.3% in 1990 to 8.4% in 2015), respectively. In 2015, Australia ranked 12th of 35 examined countries in diet-related mortality. A small improvement of rank was recorded compared to the previous 25 years. CONCLUSIONS: Despite a reduction in diet-related NCD burden over 25 years, dietary risks are still the major contributors to a high burden of NCDs in Australia. Interventions targeting NCDs should focus on dietary behaviours of individuals and population groups. PMID- 29516223 TI - A circadian rhythm-related MTNR1B genetic variant modulates the effect of weight loss diets on changes in adiposity and body composition: the POUNDS Lost trial. AB - PURPOSE: A common variant of the melatonin receptor 1B (MTNR1B) gene has been related to increased signaling of melatonin, a hormone previously associated with body fatness mainly through effects on energy metabolism. We examined whether the MTNR1B variant affects changes of body fatness and composition in response to a dietary weight loss intervention. METHODS: The MTNR1B rs10830963 variant was genotyped for 722 overweight and obese individuals, who were randomly assigned to one of four diets varying in macronutrient composition. Anthropometric and body composition measurements (DXA scan) were collected at baseline and at 6 and 24 months of follow-up. RESULTS: Statistically significant interactions were observed between the MTNR1B genotype and low-/high-fat diet on changes in weight, body mass index (BMI), waist circumference (WC) and total body fat (p interaction = 0.01, 0.02, 0.002 and 0.04, respectively), at 6 months of dietary intervention. In the low-fat diet group, increasing number of the sleep disruption-related G allele was significantly associated with a decrease in weight (p = 0.004), BMI (p = 0.005) and WC (p = 0.001). In the high-fat diet group, carrying the G allele was positively associated with changes in body fat (p = 0.03). At 2 years, the associations remained statistically significant for changes in body weight (p = 0.02), BMI (p = 0.02) and WC (p = 0.048) in the low-fat diet group, although the gene-diet interaction became less significant. CONCLUSIONS: The results suggest that carriers of the G allele of the MTNR1B rs10830963 may have a greater improvement in body adiposity and fat distribution when eating a low-fat diet. PMID- 29516224 TI - Does the MIND diet decrease depression risk? A comparison with Mediterranean diet in the SUN cohort. AB - PURPOSE: To prospectively evaluate the association of the Mediterranean-DASH diet intervention for neurodegenerative delay (MIND) diet and the Mediterranean diet (and their components), and depression risk. METHODS: We followed-up (median 10.4 years) 15,980 adults initially free of depression at baseline or in the first 2 years of follow-up. Food consumption was measured at baseline through a validated food-frequency questionnaire, and was used to compute adherence to the MIND and the Mediterranean diets. Relationships between these two diets and incident depression were assessed through Cox regression models. RESULTS: We identified 666 cases of incident depression. Comparing the highest versus the lowest quartiles of adherence, we found no association of the MIND diet and incident depression. This relation was statistically significant for the Mediterranean diet {hazard ratio (HR) 0.75, [95% confidence interval (95% CI) 0.61, 0.94]; p < 0.01}, although with departure from linearity. A reduced depression risk was associated with higher consumption of both fruits and nuts [HR 0.82 (95% CI 0.69, 0.96); p = 0.02], moderate nuts consumption [HR 0.77 (95% CI 0.64, 0.93); p = 0.01], and avoidance of fast/fried food [HR 0.63 (95% CI 0.41, 0.96); p = 0.03]. CONCLUSIONS: The Mediterranean diet was associated with reduced depression risk, but we found no evidence of such an association for the MIND diet. PMID- 29516225 TI - Diet quality in childhood: the Generation R Study. AB - PURPOSE: We aimed to evaluate diet quality of 8-year-old children in the Netherlands, to identify sociodemographic and lifestyle correlates of child diet quality, and to examine tracking of diet quality from early to mid-childhood. METHODS: For 4733 children participating in a population-based cohort, we assessed dietary intake using a validated food-frequency questionnaire at a median age of 8.1 years (interquartile range 8.0-8.2) (2011-2014). Based on dietary guidelines, we developed and validated a food-based diet quality score for children consisting of ten components (score 0-10): sufficient intake of vegetables; fruit; whole grains; fish; legumes; nuts; dairy; oils and soft fats; and low intake of sugar-containing-beverages; and high-fat and processed meat. RESULTS: We observed a mean (+/- SD) diet quality score of 4.5 (+/- 1.2) out of a maximum of 10. On average, intake of legumes, nuts, and oils or soft fats was below recommendations, whereas intake of sugar-containing beverages and high-fat or processed meat was higher than recommended. The main factors associated with higher diet quality were higher maternal educational level (beta = 0.29, 95% CI 0.21, 0.37 versus low education), higher household income (beta = 0.15, 95% CI 0.05, 0.25 versus low income), no maternal smoking (beta = 0.13, 95% CI 0.02, 0.25 versus current smoking), and less screen time (beta = 0.31, 95% CI 0.24, 0.38)-all independent of each other. For children with available dietary data at age 1 year (n = 2608), we observed only weak tracking of diet quality from early to mid-childhood (Pearson's r = 0.19, k = 0.11 for extreme quartiles). CONCLUSION: Overall diet quality of 8-year-old children did not conform to dietary guidelines, especially for children having more screen time, children of lower educated or smoking mothers, or from lower-income households. PMID- 29516227 TI - ? PMID- 29516226 TI - Chronic fructose intake does not induce liver steatosis and inflammation in female Sprague-Dawley rats, but causes hypertriglyceridemia related to decreased VLDL receptor expression. AB - PURPOSE: Sugar-sweetened beverage intake is a risk factor for insulin resistance, dyslipidemia, fatty liver, and steatohepatitis (NASH). Sub-chronic supplementation of liquid fructose, but not glucose, in female rats increases liver and plasma triglycerides without inflammation. We hypothesized that chronic supplementation of fructose would cause NASH and liver insulin resistance. METHODS: We supplemented female Sprague-Dawley rats with water or either fructose or glucose 10% w/v solutions under isocaloric conditions for 7 months. At the end, plasma analytes, insulin, and adiponectin were determined, as well as liver triglyceride content and the expression of key genes controlling inflammation, fatty acid synthesis and oxidation, endoplasmic reticulum stress, and plasma VLDL clearance, by biochemical and histological methods. RESULTS: Although sugar supplemented rats increased their energy intake by 50-60%, we found no manifestation of liver steatosis, fibrosis or necrosis, unchanged plasma or tissue markers of inflammation or fibrosis, and reduced liver expression of gluconeogenic enzymes, despite both sugars increased fatty acid synthesis, mTORC1, and IRE1 activity, while decreasing fatty acid oxidation and PPARalpha activity. Only fructose-supplemented rats were hypertriglyceridemic, showing a reduced expression of VLDL receptor and lipoprotein lipase in skeletal muscle and vWAT. Glucose-supplemented rats showed increased adiponectinemia, which would explain the different metabolic outcomes of the two sugars. CONCLUSIONS: Chronic liquid simple sugar supplementation, as the sole risk factor, is not enough for female rats to develop NASH and increased liver gluconeogenesis. Nevertheless, under isocaloric conditions, only fructose induced hypertriglyceridemia, thus confirming that also the type of nutrient matters in the development of metabolic diseases. PMID- 29516228 TI - Contrast agent concentration optimization in CTA using low tube voltage and dual energy CT in multiple vendors: a phantom study. AB - We investigated the feasibility and extent to which iodine concentration can be reduced in computed tomography angiography imaging of the aorta and coronary arteries using low tube voltage and virtual monochromatic imaging of 3 major dual energy CT (DECT) vendors. A circulation phantom was imaged with dual source CT (DSCT), gemstone spectral imaging (GSI) and dual-layer spectral detector CT (SDCT). For each scanner, a reference scan was acquired at 120 kVp using routine iodine concentration (300 mg I/ml). Subsequently, scans were acquired at lowest possible tube potential (70, 80, 80 kVp, respectively), and DECT-mode (80/150Sn, 80/140 and 120 kVp, respectively) in arterial phase after administration of iodine (300, 240, 180, 120, 60, 30 mg I/ml). Objective image quality was evaluated using attenuation, CNR and dose corrected CNR (DCCNR) measured in the aorta and left main coronary artery. Average DCCNR at reference was 227.0, 39.7 and 60.2 for DSCT, GSI and SDCT. Maximum iodine concentration reduction without loss of DCCNR was feasible down to 180 mg I/ml (40% reduced) for DSCT (DCCNR 467.1) and GSI (DCCNR 46.1) using conventional CT low kVp, and 120 mg I/ml (60% reduced) for SDCT (DCCNR 171.5) using DECT mode. Low kVp scanning and DECT allows for 40-60% iodine reduction without loss in image quality compared to reference. Optimal scan protocol and to which extent varies per vendor. Further patient studies are needed to extend and translate our findings to clinical practice. PMID- 29516229 TI - The Influence of Objectively Measured Physical Activity During Pregnancy on Maternal and Birth Outcomes in Urban Black South African Women. AB - Objectives Research indicates the beneficial effects of physical activity during pregnancy on maternal health, although controversy still exists regarding its influence on birth outcomes. Little research has been done to objectively measure physical activity during pregnancy in black African women from low-to-middle income countries. The purpose of this study was to examine the association between physical activity and maternal and birth outcomes in this unique population. Methods This observational, longitudinal study assessed total physical activity using a hip-mounted triaxial accelerometer at 14-18 weeks (second trimester, n = 120) and 29-33 weeks (third trimester, n = 90) gestation. Physical activity is expressed as gravity-based acceleration units (mg). Maternal outcomes included both weight and weight gain at 29-33 weeks gestation. Birth outcomes included gestational age, birth weight, ponderal index and Apgar score, measured within 48 h of delivery. Results There was a significant decline in physical activity from the second to the third trimester (12.8 +/- 4.1 mg vs. 9.7 +/- 3.6 mg, p <= 0.01). Physical activity at 29-33 weeks as well as a change in PA was inversely associated with weight change at 29-33 weeks (beta = - 0.24; 95% CI - 0.49; - 0.00; p = 0.05 and beta = - 0.36; 95% CI - 0.62; - 0.10; p = 0.01, respectively). No significant associations were found between physical activity and birth outcomes. Conclusions for Practice Physical activity during pregnancy may be an effective method to control gestational weight gain, whilst presenting no adverse risk for fetal development, in women from a low-income urban setting. PMID- 29516231 TI - A call for improved transparency in financial aspects of clinical trials: a case study of the CREATE-X trial in the New England Journal of Medicine. AB - Introduction Globally, laws and guidelines for managing conflict of interest are increasingly implemented to achieve transparency in financial ties between physicians and pharmaceutical and medical device industries, yet little information is available regarding the limitations of the current frameworks for disclosing these financial ties. Case In June 2017, the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial was published in the New England Journal of Medicine. In this study, which suggested the post-surgery addition of capecitabine would improve survival of high-risk breast cancer patients, the cost of capecitabine for off-label use was illegally claimed to the Japanese public health insurance system, rather than being covered by the research budget. This illegal claim led to the profit of more than 100,000,000 JPY (approximately 0.91 million USD) for Chugai Pharmaceutical Company (CPC), which manufactures capecitabine. Additional evidence suggests that the CPC made donations of at least 100,000,000 JPY (approximately 0.91 million USD) and 236,000,000 JPY (approximately 2.1 million USD) to the Japan Breast Cancer Research Group (JBCRG), the study's sponsor and funder where the majority of the Japanese authors served high-level positions, and the Advanced Clinical Research Organization, the other study funder, respectively, during the study period, though the total amount has not been clarified. Neither the CPC's involvement nor its undue profit was mentioned in the published article. Conclusion This case report highlights the lack of financial transparency in the CREATE-X trial, and discusses the potential limitations that may exist in the current frameworks for disclosing financial ties between physicians and relevant industries in clinical trials. Achieving improved transparency is essential to heighten credibility in the findings of clinical trials. PMID- 29516232 TI - Three phases of energy-dependent induction of [Formula: see text] and Chl a fluorescence in Tradescantia fluminensis leaves. AB - In plants, the short-term regulation (STR, seconds to minute time scale) of photosynthetic apparatus is associated with the energy-dependent control in the chloroplast electron transport, the distribution of light energy between photosystems (PS) II and I, activation/deactivation of the Calvin-Benson cycle (CBC) enzymes, and relocation of chloroplasts within the plant cell. In this work, using a dual-PAM technique for measuring the time-courses of P700 photooxidation and Chl a fluorescence, we have investigated the STR events in Tradescantia fluminensis leaves. The comparison of Chl a fluorescence and [Formula: see text] induction allowed us to investigate the contribution of the trans-thylakoid pH difference (DeltapH) to the STR events. Two parameters were used as the indicators of DeltapH generation: pH-dependent component of non photochemical quenching of Chl a fluorescence, and pHin-dependent rate of electron transfer from plastoquinol (PQH2) to [Formula: see text] (via the Cyt b6f complex and plastocyanin). In dark-adapted leaves, kinetics of [Formula: see text] induction revealed three phases. Initial phase is characterized by rapid electron flow to [Formula: see text] (tau1/2 ~ 5-10 ms), which is likely related to cyclic electron flow around PSI, while the outflow of electrons from PSI is restricted by slow consumption of NADPH in the CBC. The light-induced generation of DeltapH and activation of the CBC promote photooxidation of P700 and concomitant retardation of [Formula: see text] reduction (tau1/2 ~ 20 ms). Prolonged illumination induces additional slowing down of electron transfer to [Formula: see text] (tau1/2 >= 30-35 ms). The latter effect is not accompanied by changes in the Chl a fluorescence parameters which are sensitive to DeltapH generation. We suggest the tentative explanation of the latter results by the reversal of Q-cycle, which causes the deceleration of PQH2 oxidation due to the back pressure of stromal reductants. PMID- 29516230 TI - The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions. AB - Diabetes and heart failure (HF) are both global epidemics with tremendous costs on society with increased rates of HF hospitalizations and worsened prognosis when co-existing, making it a significant "deadly duo." The evidence for pharmacological treatment of HF in patients with type 2 diabetes mellitus (T2DM) stems typically from either subgroup analyses of patients that were recruited to randomized controlled trials of HF interventions, usually in patients with reduced ejection fraction (EF), or from subgroup analyses of HF patients recruited to cardiovascular (CV) outcome trials (CVOT) of glucose lowering agents involving patients with T2DM. Studies in patients with HF with preserved EF are sparse. This review summarizes the literature on pathophysiology and interventions aiming to reduce the HF burden in T2DM and includes HF trials of ACEi, digoxin, beta-blocker, ARB, If-blocker, MRA, and ARNI involving 38,600 patients, with or without prevalent diabetes, and CV outcome trials in T2DM involving 74,351 patients, with or without prevalent HF. In all HF trials, HF outcomes by prevalent diabetes were reported with an incremental risk of HF and death confessed by prevalent diabetes and a treatment effect similar to those without diabetes. All T2DM CVOTs reported on HF outcomes with heterogeneity between trials with two reporting benefits (empagliflozin and canagliflozin) and two reporting increased risk (saxagliptin, pioglitazone). In vulnerable T2DM patients with concomitant HF, guideline-recommended HF drugs are effective. When choosing glucose-lowering therapy, outcomes from available CVOTs should be considered. PMID- 29516233 TI - Modeling of methane formation in gravity sewer system: the impact of microorganism and hydraulic condition. AB - Sewer system is an important source of methane formation and emission. Although some models were developed to predict methane production in sewers, the impact of microorganism amount was indicated indirectly. Here, seven laboratory scale sewers with varied wall-shear stresses were established. The biofilm thickness, microorganism amount, DO distribution, microorganism community in the biofilms and methane production in the sewers were measured. Based on experimental data, an empirical model was developed to directly describe the relationship between methane production, microorganism amount and wall-shear stress. The results showed that DO concentration decreased significantly along the biofilm depth under varied wall-shear stress, and the DO reduction rate was positively related to the intensity of wall-shear stress. The dominant archaea species in mature biofilms were similar whereas the proportions showed remarkable differences. The abundance of Methanospirillum in biofilms cultured at 2.0 Pa wall-shear stress was 53.08% more than that at 1.29 Pa. The maximum methane production rate, 2.04 mg/L wastewater day, was obtained when the wall-shear stress kept at 1.45 Pa, which was 1.2-fold higher than the minimum in sewer at 0.5 Pa. The R2 value of the established model was 0.95, the difference between the measurement and simulation was in the rage of 1.5-13.0%. PMID- 29516234 TI - Osteomyelitis of the jaw: time to rethink the bone sampling strategy? AB - This work aims at describing the diversity of osteomyelitis of the jaw (OJ) and at assessing the relevance of a new method designed to avoid salivary contamination during bone sampling in order to improve microbiological analysis and clinical decision-making. We reviewed medical and microbiological data of patients with a suspected OJ based on clinical and/or CT-scan signs and at least one bone sample made for microbiological analysis. During the study period, a new procedure for intraoral bone sampling was elaborated by surgeons and infectious diseases specialists authoring this article (based on stratified samples, cleaning of the surgical site and change of instruments between each sample). A comparison of the microbiological analyses between the two procedures was performed. From 2012 to 2017, 56 patients were included. Median age was 58 years (11-90), sex ratio: 1.24. Main risk factors were having a dental disease (n = 24) or cancer (n = 21). Nineteen patients with the new sample procedure were compared to 37 patients with standard procedure, especially non-cancer patients (n = 16 and 19, respectively). With the new procedure, a median of 3 (1-7) microorganisms per sample was recovered, vs. 7 (1-14) with the former (p < 0.001), a significant decrease of the microbial density was observed for all types of microbes, especially in deeper samples and cultures were more frequently sterile. The way sampling is managed deeply influences microbiological analysis. This strategy facilitates the distinction between pathogens and contaminants and should constitute the first step toward an evidence-based antimicrobial strategy for OJ. PMID- 29516235 TI - Management of a type two avulsion fracture of the tibial intercondylar eminence in children: arthroscopic suture fixation versus conservative immobilization. AB - BACKGROUND: Treatment of a type II tibial eminence avulsion fracture was controversial. The aim of this study was to compare the clinical outcomes of a modified arthroscopic suture fixation versus conservative immobilization in treatment of this type fracture in immature population. METHODS: A total of 43 type II avulsion fractures of tibial intercondylar eminence in immature patients were retrospectively enrolled in the study. Twenty-two (13 males, 9 females) were treated with arthroscopic suture fixation and 21(12 males, 9 females) with conservative cast immobilization. Radiograph, Lachman test, anterior drawer test (ADT), International Knee Documentation Committee (IKDC) 2000 subjective score, and Lysholm score were used to evaluate clinical outcomes in follow-up. RESULT: All 43 paediatric or adolescent patients with a mean of 11.3 years (range, 8-16 years) were followed up for a median period of 34.5 months (range, 24-46 months). Radiographic evaluation showed optimal reduction immediately after surgery and bone union within three months. At the final follow-up, no limitation of knee motion range was found in any children. Grade II laxity was found in one case from surgical group and six from conservation group, showing significant difference based on ADT (chi2 = 7.927, P = 0.005) and Lachman tests (chi2 = 9.546, P = 0.002). IKDC and Lysholm scores were significantly improved; however, there were significant differences in the IKDC score (91.7 +/- 4.34 vs. 84.7 +/- 6.11, t = 4.35, P < 0.001) and Lysholm score (93.4 +/- 4.04 vs. 87.1 +/- 5.24, t = 4.53, P < 0.001), and the improvement of IKDC value (40.2 +/- 7.83 vs. 31.4 +/- 8.4, t = 3.57, P = 0.001) and Lysholm value (43.8 +/- 6.55 vs. 35.4 +/- 5.97, t = 4.36, P < 0.001) between the surgical group and the nonsurgical group. CONCLUSION: In treatment of type II tibial eminence avulsion fracture, a modified, 8 shape suture fixation under arthroscopy showed superior clinical outcomes than nonsurgical immobilization in term of restoring the laxity of paediatric ACL. PMID- 29516236 TI - Association of TNF-alpha-308(G/A) and -238(G/A) polymorphisms with non-traumatic osteonecrosis of the femoral head risks: a meta-analysis. AB - PURPOSE: The association between TNF-alpha-308(G/A) and -238(G/A) polymorphisms and the susceptibility of non-traumatic osteonecrosis of the femoral head (NONFH) was investigated in many studies with conflicting results. We aimed to conduct a meta-analysis to evaluate the relationship between them comprehensively. METHODS: Relevant literatures published in PubMed, Web of Science, Embase, Cochrane library databases, China National Knowledge Infrastructure (CNKI), WANFANG Data, and China Science and Technology Journal Database (CSTJ) updated to January 30, 2018, were reviewed by two investigators independently. Odds ratios (ORs) and its 95% confidence intervals (95% CIs) were calculated by a fixed-effect model based on the indistinctive heterogeneity. RESULTS: For TNF-alpha-308(G/A) polymorphism, we recruited five studies including 432 NONFH patients and 760 controls and a statistically significant association was identified in Asians in four modes consisting of alleles mode (OR = 0.648, 95% CI 0.475-0.885), homozygote mode (OR = 0.330, 95% CI 0.136-0.802), dominant mode (OR = 0.344, 95% CI 0.143-0.827), and recessive mode (OR = 0.674, 95% CI 0.468-0.971), but no significant association was observed in Caucasians. For TNF-alpha-238(G/A) polymorphism, three eligible studies including 275 cases and 610 controls were evaluated and there was a significant association in alleles mode (OR = 0.270, 95% CI 0.4148-0.490) as well as recessive mode (OR = 0.254, 95% CI 0.138-0.468). CONCLUSION: This meta analysis shows that TNF-alpha-308(G/A) and -238(G/A) polymorphisms are associated with the susceptibility of NONFH, while the significant association for 308(G/A) is mainly observed in Asians. PMID- 29516237 TI - Long-term results of extensor mechanism reconstruction using Achilles tendon allograft after total knee arthroplasty. AB - PURPOSE: Disruption of the extensor mechanism after total knee arthroplasty (TKA) is an infrequent but devastating complication. Presently, limited data exists regarding the optimal treatment and long-term outcomes. METHODS: Patients who underwent reconstruction of their knee extensor mechanism using Achilles tendon allograft following TKA between January 2003 and January 2012 were identified. Sixteen patients with 17 reconstructions (10 patellar tendons, 7 quadriceps tendons) were studied. All patients underwent evaluation at an average of 45.7 months. Ten of the patients were followed to an average of 65.4 months. RESULTS: After reconstruction, the average extensor lag was 6.6 degrees and average knee flexion was 105.1 degrees . Of the patients with a minimum follow-up of two years and an average follow-up of 65.4 months, the average extensor lag and knee flexion was 8.4 degrees and 107.9 degrees , respectively, with quadriceps strength maintained at an average of 4/5. The quadriceps tendon reconstructions had an average extensor lag and flexion of 2.9 degrees and 103 degrees , respectively. The patellar tendon reconstructions, excluding one re-rupture, had an average extensor lag and flexion of 9.6 degrees and 105.1 degrees , respectively. Four patients died during the follow-up period. All but one of the patients were below the mean for age-matched controls on the SF-36. CONCLUSION: Achilles tendon allograft reconstruction is a reliable and durable treatment for patients who sustain not only patellar tendon ruptures, but also quadriceps tendon ruptures following TKA. Despite the success of this technique, the injury and procedure have a profound impact on overall function. PMID- 29516238 TI - Healing, nonunion, and re-operation after internal fixation of diaphyseal and distal femoral fractures: a systematic review and meta-analysis. AB - PURPOSE: Nonunion is a highly morbid complication that exacerbates the pain, disability and financial burden of distal and diaphyseal femur fractures. This study examined the modern rates of healing, nonunion, and other complications requiring reoperation of different fixation methods for distal and diaphyseal femur fractures. METHODS: A systematic review and meta-analysis of all records from PubMed, Embase and the Cochrane Review system was performed. Included studies had >20 acute, non-pathologic distal or diaphyseal femur fractures treated with primary internal fixation. Excluded were studies on abnormal patient/fracture populations, external fixation, or cement/bone graft use. RESULTS: Thirty-eight studies with 2,829 femoral shaft fractures and 11 studies with 505 distal femur fractures were included. Distal fractures had a lower healing rate (86.6% vs. 93.7%) and a higher re-operation rate (13.4% vs 6.1%) than shaft fractures (p < 0.00001), primarily due to higher rates of mechanical failure (p < 0.00001). Nonunion was the most frequent complication, occurring in 4.7% of distal fractures and 2.8% of shaft fractures. There was no difference between plate and nail fixation of distal fractures in healing, nonunion, or other causes of re-operation. Shaft fractures developed nonunion in 6.6% of unreamed nails and 2.1% of reamed nails (p = 0.002). Nonunion occurred in 2.3% of antegrade nailed fractures and 1.5% of retrograde nailed fractures (p = 0.66). CONCLUSIONS: Approximately one out of every eight distal fractures and one of every 16 shaft fractures requires re-operation. The most common cause of fixation failure is nonunion. Further research is needed to improve outcomes, particularly in distal femur fractures. PMID- 29516240 TI - ECIO 2018. PMID- 29516239 TI - The burden and undertreatment of fragility fractures among senior women. AB - : Using a large population database, we showed that fragility fractures were highly prevalent in senior women and were associated with significant physical disability. However, treatment rates were low because osteoporosis treatment was not prescribed or not agreed to by the majority of women with prevalent fragility fractures. PURPOSE: The purpose of the study is to estimate prevalence of fragility fractures (FF), risk factors, and treatment rates in senior women and to assess impact of FF on physical function and quality of life. METHODS: Women aged 65 years and older from the EpiReumaPt study (2011-2013) were evaluated. Rheumatologists collected data regarding FF, clinical risk factors for fractures, and osteoporosis (OP) treatment. Health-related quality of life (EQ5D) and physical function (HAQ) were analyzed. Peripheral dual-energy X-ray absorptiometry was performed. FF was defined as any self-reported low-impact fracture that occurred after 40 years of age. Prevalence estimates of FF were calculated. RESULTS: Among 3877 subjects evaluated in EpiReumaPt, 884 were senior women. The estimated prevalence of FF was 20.7%. Lower leg was the most frequent fracture site reported (37.8%) followed by wrist (18.6%). Only 7.1% of the senior women reporting a prevalent FF were under treatment for OP, and 13.9% never had treatment. OP treatment was not prescribed in 47.7% of FF women, and 23.4% refused treatment. Age (OR = 2.46, 95% CI 1.11-5.47), obesity (OR = 2.05, 95% CI 1.14-3.70), and low wrist BMD (OR = 2.29; 95% CI 1.20, 4.35; p = 0.012) were positively associated with prevalent FF. A significantly higher proportion of women in the lowest quintile of wrist bone mineral density reported FF (OR = 2.29, 95% CI 1.20-4.35). FF were associated with greater physical disability (beta = 0.33, 95% CI 0.13-0.51) independent of other comorbidities. CONCLUSION: FF was frequently reported among senior women as an important cause of physical disability. However, the prevalence of OP treatment was low, which constitutes a public health problem in this vulnerable group. PMID- 29516241 TI - Albumin-Bilirubin and Platelet-Albumin-Bilirubin Grades Do Not Predict Survival After Transjugular Intrahepatic Portosystemic Shunt Creation. AB - PURPOSE: To evaluate the capability of albumin-bilirubin (ALBI) and platelet albumin-bilirubin (PALBI) grades in predicting transplant-free survival (TFS) in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: This single-center retrospective study included 342 ALBI and 337 PALBI patients (62% men; age 53-54 years) with cirrhosis (median MELD 15) and portal hypertension complications (variceal bleeding, 55%; ascites, 35%; other, 10%) who underwent TIPS between 1998 and 2017. Serum albumin, bilirubin, and platelet levels within 24 h prior to TIPS were used to calculate ALBI and PALBI grades. The influence of ALBI and PALBI grade on 30-day, 90-day, and overall post-TIPS TFS was assessed using C-indices, binary logistic regression, and the Cox proportional model, adjusting for Child-Pugh (CP) and MELD scores. RESULTS: The cohort spanned 110 (32%) and 232 (68%) ALBI grades 2 and 3 patients, and 40 (12%) and 297 (88%) PALBI grades 2 and 3 patients. While there were no differences in 30-day survival between ALBI and PALBI grades 2/3 (P > 0.05), 90-day and overall TFS showed statistically significant differences in survival between ALBI and PALBI grades 2/3 (P < 0.05). Nonetheless, using univariate logistic regression, ALBI-PALBI C-indices (0.55-0.58) were inferior to the MELD score (0.81-0.84). Moreover, ALBI-PALBI did not associate with TFS on multivariable models adjusting for CP and MELD. Only MELD independently associated with TFS (P < 0.001). CONCLUSIONS: ALBI and PALBI grades do not stratify survival outcomes beyond MELD score following TIPS. MELD score remains the most robust metric for predicting post-TIPS survival outcomes. PMID- 29516242 TI - Addressing Infra-popliteal Thrombus in Iliofemoral DVT: The Criss-Cross Technique. AB - PURPOSE: The purpose of this work was to describe the results of a technique of simultaneous antegrade and retrograde vascular access ("criss-cross") to the popliteal vein to achieve venous recanalization in patients with acute, extensive, iliofemoral DVT with concomitant popliteal and calf vein thrombosis. MATERIALS AND METHODS: Seven patients were treated using this technique, in three patients as a bailout option after failed posterior tibial vein puncture and in four as a first option. Antegrade popliteal venous access was performed according to the usual technique using duplex ultrasound (DUS) guidance and thrombolysis (CDT), or thrombectomy (PMT) was performed. Following this, the retrograde sheath was placed under DUS guidance, a tibial vein was selectively catheterized and CDT, and/or a PMT was performed. RESULTS: Three patients underwent isolated CDT, another three had associated PMT, and one patient underwent iliofemoral PMT and catheter thromboaspiration of the popliteal and calf veins. Median thrombolysis duration was 72 h (24-72 h). SIR grade III thrombolysis was achieved in six patients and grade II in one patient. All patients underwent subsequent stenting of their iliac vein lesions. Minor complications were observed in two patients (ecchymosis), while one patient developed a hematoma on the popliteal fossa. CONCLUSION: This "criss-cross" technique represents a safe alternative to the distal (anterior or posterior tibial) vein access both as a bailout option after failed distal venous access as well as a primary approach due to its potential advantage of clearing larger thrombus volume. Experience in ultrasound-guided popliteal vein puncture is crucial to avoid complications. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 29516243 TI - High-Frequency Jet Ventilation During Cryoablation of Small Renal Tumours. AB - AIM: To evaluate the effect of high-frequency jet ventilation (HFJV) in place of standard intermittent positive-pressure ventilation (IPPV) on procedure duration, patient radiation dose, complication rates, and outcomes during CT-guided cryoablation of small renal tumours. MATERIALS AND METHODS: One hundred consecutive CT-guided cryoablation procedures to treat small renal tumours under general anaesthesia were evaluated-50 with standard IPPV and 50 after the introduction of HFJV as standard practice. Anaesthesia and procedural times, ionising radiation dose, complications, and 1-month post-treatment outcomes were collected. RESULTS: HFJV was feasible and safe in all cases. Mean procedure time and total anaesthetic time were shorter with HFJV (p = <0.0001). The number of required CT acquisitions (p = 0.0002) and total procedure patient radiation dose (p = 0.0027) were also lower in the HFJV group compared with the IPPV group. There were a total of four complications of Clavien-Dindo classification 3 or above-three in the IPPV group and one in the HFJV group. At 1-month follow-up, two cases (both in the IPPV group) demonstrated subtotal treatment. Both cases were subsequently successfully retreated with cryoablation. CONCLUSION: By reducing target tumour motion during CT-guided renal cryoablation, HFJV can reduce procedure times and exposure to ionising radiation. HFJV provides an important adjunct to complex image-guided interventions, with potential to improve safety and treatment outcomes. PMID- 29516244 TI - Molecular characterization of the full-length genome sequences of HDV strains circulating in Tunisia. AB - While Tunisia is endemic for hepatitis B virus (HBV), a recent large-scale retrospective study, revealed a very low prevalence (2%) of hepatitis Delta virus (HDV) (Yacoubi et al. in J Clin Virol 72:126-132, 2015). All strains were classified within the genotype 1 (HDV-1) as assessed by nucleotide sequencing of the so-called 'R0' region of the genome described previously. In this study, we aimed to determine the full-length genome sequence of HDV isolates in order to fully characterize the HDV strains spreading in Tunisia. Eleven HDV antibody and RNA positive samples were obtained from the 1615 clinical samples previously studied. The whole genome sequence was obtained for 5 strains by sequencing and realignment of four overlapping regions covering the entire genome, followed by extensive phylogenetic analyses. Tunisian sequences segregated together with Turkish and African sequences and showed 60% GC content. Alignment with an HDV-1 consensus sequence revealed that they exhibited several point mutations in different functional domains of the delta proteins that, according to previous studies, might possibly affect their properties. In conclusion, the first full length genome sequences of Tunisian HDV isolates are provided, isolates which are closely related to Turkish and Sub-Saharan Africa strains, supporting the hypothesis for the spread of HDV-1-strains from Africa via Tunisia to Turkey, before spread to the rest of the world. PMID- 29516245 TI - Detection of noroviruses in free-ranging jaguars (Panthera onca) in the Pantanal, Mato Grosso, Brazil. AB - Nine free-ranging jaguars (Panthera onca) were captured, and rectal swabs were collected in the Pantanal of Caceres, Mato Grosso, Brazil. Reverse transcription polymerase chain reaction specific for noroviruses was performed. Six jaguars (66.6%) tested positive for norovirus genotype GII.11. PMID- 29516247 TI - Genomic characterization of grapevine virus J, a novel virus identified in grapevine. AB - This paper describes the nucleotide sequence and genome organization of a novel RNA virus detected in grapevine (Vitis vinifera) cultivar 'Kizil Sapak' by high throughput sequencing (HTS) and tentatively named "grapevine virus J" (GVJ). The full genome of GVJ is 7,390 nucleotides in length, which comprises five open reading frames (ORFs), including a 20K ORF (ORF 2) between the replicase (ORF 1) and the movement protein (ORF 3) genes. According to the level of sequence homology and phylogenetics, GVJ is proposed as a new member of the genus Vitivirus (subfamily Trivirinae; family Betaflexiviridae), with the closest characterized virus being grapevine virus D (GVD). PMID- 29516246 TI - A barnavirus sequence mined from a transcriptome of the Antarctic pearlwort Colobanthus quitensis. AB - Because so few viruses in the family Barnaviridae have been reported, we searched for more of them in public sequence databases. Here, we report the complete coding sequence of Colobanthus quitensis associated barnavirus 1, mined from a transcriptome of the Antarctic pearlwort Colobanthus quitensis. The 4.2-kb plus strand sequence of this virus encompasses four main open reading frames (ORFs), as expected for barnaviruses, including ORFs for a protease-containing polyprotein, an RNA-dependent RNA polymerase whose translation appears to rely on - 1 ribosomal frameshifting, and a capsid protein that is likely to be translated from a subgenomic RNA. The possible derivation of this virus from a fungus associated with C. quitensis is discussed. PMID- 29516248 TI - Molecular investigation of foot-and-mouth disease virus circulating in Pakistan during 2014-17. AB - This study reports the molecular characterization of foot-and-mouth disease virus (FMDV) in the provinces of Punjab and Sindh, Pakistan during 2014-17. FMDV genome was detected in 42 and 41 out of 46 samples (epithelial tissue and saliva) by reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Sequences of the complete VP1 coding region of the samples (n = 33) was achieved showing that 10, 4 and 19 samples belonged to serotype O, A and Asia1 respectively. Phylogenetic analysis of serotype O revealed that at least one novel sublineage within the ME-SA topotype is circulating in the region, named here as PAK-14. This sublineage showed similarity with the viruses circulating in Turkey and Pakistan during 2010 indicating that viruses circulating in these countries have common origin. Analysis of serotype A viruses revealed a new lineage is circulating in the region, reported here as A-PAK14 showing close identity with the strain prevalent in Pakistan during 2007. Circulation of these new linages in the region shows continuous evolution of the viruses. Two of the undisclosed serotype A sublineages within the Iran-05 lineage were also found circulating in the region. In addition, molecular investigation of the VP1 coding region sequences of serotype Asia1 strains revealed that they belong to Group-VII (Sindh 08). Interestingly some of the serotype Asia1 isolates (n = 6) showed 99.9% similarity (among themselves) although they were collected from different districts more than 100 Km apart from one another. This unusual conservation among serotype Asia1 over long distances can be explored by studying the role of wild animals, slaughter houses and milk collection centres in the spread the disease. PMID- 29516249 TI - Comparison of the accuracy of the London atlas and Smith method in dental age estimation in 5-15.99-year-old Iranians using the panoramic view. AB - Tooth development is widely used for age estimation and staging physical maturity. It is of great importance in dental age estimation in forensic dentistry, orthodontic treatment planning, and pediatric endocrinology. This study aimed to compare the accuracy of two age estimation methods, i.e., the London Atlas and Smith's method, using the panoramic view of developing teeth. In this descriptive-analytic study, panoramic radiographs of 339 healthy individuals, including 145 boys and 194 girls, were assessed. The participants aged between 5.00 and 15.99 years. Dental age of the subjects was determined by the London Atlas of Human Tooth Development and Eruption and Smith's method. The collected information was entered in the SPSS software (Ver.18). Differences and correlations between chronological and dental age were assessed by paired t tests and Pearson's correlation analysis. In all analyzes, the significance level was considered less than 0.05. The mean chronological age of the subjects was 10.13 +/- 2.92 years. The mean ages estimated by the London Atlas and Smith's method were 10.29 +/- 2.91 and 9.89 +/- 2.84 years, respectively. Paired t test showed that the differences between the mean chronological age and mean estimated ages using the London Atlas and Smith's method were not significant (P = 0.15 and 0.16, respectively). Our findings showed that both methods had high accuracy for age estimation, but the London Atlas is easier to use. PMID- 29516250 TI - Forensic reconstruction of two military combat related shooting incidents using an anatomically correct synthetic skull with a surrogate skin/soft tissue layer. AB - Six synthetic head models wearing ballistic protective helmets were used to recreate two military combat-related shooting incidents (three per incident, designated 'Incident 1' and 'Incident 2'). Data on the events including engagement distances, weapon and ammunition types was collated by the Defence Science and Technology Laboratory. The models were shot with 7.62 * 39 mm ammunition downloaded to mean impact velocities of 581 m/s (SD 3.5 m/s) and 418 m/s (SD 8 m/s), respectively, to simulate the engagement distances. The damage to the models was assessed using CT imaging and dissection by a forensic pathologist experienced in reviewing military gunshot wounds. The helmets were examined by an MoD engineer experienced in ballistic incident analysis. Damage to the helmets was consistent with that seen in real incidents. Fracture patterns and CT imaging on two of the models for Incident 1 (a frontal impact) were congruent with the actual incident being modelled. The results for Incident 2 (a temporoparietal impact) produced realistic simulations of tangential gunshot injury but were less representative of the scenario being modelled. Other aspects of the wounds produced also exhibited differences. Further work is ongoing to develop the models for greater ballistic injury fidelity. PMID- 29516251 TI - Carpals and epiphyses of radius and ulna as age indicators using longitudinal data: a Bayesian approach. AB - The aim of this study is to develop a new formula for age estimation in a longitudinal study of a sample from the radiological collection of wrist bones of growing infants, children, and adolescents recorded at the Burlington Growth Centre. A sample of 82 individuals (43 boys and 39 girls), aged between 3 and 16 years, were analyzed with a total of 623 X-rays of left hand-wrist bones by measuring the area of carpal bones and epiphyses of the ulna and radius (Bo) and carpal area (Ca). The intra-class correlation coefficient (ICC) and its 95% confidence interval were used to evaluate intra-observer agreement. Hierarchical Bayesian calibration has been adopted to exceed the bias deriving from the classical regression approach used for age estimation in forensic disciplines, since it tends to overestimate or underestimate the age of the individuals. Calibration distributions of the dataset obtained by the evaluation of BoCa (the ratio of Bo and Ca) suggested mean absolute errors (MAE) of 1.07 and 1.34 years in boys and girls, respectively. The mean interquartile range (MIQR) was 1.7 and 2.42 years in boys and girls, respectively. The respective bias of the estimates was betaERR = - 0.025 and - 0.074. Furthermore, a correspondence between different BoCa values and estimated age with its standard deviation (SD) was calculated for boys and girls, respectively. In conclusion, the Bayesian calibration method appears to be suitable for assessing both age and its distribution in subadults, according to hand-wrist maturity. Furthermore, it can easily incorporate other age predictors, obtaining a distribution of the subjects with multivariate predictors. PMID- 29516252 TI - Ex vivo immunomodulatory effect of ethanolic extract of propolis during Celiac Disease: involvement of nitric oxide pathway. AB - Celiac Disease (CeD) is a chronic immune-mediated enteropathy, in which dietary gluten induces an inflammatory reaction, predominantly in the duodenum. Propolis is a resinous hive product, collected by honeybees from various plant sources. Propolis is well-known for its anti-inflammatory, anti-oxidant and immunomodulatory effects, due to its major compounds, polyphenols and flavonoids. The aim of our study was to assess the ex vivo effect of ethanolic extract of propolis (EEP) upon the activity and expression of iNOS, along with IFN-gamma and IL-10 production in Algerian Celiac patients. In this context, PBMCs isolated from peripheral blood of Celiac patients and healthy controls were cultured with different concentrations of EEP. NO production was measured using the Griess method, whereas quantitation of IFN-gamma and IL-10 levels was performed by ELISA. Inducible nitric oxide synthase (iNOS) expression, NFkappaB and pSTAT-3 activity were analyzed by immunofluorescence assay. Our results showed that PBMCs from Celiac patients produced high levels of NO and IFN-gamma compared with healthy controls (HC). Interestingly, EEP reduced significantly, NO and IFN-gamma levels and significantly increased IL-10 levels at a concentration of 50 ug/mL. Importantly, EEP downmodulated the iNOS expression as well as the activity of NFkappaB and pSTAT-3 transcription factors. Altogether, our results highlight the immunomodulatory effect of propolis on NO pathway and on pro-inflammatory cytokines. Therefore, we suggest that propolis may constitute a potential candidate to modulate inflammation during Celiac Disease and has a potential therapeutic value. PMID- 29516253 TI - Effects of heavy metal pollution on enzyme activities in railway cut slope soils. AB - Railway transportation is an important transportation mode. However, railway transportation causes heavy metal pollution in surrounding soils. Heavy metal pollution has a serious negative impact on the natural environment, including a decrease of enzyme activities in soil and degradation of sensitive ecosystems. Some studies investigated the heavy metal pollution at railway stations or certain transportation hubs. However, the pollution accumulated in artificial cut slope soil all along the rails is still questioned. The interest on non-point source pollution from railways is increasing in an effort to protect the soil quality along the line. In this study, we studied spatial distributions of heavy metals and five enzyme activities, i.e., urease (UA), saccharase (SAC), protease (PRO), catalase (CAT), and polyphenol oxidase (POA) in the soil, and the correlation among them beside three different railways in Sichuan Province, China, as well. Soil samples were respectively collected from 5, 10, 25, 50, 100, and 150 m away from the rails (depth of 0-8 cm). Results showed that Mn, Cd, Cu, and Zn were influenced by railway transportation in different degrees while Pb was not. Heavy metal pollution was due to the abrasion of the gravel bed as well as the tracks and freight transportation which caused more heavy metal pollution than passenger transportation. Enzymatic activities were significantly negatively correlated with heavy metals in soils, especially Zn and Cu. Finally, it is proposed that combined use of PRO and POA activities could be an indicator of the heavy metal pollution in cut slope soils. The protective measures aimed at heavy metal pollution caused by railway transportation in cut slope soils are urgent. PMID- 29516255 TI - 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. PMID- 29516254 TI - Systemic Treatment for Adults with Synovial Sarcoma. AB - OPINION STATEMENT: Synovial sarcoma (SS) is a rare, yet highly malignant, type of soft tissue sarcoma (STS), for which survival has not improved significantly during the past years. In this review, we focus on systemic treatment in adults. Compared to other STS, SS are relatively chemosensitive. Ifosfamide and ifosfamide combinations are active in different lines of treatment. In high-risk extremity and chest wall STS, neoadjuvant doxorubicin and ifosfamide has shown as much activity as high-dose ifosfamide. There are indications that combination chemotherapy with doxorubicin and ifosfamide in this setting improves outcome. In the first-line metastatic setting, combination treatment with doxorubicin and ifosfamide is a preferred option in fit patients, while in other patients, sequential doxorubicin and ifosfamide can be considered. In second and later lines, pazopanib and trabectedin have shown activity. Many new approaches to treat metastatic SS are currently under investigation, both preclinical as well as clinical, including other receptor tyrosine kinase inhibitors, epigenetic modulators, compounds interfering with DNA damage response (DDR), and immunotherapy. PMID- 29516256 TI - Utility of C-reactive protein as predictive biomarker of anastomotic leak after minimally invasive esophagectomy. AB - BACKGROUND: Early detection of anastomotic leakage after esophagectomy has the potential to reduce morbidity and mortality. Prompt suspicion of leak may help to exclude patients from fast-track protocols, thereby avoiding early oral feeding and early hospital discharge which could aggravate the prognosis of a clinically occult leak. PATIENTS AND METHODS: Observational retrospective cohort study. Patients with diagnosis of esophageal cancer who underwent elective minimally invasive esophagectomy were included. The following data were collected: age, gender, BMI, comorbidities, ASA score, tumor histology, TNM staging, use of neo adjuvant therapy, type of operation, operative time, morbidity, and 90-day mortality. A panel of biomarkers including C-reactive protein (CRP), procalcitonin (PCT), white blood cells (WBC), and percentage of neutrophils (PN) were measured at baseline and on postoperative days 3, 5, and 7. RESULTS: Two hundred forty-three patients operated between 2012 and 2017 were included in the study. Anastomotic leakage occurred in 29 patients. There was a statistical association over time between anastomotic leakage and CRP (p < 0.001), PCT (p < 0.001), WBC (p = 0.019), and PN (p = 0.007). The cut-off value of CRP on POD 5 was 8.3 mg/dL, AUC = 0.818, negative LR = 0.176. CONCLUSIONS: Increased serum CRP, PCT, WBC, and PN after minimally invasive esophagectomy are associated with anastomotic leakage. A CRP value lower than 8.3 mg/dL, combined with reassuring clinical and radiological signs, may be useful to exclude leakage on postoperative day 5. PMID- 29516257 TI - The effects of two different doses of ultraviolet-A light exposure on nitric oxide metabolites and cardiorespiratory outcomes. AB - PURPOSE: The present study investigated different doses of ultraviolet-A (UV-A) light on plasma nitric oxide metabolites and cardiorespiratory variables. METHODS: Ten healthy male participants completed three experimental conditions, 7 days apart. Participants were exposed to no light (CON); 10 J cm2 (15 min) of UV A light (UVA10) and 20 J cm2 (30 min) of UV-A light (UVA20) in a randomized order. Plasma nitrite [NO2-] and nitrate [NO3-] concentrations, blood pressure (BP), and heart rate (HR) were recorded before, immediately after exposure and 30 min post-exposure. Whole body oxygen utilization ([Formula: see text]), resting metabolic rate (RMR) and skin temperature were recorded continuously. RESULTS: None of the measured parameters changed significantly during CON (all P > 0.05). [Formula: see text] and RMR were significantly reduced immediately after UVA10 (P < 0.05) despite no change in plasma [NO2-] (P > 0.05). Immediately after exposure to UVA20, plasma [NO2-] was higher (P = 0.014) and [Formula: see text] and RMR tended to be lower compared to baseline (P = 0.06). There were no differences in [NO2-] or [Formula: see text] at the 30 min time point in any condition. UV-A exposure did not alter systolic BP, diastolic BP or MAP (all P > 0.05). UV-A light did not alter plasma [NO3-] at any time point (all P > 0.05). CONCLUSIONS: This study demonstrates that a UV-A dose of 20 J cm2 is necessary to increase plasma [NO2-] although a smaller dose is capable of reducing [Formula: see text] and RMR at rest. Exposure to UV-A did not significantly reduce BP in this cohort of healthy adults. These data suggest that exposure to sunlight has a meaningful acute impact on metabolic function. PMID- 29516258 TI - Hepatotoxic responses of 4-nonylphenol on African catfish (Clarias gariepinus): antixoidant and histochemical biomarkers. AB - 4-Nonylphenol (NP) toxicity in fish attracts much attention due to its ability in targeting several organs; however, the researches regarding its potential hepatotoxicity are conflicting and still require further investigation. Therefore, the objective of this study is to focus on this issue from the histophysiological point of view using NP intoxicated African catfish (Clarias gariepinus) as a model of hepatotoxicity. Twelve adult fish (6 per group) were divided into two groups; the first was considered as a control and the second was exposed to NP dissolved in water at a dose of 0.1 mg/kg BW for 3 weeks. A significant reduction in the hepatic alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels was observed in NP-exposed fish. Concerning the oxidant/antioxidant balance, a significant depletion in superoxide dismutase, catalase, and glutathione peroxidase was found along with a significant elevation in total peroxide and malondialdhyde. The histopathological examination of the hepatic tissues revealed that NP had marked hepatotoxic effects including hepatitis, centrilobular and focal hydropic and fatty degeneration, fatty change (steatosis), hepatic coagulative necrosis, and nuclear alterations in addition to apoptosis of hepatocytes and necrosis of endothelial cells. Depletion of the glycogen and increased in pigments (lipofuscin and hemosiderin) content in the hepatocytes were also recorded. Hemosiderosis and proliferation of the connective tissue around the blood vessels and branches of bile ducts and in the portal areas were also observed. In light of these findings, it was concluded that NP has a well-defined hepatotoxic impact paving the road towards other studies to investigate other detrimental cyto physiological influences of this aquatic pollutant. PMID- 29516259 TI - Zygote injection of RNA encoding Cre recombinase results in efficient removal of LoxP flanked neomycin cassettes in pigs. AB - Genetically engineered pigs are often created with a targeting vector that contains a loxP flanked selectable marker like neomycin. The Cre-loxP recombinase system can be used to remove the selectable marker gene from the resulting offspring or cell line. Here is described a new method to remove a loxP flanked neomycin cassette by direct zygote injection of an mRNA encoding Cre recombinase. The optimal concentration of mRNA was determined to be 10 ng/MUL when compared to 2 and 100 ng/MUL (P < 0.0001). Development to the blastocyst stage was 14.1% after zygote injection with 10 ng/MUL. This method successfully removed the neomycin cassette in 81.9% of injected in vitro derived embryos; which was significantly higher than the control (P < 0.0001). Embryo transfer resulted in the birth of one live piglet with a Cre deleted neomycin cassette. The new method described can be used to efficiently remove selectable markers in genetically engineered animals without the need for long term cell culture and subsequent somatic cell nuclear transfer. PMID- 29516260 TI - Activation of satellite glial cells in trigeminal ganglion following dental injury and inflammation. AB - Satellite glial cells (SGCs), a peripheral neuroglial cell, surround neurons and form a complete envelope around individual sensory neurons in the trigeminal ganglia (TG), which may be involved in modulating neurons in inflammation. The purpose of this study was to determine the effect of dental injury and inflammation on SGCs in the TG. Pulp exposure (PX) was performed on the first maxillary molar of 28 rats. The neurons innervating injured tooth in TG were labeled by the retrograde transport of fluoro-gold (FG). Specimens were collected at 1, 3, 7, 14, 21 and 28 days after PX and stained immunohistochemically for glial fibrillary acid protein (GFAP), a marker of SGCs activation, in the TG. We observed that GFAP-immunoreactivity (IR) SGCs enclosed FG-labeled neurons increased in a time-dependent manner after PX. The neurons surrounded by GFAP-IR SGCs were mainly small and medium in size. The GFAP-IR SGCs encircled neurons increased significantly in the maxillary nerve region of the TG at 7-28 days following PX. The results show that dental injury and inflammation induced SGCs activation in the TG. It indicates that activation of SGCs might be implicated in the peripheral mechanisms of pain following dental injury and inflammation. PMID- 29516261 TI - Therapeutic potential of Bama miniature pig adipose stem cells induced hepatocytes in a mouse model with acute liver failure. AB - The role of mesenchymal stem cells (MSCs) in cellular therapy is well recognized in this work. MSCs have advantages of high proliferation, clone formation, multi lineage differentiation and immunosuppression. Furthermore, adipose-resident MSCs (ADSCs) are extensively employed due to its advantages of abundant source, low cost and simple operation. Many researchers have emphasized the role of adipose resident MSCs in the development of therapies for liver injury, but few attentions were paid on the use of induced functional hepatocytes. Therefore, in this work the role of adipose-resident MSCs induced functional hepatocytes was mainly investigated. The function of induced hepatocytes by ELISA and the induction rate was confirmed by flow cytometry and evaluated by experimental observations. The induced hepatocytes were firstly transplanted into CCl4-caused liver damage ICR mice by tail vein. After transplantation, both liver fibrosis and function could be improved by hepatocytes, which were examined through histology, immunofluorescence staining, serum profile and biochemical parameters levels. The production of cytokines was then compared with normal mice and injury mice to explore the therapeutic mechanisms of hepatocytes. Finally, the secretions of TGF-beta1, IL-6 and IL-10 in hepatocytes transplanted mice were determined and found to be higher than that of the normal and injury mice. The hepatocytes derived from ADSCs were proven to have a great significance in the therapeutic efficacy and clinical settings of liver disease animal models. PMID- 29516262 TI - Facile Synthesis of Ultralong and Thin Copper Nanowires and Its Application to High-Performance Flexible Transparent Conductive Electrodes. AB - A hydrothermal method for synthesizing ultralong and thin copper nanowires (CuNWs) with average diameter of 35 nm and average length of 100 MUm is demonstrated in this paper. The concerning raw materials include copric (II) chloride dihydrate (CuCl2.2H2O), octadecylamine (ODA), and ascorbic acid, which are all very cheap and nontoxic. The effect of different reaction time and different molar ratios to the reaction products were researched. The CuNWs prepared by the hydrothermal method were applied to fabricate CuNW transparent conductive electrode (TCE), which exhibited excellent conductivity-transmittance performance with low sheet resistance of 26.23 [Formula: see text] and high transparency at 550 nm of 89.06% (excluding Polyethylene terephthalate (PET) substrate). The electrode fabrication process was carried out at room temperature, and there was no need for post-treatment. In order to decrease roughness and protect CuNW TCEs against being oxidized, we fabricated CuNW/poly(methyl methacrylate) (PMMA) hybrid TCEs (HTCEs) using PMMA solution. The CuNW/PMMA HTCEs exhibited low surface roughness and chemical stability as compared with CuNW TCEs. PMID- 29516264 TI - Can positional therapy be simple, effective and well tolerated all together? A prospective study on treatment response and compliance in positional sleep apnea with a positioning pillow. AB - PURPOSE: Until now, there is no clear consensus on optimal care for mild sleep related breathing disorders (SRBD) in general or for positional obstructive sleep apnea (POSA) in particular. Most proposed treatment options are either invasive and/or expensive. Positional therapy (PT) may therefore present as a valuable first-line intervention in POSA. METHODS: Twenty-eight patients presenting with POSA were enrolled in a prospective cohort study. The protocol consisted of three nights of polysomnography (PSG) in an academic sleep lab. Inclusion was based on the first PSG. During a consecutive PSG, PT was provided by means of a sleep positioning pillow (Posiform(r)). The third PSG was performed after 1 month of PT. Sleepiness, fatigue, and sleep quality were assessed with the Epworth Sleepiness Scale (ESS), the fatigue severity scale (FSS), the Pittsburgh Sleep Quality Index (PSQI), and the Function Outcomes of Sleep Questionnaire (FOSQ) at baseline, and after 1 and at 6 months of PT alongside satisfaction and compliance ratings. RESULTS: Significant immediate treatment effects after one night and sustained after 1 month were observed by significant reductions of sleep in supine position (p < .001), sleep fragmentation (p < .05), apnea-hypopnea (p < .001), respiratory disturbance (p < .001), and oxygen desaturation (p < .001) indices. PSQI (p < .001), ESS (p < .005), and FOSQ (p < .001) also showed significant and persistent improvements. CONCLUSIONS: Combined effects on sleep related respiration and clinical symptoms were observed after PT initiation as well as after 1 month using the sleep-positioning pillow. Furthermore, reported compliance and overall satisfaction appeared to be highly concordant both at 1 month and 6 months follow-up. PMID- 29516263 TI - The Impact of Baked Egg and Baked Milk Diets on IgE- and Non-IgE-Mediated Allergy. AB - Baked milk (BM) and baked egg (BE) diets are increasingly used in the management of milk and egg allergy, rather than avoidance. Children with tolerance versus reactivity to BM and BE may have smaller skin prick test and lower specific IgE, and BM-tolerant children have less basophil reactivity and more peripheral T regulatory cells. However, most milk- and egg-allergic children tolerate BM and BE and an individual's reactivity is unpredictable. Non-reactivity is due to conformational changes in the allergens. Significant differences in the published advice about methods of introduction exist from graded introduction at home to a medically supervised full dose. These approaches carry different risks and may have different immunological effects. Reactivity to BM is a predictor of a severe milk allergy. Therefore, medical supervision for BM and BE introduction is prudent. The baked diet allows dietary liberation. Most, but not all, BM- and BE tolerant children continue eating the baked foods. The prognosis of children who can eat BM and BE is favorable with likely resolution of their allergy over the next few years. Murine models of BE diets demonstrate that heated egg can impart clinical protection against anaphylaxis and cause immune changes. Most observational human studies of BM and BE diets demonstrate clinical resolution of allergy and favorable immune changes versus regular care controls. However, the one randomized controlled trial for the BE diet in BE-tolerant children did not support an immune-modifying effect of the BE diet. Another study of BE immunotherapy is expected to be completed in 2018. There is currently no evidence for prevention of allergy with the baked diets. There may be a future role for BM and BE in liberating the diets of individuals with non-IgE-mediated allergy given recent studies that a subset of these patients can consume BM without a clinical reaction. PMID- 29516265 TI - The Path to Implementation of HIV Pre-exposure Prophylaxis for People Involved in Criminal Justice Systems. PMID- 29516266 TI - The Dual Role of Neutrophils in HIV Infection. AB - PURPOSE OF REVIEW: We summarize what is known about neutrophils in HIV infection, focusing on their potential roles in HIV protection, acquisition, and pathogenesis. RECENT FINDINGS: Recent studies have demonstrated that neutrophil associated proteins and cytokines in genital tissue pre-infection associate with HIV acquisition. However, recent in vivo assessment of highly exposed seronegative individuals and in vitro studies of anti-HIV functions of neutrophils add to older literature evidence that neutrophils may be important in a protective response to HIV infection. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species, proteases, and other potentially harmful effector molecules. Overall, there is a clear evidence for both helpful and harmful roles of neutrophils in HIV acquisition and pathogenesis. Further study, particularly of tissue neutrophils, is needed to elucidate the kinetics, phenotype, and functionality of neutrophils in HIV infection to better understand this dichotomy. PMID- 29516267 TI - The Influence of Cervicovaginal Microbiota on Mucosal Immunity and Prophylaxis in the Battle against HIV. AB - PURPOSE OF REVIEW: Young women in sub-Saharan Africa bear a disproportionate burden of the global HIV epidemic. In this review, we examine how cervicovaginal microbiota modulate structural and immune defenses in the female genital tract and influence HIV susceptibility. RECENT FINDINGS: Highly diverse, anaerobic cervicovaginal microbiota prevalent in sub-Saharan African women increase HIV acquisition risk by over fourfold. These bacteria weaken the barrier properties of the vaginal mucosa and increase local inflammation and HIV target cell recruitment, creating an environment permissive to HIV. These communities also diminish the prophylactic efficacy of topical tenofovir and therefore may modulate both biological susceptibility to HIV and the effectiveness of pre exposure prophylaxis (PrEP). Cervicovaginal bacteria influence multiple reproductive health outcomes, including HIV acquisition. High-diversity, low Lactobacillus abundance cervicovaginal communities prevalent in many regions with high HIV incidence are associated with increased HIV susceptibility. A better understanding of the host-microbial interactions mediating this risk is important to reduce HIV infections, particularly among women living in sub-Saharan Africa. PMID- 29516268 TI - Predicting mayfly recovery in acid mine-impaired streams using logistic regression models of in-stream habitat and water chemistry. AB - Mayflies (Order Ephemeroptera) require high quality water and habitat in streams to thrive, so their appearance after restoration is an indicator of ecological recovery. To better understand the importance of restoring in-stream habitat versus water chemistry for macroinvertebrate communities, we developed taxon specific models of occurrence for five mayfly genera (Caenis, Isonychia, Stenonema, Stenacron, and Baetis) inhabiting streams in the Appalachian Mountains, USA. Presence/absence records from past decades were used to develop single and multiple logistic predictive models based on catchment characteristics (drainage area, gradient), in-stream habitat variables (e.g., substrate, channel morphology, pool and riffle quality), and water chemistry. Model performance was evaluated using (a) classification rates and Hosmer-Lemeshow values for test sets of data withheld from the original model-building dataset and (b) a field comparison of predicted versus observed mayfly occurrences at 53 sites in acid mine drainage-impaired watersheds in 2012. The classification accuracies of final models for Caenis, Stenacron, and Baetis ranged from 50 to 75%. In-stream habitat features were not significant predictor variables for these three taxa, only water chemistry. Models for Isonychia and Stenonema had higher classification rates (81%) and included both habitat and chemical variables. However, actual occurrences of Isonychia and Stenonema at study sites in 2012 were low, consistent with the calculated probability of occurrence (Po) < 0.60. Caenis occurred at test sites 35% of the time when the model predicted a Po > 0.40. Stenacron showed the greatest consistency of actual versus predicted occurrences, occurring at 56% of sites when the Po (based on pH and conductivity) was > 0.50 and only at 1 site when Po < 0.5. The results demonstrate how predictive models of individual indicator taxa could be valuable for evaluating the relative impacts of restoring physical habitat versus water chemistry during stream remediation. PMID- 29516270 TI - Resection depth and layer of cold snare polypectomy versus endoscopic mucosal resection. AB - BACKGROUND: Cold snare polypectomy (CSP) has not undergone sufficient histopathological evaluation. This study aimed to clarify the histopathological features of CSP specimens, including resection depth and layer, as compared with endoscopic mucosal resection (EMR). METHODS: Polyps were recruited retrospectively. Sessile, semi-pedunculated, and 0-IIa polyps of <= 9 mm were selected by propensity score matching and classified as either a complete resection or one with an unevaluable/positive (X/+) margin. Resection depth and layer were estimated and the risk factors for an X/+ margin were evaluated. RESULTS: A total of 1072 polyps were enrolled. After matching, 184 polyp pairs were selected. An X/+ margin was seen in 105/184 (57%) vs. 70/184 (38%) CSP vs. EMR specimens (p < 0.001): specimen damage was 53/184 (29%) vs. 30/184 (16%) (p < 0.01) and vertical margin (VM) X/+ was 11/184 (6%) vs. 2/184 (1%) (p < 0.05). Among 193 completely resected specimens, resection depth from the muscularis mucosae in CSP vs. EMR was 76 vs. 338 um (p < 0.001) and resection layer was the submucosa in 7/79 (9%) vs. 105/114 (92%) (p < 0.001). In multivariate analysis, CSP was a risk factor for procedure-associated VMX/+ [odds ratio (OR) 6.80, 95% confidence interval (CI) 1.33-34.69, p < 0.05]. Sessile serrated adenoma/polyp (SSA/P) was a risk factor for VMX/+ margin in CSP specimens (OR 58.36, 95% CI 7.45-456.96, p < 0.001). CONCLUSIONS: SSA/P and colorectal cancer may not be suitable for CSP adoption. PMID- 29516269 TI - Tau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans. AB - We studied the effect of two rare mutations (rs144662445 and rs149979685) in the A-kinase anchoring protein 9 (AKAP9) gene, previously associated with Alzheimer disease (AD) in African Americans (AA), on post-translational modifications of AD related pathogenic molecules, amyloid precursor protein (APP) and microtubule associated protein Tau using lymphoblastoid cell lines (LCLs) from 11 AA subjects with at least one AKAP9 mutation and 17 AA subjects lacking these mutations. LCLs were transduced by viral vectors expressing causative AD mutations in APP or human full-length wild type Tau. Cell lysates were analyzed for total APP, Abeta40, and total and T181 phospho-Tau (pTau). AKAP9 mutations had no effect on Abeta40/APP, but significantly increased pTau/Tau ratio in LCLs treated with phosphodiesterase-4 inhibitor rolipram, which activates protein kinase A. Proteomic analysis of Tau interactome revealed enrichment of RNA binding proteins and decrease of proteasomal molecules in rolipram-treated cells with AKAP9 mutations. This study shows the impact of rare functional AKAP9 mutations on Tau, a central mechanism of AD pathogenesis, in LCLs derived from AD and control subjects. PMID- 29516271 TI - Antibody-Conjugated Silica-Modified Gold Nanorods for the Diagnosis and Photo Thermal Therapy of Cryptococcus neoformans: an Experiment In Vitro. AB - BACKGROUND: Cryptococcus neoformans is an encapsulated yeast. There is still little quick and effective solution for the diagnosis or treatment of C. neoformans infection at an early stage in clinical. Antibody-conjugated silica modified gold nanorods (GNR-SiO2-Ab) can conjugate C. neoformans selectively. It may provide a possibility for treatment of cryptococcosis safely and effectively. METHODS: Gold nanorods (GNRs) were synthesized according to the seed-mediated template-assisted protocol. Anti-C. neoformans antibody was covalently anchored on the surface of GNRs with silane coupling agent. In vitro computer tomography imaging was performed to explore the diagnostic effect of the GNR-SiO2-Ab. The viability of cells was evaluated to confirm the photo-thermal therapy effect of GNR-SiO2-Ab combined with near-infrared (NIR) laser light. RESULTS: GNR-SiO2-Ab has a potential application as a positive X-ray/CT imaging contrast agent. An antibody can induce a much greater aggregation of GNRs by binding to the surface of C. neoformans cells resulting in a much higher attenuation values than ever. After irradiation, C. neoformans cells suffered photo-thermal damages and the normal structure of cells were destroyed. The viability of cells reduced significantly compared to the untreated cells. CONCLUSIONS: Our work confirmed that antibody-conjugated silica-modified gold nanorods could enhance X-ray attenuation of C. neoformans cells in CT images. And immune GNRs, which were mediated by antibodies, could increase the effects of NIR-induced photo-thermal therapy in C. neoformans cells. PMID- 29516272 TI - Advances and Challenges in Transitional Urology: Caring for Adolescents and Young Adults with Lifelong Complex Genitourinary Conditions. AB - PURPOSE OF REVIEW: As long-term survival with complex congenital and pediatric diseases has improved, more patients with congenital genitourinary conditions are living into adulthood. These patients can continue to face lifelong issues related to their conditions, including urinary incontinence, recurrent urinary tract infections, chronic kidney disease, and difficulties with sexual health and function. RECENT FINDINGS: The practice of transitional urology continues to grow nationwide and abroad, and it will be important to develop evidence-based practices for coordinated transition of these patients into the adult health care setting. This review describes the broader attention to transitions of care in medicine and specifically evaluates spina bifida as a model disease system for implementation of transitional practices in urology. PMID- 29516273 TI - Implant failure in bilateral metal-on-metal hip resurfacing arthroplasties: a clinical and pathological study. AB - Metal-on-metal hip resurfacing arthroplasties (MoMHRAs) have a high failure rate due to pseudotumour formation. It is not certain whether pseudotumours in bilateral MoMHRAs form on the basis of an adverse reaction to metal debris (ARMD) that is entirely due to a local innate and adaptive immune response to Cobalt Chrome (Co-Cr) wear particles. To determine if there is a systemic component to ARMD in bilateral MoMHRAs, we examined the histology of ARMD in unilateral and bilateral MoMHRAs revised for pseudotumour and determined whether implant survival differed between these two groups. Periprosthetic tissue specimens from 119 hips revised for pseudotumour were examined. These were derived from 109 patients including 10 patients with bilateral MoMHRAs and 99 with sunilateral MoMHRAs including a cohort of 20 patients with bilateral MoMHRAs that had undergone only one MoMHRA revision for pseudotumour. The mean time to revision for pseudotumour of unilateral and bilateral MoMHRAs was determined. The histology of periprosthetic tissue was examined for evidence of the innate and adaptive immune response and scored semi-quantitatively. There was no significant difference in histological features of the innate / adaptive response between Group 1 bilateral pseudotumours and Group 2 and Group 3 unilateral pseudotumours. Histological features, including ALVAL scores, were similar in the periprosthetic tissues of right and left hips in Group 1 bilateral MoMHRAs. The mean time to first revision for pseudotumour of bilateral MoMHRAs (6.59 years) was not decreased compared with unilateral MoMHRAs (5.66 years) or bilateral MoMHRAs that had only one revision (7.05 years). Right and left hip pseudotumours in bilateral MoMHRAs exhibit similar histological features of the innate and adaptive immune response. Mean implant survival is not decreased in bilateral compared with unilateral MoMHRA cases. The findings suggest that pseudotumour formation is due more to a local than a systemic innate /adaptive immune response to components of metal wear. PMID- 29516274 TI - Long-term dynamics of total mercury in surficial bottom sediments of the Volga River's reservoir in central Russia. AB - The long-term dynamics of mercury in bottom sediments of Uglich Reservoir were examined. Samples of the 0-5-cm surface layer of bottom sediment collected during research expeditions in 1958, 1977, 1991, and 2012 were analyzed. An increase in the average mercury concentration from 1958 to 1977 (0.440 +/- 0.039 and 0.668 +/ 0.065 mg/kg d.w., respectively) was followed by a decrease in 2012 (0.260 +/- 0.021 mg/kg d.w.). During all years except 1991, a significant correlation was found between mercury content and the amount of organic matter in the sediments (r = 0.54-0.87, p < 0.01), flow velocity (r = 0.38-0.53, p < 0.01), and the rate of sedimentation in the reservoir (r = - 0.51 to - 0.69, p < 0.01). Calculations based on these results and previously published data from the study region on the density of atmospheric mercury precipitation showed that the watershed as a whole received 2.4-3.0 t on an annual basis, and in the same period, the water surface received 9.7-12.8 kg of mercury. The bottom sediment contained 4.31 (2012)-7.40 (1977) tons of mercury. Thus, most of the mercury in the Uglich Reservoir is assumed to originate from runoff and terrigenous sources within the watershed. PMID- 29516275 TI - Polycythemia Vera. AB - OPINION STATEMENT: Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence of thromboembolic complications, which usually occur early in the course of the disease, and the only MPN in which erythrocytosis occurs. The classical presentation of PV is characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomegaly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any combination of these. When PV is present, the peripheral blood hematocrit (or hemoglobin) determination will not accurately represent the actual volume of red cells in the body, because in PV, in contrast to other disorders causing erythrocytosis, when the red cell mass increases, the plasma volume usually increases. In fact, unless the hematocrit is greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis or thrombocytosis establishes the diagnosis. However, when a patient presents with isolated thrombocytosis and a positive JAK2 V617F assay, particularly a young woman, the possibility of PV must always be considered because of plasma volume expansion. The WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is invariably normal and a bone marrow examination will not distinguish ET from PV. Only a direct measurement of both the red cell mass and plasma volume can establish the correct diagnosis. In managing a PV patient, it is important to remember that PV is an indolent disorder in which life span is usually measured in decades, even when myelofibrosis is present, that chemotherapy is futile in eradicating the disease but does increase the incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis, and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this is necessary. PMID- 29516276 TI - Application of a commercial single-port device for robotic single-incision distal pancreatectomy: initial experience. AB - PURPOSE: Laparoscopic distal pancreatectomy has proven to be feasible and safe. Moreover, robotic surgery provides unique advantages for pancreatic procedures, although single-incision robotic pancreatic surgery is rarely discussed. We applied the single-port modified platform to accomplish robotic distal pancreatectomy in a series of patients. METHODS: The subjects of this study were ten patients who underwent robotic distal pancreatectomy in our hospital between July 1, 2015 and Dec 31, 2016. All patients were placed supine in the reverse Trendelenburg position with the legs abducted. Surgery was performed via a trans umbilical 5.0-cm incision, using a modified single-port platform (LAGIPORT(r)) combined with the da Vinci Si Surgical System. The three arms and scope (30 degree up) were inserted through the LAGIPORT(r) and positioned in a triangle. Endoscopic ultrasound was used to localize the tumor and plan the resection margin. We recorded the surgical time, operation time, blood loss, postoperative pain score, hospital stay, and complications. RESULTS: The surgical time was 236 +/- 32 min, the operation time was 172 +/- 30 min, and the blood loss was 149 +/- 65 ml. All patients underwent robot-assisted distal pancreatectomy without conversion. The average pain score on postoperative day (POD) 3 was 4.5 +/- 1. Complications included subsplenic hematoma (n = 1) and minor pancreatic leakage (n = 2). There was no surgical mortality. CONCLUSIONS: Our results demonstrate the safety and efficiency of robotic single-incision distal pancreatectomy via the modified platform (LAGIPORT(r)). PMID- 29516277 TI - Postpneumonectomy bronchopleural fistula in non-small cell lung cancer patients: incidence, survival, mortality, and treatment analysis. AB - PURPOSE: Bronchopleural fistula (BPF) is a catastrophic complication after pneumonectomy, still associated with high mortality. We reviewed our recent experience of managing BPF, particularly after right pneumonectomy for non-small cell lung cancer (NSCLC), and analyzed our findings. METHODS: A total of 436 patients underwent pneumonectomy for NSCLC in our department between January 2000 and June 2017. BPF developed during follow-up in 47 of these patients, who are the subjects of this retrospective analysis. RESULTS: The overall incidence of BPF was 10.8% (47/436), being 22.8% (33/145) after right pneumonectomy and 4.8% (14/291) after left pneumonectomy (P = 0.0001). The incidence of BPF in patients with a history of tuberculosis was 33.3% (6/18; P = 0.008). The fistula healed in 48.9% (23/47) of the patients and the rate of mortality caused by the fistula was 19.1% (9/47). CONCLUSIONS: The side of the pneumonectomy and previous tuberculosis were the two most important risk factors independent of the bronchial closure methods. The incidence of BPF was much higher after right pneumonectomy than after left pneumonectomy. The high mortality and morbidity rates show that the treatment of BPF is still not satisfactory. PMID- 29516278 TI - Calcium-Containing Crystals and Osteoarthritis: an Unhealthy Alliance. AB - PURPOSE OF REVIEW: Osteoarthritis (OA) is the most common form of joint disease globally and is associated with significant morbidity and disability. Increasing evidence points to an important inflammatory component in the development and progression of OA. The precise pathways involved in OA inflammatory processes remain to be clarified. Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPP) crystals can induce inflammation and arthritis and recent studies point to a potential pathogenic role in OA. In the light of this evidence, we explore the relationship and potential mechanistic pathways linking calcium containing crystals and OA. RECENT FINDINGS: CPP crystals induce inflammation through the NLRP3 inflammasome while BCP crystals mediate both NLRP3 dependent and independent effects. BCP crystals have been demonstrated to induce key mitogenic and inflammatory pathways and contribute to cartilage degradation. Calcium-containing crystals induce key inflammatory pathways and may represent an attractive novel target in OA, a condition devoid of effective treatments. PMID- 29516279 TI - Eculizumab reversed severe distal ischemic syndrome and glomerulonephritis with isolated C3 deposits associated with anti-factor H autoantibodies: a case report. AB - B-cell clones can produce a monoclonal immunoglobulin, which may be responsible for visceral involvements. Kidney involvement is frequent, affecting 20 to 50% of patients with multiple myeloma. One mechanism underlying this involvement is a dysregulation of the complement alternative pathway, leading to C3 glomerulopathies. We report a patient who had a multiple myeloma, C3 glomerulopathy related to factor H autoantibody, and digital ischemia, who was treated successfully with eculizumab, an anti-complement therapy, without any relapse in 2 years of follow-up. PMID- 29516280 TI - Serum BAFF in Indian patients with IIM: a retrospective study reveals novel clinico-phenotypic associations in children and adults. AB - We studied the serum levels of B cell survival factors BAFF and APRIL in patients with idiopathic inflammatory myositis (IIM) and their relation with clinical and autoantibodies. Seventy-five patients (51 females and 24 males) with IIM (Bohan and Peter's criteria 1975) and 25 healthy adults were analyzed for BAFF, APRIL and IL-17 by ELISA, and myositis-specific and associated antibodies (MSA and MAA) using line immunoblot assay. Of the 75 patients, 59 were adults, 42 had Dermatomyositis (DM), and 17 had Polymyositis. Median disease duration was 5 (3 12) months. BAFF levels were higher in IIM than healthy controls [p = 0.001], and in children with jDM than adults [p = 0.026]. BAFF levels were higher in adults with arthritis [p = 0.018], weight loss [p = 0.007], and PAH [p = 0.004]. Among the various MSAs, lowest levels were seen in those with anti-SRP [p = 0.043]. Median follow-up duration was 145 patient years. Twelve patients relapsed, while nine were in drug-free remission. BAFF were similar between these groups. Serum APRIL levels were elevated in limited number of patients with myositis, and the levels did not differ amongst the clinico-serologic phenotypes. IL-17 levels were higher in individuals positive for anti-SRP [p = 0.028]. Serum BAFF levels are elevated in IIM, more so in children. BAFF levels may be useful as biomarker for PAH and arthritis. Anti-SRP positivity is associated with elevated IL-17 levels suggesting role in pathogenesis. PMID- 29516281 TI - Clinical and laboratory aspects of dyslipidemia in Brazilian women with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is associated with dyslipidemia, atherosclerosis, and cardiovascular disease. In this study, we investigated the presence of dyslipidemia in Brazilian SLE patients by evaluating their lipid profile and immune status, including the production of autoantibodies and cytokines involved in atherogenesis. Ninety-four female SLE patients participated in this study and, based on their lipid profile, were classified as dyslipidemic or not. All were tested for antinuclear antibodies (ANAs), antiphospholipid antibodies, and autoantibodies to extractable nuclear antigens and double stranded DNA. Serum levels of apolipoproteins A and B, C3, C4, and C-reactive protein were measured, as well as serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-10. Lupus activity was scored according to the Systemic Lupus Erythematosus Disease Activity Index 2000. Sixty-nine patients (73.4%) had dyslipidemia, and the remaining 25 patients (26.6%) were non dyslipidemic. Lupus activity was correlated with non-high-density lipoprotein cholesterol and triglyceride (TG) levels (non-HDL-C, r = 0.34 and p = 0.0043 and r = 0.46 and p < 0.0001, respectively). Atherogenic indexes apolipoprotein B/apolipoprotein A and TG:HDL-C ratios were higher in dyslipidemic women, and TG:HDL was correlated with disease activity (r = 0.40, p = 0.0007). IL-6, TNF alpha, and IL-10 levels were similar between groups; however, a positive correlation between IL-6 and CRP levels was only observed in the group with dyslipidemia (r = 0.55, p < 0.0001). Female Brazilian SLE patients present a high prevalence of dyslipidemia and exhibit a higher risk of cardiovascular diseases as compared with female SLE patients without dyslipidemia and healthy individuals. PMID- 29516282 TI - Comparison of Gene Transfection and Cytotoxicity Mechanisms of Linear Poly(amidoamine) and Branched Poly(ethyleneimine) Polyplexes. AB - PURPOSE: This study aimed to further explore the mechanisms behind the ability of certain linear polyamidoamines (PAAs) to transfect cells with minimal cytotoxicity. METHODS: The transfection efficiency of DNA complexed with a PAA of a molecular weight over 10 kDa or 25 kDa branched polyethyleneimine (BPEI) was compared in A549 cells using a luciferase reporter gene assay. The impact of endo/lysosomal escape on transgene expression was investigated by transfecting cells in presence of bafilomycin A1 or chloroquine. Cytotoxicity caused by the vectors was evaluated by measuring cell metabolic activity, lactate dehydrogenase release, formation of reactive oxygen species and changes in mitochondrial membrane potential. RESULTS: The luciferase activity was ~3-fold lower after transfection with PAA polyplexes than with BPEI complexes at the optimal polymer to nucleotide ratio (RU:Nt). However, in contrast to BPEI vectors, PAA polyplexes caused negligible cytotoxic effects. The transfection efficiency of PAA polyplexes was significantly reduced in presence of bafilomycin A1 while chloroquine enhanced or decreased transgene expression depending on the RU:Nt. CONCLUSIONS: PAA polyplexes displayed a pH-dependent endo/lysosomal escape which was not associated with cytotoxic events, unlike observed with BPEI polyplexes. This is likely due to their greater interactions with biological membranes at acidic than neutral pH. PMID- 29516283 TI - CYP46A1 and the APOEepsilon4 Allele Polymorphisms Correlate with the Risk of Alzheimer's Disease. AB - Polymorphisms of the cholesterol-24S-hydroxylase (CYP46A1) and apolipoprotein E (APOE) genes are risk factors for Alzheimer's disease (AD). Plasma level of 24S hydroxcholesterol (24-OHC), the metabolite of cholesterol, is thought to correlate with AD. The present study investigated the correlation between these genetic factors and blood 24-OHC and amyloid-beta (Abeta) levels in AD patients. Association analysis, logistic regression, and linear regression were used to analyze the correlation of CYP46A1 and APOE genotypes with blood 24-OHC and Abeta levels and AD risk. We found that the APOEepsilon4 alleles were significantly higher in patients with AD and there was a potential synergistic interaction between the CYP46A1 C allele and APOEepsilon4 allele in AD. Blood 24-OHC level and Abeta level were significantly higher in AD patients than controls, indicating 24-OHC could be a marker in AD diagnosis. However, AD patients with the CYP46A1 TT, but not CC, genotype had higher 24-OHC levels, which indicated that there may be other mechanisms in the relationship between CYP46A1 polymorphisms and AD. PMID- 29516284 TI - Stimulation of ACE2/ANG(1-7)/Mas Axis by Diminazene Ameliorates Alzheimer's Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway. AB - Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-beta-induced apoptosis and neurodegeneration in Alzheimer's disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1-7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3beta along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1 7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway. PMID- 29516286 TI - NPP1 is responsible for potent extracellular ATP hydrolysis as NTPDase1 in primary cultured murine microglia. AB - The movement of microglia is regulated mainly by P1 and P2 purinergic receptors, which are activated by various nucleotides and their metabolites. Recently, such purinergic signalling has been spotlighted because of potential roles in the pathophysiologies of neurodegenerative and neuropsychiatric disorders. To understand the characteristics of microglia in relation of P1 and P2 signalling, we investigated the ectoenzymes expressed in microglia. At first, we profiled the expression of all known ectoenzymes in cultured microglia. We found that, like NTPDase1 (ectonucleoside triphosphate diphosphohydrolase 1, CD39), NPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1, PC-1) is also highly expressed in primary cultured murine microglia. Knockdown of NPP1 significantly reduced ATP hydrolysis and Pi production in cultured microglia. In addition, the knockdown of NPP1 enhanced basal nucleotide-stimulating responses of cultured microglia, such as phagocytosis and cell migration, and these results were very similar to NTPDase1 knockdown results. Moreover, inhibition of the adenosine receptors by caffeine treatment reduced phagocytosis of NPP1 knock downed cultured microglia. In conclusion, we suggest that these potent ectoenzymes of primary cultured murine microglia, NPP1 together with CD73 (ecto-5'-nucleotidase) maintain the adenosine levels for triggering nucleotide-stimulating responses. PMID- 29516285 TI - Phenolic profiles and their contribution to the antioxidant activity of selected chickpea genotypes from Mexico and ICRISAT collections. AB - Chickpea (Cicer arietinum L.) genotypes, nine kabuli from Mexico and 9 desi from other countries, were investigated for their phenolic profiles and antioxidant activity (AA). Phenolics in methanol extracts (ME) were analyzed by ultra performance liquid chromatography coupled to diode array detection and mass spectrometry (UPLC-DAD-MS), whereas the AA was measured as Trolox equivalents (TE) by ABTS, DPPH and FRAP methods. Twenty phenolic compounds were identified in the ME and their levels showed a great variability among the chickpea genotypes. Phenolic acids and flavonoids were the most abundant compounds in kabuli and desi genotypes, respectively. The AA values (MUmol TE/ 100 g dw) by ABTS (278-2417), DPPH (52-1650), and FRAP (41-1181) were mainly associated with the content of sinapic acid hexoside, gallic acid, myricetin, quercetin, catechin, and isorhamnetin, suggesting they are the main compounds responsible for the AA. The sum of the AA obtained for standards of these compounds evaluated at the concentration found in the extracts accounted for 34.3, 69.8, and 47.0% of the AA in the extract by ABTS, DPPH, and FRAP, respectively. In the AA by DPPH, most of the mixtures of these compounds resulted in synergistic interactions. Three desi genotypes with black seeds (ICC 4418, ICC 6306, and ICC 3761) showed the highest AA and flavonoids content, whereas the most promising kabuli genotypes were Surutato 77, Bco. Sin. 92, and Blanoro that showed the highest values of phenolic acids. These genotypes represent good sources of antioxidants for the improvement of nutraceutical properties in chickpea. PMID- 29516287 TI - What Is the Evidence for Treat-to-Target Serum Urate in Gout? AB - PURPOSE OF REVIEW: Most current clinical guidelines for gout management advocate a treat-to-target serum urate approach, although notable differences exist. Serum urate is a rational target for gout treatment given the central role of urate in disease causality, its association with key outcomes and its practicality of use in clinical practice. This review analyses the evidence for this strategy in gout. RECENT FINDINGS: Recent studies have confirmed the efficacy of urate lowering therapy in achieving serum urate targets, both in trials using fixed doses and those applying a treat-to-target strategy. In a limited number of long term studies (> 12-month duration), interventions that incorporate a treat-to target serum urate approach have been shown to promote regression of tophi, reduce the frequency of gout flares and improve MRI-detected synovitis. A strong case can be made for a treat-to-target serum urate strategy in gout, supported by existing knowledge of disease pathophysiology, outcomes from urate-lowering therapy studies and emerging results of randomised strategy trials of sufficient duration. PMID- 29516289 TI - Are Doctors the Best People to Manage Gout? Is There a Role for Nurses and Pharmacists? AB - PURPOSE OF REVIEW: To discuss alternate models of long-term gout management RECENT FINDINGS: Nurse-led care of gout appears to improve the uptake of and adherence to urate-lowering treatment in a research setting. Less impressive improvements were achieved with pharmacist-led remote management of gout; however, both strategies were more effective than usual primary care provider management of gout. Individualised education about gout, patient involvement in decision-making, and access to trained support in managing side-effects and gout flares can improve the uptake of fine and adherence to urate-lowering treatment. This may be best achieved with nurse-led care of gout. However, further research is required to evaluate if the model of nurse-led care of gout can be implemented in routine clinical practice and in different healthcare systems. PMID- 29516290 TI - EBV-positive PEL-like lymphoma that developed in the course of antisynthetase syndrome treated with tacrolimus. AB - Primary effusion lymphoma (PEL) is a rare type of extranodal lymphoma, typically of a B-cell origin, which presents as lymphomatous effusion with no nodal enlargement or tumor masses. The development PEL is universally associated with human herpes virus-8 (HHV-8) infection. Cases of HHV-8-negative primary lymphomatous effusion have recently been reported and referred to as HHV-8 unrelated PEL-like lymphoma. Some cases of this disease have been reported in iatrogenic immunocompromised patients. The mechanisms responsible for the inhibitory effects of the discontinuation of immunosuppressants other than methotrexate (MTX) against the disease, which have been demonstrated for MTX associated lymphoproliferative disorders, have not yet been elucidated. We describe a case of PEL-like lymphoma that developed in the course of antisynthetase syndrome and was treated with tacrolimus. A single dose of systemic chemotherapy did not improve lymphomatous effusion, whereas the discontinuation of tacrolimus resulted in the long-term remission of this disease. PMID- 29516291 TI - Etoposide-Loaded Poly(Lactic-co-Glycolic Acid) Intravitreal Implants: In Vitro and In Vivo Evaluation. AB - Etoposide-loaded poly(lactic-co-glycolic acid) implants were developed for intravitreal application. Implants were prepared by a solvent-casting method and characterized in terms of content uniformity, morphology, drug-polymer interaction, stability, and sterility. In vitro drug release was investigated and the implant degradation was monitored by the percent of mass loss. Implants were inserted into the vitreous cavity of rabbits' eye and the in vivo etoposide release profile was determined. Clinical examination and the Hen Egg Test Chorioallantoic Membrane (HET-CAM) method were performed to evaluate the implant tolerance. The original chemical structure of the etoposide was preserved after incorporation in the polymeric matrix, which the drug was dispersed uniformly. In vitro, implants promoted sustained release of the drug and approximately 57% of the etoposide was released in 50 days. In vivo, devices released approximately 63% of the loaded drug in 42 days. Ophthalmic examination and HET-CAM assay revealed no evidence of toxic effects of implants. These results tend to show that etoposide-loaded implants could be potentially useful as an intraocular etoposide delivery system in the future. PMID- 29516288 TI - Genome-wide analysis of endogenously expressed ZEB2 binding sites reveals inverse correlations between ZEB2 and GalNAc-transferase GALNT3 in human tumors. AB - BACKGROUND: ZEB2 is a transcriptional repressor that regulates epithelial-to mesenchymal transition (EMT) through binding to bipartite E-box motifs in gene regulatory regions. Despite the abundant presence of E-boxes within the human genome and the multiplicity of pathophysiological processes regulated during ZEB2 induced EMT, only a small fraction of ZEB2 targets has been identified so far. Hence, we explored genome-wide ZEB2 binding by chromatin immunoprecipitation sequencing (ChIP-seq) under endogenous ZEB2 expression conditions. METHODS: For ChIP-Seq we used an anti-ZEB2 monoclonal antibody, clone 6E5, in SNU398 hepatocellular carcinoma cells exhibiting a high endogenous ZEB2 expression. The ChIP-Seq targets were validated using ChIP-qPCR, whereas ZEB2-dependent expression of target genes was assessed by RT-qPCR and Western blotting in shRNA mediated ZEB2 silenced SNU398 cells and doxycycline-induced ZEB2 overexpressing colorectal carcinoma DLD1 cells. Changes in target gene expression were also assessed using primary human tumor cDNA arrays in conjunction with RT-qPCR. Additional differential expression and correlation analyses were performed using expO and Human Protein Atlas datasets. RESULTS: Over 500 ChIP-Seq positive genes were annotated, and intervals related to these genes were found to include the ZEB2 binding motif CACCTG according to TOMTOM motif analysis in the MEME Suite database. Assessment of ZEB2-dependent expression of target genes in ZEB2 silenced SNU398 cells and ZEB2-induced DLD1 cells revealed that the GALNT3 gene serves as a ZEB2 target with the highest, but inversely correlated, expression level. Remarkably, GALNT3 also exhibited the highest enrichment in the ChIP-qPCR validation assays. Through the analyses of primary tumor cDNA arrays and expO datasets a significant differential expression and a significant inverse correlation between ZEB2 and GALNT3 expression were detected in most of the tumors. We also explored ZEB2 and GALNT3 protein expression using the Human Protein Atlas dataset and, again, observed an inverse correlation in all analyzed tumor types, except malignant melanoma. In contrast to a generally negative or weak ZEB2 expression, we found that most tumor tissues exhibited a strong or moderate GALNT3 expression. CONCLUSIONS: Our observation that ZEB2 negatively regulates a GalNAc-transferase (GALNT3) that is involved in O-glycosylation adds another layer of complexity to the role of ZEB2 in cancer progression and metastasis. Proteins glycosylated by GALNT3 may be exploited as novel diagnostics and/or therapeutic targets. PMID- 29516292 TI - Peripheral post-ischemic vascular repair is impaired in a murine model of Alzheimer's disease. AB - The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-beta (Abeta) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Abeta in the hind limb; thus, circulating Abeta is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-beta1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD. PMID- 29516294 TI - A meta-analysis comparing open anterior component separation with posterior component separation and transversus abdominis release in the repair of midline ventral hernias. AB - PURPOSE: This study aims to compare the outcomes of posterior component separation and transversus abdominis release (PCSTAR) with the open anterior component separation (OACS) technique. OACS, first described by Ramirez et al. (Plast Reconstr Surg 86(3):519-526, 1990), has become an established technique for local myofascial advancement in abdominal hernia surgery. PCSTAR, described by Novitsky et al. (Am J Surg 204(5):709-716, 2012), is being used more frequently and is rapidly becoming the technique of choice in complex ventral hernia repair. METHODS: Analysis was conducted according to PRISMA guidelines. A systematic search of the MEDLINE, EMBASE and Pubmed databases was performed. Studies reporting exclusively on midline ventral hernia repair were reviewed. Studies describing PCSTAR were selected and compared to matched studies describing OACS. Meta-analysis was used to compare outcomes between the two pooled groups. RESULTS: Seven studies describing 281 cases of PCSTAR for midline incisional hernia using a retromuscular mesh placement were identified. Six comparable studies describing 285 cases of OACS and retromuscular mesh placement were identified from the same search. Pooled analysis demonstrated a hernia recurrence rate of 5.7% (3.0-8.5) for PCSTAR and 9.5% (4.0-14.9) for OACS. Comparative analysis demonstrated no significant difference between hernia recurrence rate (p = 0.23). The use of bridging mesh was not significantly reduced by the use of PCSTAR (3.1%) when compared to ACS (7.5%) (p = 0.22). No significant difference was found in wound complication rates between PCSTAR and OACS, respectively, 'superficial' 10.9 vs 21.6% (p = 0.15); and 'deep' 9.5 vs 12.7% (p = 0.53). CONCLUSIONS: These data suggest PCSTAR have comparable outcomes to OACS. This analysis is limited by the lack of comparative studies and heterogenicity in the OACS group. PMID- 29516293 TI - An Update on Surveillance in Ulcerative Colitis. AB - PURPOSE OF REVIEW: Patients with long-standing ulcerative colitis have an increased risk for the development of colorectal cancer (CRC). Colitis-related dysplasia appears to confer the greatest risk. Colonoscopic surveillance to detect dysplasia has been advocated by gastrointestinal societies. The aim of surveillance is the reduction of mortality and morbidity of CRC through detection and resection of dysplasia or detecting CRC at an earlier and potentially curable stage. Traditional surveillance has relied on mucosal assessment with targeted biopsy of visible lesions and random biopsy sampling on the premise that dysplasia was not visible at endoscopy. Advances in optical technology permitting increased detection of dysplasia and evidence that most dysplasia is visible has had practice-changing implications. RECENT FINDINGS: Emerging evidence favours chromoendoscopy (CE) for dysplasia detection and is gaining wider acceptance through recent international (International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease (SCENIC)) recommendations and endorsed by many gastrointestinal societies. Adoption of CE as the gold standard of surveillance has been met with by scepticism, from conflicting data, operational barriers and the need to understand the true impact of increasingly higher dysplasia detection on overall CRC mortality. Valid debate notwithstanding, implementation of a risk stratification protocol that includes CE is an effective approach allowing earlier detection of dysplasia and colorectal neoplasia, determination of surveillance intervals with appropriate allocation of resources and limiting morbidity from CRC and colonoscopy itself. Further prospective data should define the true and long-term impact of dysplasia detection with modern techniques. PMID- 29516295 TI - Synthesis and Study of Optical Characteristics of Ti0.91O2/CdS Hybrid Sphere Structures. AB - The optical properties of alternating ultrathin Ti0.91O2 nanosheets and CdS nanoparticle hybrid spherical structures designed by the layer-by-layer (LBL) assembly technique are investigated. From the photoluminescence (PL) spectral measurements on the hybrid spherical structures, a spectrum-shifted fluorescence emission occurs in this novel hybrid material. The time-resolved PL measurements exhibit a remarkably increased PL lifetime of 3.75 ns compared with only Ti0.91O2 spheres or CdS nanoparticles. The novel results were attributed to the enhanced electron-hole separation due to the new type II indirect optical transition mechanism between Ti0.91O2 and CdS in a charge-separated configuration. PMID- 29516296 TI - Two denominators for one numerator: the example of neonatal mortality. AB - Preterm delivery is one of the strongest predictors of neonatal mortality. A given exposure may increase neonatal mortality directly, or indirectly by increasing the risk of preterm birth. Efforts to assess these direct and indirect effects are complicated by the fact that neonatal mortality arises from two distinct denominators (i.e. two risk sets). One risk set comprises fetuses, susceptible to intrauterine pathologies (such as malformations or infection), which can result in neonatal death. The other risk set comprises live births, who (unlike fetuses) are susceptible to problems of immaturity and complications of delivery. In practice, fetal and neonatal sources of neonatal mortality cannot be separated-not only because of incomplete information, but because risks from both sources can act on the same newborn. We use simulations to assess the repercussions of this structural problem. We first construct a scenario in which fetal and neonatal factors contribute separately to neonatal mortality. We introduce an exposure that increases risk of preterm birth (and thus neonatal mortality) without affecting the two baseline sets of neonatal mortality risk. We then calculate the apparent gestational-age-specific mortality for exposed and unexposed newborns, using as the denominator either fetuses or live births at a given gestational age. If conditioning on gestational age successfully blocked the mediating effect of preterm delivery, then exposure would have no effect on gestational-age-specific risk. Instead, we find apparent exposure effects with either denominator. Except for prediction, neither denominator provides a meaningful way to define gestational-age-specific neonatal mortality. PMID- 29516297 TI - Physico-chemical properties influence the functions and efficacy of commercial bovine lactoferrins. AB - Human and bovine lactoferrin (hLf and bLf) are multifunctional iron-binding glycoprotein constitutively synthesized and secreted by glandular epithelial cells and by neutrophils following induction. HLf and bLf possess very high similarity of sequence. Therefore, most of the in vitro and in vivo studies are carried out with commercial bLf (cbLf), available in large quantities and recognized by Food and Drug Administration (FDA, USA) as a safe substance. Physico-chemical heterogeneity of different cbLf preparations influences their effectiveness. CbLf iron-saturation affects thermal stability and resistance to proteolysis. Moreover, other metal ions such as Al(III), Cu(II), Mg(II), Mn(II), Zn(II) are chelated by cbLf, even if at lower affinity than Fe(III). Ca(II) is also sequestered by the carboxylate groups of sialic acid present on glycan chains of cbLf thus provoking the release of LPS, contributing to bactericidal activity. Similarly to more than 50% of eukaryotic proteins, cbLf possesses five N-glycosylation sites, also contributing to the resistance to proteolysis and, putatively, to the protection of intestinal mucosa from pathogens. CbLfs possess several functions as anti-microbial, anti-biofilm, anti-adhesive, anti-invasive and anti-inflammatory activities. They are also relevant modulators of iron and inflammatory homeostasis. However, the efficacy of cbLfs in exerting several functions can be erratic mainly depending from integrity, degree of iron and other metal ions saturation, N-glycosylation sites and chains, desialylated forms, Ca(II) sequestration, presence of contaminants and finally the ability to enter inside nucleus. PMID- 29516298 TI - X-ray structure of bovine heart cytochrome c at high ionic strength. AB - Bovine heart cytochrome c (bCyt c) is an extensively studied hemoprotein of only 104 residues. Due to the existence of isoforms generated by non-enzymatic deaminidation, crystallization of bCyt c is difficult and involves extensive purification and the use of microseeding or the presence of an electric field. Taking advantage of the capacity of cytochrome c (cyt c) to bind anions on its protein surface, the commercially available bCyt c was crystallized without extra purifications, using ammonium sulfate as precipitant and nitrate ions as additives. The structure of the ferric bCyt c in a new crystal form is described and compared with that previously solved at low ionic strength and with those of human and horse cyt c. The overall structure of bCyt c is conserved, while the side chains of several residues that play a role in the interactions of cyt c with its partners have different rotamers in the two structures. The effect of the presence of nitrate ions on the structure of the protein is then evaluated and compared with that observed in the case of ferrous and ferric horse heart cyt c. PMID- 29516299 TI - Plasma metals as potential biomarkers in dementia: a case-control study in patients with sporadic Alzheimer's disease. AB - Sporadic Alzheimer's disease (AD) is a neurodegenerative disorder that causes the most prevalent form of age-related dementia but its pathogenesis remains obscure. Altered regulation of metals, particularly pan-cerebral copper deficiency, and more regionally-localized perturbation of other metals, are prominent in AD brain although data on how these CNS perturbations are reflected in the peripheral bloodstream are inconsistent to date. To assess the potential use of metal dysregulation to generate biomarkers in AD, we performed a case-control study of seven essential metals and selenium, measured by inductively coupled plasma mass spectrometry, in samples from AD and matched control cases. Metals were sodium, potassium, calcium, magnesium, iron, zinc, and copper. In the whole study-group and in female participants, plasma metal levels did not differ between cases and controls. In males by contrast, there was moderate evidence that zinc levels trended towards increase in AD [10.8 (10.2-11.5)] umol/L, mean (+/- 95% CI; P = 0.021) compared with controls [10.2 (9.6-10.4)]. Thus alterations in plasma zinc levels differed between genders in AD. In correlational analysis, there was evidence for an increased number of 'strong' metal co-regulations in AD cases and differential co-modulations of metal pairs: copper-sodium (Rcontrol = - 0.03, RAD = 0.65; P = 0.009), and copper-calcium (Rcontrol = - 0.01, RAD = 0.65; P = 0.01) were significant in AD males, potentially consistent with reported evidence for dysregulation of copper in severely damaged brain regions in AD. In conclusion, our data suggest that the measurement of metals co-regulation in plasma may provide a useful representation of those metal perturbations taking place in the AD brain and therefore might be useful as plasma-based biomarkers. PMID- 29516300 TI - Defective renal autoregulation in the chronic bile duct ligation model of liver failure. AB - BACKGROUND: Cirrhosis of the liver is often associated with an impairment of renal function that is usually not associated with consistent structural abnormalities of the renal parenchyma, but is thought to be the functional consequence of arterial underfilling and reduced arterial blood pressure. METHOD: We have used the cirrhosis model of chronic bile duct ligation (BDL) to assess the response of renal blood flow to a change of blood pressure. We have measured renal haemodynamics in BDL rats. RESULT: Three weeks after BDL, rats showed elevated levels of total bilirubin, AST, and ALT as well as reduced arterial blood pressure. Creatinine clearance was significantly reduced, and plasma creatinine and urea nitrogen were elevated. Renal blood flow at baseline blood pressure was significantly lower in the BDL group than in the sham group. Clamp induced reductions of renal perfusion pressure caused significantly greater changes of renal blood flow in BDL than control rats. The autoregulatory index over a comparable blood pressure range averaged 0.28 +/- 0.35 in control rats and 1.26 +/- 0.6 in BDL rats (p = 0.0004) indicating impairment of renal autoregulation in liver cirrhosis. CONCLUSION: Tubuloglomerular feedback (TGF) responses were significantly attenuated in BDL rats, especially in the subnormal flow range. Impairment of renal blood flow autoregulation, to some extent mediated by reduced TGF-mediated vasodilatation, may contribute to the renal vascular constrictor state in liver cirrhosis by preventing the full dilatory response to the blood pressure reduction. PMID- 29516302 TI - Optimal Model Parameter Estimation from EEG Power Spectrum Features Observed during General Anesthesia. AB - Mathematical modeling is a powerful tool that enables researchers to describe the experimentally observed dynamics of complex systems. Starting with a robust model including model parameters, it is necessary to choose an appropriate set of model parameters to reproduce experimental data. However, estimating an optimal solution of the inverse problem, i.e., finding a set of model parameters that yields the best possible fit to the experimental data, is a very challenging problem. In the present work, we use different optimization algorithms based on a frequentist approach, as well as Monte Carlo Markov Chain methods based on Bayesian inference techniques to solve the considered inverse problems. We first probe two case studies with synthetic data and study models described by a stochastic non-delayed linear second-order differential equation and a stochastic linear delay differential equation. In a third case study, a thalamo-cortical neural mass model is fitted to the EEG spectral power measured during general anesthesia induced by anesthetics propofol and desflurane. We show that the proposed neural mass model fits very well to the observed EEG power spectra, particularly to the power spectral peaks within delta - (0 - 4 Hz) and alpha - (8 - 13 Hz) frequency ranges. Furthermore, for each case study, we perform a practical identifiability analysis by estimating the confidence regions of the parameter estimates and interpret the corresponding correlation and sensitivity matrices. Our results indicate that estimating the model parameters from analytically computed spectral power, we are able to accurately estimate the unknown parameters while avoiding the computational costs due to numerical integration of the model equations. PMID- 29516303 TI - Living Slow and Being Moral : Life History Predicts the Dual Process of Other Centered Reasoning and Judgments. AB - Drawing from the dual process model of morality and life history theory, the present research examined the role of cognitive and emotional processes as bridges between basic environmental challenges (i.e., unpredictability and competition) and other-centered moral orientation (i.e., prioritizing the welfare of others). In two survey studies, cognitive and emotional processes represented by future-oriented planning and emotional attachment, respectively (Study 1, N = 405), or by perspective taking and empathic concern, respectively (Study 2, N = 424), positively predicted other-centeredness in prosocial moral reasoning (Study 1) and moral judgment dilemmas based on rationality or intuition (Study 2). Cognitive processes were more closely related to rational aspects of other centeredness, whereas the emotional processes were more closely related to the intuitive aspects of other-centeredness (Study 2). Finally, the cognitive and emotional processes also mediated negative effects of unpredictability (i.e., negative life events and childhood financial insecurity), as well as positive effects of individual-level, contest competition (i.e., educational and occupational competition) on other-centeredness. Overall, these findings support the view that cognitive and emotional processes do not necessarily contradict each other. Rather, they might work in concert to promote other-centeredness in various circumstances and might be attributed to humans' developmental flexibility in the face of environmental challenges. PMID- 29516304 TI - Role of Minimally Invasive (Micro and Ultra-mini) PCNL for Adult Urinary Stone Disease in the Modern Era: Evidence from a Systematic Review. AB - PURPOSE OF REVIEW: The role of PCNL and the expertise surrounding it has expanded in recent decades. Miniaturisation of equipment and instrument size has formed a part of this innovation. Although an increasing number of studies have been performed on miniaturised PCNL (Mi-PCNL) recently, a critical appraisal on these is lacking. We therefore conducted a systematic review of the literature to evaluate the efficacy, safety and feasibility of Mi-PCNL techniques (< 15 Fr). RECENT FINDINGS: A systematic review was conducted from 1990 to March 2017 on outcomes of Mi-PCNL [micro PCNL (m-PCNL) and ultra-mini PCNL (UMP)] in adult patients. Ten studies (three on m-PCNL and seven on UMP) were included in our study. Across the three studies, 118 patients (mean age 42.2 years, male to female ratio 1.3:1) underwent m-PCNL (4.8 Fr). For a mean stone size of 13.9 mm, a mean stone-free rate (SFR) was 89% and an overall complication rate was 15.2% [Clavien classification I (44%), II (28%), III (28%)], with no Clavien IV or V complications. Across the seven studies, 262 patients (mean age 49.4 years, male to female ratio 1.5:1) underwent UMP (13-14 Fr). For a mean stone size of 18.6 mm, a mean SFR was 88.3% and an overall complication rate was 6.2% [Clavien classification I (57%), II (36%), III (7%)], with no Clavien IV or V complications. While the transfusion rates for m-PCNL was 0.85%, only one case each in m-PCNL and UMP needed conversion to mini PCNL. Our review shows that for small- to medium-sized renal stones, Mi-PCNL can yield good stone-free rates whilst maintaining a low morbidity associated with it. There were no Clavien > III complications and no mortality with only one transfusion reported from this minimally invasive technique. PMID- 29516306 TI - Spinal Meningiomas Prognostic Evaluation Score (SPES): predicting the neurological outcomes in spinal meningioma surgery. AB - Among many factors leading to a worse functional prognosis in spinal meningioma (SM) surgery, in a previous study, we recognized anterior/anterolateral axial topography, sphincter involvement at first evaluation, surgery performed on a recurrence, and worse preoperative functional status. The purpose of this paper is to evaluate the cumulative weight of these factors on prognosis through a multinomial logistic regression model performed on an original evaluation scale designed by the authors on the ground of the experience of the neurosurgical departments of our University. The original SM database composed of 173 cases was classified in regard to sex, age, symptoms, axial and sagittal location, Simpson grade resection, and functional pre/postoperative status. Fine presurgical and follow-up reevaluations were available. The authors propose a scale (Spinal Meningiomas Prognostic Evaluation Score (SPES)) of preoperative evaluation to assess the surgery-related risk of neurological worsening experienced by the patients included in the present cohort. The authors describe a strong statistical association between the SPES and the follow-up Frankel and McCormick scores (r = - 460 and .441, p .001, both). Through a univariate ANOVA analysis, we disclosed that patients presenting scores 2 and 3 had a significantly higher association to lesser Frankel and McCormick postoperative scores, in respect to patients presenting SPES scores 0-1 (univariate ANOVA, p .008 and .011). Anterior or anterolateral axial location, operating on a recurrence of SM, sphincter involvement, and worse functional grade at onset present, along with the SPES scores are fairly predictive and reliable in respect to the long-term results of patients suffering from SM. PMID- 29516305 TI - Light-emitting diode therapy (photobiomodulation) effects on oxygen uptake and cardiac output dynamics during moderate exercise transitions: a randomized, crossover, double-blind, and placebo-controlled study. AB - Light-emitting diodes (LEDs) might have a beneficial impact on cytochrome-c oxidase enzyme activity. Thus, it was hypothesized that photobiomodulation by light-emitting diode therapy (LEDT) could influence aerobic metabolism dynamics. Possible LEDT-mediated aerobic improvements were investigated mainly by a precise characterization of the pulmonary O2 uptake dynamics during moderate exercise transitions. Eight healthy young adults were enrolled in this randomized, double blind, placebo-controlled, crossover study. A multi-diode array of LEDs was used for muscular pre-conditioning 30 min and 6 h before exercise testing. Pulmonary O2 uptake, carbon dioxide output, cardiac output, heart rate, stroke volume, and total arteriovenous oxygen difference dynamics were evaluated by frequency domain analysis. Comparisons revealed no statistical (p > 0.05) differences between LEDT and placebo, suggesting no significant changes in aerobic system dynamics. These results challenge earlier publications that reported changes in pulmonary O2 uptake during incremental exercise until exhaustion after LEDT. Perhaps, increments in peak pulmonary O2 uptake after LEDT may be a consequence of higher exercise tolerance caused by non-aerobic-related factors as opposed to an improved aerobic response. PMID- 29516307 TI - Transition of Left Ventricular Ejection Fraction in Heart Failure. AB - Along with a worldwide epidemiological transition and dramatic increase in the elderly population, both the incidence and prevalence of heart failure (HF) are increasing worldwide. This epidemic of HF is characterized by an increase of HF with preserved left ventricular ejection fraction (LVEF) (HFpEF) and a decrease of HF with reduced LVEF (HFrEF). Of note, transition between HFpEF and HFrEF has been recently highlighted, since it significantly relates with prognosis. Our recent studies indicated that temporary changes in LVEF are common and associated with prognosis in patients with HF. In this chapter, we summarize recent findings on temporal changes in LVEF and their prognostic impact in HF patients, acknowledging that further studies are needed to fully elucidate the pathophysiology of LVEF recovery and deterioration to improve clinical outcomes of HF patients, and also to develop therapies targeting novel pathways of myocardial recovery. PMID- 29516308 TI - Transplantation and Alternatives to Treat Autoimmune Diseases. AB - Transplantation is considered as one of the methods for the treatment of autoimmune diseases. There are different sorts of transplantation which improved the situation for the cure of different kinds of autoimmune diseases. Cord blood transplantation is favored over other transplant techniques. The propelled treatments incorporate interferon administrative elements and mesenchymal stromal cells for the management of immune system issue particularly in the treatment of rheumatoid joint inflammation. According to the studies conducted, it was proven that cord blood/UC mesenchymal cells along with DMARDs, without consistent organization expanded the level of administrative regulatory T-cells of the peripheral blood which might be a protected and huge technique for the treatment of patients experiencing rheumatoid joint inflammation. This review article focusses on different organ transplantation and alternative methods to treat autoimmune condition like rheumatoid arthritis. Using 3D printing and artificial intelligence are some of the recent trends that may be used for the management of autoimmune diseases. PMID- 29516309 TI - Lifestyle Intervention Program for Amelioration of Dysmetabolism in Overweight Women. AB - Overweight and obesity, a cluster of multiple risk factors for atherosclerosis such as elevated blood pressure, elevated glucose level, and dyslipidemia, increase the risk of all-cause mortality and cardiovascular morbidity and mortality. Physical activity and a proper diet are essential preventive measures. The aim of the study was to evaluate the effects of a two-month intervention program consisting of a low-caloric diet (1,500 kcal) and increased physical activity on the anthropometric parameters, body composition, resting metabolic rate, and maximum oxygen uptake. The study was conducted in 22 women aged 20-38 with diagnosed overweight or obesity. We found that after completing the eight week-long intervention program, there were significant changes in body composition, consisting of a smaller proportion of body fat and increased lean body mass. Further, we observed a decrease in body weight by 4.3 +/- 2.5 kg (p < 0.01), a reduction in waist and hip circumference of 2.6 +/- 4.5 cm (p < 0.01) and 4.4 +/- 2.9 cm (p < 0.01), respectively, and an increase in maximum oxygen uptake by about 5.2 +/- 8.4 ml/kg/min (p < 0.01). We conclude that the intervention program consisting of counseling on diet and physical activity may be highly motivational for patients with excess body weight and care givers should give it a try before commencing more aggressive psychopharmacological therapies. PMID- 29516301 TI - Convergent Mechanisms Underlying Rapid Antidepressant Action. AB - Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of alpha-amino 3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7 chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation. PMID- 29516310 TI - Non-invasive bladder volume measurement for the prevention of postoperative urinary retention: validation of two ultrasound devices in a clinical setting. AB - Ultrasound scanning of bladder volume is used for prevention of postoperative urinary retention (POUR). Accurate assessment of bladder volume is needed to allow clinical decision-making regarding the need for postoperative catheterization. Two commonly used ultrasound devices, the BladderScan(r) BVI 9400 and the newly released Prime(r) (Verathon Medical(r), Bothell, WA, USA), with or without the 'pre-scan' option, have not been validated in clinical practice. The aim of this study was to assess the performance of these devices in daily clinical practice. Between June and September 2016 a prospective observational study was conducted in 318 surgical patients (18 years or older) who needed a urinary catheter perioperatively for clinical reasons. For acceptable performance, we required that the volume as estimated by the BladderScan(r) differs by no more than 5% from the actual urine volume after catheterization. The Schuirmann's two one-sided test was performed to assess equivalence between the BladderScan(r) estimate and catheterization. The BVI 9400(r) overestimated the actual bladder volume by + 17.5% (95% CI + 8.8 to + 26.3%). The Prime(r) without pre-scan underestimated by - 4.1% (95% CI - 8.8 to + 0.5%) and the Prime(r) with pre-scan underestimated by - 6.3% (95% CI - 11.6 to - 1.1%). This study shows that while both ultrasound devices were able to approximate current bladder volume, both BVI 9400(r) and Prime(r)-with and without pre-scan-were not able to measure the actual bladder volume within our predefined limit of +/- 5%. Using the pre-scan feature of the Prime(r) did not further improve accuracy. PMID- 29516312 TI - Distribution, geochemistry, and mineralogy of aerosols in the Angouran Mine area, northwest Iran. AB - The Angouran Mine, located in northwest Iran, is the largest Zn-Pb producer in the Middle East. This study was designed to investigate the distribution, geochemistry, and mineralogy of the aerosols in the mining area and to assess their likely health impacts on the local residents. For this purpose, 36 aerosol samples were collected from 2014 to 2015 at nine sites located in mine district and upwind and downwind directions. The concentration of potentially toxic elements in the aerosols was determined using AAS instrument. Size, morphology, and mineralogy of the particles were studied using SEM and EDX spectra. The results indicate that the amount of total suspended particles in upwind, mine district, and downwind sites is 95.5, 463.4 and 287.5 ug/m3, respectively. The concentrations of PM2.5 in the three locations are 8.9, 134.7, and 51.8 ug/m3, whereas the PM10 contents are 2.9, 74.4, and 15.5 ug/m3, respectively. These observations point to the impact of mining activities on the concentration of aerosols in the local atmosphere. The values of air quality index also show the probable effects of the mining activities on the health of the local populations, especially for allergic peoples. The average concentration of Zn in the samples collected from the mining district (290 ug/kg) is much higher than its value in the upwind sites (27 ug/kg). The highest concentration of As (70 ug/kg), Cd (10 ug/kg), and Pb (3 ug/kg) is in downwind sites, which shows the negative impact of mining activities on the local air quality. Temporally, the highest concentration of the studied elements is recorded in spring season, especially for PM2.5 collected in downwind stations. Based on the results of SEM and EDX spectra, three groups of minerals, i.e., carbonates, silicates, and sulfides, are present in the aerosol particles, confirming the local source for the aerosols. SEM analyses showed that the aerosol particles with dissimilar chemical composition have different morphologies such as irregular, rounded, elongated, and angular. On the basis of the results, the mining activities in the Angouran Zn-Pb Mine may have various short- and long-term consequences on the public health, especially due to high amount of the finer particles (PM2.5) and the higher concentration of the potentially toxic elements in PM2.5 which can penetrate into the lungs. PMID- 29516311 TI - Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening. AB - Spectrophores are novel descriptors that are calculated from the three dimensional atomic properties of molecules. In our current implementation, the atomic properties that were used to calculate spectrophores include atomic partial charges, atomic lipophilicity indices, atomic shape deviations and atomic softness properties. This approach can easily be widened to also include additional atomic properties. Our novel methodology finds its roots in the experimental affinity fingerprinting technology developed in the 1990's by Terrapin Technologies. Here we have translated it into a purely virtual approach using artificial affinity cages and a simplified metric to calculate the interaction between these cages and the atomic properties. A typical spectrophore consists of a vector of 48 real numbers. This makes it highly suitable for the calculation of a wide range of similarity measures for use in virtual screening and for the investigation of quantitative structure-activity relationships in combination with advanced statistical approaches such as self-organizing maps, support vector machines and neural networks. In our present report we demonstrate the applicability of our novel methodology for scaffold hopping as well as virtual screening. PMID- 29516313 TI - Fungal diversity in the Atacama Desert. AB - Fungi are generally easily dispersed, able to colonise a wide variety of substrata and can tolerate diverse environmental conditions. However, despite these abilities, the diversity of fungi in the Atacama Desert is practically unknown. Most of the resident fungi in desert regions are ubiquitous. Some of them, however, seem to display specific adaptations that enable them to survive under the variety of extreme conditions of these regions, such as high temperature, low availability of water, osmotic stress, desiccation, low availability of nutrients, and exposure to high levels of UV radiation. For these reasons, fungal communities living in the Atacama Desert represent an unknown part of global fungal diversity and, consequently, may be source of new species that could be potential sources for new biotechnological products. In this review, we focus on the current knowledge of the diversity, ecology, adaptive strategies, and biotechnological potential of the fungi reported in the different ecosystems of the Atacama Desert. PMID- 29516314 TI - Synergistic plant-microbe interactions between endophytic bacterial communities and the medicinal plant Glycyrrhiza uralensis F. AB - Little is known about the composition, diversity, and geographical distribution of bacterial communities associated with medicinal plants in arid lands. To address this, a collection of 116 endophytic bacteria were isolated from wild populations of the herb Glycyrrhiza uralensis Fisch (licorice) in Xinyuan, Gongliu, and Tekesi of Xinjiang Province, China, and identified based on their 16S rRNA gene sequences. The endophytes were highly diverse, including 20 genera and 35 species. The number of distinct bacterial genera obtained from root tissues was higher (n = 14) compared to stem (n = 9) and leaf (n = 6) tissue. Geographically, the diversity of culturable endophytic genera was higher at the Tekesi (n = 14) and Xinyuan (n = 12) sites than the Gongliu site (n = 4), reflecting the extremely low organic carbon content, high salinity, and low nutrient status of Gongliu soils. The endophytic bacteria exhibited a number of plant growth-promoting activities ex situ, including diazotrophy, phosphate and potassium solubilization, siderophore production, auxin synthesis, and production of hydrolytic enzymes. Twelve endophytes were selected based on their ex situ plant growth-promoting activities for growth chamber assays to test for their ability to promote growth of G. uralensis F. and Triticum aestivum (wheat) plants. Several strains belonging to the genera Bacillus (n = 6) and Achromobacter (n = 1) stimulated total biomass production in both G. uralensis and T. aestivum under low-nutrient conditions. This work is the first report on the isolation and characterization of endophytes associated with G. uralensis F. in arid lands. The results demonstrate the broad diversity of endophytes associated with wild licorice and suggest that some Bacillus strains may be promising candidates for biofertilizers to promote enhanced survival and growth of licorice and other valuable crops in arid environments. PMID- 29516316 TI - Anterior segment ultrasound biomicroscopy image analysis using ImageJ software: Intra-observer repeatability and inter-observer agreement. AB - PURPOSE: In this novel study, we demonstrate a standardized imaging and measurement protocol of anterior segment (AS) structures with reliability analysis using ultrasound biomicroscopy (UBM) and ImageJ software. METHODS: Ten pediatric and young adult patients undergoing examination under anesthesia for AS pathology were imaged using UBM. Four trained observers analyzed 20 images using ImageJ. Forty-five structural parameters were measured. Those that relied on the trabecular-iris angle (TIA) as a reference landmark were labeled TIA-dependent (TD) and all others were labeled non-TIA dependent (NTD). Intra-observer repeatability (IOR) and inter-observer agreement (IOA) of measurements were determined using coefficient of variation (CV) and intra-class correlation (ICC) followed by assessment of Bland-Altman plots (BAP) for each pair of observers, respectively. RESULTS: For NTD parameters, non-ciliary body (CB) related measurements showed CV range 0.60-16.22% and ICC range 0.84-0.89, whereas CB related parameters showed CV range 2.86-23.40% and ICC range 0.29-0.92. For TD parameters, parameters < 2 degrees removed from reference showed CV range 0.02 5.40% and ICC range 0.89-1.00, whereas parameters > 1 degree removed showed CV range 0.63-27.44% and ICC range 0.22-1.00. No systematic proportional bias was detected by BAPs. CONCLUSIONS: Preplaced landmarks yielded good IOR and IOA in quantitative assessment of AS structures that were NTD and non-CB-related or less removed from the reference. CB-related NTD measurements varied greatly in IOR and IOA, indicating protocol modifications or CB qualitative assessments needed to improve accuracy. Variability in TD measurements increased the further removed from the reference, which supports implementation of a reliable reference landmark to minimize variation. PMID- 29516315 TI - Functional analysis of amino acids at stalk/head interface of human parainfluenza virus type 3 hemagglutinin-neuraminidase protein in the membrane fusion process. AB - Human parainfluenza virus type 3 (hPIV3) is an important respiratory pathogen that causes the majority of viral pneumonia of infants and young children. hPIV3 can infect host cells through the synergistic action of hemagglutinin neuraminidase (HN) protein and the homotypic fusion (F) protein on the viral surface. HN protein plays a variety of roles during the virus invasion process, such as promoting viral particles to bind to receptors, cleaving sialic acid, and activating the F protein. Crystal structure research shows that HN tetramer adopted a "heads-down" conformation, at least two heads dimmer on flank of the four-helix bundle stalk, which forms a symmetrical interaction interface. The stalk region determines interactions and activation of F protein in specificity, and the heads in down position statically shield these residues. In order to make further research on the function of these amino acids at the hPIV3 HN stalk/head interface, fifteen mutations (8 sites from stalk and 7 sites from head) were engineered into this interface by site-directed mutagenesis in this study. Alanine substitution in this region of hPIV3 HN had various effects on cell fusion promotion, receptor binding, and neuraminidase activity. Besides, L151A also affected surface protein expression efficiency. Moreover, I112A, D120A, and R122A mutations of the stalk region that were masked by global head in down position had influence on the interaction between F and HN proteins. PMID- 29516317 TI - Dysregulated genes and miRNAs in the apoptosis pathway in colorectal cancer patients. AB - Apoptosis is genetically regulated and involves intrinsic and extrinsic pathways. We examined 133 genes within these pathways to identify whether they are expressed differently in colorectal carcinoma (CRC) and normal tissue (N = 217) and if they are associated with similar differential miRNA expression. Gene expression data (RNA-Seq) and miRNA expression data (Agilent Human miRNA Microarray V19.0) were generated. We focused on dysregulated genes with a fold change (FC) of > 1.50 or < 0.67, that were significant after adjustment for multiple comparisons. miRNA:mRNA seed-region matches were determined. Twenty three genes were significantly downregulated (FC < 0.67) and 18 were significantly upregulated (FC > 1.50). Of these 41 genes, 11 were significantly associated with miRNA differential expression. BIRC5 had the greatest number of miRNA associations (14) and the most miRNAs with a seed-region match (10). Four of these matches, miR-145-5p, miR-150-5p, miR-195-5p, and miR-650, had a negative beta coefficient. CSF2RB was associated with ten total miRNAs (five with a seed region match, and one miRNA, miR-92a-3p, with a negative beta coefficient). Of the three miRNAs associated with CTSS, miR-20b-5p, and miR-501-3p, had a seed region match and a negative beta coefficient between miRNA:mRNA pairs. Several miRNAs that were associated with dysregulated gene expression, seed-region matches, and negative beta coefficients also were associated with CRC-specific survival. Our data suggest that miRNAs could influence several apoptosis-related genes. BIRC5, CTSS, and CSF2R all had seed-region matches with miRNAs that would favor apoptosis. Our study identifies several miRNA associated with apoptosis related genes, that if validated, could be important therapeutic targets. PMID- 29516319 TI - Association of XPA Polymorphisms Towards Lung Cancer Susceptibility and its Predictive Role in Overall Survival of North Indians. AB - The present study investigated the role of Xeroderma pigmentosum group A (XPA) polymorphism (A23G and G709A) with lung cancer risk and its association with overall survival in North Indians. 370 cases and 370 controls were investigated to evaluate association between XPA polymorphism (A23G and G709A) with lung cancer risk using logistic regression analysis. A follow-up study was also conducted for 291 lung cancer cases illustrating correlation between overall survival in lung cancer patients and XPA variants. GG genotype showed an increased lung cancer risk (p = 0.0007) for A23G polymorphism whereas G709A polymorphism was associated with significant protective effect in heterozygous (AG) subjects (p = 0.001). When stratified according to smoking status an increased risk for lung cancer was observed for GG genotype in A23G polymorphism (p = 0.0002). A poor survival in females carrying variant genotype (GG) was observed (p = 0.001; MST = 4.16 months) for A23G polymorphism. Adenocarcinoma patients with heterozygous genotype showed an increased hazard ratio (p = 0.02) for A23G polymorphism. G709A was associated with a reduced hazard ratio marking a better survival among mutant females (HR 0.17; p = 0.05; MST = 18.63 months). It can be concluded that A23G polymorphism might contribute to increased lung cancer risk in North Indian population emphasizing on poor survival among females. G709A polymorphism might result in protective effect in lung cancer subjects. The present study had a low sample size but it could act as reference for the large sample studies in future. PMID- 29516320 TI - Pre-diagnostic aspirin use and mortality after breast cancer. AB - BACKGROUND: Whether aspirin or other nonsteroidal anti-inflammation drug (NSAID) use is associated with mortality following breast cancer remains unclear. Consideration of use patterns and interaction with obesity may help to clarify the inconsistent results. METHODS: Pre-diagnosis NSAID use, weight, and height were assessed ~ 3 months after diagnosis through in-person interviews with a population-based cohort of 1,442 women with first primary breast cancer. Vital status was determined through the national death index after ~ 18 years of follow up (N = 237/597 breast cancer-specific/all-cause deaths). We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multiplicative interaction by body mass index (BMI) was evaluated using the likelihood ratio test. RESULTS: Ever aspirin use was inversely associated with breast cancer-specific mortality (HR 0.87, 95% CI 0.59-1.29), but positively associated with all-cause mortality (HR 1.21, 95% CI 0.99-1.48); the CIs included the null values. The HRs, however, were more pronounced for the highest level of duration, frequency, regularity, and timing for all-cause, but not breast cancer-specific mortality. Interactions with BMI revealed no significant heterogeneity (pinteraction = 0.37 and pinteraction = 0.36, respectively). CONCLUSION: Pre-diagnosis aspirin use was not strongly associated with mortality following breast cancer. The all-cause mortality associations, however, were slightly stronger when we considered patterns of use. PMID- 29516321 TI - Comparative Effectiveness of Inclisiran 100, 300, and 500 mg in a Population with Hyperlipidemia: A Network Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: To our knowledge, inclisiran was the first agent composed of small interfering RNAs (siRNAs) to be preliminarily used to reduce proatherogenic lipoprotein cholesterol levels. Inclisiran was evaluated in large clinical trials but did not receive government approval. The ability of inclisiran to reduce low density lipoprotein cholesterol (LDL-C) greatly improved its chances of becoming a novel therapeutic option for patients with hyperlipidemia. OBJECTIVE: Our goal was to summarize the preliminary effectiveness and safety data for inclisiran. METHODS: We conducted a comprehensive search of PubMed, Scopus, Web of Science, the OVID EMB Reviews database, and Clinical Trials with the keyword "inclisiran" to find all related randomized controlled trials (RCTs). Five recently published RCTs involving 583 adults aged 18-65 years with hyperlipidemia were included in the analysis. RESULTS: Subgroup analysis suggested that inclisiran 100 mg (standard mean difference [SMD] - 2.09; 95% confidence interval [CI] - 2.51 to - 1.66; p < 0.05), 300 mg (SMD - 2.74; 95% CI - 3.61 to - 1.87; p < 0.05), and 500 mg (SMD - 2.21; 95% CI - 2.62 to - 1.80; p < 0.05) significantly (p < 0.05) reduced LDL-C and total cholesterol even though pooled analysis showed no LDL-C lowering effect (SMD 0.15; 95% CI - 0.34 to 0.04; p = 0.116). Compared with patients receiving placebo, pooled and subgroup analysis of patients receiving inclisiran showed no favorable changes in triglycerides or high-density lipoprotein cholesterol (p > 0.05). The most commonly reported adverse events were musculoskeletal pain, nasopharyngitis, headache, and elevated C-reactive protein (CRP), none of which were significant (p > 0.05). CONCLUSIONS: To date, inclisiran has been effective in treating hyperlipidemia. Major adverse events were not identified, although other possible adverse events may be discovered with more RCTs and extensive long-term follow-up. PMID- 29516322 TI - CKD-MBD management: what is the role of parathyroidectomy? Results from a nationwide survey in Italy. AB - We herein report on a nationwide survey conducted in Italy to investigate the use of parathyroidectomy (PTX). In spite of the availability of newer and more effective drugs to control chronic kidney disease mineral bone disorder (CKD-MBD) biochemical abnormalities, PTX still remains a resource for nephrologists to use. However, observational analyses suggest that in recent years there has been a constant decline in the number of patients undergoing PTX. The reasons are not clear, though the increasing age and number of comorbidities of dialysis patients may partly explain this trend. Poor adherence to guidelines and/or geographical as well as logistic factors may also contribute to the lower use of PTX. The working group on CKD-MBD of the Italian Society of Nephrology launched a nationwide survey to investigate clinical practice patterns for PTX in Italy and identify modifiable factors that may limit accessibility to surgery. PMID- 29516323 TI - Toward faster inference of micron-scale axon diameters using Monte Carlo simulations. AB - OBJECT: Recent advances have allowed oscillating gradient (OG) diffusion MRI to infer the sizes of micron-scale axon diameters. Here the effects on the precision of the inferred diameters are studied when reducing the number of images collected to reduce imaging time for clinical feasibility. MATERIALS AND METHODS: Monte Carlo simulations of cosine OG sequences (50-1000 Hz) using a two compartment model on a parallel cylinder (diameters 1-5 MUm) geometry were conducted. Temporal diffusion spectroscopy was used to infer axon diameters. Three different gradient sets were simulated with different combinations of gradient strengths. RESULTS: Five frequencies were adequate for d = 3-5 MUm with single-sized cylinders and for effective mean axon diameters greater than 2 MUm for cylinders with a distributions of diameters. There was some improvement in precision for d = 1-2 MUm with 10 frequencies. It is better to repeat measurements at higher gradient strengths than to use a range of gradient strengths. The improvement tended to be greatest when using fewer frequencies and was especially noticeable at very high gradient strengths. CONCLUSION: Images can be collected with fewer gradient strengths and frequencies without sacrificing the precision of the measurements. This could be useful in reducing imaging time so that OG techniques can be used in clinical settings. PMID- 29516325 TI - Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing. AB - BACKGROUND: There is uncertainty as to the appropriate follow-up of patients who test positive on multimarker stool DNA (sDNA) testing and have a colonoscopy without neoplasia. AIMS: To determine the prevalence of missed colonic or occult upper gastrointestinal neoplasia in patients with an apparent false positive sDNA. METHODS: We prospectively identified 30 patients who tested positive with a commercially available sDNA followed by colonoscopy without neoplastic lesions. Patients were invited to undergo repeat sDNA at 11-29 months after the initial test followed by repeat colonoscopy and upper endoscopy. We determined the presence of neoplastic lesions on repeat evaluation stratified by results of repeat sDNA. RESULTS: Twelve patients were restudied. Seven patients had a negative second sDNA test and a normal second colonoscopy and upper endoscopy. In contrast, 5 of 12 subjects had a persistently positive second sDNA test, and 3 had positive findings, including a 3-cm sessile transverse colon adenoma with high-grade dysplasia, a 2-cm right colon sessile serrated adenoma with dysplasia, and a nonadvanced colon adenoma (p = 0.045). These corresponded to a positive predictive value of 0.60 (95% CI 0.17-1.00) and a negative predictive value of 1.00 (95% CI 1.00-1.00) for the second sDNA test. In addition, the medical records of all 30 subjects with apparent false positive testing were reviewed and no documented cases of malignant tumors were recorded. CONCLUSIONS: Repeat positive sDNA testing may identify a subset of patients with missed or occult colorectal neoplasia after negative colonoscopy for an initially positive sDNA. High-quality colonoscopy with careful attention to the right colon in patients with positive sDNA is critically important and may avoid false negative colonoscopy. PMID- 29516326 TI - Assessment of Serum sTREM-1 as a Marker of Subclinical Inflammation in Diarrhea Predominant Patients with Irritable Bowel Syndrome. AB - BACKGROUND: Irritable bowel disease (IBS) is viewed upon as a functional disorder of subclinical inflammatory changes in recent years, and there is no reliable biomarker. Triggering receptor expressed on myeloid cells 1 (TREM-1), also produced in a soluble form (sTREM-1), is involved in the activation of inflammatory cascades of intracellular events and may play a role in pathogenesis of IBS. AIM: To investigate whether serum sTREM-1 level can be used as a marker of subclinical inflammation in D-IBS. METHODS: Abdominal pain was quantified by a validated questionnaire. Expression level of TREM-1 in colonic mucosa as well as sTREM-1 level in serum was also detected. Furthermore, we investigated the involvement of TREM-1-associated macrophage activation in IBS-like visceral hypersensitivity. RESULTS: No evidence for obvious inflammation was found in D IBS patients. Serum sTREM-1 level in D-IBS patients was significantly higher than that in HCs, which was also significantly correlated with abdominal pain scores. We showed a marked increase in the proportion of TREM-1-expressing macrophages in D-IBS, which was significantly correlated with abdominal pain scores. Functionally, gadolinium chloride (GdCl3), a macrophage selective inhibitor, or LP17, the TREM-1-specific peptide, significantly suppressed the visceral hypersensitivity in trinitrobenzene sulfonic acid (TNBS)-treated mice with IBS like visceral hypersensitivity. CONCLUSIONS: Serum sTREM-1 level is significantly higher in D-IBS patients and positively correlates with abdominal pain, which may be initiated by TREM-1-associated macrophage activation, indicating the existence of subclinical inflammation in D-IBS. Therefore, serum sTREM-1 is a potential marker of subclinical inflammation in D-IBS. PMID- 29516324 TI - Fecal Fatty Acid Profiling as a Potential New Screening Biomarker in Patients with Colorectal Cancer. AB - BACKGROUND: The fatty acid profile of the fecal metabolome and its association with colorectal cancer (CRC) has not been fully evaluated. AIMS: We aimed to compare the fecal fatty acid profiles of CRC patients and healthy controls. METHODS: We enrolled 26 newly diagnosed CRC patients and 28 healthy individuals between July 2014 and August 2014 from our institute. Long- and short-chain fatty acids were extracted from fecal samples and analyzed using gas chromatography mass spectrometry. RESULTS: Regarding fecal long-chain fatty acids, the levels of total omega-6 polyunsaturated fatty acids and, particularly, of linoleic acid (C18:2omega-6) were significantly higher in male CRC patients than in healthy men (2.750 +/- 2.583 vs. 1.254 +/- 0.966 ug/mg feces, P = 0.040; 2.670 +/- 2.507 vs. 1.226 +/- 0.940 ug/mg feces, P = 0.034, respectively). In addition, the levels of total monounsaturated fatty acid and, particularly, of oleic acid (C18:1omega-9) were significantly higher in male CRC patients than in healthy men (1.802 +/- 1.331 vs. 0.977 +/- 0.625 ug/mg feces, P = 0.027; 1.749 +/- 1.320 vs. 0.932 +/- 0.626 ug/mg feces, P = 0.011, respectively). However, those differences were not shown in female gender. The level of fecal short-chain fatty acids was not different between CRC patients and healthy controls. CONCLUSIONS: There were changes in the profiles of fecal fatty acid metabolomes in CRC patients compared to healthy controls, implying that fecal fatty acids could be used as a novel screening tool for CRC. PMID- 29516327 TI - Pronounced Coronary Arteriosclerosis in Cirrhosis: Influence on Cardiac Function and Survival? AB - BACKGROUND: The relation between excessive alcohol consumption and coronary arteriosclerosis has remained controversial. The etiology of cirrhosis has been considered a substantial risk factor for development of arteriosclerotic lesions. The coronary artery calcium-score derived from coronary CT angiography is a robust marker of coronary arteriosclerosis. AIMS: To study the burden of coronary arteriosclerosis in cirrhotic patients of various etiologies and association to cardiac dysfunction and survival. METHODS: Fifty-seven patients with cirrhosis without cardiovascular disease underwent coronary CT angiography, tissue Doppler echocardiography, electrocardiogram and registration of clinical and biochemical characteristics. RESULTS: In patients with cirrhosis the median coronary artery calcium-score was increased in comparison with age and race-adjusted healthy reference values (men: 328 vs. 9 HU and women: 136 vs. 0 HU; p < 0.001). Moreover, the coronary artery calcium-score in alcohol-related cirrhosis was significantly higher than in nonalcohol-related cirrhosis (362 vs. 46 HU, p < 0.001). Coronary artery calcium-score correlated with age (p = 0.002) but not with established cardiovascular risk factors including smoking, type 2 diabetes, hypertension, gender, or hypercholesterolemia. Coronary artery calcium-score was associated with diastolic dysfunction, lateral e' (p = 0.025), but not with other markers of cardiac dysfunction. During a median follow-up of 25 months 12 patients (21%) died but coronary artery calcium-score was not associated with survival. CONCLUSIONS: Coronary arteriosclerosis was particular extensive in patients with alcoholic cirrhosis. However, the current results suggest that coronary arteriosclerosis only have limited influence on cardiac function and survival. Surprisingly, no other established risk factors apart from age seemed to interfere with coronary arteriosclerosis in cirrhotic patients. PMID- 29516328 TI - Persistence of Circulating Hepatitis C Virus Antigens-Specific Immune Complexes in Patients with Resolved HCV Infection. AB - BACKGROUND: Our recent study indicated the possible presence of detectable hepatitis C virus antigens (HCV-Ags) after denaturation of sera with resolved HCV (R-HCV) infection. The present study determined and characterized persistent HCV Ags-specific immune complexes (ICs) in these patients. METHODS: Sixty-eight sera with R-HCV and 34 with viremic HCV (V-HCV) infection were tested for free and IC bound HCV-Ags using HCV-Ags enzyme immunoassay (EIA), the presence of HCV-Ags specific ICs by immunoprecipitation and Western blot (IP-WB), HCV ICs containing HCV virions using IP and HCV RNA RT-PCR, and correlation of HCV ICs with clinical presentation in these patients. RESULTS: Using HCV-Ags EIA, we found 57.4% of sera with R-HCV infection were tested positive for bound, but not free HCV-Ags. Using pooled or individual anti-HCV E1/E2, cAg, NS3, NS4b, and/or NS5a to precipitate HCV-specific-Ags, we confirmed persistent HCV-Ags ICs specific to various HCV structural and non-structural proteins not only in V-HCV infection, but also in R-HCV infection. Using IP and HCV RNA PCR, we then confirmed the presence of HCV virions within circulating ICs in V-HCV, but not in R-HCV sera. Multivariable analysis indicated significant and independent associations of persistent circulating HCV-Ags-specific ICs with both age and the presence of cirrhosis in patients with R-HCV infection. CONCLUSIONS: Various HCV-Ag-specific ICs, but not virions, persist in 57.4% of patients who had spontaneous or treatment-induced HCV clearance for 6 months to 20 years. These findings enriched our knowledge on HCV pathogenesis and support further study on its long-term clinical relevance, such as extrahepatic manifestation, transfusion medicine, and hepatocarcinogenesis. PMID- 29516329 TI - Presence of Melena in Obscure Gastrointestinal Bleeding Predicts Bleeding in the Proximal Small Intestine. AB - BACKGROUND AND AIMS: Melena is a symptom of upper gastrointestinal bleeding and usually indicates bleeding proximal to the ligament of Treitz. However, whether melena predicts bleeding in the proximal small intestine in patients with obscure gastrointestinal bleeding (OGIB) is unknown and the objective of this study. METHODS: A retrospective cohort study of consecutive patients undergoing capsule endoscopy for OGIB between July 2009 and May 2016 was conducted. Subjects were categorized based on the presence of melena, and the primary outcome was identification of a bleeding source within the proximal 2/3 of the small intestine. Multi-variable regression was performed to control for confounders. RESULTS: During the study, 288 patients met the eligibility criteria. Subjects with melena accounted for 37.1% of the cohort and were more likely to be older (mean age 66.9 vs. 63.9, p = 0.0457), take warfarin (15.1 vs. 9.4%, p = 0.0122), and have a lower 12-month hemoglobin nadir (7.3 vs. 8.3 g/dL, p = 0.0002). On crude analysis, 56.1% of patients with melena had a bleeding source within the proximal small intestine compared to 34.8% for those without (RR 1.61, 95% CI 1.24-2.09, p = 0.0004). On multi-variable analysis, the presence of melena doubled the odds of finding a bleeding site within the proximal small intestine (OR 1.97, 95% CI 1.17-3.33, p = 0.010). CONCLUSIONS: The presence of melena doubles the odds of finding a bleeding site within the proximal small intestine among patients with OGIB, and deep enteroscopy, if performed before a capsule study, should begin with an antegrade approach in these patients. PMID- 29516330 TI - Application of Pharmacometric Analysis in the Design of Clinical Pharmacology Studies for Biosimilar Development. AB - This article provides an overview of four case studies to demonstrate the utility of pharmacometric analysis in biosimilar development to help design sensitive clinical pharmacology studies for the demonstration of biosimilarity. The two major factors that determine the sensitivity of a clinical pharmacokinetic/pharmacodynamic (PK/PD) study to demonstrate biosimilarity are the size of the potential difference to be detected (signal) and the inter subject variability (noise), both of which can be characterized and predicted using pharmacometric approaches. To maximize the chance to detect any potential difference between the proposed biosimilar and the reference drug, the dose selected for the clinical pharmacology study should fall on the steep part of the dose-response curve. Pharmacometric analysis can be used to characterize the dose response relationship using PD- or PK/PD-linked models. The understanding of the PD endpoints in terms of dynamic range of the response and the location of the studied dose on the dose-response curve can provide strategic advantage in the trial design. To reduce the inter-subject variability (noise), pharmacometric analysis can help avoid high variability associated with low doses, and decrease variability by controlling certain covariates in the inclusion/exclusion criteria. Pharmacometric analysis also can help select or justify margins for the equivalence test of PD endpoints. Pharmacometric analysis will assume an ever increasing role in the clinical development of biosimilar drugs, as it helps to ensure that sufficient sensitivity is built into the study design to detect potential PK and PD differences. PMID- 29516331 TI - The impact of the minimum wage on health. AB - This study evaluates the effect of minimum wage on risky health behaviors, healthcare access, and self-reported health. We use data from the 1993-2015 Behavioral Risk Factor Surveillance System, and employ a difference-in differences strategy that utilizes time variation in new minimum wage laws across U.S. states. Results suggest that the minimum wage increases the probability of being obese and decreases daily fruit and vegetable intake, but also decreases days with functional limitations while having no impact on healthcare access. Subsample analyses reveal that the increase in weight and decrease in fruit and vegetable intake are driven by the older population, married, and whites. The improvement in self-reported health is especially strong among non-whites, females, and married. PMID- 29516332 TI - A Morally Permissible Moral Mistake? Reinterpreting a Thought Experiment as Proof of Concept. AB - This paper takes the philosophical notion of suberogatory acts or morally permissible moral mistakes and, via a reinterpretation of a thought experiment from the medical ethics literature, offers an initial demonstration of their relevance to the field of medical ethics. That is, at least in regards to this case, we demonstrate that the concept of morally permissible moral mistakes has a bearing on medical decision-making. We therefore suggest that these concepts may have broader importance for the discourse on medical ethics and should receive fuller consideration by those working the field. The focus of the discussion we present is on a particular thought experiment originally presented by Sulmasy and Sugarman. Their case formed the basis of an exchange about the moral equivalence of withdrawing and withholding life-saving treatment. The analysis Sulmasy and Sugarman set out is significant because, contrary to common bioethical opinion, it implies that the difference between withdrawing and withholding life-saving treatment holds, rather than lacks, moral significance. Following a brief discussion of rejoinders to Sulmasy and Sugarman's article, we present a constructive reinterpretation of the thought experiment, one that draws on the idea of suberogatory acts or "morally permissible moral mistakes." Our analysis, or so we suggest, accounts for the differing moral intuitions that the case prompts. However, it also calls into question the degree to which this thought experiment can be thought of as illustrating the moral (non)equivalence of withdrawing and withholding life-saving treatment. Rather, we conclude that it primarily illuminates something about the ethical parameters of healthcare when family members, particularly parents, are involved in decision-making. PMID- 29516333 TI - Update on the Treatment of Anaplastic Large Cell Lymphoma. AB - PURPOSE OF REVIEW: Given the rarity of anaplastic large cell lymphoma (ALCL), studies evaluating new therapies have typically grouped ALCL together with other peripheral T cell lymphomas (PTCL). Thus, the treatment paradigm for ALCL largely mirrors that of PTCL in general. In this review, we discuss the current standard of care as well as emerging therapies, including antibody-based drugs, in systemic ALCL as well as primary cutaneous and breast implant-associated ALCL. RECENT FINDINGS: High CD30 expression in ALCL has allowed the use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in both systemic and primary cutaneous ALCL. Recent clinical trials with brentuximab have shown substantial activity in the relapsed/refractory setting. A randomized phase III study is ongoing comparing brentuximab plus CHP (cyclophosphamide, doxorubicin, prednisone) with standard CHOP in the front-line setting. The use of targeted therapies and other novel agents have improved outcomes for ALCL patients and in the future can complement or even replace the current standard of care and front line treatment options. PMID- 29516334 TI - Glioma growth modeling based on the effect of vital nutrients and metabolic products. AB - Glioma brain tumors exhibit considerably aggressive behavior leading to high mortality rates. Mathematical modeling of tumor growth aims to explore the interactions between glioma cells and tissue microenvironment, which affect tumor evolution. Leveraging this concept, we present a three-dimensional model of glioma spatio-temporal evolution based on existing continuum approaches, yet incorporating novel factors of the phenomenon. The proposed model involves the interactions between different tumor cell phenotypes and their microenvironment, investigating how tumor growth is affected by complex biological exchanges. It focuses on the separate and combined effect of vital nutrients and cellular wastes on tumor expansion, leading to the formation of cell populations with different metabolic, proliferative, and diffusive profiles. Several simulations were performed on a virtual and a real glioma, using combinations of proliferation and diffusion rates for different evolution times. The model results were validated on a glioma model available in the literature and a real case of tumor progression. The experimental observations indicate that our model estimates quite satisfactorily the expansion of each region and the overall tumor growth. Based on the individual results, the proposed model may provide an important research tool for patient-specific simulation of different tumor evolution scenarios and reliable estimation of glioma evolution. Graphical Abstract Outline of the mathematical model functionality and application to glioma growth with indicative results. PMID- 29516336 TI - Integrating a Co-occurring Disorders Intervention in Drug Courts: An Open Pilot Trial. AB - Little research has focused on systematically integrating clinical treatment within existing drug court procedures. This could be particularly useful for clients with substance use disorders, who comprise those on court dockets and often have co-existing mental health issues. This article reports on the preliminary outcomes of integrating MISSION-Criminal Justice (MISSION-CJ), a co occurring mental health and substance use wraparound intervention, within two Massachusetts drug courts. In this open pilot, clients completed intake and 6 month follow-up assessments. The participants were primarily Caucasian (86%), male (82%), had at least 2 prior arrests, and received outpatient treatment for mental health (54%), alcohol use (51%), or drug use (88%) prior to enrolling in MISSION-CJ. Six-month follow-up data suggested that participants showed statistically significant reductions in average number of nights spent in jail, alcohol use, and drug use, as well as an increase in full time employment. PMID- 29516335 TI - Stromal-derived factor 1 directly promotes genes expressed within the ovulatory cascade in feline cumulus oocyte complexes. AB - PURPOSE: We hypothesized that the chemokine SDF1/CXCR4 system was present in feline cumulus-oocyte complexes (COCs) and that COCs cultured with SDF1 would directly upregulate gene expression in the ovulatory cascade. METHODS: Ovaries (n = 50) were obtained from adult domestic cats during the breeding season and COCs were recovered from antral follicles. Because IVM media triggers cumulus-oocyte expansion, culture conditions needed to be optimized to study periovulatory genes. After optimization, the effects of 25 ng/ml SDF1 and the CXCR4 inhibitor were examined in a COC culture for 3, 12, and 24 h. RESULTS: MEM-hepes with 1% of charcoal stripped-FBS was the optimized culture medium, assessed by the expansion of COCs at 24 h in the gonadotropin (GNT) group but not in the media with serum alone. The mRNA expression of HAS2, TNFAIP6, PTX3, and AREG peaked at 3 h in GNT group as compared to all other groups (p < 0.05). COCs cultured with SDF1 showed increased HAS2 and TNFAIP6 mRNA expression at 3 h compared to negative controls and to the CXCR4 inhibitor group. CXCR4 and SDF1 immunostaining was present in both cumulus cells and the oocyte. CONCLUSIONS: These results demonstrate that GNT stimulation upregulates key periovulatory genes and expansion in feline COCs from antral follicles, and support the use of this culture system to examine molecular processes within the COC. In addition, SDF1 directly promotes key periovulatory genes in feline COCs, suggesting that the SDF1-CXCR4 pathway may extend its function beyond a chemoattractant, and may play a direct role within the COC. PMID- 29516337 TI - "Pushing the Boat Out": A Meta-synthesis of How Members, Staff and Family Experience the Clubhouse Model. AB - To explore how member, staff, and family experience the contributions of the clubhouse model to outcomes for adults with severe mental illness. Given the significant role social and vocational arenas play in promoting wellbeing, irrespective of health status, explorations of the role such arenas can play in helping individuals accomplish their life and vocational goals may be useful in guiding policy and practice. A metaethnography was conducted using 11 qualitative studies published between 2000 and 2015. Four themes and an overarching metaphor were identified: (1) Stepping out of limiting realities; (2) anchoring; (3) creating ways of flourishing; and (4) prospects of a life outside the clubhouse. "Pushing out the boat" as a metaphor holds promise in facilitating discussions about the subjective outcomes of the clubhouse model and for expanding knowledge about clubhouses as multi-dimensional programs that provide social, educational, and vocational opportunities for adults recovering from mental health problems. Our findings show that clubhouses are valuable communities for meaningful doings for individuals to build self-confidence, relations, and perspective-all crucial for processes of recovery. Clubhouses provide people a place to establish an anchor in a supportive environment where they can try things out and regain their self-confidence. From there, they may choose to push their boat out. However, many members might need to choose not to-the seas may be too rough or their boat may not yet be strong enough for the journey. Further research is needed to examine members' experiences with integration into mainstream social networks and employment. It will also be important to examine how practitioners can intentionally interact with Clubhouse members and their families to promote the individuals' processes of social integration outside the clubhouse. PMID- 29516338 TI - Using Video Modeling as an Anti-bullying Intervention for Children with Autism Spectrum Disorder. AB - In the present study, we used a multiple baseline design across participants to assess the efficacy of a video modeling intervention to teach six children with autism spectrum disorder (ASD) to assertively respond to bullying. During baseline, the children made few appropriate responses upon viewing video clips of bullying scenarios. During the video modeling intervention, participants viewed videos of models assertively responding to three types of bullying: physical, verbal bullying, and social exclusion. Results indicated that all six children learned through video modeling to make appropriate assertive responses to bullying scenarios. Four of the six children demonstrated learning in the in situ bullying probes. The results are discussed in terms of an intervention for victims of bullying with ASD. PMID- 29516339 TI - Comparison of Mental Health Treatment Adequacy and Costs in Public Hospitals in Boston and Madrid. AB - Analyses of healthcare expenditures and adequacy are needed to identify cost effective policies and practices that improve mental healthcare quality. Data are from 2010 to 2012 electronic health records from three hospital psychiatry departments in Madrid (n = 29,944 person-years) and three in Boston (n = 14,109 person-years). Two-part multivariate generalized linear regression and logistic regression models were estimated to identify site differences in mental healthcare expenditures and quality of care. Annual total average treatment expenditures were $4442.14 in Boston and $2277.48 in Madrid. Boston patients used inpatient services more frequently and had higher 30-day re-admission rates (23.7 vs. 8.7%) despite higher rates of minimally adequate care (49.5 vs. 34.8%). Patients in Madrid were more likely to receive psychotropic medication, had fewer inpatient stays and readmissions, and had lower expenditures, but had lower rates of minimally adequate care. Differences in insurance and healthcare system policies and mental health professional roles may explain these dissimilarities. PMID- 29516340 TI - Dual Trajectories of Sleep Duration and Cigarette Smoking during Adolescence: Relation to Subsequent Internalizing Problems. AB - Decreasing sleep duration and increasing cigarette smoking of adolescents are major public health concerns. However, research examining connections between the developmental trajectories of the outcomes that are evolving contemporaneously and their relation to long-term outcomes is still lacking. This study examined distinct trajectories of sleep duration and cigarette smoking during adolescence, associations between these trajectories, and links with internalizing problems during young adulthood. Data were collected from 2510 adolescents who participated in a longitudinal study spanning from 2006 through 2014 in northern Taiwan. Group-based dual trajectory modeling was used to examine the dynamic relationships between sleep duration and cigarette smoking trajectories during adolescence. Multiple linear regression was used to understand the association between the distinct trajectories and subsequent internalizing problems. Three sleep duration trajectories (short decreasing, typical sleep, and long sleep) and three cigarette smoking trajectories (nonsmokers, late increasing, and escalating smokers) were identified. We found significant inter-relationships for sleep duration and cigarette smoking trajectories during adolescence; all atypical sleep duration trajectories conferred increased risks of increased cigarette smoking and vice versa. In addition, the effects of sleep duration and cigarette smoking on later internalizing problems were found to vary by sex and trajectory patterns. These results provide insight regarding the co-development of sleep duration and cigarette smoking trajectories during adolescence. We also highlight the different roles of sleep duration and cigarette smoking trajectories and their relation to internalizing problems of young adulthood. PMID- 29516341 TI - Distance-Delivered Parent Training for Childhood Disruptive Behavior (Strongest FamiliesTM): a Randomized Controlled Trial and Economic Analysis. AB - Disruptive behavior disorders are prevalent in youth, yet most children with disruptive behavior do not have access to timely, effective treatment. Distance delivered service (e.g., via telephone, Internet) can overcome several barriers to care. This study tested the effectiveness of a 12-week parent training program, Strongest FamiliesTM Parenting the Active Child, delivered via written material, skill-based videos, and telephone coaching sessions, as compared to usual care in reducing child externalizing behavior. Participants were 172 primary caregivers of a 6- to 12-year-old (29% girls; M age = 8.5 years) recruited from community children's mental health clinics. Participants were randomized to either Strongest FamiliesTM or usual care and completed measures of child externalizing behavior, parenting practices, parent distress, and intervention services consumed at baseline and 5-, 10-, 16-, and 22-months post baseline. Growth curve analysis showed significant reductions in externalizing behavior in both conditions over time. Improvements were significantly greater at 10 months in the Strongest FamiliesTM condition (d = 0.43). At 22 months, however, the differences were not significant and small in magnitude (d = -0.05). The intervention decreased inconsistent discipline significantly more than usual care. Parents in both conditions showed significant reductions in distress. We also conducted a cost-effectiveness analysis to assess the value for money of the Strongest FamiliesTM program versus usual care. Distance parent training is a promising way to increase access to, and reduce costs associated with, mental health care for families with a child with disruptive behavior. PMID- 29516342 TI - Responsiveness of the anxiety/depression dimension of the 3- and 5-level versions of the EQ-5D in assessing mental health. AB - BACKGROUND: Anxiety and depression disorders are associated with significantly lower health-related quality of life (HRQL). The EQ-5D is a commonly used generic measure of HRQL; it captures mental health through a single domain-the anxiety/depression dimension. Evidence on the responsiveness of this measure in assessing changes in mental health changes is limited. OBJECTIVE: To examine the performance of the anxiety/depression dimension (A/D) of the 3- and 5-level (3L and 5L) versions of the EQ-5D in assessing changes in mental health. METHODS: Data from two patient populations were used: 495 adults post-discharge from general internal medicine ward (EQ-5D-3L), and 225 type 2 diabetes patients who screened positive for depressive symptoms (EQ-5D-5L). Anchor-based approach along with effect sizes (ES) and ROC analysis was used. Anchors included patient health questionnaire 9-items "PHQ9" and generalized anxiety disorder 2-item questionnaire "GAD2" for EQ-5D-3L, and PHQ9 and SF-12 mental composite summary scores (MCS) for EQ-5D-5L. A/D change was quantified as the difference between follow-up and baseline levels. RESULTS: The A/D dimension of the EQ-5D-3L showed limited responsiveness to changes in depressive symptoms measured by PHQ9 and for anxiety symptoms measured by GAD2, whereby in those who improved or deteriorated in either symptom, more than half of the patients did not have an A/D change. In the ROC analysis, the A/D dimension of the EQ-5D-3L showed weak performance with C-indices ranging from 0.58 to 0.63 and probability of detection of depressive or anxiety symptoms ranging between 20 and 40%, which are all well below acceptable ranges. Similar results were observed for the A/D dimension of the EQ-5D-5L; although the performance was slightly better, it was still below acceptable range. In patients who improved or deteriorated based on the PHQ9 or MCS, around a third had no changes on the A/D dimension. The performance of the A/D dimension of the EQ-5D-5L was also very limited with C-indices ranging between 0.67 and 0.76, and probability of detection between 50 and 67%, slightly better than that of the 3L, yet unsatisfactory. CONCLUSIONS: Although the A/D of both EQ-5D-3L and 5L was limited in capturing changes in mental health in these populations, the 5L was slightly more responsive than the 3L. While the performance was better for depressive than anxiety symptoms, it varied by the direction of change. Further research using other measures of mental health in other populations is warranted. PMID- 29516343 TI - Information needs and requirements in patients with brain tumours and their relatives. AB - Patients with brain tumours face a number of medical and social challenges. Previous studies have shown that these patients and their relatives need a high level of patient-oriented information and counselling. However, these needs are often underestimated. In this single-centre cross-sectional study, we evaluated, for the first time, the information needs of patients with brain tumours and their relatives depending on diagnosis, age and level of education. The participants were interviewed using pre-specified questionnaires. Answers were evaluated descriptively using standard statistical methods. A total of 888 questionnaires were sent out. The return rate was 50.7%. The majority of patients (nP = 103; 59.9%) and a higher proportion of relatives (nR = 103; 72.5%; p = 0.019) wished to receive a maximum of information. The majority (79.7% of patients; 83.1% of relatives) also stated that they preferred a personal, face-to face meeting as primary source of information. The need for information increased with education (p = 0.015), and decreased with tumour grade (p = 0.025) and age (p = 0.118). Our data indicate that patients with brain tumours and their relatives have high information needs throughout their disease and continuously require information and counselling. Optimal provision of information is based on personal preferences, which needs to be evaluated appropriately. Patient-oriented information and counselling are parts of a successful communication strategy that can improve cancer care significantly. PMID- 29516344 TI - A surgical strategy using a fusion image constructed from 11C-methionine PET, 18F FDG-PET and MRI for glioma with no or minimum contrast enhancement. AB - The objective of this study was to investigate the distribution of 11C-methionine (MET) and F-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) imaging and the hyperintense area in T2 weighted imaging (T2WI) in glioma with no or poor gadolinium enhancement in magnetic resonance imaging (GdMRI). Cases were also analyzed pathologically. We prospectively investigated 16 patients with non- or minimally enhancing (< 10% volume) glioma. All patients underwent MET-PET and FDG-PET scans preoperatively. After delineating the tumor based on MET uptake, integrated 3D images from FDG-PET and MRI (GdMRI, T2WI or FLAIR) were generated and the final resection plane was planned. This resection plane was determined intraoperatively using the navigation-guided fencepost method. The delineation obtained by MET-PET imaging was larger than that with GdMRI in all cases with an enhanced effect. In contrast, the T2WI-abnormal signal area (T2WI+) tended to be larger than the MET uptake area (MET+). Tumor resection was > 95% in the non-eloquent area in 4/5 cases (80%), whereas 10 of 11 cases (90.9%) had partial resection in the eloquent area. In a case including the language area, 92% resection was achieved based on the MET-uptake area, in contrast to T2WI-based partial resection (65%), because the T2WI+/MET- area defined the language area. Pathological findings showed that the T2WI+/MET+ area is glioma, whereas 6 of 9 T2WI+/MET- lesions included normal tissues. Tissue from T2W1+/MET+/FDG+/GdMRI+ lesions gave an accurate diagnosis of grade in six cases. Non- or minimally enhancing gliomas were classified as having a MET uptake area that totally or partially overlapped with the T2WI hyperintense area. Resection planning with or without a metabolically active area in non- or minimally enhancing gliomas may be useful for accurate diagnosis, malignancy grading, and particularly for eloquent area although further study is needed to analyze the T2WI+/MET- area. PMID- 29516345 TI - Informed Decision-Making in the Context of Prenatal Chromosomal Microarray. AB - The introduction of chromosomal microarray (CMA) into the prenatal setting has involved considerable deliberation due to the wide range of possible outcomes (e.g., copy number variants of uncertain clinical significance). Such issues are typically discussed in pre-test counseling for pregnant women to support informed decision-making regarding prenatal testing options. This research study aimed to assess the level of informed decision-making with respect to prenatal CMA and the factor(s) influencing decision-making to accept CMA for the selected prenatal testing procedure (i.e., chorionic villus sampling or amniocentesis). We employed a questionnaire that was adapted from a three-dimensional measure previously used to assess informed decision-making with respect to prenatal screening for Down syndrome and neural tube defects. This measure classifies an informed decision as one that is knowledgeable, value-consistent, and deliberated. Our questionnaire also included an optional open-ended question, soliciting factors that may have influenced the participants' decision to accept prenatal CMA; these responses were analyzed qualitatively. Data analysis on 106 participants indicated that 49% made an informed decision (i.e., meeting all three criteria of knowledgeable, deliberated, and value-consistent). Analysis of 59 responses to the open-ended question showed that "the more information the better" emerged as the dominant factor influencing both informed and uninformed participants' decisions to accept prenatal CMA. Despite learning about the key issues in pre-test genetic counseling, our study classified a significant portion of women as making uninformed decisions due to insufficient knowledge, lack of deliberation, value inconsistency, or a combination of these three measures. Future efforts should focus on developing educational approaches and counseling strategies to effectively increase the rate of informed decision-making among women offered prenatal CMA. PMID- 29516346 TI - Neurocognitive impairment with hepatitis C and HIV co-infection in Southern Brazil. AB - Although cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections, research on neurocognitive effects is limited in the context of HIV/HCV co-infection. The aims of this study were to explore the interplay between HIV and HCV infections in the expression of neurocognitive impairment (NCI), and to examine the differences in test performance between HIV/HCV co-infected and HIV or HCV mono infected patients. A total of 128 participants from Southern Brazil underwent a comprehensive neuropsychological (NP) battery comprising 18 tests. Participants were grouped according to their serological status: HCV mono-infected (n = 20), HIV mono-infected (n = 48), HIV/HCV co-infected (n = 12), and HIV-/HCV-uninfected controls (n = 48). The frequencies of HIV subtypes B and C between the HIV mono infected and HIV/HCV co-infected groups were comparable. There was greater prevalence of neuropsychological impairment among all three infection groups compared with the uninfected control group, but no statistically significant differences among mono- and co-infected groups were found. HCV infection was associated with cognitive deficits, independently of liver dysfunction. HCV infection did not show an additive effect on neurocognitive function among HIV+. NCI was independent of HCV RNA on peripheral blood, CSF, and hepatic injury. While we did not find additive global effect, in the present study, there was some evidence of additive HIV/HCV co-infection effects in speed of information processing, executive function, and verbal fluency domains when comparing the co infected group with the other three groups. NP impairment was not dependent on HCV subtypes. PMID- 29516347 TI - Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites. AB - Clomiphene citrate, a selective estrogen receptor modulator, is metabolized into its 4-hydroxylated active metabolites, primarily by CYP2D6. In this study, we investigated the effects of the most common CYP2D6 variant allele in Asians, CYP2D6*10, on the pharmacokinetics of clomiphene and its two active metabolites (4-OH-CLO and 4-OH-DE-CLO) in healthy Korean subjects. A single 50-mg oral dose of clomiphene citrate was given to 22 Korean subjects divided into three genotype groups according to CYP2D6 genotypes, CYP2D6*wt/*wt (n = 8; *wt = *1 or *2), CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 6). Concentrations of clomiphene and its metabolites were determined using a validated HPLC-MS/MS analytical method in plasma samples collected up to 168 h after the drug intake. There was a significant difference only in the Cmax of clomiphene between three CYP2D6 genotype groups (p < 0.05). Paradoxically, the elimination half-life (t1/2) and AUC of both active metabolites were all significantly increased in the CYP2D6*10 homozygous carriers, compared with other genotype groups (all p < 0.001). The AUCinf of corrected clomiphene active moiety in CYP2D6*10/*10 subjects was 2.95- and 2.05-fold higher than that of CYP2D6*wt/*wt and *wt/*10 genotype groups, respectively (both p < 0.001). Along with the partial impacts on the biotransformation of clomiphene and its metabolites by CYP2D6 genetic polymorphism, further studies on the effects of other CYP enzymes in a multiple dosing condition can provide more definite evidence for the inter-individual variabilities in clomiphene pharmacokinetics and/or drug response. PMID- 29516349 TI - Abstracts of the 27th Annual Conference of APASL, March 14-18, 2018, New Delhi, India. PMID- 29516348 TI - Three-dimensional visualization of internal vertebral venous plexuses relative to dural sac and spinal nerve root of spinal canal stenosis using MRI. AB - PURPOSE: The aim of this study was to introduce a new method of producing three dimensional (3D) images of vertebral venous plexuses (VVPs) by 3D-MRI with and without contrast media, to identify pathoanatomical features that might accelerate or modify spinal canal stenosis. METHODS: We used a 1.5-T MRI unit with two different 3D sequences with and without contrast media. Multi planar reconstruction (MPR) images of VVPs could be obtained by volume image subtraction methods with a workstation for dural sac from whole 3D volume MPR without contrast media, using images before and after gadoteridol injection. Three patients with degenerative lumbar spine disease and one with cervical ossification of the posterior longitudinal ligament (OPLL) were studied with and without contrast media. As three patients underwent operations, we investigated intraoperative microscopic findings, and compared VVP images. RESULTS: Abundant components of internal VVPs were identified on MRI in correlation with neural tissues such as dura and nerve roots. CONCLUSIONS: Using 3D MRI without and with gadoteridol, we can evaluate morphological changes in VVP under degenerative spinal conditions. The MR anatomy of VVPs of the spine is important, as it has been implicated in many pathophysiological mechanisms and may also cause pitfalls in MRI. PMID- 29516350 TI - CpG Island Methylation Patterns in Relapsing-Remitting Multiple Sclerosis. AB - DNA methylation may predispose to multiple sclerosis (MS), as aberrant methylation in the promoter regions across the genome seems to underlie several processes of MS. We have currently determined the methylation status of eight genes in relapsing-remitting MS patients. Methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) was used to determine the status of 31 CpG islands, located across eight genes, in 33 healthy individuals and 66 MS patients (33 in relapse and 33 in remission). The methylation levels in the examined sites ranged from 0 to 31%. Methylation positivity for RUNX3 and CDKN2A differed significantly between MS patients and healthy controls. Maximum methylation in RUNX3, CDKN2A, SOCS1, and NEUROG1 genes was significantly different between patients and controls. Roc curves demonstrated that the appropriate cut-offs to distinguish patients from healthy controls were 2% for RUNX3 (OR 3.316, CI 1.207-9.107, p = 0.024) and 3% for CDKN2A (OR 3.077, CI 1.281 7.39, p = 0.018). No difference in methylation was observed between patients in relapse and patients in remission, in any of the genes examined. Methylation patterns of RUNX3 and CDKN2A may be able to distinguish between MS patients and healthy controls, but not between MS patients in relapse and in remission. Graphical Abstract Methylation patterns of RUNX3 and CDKN2A may be able to discriminate healthy individuals from MS patients. PMID- 29516351 TI - Trichostatin A and Sirtinol Regulate the Expression and Nucleocytoplasmic Shuttling of Histone Deacetylases in All-Trans Retinoic Acid-Induced Differentiation of Neuroblastoma Cells. AB - Neuroblastoma cell differentiation is a valuable model for studying therapeutic methods in neuroblastoma and the mechanisms of neuronal differentiation. Here, we used trichostatin A (TSA) and sirtinol, which are inhibitors of cHDACs and sirtuins, respectively, to show that classical histone deacetylases (cHDACs) and sirtuins (silent mating type information regulation 2 homolog; SIRTs) affect all trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. After first determining neurite elongation and expression levels of tyrosine hydroxylase and high size neurofilament as useful differentiation markers, we observed that TSA increased neuroblastoma cell differentiation, while sirtinol had the antagonistic effect of decreasing it. The changes were also associated with the nucleocytoplasmic shuttling of cHDACs and sirtuins. ATRA significantly decreased the nuclear to cytoplasmic ratio of SIRT1 and SIRT2.1, while sirtinol inhibited that of SIRT1, and TSA increased that of SIRT1 and SIRT2.1 during early differentiation. Moreover, the effect of the sirtinol-related signal was located upstream for cHDACs and sirtuins total expression, and downstream for their subcellular localization compared with that for the TSA-related signal. These results provide a mechanistic understanding of differentiation in neuroblastoma cells and indicate that cHDACs and sirtuins are critical therapeutic targets for neuroblastoma. PMID- 29516352 TI - Reduction of respiratory ghosting motion artifacts in conventional two dimensional multi-slice Cartesian turbo spin-echo: which k-space filling order is the best? AB - The two-dimensional Cartesian turbo spin-echo (TSE) sequence is widely used in routine clinical studies, but it is sensitive to respiratory motion. We investigated the k-space orders in Cartesian TSE that can effectively reduce motion artifacts. The purpose of this study was to demonstrate the relationship between k-space order and degree of motion artifacts using a moving phantom. We compared the degree of motion artifacts between linear and asymmetric k-space orders. The actual spacing of ghost artifacts in the asymmetric order was doubled compared with that in the linear order in the free-breathing situation. The asymmetric order clearly showed less sensitivity to incomplete breath-hold at the latter half of the imaging period. Because of the actual number of partitions of the k-space and the temporal filling order, the asymmetric k-space order of Cartesian TSE was superior to the linear k-space order for reduction of ghosting motion artifacts. PMID- 29516353 TI - A cable-driven parallel manipulator with force sensing capabilities for high accuracy tissue endomicroscopy. AB - PURPOSE: Endomicroscopy (EM) provides high resolution, non-invasive histological tissue information and can be used for scanning of large areas of tissue to assess cancerous and pre-cancerous lesions and their margins. However, current robotic solutions do not provide the accuracy and force sensitivity required to perform safe and accurate tissue scanning. METHODS: A new surgical instrument has been developed that uses a cable-driven parallel mechanism (CPDM) to manipulate an EM probe. End-effector forces are determined by measuring the tensions in each cable. As a result, the instrument allows to accurately apply a contact force on a tissue, while at the same time offering high resolution and highly repeatable probe movement. RESULTS: 0.2 and 0.6 N force sensitivities were found for 1 and 2 DoF image acquisition methods, respectively. A back-stepping technique can be used when a higher force sensitivity is required for the acquisition of high quality tissue images. This method was successful in acquiring images on ex vivo liver tissue. CONCLUSION: The proposed approach offers high force sensitivity and precise control, which is essential for robotic EM. The technical benefits of the current system can also be used for other surgical robotic applications, including safe autonomous control, haptic feedback and palpation. PMID- 29516354 TI - Overuse of computed tomography for minor head injury in young patients: an analysis of promoting factors. AB - AIM: To assess the amount of computed tomography (CT) scans for minor head injury (MHI) performed in young patients in our emergency department (ED), not indicated by National Institute for Health and Clinical Excellence (NICE) and Canadian Computed Tomography Head Rules (CCHR), and to analyze factors contributing to unnecessary examinations. Secondary objectives were to calculate the effective dose, to establish the number of positive CT and to analyze which of the risk factors are correlated with positivity at CT; finally, to calculate sensitivity and specificity of NICE and CCHR in our population. MATERIALS AND METHODS: We retrospectively evaluated 493 CT scans of patients aged 18-45 years, collecting the following parameters from ED medical records: patient demographics, risk factors indicating the need of brain imaging, trauma mechanism, specialty and seniority of the referring physician. For each CT, the effective dose and the negativity/positivity were assessed. RESULTS: 357/493 (72%) and 347/493 (70%) examinations were not in line with the CCHR and NICE guidelines, respectively. No statistically significant difference between physician specialty (p = 0.29 for CCHR; p = 0.24 for NICE), nor between physician seniority and the amount of inappropriate examinations (p = 0.93 for CCHR, p = 0.97 for NICE) was found but CT scans requested by ED physicians were less inappropriate [p = 0.28, odds ratio (OR) 0.562, CI (95%) 0.336-0.939]. There was no statistically significant correlation between patient age and over-referral (p = 0.74 for NICE, p = 0.93 for CCHR). According to NICE, low speed motor vehicle accident (p = 0.009), motor vehicle accident with high energy impact (p < 0.01) and domestic injuries (p = 0.002) were associated with a higher rate of unwarranted CT; according to CCHR only motor vehicle accident with high energy impact showed a significant correlation with unwarranted CT scan (p < 0.001, OR 44.650, CI 33.123-1469.854). 2% of CT was positive. Multivariate analysis demonstrated that factors significantly associated with CT scan positivity included signs of suspected skull fracture (p < 0.001, OR 20.430, CI 2.727-153.052) and motor vehicle accident with high energy impact (p < 0.001, OR 220.650, CI 33.123-1469.854). In our series, CCHR showed sensitivity of 100%, specificity of 74%; NICE showed sensitivity of 100%, specificity of 72%. CONCLUSION: We observed an important overuse of head CT scans in MHI; the main promoting factor for inappropriate was injury mechanism. 2% of head CT were positive, correlating with signs of suspected skull fracture and motor vehicle accident with high energy impact. PMID- 29516355 TI - Organic Selenium, Probiotics, and Prebiotics Effects on Growth, Blood Biochemistry, and Carcass Traits of Growing Rabbits During Summer and Winter Seasons. AB - The effect of organic selenium, prebiotics, or probiotics on productive performances, blood biochemistry, and carcass characteristics of growing rabbits was studied throughout summer and winter seasons. In an 8-week feeding trial, a total of 100 New Zealand White rabbits were randomly distributed to 10 groups. Two seasons (winter and summer) and five diets fortified with 0 (control), 0.03 mg selenium, 3 g Bio-Mos(r), 1 g Bactocell(r) (1 * 1010 CFU) or 3 g yeast/kg diet were used in 2 * 5 factorial design. Results indicated that growth performance, feed intake (FI), and blood components (red blood cells [RBCs], serum total protein [TP], globulin [GLOB], albumin [ALB]) decreased significantly in rabbits reared during summer than in those during winter. In contrast, white blood cells, urea-N, creatinine, alanine transaminase [ALT], and aspartate transaminase [AST] increased significantly in summer. However, growth performance indices, FI, blood hemoglobin, RBCs, TP, ALB, and GLOB increased significantly in rabbits when fed the tested feed additives. The respiration rate, rectal temperature, and heart rate of the animals were significantly decreased with all feed additives. Adjusted weight of carcass, liver, kidney fat, and carcass cuts were not affected by feed additives. Final margin and margin efficiency increased in rabbit fed diets supplemented with feed additives than those fed the basal diet without any supplementation. Results of the current study concluded that a supplementation of rabbit diets with organic selenium, probiotics, and prebiotics can promote rabbit performance during mild weather and also alleviate the adverse impact of heat stress during summer season. PMID- 29516356 TI - Neurotoxic Outcomes of Subchronic Manganese Chloride Exposure via Contaminated Water in Adult Male Rats and the Potential Benefits of Ebselen. AB - The neurological effects of manganese (Mn) exposure on adults consuming contaminated water remain unclear. Accordingly, the current experiment was planned to explore the neurotoxic consequences of subchronic Mn exposure via contaminated water and to examine whether ebselen (Ebs) improved these outcomes. Rats exposed to oral MnCl2 (50 mg/kg body weight) for 30 successive days exhibited reduced rearing and ambulation. Furthermore, Mn administration increased brain Mn concentrations and induced superoxide dismutase, catalase, and glutathione depletion. Mn administration also increased lipid peroxidation biomarker levels. Additionally, Mn increased interleukin1-beta and prostaglandin E2 levels and altered caspase-3 and Bcl-2 expression. Mn intoxication also induced marked gliosis, numerous vacuolations, and disoriented and pyknotic Purkinje cells as well as marked vascular congestion in brain tissue. Meanwhile, intraperitoneal administration of Ebs (15 mg/kg body weight) to Mn-intoxicated rats improved the behavioral performance and oxidative damage as well as inflammatory, apoptotic, and histopathological changes. The above results indicate that Ebs alleviated Mn neurotoxicity via its antioxidant, anti inflammatory, and anti-apoptotic activities. Therefore, Ebs could represent a promising agent in the prevention of Mn-induced neurotoxicity. PMID- 29516357 TI - Is Alcohol and Other Substance Use Reduced When College Students Attend Alcohol Free Programs? Evidence from a Measurement Burst Design Before and After Legal Drinking Age. AB - College drinking and its negative consequences remain a major public health concern. Yet, many prevention efforts targeting college drinkers are expensive, are difficult to implement, use indicated approaches targeting only high-risk drinkers, and/or are only marginally effective. An alternative strategy taken explicitly or implicitly by many colleges is campus-led alcohol-free programming which provides students with attractive leisure alternatives to drinking on weekend nights. This study aimed to extend work by Patrick et al. (Prevention Science, 11, 155-162, 2010), who found that students drank less on weekend nights they attended LateNight Penn State (LNPS) activities during their first semester of college. Here, daily diary and longitudinal data on college students' daily lives and risk behaviors were collected from 730 students on 19,506 person-days across seven semesters at a large university in the Northeastern United States. Generalized linear mixed models were used to estimate alcohol and illegal substance use on weekend days as a function of LNPS attendance, gender, legal drinking status (>= 21 years), and day of the weekend. Across college, students who attended LNPS used alcohol and illegal substances less in general and less on days they participated compared to themselves on days they did not participate. Legal drinking status moderated the association between LNPS attendance and alcohol and illegal substance use such that levels of use were lowest for students under 21 years old on weekend days they attended LNPS. Our findings provide support for campus-led alcohol-free programming as a potential harm reduction strategy on college campuses. PMID- 29516358 TI - [Position paper about the care of refugees : A statement about the psychosocial health care of refugees]. AB - This paper is general statement about the psychosocial care of refugees, developed by the of the Austrian Society for Psychiatry, Psychotherapy and Psychosomatics as well as by the Austrian Society for Social Psychiatry. Reasons of recent wave of refugees and the usual mental disorders among refugees are described. The increasing number of refugees, asylum seekers and irregular migrants poses a challenge for mental health services in Europe. As a consequence, several expert recommendations were given. As a first step, basic needs of refugees such as regular housing facilities, sufficient nutrition and safety in everyday life should be met. Fast decisions about the applications for asylum and support of social integration through education and employment are essential for mental health. Provision of mental health care should be needs based as described by the intervention pyramid for mental health and psychosocial support as given by the Inter-Agency Standing Committee of the World Health Organization. In addition, culture-specific aspects must be considered in everyday clinical work and the training of health professionals. PMID- 29516359 TI - [Time-related aspects of suicides - suicide frequency related to birthday, major holidays, day of the week, season, month of birth and zodiac signs]. AB - BACKGROUND: Suicides are generally the consequence of overchallenged coping strategies of individual for psychological, social or internal and external biological strain factors. Timing of the suicide, too, may be influenced by external factors. Studies so far have yielded in part inconsistent results concerning the association of suicides with particular days or periods of the year. Even less is known regarding a potential effect of the time of birth on suicide risk. METHODS: The Tyrol Suicide Register (TSR) provides data on suicides occurring in the Austrian State of Tyrol including birthday of the suicide victim and day of the suicide. In the present study the frequency of suicides was analyzed with regard to birthday, day of the week, major holidays and season over a period of 17 years. Further, a potential association with month of birth and zodiac signs was studied. RESULTS: We found a significant variation in suicide frequency concerning day of the week with a peak on Mondays and Tuesdays and seasonality with increased numbers in spring and summer months. CONCLUSIONS: The increase of suicide numbers at the beginning of the week may be explained by the "broken-promise effect" which has been described as the consequence of frustrated expectations concerning the weekend. Possible explanations for the suicide peaks in spring and summer may be biological, specifically serotonergic alterations as well as the experience of depressed patients perceiving the social and emotional contrast to people who are able to enjoy these periods of pleasure and outdoor activities. PMID- 29516360 TI - No evidence of subgroups found in amphetamine consumers in Iran. AB - Amphetamine type substances are the second most commonly consumed illicit drug type and their use is an important contributor to the global burden of disease. This investigation set out to determine whether, similar to alcohol or nicotine addiction, subgroups of consumers can also be found in amphetamine addicts. 204 consumers of methamphetamine only (n = 50) or both methamphetamine and heroin (n = 154) have been investigated in Mashhad, Iran by means of "Lesch Alcoholism Typology". No significant differences in consumption pattern or age of onset have been found between the different types. Many subjects, however, reported symptoms of anxiety (n=78) or depression (n = 129) prior to drug use. These findings highlight the need for high quality epidemiological studies further addressing this issue. PMID- 29516361 TI - 'Under' Surveillance: Impact of Race and Socioeconomic Status on Post-Treatment Breast Cancer Imaging. PMID- 29516362 TI - Contrast-Enhanced Spectral Mammography is Comparable to MRI in the Assessment of Residual Breast Cancer Following Neoadjuvant Systemic Therapy. AB - PURPOSE: To evaluate the performance of contrast-enhanced spectral mammography (CESM) compared to MRI in the assessment of tumor response in breast cancer patients undergoing neoadjuvant systemic therapy (NST). METHODS: The institutional review board approved this study. From September 2014 to June 2017, we identified patients with pathologically confirmed invasive breast cancer who underwent NST. All patients had both CESM and MRI performed pre- and post-NST with pathological assessment after surgical management. Size of residual malignancy on post-NST CESM and MRI was compared with surgical pathology. Lin concordance and Pearson correlation coefficient were used to assess agreement. Bland-Altman plots were used to visualize the differences between tumor size on imaging and pathology. RESULTS: Sixty-five patients were identified. Mean age was 52.7 (range 30-76) years. Type of NST included chemotherapy in 53 (82%) and endocrine therapy in 12 (18%). Mean tumor size after NST was 14.6 (range 0-105) mm for CESM and 14.2 mm (range 0-75 mm) for MRI compared with 19.6 (range 0-100) mm on final surgical pathology. Equivalence tests demonstrated that mean tumor size measured by CESM (p = 0.009) or by MRI (p = 0.01) was equivalent to the mean tumor size measured by pathology within - 1 and 1-cm range. Comparing CESM versus MRI for assessment of complete response, the sensitivity was 95% versus 95%, specificity 66.7% versus 68.9%, positive predictive value 55.9% versus 57.6%, and negative predictive value 96.7% versus 96.9% respectively. CONCLUSIONS: CESM was comparable to MRI in assessing residual malignancy after completion of NST. PMID- 29516363 TI - The C-Reactive Protein/Albumin Ratio May Predict the Long-Term Outcome in Patients with Malignant Pleural Mesothelioma. PMID- 29516365 TI - Brodalumab: A Review in Moderate to Severe Plaque Psoriasis. AB - Brodalumab (Kyntheum(r)) is a human anti-interleukin-17 receptor A (IL-17RA) monoclonal antibody available for use in patients with moderate to severe plaque psoriasis. In the phase III AMAGINE trials in this patient population, 12 weeks of induction therapy with subcutaneous brodalumab was superior to placebo in terms of the proportion of patients with >= 75% improvement in the Psoriasis Area and Severity Index score (PASI 75) and the proportion of patients with a static Physician Global Assessment score of 0 or 1. Brodalumab was also superior to ustekinumab for PASI 100 (i.e. complete skin clearance) at week 12. Health related quality of life (HR-QOL) outcomes improved to a significantly greater extent with brodalumab than with placebo. Moreover, brodalumab was more effective than placebo in patients with difficult-to-treat nail or scalp psoriasis. Brodalumab was generally well tolerated, with low rates of immunogenicity. Efficacy was sustained and brodalumab remained well tolerated during up to 52 weeks of maintenance therapy. Thus, subcutaneous brodalumab is a useful addition to the treatment options currently available for patients with moderate to severe plaque psoriasis. PMID- 29516364 TI - Associations Between Sentinel Lymph Node Biopsy and Complications for Patients with Ductal Carcinoma In Situ. AB - PURPOSE: To examine the associations between sentinel lymph node biopsy (SLNB) and complications among older patients who underwent breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). METHODS: We identified women from the Surveillance, Epidemiology, and End Results-Medicare dataset aged 67-94 years diagnosed during 1998-2011 with DCIS who underwent BCS as initial treatment. We assessed incidence of complications, including lymphedema, wound infection, seroma, or pain, within 9 months of diagnosis. We used Mahalanobis matching and generalized linear models to estimate the associations between SLNB and complications. RESULTS: Our sample consisted of 15,515 beneficiaries, 2409 (15.5%) of whom received SLNB. Overall, 16.8% of women who received SLNB had complications, compared with 11.3% of women who did not receive SLNB (p < 0.001). Use of SLNB was associated with subsequent mastectomy but not radiotherapy. Multivariate analyses of the matched sample showed that, compared with no SLNB, SLNB use was significantly associated with incidence of any complication [adjusted odds ratio (AOR) 1.39; 99% confidence interval (CI) 1.18-1.63], lymphedema (AOR 4.45; 99% CI 2.27-8.75), wound infection (AOR 1.24; 99% CI 1.00 1.54), seroma (AOR 1.40; 99% CI 1.03-1.91), and pain (AOR 1.31; 99% CI 1.04 1.65). Sensitivity analyses excluding patients who underwent mastectomy yielded qualitatively similar results regarding the associations between SLNB and complications. CONCLUSIONS: Among older women with DCIS who received BCS, SLNB use was associated with higher risks of short-term complications. These findings support consensus guidelines recommending against SLNB for this population and provide empirical information for patients. PMID- 29516366 TI - Relationship of myocardial hibernation, scar, and angiographic collateral flow in ischemic cardiomyopathy with coronary chronic total occlusion. AB - BACKGROUND: The relationship between myocardial viability and angiographic collateral flow is not fully elucidated in ischemic cardiomyopathy (ICM) with coronary artery chronic total occlusion (CTO). We aimed to clarify the relationship between myocardial hibernation, myocardial scar, and angiographic collateral flow in these patients. METHODS AND RESULTS: Seventy-one consecutive ICM patients with 122 CTOs and 652 dysfunctional segments within CTO territories were retrospectively analyzed. Myocardial hibernation (perfusion-metabolism mismatch) and the extent of 18F-fluorodeoxyglucose (FDG) abnormalities were assessed using 99mTc-sestamibi and 18F-FDG imaging. Myocardial scar was evaluated by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging. Collateral flow observed on coronary angiography was assessed using Rentrop classification. In these patients, neither the extent nor frequency of myocardial hibernation or scar was related to the status of collateral flow. Moreover, the matching rate in determining myocardial viability was poor between any 2 imaging indices. The extent of 18F-FDG abnormalities was linearly related to the extent of LGE rather than myocardial hibernation. Of note, nearly one-third (30.4%) of segments with transmural scar still had hibernating tissue. Hibernation and non transmural scar had higher sensitivity (63.0% and 66.7%) than collateral flow (37.0%) in predicting global functional improvement. CONCLUSIONS: Angiographic collateral cannot accurately predict myocardial viability, and has lower sensitivity in prediction of functional improvement in CTO territories in ICM patients. Hence, assessment of myocardial viability with non-invasive imaging modalities is of importance. Moreover, due to the lack of correlation between myocardial hibernation and scar, these two indices are complementary but not interchangeable. PMID- 29516367 TI - Coronary microvascular dysfunction in hypertrophic cardiomyopathy detected by Rubidium-82 positron emission tomography and cardiac magnetic resonance imaging. PMID- 29516368 TI - Chemokine receptors: Key for molecular imaging of inflammation in atherosclerosis. PMID- 29516369 TI - The ubiquitin ligase COP1 regulates cell cycle and apoptosis by affecting p53 function in human breast cancer cell lines. AB - BACKGROUND: The E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) mediates cell survival, growth, and development, and interacts with the tumor suppressor protein p53 to induce its ubiquitination and degradation. Recent studies reported that COP1 overexpression is associated with increased cell proliferation, transformation, and disease progression in a variety of cancer types. In this study, we investigated whether COP1 regulates p53-mediated cell cycle arrest and apoptosis in human breast cancer cell lines. METHODS: We downregulated COP1 expression using lentiviral particles expressing short hairpin RNA (shRNA) targeting COP1 and measured the effects of the knockdown in three different breast cancer cell lines. RESULTS: COP1 silencing resulted in p53 activation, which induced the expression of p21 and p53-upregulated modulator of apoptosis (PUMA) expression, and reduced the levels of cyclin-dependent kinase 2 (CDK2). Notably, knockdown of COP1 was associated with cell cycle arrest during the G0/G1 phase. CONCLUSIONS: The COP1-mediated degradation of p53 regulates cancer cell growth and apoptosis. Our results indicate that COP1 regulates human breast cancer cell proliferation and apoptosis in a p53-dependent manner. These findings suggest that COP1 might be a promising potential target for breast cancer-related gene therapy. PMID- 29516370 TI - Novel mutation of PPOX gene in a patient with abdominal pain and syndrome of inappropriate antidiuresis. AB - PURPOSE: Acute porphyrias are metabolic disorders of heme biosynthesis characterized by acute life-threatening attacks. The diagnosis is often missed since clinical presentation is aspecific mimicking other medical and surgical conditions. Variegate porphyria (VP) is an autosomal dominant inherited disease with incomplete penetrance due to decreased activity of the Protoporphyrinogen Oxydase (PPOX) gene; most VP mutations are family specific. We report the case of a 40 year-old woman who presented many times to the emergency department complaining of unexplained abdominal pain and laboratory investigations showed repeatedly hyponatremia. Syndrome of inappropriate antidiuresis (SIAD) was confirmed and measurement of urine porphobilinogen and delta-aminolevulinic acid disclosed the diagnosis of acute porphyria. The genetic analysis of PPOX gene was performed. METHODS: The entire coding sequence and exon/intron boundaries of PPOX gene were amplified in 5 different Polymerase Chain Reaction (PCR) fragments. In silico prediction of the pathogenicity of the mutation was determined by using different tools, Polyphen2, SNPs&GO, SNPs3D. RESULTS: The genetic analysis of PPOX gene revealed a novel missense variant c.1376 G > A (p.Cys459Tyr) in heterozygous state. The same variant was later found in one of her cousins with skin lesions and other three younger asymptomatic relatives. We provided evidence that this novel mutation is likely to be pathogenetic. CONCLUSIONS: Our case highlights the importance of considering VP in the differential diagnosis of SIAD and underlines the role of genetic screening in the management of such patients. The finding of a novel mutation of PPOX gene in our index case has allowed to recognize an affected family. PMID- 29516371 TI - Targeting Neoantigens for Personalised Immunotherapy. AB - This review discusses the rapidly evolving field of immunotherapy research, focusing on the types of cancer antigens that can be recognised by the immune system and potential methods by which neoantigens can be exploited clinically to successfully target and clear tumour cells. Recent studies suggest that the likelihood of successful immunotherapeutic targeting of cancer will be reliant on immune response to neoantigens. This type of cancer-specific antigen arises from somatic variants that result in alteration of the expressed protein sequence. Massively parallel sequencing techniques now allow the rapid identification of these genomic mutations, and algorithms can be used to predict those that will be processed by the proteasome, bind to the transporter complex and encode peptides that bind strongly to individual MHC molecules. The emerging data from assessment of the immunogenicity of neoantigens suggests that only a minority of mutations will form targetable epitopes and therefore the potential for immunotherapeutic targeting will be greater in cancers with a higher frequency of protein-altering somatic variants. It is evident that neoantigens contribute to the success of some immunotherapeutic interventions and that there is significant scope for specific targeting of these antigens to develop new treatment approaches. PMID- 29516372 TI - Preoperative breast MRI and mortality in older women with breast cancer. AB - PURPOSE: The survival benefit from detecting additional breast cancers by preoperative magnetic resonance imaging (MRI) continues to be controversial. METHODS: We followed a cohort of 4454 women diagnosed with non-metastatic breast cancer (stage I-III) from 2/2005-6/2010 in five registries of the breast cancer surveillance consortium (BCSC). BCSC clinical and registry data were linked to Medicare claims and enrollment data. We estimated the cumulative probability of breast cancer-specific and all-cause mortality. We tested the association of preoperative MRI with all-cause mortality using a Cox proportional hazards model. RESULTS: 917 (20.6%) women underwent preoperative MRI. No significant difference in the cumulative probability of breast cancer-specific mortality was found. We observed no significant difference in the hazard of all-cause mortality during the follow-up period after adjusting for sociodemographic and clinical factors among women with MRI (HR 0.90; 95% CI 0.72-1.12) compared to those without MRI. CONCLUSION: Our findings of no breast cancer-specific or all-cause mortality benefit supplement prior results that indicate a lack of improvement in surgical outcomes associated with use of preoperative MRI. In combination with other reports, the results of this analysis highlight the importance of exploring the benefit of preoperative MRI in patient-reported outcomes such as women's decision quality and confidence levels with decisions involving treatment choices. PMID- 29516373 TI - Mammographic non-dense area and breast cancer risk in postmenopausal women: a causal inference approach in a case-control study. AB - PURPOSE: The association between high mammographic density (MD) and elevated breast cancer risk is well established. However, the role of absolute non-dense area remains unclear. We estimated the effect of the mammographic non-dense area and other density parameters on the risk of breast cancer. METHODS: This study utilizes data from a population-based case-control study conducted in Greater Vancouver, British Columbia, with 477 female postmenopausal breast cancer cases and 588 female postmenopausal controls. MD measures were determined from digitized screening mammograms using computer-assisted software (Cumulus). Marginal odds ratios were estimated by inverse-probability weighting using a causal diagram for confounder selection. Akaike information criteria and receiver operating characteristic curves were used to assess the goodness of fit and predictive power of unconditional logistic models containing MD parameters. RESULTS: The risk of breast cancer is 60% lower for the highest quartile compared to the lowest quartile of mammographic non-dense area (marginal OR 0.40, 95% CI 0.26-0.61, p-trend < 0.001). The cancer risk almost doubles for the highest quartile compared to the lowest quartile of dense area (marginal OR 1.81, 95% CI 1.19-2.43, p-trend < 0.001). For the highest quartile of percent density, breast cancer risk was more than three times higher than for the lowest quartile (marginal OR 3.15, 95% CI 1.90-4.40, p-trend < 0.001). No difference was seen in predictive accuracy between models using percent density alone, dense area alone, or non-dense area plus dense area. CONCLUSIONS: In this study, non-dense area is an independent risk factor after adjustment for dense area and other covariates, inversely related with the risk of breast cancer. However, non-dense area does not improve prediction over that offered by percent density or dense area alone. PMID- 29516374 TI - Use of adjuvant chemotherapy in hormone receptor-positive breast cancer patients with or without the 21-gene expression assay. AB - PURPOSE: We assessed the use of chemotherapy in breast cancer patients to investigate the factors that changed trends in chemotherapy following the adoption of the 21-gene expression assay in tumor genomic profiling. METHODS: Our study used 2033 patients from the National Cancer Center in Korea diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer (tumor size of 0.5 cm or larger and 0-3 node metastases) from 2010 to 2015. We analyzed use of the 21-gene expression assay, changes in frequency of adjuvant chemotherapy use, and clinicopathological factors related to adjuvant chemotherapy to assess the impact of the 21-gene expression assay. RESULTS: Adjuvant chemotherapy use declined from 33.33% (2011) to 13.59% (2015) [relative risk (RR), 0.71; 95% CI 0.56-0.89; ptrend = 0.004] in patients with 21 gene expression assay data. Among patients without assay data, adjuvant chemotherapy use decreased from 76.79 to 40.17% between 2010 and 2015 (RR 0.87; 95% CI 0.84-0.91; ptrend < 0.001), especially for patients with node negative/micrometastasis (RR 0.85; 95% CI 0.81-0.89; ptrend < 0.001). The frequency of adjuvant chemotherapy was significantly decreased after introduction of the 21-gene expression assay (p < 0.001). Tumor size (p < 0.001), progesterone receptor (PgR) status (p = 0.001), and proliferation index (Ki-67) levels (p < 0.001) were important factors for chemotherapy decision-making in node negative/micrometastasis patients who did not undergo the assay. CONCLUSIONS: For HR-positive, HER2-negative breast cancer patients with 0-1 node metastases, chemotherapy use declined significantly after the adoption of the 21-gene assay. PgR status and Ki-67 were useful for chemotherapy decision-making in cases without the 21-gene assay. PMID- 29516375 TI - Gonad Transcriptome Analysis of the Pacific Oyster Crassostrea gigas Identifies Potential Genes Regulating the Sex Determination and Differentiation Process. AB - The Pacific oyster Crassostrea gigas is a commercially important bivalve in aquaculture worldwide. C. gigas has a fascinating sexual reproduction system consisting of dioecism, sex change, and occasional hermaphroditism, while knowledge of the molecular mechanisms of sex determination and differentiation is still limited. In this study, the transcriptomes of male and female gonads at different gametogenesis stages were characterized by RNA-seq. Hierarchical clustering based on genes differentially expressed revealed that 1269 genes were expressed specifically in female gonads and 817 genes were expressed increasingly over the course of spermatogenesis. Besides, we identified two and one gene modules related to female and male gonad development, respectively, using weighted gene correlation network analysis (WGCNA). Interestingly, GO and KEGG enrichment analysis showed that neurotransmitter-related terms were significantly enriched in genes related to ovary development, suggesting that the neurotransmitters were likely to regulate female sex differentiation. In addition, two hub genes related to testis development, lncRNA LOC105321313 and Cg Sh3kbp1, and one hub gene related to ovary development, Cg-Malrd1-like, were firstly investigated. This study points out the role of neurotransmitter and non coding RNA regulation during gonad development and produces lists of novel relevant candidate genes for further studies. All of these provided valuable information to understand the molecular mechanisms of C. gigas sex determination and differentiation. PMID- 29516377 TI - Iron Pots for the Prevention and Treatment of Anemia in Preschoolers: Correspondence. PMID- 29516376 TI - Characterization of Spleen Transcriptome of Schizothorax prenanti during Aeromonas hydrophila Infection. AB - Schizothorax prenanti (S. prenanti) is an indigenous fish species and is popularly cultured in southwestern China. In recent years, intensive farming of S. prenanti and water quality deterioration has increased the susceptibility of this fish to various pathogens, including Aeromonas hydrophila (A. hydrophila), which has caused severe damage to S. prenanti production. However, the understanding of molecular immune response of S. prenanti to A. hydrophila infection is still lacking. In order to better comprehend the S. prenanti time series immune response process against A. hydrophila, we conducted the first transcriptomic comparison in S. prenanti spleen at 4, 24, and 48 h after the infection challenge of A. hydrophila against their control counterparts. In total, 628 million clean reads were obtained from 18 libraries and assembled into 262,745 transcripts. After eliminating sequence redundancy, 69,373 unigenes with an average length of 1476 bp were obtained. Comparative analysis revealed 1890 unigenes with significantly differential expression, including 172, 455, 589 upregulated and 27, 676, 551 unigenes downregulated genes for 4, 24, and 48 h post-infection, respectively. Differentially expressed genes (DEGs) were validated using qPCR for 15 randomly selected genes. Enrichment and pathway analysis of DEGs was carried out to understand the functions of the immune related genes. Our results revealed that many important functional genes relating to complement and coagulation cascades, chemokine signaling pathway, toll-like receptor signaling pathway, NOD-like receptor signaling pathway and leukocyte transendothelial migration were regulated during the infection of A. hydrophila, and the expression of those genes reflected the transcriptome profiles during the challenging stages. PMID- 29516378 TI - Economic Burden of Transfusion Dependent Thalassemia. PMID- 29516379 TI - Effect of temperature on development and reproduction of the carmine spider mite, Tetranychus cinnabarinus (Acari: Tetranychiae), fed on cassava leaves. AB - The effect of five constant temperatures (16, 20, 24, 28 and 32 degrees C) on the development, survival and reproduction of Tetranychus cinnabarinus (Boisduval) [= Tetranychus urticae Koch (red form)] fed on cassava leaves was examined in the laboratory at 85% relative humidity. Development time of various immature stages decreased with increasing temperature, with total egg-to-adult development time varying from 27.7 to 6.7 days. The lower thermal threshold for development was 10.8 degrees C and the thermal constant from egg to adult was 142.4 degree-days. Pre- and post-oviposition period and female longevity all decreased as temperature increased. The longest oviposition period was observed at 20 degrees C with 20.4 days. Under different temperatures, mated females laid, on average, 1.0, 2.9, 4.7, 4.7 and 4.9 eggs per day, respectively. The maximum fecundity (81.5 eggs per female) was at 28 degrees C and the intrinsic rate of increase (r m ) was highest (0.25) at 32 degrees C. The results of this study indicate that T. cinnabarinus population could increase rapidly when cassava leaves serve as a food source. At the appropriate temperature T. cinnabarinus could seriously threaten growth of cassava. PMID- 29516380 TI - Molecular identification of tick-borne pathogens in ticks collected from dogs and small ruminants from Greece. AB - Ticks are vectors for a variety of human and animal pathogens (bacteria, protozoa and viruses). In order to investigate the pathogens carried by ticks in Greece, a total of 179 adult ticks (114 female and 65 male) were collected from domestic animals (sheep, goats and dogs) from 14 prefectures of six regions of Greece. Among them, 40 were Dermacentor marginatus, 25 Haemaphysalis parva, 22 H. sulcata, one H. punctata, 13 Ixodes gibbosus, 77 Rhipicephalus sanguineus s.l. and one R. bursa. All ticks were tested for the presence of DNA of Anaplasma spp., Babesia spp., Coxiella burnetii, Rickettsia spp. and Theileria spp. The collected ticks were examined by PCR and reverse line blot (RLB) assay. A prevalence of 20.1% for Anaplasma spp., 15.6% for Babesia spp. (identifying B. bigemina, B. divergens, B. ovis and B. crassa), 17.9% for C. burnetii, 15.1% for Rickettsia spp., and 21.2% for Theileria spp. (identifying T. annulata, T. buffeli/orientalis, T. ovis and T. lestoquardi) was found. The results of this study demonstrate the variety of tick-borne pathogens of animal and human importance circulating in Greece, and that awareness is needed to minimize the risk of infection, especially among farmers and pet owners. PMID- 29516381 TI - Factors affecting prevailing population levels of Brevipalpus yothersi (Acari: Tenuipalpidae) in citrus areas affected by citrus leprosis in the State of Sao Paulo, Brazil. AB - Brevipalpus yothersi Baker (Acari: Tenuipalpidae) was recently confirmed as one of the main vectors of citrus leprosis. Knowledge about this mite's biology is essential to understand its population dynamics, in order to solve management issues in citrus orchards and explain why citrus leprosis is more severe in some regions. This paper aimed to study biological factors affecting prevailing population levels of B. yothersi and incidence of citrus leprosis. Mites were sampled from orchards in the south, north and northwestern regions of Sao Paulo State, Brazil. We assessed duration of the developmental stages, oviposition, incubation period, egg viability, longevity, net reproductive rate (Ro), mean generation time (T), intrinsic rate of increase (rm) and finite rate of increase (lambda). There were small differences in parameter values between the three populations. Our results indicated that the various measures adopted in the control of the three populations did not lead to major biological differences between populations for the evaluated parameters. PMID- 29516382 TI - Insight into microtubule destabilization mechanism of 3,4,5-trimethoxyphenyl indanone derivatives using molecular dynamics simulation and conformational modes analysis. AB - Colchicine site inhibitors are microtubule destabilizers having promising role in cancer therapeutics. In the current study, four such indanone derivatives (t1, t9, t14 and t17) with 3,4,5-trimethoxyphenyl fragment (ring A) and showing significant microtubule destabilization property have been explored. The interaction mechanism and conformational modes triggered by binding of these indanone derivatives and combretastatin at colchicine binding site (CBS) of alphabeta-tubulin dimer were studied using molecular dynamics (MD) simulation, principle component analysis and free energy landscape analysis. In the MD results, t1 showed binding similar to colchicine interacting in the deep hydrophobic core at the CBS. While t9, t14 and t17 showed binding conformation similar to combretastatin, with ring A superficially binding at the CBS. Results demonstrated that ring A played a vital role in binding via hydrophobic interactions and got anchored between the S8 and S9 sheets, H8 helix and T7 loop at the CBS. Conformational modes study revealed that twisting and bending conformational motions (as found in the apo system) were nearly absent in the ligand bound systems. Absence of twisting motion might causes loss of lateral contacts in microtubule, thus promoting microtubule destabilization. This study provides detailed account of microtubule destabilization mechanism by indanone ligands and combretastatin, and would be helpful for designing microtubule destabilizers with higher activity. PMID- 29516383 TI - A Peptide Targeting Inflammatory CNS Lesions in the EAE Rat Model of Multiple Sclerosis. AB - Multiple sclerosis is characterized by inflammatory lesions dispersed throughout the central nervous system (CNS) leading to severe neurological handicap. Demyelination, axonal damage, and blood brain barrier alterations are hallmarks of this pathology, whose precise processes are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) rat model that mimics many features of human multiple sclerosis, the phage display strategy was applied to select peptide ligands targeting inflammatory sites in CNS. Due to the large diversity of sequences after phage display selection, a bioinformatics procedure called "PepTeam" designed to identify peptides mimicking naturally occurring proteins was used, with the goal to predict peptides that were not background noise. We identified a circular peptide CLSTASNSC called "Ph48" as an efficient binder of inflammatory regions of EAE CNS sections including small inflammatory lesions of both white and gray matter. Tested on human brain endothelial cells hCMEC/D3, Ph48 was able to bind efficiently when these cells were activated with IL1beta to mimic inflammatory conditions. The peptide is therefore a candidate for further analyses of the molecular alterations in inflammatory lesions. PMID- 29516384 TI - Rene Girard and the Mimetic Nature of Eating Disorders. AB - French historian and literary critic Rene Girard (1923-2015), most widely known for the concepts of mimetic desire and scapegoating, also engaged in the discussion of the surge of eating disorders in his 1996 essay Eating Disorders and Mimetic Desire. This article explores Girard's ideas on the mimetic nature and origin of eating disorders from a clinical psychiatric perspective and contextualizes them within the field of eating disorders research as well as in relation to broader psychological, sociological and anthropological models of social comparison and non-consumption. Three main themes in Girard's thinking on the topic of eating disorders are identified and explored: the 'end of prohibitions' as a driving force in the emergence of eating disorders, eating disorders as a phenomenon specific to modernity, and the significance of 'conspicuous non-consumption' in the emergence of eating disorders. PMID- 29516385 TI - Disparities in Self-Reported Prenatal Counseling: Does Immigrant Status Matter? AB - Immigrant women face unique barriers to prenatal care access and patient-provider communication. Yet, few prior studies have examined U.S.-born/immigrant differences in the content of care. The purpose of this study was to investigate the roles of immigrant status, English proficiency and race/ethnicity on the receipt of self-reported prenatal counseling using nationally representative data. We used data from the Early Childhood Longitudinal Study-Birth Cohort (N ~ 8100). We investigated differences in self-reported prenatal counseling by immigrant status, English proficiency, and race/ethnicity using logistic regression. Counseling topics included diet, smoking, drinking, medication use, breastfeeding, baby development and early labor. In additional analyses, we separately examined these relationships among Hispanic, Mexican and Non-Hispanic (NH) Asian women. Neither immigrant status nor self-reported English proficiency was associated with prenatal counseling. However, we found that being interviewed in a language other than English language by ECLS-B surveyors was positively associated with counseling on smoking (OR, 2.599; 95% CI, 1.229-5.495) and fetal development (OR, 2.408; 95% CI, 1.052-5.507) among Asian women. Race/ethnicity was positively associated with counseling, particularly among NH black and Hispanic women. There is little evidence of systematic overall differences in self-reported prenatal counseling between U.S.-born and immigrant mothers. Future research should investigate disparities in pregnancy-related knowledge among racial/ethnic subgroups. PMID- 29516386 TI - Efficacy and safety of long-term management of patients with chronic post surgical hypoparathyroidism. AB - PURPOSE: To evaluate adherence to European Society of Endocrinology guidelines and risk of renal complications in patients with chronic post-operative hypoparathyroidism (PO-HypoPT) treated with calcium and activated vitamin D metabolites. METHODS: We evaluated 90 adult patients (68 females and 22 males) with chronic (3 years) PO-HypoPT. Total albumin-corrected (Alb-Ca) and ionized serum calcium, phosphate, creatinine, PTH, and 24-h urinary calcium were measured; renal ultrasound was also performed. Healthy hospital employers (n = 142) were used as control. RESULTS: Complete data were available in 82 patients. Twenty-eight (34.1%) met four targets (Alb-Ca, phosphate, calcium phosphate product and 24-h urinary calcium), 36 (43.9%) three, 17 (20.7%) two, and 1 (1.2%) one. Thirteen (14.4%) had Alb-Ca value below and 18 (20.0%) above the target range and 54.9% 24-h urinary calcium above the upper normal limit. Seven (7.7%) has increased serum phosphate and none an increased calcium phosphate product. Eleven (12.2%) patients had eGFR < 60 mL/min * 1.73 m2. Nephrolithiasis was present in 27 (30%) patients. Compared with the controls, patients had lower Alb Ca (8.9 +/- 0.5 vs. 9.5 +/- 0.3 mg/dL, P 0.0001) and a higher rate of kidney stones, mostly asymptomatic [27/90 (30%) vs 7/142 (5%), P < 0.0001, odd ratio 8.2 (3.4-19.9)]. Fifty-seven patients had >= four serum Ca2+ determinations during follow-up. Forty (70.2) patients had values within the target range in > 50% of cases, 18 in > 75%, and only 2 in 100%. Two patients never had values in the target range. CONCLUSIONS: Treatment of chronic PO-HypoPT with calcium and activated vitamin D metabolites is suboptimal and associated with an increased risk of renal complications. PMID- 29516387 TI - The Evolving Role of FDG-PET/CT in the Diagnosis, Staging, and Treatment of Breast Cancer. AB - The applications of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/X-ray computed tomography (PET/CT) in the management of patients with breast cancer have been extensively studied. According to these studies, PET/CT is not routinely performed for the diagnosis of primary breast cancer, although PET/CT in specific subtypes of breast cancer correlates with histopathologic features of the primary tumor. PET/CT can detect metastases to mediastinal, axial, and internal mammary nodes, but it cannot replace the sentinel node biopsy. In detection of distant metastases, this imaging tool may have a better accuracy in detecting lytic bone metastases compared to bone scintigraphy. Thus, PET/CT is recommended when advanced-stage disease is suspected, and conventional modalities are inconclusive. Also, PET/CT has a high sensitivity and specificity to detect loco-regional recurrence and is recommended in asymptomatic patients with rising tumor markers. Numerous studies support the future role of PET/CT in prediction of response to neoadjuvant chemotherapy (NAC). PET/CT has a higher diagnostic value for prognostic risk stratification in comparison with conventional modalities. With the continuing research on the treatment planning and evaluation of patients with breast cancer, the role of PET/CT can be further extended. PMID- 29516388 TI - The American Board of Internal Medicine Maintenance of Certification Examination and State Medical Board Disciplinary Actions: a Population Cohort Study. AB - BACKGROUND: Some have questioned whether successful performance in the American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) program is meaningful. The association of the ABIM Internal Medicine (IM) MOC examination with state medical board disciplinary actions is unknown. OBJECTIVE: To assess risk of disciplinary actions among general internists who did and did not pass the MOC examination within 10 years of initial certification. DESIGN: Historical population cohort study. PARTICIPANTS: The population of internists certified in internal medicine, but not a subspecialty, from 1990 through 2003 (n = 47,971). INTERVENTION: ABIM IM MOC examination. SETTING: General internal medicine in the USA. MAIN MEASURES: The primary outcome measure was time to disciplinary action assessed in association with whether the physician passed the ABIM IM MOC examination within 10 years of initial certification, adjusted for training, certification, demographic, and regulatory variables including state medical board Continuing Medical Education (CME) requirements. KEY RESULTS: The risk for discipline among physicians who did not pass the IM MOC examination within the 10 year requirement window was more than double than that of those who did pass the examination (adjusted HR 2.09; 95% CI, 1.83 to 2.39). Disciplinary actions did not vary by state CME requirements (adjusted HR 1.02; 95% CI, 0.94 to 1.16), but declined with increasing MOC examination scores (Kendall's tau-b coefficient = - 0.98 for trend, p < 0.001). Among disciplined physicians, actions were less severe among those passing the IM MOC examination within the 10-year requirement window than among those who did not pass the examination. CONCLUSIONS: Passing a periodic assessment of medical knowledge is associated with decreased state medical board disciplinary actions, an important quality outcome of relevance to patients and the profession. PMID- 29516389 TI - Retracted Publications in the Biomedical Literature from Open Access Journals. AB - The number of articles published in open access journals (OAJs) has increased dramatically in recent years. Simultaneously, the quality of publications in these journals has been called into question. Few studies have explored the retraction rate from OAJs. The purpose of the current study was to determine the reasons for retractions of articles from OAJs in biomedical research. The Medline database was searched through PubMed to identify retracted publications in OAJs. The journals were identified by the Directory of Open Access Journals. Data were extracted from each retracted article, including the time from publication to retraction, causes, journal impact factor, and country of origin. Trends in the characteristics related to retraction were determined. Data from 621 retracted studies were included in the analysis. The number and rate of retractions have increased since 2010. The most common reasons for retraction are errors (148), plagiarism (142), duplicate publication (101), fraud/suspected fraud (98) and invalid peer review (93). The number of retracted articles from OAJs has been steadily increasing. Misconduct was the primary reason for retraction. The majority of retracted articles were from journals with low impact factors and authored by researchers from China, India, Iran, and the USA. PMID- 29516392 TI - Diffuse lung disease associated with neurofibromatosis type-1 can also affect children. PMID- 29516391 TI - Evaluating the predictive factors of resting energy expenditure and validating predictive equations for Chinese obese children. AB - BACKGROUND: To study the predictive factors of resting energy expenditure (REE) and evaluate the accuracy of predicted equations with indirect calorimeter (IC) in Chinese school-age children, particularly for the obese population. METHODS: Recruited children were from the department of child healthcare in Nanjing children's hospital during July 2014-September 2015. Anthropometric parameters and body composition were measured by bioelectrical impedance. Measured REE was assessed by IC. Predicted REE was estimated using ten published equations. RESULTS: 248 children aged 7-13 years were recruited, including 148 obese [body mass index standard deviation score (BMISDS) = 2.48 +/- 0.91] and 100 non-obese (BMISDS = - 0.96 +/- 1.08). The unit mass of REE (REE/kg) in obese group (29.06 +/- 5.74) was lower than that in non-obese group (37.51 +/- 6.56). The stepwise regression showed that age, BMISDS and fat-free mass (FFM) had a major impact on REE/kg as the regression equation: Y = 54.41 - 1.36 * X1 - 2.25 * X2 - 0.16 * X3 (Y REE/kg, X1 age, X2 BMISDS, X3 FFM; R = 0.633, R2 = 0.401, P < 0.01). The accuracy of predicted REE in obese subjects was 62.16% by the new predictive equations. CONCLUSIONS: The REE/kg in obese children was lower and closely correlated with age, BMISDS and FFM. It is necessary to validate the new predictive equation in a larger sample to estimate energy requirements, particularly for children with obesity. PMID- 29516390 TI - Artificial neural network retrained to detect myocardial ischemia using a Japanese multicenter database. AB - PURPOSE: An artificial neural network (ANN) has been applied to detect myocardial perfusion defects and ischemia. The present study compares the diagnostic accuracy of a more recent ANN version (1.1) with the initial version 1.0. METHODS: We examined 106 patients (age, 77 +/- 10 years) with coronary angiographic findings, comprising multi-vessel disease (>= 50% stenosis) (52%) or old myocardial infarction (27%), or who had undergone coronary revascularization (30%). The ANN versions 1.0 and 1.1 were trained in Sweden (n = 1051) and Japan (n = 1001), respectively, using 99mTc-methoxyisobutylisonitrile myocardial perfusion images. The ANN probabilities (from 0.0 to 1.0) of stress defects and ischemia were calculated in candidate regions of abnormalities. The diagnostic accuracy was compared using receiver-operating characteristics (ROC) analysis and the calculated area under the ROC curve (AUC) using expert interpretation as the gold standard. RESULTS: Although the AUC for stress defects was 0.95 and 0.93 (p = 0.27) for versions 1.1 and 1.0, respectively, that for detecting ischemia was significantly improved in version 1.1 (p = 0.0055): AUC 0.96 for version 1.1 (sensitivity 87%, specificity 96%) vs. 0.89 for version 1.0 (sensitivity 78%, specificity 97%). The improvement in the AUC shown by version 1.1 was also significant for patients with neither coronary revascularization nor old myocardial infarction (p = 0.0093): AUC = 0.98 for version 1.1 (sensitivity 88%, specificity 100%) and 0.88 for version 1.0 (sensitivity 76%, specificity 100%). Intermediate ANN probability between 0.1 and 0.7 was more often calculated by version 1.1 compared with version 1.0, which contributed to the improved diagnostic accuracy. The diagnostic accuracy of the new version was also improved in patients with either single-vessel disease or no stenosis (n = 47; AUC, 0.81 vs. 0.66 vs. p = 0.0060) when coronary stenosis was used as a gold standard. CONCLUSION: The diagnostic ability of the ANN version 1.1 was improved by retraining using the Japanese database, particularly for identifying ischemia. PMID- 29516393 TI - Gestational weight gain among minority adolescents predicts term birth weight. AB - BACKGROUND: In adolescents, there is limited evidence on the independent and additive effect of prepregnancy body mass index (BMI) and gestational weight gain on infant birth weight. Data also show that this effect may vary by race. We sought to examine the impact of maternal prepregnancy BMI and gestational weight gain on birth weight and risk of large for gestational age (LGA) in term newborns of minority adolescent mothers. METHODS: This was a retrospective cohort study of 411 singleton live term infants born to mothers <= 18 years. Data were abstracted from electronic medical records. RESULTS: Gestational weight gain was related to infant birth weight (rho = 0.36, P < 0.0001), but BMI was not (rho = 0.025, P = 0.61). On regression analysis, gestational weight gain, gestational age and Hispanic ethnicity were independent predictors of birth weight, controlling for maternal age, BMI, parity, tobacco/drug use and preeclampsia. The probability of having an LGA infant increased with weight gain [adjusted odds ratio (aOR) 1.14, 95% confidence interval (CI) 1.07-1.21] but not with BMI. Mothers who gained weight in excess of 2009 Institute of Medicine (IOM) recommendations had a greater risk of having an LGA infant compared to those who gained within recommendations (aOR 5.7, 95% CI 1.6-19.5). CONCLUSIONS: Minority adolescents with greater gestational weight gain had infants with higher birth weight and greater risk of LGA; BMI was not associated with either outcome. Further studies are needed to examine the applicability of the 2009 BMI-specific IOM gestational weight gain recommendations to adolescents in minority populations. PMID- 29516394 TI - Calibrated Gastrojejunostomy in Gastric Bypass: It Is a Myth. AB - BACKGROUND: Many surgeons prefer a narrow gastrojejunostomy in gastric bypass believing that this provides greater weight loss. The question is whether the anastomosis remains at its initial diameter, whether it narrows or widens over time. This study tests the hypothesis that the initial diameter of the anastomosis varies over time. MATERIALS AND METHODS: One hundred obese had undergone surgery. Group A with anastomosis 1.5 cm wide and group B with anastomosis 3 cm wide. One-year follow-up was done for 83 patients. The size of the anastomosis diameter was evaluated using a balloon for cardia dilation. RESULTS: Comparing the results of surgery with the values presented 1 year after the procedure, (i) BMI decreased from 43.3 +/- 6.6 to 28.7 +/- 7.0 kg/m2 for group A and 44.6 +/- 5.9 to 29.1 +/- 6.3 kg/m2 for group B, (ii) the total weight loss was 30.6 +/- 4.7% for group A and 31.9 +/- 5.2% for group B, and (iii) the initial 1.5-cm anastomosis in group A measured 2.3 +/- 1.0 cm while the initial 3 cm anastomosis in group B measured 2.7 +/- 1.0 cm 1 year after surgery. No statistically significant difference was found for any of the variables evaluated before and after the surgical procedure. CONCLUSION: Calibrated anastomosis has no utility in increasing weight loss in gastric bypass. PMID- 29516395 TI - Anemia and Bariatric Surgery: Results of a National French Survey on Administrative Data of 306,298 Consecutive Patients Between 2008 and 2016. AB - BACKGROUND: Bariatric surgery (BS) has grown exponentially in France, and long term anemia due to micronutrient deficiencies has become common. OBJECTIVES: The objective of this study was to assess the long-term risk of anemia after BS and to investigate the factors associated with the occurrence of this complication. MATERIALS AND METHODS: Data from the French National Health Service database on patients who had undergone gastric bypass (GB), sleeve gastrectomy (SG), or adjustable gastric banding (AGB), between 2008 and 2016 were extracted. Only patients with a primary intervention were considered. RESULTS: Data from 306,298 patients (143.733 SG, 79.188 GB, and 36.413 AGB) were analyzed. Overall, 12.930 of them (5.0%) had a diagnosis of anemia due to micronutrient deficiencies as main diagnosis or related diagnosis at time of a hospital stay between 2008 and 2016. In multivariate analysis, GB surgery, female gender, age younger than 52 years, and 25-OH vitamin D deficiency were positively associated with the occurrence of anemia whereas hospital procedural volume was negatively associated. The risk to be diagnosed with anemia after BS was 13.0% after a GB, 5.6% after a SG and 4.0% after an AGB (Log-rank p < 0.0001). The hazard ratio for anemia after GB compared to SG was 2.0 (95% CI 1.9-2.1), adjusted for age and gender. CONCLUSION: In France, between 2008 and 2016, 5% of patients had anemia after BS. The risk to develop anemia was 2-fold higher after a GB than after a SG. Young women should be particularly aware of this long-term risk. PMID- 29516396 TI - Variation in Exhaled Acetone and Other Ketones in Patients Undergoing Bariatric Surgery: a Prospective Cross-sectional Study. AB - BACKGROUND: Dietary restriction together with alteration of the gastrointestinal tract results in major metabolic changes and significant weight loss in patients undergoing bariatric surgery. Current methods of measuring these changes are often inaccurate and lack a molecular basis. The objective of this study was to determine the role of exhaled ketones as non-invasive markers of nutritional status in patients undergoing surgical treatment of obesity. METHODS: Patients at different stages of treatment for obesity were recruited to this single-centre cross-sectional study. The sample time points were as follows: (i) at the time of initial attendance prior to dietary or surgical interventions, (ii) on the day of surgery following a low carbohydrate diet, and (iii) > 3 months after either Roux en-Y gastric bypass or sleeve gastrectomy. The concentrations of ketones within breath samples were analysed by selected ion flow tube mass spectrometry. RESULTS: Forty patients were recruited into each of the three study groups. Exhaled acetone concentrations increased significantly following pre-operative diet (1396 ppb) and bariatric surgery (1693 ppb) compared to the start of treatment (410 ppb, P < 0.0001). In comparison, concentrations of heptanone (6.5 vs. 4.1 vs. 1.4 ppb, P = 0.021) and octanone (3.0 vs. 1.4 vs. 0.7 ppb, P = 0.021) decreased significantly after dieting and surgical intervention. Exhaled acetone (rho - 0.264, P = 0.005) and octanone (rho 0.215, P = 0.022) concentrations were observed to correlate with excess body weight at the time of sampling. Acetone and octanone also correlated with neutrophil and triglyceride levels (P < 0.05). CONCLUSION: Findings confirm breath ketones, particularly acetone, to be a potentially clinically useful method of non-invasive nutritional assessment in obese patients. PMID- 29516397 TI - Efficacy of Postoperative Upper Gastrointestinal Series (UGI) and Computed Tomography (CT) Scan in Bariatric Surgery: a Meta-analysis on 7516 Patients. AB - BACKGROUND: To demonstrate the lack of utility and efficacy of routine early postoperative upper gastrointestinal study (UGI) in obese patients undergoing bariatric surgery and to show the higher efficacy of CT scan in cases of clinical suspicion of a leakage, a meta-analysis was performed. MATERIALS AND METHODS: A literature search including articles published in last 18 years was performed. For both UGI and CT scan, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. A first analysis considered overall patients, and a second analysis considered only symptomatic patients. RESULTS: Starting from 1233 eligible citations, 18 articles, including 7516 patients, were left. The pooled sensitivity was 54% for UGI (95% CI 34-74) with a high heterogeneity (I2 = 99.8%, p < .001), whereas CT scan showed a pooled sensitivity of 91% (95% CI 89-93) significantly higher than sensitivity of UGI series (p < 0.01), with a high heterogeneity (I2 = 98.9%, p < .001). In symptomatic patients the pooled sensitivity of UGI series was significantly lower than sensitivity of CT scan [49% (95% CI 31-68) vs 94% (95% CI 92-96), p < 0.01]. PPV showed a significant difference between UGI series and CT scan (54 vs 100%, p < 0.01). Specificity for UGI series was 98.6%, and specificity for CT scan was 99.7% (p = ns); the mean NPV was 96 and 98% for UGI series and CT scan (p = ns). CONCLUSIONS: According to our results, a CT scan triggered by clinical suspicion must be considered the first-line procedure to detect a postoperative leak following primary sleeve gastrectomy or Roux-en-Y gastric bypass. PMID- 29516398 TI - One Anastomosis Gastric Bypass and Risk of Cancer. AB - The one anastomosis gastric bypass (OAGB) is a recent procedure, which still raises controversies concerning its presumed role in the genesis of biliary reflux and the risk of developing esophageal or gastric cancer. A review of the literature in order to have evidence in favor of or against the risk of cancer after OAGB. We have conducted a review of the English literature using the MEDLINE database. The theoretical risk of asymptomatic chronic biliary reflux after OAGB exists and may be responsible for gastroesophageal cancer. It is justified to indicate OAGB for patients over 50 years of age. Otherwise, it is reasonable to indicate endoscopic gastroesophageal examination periodically after OAGB in all patients in order to screen asymptomatic biliary reflux. PMID- 29516399 TI - Lumbar sympathectomy can improve symptoms associated with ischaemia, vasculitis, diabetic neuropathy and hyperhidrosis affecting the lower extremities-a single centre experience. AB - BACKGROUND: Lumbar sympthectomy (LS) was traditionally performed for intermittent claudication but is now eclipsed by revascularisation for that indication. However, it retains a role in the management of critical limb ischaemia and other conditions causing lower limb pain with or without ischaemia. We report the role of LS in modern surgical practice when revascularisation and pain management options have been exhausted. METHODS: A medical chart review was performed on all patients who underwent LS in our unit from 2005 to 2016 (inclusive). Symptomatology, surgical indications and patient outcomes were reported. RESULTS: Twenty-seven cases were performed in total (21 unilateral, 3 bilateral). Underlying diagnoses were as follows: PAD [59.3% (n = 16)], hyperhidrosis [18.5% (n = 5)] and equal numbers of complex regional pain syndrome, diabetic neuropathy and vasculitis [7.4% (n = 2) each]. Overall, 85.2% (n = 23) had improvement or resolution of symptoms at 1 month and 70.3% (n = 19) had persistent improvement of symptoms at 1 year. Non-PAD patients had superior outcomes with 90.9% (n = 10) reporting improved symptomatology at 1 month and nearly three quarters [72.8% (n = 8)] maintaining this improvement at 1 year. Only four patients required subsequent major amputation, all in the severe PAD group. CONCLUSION: Lumbar sympathectomy can improve symptoms associated with ischaemia, vasculitis, diabetic neuropathy and hyperhidrosis. Non-PAD patients have the greatest benefit. PMID- 29516400 TI - Chasing red herrings: Memory of distractors causes fixation in creative problem solving. AB - Two experiments tested the red herring retrieval hypothesis, which states that fixation in creative problem solving is worse when memory for red herrings (i.e., inappropriate or incorrect solutions) is strengthened. In Experiment 1, when associations between Remote Associates Test (RAT) problem words (e.g., COTTAGE, SWISS, CAKE) and related red herring words (e.g., hut, chocolate, icing) were strengthened via repetition, an encoding variable, fixation was found to increase. In Experiment 2, when associations were formed between RAT problem contexts and red herrings, then subsequent reinstatement of problem contexts during RAT problem solving trials (as compared with showing new contexts) also worsened fixation effects. Our results add to the increasing body of research that connects memory with creative problem solving, and they suggest possible ways for overcoming fixation effects. PMID- 29516401 TI - When a face type is perceived as threatening: Using general recognition theory to understand biased categorization of Afrocentric faces. AB - Prior research indicates that stereotypical Black faces (e.g., wide nose, full lips: Afrocentric) are often associated with crime and violence. The current study investigated whether stereotypical faces may bias the interpretation of facial expression to seem threatening. Stimuli were prerated by face type (stereotypical, nonstereotypical) and expression (neutral, threatening). Later in a forced-choice task, different participants categorized face stimuli as stereotypical or not and threatening or not. Regardless of prerated expression, stereotypical faces were judged as more threatening than were nonstereotypical faces. These findings were supported using computational models based on general recognition theory (GRT), indicating that decision boundaries were more biased toward the threatening response for stereotypical faces than for nonstereotypical faces. GRT analysis also indicated that perception of face stereotypicality and emotional expression are dependent, both across categories and within individual categories. Higher perceived stereotypicality predicts higher perception of threat, and, conversely, higher ratings of threat predict higher perception of stereotypicality. Implications for racial face-type bias influencing perception and decision-making in a variety of social and professional contexts are discussed. PMID- 29516403 TI - Improving of Anticancer Activity and Solubility of Cisplatin by Methylglycine and Methyl Amine Ligands Against Human Breast Adenocarcinoma Cell Line. AB - Methylglycine, also known sarcosine, is dramatically used in drug molecules and its metal complexes can interact to DNA and also do cleavage. Hence, to study the influence of methylglycine ligand on biological behavior of metal complexes, two water-soluble platinum (II) complexes with the formula cis-[Pt(NH3)2(CH3-gly)]NO3 and cis-[Pt(NH2-CH3)2(CH3-gly)]NO3 (where CH3-gly is methylglycine) have been synthesized and characterized by spectroscopic methods, molar conductivity measurements, and elemental analyzes. The anticancer activity of synthesized complexes was tested against human breast adenocarcinoma cell line of MCF7 using MTT assay and results showed excellent anticancer activity with Cc50 values of 126 and 292 MUM after 24 h incubation time, for both complexes of cis [Pt(NH3)2(CH3gly)]NO3 and cis-[Pt(NH2-CH3)2(CH3gly)]NO3, respectively. Also, the interaction between Pt(II) complexes with calf thymus DNA was extensively studied by means of absorption spectroscopy, fluorescence titration spectra displacement with ethidium bromide (EtBr), and circular dichroism studied in Tris-buffer. The obtained spectroscopic results revealed that two complexes can bind to highly polymerized calf thymus DNA cooperatively and denature at micromolar concentrations. The fluorescence data indicate that quenching effect for cis [Pt(NH3)2(CH3gly)]NO3 (Ksv = 9.48 mM-1) was higher than that of cis-[Pt(NH2 CH3)2(CH3gly)]NO3 (Ksv = 1.98 mM-1). These results were also confirmed by circular dichrosim spectra. Consequently, docking data showed that cis [Pt(NH3)2(CH3gly)]NO3 with more interaction energy binds on DNA via groove binding which is more compatible with experimental results. Graphical Abstract ? Two anticancer Pt(II) complexes, cis-[Pt(NH3)2(CH3gly)]NO3 and cis-[Pt(NH2 CH3)2(CH3gly)]NO3, have been synthesized and interacted with calf thymus DNA. Improving solubility of these compounds reduce side effects and increase anticancer activity against human breast cell line. Modes of binding have been studied by electronic absorption, fluorescence, and CD measurements. Results show that both Pt(II) complexes can interact to DNA via groove binding. PMID- 29516405 TI - ? PMID- 29516404 TI - Primary central nervous system vasculitis mimicking a brain tumor on conventional magnetic resonance imaging: the usefulness of perfusion-weighted imaging. A case report. PMID- 29516402 TI - Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases. AB - Since the discovery of HLA 60 years ago, it has contributed to the understanding of the immune system as well as of the pathogenesis of several diseases. Aside from its essential role in determining donor-recipient immune compatibility in organ transplantation, HLA genotyping is meanwhile performed routinely as part of the diagnostic work-up of certain autoimmune diseases. Considering the ability of HLA to influence thymic selection as well as peripheral anergy of T cells, its role in the pathogenesis of autoimmunity is understandable. The aim of this paper is to provide a brief overview of the role and current clinical relevance of HLA B27 in spondyloarthritis and HLA-B51 in Behcet's disease as well as HLA-DQ2/DQ8 in celiac disease and HLA-DRB1 in rheumatoid arthritis and to discuss possible future implications. PMID- 29516406 TI - ? PMID- 29516407 TI - Local sustained delivery of bupivacaine HCl from a new castor oil-based nanoemulsion system. AB - Bupivacaine HCl (1-butyl-2',6'-pipecoloxylidide hydrochloride), an amide local anesthetic compound, is a local anesthetic drug utilized for intraoperative local anesthesia, post-operative analgesia and in the treatment of chronic pain. However, its utility is limited by the relative short duration of analgesia after local administration (approximately 9 h after direct injection) and risk for side effects. This work is aimed to develop a nanoemulsion of bupivacaine HCl with sustained local anesthetics release kinetics for improved pain management, by exhibiting extended analgesic action and providing reduced peak levels in the circulation to minimize side effects. Herein, biodegradable oils were evaluated for use in nanoemulsions to enable sustained release kinetics of bupivacaine HCl. Only with castor oil, a clear and stable nanoemulsion was obtained without the occurrence of phase separation over a period of 3 months. High loading of bupivacaine HCl into the castor oil-based nanoemulsion system was achieved with about 98% entrapment efficiency and the resulting formulation showed high stability under stress conditions (accelerated stability test) regarding changes in visual appearance, drug content, and droplet size. We show herein that the in vitro release and in vivo pharmacokinetic profiles as well as pharmacodynamic outcome (pain relief test) after subcutaneous administration in rats correlate well and clearly demonstrate the prolonged release and extended duration of activity of our novel nanoformulation. In addition, the lower Cmax value achieved in the blood compartment suggests the possibility that the risk for systemic side effects is reduced. We conclude that castor oil-based nanomulsion represents an attractive pain treatment possibility to achieve prolonged local action of bupivacaine HCl. PMID- 29516408 TI - Recognizing Gynecological Cancer in Primary Care: Risk Factors, Red Flags, and Referrals. AB - Early diagnosis of symptomatic gynecological cancer is likely to improve patient outcomes, including survival. The primary care practitioner has a key role to play in this-they must recognize the symptoms and signs of gynecological cancer and make prompt evidence-based decisions regarding further investigation and referral. However, this is often difficult as many of the symptoms of gynecological cancers are nonspecific and are more likely to be caused by benign rather than malignant disease. As primary care is generally the first point of patient contact, those working in this setting usually encounter cancer patients at an earlier, and possibly less symptomatic, stage than practitioners in secondary care. Despite these challenges, research has improved our understanding of the symptoms patients present to primary care with, and a range of tests and referral pathways now exist in the UK and other countries to aid early diagnosis. Primary care practitioners can also play a key role in gynecological cancer prevention. A significant proportion of gynecological cancer is preventable either through lifestyle changes such as weight loss, or, for cervical cancer, vaccination and/or engagement with screening programs. Primary care provides an excellent opportunity to discuss cancer risk with patients and to promote risk reduction strategies and lifestyle change. In this article, the first in a series discussing cancer detection in primary care, we concentrate on gynecological cancer and focus on the three most common forms that a primary care practitioner is likely to encounter: ovarian, endometrial, and cervical cancer. We outline key risk factors, briefly discuss prevention and screening strategies, and offer practical guidance on the recognition of symptoms and signs and the investigation and referral of women with suspected cancer. While this article is written from a UK primary care perspective, much of what is discussed will be of relevance to those working in other healthcare systems. PMID- 29516411 TI - Highlights from the 2017 American Heart Association Scientific Sessions in Anaheim, California. PMID- 29516410 TI - Adalimumab Reduces Extraintestinal Manifestations in Patients with Crohn's Disease: A Pooled Analysis of 11 Clinical Studies. AB - INTRODUCTION: Extraintestinal manifestations (EIMs) in patients with Crohn's disease (CD) are common and associated with additional morbidity. This study aimed to evaluate the effect of adalimumab therapy on EIM resolution and identify potential predictors of EIM resolution in adult and pediatric patients with moderate to severe CD. METHODS: EIM data were pooled from 11 induction, maintenance, and open-label extension studies of adalimumab. Resolution of EIMs was evaluated at approximately 6 months and 1 year. Median time to initial EIM resolution and first EIM recurrence (reflecting durable resolution) of any EIM and specific categories of EIMs (arthritis/arthralgia, ocular, cutaneous) were calculated. A Cox model was used to determine predictors of initial and durable EIM resolution. RESULTS: At baseline, 54% (1137/2094) of patients receiving adalimumab and 51% (297/586) receiving placebo had EIMs. EIM resolution occurred in a significantly greater proportion of adalimumab versus placebo patients at 6 months (54% vs 31%; P < .001) and 1 year (60% vs 42%; P = .008). Median time to initial resolution of any EIM, arthritis/arthralgia, and cutaneous EIMs was significantly shorter in patients receiving adalimumab versus placebo. Durable resolution of any EIM and arthritis/arthralgia was significantly longer for patients receiving adalimumab versus placebo. Clinically meaningful predictors of EIM resolution included adalimumab treatment, male sex, and moderate (versus severe) disease activity at baseline. CONCLUSION: Adalimumab is effective for achieving initial and durable resolution of any EIM and, in particular, arthritis/arthralgia in patients with moderate to severe CD. Predictors of EIM resolution included adalimumab treatment and moderate disease severity. FUNDING: AbbVie. PMID- 29516409 TI - Multidisciplinary Management of Spondyloarthritis-Related Immune-Mediated Inflammatory Disease. AB - INTRODUCTION: Immune-mediated inflammatory diseases (IMIDs) are chronic autoimmune conditions that share common pathophysiologic mechanisms. The optimal management of patients with IMIDs remains challenging because the coexistence of different conditions requires the intervention of several specialists. The aim of this study was to develop a series of statements defining overarching principles that guide the implementation of a multidisciplinary approach for the management of spondyloarthritis (SpA)-related IMIDs including SpA, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and uveitis. METHODS: A Delphi consensus-based approach was used to identify a core set of statements. The process included development of initial questions by a steering committee, an exhaustive search of the literature using complementary approaches to identify potential statements and two Delphi voting rounds for finalization of the statements. RESULTS: Consensus was achieved on the related nature of IMIDs, the existence of a high prevalence of multiple IMIDs in a single patient and the fact that a multidisciplinary approach can result in a more extensive evaluation and comprehensive approach to treatment. The goals of a multidisciplinary team should be to increase diagnosis of concomitant IMIDs, improve the decision-making process, and increase patient satisfaction and adherence. Early referral and diagnosis, early recognition of concomitant IMIDs and optimizing treatment to improve patient quality of life are some of the advantages of using multidisciplinary teams. To be effective, a multidisciplinary team should be equipped with the appropriate tools for diagnosis and follow-up, and at a minimum the multidisciplinary team should include a dermatologist, gastroenterologist and rheumatologist; providing psychologic support via a psychologist and involving an ophthalmologist, general practitioners and nurses in multidisciplinary care is also important. CONCLUSION: The present Delphi consensus identified a set of overarching principles that may be useful for implementation of a multidisciplinary approach for the management of SpA-related IMIDs. FUNDING: Aristea and Hippocrates. PMID- 29516412 TI - Oxidative stress in the brain caused by acute kidney injury. AB - Uremic encephalopathy is a severe complication of renal failure. The underlying pathogenesis is unknown although several mechanisms have been suggested. Renal failure causes oxidative stress leading to cardiovascular complications. It has been suggested as the potential mediator of uremic encephalopathy as well, but it is largely unknown whether brain tissue itself undergoes oxidative damage in uremia. The aim of our experiment was to analyze oxidative stress markers in different brain regions in an animal model of acute kidney injury (AKI). AKI was induced by ischemia-reperfusion injury in male Wistar rats. Urine was collected in metabolic cages after 24 h. Samples of plasma and several brain regions were collected after 48 h. Markers of lipid peroxidation, protein oxidation and total antioxidant capacity were assessed. Renal failure was confirmed by high plasma creatinine, urea and urinary albumin to creatinine ratio. Our data confirmed increased systemic oxidative stress in the AKI group with plasma concentrations of markers of oxidative damage being twice as high compared to the sham-operated control group. No effect was seen in the urine. In the hippocampus, lipid and protein oxidation was higher, while antioxidant capacity was lower in the rats with AKI. Lipid oxidation markers in the frontal cortex were higher by 33%. No differences to controls were found in the cerebellum and hypothalamus. In conclusion, our results indicate that AKI leads to oxidative stress in the brain, especially in the hippocampus and in the frontal cortex. This kidney-brain crosstalk mediated by increased oxidative stress might explain some of the symptoms of uremic encephalopathy. The causes and consequences of oxidative damage observed in the brain during AKI remain to be elucidated. PMID- 29516414 TI - Using task effort and pupil size to track covert shifts of visual attention independently of a pupillary light reflex. AB - We tested the link between pupil size and the task effort involved in covert shifts of visual attention. The goal of this study was to establish pupil size as a marker of attentional shifting in the absence of luminance manipulations. In three experiments, participants evaluated two stimuli that were presented peripherally, appearing equidistant from and on opposite sides of eye fixation. The angle between eye fixation and the peripherally presented target stimuli varied from 12.5 degrees to 42.5 degrees . The evaluation of more distant stimuli led to poorer performance than did the evaluation of more proximal stimuli throughout our study, confirming that the former required more effort than the latter. In addition, in Experiment 1 we found that pupil size increased with increasing angle and that this effect could not be reduced to the operation of low-level visual processes in the task. In Experiment 2 the pupil dilated more strongly overall when participants evaluated the target stimuli, which required shifts of attention, than when they merely reported on the target's presence versus absence. Both conditions yielded larger pupils for more distant than for more proximal stimuli, however. In Experiment 3, we manipulated task difficulty more directly, by changing the contrast at which the target stimuli were presented. We replicated the results from Experiment 1 only with the high contrast stimuli. With stimuli of low contrast, ceiling effects in pupil size were observed. Our data show that the link between task effort and pupil size can be used to track the degree to which an observer covertly shifts attention to or detects stimuli in peripheral vision. PMID- 29516413 TI - Interplay between adenosine receptor antagonist and cyclooxygenase inhibitor in haloperidol-induced extrapyramidal effects in mice. AB - Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status. Pre treatment with COX inhibitor; naproxen (NPx) and adenosine receptor antagonist; caffeine (CAF), showed a significant impact on HP-induced cataleptic symptoms. Adenosine exerts pivotal control on dopaminergic receptors and is also involved in receptor internalization and recycling. On the other hand, prostaglandins (PGs) are implicated as neuro-inflammatory molecules released due to microglial activation in both Parkinson's disease (PD) and antipsychotics-induced EPS. The involvement of these neuroeffector molecules has led to the possibility of use of CAF and COX inhibitors as therapeutic approaches to reduce the EPS burden of antipsychotic drugs. Both these pathways seem to be interlinked to each other, where adenosine modulates the formation of PGs through transcriptional modulation of COXs. We observed an additive effect with combined treatment of NPx and CAF against HP-induced movement disorder. These effects lead us to propose that neuromodulatory pathways of dopaminergic circuitry need to be explored for further understanding and utilizing the full therapeutic potential of antipsychotic agents. PMID- 29516415 TI - Correction to: Ayurvedic and herbal medicine-induced liver injury: It is time to wake up and take notice. AB - The published online version contains incorrect data. These have been corrected below. PMID- 29516416 TI - Efficacy of narrow-band imaging in detecting early esophageal cancer and risk factors for its occurrence. AB - OBJECTIVE: The aim of this study is to evaluate the efficacy of narrow-band imaging (NBI) in the detecting early esophageal cancer and precancerous lesions and to investigate the risk factors for its occurrence. METHODS: The esophagus was examined with ordinary endoscopy, NBI, and iodine staining. All the lesions were confirmed by histopathologically as the gold standard; NBI and intrapapillary capillary scale (IPCL) scale were compared with pathologic diagnosis. The accuracy, sensitivity, specificity, positive and negative predictive values (PPV, NPV) were calculated. Subgroup analysis was performed between the elderly vs. younger group, and head and neck squamous cell cancer (HNSCC) vs. non-HNSCC patients. RESULTS: Ninety lesions were detected with ordinary endoscopy, 108 with NBI, and 120 with iodine staining. All esophageal cancers were detected both by NBI and by iodine staining. Accuracy, sensitivity, and specificity for esophageal cancer and precancerous lesion were 67.8%, 58.1%, and 76.6%; 92%, 89.7%, and 96%; 93.4%, 93.4%, and 93.2%, respectively. NBI endoscopy and iodine staining were superior to ordinary endoscopy for detecting esophageal cancer and precancerous lesions (p < 0.05). NBI showed better detection of esophageal neoplasms in the elderly patients (p < 0.001). The incidence of multiple squamous cell cancers (SCCs) was significantly higher in non-elderly group (p = 0.009). NBI can also detect more esophageal neoplastic lesions in patients with head and neck cancers (p = 0.003). CONCLUSIONS: NBI endoscopy appears as effective as Lugol staining to detect and screen the early esophageal cancer. NBI shows better detection of esophageal neoplasms in the elderly patients. The incidence of multiple SCCs was much higher in non-elderly patients. PMID- 29516418 TI - Preparation and evaluation of wetland plant-based biochar for nitrogen removal enhancement in surface flow constructed wetlands. AB - In the present study, biochar was prepared from scrap wetland macrophyte Arundo donax at different temperatures and then was evaluated for its feasibility as substrate to enhance nitrogen removal performance of surface flow constructed wetlands (SFCWs). Three groups of SFCW systems with different addition of biochar (0, 10, 20%, v/v) were constructed to investigate the effect of dissolved organic matter (DOM) released from biochar on nitrogen transformation. Results showed that the concentration of DOM released from biochar widely ranged from 6.01 to 125.67 mg L-1, and the DOM amount decreased with increasing pyrolysis temperature. Five humic acid-like components of DOM were identified by the parallel factor analysis (PARAFAC) model. The release capacity of DOM from biochar is observed to be closely related to microbial nitrogen removal efficiency. Enhanced removal efficiencies of NO3--N (81.16%) and total nitrogen (85.62%) were achieved in SFCWs with 20% biochar, which was higher than SFCWs with 10% biochar (62.74 and 73.83%) and the control groups with no biochar (36.16 and 57.90%), respectively. Increased plant height in SFCWs with more biochar addition confirmed the positive effect of biochar on plant growth. Results from the present study suggested that the application of wetland plant-derived biochar was a promising strategy to enhance treatment performance and utilization of waste biomass resource in SFCWs. PMID- 29516417 TI - Genome Editing in Stem Cells for Disease Therapeutics. AB - Programmable nucleases including zinc finger nucleases, transcription activator like effector nucleases, and clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein have tremendous potential biological and therapeutic applications as novel genome editing tools. These nucleases enable precise modification of the gene of interest by disruption, insertion, or correction. The application of genome editing technology to pluripotent stem cells or hematopoietic stem cells has the potential to remarkably advance the contribution of this technology to life sciences. Specifically, disease models can be generated and effective therapeutics can be developed with great efficiency and speed. Here we review the characteristics and mechanisms of each programmable nuclease. In addition, we review the applications of these nucleases to stem cells for disease therapies and summarize key studies of interest. PMID- 29516419 TI - Chemical composition and antifungal activity of plant extracts traditionally used in organic and biodynamic farming. AB - Five plant extracts traditionally used in organic and biodynamic farming for pest control and antifungal (downy mildew) disease management were selected after a farmer survey and analyzed for their chemical composition in LC-PDA-MS-MS and using adapted analytical method from food chemistry for determination of class of component (e.g., protein, sugar, lipids...). Their antifungal activity against Penicillium expansum, Botrytis cinerea, Botrytis allii, brown rot causing agents (Monilinia laxa and Monilinia fructigena), and grape downy mildew (Plasmopara viticola) was examined in vitro. White willow (Salix alba) and absinthe (Artemisia absinthium) ethanolic extracts were found to be the most effective in particular against Plasmopara viticola, with a total inhibition of spores germination when applied at 1000 mg/L. These extracts also showed a relatively low toxicity during preliminary ecotoxicological assays on Daphnia pulex. Extract from the bark of white willow contained some flavonoids, especially flavanones (eriodyctiol and derivates) and flavanols (catechins and derivates), as major compounds, whereas absinthe extract was rich in O-methylated flavanols and hydroxycinnamic acids. Thujone content in this extract was also determined by external calibration in GC-MS analysis, and its value was 0.004% dry extract. PMID- 29516420 TI - Does agricultural ecosystem cause environmental pollution in Pakistan? Promise and menace. AB - The increasing trend of atmospheric carbon dioxide (CO2) is the main cause of harmful anthropogenic greenhouse gas emissions, which may result in environmental pollution, global warming, and climate change. These issues are expected to adversely affect the agricultural ecosystem and well-being of the society. In order to minimize food insecurity and prevent hunger, a timely adaptation is desirable to reduce potential losses and to seek alternatives for promoting a global knowledge system for agricultural sustainability. This paper examines the causal relationship between agricultural ecosystem and CO2 emissions as an environmental pollution indicator in Pakistan from the period 1972 to 2014 by employing Johansen cointegration, autoregressive distributed lag (ARDL) model, and Granger causality approach. The Johansen cointegration results show that there is a significant long-run relationship between the agricultural ecosystem and the CO2 emissions. The long-run relationship shows that a 1% increase in biomass burned crop residues, emissions of CO2 equivalent of nitrous oxide (N2O) from synthetic fertilizers, stock of livestock, agricultural machinery, cereal production, and other crop productions will increase CO2 emissions by 1.29, 0.05, 0.45, 0.05, 0.03, and 0.65%, respectively. Further, our finding detects that there is a bidirectional causality of CO2 emissions with rice area paddy harvested, cereal production, and other crop productions. The impulse response function analysis displays that biomass-burned crop residues, stock of livestock, agriculture machinery, cereal production, and other crop productions are significantly contributing to CO2 emissions in Pakistan. PMID- 29516421 TI - Fate of antibiotic and metal resistance genes during two-phase anaerobic digestion of residue sludge revealed by metagenomic approach. AB - The prevalence and persistence of antibiotic resistance genes in wastewater treatment plants (WWTPs) is of growing interest, and residual sludge is among the main sources for the release of antibiotic resistance genes (ARGs). Moreover, heavy metals concentrated in dense microbial communities of sludge could potentially favor co-selection of ARGs and metal resistance genes (MRGs). Residual sludge treatment is needed to limit the spread of resistance from WWTPs into the environment. This study aimed to explore the fate of ARGs and MRGs during thermophilic two-phase (acidogenic/methanogenic phase) anaerobic digestion by metagenomic analysis. The occurrence and abundance of mobile genetic elements were also determined based on the SEED database. Among the 27 major ARG subtypes detected in feed sludge, large reductions (> 50%) in 6 ARG subtypes were achieved by acidogenic phase (AP), while 63.0% of the ARG subtypes proliferated in the following methanogenic phase (MP). In contrast, a 2.8-fold increase in total MRG abundance was found in AP, while the total abundance during MP decreased to the same order of magnitude as in feed sludge. The distinct dynamics of ARGs and MRGs during the two-phase anaerobic digestion are noteworthy, and more specific treatments are required to limit their proliferation in the environment. PMID- 29516422 TI - Effect of natural gas flaring upon the butterfly, Eurema hecabe (Lepidoptera: Pieridae) and its host plant, Cassia tora (Fabales: Fabaceae) in two group gathering stations of Assam, India: an approach of environmental monitoring. AB - Apart from other pollutants, flaring of natural gas adds carbon dioxide into the environment and changes the atmospheric composition, including temperature and humidity. As a major gaseous product, carbon dioxide changes plant structural components as well as herbivores, i.e., insect by dilution of nitrogen under such circumstances. Present analysis demonstrated the impact of gas flaring upon adjoining biota especially Eurema hecabe butterfly and its host plant, Cassia tora in some wells (group gathering stations) of Assam, India. Analysis, pertaining from the current investigation, documented higher carbon dioxide as well as temperature in the studied flaring sites. Apart from this, reduction of leaf nitrogen, SLA, and chlorophyll with increasing in LDMC, thickness, and carbon in the studied plant as well as poor developmental rate, RGR, ECD with high RCR in insect indicated severe impact of flaring in those areas. Simulation studies with different concentration of CO2 in open top chamber on the plant and butterfly also revealed similar trend of results. PMID- 29516423 TI - Radionuclide uptake and dose assessment of 14 herbaceous species from the east Ural radioactive trace area using the ERICA Tool. AB - The evaluation of radiation exposure in 14 species of herbaceous plants from the East-Ural Radioactive Trace (EURT) zone was performed, using the ERICA Tool, v. 1.2. Recent (up to 2015) levels of radionuclide activity concentration were measured in soil and vegetative plant mass. 239,240Pu content was used for the first time to estimate external dose rates for herbaceous plant species along the pollution gradient. In addition, a new approach to assessing the geometry of objects was adopted, including not only aboveground but also underground plant organs. This improved approach to the evaluation of radiation exposure confirms previous findings that herbaceous plant populations currently exist under low level chronic exposure in the EURT area. This reassessment based on new data suggests a 48-977-fold increase in the total dose rate per plant organism at the most polluted site compared to background areas. The highest capacity for the transfer of 90Sr and 137Cs was observed in Taraxacum officinale and Plantago major. In these species, the total dose rate per plant exceeded 150 MUGy h-1 due to 90Sr + 137Cs + 239,240Pu radionuclide anthropogenic pollution in the EURT zone. All estimated total dose rates per plant were below the dose rate screening value of 400 MUGy h-1. PMID- 29516425 TI - Infections after photodynamic therapy in Condyloma acuminatum patients: incidence and management. AB - Condyloma acuminatum (CA), or genital wart, is a sexually transmitted infection caused by human papillomaviruses. Increasing evidences demonstrated that photodynamic therapy (PDT) is effective in eliminating latent HPV infection, the major reason for CA recurrence. We observed an increasing number of infections after PDT in CA patients, which has not been reported before. This study aims to evaluate the incidence and management of infection in CA patients after PDT procedure. CA patients received PDT from January 2015 to February 2016 at the outpatient setting. Patients were randomly divided into two groups: the control group and fusidic acid group. Patients in the fusidic acid group used topical fusidic acid (2%) and recombinant human interferon after 5-aminolevulinic acid (ALA)-PDT procedure, while patients in the control group only used recombinant human interferon. Patients came to our department for follow-up evaluations at 4, 8, and 12 weeks after treatment for three times of PDT. Patients with ALA-PDT associated infection were then randomly divided into two groups: the fusidic acid group and mupirocin group. During the 13-month study period, a total of 718 patients with 2154 times of PDT procedures were enrolled. The infection rate after PDT was 8.5% in the control group, while it was 1.1% in the prophylactic topical fusidic acid group. The cure rate of PDT-associated infection was 85.7% in the fusidic acid group and 86.7% in the mupirocin group. In conclusion, prophylactic topical antibiotic was useful for reduction of PDT-associated infection and optimal wound healing in CA patients. PMID- 29516424 TI - The different paths and potential risks of photo(-electro)-catalytic degradation for rhodamine B in water by graphene/TiO2 membrane. AB - The graphene (GR)/TiO2 membrane was prepared by the sol-gel method and coated on the indium tin oxide (ITO) conductive glass, which showed high and stable photo( electro)-catalytic activities to rhodamine B (Rh-B) in water. Characterization results showed that the GR was dispersed and wrapped in the needle-like TiO2. With GR/TiO2 membrane and simulated sunlight irradiation, the removal efficiency of Rh-B (10 mg l-1 and pH at 5.4) arrived at 87.6% within 300 min. However, the higher removal efficiency for Rh-B reached to 97.8% by the photo-electro catalytic degradation with the applied voltage 4 v for 30 min. The .OH that generated in the photo-catalytic degradation process were responsible for Rh-B decomposition. The .O2- played the significant role in the photo-electro catalytic degradation of Rh-B. Furthermore, the decarboxylation was also occurred in the photo-electro-catalytic degradation for the Rh-B in water except for the deethylation and hydroxylation in the photo-catalytic degradation. In addition, the toxicities of the intermediates were calculated using the ECOSAR program and the EPIWIN software. The results indicated that the toxicities of intermediates from photo-electro-catalytic degradation for the Rh-B were higher than photo catalytic degradation, due to the generation of decarboxylate. PMID- 29516426 TI - Characterization of industrial odor sources in Binhai New Area of Tianjin, China. AB - Samples were collected from six different organized industrial odor sources in Tianjin Binhai New Area, including pharmacy, paint spraying, oil refinery, petrochemical, resin synthesis, and rubber manufacturing. Chemical analysis was conducted to identify and quantify major odorous volatile organic compounds (VOCs) and subsequently, establish source profiles. Olfactory measurement was used to characterize the sensory stimulating intensity of odorous VOCs and express them as odor concentration. The TVOC mass concentrations of these six sources were between 10.9 and 225.3 mg/m3. Toluene was the most abundant component in profiles of both pharmacy and spraying sources with abundances of 79.1 and 94%, respectively. The petrochemical source was characterized by high levels of o,m,p-xylene (more than 60%). Sulfides were identified almost solely in the rubber manufacturing source. High levels of styrene were found in the resin synthesis source, whereas the oil refinery source was dominated by halocarbons. The odor concentration of oil refinery, spraying, rubber manufacturing, and resin synthesis all exceeded the Chinese emission standards for odor pollutants (GB14554-93) during the study period. Based on industrial processing analysis and factor analysis, toluene, m,p-xylene, carbon disulfide, toluene, three types of halogenated hydrocarbons, and styrene were the markers of pharmacy, petrochemical, rubber manufacturing, spraying, oil refinery, and resin synthesis sources, respectively. Production process and factor analysis methods were used to identify the markers of each odor source, which were based on instrument analysis and olfactory measurement. PMID- 29516427 TI - Coupling loss characteristics of runoff-sediment-adsorbed and dissolved nitrogen and phosphorus on bare loess slope. AB - Soil and nutrient loss is a common natural phenomenon but it exhibits unclear understanding especially on bare loess soil with variable rainfall intensity and slope gradient, which makes it difficult to design control measures for agricultural diffuse pollution. We employ 30 artificial simulated rainfalls (six rainfall intensities and five slope gradients) to quantify the coupling loss correlation of runoff-sediment-adsorbed and dissolved nitrogen and phosphorus on bare loess slope. Here, we show that effects of rainfall intensity on runoff yield was stronger than slope gradient with prolongation of rainfall duration, and the effect of slope gradient on runoff yield reduced gradually with increased rainfall intensity. But the magnitude of initial sediment yield increased significantly from an average value of 6.98 g at 5 degrees to 36.08 g at 25 degrees with increased slope gradient. The main factor of sediment yield would be changed alternately with the dual increase of slope gradient and rainfall intensity. Dissolved total nitrogen (TN) and dissolved total phosphorus (TP) concentrations both showed significant fluctuations with rainfall intensity and slope gradient, and dissolved TP concentration was far less than dissolved TN. Under the double influences of rainfall intensity and slope gradient, adsorbed TN concentration accounted for 7-82% of TN loss concentration with an average of 58.6% which was the main loss form of soil nitrogen, adsorbed TP concentration accounted for 91.8-98.7% of TP loss concentration with an average of 96.6% which was also the predominant loss pathway of soil phosphorus. Nitrate nitrogen (NO3- N) accounted for 14.59-73.92% of dissolved TN loss, and ammonia nitrogen (NH4+-N) accounted for 1.48-18.03%. NO3--N was the main loss pattern of TN in runoff. Correlation between dissolved TN, runoff yield, and rainfall intensity was obvious, and a significant correlation was also found between adsorbed TP, sediment yield, and slope gradient. Our results provide the underlying insights needed to guide the control of nitrogen and phosphorus loss on loess hills. PMID- 29516428 TI - Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Hepatitis C Virus-Infected Cirrhotic and Non-cirrhotic Patients: Analyses Across Nine Phase III Studies. AB - BACKGROUND: The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations. OBJECTIVE: The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis ('non-cirrhotic') and with compensated cirrhosis ('cirrhotic'), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen +/- ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities. METHODS: Pharmacokinetic data from nine clinical studies (~ 1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate-parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model. RESULTS: The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30-60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients. CONCLUSION: These differences did not warrant dose adjustments for the DAAs when used in HCV-infected patients with compensated cirrhosis. PMID- 29516429 TI - Antioxidant effect of myricitrin on hyperglycemia-induced oxidative stress in C2C12 cell. AB - Hyperglycemia induced oxidative stress inside the cells. Myricitrin, as an antioxidant plant-derived component, may be useful in hyperglycemia. Hence, the aim of this study was conducted to evaluate the antioxidant effects of myricitrin on hyperglycemia-induced oxidative damage in myotubes (C2C12 cells). In this experimental study, mouse myoblast cell line (C2C12) was obtained and divided into five groups: control, hyperglycemia, hyperglycemia + myricitrin 1, 3, and 10 MUM. After treatment period for 48 h, cells were collected, homogenized, and centrifuged at 2000 rpm for 10 min. All samples were kept at - 80 degrees C until experimental and real-time PCR assessments were performed. Hyperglycemia increased malondialdehyde (MDA) (p < 0.05), total antioxidant capacity (TAC) (p < 0.001), and cellular apoptosis, and decreased levels of superoxide dismutase (SOD), catalase (CAT) (p < 0.01), myotube glycogen content (p < 0.05), glucose transporter type 4 (Glut-4), and cellular viability (p < 0.001). Myricitrin administration improved SOD (p < 0.05), CAT (p < 0.01), muscle cell's glycogen content (p < 0.01), Glut-4 gene expression (p < 0.001), Thiazolyl blue tetrazolium bromide (MTT) (p < 0.05), and Bax to Bcl-2 ratio (p < 0.001), and reduced MDA (p < 0.05) compared to hyperglycemia group. In conclusion, hyperglycemic condition induced oxidative stress along with cellular apoptosis, and myricitrin improved these disorders. Also, low and moderate doses of myricitrin are more efficient on skeletal muscle cells exposed to hyperglycemic statues than a high concentration of this antioxidant agent. PMID- 29516431 TI - A severe case of epigastric pain, diarrhea and coffee ground vomitus. PMID- 29516432 TI - Transcatheter embolotherapy of pulmonary artery aneurysms as emergency treatment of hemoptysis in Behcet patients: experience of a referral center and a review of the literature. AB - Hemoptysis is a life-threatening complication of Behcet's disease that is likely related to pulmonary artery aneurysm (PAA). Vascular interventional radiology may offer effective emergency therapeutic option, but has not been thoroughly investigated in this setting. A case series of a French referral center for hemoptysis combined with a literature review of case reports was conducted. Between 1995 and 2016, 12 patients were referred to our center for hemoptysis revealing or complicating the course of Behcet's disease. Pulmonary artery aneurysm (PAA) was the mechanism of hemoptysis in ten patients, nine of whom were treated by a transcatheter embolotherapy. Combining an additional 8 case reports from the literature, 17 patients treated by transcatheter embolotherapy for PAA were analyzed. The duration of the course of Behcet's disease was 22 months [IQR 3-45] at the time of PAA diagnosis. Transcatheter embolotherapy of PAA was successful for immediately controlling hemoptysis in all patients, without major complication except for one. Hemoptysis recurred in seven patients (41%) within 5 months [IQR 1-12]. The use of coils for transcatheter embolotherapy was associated with hemoptysis recurrence. A bronchosystemic hypervascularization related to the previously occluded PAA was the main mechanism of bleeding recurrence, leading to bronchosystemic artery embolization in four patients and surgery in two patients. Behcet's disease-related hemoptysis is mainly due to PAA. Transcatheter embolotherapy should be considered as the first-line emergency treatment for PAA-related hemoptysis, in association with the immunosuppressive regimen. Hemoptysis may recur in half of the cases, involving preferentially a bronchosystemic arterial mechanism. PMID- 29516433 TI - Efficiency of electronic signout for ED-to-inpatient admission at a non-teaching hospital. AB - Admission handoff is a high-risk component of patient care. Previous studies have shown that a standardized physician electronic signout ("eSignout") may improve ED-to-inpatient handoff safety and efficiency in teaching hospitals. This model has not yet been studied in non-teaching hospitals. The objectives of the study were to determine the efficiency of an eSignout platform at a community affiliate hospital by comparing ED length of stay (LOS) for a 5-month period before and after implementation and to compare the quality assurance (QA) events among admitted patients for the same time period. A retrospective, interventional study was conducted with the main outcome measures including ED LOS with calculation of 95% CI, mean comparison (t test), and number of QA events before and after implementation of the eSignout model. Prior to eSignout implementation, 1045 patients were admitted [mean ED LOS 330.0 min (95% CI 318.6-341.4)]. Following implementation, 1106 patients were admitted [mean ED LOS 338.9 min (95% CI 327.4 350.4, p = 0.2853)]. Nine pre-implementation QA events and six post implementation events were identified. Use of a physician eSignout in a non teaching hospital had no statistically significant effect on ED LOS for the admitted patients. The effect of an electronic interdepartmental handoff tool for patient safety and clinical operations in the non-teaching setting is unclear. PMID- 29516434 TI - Racial and Ethnic Differences in Prostate Cancer Survivors' Perceived Engagement in Treatment Decision-Making. AB - OBJECTIVE: We examined prostate cancer patients' perceived engagement in treatment decision-making and associated factors by race/ethnicity in a multiethnic sample. METHOD: We identified patients through the California Cancer Registry. Patients completed a cross-sectional telephone interview in English, Spanish, Cantonese, or Mandarin. Multivariable logistic regression models, stratified by race/ethnicity, estimated the associations of patient demographic and health status characteristics on (1) doctor asked patient to help decide treatment plan and (2) patient and doctor worked out a treatment plan together. RESULTS: We included 855 prostate cancer patients: African American (19%), Asian American (15%), Latino (24%), and White (42%). Asian American patients were less likely than White patients to report that their doctors asked them to help decide a treatment plan (OR = 0.31; 95% CI = 0.18-0.53) and that they worked out a treatment plan with their doctors (OR = 0.54; 95% CI = 0.33-0.90). Language of interview was a significant contributing factor in stratified analysis for both outcomes. CONCLUSION: Asian American prostate cancer patients reported less engagement in treatment decision-making, with Chinese language being a significant contributing factor. Future research should identify patient-centered strategies that effectively engage underserved patients and support healthcare providers in shared decision-making with multiethnic and multilingual patients. PMID- 29516435 TI - Unequal Cumulative Incidence and Mortality Outcome in Childhood Brain and Central Nervous System Malignancy in the USA. AB - BACKGROUND: While survival in overall pediatric malignancy has improved during recent decades, brain/central nervous system (CNS) tumors has not demonstrated comparable survival advantage. Incidence and mortality data in this malignancy continue to illustrate race and sex differences; however, there are few data in the pediatric setting. This study sought to characterize brain/CNS tumors by socio-demographic and assess racial and sex variances in both cumulative incidence and mortality. METHODS: A retrospective cohort design with Surveillance, Epidemiology and End Results (SEER) 1973-2014 was used for the assessment of children aged < 1-19 years diagnosed with brain/CNS tumors. The age adjusted incidence rates were used for temporal trends, percent change, and annual percent change. We utilized binomial regression model to determine the exposure effect of race and sex on cancer mortality, adjusting for potential confounders. RESULTS: Childhood brain/CNS tumor cumulative incidence (CmI) continues to rise in annual percent change, and mortality varied by race, sex, and year of diagnosis. The CmI was highest among whites, intermediate among blacks, and lowest among Asians, as well as lower in females relative to that in males. Compared to whites, blacks were 21% more likely to die from brain/CNS tumors [risk ratio (RR) 1.21, 95% confidence interval (C.I.) 1.13-1.28], while males were 4% more likely to die relative to females (RR 1.04, 95% C.I. 1.00 1.08). After controlling for age, sex, and tumor grade, racial disparities persisted, with 16% increased risk of dying among blacks relative to whites [adjusted risk ratio 1.16, (99% C.I.) 1.08-1.25, p < 0.001]. CONCLUSION: The cumulative incidence of brain/CNS malignancy is higher among whites relative to that in blacks; however, blacks experienced survival disadvantage even after adjustment for potential tumor prognostic and predisposing factors. PMID- 29516436 TI - Targeted Nitric Oxide Synthase Inhibitors for Migraine. AB - Nitric oxide (NO) is a small gaseous signaling molecule that has important biological effects. It has been heavily implicated in migraine; and the NO donor, nitroglycerin, has been used extensively as a human migraine trigger. Correspondingly, a number of components of the NO signaling cascade have been shown to be upregulated in migraine patients. NO is endogenously produced in the body by NO synthase (NOS), of which there are three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Based on the accumulating evidence that endogenous NO regulation is altered in migraine pathogenesis, global and isoform-selective inhibitors of NOS have been targeted for migraine drug development. This review highlights the evidence for the role of NO in migraine and focuses on the use of NOS inhibitors for the treatment of this disorder. In addition, we discuss other molecules within the NO signaling pathway that may be promising therapeutic targets for migraine. PMID- 29516438 TI - The history of seabird colonies and the North Water ecosystem: Contributions from palaeoecological and archaeological evidence. AB - The North Water (NOW) polynya is one of the most productive marine areas of the Arctic and an important breeding area for millions of seabirds. There is, however, little information on the dynamics of the polynya or the bird populations over the long term. Here, we used sediment archives from a lake and peat deposits along the Greenland coast of the NOW polynya to track long-term patterns in the dynamics of the seabird populations. Radiocarbon dates show that the thick-billed murre (Uria lomvia) and the common eider (Somateria mollissima) have been present for at least 5500 cal. years. The first recorded arrival of the little auk (Alle alle) was around 4400 cal. years BP at Annikitsoq, with arrival at Qeqertaq (Salve O) colony dated to 3600 cal. years BP. Concentrations of cadmium and phosphorus (both abundant in little auk guano) in the lake and peat cores suggest that there was a period of large variation in bird numbers between 2500 and 1500 cal. years BP. The little auk arrival times show a strong accord with past periods of colder climate and with some aspects of human settlement in the area. PMID- 29516440 TI - On the crucial importance of a small bird: The ecosystem services of the little auk (Alle alle) population in Northwest Greenland in a long-term perspective. AB - The little auk is the most numerous seabird in the North Atlantic and its most important breeding area is the eastern shores of the North Water polynya. Here, a population of an estimated 33 million pairs breeds in huge colonies and significantly shapes the ecosystem. Archaeological remains in the colonies document that the little auk has been harvested over millennia. Anthropological research discloses how the little auk has a role both as social engineer and as a significant resource for the Inughuit today. The hunting can be practiced without costly equipment, and has no gender and age discrimination in contrast to the dominant hunt for marine mammals. Little auks are ecological engineers in the sense that they transport vast amounts of nutrients from sea to land, where the nutrients are deposited as guano. Here, the fertilized vegetation provides important foraging opportunities for hares, geese, fox, reindeer, and the introduced muskox. We estimate that the relative muskox density is ten times higher within 1 km of little auk fertilized vegetation hotspots. PMID- 29516437 TI - Therapeutic Approaches for the Management of Trigeminal Autonomic Cephalalgias. AB - Trigeminal autonomic cephalalgia (TAC) encompasses 4 unique primary headache types: cluster headache, paroxysmal hemicrania, hemicrania continua, and short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. They are grouped on the basis of their shared clinical features of unilateral headache of varying durations and ipsilateral cranial autonomic symptoms. The shared clinical features reflect the underlying activation of the trigeminal-autonomic reflex. The treatment for TACs has been limited and not specific to the underlying pathogenesis. There is a proportion of patients who are refractory or intolerant to the current standard medical treatment. From instrumental bench work research and neuroimaging studies, there are new therapeutic targets identified in TACs. Treatment has become more targeted and aimed towards the pathogenesis of the conditions. The therapeutic targets range from the macroscopic and structural level down to the molecular and receptor level. The structural targets for surgical and noninvasive neuromodulation include central neuromodulation targets: posterior hypothalamus and, high cervical nerves, and peripheral neuromodulation targets: occipital nerves, sphenopalatine ganglion, and vagus nerve. In this review, we will also discuss the neuropeptide and molecular targets, in particular, calcitonin gene related peptide, somatostatin, transient receptor potential vanilloid-1 receptor, nitric oxide, melatonin, orexin, pituitary adenylate cyclase-activating polypeptide, and glutamate. PMID- 29516441 TI - Walrus history around the North Water: Human-animal relations in a long-term perspective. AB - This article highlights the relationship between walruses and humans in and around the North Water polynya in a long-term perspective. The present study draws on a combination of biological, archaeological, archaeo-zoological, historical, and ethnographic sources covering the period from the 8th century AD to the late 20th century. The study demonstrates that the walrus was an important resource of meat, blubber, and other products throughout all the studied periods, if always supplemented by other kinds of game. It is suggested that walrus distribution and behaviour, as well as hunting strategies and technologies historically constituted a powerful component not only in forming human action and social life in the region but also in serving as an imaginative resource. It is further argued that the walrus and the walrus hunt still play a significant role in the present community living on the edge of the North Water, even if the hunt is increasingly circumscribed due to changing ice conditions. PMID- 29516442 TI - Introducing the North Water: Histories of exploration, ice dynamics, living resources, and human settlement in the Thule Region. AB - The North Water is a recurrent polynya in the High Arctic situated between Northwest Greenland and Ellesmere Island of Canada. The North Water makes a dynamic space, where various processes may enhance or obstruct each other, accelerating or halting particular modes of human-animal relations in the region, where life itself depends on the North Water. This will be discussed in four steps. The first step posits the North Water as a perceived oasis for explorers and whalers hailing from Europe or America in the nineteenth century. The second step concentrates on the diverse rhythms inherent in the ice conditions, as affected by trends that are set in motion elsewhere. The third step highlights the implications of the dynamics of the ice and sea currents for animal life in the region. The fourth step gives an overview of human settlement patterns around the North Water across the ages. The article shows how natural and social features are deeply implicated in each other, even if they are not directly co variant. PMID- 29516444 TI - Is sustainable resource utilisation a relevant concept in Avanersuaq? The walrus case. AB - This article addresses the role of Atlantic walrus (Odobenus rosmarus rosmarus) in present-day Avanersuaq from anthropological and biological perspectives, and asks whether or not sustainable resource utilisation is a useful concept in northwest Greenland. We describe the relations that unfold around walrus and walrus hunting, in the communities living adjacent to the North Water polynya on the eastern side of Smith Sound. We examine the interplay of walrus population abundance, hunting practices, uses, and formal (governmental) and informal (traditional) ways of regulating the hunt, and we analyse how walruses acquire multiple values as they circulate in different networks. Sustainable resource utilisation, we conclude, is a concept that is relevant in Avanersuaq and beyond, because it works as a biological standard, and hence organises laws, norms, and practices of formal management. Simultaneously, the term is problematic, because it ignores manifold levels of human and societal values connected to walrus. PMID- 29516443 TI - Interactions of climate, socio-economics, and global mercury pollution in the North Water. AB - Despite the remoteness of the North Water, Northwest Greenland, the local Inughuit population is affected by global anthropogenic pollution and climate change. Using a cross-disciplinary approach combining Mercury (Hg) analysis, catch information, and historical and anthropological perspectives, this article elucidates how the traditional diet is compromised by Hg pollution originating from lower latitudes. In a new approach we here show how the Inughuits in Avanersuaq are subject to high Hg exposure from the hunted traditional food, consisting of mainly marine seabirds and mammals. Violation of the provisional tolerably yearly intake of Hg, on average by a factor of 11 (range 7-15) over the last 20 years as well as the provisional tolerably monthly intake by a factor of 6 (range 2-16), raises health concerns. The surplus of Selenium (Se) in wildlife tissues including narwhals showed Se:Hg molar ratios of 1.5, 2.3, and 16.7 in muscle, liver, and mattak, respectively, likely to provide some protection against the high Hg exposure. PMID- 29516445 TI - Immunohistochemical mapping of neurotensin in the alpaca diencephalon. AB - INTRODUCTION: The distribution of the immunoreactive cell bodies and fibers containing neurotensin in the alpaca diencephalon was determined by an immunohistochemical technique. MATERIAL AND METHODS: The study was carried out in four male alpacas that lived at sea level. Brains of deeply anesthetized animals were fixed by perfusion with 4% paraformaldehyde. Cryostat sections were stained by a standard immunohistochemical method. RESULTS: Cell bodies containing neurotensin were observed in the zona incerta and hypothalamus. A low/moderate density of these cell bodies was observed in the lateral hypothalamic area, anterior and dorsal hypothalamic areas, suprachiasmatic nucleus, periventricular region of the hypothalamus and in the ventromedial hypothalamic nucleus. In both thalamus and hypothalamus, immunoreactive fibers showed a widespread distribution. In the thalamus, a high density of these fibers was mainly found in the midline nuclei, whereas in the hypothalamus a high density was in general observed in the whole structure. CONCLUSIONS: In comparison with other mammals, the thalamus of the alpaca showed the most widespread distribution of neurotensin immunoreactive fibers. The widespread distribution of neurotensin through the alpaca diencephalon suggests that the peptide can be involved in many physiological actions. PMID- 29516446 TI - [Twenty years of neurodevelopment]. PMID- 29516447 TI - An agenda for 21st century neurodevelopmental medicine: lessons from autism. AB - The future of neurodevelopmental medicine has the potential of situating child neurology at the forefront of a broad-based public health effort to optimize neurodevelopmental outcomes of children born with high-prevalence and diverse genetic, pre- and peri-natal, and environmental burdens compromising early brain development and leading to lifetime disabilities. Building on advancements in developmental social neuroscience and in implementation science, this shift is already occurring in the case of emblematic neurodevelopmental disorders such as autism. Capitalizing on early neuroplasticity and on quantification of trajectories of social-communicative development, new technologies are emerging for high-throughput and cost-effective diagnosis and for community-viable delivery of powerful treatments, in seamless integration across previously fragmented systems of healthcare delivery. These solutions could be deployed in the case of other groups of children at greater risk for autism and communication delays, such as those born extremely premature or with congenital heart disease. The galvanizing concept in this aspirational future is a public health focus on promoting optimal conditions for early brain development, not unlike current campaigns promoting pre-natal care, nutrition or vaccination. PMID- 29516448 TI - [Autistic regression: clinical and aetiological aspects]. AB - INTRODUCTION: Autism spectrum disorders are neurodevelopmental dysfunctions that are characterised by deficits in social integration and communication, associated with restricted interests and stereotypic behaviour. A high percentage are related to language disorders, sensory dysfunctions, attention deficit disorder, bipolarity, intellectual disability or epilepsy, among other comorbidities. It is estimated that around 30% of children with autism, with typical early development, may present regression in the first years of life, which was already reported by Kanner in one of his original cases. The term regression refers to the loss of social, communicative or motor skills. It is essential to be alert to any symptoms of autistic regression, since it is not always an unspecific usual manifestation of the clinical spectrum of autism. Although little is known about the pathogenesis of regression, it needs to be organised hierarchically, as it can be part of different conditions with a variety of causes. AIMS: The aim of this study is to analyse distinct conditions that need to be addressed in the case of a child with autistic regression, including genetic and toxic causations, autoimmune and nutritional phenomena, and epilepsies. CONCLUSION: When faced with a case of autistic regression it is essential to try to identify the possible aetiology, as this can allow specific treatment and adequate genetic counselling to be established. PMID- 29516449 TI - [Autism spectrum disorder and prematurity: towards a prospective screening program]. AB - INTRODUCTION: The prevalence of autism spectrum disorders (ASD) reported in current studies in risk groups such as preterm or low birth weight infants is higher than in the normal population. This fact has led to the increase in recent years of screening studies that investigate possible risk factors for ASD in preterm newborns and their developmental trajectory. AIM: To present the results of the main screening studies of preterm newborns in order to propose screening recommendations for this population at risk. DEVELOPMENT: The results of the studies presented suggest the possibility that the trajectory of socio communicative and behavioral development of preterm infants differed from what was expected if their birth had occurred at term. This supports the fact that screening programs are carried out based on developmental surveillance and that it is advisable to use screening tools adapted to this population at risk. CONCLUSION: Premature children are a risk group that shows differential characteristics for the screening of ASD. PMID- 29516450 TI - [Conduct disorders in autism spectrum disorders]. AB - INTRODUCTION: Autism spectrum disorders (ASD) are neurodevelopmental disorders that affect social communication and present stereotypic behaviours. Comorbidity associated to conduct disorders is frequent, starts in infancy and, in general, continues into adulthood. It is sometimes associated with aggressiveness, negativism, self-harm and breaking social norms. It causes a high degree of dysfunctionality in persons with ASD, their family, professionals and those around them, and is the main cause of pharmacological treatment, hospitalisation and special education. Factors related to the symptoms of ASD, comorbidity and social factors are associated with an increased risk of conduct disorders. In many cases it would be necessary to perform a detailed examination that includes a functional analysis and a combination of psychoeducational, social and pharmacological interventions. AIM: To review the precipitating factors, causes, evaluation and treatment of the conduct disorders associated with ASD. DEVELOPMENT: The study outlines what is understood by conduct disorders in ASD, the different clinical and cognitive mechanisms associated with it, and the most effective strategies for intervention. CONCLUSIONS: Comorbid ASD with conduct disorders is frequent, begins in early infancy and continues throughout life. A detailed evaluation that includes a functional analysis of the behaviour to be eliminated and treatment with different psychological, social educational and pharmacological strategies are essential. PMID- 29516451 TI - [Autism and intelligence quotient: stability?] AB - INTRODUCTION: Autism is a heterogeneous disorder. The possibility of determining its characteristics over time will have a great impact on the prognosis and predictions that can be made. In that regard, the intelligence quotient and its possible stability throughout the life cycle can help to better define the phenotype of the disorder and its associated needs. DEVELOPMENT: Longitudinal studies show a certain level of stability in intelligence quotient scores, especially starting from the school years. Before, in the preschool stage, there is greater variability, especially in those children who have a borderline intellectual functioning or moderate intellectual disability. CONCLUSION: More research should continue to be developed to know the cognitive profile of people with autism spectrum disorder and be able to make predictions based on their intellectual functioning. PMID- 29516452 TI - [Perisylvian magnetoencephalografic impairments in patients with autism spectrum disorders]. AB - INTRODUCTION: The perisylvian areas, located around the Sylvian fissure, are constituted by frontal, temporal and parietal brain regions. These are connected forming specialized neural networks and play a primary role in the development of linguistic skills and social cognition. These areas are a possible neuronal substrate of cognitive and behavioral impairments in patients with autism spectrum disorders (ASD). AIM: To locate and quantify epileptiform activity sources through magnetoencephalography in frontal perisylvian areas in children with idiopathic ASD. PATIENTS AND METHODS: Sixty-eight children with idiopathic ASD were studied by magnetoencephalography. The children were classified into two groups: a group of 41 children with autistic disorder and a combined group of 27 children with Asperger syndrome and children with pervasive developmental disorder not otherwise specified. The sources of magnetoencephalografic epileptiform activity detected in the frontal perisylvian were localized and quantified. RESULTS: The amount of epileptiform activity in frontal perisylvian region was significantly higher in children with autistic disorder. CONCLUSIONS: The amount of epileptiform activity in frontal perisylvian areas differed significantly between children with autistic disorder and those with Asperger syndrome and pervasive developmental disorder not otherwise specified. PMID- 29516453 TI - [Executive neurofunctionality: a comparative study in high intellectual abilities]. AB - INTRODUCTION: From a differential perspective, high intellectual ability is an expression of intellectual functioning with characteristic functional correlates and structural correlates of the underlying neural activity that suggests an improved executive capacity as a relevant characteristic, highlighting in it a more effective working memory. DEVELOPMENT: The neuroscientific evidences about the neural mechanisms that can explain the differences are analyzed between the intellectual functioning of the high intellectual ability and the typical intellectual capacity. The possibilities that offer the recording of evoked potentials to capture fundamental mental processes that allow explain the differences between them are put under review. CONCLUSIONS: Neuroscientific evidences through electroencephalography or other mental imagery techniques show that the brain, as a structural correlate of high intellectual abilities, has greater neural efficiency, interconnectivity and differences in the cytoarchitecture. It is a brain that captures, understands and interprets reality in a qualitatively different manner. But the neural differences are structural and the high intellectual capacity emerges from its plasticity functional. That is, it is a brain prepared for better executive regulation that is not always directly related with excellence and the eminent manifestation of its potentiality because it requires other conditioning factors such as motivation, the organization of knowledge, personal traits of temperament or perfectionism, and exogenous conditions. PMID- 29516454 TI - [Moyamoya disease: clinical, neuroradiological, neuropsychological and genetic perspective]. AB - INTRODUCTION: Moyamoya disease (MMD) is an occlusive cerebrovascular disease characterized by progressive stenosis or occlusion in the terminal portion of the bilateral internal carotid arteries, affecting both children and adults. AIM: To conduct a review and update on MMD from a clinical, neuroradiological, neuropsychological and genetic perspective. DEVELOPMENT: In this pathology, which occurs with ischemia or cerebral hemorrhage, an unusual compensatory vascular network (moyamoya vessels) develops at the base of the brain in the form of collateral channels. MMD can present clinically with hemiparesis, dysarthria, aphasia, headache, seizures, visual deficits, syncopes or changes in personality. At the neuropsychological level, and even in the absence of obvious strokes, patients usually present impairment of attention, memory, behavior and executive functions. High resolution angiography and magnetic resonance imaging have been a neuroradiological advance towards an early detection of this disease. At the genetic level, the RING (really interesting new gene) RNF213 has recently been identified, and it is considered the most important genetic risk factor known up to now in the MMD. CONCLUSIONS: MMD is a rare pathology that predominantly affects the frontal lobes. The genetic and neuroradiological advances, in addition to a cognitive profile, contribute to early diagnosis and treatment to improve the quality of life of these patients. PMID- 29516455 TI - [Randomised controlled study of inter-hemispheric electroencephalographic coherence following assisted therapy with dolphins in children with autism spectrum disorders]. AB - INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impairments in executive function, language, emotional function, and social function. Its anatomofunctional substrate is related to a disorganization of the brain's functional connections. The aim is to investigate the cerebral connections in subjects with ASD through the analysis of the interhemispheric coherence (IHC) of the quantified electroencephalogram and its changes after dolphin assisted therapy (DAT) versus therapeutical intervention without dolphins (TIWD). PATIENTS AND METHODS: The IHC was determined in 44 subjects with ASD before randomly assigning them to two therapeutic groups: DAT (n = 22) and TIWD (n = 22). The results were statistically analyzed through the multi-measure ANOVA test for within-subject (time) and between-subject (DAT vs TIWD) factors. RESULTS: The IHC showed a significant reduction (p < 0.05) for both groups in the delta, theta, beta, and alpha frequencies (p < 0.001) in the anterior frontal region (F3-F4), alpha in the central region (C3-C4) (p < 0.05), and alpha (p < 0.05) and beta (p < 0.001) in the temporal region (T3-T4). In the intersection with the specific treatment (DAT), the coherence in the alpha band increased in Fp1-Fp2 (p < 0.05), and the delta did not decline in F3-F4 (p < 0.05). CONCLUSION: In 5-year-old children with ASD, DAT increases the IHC in the anterior frontal region and stabilizes the tendency to reduce the delta band in the posterior frontal region. PMID- 29516456 TI - [Epilepsy, cognition and ketogenic diet]. AB - INTRODUCTION: Most individuals with epilepsy will respond to pharmacologic treatment; however, approximately 20-30% will develop medically refractory epilepsy. Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, compliance, and long-term retention of the treatment. Ketogenic diet is an effective and well-tolerated treatment for these children with refractory epilepsy without any negative effect on cognition or behavior. AIM: To review the current state of experimental and clinical data concerning the neuroprotective and cognitive effects of the ketogenic diet in both humans and animals. DEVELOPMENT: In different animal models, with or without epilepsy, the ketogenic diet seems to have neuroprotective and mood-stabilizing effects. In the observational studies in pediatric epilepsy, improvements during treatment with the ketogenic diet are reported in behavior and cognitive function, particularly with respect to attention, alertness, activity level, socialization, and sleep quality. One randomized controlled trial in patients with pediatric refractory epilepsy showed a mood and cognitive activation during ketogenic diet treatment. CONCLUSIONS: Ketogenic diet shows a positive impact on behavioral and cognitive functioning in children and adolescents with refractory epilepsy. More specifically, an improvement is observed in mood, sustained attention, and social interaction. PMID- 29516457 TI - [A communication intervention in autism spectrum disorder by means of the programme 'More than Words'. A case study]. AB - INTRODUCTION: The 'More than Words' programme aims to enable parents to take advantage of day-to-day situations as communication learning settings, through the use of instruction in responsive-type interaction strategies. AIM: To describe the effects of this programme on the communication skills of a child with autism spectrum disorder and on the language the parents use to address him. PATIENTS AND METHODS: A three-phase design (pre-intervention, intervention and post-intervention) was employed, in which the responsive interactions of the parents and the child's communicative acts were measured. RESULTS: The intervention can modify the parents' communicative style, especially when the family receives guidance from a speech therapist. Nevertheless, the responsive nature of the parents' communication tends to diminish when the intervention finishes. Conversely, the child's communicative acts increase, with a medium sized effect of the treatment. CONCLUSIONS: The 'More than Words' programme can be a good starting point for parents to become familiar with strategies that foster communication with their children who have autism spectrum disorder. PMID- 29516458 TI - [Developmental amnesia and early brain damage: neuropsychology and neuroimaging]. AB - AIM: To contribute to neuropsychological profiling of developmental amnesia subsequent to bilateral damage to both hippocampi in early age. SUBJECTS AND METHODS: The total sample of 24 schoolchildren from both sexes is distributed in three groups: perinatal hypoxic-ischaemic encephalopathy and everyday complaints of memory in school age (n = 8); perinatal hypoxic-ischaemic encephalopathy without memory complaints (n = 7); and a group of typically developing (n = 9). All participants in every groups did have normal general intelligence and attention. Both clinical groups had, as another clinical consequence, spastic cerebral palsy (diplegia). Neuropsychological exam consisted on tests of general intelligence, attentional abilities, declarative memory and semantic knowledge. All participants had a brain magnetic resonance image and spectroscopy of hippocampi. Scheltens criteria were used for visual estimation of hippocampal atrophy. Parametric and non-parametric statistical contrasts were made. RESULTS: Despite preservation of semantic and procedural learning, declarative-episodic memory is impaired in the first group versus the other two groups. A significant proportion of bilateral hippocampal atrophy is only present in the first group versus the other two non-amnesic groups using Scheltens estimation on MRI. Two cases without evident atrophy did have diminished NAA/(Cho + Cr) index in both hippocampi. CONCLUSIONS: Taken together, these results contribute to delineate developmental amnesia as an specific impairment due to early partial bihippocampal damage, in agreement with previous studies. After diagnosis of developmental amnesia, a specific psychoeducational intervention must be made; also this impairment could be candidate for pharmacological trials in the future. PMID- 29516459 TI - [Concordances between autism spectrum disorders and attention deficit hyperactivity disorder]. AB - INTRODUCTION: The current literature acknowledges an overlap of genetic, clinical and neuropsychological aspects between autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), suggesting that there may be a common pattern that covers features ranging from the common genetic and structural aetiology to shared patterns of symptoms. AIM: To review the current advances in these common aspects. DEVELOPMENT: Several studies have pointed out preschool attentional difficulties as the basis of both disorders. From the genetic perspective, it is estimated that 50-72% of the genetic factors overlap between the two disorders. They also share a decrease in the volume of the corpus callosum and left frontal grey matter, as well as functional alterations such as dorsolateral prefrontal, striato-thalamic and superior parietal hypoactivation. Results are also found regarding executive functioning, with differential profiles for the two conditions, and also concerning the relationship between the repetitive and impulsive behaviours in the early stages of ASD and ensuing problems of hyperactivity. CONCLUSIONS: This new conception of the ASD-ADHD continuum, with a common neurodevelopmental basis and associated clinical features, could be of great use in clinical practice. It is suggested that this association should be taken into account when it comes to deciding on the treatment. PMID- 29516460 TI - [Neurobiological bases of autistic spectrum disorder and attention deficit hyperactivity disorder: neural differentiation and synaptogenesis]. AB - AIM: To know the neural processes linked to the activity of brain circuits in order to understand the consequences of their dysfunction and their role in the development of neurodevelopmental diseases, such as autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). DEVELOPMENT: The activity of neuronal circuits is the neurobiological basis of behavior and mental activity (emotions, memory and thoughts). The processes of differentiation of neural cells and the formation of circuits by synaptic contacts between neurons (synaptogenesis) occur in the central nervous system during the late stages of prenatal development and the first months after birth. ASD and ADHD share biological features, mainly related to alterations in brain circuits and synaptic function, which allow us to treat them scientifically together. From the neurobiological aspect, ASD and ADHD are manifestations of anomalies in the formation of circuits and synaptic contacts in the brain regions involved in social behavior, and especially in the prefrontal cerebral cortex. These anomalies are caused by mutations in genes involved synaptogenesis and synaptic plasticity, regulation of dendritic spine morphology, synaptic cytoskeletal organization, synthesis and degradation of synaptic proteins, and control of excitatory and inhibitory balance in the synaptic function. CONCLUSIONS: ASD and ADHD are functional alterations of the cerebral cortex, which present structural anomalies in the arrangement of neurons, in the pattern of connections of cortical columns and in the structure of dendritic spines. These alterations affect mainly the prefrontal cortex and its connections. PMID- 29516461 TI - [Neurodevelopment and phenocopies of attention deficit hyperactivity disorder: differential diagnosis]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders. Other neurodevelopmental disorders may appear as a comorbidity or mimicking ADHD itself. DEVELOPMENT: This study reviews the high prevalence of other neurodevelopmental disorders (specific learning difficulties, communication disorders, etc.) in patients with ADHD. Moreover, the possible differential diagnoses include the same neurodevelopmental disorders that can occur as a comorbidity. Based on the literature, the study evaluates the role of clinical evaluation and neuropsychology in distinguishing between comorbidity and mimicry. CONCLUSIONS: The clinical evaluation could be insufficient for the comorbid diagnosis of neurodevelopmental disorders. In these cases, a neuropsychological evaluation is generally required, since it can also offer alternative diagnostic hypotheses about the symptoms observed and may therefore be a valuable aid for the differential diagnosis. PMID- 29516462 TI - [The gut-brain axis in attention deficit hyperactivity disorder: the role of the microbiota]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) has a complex aetiology, mainly attributed to a number of susceptibility genes and environmental factors. Genetic association studies, however, have been inconsistent and have identified genetic variants with a moderate effect that explain a small proportion of the estimated inheritability of the disorder (< 10%). Recent studies suggest that the gut microbiota and diet play an important role in the development and symptoms of different mental disorders. Nevertheless, no clear evidence exists on the issue. This project proposes an alternative approach to identify mechanisms by which the intestinal microbial ecosystem and diet could contribute to the presence of ADHD. AIM: To identify biomarkers for ADHD by examining the gut microbiota. SUBJECTS AND METHODS: We conducted a cross sectional study of adult patients with ADHD (n = 100) and control subjects (n = 100). Measures of ADHD evaluation and eating habits were performed in both groups. Samples of faecal material were obtained from which to extract bacterial DNA, then used to characterise the participants' gut microbiota. A meta-genomic association study was later performed to attempt to correlate the bacterial composition of the intestine with the clinical subtypes of the disorder. RESULTS AND CONCLUSIONS: Comparing the gut microbiota profiles of subjects with ADHD and controls is expected to help account for the clinical heterogeneity of the disorder and identify new mechanisms involved in its development. PMID- 29516463 TI - [Attention deficit hyperactivity disorder in preschool age children. Its epidemiological prevalence in Navarra and La Rioja, Spain]. AB - INTRODUCTION: There are few studies about preschool attention deficit hyperactivity disorder (ADHD) prevalence. AIM: To study the prevalence of ADHD in preschoolers using an specific scale (ADHD-RS-IV-P-Es) developed for this age range. SUBJECTS AND METHODS: We evaluated the prevalence of possible ADHD in a representative sample of preschoolers in Navarra and La Rioja, Spain. RESULTS: We find a range of prevalence between 2.5-4.1% depending on the criteria that was used (more or less strict). CONCLUSIONS: There are specific tools that can be use in preschool ADHD study. The prevalence of preschool ADHD in Spain is similar than in other countries. The frequency of symptoms in this age range is similar to the found in school age children. PMID- 29516464 TI - [A study of primary school teachers' knowledge of attention deficit hyperactivity disorder]. AB - INTRODUCTION: The high prevalence of attention deficit hyperactivity disorder (ADHD), with at least one pupil per classroom, poses a challenge for all the professionals in contact with them, especially for teachers. AIM: To examine how much primary school teachers know about ADHD in three areas (general information, symptoms and diagnosis, and treatment). SUBJECTS AND METHODS: 125 primary school teachers from different communities answered the Knowledge of Attention Deficit Hyperactivity Disorder Scale (KADDS). RESULTS: The teachers answered fewer than half the items correctly, the symptoms and diagnosis subscale being the one where they were seen to be most knowledgeable. Teachers who had had children with ADHD in class displayed greater knowledge in the areas of general information and treatment, but less on the symptoms and diagnosis subscale. 32.8% of the teachers reported feeling somewhat or totally unable to teach children with ADHD in an effective way and recommend special education as a better educational style. Teachers with specific training in ADHD obtained better scores than those who had not received such instruction. CONCLUSION: Teachers with training in ADHD are more knowledgeable and more confident about their abilities when it comes to teaching children with ADHD. PMID- 29516466 TI - [XX Congreso Internacional de Actualizacion en Trastornos del Neurodesarrollo. Posters]. PMID- 29516465 TI - [Adaptive behaviour and learning in children with neurodevelopmental disorders (autism spectrum disorders and attention deficit hyperactivity disorder). Effects of executive functioning]. AB - INTRODUCTION: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) present difficulties in adaptive functioning and learning, possibly associated with failures in executive functioning characteristic of both disorders. AIM: To analyze the impact of executive functioning in the adaptive behaviors of socialization and daily life and in learning behaviors in children with ASD and children with ADHD. SUBJECTS AND METHODS: The participants were 124 children matched in age and intellectual quotient: 37 children with typical development, 52 children with ASD and 35 children with ADHD. Parents reported on their children's adaptive behaviors, while teachers provided information on learning behaviors and executive functioning in daily life. RESULTS: There are significant differences between the groups with ASD and ADHD with the typical development group in all domains evaluated. In addition, the group with ASD had worse socialization skills while persistence in learning was more affected in children with ADHD. Finally, the metacognitive index of executive functioning predicted the socialization and persistence of children with ASD. On the other hand, the index of behavioral regulation and the educational level of the parents predicted the socialization skills in children with ADHD. CONCLUSIONS: The results highlight the need to include differentiated executive strategies in the intervention of children with ASD and children with ADHD. PMID- 29516467 TI - From Learning Beliefs to Achievement Among Chinese Immigrant and European American Preschool Children. AB - Little research exists on how immigrant children develop their beliefs about school learning (BASLs) in their home and host cultures. We examined the BASLs and achievement children of Chinese immigrants' (CCI) and European American (EA) children. We followed longitudinally 120 middle-class children from age 4 to 5, balanced for gender. Children heard two story beginnings depicting a child eager to attend school and another not. Children completed the stories and were tested for math and literacy achievement. We found seven BASLs. CCIs and EAs showed similar BASLs. Awareness of parental involvement and intellectual benefit consistently explained their achievement, with CCIs showing greater achievement. CCIs' (but not EAs') valuation of learning explained their net academic growth. Implications on CCIs' development are discussed. PMID- 29516468 TI - Content of Care in 15,000 Sick Child Consultations in Nine Lower-Income Countries. AB - OBJECTIVE: Describe content of clinical care for sick children in low-resource settings. DATA SOURCES: Nationally representative health facility surveys in Haiti, Kenya, Malawi, Namibia, Nepal, Rwanda, Senegal, Tanzania, and Uganda from 2007 to 2015. STUDY DESIGN: Clinical visits by sick children under 5 years were observed and caregivers interviewed. We describe duration and content of the care in the visit and estimate associations between increased content and caregiver knowledge and satisfaction. PRINCIPAL FINDINGS: The median duration of 15,444 observations was 8 minutes; providers performed 8.4 of a maximum 24 clinical actions per visit. Content of care was minimally greater for severely ill children. Each additional clinical action was associated with 2 percent higher caregiver knowledge. CONCLUSIONS: Consultations for children in nine lower-income countries are brief and limited. A greater number of clinical actions was associated with caregiver knowledge and satisfaction. PMID- 29516469 TI - Children with sickle cell disease: the case for developmental screening. PMID- 29516470 TI - Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 1. AB - OBJECTIVE: To review the scope of the problem facing individuals with migraine who are under- or uninsured. In this first of a 2-part narrative review, we will explore migraine epidemiology and the challenges that face this vulnerable population. BACKGROUND: Implementation of the Affordable Care Act has improved access to health care for many individuals who were previously uninsured, but there are many, particularly those of certain demographics, who are at high risk for worse outcomes. METHODS: A narrative review was performed after a series of discussions within the Underserved Populations in Headache Medicine Special Interest Section meetings of the American Headache Society. Literature was reviewed for key concepts underpinning conceptual boundaries and a broad overview of the subject matter. Published guidelines, state-specific Medicaid websites, headache quality measurement set, literature review, and expert opinion were used to tailor suggested treatment options and therapeutic strategies. RESULTS: Migraine is common, yet remains underdiagnosed and associated with worse outcomes among those of under-represented backgrounds and those who are underinsured or uninsured. Low socioeconomics may play an important role in the disease progression, characteristics, outcome, and quality of life of patients with migraine and other headache disorders. Other barriers to optimal care include time constraints, lack of access to specialty providers, transportation, and financial limitations. CONCLUSION: There are many barriers and challenges that affect people with migraine who are underinsured or uninsured, particularly those of under-represented racial backgrounds and of lower socioeconomic status. PMID- 29516471 TI - The effect of a major earthquake experienced during the first trimester of pregnancy on the risk of preterm birth. AB - BACKGROUND: On 22 February 2011 an earthquake (magnitude 6.3) hit Christchurch, New Zealand. Earthquakes have been associated with increased risks of preterm birth (PTB) and other adverse pregnancy outcomes. However, the literature on this subject is scarce. Maternal antenatal stress has been suggested as the link between earthquakes and PTB. In this study the Christchurch earthquake was utilised as a model of maternal stress to assess its effects on PTB rates and other pregnancy outcomes. AIM: To investigate whether women who experienced a major earthquake during the first trimester of pregnancy were at an altered risk of PTB compared to women who did not experience an earthquake during their pregnancy. METHODS: This was a retrospective cohort study. Women carrying a singleton pregnancy in their first trimester on 22 February, 2011 were identified for a post-earthquake cohort (n = 1057). A group of women pregnant in 2009 were identified for a pre-earthquake cohort (n = 1314). Data were obtained from electronic medical records and the hospital clinical coding database. Chi-square test, Fisher's exact test and Wilcoxon rank sum test were used to analyse differences in pregnancy outcomes. Statistically significant variables together with earthquake exposure were assessed as risk factors for PTB using a multivariate logistic regression model. RESULTS: No significant difference in the rate of PTB was found between the two groups P > 0.05). CONCLUSION: Women carrying a singleton pregnancy in this study who experienced a major earthquake in their first trimester do not seem to be at an increased risk of PTB. PMID- 29516472 TI - Goal-Directed Correlates and Neurobiological Underpinnings of Adolescent Identity: A Multimethod Multisample Longitudinal Approach. AB - This multimethod multisample longitudinal study examined how neurological substrates associated with goal directedness and information seeking are related to adolescents' identity. Self-reported data on goal-directedness were collected across three biannual waves in Study 1. Identity was measured one wave later. Study 1 design and measurements were repeated in Study 2 and extended with structural brain data (nucleus accumbens [NAcc] and prefrontal cortex gray matter volume [PFC]), collected across three biannual waves. Study 1 included 497 adolescents (Mage T1 = 13.03 years) and Study 2 included 131 adolescents (Mage T1 = 14.69 years). Using latent growth curve models, goal directedness, NAcc, and PFC volume predicted a stronger identity one wave later. These findings provide crucial new insights in the underlying neurobiological architecture of identity. PMID- 29516474 TI - The associations between psychological stress and psoriasis: a systematic review. AB - Psoriasis is estimated to affect around 2-3% of the general population. More than one-third of Australians report having a significant level of distress in their daily lives. Psychological stress has long been shown to play an important role in the natural history of psoriasis, but the details of this relationship remain to be clearly defined. We performed a systematic review of the literature with the aim of determining whether there is a temporal association between psychological stress as the predictor and onset and/or exacerbation of psoriasis as the outcome measure. Our secondary aim was to establish whether there is a relationship between the degree of psychological stress and clinical severity of psoriasis. Our systematic review demonstrates a probable temporal association between different measures of psychological stress and onset, recurrence, and severity of psoriasis. In the light of this, we suggest clinicians include "stress" as a trigger factor in their psoriasis assessment and consider psychological interventions as adjuncts, particularly in those who identify as "stress-responders". PMID- 29516473 TI - Provision of respiratory support compared to no respiratory support before cord clamping for preterm infants. AB - BACKGROUND: Placental transfusion (by means of delayed cord clamping (DCC), cord milking, or cord stripping) confers benefits for preterm infants. It is not known if providing respiratory support to preterm infants before cord clamping improves outcomes. OBJECTIVES: To assess the efficacy and safety of respiratory support provided during DCC compared with no respiratory support during placental transfusion (in the form of DCC, milking, or stripping) in preterm infants immediately after delivery. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL, 2017, Issue 5), MEDLINE via PubMed (1966 to 19 June 2017), Embase (1980 to 19 June 2017), and CINAHL (1982 to 19 June 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: Randomized, cluster randomized, or quasi-randomized controlled trials enrolling preterm infants undergoing DCC, where one of the groups received respiratory support before cord clamping and the control group received no respiratory support before cord clamping. DATA COLLECTION AND ANALYSIS: All review authors assisted with data collection, assessment, and extraction. Two review authors assessed the quality of evidence using the GRADE approach. We contacted study authors to request missing information. MAIN RESULTS: One study fulfilled the review criteria. In this study, 150 preterm infants of less than 32 weeks' gestation undergoing 60 second DCC were randomized to a group who received respiratory support in the form of continuous positive airway pressure (CPAP) or positive pressure ventilation during DCC and a group that did not receive respiratory support during the procedure. Mortality during hospital admission was not significantly different between groups with wide confidence intervals (CI) for magnitude of effect (risk ratio (RR) 1.67, 95% CI 0.41 to 6.73). The study did not report neurodevelopmental disability and death or disability at two to three years of age. There were no significant differences between groups in condition at birth (Apgar scores or intubation in the delivery room), use of inotropic agents (RR 1.25, CI 0.63 to 2.49), and receipt of blood transfusion (RR 1.03, 95% CI 0.70 to 1.54). In addition, there were no significant differences in the incidences of any intraventricular haemorrhage (RR 1.50, 95% CI 0.65 to 3.46) and severe intraventricular haemorrhage (RR 1.33, 95% CI 0.31 to 5.75). Several continuous variables were reported in subgroups depending on method of delivery. Unpublished data for each group as a whole was made available and showed peak haematocrit in the first 24 hours and duration of phototherapy did not differ significantly. Overall, the quality of evidence for several key neonatal outcomes (e.g. mortality and intraventricular haemorrhage) was low because of lack of precision with wide CIs. AUTHORS' CONCLUSIONS: The results from one study with wide CIs for magnitude of effect do not provide evidence either for or against the use of respiratory support before clamping the umbilical cord. A greater body of evidence is required as many of the outcomes of interest to the review occurred infrequently. Similarly, the one included study cannot answer the question of whether the intervention is or is not harmful. PMID- 29516475 TI - Psoriasis and subclinical atherosclerosis in a Chinese population. PMID- 29516476 TI - Reliable estimates of beta diversity with incomplete sampling. AB - Beta diversity, the compositional variation among communities or assemblages, is crucial to understanding the principles of diversity assembly. The mean pairwise proportional dissimilarity expresses overall heterogeneity of samples in a data set and is among the most widely used and most robust measures of beta diversity. Obtaining a complete list of taxa and their abundances requires substantial taxonomic expertise and is time consuming. In addition, the information is generally incomplete due to sampling biases. Based on the concept of the ecological significance of dominant taxa, we explore whether determining proportional dissimilarity can be simplified based on dominant species. Using simulations and six case studies, we assess the correlation between complete community compositional data and reduced subsets of a varying number of dominant species. We find that gross beta diversity is usually depicted accurately when only the 80th percentile or five of the most abundant species of each site is considered. In data sets with very high evenness, at least the 10 most abundant species should be included. Focusing on dominant species also maintains the rank order of beta diversity among sites. Our new approach will allow ecologists and paleobiologists to produce a far greater amount of data on diversity patterns with less time and effort, supporting conservation studies and basic science. PMID- 29516477 TI - CBT for Pediatric Migraine: A Qualitative Study of Patient and Parent Experience. AB - OBJECTIVE: The goal of this study was to determine which cognitive behavioral therapy (CBT-HA) treatment components pediatric headache patient stakeholders would report to be most helpful and essential to reducing headache frequency and related disability to develop a streamlined, less burdensome treatment package that would be more accessible to patients and families. BACKGROUND: Pediatric migraine is a prevalent and disabling condition. CBT-HA has been shown to reduce headache frequency and related disability, but may not be readily available or accepted by many migraine sufferers due to treatment burden entailed. Research is needed to determine systematic ways of reducing barriers to CBT-HA. METHODS: Qualitative interviews were conducted with 10 patients and 9 of their parents who had undergone CBT-HA. Interviews were analyzed using an inductive thematic analysis approach based upon modified grounded theory. Patients were 13-17.5 years of age (M = 15.4, SD = 1.63) and had undergone CBT-HA ~1-2 years prior to participating in the study. RESULTS: Overall, patients and their parents reported that CBT-HA was helpful in reducing headache frequency and related disability. Although patients provided mixed reports on the effectiveness of different CBT-HA skills, the majority of patients indicated that the mind and body relaxation skills of CBT-HA (deep breathing, progressive muscle relaxation, and activity pacing in particular) were the most helpful and most frequently used skills. Patients and parents also generally reported that treatment was easy to learn, and noted at least some aspect of treatment was enjoyable. CONCLUSIONS: Results from these qualitative interviews indicate that mind and body CBT-HA relaxation skills emerged as popular and effective based on patient and parent report. Future research examining the effectiveness of streamlined pediatric migraine nonpharmacological interventions should include these patient-preferred skills. PMID- 29516478 TI - Mycobacterium gordonae-associated skin infection in an immunocompetent patient. PMID- 29516479 TI - Protein Detection in Gels Using Fixation. AB - The most commonly used types of gels for separating proteins are SDS gels, either in a 1-D format or as the second dimension of various 2-D separations, and the most common methods of visualizing proteins in these gels use protein binding dyes after fixing the proteins in the gel matrix. In recent years, there has been a continuing trend away from preparing staining solutions in the laboratory to using commercially available kits, which are convenient, save time, have defined shelf lives, and may provide greater reproducibility than stains formulated in research laboratories. In general, when using commercial kits, satisfactory results can be readily obtained by following the manufacturer's protocols. This unit reviews commonly used fixation-based stains and provides a number of manual formulations with staining protocols for those who prefer such staining methods. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516480 TI - BioID: A Screen for Protein-Protein Interactions. AB - BioID is a unique method to screen for physiologically relevant protein interactions that occur in living cells. This technique harnesses a promiscuous biotin ligase to biotinylate proteins based on proximity. The ligase is fused to a protein of interest and expressed in cells, where it biotinylates proximal endogenous proteins. Because it is a rare protein modification in nature, biotinylation of these endogenous proteins by BioID fusion proteins enables their selective isolation and identification with standard biotin-affinity capture. Proteins identified by BioID are candidate interactors for the protein of interest. BioID can be applied to insoluble proteins, can identify weak and/or transient interactions, and is amenable to temporal regulation. Initially applied to mammalian cells, BioID has potential application in a variety of cell types from diverse species. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516481 TI - Overview of the Baculovirus Expression System. AB - This unit provides information on the replication cycle of insect baculovirus to provide an understanding of how this virus has been adapted for use as an expression vector for recombinant proteins in insect cells. We provide an overview of the virus structure and its unique bi-phasic replication cycle, which has been exploited in developing the virus as an expression vector. We also review the development of the baculovirus expression vector system (BEVS), from the mid-1980s to the present day in which the BEVS is now an established tool for the production of a range of recombinant proteins and multi-protein complexes including virus-like particles. We describe advances made to the BEVS to allow the rapid and easy production of recombinant viruses and developments to improve protein yield. We finish by describing the application of recombinant BacMam as vectors for the delivery of genes into mammalian and human cells. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516483 TI - A Convenient Split-Intein Tag Method for the Purification of Tagless Target Proteins. AB - In this work, we describe a novel self-cleaving tag technology based on a highly modified split-intein cleaving element. In this system, the N-terminal segment of an engineered split intein is expressed in E. coli and covalently immobilized onto a capture resin, while the smaller C-terminal intein segment is fused to the N-terminus of the desired target protein. The tagged target can then be expressed in an appropriate expression system, without concern for premature intein cleaving. During the purification, strong association between the intein segments effectively captures the tagged target onto the capture resin while simultaneously generating a cleaving-competent intein complex. Once the complex is purified by washing the column, intein-mediated cleavage and release of the tagless target is induced with a simple shift in buffer pH from 8.5 to 6.2. The result is a convenient and effective method for the purification of traceless and tagless target proteins, which can be used in characterization and functional studies. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516482 TI - Generation of High-Specificity Antibodies against Membrane Proteins Using DNA Gold Micronanoplexes for Gene Gun Immunization. AB - Membrane proteins are the molecular interface of the cell and its environs; however, studies of membrane proteins are highly technically challenging, mainly due to instability of the isolated protein. Towards the production of antibodies that recognize properly folded and stabilized forms of membrane protein antigen, we describe a DNA-based immunization method for mice that expresses the antigen in the membranes of dendritic cells, thus allowing direct presentation to the immune system. This genetic immunization approach employs a highly efficient method of biolistic delivery based on DNA-gold micronanoplexes, which are complexes of micron-sized gold particles that allow dermal penetration and nanometer-sized gold particles that provide a higher surface area for DNA binding than micron gold alone. In contrast to antibodies derived from immunizations with detergent-solubilized protein or with protein fragments, antibodies from genetic immunization are expected to have a high capacity for binding conformational epitopes and for modulating membrane protein activity. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516484 TI - Protein Production Using the Baculovirus Expression System. AB - Baculovirus expression systems are well established as an easy and reliable way to produce high quality recombinant proteins. Baculoviruses can also be used to transduce mammalian cells, termed 'BacMam', with considerable potential in biomedical applications. This chapter explains the process of making a recombinant baculovirus, encompassing production of a recombinant virus by homologous recombination in insect cells, followed by amplification and titration of the virus-all steps needed before commencing gene expression and protein production. We also cover the use of small-scale test expression to provide an initial indication of quality and protein yield. Whereas proteins expressed at high levels can be directly scaled up, more challenging proteins may require optimization of cell lines, growth conditions, or harvest times. Scale-up and purification approaches are discussed, focusing on working with large shake cultures and use of the Wave bioreactor. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516485 TI - Enrichment of Methylated Peptides Using an Antibody-free Approach for Global Methylproteomics Analysis. AB - Protein methylation is receiving increasing attention for its important role in regulating diverse biological processes, including epigenetic regulation of gene transcription, RNA processing, DNA damage repair, and signal transduction. Proteome level analysis of protein methylation requires the enrichment of various forms of methylated peptides. Unfortunately, immunoaffinity purification can only enrich a subset of them due to the lack of pan-specific antibodies. Chromatography-based methods, however, can enrich methylated peptides in a global manner. Here we present a chromatography-based approach for highly efficient enrichment of methylated peptides. Protocols for the of high pH SCXtip preparation and methyl-peptide purification are described in detail. Key points such as cell culture in hM-SILAC medium and protein digestion by multiple endopeptidases are also presented. This technique allows the simultaneous analysis of both lysine and arginine methylation and improved performance for methyl-arginine identification. (c) 2018 by John Wiley & Sons, Inc. PMID- 29516486 TI - Opioid-Induced "Likeability" and "Feeling Good" Are Not Associated With Return Visits to an ED Among Migraine Patients Administered IV Hydromorphone. AB - BACKGROUND: Parenteral opioids are used in more than 50% of emergency department (ED) visits for migraine. Use of opioids for migraine has been associated with subsequent ED visits, perhaps because of opioid-induced euphoria. In this study, we quantify the extent to which nontherapeutic effects of opioids influence migraine outcomes. We hypothesized that "feeling good" and medication likeability would in fact be associated with receipt of opioids (rather than relief of migraine pain) and that receipt of opioids (rather than relief of migraine pain) would be associated with return visits to the ED. METHODS: During an ED-based clinical trial, migraine patients were randomized to receive hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg IV. Thirty minutes after medication administration, we asked, (1) How much did you like the medication you received? and (2) How good did the medication make you feel? Participants were asked to provide answers on a 0-10 scale. We also determined 0-10 pain scores at baseline and 1 hour and number of return visits for headache during the subsequent month. RESULTS: Sixty-three patients received prochlorperazine and 64 hydromorphone. Prochlorperazine pain scores improved by 6.8 (SD: 2.6), hydromorphone by 4.7 (SD: 3.3) (95%CI for difference of 2.1: 1.0, 3.2). On the 0 10 likeability scale, prochlorperazine patients reported a mean of 7.2 (SD: 2.8), hydromorphone 6.9 (SD: 2.9) (95% CI for difference of 0.3: -0.7, 1.3). On the 0 10 feeling good scale, prochlorperazine patients reported a mean of 7.5 (SD: 2.3), hydromorphone 6.8 (SD: 2.8) (95%CI: for difference of 0.7: -0.2, 1.6). In the hydromorphone group, 8/57 (14%, 95%CI: 7, 26%) returned to the ED vs 5/63 (8%, 95%CI: 3,18%) in the prochlorperazine group. In regression modeling, feeling good was independently associated with pain relief (P < .01) but not with medication received (P = .67) or return visits (P = .12). Similarly, medication likeability was independently associated with pain relief (P < .01) but not medication received (P = .12) or return visits (P = .16). CONCLUSION: We did not detect an association between hydromorphone and medication likeability, feeling good, or return visits to the ED. Headache relief was associated with medication likeability and feeling good. PMID- 29516487 TI - Diagnosing diabetes mellitus in patients with porphyria cutanea tarda. AB - The prevalence of diabetes mellitus is increased in patients with porphyria cutanea tarda. Different tests are available for diagnosing and screening for type II diabetes mellitus, however choosing the most suitable test is challenging. The pitfalls in the different tests along with the interfering comorbidities and treatments concerning patients with porphyria cutanea tarda complicate diagnosing these patients with diabetes mellitus. HbA1c, fasting glucose, or oral glucose tolerance are the current available tests, with HbA1c as first choice. Measuring HbA1c requires no fasting, however HbA1c can be false low if the patient is treated with phlebotomy or has liver cirrhosis or chronic hepatitis. Instead fasting glucose and oral glucose tolerance tests can be used if the patient is not acutely ill. If either of the tests give a result in the diagnostic range, the test should be repeated if the patient has no clinical symptoms of diabetes. Diagnosing diabetes mellitus is important for the purpose of early intervention, and this review provides the knowledge needed to diagnose this special patient group properly. PMID- 29516489 TI - SARS 2018 Meeting Abstracts. PMID- 29516488 TI - Melanocyte abnormalities and senescence in the pathogenesis of idiopathic guttate hypomelanosis. AB - BACKGROUND: Idiopathic guttate hypomelanosis (IGH) is a pigmentary disorder of unknown pathogenesis characterized by small discrete white macules. In the skin, epidermal melanin unit between melanocytes and keratinocytes is responsible for melanin synthesis and equal distribution of melanin pigment. OBJECTIVE: Therefore, this study was designed to check the role of melanocytes in the pathogenesis of IGH. METHODS: For this study, six IGH patients and six controls were enrolled. Melanin content was checked in the skin sections and in the cultured melanocytes. Senescence was checked in the lesional skin of IGH patients by comparing the mRNA and protein expression of senescence markers p16, hp1, and p21. RESULTS: Cultured melanocytes from the IGH patients showed morphological changes in comparison to the control melanocytes. Melanocytes from IGH patients were bigger in size with very small and retracted dendrites as compared to the control melanocytes. Melanin accumulation was more in the IGH patients as compared to the controls. Our results showed that expression of p16, p21, and hp1 was significantly higher in lesional skin of IGH patient as compared to healthy controls. CONCLUSION: This study revealed large-sized melanocytes with small and retracted dendrites in IGH patients. Accumulation of more melanin in the IGH melanocytes might be due to problem in the transfer of melanin from melanocytes to keratinocytes. Accumulation of melanin can lead to the senescence in the melanocytes of IGH patients. PMID- 29516490 TI - The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome. AB - Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure. This pharmacokinetic-pharmacodynamic (PK PD) relationship was able to be quantified and adequately described with a mathematical model. The findings confirm a previous PK model of buprenorphine and extend the model to describe the PK of norbuprenorphine and to identify a novel PK-PD relationship of buprenorphine in NAS. This model will allow optimization of dosing strategies in future clinical trials. PMID- 29516491 TI - Orbital Pain, Ophthalmoplegia, and Oligoclonal Bands in the Cerebrospinal Fluid: A Case Report of Tolosa-Hunt Syndrome. PMID- 29516492 TI - A note on monotonicity of item response functions for ordered polytomous item response theory models. AB - A monotone relationship between a true score (tau) and a latent trait level (theta) has been a key assumption for many psychometric applications. The monotonicity property in dichotomous response models is evident as a result of a transformation via a test characteristic curve. Monotonicity in polytomous models, in contrast, is not immediately obvious because item response functions are determined by a set of response category curves, which are conceivably non monotonic in theta. The purpose of the present note is to demonstrate strict monotonicity in ordered polytomous item response models. Five models that are widely used in operational assessments are considered for proof: the generalized partial credit model (Muraki, 1992, Applied Psychological Measurement, 16, 159), the nominal model (Bock, 1972, Psychometrika, 37, 29), the partial credit model (Masters, 1982, Psychometrika, 47, 147), the rating scale model (Andrich, 1978, Psychometrika, 43, 561), and the graded response model (Samejima, 1972, A general model for free-response data (Psychometric Monograph no. 18). Psychometric Society, Richmond). The study asserts that the item response functions in these models strictly increase in theta and thus there exists strict monotonicity between tau and theta under certain specified conditions. This conclusion validates the practice of customarily using tau in place of theta in applied settings and provides theoretical grounds for one-to-one transformations between the two scales. PMID- 29516493 TI - Live-cell imaging of new polyene sterols for improved analysis of intracellular cholesterol transport. AB - Analysis of intracellular cholesterol transport by fluorescence microscopy requires suitable fluorescent analogues of cholesterol. Most existing cholesterol analogues contain lipophilic dyes which can compromise the sterol properties in membranes. An alternative strategy is to introduce additional double bonds into the sterol ring system resulting in intrinsic fluorescence, while at the same time keeping the cholesterol-like properties of the analogues. Existing polyene sterols, such as dehydroergosterol (DHE) or cholestatrienol (CTL), however, contain only three double bonds and suffer from low brightness, significant photobleaching and excitation/emission in the ultraviolet region. Thus, special equipment is required to image such sterols. Here, we describe synthesis, characterization and intracellular imaging of new polyene sterols containing four conjugated double bonds in the sterol ring system. We show that such analogues have red-shifted excitation and emission by ~20 nm compared to DHE or CTL. The red shift was even more pronounced when preventing keto-enol tautomer equilibration by protecting the 3'-hydroxy group with acetate. We show that the latter analogue can be imaged on a conventional wide field microscope with a DAPI/filipin filter cube. The new polyene sterols show reduced photobleaching compared to DHE or CTL allowing for improved deconvolution microscopy of sterol containing cellular membranes. PMID- 29516494 TI - Comparison of tissue deterioration of ripening banana fruit (Musa spp., AAA group, Cavendish subgroup) under chilling and non-chilling temperatures. AB - BACKGROUND: In fleshy fruits, induced programmed cell death (PCD) has been observed in heat-treated tomato, and in ethylene-treated and low-temperature exposure in immature cucumber. No other fleshy fruit has been evaluated for chilling-injury-induced PCD, especially mature fruit with full ripening capacity. The purpose of this research was to identify and evaluate the presence of PCD processes during the development of low-temperature-induced physiopathy of banana fruit. RESULTS: Exposure of fruit to 5 degrees C for 4 days induced degradative processes similar to those occurring during ripening and overripening of non chilled fruit. Nuclease from banana peel showed activity in both DNA substrates and RNA substrates. No exclusive low-temperature-induced proteases and nucleases were observed. DNA of chilled peel showed earlier signs of degradation and higher levels of DNA tailing during overripening. CONCLUSION: This study shows that exposure to low temperatures did not induce a pattern of degradative processes that differed from that occurring during ripening and overripening of non-chilled fruit. DNA showed earlier signs of degradation and higher levels of DNA tailing. Nuclease activity analysis showed bifunctionality in both chilled and non-chilled tissue and no chilling-exclusive protease and nuclease. Fleshy fruit might use their available resources on degradative processes and adjust them depending on environmental conditions. (c) 2018 Society of Chemical Industry. PMID- 29516495 TI - HLA-DRB1*09:01 allele is associated with anti-E immunization in a Chinese population. AB - BACKGROUND: Anti-E is the most common and important RBC alloantibody in the Chinese population. Several studies have demonstrated that the production of specific RBC alloantibodies is associated with HLA-DRB1 polymorphisms. Considering that the Chinese population has its own unique characteristics of HLA DRB1 polymorphisms, we investigate whether specific HLA-DRB1 alleles are associated with E immunization in a Chinese population. STUDY DESIGN AND METHODS: The frequencies of HLA-DRB1 phenotypes were compared among 78 patients possessing anti-E and 192 healthy blood donors. HLA-DRB1 genotyping was carried out using sequence-based typing method. The TEPITOPEpan software was used to predict E antigen-derived anchor peptides binding to HLA-DRB1 molecules. RESULTS: The frequency of HLA-DRB1*09:01 phenotype was significantly higher in the patients with anti-E than in healthy controls: 76.9% versus 27.6% (odds ratio, 8.7; 95% confidence interval, 4.7-16.2; corrected p value < 0.0034). One E antigen-derived anchor peptide (217WMFWPSVNS225) was predicted to bind three HLA-DRB1 molecules (HLA-DRB1*04:05, *04:17, and *13:02); however, no anchor peptide was predicted to bind HLA-DRB1*09:01. CONCLUSION: This study indicated that HLA-DRB1*09:01 phenotype was significantly more prevalent in E-immunized patients than the control group. It suggested that HLA-DRB1*09:01 molecule might represent a susceptibility phenotype enhancing formation of anti-E alloantibody. Further study would be necessary to identify the anchor peptide responsible for E alloimmunization by stimulation of specific T cells by peptide originating from E antigen. PMID- 29516497 TI - Platelet transfusion is not associated with increased mortality or morbidity in patients undergoing cardiac surgery. AB - BACKGROUND: Transfusion of platelets is common in cardiac surgery, and while there are guidelines for their use, there are concerns about potential risks. We aimed to assess the impact of platelet transfusion on mortality, thrombosis, and infection in this patient group. STUDY DESIGN AND METHODS: A retrospective cohort study of all patients at St Vincent's Hospital Melbourne who underwent a first cardiac surgery procedure from June 2001 to June 2014 was conducted. A propensity weighted analysis was performed to examine the association between intraoperative platelet transfusion and outcomes. RESULTS: A total of 5233 patients met inclusion criteria, and 531 (10.15%) received intraoperative platelet transfusion (median two platelet doses, interquartile range, 1-17). Patients receiving platelets were older, had higher body mass index, lower rates of diabetes and dyslipidemia, higher rates of infective endocarditis, recent myocardial infarction and unstable angina, and exposure to aspirin or clopidogrel. On univariable analysis, platelet transfusion was associated with increased 30-day mortality (2.4% vs. 10.55%, p < 0.001), return to theatre for bleeding (3.23% vs. 13.37%, p < 0.001), and rates of any infection (9.26% vs. 19.17%, p < 0.001). After adjusting for confounders, platelet transfusion was not associated with increased risk of 30-day mortality or infective complications. Platelet transfusion was associated with higher rates of return to theatre (relative risk [RR], 2.46; confidence interval [CI], 1.42, 4.04; p = 0.001) and decreased risk of thromboembolic events (RR, 0.28; CI, 0.15, 0.51; p < 0.001). CONCLUSION: Platelet transfusion was not associated with increased mortality or infective complications following first cardiac surgery. Further prospective studies are required to identify patients most likely to benefit from platelet transfusion. PMID- 29516496 TI - Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation. AB - KEY POINTS: Maternal obesity (MO) and exposure to a high-fat, high-simple carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life. Underlying molecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods. There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. ABSTRACT: Maternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life course health outcomes. Little is known about the molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high-fat, high-fructose diet. Unbiased gene and microRNA (small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by the Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/beta-catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the non-human primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential microRNA epigenetic regulators of metabolic disruption. PMID- 29516498 TI - Nitidine chloride inhibits proliferation and induces apoptosis in ovarian cancer cells by activating the Fas signalling pathway. AB - OBJECTIVES: To explore the apoptotic effects and underlying mechanisms of nitidine chloride (NC) in epithelial ovarian cancer. METHODS: The MTT cell proliferation assay was used to detect the inhibitory effects of different concentrations of NC (0, 0.3125, 0.625, 1.25, 2.5, 5 and 10 MUg/ml) in SKOV3 ovarian carcinoma cells. The number of apoptotic cells was observed by Hoechst staining and measured by flow cytometry. Quantitative PCR was used to measure the expression of Fas, Fas-associated death domain-containing protein (FADD), caspase 8 and caspase-3. RNA interference (RNAi) was used to determine whether caspase-8 played an important role in NC-induced apoptosis. KEY FINDINGS: Nitidine chloride inhibited the proliferation of SKOV3 cells (IC50 = 2.317 +/- 0.155 MUg/ml) after 24 h of treatment and induced apoptosis (15.9-64.3%). Compared with the control group, a significant increase in Fas, FADD, caspase-8 and caspase-3 gene expression was observed in the NC-treated groups (P < 0.05). After silencing caspase-8 by RNAi, the antiproliferative activity and pro-apoptotic activity of NC in SKOV3 cells decreased (P < 0.05). CONCLUSIONS: Our study showed that NC induced apoptosis in SKOV3 cells by activating the Fas signalling pathway, and caspase-8 played an important role in this process. PMID- 29516499 TI - MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream regulated gene family members in adrenocortical cancer. AB - Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using bioinformatics predictions and mRNA/miRNA expression profiles, we performed an integrated analysis to identify inversely correlated miRNA-mRNA pairs in ACC. We identified N-myc downstream regulated gene family members 2 and 4 (NDRG2 and NDRG4) as targets of miR-483-5p and miR-139-5p, respectively. NDRG2 and NDRG4 expressions were inversely correlated respectively with miR-483-5p and miR-139-5p levels in aggressive ACC samples from two independent cohorts of 20 and 44 ACC. Moreover, upregulation of miR-139-5p and downregulation of NDRG4 demonstrated a striking prognostic value. A direct interaction between miR-483-5p or miR-139-5p and their targets was demonstrated in reporter assays. Downregulation of miR-483-5p or miR-139-5p in the ACC cell lines NCI-H295R and SW13 increased NDRG2 or NDRG4 mRNA and protein expression, compromised adrenocortical cancer cell invasiveness and anchorage independent growth. MiR-483-5p or miR-139-5p overexpression and NDRG2 or NDRG4 inhibition produce similar changes, which are rescued by NDRG2 or NDRG4 ectopic expression. We established that key factors mediating epithelial-to-mesenchymal transition are downstream effectors of miR-483-5p/NDRG2 and miR-139-5p/NDRG4 pathways. Collectively, our data show for the first time that miR-483-5p/NDRG2 and miR-139-5p/NDRG4 axes promote ACC aggressiveness, with potential implications for prognosis and therapeutic interventions in adrenocortical malignancies. PMID- 29516500 TI - Application of a glass fertilizer in sustainable tomato plant crops. AB - BACKGROUND: Glass frits with a P2 O5 /K2 O ratio equal to 0.65 and different concentrations of SiO2 (6.5-56.0 wt%), CaO (0-5.1 wt%) and Al2 O3 (0-14.6 wt%) have been prepared and analysed as potential glass fertilizers (GF). RESULTS: P2 O5 and K2 O were leached primarily within the first 5 days but the total amount was dependent on the SiO2 /Al2 O3 ratio of the glass frit. Sustained P2 O5 and K2 O leaching for more than 40 days could be obtained if the glass frit contained more than 7% Al2 O3 . A final glass frit composition (29% SiO2 , 5% CaO, 7% Al2 O3 , 30% P2 O5 , 25% K2 O) was selected and used in an experimental tomato crop of 1 ha area, where one half was fertilized with an NPK conventional fertilizer and the other half with the GF fertilizer. CONCLUSION: After harvesting the tomato crops, the GF fertilizer was found to result in a higher yield than the NPK conventional fertilizer: 59980 kg and 74 360 kg for NKP and GF, respectively. The general characteristics of the harvested tomato fruits and leaves were similar in the two cases and the differences fell within statistical error. No differences in any of the soil characteristics were detected as a result of the use of GF. (c) 2018 Society of Chemical Industry. PMID- 29516501 TI - The Emotion Mapping Activity: Preliminary evaluation of a mindfulness-informed exercise to improve emotion labeling in alexithymic persons. AB - Alexithymia is a psychoemotional trait associated with many treatment-resistant psychological and social difficulties. Research suggests that these difficulties stem primarily from an inability to appropriately apply linguistic labels to emotional experiences and content. The present research introduces and preliminarily evaluates a novel mindfulness-informed exercise to improve emotion labeling ability in alexithymic persons. Based in culturally universal patterns of somatic experience, the Emotion Mapping Activity (EMA) directs alexithymic persons to reflect on their internal, somatic experiences as a source of information for interpreting and labeling emotional experiences. In the present study, 67 alexithymic persons completed a series of emotion-labeling tasks either with or without assistance of the EMA. Results suggest that completion of the EMA may improve ability to label emotions that would be otherwise misinterpreted - without interfering with labeling that is already intact. Though further research is necessary, the present study suggests that the EMA may hold the potential to be incorporated into psychotherapy protocols as an exercise for improving emotion labeling ability in alexithymic clients. PMID- 29516502 TI - Characterization of large basking shark Cetorhinus maximus aggregations in the western North Atlantic Ocean. AB - Cetorhinus maximus aggregations recorded during extensive aerial survey efforts off the north-eastern United States between 1980 and 2013 included aggregations centring on sightings with group sizes of at least 30 individuals. These aggregations occurred in summer and autumn months and included aggregation sizes of up to 1398 individuals, the largest aggregation ever reported for this species. The aggregations were associated with sea surface temperatures of 13-24 degrees C and chlorophyll-a concentrations of 0.4-2.6 mg m-3 and during one aggregation, a high abundance of zooplankton prey was present. Photogrammetric tools allowed for the estimation of total body lengths ranging between 4 and 8 m. Characterization of these events provides new insight into the potential biological function of large aggregations in this species. PMID- 29516503 TI - Blood product transfusion and wastage rates in obstetric hemorrhage. AB - BACKGROUND: Bleeding emergencies can complicate pregnancies. Understanding the disposition of the products that are issued in this clinical setting can help inform inventory levels at hospitals where obstetric patients are seen. STUDY DESIGN AND METHODS: Patients who had an obstetric hemorrhage of any etiology between January 2013 and June 2017, and whose resuscitation began with uncrossmatched red blood cells (RBCs) or emergency-issued plasma or platelets (PLT), were included. The disposition of all blood products issued within 6 hours of the first uncrossmatched or emergency-issued product was documented, as was basic patient demographic information. RESULTS: In total, 301 women with an obstetric hemorrhage from seven academic institutions were identified. Their mean +/- standard deviation age was 30.9 +/- 6.1 years, 45.2% delivered by Cesarean section, and 40.5% delivered vaginally, while 12% did not deliver. The largest single etiology of hemorrhage was related to abnormal placentation. Of the 2280 issued RBC units, 55% were transfused, 43% were returned, and 2% were wasted. The rates of transfusion of the other blood products ranged from 58% for plasma units to 82% for cryoprecipitate. Seventeen percent of the issued cryoprecipitate units were wasted, the highest of any blood product. The rate of a patient receiving a transfusion when at least one blood product had been ordered ranged from 74% for PLTs to 91% for cryoprecipitate. CONCLUSION: Although the rates of receiving a transfusion of at least one blood product when one is ordered was high, many of the issued units were returned, especially for RBCs. PMID- 29516504 TI - Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey. AB - BACKGROUND AND OBJECTIVES: Previous reports suggest that several serum biomarkers play roles in the pathogenesis, inflammatory response, and oxidative stress in periodontitis caused by bacterial infections, linking chronic periodontitis to atherosclerotic vascular disease (ASVD). The aim of this preliminary study was to investigate, in a Japanese cross-sectional community survey, potential serum biomarkers of periodontitis that are associated with ASVD and chronic periodontitis. MATERIAL AND METHODS: The study cohort included a total of 108 male subjects who underwent annual health examinations. Serum biomarkers (high sensitivity C-reactive protein [hs-CRP], proprotein convertase subtilisin/kexin type 9 [PCSK9], interleukin-6, tumor necrosis factor-alpha, soluble CD14, myeloperoxidase, matrix metalloproteinase-3, adiponectin, total bilirubin [TBIL], and serum lipids) were analyzed to determine their association (if any) with periodontal parameters. Aortic stiffness was evaluated using the brachial-ankle aortic pulse wave velocity (PWV) index and the cardio-ankle vascular index (CAVI). RESULTS: The concentrations of PCSK9 and hs-CRP were increased (P = .001 and .042, respectively), and the concentration of TBIL was decreased (P = .046), in subjects with periodontal disease (determined as a probing depth of >=4 mm in at least one site) compared with periodontally healthy subjects. The ratio of low density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol and the concentrations of triglycerides, remnant-like particles-cholesterol, and oxidized LDL were elevated in subjects with periodontal disease compared with periodontally healthy subjects (P = .038, .007, .002, and .049, respectively). Multivariate regression analyses indicated that the number of sites with a pocket depth of >=4 mm was associated with the concentration of PCSK9 and inversely associated with the concentration of TBIL independently (standardized beta = .243, P = .040; standardized beta = -.443, P = .0002; respectively). Analysis of receiver operating characteristic curves of PCSK9 indicated moderate accuracy for predicting the presence of disease sites (probing depth >= 4 mm) (area under the curve = 0.740). No significance in the values of PWV and CAVI was observed between subjects with periodontal disease and periodontally healthy subjects. CONCLUSION: In Japanese male subjects, the concentrations of serum PCSK9 and TBIL were correlated with periodontal parameters. Moreover, PCSK9 could be a candidate biomarker for diagnosing chronic periodontitis, and may also have potential to evaluate the risk for periodontitis to cause ASVD. Longitudinal studies of larger populations are necessary to confirm the exact association of periodontitis with increased serum PCSK9 and decreased TBIL. PMID- 29516505 TI - Methadone against cancer: Lost in translation. AB - Recently, the opioid analgesic d,l-methadone has gained much attention as a potential antineoplastic compound, considerably triggered through lay press and media. In consequence, physicians and pharmacists are currently confronted with numerous patients willing to use d,l-methadone against their malignancies. Well performed in vitro and in vivo models have in fact shown pro-apoptotic effects of d,l-methadone or other opioids, but also proliferation-stimulating properties. Moreover, the mechanisms of proposed opioid-stimulated apoptosis are incompletely described or contradicting. Finally, the receptors mostly responsible for induction of apoptosis by d,l-methadone remain unclear as contributions of both u opioid receptors, Fas cell death receptors, toll-like receptors, N-Methyl-d aspartate receptors and opioid growth factor receptors were suggested. Such ambiguity prevents rational application of d,l-methadone or patient stratification to enhance beneficial antineoplastic effects. From a clinical point of view, d,l-methadone and other opioids might in fact prolong survival, but such effects likely originate from their analgesic and neuro-psychotropic properties and, thus, improvements of quality of life. Crucial obstacles to the administration of d,l-methadone are incomplete knowledge about its systemic disposition, highly variable pharmacokinetics, profound drug-drug- or drug disease interaction and QT-prolongation potential. This article summarizes and rates the pharmacological basis of d,l-methadone as an antineoplastic agent and puts its administration in clinical oncology into perspective. Despite enthralling experimental findings about d,l-methadone-mediated apoptosis in cancerous cells or tissues, clinicians should realize the current lack of evidence for the use of d,l-methadone as an antineoplastic agent. Its administration against cancer pain is, however, tenable, albeit restricted to certain clinical situations. PMID- 29516506 TI - IFN-gamma-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling. AB - IFN-gamma plays a crucial role in anti-tumor responses and also induces expression of PD-L1, a well-established inhibitor of anti-tumor immune function. Understanding how molecular signaling regulates the function of IFN-gamma might improve its anti-tumor efficacy. Here, we show that the tumor expression of IFN gamma expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN-gamma and PD-L1 have the best prognosis compared to those with tumors expressing IFN-gamma or PD-L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN-gamma display gene expression associated with suppressed cell cycle progression and expansion. Unexpectedly this profile was observed in PD-L1+ but not PD-L1- tumors. The current concept is that PD-L1 functions as a shield protecting tumor cells from cytolytic T cell (CTL)-mediated anti-tumor progression. However, our data indicate that PD-L1 expression in the presence of IFN-gamma might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-gamma. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-gamma-induced activation of JAK2 STAT1 and PI3K-AKT pathways. The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-gamma. Inhibition of PI3K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-gamma, suggesting that blockade of PI3K might maximize the IFN-gamma-mediated anti-tumor effect. Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-gamma in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma. PMID- 29516508 TI - In vivo quantification of plant starch reserves at micrometer resolution using X ray microCT imaging and machine learning. AB - Starch is the primary energy storage molecule used by most terrestrial plants to fuel respiration and growth during periods of limited to no photosynthesis, and its depletion can drive plant mortality. Destructive techniques at coarse spatial scales exist to quantify starch, but these techniques face methodological challenges that can lead to uncertainty about the lability of tissue-specific starch pools and their role in plant survival. Here, we demonstrate how X-ray microcomputed tomography (microCT) and a machine learning algorithm can be coupled to quantify plant starch content in vivo, repeatedly and nondestructively over time in grapevine stems (Vitis spp.). Starch content estimated for xylem axial and ray parenchyma cells from microCT images was correlated strongly with enzymatically measured bulk-tissue starch concentration on the same stems. After validating our machine learning algorithm, we then characterized the spatial distribution of starch concentration in living stems at micrometer resolution, and identified starch depletion in live plants under experimental conditions designed to halt photosynthesis and starch production, initiating the drawdown of stored starch pools. Using X-ray microCT technology for in vivo starch monitoring should enable novel research directed at resolving the spatial and temporal patterns of starch accumulation and depletion in woody plant species. PMID- 29516507 TI - Breast cancer risk in relation to history of preeclampsia and hyperemesis gravidarum: Prospective analysis in the Generations Study. AB - Preeclampsia and hyperemesis gravidarum are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox regression adjusting for known breast cancer risk factors. During 7.5 years average follow-up of 82,053 parous women, 1,969 were diagnosed with invasive or in situ breast cancer. Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49-0.90) and of HER2-enriched tumours (HR = 0.33, 95% CI: 0.12-0.91), but there was no association with overall (HR = 0.90, 95% CI: 0.80-1.02) or postmenopausal (HR = 0.97, 95% CI: 0.85-1.12) breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2-enriched tumours (HR = 1.76, 95% CI: 1.07-2.87), but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2-enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2-enriched tumours. PMID- 29516509 TI - Development of a proof of principle for universal neutralization of antibiotics in cord blood by-products used for sterility testing. AB - BACKGROUND: Bacterial contamination of cord blood (CB) represents a safety risk for transplantation patients. CB sterility testing at Canadian Blood Services' Cord Blood Bank is performed using a 1:1 mix of CB-derived plasma and red blood cells (RBCs). Culture bottles of an automated culture system, which lack antimicrobial neutralization properties, are used for bacterial screening of CB. This process is unsuitable for CB-containing antibiotics, potentially resulting in false-negative results. This study was aimed at developing a protocol for antibiotic neutralization in CB used for sterility testing. STUDY DESIGN AND METHODS: Phase 1: four neutralizers-penicillinase, ion exchange resins L and A, lecithin + Tween80, and activated charcoal (AC)-were individually tested to neutralize penicillin or gentamicin in cultures of Staphylococcus epidermidis or Klebsiella pneumoniae, respectively, adjusted to 100 colony forming units/mL, in Muller-Hinton broth (MHB). Phase 2: combinations of penicillinase plus resin L or penicillinase plus AC were assayed for the simultaneous neutralization of both antibiotics in MHB. Phase 3: penicillinase plus resin L was used to neutralize both antibiotics in CB sterility testing samples (plasma + RBCs). RESULTS: Phase 1: penicillin was neutralized by penicillinase and resin A, while gentamicin was neutralized by resin L and AC. Phase 2: the antibiotics were simultaneously neutralized by the two neutralizer combinations tested. Phase 3: neutralization of both antibiotics in CB was achieved with penicillinase and resin L. CONCLUSION: A protocol for antibiotic neutralization in CB sterility testing samples has been successfully developed at Canadian Blood Services' Cord Blood bank. This in-house assay applies to any culture-based CB bacterial screening method. PMID- 29516510 TI - Integrated analysis of long noncoding RNA-associated competing endogenous RNA network in periodontitis. AB - BACKGROUND AND OBJECTIVES: Long noncoding RNAs (lncRNAs) play critical and complex roles in regulating various biological processes of periodontitis. This bioinformatic study aims to construct a putative competing endogenous RNA (ceRNA) network by integrating lncRNA, miRNA and mRNA expression, based on high throughput RNA sequencing and microarray data about periodontitis. MATERIAL AND METHODS: Data from 1 miRNA and 3 mRNA expression profiles were obtained to construct the lncRNA-associated ceRNA network. Gene Ontology enrichment analysis and pathway analysis were performed using the Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction network was constructed based on the Search Tool for the retrieval of Interacting Genes/Proteins. Transcription factors (TFs) of differentially expressed genes were identified based on TRANSFAC database and then a regulatory network was constructed. RESULTS: Through constructing the dysregulated ceRNA network, 6 genes (HSPA4L, PANK3, YOD1, CTNNBIP1, EVI2B, ITGAL) and 3 miRNAs (miR-125a-3p, miR-200a, miR-142-3p) were detected. Three lncRNAs (MALAT1, TUG1, FGD5-AS1) were found to target both miR-125a-3p and miR-142-3p in this ceRNA network. Protein protein interaction network analysis identified several hub genes, including VCAM1, ITGA4, UBC, LYN and SSX2IP. Three pathways (cytokine-cytokine receptor, cell adhesion molecules, chemokine signaling pathway) were identified to be overlapping results with the previous bioinformatics studies in periodontitis. Moreover, 2 TFs including FOS and EGR were identified to be involved in the regulatory network of the differentially expressed genes-TFs in periodontitis. CONCLUSION: These findings suggest that 6 mRNAs (HSPA4L, PANK3, YOD1, CTNNBIP1, EVI2B, ITGAL), 3 miRNAs (hsa-miR-125a-3p, hsa-miR-200a, hsa-miR-142-3p) and 3 lncRNAs (MALAT1, TUG1, FGD5-AS1) might be involved in the lncRNA-associated ceRNA network of periodontitis. This study sought to illuminate further the genetic and epigenetic mechanisms of periodontitis through constructing an lncRNA-associated ceRNA network. PMID- 29516511 TI - Transfusion-associated circulatory overload prevention: a retrospective observational study of diuretic use. AB - BACKGROUND AND OBJECTIVES: Approaches to preventing transfusion-associated circulatory overload (TACO) include the use of diuretics. The purpose of this study was to determine how commonly diuretics are prescribed in patients receiving a red-blood-cell (RBC) transfusion. MATERIALS AND METHODS: This was a retrospective study of 200 adult inpatient RBC transfusion orders, 50 consecutive at each of four academic institutions. Only the first transfusion order for each patient was included. Only 1 or 2 unit orders were included. The primary outcome was the percentage of patients receiving furosemide peri-transfusion. Secondary objectives included the dose, route, and timing of furosemide and the association of clinical factors with ordering furosemide. RESULTS: The median age was 62.5 years (IQR 53, 73), and 52% were female. Peri-transfusion furosemide was ordered in 16% (95% CI 11-21%). The most common dose was 20 mg (55%), the route intravenous (90%) and timing post-transfusion (74%). At least one risk factor for TACO was present in 55% of patients: renal dysfunction (33%), older than 70 years (28%), history of congestive heart failure (18%), ejection fraction <60% (16%) and diastolic dysfunction (5%). Low haemoglobin as an indication for transfusion (OR 4.2; 95% CI 1.4-12.8) and diuretics on admission (OR 3.5; 95% CI 1.5-8.0) were associated with ordering furosemide peri-transfusion. CONCLUSIONS: Furosemide is not routinely ordered for RBC transfusion, even in patients with risk factors for TACO. Studies assessing the safety, efficacy, optimal dose, and timing of furosemide in preventing TACO are justified. PMID- 29516512 TI - Common dietary patterns and risk of cancers of the colon and rectum: Analysis from the United Kingdom Women's Cohort Study (UKWCS). AB - Few prospective cohort studies in the UK have specifically focused on the associations between commonly consumed dietary patterns and colorectal cancer (CRC). The aim of our study was to assess whether red meat, poultry, fish and vegetarian dietary patterns are associated with differences in the incidence of cancers of colon and rectum in the UKWCS. Four common dietary patterns were defined based on a hierarchy of consumption of red meat, poultry and fish for each cohort participant, using a 217-item food frequency questionnaire. Cox proportional hazards regression was used to provide adjusted hazard ratios (HR) and 95% confidence intervals (CI) for CRC. A total of 32,147 women recruited and surveyed between 1995 and 1998 were followed up for a mean of 17.2 years (426,798 person-years). A total of 462 incident CRC cases were documented; 335 colon cancers (172 proximal and 119 distal) and 152 in the rectum. In multivariable adjusted models, there was no evidence of a reduction in risk of overall CRC (HR = 0.86, 95% CI: 0.66-1.12), colon cancer (HR = 0.77, 95% CI: 0.56-1.05) or rectal cancer (HR = 1.04, 95% CI: 0.66-1.63) when comparing grouped red meat free diets with diets containing red meat. Exploratory analysis suggested a reduced risk of distal colon cancer in grouped red meat free diets (HR = 0.56, 95% CI: 0.34 0.95), though numbers with this outcome were small. These results indicate that a protective association of red meat free diets specifically on distal colon cancer merits confirmation in a larger study. PMID- 29516513 TI - Using passive acoustics to assess habitat selection by the brown meagre Sciaena umbra in a northern Adriatic Sea mussel farm. AB - Passive acoustic monitoring (PAM) of the brown meagre Sciaena umbra was conducted in a northern Adriatic Sea mussel farm. The level of acoustic activity was found to be constantly high from June to August before declining sharply in September and there was significantly higher acoustic activity in the structured habitats within the mussel farm than in the bare sandy bottom outside the farm. Results are discussed in the context of the use of this species as an indicator species of artificial rocky habitats along the Mediterranean coastal environments. PMID- 29516514 TI - Clinical concentrations of peroxidases cause dysbiosis in in vitro oral biofilms. AB - BACKGROUND AND OBJECTIVE: Little is known about the initiation of dysbiosis in oral biofilms, a topic of prime importance for understanding the etiology of, and preventing, periodontitis. The aim of this study was to evaluate the effect of different concentrations of crevicular and salivary peroxidase and catalase on dysbiosis in multispecies biofilms in vitro. MATERIAL AND METHODS: The spotting technique was used to identify the effect of different concentrations of myeloperoxidase, lactoperoxidase, erythrocyte catalase, and horseradish peroxidase in salivary and crevicular fluid on the inhibitory effect of commensals on pathobiont growth. Vitality-quantitative real-time PCR was performed to quantify the dysbiotic effect of the peroxidases (adjusted to concentrations found in periodontal health, gingivitis, and periodontitis) on multispecies microbial communities. RESULTS: Agar plate and multispecies ecology experiments showed that production of hydrogen peroxide (H2 O2 ) by commensal bacteria decreases pathobiont growth and colonization. Peroxidases at concentrations found in crevicular fluid and saliva neutralized this inhibitory effect. In multispecies communities, myeloperoxidase, at the crevicular fluid concentrations found in periodontitis, resulted in a 1-3 Log increase in pathobionts when compared with the crevicular fluid concentrations found in periodontal health. The effect of salivary lactoperoxidase and salivary myeloperoxidase concentrations was, in general, similar to the effect of crevicular myeloperoxidase concentrations. CONCLUSIONS: Commensal species suppress pathobionts by producing H2 O2 . Catalase and peroxidases, at clinically relevant concentrations, can neutralize this effect and thereby can contribute to dysbiosis by allowing the outgrowth of pathobionts. PMID- 29516515 TI - Correlates of elemental-isotopic composition of stream fishes: the importance of land-use, species identity and body size. AB - The isotopic (delta13 C and delta15 N) and stoichiometric (C:N:P) compositions of four fish species (Family Centrarchidae: Lepomis auritus, Lepomis cyanellus; Family Cyprinidae: Nocomis leptocephalus, Semotilus atromaculatus) were examined across four North Carolina Piedmont streams arrayed along an urbanization gradient. Both isotopic and stoichiometric composition of fishes appeared to track changes occurring in basal resource availability. Values of delta13 C of basal resources and consumers were more enriched at the most urbanized streams. Similarly, basal resources and consumers were delta15 N-enriched at more urbanized streams. Basal resource stoichiometry varied across streams, with periphyton being the most variable. Primary consumers stoichiometry also differed across streams. Intraspecific variation in fish stoichiometry correlated with the degree of urbanization, as the two cyprinids had higher N content and L. cyanellus had higher P content in more urbanized streams, probably due to enrichment of basal resources. Intrinsic factors, specifically species identity and body size also affected stoichiometric variation. Phosphorus (P) content increased significantly with body size in centrarchids, but not in cyprinids. These results suggest that although species identity and body size are important predictors of elemental stoichiometry, the complex nature of altered urban streams may yield imbalances in the elemental composition of consumers via their food resources. PMID- 29516516 TI - Examining the visual processing patterns of lonely adults. AB - Prior research has shown that loneliness is associated with hypervigilance to social threats, with eye-tracking research showing lonely people display a specific attentional bias when viewing social rejection and social exclusion video footage (Bangee, Harris, Bridges, Rotenberg & Qualter, 2014; Qualter, Rotenberg, Barrett et al., 2013). The current study uses eye-tracker methodology to examine whether that attentional bias extends to negative emotional faces and negative social non-rejecting stimuli, or whether it could be explained only as a specific bias to social rejection/exclusion. It is important to establish whether loneliness relates to a specific or general attention bias because it may explain the maintenance of loneliness. Participants (N = 43, F = 35, Mage = 20 years and 2 months, SD = 3 months) took part in three tasks, where they viewed different social information: Task 1 - slides displaying four faces each with different emotions (anger, afraid, happy and neutral), Task 2 - slides displaying sixteen faces with varying ratios expressing happiness and anger, and Task 3 - slides displaying four visual scenes (socially rejecting, physically threatening, socially positive, neutral). For all three tasks, eye movements were recorded in real time with an eye-tracker. Results showed no association between loneliness and viewing patterns of facial expressions, but an association between loneliness and hypervigilant viewing of social rejecting stimuli. The findings indicate that lonely adults do not have a generalised hypervigilance to social threat, but have, instead, a specific attentional bias to rejection information in social contexts. Implications of the findings for interventions are discussed. PMID- 29516517 TI - Jenynsia lineata species complex, revision and new species description (Cyprinodontiformes: Anablepidae). AB - The Jenynsia lineata species complex comprises J. lineata from Montevideo, Uruguay and Jenynsia multidentata, from coastal basins of Brazil, Uruguay and Argentina up to 1200 m a.s.l. Taxonomic divisions within this group were tested using three different species delimitation methods, which found the two existing names to be synonyms and revealed a new cryptic species. Jenynsia darwini sp. nov. is distinguished from all congeners by having a unique combination of character states, including the shape of the dorsal postcleithrum (three times higher than wide v. less than two times higher than wide) and female colour pattern in the half of the caudal peduncle with rows of chromatophores segmented in unaligned spots (v. aligned spots forming lines). The new species also differs from J. lineata by having 26 nucleotide substitutions in the mitochondrial gene cytochrome c oxidase I (coI). Phylogenetic analysis of the genus based on morphological characters proposed by previous studies corroborates monophyly of the subgenera Plesiojenynsia and Jenynsia, with the new species being allocated to the subgenus Jenynsia as the sister group of J. lineata. PMID- 29516518 TI - Effects of microwave-assisted pulse-spouted bed freeze-drying (MPSFD) on volatile compounds and structural aspects of Cordyceps militaris. AB - BACKGROUND: Microwave-assisted pulse-spouted bed freeze-drying (MPSFD) uses microwave heating to substitute the customary conduction heating during freeze drying (FD), resulting in high-quality dried samples with a short drying time. The aim of this study was to determine the effect of MPSFD on volatile compounds and structural aspects of Cordyceps militaris. In order to highlight the effect of MPSFD, FD (recognized for its high-quality products) and hot-air dying (HD; the most commonly used) were also evaluated using headspace solid-phase micro extraction combined with gas chromatography-mass spectrometry and mid-Fourier transform infrared spectroscopy. RESULTS: Sixty-two components were obtained by FD, 62 compounds by MPSFD and 39 by HD. FD and MPSFD exhibited much better effects on the retention of volatile components of C. militaris than HD. Principal component analysis, hierarchical clustering analysis and E-nose analysis indicated that the volatile compounds of C. militaris dried by FD and MPSFD were similar. The spectral features of FD and MPSFD samples were also similar, whereas the HD sample presented a clearly different spectral feature around a wavenumber of 1640 cm-1 . CONCLUSION: MPSFD exhibited a beneficial effect on aroma and structure retention, with shorter drying time and lower energy consumption. (c) 2018 Society of Chemical Industry. PMID- 29516519 TI - The aldehyde dehydrogenase cord blood potency assay excludes early apoptotic cells. AB - BACKGROUND: Cord blood units (CBUs) are processed, frozen, and thawed before use in hematopoietic stem cell (HSC) transplantation. The manipulations affect HSC functionality, that is, induce apoptosis and reduce viability. HSC content, commonly expressed as CBU potency, that is, the expected ability of a CBU to restore hematopoiesis, is traditionally approximated through viable CD34+ cells and the colony-forming unit (CFU) cell cultivation assay. Alternative approaches, for example, the aldehyde dehydrogenase (ALDH) enzyme-based assay, are also forthcoming. We hypothesized that the ALDH assay might exclude apoptotic cells since it is based on enzyme activity. To investigate this, we designed a protocol for simultaneous staining of viable and apoptotic CD34+ and ALDH+ cells using 7 aminoactinomycin (7-AAD) and annexin V, in frozen-thawed CBUs. Results were correlated with results from the colony-forming unit-granulocyte/macrophage (CFU GM) assay. STUDY DESIGN AND METHODS: Samples from 57 CBUs were thawed and simultaneously analyzed for CD34+ cells, ALDH+ cells, viability (7-AAD), and apoptosis (annexin V) using flow cytometry. Enumeration of CFUs was also performed. RESULTS: No nonviable and few apoptotic cells (mean 0.7%) were identified in the ALDH+ population compared to the viable CD34+ population (mean 3.6%). The total number of ALDH+ cells correlated better than viable CD34+ cells (r = 0. 72 vs. r = 0.66; p < 0.0001) with the results of the CFU assay. CONCLUSION: The ALDH assay excludes nonviable and apoptotic cells, and therefore correlates better with CFU enumeration compared to the number of viable CD34+ cells. We propose that the ALDH assay might replace the CFU-GM method in CBU potency measurements. PMID- 29516520 TI - 25-Hydroxyvitamin D3 -enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: Periodontitis is an increasingly prevalent complication of diabetes mellitus (known as diabetes mellitus-associated periodontitis), and 25-hydroxyvitamin D3 (25VD3 ) was recently found to be a critical regulator of innate immunity in this disease, but the underlying mechanisms remain poorly understood. T-cell protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a potential downstream protein of the 25VD3 /vitamin D receptor pathway. The aim of this study was to investigate the regulation of PTPN2 in periodontal inflammation in diabetes mellitus-associated periodontitis. MATERIAL AND METHODS: Porphyromonas gingivalis-infected db/db mice were treated with 25VD3 . Their fasting blood glucose and body weight were monitored every other week, and the levels of alveolar bone loss and serum inflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-6) were determined at the time of killing. The effect of PTPN2 on human OKF6-TERT2 oral keratinocytes was examined through the knockout of PTPN2 using the CRISPR/Cas9 knockout plasmid. The expression levels of the PTPN2, vitamin D receptor and JAK1/STAT3 signaling proteins in the gingival epithelium and OKF6-TERT2 cells were determined through western blot and immunohistochemical analyses. RESULTS: After 25VD3 treatment, db/db mice exhibited alleviated serum inflammatory cytokines and alveolar bone loss, and 25VD3 -enhanced PTPN2 expression decreased the expression of the JAK1/STAT3 signaling proteins in the gingival epithelium. Analyses of human oral keratinocytes showed that 25VD3 increased the expression of PTPN2, which dephosphorylates protein substrates in the JAK1/STAT3 signaling pathway. CONCLUSION: PTPN2 contributed to a decrease in periodontal inflammation in type 2 diabetes mellitus via dephosphorylate protein substrates in the JAK1/STAT3 signaling pathway after 25VD3 treatment in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. A thorough understanding of PTPN2 and its involvement in inhibiting inflammation might provide alternative therapeutic approaches for the pathogenesis and treatment of diabetes mellitus-associated periodontitis. PMID- 29516521 TI - First record of the Pacific seahorse Hippocampus ingens in Guadalupe Island, Mexico. AB - This is the first record of the Pacific seahorse Hippocampus ingens at a northern oceanic island from the eastern Pacific Ocean. The photographic record of the juvenile female H. ingens was made in November 2015 during a cage diving trip at Guadalupe Island, Mexico. The presence of H. ingens in this area could be related to long distance dispersal mechanisms, as has been observed in other species of seahorses. PMID- 29516522 TI - Xanthohumol ameliorates 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cellular toxicity in cultured MC3T3-E1 osteoblastic cells. AB - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The aim of the current study was to explore the role of xanthohumol in modulating the toxicity of TCDD in MC3T3-E1 osteoblastic cells. In cells treated with TCDD alone, intracellular Ca2+ concentrations, mitochondrial membrane potential disruption, reactive oxygen species production, cardiolipin peroxidation, nitric oxide release and cytochrome P450 1A1 expression were significantly increased. TCDD treatment increased the mRNA levels of extracellular signal-regulated kinase 1 and nuclear factor kappa B, and significantly decreased the level of protein kinase B (AKT) in MC3T3-E1 osteoblastic cells. However, the presence of xanthohumol alleviated the pathological effects of TCDD. In addition, xanthohumol treatment significantly increased the expression of genes associated with osteoblast differentiation (alkaline phosphatase, osteocalcin, osteoprotegerin and osterix). We conclude that xanthohumol has a beneficial influence and may antagonize TCDD toxicity in osteoblastic cells. PMID- 29516524 TI - In vivo metabolite profiles of isoimperatorin and phellopterin in rats analyzed using HPLC coupled with diode array detector and electrospray ionization ion trap time-of-flight mass spectrometry technique. AB - Isoimperatorin (IP) and phellopterin (PP) are two furocoumarins existing in Angelicae Dahuricae Radix. There is an isopentenyloxyl substituted at C-5 in IP, and an isopentenyloxyl and a methoxyl substituted at C-8 and C-5, respectively, in PP. To elucidate the in vivo metabolic characteristics of PP and IP, HPLC coupled with diode array detector and electrospray ionization ion trap time-of flight mass spectrometry technique was used. In total, 111 metabolites, including 53 new ones, were identified from the urine and plasma samples of rats after oral administration of IP and PP, respectively. The metabolites were formed through eight reactions on IP and PP: oxidation, hydroxylation-hydrogenation, carboxylation on the isopentenyloxyl, O-dealkylation, hydroxylation on the furocoumarin nucleus, ring-opening reaction on the furan ring and reduction or ring-opening reaction on the lactone ring. Among these, hydroxylation on the furocoumarin nucleus was found for the first time for in vivo metabolites of PP and IP, and the ring-opening reaction on the furan ring or lactone ring was found for the first time for in vivo metabolites of isopentenyloxyl furocoumarins. The research gave us a new insight into the in vivo metabolic profiles of IP and PP, which could help us better understand their important roles as two active constituents of Angelicae Dahuricae Radix. PMID- 29516525 TI - Ultrasound Elastography of the Median Nerve in Patients With Acromegaly: A Case Control Study. AB - OBJECTIVES: The aim of this study was to compare the cross-sectional area and ultrasound elastographic findings of the median nerve of patients with acromegaly and healthy participants. METHODS: The acromegaly group comprised 15 patients with a previous diagnosis of acromegaly, and an age- and sex-matched control group included healthy participants. Strain elastographic and shear wave elastographic findings and the cross-sectional areas of the groups were compared. A 6-15-MHz multifrequency transducer was used for ultrasound evaluations. RESULTS: A total of 30 hands of 15 patients with acromegaly (7 male and 8 female) with a mean age +/- SD of 50.00 +/- 10.17 years and 40 hands of 20 healthy control participants (9 male and 11 female) with a mean age of 49.50 +/- 10.17 years were taken into consideration for statistical analyses. The cross-sectional area of the patients with acromegaly was significantly higher than that of the healthy controls (13.43 +/- 3.12 versus 8.32 +/- 1.94 mm2 ; P < .05). Median nerve stiffness was significantly increased in the acromegaly group compared with the control group (axial and longitudinal, 37.15 +/- 6.4 and 37.0 +/- 6.19 versus 18.7 +/- 4.1 and 19.2 +/- 3.58 kPa, respectively; P < .001). CONCLUSIONS: These preliminary results have demonstrated that patients with acromegaly seem to have increased stiffness and cross-sectional area of the median nerve compared with healthy participants. PMID- 29516523 TI - Algorithm-enabled partial-angular-scan configurations for dual-energy CT. AB - PURPOSE: We seek to investigate an optimization-based one-step method for image reconstruction that explicitly compensates for nonlinear spectral response (i.e., the beam-hardening effect) in dual-energy CT, to investigate the feasibility of the one-step method for enabling two dual-energy partial-angular-scan configurations, referred to as the short- and half-scan configurations, on standard CT scanners without involving additional hardware, and to investigate the potential of the short- and half-scan configurations in reducing imaging dose and scan time in a single-kVp-switch full-scan configuration in which two full rotations are made for collection of dual-energy data. METHODS: We use the one step method to reconstruct images directly from dual-energy data through solving a nonconvex optimization program that specifies the images to be reconstructed in dual-energy CT. Dual-energy full-scan data are generated from numerical phantoms and collected from physical phantoms with the standard single-kVp-switch full scan configuration, whereas dual-energy short- and half-scan data are extracted from the corresponding full-scan data. Besides visual inspection and profile-plot comparison, the reconstructed images are analyzed also in quantitative studies based upon tasks of linear-attenuation-coefficient and material-concentration estimation and of material differentiation. RESULTS: Following the performance of a computer-simulation study to verify that the one-step method can reconstruct numerically accurately basis and monochromatic images of numerical phantoms, we reconstruct basis and monochromatic images by using the one-step method from real data of physical phantoms collected with the full-, short-, and half-scan configurations. Subjective inspection based upon visualization and profile-plot comparison reveals that monochromatic images, which are used often in practical applications, reconstructed from the full-, short-, and half-scan data are largely visually comparable except for some differences in texture details. Moreover, quantitative studies based upon tasks of linear-attenuation-coefficient and material-concentration estimation and of material differentiation indicate that the short- and half-scan configurations yield results in close agreement with the ground-truth information and that of the full-scan configuration. CONCLUSIONS: The one-step method considered can compensate effectively for the nonlinear spectral response in full- and partial-angular-scan dual-energy CT. It can be exploited for enabling partial-angular-scan configurations on standard CT scanner without involving additional hardware. Visual inspection and quantitative studies reveal that, with the one-step method, partial-angular-scan configurations considered can perform at a level comparable to that of the full scan configuration, thus suggesting the potential of the two partial-angular-scan configurations in reducing imaging dose and scan time in the standard single-kVp switch full-scan CT in which two full rotations are performed. The work also yields insights into the investigation and design of other nonstandard scan configurations of potential practical significance in dual-energy CT. PMID- 29516526 TI - Pleural abnormalities and exposure to elongate mineral particles in Minnesota iron ore (taconite) workers. AB - BACKGROUND: Iron ore (taconite) mining and processing are an important industry in northern Minnesota and western Michigan. Concerns around exposures have centered largely on exposure to non-asbestiform amphibole elongate mineral particles (EMPs) found in the eastern portion of the Minnesota iron range. METHODS: A cross sectional survey was undertaken of current and former taconite workers and spouses along with a detailed exposure assessment. Participants provided an occupational history and had a chest radiograph performed. RESULTS: A total of 1188 workers participated. Potential exposures to non-amphibole EMPs were evident across multiple jobs in all active mines. Pleural abnormalities were found in 16.8% of workers. There was an association of pleural abnormalities with cumulative EMP exposure that was not specific to the eastern portion of the range. CONCLUSION: There was evidence of a mild to moderate increase in pleural abnormalities in this population of miners, associated with geographically non specific cumulative EMP exposure. PMID- 29516527 TI - Oxidative stress in organophosphate poisoning: role of standard antidotal therapy. AB - Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration. PMID- 29516528 TI - Findings in exudates can help distinguish benign gastric ulcers from ulcerated adenocarcinomas. AB - AIMS: Most gastric carcinomas develop in association with mucosal atrophy and hypochlorhydria, whereas benign peptic ulcers are acid-related. Given that acid sterilises the gastric contents, we hypothesised that ulcerated gastric cancers may be associated with increased numbers of luminal microorganisms as compared with peptic ulcers, and that this feature may represent a helpful diagnostic clue to the presence of malignancy. We performed this study to determine whether the features of luminal debris, including microorganisms, from ulcerated gastric cancers were significantly different from those of debris associated with benign ulcers. METHODS AND RESULTS: We retrospectively identified 50 ulcerated adenocarcinomas and 50 site-matched peptic ulcers. Luminal debris was evaluated for the nature of inflammation, necrosis, and the presence of mixed bacterial colonies or yeasts. Non-lesional mucosa was assessed for chronic gastritis, Helicobacter pylori, chemical gastropathy, and intestinal metaplasia. Patients in both groups were adults (mean age: 69 years and 62 years, respectively) with similar amounts of inflammation and cellular necrosis in biopsy material. However, 76% of ulcerated cancers harboured non-H. pylori bacterial colonies, as compared with only 22% of peptic ulcers (P < 0.01). Filamentous bacteria and fungi were highly specific for carcinoma (98% and P = 0.02 for both comparisons). Background intestinal metaplasia was more common among gastric cancers than among peptic ulcers (50% versus 26%, P = 0.02), whereas chemical gastropathy was more commonly associated with the latter (50% versus 10%, P < 0.01). CONCLUSION: Gastric cancers may be colonised by non-H. pylori microorganisms. Detection of numerous bacterial colonies, filamentous bacteria or fungi in biopsy material obtained from ulcerated gastric lesions should raise suspicion for underlying malignancy. PMID- 29516529 TI - Constructing Unfinalizability: A Subject Positioning Analysis of a Couple's Therapy Session Hosted by Tom Andersen. AB - The notion of subject positions is a useful tool in thinking through therapeutic interactions. In this article, I discuss positioning as an everyday phenomenon, and highlight the relational and social power dynamics that shape the subject positions persons may inhabit. Analysis is presented of the positional dynamics that play out in the couple's therapy session facilitated by Tom Andersen. Analysis suggests that Andersen adopts a not-knowing, uncertain, and curious position, while constructing the couple as competent, unfinalizable persons able to negotiate the choice-points that arise in front of them. However, if subject positions are grounded in social power dynamics, the session leaves a particular question unanswered: How will these emergent positions take hold outside of the consulting room? PMID- 29516530 TI - 'Everybody has to think - do I have any peanuts and nuts in my lunch?' School nurses, collective adherence, and children's food allergies. AB - Developing robust explanations for patients' non-adherence to medical treatments is a pressing clinical concern. Social scientists have emphasised the importance of taking a 'patient-centred' approach to the study of illness management. Using data from a qualitative study of the management of children's food allergies, I found that school nurses created what I term collective adherence - the translation of individual medical recommendations into prescriptions to be followed by entire communities. School nurses secured collective adherence by aligning physicians, schools, and families around a particular interpretation of medical recommendations, setting guidelines of behaviour for the entire school community to follow, and balancing the diverging needs of illness sufferers and non-illness sufferers. This study contributes to the study of adherence by examining the medical recommendation as a dynamic prescription, extending adherence to the study of ancillary providers' interaction with medical recommendations, and examining the impact of illness on non-family ties. I conclude with a discussion of implications for the field of school nursing; and potential applications of the collective adherence framework to the management of health conditions and health risks. PMID- 29516532 TI - Editor's Note. PMID- 29516531 TI - Trees down, hazards abound: Observations and lessons from Hurricane Sandy. AB - BACKGROUND: Given predictions that climate change will lead to an increase in severe storms, it is important to more fully understand the risks experienced by workers charged with the cleanup and removal of storm damaged trees. These hazards have received little attention in the occupational safety and health literature. METHODS: This paper is based on semi-structured interviews with 23 stakeholders involved in the Hurricane Sandy cleanup effort. RESULTS: Interview participants identified at risk sectors, gaps in training and preparedness, and raised particular concerns about storm downed trees, electrical hazards, and fatigue and suggested steps to reduce these hazards. CONCLUSIONS: Stakeholders' observations about storm response suggest directions for improving the health and safety of this critical workforce. PMID- 29516533 TI - Prevalence of exceeding maximum daily dose of paracetamol, and seasonal variations in cold-flu season. AB - AIMS: To estimate prevalence of excess intake of paracetamol and investigate seasonal variations therein. METHODS: Between 2011 and 2016, 14 481 US adults who used paracetamol in the preceding 30 days were sampled from national online panels and completed a detailed online daily diary of paracetamol medication use for 7 days. Respondents were not told that the study concerned paracetamol. Cold/flu season (CFS), identified using Google Trends data, was contrasted to off season in symptoms, use of paracetamol medications, and consumption exceeding 4 g (the recommended daily maximum). RESULTS: Overall, 6.3% [95% confidence interval: 5.9-6.7%] of users exceeded 4 g on at least one day; 3.7% [3.5-3.8%] of usage days exceeded 4 g. Cold/flu symptoms were more likely to be experienced and treated with paracetamol in CFS than off-season. Paracetamol users were more likely to exceed 4 g during CFS (6.5% vs. 5.3%; odds ratio = 1.24, 1.04-1.48); days exceeding 4 g also increased (3.9% vs. 2.8%; odds ratio = 1.37, 1.11-1.69). This was not due to differences in characteristics of individuals using paracetamol in CFS, but primarily to increased use of over-the-counter combination medications designed to treat upper respiratory cold/flu symptoms (33.2% of usage days in CFS vs. 24.8% in off-season; odds ratio = 1.58, 1.46 1.72). When such medications were omitted, there was no statistically significant seasonal variation in exceeding 4 g. CONCLUSIONS: Paracetamol use and over-dosing increases in CFS, primarily due to increased use of over-the-counter combinations treating upper respiratory cold/flu symptoms. Pharmacists should warn users to follow labelled dosing directions, especially during CFS. PMID- 29516534 TI - Proxy decision making and dementia: Using Construal Level Theory to analyse the thoughts of decision makers. AB - AIMS: This study explored the feasibility of using Construal Level Theory to analyse proxy decision maker thinking about a hypothetical ethical dilemma, relating to a person who has dementia. BACKGROUND: Proxy decision makers make decisions on behalf of individuals who are living with dementia when dementia affects that individual's decision making ability. Ethical dilemmas arise because there is a need to balance the individual's past and contemporary values and views. Understanding of how proxy decision makers respond is incomplete. Construal Level Theory contends that individuals imagine reactions and make predications about the future by crossing psychological distance. This involves abstract thinking, giving meaning to decisions. There is no empirical evidence of Construal Level Theory being used to analyse proxy decision maker thinking. Exploring the feasibility of using Construal Level Theory to understand dementia carer thinking regarding proxy decisions may provide insights which inform the support given. DESIGN: Descriptive qualitative research with semi-structured interviews. METHODS: Seven participants were interviewed using a hypothetical dementia care scenario in February 2016. Interview transcripts were analysed for themes. Construal Level Theory was applied to analyse participant responses within themes using the Linguistic Category Model. RESULTS: Participants travelled across psychological distance, using abstract thinking to clarify goals and provide a basis for decisions. When thinking concretely participants established boundaries regarding the ethical dilemma. CONCLUSION: Construal Level Theory gives insight into proxy decision maker thinking and the levels of abstraction used. Understanding what dementia carers think about when making proxy decisions may help nurses to understand their perspectives and to provide appropriate support. PMID- 29516535 TI - Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study. AB - BACKGROUND: Eradication of hepatitis C virus (HCV) infection via interferon-based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon-free treatment. AIMS: The objective of this retrospective cohort study was to examine the association of direct-acting antiviral (DAA) exposure with risk of incident liver cancer in real-world data. METHODS: From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods. RESULTS: Relative to untreated HCV patients, DAA-treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73-0.96), and relative to interferon based treatment in the pre-DAA era (HR = 0.69, 95% CI: 0.59-0.81). CONCLUSIONS: In this large, population-based study, DAA-based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon-based treatment in the pre-DAA era. As additional follow-up time of DAA-treated patients accrues, we anticipate that the long-term benefits of DAA treatment will become more apparent. PMID- 29516536 TI - Quantitative Ultrasound Assessment of the Achilles Tendon Under Varied Loads. AB - This Institutional Review Board-approved pilot study attempted to detect the correlation between ultrasound shear wave elastographic measures and tendon loads. Five male fresh-frozen cadaveric Achilles tendons were loaded in 10-N increments from 0 to 60 N. Shear wave velocity measurements within each Achilles tendon were obtained at each load in longitudinal and transverse orientations. Shear wave velocity measurements were correlated with tendon tension on both longitudinal and transverse plane imaging and showed moderate and strong positive correlation coefficients, respectively. Of note, limitations of the clinically available shear wave elastographic technology for measuring high velocities exist. PMID- 29516537 TI - Cerebral metabolic rate of oxygen (CMRO2 ) mapping by combining quantitative susceptibility mapping (QSM) and quantitative blood oxygenation level-dependent imaging (qBOLD). AB - PURPOSE: To map the cerebral metabolic rate of oxygen (CMRO2 ) by estimating the oxygen extraction fraction (OEF) from gradient echo imaging (GRE) using phase and magnitude of the GRE data. THEORY AND METHODS: 3D multi-echo gradient echo imaging and perfusion imaging with arterial spin labeling were performed in 11 healthy subjects. CMRO2 and OEF maps were reconstructed by joint quantitative susceptibility mapping (QSM) to process GRE phases and quantitative blood oxygen level-dependent (qBOLD) modeling to process GRE magnitudes. Comparisons with QSM and qBOLD alone were performed using ROI analysis, paired t-tests, and Bland Altman plot. RESULTS: The average CMRO2 value in cortical gray matter across subjects were 140.4 +/- 14.9, 134.1 +/- 12.5, and 184.6 +/- 17.9 MUmol/100 g/min, with corresponding OEFs of 30.9 +/- 3.4%, 30.0 +/- 1.8%, and 40.9 +/- 2.4% for methods based on QSM, qBOLD, and QSM+qBOLD, respectively. QSM+qBOLD provided the highest CMRO2 contrast between gray and white matter, more uniform OEF than QSM, and less noisy OEF than qBOLD. CONCLUSION: Quantitative CMRO2 mapping that fits the entire complex GRE data is feasible by combining QSM analysis of phase and qBOLD analysis of magnitude. PMID- 29516538 TI - The pharmacokinetics study of ginkgolide A, B and the effect of food on bioavailability after oral administration of ginkgolide extracts in beagle dogs. AB - Ginkgolides are the primarily active components in Ginkgo products that are popular worldwide. However, few studies have evaluated the bioavailability of ginkgolides and the effects of food on it after oral administration of ginkgolides. In this article, pharmacokinetics and absolute bioavailability of the primary components in ginkgolide extracts were evaluated in beagle dogs. For the first time, we showed that the fed dogs had significantly increased area under the concentration-time curve and peak concentration relative to the fasted dogs based on the data from both the prototype form and total lactones of ginkgolide A (GA) and ginkgolide B (GB). In terms of the free form of the prototype ginkgolides, the absolute bioavailabilities of GA and GB were 34.8 and 5.2% in the fasted dogs, respectively, which significantly increased to an average of 78.6 and 17.0%, respectively, in the fed dogs. In terms of acidified total lactones, the absolute bioavailabilities of GA and GB were 7.5 and 14.5% in the fed dogs, and the percentages declined to 4.1 and 3.7% in the fasted dogs, respectively. It was suggested that administration of ginkgolides after meals could promote the in vivo exposure and the bioavailability of GA and GB, and hence potentially enhance therapeutic outcomes. PMID- 29516539 TI - A mixed-order nonlinear diffusion compressed sensing MR image reconstruction. AB - PURPOSE: Avoid formation of staircase artifacts in nonlinear diffusion-based MR image reconstruction without compromising computational speed. METHODS: Whereas second-order diffusion encourages the evolution of pixel neighborhood with uniform intensities, fourth-order diffusion considers smooth region to be not necessarily a uniform intensity region but also a planar region. Therefore, a controlled application of fourth-order diffusivity function is used to encourage second-order diffusion to reconstruct the smooth regions of the image as a plane rather than a group of blocks, while not being strong enough to introduce the undesirable speckle effect. RESULTS: Proposed method is compared with second- and fourth-order nonlinear diffusion reconstruction, total variation (TV), total generalized variation, and higher degree TV using in vivo data sets for different undersampling levels with application to dictionary learning-based reconstruction. It is observed that the proposed technique preserves sharp boundaries in the image while preventing the formation of staircase artifacts in the regions of smoothly varying pixel intensities. It also shows reduced error measures compared with second-order nonlinear diffusion reconstruction or TV and converges faster than TV-based methods. CONCLUSION: Because nonlinear diffusion is known to be an effective alternative to TV for edge-preserving reconstruction, the crucial aspect of staircase artifact removal is addressed. Reconstruction is found to be stable for the experimentally determined range of fourth-order regularization parameter, and therefore not does not introduce a parameter search. Hence, the computational simplicity of second-order diffusion is retained. PMID- 29516541 TI - IJGO celebrates research from Africa and the Middle East. PMID- 29516540 TI - TNF alpha inhibitors in Alzheimer's disease: A systematic review. AB - OBJECTIVES: The objective of this study was to evaluate the effect of tumour necrosis factor-alpha inhibitors (TNF-alphaI) on Alzheimer's disease-associated pathology. DESIGN: A literature search of PubMed, Embase, PsychINFO, Web of Science, Scopus, and the Cochrane Library databases for human and animal studies that evaluated the use of TNF-alphaI was performed on 26 October 2016. RESULTS: The main outcomes assessed were cognition and behaviour, reduction in brain tissue mass, presence of plaques and tangles, and synaptic function. Risk of bias was assessed regarding blinding, statistical model, outcome reporting, and other biases. Sixteen studies were included, 13 of which were animal studies and 3 of which were human. All animal studies found that treatment with TNF-alphaI leads to an improvement in cognition and behaviour. None of the studies measured change in brain tissue mass. The majority of studies documented a beneficial effect in other areas, including the presence of plaques and tangles and synaptic function. The amount of data from human studies was limited. Two out of 3 studies concluded that TNF-alphaI are beneficial in Alzheimer's disease patients, with one being an observational study and the latter being a small pilot study, with a high risk of bias. CONCLUSION: It was concluded that a large-scale randomized controlled trial assessing the effectiveness of TNF-alphaI on humans is warranted. PMID- 29516542 TI - A Delphi study to identify the core components of nurse to nurse handoff. AB - AIM: The aim of this study was to identify the core components of nurse-nurse handoffs. BACKGROUND: Patient handoffs involve a process of passing information, responsibility and control from one caregiver to the next during care transitions. Around the globe, ineffective handoffs have serious consequences resulting in wrong treatments, delays in diagnosis, longer stays, medication errors, patient falls and patient deaths. To date, the core components of nurse nurse handoff have not been identified. This lack of identification is a significant gap in moving towards a standardized approach for nurse-nurse handoff. DESIGN: Mixed methods design using the Delphi technique. METHODS: From May 2016 - October 2016, using a series of iterative steps, a panel of handoff experts gave feedback on the nurse-nurse handoff core components and the content in each component to be passed from one nurse to the next during a typical unit based shift handoff. Consensus was defined as 80% agreement or higher. RESULTS/FINDINGS: After three rounds of participant review, 17 handoff experts with backgrounds in clinical nursing practice, academia and handoff research came to consensus on the core components of handoff: patient summary, action plan and nurse-nurse synthesis. CONCLUSION: This is the first study to identify the core components of nurse-nurse handoff. Subsequent testing of the core components will involve evaluating the handoff approach in a simulated and then actual patient care environment. Our long-term goal is to improve patient safety outcomes by validating an evidence-based handoff framework and handoff curriculum for pre licensure nursing programmes that strengthen the quality of their handoff communication as they enter clinical practice. PMID- 29516543 TI - Stress in nurses: The 100 top-cited papers published in nursing journals. AB - AIM: To identify and analyse the 100 most cited papers on stress in nurses published in nursing journals. BACKGROUND: The number of citations an article receives is an index of its impact on the scientific community. An analysis of the most cited articles on stress in nursing would allow us to identify the most important articles and to obtain information about this area of knowledge. DESIGN: A retrospective bibliometric analysis. DATA SOURCES: In 2016, 111 journals belonging to the "nursing" category were identified in the Science and Social Science Citation Index. A search was performed of the Science Core Collection Website for articles on stress published in these journals. REVIEW METHODS: The topic, type of article, publishing journal, countries and institutions of origin and year of publication were extracted from the articles. The impact factor, immediacy index, journal country and publisher and h index were collected from the Institute for Scientific Information. The citation density, citation tendency and Bradford's law were calculated. RESULTS: They identified articles were mostly empirical quantitative studies with a transversal design, published from 1975 - 2011 in 23 journals. They were signed by 233 authors, most of whom are English-speaking from the USA and UK. The core distribution of the publications comprises a single journal, the Journal of Advanced Nursing. CONCLUSION: The study of stress in nursing has shown increased visibility and recognition each decade. The most recent articles have the highest number of citations, are the highest in rank and have the higher citation densities. PMID- 29516544 TI - U2AF1 mutation variants in myelodysplastic syndromes and their clinical correlates. PMID- 29516545 TI - The impact of menopause on the sexual health of Chinese Cantonese women: A mixed methods study. AB - AIMS: This study explored the impact of menopause on sexual health and marital relationships, the associated factors and the support needed among middle-aged and older women. BACKGROUND: Although women experiencing menopause are more vulnerable to sexual health and marital problems, few studies have addressed this topic. DESIGN: A mixed methods design was used, comprising primarily quantitative methods with a qualitative component to evaluate the impact of menopause on sexual health. METHODS: Eligible women from community-based women centre in Hong Kong were recruited for a survey. The Female Sexual Function Index (FSFI) was used to evaluate sexual function and risk factors for developing sexual dysfunction. Purposively selected women were invited to participate in in-depth individual interviews to explore the impact of menopause on sexual health, the barriers encountered and the desired support. FINDINGS: In total, 540 respondents completed the survey with response rate of 59.7% where 30 respondents participated in the in-depth individual interview. The prevalence of sexual dysfunction in the overall respondents and postmenopause were 85.1% and 91.2% respectively. Depression was found as a strong factor associated with sexual dysfunction. The qualitative data showed that menopause had a considerable negative impact on women's sexual lives. Vaginal dryness and low sexual desire were most commonly reported. Knowledge, financial support and family understanding were important to helping women manage menopause. CONCLUSION: This study gives further knowledge for healthcare providers and policy makers to develop appropriate strategies and deliver suitable services to improve the quality of sexual health of menopausal women. PMID- 29516546 TI - The effect of neutralization of nerve growth factor (NGF) on bladder and urethral dysfunction in mice with spinal cord injury. AB - AIMS: To investigate the role of nerve growth factor (NGF) in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS: Using 4-week SCI mice, single-filling cystometry and external urethral sphincter (EUS) electromyography were performed under an awake condition. In some SCI mice, anti NGF antibodies (10 ug/kg/h) were administered for 1 or 2 weeks before the urodynamic study. NGF levels in the bladder and L6/S1 spinal cord were assayed by ELISA. The transcript levels of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured by RT-PCR. RESULTS: In SCI mice, the area under the curve of non-voiding contractions (NVCs) during the storage phase was significantly decreased in both 1- and 2-week anti-NGF antibody-treated SCI groups. However, EUS-electromyogram parameters during voiding were not altered by the treatment. Bladder mucosal and spinal NGF levels were decreased after 2 weeks of anti-NGF antibody treatment. TRPA1 and TRPV1 transcripts in L6/S1 DRG were significantly decreased after 1- or 2-week anti-NGF treatment. CONCLUSIONS: In SCI mice, NGF is involved in the emergence of NVCs in association with increased expression of TRP receptors that are predominantly found in C-fiber afferent pathways. Thus, NGF targeting treatments could be effective for treating storage problems such as detrusor overactivity after SCI. PMID- 29516547 TI - Losing the battle: Perceived status loss and contemplated or attempted suicide in older adults. AB - OBJECTIVE: While loss of socioeconomic status (SES) has been linked to suicidal behavior, it is unclear whether this experience is merely a downstream effect of psychopathology ("downward drift"), a sign of hardship, or an independent psychological contributor to suicide risk. We examined the association between the subjective experience of status loss and suicidal behavior and ideation in old age, while accounting for potential confounders. We were also interested in whether status loss was associated with mere thoughts of suicide vs. suicidal behavior. METHODS: Fifty older (55+) depressed suicide attempters, 29 depressed suicide ideators with no history of attempted suicide, 38 nonsuicidal depressed participants, and 45 nonpsychiatric controls underwent detailed clinical characterization and reported their current and highest lifetime SES. RESULTS: Suicide attempters were more likely to report a decline in their SES compared to healthy controls and nonsuicidal depressed older adults, while not differing from suicide ideators. This difference was not explained by objective predictors of SES, including education, financial difficulties, and the presence of addiction. Interestingly, while the current SES of suicide attempters was much lower than that of comparison groups, their reported highest lifetime SES was just as high, despite the differences in education. CONCLUSION: In older adults, the experience of status loss is associated with contemplated and attempted suicide even after accounting for objective indicators of social status and psychopathology. It is possible that suicidal individuals retrospectively inflate their previous status, making their current standing appear even worse by comparison. PMID- 29516548 TI - Malignant atrophic papulosis with motor aphasia and intestinal perforation: A case report and review of published works. AB - Malignant atrophic papulosis (MAP) is a rare type of obliterating vasculopathy that can present as pure cutaneous lesions or a systemic entity affecting multiple organs. Systemic disease, such as gastrointestinal or central nervous system involvement, may predispose the patients to poorer or even fatal outcomes. We present a 30-year-old female patient with systemic manifestation of MAP 10 days after delivery of a full-term pregnancy who subsequently developed motor aphasia and intestinal perforation. The patient was administrated empirical treatment with an antiplatelet, anticoagulant, methylprednisolone sodium succinate and alprostadil. Antibiotics were administrated due to intestinal perforation and secondary sepsis. Despite all treatment, the patient died a week later. We summarized all the previous reports of MAP based on thorough review of previous published work. Overall, this is the first patient with MAP combined with motor aphasia and intestinal perforation and may provide insights for future studies on the treatment of this disease. PMID- 29516549 TI - CEST-MRI studies of cells loaded with lanthanide shift reagents. AB - PURPOSE: Magnetic resonance imaging has been used extensively to track in vivo implanted cells that have been previously labeled with relaxation enhancers. However, this approach is not suitable to track multiple cell populations, as it may lead to confounding results in case the contrast agent is released from the labeled cells. This paper demonstrates how the use of CEST agents can overcome these issues. After encapsulating paramagnetic lanthanide shift reagents, we may shift the absorption frequency of the intracellular water resonance (deltaIn ), thus generating frequency-encoding CEST responsive cells that can be visualized in the MR image by applying the proper RF irradiation. METHODS: Eu-HPDO3A, Dy HPDO3A, and Tm-HPDO3A were used as shift reagents for labeling murine breast cancer cells and murine macrophages by hypotonic swelling and pinocytosis. The CEST-MR images were acquired at 7 T, and the saturation transfer effect was measured. Samples at different dilution of cells were analyzed to quantify the detection threshold. In vitro experiments of cell proliferation were carried out. Finally, murine breast cancer cells were injected subcutaneously in mice, and MR images were acquired to assess the proliferation index in vivo. RESULTS: It was found that entrapment of the paramagnetic complexes into endosomes (i.e., using the pinocytosis route) leads to an enhanced shift of the intracellular water resonance. deltaIn appears to be proportional to the effective magnetic moment (MUeff ) and to the concentration of the loaded lanthanide complex. Moreover, a higher shift is present when the complexes are entrapped in the endosomes. The cell proliferation index was assessed both in vitro and in vivo by evaluating the reduction of deltaIn value in the days after the cell labeling. CONCLUSION: Cells can be visualized by CEST MRI after loading with paramagnetic shift reagent, by exploiting the large ensemble of the properly shifted intracellular water molecules. A better performance is obtained when the complexes are entrapped inside the endosomes. The observed (deltaIn ) value is strongly correlated to the chemical nature of the probe, and to its concentration and cellular localization. Two applications of this method are reported in this paper: (1) for in vivo cell visualization and (2) for the monitoring of the cellular proliferation process, as this method is accompanied by a change in deltaIn that may be exploited as a longitudinal reporter of the proliferation rate. PMID- 29516550 TI - Gender differences for growth in North American Atlantic salmon. AB - An assumption in aquaculture of Atlantic salmon is that male and female growth within families is perfectly genetically correlated. That is, families would rank identically if based on male growth only or female growth only. Also, growth in freshwater and sea water is assumed to be highly correlated between males and females within families. However, structural analysis of the DNA of Atlantic salmon has found that the linkage maps of females differ significantly from that of males. Genetic variability for any trait measured on females could be greater or lesser than on males. Thus, male and female growth might be considered as separate traits giving rise to families ranking differently depending on gender. A multiple trait family model for weight and length at 3 years of age in Atlantic salmon according to gender was applied to data on North American Atlantic salmon obtained from the Oak Bay Hatchery in New Brunswick, Canada. Genetic correlations between male and female growth in both freshwater and sea water were estimated by Bayesian methods. The estimates support the possible existence of gender dimorphism in North American Atlantic salmon for growth traits. PMID- 29516551 TI - Application of multiplex methylated-specific PCR with capillary electrophoresis to explore prognostic value of TSGs hypermethylation for hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that severely threatens human health. To date, early detection for HCC patients is particularly significant due to their poor survival rates even after liver resection. METHODS: Therefore, an efficient and sensitive detection method for monitoring liver cancer, multiplex methylation-specific PCR (MSP) coupled with capillary electrophoresis, is developed. RESULTS: Simulations demonstrated that the methylation status of RASSF1A, p16, SFRP1, and ELF could be detected even when DNA equaled or exceeded 12.5 ng simultaneously. Also, its accuracy for methylation detection outweighed polyacrylamide gel electrophoresis (87.5%) and agarose electrophoresis (84.3%), reaching 92.1%. Subsequently, we implemented multiplex MSP with capillary electrophoresis to investigate methylation status of the four tumor suppressor genes in tissue specimens and explore the prognostic value for HCC patients. As the data suggested, multivariate cox regression analysis revealed that the recurrence-free survival of 46 patients was greatly associated with portal vein tumor thrombus (PVTT) and p16 methylation and receiver operating characteristic (ROC) curves demonstrated that the predictive range of portal vein tumor thrombus (PVTT) combined with p16 hypermethylation was more sensitive than that of either PVTT or p16 hypermethylation alone with regard to disease recurrence in patients with HCC, which could be testified as a valuable biomarker in Clinical application. CONCLUSION: Multiplex MSP coupled with capillary electrophoresis has an excellent prospect of clinical application for monitoring early liver cancer and screening valuable biomarkers for prognosis of HCC patients. PMID- 29516552 TI - Exploring the need for Transition Readiness Scales within cystic fibrosis services: A qualitative descriptive study. AB - AIMS AND OBJECTIVES: To explore healthcare professionals' and patients' perceptions of the potential use of a Transition Readiness Scale in cystic fibrosis care. This included an examination of barriers and facilitators to its implementation along with the identification of key items to include in a Transition Readiness Scale. BACKGROUND: Due to increasing life expectancy and improved quality of life, more adolescents with cystic fibrosis are transitioning from paediatric to adult health care. To assess and correctly manage this transition, a more structured approach to transition is advocated. This can be achieved using a Transition Readiness Scale to potentially identify or target areas of care in which the adolescent may have poor knowledge. These key items include education, developmental readiness taking into account relationships, reproduction, future plans and self-management skills. Existing tools to gauge readiness concentrate mainly on education and self-care needs assessment as their key items. Currently, there is no specific cystic fibrosis Transition Readiness Scale in use in Ireland or internationally. DESIGN: The study used a descriptive qualitative design. METHODS: Data were collected using semi-structured interviews (n = 8) and analysed using a thematic approach. RESULTS: The findings identified the potential benefits of this tool and second the resources which need to be in place before its development and implementation into cystic fibrosis services. CONCLUSION: Transition Readiness Scales have substantial relevance with cystic fibrosis services emphasising the importance of establishing the necessary resources prior to its implementation. These were identified as more staff, a dedicated private space and staff training and education. RELEVANCE TO CLINICAL PRACTICE: Significant resources are needed to fully integrate Transition Readiness Scales in practice. The study findings suggest multidisciplinary collaborations, and patient engagement is pivotal in planning and easing the transition process for adolescents with cystic fibrosis. PMID- 29516553 TI - "We're stuck with what we've got": The impact of lipodystrophy on body image. AB - AIMS AND OBJECTIVES: To evaluate the impact of lipodystrophy on body image and how this affects patients' daily lives. BACKGROUND: Lipodystrophy refers to a group of rare conditions characterised by generalised or partial lack of body fat and is associated with severe metabolic problems, for example, severe insulin resistance, diabetes and pancreatitis. In addition to its metabolic effect, lack of adipose tissue may have a major impact on appearance and cause distressing physical changes. While global research has focused on diagnosis and management, there is no published work investigating the psychological effects of lipodystrophy on body image. METHODS: Following ethical approval, participants with lipodystrophy were purposively sampled from the National Severe Insulin Resistance Service in Cambridge, UK, and invited to take part in a semi structured interview. Eleven (10 female, one male) interviews were conducted and digitally recorded. Data were analysed using an inductive thematic approach. RESULTS: Four main themes were identified in the data set; "Always feeling appearance was different," "a better understanding of lipodystrophy is needed," "feeling accepted" and "there's more to lipodystrophy than managing symptoms." Participants spoke of distressing cosmetic effects related to lack of fat tissue and other changes related to lipodystrophy, contributing to negative body image. For some, negative body image led to feelings of worthlessness impacting daily life and adherence to treatment. Psychological support was lacking but desired by participants. CONCLUSION: Lipodystrophy contributes to negative body image affecting patients' daily lives. Patients wanted psychological support alongside medical management. Further research is needed to determine how best to deliver psychological support and to evaluate its impact on well-being and metabolic management. RELEVANCE TO CLINICAL PRACTICE: The effects of rare diseases such as lipodystrophy on appearance can be distressing for patients. Support beyond medical management is needed to improve patients' daily lives and help them to live well with appearance-altering conditions. PMID- 29516554 TI - Cultural competence in healthcare in the community: A concept analysis. AB - This study aims to conduct a concept analysis on cultural competence in community healthcare. Clarification of the concept of cultural competence is needed to enable clarity in the definition and operation, research and theory development to assist healthcare providers to better understand this evolving concept. Rodgers' evolutionary concept analysis method was used to clarify the concept's context, surrogate terms, antecedents, attributes and consequences and to determine implications for further research. Articles from 2004 to 2015 were sought from Medline, PubMed, CINAHL and Scopus using the terms "cultural competency" AND "health," "cultural competence" OR "cultural safety" OR "cultural knowledge" OR "cultural awareness" OR cultural sensitivity OR "cultural skill" AND "Health." Articles with antecedents, attributes and consequences of cultural competence in community health were included. The 26 articles selected included nursing (n = 8), health (n = 8), psychology (n = 2), social work (n = 1), mental health (n = 3), medicine (n = 3) and occupational therapy (n = 1). Findings identify cultural openness, awareness, desire, knowledge and sensitivity and encounter as antecedents of cultural competence. Defining attributes are respecting and tailoring care aligned with clients' values, needs, practices and expectations, providing equitable and ethical care, and understanding. Consequences of cultural competence are satisfaction with care, the perception of quality healthcare, better adherence to treatments, effective interaction and improved health outcomes. An interesting finding is that the antecedents and attributes of cultural competence appear to represent a superficial level of understanding, sometimes only manifested through the need for social desirability. What is reported as critical in sustaining competence is the carers' capacity for a higher level of moral reasoning attainable through formal education in cultural and ethics knowledge. Our conceptual analysis incorporates moral reasoning in the definition of cultural competence. Further research to underpin moral reasoning with antecedents, attributes and consequences could enhance its clarity and promote a sustainable enactment of cultural competence. PMID- 29516555 TI - Methamphetamine psychosis: insights from the past. AB - BACKGROUND AND AIMS: To review early case reports and experimental inductions of amphetamine and methamphetamine psychosis, prior to the prohibition of these drugs, to gain a better understanding of the nature and aetiology of methamphetamine psychosis. METHODS: Papers considered were historical case reports and case series of psychosis relating to the use and misuse of prescription amphetamine, focusing upon papers by Young & Scoville (1938), Connell (1958), and three subsequent experimental studies published in the early 1970s (Griffith 1972, Angrist & Gershon 1970 and Bell 1973), where psychosis was induced in volunteers using high-dose amphetamine and methamphetamine. RESULTS: High-dose methamphetamine and amphetamine can result in a paranoid psychosis which remits rapidly (within days) of discontinuing use. The central feature is paranoia occurring in a clear state of consciousness. This may be accompanied by other psychotic symptoms (e.g. hallucinations). Pre-existing schizophrenia is not necessary, and the syndrome is not due to sleep deprivation. CONCLUSIONS: Research findings from the 1930s to the 1970s suggest that paranoid psychosis should be considered a probable consequence of high-dose methamphetamine use. Individuals who experience psychotic symptoms for any substantive period after intoxication has ended should be suspected of having a functional non-organic psychosis, or a latent vulnerability thereto. PMID- 29516556 TI - Free-running circadian period in adolescents and adults. AB - Sleep timing shifts later during adolescence (second decade). This trend reverses at ~20 years and continues to shift earlier into adulthood. The current analysis examined the hypothesis that a longer free-running circadian period during late adolescence (14-17 years) compared with adulthood (30-45 years) accounts for sleep timing differences. Sex and ancestry were also examined because previous reports find that women and those with African-American ancestry have shorter free-running periods. Circadian period was measured using an ultradian dark-light protocol (2 hr dark/sleep, 2 hr dim room light [~20 lux]/wake) over 3.4 days. Dim light melatonin onsets were measured before and after the ultradian protocol, from which the circadian period was derived. In contrast to our hypothesis, we found that free-running circadian period was similar in adolescents and adults. African-American adults had shorter free-running circadian periods compared with adults of other ancestries. This ancestry difference was not seen in the adolescent group. Finally, we observed a non-significant trend for shorter free running circadian periods in females compared with males. These data suggest that age-related changes in circadian period after late adolescence do not account for sleep timing differences. These data provide further support for ancestry-related differences in period, particularly in adults. Whether the large difference in circadian period between African-American and other ancestries emerges later in development should be explored. PMID- 29516558 TI - 2D Ruddlesden-Popper Perovskites Microring Laser Array. AB - 3D organic-inorganic hybrid perovskites have featured high gain coefficients through the electron-hole plasma stimulated emission mechanism, while their 2D counterparts of Ruddlesden-Popper perovskites (RPPs) exhibit strongly bound electron-hole pairs (excitons) at room temperature. High-performance solar cells and light-emitting diodes (LEDs) are reported based on 2D RPPs, whereas light amplification devices remain largely unexplored. Here, it is demonstrated that ultrafast energy transfer along cascade quantum well (QW) structures in 2D RPPs concentrates photogenerated carriers on the lowest-bandgap QW state, at which population inversion can be readily established enabling room-temperature amplified spontaneous emission and lasing. Gain coefficients measured for 2D RPP thin-films (~100 nm in thickness) are found about at least four times larger than those for their 3D counterparts. High-density large-area microring arrays of 2D RPPs are fabricated as whispering-gallery-mode lasers, which exhibit high quality factor (Q ~ 2600), identical optical modes, and similarly low lasing thresholds, allowing them to be ignited simultaneously as a laser array. The findings reveal that 2D RPPs are excellent solution-processed gain materials potentially for achieving electrically driven lasers and ideally for on-chip integration of nanophotonics. PMID- 29516557 TI - From Nanostructural Evolution to Dynamic Interplay of Constituents: Perspectives for Perovskite Solar Cells. AB - Moving away from the high-performance achievements in organometal halide perovskite (OHP)-based optoelectronic and photovoltaic devices, intriguing features have been reported in that photocarriers and mobile ionic species within OHPs interact with light, electric fields, or a combination of both, which induces both spatial and temporal changes of optoelectronic properties in OHPs. Since it is revealed that the transport of photocarriers and the migration of ionic species are affected not only by each other but also by the inhomogeneous character, which is a consequence of the route selected to deposit OHPs, understanding the nanostructural evolution during OHP deposition, in terms of the resultant structural defects, electronic traps, and nanoscopic charge behaviors, will be valuable. Investigation of the film-growth mechanisms and strategies adopted to realize OHP films with less-defective large grains is of central importance, considering that single-crystalline OHPs have exhibited the most beneficial properties, including carrier lifetimes. Critical factors governing the behavior of photocarriers, mobile ionic species, and nanoscale optoelectronic properties resulting from either or all of them are further summarized, which may potentially limit or broaden the optoelectronic and photovoltaic applications of OHPs. Through inspection of the recent advances, a comprehensive picture and future perspective of OHPs are provided. PMID- 29516559 TI - Exploring the efficacy of reintegrative shaming for non-predatory offending. AB - BACKGROUND: Since Braithwaite advanced reintegrative shaming theory about 25 years ago, the theory has almost invariably been retested only in relation to predatory offending. Few studies have tested the relevance of the theory for non predatory offending. AIM: This study aims to explore the utility of reintegrative shaming theory in explaining non-predatory crimes. Our main research question was: is acknowledgement of shame apportioned by others associated with reduction in non-predatory offending? METHODS: We used zero-inflated negative binomial modelling to analyse data from a national, longitudinal, population-based study of 1,726 adolescents. RESULTS: Overall, peer shame acknowledgement at age 18-21 was a significant predictor of no non-predatory offending at ages 21-27. Contrary to our expectation, however, similar recognition and incorporation of parental shame was not related to absence of such offending. IMPLICATIONS: Our findings add further weight to the validity of reintegrative shaming theory, showing its broader value explaining criminal behaviour-and desistance from it-beyond the original model. PMID- 29516561 TI - Ultrathin Hierarchical Porous Carbon Nanosheets for High-Performance Supercapacitors and Redox Electrolyte Energy Storage. AB - The design of advanced high-energy-density supercapacitors requires the design of unique materials that combine hierarchical nanoporous structures with high surface area to facilitate ion transport and excellent electrolyte permeability. Here, shape-controlled 2D nanoporous carbon sheets (NPSs) with graphitic wall structure through the pyrolysis of metal-organic frameworks (MOFs) are developed. As a proof-of-concept application, the obtained NPSs are used as the electrode material for a supercapacitor. The carbon-sheet-based symmetric cell shows an ultrahigh Brunauer-Emmett-Teller (BET)-area-normalized capacitance of 21.4 uF cm 2 (233 F g-1 ), exceeding other carbon-based supercapacitors. The addition of potassium iodide as redox-active species in a sulfuric acid (supporting electrolyte) leads to the ground-breaking enhancement in the energy density up to 90 Wh kg-1 , which is higher than commercial aqueous rechargeable batteries, maintaining its superior power density. Thus, the new material provides a double profits strategy such as battery-level energy and capacitor-level power density. PMID- 29516562 TI - Automatic artefact detection in single-channel sleep EEG recordings. AB - Quantitative electroencephalogram analysis (e.g. spectral analysis) has become an important tool in sleep research and sleep medicine. However, reliable results are only obtained if artefacts are removed or excluded. Artefact detection is often performed manually during sleep stage scoring, which is time consuming and prevents application to large datasets. We aimed to test the performance of mostly simple algorithms of artefact detection in polysomnographic recordings, derive optimal parameters and test their generalization capacity. We implemented 14 different artefact detection methods, optimized parameters for derivation C3A2 using receiver operator characteristic curves of 32 recordings, and validated them on 21 recordings of healthy participants and 10 recordings of patients (different laboratory) and considered the methods as generalizable. We also compared average power density spectra with artefacts excluded based on algorithms and expert scoring. Analyses were performed retrospectively. We could reliably identify artefact contaminated epochs in sleep electroencephalogram recordings of two laboratories (healthy participants and patients) reaching good sensitivity (specificity 0.9) with most algorithms. The best performance was obtained using fixed thresholds of the electroencephalogram slope, high-frequency power (25-90 Hz or 45-90 Hz) and residuals of adaptive autoregressive models. Artefacts in electroencephalogram data can be reliably excluded by simple algorithms with good performance, and average electroencephalogram power density spectra with artefact exclusion based on algorithms and manual scoring are very similar in the frequency range relevant for most applications in sleep research and sleep medicine, allowing application to large datasets as needed to address questions related to genetics, epidemiology or precision medicine. PMID- 29516563 TI - Formal Lossen Rearrangement/[3+2] Annulation Cascade Catalyzed by a Modified Cyclopentadienyl RhIII Complex. AB - It has been established that a cyclopentadienyl RhIII complex with two phenyl groups and a pendant amide moiety catalyzes the formal Lossen rearrangement/[3+2] annulation cascade of N-pivaloyl benzamides and acrylamides with alkynes leading to substituted indoles and pyrroles. Mechanistic studies revealed that this cascade reaction proceeds via not the Lossen rearrangement to form anilides or enamides but C-H bond cleavage, alkyne insertion, and the formal Lossen rearrangement. PMID- 29516564 TI - Marital relationship and health-related quality of life of patients with prostate cancer and their spouses: A longitudinal clinical study. AB - AIMS AND OBJECTIVES: To examine changes in the marital relationship 6 months after the diagnosis and the effects of these changes on the health-related quality of life of the patients with prostate cancer and their spouses. BACKGROUND: There is limited knowledge on the impact of a diagnosis of prostate cancer on the marital relationship and health-related quality of life of patients and their spouses. DESIGN: Survey with longitudinal descriptive and comparative elements. METHODS: Of 350 recruited couples (N = 700), 186 couples (n = 372) completed the Marital Questionnaire and RAND 36-Item Health Survey at the two measurement points: time of diagnosis and 6 months later. Changes in the marital relationship were analysed statistically using descriptive statistics and nonparametric tests. The influence of changes in the marital relationship on health-related quality of life was evaluated using linear regression analyses. RESULTS: The patients and their spouses reported lower marital satisfaction 6 months after the diagnosis than at the time of diagnosis. The summary score for marital satisfaction of the spouses significantly decreased during the follow-up period. In contrast, decreasing changes in the marital relationship of the patients were not statistically significant. Furthermore, the marital relationship of the patients and their spouses was not statistically significantly associated with changes in the health-related quality of life of the patients and their spouses within 6 months. CONCLUSIONS: The results of this study add to current knowledge of the marital relationship of patients with prostate cancer and their spouses. The spouses reported that their marital relationship had suffered, whereas the patients reported that the marital relationship remained unchanged. RELEVANCE TO CLINICAL PRACTICE: These findings may be useful when counselling of patients with prostate cancer and their spouses. PMID- 29516565 TI - The three-dimensional structure of NeoB: An aminotransferase involved in the biosynthesis of neomycin. AB - The aminoglycoside antibiotics, discovered as natural products in the 1940s, demonstrate a broad antimicrobial spectrum. Due to their nephrotoxic and ototoxic side effects, however, their widespread clinical usage has typically been limited to the treatment of serious infections. Neomycin B, first isolated from strains of Streptomyces in 1948, is one such drug that was approved for human use by the U.S. Food and Drug Administration in 1964. Only within the last 11 years has the biochemical pathway for its production been elaborated, however. Here we present the three-dimensional architecture of NeoB from Streptomyces fradiae, which is a pyridoxal 5'-phosphate or PLP-dependent aminotransferase that functions on two different substrates in neomycin B biosynthesis. For this investigation, four high resolution X-ray structures of NeoB were determined in various complexed states. The overall fold of NeoB is that typically observed for members of the "aspartate aminotransferase" family with the exception of an additional three stranded antiparallel beta-sheet that forms part of the subunit-subunit interface of the dimer. The manner in which the active site of NeoB accommodates quite different substrates has been defined by this investigation. In addition, during the course of this study, we also determined the structure of the aminotransferase GenB1 to high resolution. GenB1 functions as an aminotransferase in gentamicin biosynthesis. Taken together, the structures of NeoB and GenB1, presented here, provide the first detailed descriptions of aminotransferases that specifically function on aldehyde moieties in aminoglycoside biosynthesis. PMID- 29516566 TI - t-Butyl-Oxycarbonylated Diamines as Building Blocks for Isocyanate-Free Polyurethane/Urea Dispersions and Coatings. AB - t-Butyl-oxycarbonylated diamines ("di-Boc-carbamates") are investigated as dicarbamate monomers for diamine/dicarbamate polymerizations. Polyureas (PUs) and polyurethanes (PURs) with high molecular weights are prepared from stoichiometric polymerizations of diamines or diols with N-N'-di-t-butyl-oxycarbonyl isophorone diamine (DiBoc-IPDC) using KOt-Bu as a catalyst, while gelation is observed when an excess of DiBoc-IPDC is used with respect to the diamines or diols. Stable dispersions are obtained from PUs and PURs with 3,3'-diamino-N methyldipropylamine (DMDPA) as internal dispersing agent. The corresponding PU based coatings exhibit superior mechanical properties and solvent resistances compared to the polyurethane urea coatings synthesized from diols, DiBoc-IPDC, and DMDPA. PMID- 29516567 TI - Investigating piwi-interacting RNA regulome in human neuroblastoma. AB - Remarkable attempts have been exercised in recent years using high-throughput technologies to identify and decipher the functions of piRNAs in various abnormalities like cancer. However, piRNAs in the oncogenesis of neuroblastoma (NB) has not been reported yet even after their illustrated roles in neurological processes. Therefore, we investigated the piRNA transcriptome in IMR-32 and SH-SY 5Y NB cell lines by employing high-throughput next-generation sequencing after confirming the expression of three associated PIWILs both at mRNAs and protein level by qRT-PCR and immunofluroscence, respectively. We identified a common pool of 525 piRNAs of 26-32 nts long expressed in both the cell lines. The possible functions of these piRNAs were charted by predicting their targeting on retrotransposon-containing 1769 mRNAs differentially expressed in 39 NB cell lines followed by network and pathway analysis. The analysis revealed that majority of the target binding sites in NB fall within retrotransposons residing within the 3'UTR of target mRNA transcripts like miRNA-targets. Further, we validated the expression of key piRNAs and their target genes enriched in cancer related networks, pathways and biological processes which are hypothesized to play crucial roles in neoplastic events of NB. We believe that the evidence of piRNAs in human NB and their possible contribution to its pathogenesis reported in this work will open up new exciting possibilities for piRNA-mediated therapeutics for this malignancy. PMID- 29516568 TI - Maslinic acid induces autophagy by down-regulating HSPA8 in pancreatic cancer cells. AB - Maslinic acid (MA), a natural pentacyclictriterpene, displays cytotoxic activity on various types of cancer cells. However, its underlying mechanism is unclear. In this study, we assessed the effect of MA on autophagy of human pancreatic cancer cells, and the potential autophagic pathway was presented. MA inhibited the proliferation and induced autophagy of Panc-28 cells by altering the expressions of autophagy related proteins. SDS-PAGE analysis revealed that one protein band was significantly down-regulated in cells treated with MA, and the band was identified as heat shock protein HSPA8 as analyzed using Western blot and MS, MS/MS approaches. HSPA8 knockdown could significantly inhibit cell viability and enhance the cytotoxic effects of MA, whereas HSPA8 overexpression was able to enhance cell viability, diminishing the effects of MA. Western blot analysis indicated that the effect of MA on the expression of autophagy related genes was increased significantly in cells treated with HSPA8 inhibitor VER 155008, whereas HSPA8 inducer geranylgeranylacetone antagonized the effects of MA. Our study provides evidence that MA is able to induce of autophagy via down regulation of HSPA8 in Panc-28 cells. PMID- 29516569 TI - A HILIC-MS/MS method for simultaneous quantification of the lysosomal disease markers galactosylsphingosine and glucosylsphingosine in mouse serum. AB - Deficiencies of galactosylceramidase and glucocerebrosidase result in the accumulation of galactosylsphingosine (GalSph) and glucosylsphingosine (GluSph) in Krabbe and Gaucher diseases, respectively. GalSph and GluSph are useful biomarkers for both diagnosis and monitoring of treatment effects. We have developed and validated a sensitive, accurate, high-throughput assay for simultaneous determination of the concentration of GalSph and GluSph in mouse serum. GalSph and GluSph and their deuterated internal standards were extracted by protein precipitation in quantitative recoveries, baseline separated by hydrophilic interaction chromatography and detected by positive-ion electrospray mass spectrometry in multiple reaction monitoring mode. Total run time was 7 min. The lower limit of quantification was 0.2 ng/mL for both GalSph and GluSph. Sample stability, assay precision and accuracy, and method robustness were demonstrated. This method has been successfully applied to measurement of these lipid biomarkers in a natural history study in twitcher (Krabbe) mice. PMID- 29516570 TI - Stomatin-like protein 2 inhibits cisplatin-induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells. AB - Stomatin-like protein 2 (STOML2 or SLP-2) is an oncogenic anti-apoptotic protein that is upregulated in several types of cancer, including cervical cancer. However, the mechanisms responsible for the SLP-2 anti-apoptotic function remain poorly understood. Here, we show that siRNA-mediated SLP-2 suppression decreases growth of human cervical cancer HELA and SIHA cells, and increases cisplatin induced apoptosis through activation of MEK/ERK signaling and suppression of the mitochondrial pathway. The inhibition of the mitochondrial pathway is mediated by increasing the mitochondrial Ca2+ concentration and mitochondrial membrane potential, thereby downregulating p-MEK and p-ERK levels, upregulating the Bax/Bcl-2 ratio, increasing cytochrome C release from mitochondria into the cytosol, and upregulating levels of cleaved-caspase 9, cleaved-caspase 3, and cleaved poly ADP-ribose polymerase (PARP). Overexpression of SLP-2 using adenovirus-STOML2 has the opposite effect: it upregulates p-MEK and p-ERK and downregulates the Bax/Bcl-2 ratio and levels of cleaved-caspase 9 to caspase 9, cleaved-caspase 3 to caspase 3, and cleaved-PARP to PARP in cisplatin-treated cells. These data show that SLP-2 inhibits cisplatin-induced apoptosis by activating the MEK/ERK signaling and inhibiting the mitochondrial apoptosis pathway in cervical cancer cells. PMID- 29516571 TI - Opinions and attitudes on the relationship between spirituality, religiosity and health: A comparison between nursing students from Brazil and Portugal. AB - AIMS AND OBJECTIVES: To compare the opinions and attitudes of Portuguese-speaking nursing students from Brazil and Portugal on the relationship between religiosity/spirituality and the ability to approach these issues with patients, in their undergraduate training and practice. BACKGROUND: Although there are studies investigating nursing students' opinions concerning religiosity and spirituality in clinical practice, few have investigated if there are cross cultural differences between countries. DESIGN: Observational, cross-sectional and multicenter study carried out in 2010 and 2011 in Brazil and in 2016 in Portugal. METHODS: A total of 260 third and fourth year nursing students (139 from Portugal and 121 from Brazil) from four nursing schools were included. Religious beliefs (Duke Religion Index), attitudes and opinions about spirituality and health (Curlin's questionnaire) were assessed. A comparison between students from both countries was carried out. RESULTS/FINDINGS: Significant differences were found between nursing students from Brazil and Portugal, which are countries with the same language, but with different nursing training programs and population characteristics. Brazilian students were more religious and have stronger opinions on the influence and appropriateness of spirituality in clinical practice than Portuguese students. However, both groups of students indicated they should be prepared to address religiosity and spirituality with patients, that these subjects should be included in the curriculum and that they were not properly prepared to address spiritual issues. CONCLUSION: Although different opinions and attitudes were found between Brazilian and Portuguese nursing students, more training in these issues should be implemented in the undergraduate education. Cross-cultural studies could help fostering a broad discussion in the field. RELEVANCE TO CLINICAL PRACTICE: These findings could contribute to raise awareness on the importance of improving the training of relational competencies that prepare students to address the dimension of spirituality and religiosity with their patients. PMID- 29516573 TI - Prognostic factors and patterns of recurrence in lymphovascular space invasion positive women with stage IIIC endometriod endometrial cancer. AB - AIM: The purpose of this study was to determine the prognostic factors and patterns of failure in lymphovascular space invasion (LVSI)-positive women with stage IIIC endometrioid endometrial cancer (EC). METHODS: A multicenter, retrospective, department database review was performed to identify LVSI-positive patients with stage IIIC endometrioid EC at five gynecological oncology centers in Turkey. Demographic, clinicopathological and survival data were collected. RESULTS: We identified 172 LVSI-positive women with stage IIIC endometrioid EC during the study period; 75 (43.6%) were classified as Stage IIIC1 and 97 (56.4%) as Stage IIIC2 . The median age at diagnosis was 59 years, and the median duration of follow up was 34.5 months. The total number of recurrences was 46 (26.7%). We observed 14 (8.1%) locoregional recurrences, 12 (7.0%) retroperitoneal failures and 20 (11.6%) distant relapses. For the entire study cohort, 5-year progression-free survival (PFS) was 67.4%, while the 5-year overall survival (OS) rate was 75.1%. Grade 3 histology (hazard ratio [HR] 2.62, 95% confidence interval [CI] 1.34-5.12; P = 0.005), cervical stromal invasion (HR 2.33, 95% CI 1.09-4.99; P = 0.028) and myometrial invasion (MMI) >=50% (HR 4.0, 95% CI 1.16-13.69; P = 0.028) were found to be independent prognostic factors for decreased OS. CONCLUSION: Uterine factors such as grade 3 disease, cervical stromal invasion and deep MMI seem to be independently associated with decreased OS in LVSI-positive women with stage IIIC endometrioid EC. The high distant recurrence rate in this subgroup of patients warrants further studies in order to identify the most effective treatment strategy for those patients. PMID- 29516572 TI - Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect. AB - Cancer cells metabolize glucose mainly by glycolysis and are well adapted to metabolic stress. Pim1 is an oncogene that promotes colorectal cancer (CRC) growth and metastasis, and its expression is positively correlated with CRC progression. However, the mechanism underlying Pim1 overexpression during CRC progression and the role of Pim1 in CRC metabolism remains unclear. In the present study, we discovered that Pim1 expression was significantly upregulated in response to glucose deprivation-induced metabolic stress by AMP-activated protein kinase signaling. Pim1 promoted CRC cell proliferation in vitro and tumorigenicity in vivo. Clinical observations showed that Pim1 expression was higher in CRC tissues than in adjacent normal tissues. Pim1 overexpression in CRC tissues not only predicted CRC prognosis in patients but also showed a positive relationship with 18 F-fluorodeoxyglucose uptake. Further in vitro experiments showed that Pim1 promoted the Warburg effect and that Pim1 expression was positively correlated with hexokinase 2 and lactate dehydrogenase A expression. Pim1-silenced cells were more vulnerable to glucose starvation, and Pim1-induced tumor proliferation or tolerance to glucose starvation was attenuated by blocking the Warburg effect. In conclusion, glucose deprivation is one of the mechanisms that leads to elevated Pim1 expression in CRC, and Pim1 upregulation ensures CRC growth in response to glucose deprivation by facilitating the Warburg effect in a compensatory way. PMID- 29516574 TI - Reference values for circulating pregnancy-associated microRNAs in maternal plasma and their clinical usefulness in uncomplicated pregnancy and hypertensive disorder of pregnancy. AB - AIM: The aim of this study was to establish the reference values for circulating pregnancy-associated placental microRNAs in maternal plasma and clarify their clinical significance in patients with hypertensive disorder of pregnancy (HDP). METHODS: Blood samples were collected from 145 women with uncomplicated pregnancies (24, 26, 31 and 32 women at 12, 23, 30 and 36 weeks of gestation, respectively, and 32 women 1 day after delivery). Plasma concentrations of pregnancy-associated placental microRNAs (miR-515-3p, miR-517a, miR-517c and miR 518b) were measured by quantitative real-time reverse-transcription polymerase chain reaction. Reference values for each microRNA were determined by the line of best fit and 95% prediction interval and are expressed as logarithmic transformation. To clarify the clinical significance of these reference values, we measured the plasma concentrations of pregnancy-associated microRNAs in a different population comprising 33 pregnant women with HDP and 44 women with uncomplicated pregnancies. RESULTS: Reference values for circulating pregnancy associated placental microRNAs on chromosome 19 miRNA clusters showed an increasing tendency as pregnancy progressed and decreased significantly 1 day after delivery (P < 0.05). The sensitivity and specificity of each reference value were 57.6% and 93.2% for miR-515-3p, 63.6% and 75.0% for miR-517a, 75.8% and 79.5% for miR-517c and 63.6% and 75.0% for miR-518b, respectively. The positive and negative predictive values of each reference value were 86.4% and 74.5% for miR-515-3p, 65.6% and 73.3% for miR-517a, 73.5% and 81.4% for miR-517c and 65.6% and 73.3% for miR-518b, respectively. CONCLUSION: Establishing the reference values for circulating pregnancy-associated placental microRNAs in maternal plasma could be useful for the evaluation of HDP. PMID- 29516575 TI - Solitary fibrous tumor of the ovary. AB - Solitary fibrous tumors commonly occur in the pleura and are rare elsewhere, especially in the female genital system. We present a case of a solitary fibrous tumor arising from the ovary in a young female in the reproductive age group. The tumor could be excised laparoscopically. We also describe the histopathological and immunohistochemical features that can help establish its diagnosis. PMID- 29516576 TI - Immunoperinatology. PMID- 29516577 TI - Effects of prokineticin 2 on testicular inflammation in rats. AB - PROBLEM: Prokineticin 2 (PK2), a pro-inflammatory peptide, is highly expressed in primary spermatocytes. However, systematic research on PK2 and testicular inflammation is lacking to date. METHOD OF STUDY: An experimental autoimmune orchitis (EAO) model was established to detect the expression of PK2 and its receptor (prokineticin receptor 1, PKR1) 50 and 80 days after immunization. PK2 siRNA sequence was injected into the rat rete testis to downregulate the expression of PK2. PK2 was over-expressed in the testis by injecting PK2 protein through the rat rete testis at different concentrations. Testicular morphology and expression of inducible nitric oxide synthase (iNOS) were detected after the intervention. RESULTS: Results showed that PK2 and PKR1 were upregulated in EAO at 50 days and downregulated at 80 days. PK2 over-expression contributed to the apoptosis of spermatogenic epithelial cells and increased infiltration of the inflammatory cells, whereas PK2 under-expression showed no change. Furthermore, iNOS expression was increased significantly when PK2 was over-expressed. CONCLUSION: This finding demonstrated that the PK2/PKR1 signals may have an essential role in the regulation of testicular inflammation through iNOS. PK2 interference may represent a novel and promising therapeutic strategy for the clinical management of orchitis. PMID- 29516578 TI - FES-Cycling at Cybathlon 2016: Overview on Teams and Results. PMID- 29516579 TI - Normothermic Ex Vivo Perfusion of Discarded Human Pancreas. PMID- 29516580 TI - Response to Letter to the Editor: Electrochemotherapy Treatment of Canine Transmissible Venereal Tumors. PMID- 29516581 TI - Artificial Organs 2017: A Year in Review. AB - In this Editor's Review, articles published in 2017 are organized by category and summarized. We provide a brief reflection of the research and progress in artificial organs intended to advance and better human life while providing insight for continued application of these technologies and methods. Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery, and Regeneration from all over the world. Peer-reviewed Special Issues this year included contributions from the 12th International Conference on Pediatric Mechanical Circulatory Support Systems and Pediatric Cardiopulmonary Perfusion edited by Dr. Akif Undar, Artificial Oxygen Carriers edited by Drs. Akira Kawaguchi and Jan Simoni, the 24th Congress of the International Society for Mechanical Circulatory Support edited by Dr. Toru Masuzawa, Challenges in the Field of Biomedical Devices: A Multidisciplinary Perspective edited by Dr. Vincenzo Piemonte and colleagues and Functional Electrical Stimulation edited by Dr. Winfried Mayr and colleagues. We take this time also to express our gratitude to our authors for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons for their expert attention and support in the production and marketing of Artificial Organs. We look forward to reporting further advances in the coming years. PMID- 29516582 TI - Individual differences in decision making competence revealed by multivariate fMRI. AB - While an extensive literature in decision neuroscience has elucidated the neurobiological foundations of decision making, prior research has focused primarily on group-level effects in a sample population. Due to the presence of inherent differences between individuals' cognitive abilities, it is also important to examine the neural correlates of decision making that explain interindividual variability in cognitive performance. This study therefore investigated how individual differences in decision making competence, as measured by the Adult Decision Making Competence (A-DMC) battery, are related to functional brain connectivity patterns derived from resting-state fMRI data in a sample of 304 healthy participants. We examined connectome-wide associations, identifying regions within frontal, parietal, temporal, and occipital cortex that demonstrated significant associations with decision making competence. We then assessed whether the functional interactions between brain regions sensitive to decision making competence and seven intrinsic connectivity networks (ICNs) were predictive of specific facets of decision making assessed by subtests of the A DMC battery. Our findings suggest that individual differences in specific facets of decision making competence are mediated by ICNs that support executive, social, and perceptual processes, and motivate an integrative framework for understanding the neural basis of individual differences in decision making competence. PMID- 29516583 TI - Magnetic resonance imaging of degeneration of uterine adenomyosis during pregnancy and post-partum period. AB - Degeneration of adenomyosis during pregnancy and the post-partum period is very rare. A 42-year-old Japanese parous woman with four normal-term deliveries, who presented with abdominal pain and fever at 22 weeks of gestation with transient increases of the white blood cell count and C-reactive protein, demonstrated sustained inflammation after cesarean section at 29 weeks of gestation due to the occurrence of gestational hypertension with late deceleration. The noncontrast enhanced magnetic resonance imaging (MRI) at 22 weeks demonstrated a poorly demarcated hypointense area at the posterior uterine wall on T1- and T2-weighted imaging. The 2nd MRI 2 weeks after the cesarean section showed hypointensity on a T1-weighted image and hyperintensity on a T2-weighted image, allowing confirmation of the diagnosis of degeneration of adenomyosis. Repeated MRIs were clinically useful to diagnose the degeneration of adenomyosis. PMID- 29516584 TI - Retrospective study of umbilical cord ulceration related to congenital intestinal atresia: A single-center report. AB - AIM: Umbilical cord ulceration (UCU) is a disease in which an ulcer forms in the umbilical cord in the pregnant uterus and is accompanied by hemorrhaging from the same site. UCU occurs in fetuses with congenital upper-intestinal atresia (CUIA); however, its onset mechanism remains unclear. Here, we report our investigation of cases of UCU in our hospital. METHODS: Among the 9825 deliveries performed between 2007 and 2016 at this hospital, 20 fetuses were diagnosed with CUIA, 4 (20%) of which had UCU. There was no difference in the backgrounds of the fetuses with UCU (UCU group: 4 fetuses) and those without (non-UCU group: 16 fetuses). RESULTS: There was no intergroup difference in gestational age at delivery. Four cases in the UCU group had maternal age 35 weeks (26-39), weeks of delivery 35 weeks (35-36) and weight 2178.5 g (1600-2640); three out of four fetuses were female; and the location of gastrointestinal obstruction was in the duodenum in one case and in the jejunum in three cases. Death occurred in three of four fetuses in the UCU group versus none in the non-UCU group. CONCLUSION: We performed a retrospective statistical investigation on the risk of UCU onset in cases from this hospital; however, we could not identify any prognostic factors for its onset. We investigated a total of 27 past reported UCU cases and the 4 cases in this study. Mean gestational age at onset was 33.3 +/- 2.7 for all 27 cases. Various methods for the early discovery of UCU have been reported in the past; however, there is currently no gold standard. Based on this report and a review of past papers, for CUIA, it is desirable to perform in-hospital management from gestational week 30 onward and decide proper delivery timing on a case-by-case basis. PMID- 29516585 TI - Utilization of drugs with pregnancy exposure registries during pregnancy. AB - PURPOSE: To describe the utilization of drugs with pregnancy exposure registries by trimester during pregnancy, in comparison with matched nonpregnant episodes and a pre-pregnancy period. METHODS: We identified live-born deliveries from women aged 10 to 54 years and matched the pregnancies 1:1 with nonpregnant episodes from a comparator cohort not delivering live-born infants, using data from 2001 to 2013 in the Sentinel Distributed Database. We evaluated the utilization of 34 drugs with pregnancy exposure registries, comparing utilization during pregnancy to the matched nonpregnant episodes, and to the 90 days before pregnancy. RESULTS: We identified 1 895 597 pregnancies ending in live births in 1 598 697 women and 1 895 597 matched nonpregnant episodes in 1 582 581 women. We observed a lower prevalence of use for most drugs during pregnancy compared with the matched nonpregnant episodes, and the 90-day pre-pregnancy period. The median (interquartile range) prevalence ratio of use, at any time during pregnancy, for all products was 0.2 (0.1-0.3) comparing pregnant to nonpregnant episodes. Overall, there was a decrease in drug utilization by trimester; from 2.6% in the 90 days preceding pregnancy to 2.1% in the first trimester, 1.1% in the second trimester, and 0.9% in the third trimester. CONCLUSIONS: Among drugs with pregnancy exposure registries, use was less during pregnancy compared with before pregnancy and to the matched nonpregnant episodes. The lower utilization during pregnancy suggests that women may be avoiding these drugs to minimize potentially harmful exposure during pregnancy. This lower utilization may increase the challenges of further studying the safety of these drugs using pregnancy exposure registries. PMID- 29516586 TI - Multimodal imaging for diagnosis and management of parasitic peritoneal myoma with myxoid degeneration after laparoscopic-assisted myomectomy with electric power morcellation. AB - A 45-year-old multipara woman was referred due to the rapid enlargement of an asymptomatic pelvic mass that was detected during a regular check up. She had undergone laparoscopic-assisted myomectomy 15 years previously. At the time, the uncontained extraction of an intraligamental myoma with electric power morcellation had been performed. Multimodal imaging revealed a heterogeneous mass in the vesicouterine pouch that was found to be supplied by the left gastro omental and superior vesical arteries. Although malignancy could not be completely denied, parasitic peritoneal myoma with myxoid degeneration was the most probable diagnosis. Single-port laparoscopic excision of the peritoneal mass was performed along with laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy. The excised peritoneal mass was placed into a retrieval bag and extracted through the vagina. The pathological diagnosis was a parasitic peritoneal myoma with myxoid degeneration. The postoperative course was uneventful, and there was no recurrence of parasitic myoma in the 1-year follow up after surgery. PMID- 29516587 TI - Cortical activation patterns to spatially presented pure tone stimuli with different intensities measured by functional near-infrared spectroscopy. AB - Functional near-infrared spectroscopy (fNIRS) is an emerging technique for the assessment of functional activity of the cerebral cortex. Recently fNIRS was also envisaged as a novel neuroimaging approach for measuring the auditory cortex activity in the field of in auditory diagnostics. This study aimed to investigate differences in brain activity related to spatially presented sounds with different intensities in 10 subjects by means of functional near-infrared spectroscopy (fNIRS). We found pronounced cortical activation patterns in the temporal and frontal regions of both hemispheres. In contrast to these activation patterns, we found deactivation patterns in central and parietal regions of both hemispheres. Furthermore our results showed an influence of spatial presentation and intensity of the presented sounds on brain activity in related regions of interest. These findings are in line with previous fMRI studies which also reported systematic changes of activation in temporal and frontal areas with increasing sound intensity. Although clear evidence for contralaterality effects and hemispheric asymmetries were absent in the group data, these effects were partially visible on the single subject level. Concluding, fNIRS is sensitive enough to capture differences in brain responses during the spatial presentation of sounds with different intensities in several cortical regions. Our results may serve as a valuable contribution for further basic research and the future use of fNIRS in the area of central auditory diagnostics. PMID- 29516588 TI - Combining abundance and performance data reveals how temperature regulates coastal occurrences and activity of a roaming apex predator. AB - The redistribution of species has emerged as one of the most pervasive impacts of anthropogenic climate warming, and presents many societal challenges. Understanding how temperature regulates species distributions is particularly important for mobile marine fauna such as sharks given their seemingly rapid responses to warming, and the socio-political implications of human encounters with some dangerous species. The predictability of species distributions can potentially be improved by accounting for temperature's influence on performance, an elusive relationship for most large animals. We combined multi-decadal catch data and bio-logging to show that coastal abundance and swimming performance of tiger sharks Galeocerdo cuvier are both highest at ~22 degrees C, suggesting thermal constraints on performance may regulate this species' distribution. Tiger sharks are responsible for a large proportion of shark bites on humans, and a focus of controversial control measures in several countries. The combination of distribution and performance data moves towards a mechanistic understanding of tiger shark's thermal niche, and delivers a simple yet powerful indicator for predicting the location and timing of their occurrences throughout coastlines. For example, tiger sharks are mostly caught at Australia's popular New South Wales beaches (i.e. near Sydney) in the warmest months, but our data suggest similar abundances will occur in winter and summer if annual sea surface temperatures increase by a further 1-2 degrees C. PMID- 29516590 TI - Efficient Light-Induced pKa Modulation Coupled to Base-Catalyzed Photochromism. AB - Photoswitchable acid-base pairs, whose pKa values can be reversibly altered, are attractive molecular tools to control chemical and biological processes with light. A significant, light-induced pKa change of three units in aqueous medium has been realized for two thermally stable states, which can be interconverted using UV and green light. The light-induced pKa modulation is based on incorporating a 3-H-thiazol-2-one moiety into the framework of a diarylethene photoswitch, which loses the heteroaromatic stabilization of the negatively charged conjugate base upon photochemical ring closure, and hence becomes significantly less acidic. In addition, the efficiency of the photoreactions is drastically increased in the deprotonated state, giving rise to catalytically enhanced photochromism. It appears that protonation has a significant influence on the shape of the ground- and excited-state potential energy surfaces, as indicated by quantum-chemical calculations. PMID- 29516589 TI - Neuregulin-1 is a chemoattractant and chemokinetic molecule for trunk neural crest cells. AB - BACKGROUND: Trunk neural crest cells migrate rapidly along characteristic pathways within the developing vertebrate embryo. Proper trunk neural crest cell migration is necessary for the morphogenesis of much of the peripheral nervous system, melanocytes, and the adrenal medulla. Numerous molecules help guide trunk neural crest cell migration throughout the early embryo. RESULTS: The trophic factor NRG1 is a chemoattractant through in vitro chemotaxis assays and in vivo silencing via a DN-erbB receptor. Interestingly, we also observed changes in migratory responses consistent with a chemokinetic effect of NRG1 in trunk neural crest velocity. CONCLUSIONS: NRG1 is a trunk neural crest cell chemoattractant and chemokinetic molecule. Developmental Dynamics 247:888-902, 2018.. (c) 2018 Wiley Periodicals, Inc. PMID- 29516592 TI - Pain after root canal treatment with different instruments: A systematic review and meta-analysis. AB - The aims of this systematic review were to compare the incidence and intensity of postoperative pain after single-visit root canal treatment using manual, rotary, and reciprocating instruments. An extensive literature search in PubMed, EMBASE, Cochrane Library, and Web of Science was performed to identify investigations that evaluated the effects of different instruments on postendodontic pain. Meta analyses and additional analyses, including subgroup and sensitivity analyses, were conducted. We included seventeen trials in this study. Pooled results showed that patients treated with rotary instruments experienced a significantly lower incidence of postoperative pain (RR, 0.32, p = .0005) and reduced pain intensity than did patients treated with manual instruments. In addition, patients treated with multiple rotary-file systems experienced a significantly lower incidence of postoperative pain than did those treated with reciprocating systems (RR, 0.73; p < .0001). The use of rotary instruments contributed to a lower incidence and intensity of postoperative pain than did the use of hand files in patients who received single-visit root canal treatment. In addition, the use of multiple rotary-file systems contributed to a lower incidence of postoperative pain than did the use of reciprocating systems. PMID- 29516591 TI - Lead-Free Silver-Bismuth Halide Double Perovskite Nanocrystals. AB - Lead-free perovskite nanocrystals (NCs) were obtained mainly by substituting a Pb2+ cation with a divalent cation or substituting three Pb2+ cations with two trivalent cations. The substitution of two Pb2+ cations with one monovalent Ag+ and one trivalent Bi3+ cations was used to synthesize Cs2 AgBiX6 (X=Cl, Br, I) double perovskite NCs. Using femtosecond transient absorption spectroscopy, the charge carrier relaxation mechanism was elucidated in the double perovskite NCs. The Cs2 AgBiBr6 NCs exhibit ultrafast hot-carrier cooling (<1 ps), which competes with the carrier trapping processes (mainly originate from the surface defects). Notably, the photoluminescence can be increased by 100 times with surfactant (oleic acid) added to passivate the defects in Cs2 AgBiCl6 NCs. These results suggest that the double perovskite NCs could be potential materials for optoelectronic applications by better controlling the surface defects. PMID- 29516593 TI - Lower levels of brain-derived neurotrophic factor are associated with melancholic psychomotor retardation among depressed inpatients. AB - OBJECTIVES: Melancholic depression is a type of depression which is closely related to biological variables than are other types of depression. Its clinical features can be assessed using six items on the Hamilton Depression Rating Scale (HAM-D6 ). Previous studies have shown, using item response theory, that the symptom depressed mood is the least severe melancholic feature; work and activities, somatic symptoms and psychic anxiety are of moderate severity; and feelings of guilt and psychomotor retardation are the most severe. We aimed to evaluate whether the more severe melancholic signs or symptoms were associated with decreases in brain-derived neurotrophic factor (BDNF) levels. METHODS: A total of 151 severely depressed inpatients had their BDNF levels analyzed by comparing those who presented with each HAM-D6 melancholic feature to those for whom the HAM-D6 feature was absent, using multiple linear regressions. The levels of BDNF of patients who presented with each melancholic feature were also compared with those of 100 healthy controls. RESULTS: Depressed patients' median BDNF level was 44.06 ng/mL (interquartile range [IQR]: 33.99-62.4 ng/mL), and controls' median BDNF level was 65.22 ng/mL (IQR: 49.87-76.08 ng/mL) (P < .001). The presence of depressed mood, work and activities, somatic symptoms, psychic anxiety, and guilty feelings was not associated with BDNF levels. However, the presence of psychomotor retardation was associated with reduced BDNF (median reduction -10.07 ng/mL; 95% confidence interval [CI]: -19.43 to -0.71; P = .03). CONCLUSIONS: To the best of our knowledge, this study is the first to associate BDNF levels with melancholic features in a sample of severely depressed inpatients. The main finding of this study was that severely depressed inpatients who presented the most severe melancholic feature, psychomotor retardation, had significantly reduced BDNF levels in the blood. PMID- 29516594 TI - On the Origin of the Distinctly Different Reactivity of Ruthenium in [MO]+ /CH4 Systems (M=Fe, Ru, Os). AB - The thermal gas-phase reactions of [RuO]+ with methane have been explored by FT ICR mass spectrometry and high-level quantum-chemical calculations. In contrast to the previously studied [FeO]+ /CH4 and [OsO]+ /CH4 couples, which undergo oxygen/hydrogen atom transfers and dehydrogenation, respectively, the [RuO]+ /CH4 system produces selectively [Ru(CH)2 ]+ and H2 O, albeit with much lower efficiency. Various mechanistic scenarios were uncovered, and the associated electronic origins were revealed by high-level quantum-chemical calculations. The reactivity differences observed for the [MO]+ /CH4 couples (M=Fe, Ru, Os) are due to the subtle interplay of the spin-orbit coupling efficiency, orbital overlap, and relativistic effects. PMID- 29516595 TI - The effects of a heating pad on anxiety, pain, and distress during urodynamic study in the female patients with stress urinary incontinence. AB - AIMS: Although generally well tolerated, a urodynamic study is an unpleasant and stressful procedure for some patients. This study evaluated the effects of a heating pad on anxiety, pain, and distress during urodynamic studies in female patients with stress urinary incontinence. METHODS: A total of 74 female patients with stress urinary incontinence who underwent a urodynamic study between May 2015 and October 2015 were randomized to either the experimental group using a heating pad (n = 37) or control group (n = 37). In the experimental group, a heating pad was applied on the patient's sacrum during the urodynamic study. All patients completed the State-Trait Anxiety Inventory (20-80) before and after the procedure and assessed their degree of pain and distress after the procedure by the visual analog scale (0-10). Systolic and diastolic blood pressure and pulse rate were also checked before and after the procedure. RESULTS: Demographic characteristics, mean age, procedure duration, pre and post-procedural systolic, and diastolic blood pressures, and pulse rate were statistically similar between the experimental and control groups. The mean State-Trait Anxiety Inventory was significantly lower in the experimental group than in the control group (30.9 +/- 7.5 vs 42.5 +/- 10.1, P < 0.001). The experimental group showed significantly lower pain and distress scores (Visual Analog Scale, 2.7 +/- 1.5, 3.0 +/- 1.5) compared with the control group (4.0 +/- 1.6, 4.7 +/- 2.0, both P < 0.001). CONCLUSIONS: Using a heating pad for female patients with stress urinary incontinence during a urodynamic study is a simple, economical, and effective therapy that enhances patient comfort and decreases anxiety, pain, and distress. PMID- 29516596 TI - WEO Newsletter. PMID- 29516597 TI - Conformational Planarization versus Singlet Fission: Distinct Excited-State Dynamics of Cyclooctatetraene-Fused Acene Dimers. AB - A set of flapping acene dimers fused with an 8pi cyclooctatetraene (COT) ring showed distinct excited-state dynamics in solution. While the anthracene dimer showed a fast V-shaped-to-planar conformational change within 10 ps in the lowest excited singlet state, reminding us of extended Baird aromaticity, the tetracene dimer and the pentacene dimer underwent intramolecular singlet fission (SF) in different manners: A fast and reversible SF with a characteristic delayed fluorescence (FL), and a fast and quantitative SF, respectively. Conformational flexibility of the fused COT linkage plays an important role in these ultrafast dynamics, demonstrating the utility of the flapping molecular series as a versatile platform for designing photofunctional systems. PMID- 29516598 TI - Persistent nitrogen limitation of stream biofilm communities along climate gradients in the Arctic. AB - Climate change is rapidly reshaping Arctic landscapes through shifts in vegetation cover and productivity, soil resource mobilization, and hydrological regimes. The implications of these changes for stream ecosystems and food webs is unclear and will depend largely on microbial biofilm responses to concurrent shifts in temperature, light, and resource supply from land. To study those responses, we used nutrient diffusing substrates to manipulate resource supply to biofilm communities along regional gradients in stream temperature, riparian shading, and dissolved organic carbon (DOC) loading in Arctic Sweden. We found strong nitrogen (N) limitation across this gradient for gross primary production, community respiration and chlorophyll-a accumulation. For unamended biofilms, activity and biomass accrual were not closely related to any single physical or chemical driver across this region. However, the magnitude of biofilm response to N addition was: in tundra streams, biofilm response was constrained by thermal regimes, whereas variation in light availability regulated this response in birch and coniferous forest streams. Furthermore, heterotrophic responses to experimental N addition increased across the region with greater stream water concentrations of DOC relative to inorganic N. Thus, future shifts in resource supply to these ecosystems are likely to interact with other concurrent environmental changes to regulate stream productivity. Indeed, our results suggest that in the absence of increased nutrient inputs, Arctic streams will be less sensitive to future changes in other habitat variables such as temperature and DOC loading. PMID- 29516599 TI - Validity of a clinical diagnosis of bipolar disorder among participants in a multicenter study using the Mini-International Neuropsychiatric Interview. PMID- 29516600 TI - Enhancing Capacity Performance by Utilizing the Redox Chemistry of the Electrolyte in a Dual-Electrolyte Sodium-Ion Battery. AB - A strategy is described to increase charge storage in a dual electrolyte Na-ion battery (DESIB) by combining the redox chemistry of the electrolyte with a Na+ ion de-insertion/insertion cathode. Conventional electrolytes do not contribute to charge storage in battery systems, but redox-active electrolytes augment this property via charge transfer reactions at the electrode-electrolyte interface. The capacity of the cathode combined with that provided by the electrolyte redox reaction thus increases overall charge storage. An aqueous sodium hexacyanoferrate (Na4 Fe(CN)6 ) solution is employed as the redox-active electrolyte (Na-FC) and sodium nickel Prussian blue (Nax -NiBP) as the Na+ ion insertion/de-insertion cathode. The capacity of DESIB with Na-FC electrolyte is twice that of a battery using a conventional (Na2 SO4 ) electrolyte. The use of redox-active electrolytes in batteries of any kind is an efficient and scalable approach to develop advanced high-energy-density storage systems. PMID- 29516601 TI - Rigid Peptide Macrocycles from On-Resin Glaser Stapling. AB - Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled alpha-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 A) between beta-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing alpha-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 alpha-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles. PMID- 29516602 TI - Ago2 and Dicer1 are involved in METH-induced locomotor sensitization in mice via biogenesis of miRNA. AB - microRNA (miRNA) play important roles in drug addiction and act as a post transcriptional regulator of gene expression. We previously reported extensive downregulation of miRNAs in the nucleus accumbens (NAc) of methamphetamine (METH) sensitized mice. However, the regulatory mechanism of this METH-induced downregulation of miRNAs has yet to be elucidated. Thus, we examined METH-induced changes in the expression of miRNAs and their precursors, as well as the expression levels of mRNA and the proteins involved in miRNA biogenesis such as Dicer1 and Ago2, in the nucleus accumbens of METH-induced locomotor sensitized mice. miRNAs and Ago2 were significantly downregulated, while the expression of miRNA precursors remained unchanged or upregulated, which suggests that the downregulation of miRNAs was likely due to a reduction in Ago2-mediated splicing but unlikely to be regulated at the transcription level. Interestingly, the expression level of Dicer1, which is a potential target of METH-induced decreased miRNAs, such as miR-124, miR-212 and miR-29b, was significantly increased. In conclusion, this study indicates that miRNA biogenesis (such as Ago2 and Dicer1) and their miRNA products may have a role in the development of METH addiction. PMID- 29516604 TI - Neighbour tolerance, not suppression, provides competitive advantage to non native plants. AB - High competitive ability has often been invoked as a key determinant of invasion success and ecological impacts of non-native plants. Yet our understanding of the strategies that non-natives use to gain competitive dominance remains limited. Particularly, it remains unknown whether the two non-mutually exclusive competitive strategies, neighbour suppression and neighbour tolerance, are equally important for the competitive advantage of non-native plants. Here, we analyse data from 192 peer-reviewed studies on pairwise plant competition within a Bayesian multilevel meta-analytic framework and show that non-native plants outperform their native counterparts due to high tolerance of competition, as opposed to strong suppressive ability. Competitive tolerance ability of non native plants was driven by neighbour's origin and was expressed in response to a heterospecific native but not heterospecific non-native neighbour. In contrast to natives, non-native species were not more suppressed by hetero- vs. conspecific neighbours, which was partially due to higher intensity of intraspecific competition among non-natives. Heterogeneity in the data was primarily associated with methodological differences among studies and not with phylogenetic relatedness among species. Altogether, our synthesis demonstrates that non-native plants are competitively distinct from native plants and challenges the common notion that neighbour suppression is the primary strategy for plant invasion success. PMID- 29516603 TI - Evidence of subgroups in smokers as revealed in clinical measures and evaluated by neuroimaging data: a preliminary study. AB - To date, fractionation of the nicotine addiction phenotype has been limited to that based primarily on characteristics of cigarette use, although it is widely appreciated that a variety of individual factors are associated with tobacco use disorder. Identifying subtypes of tobacco use disorder based on such factors may lead to better understanding of potential treatment targets, individualize treatments and improve outcomes. In this preliminary study, to identify potential subgroups, we applied hierarchical clustering to a broad range of assessments measuring personality, IQ and psychiatric symptoms, as well as various environmental and experiential characteristics from 102 otherwise healthy cigarette smokers. The identified subgroups were further compared on various resting-state fMRI measures from a subset (N = 65) of individuals who also underwent resting-state fMRI scanning. The clustering dendrogram indicated that smokers can be divided into three subgroups. Each subgroup had unique clinical assessment characteristics. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus. Regression analyses showed that amplitude of low frequency fluctuations in the supplementary motor area/middle cingulate cortex differed between groups and were negatively correlated with the Toronto Alexithymia Scale subscale Difficulty Describing Feelings. PMID- 29516605 TI - Persistent negative temperature response of mesophyll conductance in red raspberry (Rubus idaeus L.) leaves under both high and low vapour pressure deficits: A role for abscisic acid? PMID- 29516607 TI - Amodiaquine improves insulin resistance and lipid metabolism in diabetic model mice. AB - AIMS: Although peroxisome proliferator-activated receptors (PPARs)alpha/gamma dual agonists can be beneficial for treatment of dyslipidemia in patients with type 2 diabetes, their use is limited owing to various side effects, including body weight gain, edema, and heart failure. We aimed to demonstrate that amodiaquine, an antimalarial agent, has potential as a PPARalpha/gamma dual agonist with low risk of adverse effects. METHODS: We screened a Prestwick library (Prestwick Chemical; Illkirch, France) to identify novel PPARalpha/gamma dual agonists and selected amodiaquine (4-[(7-chloroquinolin-4-yl)amino]-2 [(diethylamino)methyl]phenol), which activated both PPAR-alpha & -gamma, for further investigation. We performed both in vitro, including glucose uptake assay and fatty acid oxidation assay, and in vivo studies to elucidate the anti diabetic and anti-obesity effects of amodiaquine. RESULTS: Amodiaquine selectively activated the transcriptional activities of PPARalpha/gamma and enhanced both fatty acid oxidation and glucose uptake without altering insulin secretion in vitro. In high-fat diet-induced obese and genetically modified obese/diabetic mice, amodiaquine not only remarkably ameliorated insulin resistance, hyperlipidemia, and fatty liver but also decreased body weight gain. CONCLUSION: Our findings suggest that amodiaquine exerts beneficial effects on glucose and lipid metabolism by concurrent activation of PPARalpha/gamma. Furthermore, amodiaquine acts as an alternative insulin-sensitizing agent with a positive influence on lipid metabolism and has potential to prevent and treat type 2 diabetes while reducing the risk of lipid abnormalities. PMID- 29516606 TI - Programming Cells for Dynamic Assembly of Inorganic Nano-Objects with Spatiotemporal Control. AB - Programming living cells to organize inorganic nano-objects (NOs) in a spatiotemporally precise fashion would advance new techniques for creating ordered ensembles of NOs and new bio-abiotic hybrid materials with emerging functionalities. Bacterial cells often grow in cellular communities called biofilms. Here, a strategy is reported for programming dynamic biofilm formation for the synchronized assembly of discrete NOs or hetero-nanostructures on diverse interfaces in a dynamic, scalable, and hierarchical fashion. By engineering Escherichia coli to sense blue light and respond by producing biofilm curli fibers, biofilm formation is spatially controlled and the patterned NOs' assembly is simultaneously achieved. Diverse and complex fluorescent quantum dot patterns with a minimum patterning resolution of 100 um are demonstrated. By temporally controlling the sequential addition of NOs into the culture, multilayered heterostructured thin films are fabricated through autonomous layer-by-layer assembly. It is demonstrated that biologically dynamic self-assembly can be used to advance a new repertoire of nanotechnologies and materials with increasing complexity that would be otherwise challenging to produce. PMID- 29516608 TI - Comparison of single versus dual antiplatelet therapy after TAVR: A systematic review and meta-analysis. AB - OBJECTIVE: We aim to evaluate the efficacy of dual versus single anti-platelet therapy (SAPT) after TAVR through a systematic review and meta-analysis of published research. BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is a commonly practiced strategy after transcatheter aortic valve replacement (TAVR). However, there is lack of sufficient evidence supporting this approach. METHOD: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled trials, and the clinical trial registry maintained at clinicaltrials.gov for randomized control trials (RCT) and observational studies comparing DAPT with SAPT post TAVR. Event rates were compared using a forest plot of relative risk with 95% confidence intervals using a random-effects model assuming inter-study heterogeneity. RESULTS: A total of six studies (3 RCTs and 3 observational studies, n = 840) were included in the final analysis. Compared to SAPT, DAPT was associated with increased risk of significant bleeding (life threatening and major) [RR = 2.52 (95% CI 1.62-3.92, P < 0.0001)] with the number needed to harm for major or life-threatening bleeding calculated to be 10.4. There was no significant difference in the incidence of stroke [RR = 1.06 (95% CI, 0.43-2.60, P = 0.90)], spontaneous myocardial infarction [RR = 2.08 (95% CI, 0.56-7.70, P = 0.27)] and all-cause mortality [RR = 1.18 (95% CI, 0.68-2.05, P = 0.56] in the DAPT and SAPT groups. CONCLUSION: In this small meta-analysis of DAPT versus SAPT after TAVR, DAPT did not prevent stroke, myocardial infarction or death while the risk of bleeding was higher. Results from ongoing trials are awaited to determine the best anti-thrombotic approach after TAVR. PMID- 29516609 TI - Differences in rotational positioning and subsequent distal main branch rewiring of the Tryton stent: An optical coherence tomography and computational study. AB - OBJECTIVES: To evaluate the occurrence of rewiring through one of the panels of the Tryton stent (instead of the assumed re-wiring in-between the panels) and the influence on stent geometry and mechanics. BACKGROUND: Tryton is a side branch stent used in combination with a main branch device. It is placed without the need of rotational orientation. However, it is unknown whether main branch re wiring accidentally may occur through a panel, instead of in-between the panels. METHODS: We used three-dimensional optical coherence tomography to evaluate the location of distal main branch re-wiring through Tryton. Furthermore, we used computer simulations to evaluate the influence on stent geometry and mechanics. RESULTS: Rewiring through a panel (instead of in-between two panels) occurred in 45% of the cases. By using virtual stent deployment, we found minimal differences in ostial side branch stenoses (44.8% in-between the panels and 39.0% through a panel). There were no differences in minimum stent areas of the distal main branch (6.38 mm2 vs. 6.39 mm2 ). In both scenarios, the re-wired Tryton cell was large enough for main branch stenting (expressed as the diameter of the largest possible circle that fits within the cells): 3.40 mm (in-between the panels) vs. 3.02 mm (through a panel). CONCLUSIONS: In 45% of the Tryton implantations, distal main branch rewiring (and subsequent main branch stenting) was performed through one Tryton panel, instead of the assumed rewiring in-between the panels. However, this did not result in unfavorable stent geometries or mechanics, as evaluated with computer simulations. PMID- 29516611 TI - Sleep research and sleep medicine: A flourishing field. PMID- 29516610 TI - Optimizing the target detectability of cone beam CT performed in image-guided radiation therapy for patients of different body sizes. AB - PURPOSE: The target detectability of cone beam computed tomography (CBCT) performed in image-guided radiation therapy (IGRT) was investigated to achieve sufficient image quality for patient positioning over a course of treatment session while maintaining radiation exposure from CBCT imaging as low as reasonably achievable (ALARA). METHODS: Body CBCT scans operated in half-fan mode were acquired with three different protocols: CBCTlowD , CBCTmidD , and CBCThighD , which resulted in weighted CT dose index (CTDIw ) of 0.36, 1.43, and 2.78 cGy, respectively. An electron density phantom that is 18 cm in diameter was covered by four layers of 2.5-cm-thick bolus to simulate patients of different body sizes. Multivariate analysis was used to examine the impact of body size, radiation exposure, and tissue type on the target detectability of CBCT imaging, quantified as contrast-to-noise ratio (CNR). RESULTS: CBCTmidD allows sufficient target detection of adipose, breast, muscle, liver in a background of water for normal-weight adults with cross-sectional diameter less than 28 cm, while CBCThighD is suitable for adult patients with larger body sizes or body mass index over 25 kg/m2 . Once the cross-sectional diameter of adult patients is larger than 35 cm, the CTDIw of CBCT scans should be higher than 2.78 cGy to achieve required CNR. As for pediatric and adolescent patients with cross sectional diameter less than 25 cm, CBCTlowD is able to produce images with sufficient target detection. CONCLUSION: The target detectability of soft tissues in default CBCT scans may not be sufficient for overweight or obese adults. Contrary, pediatric and adolescent patients would receive unnecessarily high radiation exposure from default CBCT scans. Therefore, the selection of acquisition parameters for CBCT scans optimized according to patient body size was proposed to ensure sufficient image quality for daily patient positioning in radiation therapy while achieving the ALARA principle. PMID- 29516612 TI - Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study. AB - In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs. PMID- 29516613 TI - Environmentally relevant chemical mixtures of concern in waters of United States tributaries to the Great Lakes. AB - The North American Great Lakes are a vital natural resource that provide fish and wildlife habitat, as well as drinking water and waste assimilation services for millions of people. Tributaries to the Great Lakes receive chemical inputs from various point and nonpoint sources, and thus are expected to have complex mixtures of chemicals. However, our understanding of the co-occurrence of specific chemicals in complex mixtures is limited. To better understand the occurrence of specific chemical mixtures in the US Great Lakes Basin, surface water from 24 US tributaries to the Laurentian Great Lakes was collected and analyzed for diverse suites of organic chemicals, primarily focused on chemicals of concern (e.g., pharmaceuticals, personal care products, fragrances). A total of 181 samples and 21 chemical classes were assessed for mixture compositions. Basin wide, 1664 mixtures occurred in at least 25% of sites. The most complex mixtures identified comprised 9 chemical classes and occurred in 58% of sampled tributaries. Pharmaceuticals typically occurred in complex mixtures, reflecting pharmaceutical-use patterns and wastewater facility outfall influences. Fewer mixtures were identified at lake or lake-influenced sites than at riverine sites. As mixture complexity increased, the probability of a specific mixture occurring more often than by chance greatly increased, highlighting the importance of understanding source contributions to the environment. This empirically based analysis of mixture composition and occurrence may be used to focus future sampling efforts or mixture toxicity assessments. Integr Environ Assess Manag 2018;14:509-518. (c) 2018 SETAC. PMID- 29516614 TI - Rapid One-Step Synthesis of Complex-Architecture Block Polymers Using Inductively "Armed-Disarmed" Monomer Pairs. AB - A facile method is reported for rapid, room-temperature synthesis of block copolymers (BCP) of complex morphology and hence nontraditional spherical assembly. The use of solvated electrons generates radical anions on olefinic monomers, and with a felicitous choice of monomer pairs, this species will propagate bimechanistically (via radical and the anion) to form BCPs. Molecular weight of the obtained BCP range from Mw = 97 000-404 000 g mol-1 (polydispersity index, PDI = 1.4-3.0) depending on monomer pairs. The composition of the blocks can be controlled by changing monomer ratio, with the caveat that yield is affected. Detailed characterization by 2D nuclear magnetic resonance spectroscopy, differential scanning calorimetry (DSC), and analysis of the mechanisms involved indicate the structure of obtained block copolymers to be at least a triblock with a complex central unit. Evaluating trends in the Hammett parameter segregates monomer pairs into "armed and disarmed" groups with respect to radical or anionic polymerization akin to oligosaccharides synthesis. PMID- 29516615 TI - Home blood-pressure monitoring in a hypertensive pregnant population: cost minimisation study. AB - BACKGROUND: Traditional monitoring of blood pressure in hypertensive pregnant women requires frequent visits to the maternity outpatient services. Home blood pressure monitoring (HBPM) could offer a cost-saving alternative that is acceptable to patients. The main objective of this study was to undertake a health economic analysis of HBPM compared with traditional monitoring in hypertensive pregnant women. METHODS: This was a case-control study. Cases were pregnant women with hypertension who had HBPM with or without the adjunct of a smartphone app, via a specially designed pathway. The control group were managed as per existing hospital guidelines. Specific outcome measures were the number of outpatient visits, inpatient bed stays and investigations performed. Maternal, fetal and neonatal adverse outcomes were also recorded. Health economic analysis was performed using two methods: direct cost comparison of the study dataset and process scenario modelling. RESULTS: There were 108 women in the HBPM group, of whom 29 recorded their results on the smartphone app (App-HBPM) and 79 in their notes (Non-app HBPM). The control group comprised of 58 patients. There were significantly more women with chronic hypertension in the HBPM group (49.1% vs 25.9%, P = 0.004). The HBPM group had significantly longer duration of monitoring (9 weeks vs 5 weeks P = 0.004) and started monitoring from an earlier gestation (30 weeks vs 33.6 weeks, P = 0.001). Despite these differences, the mean saving per week for HBPM compared with the control group was L200.69. For the App-HBPM cohort, the saving per week compared with the control group was L286.53. The process modelling method predicted savings of between L98.32 and L245.80 per week using HBPM compared to the traditional monitoring. CONCLUSION: HBPM in hypertensive pregnancies appears to be cost-saving compared with traditional monitoring, without compromising maternal, fetal or neonatal safety. Larger studies are required to confirm these findings. PMID- 29516616 TI - Epidural Abscess During a Spinal Cord Stimulator Trial: A Case Report. AB - BACKGROUND: Spinal cord stimulation (SCS) can be beneficial for low back and radicular pain. A short trial of SCS evaluates the potential effectiveness of this therapy for a specific patient, while also decreasing the likelihood of a failed permanent implant. While rare, an epidural abscess is difficult to diagnose based on its nonspecific and unreliable clinical presentation. CASE: We present a case of an acute-onset methicillin-sensitive Staphylococcus aureus epidural abscess 72 to 96 hours into a trial of a percutaneous spinal cord stimulator. The patient had no prior medical history of an immunocompromised state or other significant risk factors. DISCUSSION: An epidural abscess can rapidly arise from an SCS trial despite strict aseptic technique and prophylactic pre-procedural antibiotics. Spinal epidural abscesses are being detected earlier, and an increasing number of patients are being managed medically. However, it may be challenging to differentiate focal back pain from acute or chronic pain, expected post-procedural pain, and a new entity such as an abscess. PMID- 29516618 TI - Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England. AB - AIMS: To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. METHODS: Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] <=58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. RESULTS: Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c <=58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels <=58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found for GLP-1 analogues. CONCLUSION: Greater use of newer agents was associated with improvement in glycaemic outcomes but was not sufficient to compensate for the prevailing decline. This may reflect wide variability in the prescribing of newer agents. We found that SGLT inhibitors may be superior to other oral agents in relation to HbA1c outcome. Serious consideration should be given to their use. PMID- 29516617 TI - Extracellular vesicle RNAs reflect placenta dysfunction and are a biomarker source for preterm labour. AB - Preterm birth (PTB) can lead to lifelong complications and challenges. Identifying and monitoring molecular signals in easily accessible biological samples that can diagnose or predict the risk of preterm labour (PTL) in pregnant women will reduce or prevent PTBs. A number of studies identified putative biomarkers for PTL including protein, miRNA and hormones from various body fluids. However, biomarkers identified from these studies usually lack consistency and reproducibility. Extracellular vesicles (EVs) in circulation have gained significant interest in recent years as these vesicles may be involved in cell-cell communication. We have used an improved small RNA library construction protocol and a newly developed size exclusion chromatography (SEC)-based EV purification method to gain a comprehensive view of circulating RNA in plasma and its distribution by analysing RNAs in whole plasma and EV-associated and EV depleted plasma. We identified a number of miRNAs in EVs that can be used as biomarkers for PTL, and these miRNAs may reflect the pathological changes of the placenta during the development of PTL. To our knowledge, this is the first study to report a comprehensive picture of circulating RNA, including RNA in whole plasma, EV and EV-depleted plasma, in PTL and reveal the usefulness of EV associated RNAs in disease diagnosis. PMID- 29516619 TI - Coronary physiological assessment combining fractional flow reserve and index of microcirculatory resistance in patients undergoing elective percutaneous coronary intervention with grey zone fractional flow reserve. AB - OBJECTIVES: The aim of this study is to investigate the association between fractional flow reserve (FFR) values and change in coronary physiological indices after elective percutaneous coronary intervention (PCI). BACKGROUND: Decision making for revascularization when FFR is 0.75-0.80 is controversial. METHODS: A retrospective analysis was performed of 296 patients with stable angina pectoris who underwent physiological examinations before and after PCI. To investigate the differences of coronary flow improvement between territories with low-FFR (<0.75) and grey-zone FFR (0.75-0.80), serial changes in physiological indices including mean transit time (Tmn), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) were compared between these two groups. RESULTS: Compared to low-FFR territories, grey-zone FFR territories showed significantly lower prevalence of Tmn shortening, CFR improvement, and decrease in IMR (Tmn shorting, 63.9% vs. 87.0%, P < .001; CFR improvement, 63.0% vs. 75.7%, P = .019; IMR decrease, 51.3% vs. 63.3%, P = .040) and lower extent of their absolute changes (Tmn shorting, 0.06 (-0.03 to 0.16) vs. 0.22 (0.07-0.45), P < .001; CFR improvement, 0.45 (-0.32 to 1.87) vs. 1.08 (0.02-2.44), P < .01; IMR decrease, 0.2 (-44.0 to 31.3) vs. 2.9 (-2.9 to 11.8), P = .022). Multivariate analysis showed that pre-PCI IMR predicted improved coronary flow profile in both groups, whereas pre-PCI FFR predicted increased coronary flow indices in low-FFR territories. CONCLUSIONS: Worsening of physiological indices after PCI was not uncommon in territories showing grey-zone FFR. Physiological assessment combining FFR and IMR may help identify patients who may benefit by PCI, particularly those in the grey zone. PMID- 29516620 TI - Trapping system comparisons for and factors affecting populations of Drosophila suzukii and Zaprionus indianus in winter-grown strawberry. AB - BACKGROUND: Drosophila suzukii (Matsumura) is a major fruit pest in temperate regions worldwide, but in subtropical Florida, winter-grown strawberries have not been severely affected. Zaprionus indianus Gupta is another invasive drosophilid species and a pest of some tropical fruits. To improve monitoring, trapping systems for D. suzukii and Z. indianus were tested. Morphology, ovarian status and the suitability and availability of non-crop hosts as possible D. suzukii population-limiting factors were assessed. RESULTS: Traps with commercial attractants captured more D. suzukii but fewer Z. indianus than those with a homemade mixture. In central and northern Florida, < 10% and 30-80% of D. suzukii, respectively, exhibited darker, winter morph coloration, and 55-75% of females from central Florida were carrying mature and/or immature eggs. Adult D. suzukii were reared from fruits of two of 28 potential hosts: elderberry (Sambucus nigra) and nightshade (Solanum americanum). Nightshade, but not elderberry, was common on field perimeters (21 and six of 36 fields, respectively). Traps placed in wooded or partially wooded field edges yielded the most D. suzukii. CONCLUSION: Florida strawberry is at risk of D. suzukii infestation, as flies were captured throughout the growing season. However, fly captures remained relatively low, peaking at 1.5 flies per trap per day. In central Florida, the low availability and suitability of non-crop hosts likely limit population growth. The finding of few flies in northern Florida may additionally be attributable to a greater proportion of flies displaying winter morph coloration than in central Florida. (c) 2018 Society of Chemical Industry. PMID- 29516621 TI - Transplant of insulin-like growth factor-1 expressing bone marrow stem cells improves functional regeneration of injured rat uterus by NF-kappaB pathway. AB - To investigate the potential beneficial effect of insulin-like growth factor-1 (IGF-1) in BMSC transplantation therapy of uterus injury and the underlying molecular mechanisms, rat BMSCs were isolated and cultured. The relative expressions of IGF-1 and IL-10 were determined by RT-PCR and immunoblotting. The secretory IL-10 and released E2 were measured using ELISA kits. The relative vWF and alpha-SMA expressions were determined by immunohistochemistry. The direct binding of NF-kappaB subunit p50 with IL-10 promoter was analysed by chromatin immunoprecipitation assay. The regulation of IL-10 expression by p50 was interrogated by luciferase reporter assay. Our data demonstrated that IGF-1 expression in BMSCs induced IL-10 expression and secretion, which was further enhanced by E2-PLGA. IGF-1 overexpression improved BMSCs transplantation therapy in rat uterus injury. We further demonstrated that both inhibition and knockdown of p50 abolished IGF-1-induced expression and secretion of IL-10 in BMSCs, which consequently compromised the IGF-1 conferred therapeutic benefits against uterus injury. Furthermore, we elucidated that p50 regulated IL-10 expression via direct association with its promoter. Our data suggested that transplantation of IGF-1 overexpressing BMSCs improved functional regeneration of injured uterus by inducing IL-10 expression and secretion via activation of NF-kappaB signalling. PMID- 29516622 TI - New insights from continuous glucose monitoring into the route to diabetes. AB - AIM: Type 2 diabetes mellitus (T2DM) is preceded by a period of impaired glucoregulation. We investigated if continuous glucose monitoring system (CGMS) (1) could improve our capacity to predict the development of T2DM in subjects at risk. (2) Find out if impaired fasting glucose/impaired glucose tolerance differentiation through CGMS would also elucidate differences in clinical phenotypes. MATERIAL AND METHODS: Observational study of 209 hypertensive patients, aged 18 to 85 years who wore at entry a CGMS. Two CGMS metrics, percent of time under the 100 mg/dL glycaemic threshold (TU100) (impaired fasting glucose surrogate phenotype) and area above the 140 mg/dL glycemic threshold (AO140) (impaired glucose tolerance surrogate phenotype) were measured. The median follow up was 32 months (6-72 mo), and there were 17 new cases of T2DM. RESULTS: In a multivariate Cox proportional hazard survival analysis including the conventional prediabetes-defining criteria and the 2 CGMS-derived variables, only TU100 and HbA1c were significant and independent variables in predicting T2DM development. An increase in 0.1 in TU100 resulted in a 0.69 (95% CI, 0.54-0.88; P < .01) odds ratio of developing T2DM. With cut-off points of 0.5 for TU100 and 5.7% for HbA1c , the test "TU < 0.5 and HbA1c > 5.7%" had a sensitivity of 0.81 (SD, 0.10), a specificity of 0.83 (SD, 0.03), and a likelihood ratio of 4.82 (SD, 1.03) for T2DM development. CONCLUSIONS: Continuous glucose monitoring system allows for a better T2DM risk-development categorization than fasting glucose and HbA1c in a high-risk population. Continuous glucose monitoring system-derived phenotyping reveals clinical differences, not disclosed by conventional fasting plasma glucose/HbA1c categorization. These differences may correlate with distinct pathophysiological mechanisms. PMID- 29516623 TI - A literature review of comfort in the paediatric critical care patient. AB - AIMS AND OBJECTIVES: To investigate the meaning of comfort and to contextualise it within the framework of paediatric critical care. BACKGROUND: The concept of comfort is closely linked to care in all health contexts. However, in specific settings such as the paediatric critical care unit, it takes on particular importance. DESIGN: A literature review was conducted. METHODS: A literature search was performed of articles in English and Spanish in international health science databases, from 1992-March 2017, applying the quality standards established by the PRISMA methodology and the Joanna Briggs Institute. RESULTS: A total of 1,203 publications were identified in the databases. Finally, 59 articles which met the inclusion criteria were entered in this literature review. Almost all were descriptive studies written in English and published in Europe. The concept of comfort was defined as the immediate condition of being strengthened through having the three types of needs (relief, ease and transcendence) addressed in the four contexts of experience (physical, psychospiritual, social and environmental). Only two valid and reliable tools for assessing comfort were found: the Comfort Scale and the Comfort Behavior Scale. CONCLUSIONS: Comfort is subjective and difficult to assess. It has four facets: physical, emotional, social and environmental. High levels of noise and light are the inputs that cause the most discomfort. Comfort is a holistic, universal concept and an important component of quality nursing care. PMID- 29516624 TI - Synthesis and pharmacological evaluation of 2,3-diphenyl acrylonitriles-bearing halogen as selective anticancer agents. AB - Eighteen novel 2,3-diphenyl acrylonitrile derivatives bearing halogens were designed, synthesized, and evaluated for biological activity. Preliminary in vitro results indicated that the majority of the compounds with a para substituted halogen had considerable antiproliferative activity against five human cancer cell lines, including MGC-803, AGS, and BEL-7402, with IC50 values in the range of 0.46-100 MUm. No significant toxic effects on the non-cancerous human liver cell line L-02 were observed. The selective inhibitory activities against cancer cells were significantly better than that of the control lead compound CA-4 and CA-4P. Particularly, potent activities were found for the derivatives of 3-(4-halogen phenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile, such as 5c (4-fluoro), 5f (4-bromo), 5h (4-chloro), and 5k (4-trifluoro- methyl), for AGS with IC50 values of 0.75 +/- 0.24, 0.68 +/- 0.21, 0.41 +/- 0.05, and 1.49 +/- 0.92 MUm, respectively. The antiproliferative effects of 5f were attributed to cell-cycle arrest in the G2 /M phase, induction of cellular apoptosis, suppression of cell migration, and inhibition of cell colony formation in AGS cells. PMID- 29516626 TI - Rebuttal: Off-label diagnostic and therapeutic utilization of perforated monorail balloon catheters in the catheterization laboratory. PMID- 29516625 TI - Anatomy-guided joint tissue segmentation and topological correction for 6-month infant brain MRI with risk of autism. AB - Tissue segmentation of infant brain MRIs with risk of autism is critically important for characterizing early brain development and identifying biomarkers. However, it is challenging due to low tissue contrast caused by inherent ongoing myelination and maturation. In particular, at around 6 months of age, the voxel intensities in both gray matter and white matter are within similar ranges, thus leading to the lowest image contrast in the first postnatal year. Previous studies typically employed intensity images and tentatively estimated tissue probabilities to train a sequence of classifiers for tissue segmentation. However, the important prior knowledge of brain anatomy is largely ignored during the segmentation. Consequently, the segmentation accuracy is still limited and topological errors frequently exist, which will significantly degrade the performance of subsequent analyses. Although topological errors could be partially handled by retrospective topological correction methods, their results may still be anatomically incorrect. To address these challenges, in this article, we propose an anatomy-guided joint tissue segmentation and topological correction framework for isointense infant MRI. Particularly, we adopt a signed distance map with respect to the outer cortical surface as anatomical prior knowledge, and incorporate such prior information into the proposed framework to guide segmentation in ambiguous regions. Experimental results on the subjects acquired from National Database for Autism Research demonstrate the effectiveness to topological errors and also some levels of robustness to motion. Comparisons with the state-of-the-art methods further demonstrate the advantages of the proposed method in terms of both segmentation accuracy and topological correctness. PMID- 29516627 TI - A comparative prospective observational study of children and adults with immune thrombocytopenia: 2-year follow-up. AB - Comparative clinical studies of children and adults with immune thrombocytopenia (ITP) are poorly covered in the literature. However, the accepted classification of ITP-childhood ITP and adult ITP-results in considerable differences in treatment protocols and practice guidelines. The analysis of the Pediatric and Adult Registry on Chronic ITP (PARC-ITP) of patients at first presentation demonstrated fewer differences in clinical and laboratory findings at initial diagnosis between children and adults than expected. The present report of 2-year follow-up data supports the hypothesis that there are common aspects of childhood and adult ITP. Data of 3360 children and 420 adults were collected during the time of 2004 until 2015 at initial diagnosis. Follow-up information was available for 51% and 33% of children and 66% and 49% of adults at 12- and 24-months, respectively. Similarities were found in unexpected areas of ITP, such as the rate of late remission at 12 and 24 months, reported bleeding sites, platelet count in bleeders, and the frequency of treated patients with persistent or chronic ITP. Differences were confirmed for the overall rate of remission and treatment modalities. Unexpected differences were found in the percentage of nonbleeders, with more adults in the nonbleeder group. More studies are needed to investigate different age groups with the aim to optimize their management. PMID- 29516628 TI - Silencing of dedicator of cytokinesis (DOCK180) obliterates pregnancy by interfering with decidualization due to blockage of nuclear entry of autoimmune regulator (AIRE). AB - PROBLEM: Dedicator of cytokinesis (DOCK 180) involved in cytoskeletal reorganization is primarily a cytosolic molecule. It is recently shown to be nuclear in HeLa cells but its nuclear function is not known. METHOD OF STUDY: The spatiotemporal distribution of DOCK180 in uterus was studied in uterine cytoplasmic and nuclear compartments during the "window of implantation." The functional significance of nuclear DOCK180 was explored by homology modeling, co immunoprecipitation assays, and mass spectrometric analysis. Dock180's role in early pregnancy was ascertained by Dock 180 silencing and subsequent quantitative real-time PCR and Western blotting analysis. RESULTS: Our study shows a nuclear DOCK180 in the uterus during "window of implantation." Estrogen and progesterone mediate expression and nuclear translocation of DOCK180. The nuclear function of DOCK180 is attributed to its ability to import autoimmune regulator (AIRE) into the nucleus. Silencing of Dock180 inhibited AIRE nuclear shuttling which influenced its downstream targets, thereby affecting decidualization with AIRE and HOXA-10 as the major players as well as lack of implantation site formation due to impact on angiogenesis-associated genes. CONCLUSION: DOCK180 has an indispensable role in pregnancy establishment as knocking down Dock180 abrogates pregnancy by a consolidated impact on decidualization and angiogenesis by regulating AIRE nuclear entry. PMID- 29516629 TI - Genomic sequences of HLA-A*68:169, HLA-B*07:298 and HLA-B*39:129. AB - Three new HLA class I alleles were described in the Spanish population. HLA A*68:169 and -B*39:129 show one amino acid replacement at the alpha1-domain, compared to A*68:02 (P47 > L47) and -B*39:06 (S11 > A11), respectively. HLA B*07:298 presents one nucleotide mutation within exon 1, resulting in a new amino acid position -14, L>Q, which has not been previously described in any HLA protein. Prediction of the B*07:298 signal peptide cleavage did not show significant differences in comparison with that obtained for the rest of HLA-B genes. PMID- 29516631 TI - Merger of Energetic Affinity and Optimal Geometry Provides New Class of Boron Nitride Based Sorbents with Unprecedented Hydrogen Storage Capacity. AB - Hydrogen is an ideal synthetic fuel because it is lightweight, abundant and its oxidation product (water) is environmentally benign. However, its utilization is impeded by the lack of an efficient storage device. A new building block approach is proposed for an exhaustive search of optimal hydrogen uptakes in a series of low density boron nitride (BN) nanoarchitectures via extensive 3868 ab initio based multiscale simulations. By probing various geometries, temperatures, pressures, and doping ratios, these results demonstrate a maximum uptake of 8.65 wt% at 300 K, the highest hydrogen uptake on sorbents at room temperature without doping. Li+ doping of the nanoarchitectures offers a set of optimal combinations of gravimetric and volumetric uptakes, surpassing the US Department of Energy targets. These findings suggest that the merger of energetic affinity and optimal geometry in BN building blocks overcomes the intrinsic limitations of sorbent materials, putting hybrid BN nanoarchitectures on equal footing with hydrides while demonstrating a superior capacity-kinetics-thermodynamics relationship. PMID- 29516630 TI - WDR79 mediates the proliferation of non-small cell lung cancer cells by regulating the stability of UHRF1. AB - WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family characterized by the presence of a series of WD-repeat domains and is a scaffold protein that participates in telomerase assembly, Cajal body formation and DNA double strand break repair. Although previous studies have revealed that WDR79 is frequently overexpressed in non-small cell lung cancer (NSCLC) and promotes the proliferation of NSCLC cells, the underlying mechanism responsible for WDR79 mediated NSCLC proliferation is not fully understood. In this study, we report a novel molecular function of WDR79 that mediates NSCLC cell proliferation by controlling the stability of UHRF1. In the nucleus, WDR79 colocalized and interacted with UHRF1. As a result, overexpression of WDR79 stabilized UHRF1, whereas ablation of WDR79 decreased the level of UHRF1. Meanwhile, we showed that WDR79 can protect UHRF1 from poly-ubiquitination-mediated proteolysis, which facilitated the stabilization of UHRF1. We further demonstrated that WDR79 exerts a proliferation effect on NSCLC cells by stabilizing UHRF1. These findings reveal that WDR79 is a novel UHRF1 regulator by maintaining UHRF1 stability, and they also provide a clue as to how to explore WDR79 for potential therapeutic application in NSCLC. PMID- 29516632 TI - Volumetric segmentation-free method for rapid visualization of vascular wall shear stress using 4D flow MRI. AB - PURPOSE: To develop a rapid segmentation-free method to visualize and compute wall shear stress (WSS) throughout the aorta using 4D Flow MRI data. WSS is the drag force-per-area the vessel endothelium exerts on luminal blood; abnormal levels of WSS are associated with cardiovascular pathologies. Previous methods for computing WSS are bottlenecked by labor-intensive manual segmentation of vessel boundaries. A rapid automated segmentation-free method for computing WSS is presented. THEORY AND METHODS: Shear stress is the dot-product of the viscous stress tensor and the inward normal vector. The inward normal vectors are approximated as the gradient of fluid speed at every voxel. Subsequently, a 4D map of shear stress is computed as the partial derivatives of velocity with respect to the inward normal vectors. We highlight the shear stress near the wall by fusing visualization with edge-emphasized anatomical data. RESULTS: As a proof of-concept, four cases with aortic pathologies are presented. Visualization allows for rapid localization of pathologic WSS. Subsequent analysis of these pathological regions enables quantification of WSS. Average WSS during peak systole measures approximately 50-60 cPa in nonpathological regions of the aorta and is elevated in regions of stenosis, coarctation, and dissection. WSS is reduced in regions of aneurysm. CONCLUSION: A volumetric technique for calculation and visualization of WSS from 4D Flow MRI data is presented. Traditional labor-intensive methods for WSS rely on explicit manual segmentation of vessel boundaries before visualization. This automated volumetric strategy for visualization and quantification of WSS may facilitate its clinical translation. PMID- 29516633 TI - Obstetric outcome in patients with a unicornuate uterus after laparoscopic resection of a rudimentary horn. AB - AIM: Previous studies have shown adverse obstetric outcomes of the laparoscopic resection of a rudimentary horn. Our study aimed to investigate the obstetric outcome in our institution and to review previous studies. METHODS: Using a retrospective analysis, data were reviewed from singleton pregnancies with maternal uterine anomalies at a medical center in Osaka, Japan, between January 2011 and March 2016. The uterine anomaly cases were divided into a 'postlaparoscopic resection of the rudimentary horn' group (study group) and an 'other uterine anomalies' (bicornuate uterus, uterine didelphys and unicornuate uterus) group (control group). Primary outcomes of interest were differences in obstetric outcomes, such as spontaneous preterm birth rate, small for gestational age (SGA) infant rate and hypertensive disorders of pregnancy (HDP) rate between the study and the control group, and the secondary outcome of interest was mode of delivery in the study group. RESULTS: Data from 40 deliveries were included in the study (7 deliveries: study group, 33 deliveries: control group). No significant difference was observed between the two groups in terms of either mean gestational weeks at delivery (36.4 weeks vs 37.1 weeks; P = .38), cesarean delivery rate (57.1% vs 57.5%; P = 1.0), SGA infant rate (<10th percentile) (0% vs 24.2%; P = .31) and HDP rate (0.0% vs 3.0%; P = 1.0). Three of seven cases with postlaparoscopic resection of the rudimentary horn were able to deliver vaginally without complications. CONCLUSION: Our study shows that the obstetric outcome observed in the study group was similar to that observed in the control group. PMID- 29516634 TI - Diminution of context association memory structure in subjects with subjective cognitive decline. AB - Alzheimer's disease (AD) progresses insidiously from the preclinical stage to dementia. While people with subjective cognitive decline (SCD) have normal cognitive performance, some may be in the preclinical stage of AD. Neurofibrillary tangles appear first in the transentorhinal cortex, followed by the entorhinal cortex in the clinically silent stage of AD. We expected the earliest changes in subjects with SCD to occur in medial temporal subfields other than the hippocampal proper. These selective structural changes would affect specific memory subcomponents. We used the Family Picture subtest of the Wechsler Memory Scale-III, which was modified to separately compute character, activity, and location subscores for episodic memory subcomponents. We recruited 43 subjects with SCD, 44 subjects with amnesic mild cognitive impairment, and 34 normal controls. MRI was used to assess cortical thickness, subcortical gray matter volume, and fractional anisotropy. The results demonstrated that SCD subjects showed significant cortical atrophy in their bilateral parahippocampus and perirhinal and the left entorhinal cortices but not in their hippocampal regions. SCD subjects also exhibited significantly decreased mean fractional anisotropy in their bilateral uncinate fasciculi. The diminution of cortical thickness over the mesial temporal subfields corresponded to brain areas with early tangle deposition, and early degradation of the uncinate fasciculus was in accordance with the retrogenesis hypothesis. The parahippocampus and perirhinal cortex contribute mainly to context association memory while the entorhinal cortex, along with the uncinate fasciculus, contributes to content-related contextual memory. We proposed that context association and related memory structures are vulnerable in the SCD stage. PMID- 29516635 TI - HMQ-T-F2 exert antitumour effects by upregulation of Axin in human cervical HeLa cells. AB - Looking for novel, effective and less toxic therapies for cervical cancer is of significant importance. In this study, we reported that HMQ-T-F2(F2) significantly inhibited cell proliferation and transplantable tumour growth. Mechanistically, HMQ-T-F2 inhibited HeLa cell growth through repressing the expression and nuclear translocation of beta-catenin, enhancing Axin expression, as well as downregulating the Wnt downstream targeted proteins. Knock-down of a checkpoint beta-catenin by siRNA significantly attenuated HeLa cell proliferation. Furthermore, XAV939, an inhibitor of beta-catenin, was used to treat HeLa cells and the results demonstrated that HMQ-T-F2 inhibited proliferation and migration via the inhibition of the Wnt/beta-catenin pathway. PMID- 29516636 TI - Spatially dynamic recurrent information flow across long-range dorsal motor network encodes selective motor goals. AB - Performing voluntary movements involves many regions of the brain, but it is unknown how they work together to plan and execute specific movements. We recorded high-resolution ultra-high-field blood-oxygen-level-dependent signal during a cued ankle-dorsiflexion task. The spatiotemporal dynamics and the patterns of task-relevant information flow across the dorsal motor network were investigated. We show that task-relevant information appears and decays earlier in the higher order areas of the dorsal motor network then in the primary motor cortex. Furthermore, the results show that task-relevant information is encoded in general initially, and then selective goals are subsequently encoded in specifics subregions across the network. Importantly, the patterns of recurrent information flow across the network vary across different subregions depending on the goal. Recurrent information flow was observed across all higher order areas of the dorsal motor network in the subregions encoding for the current goal. In contrast, only the top-down information flow from the supplementary motor cortex to the frontoparietal regions, with weakened recurrent information flow between the frontoparietal regions and bottom-up information flow from the frontoparietal regions to the supplementary cortex were observed in the subregions encoding for the opposing goal. We conclude that selective motor goal encoding and execution rely on goal-dependent differences in subregional recurrent information flow patterns across the long-range dorsal motor network areas that exhibit graded functional specialization. PMID- 29516638 TI - Catalytically Active Bacterial Nanocellulose-Based Ultrafiltration Membrane. AB - Large quantities of highly toxic organic dyes in industrial wastewater is a persistent challenge in wastewater treatment processes. Here, for highly efficient wastewater treatment, a novel membrane based on bacterial nanocellulose (BNC) loaded with graphene oxide (GO) and palladium (Pd) nanoparticles is demonstrated. This Pd/GO/BNC membrane is realized through the in situ incorporation of GO flakes into BNC matrix during its growth followed by the in situ formation of palladium nanoparticles. The Pd/GO/BNC membrane exhibits highly efficient methylene orange (MO) degradation during filtration (up to 99.3% over a wide range of MO concentrations, pH, and multiple cycles of reuse). Multiple contaminants (a cocktail of 4-nitrophenol, methylene blue, and rhodamine 6G) can also be effectively treated by Pd/GO/BNC membrane simultaneously during filtration. Furthermore, the Pd/GO/BNC membrane demonstrates stable flux (33.1 L m-2 h-1 ) under 58 psi over long duration. The novel and robust membrane demonstrated here is highly scalable and holds a great promise for wastewater treatment. PMID- 29516637 TI - Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling. AB - Neovascularization, increased basal membrane thickness and increased airway smooth muscle (ASM) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor (CTGF) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF, compared to mild and non-asthmatic (NA) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor (TGF)-beta increased CTGF expression both in NA- and A ASM cells but the expression was higher in A-ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter luciferase reporter constructs into NA- and A-ASM cells indicated that no region of the CTGF promoter (-1500 to +200 bp) displayed enhanced activity in the presence of TGF-beta. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF-beta in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post-transcriptional regulation in A-ASM cells due to enhanced mRNA stability for CTGF. In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A-ASM may contribute to airway remodelling in asthma. PMID- 29516639 TI - NF-kappaB inhibition reverses acidic bile-induced miR-21, miR-155, miR-192, miR 34a, miR-375 and miR-451a deregulations in human hypopharyngeal cells. AB - We previously demonstrated that acidic bile activates NF-kappaB, deregulating the expression of oncogenic miRNA markers, in pre-malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer-related miRNA markers that can be reversed by BAY 11-7082, a pharmacologic NF-kappaB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 MUmol/L), at pH 4.0 and 7.0, with/without BAY 11 7082 (20 MUmol/L). We centred our study on the transcriptional activation of oncogenic miR-21, miR-155, miR-192, miR-34a, miR-375, miR-451a and NF-kappaB related genes, previously linked to acidic bile-induced pre-neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11-7082 significantly reverses the acidic bile-induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11-7082 strongly inhibits the acidic bile-induced up-regulation of miR-192 and down-regulation of miR-451a and significantly decreases the miR-21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF kappaB inhibition reverses acidic bile-induced miR-21, miR-155, miR-192, miR-34a, miR-375 and miR-451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile-induced events are directly or indirectly dependent on NF-kappaB signalling. PMID- 29516640 TI - Concordance of child self-reported psychotic experiences with interview- and observer-based psychotic experiences. AB - AIM: Valid instruments for the early identification of psychotic experiences (PE) and symptoms in youths are urgently needed for large-scale preventive interventions. A new section of The-Development-and-Well-Being Assessment (DAWBA) measuring child self-reported PE has yet to be validated. The current study aimed to investigate the concurrent validity of DAWBA-based self-reported PE (PE-S) with regard to interview-based measures of PE (PE-I). METHODS: Participants were 1571 (47.8% male) children of age 11 to 12 years from the Copenhagen Child Cohort 2000 (CCC2000) with complete data from both the online PE-section of DAWBA and the following face-to-face interview and assessment of PE. The DAWBA-PE-section asks the child 10 questions covering auditory and visual hallucinations, delusional ideas and subjective thought disturbances ever in life; and attributions to sleep, fever, illness or drug intake. The interview-based assessment of PE was performed by trained professionals using 22 items from The Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime Version (KSADS-PL). The two assessments were completed independently. RESULTS: The prevalence of PE-S was 28.1% (24.3% for PE-S with no frequent attributions), compared with 10.2% for PE-I. The predictive values of PE S for any PE-I were: sensitivity = 73.8%, specificity = 77.1%, positive predictive value (PPV) = 26.8% and negative predictive value (NPV) = 96.3%. Self reported visual hallucinations had the best overall predictive values with a sensitivity of 43.1%, specificity of 94.0%, PPV of 44.8% and a NPV of 93.6% for any PE-I. CONCLUSION: The DAWBA-section proved valuable as a screening tool for PE in the youth general population. PMID- 29516641 TI - Cell-free lncRNA expression signatures in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer. AB - Cell-free long non-coding RNAs (lncRNAs) are stably present in urine and can serve as non-invasive biomarkers for cancer. We aimed to identify signatures of lncRNAs in urine for diagnosis and prognosis of bladder cancer (BC). Screening of lncRNAs by microarray analysis was performed using urine samples of 10 BC patients and 10 controls. Expressions of candidate lncRNAs were evaluated in the training and validation set including 230 BC patients and 230 controls by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A two lncRNA panel (uc004cox.4 and GAS5) was constructed and provided high diagnostic accuracy of BC with an area under the curve (AUC) of 0.885 (95% CI, 0.836-0.924). The AUCs of the lncRNA panel for Ta, T1 and T2-T4 were 0.843, 0.867 and 0.923, respectively, significantly higher than those of urine cytology (all P < .05). Kaplan-Meier analysis revealed that higher level of uc004cox.4 was associated with poor recurrence-free survival (RFS) of non-muscle invasive BC (NMIBC) (P = .008). Additionally, Cox regression analysis indicated that uc004cox.4 was an independent prognostic factor for RFS of NMIBC (P = .018). Taken together, our findings indicated that urinary lncRNA signatures possessed potential clinical value for BC diagnosis. Moreover, uc004cox.4 could provide prognostic information for NMIBC. PMID- 29516642 TI - INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway. AB - Cervical cancer continues to be among the most frequent gynaecologic cancers worldwide. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway is constitutively activated in cervical cancer. Inositol polyphosphate 4-phosphatase type II (INPP4B) is a phosphoinositide phosphatase and considered a negative regulatory factor of the PI3K/AKT pathway. INPP4B has diverse roles in various tumours, but its role in cervical cancer is largely unknown. In this study, we investigated the role of INPP4B in cervical cancer. Overexpression of INPP4B in HeLa, SiHa and C33a cells inhibited cell proliferation, metastasis and invasiveness in CCK-8, colony formation, anchorage-independent growth in soft agar and Transwell assay. INPP4B reduced the expression of some essential proteins in the PI3K/AKT/SGK3 pathway including p-AKT, p-SGK3, p-mTOR, phospho p70S6K and PDK1. In addition, overexpression of INPP4B decreased xenograft tumour growth in nude mice. Loss of INPP4B protein expression was found in more than 60% of human cervical carcinoma samples. In conclusion, INPP4B impedes the proliferation and invasiveness of cervical cancer cells by inhibiting the activation of two downstream molecules of the PI3K pathway, AKT and SGK3. INPP4B acts as a tumour suppressor in cervical cancer cells. PMID- 29516643 TI - Labor induction versus expectant management at early term in pregnancies with second trimester elevated human chorionic gonadotropin or alpha fetoprotein. AB - AIM: Elevated human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) have been linked to placental dysfunction and associated morbidities. We aimed to compare the induction of labor with expectant management at term in those pregnancies for the prevention of neonatal and maternal morbidities. METHODS: Women with second trimester HCG >= 2 and/or AFP >= 2 multiples of the median, without additional maternal or fetal complications, from their 38th gestational week were offered the choice of labor induction or expectant management. The primary outcomes were maternal composite outcome (composed of cesarean deliveries, pre-eclampsia or placental abruption) and neonatal composite outcome (composed of antenatal or neonatal death, Apgar score at 5 min < 7, admission to the neonatal intensive care unit, need for phototherapy, respiratory abnormalities, birth trauma or neonatal infection). RESULTS: Of 305 women, 124 women chose to undergo labor induction, and 181 women chose expectant management. The composite maternal outcome in the expectant management group was twice the rate of the labor induction group, although it did not reach statistical significance (18 [10%] vs 6 [5%]; P = 0.1; relative risk [expectant/induced] 2.04; 95% confidence interval 0.8-5.0). Increased rate of phototherapy led to increased neonatal composite outcomes in the labor induction group compared with the expectant management group (34 [27%] vs 27 [15%], respectively = 0.007). CONCLUSION: In pregnancies with elevated AFP and/or HCG, early term labor induction initiated a trend towards improvement in maternal outcome but increased the rate of mild neonatal morbidity. The statistical insignificance of the large effect on the maternal outcome might reflect the lack of statistical power. Further research is needed to address this limitation. PMID- 29516644 TI - Metal-Nitrogen-doped Porous Carbons Derived from Metal-Containing Ionic Liquids for Oxygen Reduction Reaction. AB - This study describes a self-doping and additive-free strategy for the synthesis of metal-nitrogen-doped porous carbon materials (CMs) via carbonizing well tailored precursors, metal-containing ionic liquids (M-ILs). The organic skeleton in M-ILs serves as both carbon and nitrogen sources, while metal ions acts as porogen and metallic dopants. A high nitrogen content, appropriate content of metallic species and hierarchical porosity synergistically endow the resultant CMs (MIBA-M-T) as effective electrocatalysts for the oxygen reduction reaction (ORR). MIBA-Fe-900 with a high specific surface area of 1567 m2 g-1 exhibits an activity similar to that of Pt/C catalyst, a higher tolerance to methanol than Pt/C, and long-term durability. This work supplies a simple and convenient route for the preparation of metal-containing carbon electrocatalysts. PMID- 29516645 TI - Woody encroachment slows decomposition and termite activity in an African savanna. AB - Woody encroachment can lead to a complete switch from open habitats to dense thickets, and has the potential to greatly alter the biodiversity and ecological functioning of grassy ecosystems across the globe. Plant litter decomposition is a critical ecosystem process fundamental to nutrient cycling and global carbon dynamics, yet little is known about how woody encroachment might alter this process. We compared grass decay rates of heavily encroached areas with adjacent nonencroached open areas in a semi-arid South African savanna using litterbags that allowed or excluded invertebrates. We also assessed the effect of woody encroachment on the activity of termites- dominant decomposer organisms in savanna systems. We found a significant reduction in decomposition rates within encroached areas, with litter taking twice as long to decay compared with open savanna areas. Moreover, invertebrates were more influential on grass decomposition in open areas and termite activity was substantially lower in encroached areas, particularly during the dry season when activity levels were reduced to almost zero. Our results suggest that woody encroachment created an unfavourable environment for invertebrates, and termites in particular, leading to decreased decomposition rates in these areas. We provide the first quantification of woody encroachment altering the functioning of African savanna ecosystems through the slowing of aboveground plant decomposition. Woody encroachment is intensifying across the globe, and our results suggest that substantial changes to the carbon balance and biodiversity of grassy biomes could occur. PMID- 29516646 TI - Photobioreactor cultivation strategies for microalgae and cyanobacteria. AB - The current burden on fossil-derived chemicals and fuels combined with the rapidly increasing global population has led to a crucial need to develop renewable and sustainable sources of chemicals and biofuels. Photoautotrophic microorganisms, including cyanobacteria and microalgae, have garnered a great deal of attention for their capability to produce these chemicals from carbon dioxide, mineralized water, and solar energy. While there have been substantial amounts of research directed at scaling-up production from these microorganisms, several factors have proven difficult to overcome, including high costs associated with cultivation, photobioreactor construction, and artificial lighting. Decreasing these costs will substantially increase the economic feasibility of these production processes. Thus, the purpose of this review is to describe various photobioreactor designs, and then provide an overview on lighting systems, mixing, gas transfer, and the hydrodynamics of bubbles. These factors must be considered when the goal of a production process is economic feasibility. Targets for improving microalgae and cyanobacteria cultivation media, including water reduction strategies will also be described. As fossil fuel reserves continue to be depleted and the world population continues to increase, it is imperative that renewable chemical and biofuel production processes be developed toward becoming economically feasible. Thus, it is essential that future research is directed toward improving these processes. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:811-827, 2018. PMID- 29516648 TI - Solvent and Autocatalytic Effects on the Stabilisation of the sigma-Complex during Electrophilic Aromatic Chlorination. AB - The solvent and autocatalytic effects of the electrophilic aromatic chlorination of benzene are studied using a combined approach of static calculations and ab initio metadynamics simulations. Different possible reaction pathways are investigated and the influence of the solvents (CCl4 , acetonitrile and acetic acid) is thoroughly assessed. Our results show that the stability and lifetime of a charged sigma-complex is increased by electrostatic stabilisation effects of the environment, which can originate from catalytic HCl, solvating effects of polar solvents (acetonitrile), or specific hydrogen bonding interactions with the solvent (acetic acid). Metadynamics simulations reveal a new chlorine addition mechanism explaining the autocatalytic effects of the reaction. The strength of combining static calculations and metadynamics simulations is highlighted, which provide complementary insight into chemical reactions in solvent. PMID- 29516647 TI - Pancreatic beta cells are a sensitive target of embryonic exposure to butylparaben in zebrafish (Danio rerio). AB - BACKGROUND: Butylparaben (butyl p-hydroxybenzoic acid) is a common cosmetic and pharmaceutical preservative reported to induce oxidative stress and endocrine disruption. Embryonic development is sensitive to oxidative stress, with redox potentials playing critical roles in progenitor cell fate decisions. Because pancreatic beta cells have been reported to have low antioxidant gene expression, they may be sensitive targets of oxidative stress. We tested the hypotheses that butylparaben causes oxidative stress in the developing embryo, and that pancreatic beta cells are a sensitive target of butylparaben embryotoxicity. METHODS: Transgenic insulin:GFP zebrafish embryos (Danio rerio) were treated daily with 0, 250, 500, 1,000, and 3,000 nM butylparaben. Pancreatic islet and whole embryo development were examined though 7 days postfertilization, and gene expression was measured by quantitative real-time PCR. Glutathione (GSH) and cysteine redox content were measured at 28 hr postfertilization using HPLC. RESULTS: Butylparaben exposure caused intestinal effusion, pericardial edema, and accelerated yolk utilization. At 250 nM, beta cell area increased by as much as 55%, and increased incidence of two aberrant morphologies were observed fragmentation of the islet cluster and ectopic beta cells. Butylparaben concentrations of 500 and 1,000 nM increased GSH by 10 and 40%, respectively. Butylparaben exposure downregulated transcription factor pdx1, as well as genes involved in GSH synthesis, while upregulating GSH-disulfide reductase (gsr). CONCLUSIONS: The endocrine pancreas is a sensitive target of embryonic exposure to butylparaben, which also causes developmental deformities and perturbs redox conditions in the embryo. PMID- 29516649 TI - VERT, a virtual clinical environment, enhances understanding of radiation therapy planning concepts. AB - INTRODUCTION: The ability to understand treatment plan dosimetry and apply this understanding clinically is fundamental to the role of the radiation therapist. This study evaluates whether or not the Virtual Environment for Radiotherapy Training (VERT) contributes to teaching treatment planning concepts to a cohort of first-year radiation therapy students. METHODS: We directly compared a custom developed VERT teaching module with a standard teaching module with respect to the understanding of treatment planning concepts using a cross-over design. Students self-reported their understanding of specific concepts before and after delivery of the VERT and standard teaching modules and evaluated aspects of VERT as a learning experience. In addition, teaching staff participated in a semi structured interview discussing the modules from an educational perspective. RESULTS: Both the standard teaching module and VERT teaching module enhanced conceptual understanding and level of confidence in the student cohort after both teaching periods. The proportion of students reporting a perceived increase in knowledge/confidence was similar for the VERT teaching module for all but two scenarios. We propose that an integrated approach, providing a strong theoretical conceptual framework, followed by VERT to situate this framework in the (simulated) clinical environment combines the best of both teaching approaches. CONCLUSION: This study has established for the first time a clear role for a tailored VERT teaching module in teaching RT planning concepts because of its ability to visualise conceptual information within a simulated clinical environment. PMID- 29516650 TI - Perceived caring attributes and priorities of preregistration nursing students throughout a nursing curriculum underpinned by person-centredness. AB - AIM AND OBJECTIVE: To explore preregistration nursing students' caring attributes development through a person-centred focused curriculum. BACKGROUND: Developing caring attributes in student nurses to the point of registration has historically been challenging. Globally, curricula have not yet demonstrated the ability to sustain and develop caring attributes in this population, despite its centrality to practice. DESIGN AND METHODS: This longitudinal cohort study tracked how University preregistration nursing students (N = 212) developed their caring attributes over the 3 years of their programme using repeated measures at the end of each year with the same cohort. The Caring Dimensions Inventory (35 item version with 25 caring items under three constructs (technical, intimacy and supporting) and 10 inappropriate or unnecessary construct items) was used and data analysed using Mokken scale analysis to create a hierarchy of actions that students deemed as caring. Repeated measures of analysis of variance enabled evaluation of changes in responses over time. RESULTS: Students developed their caring attributes throughout their programme, ranking 22 of 25 items as caring (with statistical significance) at the end of year 1, 18 at the end of year 2 and all 25 caring items at the end of their final year. No unnecessary or inappropriate construct items were ranked as caring at any data collection point. Participants consistently ranked assisting a person with an activity of living, listening to a patient and involving them in their care as the most caring actions. CONCLUSION: This study found caring attributes can not only be sustained, but can also be developed throughout a preregistration nursing education programme grounded in person-centredness. RELEVANCE TO CLINICAL PRACTICE: Internationally, caring attributes are challenging to develop and sustain throughout preregistration education, largely being diminished over time. Little published evidence evidences how person-centred frameworks are successfully integrated into preregistration nursing curricula to develop person centred nurses. PMID- 29516651 TI - Developing the experts we need: Fostering adaptive expertise through education. AB - In this era of increasing complexity, there is a growing gap between what we need our medical experts to do and the training we provide them. While medical education has a long history of being guided by theories of expertise to inform curriculum design and implementation, the theories that currently underpin our educational programs do not account for the expertise necessary for excellence in the changing health care context. The more comprehensive view of expertise gained by research on both clinical reasoning and adaptive expertise provides a useful framing for re-shaping physician education, placing emphasis on the training of clinicians who will be adaptive experts. That is, have both the ability to apply their extensive knowledge base as well as create new knowledge as dictated by patient needs and context. Three key educational approaches have been shown to foster the development of adaptive expertise: learning that emphasizes understanding, providing students with opportunities to embrace struggle and discovery in their learning, and maximizing variation in the teaching of clinical concepts. There is solid evidence that a commitment to these educational approaches can help medical educators to set trainees on the path towards adaptive expertise. PMID- 29516652 TI - Predators in the plant-soil feedback loop: aboveground plant-associated predators may alter the outcome of plant-soil interactions. AB - Plant-soil feedback (PSF) can structure plant communities, promoting coexistence (negative PSF) or monodominance (positive PSF). At higher trophic levels, predators can alter plant community structure by re-allocating resources within habitats. When predator and plant species are spatially associated, predators may alter the outcome of PSF. Here, I explore the influence of plant-associated predators on PSF using a generalised cellular automaton model that tracks nutrients, plants, herbivores and predators. I explore key contingencies in plant predator associations such as whether predators associate with live vs. senesced vegetation. Results indicate that plant-associated predators shift PSF to favour the host plant when predators colonise live vegetation, but the outcome of PSF will depend upon plant dispersal distance when predators colonise dead vegetation. I apply the model to two spider-associated invasive plants, finding that spider predators should shift PSF dynamics in a way that inhibits invasion by one forest invader, but exacerbates invasion by another. PMID- 29516653 TI - Functional neuroanatomy of gesture-speech integration in children varies with individual differences in gesture processing. AB - Gesture is an integral part of children's communicative repertoire. However, little is known about the neurobiology of speech and gesture integration in the developing brain. We investigated how 8- to 10-year-old children processed gesture that was essential to understanding a set of narratives. We asked whether the functional neuroanatomy of gesture-speech integration varies as a function of (1) the content of speech, and/or (2) individual differences in how gesture is processed. When gestures provided missing information not present in the speech (i.e., disambiguating gesture; e.g., "pet" + flapping palms = bird), the presence of gesture led to increased activity in inferior frontal gyri, the right middle temporal gyrus, and the left superior temporal gyrus, compared to when gesture provided redundant information (i.e., reinforcing gesture; e.g., "bird" + flapping palms = bird). This pattern of activation was found only in children who were able to successfully integrate gesture and speech behaviorally, as indicated by their performance on post-test story comprehension questions. Children who did not glean meaning from gesture did not show differential activation across the two conditions. Our results suggest that the brain activation pattern for gesture speech integration in children overlaps with-but is broader than-the pattern in adults performing the same task. Overall, our results provide a possible neurobiological mechanism that could underlie children's increasing ability to integrate gesture and speech over childhood, and account for individual differences in that integration. PMID- 29516655 TI - A 55-Year-Old Male with Intermittent Headache. PMID- 29516654 TI - Effects of neonatal hyperoxia on the critical period of postnatal development of neurochemical expressions in brain stem respiratory-related nuclei in the rat. AB - We have identified a critical period of respiratory development in rats at postnatal days P12-13, when inhibitory influence dominates and when the response to hypoxia is at its weakest. This critical period has significant implications for Sudden Infant Death Syndrome (SIDS), the cause of which remains elusive. One of the known risk factors for SIDS is prematurity. A common intervention used in premature infants is hyperoxic therapy, which, if prolonged, can alter the ventilatory response to hypoxia and induce sustained inhibition of lung alveolar growth and pulmonary remodeling. The goal of this study was to test our hypothesis that neonatal hyperoxia from postnatal day (P) 0 to P10 in rat pups perturbs the critical period by altering the normal progression of neurochemical development in brain stem respiratory-related nuclei. An in-depth, semiquantitative immunohistochemical study was undertaken at P10 (immediately after hyperoxia and before the critical period), P12 (during the critical period), P14 (immediately after the critical period), and P17 (a week after the cessation of hyperoxia). In agreement with our previous findings, levels of cytochrome oxidase, brain-derived neurotrophic factor (BDNF), TrkB (BDNF receptor), and several serotonergic proteins (5-HT1A and 2A receptors, 5-HT synthesizing enzyme tryptophan hydroxylase [TPH], and serotonin transporter [SERT]) all fell in several brain stem respiratory-related nuclei during the critical period (P12) in control animals. However, in hyperoxic animals, these neurochemicals exhibited a significant fall at P14 instead. Thus, neonatal hyperoxia delayed but did not eliminate the critical period of postnatal development in multiple brain stem respiratory-related nuclei, with little effect on the nonrespiratory cuneate nucleus. PMID- 29516657 TI - Screening for gene mutations in central nervous system metastases of non-small cell lung cancer. PMID- 29516656 TI - A 40-Year-Old Female with Dural-Based Lesions. PMID- 29516658 TI - A 27-Year-Old Female with Multiple Intracranial Lesions. PMID- 29516660 TI - Tauopathy with Hippocampal 4-Repeat Tau Immunoreactive Spherical Inclusions in a Patient with PSP. PMID- 29516661 TI - A 39-Year-Old Gentleman with Headache, Visual Blurring and a Renal Mass. PMID- 29516662 TI - Autism spectrum disorders: Challenges and perspectives. PMID- 29516663 TI - Serological surveillance for Tahyna virus (California encephalitis orthobunyavirus, Peribunyaviridae) neutralizing antibodies in wild ungulates in Austria, Hungary and Romania. AB - A serosurvey for Tahyna virus (TAHV), a mosquito-borne California encephalitis orthobunyavirus (Peribunyaviridae) endemic to Europe, was performed to estimate the activity of TAHV on a broad geographic scale. Sera from wild boar (Sus scrofa), roe deer (Capreolus capreolus) and red deer (Cervus elaphus) were collected from Austria, Hungary and Romania. Samples were tested for neutralizing antibodies against TAHV using a virus microneutralization assay. The results demonstrate that TAHV transmission to mammals is widespread in Europe, particularly in the wild boar population where the mean rate of seroconversion is 15.2%. PMID- 29516664 TI - A Simple One-Pot Strategy for Synthesizing Ultrafine SnS2 Nanoparticle/Graphene Composites as Anodes for Lithium/Sodium-Ion Batteries. AB - SnS2 /graphene composites have attracted extensive attention in energy storage owing to their excellent electrochemical performance. However, most of the previous methods to synthesize SnS2 /graphene composites require long times, high temperatures, or high pressures, which are obstacles for practical low-cost production. A simple one-pot strategy to prepare SnS2 /graphene composites has been developed, which is not time-consuming (1 h) and requires moderate temperature (75 degrees C) in atmosphere. Through this method, ultrafine SnS2 nanoparticles anchored on graphene nanosheets are prepared and exhibit excellent electrochemical performance for both lithium and sodium storage. Specifically, as anodes for lithium-ion batteries, the SnS2 /graphene electrode delivers a high capacity of 1480 mAh g-1 after 50 cycles at 0.2 A g-1 . Even at 10 A g-1 , the SnS2 /graphene electrode can achieve a capacity of 666 mAh g-1 . A constructed full lithium-ion cell exhibits a capacity of 957 mAh g-1 after 50 cycles at 1 A g 1 . This simple one-pot strategy may pave the way for large-scale production and practical application of SnS2 /graphene composites in energy storage. PMID- 29516665 TI - The polymorphisms of miRNA-binding site in MLH3 and ERCC1 were linked to the risk of colorectal cancer in a case-control study. AB - Colorectal cancer (CRC), as a malignant tumor of lower digestive tract, has been found to have an increasing morbidity and mortality in China. It was particularly important to find some earlier biomarkers to predict the risk and prognosis. In this study, several polymorphisms on 3'UTR of three DNA repair genes including MLH3 rs10862, ERCC1 rs3212986, ERCC1 rs735482, ERCC1 rs2336219, and OGG1 rs1052133 were chosen by bioinformatics exploration, and then, a case-control study of 200 CRC cases and controls was performed. Furthermore, a dual-luciferase assay was also carried out to certify whether the candidate miRNA can regulate its target gene and the selected SNPs have a valid effect on the target miRNA. Finally, both of ERCC1 rs3212986 and MLH3 rs108621 were shown to be associated with the risk of CRC. Comparing with rs3212986 CC genotype, AA was at a higher risk (OR = 3.079, 95% CI: 1.192-7.952). For MLH3 rs108621, comparing with TT genotype, CC and TC were at a higher risk of CRC in male (OR = 5.171, 95% CI: 1.009-26.494; OR = 1.904, 95% CI: 1.049-3.455). Interestingly, an analysis combining both ERCC1 rs3212986 and MLH3 rs108621 also showed an increased risk of CRC. In addition, a dual-luciferase assay showed that miR-193a-3p could regulate MLH3, and the polymorphism rs108621 could alter the miR-193a-3p binding to MLH3. Therefore, MLH3 rs108621 may be associated with the risk of CRC due to the effect of miR-193a-3p on MLH3, which reminded the possibility as potential susceptibility biomarkers to predict the risk of CRC. PMID- 29516666 TI - Let your fingers do the talking: Passive typing instability predicts future mood outcomes. PMID- 29516667 TI - Effusion-based lymphoma with morphological regression but with clonal genetic features after aspiration. AB - Effusion-based lymphoma (EBL) is a rare but distinct entity of large B-cell lymphoma in effusion without association with human herpes virus-8 (HHV-8). Spontaneous regression after pleurocentesis has been observed; but to our knowledge, there are no reports on the morphological and molecular features of subsequent aspirations in regressing cases. Here, we report the case of a 92-year old male with chronic obstructive pulmonary disease, who presented with right pleural effusion. He had no human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection, and CT scans revealed no mass lesion. The first pleural effusion aspiration cytology revealed large lymphoma cells with vesicular nuclei, irregular nuclear contours, and prominent nucleoli, consistent with EBL. The second aspiration cytology showed a few slightly enlarged lymphocytes in a background of small lymphocytes. Immunohistochemical study on cell block of the second aspiration revealed equal amounts of CD3-positive and CD20-positive cells. All these cells on the section tested negative for HHV-8 through immunohistochemistry and Epstein-Barr virus by in situ hybridization. Our initial impression was EBL in regression. However, flow cytometric immunophenotyping showed monotypic light chain expression of the gated B-cells. B-cell receptor gene rearrangement study showed a clonal result. Furthermore, fluorescence in situ hybridization revealed rearrangement of IGH gene. The diagnosis of the second aspiration was EBL with morphological regression but retained clonal genetic features. The patient passed away one month after diagnosis without chemotherapy. This case illustrated the importance of ancillary studies in confirming the clonal nature of a morphologically regressing EBL. PMID- 29516668 TI - Ethnic differences in insulin secretory function between black African and white European men with early type 2 diabetes. AB - AIM: To test the hypothesis that men of black (West) African ethnicity (black African men [BAM]) with early type 2 diabetes (T2D) would have greater insulin secretory deficits compared with white European men (WEM), following prediabetic hypersecretion. METHODS: In 19 BAM and 15 WEM, matched for age, body mass index and duration of diabetes, we assessed and modelled insulin secretory responses to hyperglycaemia stimulated intravenously (hyperglycaemic clamp) and orally (meal tolerance test). RESULTS: With similar post-challenge glucose responses, BAM had lower second-phase C-peptide responses to intravenous glucose (BAM 70.6 vs WEM 115.1 nmol/L/min [ratio of geometric mean 0.55, 95% confidence interval {CI} 0.37, 0.83]; P = .006) and to oral glucose (BAM 65.4 vs WEM 88.5 nmol/L/min [mean difference -23.2, 95% CI -40.0, -6.3]; P = .009). Peripheral insulin response in BAM to oral glucose was preserved (BAM 47.4 vs WEM 59.4 nmol/L/min [ratio of geometric mean 0.89, 95% CI 0.59, 1.35]; P = .566), with relative reductions in insulin clearance (BAM 506.2 vs WEM 630.1 mL/m2 BSA/min [mean difference -123.9, 95% CI -270.5, 22.6]; P = .095), associated with enhanced incretin responses (gastric inhibitory polypeptide incremental area under the curve: BAM 46.8 vs WEM 33.9 MUg/L/min [mean difference 12.9, 95% CI 2.1, 23.7]; P = .021). CONCLUSIONS: In early T2D, BAM had significantly lower insulin secretory responses to intravenous and oral stimulation than WEM. Lower insulin clearance, potentially driven by increased incretin responses, may act to preserve peripheral insulin concentrations. Tailoring early management strategies to reflect distinct ethnic specific pathophysiology may improve outcomes in this high-risk population. PMID- 29516669 TI - MIMoSA: An Automated Method for Intermodal Segmentation Analysis of Multiple Sclerosis Brain Lesions. AB - BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is crucial for in vivo detection and characterization of white matter lesions (WMLs) in multiple sclerosis. While WMLs have been studied for over two decades using MRI, automated segmentation remains challenging. Although the majority of statistical techniques for the automated segmentation of WMLs are based on single imaging modalities, recent advances have used multimodal techniques for identifying WMLs. Complementary modalities emphasize different tissue properties, which help identify interrelated features of lesions. METHODS: Method for Inter-Modal Segmentation Analysis (MIMoSA), a fully automatic lesion segmentation algorithm that utilizes novel covariance features from intermodal coupling regression in addition to mean structure to model the probability lesion is contained in each voxel, is proposed. MIMoSA was validated by comparison with both expert manual and other automated segmentation methods in two datasets. The first included 98 subjects imaged at Johns Hopkins Hospital in which bootstrap cross-validation was used to compare the performance of MIMoSA against OASIS and LesionTOADS, two popular automatic segmentation approaches. For a secondary validation, a publicly available data from a segmentation challenge were used for performance benchmarking. RESULTS: In the Johns Hopkins study, MIMoSA yielded average Sorensen-Dice coefficient (DSC) of .57 and partial AUC of .68 calculated with false positive rates up to 1%. This was superior to performance using OASIS and LesionTOADS. The proposed method also performed competitively in the segmentation challenge dataset. CONCLUSION: MIMoSA resulted in statistically significant improvements in lesion segmentation performance compared with LesionTOADS and OASIS, and performed competitively in an additional validation study. PMID- 29516670 TI - The effectiveness of age-appropriate pre-operative information session on the anxiety level of school-age children undergoing elective surgery in Jordan. AB - BACKGROUND: Undergoing surgery is an anxious experience for children. Applying anxiety reduction age-appropriate programs by nurses would be beneficial in reducing anxiety to children. AIM: To test the effectiveness of age-appropriate preoperative information session in reducing anxiety levels of school-age children undergoing elective surgery in Jordan. DESIGN: The study used a quasi experimental design. METHODS: One hundred and twenty-six children were recruited from an educational hospital in Amman from January to June 2012 and were randomly assigned to intervention and control groups. The anxiety levels of children were assessed using the State Anxiety Scale for children, and children's levels of cooperation after surgery were assessed using Children Emotional Manifestation Scale. The heart rate and blood pressure of children were also measured 1 hour before going to operation room. RESULTS: The study results revealed that children in the intervention group reported lower anxiety levels and more cooperation than children in the control group. Also, they displayed lower heart rate and blood pressure than children in the control group. CONCLUSION: The application of age appropriate preoperative intervention for children could be beneficial in decreasing anxiety levels and increasing their cooperation post surgery. PMID- 29516671 TI - Surface protein components from entomopathogenic nematodes and their symbiotic bacteria: effects on immune responses of the greater wax moth, Galleria mellonella (Lepidoptera: Pyralidae). AB - BACKGROUND: Steinernema carpocapsae is a nematocomplex widely used as an alternative to chemicals for the biological control of insect pests; this nematode is symbiotically associated with the bacterium Xenorhabdus nematophila and both contribute to host death. The architecture and functions of structures and molecular components of the surface of nematodes and their symbiont bacteria are integral to early interactions with their hosts; thus, we assessed the role of protein pools isolated from the surface of S. carpocapsae and from phase I X. nematophila against Galleria mellonella. RESULTS: Using high-salt treatments, we isolated the surface proteins and assayed them on G. mellonella haemocytes; haemocyte viability and phagocytic activity were investigated in the presence of surface proteins from nematodes or bacteria. Proteins from live S. carpocapsae possessed mild cytotoxicity on the haemocytes, whereas those from live X. nematophila markedly affected the host cells' viability. Bacterial proteins inhibited phagocytic activity, although they strongly triggered the host proPO (prophenoloxidase-phenoloxidase) system. CONCLUSION: Nematocomplex surface compounds play a key role in immunoevasion/depression of insect hosts, causing a severe physiological disorder. Natural compounds newly identified as active against pests could improve the pest management of species potentially harmful to plants in urban green spaces and agriculture. (c) 2018 Society of Chemical Industry. PMID- 29516672 TI - A novel peptide Phylloseptin-PBu from Phyllomedusa burmeisteri possesses insulinotropic activity via potassium channel and GLP-1 receptor signalling. AB - Insulin, as one of the most important hormones regulating energy metabolism, plays an essential role in maintaining glucose and lipid homeostasis in vivo. Failure or insufficiency of insulin secretion from pancreatic beta-cells increases glucose and free fatty acid level in circulation and subsequently contributes to the emergence of hyperglycaemia and dyslipidaemia. Therefore, stimulating the insulin release benefits the treatment of type 2 diabetes and obesity significantly. Frog skin peptides have been extensively studied for their biological functions, among which, Phylloseptin peptides discovered in Phyllomedusinae frogs have been found to exert antimicrobial, antiproliferative and insulinotropic activities, while the mechanism associated with Phylloseptin induced insulin secretion remains elusive. In this study, we reported a novel peptide named Phylloseptin-PBu, isolated and identified from Phyllomedusa burmeisteri, exhibited dose-dependent insulinotropic property in rat pancreatic beta BRIN-BD11 cells without altering cell membrane integrity. Further mechanism investigations revealed that Phylloseptin-PBu-induced insulin output is predominantly modulated by KATP -[K+ ] channel depolarization triggered extracellular calcium influx and GLP-1 receptor initiated PKA signalling activation. Overall, our study highlighted that this novel Phylloseptin-PBu peptide has clear potential to be developed as a potent antidiabetic agent with established function-traced mechanism and low risk of cytotoxicity. PMID- 29516673 TI - Isolation and identification of floral attractants from a nectar plant for the dried bean beetle, Acanthoscelides obtectus (Coleoptera: Chrysomelidae, Bruchinae). AB - BACKGROUND: The response of virgin females of the legume pest Acanthoscelides obtectus (Coleoptera: Bruchidae) to headspace extracts of volatiles collected from flowers of a nectar plant, Daucus carota, was investigated using behaviour (four-arm olfactometry) and coupled gas chromatography-electroantennography (GC EAG). RESULTS: Odours from inflorescences were significantly more attractive to virgin female beetles than clean air. Similarly, a sample of volatile organic compounds (VOCs) collected by air entrainment (dynamic headspace collection) was more attractive to beetles than a solvent control. In coupled GC-EAG experiments with beetle antennae and the VOC extract, six components showed EAG activity. Using coupled GC-mass spectrometry (GC-MS) and GC peak enhancement with authentic standards, the components were identified as alpha-pinene (S:R 16:1), sabinene, myrcene, limonene (S:R 1:3), terpinolene and (S)-bornyl acetate. Females preferred the synthetic blend of D. carota EAG-active volatiles to the solvent control in bioassays. When compared directly, odours of D. carota inflorescences elicited stronger positive behaviour than the synthetic blend. CONCLUSION: This is the first report of behaviourally active volatiles linked to pollen location for A. obtectus, and development of the six-component blend is being pursued, which could underpin the design of semiochemical-based field management approaches against this major pest of stored products. (c) 2018 Society of Chemical Industry. PMID- 29516675 TI - Do FHIT gene alterations play a role in human solid tumors? AB - The fragile histidine triad (FHIT) gene encloses an active common chromosomal fragile site, FRA3B. This gene is known to be associated with genomic instability, apoptosis and DNA damage. FHIT disturbances have been related to carcinogenesis in different types of human tumor. Despite this, there are some controversies about the exact role of the FHIT gene in relation to tumor biology. Several pieces of evidence support the hypothesis that FHIT acts as a tumor suppressor gene. A loss or decrease in the Fhit protein expression appears to be related to tumor progression, poor prognostic factors and lower survival rates. The most frequent causes of FHIT expression changes are gene mutations, epigenetic alteration and loss of heterozygosity. This literature review aims to clarify the involvement of the FHIT gene in carcinogenesis, tumor progression and clinical outcome in prevalent solid malignancies, such as breast, lung, cervical, esophageal, gastric and colorectal cancers. PMID- 29516674 TI - Cytokinesis arrest and multiple centrosomes in B cell chronic lymphocytic leukaemia. AB - Cytokinesis failure leads to the emergence of tetraploid cells and multiple centrosomes. Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in adults and is characterized by clonal B cell expansion. Here, we show that a significant number of peripheral blood CLL cells are arrested in cytokinesis and that this event occurred after nuclear envelope reformation and before cytoplasmic abscission. mRNA expression data showed that several genes known to be crucial for cell cycle regulation, checkpoint and centromere function, such as ING4, ING5, CDKN1A and CDK4, were significantly dysregulated in CLL samples. Our results demonstrate that CLL cells exhibit difficulties in completing mitosis, which is different from but may, at least in part, explain the previously reported accumulation of CLL cells in G0/1. PMID- 29516676 TI - Drinking despite adversity: behavioral evidence for a head down and push strategy of conflict-resistant alcohol drinking in rats. AB - Compulsive alcohol drinking, where intake persists regardless of adverse consequences, plays a major role in the substantial costs of alcohol use disorder. However, the processes that promote aversion-resistant drinking remain poorly understood. Compulsion-like responding has been considered automatic and reflexive and also to involve higher motivation, since drinking persists despite adversity. Thus, we used lickometry, where microstructural behavioral changes can reflect altered motivation, to test whether conflict-resistant intake [quinine alcohol (QuiA)] reflected greater automaticity or motivation relative to alcohol only drinking (Alc). Front-loading during QuiA and Alc suggested incentive to drink in both. However, the relationship between total licking and intake was less variable during QuiA, as was lick volume, without changes in average responding. QuiA bout organization was also less variable, with fewer licks outside of bouts (stray licks) and fewer gaps within bouts. Interestingly, QuiA avoidance of stray licking continued into short bouts, with fewer short and more medium-length bouts, which was striking given their minor impact on intake. Instead, more effort at bout onset could allow short bouts to persist longer. Indeed, while QuiA licking was overall faster, QuiA bouts were especially fast at bout initiation. However, few QuiA changes individually predicted greater intake, perhaps suggesting an overarching strategy during aversion-resistant responding. Thus, our results indicate that aversion-resistant intake exhibited less variability, where increased automaticity could decrease need for awareness, and stronger bout initiation, which might prolong responding despite adversity. This may reflect a collective strategy, which we call Head Down and Push responding that facilitates conflict-resistant, compulsion-like intake. PMID- 29516677 TI - The ULTIMATE Reagent: A Universal Photocleavable and Clickable Reagent for the Regiospecific and Reversible End Labeling of Any Nucleic Acid. AB - There is a need for methods to chemically incorporate photocleavable labels into synthetic and biologically sourced nucleic acids in a chemically defined and reversible manner. We have previously demonstrated that the light-cleaved diazo di-methoxy nitro phenyl ethyl (diazo-DMNPE) group has a remarkable regiospecificity for modifying terminally phosphorylated siRNA. Building on this observation, we have identified conditions under which a diazo-DMNPE reagent that we designed (diazo-DMNPE-azide or DDA) is able to singly modify any nucleic acid (RNA, DNA, single-stranded, double-stranded, 3' or 5' phosphate). It can then be modified with any clickable reagent to incorporate arbitrary labels such as fluorophores into the nucleic acid. Finally, native nucleic acid can be regenerated directly through photolysis of the reagent. Use of the described approach should allow for the tagging of any nucleic acid, from any source natural or unnatural-while allowing for the light-induced regeneration of native nucleic acid. PMID- 29516678 TI - UCA1 promotes cell proliferation and invasion of gastric cancer by targeting CREB1 sponging to miR-590-3p. AB - Long noncoding RNAs (lncRNAs) have emerged as regulators in a variety of biological processes, including carcinogenesis in human cancer. UCA1 has been reported to be upregulated in gastric cancer (GC); however, the underlying functional roles of UCA1 in GC have not been established. In the current study, we showed that UCA1 is significantly higher in GC tissues and cells compared with adjacent normal tissues and a gastric epithelium cell line, respectively. Higher UCA1 expression was associated with lymph node metastasis, TNM stage, and poor overall survival (OS) in GC patients. In vitro functional studies confirmed that UCA1 promotes cell proliferation, colony formation ability, and cell invasion in GC cells. We demonstrated that knockdown of UCA1 inhibits tumor growth in vivo. The double luciferase reporter, RNA-binding protein immunoprecipitation assay, and RNA pull down assay demonstrated that miR-590-3p serves as a target for UCA1. UCA1 promoted cell proliferation and invasion by negatively regulating miR-590-3p expression. Moreover, we demonstrated that CREB1 is a downstream target of miR 590-3p and UCA1 activates CREB1 expression by sponging to miR-590-3p. Thus, these results showed that UCA1 functions as an oncogene in GC and may be a target for treatment of GC. PMID- 29516679 TI - Exosomal miRNA Profiling to Identify Nanoparticle Phagocytic Mechanisms. AB - Inhaling a dangerous amount of nanoparticles leads to pulmonary inflammatory and immune disorders, which integrates several kinds of cells. Exosomes are suggested to play a crucial role in intercellular communication via miRNA transmission. To investigate the role of exosomal miRNA in nanoparticle phagocytosis, a total of 54 pneumoconiosis patients along with 100 healthy controls are recruited, exosomes derived from their venous blood are collected, and then exosomal miRNAs are profiled with high-throughput sequencing technology. miRNAs which are differentially expressed are used to predict target genes and conduct functional annotation. Interactions between miRNA hsa-let-7a-5p, hsa-let-7i-5p, and their cotarget gene WASL are found that can affect nanoparticle phagocytosis. The follow-up analysis of gene structure, tissue specificity, and miRNA-target gene regulatory mode supports the findings. Specially, the assumption is further confirmed via a series of cellular experiments, and the fibroblast transdifferentiate rate that is used as an indicator of nanoparticle phagocytosis decreased when elevating miRNA expression level. Thus, data in this study indicate that downregulation of miRNA hsa-let-7a-5p and hsa-let-7i-5p contributes to WASL elevation, promoting WASL and VASP complex formation, which is necessary for initiating Arp2/3 induced phagocytosis. PMID- 29516681 TI - Reactions of Disulfides with Silyl Phosphites to Generate Thiophosphates Under Neat Conditions. AB - An efficient procedure for the synthesis of thiophosphates is described. Without using any metallic catalyst or base, the direct sulfur-phosphorus coupling reaction of disulfides and dialkyl trimethylsilyl phosphite (DTSP) was carried out under solvent-free reaction conditions in moderate to excellent yields with good functional group compatibility. The reaction conditions represent an advance over established methods not only in omitting the need for expensive catalysts or solvents, but also in shortening the reaction time significantly.These transformations are easy to conduct and can be readily applied to gram-scale preparation. PMID- 29516682 TI - Effect of CLIC1 gene silencing on proliferation, migration, invasion and apoptosis of human gallbladder cancer cells. AB - This study aimed to explore the effects of CLIC1 gene silencing on proliferation, migration, invasion and apoptosis of human gallbladder cancer (GBC). GBC and normal gallbladder tissues were extracted for the detection of mRNA and protein expressions of CLIC1. GBC-SD and NOZ cells in the logarithmic growth phase were selected to conduct the experiment. Three different siRNA recombined expression vectors were established using CLIC1 as a target at different sites. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were, respectively, used to detect the CLIC1 mRNA and protein expressions. MTT assay was performed to detect the cell proliferation. Flow cytometry was applied to measure the cell apoptosis and cell cycle distribution. The variations of cell migration and invasion were evaluated using Transwell assay. GBC tissues showed higher CLIC1 mRNA and protein expressions than normal gallbladder tissues. The CLIC1 mRNA and protein expressions in the CLIC1 siRNA group were significantly lower than those in the NC and blank groups. Compared with the NC and blank groups, the CLIC1 siRNA group showed a significant decrease in cell proliferation but an obvious increase in apoptosis rate in GBC cells. Besides, in the CLIC1 siRNA group, cell percentage in G0/G1 and G2/M phase was gradually increased but decreased in S phases. The migration and invasion abilities in GBC cells were significantly lower than those in the NC and blank groups. Our study demonstrates that CLIC1 gene silencing could promote apoptosis and inhibit proliferation migration and invasion of GBC cells. PMID- 29516683 TI - Comments on the Serial Homology and Homologues of Vertebral Lateral Projections in Crocodylia (Eusuchia). AB - The literature on crocodylian anatomy presents the transverse process in an ambiguous meaning, which could represent all lateral expansions derived from the neural arch, including vertebrae from cervical to caudal series, or in a more restrictive meaning, being applied only to lumbar vertebrae. The lateral expansion of sacral and caudal vertebrae usually referred to as the transverse process has been discovered to be fused ribs, bringing more ambiguity to this term. Therefore, with the lack of a definition for transverse process and other associated terms, the present work aims to propose a nomenclatural standardization, as well as definitions and biological meaning, for vertebral rib related structures. Vertebra obtained from museum collections from a total of 87 specimens of 22 species of all extant Crocodylia genera were studied. All vertebrae, except cervical and first three dorsal, exhibit transverse processes. The transverse process is more developed in dorsal and lumbar vertebrae than in sacral and caudal vertebrae in which it is suppressed by the fused ribs. The serial homology hypotheses here proposed can also be aplied to other Crurotarsi and saurischian dinosaurs specimens. This standardization clarifies the understand of the serial homology among those homotypes, and reduces the ambiguity and misleadings in future work comparisons. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29516680 TI - Cytoplasmic functions of long noncoding RNAs. AB - Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides found throughout the cell that lack protein-coding function. Their functions are closely linked to their interaction with RNA-binding proteins (RBPs) and nucleic acids. Nuclear lncRNAs have been studied extensively, revealing complexes with structural and regulatory roles that enable gene organization and control transcription. Cytoplasmic lncRNAs are less well understood, but accumulating evidence indicates that they also form complexes with diverse structural and regulatory functions. Here, we review our current knowledge of cytoplasmic lncRNAs and the different levels of gene regulation controlled by cytoplasmic lncRNA complexes, including mRNA turnover, translation, protein stability, sponging of cytosolic factors, and modulation of signaling pathways. We conclude by discussing areas of future study needed to elucidate comprehensively the biology of lncRNAs, to further understand the impact of lncRNAs on physiology and design lncRNA-centered therapeutic strategies. This article is categorized under: RNA Export and Localization > RNA Localization Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Interactions with Proteins and Other Molecules > Protein RNA Interactions: Functional Implications. PMID- 29516684 TI - Meta-analysis of whole-brain radiotherapy plus temozolomide compared with whole brain radiotherapy for the treatment of brain metastases from non-small-cell lung cancer. AB - The aim of this meta-analysis was to compare the efficiency of whole-brain radiotherapy (WBRT) plus temozolomide (TMZ) with WBRT for the treatment of brain metastases from non-small-cell lung cancer (NSCLC). For dichotomous variables, outcomes were reported as relative risk ratio (RR) and 95% confidence interval (CI) was used to investigate the following outcome measures: overall response rate, headache, gastrointestinal adverse reactions, and hematological adverse reactions. Twelve randomized controlled trials involving 925 participants (480 received WBRT plus TMZ; 445 received WBRT) were included in the meta-analysis. There was a significant difference between the overall response rate (RR = 1.40, 95% CI 1.24-1.57; Z = 5.51; P < 0.00001), gastrointestinal adverse reactions (RR = 1.46, 95% CI 1.05-2.04; Z = 2.27; P = 0.02), and hematological adverse reactions (RR = 1.45, 95% CI 1.04-2.02; Z = 2.21; P = 0.03) of patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. There was no significant difference between headaches (RR = 1.11, 95% CI 0.93-1.02; Z = 1.13; P = 0.26) in patients treated with WBRT plus TMZ compared with patients treated with WBRT alone. In conclusion, the currently available evidence shows that WBRT plus TMZ increases the overall response rate in patients with brain metastases of NSCLC compared with WBRT alone. PMID- 29516685 TI - Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations. AB - BACKGROUND: Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20% 82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied. METHODS: To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent. RESULTS: TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules. CONCLUSION: We report that TSHR mutations occur in ~5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency. PMID- 29516687 TI - Stable meso-Aryl beta-Alkyl Hybrid Sapphyrin with a Warped pi-Conjugation Circuit and Neo-Confused Sapphyrin-Silver(I) Complex. AB - A meso-aryl and beta-alkyl substituted sapphyrin and its rhodium(I) and silver complexes were synthesized. This sapphyrin was so stable that the non-inverted and warped structure could be analyzed by X-ray crystallography even in its neutral state. Its bis-rhodium(I) complex has a more planar structure than the sapphyrin with enhanced aromaticity over the conjugation circuit. On the other hand, silver metalation of the sapphyrin caused a marked core rearrangement into a neo-confused sapphyrin derivative with a C(alpha)-N bond and a twisted macrocycle. PMID- 29516686 TI - Midazolam inhibits chondrogenesis via peripheral benzodiazepine receptor in human mesenchymal stem cells. AB - Midazolam, a benzodiazepine derivative, is widely used for sedation and surgery. However, previous studies have demonstrated that Midazolam is associated with increased risks of congenital malformations, such as dwarfism, when used during early pregnancy. Recent studies have also demonstrated that Midazolam suppresses osteogenesis of mesenchymal stem cells (MSCs). Given that hypertrophic chondrocytes can differentiate into osteoblast and osteocytes and contribute to endochondral bone formation, the effect of Midazolam on chondrogenesis remains unclear. In this study, we applied a human MSC line, the KP cell, to serve as an in vitro model to study the effect of Midazolam on chondrogenesis. We first successfully established an in vitro chondrogenic model in a micromass culture or a 2D high-density culture performed with TGF-beta-driven chondrogenic induction medium. Treatment of the Midazolam dose-dependently inhibited chondrogenesis, examined using Alcian blue-stained glycosaminoglycans and the expression of chondrogenic markers, such as SOX9 and type II collagen. Inhibition of Midazolam by peripheral benzodiazepine receptor (PBR) antagonist PK11195 or small interfering RNA rescued the inhibitory effects of Midazolam on chondrogenesis. In addition, Midazolam suppressed transforming growth factor-beta-induced Smad3 phosphorylation, and this inhibitory effect could be rescued using PBR antagonist PK11195. This study provides a possible explanation for Midazolam-induced congenital malformations of the musculoskeletal system through PBR. PMID- 29516688 TI - Hygiene practices: Are they protective factors for eczema symptoms? AB - INTRODUCTION: Exact etiology and proper treatment of eczema are still unknown. The hygiene hypothesis and epidermal barrier dysfunction hypothesis attempted to give some plausible explanations for these issues but they still remain unclear. The identification of factors, including hygiene practices, related to eczema symptoms (ES) could shed some light on these matters. Therefore, this study aimed to determine risk factors related to ES and the ES prevalence in two disparate areas in terms of urbanization in Aceh, Indonesia. METHODS: A cross-sectional study with convenience sampling was conducted among schoolchildren living in urban and rural Aceh. Data on ES, socio-demographic characteristics, environmental factors, partial ablution and other hygiene related factors were collected by parental questionnaires. In addition, children's anthropometric measurements were also collected. RESULTS: The prevalence of current ES in the study population was 21%. When stratifying by residency, the prevalence of ES in urban and rural area was 20.93% versus 21.05%. Partial ablution was independently associated with a reduced risk of ES (OR = 0.36; 95% CI 0.13-0.96). Important risk factors for ES were paternal history of allergic disease (OR = 4.09%; 95% CI 1.51-11.11) and belonging to the older group of schoolchildren (10-13 years old) (OR = 2.57; 95% CI 1.03-6.40). CONCLUSIONS: There were no significant differences in the prevalence of ES between urban and rural settings, and partial ablution had a protective effect on ES. These findings support the epidermal barrier dysfunction hypothesis as a possible pathway of eczema. PMID- 29516689 TI - Multimodal label-free ex vivo imaging using a dual-wavelength microscope with axial chromatic aberration compensation. AB - Label-free microscopy is a very powerful technique that can be applied to study samples with no need for exogenous fluorescent probes, keeping the main benefits of multiphoton microscopy, such as longer penetration depths and intrinsic optical sectioning while enabling serial multitechniques examinations on the same specimen. Among the many label-free microscopy methods, harmonic generation (HG) is one of the most intriguing methods due to its generally low photo-toxicity and relative ease of implementation. Today, HG and common two-photon microscopy (TPM) are well-established techniques, and are routinely used in several research fields. However, they require a significant amount of fine-tuning to be fully exploited, making them quite difficult to perform in parallel. Here, we present our designed multimodal microscope, capable of performing simultaneously TPM and HG without any kind of compromise thanks to two, separate, individually optimized laser sources with axial chromatic aberration compensation. We also apply our setup to the examination of a plethora of ex vivo samples to prove its capabilities and the significant advantages of a multimodal approach. PMID- 29516691 TI - [On the Considerations About Heating Materials and Temperature of Moxibustion in Clinical Practice]. AB - Moxibustion, one of the traditional Chinese medicine therapy, plays an important role in the treatment of a variety of clinical conditions, particularly the chronic and deficiency problems. In the present paper, the author reviewed the history of development of moxibustion therapy, and the related materials and heating temperature in ancient China, and also reviewed the history of heating therapy (similar to moxibustion) appearing in ancient Egypt, Greek, Libya, India, Europe, etc. The author thinks that the efficacy of moxibustion intervention mainly depends on the heating temperature and the heated area of the skin (not the heating materials) according to his own research group's experimental outcomes. Some problems of moxibustion should be noted, for example, the ignited moxa-smoke induced environmental contamination which may lead to chronic injury particularly to the health of the related practitioners. The author forecasts that some succedaneous materials of mugwort as physical heating energy (mechanical, electrical, microelectronic, solar energy), chemical, biological and medical heating reagents (acupoint receptor-activator), etc., high technique medical devices are probably developed in the future, minimizing some defects of moxa and expanding clinical application of moxibustion therapy. PMID- 29516690 TI - Caries detection and quantification around stained pits and fissures in occlusal tooth surfaces with fluorescence. AB - Occlusal discoloration due to staining frequently occurs on the pits and fissures of teeth. Noncariogenic discoloration (non-CD) refers to the attachment of staining chromogens to sound surfaces, whereas cariogenic discoloration (CD) represents the discoloration of porous structures due to bacterial metabolites and mineral loss from the enamel surface. This study evaluated whether it is possible to distinguish between non-CD and CD on stained occlusal surfaces with fluorescence assessed by the quantitative light-induced fluorescence (QLF) technology. Sixty-two extracted human permanent teeth with suspected discolorations on the pit and fissure were examined. The maximum values of fluorescence loss (DeltaFmax) and red fluorescence gain (DeltaRmax) were calculated using QLF images. Using histology as the gold standard, it was found that 12 teeth were sound (non-CD), while 50 teeth had enamel and dentine caries (CD). The validity tests at the enamel histological caries level, DeltaRmax (rho = 0.80) were strongly correlated with the histology (P < 0.001). At the optimum threshold (105.0) of DeltaRmax, it showed high levels of sensitivity and specificity (0.96 and 0.83, respectively). Therefore, QLF can be used to distinguish non-CD from CD on occlusal surfaces using red fluorescence values with high validity. PMID- 29516692 TI - [Effect of Different Doses of Herbal Cake-partitioned Moxibustion on Histopathological Changes of Colon Tissue in Ulcerative Colitis Rats]. AB - OBJECTIVE: To observe the effect of different-doses of herbal cake-partitioned moxibustion (Moxi) on histopathological changes of the damaged colon tissue in rats with ulcerative colitis (UC), so as to select an optimal dosage of Moxi in the treatment of UC. METHODS: Sixty-three male Sprague Dawley (SD) rats were randomized into 7 groups: normal control, model, medication, and 1, 2, 3 and 4 moxa-cone Moxi (n=9 rats per group). The UC model was developed by subcutaneous injection of emulsion (1 mL) containing colon mucosa-prepared protein suspension and complete Freund's adjuvant into the toes, groin and back. On the 38th day, enema of 3% formalin and the aforementioned emulsion was used. Herbal-cake (composed of monkshood, cinnamon, etc.) partitioned Moxi with 1 or 2 moxa-cones (about 5 min/cone) was applied to bilateral "Tianshu" (ST 25) once daily or once every other day. The rat's general conditions (diet, movement, response ability, stool, and body weight) were observed, and histopathological changes (adhesion, ulcer formation and inflammation) of colon tissues were examined after hematoxylin-eosin (HE) staining, and scored (histopathological score). Gross score was given according to the severity of adhesion, ulcer formation and inflammation of colonic tissues under stereo microscope. The average optical density (AOD) values of colonic mucins were detected after periodic acid-schiff (PAS) staining, and those of the sulfated mucus content detected after high iron dia-mine-alcian blue (HID-AB) staining. RESULTS: Compared with the normal group, rats in the model group presented loose stool, or with pus and blood, and slowly increased body weight (P<0.01), obvious congestion of colon with ulcer spots or continuous superficial ulcer regions which had irregular glandular cavities, swelling and serious inflammatory infiltration in lamina propria and submucosa, and increased score of colon tissue damage (P<0.01). PAS and HID-AB staining showed a marked decrease of AOD values of colonic mucins and sulfated mucus in the model group relevant to the normal control group (P<0.01), suggesting a reduction of mucus secretion of intestinal glands. Following the intervention, rats in the Moxi groups presented an increase of the body weight, formed feces, and an improvement of the damaged colon tissues as mucosal healing and inflammatory reduction, and a marked decrease of the damage score relevant to the model rats. No significant differences were found in the gross scores among the medication, 1, 2, 3 and 4 moxa-cone groups (P>0.05). The histopathological scores were significantly lower in the 1 and 4 moxa-cone Moxi groups than in the medication group (P<0.05, P<0.01); and significantly lower in the 1, 3, 4 moxa cone Moxi groups than in the 2 moxa-cone Moxi group (P<0.05, P<0.01). PAS staining showed a significant increase of the AOD values of colonic mucins in the 1, 2, 3 and 4 moxa-cone and medication groups relevant to the model group (P<0.01); and the AOD values of colonic mucins in the 1, 3, 4 moxa-cone Moxi groups were significantly increased than that in the 2 moxa-cone Moxi group (P<0.05, P<0.01). HID-AB staining showed that the AOD values of sulfated mucus content were significantly higher in the 2 and 4 moxa-cone Moxi groups than in the 3 moxa-cone Moxi group (P<0.01). The two-level two-factor factorial analysis showed an interaction existed between the moxa-cone number and Moxi frequency in reducing the gross score and histopathological score and in facilitating colonic mucin and sulfated mucus secretion. The histopathological score of the 4 moxa cone Moxi group was significantly lower than that of the 2 moxa-cone Moxi group (P<0.05), and the sulfated mucus content was significantly higher in the 4 moxa cone group than in the 3 moxa-cone group (P<0.01). The effect of Moxi given on alternate days was superior to that of daily Moxi in improving colonic histological damage. CONCLUSION: Herbal cake-partitioned moxibustion at ST 25 can promote repair of the damaged colonic tissue and secretion of mucin in UC rats. The number of moxa cones and intervention frequency affect the efficacy of Moxi in improving histopathological changes. The Moxi intervention on alternate days and with 2 moxa-cones every time is recommended. PMID- 29516693 TI - [Involvement of PI 3 K/Akt/mTOR Signaling in Protective Effects of Moxibustion for Premature Ovarian Failure in Rats]. AB - OBJECTIVE: To study the protective effect of moxibustion for tripterygium-induced premature ovarian failure (POF) and its underlying mechanisms in rats. METHODS: Forty-five female SD rats were randomly divided into normal control, POF model and moxibustion groups (n=15/group). The POF model was induced by intragastric administration of Triptolide (40 mg/kg), once daily for 6 weeks. From the 4th week after modeling, moxibustion was given at "Guanyuan" (CV 4) and bilateral "Sanyinjiao" (SP 6) for 10 min, once daily for 3 weeks. Pathological changes of ovary tissues were determined by hematoxylin-eosin (HE) staining. The serum estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) contents were measured by enzyme-linked immunosorbent assay (ELISA). The expression levels of phosphatidyl inositol 3- kinase (PI 3 K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) proteins of the ovarian tissue were detected by Western blot. RESULTS: After modeling, HE staining showed that the numbers of ovarian follicles and follicular granulocytes and corpora luteum layers were decreased, and the number of corpora atretica was increased in the model group. The content of serum E2 was markedly decreased and those of serum LH, FSH, IL-6 and IL-1 beta were markedly increased in the model group (P<0.01), and the expression levels of ovarian p-PI 3 K, p-Akt and p-mTOR were markedly increased after modeling relevant to the control group (P<0.01). Following moxibustion, the pathological damage of ovarian tissue was improved, the contents of serum LH, FSH, IL-6, IL-1 beta, and the levels of p-PI 3 K, p-Akt and p-mTOR proteins in the ovarian tissue were significantly decreased (P<0.05, P<0.01), and the content of serum E2 was markedly increased (P<0.05) in comparison with the model group. CONCLUSION: Moxibustion can improve POF in POF rats, which may be related to its actions in inhibiting PI 3 K/Akt/mTOR signaling, down-regulating serum IL-6, IL-1 beta, and regulating serum hormones. PMID- 29516694 TI - [Effects of Moxibustion on Ventricular Mass Index and Expression of Apoptosis Related Proteins in Myocardium of Rats with Chronic Heart Failure]. AB - OBJECTIVE: To observe the effect of moxibustion on cardiac function and the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), Fas, Fas ligand (FasL) in cardiomyocytes of chronic heart failure (CHF) rats, so as to explore its underlying mechanisms in preventing and treating CHF. METHODS: SD rats were randomly divided into normal control, model, moxibustion, Captopril and moxibustion + Captopril (M+C) groups (n=12 rats/group). The CHF model was established by intraperitoneal injection of Adriamycin (ADR, from 1 to 4 mg/kg, once every other day for 15 days). Mild moxibustion was applied to bilateral"Feishu"(BL 13) and "Xinshu"(BL 15). Rats of the Captopril group was treated by gavage of Captopril suspension (5 mg/mL, 25 mL/kg), and those of the M+C group treated by the combined two methods. All the treatments were given once a day for 3 weeks. The general conditions and behaviors of rats were observed. The left ventricular mass index (LVMI) and right ventricular mass index (RVMI) were detected for assessing the cardiac performance. Morphological changes of myocardium were observed by HE staining. Enzyme linked immunosorbent assay (ELISA) was used to detect the concentrations of B-type natriuretic peptide (BNP) and precursor N-terminal pro-brain natriuretic peptide (NT-pro BNP) in the serum. The expression levels of Bcl-2, Bax, Fas and FasL of the left ventricle of heart were detected by Western blot. RESULTS: After modeling, the pathological changes of myocardium (as myocardial cell swelling with vacuoles, myocardial fibre breakage, etc.) were obvious, the LVMI, RVMI, serum BNP and NT-pro BNP concentrations, and myocardial Bax, Fas and FasL protein expression levels were significantly increased in the model group compared with the normal group (P<0.01), while the expression level of Bcl-2 was significantly down-regulated (P<0.01). Following the interventions, the myocardial injury was reduced, both LVMI and RVMI, serum BNP concentration and Bax, Fas and FasL expression levels in the three treatment groups, and serum NT-pro BNP concentration in the moxibustion and M+C groups were significantly decreased (P<0.05, P<0.01), while the myocardial Bcl-2 protein levels in the three treatment groups were significantly increased relevant to the model group (P<0.01). Comparison among the three treatment groups showed that the effects of moxibustion + Captopril were significantly superior to those of simple moxibustion and simple Captopril in suppressing CHF-induced increased expression of myocardial Bax, Fas and FasL, and in lessening CHF-induced decrease of Bcl-2 level (P<0.05, P<0.01). No significant differences were found among the three treatment groups in down-regulating LVMI and RVMI, and serum BNP content (P>0.05).. CONCLUSION: Moxibustion can reduce myocardial injury and improve cardiac function in CHF rats, which may be related to its effects in down-regulating the expression of myocardial Bax, Fas and FasL proteins, and up-regulating the expression of Bcl-2 protein to inhibit cardiomyocyte apoptosis. PMID- 29516695 TI - [Effect of Herbal-cake-separated Moxibustion on Blood Lipid Levels and Expression of Hepatic PPARgamma and SR-B 1 Proteins and Genes in Hyperlipidemia Atherosclerosis Rabbits]. AB - OBJECTIVE: To observe the effect of herbal-cake-separated moxibustion on blood lipid levels and expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and scavenger receptor B 1 (SR-B 1) proteins and genes in liver of hyperlipidemia atherosclerosis rabbits, so as to explore its mechanism underlying anti-atherosclerosis formation. METHODS: Forty male New Zealand white rabbits were randomly divided into normal control, model, moxibustion and Simvastatin groups (n=10 rabbits in each group). The hyperlipidemia atherosclerosis model was established by high cholesterol diet and propylthiouracil for 12 weeks. Herbal cake-separated moxibustion was applied to "Juque" (CV 14), and bilateral "Tianshu" (ST 25), "Fenglong" (ST 40) (point group 1), and bilateral "Xinshu" (BL 15), "Ganshu" (BL 18) and "Pishu" (BL 20) (point group 2). The two groups of points were used alternately. Simvastatin (1.96 mg*kg-1*d-1) mixed in the forage was given to rabbits of the Simva-statin group. Both moxibustion and medication treatments were given once daily for continuous 4 weeks. Total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) levels in plasma were detected by using an automatic biochemistry analyzer. The expression levels of PPARgamma and SR-B 1 proteins and genes in the hepatic tissue were determined by Western blot and reverse transcription-polymerase chain reaction, separately. RESULTS: After modeling, plasma TC, TG and LDL-C levels in the model group were significantly increased (P<0.01), and the levels of plasma HDL-C and hepatic PPARgamma and SR-B 1 protein and mRNA expression were obviously down-regulated relevant to the normal group (P<0.01). Compared with the model group, plasma TC, TG and LDL-C levels were significantly decreased (P<0.01), and plasma HDL-C and hepatic PPARgamma and SR-B 1 protein and mRNA levels were significantly up-regulated in the two treatment groups (P<0.01, P<0.05). CONCLUSION: Herbal-cake-separated moxibustion can regulate blood lipid levels and suppress hyperlipidemia-induced decrease of expression of hepatic PPARgamma and SR-B 1 proteins and genes in hyperlipidemia atherosclerosis rabbits, which maybe contribute to its action in anti-atherosclerosis through promoting reversal of cholesterol. PMID- 29516696 TI - [Effects of Herbal-cake-separated Moxibustion on Blood Lipid Protein Levels and Expression of Toll-like Receptor and Nuclear Factor Genes in Atherosclerotic Plaques in Hyperglycemia Rabbits]. AB - OBJECTIVE: To observe the effect of herbal cake-separated moxibustion on blood lipid-apoprotein levels and the expression of Toll-like receptor 2 (TLR 2), TLR 4 and nuclear factor kappa B(NF-kappaB) mRNAs in atherosclerotic (AS) vulnerable plaques of hyperglycemia rabbits, so as to explore its mechanism underlying improvement of atherosclerosis. METHODS: Sixty New Zealand rabbits were randomly divided into 5 groups: control, model, direct moxibustion, herbal-cake-separated moxibustion and medication groups(n=12 rabbits in each group). The AS vulnerable plaque model was established by high-fat forage feeding plus balloon-induced abdominal aorta injury and gene transfection of Ad 5-p 53 recombinant vector. Direct moxibustion or herbal-cake-separated moxibustion was applied to "Juque" (CV 14) and bilateral "Tianshu" (ST 25), "Fenglong" (ST 40), or bilateral "Xinshu" (BL 15), "Pishu" (BL 20) and "Ganshu" (BL 18) for 15-20 min every time. The medication group was treated by feeding Atorvastatin. All the treatments were conducted once daily for 8 weeks. Plasma total cholesterol(TC) and triglyceri de(TG) contents were detected by enzyme method, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) contents detected by colorimetric determination, and plasma apolipoprotein A(Apo-A) and apolipoprotein B(Apo-B) levels determined by electrophoretic method. The pathological changes of vulnerable plaque and the aortic intima and media thickness were observed under light microscope after H.E. staining. The expression levels of TLR 2, TLR 4 and NF-kappaB mRNAs in AS plaques were determined by quantitative real-time PCR. RESULTS: After modeling, the levels of plasma TC, TG, LDL and Apo-B in the model group were remarkably increased (P<0.01), and Apo-A and HDL/LDL were significantly decreased in comparison with the control group (P<0.01). Additionally, the aortic intima and media thickness and the expression levels of TLR 2, TLR 4 and NF-kappaB mRNAs in AS plaques were significantly increased (P<0.01). After the treatment, the elevated levels of plasma TC, TG, LDL and Apo B, the aortic intima thickness and media thickness, and the expression levels of TLR 2, TLR 4 and NF-kappaB mRNAs in the 3 treatment groups were significantly down-regulated in comparison with the model group (P<0.05, P<0.01), while the decreased levels of Apo-A and HDL/LDL were considerably increased (P<0.01). Comparison among the 3 treatment groups showed that the therapeutic effects of the herbal-cake-separated moxibustion and medication were significantly superior to those of the direct moxibustion in down-regulating the levels of TC, TG, LDL, Apo-B, TLR 2 mRNA, TLR 4 mRNA and NF-kappaB mRNA, and reducing the thickness of the aortic intima and media, as well as in up-regulating the levels of Apo-A and HDL/LDL (P<0.05, P<0.01). No significant differences were found between the herbal-cake-separated moxibustion and medication groups in the above-mentioned indexes (P>0.05). CONCLUSION: Herbal-cake-separated moxibustion has a positive role in stabilizing AS vulnerable plaque in hyperglycemia rabbits, which may be associated with its effects in regulating blood lipid-apolipoprotein levels and inhibiting the expression of TLR 2, TLR 4 and NF-kappaB mRNAs in vulnerable plaques. PMID- 29516697 TI - [Effect of Different Concentrations of Moxa-smoke on Lung Function and TNF-alpha and IL-1 beta Levels in Serum and Lung Tissues in Normal Rats]. AB - OBJECTIVE: To study the effect of moxa-smoke inhaling on the respiratory system, so as to provide experimental data and theoretical basis for evaluating the safety of moxa-smoke inhaling during moxibustion treatment. METHODS: A total of 48 SD rats were randomized into control, low, medium and high moxa-smoke concentration groups (n=12 in each group). The low, medium and high concentrations of smoke were controlled in (0.11+/-0.05) mg/m3, (0.23+/-0.05) mg/m3 and (0.53+/-0.05) mg/m3 respectively in each of 3 glass boxes (with reference to the level of PM 2.5). The smoking was conducted 4 hours each time, twice a day for 100 days. The normal group did not receive any moxa-smoke inhaling. The histopathological changes of lung and bronchial tissues were detected by H.E. stainning, and the contents of TNF-alpha and IL-1 beta of plasma, bronchoalveolar la-vage fluid (BALF) and lung tissue detected by ELISA. The levels of forced vital capacity (FVC), forced expiratory volume (FEV), FEV 0.3/FVC (0.3= the 0.3rd second), maximal mid-expiratory flow rate(MMEF), peak expiratory flow(PEF) were detected by animal pulmonary function analysis system. RESULTS: After 100 days' moxa-smoke inhaling, the contents of TNF-alpha in the plasma, BALF and lung tissues and IL-1 beta in the lung tissue of the low, medium and high concentration moxa-smoke groups, and IL-1 beta in the plasma and BALF of the medium and high concentration groups were significantly increased relevant to the control group (P<0.05, P<0.01). H.E. stain showed various inflammatory changes in the lungs and trachea tissues, including obvious fusion of pulmonary alveoli, lymphocyte infiltration, increase of capillary permeability, red blood cell exudation, etc. in the high concentration group, these situations were milder in the medium concentration group and were not obvious in the low concentration group. Compared with the control group, there were no significant changes in the FVC, FEV, FEV 0.3/FVC, MMEF and PEF of lung function in the three concentration groups (P> 0.05).. CONCLUSION: Long term inhalation of high concentration of moxa-smoke may lead to inflammatory injury in the lung and bronchial tissues but has no significant effect on the respiratory function in rats. Nevertheless, a good air-ventilation during moxibustion in a treatment room is necessary. PMID- 29516698 TI - [Influence of Moxa Smoke on Indoor Air Quality and Strategies for Its Control]. AB - Moxibustion is an effective therapy for treatment of a lot of clinical problems, but the ignited moxa-induced smoke containing harmful substances may bring about indoor air pollution to affect both patients' and medical workers' health. However, there is no standards about controlling indoor air quality (IAQ) for moxibustion rooms in China. In the present study, the authors reviewed newly published articles about some substances released from moxa smoke as inhalable particles (PM 10 and PM 2.5), formaldehyde, benzene, methylbenzene, xylene, bene[alpha]pyrene, total volatile organic compounds, CO, CO2, NO, SO2, NH3, O3, etc. some of which affect IAQ. On this account, the authors put forward some strategies for controlling IAQ in moxibustion clinics including setting united safe standards, enhancing ventilation, controlling moxibustion material quality and strengthening scientific research on the safety of moxa smoke control, fully playing the superiority of moxibustion therapy and reducing its unfavorable aspects in clinical practice in the future. PMID- 29516699 TI - [Thunder-fire Moxibustion for Qi Deficiency-induced Fatigue in Breast Cancer Patients Under-going Chemotherapy]. AB - OBJECTIVE: To observe the clinical effect of thunder-fire moxibustion in the treatment of qi deficiency-induced fatigue in breast cancer patients undergoing chemotherapy. METHODS: Sixty breast cancer patients undergoing chemotherapy were randomly divided into thunder-fire moxibustion (Moxi) and conventional nursing (nursing) groups (n=30 in each group). Patients in the Moxi group were treated with thunder-fire moxibustion applied to the back part of body from Pishu (BL 20) to Qihaishu (BL 24) on the bilateral sides and to the abdominal part from Zhongwan (CV 12) to Guanyuan (CV 4) for 30 min, once a day for 14 days. Patients in the nursing group were treated with health education and conventional nursing care. The simple fatigue scale, traditional Chinese medicine (TCM) syndrome score, clinical curative effect were observed before and after the treatment, and white blood cell (WBC) count was observed 5 days ofter chemotherapy and after the treatment respectively. RESULTS: After the treatment, the simple fatigue scales and TCM syndrome scores were significantly decreased and WBC counts were significantly increased in both groups relevant to their individual pre-treatment (P<0.01). The therapeutic effect of the Moxi group was appa-rently superior to that of the nursing group in lowering the simple fatigue scale and TCM syndrome score and in up-regulating WBC count (P<0.01, P<0.05). The total effective rate of the Moxi group was significantly higher than that of the nursing group (83.3%[25/30]vs 36.7% [11/30], P<0.01). CONCLUSION: Thunder-fire moxibustion can effectively relieve the degree of fatigue and the symptoms of qi deficiency in breast cancer patients undergoing chemotherapy. PMID- 29516700 TI - [Effects of Acupuncture Stimulation of Different Layers of "Tianshu" (ST 25) Region on Changes of Intra-colonic Pressure in Normal Rats]. AB - OBJECTIVE: To observe the effect of manual acupuncture stimulation of different layers (skin, muscle, peritoneum, sub-peritoneum) of "Tianshu" (ST 25) region on proximal colonic pressure in normal rats. METHODS: Forty-eight male SD rats were divided into 6 groups: all layer-needling, brushing, cutaneous needling, muscular needling, peritoneum-needling and sub-peritoneum-needling groups (n=8 in each group). Manual needling or brushing was applied to "Tianshu" (ST 25) region. The colonic internal pressure was measured by using an amplifier and a pressure transducer-connected balloon which was implanted into the colonic cavity about 6 cm from the ileocecal valve. For rats of the all-layer needling group, an acupuncture needle was inserted into ST 25 about 1 cm deep and rotated for a while, for rats of the brushing group, a Chinese calligraphy brush pen was used to brush the skin hair for 1 min. For rats of the rest 4 groups, an acupuncture needle was inserted into the skin, muscle layer after cutting open the skin (about 0.1 cm), the peritoneum layer after cutting open the skin and muscle layers, and the sub-peritoneum layer after cutting open the skin, muscle and peritoneum layers, respectively, and rotated using the uniform reinforcing reducing technique for about 1 min at a frequency of 120 twirlings per minute every time. RESULTS: During manual needling stimulation of the full layers, cutaneous layer, muscle layer, peritoneum layer and the sub-peritoneum layer of bilateral "Tianshu" (ST 25), the internal pressure of proximal colon was significantly decreased relevant to pre-stimulation in each group (P<0.05), and there were no significant differences between bilateral sides needling stimulation in the decreased pressure levels (P>0.05). During hair brushing of ST 25 region, the colonic pressure was observably increased relevant to pre-needling stimulation (P<0.05). One min after the acupuncture stimulation, the decreased pressures maintained in needling the all-layer on the left side, needling the skin on the right side, needling the peritoneum layer on both sides, and needling the sub-peritoneum layer on both sides relevant to the brushing group of the same side (P<0.05). CONCLUSION: Manual acupuncture stimulation of each layer tissue of ST 25 on both sides may lower internal pressure of proximal colon in normal rats, suggesting their involvement of acupuncture effect in relaxing proximal colonic contraction. PMID- 29516701 TI - [Clinical Effectiveness of Intradermal Needle-embedding Therapy for Swallowing Function in Stroke Patients with Dysphagia]. AB - OBJECTIVE: To observe the clinical efficacy of intradermal needle-embedding therapy in the treatment of dysphagia in stroke patients. METHODS: A total of 80 stroke patients with dysphagia were randomly divided into treatment group and control group (n = 40 in each). The control group was treated with conventional medicines, neuromuscular electrical stimulation of the bilateral midlines of the neck and swallowing function training, and the treatment group treated by intradermal needle-embedding at Lianquan (CV 23), Jialianquan-point, Yifeng (TE 17), Ashi-point, etc. (once every other day for 20 days) on the basis of the treatments used in the control group. Swallowing function (0-10 points scaling, the bigger the better)and surface electromyography (sEMG) of the bilateral suprahyoid muscles and infrahyoid muscles in the relaxing, nothing swallowing and water-swallowing conditions were tested before and after the treatment. RESULTS: After treatment, the swallowing scores were significantly increased in both groups compared with those of their individual pre-treatment (P<0.05), suggesting an improvement of swallowing function. During relaxing, nothing swallowing and water-swallowing conditions, the peak amplitudes of sEMG were considerably increased in both groups relevant to those of their individual pre-treatment (P<0.05).The swallowing function score, and maximum amplitudes of sEMG during relaxing, nothing swallowing and water-swallowing conditions were significantly higher in the treatment group than in the control group (P<0.05), suggesting a better efficacy of intradermal needle-embedding treatment. CONCLUSION: Intradermal needle-embedding can significantly improve the swallowing function of stroke patients with dysphagia. PMID- 29516702 TI - [Improvement of Upper Limb and Hand Functions of Stroke Patients by Balancing Acupuncture Combined with Motor Relearning Training]. AB - OBJECTIVE: To observe the therapeutic effect of balance acupuncture combined with motor relearning training for upper limb and hand functions of stroke patients. METHODS: Sixty-two stroke patients were randomly divided into balance acupuncture group (n=31) and routine acupuncture group (n=31). For patients of the balance acupuncture group, Piantan, Jiantong and Wantong points on the healthy side were used. When Jiantong point taken, the acupuncture needle was removed after the patient experienced an electric shock-like spreading needling sensation. When Wantong point employed, the needle was removed after the patient experienced a local, intensified or spreading needling sensation. When Piantan point used, the needle was retained after the patient experienced an electric shock-like needling sensation, then, the motor relearning training was conducted, and the needle was removed immediately after the training. For patients of the routine acupuncture group, Jianyu(LI 15), Jianzhen (SI 9), Quchi (LI 11), etc. were needled with the needles retained for 30 min after getting needling sensations. The motor relearning training was also carried out after removal of the needle. The treatment in both groups was performed once daily, 6 days a week, and lasted for 8 weeks. The Fugl-Meyer score and motor function scale (MAS) of the upper limb, and the fine performance score and motor function score of the hand were assessed before and after the treatment. RESULTS: Following treatment, the Fugl-Meyer score and MAS of the upper limbs, and the motor function score and fine performance score of the hand were significantly increased in both groups compared with pre-treatment in each group (P<0.05 ), suggesting a functional improvement of both upper limb and hand. The therapeutic effect of the balance acupuncture was obviously superior to that of routine acupuncture in improving functions of both the upper limb and hand (P<0.05).. CONCLUSION: Balance acupuncture combined with motor relearning training is helpful to improve the comprehensive function of the upper limb and hand in stroke patients. PMID- 29516703 TI - [Effect of Dry Needling Stimulation of Myofascial Trigger Point on Sample Entropy of Electromyography of Gastrocnemius Injured Site in Rats]. AB - OBJECTIVE: To attempt to establish an objective quantitative indicator to characterize the trigger point activity, so as to evaluate the effect of dry needling on myofascial trigger point activity. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into blank control group, dry needling (needling) group, stretching exercise (stretching) group and needling plus stretching group (n=6 per group). The chronic myofascial pain (trigger point) model was established by freedom vertical fall of a wooden striking device onto the mid-point of gastrocnemius belly of the left hind-limb to induce contusion, followed by forcing the rat to make a continuous downgrade running exercise at a speed of 16 m/min for 90 min on the next day which was conducted once a week for 8 weeks. Electromyography (EMG) of the regional myofascial injured point was monitored and recorded using an EMG recorder via electrodes. It was considered success of the model if spontaneous electrical activities appeared in the injured site. After a 4 weeks' recovery, rats of the needling group were treated by filiform needle stimulation (lifting-thrusting-rotating) of the central part of the injured gastrocnemius belly (about 10 mm deep) for 6 min, and those of the stretching group treated by holding the rat's limb to make the hip and knee joints to an angle of about 180 degrees , and the ankle-joint about 90 degrees for 1 min every time, 3 times altogether (with an interval of 1 min between every 2 times). The activity of the trigger point was estimated by the sample entropy of the EMG signal sequence in reference to Richman's and Moorman's methods to estimate the curative effect of both needling and exercise. RESULTS: After the modeling cycle, the mean sample entropies of EMG signals was significantly decreased in the model groups (needling group [0.034+/-0.010], stretching group [0.045+/-0.023], needling plus stretching group [0.047+/-0.034]) relevant to the blank control group (0.985+/-0.196, P<0.01). After the treatment, the mean sample entropy of EMG signals was evidently increased in both needling (0.819+/-0.088), stretching (0.532+/-0.25) and needling plus stretching (0.810+/-0.117) groups (P<0.01). The mean sample entropy of the needling and needling plus stretching groups were significantly higher than that of the stretching group (P<0.01), without remarkable difference between the two needling groups in the mean sample entropy (P>0.05), suggesting a better efficacy of dry needling in easing trigger point activity. CONCLUSION: Dry needling is able to relieve myofascial trigger point activity in rats, which is better than that of simple passive stretching therapy. PMID- 29516704 TI - Use of low-dose dexmedetomidine in combination with opioids and midazolam in pediatric cardiac surgical patients: randomized controlled trial. AB - BACKGROUND: Dexmedetomidine is a selective agonist of alpha2 receptors that induces hypnotic, sedative and mild analgesic effect. The aim of our study was to test the effects of dexmedetomidine in combination with opioids and benzodiazepines compared to benzodiazepine-opioids alone. METHODS: A randomized controlled trial was conducted. Patients (children >30 days and <24 months undergoing correction of complex congenital heart diseases [CHD]) were randomized to receive 0.5 mcg/kg/h dexmedetomidine in addition to half dose of opioids and benzodiazepines (D-CASES) or standard dose opioids and benzodiazepines (CONTROLs). PRIMARY OUTCOME: to compare the duration of mechanical ventilation (MV) in D-CASEs and CONTROLs. SECONDARY OUTCOMES: 1) the degree of sedation; 2) the onset of withdrawal symptoms; 3) the occurrence bradycardia and hypotension. RESULTS: Overall, 48 patients, 26 in CONTROLs group and 22 in D-CASEs group were ultimately included in the analysis after enrollment. The median duration of MV was 33.5 (16.7-75) hours in CONTROLs and 41.5 (23.7-71.2) hours in D-CASEs (P=0.51). Dexmedetomidine did not affect COMFORT and FLACC scales but it reduced the SOS scale in 15 D-CASEs vs. 11 CONTROLs (P=0.001). The incidence of bradycardia and hypotension and vasoactive support did not show significant differences in the two groups. CONCLUSIONS: Low dose of dexmedetomidine in combination with morphine and midazolam was safe in a high-risk cohort of CHD children after cardiac surgery and reduced the onset of withdrawal symptoms. However, it did not decrease MV time and the total amount of other sedative and analgesic drugs required in the post-operative period. PMID- 29516705 TI - Comparison of the effects of low doses of dexmedetomidine and remifentanil on the maternal hemodynamic changes during caesarean delivery in patients with severe preeclampsia: a randomized trial. AB - BACKGROUND: Preoperative remifentanil administration blunts hemodynamic responses to tracheal intubation in parturients with severe preeclampsia. We hypothesized that the preoperative administration of low doses of remifentanil or dexmedetomidine would lead to comparable maternal neurohormonal responses and neonatal outcomes in patients with severe preeclampsia. METHODS: Parturients diagnosed with severe preeclampsia undergoing caesarean delivery were randomLy allocated to receive remifentanil (0.1 ug/kg/min) or dexmedetomidine (0.4 ug/kg/h) at five min and 20 min before induction, respectively. Changes in maternal mean arterial BP(MAP), clinical recovery, cortisol level, and neonatal outcome, were recorded. RESULTS: Patients who received remifentanil had higher response in MAP at the induction (94 9.8 vs. 104 4.5; P<0.001) and emergence from anesthesia (94 6.3 vs. 98 5.1; P<0.001), but shorter times to extubation (5.1 1.6 vs. 13.5 2.8 min; P<0.001). Five (27.8%) patients in the remifentanil group received ephedrine versus none in the dexmedetomidine group (P=0.023). The maternal plasma cortisol levels, the neonatal Neurologic and Adaptative Capacity Scores and acid-base satuses were similar in the two groups. Newborns in the remifentanil group presented lower Apgar scores at 1 minute (5.11 0.8 vs. 5.68 0.8; P=0.034) and a higher incidence of respiratory depression (72.2% vs. 36.8% P=0.048). CONCLUSIONS: Compared with dexmedetomidine (0.4 ug/kg/h), the preoperative administration of remifentanil (0.1 ug/kg/min) produced a significantly higher effect on maternal hemodynamic responses to caesarean delivery in patients with severe preeclampsia, however maternal hypotension and neonatal respiratory depression were more common with the use of remifentanil. PMID- 29516706 TI - The Spritztube: a new revolution in extraglottic airway devices. PMID- 29516707 TI - Palliative sedation: theoretical and clinical point of view. PMID- 29516708 TI - Effectiveness of spinal anesthesia in transanal endoscopic microsurgery: a 3-year experience. AB - BACKGROUND: The feasibility and safety of transanal endoscopic microsurgery (TEM) performed under spinal anesthesia (SA) has been recently demonstrated. This retrospective study compared the differences in opioid consumption and postoperative recovery in patients undergoing TEM under GA and SA. METHODS: All consecutive patients who underwent TEM at Citta della Salute e della Scienza Hospital of Turin (Italy) between January 2012 and December 2015 were enrolled. Data related to demographic characteristics, surgery, anesthesia management and postoperative course were recorded from the hospital electronic registry of medical records. Patients were treated according to a standardized protocol by a team of three anesthesiologists with experience in both GA and SA. RESULTS: The study included 148 patients: 77 in GA group and 71 in SA, with no switch among groups. Hospital length of stay was shorter in SA group (3 vs. 4 days, P=0.0201). SA patients were earlier mobilized and applied to oral postoperative intake (18 vs. 24 hours and 24 vs. 48 hours, respectively, P<0.0001). Peri-procedural complications, postoperative nausea, vomiting and pain were comparable between groups. Percentage of patients requiring postoperative rescue therapy with Tramadol was similar between groups, but SA patients received a lower opioid dosage (176.6+/-67.8 mg vs. 238.3+/-79.5 mg, P=0.0011). Operating room occupancy times was longer in GA group (120 vs. 100 minutes, P=0.0008). CONCLUSIONS: SA seems to be the treatment of choice, when not contraindicated, in patients undergoing TEM, allowing a reduction in perioperative opioid consumption and a faster postoperative recovery. PMID- 29516709 TI - Comparing two laryngeal masks: the twin importance of a quantitative measure of the oropharyngeal sealing pressure, and the scrupulous avoidance of an excessive intracuff pressure. PMID- 29516710 TI - From the other side of the door. PMID- 29516711 TI - ECCO2R: are we ready for the prime time? PMID- 29516712 TI - A flow-chart for a critical appraisal of new technology. The experience of near infrared spectroscopy. PMID- 29516713 TI - Does low BMI affect ART outcomes? PMID- 29516714 TI - Zika Virus Outbreak, assisted reproduction patients and pregnancy. PMID- 29516715 TI - Solution Coating of Pharmaceutical Nanothin Films and Multilayer Nanocomposites with Controlled Morphology and Polymorphism. AB - Nanosizing is rapidly emerging as an alternative approach to enhance solubility and thus the bioavailability of poorly aqueous soluble active pharmaceutical ingredients (APIs). Although numerous techniques have been developed to perform nanosizing of API crystals, precise control and modulation of their size in an energy and material efficient manner remains challenging. In this study, we present meniscus-guided solution coating as a new technique to produce pharmaceutical thin films of nanoscale thickness with controlled morphology. We demonstrate control of aspirin film thickness over more than 2 orders of magnitude, from 30 nm to 1.5 MUm. By varying simple process parameters such as the coating speed and the solution concentration, the aspirin film morphology can also be modulated by accessing different coating regimes, namely the evaporation regime and the Landau-Levich regime. Using ellipticine-a poorly water-soluble anticancer drug-as another model compound, we discovered a new polymorph kinetically trapped during solution coating. Furthermore, the polymorphic outcome can be controlled by varying coating conditions. We further performed layer-by layer coating of multilayer nanocomposites, with alternating thin films of ellipticine and a biocompatible polymer, which demonstrate the potential of additive manufacturing of multidrug-personalized dosage forms using this approach. PMID- 29516716 TI - Field-Effect Transistors Based on Networks of Highly Aligned, Chemically Synthesized N = 7 Armchair Graphene Nanoribbons. AB - We report on the experimental demonstration and electrical characterization of N = 7 armchair graphene nanoribbon (7-AGNR) field effect transistors. The back gated transistors are fabricated from atomically precise and highly aligned 7 AGNRs, synthesized with a bottom-up approach. The large area transfer process holds the promise of scalable device fabrication with atomically precise nanoribbons. The channels of the FETs are approximately 30 times longer than the average nanoribbon length of 30 nm to 40 nm. The density of the GNRs is high, so that transport can be assumed well-above the percolation threshold. The long channel transistors exhibit a maximum ION/ IOFF current ratio of 87.5. PMID- 29516717 TI - Adsorption-Assisted Interfacial Polymerization toward Ultrathin Active Layers for Ultrafast Organic Permeation. AB - Thin-film composite (TFC) membranes show exceptional permeation properties of key importance for many separations. However, their design and development need ultrathin and defect-free nanofilms as the active layer to alleviate the bottleneck of permeation-rejection trade-off. Here, a 25 nm thick film is fabricated on a porous support by introducing polydopamine (PDA) as an adsorption layer, imparting a unique adsorption-assisted interfacial polymerization (IP) strategy. The PDA layer efficiently captures and enriches amine monomers even from ultradilute solution toward uniform stacking on the support, thus generating ultrathin and defect-free films after polymerization. This is superior to the defective one from conventional IP. Such an active layer features ultrafast permeation for organics, favorable solute rejection, and excellent operation stability. Particularly, the acetone permeance of this new TFC membrane reaches 96.3 L m-2 h-1 bar-1, which exceeds that from conventional IP by more than 10 times, ranking among one of the highest performances reported to date. More significantly, the pernicious permeation-rejection trade-off of the TFC membrane is thus alleviated. Besides, this strategy is facile, versatile, and easy to scale-up, giving controllable physical and chemical structures to the active layer. This study may pave a way to well-design highly efficient film materials for various transport and separation applications. PMID- 29516718 TI - Real-Time and Accurate Identification of Single Oligonucleotide Photoisomers via an Aerolysin Nanopore. AB - Identification of the configuration for the photoresponsive oligonucleotide plays an important role in the ingenious design of DNA nanomolecules and nanodevices. Due to the limited resolution and sensitivity of present methods, it remains a challenge to determine the accurate configuration of photoresponsive oligonucleotides, much less a precise description of their photoconversion process. Here, we used an aerolysin (AeL) nanopore-based confined space for real time determination and quantification of the absolute cis/ trans configuration of each azobenzene-modified oligonucleotide (Azo-ODN) with a single molecule resolution. The two completely separated current distributions with narrow peak widths at half height (<0.62 pA) are assigned to cis/ trans-Azo-ODN isomers, respectively. Due to the high current sensitivity, each isomer of Azo-ODN could be undoubtedly identified, which gives the accurate photostationary conversion values of 82.7% for trans-to- cis under UV irradiation and 82.5% for cis-to- trans under vis irradiation. Further real-time kinetic evaluation reveals that the photoresponsive rate constants of Azo-ODN from trans-to- cis and cis-to trans are 0.43 and 0.20 min-1, respectively. This study will promote the sophisticated design of photoresponsive ODN to achieve an efficient and applicable photocontrollable process. PMID- 29516719 TI - Bioorthogonal in Situ Hydrogels Based on Polyether Polyols for New Biosensor Materials with High Sensitivity. AB - Both noncovalent and covalent encapsulations of active biomolecules, for example, proteins and oligonucleotides, for a new biosensor matrix in an in situ bioorthogonal hydrogel formation via a strain-promoted azide-alkyne cycloaddition reaction were investigated. Unspecific interaction between the gel and the biomolecules as well as protein denaturation was prevented by the bioorthogonal gel components, which ensure a uniform aqueous environment in the hydrogel network. No leaching of the active biomolecules was observed. Additionally, a much higher and also adjustable loading of biomolecules in the hydrogel matrix was achieved compared to conventional biosensor surfaces, where the sensor molecules are immobilized on monolayers (2D surfaces) or brushlike structures (3D surfaces). Spotting experiments of the hydrogel confirm the possibility to use this new surface for microarray-based multiplex applications which require very high signal-to-noise ratios. PMID- 29516720 TI - Recognition of Exogenous and Endogenous Nitroxyl in Living Cells via a Two-Photon Fluorescent Probe. AB - Nitroxyl (HNO), one electron reduced and protonated form of nitric oxide (NO), plays vital in various biological functions and pharmacological activities, such as mediating beta-agonist dobutamine, inhibiting the activity of enzyme and treating cardiovascular diseases. However, the accurate mechanism of HNO in living cells is not thoroughly understood due to lacking of effective methods. In this work, a novel two-photon fluorescent probe TP-HNO was designed and synthesized based on 6-hydroxyl-quinonline-2-benzothiazole derivatives through introducing 2-(diphenylphosphino)benzoate as the ideal HNO recognition unit, which demonstrated the merits of outstanding selectivity, excellent sensitivity (DL 0.19 MUM) and rapid response (20 min). In addition, owing to the high cell permeability and low biotoxicity of probe TP-HNO, it was successfully used for the qualitative and bioimaging of exogenous and endogenous nitroxyl concentration fluctuations in living cells via a two-photon laser confocal fluorescence microscopy, respectively, which is of importance for revealing the biological of HNO in the further. PMID- 29516721 TI - Chemical Identity and Mechanism of Action and Formation of a Cell Growth Inhibitory Compound from Polycarbonate Flasks. AB - This paper reports the chemical identity and mechanism of action and formation of a cell growth inhibitory compound leached from some single-use Erlenmeyer polycarbonate shaker flasks under routine cell culture conditions. Single-use cell culture vessels have been increasingly used for the production of biopharmaceuticals; however, they often suffer from issues associated with leachables that may interfere with cell growth and protein stability. Here, high performance liquid-chromatography preparations and cell proliferation assays led to identification of a compound from the water extracts of some polycarbonate flasks, which exhibited subline- and seeding density-dependent growth inhibition of CHO cells in suspension culture. Mass spectroscopy, nuclear magnetic resonance spectroscopy, and chemical synthesis confirmed that this compound is 3,5-dinitro bisphenol A. Cell cycle analysis suggests that 3,5-dinitro-bisphenol A arrests CHO-S cells at the G1/Go phase. Dynamic mass redistribution assays showed that 3,5-dinitro-bisphenol A is a weak GPR35 agonist. Analysis of the flask manufacturing process suggests that 3,5-dinitro-bisphenol A is formed via the combination of molding process with gamma-sterilization. This is the first report of a cell culture/assay interfering leachable compound that is formed through gamma-irradiation-mediated nitric oxide free radical reaction. PMID- 29516722 TI - PEGylated Self-Assembled Nano-Bacitracin A: Probing the Antibacterial Mechanism and Real-Time Tracing of Target Delivery in Vivo. AB - Although nano-self-assemblies of hydrophobic-modified bacitracin A with poly(d,l lactic- co-glycolic acid) (PLGA) (nano-BAPLGA) have demonstrated promising antibacterial activities, the application of nano-BAPLGA was severely compromised by low water solubility. In this study, a series of PEGylated PLGA copolymers were selected to conjugate with the N-terminus of bacitracin A to construct PEGylated self-assembled nano-BAs and to further develop nano-self-assemblies of bacitracin A with strong antibacterial potency and high solubility. Compared with nano-BAPLGA, all PEGylated nano-BAs, except nano-BA5k, exhibited strong antibacterial efficiency against both Gram-positive and Gram-negative bacteria by inducing loss of cytoplasmic membrane potential, membrane permeabilization, and leakage of calcein from artificial cell membranes. Studies elucidating the underlying mechanism of PEGylated nano-BAs against Gram-negative bacteria indicated that the strong hydrophobic and van der Waals interactions between PLGA and lipopolysaccharide (LPS) could bind, neutralize, and disassociate LPS, facilitating cellular uptake of the nanoparticles, which could destabilize the membrane, resulting in cell death. Moreover, PEGylated nano-BAs (nano-BA12k) with a longer PLGA block were expected to occupy a higher local density of BA mass on the surface and result in stronger hydrophobic and van der Waals interactions with LPS, which were responsible for the enhanced antibacterial activity against Gram-positive and emerging antibacterial activity against Gram-negative bacteria, respectively. In vivo imaging verified that PEGylated nano-BAs exhibited higher inflammatory tissue distribution and longer circulation time than nano-BAPLGA. Therefore, although PEGylation did not affect antibacterial activity, it is necessary for target delivery and resistance to clearance of the observed PEGylated nano-BAs. In vivo, nano-BA12k also showed the highest therapeutic index against infection burden in a mouse thigh infection model among the tested formulations, which showed good correlation with the in vitro results. In conclusion, nano-BA12k showed high efficacy in the treatment of invasive infections. This new approach of constructing nanoantibiotics by modification of commercially available antibiotics with PEGylated copolymers is safe, cost effective, and environmentally friendly. PMID- 29516724 TI - Divergent Strategy in Natural Product Total Synthesis. AB - The divergent total syntheses of complex natural products from a common intermediate have attracted enormous attention in the chemical community in the past few years because it can improve the efficiency of chemical synthesis. A number of powerful and unified strategies have been developed by emulating the natural biosynthesis or through innovative transformations. This review focuses on the total synthesis of natural products by applying divergent strategies and the literature covering from 2013 to June 2017. On the basis of where the diversity comes from, the examples are grouped into three parts and discussed in detail. In each group, the examples that synthesize natural products belonging to the same subfamily are put together to contrast with one another. PMID- 29516723 TI - Porous Wood Members-Based Amplified Colorimetric Sensor for Hg2+ Detection through Hg2+-Triggered Methylene Blue Reduction Reactions. AB - Wood has attracted increasing scientific interest in the field of green electronics, biological devices, bioenergy, and energy storage because of its abundance, low cost, biocompatibility, and natural vessel structure. However, its potential application in the important area of environmental monitoring has not yet been effectively explored. In this work, gold nanoparticles (NPs) encapsulated in porous wood (denoted as Au@wood) for high-performance colorimetric detection of Hg2+ in aqueous solution have been constructed. The detection mechanism is based on Hg2+-triggered methylene blue (MB) reduction assisted signal amplification. In such a detection system, Au NPs can be used as a specific identification element for the binding of Hg2+ due to the formation of gold amalgam to initiate catalytic activity of gold. The low-cost natural wood is introduced to prevent the aggregation of Au NPs and increase the contact area between MB and Au NPs in three-dimensional space. MB, as a tracer molecule, enables the output signals to be directly observed by the naked eye. Such a detection system exhibited an ultralow detection limit of 32 pM for Hg2+, which is greatly lower than the threshold levels (10 nM) for drinking water and other colorimetric methods. The proposed detection system also exhibits high selectivity against other metal ions and works well for environmental water and blood samples. The resultant Au@wood sensor is low cost, easy handling, and convenient, making it an attractive material for point-of-use monitoring of Hg2+ in environmental and biological samples. PMID- 29516725 TI - An Automated Induction Microfluidics System for Synthetic Biology. AB - The expression of a recombinant gene in a host organism through induction can be an extensively manual and labor-intensive procedure. Several methods have been developed to simplify the protocol, but none has fully replaced the traditional IPTG-based induction. To simplify this process, we describe the development of an autoinduction platform based on digital microfluidics. This system consists of a 600 nm LED and a light sensor to enable the real-time monitoring of the optical density (OD) samples coordinated with the semicontinuous mixing of a bacterial culture. A hand-held device was designed as a microbioreactor to culture cells and to measure the OD of the bacterial culture. In addition, it serves as a platform for the analysis of regulated protein expression in E. coli without the requirement of standardized well-plates or pipetting-based platforms. Here, we report for the first time, a system that offers great convenience without the user to physically monitor the culture or to manually add inducer at specific times. We characterized our system by looking at several parameters (electrode designs, gap height, and growth rates) required for an autoinducible system. As a first step, we carried out an automated induction optimization assay using a RFP reporter gene to identify conditions suitable for our system. Next, we used our system to identify active thermophilic beta-glucosidase enzymes that may be suitable candidates for biomass hydrolysis. Overall, we believe that this platform may be useful for synthetic biology applications that require regulating and analyzing expression of heterologous genes for strain optimization. PMID- 29516726 TI - Shifting Global Exposures to Poly- and Perfluoroalkyl Substances (PFASs) Evident in Longitudinal Birth Cohorts from a Seafood-Consuming Population. AB - Rapid declines in legacy poly- and perfluoroalkyl substances (PFASs) have been reported in human populations globally following changes in production since 2000. However, changes in exposure sources are not well understood. Here, we report serum concentrations of 19 PFASs (?19PFAS) measured in children between 1993 and 2012 from a North Atlantic fishing community (Faroe Islands). Median ?19PFAS concentrations in children (ages 5-13 years) peaked in 2000 (47.7 ng mL 1) and declined significantly by 14.4% year-1 until 2012. Principal component analysis (PCA) identified two groups of PFASs that likely reflect exposures from diverse consumer products and a third group that consisted of perfluorocarboxylic acids (PFCAs) with nine or more carbons (C >= 9). These C >= 9 PFASs are strongly associated with mercury in children's hair, a well-established proxy for seafood consumption, especially perfluoroundecanoic acid (PFUnDA, r = 0.72). Toxicokinetic modeling shows PFAS exposures from seafood have become increasingly important (53% of perfluorooctanesulfonate, PFOS, in 2012), despite a decline in whale consumption in recent years. We infer that even in a major seafood consuming population, declines in legacy PFAS exposure after 2000 were achieved by the rapid phase out of PFOS and its precursors in consumer products. These results emphasize the importance of better understanding exposures to replacement PFASs in these sources. PMID- 29516727 TI - Polyethylenimine Modified Graphene-Oxide Electrochemical Immunosensor for the Detection of Glial Fibrillary Acidic Protein in Central Nervous System Injury. AB - Glial fibrillary acidic protein (GFAP) is as an intermediate filament protein expressed by certain cells in the central nervous system (CNS). GFAP has been recognized as a reliable biomarker of CNS injury. However, due to the absence of rapid and easy-to-use assays for the detection of CNS injury biomarkers, measuring GFAP levels to identify CNS injury has not attained widespread clinical implementation. In the present work, we developed a polyethylenimine (PEI) coated graphene screen-printed electrode and used it for highly sensitive immunosensing of GFAP. Covalent binding of GFAP antibody to the PEI-modified electrode surface along with electrochemical impedance spectroscopy was used for detecting the change in the electrical conductivity of the electrodes. A highly linear response was recorded for various GFAP concentrations. Quantitative, selective, and label free detection was achieved in the dynamic range of 1 pg mL-1 to 100 ng mL-1 for GFAP spiked in phosphate buffer saline, artificial cerebrospinal fluid, and human blood serum. The performance of the immunosensor was further validated and correlated by testing samples with the commercially available enzyme-linked immunosorbent assay method. This functionalized electrode could be used clinically for rapid detection and monitoring of CNS injury. PMID- 29516728 TI - LiV3O8/Polydiphenylamine Composites with Significantly Improved Electrochemical Behavior as Cathode Materials for Rechargeable Lithium Batteries. AB - Although LiV3O8 is regarded as a potential cathode candidate for rechargeable lithium batteries, it has been restricted by its weak dissolution and lattice structure change. Here, polydiphenylamine is successfully introduced to trigger the evolution of LiV3O8 material through an in situ oxidative polymerization method, significantly improving the electrochemical properties and inhibiting the adverse reaction. Expectedly, the 10 wt % LiV3O8/polydiphenylamine composite delivers a high initial specific discharge capacity of 311 mAh g-1, which decreases to 272 mAh g-1 after 50 cycles at the current density of 60 mA g-1. Even at a high current density of 2000 mA g-1, it still exhibited a reversible specific capacity of 125 mAh g-1 after 50 cycles. Quantitative kinetics analysis confirms the fundamental reasons for the enhanced rate capability. The ex situ X ray diffraction and scanning electron microscopy results suggest that 10 wt % LiV3O8/polydiphenylamine composite possesses an ultrahigh structural stability during cycling. PMID- 29516729 TI - Meter-Scale Reactive Transport Modeling of CO2-Rich Fluid Flow along Debonded Wellbore Casing-Cement Interfaces. AB - Defects along wellbore interfaces constitute potential pathways for CO2 to leak from geological storage systems. In previous experimental work, we demonstrated that CO2-induced reaction over length-scales of several meters can lead to self sealing of such defects. In the present work, we develop a reactive transport model that, on the one hand, enables MUm-mm scale exploration of reactions along debonding defects and, on the other hand, allows simulation of the large, 6 m long samples used in our experiments. At these lengths, we find that interplay between flow velocity and reaction rate strongly affects opening/sealing of interfacial defects, and depth of chemical alteration. Carbonate precipitation in initially open defects decreases flow rate, leading to a transition from advection-dominated to diffusion-dominated reactive transport, with acidic conditions becoming progressively more confined upstream. We investigate how reaction kinetics, portlandite content, and the nature of the carbonate products impact the extent of cement alteration and permeability reduction. Notably, we observe that nonuniformity of the initial defect geometry has a profound effect on the self-sealing behavior and permeability evolution as observed on the meter scale. We infer that future wellbore models need to consider the effects of such aperture variations to obtain reliable upscaling relations. PMID- 29516730 TI - One Step toward Developing Knowledge from Numbers in Regional Analysis of Water Quality. PMID- 29516731 TI - Self-Cleaning Transparent Heat Mirror with a Plasma Polymer Fluorocarbon Thin Film Fabricated by a Continuous Roll-to-Roll Sputtering Process. AB - This paper proposes a novel self-cleaning transparent heat mirror (SC-THM) produced by depositing a plasma polymer fluorocarbon thin film on a silver-and SiN x multilayer structure fabricated by continuous roll-to-roll sputtering. The optimal structure and the thickness of each thin film of three-layer and five layer SC-THMs were derived from optical simulation. In the five-layer SC-THM, the visible light transmittance was 60.67% at a wavelength of 406 nm and the infrared (IR) transmittance was 6.86% at a 1000 nm wavelength and 2.50% at a 1500 nm wavelength. The value of the performance parameter Tvis/ Tsol was 1.70. The SC THM exhibited self-cleaning with a very good water repellency of more than 111 degrees , achieved by applying a low-surface-energy fluorocarbon thin film to the top layer. This study successfully demonstrated the IR blocking properties of an SC-THM through IR reflection and IR irradiation experiments. PMID- 29516732 TI - Closing Microplastic Pathways Before They Open: A Model Approach. PMID- 29516733 TI - Correlating Transport and Structural Properties in Li1+ xAl xGe2- x(PO4)3 (LAGP) Prepared from Aqueous Solution. AB - Li1+ xAl xGe2- x(PO4)3 (LAGP) is a solid lithium-ion conductor belonging to the NASICON family, representing the solid solution of LiGe2(PO4)3 and AlPO4. The typical syntheses of LAGP either involve high-temperature melt-quenching, which is complicated and expensive, or a sol-gel process requiring costly organic germanium precursors. In this work, we report a simple method based on aqueous solutions without the need of ethoxide precursors. Using synchrotron and neutron diffraction, the crystal structure, the occupancies for Al and Ge, and the distribution of lithium were determined. Substitution of germanium by aluminum allows for an increased Li+ incorporation in the material and the actual Li+ content in the sample increases with the nominal Li+ content and a solubility limit is observed for higher aluminum content. By means of impedance spectroscopy, an increase in the ionic conductivity with increasing lithium content is observed. Whereas the lithium ionic conductivity improves, due to the increasing carrier density, the bulk activation energy increases. This correlation suggests that changes in the transport mechanism and correlated motion may be at play in the Li1+ xAl xGe2- x(PO4)3 solid solution. PMID- 29516734 TI - Release of Electron Donors during Thermal Treatment of Soils. AB - Thermal treatment of soil and groundwater may provide an in situ source of soluble organic compounds and hydrogen (H2) that could stimulate microbial reductive dechlorination (MRD) at sites impacted by chlorinated solvents. The objectives of this study were to identify and quantify the release of electron donors and fermentable precursors during soil heating and to estimate availability of these compounds following thermal treatment. Fourteen solid materials containing <0.01 to 63.81 wt % organic carbon (OC) were incubated at 30, 60, or 90 degrees C for up to 180 d, leading to the release of direct electron donors (i.e., H2 and acetate) and fermentable volatile fatty acids (VFAs). Total VFA release ranged from 5 +/- 0 * 10-9 carbon per gram solid (mol C/gs) during 30 degrees C incubation of quartz sand to 820 +/- 50 * 10-6 mol C/gs during 90 degrees C incubation of humic acid, and was positively impacted by incubation time, temperature, and solid-phase OC content. H2 gas was detected at a maximum of 180 +/- 50 * 10-9 mol H2/gs, accounting for less than 0.3% of reducing equivalents associated with VFAs released under the same conditions. These findings will allow for more reliable prediction of substrate release during thermal treatment, supporting the implementation of coupled thermal and biological remediation strategies. PMID- 29516735 TI - In Situ Detection of Macronutrients and Chloride in Seawater by Submersible Electrochemical Sensors. AB - A new submersible probe for the in situ detection of nitrate, nitrite, and chloride in seawater is presented. Inline coupling of a desalination unit, an acidification unit, and a sensing flow cell containing all-solid-state membrane electrodes allows for the potentiometric detection of nitrate and nitrite after removal of the key interfering ions in seawater, chloride and hydroxide. Thus, the electrodes exhibited attractive analytical performances for the potentiometric detection of nitrate and nitrite in desalinated and acidified seawater: fast response time ( t95 < 12 s), excellent stability (long-term drifts of <0.5 mV h-1), good reproducibility (calibration parameter deviation of <3%), and satisfactory accuracy (uncertainties <8%Diff compared to reference technique). The desalination cell, which can be repetitively used for about 30 times, may additionally be used as an exhaustive, and therefore calibration-free, electrochemical sensor for chloride and indirect salinity detection. The detection of these two parameters together with nitrate and nitrite may be useful for the correlation of relative changes in macronutrient levels with salinity cycles, which is of special interest in recessed coastal water bodies. The system is capable of autonomous operation during deployment, with routines for repetitive measurements (every 2 h), data storage and management, and computer visualization of the data in real time. In situ temporal profiles observed in the Arcachon Bay (France) showed valuable environmental information concerning tide dependent cycles of nitrate and chloride levels in the lagoon, which are here observed for the first time using direct in situ measurements. The submersible probe based on membrane electrodes presented herein may facilitate the study of biogeochemical processes occurring in marine ecosystems by the direct monitoring of nitrate and nitrite levels, which are key chemical targets in coastal waters. PMID- 29516736 TI - Probing Activated and Non-Activated Single Calmodulin Molecules under a Piconewton Compressive Force. AB - Interrogating the protein structure-function inter-relationship under a piconewton force manipulation has been highly promising and informative. Although protein conformational changes under pulling force manipulations have been extensively studied, protein conformational changes under a compressive force have not been explored in detail. Using our home-modified sensitive and high signal-to-noise atomic force microscopy (AFM) approach, we have applied a piconewton compressive force, manipulating a Calmodulin (CaM) molecule to characterize two different forms of CaM, the Ca2+-ligated activated form and the Ca2+ free non-activated form (apo-CaM). We observed sudden and spontaneous structural rupture of apo-CaM under compressive force applied by an AFM tip, though no such events were recorded in the case of Ca2+-ligated activated CaM form. The sudden spontaneous structural rupture under a piconewton force compression has never been reported before, which presents an unexplored function that is likely important for protein-protein interactions and cell signaling functions. PMID- 29516738 TI - Supramolecular Association Impacts Biomolecule Adsorption onto Goethite. AB - Formation of biomolecule-rich supramolecular complexes in dissolved organic matter (DOM) and subsequent adsorption onto minerals is important for the development of mineral-stabilized organic matter, yet the impact of supramolecular association on interfacial behavior is seldom studied. A series of supramolecular complexes of model biomolecules (deoxyribonucleic acid (DNA) and bovine serum albumin (BSA)) are synthesized, characterized, and adsorbed onto goethite. Complexes represent 0.1 mg/mL DNA mixed with BSA concentrations from 0.05 to 0.5 mg/mL in 5 mM KCl at pH = 5.0. Circular dichroism demonstrates strong binding between DNA and BSA, with DNA saturation when (BSA) ~ 0.4 mg/mL. Dynamic light scattering and electrophoretic mobility measurements suggest DNA-BSA binding reduces DNA-DNA electrostatic repulsion. Spectroscopic studies of DNA/BSA complex adsorption show complexation hinders coordination of DNA phosphodiester groups with goethite. Increasing BSA (<=0.4 mg/mL) in DNA/BSA complexes enhances DNA adsorption, due to reduced repulsion between adsorbed DNA helices. When (BSA) > 0.4 mg/mL, however, DNA adsorption is decreased. We hypothesize this results from blocking of surface sites by fast adsorption of BSA loosely associated with DNA/BSA complexes. We posit an additional mechanism describing multilayered architecture formation of organo-mineral associations in soil, suggesting solution interactions may represent an overlooked factor when considering mineral retention of DOM. PMID- 29516737 TI - Role of Ligand-Driven Conformational Changes in Enzyme Catalysis: Modeling the Reactivity of the Catalytic Cage of Triosephosphate Isomerase. AB - We have previously performed empirical valence bond calculations of the kinetic activation barriers, Delta G?calc, for the deprotonation of complexes between TIM and the whole substrate glyceraldehyde-3-phosphate (GAP, Kulkarni et al. J. Am. Chem. Soc. 2017 , 139 , 10514 - 10525 ). We now extend this work to also study the deprotonation of the substrate pieces glycolaldehyde (GA) and GA.HPi [HPi = phosphite dianion]. Our combined calculations provide activation barriers, Delta G?calc, for the TIM-catalyzed deprotonation of GAP (12.9 +/- 0.8 kcal.mol-1), of the substrate piece GA (15.0 +/- 2.4 kcal.mol-1), and of the pieces GA.HPi (15.5 +/- 3.5 kcal.mol-1). The effect of bound dianion on Delta G?calc is small (<=2.6 kcal.mol-1), in comparison to the much larger 12.0 and 5.8 kcal.mol-1 intrinsic phosphodianion and phosphite dianion binding energy utilized to stabilize the transition states for TIM-catalyzed deprotonation of GAP and GA.HPi, respectively. This shows that the dianion binding energy is essentially fully expressed at our protein model for the Michaelis complex, where it is utilized to drive an activating change in enzyme conformation. The results represent an example of the synergistic use of results from experiments and calculations to advance our understanding of enzymatic reaction mechanisms. PMID- 29516739 TI - Synthesis of 2,6,7-Trisubstituted Prenylated indole. AB - Prenylated indole alkaloids bearing more than one prenyl or reverse-prenyl group show various biological activities. Among them, synthesis of trisubstituted-type prenylated indoles have not been well explored because of the difficulty in regioselective introduction of multiple prenyl and reverse-prenyl groups due to steric hindrance problems. Herein, we describe a synthesis of 2,6,7 trisubstituted prenylated indole using aza-Claisen rearrangement under mild conditions to introduce a prenyl group at C7 in the presence of the prenyl group at C6. PMID- 29516740 TI - Synthesis of Functionalized Triphenylenes via a Traceless Directing Group Strategy. AB - A novel ligand-free Pd-catalyzed cascade reaction between o-chlorobenzoic acids and cyclic diaryliodonium salts is reported. This one-pot procedure involves a carboxylic acid directed o-arylation followed by intramolecular decarboxylative annulation affording various valuable triphenylenes, which can be further transformed into diversified building blocks for material chemistry. For the first time, it was shown that an aromatic halide can react with diaryliodonium salts under the direction of carboxylic acid functionality. It was also demonstrated that the carboxylic acid could be employed as both a traceless directing group and functional handle for the atom- and step-economical one-pot double cross-coupling annulation reaction with cyclic diaryliodonium salts as the pi-extending agents. PMID- 29516742 TI - The rush from bench to bedside in electroconvulsive therapy. PMID- 29516741 TI - A sensitive method for the quantitation of the peptide-based glucagon-like peptide-1 receptor agonist liraglutide in plasma using microfluidics chromatography tandem MS. AB - AIM: An LC-MS/MS assay for the quantitation of liraglutide, a peptide-based injectable glucagon-like peptide-1 receptor agonist, has been developed as a convenient alternative to the enzyme-linked immunosorbent assay, and used to characterize liraglutide pharmacokinetics in cynomolgus monkeys. RESULTS: Assay calibration curves exhibited a linear dynamic range of 10-5000 ng/ml and correlation coefficient >=0.98. Following a 30 MUg/kg intravenous dose, liraglutide demonstrated low plasma clearance and distribution volume, which led to a terminal half-life of 6.59 h in monkeys. CONCLUSION: The dynamic range of our LC-MS/MS assay provides sufficient coverage of the average efficacious liraglutide concentrations in human plasma, and can be used for pharmacokinetics/pharmacodynamics studies in animals and potentially in humans. PMID- 29516743 TI - Bipolar II disorder: The need for clearer definition and improved management. PMID- 29516745 TI - Dying before their time: Addressing premature mortality among autistic people. PMID- 29516744 TI - Interrelationships between changes in erythropoietin, plasma volume, haemoglobin concentration, and total haemoglobin mass in endurance athletes. AB - Interrelationships between physiological changes (Delta) in erythropoietin (EPO), plasma volume (PV), haemoglobin concentration ([Hb]), and total haemoglobin mass (tHb-mass) were examined in cyclists who trained in different altitudes. Regardless of differences in pattern of changes observed in three training locations, DeltaEPO was correlated positively with DeltaPV, negatively with Delta[Hb], and trivially with DeltatHb-mass. Delta[Hb] was negatively correlated with DeltaPV. In the pooled data the Spearman's rank correlation coefficients were as follows: r = 0.783, P < 0.001; r = -0.704, P < 0.001; r = 0.136, P > 0.05; r = -0.813, P < 0.001, respectively. The obtained results have shown that EPO does not only regulate [Hb] by erythropoiesis stimulation but also by PV modulation, which probably aims at keeping proper level of arterial oxygen content for oxygen delivery to tissues. PMID- 29516746 TI - Corrigendum. PMID- 29516747 TI - Corrigendum. PMID- 29516748 TI - A contemporary 16-year review of Coxiella burnetii infective endocarditis in a tertiary cardiac center in Queensland, Australia. AB - BACKGROUND: Coxiella burnetii endocarditis can be difficult to diagnose leading to delays in treatment. This retrospective case series study was undertaken to understand the epidemiologic trends and clinical features of Q fever endocarditis in Southeast Queensland, Australia. METHODS: Clinical records of patients from a single center with coding diagnosis of C. burnetii, or serology consistent with chronic Q fever, were reviewed from 1999 to 2015. Data from patients with probable or confirmed Q fever endocarditis was abstracted. RESULTS: Thirteen patients had confirmed and 5 had probable Q fever endocarditis. Median age at diagnosis in confirmed cases was 60 years. In confirmed cases, 92% (12/13) of patients had an underlying valvular defect. Two patients in the confirmed cases had serology not consistent with a diagnosis of Q fever endocarditis. Eight patient records noted retrospective diagnosis of Q fever endocarditis after surgery. CONCLUSIONS: As pre-existing valve pathology is a major risk for developing endocarditis, prophylactic strategies such as targeted echocardiography and Q fever vaccination could be considered to reduce the incidence of Q fever endocarditis. PMID- 29516749 TI - Beyond JAK-2: potential targets for myeloproliferative neoplasm therapy. AB - INTRODUCTION: The outlook for patients with myeloproliferative neoplasms, particularly myelofibrosis, has improved in recent years, with greater understanding of the pathogenesis and the subsequent development of a plethora of new agents. Areas covered: This article will discuss some of the advances in the field in recent years and explore in greater detail some of the most advanced emerging agents as well as those with greatest potential. An extensive literature review has been performed to identify recent clinical trials and any relevant pre clinical work. Expert commentary: Important discoveries regarding molecular pathogenesis have led to advances in diagnostic algorithms, prognosis and ultimately also treatment strategies. However, the therapeutic armamentarium for MPN is still largely inadequate to cope with significant challenges including normalization of life span, reduction of cardiovascular complications, prevention of hematological progression and improved quality of life. Sadly, no currently available drugs have shown clear evidence of disease-modifying activity and results of early phase I and II clinical trials have been quite disappointing to date, with toxicities sometimes limiting and a lack of meaningful biological surrogate end points. PMID- 29516750 TI - Therapeutic approaches for refractory germ cell cancer. AB - INTRODUCTION: Most germ cell cancer patients with metastatic disease are cured by cisplatin-based combination chemotherapy. 30% of metastatic patients will develop relapse or progress despite adequate first-line treatment and will require salvage therapy, with about 10% of metastasized patients ultimately developing platinum-resistant and fatal disease. Areas covered: Based on a comprehensive literature search of MEDLINE, EMBASE and conference proceedings of ESMO, ASCO and EAU meetings, this review provides an overview on current and potential future treatment options for platinum-refractory germ cell cancer patients including cytostatics and molecularly targeted therapies. Expert commentary: Treatment of platinum-refractory disease remains challenging and long-term survival is rarely achieved despite multimodal treatment approaches. Targeted treatment approaches do not yet play a role in the treatment of platinum-refractory disease due to lacking efficacy in small, unselected clinical trials. Inclusion of patients into clinical trials is strongly recommended. PMID- 29516751 TI - Agent-based model of diffusion of N-acyl homoserine lactones in a multicellular environment of Pseudomonas aeruginosa and Candida albicans. AB - Experimental incapacity to track microbe-microbe interactions in structures like biofilms, and the complexity inherent to the mathematical modelling of those interactions, raises the need for feasible, alternative modelling approaches. This work proposes an agent-based representation of the diffusion of N-acyl homoserine lactones (AHL) in a multicellular environment formed by Pseudomonas aeruginosa and Candida albicans. Depending on the spatial location, C. albicans cells were variably exposed to AHLs, an observation that might help explain why phenotypic switching of individual cells in biofilms occurred at different time points. The simulation and algebraic results were similar for simpler scenarios, although some statistical differences could be observed (p < 0.05). The model was also successfully applied to a more complex scenario representing a small multicellular environment containing C. albicans and P. aeruginosa cells encased in a 3-D matrix. Further development of this model may help create a predictive tool to depict biofilm heterogeneity at the single-cell level. PMID- 29516753 TI - Piloting and psychometric properties of a patient-reported outcome instrument for young people with achondroplasia based on the International Classification of Functioning Disability and Health: the Achondroplasia Personal Life Experience Scale (APLES). AB - BACKGROUND: This study describes the psychometric testing of the Achondroplasia Personal Life Experience Scale (APLES): a new disease- and functioning-specific health-related quality of life instrument for young people with achondroplasia, which was developed based on the International Classification of Functioning Children and Youth Version. METHOD: The qualitative analysis of focus group statements from German patients and parents using the International Classification of Functioning-Children and Youth Version yielded 59 items, which after cognitive debriefing were included in a pilot-test. Psychometric performance was cross-culturally examined in a field- and re-test in Germany and Spain. RESULTS: Cognitive debriefing and pilot-test results suggested to reduce the 59-APLES version to a 35-items version. Field-test data showed acceptable reliability and validity, which further improved after the APLES was shortened to 21 items. CONCLUSION: Developing a disease-specific instrument within the framework of the International Classification of Functioning allows the universal assessment and comparison of perceived health. Psychometric analysis showed that the APLES fulfills psychometric quality standards and provides a way to assess health-related quality of life from self- and observer report in young persons with achondroplasia. Further studies may use the instrument in clinical research and practice to understand perceived burden and to optimize care. Implications for Rehabilitation Health-related quality of life instruments are useful tools to include in clinical research and/or practice to evaluate treatment effects directly from the patient's perspective. Cross-culturally developed health related quality of life measures that are based on the International Classification of Functioning Disability and Health provide the opportunity to assess the health status in a standardized language and to compare it across countries and health professions. All four components of the International Classification of Functioning Disability and Health - Child and Youth Version ("Body Functions & Structures", "Activities and Participation", "Environmental Factors", and "Personal Factors") have been shown to be relevant in assessing health-related quality of life and functioning in young achondroplasia patients. Results underline the important aspects associated with disproportionate short stature, emphasizing the benefits of a disease-specific instrument. PMID- 29516754 TI - Functional Exploration of the Bacterial Type VI Secretion System in Mutualism: Azorhizobium caulinodans ORS571-Sesbania rostrata as a Research Model. AB - The bacterial type VI secretion system (T6SS) has been considered the armed force of bacteria because it can deliver toxin effectors to prokaryotic or eukaryotic cells for survival and fitness. Although many legume symbiotic rhizobacteria encode T6SS in their genome, the biological function of T6SS in these bacteria is still unclear. To elucidate this issue, we used Azorhizobium caulinodans ORS571 and its symbiotic host Sesbania rostrata as our research model. By using T6SS gene deletion mutants, we found that T6SS provides A. caulinodans with better symbiotic competitiveness when coinfected with a T6SS-lacking strain, as demonstrated by two independent T6SS-deficient mutants. Meanwhile, the symbiotic effectiveness was not affected by T6SS because the nodule phenotype, nodule size, and nodule nitrogen-fixation ability did not differ between the T6SS mutants and the wild type when infected alone. Our data also suggest that under several lab culture conditions tested, A. caulinodans showed no T6SS-dependent interbacterial competition activity. Therefore, instead of being an antihost or antibacterial weapon of the bacterium, the T6SS in A. caulinodans ORS571 seems to participate specifically in symbiosis by increasing its symbiotic competitiveness. PMID- 29516752 TI - Economic analysis of BRAF gene mutation testing in real world practice using claims data: costs of single gene versus panel tests in patients with lung cancer. AB - AIMS: To assess the time to BRAF testing, compare the characteristics of tested vs not-tested patients, and describe the costs for sequential vs next-generation sequencing (NGS) BRAF testing. METHODS: Patients diagnosed with lung cancer after December 1, 2013 were identified from two US claims databases; their characteristics were assessed during the 12 months before diagnosis (index date). Testing modalities were analyzed from the index date to end of continuous health plan enrollment or data availability (December 2015), based on combinations of Current Procedural Terminology (CPT) procedure codes. Time to BRAF testing was assessed using Kaplan-Meier analysis. Costs were analyzed from a payer's perspective. RESULTS: A total of 28,011 patients newly-diagnosed with lung cancer were identified. Of them, 1,260 (4.5%) were tested for BRAF: 3.2% and 4.2% were tested at 6 and 12 months, respectively, after the index date. Compared to non tested patients, tested patients were younger (58.3 vs 65.3 years; p < .001), had a lower Charlson Comorbidity Index (2.8 vs 2.9; p = .005), and a higher proportion had metastases (70.9% vs 43.4%; p < .001). In 76.0% of cases, BRAF was tested along with KRAS. BRAF was tested using NGS in 6.6% of cases. The average reimbursed amounts for the 10 most common CPT code combinations were $207-$2,074. Using the average costs of individual mutation tests, the total cost of sequential testing comprising KRAS, EGFR, ALK, ROS1, and BRAF tests was $3,763 ($464, $696, $1,070, $1,127, and $406, respectively), that of NGS was $2,860. LIMITATIONS: Claims data did not include BRAF test results. CONCLUSIONS: Among patients newly-diagnosed with lung cancer, 4.5% were tested for BRAF. Tested patients were younger and had a lower comorbidity burden, but more advanced disease. While reimbursed amounts varied greatly based on combinations of testing procedures, NGS testing was associated with cost savings compared to sequential testing of individual mutations. PMID- 29516755 TI - Two new 2-arylbenzofurnan derivatives from the leaves of Morus alba. AB - Two new 2-arylbenzofuran derivatives, moracinfurol A and B (1-2), and ten known compounds (3-12) were isolated from the leaves of Morus alba. Their structures were determined on the basis of spectroscopic analysis including 1D, 2D NMR and HR-ESI-MS. All of the 2-arylbenzofuran derivatives were evaluated for cytotoxicity against A549 cells. Some cytotoxic 2-arylbenzofuran derivatives might induce autophagy characterized by the accumulation of LC-3 II. PMID- 29516757 TI - Determining stability in connected speech in primary progressive aphasia and Alzheimer's disease. AB - PURPOSE: Using connected speech to assess progressive language disorders is confounded by uncertainty around whether connected speech is stable over successive sampling, and therefore representative of an individual's performance, and whether some contexts and/or language behaviours show greater stability than others. METHOD: A repeated measure, within groups, research design was used to investigate stability of a range of behaviours in the connected speech of six individuals with primary progressive aphasia and three individuals with Alzheimer's disease. Stability was evaluated, at a group and individual level, across three samples, collected over 3 weeks, involving everyday monologue, narrative and picture description, and analysed for lexical content, fluency and communicative informativeness and efficiency. RESULT: Excellent and significant stability was found on the majority of measures, at a group and individual level, across all genres, with isolated measures (e.g. nouns use, communicative efficiency) showing good, but greater variability, within one of the three genres. CONCLUSION: Findings provide evidence of stability on measures of lexical content, fluency and communicative informativeness and efficiency. While preliminary evidence suggests that task selection is influential when considering stability of particular connected speech measures, replication over a larger sample is necessary to reproduce findings. PMID- 29516756 TI - An alpha-tocopheryl succinate enzyme-based nanoassembly for cancer imaging and therapy. AB - Nanoassembly (NA) based on a D-alpha-tocopherol succinate (alphaTS) conjugated lysozyme (Lys) (Lys-alphaTS) was fabricated for tumor-selective delivery of curcumin (CUR) for breast cancer therapy. Lys and alphaTS were used as a biocompatible enzyme and a hydrophobic residue, respectively, for the preparation of nanocarriers in this study. Compared with CUR-loaded cross-linked Lys (c Lys/CUR) NA, Lys-alphaTS/CUR NA exhibited a smaller hydrodynamic size (213 nm mean diameter), a narrower size distribution, and a more spherical shape. Sustained drug release was observed from the Lys-alphaTS/CUR NA for five days at a normal physiological pH (pH 7.4). The developed Lys-alphaTS/CUR NA showed enhanced cellular accumulation, antiproliferative effects, and apoptotic efficacies in MDA-MB-231 human breast adenocarcinoma cells. According to the results of optical imaging test in the MDA-MB-231 tumor-bearing mouse models, the Lys-alphaTS/CUR NA-injected group exhibited a more tumor-selective accumulation pattern, rather than being distributed in the normal tissues and organs. The observed tumor targetability of Lys-alphaTS/CUR was further studied, which revealed improved in vivo anticancer activities (better inhibition of tumor growth and induction of apoptosis in the tumor tissue) after an intravenous administration in the MDA-MB-231 tumor-bearing mouse models. All these results indicate that the newly developed enzyme-based nanocarrier, the Lys-alphaTS NA, can be a promising candidate for the therapy of breast cancers. PMID- 29516760 TI - Is dietary fibre truly protective against colon cancer? A systematic review and meta-analysis. AB - Colorectal cancer is the third most common cancer worldwide. Growing evidence shows that about 47% of cases of colorectal cancer can be prevented by a healthy lifestyle. We performed a systematic review and meta-analysis aimed to evaluate the association between dietary fibre intake and the risk of colon cancer. We performed a structured computer search on PubMed, including epidemiological studies reporting results of dietary fibre intake and risk of colon cancer in women or men. We compared subjects exposed to the highest versus the lowest consumption. The search strategy identified 376 papers. After screening, 25 datasets were included in our meta-analysis. Results suggest a protective role of dietary fibre intake on colon cancer risk ES = 0.74 (95% CI = 0.67-0.82), p value = .000, but, moderate statistical heterogeneity (chi2 = 42.73, p value = .011) was found. Due to the high mortality of colorectal cancer, it is important to identify effective preventive measures, especially those of a healthy lifestyle, such as a healthy diet. PMID- 29516759 TI - Combined sustained release of BMP2 and MMP10 accelerates bone formation and mineralization of calvaria critical size defect in mice. AB - The effect of dual delivery of bone morphogenetic protein-2 (BMP-2) and matrix metalloproteinase 10 (MMP10) on bone regeneration was investigated in a murine model of calvarial critical-size defect, hypothesizing that it would result in an enhanced bone formation. Critical-size calvarial defects (4 mm diameter) were created in mice and PLGA microspheres preloaded with either BMP-2, MMP10 or a microsphere combination of both were transplanted into defect sites at different doses. Empty microspheres were used as the negative control. Encapsulation efficiency was assessed and in vivo release kinetics of BMP-2 and MMP10 were examined over 14 days. Histological analyses were used to analyze bone formation after four and eight weeks. Combination with MMP10 (30 ng) significantly enhanced BMP-2 (600 ng)-mediated osteogenesis, as confirmed by the increase in percentage of bone fill (p < .05) at four weeks. Moreover, it also increased mineral apposition rate (p < .05), measured by double labeling with tetracycline and calceine. MMP10 accelerates bone repair by enhancing BMP-2-promoted bone healing and improving the mineralization rate. In conclusion combination of MMP10 and BMP 2 may become a promising strategy for repair and regeneration of bone defects. PMID- 29516758 TI - Targeted delivery of hyaluronic acid-coated solid lipid nanoparticles for rheumatoid arthritis therapy. AB - Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders. PMID- 29516761 TI - Once AL amyloidosis: not always AL amyloidosis. PMID- 29516762 TI - Language abilities of Indigenous and non-Indigenous Australian children from low socioeconomic backgrounds in their first year of school. AB - PURPOSE: Concern exists about the cross-cultural appropriateness of existing language assessments for non-mainstream populations, including Indigenous children who may speak a non-standard dialect of the mainstream language. This study therefore aims to investigate the language skills of Indigenous Australian children in comparison with non-Indigenous children, with a view to exploring the cultural appropriateness of language sampling assessment methods. METHOD: The performance of 51 typically developing Indigenous and non-Indigenous Australian children was compared on a standardised assessment and a spoken narrative protocol using language sample analysis measures. All children were in their first year of school and from the same regional city. RESULT: While the Indigenous children attained significantly lower receptive vocabulary scores than the non-Indigenous children, most language sampling measures from the spoken narrative protocol were similar across the two groups of children. CONCLUSION: Flexible, naturalistic language sampling approaches using a spoken narrative protocol are thus recommended for Indigenous children from the under-researched Australian context. However, normative data for language sampling are lacking, and further research is needed to explore the cultural validity of assessment and diagnostic procedures for Indigenous Australian children, as well as the influence of socioeconomic and family factors on language skills. PMID- 29516763 TI - Sentence stress in children with dysarthria and cerebral palsy. AB - PURPOSE: This study aimed to advance our understanding of how children with dysarthria and cerebral palsy (CP) realise sentence stress acoustically, and how well listeners could identify the position of the stressed word within these utterances. METHOD: Seven children with CP and eight typically developing children participated in the experiment. Stress on target words in two sentence positions was elicited through a picture-based question-answer paradigm. Acoustic parameters of stress [duration, intensity and fundamental frequency (F0)] were measured and compared between stressed and unstressed target words. For the perception experiment, ten listeners were asked to determine the position of the stressed word in the children's productions. RESULT: Acoustic measures showed that at group level the typically developing children used all three acoustic parameters to mark sentence stress, whereas the children with CP showed changes in duration only. Individual performance variations were evident in both groups. Perceptually, listeners were significantly better at identifying the stressed words in the utterances produced by the typically developing children than those of the children with CP. CONCLUSION: The results suggest that children with CP can manipulate temporal speech properties to mark stress. This ability to modulate acoustic-prosodic features could be harnessed in intervention to enhance children's functional communication. PMID- 29516764 TI - Narrative skills in two languages of Mandarin-English bilingual children. AB - PURPOSE: Narrative skills between Mandarin and English in Mandarin-English (ME) bilingual children were compared, exploring cross-linguistic interactions of these skills, and influences of age and current language experience (input and output) on narrative performance. METHOD: Macrostructure and microstructure in elicited narratives from 21 ME bilingual children were analysed. Language experience was collected by parent report and entered as a covariate. Repeated measures analysis of covariance (ANCOVA) was conducted to compare the two languages. RESULT: Children demonstrated better narrative performance in English than Mandarin, with a larger cross-linguistic difference in microstructure than macrostructure. Significant cross-linguistic correlations were only found in children with high Mandarin vocabulary. Age, associated with length of English exposure, only significantly correlated with narrative performance in English. Output had stronger correlations with narrative skills than input. CONCLUSION: Macrostructure may be less variable across languages than microstructure. Children may need to reach a threshold of vocabulary for cross-linguistic interactions of narrative skills to occur. The effect of age in English may be related to increased cumulative English experience. Children may experience a plateau in Mandarin due to insufficient Mandarin exposure. Stronger correlations between output and narrative skills may be attributed to the expressive nature of both. PMID- 29516765 TI - Bunyavirales ribonucleoproteins: the viral replication and transcription machinery. AB - The Bunyavirales order is one of the largest groups of segmented negative-sense single-stranded RNA viruses, which includes many pathogenic strains that cause severe human diseases. The RNA segments of the bunyavirus genome are separately encapsidated by multiple copies of nucleoprotein (N), and both termini of each N encapsidated genomic RNA segment bind to one copy of the viral L polymerase protein. The viral genomic RNA, N and L protein together form the ribonucleoprotein (RNP) complex that constitutes the molecular machinery for viral genome replication and transcription. Recently, breakthroughs have been achieved in understanding the architecture of bunyavirus RNPs with the determination of the atomic structures of the N and L proteins from various members of this order. In this review, we discuss the structures and functions of these bunyavirus RNP components, as well as viral genome replication and transcription mechanisms. PMID- 29516766 TI - Impact on acute myeloid leukemia relapse in granulocyte colony-stimulating factor application: a meta-analysis. AB - OBJECTIVES: This meta-analysis evaluated the impact of granulocyte colony stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML). METHODS: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 September 2016 using search terms. Studies that investigated patients with AML who underwent stem-cell transplantation were included. RESULTS: The overall analysis revealed a significant improvement in overall survival (OS) (P = .019) and disease-free survival (DFS) (P = .002) for patients receiving G-CSF with chemotherapy. Among patients without prior AML treatment, there was a significant improvement in DFS (P = .014) and reduction in incidence of relapse (P = .015) for those who received G-CSF. However, subgroup analyses found no significant difference between G-CSF (+) and G-CSF (-) treatments in rates of OS (P = .104) and complete remission (CR) (P = .572) for patients without prior AML treatment. Among patients with relapsed/refractory AML, there was no significant difference found between G-CSF (+) and G-CSF (-) groups for OS (P = .225), DFS (P = .209), and CR (P = .208). DISCUSSION: Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML. ABBREVIATIONS: AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; DFS, disease-free survival; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HR, hazard ratio; MDS, myelodysplastic syndrome; OR, odds ratio; OS, overall survival; RCTs, randomized control trials; RR, relative risk. PMID- 29516767 TI - The cognitive functioning of older adult instrumental musicians and non musicians. AB - This study examined similarities and differences in the cognitive profiles of older adult instrumental musicians and non-musicians. We compared neuropsychological test scores among older adult non-musicians, low-activity musicians (<10 years of lessons), and high-activity musicians (>=10 years of lessons), controlling for self-reported physical and social activity, years of education, and overall health. Significant differences among groups were found on tasks of visual spatial ability, naming, and executive functioning. No significant differences were found on tests of attention/processing speed, or episodic memory. The current study supports late life cognitive benefits of early musical training, but only in select cognitive domains, including language, executive functioning, and visual spatial ability. The results are discussed in the context of cognitive reserve and aging. PMID- 29516768 TI - Mackintosh lecture-: Association and cognition: Two processes, one system. AB - This article argues that the dual-process position can be a useful first approximation when studying human mental life, but it cannot be the whole truth. Instead, we argue that cognition is built on association, in that associative processes provide the fundamental building blocks that enable propositional thought. One consequence of this position is to suggest that humans are able to learn associatively in a similar fashion to a rat or a pigeon, but another is that we must typically suppress the expression of basic associative learning in favour of rule-based computation. This stance conceptualises us as capable of symbolic computation but acknowledges that, given certain circumstances, we will learn associatively and, more importantly, be seen to do so. We present three types of evidence that support this position: The first is data on human Pavlovian conditioning that directly support this view. The second is data taken from task-switching experiments that provide convergent evidence for at least two modes of processing, one of which is automatic and carried out "in the background." And the last suggests that when the output of propositional processes is uncertain, the influence of associative processes on behaviour can manifest. PMID- 29516769 TI - Rule-based processes in generalisation and peak shift in human fear conditioning. AB - Two experiments explored the role of verbalisable rules in generalisation of human differential fear conditioning with electric shock as the aversive stimulus. Two circles of different sizes served as conditioned stimuli (CS+ and CS-), before testing with a range of circle sizes. In Experiment 1, shock expectancy ratings followed a peak-shifted unimodal gradient, with maximum ratings at a test value further along the dimension from CS+ in the opposite direction to CS-. However, differentiable gradients were observed when participants were divided on the basis of the rules they reported using during the task (linear and similarity). Experiment 2 was designed to counter the contradictory feedback arising from extinction testing by removing the shock electrodes during the test phase. A more linear overall gradient was observed, and sub-groups defined by self-reported rules showed distinct gradients that were congruent with their rules. These results indicate that rule-based processes are influential in generalisation of conditioned fear along simple stimulus dimensions, and may help explain generalisation phenomena that have traditionally been attributed to automatic, similarity-based processes. PMID- 29516770 TI - Generalisation decrement and not overshadowing by associative competition among pairs of landmarks in a navigation task with humans. AB - In three experiments, a virtual preparation for humans of the Morris water task (VMWT) was used. Experiment 1 established that four landmarks were of similar salience. Then, in Experiments 2 and 3, participants were trained to locate a hidden platform in the presence or either two or four of the previous landmarks. In Experiment 2, one pair of groups was trained with four visual landmarks spaced at equal intervals around the edge of the pool, while a second pair was trained with two landmarks only, either relatively close to or far from the hidden platform. After training, a reciprocal overshadowing effect was found: on a test without the platform with two landmarks only (either close to or far from the platform position), the participants trained with four landmarks spent less time in the platform quadrant than those trained with only two. Finally, Experiment 3 showed that at least participants trained with two landmarks relatively close to the platform and then tested with four also performed worse on test than those trained and tested with two close landmarks only. This result suggests that generalisation decrement, rather than associative competition, could provide a sufficient explanation for the overshadowing observed in Experiment 2 in the proximal groups. The present set of experiments extend, although only partially, the generalisation decrement results documented in rats to human participants. PMID- 29516771 TI - Activities of daily living retraining and goal attainment during posttraumatic amnesia. AB - It is uncertain whether therapy delivered during posttraumatic amnesia (PTA) following traumatic brain injury can be effective due to risk of agitation and poor learning capacity. This study used goal attainment scaling (GAS) to assess gains in activities of daily living (ADL) retraining during PTA. Occupational therapists' perspectives on goal setting and therapy delivery were also explored qualitatively. Forty-nine rehabilitation inpatients were provided with manualised ADL retraining following errorless and procedural learning principles during PTA. From 104 GAS goals, 90% were achieved at PTA emergence. GAS T-scores changed significantly (p < .001) from baseline (M = 26.94, SD = 4.90) to post intervention (M = 61.44, SD = 11.45). Mean post-intervention T-scores correlated significantly (p < .001) with change in Functional Independence Measure scores. The four therapists reported that GAS was unfamiliar and time-consuming initially, although it aided goal-directed therapy and measurement of patient performance. Application of manualised skill retraining using errorless and procedural learning techniques was described as novel and challenging, but providing valuable structure. The intervention reportedly promoted therapeutic alliance, skill-building and meaningful time-use without elevating agitation, but fatigue impeded therapy. Overall, GAS captured positive individual change following ADL retraining during PTA and therapists indicated that the intervention and use of GAS was generally beneficial and feasible within clinical practice. PMID- 29516772 TI - Fusarium oxysporum f. sp. dianthi virus 1 Accumulation Is Correlated with Changes in Virulence and Other Phenotypic Traits of Its Fungal Host. AB - Fusarium oxysporum f. sp. dianthi virus 1 (FodV1) was detected in isolate 116 (116V+) of Fusarium oxysporum f. sp. dianthi, reaching such a high accumulation level that it was clearly visible after agarose gel electrophoresis of total DNA extracts. FodV1 consists of four double-stranded RNA segments that correspond to a new mycovirus in the Chrysoviridae family. We obtained an isolate of F. oxysporum f. sp. dianthi 116 (116V-) with only a residual level of FodV1 RNA accumulation by single-conidia selection. Compared with 116V-, isolate 116V+ showed significant phenotypic alterations in vegetative growth and virulence. Thus, the presence of a high titer of mycovirus FodV1 was associated with a modified morphology and a reduced growth of the colonies on solid medium, and with a diminished conidiation in liquid medium. Inoculation of four susceptible carnation cultivars with either 116V- or 116V+ showed that the presence of a high titer of FodV1 was also correlated with a significantly reduced virulence of its fungal host. All of the results suggest that FodV1 could be associated with hypovirulence, identifying it as a potential biocontrol agent for Fusarium wilt of carnation. This is the first report of a mycovirus potentially associated with the induction of hypovirulence in the species F. oxysporum. PMID- 29516773 TI - Letter to Dr Pierre Russo, Editor of Pediatric and Developmental Pathology, 2017. PMID- 29516774 TI - Hepatic Adenoma Arising in a Patient With Alagille Syndrome: A Case Report. AB - Alagille syndrome is associated with decreased bile ducts, cardiac abnormalities, vertebral body fusion defects, and a typical facies. While regenerative nodules and hepatocellular carcinoma have been described in these patients, hepatic adenoma has not. Herein, we present a patient with Alagille syndrome caused by a mutation in NOTCH2 with a hepatic adenoma. The clinical, imaging, and histologic features are discussed. PMID- 29516775 TI - 'Ayn mika: Traumatic experience, social invisibility, and emotional distress of sub-Saharan women with precarious status in Morocco. AB - Morocco has become a permanent transit country for tens of thousands of sub Saharan migrants heading to Europe. Many of these migrants are women who have a precarious legal status and can no longer reach Europe, whose borders have been considerably securitized since September 11, 2001. They also have no wish to risk their lives again returning south across the Sahara Desert. This paper discusses the results of an exploratory research project conducted in Morocco on the relationships between the sub-Saharan migrant women's traumatic experiences, social invisibility, and emotional distress in the context of a massive securitization of Euro-Mediterranean borders. PMID- 29516776 TI - Palliative care for people with advanced liver disease: A feasibility trial of a supportive care liver nurse specialist. AB - BACKGROUND: Liver disease is an increasing cause of death worldwide but palliative care is largely absent for these patients. AIM: We conducted a feasibility trial of a complex intervention delivered by a supportive care liver nurse specialist to improve care coordination, anticipatory care planning and quality of life for people with advanced liver disease and their carers. DESIGN: Patients received a 6-month intervention (alongside usual care) from a specially trained liver nurse specialist. The nurse supported patients/carers to live as well as possible with the condition and acted as a resource to facilitate care by community professionals. A mixed-method evaluation was conducted. Case note analysis and questionnaires examined resource use, care planning processes and quality-of-life outcomes over time. Interviews with patients, carers and professionals explored acceptability, effectiveness, feasibility and the intervention. SETTING/PARTICIPANTS: Patients with advanced liver disease who had an unplanned hospital admission with decompensated cirrhosis were recruited from an inpatient liver unit. The intervention was delivered to patients once they had returned home. RESULTS: We recruited 47 patients, 27 family carers and 13 case linked professionals. The intervention was acceptable to all participants. They welcomed access to additional expert advice, support and continuity of care. The intervention greatly increased the number of electronic summary care plans shared by primary care and hospitals. The Palliative care Outcome Scale and EuroQol-5D 5L questionnaire were suitable outcome measurement tools. CONCLUSION: This nurse led intervention proved acceptable and feasible. We have refined the recruitment processes and outcome measures for a future randomised controlled trial. PMID- 29516777 TI - The effects of shape memory alloys' tension-compression asymmetryon NiTi endodontic files' fatigue life. AB - Nowadays, NiTi rotary endodontic files are of great importance due to their flexibility which enables the device to cover all the portions of curved canal of tooth. Although this class of files are flexible, intracanal separation might happen during canal preparation due to bending or torsional loadings of the file. Since fabrication and characterization of such devices is challenging, time consuming, and expensive, it is preferable to predict this failure before fabrication using numerical models. It is demonstrated that NiTi shape memory alloy shows asymmetric material response in tension and compression which can significantly affect the lifetime of the files fabricated from. In this article, the effects of this material asymmetry on the bending response of rotary files are assessed using finite element analysis. To do so, a constitutive model which takes material asymmetry into account is used in combination with the finite element model of a RaCe file. The results show that the material asymmetry can significantly affect the maximum von Mises equivalent stress as well as the force displacement response of the tip of this file. PMID- 29516778 TI - The Influence of Physical Attractiveness on Belief in a Just World. AB - Previous work has consistently found that belief in a just world is strongly correlated with societal privilege. In the present study, we examined the influence of physical attractiveness on belief in a just world. We hypothesized that physically attractive individuals would be stronger endorsers of belief in a just world, whereas less attractive individuals would be less likely to endorse belief in a just world. Both self-rated attractiveness (experiment one) and attractiveness rated by other persons (experiment two) were found to predict endorsement of belief in a just world. Additionally, both attractiveness measures were found to have a relationship with participant's level of life satisfaction. These findings suggest that physical attractiveness powerfully affects our subjective experience as a human and that just-world beliefs are driven, at least in part, by personal experience with inequality. PMID- 29516779 TI - Erratum. PMID- 29516780 TI - Benchmark dose (BMD) modeling: current practice, issues, and challenges. AB - Benchmark dose (BMD) modeling is now the state of the science for determining the point of departure for risk assessment. Key advantages include the fact that the modeling takes account of all of the data for a particular effect from a particular experiment, increased consistency, and better accounting for statistical uncertainties. Despite these strong advantages, disagreements remain as to several specific aspects of the modeling, including differences in the recommendations of the US Environmental Protection Agency (US EPA) and the European Food Safety Authority (EFSA). Differences exist in the choice of the benchmark response (BMR) for continuous data, the use of unrestricted models, and the mathematical models used; these can lead to differences in the final BMDL. It is important to take confidence in the model into account in choosing the BMDL, rather than simply choosing the lowest value. The field is moving in the direction of model averaging, which will avoid many of the challenges of choosing a single best model when the underlying biology does not suggest one, but additional research would be useful into methods of incorporating biological considerations into the weights used in the averaging. Additional research is also needed regarding the interplay between the BMR and the UF to ensure appropriate use for studies supporting a lower BMR than default values, such as for epidemiology data. Addressing these issues will aid in harmonizing methods and moving the field of risk assessment forward. PMID- 29516781 TI - Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury. AB - Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza-infected patients. Previous experiments in our laboratory indicate that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury in mice; therefore, we sought to determine if blocking Btk activity has a protective effect in the lung during influenza induced inflammation. The Btk inhibitor ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72 h after lethal infection with IAV. Our data indicate that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but also had a dramatic effect on morphological changes to the lungs, in IAV-infected mice. Attenuation of lung inflammation indicative of acute lung injury, such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of the inflammatory mediators TNFalpha, IL-1beta, IL-6, KC, and MCP-1, strongly suggests amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps released into the lung in vivo and neutrophil extracellular trap formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza-induced lung injury, and, in general, that immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation. PMID- 29516782 TI - Greater cellular stiffness in fibroblasts from patients with idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease involving degenerative breathing capacity. Fibrotic disease is driven by dysregulation in mechanical forces at the organ, tissue, and cellular level. While it is known that, in certain pathologies, diseased cells are stiffer than healthy cells, it is not known if fibroblasts derived from patients with IPF are stiffer than their normal counterparts. Using IPF patient-derived cell cultures, we measured the stiffness of individual lung fibroblasts via high-resolution force maps using atomic force microscopy. Fibroblasts from patients with IPF were stiffer and had an augmented cytoskeletal response to transforming growth factor-beta1 compared with fibroblasts from donors without IPF. The results from this novel study indicate that the increased stiffness of lung fibroblasts of IPF patients may contribute to the increased rigidity of fibrotic lung tissue. PMID- 29516784 TI - Anticipatory Grief, Proactive Coping, Social Support, and Growth: Exploring Positive Experiences of Preparing for Loss. AB - All mental health professionals will inevitably serve clients who face the expected death of a loved one. Prominent theories on the grieving process tend to begin after a death or other loss has occurred. Many individuals experience anticipatory grief prior to the physical death. Participants in this study consisted of 120 adults who were anticipating the death of a loved one due to terminal illness. The purpose of this investigation was to assess the relationship between the positive disposition of proactive coping and two forms of growth. Both personal and posttraumatic growth were present to a significant degree, and proactive coping illustrated unique predictive power in personal growth. Social support was a significant mediator of proactive coping and growth and was determined to be an outcome of the assertive nature of this disposition. Implications for helping professionals who serve anticipatory grievers as well as directions for future research are discussed. PMID- 29516783 TI - Time-resolved proteome profiling of normal lung development. AB - Biochemical networks mediating normal lung morphogenesis and function have important implications for ameliorating morbidity and mortality in premature infants. Although several transcript-level studies have examined normal lung development, corresponding protein-level analyses are lacking. Here we performed proteomics analysis of murine lungs from embryonic to early adult ages to identify the molecular networks mediating normal lung development. We identified 8,932 proteins, providing a deep and comprehensive view of the lung proteome. Analysis of the proteomics data revealed discrete modules and the underlying regulatory and signaling network modulating their expression during development. Our data support the cell proliferation that characterizes early lung development and highlight responses of the lung to exposure to a nonsterile oxygen-rich ambient environment and the important role of lipid (surfactant) metabolism in lung development. Comparison of dynamic regulation of proteomic and recent transcriptomic analyses identified biological processes under posttranscriptional control. Our study provides a unique proteomic resource for understanding normal lung formation and function and can be freely accessed at Lungmap.net. PMID- 29516785 TI - Antifungal activity of essential oils against fungi isolated from air. AB - Fungal contamination of indoor air is an issue of increasing public health concern. Essential oils have been demonstrated to have antifungal capabilities, but there are limited studies investigating the efficacy of essential oils against fungi relevant to air quality. This study provides a preliminary screening of the antifungal properties of clove, lavender and eucalyptus essential oils against a range of fungal species isolated from environmental air samples. The ability of the essential oils to inhibit fungal growth was examined using the disk diffusion assay on malt extract agar and was compared with vinegar, bleach and limonene, with phenol as a positive control. Results identified essential oils which demonstrated antifungal potential against species of environmental origin. Clove oil was found to be most efficacious, with eucalyptus and lavender oils showing some antifungal potential albeit less broad spectrum and with less persistence over time in this assay. All essentials oils performed better than traditional cleaning compounds such as vinegar. Clove oil would be a suitable candidate for further research to validate its use in improving indoor air quality. Further research should next take into consideration the practical application method, concentration and long-term persistence of antifungal properties. PMID- 29516786 TI - Alcohol and drug use among staff at licensed premises in Norway. AB - AIMS: There is increased concern about the use of alcohol and illicit drugs in nightlife settings. Most studies of substance use in nightlife settings are from the patrons' perspective, which leaves an understudied population - the nightclub staff. The aim of this paper is to study self-reported alcohol and substance use among staff at licensed premises in Norway: types of illicit drugs used, attitudes towards drugs, and observed drug use among patrons. METHODS: A survey was conducted at server-training courses in 20 different cities in Norway during 2015. The survey included: demographics, respondents' own alcohol and drug experience, attitudes towards drug use, and observed drug use among patrons at licensed premises. RESULTS: Data were collected from 912 staff working at licensed premises. A majority reported alcohol use in the past year, and 61% reported alcohol use two or more times a month. Overall, 45% of the respondents reported ever-used of illicit drugs. The four most commonly used drugs among staff were cannabis, cocaine, ecstasy/MDMA, and amphetamine. The majority of respondents supported Norway's strict drug laws, and 63% reported observing drug intoxicated patrons at licensed premises during the past six months. CONCLUSIONS: The proportion of frequent drinkers and heavy episodic drinking among staff at licensed premises was high, and the prevalence of illicit drug use was much higher compared with the general population. Thus, staff at licensed premises can be considered a risk-group for alcohol and illicit drug use and therefore represent an important target population in club drug-prevention programmes. PMID- 29516787 TI - The moderating effect of income on the relationship between body mass index and health-related quality of life in Northern Sweden. AB - OBJECTIVES: This study aimed to investigate the relationship between body mass index (BMI) and health-related quality of life (HRQoL) and whether this relationship is influenced by the level of income in Northern Sweden. Overweight and obesity are rising major public health problems which also affect HRQoL. While socioeconomic inequalities in health are persisting or increasing in many countries, including Sweden, little attention has been paid to the more complex roles of income in relation to health. METHODS: Data were drawn from a 2014 cross sectional survey from Northern Sweden (Health on Equal Terms), comprising individuals aged 20-84 years ( N = 20,082 individuals included for analysis). BMI and HRQoL were self-reported and individual disposable income in 2012 was retrieved from population registers. Multiple linear regressions were performed with HRQoL scores regressed on BMI and income, their interaction and additional covariates. RESULTS: The underweight, overweight and obesity groups reported significantly lower HRQoL compared to the normal weight group. Moreover, the relationship between BMI and HRQoL varied significantly by level of income, with a stronger association among those with the lowest level of income. CONCLUSIONS: Income has a role as an effect modifier in the relationship between BMI and HRQoL that can be construed as an indirect income inequality. Efforts to promote HRQoL in populations should consider the different impact of being overweight and obese in different socioeconomic groups. PMID- 29516788 TI - Inequalities in smoking and obesity in Europe predicted to 2050: Findings from the EConDA project. AB - AIMS: The aim of this study was to project educational inequalities in obesity and smoking prevalence to 2050 based on past obesity and smoking trends by education level. METHODS: Data on obesity (body mass index >= 30) and smoking prevalence (current smokers) by education level (tertiary education and less than tertiary) from nationally representative cross-sectional surveys were collected for the following six countries participating in the Economics of Chronic Diseases project (EConDA): England, Finland, Lithuania, the Netherlands, Poland (obesity only) and Portugal (obesity only). A nonlinear multivariate regression model was fitted to the data to create longitudinal projections to 2050. Inequalities were measured with a prevalence ratio and a prevalence difference using projected obesity/smoking prevalence. RESULTS: Educational inequalities in obesity prevalence are projected to increase in Finland, Lithuania and England for men, and in Lithuania and Poland for women, by 2050. Obesity prevalence is projected to increase faster among the more advantaged groups in England, Portugal, Finland and the Netherlands among women, and Portugal and the Netherlands among men, narrowing inequalities. In contrast to obesity, smoking prevalence is projected to continue declining in most of the countries studied. The decline is projected to be faster in relative terms among more advantaged groups; therefore, relative educational inequalities in smoking prevalence are projected to increase in all countries. CONCLUSIONS: Widening educational inequalities in obesity and smoking prevalence are expected in several European countries if current trends in obesity and smoking prevalence are unaltered. This will impact on inequalities in morbidity and mortality of associated diseases such as diabetes, coronary heart disease and chronic obstructive pulmonary disease. PMID- 29516789 TI - Queer narratives and minority stress: Stories from lesbian, gay and bisexual individuals in Norway. AB - AIMS: This study aims to explore how minority stress related to sexual orientation is reflected in narratives from lesbian, gay and bisexual (LGB) individuals in Norway, with an impact for national public health policy. METHODS: Arthur Frank's dialogical narrative analysis was applied to personal stories from 65 persons self-referring to different categories of queer identities, submitted online anonymously to a Norwegian national archive for queer history. A purposive sample of three different stories were selected due to their capacity to illuminate how various aspects of minority stress are narrated in diverse interplays between individual voices and resources, and cultural scripts and societal influences. RESULTS: Our analysis highlighted how stories may offer significant glimpses into the dynamic and complex fashioning of sexual identities, giving precious clues to the vulnerabilities and strengths of the narrator. Contemporary queer narratives from Norway reflect meaning-making related to sexual orientation that are influenced by, and expand upon, the classical scripts dominated by tragedy and tristesse, personal progress or simply no particular tension. LGB individuals of different ages and backgrounds had experienced aspects of minority stress related to their sexual orientation, with a substantial impact on identity, even when significant others were encouraging. CONCLUSIONS: The stories indicate that positive proximal processes, such as personal resilience and sympathetic environments, can support mental health and counteract negative effects of distal processes contributing to minority stress, such as heteronormativity and subtle microaggression. Public health strategies addressing attitudes to sexual orientation among the general population may contribute to diverse affirmative cultural scripts about queer lives, thereby enhancing queer mental health. PMID- 29516822 TI - Abstracts from the 16th International Congress on Circumpolar Health. PMID- 29516790 TI - Participants at Norwegian Healthy Life Centres: Who are they, why do they attend and how are they motivated? A cross-sectional study. AB - AIMS: We examine the characteristics of participants entering Norwegian Healthy Life Centres, their reasons for attending and whether socio-economic status, motivation, self-efficacy and social support relate to physical activity and sedentary behaviour. METHODS: This cross-sectional study is part of a randomised controlled trial. Inclusion criteria are that participants should be >= 18 years old and able to take part in a physical activity group intervention. Exclusion criteria are severe mental illness and general learning disability. We analysed data using simple and multiple linear regression analyses. RESULTS: We recruited 118 participants from eight Norwegian municipalities between June 2014 and September 2015. Of these, 77% were female, mean (standard deviation) age 48.6 (13.4) years, body mass index 34.0 (5.8) kg/m2 and mean gross family income ?61,000. The proportion of participants with upper-secondary school or less as their highest level of education was 55%. The most frequent reasons given for attendance at Healthy Life Centres were being overweight, increasing physical activity, improving diet and having musculoskeletal health challenges. Participants had high levels of autonomous motivation and 79% achieved national recommendations for physical activity. Respect and appreciation in childhood, self-esteem and self-rated health were associated with self-efficacy and social support for physical activity. CONCLUSIONS: Participants were predominantly obese, physically active, female and motivated for change. A high proportion had low educational attainment and low incomes. The trial will reveal whether interventions succeed in increasing physical activity further, or in decreasing sedentary behaviour, and whether health inequalities narrow or widen across groups. PMID- 29516850 TI - Attitudes of Palestinians Toward Social Work Interventions in Cases of Wife Assault. AB - The study examined the attitudes of Palestinian adults toward social work interventions in cases of husband-to-wife assault (HWA). A survey, using self administered questionnaires and interviews, was conducted among a random sample of 624 adults from the Palestinian Authority. Results indicate higher levels of support for interventions aimed at helping the couple solve their problems than for interventions aimed at protecting the safety of battered women. However, this trend becomes reversed in cases of repeated and severe HWA. Greater support for interventions aimed at protecting the safety of battered women was found among women versus men and younger versus older adults, as well as among individuals with lower levels of justifying wife abuse and more egalitarian expectations of marriage. PMID- 29516851 TI - How accurate is the prevalence of overweight and obesity in children and adolescents derived from self-reported data? A meta-analysis. AB - OBJECTIVE: The aim of the current meta-analysis was to evaluate the accuracy of using BMI based on self-reported height and weight (BMIsr) to estimate the prevalence of overweight and obesity among children and adolescents. DESIGN: A systematic literature search was conducted to select studies that compared the prevalence rates of overweight and obesity based on BMIsr and BMIm (BMI based on measured height and weight). A random-effect model was assumed to estimate summary prevalence rates and prevalence ratio (PR). RESULTS: Thirty-seven studies were included. The aggregated prevalence of overweight and obesity based on BMIsr (0.190, 95 % CI 0.163, 0.221) was significantly lower than that based on BMIm (0.233, 95 % CI 0.203, 0.265). The pooled mean PR was 0.823 (95 % CI 0.775, 0.875). Moderator analyses showed that the underestimation was related to gender, age, weight status screened (overweight v. obesity) and weight status screening tool. CONCLUSIONS: BMIsr may produce less biased results under some conditions than others. Future researchers using BMIsr may consider these findings and avoid the conditions that could lead to more severe underestimation of the prevalence of overweight and obesity among children and adolescents. PMID- 29516852 TI - Relational use of an electronic quality of life and practice support system in hospital palliative consult care: A pilot study. AB - OBJECTIVES: This study is part of an overarching research initiative on the development and integration of an electronic Quality of Life and Practice Support System (QPSS) that uses patient-reported outcome and experience measures in clinical practice. The current study focused on palliative nurse consultants trialing the QPSS with older hospitalized adults receiving acute care. The primary aim of the study was to better understand consultants' and patients' experiences and perspectives of use. METHOD: The project involved two nurse specialists within a larger palliative outreach consult team (POCT) and consenting older adult patients (age 55+) in a large tertiary acute care hospital in western Canada. User-centered design of the QPSS was informed by three focus groups with the entire POCT team, and implementation was evaluated by direct observation as well as interviews with the POCT nurses and three patients. Thematic analysis of interviews and field notes was informed by theoretical perspectives from social sciences. Result Over 9 weeks, the POCT nurses used the QPSS at least once with 20 patients, for a total of 47 administrations. The nurses most often assisted patients in using the QPSS. Participants referenced three primary benefits of relational use: enhanced communication, strengthened therapeutic relations, and cocreation of new insights about quality of life and care experiences. The nurses also reported increased visibility of quality of life concerns and positive development as relational care providers. Significance of results Participants expressed that QPSS use positively influenced relations of care and enhanced practices consistent with person-centered care. Results also indicate that electronic assessment systems may, in some instances, function as actor-objects enabling new knowledge and relations of care rather than merely as a neutral technological platform. This is the first study to examine hospital palliative consult clinicians' use of a tablet-based system for routine collection of patient-reported outcome and experience measures. PMID- 29516853 TI - The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge. OBJECTIVE: To assess the feasibility of recruiting patients, collecting data and delivering EPR to patients with AECOPD to evaluate EPR compared with usual care. DESIGN: Parallel-group, pilot 2 * 2 factorial randomised trial with nested qualitative research and an economic analysis. SETTING: Two acute hospital NHS trusts. Recruitment was carried out from September 2015 to April 2016 and follow-up was completed in July 2016. PARTICIPANTS: Eligible patients were those aged >= 35 years who were admitted with AECOPD, who were non-acidotic and who maintained their blood oxygen saturation level (SpO2) within a prescribed range. Exclusions included the presence of comorbidities that affected the ability to undertake the interventions. INTERVENTIONS: (1) Hospital EPR: muscle training delivered at the patient's hospital bed using a cycle ergometer and (2) home EPR: a pulmonary rehabilitation programme delivered in the patient's home. Both interventions were delivered by trained physiotherapists. Participants were allocated on a 1 : 1 : 1 : 1 ratio to (1) hospital EPR (n = 14), (2) home EPR (n = 15), (3) hospital EPR and home EPR (n = 14) and (4) control (n = 15). Outcome assessors were blind to treatment allocation; it was not possible to blind patients. MAIN OUTCOME MEASURES: Feasibility of recruiting 76 participants in 7 months at two centres; intervention delivery; views on intervention/research acceptability; clinical outcomes including the 6-minute walk distance (6WMD); and costs. Semistructured interviews with participants (n = 27) and research health professionals (n = 11), optimisation assessments and an economic analysis were also undertaken. RESULTS: Over 7 months 449 patients were screened, of whom most were not eligible for the trial or felt too ill/declined entry. In total, 58 participants (76%) of the target 76 participants were recruited to the trial. The primary clinical outcome (6MWD) was difficult to collect (hospital EPR, n = 5; home EPR, n = 6; hospital EPR and home EPR, n = 5; control, n = 5). Hospital EPR was difficult to deliver over 5 days because of patient discharge/staff availability, with 34.1% of the scheduled sessions delivered compared with 78.3% of the home EPR sessions. Serious adverse events were experienced by 26 participants (45%), none of which was related to the interventions. Interviewed participants generally found both interventions to be acceptable. Home EPR had a higher rate of acceptability, mainly because patients felt too unwell when in hospital to undergo hospital EPR. Physiotherapists generally found the interventions to be acceptable and valued them but found delivery difficult because of staffing issues. The health economic analysis results suggest that there would be value in conducting a larger trial to assess the cost-effectiveness of the hospital EPR and hospital EPR plus home EPR trial arms and collect more information to inform the hospital cost and quality-adjusted life-year parameters, which were shown to be key drivers of the model. CONCLUSIONS: A full-scale randomised controlled trial using this protocol would not be feasible. Recruitment and delivery of the hospital EPR intervention was difficult. The data obtained can be used to design a full-scale trial of home EPR. Because of the small sample and large confidence intervals, this study should not be used to inform clinical practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18634494. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 11. See the NIHR Journals Library website for further project information. PMID- 29516854 TI - Glomerular and Tubular Functions in Transfusion-Dependent Thalassemia. PMID- 29516855 TI - Dual trigger with gonadotropin-releasing hormone and human chorionic gonadotropin for poor responders AB - OBJECTIVE: To compare metaphase II (MII) rate, fertilization rate, and embryo quality with dual trigger gonadotropin-releasing hormone agonist (GnRH) and normal dose human chorionic gonadotropin (hCG) versus a normal dose hCG trigger in antagonist intracytoplasmic sperm injection (ICSI) cycles of poor ovarian responders. MATERIAL AND METHODS: Patients defined as poor ovarian responders according to the Bologna criteria who underwent ICSI with GnRH antagonist protocol and triggered with dual trigger or hCG alone for oocyte maturation. Main outcome measures were MII rate, fertilization rate, and embryo quality. RESULTS: Total gonadotropin doses and E2 levels on trigger day were higher in the hCG trigger group. There were no significant differences with regard to implantation rate (p=0.304), biochemical pregnancy rate (p=0.815), clinical pregnancy rate (p=0.378), and ongoing pregnancy rate (p=0.635) between the groups. CONCLUSION: Dual trigger of oocyte maturation with GnRH agonist and normal dose hCG in poor responders does not demonstrate improved oocyte maturation, clinical pregnancy, and ongoing pregnancy rates. PMID- 29516856 TI - Habitat use pattern of the giant parasitic nematode Crassicauda magna within the pygmy sperm whale Kogia breviceps. AB - The giant (>3 m) parasitic nematode Crassicauda magna infects kogiid whales, although only 3 studies to date have provided detailed descriptions of these worms, all based upon fragmented specimens. These fragments were found within the neck region of kogiids, an unusual anatomic site for this genus of parasites. C. magna is a species-specific parasite among kogiids, infecting only pygmy sperm whales Kogia breviceps, and with a primarily cervico-thoracic distribution. To date, however, the pattern of habitat use within the host and transmission path of this parasite remain unknown. We used detailed dissections (n = 12), histological examination of host tissues (n = 2), and scanning electron microscopy of excised nematodes (n = 7) to enhance our understanding of this host parasite relationship. Results revealed that a critical habitat for the parasite is an exocrine gland in the whale's ventral cervical region. C. magna male and female tails were found intertwined within the glandular lumen, and eggs were observed within its presumed secretion, illuminating the transmission path out of the host. The cephalic ends of these worms were often meters away (curvilinearly), embedded deeply within epaxial muscle. A single worm's complete, tortuous 312 cm course, from the gland to its termination in the contralateral epaxial muscle, is described for the first time. This study also provides the first scanning electron micrographs of C. magna, which illustrate taxonomically important features of the heads and tails of both male and female worms. PMID- 29516857 TI - Prominent hepatic ductular reaction induced by Oschmarinella macrorchis in a Hubbs' beaked whale Mesoplodon carlhubbsi, with biological notes. AB - Beaked whales are among the least known group of cetaceans, and information regarding their pathology and parasitology is especially scarce. We describe a case of significant parasitism by a trematode found in the liver of an adult male Hubbs' beaked whale Mesoplodon carlhubbsi that stranded in Hokkaido, Japan. Post mortem examinations revealed a localised area of discolouration restricted to the hilar region of the left hepatic lobe, where spindle-shaped trematodes occupied the dilated and hypertrophic bile ducts. Histologically, the intrahepatic bile ducts were characterised by adenomatous hyperplasia with goblet cell metaplasia of the biliary epithelium. Findings in the adjacent hepatic parenchyma included pseudocarcinomatous ductular reactions obliterating hepatocytes, a histomorphology not previously reported in marine mammals. Morphological identification of the trematode corresponded to Oschmarinella macrorchis, which has only been reported once in a Stejneger's beaked whale, M. stejnegeri. PCR amplification and sequencing analyses of the parasite's mtDNA ND3, 18S and 28S rRNA regions generated novel gene sequences. Environmental contaminant levels were measured to explore its potential relationship with the parasitism but there was no conclusive association. A high level of polychlorinated biphenyl (30000 ng g-1 lipid weight) was detected in the blubber of this individual, when compared to those of 3 other male Hubbs' beaked whales stranded in Japan. Stomach contents were also analysed, indicating the presence of various squid species and unidentified fish. Our results contribute to the knowledge of a little-known beaked whale and provide evidence for the first time of the pathobiological response caused by O. macrorchis. PMID- 29516858 TI - Occurrence of Batrachochytrium dendrobatidis in anurans of the Mediterranean region of Baja California, Mexico. AB - Chytridiomycosis is caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd) and is regarded as one of the most significant threats to global amphibian populations. In Mexico, Bd was first reported in 2003 and has now been documented in 13 states. We visited 33 localities and swabbed 199 wild-caught anurans from 7 species (5 native, 2 exotic) across the Mediterranean region of the state of Baja California. Using quantitative PCR, Bd was detected in 94 individuals (47.2% of samples) at 25 of the 33 survey localities for 5 native and 1 exotic frog species. The exotic Xenopus laevis was the only species that tested completely negative for Bd. We found that remoteness, distance to agricultural land, and elevation were the best positive predictors of Bd presence. These are the first Bd-positive results for the state of Baja California, and its presence should be regarded as an additional conservation threat to the region's native frog species. PMID- 29516859 TI - Stress effects of amyloodiniosis in gilthead sea bream Sparus aurata. AB - Amyloodiniosis is a parasitological disease caused by one of the most common and important parasitic dinoflagellates in fish, Amyloodinium ocellatum (Brown), that represents a major bottleneck for gilthead seabream semi-intensive aquaculture in Southern Europe. In this experiment, we analyzed some metabolic, osmoregulatory and stress indicators to elucidate some of the physiological responses of gilthead sea bream when exposed to an A. ocellatum outbreak. We observed significant differences between Control and Infection groups in the cortisol, lactate and gill Na+/K+-ATPase (NKA) activity levels but that glucose, osmolarity, pH and total protein did not present such differences. This could indicate that the presence of the parasite induced a stress response, possibly enhancing the metabolization of glucose and subsequently lactate to cope with the higher energy requirements of the organism. There was also a decrease in gill NKA activity possibly due to severe epithelial damage and increased mucus production caused by the parasite A. ocellatum, which could induce anoxia and osmoregulatory impairment in the organism. However, further works must be performed to fully understand the physiological reactions of fish for A. ocellatum outbreaks. PMID- 29516860 TI - Methodological issues affecting the study of fish parasites. III. Effect of fish preservation method. AB - The aim of this study was to evaluate the influence of preservation method on the results of parasite community studies. Two host species, European perch Perca fluviatilis and European bitterling Rhodeus amarus, were examined for parasites after having been subjected to 4 different storage treatments: freezing, preservation in 4% formaldehyde or 70% ethanol and transportation of live (fresh) fish as a control. Preservation prior to dissection resulted in a loss of information, leading to incomplete quantitative data (all preservation treatments), qualitative data (ethanol and formaldehyde preservation) and a lowered ability to determine parasites to species level based on morphology compared to dissecting fresh fish. Of the more abundant taxa, only crustaceans and acanthocephalans provided relatively even results between treatments. We conclude that preservation media, such as ethanol or formaldehyde, significantly affects the ability to obtain precise parasite community data; hence, we recommend the use of freshly sacrificed fish for parasite community studies whenever possible. Alternatively, freezing may prove acceptable for evaluating parasite community taxonomic composition. PMID- 29516861 TI - Multicentric plasmacytoma in a harbor porpoise Phocoena phocoena off the coast of Whidbey Island, Washington State, USA. AB - Necropsy of a female adult pregnant harbor porpoise Phocoena phocoena revealed a multicentric plasmacytoma. The plasmacytoma infiltrated the cranial lung lobes, mediastinal lymph nodes and the spleen. Diagnosis was based on gross, histopathologic and immunohistochemical studies. Histopathology revealed a diffuse proliferation of atypical pleomorphic neoplastic round cells with plasmacytic features. Positive immunohistochemistry with anti-CD79a and anti-CD20 antibody markers and anti-multiple myeloma oncogene 1 (MUM-1) for plasmacytoma confirmed this neoplasm to be of B-cell origin. This is the first recorded case of a plasmacytoma in a harbor porpoise. Routine viral screening was negative via standard PCR for herpesvirus and reverse transcriptase PCR for morbillivirus. Retroviral screening was not performed. PMID- 29516862 TI - Cutaneous mycobacteriosis in a captive Amazonian manatee Trichechus inunguis. AB - An adult male Amazonian manatee Trichechus inunguis under human care presented with 3 circular cutaneous lesions on the dorsal aspect of the rostrum and between the nostrils (plenum). Initially these lesions were superficial, hypopigmented, without warmth and non-painful. Microbiological cultures of skin swabs isolated Candida sp. and Pseudomonas aeruginosa, and topical treatment with antiseptic, antifungal, anti-inflammatory and antibiotic medication was instituted. This treatment strategy did not lead to any clinical improvement, and after 6 mo, the lesions progressed to a confluent abscess (5.0 * 3.0 cm) with increased temperature and obvious discomfort on palpation. An impression smear of a cutaneous biopsy was submitted for Ziehl-Neelsen staining and after detection of acid-fast bacilli, the cutaneous biopsy and a swab from the lesion were sent for histopathology, culture and sensitivity testing. After 5 d of incubation and through PCR-restriction analysis of the isolates, Mycobacterium fortuitum and M. abscessus were identified. Sensitivity testing indicated that the isolates were susceptible to ciprofloxacin and clarithromycin, and after draining of the lesion and administration of systemic antibiotic treatment, there was rapid clinical improvement. This report describes non-healing lesions in an aquatic animal and illustrates the importance of evaluating the presence of non-tuberculous mycobacteria, opportunistic pathogens which are ubiquitous in the aquatic environment, in protracted, non-responsive cases. We also highlight the importance of a correct diagnosis and treatment approach, and we review concerns that these bacteria are zoonotic agents and are frequently resistant to conventional antibiotics. PMID- 29516863 TI - Survival rates and the occurrence of larval malformations, including Siamese twins, following fertilization of post-ovulatory aged oocytes in ide Leuciscus idus. AB - Embryonic development of lower vertebrates can be influenced by many factors, especially when outside of the mother's body and under the influence of variable abiotic and biotic factors. In this study, the effects of fertilization of post ovulatory aged (overmature) oocytes of ide Leuciscus idus on the risk of developing anomalies in ide larvae were assessed under controlled conditions. There was a negative effect of delayed fertilization of post-ovulatory aged (overmature) oocytes in the ovary on the quality of offspring, which caused reduced survival 3 days post-fertilization and at the hatching stage (68.3 vs. 81.2% and 47.2 vs. 79.7% for the overmature and mature groups, respectively). It also increased the occurrence of numerous developmental defects (19.3 vs. 0.8% for the overmature and mature groups, respectively), including the development of Siamese twins. This is the first reported case of the occurrence of Siamese twins in ide. The ide Siamese twins look like hen eggs with 2 heads and are different from 'typical' Siamese twins in fish. PMID- 29516864 TI - Systematic approach to isolating Batrachochytrium dendrobatidis. AB - We developed a protocol for isolating the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) from anurans. We sampled skin tissues from 2 common treefrogs, Pseudacris regilla and P. triseriata, collected from populations with high infection prevalence. We sampled tissues from 3 anatomical ventral regions (thigh, abdomen, and foot) where the pathogen is thought to concentrate. To mitigate potential bacterial contamination, we used a unique combination of 4 antibiotics. We quantified infections on frogs as zoospore equivalents (ZE) using a swabbing approach combined with quantitative real-time polymerase chain reaction. We isolated Bd from 68.9% of frogs sampled from both species. Contamination was low (9.7% of all plates), with most contamination presumed to be fungal. We found positive correlations between successful isolation attempts and infection intensity. Our levels of isolation success were 74% for P. triseriata and 100% for P. regilla once Bd detection intensities reached >=40 ZE. Of the 3 anatomical regions sampled in both species, we had significantly more success isolating Bd from foot tissue. Our results support published recommendations to focus sampling for Bd infection on feet, particularly webbing. PMID- 29516865 TI - Clinical performance of a novel textile interface for neonatal chest electrical impedance tomography. AB - OBJECTIVE: Critically ill neonates and infants might particularly benefit from continuous chest electrical impedance tomography (EIT) monitoring at the bedside. In this study a textile 32-electrode interface for neonatal EIT examination has been developed and tested to validate its clinical performance. The objectives were to assess ease of use in a clinical setting, stability of contact impedance at the electrode-skin interface and possible adverse effects. APPROACH: Thirty preterm infants (gestational age: 30.3 +/- 3.9 week (mean +/- SD), postnatal age: 13.8 +/- 28.2 d, body weight at inclusion: 1727 +/- 869 g) were included in this multicentre study. The electrode-skin contact impedances were measured continuously for up to 3 d and analysed during the initial 20-min phase after fastening the belt and during a 10 h measurement interval without any clinical interventions. The skin condition was assessed by attending clinicians. MAIN RESULTS: Our findings imply that the textile electrode interface is suitable for long-term neonatal chest EIT imaging. It does not cause any distress for the preterm infants or discomfort. Stable contact impedance of about 300 Ohm was observed immediately after fastening the electrode belt and during the subsequent 20 min period. A slight increase in contact impedance was observed over time. Tidal variation of contact impedance was less than 5 Ohm. SIGNIFICANCE: The availability of a textile 32-electrode belt for neonatal EIT imaging with simple, fast, accurate and reproducible placement on the chest strengthens the potential of EIT to be used for regional lung monitoring in critically ill neonates and infants. PMID- 29516866 TI - MR-based source localization for MR-guided HDR brachytherapy. AB - For the purpose of MR-guided high-dose-rate (HDR) brachytherapy, a method for real-time localization of an HDR brachytherapy source was developed, which requires high spatial and temporal resolutions. MR-based localization of an HDR source serves two main aims. First, it enables real-time treatment verification by determination of the HDR source positions during treatment. Second, when using a dummy source, MR-based source localization provides an automatic detection of the source dwell positions after catheter insertion, allowing elimination of the catheter reconstruction procedure. Localization of the HDR source was conducted by simulation of the MR artifacts, followed by a phase correlation localization algorithm applied to the MR images and the simulated images, to determine the position of the HDR source in the MR images. To increase the temporal resolution of the MR acquisition, the spatial resolution was decreased, and a subpixel localization operation was introduced. Furthermore, parallel imaging (sensitivity encoding) was applied to further decrease the MR scan time. The localization method was validated by a comparison with CT, and the accuracy and precision were investigated. The results demonstrated that the described method could be used to determine the HDR source position with a high accuracy (0.4-0.6 mm) and a high precision (?0.1 mm), at high temporal resolutions (0.15-1.2 s per slice). This would enable real-time treatment verification as well as an automatic detection of the source dwell positions. PMID- 29516867 TI - The observed difference of RAW264.7 macrophage phenotype on mineralized collagen and hydroxyapatite. AB - Understanding the interaction between biomaterials and the immune system has become increasingly important. Mineralized collagen (MC) has the same chemical components and microstructures to natural bone tissue, and is considered as a better biomaterial for bone prostheses compared to hydroxyapatite (HA). However, there is little information about how MC affects inflammatory responses. In this study, we investigate the inflammatory responses to MC and HA by culturing RAW264.7 cells on their surfaces. We observed that MC increases CD206+ staining and IL-10 (M2 macrophages), whereas HA shows cells expressing more CD86 and secreting more TNF-alpha. This result indicates that MC may attenuate inflammatory responses to implanted bone prostheses. PMID- 29516868 TI - Automatic online and real-time tumour motion monitoring during stereotactic liver treatments on a conventional linac by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK). AB - The purpose of this study was to develop, validate and clinically demonstrate fully automatic tumour motion monitoring on a conventional linear accelerator by combined optical and sparse monoscopic imaging with kilovoltage x-rays (COSMIK). COSMIK combines auto-segmentation of implanted fiducial markers in cone-beam computed tomography (CBCT) projections and intra-treatment kV images with simultaneous streaming of an external motion signal. A pre-treatment CBCT is acquired with simultaneous recording of the motion of an external marker block on the abdomen. The 3-dimensional (3D) marker motion during the CBCT is estimated from the auto-segmented positions in the projections and used to optimize an external correlation model (ECM) of internal motion as a function of external motion. During treatment, the ECM estimates the internal motion from the external motion at 20 Hz. KV images are acquired every 3 s, auto-segmented, and used to update the ECM for baseline shifts between internal and external motion. The COSMIK method was validated using Calypso-recorded internal tumour motion with simultaneous camera-recorded external motion for 15 liver stereotactic body radiotherapy (SBRT) patients. The validation included phantom experiments and simulations hereof for 12 fractions and further simulations for 42 fractions. The simulations compared the accuracy of COSMIK with ECM-based monitoring without model updates and with model updates based on stereoscopic imaging as well as continuous kilovoltage intrafraction monitoring (KIM) at 10 Hz without an external signal. Clinical real-time tumour motion monitoring with COSMIK was performed offline for 14 liver SBRT patients (41 fractions) and online for one patient (two fractions). The mean 3D root-mean-square error for the four monitoring methods was 1.61 mm (COSMIK), 2.31 mm (ECM without updates), 1.49 mm (ECM with stereoscopic updates) and 0.75 mm (KIM). COSMIK is the first combined kV/optical real-time motion monitoring method used clinically online on a conventional accelerator. COSMIK gives less imaging dose than KIM and is in addition applicable when the kV imager cannot be deployed such as during non coplanar fields. PMID- 29516869 TI - An antibody based approach for multi-coloring osteogenic and chondrogenic proteins in tissue engineered constructs. AB - When tissue engineering strategies rely on the combination of three-dimensional (3D) polymeric or ceramic scaffolds with cells to culture implantable tissue constructs in vitro, it is desirable to monitor tissue growth and cell fate to be able to more rationally predict the quality and success of the construct upon implantation. Such a 3D construct is often referred to as a 'black-box' since the properties of the scaffolds material limit the applicability of most imaging modalities to assess important construct parameters. These parameters include the number of cells, the amount and type of tissue formed and the distribution of cells and tissue throughout the construct. Immunolabeling enables the spatial and temporal identification of multiple tissue types within one scaffold without the need to sacrifice the construct. In this report, we concisely review the applicability of antibodies (Abs) and their conjugation chemistries in tissue engineered constructs. With some preliminary experiments, we show an efficient conjugation strategy to couple extracellular matrix Abs to fluorophores. The conjugated probes proved to be effective in determining the presence of collagen type I and type II on electrospun and additive manufactured 3D scaffolds seeded with adult human bone marrow derived mesenchymal stromal cells. The conjugation chemistry applied in our proof of concept study is expected to be applicable in the coupling of any other fluorophore or particle to the Abs. This could ultimately lead to a library of probes to permit high-contrast imaging by several imaging modalities. PMID- 29516870 TI - 2D convolution kernels of ionization chambers used for photon-beam dosimetry in magnetic fields: the advantage of small over large chamber dimensions. AB - This study aims at developing an optimization strategy for photon-beam dosimetry in magnetic fields using ionization chambers. Similar to the familiar case in the absence of a magnetic field, detectors should be selected under the criterion that their measured 2D signal profiles M(x,y) approximate the absorbed dose to water profiles D(x,y) as closely as possible. Since the conversion of D(x,y) into M(x,y) is known as the convolution with the 'lateral dose response function' K(x xi, y-eta) of the detector, the ideal detector would be characterized by a vanishing magnetic field dependence of this convolution kernel (Looe et al 2017b Phys. Med. Biol. 62 5131-48). The idea of the present study is to find out, by Monte Carlo simulation of two commercial ionization chambers of different size, whether the smaller chamber dimensions would be instrumental to approach this aim. As typical examples, the lateral dose response functions in the presence and absence of a magnetic field have been Monte-Carlo modeled for the new commercial ionization chambers PTW 31021 ('Semiflex 3D', internal radius 2.4 mm) and PTW 31022 ('PinPoint 3D', internal radius 1.45 mm), which are both available with calibration factors. The Monte-Carlo model of the ionization chambers has been adjusted to account for the presence of the non-collecting part of the air volume near the guard ring. The Monte-Carlo results allow a comparison between the widths of the magnetic field dependent photon fluence response function K M(x-xi, y-eta) and of the lateral dose response function K(x-xi, y-eta) of the two chambers with the width of the dose deposition kernel K D(x-xi, y-eta). The simulated dose and chamber signal profiles show that in small photon fields and in the presence of a 1.5 T field the distortion of the chamber signal profile compared with the true dose profile is weakest for the smaller chamber. The dose responses of both chambers at large field size are shown to be altered by not more than 2% in magnetic fields up to 1.5 T for all three investigated chamber orientations. PMID- 29516871 TI - Big data in Parkinson's disease: using smartphones to remotely detect longitudinal disease phenotypes. AB - OBJECTIVE: To better understand the longitudinal characteristics of Parkinson's disease (PD) through the analysis of finger tapping and memory tests collected remotely using smartphones. APPROACH: Using a large cohort (312 PD subjects and 236 controls) of participants in the mPower study, we extract clinically validated features from a finger tapping and memory test to monitor the longitudinal behaviour of study participants. We investigate any discrepancy in learning rates associated with motor and non-motor tasks between PD subjects and healthy controls. The ability of these features to predict self-assigned severity measures is assessed whilst simultaneously inspecting the severity scoring system for floor-ceiling effects. Finally, we study the relationship between motor and non-motor longitudinal behaviour to determine if separate aspects of the disease are dependent on one another. MAIN RESULTS: We find that the test performances of the most severe subjects show significant correlations with self-assigned severity measures. Interestingly, less severe subjects do not show significant correlations, which is shown to be a consequence of floor-ceiling effects within the mPower self-reporting severity system. We find that motor performance after practise is a better predictor of severity than baseline performance suggesting that starting performance at a new motor task is less representative of disease severity than the performance after the test has been learnt. We find PD subjects show significant impairments in motor ability as assessed through the alternating finger tapping (AFT) test in both the short- and long-term analyses. In the AFT and memory tests we demonstrate that PD subjects show a larger degree of longitudinal performance variability in addition to requiring more instances of a test to reach a steady state performance than healthy subjects. SIGNIFICANCE: Our findings pave the way forward for objective assessment and quantification of longitudinal learning rates in PD. This can be particularly useful for symptom monitoring and assessing medication response. This study tries to tackle some of the major challenges associated with self-assessed severity labels by designing and validating features extracted from big datasets in PD, which could help identify digital biomarkers capable of providing measures of disease severity outside of a clinical environment. PMID- 29516872 TI - Enhanced photocatalytic property of hybrid graphitic C3N4 and graphitic ZnO nanocomposite: the effects of interface and doping. AB - Using first-principles calculations, we present a potential new way to improve the photocatalytic efficiency of the g-C3N4 sheet by coupling with the g-ZnO sheet to form heterojunction nanostructure followed by the addition of N atom at an atomic level. The result indicates the g-C3N4/g-ZnO heterojunction is a staggered band alignment (type II) structure and a polarized field is generated by the electrons transfer across the interface simultaneously, which facilitate the separation of e--h+ pairs and promote the photocatalytic activity. Furthermore, a great difference in energy levels between redox potentials and band edges of the C3N4/g-ZnO nanocomposite ensures that the water splitting/CO2 reduction reaction is energetically favored. In addition, through the incorporation of nitrogen dopant, the g-C3N4/N-g-ZnO nanocomposite displays desirable properties. The N-derived doping peak causes a decrease of the band gap width of the g-C3N4/g-ZnO nanocomposite, resulting in the enhanced optical absorption from UV into visible light. This theoretical predictions provide insightful outlooks in understanding the effects of interface and doping on the enhanced photocatalytic property of the g-C3N4/g-ZnO nanocomposites, which will assist in engineering highly efficient g-C3N4-based photocatalysts. PMID- 29516873 TI - Differences in sympathetic nervous system activity and NMDA receptor levels within the hypothalamic paraventricular nucleus in rats with differential ejaculatory behavior. AB - Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 +/- 480 mV, 1660 +/- 600 mV, and 1680 +/- 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% +/- 8.1% in "sluggish," 48.4% +/- 7.5% in "normal," and 88.7% +/- 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN. PMID- 29516874 TI - Sperm concentration measurement with a disposable counting chamber. PMID- 29516875 TI - Anejaculation in a patient with Charcot-Marie-Tooth. PMID- 29516877 TI - Role of inhibiting LIM-kinase2 in improving erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury. AB - We evaluated whether LIM-kinase 2 inhibitor (LIMK2i) could improve erectile function by suppressing corporal fibrosis through the normalization of the Rho associated coiled-coil protein kinase 1 (ROCK1)/LIMK2/Cofilin pathway in a rat model of cavernous nerve crush injury (CNCI). Sixty 11-week-old male Sprague Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M), and high-dose (H) LIMK2i. The L, M, and H groups were treated with a daily intraperitoneal injection of LIMK2i (2.5, 5.0, and 10.0 mg kg-1 body weight, respectively) for 1 week after surgery. The erectile response was assessed using electrostimulation at 1 week, postoperatively. Penile tissues were processed for Masson's trichrome staining, double immunofluorescence, and Western blot assay. Erectile responses in the H group improved compared with the I group, while the M group showed only partial improvement. A significantly decreased smooth muscle/collagen ratio and an increased content of fibroblasts positive for phospho-LIMK2 were noted in the I group. The M and H groups revealed significant improvements in histological alterations and the dysregulated LIMK2/Cofilin pathway, except for LIMK2 phosphorylation in the M group. The inhibition of LIMK2 did not affect the ROCK1 protein expression. The content of fibroblasts positive for phospho-LIMK2 in the H group returned to the level found in the S group, whereas it did not in the M group. However, the L group did not exhibit such improvements. Our data suggest that the inhibition of LIMK2, particularly with administration of 10.0 mg kg-1 body weight LIMK2i, can improve corporal fibrosis and erectile function by normalizing the LIMK2/Cofilin pathway. PMID- 29516876 TI - Chronic epididymitis and Grade III varicocele and their associations with semen characteristics in men consulting for couple infertility. AB - Chronic epididymitis and varicocele are frequently observed genital disorders in men consulting for couple infertility, but their impact on semen characteristics at the time of infertility consultation is still a matter of debate. We investigated 652 male partners of couples who had their first infertility consultation between 1999 and 2015 in Argentina. Men with chronic epididymitis (n = 253), Grade III varicocele (n = 106), and both conditions (n = 125) were compared with a control group (n = 168) composed of men without these disorders or any other recognized causes of male infertility. We showed that men who presented isolated chronic epididymitis were more likely to have high percentages of low sperm motility and abnormal sperm morphology as well as a high number of white blood cells. Men with isolated Grade III varicocele had low sperm production and motility and an increased percentage of abnormal sperm morphology. Finally, men who simultaneously presented chronic epididymitis with Grade III varicocele had a low sperm motility and increased percentage of abnormal sperm morphology as well as a high number of white blood cells. Physical examination of the genital organs may identify common disorders, potentially involved as causal factors of patient's infertility. These disorders are associated with specific seminal profiles that should help in identifying the best treatment from the available therapeutic options, effectiveness, safety, and allowing as much as possible natural conception. PMID- 29516879 TI - Patients at high risk of tuberculosis recurrence. AB - Recurrent tuberculosis (TB) continues to be a significant problem and is an important indicator of the effectiveness of TB control. Recurrence can occur by relapse or exogenous reinfection. Recurrence of TB is still a major problem in high-burden countries, where there is lack of resources and no special attention is being given to this issue. The rate of recurrence is highly variable and has been estimated to range from 4.9% to 47%. This variability is related to differences in regional epidemiology of recurrence and differences in the definitions used by the TB control programs. In addition to treatment failure from noncompliance, there are several key host factors that are associated with high rates of recurrence. The widely recognized host factors independent of treatment program that predispose to TB recurrence include gender differences, malnutrition; comorbidities such as diabetes, renal failure, and systemic diseases, especially immunosuppressive states such as human immunodeficiency virus; substance abuse; and environmental exposures such as silicosis. With improved understanding of the human genome, proteome, and metabolome, additional host-specific factors that predispose to recurrence are being identified. Information on temporal and geographical trends of TB cases as well as studies with whole-genome sequencing might provide further information to enable us to fully understand TB recurrence and discriminate between reactivation and new infection. The recently launched World Health Organization End TB Strategy emphasizes the importance of integrated, patient-centered TB care. Continued improvement in diagnosis, treatment approaches, and an understanding of host specific factors are needed to fully understand the clinical epidemiological and social determinants of TB recurrence. PMID- 29516878 TI - Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism. AB - Pulsatile gonadotropin-releasing hormone (GnRH) may induce spermatogenesis in most patients with congenital hypogonadotropic hypogonadism (CHH) by stimulating gonadotropin production, while the predictors for a pituitary response to pulsatile GnRH therapy were rarely investigated. Therefore, the aim of our study is to investigate predictors of the pituitary response to pulsatile GnRH therapy. This retrospective cohort study included 82 CHH patients who received subcutaneous pulsatile GnRH therapy for at least 1 month. Patients were categorized into poor or normal luteinizing hormone (LH) response subgroups according to their LH level (LH <2 IU l-1 or LH >=2 IU l-1) 1 month into pulsatile GnRH therapy. Gonadotropin and testosterone levels, testicular size, and sperm count were compared between the two subgroups before and after GnRH therapy. Among all patients, LH increased from 0.4 +/- 0.5 IU l-1 to 7.5 +/- 4.4 IU l-1 and follicle-stimulating hormone (FSH) increased from 1.1 +/- 0.9 IU l-1 to 8.8 +/- 5.3 IU l-1. A Cox regression analysis showed that basal testosterone level (beta = 0.252, P = 0.029) and triptorelin-stimulated FSH60min(beta = 0.518, P = 0.01) were two favorable predictors for pituitary response to GnRH therapy. Nine patients (9/82, 11.0%) with low LH response to GnRH therapy were classified into the poor LH response subgroup. After pulsatile GnRH therapy, total serum testosterone level was 39 +/- 28 ng dl-1 versus 248 +/- 158 ng dl-1 (P = 0.001), and testicular size was 4.0 +/- 3.1 ml versus 7.9 +/- 4.5 ml (P = 0.005) in the poor and normal LH response subgroups, respectively. It is concluded that higher levels of triptorelin-stimulated FSH60minand basal total serum testosterone are favorable predictors of pituitary LH response to GnRH therapy. PMID- 29516880 TI - Proteomic analysis of hydroxyl radical-induced resuscitation of hypoxia-induced dormant mycobacterial cells. AB - Background: The genus Mycobacterium has an ability to persist in hostile environments for years before its reactivation in favorable conditions. The major bottleneck in decades of mycobacterial research is a poor understanding of molecular mechanism which assists bacteria to attain dormancy and reactivation later. Methods: In this study, hydroxyl radical was quantified in aerobically growing mycobacterial cells using 2-deoxy-D-ribose assay. Furthermore, extraneous addition of hydroxyl radical in Wayne's dormancy model induced reactivation of dormant cells. The whole proteome of all three samples, namely, aerobic, Wayne dormancy, and hydroxyl radical reactivated cells was isolated, trypsin digested, and peptides are quantitatively characterized by liquid chromatography-elevated energy mass spectrometry. Results: This study reports the generation of highly reactive hydroxyl radical by Mycobacterium smegmatis during aerobic respiration. The hydroxyl radical levels can be managed by modulation of iron ions in the cellular pool. Proteomic characterization of resuscitation process highlights the increase in the level of ATPases, iron acquisition, redox response, changes in cell membrane dynamics, and cell wall hydrophobicity which is coupled with restoration of protein synthesis, carbohydrate, and lipid metabolism. In addition, two uncharacterized universal stress proteins MSMEG5245 and MSMEG3950 were uniquely identified in reactivated cells. Conclusion: Overall, the 1 hydroxypyridine-2-thione-induced reactivation process is a controlled and stepwise exit from dormancy. PMID- 29516881 TI - Estimation of pyrazinamidase activity using a cell-free In vitro synthesis of pnca and its association with pyrazinamide susceptibility in Mycobacterium tuberculosis. AB - Background: The main mechanism of resistance to PZA in Mycobacterium tuberculosis relies on mutations on its pyrazinamidase/nicotinamidase. Recently, a rapid colorimetric test relying on the PCR-based in vitro-synthesized-PZase assay has been reported for PZase activity determination from clinical M. tuberculosis isolates but the assay has not been compared with other tests to evaluate PZA susceptibility in M. tuberculosis isolates. Methods: In this study, we have used the PCR-based in vitro-synthesized-PZase assay to analyze the specific pyrazinamidase (PZase) activity of PncA mutants and have correlated the results to the PZA susceptibility phenotype determined by culture in acidic agar medium at pH 6.0. A set of 23 clinical isolates displaying mutated pncA genes (11 PZA resistant and 12 PZA-susceptible) and 55 PZA-susceptible clinical strains displaying a wild-type pncA gene were tested. Results: Among the 23 mutants tested, 4 corresponded to mutations not reported before (I5T, Y99S, T142R and P77L+V131G). Of the 11 PncA mutants expressed from PZA-resistant clinical isolates, 9 were expressed in vitro at yields > 50% relative to the wild type enzyme. Among them, 6 enzymes (T47P, H51P, H51R, H57D, L85R and T142R) showed no detectable activity, while the relative activities for the 3 others, V9A (27%), G97D (10%) and A146V (28%) were low compared to the wild-type PZase. The remaining two mutants, I5T and V9G, presented very low relative expression (5%) and relative activities values of 12 and 1%, respectively. Twelve mutants were expressed from PZA-susceptible isolates. Their expression was similar to the wild type enzyme and behaved as active pyrazinamidase with specific relative activities ranging from 34 to 314%. Finally, discrepant results were observed for two mutants, V7A and P62T. Conclusion: Thus, this study provides the proof of concept that the PCR-based in vitro-synthesized-PZase assay represents a promising rapid approach for the evaluation of PZA susceptibility based on the estimation of the relative PZase activity from clinical isolates. PMID- 29516882 TI - Influence of interferon-gamma Receptor 1 gene polymorphisms on the susceptibility to pulmonary tuberculosis among sudanese population. AB - Background: : A variety of genetic mutations are thought to be responsible for acquisition of different infections such as tuberculosis (TB). An obvious example for these variations is the link between pulmonary TB and polymorphisms within interferon-gamma receptor 1 (IFN-gamma R1) gene. This project is designed to identify the role of IFN-gammaR1 gene polymorphism in the development of pulmonary TB among Sudanese patients attending several hospitals in Khartoum State. Methods: One hundred (n = 100) patients with active TB and fifty (n = 50) matched healthy controls were investigated for the association of two genetic polymorphisms within IFN-gammaR1 gene and their risk of developing pulmonary tuberculosis. Polymerase chain reaction (PCR) assay and PCR-restriction fragment length polymorphism were performed. Results: Migrated IFN-gammaR1 DNA bands representing genotypes and polymorphic alleles were identified. Molecular findings revealed that two genetic variants, namely, -56C and +295C deletion 12 within IFN-gammaR1 gene, were nonsignificantly linked with increased risk of development of pulmonary TB, P = 0.771 and 0.343, respectively. Two genetic variants within IFN-gammaR1 gene were examined for suggested role in inducing development of TB. Conclusion: The two genetic variants were found to have potential risk in association with active disease development among Sudanese patients. Further intensive research work involving use of large collection of samples should be conducted to verify these findings. PMID- 29516883 TI - A comparison of intradermal test with recombinant tuberculosis allergen (diaskintest) with other immunologic tests in the diagnosis of tuberculosis infection. AB - Background: The WHO strategy for eradication of tuberculosis (TB) by 2035 (The End TB Strategy) is aimed at an early and precise diagnosis and subsequent effective treatment of TB patients. Currently, there is no gold standard for the diagnosis of latent TB infection. This study evaluated the diagnostic capabilities of a new intradermal test using recombinant TB allergen (Diaskintest) compared with tuberculin skin test (TST) and commercial TB interferon-gamma release assays (IGRAs). Methods: A post-hoc data analysis that involved examining 860 HIV-negative, bacillus Calmette-Guerin (BCG)-vaccinated persons aged 1-65 years who visited the TB health-care institutions of Saint Petersburg to rule out or confirm an active TB was conducted from 2011 to 2016. Results: A high degree of consistency of the Diaskintest results with the enzyme linked immunospot and QuantiFERON-TB Gold In-Tube test (ELISPOT and QFT) results was observed in the examined pediatric population (n = 696), with a Diaskintest cutoff >=5 mm: the kappa consistency indices were 1.000 and 0.937, for ELISPOT and QFT, respectively. A high sensitivity of Diaskintest, comparable with the IGRA tests, was observed in patients with a confirmed TB diagnosis in all age groups. The sensitivity of Diaskintest in patients of the TB/MTB + group aged 18 years and older was 88.7%; of ELISPOT, 90.6%; of QFT, 87.0%. The conducted analysis has shown a high concordance of results of the commercial TB tests in adult HIV-negative patients (n = 164) with a Diaskintest cutoff >=5 mm: the kappa indices were 0.805 and 0.636 (Diaskintest vs. ELISPOT and QFT, respectively) among BCG-vaccinated people. Conclusion: According to the WHO recommendations, replacing the TST by IGRAs is not recommended as a public health intervention in resource-constrained settings because the IGRA tests are more costly and technically complex to conduct than the TST. Diaskintest has comparable complexity to the TST and its performance is close to that of IGRA in a BCG vaccinated population. Thus, our study demonstrates that replacing the TST by Diaskintest can be recommended as a public health intervention in resource constrained and universal BCG vaccination settings. PMID- 29516884 TI - Detection of multidrug-resistant tuberculosis from stored DNA Samples: A multicenter study. AB - Background: In low-income countries, rapid detection of tuberculosis (TB) drug resistance is often restricted by the difficulties of transporting and storing sputum samples from remote health centers to the reference laboratories where molecular tests are available. The aim of this study was to evaluate the performance of four transport and storage systems for molecular detection of rifampicin (RIF) and isoniazid (INH) resistance. Methods: This was a multicenter study. Molecular detection of RIF and INH resistance was performed directly from smear-positive TB sputa spotted on a slide, FTA card, GenoCard, and ethanol using the Genotype MTBDRplus assay. The performance of the DNA extraction method from each storage support to detect drug resistance was assessed by calculating their sensitivity and specificity compared to the phenotypic method. Results: From all sites, the overall sensitivity and specificity for RIF-resistance detection was 88% and 85%, respectively, for slides, 86% and 92%, respectively, for GenoCard, 87% and 89%, respectively, for FTA card, and 88% and 92%, respectively, for ethanol. For INH-resistance detection, the overall sensitivity and specificity was 82% and 90%, respectively, for slides, 85% and 96%, respectively, for GenoCard, 86% and 92%, respectively, for FTA card, and 86% and 94%, respectively, for ethanol. Conclusion: Smear slides and filter cards showed to be very useful tools to facilitate DNA extraction from sputum samples with the potential to accelerate the detection of drug resistance in remote areas. PMID- 29516885 TI - In vitro activity of seven hospital biocides against Mycobacterium abscessus: Implications for patients with cystic fibrosis. AB - Background: Mycobacterium abscessus pulmonary infection has recently emerged as a significant pathogen in patients with cystic fibrosis (CF) and is associated with significant morbidity and accelerated pulmonary decline. There is a paucity of data describing the activity of hospital biocides against this organism. Methods: M. abscessus isolates (n = 13) were recovered from CF and non-CF respiratory specimens. Seven commonly employed hospital biocides with generic ingredients as follows: acetone, propan-2-ol, diethylene glycol, 5-chloro-2-methyl-4 isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, chlorine dioxide, 4% chlorhexidine, alcohol, and disodium carbonate, compound with hydrogen peroxide, 10% sodium hypochlorite were assayed for their biocidal activity against M. abscessus. Fresh cultures of M. abscessus were exposed to biocide in liquid medium as per manufacturers' instruction and were immediately plated following the completion of the contact period. The mean concentration of M. abscessus plated was 9.82 * 106 colony-forming units (range: 1.63 * 105-1.12 * 108). In addition, the remaining bacteria/biocide solution was enriched nonselectively in Mueller Hinton broth (37 degrees C/1 week) and then plated. Results: All M. abscessus isolates survived in alkyl dimethyl benzyl ammonium chloride, 5-chloro 2-methyl-2H-isothiazol-3-one (EC No. 247-500-7) and 2-methyl-2H-isothiazol-3-one, 4% ChlorhexidineTM, O-phenylphenol and Sodium Lauryl SulfateTM and disodium carbonate, compound with hydrogen peroxide. One out of 13 M. abscessus cultures was killed by Chlorine DioxideTM and one by Sodium DichloroisocyanurateTM, representing a 5-log kill. Two isolates were killed by AlcoholTM again representing a 5 log kill. Following enrichment, O-phenylphenol and Sodium Lauryl SulfateTM showed the greatest biocidal activity with 11/13 isolates, whereas 2/13 cultures were killed by sodium dichloroisocyanurateTM. All other biocide/culture combinations yielded growth. Conclusion: These data indicate that M. abscessus may persist after exposure to several common hospital biocides. Further work is urgently needed to define unequivocal biocide contact treatments to prevent cross infection with this mycobacterial species in this patient population and thus ensure effective infection control and prevention. PMID- 29516886 TI - Virulence of Mycobacterium avium Subsp. hominissuis Human Isolates in an in vitro Macrophage Infection Model. AB - Background: Mycobacterium avium subsp. hominissuis (MAH) is an environmental opportunistic pathogen for humans and swine worldwide; in humans, the vast majority of MAH infections is due to strains belonging to specific genotypes, such as the internal transcribed spacer (ITS)-sequevars Mav-A and Mav-B that mostly cause pulmonary infections in elderly patients and severe disseminated infections in acquired immunodeficiency syndrome patients, respectively. To test whether the different types of infections in distinct patients' populations might reflect a different virulence of the infecting genotypes, MAH human isolates, genotyped by ITS sequencing and MIRU-VNTR minisatellite analysis, were studied for the capacity to infect and replicate in human macrophages in vitro. Methods: Cultures of human peripheral blood mononuclear cells and phagocytic human leukemic cell line THP-1 cells were infected with each MAH isolate and intracellular colony-forming units (CFU) were determined. Results: At 2 h after infection, i.e., immediately after cell entry, the numbers of intracellular bacteria did not differ between Mav-A and Mav-B organisms in both phagocytic cell types. At 5 days, Mav-A organisms, sharing highly related VNTR-MIRU genotypes, yielded numbers of intracellular CFUs significantly higher than Mav-B organisms in both phagocytic cell types. MIRU-VNTR-based minimum spanning tree analysis of the MAH isolates showed a divergent phylogenetic pathway of Mav-A and Mav-B organisms. Conclusion: Mav-A and Mav-B sequevars might have evolved different pathogenetic properties that might account for their association with different human infections. PMID- 29516887 TI - Utilization of molecular and conventional methods for the identification of nontuberculous mycobacteria isolated from different water sources. AB - Background: The environment is the nontuberculous mycobacteria (NTM) reservoir, opportunistic pathogens of great diversity and ubiquity, which is observed in the constant description of new species capable of causing infection. Since its introduction, molecular methods are essential for species identification. Most comparative studies between molecular and conventional methods, have used isolated strains from clinical samples. Methods: The aim of this study was to evaluate the usefulness of molecular methods, especially the hsp65-PRA (PCR Restriction Enzyme Analysis), and biochemical tests in the identification of NTM recovered from water of different origins, using the sequencing of 16S rRNA and hsp 65 genes as assessment methods of the previous ones. Species identification was performed for all 56 NTM isolates what were recovered from 32 (42.1%) positive water samples, using conventional phenotypic methods, hsp65-PRA, partial sequencing of 16S rRNA and sequencing of hsp 65 genes. Results: Phenotypic evaluation and hsp65-PRA were concordant with 23 (41.1%) isolates. Also, the PRA was concordant with 16 (28.6%) and 27 (48.2%) isolates, with the partial sequencing of 16S rRNA and sequencing of hsp 65 genes, respectively. It is considered that the 19.6% (n = 11) could not be identified. Conclusion: Identification of NTM environmental isolates to the species level, especially when they are pigmented and fast-growing, both the analysis of the restriction patterns obtained by PRA and the sequencing of the 16S rRNA and hsp 65 genes are insufficient by themselves. Although they are demanding and time-consuming, biochemical tests are very useful to support data obtained by molecular methods. PMID- 29516888 TI - Identification of potential inhibitors for mycobacterial uridine diphosphogalactofuranose-galactopyranose mutase enzyme: A novel drug target through in silico approach. AB - Background: The Mycobacterium tuberculosis (MTB) uridine diphosphogalactofuranose (UDP)-galactopyranose mutase (UGM) is an essential flavoenzyme for mycobacterial viability and an important component of cell wall. It catalyzes the interconversion of UDP-galactopyranose into UDP-galactofuranose, a key building block for cell wall construction, essential for linking the peptidoglycan and mycolic acid cell wall layers in MTB through a 2-keto intermediate. Further, as this enzyme is not present in humans, it is an excellent therapeutic target for MTB. Thus, inhibition of this UGM enzyme is a good approach to explore new anti TB drug. This study aims to find novel and effective inhibitors against UGM from reported natural phytochemicals and ZINC database using virtual screening approach. Methods: In this study, 148 phytochemicals with reported antitubercular activity and 5280 ZINC compounds with 70% structural similarity with the natural substrate of UGM (UDP-galactopyranose and UDP-galactofuranose) were screened against UGM. Results: In virtual screening, 19 phytochemicals and 477 ZINC compounds showed comparatively better binding affinity than natural substrates. Among them, best 10 compounds from each group were proposed as potential inhibitors for UGM based on the binding energy and protein-ligand interaction analysis. Among phytochemicals, three compounds, namely, tiliacorine, amentoflavone, and 2'-nortiliacorinine showed highest binding affinity (binding energy of -10.5, -10.4, and -10.3 Kcal/mol, respectively), while among ZINC compounds, ZINC08219848 and ZINC08217649, showing highest binding affinity (binding energy of -10.0 and -9.7 Kcal/mol, respectively) toward UGM as compared to its substrates. Conclusion: These selected compounds may be proposed as potential inhibitors of UGM and need to be tested in TB culture studies in vitro to assess their anti-TB activity. PMID- 29516889 TI - Mycobacterium abscessus subsp. abscessus Lung Disease: Drug Susceptibility Testing in Sputum Culture Negative Conversion. AB - Background: Among Mycobacterium abscessus complex infections, patients with M. abscessus subsp. abscessus (MAA) lung disease are difficult to treat and no standard therapy has been established. Few reports have investigated the drug susceptibility of these strains. We retrospectively investigated how in vitro drug susceptibility testing (DST) of MAA affects the induction of sputum conversion using pharmacotherapy. Methods: Patients with MAA lung disease diagnosed and treated between 2010 and 2014 at our hospital were enrolled and divided into Group A (sputum conversion without relapse within 1 year) and Group B (persistent positive cultured or negative conversion with relapse). MAA was identified in M. abscessus using sequence with genotyping, and DST of MAA was performed. Results: We assessed 23 patients (9 males and 14 females). There were 8 patients in Group A and 15 in Group B. Higher prevalence of susceptible isolates for clarithromycin (CAM) susceptibility on day 14 was noted in Group A than in Group B (P = 0.03) and no significant difference observed in the two groups for other drugs. Conclusions: In vitro DST of MAA, especially CAM susceptibility on day 14, affected the results of negative conversion. No other drugs were found to affect sputum culture negative conversion. PMID- 29516890 TI - Identification and development of novel indazole derivatives as potent bacterial peptidoglycan synthesis inhibitors. AB - Background: Tuberculosis is well-known airborne disease caused by Mycobacterium tuberculosis. Available treatment regimen was unsuccessful in eradicating the deaths caused by the disease worldwide. Owing to the drawbacks such as prolonged treatment period, side effects, and drug tolerance, there resulted in patient noncompliance. In the current study, we attempted to develop inhibitors against unexplored key target glutamate racemase. Methods: Lead identification was done using thermal shift assay from in-house library; inhibitors were developed by lead derivatization technique and evaluated using various biological assays. Results: In indazole series, compounds 11 (6.32 +/- 0.35 MUM) and 22 (6.11 +/- 0.51 MUM) were found to be most promising potent inhibitors among all. These compounds also showed their inhibition on replicating and nonreplicating bacteria. Conclusion: We have developed the novel inhibitors against M. tuberculosis capable of inhibiting active and dormant bacteria, further optimization of inhibitor derivatives can results in better compounds for eradicating tuberculosis. PMID- 29516891 TI - Enhancing antimycobacterial activity of isoniazid and rifampicin incorporated norbornene nanoparticles. AB - Background: : Tuberculosis (TB) has been identified in skeletons over 6000 years old and still remains as the most prevalent infectious disease in the world; thus, there is a need for development of new drugs or tuning of old drugs. Nanotechnology, an advanced technology, plays a vital role in research for the diagnosis and treatment of TB, thus preventing adverse effects and drug resistance. The objective of this study was to enhance the antimycobacterial activity of isoniazid- (INH) and rifampicin (RIF)-incorporated norbornene (NOR) nanoparticles in comparison with plain INH and RIF without nanoparticles. Methods: Norbornene-polyethylene glycol - Isoniazid copolymer (NOR-PEG-INH) and norbornene polyethylene rifampicin Co polymer (NOR-PEG-RIF) were used for this study. The percentage of INH and RIF in NOR nanoparticles was 35% and 74%, respectively. Mycobacterium growth indicator tube containing Middlebrook 7H9 broth, the liquid medium, was used to analyze in vitro activity of the NOR-based drug and the plain drug. Minimum inhibitory concentration (MIC) of the drugs was determined from H37Rv control strain of mycobacterium TB (MTB). Results: : The dosage of INH and RIF is minimal in the combination form with the NOR nanoparticles compared to the plain INH and RIF. The results indicate that the minimum concentration of NOR-PEG-INH and NOR-PEG-RIF required inhibiting H37Rv strain of MTB was 0.05 MUg/ml and 0.5 MUg/ml, respectively. The results were similar to plain INH and RIF MIC. Conclusion: : Low dosage of INH and RIF along with NOR nanocarrier has similar activity to that of INH and RIF; thus this is expected to reduce adverse effects and NOR did not alter the functional activity of INH and RIF, thus becoming eligible for the newer drug carrier in TB treatment. PMID- 29516892 TI - Uric acid levels in patients on antituberculosis drugs in the southwest Region of Cameroon. AB - Background: Antituberculosis drugs (ATDs) efficiently combat Mycobacterium tuberculosis either through direct molecular interactions or those of its metabolites. However, a variety of adverse effects have been reported, leading to frequent interruptions of treatment. To investigate the possible metabolic disturbances resulting from antituberculosis (TB) treatment, the uric acid (UA) level of patients on ATDs was measured in the southwest region of Cameroon. Methods: This hospital-based cross-sectional study involved 96 TB patients on ATDs and 32 controls who were neither on ATDs nor any other treatment that could increase UA levels. The hospital records of consenting participants were reviewed for medical history and questionnaires were issued. About 2 ml venous blood was collected and analyzed using spectrophotometers to determine UA levels. Results: Hyperuricemia was observed in 56/96 (58.3%) of the studied group as compared with 4/32 (12.5%) in the control group (P < 0.001). Our results indicated that treatment duration was significantly associated with hyperuricemia (P = 0.0016) while gender (P = 0.1275) was not. Conclusion: Hyperuricemia is associated with ATDs, with treatment duration being a significant factor. The disorder should be closely monitored, especially during the intensive phase of treatment. PMID- 29516893 TI - Cutaneous infection with Mycobacterium obuense. AB - This report describes the presence of cutaneous nodules and ulceration of the right leg of 1-year duration in an elderly woman. Prior biopsies had demonstrated dermal and subcutaneous granulomatous inflammation. Special stains for microorganisms and cultures were repeatedly negative. Polymerase chain reaction evaluation of the tissue block demonstrated the presence of Mycobacterium obuense. PMID- 29516894 TI - Pneumoperitoneum during treatment of abdominal tuberculosis in a Non-HIV patient: Natural progression or paradoxical worsening? AB - Paradoxical reactions during tuberculosis (TB) treatment are well-described in the HIV seropositive population but less so in the HIV seronegative group. Abdominal TB rarely presents as spontaneous perforation; cases occurring during anti-TB therapy are even rarer. We describe the clinical progress of a case of an HIV-negative patient who developed acute peritonitis while on anti-TB treatment for peritoneal TB through a series of clinical, radiological and histological images. Visceral perforation can occur as a complication of TB treatment. A high index of suspicion with early surgical intervention is crucial in the management of such cases. PMID- 29516895 TI - Reactive perforating leprosy, erythema multiforme-like reactions, sweet's syndrome-like reactions as atypical clinical manifestations of Type 2 leprosy reaction. AB - Type 2 leprosy reactions commonly known as erythema nodosum leprosum, but various clinical manifestations of type 2 leprosy reaction were exist. The highlight of this case series was to report various atypical clinical manifestations of type 2 leprosy reaction such as reactive perforating leprosy, erythema multiforme-like reaction, and sweet's syndrome (SS)-like reaction. PMID- 29516896 TI - Mediastinal ganglionar tuberculosis postcardiac transplantation. AB - The diagnosis and treatment of tuberculosis (TB) in transplanted receivers presents several challenges. TB is an opportunistic infection with high morbidity and mortality in solid organs of transplanted patients, therefore, the diagnosis difficulties. A case of a 30-year-old male, heart transplanted patient, who after being submitted to mediastinoscopy, obtained a result of lymph node TB. PMID- 29516897 TI - Mycobacterium chelonae osteomyelitis presenting as a mycobacterial spindle cell pseudotumor. AB - We report a case of an 88-year-old man with osteomyelitis of the right ankle, with histopathology demonstrating a Mycobacterium spindle cell pseudotumor. The Mycobacterium contained in this spindle cell pseudotumor was Mycobacterium chelonae. M. chelonae spindle cell pseudotumors are rare and have only been reported twice previously in the literature. Similarly, M. chelonae presenting as the pathogen in bone infection is rare. Due to this unusual presentation of M. chelonae, the antibiotic rationale was based largely on case reports and consisted of imipenem, clarithromycin, and linezolid. Antibiotic complications were experienced by the patient. Despite a renally adjusted dose of imipenem, the patient experienced imipenem toxicity and his antibiotics were modified to tigecycline and clarithromycin. Although his symptoms were clinically resolving, the patient sadly passed away before completing treatment. PMID- 29516898 TI - Does a quality assurance training course on chest radiography for radiological technologists improve their performance in Laos? PMID- 29516899 TI - Four views of trichomycosis axillaris: Clinical, Wood's lamp, dermoscopy and microscopy. PMID- 29516900 TI - Epidemiology, treatment and prevention of herpes zoster: A comprehensive review. AB - Herpes zoster is a major health burden that can affect individuals of any age. It is seen more commonly among individuals aged >=50 years, those with immunocompromised status, and those on immunosuppressant drugs. It is caused by a reactivation of varicella zoster virus infection. Cell-mediated immunity plays a role in this reactivation. Fever, pain, and itch are common symptoms before the onset of rash. Post-herpetic neuralgia is the most common complication associated with herpes zoster. Risk factors and complications associated with herpes zoster depend on the age, immune status, and the time of initializing treatment. Routine vaccination for individuals over 60 years has shown considerable effect in terms of reducing the incidence of herpes zoster and post-herpetic neuralgia. Treatment with antiviral drugs and analgesics within 72 hours of rash onset has been shown to reduce severity and complications associated with herpes zoster and post herpetic neuralgia. This study mainly focuses on herpes zoster using articles and reviews from PubMed, Embase, Cochrane library, and a manual search from Google Scholar. We cover the incidence of herpes zoster, gender distribution, seasonal and regional distribution of herpes zoster, incidence of herpes zoster among immunocompromised individuals, incidence of post-herpetic neuralgia following a zoster infection, complications, management, and prevention of herpes zoster and post-herpetic neuralgia. PMID- 29516901 TI - A case of drug-induced hypersensitivity syndrome induced by icotinib managed by intravenous immunoglobulin and systemic corticosteroids. PMID- 29516902 TI - Translational research in oral cancer: "A challenging key step in moving from bench to bedside". AB - This review summarizes and interprets the rate of improvement in cancer treatments which have remained frustratingly slow despite considerable investment in oncological research. Hence, this review emphasizes on minimizing exposure of patients to ineffective investigational therapies by decreasing the number of poorly designed clinical trials through stronger collaboration between industry and academia which can be done by multidisciplinary teams who are essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients and implementing effective interventions to ultimately improve the quality and duration of survival. Hence, it is recommended to explore all these factors which contribute toward translational lag between implementation of discoveries from basic research into clinical use. PMID- 29516903 TI - MicroRNA-associated carcinogenesis in lung carcinoma. AB - Lung carcinoma is the leading cause of cancer-related death worldwide; it has been regarded as the origin of death by melanoma universally. Frequently, lung carcinomas identified in progressive phase and have lowermost roots of existence in any category of the cancer. MicroRNAs (miRNAs) are small having 18-25 nucleotides extended noncoding RNAs regulating gene expression and elaborate in a wide assortment of cellular progressions also. Cumulative indications propose that, miRNA plays imperative and multifarious roles in cases of human lung cancer genetics. Collective studies concern with research related to lung sarcoma by using biomarkers which determine phenotypic signatures on behalf of diagnostic, prognostic, as well as therapeutic rationale. Furthermore, a number of aspects are indispensable to be deliberated while opting for miRNAs as clinical biomarkers in lung cancers, which have been recognized as imperative targets for therapeutic interventions in recent times. This review focuses inclusive information over the biogenesis of miRNA and considerable risk dynamics associated with the genetics of human lung cancer. PMID- 29516904 TI - Adjuvant therapy for intra oral surgical oncological defect with ancillary prosthesis: A literature review. AB - The role of a maxillofacial prosthodontist in the treatment of facial defects cannot be underestimated. A multidisciplinary approach is required during the rehabilitation procedure to bring out effective results. Ancillary maxillofacial prostheses limit the patient's disability and improve function. These prostheses are inevitable in restoring the function, esthetics, general, and psychological health of the patients. This article reviews the various ancillary-maxillofacial prostheses and throws light on their historical development. PMID- 29516905 TI - Comparison of full width at half maximum and penumbra of different Gamma Knife models. AB - As a radiosurgical tool, Gamma Knife has the best and widespread name recognition. Gamma Knife is a noninvasive intracranial technique invented and developed by Swedish neurosurgeon Lars Leksell. The first commercial Leksell Gamma Knife entered the therapeutic armamentarium at the University of Pittsburgh in the United States on August 1987. Since that time, different generation of Gamma Knife developed. In this study, the technical points and dosimetric parameters including full width at half maximum and penumbra on different generation of Gamma Knife will be reviewed and compared. The results of this review study show that the rotating gamma system provides a better dose conformity. PMID- 29516906 TI - Biological markers as an outcome measure of exercise in cancer rehabilitation: A systematic review. AB - The number of people living with and beyond cancer is at an all time high. These survivors are not necessarily living well, as adverse side effects from cancer and its treatment can last up to 5 years and leave patients at a higher risk of developing secondary cancers and other chronic illnesses. Exercise has been proven to be a safe and effective method of intervention to decrease mortality and overall improve health outcomes. The biological mechanism through which this occurs is an area of research that is in its infancy and not well defined. A systematic search was conducted of four databases for relevant randomized controlled trials (RCTs) published between January 2004 and December 2014. Studies had to include any blood/urine biological markers as an outcome measure to a physical activity intervention for cancer survivors posttreatment. Fifteen relevant articles were identified (12 RCTs). It was shown that randomized controlled trials of exercise for cancer survivors posttreatment may results in changes to circulating levels of insulin, insulin related pathways (insulin like growth factor II [IGF II], IGF binding protein 3), high density lipoprotein, total cholesterol, leptin, and osteocalcin. Due to small sample sizes, the evidence is still preliminary and therefore more research is warranted in this area in the form of larger, statistically powered RCTs for cancer survivors. PMID- 29516907 TI - Dosimetric verification of small fields in the lung using lung-equivalent polymer gel and Monte Carlo simulation. AB - Purpose: The main purpose of this study was evaluate a polymer-gel-dosimeter (PGD) for three-dimensional verification of dose distributions in the lung that is called lung-equivalent gel (LEG) and then to compare its result with Monte Carlo (MC) method. Materials and Methods: In the present study, to achieve a lung density for PGD, gel is beaten until foam is obtained, and then sodium dodecyl sulfate is added as a surfactant to increase the surface tension of the gel. The foam gel was irradiated with 1 cm * 1 cm field size in the 6 MV photon beams of ONCOR SIEMENS LINAC, along the central axis of the gel. The LEG was then scanned on a 1.5 Tesla magnetic resonance imaging scanner after irradiation using a multiple-spin echo sequence. Least-square fitting the pixel values from 32 consecutive images using a single exponential decay function derived the R2 relaxation rates. Moreover, 6 and 18 MV photon beams of ONCOR SIEMENS LINAC are simulated using MCNPX MC Code. The MC model is used to calculate the depth dose water and low-density water resembling the soft tissue and lung, respectively. Results: Percentages of dose reduction in the lung region relative to homogeneous phantom for 6 MV photon beam were 44.6%, 39%, 13%, and 7% for 0.5 cm * 0.5 cm, 1 cm * 1 cm, 2 cm * 2 cm, and 3 cm * 3 cm fields, respectively. For 18 MV photon beam, the results were found to be 82%, 69%, 46%, and 25.8% for the same field sizes, respectively. Preliminary results show good agreement between depth dose measured with the LEG and the depth dose calculated using MCNP code. Conclusion: Our study showed that the dose reduction with small fields in the lung was very high. Thus, inaccurate prediction of absorbed dose inside the lung and also lung/soft-tissue interfaces with small photon beams may lead to critical consequences for treatment outcome. PMID- 29516908 TI - Dose rate and energy dependence study of methacrylic acid gelatin tetrakis (hydroxymethyl) phosphonium chloride gel with flattened and unflattened photon beams. AB - Aims: The aim of this study is to evaluate the dose rate and energy dependency of methacrylic acid gelatin tetrakis (hydroxymethyl) phosphonium chloride (MAGAT) gel in unflattened photon beam using X-ray computed tomography (CT) and ultraviolet (UV)-visible spectroscopy. Materials and Methods: MAGAT gel was prepared and it was exposed to 6 MV flattened and unflattened beams. The dose selected for irradiation was ranging from 3 to 15 Gy with an increment of 3 Gy. The dose rate dependency of the gel was investigated by exposing the gel to three different dose rates of 250, 500, and 1500 cGy/min for flattening filter free (FFF). To verify the energy dependency of the gel, it was exposed by both FFF and flattening filter (FF) for constant dose rate (250 cGy/min) and different energy (6 and 10 MV X-ray photons). The exposed gels were scanned by X-ray CT and UV visible spectrophotometer. Results: The change in dose sensitivity observed over the dose rate from 250 cGy/min to 1500 cGy/min was 58.00% and 57.89% using a UV visible spectrophotometer and X-ray CT analysis method. Energy dependency was evaluated with respect to dose sensitivity and the variation between 6 MV FF and FFF photon beams was found to be 2.20% and 2.21% using UV-visible spectrophotometer analysis and X-ray CT, respectively. Similarly, the variation noticed with 10 MV FF and FFF was 2.30% using UV-visible spectrophotometer analysis and 2.22% using X-ray CT analysis. Conclusions: The results clearly show that the MAGAT gel was highly dose rate-dependent and less dependent on energy. The beam quality variation between FF and FFF was less. The similar results obtained using X-ray CT scanner and UV-visible spectrophotometer indicate that this study can be recommended for polymer gel scanning procedure. PMID- 29516910 TI - In vivo dose estimations through transit signal measured with thimble chamber positioned along the central axis at electronic portal imaging device level in medical linear accelerator in carcinoma of the middle-third esophagus patients undergoing three-dimensional conformal radiotherapy. AB - Objective: This study presents a method to estimate midplane dose (Diso, transit) in vivo from transit signal (St) measured with thimble ionization chamber in cancer of the middle-third esophagus patients treated with three-dimensional radiotherapy (RT). This detector is positioned at the level of electronic portal imaging device in the gantry of a medical linear accelerator. Materials and Methods: Efficacy of inhomogeneity corrections of three dose calculation algorithms available in XiO treatment planning system (TPS) for planned dose (for open fields) (Diso, TPS) was studied with three heterogeneous phantoms. Diso, transit represents measured signal at transit point (St) far away correlating to dose at isocenter. A locally fabricated thorax phantom was used to measure the in vivo midplane dose (Diso, mid) which was also estimated through St. Thirteen patients with carcinoma of the middle-third esophagus treated with three dimensional conformal RT were studied. St was recorded (three times, with a gap of 5-6 fractions during the treatment) to estimate Diso, transit, which was compared with the doses calculated by TPS. Results: The dose predictions by superposition algorithm were superior compared to the other algorithms. Percentage deviation of Diso, transit, Diso, mid with Diso, TPS combined all fields was 2.7 and -2.6%, respectively, with the thorax phantom. The mean percentage deviation with standard deviation of estimated Diso, transit with Diso, TPS observed in patients was within standard deviation -0.73% +/-2.09% (n = 39). Conclusions: Midplane dose estimates in vivo using this method provide accurate determination of delivered dose in the middle-third esophagus RT treatments. This method could be useful in similar clinical circumstances for dose confirmation and documentation. PMID- 29516909 TI - A novel quantification method for low-density gel dosimeter. AB - Aim: Low signal-to-noise ratio (SNR) images of lung-like (low-density [LD]) gel dosimeters, compared to unit-density (UD) gels, necessitate the use of different quantification methods. Setting and Design: In this study, a new method is introduced based on noise correction and exponential (NCEXP) fitting. The feasibility of NCEXP method for quantifying dose absorption in LD gels is evaluated. Materials and Methods: Sensitivity, dose resolution, detectable dynamic range, and correlation of the calibration curve for both UD and LD gel dosimeters are the parameters, which we analyze to investigate the consequences of new method. Results of NCEXP method are compared to maximum likelihood estimation of rician distribution (MLE-R) and variable echo number (VAREC) quantification methods. Results: Dose response of LD gel dosimeter shows wider detectable dynamic range as compared to UD gel. Using NCEXP method for both LD and UD dosimeter gels, a more sensitive calibration curve with a superior dose resolution is obtained. The advantage of new quantification method is more significant for LD dosimeter gel analysis, where SNR decreases as a result of higher absorbed doses (>=10 Gy). Despite the inverse effect of the VAREC method on detectable dose range of UD gel, no specific changes are observed in dynamic dose range of LD gel dosimeter with different quantification methods. The correlations obtained with different methods were approximately of the same order for UD and LD gels. Conclusion: NCEXP method seems to be more effective than the MLE-R and VAREC methods for quantification of LD dosimeter gel, especially where high-dose absorption and steep-dose gradients exist such as those in intensity modulated radiation therapy and stereotactic radiosurgery. PMID- 29516911 TI - Dosimetric properties of new formulation of PRESAGE(r) with tin organometal catalyst: Development of sensitivity and stability to megavoltage energy. AB - Aim: Tin-base catalyst is one of the widely used organometallic catalysts in polyurethane technology. The purpose of this study was to evaluate the effect of tin organometallic catalyst in the radiation response and radiological properties of a new formula of PRESAGE(r). Materials and Methods: In the study, two types of PRESAGE were fabricated. A very little amount of dibutyltindillaurate (DBTDL) (0.07% weight) was used as a catalyst in the fabrication of new PRESAGE (i.e., PRESAGE with catalyst), which components were: 93.93% weight polyurethane, 5% weight tetrachloride, and 1% weight leucomalachite green (LMG). For PRESAGE without catalyst, 94% weight polyurethane, 4% weight tetrachloride, and 2% weight LMG were used. Radiochromic response and postirradiation stability of PRESAGEs were determined. Also, radiological characteristics of PRESAGEs, such as mass density, electron density, mass attenuation coefficient, and mass stopping power in different photon energies were assessed and compared with water. Results: The absorption peak of new PRESAGE compared to PRESAGE without catalyst was observed without change. Sensitivity of new PRESAGE was higher than PRESAGE without catalyst and its stability after the first 1 h was relatively constant. Also, Mass attenuation coefficient of new PRESAGE in energy ranges <0.1 MeV was 10% more than water, whereas the maximum difference of mass stopping power was only 3%. Conclusions: Tin organometallic catalyst in very low concentration can be used in fabrication of radiochromic polymer gel to achieve high sensitivity and stability as well as good radiological properties in the megavoltage photon beam. PMID- 29516912 TI - The effects of gilaburu (Viburnum opulus) juice on experimentally induced Ehrlich ascites tumor in mice. AB - Objective: The aim of study was to investigate anticancer effect of Viburnum opulus (VO) on Ehrlich ascites carcinoma (EAC) bearing mice that treated with different concentrations of VO. Materials and Methods: For tumor transplantation; mice were inoculated with 1 * 106 EAC cells intraperitoneally and than divided into five groups (n = 9). Two hours after inoculation; experimental groups were treated daily with VO extract at doses of 1000 mg/kg, 2000 mg/kg, 4000 mg/kg. Results: Extracts obtained from gilaburu juice can have hinder effect on tumor cell growth. Conclusion: As far as we known, this is the first study about in vivo antitumoral activity of VOon Ehrlich ascites tumor model, and consequently VO extract exhibited anticancer activity against EAC-bearing mice. PMID- 29516913 TI - Anticancer potential of leaf and leaf-derived callus extracts of Aerva javanica against MCF-7 breast cancer cell line. AB - Background: Aerva javanica is an exotic and medicinal plant in India. Aim of the Study: The main goal of this study was to evaluate the antiproliferative properties of leaf and leaf-derived callus extracts against human breast cancer cell line MCF-7. Methods: The plant parts were sequentially extracted with hexane, chloroform, ethyl acetate, acetone, and methanol. The extract was concentrated to yield the crude extract, which was tested for anticancer potentials. The anticancer potential of cytotoxic extracts was determined by 3 (4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and DNA fragmentation assays in human breast cancer cell lines (MCF-7). Results: All the tested extracts showed significant antiproliferative activities in a concentration- and time-dependent manner. The inhibitory concentration of extract was tested against target cell line, and the results show in vitro leaf of A. javanica has higher inhibitory effect against the tested cancer cells at lower concentration (about 11.89 and 22.45 MUg/ml) followed by other samples extracts. Conclusion: The results of the present study conclude in vitro plant sample having more potent anticancer property and support the need of further studies to isolate potential anticancer drug with cancer cell-specific cytotoxicity. PMID- 29516914 TI - The effects of thymoquinone and genistein treatment on telomerase activity, apoptosis, angiogenesis, and survival in thyroid cancer cell lines. AB - Context: Thyroid cancers (TCs) are the most common endocrine malignancies. There were two problems with the current cancer chemotherapy: the ineffectiveness of treatment due to resistance to cancer cell, and the toxic effect on normal cells. Aims: This study was aimed to determine the effects of thymoquinone (TQ) and genistein (Gen) phytotherapeutics on telomerase activity, angiogenesis, and apoptosis in follicular and anaplastic thyroid cancer cells (TCCs). Materials and Methods: Cell viability, caspase-3 (CASP-3) activity, and messenger RNA (mRNA) expression levels of human telomerase reverse transcriptase (hTERT), phosphatase and tensin homolog (PTEN), nuclear factor-kappa B (NF-kB), cyclin-dependent kinase inhibitor 1 (p21), and vascular endothelial growth factor-A (VEGF-A) genes were analyzed. Results: It was found that TQ and Gen treatment on TCCs caused a statistically significant decrease of cell viability, and mRNA expression levels of hTERT, VEGF-A, and NF-kB genes, but a statistically significant increase of PTEN and p21 mRNA expression levels. In addition, TQ and Gen treatment also caused a statistically significant increase active CASP-3 protein level in TCCs. Moreover, our results demonstrated that, when compared with follicular TCCs, anaplastic TCCs were more sensitive to the treatment of TQ and Gen. Conclusions: Based on these results, two agents can be good options as potential phytochemotherapeutics against TCCs. PMID- 29516915 TI - Calculation of the contrast of the calcification in digital mammography system: Gate validation. AB - Purpose: Validation of the Gate tool in digital mammography image simulation from the viewpoint of image quality (contrast of calcifications). Materials and Methods: The polymethyl methacrylate (PMMA) phantom containing aluminum foils in different thicknesses is used for measuring the contrast of calcifications in a real system. In this research, the phantom and mammography system have been simulated by the Gate tool with the maximum possible details. The contrast of the aluminum foil in simulations and practical method has been compared with each other and the standard errors in the mean (SEM) for various voltages of X-ray tube, aluminum foil, and PMMA thicknesses have been reported. Results: Based on the obtained results, by increasing the X-ray tube voltage from 20 to 39 kVp, the image contrast has been decreased in both simulation and practical methods. The minimum and maximum average SEM of the contrast of the aluminum foils among various voltages between two simulations and practical methods for different PMMA thicknesses of 2, 4, and 6 cm have been reported as 0.0105 and 0.0117, 0.0049 and 0.0154, and 0.0037 and 0.0072, respectively. Discussion: According to the SEM rate reported in this research for calculating the contrast of the aluminum foils in the mammography system based on simulation and practical methods, the capability of the Gate tool for simulating digital mammography system and the images created in it from the viewpoint of image contrast can be confirmed. PMID- 29516916 TI - The effect of mesenchymal stem cell-conditioned medium on proliferation and apoptosis of breast cancer cell line. AB - Purpose: Bone marrow-derived mesenchymal stem cells (MSCs) have the potential ability to differentiate into bone, muscle, fat, and cartilage lineage cells. Furthermore, MSCs are known to migrate into tumor-associated stroma of cancer. This tumor microenvironment consists of a dynamic network of growth factors, immune cells, fibroblasts, extracellular matrix, and MSCs. MSCs as nonhematopoietic stem cells affect tumor, epithelial cells by alteration proliferative capacity, morphology, and aggregation pattern of tumor cells. Materials and Methods: This research aimed to further elucidate the MSCs effects in the progress of proliferation, cell cycle, and apoptosis in breast cancer by gene expression analysis in human breast cancer cell lines exposed to MSCs conditioned media (CM). Expression pattern of two genes, including survivin (Birc5) as anti-apoptotic gene and serine threonine kinase 15 as proliferative gene, were studied. Results: Anti-apoptotic and proliferative genes were up regulated in co-cultured breast tumor cells with MSCs-CM that correlate with tumor progression and poor prognosis. Conclusion: Our results and other findings indicate the interaction of breast tumor cells with MSCs through paracrine factors. Also, the applications of MSCs as therapeutic tools are facing controversial concerns. PMID- 29516917 TI - Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis. AB - Objective: Breast cancer is considered as a heterogeneous disease, characterized by different biological and phenotypic features which make its diagnosis and treatment challenging. The CXC chemokine receptor 4 (CXCR4) expression was found to be correlated with poor overall survival in invasive breast carcinoma patients. Here, we sought to investigate the expression levels of the CXCR4-CXC chemokine ligand 12 (CXCL12) chemokine axis and their association with clinicopathologic features and lymph node metastasis in invasive breast carcinoma. Materials and Methods: The expression of the CXCR4-CXCL12 chemokine axis and metastasis-related genes (E-cadherin and matrix metalloproteinase 2 [MMP2]) was measured by quantitative real-time-polymerase chain reaction. The correlation with various clinicopathologic parameters was analyzed. Results: We found upregulation of the CXCR4-CXCL12 chemokine axis in invasive breast carcinoma samples compared with normal adjacent tissues. Moreover, we observed that upregulation of this chemokine axis was correlated with tumor stages and lymph node metastasis of breast tumors. Interestingly, this correlation was affected by the expression of human epidermal growth factor receptor 2/neu. There is also a significant correlation between the expression levels of CXCR4-CXCL12 axis and metastasis-related genes (E-cadherin and MMP2) in tumor samples with advanced stages of metastasis. Conclusion: These results suggest a key role for the CXCR4-CXCL12 chemokine axis in breast cancer progression and highlight the prognostic importance of this chemokine axis for breast cancer survival. PMID- 29516918 TI - Underdosing of the maxillary sinus for small fields used in newer radiotherapy techniques: Comparison of thermoluminescent dosimeter and Monte Carlo data. AB - Aims: To evaluate the underdosing of the maxillary sinus at its distal end produced by air cavity in the path of the 6 MV photon beam. Materials and Methods: A cubic solid water slab phantom of dimensions 18 cm * 18 cm * 18 cm with 4 cm * 4 cm * 4 cm air cavity 3 cm away from its anterior surface was used in this study. The percentage depth dose (PDD) for 6 MV X-rays along the central axis of the cubical air cavity was measured using thermoluminescent dosimeter-100 chips. The EGSnrc/DOSXYZnrc Monte Carlo (MC) code was used to estimate the PDD values in both homogeneous and inhomogeneous conditions. The dose data were generated for 1 cm * 1 cm, 2 cm * 2 cm, 3 cm * 3 cm, and 5 cm * 5 cm field sizes. Results: Average percentage dose reductions at 1 mm beyond the distal surface of the maxillary sinus for the field sizes 1 * 1, 2 * 2, and 3 * 3 cm2 are 42.4%, 39.5%, and 29.4%, respectively. However, for 5 cm * 5 cm field size, there is a dose enhancement (i.e., overdosing) at 1 mm from the distal surface of the maxillary sinus and the average percentage dose enhancement is 5.9%. Also, beyond 1 cm from the air-water interface, there is dose enhancement for all the field sizes. Conclusion: This study showed that the significant dose reduction occurs near the air-water interface for the treatment techniques using small photon fields such as intensity-modulated radiotherapy or other newer techniques. MC based treatment planning calculation predicts realistic dose distribution while using small photon fields in the treatment of maxillary sinus. PMID- 29516919 TI - A study of clinicopathological characteristics of thyroid carcinoma at a Tertiary Care Center. AB - Context: To share clinicopathological data of thyroid carcinoma from a high volume Tertiary Care Centre in East India. Aim: To share the epidemiology and clinicopathological presentation of thyroid cancer at a high volume Tertiary Care Center in East India. Settings and Design: Retrospective observational study. Subjects and Methods: Forty-two consecutive patients of thyroid neoplasm diagnosed by fine needle aspiration cytology (FNAC) and primarily underwent surgical treatment from July 2005 to June 2012 were included. Retrospective data analyses of patient's records were done. Statistical Analysis Used: The statistical analysis was performed using Epi Info version 3.5.3. Results: Forty two patients underwent surgery for thyroid neoplasm. Median age of diagnosis was 39 years. It was 6 times more common in females (female:male - 6:1). Papillary carcinoma consists of 63.15%, follicular carcinoma consists of 23.68%, and medullary carcinoma and anaplastic carcinoma each consist of 5.26% of malignant cases. Out of them, lymph node metastases were seen in 17 patients (44.73%). FNAC shows positive predictive value of 89.74%. Conclusions: In our study, differentiated thyroid cancers were found to be more common in younger age group. Cervical lymph node metastases occur in a large number of patients. Central compartment lymph node dissection with exploration of lateral neck and modified neck dissection whenever needed is helpful in all cases of thyroid carcinoma for proper pathological staging. FNAC is rapid and efficient procedure with high positive predictive value in diagnosing thyroid neoplastic lesions. PMID- 29516920 TI - Morphometric computer-assisted image analysis of epithelial cells in different grades of oral squamous cell carcinoma. AB - Introduction: Oral squamous cell carcinoma (OSCC) accounts 94% of all malignant lesions in the oral cavity. In the assessment of OSCC, nowadays the WHO grading system has been followed widely but due to its subjectivity, investigators applied the sophisticated technique of computer-assisted image analysis in the grading of carcinoma in larynx, lungs, esophagus, and cervix to make it more objective. Aims and Objectives: Access, analyze, and compare the cellular area (CA); cytoplasmic area (Cyt A); nuclear area (NA); nuclear perimeter (NP); nuclear form factor (NF); and nuclear-cytoplasmic ratio (N/C) of the cells in different grades of OSCC. Materials and Methods: Fifty OSCC cases were obtained and stained with hematoxylin and eosin which were graded according to the WHO classification. The sections were subjected to morphometric analysis to analyze all the morphometric parameters in different grades of OSCC and subjected to one way ANOVA statistical analysis. Results: CA and Cyt A decreased from normal mucosa with dedifferentiation of OSCC. The NA and NP increased in carcinoma group when compared to normal mucosa but decreased with dedifferentiation of OSCC (P < 0.05). NF had no significance with normal mucosa and different grades of OSCC (P > 0.05), while N/C ratio increased from normal mucosa through increasing grades of OSCC, reaching the highest value in poorly differentiated squamous cell carcinoma (P < 0.05). Conclusion: Both cellular and nuclear variables provide a more accurate indication of tumor aggressiveness than any single parameter. Morphometric analysis can be a reliable tool to determine objectively the degree of malignancy at the invasive tumor front. PMID- 29516921 TI - Prevalence, knowledge, and attitude of gutkha chewing among school children of Arsikere, India. AB - Aims: To assess the prevalence, knowledge, and attitude of gutkha chewing among school children of Arsikere, India. Materials and Methods: Two thousand school children aged between 10 and 15 years were examined with individual interviews along with a questionnaire to evaluate the presence of betel nut and paan chewing habit in various forms. Children of both sexes were included in the study. Responses of all study population and the association between dependent and explanatory variables were assessed using Chi-square test. Results: Twenty-eight percent of children had the habit of gutkha chewing, more among boys than girls at the ratio of 4:1 which was statistically significant (P < 0.05). The habit was more common in government school children than private school children; over 70% of children believed that it is a bad habit, but half the study population was not aware of side effects; 30% of children believed that it is not a bad habit and has no side effects. Conclusion: There is a higher prevalence of gutkha chewing habit in school children who are not aware of the side effects. Children themselves purchase the gutkha and betel nut sachets, hence the Government should ban the sale and purchase by children. PMID- 29516922 TI - Effect of staining procedures on the results of micronucleus assay in the exfoliated buccal mucosal cells of smokers and nonsmokers: A pilot study. AB - Background: Tobacco consumption in smoke form causes severe health problems such as cancer. Micronuclei are structures that present after genomic damage in buccal mucosal cells which could be a good indicator of chromosomal alterations in cytological samples. The nuclear anomalies that are consequences of cell injury are also found in these cells. Aim: The present study was aimed at evaluating the effectiveness of deoxyribonucleic acid (DNA)-specific stain over DNA-nonspecific stain in exfoliated buccal mucosa cells in smokers and nonsmokers for assessment of micronuclei and nuclear anomalies. Materials and Methods: Thirty subjects were divided into three groups; Group 1 (control) nonsmokers (n = 10), Group 2 individuals with history of smoking for less than 10 years (n = 10), and Group 3 individuals with history of smoking for more than 10 years (n = 10). The exfoliated buccal mucosal cells were scrapped using wooden spatula, smeared over the glass slide, and stained with DNA-nonspecific stain, Giemsa; and DNA-specific stains, Feulgen and acridine orange. Results: We found that the mean micronuclei score with DNA-nonspecific stain, Giemsa, was significantly higher in smokers group when compared to nonsmokers group. No such significant differences were observed with DNA-specific stains. Also, in the smokers groups, mean micronuclei were higher in Group 3 when compared to Group 2. Conclusion: The score of MN assay and nuclear anomalies in exfoliated buccal mucosal cells of smokers and nonsmokers strongly depended on staining procedures and duration of smoking. Hence, these should be interpreted with caution to avoid false-positive results. PMID- 29516923 TI - Immunohistochemical evaluation of prime molecules in cervical lesions towards assessment of malignant potentiality. AB - Objective: A comparative immunohistochemical evaluation of p63, CD105, and E cadherin expression pattern in histopathologically confirmed normal cervical epithelium (NCM), dysplastic cervical epithelium (DYS) and squamous cell carcinoma (SCC) of uterine cervix towards assessing malignant potentiality of the precancerous condition. Materials and Methods: The biopsies from cervical mucosa (normal, dysplasia, and cancer) were studied by routine hematoxylin and eosin (H and E) and by immunohistochemistry for p63, E-cadherin, and CD105 expression. The expressions of these molecules were assessed in a semiquantitative way by (i) counting p63 cell population and distribution, (ii) intensity scoring of E cadherin along the expression path, and (iii) measuring CD105 expression density. Result: p63+ cells were highest in carcinomas followed by dysplasia and normal. An abrupt increase in CD105 expression was observed through change of normal to dysplasia and cancer. A decrease in membranous E-cadherin expression was noticed in the transformation from normal to precancer and cancers. Conclusion: The malignant potential of the dysplastic conditions is likely to be correlated with upregulation in p63 and CD105 expression and a simultaneous downregulation of membranous E-cadherin. PMID- 29516924 TI - Pattern of invasion as a factor in determining lymph node metastasis in oral squamous cell carcinoma. AB - Context: Lymph node metastasis (LNM) influences survival of oral squamous cell carcinoma (OSCC). Evidence supports the value of prognostic information provided by most aggressive cells that lie in the tumor invasive front. Aims: This study evaluated the clinical and histological parameters (C and HP) that would best associate with LNM in OSCC. Settings and Design: A review of records and histological examination of nonrecurrent surgically treated 182 cases. Subjects and Methods: A review of records and histological examination according to the Bryne's invasive front grading system of nonrecurrent surgically treated 182 cases (pN- =100; pN+ =82) was undertaken. The data were subjected to suitable statistical analysis to check the agreement between observers, association of the parameters to LNM, and to identify the best among all of them. Statistical Analysis Used: Kappa statistics, Pearson's Chi-square, Fisher's exact test, multiple logistic regression analysis. Results: None of the C and HP, with the exception of pattern of invasion (PI) (P = 0.000), modified degree of keratinization and nuclear polymorphism (P = 0.041, 0.022), and total malignancy score for survival (P = 0.013) showed a significant association with nodal status. PI was identified as the most influencing parameter of all. Conclusions: Factor that is primarily the manifestation of tumor and its microenvironment has taken the prime seat followed by the ones that are dictated by the tumor. The factors that are basically quantified were not able to show association. Site influences the nodal status alongside PI. PMID- 29516925 TI - Expression of p53, epidermal growth factor receptor, c-erbB2 in oral leukoplakias and oral squamous cell carcinomas. AB - Background: Oral cancer is a leading cause of cancer in India and contributes to 12% deaths worldwide. The identification of high-risk oral premalignant lesions such as leukoplakia and intervention at premalignant stages could result in significant loss of mortality and morbidity among these patients. The most frequently observed genetic aberrations in these lesions are of mutations in p53, c-erbB2, and epidermal growth factor receptor (EGFR). No specific tumor markers have been identified consistently in oral leukoplakias and the available studies show wide variations in their expression. Materials and Methods: A total of eighty cases were taken up for study which included forty cases of leukoplakia and forty cases of squamous cell carcinomas (SCCs). Results: There was a significant correlation between the expression of markers p53 and EGFR in leukoplakia and SCC. The expression of p53 was correlated between leukoplakia, SCC, and control and was found to be significant (P <= 0.001). Similarly, EGFR expression was significant (P <= 0.001) between cases of leukoplakia, SCCs, and controls. c-erbB2 was found to be negative though cytoplasmic positivity was observed in a few cases. Similarly, in SCCs, it was observed that lesser the differentiation, more is the expression of both p53 and EGFR. Similarly, a definite correlation was observed between p53 and EGFR (P <= 0.001) but not with c-erbB2 (P <= 1.000). Conclusion: Thus, the author concludes that p53 and EGFR are useful biomarkers for the diagnosis of leukoplakia and their risk of malignant transformation. PMID- 29516926 TI - Sonographic imaging of fibrosis of oral mucosa and its correlation with clinical staging in oral submucous fibrosis. AB - Background and Objectives: To evaluate the efficacy of ultrasonography (USG) as a noninvasive tool in assessing the severity of oral submucous fibrosis (OSMF) by measuring the submucosal thickness and also to correlate the sonographic changes with clinical staging. Materials and Methods: The submucosal thickness of the upper and lower labial mucosa, anterior and posterior portions of the right and left buccal mucosa were measured using ultrasound in 64 patients comprising of 32 OSMF patients and 32 controls. Among the controls, 16 were with a habit of chewing gutkha and 16 were without any habit history. Results: In OSMF group, four patients were with Stage I, 13 were with Stage II, 11 were with Stage III, and four with Stage IV. Results were analyzed by one-way analysis of variance for the significance of difference among the groups in submucosal thickness. As the stages of OSMF advanced, there was an increase in submucosal thickness of the buccal mucosa in the study group when compared with controls (P< 0.005). Conclusion: USG is an effective noninvasive zero radiation tool for assessing the progression of OSMF. PMID- 29516927 TI - Correlation between fasting blood sugar and cytomorphometric values of diabetic patient's buccal mucosa exfoliative cytology. AB - Objectives: Type-2 diabetes mellitus (DM) has considerable prevalence in India. A noninvasive diagnostic tool will be more appropriate in conditions like DM. In this study, we intend to find a difference in cytomophometric values, and glycogen accumulation (if any) in buccal mucosa exfoliated cells of type-2 DM patients when compared to nondiabetic healthy individuals, and establish its diagnostic role. Methodology: In the present study, 36 known DM patients with at least 1-year history (case group) and 36 healthy, age- (5 year interval) -matched patients (control group) were included in the study. Patients with any other systemic disease were excluded from the study. Buccal mucosa exfoliative cytology smears were prepared from all 72 patients and stained with Papanicolaou (PAP) stain. The cytomorphometric analysis was performed to evaluate nuclear area (NA), cytoplasmic area (CA), and cytoplasm to nuclear area ratio (CNR) of cells in the smear. The data were tabulated and statistically analyzed using Chi-square test, Student's t-test, Karl Pearson's correlation coefficient and significance (two tailed) test. Results: Statistically significant difference was found in NA and CNR in exfoliative cytology of DM patient group when compared to control group. Fasting blood sugar of DM patients was significantly correlated with NA and CNR of buccal mucosa exfoliated cells. Conclusion: The cytomorphometric changes in exfoliated buccal mucosa cells of type-2 DM patients can have a diagnostic value which needs to be explored further. PMID- 29516928 TI - Cyclin D1 overexpression associated with activation of STAT3 in oral carcinoma patients from South India. AB - Background: Our previous study showed that overexpression of cyclin D1 protein is associated with poor prognosis in oral squamous cell carcinoma (OSCC) patients. Regarding the alteration in the transactivating pathway regulating cyclin D1 expression is still unclear in OSCC from our population. Objectives: The major objective of this study is to understand the alteration associated with the transactivation pathway regulating the cyclin D1 overexpression in OSCC patients from our population. Materials and Methods: Alteration in the transactivation pathway regulating cyclin D1 expression was evaluated in tumor sample from OSCC patients. The findings were further validated using in vitro knockdown model in OSCC cell line. Results: Results from the patients' samples showed that the Phospho-STAT3 has a significant association with cyclin D1 overexpression in OSCC tumor samples. Further knockdown in vitro studies using SCC66 showed a significant correlation between STAT3 and cyclin D1 in OSCC. Conclusion: The results from this study showed that in our population the cyclin D1 overexpression is associated with hyperactivation of STAT3 pathway. Our previous result has shown that the cyclin D1 protein overexpression is associated with poor prognosis in OSCC patients. Hence, STAT3 pathway will be better target for the patients with increased cyclin D1 in OSCC patients from our population. PMID- 29516929 TI - Candidate biomarkers predictive of anthracycline and taxane efficacy against breast cancer. AB - Background: Since breast cancer shows diversity in clinical behaviors, a standard therapy does not always lead to favorable outcomes. Materials and Methods: The expression statuses of candidate markers, including topoisomerase-II alpha (TOP2A), beta-tubulin (B-tub), and tissue inhibitor of metalloprotease-1 (TIMP 1), were immunohistochemically evaluated in 70 breast cancer tissues from 68 patients with advanced breast cancers receiving chemotherapy. Results: The response rates to anthracycline and taxane were 70.5% and 67.2%, respectively. Overall, 25.1% +/- 29.7%, 8.32% +/- 10.1%, and 16.37% +/-17.5% of cancer cells in the tumors studied were positive for B-tub, TOP2A, and TIMP-1 expressions, respectively. However, positive molecule expression did not differ between patients who did and did not exhibit clinical responses to treatment. The proportion of TOP2A-positive cancer cells was significantly higher among anthracycline responders than among nonresponders in HR-negative cancer (15.4% +/ 17.5% vs. 2.0% +/- 2.4%, respectively, P = 0.048), whereas TOP2A and TIMP-1 expression statuses did not differ in HR-positive cancer. When patients were stratified according to B-tub, TOP2A, or TIMP-1 expression statuses (B-tub >=10% vs. <10%, TOP2A >=5% vs. <5%, TIMP-1 <=20% vs. >20%, respectively), the proportion of patients with >=10% B-tub-positive cancer cells was significantly higher in taxane responders than in nonresponders (72.4% vs. 37.5%, respectively, P = 0.016). Anthracycline responders showed a trend to have a higher proportion of patients with either >=5% TOP2A-positive cancer cells or <=20% TIMP-1-positive cancer cells compared to nonresponders (86.7% vs. 61.5%, respectively, P = 0.066). Conclusion: Immunohistochemical TOP2A, TIMP-1, and B-tub expression analyses are expected to be useful for predicting tumor responses to chemotherapy. PMID- 29516930 TI - Evaluating factors affecting survival in colon and rectum cancer: A prospective cohort study with 161 patients. AB - Context: Colorectal cancers are frequent among cancers of gastrointestinal system. Whether there are any differences between survival in rectum and colon cancer patients is controversial. Aims: In this study, we aimed to compare survival in surgically treated rectum and colon cancers and determine the factors affecting survival. Subjects and Methods: The patients with colon and rectum cancer operated between 2009 and 2013 were examined retrospectively using prospective database. Patients were categorized as colon and rectum according to the tumor's location. Survival was identified as the primary outcome. Kaplan Meier survival analysis and log-rank tests in survival assessment were used. Results: One hundred and sixty-one patients with a mean age of 62.8 +/- 12.7 years were included in the study. Male/female ratio was 1.6. Colon and rectum patients were counted as 92 (%57.1) and 69 (%42.9), respectively. Both groups were similar in demographic data (P > 0.05). It was observed that in 46 months (mean) of follow-up, 39.7% (n: 64) died, and 60.3% (n: 97) survived. Median survival time was 79 months, and 5-year cumulative survival rate was 60.8%. Five year cumulative survival rates in stages for 1, 2, 3 and 4 were 88.2%, 64.7%, 48.5%, and 37.0%, respectively. It was noted that median survival time for colon cancer was 78 months and for rectum cancer was 79 months. Five-year cumulative survival rates for colon and rectum cancers were calculated as 56.7% and 63.4%, respectively. There were no significant differences in colon and rectum cancers in the means of survival rate (P: 0.459). Conclusions: While location of colorectal cancers shows no significant effect on survival, treatment in the early stages increases survival rate. PMID- 29516931 TI - Comparison of immunohistochemical expression of vascular endothelial growth factor and CD105 in oral squamous cell carcinoma: Its correlation with prognosis. AB - Objectives: Compare and correlate immunoexpression of vascular endothelial growth factor (VEGF) and CD105 in oral squamous cell carcinoma (OSCC), and correlate its expression with the prognosis of the patient. Materials and Methods: A retrospective study was carried out on total of 49 cases of OSCC. Detailed demographic and clinical data were obtained, and tissue sections were stained with hematoxylin and eosin to grade the tumor. Later each case was subjected for immunohistochemical analysis of CD105 and VEGF. Results: All the cases showed positivity for both CD105 and VEGF but high expression was noted with CD105 compared to VEGF. Average microvascular density for CD105 was higher (69.5) in moderately differentiated squamous cell carcinoma (MDSCC) when compared to well differentiated squamous cell carcinoma (WDSCC) (52.16). When expression of CD105 and VEGF was compared in WDSCC and MDSCC, it was statistically insignificant. However when expression of CD105 and VEGF was compared with survival of the patient, survival rate was <2 years in CD105 and was statistically significant, but VEGF did not show any significant difference with survival rate. Conclusion: CD105 immunoexpression in OSCC predicts a poor outcome than VEGF. So it can be postulated that endoglin may have a particular role in the development of cancer and might be relatively more specific than commonly used endothelial markers for squamous cell carcinoma of the oral cavity. PMID- 29516932 TI - Evaluation of serum levels of oxidized and reduced glutathione and total antioxidant capacity in patients with head and neck squamous cell carcinoma. AB - Background and Aim: Squamous cell carcinoma (SCC) is the most common type of oral cancer, and it is important for it to be diagnosed in early stages. Researchers are interested in exploring the possibility of using biomarkers in the diagnosis of SCC in early stages. One of the detectable biomarkers in the serum is glutathione. Glutathione includes two forms: reduced form (or GSH) and oxidized form (or GSSG). The GSH/GSSG ratio tends to decrease in severe oxidative stress. The aim of this study was to assess the serum levels of GSH and GSSG as well as GSH/GSSG as total antioxidant capacity in patients with head and neck SCC (HNSCC) and to subsequently compare them with healthy controls. Materials and Methods: Twenty HNSCC patients as well as twenty healthy controls were included in the study. A blood sample of 5 ml was obtained from both the case and control groups. GSH, GSSG, and total antioxidant capacity were measured spectrophotometrically. Results: No significant difference in the level of GSSG was observed in the patients from the case and control groups (P = 0.796), whereas the level of GSH and GSH/GSSG was significantly lower in the case group (P = 0.002, P = 0.011, respectively). There was no significant relationship between the level of GSH, GSSG, and total antioxidant capacity, on the one hand, and the stage and grade of the tumor, on the other hand. Conclusion: Since the levels of GSH and GSH/GSSG were significantly lower in the case group, GSH/GSSG could be used as a prognostic factor for the early diagnosis of HNSCC. PMID- 29516933 TI - Does preoperative neutrophil/lymphocyte rate have an effect on survival of the bladder cancer patients who received radical cystectomy? AB - Introduction: Radical cystectomy (RC) is the standard treatment model in invasive bladder cancer patients. Risk definitions before RC is mainly based on pathological results. Neutrophil/lymphocyte (N/L) rate is one of the inflammation markers. Some other studies reported negative prognostic results with increased N/L rates. In our study, we reviewed the relationship between preoperative N/L rate and clinicopathological results following RC. Materials and Methods: Data gathered from 296 bladder cancer patients that received RC between 2002 and 2012 were retrospectively reviewed. All patients received preoperative routine hematological and biochemical tests and metastasis screening. All patients were treated with radical cystoprostatectomy and standard pelvic lymph node dissection. The cutoff value for N/L rate was calculated using a web-based "cutoff finder" software. Results: Patient mean age was calculated as 65.7 years. Mean follow-up period was 24.5 (2-84) months. Cancer-related death was seen in 132 (44.6%) patients. Multivariate analysis showed age, lymph node metastasis, and low N/L rate as significant in cancer-specific survival. Conclusion: In our study, age, lymph node metastasis presence, and preoperative low N/L rates were detected as independent risk factors in RC cases. N/L rate, which is relatively easy to assess during preoperative period, could be beneficial in planning postoperative adjuvant treatments in those patients. PMID- 29516934 TI - Patterns of tobacco use in patients with upper aero digestive tract cancers: A hospital-based study. AB - Background: Tobacco use is a major risk factor for increasing the burden of upper aero digestive tract (UADT) cancer in the population of Northeast India. Objective: The objective of this study was to investigate the pattern of tobacco use in different UADT cancer. Materials and Methods: This was a retrospective study of electronically recorded data of the Hospital Cancer Registry for the period of May 2014 to December 2014. The UADT cancers were evaluated for gender and age-group distribution, their relative proportion, and association with tobacco use and tobacco-associated risk in males to develop UADT cancers. The type of tobacco usage was clustered as chewable, smoking, and both. Relative risk (RR) of UADT with tobacco usage was identified for males. Results: A total of 1965 (n) UADT cancer patients were identified, male:female was 2.9, tobacco habits was in 1608 (81.8%) patients, both forms of tobacco use in 705 (43.8%), chewable tobacco use in 588 (36.6%) and smoking in 315 (19.6%) patients, tobacco habits in males ranges from 67.3% to 94.3% and in females range from 5.7% to 32.7%, RR of UADT cancer in males for tongue cancer was 1.5 (confidence interval [CI] =1.2-1.9), oropharynx was 1.4 (CI = 1.0-1.8), hypopharynx 1.4 (CI = 1.1 1.7), esophageal cancer was 1.4 (CI = 1.3-1.7), and for laryngeal cancer RR was 1.7 (CI = 1.0-3.0). Conclusion: Consumption of chewable tobacco is the major form of tobacco use alone or in combination in UADT cancer patients of our population. PMID- 29516935 TI - Disseminated cystic nodal metastasis in renal cell carcinoma mimicking systemic hydatidosis on imaging. AB - Cystic metastases in renal cell carcinoma (RCC) are very rare. Very few case reports can be found in literature. Retroperitoneal cystic nodal metastases have been reported in head and neck tumors. We present a very interesting case of RCC that had disseminated intraperitoneal and retroperitoneal cystic metastases that mimicked systemic hydatidosis. A detailed color Doppler sonography was followed by plain and contrast-enhanced computed tomography on a 64-slice multi-detector scanner. Imaging features were more in favor of right RCC with cystic lymph nodal metastasis. However, rare possibility of incidental hydatid disease with RCC could not be ruled out. Biopsy from left inguinal lymph nodes was taken, which confirmed metastatic deposits from RCC. PMID- 29516936 TI - Giant cells in soft tissue tumors! Is it a clue to diagnosis or cytologists mystery??? An unusual case report. AB - Giant cells in soft tissue (ST) tumors are rare, pose great challenges to treating clinicians, and diagnosing pathologists. Common lesion with giant cells includes benign conditions such as nodular fasciitis to highly malignant lesions such as giant cell variant of malignant fibrous histiocytoma and extraskeletal osteosarcoma. Giant cell tumors of ST, extension of bony lesion to the ST are also rare possibilities. Recently, giant cell fibroblastoma and dermatofibrosarcoma protuberans have also been added to this list. These tumors show unpredictable behavior; some patients are cured by simple surgical excision whereas others develop metastasis. Diagnosing these in cytology is still more challenging. We report here a rare case of a giant cell-rich dermatofibrosarcoma protuberans in a 23-year-old male who presented with ST lesion in left forearm since 6 months. The lesion was predicted in fine-needle aspiration cytology and confirmed later with histopathology. When evaluated along with clinical features, the cytological features are very useful to distinguish between these tumors with giant cell morphology. PMID- 29516937 TI - Bone metastases without primary tumor: A well-differentiated follicular thyroid carcinoma case. AB - Metastases to the bone are the most common malignant bone tumors. Prostate, breast, and lung carcinomas are the most common primaries of bone metastases. Bone metastases show poor prognosis in means of median survival; however, some patients with highly curable tumors such as thyroid carcinoma may benefit from treatment. We report and discuss a unique case of a 70-year-old female patient presenting with arm pain, diagnosed with metastatic well-differentiated follicular carcinoma without a primary tumor in the thyroid. PMID- 29516938 TI - Carcinoma esophagus with xeroderma pigmentosa: Case report on a rare association. AB - Radiation in patients with diseases such as xeroderma pigmentosa (XP), systemic lupus erythematosus, and other connective diseases is a matter of concern because of higher incidence of toxicities. Here with, we are reporting a case of carcinoma esophagus with XP, who tolerated the treatment well with sufficiently prolonged palliation of symptoms, after treatment with external beam radiotherapy. This might be attributed to the different mechanisms of DNA damage and repair mechanisms for ultraviolet (UV) rays and X-rays. UV rays cause DNA damage by dimer formation whereas X-rays will cause single- or double-stranded breaks in DNA. The repair mechanisms for UV rays are nucleotide excision repair and translesion synthesis while for X-rays, they are base excision repair, homologous recombination, and nonhomologous end joining, and these repair mechanisms for X-rays are intact in a XP patient. Hence, they can be been treated with high dose of radiation, and they do tolerate the treatment well. PMID- 29516939 TI - Verruca vulgaris of the buccal mucosa: A case report. AB - Oral verruca vulgaris is caused by human papillomavirus (HPV) infection. Verruca vulgaris most frequently occurs on the fingers, toes, soles, and dorsal surfaces of hands and is mostly asymptomatic. Varieties of verrucous and papillary lesions affect the skin as well as oral mucosa which may be either benign or reactive. Common wart is one of the most commonly observed skin growths and a lesion of childhood. Intraoral warts can occur at any age with equal incidence in both genders but are most commonly seen in the third to fifth decade. It is found commonly on the palate followed by lip, tongue, buccal mucosa, and rarely seen on gingiva. Surgical excision with adequate margins is the treatment of choice. PMID- 29516940 TI - Renal cell carcinoma presenting with heart metastasis without inferior vena caval and right atrial involvement. AB - Heart metastasis of renal cell carcinoma (RCC) without vena cava inferior involvement is exceptionally rare. Here, we presented a case of RCC presenting with the right ventricle metastasis without inferior vena caval and right atrial involvement. PMID- 29516941 TI - Cytological and histological correlation of granular cell tumor in a series of three cases. AB - Granular cell tumor (GCT) is an uncommon soft tissue tumor characterized by proliferation of cells with granular eosinophilic cytoplasm. We came across three such tumors, one in the tongue, one in the chest wall, and one in the right deltoid region, which were referred for fine-needle aspiration cytology. On cytological examination, the first two cases were diagnosed as GCT, and the mass in deltoid region was suggestive of proliferative myositis. The cytological details of these cases are discussed. The excision biopsies of the first two cases and Tru-cut biopsy of the deltoid mass confirmed the diagnosis of GCT. PMID- 29516943 TI - Aggressive laryngeal fibromatosis: A case report and brief review. AB - We describe a rare case of aggressive fibromatosis of the larynx occurring in a 72-year-old man. The lesion manifested with complaints of dyspnea and stridor. A computerized tomographic scan of the neck revealed irregular polypoidal growth invading right vocal cord, crossing midline. A malignant tumor was suspected. Although several laryngoscopy-driven biopsies were negative for malignancy, total laryngectomy was done since the lesion was not deemed amenable to conservative therapy. Tissue sections featured a moderately cellular lesion composed of spindle cells with bland, elongated nuclei, enmeshed in a variably collagenized ground substance. The spindle cells were immunopositive for vimentin and negative for cytokeratins, PGP-9.5, smooth muscle antigen, CD68, desmin, and S-100 protein and Ki-67 of 4%. No further therapy was administered. Based on the available literature, our data confirm that aggressive laryngeal fibromatosis in adult patients is a locally infiltrating disease. Total laryngectomy with clear margins is needed as to avoid the high risk of local recurrence. PMID- 29516942 TI - Treatment of breast cancer in a patient of Alport syndrome-induced chronic renal failure: A triumph story. AB - Alport syndrome is a hereditary disease of the glomerular basement membrane, characterized by the familial occurrence of progressive, hematuric nephropathy with sensorineural deafness. We are reporting here a young adult female, suffering from Alport syndrome with significant family history and on maintenance twice-weekly hemodialysis (HD), had been diagnosed with triple negative earlystage right-sided breast cancer. The patient was managed successfully with surgery and adjuvant chemotherapy with 3 cycles of 5-flurouracil, doxorubicin, and cyclophosphamide and 3 cycles of docetaxel. In this case, our clinical challenge was dose reduction of chemotherapeutic agents according to creatinine clearance and timing of HD in each cycle of chemotherapy. We confronted this by dose reduction of cyclophosphamide and timing of chemotherapy was at least 12 h after HD for each and every cycle. Patient is in regular follow-up in our department since 20 months without any recurrence of the disease. PMID- 29516944 TI - Clear cell adenocarcinoma of the urethra with inguinal lymph node metastases: A rare case report and review of literature. AB - Urethral cancer is a rare malignancy with urothelial subtype being the most common followed by adenocarcinoma. In women, the usual presentation is urinary retention and hematuria. Clear cell variety of adenocarcinoma is a rarer entity which usually has a better prognosis than other variants. Lymph node metastasis is seen in about 30% of urethral cancers. Histopathological differential diagnosis includes Skene gland carcinoma and nephrogenic adenoma. Herein, we present a 58-year-old female patient who presented for evaluation of lymph node mass in the inguinal region. The detailed evaluation revealed clear cell adenocarcinoma of the urethra as the primary with lymph node metastasis. PMID- 29516945 TI - Parosteal osteosarcoma of mandible: A rare case report. AB - With the exception of multiple myelomas, osteosarcoma is the most frequently occurring primary malignant bone tumor with an overall incidence of 1:100,000/year. It has greatest predilection for the metaphyses, most frequently femur and tibia. However, osteosarcomas affecting the craniofacial bones are infrequent. Two main types: intramedullary and juxtacortical varieties are seen. Juxtacortical variety is further subdivided into periosteal and parosteal variants. Due to its rarity, only 13 cases of parosteal osteosarcoma have been reported till date. A 35-year-old male patient with affected postirradiated mandible is being reported as the 14th case of this kind with its unique benign presentation and less aggressive nature. PMID- 29516946 TI - Circulating miR-21 as novel biomarker in gastric cancer: Diagnostic and prognostic biomarker. PMID- 29516948 TI - Erratum: Dosimetric properties of new formulation of PRESAGE(r) with tin organometal catalyst: Development of sensitivity and stability to megavoltage energy. AB - [This corrects the article DOI: 10.4103/0973-1482.183550]. PMID- 29516947 TI - Pleomorphic adenoma of palate with predominant chondroid tissue: A rarity. PMID- 29516949 TI - Erratum: Comparison of full width at half maximum and penumbra of different Gamma Knife models. AB - [This corrects the article DOI: 10.4103/0973-1482.189248]. PMID- 29516950 TI - Mechanisms correlated with chemotherapy resistance in tongue cancers. AB - Tongue cancer is one of the most common and deadly types of head and neck cancer. The incidence of tongue cancer has been particularly high and remained been increasing in some countries. A main reason for poor prognosis and clinical outcome for tongue cancer was its resistance to chemotherapies, behind which the mechanisms have been not clear. In this review, we summarized literatures published in recent years and listed the proteins, biomacromolecules, and signaling pathways related to this drug resistance. We hoped that this summary could provide reference for researchers to develop new treatment strategies for tongue cancer. PMID- 29516951 TI - Research progress on the regulation of tumor initiation and development by the forkhead box Q1 gene. AB - Transcription factor forkhead box Q1 (FOXQ1), a member of the forkhead box superfamily, has been involved in various biological processes and plays important roles in tumor initiation and progression. The FOXQ1 protein activated transcription of target genes directly by binding to the promoters of target genes or indirectly by interacting with other transcription factors. FOXQ1 affected the initiation, progression, invasion, and metastasis of many kinds of tumor by promoting the epithelial-mesenchymal transition, regulating cell cycle, promoting cell proliferation, regulating senescence-associated inflammation, and activating many cellular signal pathways. In this review, we have focused on the possible molecular mechanisms for FOXQ1 gene in tumor initiation and progression. Medline literature review related to this subject was performed by the electronically retrieval with the keywords "forkhead box Q1" and "tumor" on PubMed for including previous publications, and then, it further reviewed reference articles on the biological function of FOXQ1 gene and target genes transcription directly regulated by FOXQ1. PMID- 29516952 TI - Expert consensus statement on computed tomography-guided 125I radioactive seeds permanent interstitial brachytherapy. AB - The aim of this study is to develop expert consensus statement for recommendations of patient selection criteria, prescription dose, and procedure of computed tomography (CT)-guided 125I radioactive seeds permanent interstitial brachytherapy. Members of Chinese medical association radiation oncology branch, Chinese medical association radiation therapy professional committee, Chinese cancer society minimally invasive surgery branch seed therapy group, Chinese geriatric cancer society minimally invasive surgery branch, Beijing medical association radiation oncology professional committee, China northern radioactive seeds brachytherapy group formed a committee, which consists of physician members who come from the department of radiation oncology, surgery, intervention, internal medicine, ultrasound, and nuclear medicine. The leader of the group organized experts to write the first draft based on clinical experience and literature review and then sent the draft to the commissioner for consultation, finally reached a consensus. Guidelines for patient selection criteria, prescription dose of 125I seed for different kinds of carcinomas, activity of per seed, and workflow of CT-guided permanent interstitial radioactive seed implantation (RSI) are presented in this study. The procedure of CT-guided RSI comprised eight steps: indication selection, preoperative preparation, preoperative CT simulation and position setup, preplan, intraoperative needle insertion, RSI, postoperative dosimetric evaluation, and follow-up. Patient selection criteria are developed. Guidelines for prescription dose of 125I seed for different kinds of carcinomas, activity of per seed, and workflow of CT guided permanent interstitial RSI are provided. PMID- 29516953 TI - In silico identification of potent small molecule inhibitors targeting epidermal growth factor receptor 1. AB - Background: The receptor tyrosine kinase of the epidermal growth factor receptor (EGFR, ErbB) family played an important role in multisignaling pathways, which controlled numerous biological activities including proliferation, differentiation, apoptosis, etc. EGFR abnormalities have been associated with a variety of human tumors, which was a well-characterized target for cancer treatment. It was known to all that drug repositioning has been considered as a useful tool to accelerate the process of drug development. Materials and Methods: Herein, a total of 1408 small molecule drugs approved by the Food and Drug Administration (FDA) were employed to identify potential EGFR inhibitors by a series of bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations. Results: According to the docking score, five small molecules were chosed for further MD simulations. Following the 5 ns MD simulations, ZINC03830276 (Benzonatate) were finally recognized as "new use" of FDA-approved EGFR-targeting drug. Conclusions: Our findings suggested that the small molecule ZINC03830276 (Benzonatate) could be a promising EGFR inhibitor candidate and may also provide new ideas for designing more potent EGFR inhibitors for the future study. PMID- 29516954 TI - Heparan sulfate D-glucosamine 3-O-sulfotransferase 3B1 is a novel regulator of transforming growth factor-beta-mediated epithelial-to-mesenchymal transition and regulated by miR-218 in nonsmall cell lung cancer. AB - Background: Due to high metastasis and recurrence rate. Recent studies indicated that epithelial-to-mesenchymal transition (EMT) was involved in the progression and metastasis in cancer. Some reports also indicate that HS3ST3B1 played a role in angiogenesis and the proliferation of cancer cells. In this study, we aim to investigate its role in non-small cell lung cancer (NSCLC) . Materials and Methods: All cell lines were purchased from ATCC and cultured in our central lab. RT-PCR was performed to study the expession of HS3ST3B1 in tumors and matched normal tissues. Western-blot was used to investigate the expession of HS3ST3B1 in cell lines. We also used luciferase report system to confirm the regulation of HS3ST3B1 by miR-218 in cells. Results: In this study, we found that HS3ST3B1 was significantly upregulated in NSCLC tissues compared with matched normal tissues (P = 0.02). Its expression was also up-regulated in mesenchymal phenotype of NSCLC cell lines compared with epithelial phenotype (P < 0.05). When TGF-beta was applied to induce the epithelial phenotype to mesenchymal phenotype, it was upregulated compared with previous epithelial cell lines. When HS3ST3B1 was knocked down by specific small interfering RNA in the mesenchymal phenotype, mesenchymal phenotype was transformed to epithelial phenotype. Moreover, we also found that it could be targeted by miR-218 in NSCLC. Conclusion: These findings indicate that HS3ST3B1 is a novel regulator of TGF-beta-mediated EMT and is regulated by miR-218 in NSCLC. PMID- 29516955 TI - Three-dimensional-printed individual template-guided 125I seed implantation for the cervical lymph node metastasis: A dosimetric and security study. AB - Objective: The objective of this study is to evaluate the dosimetric accuracy and pathway safety of the three-dimensional (3D)-printed individual template-guided 125I seed implantation for the treatment of cervical lymph node metastasis. Materials and Methods: A total of 15 consecutive patients with cervical lymph node metastasis were enrolled during September 2015-July 2017 (12 patients had a history of external beam radiotherapy, with the mean dose of 63 Gy), who undergone radioactive seed implantation guided by the 3D-printed individual template. The preplan was completed based on contrast-enhanced computed tomography images, and then, the 3D-printed individual template was printed according to the preplan. After the operation, the real-time dose verification was completed: the D90 was ranged from 60 to 113 Gy with median of 93 Gy and the number of seeds was ranged from 21 to 76 with median of 53. To observe the intraoperative complications and postoperative complications in 3 days, we collected and compared the deviation of the number of seeds, target volume, and dosimetric parameters (D90, V90, V100, and V150) between preplan and postoperative plan. Result: Intraoperatively, each template was observed to exactly fit and lock on the lamina, and the operation was successfully completed. No intraoperative complications and postoperative complications were observed in 3 days. There was no significant difference in P values between the two groups for all the parameters (P > 0.05). Conclusion: The 3D-printed individual template guided 125I seed implantation for the cervical lymph node metastasis has not only reduced the dosimetric differences between pre- and postplan but also lowered the difficulty of puncture, indicating that it was a safe and accurate guidance approach. PMID- 29516956 TI - Use of simultaneous radiation boost achieves high treatment response rate in patients with metastatic gastric cancer. AB - Objective: Intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) could improve local control rates at different anatomic sites. However, little is known for its use in metastatic gastric cancer. Our study aimed to compare the treatment response rates of IMRI-SIB and conformal radiotherapy (CRT) in patients with metastatic gastric cancer. Materials and Methods: We retrospectively identified twenty patients with metastatic gastric cancer from 2013 to 2015, 12 given IMRT-SIB, and eight given CRT. Treatment response and toxicities were evaluated for all patients. The radiation target included peritoneal lymph nodes. RECIST criteria were used to assess the treatment response. Three patients of eight in the CRT group died before the end of treatment due to the progression of diseases in the field. Results: For the IMRT-SIB group, the median dose of high dose field was 60.8 Gy (50-64.4 Gy), and the median dose of low-dose field was 45 Gy (36-50.4 Gy). For the CRT group, the median dose of the total dose was 50 Gy (41.4-60 Gy). IMRT-SIB could elevate local dose significantly, compared to the CRT group. One patient of 12 in the IMRT-SIB group achieved complete response, and nine patients achieved partial response (PR), whereas no patient achieved CR in the CRT group. Two of five patients achieved PR (40%) in the CRT group. IMRT-SIB improved the treatment response rate significantly (odds ratio 8.33, 95% confidence interval: 1.03 67.14, P = 0.046). Two patients of 12 in the IMRT-SIB group developed enteritis, whereas two patients of five developed enteritis in the CRT group. Conclusions: IMRT-SIB could escalate the local dose and improve the treatment response rates in patients with metastatic gastric cancer and with acceptable toxicities. Further study with a larger population to validate our data is underway. PMID- 29516957 TI - Dynamic changes of T-cell subsets and their relation with tumor recurrence after microwave ablation in patients with hepatocellular carcinoma. AB - Aims: Thermal ablation can evoke an immune response, which may have effects on the prognosis of patients with hepatocellular carcinoma (HCC). Our aim is to investigate the changes of circulating T-cell subsets after microwave ablation (MWA) and to explore the risk factors of tumor recurrence in patients with hepatitis B virus (HBV)-related HCC. Methods: Thirty patients with HBV-related HCC were enrolled in this study. The blood samples were collected both before and after MWA (24 h, 72 h, and 1 month after MWA). The distributions of Th17 cells, regulatory Treg-cells, CD4+ T-cells, CD8+ T-cells, and CD3+ T-cells were determined by flow cytometer. The potential-related factors of tumor recurrence were analyzed by logistic regression. Results: The levels of circulating T-cell subsets, except for Th17 cells, were relatively stable after MWA. The frequency of Th17 cells increased from 3.98% +/- 2.40% before treatment to 5.53% +/-3.27% 24 h after treatment. Eight of 30 patients had a tumor recurrence. The results of logistic regression suggested that among 11 candidates, only the level of Th17 cells was the risk factor of tumor recurrence. To remove the interference from other factors, seven patients with tumor(s) >3 cm or alpha-fetoprotein >400 ng/mL were excluded in another parallel logistic regression. The results of such regression clearly demonstrated that circulating Th17 cells is indeed a related factor of tumor recurrence. Conclusions: Thermal ablation may evoke a transitional immune response by increasing the frequency of Th17 cells. Patients with high levels of baseline circulating Th17 cells, instead of the transient elevation of Th17 cells induced by MWA, are at the risk of tumor recurrence. PMID- 29516958 TI - The role of NRAGE subcellular location and epithelial-mesenchymal transition on radiation resistance of esophageal carcinoma cell. AB - Background: Neurotrophin receptor-interacting MAGE homolog (NRAGE) has been considered as a tumor suppressor. In the previous study, we established human esophageal carcinoma resistance cell line TE13R120 and found the difference of NRAGE expression between TE13 and TE13R120 cells by gene microarray. Herein, we further discuss the possible molecular mechanism of NRAGE on participating the radiation sensitivity of esophageal carcinoma cells. Materials and Methods: We used colony formation assay to measure the surviving fraction and relevant radiobiological parameters. NRAGE expression was estimated by immunofluorescence and Western blot. Tumor growth factor-beta (TGF-beta) was used for inducing epithelial-mesenchymal transition (EMT) in TE13 cells to detect the relationship between NRAGE and EMT; the capacity of cell migration was also assessed by wound healing assay. Results: TE13R120 cells were showed significantly radioresistance compared with TE13. The D0, Dq, and N value of TE13R120 were all higher than those of TE13 (2.499, 1.991, and 2.219 vs. 2.242, 0.854, and 1.645), as well as SF2 (0.734 vs. 0.538). Results of immunofluorescences showed that NRAGE was mainly expressed in the nucleus of TE13R120 cells, but in TE13 cells, it was mainly in cytoplasm. In addition, EMT phenotype was observed in TE13R120 cells and TGF-beta-induced EMT in TE13 cells, E-cadherin expression was decreased, but vimentin was upregulated. Furthermore, TE13 cells have a rising tendency in NRAGE nucleus expression after treatment with TGF-beta. Results of wound healing assay showed that the cell migration of TE13R120 and TGF-beta-induced EMT in TE13 cells were remarkably enhanced. Conclusions: Our results indicate that NRAGE subcellular localization is related to radiation resistance of esophageal carcinoma cell and EMT may be involved in NRAGE subcellular location. PMID- 29516959 TI - Clinical efficacy of endoscopic submucosal dissection in the treatment of early esophageal cancer and precancerous lesions. AB - Objective: The objective of this study was to evaluate the clinical value of endoscopic submucosal dissection (ESD) in the treatment of early esophageal cancer and precancerous lesions. Materials and Methods: We retrospectively analyzed 58 patients who suffered from early esophageal and precancerous lesions and received ESD in the First Affiliated Hospital of Zhengzhou University from February 2012 to January 2016. The clinical efficacy and safety of ESD in treating the early esophageal cancer and precancerous lesions was evaluated by analyzing the operation successful rate, postoperative pathology, complications, and follow-up data of patients who received ESD. Results: For the 58 patients, ESD was successfully completed in 56 cases with a success rate of 96.6%, whereas ESD was unsuccessful in 2 cases. Invasive lesions were observed in the esophageal muscular layer of 1 patient. Consequently, surgery was terminated and this patient was transferred to thoracotomy surgical intervention involving radical resection of esophageal cancer. Esophageal perforation was observed during the annular incision of the esophageal mucosa in another patient with early-stage cancer. This perforation was occluded with an endoscopic titanium clip and surgery was terminated. Intraoperative blood loss in 56 patients was ranged from 10 to 90 mL with an average of 28.3 +/- 17.2 mL. The diameter of ESD resection lesion was varied from 2 to 6.0 cm with an average of 3.4 +/- 1.1 cm. For the 56 patients, enbloc resection was performed in 50 patients, with an enbloc resection rate of 89.3%. Complete lesion resection was performed in 49 patients, with a complete resection rate of 87.5%. For all patients, 36 manifested with severe atypical hyperplasia confirmed by postoperative pathology, 11 showed moderate atypical hyperplasia, 2 showed carcinoma insitu, and 7 presented with esophageal squamous cell carcinoma. In these 7 patients, 6 patients whose lesions limited to their mucosa were in the early stage of cancer while 1 patient with esophageal cancer involving the incisal edge, and the submucosal layer was subjected to additional surgical treatment. In addition, 1 patient experienced postoperative delayed hemorrhage (1.79%), 6 patients suffered from fever (10.71%), 33 patients reported substernal burning pain (58.93%) that mostly lasted 1-2 days before spontaneous remission, 1 patient was observed intraoperative perforation (1.79%), and 3 patients showed postoperative esophageal stenosis (5.36%), received multiple balloon dilatations, and consumed fluids afterward. Follow-up visits were facilitated for 49 patients for more than 1 year, and their median follow-up time was 36 months. Of these patients, recurrence was observed in 3 patients, with a recurrence rate of 6.1% (3/49). Of these 3 patients, 2 received surgical treatment and 1 underwent another endoscopic lesion resection. No patient died of esophageal cancer during follow-up. Conclusion: ESD was safe and reliable for the treatment of early esophageal cancer and precancerous lesions, and its recurrence and complication rates were low. Complete pathological information could be obtained after operation, which could be applied to assess patients' condition accurately. PMID- 29516960 TI - The application value of capsule endoscopy in diagnosing small intestinal carcinoma. AB - Objective: The aim of this study was to explore the clinical value of capsule endoscopy in the diagnosis of small intestine neoplastic lesions. Materials and Methods: A retrospective analysis was conducted on the clinical data of 108 patients who underwent capsule endoscopic examination in the Endoscopy Center of Xinxiang Central Hospital from February 2010 to January 2014. The characteristics of different small bowel diseases were observed, and the prevalence rates of different small bowel lesions were calculated. Results: Of the included 108 patients who received capsule endoscopic examination, 74 cases showed lesions, with a detection rate of 68.52%. Of these 74 patients, 56 cases (51.85%) suffered from small bowel diseases and 18 cases (16.67%) were manifested with other gastrointestinal lesions. Moreover, obvious lesion was not observed in 34 cases (31.48%). Among the patients with lesions, we observed seven cases of submucosal tumor in small intestines, five cases of small intestinal carcinoma, two cases of small intestinal polyps, two cases of small intestinal roundworm, eight cases of small intestine ulcer, one case of Crohn's disease, 18 cases of enteritis, two cases of small intestine diverticula, four cases of small intestine hemangioma, one case of small intestine vascular malformation, one case of intestinal lymphangiectasia, one case of small intestine compression, two cases of small intestine hemorrhage, and two cases of small intestinal lipoma. Among the patients who showed other gastrointestinal lesions, we observed one case of esophageal diverticula, three cases of gastric erosion, six cases of superficial gastritis, four cases of gastric ulcer, one case of pyloric ulcer, one case of colonic polyps, and two cases of colon tumor. Conclusion: Capsule endoscopy demonstrated a high diagnostic value for various small bowel diseases, including both tumor and inflammatory lesions. Given its simplicity, safety, and reliability, capsule endoscopy was an important examination tool for the diagnosis of small bowel diseases. PMID- 29516961 TI - Role of inferior phrenic artery in the interventional treatment of lung metastases tumor: A report of 11 cases. AB - Background: Lung metastases have been very common in advanced cancer, which were observed in 30%-40% of cancer cases. Transarterial chemoembolization (TACE) is one of the choice for treating lung cancer. In our center, 119 cases of lung metastases were treated with TACE, and we found that inferior phrenic artery (IPA) played an important role in this procedure. Materials and Methods: From June 2011 to June 2015, 119 cases with malignant lung metastases received TACE procedure in our center. The TACE procedure was performed through bronchial artery (BA) and collateral arteries. In these 11 cases, we found that part of metastatic lesions was supplied by the IPA. Angiography and embolization technique, successful rate, safety and clinical adverse events, and survival were retrospectively studies. Results: The lung metastases were mainly supplied by BA, thoracic artery, and intercostal artery. In 11 cases, the IPA was involved in the blood supply of lung metastases (9.2%). Right IPA (RIPA), left IPA (LIPA), and both LIPA and RIPA were involved in blood supply of 6, 3, and 2 cases of lung metastases, respectively, especially for the lesions located in the lower lobe of the lung. All lesions of the 11 cases were successfully embolized; no diaphragmatic dysfunction and spinal cord injury or other serious complications were observed. The average survival time was 14.7 months since the diagnosis of lung metastases. Conclusion: The IPA was an important feeding artery for lung metastases, especially for lesions in the lower lung lobe. It should be searched as much as possible for achieving complete embolization of metastases. PMID- 29516962 TI - Increasing rates of Acinetobacter baumannii infection and resistance in an oncology department. AB - Objective: Acinetobacter baumannii is an opportunistic pathogen found in immunocompromised patients, especially cancer patients. This study was to investigate the clinical characteristics of cancer patients and the antimicrobial resistance of A.baumannii isolates. Materials and Methods: Clinical isolates were collected from the oncology department of a general teaching hospital, and the clinical and demographic information of patients was obtained from the hospital's information system. Antimicrobial susceptibility was examined using the agar dilution method. Carbapenemase-encoding genes were amplified by polymerase chain reaction, and sequence types were determined by multilocus sequence typing. Results: The isolation rate of A.baumannii increased annually in the oncology department. Multivariate analysis showed that only prior antibiotic use was an independent risk factor for A.baumannii infection. The use of antibiotics in A.baumannii-infected patients was significantly more frequent than in non A.baumannii-infected patients. A.baumannii isolates were highly resistant to most tested antibiotics. The IMP-4 and VIM-2 genes were present in 6 and 2 isolates, respectively. Sixty isolates had 12 genotypes, and ST208 was the most common genotype. Conclusion: Our results suggest that the use of antibiotics and hospital environmental pollution may be the main causes of A. baumannii infection. PMID- 29516963 TI - Relationship between resilience, social support as well as anxiety/depression of lung cancer patients: A cross-sectional observation study. AB - Objective: The mood of patients with lung carcinoma would be greatly influenced by the diagnosing and treating processes. This study was aimed to explore the effects of resilience between social assistance and anxiety/depression of patients with lung cancer, which may assist in clinical intervention. Design and Methods: A cross-sectional pilot study was conducted on lung cancer patients at Xiangya Hospital of Central South University, China. A total of 289 patients aged 25-81 years were included in this study. Results: Correlational analyses revealed that anxiety/depression was negatively associated with psychological resilience and each dimension of social assistance, including subjective support, objective support along with the supports utilization (P < 0.01). Furthermore, psychological resilience was positively related to subjective support (P < 0.01), support utilization (P < 0.01) along with objective support (P < 0.05). Mediational analyses showed that, on the one hand, resilience could partially mediate the relation between anxiety and subjective support and totally mediate the relationship between support utilization and anxiety. On the other hand, resilience could totally mediate the relation between depression and subjective support and partially mediate the relation between support utilization and depression. However, resilience did not play an intermediary role between anxiety/depression and objective support. Conclusion: Lower psychological anxiety and depression would be experienced by lung cancer patients with higher resilience and social support. The level of anxiety and depression would be indirectly affected by social support through the mediation of resilience. PMID- 29516964 TI - Enhanced antitumor effects of radiotherapy combined local nimustine delivery rendezvousing with oral temozolomide chemotherapy in glioblastoma patients. AB - Background: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery. Methods: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded. Results: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS >=70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process. Conclusions: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities. PMID- 29516965 TI - Preablation neutrophil-to-lymphocyte ratio as an independent prognostic factor in locally advanced hepatocellular carcinoma patients following radiofrequency ablation. AB - Background and Aims: Neutrophil-to-lymphocyte ratio (NLR), as an inflammation based marker, plays critical roles in hepatocellular carcinoma (HCC). This study was aimed to investigate the prognostic value of preablation NLR in locally advanced HCC patients following radiofrequency ablation (RFA) and to determine an optimal cutoff value for NLR. Materials and Methods: From September 2008 to May 2017, 402 locally advanced HCC patients treated with RFA were retrospectively evaluated. Several prognostic factors including NLR was assessed with univariate and multivariate analysis. The optimal cutoff value of NLR was determined with a maximally selected log-rank test. Other prognostic factors influenced the overall survival (OS) were also evaluated. Results: Based on the univariate analysis of 16 prognostic factors for OS, the type of hepatitis, a-fetoprotein (AFP), NLR, alanine aminotransferase, aspartate aminotransferase, and serum albumin were identified as independent prognostic factors; and based on multivariate analysis of 6 prognostic factors for OS, AFP, and NLR were identified (P < 0.05). A NLR of 2.2 was determined to be the optimal cutoff value (area under the curve = 0.855, P < 0.001). In a comparison between the high NLR group and the low NLR group, there was a difference of 7 months in the median OS (24 vs. 31 months, P < 0.001). Conclusions: Preablation NLR was a valuable predictor in locally advanced HCC patients treated with RFA. NLR >=2.2 indicated a poor prognosis. These findings suggested that preablation NLR may be a convenient, easily-obtained, low cost, and reliable biomarker with prognostic potential for HCC patients. PMID- 29516966 TI - Risk analysis on infection caused by peripherally inserted central catheter for bone tumor patients. AB - Objective: The aim of this study is to explore the related factors affecting infection risk caused by peripherally inserted central catheter (PICC) for bone tumor patients. Method: A retrospective analysis was performed for 223 bone tumor patients who received PICC and were admitted to our hospital from 2004 to 2017. A total of 18 cases (infection group) with PICC catheter-related infections and 205 cases without infection (noninfection group) were studied. First, factor analysis of variance or Chi-square test was applied to compare independent risk factors for PICC catheter-related infections, between bone tumor patients with catheter related infections and those without catheter-related infections. Results: This retrospective analysis involved a total of 18 patients with PICC infections and 205 patients without infections. The infection rate was 8.07%. Factor analysis of variance showed that many factors were related to PICC catheter-related infections, including experience of operator (chi2 = 3.48, P < 0.05), catheter retention time (chi2 = 7.478, P < 0.05), receiving chemotherapy or not (chi2 = 2.43, P < 0.05), Karnofsky Performance Scale scores (chi2 = 2.19, P < 0.05) and the frequency of replacing pad pasting on the point of puncture (chi2 = 2.23). Logistic regression analysis showed that PICC catheter retention time (odds ratio [OR] = 4.21, P < 0.05) and operator experience (OR = 2.80, P < 0.05) were independent factors affected PICC catheter-related infections. Conclusion: Catheter-related infections were related to experience of PICC operatorand length of catheter retention time. PMID- 29516967 TI - Expression and clinical significance of centrosomal protein 55 in T-cell lymphoma. AB - Context: T-cell lymphomas (TCLs) have been heterogeneous lymphoid malignancies with aggressive clinical phenotype and poor prognosis. Centrosomal protein 55 (CEP55) played a critical role in cytokinesis and served as a centrosome- and midbody-associated protein. Previous studies have reported the overexpression and clinical significance of CEP55 in various human malignancies, but the exact biological roles of CEP55 in TCLs remained unclear. Aims: In this study, we aimed to evaluate the CEP55 expression in patients with TCL and reactive hyperplasia of lymph nodes. The correlation between CEP55 levels and clinical characteristics was also explored for TCL patients. For further investigation, the cell viability of TCL cell lines after CEP55 inhibition was also assessed. Subjects and Methods: Immunohistochemistry was applied to assess the elevated level of CEP55 in TCLs. After siRNA treatment, cell viability and apoptotic rate of TCL cell lines were observed with CCK-8 assay and flow cytometry, respectively. Statistical Analysis: The Pearson's Chi-square test or Fisher's exact test was applied to analyze the correlations between CEP55 overexpression and clinical characteristics. All statistical tests were two-sided, and P < 0.05 was considered to be statistically significant. Results: CEP55 was upregulated in TCL patients and significantly correlated with Ki-67 label index. Consistently, cell viability was decreased, and apoptosis was increased after the suppression of CEP55 in TCL cell lines. Conclusions: These results suggested that target CEP55 would be a novel therapeutic strategy for the TCL. PMID- 29516968 TI - Clinical analysis of electroacupuncture and multiple acupoint stimulation in relieving cancer pain in patients with advanced hepatocellular carcinoma. AB - Objective: The objective of this study is to investigate the clinical efficacy and safety of electroacupuncture and multiple acupoint stimulation in relieving cancer pain in patients with advanced hepatocellular carcinoma. Methods: Sixty five cases of advanced hepatocellular carcinoma with cancer pain were selected in our hospital and were divided into electroacupuncture multiple acupoint stimulation group (electroacupuncture group) (n = 32) and fentanyl transdermal patch analgesia group (control group) (n = 33) according to analgesic methods and intentions. In the electroacupuncture group, electric acupuncture treatment was administered at different acupoints, including Baihui, Quchi, Neiguan, Xuehai, Zusanli, and Sanyinjiao acupoint, once a day for 7 days. In the control group, a fentanyl transdermal patch was placed on the upper left arm every 3 days and replaced with a continuous external paste once for 7 days. Pain scores in the two groups before and during the treatment were evaluated with a visual analog scale (VAS), and adverse reactions during the treatment were recorded. Results: The VAS pain score of the electroacupuncture group was significantly decreased on day 3 (P < 0.05), but the pain scores were not significantly different (P > 0.05) between the two groups 4 days after treatment. For treatment-related side effects, there were 3 cases of subcutaneous hemorrhage in the electroacupuncture group; 1 case of skin rashes and 3 cases of nausea and vomiting in the control group. The incidences of adverse reactions in the two groups were 9.4% and 12.1%, respectively, without significant difference (P > 0.05). Conclusion: Cancer pain in patients with advanced hepatocellular carcinoma can be alleviated with electroacupuncture and multiple acupoint stimulation, but the onset pain relief was slow. To improve the analgesic effects of this technique, the combination of various analgesic methods should be necessary in early stage of the treatment. PMID- 29516969 TI - Detection of epidermal growth factor receptor mutation in the peripheral blood of patients with esophageal carcinoma to guide epidermal growth factor receptor tyrosine kinase inhibitor treatment. AB - Objective: This study aimed to explore the epidermal growth factor receptor (EGFR) mutation in the peripheral blood of patients with esophageal carcinoma and analyze the relationship between EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapeutic effect and EGFR mutation in peripheral blood. Methods: A retrospective analysis was performed on 66 patients with esophageal carcinoma treated with EGFR-TKI (Gefitinib) from February 2014 to March 2017 in our hospital. Real-time polymerase chain reaction was applied to detect the mutation of the EGFR gene in peripheral blood specimens before patients were treated with EGFR-TKI. The relationship between EGFR mutation in the peripheral blood and clinical features of patients were analyzed. The correlation between EGFR mutation in peripheral blood and EGFR-TKI treatment response was also demonstrated. Results: Among the 66 patients, 18 cases were determined as EGFR mutation in peripheral blood. The mutation rate was 27.3%. Among these patients, it observed 1 case of exon 18 2155G>A mutation, 3 cases of exon 19 2235-2249Del mutation, 5 cases of 2236-2250Del mutation, 1 case of 2254-2277Del mutation, 1 case of L747-A750Del mutation, 3 cases of exon 21 2576T>G mutation, 3 cases of 2497T>G mutation, and 1 case of 2504A>T mutation. EGFR mutation in the peripheral blood of patients with esophageal carcinoma was unrelated to the gender, age, and the location of the tumor (P < 0.05). By contrast, EGFR mutation was related to the pathological types of the patients (P < 0.05). The mutation rate of the EGFR of squamous cell carcinoma patients was significantly higher than that of adenocarcinoma patients (P < 0.05). Among EGFR wild-type patients, 8 cases were stable disease (SD), and 40 cases were progressive disease (PD), after EGFR-TIK treatment. No complete response (CR) and partial response (PR) patients were reported. The overall response rate (ORR) was 0.0%. Among the EGFR mutation group, 5 were SD cases, 5 were PD cases, and 8 were PR cases. No CR case was reported. The ORR was 44.4%. The ORR of the EGFR group was significantly higher than that of the wild-type group (P < 0.05). Conclusion: The detection of EGFR mutation in peripheral blood can be applied as an effective index for EGFR-TKI (Gefitinib) treatment in patients with esophageal carcinoma. PMID- 29516970 TI - Intra-arterial chemotherapy as second-line treatment for advanced retinoblastoma: A 2-year single-center study in China. AB - Purpose: To evaluate the effectiveness and complications of intra-arterial chemotherapy (IAC) for treating advanced refractory retinoblastoma (RB) in a large single-center cohort. Patients and Methods: Eighty-four eyes of 62 consecutive patients with advanced refractory RB who received IAC were included in the study during January 2013 and April 2015. These patients failed to respond adequately to a standard systemic chemotherapy (i.e., carboplatin, vincristine, and etoposide) with or without local therapy. Clinical outcomes and complications of these patients were reviewed. Results: All of these patients received IAC of melphalan combined with topotecan. The mean follow-up period was 14.2 months after final IAC (ranged from 3 to 28 months). The rate of eye preservation was 41.67% in Group D and 20.83% in Group E of this study. Short-term ocular adverse events included eyelid edema (n = 12, 14.29%), bulbar conjunctiva congestion (n = 25, 29.76%), and excessive tearing (n = 10, 11.90%). Long-term complications included vitreous hemorrhage (n = 7, 8%), subretinal hemorrhage (n = 9, 11%), retinal vasculopathy (n = 6, 7%), and ophthalmic artery spasm with reperfusion (n = 11, 13%). Fever was observed after IAC in 14 patients; transient vomiting was observed in 17 patients; there were 8 cases of transient myelosuppression. Conclusion: IAC can be an optional treatment to save eyes of Group D RB that failed in systemic chemotherapy and were destined for enucleation. However, it should be cautioned for Group E. Both the ocular and systemic toxicities of IAC were within tolerance. PMID- 29516971 TI - miR-150 contributes to the radioresistance in nasopharyngeal carcinoma cells by targeting glycogen synthase kinase-3beta. AB - Introduction: Radiotherapy has been the primary treatment for nasopharyngeal carcinoma (NPC), but the NPC radiocurability was severely limited with the radioresistance. The research suggested the important role of miRNAs in cancer therapeutic response. Materials and Methods: A radioresistant NPC cell line CNE 2R, we exposed CNE-2 cells to a range of radiation doses. Levels of miR-150 were measured by quantitative reverse-transcriptase polymerase chain reaction in CNE 2R and CNE-2 cells. Results: In this study, a cell line CNE-2R derived from parental CNE-2 was established via being exposed to stepwise escalated radiation dose. The expression of miR-150 was upregulated in CNE-2R cells. The radioresistance of CNE-2R cells was reversed after inhibiting miR-150 with specific inhibitor, while the radioresistance of CNE-2 cells was enhanced after the overexpression of miR-150. MiR-150b elicited these responses by directly targeting GSK3beta. Moreover, GSK3beta protein expression was downregulated in CNE-2R cells and restored GSK3beta expression increased radiosensitivity of CNE 2R cells. Importantly, the negative correlation between miR-150 expression and GSK3beta protein level was confirmed in the NPC tissues. High miR-150 expression and low GSK3beta protein level were associated with poor prognosis in NPC patients. Conclusion: Our findings suggested that miR-150-GSK3beta axis may be a novel candidate for developing rational therapeutic strategies for NPC treatment. PMID- 29516972 TI - Lipopolysaccharide promoted the growth rate of MG-63 cells via the extracellular regulated kinase pathway. AB - Objective: The objective of this study is to investigate the effects of lipopolysaccharide (LPS) on the growth rate of MG-63 cells. Materials and Methods: MG-63 cells were exposed to various concentrations of LPS, and the growth rate was determined with the 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. In addition, variations in the phosphorylation state of extracellular regulated kinase (ERK1/2), Jun N-terminal kinase, and p38 were determined by western blotting. Results: There was a correlation between the increased phosphorylation of ERK1/2 and the growth of LPS-treated MG-63 cells. The increased phosphorylation was mediated by the LPS receptor toll-like receptor 4. Conclusions: LPS promoted the growth of MG-63 cells through the ERK pathway. PMID- 29516973 TI - Occludin protein expression in human cervical cancer and its association with patient's clinical characteristics. AB - Objective: The objective of the study was to investigate the expression of the tight junction protein occludin (encoded by OCLN gene) in human cervical cancer and its association with clinical features of patients. Materials and Methods: Sixty-one patients with cervical cancer were included in this study from June 30, 2015 to April 30, 2017. Immuno-histochemical assay was applied to examine the expression of occludin protein in 61 cervical cancer tissues and matched adjacent cancer normal tissues. The association of occludin protein expression with clinical pathology characteristics was analyzed. Results: Occludin protein was mainly expressed in cell membranes and cytoplasm of both the cervical cancer cell and the normal cells. The protein was manifested with brownish-yellow granules. In cervical cancer tissues, the positive rate of occludin protein was 77.05% (47/61), whereas, in adjacent normal tissues of the cancer, the positive rate was 96.72% (59/61). Therefore, the positive rate of occludin in cervical cancer tissues was significantly lower than that of the adjacent cancer tissues (P < 0.05). Occludin protein expression level was not significantly correlated with the age (P > 0.05), tumor size (P > 0.05), International Federation of Gynecology and Obstetrics staging (P > 0.05), pathological grades (P > 0.05), and lymph node metastasis (P > 0.05) of the patients. Conclusion: Occludin protein may contribute to the development of cervical cancer. However, it was not correlated with the clinical features. PMID- 29516974 TI - Multislice spiral computed tomography in the differential diagnosis of ground glass opacity. AB - Objective: This study aimed to evaluate the value of multislice spiral computed tomography (CT) in differential diagnosis of benign or malignant pulmonary ground glass opacity (GGO). Materials and Methods: A total of 68 patients with pulmonary GGO who received surgical treatment in our hospital from January 2014 to January 2017 were retrospectively analyzed. Postoperative pathology showed that there were 22 cases of benign GGO and 47 cases of malignant GGO (adenocarcinoma). The diameter, maximum CT value, and mean CT value of benign and malignant GGOs were determined and compared. The clinical value of identifying benign or malignant GGOs with these indices was analyzed through receiver operating characteristic (ROC) curve. Results: The mean GGO diameter, maximum CT value, and mean CT value in the benign group were significantly lower than those of in the malignant group, and the difference was statistically significant (P < 0.05). The diameter, maximum CT value, and mean CT value of GGO were applied to identify benign or malignant GGO: sensitivity was 60.87%, 69.57%, and 63.04%; and the specificity was 63.64%, 63.64%, and 81.82%; the cutoff values were 13.89 (mm), 26.18 (Hu), and 24.61 (Hu); and areas under the ROC curves were 0.66, 0.71, and 0.69, respectively. Conclusion: The possibility of malignancy has been significantly increased for GGOs with a large diameter, high mean CT value and maximum CT value. Surgical treatment should be performed for this type of GGOs. PMID- 29516976 TI - Meta-analysis of adjuvant chemotherapy versus surgery alone in T2aN0 stage IB non small cell lung cancer. AB - Background: Although there is a strong evidence that adjuvant chemotherapy after surgery was effective in Stages II and IIIA patients involved nonsmall cell lung cancer (NSCLC), its eligibility in Stage IB disease has been unknown. Therefore, this meta-analysis was aimed to compare the effects of adjuvant chemotherapy versus surgery alone in patients with Stage IB NSCLC. Materials and Methods: We systematically searched for articles from their inclusion to July 2016. An article search was performed in PubMed, Embase, Medline, and Cochrane Library. Irrelevant literature was excluded with the preferred reporting items for systematic reviews and meta-analysis standards. Overall survival (OS) was the primary end-point, which was defined as the time from randomization until death from any cause; our second end-point was disease-free survival (DFS). All analyses were based on intention-to-treat. Results: Six randomized controlled trials with total of 2007 patients were included in present meta-analysis. The results were expressed as risk ratios (RR) with 95% confidence intervals (CIs). Compared to surgery alone, patients can benefit from adjuvant chemotherapy after surgery in terms of 5-year OS (RR = 1.19; 95% CI, 1.03-1.37; P = 0.02) and 5-year DFS (RR = 1.36; 95% CI, 1.13-1.63; P = 0.001). There was no significant difference in terms of benefit according to certain patient characteristics, such as age, gender, tumor histology, smoking history, and resection type. Conclusion: Adjuvant chemotherapy after surgery was beneficial to the patients with Stage IB disease in terms of OS and progression-free survival. Therefore, we recommend clinicians to take this treatment strategy into account for the patients with Stage IB NSCLC. PMID- 29516975 TI - Efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization for hepatocellular carcinoma: A meta-analysis. AB - Objectives: This study was aimed to evaluate the efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). Materials and Methods: Studies were searched in Embase, PubMed, and Springer until August 10, 2016. All the studies were screened with inclusion and exclusion criteria. The quality assessment of the eligible studies was performed with the Newcastle-Ottawa Scale and the Jadad Scale. Response rate, recurrence, mortality, and thrombocytopenia were evaluated with risk ratios (RRs) with 95% confidence intervals (CIs). The heterogeneity and publication bias were assessed. Results: Ten eligible studies were included with a total of 993 objects. The data were extracted and summarized. The overall results were calculated including response rate (RR = 0.98, 95% CI: 0.83-1.15), recurrence (RR = 0.75, 95% CI: 0.58-0.96), mortality (RR = 0.71, 95% CI: 0.39 1.28), and thrombocytopenia (RR = 0.42, 95% CI: 0.09-1.93), without significant heterogeneity. There was a significant heterogeneity for mortality; thus, the random effects model was used. No publication bias was observed in this study. Conclusions: The results of meta-analysis indicated that epirubicin applied in TACE has an obvious efficacy for the treatment of HCC, with significantly decreased recurrence while without superiority of safety. PMID- 29516977 TI - Clinical efficacy of endovascular radiofrequency ablation in the treatment of portal vein tumor thrombus of primary hepatocellular carcinoma. AB - Objective: The objective of this study is to investigate the clinical efficacy and safety of HabibTM VesOpen, a new intravascular radiofrequency ablation (RFA) catheter in percutaneous puncture of portal vein tumor thrombus (PVTT) in patients with primary hepatocellular carcinoma. Materials and Methods: Collected data of patients with primary hepatocellular carcinoma with portal vein trunk or main branch who were treated by the RFA of portal vein tumor ablation with HabibTM VesOpen, a new intravascular RFA catheter. The postoperative success rate, complications, liver and kidney function, alpha-fetoprotein (AFP), portal vein patency, and tumor thrombus were analyzed, and the survival status of patients was analyzed by Kaplan-Meier survival analysis, and the COX proportional hazards regression model was used to analyze the factors influencing the clinical prognosis of patients. Results: All the 44 patients were operated successfully without complications such as vascular perforation, infection, liver abscess, and intraperitoneal hemorrhage. The liver function index, alanine aminotransferase, aspartate aminotransferase, and serum albumin (ALB) were significantly different before and after surgery at 2 weeks and 4 weeks after operation (P < 0.05); AFP before and after surgery, the difference was statistically significant (P < 0.05). Doppler ultrasonography showed blood flow through the original portal vein after 4 weeks of surgery; enhanced computed tomography examination or magnetic resonance examination on the abdomen suggested patients with varying degrees of tumor thrombosis or disappearance after 8 weeks of surgery. The overall survival time was 284.72 +/- 27.20 days (95% confidence interval: 231.42-338.02 days). The cumulative survival rates of 90, 180, and 360 days were 97.7%, 72.7%, and 17.2%, respectively. Cox multivariate regression analysis showed that tumor size and the size of ALB before RFA treatment was an independent factor in the prognosis of hepatocellular carcinoma with PVTT ablation (P < 0.05). Conclusions: The use of HabibTM VesOpen intravascular RFA catheter percutaneous puncture of the portal vein tumor RFA has positive clinical effect which is safe and reliable, expected to become one of the effective means in treatment of primary hepatocellular carcinoma with PVTT. PMID- 29516978 TI - Programmed death 1 Ligand 1 expression in breast cancer and its association with patients' clinical parameters. AB - Objective: To evaluate the expression of programmed death 1 ligand 1 (PD-L1) in the cancer tissues and tumor-adjacent normal tissues of patients with invasive ductal carcinoma of the breast and to analyze the relationship between the expression of PD-L1 and the clinicopathological features of patients. Materials and Methods: This study included 112 cases of patients with invasive ductal carcinoma of breast who received surgical treatment from March 2012 to February 2016 in Xuzhou Cancer Hospital. The clinical materials of included patients were retrospectively analyzed. The immunohistochemical assay and real-time polymerase chain reaction (PCR) assay were applied to examine the expression of mRNA and protein of PD-L1 in breast cancer specimens of 112 cases and paired tumor adjacent tissue specimens of 57 cases. The relationship between PD-L1 protein expression and clinicopathological features of patients was analyzed. Results: PD L1 protein was mainly expressed in the cytoplasm. The positive rate of PD-L1 expression in invasive ductal carcinoma was 19.6% (22/112), and the positive rate of PD-L1 expression of tumor-adjacent normal tissues was 3.5% (2/57), indicating that the positive rate of PD-L1 expression of cancerous tissues was significantly higher than that of in tumor-adjacent normal tissues (P < 0.05); the positive expression of PD-L1 was not related with the patients' age, menopause history, family history of breast cancer, tumor size, and location of the tumor (P > 0.05) while it was related with lymph node metastasis, the clinic staging, and histopathological grading (P < 0.05). Real-time PCR was applied to detect the mRNA expression of PD-L1 in breast-invasive ductal carcinoma with the mean DeltaCt value of 7.79 +/- 2.25. However, the mRNA expression of PD-L1 in normal tumor-adjacent tissues was of low expression with the mean DeltaCt value of 12.37 +/- 3.33. The difference was statistically significant (P< 0.05). Conclusion: The expression of PD-L1 in breast-invasive ductal carcinoma was significantly increased, and it was related to histological grading, clinical staging, and lymph node metastasis of breast cancer. PD-L1 may be a significant marker for the prognosis of breast cancer patients. PMID- 29516979 TI - Value of magnetic resonance images in preoperative staging and resectability assessment of pancreatic cancer. AB - Objective: The objective of this study is to evaluate the clinical value of magnetic resonance images (MRI) in preoperative staging and resectability evaluation of pancreatic cancer. Materials and Methods: Thirty-one pancreatic cancer patients who received operation from January 2012 to May 2017 were included in this study. The upper abdominal MRI of 31 cases were analyzed retrospectively. The results of operation and pathology were compared to evaluate the correlation between MRI staging and postoperative pathological staging of pancreatic cancer. Results: According to pathological staging, there were 12 cases of Stage I, 13 cases of Stage II, 4 cases of Stage III, and 2 case of Stage IV. However, for preoperative MRI stage, there were 13 cases of Stage I, 14 cases of Stage II, 4 cases of Stage III. In addition, there was no significant difference in the distribution frequency of pathological staging and MRI staging (P > 0.05). This finding indicated that the results of MRI staging were consistent with that of postoperative pathological staging. The pathology I/II or III/IV stage of pancreatic cancer patients could be predicted with preoperative abdominal MRI detection, with the sensitivity of 1.00 and the specificity of 0.67. Conclusion: MRI was clinically significant in preoperative staging and resectability assessment of pancreatic carcinoma. PMID- 29516980 TI - Apatinib for advanced nonsmall-cell lung cancer: A retrospective case series analysis. AB - Objectives: Apatinib, a tyrosine kinase inhibitor which selectively inhibits vascular endothelial growth factor receptor-2, has been shown to be beneficial to patients with a variety of cancers, including advanced nonsmall-cell lung cancer (NSCLC). Thus, this study was aimed to retrospectively assess the efficacy and safety of apatinib in patients with advanced/metastatic NSCLC who failed more than two lines of treatment. Methods: Twenty-three NSCLC patients were involved in this study, who received oral apatinib at a daily dose of 250/500/750 mg, with the progression after the failure of second-line therapy. Treatment was continued until disease progression. The tumor assessments were determined according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Safety was evaluated with adverse reactions and toxicities based on the Common Terminology Criteria for Adverse Events (version 4.0). Response and safety for the included patients were evaluated every 8 weeks. Results: In this study, 23 NSCLC patients were followed from January 2015 to December 2016. Available image efficacy was obtained in 22 patients, including 4 identified as partial responses, 17 stable disease, and 1 progressive disease; no complete responses was observed. The objective response rate was 18.2%, and the disease control rate was 95.5%. Median progression free survival and overall survival for apatinib were 203 days (95% CI, 120-269) and 227 days (95% CI, 146-294), respectively. The most frequent treatment-related adverse events were hypertension, gastrointestinal reactions, and hand-foot skin reaction. Conclusion: Apatinib exhibited modest activity and acceptable toxicity for advanced NSCLC after the failure of chemotherapy or other targeted therapy. PMID- 29516982 TI - Preliminary clinical study on brass compensator-based intensity-modulated radiation therapy. AB - Objective: The objective of this study is to preliminarily evaluate the feasibility of brass compensator-based intensity-modulated radiation therapy (CB IMRT). Materials and Methods: Ten patients (three cases of nasopharyngeal cancer, four of esophageal cancer, and three of rectal cancer) who underwent an IMRT treatment planning were selected for this study. The transmission coefficient of brass plates with different thicknesses was measured under a 6 MV photon beam used in the treatment planning system, and the equation for thickness computation was fitted out. The plan file RTPLAN file of each patient was exported from the planning system and transformed to a compensator thickness matrix; therefore, it was input into a numerical control machine for the manufacturing and cutting of the compensators. The CB-IMRT plans obtained were verified on a homogeneous phantom with commercial software. Planar doses were measured by films, and the computed ones were compared using gamma evaluation with 3-mm distance to agreement and 3% dose difference criteria adopting a pass rate of Pgamma >90%. The monitor units (MUs) of the multileaf collimator IMRT plan (MLC-IMRT) and the CB-IMRT plans were compared. Depth of cut was computed through the equation fitted from real measurements. The planned RTPLAN files were used to transform the cutting files needed by the numerical control machine. Results: Plan validations show that the minimum and maximum of gamma pass rate among the 10 patients are 90.2% and 98.2%, respectively, which both satisfy the requirements of clinical planning. The MUs of CB-IMRT are significantly smaller compared with MLC-IMRT. Conclusion: CB-IMRT satisfies the requirements of clinical therapy and can be used in a radiotherapy routine. PMID- 29516981 TI - Medical expenditure for liver cancer in urban China: A 10-year multicenter retrospective survey (2002-2011). AB - Objective: This study aims to understand the medical expenditure for liver cancer during 2002-2011 in urban areas of China. Materials and Methods: This is a retrospective study. Based on a stratified cluster sampling method, a medical expenditure survey collected basic personal information from related medical records. Two-tailed independent sample t-test, variance analysis, and Student Newman-Keuls Tests were used in cost analysis for the corresponding data types. Results: A total of 12,342 liver cancer patients were included in the analysis. Overall average medical expenditure per case for liver cancer diagnosis and treatment in China has increased from Y21, 950 to Y40, 386 over the study period. For each liver cancer patient diagnosed between 2009 and 2011, the average expenditures were 29,332 CNY for stage I, 35,754 CNY for stage II, 34,288 CNY for stage III, and 30,275 CNY for stage IV diseases (P < 0.001). Pharmaceuticals accounted for the biggest part of the medical expenditure and it rose from 48.01% to 52.96% during these ten years, and the share of nursing fee expenses was the lowest (around 1%). Over the entire 10-year data period, the per capita expenditure of the east region (32,983 CNY) was higher than that of the west region (26,219 CNY) and slightly higher than the central region (31,018 CNY, P < 0.001). Discussion: As a major cancer in China, liver cancer accounts for a large portion of health economic burden and its medical expenditure is heavy for families. Early diagnosis and treatment for liver cancer will save medical expenditure. Conclusion: The economic burden of liver cancer is high in China and related medical expenditure has increased. PMID- 29516983 TI - Association of glutathione S-transferase M1 polymorphisms in the colorectal cancer risk: A meta-analysis. AB - Purpose: The glutathione S-transferase M1 (GSTM1) as a member of phase II detoxification enzymes is expressed in many tissues and plays a critical role in preventing the occurrence of cancer. Published data regarding the associations between the GSTM1 polymorphism and colorectal cancer (CRC) risk are inconclusive. Materials and Methods: A meta-analysis of 55 case-control studies involving 17,498 cases and 26,441 controls were performed to assess the strength of association using odds ratio (OR) with 95% confidence interval (CI). Results: The meta-analysis of those studies suggested that GSTM1 null genotype was significantly associated with CRC risk (OR = 1.13, 95% CI = 1.06-1.20, P < 0.0001). In the subgroup analysis by ethnicity, significant risks were associated with GSTM1 null genotype in Caucasians (OR = 1.18, 95% CI = 1.07-1.29, P = 0.001), Asians (OR = 1.11, 95% CI = 1.02-1.22, P = 0.02), and mixed group (OR = 1.01, 95% CI = 0.90-1.14, P = 0.85). In the subgroup analysis by study design, significant elevated risks were associated with GSTM1 null genotype in hospital based case-control study group (OR = 1.20, 95% CI = 1.10-1.31, and P < 0.0001) but not in population-based case-control study group (OR = 1.03, 95% CI = 0.96 1.10, P = 0.43). Conclusions: Based on our meta-analysis, the GSTM1 null genotype is a risk factor for CRC. PMID- 29516984 TI - Investigation of the dose perturbation effect for therapeutic beams with the presence of a 1.5 T transverse magnetic field in magnetic resonance imaging guided radiotherapy. AB - Background: Magnetic resonance imaging (MRI)-guided radiotherapy is a promising image-guided cancer radiotherapy method. For MRI-guided radiotherapy, the proper energy of a therapeutic beam is important for beam-designing processes, and the magnetic-induced dose perturbation would be mainly influenced, especially the perturbation surrounding the tissue-air or air-tissue interfaces. Thus, it was necessary to investigate the impact of beam energy from photon, proton, and carbon ion beams on the magnetic-induced dose perturbations. Materials and Methods: Using a phantom of a water-air-water structure, the dose distributions were calculated with or without the presence of a 1.5 T uniform magnetic field through GEANT4. Based on the calculated doses, magnetic-induced dose perturbations were then obtained. For investigating the effects of beam energies on magnetic-induced dose perturbations, low-, middle-, and high-beam energies were adopted for each beam type. Results and Discussion: For photon beams, the dose perturbations were increased as the beam energies increased. At the up water air interface, the maximum perturbations exceeded 50%. Near the edge of the radiation field, perturbations of 5%-20% were achieved. For proton and carbon ion beams, their Bragg peaks were shifted from original positions, and the shifting distances were increased with the increased beam energies. However, no evident magnetic-induced dose perturbations were noted at the up water-air interface and bottom air-water interface for all the beam energies. To some extent, this study provided references for assessing the effects of beam energies on magnetic induced dose perturbations, especially the perturbations around the air cavities inside cancer patients. Conclusion: In MRI-guided cancer radiotherapy, the dose perturbation effects for therapeutic beams are relatively obvious, and the beam energies of therapeutic beams have large impacts on the magnetic-induced dose perturbations with the presence of a 1.5 T transverse magnetic field. PMID- 29516985 TI - Effectiveness and the strategy to treat the side effects of sorafenib administration after transarterial chemoembolization in advanced hepatocellular carcinoma patients. AB - Objective: The aim is to study the effectiveness and side effects of sorafenib administration after transarterial chemoembolization (TACE) in advanced hepatocellular carcinoma (HCC) patients. To evaluate the safety of the combination of sorafenib and TACE to treat HCC. Materials and Methods: A total of 36 unresectable HCC patients were enrolled. After TACE, administration of sorafenib was carried out. Follow-up was taken for every 4 weeks. Liver and renal function and alpha-fetoprotein were tested. Modified response evaluation criteria in solid tumors (mRECIST) was used to evaluate the clinical effect. The side effects were recorded. Results: The median overall survival (mOS) and the median time to progress were 12.5 and 8 months with the range from 6 to 32 and 4-30 months, respectively. The mOS of patients with single tumor was 18 months while that of multiple tumors in liver was 10 months (chi2 = 4.1639, P = 0.0413). According to mRECIST, there were no complete response patients, 2 partial response patients, 10 stable disease patients, and 24 progressive disease patients. Response rate was 5.5% (2/36). Disease control rate (DCR) was 33% (12/36). The main adverse events were hand-foot skin reaction and diarrhea. The frequency of Grade II, III hand-foot-skin reaction was 39%. After treatment, it decreased to 5.6%. Forty-four percentage patients suffered from diarrhea of Grades I and II. After treatment, it decreased to 28%. The mean interval of TACE was 45 days before combination therapy and 120 days after combination therapy. Conclusion: Administration of sorafenib after TACE could prolong overall survival of advanced HCC patients, keep the stable status longer and extend the interval between TACEs. The side effects are usually treatable, which proves the safety of this combination. PMID- 29516986 TI - Combining differential expression and differential coexpression analysis identifies optimal gene and gene set in cervical cancer. AB - Objective: The objective of this study is to investigate the optimal gene and functional-related gene set in cervical cancer through combing the differential expression (DE) and differential coexpression (DC) analysis. Materials and Methods: To achieve this, we first measured expression data of cervical cancer by incorporating DE and DC effects utilizing absolute t-value in t-statistic and Z test, respectively. Then, we selected the optimal threshold pair to determine both high DE and high DC (HDE_HDC) partition on the basis of Chi-square maximization, and the best threshold pair divided all genes into four parts, including HDE_HDC, high DE and low DC (HDE_LDC), low DE and high DC (LDE_HDC), and low DE and low DC (LDE_LDC). Using the known functional gene sets, functional relevance of partition genes was explored to determine the best-associated gene set based on the functional information (FI) conception. Results: Under the optimal threshold pair of 3.629 and 1.108 for DE and DC, respectively genes were divided into four partitions: HDE_HDC (311 genes), HDE_LDC (2072 genes), LDE_HDC (seventy genes), and LDE_LDC (1623 genes). Meanwhile, the gene set epidermis development was the best-associated gene set with the largest ?G* = 10.496. Among the genes of epidermis development, zinc finger protein 135 (ZNF135) attained highest minimum FI gain of 41.226. Conclusion: The combination of DE and DC analysis showed higher mean FI relative to individual DE and DC analyses. We successfully exhibited the optimal gene set epidermis development and gene ZNF135, which might be crucial for the prevention and treatment of cervical cancer. PMID- 29516987 TI - Effects of the Akt inhibitor Src-homology 5 on proliferation and apoptosis of the laryngeal squamous cell carcinoma. AB - Objective: The aim of this study was to investigate the effect of the Akt inhibitor Src-homology 5 (SH-5) on the proliferation and apoptosis of laryngeal squamous cell carcinoma cells (LSCC; Hep-2 cells) and to elucidate the possible mechanisms of such effects. Materials and Methods: Hep-2 cells were treated with different concentrations of the Akt inhibitor SH-5. The inhibitory effect of SH-5 on cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, whereas apoptosis was detected by flow cytometric based on Annexin V/propidium iodide (PI) staining. In addition, the expression level of Akt protein was evaluated by Western blot analysis. Results: MTT assay results revealed that SH-5 inhibited the proliferation of Hep-2 cells, with its greatest effect being observed at 2 MUM. Apoptosis of Hep-2 cells increased following treatment with SH-5. Treatment of Hep-2 cells with SH-5 decreased the expression of Akt, and this effect was statistically significantly when compared with that in controls (P < 0.05). Conclusion: SH-5 inhibited proliferation and induced apoptosis in the LSCC cell line Hep-2. These effects may be caused by inhibition of the phosphoinositide 3-kinase-Akt signaling pathway. We believe that our data will provide useful insights into LSCC target treatment and future researchn. PMID- 29516988 TI - Clinical significance of elevated antinuclear antibodies in patients with diffuse large B-cell lymphoma: A single center study. AB - Objective: To investigate the potential diagnostic and prognostic values of antinuclear autoantibodies (ANAs) in diffuse large B-cell lymphoma (DLBCL). Materials and Methods: Eighty-two DLBCL patients and 120 healthy controls were selected from the Department of Hematology, Jincheng Dayi Hospital between 2005 and 2014. We examined the expression of ANA in the sera of the 82 DLBCL patients at different Ann-Arbor stages (15 at Stage I, 22 at Stage II, 27 at Stage III, and 18 at Stage IV). ANA detection was performed by immunofluorescence, and the results were confirmed by Western blotting analysis. Result: ANAs were more frequently detected in DLBCL patients than in controls (P < 0.001), with 25 (30.5%) DLBCL patients and 9 (7.5%) controls displaying elevated ANA levels. However, the majority of DLBCL patients in which ANA were detected did not develop autoimmune diseases, suggesting that ANA in DLBCL might not be correlated autoimmune diseases. Furthermore, no correlation was observed between the expression of ANA and the clinical stages of DLBCL. However, ANA-positive DLBCL patients had a better survival rate (P < 0.05). Conclusions: ANA in DLBCL may be a stage-independent prognostic factor rather than an indication for autoimmune diseases and may represent an effective immune response to the tumor. PMID- 29516989 TI - Circulating microRNA-21 as a prognostic, biological marker in cholangiocarcinoma. AB - Aims: The prognosis of cholangiocarcinoma (CCA) is generally poor because there is a lack of effective diagnostic tools including laboratory assessments and imageological examination. Therefore, a novel biological marker (biomarker) to effectively diagnose cancer is highly desirable in clinical. Previously, serum microRNAs as biomarkers of cancers have been reported. However, it was still unclear about the clinical significance of serum microRNA-21 (miR-21) expression levels for CCA. Materials and Methods: The serum samples were separately collected from fifty patients of CCA, 15 patients of hepatolithiasis, and 15 healthy volunteers; quantitative real-time polymerase chain reaction was used for measuring miR-21 expression level in serum. The clinicopathological data were recorded before patients discharged. Results: In the CCA serum, the expression level of miR-21 significantly upregulated (P < 0.05). With the tumor, node, and metastasis stage developed (Stage I vs. III and IV, P < 0.05), the serum miR-21 expression level increased, but there was no statistical difference between Stage I patients and hepatolithiasis patients or healthy control (P > 0.05 for both). Furthermore, the miR-21 level was significant difference between pre- and post operative serum (P < 0.05) for the high miR-21 expression group. The serum miR-21 expression levels were defective in discriminating patients with CCA from healthy control subjects by receiver-operator curve analysis because the area under the curve (AUC) value was 0.871 which was not better than the conventional CCA markers-carbohydrate antigen 19-9 (AUC value = 0.96). However, in serum, high expression level miR-21 was significantly related to clinical stage, invasion depth, lymph vessel infiltration, metastasis status, differentiation status, whether to resection, and poor survival of CCA patients (P < 0.05 for all). Conclusions: This study suggested that serum miR-21 was a promising biomarker for diagnosing the late stage CCA and would have potential to be a useful prognostic biomarker of CCA. PMID- 29516990 TI - Clinical study on thalidomide combined with cinobufagin to treat lung cancer cachexia. AB - Objective: To discuss and assess the clinical value of treating lung cancer cachexia with thalidomide combined with cinobufagin.s. Methods: A cohort of 54 patients, who were diagnosed with lung carcinoma, was randomly divided into two groups, a trial group and a control group, respectively. The trial group was given 150 mg/day thalidomide and 2700 mg/day cinobufagin; the control group only received 2,700 mg/day cinobufagin. The therapy lasted for 12 weeks, and the nutritional status, quality of life, survival, and side effects in patients in the two groups were recorded. Results: The nutritional status, quality of life, and survival of patients with lung cancer cachexia in the trial group were significantly improved compared to the control group. The trial group received 150 mg thalidomide, which by contrast reduced the incidence of side effect and increased tolerance. Conclusion: Using thalidomide combined with cinobufagin to treat patients with lung cancer cachexia will significantly improve their nutritional status and quality of life. This therapy is better than that using cinobufagin alone and is well tolerated. PMID- 29516991 TI - Fast recovery of platelet production in NOD/SCID mice after transplantation with ex vivo expansion of megakaryocyte from cord blood CD34+ cells. AB - Background: Cord blood transplantation (CBT) can be a life-saving procedure in the treatment of a broad variety of disorders, including hematologic, immune, and genetic diseases. However, delayed platelet recovery hinders the application of CBT. Purpose: The aim of this study was to determine the optimal combination of cytokines to amplify megakaryocyte (Mk). Methods: CB CD34+ cells were obtained by immunomagnetic isolation and amplified under four different cytokine combinations. CD34+ cells of the group with thrombopoietin (TPO), stem cell factor (SCF), Flt-3 ligand (FL), and interleukin-6 (IL-6) were collected on days 0, 3, 7, 10, and 14. Immunophenotype was analyzed by flow cytometry (FCM). Polyploidic Mk cultured cells were collected on days 7 and 14 for colony-forming unit-Mk assay. The NOD/SCID mice were injected with expanded CD34+ cells, and the peripheral blood (PB) and bone marrow (BM) were tested on 3, 7, and 14 days. Results: The group with TPO, SCF, FL, and IL-6 reached the maximal total expansion fold and Mk population at day 7, which was slightly reduced later. After transplantation into NOD/SCID mice with expanded CD34+ cells, the human CD41+ cells were detected in mice PB on day 3 and in BM on day 7, then disappeared after 14 days. The expressing of activated platelet CD 42b+/CD62P+ increased gradually after transplantation. Conclusion: Platelets can recover rapidly in vivo by means of expanded CD34+ cells with various cytokines. In our system, a group of TPO, SCF, FL, and IL-6 represents the best cytokine combination for expansion of Mk progenitor cells from CB CD34+ cells. PMID- 29516992 TI - Correlation between epidermal growth factor receptor mutation and histologic subtypes or characteristics of computed tomography findings in patients with resected pulmonary adenocarcinoma. AB - Objective: To investigate the correlation between epidermal growth factor receptor (EGFR) mutation and the histologic subtypes features or computed tomography (CT) findings in patients with resected pulmonary adenocarcinoma. Materials and Methods: We retrospectively reviewed 153 patients underwent surgical resected pulmonary adenocarcinoma. EGFR mutations were detected using the amplification refractory mutation system. Histologic subtype was classified according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society pulmonary adenocarcinoma classification. Characteristics of CT in the tumor were retrospectively analyzed, and compared to mutation-negative cohort. Results: EGFR mutations were found in 67 (43.79%) cases. The prevalent histologic subtypes of invasive adenocarcinoma were acinar predominant adenocarcinoma (33.99%), papillary predominant adenocarcinoma (24.18%), micropapillary predominant adenocarcinoma (MPA; 18.95%), solid predominant adenocarcinoma (11.76%), and lepidic predominant adenocarcinoma (LPA; 11.11%). EGFR mutations were correlated with the MPA and LPA subtypes (P = 0.009 and P = 0.018) and was correlated with the air bronchograms (P = 0.008). EGFR mutations were independently associated with other CT characteristics including ground-glass opacity/tumor ratio (P = 0.054). Conclusions: Correlation exists between EGFR mutations and histologic subtypes of invasive adenocarcinoma or air bronchograms on CT images, which could use to predict EGFR mutation status in patients with pulmonary adenocarcinoma. PMID- 29516993 TI - Bipolar disorders. AB - Bipolar disorders are chronic and recurrent disorders that affect >1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease. Psychiatric and nonpsychiatric medical comorbidities are common in patients and might also contribute to increased mortality. Bipolar disorders are some of the most heritable psychiatric disorders, although a model with gene-environment interactions is believed to best explain the aetiology. Early and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression. Moreover, patients and their families do not always understand the significance of their symptoms, especially with hypomanic or manic symptoms. As specific biomarkers for bipolar disorders are not yet available, careful clinical assessment remains the cornerstone of diagnosis. The detection of hypomanic symptoms and longtudinal clinical assessment are crucial to differentiate a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary. PMID- 29516994 TI - Corrigendum: Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing. AB - This corrects the article DOI: 10.1038/srep30792. PMID- 29516995 TI - Jupiter's atmospheric jet streams extend thousands of kilometres deep. AB - The depth to which Jupiter's observed east-west jet streams extend has been a long-standing question. Resolving this puzzle has been a primary goal for the Juno spacecraft, which has been in orbit around the gas giant since July 2016. Juno's gravitational measurements have revealed that Jupiter's gravitational field is north-south asymmetric, which is a signature of the planet's atmospheric and interior flows. Here we report that the measured odd gravitational harmonics J3, J5, J7 and J9 indicate that the observed jet streams, as they appear at the cloud level, extend down to depths of thousands of kilometres beneath the cloud level, probably to the region of magnetic dissipation at a depth of about 3,000 kilometres. By inverting the measured gravity values into a wind field, we calculate the most likely vertical profile of the deep atmospheric and interior flow, and the latitudinal dependence of its depth. Furthermore, the even gravity harmonics J8 and J10 resulting from this flow profile also match the measurements, when taking into account the contribution of the interior structure. These results indicate that the mass of the dynamical atmosphere is about one per cent of Jupiter's total mass. PMID- 29516996 TI - GaN/NbN epitaxial semiconductor/superconductor heterostructures. AB - Epitaxy is a process by which a thin layer of one crystal is deposited in an ordered fashion onto a substrate crystal. The direct epitaxial growth of semiconductor heterostructures on top of crystalline superconductors has proved challenging. Here, however, we report the successful use of molecular beam epitaxy to grow and integrate niobium nitride (NbN)-based superconductors with the wide-bandgap family of semiconductors-silicon carbide, gallium nitride (GaN) and aluminium gallium nitride (AlGaN). We apply molecular beam epitaxy to grow an AlGaN/GaN quantum-well heterostructure directly on top of an ultrathin crystalline NbN superconductor. The resulting high-mobility, two-dimensional electron gas in the semiconductor exhibits quantum oscillations, and thus enables a semiconductor transistor-an electronic gain element-to be grown and fabricated directly on a crystalline superconductor. Using the epitaxial superconductor as the source load of the transistor, we observe in the transistor output characteristics a negative differential resistance-a feature often used in amplifiers and oscillators. Our demonstration of the direct epitaxial growth of high-quality semiconductor heterostructures and devices on crystalline nitride superconductors opens up the possibility of combining the macroscopic quantum effects of superconductors with the electronic, photonic and piezoelectric properties of the group III/nitride semiconductor family. PMID- 29516997 TI - Clusters of cyclones encircling Jupiter's poles. AB - The familiar axisymmetric zones and belts that characterize Jupiter's weather system at lower latitudes give way to pervasive cyclonic activity at higher latitudes. Two-dimensional turbulence in combination with the Coriolis beta effect (that is, the large meridionally varying Coriolis force on the giant planets of the Solar System) produces alternating zonal flows. The zonal flows weaken with rising latitude so that a transition between equatorial jets and polar turbulence on Jupiter can occur. Simulations with shallow-water models of giant planets support this transition by producing both alternating flows near the equator and circumpolar cyclones near the poles. Jovian polar regions are not visible from Earth owing to Jupiter's low axial tilt, and were poorly characterized by previous missions because the trajectories of these missions did not venture far from Jupiter's equatorial plane. Here we report that visible and infrared images obtained from above each pole by the Juno spacecraft during its first five orbits reveal persistent polygonal patterns of large cyclones. In the north, eight circumpolar cyclones are observed about a single polar cyclone; in the south, one polar cyclone is encircled by five circumpolar cyclones. Cyclonic circulation is established via time-lapse imagery obtained over intervals ranging from 20 minutes to 4 hours. Although migration of cyclones towards the pole might be expected as a consequence of the Coriolis beta-effect, by which cyclonic vortices naturally drift towards the rotational pole, the configuration of the cyclones is without precedent on other planets (including Saturn's polar hexagonal features). The manner in which the cyclones persist without merging and the process by which they evolve to their current configuration are unknown. PMID- 29516998 TI - CaSiO3 perovskite in diamond indicates the recycling of oceanic crust into the lower mantle. AB - Laboratory experiments and seismology data have created a clear theoretical picture of the most abundant minerals that comprise the deeper parts of the Earth's mantle. Discoveries of some of these minerals in 'super-deep' diamonds formed between two hundred and about one thousand kilometres into the lower mantle-have confirmed part of this picture. A notable exception is the high pressure perovskite-structured polymorph of calcium silicate (CaSiO3). This mineral-expected to be the fourth most abundant in the Earth-has not previously been found in nature. Being the dominant host for calcium and, owing to its accommodating crystal structure, the major sink for heat-producing elements (potassium, uranium and thorium) in the transition zone and lower mantle, it is critical to establish its presence. Here we report the discovery of the perovskite-structured polymorph of CaSiO3 in a diamond from South African Cullinan kimberlite. The mineral is intergrown with about six per cent calcium titanate (CaTiO3). The titanium-rich composition of this inclusion indicates a bulk composition consistent with derivation from basaltic oceanic crust subducted to pressures equivalent to those present at the depths of the uppermost lower mantle. The relatively 'heavy' carbon isotopic composition of the surrounding diamond, together with the pristine high-pressure CaSiO3 structure, provides evidence for the recycling of oceanic crust and surficial carbon to lower-mantle depths. PMID- 29516999 TI - Social norm complexity and past reputations in the evolution of cooperation. AB - Indirect reciprocity is the most elaborate and cognitively demanding of all known cooperation mechanisms, and is the most specifically human because it involves reputation and status. By helping someone, individuals may increase their reputation, which may change the predisposition of others to help them in future. The revision of an individual's reputation depends on the social norms that establish what characterizes a good or bad action and thus provide a basis for morality. Norms based on indirect reciprocity are often sufficiently complex that an individual's ability to follow subjective rules becomes important, even in models that disregard the past reputations of individuals, and reduce reputations to either 'good' or 'bad' and actions to binary decisions. Here we include past reputations in such a model and identify the key pattern in the associated norms that promotes cooperation. Of the norms that comply with this pattern, the one that leads to maximal cooperation (greater than 90 per cent) with minimum complexity does not discriminate on the basis of past reputation; the relative performance of this norm is particularly evident when we consider a 'complexity cost' in the decision process. This combination of high cooperation and low complexity suggests that simple moral principles can elicit cooperation even in complex environments. PMID- 29517000 TI - A suppression of differential rotation in Jupiter's deep interior. AB - Jupiter's atmosphere is rotating differentially, with zones and belts rotating at speeds that differ by up to 100 metres per second. Whether this is also true of the gas giant's interior has been unknown, limiting our ability to probe the structure and composition of the planet. The discovery by the Juno spacecraft that Jupiter's gravity field is north-south asymmetric and the determination of its non-zero odd gravitational harmonics J3, J5, J7 and J9 demonstrates that the observed zonal cloud flow must persist to a depth of about 3,000 kilometres from the cloud tops. Here we report an analysis of Jupiter's even gravitational harmonics J4, J6, J8 and J10 as observed by Juno and compared to the predictions of interior models. We find that the deep interior of the planet rotates nearly as a rigid body, with differential rotation decreasing by at least an order of magnitude compared to the atmosphere. Moreover, we find that the atmospheric zonal flow extends to more than 2,000 kilometres and to less than 3,500 kilometres, making it fully consistent with the constraints obtained independently from the odd gravitational harmonics. This depth corresponds to the point at which the electric conductivity becomes large and magnetic drag should suppress differential rotation. Given that electric conductivity is dependent on planetary mass, we expect the outer, differentially rotating region to be at least three times deeper in Saturn and to be shallower in massive giant planets and brown dwarfs. PMID- 29517001 TI - Measurement of Jupiter's asymmetric gravity field. AB - The gravity harmonics of a fluid, rotating planet can be decomposed into static components arising from solid-body rotation and dynamic components arising from flows. In the absence of internal dynamics, the gravity field is axially and hemispherically symmetric and is dominated by even zonal gravity harmonics J2n that are approximately proportional to qn, where q is the ratio between centrifugal acceleration and gravity at the planet's equator. Any asymmetry in the gravity field is attributed to differential rotation and deep atmospheric flows. The odd harmonics, J3, J5, J7, J9 and higher, are a measure of the depth of the winds in the different zones of the atmosphere. Here we report measurements of Jupiter's gravity harmonics (both even and odd) through precise Doppler tracking of the Juno spacecraft in its polar orbit around Jupiter. We find a north-south asymmetry, which is a signature of atmospheric and interior flows. Analysis of the harmonics, described in two accompanying papers, provides the vertical profile of the winds and precise constraints for the depth of Jupiter's dynamical atmosphere. PMID- 29517003 TI - Corrigendum: Landscape of X chromosome inactivation across human tissues. AB - This corrects the article DOI: 10.1038/nature24265. PMID- 29517002 TI - Monolayer atomic crystal molecular superlattices. AB - Artificial superlattices, based on van der Waals heterostructures of two dimensional atomic crystals such as graphene or molybdenum disulfide, offer technological opportunities beyond the reach of existing materials. Typical strategies for creating such artificial superlattices rely on arduous layer-by layer exfoliation and restacking, with limited yield and reproducibility. The bottom-up approach of using chemical-vapour deposition produces high-quality heterostructures but becomes increasingly difficult for high-order superlattices. The intercalation of selected two-dimensional atomic crystals with alkali metal ions offers an alternative way to superlattice structures, but these usually have poor stability and seriously altered electronic properties. Here we report an electrochemical molecular intercalation approach to a new class of stable superlattices in which monolayer atomic crystals alternate with molecular layers. Using black phosphorus as a model system, we show that intercalation with cetyl trimethylammonium bromide produces monolayer phosphorene molecular superlattices in which the interlayer distance is more than double that in black phosphorus, effectively isolating the phosphorene monolayers. Electrical transport studies of transistors fabricated from the monolayer phosphorene molecular superlattice show an on/off current ratio exceeding 107, along with excellent mobility and superior stability. We further show that several different two-dimensional atomic crystals, such as molybdenum disulfide and tungsten diselenide, can be intercalated with quaternary ammonium molecules of varying sizes and symmetries to produce a broad class of superlattices with tailored molecular structures, interlayer distances, phase compositions, electronic and optical properties. These studies define a versatile material platform for fundamental studies and potential technological applications. PMID- 29517005 TI - How female fellows fared at the Royal Society. PMID- 29517004 TI - Meta-analysis and the science of research synthesis. AB - Meta-analysis is the quantitative, scientific synthesis of research results. Since the term and modern approaches to research synthesis were first introduced in the 1970s, meta-analysis has had a revolutionary effect in many scientific fields, helping to establish evidence-based practice and to resolve seemingly contradictory research outcomes. At the same time, its implementation has engendered criticism and controversy, in some cases general and others specific to particular disciplines. Here we take the opportunity provided by the recent fortieth anniversary of meta-analysis to reflect on the accomplishments, limitations, recent advances and directions for future developments in the field of research synthesis. PMID- 29517007 TI - India and Pakistan should work together for water security. PMID- 29517008 TI - Gender parity closer among astronomers in low-income countries. PMID- 29517009 TI - Correction. PMID- 29517010 TI - Too few women authors on research papers in leading journals. PMID- 29517011 TI - The battle to tame autoimmunity. PMID- 29517012 TI - Academics should build rapport with government's policy analysts. PMID- 29517013 TI - How baby's first microbes could be crucial to future health. PMID- 29517014 TI - Mountains of diversity. PMID- 29517015 TI - Does your code stand up to scrutiny? PMID- 29517016 TI - Transistors driven by superconductors. PMID- 29517017 TI - Science PhDs lead to enjoyable jobs. PMID- 29517018 TI - The mind-reading devices that can free paralysed muscles. PMID- 29517019 TI - Canadian science wins billions in new budget. PMID- 29517020 TI - Infection forecasts powered by big data. PMID- 29517021 TI - Cleaning up pollutants to protect future health. PMID- 29517023 TI - Why scientists need to market themselves. PMID- 29517022 TI - Attack of the extreme floods. PMID- 29517024 TI - Donald Lynden-Bell (1935-2018). PMID- 29517025 TI - A deeper look at Jupiter. PMID- 29517026 TI - How CRISPR is transforming drug discovery. PMID- 29517027 TI - A new era of rationally designed antipsychotics. PMID- 29517029 TI - Penguin colony, integrity office and Curiosity's arm. PMID- 29517028 TI - Electric fish inspire inventors across the centuries. PMID- 29517030 TI - Bringing down the cost of cancer treatment. PMID- 29517031 TI - Latest US weather satellite highlights forecasting challenges. PMID- 29517032 TI - China tests giant air cleaner to combat smog. PMID- 29517033 TI - Fund ideas, not pedigree, to find fresh insight. PMID- 29517034 TI - Learn to tell science stories. PMID- 29517035 TI - A CRISPR edit for heart disease. PMID- 29517036 TI - US scientists plot return to the Moon's surface. PMID- 29517037 TI - Chinese project offers a brighter farming future. PMID- 29517038 TI - EU expected to vote on pesticide ban after major scientific review. PMID- 29517040 TI - Four stories of antibacterial breakthroughs. PMID- 29517041 TI - Simple moral code supports cooperation. PMID- 29517043 TI - The future of medicine. PMID- 29517044 TI - Surprise graphene discovery could unlock secrets of superconductivity. PMID- 29517045 TI - Isolation and alienation force women from technology positions. PMID- 29517047 TI - 'March for Science' organizers hope to repeat last year's success. PMID- 29517046 TI - Fighting the inevitability of ageing. PMID- 29517048 TI - Bipolar disorders. PMID- 29517049 TI - Corrigendum: Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP-Mediated IFN-beta Induction. AB - [This corrects the article on p. 1854 in vol. 8, PMID: 29018427.]. PMID- 29517051 TI - Ode to the humble Southern blot in the era of exomes. PMID- 29517050 TI - Anticoagulation for atrial fibrillation after intracranial hemorrhage: A systematic review. AB - Background: We summarize the existing evidence on the potential benefit of oral anticoagulation (OAC) in intracerebral hemorrhage (ICH) survivors with nonvalvular atrial fibrillation (NVAF). Methods: Systematic review of the literature to address the following issues: (1) prevalence of NVAF in ICH survivors, (2) current prescription of OAC, (3) factors associated with resumption of OAC, (4) risk of ischemic stroke (IS) and recurrent ICH, and (5) ideal timing for restarting OAC in ICH survivors with NVAF. Results: After screening 547 articles, 26 were included in the review. Only 3 focused specifically on patients with ICH as primary event, NVAF as indication for OAC, and recurrent ICH and IS as primary endpoints. In addition, 19 letters to the editor/reviews/editorials/experts' surveys/experts' opinion were used for discussion purposes. Conclusions: NVAF is highly prevalent among ICH survivors. The risks of IS, recurrent ICH, and mortality are heightened in this group. Most published data show a net benefit in terms of IS prevention and mortality when anticoagulation is restarted. However, those studies are observational and mostly retrospective, therefore selection bias may play a major role in the results observed in these cohorts. Only randomized controlled trials, either pragmatic or explanatory, can provide more conclusive answers for this important clinical question. PMID- 29517052 TI - Molecular genetic testing for hereditary ataxia: What every neurologist should know. AB - Purpose of review: Because of extensive clinical overlap among many forms of hereditary ataxia, molecular genetic testing is often required to establish a diagnosis. Interrogation of multiple genes has become a popular diagnostic approach as the cost of sequence analysis has decreased and the number of genes associated with overlapping phenotypes has increased. We describe the benefits and limitations of molecular genetic tests commonly used to determine the etiology of hereditary ataxia. Recent findings: There are more than 300 hereditary disorders associated with ataxia. The most common causes of hereditary ataxia are expansion of nucleotide repeats within 7 genes: ATXN1, ATXN2, ATXN3, ATXN7, ATXN8, CACNA1A (spinocerebellar ataxia type 6), and FXN (Friedreich ataxia). Recent reports describing the use of clinical exome sequencing to identify causes of hereditary ataxia may lead neurologists to start their clinical investigation with a less sensitive molecular test providing a misleading "negative" result. Summary: The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia. PMID- 29517054 TI - Message from the Editors to our Reviewers. PMID- 29517053 TI - Shift Work and Sleep: Medical Implications and Management. AB - The primary occupation of a worker can play an important role in achieving good sleep, as well as good physical and mental health. Shift Work Sleep Disorder (SWSD) is a condition that results from working atypical shifts (i.e. other than the typical 9 am to 5 pm schedule). Individuals who manifest SWSD usually complaint of trouble sleeping, excessive sleepiness and fatigue which interfere with overall functioning. Misalignment of circadian timing system results in undesirable health consequences. Among shift workers, good sleep is essential for efficient functioning. Disturbed sleep is associated with anxiety, depression, poor physical and mental health and eventually, leads to impaired quality of life. The economic burden of undiagnosed, under-and untreated shift work is high. The healthcare workers and policymakers can play a pivotal role in dealing with this issue by educating the public and providing them with adequate privileges to perform their work. PMID- 29517055 TI - Lower prevalence of multiple sclerosis in First Nations Canadians. AB - Background: We compared the incidence and prevalence of multiple sclerosis (MS) between First Nations (FN) and non-FN populations in Manitoba. Methods: We applied previously validated algorithms to population-based administrative (health claims) data from Manitoba, Canada, to identify all persons with MS from 1984 to 2011. We identified FN individuals using the Municipality of Registration field held at Manitoba Health. We compared the incidence and prevalence of MS between the FN and non-FN populations using negative binomial models. Results: From 1984 to 2011, 5,738 persons had MS, of whom 64 (1.1%) were of FN ethnicity. The average annual incidence rate per 100,000 population was 8.15 (95% confidence interval [CI] 5.98-11.1) in the FN population and 15.7 (95% CI 15.1-16.3) in the non-FN population (incidence rate ratio 0.52; 95% CI 0.38-0.71). In 1984, the crude prevalence of MS per 100,000 population was 35.8 (95% CI 14.9-86.1) in the FN population and 113.3 (95% CI 106.3-120.8) in the non-FN population. Between 1984 and 2011, the age-standardized prevalence of MS increased by 351% to 188.5 (95% CI 146.6-230.4) in the FN population. In contrast, the prevalence of MS per 100,000 general population increased by 225%-418.4% (95% CI 405.8-431.0). Conclusions: The incidence and prevalence of MS are twofold lower in the FN population than the non-FN population. Nonetheless, the prevalence of MS in FN Manitobans is higher than in other indigenous populations outside Canada. Given reports of more rapid disability progression among FN Canadians with MS, and the rising prevalence of MS in this population, attention should be directed to the needs of this population. PMID- 29517056 TI - Expanding incentives for coordinated, patient-centered care: Implications for neurologists. AB - Historically, payment for cognitive, nonprocedural care has required provision of face-to-face evaluation and management as part of general ambulatory or inpatient care. Although non-face-to-face patient care (e.g., care via electronic means or telephone) is commonly performed and is integral to patient-centered care, appropriate reimbursement for this type of care is lacking. Beginning in 2017, Centers for Medicare and Medicaid (CMS) has taken a large step forward in reimbursing an increased number of cognitive care and non-face-to-face codes. CMS has also included language indicating that nonphysician providers (i.e., nurse practitioners and physician assistants) can perform many of these services independently. The 2017 and now the 2018 fee schedules thus create new payments for non-face-to-face, patient-centered services, and may allow neurologists to reach out to more patients through nonphysician providers. As health care in the United States moves toward value-based incentives, these newly supported non-face to-face services will provide neurologists with new tools to deliver sustainable, high-value care. PMID- 29517057 TI - Abandoning a sport you love after concussion: Calling it quits. PMID- 29517058 TI - High-altitude cerebral edema or acute demyelinating encephalomyelitis in the Himalayas. PMID- 29517059 TI - Medical retirement from sport after concussions: A practical guide for a difficult discussion. AB - Purpose of review: In patients with a considerable history of sports-related concussion, the decision of when to discontinue participation in sports due to medical concerns including neurologic disorders has potentially life-altering consequences, especially for young athletes, and merits a comprehensive evaluation involving nuanced discussion. Few resources exist to aid the sports medicine provider. Recent findings: In this narrative review, we describe 10 prototypical vignettes based upon the authors' collective experience in concussion management and propose an algorithm to help clinicians navigate retirement discussions. Issues for consideration include absolute and relative contraindications to return to sport, ranging from clinical or radiographic evidence of lasting neurologic injury to prolonged concussion recovery periods or reduced injury threshold to patient-centered factors including personal identity through sport, financial motivations, and navigating uncertainty in the context of long-term risks. Summary: The authors propose a novel treatment algorithm based on real patient cases to guide medical retirement decisions after concussion in sport. PMID- 29517060 TI - Pilot study of volume contracted state and hospital outcome after stroke. AB - Background: An increasing body of research suggests that acute stroke patients who are dehydrated may have worsened functional outcomes. We sought to explore the relationship between a volume contracted state (VCS) at the time of ischemic stroke and hospital outcomes as compared with euvolemic patients. Methods: We enrolled a consecutive series of ischemic stroke patients from a single academic stroke center within 12 hours from stroke onset. VCS was defined via surrogate markers (blood urea nitrogen/creatinine ratio >15 and urine specific gravity >1.010). The primary outcome was change in NIH Stroke Scale (NIHSS) score from admission to discharge. Multivariable analyses included adjustment for demographics and infarct size. Results: Over an 11-month study period, 168 patients were eligible for inclusion. Of the126 with complete laboratory and MRI data, 44% were in a VCS at the time of admission. Demographics were similar in both the VCS and euvolemic groups, as were baseline NIHSS scores (6.7 vs 7.3; p = 0.63) and infarct volumes (12 vs 16 mL; p = 0.48). However, 42% of patients in a VCS demonstrated early clinical worsening, compared with 17% of the euvolemic group (p = 0.02). A VCS remained a significant predictor of worsening NIHSS in adjusted models (odds ratio 4.34; 95% confidence interval 1.75-10.76). Conclusions: Acute stroke patients in a VCS demonstrate worse short-term outcomes compared to euvolemic patients, independent of infarct size. Results suggest an opportunity to explore current hydration practices. PMID- 29517061 TI - Efficacy of oral versus insulin therapy for newly diagnosed diabetes in low income settings. AB - Background: There are conflicting recommendations and highly variable practices regarding the level of A1c to initiate insulin for individuals with newly diagnosed diabetes. This is complicated in low-income settings where adverse reactions or negative perceptions of insulin are often magnified. Objectives: Compare the clinical outcomes of insulin and Oral Agents (OAs) in low-income settings in the United States. Methods: We conducted a retrospective chart review in community clinics serving low -income individuals with newly diagnosed type 2 diabetes who were initiated on insulin or OAs. The primary outcome was change of hemoglobin A1c (A1c) from baseline to 12 months. Secondary outcomes consisted of other clinical measures including Emergency Department (ED) visits. Results: A total of 18% (88/489) of patients were started on insulin. The adjusted average decrease of A1c from baseline was greater in the OA group (insulin: -1.97% vs. OA: -2.52%; p<0.001). In a subset analysis of individuals with A1cs >11%, significantly more patients were started on OAs (insulin: n=51, OA: n=93; p<0.001) and A1c improvements were similar at 12 months (insulin: -5.06% [12.94% to 7.88%] OA: -4.62% [12.57% to 7.96%]; p=0.846). Baseline A1c predicted insulin initiation (p<0.001): For every one-unit increase in baseline A1c, the odds of insulin initiation increased by 47.5%. Individuals in the insulin group had more ED visits per year (0.169 vs. 0.0025; p<0.005). Conclusions: Given the positive clinical outcomes of OAs even with markedly elevated A1c levels in addition to the healthcare system benefits, they are a promising initial therapy for low income adults with newly diagnosed type 2 diabetes. PMID- 29517062 TI - Correction: Multiparametric imaging using 18F-FDG PET/CT heterogeneity parameters and functional MRI techniques: prognostic significance in patients with primary advanced oropharyngeal or hypopharyngeal squamous cell carcinoma treated with chemoradiotherapy. AB - [This corrects the article DOI: 10.18632/oncotarget.15904.]. PMID- 29517063 TI - Erratum: NLR-Dependent Regulation of Inflammation in Multiple Sclerosis. AB - [This corrects the article on p. 2012 in vol. 8, PMID: 29403486.]. PMID- 29517064 TI - The physician as captain of the patient-centered ship. PMID- 29517066 TI - Corrigendum: Watching More Closely: Shot Scale Affects Film Viewers' Theory of Mind Tendency But Not Ability. AB - [This corrects the article on p. 2349 in vol. 8, PMID: 29387032.]. PMID- 29517067 TI - Approach to assessing and using clinical practice guidelines. AB - Clinical practice guidelines are produced in ever-increasing numbers by the American Academy of Neurology (AAN) and other developers, with over 1,000 guidelines currently in the National Guideline Clearinghouse. Knowing when to use guidelines in clinical practice requires neurologists to assess the rigor of published guidelines and understand how guideline recommendations are best applied in individual patient encounters. This review briefly describes guideline definitions and the AAN process for guideline development, outlines key elements for assessing guideline quality, and details a practical approach for incorporating guideline recommendations when partnering with patients in shared decision-making. PMID- 29517065 TI - Obstructive Sleep Apnea and Obesity: Implications for Public Health. AB - Obstructive sleep apnea (OSA) is a global disease with a rising incidence along with its comorbidities, especially with metabolic syndrome. One of the main components contributing to sleep apnea is obesity; as well as diabetes mellitus type 2 (T2DM), hypercholesterolemia, and hypertension. OSA is a condition that requires management and the disease can be treated by using CPAP therapy. The awareness of this global issue is rising, and health care systems are providing preventive measures, diagnosis and the treatment options. The major preventable risk factors to decrease obesity are the awareness of lifestyle modification (eating behaviors, smoking, drinking alcohol, etc.) and understanding the importance of exercise. If these lifestyle modifications are widely applied, then not only will the consequences of obesity and sleep apnea be reduced, but also the incidence of cardiovascular disease will decrease greatly. Public awareness of the importance of weight loss by lifestyle modification or bariatric surgery to improve the quality of life is needed. These preventive actions, screening measures, and treatment strategies for obesity and OSA can significantly reduce the incidence of obesity, as well as OSA and the related comorbidities such as cardiovascular disease, atherosclerosis, and depression. Finally, health care costs will also be reduced. PMID- 29517068 TI - Neuroradiologic manifestations of Erdheim-Chester disease. AB - Background: We describe the neuroradiologic features of a cohort of patients with Erdheim-Chester disease. Methods: We assessed patients at Mayo Clinic Rochester between January 1, 1990, and July 31, 2016, with pathologically confirmed Erdheim Chester disease (n = 53). Results: Neuroimaging, including head CT (n = 17), brain MRI (n = 39), orbital MRI (n = 15), and spine MRI (n = 16), was available for 42 participants. Median age at diagnosis was 55 years (interquartile range 46 66) with higher male prevalence (33:20). Neurologic symptoms were identified in 47% (25/53); BRAFV600E mutation in 58% (15/26). Median follow-up was 2 years (range 0-20) with 18 patients deceased. Radiologic disease evidence was seen in dura (6/41), brainstem (9/39), cerebellum (8/39), spinal cord (2/16), spinal epidura (2/16), hypothalamic-pituitary axis (17/39), and orbits (13/42). T2 white matter abnormalities (Fazekas score >=1) were present in 21/34 patients. Diabetes insipidus was present in 30% (16/53); 8 had abnormal hypothalamic-pituitary axis imaging. Radiographic evidence of CNS involvement (i.e., dural, brain, including Fazekas score >1, or spinal cord) occurred in 55% (22/40) and was unassociated with significantly increased mortality. Conclusions: Erdheim-Chester disease commonly and variably involves the neuraxis. Patients with suspected Erdheim Chester disease should undergo MRI brain and spine and screening investigations (serum sodium, serum and urine osmolality) for diabetes insipidus to clarify extent of neurologic disease. PMID- 29517069 TI - Correction to 'Radical framing effects in the ultimatum game: the impact of explicit culturally transmitted frames on economic decision-making'. AB - [This corrects the article DOI: 10.1098/rsos.170543.]. PMID- 29517070 TI - Corrigendum to "All-Atom Four-Body Knowledge-Based Statistical Potentials to Distinguish Native Protein Structures from Nonnative Folds". AB - [This corrects the article DOI: 10.1155/2017/5760612.]. PMID- 29517071 TI - Practice Current: When do you suspect autoimmune encephalitis and what is the role of antibody testing? AB - Diagnosing autoimmune encephalitis (AE) is complicated by several factors, including issues with availability, sensitivity, and specificity of antibody testing, particularly with variability in assay techniques and new antibodies being rapidly identified; nonspecific findings on MRI, EEG, and lumbar puncture; and competing differential diagnoses. Through case-based discussions with 3 experts from 3 continents, this article discusses the challenges of AE diagnosis, important clinical characteristics of AE, preferences for methods of autoantibody testing and interpretation, and treatment-related questions. In particular, we explore the following question: If a patient's clinical presentation seems consistent with AE but antibody testing is negative, can one still diagnose the patient with AE? Furthermore, what factors does one consider when making this determination, and should treatment proceed independent of antibody testing in suspected cases? The same case-based questions were posed to the rest of our readership in an online survey, the results of which are also presented. PMID- 29517072 TI - Corrigendum: No Robust Association between Static Markers of Testosterone and Facets of Socio-Economic Decision Making. AB - [This corrects the article on p. 250 in vol. 11, PMID: 29326567.]. PMID- 29517073 TI - From Outlaw to Citizen: Police Power, Property, and the Territorial Politics of Medical Marijuana in California's Exurbs. AB - As governments worldwide justify the transformation of marijuana governance from one police power (law enforcement) to others (e.g. public health, zoning), the place of marijuana in lawful society is transforming rapidly. No venue in California is more central to this than land use regulatory bodies, which decide how marijuana rights, practices, and relations become territorial. Land use powers, as a declaration of the state's police power, require a definitional rendering of "community." This article analyzes an episode of outdoor marijuana cultivation policymaking and the struggles over the definition of community in a conservative exurban California county. From debates on fences, property line setbacks, rental terms, and nuisance complaints to racial and economic anxieties and the roaming stigma of crime, marijuana advocates confronted a powerful logic of private property and the moral-aesthetic propriety it implies. Despite the subordination of advocates' claims to the terms of private property, outlaw communities sustained their own forms of territorial governance, informal regulatory and enforcement powers, and understandings of community. This episode, which illuminates territorial production across illegal/legal lines, has implications for understandings of liberal rule of law, political possibility, and the practice of citizenship. PMID- 29517075 TI - Correction to 'Smoking status and attractiveness among exemplar and prototypical identical twins discordant for smoking'. AB - [This corrects the article DOI: 10.1098/rsos.161076.]. PMID- 29517076 TI - ERRATA. AB - [This corrects the article on p. 123 in vol. 61, PMID: 29450385.]. PMID- 29517074 TI - Influence of Protein Intake, Race, and Age on Responses to a Weight-Reduction Intervention in Obese Women. AB - Background: Women have higher rates of obesity than men and develop more pronounced functional deficits as a result. Yet, little is known about how obesity reduction affects their functional status, including whether their responses differ when protein intake is enhanced. Objective: The aim of this study was to confirm the feasibility of delivery of a higher-protein (balanced at each meal) calorie-restricted diet in obese women and determine its efficacy for influencing function and retention of lean mass. Method: Obese community-dwelling women [n = 80; body mass index (in kg/m2), in means +/- SDs: 37.8 +/- 5.9; aged 45-78 y; 58.8% white] were enrolled in a weight-loss (-500 kcal/d) study and randomly assigned to either a Control-Weight-Loss (C-WL; 0.8 g protein/kg body weight) group or a High-Protein-Weight-Loss (HP-WL; 1.2 g protein/kg body weight; 30 g protein 3 times/d) group in a 1:2 allocation. Primary outcomes were function by 6-min walk test (6MWT) and lean mass by using the BodPod (Life Measurement, Inc.) at 0, 4, and 6 mo. Results: Both groups reduced calorie intakes and body weights (P < 0.001), and the feasibility of the HP-WL intervention was confirmed. The 6MWT results improved (P < 0.01) at 4 mo in the HP-WL group and at 6 mo in both groups (P < 0.001). Both groups improved function by several other measures while slightly decreasing (P < 0.01) lean mass (-1.0 kg, C-WL; -0.6 kg, HP-WL). Weight loss was greater in white than in black women at both 4 mo (6.0 +/- 3.6 compared with 3.7 +/- 3.4 kg; P < 0.02) and 6 mo (7.2 +/- 4.8 compared with 4.0 +/- 4.7 kg; P < 0.04) and tended to be positively related to age (P < 0.06). Conclusions: A clinically important functional benefit of obesity reduction was confirmed in both study groups, with no significant group effect. Our findings of racial differences in response to the intervention and a potential influence of participant age lend support for further studies sufficiently powered to explore the interaction of race and age with functional responses to obesity reduction in women. This trial was registered at clinicaltrials.gov as NCT02033655. PMID- 29517077 TI - Wake-up stroke is not associated with sleep-disordered breathing in women. AB - Background: We sought to investigate the frequency of wake-up stroke (WUS) and its association with sleep-disordered breathing (SDB) in women. Methods: Within a population-based study, women with acute ischemic stroke were asked about their stroke symptom onset time. SDB screening was performed with the well-validated ApneaLink Plus device; SDB was defined by a respiratory event index >=10. Logistic regression was used to test the association between SDB presence and severity and WUS unadjusted and adjusted for potential confounders including prestroke depression and sleep duration. Results: Among 466 participants, the median age was 67.0 years (interquartile range [IQR] 58.0, 77.0), 55% were Mexican American, and the median initial NIH Stroke Scale score was 3.0 (IQR 1.0, 6.0). Stroke symptom onset occurred during nocturnal sleep (25.3%), during a nap (3.9%), during wakefulness (65.9%), or unknown (4.9%). In those with SDB screening performed (n = 259), a median of 11 days (IQR 5, 17) poststroke, WUS was not associated with the presence or severity (respiratory event index) of SDB in unadjusted or adjusted analysis. Conclusions: In this population-based study, WUS represented about 30% of all generally mild severity ischemic strokes in women and was not associated with SDB. PMID- 29517079 TI - MR and diffusion tensor imaging of isolated tentorial hypoplasia. PMID- 29517080 TI - Correction to: effects of dietary supplementation of a lipid-coated zinc oxide product on the fecal consistency, growth, and morphology of the intestinal mucosa of weanling pigs. AB - [This corrects the article DOI: 10.1186/s40781-017-0159-z.]. PMID- 29517078 TI - Depression, Obstructive Sleep Apnea and Psychosocial Health. AB - Depression and Obstructive sleep apnea (OSA) are the major associated comorbidities. OSA is a rapidly growing problem in the society that is connected to the rising rates of obesity; at the same time, the depression rate is also increasing day by day. Patients with OSA present with sleep problems, anxiety, and depressive symptoms, depressive patients can also present with the same symptoms. The quality of an individual's health can be improved by the early detection of the symptoms of overlapping OSA and depression. By addressing these issues early, the associated healthcare costs and burden can be reduced simultaneously. PMID- 29517081 TI - A severe, relapsing case of myelin oligodendrocyte glycoprotein IgG-associated CNS inflammation. PMID- 29517082 TI - Benralizumab for the treatment of asthma. AB - Benralizumab is a humanized monoclonal antibody directed at the a subunit of the interleukin-5 receptor (IL-5R) that is under clinical development. The binding of benralizumab with the alpha chain of IL-5R results in inhibition of hetero oligomerization of alpha and beta subunits and thus no signal transduction occurs. Consequently, this inhibition prevents proliferation of eosinophils and basophils and the cascade of events following it. Several pivotal trials have documented that benralizumab reduces asthma exacerbation rates with a significant increase in time to the next exacerbation, statistically improves prebronchodilator forced expiratory volume in 1 second (FEV1) and disease specific health-related quality of life, and is well tolerated in patients with severe asthma and blood eosinophil counts greater than or equal to 150 cells/mcL. PMID- 29517083 TI - Durvalumab for the treatment of urothelial carcinoma. AB - Immunotherapy has revolutionized cancer care in the modern era of oncology. Research in immunotherapy has led to important advances in the treatment of melanoma, non-small cell lung cancer and other malignancies using checkpoint inhibition. Multiple systemic immunotherapies have been approved or are currently being investigated for the management of urothelial malignancies (1). Five antibodies targeting the programmed cell death protein 1--programmed cell death 1 ligand 1 (PD-1--PD-L1) pathway have been approved by the U.S. Food and Drug Administration (FDA) for the management of various malignancies: pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab. Recent publications illustrate that in specific stages, immunotherapy is more effective than chemotherapy with a better toxicity profile (1). Currently, the only FDA-approved indication for the anti-PD-L1 monoclonal antibody durvalumab (MEDI-4736) is locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum based chemotherapy within 12 months of treatment. This article summarizes the milestones in the development of durvalumab leading to its approval for urothelial carcinoma. PMID- 29517084 TI - Inotuzumab ozogamicin for the treatment of patients with acute lymphocytic leukemia. AB - Inotuzumab ozogamicin is an antibody-drug conjugate comprised of a humanized anti CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic agent. Inotuzumab ozogamicin binds to CD22-expressing tumor cells, resulting in apoptotic cell death. Based on the results of the pivotal, phase III INO-VATE trial in acute lymphoblastic leukemia (ALL), approval of inotuzumab ozogamicin was recently granted for the treatment of patients with relapsed or refractory ALL, a group that otherwise has a poor prognosis with standard chemotherapy. Several ongoing clinical trials are now testing whether outcomes can be further improved by combining inotuzumab ozogamicin with low-dose chemotherapy or by including inotuzumab ozogamicin in the front-line setting. In this article we discuss the preclinical, clinical and safety data of inotuzumab ozogamicin. PMID- 29517085 TI - European Society of Cardiology Congress 2017 (August 26-30, 2017 - Barcelona, Spain). AB - The annual congress of the European Society of Cardiology (ESC) is the largest medical congress in Europe for this area of research and took place this year in Barcelona, Spain. The ESC Congress 2017 gathered more than 30,000 registered participants from over 140 countries together to share their knowledge in all cardiovascular fields, from basic science to management and prevention of cardiovascular diseases. The congress comprised 5 days of science and education with over 11,000 abstracts submitted, 500 expert sessions and over 200 exhibiting companies, making it the prime meeting platform for the profession. This year's ESC Congress Spotlight was "40 years of percutaneous coronary intervention (PCI)." PCI is a nonsurgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. PMID- 29517087 TI - Electronic and optical properties of hydrogenated group-IV multilayer materials. AB - Hydrogenated group-IV layered materials are semiconducting forms of silicene, germanene and stanene. We systematically studied the evolution of the structural, electronic and optical properties of these 2D materials as a function of the number of layers. We verify that the exfoliation energy increases upon the increase of the atomic number (Si -> Sn) of the group-IV material. We show that silicane, independent of the number of layers, is an indirect band gap (Gamma-M) material. This behavior is different from both germanane and stanane, which are direct band gap (Gamma point) semiconductors. The calculated optical spectra show, for all systems, a red shift in the absorption edges and an enhanced absorption of the visible light for the in-plane (alpha||) component upon the increase in the number of layers and, also as a function of the increasing atomic number. Our findings also indicate that: (i) (XH2)m(YH2)n vdW heterostructures will always present a type-I band alignment for X = Si and Y = Ge or Sn, whereas (ii) for X = Ge and Y = Sn, the band alignment can be tuned (type-I <-> type-II) by the number of layers (m,n). PMID- 29517086 TI - Dynamic self-assembly of DNA minor groove-binding ligand DB921 into nanotubes triggered by an alkali halide. AB - We describe a novel self-assembling supramolecular nanotube system formed by a heterocyclic cationic molecule which was originally designed for its potential as an antiparasitic and DNA sequence recognition agent. Our structural characterisation work indicates that the nanotubes form via a hierarchical assembly mechanism that can be triggered and tuned by well-defined concentrations of simple alkali halide salts in water. The nanotubes assembled in NaCl have inner and outer diameters of ca. 22 nm and 26 nm respectively, with lengths that reach into several microns. Our results suggest the tubes consist of DB921 molecules stacked along the direction of the nanotube long axis. The tubes are stabilised by face-to-face pi-pi stacking and ionic interactions between the charged amidinium groups of the ligand and the negative halide ions. The assembly process of the nanotubes was followed using small-angle X-ray and neutron scattering, transmission electron microscopy and ultraviolet/visible spectroscopy. Our data demonstrate that assembly occurs through the formation of intermediate ribbon-like structures that in turn form helices that tighten and compact to form the final stable filament. This assembly process was tested using different alkali-metal salts, showing a strong preference for chloride or bromide anions and with little dependency on the type of cation. Our data further demonstrates the existence of a critical anion concentration above which the rate of self-assembly is greatly enhanced. PMID- 29517089 TI - Revealing dynamically-organized receptor ion channel clusters in live cells by a correlated electric recording and super-resolution single-molecule imaging approach. AB - The N-methyl-d-aspartate (NMDA) receptor ion-channel is activated by the binding of ligands, along with the application of action potential, important for synaptic transmission and memory functions. Despite substantial knowledge of the structure and function, the gating mechanism of the NMDA receptor ion channel for electric on-off signals is still a topic of debate. We investigate the NMDA receptor partition distribution and the associated channel's open-close electric signal trajectories using a combined approach of correlating single-molecule fluorescence photo-bleaching, single-molecule super-resolution imaging, and single-channel electric patch-clamp recording. Identifying the compositions of NMDA receptors, their spatial organization and distributions over live cell membranes, we observe that NMDA receptors are organized inhomogeneously: nearly half of the receptor proteins are individually dispersed; whereas others exist in heterogeneous clusters of around 50 nm in size as well as co-localized within the diffraction limited imaging area. We demonstrate that inhomogeneous interactions and partitions of the NMDA receptors can be a cause of the heterogeneous gating mechanism of NMDA receptors in living cells. Furthermore, comparing the imaging results with the ion-channel electric current recording, we propose that the clustered NMDA receptors may be responsible for the variation in the current amplitude observed in the on-off two-state ion-channel electric signal trajectories. Our findings shed new light on the fundamental structure-function mechanism of NMDA receptors and present a conceptual advancement of the ion channel mechanism in living cells. PMID- 29517090 TI - One-pot synthesis of diverse N,N'-disubstituted guanidines from N chlorophthalimide, isocyanides and amines via N-phthaloyl-guanidines. AB - A sequential one-pot approach towards N,N'-disubstituted guanidines from N chlorophthalimide, isocyanides and amines is reported. This strategy provides straightforward and efficient access to diverse guanidines in yields up to 81% through previously unprecedented N-phthaloylguanidines. This protocol also features wide substrate scope and mild conditions. PMID- 29517091 TI - The role of unique spatial structure in the volume phase transition behavior of poly(N-isopropylacrylamide)-based interpenetrating polymer network microgels including a thermosensitive poly(ionic liquid). AB - Well-defined poly(N-isopropylacrylamide)/poly(tributylhexylphosphonium 3 sulfopropylmethacrylate) (PNIPAM/P[P4,4,4,6][MC3S]) interpenetrating polymer network (IPN) microgels were synthesized by two-step precipitation polymerization, and the thermally induced phase transition mechanism of IPN microgels was investigated using dynamic light scattering (DLS), temperature dependent IR spectroscopy together with the perturbation correlation moving window (PCMW) technique and two dimensional correlation spectroscopy (2Dcos). For comparison, PNIPAM/P[P4,4,4,6][MC3S] polymer mixture was also studied to reveal the influence of the complex spatial network of IPN on the thermoresponsive behavior. Due to the strong hydrophilic feature of P[P4,4,4,6][MC3S] and the special IPN structure, PNIPAM and P[P4,4,4,6][MC3S] moieties exhibited different phase transition tendencies during heating. In detail, the dehydration behavior of the PNIPAM part seemed gradual and continuous, whereas that of ester C[double bond, length as m-dash]O in the P[P4,4,4,6][MC3S] part became sharp. The two components dehydrated independently and successively in the polymer mixture without any mutual interaction. The collapse of the P[P4,4,4,6][MC3S] network at the second transition stage increased the amount of intramolecular hydrogen bonding (amide C[double bond, length as m-dash]OD-N) in the PNIPAM moiety. Additionally, the electrostatic interaction in the P[P4,4,4,6][MC3S] network played a non-ignorable role in enhancing the swelling property of PNIPAM/P[P4,4,4,6][MC3S] IPN microgels. PMID- 29517093 TI - Photocatalytic activity and charge carrier dynamics of TiO2 powders with a binary particle size distribution. AB - The effects of the particle size distribution on the charge carrier dynamics and the photocatalytic activity of mixed titanium dioxide (TiO2) powder samples were investigated in this work. Instead of the synthesis of the small semiconductor particles, the binary particle size distributions of the powders were obtained by mixing commercially available TiO2 powders with different particle sizes. The pure anatase samples (average diameters: 7, 20, and 125 nm, respectively) were created via ultrasound treatment and discreet drying. The photocatalytic activity of the powder samples was assessed by the degradation of nitric oxide (NO) and acetaldehyde in the gas phase. Furthermore, the charge carrier kinetics was determined using transient absorption spectroscopy following pulsed laser excitation. Importantly, a recently published model based on fractal dimensions was used to fit the transient signals of the photo generated charge carriers in the TiO2 powder samples. The effects of the particle size on the acetaldehyde degradation could be explained by the formation of agglomerates, which reduce the available surface area of smaller particles. The fast oxidation of acetaldehyde on the surface of TiO2 by direct hole transfer was further independent of the observed charge carrier lifetimes on the microsecond time scale. The photocatalytic NO degradation, on the other hand, increased for samples containing larger amounts of small particles. The corresponding photonic efficiencies correlated well with the charge carrier lifetimes determined by the time-resolved studies. Hence, it was concluded that a long charge carrier lifetime generally leads to higher fractional conversions of NO. The employed fractal fit function was proved to be beneficial for the kinetic analysis of charge carrier recombination in TiO2, in direct comparison with a second order fit function. PMID- 29517094 TI - One-step pathway to selenoisobenzofuran-1(3H)-imine derivatives through highly selective selenocyclization of olefinic amides with benzeneselenyl chloride. AB - A 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed selenocyclization of olefinic amides was achieved under mild reaction conditions. The reaction formed various benzeneselenyl substituted isobenzofuran-1(3H)-imine derivatives in good yields. The product was determined using single-crystal X-ray analysis. For compound 2u, the relative stereochemistry was established on the basis of NOESY NMR studies. PMID- 29517096 TI - High-performance deep ultraviolet photodetectors based on few-layer hexagonal boron nitride. AB - Hexagonal boron nitride (h-BN), an isomorph of graphene, has attracted great attention owing to its potential applications as an ultra-flat substrate or gate dielectric layer in novel graphene-based devices. Besides, h-BN appears to be a promising material for deep ultraviolet (DUV) optoelectronic applications because of its extraordinary physical properties, such as wide band gap and high absorption coefficient. In this work, two-dimensional h-BN with controllable layers was synthesized on Cu foils by ion beam sputtering deposition, and DUV photodetectors were fabricated from the transferred h-BN layers on SiO2/Si substrates. The h-BN layers synthesized at the higher substrate temperature possess a lower density of domain boundaries and higher crystalline quality, and the photodetectors based on a 3 nm h-BN layer exhibited high performance with an on/off ratio of >103 under DUV light illumination at 212 nm and a cutoff wavelength at around 225 nm. This work demonstrates that two-dimensional h-BN layers are promising for the construction of high-performance solar-blind photodetectors. PMID- 29517098 TI - Spin coupling interactions in C[double bond, length as m-dash]C or B-B-cored porphyrin-mimetic graphene patch nitroxide diradicals. AB - In view of the unique structures and promising applications of porphyrins and their derivatives, exploration of their various properties has continued to a hot topic. In this work, we combine porphyrin-mimetic graphene patches which are core modified by a C[double bond, length as m-dash]C or a B-B unit and two nitroxide radical groups to construct a series of novel diradical molecules (the CC-cored or BB-cored molecules). The spin coupling constants (J) of diradicals were calculated at the (U)B3LYP/6-311G(d,p) level by considering the different linking modes of two nitroxide groups. The results indicate that different core modification considerably affects the J values of such diradicals, and the linking modes can tune the sizes and signs of J, changing their magnetic coupling interactions with different magnitudes and the signs of J from antiferromagnetic to ferromagnetic or vice versa. More interestingly and importantly, the spin coupling interactions of the CC-cored molecules can also be tuned by stretching the core unit C-C bond, suggesting the possibility of activating specific vibrational modes of the CC-cored diradicals by energy pulses to yield variable J coupling magnitudes. On the other hand, for the BB-cored molecules, two-electron reduction can switch or tune their magnetism from ferromagnetic to antiferromagnetic. The essence of all observations is further analyzed from the structural effects and orbital and spin density distributions. The findings about magnetic regulation in these core-modified porphyrin-mimetic graphene patch nitroxide diradicals further expand the field of molecular magnets and provide a rational theoretical basis for designing novel building blocks of magnetic functional molecular materials. PMID- 29517099 TI - The n ->pi* interaction in metal complexes. AB - We report here, for the first time, the existence of n ->pi* interactions in transition metal complexes containing carbonyl ligands. This interaction has been observed to be surprisingly abundant and to stabilize precise molecular conformations that maximize the overlap between the donor and acceptor orbitals. PMID- 29517100 TI - Biosynthesis and incorporation of an alkylproline-derivative (APD) precursor into complex natural products. AB - Covering: up to 2017This review covers the biosynthetic and evolutionary aspects of lincosamide antibiotics, antitumour pyrrolobenzodiazepines (PBDs) and the quorum-sensing molecule hormaomycin. These structurally and functionally diverse groups of complex natural products all incorporate rarely occurring 4-alkyl-l proline derivatives (APDs) biosynthesized from l-tyrosine through an unusual specialized pathway catalysed by a common set of six proteins named Apd1-Apd6. We give an overview of APD formation, which involves unusual enzyme activities, and its incorporation, which is based either on nonribosomal peptide synthetase (PBDs, hormaomycin) or a unique hybrid ergothioneine-dependent condensation system followed by mycothiol-dependent sulphur atom incorporation (lincosamides). Furthermore, within the public databases, we identified 36 novel unannotated biosynthetic gene clusters that putatively encode the biosynthesis of APD compounds. Their products presumably include novel PBDs, but also novel classes of APD compounds, indicating an unprecedented potential for the diversity enhancement of these functionally versatile complex metabolites. In addition, phylogenetic analysis of known and novel gene clusters for the biosynthesis of APD compounds allowed us to infer novel evolutionary hypotheses: Apd3 methyltransferase originates from a duplication event in a hormaomycin biosynthetic gene cluster ancestor, while putative Apd5 isomerase is evolutionarily linked to PhzF protein from the biosynthesis of phenazines. Lastly, we summarize the achievements in preparing hybrid APD compounds by directing their biosynthesis, and we propose that the number of nature-like APD compounds could by multiplied by replacing l-proline residues in various groups of complex metabolites with APD, i.e. by imitating the natural process that occurs with lincosamides and PBDs, in which the replacement of l-proline for APD has proved to be an evolutionary successful concept. PMID- 29517102 TI - Light triggered uncaging of hydrogen sulfide (H2S) with real-time monitoring. AB - An ESIPT based light activated hydrogen sulfide (H2S) donor using a p hydroxyphenacyl phototrigger has been developed. The unique feature of our H2S donor system is that it provides real-time monitoring of H2S release by a non invasive fluorescence colour change approach. PMID- 29517103 TI - Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo. AB - Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1 VEGFR3, FGFR1-FGFR4, PDGFRalpha, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages. The effect of lenvatinib (1 and 100 nM; and 1, 10, 25 and 50 uM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CD nu/nu mice. Lenvatinib significantly reduced ATC cell proliferation (P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion (P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CD nu/nu mice and tumor masses were observed 20 days later. Tumor growth was significantly inhibited by lenvatinib (25 mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications. PMID- 29517104 TI - MicroRNA-448 inhibits the progression of retinoblastoma by directly targeting ROCK1 and regulating PI3K/AKT signalling pathway. AB - Retinoblastoma (RB) is the most common primary intraocular malignancy during infancy and childhood worldwide. Numerous microRNAs (miRNAs) contribute to RB initiation and progression through the regulation of cell proliferation, cycle, apoptosis, migration, invasion and metastasis. Therefore, further investigation concerning the expression, roles and associated mechanisms of RB-related miRNAs may be beneficial to develop novel strategies for patients with this malignancy. Recently, miRNA-448 (miR-448) has been reported to be aberrantly expressed and to play an important role in several types of human cancer. However, the expression patterns and biological roles of miR-448 in RB have not been studied. The aim of the present study was to detect the expression levels of miR-448 and investigate its functions in RB and its associated molecular mechanisms. In the present study, miR-448 was significantly downregulated in RB tissues and cell lines. Upregulation of miR-448 decreased cell proliferation and invasion and increased apoptosis in RB cells. Additionally, rho-associated coiled-coil containing protein kinase 1 (ROCK1) was validated as a novel direct target gene of miR-448 in RB. ROCK1 was overexpressed in RB tissues and inversely correlated with miR 448 expression. Furthermore, ROCK1 silencing induced effects on the proliferation, invasion and apoptosis of RB cells similar to those observed following miR-448 overexpression. Moreover, restoration of miR-448 expression markedly reversed the effects of miR-448 overexpression on RB cells, further supporting the hypothesis that ROCK1 is a direct functional target of miR-448 in RB. Importantly, miR-448 targeted ROCK1 to inhibit the activation of the PI3K/AKT signalling pathway in RB. These results demonstrated that miR-448 may serve as a tumour suppressor in RB by directly targeting ROCK1 and regulating the PI3K/AKT signalling pathway, thereby suggesting that miR-448 may be an effective therapeutic target for treating this aggressive cancer. PMID- 29517105 TI - Delineating the underlying molecular mechanisms and key genes involved in metastasis of colorectal cancer via bioinformatics analysis. AB - Colorectal cancer (CRC) is considered the world's fourth most deadly cancer. Its metastasis is associated with poor prognosis and weakens the effects of treatment. However, the potential molecular mechanisms and key genes involved in CRC metastasis have remained to be comprehensively elucidated. The objective of the present study was to identify the key genes and molecular pathways underlying CRC metastasis. Differentially expressed genes (DEGs) between primary CRC tissues and metastatic CRC were identified by analyzing the GSE2509 dataset from the Gene Expression Omnibus database. Subsequently, the DEGs were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses via the Database for Annotation, Visualization and Integrated Discovery (DAVID). Next, the top ten hub genes were identified in a protein protein interaction (PPI) network. Sub-network and pathway enrichment analysis were respectively performed with the plugin MCODE and DAVID. Finally, reverse transcription-quantitative polymerase chain reaction assays were performed to corroborate the expression levels of the top five potential metastasis-associated genes in the clinical samples of CRC patients. A total of 7,384 DEGs were obtained, among which 3,949 were upregulated and 3,435 were downregulated. GO and KEGG enrichment analyses identified numerous possible biological processes and pathways that may have a role in the metastasis of CRC. The leading ten hub genes, recognized from the PPI, were epidermal growth factor receptor (EGFR), Has proto-oncogene GTPase (HRas), Wnt family member 5A (Wnt5a), serine/threonine kinase 1 (Akt1), cyclin-dependent kinase inhibitor 1A (CDKN1a), early growth response 1, Ras homolog family member A, cyclin D1 and Ras-related C3 botulinum toxin substrate 1. Sub-network analysis disclosed the most prominent three modules. Ultimately, EGFR, HRas and Akt1 were verified to be upregulated DEGs, while Wnt5a and CDKN1a were downregulated DEGs when compared with the primary controls. In conclusion, the present study revealed several key genes and relevant molecular mechanisms that may enhance the current understanding of CRC metastasis, making them significant potential foci for the discovery of further CRC treatments. PMID- 29517106 TI - Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo. AB - The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 uM) was tested by WST-1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose-dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF-A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation. PMID- 29517107 TI - FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial-mesenchymal transition to gefitinib. AB - Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p-FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p-FGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK-8 assay, flow cytometry and western blotting assays. Twenty-six patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of p-FGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high p-FGFR1 level group (26.9 vs. 8.2%, P=0.003). The IC50 values of gefitinib alone and in combination with 500 nM AZD4547 were 22.9+/-2.1 and 4.13+/-0.12 uM in TE10 cells, and 9.85+/-5.5 and 3.21+/-0.76 uM in EC9706 cells, respectively. The combination of AZD4547 and gefitinib induced robust apoptosis and decreased clone formation ability compared to gefitinib monotherapy in the TE10 cells. TE10 cells exhibited a mesenchymal phenotype, with a higher level of p-FGFR1 and p-AKT than that in EC9706 cells. AZD4547 and gefitinib co-treatment resulted in a significant decrease in the level of p-AKT in TE10 cells and a complete inhibition of phosphorylation of ERK1/2 in EC9706 cells. Collectively, AZD4547 can improve sensitivity of ESCC cells to gefitinib. PMID- 29517108 TI - Vanadium pentoxide induces the secretion of CXCL9 and CXCL10 chemokines in thyroid cells. AB - Vanadium is a grey metal, existing in different states of oxidation, whose most common form in commercial products is vanadium pentoxide (V2O5). All vanadium compounds have been considered toxic. A carcinogenic role of vanadium on the thyroid has recently been proposed. However no in vivo or in vitro studies have evaluated thyroid disruption in humans and/or animals after exposure to vanadium. In the present study we evaluate the effect of V2O5 on proliferation, and chemokine secretion in normal thyrocytes. Our study demonstrated that V2O5 has no effect on thyroid follicular cell viability or proliferation, but it is able to induce the secretion of T-helper (Th)1 chemokines into the thyroid, synergistically increasing the effect of important Th1 cytokines such as interferon (IFN)gamma and tumor necrosis factor (TNF)alpha. Through this process, V2O5 promotes the induction and perpetuation of an inflammatory reaction in the thyroid. Further studies are necessary to evaluate thyroid function, and nodules, in subjects occupationally exposed, or living in polluted areas. PMID- 29517109 TI - Skepticism, cerebral palsy, and the General Movements Assessment. PMID- 29517111 TI - The Pathways and Resources for Participation and Engagement (PREP): methodological contributions to environment-focused interventions. PMID- 29517110 TI - Symptomatic hallux valgus and dorsal bunion in adolescents with cerebral palsy: clinical and biomechanical factors. AB - AIM: The prevalence of severely symptomatic deformities of the first metatarsophalangeal (MTP) joint in adolescents with cerebral palsy (CP) requiring arthrodesis is unknown. Recent literature regarding these deformities is limited. We studied the presentation of severe, symptomatic deformities of the first ray in a large population of children and adolescents with CP and their association with gross motor function, CP subtype, and other musculoskeletal deformities. METHOD: We identified 41 patients with CP and a symptomatic deformity of the first MTP joint, managed by arthrodesis, from a large population based database over a 21-year period. Information recorded included demographics, CP subtype, Gross Motor Function Classification System (GMFCS), clinical presentation, and radiological features. RESULTS: Adolescents with spastic diplegia, at GMFCS levels II and III, were the most common group to develop symptomatic hallux valgus. In contrast, non-ambulant adolescents, at GMFCS levels IV and V, with dystonia or mixed tone, more commonly had dorsal bunions. INTERPRETATION: The type of first MTP joint deformity in patients with CP may be predicted by the type and distribution of movement disorder, and by GMFCS level. Specific patterns of associated musculoskeletal deformities may contribute to the development of these disorders and may provide a guide to surgical management. WHAT THIS PAPER ADDS: The prevalence of severe bunions requiring fusion surgery was 2%. The two types of bunion were hallux valgus and dorsal bunion. The type of bunion can be identified on both clinical and radiological grounds. The cerebral palsy subtype is predictive of the type of bunion. PMID- 29517113 TI - Muscle tone is not a well-defined term. PMID- 29517112 TI - Population pharmacokinetics of ceftazidime after a single intramuscular injection in wild turtles. AB - Ceftazidime, a third-generation cephalosporin, is important for treating opportunistic bacterial infections in turtles. Antibacterial dosage regimens are not well established for wild turtles and are often extrapolated from other reptiles or mammals. This investigation used a population pharmacokinetic approach to study ceftazidime in wild turtles presented for rehabilitation. Ceftazidime was administered to 24 wild turtles presented to the Turtle Rescue Team at North Carolina State University. A sparse blood sampling protocol was used to collect samples from 0 to 120 hr with three samples per individual after injection. Plasma samples were analyzed by high-pressure liquid chromatography (HPLC). A nonlinear mixed-effects model (NLME) was fitted to the data to determine typical values for population parameters. We identified a long half life (T1/2) of approximately 35 hr and volume of distribution (VSS ) of 0.26 L/kg. We concluded that this long T1/2 will allow for a dose of 20 mg/kg injected IM to maintain concentrations above the MIC of most wild-type bacteria for 5 days. Because of long intervals between injections, stability of stored formulations was measured and showed that 90% strength was maintained for 120 hr when stored in the refrigerator and for 25 days when stored in the freezer. PMID- 29517114 TI - Nickel-Catalyzed Alkylarylation of Activated Alkenes with Benzyl-amines via C-N Bond Activation. AB - A nickel-catalyzed alkylarylation of active alkenes with tertiary benzylamines was achieved by charge-transfer-complex promoted C-N bond activation. The reaction proceeded through initial Ni-catalyzed C-N bond activation, followed by sequential radical addition, redox and proton abstraction with cleaved amine moiety in the absence of oxidant, and provides an efficient method to prepare various alkyl-substituted oxindoles and dihydroquinolinones in good yields. PMID- 29517115 TI - Influence of Social Perception and Social Monitoring on Structural Priming. AB - Although structural priming has been considered to be an independent cognitive process, recent evidence suggests that structural priming is modulated by sociocognitive factors such as social perception; speakers are more likely to mimic the sentence structure of a socially desirable interlocutor than the structure of a less desirable interlocutor. This study aims to further address the role of sociocognitive factors in language use by investigating how individual differences in social perception and tendency to align with others (i.e., social monitoring) modulate same-verb structural priming. In particular, we investigate how likely students are to repeat a sentence structure of a teacher depending on their perception of the teacher and their social monitoring tendency. Our results demonstrate that students' tendency to imitate a sentence structure of the teacher is positively influenced by their perception of the teacher but negatively by social monitoring. We suggest that the effects may be accounted for in terms of their influence on attention and memory encoding. PMID- 29517116 TI - Dermatofibrosarcoma protuberans-A rare lesion on breast. PMID- 29517117 TI - Global human papilloma virus vaccine implementation: An update. AB - Human papillomavirus (HPV) infections continue to be one of the most common sexually transmitted infections worldwide. The oncogenic potential of this virus was well established in anogenital malignancies and oropharyngeal cancers. Even though a fall in cervical cancer rates has been reported worldwide, the subsequent rise in HPV-associated head and neck cancers among men and women have been reported from developed countries, necessitating the vaccination of adolescent boys as well. The objective of this narrative review is to provide an update on the current status of HPV vaccination worldwide. This will be helpful for clinicians in counseling parents and guardians as this vaccine mainly targets sexually naive preadolescents. An electronic search of the databases was carried out to retrieve information concerning HPV vaccine implementation between July 2006 and 2017, with special emphasis on the current viewpoints, controversies and ethical issues. Globally, 74 countries have implemented the HPV vaccine in the national immunization schedule, and this vaccine is listed as an essential medicine by WHO. About 60% of the low- and lower-middle-income countries have implemented the vaccine with financial assistance from Gavi and WHO. The HPV vaccine is a safe vaccine with no serious adverse effects as per the data available from developed nations as well as low/lower middle/upper middle-income countries. However, long-term follow-up is essential to substantiate the impact of the vaccination programs in cancer prevention. PMID- 29517118 TI - Insulin treatment in patients with diabetes and heart failure: defendant on the stand. PMID- 29517119 TI - Salivary testosterone may not serve as a screening test in the diagnosis of biochemical hyperandrogenism. AB - AIM: The diagnosis of biochemical hyperandrogenism is still challenging because a set of appropriate, recommended diagnostic tests has not been established. In our study, we aimed to answer the question of whether salivary testosterone is a reliable test to establish the diagnosis of biochemical hyperandrogenism as compared to serum total testosterone (TT) measured either by liquid chromatography-tandem mass spectrometry (LC-MS/MS) or immunoassay and to assess which set of biochemical tests would be the most appropriate for the identification of biochemical hyperandrogenism. METHODS: A total of 39 women, aged 18-45 years, with clinical or biochemical hyperandrogenism and 41 healthy individuals, aged 19-45 years, were enrolled in the study. Salivary testosterone was measured using the Salimetrics test. Serum TT was measured either using the LC-MS/MS method or immunoassay, and dehydroepiandrosterone sulphate (DHEA-S) and androstenedione were measured using LC-MS/MS. RESULTS: In 15 of 17 (88%) patients with elevated serum TT measured by LC-MS/MS and in 14 of 16 (87%) measured with immunoassay, salivary testosterone showed normal levels. In 11 of 39 women (28%) with normal serum testosterone levels, DHEA-S was elevated. All patients with elevated androstenedione presented with an elevated concentration of either serum testosterone or DHEA-S. CONCLUSION: Salivary testosterone measurement may lead to the underdiagnosis of biochemical hyperandrogenism. Both serum testosterone and DHEA-S should be measured in the endocrine work-up toward biochemical hyperandrogenism. PMID- 29517120 TI - Relationship between corneal sensitivity, corneal thickness, corneal diameter, and intraocular pressure in normal cats and cats with congenital glaucoma. AB - OBJECTIVE: To determine the effect of feline congenital glaucoma (FCG) on corneal sensitivity, and relationships between corneal sensitivity, central corneal thickness (CT), and corneal diameter (CD). ANIMALS AND PROCEDURES: Corneal sensitivity (estimated by corneal touch threshold [CTT] using Cochet-Bonnet esthesiometry); CT using ultrasonic pachymetry; intraocular pressure (IOP) using rebound tonometry; and maximal horizontal CD were measured in 16 normal and 14 FCG cats, both males and females, aged 7 months-3.5 years. All procedures complied with an Institutional Animal Care and Use Committee-approved protocol. Data were analyzed by linear regression: paired Student's t tests for between-eye comparisons, and unpaired Student's t tests for comparisons between groups. Relationships between parameters were evaluated by Pearson correlation coefficients and linear mixed effects modeling. For statistical tests, with the exception of values that were Benjamini-Hochberg adjusted for multiple comparisons, P-values < 0.05 were considered significant. RESULTS: Mean CTT and CT values were lower in FCG eyes relative to normal eyes, but differences were not statistically significant. Mean CD was significantly larger in FCG eyes relative to normal eyes, and there was a significant negative correlation between CD and CTT in FCG (r = -0.8564, corrected P = 0.005). These associations were confirmed in linear mixed effects models. CONCLUSIONS: Eyes with FCG have significantly larger CDs when compared with normal eyes, and larger CDs correlated with decreased corneal sensitivity in this group. Further studies are warranted to explore the effect of buphthalmos and corneal enlargement on corneal sensitivity and innervation in feline subjects with chronic glaucoma. PMID- 29517121 TI - Effects of three gamma-alkylidene-gamma-lactams on the formation of multispecies biofilms. AB - This study evaluated the inhibitory effects of lactams on Streptococcus mutans, Enterococcus faecalis, and Candida glabrata multispecies biofilm formation. gamma Alkylidene-gamma-lactams 1, 2, and 3 [solubilized in 3.5% dimethyl sulfoxide (DMSO)] were tested. Glass coverslips were conditioned with either the lactams or 3.5% DMSO (control) for 1 h, inoculated with microbial cultures, and incubated for 48 h. To assess the effect of the lactams on biofilm formation, the following parameters were determined: the biofilm biomass (by both crystal violet staining and protein determination); the amount of insoluble polysaccharides of the extracellular matrix; and the number of viable and total cells [by both colony forming unit counting and quantitative real-time PCR (qPCR)]. Data were analysed using one-way anova and post-hoc Tukey tests. Lactams 1, 2, and 3 promoted a statistically significant reduction in the amount of biofilm biomass, but only lactam 3 resulted in a statistically significant reduction in the number of attached viable E. faecalis. Both total protein content and the amount of extracellular polysaccharides decreased significantly. The effects of gamma alkylidene-gamma-lactams 1, 2, and 3 on the inhibition of multispecies biofilm formation were evident by their ability to reduce the amount of protein and extracellular polysaccharides. PMID- 29517122 TI - Interaction of systolic blood pressure and resting heart rate with clinical outcomes in takotsubo syndrome: insights from the International Takotsubo Registry. AB - AIMS: The present study aimed to determine the prognostic impact of resting heart rate (HR) and systolic blood pressure (SBP) in takotsubo syndrome (TTS). METHODS AND RESULTS: Patients from the International Takotsubo Registry with complete data on HR and SBP were enrolled. We analysed all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE) in tertiles of HR (<77 b.p.m., 77-94 b.p.m., >94 b.p.m.) and SBP (<119 mmHg, 119-140 mmHg, >140 mmHg). In addition, linear splines with interactions between HR and SBP were analysed. The risk of all-cause mortality was higher in the second HR tertile (1.89, 1.15-3.10; P = 0.012) and the third HR tertile (3.01, 1.90-4.79; P < 0.001) than in the first tertile. Similar effects were observed for MACCE. Low SBP was related to an increased risk of all-cause mortality (P < 0.001) and MACCE (P = 0.002). In a multivariable analysis of all-cause mortality, at HR >70 b.p.m., every 1 b.p.m. increase in HR was associated with a 1.7% increase (P < 0.001), and every 1 mmHg increase in SBP up to 130 mmHg was associated with a 2% risk reduction (P < 0.001). The risk of all-cause mortality thus was particularly elevated when low SBP occurred together with high HR. CONCLUSIONS: High HR and low SBP are associated with an increased risk of all-cause mortality in TTS. HR reduction might be worthy of being investigated as a therapeutic strategy for this condition and high HR and low SBP can be used to evaluate risk in this acute presentation of TTS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01947621. PMID- 29517123 TI - In silico Predicted Glucose-1-phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence. AB - Peptidoglycan walls of gram positive bacteria are functionalized by glycopolymers called wall teichoic acid (WTA). In Listeria monocytogenes, multiple enzymes including the glucose-1-phosphate uridylyltransferase (GalU) were identified as mandatory for WTA galactosylation, so that the inhibition of GalU is associated with a significant attenuation of Listeria virulence. Herein, we report on a series of in silico predicted GalU inhibitors identified using structure-based virtual screening and experimentally validated to be effective in blocking the WTA galactosylation pathway in vitro. Several hits such as C04, a pyrimidinyl benzamide, afforded promising experimental potencies. This proof-of-concept study opens new perspectives for the development of potent and selective GalU inhibitors of high interest to attenuate Listeria virulence. It also underscores the high relevance of using molecular modeling for facilitating the identification of bacterial virulence attenuators and more generally antibacterials. PMID- 29517125 TI - Corrigendum. PMID- 29517124 TI - Acute heart failure: lessons learned, roads ahead. PMID- 29517126 TI - Detection of trace amounts of citrinin in dried orange peel by using an optimized extraction method coupled with ultra-performance liquid chromatography-tandem mass spectrometry. AB - A fast and sensitive method involving ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was introduced to detect citrinin in dried orange peel. A series of extraction, purification and chromatographic conditions was also systematically examined. With the proposed method, the obtained calibration graph was linear, with an R of 0.9996 within a concentration range of 0.5-10 ng/mL. The estimated limits of detection and quantification were 0.05 and 0.17 ng/mL, respectively. Under the selected conditions, the relative recoveries in different citrus products spiked with 1-10 ng/mL citrinin were 89.4-98.7% with RSDs of <2.5%. Compared with previously reported analytical methods, the newly developed UPLC-MS/MS method showed excellent sensitivity and good precision in detecting citrinin. The results indicated that it is a reliable and effective technique for the detection of trace citrinin in dried orange peel. PMID- 29517127 TI - Large-Scale Hospital Mattress Switch-Out Leads to Reduction Hospital-Acquired Pressure Ulcers: Operationalization of a Multidisciplinary Task Force. AB - BACKGROUND: Identifying strategies to protect patients most at risk for hospital acquired pressure ulcers (HAPU) is essential. HAPUs have significant impact on patients and their families and have profound cost and reimbursement implications. AIMS: This article describes the successful implementation of a hospital-wide mattress switch-out program using a Multidisciplinary Task Force, which resulted in a decrease in HAPUs and significant cost savings. RESULTS: As a result of this quality improvement project supported by evidence, the hospital realized a 66.6% decrease in Stage III and IV HAPUs, a 50% reduction in patient complaints about mattress comfort, a cost savings of $714,724, and an endorsement of bedside nurse clinical autonomy by nursing and executive leaders. LINKING EVIDENCE TO ACTION: Nursing leaders can effectively realize large-scale initiatives by developing and implementing wide-ranging operational projects, like this 2.5-day, 275-bed hospital mattresses switch-out. PMID- 29517128 TI - Noctural dipping status and left ventricular hypertrophy: A cardiac magnetic resonance imaging study. AB - We investigate the impact of dipper status on cardiac structure with cardiovascular magnetic resonance (CMR). Ambulatory blood pressure monitoring and 1.5T CMR were performed in 99 tertiary hypertension clinic patients. Subgroup analysis by extreme dipper (n = 9), dipper (n = 39), non-dipper (n = 35) and reverse dipper (n = 16) status was performed, matched in age, gender and BMI. Left ventricular (LV) mass was significantly higher for extreme dippers than dippers after correction for covariates (100 +/- 6 g/m2 vs 79 +/- 3 g/m2 , P = .004). Amongst extreme dippers and dippers (n = 48), indexed LV mass correlated positively with the extent of nocturnal blood pressure dipping (R = .403, P = .005). On post-hoc ANCOVA, the percentage of nocturnal dip had significant effect on indexed LV mass (P = .008), but overall SBP did not (P = .348). In the tertiary setting, we found a larger nocturnal BP drop was associated with more LV hypertrophy. If confirmed in larger studies, this may have implications on nocturnal dosing of anti-hypertensive medications. PMID- 29517129 TI - Functional mobility and self-care outcomes after multilevel orthopaedic surgery in children with cerebral palsy. PMID- 29517130 TI - Prevalence of hidradenitis suppurativa in Brazil: a population survey. PMID- 29517131 TI - Design, Synthesis, and in vitro Evaluation of Multivalent Drug Linkers for High Drug-Load Antibody-Drug Conjugates. AB - A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. ~4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS. Using this approach, ADCs with significantly lower aggregation and higher DAR than those of conventional drug linker design were obtained with highly hydrophobic cytotoxic agents such as monomethyldolastatin 10 (MMAD). The in vitro potencies of the MDL-derived conjugates matched that of ADCs of similar DAR with conventional linkers, and the potency increased proportionally with drug loading. This approach may provide a means to prepare highly potent ADCs from a broader range of drugs, including those with lower cytotoxicity or poor solubility, which otherwise limits their use for antibody-drug conjugates. This may also provide a means to further improve the potency achievable with cytotoxins currently used in ADCs. PMID- 29517132 TI - Initial Clinical Experience with AZD5718, a Novel Once Daily Oral 5-Lipoxygenase Activating Protein Inhibitor. AB - We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4 ) production in whole blood and endogenous leukotriene E (LTE4 ) in urine. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half-life of 10-12 h. Steady-state levels were achieved after ~3 days. After both SADs and MADs, a dose/concentration-effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50 ) values in the lower nM range. Based on obtained result, AZD5718 is considered as a suitable drug candidate for future evaluation in patients with coronary artery disease (CAD). PMID- 29517133 TI - Real-space grid representation of momentum and kinetic energy operators for electronic structure calculations. AB - We show that the central finite difference formula for the first and the second derivative of a function can be derived, in the context of quantum mechanics, as matrix elements of the momentum and kinetic energy operators on discrete coordinate eigenkets |xn> defined on a uniform grid. Starting from the discretization of integrals involving canonical commutations, simple closed-form expressions of the matrix elements are obtained. A detailed analysis of the convergence toward the continuum limit with respect to both the grid spacing and the derivative approximation order is presented. It is shown that the convergence from below of the eigenvalues in electronic structure calculations is an intrinsic feature of the finite difference method. (c) 2018 Wiley Periodicals, Inc. PMID- 29517135 TI - Formation of Uniform Water Microdroplets on Wrinkled Graphene for Ultrafast Humidity Sensing. AB - Portable humidity sensors with ultrafast responses fabricated in wearable devices have promising application prospects in disease diagnostics, health status monitoring, and personal healthcare data collecting. However, prolonged exposures to high-humidity environments usually cause device degradation or failure due to excessive water adsorbed on the sensor surface. In the present work, a graphene film based humidity sensor with a hydrophobic surface and uniformly distributed ring-like wrinkles is designed and fabricated that exhibits excellent performance in breath sensing. The wrinkled morphology of the graphene sensor is able to effectively prevent the aggregation of water microdroplets and thus maximize the evaporation rate. The as-fabricated sensor responds to and recovers from humidity in 12.5 ms, the fastest response of humidity sensors reported so far, yet in a very stable manner. The sensor is fabricated into a mask and successfully applied to monitoring sudden changes in respiratory rate and depth, such as breathing disorder or arrest, as well as subtle changes in humidity level caused by talking, cough and skin evaporation. The sensor can potentially enable long-term daily monitoring of breath and skin evaporation with its ultrafast response and high sensitivity, as well as excellent stability in high-humidity environments. PMID- 29517136 TI - Unilateral rapid enlargement of an adolescent breast: pseudoangiomatous stromal hyperplasia in a giant juvenile fibroadenoma. PMID- 29517134 TI - Clinical application of serum anti-Mullerian hormone as an ovarian reserve marker: A review of recent studies. AB - It has been more than 15 years since the measurement of serum anti-Mullerian hormone (AMH) first allowed the quantitative assessment of ovarian reserve. Meanwhile, the clinical implication of serum AMH has been expanding. The measurement of serum AMH has been applied in various clinical fields, including assisted reproduction, menopause, reproductive disorders and assessment of ovarian damage/toxicity. Well-known findings about the usefulness of serum AMH revealed by numerous studies executed in the early era include decline with aging, a good correlation with oocyte yield in assisted reproduction, upregulation in polycystic ovarian syndrome and a decrease on ovarian surgery and toxic treatment. More intensive research, including a meta-analysis, cutting-edge clinical trial and advances in AMH assays, has yielded newer findings and firmer clinical interpretations in serum AMH in the past few years. Variations in the AMH decline trajectory in the general population do not support the accurate prediction of menopause. The ability to predict pregnancy in infertility treatment and natural conception is poor, while a nomogram integrating serum AMH as a stimulation protocol is useful for avoiding poor and/or hyper-responses. On the other hand, improvements in measuring very low concentrations of serum AMH may be capable of distinguishing women with poor ovarian function. Age independent standardization of AMH values may be helpful for comparing ovarian reserves among women at different ages. PMID- 29517137 TI - Depression and anxiety during pregnancy: The influence of maternal characteristics. AB - BACKGROUND: Depression and anxiety during pregnancy are associated with adverse health outcomes for both mother and child. This study aims to investigate the occurrence of symptoms of depression and anxiety in early and late pregnancy, the longitudinal changes from early to late pregnancy, and factors associated with symptoms of depression and anxiety in pregnant women in the Netherlands. METHODS: We studied 2897 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study. To assess symptoms of depression and anxiety, web-based questionnaires including the Hospital Anxiety and Depression Scale (HADS) and multiple questions on maternal characteristics were completed in early and late pregnancy. Cross-sectional and longitudinal multivariable linear regression analyses were conducted. RESULTS: The depressive symptoms in our population increased, with a prevalence of probable depression from 5.4% in early pregnancy to 10.0% in late pregnancy (P < .001), whereas the anxiety symptoms decreased, with a prevalence of probable anxiety from 17.9% to 14.2% (P < .001). Characteristics associated with depressive or anxiety symptoms included low level of education, multiparity, a history of depression, severe nausea, extreme fatigue, lack of physical exercise, and negative life events. Being non-Dutch, not living with a partner, and having an unplanned pregnancy or a long time to pregnancy were associated with the depressive and/or anxiety symptoms in early pregnancy only. DISCUSSION: Symptoms of depression and anxiety are common in both early and late pregnancy. Screening for risk factors in early pregnancy is important, since prenatal depression and anxiety may be related to adverse maternal and child health outcomes. PMID- 29517138 TI - A Metal-Organic Framework with Optimized Porosity and Functional Sites for High Gravimetric and Volumetric Methane Storage Working Capacities. AB - Extensive research has been devoted to developing new porous materials with high methane storage capacity. While great progress has been made in recent years, it still remains very challenging to target simultaneously high gravimetric and volumetric methane (CH4 ) working capacities (deliverable amount between 5.8 and 65 bar) in a single material. Here, a novel metal-organic framework (termed as UTSA-110a) constructed by an extended linker containing a high density of functional nitrogen sites, exhibiting both very high gravimetric and volumetric working capacities of 317 cm3 (STP: 273.15 K, 1 atm) g-1 and 190 cm3 (STP) cm-3 , respectively, for robust MOFs, is reported. Both of these values are higher than those of two benchmark materials: HKUST-1 (207 cm3 (STP) g-1 or 183 cm3 (STP) cm 3 ) and UTSA-76a (267 cm3 (STP) g-1 or 187 cm3 (STP) cm-3 ). Computational studies reveal that it is the combination of optimized porosity and favorable binding sites that leads to the simultaneously high gravimetric and volumetric working capacities in this material. PMID- 29517139 TI - Accelerated phase contrast MRI using hybrid one- and two-sided flow encodings only (HOTFEO). AB - The aim of this work was to develop and evaluate a fast phase contrast magnetic resonance imaging (PC-MRI) technique with hybrid one- and two-sided flow encodings only (HOTFEO) for accurate blood flow and velocity measurements of three-directional velocity encoding PC-MRI. Four-dimensional (4D) PC-MRI acquires flow-compensated (FC) and three-directional flow-encoded (FE) echoes in an interleaved fashion. We hypothesize that the blood flow velocity direction (not magnitude) has minimal change between two consecutive cardiac phases. This assumption provides a velocity direction constraint that can achieve 4/3-fold acceleration using three-directional FE data to calculate FC data instead of acquiring them. The HOTFEO acquisition pattern can address the ill-conditioned constraint and improve the calculation accuracy. HOTFEO was evaluated in healthy volunteers and compared with conventional two-dimensional (2D) and 4D flow imaging techniques with FC and three-directional FE acquisitions (FC/3FE). Compared with FC/3FE, Bland-Altman tests showed that the 4/3-fold accelerated HOTFEO technique resulted in relatively small bias error for total volumetric flow (0.89% for prospective 2D data, -1.19% for retrospective 4D data and -3.40% for prospective 4D data) and maximum peak velocity (0.50% for prospective 2D data, -0.17% for retrospective 4D data and -2.00% for prospective 4D data) measurements in common carotid arteries. HOTFEO can accelerate three-directional velocity encoding PC-MRI whilst maintaining the measurement accuracy of the total volumetric flow and maximum peak velocity. PMID- 29517140 TI - A Social Approach to Rule Dynamics Using an Agent-Based Model. AB - A well-trod debate at the nexus of cognitive science and linguistics, the so called past tense debate, has examined how rules and exceptions are individually acquired (McClelland & Patterson, ; Pinker & Ullman, ). However, this debate focuses primarily on individual mechanisms in learning, saying little about how rules and exceptions function from a sociolinguistic perspective. To remedy this, we use agent-based models to examine how rules and exceptions function across populations. We expand on earlier work by considering how repeated interaction and cultural transmission across speakers affects the dynamics of rules and exceptions in language, measuring linguistic outcomes within a social system rather than focusing individual learning outcomes. We consider how population turnover and growth effect linguistic rule dynamics in large and small populations, showing that this method has considerable potential particularly in probing the mechanisms underlying the linguistic niche hypothesis (Lupyan & Dale, ). PMID- 29517141 TI - The Relationship Among Change Fatigue, Resilience, and Job Satisfaction of Hospital Staff Nurses. AB - PURPOSE: The purpose of this study was to examine relationships between change fatigue, resilience, and job satisfaction among novice and seasoned hospital staff nurses. BACKGROUND: Health care is typified by change. Frequent and vast changes in acute care hospitals can take a toll on nurses and cause change fatigue, which has been largely overlooked and under-researched. DESIGN AND METHOD: A descriptive correlational design was employed with 521 hospital staff nurses in one midwestern state. Participants completed three online surveys: (a) Change Fatigue Scale, (b) Connor-Davidson Resilience Scale, and (c) McCloskey/Mueller Satisfaction Scale. FINDINGS: In a multiple regression model, job satisfaction had a statistically significant negative association with change fatigue (p < .001) and significant positive association with resilience (p < .001). A linear trend was found with hospital size (number of beds) and change fatigue (p = .001) and education level and resilience (p = .03). CONCLUSIONS: The results are consistent with job satisfaction among hospital nursing staff being negatively influenced by change fatigue and positively influenced by resilience, although reverse causal connections are also possible. Change fatigue may be increased by larger hospital size (number of beds), and resilience may be increased by higher educational level of hospital staff nurses. CLINICAL RELEVANCE: The study advanced the nursing knowledge on change fatigue, resilience, and job satisfaction of staff nurses working in acute care hospitals. Engaging in strategies aimed at preventing change fatigue in nursing staff can enhance workplace environments, job satisfaction, and retention of nurses. PMID- 29517142 TI - A breast multi-disciplinary genomic tumor board is feasible and can provide timely and impactful recommendations. PMID- 29517143 TI - Association between demographics and resilience - a cross-sectional study among nurses in Singapore. AB - AIM: To give an overview of the level of resilience among nurses in Singapore and to examine associations between various demographics variables and resilience level. BACKGROUND: The World Health Organization reported a global needs-based shortage of over 9 million nurses and midwives in 2013. Building resilience among nurses has been postulated as one of the ways to support and retain nurses in the profession. METHOD: A self-reported questionnaire consisting of questions on demographics and the Connor-Davidson Resilience Scale CD-RISC 10 was used. RESULTS: Univariate analysis identified marital status, age group, years of experience in nursing, highest education qualification and job grade to have significant associations with resilience. During multivariate analysis, only marital status, age group, highest educational qualification and job grade remained significant. A strong association was found between highest educational qualification and resilience level; nurses with bachelor's or postgraduate degree were about three times more likely than nurses with only a general nursing certificate to be of moderate/high resilience. CONCLUSION: The experience of life events (as exemplified by marital status, age and working experience) was associated with higher resilience levels. IMPLICATIONS FOR NURSING POLICY: There is a need for healthcare organizations and nurse leaders to develop programmes focusing on building resilience among younger and less experienced nurses. Nurses should also be supported in their pursuits for higher education, which will in turn lead to higher resilience, and consequently, retention of nurses within the profession and institution. PMID- 29517144 TI - Utility of fetal anteroposterior to transverse cerebellar diameter ratio to exclude cerebellar hypoplasia in trisomy 18. AB - AIM: This study was aimed to determine reference ranges for fetal cerebellar hemisphere biometry, including the transverse cerebellar diameter (TCD), anteroposterior cerebellar diameter (APCD) and APCD/TCD ratio in normal fetuses. In addition, we investigated which parameter would be useful for cerebellar hypoplasia in trisomy 18. METHODS: This retrospective study included 340 normal singleton pregnancies and 15 cases of trisomy 18, in all of which fetal cerebellar biometry was performed between 14 and 40 weeks of gestational age (GA). The TCD, APCD and APCD/TCD ratio were assessed ultrasonographically. RESULTS: In normal fetuses, the TCD (rs = 0.876, P < 0.001) and APCD (rs = 0.791, P < 0.001) were strongly correlated with GA. However, the APCD/TCD ratio was not correlated with GA (rs = 0.058, P = 0.289), with median values of 0.52. Low TCD, APCD and APCD/TCD ratio values were detected in 53%, 100% and 100% of trisomy 18 cases, respectively. The median APCD/TCD ratio for trisomy 18 was 0.39 (range, 0.30-0.43), which was significantly lower than that of normal fetuses (P < 0.001). A cut-off APCD/TCD ratio of 0.44 served as a good predictor for trisomy 18 (sensitivity 100%, specificity 95.3% and negative predictive value 100%). CONCLUSION: This study shows that TCD and APCD are correlated with GA, while the APCD/TCD ratio is a fixed value throughout gestation. Using the APCD/TCD ratio to assess cerebellar hypoplasia in trisomy 18 is useful because it does not require the individual evaluation of the TCD and APCD. PMID- 29517145 TI - Sonographic appearance of endometrial osseous metaplasia. AB - Osseous metaplasia of the endometrium is a rare condition characterized by the presence of mature or immature bone in the endometrium. Most cases present with secondary infertility following an abortion or chronic endometritis. Some patients are asymptomatic, while others have menstrual abnormalities such as menorrhagia or oligomenorrhea. Removal of the bony fragments helps in spontaneous conception. We hereby present two cases of osseous metaplasia of the endometrium with radiological and pathological correlation. PMID- 29517146 TI - Implementation of an Evidence-Based Practice Nursing Handover Tool in Intensive Care Using the Knowledge-to-Action Framework. AB - BACKGROUND: Miscommunication during handover has been linked to adverse patient events and is an international patient safety priority. Despite the development of handover resources, standardized handover tools for nursing team leaders (TLs) in intensive care are limited. AIMS: The study aim was to implement and evaluate an evidence-based electronic minimum data set for nursing TL shift-to-shift handover in the intensive care unit using the knowledge-to-action (KTA) framework. METHODS: This study was conducted in a 21-bed medical-surgical intensive care unit in Queensland, Australia. Senior registered nurses involved in TL handover were recruited. Three phases of the KTA framework (select, tailor, and implement interventions; monitor knowledge use; and evaluate outcomes) guided the implementation and evaluation process. A postimplementation practice audit and survey were carried out to determine nursing TL use and perceptions of the electronic minimum data set 3 months after implementation. Results are presented using descriptive statistics (median, IQR, frequency, and percentage). RESULTS: Overall (86%, n = 49), TLs' use of the electronic minimum data set for handover and communication regarding patient plan increased. Key content items, however, were absent from handovers and additional documentation was required alongside the minimum data set to conduct handover. Of the TLs surveyed (n = 35), those receiving handover perceived the electronic minimum data set more positively than TLs giving handover (n = 35). Benefits to using the electronic minimum data set included the patient content (48%), suitability for short-stay patients (16%), decreased time updating (12%), and printing the tool (12%). Almost half of the participants, however, found the minimum data set contained irrelevant information, reported difficulties navigating and locating relevant information, and pertinent information was missing. Suggestions for improvement focused on modifications to the electronic handover interface. LINKING EVIDENCE TO ACTION: Prior to developing and implementing electronic handover tools, adequate infrastructure is required to support knowledge translation and ensure clinician and organizational needs are met. PMID- 29517147 TI - Ulnar Nerve Conduction Block Using Surface Kilohertz Frequency Alternating Current: A Feasibility Study. AB - The aim of this study was to test the effects of kilohertz frequency alternating current (KHFAC) surface stimulation applied to the ulnar nerve on force and myoelectrical activity of the abductor digiti minimi (ADM) muscle. Eighteen healthy volunteers (age: 27.6 +/- 7.9 years; 10 males, 8 females) were included in the study. Each subject participated in one session during which a biphasic 7 kHz rectangular pulse was delivered above the medial epicondyle of the humerus to induce ulnar nerve blocking. ADM electromyographic (EMG) activity and contraction force were measured before (Pre), immediately after, and following 5 and 10 min post stimulation (post 1, post 2). The results showed that EMG activity decreased immediately after stimulation compared to prestimulation, it returned to the level of prestimulation at 5 min (post 1), and decreased again at 10 min (post 2). Furthermore, analysis of compound adjusted z-score indicated significant decrease of force and myoelectrical activity immediately, and 10 min post stimulation. The findings, which demonstrate that KHFAC surface stimulation of the ulnar nerve may decrease the motor activity of intrinsic hand muscle, can help to develop future methods of neuromodulation to treat hand spasticity. PMID- 29517148 TI - Traumatic phacocele in an American Miniature Horse. AB - An 18-year-old American Miniature Horse mare was presented with a complaint of a scleral swelling affecting the right eye and a history of suspected trauma 6 weeks prior to evaluation. Clinical findings included severe blepharospasm, a bulbous swelling of the dorsotemporal bulbar conjunctiva, and phthisis bulbi. Ocular ultrasound was recommended but declined. Enucleation was elected for the blind, painful eye and was performed standing. Gross and histopathologic examinations of the globe were consistent with extrusion of the lens to the episcleral space, which is classified as a traumatic phacocele when associated with naturally occurring trauma. The location of lens entrapment suggested globe rupture occurred at the limbus, which is described as one of the weakest points of the equine globe. Subconjunctival dislocation of the lens and development of a traumatic phacocele should be considered as a differential diagnosis for horses presenting with subconjunctival masses, apparent aphakia, and historical trauma. PMID- 29517149 TI - Current Resources for Evidence-Based Practice, March/April 2018. PMID- 29517150 TI - Tamoxifen induced radiation recall dermatitis in a breast cancer patient. PMID- 29517151 TI - Clinical and histologic characteristics of breast cancers in women with previous pathologic diagnosis of benign breast disease in Spain. AB - Women with a benign breast disease (BBD) have an increased risk of subsequent breast carcinoma. Information is scarce regarding the characteristics of breast carcinomas diagnosed after a BBD. Our aim was to point out the differences in clinical and histologic characteristics of breast carcinomas diagnosed in women with and without a previous pathologic diagnosis of BBD in the context of population-based mammography screening. Retrospective cohort study of all women aged 50-69 years who were screened at least once in a population-based screening program in Spain, between 1994 and 2011 and followed up until December 2012. The mean follow-up was 6.1 years. We analyzed 6645 breast carcinomas, of whom 238 had a previous pathologic diagnosis of BBD. Information on clinical and histologic characteristics was collected from pathology reports. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95%CI) of occurrence of selected histologic characteristics of breast carcinomas in women with and without a previous BBD. Women with a previous BBD had a higher proportion of ductal carcinoma in situ (DCIS) compared with women without a BBD (22.1% and 13.6%, respectively). Among those diagnosed with an invasive breast carcinoma, women with previous BBD were more likely to be diagnosed with carcinomas sized >2 cm (OR = 1.46; 95%CI = 1.03-2.08), metastatic positive (OR = 2.66; 95%CI = 1.21-5.86), and with a high Ki-67 proliferation rate (OR = 1.93; 95%CI = 1.24-2.99). No differences were found across histologic subtypes of BBD. Screening participants with a previous pathologic diagnosis of BBD had a higher proportion of DCIS. However, invasive carcinomas detected in women with a BBD were associated with clinical and histologic characteristics conferring a worst prognosis. PMID- 29517152 TI - A National Survey Examining Manuscript Dissertation Formats Among Nursing PhD Programs in the United States. AB - PURPOSE: Among research-focused nursing doctoral (PhD) programs in the United States, the traditional dissertation format has recently given way to a series of publication-ready manuscripts, often bookended by introduction and conclusion chapters. To help programs make decisions about the use of these formats, this study undertook a national survey of programs offering PhDs in nursing. The purpose of this study was to explore the advantages and disadvantages of the traditional format versus manuscript option for dissertations among nursing PhD programs in the United States. DESIGN: Cross-sectional census survey of U.S. nursing PhD programs. METHODS: A web-based survey was administered to all U.S. nursing PhD programs. Respondents indicated formats offered, factors contributing to decisions of which formats to offer, and lessons learned. Descriptive statistics and inductive content analyses were used for analysis. FINDINGS: Of 121 eligible institutions, 79 provided eligible responses (66.7%). The majority (59%) offered both formats; 11% offered the manuscript option only, and 24% offered the traditional format only. Faculty support (or lack thereof) contributed to adoption (or not) of the manuscript option. Respondents' approaches to the manuscript option (e.g., number of papers) and advice are summarized. CONCLUSIONS: Manuscript option dissertations are commonly offered and provide benefits to students and faculty; however, thoughtful implementation is critical. Programs need to agree upon clear expectations and have graduate school support (e.g., formatting). Faculty need mentorship in advising manuscript option students who choose to use this format, and the time and support. Finally, students need additional writing skills that could be provided through coursework or via individual work with mentors. CLINICAL RELEVANCE: As nursing education continues to expand further into doctoral research, programs must examine dissertation formats in order to both prepare future nurse scholars and disseminate nursing research that is critical to improving nursing education, patient care, and clinical practice. PMID- 29517153 TI - Computational Models of Miscommunication Phenomena. AB - Miscommunication phenomena such as repair in dialogue are important indicators of the quality of communication. Automatic detection is therefore a key step toward tools that can characterize communication quality and thus help in applications from call center management to mental health monitoring. However, most existing computational linguistic approaches to these phenomena are unsuitable for general use in this way, and particularly for analyzing human-human dialogue: Although models of other-repair are common in human-computer dialogue systems, they tend to focus on specific phenomena (e.g., repair initiation by systems), missing the range of repair and repair initiation forms used by humans; and while self-repair models for speech recognition and understanding are advanced, they tend to focus on removal of "disfluent" material important for full understanding of the discourse contribution, and/or rely on domain-specific knowledge. We explain the requirements for more satisfactory models, including incrementality of processing and robustness to sparsity. We then describe models for self- and other-repair detection that meet these requirements (for the former, an adaptation of an existing repair model; for the latter, an adaptation of standard techniques) and investigate how they perform on datasets from a range of dialogue genres and domains, with promising results. PMID- 29517154 TI - Quantification of cystine in human renal proximal tubule cells using liquid chromatography-tandem mass spectrometry. AB - Nephropathic cystinosis is characterized by abnormal intralysosomal accumulation of cystine throughout the body, causing irreversible damage to various organs, particularly the kidneys. Cysteamine, the currently available treatment, can reduce lysosomal cystine and postpone disease progression. However, cysteamine poses serious side effects and does not address all of the symptoms of cystinosis. To screen for new treatment options, a rapid and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to quantify cystine in conditionally immortalized human proximal tubular epithelial cells (ciPTEC). The ciPTEC were treated with N-ethylmaleimide, lysed and deproteinized with 15% (w/v) sulfosalicylic acid. Subsequently, cystine was measured using deuterium-labeled cystine-D4, as the internal standard. The assay developed demonstrated linearity to at least 20 MUmol/L with a good precision. Accuracies were between 97.3 and 102.9% for both cell extracts and whole cell samples. Cystine was sufficiently stable under all relevant analytical conditions. The assay was successfully applied to determine cystine levels in both healthy and cystinotic ciPTEC. Control cells showed clearly distinguishable cystine levels compared with cystinotic cells treated with or without cysteamine. The method developed provides a fast and reliable quantification of cystine, and is applicable to screen for potential drugs that could reverse cystinotic symptoms in human kidney cells. PMID- 29517155 TI - Knowledge and attitudes about breast cancer care in female inmates in Sao Paulo State/Brazil. PMID- 29517157 TI - A Synchrotron-Based Study of the Mary Rose Iron Cannonballs. AB - Post-excavation iron corrosion may be accelerated by the presence of Cl- , leading to conservation methods designed to remove Cl. This study exploits a unique opportunity to assess 35 years of conservation applied to cast-iron cannon shot excavated from the Mary Rose. A combination of synchrotron X-ray powder diffraction (SXPD), absorption spectroscopy (XAS), and fluorescence (XRF) mapping have been used to characterise the impact of conservation on the crystalline corrosion products, chlorine distribution, and speciation. The chlorinated phase akaganeite, beta-FeO(OH,Cl), was found on shot washed in corrosion inhibitor Hostacor IT with or without an additional reduction stage. No chlorinated phases were observed on the surface of shot stored in sodium sesquicarbonate (Na2 CO3 /NaHCO3 ); however, hibbingite, beta-Fe2 (OH)3 Cl, was present in metal pores. It is proposed that surface beta-FeO(OH,Cl) formed in the early stages of active conservation owing to oxidation of beta-Fe2 (OH)3 Cl at near-neutral pH. PMID- 29517156 TI - Preoperative Lund-Mackay computed tomography score is associated with preoperative symptom severity and predicts quality-of-life outcome trajectories after sinus surgery. AB - BACKGROUND: Disagreement exists about the relationship between Lund-Mackay CT scores (LMCTS) and quality-of-life outcome (QoL) measures. We investigated whether preoperative LMCTS are associated with preoperative QoL, and whether LMCTS is predictive of postoperative QoL outcomes in chronic rhinosinusitis (CRS) patients. METHODS: Adult patients with medically recalcitrant CRS (n = 665) were enrolled in a prospective, observational cohort study. Preoperative LMCTS and pre and postoperative self-reported QoL outcomes (22-item Sino-Nasal Outcomes Test [SNOT-22]) were collected and evaluated over 12 months. Five hundred sixty-eight patients met the inclusion criteria. Longitudinal linear mixed-effects modeling was used to investigate the effect of LMCTS on QoL after functional endoscopic sinus surgery (FESS). RESULTS: Preoperative LMCTS were significantly associated with preoperative SNOT-22 scores (p < 0.01) and postoperative SNOT-22 scores (p < 0.001), driven by Extranasal and Rhinologic subdomains of the QoL questionaire. Patients in the lowest preoperative LMCTS quartile had the lowest mean change in SNOT-22 scores at 12 months (16.8 points; 95% confidence interval [CI], 12.2 21.3). Patients in the second and third lowest preoperative LMCTS quartiles had mean changes at 12 months of 21.1 points (95% CI, 16.7-25.4) and 23.1 points (95% CI, 18.3-27.9). Patients in the highest preoperative LMCTS quartile had the greatest improvement in SNOT-22 scores after FESS (29.9 points; 95% CI, 24.9 34.8). The difference in QoL change at 12 months between the highest and lowest preoperative LMCTS quartiles was 13.1 points (95% CI, 6.0-20.2; p < 0.001). CONCLUSION: Our study demonstrates that preoperative LMCTS correlate with preoperative extranasal and rhinologic symptom severity and that the LMCTS is an indicator of postsurgical QoL outcomes for medically recalcitrant chronic rhinosinusitis patients in a large tertiary otolaryngology setting. PMID- 29517158 TI - Bilateral retinoschisis in a dog: A veterinary clinical application for optical coherence tomography. AB - A 11-year-old neutered male Labrador retriever-cross dog was presented to the University of Missouri-Columbia Veterinary Ophthalmology Service for subtle visual deficits. Indirect ophthalmoscopy revealed a smooth, bullous elevation in the superior-temporal retina OU. Optical coherence tomography (OCT) performed OU showed inner retinal separation consistent with retinoschisis. Electroretinography (ERG) revealed markedly reduced b-wave amplitudes in the more severely affected eye (OD) compared with the less severely affected eye (OS). The most notable reductions were in the rod response and 30-Hz flicker b-waves OD which were approximately 50% of the corresponding amplitudes OS. Implicit times, particularly the a-wave implicit times, were noticeably longer OD compared with OS. Lesions remained unchanged over 4 months at which time the dog was humanely euthanized for reasons unrelated to the ocular disease. Significant light microscopic ocular findings were bilateral superior temporal peripheral retinoschisis. The separation of the retinal tissue was similar between eyes and effectively divided the outer plexiform layer. In addition, thinning of the surrounding retinal layers was present. To the authors' knowledge, this is the first case of canine retinoschisis diagnosed with OCT, evaluated with electroretinography, and confirmed with light microscopic examination. History, clinical, and diagnostic findings, with the absence of disease progression over time, are analogous with cases of acquired senile retinoschisis in humans. PMID- 29517159 TI - Issuing and Responding to Unusual Questions: A Conversation Analytic Account of Tom Andersen's Therapeutic Practice. AB - Tom Andersen is considered one of the key contributors to the development of postmodern practice. Little is known, however, about the ways in which his ideas and practices are routinely carried out in situ. We used Conversation Analysis (CA) to investigate a session of couple therapy facilitated by Andersen. We show how Andersen and client participants oriented to and addressed problems of understanding that occurred between them. The source of this trouble was Andersen's use of unusual question formulations. We offer preliminary evidence that such unusual formulations served particular interactional and institutional (i.e., therapeutic) functions in their local contexts of use. We conclude by considering some implications of this analysis-and of conversation analytic inquiry more generally-for the practice of family therapy. PMID- 29517160 TI - Cobalt-Catalyzed Tandem C-H Activation/C-C Cleavage/C-H Cyclization of Aromatic Amides with Alkylidenecyclopropanes. AB - A cobalt-catalyzed chelation-assisted tandem C-H activation/C-C cleavage/C-H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C-C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C-N bonds. Here the inexpensive catalyst system exhibits good functional-group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m-CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C-H cobaltation, beta-carbon elimination, and intramolecular C-H cobaltation sequence. PMID- 29517161 TI - Sleeping Sickness in the 'Omics Era. AB - Sleeping sickness is a neglected tropical disease caused by Trypanosoma brucei parasites, affecting the poorest communities in sub-Saharan Africa. The great efforts done by the scientific community, local governments, and non-governmental organizations (NGOs) via active patients' screening, vector control, and introduction of improved treatment regimens have significantly contributed to the reduction of human African trypanosomiasis (HAT) incidence during the last 15 years. Consequently, the WHO has announced the objective of HAT elimination as a public health problem by 2020. Studies at both parasite and host levels have improved our understanding of the parasite biology and the mechanisms of parasite interaction with its mammalian host. In this review, the impact that 'omics studies have had on sleeping sickness by revealing novel properties of parasite's subcellular organelles are summarized, by highlighting changes induced in the host during the infection and by proposing potential disease markers and therapeutic targets. PMID- 29517162 TI - Intraocular pressure reference intervals in eyes of clinically normal miniature donkeys (Equus africanus asinus). AB - PURPOSE: To determine intraocular pressure (IOP) reference intervals in eyes of healthy miniature donkeys (Equus africanus asinus) via rebound and applanation tonometry. METHODS: Complete ophthalmic and physical examinations were performed by board-certified veterinary ophthalmologists. Inclusion criteria for animals participating in this study were dictated by the American Society for Veterinary Clinical Pathology (ASVCP) reference interval guidelines. Intraocular pressure estimates (TonoVet(r) and TonoPen XL(r) ) were obtained in both eyes. Forty animals (San Angelo group) received intramuscular xylazine hydrochloride 10% and auriculopalpebral (AP) nerve blocks prior to obtaining measurements. Twenty-two animals (Austin group) received no sedation or AP block. Statistical analysis followed ASVCP reference interval guidelines. Analysis was performed using the software sas V9 (SAS Institute Inc., Cary, NC, USA). RESULTS: Fifty-seven (114 eyes) healthy miniature donkeys were included in this study. The mean IOP +/- standard deviation (SD) was 25.75 +/- 5.70 mm Hg for rebound tonometry with reference limits of 14.34 and 37.15. The mean IOP +/- SD was 20.69 +/- 5.06 mm Hg for applanation tonometry with reference limits of 12.82 and 33.38. No significant difference in IOP was found between the Austin and San Angelo groups (P = .34). A significant difference was noted between rebound and applanation IOP estimates (P < .0001) with rebound tonometric values being higher. CONCLUSIONS: Reference intervals for IOP's were established for this species. Intraocular pressure readings obtained by the rebound tonometer were significantly higher than with applanation. Sedation and AP block did not affect IOP estimates. PMID- 29517163 TI - Effects of an early-life paraquat exposure on adult resistance to oxidative stress, plumage colour and sperm performance in a wild bird. AB - Early-life stressful conditions can shape individual phenotypes and ultimately influence fitness. Oxidative stress is a pervasive threat that affects many fitness-related traits and can modulate life-history trade-offs. Yet, the extent to which exposure to oxidative stress during early life can have long-lasting effects on key fitness-related traits remains to be elucidated, particularly in natural populations of vertebrates. Using a wild population of great tits Parus major, we experimentally dosed 11-day-old birds with paraquat, a pro-oxidant molecule, aiming at increasing oxidative stress. One year later, we recaptured 39 of them as adult recruiting breeders and quantified effects of the paraquat exposure on their resistance to oxidative stress, carotenoid-based plumage coloration and male sperm performance. Despite the absence of a short-term effect of paraquat on oxidative stress measured two days later, the pre-fledging exposure to paraquat induced a reduction in individual oxidative damage measured at adulthood. Paraquat-dosed individuals also had brighter plumage, but no effect was observed on male sperm performance. For the first time in a natural population of vertebrates, we experimentally show that an early-life acute exposure to a pro-oxidant has long-lasting effects on individual resistance to oxidative stress at adulthood. Our results are in line with the environmental matching and the hormesis hypotheses but may also reflect selective disappearance of individuals with lower resistance to oxidative stress. PMID- 29517164 TI - Anaphylactic reaction to an ultrasound contrast agent (Lumason) in a patient with systemic mastocytosis. AB - Severe adverse reactions to ultrasound (US) contrast agents are rare, and only a few cases of anaphylaxis following the administration of US contrast agents have been reported, often without a defined etiology. We present a case of anaphylactic reaction to the injection of an US contrast agent in a patient with systemic mastocytosis, which highlights the disorder as a possible risk factor warranting additional consideration prior to performing a contrast-enhanced US examination. PMID- 29517165 TI - Do women with dense breasts have higher radiation dose during screening mammography? Reply to-Letter to the Editor. PMID- 29517166 TI - Muscular endurance and progression rates of early-stage invasive ductal carcinoma: A pilot study. PMID- 29517167 TI - How can we ensure that the global south benefits from and contributes to the field of bioethics? PMID- 29517169 TI - Author's reply re: Cassava flour slurry as a low-cost alternative to commercially available gel for obstetrical ultrasound: a blinded non-inferiority trial comparison of image quality. PMID- 29517168 TI - Indications for biopsy of imaging-detected intramammary and axillary lymph nodes in the absence of concurrent breast cancer. AB - To evaluate the prevalence of malignancy in imaging-detected abnormal lymph nodes (LNs) in women without concurrent cancer and to identify imaging features predictive of malignancy in this population. This is an IRB-approved study with waived informed consent. We retrospectively reviewed medical records of all image guided LN FNAs and CNBs performed at our institution from 1/1/08 through 12/31/10. LNs sampled in patients without concurrent breast cancer comprised our study group (SG; n = 77), and with concurrent breast cancer our reference group (RG; n = 124). Blinded to cytology/histology, imaging features of the LNs including size, loss of fatty hilum, and cortical thickness were reviewed. A low/high suspicion category was then assigned based on LN appearance. The prevalence of malignancy in LNs in SG was 6% (5/77) and in RG 52% (64/124; P < .0001). Complete loss of fatty hilum had 100% (5/5) sensitivity, and 100% (56/56) NPV for detecting cancer in SG, compared to 39% (25/64) sensitivity and 61% (60/99) NPV in RG. When a "high suspicion" imaging feature was used as a threshold to biopsy, the sensitivity (5/5) and NPV (45/45) in SG were 100%, and in RG 78% (50/64) and 77% (47/61), respectively. The prevalence of cancer in imaging-detected abnormal LNs in patients without concurrent breast cancer is low. In the absence of concurrent cancer, using highly suspicious features of loss of fatty hilum or cortical thickness >= 5 mm as a threshold to biopsy will maintain high sensitivity with lower false-positive biopsy rate. PMID- 29517171 TI - Politically Correct Headache Treatment. PMID- 29517170 TI - An Unusual Fatty Acyl:Adenylate Ligase (FAAL)-Acyl Carrier Protein (ACP) Didomain in Ambruticin Biosynthesis. AB - The divinylcyclopropane (DVC) fragment of the ambruticins is proposed to be formed by a unique polyene cyclisation mechanism, in which the unusual didomain AmbG plays a key role. It is proposed to activate the branched thioester carboxylic acid resulting from polyene cyclisation and to transfer it to its associated acyl carrier protein (ACP). After oxidative decarboxylation, the intermediate is channelled back into polyketide synthase (PKS) processing. AmbG was previously annotated as an adenylation-thiolation didomain with a very unusual substrate selectivity code but has not yet been biochemically studied. On the basis of sequence and homology model analysis, we reannotate AmbG as a fatty acyl:adenylate ligase (FAAL)-acyl carrier protein didomain with unusual substrate specificity. The expected adenylate-forming activity on fatty acids was confirmed by in vitro studies. AmbG also adenylates a number of structurally diverse carboxylic acids, including functionalised fatty acids and unsaturated and aromatic carboxylic acids. HPLC-MS analysis and competition experiments show that AmbG preferentially acylates its ACP with long-chain hydrophobic acids and tolerates a pi system and a branch near the carboxylic acid. AmbG is the first characterised example of a FAAL-ACP didomain that is centrally located in a PKS and apparently activates a polyketidic intermediate. This is an important step towards deeper biosynthetic studies such as partial reconstitution of the ambruticin pathway to elucidate DVC formation. PMID- 29517172 TI - Letters to the Editor. PMID- 29517173 TI - 41st Annual Scientific Meeting The American Association for the Study of Headache June 1l-13, 1999, Boston, Massachusetts. PMID- 29517174 TI - 41st Annual Scientific Meeting The American Association for the Study of Headache June 1l-13, 1999, Boston, Massachusetts. PMID- 29517176 TI - Automatically Programmable Shape-Memory Polymers Based on Asymmetric Swelling of Bilayer Structures. AB - Shape-memory polymers (SMPs) possess the capability to change shapes upon stimulation; however, the programming process that determines the temporary shape cannot proceed without external manipulation, which may greatly affect the shape complexity, accuracy, and reproducibility. Here, an automatically programmable SMP (AP-SMP) based on asymmetric swelling of bilayer SMP structures is demonstrated without external manipulation. In the automatic programming process, the AP-SMP can be deformed by the swelling of its hydrophilic hinge film in warm water to a temporary shape, which could be fixed by the glass transition of the two SMP films through cooling and drying in air. Owing to the unique ability, many complex shapes can be easily customized through diverse design strategies. Moreover, the AP-SMPs can reversibly transform between the permanent and temporary shapes, and both shapes are free-standing in normal conditions. The automatic programming of AP-SMPs may greatly expand the potential application range of SMPs. PMID- 29517175 TI - Mosaic male fetus of Turner syndrome with partial chromosome Y: A case report. AB - Turner syndrome, characterized by the presence of a monosomy X cell line, is a common chromosomal disorder. Patients with Turner syndrome are usually phenotypically female, and male cases are rarely reported. Here, we report a fetus with a mosaic karyotype: mos 45,X/46,X,del(Y)(q11.21). The fetus was initially misdiagnosed as female with Turner syndrome by both noninvasive prenatal testing and cytogenetic analysis of amniotic fluid and was subsequently found to have male anatomy by antenatal ultrasonography at 24 weeks gestational age. Through single nucleotide polymorphism-array and fluorescence in situ hybridization testing, we found that there was a truncated Y chromosome with sex determining region Y (SRY) present in some cells of the fetus, which caused the male features in the fetus. PMID- 29517177 TI - Basilic vein transposition for unsuitable upper arm hemodialysis needle access segment may attenuate concurrent hand ischemia. AB - INTRODUCTION: Some hemodialysis patients with a brachial arteriovenous fistula (AVF) have an unsuitable upper arm needle access segment (NAS) necessitating basilic vein transposition (BVT). It was frequently observed that a portion of these patients spontaneously experienced a warmer and less painful dialysis hand after BVT. Aim of this study was to determine whether BVT for an inadequate NAS attenuated hemodialysis access-induced distal ischemia in patients with a brachial AVF. METHODS: Patients with a brachial AVF and an unsuitable NAS also reporting hand ischemia and scheduled to undergo BVT between 2005 and 2016 in a single facility were studied. Hand ischemia was graded as proposed in a 2016 consensus meeting. Hand ischemic questionnaire (HIQ-) scores (0 points, no ischemia-500 points, maximal ischemia), digital brachial index (DBI, ischemia <0.6) and access flow (mL/min) before and after BVT were compared. The cephalic vein and all side branches of the basilic vein were ligated during the BVT. FINDINGS: Ten patients were studied (8 males, 61 [54-75] years). BVT was performed 8 [4-10] months following the initial AVF construction. HIQ-scores dropped from 220 [71-285] to 9 [0-78] (P = 0.043) postoperatively, whereas DBI increased from 0.51 [0.39-0.67] to 0.85 [0.68-0.97] (P = 0.012). DBI and HIQ scores were inversely correlated (R2 =71%, P = 0.001). Access flows dropped significantly (Flowpre 1120 mL/min [1100-2300] vs. Flowpost 700 mL/min [600 1760]; P = 0.018). Surgery-associated complications were absent and dialysis continued uninterruptedly. Eight patients reported total recovery from hand ischemia six weeks postoperatively. DISCUSSION: Basilic vein transposition for an unsuitable upper arm needle access segment may attenuate hand ischemia in patients with a brachial AVF previously reporting hemodialysis access-induced distal ischemia. PMID- 29517178 TI - The effect of medical treatments on the bacterial microbiome in patients with chronic rhinosinusitis: a pilot study. AB - BACKGROUND: Antibiotics and corticosteroids are prescribed to patients with chronic rhinosinusitis (CRS) to reduce bacterial burden and mucosal inflammation. Unfortunately, clinical improvement is often short-lived and symptoms frequently recur following cessation of treatment. The impact of these systemic therapies on bacterial communities is not well understood. Improved knowledge of how medical therapies influence the intranasal ecosystem may allow for more effective prescribing and the development of more targeted treatments. METHODS: Twenty patients with CRS were randomized to receive either doxycycline 100 mg twice daily or prednisone 30 mg once daily for 7 days. A further 6 patients with CRS were recruited as untreated controls. Swabs were taken immediately before and after the study period. Symptom scores (22-item Sino-Nasal Outcome Test [SNOT 22]) were recorded. Bacterial communities were characterized using 16S ribosomal RNA (rRNA) gene-targeted amplicon sequencing. Bacterial abundance was estimated using quantitative polymerase chain reaction (PCR) of 16S rRNA gene copies. RESULTS: Bacterial profiles were dominated by members of the genera Corynebacterium and Staphylococcus. Patients treated with either doxycycline or prednisone had variable and unpredictable changes in communities. The average relative abundance of Propionibacterium increased after treatment in the doxycycline treatment group, and Corynebacterium reduced in the prednisone group. Significant differences in clinical scores, bacterial community richness, diversity, and bacterial abundance were not seen after treatment. CONCLUSION: The short-term response of bacterial communities to antibiotic or corticosteroid therapy is unpredictable. This study suggests that the use of systemic therapy in patients with stable CRS should be rationalized to minimize antibiotic-associated morbidity and bacterial dysbiosis. PMID- 29517179 TI - Discursive psychology as a method of analysis for the study of couple and family therapy. AB - The field of couple and family therapy has benefitted from evidence generated from qualitative approaches. Evidence developed from approaches relying on language and social interaction using naturally occurring recordings of real world practice has the benefit of facilitating practice-based recommendations and informing practice. The aim of this article is to provide an overview of one approach to discourse analysis, Discursive Psychology (DP), demonstrating how a social constructionist framework and focus on discourse can provide an important contribution to the field of therapy. To illustrate the methodological decision making process for researchers and/or practitioners who utilize DP, we draw upon a video-recorded therapeutic session involving Tom Andersen. To conclude, we make recommendations for practitioners using DP to explore and examine therapeutic practice. PMID- 29517180 TI - The significance of receptor status discordance between breast cancer primary and brain metastasis. PMID- 29517181 TI - The occurrence of resveratrol in foodstuffs and its potential for supporting cancer prevention and treatment. A review AB - Over recent years, there has been increasing interest noted in those active substances derived from plants that show potential for preventing cancer development. The most promising candidate is resveratrol which can be found in large amounts in the skin of grapes, tomatoes and in red wine. Its beneficial effects on the human body are seen both in prevention and therapy. The anti carcinogenic action of resveratrol is linked with its ability to neutralise reactive oxygen species and to modulate cellular processes such as apoptosis, and both cancerous cell proliferation and differentiation. This article presents the characteristics of resveratrol as a bioactive compound derived from natural sources exhibiting anti-cancer properties, which, because of a wide spectrum of biological activities may be used in the prevention of cancer. Many in vitro and animal-based studies have demonstrated such preventative anti-cancer action in the colon, prostate, breast and lungs. The beneficial effects of resveratrol are also presented when adopted as a support to conventional treatments of cancer using chemo- and radio-therapy. PMID- 29517182 TI - Influence of selected dietary components on the functioning of the human nervous system AB - The diet is directly connected not only with the physical status but also with the functioning of the brain and the mental status. The potentially beneficial nutrients with a protective effect on the nervous system function include amino acids (tryptophan, phenylalanine, tyrosine, taurine), glucose and vitamins C, E, D and beta-carotene, B group vitamins (vitamin B12, vitamin B6, vitamin B4, vitamin B1) and minerals (selenium, zinc, magnesium, sodium, iron, copper, manganese, iodine). The presence of antioxidants in the diet protects against oxidative damage to nervous system cells. Biochemical dataindicate that polyunsaturated fatty acids such as arachidonic acid (AA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) as structural components of the nervous system play a key role in its function. The nutrition of the entire body also influences the production of neurotransmitters in the brain. A diet without an appropriate supply of protein, mineral nutrients or vitamins may result in a failure to form appropriately balanced numbers of neurotransmitters, which, as a result, may lead to neurotransmission dysfunction. This is the reason why proper nutrition is based on vegetables, fruits, whole grain cereal products supplemented with products providing full-value protein (dairy products, fish, lean meat) and high-quality fat products (vegetable oils, fish fats). PMID- 29517183 TI - Nutrition practices in nurseries in Poland - initial results of nationwide study AB - Background: Rational nutrition of infants and toddlers is essential for their normal growth and development, and for the development of proper nutritional habits. It should be preceded by proper planning. Objective: The aim of the study was to evaluate of the planning and organization of nutrition in nurseries. Material and methods: In the research conducted within the program "Eating healthy, growing healthy" (EHGH), 128 creches from all over Poland participated. The nurseries were attended by 8182 children under the age of 3. The research was carried out between 2015 and 2016. Data on the organization and quality of nutrition were collected through direct interviews with directors and / or staff responsible for feeding in creches. In addition, analysis of the decade's menu of the participating institutions (128 menus) and daily inventory reports (1280 documents) were analyzed. The data were analyzed for the total number and the type (public and non-public) of institution. The program Statistica Version 13.1 was used. Results: Half of the surveyed DCCs planned in the menu whole grains, nearly all of them served fresh vegetables and fruits to the children, and every third added them to every meal. The most common drink during the meal was compote. Access to water between meals was offered to children in majority of the DCCs. The quality of diet was differentiated by the type of nursery: depending on the type (public vs non-public), the differences in salting and sweetening meals have been shown. Public DCCs had a much lower average amount of money allocated per day to feed a child compared to non-public, most of these managed own kitchens and did not employ a dietitian. Despite the higher nutritional rates in non-public creches, some errors in nutrition planning have been observed. Conclusions: Higher average amount of money allocated per day to feed a child in non-public nurseries did not provide adequate nutrition. There is a need to publish standardized, understandable and practical recommendations in nutrition of children in nurseries. Adopting such recommendations in daily practice in all public and non-public creches should improve the nutrition of children. PMID- 29517184 TI - Nutrition-related practices in kindergartens in the context of changes to legal regulations on foodstuffs used in canteen menus for children AB - Background: In order to improve the quality of nutrition in care and educational institutions, in year 2015 a restrictive law regulation was introduced. The following year this regulation was withdrawn, and a new legal policy has been introduced. However, data on the impact of these legislations on nutrition in kindergartens are lacking. Objective: The aim of the study was to evaluate the compliance with mandatory nutrition recommendations in preschools. Material and methods: The study included 706 institutions. Data were collected during the periods when two consecutive Regulation of the Minister of Health were in force (I - 01.09.2015 - 31.08. 2016 and II - 01.09.2016 to 30.05.2017). Data were obtained by face-to-face interviews with staff with a validated questionnaire. Parameters characterizing the quality of nutrition were analyzed with focus on compliance with legal regulations. 706 decade's menus and 7060 daily inventory reports were analyzed to verify information on vegetables and fruit supply, frequency of frying and type of fat used, sweetening and salting practices. Statistical significances were determined in Statistica 13.1 with t-Student and Chi2 tests (p< 0.05).The study included 706 institutions. Data were collected during the periods when two consecutive Regulation of the Minister of Health were in force (I - 01.09.2015 - 31.08. 2016 and II - 01.09.2016 to 30.05.2017). Data were obtained by face-to-face interviews with staff with a validated questionnaire. Parameters characterizing the quality of nutrition were analyzed with focus on compliance with legal regulations. 706 decade's menus and 7060 daily inventory reports were analyzed to verify information on vegetables and fruit supply, frequency of frying and type of fat used, sweetening and salting practices. Statistical significances were determined in Statistica 13.1 with t Student and Chi2 tests (p< 0.05). Results: The preschools have implemented regulations concerning the supply of fresh fruit and vegetables (~93%), the amount of fried dish per week (~75%), and the use of suitable frying fat (~95%). About half of institutions managed to serve vegetables and/or fruits in every meal. Compliance with the regulations on sweetening and salting was unsatisfactory: about 1/4 of institutions used banned sugar, and 46% regular salt. Conclusions: Legislations influenced nutrition practices in preschools, but additional support is needed to bring all institutions into compliance with the current policies. The current law regulations are general, and allow a great flexibility in planning menus, which might has an adverse effect on menus quality. Therefore, nutrition education and more detailed mandatory nutrition standards for kindergartens are crucial. PMID- 29517185 TI - Motion detection supported exercise therapy in musculoskeletal disorders: a systematic review. AB - INTRODUCTION: Musculoskeletal disorders (MSDs) are a burden on the healthcare system. Exercise therapy is an important part of MSD rehabilitation. Motion detection systems are developed to support exercise therapy settings. This systematic review aimed: 1) at investigating which types of motion detection systems have been used as a technological support for exercise therapy; 2) at investigating the characteristics of motion detection supported exercise therapy in relation to its clinical indications; and 3) at evaluating the effectiveness of motion detection supported exercise therapy, in MSD rehabilitation. EVIDENCE AQCUISITION: A systematic literature search for RCTs was performed in six databases (PubMed, CINAHL, EMBASE, ACM, Cochrane, and IEEE). Studies eligible for inclusion had to evaluate exercise therapy for persons with MSDs, provide a motion detection system capable of as well measuring active movement of the participant during exercise therapy as evaluating the movement in order to provide qualitative feedback, and should present at least one measure of the following ICF function (pain, muscle strength, mobility), activity (disease related functional disability, balance) or participation (quality of life) level. Two reviewers independently screened articles, appraised study quality, extracted data, and evaluated effectiveness of selected outcome measures. This review was registered in the International prospective register of systematic reviews (Prospero) under registration number CRD42016035273. EVIDENCE SYNTHESIS: Nine RCTs (N.=432 participants) were included. Eight different motion detection technologies were used such as an accelerometer, gyroscope, magnetometer etc. All systems provided visual feedback. Knee disorders were evaluated most frequently, followed by low back pain and shoulder disorders. Therapy consisted of mobility, balance or proprioception exercises. Main outcomes were pain, disability, mobility and muscle strength. Motion detection supported exercise therapy showed similar or enhanced results on all outcomes compared to conventional exercise therapy. However, a limitation of this study was the low methodological quality of the studies. CONCLUSIONS: To date, a variety of motion detection systems have been developed to support the rehabilitation of MSDs. Results show similar effectiveness of motion detection supported exercise therapy compared to conventional exercise therapy. More research is needed to provide insight in the added value of motion detection systems in musculoskeletal rehabilitation. PMID- 29517186 TI - Brace treatment of idiopathic scoliosis is effective for a curve over 40 degrees, but is the evaluation of Cobb angle the only parameter for the indication of treatment? AB - BACKGROUND: The recent literature showed positive results for bracing of patients with idiopathic scoliosis above 45 degrees who refused surgery. However, no one has investigated whether other parameters can affect the results. AIM: The aim of this study was to evaluate the effectiveness of bracing in idiopathic scoliosis with curves above 40 degrees and to verify the mechanical and biological parameters which go beyond the simple bend value expressed in Cobb degrees. DESIGN: This is an observational controlled cohort study nested in a prospective clinical on-going database including 1,238 patients with idiopathic scoliosis. SETTING: Inpatients and outpatients in Rome. POPULATION: 160 patients with idiopathic scoliosis with curves above 40 degrees . METHODS: This is a prospective study based on an ongoing database including 1,238 patients with idiopathic scoliosis. The patients studied had idiopathic scoliosis with curves of 40 degrees or more, Risser grade 0-4, and had refused any surgical treatment. 160 patients met the inclusion criteria. Of these, 104 patients had a definite outcome, 28 abandoned treatment and 28 are currently under treatment. The minimum duration of follow-up was 24 months. X-rays were used to obtain Cobb degrees and torsion of the apical vertebrae (Perdriolle's method). Three outcomes were distinguished according to SRS- SOSORT criteria: correction, stabilization and progression. To achieve the second aim we divided the sample into subgroups according to Cobb degrees (<45 degrees ;>=45 degrees ), Risser (0-2; 3-4) and rotation (<20; >= 20). Furthermore, logistic regression was applied by Stepwise Regression. RESULTS: The results of our study showed that in 104 patients with a definite outcome the Cobb mean value was initially 47 +/- 5.25 SD and 34.19 +/ 8.45 SD at follow-up. Perdriolle was initially 20.04 +/- 5.53 SD and 16.76 +/- 7.04 at follow-up. Overall, 81 patients (78%) obtained a curve correction, and stabilization was achieved in 14 cases (13%). Nine patients experienced curve progression (9%), 16 patients were recommended for surgery because the curve at follow up was over 45 degrees . The analysis of subgroups shows that with Cobb < 45 degrees at baseline, the average reduction was 11.46 degrees Cobb, while in cases with Cobb >= 45 at baseline, the mean correction was 13.74 degrees Cobb. In subgroups with Perdriolle < 20 degrees at baseline, the average reduction was 16.02 degrees Cobb, while in cases with Perdriolle >= 20 degrees at baseline, the mean correction was 8.4 degrees Cobb. In subgroups with Risser 0-2 at baseline, the average reduction was 14.7 degrees Cobb, while in cases with Risser 3-4 at baseline, the mean correction was 6.7 degrees Cobb. The logistic regression model shows significance for the initial value of Perdriolle and Risser. CONCLUSIONS: Our results indicate that an adequate conservative treatment must definitely be considered for patients with scoliotic curves who refuse surgery; the results will be better particularly if the rotation is lower than 20 and Risser is between 0-2. CLINICAL REHABILITATION IMPACT: With the simultaneous evaluation of the Cobb angle, the vertebral rotation and the potential vertebral growth, it was possible to predict the final results at the start of treatment. PMID- 29517187 TI - Training for mobility with exoskeleton robot in spinal cord injury patients: a pilot study. AB - BACKGROUND: Wearable robots are people-oriented robots designed to be worn all day, thus helping in the daily activities. They can assist in walking, running, jumping higher or even lifting objects too heavy in normal conditions. AIM: The aim of this report was to investigate the changes in gait pattern through 3D gait analysis of subjects with spinal cord injury (SCI) undergoing an adaptive training with a wearable exoskeletal device (ESD). The change in the quality of life was also investigate together with the possibility to wear these devices all day, to improve the mobility. DESIGN: Prospective quasi-experimental study, pre- and post-design. SETTING: Outpatient SCI patients. POPULATION: On a voluntary basis, eight SCI patients who had never used any ESD device were recruited. METHODS: Subjects underwent a three-dimensional gait analysis (3D GA) while wearing the ESD at baseline (inclusion) (T0) and after 20 sessions of training over an expected average of 5/6 weeks (T1). The secondary outcome measures were: Participant Satisfaction Questionnaire, 6-Minute Walking Test (6MWT), Borg Scale (the test was administered in indoor and outdoor conditions) and Timed Up-and-Go test (TUG). Spatiotemporal and kinematic parameters were assessed and their change from the beginning to the end of the training was the secondary outcome. RESULTS: No dropouts were recorded during the training and all subjects were able to terminate the protocol (compliant subjects: N.=8). After the training, all person showed some significant improvements for TUG, 6MWT and 10 MWT (Z=-2.521; P=0.008) and for the spatiotemporal and kinematics parameters. CONCLUSIONS: This paper confirms that the adaptive training with ESD is safe and feasible in a heterogeneous sample of persons with SCI, especially in ameliorating the interaction between the patients and the device with an improvement of spatiotemporal and kinematics parameters. CLINICAL REHABILITATION IMPACT: Since the training has been proven safe and the hypothesis that the subjects with spinal cord injury improving their performance over time and being able to adapt at the use of device in full autonomy at home during all the activities of the daily living has strengthened. PMID- 29517189 TI - Strength training increases skeletal muscle quality but not muscle mass in old institutionalized adults: a randomized, multi-arm parallel and controlled intervention study. AB - BACKGROUND: Age related loss of skeletal muscle mass is accompanied by changes in muscle quality leading to impairment of functional status. AIM: This study investigated the effect of resistance training and nutritional supply on muscle mass and muscle quality in very old institutionalized adults. DESIGN: Prospective, randomized, multi-arm parallel and controlled intervention study. SETTING: This study was conducted in five retirement care facilities. POPULATION: This subgroup of the Vienna Active Ageing Study included 54 women and men (82.4 +/- 6.0 years) with impaired health status. Participants were randomly assigned either to elastic band resistance training (n=16), training with nutritional supplementation (n=21) or control group (n=17). METHODS: Health status was assessed at baseline with functional tests, cognitive status, nutritional status, sum of medications as well as sum of diseases. Skeletal muscle mass, determined by dual - energy X-ray absorptiometry, isokinetic knee extension and flexion force and handgrip strength were assessed at baseline and after 6 months. Muscle quality of lower extremities was defined as ratio of the extensor (MQ_LE (Ext.)) or flexor strength (MQ_LE (Flex.)) to lean leg mass. Muscle quality of upper extremity was defined as ratio of handgrip strength to lean arm mass. Follow up examinations were performed after 12 and 18 months of intervention. RESULTS: Muscle quality, but not muscle mass, showed significant correlations to functional tests at baseline (0.300 - 0.614, p<0.05). Resistance training significantly enhanced muscle quality of lower extremity after 6 months (MQ_LE (Ext.) +19.8 %, MQ_LE (Flex.) +30.8 %, p<0.05). Nutritional supplementation could not further increase the training effect. Participants with lower muscle quality at baseline benefit most from the training intervention. Skeletal muscle mass was not changed by any intervention. CONCLUSIONS: Resistance training with elastic bands improved muscle quality in very old people. Additional nutritional supplementation was not able to further improve the effects obtained by training alone. CLINICAL REHABILITATION IMPACT: Elastic band resistance training could be safely used to improve muscle quality even in old people with impaired health status. Weak and chronically ill participants benefit most from this training. PMID- 29517188 TI - Improved parent-reported mobility and achievement of individual goals on activity and participation level after functional power-training in young children with cerebral palsy: a double-baseline controlled trial. AB - BACKGROUND: In children with cerebral palsy (CP), strength training programs to improve walking capacity and participation in activities of daily living are commonly used in clinical practice, despite lacking evidence of its effectiveness. It has been suggested that strength training with high movement velocity could be more effective than traditional resistance training to improve functional abilities such as walking. In a recently published study, we have demonstrated the positive effects of functional high-velocity resistance (power) training on muscle strength and walking capacity in young children with CP. Whether this type of training is also effective in achieving individual predefined goals in daily activities and self-reported mobility limitations, has not yet been described however. AIM: To evaluate the effect of functional power training on parent-reported mobility and achievement of individual goals on activity and participation level in young children with CP. DESIGN: A double baseline design was used to compare a 14-week period usual care with a 14-week period of functional power-training (3 times a week) and a follow-up period of 14 weeks. SETTING: A rehabilitation center, two special needs schools for children with physical disabilities, and a university medical center outpatient clinic. POPULATION: Twenty-two children with spastic CP (13 bilateral, GMFCS level I [N.=10] and level II [N.=12], mean age 7.5 years [SD 1.8, range 4-10 years]) and their parents participated. METHODS: Outcome measures were goal attainment scaling (GAS) of individual daily activity related treatment goals, mobility performance as measured using the Functional Mobility Scale (FMS-5 m, 50 m and 500 m), and the parent-reported Mobility Questionnaire (MobQues). RESULTS: After power-training, 86% of children achieved or exceeded their goal, compared with 14% in the usual care period (P<.001). The probability of improvement by one point or more on the FMS-500 meter after functional power-training was 10 times higher, compared with the usual care period (Relative Risk=10.0 with 95% CI 1.4 - 71.3). No changes were found in the FMS-5m and FMS-50m categories. Improvement on the MobQues was significantly greater after power-training compared with usual care (7.9% (95% CI 2.7 - 13.0, P=.005)). The improvement in performance in the activities defined in the treatment goals continued during the follow-up period. CONCLUSIONS AND CLINICAL REHABILITATION IMPACT: The results indicated that functional power-training is an effective training to achieve personalized treatment goals for activities in daily life and parent-reported mobility performance in young children with cerebral palsy. PMID- 29517190 TI - Effect of caloric restriction on liver function in young and old ApoE/LDLr-/- mice AB - Background: Caloric restriction (CR) leads to decrease metabolic intensity, which results in a reduction of oxygen consumption and the amount of free radicals. This can affect the function of the liver. Studies show that caloric restriction does not alter or significantly increase the enzyme activity associated with gluconeogenesis, but the effect was different according to the age of the model animals. Objective: The aim of the study was to determine the effect of caloric restriction on liver function in young and old ApoE/ LDLr-/- mice. Material and methods: Dietary experiments were performed on 2 and 5 month old male ApoE/LDLr-/ mice. Animals were divided into 3 experimental groups (n=6) and fed AIN'93G diet for 8 and 5 weeks, respectively. Control animals were fed ad libitum (AL) and housed in a colony cages. These animals were checked for dietary intake. The second group were also fed ad libitum but the animals were kept individually in cages (stress AL- sAL). Similarly to sAL group, the animals from the CR group were kept individually but received a 30% less diet compared to AL group. At the end of the experiment animals were euthanized and the blood, liver and adipose tissue have been collected. Alanine aminotransferase (ALT) as well as aspartate aminotransferase (AST) were measured in plasma. Fatty acid profile was evaluated (relative %) in adipose tissue (GC-MS). Liver's stetosis was assessed. Results were analyzed statistically (ANOVA, STATISTICA v.10.0). Results: CR ApoE/LDLr-/- mice showed significantly lower body weight compared to animals, both AL and sAL. There were no significant differences between ALT and AST in both younger and older animals. However, negative tendencies were more pronounced in younger animals. In young animals CR significantly increased liver weight compared to AL (4.14 vs 3.73g/100g). In adipose tissue fatty acid profile differed in CR mice compared to control in young animals. Conclusions: Caloric restriction did not affect liver enzymes in mice. Caloric restriction showed similar but not identical metabolic activity in young and old mice. PMID- 29517191 TI - The combined effects of alcohol and tobacco use during pregnancy on birth outcomes AB - Background: Exposure to alcohol and tobacco during pregnancy may lead to developmental disorders in the foetus and can also adversely impact pregnancy outcomes and the newborn's health status. Objective: Assessment of alcohol consumption and tobacco use during pregnancy as well as their impact on pregnancy outcomes and birth parameters of the newborn in a selected group of mothers with children aged <= 2 years. Material and methods: The study was conducted in 104 mothers with children aged <= 2 years living in the Mazowiecki Voivodeship. A questionnaire was used for assessing selected lifestyle parameters tobacco and alcohol use, dietary supplements use, physical activity during pregnancy, socio demographic characteristics as well as children's birth parameters (birth weight, length, head circumference, chest circumference). Data were analyzed statistically using logistic regression analysis, Spearman's rang correlation, the Mann-Whitney U, Kruskal-Wallis, Student-t, Tukey and Chi2 tests (p<=0.05; STATISTICA 13.1 PL). Results: 22% of the participants solely smoked cigarettes, 13% solely drank alcohol while 7% smoked cigarettes and drank alcohol. Both cigarette smoking and alcohol use increased the risk of preterm birth (OR 9.6, 95% CI 2.9 - 31.4, p=0.00015; OR 5.3 95% CI 1.3 - 22.3, p=0.0199, respectively) as along with a low birth weight (OR 6.9, 95% CI 1.9 - 25.2, p=0.0028; OR 7.6, 95% CI 1.7 - 34.3, p=0.007). Cigarette smoking and alcohol use by the pregnant women also adversely impacted on children's health status (8.7 +/- 1.4 vs. 9.7 +/ 0.8, p=0.001 and 8.5 +/- 1.9 vs. 9.6 +/- 0.8, p=0.027, respectively). Simultaneous use of alcohol and cigarettes exacerbated the adverse impact of such substances on birth parameters and health status (birth weight, body length, Apgar score) as well as on pregnancy duration. Conclusions: The introduction of educational programs for high risk groups as well as prenatal obligatory consultations for mothers about the negative effects of substance use on fetus and the development of the child are warranted. Conclusions: Introducing educational programs are thus warranted for high risk groups as well as prenatal obligatory consultations for mothers about the adverse effects of such substance use on foetal and child development. PMID- 29517192 TI - Physical activity and associated socio-demographic factors in adolescents from the eastern region of Poland AB - Background: The introduction and maintenance of healthy habits in the field of physical activity at the early stage of life is particularly important for public health. With increasing of public awareness in physical activity, researchers are increasingly questioning its determinants in different age groups. In this paper we focus on variables such as age, sex and place of residence. Objectives: To determine what selected socio-demographic factors influence the level of physical activity of school youth from the eastern region of Poland in different domains of daily life. Material and Methods: A random sample of 916 Polish school youth from Secondary Schools from Eastern Region of Poland aged 16-18 was interviewed in spring 2016 by diagnostic survey method with the use of the official Polish long version of the International Physical Activity Questionnaire (IPAQ). Results: Analysing the relationship between gender and the level of physical activity statistically significant differences were found in all domains in favour of boys. The level of total physical activity in girls was 5345.5 MET min./week, whereas in boys - 6556.6 MET-min./week. In the area of total physical activity, the highest values were observed in pupils from small towns and villages, with lower values in the youth living in large and medium-sized cities. When the relationship of age with the level of physical activity in particular domains was examined, only the activity in the work/ school domain (p = 0.0129) spoke in favour of the youngest pupils (2578.7 MET-min./week) when compared to the oldest ones (2226.4 MET-min./week). Conclusions: The level of physical activity in young people from the Eastern region of Poland is decreasing with age, both in girls and boys. It is therefore important, especially for the group emerging adulthood, to offer a wide variety of updated, involving, age and gender oriented school physical activity classes that could be easily practised outside the school environment to improve the level of physical activity in leisure domain PMID- 29517193 TI - Letermovir Prophylaxis for Cytomegalovirus. PMID- 29517194 TI - Letermovir Prophylaxis for Cytomegalovirus. PMID- 29517195 TI - Letermovir Prophylaxis for Cytomegalovirus. PMID- 29517196 TI - Professional interest in dermatopathology of Stanislaw Ostrowski - the only one State Polish President among physicians. AB - President of prewar Lvov and Polish Republic on Exile, associate professor Stanislaw Ostrowski was a dermatologist with a keen interest in dermatopathology. This study was based on original resources, which - mainly reports of his own authorship - were focused on dermatopathology. Stanislaw Ostrowski provided excellent description of naevus epitheliomatosus sebaceus Wolters-Friboes both in Polish and German to be cited after decades in renowned handbooks of dermatopahtology published by Springer Verlag. His scientific output also includes meticulous presentation of Fox-Fordyce disease (apocrine miliaria) as well as gold-induced skin changes to Polish readership. Thus, this study documents dermatopahtological achievements of Stanislaw Ostrowski - the unifying statesman of society of Lvov and Polish emigration in London. PMID- 29517197 TI - Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumors. AB - The entity of hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated RCC has been proposed and integrated into the recent International Society of Urologic Pathology (ISUP) of renal tumors. This tumor is characterized by presence of cutaneous and/or uterine leiomyomas and RCC and autosomal dominant hereditary form. Grossly, HLRCC arising in the kidney show the solid tumor with frequent partial cystic area. Microscopically, the tumor typically shows papillary RCC, type 2, with eosinophilic large nucleoli reminiscent of cytomegaloviral inclusion and perinuclear clearing/haloes. Immunohistochemically, tumor cells show the overexpression for 2SC and reduced expression of FH. Germline mutation of fumarate hydratase (FH) gene, the HLRCC responsible gene mapped to chromosome 1q43, has been identified in patients with HLRCC. As the renal cancer in patients with HLRCC generally behave aggressively even in a small size, complete surgical resection and retroperitoneal lymph node resection should be performed promptly when the tumor is discovered. The surveillance of renal tumor in FH gene germline mutation-positive patients should be started from the early age using ultrasound sonography or magnetic resonance imaging. PMID- 29517198 TI - Clinical significance of nestin and its association with survival in neuroendocrine lung tumours. AB - Nestin is considered to be a cancer stem cell marker. Nestin expression in neuroendocrine tumours might be useful to predict prognosis and facilitate treatment planning. 88 patients with neuroendocrine lung tumours operated in the Department of Thoracic Surgery from 2007 to 2015 were included into the study. Immunohistochemical staining for nestin was performed. Clinicopathological and survival data were retrospectively analyzed. Nestin expression was detected in 15 (17%) specimens. Multivariate analysis showed that lymph node metastases (p = 0.0001; hazard ratio (HR) = 3.93; confidence interval (CI) 95%: 1.96-7.87), nestin expression (p = 0.034; HR = 2.30; CI 95%: 1.06-4.99) and patient's age (p = 0.024; HR = 1.04; CI 95%: 1.00-1.09) were independent negative prognostic factors. Nestin expression was significantly higher in large cell neuroendocrine carcinoma when compared with carcinoids (p = 0.001). Collected data support the thesis that nestin can be regarded as a biomarker in patients with neuroendocrine lung tumours. PMID- 29517199 TI - Survivin in breast lesions: immunohistochemical analysis of 196 cases. AB - We examined the survivin expression pattern by immunohistochemistry in 43 fibroadenomas and 153 ductal carcinomas of the breast. The subcellular localization of survivin and the intensity of immunoreaction were assessed. We analyzed the differences of survivin expression between fibroadenomas and carcinomas. We also correlated the survivin expression pattern in carcinomas with other clinicomorphological parameters such as the age of patients, the grade and size of primary tumor as well as the lymph node metastasis. Overall, survivin was detected in 107/153 carcinomas (69.9%) and in 26/43 fibroadenomas (60.5%). Statistical analysis confirmed significant correlations between the assessed parameters in fibroadenomas and carcinomas. Grade of carcinomas was significantly related to survivin expression in both subcellular localization and the intensity of immunoreaction. Tumor grade 3 was associated with nuclear positivity and combined nuclear and cytoplasmic localization. Carcinomas larger than 20 mm showed nuclear and combined localization in 81% of cases and higher intensity of survivin immunoreaction was also notably related to larger carcinomas. Statistically significant differences were also observed between subcellular survivin localization and intensity of immunoreaction. Our result suggest that nuclear accumulation of survivin is associated with proliferative fenotype and survivin was shown to be a worse prognostic marker in breast ductal carcinoma. PMID- 29517200 TI - Acquired cystic disease-associated renal cell carcinoma: a clinicopathological study of seven cases. AB - The disease entity of acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) has been recently incorporated into the international renal tumor classification. However, there are a few descriptions on clinicopathologic features. We performed a clinicopathologic study of seven cases with ACD-RCC. All tumors were incidentally found. Histologically, the tumor consisted of microcystic or cribriform pattern of neoplastic cells with deeply eosinophilic to oncocytic cytoplasm in the stroma of oxalate crystal deposition. Three cases contained the area of sarcomatoid transformation, of which one case also demonstrated rhabdoid phenotype foci. Six among seven patients had a hemodialysis history of more than 10 years and two patients showing the dedifferentiation had a hemodialysis history of more than 20 years. The follow-up duration ranged from 18 to 107 months with a mean of 59.1 months. Regarding the outcome, four patients were alive without disease. One patient was alive with metastasis 10 months after the operation. No patient died of disease. Finally, ACD-RCC generally pursues a favorable clinical course, but tumors with a hemodialysis history of more than 20 years may cause the dedifferentiation such as sarcomatoid change or rhabdoid features and this phenomenon may lead to worse clinical outcome. PMID- 29517201 TI - Effects of transforming growth factor-beta inhibitor on the proliferation of glioma stem/progenitor cell. AB - Transforming growth factor-beta (TGF-beta) signaling pathways play an important role in inhibition and promotion of cell proliferation in neural stem cells (NSCs) and glioma stem/progenitor cells (GSPCs), respectively. However, the mechanisms underlying these processes remain unknown. We presumed that there may be functional inhibition at the receptor downstream of TGF-beta signaling pathway leading to the activation of non- TGF-beta/Smad signaling pathway, which stimulates the proliferation of GSPCs. In this study, GSPCs, from glioma cell lines SHG44, were cultivated with TGF-beta receptor inhibitors (LY2157299 and LY2109761), and then the proliferative capability of GSPCs was measured; as well, the synthesis of TGF-beta ligands, and the mRNA expression level of TGF-beta and some key molecules of non-Smad signaling pathways were also detected. Our results showed that inhibitors against TGF-beta receptors could promote the proliferation of GSPCs, and the synthesis of TGF-beta ligands was enhanced. Furthermore, the inhibition of TGF-beta receptor may lead to the activation of non-Smad signaling pathways (mTOR and NF-kappaB). In conclusion, the down-regulation of TGF-beta receptor capability by TGF-beta receptor inhibitors can increase TGF-beta ligands synthesis and secretion, which then promote GSPCs proliferation by activating non Smad signaling pathways. PMID- 29517202 TI - Is the inflammation process absolutely absent in tendinopathy of the long head of the biceps tendon? Histopathologic study of the long head of the biceps tendon after arthroscopic treatment. AB - Tendinopathy of the long head of the biceps tendon is a difficult medical issue. Its pathogenesis and etiology is multifactorial and unclear. Tendinopathy is thought to be primarily degenerative in nature, as tendons are characterized by impaired regeneration and healing. Thirty-five patients with preoperatively diagnosed tendinopathy of long head of the biceps tendon were referred to the Orthopedics Department. All patients underwent an arthroscopic-assisted biceps tenodesis or tenotomy. The intra-articular portion of the long head of the biceps tendon was obtained from each of the patients who underwent arthroscopy. A macroscopic and microscopic evaluation of biceps tendon samples revealed degeneration among all specimens. This study demonstrates the prevalence of the degeneration process and the presence of marginal inflammation process in tendinopathy of the long head of biceps tendon. The role, that inflammation process plays in tendinopathy is important in the early phase and gradually becomes secondary to the developing degeneration. The inflammatory cells, occasionally seen in pathological tendons, could be an evidence of re-injury and recent healing response. PMID- 29517203 TI - Role of vascular endothelial growth factor in inducing production of angiopoetin 1 - in vivo study in Fisher rats. AB - The aim of the study was to investigate how an intramuscular injection of plasmids with genes coding various pro-angiogenic factors: angiopoetin-1 (ANGPT1), vascular endothelial growth factor (VEGF165) and hepatic growth factor (HGF), influences the production of ANGPT1. 40 Healthy Fisher rats received i.m. injections containing plasmids encoding pro-angiogenic genes in thigh muscles. They were divided into four equal groups. The first group received the plANGPT1 plasmid and the second group- the pIRES/ANGPT1/VEGF165 bicistronic plasmid. The pIRES/VEGF165/HGF bicistronic plasmid was administered to the third group and an empty plasmid (control group) to the fourth group. The animals were euthanized after 12 weeks. In each group, the number of vessels stained with the anti-ANGPT1 antibody was assessed under an optical microscope. The anti-ANGPT1 antibodies stained the vessels in all the groups. There were on average 14.1 +/-2.3 vessels in the the plANGPT1 group, 32.5 +/-10.5 in the pl/RESANGPT1/VEGF group and 30.8 +/-13.3 in the plRES/HGV/VEGF group. There were on average 7.3 +/-2.3 stained vessels (p < 0.0001) in the control group . The VEGF plays a role in the induction of the production of ANGPT1. The administration of plasmids only encoding ANGPT1 does not induce its production. PMID- 29517204 TI - [Human papilloma virus infection in basal cell carcinoma of the skin: a systematic review and meta-analysis study]. AB - Human papillomaviruses (HPVs) are a large and ubiquitous group of viruses that some of them have been suggested as a co-factor in the development of non melanoma skin cancers. The aim of this meta-analysis study was to evaluate HPVs' prevalence in basal cell carcinoma (BCC) of the skin and the risk of them in the BCC patients compared with the healthy controls. Five databases were searched from January 1980 to February 2017. A random-effects meta-analysis was done with the event rate (ER) for the prevalence of HPVs and odds ratio (OR) for estimation of the incidence of HPVs. Out of 1087 studies, 45 studies were included in the review. The pooled analysis demonstrated that the incidence of gamma-HPV was effective in the BCC patients compared with the healthy controls [OR = 1.97; 95% CI: 1.52-2.55; p < 0.00001], but not for alpha-HPV, beta-HPV and epidermodysplasia verruciformis (EV)-HPV (p > 0.05). The pooled ER of incidence of beta1-HPV in the BCC patients was z3.3% and for beta2-HPV in BCC patients was 44.2%. In conclusion, this meta-analysis showed that probably the risk of gamma HPV was more on BCC patients and also the rate of gamma-HPV was higher than alpha , beta- and EV-HPVs in the BCC patients. PMID- 29517205 TI - The role of histology, grading, location of tumour and ploidy in evaluation of outcome in patients with liposarcoma. AB - Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Krakow, Poland The review of literature indicates that several clinico-morphological factors such as location of the primary tumour as well as its size, histologic subtype, and grade or even selected molecular changes may significantly affect survival of liposarcoma (LPS) patients. Data concerning prognostic importance of DNA ploidy status in LPS cells are extremely limited and results of flow cytometry (FCM) studies have never been compiled with the current classification of malignant adipocytic tumours. Based on evaluation of material from 54 liposarcomas which was available for both histological and FCM analysis, we distinguished four prognostic groups of patients. The best prognosis was noticed for diploid and grade G1 well-differentiated or myxoid liposarcomas localised on extremities. None of the patients with lipoma-like WDLPS and myxoid liposarcoma grade 1 metastasised, while metastases were observed among patients with dedifferentiated LPS (70% of 5-year MFS) and cellular myxoid or round cell liposarcoma (20% of 5-year MFS, only). The metastasis-free survival curves for the above mentioned groups of patients differed significantly (p = 0.00001). PMID- 29517206 TI - CK5/6 expression based on morphological components in adenoid cystic carcinoma of the breast. PMID- 29517207 TI - Soft tissue metastasis of mediastinal non-functioning paraganglioma with unusual TTF-1 expression: a potential diagnostic pitfall. AB - Metastatic extra-adrenal paragangliomas are very rare and can represent diagnostic challenges. We report a case of 69-year-old man with a tumor of the right shoulder. Histologic and immunohistochemical examinations confirmed the diagnosis of paraganglioma. Surprisingly, tumor cells were diffusely thyroid transcription factor 1 (TTF-1) positive. Succinate dehydrogenase complex subunit B (SDHB) deficiency has not been detected. Inherited syndromes associated with paragangliomas were ruled out. The primary tumor was identified in the mediastinum. This is the first report of TTF-1 expression in paraganglioma. To avoid misdiagnosis, careful clinical and pathological examination of any tumor with organoid growths pattern is necessary. PMID- 29517209 TI - Medulloblastoma with extensive nodularity (SHH medulloblastoma). AB - Medulloblastoma is the most common CNS embryonal tumor and the most common malignant tumor of childhood. Its overall incidence is 1.8 cases per 1 million people, with a childhood incidence of 6 cases per 1 million. 77 percent of patients are less than 19 years old. Medulloblastoma occurs in the 4th ventricle and usually presents with symptoms of increased intracranial pressure (headaches, nausea, vomiting) and signs of obstructive hydrocephalus. Medulloblastoma is both histologically and genetically defined with prognosis that depends on classification. PMID- 29517208 TI - Asymptomatic uterus-like mass (ULM) of the extraperitoneal space - a case report of a rare finding with unusual clinical presentation and review of the literature. AB - The paper presents a case of a uterus-like mass (ULM), a rare type of tumour of the female reproductive system, which did not present any clinical symptoms described in other cases of ULMs. There are 35 reported cases of this type of tumour. It is defined as a lesion composed of smooth muscle-like stromal cells with a central cavity lined with endometrial type epithelium. There are three theories on the pathogenesis of ULMs which we discuss along with clinical presentation, diagnostic features, treatment options and potential oncological implications of this type of tumour, based on our case, and the review of the literature. PMID- 29517210 TI - Effects of Sotagliflozin Added to Insulin in Type 1 Diabetes. PMID- 29517211 TI - Effects of Sotagliflozin Added to Insulin in Type 1 Diabetes. PMID- 29517213 TI - Effects of Sotagliflozin Added to Insulin in Type 1 Diabetes. PMID- 29517212 TI - Effects of Sotagliflozin Added to Insulin in Type 1 Diabetes. PMID- 29517214 TI - Hearing Loss in Adults. PMID- 29517215 TI - Hearing Loss in Adults. PMID- 29517216 TI - Hearing Loss in Adults. PMID- 29517217 TI - Necrotizing Soft-Tissue Infections. PMID- 29517218 TI - Management of Acute Hip Fracture. PMID- 29517219 TI - Mineral-Enhanced Polyacrylic Acid Hydrogel as an Oyster-Inspired Organic Inorganic Hybrid Adhesive. AB - Underwater adhesion is crucial to many marine life forms living a sedentary lifestyle. Amongst them, mussel adhesion has been mostly studied, which inspires numerous investigations of 3,4-dihydroxyphenylalanine (DOPA)-based organic adhesives. In contrast, reef-building oysters represent another important "inorganic" strategy of marine molluscs for adhesion by generating biomineralized organic-inorganic adhesives, which is still rarely studied and no synthetic analogues have ever been reported so far. Here, a novel type of oyster-inspired organic-inorganic adhesive based on a biomineralized polyelectrolyte hydrogel is reported, which consists of polyacrylic acid physically cross-linked by very small amorphous calcium carbonate nanoparticles (<3 nm). The mineral-enhanced polyelectrolyte hydrogel adhesive is shown to be injectable, reusable, and optically clear upon curing in air. Moreover, comparable adhesion performance to DOPA-based adhesives is found for the hydrogel adhesive in both dry and wet conditions, which can even be further enhanced by introducing a small amount of second large cross-linker such as negatively charged nanoparticles. The present mineral hydrogel represents a new type of bio-inspired organic-inorganic adhesive that may find a variety of potential applications in adhesive chemistry. PMID- 29517220 TI - Coculture of Two Developmental Stages of a Marine-Derived Aspergillus alliaceus Results in the Production of the Cytotoxic Bianthrone Allianthrone A. AB - The genetically encoded, small-molecule chemical diversity of filamentous fungi is still largely unexplored and represents an attractive source for the discovery of new compounds. Here we report the production of new chlorinated bianthrones from coculture of two different developmental stages, or morphs, of a marine alga derived Aspergillus alliaceus (teleomorph: Petromyces alliaceus) strain. The vegetative stage (asexual morph) can be separated from the morph that switched to sexual development (sclerotial morph); both produce distinct secondary metabolite patterns. Ochratoxin (1) was mainly found in the monoculture of the sclerotial morph, while the anthraquinone pigment nalgiovensin (2) was produced by the asexual morph. Surprisingly, combining cultures from both developmental stages in a coculture experiment changed the metabolite profile drastically. The chlorinated congener nalgiolaxin (3) was abundant, and newly produced bianthrones were found. Allianthrone A (4) and its two diastereomers [allianthrones B (5) and C (6)] were isolated, and the new structures were determined by extensive NMR spectroscopic analysis, supported by optical properties and X-ray crystallography. All metabolites were tested in antibiotic and cytotoxicity assays, and allianthrone A (4) showed weak cytotoxic activity against the HCT-116 colon cancer and SK-Mel-5 melanoma cell lines. PMID- 29517221 TI - Metal-Organic Frameworks Supported on Nanofiber for Desalination by Direct Contact Membrane Distillation. AB - Among other applications, metal-organic frameworks (MOFs) are slowly gaining grounds as fillers for desalination composite membranes. In this study, superhydrophobic poly(vinylidene fluoride) nanofibrous membranes were fabricated with MOF (iron 1,3,5-benzenetricarboxylate) loading of up to 5 wt % via electrospinning on a nonwoven substrate. To improve the attachment of nanofibers onto the substrate, a substrate pretreatment method called "solvent basing" was employed. The iron content in the nanofiber, measured by energy-dispersive X-ray spectroscopy, increased proportionally with the increase of the MOF concentration in the spinning dope, indicating a uniform distribution of MOF in the nanofiber. The water contact angle increased up to 138.06 +/- 2.18 degrees upon the incorporation of 5 wt % MOF, and a liquid entry pressure of 82.73 kPa could be maintained, making the membrane useful for direct contact membrane distillation experiments. The membrane was stable for the entire operating period of 5 h, exhibiting 2.87 kg/m2.h of water vapor flux and 99.99% NaCl (35 g/L) rejection when the feed and permeate temperature were 48 and 16 degrees C, respectively. Immobilization of MOF on nanofibers with the enhanced attachment was proven by inductively coupled mass spectrometry analysis, by which no Fe2+ could be found in the permeate to the detection limit of ppt. PMID- 29517222 TI - Controllable and Reproducible Sheath of Carbon Fibers with Single-Walled Carbon Nanotubes through Electrophoretic Deposition for In Vivo Electrochemical Measurements. AB - The unique electronic and chemical structures of carbon nanotubes (CNTs) have well enabled their applications in electrochemistry and electroanalytical chemistry; however, the difficulty in reproducibly confining CNTs onto substrate electrodes, particularly onto microelectrodes, still remains to be addressed. In this study, we develop a method to reproducibly confine single-walled carbon nanotubes (SWNTs) onto carbon fiber microelectrodes (CFEs) with electrophoretic deposition (EPD) for in vivo measurement of ascorbate. Under 2.5 V, acid-treated SWNTs are uniformly deposited on CFEs. After thermal treatment at 300 degrees C followed by electrochemical treatment in 0.5 M H2SO4, the SWNT-sheathed CFEs exhibit good activity to accelerate the electrochemical oxidation of ascorbic acid (i.e., ascorbate, in a neutral solution) at an onset potential of -0.15 V vs Ag/AgCl and could in vivo selectively detect ascorbate. The controllable procedures employed for EPD and pretreatment avoid the deviation in the conventional manual modification methods such as drop casting and hand rolling previously used for confining SWNTs onto an electrode surface. With the electrodes prepared here, we find that level of extracellular ascorbate in the rat cortex increases by 20.4 +/- 4.8% ( n = 4), relative to its basal level, within 9 min after infusion of kainic acid into the hippocampus to evoke epilepsy. This study offers a reproducible method to prepare SWNT-sheathed CFEs for in vivo monitoring ascorbate that would largely facilitate future studies on neurochemical processes of ascorbate in various physiological and pathological events. PMID- 29517224 TI - Graphene Oxide Sponge as Nanofillers in Printable Electrolytes in High Performance Quasi-Solid-State Dye-Sensitized Solar Cells. AB - A graphene oxide sponge (GOS) is utilized for the first time as a nanofiller (NF) in printable electrolytes (PEs) based on poly(ethylene oxide) and poly(vinylidene fluoride) for quasi-solid-state dye-sensitized solar cells (QS-DSSCs). The effects of the various concentrations of GOS NFs on the ion diffusivity and conductivity of electrolytes and the performance of the QS-DSSCs are studied. The results show that the presence of GOS NFs significantly increases the diffusivity and conductivity of the PEs. The introduction of 1.5 wt % of GOS NFs decreases the charge-transfer resistance at the Pt-counter electrode/electrolyte interface ( Rpt) and increases the recombination resistance at the photoelectrode/electrolyte interface ( Rct). QS-DSSC utilizing 1.5 wt % GOS NFs can achieve an energy conversion efficiency (8.78%) higher than that found for their liquid counterpart and other reported polymer gel electrolytes/GO NFs based DSSCs. The high energy conversion efficiency is a consequence of the increase in both the open-circuit potential ( Voc) and fill factor with a slight decrease in current density ( Jsc). The cell efficiency can retain 86% of its initial value after a 500 h stability test at 60 degrees C under dark conditions. The long term stability of the QS-DSSC with GOS NFs is higher than that without NFs. This result indicates that the GOS NFs do not cause dye-desorption from the photoanode in a long-term stability test, which infers a superior performance of GOS NFs as compared to TiO2 NFs in terms of increasing the efficiency and long-term stability of QS-DSSCs. PMID- 29517223 TI - Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of beta Tubulin and the Multidrug Resistance Associated P-Glycoprotein. AB - Several next-generation taxanes have been reported to possess high potency against Taxol-resistant cancer cell lines overexpressing betaIII-tubulin and/or P glycoprotein (P-gp), both of which are involved in drug resistance. Using a photoaffinity Taxol analogue, 2-( m-azidobenzoyl)taxol, two potent next generation taxanes, SB-T-1214 and SB-CST-10202, exhibited distinct inhibitory effects on photolabeling of beta-tubulin from different eukaryotic sources that differ in beta-tubulin isotype composition. They also specifically inhibited photolabeling of P-gp, and the inhibitory effect correlated well with the steady state accumulation of [3H]vinblastine in a multidrug resistant (MDR) cell line, SKVLB1. Several microtubule-stabilizing agents (MSAs)-resistant cell lines from the human ovarian cancer cell line Hey were isolated, and their MDR1 and betaIII tubulin levels determined. Distinct potencies of the two taxanes against different MSA-resistant cells expressing unique levels of MDR1 and betaIII tubulin were found. Cytotoxicity assays, done in the presence of verapamil, indicated that SB-T-1214 is a substrate, although not as good as Taxol, for P-gp. The mechanisms involved in drug resistance are multifactorial, and the effectiveness of new Taxol analogues depends on the interaction between the drugs and all possible targets; in this case the two major cellular targets are beta tubulin and P-gp. PMID- 29517225 TI - Volatile Organic Compounds from Logwood Combustion: Emissions and Transformation under Dark and Photochemical Aging Conditions in a Smog Chamber. AB - Residential wood combustion (RWC) emits high amounts of volatile organic compounds (VOCs) into ambient air, leading to formation of secondary organic aerosol (SOA), and various health and climate effects. In this study, the emission factors of VOCs from a logwood-fired modern masonry heater were measured using a Proton-Transfer-Reactor Time-of-Flight Mass Spectrometer. Next, the VOCs were aged in a 29 m3 Teflon chamber equipped with UV black lights, where dark and photochemical atmospheric conditions were simulated. The main constituents of the VOC emissions were carbonyls and aromatic compounds, which accounted for 50%-52% and 30%-46% of the detected VOC emission, respectively. Emissions were highly susceptible to different combustion conditions, which caused a 2.4-fold variation in emission factors. The overall VOC concentrations declined considerably during both dark and photochemical aging, with simultaneous increase in particulate organic aerosol mass. Especially furanoic and phenolic compounds decreased, and they are suggested to be the major precursors of RWC-originated SOA in all aging conditions. On the other hand, dark aging produced relatively high amounts of nitrogen-containing organic compounds in both gas and particulate phase, while photochemical aging increased especially the concentrations of certain gaseous carbonyls, particularly acid anhydrides. PMID- 29517226 TI - Recombinant Protein (Luciferase-IgG Binding Domain) Conjugated Quantum Dots for BRET-Coupled Near-Infrared Imaging of Epidermal Growth Factor Receptors. AB - For the highly sensitive near-infrared (NIR) optical detection of epidermal growth factor receptors (EGFRs) expressed on cancer cells, bioluminescence resonance energy transfer (BRET) coupled NIR quantum dots (QDs) are prepared by direct conjugation of his-tagged Renilla luciferase (RLuc) recombinant protein (HisRLuc.GB1) to glutathione-coated CdSeTe/CdS QDs (GSH-QDs). The recombinant protein has two functional groups consisting of a luciferase enzyme and an immunoglobulin binding domain (GB1) of protein G. Recombinant protein (HisRLuc.GB1) conjugated QDs (GB1.RLuc-QDs) show BRET-coupled NIR emission, which results from energy transfer from luciferin to QDs with a high BRET efficiency of ca. 50%. Since the GB1.RLuc-QDs have the GB1 domain at their surface, the QDs have an ability to bind the Fc moiety of immunoglobulin G (IgG). The resulting IgG bound QDs can be used as a molecular imaging probe with NIR fluorescence and BRET-coupled NIR emission. For NIR optical detection of EGFRs on cancer cells, we conjugated anti-EGFR monoclonal antibody to the GB1.RLuc-QDs. Herein, we show that the detection sensitivity of EGFRs by BRET-coupled NIR emission of GB1.RLuc QDs is at least three times higher than that of the NIR fluorescence of the QDs. The conjugates between anti-EGFR antibody and GB1.RLuc-QDs make it possible to perform BRET-based highly sensitive NIR imaging of EGFRs in living cells. PMID- 29517227 TI - Syntheses, Structure, and 2/5 Magnetization Plateau of a 2D Layered Fluorophosphate Na3Cu5(PO4)4F.4H2O. AB - A new two-dimensional (2D) fluorophosphate compound Na3Cu5(PO4)4F.4H2O with a Cu5 cluster has been synthesized using a conventional hydrothermal method. The compound crystallizes in the orthorhombic crystal system with space group Pnma. The 2D layered structure is formed by cap-like {Cu5(PO4)4F} building units consisting of a Cu4O12F cluster plus a residual cap Cu2+ ion. Magnetic susceptibility exhibits a broad maximum at T2 = 19.2 K due to low-dimensional character followed by a long-range antiferromagnetic ordering at T1 = 11.5 K, which is further confirmed by the specific heat data. High-field magnetization measurement demonstrates a 2/5 quantum magnetization plateau above 40 T. The ESR data indicate the presence of magnetic anisotropy, in accordance with the 2D structure of the system. PMID- 29517228 TI - A Study of Through-Space and Through-Bond JPP Coupling in a Rigid Nonsymmetrical Bis(phosphine) and Its Metal Complexes. AB - A series of representative late d-block metal complexes bearing a rigid bis(phosphine) ligand, iPr2P-Ace-PPh2 (L, Ace = acenaphthene-5,6-diyl), was prepared and fully characterized by various techniques, including multinuclear NMR and single-crystal X-ray diffraction. The heteroleptic nature of the peri substituted ligand L allows for the direct observation of the JPP couplings in the 31P{1H} NMR spectra. Magnitudes of JPP are correlated with the identity and geometry of the metal and the distortions of the ligand L. The forced overlap of the phosphine lone pairs due to the constraints imposed by the rigid acenaphthene skeleton in L results in a large 4 JPP of 180 Hz. Sequestration of the lone pairs, either via oxidation of the phosphine or via metal chelation, results in distinct changes in the magnitude of JPP. For tetrahedral d10 complexes ([LMCl2], M = Zn, Cd, Hg), the JPP is comparable to or larger than (193-309 Hz) that in free ligand L, although the P...P separation in these complexes is increased by ca. 0.4 A (compare to free ligand L). The magnitude of JPP diminishes to 26-117 Hz in square planar d8 complexes ([LMX2], M = Ni, Pd, Pt; X = Cl, Br) and the octahedral Mo0 complex ([LMo(CO)4], 33 Hz). Coupling deformation density calculations indicate the through-space interaction dominates in free L, while in metal complexes the main coupling pathway is via the metal atom. PMID- 29517229 TI - Stability and Reactivity: Positive and Negative Aspects for Nanoparticle Processing. AB - Nanoparticles exist far from the equilibrium state due to their high surface energy. Nanoparticles are therefore extremely unstable and easily change themselves or react with active substances to reach a relatively stable state in some cases. This causes desired changes or undesired changes to nanoparticles and thus makes them exhibit a high reactivity and a poor stability. Such dual nature (poor stability and high reactivity) of nanoparticles may result in both negative and positive effects for nanoparticle processing. However, the existing studies mainly focus on the high reactivity of nanoparticles, whereas their poor stability has been neglected or considered inconsequential. In fact, in some cases the unstable process, which is derived from the poor stability of nanoparticles, offers an opportunity to design and fabricate unique nanomaterials, such as by chemically transforming the "captured" intermediate nanostructures during a changing process, assembling destabilized nanoparticles into larger ordered assemblies, or shrinking/processing pristine materials into the desired size or shape via selective etching. In this review, we aim to present the stability and reactivity of nanoparticles on three levels: the foundation, concrete manifestations, and applications. We start with a brief introduction of dangling bonds and the surface chemistry of nanoparticles. Then, concrete manifestations of the poor stability and high reactivity of nanoparticles are presented from four perspectives: dispersion stability, thermal stability, structural stability, and chemical stability/reactivity. Next, we discuss some issues regarding the stability and reactivity of nanomaterials during applications. Finally, conclusions and perspectives on this field are presented. PMID- 29517230 TI - Electrochemical Investigations of Hydrogenases and Other Enzymes That Produce and Use Solar Fuels. AB - Many enzymes that produce or transform small molecules such as O2, H2, and CO2 embed inorganic cofactors based on transition metals. Their active site, where the chemical reaction occurs, is buried in and protected by the protein matrix, and connected to the solvent in several ways: chains of redox cofactors mediate long-range electron transfer; static or dynamic tunnels guide the substrate, product and inhibitors; amino acids and water molecules transfer protons. The catalytic mechanism of these enzymes is therefore delocalized over the protein and involves many different steps, some of which determine the response of the enzyme under conditions of stress (extreme redox conditions, presence of inhibitors, light), the catalytic rates in the two directions of the reaction and their ratio (the "catalytic bias"). Understanding all the steps in the catalytic cycle, including those that occur on sites of the protein that are remote from the active site, requires a combination of biochemical, structural, spectroscopic, theoretical, and kinetic methods. Here we argue that kinetics should be used to the fullest extent, by extracting quantitative information from the comparison of data and kinetic models and by exploring the combination of experimental kinetics and theoretical chemistry. In studies of these catalytic mechanisms, direct electrochemistry, the technique which we use and contribute to develop, has become unescapable. It simply consists in monitoring the changes in activity of an enzyme that is wired to an electrode by recording an electric current. We have described kinetic models that can be used to make sense of these data and to learn about various aspects of the mechanism that are difficult to probe using more conventional methods: long-range electron transfer, diffusion along gas channels, redox-driven (in)activations, active site chemistry and photoreactivity under conditions of turnover. In this Account, we highlight a few results that illustrate our approach. We describe how electrochemistry can be used to monitor substrate and inhibitor diffusion along the gas channels of hydrogenases and we discuss how the kinetics of intramolecular diffusion relates to global properties such as resistance to oxygen and catalytic bias. The kinetics and/or thermodynamics of intramolecular electron transfer may also affect the catalytic bias, the catalytic potentials on either side of the equilibrium potential, and the overpotentials for catalysis (defined as the difference between the catalytic potentials and the open circuit potential). This is understood by modeling the shape of the steady-state catalytic response of the enzyme. Other determinants of the catalytic rate, such as domain motions, have been probed by examining the transient catalytic response recorded at fast scan rates. Last, we show that combining electrochemical investigations and MD, DFT, and TD-DFT calculations is an original way of probing the reactivity of the H cluster of hydrogenase, in particular its reactions with CO, O2, and light. This approach contrasts with the usual strategy which aims at stabilizing species that are presumed to be catalytic intermediates, and determining their structure using spectroscopic or structural methods. PMID- 29517231 TI - Direct Observation of Room-Temperature Stable Magnetism in LaAlO3/SrTiO3 Heterostructures. AB - Along with an unexpected conducting interface between nonmagnetic insulating perovskites LaAlO3 and SrTiO3 (LaAlO3/SrTiO3), striking interfacial magnetisms have been observed in LaAlO3/SrTiO3 heterostructures. Interestingly, the strength of the interfacial magnetic moment is found to be dependent on oxygen partial pressures during the growth process. This raises an important, fundamental question on the origin of these remarkable interfacial magnetic orderings. Here, we report a direct evidence of room-temperature stable magnetism in a LaAlO3/SrTiO3 heterostructure prepared at high oxygen partial pressure by using element-specific soft X-ray magnetic circular dichroism at both Ti L3,2 and O K edges. By combining X-ray absorption spectroscopy at both Ti L3,2 and O K edges and first-principles calculations, we qualitatively ascribe that this strong magnetic ordering with dominant interfacial Ti3+ character is due to the coexistence of LaAlO3 surface oxygen vacancies and interfacial (TiAl-AlTi) antisite defects. On the basis of this new understanding, we revisit the origin of the weak magnetism in LaAlO3/SrTiO3 heterostructures prepared at low oxygen partial pressures. Our calculations show that LaAlO3 surface oxygen vacancies are responsible for the weak magnetism at the interface. Our result provides direct evidence on the presence of room-temperature stable magnetism and a novel perspective to understand magnetic and electronic reconstructions at such strategic oxide interfaces. PMID- 29517232 TI - Transfer Hydrogenation of Alkenes Using Ethanol Catalyzed by a NCP Pincer Iridium Complex: Scope and Mechanism. AB - The first general catalytic approach to effecting transfer hydrogenation (TH) of unactivated alkenes using ethanol as the hydrogen source is described. A new NCP type pincer iridium complex (BQ-NCOP)IrHCl containing a rigid benzoquinoline backbone has been developed for efficient, mild TH of unactivated C-C multiple bonds with ethanol, forming ethyl acetate as the sole byproduct. A wide variety of alkenes, including multisubstituted alkyl alkenes, aryl alkenes, and heteroatom-substituted alkenes, as well as O- or N-containing heteroarenes and internal alkynes, are suitable substrates. Importantly, the (BQ-NCOP)Ir/EtOH system exhibits high chemoselectivity for alkene hydrogenation in the presence of reactive functional groups, such as ketones and carboxylic acids. Furthermore, the reaction with C2D5OD provides a convenient route to deuterium-labeled compounds. Detailed kinetic and mechanistic studies have revealed that monosubstituted alkenes (e.g., 1-octene, styrene) and multisubstituted alkenes (e.g., cyclooctene (COE)) exhibit fundamental mechanistic difference. The OH group of ethanol displays a normal kinetic isotope effect (KIE) in the reaction of styrene, but a substantial inverse KIE in the case of COE. The catalysis of styrene or 1-octene with relatively strong binding affinity to the Ir(I) center has (BQ-NCOP)IrI(alkene) adduct as an off-cycle catalyst resting state, and the rate law shows a positive order in EtOH, inverse first-order in styrene, and first-order in the catalyst. In contrast, the catalysis of COE has an off-cycle catalyst resting state of (BQ-NCOP)IrIII(H)[O(Et)...HO(Et)...HOEt] that features a six-membered iridacycle consisting of two hydrogen-bonds between one EtO ligand and two EtOH molecules, one of which is coordinated to the Ir(III) center. The rate law shows a negative order in EtOH, zeroth-order in COE, and first-order in the catalyst. The observed inverse KIE corresponds to an inverse equilibrium isotope effect for the pre-equilibrium formation of (BQ-NCOP)IrIII(H)(OEt) from the catalyst resting state via ethanol dissociation. Regardless of the substrate, ethanol dehydrogenation is the slow segment of the catalytic cycle, while alkene hydrogenation occurs readily following the rate-determining step, that is, beta hydride elimination of (BQ-NCOP)Ir(H)(OEt) to form (BQ-NCOP)Ir(H)2 and acetaldehyde. The latter is effectively converted to innocent ethyl acetate under the catalytic conditions, thus avoiding the catalyst poisoning via iridium mediated decarbonylation of acetaldehyde. PMID- 29517233 TI - When Do Strongly Coupled Diradicals Show Strongly Coupled Reactivity? Thermodynamics and Kinetics of Hydrogen Atom Transfer Reactions of Palladium and Platinum Bis(iminosemiquinone) Complexes. AB - The 2,2'-biphenylene-bridged bis(iminosemiquinone) complexes ( tBuClip)M [ tBuClipH4 = 4,4'-di- tert-butyl- N, N'-bis(3,5-di- tert-butyl-2-hydroxyphenyl) 2,2'-diaminobiphenyl; M = Pd, Pt] can be reduced to the bis(aminophenoxide) complexes ( tBuClipH2)M by reaction with hydrazobenzene (M = Pd) or by catalytic hydrogenation (M = Pt). The palladium complex with one aminophenoxide ligand and one iminosemiquinone ligand, ( tBuClipH)Pd, is generated by comproportionation of ( tBuClip)Pd with ( tBuClipH2)Pd in a process that is both slow (0.06 M-1 s-1 in toluene at 23 degrees C) and only modestly favorable ( Kcom = 1.9 in CDCl3), indicating that both N-H bonds have essentially the same bond strength. The mono(iminoquinone) complex ( tBuClipH)Pt has not been observed, indicating that the platinum analogue shows no tendency to comproportionate ( Kcom < 0.1). The average bond dissociation free energies (BDFE) of the complexes have been established by equilibration with suitably substituted hydrazobenzenes, and the palladium bis(iminosemiquinone) is markedly more oxidizing than the platinum compound, with hydrogen transfer from ( tBuClipH2)Pt to ( tBuClip)Pd occurring with Delta G degrees = -8.9 kcal mol-1. The palladium complex ( tBuClipH2)Pd reacts with nitroxyl radicals in two observable steps, with the first hydrogen transfer taking place slightly faster than the second. In the platinum analogue, the first hydrogen transfer is much slower than the second, presumably because the N-H bond in the monoradical complex ( tBuClipH)Pt is unusually weak. Using driving force-rate correlations, it is estimated that this bond has a BDFE of 55.1 kcal mol-1, which is 7.1 kcal mol-1 weaker than that of the first N-H bond in ( tBuClipH2)Pt. The two radical centers in the platinum, but not the palladium, complex thus act in concert with each other and display a strong thermodynamic bias toward two-electron reactivity. The greater thermodynamic and kinetic coupling in the platinum complex is attributed to the stronger metal ligand pi interactions in this compound. PMID- 29517234 TI - State-of-the-Art Computations of Vertical Ionization Potentials with the Extended Koopmans' Theorem Integrated with the CCSD(T) Method. AB - The accurate computation of ionization potentials (IPs), within 0.10 eV, is one of the most challenging problems in modern computational chemistry. The extended Koopmans' theorem (EKT) provides a systematic direct approach to compute IPs from any level of theory. In this study, the EKT approach is integrated with the coupled-cluster singles and doubles with perturbative triples [CCSD(T)] method for the first time. For efficiency, the density-fitting (DF) approximation is employed for electron repulsion integrals. Further, the EKT-CCSD(T) method is applied to a set of 23 molecules, denoted as IP23, for comparison with the experimental ionization potentials. For the IP23 set, the EKT-CCSD(T) method, along with the aug-cc-pV5Z basis set, provides a mean absolute error of 0.05 eV. Hence, our results demonstrate that direct computations of IPs at high-accuracy levels can be achieved with the EKT-CCSD(T) method. We believe that the present study may open new avenues in IP computations. PMID- 29517235 TI - Diophantine Approach to the Classification of Two-Dimensional Lattices: Surfaces of Face-Centered Cubic Materials. AB - The long-range periodic order of a crystalline surface is generally represented by means of a two-dimensional Bravais lattice, of which only five symmetrically distinct types are possible. Here, we explore the circumstances under which each type may or may not be found at the surfaces of face-centered cubic materials and provide means by which the type of lattice may be determined with reference only to the Miller indices of the surface; the approach achieves formal rigor by focusing on the number theory of integer variables rather than directly upon real geometry. We prove that the {100} and {111} surfaces are, respectively, the only exemplars of square and triangular lattices. For surfaces exhibiting a single mirror plane, we not only show that rectangular and rhombic lattices are the only two possibilities, but also capture their alternation in terms of the parity of the indices. In the case of chiral surfaces, oblique lattices predominate, but rectangular and rhombic cases are also possible and arise according to well defined rules, here partially recounted. PMID- 29517236 TI - Aqueous Polymeric Hollow Particles as an Opacifier by Emulsion Polymerization Using Macro-RAFT Amphiphiles. AB - A robust polymerization technique that enables the surfactant-free aqueous synthesis of a high solid content latex containing polymeric hollow particles is presented. Uniquely designed amphiphilic macro-reversible addition fragmentation chain transfer (RAFT) copolymers were used as sole stabilizers for monomer emulsification as well as for free-radical emulsion polymerization. The polymerization was found to be under RAFT control, generating various morphologies from spherical particles, wormlike structures to polymer vesicles. The final particles were dominantly polymeric vesicles which had a substantially uniform and continuous polymer layer around a single aqueous filled void. They produced hollow particles once dried and were successfully used as opacifiers to impart opacity into polymer paint films. This method is simple, can be performed in a controllable and reproducible manner, and may be performed using diverse procedures. PMID- 29517237 TI - When Ethyl Isocyanoacetate Meets Isatins: A 1,3-Dipolar/Inverse 1,3 Dipolar/Olefination Reaction for Access to 3-Ylideneoxindoles. AB - A new CuI/1,10-phen-catalyzed reaction for the synthesis of 3-ylideneoxindoles from readily available isatins and ethyl isocyanoacetate, in which ethyl isocyanoacetate acts as a latent two-carbon donor like the Wittig reagent, is reported. A tandem procedure including 1,3-dipolar cycloaddition/inverse 1,3 dipolar ring opening/olefination allows the preparation of 3-ylideneoxindoles with broad functional group tolerance. PMID- 29517238 TI - Catecholic Isoquinolines from Portulaca oleracea and Their Anti-inflammatory and beta2-Adrenergic Receptor Agonist Activity. AB - Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC50 = 18.0-497.7 MUM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC50 = 82.4 MUM), with EC50 values of 18.0, 18.1, 35.4, 36.3, and 58.7 MUM, respectively. Additionally, at 100 MUM, compounds 1-12 showed different degrees of beta2-adrenergic receptor (beta2-AR) agonist activity in the CHO-K1/GA15 cell line which stably expressed beta2-AR as detected by a calcium assay. The EC50 values of 2 and 10 were 5.1 MUM and 87.9 nM, respectively. PMID- 29517239 TI - Cleavage of C-C Bonds for the Synthesis of C2-Substituted Quinolines and Indoles by Catalyst-Controlled Tandem Annulation of 2-Vinylanilines and Alkynoates. AB - The strategy for the synthesis of C2-substituted indoles and quinolines from 2 vinylanilines and alkynoates through C-C bond cleavage is developed. With these general methods, 2-substituted indoles and quinolines can be accessed via tandem Michael addition and cyclization with no requirement of oxidant. This strategy not only provides a method for the synthesis C2-substituted indoles in good yields through the simultaneous cleavage of C?C and C=C bonds under metal-free conditions but also provides a simple method for the generation of the C2 substituted quinolines in moderate yields via Pd-catalyzed C=C bond cleavage. PMID- 29517240 TI - Collective Total Synthesis of (-)-Lundurines A-C. AB - A collective asymmetric total synthesis of lundurines A-C using l-pyroglutamic acid derived from the chiral pool is described. The key steps include a tandem reductive amination/lactamization sequence to introduce the pyrrolidinone ring, a palladium-catalyzed intramolecular direct C-H vinylation of indole to construct the crucial polyhydroazocine ring, and a Lewis acid promoted formal [3 + 2] cycloaddition/N2 extrusion process to install the polysubstituted cyclopropyl ring. PMID- 29517241 TI - 2-Position-Selective C-H Perfluoroalkylation of Quinoline Derivatives. AB - We developed 2-position-selective, direct C-H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of quinoline derivatives. Regioselective transformation was achieved without derivatization of the quinolines. The reaction proceeded at room temperature with high functional group tolerance, even in gram scale. Notably, the reaction was applicable to substrates containing a functional group sensitive to oxidation and a drug molecule. PMID- 29517242 TI - Phosphine-Catalyzed Anti-Hydroboration of Internal Alkynes. AB - Trialkylphosphine organocatalysts have enabled regioselective anti-hydroboration of internal alkynes with pinacolborane reagents to provide ( E)-disubstituted alkenylboronate compounds. The alkenylboronate can be used for derivatizations, such as protodeborylation, Suzuki-Miyaura coupling, conjugate reduction, and Diels-Alder reactions. PMID- 29517243 TI - Electrical Initialization of Electron and Nuclear Spins in a Single Quantum Dot at Zero Magnetic Field. AB - The emission of circularly polarized light from a single quantum dot relies on the injection of carriers with well-defined spin polarization. Here we demonstrate single dot electroluminescence (EL) with a circular polarization degree up to 35% at zero applied magnetic field. The injection of spin-polarized electrons is achieved by combining ultrathin CoFeB electrodes on top of a spin LED device with p-type InGaAs quantum dots in the active region. We measure an Overhauser shift of several microelectronvolts at zero magnetic field for the positively charged exciton (trion X+) EL emission, which changes sign as we reverse the injected electron spin orientation. This is a signature of dynamic polarization of the nuclear spins in the quantum dot induced by the hyperfine interaction with the electrically injected electron spin. This study paves the way for electrical control of nuclear spin polarization in a single quantum dot without any external magnetic field. PMID- 29517244 TI - Within-family processes: Interparental and coparenting conflict and child adjustment. AB - Previous studies have found evidence that interparental conflict, parents' coparenting behavior, and children's adjustment are reciprocally related. Most prior research, however, has failed to empirically distinguish between-family differences from within-family changes, limiting our understanding of how within family fluctuations in each construct may be interrelated over time. In the present study, we focused on within-family associations among interparental conflict factors (i.e., verbal aggression and withdrawing), coparenting conflict, and children's internalizing and externalizing problems. Longitudinal data were drawn from 5 annual waves of survey data from 537 German families (i.e., mothers, fathers, and a focal child) in the German Family Panel (pairfam) study (Bruderl et al., 2015; Huinink et al., 2011). Data were analyzed with random intercept cross-lagged panel models, which partition variance into between- and within person (or family) components in longitudinal data. Cross-lagged analyses of within-family variance revealed that fluctuations in interparental conflict did not predict child problems, but higher than typical child externalizing problems increased fathers' withdrawal and coparenting conflict in the future. Higher than average coparenting conflict within a given family predicted reductions in interparental verbal aggression, less maternal withdrawal, and fewer child externalizing problems. The findings demonstrate that analyses of within-family associations may provide new insights on mutual influences that unfold across time within families and are of particular importance for informing practice. (PsycINFO Database Record PMID- 29517245 TI - Relationships between body image, sexual satisfaction, and relationship quality in romantic couples. AB - Previous studies found important associations between body image, sexual satisfaction, and perceived romantic relationship quality, but mainly focused on one individual's perceptions rather than both partners. To take the interdependency of romantic partners into account, the present study examined these associations in romantic couples with a dyadic approach. In a cross sectional design, 151 Dutch heterosexual couples completed an online survey measuring body image, sexual satisfaction, and perceived relationship quality. Hypotheses were tested using the actor-partner interdependence model (APIM) and an APIM extended with a mediator (APIMeM), with couple members' body image as predictors, couple members' sexual satisfaction as mediators, and couple members' relationship quality as outcomes. Results indicated that within individuals, a more positive body image was linked to higher perceived romantic relationship quality through greater sexual satisfaction. No gender differences were found, implying that body image and sexual satisfaction are equally strongly associated with perceived relationship quality in women and men. Results revealed no associations of an individual's body image and sexual satisfaction with the partner's perceived relationship quality. These findings implicate that interventions focusing on developing and maintaining a positive body image may be helpful in building on a more satisfying sex life and higher perceived relationship quality. (PsycINFO Database Record PMID- 29517246 TI - Couples coping with stress: Between-person differences and within-person processes. AB - In intimate relationships, spousal support (or dyadic coping) can directly benefit relationships (i.e., direct effect) and protect the relationship against the negative spillover effects of stress (i.e., buffer effect). As stress-coping theories suggest, both processes can vary between persons as well as within persons. However, empirically, this distinction is not always made explicit, resulting in potentially misleading conclusions about dyadic stress-coping processes. In the current study, we investigated stress and coping processes in couples at both between- and within-person levels. Participants were 84 Chinese dual-earning couples (N = 168 individuals) participated in a 7-day diary study. Between persons, our multilevel analyses replicated well-established buffering effects: The link between average stress and relationship outcomes was reduced if the partner provided more support on average. Within persons, results implied a significant buffer effect only in women; their relationship satisfaction was highest on days when they experienced higher levels of stress and higher levels of partner support. The present findings demonstrate how distinguishing between- and within-person effects can provide a better conceptual understanding of dyadic processes in intimate relationships while examining stress-coping associations in an understudied group. (PsycINFO Database Record PMID- 29517247 TI - Use of redundant sets of landmark information by humans (Homo sapiens) in a goal searching task in an open field and on a computer screen. AB - Landmark-based goal-searching tasks that were similar to those for pigeons (Ushitani & Jitsumori, 2011) were provided to human participants to investigate whether they could learn and use multiple sources of spatial information that redundantly indicate the position of a hidden target in both an open field (Experiment 1) and on a computer screen (Experiments 2 and 3). During the training in each experiment, participants learned to locate a target in 1 of 25 objects arranged in a 5 * 5 grid, using two differently colored, arrow-shaped (Experiments 1 and 2) or asymmetrically shaped (Experiment 3) landmarks placed adjacent to the goal and pointing to the goal location. The absolute location and directions of the landmarks varied across trials, but the constant configuration of the goal and the landmarks enabled participants to find the goal using both global configural information and local vector information (pointing to the goal by each individual landmark). On subsequent test trials, the direction was changed for one of the landmarks to conflict with the global configural information. Results of Experiment 1 indicated that participants used vector information from a single landmark but not configural information. Further examinations revealed that the use of global (metric) information was enhanced remarkably by goal searching with nonarrow-shaped landmarks on the computer monitor (Experiment 3) but much less so with arrow-shaped landmarks (Experiment 2). The General Discussion focuses on a comparison between humans in the current study and pigeons in the previous study. (PsycINFO Database Record PMID- 29517248 TI - Emotional state and personality influence cognitive flexibility in horses (Equus caballus). AB - Emotions are recognized as strong modulators of cognitive capacities. However, studies have mainly focused on the effect of negative emotions, with few investigating positive emotions. Recent studies suggest that traits of personality can modulate the effects of emotion on cognitive performance. This study aimed to assess whether emotional states differing according to their valence influenced the ability to achieve instrumental conditioning and learning flexibility and to determine the influence of personality. After being tested for their personality, 55 mares underwent acquisition and extinction procedures of instrumental conditioning in a box previously associated with negative events (e.g., novel and sudden stimuli; E-), positive events (e.g., food reward; E+), or no particular event (E0). This contextual conditioning induced contrasting behavioral and physiological responses during acquisition, indicating that E- horses were in a negative and E+ horses were in a positive emotional state. Although acquisition performance did not differ between groups, E+ horses showed a greater flexibility in the extinction phase of instrumental learning than E- and E0 horses. Furthermore, fearless personality was related to better acquisition and increased cognitive flexibility. This study demonstrates that horses were able to undergo contextual conditioning that induced negative or more positive emotional states and that this latter emotional state enhanced cognitive flexibility. (PsycINFO Database Record PMID- 29517249 TI - Through their eyes: The influence of social models on attention and memory in capuchin monkeys (Sapajus apella). AB - The ability to learn socially is of critical importance across a wide variety of species, as it allows knowledge to be passed quickly among individuals without the need of time-consuming trial-and-error learning. Among primates, social learning research has been particularly focused on foraging tasks, including transmission dynamics and the demonstration characteristics that appear to support social learning. Less work has focused on the attentional salience of the information being viewed, especially in New World monkeys. We used a noninvasive eye-tracking paradigm previously used in human infants and great apes to examine the salience of social modeling for memory in capuchin monkeys. Like human infants and apes, capuchins were significantly more likely to remember an event that included a social model as opposed to a nonsocial model. This article provides some of the first evidence that capuchin memory is altered by the presence of a social model and presents a novel method for assessing cognitive capabilities in this species. Whether this "social memory bias" is shared across the primate order, or is present only in taxa that regularly rely on social information, is an important avenue for future research. (PsycINFO Database Record PMID- 29517250 TI - Predictors of eating behavior in middle childhood: A hybrid fixed effects model. AB - Children's eating behavior influences energy intake and thus weight through choices of type and amount of food. One type of eating behavior, food responsiveness, defined as eating in response to external cues such as the sight and smell of food, is particularly related to increased caloric intake and weight. Because little is known about the potential determinants of such behavior, we focus herein on child and parent predictors of food responsiveness in a large community sample of Norwegian 6-year-olds, followed up at ages 8 and 10. To measure children's food responsiveness, parents completed the Children's Eating Behavior Questionnaire. Potential predictors were children's inhibition and symptoms of attention-deficit/hyperactivity disorder and depression, and parents' instrumental and controlling feeding practices as well as parental restrained eating. After accounting for children's initial levels of food responsiveness within a hybrid fixed effects method that takes into consideration all unmeasured time-invariant confounders, more child attention deficit/hyperactivity disorder symptoms and greater restrained eating by parents predicted more food responsiveness at both ages 8 and 10. These results may provide important insights for efforts to prevent overeating. (PsycINFO Database Record PMID- 29517251 TI - How high can you count? Probing the limits of children's counting. AB - While much research has focused on understanding the process by which young children learn to count, little work has explored the effects of direct instruction on this process. In the current study, we explored the impacts of training children in an explicit counting procedure on two distinct cardinality tasks. Two- to 5-year-old children first participated in a Give-N task in which counting proficiency was assessed, and then participated in a short instruction session where explicit counting was modeled and encouraged. Following training, children were significantly better at identifying which of two cards contained a set size outside of their range of counting mastery (Huang, Spelke, & Snedeker, 2010) and were more likely to improve on a secondary numerical production task (Give-N; Wynn, 1990, 1992) compared with children in the control group. Not surprisingly, a greater proportion of children in the count training condition overtly counted during the cardinality task, a strategy that was found to be the strongest indicator of performance. Together, results reveal that even 5 min of counting instruction greatly increases the likelihood that a child will engage in counting behavior and results in improvements in cardinality judgments in two distinct numerical tasks. (PsycINFO Database Record PMID- 29517252 TI - What happens after prejudice is confronted in the workplace? How mindsets affect minorities' and women's outlook on future social relations. AB - Organizations are increasingly concerned with fostering successful diversity. Toward this end, diversity research has focused on trying to reduce prejudice and biased behavior. But what happens when prejudice in the workplace inevitably occurs? Research also needs to focus on whether recovery and repair of social relations after expressions of prejudice are possible. To begin investigating this question, we develop a new framework for understanding reactions to prejudice in the workplace. We hypothesized that when women and minorities choose to confront a prejudiced comment in a workplace interaction (vs. remain silent) and hold a growth (vs. fixed) mindset-the belief that others can change-they remain more positive in their subsequent outlook in the workplace. Studies 1a, 1b, and 2 used hypothetical workplace scenarios to expose participants to someone who expressed bias; Study 3 ensured real-world relevance by eliciting retrospective accounts of workplace bias from African American employees. Across studies, women and minorities who confronted the perpetrator of prejudice exhibited more positive subsequent expectations of that coworker when they held a growth mindset. It is important that these more positive expectations were associated with reports of greater workplace belonging (Study 2), ratings of improved relations with coworkers who had displayed bias (Study 3), and greater workplace satisfaction (Studies 2-3). Thus, a growth mindset contributes to successful workplace diversity by protecting women's and minorities' outlook when they opt to confront expressions of bias. (PsycINFO Database Record PMID- 29517253 TI - Reaching the limits of reciprocity in favor exchange: The effects of generous, stingy, and matched favor giving on social status. AB - Group members gain social status via giving favors to others, but why and when they do so remain unclear in the literature. Building on social exchange theory and social status literature, we identify three types of favor giving among group members (generous, stingy, and matched) and propose that an affective mechanism (i.e., gratitude) and a cognitive mechanism (i.e., perceived competence) underlie the relationship between favor giving and status attainment. Specifically, generous/stingy favor giving has a linear relationship with status attainment through both gratitude and perceived competence, whereas matched favor giving has a curvilinear relationship with status attainment only through perceived competence. An experimental study and a field study lend support to our propositions. Our study complements the literature by offering a complete picture of how three types of favor giving among group members shape their social status in different ways. (PsycINFO Database Record PMID- 29517254 TI - Mental health care consumers' relative valuing of clinician performance information. AB - BACKGROUND: Research demonstrates significant variability in mental health clinicians' overall and domain-specific effectiveness with their patients. Despite calls to increase patient access to performance information, little is known about patients' relative valuing of this information in the context of other treatment factors. OBJECTIVE: We aimed to obtain an understanding of patients' relative valuing of provider performance track records and other therapist and treatment characteristics for their mental health care decision making. METHOD: Participants were 403 (Mage = 41.20; 66.5% female) community mental health patients who completed a multicomponent survey that included an adapted delayed-discounting paradigm to examine the relative valuing. Multiple descriptive, quantitative indices of relative valuing were calculated, as well as an exploratory latent profile analysis to ascertain the presence of homogenous relative-valuing subgroups. RESULTS: Overall, participants valued provider track record information. They also evidenced relatively higher preference values for working with therapists who had specific efficacy in treating their primary problem domain, charged less, and with whom there is a high likelihood of establishing a good alliance. Two latent profiles were identified: one representing higher valuing of provider performance and another consistently representing less emphasis. Participants with higher track-record valuing were younger, believed that therapists are not interchangeable, and endorsed trust in the collection and use of performance information. CONCLUSION: Harnessing clinician information to make more personalized and informed treatment decisions could potentially promote better treatment engagement, retention, and outcomes. (PsycINFO Database Record PMID- 29517255 TI - Counseling dropout, retention, and ethnic/language match for Asian Americans. AB - As a heterogeneous population, Asian Americans are typically studied as homogenous, as opposed to making distinctions among nationalities and first languages. The current study examined whether ethnic/language match and mismatch among 150 Asian client/counselor pairs predicted successful completion of counseling and number of treatment sessions while controlling for counseling dropout and retention predictors such as socioeconomic status and acculturation. The participant data were obtained from a deidentified database of clients and counselors at a community mental health center for Asian Americans in the Southwest region of the United States. The main finding was that ethnic/language matching of Asian client and counselor pairs predicted successful completion of counseling and number of treatment sessions. The results of the study suggest that, when feasible, ethnic/language matching of Asian American clients and counselors may minimize patient dropout from counseling. Given that this matching is usually unfeasible, the authors suggest several strategies for improving the retention of Asian-American clients (as well as other clients from international backgrounds) in counseling. (PsycINFO Database Record PMID- 29517256 TI - Personality and mental health treatment: Traits as predictors of presentation, usage, and outcome. AB - Self-report scores on personality inventories predict important life outcomes, including health and longevity, marital outcomes, career success, and mental health problems, but the ways they predict mental health treatment have not been widely explored. Psychotherapy is sought for diverse problems, but about half of those who begin therapy drop out, and only about half who complete therapy experience lasting improvements. Several authors have argued that understanding how personality traits relate to treatment could lead to better targeted, more successful services. Here self-report scores on Big Five and Big Six personality dimensions are explored as predictors of therapy presentation, usage, and outcomes in a sample of community clinic clients (N = 306). Participants received evidence-based treatments in the context of individual-, couples-, or family therapy sessions. One measure of initial functioning and three indicators of outcome were used. All personality trait scores except Openness associated with initial psychological functioning. Higher Conscientiousness scores predicted more sessions attended for family therapy but fewer for couples-therapy clients. Higher Honesty-Propriety and Extraversion scores predicted fewer sessions attended for family-therapy clients. Better termination outcome was predicted by higher Conscientiousness scores for family- and higher Extraversion scores for individual-therapy clients. Higher Honesty-Propriety and Neuroticism scores predicted more improvement in psychological functioning in terms of successive Outcome Questionnaire-45 administrations. Taken together, the results provide some support for the role of personality traits in predicting treatment usage and outcome and for the utility of a 6-factor model in this context. (PsycINFO Database Record PMID- 29517258 TI - The moral standing of animals: Towards a psychology of speciesism. AB - We introduce and investigate the philosophical concept of 'speciesism' -the assignment of different moral worth based on species membership -as a psychological construct. In five studies, using both general population samples online and student samples, we show that speciesism is a measurable, stable construct with high interpersonal differences, that goes along with a cluster of other forms of prejudice, and is able to predict real-world decision-making and behavior. In Study 1 we present the development and empirical validation of a theoretically driven Speciesism Scale, which captures individual differences in speciesist attitudes. In Study 2, we show high test-retest reliability of the scale over a period of four weeks, suggesting that speciesism is stable over time. In Study 3, we present positive correlations between speciesism and prejudicial attitudes such as racism, sexism, homophobia, along with ideological constructs associated with prejudice such as social dominance orientation, system justification, and right-wing authoritarianism. These results suggest that similar mechanisms might underlie both speciesism and other well-researched forms of prejudice. Finally, in Studies 4 and 5, we demonstrate that speciesism is able to predict prosociality towards animals (both in the context of charitable donations and time investment) and behavioral food choices above and beyond existing related constructs. Importantly, our studies show that people morally value individuals of certain species less than others even when beliefs about intelligence and sentience are accounted for. We conclude by discussing the implications of a psychological study of speciesism for the psychology of human animal relationships. (PsycINFO Database Record PMID- 29517257 TI - Asymmetries in unimodal visual vowel perception: The roles of oral-facial kinematics, orientation, and configuration. AB - Masapollo, Polka, and Menard (2017) recently reported a robust directional asymmetry in unimodal visual vowel perception: Adult perceivers discriminate a change from an English /u/ viseme to a French /u/ viseme significantly better than a change in the reverse direction. This asymmetry replicates a frequent pattern found in unimodal auditory vowel perception that points to a universal bias favoring more extreme vocalic articulations, which lead to acoustic signals with increased formant convergence. In the present article, the authors report 5 experiments designed to investigate whether this asymmetry in the visual realm reflects a speech-specific or general processing bias. They successfully replicated the directional effect using Masapollo et al.'s dynamically articulating faces but failed to replicate the effect when the faces were shown under static conditions. Asymmetries also emerged during discrimination of canonically oriented point-light stimuli that retained the kinematics and configuration of the articulating mouth. In contrast, no asymmetries emerged during discrimination of rotated point-light stimuli or Lissajou patterns that retained the kinematics, but not the canonical orientation or spatial configuration, of the labial gestures. These findings suggest that the perceptual processes underlying asymmetries in unimodal visual vowel discrimination are sensitive to speech-specific motion and configural properties and raise foundational questions concerning the role of specialized and general processes in vowel perception. (PsycINFO Database Record PMID- 29517259 TI - Age-, sex-, and education-specific norms for an extended CERAD Neuropsychological Assessment Battery-Results from the population-based LIFE-Adult-Study. AB - OBJECTIVE: To provide new age-, sex-, and education-specific reference values for an extended version of the well-established Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-NAB) that additionally includes the Trail Making Test and the Verbal Fluency Test-S-Words. METHOD: Norms were calculated based on the cognitive performances of n = 1,888 dementia-free participants (60-79 years) from the population-based German LIFE Adult-Study. Multiple regressions were used to examine the association of the CERAD-NAB scores with age, sex, and education. In order to calculate the norms, quantile and censored quantile regression analyses were performed estimating marginal means of the test scores at 2.28, 6.68, 10, 15.87, 25, 50, 75, and 90 percentiles for age-, sex-, and education-specific subgroups. RESULTS: Multiple regression analyses revealed that younger age was significantly associated with better cognitive performance in 15 CERAD-NAB measures and higher education with better cognitive performance in all 17 measures. Women performed significantly better than men in 12 measures and men than women in four measures. The determined norms indicate ceiling effects for the cognitive performances in the Boston Naming, Word List Recognition, Constructional Praxis Copying, and Constructional Praxis Recall tests. CONCLUSIONS: The new norms for the extended CERAD-NAB will be useful for evaluating dementia-free German-speaking adults in a broad variety of relevant cognitive domains. The extended CERAD-NAB follows more closely the criteria for the new DSM-5 Mild and Major Neurocognitive Disorder. Additionally, it could be further developed to include a test for social cognition. (PsycINFO Database Record PMID- 29517260 TI - The relation of attachment security status to effortful self-regulation: A meta analysis. AB - Secure attachment relationships have been described as having a regulatory function in regard to children's emotions, social cognition, and behavior. Although some theorists and researchers have argued that attachment affects children's self-regulation, most attachment theorists have not strongly emphasized this association. The goal of the current meta-analysis was to determine the magnitude of the relation between attachment security status and effortful control (EC)/top-down self-regulation in children up to 18 years of age. One hundred six papers met the inclusion criteria and 101 independent samples were used in analyses. When secure attachment status was compared with insecure attachment status, a significant relation (effect size [ES]) with EC favoring children with a secure attachment was found (100 studies; 20,350 participants; r = .20). A stronger relation was found when the same coder evaluated attachment than when the coder was different and when the measure of attachment was continuous; other moderators were not significant. Securely attached children were higher in EC than their avoidant (r = .10) or resistant (r = .17) counterparts. Children with organized attachments were higher in EC than those with disorganized attachments (r = .17), although this finding could be due to publication bias. For some comparisons of subgroups (B vs. A, B vs. C, and/or D vs. all others), moderation was found by source of information (higher ES for same reporter), age at assessment of EC and/or attachment (higher ES at older ages), method of attachment (lower ES for observational measures), time difference between assessments or research design (higher ESs for smaller time differences and concurrent findings), and published versus unpublished studies (higher ES for unpublished studies for A vs. B). (PsycINFO Database Record PMID- 29517261 TI - Cognitive structure, flexibility, and plasticity in human multitasking-An integrative review of dual-task and task-switching research. AB - Numerous studies showed decreased performance in situations that require multiple tasks or actions relative to appropriate control conditions. Because humans often engage in such multitasking activities, it is important to understand how multitasking affects performance. In the present article, we argue that research on dual-task interference and sequential task switching has proceeded largely separately using different experimental paradigms and methodology. In our article we aim at organizing this complex set of research in terms of three complementary research perspectives on human multitasking. One perspective refers to structural accounts in terms of cognitive bottlenecks (i.e., critical processing stages). A second perspective refers to cognitive flexibility in terms of the underlying cognitive control processes. A third perspective emphasizes cognitive plasticity in terms of the influence of practice on human multitasking abilities. With our review article we aimed at highlighting the value of an integrative position that goes beyond isolated consideration of a single theoretical research perspective and that broadens the focus from single experimental paradigms (dual task and task switching) to favor instead a view that emphasizes the fundamental similarity of the underlying cognitive mechanisms across multitasking paradigms. (PsycINFO Database Record PMID- 29517262 TI - Automatic imitation: A meta-analysis. AB - Automatic imitation is the finding that movement execution is facilitated by compatible and impeded by incompatible observed movements. In the past 15 years, automatic imitation has been studied to understand the relation between perception and action in social interaction. Although research on this topic started in cognitive science, interest quickly spread to related disciplines such as social psychology, clinical psychology, and neuroscience. However, important theoretical questions have remained unanswered. Therefore, in the present meta analysis, we evaluated seven key questions on automatic imitation. The results, based on 161 studies containing 226 experiments, revealed an overall effect size of gz = 0.95, 95% CI [0.88, 1.02]. Moderator analyses identified automatic imitation as a flexible, largely automatic process that is driven by movement and effector compatibility, but is also influenced by spatial compatibility. Automatic imitation was found to be stronger for forced choice tasks than for simple response tasks, for human agents than for nonhuman agents, and for goalless actions than for goal-directed actions. However, it was not modulated by more subtle factors such as animacy beliefs, motion profiles, or visual perspective. Finally, there was no evidence for a relation between automatic imitation and either empathy or autism. Among other things, these findings point toward actor-imitator similarity as a crucial modulator of automatic imitation and challenge the view that imitative tendencies are an indicator of social functioning. The current meta-analysis has important theoretical implications and sheds light on longstanding controversies in the literature on automatic imitation and related domains. (PsycINFO Database Record PMID- 29517263 TI - Metaphor comprehension: A critical review of theories and evidence. AB - We review psychological research bearing on major theories of metaphor comprehension. A broad survey of behavioral studies is coupled with findings from recent meta-analyses of neuroimaging studies of metaphor processing. We identify three broad theoretical positions that have been the foci of research efforts: analogy, categorization, and conceptual mapping. The first two of these emphasize relatively well-specified information-processing models; the third links metaphor comprehension to embodied cognition. Our review evaluates the evidence that has been taken as support for each view, and then critically examines studies that bear on competing hypotheses derived from opposing theories. Finally, we discuss issues that future research on metaphor should address. In particular, we call for greater consideration of the pragmatic functions of metaphor in context, of its emotional impact, and of its links to literary interpretation. We suggest ways in which mechanisms based on analogy and conceptual combination might be integrated to create a richer conception of metaphor understanding. (PsycINFO Database Record PMID- 29517264 TI - Outgoing editorial. AB - This first issue of 2018 marks the beginning of a year of editorial transition at the Canadian Journal of Experimental Psychology (CJEP). The author describes the winding down of her term as CJEP Editor. (PsycINFO Database Record PMID- 29517265 TI - Remembering 'primed' words: The effect of prime encoding demands. AB - Rosner, Lopez-Benitez, D'Angelo, Thomson, and Milliken (2017) reported a novel recognition memory effect using an immediate repetition method during the study phase. During each trial of an incidental study phase, participants named a target word that followed a prime word that had the same identity (repeated trials) or a different identity (not-repeated trials). Recognition in the following test phase was better for the not-repeated trials. In the present study, we examined the influence of prime encoding demands on this counterintuitive effect. In Experiment 1, we instructed 1 group to simply ignore the prime, as in the original study. A second group completed a divided attention task on prime presentation. Recognition memory was better for not-repeated than repeated words in both groups. In Experiment 2, encoding of the prime varied across 3 groups: 1 group named each prime, a second group counted the vowels in each prime, and a third group made a semantic discrimination for each prime. Recognition was better for repeated than for not-repeated words in the semantic group and did not differ across conditions for the other 2 groups. Finally, in Experiment 3, we assessed memory for not-repeated primes in addition to memory for targets (as in Experiments 1 and 2). The results confirmed that poor memory for the primes plays a significant role in producing the previously described effects. The results are discussed in relation to transient processing adaptations that affect memory encoding. (PsycINFO Database Record PMID- 29517266 TI - Remembering "primed" words: A counter-intuitive effect of repetition on recognition memory. AB - The present study examines the effect of immediate repetition on recognition memory. In a series of 4 experiments, the study phase task was to name aloud a word that was immediately preceded by either the same word (repeated trials) or a different word (not-repeated trials). Across experiments, performance in the study phase demonstrated the anticipated benefit in naming times for repeated trials. More important, performance in the test phase revealed greater sensitivity for not-repeated than repeated trials. This effect was observed even when repetitions at study were separated by an unrelated word (Experiment 3), and was eliminated only when participants named both words in succession at study (Experiment 4). These findings fit nicely with the desirable difficulty principle (R. A. Bjork, 1994), as they demonstrate that items more easily processed at study (i.e., repeated items) are not as well-encoded as items that are more difficult to process at study (i.e., not-repeated items). Furthermore, the current study points to the possibility that attentional orienting in response to processing difficulty may constitute a broadly important cognitive control adaptation that impacts memory encoding. (PsycINFO Database Record PMID- 29517267 TI - Student, teacher, and classroom predictors of between-teacher variance of students' teacher-rated behavior. AB - The current study examined between-teacher variance in teacher ratings of student behavioral and emotional risk to identify student, teacher and classroom characteristics that predict such differences and can be considered in future research and practice. Data were taken from seven elementary schools in one school district implementing universal screening, including 1,241 students rated by 68 teachers. Students were mostly African America (68.5%) with equal gender (female 50.1%) and grade-level distributions. Teachers, mostly White (76.5%) and female (89.7%), completed both a background survey regarding their professional experiences and demographic characteristics and the Behavior Assessment System for Children (Second Edition) Behavioral and Emotional Screening System-Teacher Form for all students in their class, rating an average of 17.69 students each. Extant student data were provided by the district. Analyses followed multilevel linear model stepwise model-building procedures. We detected a significant amount of variance in teachers' ratings of students' behavioral and emotional risk at both student and teacher/classroom levels with student predictors explaining about 39% of student-level variance and teacher/classroom predictors explaining about 20% of between-teacher differences. The final model fit the data (Akaike information criterion = 8,687.709; pseudo-R2 = 0.544) significantly better than the null model (Akaike information criterion = 9,457.160). Significant predictors included student gender, race ethnicity, academic performance and disciplinary incidents, teacher gender, student-teacher gender interaction, teacher professional development in behavior screening, and classroom academic performance. Future research and practice should interpret teacher-rated universal screening of students' behavioral and emotional risk with consideration of the between-teacher variance unrelated to student behavior detected. (PsycINFO Database Record PMID- 29517268 TI - The effect of measurement quality on targeted structural model fit indices: A comment on Lance, Beck, Fan, and Carter (2016). AB - Lance, Beck, Fan, and Carter (2016) recently advanced 6 new fit indices and associated cutoff values for assessing data-model fit in the structural portion of traditional latent variable path models. The authors appropriately argued that, although most researchers' theoretical interest rests with the latent structure, they still rely on indices of global model fit that simultaneously assess both the measurement and structural portions of the model. As such, Lance et al. proposed indices intended to assess the structural portion of the model in isolation of the measurement model. Unfortunately, although these strategies separate the assessment of the structure from the fit of the measurement model, they do not isolate the structure's assessment from the quality of the measurement model. That is, even with a perfectly fitting measurement model, poorer quality (i.e., less reliable) measurements will yield a more favorable verdict regarding structural fit, whereas better quality (i.e., more reliable) measurements will yield a less favorable structural assessment. This phenomenon, referred to by Hancock and Mueller (2011) as the reliability paradox, affects not only traditional global fit indices but also those structural indices proposed by Lance et al. as well. Fortunately, as this comment will clarify, indices proposed by Hancock and Mueller help to mitigate this problem and allow the structural portion of the model to be assessed independently of both the fit of the measurement model as well as the quality of indicator variables contained therein. (PsycINFO Database Record PMID- 29517269 TI - Characterization of prevalent bacterial pathogens associated with pododermatitis in table egg layers. AB - Pododermatitis has been observed in several layer flocks in Denmark during 2015. The aetiology is complex, including litter quality, nutrition and management. Bacterial pathogens associated with pododermatitis, however, have not received much attention. The aim of the present study was, therefore, to identify 106 bacterial isolates obtained from pododermatitis in table egg layers in addition to five isolates from spleen/bursa presternalis. Isolates were obtained from layers from six affected flocks. All isolates were identified by standard bacterial methods, species-specific PCRs, 16S rRNA sequencing or matrix-assisted laser desorption-ionization identification. Staphylococcus aureus and Enterococcus faecalis made up 75/111 (68%) and 15/111 (14%) of the isolates from pododermatitis, respectively; the remaining isolates represented Escherichia coli (10), Staphylococcus hyicus (5), Gallibacterium anatis (3), Trueperella pyogenes (2) and Aerococcus urinaeequi (1). All isolates of S. aureus were spa-typed. Spa type t8646 and t002 made up 72% and 26% of the S. aureus isolates, respectively. The same types were also demonstrated from spleen/bursa presternalis. The same or closely related spa-types were found among 6/11 sepsis-affected day-old chicks included for comparison, indicating that these types of S. aureus are ubiquitous pathogens in poultry. In contrast, isolates of E. faecalis and E. coli showed major population diversity. In conclusion, the results suggest that S. aureus is a major pathogen associated with pododermatitis abscesses, which could be from a common source, whereas the diversity among the E. faecalis and E. coli populations suggests that these bacteria might originate from multiple sources. PMID- 29517270 TI - Psychometric validation of Fuld Object Memory Evaluation in older adults with cognitive impairments. AB - OBJECTIVES: Mild cognitive impairment (MCI) refers to an early but abnormal state of cognitive impairment with minimal functional impairment. The present study aimed to evaluate the validity of Fuld Object Memory Evaluation (FOME) as a measure of episodic memory function. METHOD: The study sample included 204 Chinese older adults with cognitive impairments. The participants completed five recall trials and a delayed trial in FOME, neurocognitive measures on digit spans and trail making, and daily functioning. Discriminative power of FOME to differentiate between MCI and dementia was inspected via receiver operating characteristic curve analysis. RESULTS: FOME showed good test-retest reliability and convergent validity with digit spans and trail making. Controlling for gender, age, and education, lower levels of FOME total retrieval, verbal fluency, and daily functioning significantly predicted a higher likelihood of dementia compared to MCI. The optimal cut-off scores for total retrieval, verbal fluency, and daily functioning to differentiate dementia were 37/38 (77% sensitivity and 83% specificity), 28/29 (85% sensitivity and 72% specificity), and 14/15 (92% sensitivity and 78% specificity), respectively, in the younger subgroup. The corresponding figures were 34/35 (69% sensitivity and 76% specificity) and 27/28 (92% sensitivity and 62% specificity), and 11/12 (74% sensitivity and 80% specificity), respectively, in the older subgroup. CONCLUSION: The findings support the FOME as a valid assessment tool of episodic memory function in older Chinese adults. The combined use of FOME and daily functioning is recommended to distinguish persons with dementia from MCI. PMID- 29517271 TI - The search for noninvasive methods to identify liver fibrosis in children with nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic. Recent studies have clearly shown that the stage of fibrosis in adults with NAFLD is the most important histological feature in long-term outcomes and the development of liver-related complications. Despite the paucity of data regarding the natural history of pediatric NAFLD, its progression to cirrhosis and end-stage liver disease requiring liver transplantation is well documented. Given the high prevalence of NAFLD in children and adults, there is an urgent need to find safe and cost-effective alternatives to biopsy to determine the stage of liver fibrosis. In this review, we provide a concise overview of different noninvasive methods for diagnosing and staging liver fibrosis in children with NAFLD. PMID- 29517272 TI - Characterization of field infectious bursal disease viruses in Zambia: evidence of co-circulation of multiple genotypes with predominance of very virulent strains. AB - Infectious bursal disease (IBD) is a highly contagious, immunosuppressive disease of chickens and causes substantial economic losses to the poultry industry globally. This study investigated the genetic characteristics and pathological lesions induced by IBD viruses (IBDVs) that were associated with 60 suspected outbreaks in chickens during 2015-2016 in Lusaka Province, Zambia. Nucleotide sequences of VP2 hypervariable region (VP2-HVR) (n = 38) and part of VP1 (n = 37) of Zambian IBDVs were phylogenetically analysed. Phylogenetic analysis of the VP2 HVR and VP1 revealed that most viruses (n = 31 of each genome segment) clustered with the very virulent (vv) strains. The rest of the viruses clustered with the classical strains, with two of the viruses being closely related to attenuated vaccine isolates. Two of the viruses that belonged to the vv genotype had a unique amino acid (aa) substitution Q324L whereas one virus had two unique changes, N280S and E300A in the VP2-HVR aa sequence. Although Zambian strains with a vv genotype possessed virulence marker aa within VP1 at 145T, 146D and 147N, two viruses showed unique substitutions, with one virus having 147T while the other had 147H. Pathologically, it was noted that only viruses with a vv genotype appeared to be associated with inducing pathological lesions in non lymphoid organs (proventriculus and gizzard). Whilst documenting for the first time the presence of classical virulent IBDVs, this study demonstrates the involvement of multiple genotypes, with predominance of vvIBDVs in the epidemiology of IBD in Zambia. PMID- 29517273 TI - Abstracts of the 2018 AANS/CNS Joint Section on Disorders of the Spine and Peripheral Nerves Annual Meeting. AB - Abstracts of the 2018 AANS/CNS Joint Section on Disorders of the Spine and Peripheral Nerves Annual Meeting. PMID- 29517274 TI - Comparative evaluation of treatment effects between two fixed functional appliances for correction of Class II malocclusion: A single-center, randomized controlled trial. AB - OBJECTIVE: The objective of this study was to evaluate and compare the effects of PowerScope and Forsus in the treatment of Class II division 1 malocclusion. MATERIALS AND METHODS: This was a 2-arm parallel, double-blind, randomized, controlled trial. A total of 28 Class II division 1 malocclusion patients indicated for treatment with fixed functional appliances were randomized and equally divided (n = 14) among PowerScope (American Orthodontics, Sheboygan, Wis; mean age 14.11 +/- 1.3 years) and Forsus (3M Unitek Corp, Monrovia, Calif; mean age 15.5 +/- 1.1 years) groups. Skeletal and dentoalveolar effects of PowerScope and Forsus were compared. The secondary outcomes were evaluation of patient comfort and operator convenience. Randomization was accomplished with a 1:1 allocation ratio, and concealment was achieved by sealed opaque envelopes. The participants and data collectors were all blinded to study group allocation. Data were analyzed for 26 patients, 13 in each group, as one patient from each group discontinued treatment. Statistical comparisons were carried out using Student's t-tests and chi square tests ( P <= .05). RESULTS: A significantly greater mesial mandibular movement and improvement in sagittal skeletal relation were found in the Forsus patients ( P <= .05). The forward movement of the mandibular molar and incisors were greater in the PowerScope patients (2.3 mm and 2.80 mm) than in the Forsus patients (1.9 mm and 2.38 mm). CONCLUSIONS: Both PowerScope and Forsus are effective in correcting Class II malocclusion. The percentage of dentoalveolar effects in correcting Class II malocclusion is more for PowerScope when compared with Forsus. Patient comfort was the same with both appliances. This trial was registered. PMID- 29517275 TI - Comparison of complications in the conventional telescopic Herbst rod and tube and Manni telescopic Herbst: A retrospective clinical study. AB - OBJECTIVES: To compare the prevalence of clinical complications between two different telescopic Herbst systems: the conventional telescopic system, with traditional rod and tube (RMS), and the Manni telescopic Herbst appliance (MTH). MATERIALS AND METHODS: Ninety subjects treated with RMS were compared to 89 patients treated with MTH. All of the complications that occurred were reported, and percentages of prevalence were calculated. RESULTS: MTH showed a significantly lower percentage of reversible complications (that did not require appliance removal) when compared to the reversible complications during RMS treatment (20.2% vs 51.1%). No statistically significant differences were found between RMS and MTH regarding irreversible complications (that required appliance removal and full re-make). All of the irreversible complications occurred after reversible complications in the RMS group, while most of the irreversible complications in the MTH group occurred without any previous reversible complication. CONCLUSIONS: MTH exhibited a smaller number of clinical complications during Class II skeletal malocclusion therapy. PMID- 29517276 TI - Is promoting six hours of standing an appropriate public health message? PMID- 29517277 TI - Why green tea reduces heart disease risks. PMID- 29517278 TI - The role of the outer membrane protein gene ybjX in the pathogenicity of avian pathogenic Escherichia coli. AB - Avian pathogenic Escherichia coli (APEC) are important pathogens that cause serious economic losses to the poultry industry worldwide. The PhoP/Q system is essential for APEC pathogenicity, and its mutation leads to a decrease in ybjX gene expression, but whether ybjX regulated by PhoP/Q plays a role in pathogenicity remains unclear. The role of ybjX in APEC pathogenicity was investigated using a ybjX mutant strain constructed from APEC strain AE17 by the Red recombination method. The mutant strain displayed significantly reduced adherence to and invasion of chicken embryo fibroblast cell line (DF-1) cells. Moreover, N-phenyl-1-naphthylamine (NPN) assays revealed an increase in outer membrane permeabilization for the ybjX mutant, suggesting ybjX affected susceptibility to avian beta-defensin through this mechanism. The ybjX mutation increased susceptibility to avian beta-defensin 9 (AvBD9), and in vivo LD50 assays revealed reduced bacterial virulence in a chicken model. Taken together, these results indicated that mutation of ybjX may attenuate APEC pathogenicity, not only by affecting bacterial adhesion and invasion, but also via reducing resistance to avian beta-defensin by increasing outer membrane permeabilization of bacteria. PMID- 29517279 TI - Association of serum procalcitonin level with in-stent restenosis in patients undergoing bare-metal stent implantation. AB - AIM: Procalcitonin (PCT) is an inflammatory marker and elevated PCT levels are associated with cardiovascular events. We assessed whether PCT level is an independent predictor of bare-metal stent (BMS) in-stent restenosis (ISR). PATIENTS & METHODS: We evaluated 240 patients undergoing BMS implantation. Serum PCT levels were measured before procedure. Patients were classified as ISR(-) group (n = 120) and ISR(+) group (n = 120). RESULTS: Serum PCT levels were higher in the ISR (+) group (p < 0.001). At multivariate analysis, PCT (odds ratio [OR] 1.561; p = 0.012), stent length (OR: 1.089), stent diameter (OR: 0.141) and uric acid (OR: 1.465) were independent predictors of ISR. CONCLUSION: Serum PCT is independently associated with ISR and increased PCT levels may provide useful information for the risk of BMS-ISR. PMID- 29517280 TI - Index of cardiac electrophysiological balance and transmural dispersion of the repolarization index relationships with pericardial fat volume and coronary calcification. AB - AIM: To assess the possible relationship between coronary atherosclerosis markers, pericardial fat volume (PFV) and coronary artery calcification, with ECG markers of index of the cardiac electrophysiological balance (iCEB) and transmural dispersion of the repolarization in patients with suspected coronary artery disease. METHODOLOGY: One hundred patients who underwent 64-slice multidetector computed tomography angiography were found to be eligible and were enrolled in the study. RESULTS: Patients with high iCEB levels tended to have a higher PFV values compared with patients with low iCEB levels (median [interquartile range]) (152 [29-206] vs 96 [14-177]; p = 0.03). No significant differences in coronary artery calcification values were observed between iCEB and transmural dispersion of the repolarization groups. CONCLUSION: A higher PFV value was observed in patients with high iCEB. Larger prospective studies are required to confirm the results. PMID- 29517281 TI - YB-1 promotes laryngeal squamous cell carcinoma progression by inducing miR-155 expression via c-Myb. AB - AIM: In this study, we investigated the role of Y-box binding protein-1 (YB-1), c Myb and miR-155 in human laryngeal squamous cell carcinoma (LSCC) progression. MATERIALS & METHODS: Quantitative real-time PCR, western blot, MTT and Transwell were conducted to determine the expression and function of YB-1/miR-155 pathway. Univariate and multivariate analyses were used to determine the prognostic factors. RESULTS: Expression of YB-1, c-Myb and miR-155 was higher in LSCC tissues. YB-1 promoted proliferation, invasiveness and migration of Hep-2 cells in vitro. Patients with higher YB-1 correlated with advanced T stage, poor differentiation and cervical metastasis. LSCC patients with high YB-1 expression showed poor overall survival. CONCLUSION: YB-1 promotes LSCC progression by increasing miR-155 levels via c-Myb and acts as a prognostic factor. PMID- 29517282 TI - Co-infection of turkeys with Escherichia coli (O78) and H6N1 avian influenza virus. AB - Respiratory diseases are responsible for major economic losses in poultry farms. While in most cases a single pathogen is not alone responsible for the clinical outcome, the impact of co-infections is not well known, especially in turkeys. The purpose of this study was to assess the possible synergism between Escherichia coli (O78) and low pathogenic avian influenza virus (LPAIV, H6N1), in the turkey model. Four-week-old commercial turkeys were inoculated with either H6N1, O78 or both agents simultaneously or three days apart. We have established an experimental infection model of turkeys using aerosolization that better mimics field infections. Birds were observed clinically and swabbed on a daily basis. Necropsies were performed at 4 and 14 days post single or dual inoculation and followed by histological and immunohistochemical analyses. Combined LPAIV/E. coli infections resulted in more severe clinical signs, were associated with higher mortality and respiratory organ lesions (mucous or fibrinous exudative material in lungs and air sacs), in comparison with the groups given single infections (P < 0.05). The time interval or the sequence between H6N1 and E. coli inoculation (none or three days) did not have a significant effect on the outcome of the dual infection and disease although slightly greater (P > 0.05) respiratory signs were observed in turkeys of the E. coli followed by H6N1 inoculated group. Microscopic lesions and immunohistochemical staining supported clinical and macroscopic findings. Efficient virus and bacteria replication was observed in all inoculated groups. E. coli and H6N1 thus exercise an additive or synergistic pathogenic effect in the reproduction of respiratory disease. PMID- 29517283 TI - Could vaccination against Neisseria gonorrhoeae be on the horizon? PMID- 29517284 TI - Thermal ablation versus surgical resection for localized hepatocellular carcinoma: a population study using the SEER database. AB - AIM: To compare overall survival (OS) and liver cancer-specific survival (LCSS) in patients with localized hepatocellular carcinoma treated with surgical resection (SR) or thermal ablation (TA) using the Surveillance, Epidemiology and End Results database. MATERIALS & METHODS: Kaplan-Meier, competing risk and Cox regression analyses were performed after identifying patients. Propensity score matching was then applied. RESULTS: There was significantly better OS in the SR group and significantly lower probability of LCSS in the TA group. After matching, there was significantly longer OS in the SR group and a lower probability of LCSS in the TA group. CONCLUSION: SR offered a significant survival benefit over TA for localized hepatocellular carcinoma. PMID- 29517285 TI - Multidrug-resistant Neisseria gonorrhoeae: future therapeutic options. PMID- 29517287 TI - The psychology of babies: how relationships support development from birth to two. PMID- 29517286 TI - Vital correspondence: Exploring tactile experience with resident-focused mandalas in long-term care (Innovative practice). AB - The materiality of long-term care and its relationship to a resident's identity is often overlooked. In response to the call for more attention to the meaningful aspects of doing art, the tactile experience of residents with dementia is considered in the context of a mandala project at a Canadian seniors' long-term care facility. The significance of making mandalas for residents is explored through three key themes: identity integration through gesture, the importance of artistic discernment and decision-making, and the value of corresponding with recalcitrant materials. Residents' experiences are analysed through a phenomenological lens. PMID- 29517288 TI - Effects of life events on infertility diagnosis: comparison with presumably fertile men and women. AB - OBJECTIVE: To compare the occurrence and degree of stress attributed to life events during childhood/adolescence and adulthood between individuals diagnosed with infertility and presumably fertile individuals, and to examine the effect of life events occurrence and stress levels on an infertility diagnosis. BACKGROUND: Although stress has been explored as a consequence of the experience of infertility, its role as a predictor of this disease still lacks research, particularly regarding the use of adequate control groups composed of non parents. METHODS: The final sample had 151 infertile subjects (74 males and 77 females) and 225 presumably fertile participants (95 males and 130 females), who completed a questionnaire indicating occurrence (y/n) and degree of stress of life events (1-5) during childhood/adolescence and adulthood. RESULTS: Significant differences regarding occurrence were found in seven stressful life events in men and in nine events in women, with infertile groups presenting higher occurrence than presumably fertile groups. Eleven stressful life events were rated differently by men and women regarding the degree of stress, with group significant differences observed in both directions. While most events were rated as more stressful by infertile men, infertile women reported less stress resulting from these events than presumably fertile women. After controlling for age, the degree of stress induced by life events in childhood/adolescence and adulthood were not significant predictors of infertility diagnosis, for both men and women. CONCLUSION: The amount of stress associated with earlier or concurrent life events does not seem to be related with infertility. Further prospective research is needed to validate these findings. PMID- 29517289 TI - Paternal adaptation in first-time fathers: a phenomenological study. AB - OBJECTIVE: This study aimed to explore men's experiences of paternal adaptation during their first year of transition to parenthood. BACKGROUND: Stepping into fatherhood is one of the most important events that may occur in a man's life and can lead to fundamental changes in their identity and lifestyle. However, to our knowledge, no studies have been conducted on men's experiences of paternal adaptation in an Iranian context. METHODS: In this phenomenological study, 15 Iranian men who had the experience of parenting for the first time were recruited using the purposeful sampling method. In-depth semi-structured interviews guided by a questionnaire were used to collect data. The data were analysed using interpretative phenomenological analysis. RESULTS: The data analysis resulted in the development of 26 themes, 8 subordinate themes and 3 superordinate themes. The superordinate themes included 'steps toward adaptation', 'obstacles to the path of adaptation' and 'stabilisation in the paternal position'. CONCLUSION: Perceived self-efficacy and satisfaction in fatherhood means an adaptation to the paternal role. Factors influencing paternal adaptation can be classified into the domains of 'facilitating factors' and 'inhibiting factors'. PMID- 29517290 TI - Object relations, unconscious defences and fear of childbirth, as reflected in maternal-request caesarean section. AB - OBJECTIVE: To examine a possible association between maternal-request caesarean section (CS) and two intrapsychic psychoanalytic personality variables: object relations (OR) and unconscious defences. BACKGROUND: While maternal-request CS is a growing phenomenon, studies are lacking regarding personality variables that may be associated with it. METHODS: A cross-sectional questionnaire was conducted in one delivery ward. During 2009, 59 primigravida, healthy women were recruited; 28 who had requested and delivered by CS without an obstetrical indication and 31 who opted for a spontaneous vaginal delivery. Due to missing data for some measures, only 27 participants were analysed in each group. All women completed the fear of childbirth (FOC) questionnaire, and the object relations (SCORS) and unconscious defences (DMM) measures of the Thematic Apperception Test (TAT), as well as questionnaires assessing background variables. Multivariate analysis of variance (MANOVA) and a logistic hierarchical multiple regression were performed. RESULTS: Preliminary MANOVA showed significant differences between groups in age, FOC and use of the defence mechanism projection. Hence, these variables entered as predictors of maternal-request CS to a logistic hierarchical multiple regression model. The model was found to have a good fit [chi2(4) = 38.19, p < 0.001]. Age, FOC and projection defence were found to be significant factors associated with maternal-request CS. CONCLUSION: Maternal-request CS was found to be strongly associated with age and FOC. Except for unconscious defence of projection, intrapsychic variables were not found to be associated with maternal request CS. Possible implications are discussed. PMID- 29517291 TI - Mapping people's views regarding the acceptability of surrogate motherhood. AB - The aims of the present study were to map French laypersons' views regarding the acceptability of maternal surrogacy and to delineate the circumstances under which surrogacy is considered, by different groups of people, as especially problematic. Participants (N = 236) were presented with a number of scenarios depicting the circumstances in which a couple has contracted with a surrogate mother and were asked to indicate the extent to which such a contract may present a moral problem. The scenarios were created by varying four factors: the type of surrogacy (traditional or gestational), the surrogate mother's level of autonomy, the family context in which the surrogate mother lives, and whether surrogacy was commercial or altruistic. Three qualitatively different personal positions were found: (a) a majority group for which surrogacy always (30%) or often (34%) presents a moral problem, (b) a minority group (14%) for which maternal surrogacy does not systematically present a moral problem, and PMID- 29517292 TI - Breaking bad news in prenatal medicine: a literature review. AB - BACKGROUND: The diagnosis of a fetal anomaly in perinatal medicine forces expectant parents and healthcare providers to face the difficult process of breaking bad news. OBJECTIVES: This exploratory literature review was aimed at providing a medical and psychological view of the psychological experience in expectant parents and physicians in the context of prenatal diagnosis of a fetal anomaly. METHOD: An exploratory search of PubMed and PsycINFO/PsycARTICLES databases performed by an interdisciplinary team composed of a physician and psychologists. Search terms were: prenatal diagnosis AND bad news; prenatal diagnosis AND psychological consequences; prenatal diagnosis AND psychological sequelae; prenatal diagnosis AND fetal abnormality. The processing of selected articles followed a standardised five-step procedure. RESULTS: A total of 860 articles were screened of which 32 were retained for analysis. Four main themes emerged from the explanatory content analysis: (1) parents' subjective experience; (2) physicians' subjective experience; (3) encounters between expectant parents and professionals; and (4) ethical challenges in breaking bad news in prenatal medicine. CONCLUSION: Expectant parents go through a complex and multidimensional experience when the diagnosis of a fetal anomaly is disclosed. Simultaneously, physicians consider breaking bad news as a very stressful event and are poorly prepared in this regard. A better knowledge of factors underlying psychological adjustment of the parental dyad and on the subjective experience of physicians delivering these diagnoses could enable better adaptation for both patients and professionals. PMID- 29517293 TI - The impact of miscarriage and stillbirth on maternal-fetal relationships: an integrative review. AB - OBJECTIVE: To synthesise and summarise existing literature investigating whether and how psychological distress as a consequence of perinatal loss and associated coping impact upon maternal-fetal relationships subsequent to miscarriage and stillbirth. BACKGROUND: Although now widely accepted that the relationship between mother and child develops in utero, little is known about how a previous miscarriage or stillbirth impacts upon these processes in a subsequent pregnancy. METHODS: An integrative review methodology was chosen for the review. RESULTS: Fifteen empirical and theoretical articles were reviewed and summated into two topic areas: psychological distress following perinatal loss and the subsequent maternal-fetal relationship, and coping following perinatal loss and the subsequent maternal-fetal relationship. CONCLUSIONS: Studies show that perinatal loss can cause psychological distress in subsequent pregnancy. It is not clear whether and how such distress impacts on maternal-fetal relationships because studies have yielded mixed findings. Mothers employ a complex self-protective mechanism to cope with this distress, and use strategies to reassure themselves and to maintain hope that the pregnancy will result in a live birth. It is not clear whether the use of this mechanism impacts upon the development of the mother-fetus relationship in subsequent pregnancy. Further research is now required to determine how these strategies are employed, the impact of these strategies on pregnancy-specific anxiety, maternal-fetal relationships and the postnatal attachment relationship. Health professionals working with parents in these circumstances should acknowledge that anxiety and associated coping behaviours are common, and support be provided when parents show signs of considerable psychological distress. PMID- 29517294 TI - Women's views on anxiety in pregnancy and the use of anxiety instruments: a qualitative study. AB - OBJECTIVE: To explore women's experience of anxiety in pregnancy and views on the use of anxiety instruments in antenatal care. BACKGROUND: Anxiety in pregnancy is associated with adverse birth outcomes, developmental and behavioural problems in infants and postnatal depression. Despite recommendations for routine psychological assessment in pregnancy, the optimal methods to identify anxiety in pregnancy have not been confirmed. METHODS: A qualitative study using two focus group discussions was undertaken. Focus group one included women in a community setting and focus group two included women in a hospital clinic setting who had received additional support for anxiety in pregnancy. Participants were women who had given birth within the past nine months and considered themselves to have been anxious during their pregnancy. RESULTS: Three main themes were identified using template analysis: sources of support, administration of anxiety instruments and the use of instruments to prompt discussion. Women stated that anxiety instruments could help them to identify their anxious feelings and prompt a discussion around those feelings. However, they expressed concerns surrounding the administration of anxiety instruments and questioned how useful they would be in helping women access help and support. CONCLUSIONS: The introduction of anxiety instruments in antenatal care may present an opportunity to discuss women's emotional health and anxieties. Providing women with sufficient time to discuss their anxious feelings, identified by such instruments, could facilitate access to additional support. PMID- 29517295 TI - Health behaviour and pregnancy: a time for change. PMID- 29517296 TI - A pot of gold at the end of the rainbow? A spectrum of attitudes to assisted reproductive technologies in Ireland. AB - OBJECTIVE: New technologies present new ethical dilemmas. Our ethical intuitions may mislead us in relation to new technologies such as nuclear power, vaccines, GMOs and assistive reproductive technologies (ART). Between 1999 and 2008 the number of ART treatment cycles increased by 265% in Ireland. The implications and potentials of such technologies are profound - challenging existing understanding of humans' relationships to reproduction. Because such technologies are comparatively unregulated, and their use has only been occurring for a single generation, detailed investigation of how awareness of ART influences understanding of personal fertility is needed. METHOD: Data from a general Irish population of varied ages and both sexes (N = 611) were collected through an online survey which included demographics, knowledge of fertility, knowledge of ART and personal fertility. RESULTS: Latent class analysis revealed a typology of five groups of responders to ART distinguished by their attitudes and knowledge of this technology. These groups are labelled as 'Worried Yet Willing', 'Live and Let Live', 'Disengaged', 'Judgemental' and 'Conflicted'. CONCLUSION: Responses to the introduction of ART in Ireland fall into at least five distinct groups. Understanding of the distinguishing features of these types of responders is important for fertility healthcare professionals in terms of service development and delivery. Implications for the direction of future related research is discussed. PMID- 29517297 TI - Personality and labor: a retrospective study of the relationship between personality traits and birthing experiences. AB - OBJECTIVE: In the current study, we explored the relationship between a woman's personality, epidural use and perceptions of the labour and birth experience. BACKGROUND: Having a positive birthing experience is relevant to predicting a range of important outcomes including mother-infant bonding, fertility rates and delivery interventions. However, limited research has addressed the kinds of individual differences that may affect a woman's subjective birthing experience. METHODS: One hundred and twenty-five women were surveyed about subjective aspects of the labour and birthing experience of their first-born child, including use of epidural, perceived pain, anxiety, self-capacity and positive experiences. The women also completed the Big Five personality inventory, which measures five dimensions of stable personality characteristics. RESULTS: Results show that four of the Big Five personality traits were found to correlate to the four different aspects of the labour and birth experience, and that these relationships were largely moderated by a woman's decision to have an epidural. CONCLUSION: These findings add to the limited body of research on the relationships between personality and the labour experience. They also highlight the importance of considering pain management decisions in understanding this relationship. Future research in this area may provide a new way for doctors, midwives and doulas to tailor support and intervention for women during the birthing process based on individual differences to help more women have positive birthing experiences. PMID- 29517298 TI - Maternal attachment style during pregnancy and becoming a mother in Poland. AB - OBJECTIVE: This paper investigates the connections in pregnant women between their mother attachment style and their self-image as a mother, the image of their mother as a mother, and their bond with the unborn child. BACKGROUND: The relationship with one's mother plays a crucial role in the process of becoming a mother. It influences what a pregnant woman thinks about herself as a mother. This relationship is a predictor of the bond with the child during the pregnancy. METHODS: This research was participated in by 165 pregnant women. They completed the following: a modified version of the Experiences in Close Relationships (ECR) questionnaire, investigating a mother's attachment to her own mother; the Adjective Check List (ACL), developed by Gough and Heilbrun; the Maternal-Fetal Attachment Scale (MFAS); and a sociodemographic survey. RESULTS: A mother's attachment style is connected with the need for autonomy, as measured by the ACL, and with 'assuming a parental role' in the MFAS questionnaire. The strongest connection was found between a mother's attachment style and the image of one's own mother as a mother. Statistically-significant correlations were found for 32 of 37 scales on the ACL. CONCLUSION: Attachment style exerts influence upon a mother's self-image, the image of one's own mother as a mother and the bond with the unborn child. PMID- 29517299 TI - Development and validation of the Australian version of the Birth Satisfaction Scale-Revised (BSS-R). AB - OBJECTIVE AND BACKGROUND: The 10-item Birth Satisfaction Scale-Revised (BSS-R) has recently been endorsed by international expert consensus for global use as the birth satisfaction outcome measure of choice. English-language versions of the tool include validated UK and US versions; however, the instrument has not, to date, been contextualised and validated in an Australian English-language version. The current investigation sought to develop and validate an English language version of the tool for use within the Australian context. METHODS: A two-stage study. Following review and modification by expert panel, the Australian BSS-R (A-BSS-R) was (Stage 1) evaluated for factor structure, internal consistency, known-groups discriminant validity and divergent validity. Stage 2 directly compared the A-BSS-R data set with the original UK data set to determine the invariance characteristics of the new instrument. Participants were a purposive sample of Australian postnatal women (n = 198). RESULTS: The A-BSS-R offered a good fit to data consistent with the BSS-R tridimensional measurement model and was found to be conceptually and measurement equivalent to the UK version. The A-BSS-R demonstrated excellent known-groups discriminant validity, generally good divergent validity and overall good internal consistency. CONCLUSION: The A-BSS-R represents a robust and valid measure of the birth satisfaction concept suitable for use within Australia and appropriate for application to International comparative studies. PMID- 29517300 TI - Fine tuning fear of childbirth: the relationship between Childbirth Fear Questionnaire subscales and demographic and reproductive variables. AB - OBJECTIVE: The objective of the current study was to investigate the relationship between the newly developed Childbirth Fear Questionnaire (CFQ) and demographic and reproductive variables. BACKGROUND: The CFQ was developed in an effort to improve measurement and understanding of women's childbirth fears. To our knowledge the CFQ is the only multidimensional measure of childbirth fears in which (a) multiple domains of childbirth fear are assessed and (b) individual subscales have been psychometrically developed. METHODS: Participants were 643 pregnant women residing in English-speaking countries, recruited via online forums. Participants completed a set of questionnaires, including the multidimensional CFQ, via an online survey. Given the differences in childbirth fear between nulliparous and multiparous women, findings are stratified by parity. RESULTS: Gestational age was largely unrelated to fear of childbirth. Age, income and education were negatively related to fear of childbirth. Assisted vaginal delivery and episiotomy in a previous pregnancy were positively associated with a fear of pain. Self-reported history of traumatic vaginal birth was associated with higher scores on all aspects of fear of childbirth. History of caesarean birth was not generally associated with increased childbirth fears, but women with a prior, self-reported traumatic caesarean birth reported more fear of future caesarean births. CONCLUSIONS: Findings are consistent with previous reports of fear of childbirth. However, the CFQ provides increased specificity with respect to women's childbirth fears. This information is relevant to both education and treatment planning for pregnant women and women wishing to reproduce. PMID- 29517301 TI - Emotions in labour: Italian obstetricians' experiences of presence during childbirth. AB - OBJECTIVE: The present study represents a qualitative research aimed to explore the obstetricians' psychological experiences of birth. BACKGROUND: During labour the role of obstetricians assumes a fundamental importance in hospitalised childbirth. However, literature analysis has shown that the psychological side of birth has been investigated only considering the woman's and midwife's points of view. The obstetricians' psychological experiences have not been considered enough and only a few studies at a quantitative level have been performed. METHODS: Seven focus groups for a total of 72 obstetricians were conducted in hospital contexts in Italy. The qualitative methodology of grounded theory was adopted. FINDINGS: The results were divided into three different core themes: obstetricians' approaches to delivery, critical aspects about relationships in the delivery room, and obstetricians' feelings and emotions in the delivery room. Each theme was subdivided into different subthemes. CONCLUSION: The results highlight different ways obstetricians approach their profession, the complex and multifaceted relationship with the woman and the extraordinary variety of feelings and emotions, which enrich, but also may complicate, life in the delivery room. Further studies could provide more details to help researchers to develop new and more effective strategies to support obstetricians' training and work. PMID- 29517302 TI - The associations between depressive and anxiety symptoms, body image, and weight in the first year postpartum: a rapid systematic review. AB - OBJECTIVE: The aim of this study was to conduct a rapid systematic review of the evidence of associations between postpartum depressive symptoms, anxiety symptoms, body image and weight status in the first 12 months post birth. BACKGROUND: The postpartum period places the mother and infant at risk of a number of negative health outcomes. Mental health conditions such as depression and anxiety are common in the postpartum, as are poor body image and excessive weight retention as women adjust to their post pregnancy body. However, the associations between body image, weight status and psychological distress are not currently well understood. METHODS: Articles in English, published between 2006 and 2017, involving singleton pregnancies of normally developing infants and maternal depression or anxiety were eligible for this systematic review. RESULTS: From the total of 1805 articles located, 12 were identified as relevant and were subsequently reviewed in full. In the nine studies of depressive symptoms, body image or weight status, four found a significant relationship. Significant associations were not found in the three studies investigating postpartum anxiety symptoms, body image or weight. Body dissatisfaction was associated significantly with poorer postpartum weight status in all nine studies. CONCLUSIONS: Further research is needed to determine the nature of the relationships between body image, weight status and depressive and anxiety symptoms across the first year after birth. This information will assist health professionals to promote healthy lifestyle behaviours in the postpartum, as well as inform clinical interventions that target behaviour change to prevent the worsening of these issues and related negative outcomes. PMID- 29517303 TI - The impact of childbirth-related post-traumatic stress on a couple's relationship: a systematic review and meta-synthesis. AB - OBJECTIVE: This review aimed to identify the impact of childbirth-related post traumatic stress disorder (PTSD) or symptoms (PTSS) on a couple's relationship. BACKGROUND: Childbirth can be psychologically traumatic and can lead to PTSD. There is emerging evidence that experiencing a traumatic birth can affect the quality of the couple's relationship. This is an important issue because poor quality relationships can impact on the well-being of partners, their parenting and the welfare of the infant. METHODS: A systematic search was conducted of Amed, CENTRAL, Cinahl, Embase, Maternity and Infant Care, Medline, MITCognet, POPLINE, PsycARTICLES, PsycBITE, PsycINFO, Pubmed and Science Direct. Additionally, grey literature, citation and reference searches were conducted. Papers were eligible for inclusion if they reported qualitative data about parents who had experienced childbirth and measures of PTSD or PTSS and the relationship were taken. Analysis was conducted using meta-ethnography. RESULTS: Seven studies were included in the meta-synthesis. Results showed that childbirth related PTSD or PTSS can have a perceived impact on the couple's relationship and five themes were identified: negative emotions; lack of understanding and support; loss of intimacy; strain on the relationship; and strengthened relationships. A model of proposed interaction between these themes is presented. CONCLUSIONS: The impact of childbirth-related PTSD or PTSS on the couple's relationships is complex. As the quality of the couple relationship is important to family well-being, it is important that healthcare professionals are aware of the impact of experiencing psychologically traumatic childbirth as impetus for prevention and support. PMID- 29517304 TI - Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache. AB - OBJECTIVE: We tested the hypothesis of a defective functional connectivity between the posterior hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache based on: a) clinical and neuro-endocrinological findings in cluster headache patients; b) neuroimaging findings during cluster headache attacks; c) neuroimaging findings in drug-refractory chronic cluster headache patients improved after successful deep brain stimulation. METHODS: Resting state functional magnetic resonance imaging, associated with a seed-based approach, was employed to investigate the functional connectivity of the posterior hypothalamus in chronic cluster headache patients (n = 17) compared to age and sex-matched healthy subjects (n = 16). Random-effect analyses were performed to study differences between patients and controls in ipsilateral and contralateral-to-the-pain posterior hypothalamus functional connectivity. RESULTS: Cluster headache patients showed an increased functional connectivity between the ipsilateral posterior hypothalamus and a number of diencephalic mesencephalic structures, comprising ventral tegmental area, dorsal nuclei of raphe, and bilateral substantia nigra, sub-thalamic nucleus, and red nucleus ( p < 0.005 FDR-corrected vs . control group). No difference between patients and controls was found comparing the contralateral hypothalami. CONCLUSIONS: The observed deranged functional connectivity between the posterior ipsilateral hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache patients mainly involves structures that are part of (i.e. ventral tegmental area, substantia nigra) or modulate (dorsal nuclei of raphe, sub-thalamic nucleus) the midbrain dopaminergic systems. The midbrain dopaminergic systems could play a role in cluster headache pathophysiology and in particular in the chronicization process. Future studies are needed to better clarify if this finding is specific to cluster headache or if it represents an unspecific response to chronic pain. PMID- 29517306 TI - Identifying perinatal depression and anxiety: evidence based practice in screening, psychosocial assessment and management. PMID- 29517305 TI - Lifestyle factors and risk of migraine and tension-type headache. Follow-up data from the Nord-Trondelag Health Surveys 1995-1997 and 2006-2008. AB - AIMS: The aim of this population-based historical cohort study was to investigate the influence of lifestyle factors on the risk of developing migraine or tension type headache (TTH). METHODS: Data from the Nord-Trondelag Health Study performed in 1995-1997 and 2006-2008 was used. A total of 15,276 participants without headache at baseline were included. A Poisson regression was used to evaluate the associations between lifestyle factors and risk ratios (RRs) of migraine and TTH 11 years later. Precision of the estimates was assessed by 95% confidence interval (CIs). RESULTS: Increased risk of migraine (RR 1.30, 95% CI 1.11-1.52) was found in smokers (past or current) compared to those who had never smoked. Hard physical exercise 1-2 hours per week reduced the risk of migraine (OR 0.71, 95% CI 0.54-0.94) compared to inactivity, and the risk of migraine was also lower among those who consumed alcohol (RR 0.73, 95% CI 0.57-0.94) compared to abstainers. No association was found between smoking, physical activity, alcohol use and risk of TTH. CONCLUSIONS: The main finding was that current and previous smoking was associated with increased risk of migraine, but not of TTH. PMID- 29517307 TI - If gender matters in maternity care, does it matter in maternity care research? PMID- 29517308 TI - Prenatal attachment and sociodemographic and clinical factors in Portuguese couples. AB - OBJECTIVES: To observe differences between maternal and paternal prenatal attachment as a function of sociodemographic and clinical/obstetric factors. METHODS: Quantitative descriptive correlational study. INSTRUMENTS: Sociodemographic and Clinical Questionnaire; Maternal and Paternal Antenatal Attachment Scale (Portuguese version by Camarneiro & Justo). Assessments were conducted in antenatal clinics in Central Portugal. PARTICIPANTS: Couples (N = 407), women and men in the second trimester of pregnancy. RESULTS: Significant differences in maternal prenatal attachment were observed as a function of age, education, socioeconomic status, pregnancy planning, previous pregnancies, pregnancy interruptions and gestational age. Significant differences in paternal prenatal attachment were observed as a function of age, number of children, socioeconomic status, occupational status, family household and pregnancy planning. CONCLUSIONS: Women and men present variations in prenatal attachment according to some sociodemographic and clinical variables. These results should be taken into account in interventions focused on the promotion of prenatal attachment. PMID- 29517309 TI - Nordic fathers' willingness to participate during pregnancy. AB - OBJECTIVE: This study aims to illuminate expectant first-time fathers' experiences of participation during pregnancy in three Nordic countries. Background: Fathers' participation in pregnancy is associated with improved health for the family as a whole. Research so far has primarily explored fathers' participation in pregnancy within health care settings. It is important to know more about how fathers today engage in all aspects of pregnancy. Methods: Content analysis was used to analyse semi-structured interviews with 31 first time fathers from Denmark, Finland and Sweden. Interviews were undertaken when their partner was pregnant 30 weeks or more. Results: Data analysis resulted in the main category 'Willingness to participate' and the two generic categories: 'Being beside the "bump"' and 'Cementing the partnership'. 'Being beside the "bump"' was supported by the subcategories: 'Visualising the unborn child', 'Being included in the rites of motherhood,' 'Lacking full control', 'Compensating for lack of embodiment' and 'Adopting an active father role'. 'Cementing the partnership' encompassed the subcategories: 'Strengthening the partner relationship', 'Meeting the professionals, 'Sharing experiences with peers' and 'Protecting their child and their partner'. CONCLUSION: Fathers wanted to participate and be responsible from the beginning of pregnancy. Fathers' participation in pregnancy involves a wide range of activities and strategies both within the domestic and the professional care-giving sphere. Health care professional's approaches to the father-to-be can enhance or reduce experiences of inclusion in antenatal care. PMID- 29517310 TI - Associations between perfectionism cognitions, religiosity and desired number of children in Iranian women. AB - OBJECTIVE: This study aimed to investigate the associations between perfectionism cognitions, religiosity and the desired number of children in young women. BACKGROUND: The desired number of children has been found to correlate with personality and individual difference. METHODS: A sample of 281 women was selected from university settings in Tehran, Iran. Participants ranged in age from 18 to 39 years (M = 23.7, SD = 3.7). All participants responded to a paper and-pencil survey consisting of measures of perfectionism cognitions, intrinsic religiosity and the desired number of children. RESULTS: Bivariate correlations indicated that, as hypothesised, perfectionism cognitions were negatively associated with the number of children desired (p < .05). Additionally, intrinsic religiosity was positively associated with the desired number of children (p < .01). Finally, regression analysis suggested that, as hypothesised, perfectionism cognitions and intrinsic religiosity could significantly predict the desired number of children (R2 = .19). CONCLUSION: Findings of the present study were explained in the light of an evolutionary approach on reproductive psychology. Those with high perfectionistic cognitions desire a smaller number of children and more religious women desire a larger number of children. PMID- 29517311 TI - Attitudinal barriers to help-seeking and preferences for mental health support among Australian fathers. AB - OBJECTIVE: To (a) identify attitudinal barriers to help-seeking for mental health difficulties among fathers of young children; (b) explore the relationships between perceived barriers to help-seeking and mental health difficulties (i.e. depressive, anxiety, stress symptoms); (c) identify socio-demographic factors associated with barriers to help-seeking; and (d) identify fathers' preferences for mental health support. BACKGROUND: One in 10 Australian fathers experience mental health difficulties in the early parenting period. Low rates of help seeking and under-utilisation of health care services are key issues for the provision of mental health support to fathers at this important life stage. METHOD: The sample consisted of 154 fathers of young children (aged 0-8 years) participating in an Australian online survey on parent wellbeing and parenting. The Barriers to Help-Seeking Scale assessed fathers' attitudinal barriers to help seeking for mental health support. Socio-demographic factors related to fathers' employment, education, and family composition were assessed. RESULTS: The most common attitudinal barriers to help-seeking were: (a) the need for control and self-reliance in managing one's own problems, (b) a tendency to downplay or minimise problems, and (c) a sense of resignation that nothing will help. A range of demographic (i.e. age, educational attainment) factors were associated with these barriers. The most common preferences for support were internet-based information resources, followed by support provided by general practitioners and maternal child health nurses. CONCLUSIONS: These findings have important implications for health promotion, health services and clinical approaches to promoting the health and wellbeing of fathers. PMID- 29517312 TI - Cross-cultural invariance of the Birth Satisfaction Scale-Revised (BSS-R): comparing UK and US samples. AB - OBJECTIVE: This research sought to test the measurement invariance of the Birth Satisfaction Scale-Revised (BSS-R) across United States (US) and United Kingdom (UK) samples. Multiple-group measurement was tested and latent means analysis compared levels of birth satisfaction across the samples. METHOD: Using Confirmatory Factor Analysis (CFA), data previously collected from 409 mothers (181 US mothers; 228 UK mothers) were used to examine the multiple-group measurement invariance of the BSS-R across US and UK samples. RESULTS: A correlated factors BSS-R model demonstrated partial measurement invariance. US mothers had significantly lower birth satisfaction levels on the three BSS-R subscales. CONCLUSIONS: This research demonstrates that the BSS-R is a robust tool that can be used to reliably measure women's birth satisfaction within and across the US and UK. PMID- 29517313 TI - How am I, really? Perceptions of health and distress by women and their midwives. AB - OBJECTIVE: This study examined agreement between ratings of health and emotional distress by women and their midwives. BACKGROUND: Physical complaints and medical complications during pregnancy can significantly impact a woman's experience of pregnancy. Previous studies have found that women and their healthcare providers may have differing perceptions of their condition and how they are coping with the challenges of pregnancy. METHODS: This study used questionnaires completed by women and their midwives to assess perceptions of health and emotional distress in two contexts. Sixty-eight of the women were on an antenatal unit, hospitalised for complications of their pregnancy; 33 women were a comparison group in community maternity care. FINDINGS: Many women in the hospital experienced high levels of emotional distress and worry about their pregnancy; 45% scored in the clinical range on state anxiety, and 28% screened positive for depression. However, midwives rating emotional distress did not pick up on this consistently, and women and hospital midwives often viewed their health status differently. In the community, women's ratings of their health were more consistent with the ratings of their midwives, and midwives were attuned to acute anxiety, but had more difficulty picking up on cues to depression. CONCLUSION: It is challenging, particularly in the unfamiliar and stressful environment of the antenatal unit, for midwives to assess emotional distress and needs for health information. Deliberate screening for antenatal distress might provide the opening for midwives to empower women to identify their options, strengths, and strategies for self-care and emotional resilience. PMID- 29517314 TI - The City MISS: development of a scale to measure stigma of perinatal mental illness. AB - OBJECTIVE: This study aimed to develop and validate a scale to measure perceived stigma for perinatal mental illness in women. BACKGROUND: Stigma is one of the most frequently cited barriers to seeking treatment and many women with perinatal mental illness fail to get the treatment they need. However, there is no psychometric scale that measures how women may experience the unique aspects of perinatal mental illness stigma. METHOD: A draft scale of 30 items was developed from a literature review. Women with perinatal mental illness (n = 279) were recruited to complete the City Mental Illness Stigma Scale. Concurrent validity was measured using the Internalised Stigma of Mental Illness Scale. Factor analysis was used to create the final scale. RESULTS: The final 15-item City Mental Illness Stigma Scale has a three-factor structure: perceived external stigma, internal stigma and disclosure stigma. The scale accounted for 54% of the variance and had good internal reliability and concurrent validity. CONCLUSION: The City Mental Illness Stigma Scale appears to be a valid measure which provides a potentially useful tool for clinical practice and research in stigma and perinatal mental illness, including assessing the prevalence and characteristics of stigma. This research can be used to inform interventions to reduce or address the stigma experienced by some women with perinatal mental illness. PMID- 29517315 TI - Internet-based interventions for postpartum anxiety: exploring health visitors' views. AB - OBJECTIVE: This study aimed to explore health visitors' (HVs) views on the acceptability and potential implementation of internet-based postpartum anxiety interventions in their practice. BACKGROUND: Internet-based self-help has been shown to be effective and acceptable for postpartum depression. Recently, an internet-based intervention has been developed for postpartum anxiety. Before implementing new anxiety interventions in postpartum care, it is important to determine the acceptability and ways of implementing such interventions. This study therefore explored HVs' views on this, as they are the some of the key healthcare professionals supporting women postpartum. METHODS: Semi-structured interviews were conducted with 13 HVs across the UK. Audio-recorded interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Five themes emerged - suitability; benefits; concerns; importance of one-to-one support; implementation. Internet-based interventions were seen as suitable as an additional option for a sub-group of postpartum women. Identified benefits included increased availability of a treatment tool for postpartum anxiety and treatment anonymity and flexibility. Reported concerns were the women's state of mind, decreased human and professional contact, as well as IT access and literacy and language skills. HVs considered the most feasible way to implement internet based interventions would be to have flyers for HVs to include with other information provided after birth or to hand out and discuss during their visits. The need for sufficient evidence of treatment efficacy and appropriate training was highlighted. CONCLUSION: This study highlights the opportunities and challenges that need to be considered before implementing internet-based interventions for postpartum anxiety in the postpartum care. PMID- 29517316 TI - Factor analysis of the Parental Stressor Scale in parents of term and near-term surgical newborns. AB - OBJECTIVE: A confirmatory factor analysis (CFA) of the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) in parents of term and near-term surgical newborns. BACKGROUND: The PSS:NICU is a common measure of the stressors experienced by parents of NICU newborns. A CFA of the PSS:NICU has not been published. METHODS: A CFA of the 26-item version of the PSS:NICU (PSS:NICU-26) was conducted using data from 216 parents of term and near-term surgical newborns. A multigroup CFA analysis was conducted to determine if the factor structure of the final PSS:NICU model was invariant across gender. RESULTS: CFA showed the PSS:NICU-26 model was a poor fit for the data. Exploratory factor analysis and CFAs with post hoc modifications resulted in the exclusion of 10 PSS:NICU-26 items. The resultant PSS:NICU-16 model was a good fit for the data and the factor structure was invariant across gender. CONCLUSION: The PSS:NICU-16 is a reliable measure of NICU-related parental stressors with a structure that is invariant across gender. Although the study findings should be replicated, researchers should consider using the PSS:NICU-16 in studies of parents of term and near-term surgical newborns and studies where a more parsimonious model of the PSS:NICU may be preferred. PMID- 29517317 TI - Increasing participation of people with learning disabilities in bowel screening. AB - Learning disability nurses have a key role in addressing the health inequalities experienced by people with learning disabilities. People with learning disabilities are less likely to participate in bowel screening than other sectors of the population, despite there being evidence of this population being at an increased risk of developing bowel cancer. There are a range of barriers at individual and systemic levels that impact on participation in bowel screening by people with learning disabilities. Actions to address these barriers have been identified in the literature and learning disability nurses are a key agent of change in enabling people with learning disabilities to participate in the national screening programmes. PMID- 29517318 TI - Updating the National Early Warning Score algorithm: saving more lives. AB - Emeritus Professor Alan Glasper, University of Southampton, discusses the contribution of the Royal College of Physicians to effective monitoring of sick patients in hospital. PMID- 29517319 TI - Improving the National Reporting and Learning System and responses to it. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses some recent patient safety reports from NHS Improvement. PMID- 29517320 TI - Organisational culture: why is it important? AB - Janet Scammell, Associate Professor (Nursing), Bournemouth University, considers what organisational culture is, and how it can affect the student experience and, ultimately, the quality of care provision. PMID- 29517321 TI - Ostomy skin complications treated with rhassoul: case studies. AB - Skin complications are common in people who have an ostomy, and often involve the skin's function as a barrier breaking down. Many products have been developed to prevent and treat complications. However, in developing countries, they may be too expensive for patients to buy or not be available. Three case studies found the use of rhassoul, an affordable clay that is readily available in Morocco, to manage peristomal skin damage and protect the skin. Its protective properties are believed to include its ability to absorb and neutralise substances in ostomy output that damage skin and to act as a barrier. PMID- 29517322 TI - Self-rostering can improve work-life balance and staff retention in the NHS. AB - Renee Barrett, Staff Nurse, ITU, Great Ormond Street Hospital NHS Trust, renee.barrett@gosh.nhs.uk , and Annie Holme, Lecturer, King's College London, look at how e-rostering can benefit health organisations and staff. PMID- 29517323 TI - Black, Asian and minority ethnic female nurses: colonialism, power and racism. AB - The history of black, Asian and minority ethnic (BAME) women who came to the UK to work as nurses is interwoven with the history of the NHS. The colonial construct of the BAME female nurse is embedded in British society. From the post second-world-war years to the 1960s, to today, BAME women chose to become nurses and work in the 'motherland', a term regularly used by those immigrating to England from the former colonies. The experiences of the BAME female nurse in the 1970s and early 1980s were of overt racism and lack of advancement. Although racism was less overt in the late 1980s and 1990s, these experiences continued and BAME female nurse advancement levels remained lower than among their white female counterparts. In the 21st century there continues to be significant differences in treatment of BAME female nurses compared with white nursing colleagues, with the enduring effects of the coloniser holding the power to impact on the BAME female nurse who is the colonised, racially stereotyped and less powerful. There are multifaceted reasons for the unequal treatment of BAME female nurses. However, the persistent construct of colonialism and power needs to be recognised if the NHS is to acknowledge ongoing racialised inequalities experienced by BAME female nurses. A recognition of racist and sexist discriminatory actions must occur to permit the development of equal opportunity strategies to address these unacceptable inequalities and generate a real cultural shift. PMID- 29517324 TI - A nurse's duty to warn of risks extends to aftercare as well as initial consent. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses the nurse's duty to give patients information about the risks to look out for after treatment or surgery and what to do if an adverse event occurs. PMID- 29517325 TI - What's in a name: friend or foe? Coping strategies used by stoma patients. PMID- 29517326 TI - Which resources are most helpful to support development of an ePortfolio? AB - AIM: To identify which resources BSc Nursing students found most beneficial in developing and maintaining their ePortfolio. DESIGN: This study evaluates the benefit of resources available in developing and maintaining an undergraduate nursing student ePortfolio. A mixed-methods approach was taken during 2016, using an internet polling tool. The polling tool was available for 3 months before closing and was available to all fields of BSc Nursing student from any year of their 3-year nursing programme. FINDINGS: The qualitative data was coded thematically and generated three themes: student workshops, textual guidance and pre-recorded video support. The quantitative data identified that the most beneficial resource was the student workshops facilitated by student academic mentors (SAMs). CONCLUSION: SAMs provide an invaluable service to students, by sharing their knowledge and experiences, while enhancing a student's perceptions of self-efficacy. PMID- 29517327 TI - Reflections on a sandwich. AB - Duncan Hamilton, final year adult nursing student at the University of Surrey, questions the practicality of making nurses lead healthy lifestyles-and the motivations behind this. PMID- 29517328 TI - Expansion of the CQC's role. PMID- 29517329 TI - Creative care and crises. PMID- 29517330 TI - Developing advanced clinical practice skills in gastrointestinal consequences of cancer treatment. AB - This article explores the transition from a clinical nurse specialist (CNS) towards developing advanced clinical practice skills within a gastrointestinal consequences of cancer clinic. It presents data on the first 50 patients assessed by the CNS from a prospective service evaluation, demonstrating how this informed the nurse's future learning. There is high demand for advanced clinical practice skills to address unmet health needs and improve the quality, efficiency, and sustainability of healthcare services. However, a literature review found no literature on developing advanced clinical practice skills in this setting. Emerging themes from the service evaluation focused on barriers and enablers, ongoing support, organisational commitment and working in a multidisciplinary team. Blended learning provided both structured and opportunistic learning, embedding both formal and tacit knowledge, as roles require increasing flexibility. Clinical supervision and reflective practice were key in maintaining professional and peer support. PMID- 29517331 TI - Using tube feeding and levodopa-carbidopa intestinal gel application in advanced Parkinson's disease. AB - The inability to achieve adequate nutrition and weight loss are serious problems for patients with advanced Parkinson's disease (PD). To ensure the optimal intake of nutrition and fluids and to administer levodopa-carbidopa intestinal gel (LCIG) (which patients need to increase or maintain their mobility as long as possible), different artificial feeding tubes can be used. Although percutaneous endoscopic gastrostomy (PEG) tubes are frequently used in medical practice, there is little research that addresses key questions, including if and when to administer artificial fluids, nutrition and/or LCIG via tubes. Weight gain through tube feeding is only possible for some patients; nurses should keep in mind that tube insertion and feeding may lead to frequent adverse events. Administering LCIG via tubes is usually advisable as it seems to enhance patients' mobility and therefore has positive outcomes in terms of the quality of life of patients and their families ( Lim et al, 2015 ). The authors aimed to examine the use and consequences of providing nutrition and LCIG via gastrostomy tubes in PD patients with advanced disease. PMID- 29517332 TI - Sharing the results of a patient satisfaction audit. AB - Regular service audits since 2008 gave a stoma care department confidence in the service it provides. In 2016 the department undertook a new audit to benchmark its services, using the Association of Stoma Care Nurses (ASCN) UK Revised Stoma Care Nursing Standards and Audit Tool (2015) . Of the 60 questionnaires given out, 43 were returned (71%). The results highlighted areas of good practice with positive patient feedback. However, it also identified that the team needed to improve documentation when offering patients the opportunity to meet a former patient with a stoma preoperatively and when discussing lifestyle issues. The results demonstrated poor preoperative compliance; this was lower than expected and did not concur with department statistics. The audit highlights the importance of clarity when developing a questionnaire to ensure all respondents not only interpret its meaning in the same way, but also only answer the questions specific to them. PMID- 29517334 TI - Embracing a digital age. PMID- 29517333 TI - Using a risk assessment tool for parastomal hernia prevention. AB - All patients with a stoma are at risk of developing some degree of parastomal herniation given enough follow-up time. Based on current evidence, preventive measures are strongly advised to minimise the incidence of a parastomal hernia forming. This article explores the evidence for consistency in care and management of parastomal hernia, focusing on the development of a risk assessment tool, taking into consideration the patient's and the nurse's perspective. PMID- 29517335 TI - Last 1000 days: valuing patients' time. AB - Sam Foster, Chief Nurse, Oxford University Hospitals, considers the value of time for older patients and why a hospital bed might not be the safest place for them after all. PMID- 29517336 TI - Development and preliminary evaluation of a group intervention targeting maternal mental health and mother-infant interactions: a combined qualitative and case series report. AB - OBJECTIVE AND BACKGROUND: The purpose of this study was to investigate the outcomes of an Emotional Wellbeing Group intervention developed to treat maternal depression and anxiety while concurrently supporting positive development of the mother-infant relationship. METHOD: Five women diagnosed with depressive and/or anxiety disorders and their infants completed the Emotional Wellbeing Group. The participants completed pre- and post- intervention assessments which included self-report measures of mood and the motherhood experience, and a video-taped, unstructured play session between mothers and their infants. RESULTS: Four of the participants reported a clinically significant decrease in their symptoms of anxiety. All mothers reported more positive perceptions of their infants and their experience of motherhood, and showed enhanced maternal sensitivity and responsiveness towards their infants. Depression levels were not shown to improve consistently. CONCLUSION: This study provides initial positive evidence to support future research directions and clinical efforts to develop interventions that target both the treatment of perinatal depression and anxiety and the quality of mother-infant interactions. Clinical insights for mental health professionals working with mothers and infants are presented. PMID- 29517337 TI - 'Removed from humanity': a qualitative analysis of attitudes toward abortion providers in anti-abortion individuals in Canada. AB - OBJECTIVE: The present study explores the content of abortion provider stigma. BACKGROUND: Abortion stigma extends beyond women who have abortions to abortion providers. Previous analyses of anti-abortion bills and rhetoric have revealed stereotypes of abortion providers as dangerous and less trustworthy than other health professionals. METHODS: We present a thematic analysis of one-on-one interviews about attitudes toward abortion providers with Canadian individuals (N = 21) holding an anti-abortion stance. RESULTS: We found participants held two kinds of beliefs about abortion providers: (1) providers are agentic and intentional actors and (2) providers are non-agentic victims of a larger system. While the former subtype of provider was viewed with hostility and disgust, the latter was viewed with pity, with participants suggesting that restriction of abortion would be beneficial for provider well-being. CONCLUSION: We document a new component of abortion provider stigma: the belief that abortion providers are harmed by abortion and that they are to be pitied for this. This 'abortion harms providers' attitude parallels recent anti-abortion arguments that abortion harms women. These stigmatising attitudes both construct the provider as untrustworthy and unable to properly care for women. PMID- 29517338 TI - Infant behaviour questionnaire - revised version: a psychometric study in a Portuguese sample. AB - BACKGROUND: Although the original characteristics of temperament tend to remain constant over the course of development, environmental circumstances may influence infants' reactions and behaviour. Parents' reports of infant temperament are rich informants of infant behaviours in different contexts. OBJECTIVE: This study aimed to examine the psychometric properties of the Portuguese version of the Infant Behaviour Questionnaire - Revised (IBQ-R) and test the adequacy of the original and other previously published structures to the Portuguese data. METHOD: 330 mothers and 81 fathers of children aged between 3 and 12 months completed the Portuguese version of the IBQ-R. RESULTS: The confirmatory factorial analysis revealed a non-adequate model fit of the IBQ-R original structure to the Portuguese data; nonetheless, it did reveal an adequate model fit of a previous published IBQ-R structure. This structure, although only slightly different from the original one, seems to be more suitable for the Portuguese data. CONCLUSION: This study provides data that indicates that the IBQ R is a reliable questionnaire to evaluate infant temperament in the Portuguese culture. PMID- 29517339 TI - The reaction of firstborn children to a sibling before the birth: the role of the time at which they are told about the mother's pregnancy and their effortful control. AB - OBJECTIVES: The reaction of firstborns to the impending arrival of a sibling has received little attention from family psychologists. The present study examined whether firstborns' positive feelings about their sibling before the birth were related to the time at which they were told about the mother's pregnancy and their effortful control, which was defined as the self-regulatory ability to inhibit a dominant response to perform a subdominant response. The goal of this research was to provide preliminary evidence in the social context of the two child policy in China. METHODS: The sample included 52 Chinese parents and their firstborns when mothers were in their third trimester of pregnancy with their second child. Data were obtained by means of observation and parent-reported questionnaires. RESULTS: Firstborn children who were told earlier in their mothers' pregnancy were more likely to have positive feelings about their sibling before the birth. In addition, firstborns' effortful control was positively associated with positive feelings about a sibling before the birth. Last, firstborns' effortful control moderated the association between the time at which they were told and positive feelings about the sibling before the birth. Specifically, only when firstborns had low levels of effortful control, being told later about the pregnancy, was related to lower levels of positive feelings about the sibling. CONCLUSIONS: Findings enhanced our understanding of how parents' preparation and firstborns' individual characteristics may have a role on firstborns' positive adjustment before the birth of a sibling. PMID- 29517340 TI - Maternal burn-out: an exploratory study. AB - INTRODUCTION: Maternal burn-out is a psychological, emotional and physiological condition resulting from the accumulation of various stressors characterised by a moderate but also a chronic and repetitive dimension. Little research has focused on this syndrome. OBJECTIVE: The current study aims to assess maternal burn-out rate and to identify factors associated with this state of exhaustion. METHOD: 263 French mothers aged between 20 and 49 years answered five scales quantifying maternal burn-out, perceived social support, parental stress, depression and anxiety symptoms and history of postnatal depression. RESULTS: About 20% of mothers were affected by maternal burn-out. The main factors related to maternal burn-out were having a child perceived as difficult, history of postnatal depression, anxiety, satisfaction of a balance between professional and personal life and parental stress. CONCLUSION: This research shows the need for further work on maternal burn-out to better understand and prevent this syndrome. PMID- 29517341 TI - Do mothers enjoy playing sensitively with their infants? AB - BACKGROUND: Early sensitive caregiver-infant interactions form an important foundation for infant development. Although mutual enjoyment is thought to motivate proximity and continued interactions, there is no empirical evidence that mothers enjoy interacting and behaving sensitively. Research to date has focused on the influence of stable/pathological maternal negative emotions on parenting, with parenting often assessed on one occasion only. Therefore, little is known about what accounts for the variability in sensitivity across interactions. OBJECTIVES: The objective of the present study was to evaluate what makes sensitivity reinforcing to typical mothers and thus more likely to be repeated. We hypothesised that 15- to 28-week-old infants' positive and active engagement would mediate the relationship between their mothers' sensitivity and change in emotion state from pre- to post-interaction. METHOD: Using a naturalistic, repeated-measures design, 390 unique interactions from 49 mothers (mean age: M = 29.90 years, SD = 5.41) and their infants (25 female; mean age: M = 22.53 weeks, SD = 3.77) were rated using the Global Rating Scales of Mother Infant Interaction. Mothers completed measures of their own mood (Profile of Mood States - 15) before and after each interaction. RESULTS: Mothers reported feeling slightly less negative and more vigorous after interacting with their infants. The more sensitively they behaved, the more engaged their infants were and the more vigorous the mothers felt thereafter. Infant engagement did not mediate the relationship between sensitivity and change in negative emotion or in vigour. CONCLUSIONS: Results suggest that upon behaving sensitively, mothers feel more vigorous regardless of their infants' engagement. PMID- 29517342 TI - Support for family diversity: a three-country study. AB - OBJECTIVE: To understand levels of support for differences between families in terms of sexuality and mode of family formation across three countries. BACKGROUND: Previous research has found that attitudes towards family diversity continue to improve over time, although differences remain. METHODS: Subjects were 1605 people living in Australia, the United Kingdom or the United States who completed a questionnaire which sought to explore levels of support for a diverse range of family forms and modes of family formation. RESULTS: Religiosity, political leanings and beliefs about the importance of genetic relatedness were all correlated with level of support. Gender of participant was a predictor of level of support. Cluster analysis indicated three clusters (unsupportive, neutral and supportive) for level of support, for which both sexuality and parent status were predictors. CONCLUSION: Findings highlight the normative status of reproductive heterosex, and demonstrate the considerable value accorded to genetic relatedness. PMID- 29517343 TI - The influence of psychological factors on postpartum weight retention 12 months post-birth. AB - Background During the first postpartum year 20% of women retain excessive weight from pregnancy (postpartum weight retention; PPWR), which predicts long-term overweight/obesity. Objective The aim of this study was to explore the associations between psychological factors (depression, anxiety and stress symptoms and body attitudes) in late gestation and at 12-months postpartum with PPWR one-year post-birth. Methods Pregnant women (N = 176) completed questionnaires in early-mid pregnancy (Time 1; mean (SD) = 16.97 (1.35) weeks), late pregnancy (Time 2; mean (SD) = 33.33 (2.05) weeks), and one year postpartum (Time 3; mean (SD) = 53.12 (3.34) weeks). Women provided demographic characteristics, height and pre-pregnancy weight at Time 1. At Times 2 and 3, weight, depressive, anxiety and stress symptoms and body attitudes (salience of weight and shape, attractiveness, feeling fat, and strength and fitness) were assessed in addition to physiological, socio-contextual and lifestyle factors. Gestational weight gain and PPWR were calculated. Hierarchical linear regression models were conducted to explore variance in 12-month PPWR. Results Overall, models explained 26-39% variance in PPWR. Gestational weight gain in late pregnancy and low attractiveness at 12 months postpartum were the only variables associated significantly with 12-month PPWR. Conclusion While psychological factors did not appear to be important direct contributors to PPWR at 12 months, the overall contribution of all variables suggests that such factors may be implicated in a small and incremental way. Exploration of the interactions between variables will help unpack potential mechanisms of the development of PPWR at 12 months post-birth. PMID- 29517344 TI - We wanted to choose us: how embryo donors choose recipients for their surplus embryos. AB - OBJECTIVE: This study aimed to explore factors affecting donors' choice of recipients for their surplus embryos in the New Zealand context of conditional, known donations. BACKGROUND: Internationally, embryo donation has a low uptake in spite of large numbers of cryopreserved embryos. Possible reasons include a lack of knowledge about and concern for the future welfare of the resultant offspring. In New Zealand, donors and recipients meet prior to donation and legislation supports disclosure and access to genetic knowledge. METHOD: Twenty-two embryo donors (10 couples, two individuals) were interviewed between March 2012 and February 2013 about their experiences of donation and factors affecting their donation. Interview data were analysed thematically. RESULTS: In the interests of the welfare of the child resulting from donation, donors were invested in choosing recipients who would make suitable parents. They attempted to choose recipients similar to themselves, as well as those that they trusted to disclose the manner of conception and facilitate agreed-upon information exchange and contact. CONCLUSION: The interest of donors in ensuring offspring well-being may lend support to conditional forms of open donation, allowing for assessment of recipients' suitability to parent, and for negotiation around information exchange and contact. PMID- 29517345 TI - Is partners' mental health and well-being affected by holding the baby after stillbirth? Mothers' accounts from a national survey. AB - OBJECTIVE: This study aimed to assess the effects on partners' health and well being of holding a stillborn baby. BACKGROUND: Findings from quantitative and qualitative studies have produced inconsistent results concerning the effects of holding a stillborn baby on parents. METHODS: Secondary analyses were conducted on postal questionnaire data relating to 455 partners of women who had a stillbirth. Women answered questions about their partners' behaviour, perceptions of care, mental health and well-being at three and nine months after the stillbirth. Demographic, clinical and care characteristics were compared between partners who, according to the mothers, did and did not hold their baby. Sub group analyses assessed hypothesised moderating effects. RESULTS: Mothers reported that most partners saw (92%) and held (82%) their stillborn baby. However, partners born outside the UK were less likely to have held their baby. Higher gestational age, shorter time interval between antepartum death and delivery, and mother's holding the baby all predicted a higher rate of partner's holding. There was a consistent negative effect of holding the baby across mental health and well-being outcomes, although after adjustment only higher odds of depression (OR 2.72, 95% CI 1.35-5.50) and post-traumatic stress type symptoms (OR 1.95, 95% CI 1.01-3.78) at 3 months were significantly associated with having held the baby following stillbirth. CONCLUSIONS: This study is the first to assess the impact of holding the baby on partners' mental health and well-being. The prevalence of depression and anxiety were high, and the negative effects of holding the baby were significant 3 months later. PMID- 29517346 TI - Endurance with partnership: a preliminary conceptual framework for couples undergoing in vitro fertilisation treatment. AB - BACKGROUND/OBJECTIVES: Infertility affects both women and men in the physical, emotional, existential, and interpersonal realms. When couples seek in vitro fertilisation (IVF) treatment, they further suffer from the difficulties of the treatment and the uncertainty of its outcome. The aim of this study was to develop a preliminary conceptual framework for couples undergoing IVF treatment to give health professionals a better understanding of the experiences of such couples, and to guide the development of an intervention. METHODS: The process of identifying frameworks adopted in intervention studies confirmed that there is no established framework for infertile couples undergoing IVF treatment. A skeletal framework identified from previous studies provides an internal structure for the proposed framework for couples undergoing IVF treatment, filled out with concepts drawn from a concept analysis and a qualitative study, knitting the structure together. RESULTS: This preliminary framework is the Endurance with Partnership Conceptual Framework (P-EPCF). It consists of four domains: the impacts of infertility and stressors, dyadic mediators, dyadic moderators and dyadic outcomes. According to the P-EPCF, the impacts of infertility and IVF treatment can be mediated by the couples' partnership and dyadic coping. Improvements in the psychological well-being and marital functioning of IVF couples can then be expected. CONCLUSIONS: The P-EPCF would be potentially valuable in guiding the development of a complex, couple-based intervention, which could focus on enhancing the partnership of couples and their coping strategies. PMID- 29517347 TI - Peer support workers' experiences of supporting women with postnatal depression: a constant comparative exploration. AB - OBJECTIVE: To explore the lived experiences of peer support workers (PSWs) during their intervention with mothers suffering from postnatal depression (PND). BACKGROUND: Postnatal depression is a major public health concern affecting approximately 13% of women worldwide. There is evidence within recent literature that peer support may have a positive effect upon women suffering with PND. METHODS: Written data from the PSW's logbooks, interviews and supervisory sessions was collected and thematically analysed. RESULTS: Data were analysed using a constant comparative method and four key themes emerged. These were: changing perspectives of the PSW, their personal self-analysis and recognition, concern about the abandonment of the women that they had been supporting and self recovery from postnatal depression. CONCLUSION: Findings indicate that PSWs choose to offer support based upon their own experiences, rejecting formal counselling therapies. This study found that peer-designed interventions do appear to have some merit. PMID- 29517348 TI - Avian coronavirus isolated from a pigeon sample induced clinical disease, tracheal ciliostasis, and a high humoral response in day-old chicks. AB - The detection of avian coronaviruses (AvCoV) in wild birds and the emergence of new AvCoV have increased in the past few years. In the present study, the pathogenicity of three AvCoV isolates was investigated in day-old chicks. One AvCoV isolated from a pigeon, which clustered with the Massachusetts vaccine serotype, and two AvCoV isolated from chickens, which grouped with a Brazilian genotype lineage, were used. Clinical signs, gross lesions, histopathological changes, ciliary activity, viral RNA detection, and serology were evaluated during 42 days post infection. All AvCoV isolates induced clinical signs, gross lesions in the trachea, moderate histopathological changes in the respiratory tract, and mild changes in other tissues. AvCoV isolated from the pigeon sample caused complete tracheal ciliostasis over a longer time span. Specific viral RNA was detected in all tissues, but the highest RNA loads were detected in the digestive tract (cloacal swabs and ileum). The highest antibody levels were also detected in the group infected with an isolate from the pigeon. These results confirm the pathogenicity of Brazilian variants, which can cause disease and induce gross lesions and histopathological changes in chickens. Our results suggest that non-Galliformes birds can also play a role in the ecology of AvCoV. PMID- 29517349 TI - miR-181a targets GATA6 to inhibit the progression of human laryngeal squamous cell carcinoma. AB - AIM: We sought to determine the function of miR-181a/GATA6 pathway in the progression of laryngeal squamous cell carcinoma (LSCC). MATERIALS & METHODS: The expression of miR-181a and GATA6 were detected using quantitative real-time-PCR and western blotting in 127 LSCC samples and 32 corresponding control mucosa tissues. Cell death, migration and apoptosis were measured in Hep-2 cells using 3 (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), Transwell migration assay and apoptosis assay, respectively. The prognosis was determined by the follow-up, univariate analysis and multivariate analysis. RESULTS: We observed decreased miR-181a levels and increased GATA6 expression in LSCC samples compared with control mucosa tissues. Transfection of miR-181a decreased GATA6 expression, suppressed migration and promoted apoptosis in Hep-2 cells. Furthermore, silencing GATA6 suppressed cell migration and promoted apoptosis in Hep-2 cells. Notably, patients with high miR-181a levels had a longer life span. CONCLUSION: MiR-181a inhibits LSCC progression via suppressing GATA6 expression. MiR-181a is an independent prognostic factor in LSCC patients. PMID- 29517350 TI - Development and Validation of a New Protocol for Detecting and Recovering Clostridium difficile from Meat Samples. AB - There is no recommended protocol for detecting and isolating Clostridium difficile present in food samples. Here, we have evaluated the recovery of C. difficile in meat samples after incubating them in various enrichment broths. The media were as follows: cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, d-cycloserine, cefoxitin, and lysozyme; cycloserine-cefoxitin mannitol broth with taurocholate and lysozyme; and cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, C. difficile moxalactam norfloxacin selective supplement, and lysozyme. Samples were inoculated with various strains and quantities of C. difficile and then enriched in the different broths for 1, 4, and 7 days. C. difficile was isolated on agar plates and detected with quantitative real-time PCR (qPCR). The procedure using enrichment in cycloserine cefoxitin fructose broth supplemented with taurocholic acid, d-cycloserine, cefoxitin, and lysozyme and incubation for 4 days for qPCR detection and 7 days for isolation (plating on C. difficile agar base with added C. difficile selective supplement and 7% [v/v] defibrinated horse blood after alcoholic shock and centrifugation) was validated. Samples of different kinds of meat and meat preparation were contaminated and used for validation of the chosen protocol. The sensitivity of detection with qPCR was 100%, and the sensitivity of the isolation method was 96%. PMID- 29517351 TI - Control of Listeria innocua Biofilms on Food Contact Surfaces with Slightly Acidic Electrolyzed Water and the Risk of Biofilm Cells Transfer to Duck Meat. AB - Biofilm formation on food contact surfaces is a potential hazard leading to cross contamination during food processing. We investigated Listeria innocua biofilm formation on various food contact surfaces and compared the washing effect of slightly acidic electrolyzed water (SAEW) at 30, 50, 70, and 120 ppm with that of 200 ppm of sodium hypochlorite (NaClO) on biofilm cells. The risk of L. innocua biofilm transfer and growth on food at retail markets was also investigated. The viability of biofilms that formed on food contact surfaces and then transferred cells to duck meat was confirmed by fluorescence microscopy. L. innocua biofilm formation was greatest on rubber, followed by polypropylene, glass, and stainless steel. Regardless of sanitizer type, washing removed biofilms from polypropylene and stainless steel better than from rubber and glass. Among the various SAEW concentrations, washing with 70 ppm of SAEW for 5 min significantly reduced L. innocua biofilms on food contact surfaces during food processing. Efficiency of transfer of L. innocua biofilm cells was the highest on polypropylene and lowest on stainless steel. The transferred biofilm cells grew to the maximum population density, and the lag time of transferred biofilm cells was longer than that of planktonic cells. The biofilm cells that transferred to duck meat coexisted with live, injured, and dead cells, which indicates that effective washing is essential to remove biofilm on food contact surfaces during food processing to reduce the risk of foodborne disease outbreaks. PMID- 29517352 TI - Prevalence of Vibrio spp. in Retail Seafood in Berlin, Germany. AB - This study was conducted to determine the prevalence of Vibrio spp. in retail seafood in Berlin, Germany. A total of 160 raw seafood samples from supermarkets and seafood shops, consisting of shrimp ( n = 80) and bivalves ( n = 80), were investigated for the presence of Vibrio spp. using the International Organization for Standardization ISO/TS 21872 method and a multiplex PCR. The overall prevalence of Vibrio spp. in retail seafood was 55% (95% CI: 47.2 to 62.8%). The prevalence of Vibrio spp. in shrimp was slightly higher than in bivalves (57.5 versus 52.5%); however, the difference was not statistically significant. Vibrio alginolyticus was the most prevalent species (35.6%), followed by Vibrio parahaemolyticus (27.5%), Vibrio cholerae (6.3%), and Vibrio vulnificus (0.6%). None of the V. parahaemolyticus ( n = 110) isolates encoded tdh/ trh genes, whereas all V. cholerae isolates ( n = 27) were lacking ctxA. Among the chilled samples ( n = 105), the prevalence of Vibrio spp. in unpacked samples was significantly higher than in packed samples ( P = 0.006). Among the packed samples ( n = 55), no significant difference in the prevalence of Vibrio spp. was observed between chilled or frozen products. The results of this study indicated a high prevalence of Vibrio spp. in retail seafood in Germany; positive samples were detected in all types of seafood investigated. The detection of tdh/ trh negative V. parahaemolyticus isolates should not be neglected because of previous findings on pathogenic strains lacking these virulence markers. Even though thorough cooking might limit the risk of foodborne illness caused by Vibrio, potential cross-contamination during preparation or consumption of raw and undercooked seafood might represent a risk of Vibrio infections. PMID- 29517354 TI - The circle of security intervention: Enhancing attachment in early parent-child relationships. PMID- 29517353 TI - Behavioral Observation and Microbiological Analysis of Older Adult Consumers' Cross-Contamination Practices in a Model Domestic Kitchen. AB - The incidence of foodborne illness is higher in older adults because of their increased susceptibility; therefore, food safety practices are important. However, inadequate knowledge and negative attitudes toward food safety have been reported, which may increase use of unsafe food handling practices. Data on the actual food safety behaviors of older adults are lacking. In this study, food safety practices of older adults were observed and linked to microbiological analysis of kitchen surfaces to identify suspected routes of contamination. Older adults (>=60 years, n = 100) prepared a set meal in a model domestic kitchen sanitized according to a validated protocol to ensure minimal and consistent microbiological loads. Food safety behaviors were observed using ceiling-mounted cameras and recorded using a predetermined behavioral checklist. Surface microbiological contamination also was determined after food preparation. Overall, older adults frequently implemented unsafe food handling practices; 90% failed to implement adequate hand decontamination immediately after handling raw chicken. For older adults who used a larger number of adequate hand decontamination attempts, microbiological contamination levels in the kitchen following the food preparation session were significantly lower ( P < 0.001). The novel utilization of behavioral observation in conjunction with microbiological analysis facilitated identification of potentially unsafe food handling practices as suspected routes of microbiological cross-contamination in a model domestic kitchen. Findings indicate the potential impact on domestic food safety of unsafe food handling practices used by older adult consumers. This innovative approach revealed that a large proportion of older adults implement behaviors resulting in microbiological cross-contamination that may increase the risk of foodborne illness in the home. PMID- 29517355 TI - The experience of stillbirth. PMID- 29517356 TI - Men's accounts of infertility within their intimate partner relationships: an analysis of online forum discussions. AB - OBJECTIVE: This article aims to provide insights into men's accounts of infertility in the context of their intimate partnerships. BACKGROUND: Although we are beginning to understand that men experience the emotions of infertility acutely, little is known about how such emotions impact on men's intimate partner relationships. Evidence suggests that infertility can impact intimate partner relationships (both positively and negatively), but there is a paucity of research around how men talk about such relationship impacts, and how they share their stories with other men. Men are often viewed as the silent supporting partner within infertility contexts, with women narrated as taking the burden within the relationship. METHODOLOGY: The paper draws on data from a general discussion board on an online men-only forum. Inductive thematic analysis was utilised to identify key themes across the men's online posts. RESULTS: Men's posts demonstrate that infertility challenges relationships, and that men use the forum examined to offer each other advice on coping with infertility in their relationships. Men highlighted a sense of having less agency than their female partners in relation to infertility and that they were less able to access support for themselves as a result. CONCLUSION: We argue that infertility can be a challenging and complex time within intimate partner relationships and that men construct this situation with reference to gendered norms and constraints within their online accounts. Consideration of both parties in couples experiencing infertility is important for supporting relationships during any diagnosis and treatment processes for infertility. PMID- 29517357 TI - Characteristics and circumstances of women in Australia who cryopreserved their oocytes for non-medical indications. AB - OBJECTIVE: This study aimed to explore the characteristics and circumstances of women who cryopreserved their oocytes for non-medical indications and their reasons for cryopreservation. BACKGROUND: Oocyte cryopreservation for non-medical reasons is becoming increasingly common. Little is known about women who freeze their oocytes in this context. METHODS: All women who had cryopreserved oocytes for non-medical indications at a large Australian fertility treatment centre from 1999 to 2014 were invited to complete an anonymous postal survey. RESULTS: Of the 193 questionnaires mailed, 10 were returned to sender; 96/183 (53%) were completed and returned. Most respondents had completed tertiary education (90%) and were employed in professional occupations (89%). At the time of oocyte cryopreservation, 48% of women were aged at least 38 years (range 28-44 years). Most (90%) women were single when their oocytes were frozen. The lack of a partner or having a partner unwilling to commit to fatherhood were the most common reasons for oocyte freezing, which was viewed as an investment in hope against the possibility of remaining in these predicaments. Some women reported that discussions in the media and interactions with peers influenced their decisions. A few women were influenced by tests indicating a low ovarian reserve. CONCLUSION: These data provide new evidence about women's characteristics, circumstances, and reasons for oocyte cryopreservation for non-medical indications that do not support pejorative conceptualisations of these women as selfish and hedonistic. PMID- 29517358 TI - Functional hypothalamic amenorrhea and its psychological correlates: a controlled comparison. AB - OBJECTIVE: The goal of the study was to examine differences between adolescents and young women with functional hypothalamic amenorrhea (FHA) and control groups in personality traits, eating attitudes and behaviours, and perception of parental behaviour. BACKGROUND: The FHA is stress-induced anovulation, both related to metabolic challenges, such as excessive exercise and malnutrition, and psychogenic challenges, such as perfectionism and poor coping strategies. METHODS: Three groups of adolescents and young women participated in the study: the FHA group (N = 25), the organic anovulation group (N = 21) and the eumenorrheic group with regular menstrual cycle (N = 20). Questionnaires on multidimensional perfectionism, self-control methods, eating attitudes and behaviours and perception of parental behaviour were administered. A clinical interview (SCID) was conducted with each participant. RESULTS: The FHA group had higher levels of perfectionism traits, i.e. higher levels of concerns over mistakes and personal standards, compared to control groups. The FHA group did not engage in disordered eating behaviours more often in comparison with control groups, but reported more prevalent history of anorexia nervosa. The FHA group did not differ from controls in perception of parental rejection, emotional warmth or overprotection. CONCLUSION: The findings suggest that FHA can be characterised by the subtle psychological differences in personality traits, so the patients need to be diagnosed carefully. PMID- 29517359 TI - Predictors of health expectation and health anxiety among post-salpingectomy patients in Ibadan Nigeria. AB - OBJECTIVE: Salpingectomy is the surgical removal of a fallopian tube, often as a result of tubal pregnancy. Little is known about the role of self-efficacy, health consciousness and health locus of control in health expectation and health anxiety among post-salpingectomy patients. BACKGROUND: An ectopic pregnancy and subsequent salpingectomy could present significant life crises for any woman with far-reaching implications. METHODS: Sixty purposively selected post-salpingectomy women (gravida 0-6; parity 0-4; mean age 34 +/- 4.05 years) were included in the cross-sectional survey. A 49-item questionnaire made up of the perceived self efficacy scale, as well as health consciousness, health orientation, health anxiety and health expectation subscales of Snell's Health Orientation Scale, was used for data collection. Descriptive (means; SD; and %) and inferential (multiple regression; t-test; and Zero-Order correlation) statistics were employed in analysis, with two hypotheses tested at p < 0.05. RESULTS: Health consciousness, health locus of control and self-efficacy jointly predicted health expectation and health anxiety with differences in independent prediction of health expectation and health anxiety. Participants with a low level of health consciousness reported a higher level of health expectation and health anxiety. A low level of self-efficacy yielded a higher level of health expectation. Participants with external health locus of control reported significantly higher levels of health anxiety. CONCLUSION: These psychological factors are pertinent in forecasting health expectation and health anxiety among post-salpingectomy patients. Attention to these psychological factors in the management of patients with reproductive and surgical challenges would enhance a patient-centred approach to care. PMID- 29517360 TI - Psychosocial adjustment after induced abortion and its explanatory factors among adolescent and adult women. AB - OBJECTIVE: To compare the depressive symptoms and quality of life (QoL) among adolescents (<20 years) and adult women who have had an abortion and to explore individual, social, relational and decision-making explanatory factors for (mal)adjustment in each group. BACKGROUND: International findings are not consistent regarding the presence of negative psychosocial outcomes after abortion or about the explanatory factors for occurrence among adolescents and adult women. METHODS: In this cross-sectional study, 177 adolescents (65.1%) and 95 adult women (34.9%) who underwent abortion were recruited. Data on individual, social, relational and decision-making characteristics, depressive symptoms (Edinburgh Postnatal Depression Scale) and QoL (EUROHIS-QOL-8) were collected through self-report questionnaires at 16 healthcare services that provide abortion. RESULTS: Although adolescents are not at greater risk of maladjustment than adult women, abortion may be an emotionally significant event for both age groups. Regarding adolescents, feelings of being pressured into abortion and lower satisfaction with the abortion decision were significantly associated with depressive symptoms and lower QoL. Lower support from the mother was also associated with lower QoL. With regard to adult women, lower satisfaction with the abortion decision was significantly associated with depressive symptoms. None of variables was significantly associated with QoL. CONCLUSION: Our results suggest that adolescents are not at greater risk of psychosocial maladjustment than are adult women. Factors from different ecological contexts and specific factors depending on age group should be considered in preventive interventions for (mal)adjustment after abortion. PMID- 29517361 TI - The effect of cognitive-behavioural and solution-focused counselling on prevention of postpartum depression in nulliparous pregnant women. AB - OBJECTIVE: The aim of this study was to evaluate the effect of cognitive behavioural approach and solution-focused counselling on prevention of postpartum depression in nulliparous pregnant women. BACKGROUND: Maternity blues is a common disorder and postpartum depression is a serious disorder. Therefore, the use of preventive measures and timely intervention is of particular importance. METHODS: In this randomised clinical trial, 85 nulliparous pregnant women at 30-35 weeks were randomly divided into three groups: cognitive-behavioural counselling (n = 25), solution-focused counselling (n = 25) and control (n = 35). Counselling meetings were held on a weekly basis. The cognitive-behavioural group received four sessions of counselling and the solution-focused group received three sessions of counselling. The control group received only routine pregnancy healthcare services. Maternity blues and postpartum depression were, respectively, measured on postpartum days 5 and 15 through the Austin Inventory and Edinburgh Postnatal Depression Scale. The mean scores of the three groups were compared using one-way ANOVA. RESULTS: The results of this study showed that the maternity blues mean scores of the three groups of cognitive-behavioural counselling, solution-focused counselling and control groups were 6.1 +/- 4.6, 4.2 +/- 3.6 and 6.7 +/- 4.9, respectively, and the difference between the scores was significant. The mean scores of postnatal depression on the 15th postpartum day in the three groups were 6.7 +/- 5.3, 4.4 +/- 4.4 and 10.4 +/- 5.9, respectively. The results showed that cognitive-behavioural and solution-focused counselling significantly reduced the maternity blues and postpartum depression scores compared with the control group and no difference was observed between the scores of these two counselling methods. The odds ratio of being depressed in women with maternity blues was 7.6 (95% CI: 2.1-27.5). CONCLUSION: Integration of solution-focused and cognitive-behavioural counselling programmes in prenatal care can be effective for improving the mental health of pregnant women. PMID- 29517362 TI - Psychological well-being and depression from pregnancy to postpartum among primiparous and multiparous women. AB - BACKGROUND: The bulk of research on motherhood has focused on perinatal depression, largely overlooking indicators of women's positive mental health which can likewise have pervasive consequences on family functioning. OBJECTIVE: The aim of the present study was to address this issue by exploring the impact of parity and childbirth on both women's perinatal depression and psychological well being. METHODS: A convenience sample of 81 women was followed during pregnancy (Time 1) and postpartum (Time 2). At both times, participants completed the Edinburgh Depression Scale and the Psychological Well-being Scales, measuring perceived autonomy, environmental mastery, personal growth, positive relations, purpose in life, and self-acceptance. RESULTS: Significant negative correlations were observed between depression and psychological well-being dimensions. ANCOVA and mixed ANOVA analyses showed that depression levels did not differ between primiparous and multiparous women, or between pre- and postpartum assessments. By contrast, after childbirth, primiparous women reported higher values of environmental mastery and self-acceptance than multiparous women. In addition, levels of self-acceptance and personal growth increased from pregnancy to postpartum among primiparous women, while no differences were detected over time in the scores of all the psychological well-being dimensions among multiparous women. CONCLUSIONS: This study highlighted some dimensions of positive psychological functioning that specifically contribute to women's well-being in the transition to motherhood, and their different relevance for primiparous and multiparous mothers. Future trials are needed to integrate this information in tailored intervention for the promotion of mothers' complete mental health. PMID- 29517363 TI - Psychological assessment among immigrant and Spanish women during the postpartum period in Spain. AB - OBJECTIVE: to describe whether there were differences in sociodemographic, obstetric, perinatal and psychological variables between immigrant women and native-born women in Spain during the first 24 h after delivery. BACKGROUND: The immediate postpartum period is a critical time when physical and psychological disorders are likely to occur. Immigrant women have, in general, poor perinatal and psychological results during this time. METHODS: One hundred and three women at the Virgen de las Nieves University Hospital (Granada, Spain) were divided into two groups: 50 Spanish and 53 immigrants. The instruments used were the Life Orientation Test, the Stress Vulnerability Inventory, the Perceived Stress Scale and the Symptom Checklist-90-Revised (SCL-90-R). Sociodemographic and obstetric data were obtained from the healthcare providers reports. RESULTS: During the postpartum period, the immigrant women had higher mean scores on the following subscales: interpersonal sensitivity (F(1,102) = 4.06; p < 0.05); depression (F(1,102) = 7.24; p < 0.01); phobic anxiety (F(1,102) = 4.83; p < 0.05), paranoid ideation (F(1,102) = 7.20; p < 0.01); and psychoticism (F(1,102) = 4.04; p < 0.05). When considering age, education, profession, job situation, immigrant status of the partner and duration of time in Spain as covariates, differences between groups were significant on obsessive-compulsiveness (F(1,102) = 5.37; p < 0.05) and depression (F(1,102) = 6.89; p < 0.05). CONCLUSIONS: Immigrant women are in need of more psychological and emotional support from their families, midwives and the rest of healthcare providers than are native Spaniards immediately after delivery. PMID- 29517364 TI - Does upper respiratory infection exacerbate symptoms of multiple sclerosis? PMID- 29517365 TI - A reference equation for maximal aerobic power for treadmill and cycle ergometer exercise testing: Analysis from the FRIEND registry. AB - Background Maximal oxygen uptake (VO2max) is a powerful predictor of health outcomes. Valid and portable reference values are integral to interpreting measured VO2max; however, available reference standards lack validation and are specific to exercise mode. This study was undertaken to develop and validate a single equation for normal standards for VO2max for the treadmill or cycle ergometer in men and women. Methods Healthy individuals ( N = 10,881; 67.8% men, 20-85 years) who performed a maximal cardiopulmonary exercise test on either a treadmill or a cycle ergometer were studied. Of these, 7617 and 3264 individuals were randomly selected for development and validation of the equation, respectively. A Brazilian sample (1619 individuals) constituted a second validation cohort. The prediction equation was determined using multiple regression analysis, and comparisons were made with the widely-used Wasserman and European equations. Results Age, sex, weight, height and exercise mode were significant predictors of VO2max. The regression equation was: VO2max (ml kg-1 min-1) = 45.2 - 0.35*Age - 10.9*Sex (male = 1; female = 2) - 0.15*Weight (pounds) + 0.68*Height (inches) - 0.46*Exercise Mode (treadmill = 1; bike = 2) ( R = 0.79, R2 = 0.62, standard error of the estimate = 6.6 ml kg-1 min-1). Percentage predicted VO2max for the US and Brazilian validation cohorts were 102.8% and 95.8%, respectively. The new equation performed better than traditional equations, particularly among women and individuals >=60 years old. Conclusion A combined equation was developed for normal standards for VO2max for different exercise modes derived from a US national registry. The equation provided a lower average error between measured and predicted VO2max than traditional equations even when applied to an independent cohort. Additional studies are needed to determine its portability. PMID- 29517366 TI - Mechanisms of coronary ischaemia in women: Are we any closer to deciphering the code? PMID- 29517367 TI - Validation of the 2016 USPSTF recommendations for primary cardiovascular prevention in a large contemporary cohort. AB - Aims The aim of this study was to evaluate the performance of the US Preventive Services Task Force (USPSTF) cholesterol recommendations in a contemporary non-US cohort. Methods and results This is a historical cohort analysis of electronic records from Israel's largest health provider. All patients in the Tel Aviv district eligible for primary cardiovascular prevention were followed between January 2005 and December 2015. Risk was estimated by the pooled cohort equations. Statin eligibility was determined by USPSTF and American College of Cardiology and American Heart Association (ACC/AHA) recommendations. Atherosclerotic cardiovascular disease events were retrieved from electronic registration. The mean +/- standard deviation age of the 10,889 (98,258 person years) participants was 60.3 +/- 9.4 years, and 69.1% were women. Outcome events were recorded for 1351 patients (12.4%). Treatment recommendations were discordant in 901 patients (8.3%) whose treatment was indicated only by the ACC/AHA guidelines, implying a 26% reduction in newly eligible patients for statin treatment had the USPSTF recommendations been implemented. Among the statin-naive patients, the pooled cohort equations underestimated the risk, with a predicted-to-observed event ratio of 0.88. The recommended treatment thresholds provided excellent calibration, with ratios of 1.0 for USPSTF and 0.98 for ACC/AHA-eligible patients. Both models showed similar discrimination (Harrel's C = 0.63 (0.62-0.65) for USPSTF vs. 0.64 (0.63-0.66) for ACC/AHA, P = 0.26). The USPSTF recommendations were less sensitive and more specific for the detection of outcome events than the ACC/AHA recommendations (61% vs. 75% and 68% vs. 55%, respectively). The net reclassification index was -0.01. Conclusions Calibration, discrimination and net reclassifications were very similar for USPSTF and ACC/AHA recommendations. Applying the USPSTF recommendations could reduce over-treatment. PMID- 29517368 TI - Fathers in the birth room: choice or coercion? Help or hindrance? PMID- 29517369 TI - Satisfaction in life among fathers following fertility treatment. AB - OBJECTIVE: The study aimed at (a) gaining a better understanding of how fertility history (ART/spontaneous) is associated with life satisfaction among new fathers; and (b) identifying personal and interpersonal risk factors for lower satisfaction in life during the transition to fatherhood. DESIGN: This cross sectional study comprised 172 Israeli fathers (76 who became fathers following ART and 96 following spontaneous pregnancy), who completed a series of self report questionnaires 5-18 months after the birth of their first child. RESULTS: No differences were found in life satisfaction between fathers in the two fertility history groups. Regression analysis indicated that younger age and higher economic status, as well as lower attachment anxiety and avoidance and better marital relationship, were associated with a higher level of life satisfaction among new fathers. CONCLUSION: Although the life satisfaction of new fathers does not appear to be affected by their fertility history, it may be hampered by personal and interpersonal risk factors. These results have practical implications for professionals who come into contact with this population. PMID- 29517371 TI - Student midwives' awareness, knowledge, and experiences of antenatal anxiety within clinical practice. AB - OBJECTIVE: The current study aimed to explore student midwives' awareness, knowledge, and experiences of supporting women with antenatal anxiety (ANA) within clinical practice. BACKGROUND: ANA is associated with negative outcomes for mother and baby. Midwives play a key role in the screening of antenatal mental health and care of women suffering from ANA. METHODS: This study was conducted with student midwives at one UK university in the north-west of England. Twenty-five midwifery students completed a brief online survey informed by National Institute of Health and Care Excellence (NICE) guidelines. Of these, seven volunteered to participate in semi-structured interviews exploring the survey data. The interview topic guide was designed based on the findings of the survey. RESULTS: Thematic analysis of the seven interviews revealed four overarching themes: Perpetuating factors, Barriers to care, Skills required in role and Suggestions for future directions. Midwives had a varied knowledge and understanding of ANA and expressed a desire to learn more about their role in supporting women with ANA. CONCLUSION: Although a small study, the results highlight the need for education to be improved in order to best prepare student midwives for cases of ANA, with emphasis on integrating psychology and mental health information into teaching as well as time spent in clinical practice. Midwives are key in the screening of women for ANA and are in an ideal position to signpost for specialist care. PMID- 29517370 TI - When time runs out: reconciling permanent childlessness after delayed childbearing. AB - OBJECTIVE: This study aimed to examine the experience of permanent childlessness after delayed childbearing. BACKGROUND: More women are delaying childbearing while they pursue a career, gain financial stability and seek an appropriate partner. However, given that fertility declines with age, there is concern that more women will end up permanently, unintentionally childless after postponing childbearing. There is little known about this growing and invisible group. METHODS: An interpretive phenomenological analysis was used to conduct the study. A purposive sample of 15 women who identified as being permanently childless after delaying childbearing participated in the study. Data were collected using in-depth semi-structured interviews. RESULTS: Themes included feelings of grief, loss and isolation; a need to make sense of their childlessness; and a need to rebuild and refocus their lives and identities regardless of whether they had actually tried to conceive during their childbearing years. Women struggled with feelings of regret and the need to reconcile the reality of their choice to delay childbearing based on their values and beliefs about the ideal conditions within which to raise a child with feelings of powerlessness to pursue motherhood when they were likely still fertile. CONCLUSION: Women who are permanently childless after delaying childbearing experience similar feelings to those who are childless after infertility and failed fertility treatments regardless of whether they tried to conceive during their reproductive years. However, this group has unique needs based on their feelings of regret, powerlessness and responsibility for their childlessness. PMID- 29517372 TI - Living through unsuccessful conception attempts: a grounded theory of resilience among women undergoing fertility treatment. AB - OBJECTIVE: To provide a model of resilience among women undergoing fertility treatments, who experience repeated unsuccessful conception attempts. BACKGROUND: Assisted reproductive treatment is emotionally and physically challenging. Women undergoing such treatments report experiencing high levels of anxiety and depression. There continues to be a lack of understanding of the process women go through to adapt to the challenges associated with fertility treatment, in order to continue to pursue their goal of pregnancy. METHOD: The study employed a qualitative Grounded Theory design. Eleven women aged between 24 and 42 years took part in individual semi-structured interviews around their experiences of living through unsuccessful fertility treatment attempts. RESULTS: Three core categories were identified: 'Appraisal'; 'Stepping away from treatment'; and 'Building self up for the next attempt'. Following the failure of treatment, participants appraised their ability to carry on with further treatment attempts. Those who felt they had depleted their resources through the cycle of attempting pregnancy had taken a step back from the treatment cycle to reconnect with themselves and gather sufficient resources to attempt treatment again. During preparation for the next treatment, participants demonstrated their resilience by taking steps to build up their resources, such as nurturing their strength and taking control of their fertility experience. CONCLUSIONS: Women undergoing fertility treatment demonstrate their resilience through a variety of actions that enable them to continue to pursue their pregnancy goal. Clinical staff should be mindful of their clients' need to withdraw from the treatment cycle and offer support to enable them to do this. PMID- 29517373 TI - Interest in web-based treatments for postpartum anxiety: an exploratory survey. AB - OBJECTIVE: This study aimed to explore women's interest in web-based treatments for postpartum anxiety and determine the feasibility of reaching women with postpartum anxiety online. BACKGROUND: Anxiety in the postpartum period is common and often untreated. One innovative approach of offering treatment during this period is through web-based self-help. Assessing women's interest in new treatments, such as a web-based self-help, is an important step prior to development efforts. METHODS: A cross-sectional online survey was created and promoted for 4 months via unpaid social media posts (Facebook and Twitter). To be eligible, women had to be over the age of 18, live in England, fluent in English, be within 12 months postpartum and self-report at least mild levels of anxiety. RESULTS: A sample of 114 eligible women were recruited. The majority were Caucasian, well-educated, middle-class women. Seventy percent reported moderate or severe anxiety. Sixty-one percent of women expressed interest in web-based postpartum anxiety treatments. Women preferred treatment in a smartphone/tablet application format, presented in brief modules and supported by a therapist via email or chat/instant messaging. CONCLUSIONS: Based on the stated preferences of participating women it is recommended that postpartum anxiety web-based treatments include different forms of therapist support and use a flexibly accessible smartphone/tablet application format with content split into short sections. The findings also suggest that unpaid social media can be feasible in reaching women with postpartum anxiety, but additional efforts are needed to reach a more diverse population. PMID- 29517374 TI - A psychological study of male, female related and unexplained infertility in Indian urban couples. AB - OBJECTIVE: The study intended to see the impact of infertility on experience of emotional trauma, belief pattern and formation of psychopathology and also to explore the psychopathology with respect to degree of infertility related stress impact among male, female and unexplained factor infertility in couples suffering from primary infertility. DESIGN: This was a clinic-based, cross-sectional comparative study based on a consecutive sampling method. SUBJECTS: Sixty couples were studied of whom 10 couples had male-related infertility (MF), 10 had female related infertility (FF) and 10 unexplained infertility (UF). Another 30 fertile couples were also included as comparative group (CG) after matching on certain sociodemographic variables with the clinical groups. MEASURES: Impact of Event Scale, Symptom Checklist-90 Revised and Irrational Belief Scale were used. RESULTS: The impact of emotional trauma and irrational belief was greatest in the male-related infertility couples, and somatisation in the unexplained group, whereas depression and interpersonal sensitivity were higher in the female related infertility couples. An impact of moderate to severe infertility-related stress on depression and irrational beliefs was also observed. Gender difference was evident with respect to psychopathology and types of infertility. CONCLUSION: The impact of infertility is evident with respect to psychopathology with differential impact of various types of infertility groups among Indian couples. PMID- 29517375 TI - Hole in the heart: bringing up Beth. PMID- 29517376 TI - Owning the birth experience: what factors influence women's vaginal birth after caesarean decision? AB - OBJECTIVE: Our quantitative analysis examined what factors influence pregnant women to choose a vaginal birth after a caesarean (VBAC). BACKGROUND: There is growing concern over the high rates of caesarean section; much of the high rate is driven by repeat caesareans. A trial of labour after a previous caesarean is an option for many women increasingly supported by medical literature. METHODS: Survey data from 173 pregnant women who had had only one birth by caesarean were analysed using a hierarchical binary logistic regression model. RESULTS: Desire for the experience of a vaginal birth strongly predicted choice of VBAC; however, this relationship was dampened among women with a high (versus low) powerful others (e.g. doctors and nurses) locus of control. Prior reason for a caesarean section and practical factors also play a role. CONCLUSION: Women may be more likely to choose VBAC if they are encouraged to believe that they can help control the outcome, especially if their desire for a vaginal birth experience is high. PMID- 29517377 TI - Experiences of physical activity during pregnancy resulting from in vitro fertilisation: an interpretative phenomenological analysis. AB - OBJECTIVE: To explore the qualitative experiences and decision-making processes surrounding physical activity (PA) for women who have undergone IVF treatment. BACKGROUND: PA during pregnancy is safe for both mother and fetus in the majority of cases, including for women who have undergone in vitro fertilisation (IVF) treatment; however, there is a paucity of research into decision-making and PA in this population. METHODS: Eight women, who had undergone successful IVF treatment and were currently pregnant or had given birth within the last two years, participated in semi-structured interviews about their experiences of infertility and PA during pregnancy. Interview transcripts were analysed using interpretative phenomenological analysis. RESULTS: Three superordinate themes emerged from the data: 'navigating away from childlessness and towards motherhood', 'negotiating a safe passage' and 'balancing the challenges of pregnancy with the needs of the self'. Ten subthemes indicated the processes adopted to navigate experiences of infertility, the IVF process, and subsequent decision-making about PA during pregnancy. CONCLUSION: PA during pregnancy was experienced as a way to soothe the self and control the experience of pregnancy; however, this was mediated by concerns about safety and physical limitations on PA. Limitations of the study are considered, as well as implications for clinical practice and directions for future research. PMID- 29517378 TI - The Oxford handbook of perinatal psychology. PMID- 29517380 TI - Birth trauma and post-traumatic stress disorder: the importance of risk and resilience. PMID- 29517381 TI - Premature birth: complexities and difficulties in building the mother-child relationship. AB - AIM: This paper aims to investigate if the dyadic interactive behaviours were influenced by parental stress and feelings both in preterm and full-term mother child dyads. METHODS: 45 mothers (age = 35.29 +/- 5.38) and fathers (age = 36.77 +/- 6.89) of preterm infants (GA = 30.25 +/- 2.95; BW = 1288.02 +/- 488.76), and 36 mothers (age = 32.60 +/- 4.56) and fathers (age = 35.54 +/- 5.16) of full-term (GA = 39.88 +/- 1.38; BW = 3156.39 +/- 493.81) were involved. Parents filled out the Impact of Event Scale Revised (IES-R), Profile of Mood States (POMS) and Parenting Stress Index Short Form (PSI-SF) and interactive behaviours (Global Rating Scale) was videotaped after 3 months. RESULTS: Mothers of preterm children showed higher level of Intrusiveness (Mpreterm = 4.07 +/- .74, Mfullterm = 4.39 +/- .51, t = 2.22, p = .029) and Remoteness (Mpreterm = 4.45 +/- .83, Mfullterm = 4.79 +/- .34, t = 2.51, p = .015) than mothers of term children. In preterm mothers' lower levels of Sensitivity, higher levels of Intrusiveness, Remoteness and Depression are associated with the presence of negative feelings and parental stress in both parents. Moreover, higher children Distress is associated to parental negative feelings, paternal stress and post-traumatic symptoms. A higher score of parental negative feelings and parental stress predicted lower scores in Global RatingScale dimensions. CONCLUSIONS: Our results underline that preterm birth could be a risk factor for the co-construction of interactive exchanges between mother and premature baby. This study could help practitioners to better consider parental roles and to carry out specific supportive interventions for both parents and children. PMID- 29517382 TI - Mapping French people's views regarding posthumous reproduction. AB - OBJECTIVE: The study mapped French people's views regarding the acceptability of posthumous reproduction. BACKGROUND: Posthumous reproduction - the use of a deceased person's gametes for procreative purposes -is a controversial procedure because it involves a series of ethical issues, namely the surviving partner's rights to procreation, the emotional feelings and financial interests of other family members, and the government's interest in maintaining orderly inheritance rules. METHODS: A convenience sample of participants aged 19-68 (104 lay people, 47 health professionals and 15 lawyers) were presented with 48 realistic stories that were composed according to a four-factor within-subject design: marital status (married for about 10 years with children, married for about three years without children, and cohabiting for three years without children) * attitude of the deceased's parents (favourable vs. unfavourable to posthumous procreation) * time elapsed since the partner's death (three months vs. nine months) * deceased's wishes (written consent, oral consent given in front of credible witnesses, unknown wishes, and unfavourable attitude). RESULTS: Through cluster analysis, four qualitatively different positions were found. They were called Never Acceptable (35% of the sample, mostly health professionals, lawyers and regular attendees to the church or temple), Tolerable in a Few Cases (28%), Depends on Deceased's Wishes (22%, mostly lay people) and Quite Acceptable (16%, mostly lay people). CONCLUSIONS: About half of French lay people view the current legislation regarding posthumous assisted reproduction in a country such as the UK as more appropriate than the French legislation. PMID- 29517383 TI - Surveying prenatal attachment in fathers: the Italian adaptation of the Paternal Antenatal Attachment Scale (PAAS-IT). AB - OBJECTIVE: This study focuses on the process of the father's bonding with the fetus and aims to assess the psychometric properties of the Italian translation of the Paternal Antenatal Attachment Scale (PAAS). BACKGROUND: The construct of prenatal attachment has been created to systematically investigate the nature of the particular bond that develops in the minds of parents expecting a child. Paternal attachment to the unborn child has not been well explored until now, despite its undoubted importance. The PAAS is a 16-item questionnaire evaluating paternal thoughts, feelings, attitudes and emotions towards the fetus validated with Australian fathers. METHODS: This is a cross-sectional study. A forward backward translation was used to obtain the PAAS Italian version (PAAS-IT). A sample of 165 Italian fathers completed the PAAS-IT, the 20-Toronto Alexithymia Scale and a sociodemographic questionnaire also investigating the father's attitudes towards the fetus. The reliability and construct validity of the PAAS IT were evaluated. A Principal Component Analysis (PCA) and a Confirmatory Factor Analysis (CFA) using Structural Equation Modelling (SEM) were conducted. RESULTS: The PAAS-IT psychometric characteristics were adequate. The PCA yielded a two dimensional model explaining 34% of the variance. The CFA acknowledges the truthfulness of this model. The items loading on the two factors did not exactly match that found in the original PAAS, suggesting the influence of specific cultural features. CONCLUSIONS: The PAAS-IT is a reliable and valid instrument to use in Italian clinical settings to investigate the development of the paternal attachment towards the unborn child. PMID- 29517384 TI - Antenatal mother-infant bonding scores are related to maternal reports of infant crying behaviour. AB - OBJECTIVE: To assess the relation between antenatal mother-infant bonding scores and maternal reports of infant crying behaviour. BACKGROUND: Crying is normal behaviour and it is important for parent-infant bonding. Even though bonding starts antenatally, the relation between antenatal bonding scores and infant crying behaviour has never been studied. METHOD: A secondary analysis was performed on data that were gathered in a large prospective study within our region. Bonding was assessed using an antenatal bonding questionnaire at 32 weeks gestational age. The crying behaviour of infants was assessed with three questions at six weeks postpartum. Crying was termed excessive (EC+) when mothers perceived the crying to be 'every day', 'often' or 'very often', and with 'crying episodes lasting more than 30 minutes'; in other words, when mothers scored high on all three questions. The relation between bonding and crying was examined using a multiple logistic regression analysis, including adjustment for relevant variables, especially maternal depression as measured with the Edinburgh Depression Scale. RESULTS: In total, 894 women were included of whom 47 reported EC+ infants (5.3%). Antenatal bonding scores were significantly related to the reporting of crying behaviour, even after adjustment for relevant variables (p = 0.02). Each extra point on the bonding scale reduced the EC+ risk with 14% (OR = 0.86, 95% CI [0.76-0.97]). CONCLUSION: Mothers with lower antenatal bonding scores were more likely to report an EC+ infant. Future research should further explore the concept of antenatal bonding, its relation with EC and risks associated with EC. PMID- 29517385 TI - Anxiety and depressive symptoms in women and men from early pregnancy to 30 months postpartum. AB - AIMS: The aims of this study were to analyse the changes in anxiety and depression symptoms from early pregnancy to 30 months postpartum according to gender and parity. METHOD: 129 couples (N = 258) recruited from an obstetrics unit completed self-report measures of anxiety and depression at each pregnancy trimester, childbirth, 3 and 30 months postpartum. Using multilevel modelling, piecewise dyadic growth curve models were performed, assessing time, gender and parity as predictors of anxiety and depression symptoms. RESULTS: Anxiety and depression symptoms decreased from the first trimester to 3 months postpartum and increased from 3 to 30 months postpartum, returning to the baseline levels in the overall sample. The symptoms were positively correlated within-dyad; in a given time point when a partner reported more symptoms, the other reported more symptoms as well. Changes in anxiety and depression symptoms over time were different according to gender and parity, especially from 3 to 30 months postpartum. Primiparous women revealed low stable symptoms, whereas multiparous women revealed the steepest symptoms increase (in comparison to primiparous men and women and multiparous men). CONCLUSIONS: This study corroborates the literature considering that the transition to parenthood can last until the child's age of 2 or 3 years. Results point out that the risk for anxiety and depression symptoms increasing over the postpartum period is greater for multiparous and lesser for primiparous women. Future studies should explore the factors that contribute to the high risk of symptoms increase over the postpartum period for multiparous women. Screening and intervention should target couples and not only women. PMID- 29517386 TI - Prenatal Attachment Inventory: expanding the reliability and validity evidence using a sample of Italian women. AB - BACKGROUND: The Prenatal Attachment Inventory (PAI) is a widely used questionnaire to measure prenatal attachment. However, its internal structure is controversial. None of the previous studies have investigated the dimensions of the Italian version of the scale using both an exploratory and a confirmatory approach. There is also a need to explore extensively the external validity of the Italian PAI. OBJECTIVE: We designed a study aimed at shedding further light on the dimensionality of the questionnaire and expanding the evidence of its reliability and validity. METHOD: Five-hundred and thirty-five Italian expectant mothers participated in the prenatal phase; a subsample of 100 women participated in the postnatal phase of the study. The PAI was administered together with other scales measuring maternal-fetal attachment, psychological wellbeing and relational variables. RESULTS: The hypothesised relationships with external criteria were substantiated overall. The five dimensions described in the Italian study by Barone, Lionetti, and Dellagiulia also emerged from our factor analyses, with the exception of two items. Internal consistency was adequate for the total scale and for four of the five subscales. CONCLUSION: As the Fantasy subscale showed poor internal consistency, we advise against its use as an independent measure. However, when used as a global score, the PAI is a reliable and valid measure of prenatal attachment in Italian women. Thus, it can be used for research purposes. The use of the PAI could also be very helpful in clinical settings, in order to identify expectant mothers who have difficulty in establishing an affective bond with their unborn infants. To this end, further research should study the characteristics of the PAI on high-risk groups and clinical samples in order to obtain clinical cut-offs. PMID- 29517387 TI - Psychometric properties of the attachment style questionnaire in Swedish pregnant women: short and full versions. AB - OBJECTIVES: (i) To evaluate the reliability and factor structure of the Attachment Style Questionnaire - Short Form (ASQ-SF) for use in pregnant women and (ii) to compare the reliability and factor structure of the short- and full version-ASQ among pregnant women. BACKGROUND: Adult attachment insecurity is currently included as a major risk factor in studies of perinatal health. None of the self-report measures with a Swedish translation have been psychometrically evaluated in a pregnant cohort. METHODS: A population-based cohort of 1631 pregnant women answered the ASQ in late pregnancy. Internal consistency (item subscale correlations, Cronbach's alpha, and alpha if item deleted) was evaluated for the seven available subscales. Confirmatory factor analysis (CFA) was run to examine the factor structure of the short form compared with the full-version. Test-retest correlations were assessed in a subgroup (n = 48). RESULTS: All mean item-subscale correlations for the ASQ-SF were > 0.30. Cronbach's alpha's for ASQ SF dimensions were as follows: Avoidance (0.87); Anxiety (0.89); Discomfort with Closeness (0.85); Relationships as Secondary (0.54); Confidence (0.83); Need for Approval (0.76); and Preoccupation with Relationships (0.77). No item removal substantively increased subscale alpha's. The CFA demonstrated better model fit for the ASQ-SF than for the full-version ASQ, while other reliability measures were similar. Test-retest correlations ranged from 0.65 to 0.84. CONCLUSION: The ASQ-SF showed similar psychometric properties in pregnant women as in the general population and had good reliability, but the optimal factor structure needs to be studied further. Results support the usage of the ASQ-SF in pregnant cohorts. PMID- 29517388 TI - Changes in peripapillary blood vessel density in Graves' orbitopathy after orbital decompression surgery as measured by optical coherence tomography angiography. AB - The purpose is to evaluate the utility of optical coherence tomography (OCT) angiography in the evaluation of Graves' orbitopathy (GO) and response to orbital decompression in patients with and without dysthyroid optic neuropathy (DON). This was a single-center, prospective case series in a cohort of 12 patients (24 orbits) with GO and +/-DON, (6 orbits) who underwent bilateral orbital decompression. All patients underwent pre- and postoperative OCT angiography of the peripapillary area. Vessel density indices were calculated in a 4.5 mm * 4.5 mm ellipsoid centered on the optic disk using split-spectrum amplitude decorrelation angiography algorithm, producing the vessel density measurements. Mean change in vessel density indices was compared between pre- and postoperative sessions and between patients with and without DON. Patient 1, a 34-year-old male with GO and unilateral DON OD, showed a significant reduction in blood vessel density indices oculus dexter (OD) (DON eye) after decompression while a more modest reduction was found oculus sinister (OS) with the greatest change noted intrapapillary. Patient 2, a 50-year-old male with DON OU, showed worsening neuropathy following decompression OD that was confirmed by angiographic density indices. Patient 3, a 55-year-female with DON, showed a reduction in blood vessel density OD and increased density OS. Patients without DON showed overall less impressive changes in indices as compared to those with DON. Using OCT angiography, response to surgical treatment in GO orbits, more so in orbits with DON, can be demonstrated and quantified using vessel density indices with reproducibility. PMID- 29517389 TI - Difficulty hearing in noise: a sequela of concussion in children. AB - OBJECTIVE: Concussions can result in auditory processing deficits even in the absence of hearing loss. In children and adolescents, the extent to which these impairments have functional consequences for everyday listening, such as the ability to understand speech in noisy environments, is unknown. RESEARCH DESIGN: Case-control study. SUBJECTS AND METHODS: Forty youth comprised the participants: 20 had sustained a concussion and were recovering from their injury, and 20 controls had sustained non-concussive orthopaedic (e.g. musculoskeletal) injuries. All were evaluated on the Hearing in Noise Test, an audiologic index of the ability to hear sentences in adverse listening conditions. RESULTS: Children and adolescents recovering from concussions demonstrated an overall impaired ability to perceive speech in noisy backgrounds compared to a peer control group. This deficit also emerged across trials in the most taxing listening condition, and with respect to published, age-normative values. CONCLUSIONS: Functional listening skills-such as the ability to understand speech in noise, and the ability to sustain performance over time in taxing auditory conditions-may be compromised in children with concussions. These impairments may exacerbate cognitive and academic challenges associated with concussion injuries, and should be considered in return-to-learn and return-to-play decisions. PMID- 29517390 TI - Targeted therapy to annihilate the immune-evading phenotype in cancer evolution. PMID- 29517391 TI - Evolution of GAPDH as a druggable target of tumor glycolysis? PMID- 29517392 TI - Evaluation of a new equation for LDL-c estimation and prediction of death by cardiovascular related events in a German population-based study cohort. AB - A simple equation established by Cordova & Cordova (LDL-COR) was developed to provide an improved estimation of LDL-cholesterol in a large Brazilian laboratory database. We evaluated this new equation in a general population cohort in Pomerania, north-eastern Germany (SHIP Study) compared to other existing formulas (Anandaraja, Teerakanchana, Chen, Hattori, Martin, Friedewald and Ahmadi), and its power in the prediction of death by atherosclerosis related events as the primary outcome. Analysis was conducted on a cohort of 4075 individuals considering age, gender, use of lipid lowering therapy and associated co morbidities such as diabetes, hepatic, kidney and thyroid disease. LDL-COR values had a lower standard deviation compared to the previously published equations: 0.92 versus 1.02, 1.02, 1.03, 1.04, 1.09, 1.10 and 1.74 mmol/L, respectively. All of the factors known to affect the results obtained by the Friedewald's equation (LDL-FW), except fibrate use, were associated with the difference between LDL-COR and LDL-FW (p < .01), with TSH being borderline (p = .06). LDL-COR determined a higher hazard ratio (1.23 versus 1.12, 1.19, 1.21, 1.19, 1.21 and 1.19) for cardiovascular disease related mortality, incident stroke or myocardial infarction compared to the other evaluated formulas, except for Ahmadi's (1.24), and the same adjusted predictive power considering all confounding factors. The proposed simple equation was demonstrated to be suitable for a more precise LDL-c estimation in the studied population. Since LDL-c is a parameter frequently requested by medical laboratories in clinical routine, and will probably remain so, precise methods for its estimation are needed when direct measurement is not available. PMID- 29517393 TI - Traumatic life events and development of post-traumatic stress disorder among female factory workers in a developing country. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) may be more prevalent and burdensome in developing countries. AIMS: The goals of this study were to (1) determine the prevalence of PTSD, (2) identify types and number of traumas related to screening positive for PTSD and (3) determine other sociodemographic risk factors and health/medical conditions that may be correlated to PTSD among garment-factory workers and a comparable working population in Bangladesh. METHOD: A survey was administered to a convenient sample of 607 lower socio economic status (SES) working women in Bangladesh, 310 of who were garment workers. The primary outcome PTSD was measured by the PTSD Checklist. The Life Events Checklist determined the number and type of traumatic events. RESULTS: The prevalence of PTSD was found to be 17.79% - 7.25% in garment workers and 21.55% in the comparison worker group. In multivariate analysis, PTSD was found to be significantly associated with age, income, chronic pain and number of stressful events. Participants between 45-50 years of age had the greatest odds of reporting PTSD - 15.68 fold (95% confidence interval (CI) = 4.08, 60.29) compared with those younger than 24 years. PTSD was more common in those with lower income (2,000-4,000 taka) (odds ratio (OR) = 1.60; 95% CI = 0.79, 3.26), who had chronic pain (OR = 2.48; 95% CI = 1.51, 4.07) and who experienced over three traumatic life events (OR = 11.25; 95% CI = 4.59, 27.59). The mean number of traumatic events experienced by this entire population was 4.9 with PTSD being more likely in those who experienced physical assault (OR = 6.35; 95% CI = 4.07, 9.90), who caused serious harm or death to someone else (OR = 4.80; 95% CI = 1.36, 16.87) and who had exposure to combat or war (OR = 4.76; 95% CI = 1.17, 19.34). CONCLUSION: Undiagnosed and untreated PTSD impacts the quality of life and decrease worker productivity among working-age women in this developing country. PMID- 29517394 TI - Influencing factors of attitudes toward seeking professional help for mental illness among Korean adults. AB - OBJECTIVES: Identifying predictors of psychological help-seeking attitudes is essential to improve access to needed mental health services. We investigated factors - particularly Big Five personality traits - that affect attitudes toward seeking professional psychological help for mental illness among Korean adults. METHODS: A total of 654 participants aged 15-54 years were recruited through an online panel survey. Help-seeking attitudes for mental illness were measured by the Attitudes Toward Seeking Professional Psychological Help Scale (ATSPPH), and personality traits were measured by the Big Five Personality Inventory-10. RESULTS: Multivariate analyses showed that female gender, history of psychiatric diagnosis, agreeableness and openness to experience were significantly associated with positive attitudes toward seeking professional psychological help for mental illness. CONCLUSIONS: These findings suggest that specific personality traits should be considered when developing strategies to promote positive attitudes toward seeking professional psychological help. Further research using a representative community sample is needed to generalize our findings. PMID- 29517395 TI - Biochemical analysis of the Cas6-1 RNA endonuclease associated with the subtype I D CRISPR-Cas system in Synechocystis sp. PCC 6803. AB - Specialized RNA endonucleases are critical for efficient activity of the CRISPR Cas defense mechanisms against invading DNA or RNA. Cas6-type enzymes are the RNA endonucleases in many type I and type III CRISPR-Cas systems. These enzymes are diverse and critical residues involved in the recognition and cleavage of RNA substrates are not universally conserved. Cas6 endonucleases associated with the CRISPR-Cas subtypes I-A, I-B, I-C, I-E and I-F, as well as III-B have been studied from three archaea and four bacteria thus far. However, until now information about subtype I-D specific Cas6 endonucleases has remained scarce. Here, we report the biochemical analysis of Cas6-1, which is specific for the crRNA maturation from the subtype I-D CRISPR-Cas system of Synechocystis sp. PCC 6803. Assays of turnover kinetics suggest a single turnover mechanism for Cas6-1. The mutation of conserved amino acids R29A, H32A-S33A and H51A revealed these as essential, whereas the parallel mutation of R175A-R176A led to a pronounced and the K155A mutation to a slight reduction in enzymatic activity. In contrast, the mutations R67A, R81A and K231A left the enzymatic activity unchanged. These results are in accordance with the predominant role of histidine residues in the active site and of positively charged residues in RNA binding. Nevertheless, the protein-RNA interaction site seems to differ from other known systems, since imidazole could not restore the mutated histidine site. PMID- 29517396 TI - Immunogenicity, safety, and effectiveness of seasonal influenza vaccination in patients with diabetes mellitus: A systematic review. AB - Influenza is associated with an increased risk of complications, especially in diabetic mellitus patients who are more susceptible to influenza infection. Despite recommendations of the WHO and public health authorities, vaccination uptake in this population remains suboptimal. This systematic review identified 15 studies published between January 2000-March 2017 in PubMed, Embase and Cochrane Library, which provided data on immunogenicity, safety, effectiveness, and/or cost-effectiveness of seasonal influenza vaccination in diabetic patients. Immunogenicity of seasonal influenza vaccination in diabetic patients was generally comparable to that of healthy participants. One month after vaccination of diabetic patients, seroconversion rates and seroprotection ranged from 24.0 58.0% and 29.0-99.0%, respectively. Seasonal influenza vaccination reduced the risk of hospitalization and mortality in diabetic patients, particularly those aged >=65 years. These review results demonstrate and reinforce the need and value of annual influenza vaccination in diabetic patients, particularly in alleviating severe complications such as hospitalization or death. PMID- 29517397 TI - Corrigendum. PMID- 29517399 TI - Active ageing, emotional care and the threat of stigma: Identity management in older adults using sleeping medication long-term. AB - Amid fears about the medicalisation of old age, the high prevalence of sleeping medication use in older cohorts is a significant public health concern. Long-term use is associated with a plethora of negative effects, such as cognitive impairment and risk of addiction. However, little is known about the lived experience of older adults using sleeping medication longer term. Episodic interviews lasting approximately 90 minutes were conducted with 15 independently living adults, aged 65-88 years, who were using sedative-hypnotic or tricyclic sleeping medication for more than 11 years on average. Thematic analysis shows that participants divided their rationale for use into two temporal periods: (1) to ensure physical ability in the daytime and (2) to ensure emotional stability at night. Long-term sleeping medication was thus characterised as a form of 'emotional self-management' of the negative emotions associated with later life, blotting out feelings of loss and loneliness by inducing sleep. Participants feared loss of access to their medication 'supply', employing strategies to ensure its continuity, while expressing shame about their dependence. However, identity management, in the form of explanations, minimisations and social comparisons, functioned to downplay their addiction. Through this, long-term sleeping medication users were able to elude the spoiled identities and multiple stigmas of both the 'out of control' addict and the unsuccessful older adult by asserting a positive identity; that of the 'new' older adult, actively medicating for success both day and night. PMID- 29517398 TI - Laminopathy-causing lamin A mutations reconfigure lamina-associated domains and local spatial chromatin conformation. AB - The nuclear lamina contributes to the regulation of gene expression and to chromatin organization. Mutations in A-type nuclear lamins cause laminopathies, some of which are associated with a loss of heterochromatin at the nuclear periphery. Until recently however, little if any information has been provided on where and how lamin A interacts with the genome and on how disease-causing lamin A mutations may rearrange genome conformation. Here, we review aspects of nuclear lamin association with the genome. We highlight recent evidence of reorganization of lamin A-chromatin interactions in cellular models of laminopathies, and implications on the 3-dimensional rearrangement of chromatin in these models, including patient cells. We discuss how a hot-spot lipodystrophic lamin A mutation alters chromatin conformation and epigenetic patterns at an anti adipogenic locus, and conclude with remarks on links between lamin A, Polycomb and the pathophysiology of laminopathies. The recent findings presented here collectively argue towards a deregulation of large-scale and local spatial genome organization by a subset of lamin A mutations causing laminopathies. PMID- 29517400 TI - Platelet function in disseminated intravascular coagulation: A systematic review. AB - Disseminated intravascular coagulation (DIC) has a well-examined pathophysiology, yet some essential elements remain undetermined. During DIC, platelets play an important role in the development of micro thrombosis, but changes in platelet function parameters and their association with development of DIC have not been established. The present systematic review investigated reported associations between platelet function (activation, aggregation, and adhesion) and DIC. We performed a literature search in Embase and PubMed, following the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines. In total, 22 articles were included; 14 human studies, seven animal studies, and one with both human and animal subjects. Platelet activation markers were generally reported to be higher in both DIC patients and animals with DIC than healthy controls, and higher among patients with DIC than patients without DIC. Six human and six animal studies investigated platelet aggregation, which were overall reported to be lower in DIC than in non-DIC or in healthy controls in both human and animal studies. Platelet aggregation was deemed to be confounded by low platelet counts, which are known to affect platelet aggregation analyses even within the reference interval. In conclusion, platelet activation analyses showed promise in diagnosis of DIC, but semi-automatization and standardization are warranted before these can be implemented in daily clinical practice. Changes in platelet aggregation analyses during DIC remain inconclusive, and further studies including adjustment for low platelet count are needed to clarify the role of platelet aggregation in DIC. PMID- 29517401 TI - Revision eDCR using a superior pedicled mucosal flap. AB - BACKGROUND: Endoscopic dacryocystorhinostomies (eDCRs) show patency rates between 81% and 94%. However, dacryocystorhinostomy (DCR) failure and the need for revision remain a significant challenge. One of the principal challenges in revision eDCR is the need to surgically identify the correct osteotomy site and maintain long-term patency in the setting of previously instrumented and potentially scarred tissue. At the same time, the surgeon must assume that the blood supply to the commonly described anterior and posteriorly pedicled flaps has been compromised. OBJECTIVE: The objective of the study is to describe a novel flap technique for revision eDCR. METHODS: The superior based mucosal flap is a novel technique that provides a vascularized mucosa preserving technique in revision eDCR despite previous instrumentation of the lacrimal system. This technique provides wide exposure of the revision osteotomy site while simultaneously allowing a viable mucosal flap to be replaced at the conclusion of the procedure, thereby minimizing bone exposure and cicatricial restenosis. RESULTS: The authors have utilized this technique in 13 procedures with 100% positive identification of the lacrimal sac, a 0% complication rate, and a 100% success rate after a mean follow-up of 26.93 +/- 10.33 months (range 6-35 months). CONCLUSION: The eDCR using the superior pedicled mucosal flap provides excellent exposure of the maxillary bone and the lacrimal sac. This method preserves vascularity of the flap using a superiorly based pedicle which is typically inviolate during both open and endoscopic primary DCR. The mucosal flap can then be replaced, thereby minimizing bone exposure and optimizing patency. PMID- 29517402 TI - Frequency of Virus Coinfection in Raccoons ( Procyon lotor) and Striped Skunks ( Mephitis mephitis) During a Concurrent Rabies and Canine Distemper Outbreak. AB - Rabies and canine distemper virus infections in wildlife share similar presenting signs. Canine distemper virus was detected using real-time PCR of conjunctival swabs in rabies positive raccoons (22/32) and skunks (7/34) during a concurrent rabies and canine distemper outbreak in Ontario, Canada in 2015-16. Coinfections with both viruses should be considered, particularly in distemper endemic areas that are at risk of rabies incursion. PMID- 29517403 TI - Genetic Diversity of Avian Paramyxovirus Type 6 Isolated from Wild Ducks in the Republic of Korea. AB - Eleven avian paramyxovirus type 6 (APMV-6) isolates from Eurasian Wigeon ( n=5; Anas penelope), Mallards ( n=2; Anas platyrhynchos), and unknown species of wild ducks ( n=4) from Korea were analyzed based on the nucleotide (nt) and deduced amino acid sequences of the fusion (F) gene. Fecal samples were collected in 2010 14. Genotypes were assigned based on phylogenetic analyses. Our results revealed that APMV-6 could be classified into at least two distinct genotypes, G1 and G2. The open reading frame (ORF) of the G1 genotype was 1,668 nt in length, and the putative F0 cleavage site sequence was 113PAPEPRL119. The G2 genotype viruses included five isolates from Eurasian wigeons and four isolates from unknown waterfowl species, together with two reference APMV-6 strains from the Red-necked Stint ( Calidris ruficollis) from Japan and an unknown duck from Italy. There was an N-truncated ORF (1,638 nt), due to an N-terminal truncation of 30 nt in the signal peptide region of the F gene, and the putative F0 cleavage site sequence was 103SIREPRL109. The genetic diversity and ecology of APMV-6 are discussed. PMID- 29517405 TI - Erratum: Berryman et al (2018). AB - In the article by Berryman N, Mujika I, Arvisais D, Roubeix M, Binet C, Bosquet L. Strength training for middle- and long-distance performance: a meta-analysis. Int J Sports Physiol Perform. 2018;13(1):57-63. doi: 10.1123/ijspp.2017-0032 , there were errors in an author's name and with 2 author affiliations: (1) Inigo Mujika was incorrectly spelled as Inigo Mujika, (2) Mujika's second affiliation (School of Kinesiology, Universidad Finis Terrae, Santiago, Chile) was absent, and (c) University of Poitiers was incorrectly spelled as University or Poitiers. The online version of this article has been corrected. We apologize for these errors. PMID- 29517404 TI - The immunomodulatory effects of Zn-incorporated micro/nanostructured coating in inducing osteogenesis. AB - Micro/nanostructured TiO2/ZnO coating has been shown to possess multiple functions, including antibacterial activity and bioactivity. Osteoblast-like SaOS 2 cells were employed for evaluating the in vitro osteogenic capacity of this coating and positive results were obtained. However, traditional principles of osseointegration focus only on the osteogenic differentiation alone. The effects of immunomodulation on the osteogenic activity have been largely ignored. In this study, the inflammatory responses of macrophages on the micro/nanostructured TiO2/ZnO coating were investigated. The extract media of macrophage cell line RAW264.7 cultured on the TiO2/ZnO coating were collected as indirect co-culture conditioned media. The osteogenic activity of SaOS-2 cells in the conditioned media was investigated. Adhesion, ALP activity and extracellular mineralization of cells grown in the conditioned media extracted from the micro/nanostructured TiO2/ZnO coating were found to be enhanced, compared to those grown in the conditioned media extracted from the macroporous TiO2 coating. The immune microenvironment produced by the micro/nanostructured TiO2/ZnO coating showed excellent capacity to promote osteogenesis, indicating that this coating could be a promising candidate for implant surface modification in orthopaedic and dental applications. Furthermore, this work could help us understand the interplay between the host immune system and the osteoimmunomodulatory properties of the biomaterials, and optimize the design for coating biomaterials. PMID- 29517406 TI - Detoxification of polluted marine sediments using water treatment sludge. AB - The purpose of this study was development of the optimal conditions for the inertization of the polluted marine sediments using groundwater treatment sludge highly enriched in iron and aluminum. For that purpose fine-grained sediment (>85% clay and silt fraction) highly enriched in copper and zinc was amended with the waste sludge (from 10% to 50%). The sample with the optimum percentage of the waste sludge was further subjected the thermal treatment at 200-800 degrees C. The efficiency of the treatment was determined by the leaching tests and toxicity testing using Hordeum vulgare L. as biosystem. The percentage of the seed germination, the root elongation, and the germination index before and following the treatment were determined. Untreated sediment leachate caused significant arrest in the percentage of the seed germination (6.7 +/- 6.7%), the root elongation (1.9 +/- 2.2%), and the germination index (0.2 +/- 0.3%) with EC50 of 24.9%, suggesting a significant toxic potential of the sediments. After amendment with 30% of the waste sludge the concentrations of the considered micropollutants decreased below regulated values while all three toxicological parameters showed no significant difference compared to the negative control. The toxicity of the sediment was completely removed following the thermal treatment at 400 degrees C. PMID- 29517407 TI - Does the Intake of Selective Serotonin Reuptake Inhibitors Negatively Affect Dental Implant Osseointegration? A Retrospective Study. AB - The success of osseointegration is influenced by several factors that affect bone metabolism and by certain systemic medications. Selective serotonin reuptake inhibitors (SSRIs) have been previously suggested to be among these medications. This study aims to investigate the association between systemic intake of SSRIs and failure of osseointegration in patients rehabilitated with dental implants. A retrospective cohort study was conducted, including a total of 2055 osseointegrated dental implants in 631 patients (109 implants in 36 SSRI ?users and 1946 in 595 nonusers). Predictor and outcome variables were SSRI intake and osseointegration failure, respectively. The data were analyzed with Mann-Whitney test or Fisher exact test accordingly. Both patient-level and implant-level models were implemented to evaluate the effect of SSRI exposure on the success of osseointegration of dental implants. Median duration of follow-up was 21.5 months (range = 4-56 months) for SSRI users and 23 months (range -60 months) for nonusers ( P = .158). Two of 36 SSRI users had 1 failed implant each; thus, the failure rate was 5.6%. Eleven nonusers also had 1 failed implant each; thus, the failure rate was 1.85%. The difference between the 2 groups failed to reach statistical significance at patient and implant levels ( P = .166, P = .149, respectively). The odds of implant failure were 3.123 times greater for SSRI users compared with nonusers. Patients using SSRIs were found to be 3.005 times more likely to experience early implant failure than nonusers. The results of this study suggest that SSRIs may lead to increase in the rate of osseointegration failure, although not reaching statistical significance. PMID- 29517408 TI - Magnetic resonance imaging in the diagnosis of white matter signal abnormalities. AB - Background White matter abnormalities (WMAs) pose a diagnostic challenge when trying to establish etiologic diagnoses. During childhood and adult years, genetic disorders, metabolic disorders and acquired conditions are included in differential diagnoses. To assist clinicians and radiologists, a structured algorithm using cranial magnetic resonance imaging (MRI) has been recommended to aid in establishing working diagnoses that facilitate appropriate biochemical and genetic investigations. This retrospective pilot study investigated the validity and diagnostic utility of this algorithm when applied to white matter signal abnormalities (WMSAs) reported on imaging studies of patients seen in our clinics. Methods The MRI algorithm was applied to 31 patients selected from patients attending the neurometabolic/neurogenetic/metabolic/neurology clinics at a tertiary care hospital. These patients varied in age from 5 months to 79 years old, and were reported to have WMSAs on cranial MRI scans. Twenty-one patients had confirmed WMA diagnoses and 10 patients had non-specific WMA diagnoses (etiology unknown). Two radiologists, blinded to confirmed diagnoses, used clinical abstracts and the WMSAs present on patient MRI scans to classify possible WMA diagnoses utilizing the algorithm. Results The MRI algorithm displayed a sensitivity of 100%, a specificity of 30.0% and a positive predicted value of 74.1%. Cohen's kappa statistic for inter-radiologist agreement was 0.733, suggesting "good" agreement between radiologists. Conclusions Although a high diagnostic utility was not observed, results suggest that this MRI algorithm has promise as a clinical tool for clinicians and radiologists. We discuss the benefits and limitations of this approach. PMID- 29517410 TI - Optimizing Anterior Implant Esthetics With a Vascularized Interpositional Periosteal Connective Tissue Graft for Ridge Augmentation: A Case Report. AB - Achieving excellence in anterior rehabilitations requires close cooperation between the periodontist and the prosthodontist. Many techniques can be used to restore the lost alveolar hard and soft tissues. The more severe the peri-implant defect, the higher the challenge and lower the predictability of the procedure. The present case consists of Seibert Class III with malaligned implants in the esthetic zone resolved with a cost-modified treatment plan to reestablish esthetics in the anterior maxilla using a rotated palatal flap. The vascularized interpositional periosteal connective tissue graft was effective in augmenting the soft tissue in the esthetic zone and remained stable over a 2-year period. Additional long-term clinical studies are necessary to support these results. PMID- 29517409 TI - Genetic predictors of efficacy and toxicity of iguratimod in patients with rheumatoid arthritis. AB - : Iguratimod (IGU) is a novel disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). Like other DMARDs, IGU exhibited significant differences in effectiveness and safety. AIM: The aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA. MATERIALS & METHODS: Seven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA. Results: ABCG2 rs2231142 A allele conferred a higher response to IGU, while NAT2 rs1495742 G carriersconferred a lower response to IGU. CYP2C19*2 rs4244285 A carriers had higher risk for IGU-induced toxicity compared to the GG carriers. CONCLUSION: Our study suggests that the polymorphisms of ABCG2 (rs2231142), NAT2 (rs1495741)and CYP2C19*2 (rs4244285) may help to predict thetherapeutic effectiveness and toxicity of IGU in patients with RA. PMID- 29517411 TI - Chaperone complex formation of the transcription factor MalR involved in maltose utilization and amylolytic enzyme production in Aspergillus oryzae. AB - The Zn2Cys6-type transcription factor MalR controls the expression of maltose utilizing (MAL) cluster genes and the production of amylolytic enzymes in Aspergillus oryzae. In the present study, we demonstrated that MalR formed a complex with Hsp70 and Hsp90 chaperones under non-inducing conditions similar to the yeast counterpart Mal63 and that the complex was released from the chaperone complex after the addition of the inducer maltose. The MalR protein was constitutively localized in the nucleus and mutation in both the putative nuclear localization signals (NLSs) located in the zinc finger motif and the C-terminal region resulted in the loss of nuclear localization. This result indicated the involvement of NSLs in the MalR nuclear localization. However, mutation in both NLSs did not affect the dissociation mode of the MalR-Hsp70/Hsp90 complex, suggesting that MalR activation induced by maltose can occur regardless of its intracellular localization. PMID- 29517412 TI - Distribution of lower extremity work during clean variations performed with different effort. AB - The purpose of this research was to investigate how lower extremity work was distributed during the pull of cleans performed lifting the barbell to the minimum height required to receive it in a full squat (minimal height clean); or with maximum effort to elevate the barbell as high as possible and receiving it in either a full (maximal effort clean) or partial (power clean) squat. Eight weightlifters screened for proficient technique performed these clean variations at 80% of one repetition maximum. Work performed on the barbell and by the lower extremity net joint moments (NJM) was computed from marker trajectories and ground reaction forces. Total barbell work, lower extremity NJM work, knee extensor work, and knee joint excursion during the second pull was lower in the minimal height clean than the maximal effort and power cleans (P < 0.05). This research demonstrates that more knee extensor work is performed in the second pull of maximal effort and power cleans compared to the minimal height clean. The larger knee extensor work performed is due to larger knee joint excursion during the second pull of the maximal effort and power cleans, but not larger knee extensor NJM. PMID- 29517413 TI - A near-infrared reflectance spectroscopic method for the direct analysis of several fodder-related chemical components in drumstick (Moringa oleifera Lam.) leaves. AB - The drumstick tree has traditionally been used as foodstuff and fodder in several countries. Due to its high nutritional value and good biomass production, interest in this plant has increased in recent years. It has therefore become important to rapidly and accurately evaluate drumstick quality. In this study, we addressed the optimization of Near-infrared spectroscopy (NIRS) to analyze crude protein, crude fat, crude fiber, iron (Fe), and potassium (K) in a variety of drumstick accessions (N = 111) representing different populations, cultivation programs, and climates. Partial least-squares regression with internal cross validation was used to evaluate the models and identify possible spectral outliers. The calibration statistics for these fodder-related chemical components suggest that NIRS can predict these parameters in a wide range of drumstick types with high accuracy. The NIRS calibration models developed in this study will be useful in predicting drumstick forage quality for these five quality parameters. PMID- 29517414 TI - Rectangularization of the survival curve reconsidered: The maximum inner rectangle approach. AB - Rectangularization of the survival curve-a key analytical framework in mortality research-relies on assumptions that have become partially obsolete in high-income countries due to mortality reductions among the oldest old. We propose refining the concept to adjust for recent and potential future mortality changes. Our framework, the 'maximum inner rectangle approach' (MIRA) considers two types of rectangularization. Outer rectangularization captures progress in mean lifespan relative to progress in maximum lifespan. Inner rectangularization captures progress in lifespan equality relative to progress in mean lifespan. Empirical applications show that both processes have generally increased since 1850. However, inner rectangularization has displayed country-specific patterns since the onset of sustained old-age mortality declines. Results from separating premature and old-age mortality, using the MIRA, suggest there has been a switch from reducing premature deaths to extending the premature age range; a shift potentially signalling a looming limit to the share of premature deaths. PMID- 29517415 TI - A multi-method analysis of the interaction between humic acids and heavy metal ions. AB - Understanding of the interaction between humic acids (HAs) and heavy metal ions (HMIs) is essential for the assessment of environmental and health risks of HMIs. Multiple analyses, including fluorescence quenching of HAs; solution pH, zeta potential, and hydrodynamic size changes; and coprecipitation of HAs and HMIs, were carried out to investigate the interaction between two HAs and four HMIs (Ag+, Pb2+, Cd2+, and Cr3+). The HA-HMI interaction mainly included chemical complexation, H+-HMI exchange, electrostatic attraction, and flocculation. The chemical complexation between HAs and HMIs revealed by the Stern-Volmer quenching constant was ordered as Ag < Cd < Pb < Cr. HMIs replaced protons in the acidic functional groups of HAs and thus lowered the pH of the solution. The electrostatic interaction between the negatively charged HAs and HMIs reduced the electronegativity of HAs. Interaction with HMIs, especially the high-valent ions, induced aggregation of HAs, causing precipitation of both HAs and HMIs in the sorptive solution. Cr3+ flocculated and precipitated HAs, but at high concentrations, it reversed the surface charge of HAs and resuspended them. The HA-HMI interaction increased as the HA acidity and solution pH increased. PMID- 29517416 TI - Reconnoitering the linkage between cardiovascular disease mortality and long-term exposures to outdoor environmental factors in the USA using remotely-sensed data. AB - This ecological study aimed to assess the association between long-term exposures to outdoor environmental factors and mortality rate from cardiovascular disease (CVD) in a diverse and spatially distributed population from 3,094 counties within the U.S. (n > 3,780,000 CVD deaths) using satellite-derived data of PM2.5 concentrations, sunlight, and maximum heat index. Multivariable logistic regression analyses were conducted to determine whether PM2.5, sunlight and maximum heat index were related to the odds of the total CVD death rate based on gender, race, and age taking into consideration the confounding risk factors of diabetes, obesity, leisure- time physical inactivity, smoking and socioeconomic status. The study has shown that elevated levels of PM2.5, sunlight and heat long term exposures are significantly associated with an increase in the odds ratio of the total CVD mortality. The results suggest a 9.8% (95% CI = 6.3% - 13.4%), 0.9% (95% CI = 0.5% - 1.2%), and 0.7% (95% CI = 0.5% - 11.2%) increase in total CVD mortality associated with 10 MUg/m3 increase in PM2.5 concentrations, 1,000 kJ/m2 increases in sunlight, and 1 oF increase in heat index, respectively. The odds ratios for the CVD death rate due to long-term exposures of PM2.5, sunlight, and heat index were significantly greater than 1.0 for all categories except for Asians, Hispanics, and American Indians, indicating that the effect of long-term exposures to particulate matter, sunlight radiation, and maximum heat on CVD mortality is trivial for Asians, Hispanics, and American Indians. Among the categories of age, the group of 65 years and older had the highest odds ratios, suggesting that the age group of 65 years and older are the most vulnerable group to the environmental exposures of PM2.5 (OR = 1.179, 95% CI = 1.124 - 1.237), sunlight (OR = 1.047, 95% CI = 1.041 - 1.053), and maximum heat (OR = 1.014, 95% CI = 1.011 - 1.016). The odds ratios of CVD mortality due to the environmental exposures were higher for Blacks than those for Whites. The odds ratios for all categories were attenuated with the inclusion of diabetes, obesity, leisure-time physical inactivity, smoking, and income covariates, reflecting the effect of other medical conditions, lifestyle, behavioral and socioeconomic factors on the CVD death rate besides the environmental factors. PMID- 29517417 TI - Octagam(r) for chronic inflammatory demyelinating polyneuropathy: results from three observational studies. AB - AIM: To present data from three studies of a Post-Authorization Safety Surveillance (PASS) program for the subset of patients receiving Octagam(r) 5% or 10% for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Data on patients with CIDP treated with Octagam were analyzed to assess its safety and tolerability. RESULTS: Of 2314 patients included in the studies, 58 patients (mean age: 64.6 years) received Octagam for CIDP, mean dose of which was 0.8 g/kg bodyweight/course. 81% of observations for clinical appearance since last observation were assessed as stable and 16.6% showed an improved clinical appearance with treatment. Adverse drug reactions were rare (<0.7% of infusions). CONCLUSION: Octagam was effective and well-tolerated in patients with CIDP. PMID- 29517418 TI - SNPs affecting the clinical outcomes of regularly used immunosuppressants. AB - Recent studies have suggested that genomic diversity may play a key role in different clinical outcomes, and the importance of SNPs is becoming increasingly clear. In this article, we summarize the bioactivity of SNPs that may affect the sensitivity to or possibility of drug reactions that occur among the signaling pathways of regularly used immunosuppressants, such as glucocorticoids, azathioprine, tacrolimus, mycophenolate mofetil, cyclophosphamide and methotrexate. The development of bioinformatics, including machine learning models, has enabled prediction of the proper immunosuppressant dosage with minimal adverse drug reactions for patients after organ transplantation or for those with autoimmune diseases. This article provides a theoretical basis for the personalized use of immunosuppressants in the future. PMID- 29517419 TI - Exercise testing protocol using a roller system for manual wheelchair users with spinal cord injury. AB - OBJECTIVE: Determine the validity and reliability of an exercise testing protocol to evaluate cardiorespiratory measures in manual wheelchair users (MWUs) with spinal cord injury (SCI) using a roller-based (RS) wheelchair system. DESIGN: Repeated measures within-subject design. SETTING: Community-based research laboratory. PARTICIPANTS: Ten adults with SCI requiring the use of a manual wheelchair. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Cardiorespiratory measures (peak oxygen consumption [VO2peak], respiratory exchange ratio [RER], pulmonary ventilation [VE], energy expenditure [EE], heart rate [HR], accumulated kilocalories [AcKcal]) and perceived exertion (RPE) were measured during three separate maximal exercise tests using an arm crank ergometer (ACE) and an RS. RESULTS: At maximal exertion, there were no significant differences in variables between groups, with moderate-to-strong correlations (P < 0.05, r = 0.79-0.90) for VO2, HR, RPE, AcKcal, and rate of EE between RS and ACE trials. Significant moderate-to-strong correlations existed between RS trials for VO2, AcKcal, rate of EE, and peak power output (P < 0.01, r = 0.77-0.97). CONCLUSIONS: VO2peak was highly correlated between ACE and RS trials and between the two RS trials, indicating the RS protocol to be reliable and valid for MWUs with SCI. Differences in perceived exertion and efficiency at submaximal workloads and maximal pulmonary ventilation at peak workloads indicated potential advantages to using the RS. PMID- 29517420 TI - Identification and quantification of human microcirculatory leukocytes using handheld video microscopes at the bedside. AB - Leukocyte recruitment and adhesion to the endothelium are hallmarks of systemic inflammation that manifest in a wide range of diseases. At present, no method is available to directly measure leukocyte kinetics at the bedside. In this study, we validate a new method to identify and quantify microcirculatory leukocytes observed by handheld vital microscopy (HVM) using space-time diagram (STD) analysis. Video clips ( n = 59) containing one capillary-postcapillary venule unit where leukocytes could be observed emanating from a capillary into a venule in cardiac surgery patients ( n = 20) were included. STD analysis and manual counting were used to quantify the number of leukocytes (total, rolling, and nonrolling). Pearson's correlation and Bland-Altman analysis were used to determine agreement between the STDs and manual counting. For reproducibility, intra- and interobserver coefficients of variation (CVs) were assessed. Leukocyte (rolling and nonrolling) and red blood cell velocities were assessed. The STDs and manual counting procedures for the quantification of rolling leukocytes showed good agreement ( r = 0.8197, P < 0.0001), with a Bland-Altman analysis mean difference of -0.0 (-6.56; 6.56). The overall intraobserver CV for the STD method was 1.5%. The overall interobserver CVs for the STD and the manual method were 5.6% and 9.4%, respectively. The nonrolling velocity was significantly higher than the rolling velocity (812 +/- 519 um/s vs. 201 +/- 149 um/s, P = 0.001). STD results agreed with the manual counting procedure results, had a better reproducibility, and could assess the leukocyte velocity. STD analysis using bedside HVM imaging presented a new methodology for quantifying leukocyte kinetics and functions in the microcirculation. NEW & NOTEWORTHY In this study, we introduce space-time diagram analysis of sublingual microcirculation imaging using handheld vital microscopy to identify and quantify the presence and kinetics of human microcirculatory leukocytes. We validated the methodology by choosing anatomical units consisting of a capillary connected to a venule, which allowed precise identification of leukocytes. PMID- 29517422 TI - Locomotor-respiratory coupling is maintained in simulated moderate altitude in trained distance runners. AB - To determine whether acute exposure to simulated moderate altitude alters locomotor-respiratory coupling (LRC) patterns in runners, 13 trained male distance runners performed a running economy and maximal oxygen uptake (Vo2max) test in normoxia (NORM) and hypoxia (HYP) ([Formula: see text]= 15.8%; ~2,400 m/8,000 ft) on separate days. Running economy (RE), the degree of LRC, stride frequency-to-breathing frequency quotients (SF/fb), ratings of perceived exertion (RPE), and dyspnea were assessed at three common submaximal speeds and Vo2max. SF/fb were significantly lower at each submaximal speed in HYP (12.9 km/h: 2.91 +/- 0.20 vs. 2.45 +/- 0.17, 14.3 km/h: 2.53 +/- 0.17 vs. 2.21 +/- 0.14, 16.1 km/h: 2.22 +/- 0.14 vs. 1.95 +/- 0.09; P < 0.05). The degree of LRC (range: 36 99%) in HYP was not significantly different than NORM at any of the three common submaximal speeds. However, the degree of LRC was significantly higher at Vo2max in HYP than NORM (43.8 +/- 3.4% vs. 57.1 +/- 3.8%; P < 0.05). RE and RPE were similar at all running speeds. Dyspnea was significantly greater in HYP compared with NORM at 16.1 km/h ( P < 0.05). Trained distance runners are able to maintain LRC in HYP, despite increases in breathing frequency. Within this unique population, years of training may enhance and optimize the ability to maintain LRC to minimize metabolic costs and dyspnea. NEW & NOTEWORTHY Exposure to acute altitude causes increases in ventilation at rest and any submaximal exercising workload, which may alter locomotor-respiratory coupling (LRC). Our data suggest that trained distance runners can maintain LRC during acute exposure to simulated moderate altitude, even when breathing frequency is increased at any submaximal pace. PMID- 29517423 TI - Heritability of proprioceptive senses. AB - Heritability studies using the twin model have provided the basis to disentangle genetic and environmental factors that contribute to several complex human traits. However, the relative importance of these factors to individual differences in proprioception is largely unknown despite the fact that proprioceptive senses are of great importance, allowing us to respond to stimuli stemming from the space around us and react to altering circumstances. Hence, a total of 44 healthy male twins (11 MZ and 11 DZ pairs), 19-28 yr old, were examined for movement, position, and force sense at the elbow joint, and their heritability estimates were computed. Results showed that genetic factors explained 1) 72 and 76% of the total variance of movement sense at the start and the end of the movement, respectively, 2) 60 to 77% of the total variance of position sense, depending on the angle of elbow flexion and whether forearm positioning was active or passive, and 3) 73 and 70% of the total variance of the force sense at 90 and 60 degrees of elbow flexion, respectively. It is concluded that proprioception assessed by these conscious sensations is to a substantial degree genetically dependent, with heritability indexes ranging from 0.60 to 0.77, depending on the task. NEW & NOTEWORTHY Proprioceptive acuity varies among people, but it is not known how much of this variability is due to differences in their genes. This study is the first to report that proprioception, expressed as movement sense, position sense, and force sense, is substantially heritable, and it is conceivable that this may have implications for motor learning and control, neural development, and neurorehabilitation. PMID- 29517421 TI - Development of a polarized pancreatic ductular cell epithelium for physiological studies. AB - Pancreatic ductular epithelial cells comprise the majority of duct cells in pancreas, control cystic fibrosis transmembrane conductance regulator (CFTR) dependent bicarbonate ([Formula: see text]) secretion, but are difficult to grow as a polarized monolayer. Using NIH-3T3-J2 fibroblast feeder cells and a Rho associated kinase inhibitor, we produced well-differentiated and polarized porcine pancreatic ductular epithelial cells. Cells grown on semipermeable filters at the air-liquid interface developed typical epithelial cell morphology and stable transepithelial resistance and expressed epithelial cell markers (zona occludens-1 and beta-catenin), duct cell markers (SOX-9 and CFTR), but no acinar (amylase) or islet cell (chromogranin) markers. Polarized cells were studied in Ussing chambers bathed in Krebs-Ringer [Formula: see text] solution at 37 degrees C gassed with 5% CO2 to measure short-circuit currents ( Isc). Ratiometric measurement of extracellular pH was performed with fluorescent SNARF-conjugated dextran at 5% CO2. Cells demonstrated a baseline Isc (12.2 +/- 3.2 MUA/cm2) that increased significantly in response to apical forskolin-IBMX (? Isc: 35.4 +/- 3.8 MUA/cm2, P < 0.001) or basolateral secretin (? Isc: 31.4 +/- 2.5 MUA/cm2, P < 0.001), both of which increase cellular levels of cAMP. Subsequent addition of apical GlyH-101, a CFTR inhibitor, decreased the current (? Isc: 20.4 +/- 3.8 MUA/cm2, P < 0.01). Extracellular pH and [Formula: see text] concentration increased significantly after forskolin-IBMX (pH: 7.18 +/- 0.23 vs. 7.53 +/- 0.19; [Formula: see text] concentration, 14.5 +/- 5.9 vs. 31.8 +/- 13.4 mM; P < 0.05 for both). We demonstrate the development of a polarized pancreatic ductular epithelial cell epithelium with CFTR-dependent [Formula: see text] secretion in response to secretin and cAMP. This model is highly relevant, as porcine pancreas physiology is very similar to humans and pancreatic damage in the cystic fibrosis pig model recapitulates that of humans. NEW & NOTEWORTHY Pancreas ductular epithelial cells control cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion. Their function is critical because when CFTR is deficient in cystic fibrosis bicarbonate secretion is lost and the pancreas is damaged. Mechanisms that control pancreatic bicarbonate secretion are incompletely understood. We generated well-differentiated and polarized porcine pancreatic ductular epithelial cells and demonstrated feasibility of bicarbonate secretion. This novel method will advance our understanding of pancreas physiology and mechanisms of bicarbonate secretion. PMID- 29517425 TI - INVESTIGATIONS INTO CAUSES OF NEUROLOGIC SIGNS AND MORTALITY AND THE FIRST IDENTIFICATION OF SARCOCYSTIS CALCHASI IN FREE-RANGING WOODPECKERS IN GERMANY. AB - Between June and November 2015, 25 woodpeckers (Picidae) with neurologic signs or unknown cause of death were admitted to a veterinary clinic. Alive birds were clinically examined. Birds that were found dead or died despite intensive care treatment were forwarded to a pathologic examination. Necropsy and subsequent tests included screening for several infectious agents and toxins. Three birds tested positive for Sarcocystis calchasi. Toxoplasma gondii was detected in one bird demonstrating intracerebral cysts. Mycoplasma gypis was detected in one woodpecker in the absence of respiratory signs. Several microbial pathogens (eg, Aspergillus fumigatus, Clostridium perfringens, and Escherichia coli) were isolated from single individuals. However, there was no consistent finding in all birds that could explain nervous signs and mortality of the woodpeckers examined. To the authors' knowledge, M. gypis and S. calchasi were detected in a woodpecker for the first time in this study. PMID- 29517426 TI - COMPARISON OF INTRAMUSCULAR FENTANYL-MIDAZOLAM, FENTANYL-MIDAZOLAM-KETAMINE, AND KETAMINE-MEDETOMIDINE FOR IMMOBILIZATION OF JAPANESE MACAQUES ( MACACA FUSCATA). AB - The combination of fentanyl and midazolam is commonly used as a sedative in humans. The objective of this study was to evaluate the sedative properties and physiological effects of fentanyl-midazolam and fentanyl-midazolam-ketamine compared with medetomidine-ketamine given intramuscularly in Japanese macaques ( Macaca fuscata). In a randomized crossover design, eight Japanese macaques were hand-injected with either 30 MUg/kg fentanyl + 0.3 mg/kg midazolam (FM), 15 MUg/kg fentanyl + 0.3 mg/kg midazolam + 5.0 mg/kg ketamine (FMK), or 0.05 mg/kg medetomidine + 5.0 mg/kg ketamine (MedK). Heart rate; indirect systolic, mean, and diastolic arterial pressure; respiratory rate; blood gas concentrations; rectal temperature; and duration of immobilization were recorded. Mixed linear models were used to evaluate the effects of drug treatment on all continuous variables, with a significance level of P < 0.05. Only three of seven animals receiving FM were successfully immobilized. All eight animals in both the FMK and MedK treatment groups had a rapid, smooth induction and were successfully immobilized. Both FMK and MedK treatments resulted in significant hypoxia and the animals required supplemental oxygen via face mask. The mean duration of FMK immobilization was 42 +/- 10 min, significantly shorter than the 65 +/- 14 min for the animals receiving MedK. Immobilization with MedK resulted in significantly lower heart rates, and significantly higher arterial pressure compared with FMK. Hypoventilation was significantly more pronounced in FMK treated animals compared with MedK treatments. Immobilization with FMK resulted in a gradual, slow recovery whereas MedK-treated animals woke up more rapidly. Fentanyl-midazolam alone is not a useful sedative in Japanese macaques. A combination of fentanyl and midazolam with ketamine can be used as an alternative to medetomidine-ketamine in this species. PMID- 29517427 TI - INVESTIGATION OF THE TRACHEAL MUCOCILIARY CLEARANCE IN SNAKES WITH AND WITHOUT BOID INCLUSION BODY DISEASE AND LUNG PATHOLOGY. AB - Pneumonia is a common complication of boid inclusion body disease (BIBD) in snakes. The tracheal mucociliary apparatus of eight boas ( Boa constrictor) and two pythons ( Python regius, Morelia viridis) was examined to assess whether absent or reduced mucociliary clearance could be a predisposing factor. Nine of the examined snakes were positive for BIBD by detection of inclusion bodies and three had lung pathologies other than the formation of inclusion bodies. A considerable individual variation of ciliary beat frequency (CBF, 3.0 +/- 0.75 Hz to 7.8 +/- 1.27 Hz), transport speed (23.1 +/- 12.56 MUm/sec to 189.2 +/- 41.17 MUm/sec), and transport direction (-12.5 degrees +/- 11.43 degrees to 36.1 degrees +/- 7.53 degrees ) was found. CBFs of the BIBD-affected snakes with or without lung pathologies were markedly lower than ranges published for birds or mammals, but the net transport speeds and directions lay well within. The present investigation does therefore not reveal any signs of an inadequate mucociliary clearance in BIBD-affected snakes. PMID- 29517428 TI - VERY LOW INFLUENZA A VIRUS PREVALENCE IN CERVIDS IN GERMAN NATIONAL PARKS. AB - Influenza A viruses are one of the most important and most studied pathogens in humans and domestic animals but little is known about viral prevalence in non avian wildlife. Serum samples from three free-ranging cervid species (red [ Cervus elaphus], fallow [ Dama dama] , and roe deer [ Capreolus capreolus]) were collected from six German national parks between 2000 and 2002. The serum was tested for the presence of influenza A antibodies using a commercial competitive enzyme-linked immunosorbent assay. Only one of 137 samples tested positive. PMID- 29517429 TI - TREATMENT OF MYCOTIC RHINOSINUSITIS IN A BENNETT'S WALLABY ( MACROPUS RUFOGRISEUS) USING TOPICAL VORICONAZOLE SUSPENDED IN A REVERSE THERMODYNAMIC PLURONIC GEL. AB - An approximately 4-yr-old female Bennett's wallaby ( Macropus rufogriseus) was evaluated for chronic left-sided facial swelling and nasal discharge. Computed tomography, endoscopy, biopsy, mycologic culture, and panfungal polymerase chain reaction were consistent with destructive mycotic rhinosinusitis. The patient's infection was treated with a long-term injectable antibiotic, oral antifungal therapy, and multiple intranasal infusions of voriconazole suspended in a reverse thermodynamic pluronic gel. This case represents the first documented case of mycotic rhinosinusitis in a macropod and underlines the importance of advanced cross-sectional imaging in the diagnosis, monitoring, and management of nasal cavity disease in zoo animals. PMID- 29517430 TI - CLINICOPATHOLOGIC FEATURES OF INFECTION WITH NOVEL BRUCELLA ORGANISMS IN CAPTIVE WAXY TREE FROGS ( PHYLLOMEDUSA SAUVAGII) AND COLORADO RIVER TOADS ( INCILIUS ALVARIUS). AB - Two novel and distinct Brucella strains were recovered from 5 of 10 adult, sex undetermined, captive waxy tree frogs ( Phyllomedusa sauvagii) and two of five adult, sex undetermined, captive Colorado river toads ( Incilius alvarius) held in a zoologic collection with clinical and pathologic findings of bacterial disease. These amphibians originated from three separate private breeding facilities over several years and exhibited disease 9-49 mo following release from quarantine. Common presenting signs were vague but included focal abscessation, weight loss, change in coloration, anorexia, and decreased perching. Two waxy tree frogs and one Colorado river toad recovered with supportive care and antimicrobial treatment based on susceptibility testing. Microgranulomatosis, subcutaneous and renal abscessation, femoral osteomyelitis, and multicentric infection were the most common histologic findings. The organisms were identified antemortem in samples from subcutaneous abscesses, cloaca, and skin and from a variety of organ systems postmortem, and demonstrated a consistent susceptibility pattern. Initial isolates were misidentified as Ochrobactrum anthropi. Polymerase chain reaction and sequencing of the 16S rRNA gene identified the two organisms as novel Brucella strains similar to Brucella inopinata-like sp. and other novel organisms within the emerging "BO clade." Brucella strain oaks (isolated from waxy tree frogs) and Brucella strain leathers (isolated from Colorado river toads) differed from each other by 16 of 571 base pairs in a region of chromosome 2, and did not closely match any previous GenBank entries. This report describes the clinicopathologic features of infection by these bacteria in two amphibian species and expands the range of novel Brucella organisms from amphibian reservoirs. PMID- 29517431 TI - CARDIOVASCULAR EFFECTS OF ALFAXALONE AND PROPOFOL IN THE BULLFROG, LITHOBATES CATESBEIANUS. AB - Alfaxalone is becoming a popular anesthetic for nonmammalian vertebrates, but the physiological effects of its administration remain largely unknown in these taxa. Therefore, the cardiovascular responses to a clinically relevant dose of alfaxalone (10 mg/kg) are reported in the bullfrog ( Lithobates catesbeianus), following intramuscular (IM) and intravascular (IV) administration (via a femoral artery catheter) and compared with an IV dose of propofol, another parenteral GABA (gamma-aminobutyric acid) agonist in common veterinary use as an induction agent. Heart rate (HR) and mean arterial blood pressure (MAP) (assessed by direct measurement from the catheter) are reported from under undisturbed conditions to assess both the direct effects of the drugs and the interaction with the stress of handling associated with IM injection of alfaxalone where IM administration is possible. Alfaxalone caused HR to increase significantly for over 45 min in both groups from a baseline of approximately 30 beats/min. This was significantly different from the lack of significant HR response on the IV administration of propofol. MAP increased in the peri-injection period with both routes of administration for alfaxalone but after IV use decreased significantly from 10 min following administration. Propofol did not affect blood pressure after 5 min from injection. Assessment of immobilization following intramuscular injection of alfaxalone in a pilot study was in accordance with the literature, as it provided no antinociception as a sole agent but did produce sedation and loss of righting reflex. PMID- 29517432 TI - A TECHNIQUE FOR DEPLOYMENT OF RUMEN BOLUS TRANSMITTERS IN FREE-RANGING MOOSE ( ALCES ALCES). AB - Recent uses for rumen boluses, such as mortality implant transmitters (MITs), in wildlife have made it necessary to adapt deployment techniques developed for livestock. In 29 and 30 attempts to place MITs in Minnesota free-ranging moose ( Alces alces) in 2013 and 2014, respectively, success was achieved 83% and 63% of the time. In 2014, new methods for MIT deployment were evaluated in captive moose in Alaska. Mandible measurements provided guidance for selection of an appropriate-sized bolus applicator. A Schulze mouth gag was used to aid insertion of the applicator, and canola oil was used to lubricate the bolus to facilitate swallowing. Time to first swallow and time to continuous swallow following sedative reversal was measured to gauge appropriate timing for bolus administration. Using the adapted technique with trained personnel, success rates for MIT deployment were 100% (10/10) for captive moose and 88% (21/24) for free ranging moose in Minnesota in 2015. PMID- 29517433 TI - BENIGN IDIOPATHIC ESOPHAGEAL STRICTURE IN A LION ( PANTHERA LEO): DILATION BY AN ACHALASIA BALLOON. AB - A 1-yr old female lion ( Panthera leo) was referred with a 10-mo history of dysphagia for solid food (meat), episodic regurgitation, and poor weight gain. Esophagoscopy confirmed an esophagitis (midesophagus) and a stricture estimated to be of 13 mm diameter. This was subsequently dilated using a 20-mm-diameter balloon for 2 min followed by a 35-mm achalasia balloon for 3 min. The etiology remains undetermined in spite of a thorough history. The animal progressed satisfactorily, reaching 124 kg after 1 yr and has had no further signs. To the authors' knowledge, neither idiopathic esophageal stricture nor dilation using an achalasia balloon has been reported in Panthera spp. PMID- 29517434 TI - DETECTION OF OPHIDIOMYCES OPHIODIICOLA IN TWO CAPTIVE BOCOURT WATER SNAKES ( SUBSESSOR BOCOURTI) AND ONE CAPTIVE PUEBLAN MILK SNAKE ( LAMPROPELTIS TRIANGULUM CAMPBELLI). AB - Two captive Bocourt water snakes ( Subsessor bocourti) presented with chronic white skin lesions on their heads; Ophidiomyces ophiodiicola was identified by culture and polymerase chain reaction (PCR) in skin scrapings from both snakes. Histopathology performed in one Bocourt water snake revealed fungal hyphae in epidermal structures of lesions. One Pueblan milk snake ( Lampropeltis triangulum campbelli) from the same zoologic institution presented with yellow crusts and white blisters on its body, from which O. ophiodiicola was identified by culture and PCR. Two of the three snakes apparently recovered from lesions after multiple natural sheds, whereas the third snake died. This is the first report of O. ophiodiicola infection in Bocourt water snakes and in a Pueblan milk snake, as well as the first report of O. ophiodiicola in France. PMID- 29517435 TI - ATYPICAL CHLAMYDIACEAE IN WILD POPULATIONS OF HAWKS ( BUTEO SPP.) IN CALIFORNIA. AB - Chlamydiaceae bacteria infect many vertebrate hosts, and previous reports based on polymerase chain reaction (PCR) assays and serologic assays that are prone to cross-reaction among chlamydial organisms have been used to describe the prevalence of either DNA fragments or antibodies to Chlamydia spp. in wild raptorial populations. This study reports the PCR-based prevalence of Chlamydiaceae DNA that does not 100% match any avian or mammalian Chlamydiaceae in wild populations of hawks in California Buteo species. In this study, multimucosal swab samples ( n = 291) for quantitative PCR (qPCR) and plasma ( n = 78) for serology were collected from wild hawks. All available plasma samples were negative for antibodies using a C. psittaci-specific elementary body agglutination test (EBA; n = 78). For IgY antibodies all 51 available samples were negative using the indirect immunofluorescent assay. The overall prevalence of Chlamydiaceae DNA detection in wild Buteo species sampled was 1.37% (4/291) via qPCR-based analysis. Two fledgling Swainson's hawks ( Buteo swainsoni) and two juvenile red-tailed hawks ( Buteo jamaicensis) were positive by qPCR-based assay for an atypical chlamydial sequence that did not 100% match any known C. psittaci genotype. Positive swab samples from these four birds were sequenced based on the ompA gene and compared by high-resolution melt analysis with all known avian and mammalian Chlamydiaceae. The amplicon sequence did not 100% match any known avian chlamydial sequence; however, it was most similar (98.6%) to C. psittaci M56, a genotype that is typically found in muskrats and hares. Culture and full genome sequence analysis of Chlamydia spp. isolated from diseased hawks will be necessary to classify this organism and to better understand its epizootiology and potential health impact on wild Buteo populations in California. PMID- 29517436 TI - IRON STORAGE DISEASE IN AFRICAN GREY PARROTS ( PSITTACUS ERITHACUS) EXPOSED TO A CARNIVOROUS DIET. AB - Within a 2-wk period, three African grey parrots ( Psittacus erithacus) presented for emergency treatment. All three parrots had depressed behavior, an inability to fly, and significant weight loss. Plasma chemistry abnormalities included severe hypoproteinemia and elevated liver enzymes in all parrots. Two of the parrots died, and histologic examination with hematoxylin and eosin and Prussian blue stains revealed severe hepatic iron storage. Quantitative analysis confirmed high hepatic iron concentrations. Iron accumulation was attributed to ingestion of a carnivorous bird diet or selectively eating too much fruit and vegetables high in ascorbic acid. Management entailed husbandry changes including switching the remaining parrots to a low-iron diet. Psittacine species exposed to carnivorous bird diets are at risk of developing iron storage disease. PMID- 29517437 TI - GASTROINTESTINAL PARASITES IN CAPTIVE AND FREE-RANGING BIRDS AND POTENTIAL CROSS TRANSMISSION IN A ZOO ENVIRONMENT. AB - Gastrointestinal parasites are commonly reported in wild birds, but transmission amongst avifauna in zoological settings, and between these captive birds and wild birds in surrounding areas, remains poorly understood. A survey was undertaken to investigate the occurrence of gastrointestinal parasites in captive and free ranging birds at Bristol Zoo Gardens between May and July 2016. A total of 348 fecal samples from 32 avian species were examined using the Mini-FLOTAC flotation method. Parasites were detected in 31% (45/145) of samples from captive birds and in 65.5% (133/203) of samples from free-ranging birds. Parasites of captive individuals included ascarids ( Heterakis spp. and other morphotypes), capillarids, oxyurids, strongyles, a trematode, and protozoans ( Eimeria spp., Isospora spp., Caryospora sp., and Entamoeba spp.). Parasites of free-ranging birds included ascarids ( Ascaridia spp., Porrocaecum spp., and other morphotypes), capillarids, oxyurids, strongyles ( Syngamus spp. and other morphotypes), cestodes ( Choanotaenia spp., Hymenolepis spp., and other morphotypes), a trematode, and protozoans ( Eimeria spp., Isospora spp., Entamoeba spp.). Similar types of parasites were detected in captive and free ranging birds, but capillarid ova morphology was similar only between closely related species, eg in corvids (captive azure-winged magpies [ Cyanipica cyana] and wild jackdaws [ Corvus monedula]) and between wild columbids (collared doves [ Streptopelia decaocto], rock doves [ Columba livia], and wood pigeons [ Columba palumbus]). The prevalence and intensity of nematodes and coccidia in birds housed outdoors did not differ statistically from species housed indoors. Results indicate that captive and free-ranging birds may share parasites when closely related, but this would need to be confirmed by the study of adult specimens and molecular tests. Determining which parasites are present in captive and free ranging species in zoological parks will support the establishment of effective husbandry practices to maintain the health status of managed species. PMID- 29517438 TI - HISTOPATHOLOGIC CHARACTERISTICS OF THYROID GLAND NEOPLASMS IN THOMSON'S GAZELLES ( EUDORCUS THOMSONII). AB - Published reports of neoplasms in Thomson's gazelles ( Eudorcas thomsonii) are very rare, but thyroid tumors were the most common neoplasm of this species, accounting for 12% of reported pathologies in a 1998-2012 retrospective study of cases submitted for histologic review of grossly enlarged thyroid glands. This report describes the histological and immunohistochemical characteristics of thyroid neoplasms in 10 Thomson's gazelles from five different zoological collections. Neoplasms were submitted as biopsies from six gazelles or collected during necropsy from four gazelles. The most common clinical findings included a palpable mass on the ventral neck and progressive weight loss. Radiographic mineral density was detected in one of the neoplastic masses. Histologically, the neoplasms were classified as microfollicular thyroid adenoma ( n = 2), solid thyroid adenoma ( n = 2), papillary thyroid adenoma ( n = 1), and solid thyroid carcinoma ( n = 5). Neoplastic cells in all 10 neoplasms were positive for thyroid transcription factor 1 and thyroglobulin, but negative for calcitonin. While five cases had histologic features of malignancy, there was no evidence of metastatic disease either clinically (biopsies) or on necropsy. Numerous concurrent diseases, including cardiomyopathies and nephropathies, were present and led to choice for euthanasia in several cases. PMID- 29517439 TI - REFERENCE RANGES AND AGE-RELATED AND DIVING EXERCISE EFFECTS ON HEMATOLOGY AND SERUM CHEMISTRY OF FEMALE STELLER SEA LIONS ( EUMETOPIAS JUBATUS). AB - Decreased health may have lowered the birth and survival rates of Steller sea lions ( Eumetopias jubatus) in the Gulf of Alaska and Aleutian Islands over the past 30 yr. Reference ranges for clinical hematology and serum chemistry parameters needed to assess the health of wild sea lion populations are limited. Here, blood parameters were serially measured in 12 captive female Steller sea lions ranging in age from 3 wk to 16 yr to establish baseline values and investigate age-related changes. Whether diving activity affects hematology parameters in animals swimming in the ocean compared with animals in a traditional aquarium setting was also examined. Almost all blood parameters measured exhibited significant changes with age. Many of the age-related changes reflected developmental life history changes, including a change in diet during weaning, an improvement of diving capacity, and the maturity of the immune system. Mean corpuscular hemoglobin and mean corpuscular volume were also higher in the ocean diving group compared with the aquarium group, likely reflecting responses to increased exercise regimes. These data provide ranges of hematology and serum chemistry values needed to evaluate and compare the health and nutritional status of captive and wild Steller sea lions. PMID- 29517440 TI - HEMATOLOGIC EVALUATION IN GUANS ( PENELOPE OBSCURA) UNDER PHYSICAL RESTRAINT AND ISOFLURANE ANESTHESIA. AB - Hematology is an important health indicator in birds, but the stress from capture or anesthesia can cause alterations in blood count. This study aimed to evaluate the differences found in blood counts among guans ( Penelope obscura) under physical restraint and anesthetized with isoflurane. Thirty-two free-range guans from the Brazilian Institute of Environment and Renewable Natural Resources (IBAMA) Park were enrolled in the study. After physical restraint, blood samples were obtained from the ulnar vein and placed in heparinized tubes. The birds were anesthetized with isoflurane and after 45 min, when the animals were still anesthetized, a blood sample from the jugular vein was collected. Data were analyzed by paired t-test, and the differences were analyzed with Tukey's test. Decreases in red blood cell counts, hemoglobin concentrations, and packed cell volumes, and increased mean corpuscular hemoglobin concentrations were observed when animals were under general anesthesia. Decreases in total plasma protein, fibrinogen, and thrombocytes were detected after anesthesia. It was concluded that isoflurane influences the hematologic parameters, and those effects should be considered when interpreting hematologic values. PMID- 29517441 TI - AGE-RELATED CHANGES IN HEMATOLOGY AND BLOOD BIOCHEMISTRY VALUES IN ENDANGERED, WILD RING-TAILED LEMURS ( LEMUR CATTA) AT THE BEZA MAHAFALY SPECIAL RESERVE, MADAGASCAR. AB - The health of 44 wild ring-tailed lemurs ( Lemur catta) at the Beza Mahafaly Special Reserve was assessed across three age classes: <5 yr (young), 5-9 yr (adult), and >=10 yr (old). Hematology and biochemistry tests were performed manually (leukocyte count and differential, packed cell volume, total protein) and using a point-of-care analyzer (hematocrit, hemoglobin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, ionized calcium, total carbon dioxide, anion gap), respectively. Urine specific gravity was measured via refractometry. Age- and sex-related differences were detected. Old lemurs had significantly lower lymphocyte count than adult and young lemurs, leading to markedly lower total leukocyte count and higher neutrophil-to-lymphocyte ratio. Decreased lymphocyte count with advanced age is consistent with immunosenescence. Young lemurs had significantly higher total protein, monocyte count, and potassium than adult and old lemurs but significantly lower ionized calcium than adult lemurs. Males had significantly higher leukocyte, neutrophil, and monocyte counts; lower percentage basophils; and higher blood urea nitrogen than females. Females had markedly higher glucose than males. Young females had the highest monocyte count and total protein, which were significantly lower in the adult and old age classes. Basophil count was stable in females across age but dropped precipitously in males in the adult and old age classes. Within adult and old age classes, males had significantly higher blood urea nitrogen and lower basophils than females. Glucose was significantly higher after alpha2 agonist administration. Identifying age-related hematologic and biochemical changes in apparently healthy wild ring-tailed lemurs will aid in clinical diagnosis and treatment of lemurs in human care, which is especially relevant for management of geriatric animals in zoo populations. Equally important, a better understanding of the ability of aging lemurs to tolerate environmental stressors will inform the capacity for this species to cope with ongoing and future habitat alteration. PMID- 29517442 TI - BASELINE CORTICOSTERONE, HEMATOLOGY, AND BIOCHEMISTRY RESULTS AND CORRELATIONS TO REPRODUCTIVE SUCCESS IN NESTING LOGGERHEAD SEA TURTLES ( CARETTA CARETTA). AB - Characterizing the health status and reproductive success of wild populations of sea turtles can be difficult; however, obtaining data to do this can provide important insight into the stability and long-term success of a population. This study examined the use of baseline corticosterone to assess reproductive success of a population of nesting loggerhead sea turtles ( Caretta caretta) on Jekyll Island, Georgia and investigated hematological and biochemical trends in this population. A total of 37 nesting loggerhead sea turtles was sampled for this study. Eleven (29.7%) turtles were sampled in 2013 and 26 (70.3%) were sampled in 2014. A majority of the turtles sampled successfully nested (29/37, 78.4%; false crawls: 8/37, 21.6%). There was no significant correlation between baseline corticosterone concentrations and reproductive success (hatch success or emergence success) in this population. There was a significant positive correlation ( r = 0.461, P = 0.02) between corticosterone concentrations and absolute monocyte counts. There was a significant negative correlation between monocyte count and hatch success ( r = -0.464, P = 0.05) and a positive correlation between phosphorus and hatch success ( r = 0.405, P = 0.05). Calcium concentrations were significantly different ( P = 0.01) between animals that false crawled and those that nested, with nesting turtles having lower calcium concentrations than those that false crawled. Turtles that false crawled were significantly ( P = 0.008) more likely to have elevated potassium concentrations than turtles that nested. This study provides the first attempt at characterizing baseline corticosterone, hematology, and biochemistry data and correlations with reproductive success in nesting loggerhead sea turtles. Overall, loggerhead sea turtles capable of nesting were found to be in good health and have good reproductive success while maintaining low levels of corticosterone during reproductive activities. PMID- 29517443 TI - SELECTED OPHTHALMIC PARAMETERS AND POTENTIAL RISK FOR LIGHT-INDUCED CATARACTS IN TWO COLONIES OF CAPTIVE INDIAN FLYING FOXES ( PTEROPUS GIGANTEUS). AB - Indian flying foxes ( Pteropus giganteus) are adapted to visual foraging in dim light. Nine Indian flying foxes were taken from a captive colony of 25 animals and placed in quarantine, off exhibit, in preparation for shipment to another institution. The exhibit had indirect, natural sunlight and was large enough to allow for flight. The quarantine enclosure was subject to >12 hr/day artificial lighting and did not allow for flight or gliding. Diet was identical between groups. After 13 mo, ophthalmic examination was performed on each animal including evaluation of the anterior chamber, rebound tonometry in upright and hanging positions, measurement of palpebral fissure length, and vertical and horizontal corneal diameters. Bilateral cataracts were observed in 55% (5/9) of the quarantined animals but in none of the animals that remained on exhibit (0/16). Bats housed in the quarantine enclosure had a risk of having cataracts 18 times greater than did bats in the exhibit enclosure (relative risk [RR]: 18.70; 95% confidence interval [CI]: 1.15-303.77). There was no association between cataract presence and age (odds ratio [OR]: 0.99; 95% CI: 0.97-1.02; P = 0.7) or sex (OR: 1.24; 95% CI: 0.17-9.25), but lower body weight was associated with presence of cataracts (OR: 0.98; 95% CI: 0.96-0.99). Other ophthalmic parameters observed were similar to those previously reported for other captive Megachiroptera. This study suggests that chronic exposure to artificial lighting predisposes fruit bats to developing light-induced cataracts. PMID- 29517444 TI - SURGICAL MANAGEMENT OF UTERINE LESIONS IN TWO CAPTIVE ORANGUTANS ( PONGO SPP.). AB - Uterine lesions in two orangutans were effectively managed with surgical intervention. A 26-year-old hybrid orangutan ( Pongo spp.) was diagnosed with uterine adenomyosis based on advanced imaging. Histologic evaluation identified multifocal myometrial endometriosis, a variant of adenomyosis. A 27-year-old Bornean orangutan ( Pongo pygmaeus) was diagnosed with a focal uterine fibroid based on histologic examination. The animals were housed at separate institutions and initially presented with dysmenorrhea and menorrhagia. Both animals were treated intermittently for episodes of dysmenorrhea, with recurrence of clinical signs after each treatment. Due to the lack of consistent response to medical management, an ovariohysterectomy in the hybrid orangutan and a myomectomy in the Bornean orangutan were performed and resulted in complete resolution of clinical signs. Surgical management of adenomyosis and neoplasia has previously been reported in nonhuman primates. These cases are the first known documentation of surgical management of multifocal myometrial endometriosis and a fibroid in orangutans. PMID- 29517445 TI - FECAL PROGESTERONE METABOLITES IN POSTPARTUM SIBERIAN FLYING SQUIRRELS. AB - The Siberian flying squirrel ( Pteromys volans) produces up to two litters a year. To deliver second litters in breeding season, P. volans may have a postpartum estrus similarly to that of a variety of small mammals. If this were the case, females would have periods of elevated progesterone levels because of the formation of corpora lutea (CL) after postpartum ovulation. To test this hypothesis, fecal progesterone metabolite dynamics was investigated during lactation in this species using an enzyme immunoassay. In five of the six lactating females, periods of high fecal progesterone metabolite concentration were observed, and, furthermore, progesterone secretion patterns were periodic. Therefore, the source of progesterone during lactation could be arising CL from postpartum ovulation, indicating that ovarian activity was reinitiated after parturition and the CL that formed began secreting progesterone. This study thus showed that P. volans likely has the physiologic potential to mate during lactation. PMID- 29517446 TI - ASPIRATION PNEUMONIA IN TWO TIBETAN YAK BULLS ( BOS GRUNNIENS) AS A COMPLICATION OF KETAMINE-XYLAZINE-BUTORPHANOL ANESTHESIA FOR RECUMBENT CASTRATION. AB - Among members of the genus Bos, aspiration pneumonia has been described in domestic cattle ( Bos taurus and Bos indicus). In these species, aspiration pneumonia is most commonly a sequelae to oral administration of fluids or medications, as well as aspiration during procedures under anesthesia. Management of aspiration pneumonia secondary to complications from anesthesia for short duration surgical procedures is minimally reported in the Tibetan yak ( Bos grunniens). Although regurgitation under anesthesia has been reported in the yak, there are no reports of aspiration pneumonia treatment. This case report describes the diagnosis and management of aspiration pneumonia in two Tibetan yaks undergoing castration under injectable ketamine-xylazine-butorphanol anesthesia. This case report also describes the gross and pathologic characteristics of anesthesia-induced aspiration pneumonia in one Tibetan yak, as well as successful treatment in another. PMID- 29517448 TI - CLINICAL EFFECT OF HEMOPARASITE INFECTIONS IN SNOWY OWLS ( BUBO SCANDIACUS). AB - Vector-borne hemoparasites are commonly found in avian species. Plasmodium spp., the causative agent of avian malaria, are intraerythrocytic parasites that can cause signs ranging from subclinical infection to severe acute disease. In raptor species, most hemoparasites are associated with subclinical infection and are generally not treated when seen on blood evaluation. This case series reviews five cases of hemoparasite infection in snowy owls ( Bubo scandiacus). These animals were infected with a variety of hemoparasites, including Plasmodium, Haemoproteus, and Leukocytozoon spp. Death of one of these birds due to hemoparasite burden led to a change in the monitoring for and treatment of subclinical hemoparasitic infections in this species. Three subsequently infected snowy owls have been treated with primaquine and chloroquine. The birds that were treated survived infection, and parasite burdens in peripheral blood diminished. Postulated reasons for increased morbidity and mortality associated with hemoparasitic infections in captive snowy owls, as opposed to other raptor species, include stress, concurrent disease, novel pathogen exposure, and elevated environmental temperatures. PMID- 29517447 TI - LESIONS OF THE FEMALE REPRODUCTIVE TRACT IN JAPANESE MACAQUE ( MACACA FUSCATA) FROM TWO CAPTIVE COLONIES. AB - Reproductive lesions have been described in various nonhuman primate species, including rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), baboons ( Papio spp.), squirrel monkeys ( Saimiri sciureus), and chimpanzees ( Pan spp.); however, there are few publications describing reproductive disease and pathology in Japanese macaques ( Macaca fuscata). A retrospective evaluation of postmortem reports for two captive M. fuscata populations housed within zoos from 1982 through 2015 was completed, comparing reproductive diseases diagnosed by gross pathology and histopathology. Disease prevalence, organs affected, and median age at death between the two institutions was also compared. Fifteen female captive M. fuscata, ranging in age from 15 to 29 yr were identified with reproductive tract lesions, including endometriosis, endometritis, leiomyoma, leiomyosarcoma, and adenomyosis. No significant differences were identified in disease prevalence, organs affected, and median age of death between the two institutions. Endometriosis was the most common disease process identified and was found in 10 of the 15 cases (66.7%), followed by leiomyoma (4 of 15; 26.7%). In four cases (26.7%), severe endometriosis and secondary hemorrhage was indicated as the cause of death or the primary reason for humane euthanasia. These findings were compared with a separate population of Japanese macaques managed within a research facility in the United States, with a prevalence of endometriosis of 7.6%. This study discusses possible risk factors and potential treatment options for the management of endometriosis in captive M. fuscata. PMID- 29517449 TI - MELANOMA IN GOLDEN AND KING WILDEBEESTS ( CONNOCHAETES TAURINUS). AB - Pigmentation of the skin is a crucial component in the pathogenesis of melanocytic neoplasms and other skin-related tumors, as melanin is known to function in both the absorbance of ultraviolet radiation and as an antioxidant. Very limited information exists regarding the incidence and metastatic potential of neoplastic conditions of the skin in game animals, especially wildebeests, relative to domestic animals. Four cases of cutaneous melanoma in color-variant golden and king wildebeests ( Connochaetes taurinus) (from 2014 to 2015) in South Africa were investigated. Melanoma in these captive animals was characterized using histopathology, transmission electron microscopy, and an immunohistochemistry panel, which consisted of monoclonal antibodies against three melanocytic markers: Melan A, PNL2, and S100. Overall, 2/4 cases (50%) of the melanocytic neoplasms stained strongly positive for all the melanocytic markers, while 4/4 cases (100%) stained positively for at least one of the markers. Cutaneous melanocytic neoplasia has not been reported in wildebeests; the current study suggests that selection of wildebeests for coat color potentially predisposes to this condition. PMID- 29517450 TI - USE OF GLUE-ON SHOES TO IMPROVE CONFORMATIONAL ABNORMALITIES IN TWO ASIAN ELEPHANTS ( ELEPHAS MAXIMUS). AB - This report describes the use of custom-made, glue-on shoes for the front feet of two female adult Asian elephants ( Elephas maximus) with conformational abnormalities. Both elephants had unequal leg lengths. The first elephant also had bilateral fetlock varus causing recurrent nail infections of the fourth digits of the front feet. The second elephant displayed weight shifting. Over several years, multiple shoe prototypes were tested. The current version is made of two types of shoe rubber, glued together and attached to the pad of the shorter leg with a liquid adhesive. The first elephant also has bilateral wedge pads to offload pressure from the fourth nails. The shoes are removed each month for foot care, then replaced. Within several months of wearing shoes, the first elephant's nail infections healed and the second elephant stopped weight shifting. Both elephants' gaits became smoother. This is the first description of corrective shoeing in elephants. PMID- 29517451 TI - ASSESSING THE EFFICACY OF DESLORELIN ACETATE IMPLANTS (SUPRELORIN) IN ALTERNATIVE PLACEMENT SITES. AB - Hormonal contraception is being increasingly used to manage captive animals in zoological collections. Many of the animals placed on contraception are of genetic importance within captive breeding programs; therefore, it is imperative that the application of contraceptive products minimize potential side effects and facilitate a return to fertility if required. Deslorelin acetate implants (Suprelorin(r)) are one example of a hormonal contraceptive that is frequently used in captivity as they are easy to use and effective in most species. It is hypothesized that removing implants may hasten reversal of contraception treatment; therefore, placement in a location where they can easily be recovered is advocated. In this report, the efficacy and safety of Suprelorin implants placed in their recommended site between the scapulae is compared with alternative placement sites where implants can more easily be located for removal. Using the European Association of Zoos and Aquariums (EAZA) Group on Zoo Animal Contraception (EGZAC) Contraception Database, rates of success, failure, and reversal in 561 records of Suprelorin use in European collections are compared. Of these, 357 have information relating to the location of implant placement. When correctly applied, rates of efficacy were high (>99%) irrespective of placement site. Rates of reversal were 33.3% higher in alternative placement sites, although in most cases it is unknown whether implants were removed or not. In conclusion, the placement of Suprelorin implants in alternative sites does not negatively affect the efficacy, facilitating at the same time implant removal, minimizing potential side effects, and reducing reversal time, allowing for effective use in captive conservation breeding programs. PMID- 29517452 TI - RETROSPECTIVE EVALUATION OF A NOVEL SUSTAINED-RELEASE IVERMECTIN VARNISH FOR TREATMENT OF WOUND MYIASIS IN ZOO-HOUSED ANIMALS. AB - Myiasis is a major disease condition in human and veterinary medicine. Domestic, free-ranging, and zoo-housed animals can be severely affected by myiasis. Depending on case severity, multiple treatment episodes may be indicated and can lead to recurrent capturing, handling stress, and anesthetics, all of which increase the risk of adverse responses (including death) individually and also in the herd. As an insecticide, ivermectin is often used for larval control. A total of 28 individual myiasis cases were retrospectively evaluated, out of which 11 cases were also treated using an ivermectin sustained-release varnish (SRV). The clinical outcome of all cases was assessed and the results suggest that the use of a topical ivermectin SRV (with or without concurrent injectable ivermectin) can reduce handling and treatments, has no adverse effects, and has minimal recurrence of the disease when compared with cases treated without it. PMID- 29517453 TI - SUSPECTED HYPERVITAMINOSIS D IN RED-RUMPED AGOUTI ( DASYPROCTA LEPORINA) RECEIVING A COMMERCIAL RODENT DIET. AB - An 8 yr, intact male red-rumped agouti ( Dasyprocta leporina) was evaluated for weight loss. Examination revealed poor body condition, hypercalcemia, elevated serum 25-hydroxyvitamin D, metastatic calcification of soft tissues, and hyperechoic kidneys. The diet, formulated for laboratory rodents, contained elevated levels of vitamin D3. Histopathology from a female conspecific that died 5 mo prior identified dystrophic mineralization and nephrosclerosis, suggestive of a vitamin D3 toxicity. The male agouti responded well to a dietary reduction in vitamin D3 and calcium. Six months into therapy, progressive renal failure was identified and was further managed with enalapril, phosphorus binders, and dietary manipulation. Suspected vitamin D3 toxicity has been reported in pacas ( Cuniculus paca) and agouti and has been linked to exposure to New World primate diets. In this brief communication, an agouti developed suspected hypervitaminosis D after receiving a commercial rodent diet commonly fed to this species in captivity. PMID- 29517454 TI - RADIOGRAPHIC ABDOMINAL ANATOMY IN CAPTIVE RED PANDAS ( AILURUS FULGENS). AB - The red panda ( Ailurus fulgens) is classified as an endangered species by the International Union for Conservation of Nature and Natural Resources. The aim of this study was to describe the normal radiographic abdominal anatomy in red pandas to provide guidance for clinical use. Radiography of the abdomen was performed in nine captive red pandas during their annual health examinations. Seven of nine animals had six lumbar vertebrae. The sacrum consisted mainly (8/9) of three fused segments. Hypaxial muscles were easily seen in animals weighing 5 kg and above. The pylorus was located to the right of the midline and cranially to the fundus in 8/9 individuals. Bunching of small intestine in the right central abdomen occurred in animals weighing 6 kg and above. The spleen was prominent. Knowledge of the normal radiographic abdominal anatomy of red pandas is important in the diagnosis of diseases and in routine health examinations. PMID- 29517455 TI - PUSTULAR DERMATITIS CAUSED BY IMPETIGO IN RED-TAILED MONKEYS ( CERCOPITHECUS ASCANIUS). AB - Impetigo is a bacterial infection of the superficial layer of the epidermis with crusting or bullae caused by Streptococcus spp., Staphylococcus spp., or both. A 14-yr-old red-tailed monkey ( Cercopithecus ascanius) presented with recurrent scabbing and ulceration under the nares over an 8-yr period. Repeated cultures and biopsy samples led to a presumptive diagnosis of impetigo, later confirmed on necropsy. Multiple antibiotic regimens were employed with varying success during multiple episodes, while lesions resolved on their own at other times. This condition has not been previously reported in a nonhuman primate, although it is not uncommon in humans. PMID- 29517456 TI - ACUTE NONCOMPRESSIVE NUCLEUS PULPOSUS EXTRUSION CAUSING PARAPLEGIA IN A SIBERIAN TIGER ( PANTHERA TIGRIS ALTAICA). AB - A neutered male Siberian tiger ( Panthera tigris altaica) presented with paraplegia of 5 days' duration. Thoracolumbar magnetic resonance imaging (MRI) revealed a focal, linear T2-W hyperintense intramedullary lesion at the level of T10-11 as well as reduced size of the nucleus pulposus of the T10-11 intervertebral disc. The animal was humanely euthanatized as a result of the severity of clinical signs and the poor prognosis. Gross necropsy revealed a dark red, firm focus on the spinal cord at the level of the T11 nerve roots. Histopathology revealed liquefactive necrosis of the ventral spinal cord at the level of T9-11, with hemorrhage and vascular changes within the cord and associated meninges. Fibrovascular tissue with hemorrhage, fibrin, and fragments of cartilage consistent with nucleus pulposus material was identified extradurally at this level. The findings were consistent with acute noncompressive nucleus pulposus extrusion. PMID- 29517457 TI - ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS ASSOCIATED WITH CLOSTRIDIUM PERFRINGENS INFECTION IN TWO ASIAN ELEPHANT ( ELEPHAS MAXIMUS) CALVES. AB - Elephant endotheliotropic herpesvirus (EEHV) is an infection associated with fatal hemorrhagic disease in young Asian elephants ( Elephas maximus). This brief communication describes the postmortem evaluation of two Asian elephant calves diagnosed with EEHV4 and EEHV1A in conjunction with Clostridium perfringens infection. Case 1 was a 7-mo-old, male captive-born Asian elephant that developed diarrhea and died 2 days after clinical presentation. Examination of the heart, lungs, liver, and spleen revealed predominantly basophilic intranuclear inclusion bodies in the endothelial cells of the blood vessels. Case 2 was a 3-mo-old, female wild-born Asian elephant that showed signs of lethargy, anorexia, and convulsions and died 6 hr after clinical presentation. No intranuclear inclusion bodies were observed. The heart, lung, liver, and spleen of both calves tested positive for EEHV by polymerase chain reaction. Phylogenetic analysis identified EEHV4 and EEHV1A in Case 1 and 2, respectively. Additionally, liver, spleen, and hemorrhagic intestinal tissue samples tested positive for C. perfringens alpha, beta, and epsilon toxins. This is the first reported case to describe coinfection of EEHV and C. perfringens in Asian elephant calves. PMID- 29517458 TI - THROMBOELASTOGRAPHY IN THE HEALTHY ASIAN ELEPHANT ( ELEPHAS MAXIMUS): REFERENCE INTERVALS AND EFFECTS OF STORAGE. AB - Hemorrhagic disease associated with elephant endotheliotropic herpesvirus infection is the most-frequent cause of mortality in captive Asian elephants ( Elephas maximus). Survival relies on intensive monitoring of hemostatic status. Thromboelastography (TEG) utilizes whole blood samples containing all the blood components of hemostasis and is therefore a sensitive indicator of the clinical status in the patient. This study was performed to assess the practicability of TEG in Asian elephants in a zoo environment. Citrated stabilized whole blood samples were obtained from 44 healthy Asian elephants. Kaolin-activated TEG was performed on whole blood at 60 min and 24 hr postsampling (to replicate shipment to an external laboratory) as well as on freeze-thawed plasma samples, 12-14 mo postsampling. Reference intervals were calculated for fresh whole blood and freeze-thawed plasma samples. In the 24-hr analysis, storage artifacts, likely due to cellular degeneration, resulted in a hypercoagulable thromboelastogram and thus reduced sensitivity for detecting coagulopathies. Therefore, delayed analysis of whole blood samples is not recommended. PMID- 29517459 TI - A RETROSPECTIVE STUDY OF MORBIDITY AND MORTALITY IN THE NORTH AMERICAN AMUR LEOPARD ( PANTHERA PARDUS ORIENTALIS) POPULATION IN ZOOLOGIC INSTITUTIONS FROM 1992 TO 2014. AB - The Amur leopard ( Panthera pardus orientalis) is one of the most critically endangered leopards on the International Union for the Conservation of Nature red list. The primary objective of this retrospective study was to identify common and significant causes of morbidity and mortality in the North American Amur leopard zoo population. This information provides insights that contribute to their improved care, health, and medical management and, ultimately, affects the sustainability of this leopard subspecies in the wild. Medical records and complete postmortem reports were requested from all North American zoologic institutions that held Amur leopards in their collections from 1992 to 2014. Information from 175 individuals, representing 93% of the population (188 animals), was received. Data were reviewed generally and by subdivision into the following age groups: neonate: 0 day-3 mo ( n = 45); juvenile-young adult: 3 mo-5 yr ( n = 21); adult: 5-10 yr ( n = 17); senior: 10-15 yr ( n = 31); or geriatric: >15 yr ( n = 61). The major causes of morbidity, listed by body system for the study population, excluding neonates, were musculoskeletal (40%), reproductive (24%), dental (19%), cardiopulmonary (13%), gastrointestinal (13%), and urogenital (12%). The two most common causes of death or euthanasia, primarily in senior and geriatric animals, were chronic renal disease and neoplasia; maternal neglect and maternal trauma were most common in neonates. The largest populations in this study were neonates and geriatrics, indicating that if animals survive the neonatal period, they often live into their late teens to early 20s. This is the first comprehensive study of the causes of morbidity and mortality in the Amur leopard zoo population in North America. PMID- 29517462 TI - ERRATUM. PMID- 29517460 TI - SURGICAL MANAGEMENT OF APPENDICULAR LONG-BONE FRACTURES IN FREE-RANGING FLORIDA PANTHERS ( PUMA CONCOLOR CORYI): SIX CASES (2000-2014). AB - The clinical outcomes of six free-ranging Florida panthers ( Puma concolor coryi) that underwent surgical stabilization of appendicular long-bone fractures (three femoral fractures, one tibial and one tibial and fibular fracture and two radial and ulnar fractures) were evaluated. These panthers presented to the University of Florida from 2000-2014. Estimated age of the panthers ranged from 0.5 to 4.5 yr, and weights ranged from 22 to 65 kg. Causes of injuries were vehicular collision ( n = 4) and capture related ( n = 2). All panthers underwent open reduction and fracture stabilization. Fixation failure necessitated three subsequent surgeries in one panther. Five panthers survived the immediate postoperative period, and all of these panthers' fractures obtained radiographic union (range, 8-36 [mean, 22] wk). The five surviving panthers underwent convalescence for 7-14 mo at White Oak Conservation Center before being released back into the wild; however, one panther was killed when hit by a car 3 days after release. The remaining four panthers were tracked for up to 106 mo in the wild and successfully integrated back into the native population. Surgical stabilization of appendicular long-bone fractures in free-ranging Florida panthers can be successful, but must take into account the stress that a large, undomesticated felid will place on the stabilized limb during convalescence as well as the difficulties involved in rehabilitating a wild panther in captivity. PMID- 29517464 TI - AAZV PUBLICATIONS AVAILABLE. PMID- 29517463 TI - PHARMACOKINETICS OF CEFTIOFUR CRYSTALLINE FREE ACID STERILE SUSPENSION IN GREEN IGUANAS ( IGUANA IGUANA) AFTER SINGLE INTRAMUSCULAR ADMINISTRATION. AB - The objective of this study was to establish the pharmacokinetic parameters of ceftiofur crystalline free acid (CCFA) for a single intramuscular injection in green iguanas ( Iguana iguana). Six green iguanas received an injection of 5 mg/kg CCFA into the triceps muscle. Using high-performance liquid chromatography, concentrations of ceftiofur free acid equivalents in plasma samples collected at predetermined time points were evaluated up to 21 days following drug administration. Noncompartmental pharmacokinetic analysis was applied to the data. The observed maximum plasma concentration (Cmax obs) was 2.765 +/- 0.864 MUg/mL, and the time of observed maximum concentration (Tmax obs) was 6.1 +/- 9.2 hr. The area under the curve (0 to infinity) was 239.3 +/- 121.1 MUg.hr/mL. No significant adverse drug reactions were clinically observed, and no visible injection site reactions were noted. Minimum inhibitory concentrations of bacterial isolates from iguanas were used to establish a target plasma concentration of 2.0 MUg/mL. Based on the results from this study, a potential dosing interval for ceftiofur crystalline free acid administered at 5 mg/kg intramuscularly for iguanas maintained at a temperature of 30 degrees C would be 24 hr based on a target plasma concentration of 2 MUg/mL; however, multidose studies still need to be performed. PMID- 29517465 TI - Pteris multifida, Cortex phellodendri, and probiotics attenuated inflammatory status and immunity in mice with a Salmonella enterica serovar Typhimurium infection. AB - Pteris multifida (PM) and Cortex phellodendri (CP) are medicinal foods used for gastrointestinal protection. Lactic-acid bacteria are probiotics. Salmonella Typhimurium strain ST21-infected mice were used to examine the alleviative effects of two lactic-acid bacteria (LAB) as well as aqueous extracts of PM and CP for a 4-day treatment. CP and LAB decreased fecal ST counts. CP and PM reduced the ST21 count in the blood, intestine, and liver. LAB lowered the ST21 count in the intestine and spleen. CP and LAB decreased the IFN-gamma level; PM lowered the TNF-alpha level; and both LAB and PM reduced the IL-1beta level in serum. PM and CP lowered the IgG level in serum. The data in a macrophage infection model indicate that TNF-alpha was partial involved in this alleviative effects, other mechanisms might be involved. In sum, these novel findings suggest that PM, CP, and LAB probiotics are potential anti-Salmonellae agents. PMID- 29517466 TI - Allelic frequencies of 60 pharmacogene variants assessed within a Burmese population residing in northeast Indiana, USA. AB - AIM: The aim of this study was to investigate 60 SNPs pertaining to drug metabolism and pharmacodynamics in the Burmese refugee population in the Fort Wayne, Indiana area to better inform patient care. MATERIALS & METHODS: Sixty-two self-identified Burmese refugees were genotyped for 60 common SNPs pertaining to pharmacokinetic and pharmacodynamic pharmacogenes. The resulting allelic frequencies were compared with Ensembl's database for surrounding populations to Myanmar and America. RESULTS: The frequency of OPRM1, CYP2D6, SLCO1B1, MTHFR and VKORC1 were approximately 20% different in the Burmese refugee population as compared with the Ensembl populations. CONCLUSION: Our study demonstrates that genetic differences are expected to affect drug efficacy in patients with a Burmese background. PMID- 29517467 TI - Editorial: The Expanding Landscape of Graph Theoretic Molecular Descriptors: Development, Gradual Diversification of Descriptor Space, and Applications in QSAR/ QMSA and New Drug Discovery. PMID- 29517468 TI - Editorial: Delving into the Fundamental Aspects of Drug-Receptor Interaction. PMID- 29517469 TI - Preface. PMID- 29517470 TI - Editorial: Cancer Epigenetics. PMID- 29517471 TI - Editorial: Recent Advances of Cell and Gene Therapy in Kidney Diseases. PMID- 29517472 TI - Curved adjustable fibre-optic diode laser in microscopic cholesteatoma surgery: description of use and review of the relevant literature. AB - OBJECTIVE: The use of lasers in cholesteatoma surgery is common and well accepted. The most commonly used laser fibres are straight and non-adjustable; these have several limitations. This paper describes the use of an alternative laser fibre. METHOD: This 'How I Do It' paper describes and illustrates the use of an alternative curved adjustable fibre-optic diode laser in microscopic cholesteatoma surgery. RESULTS: The curved, adjustable laser fibre allows accurate and atraumatic disease removal when the use of a straight laser fibre may be less effective or accurate. It reduces potential damage to delicate structures without the need for extra drilling or bone removal. CONCLUSION: It is suggested that the curved adjustable laser fibre is superior to the traditional straight fibre for cholesteatoma surgery. PMID- 29517473 TI - Nutrition and mental health: bidirectional associations and multidimensional measures. PMID- 29517474 TI - Determinants of re-operation for bleeding in head and neck cancer surgery. AB - OBJECTIVE: Post-operative bleeding in the head and neck area is potentially fatal. This 'real world' study sought to assess factors that increase the risk of re-operation for post-operative bleeding in head and neck cancer surgery. METHODS: A total of 456 patients underwent surgery for head and neck cancer (591 operations). The primary endpoint was re-operation for bleeding. RESULTS: The rate of re-operation for bleeding was 5 per cent of all operations. Re-operation for bleeding was an independent risk factor for 30-day mortality (odds ratio = 5.27, p = 0.014). Risk factors for re-operation because of bleeding included excessive (more than 4000 ml) fluid administration (over 24 hours) (p < 0.001), heavy alcohol consumption (p = 0.014), pre-operative oncological treatment (p = 0.017), advanced disease stage (p = 0.020) and higher tumour (T) classification (p = 0.034). Operations with more excessive bleeding (700 ml or more) were associated with an increased risk (p = 0.001) of re-operation for post-operative bleeding. Moreover, the risk of re-operation was significantly higher in patients undergoing microvascular surgery compared to those who had no oncological treatment pre-operatively (18 vs 6 per cent, p = 0.001). CONCLUSION: The 30-day mortality risk increased over 5-fold in patients undergoing re-operation for bleeding. PMID- 29517475 TI - Rathayibacter oskolensis sp. nov., a novel actinobacterium from Androsace koso poljanskii Ovcz. (Primulaceae) endemic to the Central Russian Upland. AB - A rod-shaped, non-endospore-forming and non-motile bacterium, strain DL-329T, was isolated from the above-ground part of a plant, Androsace koso-poljanskii Ovcz. (Primulaceae), at the the State Natural Reserve 'Belogorie', Russia. On the basis of 16S rRNA gene sequence comparisons, the strain clustered with members of the genus Rathayibacter, showing the highest sequence similarity to Rathayibacter tritici (98.89 %), Rathayibacter rathayi (98.82 %) and Rathayibacter festucae (98.82 %). The DNA hybridization experiments demonstrated that strain DL-329T represents a separate genomic species. The results of comparative studies of physiological and chemotaxonomic characteristics, including cell-wall sugar patterns, polar lipid profiles, and the matrix-assisted laser desorption/ionization time-of-flight mass spectra of bacterial cells, allowed clear differentiation of VKM Ac-2121T from the recognized Rathayibacter species at the phenotypic level. Based on the data obtained, a new species, Rathayibacter oskolensis sp. nov., is proposed, with DL-329T (=VKM Ac-2121T=LMG 22542T) as the type strain. PMID- 29517476 TI - Complete genome characterization of a rotavirus B (RVB) strain identified in Alpine goat kids with enteritis reveals inter-species transmission with RVB bovine strains. AB - Rotavirus B (RVB) has been associated with enteric disease in many animal species. An RVB strain was identified in pooled intestinal samples from Alpine caprine kids (between 2 and 3 days of age) experiencing high (>90 %) morbidity, and the complete caprine RVB genome was characterized. Histology revealed villus atrophy, the samples tested positive for RVB by real-time RT-PCR and metagenomic next-generation sequencing identified only RVB and orf virus. In the VP4 gene segment, the caprine RVB strain had a higher percentage nucleotide identity to the Indian bovine RVB strains than to the Japanese bovine RVB strains, but the VP7, VP6, VP2, NSP1, NSP2 and NSP5 gene segments of the American caprine RVB strain were genetically related to the Japanese bovine RVB strains. The results indicate a lack of RVB sequences to understand reassortment or the evolutionary relationship of RVB strains from cattle and goats. PMID- 29517478 TI - Heterogeneity of clinical isolates of chikungunya virus and its impact on the responses of primary human fibroblast-like synoviocytes. AB - Low-passage clinical isolates of chikungunya virus (CHIKV) were found to be a mixture of large- and small-plaque viruses, with small-plaque viruses being the predominant species. To investigate the contribution of plaque variants to the pathology of the joint, primary human fibroblast-like synoviocytes (HFLS) were used. Large- and small-plaque viruses were purified from two clinical isolates, CHIKV-031C and CHIKV-033C, and were designated CHIKV-031L and CHIKV-031S and CHIKV-033L and CHIKV-033S, respectively. The replication efficiencies of these viruses in HFLSs were compared and it was found that CHIKV-031S and CHIKV-033S replicated with the highest efficiency, while the parental clinical isolates had the lowest efficiency. Interestingly, the cytopathic effects (CPE) induced by these viruses correlated with neither the efficiency of replication nor the plaque size. The small-plaque viruses and the clinical isolates induced cell death rapidly, while large-plaque viruses induced slow CPE in which only 50 % of the cells in infected cultures were rounded up and detached on day 5 of infection. The production of proinflammatory cytokines and chemokines from infected HFLSs was evaluated. The results showed that the large-plaque viruses and the clinical isolates, but not small-plaque variants, were potent inducers of IL-6, IL-8 and MCP-1, and were able to migrate monocytes/macrophages efficiently. Sequencing data revealed a number of differences in amino acid sequences between the small- and large-plaque viruses. The results suggest that it is common for clinical isolates of CHIKV to be heterogeneous, while the variants may have distinct roles in the pathology of the joint. PMID- 29517477 TI - A field strain of minute virus of mice (MVMm) exhibits age- and strain-specific pathogenesis. AB - The influence of mouse strain, immune competence and age on the pathogenesis of a field strain of minute virus of mice (MVMm) was examined in BALB/c, C3H, C57BL/6 and SCID mice experimentally infected as neonates, weanlings and adults. Sera, bodily excretions and tissues were harvested at 7, 14, 28 and 56 days after inoculation and evaluated by serology, quantitative PCR and histopathology. Seroconversion to recombinant viral capsid protein 2 was consistently observed in all immunocompetent strains of mice, regardless of the age at which they were inoculated, while seroconversion to the viral nonstructural protein 1 was only consistently detected in neonate inoculates. Viral DNA was detected by quantitative PCR in multiple tissues of immunocompetent mice at each time point after inoculation, with the highest levels being observed in neonate inoculates at 7 days after inoculation. In contrast, viral DNA levels in tissues and bodily excretions increased consistently over time in immunodeficient SCID mice, regardless of the age at which they were inoculated, with mortality being observed in neonatal inoculates between 28 and 56 days after inoculation. Overall, productive infection was observed more frequently in immunocompetent mice inoculated as neonates as compared to those inoculated as weanlings or adults, and immunodeficient SCID mice developed persistent, progressive infection, with mortality being observed in mice inoculated as neonates. Importantly, the clinical syndrome observed in experimentally infected SCID neonatal mice recapitulates the clinical presentation reported for the naturally infected immunodeficient NOD u-chain knockout mice from which MVMm was initially isolated. PMID- 29517480 TI - An ascovirus isolated from Spodoptera litura (Noctuidae: Lepidoptera) transmitted by the generalist endoparasitoid Meteorus pulchricornis (Braconidae: Hymenoptera). AB - The family Ascoviridae is a recently described virus family whose members are transmitted by parasitoids and cause chronic and lethal infections in lepidopteran insects. Little is known about the biology and ecology of ascoviruses, and few isolates have been found outside the United States. We report here the isolation of a new ascovirus variant from Spodoptera litura in Japan. Full genome sequence and phylogenetic analyses showed that this virus was closely related to variants in Heliothis virescens ascovirus-3a, and it was named HvAV-3j. HvAV-3j has a DNA genome of 191 718 bp, with 189 putative ORFs and a GC content of 45.6 %, and is highly similar to HvAV-3h, which was isolated in China. In a field survey, the endoparasitoid Meteorus pulchricornis caused a high percentage of parasitization in populations of S. litura larvae, and under laboratory conditions M. pulchricornis was able to transmit HvAV-3j from infected to uninfected larvae by oviposition. Meteorus pulchricornis is thus likely to be a major vector for HvAV-3j transmission in Japan. This species is recognized here for the first time as a vector of ascoviruses that parasitizes a range of host species that extends across families. PMID- 29517479 TI - Differential requirements for processing and transport of short-chain versus long chain O-acylcarnitines in Pseudomonas aeruginosa. AB - The opportunistic pathogen Pseudomonas aeruginosa can metabolize carnitine and O acylcarnitines, which are abundant in host muscle and other tissues. Acylcarnitines are metabolized to carnitine and a fatty acid. The liberated carnitine and its catabolic product, glycine betaine, can be used as osmoprotectants, to induce the secreted phospholipase C PlcH, and as sole carbon, nitrogen and energy sources. P. aeruginosa is incapable of de novo synthesis of carnitine and acylcarnitines, therefore they must be imported from an exogenous source. In this study, we present the first characterization of bacterial acylcarnitine transport. Short-chain acylcarnitines are imported by the ABC transporter CaiX-CbcWV. Medium- and long-chain acylcarnitines (MCACs and LCACs) are hydrolysed extracytoplasmically and the free carnitine is transported primarily through CaiX-CbcWV. These findings suggest that the periplasmic protein CaiX has a binding pocket that permits short acyl chains on its carnitine ligand and that there are one or more secreted hydrolases that cleave MCACs and LCACs. To identify the secreted hydrolase(s), we used a saturating genetic screen and transcriptomics followed by phenotypic analyses, but neither led to identification of a contributing hydrolase, supporting but not conclusively demonstrating redundancy for this activity. PMID- 29517481 TI - Hydrophobins contribute to root colonization and stress responses in the rhizosphere-competent insect pathogenic fungus Beauveria bassiana. AB - The hyd1/hyd2 hydrophobins are important constituents of the conidial cell wall of the insect pathogenic fungus Beauveria bassiana. This fungus can also form intimate associations with several plant species. Here, we show that inactivation of two Class I hydrophobin genes, hyd1 or hyd2, significantly decreases the interaction of B. bassiana with bean roots. Curiously, the ?hyd1/?hyd2 double mutant was less impaired in root association than Deltahyd1 or Deltahyd2. Loss of hyd genes affected growth rate, conidiation ability and oosporein production. Expression patterns for genes involved in conidiation, cell wall integrity, insect virulence, signal transduction, adhesion, hydrophobicity and oosporein production were screened in the deletion mutants grown in different conditions. Repression of the major MAP-Kinase signal transduction pathways (Slt2 MAPK pathway) was observed that was more pronounced in the single versus double hyd mutants under certain conditions. The ?hyd1/?hyd2 double mutant showed up regulation of the Hog1 MAPK and the Msn2 transcription factor under certain conditions when compared to the wild-type or single hyd mutants. The expression of the bad2 adhesin and the oosporein polyketide synthase 9 gene was severely reduced in all of the mutants. On the other hand, fewer changes were observed in the expression of key conidiation and cell wall integrity genes in hyd mutants compared to wild-type. Taken together, the data from this study indicated pleiotropic consequences of deletion of hyd1 and hyd2 on signalling and stress pathways as well as the ability of the fungus to form stable associations with plant roots. PMID- 29517482 TI - Amycolatopsis oliviviridis sp. nov., a novel polylactic acid-bioplastic-degrading actinomycete isolated from paddy soil. AB - A novel bioplastic-degrading actinomycete, strain SCM_MK2-4T, was isolated from paddy soil in Thailand. The 16S rRNA gene sequence showed that strain SCM_MK2-4T belonged to the genus Amycolatopsis, with the highest sequence similarity to Amycolatopsisazurea JCM 3275T (99.4 %), and was phylogenetically clustered with this strain along with Amycolatopsislurida JCM 3141T (99.3 %), A. japonica DSM 44213T (99.2 %), A. decaplanina DSM 44594T (99.0 %), A. roodepoortensis M29T (98.9 %), A. keratiniphilasubsp. nogabecina DSM 44586T (98.8 %), A. keratiniphilasubsp. keratiniphila DSM 44409T (98.5 %), A. orientalis DSM 40040T (98.4 %) and A. regifaucium GY080T (98.3 %). A combination of DNA-DNA hybridization results ranging from 42.8+/-3.2 to 66.2+/-1.4 % with the type strains of A. azurea and A. lurida and some different phenotypic characteristics indicated that the strain could be distinguished from its closest phylogenetic neighbours. Whole-cell hydrolysates of the strain were shown to contain meso diaminopimelic acid, arabinose, galactose, glucose, ribose, mannose, rhamnose and xylose. The predominant menaquinone was MK-9(H4). The major cellular fatty acid profile consisted of iso-C15 : 0, iso-C16 : 0, summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2OH) and C16 : 0. The polar lipid composition of the strain consisted of phosphatidyl-N-methylethylethanolamine, phosphatidylethanolamine, hydroxyphosphatidylethanolamine, phosphatidylglycerol, aminophospholipids, an unidentified phospholipid and two unidentified glycolipids. The G+C content of the genomic DNA was 68.2 mol%. On the basis of phylogenetic analyses, DNA-DNA hybridization experimentation and the phenotypic characteristics, it was concluded that strain SCM_MK2-4T represents a novel species of the genus Amycolatopsis, for which the name Amycolatopsis oliviviridis sp. nov. is proposed. The type strain is SCM_MK2-4T (=TBRC 7186T=JCM 32134T). PMID- 29517483 TI - Fish polyomaviruses belong to two distinct evolutionary lineages. AB - The Polyomaviridae is a diverse family of circular double-stranded DNA viruses. Polyomaviruses have been isolated from a wide array of animal hosts. An understanding of the evolutionary and ecological dynamics of these viruses is essential to understanding the pathogenicity of polyomaviruses. Using a high throughput sequencing approach, we identified a novel polyomavirus in an emerald notothen (Trematomus bernacchii) sampled in the Ross sea (Antarctica), expanding the known number of fish-associated polyomaviruses. Our analysis suggests that polyomaviruses belong to three main evolutionary clades; the first clade is made up of all recognized terrestrial polyomaviruses. The fish-associated polyomaviruses are not monophyletic, and belong to two divergent evolutionary lineages. The fish viruses provide evidence that the evolution of the key viral large T protein involves gain and loss of distinct domains. PMID- 29517486 TI - InGaAs/InP quantum wires grown on silicon with adjustable emission wavelength at telecom bands. AB - We report the growth of vertically stacked InGaAs/InP quantum wires on (001) Si substrates with adjustable room-temperature emission at telecom bands. Based on a self-limiting growth mode in selective area metal-organic chemical vapor deposition, crescent-shaped InGaAs quantum wires with variable dimensions are embedded within InP nano-ridges. With extensive transmission electron microscopy studies, the growth transition and morphology change from quantum wires to ridge quantum wells (QWs) have been revealed. As a result, we are able to decouple the quantum wires from ridge QWs and manipulate their dimensions by scaling the growth time. With minimized lateral dimension and their unique positioning, the InGaAs/InP quantum wires are more immune to dislocations and more efficient in radiative processes, as evidenced by their excellent optical quality at telecom bands. These promising results thus highlight the potential of combining low dimensional quantum wire structures with the aspect ratio trapping process for integrating III-V nano-light emitters on mainstream (001) Si substrates. PMID- 29517484 TI - Sumoylation promotes optimal APC/C Activation and Timely Anaphase. AB - The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin E3 ligase that functions as the gatekeeper to mitotic exit. APC/C activity is controlled by an interplay of multiple pathways during mitosis, including the spindle assembly checkpoint (SAC), that are not yet fully understood. Here, we show that sumoylation of the APC4 subunit of the APC/C peaks during mitosis and is critical for timely APC/C activation and anaphase onset. We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core. Our findings provide evidence of an important regulatory role for SUMO modification and binding in affecting APC/C activation and mitotic exit. PMID- 29517485 TI - Single-exposure visual memory judgments are reflected in inferotemporal cortex. AB - Our visual memory percepts of whether we have encountered specific objects or scenes before are hypothesized to manifest as decrements in neural responses in inferotemporal cortex (IT) with stimulus repetition. To evaluate this proposal, we recorded IT neural responses as two monkeys performed a single-exposure visual memory task designed to measure the rates of forgetting with time. We found that a weighted linear read-out of IT was a better predictor of the monkeys' forgetting rates and reaction time patterns than a strict instantiation of the repetition suppression hypothesis, expressed as a total spike count scheme. Behavioral predictions could be attributed to visual memory signals that were reflected as repetition suppression and were intermingled with visual selectivity, but only when combined across the most sensitive neurons. PMID- 29517487 TI - Controlled deposition of size-selected MnO nanoparticle thin films for water splitting applications: reduction of onset potential with particle size. AB - Emulating water oxidation catalyzed by the oxomanganese clusters in the photosynthetic apparatus of plants has been a long-standing scientific challenge. The use of manganese oxide films has been explored, but while they may be catalytically active on the surface, their poor conductivity hinders their overall performance. We have approached this problem by using manganese oxide nanoparticles with sizes of 4, 6 and 8 nm, produced in a sputter-gas-aggregation source and soft-landed onto conducting electrodes. The mass loading of these catalytic particles was kept constant and corresponded to 45%-80% of a monolayer coverage. Measurements of the water oxidation threshold revealed that the onset potential decreases significantly with decreasing particle size. The final stoichiometry of the catalytically active nanoparticles, after exposure to air, was identified as predominantly MnO. The ability of such a sub-monolayer film to lower the reaction threshold implies that the key role is played by intrinsic size effects, i.e., by changes in the electronic properties and surface fields of the nanoparticles with decreasing size. We anticipate that this work will serve to bridge the knowledge gap between bulk thick film electrocatalysts and natural photosynthetic molecular-cluster complexes. PMID- 29517488 TI - Synthesis and characterization of pH-sensitive drinkable nanoparticles for oral delivery of ibuprofen. AB - Ibuprofen (IBU) is a widespread drug used to treat both acute and chronic disorders. It is generally taken orally but the free drug can induce the irritation of the gastric mucosa due to its acid nature. In literature, different approaches have been adopted to prevent the release in the stomach, such as physical entrapment with film-coated tablets and drug-conjugates. Nevertheless, these solutions have many disadvantages, including the fast release of the drug and the difficulty to swallow the tablet, especially for children who may vomit or refuse the tablet. For this reason, in this work, novel formulations are proposed that do not require the encapsulation of the drug into a solid form and, in turn, their assumption as a pill. IBU has been linked to different types of methacrylates via ester bond in order to produce pH-responsive macromolecular monomers. The novelty is related to the use of these drug-conjugates macromonomer for the production of nanoparticles (NPs) via emulsion polymerization (EP), using water as solvent. The final emulsion is able to load up to 30 mg ml-1 of IBU, so less than 10 ml is required to be assumed to reach the minimum therapeutic dose of the drug (200 mg). Finally, the release of IBU from these novel drinkable formulations has been investigated in the gastric and intestinal simulated fluids to show the preferential release of IBU from the NPs in basic conditions. A comparison with an existing oral suspension has been performed to highlight the slower release in acid environment of these new formulations. Afterwards, the IBU loaded NPs were tested in vitro showing lower toxicity compared to the free drug. PMID- 29517489 TI - Facile approach to fabricate BCN/Fe x (B/C/N) y nano-architectures with enhanced electromagnetic wave absorption. AB - Carbon-based materials have excited extensive interest for their remarkable electrical properties and low density for application in electromagnetic (EM) wave absorbents. However, the processing of heteroatoms doping in carbon nanostructures is an insuperable challenge for attaining effective reflection loss and EM matching. Herein, a facile method for large-scale synthesis of boron and nitrogen doped carbon nanotubes decorated by ferrites particles is proposed. The BCN nanotubes (50-100 nm in diameter) imbedded with nanosized Fe x (B/C/N) y (10-20 nm) are successfully constructed by two steps of polymerization and carbonthermic reduction. The product exhibits an outstanding reflection loss (RL) performance, in that the minimum RL is -47.97 dB at 11.44 GHz with a broad bandwidth 11.2 GHz (from 3.76 to 14.9 GHz) below -10 dB indicating a competitive absorbent in stealth materials. Crystalline and theoretical studies of the absorption mechanism indicate a unique dielectric dispersion effect in the absorbing bandwidth. PMID- 29517490 TI - Excitation of hybridized Dirac plasmon polaritons and transition radiation in multi-layer graphene traversed by a fast charged particle. AB - We analyze the energy loss channels for a fast charged particle traversing a multi-layer graphene (MLG) structure with N layers under normal incidence. Focusing on a terahertz (THz) range of frequencies, and assuming equally doped graphene layers with a large enough separation d between them to neglect interlayer electron hopping, we use the Drude model for two-dimensional conductivity of each layer to describe hybridization of graphene's Dirac plasmon polaritons (DPPs). Performing a layer decomposition of ohmic energy losses, which include excitation of hybridized DPPs (HDPPs), we have found for N = 3 that the middle HDPP eigenfrequency is not excited in the middle layer due to symmetry constraint, whereas the excitation of the lowest HDPP eigenfrequency produces a Fano resonance in the graphene layer that is first traversed by the charged particle. While the angular distribution of transition radiation emitted in the far field region also shows asymmetry with respect to the traversal order by the incident charged particle at supra-THz frequencies, the integrated radiative energy loss is surprisingly independent of both d and N for N <= 5, which is explained by a dominant role of the outer graphene layers in transition radiation. We have further found that the integrated ohmic energy loss in optically thin MLG scales as ?1/N at sub-THz frequencies, which is explained by exposing the role of dissipative processes in graphene at low frequencies. Finally, prominent peaks are observed at supra-THz frequencies in the integrated ohmic energy loss for MLG structures that are not optically thin. The magnitude of those peaks is found to scale with N for N >= 2, while their shape and position replicate the peak in a double-layer graphene (N = 2), which is explained by arguing that plasmon hybridization in such MLG structures is dominated by electromagnetic interaction between the nearest-neighbor graphene layers. PMID- 29517491 TI - Fano resonances in bilayer phosphorene nanoring. AB - Tunable transport properties and Fano resonances are predicted in a circular bilayer phosphorene nanoring. The conductance exhibits Fano resonances with varying incident energy and applied perpendicular magnetic field. These Fano resonance peaks can be accurately fitted with the well known Fano curves. When a magnetic field is applied to the nanoring, the conductance oscillates periodically with magnetic field which is reminiscent of the Aharonov-Bohm effect. Fano resonances are tightly related to the discrete states in the central nanoring, some of which are tunable by the magnetic field. PMID- 29517493 TI - In situ study on surface roughening in radiation-resistant Ag nanowires. AB - Metallic materials subjected to heavy ion irradiation experience significant radiation damage. Free surface is a type of effective defect sinks to improve the radiation resistance in metallic materials. However, the radiation resistance of metallic nanowires (NWs) is largely unknown. Here we show, via in situ Kr ion irradiations in a transmission electron microscope, Ag NWs exhibited much better radiation resistance than coarse-grained Ag. Irradiation-induced prominent surface roughening in Ag NWs provides direct evidence for interaction between defect clusters and free surface. Diameter dependent variation of the surface roughness in irradiated Ag NWs has also been observed. This study provides insight on mechanisms of enhanced radiation resistance via free surfaces in metallic NWs. PMID- 29517492 TI - Quantitative assessment of cervical softening during pregnancy in the Rhesus macaque with shear wave elasticity imaging. AB - Abnormal parturition, e.g. pre- or post-term birth, is associated with maternal and neonatal morbidity and increased economic burden. This could potentially be prevented by accurate detection of abnormal softening of the uterine cervix. Shear wave elasticity imaging (SWEI) techniques that quantify tissue softness, such as shear wave speed (SWS) measurement, are promising for evaluation of the cervix. Still, interpretation of results can be complicated by biological variability (i.e. spatial variations of cervix stiffness, parity), as well as by experimental factors (i.e. type of transducer, posture during scanning). Here we investigated the ability of SWEI to detect cervical softening, as well as sources of SWS variability that can affect this task, in the pregnant and nonpregnant Rhesus macaque. Specifically, we evaluated SWS differences when imaging the cervix transabdominally with a typical linear array abdominal transducer, and transrectally with a prototype intracavitary linear array transducer. Linear mixed effects (LME) models were used to model SWS as a function of menstrual cycle day (in nonpregnant animals) and gestational age (in pregnant animals). Other variables included parity, shear wave direction, and cervix side (anterior versus posterior). In the nonpregnant cervix, the LME model indicated that SWS increased by 2% (95% confidence interval 0-3%) per day, starting eight days before menstruation. During pregnancy, SWS significantly decreased at a rate of 6% (95% CI 5-7%) per week (intracavitary approach) and 3% (95% CI 2-4%) per week (transabdominal approach), and interactions between the scanning approach and other fixed effects were also significant. These results suggest that, while absolute SWS values are influenced by factors such as scanning approach and SWEI implementation, these sources of variability do not compromise the sensitivity of SWEI to cervical softening. Our results also highlight the importance of standardizing SWEI approaches to improve their accuracy for cervical assessment. PMID- 29517494 TI - Clinical presentation, assessment, and management of inducible laryngeal obstruction. AB - PURPOSE OF REVIEW: Many aspects of inducible laryngeal obstruction (ILO) are still poorly understood. However, in recent years there have been advances made and an international consensus has achieved a standardized taxonomy. This review will synthesize recent research; specifically, relating to clinical presentation, assessment, and therapeutic interventions. RECENT FINDINGS: The evidence base is growing but still limited for ILO and mostly comprises retrospective reviews, case studies, and anecdotal reports. The proposed relationship between ILO and other manifestations of laryngeal dysfunction via laryngeal hypersensitivity and hyperresponsiveness warrants further investigation. Progress has been made with guidelines published on laryngoscopy reporting procedures and validated symptom questionnaires produced for clinical use, although diagnostic algorithms are yet to be established. Emerging conservative and surgical interventions show promise, although as yet there are no randomized controlled trials investigating treatment efficacy. SUMMARY: The field is in an embryonic state and key research priorities, acknowledged in the current literature, need to be addressed to positively impact patient care. PMID- 29517495 TI - Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update. AB - PURPOSE OF REVIEW: Antimalarial drugs including chloroquine, its less toxic quinolone-derivative hydroxychloroquine (HCQ), and quinacrine have become cornerstones in the treatment of autoimmune diseases including systemic lupus, rheumatoid arthritis, sarcoidosis, and Sjogren syndrome; cutaneous disorders, antiphospholipid syndrome, and have recently been employed at higher dioses in oncology. Benefits include anti-inflammatory effects, protection against thrombosis, and improved control of hyperglycemia and hyperlipidemia. In general, both the therapeutic advantages and the toxic effects of the drugs correlate with the dose and the duration of therapy. Here we summarize the current literature regarding the administration and the safety profile of HCQ in management of rheumatologic disease and focus on the most recent revised American Academy of Ophthalmology (AAO) guidelines for prevention and detection of hydroxychloroquine retinopathy to help guide therapeutic decision-making for patients. RECENT FINDINGS: The risk of antimalarial-induced retinal toxicity is better predicted by calculating the daily dosage based on 5 mg/kg total body weight rather than 6.5 mg/kg lean body weight and reducing dosage in patients with risk factors such as renal failure. The risk of retinal toxicity after 5 years is substantially increased even when these guidelines are followed; hence dose reduction is appropriate with long-term use. Newer techniques provide improved detection of early signs of retinal damage. These advances are reflected in the revised AAO guidelines 2016, which are in part based on the retrospective study by Melles and Marmor of HCQ toxicity. SUMMARY: The most important changes in practice guidelines include dose calculation based on total body weight, dose reduction after long-term use, and intensified screening with techniques including optical coherence tomography (OCT) after 5 years. PMID- 29517496 TI - Intraoperative Immunostaining for Cytokeratin-7 During Mohs Micrographic Surgery Demonstrates Low Local Recurrence Rates in Extramammary Paget's Disease. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is a rare intraepithelial malignancy with high recurrence rates following standard surgical treatments, ranging from 22% to 60% in large retrospective reviews. OBJECTIVE: To evaluate the local recurrence rate of Mohs micrographic surgery (MMS) supplemented with intraoperative immunohistochemistry for cytokeratin-7 (MMS + CK-7) for primary and recurrent EMPD. MATERIALS AND METHODS: Retrospective, multi-center, cross sectional study of patients treated using MMS + CK-7. Demographic, clinicopathologic, treatment, and follow-up data were obtained by chart review. RESULTS: The observed local recurrence rate for MMS + CK-7 is 3.3% (2/61 tumors) with a mean follow-up of 43.5 months (1-120 months). Local recurrence occurred in 2.3% (1/43) of primary tumors and 5.6% (1/18) of recurrent tumors. Kaplan-Meier 5 year tumor-free rates are 94.6% overall, 97.1% for primary tumors, and 80.0% for recurrent tumors. The Kaplan-Meier 5-year tumor-free rates for all EMPD tumors treated with MMS + CK-7 versus a historical cohort of MMS alone are 94.6% versus 72.0% (p = .012). CONCLUSION: MMS + CK-7 is an effective treatment for EMPD, demonstrating improved outcomes compared with historical controls. PMID- 29517497 TI - Residual Squamous Cell Carcinoma After Shave Biopsy in Solid Organ Transplant Recipients. AB - BACKGROUND: After histopathological confirmation of a biopsy sample, cutaneous squamous cell carcinoma (cSCC) is often treated surgically; yet, residual tumor within the excision sample is not always found. The prevalence of residual cSCC after shave biopsy in solid organ transplant recipients (SOTRs) is unknown. OBJECTIVE: Determine the prevalence of residual cSCC after shave biopsy in SOTRs. METHODS: A retrospective case-controlled review was performed from a single center. Data were collected for 117 SOTRs and 117 age-matched nonimmunosuppressed controls diagnosed with shave biopsy-proven cSCC who underwent subsequent wide local excision from January 2004 to December 2016. Multivariable conditional logistic regression was used to determine variables associated with residual tumor in the combined population. Univariate logistic regression was used to investigate if transplant-related variables were associated with residual tumor in the SOTR group. RESULTS: Of the 117 SOTRs, 57 (48.7%) had residual tumor within the excisional specimen. Of the 117 controls, 31 (26.5%) had residual tumor within the excisional specimen. Solid organ transplant recipients have 2.59 times greater odds of having residual cSCC after shave biopsy (95% confidence interval: 1.29-5.22, p = .0076). CONCLUSION: Solid organ transplant recipients have a higher prevalence of residual cSCC after shave biopsy when compared with nonimmunosuppressed controls and should be prioritized for margin-controlled surgery. PMID- 29517498 TI - Commentary on Restoration of Visual Loss With Retrobulbar Hyaluronidase Injection After Hyaluronic Acid Filler. PMID- 29517499 TI - Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility. AB - P53 immunohistochemistry has evolved into an accurate surrogate reflecting the underlying TP53 mutation status of a tumor, and has utility in the diagnostic workup of endometrial carcinomas. Recent work predominantly carried out in tubo ovarian high-grade serous carcinoma has revealed 4 main patterns of p53 staining (normal/wild-type, complete absence, overexpression, and cytoplasmic); the latter 3 patterns are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation. The aim of this review is to provide practical advice to pathologists regarding various aspects of p53 immunohistochemical staining. These include laboratory methods to optimize staining, a description of the different patterns of staining, advice regarding the interpretation, and reporting of p53 staining and practical uses of p53 staining in endometrial carcinoma diagnosis. Illustrations are provided to aid in the interpretational problems. PMID- 29517500 TI - HIV and adolescents: challenges and opportunities. PMID- 29517501 TI - Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome. AB - PURPOSE OF REVIEW: The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). RECENT FINDINGS: C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis. They suggest that there may be considerable overlap in pathogenesis between these entities and have indicated novel ways in which classification may be improved. There is increasing evidence that monoclonal gammopathy may cause C3 glomerulopathy or aHUS in older patients and emerging evidence that treatment of the underlying plasma cell clone may ameliorate the kidney disease. SUMMARY: Recent work has provided new insights into the causes of C3 glomerulopathy and aHUS, and the mechanism by which complement is dysregulated. This is of particular importance with the advent of new therapeutic agents which can specifically target different parts of the complement cascade. PMID- 29517502 TI - Direct-acting antiviral treatment for patients with hepatocellular carcinoma. AB - PURPOSE OF REVIEW: Hepatocellular carcinoma (HCC) affects a significant portion of patients with hepatitis C. The use of direct-acting antiviral (DAA) agents has transformed the disease outcomes in this patient group. RECENT FINDINGS: Hepatitis C virus (HCV) response to DAAs can be affected by the presence of HCC, whereas DAA therapy may affect the risk of HCC recurrence in patients with a history of HCC. SUMMARY: Emerging data are demonstrating lower sustained virologic response (SVR) rates in patients with HCC compared with patients without HCC. Conflicting studies have also suggested that rates of HCC recurrence in patients with a history of HCC can potentially be increased or decreased on DAA therapy. This review will provide a brief overview of these data and inform practitioners on important considerations to make when prescribing DAA therapy for patients with HCV and HCC. PMID- 29517504 TI - Somatic Mutations and Intratumoral Heterogeneity of MYH11 Gene in Gastric and Colorectal Cancers. AB - MYH11 functions as a contractile protein, converting chemical energy into mechanical energy through adenosine triphosphate hydrolysis. In cancers, an oncogenic fusion CBFB/MYH11 and frameshift mutations have been reported. Truncating mutants of MYH11 exhibited increased ATPase and motor activity, suggesting their roles in energy balance and movement of cancer cells. MYH11 gene has a mononucleotide repeat (C8) in the coding sequences that could be a mutational target in the cancers exhibiting microsatellite instability (MSI). We analyzed the C8 repeat in 79 gastric cancers (GCs) and 124 colorectal cancers (CRCs) including 113 high MSI (MSI-H) and 90 microsatellite stable/low MSI cases. We detected MYH11 frameshift mutations in 4 (11.8%) GCs and 17 (21.5%) CRCs with MSI-H (21/113, 18.6%), but not in microsatellite stable/low MSI cancers (0/90) (P<0.001). We also analyzed intratumoral heterogeneity (ITH) of the MYH11 frameshift mutations and found that 10 of 16 CRCs (62.5%) harbored the regional ITH. Our results show that MYH11 gene harbors somatic frameshift mutations mostly associated with mutational ITH, which together may be features of MSI-H GCs and CRCs. Practically, the data suggest that multiregional analysis is needed for a better evaluation of mutation status in MSI-H tumors to overcome ITH. PMID- 29517503 TI - Complement-coagulation connections. AB - : Complement and coagulation are evolutionarily related proteolytic cascades in the blood that are critical for effecting an appropriate innate response to injury that limits bleeding and infection, while promoting healing. Although often viewed as distinct, it has long been recognized that cross-talk likely exists between these pathways. Only recently have molecular links been established. These are providing insights that are revealing opportunities for the development of novel therapeutic strategies to better treat a wide range of thrombotic, inflammatory, immune, infectious, and malignant diseases. In this brief review, the complex relationship between complement and coagulation is highlighted, underlining some of the newly uncovered interactions, in the hopes of stimulating innovative research that will yield improvements in patient outcomes. PMID- 29517505 TI - Immunohistochemical Detection of gamma/delta T Lymphocytes in Formalin-fixed Paraffin-embedded Tissues. AB - T lymphocytes can be distinguished based on the composition of the T-cell receptor (TCR) chain in alpha/beta T cells and gamma/delta T cells. Correspondingly, alpha/beta lymphomas can be distinguished from gamma/delta lymphomas. The latter are rare neoplasms, which are usually confined to particular organs and tissues and carry a dismal prognosis. Until recently, monoclonal antibody (mAb) clone g3.20 to the TCR gamma-chain was the reagent of choice for the immunohistochemical detection of gamma/delta T cells and lymphomas in standard formalin-fixed paraffin-embedded tissues. However, due to technical problems, mAb g3.20 became recently unavailable. Our attempts to identify another commercially available clone to the TCR gamma-chain were unsuccessful. However, we were able to identify a mAb (clone H-41, SC-100289; Santa Cruz, Dallas, TX) to the TCR delta-chain. H-41 works well in immunohistochemistry on paraffin-embedded tissue and comparison with previously stained cases, shows superior immunolabeling to mAb g3.20. H-41 to the TCR delta-chain appears to be a suitable reagent for the replacement of mAb g3.20. PMID- 29517508 TI - Editorial. PMID- 29517509 TI - Interventions for chronic kidney disease-associated restless legs syndrome. PMID- 29517506 TI - Absolute risks of obstetric outcomes by maternal age at first birth: a population based cohort. AB - BACKGROUND: First deliveries in women older than 35, 40, or 45 years are at increased risk for adverse pregnancy outcomes compared with those in younger women. However, specific relationships between each additional year of maternal age and pregnancy risks remain unclear, and absolute risks at each maternal age are not known. METHODS: Using a population-based cohort of nulliparous women in British Columbia, Canada, from 2004 to 2014 (n = 203,414), We examined relationships between maternal age (modeled flexibly to allow curvilinear shapes) and pregnancy outcomes using logistic regression. We plotted absolute predicted risks to display curves from age 20 to 50 estimated for two risk profiles: (1) population average values of all risk factors; (2) a low-risk profile without preexisting diabetes/hypertension, smoking, prior spontaneous/therapeutic abortion, diagnosed infertility, inadequate prenatal care, low income, rural residence, or obesity. RESULTS: Risks of hypertensive disorders increased gradually until age 35, then accelerated. Risk of multiple gestations, major congenital anomalies, and maternal mortality or severe morbidity increased slowly until age 30, then accelerated. Cesarean delivery and gestational diabetes risks increased linearly with age. While indicated preterm delivery increased rapidly with maternal age, spontaneous preterm delivery did not. Stillbirth, neonatal mortality, and infant mortality had j-shaped relationships with maternal age, with nadirs near 30. Despite age-related increases, risks of severe outcomes remained low for women 35 and 40: < 1-2% for severe maternal morbidity and 5-7% for fetal-infant composite. CONCLUSIONS: This study provides risks for specific maternal ages to inform clinical counseling and public health messaging regarding the potential implications of delayed childbearing. PMID- 29517510 TI - Penile cancer: Providing patient support. PMID- 29517511 TI - Implanted In-Body Tissue-Engineered Heart Valve Can Adapt the Histological Structure to the Environment. AB - Tissue-engineered heart valves (TEHVs) are expected to be viable grafts. However, it is unknown whether they transit their histological structure after implantation. We developed a novel autologous TEHV (named stent biovalve) for transcatheter implantation, using in-body tissue engineering based on a tissue encapsulation phenomenon. In this study, a time-course histological transition of implanted biovalves was investigated in goats. Three types of stent biovalves were prepared by 2 month embedding of plastic molds mounted with metallic stents, in the subcutaneous spaces. After extracting the molds with tissue and removing the molds only, stent biovalves were constituted entirely from the connective tissues. Stent biovalves were implanted in the aortic or pulmonary valve position of other goats with transcatheter technique. In each animal, the stent biovalve was explanted at 1 month step (from 1 to 6 months) or as long as possible. Total 12 goats (five for aortic and seven for pulmonary) were successfully implanted. The maximum duration became 19 months as a result. Even then the leaflets of the biovalves kept their shape and elasticity, and neither calcification nor thrombi were observed in any cases and duration. Histology showed the recipients' cells covering the laminar surface of the leaflets like the endothelium even after 1 month. The cells have also migrated in the leaflets gradually and finally constructed characteristic 3 layered tissues like native leaflets. Implanted stent biovalves can adapt their histological structure to the environment. They have a potential as viable grafts keeping better function and biocompatibility. PMID- 29517512 TI - Left Ventricular Assist Device Thrombosis-Amiodarone-Induced Hyperthyroidism: Causal Link? AB - Ventricular arrhythmias occurs in 20-50% of patients supported with left ventricular assist devices (LVAD). Ventricular arrhythmias are well tolerated with LVAD support but long-term consequences include worsening right ventricular function. Management of ventricular arrhythmias in LVAD patients includes use of antiarrhythmic agents or ablation. Amiodarone has been used a first-line agent to treat ventricular arrhythmias post-LVAD implantation. Chronic treatment with amiodarone for arrhythmias can result in hyperthyroidism and hypothyroidism in 5 10% of patients. Hyperthyroidism is known to cause endothelial dysfunction, alterations in coagulation, and fibrinolytic pathways favoring hypercoagulable state. We describe two cases of left ventricular assist device (LVAD) thrombosis potentiated by amiodarone-induced hyperthyroidism (AIT) and discuss pathophysiological mechanisms for hypercoagulable state induced by hyperthyroidism. PMID- 29517513 TI - Cannula-Related Infection in Patients Supported by Peripheral ECMO: Clinical and Microbiological Characteristics. AB - Little is known about cannula-related infection (CRI) in patients supported by extracorporeal membrane oxygenation (ECMO). The aim of this study was to assess the incidence, the risk factors, prognosis, and microbiological characteristics of CRI in patients supported by ECMO. This retrospective cohort study was conducted in one intensive care unit (ICU). Among 220 consecutive patients with peripheral ECMO, 39 (17.7%) developed CRI. The incidence of CRI was 17.2 per 1,000 ECMO days. The main isolated microorganisms were Enterobacteriaceae (38%), Staphylococcus spp. (28.2%; 8.5% were methicillin-sensitive Staphylococcus aureus and 19.7% were coagulase-negative staphylococci), and Pseudomonas aeruginosa (18.3%). Bacteremia was present in 23 cases (59.7%). In multivariate analysis, the risk factors for CRI were longer ECMO duration (p = 0.006) and higher Simplified Acute Physiology Score 2 (p = 0.004). Forty-one percentage of patients with CRI needed surgical management of the infected site. Cannula-related infection was not associated with higher in-hospital mortality (p = 0.73), but it was associated with a longer stay in ICU (p < 0.0001) and a longer stay in hospital (p = 0.002). In conclusion, CRI is frequent in patients with ECMO and associated with a longer stay in hospital. Risk factors for CRI were longer ECMO duration and higher Simplified Acute Physiology Score 2. Concomitant bacteremia was frequent (59.7%) and CRI should be strongly investigated in cases of positive blood culture. PMID- 29517514 TI - Clinical Utility of Imaging Left Ventricular Assist Devices with 320 Row Multidetector Computed Tomography. AB - Evaluation of left ventricular devices is becoming increasingly important as the implantation of these devices increases. Cardiac computed tomography angiography (CCTA) has many potential advantages compared with plain radiographs and echocardiography to troubleshoot these devices and potentially help guide therapy. Heart failure (HF) remains a deadly, progressive disease with substantive and increasing morbidity, mortality, cost, and prevalence. Use of left ventricular assist devices (LVAD) as treatment for refractory HF has been steadily rising during the last decade. Seventy-four LVAD recipients who met an indication for CCTA were referred for scanning at our center for a total of 94 studies. All recipients had received a Heart Mate II (Thoratec, Pleasanton, CA) LVAD at a previous time. All patients underwent gated CCTA on a 320 row multidetector scanner (Aquilion ONE, Toshiba Medical Systems, Irvine, California, USA). Images were then reconstructed and analysis was performed using multiple oblique views. All 94 studies had technically good images. In survival analysis, 43 of the 74 LVAD patients had normal CCTA findings while 31 had abnormal CCTA results. The 6, 12, and 18 months survival was 93%, 79%, and 77% in those with normal results and 71%, 61%, and 61%, respectively, in the abnormal CCTA findings. Overall survival was statistically significant in when comparing the two groups (p = 0.003). Cardiac computed tomography angiography may be used as an aid for risk stratification and a potential indicator of short- and long-term prognosis in LVAD patients. PMID- 29517515 TI - Left Ventricular Unloading During Veno-Arterial ECMO: A Simulation Study. AB - Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is widely used in cardiogenic shock. It provides systemic perfusion, but left ventricular (LV) unloading is suboptimal. Using a closed-loop, real-time computer model of the human cardiovascular system, cardiogenic shock supported by peripheral VA ECMO was simulated, and effects of various adjunct LV unloading interventions were quantified. After VA ECMO initiation (4 L/min) in cardiogenic shock (baseline), hemodynamics improved (increased to 85 mm Hg), while LV overload occurred (10% increase in end-diastolic volume [EDV], and 5 mm Hg increase in pulmonary capillary wedge pressure [PCWP]). Decreasing afterload (65 mm Hg mean arterial pressure) and circulating volume (-800 mL) reduced LV overload (12% decrease in EDV and 37% decrease in PCWP) compared with baseline. Additional intra-aortic balloon pumping only marginally decreased cardiac loading. Instead, adjunct Impella enhanced LV unloading (23% decrease in EDV and 41% decrease in PCWP). Alternative interventions, for example, left atrial/ventricular venting, yielded substantial unloading. We conclude that real-time simulations may provide quantitative clinical measures of LV overload, depending on the degree of VA ECMO support and adjunct management. Simulations offer insights into individualized LV unloading interventions in cardiogenic shock supported by VA ECMO as a proof of concept for potential future applications in clinical decision support, which may help to improve individualized patient management in complex cardiovascular disease.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 29517516 TI - Hybrid coronary revascularization versus percutaneous strategies in left main stenosis: a propensity match study. AB - AIMS: Hybrid revascularization (HCR) has been recently proposed as an alternative strategy in multivessel coronary disease, particularly in patients with high SYNTAX scores and risk scores. The objective of this study is to evaluate the outcomes of HCR versus percutaneous coronary intervention (PCI) drug-eluting stenting in left main treatment. METHODS: A series of 198 consecutive patients with left main stenosis have been treated. HCR, was performed in 77 patients (G1) whereas 121 patients (G2) received PCI on left main. An adjusted analysis using inverse probability weighting (IPW) was performed. Primary outcomes include: 30 day mortality, postoperative acute myocardial infarction, 18 months' MACCEs: cardiac death, stroke, acute myocardial infarction (AMI), repeated target vessel revascularization (TVR). RESULTS: SYNTAX score was 29.5 +/- 6.9 in G1 and 29.1 +/ 6.5 in G2 (P = 0.529). In G2, three patients (2.7%) died because of cardiogenic shock; no deaths occurred in G1 (P = 0.603). No major complications were reported in G1 and there was no mortality at 18 months' follow-up in both groups. Survival freedom from MACCEs at 18 months' follow-up was significantly higher in G1 (G1: 93.3 +/- 4.6% versus G2: 72.3 +/- 6.3; P = 0.001) mostly because of the higher freedom from TVR (G1: 93.3 +/- 4.6% versus G2: 75.5 +/- 5.6; P = 0.002). At Cox regression analysis, PCI was an independent predictor of MACCEs and TVR (hazard ratio 3.9, CI 1.36-9.6; P = 0.027). CONCLUSION: PCI in patients with left main and multivessel disease is a viable strategy, with a good outcome. HCR, demonstrated a lower incidence of cardiac adverse events such as AMI and TVR. Future comparative studies will be helpful to identify the optimal patient population for HCR. PMID- 29517517 TI - The Anterolateral Complex and Anterolateral Ligament of the Knee. AB - The anterolateral structures of the knee have recently garnered considerable interest regarding their role in rotatory knee instability related to anterior cruciate ligament tears. Isolated anterior cruciate ligament reconstruction may not always restore rotatory stability of the knee. In these patients, additional procedures, such as lateral reconstruction or tenodesis, may be indicated. The anatomy of the anterolateral structures of the knee has been well described. Histologic and anatomic studies have reported conflicting findings regarding the presence of a discrete ligament. The biomechanical role of the anterolateral capsule in restraining internal tibial rotation has been described as negligible. The existing body of research on the anterolateral knee structures provides insight into the composition of the anterolateral complex of the knee. PMID- 29517519 TI - Sudden death in schizophrenia. AB - PURPOSE OF REVIEW: To examine the recent literature regarding sudden death in patients with schizophrenia and synthesize salient conclusions based on this evidence. RECENT FINDINGS: Sudden cardiac death (SCD) is the largest subset of sudden unexpected death (SUD), with up to 40% of SUD from cardiovascular causes. SCD has been associated with exposure to both first and second-generation antipsychotics. Clozapine [odds ratio (OR) 3.67, 95% confidence interval (CI) 1.94-6.94] confers the highest risk of SCD followed by risperidone (OR 3.04, 95% CI 2.39-3.86) then olanzapine (OR 2.04, 95% CI 1.52-2.74). SCD not associated with antipsychotic use has been correlated to several modifiable and nonmodifiable risk factors - obesity, smoking, dyslipidemia, diabetes, hypertension, age, sex, and history of cardiovascular disease. Other subsets of SUD include hematological and pulmonary causes, including agranulocytosis leading to sepsis, deep vein thrombosis leading to pulmonary embolisms, and aspiration pneumonia leading to sepsis. SUMMARY: There is a huge paucity in genetic and pharmacogenetic data focused on SUD in schizophrenia. Future studies should emphasize the genetic aspects as well as clarify the underlying molecular mechanisms of these pathways. Additionally, early detection of those patients at high risk for SUD and discovery of preventive measures should also be emphasized. PMID- 29517518 TI - PharmGKB summary: atazanavir pathway, pharmacokinetics/pharmacodynamics. PMID- 29517521 TI - Sonority's Effect as a Surface Cue on Lexical Speech Perception of Children With Cochlear Implants. AB - OBJECTIVES: Sonority is the relative perceptual prominence/loudness of speech sounds of the same length, stress, and pitch. Children with cochlear implants (CIs), with restored audibility and relatively intact temporal processing, are expected to benefit from the perceptual prominence cues of highly sonorous sounds. Sonority also influences lexical access through the sonority-sequencing principle (SSP), a grammatical phonotactic rule, which facilitates the recognition and segmentation of syllables within speech. The more nonsonorous the onset of a syllable is, the larger is the degree of sonority rise to the nucleus, and the more optimal the SSP. Children with CIs may experience hindered or delayed development of the language-learning rule SSP, as a result of their deprived/degraded auditory experience. The purpose of the study was to explore sonority's role in speech perception and lexical access of prelingually deafened children with CIs. DESIGN: A case-control study with 15 children with CIs, 25 normal-hearing children (NHC), and 50 normal-hearing adults was conducted, using a lexical identification task of novel, nonreal CV-CV words taught via fast mapping. The CV-CV words were constructed according to four sonority conditions, entailing syllables with sonorous onsets/less optimal SSP (SS) and nonsonorous onsets/optimal SSP (NS) in all combinations, that is, SS-SS, SS-NS, NS-SS, and NS NS. Outcome measures were accuracy and reaction times (RTs). A subgroup analysis of 12 children with CIs pair matched to 12 NHC on hearing age aimed to study the effect of oral-language exposure period on the sonority-related performance. RESULTS: The children groups showed similar accuracy performance, overall and across all the sonority conditions. However, within-group comparisons showed that the children with CIs scored more accurately on the SS-SS condition relative to the NS-NS and NS-SS conditions, while the NHC performed equally well across all conditions. Additionally, adult-comparable accuracy performance was achieved by the children with CIs only on the SS-SS condition, as opposed to NS-SS, SS-NS, and SS-SS conditions for NHC. Accuracy analysis of the subgroups of children matched in hearing age showed similar results. Overall longer RTs were recorded by the children with CIs on the sonority-treated lexical task, specifically on the SS-SS condition compared with age-matched controls. However, the subgroup analysis showed that both groups of children did not differ on RTs. CONCLUSIONS: Children with CIs performed better in lexical tasks relying on the sonority perceptual prominence cues, as in SS-SS condition, than on SSP initial relying conditions as NS-NS and NS-SS. Template-driven word learning, an early word learning strategy, appears to play a role in the lexical access of children with CIs whether matched in hearing age or not. The SS-SS condition acts as a preferred word template. The longer RTs brought about by the highly accurate SS SS condition in children with CIs is possibly because listening becomes more effortful. The lack of RTs difference between the children groups when matched on hearing age points out the importance of oral-language exposure period as a key factor in developing the auditory processing skills. PMID- 29517520 TI - Optimizing Clinical Interpretation of Distortion Product Otoacoustic Emissions in Infants. AB - OBJECTIVES: The purpose of this study was to analyze distortion product otoacoustic emission (DPOAE) level and signal to noise ratio in a group of infants from birth to 4 months of age to optimize prediction of hearing status. DPOAEs from infants with normal hearing (NH) and hearing loss (HL) were used to predict the presence of conductive HL (CHL), sensorineural HL (SNHL), and mixed HL (MHL). Wideband ambient absorbance was also measured and compared among the HL types. DESIGN: This is a prospective, longitudinal study of 279 infants with verified NH and HL, including conductive, sensorineural, and mixed types that were enrolled from a well-baby nursery and two neonatal intensive care units in Cincinnati, Ohio. At approximately 1 month of age, DPOAEs (1-8 kHz), wideband absorbance (0.25-8 kHz), and air and bone conduction diagnostic tone burst auditory brainstem response (0.5-4 kHz) thresholds were measured. Hearing status was verified at approximately 9 months of age with visual reinforcement audiometry (0.5-4 kHz). Auditory brainstem response air conduction thresholds were used to assign infants to an NH or HL group, and the efficacy of DPOAE data to classify ears as NH or HL was analyzed using receiver operating characteristic (ROC) curves. Two summary statistics of the ROC curve were calculated: the area under the ROC curve and the point of symmetry on the curve at which the sensitivity and specificity were equal. DPOAE level and signal to noise ratio cutoff values were defined at each frequency as the symmetry point on their respective ROC curve, and DPOAE results were combined across frequency in a multifrequency analysis to predict the presence of HL. RESULTS: Single-frequency test performance of DPOAEs was best at mid to high frequencies (3-8 kHz) with intermediate performance at 1.5 and 2 kHz and chance performance at 1 kHz. Infants with a conductive component to their HL (CHL and MHL combined) displayed significantly lower ambient absorbance values than the NH group. No differences in ambient absorbance were found between the NH and SNHL groups. Multifrequency analysis resulted in the best prediction of HL for the SNHL/MHL group with poorer sensitivity values when infants with CHL were included. CONCLUSIONS: Clinical interpretation of DPOAEs in infants can be improved by using age-appropriate normative ranges and optimized cutoff values. DPOAE interpretation is most predictive at higher F2 test frequencies in young infants (2-8 kHz) due to poor test performance at 1 to 1.5 kHz. Multifrequency rules can be used to improve sensitivity while balancing specificity. Last, a sensitive middle ear measure such as wideband absorbance should be included in the test battery to assess possibility of a conductive component to the HL. PMID- 29517522 TI - Current and Optimal Training in High-Value Care in the Internal Medicine Clerkship: A National Curricular Needs Assessment. AB - PURPOSE: The clinical skills needed to practice high-value care (HVC) are core to all medical disciplines. Medical students form practice habits early, and HVC instruction is essential to this formation. The purpose of this study was to describe the state of HVC instruction and assessment in internal medicine clerkships and identify needs for additional curricula. METHOD: In 2014, the Clerkship Directors in Internal Medicine conducted its annual survey of 121 U.S. and Canadian medical schools. The authors evaluated a subset of questions from that survey asking clerkship directors about the perceived importance of HVC instruction, type and amount of formal instruction and assessment, achievement of student competence, prioritization of topics, and barriers to curriculum implementation. Descriptive statistics were used to summarize responses, and chi square tests were used to examine associations between response categories. RESULTS: The overall response rate was 77.7% (94/121). The majority (85; 91.4%) agreed that medical schools have a responsibility to teach about HVC across all phases of the curriculum. Of respondents, 31 (32.9%) reported their curricula as having some formal instruction on HVC, and 66 (70.2%) felt the amount was inadequate. Highest-priority topics for inclusion included overuse of diagnostic tests and treatments, defining value and its application to clinical reasoning, and balancing benefit and harm. Only 11 (17.8%) assessed students' competence in HVC. CONCLUSIONS: Internal medicine clerkship directors reported that HVC is insufficiently taught and assessed in medical school, despite relevance to practice. Developing generalizable curricular materials, faculty development, and dedicated curricular time may enhance HVC education. PMID- 29517523 TI - About Politeness, Face, and Feedback: Exploring Resident and Faculty Perceptions of How Institutional Feedback Culture Influences Feedback Practices. AB - PURPOSE: To explore resident and faculty perspectives on what constitutes feedback culture, their perceptions of how institutional feedback culture (including politeness concepts) might influence the quality and impact of feedback, feedback seeking, receptivity, and readiness to engage in bidirectional feedback. METHOD: Using a constructivist grounded theory approach, five focus group discussions with internal medicine residents, three focus group discussions with general medicine faculty, and eight individual interviews with subspecialist faculty were conducted at Brigham and Women's Hospital between April and December 2016. Discussions and interviews were audiotaped and transcribed verbatim; concurrent data collection and analysis were performed using the constant comparative approach. Analysis was considered through the lens of politeness theory and organizational culture. RESULTS: Twenty-nine residents and twenty-two general medicine faculty participated in focus group discussions, and eight subspecialty faculty participated in interviews. The institutional feedback culture was described by participants as (1) a culture of politeness, in which language potentially damaging to residents' self-esteem was discouraged; and (2) a culture of excellence, in which the institution's outstanding reputation and pedigree of trainees inhibited constructive feedback. Three key themes situated within this broader cultural context were discovered: normalizing constructive feedback to promote a culture of growth, overcoming the mental block to feedback seeking, and hierarchical culture impeding bidirectional feedback. CONCLUSIONS: An institutional feedback culture of excellence and politeness may impede honest, meaningful feedback and may impact feedback seeking, receptivity, and bidirectional feedback exchanges. It is essential to understand the institutional feedback culture before it can be successfully changed. PMID- 29517524 TI - A Proposal for a Shared Medical School Curricular Ecosystem. AB - New digital platforms are transforming learning in higher education and providing high-quality education content at little or no cost. Educators can now reach large, even global audiences. Yet, many medical schools continue to develop and maintain custom but duplicative curricular content despite having limited faculty and financial resources. In addition, medical students are faced with a multitude of potentially unaligned curricula driven by the school, national licensing exams, and the students' own perceived clinical training needs. The authors propose the creation of a common curricular component ecosystem that is developed around consensus-built foundational learning objectives aligned with core competencies that must be acquired by all students graduating medical school. Identifying and developing common curricula with standardized learning outcomes ideally should involve leading medical education, accreditation, and certification bodies in the United States. Curriculum component standards will be necessary to enable curriculum development, sharing, and adoption at scale. A shared medical curriculum ecosystem would free up faculty time to develop high value teaching activities at individual medical schools. Students would benefit from a consistent education experience that better aligns with national licensure exams. A shared, core curriculum system could begin to bend the cost curve for medical education in the United States and scale internationally to help address the increasing global shortage of health care workers. PMID- 29517525 TI - Where Hospital Boards Often Fail: Auditing Leadership Performance. AB - Hospital boards address quality of care and patient safety as well as financial performance through long-accepted practices. By contrast, a hospital's administrative operations and institutional culture are not usually subject to such detailed scrutiny. Yet, despite a healthy bottom line and patient commendations, hospital personnel can be underperforming, burdened with poor morale, and suffering from less-than-optimal leadership, unwarranted inefficiency, and ethically questionable management practices. The resulting employee dissatisfaction or disengagement can affect productivity, quality, turnover, innovation, patient and donor attraction and retention, public image, etc., and can be missed by an unsuspecting board. While boards do not scrutinize most administrative operations, they do examine financial performance, through review of the independent auditor's Management Letter. Designed to help the chief financial officer (CFO) improve the efficiency and integrity of the hospital's financial systems and to recommend improvements to the board for implementation (rather than to assess the CFO's performance), the Management Letter has no equal with respect to a comparable evaluation of the hospital's administrative performance and workplace culture. When, as is often the case, there is only superficial review of the chief executive officer, the board has no source of analysis or recommendations to improve the hospital's institutional environment. In this Invited Commentary, the authors suggest a methodology to provide such a review, leading to a Leadership Letter, and discuss its utility for both nonprofit and for-profit organizations. PMID- 29517526 TI - When Everything Was Vibrant. PMID- 29517527 TI - Transitioning to Medical School: Growth During the Application Cycle. PMID- 29517528 TI - The Pictures on the Wall: Transitioning From a Historically Black College/University (HBCU) to an Ivy League Medical School. PMID- 29517529 TI - The Medical Student Compass. PMID- 29517530 TI - "Full Disclosure: Secrets of a Med Student". PMID- 29517531 TI - Why Public Comments Matter: The Case of the National Institutes of Health Policy on Single Institutional Review Board Review of Multicenter Studies. AB - PURPOSE: In 2014, the National Institutes of Health (NIH) requested public comments on a draft policy requiring NIH-funded, U.S.-based investigators to use a single institutional review board (sIRB) for ethical review of multicenter studies. The authors conducted a directed content analysis and qualitative summary of the comments and discuss how they shaped the final policy. METHOD: Two reviewers independently assessed support for the policy from a review of comments on the draft policy in 2016. A reviewer conducted an open text review to identify prespecified and additional comment themes. A second researcher reviewed 20% of comments; discrepancies were resolved through discussion. RESULTS: The NIH received 167 comments: 65% (108/167) supportive of the policy, 23% (38/167) not supportive, and 12% (21/167) not indicating support. Clarifications or changes to the policy were suggested in 102/167 comments (61%). Criteria for selecting sIRBs were addressed in 32/102 comments (31%). Also addressed were institutional review board (IRB) responsibilities (39/102; 38%), cost (27/102; 26%), the role of local IRBs (14/102; 14%), and allowable policy exceptions (19/102; 19%). The NIH further clarified or provided guidance for selection criteria, IRB responsibilities, and cost in the final policy (June 2016). Local IRB reviews and exemptions guidance were unchanged. CONCLUSIONS: In this case study, public comments were effective in shaping policy as the NIH modified provisions or planned supplemental guidance in response to comments. Yet critical knowledge gaps remain, and empirical data are necessary. The NIH is considering mechanisms to support the establishment of best practices for sIRB implementation. PMID- 29517533 TI - A 20-Minute Cup of Coffee. PMID- 29517532 TI - A Call for Mixed Methods in Competency-Based Medical Education: How We Can Prevent the Overfitting of Curriculum and Assessment. AB - Competency-based medical education (CBME) has been the subject of heated debate since its inception in medical education. Despite the many challenges and pitfalls of CBME that have been recognized by the medical education community, CBME is now seeing widespread implementation. However, the biggest problems with CBME still have not been solved. Two of these problems, reductionism and loss of authenticity, present major challenges when developing curricula and assessment tools.The authors address these problems by making a call for flexibility in competency definitions and for the use of mixed methods in CBME. First, they present the issue of reductionism and a similar concept from the field of data science, overfitting. Then they outline several solutions, both conceptual and concrete, to prevent undue reductionist tendencies in both competency definitions and in tools of assessment. Finally, they propose the reintroduction of qualitative methods to balance the historically quantitative emphasis of assessment in medical education.The authors maintain that mixed-methods assessment with multiple assessors in differing contexts can yield a more accurate representation of a medical trainee's skills and abilities, deter the loss of authenticity, and increase the willingness of medical educators to adopt a feasible form of CBME. Finally, they propose the deployment of dedicated faculty assessors and physician coaches (which will reduce training requirements for other faculty), as well as the use of formal qualitative tools of assessment alongside established quantitative tools, to encourage a truly mixed-methods approach to assessment. PMID- 29517535 TI - The institutional development award states pediatric clinical trials network: building research capacity among the rural and medically underserved. AB - PURPOSE OF REVIEW: The institutional development award (IDeA) program was created to increase the competitiveness of investigators in states with historically low success rates for National Institutes of Health (NIH) research funding applications. IDeA states have high numbers of rural and medically underserved residents with disproportionately high rates of infant mortality, obesity, and poverty. This program supports the development and expansion of research infrastructure and research activities in these states. The IDeA States Pediatric Clinical Trials Network (ISPCTN) is part of the environmental influences on child health outcomes program. Its purpose is to build research capacity within IDeA states and provide opportunities for children in IDeA states to participate in clinical trials. This review describes the current and future activities of the network. RECENT FINDINGS: In its initial year, the ISPCTN created an online series on clinical trials, initiated participation in a study conducted by the pediatric trials network, and proposed two novel clinical trials for obese children. Capacity building and clinical trial implementation will continue in future years. SUMMARY: The ISPCTN is uniquely poised to establish and support new pediatric clinical research programs in underserved populations, producing both short and long-term gains in the understanding of child health. PMID- 29517537 TI - Detection of surgical margins in oral cavity cancer: the role of dynamic optical contrast imaging. AB - PURPOSE OF REVIEW: The quantity of tissue removed during an oncologic surgical procedure is not standardized and there are numerous reports of local recurrence despite histologically adequate resection margins. The oral cavity is one of the sites in the head and neck with high chances of recurrence following negative margins. To address this need, this article reviews the recent applications of Dynamic Optical Contrast Imaging (DOCI) towards both oral screening and the intraoperative evaluation of tumor margins in head and neck surgery. RECENT FINDINGS: Human ex-vivo and in-vivo trials suggest DOCI is well tolerated, low cost, and sensitive for differentiating cancerous from normal tissues throughout the head and neck, in addition to the oral cavity. Ex-vivo imaging of OSCC specimens generated histologically verified image contrast. Furthermore, in-vivo intraoperative results demonstrate significant potential for image-guided detection and resection of oral cavity squamous cell carcinoma (OSCC). SUMMARY: DOCI augments tissue contrast and may enable surgeons to clinically screen patients for oral cancer, make histologic evaluations in vivo with fewer unnecessary biopsies, delineate clinical margins for tumor resection, provide guidance in the choice of biopsy sites, and preserve healthy tissue to increase the postoperative functionality and quality of life of the patient. PMID- 29517538 TI - Fibrous Dysplasia of the Rib Mimicking a Malignant Bone Tumor at SPECT/CT with 99mTc-MDP. AB - We herein report a case of a 43-year-old man with a right 8th-rib bone tumor exhibiting features of malignancy at CT-scan. Considering that a SPECT/CT with Tc MDP showed solitary intense radio-tracer uptake and the inconclusive results from a fine-needle biopsy, surgical en bloc tumor resection was performed. Pathologic analysis revealed a well-limited benign bone lesion ("fibrous rib dysplasia") composed by a cellular fibrous proliferation. Since benign osseous diseases may present an intense scintigraphic tracer uptake (as in this case), we suggest a certain caution when interpreting the results of SPECT/CT with Tc-MDP in order to avoid misdiagnosis and wrong treatments. PMID- 29517540 TI - 99mTc-Methionine Hybrid SPECT/CT for Detection of Recurrent Glioma: Comparison With 18F-FDG PET/CT and Contrast-Enhanced MRI. AB - OBJECTIVES: Posttherapy changes in treated glioma patients cannot be reliably differentiated from tumor recurrence. We evaluated the role of Tc-methionine SPECT/CT for the detection of recurrent glioma and compared the same with F-FDG PET/CT and contrast-enhanced MRI (CeMRI). METHODS: Forty-four patients with histologically proven, previously treated glioma and clinical suspicion of recurrence were prospectively enrolled in the study. Of these 44 patients, 39 (28 male and 11 female subjects; age, 38.05 +/- 9.7 years) underwent Tc-methionine SPECT/CT, F-FDG PET/CT, and CeMRI of the brain and were included for final analysis. Combination of repeat imaging, biopsy, and/or clinical follow-up (6-36 months) was taken as reference standard. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Diagnostic values among modalities were compared. RESULTS: Positive predictive value and negative predictive value for Tc-methionine SPECT/CT, F-FDG PET/CT, and CeMRI were 95.6% and 56.2%, 92.3% and 61.5%, and 79.4% and 42.9%, respectively. Sensitivity and specificity for the 3 modalities were 75.9% and 90%, 82.8% and 80%, and 87.1% and 30%. Specificity of Tc-methionine SPECT/CT was significantly higher than that of CeMRI (P < 0.0001) but not of F-FDG PET/CT (P = 0.36). No significant difference was seen between the modalities for sensitivity and accuracy. CONCLUSIONS: Tc-methionine is a promising tracer for detection of recurrent glioma. Diagnostic values of Tc-methionine SPECT/CT are similar to F FDG, although it is more specific than CeMRI. So it may be used as a cost effective alternative and also where PET/CT is not available. PMID- 29517539 TI - 67Ga Scintigraphy for Assessment of Disease Severity and Treatment Response in Patients With Paracoccidioidomycosis. AB - OBJECTIVE: The evaluation of therapy response of patients with deep mycosis is a major challenge. The aim of this study was to assess the severity of disease at admission and evaluate treatment response of patients with paracoccidioidomycosis using Ga scintigraphy. SUBJECTS AND METHODS: Seventy-three patients with fully active disease were enrolled. A scoring system based on clinicoradiological and serological evaluation and Ga scan was devised. Pretherapy Ga score of 73 patients was compared with clinicoradiological and serological scores. A subgroup of 23 patients was followed up during treatment, and the rates of improvement of their clinicoradiological, serological, and Ga scores during treatment were compared at 3 time points (fully active phase, after clinical improvement, and clinically inactive disease). RESULTS: The correlations between scores before therapy were statistically significant. Ga score correlated with clinical score (r = 0.47, P < 0.001). Serological score correlated with both Ga and clinical scores (r = 0.32, P = 0.006, and r = 0.25, P = 0.034, respectively). Concerning evaluation of therapy response, clinicoradiological, serological, and Ga scores decreased significantly after therapy (P < 0.001). Notably, Ga score was the single one to become negative in most patients at the end of treatment (20 of 23 patients compared with 7 on clinicoradiological evaluation and 10 on serology, P = 0.003). CONCLUSIONS: In patients with paracoccidioidomycosis, pretherapy Ga scintigraphy correlates with disease severity. Serial Ga scans seem to be helpful in evaluating the response to therapy. PMID- 29517541 TI - Periurethral Mass Mimicking Neoplasm After Injection of Macroplastique for Postprostatectomy Stress Incontinence: A Pitfall on 18F-FDG PET/CT. AB - A 64-year-old man underwent initial F-FDG PET/CT staging for gastric cardia adenocarcinoma, which showed the primary gastric tumor, several bone metastases, and high uptake in a periurethral mass mimicking pelvic neoplasm developed after injection of polydimethylsiloxane (Macroplastique) urethral bulking agent 6 years ago for postprostatectomy stress urinary incontinence. This case showed a very rare complication of silicon particle injection therapy, and the intense uptake is likely due to granulomatous reaction around the implant. PMID- 29517542 TI - Prominent Pulmonary Metastases Without Concurrent Intra-abdominal Metastasis in a Case of Ovarian Carcinoma. AB - Because ovarian cancer often advances by dissemination, pulmonary metastases are rarely unaccompanied by intra-abdominal metastases. We report a case of ovarian clear cell carcinoma having multiple bilateral lung metastases and without concurrent intra-abdominal lesions, as demonstrated by FDG PET/CT scan. PMID- 29517543 TI - Iodine/FDG "Flip-Flop" Phenomenon Inside a Large Metastatic Thyroid Cancer Lesion Better Characterized on SPECT/CT and PET/CT Studies. AB - Iodine/FDG "flip-flop" phenomenon inside large metastatic thyroid cancer lesions has been rarely described. We present a case of this phenomenon better characterized using SPECT/CT and PET/CT studies. PMID- 29517544 TI - FDG PET/CT in 2 Cases of Hepatic Pseudolymphoma. AB - Hepatic pseudolymphoma, also known as reactive lymphoid hyperplasia or nodular lymphoid hyperplasia, is a rare benign lymphoproliferative lesion. Preoperative diagnosis of hepatic pseudolymphoma is challenging. We present 2 cases of hepatic pseudolymphoma with focal intense FDG uptake on FDG PET/CT mimicking malignancy. These 2 cases suggest that hepatic pseudolymphoma should be considered as a rare differential diagnosis in patients with focal hypermetabolic hepatic lesion. PMID- 29517545 TI - False-Positive Uptake of 131I Due to Tubal Ligation in a Patient With Papillary Thyroid Cancer. AB - A 39-year-old woman with papillary thyroid cancer underwent I therapy after thyroidectomy. Posttherapeutic I whole-body scan accidentally showed symmetric "hot spots" in the pelvic region beyond known bone metastases. SPECT/CT was immediately added and revealed metal artifacts with I accumulation in the nearby uterus. Further inquiry discovered that she underwent tubal ligation 19 years ago. Our case demonstrates that I accumulation can occur at the site of oviducts many years after tubal ligation, which should be distinguished from I-avid metastases. PMID- 29517546 TI - Anal Malignant Melanoma Manifesting Hepatic Metastases Shown on FDG PET/CT. AB - Multiple hepatic metastases are uncommon as initial presentation of primary anal malignant melanoma. We report FDG PET/CT findings of pathology-proven hepatic metastases from anal malignant melanoma of unknown origin in a 43-year-old woman whose initial presentation was worsening abdominal pain. PMID- 29517547 TI - Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a): Reply. PMID- 29517548 TI - Impending Atypical Femoral Fracture in a Patient of Breast Cancer With Bone Metastases Receiving Long-term Denosumab. AB - Atypical femoral fractures (AFFs) occur in both osteoporosis patients and cancer patients who receive long-term bisphosphonate treatment. Denosumab offers an alternative approach for the treatment of bone metastases. We describe a 59-year old woman with a history of breast carcinoma and bone metastasis who was prescribed denosumab for 4 years. The patient had no history of any prior bisphosphonate use. Bone scintigraphy showed an abnormal uptake in the right femur, which was confirmed as an impending AFF or atypical femoral stress reaction. In oncological patients receiving long-term denosumab, AFF should be included as a differential diagnosis for focal femoral findings. PMID- 29517549 TI - Renal Blood Flow, Glomerular Filtration Rate, and Renal Oxygenation in Early Clinical Septic Shock. AB - OBJECTIVE: Data on renal hemodynamics, function, and oxygenation in early clinical septic shock are lacking. We therefore measured renal blood flow, glomerular filtration rate, renal oxygen consumption, and oxygenation in patients with early septic shock. DESIGN: Prospective comparative study. SETTING: General and cardiothoracic ICUs. PATIENTS: Patients with norepinephrine-dependent early septic shock (n = 8) were studied within 24 hours after arrival in the ICU and compared with postcardiac surgery patients without acute kidney injury (comparator group, n = 58). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data on systemic hemodynamics and renal variables were obtained during two 30 minute periods. Renal blood flow was measured by the infusion clearance of para aminohippuric acid, corrected for renal extraction of para-aminohippuric acid. Renal filtration fraction was measured by renal extraction of chromium-51 labeled EDTA. Renal oxygenation was estimated from renal oxygen extraction. Renal oxygen delivery (-24%; p = 0.037) and the renal blood flow-to-cardiac index ratio (-21%; p = 0.018) were lower, renal vascular resistance was higher (26%; p = 0.027), whereas renal blood flow tended to be lower (-19%; p = 0.068) in the septic group. Glomerular filtration rate (-32%; p = 0.006) and renal sodium reabsorption (-29%; p = 0.014) were both lower in the septic group. Neither renal filtration fraction nor renal oxygen consumption differed significantly between groups. Renal oxygen extraction was significantly higher in the septic group (28%; p = 0.022). In the septic group, markers of tubular injury were elevated. CONCLUSIONS: In early clinical septic shock, renal function was lower, which was accompanied by renal vasoconstriction, a lower renal oxygen delivery, impaired renal oxygenation, and tubular sodium reabsorption at a high oxygen cost compared with controls. PMID- 29517550 TI - Hepcidin and Anemia in Surgical Critical Care: A Prospective Cohort Study. AB - OBJECTIVE: Because anemia of inflammation is common in ICU patients and hepcidin is the key regulator of iron homeostasis, we examined time-dependent changes in hepcidin, erythropoietin, iron, and inflammatory markers in surgical ICU patients with anemia. DESIGN: Prospective single-center clinical noninterventional study. SETTING: Surgical ICUs; U.S. university hospital. PATIENTS: One hundred surgical adult ICU patients. MEASUREMENTS AND MAIN RESULTS: Time-dependent changes in serum hepcidin, hematologic, and erythropoietic studies were performed on ICU admission and at serial time-points through day 28, and correlated with hematologic and iron parameters and inflammatory response. Median serum hepcidin levels were significantly increased at ICU admission and decreased over time (144 36 ng/mL; p < 0.0001). Despite increased reticulocyte counts (1.3-2.9%), mean serum erythropoietin levels remained low (29-44 mU/mL) and hemoglobin did not significantly change. Hepcidin was positively correlated with RBC transfusion, C reactive protein, interleukin-6, ferritin, and negatively correlated with iron, total iron binding capacity, transferrin, and reticulocyte response. Hepcidin did not correlate with tumor necrosis factor-alpha serum concentrations. Regression analyses confirmed that ferritin, C-reactive protein, and reticulocyte number were predictive of same-day hepcidin; hepcidin and C-reactive protein were predictive of same-day reticulocyte count. CONCLUSIONS: Hepcidin serum concentrations are markedly increased on ICU admission, and decrease significantly over the course of the ICU stay (28 d). Decreased hepcidin concentrations are associated with increased reticulocyte response and decreased inflammatory response reflected by decreased interleukin-6 and C-reactive protein concentrations, but not with anemia resolution. PMID- 29517552 TI - Validation of SIMPLE Index for Lupus Disease Activity. AB - OBJECTIVE: An easy, quick tool requiring minimal training or health care provider input would potentially have greater uptake for clinical use among rheumatologists and primary care physicians for assessment of disease activity in systemic lupus erythematosus (SLE). SIMPLE (SIMple Disease Assessment for People with Lupus Erythematosus) index is a composite numeric tool that is easy and quick to calculate. We prospectively assessed the performance of the SIMPLE index as a disease activity surrogate against physician-based disease activity measures. METHODS: Ninety-nine consenting patients meeting American College of Rheumatology SLE classification criteria were recruited. Safety of Estrogen in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), physician global assessment, and SIMPLE index were obtained during routine visits. SIMPLE index is a 17-item patient-reported questionnaire that includes 2 laboratory tests. Health care provider input is needed only to provide laboratory results (normal/abnormal) and confirming patient-reported current use and dosing of glucocorticoids. We performed Spearman test to assess correlation of SIMPLE index with SELENA-SLEDAI and physician global assessment. RESULTS: Mean age (SD) was 39.7 (12.3) years. The correlation coefficient between SIMPLE index and SELENA-SLEDAI was 0.56 (P = 0.0001), and that between SIMPLE index and physician global assessment was 0.54 (P = 0.0001). In SLE patients without fibromyalgia (FM), the correlation of SIMPLE index with SELENA-SLEDAI and physician global assessment was 0.58 (P = 0.0001) and 0.57 (P = 0.0001), respectively. CONCLUSIONS: SIMPLE index is strongly correlated with formal physician assessments of disease activity in SLE, and correlation was marginally higher among those without FM. SIMPLE index can be performed easily in places with limited physician and laboratory resources. PMID- 29517553 TI - Pseudotumor of the Odontoid Process in Calcium Pyrophosphate Deposition Disease. PMID- 29517551 TI - RBC Transfusion Practice in Pediatric Extracorporeal Membrane Oxygenation Support. AB - OBJECTIVES: To determine RBC transfusion practice and relationships between RBC transfusion volume and mortality in infants and children treated with extracorporeal membrane oxygenation. DESIGN: Secondary analysis of a multicenter prospective observational study. SETTING: Eight pediatric institutions within the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Collaborative Pediatric Critical Care Research Network. PATIENTS: Patients age less than 19 years old treated with extracorporeal membrane oxygenation at a participating center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data and target hemoglobin or hematocrit values (if set) were recorded daily by trained bedside extracorporeal membrane oxygenation specialists and research coordinators. Laboratory values, including hemoglobin and hematocrit, were recorded daily using the value obtained closest to 8:00 AM. RBC transfusion was recorded as total daily volume in mL/kg. Multivariable logistic regression was used to determine the relationship between RBC transfusion volume and hospital mortality, accounting for potential confounders. Average goal hematocrits varied across the cohort with a range of 27.5-41.3%. Overall, actual average daily hematocrit was 36.8%, and average RBC transfusion volume was 29.4 mL/kg/d (17.4-49.7 mL/kg/d) on extracorporeal membrane oxygenation. On multivariable analysis, each additional 10 mL/kg/d of RBC transfusion volume was independently associated with a 9% increase in odds of hospital mortality (adjusted odds ratio, 1.09 [1.02-1.16]; p = 0.009). CONCLUSIONS: In this multicenter cohort of pediatric extracorporeal membrane oxygenation patients, daily hematocrit levels were maintained at normal or near-normal values and RBC transfusion burden was high. RBC transfusion volume was independently associated with odds of mortality. Future clinical studies to identify optimum RBC transfusion thresholds for pediatric extracorporeal membrane oxygenation are urgently needed. PMID- 29517554 TI - Effectiveness and Drug Survival of Anti-Tumor Necrosis Factor alpha Therapies in Patients With Spondyloarthritis: Analysis From the Thai Rheumatic Disease Prior Authorization Registry. AB - OBJECTIVE: This study aimed to evaluate the long-term effectiveness and safety of the first anti-tumor necrosis factor alpha therapy (TNFi) and to identify the associated factors of drug discontinuation in patients with spondyloarthritis. METHODS: This was a retrospective cohort study. Patients with spondyloarthritis who were prescribed the first TNFi between December 2009 and October 2014 in the Rheumatic Disease Prior Authorization registry were enrolled. Baseline clinical data were retrieved. The Cox proportional hazards model was used to identify factors associated with discontinuation of drugs. RESULTS: Among 138 patients, 97 had ankylosing spondylitis (AS), and 41 had psoriatic arthritis (PsA). The effectiveness of TNFi in AS and PsA was 55% to 59% at 4 months and 75% to 96% at 3 years, as measured by a 50% decrease in the Bath Ankylosing Spondylitis Disease Activity Index from baseline. For PsA with peripheral arthritis, improvement of the joint count by 50% was observed in 61.8% of patients at 4 months and 100% at 3 years. Survival from TNFi was 63% for AS and 56% for PsA at 3 years. For AS, the factors associated with good response leading to discontinuation of TNFi were baseline patient global assessment 3 to 6/10 (hazard ratio [HR], 6.3) and the use of leflunomide (HR, 6.0) and infliximab (HR, 4.8). A good response (38.5%) was the most common cause of discontinuation of the first TNFi, followed by toxicity (28.2%), nonadherence (20.5%), and lack of effectiveness (12.8%). CONCLUSIONS: Ankylosing spondylitis and PsA responded well to TNFi during the 3-year follow up. The retention rate was approximately 60% for AS and PsA. A good response to the first TNFi was the most common reason for discontinuation. PMID- 29517557 TI - Modified Subcutaneous Buried Horizontal Mattress Suture Compared With Vertical Buried Mattress Suture: Erratum. PMID- 29517555 TI - Prevalence of Crystals in Knee Osteoarthritis: Experience From Patients Undergoing Arthroscopic Procedures. PMID- 29517558 TI - High SBP trajectories are associated with risk of all-cause death in general Chinese population. AB - OBJECTIVE: This study aimed to investigate whether long-term trajectories of high SBP can further predict risk of all-cause death in Chinese adults. METHODS: We used a community-based cohort of 84 363 participants without myocardial infarction, stroke, or cancer, in 2010. SBP trajectories used latent mixture modeling with data from 2006, 2008, and 2010. Cox proportional hazards models were used to examine the association between SBP trajectories and risk of all cause death in 2010-2015. RESULTS: We identified five distinct SBP trajectory patterns based on the 2006 status and the pattern of change during 2006-2010. Each pattern was labeled according to the SBP levels and pattern over time: low stable (n = 21 249), moderate-stable (n = 39 390), moderate-increasing (n = 9634), elevated-decreasing (n = 9094) and elevated-stable (n = 4996). During 5.24 +/- 1.04 years of follow-up, we documented 4131 deaths. After adjusting for potential confounding factors and using the low-stable group as a reference, hazard ratios [95% confidence interval (CI)] of all-cause death for the moderate stable, moderate-increasing, elevated-decreasing, and elevated-stable groups were 1.32 (1.12-1.56), 1.60 (1.26-2.04), 1.69 (1.38-2.07), and 1.75 (1.33-2.32), respectively. Although the moderate-stable trajectory exhibited SBP ranges within the 'normal' range (126.90-130.09 mmHg) in 2006-2010, this group had higher all cause death risk relative to the low-stable trajectory group (109.86-112.46 mmHg) (adjusted hazard ratio = 1.32, 95% CI 1.12-1.56). CONCLUSION: High SBP trajectories are independent risk factors for all-cause death. Our findings suggest increasing SBP trajectories within the currently designated 'normal' range may still increase risk of all-cause death. PMID- 29517559 TI - Persistence of elevated blood pressure during childhood and adolescence: a school based multiple cohorts study. AB - OBJECTIVE: Blood pressure (BP) screening is advocated in children. However, identification of children with sustained elevated BP is difficult because of high BP variability. We assessed the tracking of BP and the persistence of elevated BP across childhood and adolescence. METHODS: Three cohorts of children from schools in the Seychelles were examined on two occasions at 3-4-year intervals. Obesity was defined as BMI at least 95th sex-specific, and age specific percentile. On each visit, BP was based on the average of two readings and elevated BP was defined as BP at least 95th sex-specific, age-specific, and height-specific percentile. RESULTS: Data was collected in 4519 children of mean ages of 5.5 and 9.2 years, 6065 of ages of 9.2 and 12.5 years, and 5967 of ages of 12.5 and 15.6 years, respectively. Prevalence of elevated BP was 10% at age 5.5 years, 10% at 9.2 years, 7% at 12.5 years, and 9% at 15.6 years, respectively. Among children with elevated BP at the initial visit, the proportions who had elevated BP at the subsequent visit 3-4 years later was 13% between ages of 5.5 and 9.2 years, 19% between 9.2 and 12.5 years, and 27% between 12.5 and 15.6 years. These proportions were higher among obese children with elevated BP, that is, 33, 35, and 39%, in each cohort, respectively. Tracking coefficients were slightly larger for SBP (range of tracking coefficients: 0.23-0.40) than for DBP (range: 0.19-0.35), and increased with age. By comparisons, tracking coefficients for BMI were much higher (range: 0.74 0.84). CONCLUSION: During childhood and adolescence, having an elevated BP on one occasion is a weak predictor of elevated BP 3-4 years later. Tracking is, however, larger in older and obese children than in younger and nonobese children. PMID- 29517560 TI - Night-time heart rate nondipping: clinical and prognostic significance in the general population. AB - AIM: Studies addressing the association between a reduced drop of heart rate (HR) at night with subclinical organ damage and cardiovascular events in the general population are scanty. We evaluated this issue in individuals enrolled in the Pressioni Monitorate E Loro Associazioni study. METHODS: At entry, 2021 individuals underwent diagnostic tests including laboratory investigations, 24-h ambulatory blood pressure (BP) monitoring and echocardiography. Participants were followed from the initial medical visit for a time interval of 148 +/- 27 months. To explore the association of circadian HR rhythm and outcomes, participants were classified in the primary analysis according to quartiles of nocturnal HR decrease. In secondary analyses, the population was also classified according nondipping nocturnal HR (defined as a drop in average HR at night lower than 10% compared with day-time values) and next in four categories: first, BP/HR dipper, second, BP/HR nondipper, third, HR dipper/BP nondipper, fourth, HR nondipper/BP dipper). RESULTS: A flattened circadian HR rhythm (i.e. lowest quartile of night time HR dip) was independently associated with left atrial enlargement, but not to left ventricular hypertrophy; moreover, it was predictive of fatal and nonfatal cardiovascular events, independently of several confounders (hazard ratio 1.8, confidence interval: 1.13-2.86, P < 0.01 vs. highest quartile). CONCLUSION: A blunted dipping of nocturnal HR is associated with preclinical cardiac damage in terms of left atrial enlargement and is predictive cardiovascular morbidity and mortality in the general population. PMID- 29517561 TI - Prospective Evaluation of Results of Reoperation in Zollinger-Ellison Syndrome. AB - OBJECTIVE: To determine the role of reoperation in patients with persistent or recurrent Zollinger-Ellison Syndrome (ZES). BACKGROUND: Approximately, 0% to 60% of ZES patients are disease-free (DF) after an initial operation, but the tumor may recur. METHODS: A prospective database was queried. RESULTS: A total of 223 patients had an initial operation for possible cure of ZES and then were subsequently evaluated serially with cross sectional imaging-computed tomography, magnetic resonance imaging, ultrasound, more recently octreoscan-and functional studies for ZES activity. The mean age at first surgery was 49 years and with an 11-year mean follow-up 52 patients (23%) underwent reoperation when ZES recurred with imageable disease. Results in this group are analyzed in the current report. Reoperation occurred on a mean of 6 years after the initial surgery with a mean number of reoperations of 1 (range 1-5). After reoperation 18/52 patients were initially DF (35%); and after a mean follow-up of 8 years, 13/52 remained DF (25%). During follow-up, 9/52 reoperated patients (17%) died, of whom 7 patients died a disease-related death (13%). The overall survival from first surgery was 84% at 20 years and 68% at 30 years. Multiple endocrine neoplasia type 1 status did not affect survival, but DF interval and liver metastases did. CONCLUSIONS: These results demonstrate that a significant proportion of patients with ZES will develop resectable persistent or recurrent disease after an initial operation. These patients generally have prolonged survival after reoperation and 25% can be cured with repeat surgery, suggesting all ZES patients postresection should have systematic imaging, and if tumor recurs, advise repeat operation. PMID- 29517562 TI - Enteral Versus Total Parenteral Nutrition in Patients Undergoing Pancreaticoduodenectomy: A Randomized Multicenter Controlled Trial (Nutri-DPC): Let's Take a Closer Look at the Pancreas! PMID- 29517564 TI - In the Next Issue. PMID- 29517563 TI - Reply to: "Surgeon Volume Threshold for Total Thyroidectomy". PMID- 29517566 TI - Cardiac Arrest in the Operating Room: Part 2-Special Situations in the Perioperative Period: Erratum. PMID- 29517565 TI - Letter to the Editor Regarding Tsujikawa and Lipid Emulsion. PMID- 29517567 TI - Utilizing Patient E-learning in an Intervention Study on Preoperative Smoking Cessation. AB - BACKGROUND: Patients who smoke put themselves at increased risk for serious surgical complications, yet it is not currently routine practice to educate patients about the risk of complications due to smoking. Computer-based smoking cessation programs are increasingly being utilized in the general population and may overcome some of the barriers such as lack of time, knowledge, and training to provide interventions. Our objective was to develop and implement a patient e learning program designed for surgical patients as part of a multifaceted program aimed at assisting them to quit smoking and to determine the factors cross sectionally and longitudinally associated with abstinence. METHODS: In this prospective multicenter study, smokers undergoing elective noncardiac surgery participated in a preoperative smoking cessation program consisting of a patient e-learning program, brief advice, educational pamphlet, tobacco quitline referral, letter to the primary care physician, and pharmacotherapy. The patient e-learning program described (1) the benefits of quitting smoking before surgery; (2) how to quit smoking; and (3) how to cope while quitting. The 7-day point prevalence (PP) abstinence on the day of surgery and at 1, 3 and 6 six months after surgery was separately assessed, and factors most associated with abstinence were identified using multivariable logistic regression analysis. Generalized estimating equation methods were used to estimate effect of the factors associated with abstinence longitudinally. The reach of the program was assessed with the number of smokers who participated in the program versus the number of patients who were referred to the program. RESULTS: A total of 459 patients (68.9% of eligible patients) participated. The 7-day PP abstinence at day of surgery, 1 month, 3 months, and 6 months was 22%, 29%, 25%, and 22%, respectively. The variables predicting abstinence at 6 months were use of pharmacotherapy (odds ratio [OR], 7.32; 95% confidence interval [CI], 3.71-14.44; P < .0001) and number of contacts with a tobacco quitline (OR, 1.60; 95% CI, 1.35 1.90; P < .0001). Presence of other smokers in the household (OR, 0.39; 95% CI, 0.21-0.72; P = .0030) and amount spent on cigarettes weekly at baseline (per $10 increase) (OR, 0.73; 95% CI, 0.61-0.87; P = .0004) were barriers to abstinence. CONCLUSIONS: Our preoperative smoking cessation program resulted in a 7-day PP abstinence of 22% at 6 months. A multifaceted intervention including a patient e learning program may be a valuable tool to overcome some of the barriers to help surgical patients quit smoking. PMID- 29517568 TI - Research Productivity and Rankings of Anesthesiology Departments in Canada and the United States: The Relationship Between the h-Index and Other Common Metrics: Retraction Notice. PMID- 29517569 TI - Lack of Translatable Proinflammatory Cytokines in Cerebrospinal Fluid in Rats With Increased Hyperalgesia With or Without Fentanyl Treatment. PMID- 29517570 TI - In Response. PMID- 29517572 TI - Perioperative Cardiac Arrest: Focus on Malignant Hyperthermia (MH): Erratum. PMID- 29517571 TI - In Response. PMID- 29517573 TI - Usefulness of Basophil Activation Tests for Diagnosis of Sugammadex-Induced Anaphylaxis. AB - BACKGROUND: Sugammadex is used to reverse the effects of neuromuscular blocking agents in many cases of general anesthesia. However, there are several reports of anaphylaxis after its use. Skin testing is the gold standard for detecting the causative agent of anaphylaxis. However, due to the lack of validated protocols for skin testing with sugammadex, the diagnostic accuracy might be inadequate. Recently, the basophil activation test (BAT) has been established as a tool to detect the causative agent of anaphylaxis with high sensitivity and specificity. However, few studies have investigated the utility of the BAT for sugammadex induced anaphylaxis. METHODS: Eight patients who presented with immediate hypersensitivity to sugammadex during general anesthesia were included in this study. We conducted skin tests to confirm the diagnosis of sugammadex-induced anaphylaxis. Twenty-one sugammadex-naive individuals who had a negative skin test for allergy to this drug were enrolled as controls. Basophils were selected on a CD3/CRTH2 gate and labeled with CD63 and CD203c. RESULTS: The ratios of activated basophils in the patients were much higher than those in controls: the median values of areas under the curves in the patients and controls for CD203c were 1,265,985 (95% confidence interval [CI], 77,580-5,040,270) and 116,325 (95% CI, 268,605 to 232,690), respectively (Mann-Whitney U test, P < .01), and the areas under the curves in the patients and controls for CD63 were 788,647 (95% CI, 120,285-3,523,410) and 220,005 (95% CI, -50,346 to 404,680), respectively (Mann Whitney U test, P < .01). The patients, but not controls, demonstrated clear dose dependent CD203c upregulation. This was also true for CD63. In the case of CD203c, the sensitivity of the BAT for sugammadex was 88% (95% CI, 47%-100%), and specificity was 100% (95% CI, 84%-100%), while sensitivity and specificity for CD63 were 75% (95% CI, 35%-97%) and 100% (95% CI, 84%-100%), respectively. CONCLUSIONS: The BAT seems to have comparable accuracy to skin tests for the diagnosis of sugammadex-induced anaphylaxis. For this purpose, both CD203c and CD63 can be used to detect activated basophils. PMID- 29517574 TI - Perioperative Management May Improve Long-term Survival in Patients After Lung Cancer Surgery: A Retrospective Cohort Study. AB - BACKGROUND: Surgical resection is the main treatment for patients with non-small cell lung cancer (NSCLC), but patients' long-term outcome is still challenging. The purpose of this study was to identify predictors of long-term survival in patients after lung cancer surgery. METHODS: Patients who underwent surgery for NSCLC from January 1, 2006, to December 31, 2009, were enrolled into this retrospective cohort study. The primary outcome was the survival length after surgery. Predictors of long-term survival were screened with the multivariable Cox proportional hazard model. RESULTS: Postoperative follow-up was completed in 588 patients with a median follow-up duration of 5.2 years (interquartile range, 2.0-6.8). Two hundred ninety-one patients (49.5%) survived at the end of follow up with median survival duration of 64.3 months (interquartile range, 28.5-81.6). The overall survival rates were 90.8%, 70.0%, and 57.1% at the end of the first, third, and fifth year after surgery, respectively. Limited resection (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.08-1.98; P = .013) and large tumor size (HR, 1.29; 95% CI, 1.17-1.42; P < .001) were associated with short survival; whereas high body mass index grade (HR, 0.82; 95% CI, 0.69-0.97; P = .021), highly differentiated tumor (HR, 0.59; 95% CI, 0.37-0.93; P = .024), dissection of mediastinal lymph node during surgery (HR, 0.45; 95% CI, 0.30-0.67; P < .001), and perioperative use of dexamethasone (HR, 0.70; 95% CI, 0.54-0.90; P = .006) were associated with long survival. No association was found between perioperative use of flurbiprofen axetil and long survival (HR, 0.80; 95% CI, 0.62-1.03; P = .086). However, combined administration of dexamethasone and flurbiprofen axetil was associated with longer survival (compared to no use of both: adjusted HR, 0.57; 95% CI, 0.38-0.84; P = .005). CONCLUSIONS: Certain factors in particular perioperative dexamethasone and flurbiprofen axetil therapy may improve patients' long-term survival after surgery for NSCLC. Given the small sample size, these findings should be interpreted with caution, and randomized clinical trials are needed for further clarification. PMID- 29517575 TI - Variability in Case Durations for Common Surgical Procedures. AB - BACKGROUND: Under the Merit-based Incentive Payment System, physician payment will be adjusted using a composite performance score that has 4 components, one of which is resource use. The objective of this exploratory study is to quantify the facility-level variation in surgical case duration for common surgeries to examine the feasibility of using surgical case duration as a performance metric. METHODS: We used data from the National Anesthesia Clinical Outcomes Registry on 404,987 adult patients undergoing one of 6 general surgical or orthopedic procedures: laparoscopic appendectomy, laparoscopic cholecystectomy, laparoscopic cholecystectomy with intraoperative cholangiogram, knee arthroscopy, laminectomy, and total hip replacement. We constructed separate mixed-effects multivariable time-to-event models (survival analysis) for each of the 6 procedures to model surgical case duration. RESULTS: We identified performance outliers, based on surgical case duration, using 2013 data and then quantified the gap between high- and low-performance outliers using 2014 data. After adjusting for patient risk, patients undergoing surgery at high-performance facilities were between 54% and 79% more likely to exit the operating room (OR) per unit time compared to average performing facilities, depending on the procedure. For example, patients undergoing a laparoscopic appendectomy at high-performance facilities were 68% more likely to exit the OR per unit time (hazard ratio, 1.68; 95% CI, 1.40-2.02; P < .001) compared to average-performing facilities. Patients undergoing a laparoscopic appendectomy at low-performance facilities were 41% less likely to exit the OR per unit time (hazard ratio, 0.59; 95% CI, 0.47-0.74; P < .001) compared to average-performing facilities. The adjusted median surgical case duration for patients undergoing laparoscopic appendectomy was 69 minutes at high performance centers and 92 minutes at low-performance centers. Similar results were obtained for the other procedures. CONCLUSIONS: There was wide variation in surgery case duration for patients undergoing common general surgical and orthopedic surgeries. This variability in care delivery may represent an important opportunity to promote more efficient use of health care resources. PMID- 29517576 TI - Pretherapeutic 124I dosimetry reliably predicts intratherapeutic blood kinetics of 131I in patients with differentiated thyroid carcinoma receiving high therapeutic activities. AB - AIM: The aim of this study was to assess the agreement between predicted blood uptake values using I and actually measured I blood uptake values (reference) in patients with differentiated thyroid carcinoma receiving largely high therapeutic activities. PATIENTS AND METHODS: Fourteen patients were analyzed retrospectively, who underwent a series of both pretherapeutic and intratherapeutic blood sampling using median I activities of 23 MBq and median therapy I activities of 10 GBq. Data of five blood samples from each patient were analyzed. Lin's concordance correlation coefficient analysis was carried out to assess the kinetic agreement. The time-integrated I activity coefficient (TIAC) for the blood compartment and the effective I clearance time (ECT), expressed as effective I half-life on the basis of a monoexponential model, were ascertained. For each patient, the (intrapatient) percentage differences between pretherapeutic and intratherapeutic TIACs and ECTs were calculated. The (interpatient) difference in TIACs and ECTs between pretherapy and intratherapy groups was evaluated using the Mann-Whitney U-test. RESULTS: Lin's concordance correlation coefficient was at least 0.97, indicating substantial kinetic agreement between pretherapeutic and intratherapeutic radioiodine kinetics. The mean (median)+/-SD (range) of the absolute percentage difference was 9% (11%)+/ 7% (0.33-20%) for the TIAC and 11% (10%)+/-10% (0-23%) for the ECT. A slightly higher median TIAC was observed in intratherapy (2.8 vs. 3.3 h), but this was not statistically significant (P=0.15), whereas no remarkable ECT difference (P=0.62) was found. CONCLUSION: The pretherapeutic blood kinetics derived from diagnostic I activities provides a reliable estimation of the intratherapeutic I blood kinetics in patients receiving largely high therapy activities, showing its potential for radioiodine treatment planning. PMID- 29517577 TI - Contrast-enhanced computed tomography does not improve the diagnostic value of parathyroid dual-phase MIBI SPECT/CT. AB - OBJECTIVE: The aim of this study was to investigate the contribution of contrast enhanced computed tomography (CE-CT) to the localization of parathyroid adenomas compared with the dual-phase Tc-99m MIBI SPECT with low-dose CT (LD-CT). PATIENTS AND METHODS: This retrospective study included consecutive patients with primary hyperparathyroidism who underwent a preoperative dual-phase MIBI SPECT/CT followed by surgical resection. The standard of care was dual-phase MIBI SPECT/CT, acquired with LD-CT in the early phase and CE-CT in the late phase (SPECT/CE-CT). The presence and localization of positive sites were extracted from study reports. To examine the role of CE-CT, patient cases were independently re-reviewed, with the early LD-CT fused with early and late SPECT (SPECT/LD-CT). The two SPECT/CT methods were compared for sensitivity, and the positive predictive value and histopathology were used as a reference. RESULTS: In total, 138 patients were included. The investigation was positive for suspected adenomas in 124 patients using SPECT/CE-CT and in 122 patients using SPECT/LD-CT. The per-patient sensitivity was 87.5% [95% confidence interval (CI): 80.7-92.6%] for SPECT/CE-CT and was not statistically significantly different from SPECT/LD-CT (85.3%; 95% CI: 78.2-90.8%) (P=0.39). The positive predictive value was 95.2% (95% CI: 95.4-99.9%) with SPECT/CE-CT versus 100% (95% CI: 96.8 100%) with SPECT/LD-CT. For small adenomas (<=500 mg), the sensitivity was low with SPECT/CE-CT (67%) as well as with SPECT/LD-CT (64%). CONCLUSION: Late CE-CT, compared with late LD-CT, did not significantly improve the sensitivity of dual phase Tc-99m MIBI parathyroid SPECT/CT in a population of patients with primary hyperparathyroidism. These findings were consistent regardless of the size, location, or histology of the adenomas. PMID- 29517578 TI - Pilocarpine effect on dose rate of salivary gland in differentiated thyroid carcinoma patients treated with radioiodine. AB - OBJECTIVE: Although different methods have been suggested on reducing salivary gland radiation after radioiodine administration, an effective preventive or therapeutic measure is still up for debate. The aim of this study was to evaluate the effect of pilocarpine, as a sialagogue drug on the radioiodine content of the salivary gland, and radioiodine-induced symptoms of salivary gland dysfunction. PATIENTS AND METHODS: Patients who were referred for radioiodine therapy were randomized into pilocarpine and placebo groups. The patients as well as the nurse who administered the tablets, and the specialist who analyzed the images, were all unaware of the patients' group. Anterior and posterior planar images including that of both the head and neck were obtained 2, 6, 12, 24, and 48 h after the administration of radioiodine in all patients, and round regions of interest were drawn for both left and right parotid glands, with a rectangular region of interest in the region of the cerebrum as background. All patients were interrogated once, 6 months after radioiodine administration, by a phone call for subjective evaluation of symptoms related to salivary gland damage. RESULTS: There was no significant difference between the two groups with regard to the mean age, sex, and initial iodine activity. The geometric mean of background corrected count per administered dose and acquisition time was calculated for the bilateral parotid glands. This normalized parotid count showed a significant reduction in net parotid count in both groups during the first 48 h after radioiodine administration. However, no significant difference was found between the groups according to the amount and pattern of dose reduction in this time period. CONCLUSION: This study revealed that pilocarpine had no significant effect on the radioiodine content of parotid glands during the first 48 h after radioiodine administration. No significant difference was found in the incidence of symptoms between the two groups treated with placebo and pilocarpine. PMID- 29517579 TI - LONGITUDINAL CHANGES IN CHOROIDAL AND RETINAL THICKNESSES IN CHILDREN WITH MYOPIC SHIFT. AB - PURPOSE: To elucidate the development of the choroid and retina in children, and to explore changes in these during myopic shift. METHODS: A total of 118 children aged 7 to 12 years participated in this 1-year longitudinal study. Children underwent several examinations at baseline and follow-up, including cycloplegic refraction, axial length measurement, and swept-source optical coherence tomography. Thickness changes in the choroid and retina were compared among children with or without myopic shift. RESULTS: Eighty-eight children (74.6%) developed a myopic shift after 1 year, and their central foveal choroid was significantly attenuated (P < 0.01). No significant change was observed in choroids of children without myopic shift (P = 0.83). Choroidal thickness decreased in all subfields during myopic shift, whereas the thickness of the retinal layers increased or were unchanged in most subfields. Axial length increase and central foveal choroidal thinning were associated with myopic shift (R = 0.157, P < 0.01), but axial length increase was not significantly related to choroidal thinning (P > 0.05). CONCLUSION: Choroidal thinning occurs early in myopic progression. Axial length increase and choroidal thinning are independently associated with myopic shift.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29517581 TI - PHOTODYNAMIC THERAPY FOR SYMPTOMATIC SUBFOVEAL RETINAL PIGMENT EPITHELIAL DETACHMENT IN CENTRAL SEROUS CHORIORETINOPATHY: Outcomes and Prognostic Factors. AB - PURPOSE: To report the clinical outcomes of reduced-fluence photodynamic therapy (PDT) for symptomatic subfoveal retinal pigment epithelial detachment (RPED) in central serous chorioretinopathy and identify prognostic factors affecting treatment outcome. METHODS: This retrospective interventional study included 35 eyes of 35 patients with serous subfoveal RPED with choroidal hyperpermeability. Cases with evidence of age-related macular degeneration were excluded from the study. Reduced-fluence PDT was applied to each patient. Best-corrected visual acuity, anatomical resolution of RPED, subjective symptom improvement, and complications were analyzed. RESULTS: One month after reduced-fluence PDT, 28 eyes (80.0%) manifested complete resolution of subfoveal RPED. Among the patients whose eyes manifested complete resolution, 19 (67.9%) reported subjective vision improvement. This subjective improvement was significantly associated with the presence of dysmorphopsia at baseline. Logarithm of the minimal angle of resolution visual acuity improved from 0.15 (Snellen equivalent of 20/28) to 0.09 (20/25) between baseline and 3 months after PDT (P = 0.008). Older age and increased RPED height were independent risk factors of poor resolution of RPED after PDT. The mean follow-up period after treatment was 10.4 +/- 13.6 months; recurrence of RPED did not occur in any case. CONCLUSION: Subfoveal RPED in central serous chorioretinopathy responded well to reduced-fluence PDT, especially in younger patients with less RPED. Dysmorphopsia, rather than decreased visual acuity, is a main symptomatic presentation in subfoveal RPED. PMID- 29517580 TI - EFFECT OF INTRAOCULAR PRESSURE-LOWERING MEDICATIONS ON NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATMENT OUTCOMES IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENT TRIALS. AB - PURPOSE: To evaluate the effect of intraocular pressure-lowering medications on treatment outcomes in the Comparison of AMD Treatments Trials. METHODS: Secondary analysis of Comparison of AMD Treatments Trials data. Medication logs were reviewed for continuous 2-year use of agents that increased aqueous outflow (Group A: topical prostaglandins) or suppressed aqueous production (Group B: topical beta blockers and carbonic anhydrase inhibitors). Eyes were excluded if mixed-mechanism intraocular pressure-lowering agents or medications from more than one group were taken. Anatomical and vision responses to treatment at years 1, 2, and over the entire 2-year period in each group were compared with controls (no intraocular pressure-lowering medications). RESULTS: Inclusion criteria were met by 28 Group A patients, 19 Group B patients, and 857 controls. After 2 years, the control group had a mean visual acuity improvement of +6.3 letters from baseline, compared with +3.5 letters in Group A (P = 0.38), and +13.8 letters in Group B (P = 0.052). Mean retinal thickness change from baseline was -54.9 MUm in controls, -80.6 MUm in Group A (P = 0.26), and -96.8 MUm in Group B (P = 0.13). Mean total thickness change from baseline was -163 MUm in controls, -180 MUm in Group A (P = 0.63), and -238 MUm in Group B (P = 0.08). In longitudinal analysis with adjustment by their baseline values, anti-vascular endothelial growth factor treatment drug and regimen, Group B had more visual acuity improvement (difference of 2.6 letters, 95% confidence interval: -3.4-8.5 letters), more reduction in the retinal thickness (-17.9 MUm, 95% confidence interval: -36.5 to 0.7 MUm), and total thickness from baseline (mean difference of -54.7 MUm, 95% confidence interval: -103 to 6.2 MUm) compared with the control group. CONCLUSION: Concurrent aqueous suppressant use during anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration was associated with a trend toward greater reductions in retinal and total thickness as well as improved visual outcomes over 2 years. A similar effect was not observed to the same extent with agents that increase aqueous outflow. Because of the small sample size and secondary analysis, these findings must be cautiously interpreted and perhaps serve as a basis for future prospective studies. PMID- 29517582 TI - PRESERVATION OF THE FOVEAL FLAP IN MACULAR HOLE SURGERY. AB - PURPOSE: To investigate the impact of preserving the foveal flap on surgical outcomes of full-thickness macular hole (MH) with foveal flaps. METHODS: We retrospectively reviewed patients with Stages 2 and 3 idiopathic MH, who underwent pars plana vitrectomy by a single surgeon at Asan Medical Center from November 2011 to November 2016. In the study group, we included eyes with MH and a foveal flap on preoperative spectral domain optical coherence tomography and successfully preserved the flap during surgery. The control group included eyes with MH and an operculum in the posterior vitreous plane on preoperative optical coherence tomography. We compared the anatomical and functional surgical outcomes between these groups. RESULTS: Postoperative mean best-corrected visual acuity at the last visit was 20/25 and 20/33 in the study (9 eyes) and control (23 eyes) groups, respectively. The study group showed a significantly better postoperative best-corrected visual acuity (P < 0.05). Restoration of both the external limiting membrane and ellipsoid zone, as assessed by spectral domain optical coherence tomography, was achieved in 9 (100%) and 15 (65.2%) eyes of the study and control groups, respectively. CONCLUSION: Preserving the foveal flap might improve both functional and anatomical outcomes of vitrectomy for MHs with a foveal flap. PMID- 29517583 TI - SIGNIFICANCE OF PREOPERATIVE EXTERNAL LIMITING MEMBRANE HEIGHT ON VISUAL PROGNOSIS IN PATIENTS UNDERGOING MACULAR HOLE SURGERY. AB - PURPOSE: To investigate the association between the vertical elevation of the external limiting membrane (ELM) and visual outcome in patients undergoing surgery for idiopathic full-thickness macular hole. METHODS: Retrospective observational study of a consecutive cohort of patients undergoing vitrectomy to treat macular hole. The greatest vertical height of the central ELM above the retinal pigment epithelium (ELM height) was measured on spectral domain optical coherence tomography preoperatively. The relationship of ELM height to other preoperative and postoperative variables, including macular hole width and height, and visual acuity was analyzed. RESULTS: Data from 91 eyes of 91 patients who had undergone successful hole closure were included. The mean ELM height was 220 MUm (range 100-394). There were significant correlations between the ELM height and the diameter of the hole, hole height, and worsening preoperative visual acuity. For holes less than 400 MUm in width, better postoperative visual acuity was significantly predicted by a lower ELM height. CONCLUSION: The ELM height varies widely in idiopathic macular hole. It is higher in eyes where the hole is wider and also when the hole itself is higher. For holes of less than 400 MUm in width, a lower ELM height is a strong independent predictor of a good postoperative outcome. PMID- 29517584 TI - Disease-modifying genetic factors in cystic fibrosis. AB - PURPOSE OF REVIEW: To compile data from the past 10 years regarding the role of modifying genes in cystic fibrosis (CF). RECENT FINDINGS: CF is a model disease for understanding of the action of modifying genes. Although it is a monogenic (CFTR) autosomal recessive disease, CF presents with wide phenotypic variability. In CF, variability occurs with different intensity among patients by each organ, being organ-specific, resulting from the mutual interaction of environmental and genetic factors, including CFTR mutations and various other genes, most of which are associated with inflammatory processes. In individuals, using precision medicine, gene modification studies have revealed individualized responses to drugs depending on particular CFTR mutations and modifying genes, most of which are alternative ion channels. SUMMARY: Studies of modifying genes in CF allow: understanding of clinical variability among patients with the same CFTR genotype; evaluation of precision medicine; understanding of environmental and genetic effects at the organ level; understanding the involvement of genetic variants in inflammatory responses; improvements in genetic counseling; understanding the involvement of genetic variants in inflammatory responses in lung diseases, such as asthma; and understanding the individuality of the person with the disease. PMID- 29517585 TI - Genetic causes and clinical management of pediatric interstitial lung diseases. AB - PURPOSE OF REVIEW: Interstitial lung disease (ILD) in children (chILD) is an umbrella term for a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and implicates genetic contributors. The purpose of this review is to provide updated information on the molecular defects associated with the development of chILD. RECENT FINDINGS: Currently, the main mutations are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, and NKX2-1. In addition, pulmonary alveolar proteinosis is associated with mutations in CSF2RA, CSF2RB, and MARS, and specific auto-inflammatory forms of chILD implicate STING and COPA disorders. The relationships between the genetic defects and the disease expression remain poorly understood, with no genotype phenotype correlations identified so far. Although targeted therapies are emerging, the management strategies are still largely empirical, relying mostly on corticosteroids. SUMMARY: Genetic factors play an important role in chILD, and the ongoing development of novel technologies will rapidly broaden the genetic landscape of chILD. Therefore, in the coming years, it is expected that newly identified molecular defects and markers will help predicting disease courses and tailoring individual therapies. PMID- 29517587 TI - Chest imaging for the diagnosis of complicated parapneumonic effusions. AB - PURPOSE OF REVIEW: To provide an overview of the contribution of thoracic ultrasound (TUS) and computed tomography (CT) in the identification of complicated parapneumonic effusions (CPPE), defined as those which need chest tube drainage for resolution. RECENT FINDINGS: A recent retrospective study found that visualization of complex (nonanechoic) effusions on TUS (likelihood ratio positive = 6.92) outperformed the recognition of loculated/septated effusions on CT (likelihood ratio = 2.20) or chest radiographs (likelihood ratio = 1.54) for predicting a CPPE. In another retrospective study, a weighted CT scoring system consisting of pleural contrast enhancement (three points), pleural microbubbles, increased extrapleural fat attenuation, and fluid volume at least 400 ml (one point each) had relatively good accuracy for labeling CPPE (likelihood ratio positive = 3.4; likelihood ratio negative = 0.22) when four or more points were achieved. SUMMARY: Although a gold standard for CPPE diagnosis is lacking, bedside TUS primarily, and CT scan in certain circumstances, may help to drive clinical decisions regarding chest tube placement in parapneumonic effusions (PPE). However, recommendations are limited by the absence of prospective trials. PMID- 29517588 TI - Defense and Veterans Brain Injury Center: The First 25 Years. PMID- 29517586 TI - Trade-offs in aging lung diseases: a review on shared but opposite genetic risk variants in idiopathic pulmonary fibrosis, lung cancer and chronic obstructive pulmonary disease. AB - PURPOSE OF REVIEW: The process of aging involves biological changes that increases susceptibility for disease. In the aging lung disease IPF, GWAS studies identified genes associated with risk for disease. Recently, several of these genes were also found to be involved in risk for COPD or lung cancer. This review describes GWAS-derived risk genes for IPF that overlap with risk genes for lung cancer or COPD. RECENT FINDINGS: Risk genes that overlap between aging lung diseases, include FAM13A, DSP and TERT. Most interestingly, disease predisposing alleles for IPF are opposite to those for COPD or lung cancer. Studies show that the alleles are associated with differential gene expression and with physiological traits in the general population. The opposite allelic effect sizes suggest the presence of trade-offs in the aging lung. For TERT, the trade-off involves cellular senescence versus proliferation and repair. For FAM13A and DSP, trade-offs may involve protection from noxious gases or tissue integrity. SUMMARY: The overlap in risk genes in aging lung diseases provides evidence that processes associated with FAM13A, DSP and TERT are important for healthy aging. The opposite effect size of the disease risk alleles may represent trade-offs, for which a model involving an apicobasal gene expression gradient is presented. PMID- 29517589 TI - Neuropsychological Performance and Subjective Symptom Reporting in Military Service Members With a History of Multiple Concussions: Comparison With a Single Concussion, Posttraumatic Stress Disorder, and Orthopedic Trauma. AB - OBJECTIVE: To examine differences in objective neurocognitive performance and subjective cognitive symptoms in individuals with a history of a single concussion, multiple concussions, orthopedic injuries, and posttraumatic stress disorder (PTSD). METHOD: Participants included 116 military service members who sustained a mild traumatic brain injury (mTBI) during combat deployment. Subjects were subdivided into groups based on concussion frequency: a single concussion (n = 42), 2 concussions (n = 21), and 3 or more concussions (n = 53). Eighty-one subjects sustained an orthopedic injury (n = 60) during deployment or were diagnosed with PTSD (n = 21), but had no history of mTBI. Subjects completed a battery of neuropsychological tests and self-report measures of postconcussive symptoms, PTSD symptoms, and psychopathology. RESULTS: No differences were found among the concussion groups on a composite neuropsychological measure. The PTSD group had the highest number of symptom complaints, with the 2-concussion and 3 plus-concussion groups being most similar to the PTSD group. The concussion groups showed a nonsignificant pattern of increasing distress with increasing number of concussions. CONCLUSIONS: The current findings are consistent with meta analytic results showing no differential effect on neuropsychological functioning due to multiple concussions. Results also support the burden of adversity hypothesis suggesting increasing symptom levels with increasing psychological or physically traumatic exposures. PMID- 29517590 TI - A Clinical Evidence-Based Approach to Examine the Effects of mTBI and PTSD Symptoms on ANAM Performance in Recently Deployed Active Duty Soldiers: Results From the Warrior Strong Study. AB - OBJECTIVE: Service members are frequently diagnosed with comorbid mild traumatic brain injury (mTBI) and posttraumatic stress disorder after returning from Afghanistan and Iraq. Little is known about how mTBI in the postacute and chronic phases combined with current posttraumatic stress disorder symptoms (PTS) affects performance on the Automated Neuropsychological Assessment Metrics, Version 4, Traumatic Brain Injury-Military (ANAM4) battery used by the US military. We examined postdeployment ANAM4 performance using conventional statistical methods, as well as rates of poor performance, below established cutoffs (<10th and <=2nd percentile). METHODS: A total of 868 soldiers were assessed for history of mTBI during the most recent deployment, as well as, lifetime mTBI, current PTS, and current pain-related symptoms. The ANAM4 was also administered. RESULTS: Soldiers with PTS and/or mTBI performed worse on ANAM4 relative to controls with those with both conditions performing worst. However, a nontrivial minority (~10%-30%) of individuals with mTBI, PTS, or both had scores that were at or below the second percentile. CONCLUSION: Our results illustrate that a combination of mTBI and PTS is associated with worse ANAM4 performance than either condition alone. Furthermore, only a minority of soldiers with any, or both, of the conditions had ANAM deficits. The long-lasting impacts and unique contribution of each condition have yet to be determined. PMID- 29517591 TI - Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury. AB - OBJECTIVE: To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. PARTICIPANTS: Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. RESULTS: Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. CONCLUSION: Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population. PMID- 29517592 TI - Mortality Following Hospital Admission for US Active Duty Service Members Diagnosed With Penetrating Traumatic Brain Injury, 2004-2014. AB - OBJECTIVE: To examine mortality among active duty US military service members (SMs) with the diagnosis of penetrating traumatic brain injury (PTBI) and a hospital admission between 2004 and 2014. DESIGN: Data on SMs with PTBI and an admission to a military or civilian hospital were obtained from the 2004 to 2014 Military Health System data repository. After applying exclusion criteria, data on 1226 SMs were analyzed. MAIN MEASURES: The number of observed deaths per 100 identified patients with PTBI and time to death from admission were used as main measures. RESULTS: Approximately 25% of the 1226 patients with PTBI included in this study died following admission, with 44.6% of the all deaths occurring within a day following hospital admission and 75% occurring within the first week. Severe comorbid conditions and intentionally self-inflicted injuries are associated with higher mortality rate. SMs' gender, age, year of hospital admission, and service were significantly associated with likelihood of death following PTBI hospitalization. Males had a higher likelihood of dying following hospital admission compared with females (odds ratio = 2.7, confidence interval = 1.03-7.9). SMs in the 35- to 44-year-old and 45- to 64-year-old groups had up to a 2.6 times higher odds of death following their admission compared with the 25- to 34-year-old group. Age, admission year, service, and rank were significantly associated with SMs' time to death from hospitalization. Patients between the ages of 45 and 64 years were significantly more likely to die earlier than other age groups. Furthermore, cases in the Navy Afloat group had a higher fatality rate and were more likely to die earlier than patients in other services. PTBI comorbid conditions and injury type did not significantly affect time to death. CONCLUSION: This study quantifies case fatality rate among hospitalized US SMs with the diagnosis of PTBI. We report a 23.1% crude case fatality rate among the current cohort. Early intensive care for these patients may be the key to improving survival rates. PMID- 29517593 TI - Characteristics and Health Outcomes of Post-9/11 Caregivers of US Service Members and Veterans Following Traumatic Brain Injury. AB - OBJECTIVES: To (a) characterize a sample of post-9/11 caregivers providing help to service members and veterans (SMV) following traumatic brain injury (TBI), (b) examine the level of support provided, and (c) determine caregiver health and well-being outcomes. SETTING: Military treatment facility. PARTICIPANTS: Caregivers (N = 278) of SMVs who sustained a mild, moderate, severe, or penetrating TBI (96.0% female; 86.0% spouse/partner; age: M = 38.7 years, SD = 10.4). Participants were divided into 3 groups on the basis of the level of support provided (low, medium, high). DESIGN: Prospective observational. MAIN MEASURES: Caregiver Appraisal Scale, SF-36v2 Health Survey, Mayo-Portland Adaptability Inventory-4, Caregiver Questionnaire. RESULTS: The majority of caregivers were helping an SMV with mild TBI and comorbid posttraumatic stress disorder/depression, who was injured in a blast-related incident during combat. Caregivers helped predominantly with activities of daily living and/or instrumental activities of daily living and spent more than 40 hours per week providing care. High-support caregivers were more likely to be caring for an SMV with comorbid posttraumatic stress disorder, report poor physical and mental health outcomes, and have a negative impact on employment and finances. CONCLUSIONS: A better understanding of protective factors is required to ensure that burden of care does not exceed the caregiver's health and financial capacity, or undermine the care, well-being, and recovery of the SMV. PMID- 29517594 TI - Orbital Radiotherapy Combined With Corticosteroid Treatment for Thyroid Eye Disease-Compressive Optic Neuropathy. AB - PURPOSE: To evaluate the effectiveness of orbital radiotherapy (ORT) in the treatment of thyroid eye disease (TED)-compressive optic neuropathy. METHODS: A retrospective review of patients with corticosteroid-responsive compressive optic neuropathy due to TED treated with ORT. Study was conducted in compliance with Health Insurance Portability and Accountability Act. One hundred four patients (163 orbits) with a mean age of 61.7 years met inclusion criteria. Seventy-four percent (77/104) were female, and 32.7% (34/104) were current or previous smokers. A total absorbed dose of 2000 cGy fractionated in 10 treatment doses over the course of 2 weeks was administered to the retroocular tissues according to a standard protocol. The primary end point was failure of ORT, defined as persistent optic neuropathy following completion of radiotherapy that mandated urgent orbital decompression surgery. RESULTS: Ninety-eight of 104 (94%) patients or 152 of 163 (93.3%) orbits did not require orbital decompression surgery during the acute phase. Patients who responded successfully to ORT had similar improvements in visual acuity, color vision, Humphrey threshold visual field testing, and afferent pupillary defects compared with patients who failed ORT and underwent urgent decompression surgery. Only 36.7% of successfully treated patients ultimately underwent elective surgery, including orbital decompression, strabismus, or eyelid surgery, during the inactive phase of TED. CONCLUSIONS: The data from this study, the largest retrospective review reported to date, supports the use of ORT in eyes with corticosteroid-responsive TED-compressive optic neuropathy. ORT may favorably alter the natural history of active-phase TED by preventing recurrent compressive optic neuropathy after withdrawal of corticosteroids. PMID- 29517595 TI - Three-dimensionally Printed Facial Mask to Aid the Treatment of Contracted Socket After Radiation Damage in Retinoblastoma. PMID- 29517596 TI - Neurotoxicity Secondary to Bismuth Iodoform Paraffin Paste Packing in an Orbital Exenteration Cavity. PMID- 29517597 TI - Re: "The Bleph and the Brain: The Effect of Upper Eyelid Surgery on Chronic Headaches". PMID- 29517598 TI - Reply re: "The Bleph and the Brain: The Effect of Upper Eyelid Surgery on Chronic Headaches". PMID- 29517599 TI - Re: "Simultaneous Versus Sequential Ptosis and Strabismus Surgery in Children". PMID- 29517600 TI - Reply re: "Simultaneous Versus Sequential Ptosis and Strabismus Surgery in Children". PMID- 29517601 TI - Re: "Marcus Gunn Jaw-Winking Syndrome: A Comprehensive Review and Report of Four Novel Cases". PMID- 29517602 TI - Reply re: "Marcus Gunn Jaw-Winking Syndrome: A Comprehensive Review and Report of Four Novel Cases". PMID- 29517603 TI - Re: "A Single- Versus Double-Layered Closure Technique in Anophthalmic Surgery". PMID- 29517604 TI - Reply re: "A Single- Versus Double-Layered Closure Technique in Anophthalmic Surgery". PMID- 29517606 TI - Reply re: "Postoperative Changes in Strabismus, Ductions, Exophthalmometry, and Eyelid Retraction After Orbital Decompression for Thyroid Orbitopathy". PMID- 29517605 TI - Re: "Postoperative Changes in Strabismus, Ductions, Exophthalmometry, and Eyelid Retraction After Orbital Decompression for Thyroid Orbitopathy". PMID- 29517608 TI - Editorial introduction. PMID- 29517607 TI - Assessing the Effectiveness of Arnica montana and Rhododendron tomentosum (Ledum palustre) in the Reduction of Ecchymosis and Edema After Oculofacial Surgery: Preliminary Results: Erratum. PMID- 29517609 TI - Lipid metabolism: spotlight on modulators of lipoprotein lipase activity. PMID- 29517610 TI - Branched-chain amino acids and atherosclerosis: friends or foes? PMID- 29517611 TI - Integrating Continuing Education, Quality Improvement, Faculty Development, Knowledge Translation, and Patient Safety in JCEHP. PMID- 29517612 TI - Systematic Review of Standardized Patient Use in Continuing Medical Education. AB - INTRODUCTION: The standardized patient (SP) has assumed a fundamental role in undergraduate medical education since first conceived over 50 years ago. While widely used in student training and assessment of communication and clinical examination across health disciplines, little is known how SPs enhance knowledge or skill development among professionals. We conducted a systematic review to determine the effectiveness of SPs in continuing medical education (CME) programs. METHODS: Authors independently searched for studies published between 1966 and 2016, describing CME initiatives using SP encounters as practice for participants compared with those which did not. Studies assessing virtual patients or mannequins or employing SPs for assessment only were excluded. Learning outcomes were characterized according to the Kirkpatrick framework for determining the effectiveness of training programs. RESULTS: Four hundred eighty eight studies were identified, but only five were eligible for analysis. Most were conducted with small numbers of primary care physicians in North America. CME topics related to opioid prescribing, breast cancer examination and cancer screening, smoking cessation, and chronic asthma management. In the two studies testing knowledge, no difference was found between intervention and control groups (Kirkpatrick level 2). Improved behaviors were demonstrated in breast cancer patient examination and interview and decreased opioid-prescribing rates among selected participants in two studies (Kirkpatrick level 3). Only one study investigated patient outcomes and found reduced rates of uncontrolled asthma in practices of physicians who were assigned to SP practice encounters in the CME training (Kirkpatrick level 4). DISCUSSION: There is little rigorous outcome study of CME programs incorporating SPs. Given the necessary human and fiscal resources associated with their use, our review highlights the need to reconsider the SP role in CME unless further purposeful evaluation to determine participant behavior change and related patient outcomes is pursued. PMID- 29517613 TI - Assessment of Interprofessional Team Collaboration Scale (AITCS): Further Testing and Instrument Revision. AB - INTRODUCTION: The need to be able to assess collaborative practice in health care teams has been recognized in response to the direction for team-based care in a number of policy documents. The purpose of this study is to report on further refinement of such a measurement instrument, the Assessment of Interprofessional Team Collaboration Scale (AITCS) first published in 2012. To support this refinement, two objectives were set: Objective 1: to determine whether the items from the data collected in 2016 load on the same factors as found for the 2012 version of the 37-item AITCS. Objective 2: to determine whether the items in the subscales of the AITCS could be reduced while retaining psychometric properties similar to those from the earlier versions of the AITCS. METHODS: Initially, the overall data sets of 1002 respondents from two hospitals and four community agencies were analyzed for demographics and scale and subscale mean values, SDs, and mean item scores. After deletion of respondents because of missing data, 967 respondents were available for the first analysis. An exploratory factor analysis was then conducted to determine the factor structure. All respondents with any random missing data were further removed to reduce the data set to 676 responses, followed by a confirmatory factor analysis to find a model fit resulting in an item reduction in the scale. RESULTS: The result was a 23-item AITCS-II for practitioners that retained acceptable levels of reliability and validity within 3 subscales-partnership (8 items), cooperation (8 items), and coordination (7 items). DISCUSSION: The shortened version of the AITCS-II is a valid and reliable instrument that can be used to assess collaboration in health care teams in practice settings. PMID- 29517614 TI - Project ECHO: A Telementoring Network Model for Continuing Professional Development: Erratum. PMID- 29517615 TI - Living High and Feeling Low: Altitude, Suicide, and Depression. AB - LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:* Assess epidemiologic evidence that increased altitude of residence is linked to increased risk of depression and suicide* Evaluate strategies to address hypoxia-related depression and suicidal ideation ABSTRACT: Suicide and major depressive disorder (MDD) are complex conditions that almost certainly arise from the influences of many interrelated factors. There are significant regional variations in the rates of MDD and suicide in the United States, suggesting that sociodemographic and environmental conditions contribute. Here, we review epidemiological evidence that increases in the altitude of residence are linked to the increased risk of depression and suicide. We consider the possibility that chronic hypobaric hypoxia (low blood oxygen related to low atmospheric pressure) contributes to suicide and depression, which is suggested by animal models, short-term studies in humans, and the effects of hypoxic medical conditions on suicide and depression. We argue that hypobaric hypoxia could promote suicide and depression by altering serotonin metabolism and brain bioenergetics; both of these pathways are implicated in depression, and both are affected by hypoxia. Finally, we briefly examine treatment strategies to address hypoxia-related depression and suicidal ideation that are suggested by these findings, including creatine monohydrate and the serotonin precursors tryptophan and 5-hydroxytryptophan. PMID- 29517617 TI - Too many pills on the kitchen table. PMID- 29517618 TI - Beyond skin deep: Managing pressure injuries. AB - Pressure injuries (previously called pressure ulcers) are a common finding among patients in acute, long-term, or home settings. Numerous pathophysiologic and risk mechanisms factor into the development of pressure injuries. The timely recognition of these injuries is imperative. Many treatments exist for pressure injuries but the focus of patient management should be on preventing injury related complications. PMID- 29517616 TI - A Dose-escalation Study of Recombinant Human Interleukin-18 in Combination With Ofatumumab After Autologous Peripheral Blood Stem Cell Transplantation for Lymphoma. AB - Interleukin-18 (IL-18) is an immunostimulatory cytokine that augments antibody dependent cellular cytotoxicity mediated by human natural killer cells against antibody-coated lymphoma cells in vitro and that has antitumor activity in animal models. Ofatumumab is a CD20 monoclonal antibody with activity against human B cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with ofatumumab was undertaken in patients with CD20 lymphoma who had undergone high dose chemotherapy and autologous peripheral blood stem cell transplantation. Cohorts of 3 patients were given intravenous infusions of ofatumumab 1000 mg weekly for 4 weeks with escalating doses of rhIL-18 as a intravenous infusion weekly for 8 consecutive weeks. Nine male patients with CD20 lymphomas were given ofatumumab in combination with rhIL-18 at doses of 3, 10, and 30 MUg/kg. No unexpected or dose-limiting toxicities were observed. The mean reduction from predose levels in the number of peripheral blood natural killer cells after the first rhIL-18 infusion was 91%, 96%, and 97% for the 3, 10, and 30 MUg/kg cohorts, respectively. Serum concentrations of interferon-gamma and chemokines transiently increased following IL-18 dosing. rhIL-18 can be given in biologically active doses by weekly infusions in combination with ofatumumab after peripheral blood stem cell transplantation to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus ofatumumab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted. PMID- 29517619 TI - Sandifer syndrome. AB - Sandifer syndrome is a rare complication of gastroesophageal reflux disease that may be more common than reported. This syndrome was first mentioned more than 50 years ago with minimal documentation in the medical literature. Because of the presentation, the patient may be referred for lengthy, expensive, and unnecessary neurologic testing. This may lead to a missed or delayed diagnosis, mismanagement, and the use of inappropriate medication. Providers should be aware of Sandifer syndrome when evaluating a child with torticollis or unusual posturing that is not associated with neuromuscular disease or injury. PMID- 29517620 TI - Response to the article by Bousman and colleagues: 'Systematic evaluation of commercial pharmacogenetic testing in psychiatry'. PMID- 29517621 TI - Reply to Searcy and colleagues. PMID- 29517623 TI - Ultrasonography as a Diagnostic, Therapeutic, and Research Tool in Orthopaedic Surgery. AB - Ultrasonography is an imaging modality that facilitates the diagnosis of pathology and injection therapy without exposing the patient to radiation. In addition, ultrasonography has become popular because of its portability, low cost, and production of real-time tomographic images that provide a cross sectional view of anatomic structures. Despite its benefits and widespread adoption in general medicine and other specialties, however, ultrasonography is not as well adapted as a diagnostic and research tool in orthopaedic surgery. An understanding of the basic principles of ultrasonography and the evidence supporting its use can aid the orthopaedic surgeon in applying this modality appropriately in clinical practice. PMID- 29517622 TI - PharmGKB summary: clobazam pathway, pharmacokinetics. PMID- 29517624 TI - Sleep Quality in Patients With Rotator Cuff Disease. AB - BACKGROUND: Little is known about the influence of rotator cuff pathology on sleep. The purpose of this study was to determine which patient-reported factors correlate with sleep disturbance in patients with rotator cuff disease. METHODS: A nonrandomized, cross-sectional cohort study was performed to evaluate the effects of rotator cuff disease on sleep quality. Data collected at time zero (before any treatment) included the Single Assessment Numeric Evaluation rating, the American Shoulder and Elbow Surgeons score, the Pittsburgh Sleep Quality Index, patient demographics, and medical comorbidities. Statistical analysis included the Pearson correlation and multiple regression analysis to determine which patient-reported factors were associated with sleep disturbance. RESULTS: Nocturnal pain was reported by 91% of the 391 participants (274 with tendinitis and 117 with rotator cuff tears). Participants had a mean age of 57 years. Pearson correlation coefficients determined that poor sleep quality in one group or both the tendinitis and the rotator cuff tear groups was associated with higher pain visual analog scale scores (0.27 and 0.31; P = 0.004 and P < 0.0001, respectively), depression (0.27 and 0.30; P < 0.01), female sex (0.24 and 0.27; P < 0.001), presence of low back pain (0.25 and 0.27; P < 0.01), diabetes mellitus (0.24 in the rotator cuff tear group; P < 0.01), and increased body mass index (0.22 and 0.27; P = 0.02). DISCUSSION: The status of the rotator cuff did not correlate with increasing symptoms of shoulder pain or with worse sleep quality as measured by the Pittsburgh Sleep Quality Index. These results support the theory that worsening symptoms of shoulder pain may not be clearly associated with rotator cuff disease severity. CONCLUSION: Worse sleep quality scores in patients with rotator cuff disease are associated with pain, depression, female sex, low back pain, diabetes mellitus, and high body mass index. Overall, sleep quality did not differ among patients with varying rotator cuff disease severity. Only hypertension (in patients with rotator cuff tears) and concurrent cervical pathology (in patients with tendinitis) were uniquely related to the disease classification. Further investigation is needed to better define how these factors interact and influence nocturnal shoulder pain and sleep quality in patients with rotator cuff disease. LEVEL OF EVIDENCE: Level III prognostic cohort study. PMID- 29517625 TI - No Difference Between Bracing and No Bracing After Open Reduction and Internal Fixation of Tibial Plateau Fractures. AB - INTRODUCTION: The use of a postoperative brace may be beneficial after open reduction and internal fixation of tibial plateau fractures. However, bracing has potential drawbacks related to cost, fitting, wound complications, and compliance. We hypothesized that no difference will be found between patients with and without bracing after open reduction and internal fixation of tibial plateau fractures. METHODS: In this prospective, comparative trial, patients were randomized to 6 weeks of bracing or no bracing after open reduction and internal fixation of tibial plateau fractures. Functional, subjective, and radiographic outcomes were recorded. Patients with an open physis, unstable ligamentous injuries, extensor mechanism disruption, and/or <6 months of prospective outcome data were excluded. RESULTS: The 24 patients with bracing (average age, 50 +/- 16 years; 14 women and 10 men) were compared with the 25 patients without bracing (average age, 51 +/- 12 years [P = 0.74]; 9 women and 16 men). No statistically significant differences were found in most of the functional, subjective, and radiographic outcomes, including fracture characteristics, complications, postoperative range of motion, Medical Outcomes Study 36-Item Short Form scores, and union rates. In the nonbraced group, one patient had late joint collapse with valgus malalignment (>10 degrees ). Two wound complications occurred in the braced group and four wound complications occurred in the nonbraced group, but this difference was not statistically significant. DISCUSSION: Improvements in conventional and locking plate technology have allowed more reliable rigid internal fixation of tibial plateau fractures. However, the use of a brace for postoperative rehabilitation after open reduction and internal fixation of tibial plateau fractures continues to be debated. CONCLUSION: Our prospective study showed no statistically significant difference between bracing and no bracing after open reduction and internal fixation of tibial plateau fractures in terms of functional, subjective, and radiographic outcomes. LEVEL OF EVIDENCE: Therapeutic level II. PMID- 29517626 TI - Weekend Effect in Acute Pancreatitis-Related Hospital Admissions in the United States: An Analysis of the Nationwide Inpatient Sample. AB - OBJECTIVE: This study aimed to assess the difference in overall outcomes between weekend admissions for acute pancreatitis (AP) and weekday admissions. METHODS: Between 2005 and 2012, data were extracted from the Nationwide Inpatient Sample on adult patients with AP. Exclusion criteria were applied for chronic pancreatitis and other pancreatic and biliary malignancies. In-hospital mortality, length of stay, hospitalization costs, comorbidities, complications, and intervention rates were compared between the weekend and weekday admissions. RESULTS: During the study period, there were a total of 432,303 weekday admissions and 147,435 weekend admissions for AP in the United States hospitals. Weekend AP admissions were more likely to develop alcohol withdrawal (5.9% vs 5.7%, P = 0.001) and ileus (4.1% vs 3.1%, P = 0.04). They were also more likely to develop acute respiratory distress syndrome (4.7% vs 4.4%, P < 0.001) and required more endotracheal intubation (3.9% vs 3.6%, P < 0.001). There was no significant in-hospital mortality difference between the weekend and weekday admissions on both univariate and multivariate analysis. CONCLUSIONS: Weekend AP admissions develop more severe complications requiring intensive care. Despite this, there was no weekend effect for in-hospital mortality for AP-related admissions. PMID- 29517627 TI - Relative Rise of Serum IgG4 Levels After Steroid Therapy for Autoimmune Pancreatitis Predicts the Likelihood of Relapse. AB - OBJECTIVES: Serum IgG4 level is a useful diagnostic marker of autoimmune pancreatitis (AIP); however, it is difficult to predict relapse. We investigated whether a change in serum IgG4 is predictive of AIP relapse during maintenance therapy. METHODS: Seventy-three patients with AIP treated with steroids were divided into 3 groups according to their initial serum IgG4 levels: level 1 group (>2-fold upper limit), level 2 group (1- to 2-fold upper limit), and a normal group. The relapse rate and the prevalence of extrapancreatic lesions were compared between the 3 groups. The correlation between the relative rise of serum IgG4 levels and relapse during maintenance therapy was analyzed. RESULTS: There were no differences in serum IgG4 levels in the presence or absence of relapse. The average number of extrapancreatic lesions was 1.02, 0.47, and 0.27 in level 1, level 2, and the normal group, respectively. The relative rise of serum IgG4 levels after steroid therapy was significantly higher in relapse than in nonrelapse cases. The area under the receiver operating characteristic curve of the relative rise of IgG4 levels for discriminating between the relapse and the nonrelapse cases was 0.85. CONCLUSIONS: The relative rise of serum IgG4 levels after steroid therapy may provide an indication of relapse. PMID- 29517628 TI - TH1 and TH2 Cytokine Profiles as Predictors of Severity in Acute Pancreatitis. AB - OBJECTIVES: Acute pancreatitis (AP) is severe in up to 20% of patients, with a high mortality rate. Quantification of serum TH1 and TH2 cytokines may provide objective evidence to assess the severity of AP and predict its course. METHODS: One hundred seventeen patients were studied, measuring serum concentrations of interleukin (IL)1beta, IL2, IL4, IL5, IL6, IL10, IL12p70, IL13, IL18, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN) gamma, and tumor necrosis factor (TNF) alpha. RESULTS: Significant differences were found between patients with severe AP and those with mild or moderately severe AP in IFN-gamma (P < 0.001), IL6 (P < 0.001), TNF-alpha (P = 0.002), GM-CSF (P < 0.001), IL4 (P = 0.002), IL1b (P = 0.017), and IL13 (P < 0.001) concentrations. Interferon-gamma, IL6, and TNF-alpha were associated with severe AP, whereas GM-CSF, IL4, IL1b, and IL13 were associated with mild or moderately severe AP. The IL13/IFNgamma ratio was significantly higher in patients with mild AP (P = 7.36 * 10). CONCLUSIONS: A TH1 profile was associated with severe AP and a TH2 profile with mild or moderately severe AP. We report an IL13/IFNgamma ratio of potential value to predict the prognosis in AP. PMID- 29517629 TI - E and P Selectins as Potential Markers in the Assessment of the Severity of Acute Pancreatitis. AB - OBJECTIVES: Acute pancreatitis (AP) is commonly associated with the release of adhesion molecules such as E and P selectins. We designed the present study to evaluate the role of selectins as potential markers that could reflect the severity of the disease. METHODS: One hundred fifty patients with AP constituted the patient group, whereas 70 healthy volunteers established the control group. In both groups, blood samples were taken for measurements of E selectin, P selectin, caspase-cleaved cytokeratin 18, and total soluble cytokeratin 18 levels on admission and days 1, 2, 4, and 6. RESULTS: Values of E and P selectins on admission were both elevated compared with control subjects (P < 0.01). The nonsurvivors had higher values of E selectin (P < 0.04) and P selectin (P < 0.03) on admission. Levels of E and P selectin showed positive correlation with the length of stay (P < 0.05). E selectin on admission yielded a sensitivity of 75% and 78% specificity, whereas P selectin had a sensitivity of 67% and 91% specificity. CONCLUSIONS: Selectin values in the early course of AP may play a role as indicators of overall prognosis, which may help physicians in better understanding the pathophysiology of a benign disease that may have serious and detrimental complications. PMID- 29517630 TI - Impact of Antibiotic-Resistant Bacterial and Fungal Infections in Outcome of Acute Pancreatitis. AB - OBJECTIVES: The knowledge about pathogens and their antibiotic susceptibility patterns is essential to select an appropriate antibiotic. METHODS: We investigated the microbiological profile in pancreatic and extrapancreatic infections, and antibiotic sensitivity pattern in patients with acute pancreatitis. RESULTS: Of 556 patients with acute pancreatitis, only 189 developed bacterial infection; however, bacteremia was present in 42 patients (7.6%). Culture-proven infected pancreatic necrotic collection was present in 161 patients (29%). Escherichia coli and Klebsiella pneumoniae were the most common organisms. Among the bacterial infection cohort, 164 patients developed multidrug resistant bacterial infection. Infection with multidrug-resistant bacteria, especially at multiple sites, increased mortality. Nearly 50% of patients (n = 94) acquired extremely drug-resistant bacterial infection at some time and emerged as key reason for prolonged hospital and intensive care unit stay. Colistin resistance and tigecycline resistance were documented in 2.1% and 17.2% of the specimens at admission and in 4.6% and 21% of specimens during the hospital stay. Of 556 patients, 102 patients developed fungal infection and 28 patients had only fungal infection without bacterial infection. CONCLUSIONS: Colistin and tigecycline are best reserved as last-resort antibiotics. Fungal infection was found to be associated with increased mortality, median hospital stay, and intensive care unit stay. PMID- 29517631 TI - Prospective Follow-up Study of the Recurrence of Pancreatic Cancer Diagnosed at an Early Stage: The Value of Endoscopic Ultrasonography for Early Diagnosis of Recurrence in the Remnant Pancreas. AB - OBJECTIVES: Most patients with pancreatic cancer (PC) demonstrate recurrences in the form of metastatic disease. We prospectively evaluated recurrence in PC cases diagnosed at an early stage. METHODS: Thirty cases of PC stage 0 or IA were prospectively followed for at least 1 year after initial surgery. We performed blood tests and contrast-enhanced computed tomography (CT) every 3 to 6 months. Endoscopic ultrasonography (EUS) was performed if CT revealed abnormal findings in the remnant pancreas (RP). RESULTS: The median follow-up period was 53.9 months. Pancreatic cancer recurred in the RP (n = 8) and liver (n = 1). Computed tomography revealed mass lesions in 5 cases, a cystic lesion in 2 cases, and pancreatic duct dilatation in 1 case. Endoscopic ultrasonography detected mass lesions in 3 cases without a detectable mass on CT. The sensitivity of EUS-guided fine-needle aspiration and pancreatic juice cytology was 75%. Five of 8 cases underwent total resection of the RP, with pathologic findings revealing stage IA in 1 case, stage II in 1 case, and stage III in 3 cases. CONCLUSIONS: Careful long-term follow-up including EUS should be performed in resected PC cases diagnosed at an early stage to check recurrence in the RP. PMID- 29517632 TI - Clinical Significance of Histological Effect and Intratumor Stromal Expression of Tenascin-C in Resected Specimens After Chemoradiotherapy for Initially Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVES: Tenascin-C (TN-C) is an extracellular matrix protein that is up regulated in pancreatic ductal adenocarcinoma (PDAC) stroma and associated with tumor invasion. We examined intratumor stromal expression of TN-C in resected specimens and the histologic effect of chemoradiotherapy (CRT) as prognostic indicators in initially locally advanced unresectable (UR-LA) PDAC. METHODS: Among 110 UR-LA PDAC patients enrolled in the CRT protocol from February 2005 to December 2015, 46 who underwent curative-intent resection were classified as high (tumor destruction >50%) and low (<=50%) responders according to the Evans grading system. Tenascin-C expression was immunohistologically evaluated in all patients except one with complete response. RESULTS: The 12 high responders achieved a significantly higher R0 rate than did the 34 low responders (83.3 vs 47.1%), but disease-specific survival (DSS) time was not significantly different (median survival time, 29.8 vs 21.0 months). Tenascin-C expression was inversely correlated with histologic effect of CRT. The 22 patients with negative TN-C had significantly longer DSS time than did the 23 with positive TN-C (29.3 vs 17.1 months). In multivariate analysis, only TN-C expression was a significant prognostic factor for DSS. CONCLUSIONS: Intratumor stromal expression of TN-C is a strong prognostic indicator in UR-LA PDAC patients with resection after CRT. PMID- 29517633 TI - Potential Prediction of Acute Biliary Pancreatitis Outcome on Admission. AB - OBJECTIVES: This pilot study aimed to determine the feasibility of serum values of osteonectin, adiponectin, transforming growth factor beta 1, and neurotensin being used in clinical practice to predict the severity of acute pancreatitis. METHODS: Blood samples were collected from 45 consecutive newly diagnosed acute pancreatitis patients and 30 matched healthy controls. The 2 groups were matched according to age, sex, weight, height, diabetes, smoking, and alcohol consumption. The aforementioned markers were measured using enzyme-linked immunosorbent assay kits. RESULTS: Characteristics of acute pancreatitis patients and healthy controls were comparable. Osteonectin values differed significantly (P < 0.0001). Median/lower quartile/upper quartile of osteonectin levels for acute pancreatitis patients and healthy controls were 263.5/110.3/490.36 and 63.2/46.1/87.2 ng/mL, respectively. Two patients died, 1 patient underwent necrosectomy, and 4 patients had a prolonged intensive care unit/hospital stay. Acute Physiology and Chronic Health Evaluation II and Systemic Inflammatory Response Syndrome scores neither predicted serum values of any of the measured substances nor the clinical outcome (need for intervention, prolonged intensive care unit/hospital stay and mortality). Osteonectin was the only independent predictor for clinical outcome (P = 0.007). CONCLUSIONS: Serum osteonectin strongly discriminates healthy individuals from acute pancreatitis patients. Serum osteonectin shows promise in the prediction of the clinical outcome. PMID- 29517634 TI - Age and Disease Duration Impact Outcomes of Total Pancreatectomy and Islet Autotransplant for PRSS1 Hereditary Pancreatitis. AB - OBJECTIVES: We investigated the impact of patient age and disease duration on islet isolation results, diabetes outcomes, and pain outcomes after total pancreatectomy with islet autotransplant (TPIAT) performed in 64 patients with hereditary pancreatitis due to PRSS1 gene mutation. METHODS: We evaluated the association of patient age and disease duration on islet isolation results and opioid use at 1 year using logistic regression and on graft function using 1-way analysis of variance. RESULTS: Islet mass was negatively associated with increasing age and longer disease duration, with a 13% reduction (95% confidence interval [CI], 3%-22%) and 22% (95% CI, 14%-29%) reduction in islet equivalents per kilogram body weight (IEQ/kg) for each 5 years of age and disease duration, respectively. Full graft function was associated with younger age and shorter duration of disease (P < 0.01). Persistent opioid use (15% of patients at 1 year) increased with age (P = 0.05) and disease duration (P = 0.04). CONCLUSIONS: The TPIAT outcomes were adversely impacted by older age and prolonged disease. In particular, islet mass is lower and risk of diabetes high in older patients with prolonged disease. This should be considered when counseling this subgroup of TPIAT recipients on expected outcomes. PMID- 29517635 TI - Establishment and Verification of a Scoring Model for the Differential Diagnosis of Pancreatic Cancer and Chronic Pancreatitis. AB - OBJECTIVES: The aims of this study were to establish a scoring model for the differential diagnosis of pancreatic cancer (PC) and chronic pancreatitis (CP) and to evaluate its diagnostic efficacy. METHODS: The data of 502 patients with PC and 210 patients with CP at the Peking Union Medical College Hospital from January 1999 to December 2013 were retrospectively analyzed. Binary logistic regression was applied to establish the prediction model for the differential diagnosis. The model was verified using the method of leave-one-out cross validation. RESULTS: The scoring system was established with 5 variables including age, carbohydrate antigen 19-9 level, splenic vein invasion, irregular dilatation of the pancreatic duct, and nontruncated pancreatic duct stenosis. The score range was from -2 to 3. The area under the receiver operating characteristic curve of the objects was 0.779 (95% confidence interval, 0.744 0.814) (P < 0.01), indicating that the scoring system is good at differentiation of PC with CP. With a score of 1 as the diagnostic cut-off value, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate were 71.3%, 69.0%, 70.0%, 71.4%, and 70.2%, respectively. CONCLUSIONS: The scoring model may improve the differential diagnosis of PC and CP and be useful in clinical practice. PMID- 29517636 TI - A New 2-Step Acceleration Protocol Using a Histone Deacetylase Inhibitor to Generate Insulin-Producing Cells From Adipose-Derived Mesenchymal Stem Cells. AB - OBJECTIVES: We aimed to develop a simple protocol for deriving insulin-producing cells (IPCs) from adipose-derived mesenchymal stem cells (ADSCs). We established a 2-step creation method and an acceleration strategy with a histone deacetylase inhibitor that promoted a pro-endocrine pancreatic lineage. METHODS: We seeded ADSCs in 96-well dishes and cultured in Dulbecco's modified Eagle's medium/F12 medium containing 1% fetal bovine serum, 1% B27 supplement, 1% N2 supplement, 50 ng/mL human activin A, and 10-nM exendin-4 for step 1 of differentiation (7 days). Then 10-mM nicotinamide and 50-ng/mL human hepatocyte growth factor, with or without 1 mM histone deacetylase inhibitor, were added for step 2 of differentiation (14 days). After the 2-step differentiation was complete, cell morphology, immunohistochemistry, messenger RNA expression, and function were investigated. RESULTS: Our new differentiation protocol with the histone deacetylase inhibitor significantly accelerated IPC differentiation compared with the conventional protocol without the histone deacetylase inhibitor (median, 21.6 vs 38.8 days; P < 0.05). It also improved the islet morphology score (P < 0.05) and the glucose stimulation index (3.1). CONCLUSIONS: By applying our new and easy 2-step protocol using a histone deacetylase inhibitor, ADSCs may be an effective cell source for differentiation of IPCs. PMID- 29517637 TI - Early Endoscopic Retrograde Cholangiopancreatography Versus Conservative Treatment in Patients With Acute Biliary Pancreatitis: Systematic Review and Meta analysis of Randomized Controlled Trials. AB - OBJECTIVES: The aim of the study was to evaluate the role of early endoscopic retrograde cholangiopancreatography (ERCP) in the treatment of acute biliary pancreatitis, in comparison with conservative treatment. METHODS: Systematic review via databases (MEDLINE [PubMed], Latin-American and Caribbean Health Sciences Literature database, Embase, Cochrane Central, and the [Brazilian] Regional Library of Medicine) is conducted. We analyzed 10 randomized controlled trials (1091 patients). Outcomes were the following: local and systemic adverse events; acute cholangitis; death; length of hospital stay; cost; abdominal pain; and time to a reduction in body temperature. For the meta-analysis, we used risk difference (RD) and mean with standard deviation as measures of variability. RESULTS: There was a statistically significant difference between the patients submitted to ERCP in terms of the following: local adverse events (RD, 0.74; 95% confidence interval [CI], 0.55-0.99), time to pain relief and time to a reduction in axillary temperature (RD, -5.01; 95% CI, -6.98 to -3.04, and RD, -1.70; 95 CI%, -2.33 to -1.08, respectively). Patients undergoing ERCP spent less time in hospital (RD, -11.04; 95% CI, -15.15 to -6.93). Cost was lower in the group treated with ERCP. CONCLUSIONS: Early ERCP decreases local adverse events, shortening the time to pain relief, to a reduction in axillary temperature, hospital stays, and cost in patients with acute biliary pancreatitis. PMID- 29517639 TI - Risk Factors for the Need of Surgical Necrosectomy After Percutaneous Catheter Drainage in the Management of Infection Secondary to Necrotizing Pancreatitis. AB - OBJECTIVES: This study aimed to assess the need of surgical necrosectomy after percutaneous catheter drainage (PCD) for infected necrotizing pancreatitis. METHODS: The clinical data of documented/suspected patients who were treated with a step-up approach were extracted and analyzed. RESULTS: Of the 329 patients enrolled, the initial PCD was performed at 12 (interquartile range, 9-15) days since onset and 35.3% were cured by PCD alone. In the pre-PCD model, mean computed tomographic (CT) density of necrotic fluid collection (NFC; P < 0.001), and multiple-organ failure (MOF; P < 0.001) within 24 hours before the initial PCD were independent risk factors, and a combination of the previously mentioned 2 factors produced an area under the curve of 0.775. In the post-PCD model, mean CT density of NFC (P = 0.041), MOF (P = 0.002), and serum procalcitonin level (P = 0.035) 3 days after the initial PCD were independent risk factors, and a combination of these previously mentioned factors produced an area under the curve of 0.642. CONCLUSIONS: Both mean CT density of NFC and MOF are independent pre- and post-PCD risk factors for the need of necrosectomy after PCD. Post-PCD serum procalcitonin level might be a respondent factor that is correlated with the necessity of necrosectomy. PMID- 29517638 TI - Endoscopic Retrograde Cholangiopancreatography Decreases All-Cause and Pancreatitis Readmissions in Patients With Acute Gallstone Pancreatitis Who Do Not Undergo Cholecystectomy: A Nationwide 5-Year Analysis. AB - OBJECTIVES: Cholecystectomy is the definitive management of gallstone pancreatitis (GSP). The benefit of endoscopic retrograde cholangiopancreatography (ERCP) in patients who do not undergo cholecystectomy remains unclear. This study aims to evaluate the effect of ERCP on all-cause and pancreatitis readmissions in GSP. METHODS: Adult hospitalizations for GSP in the 2010-2014 National Readmissions Database were divided into the following 3 groups: (1) no cholecystectomy nor ERCP, (2) no cholecystectomy with ERCP, and (3) cholecystectomy group. A multivariable Cox model was used to compare the 60-day readmission rates controlling for significant confounders. RESULTS: There were 153,480 GSP admissions, 29.2% did not undergo cholecystectomy or ERCP, 12.0 % underwent ERCP only, and 58.8% had cholecystectomy. In the no cholecystectomy group, ERCP was associated with lower all-cause readmissions (adjusted hazard ratio, 0.80; 95% confidence interval, 0.76-0.83; P < 0.0001) and pancreatitis readmissions rate (adjusted hazard ratio, 0.51; 95% confidence interval, 0.47 0.55; P < 0.0001) compared with no ERCP. The protective effect of ERCP remained significant in severe pancreatitis. Cholecystectomy had the strongest protective effect against readmissions. CONCLUSIONS: In this large, nationally representative sample, ERCP was associated with reduced readmissions in patients with GSP who did not undergo cholecystectomy. Although cholecystectomy remains the most important intervention to prevent readmissions, these results support performing ERCP in patients unfit for surgery. PMID- 29517640 TI - No association of leg strength asymmetry with walking ability, fatigability, and fatigue in multiple sclerosis. AB - This cross-sectional study aims to determine whether leg strength asymmetries are associated with walking ability, objective measures of fatigability, or subjective perceptions of fatigue. Maximal knee extensor strength was assessed in 19 patients with multiple sclerosis (PwMS), and a symmetry index was calculated. Walking ability was determined through the total distance covered during a 6-min walk test (6MWT) and fatigability by calculating the change in distance covered between minutes 6 and 1. Perceptions of fatigue were assessed using the Fatigue Severity Scale and by obtaining ratings of perceived exertion during the first and final minute of the 6MWT. PwMS covered less distance (P=0.01) and perceived greater exertion (P<0.01) during minute 6 compared with minute 1. Knee extensor strength was asymmetric (P<0.01). The magnitude of asymmetry did not correlate with walking ability, fatigability, or measures of fatigue. Knee extensor strength asymmetry may not play an important role in prolonged walking performance in PwMS. PMID- 29517642 TI - The Orbit. PMID- 29517641 TI - Implant-Supported Fixed Partial Prostheses With Different Prosthetic Materials: A Three-Dimensional Finite Element Stress Analysis. AB - PURPOSE: To evaluate the effects of prosthetic material on the degree of stress to the cortical bone, trabecular bone, framework, and implants using finite element analysis (FEA). MATERIALS AND METHODS: A mandibular implant-supported fixed prosthesis was designed. Different prosthetic materials [cobalt-chromium supported ceramic, zirconia-supported ceramic, and zirconia-reinforced polymethyl methacrylate (ZRPMMA)-supported resin] were used. FEA was used to evaluate stress under different loading conditions. Maximum principal (sigmamax), minimum principal (sigmamin), and von Mises (sigmavM) stress values were obtained. RESULTS: Similar sigmamax, sigmamin, and sigmavM values were observed in the cortical and trabecular bones and in implants under both loading conditions, with the exception of the ZRPMMA model, which showed the highest sigmamax, sigmamin, and sigmavM values in oblique loading. The ZRPMMA model had the lowest sigmavM value in the framework under both loading conditions. CONCLUSION: ZRPMMA had the lowest stress values in the framework, with increased stress values in the implants and bone tissue. Framework and veneering materials may influence stress values under different loading conditions. PMID- 29517643 TI - Orbital Anatomy. PMID- 29517644 TI - CT and MRI of the Orbit. PMID- 29517645 TI - Orbital Surgery: Approaches and Techniques. PMID- 29517646 TI - Endoscopic Endonasal Approaches to the Orbit. PMID- 29517647 TI - Transcranial Approaches to the Orbit. PMID- 29517648 TI - Diagnosis and Management of Pediatric Orbital Diseases. PMID- 29517650 TI - Orbital Tumors and Inflammatory Disorders: Diagnosis and Management. PMID- 29517649 TI - Thyroid Orbitopathy. PMID- 29517651 TI - Lacrimal Gland Tumors. PMID- 29517652 TI - Tumors of the Optic Nerve and its Sheath. PMID- 29517653 TI - Orbital Infections: Current Standards and Future Directions. PMID- 29517654 TI - Carotid-Cavernous Fistulae: A Review of Clinical Presentation, Therapeutic Options, and Visual Prognosis. PMID- 29517656 TI - Comparison of magnetic resonance imaging for patients with acute and chronic anterior cruciate ligament tears. AB - To compare the direct and indirect signs on magnetic resonance imaging (MRI) for patients with acute and chronic anterior cruciate ligament (ACL) tears.Two independent reviewers retrospectively evaluated the MRI images of 377 patients with ACL tear confirmed by arthroscopy. There were 160 cases with acute ACL tear and 217 cases with chronic ACL tear. Direct signs in T1- and T2-wighted images and indirect signs including meniscus injury, the collateral ligament injury, cartilage damage or osteoarthritis, kissing contusion, Notch syndrome and abnormal posterior cruciate ligament (PCL) and other indirect signs were evaluated.For direct signs on MRI, no significant differences were found between the acute and chronic ACL tear in prevalence of focal high signal in substance of T2-wighted images and in that of abnormal orientation, discontinuity, thickening, or focal masses in substance of T1-weighted images. However, higher incidence of diffuse high signal of T2-weighted images for acute ACL tear was found compared to that for chronic ACL tear (55.0% vs 3.2%). For indirect signs on MRI, the collateral ligament tear (20.6% vs 2.3%), cartilage damage or osteoarthritis (14.4% vs 25.8%), kissing contusion (57.4% vs 0%), Notch syndrome (28.1% vs 3.2%), and bowing type of PCL (33.1% vs 47.0%) can differentiate the acute from chronic ACL tear.Some direct and indirect signs on MRI are closely related to the acute and chronic ACL tear. PMID- 29517657 TI - Minimal invasive nonfusion technique for the treatment of noncontiguous lumbar burst fractures in young age patient: A case report. AB - RATIONALE: In the treatment of noncontiguous lumbar burst fractures, there still remains controversy over proper surgical procedures. PATIENT CONCERNS: A 19-year old female patient visited our hospital after fall down from 3 m high. DIAGNOSES: Initial neurologic examination revealed an incomplete spinal cord injury characterized by hypoesthesia and motor grade of 2 below the L2 segment. Lumbar computed tomography and magnetic resonance imaging demonstrated L2 and L5 burst fractures severely obliterating the spinal canal. INTERVENTIONS: She underwent emergent PSSPSF at L1-2-3 and L4-5-S1 following bilateral L1 and L4 laminotomy with reduction of bony fragments by tapping method. OUTCOMES: She was gradually recovered and able to walk with assistance two weeks after surgery. Removal of implants was performed at 12 months after surgery. Follow-up radiography showed well-preserved segmental motion and adequate decompressed spinal canal with fused fractured bony fragment. She returned to her normal daily activities without any neurologic deficits and pain. LESSONS: Noncontiguous burst fracture of the lumbar spine is an unusual injury. For the adequate management in patient with neurologic deficit, reduction of the fractured body and stabilization of vertebral column is necessary. It is also important to preserve the segmental motion in young age patients. From that point of view, temporary PSSPSF with spinal canal decompression is considered as minimal invasive surgery with significant low morbidity, providing stability with motion saving and good clinical outcome. PMID- 29517658 TI - The role of definitive local treatment in metastatic hepatocellular carcinoma patients: A SEER-based study. AB - In the present study, we aimed to investigate the survival benefit from definitive local treatment (LT) for hepatocellular carcinoma patients with distant metastasis (mHCC).We retrospectively analyzed mHCC patients from Surveillance, Epidemiology, and End Results (SEER) Database. The patients' clinical and pathological characteristics were analyzed. Overall survival (OS) was calculated by Kaplan-Meier method. Independent risk factors associated with disease special mortality (DSM) were identified by multivariable regression analysis.A total of 7187 mHCC patients from SEER database were identified. A total of 258 (3.6%) patients had received surgery treatment (ST), 64 (0.9%) patients underwent radiotherapy (RT), and 6865 (95.5%) patients were identified to no surgery or radiation therapy group (NSR). Compared with the patients in NSR group, patients who received ST (hazard ratio [HR]: 0.26, 95% confidence interval [CI] 0.22-0.31, P < .001) and RT (HR: 0.51, 95% CI 0.38-0.67, P < .001) had decreased DSM. Patients with age >50 years, female, and T3 or higher stage were associated with increased DSM.The present study demonstrated the survival benefit of definitive LT in mHCC patients. However, a large randomized clinical trial to validate the role of LT in mHCC is necessary in the future. PMID- 29517659 TI - ELANE gene mutation-induced cyclic neutropenia manifesting as recurrent fever with oral mucosal ulcer: A case report. AB - BACKGROUND: Cyclic neutropenia (CyN) is a rare hematological disease. Herein, a CyN girl, aged 3 years and 2 months, with recurrent fever and oral mucosal ulcer caused by neutrophil elastase (ELANE) gene mutation is reported. CASE PRESENTATION: A 3 years and 2 months old girl presented with recurrent fever and oral mucosal ulcer for 1 year. Routine blood test revealed that her absolute neutrophil count repeatedly decreased (minimum 0. 04 * 10/L) every 21 days on an average. Gene testing showed that the patient suffered from ELANE gene heterozygous mutation (c.197T>G) (exon2) (p.M66R). She was finally diagnosed as CyN. The patient's symptoms were relieved after infection prevention and treatment as well as granulocyte-colony stimulating factor (G-CSF) therapy. Her condition continues to remain stable. CONCLUSION: Active prevention and treatment of infection as well as G-CSF therapy can successfully control CyN. PMID- 29517660 TI - Major influence of postoperative complications on costs of cytoreductive surgery and HIPEC in patients with colorectal peritoneal metastases. AB - Complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) result in impaired short- and long-term outcomes. However, financial consequences of complications after CRS and HIPEC in a European health care setting are unknown. This study aims to assess the consequences of complications on hospital costs after CRS and HIPEC.In this prospective observational cohort study, patients with colorectal peritoneal metastases treated with CRS and HIPEC were included. Financial information was collected according to the Dutch manual for costs analyses. Costs were compared between patients without complications (NC), minor complications (MC), or severe complications (SC), according to the Clavien-Dindo classification.One hundred and sixty-one patients were included, of whom 42% experienced NC, 27% MC and 31% SC. Mean hospital costs were &OV0556;9.406 +/- 2.235 in NC patients, &OV0556;12.471 +/- 3.893 in MC patients, and &OV0556;29.409 +/- 22.340 in SC patients. The 31% of patients with severe complications accounted for 56% of all hospital costs. Hospital admission costs in SC patients were 320% higher compared to NC patients. Costs of complications were estimated to be 43% of all admission costs.Severe postoperative complications have major influence on costs after CRS and HIPEC and result in a threefold increase of hospital costs in affected patients. This finding stresses the need for adequate risk assessment of developing severe complications after CRS and HIPEC. PMID- 29517661 TI - Prognostic value of carcinoembryonic antigen level in patients with colorectal cancer liver metastasis treated with percutaneous microwave ablation under ultrasound guidance. AB - Thermal ablation is an alternative treatment for colorectal cancer liver metastasis (CRLM). However, prognostic factors in patients with CRLM who have undergone microwave ablation (MWA) have not been clearly defined. Therefore, this study aimed to analyze the risk factors associated with early recurrence in patients with CRLM treated with MWA.Herein, we retrospectively analyzed data for 140 patients with CRLM who underwent MWA from 2013 to 2015 in our institution. Patients were grouped by median pretreatment carcinoembryonic antigen (CEA) level into the high CEA level (>3.7 ng/mL) group and low CEA level (<=3.7 ng/mL) group. Variables that might affect overall survival were subjected to univariable and multivariable Cox regression analysis.Our results showed a median progression free survival (PFS) and median liver progression-free survival (LPFS) of 9 and 11.5 months, respectively, for the 99 CRLM patients analyzed. Both the median PFS duration (7.5 vs. 12.0 months; hazard ratio [HR]: 1.852; 95% confidence interval [CI]: 1.131-3.034; P = .014) and LPFS duration (7.5 vs 14.0 months; HR: 2.117; 95% CI: 1.247-3.593; P = .005) were significantly shorter in the high CEA level group than in the low level group. In multivariable analysis, high CEA level, >3 tumors, and positive node status for the primary tumor were independent factors for PFS, with corrected HRs of 2.11 (95% CI: 1.257-3.555; P = .005), 2.450 (95% CI: 1.420-4.226; P = .001), and 2.265 (95% CI: 1.304-3.935; P = .004), respectively. However, age, tumor size, regional lymph node were not associated with LPFS.CEA level could be a valuable prognostic factor for early recurrence in patients with CRLM after MWA irrespective of the presence of early local recurrence in the liver or disease progression. PMID- 29517662 TI - Prediction of pituitary stalk position in pituitary adenomas by visualization of the hypothalamo-hypophyseal tract using diffusion tensor imaging tractography. AB - The preservation of pituitary stalk during surgery is very important for neurosurgeons. Sometimes, it is hard to identify the pituitary stalk in the operation. The hypothalamo-hypophyseal tract (HHT) projects through the pituitary stalk to the posterior pituitary gland. If the HHT can be identified, the position of pituitary stalk will be visualized. The diffusion tensor imaging (DTI) fiber tracking technique has been widely used for the quantitative assessment of the white matter integrity and thus may be suitable for the evaluation of the HHT.DTI was used to track the HHT in 11 patients with pituitary adenoma, and the location of the tract was compared with the pituitary stalk of postoperative image in those patients.The fiber tracking and 3D visualization of the HHT were successfully carried out in all 11 patients. Comparison between the tract and pituitary stalk of postoperative magnetic resonance imaging (MRI) was carried out in 9 patients. The results revealed that the position of tract was consistent with the pituitary stalk of postoperative MRI image in 8 patients (88.9%). The properties of tract showed that the median number of tract was 5.18 +/- 7.00, the median fractional anisotropy (FA) was 0.14 +/- 0.04, and the median length was 28.81 +/- 7.94 mm.HHT can be tracked and visualized with the DTI-FT technique. It will be helpful to identify the location of pituitary stalk preoperatively. PMID- 29517664 TI - A case report of neuromyelitis optica spectrum disorder with peripheral neuropathy as the first episode. AB - RATIONALE: Neuromyelitis optica spectrum disorders (NMOSDs) represent recurrent autoimmune diseases, generally beginning with optic nerve neuritis or acute transverse myelitis. PATIENT CONCERNS: A 57-year-old male with long-term alcohol intake was hospitalized because of limb numbness. EMG examination showed the peripheral sensory nerve was in demyelination and an axonal injury was found. His symptoms could not be improved by vitamin B injection but were later significantly attenuated by dexamethasone treatment. Four months later, symptoms of optic neuritis in the left eye appeared, and 6 months later he exhibited peripheral neuropathy with acute myelitis. DIAGNOSES: He was diagnosed NMOSD. OUTCOMES: Immunotherapy improved his peripheral neuropathy and myelitis symptoms. LESSONS: NMOSD patients could represent peripheral neuropathy as the first episode. PMID- 29517663 TI - Heterotopic gastric mucosa in gallbladder-A rare differential diagnosis to gallbladder masses: A systematic review. AB - BACKGROUND: Heterotopic gastric tissue can be found in the entire gastrointestinal tract. It is usually located in the upper intestine. Rarely, it can be found in the gallbladder. This study describes several clinically, imaging features as well as histopathology findings of heterotopic gastric tissue in gallbladder (HGM). METHODS: The radiologic database of 1 tertiary university hospital was retrospectively screened for HGM. Additionally, a systemic review of the Medline database was conducted to identify previously published cases reports. In all cases clinical, imaging as well as histopathology features were retrieved from the papers. RESULTS: In our databases, 1 patient with HGM was identified. Additionally, the systemic review yielded 32 suitable papers with 34 patients. Clinically, most of the patients suffered from abdominal discomfort. Most of the lesions were located in the lower gallbladder, especially (n = 14, 40%) in the gallbladder neck. On sonography, in 20.7% a broad-based mass was described. In 10.3% a sessile polyp was identified. In 5 cases, the mass was characterized as hyperechoic (55.5%), as isoechoic in 3 (33.3%) cases, and hypoechoic in 1 (11.1%). On computed tomography (CT), the lesions were most frequently hyperdense and all of them showed a slightly enhancement after application of contrast medium. On histopathology, most cases revealed heterotopic gastric mucosa of body-fundic type (60%) with chief and parietal cells, followed by pyloric type glands (20%). Every patient was treated with cholecystectomy and all had an uneventful recovery. CONCLUSION: HGM is a rare disorder with several differential diagnoses. Typically features were described to identify HGM in clinical routine and rule out malignant diseases like gallbladder carcinoma. PMID- 29517665 TI - Acupuncture for common cold: A systematic review and meta-analyze protocol. AB - BACKGROUND: The common cold (CC) is the most common syndromes of infection in human beings, but there is currently no special treatment. For this reason, acupuncture is used to relieve the symptoms of the CC. Acupuncture is a traditional Chinese medicine (TCM) therapy that has been used for over 2000 years to treat various diseases. However, few studies have provided evidence for the efficacy and safety of acupuncture for the CC. This study aims to evaluate the effectiveness and safety of acupuncture on CC periods and its symptoms. METHODS: The following electronic databases will be searched for studies conducted through January 1, 2019: Web of Science, Cochrane Library, EBASE, World Health Organization International Clinical Trials Registry Platform, Springer, Wan-fang database, Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI), and other sources. All randomized controlled trials on acupuncture for common cold will be included. Risk of bias will be assessed using the Cochrane risk of bias assessment tool, while RevMan V.5.3.5 software will be implemented for the assessment of bias risk, data synthesis, subgroup analysis, and meta-analyses if conditions are met. Continuous outcomes will be presented as mean difference (MD) or standard mean difference (SMD), while dichotomous data will be expressed as relative risk. RESULTS: A high-quality synthesis of current evidence of acupuncture for CC will be stated from several aspect using subjective reports and objective measures of performance. The reduction rate of common cold symptoms after initial treatment, resolved cold symptoms, and reduced cold duration will be collected. CONCLUSION: This protocol will present the evidence of whether acupuncture therapy is an effective intervention for CC. PMID- 29517666 TI - Multimodal intraoperative monitoring during reduction of spine burst fracture and dislocation prevents neurologic injury. AB - This study aims to evaluate the application of multimodal intraoperative monitoring (MIOM) in surgical treatment for spine burst fracture and dislocation (SBFD) patients.Eleven patients who underwent posterior reduction and instrumentation (PRI) for SBFD from June 2014 to July 2016 were included into the study. The function of the spinal cord was monitored by MIOM. The muscle strength of the lower extremities and American Spinal Injury Association (ASIA) scores were, respectively, evaluated (before surgery, and at 1, 3, 6, and 12 months after surgery). Furthermore, the extent of reduction was also assessed.Muscle strength recovery, ASIA score changes, and the extent of reduction were correlated with MIOM results. Among the 11 patients who received surgery under MIOM, 8 patients with negative MIOM results during the operation did not demonstrate neurological deterioration postoperatively and exhibited improvements in ASIA scores during follow-ups. However, among the 3 patients who encountered MIOM events (case 4, 7, and 8), 2 patients avoided nerve lesion and 1 patient suffered from neurologic deterioration postoperatively.The application of MIOM technology during PRI surgery may detect spinal cord impairment at the early stage, and operative schemes can be modified before permanent nerve compromise is triggered by surgical manipulation. PMID- 29517667 TI - Aggravation and subsequent disappearance of cervical disc herniation after cervical open-door laminoplasty: A case report. AB - RATIONALE: Cervical open-door laminoplasty can enlarge the volume of the cervical vertebral canal and thus has become an effective and safe treatment for multilevel cervical disc herniation and cervical stenosis. Some post-surgery complications exist, such as reduction of cervical alignment and local kyphosis. However, aggravation of cervical disc herniation at the surgical level during short-term follow-up has not been discussed. Additionally, spontaneous disappearance of herniated disc pulposus is a common phenomenon in the lumbar region but is relatively rare in the cervical region. PATIENT CONCERNS: A 42-year old female presented with a 7-year history of neck pain and a 2-year history of paresthesia and weakness in the upper and lower limbs. The sensations and muscle strength of both upper and lower limbs were decreased. The radiological findings showed that the Pavlov ratios from C3-7 were decreased obviously. Osteophytes as well as spinal cord compression were observed at C4/5, C5/6, and C6/7. DIAGNOSES: Considering the symptoms and clinical examinations, the patient was diagnosed with cervical stenosis. INTERVENTIONS: We performed cervical open-door laminoplasty at C3-7 to enlarge the space of the cervical vertebral canal. OUTCOMES: At the 6-month post-surgery follow-up, the patient showed obvious improvement in paresthesia and weakness in the upper limbs. The cervical disc herniation at C3/4 was aggravated. However, at the 18-month follow-up, the symptoms were relieved, and the herniated cervical disc at C3/4 spontaneously disappeared without any special treatment. LESSONS: We suggest that the attachment points of deep muscles in the neck region should be carefully protected during this surgery. Patients who undergo cervical open-door laminoplasty should pay attention to their cervical position and perform neck exercises to train their neck muscles. MRI is an important imaging method to observe dynamic changes in herniated discs for patients with cervical disc herniation. PMID- 29517668 TI - The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis. AB - BACKGROUND: Oral bosentan has been widely applied in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). A systemic review and meta-analysis was conducted for a therapeutic evaluation of oral bosentan in both adult and pediatric patients with PAH-CHD. The acute responses and a long-term effect were respectively assessed in a comparison with baseline characteristics, and the improvement of exercise tolerance was analyzed. METHODS: PubMed, Medline, Embase, and Cochrane Central Register of clinical controlled trails or observational studies have been searched for a recording of bosentan effects on the PAH-CHD participants. For mortality and rate of adverse events (AEs), it was described in detail. Randomized-effects model or fixed-effects model was used to calculate different effective values with a sensitivity analysis. RESULTS: Seventeen studies were pooled in this review, and 3 studies enrolled the pediatric patients. Among all studies, 456 patients were diagnosed with PAH-CHD, and 91.7% were treated with oral bosentan. With a term less than 6 months of bosentan therapy, there existed a significant improvement in 6-minute walk distance (6MWD) and the World Health Organization functional class (WHO-FC), but no such differences in Borg dyspnea index scores (BDIs) and the resting oxygen saturation (SpO2). Although with a prolonged treatment, not only 6MWD and FC, but also the resting SpO2 and heart rate were changed for a better exercise capability. Additionally, compared with the basic cardiopulmonary hemodynamics, it showed a statistically significant difference in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although a limitation of pooled studies with comparative outcomes of different terms, outcomes presented a lower WHO-FC which contributes to a success in a prolonged treatment. CONCLUSIONS: Bosentan in PAH-CHD is well established and still requires clinical trials for an identification of its efficiency on CHD patients for an optimized period lessening a serious complication and the common AEs. PMID- 29517669 TI - Hemichorea after hyperglycemia correction: A case report and a short review of hyperglycemia-related hemichorea at the euglycemic state. AB - RATIONALE: Hyperglycemic hemichorea tends to affect elderly patients with type 2 diabetes, women, and the Asian population. The onset of involuntary movement typically occurs at the hyperglycemic state and subsides at the euglycemic state. In this report, we present an unusual case that developed delayed-onset hemichorea after hyperglycemia correction. PATIENT CONCERNS: A 70-year-old man was admitted to neurology ward with symptoms of subacute dizziness. Hyperglycemia and high level ketone body was incidentally noted. Hemichorea occurred in his left limbs 2 days after hyperglycemia correction. DIAGNOSES: Patient remained conscious, and no other focal neurological deficits were noted while hemichorea occurred. Blood test revealed no contributory cause. Brain magnetic resonance imaging revealed no lesions in the putamen or subthalamus. A diagnosis of probable hyperglycemia-related hemichorea was made. INTERVENTIONS: Haloperidol (2 mg, 3 times per day) was prescribed. OUTCOMES: Hemichorea improved gradually before discharge and resolved 4 months later. LESSONS: Differential diagnosis of hemichorea should include delayed-onset hemichorea after hyperglycemia correction. PMID- 29517670 TI - A case report of primary central nervous system lymphoma with intestinal obstruction as the initial symptom. AB - RATIONALE: Primary central nervous system lymphoma (PCNSL) with initial manifestations of constipation and intestinal obstruction (IO) is rare. PATIENT CONCERNS: A 50-year-old Chinese male patient was admitted to the gastroenterology department due to constipation and abdominal distention for 8 days. He had experienced intermittent back pain for 3 years prior to admission. Based on abdominal radiography, he was initially diagnosed with IO and treated with meal restriction and enemas. However, his symptoms worsened, and progressive lower limb weakness was observed. DIAGNOSES: A colonoscopy was inconclusive due to the IO. Computed tomography and magnetic resonance imaging revealed space-occupying lesions near centrums 9-11 of the thoracic vertebrae. The patient underwent spinal decompression surgery, and pathologic examination led to a diagnosis of PCNSL (diffuse large B cell lymphoma). OUTCOMES: The symptoms of the IO improved postoperatively, and the patient partially recovered his lower limb muscle strength. He returned to his homeland for chemotherapy. LESSONS: IO can be an initial, unspecific symptom of spinal cord compression in patients with PCNSL. PMID- 29517671 TI - Comparison of the McGrath videolaryngoscope and the Macintosh laryngoscope for double lumen endobronchial tube intubation in patients with manual in-line stabilization: A randomized controlled trial. AB - BACKGROUND: Double lumen endobronchial tube (DLT) intubation is commonly used for one-lung ventilation in thoracic surgery. However, because of its large size and shape, it is difficult to perform intubation compared with a single lumen tube. The aim of this randomized controlled trial was to determine whether the McGrath videolaryngoscope has any advantage over the direct Macintosh laryngoscope for DLT intubation in patients with a simulated difficult airway. METHODS: Forty-four patients (19-60 years of age); scheduled to undergo general anesthesia with one lung ventilation were assigned to 1 of 2 groups: DLT intubation with the McGrath videolaryngoscope (ML group [n = 22]); or conventional Macintosh laryngoscope (DL group [n = 22]). After manual in-line stabilization was applied as a way of simulating a difficult airway, the time required for intubation and the quality of glottic view were evaluated. RESULTS: The time to successful intubation was not different between the 2 groups (ML group, 45 s [interquartile range, 38-52 s] versus DL group, 54 s [45-59 s]; P = .089). The McGrath videolaryngoscope, however, provided a significantly better glottic view. Modified Cormack and Lehane grade was better (P < .001), and the percentage of glottis opening score was higher in the ML group (P < .001). Overall intubation difficulty scale score was lower in the ML group (1 [0-2]) versus the DL group (3 [2-4]) (P < .001). CONCLUSION: The McGrath videolaryngoscope improved glottic view and resulted in lower overall intubation difficulty scale score in patients with in-line stabilization. PMID- 29517673 TI - Late-onset descemet membrane detachment and corneal decompensation after laser peripheral iridotomy: A case report. AB - RATIONALE: The incidence of cornea disorders after laser peripheral iridotomy (LPI) is extremely low. However, cornea Descemet membrane detachment (DMD) combined with corneal decompensation after LPI could still occur. PATIENT CONCERNS: A 69-year-old Chinese woman presented with persistent widespread corneal edema and inferior bullous lesions in her right eye for half a year. She had undergone LPI in both eyes 10 years ago for a prophylactic treatment. The patient received a detailed examination of vivo corneal confocal microscopy and sept-source optical coherence tomography (SS-OCT). DIAGNOSES: It was a late-onset DMD that has a positional relationship with LPI, combined with corneal decompensation. INTERVENTION: Treatment was only supportive with artificial tears and soft contact lenses. OUTCOMES: This patient declined to accept keratoplasty because of financial difficulties. LESSONS: Laser peripheral iridotomy may cause spontaneous, late-onset DMD and corneal decompensation. Ophthalmologists should be aware of this potential complication and proceed carefully. A careful examination of cornea especially around the LPI before keratoplasty seems to be necessary to circumvent other complication. PMID- 29517672 TI - Dynamic spinal compression revealed by computed tomography myelography in overshunting-associated myelopathy: A case report. AB - RATIONALE: OSAM is a rare ventriculoperitoneal (VP) shunt complication where cervical spinal cord compression by epidural venous plexus engorgement is caused by cerebrospinal fluid (CSF) overdrainage. Symmetrically indented deformity of the upper cervical spinal cord and surrounding epidural venous engorgement are characteristic radiological findings. Both of them are typically detected on magnetic resonance imaging (MRI) and enhanced computed tomography (CT). PATIENT CONCERNS: The 77-year-old man who underwent the placement of a VP shunt without an antisiphon device to treat post-subarachnoid hemorrhage (SAH) hydrocephalus presented with progressive quadriplegia 10 years postoperatively. DIAGNOSIS: MRI revealed a symmetrically indented spinal cord from the craniocervical junction (CCJ) to the C2 level and enhanced CT showed the epidural venous engorgement, which were characteristic radiological findings of overshunting-associated myelopathy (OSAM). However, MRI atypically failed to detect the engorged epidural vein and showed no compressive lesion around the spinal cord. INTERVENTION: In order to reveal how the cervical spinal cord was deformed and compressed by engorged epidural vein, CT myelography was performed. OUTCOMES: CT myelography proved that the epidural vein dynamically engorged and compressed the cervical spinal cord immediately after rotation and extension of the neck. LESSONS: CT myelography combined with neck rotation and extension revealed the dynamic change of the epidural venous engorgement, and is useful for evaluation and diagnosis of OSAM especially when epidural venous engorgement was not detectable on MRI. PMID- 29517674 TI - Esophageal transit time in patients with chagasic megaesophagus: Lack of linear correlation between dysphagia and grade of dilatation. AB - The aim of this study was to determine the esophageal transit time in control individuals and in chagasic patients with or without megaesophagus.A total of 148 patients were allocated in 6 groups according to serological diagnostic of Chagas disease and the degree of esophageal dilatation: A, control healthy individuals (n = 34, 22.9%); B, indeterminate form (n = 23, 15.5%); C, megaesophagus I (n = 37, 25.0%); D, megaesophagus II (n = 19, 12.8%); E, megaesophagus III (n = 21, 14.2%); and F, megaesophagus IV (n = 14, 9.5%). After 8-hour fasting, patients were asked to swallow 75 mL of barium sulfate solution. x-Rays were obtained after 8, 30, 60, and 90 seconds, 5, 10, 30, 60, and 90 minutes, 2, 6, 12, 24 hours, and at every 12 hours until no more contrast was seen in the esophagus. This was the transit time.The transit time varied from 8 seconds to 36 hours (median = 90 seconds). A linear correlation was observed between transit time and megaesophagus grade: 8 seconds in groups A and B, 5 minutes in C, 30 minutes in D, 2 hours in E, and 9:15 hours in F. Dysphagia was not reported by 60 of 114 (52.6%) patients with positive serological tests for Chagas disease (37/91-40.7% of patients with megaesophagus I-IV grades). The esophageal transit time increased with the grade of megaesophagus.The esophageal transit time has a direct correlation with the grade of megaesophagus; dysphagia complaint correlates with the grade of megaesophagus. However, many patients with megaesophagus do not report dysphagia. PMID- 29517675 TI - Effects of Shenmai injection on the values of CO, SV, and EF in patients undergoing off-pump coronary artery bypass graft: A randomized, clinical trial. AB - BACKGROUND: To explore the effects of Shenmai (SM) injection on the values of cardiac output (CO), stroke volume (SV), and the ejection fraction (EF) in patients treated with off-pump coronary artery bypass graft (OPCABG). METHODS: Forty patients undergoing OPCABG were randomly divided into SM group (n = 20) and the 5% glucose (G) group (n = 20). The control liquids were injected from the beginning of the operation to the start of coronary artery bypass graft (CABG). The values of CO, SV, and EF before induction (t1), at the beginning of operation (t2), 30 minutes after the start of operation (t3), at the beginning of coronary artery bypass graft (t4), at the end of coronary artery bypass graft (CABG) (t5), and at the end of operation (t6) were recorded. RESULTS: The values of CO, SV, and EF in the patients of SM group at t3 to t6 were found to be significantly higher than those at t1 (P < .05). The values of CO, SV, and EF in the patients of G group were found to be increased at t5 and t6 (P < .05). At t3 and t4, the values of CO, SV, and EF in SM group were significantly higher than those in the G group (P < .05). CONCLUSION: In patients with OPCABG, the infusion of SM injection can effectively increase the values of CO, SV, and EF and increase the safety of anesthesia management. PMID- 29517676 TI - Evaluation the efficacy and safety of simultaneous splenectomy in liver transplantation patients: A meta-analysis. AB - BACKGROUND: Simultaneous splenectomy during liver transplantation (LT) is debated. The present meta-analysis assessed the efficacy and safety of splenectomy on the outcome of LT patients. METHODS: We searched PubMed, Embase, and Wanfang databases for relevant studies published until the date of July 15, 2017. Quality assessment of the included studies was performed using a modified Newcastle-Ottawa Scale judgment. The data were analyzed using RevMan5.3 software. RESULTS: A total of 16 studies consisting of 2198 patients (892 patients received splenectomy during LT [SPLT group] and 1306 patients received LT only [LT group]) were included in the present meta-analysis. Efficacy analysis revealed that pooled hazard ratio for overall survival (OS) between 2 groups was not significantly different (hazard ratio = 1.03; 95% confidence interval [CI]: 0.71 1.50). SPLT group had less postoperative rejection (odds ratio [OR] = 0.63, 95% CI: 0.50-0.79) and small for size syndrome (OR = 0.23, 95% CI: 0.07-0.79). SPLT group had significantly lower preoperative platelet (mean difference [MD] = 17.23, 95% CI: -19.54, -14.91), but significantly higher postoperative platelet (MD = 170.45, 95% CI: 108.33-232.56). Conversely, SPLT group had significant higher preoperative portal pressure (MD = 1.54, 95% CI: 0.75-2.33) and significant lower postoperative portal pressure (MD = -1.17, 95% CI: -2.24, 0.11). Safety analysis revealed that SPLT group had significantly longer operation time (MD = 56.66, 95% CI: 35.96-77.35), more intraoperative blood loss (MD = 1.08, 95% CI: 0.25-1.91), and more intraoperative red blood cell (RBC) transfusion (MD = 3.77, 95% CI: 3.22-4.33). Furthermore, SPLT group had significantly higher incidence of postoperative hemorrhage (OR = 3.07, 95% CI: 1.92-4.91), postoperative thrombosis (OR = 3.63, 95% CI: 1.06-12.45), and perioperative infection (OR = 2.62, 95% CI: 1.76-3.90). In addition, perioperative mortality was significantly higher in the SPLT group (OR = 3.14, 95% CI: 1.31-7.52). Postoperative hospital stay did not differ significantly between 2 groups (OR = -1.75, 95% CI: -3.66-0.16). CONCLUSIONS: Splenectomy benefits LT patients in increasing platelet count. However, splenectomy is a morbid procedure as splenectomy increases operation time, intraoperative blood loss, intraoperative RBC transfusion, and postoperative complications. Splenectomy does not improve OS but increase perioperative mortality. Therefore, splenectomy should be performed only in selective patients. PMID- 29517677 TI - The efficacy and safety of nefopam for pain relief during laparoscopic cholecystectomy: A meta-analysis. AB - BACKGROUND: Pain control after laparoscopic cholecystectomy (LC) has become an important topic. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of nefopam for pain management after LC. METHODS: PubMed, Medline, Embase, ScienceDirect, and the Cochrane Library were searched up to November 2017 for comparative articles involving nefopam and placebo for reducing postoperative pain after LC. Primary outcomes were postoperative pain scores and opioid consumption. Secondary outcomes were length of hospital stay, opioid-related adverse effects, and postoperative complications. We assessed statistical heterogeneity for each RCT by using a standard Chi test and the I statistic. The meta-analysis was undertaken using Stata 12.0. RESULTS: A total of 215 patients were analyzed across 4 RCTs. We found that there were significant differences between nefopam and placebo groups regarding the postoperative pain scores and opioid requirements at 6, 12, and 24 hours. Moreover, there was a decreased risk of opioid-related adverse effects in the nefopam groups. No significant differences were identified in terms of the incidence of postoperative complications. CONCLUSION: Intravenous nefopam infusion resulted in significant reduction in postoperative pain scores and opioid requirements while decreasing opioid-related adverse effects. Additionally, no increased risk of venous thromboembolism was found. The current evidence suggests that more RCTs will be needed in further investigations. PMID- 29517678 TI - The clinical significance of COL5A2 in patients with bladder cancer: A retrospective analysis of bladder cancer gene expression data. AB - The present study was aimed to investigate the relationship between the expression of collagen type V alpha 2 chain (COL5A2) and clinical outcomes of patients with bladder cancer.Chi-square test and log-rank-based survival analysis were performed to assess the correlation of COL5A2 expression with clinical characteristics and survivals of patients with bladder cancer using GSE13507. Gene set enrichment analysis was conducted to study the relevant mechanisms.Bladder cancer patients in COL5A2 low expression group were associated with better invasiveness (P < .0001), tumor grade (P = .001), T staging (P < .0001), N staging (P = .002), cancer specific survival (P < .0001), overall survival (P < .0001), and a trend of better M staging (P = .053) than those in COL5A2 high expression group.COL5A2 might affect the progression of bladder cancer through "Coagulation," "Hypoxia," "Apical junction," "Ultraviolet response," "Epithelial mesenchymal transition," "Angiogenesis," "KRAS (KRAS proto oncogene, GTPase) signaling,""Complement,""IL2-STAT5-signaling," "Inflammatory response," "IL6-JAK-STAT3-signaling," "Myogenesis," "TNF alpha signaling," "Apoptosis," and "Hedgehog-signaling."Our results demonstrated that COL5A2 was correlated with poor clinical outcomes and survivals of patients with bladder cancer, suggesting that it could be regarded as a biomarker of bladder cancer. PMID- 29517679 TI - Observational study pelvic ultrasound a useful tool in the diagnosis and differentiation of precocious puberty in Chinese girls. AB - Rapid and noninvasive diagnosis on and differentiation between normal, central precocious puberty (CPP), and isolated precocious puberty (IPP) is imperative before a decision can be made with gonadotropin-releasing hormone (GnRH) agonist treatment. Our study aims to evaluate such a role by pelvic ultrasound.We consecutively enrolled 84 cases of IPP (59 with premature thelarche/ pubarche and 25 with premature menarche), 47 CPP, and 177 age-matched normal controls. The IPP and CPP were diagnosed by clinical examination and GnRH-stimulation test and confirmed by over 2 years' follow-up. All subjects underwent pelvic ultrasound examination for length, width, thickness, volume of uterine/cervix/ovaries, fundal/cervical thickness ratio, endometrial thickness, and averaged maximal diameter of largest follicles. Statistical comparisons of these sonographic parameters between disease groups were made according to age intervals.It was found that between CPP and normal girls, 10 and 12 ultrasound parameters differed significantly in the >6 to 8 and >8 to 10 years age interval, respectively. Cervical thickness and endometrial thickness was the best discriminating parameter in the 2 intervals by receiver operating characteristic (ROC) curve analysis, and the cutoff, sensitivity and specificity associated with was 0.73 cm, 93.30%, 85.70%, and 0.26 cm, 76.92%, 100%, respectively. Between CPP and IPP, 2 and 5 parameters differed significantly in the >6 to 8 and >8 to 10 years age interval. Cervical length was the best discriminating parameter in both age intervals. The cutoff, sensitivity, and specificity associated were 1.49 cm, 93.33%, 55.17%, and 1.88 cm, 100%, 71.43%, respectively; Finally between normal and IPP girls, 4, 7, and 5 parameters differed significantly in the 0 to 6, >6 to 8, and >8 to 10 years intervals, respectively. Ovarian thickness, ovarian width, and cervix thickness was the best parameter for the 3 age interval respectively, and the cutoff, sensitivity and specificity associated were 0.98 cm, 76.46%, 84.85%, 1.39 cm, 85.71%,73.81%, and 0.75 cm, 90.48%, 64.21%, respectively.Our results indicate that pelvic ultrasonography could serve as a complementary tool for differentiation between normal girls and girls with different forms of sexual precocity in China. The best discriminating parameter changes according to precocity forms and age intervals. PMID- 29517680 TI - An ovarian Leydig cell tumor of ultrasound negative in a postmenopausal woman with hirsutism and hyperandrogenism: A case report. AB - RATIONALE: The incidence of severe hyperandrogenism associated with masculinity in women is very low. While rare and difficult to diagnose, androgen secreting tumors should be suspected in women with hyperandrogenism and hirsutism, especially in the postmenopausal population. Herein we present one case of ovarian Leydig cell tumor (LCT) with markedly elevated serum testosterone levels and frank hirsutism. PATIENT CONCERNS: A 60-year-old woman, presented with increased hair growth and androgenic alopecia and the hormonal laboratory examination showed that she had elevated serum testosterone level and normal dehydroepiandrosterone sulfate (DHEAS), androstenedione, 17- hydroxyprogesterone, cortisol and thyroid stimulating hormone (TSH). DIAGNOSES: The diagnosis of possible testosterone secreting tumor was performed when pelvic computed tomography (CT) and magnetic resonance image (MRI) showed a right adnexal mass of 15mm*16mm indicative of sex cord- stromal tumors. INTERVENTIONS: The patient received laparoscopic total abdominal hysterectomy and bilateral salpingo oophorectomy. OUTCOMES: After operation, testosterone got back to the normal level and clinical symptoms subsided. LESSONS: It is common that postmenopausal androgen excess is a state of relative or absolute androgen excess originating from the adrenal gland and/or ovaries. In either case, doctors need to assess such patients and exclude relatively rare potential causes of tumors. Any woman who has hirsutism or frank evidence of markedly increased testosterone should exclude this kind of possibility of androgen producing tumors. It is possible to determine the origin of androgen hypersecretion with the severity of symptoms, the extent of androgen excess, and the relevant imaging studies. Since LCT are rare ovarian sex-cord stromal tumors, it can be beneficial for diagnosis with careful research of patient history of the defeminization followed by virilization, and a CT and MRI image. PMID- 29517681 TI - Conversion between 2 military combat-related injury coding systems. AB - Deployable medical systems(DEPMEDS) patient conditions (PCs) and Military Combat Injury Scale (MCIS) are 2 important military medical coding systems. However, both of them have defects when applied in military medical planning. Although each PC code contains information about treatment, intensity of care, treatment time, length of stay, and probability of disposition that is relevant to simulation, its description is too comprehensive and ambiguous to code historical military medical records. Therefore, conversion between PC and other medical coding systems applied in standard medical data is required when validity is required following simulation. The information linked to each PC code is based on subject matter expert opinion instead of standard medical data from the theater that need to be continuously updated depending on the results of medical data analysis. MCIS, a combat-related injury coding system, shows significant promise in coding real medical data, but it does not seek detailed information important for prediction and simulation unlike PCs. Therefore, MCIS cannot be used in planning tools directly. Thus, the effort to map MCIS to PCs is significant for medical logistic planning. We aim to identify whether conversion between PCs and MCIS is possible and to evaluate inter-coder reliability.Three senior coders assigned all possible MCIS codes to 187 combat-related PC codes. The data records were structured based on an earlier study. Inter-rater reliability was measured by using Cohen's k statistic and percent agreement.Low inter-rater reliability indicated the difficulty in conversion between PCs and MCIS.The injury descriptors of PCs should be expanded by referring to new standard medical data. The existing MCIS codes need to be modified to include more information on treatment brief, treatment time, length of stay, and other key information, and historical data statistics need to be developed. PMID- 29517682 TI - FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer: A meta-analysis. AB - BACKGROUND: The efficacy of oxaliplatin-based chemotherapy combined with anti epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis. METHODS: RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3. RESULTS: The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients. CONCLUSION: So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently. PMID- 29517683 TI - A case report of nodal CD4-positive T-cell lymphoproliferative disorder with an indolent course. AB - RATIONALE: Primary nodal CD4-positive T-cell lymophoproliferative disorder with a relatively indolent process is a rare kind of lymphoproliferative disease. Here we report the first case of a 49 year-old man developed indolent nodal CD4 positive T-cell lymophoproliferative disorder. To our knowledge, based on a careful search of PubMed, it is the first case of primary nodal CD4-positive T cell lymophoproliferative disorder. PATIENT CONCERNS: A 49-year-old Chinese man presented to our hospital with fever, enlargement of multiple superficial lymphonodes more than 14 years and splenomegaly. Clinical and pathological data were collected under treatment. This case was diagnosed based on histologically characteristic, immunohistochemical staining, and lymphoid clonality testing. On immunohistochemical staining, the abnormal T-cells were CD4 positive and CD8 negative. The lymphoid clonality testing showed positive results. The patient also has enlarged spleen. DIAGNOSES: The patient was diagnosed with nodal CD4 positive T-cell lymophoproliferative disorder. INTERVENTIONS: A watch-and-wait stratagem was performed without any chemotherapy or radiation therapy. OUTCOMES: During 17 years of follow-up, this case presented an indolent course without evidence of systemic dissemination. LESSONS: This report presents the first case of indolent nodal CD4-positive T-cell lymophoproliferative disorder. In this case, the proliferated T-cell in the paracortex of lymph node showed T-cell receptor gene rearrangement, which indicated a clonal proliferation. There are several kinds of nodal CD4-positive T-cell lymphoma, which have a relatively aggressive course; however, this case has a relatively indolent course. PMID- 29517684 TI - CXCL14 and NOS1 expression in specimens from patients with stage I-IIIA nonsmall cell lung cancer after curative resection. AB - Many studies show that CXC chemokine ligand 14 (CXCL14) is highly expressed in tumor-associated stromal cells, promoting tumor cell growth, and invasion. Because of its unclear receptors, CXCL14-initiated intracellular signal cascades remain largely unknown. However, CXCL14 can regulate nitric oxide synthase 1 (NOS1) as its intracellular molecular target. In this paper, we investigated the expression of CXCL14 and NOS1 in specimens from patients with stage I-IIIA nonsmall cell lung cancer (NSCLC) after curative resection, and evaluated the prognostic significance of this gene expression in stromal fibroblasts and cancer cells.Immunohistochemistry was used to detect the expression of CXCL14 and NOS1 in 106 formalin fixed, paraffin-embedded specimens from patients with stage I IIIA NSCLC. The chi-square test was performed to examine the correlation of CXCL14 and NOS1 expression level with clinicopathological features. The effects of the expression of CXCL14 or NOS1 on progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier and Cox hazard proportional model.The percentages of high CXCL14 expression in stromal fibroblasts and that in cancer cells were 46.2% (49/106) and 23.6% (25/106), respectively. The positive expression rates of NOS1 in cancer cells were 42.5% (45/106). The result indicated that there was a significant positive correlation between CXCL14 expression level in stromal fibroblasts and that in cancer cells (chi = 4.158, P = .041). In addition, the expression of CXCL14 in stromal fibroblasts was significantly correlated with NOS1 expression in cancer cells (chi = 16.156, P < .001). The 5-year PFS rates with low and high CXCL14 expression in stromal fibroblasts were 66.7% and 14.3% (chi = 44.008, P < .001), respectively, and the 5-year OS rates with those were 87.1% and 43.5% (chi = 21.531, P < .001), respectively. The 5-year PFS rates with negative and positive expression of NOS1 in cancer cells were 62.3% and 15.6% (chi = 33.756, P < .001), respectively, and the 5-year OS rates with those were 86.4% and 40.1% (chi = 24.430, P < 0.01), respectively.Both the high expression of CXCL14 in stromal fibroblasts and the positive expression of NOS1 in cancer cells are independent negative predictors of PFS and OS in patients with stage I-IIIA NSCLC after curative resection. PMID- 29517685 TI - The altered Granger causality connection among pain-related brain networks in migraine. AB - Numerous fMRI studies have confirmed functional abnormalities in resting-state brain networks in migraine patients. However, few studies focusing on causal relationships of pain-related brain networks in migraine have been conducted. This study aims to explore the difference of Granger causality connection among pain-related brain networks in migraine without aura (MWoA) patients.Twenty two MWoA patients and 17 matched healthy subjects were recruited to undergo resting state fMRI scanning. Independent component analysis was used to extract pain related brain networks, and Granger causality analysis to characterize the difference of Granger causality connection among pain-related brain networks was employed.Seven pain-related brain networks were identified, and MwoA patients showed more complex Granger causality connections in comparison with healthy subjects. Two-sample t test results displayed that there was the significant difference between right-frontoparietal network (RFPN) and executive control network (ECN).This study indicates that the specific intrinsic brain Granger causality connectivity among pain-related networks in MwoA patients are affected after long-term migraine attacks. PMID- 29517686 TI - The safety of isometric exercise: Rethinking the exercise prescription paradigm for those with stage 1 hypertension. AB - Few studies have investigated the relative safety of prescribing isometric exercise (IE) to reduce resting blood pressure (BP). This study aimed to ascertain the safety of the hemodynamic response during an IE wall squat protocol.Twenty-six hypertensive (BP of 120-139 mm Hg systolic and/or 80-90 mm Hg diastolic) males (45 +/- 8 years; 1.78 +/- 0.07 m; 89.7 +/- 12.3 kg; mean +/- SD), visited the laboratory on 2 separate occasions. Heart rate (HR) and BP were measured at rest and continuously throughout exercise. In visit 1, participants completed a continuous incremental isometric wall squat exercise test, starting at 135 degrees of knee flexion, decreasing by 10 degrees every 2 minutes until 95 degrees (final stage). Exercise was terminated upon completion of the test or volitional fatigue. The relationship between knee joint angle and mean HR was used to calculate the participant-specific knee joint angle required to elicit a target HR of 95% HRpeak. This angle was used to determine exercise intensity for a wall squat training session consisting of 4 * 2 minute bouts (visit 2).Systolic BPs during the exercise test and training were 173 +/- 21 mm Hg and 171 +/- 19 mm Hg, respectively, (P > .05) and were positively related (r = 0.73, P < .05) with ratio limits of agreement (LoA) of 0.995 *// 1.077. Diastolic BPs were 116 +/- 14 mm Hg and 113 +/- 11 mm Hg, respectively, (P > .05) and were positively related (r = 0.42, P < .05) with ratio LoA of 0.99 *// 1.107. No participant recorded a systolic BP > 250 mm Hg. Diastolic BP values > 115 mm Hg were recorded in 12 participants during the incremental test and 6 participants during the training session. Peak rate pressure product was 20681 +/- 3911 mm Hg bpm during the IE test and was lower (18074 +/- 3209 mm Hg bpm) during the IE session (P = .002). No adverse effects were reported.Based on the current ACSM guidelines for aerobic exercise termination, systolic BP does not reach the upper limit during IE in this population. Diastolic BP exceeds 115 mm Hg in some during the IE protocol, which may suggest the need to individualise IE training prescription in some with suboptimal BP control. Future research is required to ascertain if IE requires modified BP termination guidelines. PMID- 29517687 TI - Suspected brain metastasis from lung cancer mimicking intracerebral hemorrhage: A case report. AB - RATIONALE: Hemorrhage rarely occurs in a solitary brain metastasis from lung carcinoma. PATIENT CONCERNS: We report on a 54-year-old man who presented with a severe headache for 4 days. DIAGNOSES: Based on computed tomography and magnetic resonance imaging enhancement, the patient was diagnosed with a suspected hemorrhagic brain metastasis from lung carcinoma. INTERVENTIONS: The patient's family rejected a pathological examination. OUTCOMES: The patient's family requested discharge after diagnosis. LESSONS: The present case emphasizes the need to consider hemorrhagic metastasis as a differential diagnosis in patients presenting with solitary intracerebral hemorrhage whose location is uncommon, especially when the poor general state of the patient cannot be attributed to hypertensive intracerebral hemorrhage. PMID- 29517688 TI - Endocytoscopic classification can be predictive for relapse in ulcerative colitis. AB - The present study was conducted to explore the association of endocytoscopy (EC) classification with microscopic inflammatory features of ulcerative colitis (UC) and disease relapse.EC was performed for mild-to-moderate UC 32 cases from January 2010 to August 2016. EC appearance was stratified into 4 categories: EC A, regular arrangement of round to oval pits; EC-B, irregular arrangement with/without enlarged spaces between regular pits; EC-C, deformed pits with distorted crypt lumen which are unordered in arrangement but not disrupted; and EC-D, disruptive or disappeared pits. We evaluated the association of EC classification with Mayo endoscopic subscores (MES) and the clinically active state. Microscopic features including the severity in mucosal inflammatory infiltrates the presence of crypt abscess and goblet cell depletion were assessed by an experienced pathologist who was blinded to clinical and endoscopic information. Clinical follow-up was provided for treating 22 UC patients more than 60 months after EC.There were 15 cases in EC-A, 8 in EC-B, 5 in EC-C, and 4 in EC-D. Interobserver agreement was excellent with kappa value of 0.77. There were 13 patients in active disease stage, while 19 in remission. Each EC-A case was in clinically remission stage, while all the EC-C and EC-D cases were in the active stage. There were 4 and 4 EC-B cases in remission and active stage, respectively. The EC-A group consisted of 11 MES0 and 4 MES1 cases, whereas the EC-B group consisted of 2 MES0 and 6 MES1 cases. There were no cases of MES0 in the EC-C and -D groups. The EC stratification was significantly associated with pathognomonic microscopic features for UC. There were significant differences in the remission rate among the EC groups. None had relapse in the EC-A group during the follow-up period.EC stratification could be predictive for relapse in UC. Moreover, EC is reliable to assess UC specific microscopic features. PMID- 29517689 TI - Simple screening tools to identify limited health literacy in a low-income patient population. AB - Adults with limited health literacy have difficulty managing chronic conditions, higher hospitalization rates, and more healthcare expenditures. Simple screening tools have been developed, but limited work has evaluated instruments among low income populations. This study assessed health literacy among primary care patients of a federally qualified health center, and compared a single screening question about perceived difficulty completing medical forms.A cross-sectional survey was administered to English-speaking patients >=40 years. Both the Newest Vital Sign (NVS), a 6-item questionnaire, and a single-item screening question about perceived difficulty with completing medical forms, assessed health literacy. Logistic regression was used to identify predictors of inadequate health literacy and receiver operator curves compared the NVS and single-item question.Participants (n = 406) were, on average, aged 58.5 years (+/-11.3), 72.2% female, and identified as Hispanic/Latino (19.2%), non-Hispanic white (31.0%), non-Hispanic black (40.9%), or other (8.9%). Of the 406 participants, 335 (82.5%) completed the NVS. Patients who declined NVS were more likely to be older (P < .001) and male (P = .01). Only 13.7% had adequate health literacy. Older adults, Hispanic and non-Hispanic black patients, patients with missed office visits, and those reporting less confidence completing medical forms were significantly more likely to have inadequate health literacy. Perceived confidence completing medical forms demonstrated low sensitivity but high specificity at multiple thresholds.This is the first investigation to compare the NVS and confidence completing medical forms question. Many patients declined health literacy assessments, but health literacy screening may identify patients who need additional health education and resources. PMID- 29517691 TI - Economic evaluation of weekends-off antiretroviral therapy for young people in 11 countries: Erratum. PMID- 29517690 TI - Determinate factors of mental health status in Chinese medical staff: A cross sectional study. AB - Numerous previous studies have investigated the mental health status of medical staff in China and explored its associated determinate factors; however, scope and methods associated with these have introduced uncertainty regarding the results. The aim of this study was to perform a comprehensive examination of the mental health status of Chinese medical staff and its relative risk factors based on a cross-sectional survey.We conducted a broad area, cross-sectional, questionnaire-based survey of Chinese medical workers. Participants were randomly selected from 27 hospitals in the Heilongjiang province. The questionnaire that was distributed consisted of 5 parts: the demographic characteristics of the participant; questions related to the relative risk factors of psychological health; the posttraumatic stress disorder (PTSD) Checklist-Civilian Version (PCL C); the Self-rating Depression Scale (SDS); and the Self-rating Anxiety Scale (SAS). The last 3 components were used to evaluate the mental health status of the target population. Logistic and linear regression were used to analyze the determinate factors of the mental health status of Chinese medical staff.Of the 1679 questionnaires distributed, 1557 medical workers responded (response rate: 92.73%; male: 24.1%; female 75.9%). The results of mental health status self assessments indicated that 32.3% of participants were considered to have some degree of PTSD (based on the PCL-C). The SDS index was 0.67 and the mean score from SAS was 55.26; a result higher than found in the general population. Multivariate logistic regression analysis revealed that being female, dissatisfaction or average satisfaction with income, and good or very good self perceived psychological endurance when faced with an emergency were associated with a reduction of PTSD symptoms. A frequency of verbal abuse incidents greater than 4 was associated with an increase in PTSD symptoms.The mental health status of Chinese medical staff is poor. While the determinate factors based on different measurement standards were not completely consistent, the overlapping major risk factors identified that influenced psychological health were the amount of education, the perceived level of respect, and psychological endurance. PMID- 29517692 TI - Blood transfusion and risk of atrial fibrillation after coronary artery bypass graft surgery: A meta-analysis of cohort studies. AB - The aim of this study was to systematically evaluate the effect of blood transfusion (BT) on postoperative atrial fibrillation (AF) in adult patients who had undergone coronary artery bypass grafting (CABG) surgery.PubMed, Embase, and Cochrane Library databases from inception to January 2017 were searched. Cohort studies were searched that evaluated the association between BT and the risk of postoperative AF in adult patients who had undergone CABG surgery. Study quality was assessed by using the Newcastle-Ottawa scale (NOS). A meta-analysis was performed with the random-effect model.Eight cohort studies involving 7401 AF cases and 31,069 participants were identified and included in our data analysis. The pooled odds ratio of postoperative AF in patients with BT was 1.45 (95% confidence interval, 1.26-1.67), with significant heterogeneity (P < .0001, I = 79%). Excluding one study that had an off-pump CABG did not significantly impact this result (odds ratio, 1.36; 95% confidence interval, 1.23-1.50; n = 7). To examine the stability of the primary results, we performed subgroup analyses. The association between BT and the risk of postoperative AF was similar, as determined in the stratified analyses conducted according to study design, type of surgery, and country.The findings of the present meta-analysis demonstrated a statistically significant increase in postoperative AF risk among adult patients with BT. Further prospective large-scale studies are needed to establish causality and to elucidate the underlying mechanisms. PMID- 29517693 TI - The anteroposterior diameter of nodules in the risk assessment of papillary thyroid microcarcinoma. AB - This study investigates the application of ultrasound, especially the anteroposterior diameter of nodules in the malignancy and metastasis risk assessment of papillary thyroid microcarcinoma through a retrospective analysis of 500 cases of thyroid nodule ultrasonography.We selected 500 patients with thyroid nodules (maximum nodule diameter <=2.0 cm) that had been diagnosed clinically and graded TI-RADS 4c by ultrasonography and surgically treated. Among these, there were 258 cases of pathologically diagnosed papillary thyroid microcarcinoma, 72 cases of nodular goiter or adenoma, 137 cases of papillary thyroid carcinoma, 28 cases of acinar cell carcinoma, and 5 cases of undifferentiated carcinoma. In all cases, color Doppler ultrasonography had been performed preoperatively to determine the size and number of nodules, surrounding lymph node metastasis, and TI-RADS grading. Cases of papillary thyroid microcarcinoma diagnosed by pathology were selected as the study group, and cases of nodular goiter or adenoma as the control group. Each group was further subdivided based on the anteroposterior, vertical, and transverse nodule diameters. Intergroup statistical analysis was also performed. Receiver operating characteristic (ROC) curve analysis was conducted on the study and control groups based on the anteroposterior nodule diameters, and the optimal critical value for malignancy risk was determined. Thyroid nodules in the study group were divided into groups based on the presence or absence of lymph node metastasis. Based on the anteroposterior nodule diameter, ROC curve analysis was performed, and the optimal critical value for metastasis risk was determined.There were 500 cases of malignant nodules diagnosed by ultrasound. Among these, there were 428 cases of malignant nodules diagnosed by pathology. The coincidence rate of the ultrasound diagnosis with pathological diagnosis was 85.60%. While, interestingly, There was a significant statistical difference between the study and control groups based on the anteroposterior nodule diameter. When the anteroposterior nodule diameter was 0.7 cm, sensitivity of malignant diagnosis was 76.70% and specificity of that was 66.70%, and the Youden index was the highest. The lymph node metastasis rate for papillary thyroid microcarcinoma was 13.95%. Within this group, the lymph node metastasis rate for nodules >=0.9 cm (anteroposterior diameter) was 38.46%. When the anteroposterior nodule diameter was equal to 0.9 cm, sensitivity of diagnosis was 83.30%, and specificity of that was 77.80%, and the Youden index was the highest.The anteroposterior diameter of thyroid nodules is more suitable for assessing their malignancy with 0.7 cm, which can be used as the critical value. Nodules >= 0.7 cm require surgical treatment, and those <0.7 cm can be observed. An anteroposterior diameter of 0.9 cm can be used as the critical value for assessing the metastasis risk of malignant thyroid nodules. During surgery, the dissection of central cervical lymph nodes is required for nodules >=0.9 cm. PMID- 29517694 TI - Occlusal adjustment after local resection of type 1 condylar osteochondroma. AB - To evaluate the feasibility of the orthodontic traction after local resection of the condylar osteochondroma (OC).From November 2011 to September 2016, consecutive patients with condylar OC who underwent orthodontic extraction after local resection of the mass were reviewed. Clinical data and cone-beam computed tomography (CT) were obtained before treatment (T0), 1 week after surgery (T1), and at least 6-month follow-up after OC resection (T2). Repeated-measures analysis of variance with Bonferroni multiple-comparison test was used to compare the 3-dimensional cephalometric variables at different time points and the paired t test was used to compare changes of temporomandibular joint (TMJ) space between the 2 sides at T1 and T2.The sample consisted of 23 patients (16 females and 7 males). The mean postoperative follow-up interval was 10.9 months. No recurrence was observed during the postoperative follow-up period. Facial symmetry and occlusion were greatly improved. B deviation and the distance of gonion on the OC affected side to the Frankfort horizontal (FH) were significantly improved from T0 to T1 and T2 (P < .01). The anterior space (AS) and superior space (SS) of the OC-affected side were significantly larger than that of the contralateral side at T1 in parasagittal CT views (P < .05), while no difference was found between the two sides at T2.Local resection is an effective technique with less damage to the condyle. The application of postoperative directional traction could guide the condyle into the fossa, achieve normal TMJ space and stable occlusion, and eventually provide functional and esthetic outcomes. PMID- 29517695 TI - Optimal dose of combined rocuronium and cisatracurium during minor surgery: A randomized trial. AB - BACKGROUND: Combined rocuronium and cisatracurium have synergistic effects. We investigated whether reduced doses are effective during coadministration, by monitoring neuromuscular relaxation during surgery. METHODS: This randomized, controlled clinical trial was registered at http://clinicaltrials.gov (registration number NCT02495038). The participants were 81 patients scheduled for elective mastoidectomy and tympanoplasty. Participants were assigned to groups, including the intubating dose group (Group I, n = 27; combined ED95 rocuronium and ED95 cisatracurium), the small reduction group (Group S, n = 27; dose reduced by 10% of each ED95), or the large reduction group (Group L, n = 27; dose reduced by 20% of each ED95). Drugs were administered to patients and a timer was started using TOF-Watch monitoring. TOF (train-of-four) was monitored at the ulnar nerve, at a setting of 2 Hz/12 s. We recorded the time to TOF ratio = 0 (onset), time to first TOF ratio > 25% (duration 25%), and TOF 25-75% (recovery index) under total intravenous anesthesia. One-way analysis of variance was used for statistical analyses (alpha = 0.05, beta = 0.2). RESULTS: There were no significant demographic differences between groups. Group L had a longer duration to onset (mean +/- standard deviation, 399.3 +/- 147.8 seconds) and shorter duration 25% (39.4 +/- 6.8 minutes) compared to Group I (212.8 +/- 56.0 s and 51.3 +/- 8.47 minutes, respectively) and Group S (230.7 +/- 60.6 s and 47.9 +/- 10.7 minutes, respectively). There were no other significant differences between groups. CONCLUSION: Our findings contribute to determining clinically effective combinations of rocuronium and cisatracurium, as well as to predicting the pharmacokinetic characteristics of the synergistic effects. We suggest that reducing doses of both drugs by approximately 10% of their respective ED95 values is sufficient to maintain neuromuscular relaxation during minor surgery. PMID- 29517696 TI - Role of IL-28B genetic variants in HCV-related liver disease severity in patients with different viral genotypes. AB - Reports of the role of host interleukin 28B (IL-28B) genetic variants in liver disease severity in patients with chronic hepatitis C (CHC) have obtained conflicting results. The impact of IL-28B in Asian patients with different viral genotypes remains elusive.We try to elucidate the effect of IL-28B genetic variants in a large Asian cohort with different viral genotypes.The association between the IL-28B rs8099917 genotype and liver fibrosis was investigated in 1288 patients with biopsy-proven CHC.Patients with hepatitis C virus genotype 1 (HCV 1) infection comprised 59.4% of the population. The remaining 40.6% (518 patients) did not have HCV-1 infection. Of the 1084 patients with the IL-28 genotype, 85.6% (928 patients) had the TT genotype. Univariate analysis revealed that, compared to patients without advanced liver fibrosis, patients with advanced liver fibrosis (Metavir fibrosis score 3-4) had an older age, a lower platelet count, a higher alpha-fetoprotein level, a higher alanine aminotransferase level, a higher incidence of diabetes, and a higher frequency of rs8099917 non-TT genotype carriage.Logistic regression analysis revealed that factors significantly associated with advanced liver fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 1.023/1.009-1.037, P = .001), diabetes (OR/CI: 1.736/1.187-2.539, P = .004), alpha-fetoprotein (OR/CI: 1.007/1.002 1.012, P = .009), platelet count (OR/CI: 0.991/0.988-0.993, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.585/0.400-0.856, P = .006). When patients were classified by viral genotype, factors that had significant independent associations with advanced liver fibrosis in patients with HCV-1 infection included diabetes (OR/CI: 2.379/1.452-3.896, P = .001), alpha fetoprotein (OR/CI: 1.023/1.012-1.035, P < .001), platelet count (OR/CI: 0.99/0.987-0.994, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.529/0.328-0.854, P = .009). In patients who had advanced liver fibrosis but not HCV-1 infection, factors that had significant independent associations with advanced liver fibrosis included age (OR/CI: 1.039/1.016-1.063, P = .001) and platelet count (OR/CI: 0.99/0.986-0.995, P < .001); additionally, IL-28B genetic variants were not associated with liver disease severity.Unfavorable IL 28B genetic variants were associated with advanced liver disease. The genetic effect is limited to patients with HCV-1 infection. PMID- 29517697 TI - Prognostic value of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography in primary hepatic mucosa-associated lymphoid tissue lymphoma: A case report and review of the literature. AB - INTRODUCTION: Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is extremely rare and we herein report a case of a patient suffering from primary hepatic MALT lymphoma with concomitant hepatitis B virus infection. DIAGNOSTIC MODALITIES AND OUTCOME: Double masses were found in a 59-year-old Chinese female patient. We reported the laboratory results, computed tomography (CT) and fluorine-18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/CT images among other findings. As far as we know, only 9 cases have been reported till now using F-FDG PET/CT imaging. Our patient's lesions were found to conform to standard uptake values of FDG. CONCLUSION: It indicates that hepatic MALT lymphoma can be studied with F-FDG PET/CT like other F-FDG-avid lymphomas. It was also noted that delayed-time-point FDG PET imaging may further improve the detection of the MALT lymphoma in liver. Although the patient in this case refused further treatment, potential management options, including rituximab, which is also discussed in this review. PMID- 29517698 TI - Prevalence of and risk factors for anal high-risk HPV among HIV-negative and HIV positive MSM and transgender women in three countries at South-East Asia. AB - This study aimed to assess the prevalence of and associated risk factors for anal high-risk human papillomavirus (hr-HPV) infection among men who have sex with men (MSM) and transgender women (TGW) in Indonesia, Thailand, and Malaysia.This was baseline data from a prospective cohort study with clinic sites in Jakarta and Bali (Indonesia), Bangkok (Thailand), and Kuala Lumpur (Malaysia).MSM and TGW aged 18 years and older from Indonesia, Thailand, and Malaysia were enrolled. Demographic and behavioral characteristics were assessed, and anal samples were collected for HPV genotyping. Multivariate logistic regression models were used to assess risk factors for anal hr-HPV overall and among HIV-positive participants.A total of 392 participants were enrolled, and 48 were TGW. As many as 245 were HIV-positive, and 78.0% of the participants were on combination antiretroviral therapy (cART). Median CD4 count was 439 cells/mm and 68.2% had undetectable HIV-RNA. HIV-positive participants had significantly more hr-HPV compared to HIV-negative participants (76.6% vs 53.5%, P < .001). HPV-16 was the most common high-risk type (20%), whereas HPV-33, -39, and -58 were significantly more common among HIV-positive participants. HIV-positive participant significantly associated with anal hr-HPV infection compared with HIV-negative (OR: 2.87, 95% CI: 1.76-4.70, P <= .001), whereas among HIV-positive participants transgender identity had lower prevalence of hr-HPV infection (OR: 0.42, 95% CI: 0.19-0.91, P = .03).High-risk HPV infection was very common among MSM and TGW in South-East Asia. Overall, HIV-infection, regardless of cART use and immune status, significantly increased the risk, while among HIV-positive participants transgender identity seemed to decrease the risk of anal hr-HPV. PMID- 29517699 TI - Misdiagnosis of aggressive fibromatosis of the abdominal wall: A case report and literature review. AB - RATIONALE: Aggressive fibromatosis (AF) of abdominal wall is also called desmoid tumor, ligament tumor, fibrous tissue tumor hyperplasia, tendon membrane fibroma or soft tissue ligament fibroma, etc. Aggressive fibromatosis of abdominal wall was first described by MacFarlane in 1832, and it was named for the first time by Muller according to its general appearance and texture in 1838. This disease has been mistaken for a benign lesions for a long time because when the cells were examined by pathology often show normal mitosis, and distant metastases are not found clinically, but actually the disease is locally invasive and shows a local invasive growth. So it is a rare low-grade malignant soft tissue tumor. At present, the main treatment for the disease is operation, and radiotherapy and hormone therapy have a certain effect, but these therapies are not ideal. PATIENT CONCERNS: A 32-year-old woman, who underwent cesarean section three years ago came to the hospital for finding a mass on abdominal wall for half a month. DIAGNOSES: Mass of abdominal wall. INTERVENTIONS: Underwent surgery. OUTCOMES: Pathology: The lesion is aggressive fibromatosis of abdominal wall (ligament tumor of abdominal wall). LESSONS: We discussed the particularity of its clinical characteristics, treatment strategies and prognosis combined with literature review, and we think the surgeons need to pay high attention to this disease and make more patients get timely, correct and reasonable treatment, so as to improve the quality of life. PMID- 29517700 TI - Diagnostic indicator of acute lung injury for pediatric critically ill patients at a tertiary pediatric hospital. AB - Early identification of acute lung injury (ALI) in pediatric patients at risk of mortality is important for improving outcome.Assessment of soluble form of receptor for advanced glycation end products (sRAGE) as a valid biomarker for diagnosis of ALI among critically ill, pediatric patients in addition to correlating levels of sRAGE and different outcomes of those patients.A Hospital based case-control study was conducted in pediatric intensive care units (PICUs) at Cairo University Hospital, along a period of 6 months. Total of 68 pediatric patients following inclusion criteria were classified into: patients with ALI; with both ALI and sepsis; with sepsis and control patients. They were prospectively followed and their laboratory and immunological workup (at days 1 and 9) was done to measure serum sRAGE levels and detect (sRAGE) genotypes.The age of the included children ranged from 8 to 84 months. Plasma level of sRAGE was significantly higher in plasma from patients with ALI regardless of associated sepsis. Plasma sRAGE levels were positively correlated with lung injury score. When assessing sRAGE genotypes, TA and TT genotypes were significant in most of the ALI with and without sepsis patients.Monitoring levels of sRAGE and genotypes can significantly affect the survival of ALI children. PMID- 29517701 TI - Evaluation of a new matrix regenerating agent in patients with Sjogren syndrome and superficial ulcerative keratitis resistant to conventional therapy: A report of 3 cases. AB - RATIONALE: Sjogren syndrome (SS) is frequently associated with ulcerative keratitis, which is difficult to treat due to lacrimal tear deficiency and inflammation of the ocular surface. PATIENT CONCERNS: We report the successful additive effect of a matrix regenerating agent (RGTA, Cacicol) in SS patients with severe superficial ulcerative keratitis resistant to conventional therapy. DIAGNOSES: Retrospective, noncomparative case series of patients with primary or secondary SS associated with chronic diffuse keratitis. INTERVENTIONS: All patients (3 women, aged 46, 59, and 84 years) had several years of dry-eye disease history and recurrent keratitis despite having used maximal dose topical therapies including artificial tear substitutes, topical vitamin A, and cyclosporine 0.05% emulsion. All patients suffered from dry, diffuse, and chronic superficial keratitis of at least 75% of the corneal surface, with no sign of corneal neovascularization or opacity. OUTCOMES: RGTA treatment led to a rapid and marked decrease of ocular pain, burning, irritation, foreign body sensation, and improvement of visual acuity. Total diffuse keratitis healing occurred after several months of treatment. Discontinuation of RGTA administration led to the recurrence of severe keratitis; re-introduction of RGTA was successful. No local or systemic adverse effects related to treatment were reported. LESSONS: RGTA treatment was effective and safe in this small series of 3 patients suffering from SS associated with recurrent or chronic superficial ulcerative keratitis resistant to conventional therapy. PMID- 29517702 TI - Cadaveric organ donation in China: A crossroads for ethics and sociocultural factors. AB - In this paper, we will discuss several ethical issues concerning cadaveric organ donation from the perspective of sociocultural factors that are unique to China under the condition that China has ended the use of executed prisoner's organs for transplants. It is found that though great developments have been made in organ transplantation, the ethical issues relating to organ transplantation still face dilemmas in China. It is argued that organ donation and transplantation in China could make further progress if the ethical issues proposed in this paper can be carefully considered. PMID- 29517703 TI - Effectiveness of revascularization interventions compared with medical therapy in patients with ischemic cardiomyopathy: A systematic review protocol. AB - BACKGROUND: Cardiomyopathies is a group of heart diseases that directly affects the heart muscle, and their causes is not just high blood pressure, congenital and pericardial diseases but ischemic cardiomyopathy disease are also caused by vascular disorders, and to confirm the diagnosis, angiography is required. There are several methods for treating and controlling ischemic cardiomyopathy in world health systems and especially in the Iran health system, which include medical treatment, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG). METHODS: This systematic review will includes observational and interventional studies in English and Persian languages and evaluates effectiveness of revascularization interventions and medical therapy in patients with ischemic cardiomyopathy. Animal studies will not be considered. In this systematic review, our sources of information will be electronic databases, trial registries, and different types of grey literature. An electronic search is performed through PubMed, Cochrane library, Scopus, Web of Science, EMBASE, Tufts Medical Center Cost-Effectiveness Analysis Registry, NHS Economic Evaluations Database. To integrate the results of studies with similar results, meta-analysis will be used, for which Comprehensive Meta-Analysis (CMA) software will be used. Results are provided using relative risk with a 95% confidence interval for information. RESULTS: The results of this systematic review will be published in a peer-reviewed journal. CONCLUSION: To our knowledge, this systematic review will be the first to evaluate existing research on the effectiveness of revascularization interventions compared with medical therapy in patients with ischemic cardiomyopathy. The review will benefit patients, healthcare providers, and policymakers. PMID- 29517704 TI - Injury of leg somatotopy of corticospinal tract at corona radiata by ventriculoperitoneal shunt: A case report. AB - RATIONALE: A 45-year-old right-handed female patient suffered head trauma after being hit by a truck that ran into a house. PATIENT CONCERNS: The patient lost consciousness for 1 hour and experienced posttraumatic amnesia for 1 month after the accident. DIAGNOSES: She underwent conservative management for a subdural hematoma in the left frontotemporal lobes and intracerebral hematoma in the left frontal lobe. INTERVENTIONS: The patient's Glasgow Coma Scale score was 11. She underwent a VP shunt operation, approached through the right posterior parietal area of the brain, at 4 months after onset. Approximately, 6 months after onset, she was admitted to the rehabilitation department of a university hospital. She presented with moderate weakness of the left leg: Medical Research Council scores: hip flexor; 3, knee extensor; 3+, ankle dorsiflexor; 3-. Brain magnetic resonance imaging revealed a leukomalactic lesion in the right posterior corona radiata along the shunt. OUTCOMES: On 6-month (2 months after the shunt operation) diffusion tensor tractography, the left CST showed partial injury in the posterior portion compared with the right CST. On 6-month transcranial magnetic stimulation study, the motor-evoked potential obtained at the left tibialis anterior muscle revealed lower amplitude than that on the right side. LESSONS: Injury of leg somatotopy of a CST was demonstrated in a patient with leg weakness following a VP shunt operation. PMID- 29517706 TI - Esophageal Food Impaction: Causes, Elective Intubation, and Associated Adverse Events. AB - GOALS: The goal of this study is to examine the causes, type of adverse events (AE), and effects of elective intubation in outcomes associated with esophageal food impaction (EFI). BACKGROUND: EFI is a gastrointestinal emergency requiring immediate medical attention. STUDY: Retrospective review of all EFI cases presenting at 3 large tertiary centers from October 1, 2011 to October 31, 2014 and all cases registered in the Clinical Outcome Research Initiative (CORI) database from January 1, 2000 to December 31, 2012. Statistical analysis compared health care utilization, AEs, and outcomes in patients with or without elective intubation. RESULTS: A total of 214 cases presenting with EFI at our 3 referral hospitals and 4950 cases in the CORI database met inclusion criteria. Prevalence of structural disorders was similar in the Mayo Clinic and CORI datasets: 24.3% and 27.7% had strictures, and 3.8% and 2.5% had a tumor, respectively. AEs in the nonintubation group were 14.7% compared with 33.3% in the elective intubation group (P=0.003); however, 71.0% of these events were associated with EFI itself and not therapeutic procedure. Esophageal AEs were common (15.0%), followed by pulmonary and cardiovascular events with 3.0% and 1.4%, respectively. Severity of the AEs was influenced by the impaction-to-endoscopy time. CONCLUSIONS: Prevalence of structural esophageal disorders was similar to previous smaller studies. Elective intubation was associated with increased AEs; however, this is felt to be because of the nature of EFI itself and not by therapeutic endoscopy. Prolonged impaction-to-endoscopy time was associated with severe AEs. PMID- 29517707 TI - Hospital Utilization in Patients With Gastric Cancer and Factors Affecting In Hospital Mortality, Length of Stay, and Costs. AB - INTRODUCTION: Although gastric cancer (GC) rates have been declining in the United States, it continues to be a major cause of morbidity. This study examined trends in hospital admissions, in-hospital mortality, length of stay (LOS), and inpatient costs related to GC. In addition, various factors associated with in hospital mortality, LOS, and inpatient costs were examined. METHODS: National inpatient sample-the largest publicly available all-payer inpatient care database was interrogated to obtain information about various demographic and hospital related factors (including those mentioned above) in patients who were primarily admitted for GC between the years 1998 to 2013. These trends were analyzed. Multivariate analysis was also performed to identify risk factors associated with LOS, costs, and mortality. RESULTS: A total of 679,330 hospital discharges with the principal diagnosis of GC were obtained. Hospital stays increased by approximately 340 stays per year (+/-110; P=0.00079). However, inpatient mortality rate and LOS declined by 0.36% per year (+/-0.024%; P<0.0001), and 0.11 days per year (+/-0.01; P<0.0001), respectively. The inpatient charges have increased at the rate of $3241 per year (+/-133.3; P<0.0001). Differences in mortality rate, LOS, and inpatient costs were affected by multiple factors. CONCLUSIONS: Despite the overall decline in GC incidence, the incidence of hospitalizations per 100,000 US population related to GC did not change significantly. Although LOS and mortality declined, inpatient charges increased over the study period. PMID- 29517708 TI - The Accurate Sample Size: A Rather Daunting Task When Evaluating New Endoscopes. PMID- 29517709 TI - Comparative Efficacy of Anti-TNF Therapies For The Prevention of Postoperative Recurrence of Crohn's Disease: A Systematic Review and Network Meta-Analysis of Prospective Trials. AB - INTRODUCTION: There is a lack of studies on the optimal anti-tumor necrosis factor (anti-TNF) agent for postoperative prophylaxis of Crohn's disease (CD) recurrence. Therefore, we conducted a network meta-analysis (NMA) of prospective trials to compare the efficacy of anti-TNF agents in the prevention of postoperative endoscopic and clinical recurrence of CD following ileocolonic resection. METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and recent American gastroenterology association (AGA) meeting abstracts through August 2017. We selected prospective studies comparing anti-TNF agents among each other or to other agents in the setting of postoperative prevention of CD recurrence. We performed a NMA using a frequentist approach with generalized pairwise modeling and inverse variance heterogeneity method. RESULTS: We identified 9 studies, including 571 patients and 5 treatment agents, among which 2 anti-TNF drugs (adalimumab and infliximab). Compared with infliximab, our NMA yielded the following results for endoscopic recurrence: adalimumab [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.18-4.75], thiopurines (OR, 4.11; 95% CI, 0.68-24.78), placebo (OR, 4.39; 95% CI, 0.70-27.68), and Mesalamine (OR, 37.84; 95% CI, 3.77-379.42). For clinical recurrence: adalimumab (OR, 1.03; 95% CI, 0.17-6.03), thiopurines (OR, 1.40; 95% CI, 0.20-10.02), placebo (OR, 1.77; 95% CI, 1.01-3.10), and mesalamine (OR, 16.54; 95% CI, 1.55-176.24). CONCLUSIONS: On the basis of a NMA combining direct and indirect evidence either adalimumab or infliximab may be used in the postoperative prophylaxis of CD recurrence. There is currently a lack of evidence on the use of other anti-TNF agents in this setting. PMID- 29517710 TI - Persistent Increased Enteric Glial Expression of S100beta is Associated With Low grade Inflammation in Patients With Diverticular Disease. AB - BACKGROUND: Diverticular disease (DD) is a common gastrointestinal inflammatory disorder associated with an enteric neuropathy. Although enteric glial cells (EGCs) are essential regulators of intestinal inflammation and motility functions, their contribution to the pathophysiology of DD remains unclear. Therefore, we analyzed the expression of specific EGC markers in patients with DD. MATERIALS AND METHODS: Expression of the glial markers S100beta, GFAP, Sox10, and Connexin 43 was analyzed by real-time quantitative PCR in colonic specimens of patients with DD and in that of controls. Protein expression levels of S100beta, GFAP, and Connexin 43 were further analyzed using immunohistochemistry in the submucosal and myenteric plexus of patients with DD and in that of controls. Expression of the inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 was quantified using qPCR, and infiltration of CD3+ lymphocytes was determined using immunohistochemistry. RESULTS: Expression of S100beta was increased in the submucosal and myenteric plexus of patients with DD compared with that in controls, whereas expression of other glial factors remained unchanged. This increased expression of S100beta was correlated to CD3+ lymphocytic infiltrates in patients with DD, whereas no correlation was observed in controls. CONCLUSIONS: DD is associated with limited but significant alterations of the enteric glial network. The increased expression of S100beta is associated with a persistent low-grade inflammation reported in patients with DD, further emphasizing the role of EGCs in intestinal inflammation. PMID- 29517711 TI - Incidence and Risk Factors of Intrauterine Transmission Among Pregnant Women With Chronic Hepatitis B Virus Infection. AB - GOALS: To identify the potential risk factors of hepatitis B virus (HBV) intrauterine transmission and predict the incidence of HBV intrauterine transmission among hepatitis B surface antigen-positive pregnant women with diverse viral load. BACKGROUND: The intrauterine transmission of HBV significantly contributes to the persistence of a high number of patients infected with HBV. However, its risk factors remain unclear. MATERIALS AND METHODS: A prospective study was performed on hepatitis B surface antigen positive pregnant women who delivered from June 2012 to December 2016 at Wuhan Medical Care Center for Women and Children, Wuhan, China. RESULTS: In total, 1200 women paired with 1219 infants were enrolled. In total, 11 (0.9%) infants were identified with intrauterine transmission. We observed that all infants with intrauterine transmission were born to hepatitis B e antigen-positive mothers who had serum HBV DNA levels >7 log10 copies/mL. Our study suggested that the HBV DNA levels (for each log10 copies/mL increase, odds ratio=5.43; 95% confidence interval, 1.31-22.43; P=0.019) had independent effects on HBV intrauterine transmission in a multivariate logistic regression model. Moreover, cesarean section (odds ratio=0.18; 95% confidence interval, 0.04-0.74; P=0.018) was associated with a reduced risk of HBV intrauterine transmission. The predictive rates of intrauterine transmission were 0.06%, 0.50%, 2.81%, 8.89% in infants with maternal HBV DNA levels of 10, 10, 10, 10 copies/mL, respectively. CONCLUSIONS: Our data confirmed that increasing maternal viral load has the ability to predict intrauterine HBV transmission. Vaginal delivery increased risk of HBV transmission in infants compared with cesarean section. Further studies are warranted to clarify the possible mechanism underlying these associations. PMID- 29517712 TI - Inflammatory Cytokine Profile in Crohn's Disease Nonresponders to Optimal Antitumor Necrosis Factor Therapy. AB - BACKGROUND: A significant number of patients receiving therapy with antitumor necrosis factor (TNF) agents for Crohn's disease experience primary or secondary nonresponse. The aim of this study was to assess whether patients with nonresponse to anti-TNF agents have increased expression of alternative cytokine pathways. METHODS: We designed a prospective, cross-sectional study that included patients with Crohn's disease receiving anti-TNF undergoing colonoscopy with adequate serum trough drug levels (>=8 ug/mL) and without anti-drug antibodies. Inflammatory cytokines and cell adhesions markers measured included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, interleukin (IL) 8, IL-1beta, and IL-6. The primary outcome was the presence of active endoscopic inflammation defined as the presence of at least 1 ulceration >=5 mm. RESULTS: In total, 47 patients were included. Patients with active inflammation had significantly higher levels of ICAM-1 and IL-1beta when compared with those without intestinal inflammation (45.9 vs. 35.8 ng/mL, P<0.0001 and 3.2 vs. 1.5 pg/mL, P=0.002, respectively). There were no significant differences in the other study variables. Using receiving operating curves, ICAM and IL-1beta had a good correlation (receiver operating characteristic >=0.8) with inflammation in this cohort of patients with "anti-TNF resistance." The results were similar in the group of patients with previous anti-TNF exposure. CONCLUSION: Our study suggests that patients who have active inflammation with seemingly adequate serum anti-TNF levels have increased levels of specific inflammatory pathways that may serve as biomarkers of nonresponse as well as potential targets of therapy in anti-TNF nonresponders. PMID- 29517714 TI - European summit: Unanimity but little of substance. PMID- 29517713 TI - Digital Pancreaticocholangioscopy for Mapping of Pancreaticobiliary Neoplasia: Can We Alter the Surgical Resection Margin? AB - INTRODUCTION: In patients with pancreaticobiliary lesions anticipating surgical resection, digital pancreaticocholangioscopy can be used to identify the extent of disease. This presurgical"mapping" could change the surgical plan and optimize patient care. MATERIALS AND METHODS: Patients with pancreaticobiliary lesions anticipating surgery who underwent endoscopic retrograde cholangiopancreatography with digital pancreaticocholangioscopy from 9 international centers were included. Primary outcome was whether pancreaticocholangioscopy altered the surgical plan. Secondary outcome was correlation between surgical and endoscopic histology and adverse events. RESULTS: A total of 118 patients were included (64% male, mean age 69 y): cholangioscopy in 105 patients (89%), pancreatoscopy in 13 patients (11%). Pancreaticocholangioscopy changed the surgical plan in 39 (34%) of patients: 8 of 13 in the pancreatic duct, 32 of 105 in the bile duct. In the bile duct, 6 patients (5%) had less extensive surgery, 26 patients (25%) avoided surgery. In the pancreatic duct, 4 patients (31%) had more extensive surgery and 4 patients (31%) had less extensive surgery. Four patients with downstaged surgery had positive margins on surgical resection; 1 required additional surgical intervention. Overall correlation between endoscopy and surgical histology was 88%. Adverse events included post endoscopic retrograde cholangiopancreatography pancreatitis in 3 patients (2.5%). CONCLUSION: Digital pancreaticocholangioscopy can be effectively used as a mapping tool to delineate the degree of involvement of biliary lesions before surgical resection, in some cases altering the surgical plan. Prospective studies are needed, especially when downstaging surgery. PMID- 29517716 TI - Northern waters. PMID- 29517715 TI - Diagenesis of US Gulf Coast shales. AB - The burial diagenesis of mudstones is of major interest in petroleum geology1-3. Key questions which remain incompletely answered include the relative importance of temperature, time, changes in pore-water chemistry and organic maturation as driving mechanisms, and the relationship between diagenesis in mudstones and neighbouring sandstones4-7. We reconsider here the nature and timing of diagenesis in Gulf Coast Tertiary mudstones using data obtained by backscattered electron microscopy (BSEM) and energy-dispersive X-ray analysis (EDS) of cuttings from two Texas wells. Our observations confirm the mineralogical trends with depth reported by Hower et al.1 and suggest new evidence concerning the timing and causes of the changes. The most important mineralogical changes occurred in the zone of organic matter decarboxylation (zone IV8). We show that the sequence of burial diagenetic events can be established quickly and reliably by BSEM examination of shale cuttings, and demonstrate the use of foram tests and their authigenic mineral infillings as indicators of diagenesis in soft, fine-grained shales. PMID- 29517717 TI - Maori victory. PMID- 29517719 TI - 100 years ago. PMID- 29517718 TI - After the riots the politics: Chirac drops university reform bill to buy time. PMID- 29517720 TI - Weakening of rock salt by water during long-term creep. AB - The rheological properties of rock salt are of fundamental importance in predicting the long-term evolution of salt-based radioactive waste repositories and strategic storage caverns, and in modelling the formation of salt diapirs and associated oil traps1,2. The short-term, high-stress rheology of rock salt is well known from laboratory experiments; however, extrapolation to appropriately low stresses fails to predict the rapid flow seen in certain natural structures. Furthermore, experiments have failed to reproduce the recrystallized microstructure of naturally deformed salt. Here we report experiments indicating that the above discrepancies can be explained by taking into account the influence of trace amounts of brine. Trace brine is always present in natural salt but sometimes escapes during experiments. Our tests on dry dilated salt show more or less conventional dislocation creep behaviour, but brine-bearing samples show marked weakening at low strain rates. This is associated with dynamic recrystallization and a change of deformation mechanism to solution transfer creep. Because natural rock salt always contains some brine, these results cast substantial doubt on the validity of presently accepted dislocation creep laws for predicting the long-term rheological behaviour of salt in nature. PMID- 29517721 TI - Detecting Earth-like planets. PMID- 29517723 TI - Phylogeny: The German 'ostrich' and the molecular clock. PMID- 29517722 TI - Cosmic microwave background anisotropy. AB - Current hypotheses for the origin of structure in the Universe lead to predictions of the amplitudes of anisotropies in the cosmic microwave background radiation. The dipole anisotropy is related to density fluctuations on large scales and to other determinations of our motion relative to distant galaxies. Observation and theory are coming tantalizingly close to measuring the elusive anisotropy, or to revealing that our ideas about the origin of galaxies and large scale structures are in need of substantial revision. PMID- 29517724 TI - UK-Dutch telescope. PMID- 29517726 TI - The music of digital computers. PMID- 29517725 TI - Phospholipid vesicles as a model system for biomineralization. AB - The tailoring of inorganic minerals such as iron oxides for functional use in biological systems for iron storage1, structural support2 and magnetoreception3 involves biological regulation of crystal structure, particle size, morphology and crystallographic organization. The encapsulation of crystallochemical reactions within enclosed biological microvolumes enables control to be exerted over: (1) the chemical regulation, by passive or facilitated ion-transport, of localised supersaturation levels (2) the stereochemical requirements for ion binding, redox and nucleation events at the organic matrix interface and (3) the spatial organization of crystal growth and morphology4,5. Matrix-mediated growth of inorganic materials has not been systematically investigated in vitro even though it may have applications in crystal engineering and materials science6. We have used phospholipid unilamellar vesicles of ~300 A diameter to study membrane mediated processes of iron oxide crystal growth. Intravesicular deposits differ in structure, morphology and size from precipitates formed from reactions in bulk aqueous solution. Mediating factors include vesicle shape and dimension, diffusion-limited processes of ion-transport and ion-binding at the curved lipid headgroup surface. These results help elucidate biomineralization and have technological relevance to the controlled synthesis of monodisperse sols with catalytic and magnetic properties. PMID- 29517727 TI - When firsts come only second. PMID- 29517728 TI - Organ pipe radiant modes of periodic micromachined silicon surfaces. AB - In recent studies on small pyroelectric thermal anemometers with roughened surfaces we showed that one of the most widely used heat transfer models1,2 yielded calculated anemometer responses for flow and geometric behaviour that agreed functionally with observations, but were significantly smaller than the experimental data3-5. As the first stage in investigating the role of small structures in heat transfer, we initiated a study of emittance from deep gratings. Here we report measurements at 400 degrees C of infrared (3 um?lambda?14 um), normal, s- and p-polarized spectral emittances of 45 um deep, near square-wave gratings of heavily phosphorus doped (110) silicon (P content ~5 * 1019 cm-3). The grating surface repeat scales, Lambda, were 10, 14, 18 and 22um, yielding a range of Lambda/lambda from 0.14 to 7.33. The s-polarization vector was parallel to the grating slots. Both s and p spectral emittances had pronounced resonant periodicities with a characteristic length of ~42 um. A reasonable explanation for this behaviour is the presence of standing waves in the air slots perpendicular to the silicon surface similar to those in an organ pipe. While the resonant amplitude of the s polarization does not depend significantly on Lambda it does for the p polarization. No explanation for the Lambda dependence of the p polarization is known. PMID- 29517729 TI - Solid-state chemistry: Novel molecular metals. PMID- 29517730 TI - Space Station cooperation: Money the root of conflict. PMID- 29517731 TI - Plasma physics: Nuclear fusion comes closer. PMID- 29517732 TI - Thermal erosion by komatiites at Kambalda. PMID- 29517734 TI - Bhopal: Liability for disaster still disputed. PMID- 29517733 TI - Indian resources: National water policy at last. PMID- 29517736 TI - Do continental shelves export organic matter? AB - It has been suggested that biological production and consumption of organic matter is not balanced in coastal marine ecosystems1,2. If, as suggested, 90% of the phytoplankton produced during the spring bloom period were exported, excess organic carbon would be sequestered on the continental slope below the permanent thermocline. Here we summarize the shelf-edge exchange processes (SEEP) experiment, designed to test the export hypothesis. The absence of a positive imbalance in the organic carbon budget, reinforced by modest sediment deposition and biomass on the continental slope, led us to reject the concept. Only a small fraction of continental shelf phytodetritus is exported; that not consumed in the spring is for the most part used on the continental shelf during the ensuing stratified season. The original hypothesis failed to recognize the contribution of pelagic microbial consumption and the lag in coupling between seasonal production and consumption processes. PMID- 29517735 TI - Infrared variability of the BL lacertae object OJ287 since its outburst in 1983. AB - In early 1983, OJ287 was seen to undergo an outburst in its optical and infrared emission1. Since then optical monitoring studies2-4 have shown a general decline in the source brightness, with considerable fluctuations. We have monitored the near-infrared emission since the outburst. The fluxes have fluctuated considerably, with the lowest recordings being an order of magnitude less than those measured during the outburst. We have found an excellent correlation between infrared flux and spectral index; as the source gets fainter the spectrum gets steeper, and vice versa. We interpret this in terms of outbursts being due to injection or reacceleration of electrons with a constant energy index which subsequently steepens as the electrons are affected by radiation losses. PMID- 29517737 TI - Does nuclear integration of mitochondrial sequences occur during senescence in Podospora? AB - Observations in various organisms1-3 suggest that the transfer of mitochondrial DNA sequences to the nucleus has occurred in the course of evolution. Wright and Cummings have reported4, on the basis of hybridization experiments, that there is such a transposition in the fungus Podospora anserina during senescence5 (arrest of vegetative growth) which is accompanied by amplification of specific mitochondrial sequences6-9. They suggested that this transposition could explain senescence, and, as it could be regularly observed under laboratory conditions, senescence in Podospora could constitute a model system to study the molecular mechanisms of the transfer of DNA sequences from mitochondria to the nucleus. We report here experiments similar to those of Wright and Cummings4 but include additional critical controls. Our results do not confirm the data of Wright and Cummings; the only positive signals we observed after hybridization of mitochondrial DNA sequences on nuclear DNAs can be attributed to contaminating DNA from mitochondria or plasmids. PMID- 29517738 TI - Pan(da)selectionism. PMID- 29517739 TI - Biological diversity: How many species are there? PMID- 29517740 TI - Vera Rich was in Paris when the students' patience ran out ... PMID- 29517741 TI - Meaning from numbers. PMID- 29517743 TI - Independence for UK space centre? PMID- 29517742 TI - Parasitic puzzles. PMID- 29517744 TI - Pattern formation: Form and diffusion. PMID- 29517745 TI - Detecting Earth-like planets (reply). PMID- 29517747 TI - Undirectional spin. PMID- 29517746 TI - Is the reductionist beyond belief? PMID- 29517748 TI - Evidence for a link between atmospheric thermonuclear detonations and nitric acid. AB - Suitably located glacier cores, obtained from high-altitude, low-temperature sites, can reveal detailed information about atmospheric air chemistry at sub annual resolution1. Such data may provide input to climate-change models, the study of acid precipitation patterns and many other phenomena. Here I present data from an ice core which show that during the era of intense atmospheric thermonuclear weapons testing (ATWT) a significant part of the nitrate content in the snow was modulated by the intensity of the nuclear detonations. The fixation of nitrogen by nuclear fireballs leads to NOx gases in the atmosphere2 and ultimately to nitric acid in precipitation. At certain concentrations, these gases and the associated aerosols may perturb the climate3,4. PMID- 29517749 TI - A new low-dimensional metal, Cs[Pd(S2C2(CN)2)2].0.5 H2O. AB - The discovery of a low-temperature superconducting state in organic compounds of the type (TMTSF)2CIO4 (Tc = 1.2 K) and (BEDT-TTF)2AuI2 (TC = 4 K) (where TMTSF is tetramethyltetraselenafulvalene, BEDT-TTF is bis(ethylenedithiolo)tetrathiafalvalene and Tc is the superconducting transition temperature) has stimulated the search for new materials that may show higher values of Tc (refs 1-3). The general problem encountered in molecular charge transfer salts of this type, which have conduction bands formed by intermolecular overlap of pi-electron systems, is that conduction is usually quasi-one dimensional, with good conduction along the stacking direction. Metals with this one-dimensional character are unstable, and undergo a Peierls transition4 to a semiconducting state at low temperatures. The relatively few exceptions (mentioned above), which remain metallic down to low temperatures, are considered to do so because they show stronger interstack interactions. We report here a new material with inherently two-dimensional interactions between the molecular pi electron systems and which we are able to stabilize as a metal down to low temperatures (1.4 K) under hydrostatic pressure (12 kbar). PMID- 29517750 TI - Climatic prediction: Could this be an El Nino? PMID- 29517751 TI - Italian research reorganization. PMID- 29517752 TI - Amazon rainforests: Brazil invites RGS explorers. PMID- 29517753 TI - Space shuttle: Money-saving move on fuel tanks. PMID- 29517754 TI - Shades of 1968? PMID- 29517755 TI - Ostrich ancestors found in the Northern Hemisphere suggest new hypothesis of ratite origins. AB - Modern ratites (ostriches, rheas, cassowaries, emus, and kiwis) are flightless birds which have a palatal structure termed 'palaeog-nathous'1 and are found on daughter-landmasses of the Mesozoic supercontinent Gondwanaland. It has been suggested2-4 that a single flightless ancestor, widely distributed in Gondwanaland, gave rise to the various lineages of ratite birds. The temporal calibration of the DNA molecular clock is primarily based on the divergence of ratites, and depends on the validity of this hypothesis. Newly studied fossils suggest that the ancestors of ostriches are instead among a group of North American and European birds, the 'Lithornis-cohort', that had the potential of flight and from which the kiwis may have arisen separately. PMID- 29517756 TI - Biotechnology patents: Don't say just what you mean. PMID- 29517757 TI - Super-collider still fighting for funds. PMID- 29517758 TI - Halite rheology: Salt with a pinch of water. PMID- 29517759 TI - A thylakoid processing protease is required for complete maturation of the lumen protein plastocyanin. AB - Plastocyanin, a photosynthetic electron carrier functional in the chloroplast lumen, is synthesized in the cytosol as a precursor (preplastocyanin) with an amino-terminal transit sequence1. This transit peptide contains the information specifying import into and routing within the chloroplasts and is removed in at least two steps2. An intermediate is observed in the stroma after the transport of preplastocyanin through the chloroplast envelope; mature plastocyanin is present in the lumen, after transport over the thylakoid membrane. We show here that the stromal processing protease3 is not responsible for both processing events. It cleaves the precursor protein only to the intermediate size and a novel protease located in the thylakoids processes this intermediate to the mature protein. This second protease recognizes the processing intermediate but not the precursor. Thus plastocyanin import involves cleavage at the intermediate processing site mediated by the stromal protease and then cleavage at the mature processing site mediated by the thylakoid protease. PMID- 29517761 TI - Another nuclear power station? PMID- 29517760 TI - Unsure accuracy. PMID- 29517762 TI - Functions of leaf fall. PMID- 29517763 TI - Japanese technology: Old computers may prove best. PMID- 29517764 TI - Identification of novel widely distributed sedimentary acyclic sesterterpenoids. AB - Isoprenoids, the general class of natural products biosynthesized from isoprene units, are abundant in nature. Many isoprenoids are also found in sediments, sedimentary rocks and crude oils where they have proved useful as 'chemical fossils' of biological activity and as indicators of geothermal stress1. However, acyclic isoprenoids with 25 carbon atoms-so-called sesterterpenoids-have been reported only rarely in the biosphere and the geosphere. Indeed, the only acyclic sesterterpenoids of confirmed structure reported in sediments are of pentamethyleicosane structural isomers (Fig. 1, carbon skeleton I). For example, 2,6,10,14,18-pentamethyleicosane has been proposed as a marker for halophilic bacteria and the 2,6,10,15,19-isomer (I) as an indicator of methanogens2. We have now identified a group of novel sesterterpenoids that are major components of the hydrocarbons of recent freshwater, marine and hypersaline sediments from many different parts of the globe. Because they have unusual structures, these sesterterpenes show promise as a new class of biological marker compounds. PMID- 29517766 TI - Prenatal upper-limb mesomelia and 2q31.1 microdeletions affecting the regulatory genome. PMID- 29517765 TI - Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison. AB - PURPOSE: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood-brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age. METHODS: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. RESULTS: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. CONCLUSION: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT. PMID- 29517767 TI - "Well, good luck with that": reactions to learning of increased genetic risk for Alzheimer disease. AB - PURPOSE: Apolipoprotein-E (APOE) genetic testing to estimate risk for developing late-onset Alzheimer disease is increasingly being offered without prior genetic counseling or preparation. Consumer interest continues to grow, raising the question of how best to conduct such testing. METHODS: Twenty-six semistructured interviews were carried out to study the reactions of individuals who had already learned of their higher risk after APOE testing had been done because of a family history of Alzheimer disease, or from genetic tests done for other health-related or general-interest reasons. RESULTS: Adverse psychological reactions were reported by a substantial fraction of the participants, including those who had specifically sought testing, those for whom the information came as a surprise, those with a family history, and those with no known history. Still, nearly all of those interviewed said that they had benefited in the long term from lifestyle changes, often learned from online sources, that they subsequently made. CONCLUSION: The results show that people should be prepared prior to any genetic testing and allowed to opt out of particular tests. If testing is carried out and a higher risk is revealed, they should be actively assisted in deciding how to proceed. PMID- 29517768 TI - Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease. AB - PURPOSE: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease. METHODS: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. RESULTS: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2 oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis. CONCLUSION: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease. PMID- 29517769 TI - Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy. AB - PURPOSE: We evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM. METHODS: We identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis. RESULTS: We reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%. CONCLUSION: We propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings. PMID- 29517772 TI - Ab initio derived group additivity model for intramolecular hydrogen abstraction reactions. AB - A set of group additivity values for intramolecular hydrogen abstraction reactions of alkanes, alkenes and alkynes is reported. Calculating 448 reaction rate coefficients at the CBS-QB3 level of theory for 1-2 up to 1-7 hydrogen shift reactions allowed the estimation of DeltaGAV degrees values for 270 groups. The influence of substituents on (1) the attacking radical, (2) the attacked carbon atom, and (3) the carbon chain between the attacking and attacked reactive atom has been systematically studied. Substituents have been varied between hydrogen atoms and sp3, sp2 and sp hybridized carbon atoms. It has been assumed that substituents further away from the reactive atoms or their connecting carbon chain have negligible influences on the kinetics. This group additivity model is applicable to a wide variety of reactions in the 300-1800 K temperature range. Correlations for tunneling coefficients have been generated which are complementary to the DeltaGAV degrees 's to obtain accurate rate coefficients without the need for imaginary frequencies or electronic energies of activation. These correlations depend on the temperature and activation energy of the exothermic step. The group additivity model has been successfully applied to a test set of reactions also calculated at the CBS-QB3 level of theory. A mean absolute deviation of 1.18 to 1.71 has been achieved showing a good overall accuracy of the model. PMID- 29517773 TI - Efficient prediction of suitable functional monomers for molecular imprinting via local density of states calculations. AB - Synthetic molecular recognition materials, such as molecularly imprinted polymers (MIPs), are of increasing importance in biotechnology and analytical chemistry, as they are able to selectively bind their respective template. However, due to their specificity, each MIP has to be individually designed for the desired target leading to a molecularly tailored synthesis strategy. While trial-and error remains the common approach for selecting suitable functional monomers (FMs), the study herein introduces a radically new approach towards rationally designing MIPs by rapidly screening suitable functional monomers based on local density of states (LDOS) calculations in a technique known as Electronic Indices Methodology (EIM). An EIM-based method of classification of FMs according to their suitability for imprinting was developed. Starting from a training set of nine different functional monomers, the prediction of suitability of four functional monomers was possible. These predictions were subsequently experimentally confirmed. PMID- 29517770 TI - Investigation of higher-order RNA G-quadruplex structures in vitro and in living cells by 19F NMR spectroscopy. AB - Growing evidence indicates that RNA G-quadruplexes have important roles in various processes such as transcription, translation, regulation of telomere length, and formation of telomeric heterochromatin. Investigation of RNA G quadruplex structures associated with biological events is therefore essential to understanding the functions of these RNA molecules. We recently demonstrated that the sensitivity and simplicity of 19F NMR can be used to directly observe higher order telomeric G-quadruplexes of labeled RNA molecules in vitro and in living cells, as well as their interactions with ligands and proteins. This protocol describes detailed procedures for preparing 19F-labeled RNA, the evaluation of 19F-labeled RNA G-quadruplexes in vitro and in living Xenopus laevis oocytes by 19F NMR spectroscopy, the quantitative characterization of thermodynamic properties of the G-quadruplexes, and monitoring of RNA G-quadruplex interactions with ligand molecules and proteins. This approach has several advantages over existing techniques. First, it is relatively easy to prepare 19F-labeled RNA molecules by introducing a 3,5-bis(trifluoromethyl) benzene moiety into its 5' terminus. Second, the absence of any natural fluorine background signal in RNA and cells results in a simple and clear 19F NMR spectrum and does not suffer from high background signals as does 1H NMR. Finally, the simplicity and sensitivity of 19F NMR can be used to easily distinguish different RNA G-quadruplex conformations under various conditions, even in living cells, and to obtain the precise thermodynamic parameters of higher-order G-quadruplexes. This protocol can be completed in 2 weeks. PMID- 29517771 TI - Assessing protein-ligand interaction scoring functions with the CASF-2013 benchmark. AB - Scoring functions are a group of computational methods widely applied in structure-based drug design for fast evaluation of protein-ligand interactions. To date, a whole spectrum of scoring functions have been developed based on different assumptions or algorithms. Therefore, it is important to both the end users and the developers of scoring functions that their performance be objectively assessed. We have developed the comparative assessment of scoring functions (CASF) benchmark as an open-access solution for scoring function evaluation. The latest CASF-2013 benchmark enables evaluation of the so-called 'scoring power', 'ranking power', 'docking power', and 'screening power' of a given scoring function with a high-quality test set of 195 complexes formed between diverse protein molecules and their small-molecule ligands. Evaluation results of the standard scoring functions implemented in several mainstream software programs (including Schrodinger, MOE, Discovery Studio, SYBYL, and GOLD) are provided as reference. This benchmark has become popular among the scoring function community since its first release. In this protocol, we provide detailed descriptions of the data files included in the CASF-2013 package and step-by-step instructions on how to conduct the performance tests with the ready-to-use computer scripts included in the package. This protocol is expected to lower the technical hurdles in front of new and existing users of the CASF-2013 benchmark. On a standard desktop workstation, it takes roughly half an hour to complete the whole evaluation procedure for one scoring function, once the required inputs, i.e., the results computed on the test set, are ready to use. PMID- 29517774 TI - Can coconut oil and treadmill exercise during the critical period of brain development ameliorate stress-related effects on anxiety-like behavior and episodic-like memory in young rats? AB - OBJECTIVE: Virgin coconut oil (CO) and treadmill exercise have been reported to improve memory performance in young rats. CO has also been associated with antistress properties in young, stressed mice. Therefore, in this study we aimed to investigate whether CO and treadmill exercise could synergistically ameliorate the effects of chronic stress on anxiety-like behavior and episodic-like memory in young rats. METHODS: The rats received CO and were exercised (Ex) from the 15th to the 45th day of life. The animals were supplemented with CO (10 mL kg-1 day-1) or a vehicle (V, distilled water and 0.009% Cremophor) via oral gavage. The Ex animals were placed for 30 min day-1 on a treadmill, with the speed gradually increasing from the first week to the last. From the 46th to the 54th postnatal day, with the exception of the 51st and the 52nd day, all rats were subjected to restraint stress. Afterwards, all rats underwent the open-field test to evaluate locomotor activity and anxiety-like behavior. To evaluate episodic like memory, all animals underwent tests to recognize object identity and special location. Lastly, lipid profile and murinometric parameters were evaluated. RESULTS: A two-way ANOVA test followed by a Tukey test demonstrated that the CO&Ex group explored more of the unprotected central area of the OFT (27.04 +/- 4.03 s, p < 0.01), when compared to the control group (15.36 +/- 2.54 s). CO&Ex spent more time exploring the novel location of the object (71.62 +/- 3.04%, p < 0.01), when compared to the control group (58.62 +/- 2.48%). DISCUSSION: CO and exercise during lactation can ameliorate the effects of stress on anxiety-like behavior and episodic-like memory in young rats. PMID- 29517775 TI - Base-controlled chemoselectivity reaction of vinylanilines with isothiocyanates for synthesis of quinolino-2-thione and 2-aminoquinoline derivatives. AB - Here, we report a base-controlled chemo-selective reaction of vinylanilines with alkyl/aryl isothiocyanates to afford quinolino-2-thione and 2-aminoquinoline derivatives. The quinolino-2-thiones could be obtained in high yields in the presence of Et3N. Particularly interesting is that the reaction could produce the 2-aminoquinolines in the presence of K3PO4 with high selectivity. PMID- 29517776 TI - Photochemistry of glyoxylate embedded in sodium chloride clusters, a laboratory model for tropospheric sea-salt aerosols. AB - Although marine aerosols undergo extensive photochemical processing in the troposphere, a molecular level understanding of the elementary steps involved in these complex reaction sequences is still missing. As a defined laboratory model system, the photodissociation of sea salt clusters doped with glyoxylate, [NanCln 2(C2HO3)]+, n = 5-11, is studied by a combination of mass spectrometry, laser spectroscopy and ab initio calculations. Glyoxylate acts as a chromophore, absorbing light below 400 nm via two absorption bands centered at about 346 and 231 nm. Cluster fragmentation dominates, which corresponds to internal conversion of the excited state energy into vibrational modes of the electronic ground state and subsequent unimolecular dissociation. Photochemical dissociation pathways in electronically excited states include CO and HCO elimination, leading to [Nan xCln-x-2HCOO]+ and [NanCln-2COO]+ with typical quantum yields in the range of 1 3% and 5-10%, respectively, for n = 5. The latter species contains CO2- stabilized by the salt environment. The comparison of different cluster sizes shows that the fragments containing a carbon dioxide radical anion appear in a broad spectral region of 310-380 nm. This suggests that the elusive CO2- species may be formed by natural processes in the troposphere. Based on the photochemical cross sections obtained here, the photolysis lifetime of glyoxylate in a dry marine aerosol is estimated as 10 h. Quantum chemical calculations show that dissociation along the C-C bond in glyoxylic acid as well as glyoxylate embedded in the salt cluster occurs after reaching the S1/S0 conical intersection, while this conical intersection is absent in free glyoxylate ions. PMID- 29517777 TI - Synthesis of a new series of Ni(ii), Cu(ii), Co(ii) and Pd(ii) complexes with an ONS donor Schiff base: crystal structure, DFT study and catalytic investigation of palladium and nickel complexes towards deacylative sulfenylation of active methylenes and regioselective 3-sulfenylation of indoles via thiouronium salt formation. AB - A series of Ni(ii), Cu(ii), Co(ii), and Pd(ii) complexes have been synthesized with a chelating Schiff base ligand coordinated to a metal center with ONS donor atoms. The ligand and complexes are characterized by elemental analysis and spectroscopic techniques like FT-IR, 1H-NMR, and UV-Visible spectroscopy. The single crystal structure of the Pd(ii) complex is obtained by X-ray diffraction analysis and exhibits slightly distorted square planar geometry. The structure is optimized by DFT, TD-DFT calculation to elaborate the electronic structure and NBO for the charge distribution analysis of the Pd(ii) complex. The synthesized Pd(ii) and Ni(ii) complexes as catalysts have been investigated in the C-S cross coupling of indoles and active methylenes. The metal propelled regioselective transformation afforded 3-sulfenylated indoles while beta-diketones favored deacylated monosulfenyl ketones in an excellent yield via thiouronium salt formation. The Pd(ii) complex displays slightly better reactivity whereas the Ni(ii) complex is cost-efficient. The method is fast, easy to handle and cost effective in terms of high reactivity of catalysts, use of non-toxic solvents, and cheaper aryl halides and thiourea replace conventional sulfur sources, providing a practical access to organic transformations. PMID- 29517778 TI - Ultrasound-assisted aqueous extraction, LC-MS/MS analysis and radiomodulating capability of autochthonous Italian sweet cherry fruits. AB - The current cancer treatment scenario lacks drugs acting as both radiosensitizer and radioprotector agents. In this context, the radiomodulatory properties exerted by an aqueous extract from the fruits of the Italian Prunus avium cv. Della Recca (PaDRw) were investigated. The extract, obtained through an environmentally-friendly ultrasound-assisted extraction, seemed to act as a radioprotector at lower tested doses (25 and 50 MUg mL-1) and a radiosensitizer at 400 and 500 MUg mL-1 dose levels towards the neuroblastoma SH-SY5Y cell line, irradiated with four graded X-ray doses (0, 0.5, 2, and 4 Gy). The fractionation of PaDRw by Amberlite XAD-4 non-ionic polymeric resin, coupled to LC-UV-MS/MS techniques, proved to be efficient also in the disclosure of lower constituents. About 63% of the whole PaDRw extract was constituted of hexitol, followed by fructose (~22.8%) and glucose (~10.7%). Chlorogenic acids and flavonoids, which accounted only for ~2.2%, were hypothesized to be the main actors in PaDRw induced radiomodulation. PMID- 29517779 TI - Photoreaction of BlrP1: the role of a nonlinear photo-intensity sensor. AB - Blue-light-regulated phosphodiesterase 1 (BlrP1) is a blue light sensor protein that controls the hydrolysis of cyclic dimeric guanosine monophosphate, which regulates cellular motility, virulence, and formation of biofilms. In this report, the photoreaction dynamics of BlrP1 and its blue light sensor using a flavin adenine dinucleotide (BLUF) domain were investigated by the time-resolved transient grating method. Only a minor conformational change of the BlrP1-BLUF domain was observed. In contrast, a significant conformational change of the full length BlrP1 was detected as a diffusion change with a time constant of 21 ms. Interestingly, the extent of the conformational change was concentration dependent and the dimer form of BlrP1 was found to be the species that exhibited the conformational change. In combination with circular dichroic measurements, a quaternary structural change was determined to be the main origin of the diffusion change. Surprisingly, this conformational change was found to depend strongly on the excitation light intensity. This light-intensity-dependence indicates that the conformational change is induced by the photoexcitation of two monomer units of the dimer. The results suggest that BlrP1 is not only a photosensor but also a light intensity sensor possessing a nonlinear response. PMID- 29517780 TI - CaRMeN: a tool for analysing and deriving kinetics in the real world. AB - This paper presents the concepts of an open software tool (CaRMeN) that can be used to rapidly analyse and derive models, in particular chemical kinetics. The software automates the workflow of comparing model vs. experiment, which must currently be done manually and is thus a time-consuming and error-prone task. The capabilities of the software are illustrated through a case study. Experimental data for the conversion of methane over rhodium catalysts in a wide range of conditions and experimental setups are numerically simulated using five different mechanisms from the literature. The applicability of the mechanisms as well as differences between flow and diffusion models are evaluated. The results show that no single mechanism reliably predicts the chemical conversions of all of the experiments. Although the software was initially developed for chemical kinetics applications, it can also be extended to run any simulation code, and can therefore be applied in other scenarios. PMID- 29517781 TI - Large-scale synthesis of fluorinated graphene by rapid thermal exfoliation of highly fluorinated graphite. AB - Weakly fluorinated graphene nanosheets were efficiently prepared via fast thermal exfoliation of highly fluorinated graphite. This scalable method consists of a fast temperature increase (around 10 degrees C s-1) of fluorinated HOPG performed under an argon atmosphere, without any post-treatment. The mechanism of exfoliation induced by the defluorination step, evolving volatile fluorocarbons, has been highlighted thanks to thermogravimetric analysis (TGA), high temperature X-ray diffraction (HTK-XRD), X-ray Photoelectron Spectrometry (XPS) studies on temperature, and Raman and infrared spectroscopy. The advantages of the described process are its high-yield for the preparation of fluorinated graphene nanosheets, its ease of implementation and scalability. Moreover, the fluorine content drastically decreases during such a process and graphene layers are slightly functionalized, i.e. conductive contrary to the precursor. PMID- 29517782 TI - Antidiabetic effects and erythrocyte stabilization by red cabbage extract in streptozotocin-treated rats. AB - The protective effect of red cabbage extract (RCE) was evaluated in rats with streptozotocin-induced diabetes, assessing a probable role of this extract in the prevention of erythrocyte impairments associated with a high risk of vascular complications in diabetes. RCE was analyzed by ultrahigh performance liquid chromatography and mass spectrometry, and 11 anthocyanins, 3 hydroxybenzoic acids and 9 hydroxycinnamic acids were identified. Type 1 diabetes was induced by streptozotocin (60 mg kg-1) in Wistar male rats (n = 8 per group). After 7 days of acclimatization, streptozotocin-treated rats were given RCE (800 mg kg-1) or vehicle by intragastric administration for 4 weeks. The RCE treatment lowered blood glucose, and glycated and fetal hemoglobin concentrations and improved glucose tolerance as well as considerably raised serum insulin, proinsulin and C peptide levels in streptozotocin-treated rats. Simultaneously, RCE improved pancreatic islet morphology, increasing the amount of pancreatic beta-cells in diabetic animals. The RCE administration prevented anemia in rats with streptozotocin-induced diabetes, enhanced erythrocyte resistance to acid hemolysis, and normalized reticulocyte production as well as sialic acid content in erythrocyte membranes. The enhanced lectin-induced erythrocyte aggregation in diabetic rats was significantly lowered after the RCE treatment. RCE demonstrated a significant antioxidant effect, decreasing MDA and protein carbonyl contents and increasing catalase and glutathione peroxidase activities in erythrocytes. These results indicate that RCE can be considered as a promising candidate for use as a drug or a food supplement to alleviate diabetes and its vascular complications. PMID- 29517783 TI - Sensitive detection of formamidopyrimidine-DNA glycosylase activity based on target-induced self-primed rolling circle amplification and magnetic nanoprobes. AB - We developed a novel approach to determine formamidopyrimidine DNA glycosylase (FPG) activity by taking advantage of target-induced self-primed rolling circle amplification (RCA) and magnetic nanoprobes. Herein, a unique nick (8-oxoguanine, 8-oxoG) was positioned in duplex DNA containing P-circle and P1, which together serve as a FPG substrate, RCA template, and RCA primer probe. The presence of FPG specifically binds 8-oxoG and cleaves the P-circle into two parts, producing 5' phosphoryl termini. A phosphodiester bond between the 5'-phosphoryl and 3' hydroxyl termini was formed with the addition of T4 DNA ligase, producing an unnicked circular strand. Using the unnicked strand as the RCA template, the P1 hybridized with the circle probe as a primer will trigger the RCA process. The RCA reaction produces amounts of long tandem-repeat DNA tiles with multiple recognizing regions for the FAM modified DNA probes (FP) and biotin-modified DNA probes (BP). With the streptavidin-biotin interaction, the BPs and FPs can be easily immobilized on the surface of streptavidin-modified magnetic microbeads (MBs). Due to the RCA enhanced and highly-concentrated fluorescence accumulation on the MBs, an ultralow detection limit of 1.033 U mL-1 for FPG was obtained. Combined with the high tolerance capability of human blood serum owing to magnetic isolation, the FPG assays in human blood serum were also obtained using fluorescence and confocal laser scanning microscopy. These results indicate that this robust self-primed RCA combined with magnetic nanoprobes is an excellent candidate for quantitatively monitoring the FPG activity responsible for DNA oxidative damage-related clinical diagnosis and therapy. PMID- 29517786 TI - Molecular engineering of polymeric carbon nitride: advancing applications from photocatalysis to biosensing and more. AB - As a promising two-dimensional (2D) conjugated polymer, polymeric carbon nitride (CN) is attracting dramatically increasing interest due to its unusual properties, facile synthesis from abundant and inexpensive starting materials, and promising applications ranging from (photo)catalysis, and photoelectrochemistry, to biosensors. The polymeric feature and facile synthesis of CN allow easy engineering of its structure at the molecular level. For instance, the moderate reactivity of CN at the interface, together with the aromatic pi-conjugated framework and intralayer hydrogen bonds, provides ample possibilities to control its molecular structure and properties to meet task specific applications. This review summarizes and highlights a panorama of the latest advancements related to the design and construction of the molecular structure of CN, such as by doping and copolymerization, engineering of the polymerization degree, coordination interaction, covalent and noncovalent functionalization, and modulation of intralayer hydrogen bonding. Beyond photocatalysis, the emerging applications of CN are also briefly discussed with a special emphasis on sensing, bioimaging and biotherapy, smart responsive systems and photoelectrochemical devices. This review ends with perspectives on the challenges and future prospects of molecular engineering of CN. PMID- 29517787 TI - Au nanoparticles on two-dimensional MoS2 nanosheets as a photoanode for efficient photoelectrochemical miRNA detection. AB - MiRNAs are small regulatory RNAs that play crucial roles in the oncogenic state in various cancers and have shown highly promising clinical applications as plasma-based markers for cancer classification and prognostication. Due to their electroanalytical advantages, photoelectrochemical biosensors are a very attractive alternative technology for miRNA sensing and detection. In this work, we demonstrated a novel photoelectrochemical (PEC) sensor using the in situ grown Au nanoparticles/two-dimensional molybdenum disulfide (MoS2) nanosheet heterojunction (MoS2-AuNPs) on ITO glass as the photoanode (MoS2-AuNPs/ITO). AuNPs were used as a photoelectronic transfer promoter and DNA probe immobilization carrier as well. The thiol modified biotin DNA with a hairpin structure was tethered to the MoS2-AuNPs/ITO surface to form a specific capturing layer for miRNA detection. The biotin specific protein streptavidin was used as the signal amplifying species. This PEC sensor is structurally simple and possesses sensitivity and specificity toward miRNA. The CV and EIS responses were evaluated to monitor the PEC anode fabrication. The stability and reproducibility of this PEC design strategy were both evaluated before it was used in analyzing the samples of miRNA in human serum. Finally, we found that this PEC sensor displayed a broad detection linear range and a low detection limit of 4.21 fM, and it can excellently discriminate the mismatched miRNA. These findings pave the way for developing PEC sensors targeting miRNA by using noble metals/MoS2 heterojunctions. PMID- 29517788 TI - Shining a light on the photo-sensitisation of organic-inorganic hybrid polyoxometalates. AB - Finding new ways of using visible light (or, more specifically, solar irradiation) to drive commercially significant and/or challenging chemical processes is an ongoing research goal. Polyoxometalates (POMs) are discrete, metal-oxide clusters which are cheap, robust and easily synthesised but can also act as versatile molecular building blocks, allowing for astonishing variety in their structures and properties. In particular, the rich redox chemistry and inherent photo-activity of POMs makes them attractive for use in a variety of photochemical applications, however POMs characteristically only absorb strongly in the UV region. In this perspective, we discuss the various strategies which have been employed in order to sensitise POMs to visible light, with a particular focus on hybrid inorganic-organic POM species. We will discuss the two clear photo-activation mechanisms which have been developed to date and provide an outlook on some of the possible future directions of the field. PMID- 29517789 TI - A target-induced logically reversible logic gate for intelligent and rapid detection of pathogenic bacterial genes. AB - For the first time, a target (pathogenic bacterial gene)-induced logically reversible logic gate was constructed as an intelligent biosensor, which has one to-one mapping functionality and can rapidly distinguish all information of the two targets, the presence of any target and the absence (or presence) of both of the targets, from the unique output signal pattern. PMID- 29517790 TI - Functional conjugated pyridines via main-group element tuning. AB - Pyridine-based materials have seen widespread attention for the development of n type organic materials. In recent years, the incorporation of main-group elements has also explored significant advantages for the development and tunability of organic conjugated materials. The unique chemical and electronic structure of main-group elements has led to several enhancements in conventional organic materials. This Feature article highlights recent main-group based pyridine materials by discussing property enhancements and application in organic electronics. PMID- 29517791 TI - An ultrafast one-step assay for the visual detection of RNA virus. AB - A one-step, rapid, and visual method was developed for the detection of RNA viruses and a few copies of the Zika RNA virus were directly detected within 25 min by naked-eye observation. This method will prove to be promising for point-of care testing in out-of-lab and inconvenient settings. PMID- 29517792 TI - Fmoc-phenylalanine displays antibacterial activity against Gram-positive bacteria in gel and solution phases. AB - In the quest for new antimicrobial materials, hydrogels of Fmoc-protected peptides and amino acids have gained momentum due to their ease of synthesis and cost effectiveness; however, their repertoire is currently limited, and the mechanistic details of their function are not well understood. Herein, we report the antibacterial activity of the hydrogel and solution phases of Fmoc phenylalanine (Fmoc-F) against a variety of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Fmoc-F, a small molecule hydrogelator, reduces the bacterial load both in vitro and in the skin wound infections of mice. The antibacterial activity of Fmoc-F is predominantly due to its release from the hydrogel. Fmoc-F shows surfactant-like properties with critical micelle concentration nearly equivalent to its minimum bactericidal concentration. Similar to Fmoc-F, some Fmoc-conjugated amino acids (Fmoc-AA) have also shown antibacterial effects that are linearly correlated with their surfactant properties. At low concentrations, where Fmoc-F does not form micelles, it inhibits bacterial growth by entering the cell and reducing the glutathione levels. However, at higher concentrations, Fmoc-F triggers oxidative and osmotic stress and, alters the membrane permeabilization and integrity, which kills Gram-positive bacteria. Herein, we proposed the use of the Fmoc-F hydrogel and its solution for several biomedical applications. This study will open up new avenues to enhance the repertoire of Fmoc-AA to act as antimicrobial agents and improve their structure-activity relationship. PMID- 29517793 TI - Molecular mechanism of vesicle division induced by coupling between lipid geometry and membrane curvatures. AB - We investigated the effects of lipid geometry on vesicle division using coarse grained molecular dynamics simulations. When the vesicle is composed of zero and negative spontaneous curvature lipids (ZSLs and NSLs), the difference in their molecular spontaneous curvatures destabilizes the neck of the limiting shape vesicle. In the vesicle division pathway, the neck developed into the stalk intermediates. The stalk was broken when the NSLs were expelled from the stalk. Free energy analysis shows that the coupling between the lipid geometry and the Gaussian rigidity is responsible for the observed vesicle division. PMID- 29517794 TI - Evaluation of novel platinum(ii) based AIE compound-encapsulated mesoporous silica nanoparticles for cancer theranostic application. AB - Advanced biomedical research has established that cancer is a multifactorial disorder which is highly heterogeneous in nature and responds differently to different treatment modalities, due to which constant monitoring of therapy response is becoming extremely important. To accomplish this, different theranostic formulations have been evaluated. However, most of them are found to suffer from several limitations extending from poor resolution, radiation damage, to high costs. In order to develop a better theranostic modality, we have designed and synthesized a novel platinum(ii)-based 'aggregation induced emission' (AIE) molecule (named BMPP-Pt) which showed strong intra-cellular fluorescence and also simultaneously exhibited potent cytotoxic activity. Due to this dual functionality, we wanted to explore the possibility of using this compound as a single molecule based theranostic modality. This compound was characterized using elemental analysis, NMR and IR spectroscopy, mass spectrometry and single crystal X-ray structure determination. BMPP-Pt was found to exhibit a high AIE property with emission maxima at 497 nm. For more efficient cancer cell targeting, BMPP-Pt was encapsulated into mesoporous silica nanoparticles (Pt-MSNPs) and the MSNPs were further surface modified with an anti EpCAM aptamer (Pt-MSNP-E). Pt-MSNPs exhibited higher intracellular fluorescence compared to free BMPP-Pt, though both of them induced a similar degree of cell death via the apoptosis pathway, possibly via cell cycle arrest in the G1 phase. Anti-EpCAM aptamer modification was found to increase both cytotoxicity and intracellular fluorescence compared to unmodified MSNPs. Our study showed that EpCAM functionalized BMPP-Pt loaded MSNPs can efficiently internalize and induce apoptosis of cancer cells as well as show strong intracellular fluorescence. This study provides clues towards the development of a potential single compound based theranostic modality in future. PMID- 29517797 TI - Improving curcumin solubility and bioavailability by encapsulation in saponin coated curcumin nanoparticles prepared using a simple pH-driven loading method. AB - Curcumin is a bioactive phytochemical that can be utilized as a nutraceutical or pharmaceutical in functional foods, supplements, and medicines. However, the application of curcumin as a nutraceutical in commercial food and beverage products is currently limited by its low water-solubility, chemical instability, and poor oral bioavailability. In this study, all-natural colloidal delivery systems were developed to overcome these challenges, which consisted of saponin coated curcumin nanoparticles formed using a pH-driven loading method. The physicochemical and structural properties of the curcumin nanoparticles formed using this process were characterized, including particle size distribution, surface potential, morphology, encapsulation efficiency, and loading capacity. Fourier transform infrared spectroscopy and X-ray diffraction indicated that curcumin was present in the nanoparticles in an amorphous form. The curcumin nanoparticles were unstable to aggregation at low pH values (<3) and high NaCl concentrations (>200 mM), which was attributed to a reduction in electrostatic repulsion between them. However, they were stable at higher pH values (3 to 8) and lower NaCl levels (0 to 200 mM), due to a stronger electrostatic repulsion between them. They also exhibited good stability during refrigerated storage (4 degrees C) or after conversion into a powdered form (lyophilized). A simulated gastrointestinal tract study demonstrated that the in vitro bioaccessibility was around 3.3-fold higher for curcumin nanoparticles than for free curcumin. Furthermore, oral administration to Sprague Dawley rats indicated that the in vivo bioavailability was around 8.9-fold higher for curcumin nanoparticles than for free curcumin. These results have important implications for the development of curcumin-enriched functional foods, supplements, and drugs. PMID- 29517798 TI - Neutral and anionic zinc compounds supported by a bis(imino)phenyl NCN ligand. AB - The new zinc complexes 2,6-(ArN[double bond, length as m-dash]CH)2C6H3ZnBu (6) and 2,6-(ArN[double bond, length as m-dash]CH)2C6H3ZnCl2Li(THF)3 (7), supported by a bis(imino)phenyl NCN pincer ligand, were prepared (Ar = 2,6-iPr2C6H3). The reaction of complex 7 with LiHBEt3 resulted in a hydride transfer to the C[double bond, length as m-dash]N imine group to afford an unusual zinc dimer [eta1(C),kappa1(Nimine)-2-(ArN[double bond, length as m-dash]CH)-6-(Zn N(Ar)CH2)C6H3Zn]2 (9). The latter transformation occurs via the formation of compound (eta1(C),kappa1(N)-2,6-(ArN[double bond, length as m-dash]CH)2C6H3)2Zn (8) which can also be accessed by the reduction of 7 with KC8. PMID- 29517799 TI - Implications of DSM-5 for the diagnosis of pediatric eating disorders. AB - OBJECTIVE: The aim of the study was to compare the DSM-IV, DSM-5, and ICD-10 eating disorders (ED) nomenclatures to assess their value in the classification of pediatric eating disorders. We investigated the prevalence of the disorders in accordance with each system's diagnostic criteria, diagnostic concordance between the systems, and interrater reliability. METHOD: Participants were 1062 children and adolescents assessed at intake to a specialist Eating Disorders Program (91.6% female, mean age 14.5 years, SD = 1.75). Measures were collected from routine intake assessments. RESULTS: DSM-5 categorization led to a lower prevalence of unspecified EDs when compared with DSM-IV. There was almost complete overlap for specified EDs. Kappa values indicated almost excellent agreement between the two coders on all three diagnostic systems, although there was higher interrater reliability for DSM-5 and ICD-10 when compared with DSM-IV. DISCUSSION: DSM-5 nomenclature is useful in classifying eating disorders in pediatric clinical samples. PMID- 29517800 TI - Chronic urticaria can be caused by cancer and resolves with its cure. PMID- 29517801 TI - WITHDRAWN: Extraction of primary (baby) teeth for unerupted palatally displaced permanent canine teeth in children. AB - BACKGROUND: The permanent canine tooth in the maxillary (upper) jaw sometimes does not erupt into the mouth correctly. In about 1% to 3% of the population these teeth will be diverted into the roof of the mouth (palatally). It has been suggested that if the primary canine is removed at the right time this palatal eruption might be avoided. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To evaluate the effect of extracting the primary maxillary canine on the eruption of the palatally ectopic maxillary permanent canine. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 20 April 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE via OVID (1946 to 20 April 2012) and EMBASE via OVID (1980 to 20 April 2012). There were no restrictions regarding language or date of publication. SELECTION CRITERIA: Trials were selected if they met the following criteria: a randomised or quasi-randomised controlled trial, involving the extraction of the deciduous maxillary canine and assessing eruption/non-eruption of the palatally displaced maxillary permanent canine. DATA COLLECTION AND ANALYSIS: Data extraction was undertaken independently by two review authors. The primary outcome was the reported prevalence of eruption or non-eruption of the ectopic permanent canine into the mouth following observation or intervention. Results were to be expressed as risk ratios for dichotomous outcomes with 95% confidence intervals and mean differences for continuous outcomes. Heterogeneity was to be investigated, including both clinical and methodological factors. Authors of trials were contacted to request unpublished data. MAIN RESULTS: Reports of two randomised controlled trials previously excluded from an earlier version of the review due to "deficiencies in reporting, insufficient data" have now been included. These two trials included approximately 128 children, with more than 150 palatally displaced canine teeth, and both were conducted by the same research group. Data presented in the trial reports are either incomplete or inconsistent. Both trials are at high risk of bias. It must be emphasised that both trials have serious deficiencies in the way they were designed, conducted, and reported, and attempts to contact the authors to obtain detailed information and clarify inconsistencies have been unsuccessful. Allocation to treatment appears to be at the level of the individual, but outcomes of successful treatment relate to included teeth and data are not reported for each treatment group. Adverse effects are not reported. Neither trial provides any evidence to guide clinical decision making. AUTHORS' CONCLUSIONS: There is currently no evidence of the effects of extraction of primary canine teeth in 10-13 year old children with one or two palatally displaced permanent canine teeth. PMID- 29517802 TI - Protocol for digital intervention for effective health promotion of small children-A cluster randomized trial. AB - AIM: This article introduces the protocol of a study aiming to evaluate the effectiveness of digital WellWe intervention in supporting the participation of families with small children in the promotion of their health. BACKGROUND: Early childhood is a meaningful period for building a strong base for good health. Parents play a key role in affecting the health behaviour and psychosocial development of their children. A family-centred approach makes it possible to support families' individual health literacy needs and empower them to take actions towards promoting healthier behaviour. However, there are a lack of family-centred digital health interventions intended for parents and their small children. DESIGN: The study is designed as a two-arm cluster, randomized, controlled trial with a 4-month follow-up. METHODS: The data are being collected from 200 families with a 4-year-old child. Cluster randomization is being performed at the municipality level. Municipalities (N = 4) located in Southwest Finland, comprising child health clinics (N = 15) with their family clients, were randomly allocated to either an intervention (WellWe intervention) or a control group (usual care). The outcome measures include parental self-efficacy for healthy behaviours, mindfulness in parenting and the family-centred approach of the extensive health examination. Data collection is being performed at baseline, after the intervention and at a 4-month follow-up. DISCUSSION: The results from this study will make it possible to determine whether this new method can be recommended for implementation in child health clinic settings to support the participation of families with small children in promoting their health. PMID- 29517804 TI - The legacy of Tom Andersen: The ethics of reflecting processes. AB - Tom Andersen and his pioneering work with reflecting conservations has had a lasting influence on the field of family therapy and mental health more broadly. Most family therapists are familiar with his contributions related to reflecting teams; however, fewer are familiar with his conceptualization of reflecting processes, which offer practical ways to approach therapeutic conversations to address challenging problems. This article provides a brief history of Andersen's career and reviews four key elements of his approach, including: (a) his way of being in relationship, (b) appropriately unusual comments, (c) inner and outer dialogs, and (d) ethics of dialogical relating. Finally, this article introduces readers to the context of the video that will be analyzed in the articles that follow in this special section. PMID- 29517803 TI - Thyroid hormones and menstrual cycle function in a longitudinal cohort of premenopausal women. AB - BACKGROUND: Previous studies have reported that hyperthyroid and hypothyroid women experience menstrual irregularities more often compared with euthyroid women, but reasons for this are not well-understood and studies on thyroid hormones among euthyroid women are lacking. In a prospective cohort study of euthyroid women, this study characterised the relationship between thyroid hormone concentrations and prospectively collected menstrual function outcomes. METHODS: Between 2004-2014, 86 euthyroid premenopausal women not lactating or taking hormonal medications participated in a study measuring menstrual function. Serum thyroid hormones were measured before the menstrual function study began. Women then collected first morning urine voids and completed daily bleeding diaries every day for three cycles. Urinary oestrogen and progesterone metabolites (estrone 3-glucuronide (E1 3G) and pregnanediol 3-glucuronide (Pd3G)) and follicle-stimulating hormone were measured and adjusted for creatinine (Cr). RESULTS: Total thyroxine (T4 ) concentrations were positively associated with Pd3G and E1 3G. Women with higher (vs lower) T4 had greater luteal phase maximum Pd3G (Pd3G = 11.7 MUg/mg Cr for women with high T4 vs Pd3G = 9.5 and 8.1 MUg/mg Cr for women with medium and low T4 , respectively) and greater follicular phase maximum E1 3G (E1 3G = 41.7 ng/mg Cr for women with high T4 vs E1 3G = 34.3 and 33.7 ng/mg Cr for women with medium and low T4 , respectively). CONCLUSIONS: Circulating thyroid hormone concentrations were associated with subtle differences in menstrual cycle function outcomes, particularly sex steroid hormone levels in healthy women. Results contribute to the understanding of the relationship between thyroid function and the menstrual cycle, and may have implications for fertility and chronic disease. PMID- 29517805 TI - Self-objectification and disordered eating: A meta-analysis. AB - OBJECTIVE: Objectification theory posits that self-objectification increases risk for disordered eating. METHOD: The current study sought to examine the relationship between self-objectification and disordered eating using meta analytic techniques. RESULTS: Data from 53 cross-sectional studies (73 effect sizes) revealed a significant moderate positive overall effect (r = .39), which was moderated by gender, ethnicity, sexual orientation, and measurement of self objectification. Specifically, larger effect sizes were associated with female samples and the Objectified Body Consciousness Scale. Effect sizes were smaller among heterosexual men and African American samples. Age, body mass index, country of origin, measurement of disordered eating, sample type and publication type were not significant moderators. DISCUSSION: Overall, results from the first meta-analysis to examine the relationship between self-objectification and disordered eating provide support for one of the major tenets of objectification theory and suggest that self-objectification may be a meaningful target in eating disorder interventions, though further work is needed to establish temporal and causal relationships. Findings highlight current gaps in the literature (e.g., limited representation of males, and ethnic and sexual minorities) with implications for guiding future research. PMID- 29517806 TI - Identification of specifically reduced Th2 cell subsets in allergic rhinitis patients after sublingual immunotherapy. AB - BACKGROUND: Although Th2 cells are well known to play important roles in allergic diseases including allergic rhinitis (AR), the factors that induce and sustain the pathogenesis of AR remain unclear. The recent development of sublingual immunotherapy (SLIT) is expected to allow changes to the underlying pathogenesis of AR. However, which Th2 cell subsets are important in house dust mite-induced AR (HDM-AR), the influence of SLIT on the pathogenic Th2 cells, and the association of Th2 cell subsets with SLIT efficacy have not been clarified. METHODS: The cytokine production and frequency of HDM-reactive T-cell subsets in peripheral blood mononuclear cells (PBMCs) were evaluated using flow cytometry in 89 HDM-AR patients (placebo [n = 43] and HDM 300 IR [n = 46]) who participated in a placebo-controlled study of SLIT with HDM tablets. All patients provided samples both before treatment as a baseline and at the end of the 52-week study. The PBMCs were stained with CellTraceTM Violet (CTV) before culture with HDM extract, and HDM-reactive T cells were detected as the proliferated cells with diminished CTV. RESULTS: HDM-reactive IL-5+ IL-13+ CD27- CD161+ CD4+ cells and ST2+ CD45RO+ CD4+ cells were observed in the peripheral blood from each patient with HDM-AR; these cells significantly decreased after SLIT in the group treated with active tablets. HDM-reactive ST2+ CD45RO+ CD4+ cells were significantly lower in active-responders. CONCLUSION: Allergen-reactive ST2+ CD45RO+ CD4+ cells or those combined with IL-5+ IL-13+ CD27- CD161+ CD4+ cells may be useful as markers indicating the successful treatment of SLIT. These cells may play a crucial role in the pathogenesis of AR as pathogenic memory Th2 cells. PMID- 29517807 TI - Development of the functional social network index for adolescent and young adult cancer survivors. AB - BACKGROUND: To the authors' knowledge, social network status in adolescent and young adult (AYA) cancer survivors has not been adequately studied to date. The authors developed and validated a functional social network index (FSNI) for AYA survivors, and compared its performance with that of 2 traditional indices (density and betweenness centrality). METHODS: A total of 102 AYA survivors and 102 noncancer controls who were matched for age, sex, and race were recruited from an Internet panel. Each participant reported relationships with up to 25 close friends and/or relatives. The authors developed a FSNI with reported marital status, contact frequency with friends/relatives, available resources for emotional and tangible support, and available resources for physical activity and weight management advice. Linear regression was used to analyze associations between the FSNI and cancer diagnoses, treatments, and coping skills. RESULTS: Based on the FSNI, survivors were found to have more available resources for emotional support (beta [b] = 3.02; P = .003), tangible support (b = 4.17; P<.001), physical activity advice (b = 3.94; P<.001), and weight management advice (b = 4.10; P<.001) compared with noncancer controls. Survivors of lymphoma had the largest FSNI, whereas survivors of central nervous system malignancies had the smallest (b = 2.77; P = .02). A higher FSNI was associated with better coping skills: less denial (b = 0.10; P = .01), using emotional support (b = 0.08; P = .04), using instrumental support (b = 0.12; P<.001), less behavioral disengagement (b = 0.08; P = .04), venting of emotions (b = 0.10; P = .004), positive reframing (b = 0.12; P = .003), planning for the future (b = 0.08; P = .03), and religious engagement (b = 0.16; P<.001). Density and betweenness centrality indices demonstrated neither significant differences in social networks between cancer survivors and controls (all P values >.05) nor significant associations with coping skills (all P values >.05). CONCLUSIONS: The FSNI appears to provide a better social network assessment for AYA cancer survivors than traditional indices. Cancer 2018;124:2220-7. (c) 2018 American Cancer Society. PMID- 29517809 TI - Fibre sub-type specific conduction reveals metabolic function in mouse sciatic nerve. AB - KEY POINTS: We have developed an improved method that enables simultaneous recording of stimulus evoked compound action potentials from large myelinated A fibres and small unmyelinated C fibres in mouse sciatic nerves. Investigations into the ability of fructose to support conduction in sciatic nerve revealed a novel glia-to-axon metabolic pathway in which fructose is converted in Schwann cells to lactate for subsequent shuttling to A fibres. The C fibres most likely directly take up and metabolise fructose. These differences are indicative of fibre sub-type specific metabolic profiles. These results demonstrate that the physiological insights provided by the method can be applied to investigations of peripheral nerve, with a view to understanding the metabolic disruptions that underlie diabetic neuropathy. ABSTRACT: The stimulus evoked compound action potential (CAP), recorded using suction electrodes, provides an index of the relative number of conducting axons within a nerve trunk. As such the CAP has been used to elucidate the diverse mechanisms of injury resulting from a variety of metabolic insults to central nervous white matter, whilst also providing a model with which to assess the benefits of clinically relevant neuroprotective strategies. In addition the technique lends itself to the study of metabolic cell to-cell signalling that occurs between glial cells and neurones, and to exploring the ability of non-glucose substrates to support axon conduction. Although peripheral nerves are sensitive to metabolic insult and are susceptible to diabetic neuropathy, there is a lack of fundamental information regarding peripheral nerve metabolism. A confounding factor in such studies is the extended duration demanded by the experimental protocol, requiring stable recording for periods of many hours. We describe a method that allows us to record simultaneously the stimulus evoked CAPs from A and C fibres from mouse sciatic nerve, and demonstrate its utility as applied to investigations into fibre sub type substrate use. Our results suggest that C fibres directly take up and metabolise fructose, whereas A fibre conduction is supported by fructose-derived lactate, implying there exist unique metabolic profiles in neighbouring fibre sub types present within the same nerve trunk. PMID- 29517808 TI - Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study. AB - BACKGROUND: Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. METHODS: In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. RESULTS: We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). CONCLUSIONS: The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level. PMID- 29517810 TI - Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. AB - BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24. (c) 2018 American Cancer Society. PMID- 29517811 TI - The use of a rein tension device to compare different training methods for neck flexion in base-level trained Warmblood horses at the walk. AB - BACKGROUND: Debate surrounds the use of high rein tension for obtaining different head and neck positions in the training of sport horses on account of possible welfare issues. OBJECTIVES: To compare auxiliary rein tension in two methods (Draw Reins and Concord Leader) for obtaining a standardised head and neck position on a hard and a soft surface. STUDY DESIGN: Intervention study. METHODS: Left and right rein tensions were measured in 11 base-level trained client-owned sport horses (mean age +/- s.d.; 10 +/- 3.2 years) exercised in-hand with, in a random order, conventional draw reins or the newly developed Concord Leader in a standardised head and neck position. Rein tension was measured using a calibrated device operating at 10 Hz during six runs of 15 s in a straight line for each training method on both a hard and a soft surface. A linear mixed model and grouped logistic regression analysis were applied to compare the two methods (P<0.05). RESULTS: The odds of a tension of 0 N were lower with draw reins than with the Concord Leader. The rein tension (mean sum of the force applied, in N) of the draw reins was 13.8 times higher than that of the Concord Leader. MAIN LIMITATIONS: This study was performed on horses exercised in-hand; however, these auxiliary aids are normally used when lungeing. Possible redirection of rein tension towards the poll was not measured. CONCLUSIONS: We showed that when using the Concord Leader a similar head and neck position is achieved with a much lower rein tension than with the draw reins and, more importantly, with a much greater likelihood of 0 N. It is unnecessary to use high auxiliary rein tension to obtain a standard, flexed head and neck position. PMID- 29517812 TI - MicroRNA-146a and microRNA-155 as novel crevicular fluid biomarkers for periodontitis in non-diabetic and type 2 diabetic patients. AB - AIM: Recent studies point at the crucial role of epigenetic mechanisms in the development of multifactorial diseases such as periodontitis and diabetes mellitus (DM) type 2. In addition, circulatory microRNAs (miRs) have emerged as novel biomarkers for various diseases. Aim of this study was to investigate the levels of miR-146a and miR-155 and superoxide dismutase (SOD) activity in gingival crevicular fluid (GCF) of periodontitis patients with (CPDM) and without (CP) DM type 2 as well as in periodontally healthy, control groups (PHDM and PH, respectively). MATERIAL AND METHODS: miR modulation was analysed using quantitative real-time PCR while SOD activity was measured spectrophotometrically. RESULTS: The upregulation of miR-146a and miR-155 was observed in CP and CPDM patients' baseline, while the levels decreased after 6 weeks of the non-surgical therapy to the levels comparable to PH and PHDM, respectively. Expression levels of miRs positively correlated with SOD activity. Levels of miR-146a were higher in PHDM compared to PH patients. Multivariate analysis revealed that levels of miR-146a and miR-155 were significantly associated with periodontitis when adjusting for age and gender. CONCLUSIONS: miR 146a and miR-155 may be considered as possible novel biomarkers for periodontitis in non-diabetic and type 2 diabetic patients. PMID- 29517814 TI - The challenges posed by equine arboviruses. AB - Equine populations worldwide are at increasing risk of infection by viruses transmitted by biting arthropods, including mosquitoes, biting midges (Culicoides), sandflies and ticks. These include the flaviviruses (Japanese encephalitis, West Nile and Murray Valley encephalitis), alphaviruses (eastern, western and Venezuelan encephalitis) and the orbiviruses (African horse sickness and equine encephalosis). This review provides an overview of the challenges faced in the surveillance, prevention and control of the major equine arboviruses, particularly in the context of these viruses emerging in new regions of the world. PMID- 29517813 TI - The association between nurse staffing and omissions in nursing care: A systematic review. AB - AIMS: To identify nursing care most frequently missed in acute adult inpatient wards and to determine evidence for the association of missed care with nurse staffing. BACKGROUND: Research has established associations between nurse staffing levels and adverse patient outcomes including in-hospital mortality. However, the causal nature of this relationship is uncertain and omissions of nursing care (referred as missed care, care left undone or rationed care) have been proposed as a factor which may provide a more direct indicator of nurse staffing adequacy. DESIGN: Systematic review. DATA SOURCES: We searched the Cochrane Library, CINAHL, Embase and Medline for quantitative studies of associations between staffing and missed care. We searched key journals, personal libraries and reference lists of articles. REVIEW METHODS: Two reviewers independently selected studies. Quality appraisal was based on the National Institute for Health and Care Excellence quality appraisal checklist for studies reporting correlations and associations. Data were abstracted on study design, missed care prevalence and measures of association. Synthesis was narrative. RESULTS: Eighteen studies gave subjective reports of missed care. Seventy-five per cent or more nurses reported omitting some care. Fourteen studies found low nurse staffing levels were significantly associated with higher reports of missed care. There was little evidence that adding support workers to the team reduced missed care. CONCLUSIONS: Low Registered Nurse staffing is associated with reports of missed nursing care in hospitals. Missed care is a promising indicator of nurse staffing adequacy. The extent to which the relationships observed represent actual failures, is yet to be investigated. PMID- 29517815 TI - Systematic review and meta-analysis of post-transplant lymphoproliferative disorder in lung transplant recipients. AB - A systematic review of papers in English on post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random-effects model, and heterogeneity among studies was quantitated using I2 values. Fourteen studies published from 2005 to 2015 were included in the meta-analysis. One hundred and sixty-four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67-fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98-29.70; P = .003). pOR of death for early onset PTLD (<1 year post-LT) vs late onset (>1 year post-LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20-1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI -0.48-0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08-2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31-3.52, P = .94). This meta-analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD. PMID- 29517816 TI - Stroke survivors' and carers' experiences of a systematic voiding programme to treat urinary incontinence after stroke. AB - AIMS AND OBJECTIVES: To explore the views and experiences of stroke survivors and carers about a systematic voiding programme for poststroke incontinence. BACKGROUND: Urinary incontinence after stroke is common and associated with poorer functional outcome. Structured assessment and management are potentially effective interventions, but it is important that there is a good understanding of stroke survivors' and carers' views of their acceptability and implementation. DESIGN: A qualitative study within a feasibility trial. METHODS: Sixteen participants (12 stroke survivors and four carers) were interviewed using a structured schedule shortly before discharge from one of six inpatient stroke units across six hospitals. Interviews were audio-recorded and transcribed verbatim, and thematic analysis was conducted. FINDINGS: Participants included seven male and five female stroke survivors (mean age 76 years) and four female carers (two wives and two daughters). Themes relating to the preliminary (assessment) phase of the programme were as follows: physical impact, psychological impact, beliefs about incontinence, and the assessment process itself. Main themes relating to the implementation of the programme included the following: timed voiding decisions, adapting the programme or the timed voiding schedule, and urinary incontinence management techniques. Participants felt that the programme helped them to re-establish a regular pattern of micturition and to regain autonomy. CONCLUSIONS: The effectiveness of a systematic voiding programme may partly lie in its educational component, challenging patients' and carers' assumptions that poststroke incontinence is inevitable. Individual adaptation of the programme and the ability to incorporate it alongside other aspects of care are likely to be key factors influencing implementation. RELEVANCE TO CLINICAL PRACTICE: Urinary incontinence is common after stroke. To maximise benefits from a systematic voiding programme, nurses should support stroke survivors to overturn erroneous beliefs, to participate in tailoring of the programme, and in self-management where appropriate. PMID- 29517817 TI - Magnetic susceptibility increases as diamagnetic molecules breakdown: Myelin digestion during multiple sclerosis lesion formation contributes to increase on QSM. AB - BACKGROUND: The pathological processes in the first weeks of multiple sclerosis (MS) lesion formation include myelin digestion that breaks chemical bonds in myelin lipid layers. This can increase lesion magnetic susceptibility, which is a potentially useful biomarker in MS patient management, but not yet investigated. PURPOSE: To understand and quantify the effects of myelin digestion on quantitative susceptibility mapping (QSM) of MS lesions. STUDY TYPE: Histological and QSM analyses on in vitro models of myelin breakdown and MS lesion formation in vivo. POPULATION/SPECIMENS: Acutely demyelinating white matter lesions from MS autopsy tissue were stained with the lipid dye oil red O. Myelin basic protein (MBP), a major membrane protein of myelin, was digested with trypsin. Purified human myelin was denatured with sodium dodecyl sulfate (SDS). QSM was performed on phantoms containing digestion products and untreated controls. In vivo QSM was performed on five MS patients with newly enhancing lesions, and then repeated within 2 weeks. FIELD STRENGTH/SEQUENCE: 3D ASSESSMENT: Region of interest analyses were performed by a biochemist and a neuroradiologist to determine susceptibility changes on in vitro and in vivo QSM images. STATISTICAL TESTS: Not applicable. RESULTS: MBP degradation by trypsin increased the QSM measurement by an average of 112 +/- 37 ppb, in excellent agreement with a theoretical estimate of 111 ppb. Degradation of human myelin by SDS increased the QSM measurement by 23 ppb. As MS lesions changed from gadolinium enhancing to nonenhancing over an average of 15.8 +/- 3.7 days, their susceptibility increased by an average of 7.5 +/- 6.3 ppb. DATA CONCLUSION: Myelin digestion in the early stages of MS lesion formation contributes to an increase in tissue susceptibility, detectable by QSM, as a lesion evolves from gadolinium enhancing to nonenhancing. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1281-1287. PMID- 29517818 TI - Prospective Validation of Clinical Criteria to Identify Emergency Department Patients at High Risk for Adverse Drug Events. AB - OBJECTIVES: Adverse drug events (ADEs) cause or contribute to one in nine emergency department (ED) presentations in North America and are often misdiagnosed. EDs have insufficient clinical pharmacists to complete medication reviews in all incoming patients, even though pharmacist-led medications reviews have been associated with improved health outcomes. Our objective was to validate clinical decision rules to identify patients presenting with ADEs so they could be prioritized for pharmacist-led medication review. METHODS: This multicenter, prospective study was conducted in two tertiary and one community hospital in Canada. We enrolled 1,529 adults presenting to EDs over 12 months. We applied two clinical decision rules and collected baseline variables prior to assessments by clinical pharmacists and physicians. We compared the physician and pharmacist diagnoses with the decision rule results. The primary outcome was a moderate or severe ADE, defined as an unintended and harmful event related to medication use or misuse, which required a change in medical therapy, diagnostic testing, consultation, or admission. An independent committee adjudicated uncertain and discordant cases. We calculated the diagnostic accuracy of both rules. RESULTS: Among 1,529 patients, 184 (12.0%) were diagnosed with an ADE. Rule 1 contained the variables 1) having a preexisting medical condition or having taken antibiotics within 1 week and 2) age > 80 years or having a medication change within 28 days. They had a sensitivity of 91.3% (95% confidence interval [CI] = 86.3%-95.0%) and a specificity of 37.9% (95% CI = 35.3%-40.6%) for ADEs. CONCLUSIONS: Our study validated clinical decision rules that can be applied by clinical pharmacists to limit the number of patients requiring medication review, while identifying the majority of patients presenting with clinically significant ADEs. PMID- 29517819 TI - MR-assisted PET motion correction in simultaneous PET/MRI studies of dementia subjects. AB - BACKGROUND: Subject motion in positron emission tomography (PET) studies leads to image blurring and artifacts; simultaneously acquired magnetic resonance imaging (MRI) data provides a means for motion correction (MC) in integrated PET/MRI scanners. PURPOSE: To assess the effect of realistic head motion and MR-based MC on static [18 F]-fluorodeoxyglucose (FDG) PET images in dementia patients. STUDY TYPE: Observational study. POPULATION: Thirty dementia subjects were recruited. FIELD STRENGTH/SEQUENCE: 3T hybrid PET/MR scanner where EPI-based and T1 weighted sequences were acquired simultaneously with the PET data. ASSESSMENT: Head motion parameters estimated from high temporal resolution MR volumes were used for PET MC. The MR-based MC method was compared to PET frame-based MC methods in which motion parameters were estimated by coregistering 5-minute frames before and after accounting for the attenuation-emission mismatch. The relative changes in standardized uptake value ratios (SUVRs) between the PET volumes processed with the various MC methods, without MC, and the PET volumes with simulated motion were compared in relevant brain regions. STATISTICAL TESTS: The absolute value of the regional SUVR relative change was assessed with pairwise paired t-tests testing at the P = 0.05 level, comparing the values obtained through different MR-based MC processing methods as well as across different motion groups. The intraregion voxelwise variability of regional SUVRs obtained through different MR-based MC processing methods was also assessed with pairwise paired t-tests testing at the P = 0.05 level. RESULTS: MC had a greater impact on PET data quantification in subjects with larger amplitude motion (higher than 18% in the medial orbitofrontal cortex) and greater changes were generally observed for the MR-based MC method compared to the frame-based methods. Furthermore, a mean relative change of ~4% was observed after MC even at the group level, suggesting the importance of routinely applying this correction. The intraregion voxelwise variability of regional SUVRs was also decreased using MR-based MC. All comparisons were significant at the P = 0.05 level. DATA CONCLUSION: Incorporating temporally correlated MR data to account for intraframe motion has a positive impact on the FDG PET image quality and data quantification in dementia patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1288-1296. PMID- 29517820 TI - From Mesocates to Helicates: Structural, Magnetic and Chiro-Optical Studies on Nickel(II) Supramolecular Assemblies Derived from Tetradentate Schiff Bases. AB - The systematic reactions of a family of tetradentate pyridyl/imine and quinolyl/imine racemic or enantiopure Schiff bases with Ni(NO3 )2 or Ni(ClO4 )2 in the presence of sodium azide yielded, as a function of the starting racemic, chiral or achiral base, a set of chiral, meso or achiral complexes. In all cases, the compounds consist of two NiII cations linked by a double azido bridge in its end-on coordination mode. All the dimers exhibit a mesocate supramolecular structure and one of them, the unprecedented mix of helicate and mesocate in 2:1 ratio. The transition from mesocate to helicate conformation has been reached by tuning the flexibility of the central spacers of the Schiff bases and the size of the substituents. Electronic circular dichroism (ECD) studies have been performed for two pairs of enantiomers and interpreted by means of DFT calculations. Susceptibility measurements show a ferromagnetic coupling between the NiII cations mediated by the end-on azido bridges. PMID- 29517821 TI - An Unprecedented Retro-Mumm Rearrangement Revealed by ESI-MS/MS, IRMPD Spectroscopy, and DFT Calculations. AB - Bronsted acids and protic solvents mediate acyl transfer, known as the Mumm rearrangement, from imidates to the corresponding acylamides. This represents a key step in several reactions, for example, the Ugi four-component reaction (U 4CR) and Passerini three-component reaction (P-3CR). Herein, an unprecedented break of the non-reversibility of the Mumm rearrangement is reported. A combination of electrospray tandem mass spectrometry (ESI-MS/MS), infrared multiphoton dissociation (IRMPD) ion spectroscopy and theoretical calculations demonstrates the occurrence of the retro-Mumm rearrangement of protonated isopeptides in the gas phase. In the gas phase, the extra proton acquired during ESI promotes the backward isomerisation reaction in a catalytic fashion. PMID- 29517822 TI - Dynamic contrast-enhanced imaging in localizing local recurrence of prostate cancer after radiotherapy: Limited added value for readers of varying level of experience. AB - BACKGROUND: The incremental value of dynamic contrast-enhanced (DCE) imaging in localizing radiorecurrent prostate cancer is uncertain. PURPOSE: To assess the added-value of DCE imaging to the combination T2 -weighted imaging (T2 W)+diffusion-weighted imaging (DWI) in detecting locally radiorecurrent prostate cancer (PCa), by radiologists with different levels of experience. STUDY TYPE: Analytic retrospective study. POPULATION: In all, 52 men with biological suspected PCa recurrence after radiotherapy were retrospectively included. FIELD STRENGTH/SEQUENCE: All men underwent prostatic MRI (1.5T or 3T), including T2 W, DWI, and DCE imagings, before biopsies. ASSESSMENT: Two junior (6 months' experience) and two senior readers (more than 3 years' experience) independently assigned a Likert score for each prostatic sextant on T2 W+DW+DCE imagings, then on T2 W+DW imagings, 4 weeks later. STATISTICAL TESTS: The reference standard was prostatic biopsies. For two levels of positivity of Likert score, 3/5 and 4/5, sensitivity, specificity, area under the receiver operating curve (AUC), and interreader agreement were compared. RESULTS: T2 W+DWI+DCE and T2 W+DWI imaging had similar AUC at lobe and sextant level (0.853-0.946 vs. 0.819-0.955, P from 0.071-0.534). Using a Likert score >=4/5, T2 W+DWI+DCE significantly improved the sensitivity for junior readers at the patient, lobe, and sextant level (40-80% vs. 22-66%, P < 0.0001-0.041). Sensitivity was not significantly modified with DCE imaging for senior readers (54-95% vs. 50-91%, P from 0.074-1). Specificity was not modified for all readers (50-100% vs. 50%-100%, P from 0.134-1). DCE imaging improved interreader agreement for a Likert score >=4/5 (kappa from 0.6 0.73 vs. 0.38-0.73). DATA CONCLUSION: The addition of DCE imaging did not significantly improve accuracy in recurrent PCa detection after radiotherapy, whatever the level of experience of the readers. However, the addition of DCE imaging slightly improved the sensitivity for less-experienced readers and increased their diagnostic confidence. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1012-1023. PMID- 29517823 TI - Aerogels Derived from Polymer Nanofibers and Their Applications. AB - Aerogels are gels in which the solvent is supplanted by air while the pores and networks are largely maintained. Owing to their low bulk density, high porosity, and large specific surface area (SSA), aerogels are promising for many applications. Various inorganic aerogels, e.g., silica aerogels, are intensively studied. However, the mechanical brittleness of common inorganic aerogels has seriously restricted their applications. In the past decade, nanofibers have been developed as building blocks for the construction of aerogels to improve their mechanical property. Unlike traditional frameworks constructed by interconnected particles, nanofibers can form chemically cross-linked and/or physically entangled 3D skeletons, thus showing flexibility instead of brittleness. Therefore, excellent elasticity and toughness, ultralow density, high SSA, and tunable chemical composition can be expected for the polymer nanofiber-derived aerogels (PNAs). In this review, recent research progress in the fabrication, properties, and applications of PNAs is summarized. Various nanofibers, including nanocelluloses, nanochitins, and electrospun nanofibers are included, as well as carbon nanofibers from the corresponding organic precursors. Typical applications in supercapacitors, electrocatalysts for oxygen reduction reaction, flexible electrodes, oil absorbents, adsorbents, tissue engineering, stimuli-responsive materials, and catalyst carriers, are presented. Finally, the challenges and future development of PNAs are discussed. PMID- 29517824 TI - In vitro activity of azole derivatives and griseofulvin against planktonic and biofilm growth of clinical isolates of dermatophytes. AB - As shown by recent research, most of the clinically relevant fungi, including dermatophytes, form biofilms in vitro and in vivo, which may exhibit antimicrobial tolerance that favour recurrent infections. The aim of this study was to determine the minimum inhibitory concentrations (MICs) of itraconazole (ITC), voriconazole (VCZ) and griseofulvin (GRI) against Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Microsporum canis and Microsporum gypseum in planktonic and biofilm growth. For the planktonic form, susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI), document M38-A2, while biofilm susceptibility was evaluated using the XTT colorimetric essay. The planktonic growth of all strains was inhibited, with MIC values ranging from 0.00195 to 0.1225 MUg/mL for VRC, 0.00195 to 0.25 MUg/mL for ITC and <0.0039 to 4 MUg/mL for GRI, while a 50-fold increase in the MIC was required to significantly reduce the metabolic activity (P < .05) of dermatophyte biofilms. In brief, the ability of dermatophytes to form biofilms may be a contributing factor for the recalcitrance of dermatophytoses or the dissemination of the disease. PMID- 29517825 TI - Combination of essential oil and ciprofloxacin to inhibit/eradicate biofilms in multidrug-resistant Klebsiella pneumoniae. AB - AIM: This study aimed to test biofilm inhibition activities of each of essential oils (EOs), main compounds of EOs and enzymes against pathogenic Klebsiella pneumoniae. METHODS AND RESULTS: The effect of seven EOs and three enzymes was tested on formation and eradication of K. pneumoniae biofilm. Peppermint oil showed a robust biofilm inhibitory effect, causing inhibition that ranged from 69.2 to 98.2% at 5 MUl ml-1 . Thyme oil was found to have the best biofilm eradication ability, causing eradication that ranged from 80.1 to 98.0% at 10 MUl ml-1 . The most effective EOs were analysed by GC/MS, to determine the major chemical constitutes of each oil. Pure menthol was found to cause 75.3-97.5% biofilm inhibition at 2.5 MUg ml-1 , whereas thymol caused 85.1-97.8% biofilm eradication at 5 MUg ml-1 . However, moderate inhibition activity was detected for alpha-amylase and bromelain, while poor activity was detected for beta amylase. Ciprofloxacin combination with thyme oil and thymol was found to enhance antibiotic activity, and affect biofilm cell viability. The observed inhibitory/eradication activity on K. pneumoniae biofilms was confirmed by scanning electron microscopy. CONCLUSIONS: Thyme and peppermint EOs, and their active components are promising antibiofilm agents alone and/or in combination with ciprofloxacin to inhibit/eradicate biofilms of K. pneumoniae. SIGNIFICANCE AND IMPACT OF THE STUDY: The presented results suggest the potential application of EOs against infections, caused by biofilm-producing K. pneumoniae, to prevent biofilm formation or decrease their resistance threshold. Moreover, the combination of EOs with ciprofloxacin minimizes the antibiotic concentration used and accordingly the potential accompanying toxic side effects. PMID- 29517826 TI - A Cut-and-Paste Approach to 3D Graphene-Oxide-Based Architectures. AB - Properly cut sheets can be converted into complex 3D structures by three basic operations including folding, bending, and pasting to render new functions. Folding and bending are extensively employed in crumpling, origami, and pop-up fabrications for 3D structures. Pasting joins different parts of a material together, and can create new geometries that are fundamentally unattainable by folding and bending. However, it has been much less explored, likely due to limited choice of weldable thin film materials and residue-free glues. Here it is shown that graphene oxide (GO) paper is one such suitable material. Stacked GO sheets can be readily loosened up and even redispersed in water, which upon drying, restack to form solid structures. Therefore, water can be utilized to heal local damage, glue separated pieces, and release internal stress in bent GO papers to fix their shapes. Complex and dynamic 3D GO architectures can thus be fabricated by a cut-and-paste approach, which is also applicable to GO-based hybrid with carbon nanotubes or clay sheets. PMID- 29517827 TI - Does non-invasive ventilation confer a lung protective effect and improve long term pulmonary outcomes? PMID- 29517828 TI - Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury. AB - Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. Stem Cells 2018;36:737-750. PMID- 29517829 TI - It's Not a Bug, It's a Feature: Functional Materials in Insects. AB - Over the course of their wildly successful proliferation across the earth, the insects as a taxon have evolved enviable adaptations to their diverse habitats, which include adhesives, locomotor systems, hydrophobic surfaces, and sensors and actuators that transduce mechanical, acoustic, optical, thermal, and chemical signals. Insect-inspired designs currently appear in a range of contexts, including antireflective coatings, optical displays, and computing algorithms. However, as over one million distinct and highly specialized species of insects have colonized nearly all habitable regions on the planet, they still provide a largely untapped pool of unique problem-solving strategies. With the intent of providing materials scientists and engineers with a muse for the next generation of bioinspired materials, here, a selection of some of the most spectacular adaptations that insects have evolved is assembled and organized by function. The insects presented display dazzling optical properties as a result of natural photonic crystals, precise hierarchical patterns that span length scales from nanometers to millimeters, and formidable defense mechanisms that deploy an arsenal of chemical weaponry. Successful mimicry of these adaptations may facilitate technological solutions to as wide a range of problems as they solve in the insects that originated them. PMID- 29517830 TI - 1 H-MRS for the assessment of renal triglyceride content in humans at 3T: A primer and reproducibility study. AB - BACKGROUND: Renal steatosis (fatty kidney) is a potential biomarker for obesity related renal disease; however, noninvasive assessment of renal fat content remains a technical challenge. PURPOSE: To evaluate reproducibility and explore clinical application of renal metabolic imaging for the quantification of renal triglyceride content (TG) using proton magnetic resonance spectroscopy (1 H-MRS). STUDY TYPE: Reproducibility and clinical cohort study. POPULATION: Twenty-three healthy volunteers (mean age 30.1 +/- 13.4 years) and 15 patients with type 2 diabetes mellitus (T2DM) (mean age 59.3 +/- 7.0 years). FIELD STRENGTH/SEQUENCE: 3T, single-voxel point resolved spectroscopy (PRESS). ASSESSMENT: Intra- and interexamination reproducibility of renal TG was assessed in healthy volunteers, and compared to T2DM patients. Intraexamination differences were obtained by repeating the 1 H-MRS measurement directly after the first 1 H-MRS without repositioning of the subject or changing surface coil and measurement volumes. Interexamination variability was studied by repeating the scan protocol after removal and replacement of the subject in the magnet, and subsequent repositioning of body coil and measurement volumes. STATISTICAL TESTS: Reproducibility was determined using Pearson's correlation and Bland-Altman analyses. Differences in TG% between healthy volunteers and T2DM patients were assessed using the Mann-Whitney U-test. RESULTS: After logarithmic (log) transformation, both intraexamination (r = 0.91, n = 19) and interexamination (r = 0.73, n = 9) measurements of renal TG content were highly correlated with the first renal TG measurements. Intraexamination and interexamination limits of agreement of renal log TG% were respectively [-1.36%, + 0.84%] and [-0.77%, + 0.62%]. Backtransformed limits of agreement were [-0.89%,+0.57%] and [-0.55%, + 0.43%] multiplied by mean TG for intra- and interexamination measurements. Overall median renal TG content was 0.12% [0.08, 0.22; 25th percentile, 75th percentile] in healthy volunteers and 0.20% [0.13, 0.22] in T2DM patients (P = 0.08). DATA CONCLUSION: Renal metabolic imaging using 3T 1 H-MRS is a reproducible technique for the assessment of renal triglyceride content. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:507-513. PMID- 29517831 TI - Variable flip angle 3D ultrashort echo time (UTE) T1 mapping of mouse lung: A repeatability assessment. AB - BACKGROUND: Lung T1 is a potential translational biomarker of lung disease. The precision and repeatability of variable flip angle (VFA) T1 mapping using modern 3D ultrashort echo time (UTE) imaging of the whole lung needs to be established before it can be used to assess response to disease and therapy. PURPOSE: To evaluate the feasibility of regional lung T1 quantification with VFA 3D-UTE and to investigate long- and short-term T1 repeatability in the lungs of naive mice. STUDY TYPE: Prospective preclinical animal study. POPULATION: Eight naive mice and phantoms. FIELD STRENGTH/SEQUENCE: 3D free-breathing radial UTE (8 MUs) at 4.7T. ASSESSMENT: VFA 3D-UTE T1 calculations were validated against T1 values measured with inversion recovery (IR) in phantoms. Lung T1 and proton density (S0 ) measurements of whole lung and muscle were repeated five times over 1 month in free-breathing naive mice. Two consecutive T1 measurements were performed during one of the imaging sessions. STATISTICAL TESTS: Agreement in T1 between VFA 3D UTE and IR in phantoms was assessed using Bland-Altman and Pearson 's correlation analysis. The T1 repeatability in mice was evaluated using coefficient of variation (CV), repeated-measures analysis of variance (ANOVA), and paired t test. RESULTS: Good T1 agreement between the VFA 3D-UTE and IR methods was found in phantoms. T1 in lung and muscle showed a 5% and 3% CV (1255 +/- 63 msec and 1432 +/- 42 msec, respectively, mean +/- SD) with no changes in T1 or S0 over a month. Consecutive measurements resulted in an increase of 2% in both lung T1 and S0 . DATA CONCLUSION: VFA 3D-UTE shows promise as a reliable T1 mapping method that enables full lung coverage, high signal-to-noise ratio (~25), and spatial resolution (300 MUm) in freely breathing animals. The precision of the VFA 3D-UTE method will enable better design and powering of studies. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29517832 TI - Epitaxial Growth of Honeycomb Monolayer CuSe with Dirac Nodal Line Fermions. AB - 2D transition metal chalcogenides have attracted tremendous attention due to their novel properties and potential applications. Although 2D transition metal dichalcogenides are easily fabricated due to their layer-stacked bulk phase, 2D transition metal monochalcogenides are difficult to obtain. Recently, a single atomic layer transition metal monochalcogenide (CuSe) with an intrinsic pattern of nanoscale triangular holes is fabricated on Cu(111). The first-principles calculations show that free-standing monolayer CuSe with holes is not stable, while hole-free CuSe is endowed with the Dirac nodal line fermion (DNLF), protected by mirror reflection symmetry. This very rare DNLF state is evidenced by topologically nontrivial edge states situated inside the spin-orbit coupling gaps. Motivated by the promising properties of hole-free honeycomb CuSe, monolayer CuSe is fabricated on Cu(111) surfaces by molecular beam epitaxy and confirmed success with high resolution scanning tunneling microscopy. The good agreement of angle resolved photoemission spectra with the calculated band structures of CuSe/Cu(111) demonstrates that the sample is monolayer CuSe with a honeycomb lattice. These results suggest that the honeycomb monolayer transition metal monochalcogenide can be a new platform to study 2D DNLFs. PMID- 29517833 TI - Formulation, stability study and preclinical evaluation of a vaginal cream containing curcumin in a rat model of vulvovaginal candidiasis. AB - Owing to the growing resistance among isolates of Candida species to usual antifungal agents and the well-known therapeutic potential of curcumin, the purpose of this study was to develop and validate a vaginal formulation containing this substance and to evaluating its effectiveness in the treatment of experimental vulvovaginal candidiasis. Curcumin was incorporated in a vaginal cream in three concentrations (0.01%, 0.1% and 1.0%). The different concentrations of the cream and its controls were intravaginally administered in an immunosuppressed rat model to evaluate the efficacy in the treatment of experimental vulvovaginal candidiasis. Samples of the cream were also subjected to centrifugation and physical stability tests and an analytical method for quantification of curcumin was validated based on HPLC. The formulation was stable and the HPLC method could be considered suitable for the quantitative determination of curcumin in the cream. After 6 days of preclinical study, the number of infected animals was 1/6 in all groups treated with curcumin vaginal cream and the fungal burden showed a progressive reduction. Reduction in the inflammatory infiltrate was observed in the group treated with 1.0% cream. Vaginal cream containing curcumin could be considered a promising effective antifungal medicine in the treatment of vulvovaginal candidiasis. PMID- 29517834 TI - Properties of the vastus lateralis muscle in relation to age and physiological function in master cyclists aged 55-79 years. AB - In this study, results are reported from the analyses of vastus lateralis muscle biopsy samples obtained from a subset (n = 90) of 125 previously phenotyped, highly active male and female cyclists aged 55-79 years in regard to age. We then subsequently attempted to uncover associations between the findings in muscle and in vivo physiological functions. Muscle fibre type and composition (ATPase histochemistry), size (morphometry), capillary density (immunohistochemistry) and mitochondrial protein content (Western blot) in relation to age were determined in the biopsy specimens. Aside from an age-related change in capillary density in males (r = -.299; p = .02), no other parameter measured in the muscle samples showed an association with age. However, in males type I fibres and capillarity (p < .05) were significantly associated with training volume, maximal oxygen uptake, oxygen uptake kinetics and ventilatory threshold. In females, the only association observed was between capillarity and training volume (p < .05). In males, both type II fibre proportion and area (p < .05) were associated with peak power during sprint cycling and with maximal rate of torque development during a maximal voluntary isometric contraction. Mitochondrial protein content was not associated with any cardiorespiratory parameter in either males or females (p > .05). We conclude in this highly active cohort, selected to mitigate most of the effects of inactivity, that there is little evidence of age-related changes in the properties of VL muscle across the age range studied. By contrast, some of these muscle characteristics were correlated with in vivo physiological indices. PMID- 29517836 TI - Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle 23 Has Negligible Impact on Its Biological Profile and Potency. AB - Important strides are being made in understanding the effects of structural features of bryostatin 1, a candidate therapeutic agent for cancer and dementia, in conferring its potency toward protein kinase C and the unique spectrum of biological responses that it induces. A critical pharmacophoric element in bryostatin 1 is the secondary hydroxy group at the C26 position, with a corresponding primary hydroxy group playing an analogous role in binding of phorbol esters to protein kinase C. Herein, we describe the synthesis of a bryostatin homologue in which the C26 hydroxy group is primary, as it is in the phorbol esters, and show that its biological activity is almost indistinguishable from that of the corresponding compound with a secondary hydroxy group. PMID- 29517835 TI - Consistency of Multiple Renal Functional MRI Measurements Over 18 Months. AB - BACKGROUND: Identification of patients with progressive chronic kidney disease (CKD) and those likely to respond to candidate therapeutics is urgently needed. Functional MRI measurements have shown promise. However, knowledge about the consistency of the measurements is essential to conduct longitudinal studies. PURPOSE/HYPOTHESIS: To investigate the consistency of repeated functional MRI measurements in healthy subjects. STUDY TYPE: Prospective, longitudinal study. SUBJECTS: Seventeen healthy subjects were examined on two different occasions, 18 months apart. FIELD STRENGTH/SEQUENCE: Multiple gradient-recalled-echo, 2D navigator-gated flow-sensitive alternating inversion recovery True-FISP and spin echo planar diffusion-weighted sequences were used on a 3T scanner. Images were acquired on two different scanner configurations. ASSESSMENT: Blood oxygenation level-dependent (BOLD) R2*, arterial spin labeling (ASL) perfusion-derived blood flow (BF) and apparent diffusion coefficient (ADC) maps were analyzed using a custom image processing toolbox. Regions of interest (ROIs) were placed on renal cortex, medulla, and whole kidney. Multiple researchers were involved in defining the ROIs. STATISTICAL TESTS: Intra- and intersubject coefficients of variation (CV) and Bland-Altman plots were used to measure consistency and evaluate bias in the measurements. A nonparametric Wilcoxon test was used to compare differences between two timepoints. RESULTS: The intrasubject CV for R2* and ADC were 6.8% and 5.3% with small (-3.8 and 5.3%) bias, respectively, comparing baseline and 18 month data. Intrasubject CV for renal cortex BF was higher (18.7%) compared to R2* and ADC, but comparable to prior literature values over shorter durations. It also exhibited a larger bias (-15.4%) between two timepoints and significantly lower values (P = 0.022) at 18-month data. DATA CONCLUSION: All three MRI parameters over 18 months, even with a scanner upgrade and involving multiple observers, showed good consistency. These results are useful for the interpretation of longitudinal data and support the use of these methods to monitor progression in patients with CKD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:514-521. PMID- 29517837 TI - Highly Active, Durable Ultrathin MoTe2 Layers for the Electroreduction of CO2 to CH4. AB - The electroreduction of CO2 to CH4 is a highly desirable, challenging research topic. In this study, an electrocatalytic system comprising ultrathin MoTe2 layers and an ionic liquid electrolyte for the reduction of CO2 to methane is reported, efficiently affording methane with a faradaic efficiency of 83 +/- 3% (similar to the best Cu-based catalysts reported thus far) and a durable activity of greater than 45 h at a relatively high current density of 25.6 mA cm-2 (-1.0 VRHE ). The results obtained can facilitate research on the design of other transition-metal dichalcogenide electrocatalysts for the reduction of CO2 to valuable fuels. PMID- 29517838 TI - Soft Robotics. AB - This description of "soft robotics" is not intended to be a conventional review, in the sense of a comprehensive technical summary of a developing field. Rather, its objective is to describe soft robotics as a new field-one that offers opportunities to chemists and materials scientists who like to make "things" and to work with macroscopic objects that move and exert force. It will give one (personal) view of what soft actuators and robots are, and how this class of soft devices fits into the more highly developed field of conventional "hard" robotics. It will also suggest how and why soft robotics is more than simply a minor technical "tweak" on hard robotics and propose a unique role for chemistry, and materials science, in this field. Soft robotics is, at its core, intellectually and technologically different from hard robotics, both because it has different objectives and uses and because it relies on the properties of materials to assume many of the roles played by sensors, actuators, and controllers in hard robotics. PMID- 29517839 TI - PCMT1 is an unfavorable predictor and functions as an oncogene in bladder cancer. AB - The role of protein l-isoaspartate (d-aspartate) O-methyltransferase (PCMT1) in human cancer was generally cognized. The clinical significance and biological function of PCMT1 in bladder cancer is still unknown. PCMT1 mRNA and protein expression levels in bladder cancer tissues and cell lines were detected by qRT PCR, immunohistochemistry, or western blot. The correlation between PCMT1 expression and clinicopathological factors was analyzed through immunohistochemistry in 108 bladder cancer patients. Loss-of-function and gain-of function studies were conducted to explore the biological function of PCMT1 in bladder cancer cell lines in regulating cell proliferation, migration, and invasion. In our results, we found that PCMT1 was overexpressed in bladder cancer tissues compared with normal urothelium tissues in microarray datasets (GSE3167). Then, we confirmed PCMT1 mRNA and protein expression were increased in bladder cancer tissues and cell lines compared with paired normal urothelium tissues and normal uroepithelial cell line. PCMT1 protein expression was obviously correlated with clinical stage, muscularis invasion, lymph node metastasis, and distant metastasis. Survival analysis showed that PCMT1 protein high-expression was an independent unfavorable prognostic factor for bladder cancer patients. The in vitro experiments showed PCMT1 regulated bladder cancer cells migration and invasion through modulating epithelial-mesenchymal transition (EMT)-associated genes expression including E-cadherin, vimentin, Snail and Slug, but had no effect on proliferation. In conclusion, PCMT1 is an unfavorable prognostic biomarker and involves in cells migration and invasion through regulating EMT associated genes. (c) 2018 IUBMB Life, 70(4):291-299, 2018. PMID- 29517840 TI - Olive anthracnose: a yield- and oil quality-degrading disease caused by several species of Colletotrichum that differ in virulence, host preference and geographical distribution. AB - : Olive anthracnose causes fruit rot leading to its drop or mummification, resulting in yield losses and the degradation of oil quality. TAXONOMY AND DISTRIBUTION: The disease is caused by diverse species of Colletotrichum, mostly clustering in the C. acutatum species complex. Colletotrichum nymphaeae and C. godetiae are the prevalent species in the Northern Hemisphere, whereas C. acutatum sensu stricto is the most frequent species in the Southern Hemisphere, although it is recently and quickly emerging in the Northern Hemisphere. The disease has been reported from all continents, but it attains higher incidence and severity in the west of the Mediterranean Basin, where it is endemic in traditional orchards of susceptible cultivars. LIFE CYCLE: The pathogens are able to survive on vegetative organs. On the fruit surface, infections remain quiescent until fruit maturity, when typical anthracnose symptoms develop. Under severe epidemics, defoliation and death of branches can also occur. Pathogen species differ in virulence, although this depends on the cultivar. CONTROL: The selection of resistant cultivars depends strongly on pathogen diversity and environmental conditions, posing added difficulties to breeding efforts. Chemical disease control is normally achieved with copper-based fungicides, although this may be insufficient under highly favourable disease conditions and causes concern because of the presence of fungicide residues in the oil. In areas in which the incidence is high, farmers tend to anticipate harvest, with consequences in yield and oil characteristics. CHALLENGES: Olive production systems, harvest and post harvest processing have experienced profound changes in recent years, namely new training systems using specific cultivars, new harvest and processing techniques and new organoleptic market requests. Changes are also occurring in both the geographical distribution of pathogen populations and the taxonomic framework. In addition, stricter rules concerning pesticide use are likely to have a strong impact on control strategies. A detailed knowledge of pathogen diversity, population dynamics and host-pathogen interactions is basal for the deployment of durable and effective disease control strategies, whether based on resistance breeding, agronomic practices or biological or chemical control. PMID- 29517841 TI - Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins. AB - Transition metal (TM)-catalyzed difunctionalization of unactivated olefins with two carbon-based entities is a powerful method to construct complex molecular architectures rapidly from simple and readily available feedstock chemicals. While dicarbofunctionalization of unactivated olefins has a long history typically with the use of either carbon monoxide to intercept C(sp3 )-[M] (alkyl TM) species or substrates lacking in beta-hydrogen (beta-Hs), development of this class of reaction still remains seriously limited due to complications of beta-H elimination arising from the in situ-generated C(sp3 )-[M] intermediates. Over the years, different approaches have been harnessed to suppress beta-H elimination, which have led to the development of various types of olefin dicarbofunctionalization reactions even in substrates that generate C(sp3 )-[M] intermediates bearing beta-Hs with a wide range of electrophiles and nucleophiles. In this review, these developments will be discussed both through the lens of historical perspectives as well as the strategies scrutinized over the years to address the issue of beta-H elimination. However, this review article by no means is designed to be exhaustive in the field, and is merely presented to provide the readers an overview of the key reaction developments. PMID- 29517842 TI - Serum testosterone and non-alcoholic fatty liver disease in men and women in the US. AB - BACKGROUND & AIMS: Testosterone plays a role in predisposing individuals to cardiovascular and metabolic diseases, but its effects differ between men and women. We investigated the association between serum total testosterone and non alcoholic fatty liver disease in adults in the US. METHODS: A cross-sectional analysis of data from participants in the 2011-2012 National Health and Nutrition Examination Survey was performed. Subjects with significant alcohol consumption and those with viral hepatitis were excluded. We used the highest sex-specific quartiles of serum total testosterone as references. Suspected non-alcoholic fatty liver disease was diagnosed when serum alanine aminotransferase was >30 IU/L for men and >19 IU/L for women. RESULTS: Of the 4758 subjects (49.4% men), the prevalence of suspected non-alcoholic fatty liver disease was inversely correlated with the sex-specific quartiles of testosterone in men and women. In a multivariate model, low total testosterone levels were associated with progressively higher odds of suspected non-alcoholic fatty liver disease in men after adjusting for age, obesity and other metabolic risk factors (P values for trends <.01). When the women were divided into 2 groups according to menopausal status, a significant correlation was observed only in the post-menopausal women (P values for trends <.01). The adjusted odds ratios for suspected non-alcoholic fatty liver disease were 1.72-1.99 in men and 2.15-2.26 in post-menopausal women (lowest quartile vs highest quartile). CONCLUSIONS: In this nationally representative sample of adults in the US, low total testosterone levels were associated with suspected non-alcoholic fatty liver disease in men and post menopausal women independent of known risk factors. PMID- 29517843 TI - Diverging Mechanisms: Cytochrome-P450-Catalyzed Demethylation and gamma-Lactone Formation in Bacterial Gibberellin Biosynthesis. AB - Biosynthesis of the gibberellin (GA) plant hormones evolved independently in plants and microbes, but the pathways proceed by similar transformations. The combined demethylation and gamma-lactone ring forming transformation is of significant mechanistic interest, yet remains unclear. The relevant CYP112 from bacteria was probed by activity assays and 18 O2 -labeling experiments. Notably, the ability of tert-butyl hydroperoxide to drive this transformation indicates use of the ferryl-oxo (Compound I) from the CYP catalytic cycle for this reaction. Together with the confirmed loss of C20 as CO2 , this necessitates two catalytic cycles for carbon-carbon bond scission and gamma-lactone formation. The ability of CYP112 to hydroxylate the delta-lactone form of GA15 , shown by the labeling studies, is consistent with the implied use of a further oxygenated heterocycle in the final conversion of GA24 into GA9 , with the partial labeling of GA9 , thus demonstrating that CYP112 partitions its reactants between two diverging mechanisms. PMID- 29517844 TI - Stimuli-Responsive NO Release for On-Demand Gas-Sensitized Synergistic Cancer Therapy. AB - Featuring high biocompatibility, the emerging field of gas therapy has attracted extensive attention in the medical and scientific communities. Currently, considerable research has focused on the gasotransmitter nitric oxide (NO) owing to its unparalleled dual roles in directly killing cancer cells at high concentrations and cooperatively sensitizing cancer cells to other treatments for synergistic therapy. Of particular note, recent state-of-the-art studies have turned our attention to the chemical design of various endogenous/exogenous stimuli-responsive NO-releasing nanomedicines and their biomedical applications for on-demand NO-sensitized synergistic cancer therapy, which are discussed in this Minireview. Moreover, the potential challenges regarding NO gas therapy are also described, aiming to advance the development of NO nanomedicines as well as usher in new frontiers in this fertile research area. PMID- 29517846 TI - A dual role for proline iminopeptidase in the regulation of bacterial motility and host immunity. AB - During plant-pathogen interactions, pathogenic bacteria have evolved multiple strategies to cope with the sophisticated defence systems of host plants. Proline iminopeptidase (PIP) is essential to Xanthomonas campestris pv. campestris (Xcc) virulence, and is conserved in many plant-associated bacteria, but its pathogenic mechanism remains unclear. In this study, we found that disruption of pip in Xcc enhanced its flagella-mediated bacterial motility by decreasing intracellular bis (3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) levels, whereas overexpression of pip in Xcc restricted its bacterial motility by elevating c-di GMP levels. We also found that PIP is a type III secretion system-dependent effector capable of eliciting a hypersensitive response in non-host, but not host plants. When we transformed pip into the host plant Arabidopsis, higher bacterial titres were observed in pip-overexpressing plants relative to wild-type plants after Xcc inoculation. The repressive function of PIP on plant immunity was dependent on PIP's enzymatic activity and acted through interference with the salicylic acid (SA) biosynthetic and regulatory genes. Thus, PIP simultaneously regulates two distinct regulatory networks during plant-microbe interactions, i.e. it affects intracellular c-di-GMP levels to coordinate bacterial behaviour, such as motility, and functions as a type III effector translocated into plant cells to suppress plant immunity. Both processes provide bacteria with the regulatory potential to rapidly adapt to complex environments, to utilize limited resources for growth and survival in a cost-efficient manner and to improve the chances of bacterial survival by helping pathogens to inhabit the internal tissues of host plants. PMID- 29517845 TI - Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. AB - It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55-79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age-matched older adults and 55 young adults not involved in regular exercise. The frequency of naive T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL-7 and lower IL-6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28-ve CD57+ve senescent CD8 T-cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age. PMID- 29517847 TI - Hydroxyl-Mediated Non-oxidative Propane Dehydrogenation over VOx /gamma-Al2 O3 Catalysts with Improved Stability. AB - Supported vanadium oxides are one of the most promising alternative catalysts for propane dehydrogenation (PDH) and efforts have been made to improve its catalytic performance. However, unlike Pt-based catalysts, the nature of the active site and surface structure of the supported vanadium catalysts under reductive reaction conditions still remain elusive. This paper describes the surface structure and the important role of surface-bound hydroxyl groups on VOx / gamma Al2 O3 catalysts under reaction conditions employing in situ DRIFTS experiments and DFT calculations. It is shown that hydroxyl groups on the VOx /Al2 O3 catalyst (V-OH) are produced under H2 pre-reduction, and the catalytic performance for PDH is closely connected to the concentration of V-OH species on the catalyst. The hydroxyl groups are found to improve the catalyst that leads to better stability by suppressing the coke deposition. PMID- 29517848 TI - The apparent non-host resistance of Ethiopian mustard to a radish-infecting strain of Turnip mosaic virus is largely determined by the C-terminal region of the P3 viral protein. AB - Two different isolates of Turnip mosaic virus (TuMV: UK 1 and JPN 1) belonging to different virus strains were tested on three different Brassica species, namely turnip (Brassica rapa L.), Indian mustard (Brassica juncea L.) and Ethiopian mustard (Brassica carinata A. Braun). Although all three hosts were readily infected by isolate UK 1, isolate JPN 1 was able to establish a visible systemic infection only in the first two. Ethiopian mustard plants showed no local or systemic symptoms, and no virus antigens could be detected by enzyme-linked immunosorbent assay (ELISA). Thus, this species looks like a non-host for JPN 1, an apparent situation of non-host resistance (NHR). Through an experimental approach involving chimeric viruses made by gene interchange between two infectious clones of both virus isolates, the genomic region encoding the C terminal domain of viral protein P3 was found to bear the resistance determinant, excluding any involvement of the viral fusion proteins P3N-PIPO and P3N-ALT in the resistance. A further determinant refinement identified two adjacent positions (1099 and 1100 of the viral polyprotein) as the main determinants of resistance. Green fluorescent protein (GFP)-tagged viruses showed that the resistance of Ethiopian mustard to isolate JPN 1 is only apparent, as virus induced fluorescence could be found in discrete areas of both inoculated and non inoculated leaves. In comparison with other plant-virus combinations of extreme resistance, we propose that Ethiopian mustard shows an apparent NHR to TuMV JPN 1, but not complete immunity or extreme resistance. PMID- 29517850 TI - New tools to assess cell polarity and division in the developing Arabidopsis embryo. PMID- 29517851 TI - Impact of veA on the development, aggressiveness, dissemination and secondary metabolism of Penicillium expansum. AB - Penicillium expansum, the causal agent of blue mould disease, produces the mycotoxins patulin and citrinin amongst other secondary metabolites. Secondary metabolism is associated with fungal development, which responds to numerous biotic and abiotic external triggers. The global transcription factor VeA plays a key role in the coordination of secondary metabolism and differentiation processes in many fungal species. The specific role of VeA in P. expansum remains unknown. A null mutant PeDeltaveA strain and a complemented PeDeltaveA:veA strain were generated in P. expansum and their pathogenicity on apples was studied. Like the wild-type and the complemented strains, the null mutant PeDeltaveA strain was still able to sporulate and to colonize apples, but at a lower rate. However, it could not form coremia either in vitro or in vivo, thus limiting its dissemination from natural substrates. The impact of veA on the expression of genes encoding proteins involved in the production of patulin, citrinin and other secondary metabolites was evaluated. The disruption of veA drastically reduced the production of patulin and citrinin on synthetic media, associated with a marked down-regulation of all genes involved in the biosynthesis of the two mycotoxins. Moreover, the null mutant PeDeltaveA strain was unable to produce patulin on apples. The analysis of gene expression revealed a global impact on secondary metabolism, as 15 of 35 backbone genes showed differential regulation on two different media. These findings support the hypothesis that VeA contributes to the pathogenicity of P. expansum and modulates its secondary metabolism. PMID- 29517849 TI - Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition. AB - There is growing evidence to suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumour stroma. Here, we investigated the cross talk between BM-MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM-MSCs towards these tumour cells and identified monocyte chemoattractant protein (MCP)-1, growth-regulated oncogene (GRO)-alpha and transforming growth factor (TGF)-beta1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs trans-differentiate into cancer-associated fibroblasts, further increasing MCP-1, GRO-alpha, interleukin (IL)-6 and IL-8 levels in the tumour microenvironment. These cytokines promote mesenchymal to amoeboid transition (MAT), driven by activation of the small GTPase RhoA, in OS cells, as illustrated by the in vitro assay and live imaging. The outcome is a significant increase of aggressiveness in OS cells in terms of motility, invasiveness and transendothelial migration. In keeping with their enhanced transendothelial migration abilities, OS cells stimulated by BM-MSCs also sustain migration, invasion and formation of the in vitro capillary network of endothelial cells. Thus, BM-MSC recruitment to the OS site and the consequent cytokine-induced MAT are crucial events in OS malignancy. PMID- 29517852 TI - A novel flow cytometry tool for fibrosis scoring through hepatic stellate cell differentiation. AB - Hepatic stellate cells (HSCs) are a central fibrogenic cell type that contributes to collagen accumulation during chronic liver disease. Peripheral blood lymphocytes from HCV patients are phagocytized by HSCs and induce their differentiation. This study aimed to characterize HSCs differentiation using a flow cytometry tool for fibrosis scoring. NK cells from healthy donors and from patients with chronic HCV with various severities of fibrosis were co-cultured with a human HSC line (LX2). LX2 phagocytosis of NK cells were stained for NK cells (CD45/CD56/CD3) and NK activation marker (CD107a) as well as INF-gamma, apoptosis (Annexin-V) and alpha-smooth-muscle-actin (alphaSMA, as a marker of LX2 activation). In addition, reactive oxygen species (ROS) and the senescence marker P15 were analyzed prior to flow cytometry analysis. LX2 mono-cultures demonstrated a homogenous cell-population according to size (forward-scattered; FSC), granularity and alphaSMA expressions. However, on their co-culture with NK cells, the HSCs formed four subpopulations, which were stratified by alphaSMA intensities and cell size. NK cells isolated from heathy donors did not activate LX2-cells. In contrast, HCV exposed to NK cells from both F1 and F4 fibrosis grade patients, showed elevated CD107a and INF-gamma levels and increased alphaSMA intensities in two of the four cell populations, with fibrosis scoring showing a linear correlation with alphaSMA intensities and NK phagocytosis. The alphaSMAintermediate /SizeLow HSCs sub-population showed higher proliferation following F4-NK cells with higher phagocytosis ability, suggesting an active/regulatory population. The alphaSMAhigh /Sizehigh subpopulations showed low proliferation and phagocytosis capacity, and were correlated with higher apoptosis, increased ROS and P15 intensities, suggesting senescing cells. Taken together, NK cells lead to heterogeneous differentiation of HSCs. Flow-cytometry may provide a novel means of characterizing HSCs in relation to the severity of liver fibrosis. (c) 2017 International Society for Advancement of Cytometry. PMID- 29517853 TI - Tailoring Functional Chitosan-Based Composites for Food Applications. AB - Chitosan-based functional materials are emerging for food applications. The covalent bonding of molecular entities demonstrates to enhance resistance to the typical acidity of food assigning mechanical and moisture/gas barrier properties. Moreover, the grafting to chitosan of some functional molecules, like phenolic compounds or essential oils, gives antioxidant, antimicrobial, among others properties to chitosan. The addition of nanofillers to chitosan and other biopolymers improves the already mentioned required properties for food applications and can attribute electrical conductivity and magnetic properties for active and intelligent packaging. Electrical conductivity is a required property for the processing of food at low temperature using electric fields or for sensors application. PMID- 29517854 TI - Isochorismate-based salicylic acid biosynthesis confers basal resistance to Fusarium graminearum in barley. AB - Salicylic acid (SA) plays an important role in signal transduction and disease resistance. In Arabidopsis, SA can be made by either of two biosynthetic branches, one involving isochorismate synthase (ICS) and the other involving phenylalanine ammonia-lyase (PAL). However, the biosynthetic pathway and the importance of SA remain largely unknown in Triticeae. Here, we cloned one ICS and seven PAL genes from barley, and studied their functions by their overexpression and suppression in that plant. Suppression of the ICS gene significantly delayed plant growth, whereas PAL genes, both overexpressed and suppressed, had no significant effect on plant growth. Similarly, suppression of ICS compromised plant resistance to Fusarium graminearum, whereas similar suppression of PAL genes had no significant effect. We then focused on transgenic plants with ICS. In a leaf-based test with F. graminearum, transgenic plants with an up-regulated ICS were comparable with wild-type control plants. By contrast, transgenic plants with a suppressed ICS lost the ability to accumulate SA during pathogen infection and were also more susceptible to Fusarium than the wild-type controls. This suggests that ICS plays a unique role in SA biosynthesis in barley, which, in turn, confers a basal resistance to F. graminearum by modulating the accumulation of H2 O2 , O2- and reactive oxygen-associated enzymatic activities. Although SA mediates systemic acquired resistance (SAR) in dicots, there was no comparable SAR response to F. graminearum in barley. This study expands our knowledge about SA biosynthesis in barley and proves that SA confers basal resistance to fungal pathogens. PMID- 29517855 TI - Immunohistochemical characterization of feline lymphoplasmacytic anterior uveitis. AB - OBJECTIVE: To characterize the immune cells present in different forms of feline anterior uveitis. SAMPLES: Eyes were obtained from 49 cats diagnosed with chronic idiopathic lymphoplasmacytic anterior uveitis, 7 cats with feline infectious peritonitis (FIP), and 9 cats euthanized for nonocular disease. METHODS: H&E sections were scored on the level of infiltrate in the anterior uvea. Immunohistochemistry was performed for FoxP3, CD3, and IL-17A, and positive cells were quantified in multiple images of each sample. A generalized estimating equation tested for an association between the level of inflammation and the prevalence of these cell types. RESULTS: Cells stained positive for IL-17A in idiopathic uveitis but not in FIP samples. We found significantly fewer FoxP3+ and CD3+ cells in low-grade compared with high-grade inflammation in idiopathic uveitis or FIP samples (P values all <.005), but no difference between FIP and high-grade samples. CONCLUSIONS: Idiopathic, but not FIP-associated, uveitis appears to have Th17 cell involvement. The numbers of FoxP3+ and CD3+ T-cells present appear directly correlated; thus, the severity of disease does not appear directly determined by the numbers of regulatory cells. PMID- 29517856 TI - Interactions between Biological Cells and Layered Double Hydroxides: Towards Functional Materials. AB - This review highlights the current research on the interactions between biological cells and Layered Double Hydroxides (LDH). The as-prepared biohybrid materials appear extremely attractive in diverse fields of application relating to health care, environment and energy production. We describe how thanks to the main features of biological cells and LDH layers, various strategies of assemblies can be carried out for constructing smart biofunctional materials. The interactions between the two components are described with a peculiar attention to the adsorption, biocompatibilization, LDH layer internalization, antifouling and antimicrobial properties. The most significant achievements including authors' results, involving biological cells and LDH assemblies in waste water treatment, bioremediation and bioenergy generation are specifically addressed. PMID- 29517857 TI - Neural mechanisms of behavioral change in young adults with high-functioning autism receiving virtual reality social cognition training: A pilot study. AB - : Measuring treatment efficacy in individuals with Autism Spectrum Disorder (ASD) relies primarily on behaviors, with limited evidence as to the neural mechanisms underlying these behavioral gains. This pilot study addresses this void by investigating neural and behavioral changes in a Phase I trial in young adults with high-functioning ASD who received an evidence-based behavioral intervention, Virtual Reality-Social Cognition Training over 5 weeks for a total of 10 hr. The participants were tested pre- and post-training with a validated biological/social versus scrambled/nonsocial motion neuroimaging task, previously shown to activate regions within the social brain networks. Three significant brain-behavior changes were identified. First, the right posterior superior temporal sulcus, a hub for socio-cognitive processing, showed increased brain activation to social versus nonsocial stimuli in individuals with greater gains on a theory-of-mind measure. Second, the left inferior frontal gyrus, a region for socio-emotional processing, tracked individual gains in emotion recognition with decreased activation to social versus nonsocial stimuli. Finally, the left superior parietal lobule, a region for visual attention, showed significantly decreased activation to nonsocial versus social stimuli across all participants, where heightened attention to nonsocial contingencies has been considered a disabling aspect of ASD. This study provides, albeit preliminary, some of the first evidence of the harnessable neuroplasticity in adults with ASD through an age-appropriate intervention in brain regions tightly linked to social abilities. This pilot trial motivates future efforts to develop and test social interventions to improve behaviors and supporting brain networks in adults with ASD. Autism Res 2018, 11: 713-725. (c) 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: This study addresses how the behavioral changes after treatment for ASD reflect underlying brain changes. Before and after receiving VR-SCT, young adults with high-functioning ASD passively viewed biological motion stimuli in a MRI scanner, tapping changes in the social brain network. The results reveal neuroplasticity in this age population, extending the window of opportunity for interventions to impact social competency in adults with ASD. PMID- 29517858 TI - Clinicopathological features of younger (aged <= 50 years) lung adenocarcinoma patients harboring the EML4-ALK fusion gene. AB - BACKGROUND: The EML4-ALK fusion gene has recently been identified as a driver mutation in a subset of non-small cell lung cancers. In subsequent studies, EML4 ALK has been detected in a low percentage of patients, and was associated with a lack of EGFR or KRAS mutations, younger age, and adenocarcinoma with acinar histology. Cases with the EML4-ALK fusion gene were examined to clarify the clinicopathological characteristics of young adenocarcinoma patients. METHODS: Between December 1998 and May 2009, 85 patients aged <= 50 with lung adenocarcinoma were treated at our hospital. We examined 49 samples from adenocarcinoma patients who underwent surgical resection, chemotherapy, and/or radiotherapy for the EML4-ALK gene. None of the patients received ALK inhibitors because these drugs had not been approved in Japan before 2012. EML4-ALK fusion genes were screened using multiplex reverse-transcription PCR assay, and were confirmed by direct sequencing. RESULTS: The EML4-ALK fusion gene was detected in five tumors (10.2%). One patient had stage IB disease, one had stage IIIA, and three had stage IV. Histologically, there was one solid adenocarcinoma, two acinar adenocarcinomas, and two papillary adenocarcinomas. EML4-ALK fusion genes were mutually exclusive to EGFR and KRAS mutations. The five-year survival rate was 59.4% in patients without EML4-ALK fusion and was not reached in patients with EML4-ALK fusion. CONCLUSION: The EML4-ALK fusion gene may be a strong oncogene in younger patients with lung adenocarcinoma. PMID- 29517859 TI - Knowledge about emergency dental trauma management among school teachers in Colombia: A baseline study to develop an education strategy. AB - BACKGROUND/AIM: Dental trauma in school populations has a high frequency and school teachers are often close to the place where such injuries occur. However, many studies have confirmed the lack of knowledge as to how to act in these cases. The aim of this study was to determine the knowledge in regard to dental trauma of school teachers in Colombia. MATERIALS AND METHODS: A multicentre, descriptive cross-sectional study was performed in 251 schools using a stratified randomized sampling. A structured hard copy survey was personally delivered to 2390 school teachers in the selected schools. The survey contained questions related to work experience, teaching level and demographic data, as well as questions related to their knowledge of and attitude towards emergency dental trauma management. RESULTS: The response rate was 96%. Most of the school teachers (95%) had never received training related to dental trauma, although 35% had witnessed at least 1 case. Of 2296 school teachers surveyed, only 5.8% would have replanted an avulsed tooth. An association was found between work experience and appropriate management of an avulsed tooth. No significant differences were found in regard to school location (city), school type (private/public), gender and school teachers' education level. CONCLUSIONS: The knowledge of school teachers in Colombia about emergency dental trauma management is inadequate. The findings strongly suggest a need for an education strategy with the involvement of the government, dentistry schools and private organizations. PMID- 29517860 TI - CEP72-ROS1: A novel ROS1 oncogenic fusion variant in lung adenocarcinoma identified by next-generation sequencing. AB - ROS1 rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC) and represents a small subset (1-2%) of NSCLC. A total of 17 different fusion partner genes of ROS1 in NSCLC have been reported. The multi targeted MET/ALK/ROS1 tyrosine kinase inhibitor (TKI) crizotinib has demonstrated remarkable efficacy in ROS1-rearranged NSCLC. Consequently, ROS1 detection assays include fluorescence in situ hybridization, immunohistochemistry, and real-time PCR. Next-generation sequencing (NGS) assay covers a range of fusion genes and approaches to discover novel receptor-kinase rearrangements in lung cancer. A 63 year-old male smoker with stage IV NSCLC (TxNxM1) was detected with a novel ROS1 fusion. Histological examination of the tumor showed lung adenocarcinoma. NGS analysis of the hydrothorax cellblocks revealed a novel CEP72-ROS1 rearrangement. This novel CEP72-ROS1 fusion variant is generated by the fusion of exons 1-11 of CEP72 on chromosome 5p15 to exons 23-43 of ROS1 on chromosome 6q22. The predicted CEP72-ROS1 protein product contains 1202 amino acids comprising the N-terminal amino acids 594-647 of CEP72 and C-terminal amino acid 1-1148 of ROS1. CEP72-ROS1 is a novel ROS1 fusion variant in NSCLC discovered by NGS and could be included in ROS1 detection assay, such as reverse transcription PCR. Pleural effusion samples show good diagnostic performance in clinical practice. PMID- 29517861 TI - Blind spot in lung cancer lymph node metastasis: Cross-lobe peripheral lymph node metastasis in early stage patients. AB - BACKGROUND: At present, it has not yet been determined whether metastasis can be transferred cross-lobe to peripheral lymph nodes (LNs) from other lobes in early stages of lung cancer, especially without any direct involvement to the pleura and parenchyma of the lobe. This study was conducted to investigate this issue. METHODS: A retrospective analysis was conducted at the Chinese Academy of Medical Sciences. Patients undergoing right middle and lower lobectomy with lymphadenectomy for preoperative clinical stage Ia-IIIa from 2014 to 2015 were identified. To avoid interference, cases were limited to tumors within the primary lobe. When a tumor is completely located in the lower lobe, no direct invasion occurs into the visceral pleura/bronchus/parenchyma of the middle lobe and tumor cell metastasis into the peripheral LNs (stations 12-14) in the middle lobe is defined as cross-lobe lymph node metastasis (CLM). RESULTS: A total of 68 patients were identified, of which nine (13.2%) had CLM. Seven had squamous cell carcinoma, one adenocarcinoma, and one small cell carcinoma. Seven cases (77.8%) had intermediate bronchus invasion, and seven cases (77.8%) intermediate bronchus adjacent lymph node involvement (station 11). Compared to non-CLM patients, tumor diameter (5.2 vs. 3.2; P = 0.28), N2 lymph node metastasis rate (66.7% vs. 28.8%; P = 0.03), late stage (IIIa 77.8% vs. 35.6%; P = 0.04), and invasion of intermediate bronchus (77.8% vs. 45.8%; P = 0.07) relatively increased. CONCLUSION: Non-primary lobe peripheral LN metastasis exists in lung cancer and requires greater attention and further study. PMID- 29517862 TI - Safety, Tolerability, and Pharmacokinetics of 3 g of Ceftolozane/Tazobactam in Healthy Adults: A Randomized, Placebo-Controlled, Multiple-Dose Study. AB - Ceftolozane/tazobactam is an antibacterial approved at 1.5 g (1g/0.5 g) every 8 hours (q8h); higher doses may provide additional benefits in difficult-to-treat infections. We conducted a phase I trial in healthy adults evaluating safety, tolerability, and pharmacokinetics of 3 g (2 g/1 g) ceftolozane/tazobactam administered q8h for 10 days. Sixteen participants were randomized (2:1:1) to 3 g ceftolozane/tazobactam, 1.5 g ceftolozane/tazobactam, or placebo. Participants underwent regular safety and plasma drug level assessments, with a follow-up safety visit 7 days after completion. No adverse events (AEs) were reported with placebo; 75% of participants in the 1.5-g and 50% in the 3-g arm experienced AEs. AE types were similar between the ceftolozane/tazobactam groups; all AEs were mild. No participants experienced clinically meaningful laboratory assessment or electrocardiogram abnormalities. Both ceftolozane and tazobactam exhibited dose proportional pharmacokinetics without accumulation and without substantial differences in clearance and volume of distribution between groups. In the 3-g group, mean ceftolozane parameters were: peak concentration 104 MUg/mL (day 1), 112 MUg/mL (day 10); half-life 3 hours (day 10); area under the concentration time curve (AUC(0-t) ) 272 MUg.h/mL (day 1), 300MUg.h/mL (day 10). Mean tazobactam parameters were: peak concentration 28 MUg/mL (day 1), 26 MUg/mL (day 10); half-life 1 hour (day 10); AUC(0-t) 47MUg.h/mL (day 1), 41MUg.h/mL (day 10). Administration of 3 g ceftolozane/tazobactam q8h for 10 days was safe and well tolerated in healthy volunteers. PMID- 29517863 TI - The interaction of ozone and copy number variation on risk for autism: Does environmental exposure to nitrous oxide explain the interaction? PMID- 29517864 TI - Cellulose-Based Nanomaterials for Energy Applications. PMID- 29517865 TI - [Image of the month: Cerebral abscess and acute behavioral disorder]. PMID- 29517866 TI - [Subtrochanteric pathological fracture on bisphosphonates]. AB - Bisphosphonates have frequently shown their efficacy in the treatment of osteoporosis, including ibandronate and alendronate. But more and more mention is made in the literature of patients taking a long-term bisphosphonate and undergoing an atypical fracture associated with this therapy. These complications are most often femoral fractures in the proximal part of the femoral diaphysis. We report the case of a 73-year-old patient who had a subtrochanteric pathological fracture after a prolonged intake of alendronate followed by ibandronate. PMID- 29517867 TI - [Severe Mast Cell Activation Syndrome in a 15-year-old patient with an hypermobile Ehlers-Danlos syndrome]. AB - We report the history of a 15-year old patient with a hypermobile Ehlers-Danlos syndrome (hEDS) (his mother, his two brothers and his sister have the same phenotype as him). He suffers mainly from a severe mast cell activation syndrome (MCAS) with an overreaction of the skin to any kind of contact (water of the shower, clothes, bed sheets) but he has also fatigue, headaches, and rash. This impressive rash is exacerbated after the shower and he has the urge to rest ("shower's sign"). We describe the MCAS and its easy, fast and very effective medication management, without any significant side effects as well as its frequent association with the hEDS. We finally introduce the original term of "MASED" to this MCAS, associated, linked or entangled to hEDS. PMID- 29517868 TI - [Multidisciplinary management of a giant hepatic hydatidosis]. AB - Cystic echinococcosis or hydatidosis, is a zoonosis caused by larval stages of Echinococcus granulosus that can be encountered in Belgium in patients originating from endemic countries. The liver is the most commonly affected organ. In this paper, the authors describe the multidisciplinary management of this pathology based on the clinical case of a patient suffering from a 28 cm cystic echinococcosis treated by combination of albendazole and liver resection. Several treatment options are described in the literature although there is currently no clear consensus on the management of this condition. PMID- 29517869 TI - [School bullying]. AB - School bullying consists of harassment behaviours in a school setting and is characterized by violence acts, mockery or even humiliations between students. More recently, with the development of new technologies, our society has seen the cyber-bullying born. This new type of harassment "on-line" comes and intersects the harassment at school. After the description of a clinical situation, we describe the impact of this phenomenon on the different actors concerned, the lines for prevention and for appropriate support. PMID- 29517870 TI - [Minimally invasive aortic valve surgery. Experience of the academic hospital of Liege and review of the literature]. AB - Minimally invasive aortic valve surgery aims at reducing surgical invasiveness whilst preserving the high efficacy of surgical aortic valve replacement. As such it increases the value of the overall procedure. The surgical experience at the ULg is reported and replaced in the context of the pertinent related litterature. PMID- 29517871 TI - [Lithium toxicity after bariatric surgery]. AB - Since many years a correlation between neuropsychiatric disorders and eating disorders resulting in obesity is well established. According to different studies, 1.2 - 4 % of patients scheduled for bariatric surgery are taking lithium as a mood stabilizer treatment for bipolar disorder. We are presenting a case of lithium toxicity after vertical sleeve gastrectomy surgery in a 40 years-old female. The patient developed severe neurological and renal signs needing an intensive care unit admission and continuous veno-venous hemodiafiltration. A literature review provides insights into physiological and pharmacokinetics changes that could contribute to lithium poisoning after bariatric surgery. This article illustrates the need for closer monitoring of lithium serum levels following bariatric surgery and presents guidance in managing lithium therapy during perioperative period based on experts' opinion. PMID- 29517872 TI - [A virtual patient to improve doctor-patient communication : reality or fiction ?] AB - The transformations of the health system and the preferences of the patients themselves have led healthcare professionals to rethink the place and role of the patient in the healthcare system, putting the caregivercare relationship and communication at the heart of public health issues. The literature shows that empathic communication is associated with better adherence to treatment, better patient satisfaction and less litigation. However, the initial training programs of health professionals are little oriented towards this field. Moreover, they are mainly based on a direct transition from theory to clinical practice with all the risks that this entails for patients. Some recent studies suggest an interest in virtual reality simulation for the development of these communication skills. This article offers an overview of the potential of virtual clinical simulation as a complementary or even alternative method to traditional teaching methods. Different studies will illustrate these innovations in the training of physicians in clinical reasoning, empathic communication, and in a highly emotional situation such as breaking bad news. PMID- 29517874 TI - [Lower limb oedema in a patient with type 2 diabetes]. AB - Differential diagnosis of lower limb oedema is a common exercise in clinical practice. Taking the example of a patient presenting with such clinical picture in the presence of type 2 diabetes and arterial hypertension with coronary heart disease and chronic kidney disease as comorbidities, we discuss here the respective contributions of congestive heart failure, renal impairment (and possibly nephrotic syndrome) and liver disease in the development of lower limb oedema. The focus is made on a careful patient history and a meticulous clinical examination, two crucial steps that should allow prescribing well selected simple complementary procedures and rapidly make the final diagnosis. PMID- 29517873 TI - [Prescriptions in child psychiatry, on the use of antipsychotic drugs for children and Adolescents]. AB - In line with Evidence-based medicine and more recently with the emergence of Evidence-based practice in psychology, what are the current trends in medical prescriptions in child psychiatry? The use of psychotropic drugs for children and adolescents is constantly increasing, although most pharmacological prescriptions in child psychiatry result in off-label drug use. This article aims at understanding the legal and scientific framework that regulates the prescription of psychopharmacological treatments for children and adolescents. In the absence of clear therapeutic indications, which scientific data should be used to lead our prescribing practice? This topic is illustrated by a common case in child psychiatry: the prescription of medicines to treat psychotic disorders. PMID- 29517875 TI - Survival Rates and Complications for Zirconia-Based Fixed Dental Prostheses in a Period up to 10 Years: A Systematic Review. AB - AIMS: The purpose of this study was to methodically review the literature concerning the success and survival rates of zirconia fixed dental prostheses (FDPs). METHODS: A systematic search was conducted of MEDLINE, Elsevier and the Cochrane Library to identify relevant articles about zirconia FDPs. In order to obtain suitable articles, rigorous criteria were applied. The minimum follow-up period was five years. RESULTS: From a total of 986 articles identified in the first electronic search, only 10 matched the inclusion criteria. A total of 368 patients with 430 zirconia FDPs were included in this systematic review. The survival rate was 89.43% +/- 10.01% and chipping of the veneering ceramic occurred in 16.97% of the cases. CONCLUSION: Zirconia-based fixed dental prostheses perform reasonably well and can serve as an alternative to metal ceramic fixed dental prostheses. PMID- 29517876 TI - Surveys of Current Teaching and Practice for Impressions for Complete Dentures. AB - OBJECTIVES: The 3 objectives are to assess current preferences for impressions for complete dentures, audit practice and compare practice to current UK teaching. METHODS: Three surveys where undertaken; a survey of GDPs preferences, an audit of practice and a survey of teaching in UK dental schools. RESULTS: UK Universities advocate border moulded custom trays. In stated preferences, 99% of practitioners used custom trays for private practice; 67% for NHS work. In actual use, the audit found 91% practitioners in private practice used custom trays; in NHS practice 78% did so. The most widely taught materials were silicone (43%), alginate (29%), & zinc oxide eugenol paste (19%). In practitioners stated preferences, 97% of NHS and 53% of private dentists listed alginate as an option; however the audit showed only 74% (NHS) and 52% (private) actually used alginate, with 20% (NHS) and 48% (private) using silicone. CONCLUSIONS: Definitive impressions in custom trays are used by GDPs for both private and NHS work; they are universally taught at UK dental schools. Alginate is popular in NHS practice; however, silicone is more widely taught in UK Universities. The use of silicone materials for definitive impressions has increased since 1999. In UK private practice silicone usage is aligned in popularity with alginate. PMID- 29517877 TI - Patient Cost Sharing in Low Income Populations. PMID- 29517878 TI - An Individual Health Plan Exchange: Which Employees Would Benefit and Why? PMID- 29517879 TI - Are Health Insurance Markets Competitive? AB - To gauge the competitiveness of the group health insurance industry, I investigate whether health insurers charge higher premiums, ceteris paribus, to more profitable firms. Such "direct price discrimination" is feasible only in imperfectlycompetitive settings. Using a proprietary national database of health plans offered by a sample of large, multisite firms from 1998-2005, I find firms with positive profit shocks subsequently face higher premium growth, even for the same health plans. Moreover, within a given firm, those sites located in concentrated insurance markets experience the greatest premium increases. The findings suggest health care insurers are exercising market power in an increasingnumber of geographic markets. PMID- 29517880 TI - Quality Adjustment for Health Care Spending on Chronic Disease: Evidence from Diabetes Treatment, 1999-2009. AB - US health care expenditures reached $2.5 trillion in 2009, representing 17.6 percent of gross domestic product (GDP) and $8,086 per person (US Department of Health and Human Services Centers for Medicare and Medicaid Services2011). Since health care represents a large and growing share of the economy, and factors such as population aging imply that chronic disease treatment will continue to expand as a share of health expenditures, developing methods for assessing the value of quality improvement for chronic disease spending is of increasing importance for accurately measuring real economic activity. This paper develops a method for assessing the value of quality changes associated with health care for patients living with one important chronic disease, diabetes mellitus, using 11 years of detailed data on spending and quality of care for over 800 patients. We first provide an overview of measurement issues for healthcare quality, and then present our data, methods, results, and a brief discussion. PMID- 29517881 TI - Have Gender Gaps in Insurance Coverage and Access to Care Narrowed under Health Reform? Findings from Massachusetts. PMID- 29517886 TI - Dynamic Inefficiencies in an Employment-Based Health Insurance System: Theory and Evidence. AB - We investigate the effects of the institutional settings of the US health care system on individuals' life-cycle medical expenditures. Health is a form of general human capital; labor turnover and labor-market frictions prevent an employer-employee pair from capturing the entire surplus from investment in an employee's health. Thus, the pair underinvests in health during working years, thereby increasing medical expenditures during retirement. We provide empirical evidence consistent with the comparative statics predictions of our model using the Medical Expenditure Panel Survey (MEPS) and the Health and Retirement Study (HRS). Our estimates suggest significant inefficiencies in health investment in the United States. PMID- 29517887 TI - Redevelopment 'challenged conventional wisdom'. AB - In a paper awarded 'Best Member Paper' at the 2016 Institute of Hospital Engineering, Australia (IHEA) National Conference held at the Adelaide Oval last October, Mark Hooper BEng, executive project manager at Echuca Regional Health in Victoria, Australia, describes a A$66 million redevelopment project at the hospital--which is located in the historic port town of Echuca on the Murray river, two and a half hours north of Melbourne. He highlights some of the significant innovation that went into the project, in areas including plant operation and maintenance, emergency planning, resilience, and patient and staff comfort. PMID- 29517888 TI - A Canadian first for Chinook facility. AB - Gerrett Lim, a sustainable building and LEED technical advisor at architecture and design firm, Perkins+Will, describes how the design and construction of a new a five-storey, 205,000 ft(2) wing at the Chinook Regional Hospital in Lethbridge, Alberta, was the first healthcare project in Canada to register with the new LEED HC rating system. PMID- 29517889 TI - Trends in Employment and Earnings of Allowed and Rejected Applicants to the Social Security Disability Insurance Program. PMID- 29517890 TI - Investment vital to deliver 5YFV goals. AB - Without substantial investment in the NHS estate, the Five Year Forward View cannot be delivered, and the estate will 'remain unfit for purpose and continue to deteriorate', an independent review of NHS property and estate in England headed by Sir Robert Naylor, the former CEO of University College London Hospitals NHS Foundation Trust (pictured), concludes. Among the recommendations of the DH-commissioned review--which considers the opportunities to generate valuable funds via the sale of under-utilised NHS properties--is the establishment of 'a powerful new NHS Property Board', to 'provide leadership to the centre, and expertise and delivery support to Sustainability and Transformation Plans'. PMID- 29517891 TI - Trusts' forward-thinking approach recognised. AB - It is often said that the quality of the parking experience at a hospital or other healthcare facility makes one of the most lasting impressions on visitors. HEJ editor, Jonathan Baillie, spoke to Phillip Herring, managing director at Indigo, the UK arm of one of Europe's leading 'bespoke parking solution' providers, to discover how, harnessing first-class customer service, the latest technology, and the ability to offer anything from simple car park management to 30-year Design Build Finance Operate (DBFO) packages, the company is looking to extend a UK healthcare parking contract portfolio which already sees it work with 11 NHS Trusts across England, Scotland, and Wales. PMID- 29517892 TI - UK's first NHS high-energy proton beam facility. AB - With the UK's first high-energy Proton Beam Therapy Centre set to open next year at Manchester's The Christie, young patients with head and neck tumours, cancers close to the skull or spine, or a variety of soft tissue tumours, and adults with cancers difficult to treat using 'conventional' photon-based radiotherapy will, for the first time, be able to receive NHS proton beam therapy (PBT) without having to travel overseas. HEJ editor, Jonathan Baillie, visited the site of The Christie's new L135 million PBT Centre to find out more about the design and construction of a facility which interserve construction director for the North West, Phil Shaw, describes as one of the most complex and specialist he has worked on. PMID- 29517893 TI - Career takes off after aviation adventure. AB - Founder and director of Bristol-based arts consultancy, Willis Newson, Jane Willis, describes how the firm worked closely with a number of teams at University Hospitals Bristol NHS Foundation Trust and commissioned artists to redesign the Bereavement Suite and Sanctuary Space at Bristol Royal infirmary to provide more solace and comfort to bereaved visitors and relatives as part of a major conversion and extension project. PMID- 29517894 TI - Ultrafastly Interweaving Graphdiyne Nanochain on Arbitrary Substrates and Its Performance as a Supercapacitor Electrode. AB - A moderate method is first developed here for superfast (in seconds) growth of an ultrafine graphdiyne (GDY) nanochain on arbitrary substrates in the atmosphere. This is an environmentally friendly and metal-catalyst-free method, efficiently eliminating extraneous contaminations for the carbon materials. The seamless GDY coating on any substrates demonstrates that an all-carbon GDY possesses outstanding controllability and processability, perfectly compensating for the drawbacks of prevailing all-carbon materials. After the decoration of 3D GDY nanostructures, the substrates become superhydrophobic with contact angles high up to of 148 degrees and can be used as outstanding frameworks for storing organic pollution. Because of the reasonable porous and 3D continuous features, the as-prepared samples can be applied as high-performance binder-free supercapacitor electrodes with high area capacitance of up to 53.66 mF cm -2, prominent power performance, and robust long-term retention (99% after 1300 cycles). PMID- 29517895 TI - Taylor Dispersion of Polydisperse Nanoclusters and Nanoparticles: Modeling, Simulation, and Analysis. AB - The dimensions of ultrasmall inorganic nanoparticles (US-NPs) is in the heart of the design of diagnostic and therapeutic efficacy; yet its accurate measurement is challenging for most experimental techniques. We show here how to design and analyze Taylor dispersion experiments to characterize the two most sought-after parameters describing size distributions: the number-averaged mean size and polydispersity index. To demonstrate the power of the method, we simulated and analyzed taylograms corresponding to gold US-NPs distributed normally. By using simulation and including experimental noise, we had the advantage that the true values describing size distribution were known exactly, and thus, we were able test the absolute accuracy of our analysis and its robustness against noise. Theory and computational experiments were found in very good agreement, providing a significant step in the analysis of ultrasmall inorganic nanoparticles and Taylor dispersion experiments. PMID- 29517896 TI - Novel Multicharge Hydroacid Complexes That Effectively Remove Heavy Metal Ions from Water in Forward Osmosis Processes. AB - Suitable draw solutes are crucial to maximize the potential of forward osmosis (FO) in water treatment. In this study, a novel three-dimensional, multicharge draw solute of oxalic acid (OA) chromium complex in a tetramethylammonium salt of [N(CH3)4]3[Cr(C2O4)3] (NMe4-Cr-OA) was developed for electroplating wastewater treatment using FO processes. The newly designed NMe4-Cr-OA has a Cr-centered octahedral structure and can ionize a multicharge anion [Cr(C2O4)3]3- and three cations [N(CH3)4]- in its aqueous solution. Such characteristics are conducive to not only generating a high osmotic pressure but also minimizing reverse solute flux in an FO process, thus resulting in good FO performance. A high water recovery with a negligible reverse solute flux was achieved for NMe4-Cr-OA in electroplating wastewater treatment via the FO process. Furthermore, a significant increase of 77% in FO efficiency was obtained when NMe4-Cr-OA replaced the conventional draw solute of NH4HCO3 for FO electroplating wastewater treatment with a copper rejection higher than 99.9%, which surpasses the best performance of other technologies reported for copper ion removal. PMID- 29517897 TI - All-Inorganic CsPbI2Br Perovskite Solar Cells with High Efficiency Exceeding 13. AB - All-inorganic perovskite solar cells provide a promising solution to tackle the thermal instability problem of organic-inorganic perovskite solar cells (PSCs). Herein, we designed an all-inorganic perovskite solar cell with novel structure (FTO/NiO x/CsPbI2Br/ZnO@C60/Ag), in which ZnO@C60 bilayer was utilized as the electron-transporting layers that demonstrated high carrier extraction efficiency and low leakage loss. Consequently, the as-fabricated all-inorganic CsPbI2Br perovskite solar cell yielded a power conversion efficiency (PCE) as high as 13.3% with a Voc of 1.14 V, Jsc of 15.2 mA.cm-2, and FF of 0.77. The corresponding stabilized power output (SPO) of the device was demonstrated to be ~12% and remarkably stable within 1000 s. Importantly, the obtained all-inorganic PSCs without encapsulation exhibited only 20% PCE loss with thermal treatment at 85 degrees C for 360 h, which largely outperformed the organic-species containing PSCs. The present study demonstrates potential in overcoming the intractable issue concerning the thermal instability of perovskite solar cells. PMID- 29517898 TI - Relationship of Sequence and Phase Separation in Protein Low-Complexity Regions. AB - Liquid-liquid phase separation seems to play critical roles in the compartmentalization of cells through the formation of biomolecular condensates. Many proteins with low-complexity regions are found in these condensates, and they can undergo phase separation in vitro in response to changes in temperature, pH, and ion concentration. Low-complexity regions are thus likely important players in mediating compartmentalization in response to stress. However, how the phase behavior is encoded in their amino acid composition and patterning is only poorly understood. We discuss here that polymer physics provides a powerful framework for our understanding of the thermodynamics of mixing and demixing and for how the phase behavior is encoded in the primary sequence. We propose to classify low-complexity regions further into subcategories based on their sequence properties and phase behavior. Ongoing research promises to improve our ability to link the primary sequence of low-complexity regions to their phase behavior as well as the emerging miscibility and material properties of the resulting biomolecular condensates, providing mechanistic insight into this fundamental biological process across length scales. PMID- 29517899 TI - Photochemical Control of Protein Arginine Deiminase (PAD) Activity. AB - Protein arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis, and breast cancer. Therefore, the development of PAD inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-amidine afforded compounds 1 and 2 as the most promising candidates for the light controlled inhibition of PAD2; the cis isomer of 1 is 10-fold more potent than its trans isomer, whereas the trans isomer of 2 is 45-fold more potent than the corresponding cis isomer. The altered inhibitory potency upon photoisomerization has been confirmed in a competitive activity-based protein profiling (ABPP) assay. Further investigations indicate that the trans isomer of 2 is an irreversible inhibitor, whereas the cis isomer acts as a competitive inhibitor. In cells, the trans isomer of compound 1 is completely inactive, whereas the cis isomer inhibits histone H3-citrullination in a dose-dependent manner. Taken together, 1 serves as the foundation for developing photopharmaceuticals that can be activated at the desired tissue, using light, to treat diseases where PAD activity is dysregulated. PMID- 29517900 TI - Physiological and Agronomic Performance of the Coffee Crop in the Context of Climate Change and Global Warming: A Review. AB - Coffee is one of the most important global crops and provides a livelihood to millions of people living in developing countries. Coffee species have been described as being highly sensitive to climate change, as largely deduced from modeling studies based on predictions of rising temperatures and changing rainfall patterns. Here, we discuss the physiological responses of the coffee tree in the context of present and ongoing climate changes, including drought, heat, and light stresses, and interactions between these factors. We also summarize recent insights on the physiological and agronomic performance of coffee at elevated atmospheric CO2 concentrations and highlight the key role of CO2 in mitigating the harmful effects of heat stress. Evidence is shown suggesting that warming, per se, may be less harmful to coffee suitability than previously estimated, at least under the conditions of an adequate water supply. Finally, we discuss several mitigation strategies to improve crop performance in a changing world. PMID- 29517901 TI - Three-Dimensional Bioprinting of Oppositely Charged Hydrogels with Super Strong Interface Bonding. AB - A novel strategy to improve the adhesion between printed layers of three dimensional (3D) printed constructs is developed by exploiting the interaction between two oppositely charged hydrogels. Three anionic hydrogels [alginate, xanthan, and kappa-carrageenan (Kca)] and three cationic hydrogels [chitosan, gelatin, and gelatin methacrylate (GelMA)] are chosen to find the optimal combination of two oppositely charged hydrogels for the best 3D printability with strong interface bonding. Rheological properties and printability of the hydrogels, as well as structural integrity of printed constructs in cell culture medium, are studied as functions of polymer concentration and the combination of hydrogels. Kca2 (2 wt % Kca hydrogel) and GelMA10 (10 wt % GelMA hydrogel) are found to be the best combination of oppositely charged hydrogels for 3D printing. The interfacial bonding between a Kca layer and a GelMA layer is proven to be significantly higher than that of the bilayered Kca or bilayered GelMA because of the formation of polyelectrolyte complexes between the oppositely charged hydrogels. A good cell viability of >96% is obtained for the 3D-bioprinted Kca GelMA construct. This novel strategy has a great potential for 3D bioprinting of layered constructs with a strong interface bonding. PMID- 29517902 TI - M2B10O14F6 (M = Ca, Sr): Two Noncentrosymmetric Alkaline Earth Fluorooxoborates as Promising Next-Generation Deep-Ultraviolet Nonlinear Optical Materials. AB - Two novel noncentrosymmetric alkaline earth fluorooxoborates, M2B10O14F6 (M = Ca, Sr), were synthesized and characterized. Both of these two isostructural compounds had layered [B5O7F3]infinity structures with large second harmonic generation (SHG) responses ranging from 2.3 to 2.5 * KH2PO4 (KDP) and short UV absorption edges (<200 nm). The first-principles calculation demonstrated that their nonlinear optical (NLO) properties were superior to those of KBe2BO3F2 (KBBF). In contrast to the alkali fluorooxoborates, these two fluorooxoborates showed not only remarkable stability against air and moisture but also high thermal stability. Therefore, M2B10O14F6 (M = Ca, Sr) should be promising deep ultraviolet (DUV) NLO materials. PMID- 29517903 TI - New Gastrin Releasing Peptide Receptor-Directed [99mTc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation. AB - We have previously reported on the gastrin releasing peptide receptor (GRPR) antagonist [99mTc]1, ([99mTc]demobesin 1, 99mTc-[N4'-diglycolate-dPhe6,Leu NHEt13]BBN(6-13)). [99mTc]1 has shown superior biological profile compared to analogous agonist-based 99mTc-radioligands. We herein present a small library of [99mTc]1 mimics generated after structural modifications in (a) the linker ([99mTc]2, [99mTc]3, [99mTc]4), (b) the peptide chain ([99mTc]5, [99mTc]6), and (c) the C-terminus ([99mTc]7 or [99mTc]8). The effects of above modifications on the biological properties of analogs were studied in PC-3 cells and tumor-bearing SCID mice. All analogs showed subnanomolar affinity for the human GRPR, while most receptor-affine 4 and 8 behaved as potent GRPR antagonists in a functional internalization assay. In mice bearing PC-3 tumors, [99mTc]1-[99mTc]6 exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [99mTc]4 displayed the highest tumor uptake (28.8 +/- 4.1%ID/g at 1 h pi), which remained high even after 24 h pi (16.3 +/- 1.8%ID/g), well surpassing that of [99mTc]1 (5.4 +/- 0.7%ID/g at 24 h pi). PMID- 29517904 TI - Anomalous Effect of Intramolecular Charge Transfer on the Light Emitting Properties of BODIPY. AB - A new way to approaching highly emissive BODIPY dyes in both solution and solid state is achieved by introducing intramolecular charge transfer (ICT). A hybrid excited state that shows behaviors of both the ICT excited state and local excited state is discovered to be beneficial in avoiding the disturbance from the rotation vibration of the flexible phenyl substituents. Thus, the nonradiative transition process is suppressed, and the fluorescence efficiency goes up. By modification of the excited state, we realize emission enhancement of crystalline BODIPY derivatives with a PLQY from 0.08 to 0.27, and the compound expresses a good potential application prospect in organic semiconductors. PMID- 29517906 TI - Pd-Catalyzed Substitution of the OH Group of Nonderivatized Allylic Alcohols by Phenols. AB - Nonactivated phenols have been employed as nucleophiles in the allylation of nonderivatized allylic alcohols to generate allylated phenolic ethers with water as the only byproduct. A Pd[BiPhePhos] catalyst was found to be reactive to give the O-allylated phenols in good to excellent yields in the presence of molecular sieves. The reactions are chemoselective in which the kinetically favored O allylated products are formed exclusively over the thermodynamically favored C allylated products. PMID- 29517905 TI - Neutron Crystallography Detects Differences in Protein Dynamics: Structure of the PKG II Cyclic Nucleotide Binding Domain in Complex with an Activator. AB - As one of the main receptors of a second messenger, cGMP, cGMP-dependent protein kinase (PKG) isoforms I and II regulate distinct physiological processes. The design of isoform-specific activators is thus of great biomedical importance and requires detailed structural information about PKG isoforms bound with activators, including accurate positions of hydrogen atoms and a description of the hydrogen bonding and water architecture. Here, we determined a 2.2 A room temperature joint X-ray/neutron (XN) structure of the human PKG II carboxyl cyclic nucleotide binding (CNB-B) domain bound with a potent PKG II activator, 8 pCPT-cGMP. The XN structure directly visualizes intermolecular interactions and reveals changes in hydrogen bonding patterns upon comparison to the X-ray structure determined at cryo-temperatures. Comparative analysis of the backbone hydrogen/deuterium exchange patterns in PKG II:8-pCPT-cGMP and previously reported PKG Ibeta:cGMP XN structures suggests that the ability of these agonists to activate PKG is related to how effectively they quench dynamics of the cyclic nucleotide binding pocket and the surrounding regions. PMID- 29517907 TI - Design of Single-Atom Co-N5 Catalytic Site: A Robust Electrocatalyst for CO2 Reduction with Nearly 100% CO Selectivity and Remarkable Stability. AB - We develop an N-coordination strategy to design a robust CO2 reduction reaction (CO2RR) electrocatalyst with atomically dispersed Co-N5 site anchored on polymer derived hollow N-doped porous carbon spheres. Our catalyst exhibits high selectivity for CO2RR with CO Faradaic efficiency (FECO) above 90% over a wide potential range from -0.57 to -0.88 V (the FECO exceeded 99% at -0.73 and -0.79 V). The CO current density and FECO remained nearly unchanged after electrolyzing 10 h, revealing remarkable stability. Experiments and density functional theory calculations demonstrate single-atom Co-N5 site is the dominating active center simultaneously for CO2 activation, the rapid formation of key intermediate COOH* as well as the desorption of CO. PMID- 29517909 TI - Sifting Through the Embers. PMID- 29517908 TI - Isochromophilones A-F, Cytotoxic Chloroazaphilones from the Marine Mangrove Endophytic Fungus Diaporthe sp. SCSIO 41011. AB - Six new highly oxygenated chloroazaphilone derivatives, isochromophilones A-F (1 6), were obtained from the mangrove-derived fungus Diaporthe sp. SCSIO 41011, together with six known analogues (7-12). The structures of 1-6 including absolute configurations were determined by detailed NMR, MS spectroscopic analyses, and electronic circular dichroism spectra. Compounds 1 and 2 represent the first reported azaphilones lacking a carbonyl group at C-6. Compound 8 exhibited cytotoxic activities against three renal carcinoma cell lines, ACHN, OS RC-2, and 786-O cells, with IC50 values ranging from 3.0 to 4.4 MUM, and 4 showed activity against 786-O cells with an IC50 of 8.9 MUM. Further studies indicated that 4 induced apoptosis in 786-O cells in a dose- and time-dependent manner. PMID- 29517911 TI - Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema. AB - Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ~40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema. PMID- 29517912 TI - Electrical Conductivity of Copper Hexamers Tuned by their Ground-State Valences. AB - A new design concept has been realized for the construction of molecular conductors, whereby the building unit contains a core reservoir of carriers made up of metal ions with controllable valence states and shelled by flat organic ligands having an extended pi-system to promote supramolecular electronic communication. Therefore, reacting the conjugated multidentate ligand 5,5' pyridyl-3,3'-bi-1 H-pyrazole with different copper salts solvothermally led to three interesting hexameric salts having different ground-state valences, [CuII6(L)4(NO3)(CH3OH)2](NO3)3.4CH3OH, [(CH3)2NH2][CuICuII5(L)4](SO4)2.4H2O, and [CuI2CuII4(L)4](NO3)2.2CH3OH. The monovalent CuII6 salt is an insulator, but the mixed-valent CuII5-CuI and CuII4-CuI2 salts are semiconductors. Magnetic exchange interactions up to JNN = -158 cm-1 dominate the susceptibilities and lead to ground-state spin ST = 1 (CuII6), 1/2 (CuII5-CuI), and 0 (CuII4-CuI2) at 40 K. Cyclic voltammetry shows the stepwise one-electron oxidation-reduction through all the possible valence states. The theoretical calculations of the electronic and band structures of the three compounds substantiate the experimentally observed physical properties. PMID- 29517913 TI - Dinitrogen as a Sensor for Metastable Carboxylic Acid Dimers and a Weak Hydrogen Bond Benchmarking Tool. AB - Molecular nitrogen as a weak hydrogen bond acceptor is added to formic and acetic acid and their monodeuterated isotopologues. FTIR spectroscopy of supersonic expansions in the O-H stretching region reveals the formation of the weakly bound N2-carboxylic acid complexes. Their respective spectral downshifts from the monomer fundamental vibration are used to benchmark electronic structure calculations and vibrational perturbation theory. The small size of the investigated systems allows for a wide range of electronic structure levels to be explored. The O-H stretching vibration of an open dimer of acetic acid can be discriminated from the cyclic dimer vibrations by its higher susceptibility to coexpanded nitrogen. PMID- 29517914 TI - Thiol-Catalyzed Radical Decyanation of Aliphatic Nitriles with Sodium Borohydride. AB - Radical decyanation of aliphatic nitriles was achieved in the presence of NaBH4 and a thiol. The reaction proceeds via a radical mechanism involving borane radical anion addition to nitrile to form an iminyl radical, which undergoes carbon-carbon cleavage. Reductive radical addition to acrylonitrile is followed by decyanation to give a two-carbon homologated product in a net radical ethylation reaction. PMID- 29517915 TI - Polylactic Acid Nanopillar Array-Driven Osteogenic Differentiation of Human Adipose-Derived Stem Cells Determined by Pillar Diameter. AB - Numerous studies have determined that physical cues, especially the nanotopography of materials, play key roles in directing stem cell differentiation. However, most research on nanoarrays for stem cell fate regulation is based on nonbiodegradable materials, such as silicon wafers, TiO2, and poly(methyl methacrylate), which are rarely used as tissue engineering biomaterials. In this study, we prepared biodegradable polylactic acid (PLA) nanopillar arrays with different diameters but the same center-to-center distance using a series of anodic aluminum oxide nanowell arrays as templates. Human adipose-derived stem cells (hADSCs) were selected to investigate the effect of the diameter of PLA nanopillar arrays on stem cell differentiation. By culturing hADSCs without the assistance of any growth factors or osteogenic-induced media, the differentiation tendencies of hADSCs on the nanopillar arrays were assessed at the gene and protein levels. The assessment results suggested that the osteogenic differentiation of hADSCs can be driven by nanopillar arrays, especially by nanopillar arrays with a diameter of 200 nm. Moreover, an in vivo animal model of the samples demonstrated that PLA film with the 200 nm pillar array exhibits an improved ectopic osteogenic ability compared with the planar PLA film after 4 weeks of ectopic implantation. This study has provided a new variable to investigate in the interaction between stem cells and nanoarray structures, which will guide the bone regeneration clinical research field. This work paves the way for the utility of degradable biopolymer nanoarrays with specific geometrical and mechanical signals in biomedical applications, such as patches and strips for spine fusion, bone crack repair, and restoration of tooth enamel. PMID- 29517916 TI - Identification of Intermediates during the Hydration of Na8[AlSiO4]6(BH4)2: A Combined Theoretical and Experimental Approach. AB - Tetrahydroborate sodalites have been discussed as possible materials for reversible hydrogen storage. In order to access the suitability of Na8[AlSiO4]6(BH4)2, its reaction with water was investigated theoretically and experimentally. Density functional theory (DFT) calculations at the generalized gradient approximation (GGA) level were performed to identify the reaction intermediates. We compared experimental IR spectra and 11B NMR chemical shifts with theoretical results for selected molecules in the sodalite cage. Furthermore, the free energies of reaction of the intermediates with respect to Na8[AlSiO4]6(BH4)2, gaseous water, and molecular hydrogen at different temperatures were also calculated. PMID- 29517917 TI - Nanoscale Electrochemical Sensing and Processing in Microreactors. AB - In this review, we summarize recent advances in nanoscale electrochemistry, including the use of nanoparticles, carbon nanomaterials, and nanowires. Exciting developments are reported for nanoscale redox cycling devices, which can chemically amplify signal readout. We also discuss promising high-frequency techniques such as nanocapacitive CMOS sensor arrays or heterodyning. In addition, we review electrochemical microreactors for use in (drug) synthesis, biocatalysis, water treatment, or to electrochemically degrade urea for use in a portable artificial kidney. Electrochemical microreactors are also used in combination with mass spectrometry, e.g., to study the mimicry of drug metabolism or to allow electrochemical protein digestion. The review concludes with an outlook on future perspectives in both nanoscale electrochemical sensing and electrochemical microreactors. For sensors, we see a future in wearables and the Internet of Things. In microreactors, a future goal is to monitor the electrochemical conversions more precisely or ultimately in situ by combining other spectroscopic techniques. PMID- 29517910 TI - Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens. AB - Superoxide anion radical is generated as a natural byproduct of aerobic metabolism but is also produced as part of the oxidative burst of the innate immune response design to kill pathogens. In living systems, superoxide is largely managed through superoxide dismutases (SODs), families of metalloenzymes that use Fe, Mn, Ni, or Cu cofactors to catalyze the disproportionation of superoxide to oxygen and hydrogen peroxide. Given the bursts of superoxide faced by microbial pathogens, it comes as no surprise that SOD enzymes play important roles in microbial survival and virulence. Interestingly, microbial SOD enzymes not only detoxify host superoxide but also may participate in signaling pathways that involve reactive oxygen species derived from the microbe itself, particularly in the case of eukaryotic pathogens. In this Review, we will discuss the chemistry of superoxide radicals and the role of diverse SOD metalloenzymes in bacterial, fungal, and protozoan pathogens. We will highlight the unique features of microbial SOD enzymes that have evolved to accommodate the harsh lifestyle at the host-pathogen interface. Lastly, we will discuss key non-SOD superoxide scavengers that specific pathogens employ for defense against host superoxide. PMID- 29517918 TI - Correction. PMID- 29517919 TI - Modeling Cell Size Regulation: From Single-Cell-Level Statistics to Molecular Mechanisms and Population-Level Effects. AB - Most microorganisms regulate their cell size. In this article, we review some of the mathematical formulations of the problem of cell size regulation. We focus on coarse-grained stochastic models and the statistics that they generate. We review the biologically relevant insights obtained from these models. We then describe cell cycle regulation and its molecular implementations, protein number regulation, and population growth, all in relation to size regulation. Finally, we discuss several future directions for developing understanding beyond phenomenological models of cell size regulation. PMID- 29517920 TI - Genetic bases of the nutritional approach to migraine. AB - Migraine is a common multifactorial and polygenic neurological disabling disorder characterized by a genetic background and associated to environmental, hormonal and food stimulations. A large series of evidence suggest a strong correlation between nutrition and migraine and indicates several commonly foods, food additives and beverages that may be involved in the mechanisms triggering the headache attack in migraine-susceptible persons. There are foods and drinks, or ingredients of the same, that can trigger the migraine crisis as well as some foods play a protective function depending on the specific genetic sensitivity of the subject. The recent biotechnological advances have enhanced the identification of some genetic factors involved in onset diseases and the identification of sequence variants of genes responsible for the individual sensitivity to migraine trigger-foods. Therefore many studies are aimed at the analysis of polymorphisms of genes coding for the enzymes involved in the metabolism of food factors in order to clarify the different ways in which people respond to foods based on their genetic constitution. This review discusses the latest knowledge and scientific evidence of the role of gene variants and nutrients, food additives and nutraceuticals interactions in migraine. PMID- 29517921 TI - Activity Metabolism of Anuran Amphibians: Implications for the Origin of Endothermy. AB - A model has been proposed for the evolution of endothermy from ectothermic progenitors that assumes a positive correlation between resting rates of oxygen consumption ( $$?dot{V}_{O_{2}}$$ rest) and maximum rates of oxygen consumption ( $$?dot{V}_{O_{2}}$$ max) for species of terrestrial vertebrates. Selection for enhanced aerobic capacity during activity is presumed to have resulted in elevated resting rates of oxygen consumption. The assumption that underlies this evolutionary argument was tested using 17 species of anuran amphibians. These species exhibit considerable variation in both $$?dot{V}_{O_{2}}$$ rest and $$?dot{V}_{O_{2}}$$ max. A highly significant, positive correlation was found between these metabolic parameters. Those species with higher than average maximum rates of oxygen consumption are also characterized by high resting levels. Low $$?dot{V}_{O_{2}}$$ max values were associated with low resting rates. The possibility that metabolic characteristics of anuran amphibians are seasonally variable, potentially giving rise to a spurious relationship between $$?dot{V}_{O_{2}}$$ rest and $$?dot{V}_{O_{2}}$$ max, was also investigated. No significant differences were observed between breeding and nonbreeding individuals in either $$?dot{V}_{O_{2}}$$ rest or $$?dot{V}_{O_{2}}$$ max for three species. The positive correlation between $$?dot{V}_{O_{2}}$$ rest and $$?dot{V}_{O_{2}}$$ max is consistent with evolutionary arguments that view metabolic response to exercise as an important factor in a selection process that led ultimately to the endothermic condition. PMID- 29517922 TI - Outcrossing and Sex Function in Hermaphrodites: A Resource-Allocation Model. AB - Genetic estimates of outcrossing rates in seed plants usually measure the ovule or seed outcrossing rate only. However, there is good evidence for population variation in pollen fertility, which may result in sharply different ovule and pollen outcrossing rates. Therefore, a new combined ovule and pollen outcrossing rate, which depends upon the concept of successful gametes, is proposed. This rate estimates the number of ovules and pollen grains which take part in crossing, as a proportion of all successful ovules and pollen grains (fitness value). Fertility variation also causes unequal male/female functioning of hermaphrodites, and the degree of female function (functional sex) is defined as the number of successful ovules as a proportion of all successful gametes. This is a number between 0 (for males) and 1 (for females), and seldom equals 0.5 for non-fully-selfed hermaphrodites. All of these quantities are frequency dependent, since a common component (the number of successful cross-fertilizing pollen grains) is frequency dependent because of the variation in ovule and pollen fertility. These quantities are studied by means of a one-locus two-allele model of male/female resource allocation, with dominance, in which all genotypes have the same reproductive resources. For 0 < sigma < 1, in which sigma is the ovule selfing rate, the phenotype with the greater pollen fertility has the greater combined outcrossing rate. For polymorphic populations and 0 < sigma < 1, all genotypic combined outcrossing rates are increasing functions of the frequency of the more ovule-fertile phenotype. For sigma < 1, functional sex is an increasing and fitness a decreasing function of the frequency of the more pollen-fertile phenotype. Optimal resource allocation for a genotype is defined as that which results in the fixation of that genotype. The genotypic proportion of resources devoted to seeds (Rij) is optimally 1/2 for sigma = 0, and increases with sigma. Optimal combined outcrossing and functional sex are similarly defined. Population dynamics can be described in terms of resource allocation as follows: If one genotypic R value is less than and the other greater than 1/2(1 + sigma), then $$?hat{?bar{R}}$$ , the mean seed resource allocation in equilibrium populations, equals 1/2(1 + sigma), whereas if both R's are less than or greater than 1/2(1 + sigma), $$?hat{?bar{R}}$$ equals the genotypic value nearest to 1/2(1 + sigma). Unlike the classical selection model, there may be a polymorphism despite dominance, and mean population fitness may decrease with selection, since polymorphic equilibrium mean fitness is an increasing function of sigma. The mean combined outcrossing rate and functional sex equal the ovule outcrossing rate 1 - sigma and 1/2, respectively, in equilibrium populations. PMID- 29517923 TI - Anatomic Predictors of Sagittal Hip and Pelvic Motions in Patients With a Cam Deformity. AB - BACKGROUND: As there is a high prevalence of patients with cam deformities and no ongoing hip dysfunction, understanding the biomechanical factors predicting the onset of symptoms and degenerative changes is critical. One such variable is how the spinopelvic parameters may influence hip and pelvic sagittal mobility. Hypothesis/Purpose: Pelvic incidence may predict sagittal hip and pelvic motions during walking and squatting. The purpose was to determine which anatomic characteristics were associated with symptoms and how they influenced functional hip and pelvic ranges of motion (ROMs) during walking and squatting. STUDY DESIGN: Controlled laboratory study. METHODS: Fifty-seven participants underwent computed tomography and were designated either symptomatic (n = 19, cam deformity with pain), asymptomatic (n = 19, cam deformity with no pain), or control (n = 19, no cam deformity or pain). Multiple femoral (cam deformity, neck angle, torsion), acetabular (version, coverage), and spinopelvic (pelvic tilt, sacral slope, pelvic incidence) parameters were measured from each participant's imaging data, and sagittal hip and pelvic ROMs during walking and squatting were recorded using a motion capture system. RESULTS: Symptomatic participants had large cam deformities, smaller femoral neck-shaft angles, and larger pelvic incidence angles compared with the asymptomatic and control participants. Discriminant function analyses confirmed that radial 1:30 alpha angle (lambda1 = 0.386), femoral neck-shaft angle (lambda2 = 0.262), and pelvic incidence (lambda3 = 0.213) ( P < .001) were the best anatomic parameters to classify participants with their groups. Entering these 3 parameters into a hierarchical linear regression, significant regressions were achieved for hip ROM only when pelvic incidence was included for walking ( R2 = 0.20, P = .01) and squatting ( R2 = 0.14, P = .04). A higher pelvic incidence decreased walking hip ROM ( r = -0.402, P = .004). Although symptomatic participants indicated a trend of reduced squatting hip and pelvic ROMs, there were no significant regressions with the anatomic parameters. CONCLUSION: A cam deformity alone may not indicate early clinical signs or decreased ROM. Not only was pelvic incidence a significant parameter to classify the participants, but it was also an important parameter to predict functional ROM. Symptomatic patients with a higher pelvic incidence may experience limited sagittal hip mobility. CLINICAL RELEVANCE: Patients with symptomatic femoroacetabular impingement showed a higher pelvic incidence and, combined with a cam deformity and varus neck, can perhaps alter the musculature of their iliopsoas, contributing to a reduced sagittal ROM. With an early and accurate clinical diagnosis, athletes could benefit from a muscle training strategy to protect their hips. PMID- 29517924 TI - Meaningful Change Scores in the Knee Injury and Osteoarthritis Outcome Score in Patients Undergoing Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Meaningful change scores in the Knee injury and Osteoarthritis Outcome Score (KOOS) in patients undergoing anterior cruciate ligament (ACL) reconstruction have not yet been established. PURPOSE: To define the minimal important change (MIC) for the KOOS after ACL reconstruction. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: KOOS and anchor questions with 7-point scales ranging from "better, an important improvement" to "worse, an important worsening" were completed postoperatively by randomly chosen participants from the Norwegian Knee Ligament Registry. Presurgery KOOS scores were retrieved from the registry. The MIC for improvement was calculated with anchor-based approaches using the predictive modeling method adjusted for the proportion of improved patients, the mean change method, and the receiver operating characteristic (ROC) method. RESULTS: Complete data for at least one of the KOOS subscales were obtained from 542 (45.3%) participants. Predictive modeling MIC values were 12.1 for the KOOS subscales of Sport and Recreational Function and 18.3 for Knee-Related Quality of Life. These values aid in interpreting within-group improvement over time and can be used as responder criteria when comparing groups. The corresponding and much lower values for the subscales of Pain (2.5), Symptoms (-1.2), and Activities of Daily Living (2.4) are the results from patients reporting, on average, only mild problems with these domains preoperatively. Although 4% to 10% of patients reported subscale specific worsening, MIC deterioration calculations were not possible. The ROC MIC values were associated with high degrees of misclassification. Values obtained by the mean change method were considered less reliable because these estimates are derived from subgroups of patients. Average KOOS change scores were approximately similar for patients reporting acceptable symptoms postoperatively and patients reporting important improvements on the anchor items after surgery. CONCLUSION: KOOS users should apply subscale-specific cutoffs for meaningful improvement. Our results confirm using the subscales of Sport and Recreational Function and Knee Related Quality of Life as primary patient-reported outcomes after ACL reconstruction. The predictive modeling approach gave the most robust estimates of MIC values. Our data suggest that reporting acceptable symptoms postoperatively corresponds to reporting an important improvement after ACL reconstruction. PMID- 29517925 TI - Meniscus Root Repair vs Meniscectomy or Nonoperative Management to Prevent Knee Osteoarthritis After Medial Meniscus Root Tears: Clinical and Economic Effectiveness. AB - BACKGROUND: Medial meniscus root tears are a common knee injury and can lead to accelerated osteoarthritis, which might ultimately result in a total knee replacement. PURPOSE: To compare meniscus repair, meniscectomy, and nonoperative treatment approaches among middle-aged patients in terms of osteoarthritis development, total knee replacement rates (clinical effectiveness), and cost effectiveness. STUDY DESIGN: Meta-analysis and cost-effectiveness analysis. METHODS: A systematic literature search was conducted. Progression to osteoarthritis was pooled and meta-analyzed. A Markov model projected strategy specific costs and disutilities in a cohort of 55-year-old patients presenting with a meniscus root tear without osteoarthritis at baseline. Failure rates of repair and meniscectomy procedures and disutilities associated with osteoarthritis, total knee replacement, and revision total knee replacement were accounted for. Utilities, costs, and event rates were based on literature and public databases. Analyses considered a time frame between 5 years and lifetime and explored the effects of parameter uncertainty. RESULTS: Over 10 years, meniscus repair, meniscectomy, and nonoperative treatment led to 53.0%, 99.3%, and 95.1% rates of osteoarthritis and 33.5%, 51.5%, and 45.5% rates of total knee replacement, respectively. Meta-analysis confirmed lower osteoarthritis and total knee replacement rates for meniscus repair versus meniscectomy and nonoperative treatment. Discounted 10-year costs were $22,590 for meniscus repair, as opposed to $31,528 and $25,006 for meniscectomy and nonoperative treatment, respectively; projected quality-adjusted life years were 6.892, 6.533, and 6.693, respectively, yielding meniscus repair to be an economically dominant strategy. Repair was either cost-effective or dominant when compared with meniscectomy and nonoperative treatment across a broad range of assumptions starting from 5 years after surgery. CONCLUSION: Repair of medial meniscus root tears, as compared with total meniscectomy and nonsurgical treatment, leads to less osteoarthritis and is a cost-saving intervention. While small confirmatory randomized clinical head-to head trials are warranted, the presented evidence seems to point relatively clearly toward adopting meniscus repair as the preferred initial intervention for medial meniscus root tears. PMID- 29517926 TI - The multiple faces of inflammatory enteric glial cells: is Crohn's disease a gliopathy? AB - Gone are the days when enteric glial cells (EGC) were considered merely satellites of enteric neurons. Like their brain counterpart astrocytes, EGC express an impressive number of receptors for neurotransmitters and intercellular messengers, thereby contributing to neuroprotection and to the regulation of neuronal activity. EGC also produce different soluble factors that regulate neighboring cells, among which are intestinal epithelial cells. A better understanding of EGC response to an inflammatory environment, often referred to as enteric glial reactivity, could help define the physiological role of EGC and the importance of this reactivity in maintaining gut functions. In chronic inflammatory disorders of the gut such as Crohn's disease (CD) and ulcerative colitis, EGC exhibit abnormal phenotypes, and their neighboring cells are dysfunctional; however, it remains unclear whether EGC are only passive bystanders or active players in the pathophysiology of both disorders. The aim of the present study is to review the physiological roles and properties of EGC, their response to inflammation, and their role in the regulation of the intestinal epithelial barrier and to discuss the emerging concept of CD as an enteric gliopathy. PMID- 29517927 TI - Modulations in extracellular calcium lead to H+-ATPase-dependent acid secretion: a clarification of PPI failure. AB - The H+,K+-ATPase was identified as the primary proton secretory pathway in the gastric parietal cell and is the pharmacological target of agents suppressing acid secretion. Recently, we identified a second acid secretory protein expressed in the parietal cell, the vacuolar H+-ATPase (V-type ATPase). The aim of the present study was to further characterize H+-ATPase activation by modulations in extracellular calcium via the calcium sensing receptor (CaSR). Isolated gastric glands were loaded with the pH indicator dye BCECF-AM [2',7'-bis-(2-carboxyethyl) 5-(and-6)-carboxyfluorescein acetoxymethyl ester] to measure intracellular pH. Experiments were conducted in the absence of sodium and potassium to monitor H+ ATPase-specific transport activity. CaSR was activated with the calcimimetic R568 (400 nM) and/or by modulations in extracellular Ca2+. Elevation in calcium concentrations increased proton extrusion from the gastric parietal cell. Allosteric modification of the CaSR via R568 and calcium increased vacuolar H+ ATPase activity significantly (DeltapH/minlowCa2+(0.1mM) = 0.001 +/- 0.001, DeltapH/minnormalCa2+(1.0mM) = 0.033 +/- 0.004, DeltapH/minhighCa2+(5.0mM) = 0.051 +/- 0.005). Carbachol significantly suppressed calcium-induced gastric acid secretion via the H+-ATPase under sodium- and potassium-free conditions. We conclude that the V-type H+-ATPase is tightly linked to CaSR activation. We observed that proton pump inhibitor (PPI) exposure does not modulate H+-ATPase activity. This elevated blood calcium activation of the H+-ATPase could provide an explanation for recurrent reflux symptoms while taking a PPI therapy. NEW & NOTEWORTHY This study emphasizes the role of the H+-ATPase in acid secretion. We further demonstrate the modification of this proton excretion pathway by extracellular calcium and the activation of the calcium sensing receptor CaSR. The novelty of this paper is based on the modulation of the H+-ATPase via both extracellular Ca (activation) and the classical secretagogues histamine and carbachol (inactivation). Both activation and inactivation of this proton pump are independent of PPI modulation. PMID- 29517928 TI - The Condition-Dependent Development of Carotenoid-Based and Structural Plumage in Nestling Blue Tits: Males and Females Differ. AB - Despite the importance of proximate mechanisms for understanding costs and functions of signals, relatively little is known about physiological processes underlying colorful plumage production. We investigated yellow carotenoid-based breast plumage and ultraviolet (UV)/blue structural color of tail feathers in nestling blue tits. At peak plumage production and at fledging, we examined plasma concentration of protein, the substance of feathers, and levels of carotenoids, which are deposited in yellow plumage and also required for support of growth and immune development. Males showed more UV-shifted hue and higher chroma and UV chroma of the tail feathers. In males only, tail chroma and UV chroma were strongly but negatively related to circulating plasma protein at the period of peak feather production. Breast plumage was more chromatic in males, and yellow coloration was strongly condition dependent in males only. Production of more chromatic plumage appeared to deplete carotenoids from plasma, since male fledglings had less circulating carotenoids than females. This had no obvious consequences for these males, since coloration was unrelated to cell-mediated immune responses, humoral immune status, stress, and parasitism. Nonetheless, the pronounced sex specificity of condition dependence of structural and carotenoid based coloration is suggestive of a signaling function of the fledgling plumage. PMID- 29517929 TI - Simultaneous Crypsis and Conspicuousness in Color Patterns: Comparative Analysis of a Neotropical Rainforest Bird Community. AB - Understanding how animals achieve simultaneous conspicuousness to intended receivers and crypsis to unintended receivers requires investigating the distribution, size, and spectral characteristics of color patches. Here we characterize plumage patterns of 40 rainforest bird species living in understory or canopy. Visual signals maximizing (or minimizing) detection are expected to differ between these contrasted light habitats, making rainforests appropriate to test hypotheses of color signal evolution. Using spectrometry and comparative analyses, we show that canopy and understory act as distinct selective regimes that strongly influence bird coloration. Birds reduce detectability by displaying countershaded patterns, by matching background color and contrast, and by reducing in size the most conspicuous patches. More intense on males than on females, selection for conspicuousness acts on large patches by increasing contrast on ventral parts likely to be seen by conspecifics. It also operates on small patches by focusing visual contrast on chest, head, and tail in understory and on wing and tail in canopy, by increasing local brightness contrast compared to general contrast in canopy, and by exploiting different wavelengths for contrast (short in canopy and long in understory). These results are of general interest to understanding the evolution of color patterns for all organisms living in contrasted light environments. PMID- 29517930 TI - The Evolution of Signal Design in Manakin Plumage Ornaments. AB - Animal signals are characterized by two design components: efficacy (detectability) and content (message being conveyed). Selection for efficient signal perception should favor the evolution of traits that exhibit an optimal balance between these two design components. We examined the evolution of signal design in the colorful plumage ornaments of manakins (Aves: Pipridae). We used a model of avian color space to quantify how differences in plumage coloration would be perceived by a typical passerine bird and examined patterns of coloration across 50 species of manakin. Using phylogenetically independent contrasts, we show that plumage contrast against the background increases with sexual dichromatism in males but not females, suggesting that sexual selection has favored the evolution of male plumage ornaments that enhance signal efficacy. Plumage contrast within individuals also increased with dichromatism in males but not females. Finally, plumage colors produced by different mechanisms, which may reveal different aspects of quality, resulted in different degrees of contrast against the background. Our findings suggest that selection for signal efficacy and content may sometimes be opposing, creating a trade-off between these two components of signal design. Manakins may mediate this trade-off by combining multiple plumage ornaments that differ in efficacy and content. PMID- 29517931 TI - Are people living with HIV less productive at work? AB - Health problems may cause decreased productivity among working people. It is unclear if this also applies for people living with HIV (PLWH). This cross sectional study compares data of PLWH of one of the main HIV treatment centres in the Netherlands (n = 298) to data of the general working population from a previously conducted study (n = 986). We investigate whether productivity at work differs between these groups. The questionnaires used in these studies contained a core of identical questions regarding productivity losses, in the form of absenteeism and presenteeism, over a four-week period and a variety of baseline characteristics, including health status measured with EQ-5D. For PLWH additional clinical data were collected from patient records. From the data, descriptive statistics were computed to characterize the samples. Pearson correlations were used to explore significant associations of productivity with baseline characteristics. A two-part model was used to evaluate both the occurrence and of size of productivity losses in working PLWH and an aggregated sample of PLWH and the general population. It was observed that, on average, total productivity losses do not differ significantly between working PWLH and the general working population, but that the occurrence and size of absenteeism and presenteeism were different. Furthermore, more health problems were associated with higher productivity losses. HIV status was not significantly associated with productivity losses. We conclude that among working people, health status was related to productivity losses but HIV status was not. However, further research is needed into the relation between HIV status and unemployment. PMID- 29517936 TI - In Search of Likes: Longitudinal Associations Between Adolescents' Digital Status Seeking and Health-Risk Behaviors. AB - This study introduces a new construct-digital status seeking-which reflects a set of behaviors made possible by the social media environment. Digital status seeking is defined as the investment of significant effort into the accumulation of online indicators of peer status and approval. The concurrent validity of this construct was examined, as well as the longitudinal implications of digital status seeking for adolescents' engagement in health-risk behaviors. A school based sample of 716 participants (Mage = 16.01 at Time 1; 54.2% female) participated at 2 time points, 1 year apart. Sociometric nomination procedures were used to assess digital status seeking and peer status. Participants self reported indices of social media use, peer importance, and risky behavior engagement (substance use, sexual risk behavior). For a subset of participants, social media pages were observationally coded for status indicators (i.e., likes, followers) and status-seeking behaviors. Adolescents with greater reputations of digital status seeking reported more frequent social media use, desire for popularity, belief in the importance of online status indicators, and use of strategies to obtain these indicators. Multiple group path analyses indicated that for both genders, digital status seekers engaged in higher levels of substance use and sexual risk behavior 1 year later. Moderation of this effect by race/ethnicity and socioeconomic status was explored. This novel, multimethod investigation reveals digital status seeking as an important construct for future study and offers preliminary evidence for the unique role of social media experiences in contributing to adolescent adjustment. PMID- 29517937 TI - Editorial. PMID- 29517939 TI - Tribute to Behavioral Sleep Medicine Reviewers. PMID- 29517938 TI - Carole L. Marcus, M.B.B.Ch. (1960 - 2017). PMID- 29517940 TI - Clinical features predicting group A streptococcal pharyngitis in a Japanese paediatric primary emergency medical centre. AB - Objectives To identify clinical features that predict Group A streptococcal (GAS) pharyngitis in a Japanese paediatric primary emergency medical centre. Methods The prevalence of GAS pharyngitis according to age and body temperature (BT) was calculated among 3098 paediatric patients with pharyngitis. The numbers of GAS positive and -negative patients for each clinical parameter, and each point increase in the McIsaac score were compared and likelihood ratios (LRs) were calculated. Results The prevalence of GAS pharyngitis was extremely low in patients aged < 1 (1.2%) and 1 year (3.9%). The GAS-positive rate was significantly higher in patients with a BT < 38.0 degrees C compared with >= 38.0 degrees C (30.0% vs. 19.8%). A BT >= 38.0 degrees C was not a predictive finding for GAS pharyngitis (positive LR: 0.82). Rash was the most useful individual predictor, and a McIsaac score of 4 or 5 increased the probability; however, the positive LRs were 1.74 and 1.30, respectively. Conclusions The prevalence of GAS pharyngitis is extremely low in patients aged < 1 and 1 year, and a BT >= 38.0 degrees C is not a predictive symptom. Although a rash and McIsaac score of 4 or 5 are associated with an increased probability, they cannot be used to confirm GAS infection. PMID- 29517941 TI - Polysaccharide from Angelica sinensis protects H9c2 cells against oxidative injury and endoplasmic reticulum stress by activating the ATF6 pathway. AB - Objectives Angelica sinensis exerts various pharmacological effects, such as antioxidant and anti-apoptotic activity. This study aimed to investigate the active ingredients in A. sinensis with antioxidant properties and whether A. sinensis polysaccharide (ASP) protects H9c2 cells against oxidative and endoplasmic reticulum (ER) stress. Methods The ingredients of A. sinensis and their targets and related pathways were determined using web-based databases. Markers of oxidative stress, cell viability, apoptosis, and ER stress-related signalling pathways were measured in H9c2 cells treated with hydrogen peroxide (H2O2) and ASP. Results The ingredient-pathway-disease network showed that A. sinensis exerted protective effects against oxidative injury through its various active ingredients on regulation of multiple pathways. Subsequent experiments showed that ASP pretreatment significantly decreased H2O2-induced cytotoxicity and apoptosis in H9c2 cells. ASP pretreatment inhibited H2O2-induced reactive oxygen species generation, lactic dehydrogenase release, and malondialdehyde production. ASP exerted beneficial effects by inducing activating transcription factor 6 (ATF6) and increasing ATF6 target protein levels, which in turn attenuated ER stress and increased antioxidant activity. Conclusions Our findings indicate that ASP, a major water-soluble component of A. sinensis, exerts protective effects against H2O2-induced injury in H9c2 cells by activating the ATF6 pathway, thus ameliorating ER and oxidative stress. PMID- 29517943 TI - Isoform-Selective Phosphatidylinositol 3-Kinase Inhibition in Cancer. PMID- 29517942 TI - Effect of alpha-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. AB - Objective To examine the effect of alpha-lipoic acid on neuropathic symptoms in patients with diabetic neuropathy (DN). Methods Patients with painful DN were treated with 600 mg/day alpha-lipoic acid, orally, for 40 days. Neuropathy Symptom Score (NSS), Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ) and douleur neuropathique (DN)4 questionnaire scores were assessed at baseline and day 40. Quality-of-life treatment effects were assessed by Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI) and Sheehan Disability Scale (SDS). Changes in body weight, arterial blood pressure, fasting serum glucose and lipids were also assessed. Results Out of 72 patients included, significant reductions in neuropathic symptoms were shown by reduced NSS, SPNSQ and DN4 scores at day 40 versus baseline. BPI, NPSI, and SDS in terms of work disability, social life disability, and family life disability scores were also significantly reduced. Moreover, 50% of patients rated their health condition as 'very much better' or 'much better' following alpha-lipoic acid administration. Fasting triglyceride levels were reduced, but no difference was found in body weight, blood pressure, fasting glucose, or other lipids at day 40 versus baseline. Conclusions A-lipoic acid administration was associated with reduced neuropathic symptoms and triglycerides, and improved quality of life. PMID- 29517945 TI - Management of Ocular Cicatricial Pemphigoid with Intravenous Immunoglobulin Monotherapy. AB - PURPOSE: To assess the long-term efficacy and safety of IVIg monotherapy in patients with recalcitrant ocular cicatricial pemphigoid (OCP). METHODS: A chart review of all OCP patients seen at the Massachusetts Eye Research and Surgery Institution (MERSI) between 2005 and 2015 was completed. Stage was graded by using the Foster grading system. IVIg infusion was 2g/kg/cycle administered in 3 consecutive days monthly. RESULTS: Of 512 OCP patients, 17 patients (34 eyes) treated with IVIg monotherapy were identified. Seven were female and ten were male. The average age at diagnosis was 60.7-year-old. The follow up time ranged from 12 to 140 months. Twenty-six eyes (76.5%) achieved remission. Nine remission eyes received cataract surgeries, and 2 of them had relapse (22.2%). The other 17 eyes did not undergo ocular surgery and remained in remission. IVIg monotherapy showed high efficacy in stage 1 OCP (7/7, 100%). Ocular surgery can be associated with OCP relapse (Table 2). CONCLUSIONS: IVIg monotherapy is an effective and safe therapy in patients with recalcitrant OCP. Ocular surgery can be associated with OCP relapse. PMID- 29517944 TI - Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates. AB - Alcohol use disorder (AUD) results in increased intestinal permeability, nutrient malabsorption, and increased risk of colorectal cancer (CRC). Our understanding of the mechanisms underlying these morbidities remains limited because studies to date have relied almost exclusively on short-term heavy/binge drinking rodent models and colonic biopsies/fecal samples collected from AUD subjects with alcoholic liver disease (ALD). Consequently, the dose- and site-dependent impact of chronic alcohol consumption in the absence of overt liver disease remains poorly understood. In this study, we addressed this knowledge gap using a nonhuman primate model of voluntary ethanol self-administration where rhesus macaques consume varying amounts of 4% ethanol in water for 12 months. Specifically, we performed RNA-Seq and 16S rRNA gene sequencing on duodenum, jejunum, ileum, and colon biopsies collected from 4 controls and 8 ethanol consuming male macaques. Our analysis revealed that chronic ethanol consumption leads to changes in the expression of genes involved in protein trafficking, metabolism, inflammation, and CRC development. Additionally, we observed differences in the relative abundance of putatively beneficial bacteria as well as those associated with inflammation and CRC. Given that the animals studied in this manuscript did not exhibit signs of ALD or CRC, our data suggest that alterations in gene expression and bacterial communities precede clinical disease and could serve as biomarkers as well as facilitate future studies aimed at developing interventions to restore gut homeostasis. PMID- 29517946 TI - Transcriptomic analysis of Arabidopsis thaliana plants treated with the Ky-9 and Ky-72 histone deacetylase inhibitors. AB - Histone acetylation plays a pivotal role in plant growth and development, and is regulated by the antagonistic relationship between histone acetyltransferase (HAT) and histone deacetylase (HDAC). We previously revealed that some HDAC inhibitors confer high-salinity stress tolerance in plants. In this study, we identified two HDAC inhibitors, namely Ky-9 and Ky-72, which enhanced the high salinity stress tolerance of Arabidopsis thaliana. Ky-9 and Ky-72 are structurally similar chlamydocin analogs. However, the in vitro inhibitory activity of Ky-9 against mammalian HDAC is greater than that of Ky-72. A western blot indicated that Ky-9 and Ky-72 increased the acetylation levels of histone H3, suggesting they exhibit HDAC inhibitory activities in plants. We conducted a transcriptomic analysis to investigate how Ky-9 and Ky-72 enhance high-salinity stress tolerance. Although Ky-9 upregulated the expression of more genes than Ky 72, similar gene expression patterns were induced by both HDAC inhibitors. Additionally, the expression of high-salinity stress tolerance-related genes, such as anthocyanin-related genes and a small peptide-encoding gene, increased by Ky-9 and Ky-72. These data suggest that slight structural differences in chemical side chain between HDAC inhibitors can alter inhibitory effect on HDAC protein leading to influence gene expression, thereby enhancing high-salinity stress tolerance in different extent. PMID- 29517947 TI - Implications of electric potentials applied on a denitrifying process. AB - The effect of three electric potentials (EP) (+104, -187 and -279 mV) applied to the denitrifying process was explored. It was observed that the denitrifying sludge was able to support the oxidation of p-cresol with the application of the EP in the absence of nitrate, but it was unable to drive the denitrification without an organic electron donor. On denitrification, the applied EP uncoupled the oxidative from the reductive process, favoring the p-cresol oxidation over the production of N2. Additionally, biochemical level effects were observed. At +104 and -279 mV potentials, the nitrate and nitrite consumption was affected as well as the p-hydroxybenzoate transformation. However, at -187 mV, effects seemed to occur only on the transport of substrates. This paper presents evidence that denitrification has very characteristic and different physiological behaviors for each EP assayed. PMID- 29517948 TI - The Value of Wellness. PMID- 29517949 TI - Lichenicolous species of Hainesia belong to Phacidiales (Leotiomycetes) and are included in an extended concept of Epithamnolia. AB - The lichenicolous taxa currently included in the genus Hainesia were studied based on the nuclear rDNA (18S, 28S, and internal transcribed spacer [ITS]) genes. The authors found that lichenicolous taxa form a distinct lineage sister to Epiglia gloeocapsae (Phacidiales, Leotiomycetes), only distantly related to the type species of Hainesia (Chaetomellaceae, Helotiales). Owing to morphological similarities, the authors include the lichenicolous species into the previously monotypic genus Epithamnolia. A new species, Epithamnolia rangiferinae, is described, several names are reduced into synonymy, and a key to the species of Epithamnolia is provided. The incorporation of public environmental ITS sequences showed that the closest relatives of these lichenicolous taxa are various endophytic, endolichenic, and soil-inhabiting fungi. PMID- 29517950 TI - Calcium in plant peroxisomes. What for? AB - Peroxisome organelles have a versatile metabolism whose enzymatic content can be modulated by physiological and environment-dependent cellular conditions. They are characterized by a highly active nitro-oxidative metabolism and basic elements (H2O2 and nitric oxide (NO)) with signaling properties. However, new elements have increased our understanding of the connections between peroxisomes and other cellular compartments. Furthermore, the presence of calcium (Ca2+) intensifies communication between different signaling molecules and the relationship of Ca2+ itself with NO and H2O2. PMID- 29517951 TI - Knotless retroperitoneoscopic nephron-sparing surgery for small renal masses: Comparison of bipolar sutureless technique and barbed suture technique. AB - Objective Laparoscopic knot-tying and suturing are the most difficult steps in shortening the warm ischemia time and learning curve of laparoscopic nephron sparing surgery. This study was performed to demonstrate the safety, oncological efficacy, and technical tips of sutureless retroperitoneal laparoscopic nephron sparing surgery (RPNSS). Methods This retrospective study included 78 cases of RPNSS using a sutureless technique and 126 cases of RPNSS using a single-layer barbed self-retaining suture technique performed from December 2012 to December 2016. Results The mean warm ischemia time was significantly shorter in the sutureless technique group than in the barbed self-retaining suture technique group (6.8 vs. 21.1 minutes, respectively). There was no significant difference in the mean age, body mass index, R.E.N.A.L. Nephrometry score, operative time, maximal tumor diameter, intraparenchymal depth, blood loss, operative time, transfusion rate, complication rate, or postoperative hospital stay between the two groups. No open conversion was needed. No positive margins or local recurrence were observed during follow-up. Conclusions The sutureless technique was proven to be safe and oncologically effective and may allow novice laparoscopic surgeons to easily and quickly master RPNSS, a technically difficult procedure. PMID- 29517952 TI - Optimizing stability in AO/OTA 31-A2 intertrochanteric fracture fixation in older patients with osteoporosis. AB - Objectives To compare the functional and radiographic outcomes of InterTAN nail (IT) and proximal femoral nail anti-rotation (PFNA) for managing primary AO/OTA 31-A2 intertrochanteric hip fractures (IHFs) in older osteoporotic patients. Methods Patients aged 60 years or older who received surgical treatment for IHFs (AO/OTA 3.1A2.1-A2.3) with IT or PFNA were retrospectively evaluated. The primary outcome was the postoperative treatment failure rate. The secondary outcome was the Harris Hip Score (HHS). Results A total of 326 osteoporotic cases (326 hips: IT, n = 162; PFNA, n = 164) were assessed with a mean follow-up of 43.5 months (range, 38-48 months). For the entire cohort, the incidence of postoperative treatment failure (periprosthetic fracture and reoperation) was 29/326 (8.9%); the IT-treated cohort (7/162, 4.3%) had a significantly lower rate compared with the PFNA-treated cohort (22/165, 13.3%). The incidence of postoperative periprosthetic fractures was significantly lower in the IT-treated cohort than in the PFNA-treated cohort (2.5% vs 7.9%). The postoperative HHS at the final follow up was not significantly different between the groups. Conclusion IT might show a better outcome in managing osteoporotic AO/OTA 31-A2 IHFs in terms of periprosthetic fracture and reoperation compared with PFNA. PMID- 29517953 TI - Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update Summary. PMID- 29517954 TI - Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. PMID- 29517955 TI - Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline Summary. PMID- 29517956 TI - Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update Summary. PMID- 29517957 TI - Assessing New Diagnoses of HIV Among American Indian/Alaska Natives Served by the Indian Health Service, 2005-2014. AB - OBJECTIVES: The objectives of this study were to use Indian Health Service (IHS) data from electronic health records to analyze human immunodeficiency virus (HIV) diagnoses among American Indian/Alaska Natives (AI/ANs) and to identify current rates and trends that can support data-driven policy implementation and resource allocation for this population. METHODS: We analyzed provider visit data from IHS to capture all AI/AN patients who met a definition of a new HIV diagnosis from 2005 through 2014 by using International Classification of Diseases, Ninth Revision, Clinical Modification codes. We calculated rates and trends of new HIV diagnoses by age, sex, region, and year per 100 000 AI/ANs in the IHS user population. RESULTS: A total of 2273 AI/ANs met the definition of newly diagnosed with HIV from 2005 through 2014, an average annual rate of 15.1 per 100 000 AI/ANs. Most (356/391) IHS health facilities recorded at least 1 new HIV diagnosis. The rate of new HIV diagnoses among males (21.3 per 100 000 AI/ANs) was twice as high as that among females (9.5 per 100 000 AI/ANs; rate ratio = 2.2; 95% confidence interval, 2.1-2.4); by age, rates were highest among those aged 20-54 for males and females. By region, the Southwest region had the highest number (n = 1016) and rate (19.9 per 100 000 AI/ANs) of new HIV diagnoses. Overall annual rates of new HIV diagnoses were stable from 2010 through 2014, although diagnosis rates increased among males ( P < .001) and those aged 15-19 ( P < .001), 45-59 ( P < .001), and 50-54 ( P = .01). CONCLUSIONS: New HIV diagnoses, derived from provider visit data, among AI/ANs were stable from 2010 through 2014. AI/ANs aged 20-54, particularly men, may benefit from increased HIV prevention and screening efforts. Additional services may benefit patients in regions with higher rates of new diagnoses and in remote settings in which reported HIV numbers are low. PMID- 29517958 TI - ATXR2 as a core regulator of de novo root organogenesis. AB - Tissue identity is plastically regulated in plants, and chromatin modifiers/remodelers are main players of cell fate changes. Callus formation is an intriguing example of cell fate transition. Leaf explants can form callus tissues, which resemble lateral root primordium, on callus-inducing medium (CIM). We recently demonstrated that the ARABIDOPSIS TRITHORAX-RELATED 2 (ATXR2) protein, which deposits H3K36me3 at genomic level, regulates callus formation on CIM. Consistent with the role of ATXR2 in conferring root identity, lateral root formation was significantly reduced in atxr2-deficient mutants. Furthermore, atxr2 mutants also displayed defects in adventitious root formation from wounded leaf tissues on hormone-free medium. Our findings indicate that ATXR2 is a genuine regulator of de novo root organogenesis. PMID- 29517959 TI - Estimating physical activity in youth using an ankle accelerometer. AB - This study developed and validated a vector magnitude (VM) two-regression model (2RM) for use with an ankle-worn ActiGraph accelerometer. For model development, 181 youth (mean +/- SD; age, 12.0 +/- 1.5 yr) completed 30 min of supine rest and 2-7 structured activities. For cross-validation, 42 youth (age, 12.6 +/- 0.8 yr) completed approximately 2 hr of unstructured physical activity (PA). PA data were collected using an ActiGraph accelerometer, (non-dominant ankle) and the VM was expressed as counts/5-s. Measured energy expenditure (Cosmed K4b2) was converted to youth METs (METy; activity VO2 divided by resting VO2). A coefficient of variation (CV) was calculated for each activity to distinguish continuous walking/running from intermittent activity. The ankle VM sedentary behavior threshold was <=10 counts/5-s, and a CV<=15 counts/5-s was used to identify walking/running. The ankle VM2RM was within 0.42 METy of measured METy during the unstructured PA (P > 0.05). The ankle VM2RM was within 5.7 min of measured time spent in sedentary, LPA, MPA, and VPA (P > 0.05). Compared to the K4b2, the ankle VM2RM provided similar estimates to measured values during unstructured play and provides a feasible wear location for future studies. PMID- 29517960 TI - A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota. AB - Antibiotics offer an efficient means for managing diseases caused by bacterial pathogens. However, antibiotics are typically broad spectrum and they can indiscriminately kill beneficial microbes in body habitats such as the gut, deleteriously affecting the commensal gut microbiota. In addition, many bacteria have developed or are developing resistance to antibiotics, which complicates treatment and creates significant challenges in clinical medicine. Therefore, there is a real and urgent medical need to develop alternative antimicrobial approaches that will kill specific problem-causing bacteria without disturbing a normal, and often beneficial, gut microbiota. One such potential alternative approach is the use of lytic bacteriophages for managing bacterial infections, including those caused by multidrug-resistant pathogens. In the present study, we comparatively analysed the efficacy of a bacteriophage cocktail targeting Escherichia coli with that of a broad-spectrum antibiotic (ciprofloxacin) using an in vitro model of the small intestine. The parameters examined included (i) the impact on a specific, pre-chosen targeted E. coli strain, and (ii) the impact on a selected non-targeted bacterial population, which was chosen to represent a defined microbial consortium typical of a healthy small intestine. During these studies, we also examined stability of bacteriophages against various pH and bile concentrations commonly found in the intestinal tract of humans. The bacteriophage cocktail was slightly more stable in the simulated duodenum conditions compared to the simulated ileum (0.12 vs. 0.58 log decrease in phage titers, respectively). It was equally effective as ciprofloxacin in reducing E. coli in the simulated gut conditions (2-3 log reduction), but had much milder (none) impact on the commensal, non-targeted bacteria compared to the antibiotic. PMID- 29517962 TI - Temporal Trends (1999-2015) in the Impact Factor of Biomedical Journals Published by US and EU Scientific Societies. AB - OBJECTIVE: The impact factor has emerged as the most popular index of scientific journals' resonance. In this study we aimed to examine the impact factor trends of journals published by scientific bodies in the United States of America (USA) and Europe (EU). METHODS: We randomly chose 11 categories of Journal of Citation Reports and created three research classes: clinical medicine, laboratory medicine, and basic science. The impact factor values for the years 1999-2015 were abstracted, and the impact factor of US and EU journals was studied through the years. RESULTS: A total of 265 journals were included in the final analysis. The impact factor of US journals was higher than that of EU journals throughout the study period. In addition, for both US and EU journals the median impact factor increased throughout the study period. The rate of annual change in the impact factor throughout the study period was lower for US than EU journals (1.85% versus 3.55%, P=0.019). A higher median annual increase was seen in the impact factor during the period 1999-2008 compared to the period 2009-2015 for both US (P<0.001) and EU (P=0.001) journals. In fact, during the second period the US median impact factor value did not show significant changes (P=0.31), while the EU median impact factor continued to increase (P<0.001). CONCLUSION: The impact factor of EU journals increased at a significantly higher rate than and approached that of the US journals during the last 16 years. PMID- 29517963 TI - Non-replacement therapy for haemophilia treatment: fetching the east by the west. PMID- 29517964 TI - The use of viscoelastic haemostatic assays in non-cardiac surgical settings: a systematic review and meta-analysis. PMID- 29517965 TI - A model-based cost-effectiveness analysis of Patient Blood Management. AB - BACKGROUND: Patient blood management (PBM) is a multidisciplinary concept focused on the management of anaemia, minimisation of iatrogenic blood loss and rational use of allogeneic blood products. The aims of this study were: (i) to analyse post-operative outcome in patients with liberal vs restrictive exposure to allogeneic blood products and (ii) to evaluate the cost-effectiveness of PBM in patients undergoing surgery. MATERIALS AND METHODS: A systematic literature review and meta-analysis were performed to compare post-operative complications in predominantly non-transfused patients (restrictive transfusion group) and patients who received one to three units of red blood cells (liberal transfusion group). Outcome measures included sepsis with/without pneumonia, acute renal failure, acute myocardial infarction and acute stroke. In a second step, a health economic model was developed to calculate cost-effectiveness of PBM (PBM-arm vs control-arm) for simulated cohorts of 10,000 cardiac and non-cardiac surgical patients based on the results of the meta-analysis and costs. RESULTS: Out of 478 search results, 22 studies were analysed in the meta-analysis. The pooled relative risk of any complication in the restrictive transfusion group was 0.43 for non-cardiac and 0.34 for cardiac surgical patients. In the simulation model, PBM was related to reduced complications (1,768 vs 1,245) and complication related deaths (411 vs 304) compared to standard care. PBM-related costs of therapy exceeded costs of the control arm by ? 150 per patient. However, total costs, including hospitalisation, were higher in the control-arm for both non cardiac (? 2,885.11) and cardiac surgery patients (? 1,760.69). The incremental cost-effectiveness ratio including hospitalisation showed savings of ? 30,458 (non-cardiac and cardiac surgery patients) for preventing one complication and ? 128,023 (non-cardiac and cardiac surgery patients) for prevention of one complication-related death in the PBM-arm. DISCUSSION: Our results indicate that PBM may be associated with fewer adverse clinical outcomes compared to control management and may, thereby, be cost-effective. PMID- 29517966 TI - Screening and identification of RhD antigen mimic epitopes from a phage display random peptide library for the serodiagnosis of haemolytic disease of the foetus and newborn. AB - BACKGROUND: Identification of RhD antigen epitopes is a key component in understanding the pathogenesis of haemolytic disease of the foetus and newborn. Research has indicated that phage display libraries are useful tools for identifying novel mimic epitopes (mimotopes) which may help to determine antigen specificity. MATERIALS AND METHODS: We selected the mimotopes of blood group RhD antigen by affinity panning a phage display library using monoclonal anti-D. After three rounds of biopanning, positive phage clones were identified by enzyme linked immunosorbent assay (ELISA) and then sent for sequencing and peptides synthesis. Next, competitive ELISA and erythrocyte haemagglutination inhibition tests were carried out to confirm the inhibitory activity of the synthetic peptide. To evaluate the diagnostic performance of the synthetic peptide, a diagnostic ELISA was examined. RESULTS: Fourteen of 35 phage clones that were chosen randomly from the titering plate were considered to be positive. Following DNA sequencing and translation, 11 phage clones were found to represent the same peptide - RMKMLMMLMRRK (P4) - whereas each of the other three clones represented a unique peptide. Through the competitive ELISA and erythrocyte haemagglutination inhibition tests, the peptide (P4) was verified to have the ability to mimic the RhD antigen. The diagnostic ELISA for P4 proved to be sensitive (82.61%) and specific (88.57%). DISCUSSION: This study reveals that the P4 peptide can mimic RhD antigen and paves the way for the development of promising targeted diagnostic and therapeutic platforms for haemolytic disease of the foetus and newborn. PMID- 29517967 TI - The use of viscoelastic haemostatic assays in non-cardiac surgical settings: a systematic review and meta-analysis. AB - BACKGROUND: Thrombelastography (TEG) and rotational thromboelastometry (ROTEM) are viscoelastic haemostatic assays (VHA) which exploit the elastic properties of clotting blood. The aim of this systematic review and meta-analysis was to evaluate the usefulness of these tests in bleeding patients outside the cardiac surgical setting. MATERIALS AND METHODS: We searched the Cochrane Library, MEDLINE, EMBASE and SCOPUS. We also searched clinical trial registries for ongoing and unpublished studies, and checked reference lists to identify additional studies. RESULTS: We found 4 randomised controlled trials (RCTs) that met our inclusion criteria with a total of 229 participants. The sample size was small (from 28 to 111 patients) and the follow-up periods very heterogenous (from 4 weeks to 3 years). Pooled data from the 3 trials reporting on mortality (199 participants) do not show any effect of the use of TEG on mortality as compared to standard monitoring (based on the average treatment effect from a fixed effects model): Risk Ratio (RR) 0.71; 95% Confidence Interval (CI): 0.43 to 1.16. Likewise, the use of VHA does not reduce the need for red blood cells (mean difference -0.64; 95% CI: -1.51 to 0.23), platelet concentrates (mean difference 1.12; 95% CI: -3.25 to 1.02), and fresh frozen plasma (mean difference -0.91; 95% CI: -2.02 to 0.19) transfusion. The evidence on mortality and other outcomes was uncertain (very low-certainty evidence, down-graded due to risk of biases, imprecision, and inconsistency). CONCLUSIONS: Overall, the certainty of the evidence provided by the trials was too low for us to be certain of the benefits and harms of viscoelastic haemostatic assay in non-cardiac surgical settings. More, larger, and better-designed RCTs should be carried out in this area. PMID- 29517968 TI - Intravenous iron administration for post-operative anaemia management after colorectal cancer surgery in clinical practice: a single-centre, retrospective study. AB - BACKGROUND: Evidence on the role of intravenous iron (IVI) supplementation after colorectal cancer (CRC) surgery is rather scant. This study was aimed at assessing the benefit of post-operative IVI administration after elective CRC surgery at our institution. MATERIALS AND METHODS: This was a single-centre, retrospective observational study including all patients who underwent CRC surgery during 2014. Anaemia was defined as a haemoglobin (Hb) <13 g/dL, regardless of gender. Anaemic patients received 200 mg IVI up to three times a week to cover iron deficiency (IVI group). Those who did not receive IVI were placed on standard care (NIVI group). The primary outcome was the proportion of anaemic patients on post-operative day (POD)1 and POD30. Secondary outcomes included Hb changes from POD1 to POD30, transfusion requirements and complication rates. RESULTS: Of the 159 patients studied, 139 (87%) presented with anaemia: 47 (34%) of these received post-operative IVI and 92 (66%) did not. Patients in the IVI group had lower POD1 Hb levels compared to those in the NIVI group (p=0.001). On POD30, only 103 had their Hb measured (34 IVI, 69 NIVI). Anaemia was more prevalent and more severe among the patients in the IVI group (p=0.027), despite their greater increment in Hb (2.0+/-1.5 g/dL vs 1.1+/-1.2 g/dL; p=0.001). Eleven patients needed post-operative transfusions (7 IVI, 4 NIVI; p=0.044). There were no differences in post-operative complication rates between the groups. No IVI related adverse events were recorded DISCUSSION: Compared with standard care, post-operative IVI administration to anaemic patients improved the recovery of Hb levels at POD30, without increasing post-operative complications. PMID- 29517969 TI - ABO blood groups and psychiatric disorders: a Croatian study. AB - BACKGROUND: The prevalence of ABO alleles is different in different populations, and many studies have shown a correlation between the occurrences of some diseases and different genotypes of ABO blood groups. The aim of this study was to determine whether there is a significant association between psychiatric syndromes and ABO blood groups. MATERIALS AND METHODS: This case-control study involved 156 psychiatric patients and 303 healthy, unrelated, voluntary blood donors. Genomic DNA was isolated from blood on a QIAcube device using a QIAamp DNA Blood mini QIAcube kit. ABO genotyping on five basic ABO alleles was performed using allele-specific polymerase chain reaction analysis. RESULTS: Compared with healthy subjects, a significantly higher proportion of psychiatric patients had AB blood group (chi2=9.359, df=3, p=0.025) and, accordingly, a significantly higher incidence of A1B genotype (chi2=8.226, df=3, p=0.042). The odds ratio showed that psychiatric disorders occur almost three times more frequently in carriers of AB group compared to other blood groups. However, no statistically significant difference was found in the distribution of ABO blood groups among patients with different psychiatric diagnoses. Likewise, no correlations were found between ABO blood groups and other characteristics of the psychiatric patients (sex, psychiatric heredity, somatic comorbidity, suicidality). CONCLUSIONS: The results of this study support the hypothesis of an association between psychiatric disorders and ABO blood groups. The probability is that psychiatric disorders will occur almost three times more frequently in carriers of AB group compared to other ABO blood groups in the Croatian population. PMID- 29517970 TI - SMIM1 polymorphisms in a donor population from southeast Brazil and their correlation with VEL expression. AB - BACKGROUND: Vel is a high frequency blood group antigen and its alloantibody is involved in haemolytic transfusion reactions. After elucidation of the molecular basis of the Vel-negative phenotype defined by a 17-base pair deletion in SMIM1, genotyping has been the technique of choice to identify the Vel-negative phenotype, and molecular investigations have contributed to explain Vel expression variability. The present study was aimed at screening for Vel negative blood donors and characterising the genetic changes found in Brazilian donors with altered Vel expression. MATERIALS AND METHODS: Molecular screening for the SMIM1*64_80del allele was performed in 1,595 blood donor samples using a SNaPshot protocol previously standardised in our laboratory. Four hundred donor samples were also submitted to serological screening using a polyclonal anti-Vel from our inventory. Samples with variability in antigen strength were selected for SMIM1 sequencing. RESULTS: No homozygous SMIM1*64_80del allele was found and the SMIM1*64_80del allele frequency was 1.01%. Different patterns of reactivity were observed in serological testing varying from negative to 3+. Through sequencing analysis we highlighted two polymorphisms: rs1175550 and rs6673829. The minor G allele of rs1175550 was found in 16/20 samples reacting 3+, while the major A allele was found in 21/23 samples reacting 2+. Regarding rs6673829, the minor A allele was present in 14/23 and 3/20 samples reacting 2+ and 3+ respectively. DISCUSSION: We included molecular VEL screening in a previously standardised SNaPshot protocol, which besides enabling detection of Vel-negative donors, also searches for eight other rare blood types. Additionally, the present study demonstrated that although the SMIM1*64_80del allele is responsible for some variation of Vel phenotype in this donor population, Vel expression is also controlled by molecular changes in SMIM1 intron 2. PMID- 29517971 TI - Non-factor replacement therapy for haemophilia: a current update. AB - One of the most challenging issues facing us in the treatment of haemophilia is the development of alloantibodies against infused factor VIII (FVIII) or factor IX (FIX). Inhibitors render factor replacement therapy ineffective, exposing patients to an unacceptably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in a new class of therapeutic agents which act by enhancing coagulation (i.e. emicizumab) or inhibiting anticoagulant pathways (i.e. fitusiran and concizumab). This review will focus on these innovative therapies, providing an update on their current stage of clinical development. PMID- 29517972 TI - The post-operative management of anaemia: more efforts are needed. PMID- 29517973 TI - Molecular immunohaematology round table discussions at the AABB Annual Meeting, Orlando 2016. PMID- 29517974 TI - High resolution melting for F9 gene mutation analysis in patients with haemophilia B. AB - BACKGROUND: Since 2001, we have used conformation sensitive gel electrophoresis (CSGE) as our first choice for F9 gene mutation screening, leading to the identification of about 300 mutations causing haemophilia B (HB). To circumvent the disadvantages of CSGE, we recently evaluated high-resolution melting analysis (HRM), which represents the next-generation mutation scanning technology. MATERIALS AND METHODS: In order to explore and validate HRM as a new screening method, we analysed 26 HB patients with previous CSGE-detected mutations, 22 patients with CSGE-undetectable mutations and 13 HB patients who had not been previously investigated. RESULTS: All 61 investigated samples, including the previously investigated and not previously investigated samples, proved to be HRM positive, with the new screening method showing good efficiency and higher sensitivity than the previously used method. Mixing normal and unknown DNA to generate heterozygote conditions proved an excellent strategy to push the detection performance to its maximum. DISCUSSION: Mutation scanning by HRM analysis seems to be ideal in our context because it is rapid, cheap and capable of detecting the vast majority of mutations in HB patients. Nevertheless, to improve the detection ability of this scanning technology, it is recommended to start with a good strategy, based on good quality samples and optimised polymerase chain reaction amplification parameters, especially regarding primers and length of the amplicons. PMID- 29517976 TI - Notes on Test and Estimation in Comparison of Three Treatments under A Simple Carry-Over Three-Period Model. AB - Under the three-treatment three-period crossover design with simple carry-over effects, we derive the least-squares estimators for period effects, treatment effects and carry-over effects, as well as their covariance matrix in closed and explicit expressions. Using Monte Carlo simulation, we compare the test procedure adjusting carry-over with that ignoring carry-over with respect to Type I error and power. We further compare interval estimators adjusting carry-over with those ignoring carry-over with respect to the coverage probability and the average length. When the variation of responses within patients is small, the test procedure and interval estimators ignoring carry-over can lose accuracy in the presence of carry-over effects. When the variation of responses within patients is large, this loss of accuracy may become small or even minimal. We note that the loss of efficiency due to the adjustment of carry-over under the simple carry over three-period crossover design is moderate, and is much less than that found for a two-period crossover design. We use the double-blind three-period crossover trial comparing formoterol solution aerosol and salbutamol suspension aerosol with a placebo for patients suffering from exercise-induced asthma on the forced expiratory volume in one second (FEV1) to illustrate the use of test procedures and interval estimators discussed here. PMID- 29517977 TI - Nanospikes functionalization as a universal strategy to disperse hydrophilic particles in non-polar media. AB - Dispersion of hydrophilic particles in non-polar media has many important applications yet remains difficult. Surfactant or amphiphilic functionalization was conventionally applied to disperse particles but is highly dependent on the particle/solvent system and may induce unfavorable effects and impact particle hydrophilic nature. Recently 2 MUm size polystyrene microbeads coated with ZnO nanospikes have been reported to display anomalous dispersity in phobic media without using surfactant or amphiphilic functionalization. However, due to the lack of understanding whether this phenomenon was applicable to a wider range of conditions, little application has been derived from it. Here the anomalous dispersity phenomenons of hydrophilic microparticles covered with nanospikes were systematically assessed at various conditions including different particle sizes, material compositions, particle morphologies, solvent hydrophobicities, and surface polar groups. Microparticles were functionalized with nanospikes through hydrothermal route, followed by dispersity test in hydrophobic media. The results suggest nanospikes consistently prevent particle aggregation in various particle or solvent conditions, indicating the universal applicability of the anomalous dispersion phenomenons. This work provides insight on the anomalous dispersity of hydrophilic particles in various systems and offers potential application to use this method for surfactant-free dispersions. PMID- 29517975 TI - Temporal transitions of spontaneous brain activity. AB - Spontaneous brain activity, typically investigated using resting-state fMRI (rsfMRI), provides a measure of inter-areal resting-state functional connectivity (RSFC). Although it has been established that RSFC is non-stationary, previous dynamic rsfMRI studies mainly focused on revealing the spatial characteristics of dynamic RSFC patterns, but the temporal relationship between these RSFC patterns remains elusive. Here we investigated the temporal organization of characteristic RSFC patterns in awake rats and humans. We found that transitions between RSFC patterns were not random but followed specific sequential orders. The organization of RSFC pattern transitions was further analyzed using graph theory, and pivotal RSFC patterns in transitions were identified. This study has demonstrated that spontaneous brain activity is not only nonrandom spatially, but also nonrandom temporally, and this feature is well conserved between rodents and humans. These results offer new insights into understanding the spatiotemporal dynamics of spontaneous activity in the mammalian brain. PMID- 29517979 TI - Refining neonatal therapies and monitoring strategies. PMID- 29517978 TI - TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury. AB - Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatment of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We used the Fah-/- mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes. We uncovered upstream regulators and important signaling pathways that are highly enriched in genes changed in regenerating hepatocytes. Specifically, we found that glutathione metabolism, particularly the gene Slc7a11 encoding the cystine/glutamate antiporter (xCT), is massively upregulated during liver regeneration. Furthermore, we show that Slc7a11 overexpression in hepatocytes enhances, and its suppression inhibits, repopulation following toxic injury. TRAP seq allows cell type-specific expression profiling in repopulating hepatocytes and identified xCT, a factor that supports antioxidant responses during liver regeneration. xCT has potential as a therapeutic target for enhancing liver regeneration in response to liver injury. PMID- 29517980 TI - Role of hypertension in progression of chronic kidney disease in children. AB - PURPOSE OF REVIEW: Hypertension is an independent risk factor for progression of chronic kidney disease (CKD) in children. Children with early CKD develop hypertension secondary to renal disease. This review aims to highlight recent advances that help us better understand the current role of hypertension in progression of CKD in children. RECENT FINDINGS: There is increasing evidence that children with CKD who have hypertension develop early atherosclerosis and cardiac adaptive changes. Emerging data from pediatric research in CKD show that elevated blood pressure is associated with the presence of abnormal subclinical markers of cardiovascular disease including increased carotid intima-media thickness, pulse wave velocity and left ventricular mass index. There is also some evidence that these early cardiovascular changes are reversible. Twenty-four hour ambulatory blood pressure monitoring (ABPM) is recommended in children with CKD by the American Academy of Pediatrics to diagnose hypertension. SUMMARY: Hypertension is associated with subclinical cardiovascular disease in children with CKD. Early diagnosis of hypertension by ABPM and identification of subclinical cardiovascular changes provide a window for intervention, which may reverse early cardiovascular disease, thereby delaying dialysis and improving cardiovascular morbidity and mortality. PMID- 29517981 TI - Pain management in neurocritical care; an update. AB - PURPOSE OF REVIEW: Pain management in neurocritical care is a subject often avoided because of concerns over the side-effects of analgesics and the potential to cause additional neurological injury with treatment. The sedation and hypercapnia caused by opioids have been feared to mask the neurological examination and contribute to elevations in intracranial pressure. Nevertheless, increasing attention to patient satisfaction has sparked a resurgence in pain management. As opioids have remained at the core of analgesic therapy, the increasing attention to pain has contributed to a growing epidemic of opioid dependence. In this review, we summarize the most recent literature regarding opioids and their alternatives in the treatment of acute pain in patients receiving neurocritical care. RECENT FINDINGS: Studies on pain management in neurocritical care continue to explore nonopioid analgesics as part of a multimodal strategy aimed at decreasing overall opioid consumption. Agents including local anesthetics, acetaminophen, ketamine, gabapentinoids, and dexmedetomidine continue to demonstrate efficacy. In addition, the prolonged longitudinal course of many recent trials has also revealed more about the transition from acute to chronic pain following hospitalization. SUMMARY: In an era of increasing attention to patient satisfaction mitigated by growing concerns over the harms imposed by opioids, alternative analgesic therapies are being investigated with promising results. PMID- 29517982 TI - DNA methylation in human lipid metabolism and related diseases. AB - PURPOSE OF REVIEW: It is becoming increasingly evident that epigenetic mechanisms, particularly DNA methylation, play a role in the regulation of blood lipid levels and lipid metabolism-linked phenotypes and diseases. RECENT FINDINGS: Recent genome-wide methylation and candidate gene studies of blood lipids have highlighted several robustly replicated methylation markers across different ethnicities. Furthermore, many of these lipid-related CpG sites associated with blood lipids are also linked to lipid-related phenotypes and diseases. Integrating epigenome-wide association studies (EWAS) data with other layers of molecular data such as genetics or the transcriptome, accompanied by relevant statistical methods (e.g. Mendelian randomization), provides evidence for causal relationships. Recent data suggest that epigenetic changes can be consequences rather than causes of dyslipidemia. There is sparse information on many lipid classes and disorders of lipid metabolism, and also on the interplay of DNA methylation with other epigenetic layers such as histone modifications and regulatory RNAs. SUMMARY: The current review provides a literature overview of epigenetic modifications in lipid metabolism and other lipid-related phenotypes and diseases focusing on EWAS of DNA methylation from January 2016 to September 2017. Recent studies strongly support the importance of epigenetic modifications, such as DNA methylation, in lipid metabolism and related diseases for relevant biological insights, reliable biomarkers, and even future therapeutics. PMID- 29517983 TI - A Removable Long-arm Soft Cast to Treat Nondisplaced Pediatric Elbow Fractures: A Randomized, Controlled Trial. AB - BACKGROUND: The ideal type of immobilization for nondisplaced pediatric elbow fractures has not been established. We hypothesized that the use of a long-arm cylinder made of soft cast material will result in similar outcomes to those obtained with a traditional long-arm hard cast. METHODS: We randomly assigned 100 consecutive children who presented with a closed, nondisplaced, type I supracondylar humeral fracture or an occult, closed, acute elbow injury, to 1 of 2 groups: group A (n=50) received a long-arm, traditional fiberglass (hard) cast. Group B (n=50) received a long-arm, soft fiberglass cast. After 4 weeks, the cast was removed in group A by a member of our staff using a cast saw, and in group B by one of the patient's parents by rolling back the soft fiberglass material. We compared the amount of fracture displacement and/or angulation, recovery of range of motion, elbow pain, and patient satisfaction. RESULTS: There were no instances of unplanned removal of the cast by the patient or parent. No evidence of fracture displacement or angulation was seen in either group. The final carrying angle of the affected elbow was nearly identical of that of the normal, contralateral elbow in both groups (P=0.64). At the latest follow-up appointment, elbows in groups A and B had a similar mean arc of motion (156 vs. 154 degrees; P=0.45), and had achieved identical relative arc of motion of 99.6% and 99.5% of that of the normal, contralateral side, respectively (P=0.94). Main pain scores were low and comparable over the study period. All patients in both groups reported the highest rate of satisfaction at the eighth week of follow-up. CONCLUSIONS: The results indicate that children with nondisplaced supracondylar humeral fractures can be successfully managed with the use of a removable long arm soft cast, maintaining fracture alignment and resulting in comparable rates of range of motion, pain, and patient satisfaction. The use of a removable immobilization that can reliably maintain fracture alignment and result in similar outcomes, while minimizing the risk of noncompliance, could be advantageous. Although we elected to remove the soft cast during a scheduled follow-up, it appears that such immobilization could be removed easily and safely at home, potentially resulting in a lower number of patient visits, decreased health care costs, and higher patient/parent satisfaction. LEVEL OF EVIDENCE: Level I. PMID- 29517984 TI - Single Center Experience of a New Endoscopic Clip in Managing Nonvariceal Upper Gastrointestinal Bleeding. AB - BACKGROUND: To assess the safety and efficacy of the Instinct clip in the acute endoscopic treatment of upper gastrointestinal bleeding (UGIB). MATERIALS AND METHODS: This is the first large series reporting this clip in achieving hemostasis. A retrospective descriptive chart review was performed on patients presenting with recent overt GI bleeding treated with endoclip therapy at Mount Sinai Beth Israel Medical Center between May 2013 and January 2016. Results are expressed in absolute numbers, percentages, and trends. RESULTS: In total, 178 consecutive patients with UGIB were included. Source of bleeding was identified as duodenal ulcer (29.2%), gastric ulcer (22.5%), gastro-esophageal junction tear (8.4%), anastomosis (5.6%), erosive gastropathy (5.6%), Dieulafoy (5.1%), gastric polyp (4.5%), postendoscopic procedure (3.9%), angioectasia (3.4%), esophageal ulcer (2.8%), benign duodenal mass (2.8%), peg tube site (2.3%), gastric neoplasm (1.7%), esophagitis (1.1%), and small bowel ulcer (1.1%). Lesions demonstrated active bleeding in 47.5% (11.3% spurting and 36.2% oozing) and nonbleeding lesions in 52.5% (25.0% visible vessel, 11.9% hematin in ulcer base, 10.0% adherent clot, 5.6% flat spot). Initial hemostasis was achieved in 96.6%. Additional methods were used in 24.1% (argon plasma coagulation and epinephrine injection in 21.3%, surgery in 0.6%, and interventional radiology in 2.2%). There were no adverse events. In-hospital rebleeding was 7.3% and 3.9% presented with rebleeding within 30 days. Average procedure duration was 22.9 minutes and average length of hospital stay was 11.3 days. CONCLUSIONS: The Instinct clip, when used for UGIB, seems to be safe and effective with similar rebleeding rates compared with other modalities. PMID- 29517985 TI - The NLS-Based Nonlinear Grey Multivariate Model for Forecasting Pollutant Emissions in China. AB - The relationship between pollutant discharge and economic growth has been a major research focus in environmental economics. To accurately estimate the nonlinear change law of China's pollutant discharge with economic growth, this study establishes a transformed nonlinear grey multivariable (TNGM (1, N)) model based on the nonlinear least square (NLS) method. The Gauss-Seidel iterative algorithm was used to solve the parameters of the TNGM (1, N) model based on the NLS basic principle. This algorithm improves the precision of the model by continuous iteration and constantly approximating the optimal regression coefficient of the nonlinear model. In our empirical analysis, the traditional grey multivariate model GM (1, N) and the NLS-based TNGM (1, N) models were respectively adopted to forecast and analyze the relationship among wastewater discharge per capita (WDPC), and per capita emissions of SO2 and dust, alongside GDP per capita in China during the period 1996-2015. Results indicated that the NLS algorithm is able to effectively help the grey multivariable model identify the nonlinear relationship between pollutant discharge and economic growth. The results show that the NLS-based TNGM (1, N) model presents greater precision when forecasting WDPC, SO2 emissions and dust emissions per capita, compared to the traditional GM (1, N) model; WDPC indicates a growing tendency aligned with the growth of GDP, while the per capita emissions of SO2 and dust reduce accordingly. PMID- 29517987 TI - Conversion of Squid Pens to Chitosanases and Proteases via Paenibacillus sp. TKU042. AB - Chitosanases and proteases have received much attention due to their wide range of applications. Four kinds of chitinous materials, squid pens, shrimp heads, demineralized shrimp shells and demineralized crab shells, were used as the sole carbon and nitrogen (C/N) source to produce chitosanases, proteases and alpha glucosidase inhibitors (alphaGI) by four different strains of Paenibacillus. Chitosanase productivity was highest in the culture supernatants using squid pens as the sole C/N source. The maximum chitosanase activity of fermented squid pens (0.759 U/mL) was compared to that of fermented shrimp heads (0.397 U/mL), demineralized shrimp shells (0.201 U/mL) and demineralized crab shells (0.216 U/mL). A squid pen concentration of 0.5% was suitable for chitosanase, protease and alphaGI production via Paenibacillus sp. TKU042. Multi-purification, including ethanol precipitation and column chromatography of Macro-Prep High S as well as Macro-Prep DEAE (diethylaminoethyl), led to the isolation of Paenibacillus sp. TKU042 chitosanase and protease with molecular weights of 70 and 35 kDa, respectively. For comparison, 16 chitinolytic bacteria, including strains of Paenibacillus, were investigated for the production of chitinase, exochitinase, chitosanase, protease and alphaGI using two kinds of chitinous sources. PMID- 29517988 TI - Electrospun F18 Bioactive Glass/PCL-Poly (epsilon-caprolactone)-Membrane for Guided Tissue Regeneration. AB - Barrier membranes that are used for guided tissue regeneration (GTR) therapy usually lack bioactivity and the capability to promote new bone tissue formation. However, the incorporation of an osteogenic agent into polymeric membranes seems to be the most assertive strategy to enhance their regenerative potential. Here, the manufacturing of composite electrospun membranes made of poly (epsilon caprolactone) (PCL) and particles of a novel bioactive glass composition (F18) is described. The membranes were mechanically and biologically tested with tensile strength tests and tissue culture with MG-63 osteoblast-like cell line, respectively. The PCL-F18 composite membranes demonstrated no increased cytotoxicity and an enhanced osteogenic potential when compared to pure PCL membranes. Moreover, the addition of the bioactive phase increased the membrane tensile strength. These preliminary results suggested that these new membranes can be a strong candidate for small bone injuries treatment by GTR technique. PMID- 29517986 TI - Evolution and Stress Responses of Gossypium hirsutum SWEET Genes. AB - The SWEET (sugars will eventually be exported transporters) proteins are sugar efflux transporters containing the MtN3_saliva domain, which affects plant development as well as responses to biotic and abiotic stresses. These proteins have not been functionally characterized in the tetraploid cotton, Gossypium hirsutum, which is a widely cultivated cotton species. In this study, we comprehensively analyzed the cotton SWEET gene family. A total of 55 putative G. hirsutumSWEET genes were identified. The GhSWEET genes were classified into four clades based on a phylogenetic analysis and on the examination of gene structural features. Moreover, chromosomal localization and an analysis of homologous genes in Gossypium arboreum, Gossypium raimondii, and G. hirsutum suggested that a whole-genome duplication, several tandem duplications, and a polyploidy event contributed to the expansion of the cotton SWEET gene family, especially in Clade III and IV. Analyses of cis-acting regulatory elements in the promoter regions, expression profiles, and artificial selection revealed that the GhSWEET genes were likely involved in cotton developmental processes and responses to diverse stresses. These findings may clarify the evolution of G. hirsutum SWEET gene family and may provide a foundation for future functional studies of SWEET proteins regarding cotton development and responses to abiotic stresses. PMID- 29517989 TI - Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX. AB - Hypoxia is a prominent feature of the tumor microenvironment (TME) and cancer cells must dynamically adapt their metabolism to survive in these conditions. A major consequence of metabolic rewiring by cancer cells in hypoxia is the accumulation of acidic metabolites, leading to the perturbation of intracellular pH (pHi) homeostasis and increased acidosis in the TME. To mitigate the potentially detrimental consequences of an increasingly hypoxic and acidic TME, cancer cells employ a network of enzymes and transporters to regulate pH, particularly the extracellular facing carbonic anhydrase IX (CAIX) and CAXII. In addition to the role that these CAs play in the regulation of pH, recent proteome wide analyses have revealed the presence of a complex CAIX interactome in cancer cells with roles in metabolite transport, tumor cell migration and invasion. Here, we explore the potential contributions of these interactions to the metabolic landscape of tumor cells in hypoxia and discuss the role of CAIX as a hub for the coordinated regulation of metabolic, migratory and invasive processes by cancer cells. We also discuss recent work targeting CAIX activity using highly selective small molecule inhibitors and briefly discuss ongoing clinical trials involving SLC-0111, a lead candidate small molecule inhibitor of CAIX/CAXII. PMID- 29517990 TI - Effects of 12-Week Low or Moderate Dietary Acid Intake on Acid-Base Status and Kidney Function at Rest and during Submaximal Cycling. AB - Prolonged effects of dietary acid intake on acid-base status and kidney function have not yet been studied in an intervention study in healthy subjects. Dietary acid load can be estimated by calculating the potential renal acid load (PRAL) of foods. Effects of low-PRAL and moderate-PRAL diets on acid-base status and kidney function were investigated during a 12-week exercise training period. Healthy, 20 50-year-old men (n = 21) and women (n = 25) participated in the study and were randomly divided into low-PRAL and moderate-PRAL groups. Before (PRE), mid-phase (MID) and after the intervention (POST), the subjects participated in measurement sessions, where a 12-h urine sample and fasting blood samples were collected, and a submaximal cycle ergometer test was performed. Net acid excretion was significantly lower after 12 weeks of the low-PRAL diet as compared to the moderate-PRAL diet, both in men and women. In low-PRAL females, capillary pH and bicarbonate were significantly higher at 75% of VO2max at POST as compared to PRE. Glomerular filtration rate decreased over the study period in moderate-PRAL men and women. The results of the present study suggest that an acidogenic diet and regularly training together may increase the acidic load of the body and start to impair the kidney function in recreationally active subjects. PMID- 29517991 TI - A Reliable Methodology for Determining Seed Viability by Using Hyperspectral Data from Two Sides of Wheat Seeds. AB - This study investigated the possibility of using visible and near-infrared (VIS/NIR) hyperspectral imaging techniques to discriminate viable and non-viable wheat seeds. Both sides of individual seeds were subjected to hyperspectral imaging (400-1000 nm) to acquire reflectance spectral data. Four spectral datasets, including the ventral groove side, reverse side, mean (the mean of two sides' spectra of every seed), and mixture datasets (two sides' spectra of every seed), were used to construct the models. Classification models, partial least squares discriminant analysis (PLS-DA), and support vector machines (SVM), coupled with some pre-processing methods and successive projections algorithm (SPA), were built for the identification of viable and non-viable seeds. Our results showed that the standard normal variate (SNV)-SPA-PLS-DA model had high classification accuracy for whole seeds (>85.2%) and for viable seeds (>89.5%), and that the prediction set was based on a mixed spectral dataset by only using 16 wavebands. After screening with this model, the final germination of the seed lot could be higher than 89.5%. Here, we develop a reliable methodology for predicting the viability of wheat seeds, showing that the VIS/NIR hyperspectral imaging is an accurate technique for the classification of viable and non-viable wheat seeds in a non-destructive manner. PMID- 29517992 TI - Multi-Scale Assessments of Cardiac Electrophysiology Reveal Regional Heterogeneity in Health and Disease. AB - The left and right ventricles of the four-chambered heart have distinct developmental origins and functions. Chamber-specific developmental programming underlies the differential gene expression of ion channel subunits regulating cardiac electrophysiology that persists into adulthood. Here, we discuss regional specific electrical responses to genetic mutations and cardiac stressors, their clinical correlations, and describe many of the multi-scale techniques commonly used to analyze electrophysiological regional heterogeneity. PMID- 29517993 TI - Proviruses with Long-Term Stable Expression Accumulate in Transcriptionally Active Chromatin Close to the Gene Regulatory Elements: Comparison of ASLV-, HIV- and MLV-Derived Vectors. AB - Individual groups of retroviruses and retroviral vectors differ in their integration site preference and interaction with the host genome. Hence, immediately after infection genome-wide distribution of integrated proviruses is non-random. During long-term in vitro or persistent in vivo infection, the genomic position and chromatin environment of the provirus affects its transcriptional activity. Thus, a selection of long-term stably expressed proviruses and elimination of proviruses, which have been gradually silenced by epigenetic mechanisms, helps in the identification of genomic compartments permissive for proviral transcription. We compare here the extent and time course of provirus silencing in single cell clones of the K562 human myeloid lymphoblastoma cell line that have been infected with retroviral reporter vectors derived from avian sarcoma/leukosis virus (ASLV), human immunodeficiency virus type 1 (HIV) and murine leukaemia virus (MLV). While MLV proviruses remain transcriptionally active, ASLV proviruses are prone to rapid silencing. The HIV provirus displays gradual silencing only after an extended time period in culture. The analysis of integration sites of long-term stably expressed proviruses shows a strong bias for some genomic features-especially integration close to the transcription start sites of active transcription units. Furthermore, complex analysis of histone modifications enriched at the site of integration points to the accumulation of proviruses of all three groups in gene regulatory segments, particularly close to the enhancer loci. We conclude that the proximity to active regulatory chromatin segments correlates with stable provirus expression in various retroviral species. PMID- 29517994 TI - Fatty Acids Dietary Supplements Exert Anti-Inflammatory Action and Limit Ganglion Cell Degeneration in the Retina of the EAE Mouse Model of Multiple Sclerosis. AB - Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON) and is an initial symptom of multiple sclerosis (MS). Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC) loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG), were found to develop inflammation, Muller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM), a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration. Immunolabeling of retinal whole mounts with a Brn3a antibody demonstrated drastic RGC loss. Dietary supplementation with Neuro FAG (nFAG(r)), a balanced mixture of fatty acids (FAs), counteracted inflammatory and gliotic processes in the retina. In contrast, infiltration of macrophages and their production of OCM remained at elevated levels thus eventually preserving OCM trophic activity. In addition, the diet supplement with nFAG exerted a neuroprotective effect preventing MOG-induced RGC death. In conclusion, these data suggest that the balanced mixture of FAs may represent a useful form of diet supplementation to limit inflammatory events and death of RGCs associated to optic neuritis. This would occur without affecting macrophage infiltration and the release of OCM thus favoring the maintenance of OCM neuroprotective role. PMID- 29517995 TI - Iodine Intake Estimation from the Consumption of Instant Noodles, Drinking Water and Household Salt in Indonesia. AB - The objective of this study was to assess the contribution of iodine intake from iodised household salt, iodised salt in instant noodles, and iodine in ground water in five regions of Indonesia. Secondary data analysis was performed using the 2013 Primary Health Research Survey, the 2014 Total Diet Study, and data from food industry research. Iodine intake was estimated among 2719 children, 10-12 years of age (SAC), 13,233 women of reproductive age (WRA), and 578 pregnant women (PW). Combined estimated iodine intake from the three stated sources met 78%, 70%, and 41% of iodine requirements for SAC, WRA and PW, respectively. Household salt iodine contributed about half of the iodine requirements for SAC (49%) and WRA (48%) and a quarter for PW (28%). The following variations were found: for population group, the percentage of estimated dietary iodine requirements met by instant noodle consumption was significantly higher among SAC; for region, estimated iodine intake was significantly higher from ground water for WRA in Java, and from household salt for SAC and WRA in Kalimantan and Java; and for household socio-economic status (SES), iodine intake from household salt was significantly higher in the highest SES households. Enforcement of clear implementing regulations for iodisation of household and food industry salt will promote optimal iodine intake among all population groups with different diets. PMID- 29517997 TI - Sensitive Detection of 8-Nitroguanine in DNA by Chemical Derivatization Coupled with Online Solid-Phase Extraction LC-MS/MS. AB - 8-Nitroguanine (8-nitroG) is a major mutagenic nucleobase lesion generated by peroxynitrite during inflammation and has been used as a potential biomarker to evaluate inflammation-related carcinogenesis. Here, we present an online solid phase extraction (SPE) LC-MS/MS method with 6-methoxy-2-naphthyl glyoxal hydrate (MTNG) derivatization for a sensitive and precise measurement of 8-nitroG in DNA. Derivatization optimization revealed that an excess of MTNG is required to achieve complete derivatization in DNA hydrolysates (MTNG: 8-nitroG molar ratio of 3740:1). The use of online SPE effectively avoided ion-source contamination from derivatization reagent by washing away all unreacted MTNG before column chromatography and the ionization process in mass spectrometry. With the use of isotope-labeled internal standard, the detection limit was as low as 0.015 nM. Inter- and intraday imprecision was <5.0%. This method was compared to a previous direct LC-MS/MS method without derivatization. The comparison showed an excellent fit and consistency, suggesting that the present method has satisfactory effectiveness and reliability for 8-nitroG analysis. This method was further applied to determine the 8-nitroG in human urine. 8-NitroG was not detectable using LC-MS/MS with derivatization, whereas a significant false-positive signal was detected without derivatization. It highlights the use of MTNG derivatization in 8-nitroG analysis for increasing the method specificity. PMID- 29517996 TI - From the Psychiatrist's Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish. AB - Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype in disease-relevant tissues and cell types. Neural cells generated from BD-specific iPSCs are thought to capture associated genetic risk factors, known and unknown, and to allow the analysis of their effects on cellular and molecular phenotypes. Interestingly, an increasing number of studies on BD derived iPSCs report distinct alterations in neural patterning, postmitotic calcium signaling, and neuronal excitability. Importantly, these alterations are partly normalized by lithium, a first line treatment in BD. In light of these exciting findings, we discuss current challenges to the field of iPSC-based disease modelling and future steps to be taken in order to fully exploit the potential of this approach for the investigation of BD and the development of new therapies. PMID- 29517998 TI - Low Molecular Weight Chitosan-Coated PLGA Nanoparticles for Pulmonary Delivery of Tobramycin for Cystic Fibrosis. AB - (1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to LMWC were prepared: control (0:0.50), F0 (1:0.25), F0.5 (1:0.5), and F1 (1:1). (3) Results: The results showed that the size of the particles increased from 220.7 nm to 575.77 nm as the concentration of LMWC used in the formulation increased. The surface charge was also affected by the amount of LMWC, where uncoated-PLGA nanoparticles had negative charges (-2.8 mV), while coated-PLGA NPs had positive charges (+33.47 to +50.13 mV). SEM confirmed the size and the spherical homogeneous morphology of the NPs. Coating the NPs with LMWC enhanced the mucoadhesive properties of the NPs and sustained the tobramycin release over two days. Finally, all NPs had antimicrobial activity that increased as the amount of LMWC increased. (4) Conclusion: In conclusion, the formulation of mucoadhesive, controlled-release, tobramycin-LMWC-PLGA nanoparticles for the treatment of P. aeruginosa in cystic fibrosis patients is possible, and their properties could be controlled by controlling the concentration of LMWC. PMID- 29517999 TI - Role of Polyamines in Immune Cell Functions. AB - The immune system is remarkably responsive to a myriad of invading microorganisms and provides continuous surveillance against tissue damage and developing tumor cells. To achieve these diverse functions, multiple soluble and cellular components must react in an orchestrated cascade of events to control the specificity, magnitude and persistence of the immune response. Numerous catabolic and anabolic processes are involved in this process, and prominent roles for l arginine and l-glutamine catabolism have been described, as these amino acids serve as precursors of nitric oxide, creatine, agmatine, tricarboxylic acid cycle intermediates, nucleotides and other amino acids, as well as for ornithine, which is used to synthesize putrescine and the polyamines spermidine and spermine. Polyamines have several purported roles and high levels of polyamines are manifest in tumor cells as well in autoreactive B- and T-cells in autoimmune diseases. In the tumor microenvironment, l-arginine catabolism by both tumor cells and suppressive myeloid cells is known to dampen cytotoxic T-cell functions suggesting there might be links between polyamines and T-cell suppression. Here, we review studies suggesting roles of polyamines in normal immune cell function and highlight their connections to autoimmunity and anti-tumor immune cell function. PMID- 29518001 TI - Design and Characterization of Dicyanovinyl Reactive Dyes for the Colorimetric Detection of Thiols and Biogenic Amines. AB - The synthesis of two new azobenzene dyes, namely CR-528 and CR-555, and their spectral properties in ethanol solution are described. The recognition of sulfur containing analytes (2-mercaptoethanol (2-ME), sodium hydrosulfide (NaHS)), and biogenic amines (spermine, spermidine, ethanolamine) bestowed significant spectral changes with color changes from pink/purple to pale yellow/orange yellow. The nitro acceptor group in the dicyanovinyl reactive dye contributes to higher sensitivity and lower detected analyte concentrations. The absorption maxima of both the dyes are at wavelengths compatible with low-cost light sources and detectors, making them excellent candidates for optical probes that are economic, simple to use, and do not require well-trained personnel. PMID- 29518000 TI - Novel Sequence Features of DNA Repair Genes/Proteins from Deinococcus Species Implicated in Protection from Oxidatively Generated Damage. AB - Deinococcus species display a high degree of resistance to radiation and desiccation due to their ability to protect critical proteome from oxidatively generated damage; however, the underlying mechanisms are not understood. Comparative analysis of DNA repair proteins reported here has identified 22 conserved signature indels (CSIs) in the proteins UvrA1, UvrC, UvrD, UvsE, MutY, MutM, Nth, RecA, RecD, RecG, RecQ, RecR, RuvC, RadA, PolA, DnaE, LigA, GyrA and GyrB, that are uniquely shared by all/most Deinococcus homologs. Of these CSIs, a 30 amino acid surface-exposed insert in the Deinococcus UvrA1, which distinguishes it from all other UvrA homologs, is of much interest. The uvrA1 gene in Deinococcus also exhibits specific genetic linkage (predicted operonic arrangement) to genes for three other proteins including a novel Deinococcus specific transmembrane protein (designated dCSP-1) and the proteins DsbA and DsbB, playing central roles in protein disulfide bond formation by oxidation reduction of CXXC (C represents cysteine, X any other amino acid) motifs. The CXXC motifs provide important targets for oxidation damage and they are present in many DNA repair proteins including five in UvrA, which are part of Zinc-finger elements. A conserved insert specific for Deinococcus is also present in the DsbA protein. Additionally, the uvsE gene in Deinococcus also shows specific linkage to the gene for a membrane-associated protein. To account for these novel observations, a model is proposed where specific interaction of the Deinococcus UvrA1 protein with membrane-bound dCSP-1 enables the UvrA1 to receive electrons from DsbA-DsbB oxido-reductase machinery to ameliorate oxidation damage in the UvrA1 protein. PMID- 29518002 TI - The Detailed Bactericidal Process of Ferric Oxide Nanoparticles on E. coli. AB - While nanoparticles exert bactericidal effects through the generation of reactive oxygen species (ROS), the processes of the internalization of and the direct physical damage caused by iron oxide nanoparticles are not completely clear. We hypothesize that direct physical or mechanical damage of the cell membrane and cytoplasmic integrity by nanoparticles is another major cause of bacterial death besides ROS. The aim of this study is to investigate the process of the internalization of iron oxide nanoparticles, and to evaluate the effect of direct physical or mechanical damage on bacterial cell growth and death. The results demonstrate that iron oxide nanoparticles not only inhibited E. coli cell growth, but also caused bacterial cell death. Iron oxide nanoparticles produced significantly elevated ROS levels in bacteria. Transmission electronic microscopy demonstrated that iron oxide nanoparticles were internalized into and condensed the cytoplasm. Strikingly, we observed that the internalized nanoparticles caused intracellular vacuole formation, instead of simply adsorbing thereon; and formed clusters on the bacterial surface and tore up the outer cell membrane to release cytoplasm. This is the first time that the exact process of the internalization of iron oxide nanoparticles has been observed. We speculate that the intracellular vacuole formation and direct physical or mechanical damage caused by the iron oxide nanoparticles caused the bactericidal effect, along with the effects of ROS. PMID- 29518004 TI - Host and Cropping System Shape the Fusarium Population: 3ADON-Producers Are Ubiquitous in Wheat Whereas NIV-Producers Are More Prevalent in Rice. AB - In recent years, Fusarium head blight (FHB) outbreaks have occurred much more frequently in China. The reduction of burning of the preceding crop residues is suggested to contribute to more severe epidemics as it may increase the initial inoculum. In this study, a large number of Fusarium isolates was collected from blighted wheat spikes as well as from rice stubble with perithecia originating from nine sampling sites in five provinces in Southern China. Fusarium asiaticum dominated both wheat and rice populations, although rice populations showed a higher species diversity. Chemotype analysis showed that rice is the preferred niche for NIV mycotoxin producers that were shown to be less virulent on wheat. In contrast, 3ADON producers are more prevalent on wheat and in wheat producing areas. The 3ADON producers were shown to be more virulent on wheat, revealing the selection pressure of wheat on 3ADON producers. For the first time, members of the Incarnatum-clade of FusariumIncarnatum-Equiseti Species Complex (FIESC) were found to reproduce sexually on rice stubble. The pathogenicity of FIESC isolates on wheat proved very low and this may cause the apparent absence of this species in the main wheat producing provinces. This is the first report of the Fusarium population structure including rice stubble as well as a direct comparison with the population on wheat heads in the same fields. Our results confirm that the perithecia on rice stubble are the primary inoculum of FHB on wheat and that cropping systems affect the local Fusarium population. PMID- 29518003 TI - Insulin-Sensitizer Effects of Fenugreek Seeds in Parallel with Changes in Plasma MCH Levels in Healthy Volunteers. AB - In developed, developing and low-income countries alike, type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases, the severity of which is substantially a consequence of multiple organ complications that occur due to long-term progression of the disease before diagnosis and treatment. Despite enormous investment into the characterization of the disease, its long-term management remains problematic, with those afflicted enduring significant degradation in quality-of-life. Current research efforts into the etiology and pathogenesis of T2DM, are focused on defining aberrations in cellular physiology that result in development of insulin resistance and strategies for increasing insulin sensitivity, along with downstream effects on T2DM pathogenesis. Ongoing use of plant-derived naturally occurring materials to delay the onset of the disease or alleviate symptoms is viewed by clinicians as particularly desirable due to well-established efficacy and minimal toxicity of such preparations, along with generally lower per-patient costs, in comparison to many modern pharmaceuticals. A particularly attractive candidate in this respect, is fenugreek, a plant that has been used as a flavouring in human diet through recorded history. The present study assessed the insulin-sensitizing effect of fenugreek seeds in a cohort of human volunteers, and tested a hypothesis that melanin-concentrating hormone (MCH) acts as a critical determinant of this effect. A test of the hypothesis was undertaken using a hyperinsulinemic euglycemic glucose clamp approach to assess insulin sensitivity in response to oral administration of a fenugreek seed preparation to healthy subjects. Outcomes of these evaluations demonstrated significant improvement in glucose tolerance, especially in patients with impaired glucose responses. Outcome data further suggested that fenugreek seed intake-mediated improvement in insulin sensitivity correlated with reduction in MCH levels. PMID- 29518006 TI - Detection of Internal Metal Loss in Steel Pipes and Storage Tanks via Magnetic Based Fiber Optic Sensor. AB - A monitoring solution was developed for detection of material loss in metals such as carbon steel using the force generated by permanent magnets in addition to the optical strain sensing technology. The working principle of the sensing system is related to the change in thickness of a steel plate, which typically occurs due to corrosion. As thickness decreases, the magnetostatic force between the magnet and the steel structure also decreases. This, in turn, affects the strain measured using the optical fiber. The sensor prototype was designed and built after verifying its sensitivity using a numerical model. The prototype was tested on steel plates of different thicknesses to establish the relationship between the metal thickness and measured strain. The results of experiments and numerical models demonstrate a strong relationship between the metal thickness and the measured strain values. PMID- 29518005 TI - PET Imaging of Microglial Activation-Beyond Targeting TSPO. AB - Neuroinflammation, which involves microglial activation, is thought to play a key role in the development and progression of neurodegenerative diseases and other brain pathologies. Positron emission tomography is an ideal imaging technique for studying biochemical processes in vivo, and particularly for studying the living brain. Neuroinflammation has been traditionally studied using radiotracers targeting the translocator protein 18 kDa, but this comes with certain limitations. The current review describes alternative biological targets that have gained interest for the imaging of microglial activation over recent years, such as the cannabinoid receptor type 2, cyclooxygenase-2, the P2X7 receptor and reactive oxygen species, and some promising radiotracers for these targets. Although many advances have been made in the field of neuroinflammation imaging, current radiotracers all target the pro-inflammatory (M1) phenotype of activated microglia, since the number of known biological targets specific for the anti inflammatory (M2) phenotype that are also suited as a target for radiotracer development is still limited. Next to proceeding the currently available tracers for M1 microglia into the clinic, the development of a suitable radiotracer for M2 microglia would mean a great advance in the field, as this would allow for imaging of the dynamics of microglial activation in different diseases. PMID- 29518007 TI - Hyper-Uricemia and Gouty Access in the Adult Population of the Southeast of Gabon: Biochemical Aspects. AB - Gout is caused by a chronic hyperuricemia whose complications are not currently well evaluated in Africa. The aim of this study was to determine the prevalence and risk factors of hyperuricemia and gout in 85 patients recruited. A total of 26 cases of hyperuricemia, i.e., 30.6% of the study population, with 12 cases of gout and seven cases of gouty access. In this population, hyperuricemia was proportional to age (p-value < 10-4, OR = 2.6), but it was more prevalent in men, 23.5% versus 7.1% for women (p-value = 0.0047). In addition, none of these women showed signs of a gouty affection. Consumption of alcohol (OR = 13) and nucleoprotein-rich foods, obesity (BMI 30 kg/m2; OR = 6), family history of gout (OR = 6.8), as well as diseases such as high blood pressure (associated with taking diuretics; OR = 1.7), renal insufficiency (OR = 4.4) and diabetes (p < 0.049) were the main factors of the diseases associated with gout and hyperuricemia in this population. The biochemical role of these factors may increase and/or decrease the processes of synthesis and/or elimination of uric acid by acting on metabolites involved in the regulation of urate production. PMID- 29518008 TI - Pathogens and Disease Play Havoc on the Host Epiproteome-The "First Line of Response" Role for Proteomic Changes Influenced by Disorder. AB - Organisms face stress from multiple sources simultaneously and require mechanisms to respond to these scenarios if they are to survive in the long term. This overview focuses on a series of key points that illustrate how disorder and post translational changes can combine to play a critical role in orchestrating the response of organisms to the stress of a changing environment. Increasingly, protein complexes are thought of as dynamic multi-component molecular machines able to adapt through compositional, conformational and/or post-translational modifications to control their largely metabolic outputs. These metabolites then feed into cellular physiological homeostasis or the production of secondary metabolites with novel anti-microbial properties. The control of adaptations to stress operates at multiple levels including the proteome and the dynamic nature of proteomic changes suggests a parallel with the equally dynamic epigenetic changes at the level of nucleic acids. Given their properties, I propose that some disordered protein platforms specifically enable organisms to sense and react rapidly as the first line of response to change. Using examples from the highly dynamic host-pathogen and host-stress response, I illustrate by example how disordered proteins are key to fulfilling the need for multiple levels of integration of response at different time scales to create robust control points. PMID- 29518009 TI - miR-25-3p, Positively Regulated by Transcription Factor AP-2alpha, Regulates the Metabolism of C2C12 Cells by Targeting Akt1. AB - miR-25, a member of the miR-106b-25 cluster, has been reported as playing an important role in many biological processes by numerous studies, while the role of miR-25 in metabolism and its transcriptional regulation mechanism remain unclear. In this study, gain-of-function and loss-of-function assays demonstrated that miR-25-3p positively regulated the metabolism of C2C12 cells by attenuating phosphoinositide 3-kinase (PI3K) gene expression and triglyceride (TG) content, and enhancing the content of adenosine triphosphate (ATP) and reactive oxygen species (ROS). Furthermore, the results from bioinformatics analysis, dual luciferase assay, site-directed mutagenesis, qRT-PCR, and Western blotting demonstrated that miR-25-3p directly targeted the AKT serine/threonine kinase 1 (Akt1) 3' untranslated region (3'UTR). The core promoter of miR-25-3p was identified, and the transcription factor activator protein-2alpha (AP-2alpha) significantly increased the expression of mature miR-25-3p by binding to its core promoter in vivo, as indicated by the chromatin immunoprecipitation (ChIP) assay, and AP-2alpha binding also downregulated the expression of Akt1. Taken together, our findings suggest that miR-25-3p, positively regulated by the transcription factor AP-2alpha, enhances C2C12 cell metabolism by targeting the Akt1 gene. PMID- 29518010 TI - Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction. AB - Keratinocytes are non-professional immune cells contributing actively to innate immune responses partially by reacting to a wide range of molecular patterns by activating pattern recognition receptors. Cytosolic nucleotide fragments as pathogen- or self-derived trigger factors are activating inflammasomes and inducing anti-viral signal transduction pathways as well as inducing expression of inflammatory cytokines. We aimed to compare the induced inflammatory reactions in three keratinocyte cell types-normal human epidermal keratinocytes, the HaCaT cell line and the HPV-KER cell line-upon exposure to the synthetic RNA and DNA analogues poly(I:C) and poly(dA:dT) to reveal the underlying signaling events. Both agents induced the expression of interleukin-6 and tumor necrosis factor alpha in all cell types; however, notable kinetic and expression level differences were found. Western blot analysis revealed rapid activation of the nuclear factor kappaB (NF-kappaB), mitogen activated protein kinase and signal transducers of activator of transcription (STAT) signal transduction pathways in keratinocytes upon poly(I:C) treatment, while poly(dA:dT) induced slower activation. Inhibition of NF-kappaB, p38, STAT-1 and STAT-3 signaling resulted in decreased cytokine expression, whereas inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling showed a negative feedback role in both poly(I:C)- and poly(dA:dT)-induced cytokine expression. Based on our in vitro results nucleotide fragments are able to induce inflammatory reactions in keratinocytes, but with different rate and kinetics of cytokine expression, explained by faster activation of signaling routes by poly(I:C) than poly(dA:dT). PMID- 29518011 TI - PEO-PPO-PEO Tri-Block Copolymers for Gene Delivery Applications in Human Regenerative Medicine-An Overview. AB - Lineal (poloxamers or Pluronic(r)) or X-shaped (poloxamines or Tetronic(r)) amphiphilic tri-block copolymers of poly(ethylene oxide) and poly(propylene oxide) (PEO-PPO-PEO) have been broadly explored for controlled drug delivery in different regenerative medicine approaches. The ability of these copolymers to self-assemble as micelles and to undergo sol-to-gel transitions upon heating has endowed the denomination of "smart" or "intelligent" systems. The use of PEO-PPO PEO copolymers as gene delivery systems is a powerful emerging strategy to improve the performance of classical gene transfer vectors. This review summarizes the state of art of the application of PEO-PPO-PEO copolymers in both nonviral and viral gene transfer approaches and their potential as gene delivery systems in different regenerative medicine approaches. PMID- 29518012 TI - Individual and Neighborhood Stressors, Air Pollution and Cardiovascular Disease. AB - Psychosocial and environmental stress exposures across the life course have been shown to be relevant in the development of cardiovascular disease (CVD). Assessing more than one stressor from different domains (e.g., individual and neighborhood) and across the life course moves us towards a more integrated picture of how stress affects health and well-being. Furthermore, these individual and neighborhood psychosocial stressors act on biologic pathways, including immune function and inflammatory response, which are also impacted by ubiquitous environmental exposures such as air pollution. The objective of this study is to evaluate the interaction between psychosocial stressors, at both the individual and neighborhood level, and air pollution on CVD. This study used data from the 2009-2011 Behavioral Risk Factor Surveillance System (BRFSS) from Washington State. Adverse childhood experiences (ACEs) measured at the individual level, and neighborhood deprivation index (NDI) measured at the zip code level, were the psychosocial stressors of interest. Exposures to three air pollutants particulate matter (both PM2.5 and PM10) and nitrogen dioxide (NO2)-were also calculated at the zip code level. Outcome measures included several self-reported CVD-related health conditions. Both multiplicative and additive interaction quantified using the relative excess risk due to interaction (RERI), were evaluated. This study included 32,151 participants in 502 unique zip codes. Multiplicative and positive additive interactions were observed between ACEs and PM10 for diabetes, in models adjusted for NDI. The prevalence of diabetes was 1.58 (95% CI: 1.40, 1.79) times higher among those with both high ACEs and high PM10 compared to those with low ACEs and low PM10 (p-value = 0.04 for interaction on the multiplicative scale). Interaction was also observed between neighborhood level stressors (NDI) and air pollution (NO2) for the stroke and diabetes outcomes on both multiplicative and additive scales. Modest interaction was observed between NDI and air pollution, supporting prior literature on the importance of neighborhood-level stressors in cardiovascular health and reinforcing the importance of NDI on air pollution health effects. ACEs may exert health effects through selection into disadvantaged neighborhoods and more work is needed to understand the accumulation of risk in multiple domains across the life course. PMID- 29518014 TI - Data-Prefetching Scheme Based on Playback Delay and Positioning Satisfaction in Peer-To-Peer Video-On-Demand System. AB - As one of the most important applications in peer-to-peer (P2P) networks, the video-on-demand (VoD) system freely supports video cassette recorder (VCR) operation for users. However, the users may experience significant playback delay after frequent VCR operations in the VoD system, which will affect the quality of experience (QoE) of the users. Hence, selecting an appropriate data-prefetching strategy to support better VCR operation is an important approach to improve the QoE. This paper proposes a data-prefetching strategy (DSA) to determine the most suitable anchor interval by considering the playback delay and positioning satisfaction. According to the DSA, we use the multiple-attribute decision-making (MADM) theory to model the selection of intervals of prefetching data blocks (i.e., anchor interval) and the technique for ordering preference by similarity to an ideal solution (TOPSIS) algorithm to solve the MADM. The simulation results show that the DSA strategy obtains higher positioning satisfaction than the existing schemes, which is approximately 60% higher than the anchor points, popular parts of video, and user interests (API)-based method. Moreover, with the increase in network bandwidth, the DSA strategy can minimize the playback delay after VCR operation using relative few extra bandwidths. PMID- 29518013 TI - Immunogenicity and Safety of the New Inactivated Quadrivalent Influenza Vaccine Vaxigrip Tetra: Preliminary Results in Children >=6 Months and Older Adults. AB - Since the mid-1980s, two lineages of influenza B viruses have been distinguished. These can co-circulate, limiting the protection provided by inactivated trivalent influenza vaccines (TIVs). This has prompted efforts to formulate quadrivalent influenza vaccines (QIVs), to enhance protection against circulating influenza B viruses. This review describes the results obtained from seven phase III clinical trials evaluating the immunogenicity, safety, and lot-to-lot consistency of a new quadrivalent split-virion influenza vaccine (Vaxigrip Tetra(r)) formulated by adding a second B strain to the already licensed TIV. Since Vaxigrip Tetra was developed by means of a manufacturing process strictly related to that used for TIV, the data on the safety profile of TIV are considered supportive of that of Vaxigrip Tetra. The safety and immunogenicity of Vaxigrip Tetra were similar to those of the corresponding licensed TIV. Moreover, the new vaccine elicits a superior immune response towards the additional strain, without affecting immunogenicity towards the other three strains. Vaxigrip Tetra is well tolerated, has aroused no safety concerns, and is recommended for the active immunization of individuals aged >=6 months. In addition, preliminary data confirm its immunogenicity and safety even in children aged 6-35 months and its immunogenicity in older subjects (aged 66-80 years). PMID- 29518015 TI - Capturing the Alternative Cleavage and Polyadenylation Sites of 14 NAC Genes in Populus Using a Combination of 3'-RACE and High-Throughput Sequencing. AB - Detection of complex splice sites (SSs) and polyadenylation sites (PASs) of eukaryotic genes is essential for the elucidation of gene regulatory mechanisms. Transcriptome-wide studies using high-throughput sequencing (HTS) have revealed prevalent alternative splicing (AS) and alternative polyadenylation (APA) in plants. However, small-scale and high-depth HTS aimed at detecting genes or gene families are very few and limited. We explored a convenient and flexible method for profiling SSs and PASs, which combines rapid amplification of 3'-cDNA ends (3'-RACE) and HTS. Fourteen NAC (NAM, ATAF1/2, CUC2) transcription factor genes of Populus trichocarpa were analyzed by 3'-RACE-seq. Based on experimental reproducibility, boundary sequence analysis and reverse transcription PCR (RT PCR) verification, only canonical SSs were considered to be authentic. Based on stringent criteria, candidate PASs without any internal priming features were chosen as authentic PASs and assumed to be PAS-rich markers. Thirty-four novel canonical SSs, six intronic/internal exons and thirty 3'-UTR PAS-rich markers were revealed by 3'-RACE-seq. Using 3'-RACE and real-time PCR, we confirmed that three APA transcripts ending in/around PAS-rich markers were differentially regulated in response to plant hormones. Our results indicate that 3'-RACE-seq is a robust and cost-effective method to discover SSs and label active regions subjected to APA for genes or gene families. The method is suitable for small scale AS and APA research in the initial stage. PMID- 29518016 TI - Mediterranean Diet and Breast Cancer Risk. AB - The Mediterranean diet has been related to a reduced risk of several common cancers but its role on breast cancer has not been quantified yet. We investigated the association between adherence to the Mediterranean diet and breast cancer risk by means of a hospital-based case-control study conducted in Italy and Switzerland. 3034 breast cancer cases and 3392 controls admitted to the same network of hospitals for acute, non-neoplastic and non-gynaecologic diseases were studied. Adherence to the Mediterranean diet was quantitatively measured through a Mediterranean Diet Score (MDS), summarizing the major characteristics of the Mediterranean dietary pattern and ranging from 0 (lowest adherence) to 9 (highest adherence). We estimated the odds ratios (ORs) of breast cancer for the MDS using multiple logistic regression models, adjusting for several covariates. Compared to a MDS of 0-3, the ORs for breast cancer were 0.86 (95% confidence interval, CI, 0.76-0.98) for a MDS of 4-5 and 0.82 (95% CI, 0.71-0.95) for a MDS of 6-9 (p for trend = 0.008). The exclusion of the ethanol component from the MDS did not materially modify the ORs (e.g., OR = 0.81, 95% CI, 0.70-0.95, for MDS >= 6). Results were similar in pre- and post-menopausal women. Adherence to the Mediterranean diet was associated with a reduced breast cancer risk. PMID- 29518017 TI - Adherence to Oral Anticancer Medications: Evolving Interprofessional Roles and Pharmacist Workforce Considerations. AB - Interprofessional care is exhibited in outpatient oncology practices where practitioners from a myriad of specialties (e.g., oncology, nursing, pharmacy, health informatics and others) work collectively with patients to enhance therapeutic outcomes and minimize adverse effects. Historically, most ambulatory based anticancer medication therapies have been administrated in infusion clinics or physician offices. Oral anticancer medications (OAMs) have become increasingly prevalent and preferred by patients for use in residential or other non-clinic settings. Self-administration of OAMs represents a significant shift in the management of cancer care and role responsibilities for patients and clinicians. While patients have a greater sense of empowerment and convenience when taking OAMs, adherence is a greater challenge than with intravenous therapies. This paper proposes use of a qualitative systems evaluation, based on theoretical frameworks for interdisciplinary team collaboration and systems science, to examine the social interactionism involved with the use of intravenous anticancer treatments and OAMs (as treatment technologies) by describing patient, organizational, and social systems considerations in communication, care, control, and context (i.e., Kaplan's 4Cs). This conceptualization can help the healthcare system prepare for substantial workforce changes in cancer management, including increased utilization of oncology pharmacists. PMID- 29518018 TI - Protein Expression Modifications in Phage-Resistant Mutants of Aeromonas salmonicida after AS-A Phage Treatment. AB - The occurrence of infections by pathogenic bacteria is one of the main sources of financial loss for the aquaculture industry. This problem often cannot be solved with antibiotic treatment or vaccination. Phage therapy seems to be an alternative environmentally-friendly strategy to control infections. Recognizing the cellular modifications that bacteriophage therapy may cause to the host is essential in order to confirm microbial inactivation, while understanding the mechanisms that drive the development of phage-resistant strains. The aim of this work was to detect cellular modifications that occur after phage AS-A treatment in A. salmonicida, an important fish pathogen. Phage-resistant and susceptible cells were subjected to five successive streak-plating steps and analysed with infrared spectroscopy, a fast and powerful tool for cell study. The spectral differences of both populations were investigated and compared with a phage sensitivity profile, obtained through the spot test and efficiency of plating. Changes in protein associated peaks were found, and these results were corroborated by 1-D electrophoresis of intracellular proteins analysis and by phage sensitivity profiles. Phage AS-A treatment before the first streaking-plate step clearly affected the intracellular proteins expression levels of phage resistant clones, altering the expression of distinct proteins during the subsequent five successive streak-plating steps, making these clones recover and be phenotypically more similar to the sensitive cells. PMID- 29518019 TI - Network-Based Identification of Altered Stem Cell Pluripotency and Calcium Signaling Pathways in Metastatic Melanoma. AB - Malignancy of cancer has been linked to distinct subsets of stem-like cells, the so-called cancer stem cells (CSCs), which persist during treatment and seem to lead to drug-resistant recurrence. Metastatic spread of cancer cells is one of the hallmarks of malignancy and contributes to most human melanoma-related deaths. Recently, overlapping groups of proteins and pathways were shown to regulate stem cell migration and cancer metastasis, raising the question of whether genes/proteins involved in stem cell pluripotency may have important implications when applied to the biology of cancer metastasis. Furthermore, it is well known that ion channels and receptors, particularly those responsible for calcium (Ca2+) signal generation, are critical in determining the cellular fate of stem cells (SCs). In the present study, we searched for evidence of altered stem cell pluripotency and Ca2+ signaling-related genes in the context of melanoma metastasis. We did this by using network analysis of gene expression in tissue biopsies from three different independent datasets of patients. First, we created an in silico network model ("STEMCa" interactome) showing the landscape of interactions between stem cell pluripotency and Ca2+ signaling-related genes/proteins, and demonstrated that around 51% (151 out of 294) of the genes within this model displayed significant changes of expression (False Discovery Rate (FDR), corrected p-value < 0.05) in at least one of the datasets of melanoma metastasis when compared with primary tumor biopsies (controls). Analysis of the properties (degree and betweenness) of the topological network revealed 27 members as the most central hub (HB) and nonhub-bottlenecks (NH-B) among the 294 genes/proteins of the whole interactome. From those representative genes, CTNNB1, GNAQ, GSK3B, GSTP1, MAPK3, PPP1CC, PRKACA, and SMAD4 showed equal up- or downregulation (corrected p-value < 0.05) in at least 2 independent datasets of melanoma metastases samples and PTPN11 showed upregulation (corrected p-value < 0.05) in three of them when compared with control samples. We postulate that altered expression of stem cell pluripotency and Ca2+ signaling pathway-related genes may contribute to the metastatic transformation, with these central members being an optimal candidate group of biomarkers and in silico therapeutic targets for melanoma metastasis, which deserve further investigation. PMID- 29518021 TI - Karyotype Variability and Inter-Population Genomic Differences in Freshwater Ostracods (Crustacea) Showing Geographical Parthenogenesis. AB - Transitions from sexual to asexual reproduction are often associated with polyploidy and increased chromosomal plasticity in asexuals. We investigated chromosomes in the freshwater ostracod species Eucypris virens (Jurine, 1820), where sexual, asexual and mixed populations can be found. Our initial karyotyping of multiple populations from Europe and North Africa, both sexual and asexual, revealed a striking variability in chromosome numbers. This would suggest that chromosomal changes are likely to be accelerated in asexuals because the constraints of meiosis are removed. Hence, we employed comparative genomic hybridization (CGH) within and among sexual and asexual populations to get insights into E. virens genome arrangements. CGH disclosed substantial genomic imbalances among the populations analyzed, and three patterns of genome arrangement between these populations: 1. Only putative ribosomal DNA (rDNA) bearing regions were conserved in the two populations compared indicating a high sequence divergence between these populations. This pattern is comparable with our findings at the interspecies level of comparison; 2. Chromosomal regions were shared by both populations to a varying extent with a distinct copy number variation in pericentromeric and presumable rDNA-bearing regions. This indicates a different rate of evolution in repetitive sequences; 3. A mosaic pattern of distribution of genomic material that can be explained as non-reciprocal genetic introgression and evidence of a hybrid origin of these individuals. We show an overall increased chromosomal dynamics in E. virens that is complementary with available phylogenetic and population genetic data reporting highly differentiated diploid sexual and asexual lineages with a wide variety of genetic backgrounds. PMID- 29518020 TI - Accuracy of a Wrist-Worn Heart Rate Sensing Device during Elective Pediatric Surgical Procedures. AB - The reliability of wearable photoplethysmography (PPG) sensors to measure heart rate (HR) in hospitalized patients has only been demonstrated in adults. We evaluated the accuracy of HR monitoring with a personal fitness tracker (PFT) in children undergoing surgery. HR monitoring was performed using a wrist-worn PFT (Fitbit Charge HR) in 30 children (8.21 +/- 3.09 years) undergoing laparoscopy (n = 8) or open surgery (n = 22). HR values were analyzed preoperatively and during surgery. The accuracy of HR recordings was compared with measurements recorded during continuous electrocardiographic (cECG) monitoring; HRs derived from continuous monitoring with pulse oximetry (SpO2R) were used as a positive control. PFT-derived HR values were in agreement with those recorded during cECG (r = 0.99) and SpO2R (r = 0.99) monitoring. PFT performance remained high in children < 8 years (r = 0.99), with a weight < 30 kg (r = 0.99) and when the HR was < 70 beats per minute (bpm) (r = 0.91) or > 140 bpm (r = 0.99). PFT accuracy was similar during laparoscopy and open surgery, as well as preoperatively and during the intervention (r > 0.9). PFT-derived HR showed excellent accuracy compared with HRs measured by cECG and SpO2R during pediatric surgical procedures. Further clinical evaluation is needed to define whether PFTs can be used in different health care settings. PMID- 29518022 TI - In Vitro Analysis of the Fracture Resistance of CAD/CAM Denture Base Resins. AB - Computer-aided design and computer-aided manufacturing (CAD/CAM) denture base manufacturers claim to produce their resin pucks under high heat and pressure. Therefore, CAD/CAM dentures are assumed to have enhanced mechanical properties and, as a result, are often produced with lower denture base thicknesses than conventional, manually fabricated dentures. The aim of this study was to investigate if commercially available CAD/CAM denture base resins have more favourable mechanical properties than conventionally processed denture base resins. For this purpose, a series of three-point bending tests conforming to ISO specifications were performed on a total of 80 standardised, rectangular CAD/CAM denture base resin specimens from five different manufacturers (AvaDent, Baltic Denture System, Vita VIONIC, Whole You Nexteeth, and Wieland Digital Dentures). A heat-polymerising resin and an autopolymerising resin served as the control groups. The breaking load, fracture toughness, and the elastic modulus were assessed. Additionally, the fracture surface roughness and texture were investigated. Only one CAD/CAM resin showed a significantly increased breaking load. Two CAD/CAM resins had a significantly higher fracture toughness than the control groups, and all CAD/CAM resins had higher elastic moduli than the controls. Our results indicate that CAD/CAM denture base resins do not generally have better mechanical properties than manually processed resins. Therefore, the lower minimum denture base thicknesses should be regarded with some caution. PMID- 29518023 TI - Cyber and Physical Security Vulnerability Assessment for IoT-Based Smart Homes. AB - The Internet of Things (IoT) is an emerging paradigm focusing on the connection of devices, objects, or "things" to each other, to the Internet, and to users. IoT technology is anticipated to become an essential requirement in the development of smart homes, as it offers convenience and efficiency to home residents so that they can achieve better quality of life. Application of the IoT model to smart homes, by connecting objects to the Internet, poses new security and privacy challenges in terms of the confidentiality, authenticity, and integrity of the data sensed, collected, and exchanged by the IoT objects. These challenges make smart homes extremely vulnerable to different types of security attacks, resulting in IoT-based smart homes being insecure. Therefore, it is necessary to identify the possible security risks to develop a complete picture of the security status of smart homes. This article applies the operationally critical threat, asset, and vulnerability evaluation (OCTAVE) methodology, known as OCTAVE Allegro, to assess the security risks of smart homes. The OCTAVE Allegro method focuses on information assets and considers different information containers such as databases, physical papers, and humans. The key goals of this study are to highlight the various security vulnerabilities of IoT-based smart homes, to present the risks on home inhabitants, and to propose approaches to mitigating the identified risks. The research findings can be used as a foundation for improving the security requirements of IoT-based smart homes. PMID- 29518024 TI - Fungal Disease Prevention in Seedlings of Rice (Oryza sativa) and Other Grasses by Growth-Promoting Seed-Associated Endophytic Bacteria from Invasive Phragmites australis. AB - Non-cultivated plants carry microbial endophytes that may be used to enhance development and disease resistance of crop species where growth-promoting and protective microbes may have been lost. During seedling establishment, seedlings may be infected by several fungal pathogens that are seed or soil borne. Several species of Fusarium, Pythium and other water moulds cause seed rots during germination. Fusarium blights of seedlings are also very common and significantly affect seedling development. In the present study we screened nine endophytic bacteria isolated from the seeds of invasive Phragmites australis by inoculating onto rice, Bermuda grass (Cynodon dactylon), or annual bluegrass (Poa annua) seeds to evaluate plant growth promotion and protection from disease caused by Fusarium oxysporum. We found that three bacteria belonging to genus Pseudomonas spp. (SLB4-P. fluorescens, SLB6-Pseudomonas sp. and SY1-Pseudomonas sp.) promoted seedling development, including enhancement of root and shoot growth, and stimulation of root hair formation. These bacteria were also found to increase phosphate solubilization in in vitro experiments. Pseudomonas sp. (SY1) significantly protected grass seedlings from Fusarium infection. In co-culture experiments, strain SY1 strongly inhibited fungal pathogens with 85.71% growth inhibition of F. oxysporum, 86.33% growth inhibition of Curvularia sp. and 82.14% growth inhibition of Alternaria sp. Seedlings previously treated with bacteria were found much less infected by F. oxysporum in comparison to non-treated controls. On microscopic observation we found that bacteria appeared to degrade fungal mycelia actively. Metabolite products of strain SY1 in agar were also found to inhibit fungal growth on nutrient media. Pseudomonas sp. (SY1) was found to produce antifungal volatiles. Polymerase chain reaction (PCR) amplification using specific primers for pyrrolnitirin synthesis and HCN (hydrogen cyanide) production suggested presence of genes for both compounds in the genome of SY1. HCN was detected in cultures of SY1. We conclude that microbes from non cultivated plants may provide disease protection and promote growth of crop plants. PMID- 29518026 TI - First Look at the Venom of Naja ashei. AB - Naja ashei is an African spitting cobra species closely related to N. mossambica and N. nigricollis. It is known that the venom of N. ashei, like that of other African spitting cobras, mainly has cytotoxic effects, however data about its specific protein composition are not yet available. Thus, an attempt was made to determine the venom proteome of N. ashei with the use of 2-D electrophoresis and MALDI ToF/ToF (Matrix-Assisted Laser Desorption/Ionization Time of Flight) mass spectrometry techniques. Our investigation revealed that the main components of analysed venom are 3FTxs (Three-Finger Toxins) and PLA2s (Phospholipases A2). Additionally the presence of cysteine-rich venom proteins, 5'-nucleotidase and metalloproteinases has also been confirmed. The most interesting fact derived from this study is that the venom of N. ashei includes proteins not described previously in other African spitting cobras-cobra venom factor and venom nerve growth factor. To our knowledge, there are currently no other reports concerning this venom composition and we believe that our results will significantly increase interest in research of this species. PMID- 29518025 TI - Emerging Roles of p53 Family Members in Glucose Metabolism. AB - Glucose is the key source for most organisms to provide energy, as well as the key source for metabolites to generate building blocks in cells. The deregulation of glucose homeostasis occurs in various diseases, including the enhanced aerobic glycolysis that is observed in cancers, and insulin resistance in diabetes. Although p53 is thought to suppress tumorigenesis primarily by inducing cell cycle arrest, apoptosis, and senescence in response to stress, the non-canonical functions of p53 in cellular energy homeostasis and metabolism are also emerging as critical factors for tumor suppression. Increasing evidence suggests that p53 plays a significant role in regulating glucose homeostasis. Furthermore, the p53 family members p63 and p73, as well as gain-of-function p53 mutants, are also involved in glucose metabolism. Indeed, how this protein family regulates cellular energy levels is complicated and difficult to disentangle. This review discusses the roles of the p53 family in multiple metabolic processes, such as glycolysis, gluconeogenesis, aerobic respiration, and autophagy. We also discuss how the dysregulation of the p53 family in these processes leads to diseases such as cancer and diabetes. Elucidating the complexities of the p53 family members in glucose homeostasis will improve our understanding of these diseases. PMID- 29518027 TI - Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract. AB - Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, including c-fos proto-oncogene, induces bladder cancer outgrowth. Here, we immunohistochemically determined the expression status of phospho-ELK1, an activated form of ELK1, in upper urinary tract urothelial carcinoma (UUTUC). Overall, phospho-ELK1 was positive in 47 (47.5%; 37 weak (1+) and 10 moderate (2+)) of 99 UUTUCs, which was significantly (P = 0.002) higher than in benign urothelium (21 (25.3%) of 83; 17 1+ and 4 2+) and was also associated with androgen receptor expression (P = 0.001). Thirteen (35.1%) of 37 non-muscle-invasive versus 34 (54.8%) of 62 muscle-invasive UUTUCs (P = 0.065) were immunoreactive for phospho-ELK1. Lymphovascular invasion was significantly (P = 0.014) more often seen in phospho-ELK1(2+) tumors (80.0%) than in phospho-ELK1(0/1+) tumors (36.0%). There were no statistically significant associations between phospho-ELK1 expression and tumor grade, presence of concurrent carcinoma in situ or hydronephrosis, or pN status. Kaplan-Meier and log-rank tests revealed that patients with phospho-ELK1(2+) tumor had marginally and significantly higher risks of disease progression (P = 0.055) and cancer specific mortality (P = 0.008), respectively, compared to those with phospho ELK1(0/1+) tumor. The current results thus support our previous observations in bladder cancer and further suggest that phospho-ELK1 overexpression serves as a predictor of poor prognosis in patients with UUTUC. PMID- 29518029 TI - Modeling Pediatric Body Mass Index and Neighborhood Environment at Different Spatial Scales. AB - In public health research, it has been well established that geographic location plays an important role in influencing health outcomes. In recent years, there has been an increased emphasis on the impact of neighborhood or contextual factors as potential risk factors for childhood obesity. Some neighborhood factors relevant to childhood obesity include access to food sources, access to recreational facilities, neighborhood safety, and socioeconomic status (SES) variables. It is common for neighborhood or area-level variables to be available at multiple spatial scales (SS) or geographic units, such as the census block group and census tract, and selection of the spatial scale for area-level variables can be considered as a model selection problem. In this paper, we model the variation in body mass index (BMI) in a study of pediatric patients of the Virginia Commonwealth University (VCU) Medical Center, while considering the selection of spatial scale for a set of neighborhood-level variables available at multiple spatial scales using four recently proposed spatial scale selection algorithms: SS forward stepwise regression, SS incremental forward stagewise regression, SS least angle regression (LARS), and SS lasso. For pediatric BMI, we found evidence of significant positive associations with visit age and black race at the individual level, percent Hispanic white at the census block group level, percent Hispanic black at the census tract level, and percent vacant housing at the census tract level. We also found significant negative associations with population density at the census tract level, median household income at the census tract level, percent renter at the census tract level, and exercise equipment expenditures at the census block group level. The SS algorithms selected covariates at different spatial scales, producing better goodness-of-fit in comparison to traditional models, where all area-level covariates were modeled at the same scale. These findings underscore the importance of considering spatial scale when performing model selection. PMID- 29518030 TI - Absolute Oral Bioavailability of Creatine Monohydrate in Rats: Debunking a Myth. AB - Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile. Our objective was to determine the oral bioavailability of CM and the influence of dose on oral absorption. Rats were dosed orally with low dose (10 mg/kg) or high dose (70 mg/kg) 13C-labeled CM. Blood samples were removed at various time points. Muscle and brain tissue were collected at the conclusion of the study. Plasma and tissue levels of 13C-labeled creatine were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Physiologically based pharmacokinetic (PBPK) models of CM were built using GastroPlusTM. These models were used to predict the plasma concentration-time profiles of creatine hydrochloride (CHCL), which has improved aqueous solubility compared to CM. Absolute oral bioavailability for low dose CM was 53% while high dose CM was only 16%. The simulated Cmax of 70 mg/kg CHCL was around 35 MUg/mL compared to 14 MUg/mL for CM with a predicted oral bioavailability of 66% with CHCL compared to 17% with CM. Our results suggest that the oral bioavailability of CM is less than complete and subject to dose and that further examination of improved dosage formulations of creatine is warranted. PMID- 29518031 TI - Cell-Penetrating Function of the Poly(ADP-Ribose) (PAR)-Binding Motif Derived from the PAR-Dependent E3 Ubiquitin Ligase Iduna. AB - Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates cellular responses such as proteasomal degradation and DNA repair upon interaction with its substrate. We identified a highly cationic region within the PAR-binding motif of Iduna; the region was similar among various species and showed amino acid sequence similarity with that of known cell-penetrating peptides (CPPs). We hypothesized that this Iduna-derived cationic sequence-rich peptide (Iduna) could penetrate the cell membrane and deliver macromolecules into cells. To test this hypothesis, we generated recombinant Iduna-conjugated enhanced green fluorescent protein (Iduna-EGFP) and its tandem-repeat form (d Iduna-EGFP). Both Iduna-EGFP and d-Iduna-EGFP efficiently penetrated Jurkat cells, with the fluorescence signals increasing dose- and time-dependently. Tandem-repeats of Iduna and other CPPs enhanced intracellular protein delivery efficiency. The delivery mechanism involves lipid-raft-mediated endocytosis following heparan sulfate interaction; d-Iduna-EGFP was localized in the nucleus as well as the cytoplasm, and its residence time was much longer than that of other controls such as TAT and Hph-1. Moreover, following intravenous administration to C57/BL6 mice, d-Iduna-EGFP was efficiently taken up by various tissues, including the liver, spleen, and intestine suggesting that the cell penetrating function of the human Iduna-derived peptide can be utilized for experimental and therapeutic delivery of macromolecules. PMID- 29518032 TI - An Investigation of Atomic Structures Derived from X-ray Crystallography and Cryo Electron Microscopy Using Distal Blocks of Side-Chains. AB - Cryo-electron microscopy (cryo-EM) is a structure determination method for large molecular complexes. As more and more atomic structures are determined using this technique, it is becoming possible to perform statistical characterization of side-chain conformations. Two data sets were involved to characterize block lengths for each of the 18 types of amino acids. One set contains 9131 structures resolved using X-ray crystallography from density maps with better than or equal to 1.5 A resolutions, and the other contains 237 protein structures derived from cryo-EM density maps with 2-4 A resolutions. The results show that the normalized probability density function of block lengths is similar between the X-ray data set and the cryo-EM data set for most of the residue types, but differences were observed for ARG, GLU, ILE, LYS, PHE, TRP, and TYR for which conformations with certain shorter block lengths are more likely to be observed in the cryo-EM set with 2-4 A resolutions. PMID- 29518028 TI - The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis. AB - The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression. PMID- 29518033 TI - Anthocyanin-Rich Grape Pomace Extract (Vitis vinifera L.) from Wine Industry Affects Mitochondrial Bioenergetics and Glucose Metabolism in Human Hepatocarcinoma HepG2 Cells. AB - Cancer cells demand high ATP provisions to support proliferation, and targeting of energy metabolism is a good strategy to increase their sensitivity to treatments. In Brazil, wine manufacture is expanding, increasing the amount of pomace that is produced. We determined the phenolic composition and antioxidant properties of a dark skin Grape Pomace Extract and its effects on metabolism and redox state in human hepatocarcinoma HepG2 cells. The material and the methods used represented the industrial process since pomace derived from white wine production and the extract concentrated by pilot plant scale reverse osmosis. Grape pomace extract was rich in polyphenols, mainly anthocyanins, and presented high antioxidant capacity. Short-term metabolic effects, irrespective of any cytotoxicity, involved increased mitochondrial respiration and antioxidant capacity and decreased glycolytic metabolism. Long-term incubation was cytotoxic and cells died by necrosis and GPE was not toxic to non-cancer human fibroblasts. To the best of our knowledge, this is the first report to characterize pomace extract from white wine production from Brazilian winemaking regarding its effects on energy metabolism, suggesting its potential use for pharmaceutical and nutraceutical purposes. PMID- 29518034 TI - From the Synthesis of Nanovehicles to Participation in the First Nanocar Race View from the French Team. AB - This review article presents our accomplished work on the synthesis of molecular triptycene wheels and their introduction into nanovehicles such as wheelbarrows and nanocars, equipped with two and four wheels, respectively. The architecture of nanovehicles is based on polycyclic aromatic hydrocarbons, which provide a potential cargo zone. Our strategy allowed us to obtain planar or curved nanocars, exhibiting different mobilities on metallic surfaces. Our curved nanocar participated in the first nanocar race organized in Toulouse (France) on 28 and 29 April 2017. PMID- 29518035 TI - Variable Levels of Tolerance to Water Stress (Drought) and Associated Biochemical Markers in Tunisian Barley Landraces. AB - Due to its high tolerance to abiotic stress, barley (Hordeum vulgare) is cultivated in many arid areas of the world. In the present study, we evaluate the tolerance to water stress (drought) in nine accessions of "Ardhaoui" barley landraces from different regions of Tunisia. The genetic diversity of the accessions is evaluated with six SSR markers. Seedlings from the nine accessions are subjected to water stress by completely stopping irrigation for three weeks. A high genetic diversity is detected among the nine accessions, with no relationships between genetic distance and geographical or ecogeographical zone. The analysis of growth parameters and biochemical markers in the water stress treated plants in comparison to their respective controls indicated great variability among the studied accessions. Accession 2, from El May Island, displayed high tolerance to drought. Increased amounts of proline in water stressed plants could not be correlated with a better response to drought, as the most tolerant accessions contained lower levels of this osmolyte. A good correlation was established between the reduction of growth and degradation of chlorophylls and increased levels of malondialdehyde and total phenolics. These biochemical markers may be useful for identifying drought tolerant materials in barley. PMID- 29518036 TI - An Optimization Study on Listening Experiments to Improve the Comparability of Annoyance Ratings of Noise Samples from Different Experimental Sample Sets. AB - Annoyance ratings obtained from listening experiments are widely used in studies on health effect of environmental noise. In listening experiments, participants usually give the annoyance rating of each noise sample according to its relative annoyance degree among all samples in the experimental sample set if there are no reference sound samples, which leads to poor comparability between experimental results obtained from different experimental sample sets. To solve this problem, this study proposed to add several pink noise samples with certain loudness levels into experimental sample sets as reference sound samples. On this basis, the standard curve between logarithmic mean annoyance and loudness level of pink noise was used to calibrate the experimental results and the calibration procedures were described in detail. Furthermore, as a case study, six different types of noise sample sets were selected to conduct listening experiments using this method to examine the applicability of it. Results showed that the differences in the annoyance ratings of each identical noise sample from different experimental sample sets were markedly decreased after calibration. The determination coefficient (R2) of linear fitting functions between psychoacoustic annoyance (PA) and mean annoyance (MA) of noise samples from different experimental sample sets increased obviously after calibration. The case study indicated that the method above is applicable to calibrating annoyance ratings obtained from different types of noise sample sets. After calibration, the comparability of annoyance ratings of noise samples from different experimental sample sets can be distinctly improved. PMID- 29518038 TI - The Formation Mechanism and Corrosion Resistance of a Composite Phosphate Conversion Film on AM60 Alloy. AB - Magnesium alloy AM60 has high duc and toughness, which is expected to increase in demand for automotive applications. However, it is too active, and coatings have been extensively studied to prevent corrosion. In this work, a Ba-containing composite phosphate film has been prepared on the surface of AM60. The composition and formation mechanism of the film have been investigated using a scanning electronic microscope equipped with energy dispersive X-ray spectroscopy, Fourier transform infrared, X-ray photoelectron spectroscopy, and X ray diffractometry tests. The corrosion resistance of the film has been measured by electrochemical and immersion tests. The results show that the deposition film has fully covered the substrate but there are some micro-cracks. The structure of the film is complex, and consists of MgHPO4.3H2O, MnHPO4.2.25H2O, BaHPO4.3H2O, BaMg2(PO4)2, Mg3(PO4)2.22H2O, Ca3(PO4)2.xH2O, and some amorphous phases. The composite phosphate film has better anticorrosion performance than the AM60 and can protect the bare alloy from corrosion for more than 12 h in 0.6 M NaCl. PMID- 29518037 TI - The Modulatory Roles of N-glycans in T-Cell-Mediated Autoimmune Diseases. AB - Glycosylation is a ubiquitous posttranslational modification of proteins that occurs in the endoplasmic reticulum/Golgi. N-glycans and mucin-type O-glycans are achieved via a series of glycohydrolase- and glycosyltransferase-mediated reactions. Glycosylation modulates immune responses by regulating thymocyte development and T helper cell differentiation. Autoimmune diseases result from an abnormal immune response by self-antigens and subsequently lead to the destruction of the target tissues. The modification of N-glycans has been studied in several animal models of T-cell-mediated autoimmune diseases. This review summarizes and highlights the modulatory effects of N-glycosylation in several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and type 1 diabetes mellitus. PMID- 29518040 TI - Construction and Analysis of Gene Co-Expression Networks in Escherichia coli. AB - Network-based systems biology has become an important method for analyzing high throughput gene expression data and gene function mining. Escherichia coli (E. coli) has long been a popular model organism for basic biological research. In this paper, weighted gene co-expression network analysis (WGCNA) algorithm was applied to construct gene co-expression networks in E. coli. Thirty-one gene co expression modules were detected from 1391 microarrays of E. coli data. Further characterization of these modules with the database for annotation, visualization, and integrated discovery (DAVID) tool showed that these modules are associated with several kinds of biological processes, such as carbohydrate catabolism, fatty acid metabolism, amino acid metabolism, transportation, translation, and ncRNA metabolism. Hub genes were also screened by intra-modular connectivity. Genes with unknown functions were annotated by guilt-by association. Comparison with a previous prediction tool, EcoliNet, suggests that our dataset can expand gene predictions. In summary, 31 functional modules were identified in E. coli, 24 of which were functionally annotated. The analysis provides a resource for future gene discovery. PMID- 29518039 TI - New Crambescidin-Type Alkaloids from the Indonesian Marine Sponge Clathria bulbotoxa. AB - A crude methanolic extract of the Indonesian sponge Clathria bulbotoxa showed a potent cytotoxic activity against the human epidermoid carcinoma A431 cells. An investigation of the active components led to the isolation of three new compounds named crambescidins 345 (1), 361 (2), and 373 (3), together with the known related metabolites crambescidins 359 (4), 657 (5), and 800 (6). The structures of the compounds were determined by spectroscopic analysis. These compounds 1-4 that possess a simple pentacyclic guanidine core exhibited moderate cytotoxicity against the A431 cells with the IC50 values of 7.0, 2.5, 0.94, and 3.1 MUM, respectively, while the known compounds 5 and 6 that possess a long aliphatic side chain were found to be significantly cytotoxic. On the other hand, in an anti-oomycete activity test against the fungus-like plant pathogen Phytophthora capsici, 1-4 showed a higher activity than that of 5 and 6, suggesting that the long aliphatic side chain plays a significant role for cytotoxicity, but is not effective or suppressive for anti-oomycete activity. PMID- 29518041 TI - Electrospun Zein Fibers Incorporating Poly(glycerol sebacate) for Soft Tissue Engineering. AB - For biomedical applications such as soft tissue engineering, plant proteins are becoming increasingly attractive. Zein, a class of prolamine proteins found in corn, offers excellent properties for application in the human body, but has inferior mechanical properties and lacks aqueous stability. In this study, electrospun scaffolds from neat zein and zein blended with prepolymer and mildly cross-linked poly(glycerol sebacate) (PGS) were fabricated. Less toxic solvents like acetic acid and ethanol were used. The morphological, physiochemical and degradation properties of the as-spun fiber mats were determined. Neat zein and zein-PGS fiber mats with high zein concentration (24 wt % and 27 wt %) showed defect-free microstructures. The average fiber diameter decreased with increasing PGS amount from 0.7 +/- 0.2 um to 0.09 +/- 0.03 um. The addition of PGS to zein resulted in a seven-fold increase in ultimate tensile strength and a four-fold increase in failure strain, whereas the Young's Modulus did not change significantly. Degradation tests in phosphate buffered saline revealed the morphological instability of zein containing fiber mats in contact with aqueous media. Therefore, the fibers were in situ cross-linked with N-(3 Dimethylaminopropyl)-N'-ethylcarbodiimide (EDC)/N-Hydroxysuccinimide (NHS), which led to improved morphological stability in aqueous environment. The novel fibers have suitable properties for application in soft tissue engineering. PMID- 29518042 TI - Poor Dietary Guidelines Compliance among Low-Income Women Eligible for Supplemental Nutrition Assistance Program-Education (SNAP-Ed). AB - The Supplemental Nutrition Assistance Program-Education (SNAP-Ed) program aims to improve nutritional intakes of low-income individuals (<185% poverty threshold). The objective of this study was to describe the compliance with Dietary Guidelines for Americans (DGA) recommendations for fruits, vegetables, and whole grains among SNAP-Ed eligible (n = 3142) and ineligible (n = 3168) adult women (19-70 years) nationwide and SNAP-Ed participating women in Indiana (n = 2623), using the NHANES 2007-2012 and Indiana SNAP-Ed survey data, respectively. Sensitivity analysis further stratified women by race/ethnicity and by current SNAP participation (<130% poverty threshold). Nationally, lower-income women were less likely to meet the fruit (21% vs. 25%) and vegetable (11% vs. 19%) guidelines than higher-income women, but did not differ on whole grains, which were ~5% regardless of income. The income differences in fruit and vegetable intakes were driven by non-Hispanic whites. Fewer SNAP-Ed-eligible U.S. women met fruit (21% vs. 55%) and whole grain (4% vs. 18%) but did not differ for vegetable recommendations (11% vs. 9%) when compared to Indiana SNAP-Ed women. This same trend was observed among current SNAP participants. Different racial/ethnic group relationships with DGA compliance were found in Indiana compared to the nation. Nevertheless, most low-income women in the U.S. are at risk of not meeting DGA recommendations for fruits (79%), vegetables (89%), and whole grains (96%); SNAP Ed participants in Indiana had higher compliance with DGA recommendations. Increased consumption of these three critical food groups would improve nutrient density, likely reduce calorie consumption by replacing high calorie choices, and improve fiber intakes. PMID- 29518043 TI - The Performance of Three Immune Assays to Assess the Serological Status of Cattle Experimentally Exposed to Mycoplasma bovis. AB - Mycoplasma bovis is associated with several clinical syndromes of cattle. Currently, limited information is available on the sensitivity (Se) and specificity (Sp) of serological assays used for the detection of M. bovis specific antibodies. Consequently, it is difficult to critically evaluate the outcomes of studies that use these assays. Therefore, the current study used bovine sera sourced from M. bovis exposure studies from three countries to estimate the Se and Sp of two commercial M. bovis enzyme-linked immunosorbent assays (ELISA), BIO K302 and BIO K260, and Western blotting. Western blotting had the highest Se estimate of 74% (95% confidence interval (CI): 16-98%), compared to the BIO K302: 47% (95% CI: 10-87%) and BIO K260: 28% (95% CI: 1-92%). However, for Sp, the BIO K302: 96% (95% CI: 87-99%) and the BIO K260: 100% (95% CI: 93 100%) out-performed Western blotting: 88% (95% CI: 56-98%). Western blotting was the best assay for detecting seroconversion, correctly identifying 61% (95% CI: 29-86%) of exposed animals compared to 35% for BIO K302 (95% CI: 21-54%) and 8% for BIO K260 (95% CI: 0-87%). While none of the methods assessed had high Se and Sp, the availability of these estimates will aid in the interpretation of studies that use these assays. The results of this study highlight the difficulties encountered when using serology to detect exposure to M. bovis in cattle. PMID- 29518045 TI - An Estimate of Severe and Chronic Fungal Diseases in the Republic of Kazakhstan. AB - : Our work aimed to generate a preliminary estimation of severe and chronic fungal diseases in the Republic of Kazakhstan with a model proposed by LIFE (Leading International Fungal Education). Calculations were carried out on data from 2015. Published results of studies of mycoses in Kazakhstan were identified; in the absence of national data from the scientific literature, the frequency of life-threatening and serious mycoses in defined groups of patients at risk from other countries were taken into account. We also used analogous estimations of mycoses in the Russian Federation. We estimate that 300,824 patients (1.7% of the population) were affected by severe and chronic mycotic diseases. There were an estimated 15,172 cases of acute mycoses, notably tinea capitis in children (11,847), Pneumocystis pneumonia and invasive candidiasis, and 285,652 of chronic fungal diseases. The most frequent were chronic recurrent vulvovaginal candidiasis (273,258 cases) and chronic pulmonary aspergillosis (6231). There is uncertainty about the prevalence of asthma in adults; the official number is 12,478 patients, but a prevalence estimate of 1.47% from a WHO consortium yields a prevalence of ~170,000 affected. We have used the official figures to generate the prevalence of fungal asthma, but it is likely to be a significant underestimate. CONCLUSION: Results of investigation indicate significant prevalence of severe and chronic mycoses in the Republic of Kazakhstan. PMID- 29518044 TI - CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance. AB - Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. This review examines evidence that the SCF/CD117 signaling axis may contribute to the control of cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors. PMID- 29518046 TI - Analysis of Gene Regulatory Networks of Maize in Response to Nitrogen. AB - Nitrogen (N) fertilizer has a major influence on the yield and quality. Understanding and optimising the response of crop plants to nitrogen fertilizer usage is of central importance in enhancing food security and agricultural sustainability. In this study, the analysis of gene regulatory networks reveals multiple genes and biological processes in response to N. Two microarray studies have been used to infer components of the nitrogen-response network. Since they used different array technologies, a map linking the two probe sets to the maize B73 reference genome has been generated to allow comparison. Putative Arabidopsis homologues of maize genes were used to query the Biological General Repository for Interaction Datasets (BioGRID) network, which yielded the potential involvement of three transcription factors (TFs) (GLK5, MADS64 and bZIP108) and a Calcium-dependent protein kinase. An Artificial Neural Network was used to identify influential genes and retrieved bZIP108 and WRKY36 as significant TFs in both microarray studies, along with genes for Asparagine Synthetase, a dual specific protein kinase and a protein phosphatase. The output from one study also suggested roles for microRNA (miRNA) 399b and Nin-like Protein 15 (NLP15). Co expression-network analysis of TFs with closely related profiles to known Nitrate responsive genes identified GLK5, GLK8 and NLP15 as candidate regulators of genes repressed under low Nitrogen conditions, while bZIP108 might play a role in gene activation. PMID- 29518047 TI - Metagenomic Insights into the Phylogenetic and Metabolic Diversity of the Prokaryotic Community Dwelling in Hypersaline Soils from the Odiel Saltmarshes (SW Spain). AB - Hypersaline environments encompass aquatic and terrestrial habitats. While only a limited number of studies on the microbial diversity of saline soils have been carried out, hypersaline lakes and marine salterns have been thoroughly investigated, resulting in an aquatic-biased knowledge about life in hypersaline environments. To improve our understanding of the assemblage of microbes thriving in saline soils, we assessed the phylogenetic diversity and metabolic potential of the prokaryotic community of two hypersaline soils (with electrical conductivities of ~24 and 55 dS/m) from the Odiel saltmarshes (Spain) by metagenomics. Comparative analysis of these soil databases with available datasets from salterns ponds allowed further identification of unique and shared traits of microbial communities dwelling in these habitats. Saline soils harbored a more diverse prokaryotic community and, in contrast to their aquatic counterparts, contained sequences related to both known halophiles and groups without known halophilic or halotolerant representatives, which reflects the physical heterogeneity of the soil matrix. Our results suggest that Haloquadratum and certain Balneolaeota members may preferentially thrive in aquatic or terrestrial habitats, respectively, while haloarchaea, nanohaloarchaea and Salinibacter may be similarly adapted to both environments. We reconstructed 4 draft genomes related to Bacteroidetes, Balneolaeota and Halobacteria and appraised their metabolism, osmoadaptation strategies and ecology. This study greatly improves the current understanding of saline soils microbiota. PMID- 29518048 TI - Meat Quality Derived from High Inclusion of a Micro-Alga or Insect Meal as an Alternative Protein Source in Poultry Diets: A Pilot Study. AB - The effects on meat quality resulting from alternative dietary protein sources (Spirulina and Hermetia meal) in poultry diets are studied to determine the overall suitability of these ingredients considering state-of-the-art packaging practices-highly oxygenated modified atmosphere packaging (HiOx MAP). We monitored standard slaughterhouse parameters, such as live weight, carcass weight, dressed yield, and pH at 20 min and 24 h post mortem. In addition, we studied the effects that 3 and 7-day storage in HiOx MAP has on the overall product physico-chemical and sensory properties. In addition to previously supported effects of HiOx MAP, we found that meat quality could be improved when Spirulina replaces 50% of the soy protein in broiler diets; however, this substitution results in a dark reddish-yellowish meat colour. On the other hand, the substitution with Hermetia larval meal results in a product that does not differ from the standard fed control group, with the exception that the breast filet has a more intense flavour that decreases over storage time. All-in-all Spirulina and Hermetia meal have the potential to replace soybean meal in broiler diets without deteriorating meat quality. PMID- 29518050 TI - Problematic Use of the Internet and Smartphones in University Students: 2006 2017. AB - It has been more than a decade since a concern about the addictive use of the Internet and mobile phones was first expressed, and its possible inclusion into the lists of mental disorders has recently become a popular topic of scientific discussion. Thus, it seems to be a fitting moment to investigate the prevalence of this issue over time. The aim of the present study was to analyze the prevalence of the perception of problematic Internet and smartphone use in young people over the period 2006-2017. To this end, a questionnaire on Internet use habits and two questionnaires on the negative consequences of Internet and smartphone use were administered to a sample of 792 university students. The scores were then compared with the results of former studies that had used these questionnaires. The perception of problematic Internet and mobile phone use has increased over the last decade, social networks are considered responsible for this increase, and females are perceived to be more affected than males. The current study shows how strong smartphone and Internet addiction and social media overlap. Participants from 2017 report higher negative consequences of both Internet and mobile phone use than those from 2006, but long-term observations show a decrease in problematic use after a sharp increase in 2013. We conclude that the diagnosis of technological addictions is influenced by both time and social and culture changes. PMID- 29518049 TI - Control of Bovine Viral Diarrhea. AB - Bovine viral diarrhea (BVD) is one of the most important infectious diseases of cattle with respect to animal health and economic impact. Its stealthy nature, prolonged transient infections, and the presence of persistently infected (PI) animals as efficient reservoirs were responsible for its ubiquitous presence in cattle populations worldwide. Whereas it was initially thought that the infection was impossible to control, effective systematic control strategies have emerged over the last 25 years. The common denominators of all successful control programs were systematic control, removal of PI animals, movement controls for infected herds, strict biosecurity, and surveillance. Scandinavian countries, Austria, and Switzerland successfully implemented these control programs without using vaccination. Vaccination as an optional and additional control tool was used by e.g., Germany, Belgium, Ireland, and Scotland. The economic benefits of BVD control programs had been assessed in different studies. PMID- 29518051 TI - Multi-Target Anti-Alzheimer Activities of Four Prenylated Compounds from Psoralea Fructus. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease that is mediated by multiple signaling pathways. In recent years, the components of Psoralea Fructus (PF) have demonstrated some anti-Alzheimer effects both in vitro and in vivo. To further reveal the active compounds of PF and their mechanisms regulating key targets of AD, in this study, we identified four prenylated compounds from the 70% ethanolic aqueous extract of PF, namely bavachin, bavachinin, bavachalcone, and isobavachalcone. Multi-target bioactivity analysis showed that these compounds could differentially inhibit neuroinflammation, oxidative damage, and key AD-related protein targets, such as amyloid beta peptide 42, beta-secretase, glycogen synthase kinase 3beta, and acetylcholinesterase. These compounds may generate beneficial effects in AD prevention and treatment. PMID- 29518052 TI - The Effects of Aronia melanocarpa 'Viking' Extracts in Attenuating RANKL-Induced Osteoclastic Differentiation by Inhibiting ROS Generation and c-FOS/NFATc1 Signaling. AB - This study aimed to determine the anti-osteoclastogenic effects of extracts from Aronia melanocarpa 'Viking' (AM) and identify the underlying mechanisms in vitro. Reactive oxygen species (ROS) are signal mediators in osteoclast differentiation. AM extracts inhibited ROS production in RAW 264.7 cells in a dose-dependent manner and exhibited strong radical scavenging activity. The extracts also attenuated the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. To attain molecular insights, the effect of the extracts on the signaling pathways induced by receptor activator of nuclear factor kappa B ligand (RANKL) were also investigated. RANKL triggers many transcription factors through the activation of mitogen-activated protein kinase (MAPK) and ROS, leading to the induction of osteoclast-specific genes. The extracts significantly suppressed RANKL-induced activation of MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 and consequently led to the downregulation of c-Fos and nuclear factor of activated T cells 1 (NFATc1) protein expression which ultimately suppress the activation of the osteoclast-specific genes, cathepsin K, TRAP, calcitonin receptor and integrin beta3. In conclusion, our findings suggest that AM extracts inhibited RANKL-induced osteoclast differentiation by downregulating ROS generation and inactivating JNK/ERK/p38, nuclear factor kappa B (NF-kappaB) mediated c-Fos and NFATc1 signaling pathway. PMID- 29518054 TI - Preparation and Dielectric Properties of SiC/LSR Nanocomposites for Insulation of High Voltage Direct Current Cable Accessories. AB - The conductivity mismatch in the composite insulation of high voltage direct current (HVDC) cable accessories causes electric field distribution distortion and even insulation breakdown. Therefore, a liquid silicone rubber (LSR) filled with SiC nanoparticles is prepared for the insulation of cable accessories. The micro-morphology of the SiC/LSR nanocomposites is observed by scanning electron microscopy, and their trap parameters are characterized using thermal stimulated current (TSC) tests. Moreover, the dielectric properties of SiC/LSR nanocomposites with different SiC concentrations are tested. The results show that the 3 wt % SiC/LSR sample has the best nonlinear conductivity, more than one order of magnitude higher than that of pure LSR with improved temperature and nonlinear conductivity coefficients. The relative permittivity increased 0.2 and dielectric loss factor increased 0.003, while its breakdown strength decreased 5 kV/mm compared to those of pure LSR. Moreover, the TSC results indicate the introduction of SiC nanoparticles reduced the trap level and trap density. Furthermore, the SiC nanoparticles filling significantly increased the sensitivity of LSR to electric field stress and temperature changes, enhancing the conductivity and electric field distribution within the HVDC cable accessories, thus improving the reliability of the HVDC cable accessories. PMID- 29518055 TI - Marine Bacterial Polysaccharide EPS11 Inhibits Cancer Cell Growth via Blocking Cell Adhesion and Stimulating Anoikis. AB - Tumor cells that acquire metastatic potential have developed resistance to anoikis, a cell death process, after detachment from their primary site to the second organ. In this study, we investigated the molecular mechanisms of a novel marine bacterial polysaccharide EPS11 which exerts its cytotoxic effects through affecting cancer cell adhesion and anoikis. Firstly, we found that EPS11 could significantly affect cell proliferation and block cell adhesion in A549 cells. We further demonstrated that the expression of several cell adhesion associated proteins is downregulated and the filiform structures of cancer cells are destroyed after EPS11 treatment. Interestingly, the destruction of filiform structures in A549 cells by EPS11 is in a dose-dependent manner, and the inhibitory tendency is very consistent with that observed in the cell adhesion assay, which confirms that filiform structures play important roles in modulating cell adhesion. Moreover, we showed that EPS11 induces apoptosis of A549 cells through stimulating betaIII-tubulin associated anoikis: (i) EPS11 inhibits the expression of betaIII-tubulin in both transcription and translation levels; and (ii) EPS11 treatment dramatically decreases the phosphorylation of protein kinase B (PKB or AKT), a critical downstream effector of betaIII-tubulin. Importantly, EPS11 evidently inhibits the growth of A549-derived tumor xenografts in vivo. Thus, our results suggest that EPS11 may be a potential candidate for human non small cell lung carcinoma treatment via blocking filiform structure mediated adhesion and stimulating betaIII-tubulin associated anoikis. PMID- 29518053 TI - Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines. AB - Flavokawain B (1) is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB), about 23 analogs have been synthesized. Among them, compounds 8, 13 and 23 were found in new FKB derivatives. All compounds were evaluated for their cytotoxic properties against two breast cancer cell lines, MCF-7 and MDA-MB-231, thus establishing the structure-activity relationship. The FKB derivatives 16 (IC50 = 6.50 +/- 0.40 and 4.12 +/- 0.20 MUg/mL), 15 (IC50 = 5.50 +/- 0.35 and 6.50 +/- 1.40 MUg/mL) and 13 (IC50 = 7.12 +/- 0.80 and 4.04 +/- 0.30 MUg/mL) exhibited potential cytotoxic effects on the MCF-7 and MDA-MB-231 cell lines. However, the methoxy group substituted in position three and four in compound 2 (IC50 = 8.90 +/- 0.60 and 6.80 +/- 0.35 MUg/mL) and 22 (IC50 = 8.80 +/- 0.35 and 14.16 +/- 1.10 MUg/mL) exhibited good cytotoxicity. The lead compound FKB (1) showed potential cytotoxicity (IC50 = 7.70 +/- 0.30 and 5.90 +/- 0.30 MUg/mL) against two proposed breast cancer cell lines. It is evident that the FKB skeleton is unique for anticancer agents, additionally, the presence of halogens (Cl and F) in position 2 and 3 also improved the cytotoxicity in FKB series. These findings could help to improve the future drug discovery process to treat breast cancer. A molecular dynamics study of active compounds revealed stable interactions within the active site of Janus kinase. The structures of all compounds were determined by 1H-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques. PMID- 29518056 TI - 20(S)-Ginsenoside Rh2 Induce the Apoptosis and Autophagy in U937 and K562 Cells. AB - Acute myeloid leukemia (AML) and Chronic myelogenous leukemia (CML) are common leukemia in adults. 20(S)-GRh2 is an important bioactive substance that is present in Panax ginseng. However, there are no investigations that deal with the comparison of apoptosis, the occurrence of autophagy, and the relationship between apoptosis and autophagy after being treated with 20(S)-GRh2 in AML and CML. In this study, we explored the effect of 20(S)-GRh2 on the AML and CML (U937 and K562). Fluorescence microscopy, CCK-8, Quantitative realtime PCR, Western blot, transmission electron microscopy (TEM), and flow cytometric analysis were used to detect the occurrence of cell proliferation inhibition, apoptosis, and autophagy. By using the above methods, it was determined that apoptosis induced by 20(S)-GRh2 was more obvious in K562 than U937 cells and 20(S)-GRh2 could generate autophagy in K562 and U937 cells. When pretreated by a specific inhibitor of autophagy, (3-methyladenine), the 20(S)-GRh2-induced apoptosis was enhanced, which indicated that 20(S)-GRh2-induced autophagy may protect U937 and K562 cells from undergoing apoptotic cell death. On the other hand, pretreated by an apoptosis suppressor (Z-VAD-FMK), it greatly induced the autophagy and partially prevented 20(S)-GRh2 induced apoptosis. This phenomenon indicated that 20(S)-GRh2-induced autophagy may serve as a survival mechanism and apoptosis and autophagy could act as partners to induce cell death in a cooperative manner. These findings may provide a rationale for future clinical application by using 20(S)-GRh2 combined autophagy inhibitors for AML and CML. PMID- 29518057 TI - Transport and Field Emission Properties of MoS2 Bilayers. AB - We report the electrical characterization and field emission properties of MoS 2 bilayers deposited on a SiO 2 / Si substrate. Current-voltage characteristics are measured in the back-gate transistor configuration, with Ti contacts patterned by electron beam lithography. We confirm the n-type character of as-grown MoS 2 and we report normally-on field-effect transistors. Local characterization of field emission is performed inside a scanning electron microscope chamber with piezo controlled tungsten tips working as the anode and the cathode. We demonstrate that an electric field of ~ 200 V / MU m is able to extract current from the flat part of MoS 2 bilayers, which can therefore be conveniently exploited for field emission applications even in low field enhancement configurations. We show that a Fowler-Nordheim model, modified to account for electron confinement in two dimensional (2D) materials, fully describes the emission process. PMID- 29518058 TI - Ultra-Fine Bubble Distributions in a Plant Factory Observed by Transmission Electron Microscope with a Freeze-Fracture Replica Technique. AB - Water containing ultra-fine bubbles (UFB) may promote plant growth. But, as UFBs are too small to distinguish from other impurities in a nutrient solution, it is not known if UFBs survive transport from the water source to the rhizosphere. Here we use the freeze-fracture replica method and a transmission electron microscope (TEM) to observe UFBs in the nutrient solutions used in a crop-growing system known as a plant factory. In this factory, TEM images taken from various points in the supply line indicate that the concentration of UFBs in the nutrient solution is conserved, starting from their addition to the nutrient solution in the buffer tank, through the peat-moss layer, all the way to the rhizosphere. Measurements also show that a thin film formed on the surface of UFBs in the nutrient solution, with greater film thickness at the rhizosphere. This film is considered to be made from the accumulation of impurities coming from solute and the peat-moss layer. PMID- 29518059 TI - A Miniaturized Colorimeter with a Novel Design and High Precision for Photometric Detection. AB - Water quality detection plays an increasingly important role in environmental protection. In this work, a novel colorimeter based on the Beer-Lambert law was designed for chemical element detection in water with high precision and miniaturized structure. As an example, the colorimeter can detect phosphorus, which was accomplished in this article to evaluate the performance. Simultaneously, a modified algorithm was applied to extend the linear measurable range. The colorimeter encompassed a near infrared laser source, a microflow cell based on microfluidic technology and a light-sensitive detector, then Micro Electro-Mechanical System (MEMS) processing technology was used to form a stable integrated structure. Experiments were performed based on the ammonium molybdate spectrophotometric method, including the preparation of phosphorus standard solution, reducing agent, chromogenic agent and color reaction. The device can obtain a wide linear response range (0.05 mg/L up to 7.60 mg/L), a wide reliable measuring range up to 10.16 mg/L after using a novel algorithm, and a low limit of detection (0.02 mg/L). The size of flow cell in this design is 18 mm * 2.0 mm * 800 MUm, obtaining a low reagent consumption of 0.004 mg ascorbic acid and 0.011 mg ammonium molybdate per determination. Achieving these advantages of miniaturized volume, high precision and low cost, the design can also be used in automated in situ detection. PMID- 29518060 TI - A Wireless Sensor Network for the Real-Time Remote Measurement of Aeolian Sand Transport on Sandy Beaches and Dunes. AB - Direct measurements of aeolian sand transport on coastal dunes and beaches is of paramount importance to make correct decisions about coast management. As most of the existing studies are mainly based on a statistical approach, the solution presented in this paper proposes a sensing structure able to orient itself according to wind direction and directly calculate the amount of wind-transported sand by collecting it and by measuring its weight. Measurements are performed remotely without requiring human action because the structure is equipped with a ZigBee radio module, which periodically sends readings to a local gateway. Here data are processed by a microcontroller and then transferred to a remote data collection centre, through GSM technology. The ease of installation, the reduced power consumption and the low maintenance required, make the proposed solution able to work independently, limiting human intervention, for all the duration of the expected experimental campaign. In order to analyze the cause-effect relationship between the transported sand and the wind, the sensing structure is integrated with a multi-layer anemoscope-anemometer structure. The overall sensor network has been developed and tested in the laboratory, and its operation has been validated in field through a 48 h measurement campaign. PMID- 29518062 TI - Robust Segmentation of Planar and Linear Features of Terrestrial Laser Scanner Point Clouds Acquired from Construction Sites. AB - Automated segmentation of planar and linear features of point clouds acquired from construction sites is essential for the automatic extraction of building construction elements such as columns, beams and slabs. However, many planar and linear segmentation methods use scene-dependent similarity thresholds that may not provide generalizable solutions for all environments. In addition, outliers exist in construction site point clouds due to data artefacts caused by moving objects, occlusions and dust. To address these concerns, a novel method for robust classification and segmentation of planar and linear features is proposed. First, coplanar and collinear points are classified through a robust principal components analysis procedure. The classified points are then grouped using a new robust clustering method, the robust complete linkage method. A robust method is also proposed to extract the points of flat-slab floors and/or ceilings independent of the aforementioned stages to improve computational efficiency. The applicability of the proposed method is evaluated in eight datasets acquired from a complex laboratory environment and two construction sites at the University of Calgary. The precision, recall, and accuracy of the segmentation at both construction sites were 96.8%, 97.7% and 95%, respectively. These results demonstrate the suitability of the proposed method for robust segmentation of planar and linear features of contaminated datasets, such as those collected from construction sites. PMID- 29518061 TI - Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism. AB - The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways. PMID- 29518063 TI - 4-Methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3-carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties. AB - In order to determine the regularities of the structure-analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3 carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4 methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4 methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form. It has been shown that 4-methyl 2,2-dioxo-1H-2lambda6,1-benzothiazine is easily formed during the decarboxylation of not only 4-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3-carboxylic acid, but also its sodium salt, which is capable of losing SO2 both in rather soft conditions of boiling in an aqueous solution, and in more rigid conditions of dry heating. The NMR spectra of the compounds synthesized are given; their spatial structure is discussed. To study the biological properties of 4-methyl-2,2-dioxo 1H-2lambda6,1-benzothiazine-3-carboxylic acid and its sodium salt, the experimental model of inflammation caused by subplantar introduction of the carrageenan solution in one of the hind limbs of white rats was used. The anti inflammatory activity and analgesic effect were assessed by the degree of edema reduction and the ability to affect the pain response compared to the animals of control groups. According to the results of the tests performed, it has been found that after intraperitoneal injection, the substances synthesized demonstrate a moderate anti-inflammatory action and simultaneously increase the pain threshold of the experimental animals very effectively, exceeding Lornoxicam and Diclofenac in a similar dose by their analgesic activity. PMID- 29518065 TI - QuickStats: Percentage* of Adults Aged >=20 Years Reporting Depressive Symptoms? in the Past 2 Weeks, by Sex - National Health and Nutrition Examination Survey, United States, 2013-2016. AB - During 2013-2016, 76.3% of adults aged >=20 years had no or minimal depressive symptoms, 15.6% had mild symptoms, 5.1% had moderate symptoms, and 2.9% had severe depressive symptoms. A lower percentage of women than men had no or minimal depressive symptoms (71.3% versus 81.6%), but a higher percentage of women than men had mild (18.3% versus 12.8%), moderate (6.7% versus 3.4%), or severe (3.7% versus 2.1%) symptoms. PMID- 29518064 TI - Risk Factors for Depression in Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND Depression is a major comorbidity in Chronic Obstructive Pulmonary Disease (COPD). The aim of this study was to explore cytokine levels, and socio demographic and clinical factors that may affect COPD-related depression. MATERIAL AND METHODS This prospective study enrolled 53 consecutive COPD patients, without any other lower respiratory tract diseases, psychiatric disorders, family history or cognitive disorders, who were hospitalized in the Department of Respiratory Medicine of Hefei First People's Hospital, China between October 2015 and October 2016. All patients were investigated for depression, and the serum levels of C-reactive protein (CRP), interleukin-6 (IL 6), interleukin-8 (IL-8) and Tumor Necrosis Factor-alpha (TNF-alpha) were measured. The factors that may affect COPD-related depression were analyzed. RESULTS There were 40 (75.47%) patients with depression. There were differences in gender, smoking, time of cough, education, forced expiratory volume in the first second (FEV1) and serum CRP levels between COPD patients with or without depression. In a univariate analysis, gender, smoking, education, FEV1, time of cough and serum CRP level were associated with depression. In a multivariate logistic regression model, serum CRP level and FEV1 were risk factors for depression. CONCLUSIONS Male patients, heavy smoking, higher academic qualifications, cough, and high serum CRP level were linked to higher incidence rate of depression. High serum CRP level and low FEV1 were the risk factors for COPD-related depression. PMID- 29518066 TI - Notes from the Field: Brucella abortus Vaccine Strain RB51 Infection and Exposures Associated with Raw Milk Consumption - Wise County, Texas, 2017. PMID- 29518067 TI - Update: Noncongenital Zika Virus Disease Cases - 50 U.S. States and the District of Columbia, 2016. AB - Zika virus is a flavivirus primarily transmitted to humans by Aedes aegypti mosquitoes (1). Zika virus infections also have been documented through intrauterine transmission resulting in congenital infection; intrapartum transmission from a viremic mother to her newborn; sexual transmission; blood transfusion; and laboratory exposure (1-3). Most Zika virus infections are asymptomatic or result in mild clinical illness, characterized by acute onset of fever, maculopapular rash, arthralgia, or nonpurulent conjunctivitis; Guillain Barre syndrome, meningoencephalitis, and severe thrombocytopenia rarely have been associated with Zika virus infection (1). However, congenital Zika virus infection can result in fetal loss, microcephaly, and other birth defects (1,2). In 2016, a total of 5,168 noncongenital Zika virus disease cases were reported from U.S. states and the District of Columbia. Most cases (4,897, 95%) were in travelers returning from Zika virus-affected areas. A total of 224 (4%) cases were acquired through presumed local mosquitoborne transmission, and 47 (1%) were acquired by other routes. It is important that providers in the United States continue to test symptomatic patients who live in or recently traveled to areas with ongoing Zika virus transmission or had unprotected sex with someone who lives in or traveled to those areas. All pregnant women and their partners should take measures to prevent Zika virus infection during pregnancy. A list of affected areas and specific recommendations on how to prevent Zika virus infection during pregnancy are available at https://www.cdc.gov/pregnancy/zika/protect-yourself.html. PMID- 29518068 TI - Update: Dura Mater Graft-Associated Creutzfeldt-Jakob Disease - Japan, 1975-2017. AB - Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft-associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975-2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non-life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD. PMID- 29518069 TI - Vital Signs: Trends in Emergency Department Visits for Suspected Opioid Overdoses - United States, July 2016-September 2017. AB - INTRODUCTION: From 2015 to 2016, opioid overdose deaths increased 27.7%, indicating a worsening of the opioid overdose epidemic and highlighting the importance of rapid data collection, analysis, and dissemination. METHODS: Emergency department (ED) syndromic and hospital billing data on opioid-involved overdoses during July 2016-September 2017 were examined. Temporal trends in opioid overdoses from 52 jurisdictions in 45 states were analyzed at the regional level and by demographic characteristics. To assess trends based on urban development, data from 16 states were analyzed by state and urbanization level. RESULTS: From July 2016 through September 2017, a total of 142,557 ED visits (15.7 per 10,000 visits) from 52 jurisdictions in 45 states were suspected opioid involved overdoses. This rate increased on average by 5.6% per quarter. Rates increased across demographic groups and all five U.S. regions, with largest increases in the Southwest, Midwest, and West (approximately 7%-11% per quarter). In 16 states, 119,198 ED visits (26.7 per 10,000 visits) were suspected opioid involved overdoses. Ten states (Delaware, Illinois, Indiana, Maine, Missouri, Nevada, North Carolina, Ohio, Pennsylvania, and Wisconsin) experienced significant quarterly rate increases from third quarter 2016 to third quarter 2017, and in one state (Kentucky), rates decreased significantly. The highest rate increases occurred in large central metropolitan areas. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: With continued increases in opioid overdoses, availability of timely data are important to inform actions taken by EDs and public health practitioners. Increases in opioid overdoses varied by region and urbanization level, indicating a need for localized responses. Educating ED physicians and staff members about appropriate services for immediate care and treatment and implementing a post-overdose protocol that includes naloxone provision and linking persons into treatment could assist EDs with preventing overdose. PMID- 29518070 TI - Dental Personnel Treated for Idiopathic Pulmonary Fibrosis at a Tertiary Care Center - Virginia, 2000-2015. AB - In April 2016, a Virginia dentist who had recently received a diagnosis of idiopathic pulmonary fibrosis (IPF) and was undergoing treatment at a specialty clinic at a Virginia tertiary care center contacted CDC to report concerns that IPF had been diagnosed in multiple Virginia dentists who had sought treatment at the same specialty clinic. IPF is a chronic, progressive lung disease of unknown cause and associated with a poor prognosis (1). Although IPF has been associated with certain occupations (2), no published data exist regarding IPF in dentists. The medical records for all 894 patients treated for IPF at the Virginia tertiary care center during September 1996-June 2017 were reviewed for evidence that the patient had worked as a dentist, dental hygienist, or dental technician; among these patients, eight (0.9%) were identified as dentists and one (0.1%) as a dental technician, and each had sought treatment during 2000-2015. Seven of these nine patients had died. A questionnaire was administered to one of the living patients, who reported polishing dental appliances and preparing amalgams and impressions without respiratory protection. Substances used during these tasks contained silica, polyvinyl siloxane, alginate, and other compounds with known or potential respiratory toxicity. Although no clear etiologies for this cluster exist, occupational exposures possibly contributed. This cluster of IPF cases reinforces the need to understand further the unique occupational exposures of dental personnel and the association between these exposures and the risk for developing IPF so that appropriate strategies can be developed for the prevention of potentially harmful exposures. PMID- 29518071 TI - Stoichiometric balance of protein copy numbers is measurable and functionally significant in a protein-protein interaction network for yeast endocytosis. AB - Stoichiometric balance, or dosage balance, implies that proteins that are subunits of obligate complexes (e.g. the ribosome) should have copy numbers expressed to match their stoichiometry in that complex. Establishing balance (or imbalance) is an important tool for inferring subunit function and assembly bottlenecks. We show here that these correlations in protein copy numbers can extend beyond complex subunits to larger protein-protein interactions networks (PPIN) involving a range of reversible binding interactions. We develop a simple method for quantifying balance in any interface-resolved PPINs based on network structure and experimentally observed protein copy numbers. By analyzing such a network for the clathrin-mediated endocytosis (CME) system in yeast, we found that the real protein copy numbers were significantly more balanced in relation to their binding partners compared to randomly sampled sets of yeast copy numbers. The observed balance is not perfect, highlighting both under and overexpressed proteins. We evaluate the potential cost and benefits of imbalance using two criteria. First, a potential cost to imbalance is that 'leftover' proteins without remaining functional partners are free to misinteract. We systematically quantify how this misinteraction cost is most dangerous for strong binding protein interactions and for network topologies observed in biological PPINs. Second, a more direct consequence of imbalance is that the formation of specific functional complexes depends on relative copy numbers. We therefore construct simple kinetic models of two sub-networks in the CME network to assess multi-protein assembly of the ARP2/3 complex and a minimal, nine-protein clathrin coated vesicle forming module. We find that the observed, imperfectly balanced copy numbers are less effective than balanced copy numbers in producing fast and complete multi-protein assemblies. However, we speculate that strategic imbalance in the vesicle forming module allows cells to tune where endocytosis occurs, providing sensitive control over cargo uptake via clathrin-coated vesicles. PMID- 29518072 TI - Ten simple rules to create a serious game, illustrated with examples from structural biology. PMID- 29518075 TI - Participatory approaches and open data on venomous snakes: A neglected opportunity in the global snakebite crisis? PMID- 29518073 TI - Method for the simulation of blood platelet shape and its evolution during activation. AB - We present a simple physically based quantitative model of blood platelet shape and its evolution during agonist-induced activation. The model is based on the consideration of two major cytoskeletal elements: the marginal band of microtubules and the submembrane cortex. Mathematically, we consider the problem of minimization of surface area constrained to confine the marginal band and a certain cellular volume. For resting platelets, the marginal band appears as a peripheral ring, allowing for the analytical solution of the minimization problem. Upon activation, the marginal band coils out of plane and forms 3D convoluted structure. We show that its shape is well approximated by an overcurved circle, a mathematical concept of closed curve with constant excessive curvature. Possible mechanisms leading to such marginal band coiling are discussed, resulting in simple parametric expression for the marginal band shape during platelet activation. The excessive curvature of marginal band is a convenient state variable which tracks the progress of activation. The cell surface is determined using numerical optimization. The shapes are strictly mathematically defined by only three parameters and show good agreement with literature data. They can be utilized in simulation of platelets interaction with different physical fields, e.g. for the description of hydrodynamic and mechanical properties of platelets, leading to better understanding of platelets margination and adhesion and thrombus formation in blood flow. It would also facilitate precise characterization of platelets in clinical diagnosis, where a novel optical model is needed for the correct solution of inverse light scattering problem. PMID- 29518076 TI - Bat detective-Deep learning tools for bat acoustic signal detection. AB - Passive acoustic sensing has emerged as a powerful tool for quantifying anthropogenic impacts on biodiversity, especially for echolocating bat species. To better assess bat population trends there is a critical need for accurate, reliable, and open source tools that allow the detection and classification of bat calls in large collections of audio recordings. The majority of existing tools are commercial or have focused on the species classification task, neglecting the important problem of first localizing echolocation calls in audio which is particularly problematic in noisy recordings. We developed a convolutional neural network based open-source pipeline for detecting ultrasonic, full-spectrum, search-phase calls produced by echolocating bats. Our deep learning algorithms were trained on full-spectrum ultrasonic audio collected along road-transects across Europe and labelled by citizen scientists from www.batdetective.org. When compared to other existing algorithms and commercial systems, we show significantly higher detection performance of search-phase echolocation calls with our test sets. As an example application, we ran our detection pipeline on bat monitoring data collected over five years from Jersey (UK), and compared results to a widely-used commercial system. Our detection pipeline can be used for the automatic detection and monitoring of bat populations, and further facilitates their use as indicator species on a large scale. Our proposed pipeline makes only a small number of bat specific design decisions, and with appropriate training data it could be applied to detecting other species in audio. A crucial novelty of our work is showing that with careful, non-trivial, design and implementation considerations, state-of-the-art deep learning methods can be used for accurate and efficient monitoring in audio. PMID- 29518074 TI - RNA helicase, DDX27 regulates skeletal muscle growth and regeneration by modulation of translational processes. AB - Gene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to the production of specific proteins that are important determinants of cellular identity. Ribosomes are a central component of the protein biosynthesis machinery in cells; however, their regulatory roles in the translational control of gene expression in skeletal muscle remain to be defined. In a genetic screen to identify critical regulators of myogenesis, we identified a DEAD-Box RNA helicase, DDX27, that is required for skeletal muscle growth and regeneration. We demonstrate that DDX27 regulates ribosomal RNA (rRNA) maturation, and thereby the ribosome biogenesis and the translation of specific transcripts during myogenesis. These findings provide insight into the translational regulation of gene expression in myogenesis and suggest novel functions for ribosomes in regulating gene expression in skeletal muscles. PMID- 29518078 TI - Factors associated with knee pain in 5148 women aged 50 years and older: A population-based study. AB - OBJECTIVE: This study was performed to investigate the factors associated with the level of knee pain in a nationally representative sample of noninstitutionalized women aged 50 years or older. METHODS: Women aged 50 years or older were selected and included in the data analyses from the Korean National Health and Nutrition Examination Surveys (2010-2013). Those having malignant diseases or using osteoarthritis medication were excluded. Significant factors associated with the level of knee pain were analyzed using multivariate regression analysis. RESULTS: A total of 5148 women (average age, 62.9 years; standard deviation, 9.3 years) were included. For women without knee osteoarthritis, level of hip pain (p<0.001), presence of back pain (p<0.001), age (p<0.001), and body mass index (BMI) (p<0.001) were found to be significant factors associated with the level of knee pain. For women with knee osteoarthritis, the radiographic grade of knee osteoarthritis (p<0.001), presence of back pain (p<0.001), level of hip pain (p<0.001), presence of depressive symptoms (p<0.001), and BMI (p = 0.026) were the factors significantly associated with the level of knee pain. CONCLUSIONS: Women without knee osteoarthritis tended to report increasing knee pain with increasing age. BMI is considered a significant controllable factor in knee pain in women regardless of the presence of radiographic knee osteoarthritis. The presence of depressive symptoms may aggravate knee pain in women with knee osteoarthritis. Attention needs to be focused on concomitant musculoskeletal problems such as lumbar spinal and hip diseases in women with knee pain. PMID- 29518079 TI - Cuticular fatty acids of Galleria mellonella (Lepidoptera) inhibit fungal enzymatic activities of pathogenic Conidiobolus coronatus. AB - The entomopathogenic fungus Conidiobolus coronatus produces enzymes that may hydrolyze the cuticle of Galleria mellonella. Of these enzymes, elastase activity was the highest: this figure being 24 times higher than NAGase activity 553 times higher than chitinase activity and 1844 times higher than lipase activity. The present work examines the differences in the hydrolysis of cuticles taken from larvae, pupae and adults (thorax and wings), by C. coronatus enzymes. The cuticles of the larvae and adult thorax were the most susceptible to digestion by proteases and lipases. Moreover, the maximum concentration of free N-glucosamine was in the hydrolysis of G. mellonella thorax. These differences in the digestion of the various types of cuticle may result from differences in their composition. GC-MS analysis of the cuticular fatty acids isolated from pupae of G. mellonella confirmed the presence of C 8:0, C 9:0, C 12:0, C 14:0, C 15:0, C 16:1, C 16:0, C 17:0, C 18:1, C 18:0, with C 16:0 and C 18:0 being present in the highest concentrations. Additional fatty acids were found in extracts from G. mellonella imagines: C 10:0, C 13:0, C 20:0 and C 20:1, with a considerable dominance of C 16:0 and C 18:1. In larvae, C 16:0 and C 18:1 predominated. Statistically significant differences in concentration (p<=0.05) were found between the larvae, pupae and imago for each fatty acid. The qualitative and quantitative differences in the fatty acid composition of G. mellonella cuticle occurring throughout normal development might be responsible for the varied efficiency of fungal enzymes in degrading larval, pupal and adult cuticles. PMID- 29518077 TI - Changes of attachment characteristics during psychotherapy of patients with social anxiety disorder: Results from the SOPHO-Net trial. AB - OBJECTIVES: Within a randomized controlled trial contrasting the outcome of manualized cognitive-behavioral (CBT) and short term psychodynamic therapy (PDT) compared to a waiting list condition (the SOPHO-Net trial), we set out to test whether self-reported attachment characteristics change during the treatments and if these changes differ between treatments. RESEARCH DESIGN AND METHODS: 495 patients from the SOPHO-Net trial (54.5% female, mean age 35.2 years) who were randomized to either CBT, PDT or waiting list (WL) completed the partner-related revised Experiences in Close Relationships Questionnaire (ECR-R) before and after treatment and at 6 and 12 months follow-up. The Liebowitz Social Anxiety Scale (LSAS) was administered at pre-treatment, post-treatment, and at 6-month and 1 year follow-up. ECR-R scores were first compared to a representative healthy sample (n = 2508) in order to demonstrate that the clinical sample differed significantly from the non-clinical sample with respect to attachment anxiety and avoidance. RESULTS: LSAS scores correlated significantly with both ECR-R subscales. Post-therapy, patients treated with CBT revealed significant changes in attachment anxiety and avoidance whereas patients treated with PDT showed no significant changes. Changes between post-treatment and the two follow-ups were significant in both conditions, with minimal (insignificant) differences between treatments at the 12- month follow-up. CONCLUSIONS: The current study supports recent reviews of mostly naturalistic studies indicating changes in attachment as a result of psychotherapy. Although there were differences between conditions at the end of treatment, these largely disappeared during the follow-up period which is line with the other results of the SOPHO-NET trial. TRIAL REGISTRATION: Controlled-trials.com ISRCTN53517394. PMID- 29518080 TI - Biophysical subsets of embryonic stem cells display distinct phenotypic and morphological signatures. AB - The highly proliferative and pluripotent characteristics of embryonic stem cells engender great promise for tissue engineering and regenerative medicine, but the rapid identification and isolation of target cell phenotypes remains challenging. Therefore, the objectives of this study were to characterize cell mechanics as a function of differentiation and to employ differences in cell stiffness to select population subsets with distinct mechanical, morphological, and biological properties. Biomechanical analysis with atomic force microscopy revealed that embryonic stem cells stiffened within one day of differentiation induced by leukemia inhibitory factor removal, with a lagging but pronounced change from spherical to spindle-shaped cell morphology. A microfluidic device was then employed to sort a differentially labeled mixture of pluripotent and differentiating cells based on stiffness, resulting in pluripotent cell enrichment in the soft device outlet. Furthermore, sorting an unlabeled population of partially differentiated cells produced a subset of "soft" cells that was enriched for the pluripotent phenotype, as assessed by post-sort characterization of cell mechanics, morphology, and gene expression. The results of this study indicate that intrinsic cell mechanical properties might serve as a basis for efficient, high-throughput, and label-free isolation of pluripotent stem cells, which will facilitate a greater biological understanding of pluripotency and advance the potential of pluripotent stem cell differentiated progeny as cell sources for tissue engineering and regenerative medicine. PMID- 29518081 TI - Study of diagnostic accuracy of Helmintex, Kato-Katz, and POC-CCA methods for diagnosing intestinal schistosomiasis in Candeal, a low intensity transmission area in northeastern Brazil. AB - Control initiatives have successfully reduced the prevalence and intensity of schistosomiasis transmission in several localities around the world. However, individuals that release low numbers of eggs in their feces may not be detected by classical methods that are limited by low sensitivity. Given that accurate estimates of prevalence are key to implementing planning control actions for the elimination of schistosomiasis, new diagnostic tools are needed to effectively monitor infections and confirm transmission interruption. The World Health Organization recommends the Kato-Katz (KK) thick smear as a parasitological test for epidemiological surveys, even though this method has been demonstrated to underestimate prevalence when egg burdens are low. The point-of-care immunodiagnostic for detecting schistosome cathodic circulating antigen (POC-CCA) method has been proposed as a more sensitive substitute for KK in prevalence estimations. An alternative diagnostic, the Helmintex (HTX) method, isolates eggs from fecal samples with the use of paramagnetic particles in a magnetic field. Here, a population-based study involving 461 individuals from Candeal, Sergipe State, Brazil, was conducted to evaluate these three methods comparatively by latent class analysis (LCA). The prevalence of schistosomiasis mansoni was determined to be 71% with POC-CCA, 40.% with HTX and 11% with KK. Most of the egg burdens of the individuals tested (70%) were < 1 epg, thereby revealing a dissociation between prevalence and intensity in this locality. Therefore, the present results confirm that the HTX method is a highly sensitive egg detection procedure and support its use as a reference method for diagnosing intestinal schistosomiasis and for comparative evaluation of other tests. PMID- 29518082 TI - Determinants of late antenatal care presentation in rural and peri-urban communities in South Africa: A cross-sectional study. AB - OBJECTIVE: To investigate and compare determinates for delayed first presentation to antenatal care (ANC) services. METHODS: A cross-sectional study was conducted amongst pregnant women attending their first ANC visit in rural Capricorn District and peri-urban Tlokwe sub-district communities in South Africa. Data collection included questionnaires and medical record abstraction. Bivariate and multivariate analyses assessed factors associated with late ANC presentation. RESULTS: We recruited 807 pregnant women. Of these, 51% of rural women and 28% of peri-urban women presented late for first ANC. Rural women were more likely to present late for first ANC (AOR = 2.65; 95% CI 1.98-3.55) and report barriers to accessing ANC services (P<0.0001). Late ANC presentation in rural communities was associated with being married (AOR = 2.36; 95% CI 1.33-4.19), employed (AOR = 1.90; 95% CI 1.03-3.50), <20 years of age (AOR = 2.19; 95% CI 1.10-4.37), and reporting an unplanned pregnancy (AOR = 2.21; 95% CI 1.40-3.50). Late presentation in peri-urban communities was associated with unplanned pregnancy (AOR = 1.67; 95% CI 1.01-2.74), being told to come back later to initiate ANC after presenting early (AOR 0.51; 95% CI 0.30-0.89) and being pregnant for the first time (AOR = 0.56; 95% CI 0.34-0.94). CONCLUSION: Both rural and peri-urban women had high rates of late presentation for first ANC. However, women in the rural communities were more likely to present late. Unplanned pregnancy was an independent risk factor in both rural and peri-urban communities. Interventions around family planning, especially for adolescent girls and young women, are needed to improve early presentation for ANC. PMID- 29518083 TI - An acute acalculous cholecystitis in a returned travel couple. PMID- 29518084 TI - Childhood leptospirosis in an industrialized country: Population-based study in Okinawa, Japan. AB - Leptospirosis is considered underdiagnosed because of its nonspecific presentation and lack of proper understanding of its epidemiology. Early diagnosis and treatment are crucial. However, few data are available on confirmed leptospirosis cases in children in industrialized countries. We therefore aimed to describe epidemiologic and clinical characteristics of laboratory-confirmed childhood leptospirosis in Okinawa, Japan. We reviewed the national surveillance data of pediatric leptospirosis in Okinawa, Japan from January 2003 through December 2015. The database included all of laboratory-confirmed leptospirosis diagnosed at the only central laboratory for leptospirosis in the region. There were 44 children (0-20 years of age) with laboratory-confirmed leptospirosis. Of these, 90% were male, 91% were 10-20 years of age, and 96% of cases occurred in August and September. The number of laboratory-confirmed patients ranged from 0 to 11 per year (mean: 3.3 per year), and the estimated annual rate was 1.0 per 100,000 pediatric populations. In all cases, the presumed infection route was recreational exposure to river water. Commonly observed manifestations include fever (95%), myalgia (52%), and conjunctival suffusion (52%). Childhood leptospirosis in Okinawa, Japan occurred predominantly in teenage boys after freshwater exposure in summer, and most patients had characteristic conjunctival suffusion. Cohort studies would be helpful to better understand more detailed clinical manifestations in association with prognosis. PMID- 29518085 TI - Effects of packaging materials on storage quality of peanut kernels. AB - In order to obtain optimum packaging materials for peanut kernels, the effects of four types of packaging materials on peanut storage quality (coat color, acid value, germination rate, relative damage, and prevention of aflatoxin contamination) were examined. The results showed that packaging materials had a major influence on peanut storage quality indexes. The color of the peanut seed coat packaged in the polyester/aluminum/polyamide/polyethylene (PET/AL/PA/PE) composite film bag did not change significantly during the storage period. Color deterioration was slower with polyamide/polyethylene (PA/PE) packaging materials than with polyethylene (PE) film bags and was slower in PE bags than in the woven bags. The use of PET/AL/PA/PE and PA/PE bags maintained peanut quality and freshness for more than one year and both package types resulted in better germination rates. There were significant differences between the four types of packaging materials in terms of controlling insect pests. The peanuts packaged in the highly permeable woven bags suffered serious invasion from insect pests, while both PET/AL/PA/PE and PA/PE bags effectively prevented insect infection. Peanuts stored in PET/AL/PA/PE and PA/PE bags were also better at preventing and controlling aflatoxin contamination. PMID- 29518086 TI - Imidacloprid soil movement under micro-sprinkler irrigation and soil-drench applications to control Asian citrus psyllid (ACP) and citrus leafminer (CLM). AB - Imidacloprid (IM) is used to control the Asian Citrus Psyllid (ACP) and citrus leafminer (CLM), which are related to the spread of huanglongbing (HLB or citrus greening) and citrus canker diseases, respectively. In Florida citrus, imidacloprid is mainly soil-drenched around the trees for proper root uptake and translocation into plant canopy to impact ACP and CLM. The objective of this study was to determine the effect of imidacloprid rate, and irrigate amount on concentration of imidacloprid in the soil following drench application to citrus trees in three age classes. The plots were established at the Southwest Florida Research and Education Center, Immokalee, using a randomized complete-block design for three age classes of trees: one-year-old trees (B1), three to five year-old trees (B2), and eight-year-old trees (B3). The treatments were a combination of two rates each of imidacloprid (1D, 2D) and micro-sprinkling irrigation (1I, 2I). Imidacloprid and bromide (Br-) used as tracer were applied simultaneously. Soil moisture and concentrations of imidacloprid and Br were monitored using soil cores from hand held augers. Soil moisture content (thetaV) did not differ under two irrigation rates at any given observation day or depth, except following heavy rainfall events. Br- was lost from the observation depths (0-45 cm) about two weeks after soil-drench. Contrarily, imidacloprid persisted for a much longer time (4-8 weeks) at all soil depths, regardless of treatment combinations. The higher retardation of imidacloprid was related to the predominantly unsaturated conditions of the soil (which in turn reduced soil hydraulic conductivities by orders of magnitude), the imidacloprid sorption on soil organic matter, and the citrus root uptake. Findings of this study are important for citrus growers coping with the citrus greening and citrus canker diseases because they suggest that imidacloprid soil drenches can still be an effective control measure of ACP and CLM, and the potential for imidacloprid leaching to groundwater is minimal. PMID- 29518088 TI - Short term dynamics of the sputum microbiome among COPD patients. AB - Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by incompletely reversible airflow obstruction. The complexity of the lung microbial community in COPD patients has been highlighted in recent years. Evidence suggests that transplantation, medications, age, and disease severity influence microbial community membership. However, the dynamics of the lung microbiome in stable COPD patients remain poorly understood. In this study, we completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on replicate sputum samples collected from 4 former smokers with COPD (Stage 2) within a 2-day time period. Samples from each individual over the two-day period were similar based on alpha-diversity, principle component analysis and taxonomy at the phyla and genera level. Sputum samples from COPD patients were also collected between 2-9 months of follow-up. Data suggest an increased variability of the sputum microbiota when comparing samples collected <= 3 months compared to those collected >= 4 months; however, no statistically significant shifts in the abundance (>2-fold) of taxa between the two time points was observed. Bacterial composition and the number of operational taxonomic units (OTUs) remained similar over time. Results from this study suggest that the sputum microbiome is relatively stable in clinically stable COPD patients (Stage 2). This study furthers our understanding of the dynamics of the lung microbiome in COPD patients. PMID- 29518089 TI - Differential desulfurization of dibenzothiophene by newly identified MTCC strains: Influence of Operon Array. AB - Since the sulfur specific cleavage is vital for the organic sulfur removal from fossil fuel, we explored potential bacterial strains of MTCC (Microbial Type Culture Collection) to desulfurize the Dibenzothiophene (DBT) through C-S bond cleavage (4-S pathway). MTCC strains Rhodococcus rhodochrous (3552), Arthrobacter sulfureus (3332), Gordonia rubropertincta (289), and Rhodococcus erythropolis (3951) capable of growing in 0.5 mM DBT were examined for their desulfurization ability. The presence of dsz genes as well as the metabolites was screened by polymerase chain reaction (PCR) and HPLC, respectively. All these strains showed > 99% DBT desulfurization with 10 days of incubation in minimal salt medium. From the HPLC analysis it was further revealed that these MTCC strains show differences in the end metabolites and desulfurize DBT differently following a variation in the regular 4-S pathway. These findings are also well corroborating with their respective organization of dszABC operons and their relative abundance. The above MTCC strains are capable of desulfurizing DBT efficiently and hence can be explored for biodesulfurization of petrochemicals and coal with an eco-friendly and energy economical process. PMID- 29518087 TI - Fibroblast growth factor 23 is upregulated in the kidney in a chronic kidney disease rat model. AB - The hormone fibroblast growth factor 23 (FGF23) is secreted from bone and is involved in phosphorus (P) metabolism. FGF23 mainly binds the FGF receptor, which interacts with alphaKlotho in the kidney or parathyroid and regulates Na dependent phosphate co-transporter type IIa (NaPi-IIa) and type IIc (NaPi-IIc) expression, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity, and parathyroid hormone (PTH) secretion. In this study, we utilized hemi-nephrectomized rats fed a high-P diet (HP Nx), rats subjected to a partial nephrectomy (PN) and rats with doxorubicin-induced renal failure (DXR) as chronic kidney disease (CKD) animal models and analyzed the P metabolism and FGF23 expression in the kidneys in each CKD model. We cultured HK2 cells with a high level of P, 1,25(OH)2D3 or transforming growth factor-beta1 (TGFbeta1) to investigate the FGF23 expression mechanism. In both the HP Nx and PN rats, the blood FGF23 and PTH levels were increased. However, the 1,25(OH)2D3 level was increased in the HP Nx rats and decreased in the PN rats. In all three animal models, the mRNA expression of alphaKlotho, NaPi-IIa and NaPi-IIc was decreased, and the mRNA expression of TGFbeta1, collagen1a1, osteopontin and FGF23 was elevated in the kidney. FGF23 protein and mRNA were expressed at high levels in the extended tubule epithelium, which was an osteopontin-positive region in the HP and PN rats. FGF23 and osteopontin mRNAs were expressed in HK2 cells incubated with TGFbeta1; however, these levels were not altered in HK2 cells incubated with 1,25(OH)2D3 and high P levels in vitro. Altogether, FGF23 is expressed in the kidneys in CKD model rats. Following stimulation with TGFbeta1, the injured renal tubular epithelial cells are strongly suspected to express both FGF23 and osteopontin. FGF23 produced in the kidney might contribute to P metabolism in subjects with CKD. PMID- 29518090 TI - Gait phenotypes in paediatric hereditary spastic paraplegia revealed by dynamic time warping analysis and random forests. AB - The Hereditary Spastic Paraplegias (HSP) are a group of heterogeneous disorders with a wide spectrum of underlying neural pathology, and hence HSP patients express a variety of gait abnormalities. Classification of these phenotypes may help in monitoring disease progression and personalizing therapies. This is currently managed by measuring values of some kinematic and spatio-temporal parameters at certain moments during the gait cycle, either in the doctor's surgery room or after very precise measurements produced by instrumental gait analysis (IGA). These methods, however, do not provide information about the whole structure of the gait cycle. Classification of the similarities among time series of IGA measured values of sagittal joint positions throughout the whole gait cycle can be achieved by hierarchical clustering analysis based on multivariate dynamic time warping (DTW). Random forests can estimate which are the most important isolated parameters to predict the classification revealed by DTW, since clinicians need to refer to them in their daily practice. We acquired time series of pelvic, hip, knee, ankle and forefoot sagittal angular positions from 26 HSP and 33 healthy children with an optokinetic IGA system. DTW revealed six gait patterns with different degrees of impairment of walking speed, cadence and gait cycle distribution and related with patient's age, sex, GMFCS stage, concurrence of polyneuropathy and abnormal visual evoked potentials or corpus callosum. The most important parameters to differentiate patterns were mean pelvic tilt and hip flexion at initial contact. Longer time of support, decreased values of hip extension and increased knee flexion at initial contact can differentiate the mildest, near to normal HSP gait phenotype and the normal healthy one. Increased values of knee flexion at initial contact and delayed peak of knee flexion are important factors to distinguish GMFCS stages I from II-III and concurrence of polyneuropathy. PMID- 29518091 TI - Rapid environmental effects on gut nematode susceptibility in rewilded mice. AB - Genetic and environmental factors shape host susceptibility to infection, but how and how rapidly environmental variation might alter the susceptibility of mammalian genotypes remains unknown. Here, we investigate the impacts of seminatural environments upon the nematode susceptibility profiles of inbred C57BL/6 mice. We hypothesized that natural exposure to microbes might directly (e.g., via trophic interactions) or indirectly (e.g., via microbe-induced immune responses) alter the hatching, growth, and survival of nematodes in mice housed outdoors. We found that while C57BL/6 mice are resistant to high doses of nematode (Trichuris muris) eggs under clean laboratory conditions, exposure to outdoor environments significantly increased their susceptibility to infection, as evidenced by increased worm burdens and worm biomass. Indeed, mice kept outdoors harbored as many worms as signal transducer and activator of transcription 6 (STAT6) knockout mice, which are genetically deficient in the type 2 immune response essential for clearing nematodes. Using 16S ribosomal RNA sequencing of fecal samples, we discovered enhanced microbial diversity and specific bacterial taxa predictive of nematode burden in outdoor mice. We also observed decreased type 2 and increased type 1 immune responses in lamina propria and mesenteric lymph node (MLN) cells from infected mice residing outdoors. Importantly, in our experimental design, different groups of mice received nematode eggs either before or after moving outdoors. This contrasting timing of rewilding revealed that enhanced hatching of worms was not sufficient to explain the increased worm burdens; instead, microbial enhancement and type 1 immune facilitation of worm growth and survival, as hypothesized, were also necessary to explain our results. These findings demonstrate that environment can rapidly and significantly shape gut microbial communities and mucosal responses to nematode infections, leading to variation in parasite expulsion rates among genetically similar hosts. PMID- 29518092 TI - Paradoxical worsening of Emergomyces africanus infection in an HIV-infected male on itraconazole and antiretroviral therapy. PMID- 29518093 TI - Selection and characterization of probiotic lactic acid bacteria and its impact on growth, nutrient digestibility, health and antioxidant status in weaned piglets. AB - The present study was aimed to develop an effective probiotic lactic acid bacteria (LAB) from piglet feces and in vitro characterization of probiotic properties. To confirm host-species specificity of probiotics, the efficacy of isolated LAB on growth, nutrient utilization, health and antioxidant status was observed in early weaned piglets. A total of 30 LAB were isolated from feces of five healthy piglets (28d old). All isolates were Gram positive, cocco-bacilli and catalase negative. Out of thirty LAB isolates, twenty were shortlisted on the basis of their tolerance to pH (3.0, 4.0, 7.0 and 8.0) and bile salts (0.075, 0.15, 0.3 and 1.0%). Whereas, fourteen isolates were selected for further in vitro probiotic characterization due higher (P<0.05) cell surface hydrophobicity to toluene (>45 percent). These isolates fermented twenty-seven different carbohydrates but were negative for ONPG, citrate and malonate. Also enabled to synthesize amylase, protease, lipase and phytase. They were sensitive to penicillin, azithromycin, lincomycin, clindamycin, erythromycin, cephalothin and chloramphenicol and resistant to ciprofloxacin, ofloxacin, gatifloxacin, vancomycin and co-trimoxazole. Except three isolates, all showed antagonistic activity (>60% co-culture activity) against Escherichia coli, Salmonella Enteritidis, Salmonella serotype (ser.) Typhimurium, Staphylococcus intermedius, Staph. chromogenes, Proteus mirabillis, Areomonas veonii, Bordetella bronchioseptica and Klebsialla oxytoca. The isolate Lacp28 exhibited highest tolerance to acidic pH and bile salts (up to 0.3%), phytase activity, cell surface hydrophobicity, antagonistic activity and co-culture assay (>80% growth inhibition). Host specificity of Lacp28 was further confirmed by heavy in vitro adhesion to pig intestinal epithelium cells compared to chicken. Hence, Lacp28 was selected and identified by phylogenetic analysis of 16S rRNA as Pediococcus acidilactici strain FT28 with 100% similarity (GenBank accession nos. KU837245, KU837246 and KU837247). The Pediococcus acidilactici FT28 was selected as potential probiotic candidature for in vivo efficacy in weaned pigs. Thirty-six crossbred piglets (28d) were randomly distributed into three groups (four replicates of three each) namely, basal diet without probiotics (T0) or with Lactobacillus acidophilus NCDC15 (conventional dairy-specific probiotic; T1) or Pediococcus acidilactici FT28 (swine-specific probiotic; T2). At end of the experiment, six piglets of similar body weight were selected to conduct digestion trial for estimation of nutrient digestibility. Results of the study indicated that supplementation of both probiotics improved (P<0.001) FCR compared to control without significant effect in average daily gain and DM intake. However, the apparent digestibility of crude protein and ether extract was better (P<0.01) in pigs fed P. acidilactici FT28 compared control and L. acidophilus fed groups. The total WBC and RBC count, serum glucose, total protein, albumin and globulin concentration was higher (P<0.05) in P. acidilactici FT28 fed group with better (P<0.05) catalase and superoxide dismutase activity measured in erythrocyte. It is concluded that species-specific Pediococcus acidilactici FT28 isolated with potential in vitro probiotic properties and also hold probiotic candidature by showing the potential capabilities with higher nutrient digestibility, heamato biochemical and antioxidant status compared to control and Lactobacillus acidophilus NCDC15. PMID- 29518094 TI - A randomized controlled trial-based algorithm for insulin-pump therapy in hyperglycemic patients early after kidney transplantation. AB - Treating hyperglycemia in previously non-diabetic individuals with exogenous insulin immediately after kidney transplantation reduced the odds of developing Posttransplantation Diabetes Mellitus (PTDM) in our previous proof-of-concept clinical trial. We hypothesized that insulin-pump therapy with maximal insulin dosage during the afternoon would improve glycemic control compared to basal insulin and standard-of-care. In a multi-center, randomized, controlled trial testing insulin isophane for PTDM prevention, we added a third study arm applying continuous subcutaneous insulin lispro infusion (CSII) treatment. CSII was initiated in 24 patients aged 55+/-12 years, without diabetes history, receiving tacrolimus. The mean daily insulin lispro dose was 9.2+/-5.2 IU. 2.3+/-1.1% of the total insulin dose were administered between 00:00 and 6:00, 19.5+/-11.6% between 6:00 and 12:00, 62.3+/-15.6% between 12:00 and 18:00 and 15.9+/-9.1% between 18:00 and 24:00. Additional bolus injections were necessary in five patients. Mild hypoglycemia (52-60 mg/dL) occurred in two patients. During the first post-operative week glucose control in CSII patients was overall superior compared to standard-of-care as well as once-daily insulin isophane for fasting and post-supper glucose. We present an algorithm for CSII treatment in kidney transplant recipients, demonstrating similar safety and superior short-term efficacy compared to standard-of-care and once-daily insulin isophane. PMID- 29518095 TI - Increase of Neisseria meningitidis W:cc11 invasive disease in Chile has no correlation with carriage in adolescents. AB - Neisseria meningitidis is a human exclusive pathogen that can lead to invasive meningococcal disease or may be carried in the upper respiratory tract without symptoms. The relationship between carriage and disease remains poorly understood but it is widely accepted that decreasing carriage by immunization should lead to a reduction of invasive cases. Latin America has experienced an increased incidence of serogroup W invasive cases of Neisseria meningitidis in the last decade. Specifically in Chile, despite low total incidence of invasive cases, serogroup W has become predominant since 2011 and has been associated with elevated mortality. Expecting to gain insight into the epidemiology of this disease, this study has used molecular typing schemes to compare Neisseria meningitidis isolates causing invasive disease with those isolates collected from adolescent carriers during the same period in Chile. A lower carriage of the serogroup W clonal complex ST-11/ET37 than expected was found; whereas, the same clonal complex accounted for 66% of total invasive meningococcal disease cases in the country that year. A high diversity of PorA variable regions and fHbp peptides was also ascertained in the carrier isolates compared to the invasive ones. According to the results shown here, the elevated number of serogroup W invasive cases in our country cannot be explained by a rise of carriage of pathogenic isolates. Overall, this study supports the idea that some strains, as W:cc11 found in Chile, possess an enhanced virulence to invade the host. Notwithstanding hypervirulence, this strain has not caused an epidemic in Chile. Finally, as genetic transfer occurs often, close surveillance of Neisseria meningitidis strains causing disease, and particularly hypervirulent W:cc11, should be kept as a priority in our country, in order to prepare the best response to face genetic changes that could lead to enhanced fitness of this pathogen. PMID- 29518096 TI - Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: Autoantibody profiles and clinical features. AB - Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis. PMID- 29518097 TI - Anti-TNFalpha therapy in IBD alters brain activity reflecting visceral sensory function and cognitive-affective biases. AB - BACKGROUND: In inflammatory bowel disease (IBD), immune activation with increased circulating TNF-alpha is linked to the intensity of gastrointestinal symptoms and depression or anxiety. A central feature of depression is cognitive biases linked to negative attributions about self, the world and the future. We aimed to assess the effects of anti-TNFalpha therapy on the central processing of self attribution biases and visceral afferent information in patients with Crohn's disease. METHODS: We examined 9 patients with Crohn's disease (age 26.1+/-10.6. yrs, 5 female, 5 ileocolonic, 2 colonic and 2 ileal disease) during chronic anti TNFalpha therapy (5 adalimumab, 4 infliximab). Patients were studied twice in randomized order before and after anti-TNFalpha administration. On each occasion patients underwent functional magnetic resonance imaging (fMRI) of the brain during a test of implicit attribution biases regarding sickness/health and undertook a standardized nutrient challenge. RESULTS: Following anti-TNFalpha treatment, ratings of 'fullness' following nutrient challenge reduced compared to pre-treatment ratings (p<0.05). Reaction times revealed improved processing of self-related and positive health words, consistent with improved implicit sense of wellbeing that correlated with improvements in sensory function after treatment (r = 0.67, p<0.05). Treatment-associated improvements in implicit processing were mirrored by alterations of prefrontal, amygdala, posterior cingulate and visual regions. Between patients, the degree of functional amygdala change was additionally explained by individual differences in attention regulation and body awareness rankings. CONCLUSION: In patients with Crohn's disease, anti-TNFalpha administration reduces visceral sensitivity and improves implicit cognitive-affective biases linked to alterations in limbic (amygdala) function. PMID- 29518098 TI - Outcomes of HIV-infected versus HIV-non-infected patients treated for drug resistance tuberculosis: Multicenter cohort study. AB - BACKGROUND: The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance. METHODS: We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan. RESULTS: Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients. CONCLUSIONS: As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co infected patients. PMID- 29518099 TI - Genetic polymorphisms of NOS2 and predisposition to fracture non-union: A case control study based on Han Chinese population. AB - A non-union, especially atrophic non-unions, is a permanent failure of healing following a fracture and can be difficult to treat. Approximately 5-10% of fractures will result in a non-union during the healing process. non-unions can be classified into two types: atrophic non-union which is often due to impaired bone healing with a potential biological mechanism, and hypertrophic non-union which is due to inadequate fixation after fracture. Genetic variations also play an important role in the fracture healing response. Previous studies based on animal models have indicated that NOS2 might be greatly involved in the bone fracture healing process. In this case-control study, 346 nonunion patients were compared to 883 patients with normal fracture healing to investigate the potential genetic association between NOS2 and the fracture healing process using study subjects of Chinese Han ancestry. Twenty-seven single nucleotide polymorphisms (SNPs) covering NOS2 were genotyped in our study subjects and analyzed. In addition to the single marker-based analysis, we performed a gene-by environment analysis to examine the potential interactions between genetic polymorphisms and some environmental factors. SNP rs2297514 showed significant association with the fracture healing process after adjusting for age and gender (OR = 1.38, P = 0.0005). Our results indicated that the T allele of rs2297514 significantly increased the risk of a non-union during the fracture healing process by 38% compared to the C allele. Further stratification analyses conducted for this SNP using data from subgroups classified by different sites of fracture indicated that significance could only be observed in the tibial diaphysis subgroup (N = 428, OR = 1.77, P = 0.0007) but not other groups including femur diaphysis, humeral shaft, ulnar shaft, and femur neck. Gene-by environment interaction analyses of the three environmental factors showed no significant results. In this study, rs2297514 was significantly associated with the non-union status of fracture healing using a large Chinese population-based study sample. Our findings replicated those of a previous preliminary study and offered strong evidence linking NOS2 and fracture healing. PMID- 29518100 TI - Associations between sun sensitive pigmentary genes and serum prostate specific antigen levels. AB - BACKGROUND: Melanoma and prostate cancer may share risk factors. This study examined the association between serum PSA levels, which is a risk factor for prostate cancer, and variants in some melanoma-associated pigmentary genes. METHODS: We studied participants, all aged 70+ years, in the Concord Health and Ageing in Men Project who had no history of prostatitis or received treatment for prostate disease (n = 1033). We genotyped variants in MC1R (rs1805007, rs1805008), ASIP (rs4911414, rs1015362), SLC45A2 (rs28777, rs16891982), IRF4 (rs12203592), TYRP1 (rs1408799), TYR (rs1126809, rs1042602), SLC24A2 (rs12896399), and OCA2 (rs7495174). Generalised linear dominant models with Poisson distribution, log link functions and robust variance estimators estimated adjusted percentage differences (%PSA) in mean serum PSA levels (ng/mL) between variant and wildtype (0%PSA = reference) genotypes, adjusting for age, body mass index, serum 25OHD levels and birth regions (Australia or New Zealand (ANZ), Europe or elsewhere). RESULTS: Serum PSA levels were strongly associated with advancing age and birth regions: mean PSA levels were lower in Europe-born ( 29.7%) and elsewhere-born (-11.7%) men than ANZ-born men (reference). Lower %PSA was observed in men with variants in SLC45A2: rs28777 (-19.6;95%CI: -33.5, -2.7), rs16891982 (-17.3;95%CI:-30.4,-1.7) than in wildtype men (reference). There were significant interactions between birth regions and PSA levels in men with variants in MC1R (rs1805007; p-interaction = 0.0001) and ASIP (rs4911414; p interaction = 0.007). For these genes %PSA was greater in ANZ-born men and lower in Europe- and elsewhere-born men with the variant than it was in wildtype men. In a post hoc analysis, serum testosterone levels were increased in men with MC1R rs1805007 and serum dihydrotestosterone in men with ASIP rs1015362. CONCLUSION: Men with SNPs in SLC45A2, who have less sun sensitive skin, have lower PSA levels. Men with SNPs in MC1R and ASIP, who have more sun sensitive skin, and were born in ANZ, have higher PSA levels. Androgens may modify these apparent associations of pigmentary genes and sun exposure with PSA levels. IMPACT: PSA levels and possibly prostate cancer risk may vary with sun sensitivity and sun exposure, the effects of which might be modified by androgen levels. PMID- 29518101 TI - Dramatic action: A theater-based paradigm for analyzing human interactions. AB - Existing approaches to describe social interactions consider emotional states or use ad-hoc descriptors for microanalysis of interactions. Such descriptors are different in each context thereby limiting comparisons, and can also mix facets of meaning such as emotional states, short term tactics and long-term goals. To develop a systematic set of concepts for second-by-second social interactions, we suggest a complementary approach based on practices employed in theater. Theater uses the concept of dramatic action, the effort that one makes to change the psychological state of another. Unlike states (e.g. emotions), dramatic actions aim to change states; unlike long-term goals or motivations, dramatic actions can last seconds. We defined a set of 22 basic dramatic action verbs using a lexical approach, such as 'to threaten'-the effort to incite fear, and 'to encourage'-the effort to inspire hope or confidence. We developed a set of visual cartoon stimuli for these basic dramatic actions, and find that people can reliably and reproducibly assign dramatic action verbs to these stimuli. We show that each dramatic action can be carried out with different emotions, indicating that the two constructs are distinct. We characterized a principal valence axis of dramatic actions. Finally, we re-analyzed three widely-used interaction coding systems in terms of dramatic actions, to suggest that dramatic actions might serve as a common vocabulary across research contexts. This study thus operationalizes and tests dramatic action as a potentially useful concept for research on social interaction, and in particular on influence tactics. PMID- 29518102 TI - Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection. AB - INTRODUCTION: T-cell exhaustion has been involved in the pathogenesis of HIV infection. We have longitudinally analyzed PD1 and Tim3 surrogate markers of T cells exhaustion, in parallel with other markers of HIV progression, and its potential association with CD4 changes in treated and untreated infection. PATIENTS AND METHODS: 96 HIV patients, 49 of them followed in the absence of cART (cART-naive group) and 47 after initiation of cART (cART group) were included and followed for a median of 43 [IQR: 31-60] months. PD1 and Tim3 expression, CD8 T cells activation, recent thymic emigrants, activation/apoptosis and turnover of CD4 cells were assessed at baseline and during follow up. Univariate and multivariate associations with CD4 evolution were explored. RESULTS: Parameters significantly associated with CD4 depletion in cART-naive group were: baseline level (p = 0.02) and variation (p = 0.002) of PD1 and Tim3 co-expression on CD8, and variation of CD95 expression on CD4 (p = 0.007). Parameters significantly associated with CD4 restoration in cART group were: baseline level of CD38+HLADR- subset of CD8 (p = 0.01), variation of PD1 expression on CD8 (p = 0.036), variation of Tim3 expression on CD4 (p = 0.039) and variation of CD95 expression on CD4 (p = 0.035). CONCLUSIONS: Our results suggest that PD1 and Tim3 markers of exhaustion have a pivotal role in CD4 dynamics in HIV patients and its down regulation would be a desirable effect of immunotherapies aimed to restore CD4 T cell pool during progression of HIV infection. PMID- 29518104 TI - Individual differences in satisfaction with activity-based work environments. AB - Satisfaction with activity-based work environments (ABW environments) often falls short of expectations, with striking differences among individual workers. A better understanding of these differences may provide clues for optimising satisfaction with ABW environments and associated organisational outcomes. The current study was designed to examine how specific psychological needs, job characteristics, and demographic variables relate to satisfaction with ABW environments. Survey data collected at seven organizations in the Netherlands (N = 551) were examined using correlation and regression analyses. Significant correlates of satisfaction with ABW environments were found: need for relatedness (positive), need for privacy (negative), job autonomy (positive), social interaction (positive), internal mobility (positive), and age (negative). Need for privacy appeared to be a powerful predictor of individual differences in satisfaction with ABW environments. These findings underline the importance of providing work environments that allow for different work styles, in alignment with different psychological need strengths, job characteristics, and demographic variables. Improving privacy, especially for older workers and for workers high in need for privacy, seems key to optimizing satisfaction with ABW environments. PMID- 29518103 TI - Inhibitor of apoptosis proteins, NAIP, cIAP1 and cIAP2 expression during macrophage differentiation and M1/M2 polarization. AB - Monocytes and macrophages constitute the first line of defense of the immune system against external pathogens. Macrophages have a highly plastic phenotype depending on environmental conditions; the extremes of this phenotypic spectrum are a pro-inflammatory defensive role (M1 phenotype) and an anti-inflammatory tissue-repair one (M2 phenotype). The Inhibitor of Apoptosis (IAP) proteins have important roles in the regulation of several cellular processes, including innate and adaptive immunity. In this study we have analyzed the differential expression of the IAPs, NAIP, cIAP1 and cIAP2, during macrophage differentiation and polarization into M1 or M2. In polarized THP-1 cells and primary human macrophages, NAIP is abundantly expressed in M2 macrophages, while cIAP1 and cIAP2 show an inverse pattern of expression in polarized macrophages, with elevated expression levels of cIAP1 in M2 and cIAP2 preferentially expressed in M1. Interestingly, treatment with the IAP antagonist SMC-LCL161, induced the upregulation of NAIP in M2, the downregulation of cIAP1 in M1 and M2 and an induction of cIAP2 in M1 macrophages. PMID- 29518105 TI - Growth, developmental achievements and vaccines timeliness of undocumented migrant children from Eritrea compared with Israelis. AB - INTRODUCTION: Israel has absorbed >40,000 Eritrean undocumented migrants since 2007, while the majority live in the southern neighborhoods of Tel-Aviv. As non citizens and citizens infants in Israel receive free preventive treatment at the mother and child health clinics (MCHC), this study aimed to compare development and growth achievements between children of Eritrean mothers (CE) to children of Israeli mothers (CI), and assess their compliance to routine follow-up and vaccination-timeliness. METHODS: This cohort study included all Israeli-born CE between 2009 and 2011, compared with a random sample of CI and treated at the same MCHC and followed-up to the age of 30-months. Dependent outcomes included anthropometric measurements, developmental achievements and adherence to immunization schedule. RESULTS: Of all 271 CE who were compared with 293 CI, no statistically significant differences were found in birth anthropometric measurements. Yet, CE had increased weight and length than CI after reaching one year of age (p<0.05). CE were more likely to fail in tests assessing fine-motor skills, linguistic and socio-emotional domains than CI, while no statistical difference was found in gross-motor achievements. At the end of follow-up, 203 (74.9%) of the CE and 271 (74.1%) of the CI completed the vaccination schedule, p = 0.9. CONCLUSION: CE had greater anthropometric measurements than CI after one year of age, and showed higher impairments in fine motor, linguistic and socio emotional domains. Adherence to vaccination was similar. The inequalities in child health should be responded in the MCTC, and Eritrean mothers should be trained with the current recommendations for child well-being. PMID- 29518106 TI - Multiplexed chemostat system for quantification of biodiversity and ecosystem functioning in anaerobic digestion. AB - Continuous cultures in chemostats have proven their value in microbiology, microbial ecology, systems biology and bioprocess engineering, among others. In these systems, microbial growth and ecosystem performance can be quantified under stable and defined environmental conditions. This is essential when linking microbial diversity to ecosystem function. Here, a new system to test this link in anaerobic, methanogenic microbial communities is introduced. Rigorously replicated experiments or a suitable experimental design typically require operating several chemostats in parallel. However, this is labor intensive, especially when measuring biogas production. Commercial solutions for multiplying reactors performing continuous anaerobic digestion exist but are expensive and use comparably large reactor volumes, requiring the preparation of substantial amounts of media. Here, a flexible system of Lab-scale Automated and Multiplexed Anaerobic Chemostat system (LAMACs) with a working volume of 200 mL is introduced. Sterile feeding, biomass wasting and pressure monitoring are automated. One module containing six reactors fits the typical dimensions of a lab bench. Thanks to automation, time required for reactor operation and maintenance are reduced compared to traditional lab-scale systems. Several modules can be used together, and so far the parallel operation of 30 reactors was demonstrated. The chemostats are autoclavable. Parameters like reactor volume, flow rates and operating temperature can be freely set. The robustness of the system was tested in a two-month long experiment in which three inocula in four replicates, i.e., twelve continuous digesters were monitored. Statistically significant differences in the biogas production between inocula were observed. In anaerobic digestion, biogas production and consequently pressure development in a closed environment is a proxy for ecosystem performance. The precision of the pressure measurement is thus crucial. The measured maximum and minimum rates of gas production could be determined at the same precision. The LAMACs is a tool that enables us to put in practice the often-demanded need for replication and rigorous testing in microbial ecology as well as bioprocess engineering. PMID- 29518108 TI - Peptidylarginine deiminase 4 -104C/T polymorphism and risk of rheumatoid arthritis: A pooled analysis based on different populations. AB - BACKGROUND: Many studies have analyzed the association between peptidylarginine deiminase 4 (PADI4) -104C/T polymorphism and rheumatoid arthritis (RA). However, the results are inconsistent. This meta-analysis, based on different populations, updated and reevaluated the possible associations between PADI4 -104C/T polymorphism and the susceptibility to RA. METHODS: A literature search was performed on PubMed and related Chinese databases up to April 2017. The association between PADI4 -104C/T polymorphism and RA risk was evaluated by calculating pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of seventeen studies, including 5,756 RA cases and 4,987 controls, were screened out. In the overall population, PADI -104C/T polymorphism was significantly associated with an increased RA risk. In this meta-analysis stratified by ethnicity, a significant association between PADI -104C/T polymorphism and RA risk was established in China and Japan. CONCLUSIONS: Our study indicated a significantly increased association between PADI -104C/T polymorphism and RA in Chinese and Japanese populations. Because most included populations in this meta-analysis were Asian, further studies are needed to elucidate whether the PADI4 -104C/T gene confers RA in other ethnic groups. PMID- 29518107 TI - Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE alleles in cognitive impairment diseases. AB - Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5 fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels. PMID- 29518109 TI - Reduced skin lipid content in obese Japanese women mediated by decreased expression of rate-limiting lipogenic enzymes. AB - Skin barrier function is often deficient in obese individuals, but the underlying molecular mechanisms remain unclear. This study investigated how skin structure and lipid metabolism, factors strongly associated with barrier function, differed among 50 Japanese women of greatly varying body mass index (BMI). Subjects receiving breast reconstruction surgery were chosen for analysis to obtain skin samples from the same site. The subjects were classified into two groups, control (BMI < 25 kg/m2) and obese (25 kg/m2 <= BMI < 35 kg/m2), according to standards in Japan. Hematoxylin and eosin staining was used to assess skin thickness, Ki-67 immunostaining to examine keratinocyte proliferation, and real-time polymerase chain reaction to measure skin expression levels of genes associated with lipid metabolism. Total lipids, cholesterol, and fatty acids were also measured from these same skin samples. In the obese group, structural changes included epidermal thickening and an increase in the number of Ki-67-positive (proliferating) cells. Both skin cholesterol and fatty acid levels exhibited an "inverted-U" relationship with BMI, suggesting that there is an optimal BMI for peak lipid content and barrier function. Decreased lipid levels at higher BMI were accompanied by downregulated expression of PPARdelta and other genes related to lipid metabolism, including those encoding acetyl-CoA carboxylase and HMG-CoA reductase, the rate-limiting enzymes for fatty acid and cholesterol synthesis, respectively. Thus, elevated BMI may lead to deficient skin barrier function by suppressing local lipid synthesis. PMID- 29518110 TI - Cryo-electron microscopy structure of a human PRMT5:MEP50 complex. AB - Protein arginine methyl transferase 5 (PRMT5) is a signaling protein and histone modifying enzyme that is important in many cellular processes, including regulation of eukaryotic gene transcription. Reported here is a 3.7 A structure of PRMT5, solved in complex with regulatory binding subunit MEP50 (methylosome associated protein 50, WDR77, p44), by single particle (SP) cryo-Electron Microscopy (cryo-EM) using micrographs of particles that are visibly crowded and aggregated. Despite suboptimal micrograph appearance, this cryo-EM structure is in good agreement with previously reported crystal structures of the complex, which revealed a 450 kDa hetero-octameric assembly having internal D2 symmetry. The catalytic PRMT5 subunits form a core tetramer and the MEP50 subunits are arranged peripherally in complex with the PRMT5 N-terminal domain. The cryo-EM reconstruction shows good side chain definition and shows a well-resolved peak for a bound dehydrosinefungin inhibitor molecule. These results demonstrate the applicability of cryo-EM in determining structures of human protein complexes of biomedical significance and suggests cryo-EM could be further utilized to understand PRMT5 interactions with other biologically important binding proteins and ligands. PMID- 29518112 TI - Mosquito pornoscopy: Observation and interruption of Aedes aegypti copulation to determine female polyandric event and mixed progeny. AB - Ades aegypti is the most important arbovirus vector in the world, and new strategies are under evaluation. Biological studies mentioning the occurrence of a second mate in Aedes aegypti can interfere with vector control program planning, which involves male mosquito release technique. This study presents different experiments to show the occurrence of mixed progeny. Mixed male crosses (using a combination of different type of males in confinement with virgin females) showed no polyandric female. Individual crosses with male substitution in every gonotrophic cycle also did not show any polyandric female. Individual crosses with a 20 minutes interval, with subsequent male change, showed that only a few females presented mixed offspring. The copulation breach in three different moments, group A with full coitus length, group B the coitus was interrupted in 5 7 seconds after the start; and group C, which the copulation was interrupted 3 seconds after started. In summary, group A showed a majority of unique progeny from the first male; group B showed the higher frequency of mixed offspring and group C with the majority of the crosses belonging to the second male. To conclude, the occurrence of a viable second mate and mixed offspring is only possible when the copulation is interrupted; otherwise, the first mate is responsible for mixed progeny. PMID- 29518111 TI - Cardiac parasympathetic index identifies subjects with adult obstructive sleep apnea: A simultaneous polysomnographic-heart rate variability study. AB - OBJECTIVE: To evaluate circadian fluctuations and night/day ratio of Heart Rate Variability (HRV) spectral components in patients with obstructive sleep apnea (OSA) in comparison with controls. PARTICIPANTS AND METHODS: This is a simultaneous HRV-polysomnographic (PSG) study including 29 patients with OSA and 18 age-sex-matched controls. Four patients with OSA dropped out. All participants underwent PSG and HRV analysis. We measured the 24-hour fluctuations and the night/day ratio of low frequency (LF) and high frequency (HF) spectral components of HRV in all subjects and controls. The LF night/day ratio was termed the cardiac sympathetic index while the HF night/day ratio was termed the cardiac parasympathetic index. RESULTS: All twenty-five OSA patients were PSG positive (presence of OSA) while 18 controls were PSG negative (absence of OSA). There was no significant difference in LF and HF 24-hour fluctuation values between OSA patients and controls. In OSA patients, LF and HF values were significantly higher during night-time than day time recordings (p<0.001). HF night/day ratio (cardiac parasympathetic index) accurately (100%) differentiated OSA patients from controls without an overlap of individual values. The LF night/day ratio (cardiac sympathetic index) had sensitivity of 84%, specificity of 72.2% and accuracy of 79.1% in distinguishing between groups. CONCLUSIONS: The cardiac parasympathetic index accurately differentiated patients with OSA from controls, on an individual basis. PMID- 29518113 TI - Incompatible amount of 3-D and 2-D periodontal attachments on micro-CT scanned premolars. AB - Micro-computed tomography (micro-CT) was employed to relate the root surface area (RSA) to the periodontal attachment levels (PALs) of extracted premolars to diagnose periodontitis. Single-rooted human maxillary and mandibular premolars 31 and 36, respectively, were surveyed by micro-CT and its associated software. RSA levels from the 1st to 10th mm, corono-apically, were analyzed using statistical t tests. The average root length (RL) and RSA of the maxillary and mandibular premolars were significantly different (p < 0.05). Both premolars demonstrated a non-significant RSA percentage comparison at the evaluated PALs. For the 30% coronal 2-D radiographic RL, the 3-D RSAs 3.77 mm and 3.99 mm apical to the cementoenamel junction (CEJ) were 39.48% and 40.65% for maxillary and mandibular premolars, respectively. At the 15% coronal 2-D RL, the 3-D RSA 2 mm apical to the CEJ of the premolars was approximately 21%. At the 50% coronal 2-D RL level, approximately 62% coronal 3-D RSA and 6.5 mm RL decreased. The amount of decrease of the RSA attachment is significant in every 2-mm measurement for both premolars. Sampling periodontal microbial pathogens based on the condition of 2-D radiographic bone and clinical attachment losses without considering 3-D RSA is potentially inadequate and may underestimate the severity of the periodontitis. PMID- 29518114 TI - GATA factor genes in the Drosophila midgut embryo. AB - The Drosophila GATA factor gene serpent (srp) is required for the early differentiation of the anterior and posterior midgut primordia. In particular, srp is sufficient and necessary for the primordial gut cells to undertake an epithelial-to-mesenchimal transition (EMT). Two other GATA factor genes, dGATAe and grain (grn), are also specifically expressed in the midgut. On the one hand, dGATAe expression is activated by srp. Embryos homozygous for a deficiency uncovering dGATAe were shown to lack the expression of some differentiated midgut genes. Moreover, ectopic expression of dGATAe was sufficient to drive the expression of some of these differentiation marker genes, thus establishing the role of dGATAe in the regulation of their expression. However, due to the gross abnormalities associated with this deficiency, it was not possible to assess whether, similarly to srp, dGATAe might play a role in setting the midgut morphology. To further investigate this role we decided to generate a dGATAe mutant. On the other hand, grn is expressed in the midgut primordia around stage 11 and remains expressed until the end of embryogenesis. Yet, no midgut function has been described for grn. First, here we report that, as for dGATAe, midgut grn expression is dependent on srp; conversely, dGATAe and grn expression are independent of each other. Our results also indicate that, unlike srp, dGATAe and grn are not responsible for setting the general embryonic midgut morphology. We also show that the analysed midgut genes whose expression is lacking in embryos homozygous for a deficiency uncovering dGATAe are indeed dGATAe-dependent genes. Conversely, we do not find any midgut gene to be grn-dependent, with the exception of midgut repression of the proventriculus iroquois (iro) gene. In conclusion, our results clarify the expression patterns and function of the GATA factor genes expressed in the embryonic midgut. PMID- 29518115 TI - The influence of age, anthropometric and metabolic variables on LDIFLARE and corneal confocal microscopy in healthy individuals. AB - INTRODUCTION: The laser Doppler imaging (LDI) FLARE and corneal confocal microscopy (CCM) are reliable markers of small fibre function (SFF) and structure (SFS), respectively, but the impact of potential confounding variables needs to be defined. The objective of this study was to determine the influence of age, anthropometric and biochemical variables on LDI and CCM. METHODS: 80 healthy volunteers (43 males) (age: 39.7+/-15.2 yrs.) underwent LDIFLARE and CCM assessment and the effect of age, anthropometric and biochemical variables was determined using multivariate analysis. RESULTS: There was an age-related decline in LDIFLARE (0.07cm2/yr; R2 = 0.669; p = <0.0001) and CCM parameters (CNFD: 0.05 fibres/mm2 /yr; R2 = 0.590; p = <0.0001, CNBD: 0.06 branches/mm2/yr; R2 = 0.549; p = 0.001and CNFL 0.07 mm/mm2/yr; R2 = 0.369; p = 0.009). BMI did not influence SFF (p = 0.08) but had a significant independent association with CNFD (p = 0.01). Fasting triglycerides (TG) independently influenced the LDIFLARE (betac: 0.204; p = 0.008) and all CCM indices (betac:-0.191 to -0.243; p = <0.05). HbA1c was significantly associated with CNFD only (p = 0.001) but not with LDIFLARE, CNBD or CNFL (p = >=0.05). Blood pressure and total cholesterol were not associated with LDIFLARE or any CCM parameters. There was a significant correlation between LDIFLARE and all CCM parameters (p = <=0.01). CONCLUSIONS: This study shows that in healthy controls, both SFF measured by LDIFLARE and SFS assessed by CCM showed a significant inverse correlation with age and triglycerides, perhaps suggesting the use of age-specific normative values when interpreting these outcomes. Furthermore, this study shows that in healthy controls, despite measuring different neural parameters, both methods correlated significantly with each other. PMID- 29518116 TI - Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages. AB - Increased consumption of Western-type diets and environmental insults lead to wide-spread increases in the plasma levels of saturated fatty acids and lipoprotein oxidation. The aim of this study is to examine whether palmitate and minimally modified low-density lipoprotein (mmLDL) exert an additive effect on macrophage activation. We found that CXCL2 and TNF-alpha secretion as well as ERK and p38 phosphorylation were additively increased by co-treatment of J774 macrophages with palmitate and mmLDL in the presence of lipopolysaccharide (LPS). Furthermore, the analysis of differentially expressed genes using the KEGG database revealed that several pathways, including cytokine-cytokine receptor interaction, and genes were significantly altered. These results were validated with real-time PCR, showing upregulation of Il-6, Csf3, Il-1beta, and Clec4d. The present study demonstrated that palmitate and mmLDL additively potentiate the LPS induced activation of macrophages. These results suggest the existence of synergistic mechanisms by which saturated fatty acids and oxidized lipoproteins activate immune cells. PMID- 29518117 TI - Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers. AB - Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease, in which genetic determinants are modulated by hormonal, lifestyle, environmental, and nutritional factors. Therefore, investigating these multiple factors, and the interactions between them, might lead to a better understanding of osteoporosis pathogenesis, and possible therapeutic interventions. The objective of this study was to identify the relationship between three blood metals (Pb, Cd, and Al), in smoking and nonsmoking patients' sera, and prevalence of osteoporosis. In particular, we focused on gene-environment interactions of metal exposure, including a dataset obtained through genome-wide association study (GWAS). Subsequently, we conducted a pathway-based analysis, using a GWAS dataset, to elucidate how metal exposure influences susceptibility to osteoporosis. In this study, we evaluated blood metal exposures for estimating the prevalence of osteoporosis in 443 participants (aged 53.24 +/- 8.29), from the Republic of Korea. Those analyses revealed a negative association between lead blood levels and bone mineral density in current smokers (p trend <0.01). By further using GWAS-based pathway analysis, we found nuclear receptor (FDR<0.05) and VEGF pathways (FDR<0.05) to be significantly upregulated by blood lead burden, with regard to the prevalence of osteoporosis, in current smokers. These findings suggest that the intracellular pathways of angiogenesis and nuclear hormonal signaling can modulate interactions between lead exposure and genetic variation, with regard to susceptibility to diminished bone mineral density. Our findings may provide new leads for understanding the mechanisms underlying the development of osteoporosis, including possible interventions. PMID- 29518118 TI - An analytical comparison of three immunoassay platforms for subpicomolar detection of protein biomarker GAD65. AB - A disproportional increase of circulating GAD65 within hours from an intraportal islet allotransplantation has been validated as biomarker of beta cell loss and poor functional outcome. More sensitive assays are, however, needed to allow detection of episodes of subtle beta cell loss during late-stage graft rejection or in the peri-onset period of type 1 diabetes. We applied the same sandwich monoclonal antibody couple reactive towards the C- and N-terminus of GAD65 on three advanced immunoassay platforms-the Cytometric Bead Array (CBA, Becton, Dickinson and Company), ElectroChemiLuminescence ImmunoAssay (ECLIA, Meso Scale Discovery) and digital ELISA technology (Single Molecule Array-SIMOA, Quanterix. We then compared analytical performance (linearity, imprecision, limit of detection and functional sensitivity), correlation of results, and practicality. All evaluated techniques showed linearity up to at least 500 ng/dL (76.9 pmol/L). SIMOA achieved the lowest imprecision. The 3 platforms correlate well with each other and could all detect subpicomolar concentrations of GAD65 in plasma, but only SIMOA and CBA could quantify down to that range. SIMOA can achieve the highest sample throughput. The three methods tested allow sensitive detection of GAD65, but SIMOA appears best suited for automated quantification of subpicomolar concentrations. PMID- 29518119 TI - Arylamine N-acetyltransferase 1 protects against reactive oxygen species during glucose starvation: Role in the regulation of p53 stability. AB - Human arylamine N-acetyltransferase 1 (NAT1) has been associated with cancer cell growth and invasion, but the underlying molecular mechanisms remain unknown. NAT1 is located on the short arm of chromosome 8 (8p21), a region that is commonly deleted in colon cancer. Previously, it was reported that HT-29 colon cancer cells, which have a large deletion at 8p21-22, show marked morphological changes, increased E-cadherin expression and altered cell-cell contact inhibition following down-regulation of NAT1 with shRNA. By contrast, no effects on growth were observed in HeLa cells. In the present study, cellular changes following knockout of NAT1 with CRISPR/Cas9 in HT-29 and HeLa cells were compared in the presence and absence of glucose. Cell growth decreased in both cell-lines during glucose starvation, but it was enhanced in HT-29 cells following NAT1 deletion. This was due to an increase in ROS production that induced cell apoptosis. Both ROS production and cell death were prevented by the glutathione precursor N acetylcysteine. NAT1 knockout also resulted in a loss of the gain-of-function p53 protein in HT-29 cells. When p53 expression was inhibited with siRNA in parental HT-29 cells, ROS production and apoptosis increased to levels seen in the NAT1 knockout cells. The loss of p53 may explain the decreased colony formation and increased contact inhibition previously reported following NAT1 down-regulation in these cells. In conclusion, NAT1 is important in maintaining intracellular ROS, especially during glucose starvation, by stabilizing gain-of-function p53 in HT-29 cells. These results suggest that NAT1 may be a novel target to decrease intracellular gain-of -function p53. PMID- 29518121 TI - Modeling and simulation of different and representative engineering problems using Network Simulation Method. AB - Mathematical models simulating different and representative engineering problem, atomic dry friction, the moving front problems and elastic and solid mechanics are presented in the form of a set of non-linear, coupled or not coupled differential equations. For different parameters values that influence the solution, the problem is numerically solved by the network method, which provides all the variables of the problems. Although the model is extremely sensitive to the above parameters, no assumptions are considered as regards the linearization of the variables. The design of the models, which are run on standard electrical circuit simulation software, is explained in detail. The network model results are compared with common numerical methods or experimental data, published in the scientific literature, to show the reliability of the model. PMID- 29518120 TI - Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms. AB - Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated genes between spasms and non-spasms groups in a multicenter cohort of 509 infants (<12months) with newly-diagnosed epilepsy. Gene ontology and pathway enrichment analysis of clinical laboratory-confirmed pathogenic variant-harboring genes was performed. Pathways, functions, and cellular compartments between spasms and non spasms groups were compared. Spasms onset age was similar in infants initially presenting with spasms (6.1 months) versus developing spasms as a later seizure type (6.9 months) but lower in the non-spasms group (4.7 months, p<0.0001). This pattern held across most etiological categories. Gestational age negatively correlated with spasms onset-age (r = -0.29, p<0.0001) but not with non-spasm seizure age. Spasms were significantly preferentially associated with broad developmental and regulatory pathways, whereas motor functions and pathways including cellular response to stimuli, cell motility and ion transport were preferentially enriched in non-spasms. Neuronal cell-body organelles preferentially associated with spasms, while, axonal, dendritic, and synaptic regions preferentially associated with other seizures. Spasms are a clinically and biologically distinct infantile seizure type. Comparative clinical epidemiological analyses identify the middle of the first year as the time of peak expression regardless of etiology. The inverse association with gestational age suggests the preterm brain must reach a certain post-conceptional, not just chronological, neurodevelopmental stage before spasms manifest. Clear differences exist between the biological pathways leading to spasms versus other seizure types and suggest that spasms result from dysregulation of multiple developmental pathways and involve different cellular components than other seizure types. This deeper level of understanding may guide investigations into pathways most critical to target in future precision medicine efforts. PMID- 29518123 TI - Effects of competitive learning tools on medical students: A case study. AB - OBJECTIVE: Competitive learning techniques are being successfully used in courses of different disciplines. However, there is still a significant gap in analyzing their effects in medical students competing individually. The authors conducted this study to assess the effectiveness of the use of a competitive learning tool on the academic achievement and satisfaction of medical students. METHODS: The authors collected data from a Human Immunology course in medical students (n = 285) and conducted a nonrandomized (quasi-experimental) control group pretest posttest design. They used the Mann-Whitney U-test to measure the strength of the association between two variables and to compare the two student groups. RESULTS: The improvement and academic outcomes of the experimental group students were significantly higher than those of the control group students. The students using the competitive learning tool had better academic performance, and they were satisfied with this type of learning. The study, however, had some limitations. The authors did not make a random assignment to the control and experimental groups and the groups were not completely homogenous. CONCLUSION: The use of competitive learning techniques motivates medical students, improves their academic outcomes and may foster the cooperation among students and provide a pleasant classroom environment. The authors are planning further studies with a more complete evaluation of cognitive learning styles or incorporating chronometry as well as team-competition. PMID- 29518122 TI - A common copy-number variant within SIRPB1 correlates with human Out-of-Africa migration after genetic drift correction. AB - Previous reports have proposed that personality may have played a role on human Out-Of-Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization. Circular Chromosome Conformation Capture (4C-seq) experiments from the SIRPB1 promoter revealed important 3D modifications in the locus depending on the presence or absence of the duplication variant. In addition, a 3' enhancer showed neural activity in transgenic models, suggesting that the presence of the CNV may compromise the expression of SIRPB1 in the central nervous system, paving the way to construct a molecular explanation of the SIRPB1 variants role in human migration. PMID- 29518124 TI - Metabolic syndrome is associated with incidence of deep cerebral microbleeds. AB - Metabolic syndrome (MetS) has been associated with silent brain lesions; however, there are no data on the relationship between MetS and the incidence of cerebral microbleeds (CMBs) in Asian populations. The aim of this study was to evaluate the longitudinal association between MetS and incidence of CMBs in the Japanese population. We performed a prospective cohort study involving 684 Japanese participants (mean age, 61.7 years) with a mean 6.5 +/- 3.4 years follow-up. All participants underwent 1.5 T magnetic resonance imaging, and CMBs were classified by their locations. Logistic regression analyses were performed to examine the relationship of MetS and its components with the incidence of CMBs. MetS was observed in 7.5% of the study population. Forty-nine (7.2%) subjects (36 had new deep or infratentorial CMBs, 13 had new strictly lobar CMBs) developed new CMBs during the follow-up period. In multivariable analysis, MetS was significantly associated with the incidence of deep or infratentorial CMBs (odds ratio, 4.03; 95% confidence interval, 1.72-9.41), and the elevated blood pressure component was most robustly associated with the incidence of deep or infratentorial CMBs (odds ratio, 5.16; 95% confidence interval, 2.02-13.2). Increased body mass index was also associated with incidence of deep or infratentorial CMBs (odds ratio, 2.45; 95% confidence interval, 1.06-5.67). The present study showed that MetS predicts incidence of CMBs in the deep brain regions and high blood pressure is the most important among the MetS components. PMID- 29518125 TI - Identification and validation of a major chromosome region for high grain number per spike under meiotic stage water stress in wheat (Triticum aestivum L.). AB - Grain number is a major trait for wheat yield under dryland farming. An International Triticeae Mapping Initiative (ITMI) mapping population comprising 105 recombinant inbred lines (RIL) developed from a cross between a Synthetic hexaploid wheat (Triticum aestivum) 'W7984' and a spring wheat variety 'Opata M85' was used to identify quantitative trait loci (QTL) associated with grain number per spike under two treatment conditions, normal watering and water stress during meiosis. Two major QTL for grain number per spike on the main stem Q.Gnu.uwa-5A-1 and Q.Gnu.uwa-5A-2 with phenotypic variations of 25.71% and 24.93%, respectively, were detected on the long arm of chromosome 5A when plants were exposed to water stress during meiosis. One QTL (Q.Gnu.uwa-2A) with a LOD score of 2.8 was detected on the long arm of chromosome 2A under normal watering condition. The alleles associated with higher grain number per spike under different treatment conditions came from the Synthetic W7984 parent. Two populations developed from crosses Synthetic W7984 * Lang and Synthetic W7984 * Westonia were used to validate the identified QTL under water stress during meiosis. SSR markers Xbarc230 and Xbarc319 linked with the identified QTL on chromosome 5AL were validated in the two F2:4 segregating populations. These closely linked SSR markers could potentially be utilized in marker-assisted selection to reduce yield loss in regions where water stress during meiosis occurs frequently. The identified QTL can be incorporated into elite lines / cultivars to improve wheat grain yield. PMID- 29518126 TI - Nonnegative Matrix Factorization for identification of unknown number of sources emitting delayed signals. AB - Factor analysis is broadly used as a powerful unsupervised machine learning tool for reconstruction of hidden features in recorded mixtures of signals. In the case of a linear approximation, the mixtures can be decomposed by a variety of model-free Blind Source Separation (BSS) algorithms. Most of the available BSS algorithms consider an instantaneous mixing of signals, while the case when the mixtures are linear combinations of signals with delays is less explored. Especially difficult is the case when the number of sources of the signals with delays is unknown and has to be determined from the data as well. To address this problem, in this paper, we present a new method based on Nonnegative Matrix Factorization (NMF) that is capable of identifying: (a) the unknown number of the sources, (b) the delays and speed of propagation of the signals, and (c) the locations of the sources. Our method can be used to decompose records of mixtures of signals with delays emitted by an unknown number of sources in a nondispersive medium, based only on recorded data. This is the case, for example, when electromagnetic signals from multiple antennas are received asynchronously; or mixtures of acoustic or seismic signals recorded by sensors located at different positions; or when a shift in frequency is induced by the Doppler effect. By applying our method to synthetic datasets, we demonstrate its ability to identify the unknown number of sources as well as the waveforms, the delays, and the strengths of the signals. Using Bayesian analysis, we also evaluate estimation uncertainties and identify the region of likelihood where the positions of the sources can be found. PMID- 29518127 TI - Predicting the clinical performance of dental students with a manual dexterity test. AB - Dentists must be skilled when using dental mirrors. Working with mirrors requires spatial perception, bimanual coordination, perceptual learning and fine motor skills. Many studies have attempted to determine the predictors of manual skills among pre-clinical students, but consensus has yet to be reached. We hypothesized that valid and reliable occupational therapy test performance regarding indirect vision would differ between dental students and junior dentists and would explain the variance in manual skill performance in pre-clinical courses. To test this hypothesis, we applied the Purdue Pegboard test and O'Connor Tweezer Dexterity test under different conditions of direct and indirect vision. We administered these tests to students in phantom-head academic courses in 2015 and 2016 and to junior dentists. Students performed the tests at three time points: before phantom training (T0), at the end of the training (T1) and in the middle of the following year of study (T2). Dentists performed the same tests twice at 1st and 2nd trials one week apart. The results showed that indirect tasks were significantly more difficult to perform for both groups. These dexterity tests were sensitive enough to detect students' improvement after phantom training. The dentists' performances were significantly better than those of students at T0, specifically with regard to the use of tweezers under direct and indirect vision (the O'Connor test). A regression analysis showed that students' manual grades obtained at the beginning of the phantom course, their performance on the Purdue test using both hands, and their performance on the O'Connor test under indirect vision predicted phantom course success in 80% of cases. The O'Connor test under indirect vision is the most informative means of monitoring and predicting the manual skills required in the pre-clinical year of dentistry studies. PMID- 29518128 TI - E-mail communication patterns and job burnout. AB - A considerable body of research has documented the negative effects of job burnout on employees and their organizations, emphasizing the importance of the identification of early signs of the phenomenon for the purposes of prevention and intervention. However, such timely identification is difficult due to the time and cost of assessing the burnout levels of all employees in an organization using established scales. In this paper, we propose an innovative way to identify employees at risk of job burnout by analyzing their e-mail communication patterns. Building on the Job Demands-Resources model, we theorize about the relationship between e-mail communication patterns and levels of employee exhaustion and disengagement (two dimensions of burnout). We analyzed 52,190 e mails exchanged between 57 employees of a medium sized R&D company over a five month period. We then related these employees' communication patterns to their levels of burnout, collected using an established scale (the OLBI-Oldenburg Burnout Inventory). Our results provide support for the overall proposition of the paper, that e-mail communications can be used to identify individuals at risk of job burnout. Our models explain up to 34% of the variance of burnout and up to 37% and 19% respectively of the variance of exhaustion and disengagement. They also successfully distinguish between employees with a higher risk of burnout and those with lower levels of risk (F1 score of 84% with recall of 100% and 73% precision). We discuss the implications of our results and present suggestions for future research. PMID- 29518129 TI - STAT3 precedes HIF1alpha transcriptional responses to oxygen and oxygen and glucose deprivation in human brain pericytes. AB - Brain pericytes are important to maintain vascular integrity of the neurovascular unit under both physiological and ischemic conditions. Ischemic stroke is known to induce an inflammatory and hypoxic response due to the lack of oxygen and glucose in the brain tissue. How this early response to ischemia is molecularly regulated in pericytes is largely unknown and may be of importance for future therapeutic targets. Here we evaluate the transcriptional responses in in vitro cultured human brain pericytes after oxygen and/or glucose deprivation. Hypoxia has been widely known to stabilise the transcription factor hypoxia inducible factor 1-alpha (HIF1alpha) and mediate the induction of hypoxic transcriptional programs after ischemia. However, we find that the transcription factors Jun Proto-Oncogene (c-JUN), Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B-Cells (NFkappaB) and signal transducer and activator of transcription 3 (STAT3) bind genes regulated after 2hours (hs) of omitted glucose and oxygen before HIF1alpha. Potent HIF1alpha responses require 6hs of hypoxia to substantiate transcriptional regulation comparable to either c-JUN or STAT3. Phosphorylated STAT3 protein is at its highest after 5 min of oxygen and glucose (OGD) deprivation, whereas maximum HIF1alpha stabilisation requires 120 min. We show that STAT3 regulates angiogenic and metabolic pathways before HIF1alpha, suggesting that HIF1alpha is not the initiating trans-acting factor in the response of pericytes to ischemia. PMID- 29518130 TI - ABrox-A user-friendly Python module for approximate Bayesian computation with a focus on model comparison. AB - We give an overview of the basic principles of approximate Bayesian computation (ABC), a class of stochastic methods that enable flexible and likelihood-free model comparison and parameter estimation. Our new open-source software called ABrox is used to illustrate ABC for model comparison on two prominent statistical tests, the two-sample t-test and the Levene-Test. We further highlight the flexibility of ABC compared to classical Bayesian hypothesis testing by computing an approximate Bayes factor for two multinomial processing tree models. Last but not least, throughout the paper, we introduce ABrox using the accompanied graphical user interface. PMID- 29518132 TI - A comparison of smartphone and paper data-collection tools in the Burden of Obstructive Lung Disease (BOLD) study in Gezira state, Sudan. AB - INTRODUCTION: Data collection using paper-based questionnaires can be time consuming and return errors affect data accuracy, completeness, and information quality in health surveys. We compared smartphone and paper-based data collection systems in the Burden of Obstructive Lung Disease (BOLD) study in rural Sudan. METHODS: This exploratory pilot study was designed to run in parallel with the cross-sectional household survey. The Open Data Kit was used to programme questionnaires in Arabic into smartphones. We included 100 study participants (83% women; median age = 41.5 +/- 16.4 years) from the BOLD study from 3 rural villages in East-Gezira and Kamleen localities of Gezira state, Sudan. Questionnaire data were collected using smartphone and paper-based technologies simultaneously. We used Kappa statistics and inter-rater class coefficient to test agreement between the two methods. RESULTS: Symptoms reported included cough (24%), phlegm (15%), wheezing (17%), and shortness of breath (18%). One in five were or had been cigarette smokers. The two data collection methods varied between perfect to slight agreement across the 204 variables evaluated (Kappa varied between 1.00 and 0.02 and inter-rater coefficient between 1.00 and -0.12). Errors were most commonly seen with paper questionnaires (83% of errors seen) vs smartphones (17% of errors seen) administered questionnaires with questions with complex skip-patterns being a major source of errors in paper questionnaires. Automated checks and validations in smartphone-administered questionnaires avoided skip-pattern related errors. Incomplete and inconsistent records were more likely seen on paper questionnaires. CONCLUSION: Compared to paper-based data collection, smartphone technology worked well for data collection in the study, which was conducted in a challenging rural environment in Sudan. This approach provided timely, quality data with fewer errors and inconsistencies compared to paper-based data collection. We recommend this method for future BOLD studies and other population-based studies in similar settings. PMID- 29518131 TI - Are the immunomodulatory properties of Lactobacillus rhamnosus CRL1505 peptidoglycan common for all Lactobacilli during respiratory infection in malnourished mice? AB - Previously, we reported that Lactobacillus rhamnosus CRL1505 peptidoglycan (PG05) improves the innate immune response in immunocompromised-malnourished mice after Streptococcus pneumoniae infection. This study extends those previous findings by demonstrating that the dietary recovery of malnourished mice with nasal administration of PG05 improves not only the innate immune response but the respiratory and systemic adaptive humoral response as well. PG05 enhanced the Th2 response, the recovery of B cells, and the concentration and opsonophagocytic activity of anti-pneumococcal antibodies. In addition, by performing comparative studies with the peptidoglycans from lactobacilli of the same species (L. rhamnosus CRL534) or with similar immunomodulatory properties (L. plantarum CRL1506), we demonstrated here that PG05 has unique immunomodulatory properties that cannot be extended to peptidoglycans from other probiotic strains. However, the knowledge of the molecular characteristics of PG05 is indispensable to understand immunomodulatory abilities of L. rhamnosus CRL1505. PMID- 29518133 TI - ICU mortality following ICU-acquired primary bloodstream infections according to the type of pathogen: A prospective cohort study in 937 Germany ICUs (2006-2015). AB - OBJECTIVE: Mortality due to intensive care unit (ICU) acquired primary blood stream infections (PBSI) is related primarily to patient co-morbidities, types of pathogens and quality of care. The objective of this study is to determine the impact of various types of pathogen on ICU mortality. METHODS: Data from the German National Nosocomial Infection Surveillance System of patients with PBSI from 2006 to 2015 was used for this analysis. A BSI is primary when the pathogen recognized is not related to an infection on another site. Only mono-microbial infections stratified into the 13 pathogens most frequently causing PBSI were considered. Univariate and multivariate risk factor analyses were performed using the following risk factors: Sex, age, length of stay, device use, time until onset of PBSI, type and size of hospital, type of ICU and type of pathogen. ICU mortality following S.aureus PBSI was used as the reference value. RESULTS: A total of 4,556,360 patients with 16,978,882 patient days from 937 ICUs were considered in the analysis. Of 14,626 PBSI in total, 12,745 mono-microbial PBSI were included. The ICU mortality was 18.6%. Compared with S.aureus and adjusted by age, sex and type of ICU, S.maltophilia was associated with significantly higher ICU mortality (OR 1.71; 95%CI 1.19-2.47) as followed by Enterococci (OR 1.20; 95%CI 1.06-1.36), E.coli (OR 1.24; 95%CI 1.02-1.49), C.albicans (OR 1.37; 95%CI 1.16-1.61), non albicans Candida spp. (OR 1.49; 95%CI 1.18-1.88) and P.aeruginosa (OR 1.49; 95%CI 1.21-1.84). Coagulase negative Staphylococci were associated with significant lower ICU mortality (OR 0.86; 95%CI 0.75-0.99). CONCLUSION: Because of the limitation of the study in adjusting for severity of illness and appropriateness of therapy, the differences between the pathogens may not only be explained by differences in virulence, but may reflect the prognosis after receiving the microbiological results and may therefore be useful for intensive care physicians. PMID- 29518135 TI - Impact of introduction of Xpert MTB/RIF test on tuberculosis (TB) diagnosis in a city with high TB incidence in Brazil. AB - BACKGROUND: Xpert MTB/RIF is increasingly used in many countries as the initial diagnostic test for tuberculosis (TB). Few studies have evaluated the effect of Xpert on TB diagnosis under programmatic conditions in Brazil. The aim of the present study was to evaluate the impact of introduction of Xpert MTB/RIF on TB diagnosis in a city with high TB incidence in Brazil. METHODS: We included patients evaluated with conventional diagnostic tests during one year before Xpert introduction (pre-Xpert group) and patients evaluated using Xpert during one year after the test introduction (post-Xpert group). RESULTS: 620 patients met the inclusion criteria (208 in the pre-Xpert group and 412 in the post-Xpert group) and were included in the analysis. The time until TB diagnosis was shorter in post-Xpert group (0.7 day, IQR: 0.5-1.0 day) than in pre-Xpert group (2.0 days, IQR: 2.0-2.0 days) (p<0.0001). Atypical disease characteristics, such as less weight loss, fever, dyspnea, night sweats, and hemoptysis; a negative sputum smear; a negative culture, and a chest X-ray atypical of TB were more common in post-Xpert group than in pre-Xpert group (p<0.0001 for all). CONCLUSIONS: We found that the implementation of the Xpert MTB/RIF assay, under programmatic conditions, improve and facilitate TB diagnosis, especially in cases with atypical disease manifestations. These results are likely to be generalizable to settings with a similar high TB incidence. PMID- 29518134 TI - Digoxin for atrial fibrillation and atrial flutter: A systematic review with meta analysis and trial sequential analysis of randomised clinical trials. AB - BACKGROUND: During recent years, systematic reviews of observational studies have compared digoxin to no digoxin in patients with atrial fibrillation or atrial flutter, and the results of these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless of concomitant heart failure. Our objective was to assess the benefits and harms of digoxin for atrial fibrillation and atrial flutter based on randomized clinical trials. METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, BIOSIS for eligible trials comparing digoxin versus placebo, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter in October 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were heart failure, stroke, heart rate control, and conversion to sinus rhythm. We performed both random-effects and fixed-effect meta-analyses and chose the more conservative result as our primary result. We used Trial Sequential Analysis (TSA) to control for random errors. We used GRADE to assess the quality of the body of evidence. RESULTS: 28 trials (n = 2223 participants) were included. All were at high risk of bias and reported only short-term follow-up. When digoxin was compared with all control interventions in one analysis, we found no evidence of a difference on all-cause mortality (risk ratio (RR), 0.82; TSA-adjusted confidence interval (CI), 0.02 to 31.2; I2 = 0%); serious adverse events (RR, 1.65; TSA-adjusted CI, 0.24 to 11.5; I2 = 0%); quality of life; heart failure (RR, 1.05; TSA-adjusted CI, 0.00 to 1141.8; I2 = 51%); and stroke (RR, 2.27; TSA-adjusted CI, 0.00 to 7887.3; I2 = 17%). Our analyses on acute heart rate control (within 6 hours of treatment onset) showed firm evidence of digoxin being superior compared with placebo (mean difference (MD), -12.0 beats per minute (bpm); TSA-adjusted CI, -17.2 to -6.76; I2 = 0%) and inferior compared with beta blockers (MD, 20.7 bpm; TSA-adjusted CI, 14.2 to 27.2; I2 = 0%). Meta-analyses on acute heart rate control showed that digoxin was inferior compared with both calcium antagonists (MD, 21.0 bpm; TSA-adjusted CI, 30.3 to 72.3) and with amiodarone (MD, 14.7 bpm; TSA-adjusted CI, -0.58 to 30.0; I2 = 42%), but in both comparisons TSAs showed that we lacked information. Meta analysis on acute conversion to sinus rhythm showed that digoxin compared with amiodarone reduced the probability of converting atrial fibrillation to sinus rhythm, but TSA showed that we lacked information (RR, 0.54; TSA-adjusted CI, 0.13 to 2.21; I2 = 0%). CONCLUSIONS: The clinical effects of digoxin on all-cause mortality, serious adverse events, quality of life, heart failure, and stroke are unclear based on current evidence. Digoxin seems to be superior compared with placebo in reducing the heart rate, but inferior compared with beta blockers. The long-term effect of digoxin is unclear, as no trials reported long-term follow up. More trials at low risk of bias and low risk of random errors assessing the clinical effects of digoxin are needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016052935. PMID- 29518136 TI - Reduced inflammation and cytokine production in NKLAM deficient mice during Streptococcus pneumoniae infection. AB - Streptococcus pneumoniae is a leading cause of pneumonia and a significant economic burden. Antibiotic-resistant S. pneumoniae has become more prevalent in recent years and many pneumonia cases are caused by S. pneumoniae that is resistant to at least one antibiotic. The ubiquitin ligase natural killer lytic associated molecule (NKLAM/RNF19b) plays a role in innate immunity and studies using NKLAM-knockout (NKLAM-KO) macrophages have demonstrated that NKLAM positively affects the transcriptional activity of STAT1. Using an inhalation infection model, we found that NKLAM-KO mice had a significantly higher lung bacterial load than WT mice but had less lung inflammation. Coincidently, NKLAM KO mice had fewer neutrophils and NK cells in their lungs. NKLAM-KO mice also expressed less iNOS in their lungs as well as less MCP-1, MIP1alpha, TNFalpha, IL 12, and IFNgamma. Both neutrophils and macrophages from NKLAM-KO mice were defective in killing S. pneumoniae as compared to wild type cells (WT). The phosphorylation of STAT1 and STAT3 in NKLAM-KO lungs was lower than in WT lungs at 24 hours post-infection. NKLAM-KO mice were afforded some protection against a lethal dose of S. pneumoniae compared to WT mice. In summary, our novel data demonstrate a role for E3 ubiquitin ligase NKLAM in modulating innate immunity via the positive regulation of inflammatory cytokine expression and bactericidal activity. PMID- 29518137 TI - Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model. AB - Breast cancer is the most common malignancy in women of the Western world. Doxorubicin (DOX) continues to be used extensively to treat early-stage or node positive breast cancer, human epidermal growth factor receptor-2 (HER2)-positive breast cancer, and metastatic disease. We have previously demonstrated in a mouse model that sulforaphane (SFN), an isothiocyanate isolated from cruciferous vegetables, protects the heart from DOX-induced toxicity and damage. However, the effects of SFN on the chemotherapeutic efficacy of DOX in breast cancer are not known. Present studies were designed to investigate whether SFN alters the effects of DOX on breast cancer regression while also acting as a cardioprotective agent. Studies on rat neonatal cardiomyocytes and multiple rat and human breast cancer cell lines revealed that SFN protects cardiac cells but not cancer cells from DOX toxicity. Results of studies in a rat orthotopic breast cancer model indicated that SFN enhanced the efficacy of DOX in regression of tumor growth, and that the DOX dosage required to treat the tumor could be reduced when SFN was administered concomitantly. Additionally, SFN enhanced mitochondrial respiration in the hearts of DOX-treated rats and reduced cardiac oxidative stress caused by DOX, as evidenced by the inhibition of lipid peroxidation, the activation of NF-E2-related factor 2 (Nrf2) and associated antioxidant enzymes. These studies indicate that SFN not only acts synergistically with DOX in cancer regression, but also protects the heart from DOX toxicity through Nrf2 activation and protection of mitochondrial integrity and functions. PMID- 29518138 TI - Cell-intrinsic sphingosine kinase 2 promotes macrophage polarization and renal inflammation in response to unilateral ureteral obstruction. AB - Sphingosine Kinase-2 (Sphk2) is responsible for the production of the bioactive lipid Sphingosine-1 Phosphate, a key regulator of tissue repair. Here we address the in vivo significance of Sphingosine Kinase -2 in renal inflammation/fibrosis in response to unilateral ureteral obstruction using both genetic and pharmacological strategies. Obstructed kidneys of Sphk2-/- mice showed reduced renal damage and diminished levels of the renal injury markers TGFbeta1 and alphaSMA when compared to wild type controls. We found a consistently significant increase in anti-inflammatory (M2) macrophages in obstructed Sphk2-/- kidneys by flow cytometry and a decrease in mRNA levels of the inflammatory cytokines, MCP1, TNFalpha, CXCL1 and ILbeta1, suggesting an anti-inflammatory bias in the absence of Sphk2. Indeed, metabolic profiling showed that the pro-inflammatory glycolytic pathway is largely inactive in Sphk2-/- bone marrow-derived macrophages. Furthermore, treatment with the M2-promoting cytokines IL-4 or IL-13 demonstrated that macrophages lacking Sphk2 polarized more efficiently to the M2 phenotype than wild type cells. Bone marrow transplant studies indicated that expression of Sphk2-/- on either the hematopoietic or parenchymal cells did not fully rescue the pro-healing phenotype, confirming that both infiltrating M2-macrophages and the kidney microenvironment contribute to the damaging Sphk2 effects. Importantly, obstructed kidneys from mice treated with an Sphk2 inhibitor recapitulated findings in the genetic model. These results demonstrate that reducing Sphk2 activity by genetic or pharmacological manipulation markedly decreases inflammatory and fibrotic responses to obstruction, resulting in diminished renal injury and supporting Sphk2 as a novel driver of the pro inflammatory macrophage phenotype. PMID- 29518139 TI - Frazzled can act through distinct molecular pathways in epithelial cells to regulate motility, apical constriction, and localisation of E-Cadherin. AB - Netrin receptors of the DCC/NEO/UNC-40/Frazzled family have well established roles in cell migration and axon guidance but can also regulate epithelial features such as adhesion, polarity and adherens junction (AJ) stability. Previously, we have shown that overexpression of Drosophila Frazzled (Fra) in the peripodial epithelium (PE) inhibits wing disc eversion and also generates cellular protrusions typical of motile cells. Here, we tested whether the molecular pathways by which Fra inhibits eversion are distinct from those driving motility. We show that in disc proper (DP) epithelial cells Fra, in addition to inducing F-Actin rich protrusions, can affect localization of AJ components and columnar cell shape. We then show that these phenotypes have different requirements for the three conserved Fra cytoplasmic P-motifs and for downstream genes. The formation of protrusions required the P3 motif of Fra, as well as integrins (mys and mew), the Rac pathway (Rac1, wave and, arpc3) and myosin regulatory light chain (Sqh). In contrast, apico-basal cell shape change, which was accompanied by increased myosin phosphorylation, was critically dependent upon the P1 motif and was promoted by RhoGef2 but inhibited by Rac1. Fra also caused a loss of AJ proteins (DE-Cad and Arm) from basolateral regions of epithelial cells. This phenotype required all 3 P-motifs, and was dependent upon the polarity factor par6. par6 was not required for protrusions or cell shape change, but was required to block eversion suggesting that control of AJ components may underlie the ability of Fra to promote epithelial stability. The results imply that multiple molecular pathways act downstream of Fra in epithelial cells. PMID- 29518140 TI - Optimisation of growth conditions for ovine airway epithelial cell differentiation at an air-liquid interface. AB - Respiratory tract infections are of significant concern in the agriculture industry. There is a requirement for the development of well-characterised in vitro epithelial cell culture models in order to dissect the diverse molecular interactions occurring at the host-pathogen interface in airway epithelia. We have analysed key factors that influence growth and differentiation of ovine tracheal epithelial cells in an air-liquid interface (ALI) culture system. Cellular differentiation was assessed at 21 days post-ALI, a time-point which we have previously shown to be sufficient for differentiation in standard growth conditions. We identified a dose-dependent response to epidermal growth factor (EGF) in terms of both epithelial thickening and ciliation levels. Maximal ciliation levels were observed with 25 ng ml-1 EGF. We identified a strict requirement for retinoic acid (RA) in epithelial differentiation as RA exclusion resulted in the formation of a stratified squamous epithelium, devoid of cilia. The pore-density of the growth substrate also had an influence on differentiation as high pore-density inserts yielded higher levels of ciliation and more uniform cell layers than low pore-density inserts. Differentiation was also improved by culturing the cells in an atmosphere of sub-ambient oxygen concentration. We compared two submerged growth media and observed differences in the rate of proliferation/expansion, barrier formation and also in terminal differentiation. Taken together, these results indicate important differences between the response of ovine tracheal epithelial cells and other previously described airway epithelial models, to a variety of environmental conditions. These data also indicate that the phenotype of ovine tracheal epithelial cells can be tailored in vitro by precise modulation of growth conditions, thereby yielding a customisable, potential infection model. PMID- 29518141 TI - The impact of menopausal hormone therapy (MHT) on cardiac structure and function: Insights from the UK Biobank imaging enhancement study. AB - BACKGROUND: The effect of menopausal hormone therapy (MHT)-previously known as hormone replacement therapy-on cardiovascular health remains unclear and controversial. This cross-sectional study examined the impact of MHT on left ventricular (LV) and left atrial (LA) structure and function, alterations in which are markers of subclinical cardiovascular disease, in a population-based cohort. METHODS: Post-menopausal women who had never used MHT and those who had used MHT >=3 years participating in the UK Biobank who had undergone cardiovascular magnetic resonance (CMR) imaging and free of known cardiovascular disease were included. Multivariable linear regression was performed to examine the relationship between cardiac parameters and MHT use >=3 years. To explore whether MHT use on each of the cardiac outcomes differed by age, multivariable regression models were constructed with a cross-product of age and MHT fitted as an interaction term. RESULTS: Of 1604 post-menopausal women, 513 (32%) had used MHT >=3 years. In the MHT cohort, median age at menopause was 50 (IQR: 45-52) and median duration of MHT was 8 years. In the non-MHT cohort, median age at menopause was 51 (IQR: 48-53). MHT use was associated with significantly lower LV end-diastolic volume (122.8 ml vs 119.8 ml, effect size = -2.4%, 95% CI: -4.2% to -0.5%; p = 0.013) and LA maximal volume (60.2 ml vs 57.5 ml, effect size = -4.5%, 95% CI: -7.8% to -1.0%; p = 0.012). There was no significant difference in LV mass. MHT use significantly modified the effect between age and CMR parameters; MHT users had greater decrements in LV end-diastolic volume, LV end-systolic volume and LA maximal volume with advancing age. CONCLUSIONS: MHT use was not associated with adverse, subclinical changes in cardiac structure and function. Indeed, significantly smaller LV and LA chamber volumes were observed which have been linked to favourable cardiovascular outcomes. These findings represent a novel approach to examining MHT's effect on the cardiovascular system. PMID- 29518142 TI - Altered heat nociception in cockroach Periplaneta americana L. exposed to capsaicin. AB - Some natural alkaloids, e.g. capsaicin and camphor, are known to induce a desensitization state, causing insensitivity to pain or noxious temperatures in mammals by acting on TRP receptors. Our research, for the first time, demonstrated that a phenomenon of pharmacological blockade of heat sensitivity may operate in American cockroach, Periplaneta americana (L.). We studied the escape reaction time from 50 degrees C for American cockroaches exposed to multiple doses of different drugs affecting thermo-TRP. Capsaicin, capsazepine, and camphor induced significant changes in time spent at noxious ambient temperatures. Moreover, we showed that behavioral thermoregulation in normal temperature ranges (10-40 degrees C) is altered in treated cockroaches, which displayed a preference for warmer regions compared to non-treated insects. We also measured the levels of malondialdehyde (MDA) and catalase activity to exclude the secondary effects of the drugs on these processes. Our results demonstrated that increase in time spent at 50 degrees C (five versus one trial at a heat plate) induced oxidative stress, but only in control and vehicle treated groups. In capsaicin, capsazepine, menthol, camphor and AITC-treated cockroaches the number of exposures to heat had no effect on the levels of MDA. Additionally, none of the tested compounds affected catalase activity. Our results demonstrate suppression of the heat sensitivity by repeated capsazepine, camphor and capsaicin administration in the American cockroach. PMID- 29518143 TI - Specialized core bacteria associate with plants adapted to adverse environment with high calcium contents. AB - Karst topography is formed from the dissolution of soluble rocks, such as limestone and dolomite. In soils of such a landform, excessive contents of exchangeable calcium seriously limit the growth of vegetations. Researches have proved that rhizosphere microorganisms and endophytes help host plants to adapt to various adverse environments. The adaptive capacity of plants that grow in adverse environment with salt, drought, thermal and heavy metal stresses partially or completely comes from symbiotic microorganisms. By using the high throughput amplicon sequencing, the bacterial community structures in soil with high calcium contents and roots and leaves of Cochlearia henryi that is commonly seen in karst area were analyzed. The bacteria community structures in these three compartments showed obvious differences. This indicates that C. henryi, which is adaptive to high calcium stress, selectively co-exists with specific bacteria. Although the bacteria community structures in these three compartments differed significantly, there were 73 operational taxonomic units (OTUs) shared by karst soils as well as roots and leaves of C. henryi. The phylogenetic diversity of these 73 OTUs differed significantly from that of overall OTUs detected. There were also obvious differences in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and abundance values between the 73 OTUs and overall bacterial communities. A large number of OTUs shared by the karst soils, roots and leaves of C. henryi had close genetic relationship with known stress resistant bacterial strains. Our results showed that the functional bacteria can be predicted by exploring core bacteria, bacteria shared by soils, adaptable plant roots and leaves. This information will potentially accelerate studies on natural microbial communities which can promote the adaptive capacity of host plants to high calcium stress, and will be valuable for finding microbial strains for field application in karst topography. PMID- 29518144 TI - Novel mouse monoclonal antibodies specifically recognize Aspergillus fumigatus galactomannan. AB - A panel of specific monoclonal antibodies (mAbs) against synthetic pentasaccharide beta-D-Galf-(1->5)-[beta-D-Galf-(1->5)]3-alpha-D-Manp, structurally related to Aspergillus fumigatus galactomannan, was generated using mice immunized with synthetic pentasaccharide-BSA conjugate and by hybridoma technology. Two selected mAbs, 7B8 and 8G4, could bind with the initial pentasaccharide with affinity constants of approximately 5.3 nM and 6.4 nM, respectively, based on surface plasmon resonance-based biosensor assay. The glycoarray, built from a series of synthetic oligosaccharide derivatives representing different galactomannan fragments, demonstrated that mAb 8G4 could effectively recognize the parental pentasaccharide while mAb 7B8 recognizes its constituting trisaccharide parts. Immunofluorescence studies showed that both 7B8 and 8G4 could stain A. fumigatus cells in culture efficiently, but not the mutant strain lacking galactomannan. In addition, confocal microscopy demonstrated that Candida albicans, Bifidobacterium longum, Lactobacillus plantarum, and numerous gram-positive and gram-negative bacteria were not labeled by mAbs 7B8 and 8G4. The generated mAbs can be considered promising for the development of a new specific enzyme-linked assay for detection of A. fumigatus, which is highly demanded for medical and environmental controls. PMID- 29518145 TI - Hydrogen sulfide mediates athero-protection against oxidative stress via S sulfhydration. AB - S-sulfhydration is a signalling pathway of hydrogen sulfide (H2S), which is suggested as an anti-atherogenic molecule that may protect against atherosclerosis. The identification of S-sulfhydrated proteins by proteomic approach could be a major step towards understanding the mechanisms of H2S in response to atherosclerosis. The present study studied targeted S-sulfhydrated proteins using the modified biotin switch method followed by matrix-assisted laser desorption/ionisation time of flight tandem mass spectrometry identification. The results showed that H2S can protect against atherosclerosis by reducing body weight gain and alleviating aortic plaque formation. In addition, H2S treatment can increase aortic protein S-sulfhydration. Seventy targeted S-sulfhydrated aortic proteins were identified, mainly involved in metabolism, stimulus response and biological regulation, as determined by gene ontology database analysis. H2S also induced S-sulfhydration of glutathione peroxidase 1 and further reduced lipid peroxidation and increased antioxidant defence in the aorta by prompting glutathione synthesis. Our data suggest that H2S is a cardiovascular-protective molecule that S-sulfhydrates a subset of proteins that are mainly responsible for lipid metabolism and exerts its cytoprotective effects to clear free radicals and inhibit oxidative stress through cysteine S-sulfhydration. PMID- 29518146 TI - Relevance of the protein macrodipole in the membrane-binding process. Interactions of fatty-acid binding proteins with cationic lipid membranes. AB - The fatty acid-binding proteins L-BABP and Rep1-NCXSQ bind to anionic lipid membranes by electrostatic interactions. According to Molecular Dynamics (MD) simulations, the interaction of the protein macrodipole with the membrane electric field is a driving force for protein binding and orientation in the interface. To further explore this hypothesis, we studied the interactions of these proteins with cationic lipid membranes. As in the case of anionic lipid membranes, we found that both proteins, carrying a negative as well as a positive net charge, were bound to the positively charged membrane. Their major axis, those connecting the bottom of the beta-barrel with the alpha-helix portal domain, were rotated about 180 degrees as compared with their orientations in the anionic lipid membranes. Fourier transform infrared (FTIR) spectroscopy of the proteins showed that the positively charged membranes were also able to induce conformational changes with a reduction of the beta-strand proportion and an increase in alpha-helix secondary structure. Fatty acid-binding proteins (FABPs) are involved in several cell processes, such as maintaining lipid homeostasis in cells. They transport hydrophobic molecules in aqueous medium and deliver them into lipid membranes. Therefore, the interfacial orientation and conformation, both shown herein to be electrostatically determined, have a strong correlation with the specific mechanism by which each particular FABP exerts its biological function. PMID- 29518147 TI - What seems to matter in public policy and the health of informal caregivers? A cross-sectional study in 12 European countries. AB - In Europe, informal caregiving is frequent and is expected to grow. Caregiving has an impact on caregivers' health, but its effect may vary according to the policies of support that are available to caregivers. The aim of this study was to assess the association between the policies of support to caregivers available in 12 European countries and the health of caregivers, considering separately the policies based on financial help and those based on training and other non- financial services. We used data from 13,507 caregivers from 12 European countries from the fifth wave of the Survey of Health, Ageing and Retirement in Europe (SHARE) to build a path model. Poor health among caregivers was associated with living in a family-based care country (beta = 0.50; 95% CI = 0.42-0.59), and with an increased extent of caregiving (beta = 0.18; 95% CI = 0.15-0.22). Non financial support measures seem to have a larger protective impact (beta = -0.33; 95% CI = -0.38 - -0.28) on the health of caregivers than do financial support measures (beta = 0.03; 95% CI = 0.01-0.04), regardless of the gender of the caregiver. According to our results, the currently available policies of support associated with better health among caregivers are those that: 1) provide them with some free time, 2) help them to deal emotionally with caregiving, and 3) give them skills to both improve the care situation and to deal with it better. PMID- 29518148 TI - Beneficial effects of fingolimod in MS patients with high serum Sema4A levels. AB - We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels are resistant to IFN-beta therapy. To further elucidate the role of serum Sema4A as a biomarker for therapeutic stratification in MS patients, it is important to clarify the efficacy of other disease-modifying drugs (DMD) in those with high serum Sema4A levels. Thus, in this study we investigated whether fingolimod has beneficial effects on MS patients with high Sema4A levels. We retrospectively analyzed annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) change in 56 relapsing-remitting multiple sclerosis (RRMS) patients who had been treated with fingolimod, including those who switched from IFN-beta therapy. The levels of Sema4A in the sera were measured by sandwich ELISA. The implications of Sema4A on the efficacy of fingolimod were investigated by administering recombinant Sema4A-Fc and fingolimod to mice with experimental autoimmune encephalomyelitis (EAE). Retrospective analysis of MS cohort (17 high Sema4A and 39 low Sema4A) demonstrated the effectiveness of fingolimod in those with high serum Sema4A levels, showing reduction of ARR (from 1.21 to 0.12) and EDSS progression (from 0.50 to 0.04). Consistent with this observation, improvement in the disease severity of EAE mice receiving recombinant Sema4A-Fc was also observed after fingolimod treatment. These data suggest that fingolimod could serve as a candidate DMD for managing the disease activity of MS patients with high Sema4A levels. PMID- 29518149 TI - Secretory microRNA-29 expression in gingival crevicular fluid during orthodontic tooth movement. AB - Secretory microRNAs (miRNAs) have been used increasingly as biomarkers for cancers, autoimmune diseases and inflammatory diseases. They are reported as being freely circulated or encapsulated in microvesicles such as exosomes. This study was performed to elucidate the presence of miRNAs with exosomes in human gingival crevicular fluid (GCF), and the expression profile of miRNA-29 during orthodontic tooth movement. Four healthy volunteer and fifteen orthodontic patients were enrolled in the study. Secretory miRNA in GCF was collected and analyzed using a bioanalyzer, realtime PCR and Western blot analysis. The expression profile of secretory miR-29 family in GCF was analyzed during the course of canine retraction for 6 weeks. The results demonstrated the presence of miRNAs in the GCF. After series of ultracentrifugation and RT-PCR array, exosome depleted fractions and pellets were isolated and we found that secretory miRNAs were detected in both the exosome-associated fraction and the exosome-depleted supernatant fraction; however, the concentration of miRNAs was higher in the exosome-associated fraction than in the exosome-depleted fraction suggesting a close association between the secretory miRNAs and exosomes in GCF. We also demonstrated the increased expression profiles of miR-29 family during six weeks of orthodontic tooth movement in humans. Secretory miRNAs are present in GCF and secretory miRNA-29 family expression profiles increase during the tooth movement in humans. Secretory miRNA-29 in GCF could serve as potential biomarkers for periodontal remodeling. PMID- 29518150 TI - Mating system and extra-pair paternity in the Fan-tailed Gerygone Gerygone flavolateralis in relation to parasitism by the Shining Bronze-cuckoo Chalcites lucidus. AB - Extra-pair copulation can increase genetic diversity and offspring fitness. However, it may also increase intra-nest variability in avian hosts of brood parasites, which can decrease the discrimination ability of host parents towards the parasite. In New Caledonia, the Fan-tailed Gerygone (Gerygone flavolateralis), which is parasitized by the Shining Bronze-cuckoo (Chalcites lucidus), has two nestling morphs, dark and bright, that can occur in monomorphic and polymorphic broods. Gerygone parents recognize and eject parasite nestlings from their nest, but the presence of polymorphic broods may increase the chances of recognition errors. Using 17 microsatellite markers, we investigated the mating system of the Fan-tailed Gerygone to understand the mechanisms underlying nestling polymorphism. We hypothesised that extra-pair copulations would lead to a higher proportion of polymorphic broods caused by higher genetic variability, thus creating a trade-off between genetic benefits and host defence reliability. Extra-pair paternity occurred in 6 of 36 broods, which resulted in 6 of 69 offspring sired by extra-pair males. Broods with and without mixed paternity were comparably often parasitized. Extra-pair paternity did not influence the proportions of bright, dark and polymorphic broods. Compared to bright siblings in polymorphic broods, dark nestlings tended to have lower heterozygosity, particularly in loci associated with skin coloration. The results also suggested that there is no obstacle for genetic exchange between individuals from forest and savannah, possibly due to dispersal of offspring. We conclude that the Fan tailed Gerygone is a socially monogamous species with a low rate of extra-pair paternity compared to closely related species. Extra-pair paternity increased offspring genetic variability without measurable associated costs by brood parasitism. The results highlight the importance of studying host mating systems to assess the trade-offs between host defence and offspring fitness in co evolutionary arms races. PMID- 29518151 TI - Does the common sexually transmitted parasite Trichomonas vaginalis have sex? PMID- 29518152 TI - The quest for good explanations. PMID- 29518154 TI - Correction: Lipoproteins comprise at least 10 different classes in rats, each of which contains a unique set of proteins as the primary component. AB - [This corrects the article DOI: 10.1371/journal.pone.0192955.]. PMID- 29518153 TI - Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes. AB - HIV-1 arose as the result of spillover of simian immunodeficiency viruses (SIVs) from great apes in Africa, namely from chimpanzees and gorillas. Chimpanzees and gorillas were, themselves, infected with SIV after virus spillover from African monkeys. During spillover events, SIV is thought to require adaptation to the new host species. The host barriers that drive viral adaptation have predominantly been attributed to restriction factors, rather than cofactors (host proteins exploited to promote viral replication). Here, we consider the role of one cofactor, RanBP2, in providing a barrier that drove viral genome evolution during SIV spillover events. RanBP2 (also known as Nup358) is a component of the nuclear pore complex known to facilitate nuclear entry of HIV-1. Our data suggest that transmission of SIV from monkeys to chimpanzees, and then from chimpanzees to gorillas, both coincided with changes in the viral capsid that allowed interaction with RanBP2 of the new host species. However, human RanBP2 subsequently provided no barrier to the zoonotic transmission of SIV from chimpanzees or gorillas, indicating that chimpanzee- and gorilla-adapted SIVs are pre-adapted to humans in this regard. Our observations are in agreement with RanBP2 driving virus evolution during cross-species transmissions of SIV, particularly in the transmissions to and between great ape species. PMID- 29518155 TI - Correction: Shared trauma reality in war: Mental health therapists' experience. AB - [This corrects the article DOI: 10.1371/journal.pone.0191949.]. PMID- 29518157 TI - Correction: Modulation of Pathways Underlying Distinct Cell Death Mechanisms in Two Human Lung Cancer Cell Lines in Response to SN1 Methylating Agents Treatment. AB - [This corrects the article DOI: 10.1371/journal.pone.0160248.]. PMID- 29518156 TI - CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection. AB - Plasmodium relies on numerous agonists during its journey through the mosquito vector, and these agonists represent potent targets for transmission-blocking by either inhibiting or interfering with them pre- or post-transcriptionally. The recently developed CRISPR/Cas9-based genome editing tools for Anopheles mosquitoes provide new and promising opportunities for the study of agonist function and for developing malaria control strategies through gene deletion to achieve complete agonist inactivation. Here we have established a modified CRISPR/Cas9 gene editing procedure for the malaria vector Anopheles gambiae, and studied the effect of inactivating the fibrinogen-related protein 1 (FREP1) gene on the mosquito's susceptibility to Plasmodium and on mosquito fitness. FREP1 knockout mutants developed into adult mosquitoes that showed profound suppression of infection with both human and rodent malaria parasites at the oocyst and sporozoite stages. FREP1 inactivation, however, resulted in fitness costs including a significantly lower blood-feeding propensity, fecundity and egg hatching rate, a retarded pupation time, and reduced longevity after a blood meal. PMID- 29518159 TI - Correction: The Sulfated Laminarin Triggers a Stress Transcriptome before Priming the SA- and ROS-Dependent Defenses during Grapevine's Induced Resistance against Plasmopara viticola. AB - [This corrects the article DOI: 10.1371/journal.pone.0088145.]. PMID- 29518158 TI - Inclusion bodies of human parainfluenza virus type 3 inhibit antiviral stress granule formation by shielding viral RNAs. AB - Viral invasion triggers the activation of the host antiviral response. Besides the innate immune response, stress granules (SGs) also act as an additional defense response to combat viral replication. However, many viruses have evolved various strategies to suppress SG formation to facilitate their own replication. Here, we show that viral mRNAs derived from human parainfluenza virus type 3 (HPIV3) infection induce SG formation in an eIF2alpha phosphorylation- and PKR dependent manner in which viral mRNAs are sequestered and viral replication is inhibited independent of the interferon signaling pathway. Furthermore, we found that inclusion body (IB) formation by the interaction of the nucleoprotein (N) and phosphoprotein (P) of HPIV3 correlated with SG suppression. In addition, co expression of P with NL478A (a point mutant of N, which is unable to form IBs with P) or with NDeltaN10 (lacking N-terminal 10 amino acids of N, which could form IBs with P but was unable to synthesize or shield viral RNAs) failed to inhibit SG formation, suggesting that inhibition of SG formation also correlates with the capacity of IBs to synthesize and shield viral RNAs. Therefore, we provide a model whereby viral IBs escape the antiviral effect of SGs by concealing their own newly synthesized viral RNAs and offer new insights into the emerging role of IBs in viral replication. PMID- 29518160 TI - Correction: Management of the soybean cyst nematode Heterodera glycines with combinations of different rhizobacterial strains on soybean. AB - [This corrects the article DOI: 10.1371/journal.pone.0182654.]. PMID- 29518161 TI - Toll-like receptor expression in pulmonary sensory neurons in the bleomycin induced fibrosis model. AB - Airway sensory nerves are known to express several receptors and channels that are activated by exogenous and endogenous mediators that cause coughing. Toll like receptor (TLR) s are expressed in nociceptive neurons and play an important role in neuroinflammation. However, there have been very few studies of TLR expression in lung-derived sensory neurons or their relevance to respiratory symptoms such as cough. We used the bleomycin-induced pulmonary fibrosis model to investigate the change in TLR expression in pulmonary neurons and the association of TLRs with transient receptor potential (TRP) channels in pulmonary neurons. After 2 weeks of bleomycin or saline administration, pulmonary fibrosis changes were confirmed using tissue staining and the SIRCOL collagen assay. TLRs (TLR 1 9) and TRP channel expression was analyzed using single cell reverse transcription polymerase chain reaction (RT-PCR) in isolated sensory neurons from the nodose/jugular ganglion and the dorsal root ganglion (DRG). Pulmonary sensory neurons expressed TLR2 and TLR5. In the bleomycin-induced pulmonary fibrosis model, TLR2 expression was detected in 29.5% (18/61) and 26.9% (21/78) of pulmonary nodose/jugular neurons and DRG neurons, respectively. TLR5 was also detected in 55.7% (34/61) and 42.3% (33/78) of pulmonary nodose/jugular neurons and DRG neurons, respectively, in the bleomycin-induced pulmonary fibrosis model. TLR5 was expressed in 63.4% of TRPV1 positive cells and 43.4% of TRPM8 positive cells. In conclusion, TLR2 and TLR5 expression is enhanced, especially in vagal neurons, in the bleomycin-induced fibrosis model group when compared to the saline treated control group. Co-expression of TLR5 and TRP channels in pulmonary sensory neurons was also observed. This work sheds new light on the role of TLRs in the control and manifestation of clinical symptoms, such as cough. To understand the role of TLRs in pulmonary sensory nerves, further study will be required. PMID- 29518162 TI - Variability and validity of intimate partner violence reporting by couples in Tanzania. AB - In recent years, major global institutions have amplified their efforts to address intimate partner violence (IPV) against women-a global health and human rights violation affecting 15-71% of reproductive aged women over their lifetimes. Still, some scholars remain concerned about the validity of instruments used for IPV assessment in population-based studies. In this paper, we conducted two validation analyses using novel data from 450 women-men dyads across nine villages in Northern Tanzania. First, we examined the level of inter partner agreement in reporting of men's physical, sexual, emotional and economic IPV against women in the last three and twelve months prior to the survey, ever in the relationship, and during pregnancy. Second, we conducted a convergent validity analysis to compare the relative efficacy of men's self-reports of perpetration and women's of victimization as a valid indicator of IPV against Tanzanian women using logistic regression models with village-level clustered errors. We found that, for every violence type across the recall periods of the last three months, the last twelve months and ever in the relationship, at least one in three couples disagreed about IPV occurrences in the relationship. Couples' agreement about physical, sexual and economic IPV during pregnancy was high with 86-93% of couples reporting concordantly. Also, men's self-reported perpetration had statistically significant associations with at least as many validated risk factors as had women's self-reported victimization. This finding suggests that men's self-reports are at least as valid as women's as an indicator of IPV against women in Northern Tanzania. We recommend more validation studies are conducted in low-income countries, and that data on relationship factors affecting IPV reports and reporting are made available along with data on IPV occurrences. PMID- 29518163 TI - Optimizing single irrigation scheme to improve water use efficiency by manipulating winter wheat sink-source relationships in Northern China Plain. AB - Improving winter wheat grain yield and water use efficiency (WUE) with minimum irrigation is very important for ensuring agricultural and ecological sustainability in the Northern China Plain (NCP). A three-year field experiment was conducted to determine how single irrigation can improve grain yield and WUE by manipulating the "sink-source" relationships. To achieve this, no-irrigation after sowing (W0) as a control, and five single irrigation treatments after sowing (75 mm of each irrigation) were established. They included irrigation at upstanding (WU), irrigation at jointing (WJ), irrigation at booting (WB), irrigation at anthesis (WA) and irrigation at medium milk (WM). Results showed that compared with no-irrigation after sowing (W0), WU, WJ, WB, WA and WM significantly improved mean grain yield by 14.1%, 19.9%, 17.9%, 11.6%, and 7.5%, respectively. WJ achieved the highest grain yield (8653.1 kg ha-1) and WUE (20.3 kg ha-1 mm-1), and WB observed the same level of grain yield and WUE as WJ. In comparison to WU, WJ and WB coordinated pre- and post-anthesis water use while reducing pre-anthesis and total evapotranspiration (ET). They also retained higher soil water content above 180 cm soil layers at anthesis, increased post anthesis water use, and ultimately increased WUE. WJ and WB optimized population quantity and individual leaf size, delayed leaf senescence, extended grain filling duration, improved post-anthesis biomass and biomass remobilization (source supply capacity) as well as post-anthesis biomass per unit anthesis leaf area (PostBA-leaf ratio). WJ also optimized the allocation of assimilation, increased the spike partitioning index (SPI, spike biomass/biomass at anthesis) and grain production efficiency (GPE, the ratio of grain number to biomass at anthesis), thus improved mean sink capacity by 28.1%, 5.7%, 21.9%, and 26.7% in comparison to W0, WU, WA and WM, respectively. Compared with WA and WM, WJ and WB also increased sink capacity, post-anthesis biomass and biomass remobilization. These results demonstrated that single irrigation at jointing or booting could improve grain yield and WUE via coordinating the "source-sink" relationships with the high sink capacity and source supply capacity. Therefore, we propose that under adequate soil moisture conditions before sowing, single irrigation scheme from jointing to booting with 75 mm irrigation amount is the optimal minimum irrigation practice for wheat production in this region. PMID- 29518164 TI - MtDNA genetic diversity and structure of Eurasian Collared Dove (Streptopelia decaocto). AB - The Eurasian Collared Dove (Streptopelia decaocto) is one of the most successful biological invaders among terrestrial vertebrates. However, little information is available on the genetic diversity of the species. A total of 134 Eurasian Collared Doves from Europe, Asia and the Caribbean (n = 20) were studied by sequencing a 658-bp length of mitochondrial DNA (mtDNA) cytochrome oxidase I (COI). Fifty-two different haplotypes and relatively high haplotype and nucleotide diversities (Hd+/-SD = 0.843+/-0.037 and pi+/-SD = 0.026+/-0.013) were detected. Haplotype Ht1 was particularly dominant: it included 44.03% of the studied individuals, and contained sequences from 75% of the studied countries. Various analyses (FST, AMOVA, STRUCTURE) distinguished 2 groups on the genetic level, designated 'A' and 'B'. Two groups were also separated in the median joining network and the maximum likelihood tree. The results of the neutrality tests were negative (Fu FS = -25.914; Tajima D = -2.606) and significantly different from zero (P<=0.001) for group A, whereas both values for group B were positive (Fu FS = 1.811; Tajima D = 0.674) and not significant (P>0.05). Statistically significant positive autocorrelation was revealed among individuals located up to 2000 km apart (r = 0.124; P = 0.001). The present results provide the first information on the genetic diversity and structure of the Eurasian Collared Dove, and can thereby serve as a factual and comparative basis for similar studies in the future. PMID- 29518165 TI - No better moment to score a goal than just before half time? A soccer myth statistically tested. AB - We test the soccer myth suggesting that a particularly good moment to score a goal is just before half time. To this end, rich data on 1,179 games played in the UEFA Champions League and UEFA Europa League are analysed. In contrast to the myth, we find that, conditional on the goal difference and other game characteristics at half time, the final goal difference at the advantage of the home team is 0.520 goals lower in case of a goal just before half time by this team. We show that this finding relates to this team's lower probability of scoring a goal during the second half. PMID- 29518167 TI - Correction: Recovery from Toxic-Induced Demyelination Does Not Require the NG2 Proteoglycan. AB - [This corrects the article DOI: 10.1371/journal.pone.0163841.]. PMID- 29518166 TI - Diagnostic accuracy of antigen-based immunochromatographic rapid diagnostic tests for the detection of Salmonella in blood culture broth. AB - BACKGROUND: In low resource settings, Salmonella serovars frequently cause bloodstream infections. This study investigated the diagnostic performance of immunochromatographic rapid diagnostic tests (RDTs), which detect Salmonella antigens, when applied to stored grown blood culture broth. MATERIAL/METHODS: The SD Bioline One Step Salmonella Typhi Ag Rapid Detection Kit (Standard Diagnostics, Republic of Korea), marketed for the detection of Salmonella enterica serovar Typhi (Salmonella Typhi) in stool and the Salmonella Ag Rapid Test (Creative Diagnostics, USA), marketed for the detection of all Salmonella serotypes in stool, were selected for evaluation based on a pre-test evaluation of six RDT products. The limits of detection (LOD) for culture suspensions were established and the selected RDT products were assessed on 19 freshly grown spiked blood culture broth samples and 413 stored clinical blood culture broth samples, collected in Cambodia and the Democratic Republic of the Congo. RESULTS: The LOD of both products was established as 107-108 CFU/ml. When applied to clinical blood culture broth samples, the diagnostic sensitivity and specificity of the SD Bioline RDT were respectively 100% and 79.7% for the detection of Salmonella Typhi; 94.4% (65/69) of false-positive results were caused by Salmonella Enteritidis. When considering the combined detection of Salmonella Typhi and Enteritidis (both group D Salmonella), sensitivity and specificity were 97.9% and 98.5% respectively. For Creative Diagnostics, diagnostic sensitivity was 78.3% and specificity 91.0% for all Salmonella serotypes combined; 88.3% (53/60) of false negative results were caused by Salmonella Paratyphi A. CONCLUSIONS: When applied to grown blood culture broths, the SD Bioline RDT had a good sensitivity and specificity for the detection of Salmonella Typhi and Salmonella Enteritidis. The Creative Diagnostics product had a moderate sensitivity and acceptable specificity for the detection of all Salmonella serovars combined and needs further optimization. A RDT that reliably detects Salmonella Paratyphi A is needed. PMID- 29518168 TI - Psychological consequences of child trafficking: An historical cohort study of trafficked children in contact with secondary mental health services. AB - BACKGROUND: Child trafficking is the recruitment and movement of people aged younger than 18 for the purposes of exploitation. Research on the mental health of trafficked children is limited, and little is known about the use of mental health services by this group. This study aimed to investigate the mental health and service use characteristics of trafficked children in contact with mental health services in England. METHODS & FINDINGS: The study employed an historical cohort design. Electronic health records of over 250,000 patients were searched to identify trafficked children, and a matched cohort of non-trafficked children was randomly selected. Data were extracted on the socio-demographic and clinical characteristics, abuse history, and trafficking experiences of the trafficked children. Logistic and linear random effects regression models were fitted to compare trafficked and non-trafficked children on their clinical profiles and service use characteristics. Fifty-one trafficked children were identified, 78% were female. The most commonly recorded diagnoses for trafficked children were post-traumatic stress disorder (PTSD) (22%) and affective disorders (22%). Records documented a high prevalence of physical violence (53%) and sexual violence (49%) among trafficked children. Trafficked children had significantly longer duration of contact with mental health services compared to non-trafficked controls (b = 1.66, 95% CI 1.09-2.55, p<0.02). No significant differences were found, however, with regards to pathways into care, prevalence of compulsory psychiatric admission, length of inpatient stays, or changes in global functioning. CONCLUSIONS: Child trafficking is associated with high levels of physical and sexual abuse and longer duration of contact with mental health services. Research is needed on most effective interventions to promote recovery for this vulnerable group. PMID- 29518169 TI - Distribution path robust optimization of electric vehicle with multiple distribution centers. AB - To identify electrical vehicle (EV) distribution paths with high robustness, insensitivity to uncertainty factors, and detailed road-by-road schemes, optimization of the distribution path problem of EV with multiple distribution centers and considering the charging facilities is necessary. With the minimum transport time as the goal, a robust optimization model of EV distribution path with adjustable robustness is established based on Bertsimas' theory of robust discrete optimization. An enhanced three-segment genetic algorithm is also developed to solve the model, such that the optimal distribution scheme initially contains all road-by-road path data using the three-segment mixed coding and decoding method. During genetic manipulation, different interlacing and mutation operations are carried out on different chromosomes, while, during population evolution, the infeasible solution is naturally avoided. A part of the road network of Xifeng District in Qingyang City is taken as an example to test the model and the algorithm in this study, and the concrete transportation paths are utilized in the final distribution scheme. Therefore, more robust EV distribution paths with multiple distribution centers can be obtained using the robust optimization model. PMID- 29518171 TI - Is aldehyde dehydrogenase inhibited by sulfur compounds? In vitro and in vivo studies. AB - Aldehyde dehydrogenase (ALDH) catalyzes the critical step of ethanol metabolism, i.e. transformation of toxic acetaldehyde to acetic acid. It is a redox sensitive protein with the key Cys in its active site. Recently, it has been documented that activity of some proteins can be modified by sulfur-containing molecules called reactive sulfur species leading to the formation of hydro- persulfides. The aim of the present study was to examine whether ALDH activity can be modified in this way. Studies were performed in vitro using yeast ALDH and various reactive sulfur species, including Na2S, GSSH, K2Sx, Na2S2O3, and garlic-derived allyl sulfides. The effect of garlic-derived trisulfide on ALDH activity was also studied in vivo in the rat liver. The obtained results clearly demonstrated that ALDH could be regulated by sulfur species which inhibited its enzymatic activity. The results also suggested that not H2S but polysulfides or hydropersulfides were the oxidizing species responsible for this modification. This process was easily reversible by reducing agents. After the treatment with polysulfides or hydropersulfides the level of protein-bound sulfur increased, while the activity of the enzyme dramatically decreased. Moreover, the study demonstrated that ALDH activity was inhibited in vivo in the rat liver after garlic-derived trisulfide administration. This is the first study reporting the regulation of ALDH activity by sulfane sulfur species and the results suggest that it leads to the inhibition of the enzyme. PMID- 29518176 TI - Cerebrospinal Fluid Vancomycin Dosing and Monitoring: The Quandary Posed by Guideline Recommendations. PMID- 29518170 TI - Instar- and host-associated differentiation of bacterial communities in the Mediterranean fruit fly Ceratitis capitata. AB - Microorganisms are acknowledged for their role in shaping insects' evolution, life history and ecology. Previous studies have shown that microbial communities harbored within insects vary through ontogenetic development and among insects feeding on different host-plant species. In this study, we characterized the bacterial microbiota of the highly polyphagous Mediterranean fruit fly, Ceratitis capitata (Diptera: Tephritidae), at different instars and when feeding on different host-plant species. Our results show that the bacterial microbiota hosted within the Mediterranean fruit fly differs among instars and host-plant species. Most of the bacteria harbored by the Mediterranean fruit fly belong to the phylum Proteobacteria, including genera of Alphaproteobacteria such as Acetobacter and Gluconobacter; Betaprotobacteria such as Burkholderia and Gammaproteobacteria such as Pseudomonas. PMID- 29518177 TI - Genomic and epigenomic perspectives of T-cell exhaustion in cancer. AB - In chronic infection and cancer, T cells gradually become exhausted because of the persistent stimulation by antigens. In this process, the overexpression of multiple inhibitory receptors is induced, the production of effective cytokines decreases and the cytotoxicity and proliferation of T cells impairs, all contributing to the failure of T cells in fighting against cancer. Reversing T cell exhaustion is a promising immunotherapy for cancer that has yielded encouraging results. In this review, we discuss the genomic and epigenomic landscape of T-cell exhaustion in cancer. Also, we introduce the relevant therapeutic interventions for T-cell exhaustion in clinical trials. PMID- 29518179 TI - The Top 100 Social Media Influencers in Plastic Surgery on Twitter: Who Should You Be Following? AB - Background: Recent studies demonstrate that board-certified plastic surgeons are underrepresented amongst individuals posting public-directed marketing plastic surgery-related content on Instagram. However, peer-to-peer and education-based social media influence has not been studied. Twitter is a social media platform has been suggested to be useful for educating the masses and connecting with colleagues. Objectives: The purpose of this study is to identify the top influencers in plastic surgery on Twitter, characterize who they are, and relate their social media influence to academic influence. Methods: Twitter influence scores for the topic search "plastic surgery" were collected in July 2017 using Right Relevance software. The accounts associated with the highest influencer scores were linked to individual names, status as a plastic surgeon, board certification, location, and academic h-index. Results: The top 100 Twitter influencers in plastic surgery are presented. Seventy-seven percent of the top influencers are trained as plastic surgeons or facial plastic surgeons. Sixty-one percent of influencers are board-certified plastic surgeons or board eligible/future eligible trainees. International plastic surgeons made up 16% of influencers. Other medical doctors made up another 10%. The other 13% of influencers were nonphysicians. Three-quarters of social media influencers were physically located in the United States. Academic h-index of social media influencers ranged from 0 to 62 (mean, 8.6). Conclusions: This study shows that the top plastic surgery social media influencers on Twitter are predominantly board-certified or eligible plastic surgeons and physically based in the United States. This study also provides the influencer network for other plastic surgeons to engage with to improve their own influence within the plastic surgery social media sphere. PMID- 29518180 TI - Reappraising 'the good death' for populations in the age of ageing. AB - This is the second in an occasional series of paired commentaries in Age and Ageing, the Journal of the British Geriatrics Society and the Journal of the American Geriatrics Society (JAGS). The aim is to address issues of current significance and to foster dialogue and increased understanding between academics and clinicians working in comparative international settings. Both commentaries address the urgent need to improve palliative care for older people, with a critique of some stereotypes surrounding palliative care and the 'good death'. The companion commentary, published in JAGS, was written by Alexander Smith and Vyjeyanthi Periyakoil, and is grounded in their experience as academic clinicians (Smith AK, Periyakoil V. Should we bury 'The Good Death'? Journal of the American Geriatrics Society 2018; in press). In the present paper, we offer a perspective on the outcome and wider consequences of misalignment between current UK policy and aspirations for end of life care in relation to epidemiological trends and patient experience of death and dying. PMID- 29518178 TI - A Comparison of the Efficacy and Safety of Intravenous Followed by Oral Delafloxacin With Vancomycin Plus Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections: A Phase 3, Multinational, Double-Blind, Randomized Study. AB - Background: Delafloxacin is an intravenous (IV)/oral anionic fluoroquinolone with activity against gram-positive (including methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative, atypical, and anaerobic organisms. It is approved in the United States for acute bacterial skin and skin structure infections (ABSSSIs) caused by designated susceptible gram-positive and gram-negative organisms, and is in development for the treatment of community-acquired bacterial pneumonia. Methods: A multicenter, randomized, double-blind trial of 850 adults with ABSSSI compared delafloxacin 300 mg IV every 12 hours for 3 days with a switch to 450 mg oral delafloxacin, to vancomycin 15 mg/kg IV with aztreonam for 5-14 days. The primary endpoint was objective response at 48-72 hours. Investigator-assessed response based on resolution of signs and symptoms at follow-up (day 14 +/- 1), and late follow-up (day 21-28) were secondary endpoints. Results: In the intent-to-treat analysis set, the objective response was 83.7% in the delafloxacin arm and 80.6% in the comparator arm. Investigator assessed success was similar at follow-up (87.2% vs 84.4%) and late follow-up (83.5% vs 82.2%). Delafloxacin was comparable to vancomycin + aztreonam in eradication of MRSA at 96.0% vs 97.0% at follow-up. Frequency of treatment emergent adverse events between the groups was similar. Treatment-emergent adverse events leading to study drug discontinuation was higher in the vancomycin + aztreonam group (1.2% vs 2.4%). Conclusions: In ABSSSI patients, IV/oral delafloxacin monotherapy was noninferior to IV vancomycin + aztreonam combination therapy for both the objective response and the investigator-assessed response at follow-up and late follow-up. Delafloxacin was well tolerated as monotherapy in treatment of ABSSSIs. Clinical Trials Registration: NCT01984684. PMID- 29518181 TI - CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. AB - Background: The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Patients and methods: Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. Results: BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group. Conclusions: BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors. PMID- 29518182 TI - Homologue-specific chromosome sequencing characterizes translocation junctions and permits allelic assignment. AB - Chromosome translocations can be detected by cytogenetic analysis, but it is hard to characterize the breakpoints at the sequence level. Chromosome sorting by flow cytometry produces flow karyotypes that enable the isolation of abnormal chromosomes and the generation of chromosome-specific DNA. In this study, a derivative chromosome t(9; 14) and its homologous normal chromosomes 9 and 14 from the Ishikawa 3-H-12 cell line were sorted to collect homologue-specific samples. Chromosome sequencing identified the breakpoint junction in the der(9) at 9p24.3 and 14q13.1 and uncovered the formation of a fusion gene, WASH1-NPAS3. Amplicon sequencing targeted for neighbouring genes at the fusion breakpoint revealed that the variant frequencies correlate with the allelic copy number. Sequencing of sorted chromosomes permits the assignment of allelic variants and can lead to the characterization of abnormal chromosomes. We show that allele specific chromosome sequencing of homologues is a robust technique for distinguishing alleles and this provides an efficient approach for the comprehensive analysis of genomic changes. PMID- 29518183 TI - Cardioprotection by cardiac progenitor cell-secreted exosomes: role of pregnancy associated plasma protein-A. AB - Aims: Cell therapy trials using cardiac-resident progenitor cells (CPCs) and bone marrow-derived mesenchymal stem/progenitor cells (BMCs) in patients after myocardial infarction have provided encouraging results. Exosomes, nanosized extracellular vesicles of endosomal origin, figure prominently in the bioactivities of these cells. However, a head-to-head comparison of exosomes from the two cell types has not been performed yet. Methods and results: CPCs and BMCs were derived from cardiac atrial appendage specimens and sternal bone marrow, respectively, from patients (n = 20; age, 69.9 +/- 10.9) undergoing heart surgery for aortic valve disease and/or coronary artery disease. Vesicles were purified from cell conditioned media by centrifugation/filtration and ultracentrifugation. Vesicle preparations were predominantly composed of exosomes based on particle size and marker expression (CD9, CD63, CD81, Alix, and TSG-101). CPC-secreted exosomes prevented staurosporine-induced cardiomyocyte apoptosis more effectively than BMC-secreted exosomes. In vivo, CPC-secreted exosomes reduced scar size and improved ventricular function after permanent coronary occlusion in rats more efficiently than BMC-secreted exosomes. Both types of exosomes stimulated blood vessel formation. CPC-secreted exosomes, but not BMC-derived exosomes, enhanced ventricular function after ischaemia/reperfusion. Proteomics profiling identified pregnancy-associated plasma protein-A (PAPP-A) as one of the most highly enriched proteins in CPC vs. BMC exosomes. The active form of PAPP-A was detected on CPC exosome surfaces. These vesicles released insulin-like growth factor-1 (IGF-1) via proteolytic cleavage of IGF-binding protein-4 (IGFBP-4), resulting in IGF-1 receptor activation, intracellular Akt and ERK1/2 phosphorylation, decreased caspase activation, and reduced cardiomyocyte apoptosis. PAPP-A knockdown prevented CPC exosome-mediated cardioprotection both in vitro and in vivo. Conclusion: These results suggest that CPC-secreted exosomes may be more cardioprotective than BMC-secreted exosomes, and that PAPP-A-mediated IGF-1 release may explain the benefit. They illustrate a general mechanism whereby exosomes may function via an active protease on their surface, which releases a ligand in proximity to the transmembrane receptor bound by the ligand. PMID- 29518184 TI - Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. AB - Background and Aims: Ocular extraintestinal manifestations [O-EIMs] are known complications of Crohn's disease [CD], ulcerative colitis [UC], and inflammatory bowel disease unclassified [IBD-U]. However, data on their prevalence in children are scarce and there are no clear recommendations on what follow-up should be offered. We aimed to review available data on O-EIMs in children. Methods: In January 2018, we performed a systematic review of published English literature using PubMed and EMBASE databases and disease-specific queries. Results: Fifteen studies [7467 patients] reported data on O-EIMs prevalence in children. Overall prevalence of O-EIMs was 0.62-1.82%. Uveitis was the most common O-EIM. Meta analysis showed that children with CD are at increased risk of O-EIMs as compared with children with UC and IBD-U (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.51-4.83). Five studies [357 patients] reported data on ophthalmological screening in asymptomatic children: mild asymptomatic uveitis was identified in a variable proportion of patients [1.06-23.1%], more frequently in male patients with CD and colonic involvement. No evidence of ocular complications from untreated uveitis was detected. A total of 23 case reports [24 patients] were identified. Conclusions: Data on O-EIMs in children are scarce. Prevalence of O EIMs is lower than in adults but may be underestimated because of the possibility of asymptomatic uveitis; however, the long-term significance of this condition is unknown. Children with CD may be at increased risk of O-EIMs. No recommendations on routine ophthalmological examination can be made, but a low threshold for ophthalmological referral should be maintained. Larger studies in paediatric IBD populations are needed. PMID- 29518185 TI - Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. AB - Background: Myelosuppression-related infections remain important causes of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). Methods: By analyzing fecal samples collected at diagnosis and after each of the initial 3 phases of chemotherapy, we evaluated the role of gut microbiota in predicting infections in 199 children with newly diagnosed ALL. The bacterial 16S rRNA gene was analyzed by high-depth sequencing to determine the diversity and composition of the microbiome. Results: After the induction and reinduction I phases of chemotherapy, microbial diversity decreased significantly relative to the prechemotherapy value. After chemotherapy, the relative abundance of certain bacterial taxa (eg, Bacteroidetes) decreased significantly, whereas that of other taxa (eg, Clostridiaceae and Streptococcaceae) increased. A baseline gut microbiome characterized by Proteobacteria predicted febrile neutropenia. Adjusting for the chemotherapy phase and ALL risk level, Enterococcaceae dominance (relative abundance >=30%) predicted significantly greater risk of subsequent febrile neutropenia and diarrheal illness, whereas Streptococcaceae dominance predicted significantly greater risk of subsequent diarrheal illness. Conclusions: In children undergoing therapy for newly diagnosed ALL, the relative abundance of Proteobacteria before chemotherapy initiation predicts development of febrile neutropenia, and domination of the gut microbiota by Enterococcaceae or Streptococcaceae at any time during chemotherapy predicts infection in subsequent phases of chemotherapy. Clinical Trial Registration: NCT00549848. PMID- 29518186 TI - Influence of Long-Term Salt Diets on Cardiac Ca2+ Handling and Contractility Proteins in Hypertensive Rats. AB - BACKGROUND: High sodium intake contributes to the pathogenesis of hypertension and adversely affects cardiac function. Conversely, sodium reduction is associated with a blood pressure decrease and improved cardiovascular function. However, the mechanisms that underlie the cardiac effects induced by salt intake in hypertension have not been fully elucidated. Ca2+ handling is critical for efficient myocardial function; thus, we aimed to investigate the long-term effects of diets with different salt contents on cardiac function and Ca2+ handling proteins in spontaneously hypertensive rats (SHRs). METHODS: Cardiac function was evaluated by catheterization. Ca2+ handling and contractile proteins were evaluated by immunoblotting in hearts from SHRs fed for 6 months with diets containing high (HS, 3%), low (LS, 0.03%), or normal salt content (NS, 0.3%). Diets were introduced immediately after weaning. Tail cuff pletismography was assessed at the 3rd and 7th months of follow-up. RESULTS: Compared to the NS group, the HS group exhibited worsened hypertension, increased cardiac expression of beta-myosin heavy chain (MHC), a decreased alpha/beta-MHC ratio and reduced expression of both phospholamban (PLB) and Na+/Ca2+ exchanger (NCX). LS intake attenuated the blood pressure increase and left ventricle hypertrophy, slightly decreased the cardiac contractility and relaxation index, and increased the alpha/beta-MHC ratio. These effects were accompanied by increased cardiac PLB expression and decreased Ca2+ L-type channel and NCX expression. CONCLUSIONS: These findings indicate that the modulation of Ca2+ handling may be one of the molecular mechanisms underlying the effect of salt intake on myocardial function in hypertension. PMID- 29518188 TI - Pacemaker dependency: how should it be defined?-Authors' reply. PMID- 29518187 TI - Potent and rapid activation of tropomyosin-receptor kinase A in endometrial stromal fibroblasts by seminal plasma. AB - Seminal plasma (SP), the liquid fraction of semen, is not mandatory for conception, but clinical studies suggest that SP improves implantation rates. Prior in vitro studies examining the effects of SP on the endometrium, the site of implantation, surprisingly revealed that SP induces transcriptional profiles associated with neurogenesis. We investigated the presence and activity of neurogenesis pathways in the endometrium, focusing on TrkA, one of the canonical receptors associated with neurotrophic signaling. We demonstrate that TrkA is expressed in the endometrium. To determine if SP activates TrkA signaling, we isolated the two most abundant endometrial cell types-endometrial epithelial cells (eEC) and endometrial stromal fibroblasts (eSF)-and examined TrkA activity in these cells after SP exposure. While SP only moderately activated TrkA in eEC, it potently and rapidly activated TrkA in eSF. This activation occurred in both non-decidualized and decidualized eSF. Blocking this pathway resulted in dysregulation of SP-induced cytokine production by eSF. Surprisingly, while the canonical TrkA agonist nerve growth factor was detected in SP, TrkA activation was principally induced by a 30-100-kDa protein whose identity remains to be established. Our results show that TrkA signaling is highly active in eSF and is rapidly induced by SP. PMID- 29518189 TI - Epithelial cell lysates induce ExoS expression and secretion by Pseudomonas aeruginosa. AB - The type three secretion system (T3SS) is important for the intracellular survival of Pseudomonas aeruginosa. Known T3SS inducers include low Ca2+, serum or host cell contact. Here, we used corneal epithelial cell lysates to test if host cytosolic factors could also induce the T3SS. Invasive P. aeruginosa strain PAO1 was exposed to cell lysates for 16 h, and expression of T3SS effectors determined by q-PCR and Western immunoblot. Lysate exposure reduced PAO1 growth (~5-fold) versus trypticase soy broth (TSB), but also resulted in appearance of a protein in culture supernatants, but not bacterial cell pellets, which reacted with antibody raised against ExoS. T3SS-inducing media (TSBi) caused the expression and secretion of ExoS and ExoT. Heat-treated lysates induced the protein; 1:3 diluted lysates did not. The protein that bound anti-ExoS antibody was found in supernatants of lysate-exposed exoT mutants, but not exoS or pscC mutants, suggesting a secreted form of ExoS, albeit slightly larger than that induced by TSBi. Lysate-exposed strain PAK expressed the same protein. Lysates caused PAO1 exoS and exoT gene expression, but only ~20% and ~6% of TSBi, respectively. T3SS induction by epithelial cell lysates could help explain T3SS expression by internalized P. aeruginosa. PMID- 29518190 TI - Coexistence of two distinct Sulfurospirillum populations respiring tetrachloroethene-genomic and kinetic considerations. AB - Two anaerobic bacterial consortia, each harboring a distinct Sulfurospirillum population, were derived from a 10 year old consortium, SL2, previously characterized for the stepwise dechlorination of tetrachloroethene (PCE) to cis dichloroethene (cis-DCE) via accumulation of trichloroethene (TCE). Population SL2-1 dechlorinated PCE to TCE exclusively, while SL2-2 produced cis-DCE from PCE without substantial TCE accumulation. The reasons explaining the long-term coexistence of the populations were investigated. Genome sequencing revealed a novel Sulfurospirillum species, designated 'Candidatus Sulfurospirillum diekertiae', whose genome differed significantly from other Sulfurospirillum spp. (78%-83% ANI). Genome-wise, SL2-1 and SL2-2 populations are almost identical, but differences in their tetrachloroethene reductive dehalogenase sequences explain the distinct dechlorination patterns. An extended series of batch cultures were performed at PCE concentrations of 2-200 MUM. A model was developed to determine their dechlorination kinetic parameters. The affinity constant and maximal growth rate differ between the populations: the affinity is 6- to 8-fold higher and the growth rate 5-fold lower for SL2-1 than SL2-2. Mixed cultivation of the enriched populations at 6 and 30 MUM PCE showed that a low PCE concentration could be the driving force for both functional diversity of reductive dehalogenases and niche specialization of organohalide-respiring bacteria with overlapping substrate ranges. PMID- 29518191 TI - Pacemaker dependency: how should it be defined? PMID- 29518192 TI - A large left ventricular tumour protruding through the aortic valve. PMID- 29518193 TI - Disciplinary differences of the impact of altmetric. AB - The main objective of this work was to group altmetric indicators according to their relationships and detect disciplinary differences with regard to altmetric impact in a set of 3793 research articles published in 2013. Three of the most representative altmetric providers (Altmetric, PlumX and Crossref Event Data) and Scopus were used to extract information about these publications and their metrics. Principal component analysis was used to summarize the information on these metrics and detect groups of indicators. The results show that these metrics can be grouped into three components: social media, gathering metrics from social networks and online media; usage, including metrics on downloads and views; and citations and saves, grouping metrics related to research impact and saves in bookmarking sites. With regard to disciplinary differences, articles in the General category attract more attention from social media, Social Sciences articles have higher usage than Physical Sciences, and General articles are more cited and saved than Health Sciences and Social Sciences articles. PMID- 29518194 TI - Randomized trials and big data analysis: we need the best of both worlds. PMID- 29518195 TI - Atrial fibrillation progression and outcome in patients with young-onset atrial fibrillation. AB - Aims: Clinicians increasingly encounter patients with young-onset atrial fibrillation (AF). Aim is to study clinical profile, AF progression, and outcome of patients with young-onset AF. Methods and results: A total of 468 patients with paroxysmal or persistent AF starting <60 years of age were included. Clinical profile, AF progression, defined as development of permanent AF, and cardiovascular events were prospectively collected. Onset of AF was at 46 +/- 10 years, 354 (76%) were men, 329 (70%) had paroxysmal AF, 50 (11%) had AF without risk factors or comorbidities, and 118 (25%) had familial AF. Hypertension was present in 207 (44%), heart failure in 44 (9%). During 7.2 (2.7-10.0) years, 56 (11%) had AF progression (2.0%/year). Progression rate in patients receiving antiarrhythmic drugs or pulmonary vein isolation during follow-up was not different from patients who did not. Multivariable determinants of AF progression included diastolic blood pressure [hazard ratio (HR) 1.031, 95% confidence interval (95% CI) 1.007-1.055; P = 0.010] and left atrial size (HR 1.055, 95% CI 1.012-1.099; P = 0.012). Cardiovascular events occurred in 61 patients (13%; 2.4%/year). Multivariable determinants of cardiovascular events were PR interval (HR 1.015, 95% CI 1.005-1.024; P = 0.002) and left ventricular hypertrophy (HR 3.429, 95% CI 1.712-6.868; P = 0.001). Yearly event rate was higher in patients who had developed AF progression, compared to patients without progression [4.9 (2.3-9.0)% vs. 1.9 (1.4-2.6)%; P = 0.006]. Conclusion: Nine of 10 patients with young-onset AF had risk factors and comorbidities, 25% had familial AF. Atrial fibrillation progression to permanent AF and cardiovascular events occurred in 2.0% and 2.4% per year, respectively. Cardiovascular events increased after AF progression had occurred. PMID- 29518197 TI - Multipolarity of cytokine axes in the pathogenesis of atopic dermatitis in terms of age, race, species, disease stage and biomarkers. AB - Atopic dermatitis (AD) is a common T-cell-mediated inflammatory disease of the skin. Signatures of AD are characterized by an impaired skin barrier, aberrant Th2-type cytokine production and intensive pruritus. Transcriptomic analysis, however, has revealed a heterogeneous pathogenesis and the co-existence of multiple cytokine axes of Th17, Th22 and Th1 types, especially in intrinsic (a subtype of AD without skin barrier impairment), pediatric and Asian types of AD. Furthermore, the therapeutic effect of anti-IL-4 receptor alpha against AD was not as high as that of IL-17 blockage against psoriasis, which implies a modification of the disease spectrum by non-Th2-type cytokine axes in AD. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD. PMID- 29518196 TI - Evolution of heterotrophy in chrysophytes as reflected by comparative transcriptomics. AB - Shifts in the nutritional mode between phototrophy, mixotrophy and heterotrophy are a widespread phenomenon in the evolution of eukaryotic diversity. The transition between nutritional modes is particularly pronounced in chrysophytes and occurred independently several times through parallel evolution. Thus, chrysophytes provide a unique opportunity for studying the molecular basis of nutritional diversification and of the accompanying pathway reduction and degradation of plastid structures. In order to analyze the succession in switching the nutritional mode from mixotrophy to heterotrophy, we compared the transcriptome of the mixotrophic Poterioochromonas malhamensis with the transcriptomes of three obligate heterotrophic species of Ochromonadales. We used the transcriptome of P. malhamensis as a reference for plastid reduction in the heterotrophic taxa. The analyzed heterotrophic taxa were in different stages of plastid reduction. We investigated the reduction of several photosynthesis related pathways e.g. the xanthophyll cycle, the mevalonate pathway, the shikimate pathway and the tryptophan biosynthesis as well as the reduction of plastid structures and postulate a presumable succession of pathway reduction and degradation of accompanying structures. PMID- 29518198 TI - Molecular epidemiology of NDM-1- and OXA-48-producing Klebsiella pneumoniae in an Iranian hospital: clonal dissemination of ST11 and ST893. AB - Objectives: Despite the fact that the blaOXA-48 and blaNDM-1 genes have successfully disseminated among Klebsiella pneumoniae isolates worldwide, outbreaks remain unidentified in Iran. Here we examined the molecular epidemiology of 96 carbapenem-resistant K. pneumoniae recovered from an Iranian hospital. Methods: A total of 96 non-replicate carbapenem-resistant K. pneumoniae were recovered from clinical specimens in a university hospital. Detection of ESBLs and carbapenemases produced by studied strains was performed using PCR and DNA sequencing. The bacterial isolates were assigned to clonal lineages by PFGE and MLST. In addition, plasmids were analysed by PCR-based replicon typing and conjugation assays. Results: All isolates harboured blaOXA-48 and blaNDM-1 genes together or alone. Almost all strains also carried ESBL genes. Eighty-seven isolates of K. pneumoniae were categorized into seven pulsotypes. The predominant strain clusters/pulsotypes associated with the outbreak corresponded to ST11 (48/96) and ST893 (31/96). Plasmids carrying blaOXA-48 and blaNDM-1 were successfully transferred to Escherichia coli K12 as the recipient strain. blaOXA 48 was located on IncL/M plasmids of ~39 kb, while blaNDM-1 was carried by either an IncFII plasmid of ~50 kb or an untypeable plasmid of ~4 or 10 kb. Conclusions: We describe two separate outbreaks of blaOXA-48- and blaNDM-1-carrying K. pneumoniae strains associated with dissemination of the ST11 and ST893 clones, with the ICU acting as the epicentre. The spread of plasmids carrying carbapenemase genes resulting in fulminant antimicrobial resistance is a severe concern. PMID- 29518199 TI - The clinical Biofilm Ring Test: a promising tool for the clinical assessment of biofilm-producing Candida species. AB - Candida species are opportunistic pathogens responsible for a variety of diseases, ranging from skin and mucosal lesions to severe systemic, life threatening infections. Candida albicans accounts for more than 70% of all Candida infections, however, the clinical relevance of other species such as Candida parapsilosis and Candida krusei are being increasingly recognized. Biofilm-producing yeasts cells acquire an increased resistance to antifungal agents, often leading to therapeutic failure and chronic infection. Conventional methods such as crystal violet (CV) and tetrazolium (XTT) reduction assay, developed to evaluate biofilm formation in Candida species are usually time consuming, present a high intra- and inter-assay variability of the results and are therefore hardly applicable to routine diagnostics. This study describes an in-vitro assay developed for the measurement of biofilm formation in Candida species based on the clinical Biofilm Ring Test(r) (cBRT). We found a significant concordance between the cBRT and both CV (k = 0.74) and XTT (k = 0.62), respectively. Nevertheless, the cBRT resulted more reliable and reproducible than CV and XTT, requiring a minimal sample manipulation and allowing a high throughput assessment, directly on viable cells. The results indicate that the cBRT may provide a suitable, cost-effective technique for routine biofilm testing in clinical microbiology. PMID- 29518200 TI - I am quitting my job. Specialist nurses in perioperative context and their experiences of the process and reasons to quit their job. AB - The lack of specialist nurses in operating theatres is a serious problem. The aim of this study was to describe reasons why specialist nurses in perioperative care chose to leave their workplaces and to describe the process from the thought to the decision. Twenty specialist nurses (i.e. anaesthesia, NA, and operating room nurses) from seven university- and county hospitals in Sweden participated in qualitative individual in-depth interviews. Data were analysed by systematic text condensation. We identified four themes of reasons why specialist nurses quitted their jobs: the head nurses' betrayal and dismissive attitude, and not feeling needed; inhumane working conditions leading to the negative health effects; not being free to decide about one's life and family life being more important than work; and, colleagues' diminishing behaviour. Leaving one's job was described as a process and specialist nurses had thought about it for some time. Two main reasons were described; the head nurse manager's dismissive attitude and treatment of their employees and colleagues' mistreatment and colleagues' diminishing behaviour. Increasing knowledge on the role of the head nurse managers in specialist nurses' decision making for leaving their workplace, and creating a friendly, non-violent workplace, may give the opportunity for them to take action before it is too late. PMID- 29518201 TI - Estimates of diet selection in cattle grazing cornstalk residues by measurement of chemical composition and near infrared reflectance spectroscopy of diet samples collected by ruminal evacuation. AB - Six ruminally cannulated cows (570 +/- 73 kg) fed corn residues were placed in a 6 * 6 Latin square to evaluate predictions of diet composition from ruminally collected diet samples. After complete ruminal evacuation, cows were fed 1-kg meals (dry matter [DM]-basis) containing different combinations of cornstalk and leaf and husk (LH) residues in ratios of 0:100, 20:80, 40:60, 60:40, 80:20, and 100:0. Diet samples from each meal were collected by removal of ruminal contents after 1-h and were either unrinsed, hand-rinsed or machine-rinsed to evaluate effects of endogenous compounds on predictions of diet composition. Diet samples were analyzed for neutral (NDF) and acid (ADF) detergent fiber, acid detergent insoluble ash (ADIA), acid detergent lignin (ADL), crude protein (CP), and near infrared reflectance spectroscopy (NIRS) to calculate diet composition. Rinsing type increased NDF and ADF content and decreased ADIA and CP content of diet samples (P < 0.01). Rinsing tended to increase (P < 0.06) ADL content of diet samples. Differences in concentration between cornstalk and LH residues within each chemical component were standardized by calculating a coefficient of variation (CV). Accuracy and precision of estimates of diet composition were analyzed by regressing predicted diet composition and known diet composition. Predictions of diet composition were improved by increasing differences in concentration of chemical components between cornstalk and LH residues up to a CV of 22.6 +/- 5.4%. Predictions of diet composition from unrinsed ADIA and machine rinsed NIRS had the greatest accuracy (slope = 0.98 and 0.95, respectively) and large coefficients of determination (r2 = 0.86 and 0.74, respectively). Subsequently, a field study (Exp. 2) was performed to evaluate predictions of diet composition in cattle (646 +/- 89 kg) grazing corn residue. Five cows were placed in 1 of 10 paddocks and allowed to graze continuously or to strip-graze corn residues. Predictions of diet composition from ADIA, ADL, and NIRS did not differ (P = 0.99), and estimates of cornstalk intake tended to be greater (P = 0.09) in strip-grazed compared to continuously grazed cows. These data indicate that diet composition can be predicted by chemical components or NIRS by ruminal collection of diet samples among cattle grazing corn residues. PMID- 29518202 TI - Identification of redox imbalance as a prominent metabolic response elicited by rapeseed feeding in swine metabolome. AB - Rapeseed (RS) is an abundant and inexpensive source of energy and AA in diets for monogastrics and a sustainable alternative to soybean meal. It also contains diverse bioactive phytochemicals that could have antinutritional effects at high dose. When the RS-derived feed ingredients (RSF) are used in swine diets, the uptake of these nutrients and phytochemicals is expected to affect the metabolic system. In this study, 2 groups of young pigs (17.8 +/- 2.7 kg initial BW) were equally fed a soybean meal-based control diet and an RSF-based diet, respectively, for 3 wk. Digesta, liver, and serum samples from these pigs were examined by liquid chromatography-mass spectrometry-based metabolomic analysis to determine the metabolic effects of the 2 diets. Analyses of digesta samples revealed that sinapine, sinapic acid, and gluconapin were robust exposure markers of RS. The distribution of free AA along the intestine of RSF pigs was consistent with the reduced apparent ileal digestibility of AA observed in these pigs. Despite its higher fiber content, the RSF diet did not affect microbial metabolites in the digesta, including short-chain fatty acids and secondary bile acids. Analyses of the liver and serum samples revealed that RSF altered the levels of AA metabolites involved in the urea cycle and 1-carbon metabolism. More importantly, RSF increased the levels of multiple oxidized metabolites and aldehydes while decreased the levels of ascorbic acid and docosahexaenoic acid containing lipids in the liver and serum, suggesting that RSF could disrupt redox balance in young pigs. Overall, the results indicated that RSF elicited diverse metabolic events in young pigs through its influences on nutrient and antioxidant metabolism, which might affect the performance and health in long-term feeding and also provide the venues for nutritional and processing interventions to improve the utilization of RSF in pigs. PMID- 29518204 TI - Lung Cancer, Smoking, and Obesity: It's Complicated. PMID- 29518203 TI - Overall and Central Obesity and Risk of Lung Cancer: A Pooled Analysis. AB - Background: The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity and tumor histology are largely unexplored. Methods: We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated. Results: During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC. Conclusions: The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer. PMID- 29518205 TI - The combination of ionizing radiation and proteasomal inhibition by bortezomib enhances the expression of NKG2D ligands in multiple myeloma cells. AB - Bortezomib, which is a potent proteasome inhibitor, has been used as a first-line drugs to treat multiple myeloma for a few decades, and radiotherapy has frequently been applied to manage acute bone lesions in the patients. Therefore, it was necessary to investigate what the benefits might be if the two therapies were applied simultaneously in the treatment of multiple myeloma. Since it was known that radiotherapy and proteasome inhibitors could increase the expression of NKG2D ligands through induction of protein synthesis and suppression of protein degradation of NKG2D ligands, respectively, we supposed that the combined treatment might further enhance the expression of NKG2D ligands. In this study, we analyzed the expression level of NKG2D ligands using multiplex PCR and flow cytometry after treatment of IM-9 and RPMI-8226 myeloma cells with bortezomib and ionizing radiation; we then assayed the susceptibility to NK-92 cells. Although the expression of only some kinds of NKG2D ligands were increased by treatment with bortezomib alone, five kinds of NKG2D ligands that we assayed were further induced at the surface protein level after combined treatment with ionizing radiation and bortezomib. Furthermore, combined treatment made myeloma cells more susceptible to NK-92 cells, compared with treatment with bortezomib alone. In conclusion, the combination therapy of ionizing radiation plus the proteasome inhibitor bortezomib is a promising therapeutical strategy for enhancing NK cell mediated anticancer immune responses. PMID- 29518208 TI - 1,2,4-Oxadiazole antimicrobials act synergistically with daptomycin and display rapid kill kinetics against MDR Enterococcus faecium. AB - Background: Enterococcus faecium is an important nosocomial pathogen. It has a high propensity for horizontal gene transfer, which has resulted in the emergence of MDR strains that are difficult to treat. The most notorious of these, vancomycin-resistant E. faecium, are usually treated with linezolid or daptomycin. Resistance has, however, been reported, meaning that new therapeutics are urgently needed. The 1,2,4-oxadiazoles are a recently discovered family of antimicrobials that are active against Gram-positive pathogens and therefore have therapeutic potential for treating E. faecium. However, only limited data are available on the activity of these antimicrobials against E. faecium. Objectives: To determine whether the 1,2,4-oxadiazole antimicrobials are active against MDR and daptomycin-non-susceptible E. faecium. Methods: The activity of the 1,2,4 oxadiazole antimicrobials against vancomycin-susceptible, vancomycin-resistant and daptomycin-non-susceptible E. faecium was determined using susceptibility testing, time-kill assays and synergy assays. Toxicity was also evaluated against human cells by XTT and haemolysis assays. Results: The 1,2,4-oxadiazoles are active against a range of MDR E. faecium, including isolates that display non susceptibility to vancomycin and daptomycin. This class of antimicrobial displays rapid bactericidal activity and demonstrates superior killing of E. faecium compared with daptomycin. Finally, the 1,2,4-oxadiazoles act synergistically with daptomycin against E. faecium, with subinhibitory concentrations reducing the MIC of daptomycin for non-susceptible isolates to a level below the clinical breakpoint. Conclusions: The 1,2,4-oxadiazoles are active against MDR and daptomycin-non-susceptible E. faecium and hold great promise as future therapeutics for treating infections caused by these difficult-to-treat isolates. PMID- 29518207 TI - Estimation of the effects of medical diagnostic radiation exposure based on DNA damage. AB - X-rays are widely applied in the medical field for the diagnosis and treatment of diseases. Among the uses of X-rays in diagnosis, computed tomography (CT) has been established as one of the most informative diagnostic radiology examinations. Moreover, recent advances in CT scan technology have made this examination much easier and more informative and increased its application, especially in Japan. However, the radiation dose of CT scans is higher than that of simple X-ray examinations. Therefore, the health risk of a CT scan has been discussed in various studies, but is still controversial. Consequently, the biological and cytogenetic effects of CT scans are being analyzed. Here, we summarize the recent findings concerning the biological and cytogenetic effects of ionizing radiation from a CT scan, by focusing on DNA damage and chromosome aberrations. PMID- 29518209 TI - A germline-specific role for the mTORC2 component Rictor in maintaining spermatogonial differentiation and intercellular adhesion in mouse testis. AB - STUDY QUESTION: What is the physiological role of Rictor in spermatogenic cells? SUMMARY ANSWER: Germline expression of Rictor regulates spermatogonial differentiation and has an essential role in coordinating germ cells and Sertoli cells in maintaining intact cell-cell adhesion dynamics and cytoskeleton-based architecture in the seminiferous epithelium. WHAT IS KNOWN ALREADY: The mechanistic target of rapamycin (mTOR) resides in its functions as the catalytic subunits of the structurally and functionally distinct mTORC1 and mTORC2 complexes. In the mammalian testis, mTORC1 regulates spermatogonial stem cell self-renewal and differentiation, whereas mTORC2 is required for Sertoli cell function. In contrast to mTORC1, mTORC2 has been much less well studied. Rictor is a distinct component of the mTORC2 complex. STUDY DESIGN, SIZE, DURATION: We investigated the effects of germ cell-specific ablation of Rictor on testicular development by using a mouse model of germline-specific ablation of Rictor. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed the in-vivo functions of Rictor through different methods including histology, immunofluorescent staining, chromosome spreads, blood-testis barrier (BTB) integrity assays and RNA sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Mutant mice did not show a defect in meiotic synapsis or recombination, but exhibited compromised spermatogonial differentiation potential, disorganized cell-cell junctions, impaired BTB dynamics and defective spermiogenesis. Concomitantly, RNA-seq profiling revealed that many genes involved in adhesion and migration were expressed inappropriately. LARGE SCALE DATA: RNA-seq data are published in the SRA database (PRJNA419273). LIMITATIONS REASONS FOR CAUTION: A detailed analysis of the mechanisms underlying the phenotype needs further investigations. WIDER IMPLICATIONS OF THE FINDINGS: Our work provides previously unidentified in-vivo evidence that germline expression of Rictor plays a role in maintaining spermatogonial differentiation and cell-cell adhesion. These findings are important for understanding the regulation of spermatogenesis and have clinical implications for the effect of mTOR inhibitors on human fertility. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by National Key R&D Program of China (2016YFA0500902), National Natural Science Foundation of China (31471228 and 31771653), Jiangsu Science Foundation for Distinguished Young Scholars (BK20150047), and Natural Science Foundation of Jiangsu Province (BK20140897, 14KJA180005 and 14KJB310004) to K.Z. The authors declare no competing or financial interests. PMID- 29518210 TI - The clinical trials landscape for glioblastoma: is it adequate to develop new treatments? AB - Background: There have been few treatment advances for patients with glioblastoma (GBM) despite increasing scientific understanding of the disease. While factors such as intrinsic tumor biology and drug delivery are challenges to developing efficacious therapies, it is unclear whether the current clinical trial landscape is optimally evaluating new therapies and biomarkers. Methods: We queried ClinicalTrials.gov for interventional clinical trials for patients with GBM initiated between January 2005 and December 2016 and abstracted data regarding phase, status, start and end dates, testing locations, endpoints, experimental interventions, sample size, clinical presentation/indication, and design to better understand the clinical trials landscape. Results: Only approximately 8% 11% of patients with newly diagnosed GBM enroll on clinical trials with a similar estimate for all patients with GBM. Trial duration was similar across phases with median time to completion between 3 and 4 years. While 93% of clinical trials were in phases I-II, 26% of the overall clinical trial patient population was enrolled on phase III studies. Of the 8 completed phase III trials, only 1 reported positive results. Although 58% of the phase III trials were supported by phase II data with a similar endpoint, only 25% of these phase II trials were randomized. Conclusions: The clinical trials landscape for GBM is characterized by long development times, inadequate dissemination of information, suboptimal go/no-go decision making, and low patient participation. PMID- 29518211 TI - Letter: Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. PMID- 29518213 TI - Novel Endovascular Treatment of a Large Basilar Apex Aneurysm With Neck Reconstruction (Barrel Stent) and Coiling Technique: 2-Dimensional Operative Video. PMID- 29518212 TI - Myocardial T1 mapping and extracellular volume quantification in patients with left ventricular non-compaction cardiomyopathy. AB - Aims: From pathophysiological mechanisms to risk stratification and management, much debate and discussion persist regarding left ventricular non-compaction cardiomyopathy (LVNC). This study aimed to characterize myocardial T1 mapping and extracellular volume (ECV) fraction by cardiovascular magnetic resonance (CMR), and investigate how these biomarkers relate to left ventricular ejection fraction (LVEF) and ventricular arrhythmias (VA) in LVNC. Methods and results: Patients with LVNC (n = 36) and healthy controls (n = 18) were enrolled to perform a CMR with T1 mapping. ECV was quantified in LV segments without late gadolinium enhancement (LGE) areas to investigate diffuse myocardial fibrosis. Patients with LVNC had slightly higher native T1 (1024 +/- 43 ms vs. 995 +/- 22 ms, P = 0.01) and substantially expanded ECV (28.0 +/- 4.5% vs. 23.5 +/- 2.2%, P < 0.001) compared to controls. The ECV was independently associated with LVEF (beta = 1.3, P = 0.001). Among patients without LGE, VAs were associated with higher ECV (27.7% with VA vs. 25.8% without VA, P = 0.002). Conclusion: In LVNC, tissue characterization by T1 mapping suggests an extracellular expansion by diffuse fibrosis in myocardium without LGE, which was associated with myocardial dysfunction and VA, but not with the amount of non-compacted myocardium. PMID- 29518214 TI - Perfluorohexane Sulfonate (PFHxS) and a Mixture of Endocrine Disrupters Reduce Thyroxine Levels and Cause Antiandrogenic Effects in Rats. AB - The developmental toxicity of perfluorohexane sulfonate (PFHxS) is largely unknown despite widespread environmental contamination and presence in human serum, tissues and milk. To thoroughly investigate PFHxS toxicity in developing rats and to mimic a realistic human exposure situation, we examined a low dose close to human relevant PFHxS exposure, and combined the dose-response studies of PFHxS with a fixed dose of 12 environmentally relevant endocrine disrupting chemicals (EDmix). Two reproductive toxicity studies in time-mated Wistar rats exposed throughout gestation and lactation were performed. Study 1 included control, two doses of PFHxS, and two doses of PFHxS + EDmix (n = 5-7). Study 2 included control, 0.05, 5, or 25 mg/kg body weight/day PFHxS, EDmix-only, 0.05, 5, or 25 mg PFHxS/kg plus EDmix (n = 13-20). PFHxS caused no overt toxicity in dams and offspring but decreased male pup birth weight and slightly increased liver weights at high doses and in combination with the EDmix. A marked effect on T4 levels was seen in both dams and offspring, with significant reductions from 5 mg/kg/day. The EDmix caused antiandrogenic effects in male offspring, manifested as slight decreases in anogenital distance, increased nipple retention and reductions of the weight of epididymides, ventral prostrate, and vesicular seminalis. PFHxS can induce developmental toxicity and in addition results of the co-exposure studies indicated that PFHxS and the EDmix potentiate the effect of each other on various endpoints, despite their different modes of action. Hence, risk assessment may underestimate toxicity when mixture toxicity and background exposures are not taken into account. PMID- 29518215 TI - Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4. AB - RNA-binding motif protein 20 (RBM20) is a cardiac splice regulator that adapts cardiac filling via its diverse substrates-including the sarcomeric protein titin. The molecular basis and regulation of RBM20-dependent exon exclusion are largely unknown. In tissue culture experiments, we show that the combination of RNA recognition motif (RRM) and C-terminus is necessary and sufficient for RBM20 activity, indicating an important function of the ZnF2 domain in splicing repression. Using splice reporter and in vitro binding assays targeting titin exons 241-243, we identified a minimal genomic segment that is necessary for RBM20-mediated splicing repression of the alternative exon. Here, RBM20 binds the cluster containing most RBM20 binding motifs through its RRM domain and represses the upstream and downstream introns. For subsequent exon exclusion, specific regions upstream, downstream and within the alternative exon 242 are required. Regulation of exon exclusion involves PTB4 as a novel titin splice regulator, which counteracts RBM20 repressor activity in HEK293 cells. Together, these mechanistic insights into the regulation and action of RBM20 and PTB4 provide a basis for the future development of RBM20 modulators that adapt titin elasticity in cardiac disease. PMID- 29518217 TI - Letter: Challenges to Neuroendovascular Care in Developing Countries: Example of Pakistan in Global Perspective. PMID- 29518216 TI - A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human. AB - Thousands of human disease-associated single nucleotide polymorphisms (SNPs) lie in the non-coding genome, but only a handful have been demonstrated to affect gene expression and human biology. We computationally identified risk-associated SNPs in deeply conserved non-exonic elements (CNEs) potentially contributing to 45 human diseases. We further demonstrated that human CNE1/rs17421627 associated with retinal vasculature defects showed transcriptional activity in the zebrafish retina, while introducing the risk-associated allele completely abolished CNE1 enhancer activity. Furthermore, deletion of CNE1 led to retinal vasculature defects and to a specific downregulation of microRNA-9, rather than MEF2C as predicted by the original genome-wide association studies. Consistent with these results, miR-9 depletion affects retinal vasculature formation, demonstrating MIR 9-2 as a critical gene underpinning the associated trait. Importantly, we validated that other CNEs act as transcriptional enhancers that can be disrupted by conserved non-coding SNPs. This study uncovers disease-associated non-coding mutations that are deeply conserved, providing a path for in vivo testing to reveal their cis-regulated genes and biological roles. PMID- 29518218 TI - Kissing balloon technique to secure the neo-left ventricular outflow tract in transcatheter mitral valve implantation. PMID- 29518206 TI - The Science of Obesity Management: An Endocrine Society Scientific Statement. AB - The prevalence of obesity, measured by body mass index, has risen to unacceptable levels in both men and women in the United States and worldwide with resultant hazardous health implications. Genetic, environmental, and behavioral factors influence the development of obesity, and both the general public and health professionals stigmatize those who suffer from the disease. Obesity is associated with and contributes to a shortened life span, type 2 diabetes mellitus, cardiovascular disease, some cancers, kidney disease, obstructive sleep apnea, gout, osteoarthritis, and hepatobiliary disease, among others. Weight loss reduces all of these diseases in a dose-related manner-the more weight lost, the better the outcome. The phenotype of "medically healthy obesity" appears to be a transient state that progresses over time to an unhealthy phenotype, especially in children and adolescents. Weight loss is best achieved by reducing energy intake and increasing energy expenditure. Programs that are effective for weight loss include peer-reviewed and approved lifestyle modification programs, diets, commercial weight-loss programs, exercise programs, medications, and surgery. Over-the-counter herbal preparations that some patients use to treat obesity have limited, if any, data documenting their efficacy or safety, and there are few regulatory requirements. Weight regain is expected in all patients, especially when treatment is discontinued. When making treatment decisions, clinicians should consider body fat distribution and individual health risks in addition to body mass index. PMID- 29518219 TI - Spontaneous Regression of a Retroodontoid Transverse Ligament Cyst: A Case Report. AB - BACKGROUND AND IMPORTANCE: Transverse ligament cysts (TLC) are rare, surgically complex lesions arising posterior to the odontoid process of C2. Direct compression of the cervicomedullary junction is a devastating consequence of untreated lesions. We report the first case of spontaneous TLC regression without surgical intervention. CLINICAL PRESENTATION: A 75-yr-old woman presented to an outside hospital with acute episodes of left face and upper extremity numbness. Magnetic resonance imaging (MRI) demonstrated a well-circumscribed 5.8 mm cystic mass at the atlantoaxial junction, posterior to the odontoid process, most consistent with a TLC. She presented to our institution 1 yr later with symptoms of progressive occipital neuralgia seeking surgical treatment. No evidence of cervical myelopathy was identified on clinical examination. Repeat MRI showed near doubling of the cyst, with no brainstem edema. The patient elected for surveillance of the cyst with a transforaminal steroid injection at C1-C2 for her occipital neuralgia. One year later, symptoms of occipital neuralgia had resolved and she remained neurologically intact; MRI of the cervical spine showed near complete involution of the cyst. CONCLUSION: Symptomatic TLCs are often managed with surgical decompression and, in selected cases, fusion with good functional outcome. However, these interventions carry high risk of postoperative morbidity, particularly in the elderly. Conservative surveillance is rarely reported as a viable option. We present the first case of spontaneous TLC regression in the absence surgery or neck bracing. In select patients without acute myelopathy, clinical and radiographic surveillance may be considered for the management of TLCs. PMID- 29518221 TI - Temporal Dynamics of Pseudoprogression After Gamma Knife Radiosurgery for Vestibular Schwannomas-A Retrospective Volumetric Study. AB - BACKGROUND: The optimal observation interval after the radiosurgical treatment of a sporadic vestibular schwannoma, prior to salvage intervention, is unknown. OBJECTIVE: To determine an optimal postradiosurgical treatment interval for differentiating between pseudoprogression and true tumor growth by analyzing serial volumetric data. METHODS: This single-institution retrospective study included all sporadic vestibular schwannomas treated with Gamma Knife radiosurgery (Eketa AB, Stockholm, Sweden; 12-13 Gy) from 2002 to 2014. Volumetric analysis was performed on all available pre- and posttreatment magnetic resonance imaging scans. Tumors were classified as "stable/decreasing," "transient enlargement", or "persistent growth" after treatment, based on incrementally increasing follow-up durations. RESULTS: A total of 118 patients included in the study had a median treatment tumor volume of 0.74 cm3 (interquartile range [IQR] = 0.34-1.77 cm3) and a median follow-up of 4.1 yr (IQR = 2.6-6.0 yr). Transient tumor enlargement was observed in 44% of patients, beginning at a median of 1 yr (IQR = 0.6-1.4 yr) posttreatment, with 90% reaching peak volume within 3.5 yr, posttreatment. Volumetric enlargement resolved at a median of 2.4 yr (IQR 1.9-3.6 yr), with 90% of cases resolved at 6.9 yr. Increasing follow-up revealed that many of the tumors initially enlarging 1 to 3 yr after stereotactic radiosurgery ultimately begin to shrink on longer follow-up (45% by 4 yr, 77% by 6 yr). CONCLUSION: Tumor enlargement within ~3.5 yr of treatment should not be used as a sole criterion for salvage treatment. Patient symptoms and tumor size must be considered, and giving tumors a chance to regress before opting for salvage treatment may be worthwhile. PMID- 29518220 TI - Purification and characterisation of a quorum quenching AHL-lactonase from the endophytic bacterium Enterobacter sp. CS66. AB - The quorum quenching (QQ) activity of endophytic bacteria associated with medicinal plants was explored. Extracts of the Gram-negative Enterobacter sp. CS66 possessed potent N-acylhomoserine lactone (AHL) hydrolytic activity in vitro. Using degenerate primers, we PCR-amplified an open reading frame (denoted aiiE) from CS66 that was 96% identical to the well-characterised AHL-lactonase AiiA from Bacillus thuringiensis, but only 30% was identical to AHL-lactonases from other Gram-negative species. This confirms that close AiiA homologs can be found in both Gram-positive and Gram-negative bacteria. Purified AiiE exhibited potent AHL-lactonase activity against a broad range of AHLs. Furthermore, aiiE was able to reduce the production of secreted plant cell wall-degrading hydrolytic enzymes when expressed in trans in the economically important plant pathogen, Pectobacterium atrosepticum. Our results indicate the presence of a novel AHL-lactonase in Enterobacter sp. CS66 with significant potential as a biocontrol agent. PMID- 29518223 TI - Building prognostic models for adverse outcomes in a prospective cohort of hospitalised patients with acute leptospirosis infection in the Philippines. AB - Leptospirosis is endemic to the Philippines. Ten per cent of cases will develop severe or fatal disease. Predicting progression to severity is difficult. Risk factors have been suggested, but few attempts have been made to create predictive models to guide clinical decisions. We present two models to predict the risk of mortality and progression to severe disease. Data was used from a prospective cohort study conducted between 2011 and 2013 in San Lazaro Hospital, Manila. Predictive factors were identified from a literature review. A strategy utilizing backwards stepwise-elimination and multivariate fractional polynomials identified key predictive factors. A total of 203 patients met the inclusion criteria. The overall mortality rate was 6.84%. Multivariable logistic regression revealed that neutrophil counts [OR 1.38, 95% CI 1.15-1.67] and platelet counts [OR 0.99, 95% CI 0.97-0.99] were predictive for risk of mortality. Multivariable logistic regression revealed that male sex (OR 3.29, 95% CI 1.22-12.57) and number of days between symptom onset and antibiotic use (OR 1.28, 95% CI 1.08-1.53) were predictive for risk of progression to severe disease. The multivariable prognostic models for the risks of mortality and progression to severe disease developed could be useful in guiding clinical management by the early identification of patients at risk of adverse outcomes. PMID- 29518222 TI - Genome-wide average DNA methylation is determined in utero. AB - Background: Investigating the genetic and environmental causes of variation in genome-wide average DNA methylation (GWAM), a global methylation measure from the HumanMethylation450 array, might give a better understanding of genetic and environmental influences on methylation. Methods: We measured GWAM for 2299 individuals aged 0 to 90 years from seven twin and/or family studies. We estimated familial correlations, modelled correlations with cohabitation history and fitted variance components models for GWAM. Results: The correlation in GWAM for twin pairs was ~0.8 at birth, decreased with age during adolescence and was constant at ~0.4 throughout adulthood, with no evidence that twin pair correlations differed by zygosity. Non-twin first-degree relatives were correlated, from 0.17 [95% confidence interval (CI): 0.05-0.30] to 0.28 (95% CI: 0.08-0.48), except for middle-aged siblings (0.01, 95% CI: -0.10-0.12), and the correlation increased with time living together and decreased with time living apart. Spouse pairs were correlated in all studies, from 0.23 (95% CI: 0.3-0.43) to 0.31 (95% CI: 0.05-0.52), and the correlation increased with time living together. The variance explained by environmental factors shared by twins alone was 90% (95% CI: 74-95%) at birth, decreased in early life and plateaued at 28% (95% CI: 17-39%) in middle age and beyond. There was a cohabitation-related environmental component of variance. Conclusions: GWAM is determined in utero by prenatal environmental factors, the effects of which persist throughout life. The variation of GWAM is also influenced by environmental factors shared by family members, as well as by individual-specific environmental factors. PMID- 29518224 TI - In vivo ultrasound and biometric measurements predict the empty body chemical composition in Nellore cattle. AB - Evaluation of the body chemical composition of beef cattle can only be measured postmortem and those data cannot be used in real production scenarios to adjust nutritional plans. The objective of this study was to develop multiple linear regression equations from in vivo measurements, such as ultrasound parameters [backfat thickness (uBFT, mm), rump fat thickness (uRF, mm), and ribeye area (uLMA, cm2)], shrunk body weight (SBW, kg), age (AG, d), hip height (HH, m), as well as from postmortem measurements (composition of the 9th to 11th rib section) to predict the empty body and carcass chemical composition for Nellore cattle. Thirty-three young bulls were used (339 +/- 36.15 kg and 448 +/- 17.78 d for initial weight and age, respectively). Empty body chemical composition (protein, fat, water, and ash in kg) was obtained by combining noncarcass and carcass components. Data were analyzed using the PROC REG procedure of SAS software. Mallows' Cp values were close to the ideal value of number of independent variables in the prediction equations plus one. Equations to predict chemical components of both empty body and carcass using in vivo measurements presented higher R2 values than those determined by postmortem measurements. Chemical composition of the empty body using in vivo measurements was predicted with R2 > 0.73. Equations to predict chemical composition of the carcass from in vivo measurements showed R2 lower (R2< 0.68) than observed for empty body, except for the water (R2 = 0.84). The independent variables SBW, uRF, and AG were sufficient to predict the fat, water, energy components of the empty body, whereas for estimation of protein content the uRF, HH, and SBW were satisfactory. For the calculation of the ash, the SBW variable in the equation was sufficient. Chemical compounds from components of the empty body of Nellore cattle can be calculated by the following equations: protein (kg) = 47.92 + 0.18 * SBW - 1.46 * uRF - 30.72 * HH (R2 = 0.94, RMSPE = 1.79); fat (kg) = 11.33 + 0.16 * SBW + 2.09 * uRF 0.06 * AG (R2 = 0.74, RMSPE = 4.18); water (kg) = - 34.00 + 0.55 * SBW + 0.10 * AG - 2.34 * uRF (R2 = 0.96, RMSPE = 5.47). In conclusion, the coefficients of determination (for determining the chemical composition of the empty body) of the equations derived from in vivo measures were higher than those of the equations obtained from rib section measurements taken postmortem, and better than coefficients of determination of the equations to predict the chemical composition of the carcass. PMID- 29518226 TI - Application of different markers and data-analysis tools to the examination of biodiversity can lead to different results: a case study with Starmerella bacillaris (synonym Candida zemplinina) strains. AB - Starmerella bacillaris (Candida zemplinina) is a genetically heterogeneous species. In this work, the diversity of 41 strains of various origins is examined and compared by the analysis of the length polymorphism of nuclear microsatellites and the RFLP of mitochondrial genomes. The band patterns are analysed with UPGMA, neighbor joining, neighbor net, minimum spanning tree and non-metric MDS algorithms. The results and their comparison to previous analyses demonstrate that different markers and different clustering methods can result in very different groupings of the same strains. The observed differences between the topologies of the dendrograms also indicate that the positions of the strains do not necessarily reflect their real genetic relationships and origins. The possibilities that the differences might be partially due to different sensitivity of the markers to environmental factors (selection pressure) and partially to the different grouping criteria of the algorithms are also discussed. PMID- 29518227 TI - Yleaf: Software for Human Y-Chromosomal Haplogroup Inference from Next-Generation Sequencing Data. AB - Next-generation sequencing (NGS) technologies offer immense possibilities given the large genomic data they simultaneously deliver. The human Y-chromosome serves as good example how NGS benefits various applications in evolution, anthropology, genealogy, and forensics. Prior to NGS, the Y-chromosome phylogenetic tree consisted of a few hundred branches, based on NGS data, it now contains many thousands. The complexity of both, Y tree and NGS data provide challenges for haplogroup assignment. For effective analysis and interpretation of Y-chromosome NGS data, we present Yleaf, a publically available, automated, user-friendly software for high-resolution Y-chromosome haplogroup inference independently of library and sequencing methods. PMID- 29518225 TI - Effects of Mn supplementation in late-gestating and lactating red deer (Cervus elaphus hispanicus) on milk production, milk composition, and calf growth. AB - This study describes the effects of Mn supplementation of 20 late-gestating and lactating Iberian red deer (Cervus elaphus hispanicus) females (hinds) fed a balanced diet on milk production and milk composition over the lactation period. Body weight of their calves at birth and at weaning was also evaluated. In addition, the effect of lactation stage was studied. For these purposes, 2 groups of hinds, one composed by 12 individuals (experimental) and the other by 8 individuals (control) were compared. Experimental hinds were s.c. injected weekly with Mn (2 mg Mn/kg BW) from day 140 of gestation until the end of lactation (week 18; forced weaning by physical separation). Control hinds were injected with a physiological saline solution with the same volume and at the same frequency as the experimental group. Serum Mn content of hinds was assessed just before the first Mn injection and at week 10 of lactation to assess whether the injected Mn increased Mn concentrations in blood. No differences were observed for BW of calves at birth but calves whose mothers were injected with Mn tended (P = 0.07) to have greater gain of BW from birth to weaning in proportion of BW at birth compared to calves from control hinds. In addition, supplementation with Mn increased (P <= 0.05) daily milk production by 10.2%, milk fat content by 11.2%, and total fat yield by 17.8%. Also, milk from hinds supplemented with Mn had more Ca (P < 0.001) and P (P < 0.05) than milk from control hinds. Manganese supplementation did not influence Mn serum content when blood was analyzed at week 10 of lactation, but increased the Mn content of milk by 18.3% (P < 0.001). Lactation stage affected (P < 0.001) fat, protein, lactose, and DM. Their contents increased as lactation proceeded, and protein was substituted by fat. Therefore, results suggest that Mn supplementation of hinds is recommended, even when they are fed a balanced diet, to increase milk production and the content of fat, Ca, P, and Mn of milk. PMID- 29518228 TI - NLRP3 Inflammasome Activation Mediates Zika Virus-Associated Inflammation. AB - Zika virus (ZIKV) is a mosquito-borne virus that has been identified as a cause of several severe disease manifestations, including congenital microcephaly and Guillain-Barre syndrome, meningoencephalitis, and myelitis. Previous studies showed that ZIKV-infected patients exhibited elevated plasma levels of interleukin 1beta (IL-1beta), indicating that ZIKV may activate inflammasomes. However, the molecular basis for its viral pathogenesis remains poorly understood. In this current study, we found that ZIKV infection caused severe inflammatory pathological changes and promoted IL-1beta production in vitro and in vivo. We here demonstrate that the maturation and secretion of IL-1beta during ZIKV infection was mediated by NLRP3 inflammasome activation and that ZIKV nonstructural protein 5 (NS5) facilitated the assembly of the NLRP3 inflammasome complex, leading to IL-1beta activation through interaction with NLRP3 and induction of reactive oxygen species production. Collectively, our data identify NLRP3 inflammasome-derived IL-1beta production as a critical feature of inflammation during ZIKV infection. These findings offer new insights into inflammasome-mediated diseases and may provide new therapeutic options for ZIKV associated diseases. PMID- 29518229 TI - Case Report: Metastasis of a Trigeminal Malignant Peripheral Nerve Sheath Tumor to the Corpus Callosum. AB - BACKGROUND AND IMPORTANCE: Malignant peripheral nerve sheath tumors (MPNST) are relatively rare tumors of peripheral nerves that are notable for their locally aggressive nature, ability to metastasize, poor prognosis, and association with Neurofibromatosis type I. We present the case of a patient with a trigeminal nerve MPNST who developed an unusual metastasis to the corpus callosum, in the absence of any other central nervous system or systemic metastatic disease. We review the pathology and presentation of MPNST. CLINICAL PRESENTATION: A 53-yr old woman presented with a 1-yr history of paroxysmal facial pain and dysesthesias in the right V1 and V2 distributions of the trigeminal nerve. She was initially diagnosed with trigeminal neuralgia although further imaging showed a cavernous sinus mass extending along the trigeminal nerve. She later developed an isolated lesion in the corpus callosum that was biopsied and consistent with MPNST. CONCLUSION: This case reviews the pathology and aggressive nature of MPNST and demonstrates an unusual site of metastasis. Clinicians should remain aware that MPNST can metastasize to sites in the central nervous system as well as systemically. Furthermore, clinicians should have a high index of suspicion for secondary causes of trigeminal neuralgia in cases with atypical features. PMID- 29518230 TI - Effectiveness of Acceptance and Commitment Therapy in Increasing Resilience and Reducing Attrition of Injured US Navy Recruits. AB - Introduction: US Navy recruits who have injuries preventing them from participating in intense physical conditioning are pulled out of boot camp training and receive treatment that includes daily physical therapy, pain medications, and psychoeducational groups. Graduation from boot camp for these recruits requires not only recovering from their injuries but also passing a required Physical Fitness Assessment consisting of a timed 1.5-mile run, curl ups, and push-ups. About 50-60% of these recruits will eventually be separated out and sent home. The purpose of this study is to examine the effectiveness of an Acceptance and Commitment Therapy (ACT)-based program called Mindfulness for Pain and Performance Enhancement (MPPE). This treatment program was designed to help recruits effectively handle pain and assist them in improving their physical performance in the service of recovery, boot camp completion, and entrance into the Navy. Materials and Methods: This study was approved by the Edward Hines VA Hospital/Captain James A. Lovell Federal Health Care Center Institutional Review Board and the Naval Services Training Command. Treatment was voluntary and a total of 373 recruits enrolled in one of the 32 cycles of MPPE administered. Attrition was 35.1% (131 recruits). The control group comprised 310 recruits who did not enroll in MPPE. Recruits continued to receive standard treatment services (e.g., physical therapy, medical interventions, and psychoeducational groups) while participating in MPPE. Chi-square tests and one-way analysis of variance were used to analyze comparisons among treatment, control, and attrition groups on demographic, clinical, and boot camp training variables. Paired sample t-tests and Cohen's d effect sizes were computed to assess change on treatment outcome measures. Logistic regression was performed to identify demographic, clinical, and boot camp training variables predictive of graduation. Results: All of the pre- to post-treatment outcome measures were significant and Cohen's d effect sizes ranged from 0.41 to 0.84. Effect size changes were small for anxiety and experiential avoidance; moderate for pain acceptance, mindfulness, cognitive inflexibility, and depression; and large for pain reduction. Treatment completers graduated at a higher rate (58.3%) than attrites (34.4%) or controls (45.5%). Based on a logistic regression model, variables predictive of graduation included MPPE completion, age, and reported pain rating. Conclusion: MPPE is a six session, 2-wk-long Acceptance and Commitment Therapy-based approach to pain and physical performance that was added to existing treatment services. Results supported the use of this program for helping recruits recover from injuries and successfully pass physical training requirements for graduation. Recruits were not randomly assigned to treatment, thus limiting the interpretation of outcomes. Incorporating this treatment earlier in boot camp training and making it available to more recruits (i.e., not only injured recruits) may further reduce attrition and contribute to greater resiliency of sailors within the US Navy fleet. PMID- 29518231 TI - Understanding the glycome: an interactive view of glycosylation from glycocompositions to glycoepitopes. AB - Nowadays, due to the advance of experimental techniques in glycomics, large collections of glycan profiles are regularly published. The rapid growth of available glycan data accentuates the lack of innovative tools for visualizing and exploring large amount of information. Scientists resort to using general purpose spreadsheet applications to create ad hoc data visualization. Thus, results end up being encoded in publication images and text, while valuable curated data is stored in files as supplementary information. To tackle this problem, we have built an interactive pipeline composed with three tools: Glynsight, EpitopeXtractor and Glydin'. Glycan profile data can be imported in Glynsight, which generates a custom interactive glycan profile. Several profiles can be compared and glycan composition is integrated with structural data stored in databases. Glycan structures of interest can then be sent to EpitopeXtractor to perform a glycoepitope extraction. EpitopeXtractor results can be superimposed on the Glydin' glycoepitope network. The network visualization allows fast detection of clusters of glycoepitopes and discovery of potential new targets. Each of these tools is standalone or can be used in conjunction with the others, depending on the data and the specific interest of the user. All the tools composing this pipeline are part of the Glycomics@ExPASy initiative and are available at https://www.expasy.org/glycomics. PMID- 29518232 TI - IRRADIATOR SYSTEM FOR MANGANESE SULFATE BATH EFFICIENCY MEASUREMENTS USING A PLUTONIUM-BERYLLIUM NEUTRON SOURCE. AB - This study describes the use of a neutron irradiator system based on a plutonium beryllium neutron source for MnSO4 solution activation for use to determine the MSB system efficiency. Computational simulations using Monte Carlo code were performed to establish the main characteristics of the irradiator system. Among the simulated geometries and volumes, semi-cylindrical shape with 84.5 cm3 of MnSO4 solution yielded the best option to be built. Activity measurements were performed with a high-pure germanium detector to validate the new irradiation system. Results showed an average efficiency and uncertainty of the experimental standard deviation of the mean: 5.742 * 10-4 +/- 0.036 * 10-4 (coverage factor k = 1), for MSB system. Efficiency value obtained shows good correlation to other published methods (i.e. a relative difference of 0.07%). This alternative metrological method demonstrated the utility of neutron sources for the irradiation of solutions in metrology laboratories providing a cost-efficient alternative to nuclear reactors or particle accelerators. PMID- 29518233 TI - Saccharomyces cerevisiae variety diastaticus friend or foe?-spoilage potential and brewing ability of different Saccharomyces cerevisiae variety diastaticus yeast isolates by genetic, phenotypic and physiological characterization. AB - Saccharomyces cerevisiae variety diastaticus is generally considered to be an obligatory spoilage microorganism and spoilage yeast in beer and beer-mixed beverages. Their super-attenuating ability causes increased carbon dioxide concentrations, beer gushing and potential bottle explosion along with changes in flavor, sedimentation and increased turbidity. This research shows clear differences in the super-attenuating properties of S. cerevisiae var. diastaticus yeast strains and their potential for industrial brewing applications. Nineteen unknown spoilage yeast cultures were obtained as isolates and characterized using a broad spectrum of genetic and phenotypic methods. Results indicated that all isolates represent genetically different S. cerevisiae var. diastaticus strains except for strain TUM PI BA 124. Yeast strains were screened for their super attenuating ability and sporulation. Even if the STA1 gene responsible for super attenuation by encoding for the enzyme glucoamylase could be verified by real time polymerase chain reaction, no correlation to the spoilage potential could be demonstrated. Seven strains were further characterized focusing on brewing and sensory properties according to the yeast characterization platform developed by Meier-Dornberg. Yeast strain TUM 3-H-2 cannot metabolize dextrin and soluble starch and showed no spoilage potential or super-attenuating ability even when the strain belongs to the species S. cerevisiae var. diastaticus. Overall, the beer produced with S. cerevisiae var. diastaticus has a dry and winey body with noticeable phenolic off-flavors desirable in German wheat beers. PMID- 29518234 TI - Comparison of dosimetric parameters in the treatment planning of magnetic resonance imaging-based intracavitary image-guided adaptive brachytherapy with and without optimization using the central shielding technique. AB - This study aimed to compare dosimetric parameters between non-optimized and optimized treatment planning (NOP and OP, respectively) of magnetic resonance imaging (MRI) -based intracavitary (IC) image-guided adaptive brachytherapy (IGABT) using the central shielding (CS) technique for cervical cancer. Fifty three patients treated with external beam radiotherapy using CS and MRI-based IGABT with the IC approach alone were evaluated. The total high-risk clinical target volume (HR-CTV) D90 was aimed at >70 Gy equivalent dose in 2 Gy fractions (EQD2). In the small HR-CTV group (<=30 cm3), the mean D90s for NOP/OP were 98.6/80.7 Gy. In the large (30.1-40 cm3) and extensive (>40 cm3) HR-CTV groups, the mean D90s were 81.9/77.5 and 71.1/73.6 Gy, respectively. The mean D2cc values for organs at risks (OARs) in OP were acceptable in all groups, despite the high bladder D2cc in the NOP. The correlation between HR-CTV at first brachytherapy (BT) and NOP D90 was stronger than that between HR-CTV at first BT and OP D90. The targeted HR-CTV D90 and dose constraints of D2cc for OARs were both achieved in 16 NOP/47 OP patients for the bladder, 39/50 for the rectum, and 47/50 for the sigmoid colon (P < 0.001, P = 0.007, and P = 0.34, respectively). For small tumors, the role of optimization was to reduce the D2cc for OARs while maintaining the targeted D90. However, optimization was of limited value for extensive tumors. Methods of optimization in IGABT with CS for cervical cancer should be standardized while considering its effectiveness and limitations. PMID- 29518235 TI - Low Yield of Cerebral Angiography in Adequately Occluded Aneurysms After Flow Diversion. AB - BACKGROUND: Flow diversion has emerged as a highly effective treatment for intracranial aneurysms. OBJECTIVE: To assess the yield of further angiographic follow-up in aneurysms that have achieved adequate occlusion after treatment with the Pipeline Embolization Device (PED; Medtronic Inc, Dublin, Ireland). METHODS: This is a single-institution, retrospective study. Inclusion criteria were as follows: (1) patients with 1 or more aneurysms treated with PED, (2) available short-term (<12 mo) follow-up digital subtraction angiography (DSA), (3) complete (100%) or near-complete (>95%) occlusion on short-term follow-up DSA, and (4) available further angiographic follow-up (DSA, Magnetic Resonance Angiography (MRA), or Computed Tomography Angiography (CTA)). RESULTS: A total of 146 patients were identified. Aneurysm size was 8.4 +/- 5.1 mm on average. Mean angiographic follow-up time was 29.7 +/- 12.2 mo. On short-term follow-up DSA images, 132 (90.4%) had complete aneurysm occlusion and 14 (9.6%) had near complete occlusion. Four patients (3%) had further DSA follow-up alone, 30 patients (21%) had further DSA and MRA/CTA follow-up, and 112 patients (76%) had further MRA/CTA follow-up alone. On further angiographic follow-up (DSA, MRA, and/or CTA), no patient had a decrease in the degree of aneurysm occlusion (recurrence) or required retreatment. Of the 14 patients with near-complete occlusion on initial DSA images, 7 patients (50%) progressed to complete aneurysm occlusion on further angiographic follow-up. CONCLUSION: This study did not find any diagnostic yield in repeating cerebral angiography in adequately occluded aneurysms with the PED. We do not recommend repeat angiographic follow-up once aneurysms have achieved complete occlusion with the PED unless clinically warranted. PMID- 29518236 TI - Effects of crude glycerin from biodiesel on the diets of lambs: intake, digestibility, performance, feeding behavior, and serum metabolites. AB - This study was conducted to test the hypothesis that the inclusion of crude glycerin of up to 21% of DM in the diets of lambs will not compromise variables related to animal production or health. Forty-four uncastrated Santa Ines crossbreed lambs with an average age of 5 mo and a BW average of 23.9 +/- 0.34 kg (mean +/- SD) were distributed into four treatment groups (11 replicates per group) including 0%, 7%, 14%, or 21% crude glycerin on a DM basis. The inclusion of crude glycerin in the diets promoted a quadratic increase in DM (P = 0.018), CP (P = 0.004), and TDN (P = 0.017). There was a linear decrease (P < 0.001) in NDF and nonfibrous carbohydrate (NFC) intake caused by glycerin in the diets. There was a linear increase (P < 0.001) in ether extract (EE) intake. There was a linear reduction in NDF (P = 0.011) and NFC (P < 0.001) for effective consumption of the diets. There was a linear increase (P < 0.001) in EE effectively consumed by the lambs, and there were no differences in the CP that was effectively consumed (P = 0.267) by glycerin. Digestibility coefficients of DM, CP, NDF, NFC, and TDN presented a linear decrease in crude glycerin inclusion. The EE digestibility presented a linear increase. The inclusion of crude glycerin in the diets promoted a quadratic increase in final BW (P = 0.015), ADG (P < 0.001), and G:F ratio (P < 0.001). There was no effect (P > 0.05) of crude glycerin inclusion in the diets on time spent (%); number of events per day; duration of events (minutes) for feeding, rumination, and idling; number of chews per bolus; or total chewing time for the lambs. The inclusion of crude glycerin in the diets improved feeding efficiency of DM (P = 0.005) and NDF (P = 0.004). The rumination efficiency of DM (P < 0.001) and NDF (P < 0.001) presented a linear decrease. The total protein, albumin, globulin, albumin:globulin ratio, triglycerides, alanine aminotransferase levels, aspartate aminotransferase, and gamma glutamyl transferase serum concentrations did not differ (P > 0.05) through the addition of crude glycerin to the diets of the lambs. However, the crude glycerin in the diets led to a linear decrease in urea-N (P = 0.004) and glucose (P <0.001), as well as a linear increase in the cholesterol (P = 0.043) serum concentrations of the lambs. The recommended inclusion of crude glycerin is up to a 4.7% DM level because of improved performance growth without compromising feeding behavior and blood metabolites. PMID- 29518237 TI - Genetic and epigenetic variation in 5S ribosomal RNA genes reveals genome dynamics in Arabidopsis thaliana. AB - Organized in tandem repeat arrays in most eukaryotes and transcribed by RNA polymerase III, expression of 5S rRNA genes is under epigenetic control. To unveil mechanisms of transcriptional regulation, we obtained here in depth sequence information on 5S rRNA genes from the Arabidopsis thaliana genome and identified differential enrichment in epigenetic marks between the three 5S rDNA loci situated on chromosomes 3, 4 and 5. We reveal the chromosome 5 locus as the major source of an atypical, long 5S rRNA transcript characteristic of an open chromatin structure. 5S rRNA genes from this locus translocated in the Landsberg erecta ecotype as shown by linkage mapping and chromosome-specific FISH analysis. These variations in 5S rDNA locus organization cause changes in the spatial arrangement of chromosomes in the nucleus. Furthermore, 5S rRNA gene arrangements are highly dynamic with alterations in chromosomal positions through translocations in certain mutants of the RNA-directed DNA methylation pathway and important copy number variations among ecotypes. Finally, variations in 5S rRNA gene sequence, chromatin organization and transcripts indicate differential usage of 5S rDNA loci in distinct ecotypes. We suggest that both the usage of existing and new 5S rDNA loci resulting from translocations may impact neighboring chromatin organization. PMID- 29518238 TI - The DNMT3A R882H mutant displays altered flanking sequence preferences. AB - The DNMT3A R882H mutation is frequently observed in acute myeloid leukemia (AML). It is located in the subunit and DNA binding interface of DNMT3A and has been reported to cause a reduction in activity and dominant negative effects. We investigated the mechanistic consequences of the R882H mutation on DNMT3A showing a roughly 40% reduction in overall DNA methylation activity. Biochemical assays demonstrated that R882H does not change DNA binding affinity, protein stability or subnuclear distribution of DNMT3A. Strikingly, DNA methylation experiments revealed pronounced changes in the flanking sequence preference of the DNMT3A R882H mutant. Based on these results, different DNA substrates with selected flanking sequences were designed to be favored or disfavored by R882H. Kinetic analyses showed that the R882H favored substrate was methylated by R882H with 45% increased rate when compared with wildtype DNMT3A, while methylation of the disfavored substrate was reduced 7-fold. Our data expand the model of the potential carcinogenic effect of the R882H mutation by showing CpG site specific activity changes. This result suggests that R882 is involved in the indirect readout of flanking sequence preferences of DNMT3A and it may explain the particular enrichment of the R882H mutation in cancer patients by revealing mutation specific effects. PMID- 29518239 TI - Genotyping of Giardia duodenalis in vegetables cultivated with organic and chemical fertilizer from street markets and community vegetable gardens in a region of Southern Brazil. AB - Background: In order to investigate the occurrence of Giardia duodenalis and its genotypes in vegetables that are consumed raw, we analyzed samples cultivated with organic or chemical fertilizer, sold in street markets and from community vegetable gardens in an urban area located in Southern Brazil. Methods: We analyzed 130 samples of vegetables such as crisp lettuce, regular lettuce, kale, chicory and rocket, from street markets, and 130 from community gardens. From each sample, 50 g were washed in Tween 80 solution (1%) and the solution obtained was filtered through a cellulose acetate membrane. The retained material was used for DNA extraction with the commercial kit Purelink(r). GDH gene was amplified by semi-nested PCR using the GDHeF, GDHiR and GDHiF primers. Positive samples were genotyped using the PCR-RFLP technique with the restriction enzyme NlaIV. Results: We obtained 7.3% (19/260) positive samples for G. duodenalis, both from street markets (10/130) and from community gardens (9/130), including organic and non-organic products. The assemblage AI was predominant, but assemblages B and E were also found. Conclusions: The molecular technique revealed genotypes with zoonotic potential, evidencing the importance of investigating commercialized vegetables that are consumed raw and establishing a more rigid quality control. PMID- 29518240 TI - Letter: Visualization of Cranial Nerves Using High-Definition Fiber Tractography. PMID- 29518241 TI - Relationships Between Secondhand Smoke Incursion and Wheeze, Rhinitis, and Eczema Symptoms in Children Living in Homes Without Smokers in Multi-Unit Housing. AB - Introduction: Secondhand smoke (SHS) incursion can occur in units of multi-unit housing (MUH). The purpose of this study was to determine the relationship between SHS incursion and allergic symptoms in children living in MUH without smokers. Methods: We conducted a cross-sectional study from May to September 2015 in Seoul, Korea. Children were recruited from elementary schools, kindergartens, and daycare centers. In total, 16676 children between 1 and 13 years of age living in MUH without smokers were included in the analysis. Allergic symptoms during the previous 12 months (current wheeze, rhinitis, and eczema) and home environmental factors, including the frequency of SHS incursion during the previous 12 months, were examined using a questionnaire filled out by the parents or guardians of the children. Results: The prevalence of current allergic symptoms in children was 4.9% for wheeze, 42.0% for rhinitis, and 28.1% for eczema. The prevalence of SHS incursion into the children's homes was 61.6%. In a multivariable logistic regression analysis adjusted for demographic and home environmental factors, children living in homes with SHS incursion (either no more than once a month or more than once a month) were more likely to have current wheeze, rhinitis, and eczema than those with no SHS incursion. Conclusions: More than half of the children's homes in MUH without smokers had SHS incursion. SHS incursion into homes was associated with wheeze, rhinitis, and eczema symptoms in children. Implications: Children living in multi-unit housing (MUH) can be exposed to secondhand smoke (SHS) from smoke transferred from neighboring units with smokers. This study found that more than half of the children's homes without smokers in MUH had SHS incursion. Children living in homes with SHS incursion (either no more than once a month or more than once a month) were more likely to have current wheeze, rhinitis, and eczema than those with no SHS incursion. We confirmed that SHS incursion was associated with allergic symptoms in children. PMID- 29518242 TI - Exploring anti-quorum sensing and anti-virulence based strategies to fight Candida albicans infections: an in silico approach. AB - The complex virulence attributes of Candida albicans are an attractive target to exploit in the development of new antifungals and anti-virulence strategies to combat C. albicans infections. Particularly, quorum sensing (QS) has been reported as critical for virulence regulation in C. albicans. This work presents two knowledge networks with up-to-date information about QS regulation and experimentally tested anti-QS and anti-virulence agents for C. albicans. A semi automatic bioinformatics workflow that combines literature mining and expert curation was used to retrieve otherwise scattered information from the scientific literature. The network representation offers an innovative and continuously updatable means for the Candida research community to query QS and virulence data systematically and in a user-friendly way. Notably, the reconstructed networks show the complexity of QS regulation and the impact that some molecules have on the inhibition of virulence mechanisms responsible for infection establishment (e.g. hyphal development) and perseverance (e.g. biofilm formation). In the future, the compiled knowledge may be used to build decision-making models that help infer new knowledge of practical significance. The knowledge networks are publicly available at http://pcquorum.org/. This Web platform enables the exploration of fungal virulence cues as well as reported inhibitors in a user friendly fashion. PMID- 29518243 TI - Hirayama disease: oblique amyotrophy and characteristic magnetic resonance imaging findings. PMID- 29518244 TI - Polyadenylation and degradation of structurally abnormal mitochondrial tRNAs in human cells. AB - RNA 3' polyadenylation is known to serve diverse purposes in biology, in particular, regulating mRNA stability and translation. Here we determined that, upon exposure to high levels of the intercalating agent ethidium bromide (EtBr), greater than those required to suppress mitochondrial transcription, mitochondrial tRNAs in human cells became polyadenylated. Relaxation of the inducing stress led to rapid turnover of the polyadenylated tRNAs. The extent, kinetics and duration of tRNA polyadenylation were EtBr dose-dependent, with mitochondrial tRNAs differentially sensitive to the stress. RNA interference and inhibitor studies indicated that ongoing mitochondrial ATP synthesis, plus the mitochondrial poly(A) polymerase and SUV3 helicase were required for tRNA polyadenylation, while polynucleotide phosphorylase counteracted the process and was needed, along with SUV3, for degradation of the polyadenylated tRNAs. Doxycycline treatment inhibited both tRNA polyadenylation and turnover, suggesting a possible involvement of the mitoribosome, although other translational inhibitors had only minor effects. The dysfunctional tRNALeu(UUR) bearing the pathological A3243G mutation was constitutively polyadenylated at a low level, but this was markedly enhanced after doxycycline treatment. We propose that polyadenylation of structurally and functionally abnormal mitochondrial tRNAs entrains their PNPase/SUV3-mediated destruction, and that this pathway could play an important role in mitochondrial diseases associated with tRNA mutations. PMID- 29518246 TI - Stereovision Co-Registration in Image-Guided Spinal Surgery: Accuracy Assessment Using Explanted Porcine Spines. AB - BACKGROUND: Current methods of spine registration for image guidance have a variety of limitations related to accuracy, efficiency, and cost. OBJECTIVE: To define the accuracy of stereovision-mediated co-registration of a spinal surgical field. METHODS: A total of 10 explanted porcine spines were used. Dorsal soft tissue was removed to a variable degree. Bone screw fiducials were placed in each spine and high-resolution computed tomography (CT) scanning performed. Stereoscopic images were then obtained using a tracked, calibrated stereoscopic camera system; images were processed, reconstructed, and segmented in a semi automated manner. A multistart registration of the reconstructed spinal surface with preoperative CT was performed. Target registration error (TRE) in the region of the laminae and facets was then determined, using bone screw fiducials not included in the original registration process. Each spine also underwent multilevel laminectomy, and TRE was then recalculated for varying amounts of bone removal. RESULTS: The mean TRE of stereovision registration was 2.19 +/- 0.69 mm when all soft tissue was removed and 2.49 +/- 0.74 mm when limited soft tissue removal was performed. Accuracy of the registration process was not adversely affected by laminectomy. CONCLUSION: Stereovision offers a promising means of registering an open, dorsal spinal surgical field. In this study, overall mean accuracy of the registration was 2.21 mm, even when bony anatomy was partially obscured by soft tissue or when partial midline laminectomy had been performed. PMID- 29518245 TI - Sire contribution to pregnancy loss and pregnancy-associated glycoprotein production in Nelore cows. AB - Pregnancy loss is a major contributing factor to reproductive inefficiency in both the beef and dairy industries. Sires can have a significant influence on the amount of pregnancy loss; however, this relationship is still poorly investigated. The primary objective of this study was to identify sires associated with high or low incidence of pregnancy loss (between d 30 and 100 of gestation) and investigate their effect on concentration of circulating pregnancy associated glycoproteins (PAGs). Postpartum multiparous Nelore cows were inseminated artificially at a fixed time (FTAI, d 0) after synchronization of ovulation. A total of 736 cows were assigned randomly to be inseminated with semen from either of 6 Angus sires, whereas a separate subset of 492 cows were inseminated randomly with semen from either of 3 Nelore (n = 235) or either of 2 Angus sires (n = 257). Estrus expression was evaluated on d 0 using Estrotect Heat Detector patches. Blood samples were collected on d 30 of gestation for quantification of PAGs and pregnancy diagnosis was performed by ultrasound on d 30 and 100 after FTAI. Cows diagnosed pregnant at the first examination but not pregnant at the second were defined to have pregnancy loss. Overall pregnancy rate at d 30 was 54% (660/1,228) and pregnancy loss was 6.21% (41/660). Cows receiving semen from Nelore sires had greater (P < 0.001) pregnancy rate, greater (P = 0.014) pregnancy loss, and lesser (P = 0.002) PAG concentrations at d 30 of gestation compared with cows receiving Angus semen. Circulating PAG concentrations were lower (P = 0.008) in cows that had pregnancy loss (9.76 +/- 0.25 vs. 7.41 +/- 1.02 ng/mL). Angus sires were retrospectively classified according to percentage of pregnancy loss as either high pregnancy loss (mean of 7.25% or 67% of total) or low pregnancy loss (mean of 3.93% or 33% of total). Cows receiving semen from high pregnancy loss sires had 1.9 times greater (P = 0.123) rate of pregnancy loss and had lower (P = 0.059) PAG concentrations at d 30 of gestation compared with cows mated to low pregnancy loss sires. In summary, PAG concentrations reflected probability of pregnancy maintenance and were influenced by both sire and sire breed used at FTAI. Variation in the incidence of pregnancy loss was detected among sires that could not be predicted with standard semen fertility evaluations. Exploring the relationship of sire and PAG production might be promising to improve sire selection with regard to pregnancy loss. PMID- 29518247 TI - Evaluation of PAI-1 in endometriosis using a homologous immunocompetent mouse model. AB - To analyze the role of PAI-1 (plasminogen activator inhibitor 1) in endometriotic lesion growth, we studied the effect of PAI-1 inhibition by PAI-039 using a homologous mouse model of endometriosis that allows noninvasive monitoring. Endometrial tissue from donor mice was collected, labeled with mCherry adenovirus, and implanted into a subcutaneous pocket on the ventral abdomen of recipient mice. Seven days after transplantation, mice were randomly allocated in two groups and treated once daily for 2 weeks with either vehicle (control group) or PAI-1 inhibitor (PAI-039 group). Endometriotic lesion size generated in recipient mice was monitored by mCherry signal. Animals were euthanized 21 days after endometrial tissue implantation and endometriotic lesions were harvested for fibrin deposit and vascularization analyses. Collagen content was also examined to determine the overall effects of proteolysis on extracellular matrix degradation. We demonstrated that endometriotic lesions generated in recipient mice from both groups presented characteristics typical of human endometriotic lesions. We observed a significant decrease in fluorescence signal in endometriotic lesions from the PAI-039 group at the beginning of the treatment correlated with a decrease in endometriotic lesion size. PAI-1 inhibition significantly decreased lesion cell proliferation. In addition, endometriotic lesions from the PAI-1 inhibition group showed a decreased percentage of neovascularization as well as fibrin deposits. However, the density and distribution of collagen were not affected by PAI-039. Our results suggest that in vivo inhibition of PAI-1 by PAI-039 may be a useful strategy to reduce endometriotic lesion size by blocking angiogenesis. PMID- 29518249 TI - Characteristics and Long-Term Outcome of 127 Children With Cerebral Arteriovenous Malformations. AB - BACKGROUND: Population-based long-term data on pediatric patients with cerebral arteriovenous malformations (AVMs) are limited. OBJECTIVE: To clarify the characteristics and long-term outcome of pediatric patients with AVM. METHODS: A retrospective analysis was performed on 805 consecutive brain AVM patients admitted to a single center between 1942 and 2014. The patients were defined as children if they were under 18 yr at admission. Children were compared to an adult cohort. Changing patterns of presentation were also analyzed by decades of admission. RESULTS: The patients comprised 127 children with a mean age of 12 yr. The mean follow-up time was 21 yr (range 0-62). Children presented more often with intracerebral hemorrhage (ICH) but less often with epilepsy than adults. Basal ganglia, cerebellar, and posterior paracallosal AVMs were more common in pediatric than in adult patients. Frontal and temporal AVMs, in contrast, were more common in adult than in pediatric patients. As the number of incidentally and epilepsy-diagnosed AVMs increased, ICH rates dropped in both cohorts. In total, 22 (82%) pediatric and 108 (39%) adult deaths were assessed as AVM related. After multivariate analysis, small AVM size and surgical treatment correlated with a favorable long-term outcome. CONCLUSION: Hemorrhagic presentation was more common in children than in adults. This was also reflected as lower prevalence of epileptic presentation in the pediatric cohort. Lobar and cortical AVM locations were less frequent, whereas deep and cerebellar AVMs were more common in children. Hemorrhagic presentation correlated negatively with incidentally and epilepsy-diagnosed AVMs. In children, AVM was a major cause of death, but in adults, other factors contributed more commonly to mortality. PMID- 29518248 TI - Defective mitochondrial protease LonP1 can cause classical mitochondrial disease. AB - LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues. PMID- 29518250 TI - Untitled by Ann Davis. PMID- 29518251 TI - Low 5-year cumulative incidence of post-transplant lymphoproliferative disorders after solid organ transplantation in Switzerland. AB - BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of transplantation occurring in the setting of immunosuppression and oncogenic viral infections. However, little is known about the cumulative incidence, histological subtypes, risk determinants and outcome of PTLD in solid organ transplant (SOT) recipients in Switzerland. METHODS: This retrospective observational study investigated adult SOT recipients from two sequential cohorts, the pre-SCTS (Swiss Transplant Cohort Study) series, with data collected from January 1986 to April 2008, and the STCS series, with data collected from May 2008 to December 2014 in Switzerland. SOT recipients were cross-referenced with the data of all the patients with a lymphoma diagnosis in each transplant centre and with the data of the Swiss Transplant Cohort Study (STCS) to determine the cumulative incidence of PTLD, pre-therapeutic clinical features, clinical course and outcome. Kaplan-Meier analysis was performed for overall survival after PTLD. RESULTS: We identified 79 cases of PTLD during the study period in the two cohorts: pre-STCS from 1986 to 2008 (n = 62) and STCS from 2008 to 2014 (n = 17). Histological subgroups included: early lesions (pre STCS n = 2, STCS n = 0); polymorphic PTLD (pre-STCS n = 8, STCS n = 7); monomorphic PTLD (pre-STCS n = 47, STCS n = 10), and Hodgkin's lymphoma (pre-STCS n = 5, STCS n = 0). Median time to PTLD diagnosis was 90 months (range 3-281 months) and 14 months (range 2-59 months) in the pre-STCS and STCS cohorts, respectively. Median follow-up after transplantation was 141 months for the pre STCS patients and 33 months for the STCS patients. Cumulative incidences of PTLD during the STCS period at 0.5, 1 and 5 years were 0.17% (95% confidence interval 0.07-0.46%), 0.22% (0.09-0.53%) and 0.96% (0.52-1.80%), respectively. For the pre STCS case series, it was not possible to estimate the incidence rate of PTLD. Survival after PTLD diagnosis was 80% (68-87%) at 1 year and 56% (42-68%) at 5 years for the pre-STCS and STCS cohorts combined. CONCLUSIONS: At 5 years, the cumulative incidence of PTLD, regardless of the organ transplanted, was only 0.96% in the STCS cohort, which is lower than that reported in the literature. PMID- 29518252 TI - Interventions for autumn exacerbations of asthma in children. AB - BACKGROUND: Asthma exacerbations in school-aged children peak in autumn, shortly after children return to school following the summer holiday. This might reflect a combination of risk factors, including poor treatment adherence, increased allergen and viral exposure, and altered immune tolerance. Since this peak is predictable, interventions targeting modifiable risk factors might reduce exacerbation-associated morbidity and strain upon health resources. The peak occurs in September in the Northern Hemisphere and in February in the Southern Hemisphere. OBJECTIVES: To assess the effects of pharmacotherapy and behavioural interventions enacted in anticipation of school return during autumn that are designed to reduce asthma exacerbations in children during this period. SEARCH METHODS: We searched the Cochrane Airways Group Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, reference lists of primary studies and existing reviews, and manufacturers' trial registries (Merck, Novartis and Ono Parmaceuticals). We searched databases from their inception to 1 December 2017, and imposed no restriction on language of publication. SELECTION CRITERIA: We included all randomised controlled trials comparing interventions aimed specifically at reducing autumn exacerbations with usual care, (no systematic change in management in preparation for school return). We included studies providing data on children aged 18 years or younger. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently screened records identified by the search and then extracted data and assessed bias for trials meeting the inclusion criteria. A third review author checked for accuracy and mediated consensus on disagreements. The primary outcome was proportion of children experiencing one or more asthma exacerbations requiring hospitalisation or oral corticosteroids during the autumn period. MAIN RESULTS: Our searches returned 546 trials, of which five met our inclusion criteria. These studies randomised 14,252 children to receive either an intervention or usual care. All studies were conducted in the Northern Hemisphere. Three interventions used a leukotriene receptor antagonist, one used omalizumab or a boost of inhaled corticosteroids, and the largest study, (12,179 children), used a medication reminder letter. Whilst the risk of bias within individual studies was generally low, we downgraded the evidence quality due to imprecision associated with low participant numbers, poor consistency between studies, and indirect outcome ascertainment.A US study of 513 children with mild/severe asthma and allergic sensitisation was the only study to provide data for our primary outcome. In this study, the proportion of participants experiencing an exacerbation requiring oral corticosteroids or hospital admission in the 90 days after school return was significantly reduced to 11.3% in those receiving omalizumab compared to 21.0% in those receiving placebo (odds ratio 0.48, 95% confidence interval 0.25 to 0.92, moderate-quality evidence). The remaining studies used alternative exacerbation definitions. When data from two leukotriene receptor antagonist studies with comparable outcomes were combined in a random-effects model, there was no evidence of an effect upon exacerbations. There was no evidence that a seasonal medication reminder letter decreased unscheduled contacts for a respiratory diagnosis between September and December.Four studies recorded adverse events. There was no evidence that the proportion of participants experiencing at least one adverse event differed between intervention and usual care groups. Lack of data prevented planned subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS: Seasonal omalizumab treatment from four to six weeks before school return might reduce autumn asthma exacerbations. We found no evidence that this strategy is associated with increased adverse effects other than injection site pain, but it is costly. There were no data upon which to judge the effect of this or other seasonal interventions on asthma control, quality of life, or asthma-related death. In future studies definitions of exacerbations should be provided, and standardised where possible. To investigate possible differential effects according to subgroup, participants in future trials should be well characterised with respect to baseline asthma severity and exacerbation history in addition to age and gender. PMID- 29518253 TI - Endovascular revascularisation versus conservative management for intermittent claudication. AB - BACKGROUND: Intermittent claudication (IC) is the classic symptomatic form of peripheral arterial disease affecting an estimated 4.5% of the general population aged 40 years and older. Patients with IC experience limitations in their ambulatory function resulting in functional disability and impaired quality of life (QoL). Endovascular revascularisation has been proposed as an effective treatment for patients with IC and is increasingly performed. OBJECTIVES: The main objective of this systematic review is to summarise the (added) effects of endovascular revascularisation on functional performance and QoL in the management of IC. SEARCH METHODS: For this review the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (February 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). The CIS also searched trials registries for details of ongoing and unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing endovascular revascularisation (+/- conservative therapy consisting of supervised exercise or pharmacotherapy) versus no therapy (except advice to exercise) or versus conservative therapy (i.e. supervised exercise or pharmacotherapy) for IC. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data, and assessed the methodological quality of studies. Given large variation in the intensity of treadmill protocols to assess walking distances and use of different instruments to assess QoL, we used standardised mean difference (SMD) as treatment effect for continuous outcome measures to allow standardisation of results and calculated the pooled SMD as treatment effect size in meta-analyses. We interpreted pooled SMDs using rules of thumb (< 0.40 = small, 0.40 to 0.70 = moderate, > 0.70 = large effect) according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated the pooled treatment effect size for dichotomous outcome measures as odds ratio (OR). MAIN RESULTS: We identified ten RCTs (1087 participants) assessing the value of endovascular revascularisation in the management of IC. These RCTs compared endovascular revascularisation versus no specific treatment for IC or conservative therapy or a combination therapy of endovascular revascularisation plus conservative therapy versus conservative therapy alone. In the included studies, conservative treatment consisted of supervised exercise or pharmacotherapy with cilostazol 100 mg twice daily. The quality of the evidence ranged from low to high and was downgraded mainly owing to substantial heterogeneity and small sample size.Comparing endovascular revascularisation versus no specific treatment for IC (except advice to exercise) showed a moderate effect on maximum walking distance (MWD) (SMD 0.70, 95% confidence interval (CI) 0.31 to 1.08; 3 studies; 125 participants; moderate-quality evidence) and a large effect on pain-free walking distance (PFWD) (SMD 1.29, 95% CI 0.90 to 1.68; 3 studies; 125 participants; moderate-quality evidence) in favour of endovascular revascularisation. Long-term follow-up in two studies (103 participants) showed no clear differences between groups for MWD (SMD 0.67, 95% CI -0.30 to 1.63; low quality evidence) and PFWD (SMD 0.69, 95% CI -0.45 to 1.82; low-quality evidence). The number of secondary invasive interventions (OR 0.81, 95% CI 0.12 to 5.28; 2 studies; 118 participants; moderate-quality evidence) was also not different between groups. One study reported no differences in disease-specific QoL after two years.Data from five studies (n = 345) comparing endovascular revascularisation versus supervised exercise showed no clear differences between groups for MWD (SMD -0.42, 95% CI -0.87 to 0.04; moderate-quality evidence) and PFWD (SMD -0.05, 95% CI -0.38 to 0.29; moderate-quality evidence). Similarliy, long-term follow-up in three studies (184 participants) revealed no differences between groups for MWD (SMD -0.02, 95% CI -0.36 to 0.32; moderate-quality evidence) and PFWD (SMD 0.11, 95% CI -0.26 to 0.48; moderate-quality evidence). In addition, high-quality evidence showed no difference between groups in the number of secondary invasive interventions (OR 1.40, 95% CI 0.70 to 2.80; 4 studies; 395 participants) and in disease-specific QoL (SMD 0.18, 95% CI -0.04 to 0.41; 3 studies; 301 participants).Comparing endovascular revascularisation plus supervised exercise versus supervised exercise alone showed no clear differences between groups for MWD (SMD 0.26, 95% CI -0.13 to 0.64; 3 studies; 432 participants; moderate-quality evidence) and PFWD (SMD 0.33, 95% CI -0.26 to 0.93; 2 studies; 305 participants; moderate-quality evidence). Long-term follow up in one study (106 participants) revealed a large effect on MWD (SMD 1.18, 95% CI 0.65 to 1.70; low-quality evidence) in favour of the combination therapy. Reports indicate that disease-specific QoL was comparable between groups (SMD 0.25, 95% CI -0.05 to 0.56; 2 studies; 330 participants; moderate-quality evidence) and that the number of secondary invasive interventions (OR 0.27, 95% CI 0.13 to 0.55; 3 studies; 457 participants; high-quality evidence) was lower following combination therapy.Two studies comparing endovascular revascularisation plus pharmacotherapy (cilostazol) versus pharmacotherapy alone provided data showing a small effect on MWD (SMD 0.38, 95% CI 0.08 to 0.68; 186 participants; high-quality evidence), a moderate effect on PFWD (SMD 0.63, 95% CI 0.33 to 0.94; 186 participants; high-quality evidence), and a moderate effect on disease-specific QoL (SMD 0.59, 95% CI 0.27 to 0.91; 170 participants; high quality evidence) in favour of combination therapy. Long-term follow-up in one study (47 participants) revealed a moderate effect on MWD (SMD 0.72, 95% CI 0.09 to 1.36; P = 0.02) in favour of combination therapy and no clear differences in PFWD between groups (SMD 0.54, 95% CI -0.08 to 1.17; P = 0.09). The number of secondary invasive interventions was comparable between groups (OR 1.83, 95% CI 0.49 to 6.83; 199 participants; high-quality evidence). AUTHORS' CONCLUSIONS: In the management of patients with IC, endovascular revascularisation does not provide significant benefits compared with supervised exercise alone in terms of improvement in functional performance or QoL. Although the number of studies is small and clinical heterogeneity underlines the need for more homogenous and larger studies, evidence suggests that a synergetic effect may occur when endovascular revascularisation is combined with a conservative therapy of supervised exercise or pharmacotherapy with cilostazol: the combination therapy seems to result in greater improvements in functional performance and in QoL scores than are seen with conservative therapy alone. PMID- 29518254 TI - Granulomatous responses in larval taeniid infections. AB - Granulomas are responses to persistent nonliving bodies or pathogens, centrally featuring specialized macrophage forms called epithelioid and multinucleated giant cells. The larval stages of the cestode parasites of the Taeniidae family (Taenia, Echinococcus) develop for years in fixed tissue sites in mammals. In consequence, they are targets of granulomatous responses. The information on tissue responses to larval taeniids is fragmented among host and parasite species and scattered over many decades. We attempt to draw an integrated picture of these responses in solid tissues. The intensity of inflammation around live parasites spans a spectrum from minimal to high, parasite vitality correlating with low inflammation. The low end of the inflammatory spectrum features collagen capsules proximal to the parasites and moderate distal infiltration. The middle of the spectrum is dominated by classical granulomatous responses, whereas the high end features massive eosinophil invasions. Across the range of parasite species, much observational evidence suggests that eosinophils are highly effective at killing larval taeniids in solid tissues, before and during chronic granulomatous responses. The evidence available also suggests that these parasites are adapted to inhibit host granulomatous responses, in part through the exacerbation of host regulatory mechanisms including regulatory T cells and TGF-beta. PMID- 29518255 TI - Quantification and decomposition of environment-selection relationships. AB - In nature, selection varies across time in most environments, but we lack an understanding of how specific ecological changes drive this variation. Ecological factors can alter phenotypic selection coefficients through changes in trait distributions or individual mean fitness, even when the trait-absolute fitness relationship remains constant. We apply and extend a regression-based approach in a population of Soay sheep (Ovis aries) and suggest metrics of environment selection relationships that can be compared across studies. We then introduce a novel method that constructs an environmentally structured fitness function. This allows calculation of full (as in existing approaches) and partial (acting separately through the absolute fitness function slope, mean fitness, and phenotype distribution) sensitivities of selection to an ecological variable. Both approaches show positive overall effects of density on viability selection of lamb mass. However, the second approach demonstrates that this relationship is largely driven by effects of density on mean fitness, rather than on the trait fitness relationship slope. If such mechanisms of environmental dependence of selection are common, this could have important implications regarding the frequency of fluctuating selection, and how previous selection inferences relate to longer term evolutionary dynamics. PMID- 29518256 TI - Homicide in a Horse Barn? AB - As forensic scientists and physicians, forensic pathologists are duty-bound to perform their examinations with integrity and professionalism. The practice of medicine requires knowledge regarding the history and presentation of the patient. In forensic pathology, the history includes scene and other investigative information, and the decedent's medical and social history. Such information is important for the correct certification of the cause and manner of death. Herein, the authors present a case originally thought by police and death investigators to represent a sexual-assault-related homicide, as an elderly female's body was found partially nude, and apparently beaten, on the muddy floor of her horse barn. At autopsy, some of the injuries were determined to be postmortem and caused by horses. Additionally, gastric Wishnewsky spots indicated hypothermia as a probable mechanism of death. Finally, an acute hip fracture was identified, which explained why she was incapable of moving from her potentially dangerous environment. PMID- 29518258 TI - Discursive Methodologies for Couple and Family Therapy Research: Editorial to Special Section. AB - In this article, we aim to introduce the special JMFT section on discursive research methodologies for couple and family therapy research. These are qualitative research methodologies which resonate with the systemic emphasis on the semantics and the pragmatics of therapy discourse. First, we provide a brief overview of such methodologies and their use in the family therapy field. We then introduce the context and the content of the special section, where four approaches, including conversation analysis, discursive psychology type of discourse analysis, poststructurally informed discourse analysis (subject positioning analysis), and semantic analysis, are introduced by means of analyzed extracts from a Tom Andersen consultation session with a couple in distress and their therapist. We conclude with implications for the field. For Tom and Michael. PMID- 29518257 TI - Reduced contrast sensitivity among older women is associated with increased risk of cognitive impairment. AB - OBJECTIVE: Several cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population-based cohort with final adjudication of mild cognitive impairment (MCI)/dementia. METHODS: In a prospective, community based study of aging women (Study of Osteoporotic Fractures), we analyzed whether visual contrast sensitivity was associated with increased risk of MCI or dementia and/or worse performance on various cognitive tests assessed 10 years later. Contrast sensitivity was assessed at baseline in each eye using a VISTECH VCTS 6500 wall chart. MCI/dementia was adjudicated by an expert panel. Multivariate logistic and linear regression models were analyzed. RESULTS: Of 1,352 white (88.2%) and African American (11.8%) women with a mean age of 77.7 years (standard deviation = 3.3), 536 (39.6%) went on to develop MCI/dementia over 10 years. MCI/dementia risk was more than doubled (odds ratio = 2.16, 95% confidence interval = 1.58-2.96) in women with the lowest quartile of contrast sensitivity compared to the highest (p < 0.0001 for the linear trend). Reduced baseline contrast sensitivity was also associated with lower performance on several cognitive measures assessed 10 years later. INTERPRETATION: Among older women, reduced contrast sensitivity is associated with a greater risk of MCI/dementia. These findings suggest that visual system neurodegeneration or dysfunction may parallel or precede dementia-related cortical or subcortical degeneration, and that contrast sensitivity testing may be useful in identifying aging adults at high risk for dementia. Ann Neurol 2018;83:730-738. PMID- 29518259 TI - Detection of Fingermarks-Applicability to Metallic Surfaces: A Literature Review. AB - There are many different fingermark visualization techniques available, and the choice of methodology employed may be dependent on the surface type. This comprehensive review of the scientific literature evaluates the methodologies of fingermark enhancement methods that are applicable to metallic surfaces; optical, physical, chemical, and physicochemical methods are critically discussed. Methods that are currently used and those that have the potential to reduce the cost and time required to process evidence and increase the recovery rates are considered and are assessed against the Centre for Applied Science and Technology (CAST) and the International Fingerprint Research Group (IFRG) guidelines. The use of chemical imaging techniques in particular has increased the potential to recover fingermarks of sufficient quality for identification purposes. Presently, there appears to be a lack of detailed research pertaining to validation and thorough casework studies for fingermark enhancement techniques. Further studies incorporating these guidelines are recommended. PMID- 29518260 TI - Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. AB - OBJECTIVE: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of proinflammatory cytokines (IFNgamma, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTalpha, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNgamma, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739-755. PMID- 29518261 TI - Suitable simple and fast methods for selective isolation of phospholipids as a tool for their analysis. AB - Lipids are gaining relevance over the last 20 years, as our knowledge about their role has changed from merely energy/structural molecules to compounds also involved in several biological processes. This led to the creation in 2003 of a new emerging research field: lipidomics. In particular the phospholipids have pharmacological/food applications, participate in cell signalling/homeostatic pathways while their analysis faces some challenges. Their fractionation/purification is, in fact, especially difficult, as they are amphiphilic compounds. Moreover, it usually involves SPE or TLC procedures requiring specific materials hampering their suitableness for routine analysis. Finally, they can interfere with the ionization of other molecules during mass spectrometry analysis. Thus, simple high-throughput reliable methods to selectively isolate these compounds based on the difference between chemical characteristics of lipids would represent valuable tools for their study besides that of other compounds. The current review work aims to describe the state-of the-art related to the extraction of phospholipids using liquid-liquid methods for their targeted isolation. The technological and biological importance of these compounds and ion suppression phenomena are also reviewed. Methods by precipitation with acetone or isolation using methanol seem to be suitable for selective isolation of phospholipids in both biological and food samples. PMID- 29518262 TI - The evolution of ontogenetic allometric trajectories in mammalian domestication. AB - Morphological divergence of domesticated as compared to wild forms must result from changes in the ontogenetic process. Species-specific tests for heterochrony have rejected a single explanation of domestic forms representing juveniles of their wild relatives. Ontogenetic allometric trajectories for 12 pairs of wild and domestic mammals were examined using skull growth data for 1070 specimens, including representatives from all lineages in which domestication has occurred. A suite of tests were performed to quantify allometric disparity in wild and domestic forms and assess the extent and patterning of modification to allometric trajectories. Domestication has modified postnatal ontogenetic allometric trajectories in mammals, and has generated disparity, achieved through lengthening of trajectory slopes and alteration to slope angles. Allometric disparity was similar for domestic forms compared to their wild relatives, whereas the magnitude of dispersion along allometric vectors differed between precocial mammals and altricial mammals, underscoring the importance of life history and shared evolutionary history in patterns of ontogenetic variation. The results verify the importance of scaling in the morphological changes associated with domestication. The response to domestication for all measured trajectory parameters was variable across species, suggesting multiple pathways of change. PMID- 29518263 TI - From the Editors. PMID- 29518264 TI - External implantable defibrillator as a bridge to reimplant after explant for infection: Experience from two centers. AB - BACKGROUND: The management of patients explanted for implantable converter defibrillator (ICD) infections may be complex when anti-bradycardia pacing and tachyarrhythmia protection are needed. We aimed to test the efficacy and safety of a conventional ICD externally connected to a transvenous dual-coil lead as bridging therapy before the reimplantation. METHODS AND RESULTS: We enrolled seven patients explanted for ICD infections and needed prolonged antibiotic therapy in two high-volume hospitals in Italy and treated them with a passive-can external ICD for a mean of 13 (4-30) days before reimplant. One patient experienced an electrical storm, efficaciously recognized by the external ICD and treated with antitachycardia pacing and shocks. On-demand pacing was granted for all the patients. No device-related complications were reported. CONCLUSIONS: An external ICD seems safe and efficacious as a bridge to reimplant in patients explanted for ICD infections. PMID- 29518265 TI - Attempted salvage of infected cardiovascular implantable electronic devices: Are there clinical factors that predict success? AB - BACKGROUND: Published guidelines mandate complete device removal in cases of cardiovascular implantable electronic device (CIED) infection. Clinical predictors of successful salvage of infected CIEDs have not been defined. METHODS: Data from the Multicenter Electrophysiologic Device Infection Collaboration, a prospective, observational, multinational cohort study of CIED infection, were used to investigate whether clinical predictors of successful salvage of infected devices could be identified. RESULTS: Of 433 adult patients with CIED infections, 306 (71%) underwent immediate device explantation. Medical management with device retention and antimicrobial therapy was initially attempted in 127 patients (29%). "Early failure" of attempted salvage occurred in 74 patients (58%) who subsequently underwent device explantation during the index hospitalization. The remaining 53 patients (42%) in the attempted salvage group retained their CIED. Twenty-six (49%) had resolution of CIED infection (successful salvage group) whereas 27 patients (51%) experienced "late" salvage failure. Upon comparing the salvage failure group, early and late (N = 101), to the group experiencing successful salvage of an infected CIED (N = 26), no clinical or laboratory predictors of successful salvage were identified. However, by univariate analysis, coagulase-negative staphylococci as infecting pathogens (P = 0.0439) and the presence of a lead vegetation (P = 0.024) were associated with overall failed salvage. CONCLUSIONS: In patients with definite CIED infections, clinical and laboratory variables cannot predict successful device salvage. Until new data are forthcoming, device explantation should remain a mandatory and early management intervention in patients with CIED infection in keeping with existing expert guidelines unless medical contraindications exist or patients refuse device removal. PMID- 29518266 TI - Caring for patients on home enteral nutrition: Reported complications by home carers and perspectives of community nurses. AB - AIMS AND OBJECTIVES: To explore the experiences of community nurses and home carers, in caring for patients on home enteral nutrition. BACKGROUND: The number of patients on home enteral nutrition is on the increase due to advancement in technology and shift in focus of providing care from acute to community care settings. METHODS: A mixed-method approach was adopted. (i) A face-to-face survey design was used to elicit experience of carers of patients on home enteral nutrition. (ii) Focus group interviews were conducted with community nurses. RESULTS: Ninety-nine carers (n = 99) were recruited. Patient's mean age that they cared for was aged 77.7 years (SD = 11.2), and they had been on enteral feeding for a mean of 29 months (SD = 23.0). Most were bed-bound (90%) and required full assistance with their feeding (99%). Most were not on follow-up with dietitians (91%) and dentists (96%). The three most common reported gastrointestinal complications were constipation (31%), abdominal distension (28%) and vomiting (22%). Twenty community nurses (n = 20) were recruited for the focus group interviews. Four main themes emerged from the analysis: (i) challenge of accessing allied health services in the community; (ii) shorter length of stay in the acute care setting led to challenges in carers' learning and adaptation; (iii) transition gaps between hospital and home care services; and (iv) managing expectations of family. CONCLUSION: To facilitate a better transition of care for patients, adequate training for carers, standardising clinical practice in managing patients with home enteral nutrition and improving communication between home care services and the acute care hospitals are needed. RELEVANCE TO CLINICAL PRACTICE: This study highlighted the challenges faced by community home care nurses and carers. Results of this study would help to inform future policies and practice changes that would improve the quality of care received by patients on home enteral nutrition. PMID- 29518267 TI - Reply to "are spikes noninferior to high-frequency oscillations?" PMID- 29518268 TI - Feasibility of the echocardiographic subcostal view in newborn foals: two dimensional and Doppler aortic findings. AB - BACKGROUND: In dogs, due to better alignment with the aortic outflow, the subcostal (SC) transducer site provides greater Doppler-derived velocities than those obtained from the left parasternal view. The feasibility of this imaging approach has never been described in equine echocardiography. OBJECTIVES: The objective of this study was to evaluate the feasibility of the SC view in newborn foals and compare aortic two-dimensional and Doppler-derived velocity measurements with those of standard parasternal long-axis (LAX) views. STUDY DESIGN: A prospective observational study. METHODS: Twenty-three newborn healthy Standardbred and Warmblood foals, aged from 7 h to 6 days, underwent transthoracic two-dimensional (2DE), M-mode and Doppler echocardiography that was performed in lateral recumbency. Right and left parasternal long-axis (R-LAX, L LAX) and SC views were obtained to perform 2DE and Doppler assessments of the aortic valve (AoV). Aortic diameter at the sinus of Valsalva (AoS D) was measured from R-LAX and SC images. Aortic maximal velocity (AoV Velmax ), velocity time integral (AoV VTI) and pressure gradient (AoV PG) were obtained by pulsed wave Doppler spectra from SC and L-LAX views. RESULTS: The SC view was feasible in all foals. No significant difference was found in AoS D between different views (P = 0.06), and no significant correlation was detected for bodyweight (BW). AoV Velmax , VTI and PG obtained from the SC view were greater than from the L-LAX view (P<0.0001, P = 0.0001 and P<0.0001 respectively), especially in foals with lower BW. MAIN LIMITATIONS: The order of the transducer site was not randomised among foals, and the observer was not blinded during offline measurement. CONCLUSIONS: The SC view can be easily obtained in recumbent newborn foals and provides optimal alignment with aortic outflow, leading to more reliable Doppler flow velocity than the conventional L-LAX view. Further investigations of the potential use of this view in Doppler estimation of aortic outflow and cardiac assessment of sick foals are recommended. PMID- 29518269 TI - Viral etiologies of influenza-like illness and severe acute respiratory infections in Thailand. AB - BACKGROUND: Information on the burden, characteristics and seasonality of non influenza respiratory viruses is limited in tropical countries. OBJECTIVES: Describe the epidemiology of selected non-influenza respiratory viruses in Thailand between June 2010 and May 2014 using a sentinel surveillance platform established for influenza. METHODS: Patients with influenza-like illness (ILI; history of fever or documented temperature >=38 degrees C, cough, not requiring hospitalization) or severe acute respiratory infection (SARI; history of fever or documented temperature >=38 degrees C, cough, onset <10 days, requiring hospitalization) were enrolled from 10 sites. Throat swabs were tested for influenza viruses, respiratory syncytial virus (RSV), metapneumovirus (MPV), parainfluenza viruses (PIV) 1-3, and adenoviruses by polymerase chain reaction (PCR) or real-time reverse transcriptase-PCR. RESULTS: We screened 15 369 persons with acute respiratory infections and enrolled 8106 cases of ILI (5069 cases <15 years old) and 1754 cases of SARI (1404 cases <15 years old). Among ILI cases <15 years old, influenza viruses (1173, 23%), RSV (447, 9%), and adenoviruses (430, 8%) were the most frequently identified respiratory viruses tested, while for SARI cases <15 years old, RSV (196, 14%) influenza (157, 11%) and adenoviruses (90, 6%) were the most common. The RSV season significantly overlapped the larger influenza season from July to November in Thailand. CONCLUSIONS: The global expansion of influenza sentinel surveillance provides an opportunity to gather information on the characteristics of cases positive for non-influenza respiratory viruses, particularly seasonality, although adjustments to case definitions may be required. PMID- 29518271 TI - Selective Etching of Silicon from Ti3 SiC2 (MAX) To Obtain 2D Titanium Carbide (MXene). AB - Until now, MXenes could only be produced from MAX phases containing aluminum, such as Ti3 AlC2 . Here, we report on the synthesis of Ti3 C2 (MXene) through selective etching of silicon from titanium silicon carbide-the most common MAX phase. Liters of colloidal solutions of delaminated Ti3 SiC2 -derived MXene (0.5 1.3 mg mL-1 ) were produced and processed into flexible and electrically conductive films, which show higher oxidation resistance than MXene synthesized from Ti3 AlC2 . This new synthesis method greatly widens the range of precursors for MXene synthesis. PMID- 29518272 TI - Calcium Fluoride Nanocrystals: Tracers for In Vivo 19 F Magnetic Resonance Imaging. AB - Inorganic nanocrystals (NCs) have been extensively developed for a variety of uses. The ability to obtain high-resolution NMR signals from the core nuclei of NCs in solution could offer new opportunities in materials sciences and MR imaging. Herein, we demonstrate that small, water-soluble 19 F-ionic NCs can average out homonuclear dipolar interactions, enabling one to obtain high resolution 19 F NMR signals in solution that reflect the MR properties of F- in the crystal core. Decorating 19 F-NC surfaces with a biocompatible poly(ethylene glycol) coating maintains colloidal stability in water while preserving the NC high-resolution 19 F NMR properties, even after further functionalization. The high content and magnetic equivalence of the fluorides within the NCs enable their use as imaging tracers for in vivo 19 F MRI by facilitating a "hot-spot" display of their distribution. PMID- 29518270 TI - Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination. AB - OBJECTIVE: Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. METHODS: Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological, and biochemical approaches. RESULTS: We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with nonuniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies, which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/- ). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve-blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+ . Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. INTERPRETATION: Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+ . Injection of a Ca2+ chelator into Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. Ann Neurol 2018;83:756-770. PMID- 29518273 TI - Oligonucleotide Length-Dependent Formation of Virus-Like Particles. AB - Understanding the assembly pathway of viruses can contribute to creating monodisperse virus-based materials. In this study, the cowpea chlorotic mottle virus (CCMV) is used to determine the interactions between the capsid proteins of viruses and their cargo. The assembly of the capsid proteins in the presence of different lengths of short, single-stranded (ss) DNA is studied at neutral pH, at which the protein-protein interactions are weak. Chromatography, electrophoresis, microscopy, and light scattering data show that the assembly efficiency and speed of the particles increase with increasing length of oligonucleotides. The minimal length required for assembly under the conditions used herein is 14 nucleotides. Assembly of particles containing such short strands of ssDNA can take almost a month. This slow assembly process enabled the study of intermediate states, which confirmed a low cooperative assembly for CCMV and allowed for further expansion of current assembly theories. PMID- 29518274 TI - Trait differentiation and adaptation of plants along elevation gradients. AB - Studies of genetic adaptation in plant populations along elevation gradients in mountains have a long history, but there has until now been neither a synthesis of how frequently plant populations exhibit adaptation to elevation nor an evaluation of how consistent underlying trait differences across species are. We reviewed studies of adaptation along elevation gradients (i) from a meta-analysis of phenotypic differentiation of three traits (height, biomass and phenology) from plants growing in 70 common garden experiments; (ii) by testing elevation adaptation using three fitness proxies (survival, reproductive output and biomass) from 14 reciprocal transplant experiments; (iii) by qualitatively assessing information at the molecular level, from 10 genomewide surveys and candidate gene approaches. We found that plants originating from high elevations were generally shorter and produced less biomass, but phenology did not vary consistently. We found significant evidence for elevation adaptation in terms of survival and biomass, but not for reproductive output. Variation in phenotypic and fitness responses to elevation across species was not related to life history traits or to environmental conditions. Molecular studies, which have focussed mainly on loci related to plant physiology and phenology, also provide evidence for adaptation along elevation gradients. Together, these studies indicate that genetically based trait differentiation and adaptation to elevation are widespread in plants. We conclude that a better understanding of the mechanisms underlying adaptation, not only to elevation but also to environmental change, will require more studies combining the ecological and molecular approaches. PMID- 29518275 TI - Attributions of victim blame in stranger and acquaintance rape: A quantitative study. AB - AIMS AND OBJECTIVES: To, on a sample of nurses and the general public, examine whether victim blame varies according to level of familiarly between victim and perpetrator. It also examines how Ambivalent Sexism and Rape Myth Acceptance impact on this. BACKGROUND: Around one in five women will be victims of sexual assault during their lifetime. The majority are acquaintance rapes, and these victims are generally attributed more blame than victims of stranger rape. Research indicates that nurses hold similar attitudes on gender roles and victim blame as do the general public. METHODS: Eighty-one participants read a story depicting a sexual assault of a woman by either a stranger or an acquaintance and completed scales measuring victim blame, Ambivalent Sexism and Rape Myth Acceptance. RESULTS: The results of this study indicated that victim-perpetrator relationship, Benevolent Sexism, Hostile Sexism and whether the participant was a nurse contributed to the variance in attributed victim blame. Hierarchical regressions revealed that whether or not the participant was a nurse contributed to the variance in victim blame in the acquaintance rape condition, and Hostile Sexism and Benevolent Sexism contributed to the variance in victim blame in the stranger rape condition. CONCLUSIONS: This paper gives a novel insight into attitudes involved in victim blame in rape cases and makes a unique comparison between nurses and the general public. Findings suggest that victim blame correlates primarily with aggressively sexist attitudes and that nurses generally attribute more blame to the victim of acquaintance rape. RELEVANCE TO CLINICAL PRACTICE: This study has practical implications for the provision of medical services for victims of sexual assault, as it highlights problems in identifying and accessing rape victims, as well as recommending the sexual assault training of all practicing nurses. PMID- 29518276 TI - Authorship of phase 3 trials in multiple sclerosis. PMID- 29518277 TI - The meaning of living with uncertainty for people with motor neurone disease. AB - AIMS AND OBJECTIVES: To explore the meaning of living with uncertainty for people diagnosed with motor neurone disease (MND). BACKGROUND: Motor neurone disease is a progressive neurodegenerative condition resulting in multiple needs, arising from the complex nature of the disease trajectory. People with MND are often required to make decisions for symptom management and end-of-life care. Research into the lived experience of MND has previously highlighted the following: the shock of receiving such a diagnosis and prognosis; subsequent concerns relating to the future and loss; and the existential suffering for a person with MND. The lived experiences of MND accentuate the devastating nature of the disease, and this can impact upon how people respond to care. DESIGN: Hermeneutic (interpretive) phenomenology: suitable for studying lifeworld experiences. METHOD: Life story interviews were conducted with four participants and subjected to interpretive analysis. RESULTS: Three phases of the MND illness trajectory emerged: "body failing prematurely and searching for answers," "body deterioration and responses to care" and "body nearing its end and needing to talk." These phases highlight the phenomenon under study, all relating to uncertainty for people living with MND. CONCLUSIONS: This study showed that people with MND are living with uncertainty and other concerns throughout their illness trajectory. People are having to turn to palliative care professionals who are more able to meet their concerns than those caring for other aspects of their disease. RELEVANCE TO CLINICAL PRACTICE: Motor neurone disease is a complex disease, and it is important that professionals continue to provide holistic care throughout the illness trajectory. The identification of three distinct phases of the MND illness trajectory will help nurses and other professionals to better understand the meaning of uncertainty and other concerns for people with MND. PMID- 29518278 TI - Electronic Transmutation (ET): Chemically Turning One Element into Another. AB - The concept of electronic transmutation (ET) depicts the processes that by acquiring an extra electron, an element with the atomic number Z begins to have properties that were known to only belong to its neighboring element with the atomic number Z+1. Based on ET, signature compounds and chemical bonds that are composed of certain elements can now be designed and formed by other electronically transmutated elements. This Minireview summarizes the recent developments and applications of ET on both the theoretical and experimental fronts. Examples on the ET of Group 13 elements into Group 14 elements, Group 14 elements into Group 15 elements, and Group 15 elements into Group 16 elements are discussed. Compounds and chemical bonding composed of carbon, silicon, germanium, phosphorous, oxygen and sulfur now have analogues using transmutated boron, aluminum, gallium, silicon, nitrogen, and phosphorous. PMID- 29518279 TI - Transcriptomic analysis of FUCA1 knock-down in keratinocytes reveals new insights into the pathogenesis of fucosidosis skin lesions. AB - Fucosidosis is a rare lysosomal storage disease which has been classified into two subtypes, depending on the severity of clinical signs and symptoms. Fucosidosis patients' skin abnormalities include angiokeratoma corporis diffusum, widespread telangiectasia, thick skin, hyperhidrosis and hypohidrosis, acrocyanosis and distal transverse nail bands. It has been described that >50% of fucosidosis patients have angiokeratoma. At molecular level, fucosidosis is caused by lysosomal alpha-L-fucosidase (FUCA1) gene mutations. Obtaining samples for functional studies has been challenging due to the inherent difficulty in finding affected individuals. The effect of FUCA1 dysfunction on gene expression is unknown. The aim of this study was to analyse, in keratinocytes, the transcriptomic effect of FUCA1 knock-down for a better understanding of skin lesions' pathogenesis affecting fucosidosis patients. FUCA1 knock-down (siRNA) was performed in human HaCaT immortalised keratinocytes. Affymetrix arrays and qPCR were used for analysing gene expression. Bioinformatics was used for functional clustering of modified genes. In total, 387 genes showed differential expression between FUCA1 silenced and non-silenced cells (222 up-regulated and 165 down-regulated). Up-regulated genes belonged to two major groups: keratinocyte differentiation/epidermal development (n = 17) and immune response (n = 61). Several transcription factors were up-regulated in FUCA1-siRNA transfected cells. This effect might partly have been produced by abnormal transcription factor expression, that is FOXN1. We thus propose that fucosidosis related skin lesions (eg angiokeratoma) and those of other diseases (eg psoriasis) might be caused by dysfunctions in common aetiological overlapping molecular cascades. PMID- 29518280 TI - Phenological shifts in North American red squirrels: disentangling the roles of phenotypic plasticity and microevolution. AB - Phenological shifts are the most widely reported ecological responses to climate change, but the requirements to distinguish their causes (i.e. phenotypic plasticity vs. microevolution) are rarely met. To do so, we analysed almost two decades of parturition data from a wild population of North American red squirrels (Tamiasciurus hudsonicus). Although an observed advance in parturition date during the first decade provided putative support for climate change-driven microevolution, a closer look revealed a more complex pattern. Parturition date was heritable [h2 = 0.14 (0.07-0.21 (HPD interval)] and under phenotypic selection [beta = -0.14 +/- 0.06 (SE)] across the full study duration. However, the early advance reversed in the second decade. Further, selection did not act on the genetic contribution to variation in parturition date, and observed changes in predicted breeding values did not exceed those expected due to genetic drift. Instead, individuals responded plastically to environmental variation, and high food [white spruce (Picea glauca) seed] production in the first decade appears to have produced a plastic advance. In addition, there was little evidence of climate change affecting the advance, as there was neither a significant influence of spring temperature on parturition date or evidence of a change in spring temperatures across the study duration. Heritable traits not responding to selection in accordance with quantitative genetic predictions have long presented a puzzle to evolutionary ecologists. Our results on red squirrels provide empirical support for one potential solution: phenotypic selection arising from an environmental, as opposed to genetic, covariance between the phenotypic trait and annual fitness. PMID- 29518281 TI - Recessive mutations in >VPS13D cause childhood onset movement disorders. AB - VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095. PMID- 29518283 TI - An Alumino-Mannich Reaction of Organoaluminum Reagents, Silylated Amines, and Aldehydes. AB - A multi-component coupling using organoaluminum reagents, silylated amines, and aldehydes results in the formation of tertiary amines. Both alkenyl- and alkylaluminum reagents undergo reaction with iminium ion substrates for which the corresponding Petasis borono-Mannich reactions are unsuccessful. PMID- 29518282 TI - Positron emission tomography-guided magnetic resonance spectroscopy in Alzheimer disease. AB - OBJECTIVE: To determine whether the level of metabolites in magnetic resonance spectroscopy (MRS) is a representative marker of underlying pathological changes identified in positron emission tomographic (PET) images in Alzheimer disease (AD). METHODS: We performed PET-guided MRS in cases of probable AD, mild cognitive impairment (MCI), and healthy controls (HC). All participants were imaged by 11 C-Pittsburgh compound B (11 C-PiB) and 18 F-fluorodeoxyglucose (18 F FDG) PET followed by 3T MRS. PET images were assessed both visually and using standardized uptake value ratios (SUVRs). MRS voxels were placed in regions with maximum abnormality on amyloid (Abeta+) and FDG (hypometabolic) areas on PET scans. Corresponding normal areas were selected in controls. The ratios of total N-acetyl (tNA) group, myoinositol (mI), choline, and glutamate + glutamine over creatine (Cr) were compared between these regions. RESULTS: Abeta + regions had significantly higher (p = 0.02) mI/Cr and lower tNA/Cr (p = 0.02), whereas in hypometabolic areas only tNA/Cr was reduced (p = 0.003). Multiple regression analysis adjusting for sex, age, and education showed mI/Cr was only associated with 11 C-PiB SUVR (p < 0.0001). tNA/Cr, however, was associated with both PiB (p = 0.0003) and 18 F-FDG SUVR (p = 0.006). The level of mI/Cr was not significantly different between MCI and AD (p = 0.28), but tNA/Cr showed significant decline from HC to MCI to AD (p = 0.001, p = 0.04). INTERPRETATION: mI/Cr has significant temporal and spatial associations with Abeta and could potentially be considered as a disease state biomarker. tNA is an indicator of early neurodegenerative changes and might have a role as disease stage biomarker and also as a valuable surrogate marker for treatment response. Ann Neurol 2018;83:771-778. PMID- 29518284 TI - Basic weapons to degrade C3a and C5a. PMID- 29518285 TI - Beliefs and implementation of evidence-based practice among community health nurses: A cross-sectional descriptive study. AB - AIMS AND OBJECTIVES: To describe beliefs about evidence-based practice and record levels of implementation among community health nurses working independently and in community healthcare centres in the canton of Valais, Switzerland. BACKGROUND: In many settings, evidence-based practice is considered a key means of delivering better and secure health care. However, there is a paucity of published studies on the implementation of evidence-based practice in community health care. DESIGN: Cross-sectional descriptive study (n = 100). METHODS: Beliefs about evidence-based practice and levels of implementation were measured using validated scales developed by Melnyk et al. (Worldviews on Evidence-Based Nursing, 5, 2008, 208). Information on respondents' sociodemographic and professional characteristics was collected. Data were analysed using descriptive and inferential statistics. RESULTS: The final response rate was 32.3% (n = 100). More than half of respondents had previously heard about evidence-based practice; most believed in the value of using evidence to guide their practice and were prepared to improve their skills to be able to do so. However, the rate of implementation of evidence-based practice in daily practice in the 8 weeks before the survey was poor. Statistically significant positive associations were found between beliefs about evidence-based practice and how respondents had heard about it and between implementation rates and whether they had heard about evidence based practice and how they had done so. Evidence-based practices requiring scientific knowledge and skills were implemented less frequently. Greater professional community healthcare experience and management roles did not increase implementation of evidence-based practice. CONCLUSIONS: The systematic implementation of evidence-based practice by community health nurses working independently and in healthcare centres in Valais was rare, despite their positive beliefs about it. RELEVANCE TO CLINICAL PRACTICE: These results revealed the level of implementation of evidence-based practice by nurses in community healthcare settings in Valais. Further research is required to better understand their needs and expectations and to develop suitable strategies that will allow the integration of evidence-based practice into nurses' daily practice. PMID- 29518286 TI - Ingestion of partially hydrolyzed whey protein suppresses epicutaneous sensitization to beta-lactoglobulin in mice. AB - BACKGROUND: Epicutaneous sensitization to food allergens can occur through defective skin barriers. However, the relationship between oral tolerance and epicutaneous sensitization remains to be elucidated. We aimed to determine whether prior oral exposure to whey proteins or their hydrolysates prevents epicutaneous sensitization and subsequent food-allergic reaction to the whey protein, beta-lactoglobulin (beta-LG), and investigated the underlying mechanisms. METHODS: BALB/c mice were given whey protein concentrate (WPC), two kinds of partial whey protein hydrolysate (PWH1 or PWH2), or extensive whey protein hydrolysate (EWH) in drinking water for 21 days. The mice were then epicutaneously sensitized with beta-LG on tape-stripped skin. Sensitization was assessed by basophil activation tests and by measuring the level of serum beta-LG specific antibodies and cytokines secreted from beta-LG-restimulated spleen and mesenteric lymph node (MLN) cells. Development of an allergic reaction was assessed by monitoring body temperature and by measuring mast cell protease-1 level in plasma after the beta-LG oral challenge. Activated T-cell population among beta-LG-restimulated MLN cells was also analyzed. RESULTS: In mice fed with WPC, PWH1, or PWH2, sensitization and the development of an allergic reaction were totally reduced. The acceleration of cytokine release from the spleen and MLN cells or T-cell activation was not evident after beta-LG restimulation. In EWH-fed mice, a suppressive effect, though milder than that in WPC-, PWH1-, or PWH2-fed mice, was observed during the development of the allergic reaction. CONCLUSIONS: Prior oral exposure to partially hydrolyzed whey protein prevents epicutaneous sensitization and subsequent allergic response to beta-LG in mice. PMID- 29518287 TI - 3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function. AB - The skin barrier is an important shield regulating the outside-in as well as inside-out penetration of water, nutrients, ions and environmental stimuli. We can distinguish four different barrier compartments: the physical, chemical, immunological and microbial skin barrier. Well-functioning of those is needed to protect our body from the environment. To better understand the function and the contribution of barrier dysfunction in skin diseases, 3D skin or epidermal models are a valuable tool for in vitro studies. In this review, we summarize the development and application of different skin models in skin barrier research. During the last years, enormous effort was made on optimizing these models to better mimic the in vivo composition of the skin, by fine-tuning cell culture media, culture conditions and including additional cells and tissue components. Thereby, in vitro barrier formation and function has been improved significantly. Moreover, in this review we point towards changes and chances for in vitro 3D skin models to be used for skin barrier research in the nearby future. PMID- 29518288 TI - Selective Polymerization Catalysis from Monomer Mixtures: Using a Commercial Cr Salen Catalyst To Access ABA Block Polyesters. AB - ABA triblock polyesters are synthesized using a commercially available chromium salen catalyst, in one pot, from monomer mixtures comprising epoxide, anhydride and lactone. The catalysis is highly selective and applies a single catalyst in two distinct pathways. It occurs first by epoxide/anhydride ring-opening copolymerization and subsequently by lactone ring-opening polymerization. It is used to produce various new ABA polyester polyols; these polyols can undergo post functionalization and chain-extension reactions. The ability to use a commercial catalyst and switchable catalysis with monomer mixtures is expected to facilitate future explorations of new classes of block polymers. PMID- 29518289 TI - Sarcomeric and nonmuscle alpha-actinin isoforms exhibit differential dynamics at skeletal muscle Z-lines. AB - The alpha-actinin proteins are a highly conserved family of actin crosslinkers that mediate interactions between several cytoskeletal and sarcomeric proteins. Nonsarcomeric alpha-actinin-1 and alpha-actinin-4 crosslink actin filaments in the cytoskeleton, while sarcomeric alpha-actinin-2 and alpha-actinin-3 serve a crucial role in anchoring actin filaments to the muscle Z-line. To assess the difference in turnover dynamics and structure/function properties between the alpha-actinin isoforms at the sarcomeric Z-line, we used Fluorescence Recovery After Photobleaching (FRAP) in primary myofiber cultures. We found that the recovery kinetics of these proteins followed three distinct patterns: alpha actinin-2/alpha-actinin-3 had the slowest turn over, alpha-actinin-1 recovered to an intermediate degree, and alpha-actinin-4 had the fastest recovery. Interestingly, the isoforms' patterns of recovery were reversed at adhesion plaques in fibroblasts. This disparity suggests that the different alpha-actinin isoforms have unique association kinetics in myofibers and that nonmuscle isoform interactions are more dynamic at the sarcomeric Z-line. Protein domain-specific investigations using alpha-actinin-2/4 chimeric proteins showed that differential dynamics between sarcomeric and nonmuscle isoforms are regulated by cooperative interactions between the N-terminal actin-binding domain, the spectrin-like linker region and the C-terminal calmodulin-like EF hand domain. Together, these findings demonstrate that alpha-actinin isoforms are unique in binding dynamics at the Z-line and suggest differentially evolved interactive and Z-line association capabilities of each functional domain. PMID- 29518291 TI - Frequency of Dermatologic Findings at Autopsy. AB - A complete academic autopsy includes an external examination with inspection of gross dermatologic findings. At our institution, the postmortem examination also includes a standard skin biopsy. We determined the microscopic yield of this standard postmortem skin biopsy and the overall frequency of macroscopic dermatologic diagnoses. We reviewed 389 complete autopsies conducted between 2012 and 2014. Both microscopic and macroscopic dermatologic diagnoses were analyzed. A macroscopic dermatologic diagnosis was made in 32% of cases while a microscopic diagnosis was recorded in 10% of cases. Dermatologic diagnoses were identified as leading directly to cause of death in 4% of patients and as contributing to death in another 20%. Targeted biopsies were more likely to reveal histologic abnormalities than routine biopsies from a standard anatomic site. Better training in skin gross examination in addition to systematic sampling of both skin lesions and grossly normal skin may improve diagnostic accuracy and enhance clinical pathologic correlations. PMID- 29518290 TI - Subjecting appropriate lung adenocarcinoma samples to next-generation sequencing based molecular testing: challenges and possible solutions. AB - Next-generation sequencing (NGS) has recently been rapidly adopted in the molecular diagnosis of cancer, but it still faces some obstacles. In this study, 665 lung adenocarcinoma samples (558 TKI-naive and 107 TKI-relapsed samples) were interrogated using NGS, and the challenges and possible solutions of subjecting appropriate tissue samples to NGS testing were explored. The results showed that lower frequencies of HER2/BRAF/PIK3CA and acquired EGFR T790M mutations were observed in biopsy samples with <20% tumor cellularity than in those with >=20%, but there were no significant differences in the frequencies of EGFR or KRAS mutations. Moreover, tumor heterogeneity was assessed by heterogeneity score (HS), which was calculated through multiplying by 2 the mutant allele frequency (MAF) of tumor cells. In TKI-naive samples, intratumor heterogeneity could occur in EGFR, KRAS, HER2, BRAF, and PIK3CA mutant tumors, but the degree was variable. Higher EGFR, but lower BRAF and PIK3CA HS values were observed compared with KRAS HS. In TKI-relapsed samples, analysis of concomitant sensitizing EGFR and T790M MAFs showed that intratumor heterogeneity was common in acquired EGFR T790M mutant tumors. The mutational status between primary and metastatic tumors was usually concordant, but KRAS, HER2, and PIK3CA HS were significantly higher in metastatic tumors than in primary tumors. Additionally, the discordance rate of mutational status in multifocal lung adenocarcinomas diagnosed as equivocal or multiple primary tumors was high. Together, our findings demonstrate that a comprehensive quality assessment is necessary during tissue process to mitigate the challenges of poor tumor cellularity, tumor heterogeneity, and multifocal clonally independent tumors. PMID- 29518292 TI - The prevalence of depressive symptoms and associated factors in countryside dwelling older Chinese patients with hypertension. AB - AIMS AND OBJECTIVES: To estimate the prevalence of depressive symptoms in older people with hypertension in rural areas of China and to clarify the predictors influencing depressive symptoms in these patients. BACKGROUND: Although many studies have described the prevalence of depressive symptoms in older people, these studies mainly focused on those in urban areas. Few studies explicitly clarify the depressive symptoms of older patients with hypertension in rural China. DESIGN: A cross-sectional design was adopted for the study. METHODS: A convenience sampling method was used to recruit the participants. The data were collected by questionnaire survey from the medical outpatient department of five rural township hospitals in Jinzhong City of Shanxi Province, northern China. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale-D, social support by the Social Support Rating Scale and activities of daily living by the Barthel Index. RESULTS: Nine hundred forty-two rural older people with hypertension participated in the study. Of those, 560 patients (59.4%) had no depressive symptoms and 382 (40.6%) had depressive symptoms. The total mean scores of Center for Epidemiologic Studies Depression Scale-D for the normal group were 8.45 +/- 6.47, and 14.18 +/- 5.91 for the group with depressive symptoms; the statistical difference was observed by comparing the mean scores of Center for Epidemiologic Studies Depression Scale-D between the two groups (t = 2.18, p = .027). The binary logistic regression showed that the presence of depressive symptoms for older rural participants with hypertension was associated with the following factors: female (odds ratio [OR] = 1.19, 95% CI 1.10-1.37), unmarried status (OR = 1.36, 95% CI 1.19-1.65), low household income (OR = 0.80, 95% CI 0.74-0.93), living alone (OR = 1.76, 95% CI 1.45-1.90), the presence of hypertension complications and comorbid chronic diseases (OR = 0.63, 95% CI 0.42-0.74; OR = 0.55, 95% CI 0.41-0.69), dependent activities of daily living status (OR = 1.47, 95% CI 1.36-1.64) and low social support (OR = 1.66, 95% CI 1.57-1.89). CONCLUSIONS: Depressive symptoms are common among older people with hypertension in rural China. The older patients with hypertension who are liable to have depressive symptoms warrant close attention from medical institutions and governments. RELEVANCE TO CLINICAL PRACTICE: The study explores the potential factors related to depressive symptoms, understanding of which can contribute to the development of effective measures to ameliorate depressive symptoms and improve the healthcare outcomes for rural older people with hypertension. PMID- 29518293 TI - [The challenges of the 21st century in orthopedic surgery]. AB - No Abstract available. PMID- 29518294 TI - [Functional comparison in the treatment of Weber type B ankle fractures with suture device versus screw]. AB - BACKGROUND: Ten percent of all ankle fractures, 20% of the fractures treated surgically, and 1-18% of all sprains involve a syndesmosis injury. The methods used for reduction are metal or bioabsorbable syndesmotic set screws, direct repair, and sutures with or without buttons. The purpose of this study was to compare the clinical function of patients who sustained Weber B ankle fractures and were treated with the TightRope system or a syndesmotic set screw. MATERIAL AND METHODS: An observational, comparative, cross-sectional study was conducted between March 2012 and March 2015. The AOFAS ankle scale was used to assess function in patients with Weber B fractures with a syndesmosis injury treated with a 3.5 mm tricortical set screw or with the TightRope system. RESULTS: Forty three patients were included, their mean age was 47 years. The single-factor ANOVA test was used to compare the results of both groups. The latter showed that at 3, 6 and 12 months the TightRope group showed a significant improvement based on the AOFAS score, compared with the set screw group (p = 0.05). DISCUSSION: The use of the TightRope system results in better clinical function in the short term compared with the 3.5 mm tricortical set screw, according to the AOFAS scale. PMID- 29518295 TI - [Intrarticular infiltration of bupivacaine and magnesium sulfate in distal radius fractures. A pilot study]. AB - BACKGROUND: The distal radius fracture represent until 15% of all bone injuries in adults. The key in the recovery of mobility and functional outcomes are rehabilitation. The intra-articular application of magnesium sulphate has been used for postoperative pain. The objective was to determinate the improvement in pain and functional outcome of patients with distal radius fracture using intra articular magnesium sulphate. MATERIAL AND METHODS: Patients with distal radius fracture treated with percutaneous pinning and cast immobilization was included and randomized into two groups. The group 1 was applied 1.0 ml of magnesium sulphate and 1.5 ml of injectable water; meanwhile the group 2, the water was replaced with 1 ml of bupivacaine (5 mg/ml). The intra-articular infiltration was applied at the end of immobilization. Pain, functionality and movement of the wrist was evaluated for two weeks. RESULTS: Twenty patients, 8 male and twelve females, with a mean age of 53 years (+/- 17 SD) was evaluated. A significative reduction of pain during the first minute and at three minutes after intra articular infiltration in group 2 (p 0.05). Both groups presented better articular outcomes at the two weeks (p 0.05), and a better articular movement at same point (p 0.05). CONCLUSIONS: The intra-articular infiltration of magnesium sulphate plus bupivacaine help to reduces the pain. PMID- 29518296 TI - [The importance of the restoration of the joint line in revision total knee arthroplasty. Clinical indexes, quality of life and survival]. AB - INTRODUCTION: The reproduction of the anatomical joint line could be a good index to obtain good results in knee prosthesis surgery, although in revision surgery has not been enough studied. A search for a simple and reproducible method is needed to review these results. MATERIAL AND METHODS: A retrospective study was conducted between January 2000 and December 2013. A total of 97 total revision knee arthroplasties were implanted. Finally, the study group consisted of 67 patients. To perform our study, the joint line was evaluated according to the method described by Hofmann A. The evaluation of the clinical results included the following main variables: Flexion, extension, range of motion, WOMAC, SF-36, KSS (Knee Society Score) and functional KSS. The survival of the arthroplasties was studied. (p = 0.05). RESULTS: The variables of flexion, extension and range of postoperative movement are statistically correlated with this measure. The KSS was statistically related in its joint aspect with the restoration of the joint line. For the other scales, SF-36 and WOMAC, the figures were higher but did not correlate with the accepted p. CONCLUSION: In view of these results, we can say that the restoration of the anatomical joint line improves the clinical results of revision total knee arthroplasty. PMID- 29518297 TI - [Rotator cuff tear athropathy prevalence]. AB - INTRODUCTION: Glenohumeral arthritis secondary to massive rotator cuff tear presents with a superior displacement and femoralization of the humeral head with coracoacromial arch acetabularization. The purpose of this study was to establish prevalence of rotator cuff tear artropathy (CTA) at our institution. MATERIAL AND METHODS: Four hundred electronic records were reviewed from which we identified 136 patients with rotator cuff tears. A second group was composed with patients with massive cuff tears that were analized and staged by the Seebauer cuff tear arthropathy classification. RESULTS: Thirty four patients with massive rotator cuff tears were identified, 8 male and 26 female (age 60.1 +/- 10.26 years). Massive rotator cuff tear prevalence was 25%. CTA prevalence found in the rotator cuff group was 19 and 76% in the massive cuff tears group. Patients were staged according to the classification with 32% in stage 1a, 11% 1b, 32% 2a and 0% 2b. CONCLUSION: CTA prevalence in patients with rotator cuff tears and massive cuff tears is higher than the one reported in American population. We consider that a revision of the Seebauer classification to be appropriate to determine its reliability. PMID- 29518298 TI - [Post-traumatic elbow stiffness: arthroscopic release, short-term results]. AB - BACKGROUND: Open "arthrolysis" has been the standard treatment for elbow stiffness, with good results. However, the associated complications of open arthrolysis and the advancements in arthroscopic surgery have allowed including the latter as an additional approach. MATERIAL AND METHODS: Between January 2014 and March 2016, 6 patients with posttraumatic elbow stiffness underwent arthroscopic surgery by the same surgical team. Pre- and post-operative assessment included pain with a numerical visual analogue scale, elbow joint range of motion with a goniometer and the Mayo Elbow Performance Index questionnaire. RESULTS: Mean patient follow-up was 14.5 months. The mean VAS score decreased from 4.5 to 0.3. The mean elbow range of motion increased from 55.3o to 130o, with a mean gain of 75o. The mean MEPI questionnaire score went from 46.6 to 95, with a mean gain of 48.4 points. The procedures associated with arthroscopic "arthrolysis" included removal of the synthesis material from the 3 olecranon fractures. No cases of heterotopic ossification, superficial infection or ulnar neuropathy were reported. None of the patients required surgical reintervention to perform a new "arthrolysis", whether arthroscopic or open. CONCLUSIONS: Arthroscopic release to treat posttraumatic elbow stiffness is an effective technique to restore mobility in the short term. PMID- 29518299 TI - [Bilateral amputation in diabetic patient with blindness, the use of inadequate prosthesis. Case report]. AB - The most frequent diabetes-related complications are diabetic foot and glaucoma, which lead to amputation and loss of vision, respectively. Current scientific and technologic developments have permitted the design and implementation of prosthetic systems that are optimal for these patients, as the latter adapt themselves to them and can resume activities of daily living. The lack of economic resources compromises the quality of the prostheses patients can afford, as they resort to "artisanal" or "rustic" systems that hamper their adaptation process. We present herein the case of a 47 year-old female patient, housewife, with bilateral paresthesias and phantom limb sensation associated with amputation neuromas resulting from type II diabetes mellitus that had affected the patient for eight years. This patient of a low socioeconomic stratum underwent a post amputation assessment and was diagnosed as being heavily dependent when performing activities of daily living and required assisted wheelchair for ambulation. This is a frequent variant resulting from bilateral loss of lower limbs together with complete loss of vision. We describe the rehabilitation therapy during the pre- and post-prosthetic stages, together with the results of the assessments to show the effectiveness of the treatment process, without forgetting the participation of the caregiver as a fundamental co-therapeutic element in this process. PMID- 29518300 TI - [Giant lipoma of the thigh. Case report]. AB - Lipoma is a tumor of adipose tissue cells that can develop in any part of the body; We present the case of an 86-year-old woman with a lesion of the left thigh as well as her diagnostic approach, specific surgical treatment and histopathological analysis. Three years after its resection, the function of the lower extremity was preserved. PMID- 29518301 TI - [Acute rupture of the tibialis anterior tendon]. AB - : Tibialis anterior tendon rupture is a relatively rare injury, with diverse etiologies, that can cause significant deficits in the functionality of the ankle. These injuries are sometimes diagnosed too late, being in many occasions the alteration in walking the symptom that makes the patient go to the doctor. The six weeks will mark the limit between acute and chronic injury, requiring different therapeutic approaches, along with other parameters such as age, functional demand or concomitant pathologies. OBJECTIVE: To present two cases of acute rupture, with different etiology, the surgical technique used and the final results. MATERIAL AND METHODS: We present two cases of acute rupture of the tibialis anterior tendon in the critical hipovascular area, a male and a female, with posttraumatic and spontaneous etiology, respectively, in which tendon reinsertion was performed on the tarsal scaphoid with a biothenodesis screw, followed by immobilization with permission to walk at three weeks and subsequent physiotherapy. RESULTS: In both cases a satisfactory final functional result was obtained, with a significant improvement in the AOFAS score, returning to their work and sports activities at 3 and 4 months of surgery respectively, with a follow-up of 7.5 years and 10 months. DISCUSSION: This technique, within the variety described in the medical literature, has provided us excellent results, restoring the functionality of the anterior tibialis tendon and being reproducible for its simplicity, providing a high degree of safety when performing an early physiotherapy. PMID- 29518302 TI - BIM and its benefits explained. AB - A high-level look at Building Information Modelling's key benefits, the potential pitfalls, and the priorities for successful implementation, in the wake of the recent Government mandate that all centrally procured public sector construction projects commenced after 4 April this year be implementing BIM Level 2, was given by Chartered Quantity Surveyor, Gary Allen, of IDC-Consult, at the first in a series of planned IHEEM/HefmA joint seminars on the topic held recently at the headquarters of the Royal Institution of Chartered Surveyors (RICS) in London. HEJ editor, Jonathan Baillie, reports. PMID- 29518303 TI - High profile backing for GS1 drive. AB - At the 2016 GS1 UK Healthcare Conference in London, delegates heard from speakers including Pat Mills, the Department of Health's commercial director, on the ongoing work to embed GS1 standards throughout the NHS in England in line with the DH's eProcurement Strategy, published in April 2014. This mandated that any service or product procured by an English NHS acute Trust comply with the standards--one of the most obvious representations of which is on barcodes--'to enable Trusts to manage their non-pay spending by adopting master procurement data, automating the exchange of such data, and benchmarking their procurement against other Trusts and healthcare providers'. One of six 'demonstrator site' Trusts to provide a speaker at the 2016 GS1 UK national conference to report on their progress to date was Leeds Teaching Hospitals NHS Trust. Shortly after, HEJ editor, Jonathan Baillie, spoke to the Trust's associate director, Commercial and Procurement, Chris Slater, and to head of Healthcare at GS1 UK, Glen Hodgson. PMID- 29518304 TI - Special requirements in UCV theatres. AB - Graeme Hall FIHEEM, MIET, managing director of Brandon Medical, considers in detail the particular requirements and criteria for operating lights used in ultraclean ventilation (UCV) theatres, and explains how the recent establishment of a standard for testing of lighting's suitability for such theatre environments will help designers and manufacturers, as well as those specifying UCV theatre illumination, going forward. PMID- 29518305 TI - A 'future-proof' urgent care facility. AB - A L35 m project to create what the Aintree University Hospital NHS Foundation Trust says will be 'a new, world-class urgent care and trauma centre' at Aintree University Hospital just north of Liverpool is nearing its conclusion, with the final phases due for completion by the year-end. As HEJ editor, Jonathan Baillie, discovered on meeting with construction manager--North West at BAM Construction, Rob Bailey, who is leading the construction scheme, and Paul Fitzpatrick, director of Estates and Facilities at the Trust, a complex scheme which has involved transferring some departments to temporary facilities, and ensuring that clinical activities continue uninterrupted throughout, has progressed on schedule thanks to effective multidisciplinary and multi-party collaboration. PMID- 29518306 TI - 'Hidden risks' in legacy buildings. AB - Andrew Steel, managing director of air hygiene and water treatment specialist, Airmec, considers some of the key priorities for estates and facilities teams managing older healthcare estates to ensure that both the buildings, and the plant and equipment within them, are maintained in a safe, fit-for-purpose condition. He stresses the need both for accurate and proper risk assessment- particularly when 'legacy' buildings have been regularly adapted, updated, or refurbished over time, and, equally, to maintain up-to-date and comprehensive asset registers. PMID- 29518307 TI - A 'live-in' security solution examined. AB - Simon Finneran, managing director of vacant property protection specialist, Ad Hoc Property Management (pictured), discusses how, in the company's words, estates managers in the healthcare sector "can make significant savings when looking for vacant property security solutions by installing salaried individuals in disused buildings to act as 'live in security'. PMID- 29518308 TI - The RCT equivalence route to registration. AB - Iain Threlkeld BEng(Hons), CEng, FIHEEM, MIPEM, head of Clinical Engineering at Bradford Teaching Hospitals NHS Foundation Trust, looks at the background to the establishment of the Register of Clinical Technologists, and describes a new 'equivalence route' to registration designed for experienced clinical technologists with a suitable degree-level qualification. PMID- 29518309 TI - Superhydrophobic Paper from Nanostructured Fluorinated Cellulose Esters. AB - The development of economically and ecologically viable strategies for superhydrophobization offers a vast variety of interesting applications in self cleaning surfaces. Examples include packaging materials, textiles, outdoor clothing, and microfluidic devices. In this work, we produced superhydrophobic paper by spin-coating a dispersion of nanostructured fluorinated cellulose esters. Modification of cellulose nanocrystals was accomplished using 2 H,2 H,3 H,3 H-perfluorononanoyl chloride and 2 H,2 H,3 H,3 H-perfluoroundecanoyl chloride, which are well-known for their ability to reduce surface energy. A stable dispersion of nanospherical fluorinated cellulose ester was obtained by using the nanoprecipitation technique. The hydrophobized fluorinated cellulose esters were characterized by both solid- and liquid-state nuclear magnetic resonance, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and contact angle measurements. Further, we investigated the size, shape, and structure morphology of nanostructured fluorinated cellulose esters by dynamic light scattering, scanning electron microscopy, and X-ray diffraction measurements. PMID- 29518310 TI - Single-Atom Au/NiFe Layered Double Hydroxide Electrocatalyst: Probing the Origin of Activity for Oxygen Evolution Reaction. AB - A fundamental understanding of the origin of oxygen evolution reaction (OER) activity of transition-metal-based electrocatalysts, especially for single precious metal atoms supported on layered double hydroxides (LDHs), is highly required for the design of efficient electrocatalysts toward further energy conversion technologies. Here, we aim toward single-atom Au supported on NiFe LDH (sAu/NiFe LDH) to clarify the activity origin of LDHs system and a 6-fold OER activity enhancement by 0.4 wt % sAu decoration. Combining with theoretical calculations, the active behavior of NiFe LDH results from the in situ generated NiFe oxyhydroxide from LDH during the OER process. With the presence of sAu, sAu/NiFe LDH possesses an overpotential of 0.21 V in contrast to the calculated result (0.18 V). We ascribe the excellent OER activity of sAu/NiFe LDH to the charge redistribution of active Fe as well as its surrounding atoms causing by the neighboring sAu on NiFe oxyhydroxide stabilized by interfacial CO32- and H2O interfacing with LDH. PMID- 29518311 TI - Structural, Magnetic, and Electronic Properties of CaBaCo4- xM xO7 (M = Fe, Zn). AB - The effect of substituting iron and zinc for cobalt in CaBaCo4O7 was investigated using neutron diffraction and X-ray absorption spectroscopy techniques. The orthorhombic distortion present in the parent compound CaBaCo4O7 decreases with increasing the content of either Fe or Zn. The samples CaBaCo3ZnO7 and CaBaCo4- xFe xO7 with x >= 1.5 are metrically hexagonal, but much better refinements in the neutron diffraction patterns are obtained using an orthorhombic unit cell. The two types of substitution have opposite effects on the structural and magnetic properties. Fe atoms preferentially occupy the sites at the triangular layer. Thus, the replacement of Co by Fe suppresses the ferrimagnetic ordering of the parent compound, and CaBaCo4- xFe xO7 (0.5 <= x <= 2) samples are antiferromagnetically ordered following a new propagation vector k = (1/3,0,0). However, the Zn atoms prefer occupying the Kagome layer, which is very detrimental for the long-range magnetic interactions giving rise to a magnetic glass-like behavior in the CaBaCo3ZnO7 sample. The oxidation states of iron and zinc are found to be 3+ and 2+, respectively, independently of the content, as confirmed by X-ray absorption spectroscopy. Therefore, the average Co oxidation state changes accordingly with the Fe3+ or Zn2+ doping. Also, X-ray absorption spectroscopy data confirm the different preferential occupation for both Fe and Zn cations. The combined information obtained by neutron diffraction and X-ray absorption spectroscopy indicates that cobalt atoms can be either in a fluctuating Co2+/Co3+ valence state or, alternatively, Co2+ and Co3+ ions being randomly distributed in the lattice. These results explain the occurrence of local disorder in the CoO4 tetrahedra obtained by EXAFS. An anomaly in the lattice parameters and an increase in the local disorder are observed only at the ferrimagnetic transition for CaBaCo4O7, revealing the occurrence of local magneto elastic coupling. PMID- 29518312 TI - Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer. AB - A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-Cyclopentyl-6 (dimethylcarbamoyl)-7 H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)phenyl)- N8 hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC50 = 8.8, 12, and 2.2 nM, respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity. Compound 6e induces G2/M arrest in high concentration and G0/G1 arrest in low concentration to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with 6e showed significant antitumor efficacy. The insight into mechanisms of 6e indicated that it could induce cancer cell death via cell apoptosis based on CDK4/9 and HDAC1 repression and phosphorylation of p53. Our data demonstrated the novel compound 6e could be a promising drug candidate for cancer therapy. PMID- 29518313 TI - Understanding Mechanisms of Synergy between Acidification and Ultrasound Treatments for Activated Sludge Dewatering: From Bench to Pilot-Scale Investigation. AB - Enhancing activated sludge dewaterability is of scientific and engineering importance in the face of accelerated urbanization and stringent environmental regulations. In this study, we investigated the integration of acidification and ultrasound (A/US) treatment for improving sludge dewaterability at both bench- and pilot-scales. Our results showed that the A/US process exhibited significantly improved sludge dewatering performance, characterized by capillary suction time, cake moisture, and water/solid content of sludge cake. Synergistic dewatering mechanisms were elucidated with a suite of macro and spectroscopic evidence. Characterization of treated sludge revealed that US-induced thermal, mechanical shearing force, and radical oxidation effects disrupts floc cells and accelerates the decomposition of extracellular polymeric substances (EPS), releasing bound water into the bulk phase. In addition to enhancing hydrolysis of EPS, the acidic pH environment caused the protonation of functional groups on EPS, facilitating the reflocculation of US decomposed sludge for improved filterability. Our bench-scale and pilot-scale investigations provide a mechanistic basis for better understanding of the A/US process, and enable development of a viable and economical dewatering technology. PMID- 29518314 TI - Temperature-Dependent Lipid Extraction from Membranes by Boron Nitride Nanosheets. AB - Two-dimensional (2D) materials can mechanically insert into cell membranes and extract lipids out, thus leading to the destruction of cell integrity. On the one hand, the cytotoxicity of 2D materials can be harnessed in surface engineering to resist biofouling, and on the other hand, it causes great concern with in vivo biomedical applications ranging from drug delivery to nanoimaging. To understand the nature of this cytotoxic behavior and find strategies to control it, we performed molecular dynamics (MD) simulations on the lipid extraction of hexagonal boron nitride (BN) nanosheets from lipid membranes. Interestingly, we observed that the lipid extraction behavior suddenly disappears as temperature decreases. Structural analyses revealed that this temperature dependence is related to the lipid membrane phase transition, which was confirmed by an additional membrane model with phase state regulated by cholesterol. The potential of mean force calculation was adopted to clarify the thermodynamic origin of these results, which also indicates directions to adjust the lipid extraction behavior of nanomaterials. Overall, this work suggests that the cytotoxic mechanical interactions between 2D materials and cell membranes can be controlled by temperature and other factors which can induce phase transitions of lipid membranes and that the thermodynamic threshold of the lipid extraction varies for surfaces with different curvature. This work clarifies the thermodynamics in the lipid extraction phenomenon of 2D materials and indicates possible strategies to adjust the antibacterial performance or cytotoxicity of 2D materials. PMID- 29518315 TI - Nontransgenic Marker-Free Gene Disruption by an Episomal CRISPR System in the Oleaginous Microalga, Nannochloropsis oceanica CCMP1779. AB - Utilization of microalgae has been hampered by limited tools for creating loss-of function mutants. Furthermore, modified strains for deployment into the field must be free of antibiotic resistance genes and face fewer regulatory hurdles if they are transgene free. The oleaginous microalga, Nannochloropsis oceanica CCMP1779, is an emerging model for microalgal lipid metabolism. We present a one vector episomal CRISPR/Cas9 system for N. oceanica that enables the generation of marker-free mutant lines. The CEN/ARS6 region from Saccharomyces cerevisiae was included in the vector to facilitate its maintenance as circular extrachromosal DNA. The vector utilizes a bidirectional promoter to produce both Cas9 and a ribozyme flanked sgRNA. This system efficiently generates targeted mutations, and allows the loss of episomal DNA after the removal of selection pressure, resulting in marker-free nontransgenic engineered lines. To test this system, we disrupted the nitrate reductase gene ( NR) and subsequently removed the CRISPR episome to generate nontransgenic marker-free nitrate reductase knockout lines (NR-KO). PMID- 29518316 TI - Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists. AB - The opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood-brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD-2) and blocks innate immune TLR4 signaling. However, the details of the molecular interactions of (+)-naltrexone and its derivatives with MD-2 are not fully understood, which hinders the ligand-based drug discovery. Herein, in silico and in vitro assays were performed to elucidate the innate immune recognition of the opioid inactive (+)-isomers. The results showed that the conserved LPS binding pocket of MD-2 accommodated these opioid inactive (+)-isomers. The calculated binding free energies of (+)-naltrexone and its derivatives in complex with MD-2 correlated well with their experimental binding affinities and TLR4 antagonistic activities. Hydrophobic residues in the MD-2 cavity interacted directly with these (+)-naltrexone based TLR4 antagonists and principally participated in ligand binding. Increasing the hydrophobicity of substituted group at N-17 improved its TLR4 antagonistic activity, while charged groups disfavored the binding with MD-2. Molecular dynamics (MD) simulations showed the binding of (+)-naltrexone or its derivatives to MD-2 stabilized the "collapsed" conformation of MD-2, consequently blocking the binding and signaling of TLR4. Thermodynamics and dynamic analysis showed the topology of substituted group at N-17 of (+)-naltrexone affected the binding with MD-2 and TLR4 antagonistic activity. This study provides a molecular insight into the innate immune recognition of opioid inactive (+)-isomers, which would be of great help for the development of next-generation of (+)-opioid based TLR4 antagonists. PMID- 29518317 TI - Photochemical Synthesis and Electronic Properties of Extended Corannulenes with Variable Fluorination Pattern. AB - The first family of extended and fluorinated corannulenes is prepared through a highly efficient and modular synthetic strategy. In this strategy, corannulene aldehyde could be combined with the fluorine-carrying phosphonium ylides to furnish stilbene-like vinylene precursors. A photochemically induced oxidative cyclization process of these precursors gives rise to the fluorinated and curved polycyclic aromatic hydrocarbons. A UV-vis absorption study shows that aromatic extension results in a bathochromic shift of about 12 nm. Fluorination further shifts the absorption spectrum to the red region, and a maximum shift of about 22 nm is detected for a compound carrying two trifluoromethyl groups. A cyclic and square-wave voltammetry investigation reveals that the extension of the corannulene scaffold increases the reduction potential by 0.11 V. Placement of fluorine or trifluoromethyl groups further enhances the electron affinities. In this regard, the presence of one trifluoromethyl group equals the effect of three aromatic fluorine atoms. Molecules with two trifluoromethyl groups, meanwhile, exhibit the highest reduction potentials of -1.93 and -1.83 V. These values are 0.37 and 0.46 V higher than those of the parental corannulene and demonstrate the utility of the present design concept by efficiently accessing effective electron acceptors based on the buckybowl motif. PMID- 29518318 TI - Enhanced Water Barrier Properties of Surfactant-Free Polymer Films Obtained by MacroRAFT-Mediated Emulsion Polymerization. AB - The presence of low-molar-mass surfactants in latex films results in detrimental effects on their water permeability, gloss, and adhesion. For applications such as coatings, there is a need to develop formulations that do not contain surfactants and have better water barrier properties. Having previously reported the synthesis of surfactant-free latex particles in water using low amounts (<2 wt %) of chains synthesized by controlled radical polymerization (Lesage de la Haye et al. Macromolecules 2017, 50, 9315-9328), here we study the water barrier properties of films made from these particles and their application in anticorrosion coatings. When films cast from aqueous dispersions of acrylate copolymer particles stabilized with poly(sodium 4-styrenesulfonate) (PSSNa) were immersed in water for 3 days, they sorbed only 4 wt % water. This uptake is only slightly higher than the value predicted for the pure copolymer, indicating that the negative effects of any particle boundaries and hydrophilic-stabilizing molecules are minimal. This sorption of liquid water is 5 times lower than what is found in films cast from particles stabilized with the same proportion of poly(methacrylic acid) (PMAA), which is more hydrophilic than PSSNa. In water vapor with 90% relative humidity, the PSSNa-based film had an equilibrium sorption of only 4 wt %. A small increase in the PMAA content has a strong and negative impact on the barrier properties. Nuclear magnetic resonance relaxometry on polymer films after immersion in water shows that water clusters have the smallest size in the films containing PSSNa. Furthermore, these films retain their optical clarity during immersion in liquid water for up to 90 min, whereas all other compositions quickly develop opacity ("water whitening") as a result of light scattering from sorbed water. This implies a remarkably complete coalescence and a very small density of defects, which yields properties matching those of some solvent-borne films. The latex stabilized with PSSNa is implemented as the binder in a paint formulation for application as an anticorrosive barrier coating on steel substrates and evaluated in accelerated weathering and corrosion tests. Our results demonstrate the potential of self-stabilized latex particles for the development of different applications, such as waterborne protective coatings and pressure-sensitive adhesives. PMID- 29518319 TI - Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents. AB - The vitamin D3 receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential molecular target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC50 values in the submicromolar-concentration range. In addition, 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities determined by dual-luciferase-reporter assays and human-leukemia-cell line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy. PMID- 29518320 TI - Core-Shell Fe1- xS@Na2.9PS3.95Se0.05 Nanorods for Room Temperature All-Solid State Sodium Batteries with High Energy Density. AB - High ionic conductivity electrolyte and intimate interfacial contact are crucial factors to realize high-performance all-solid-state sodium batteries. Na2.9PS3.95Se0.05 electrolyte with reduced particle size of 500 nm is first synthesized by a simple liquid-phase method and exhibits a high ionic conductivity of 1.21 * 10-4 S cm-1, which is comparable with that synthesized with a solid-state reaction. Meanwhile, a general interfacial architecture, that is, Na2.9PS3.95Se0.05 electrolyte uniformly anchored on Fe1- xS nanorods, is designed and successfully prepared by an in situ liquid-phase coating approach, forming core-shell structured Fe1- xS@Na2.9PS3.95Se0.05 nanorods and thus realizing an intimate contact interface. The Fe1- xS@Na2.9PS3.95Se0.05/Na2.9PS3.95Se0.05/Na all-solid-state sodium battery demonstrates high specific capacity and excellent rate capability at room temperature, showing reversible discharge capacities of 899.2, 795.5, 655.1, 437.9, and 300.4 mAh g-1 at current densities of 20, 50, 100, 150, and 200 mA g 1, respectively. The obtained all-solid-state sodium batteries show very high energy and power densities up to 910.6 Wh kg-1 and 201.6 W kg-1 based on the mass of Fe1- xS at current densities of 20 and 200 mA g-1, respectively. Moreover, the reaction mechanism of Fe1- xS is confirmed by means of ex situ X-ray diffraction techniques, showing that partially reversible reaction occurs in the Fe1- xS electrode after the second cycle, which gives the obtained all-solid-state sodium battery an exceptional cycling stability, exhibiting a high capacity of 494.3 mAh g-1 after cycling at 100 mA g-1 for 100 cycles. This contribution provides a strategy for designing high-performance room temperature all-solid-state sodium battery. PMID- 29518321 TI - Copper Silicate Hollow Microspheres-Incorporated Scaffolds for Chemo-Photothermal Therapy of Melanoma and Tissue Healing. AB - The treatment of melanoma requires complete removal of tumor cells and simultaneous tissue regeneration of tumor-initiated cutaneous defects. Herein, copper silicate hollow microspheres (CSO HMSs)-incorporated bioactive scaffolds were designed for chemo-photothermal therapy of skin cancers and regeneration of skin tissue. CSO HMSs were synthesized with interior hollow and external nanoneedle microstructure, showing excellent drug-loading capacity and photothermal effects. With incorporation of drug-loaded CSO HMSs into the electrospun scaffolds, the composite scaffolds exhibited excellent photothermal effects and controlled NIR-triggered drug release, leading to distinctly synergistic chemo-photothermal therapy of skin cancer both in vitro and in vivo. Furthermore, such CSO HMSs-incorporated scaffolds could promote proliferation and attachment of normal skin cells and accelerate skin tissue healing in tumor bearing and diabetic mice. Taken together, CSO HMSs-incorporated scaffolds may be used for complete eradication of the remaining tumor cells after surgery and simultaneous tissue healing, which offers an effective strategy for therapy and regeneration of tumor-initiated tissue defects. PMID- 29518322 TI - In Vitro Effects of Chronic Spirolide Treatment on Human Neuronal Stem Cell Differentiation and Cholinergic System Development. AB - Spirolides (SPX) are marine toxins, produced by dinoflagellates that act as potent antagonists of nicotinic acetylcholine receptors. These compounds are not toxic for humans, and since there are no reports of human intoxications caused by this group of toxins they are not yet currently regulated in Europe. Currently 13 desmethyl spirolide C, 13,19-didesmethyl spirolide C, and 20-methyl spirolide G are commercially available as reference materials. Previous work in our laboratory has demonstrated that after 4 days of treatment of primary mice cortical neurons with 13-desmethyl spirolide C, the compound ameliorated the glutamate induced toxicity and increased acetylcholine levels and the expression of the acetylcholine synthesizing enzyme being useful both in vitro and in vivo to decrease the brain pathology associated with Alzheimer's disease. In this work, we aimed to extend the study of the neuronal effects of spirolides in human neuronal cells. To this end, human neuronal progenitor cells CTX0E16 were employed to evaluate the in vitro effect of spirolides on neuronal development. The results presented here indicate that long-term exposure (30 days) of human neuronal stem cells to SPX compounds, at concentrations up to 50 nM, ameliorated the MPP+-induced neurotoxicity and increased the expression of neuritic and dendritic markers, the levels of the choline acetyltransferase enzyme and the protein levels of the alpha7 subunit of nicotinic acetylcholine receptors. These effects are presumably due to the previously described interaction of these compounds with nicotinic receptors containing both alpha7 and alpha4 subunits. All together, these data emphasize the idea that SPX could be attractive lead molecules against neurodegenerative disorders. PMID- 29518323 TI - Integrated Reaction Path Processing from Sampled Structure Sequences. AB - Sampled structure sequences obtained, for instance, from real-time reactivity explorations or first-principles molecular dynamics simulations contain valuable information about chemical reactivity. Eventually, such sequences allow for the construction of reaction networks that are required for the kinetic analysis of chemical systems. For this purpose, however, the sampled information must be processed to obtain stable chemical structures and associated transition states. The manual extraction of valuable information from such reaction paths is straightforward but unfeasible for large and complex reaction networks. For real time quantum chemistry, this implies automatization of the extraction and relaxation process while maintaining immersion in the virtual chemical environment. Here, we describe an efficient path processing scheme for the on-the fly construction of an exploration network by approximating the explored paths as continuous basis-spline curves. PMID- 29518324 TI - Deficient Lipid A Remodeling by the arnB Gene Promotes Biofilm Formation in Antimicrobial Peptide Susceptible Pseudomonas aeruginosa. AB - Multidrug resistant bacteria possess various mechanisms that can sense environmental stresses such as antibiotics and antimicrobial peptides and rapidly respond to defend themselves. Two known defense strategies are biofilm formation and lipopolysaccharide (LPS) modification. Though LPS modifications are observed in biofilm-embedded bacteria, their effect on biofilm formation is unknown. Using biochemical and biophysical methods coupled with confocal microscopy, atomic force microscopy, and transmission electron microscopy, we show that biofilm formation is promoted in a Pseudomonas aeruginosa PAO1 strain with a loss of function mutation in the arnB gene. This loss of function prevents the addition of the positively charged sugar 4-amino-4-deoxy-l-arabinose to lipid A of LPS under restrictive magnesium conditions. The data reveal that the arnB mutant, which is susceptible to antimicrobial peptides, forms a biofilm that is more robust than that of the wild type. This is in line with the observations that the arnB mutant exhibits outer surface properties such as hydrophobicity and net negative charge that promote the formation of biofilms. Moreover, when grown under Mg2+ limitation, both the wild type and the arnB mutant exhibited a reduction in the level of membrane-bound polysaccharides. The data suggest that the loss of polysaccharides exposes the membrane and alters its biophysical properties, which in turn leads to more biofilm formation. In summary, we show for the first time that blocking a specific lipid A modification promotes biofilm formation, suggesting a trade-off between LPS remodeling and resistance mechanisms of biofilm formation. PMID- 29518325 TI - Recoupling Industrial Dairy Feedlots and Industrial Farmlands Mitigates the Environmental Impacts of Milk Production in China. AB - Dairy production is becoming more industrialized globally, especially in developing countries. The large amount of animal wastes from industrial feedlots cannot be fully used on nearby farmlands, leading to severe environmental problems. Using China as a case study, we found that most dairy feedlots employ a semicoupled mode that only recycles solid manure to farmlands, and only a few dairy feedlots employ a fully coupled mode that recycles both solid and liquid animal manure. To produce 1 ton of milk, the fully coupled mode could reduce greenhouse gas (including carbon dioxide, methane, and nitrous oxide in this paper) emissions by 24%, ammonia emissions by 14%, and N discharge into water by 29%, compared with the semicoupled systems. Coupling feedlots with constructed wetlands can further result in greater mitigation of N leaching into groundwater. However, the fully coupled system has not been widely used due to the low benefit to farmers and the institutional barrier that the feedlot owners have no right to use adjacent farmlands. Since a fully coupled system improves net ecosystem services that favor the public, a policy that supports removing the economic and institutional barriers is necessary. Our approach provides a template for mitigating environmental impacts from livestock production without sacrificing milk production. PMID- 29518326 TI - Nitric Oxide Inhibitory Sesquiterpenoids and Its Dimers from Artemisia freyniana. AB - Two new disesquiterpenoids (1 and 2) and 11 new (3-13) and 10 known (14-23) sesquiterpenoids were isolated from the whole plants of Artemisia freyniana. Their structures were elucidated by spectroscopic data analysis and comparison with published NMR data. The absolute configurations of the new isolates (1-13) were assigned based on single-crystal X-ray diffraction data and comparison of the experimental and calculated ECD data. The eremophilane derivatives 8 and 9 possess an unprecedented 2-isopropyl-3,7,7a-trimethyl-2,4,5,6,7,7a-hexahydro-1 H indene scaffold, and a putative biosynthetic pathway for these compounds is proposed. Compounds 4, 5, and 9 exhibited inhibitory effects against LPS stimulated nitric oxide (NO) production in RAW 264.7 macrophage cells with IC50 values of 10.8, 12.6, and 11.7 MUM, respectively. PMID- 29518327 TI - One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides. AB - A facile, one-pot approach for synthesizing deuterated aldehydes from arylmethyl halides was developed using D2O as the deuterium source. The efficient process is realized by a sequence of formation, H/D exchange, and oxidation of pyridinium salt intermediates. The mild and air-compatible reaction conditions enable efficient synthesis of diverse deuterated aldehydes with high deuterium incorporation. PMID- 29518328 TI - Model Selection Using BICePs: A Bayesian Approach for Force Field Validation and Parameterization. AB - The Bayesian Inference of Conformational Populations (BICePs) algorithm reconciles theoretical predictions of conformational state populations with sparse and/or noisy experimental measurements. Among its key advantages is its ability to perform objective model selection through a quantity we call the BICePs score, which reflects the integrated posterior evidence in favor of a given model, computed through free energy estimation methods. Here, we explore how the BICePs score can be used for force field validation and parametrization. Using a 2D lattice protein as a toy model, we demonstrate that BICePs is able to select the correct value of an interaction energy parameter given ensemble averaged experimental distance measurements. We show that if conformational states are sufficiently fine-grained, the results are robust to experimental noise and measurement sparsity. Using these insights, we apply BICePs to perform force field evaluations for all-atom simulations of designed beta-hairpin peptides against experimental NMR chemical shift measurements. These tests suggest that BICePs scores can be used for model selection in the context of all atom simulations. We expect this approach to be particularly useful for the computational foldamer design as a tool for improving general-purpose force fields given sparse experimental measurements. PMID- 29518329 TI - Twisted Intramolecular Charge Transfer States in Trinary Star-Shaped Triphenylamine-Based Compounds. AB - Excited state dynamics of trinary star-shaped dendritic compounds with triphenylamine arms and different cores were studied by means of time-resolved fluorescence and transient absorption. Under optical excitation, nonpolar C3 symmetry molecules form polar excited states localized on one of the molecular substituents. Conformational excited state stabilization of molecules with an electron-accepting core causes a formation of twisted internal charge transfer (TICT) states in polar solvents. A low transition dipole moment from TICT state to the ground state causes very weak fluorescence of those compounds and strong dependence on the solvent polarity. The compound formed from the triphenylamine central core and identical arms also experiences excited state twisting, however, weakly sensitive to the solvent polarity. PMID- 29518330 TI - Cyanamide as an Infrared Reporter: Comparison of Vibrational Properties between Nitriles Bonded to N and C Atoms. AB - Infrared (IR) probes based on terminally blocked beta-cyanamidoalanine (AlaNHCN) 1 and p-cyanamidophenylalanine (PheNHCN) 2 were synthesized, and the vibrational properties of their CN stretch modes were studied using Fourier transform infrared (FTIR) and femtosecond IR pump-probe spectroscopies in combination with quantum chemical calculations. From FTIR studies, it is found that the transition dipole strengths of the cyanamide (NHCN) group in 1 and 2 are much larger than those of the nitrile (CN) group but comparable to those of the isonitrile (NC) and azido (N3) groups in their previously studied analogs. The CN stretch frequencies in 1 and 2 are red-shifted from those in their nitrile analogs but more blue-shifted from the NC and N3 stretch frequencies in their isonitrile and azido analogs. The much larger transition dipole strength and the red-shifted frequency of the cyanamide relative to nitrile group originates from the n -> pi* interaction between the N atom's nonbonding (n) and CN group's antibonding (pi*) orbitals of the NHCN group. Unlike aliphatic cyanamide 1, aromatic cyanamide 2 shows a complicated line shape of the CN stretch spectra. Such a complicated line shape arises from the Fermi resonance between the CN stretch mode of the NHCN group and one of the overtones of the phenyl ring vibrations and can be substantially simplified by deuteration of the NHCN into NDCN group. From IR pump probe experiments, the vibrational lifetimes of the CN stretch mode in 1 were determined to be 0.58 +/- 0.04 ps in D2O and 0.89 +/- 0.09 ps in H2O and those in 2 were determined to be 1.64 +/- 0.13 ps in CH3OD/dimethyl sulfoxide and 0.30 +/- 0.05 and 2.62 +/- 0.26 ps in CH3OH. The short time component (0.30 +/- 0.05 ps) observed for 2 in CH3OH is attributed to the vibrational relaxation through Fermi resonance. These vibrational lifetimes are close to those of the nitrile and azido groups but shorter than those of the isonitrile group. Consequently, cyanamide behaves like an apparent vibrational hybrid of nitrile and isonitrile in that cyanamide is similar to nitrile in vibrational frequency and lifetime but to isonitrile in transition dipole strength. It is believed that cyanamide has the potential to be a strongly absorbing IR reporter of the conformational and environmental structure and dynamics of biomolecules in comparison to nitrile, a weak absorber. PMID- 29518331 TI - Interactome Analysis Reveals Regulator of G Protein Signaling 14 (RGS14) is a Novel Calcium/Calmodulin (Ca2+/CaM) and CaM Kinase II (CaMKII) Binding Partner. AB - Regulator of G Protein Signaling 14 (RGS14) is a complex scaffolding protein that integrates G protein and MAPK signaling pathways. In the adult mouse brain, RGS14 is predominantly expressed in hippocampal CA2 neurons where it naturally inhibits synaptic plasticity and hippocampus-dependent learning and memory. However, the signaling proteins that RGS14 natively engages to regulate plasticity are unknown. Here, we show that RGS14 exists in a high-molecular-weight protein complex in brain. To identify RGS14 neuronal interacting partners, endogenous RGS14 immunoprecipitated from mouse brain was subjected to mass spectrometry and proteomic analysis. We find that RGS14 interacts with key postsynaptic proteins that regulate plasticity. Gene ontology analysis reveals the most enriched RGS14 interactors have functional roles in actin-binding, calmodulin(CaM)-binding, and CaM-dependent protein kinase (CaMK) activity. We validate these findings using biochemical assays that identify interactions with two previously unknown binding partners. We report that RGS14 directly interacts with Ca2+/CaM and is phosphorylated by CaMKII in vitro. Lastly, we detect that RGS14 associates with CaMKII and CaM in hippocampal CA2 neurons. Taken together, these findings demonstrate that RGS14 is a novel CaM effector and CaMKII phosphorylation substrate thereby providing new insight into mechanisms by which RGS14 controls plasticity in CA2 neurons. PMID- 29518332 TI - Catalytic Effect of Aqueous Solution in Water-Assisted Proton-Transfer Mechanism of 8-Hydroxy Guanine Radical. AB - Water-assisted proton-transfer process is a key step in guanine damage reaction by hydroxyl radical in aqueous solution. In this article, we quantitatively determine the solvent effect in water-assisted proton-transfer mechanism of 8 hydroxy guanine radical using combined quantum mechanics and molecular mechanism with an explicit solvation model. Atomic-level reaction pathway was mapped, which shows a synchronized two-proton-transfer mechanism between the assistant water molecule and 8-hydroxy guanine radical. The transition-state dipole moment is the largest along the reaction pathway, which electrostatically stabilizes the proton transfer transition-state complex. The free-energy reaction barrier for this water-assisted proton-transfer reaction was calculated at 19.2 kcal/mol with the density functional theory/M08-SO/cc-pVTZ+/molecular mechanics level of theory. The solvent effect not only has a big impact on geometries, but also dramatically changes the energetics along the reaction pathway. Among the solvent effect contributions to the transition state, the solvent energy contribution is -28.5 kcal/mol and the polarization effect contribution is 19.9 kcal/mol. In total, the solvent effect contributes -8.6 kcal/mol to the free-energy barrier height, which means that the presence of aqueous solution has a catalytic effect on the reaction mechanism and enhances the proton-transfer reactivity in aqueous solution. PMID- 29518333 TI - How the Arrangement of Alkyl Substituents Affects the Stability of Delocalized Carbocations. AB - G-4 calculations are used to explore which carbon atoms of methylated butadienes, methylated cyclopentadienes, and methylated benzenes are most readily protonated to yield delocalized allyl and pentadienyl cations. While it is not surprising that alkylation of the positions bearing formal positive charge stabilizes these cations, several other effects are less obvious. First, alkylation of positions in the delocalized cation that do not bear formal charge is beneficial, to an extent about a quarter to a third as great as at charged positions. Second, alkylation of the position receiving the proton disfavors protonation. Finally, at least in the acyclic systems, the more symmetrical substitution pattern that is 2 degrees at both ends is moderately preferred to the less symmetrical pattern that is 3 degrees at one end and 1 degrees at the other. Taking all three of these factors into account, as well as substitution at the formally charged centers, models the stability of all 94 delocalized cations quite well. PMID- 29518335 TI - Dynamic Changes in the Protein Localization in the Nuclear Environment in Pancreatic beta-Cell after Brief Glucose Stimulation. AB - Characterization of molecular mechanisms underlying pancreatic beta-cell function in relation to glucose-stimulated insulin secretion is incomplete, especially with respect to global response in the nuclear environment. We focus on the characterization of proteins in the nuclear environment of beta-cells after brief, high glucose stimulation. We compared purified nuclei derived from beta cells stimulated with 17 mM glucose for 0, 2, and 5 min using quantitative proteomics, a time frame that most likely does not result in translation of new protein in the cell. Among the differentially regulated proteins, we identified 20 components of the nuclear organization processes, including nuclear pore organization, ribonucleoprotein complex, and pre-mRNA transcription. We found alteration of the nuclear pore complex, together with calcium/calmodulin-binding chaperones that facilitate protein and RNA import or export to/from the nucleus to the cytoplasm. Putative insulin mRNA transcription-associated factors were identified among the regulated proteins, and they were cross-validated by Western blotting and confocal immunofluorescence imaging. Collectively, our data suggest that protein translocation between the nucleus and the cytoplasm is an important process, highly involved in the initial molecular mechanism underlying glucose stimulated insulin secretion in pancreatic beta-cells. PMID- 29518336 TI - Interaction of Hydrophobic Ionic Liquids with Lipids in Langmuir Monolayers. AB - The interaction of two ionic liquids, trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)-imide and trihexyl(tetradecyl)phosphonium dicyanamide, [P6 6 6 14][Ntf2] and [P6 6 6 14]/[N(CN)2], with several long chained lipids with a different net charge at the hydrophilic group, a cationic surfactant, dioctadecyldimethylammonium bromide (DODAB), a zwitterionic phospholipid (DPPC), an anionic phospholipid (DPPG), and the neutral stearic acid (SA), was investigated at the air-water interface using the Langmuir trough technique. The experimental surface pressure-area (pi- A) isotherms obtained for selected compositions of each binary system reveal distinct interfacial behavior. The degree and the nature of the IL-lipid interaction strongly depend on the charge distribution in the lipid polar group. Miscibility, or immiscibility, at the monolayer was inferred from the comparison of the experimental pi- A isotherm with the theoretical curve calculated for the corresponding ideal mixture based on the pi- A isotherms of the pure components. Phase separation and partial miscibility occurred in IL/DODAB and IL/DPPC systems, respectively. In both the IL/DPPG and the IL/SA systems, a new catanionic complex was found. For the IL/SA system, the catanionic complex formation varies with the subphase pH. PMID- 29518337 TI - Photoreleasable Protecting Groups Triggered by Sequential Two-Photon Absorption of Visible Light: Release of Carboxylic Acids from a Linked Anthraquinone- N Alkylpicolinium Ester Molecule. AB - A photoreleasable protecting group activated by sequential absorption of two visible photons is designed, synthesized, and tested. Specifically, an anthraquinone-based chromophore is covalently attached to an N-alkylpicolinium ester. Photolysis of this linked system results in the clean release of a corresponding carboxylic acid. Through product analysis, laser flash photolysis, and steady-state UV-vis spectroscopy, it is demonstrated that carboxylate ion release is affected by sequential absorption of two photons. The initial photochemical step results in reduction of an anthraquinone chromophore to the corresponding hydroquinone. The latter either reacts with O2 to regenerate the starting material, or absorption of a second photon causes an electron transfer to the picolinium group triggering C-O bond scission and release of the carboxylate. PMID- 29518334 TI - Neuropeptidomics of the Rat Habenular Nuclei. AB - Conserved across vertebrates, the habenular nuclei are a pair of small symmetrical structures in the epithalamus. The nuclei functionally link the forebrain and midbrain by receiving input from and projecting to several brain regions. Each habenular nucleus comprises two major asymmetrical subnuclei, the medial and lateral habenula. These subnuclei are associated with different physiological processes and disorders, such as depression, nicotine addiction, and encoding aversive stimuli or omitting expected rewarding stimuli. Elucidating the functions of the habenular nuclei at the molecular level requires knowledge of their neuropeptide complement. In this work, three mass spectrometry (MS) techniques-liquid chromatography (LC) coupled to Orbitrap tandem MS (MS/MS), LC coupled to Fourier transform (FT)-ion cyclotron resonance (ICR) MS/MS, and matrix assisted laser desorption/ionization (MALDI) FT-ICR MS-were used to uncover the neuropeptide profiles of the rodent medial and lateral habenula. With the assistance of tissue stabilization and bioinformatics, a total of 262 and 177 neuropeptides produced from 27 and 20 prohormones were detected and identified from the medial and lateral habenula regions, respectively. Among these neuropeptides, 136 were exclusively found in the medial habenula, and 51 were exclusively expressed in the lateral habenula. Additionally, novel sites of sulfation, a rare post-translational modification, on the secretogranin I prohormone are identified. The results demonstrate that these two small brain nuclei have a rich and differentiated peptide repertoire, with this information enabling a range of follow-up studies. PMID- 29518338 TI - Measuring the Vibrational Density of States of Nanocrystal-Based Thin Films with Inelastic X-ray Scattering. AB - Knowledge of the vibrational structure of a semiconductor is essential for explaining its optical and electronic properties and enabling optimized materials selection for optoelectronic devices. However, measurement of the vibrational density of states of nanomaterials is challenging. Here, using the example of colloidal nanocrystals (quantum dots), we show that the vibrational density of states of nanomaterials can be accurately and efficiently measured with inelastic X-ray scattering (IXS). Using IXS, we report the first experimental measurements of the vibrational density of states for lead sulfide nanocrystals with different halide-ion terminations and for CsPbBr3 perovskite nanocrystals. IXS findings are supported with ab initio molecular dynamics simulations, which provide insight into the origin of the measured vibrational structure and the effect of nanocrystal surface. Our findings highlight the advantages of IXS compared to other methods for measuring the vibrational density of states of nanocrystals such as inelastic neutron scattering and Raman scattering. PMID- 29518339 TI - High-Pressure Limit Rate Rules for alpha-H Isomerization of Hydroperoxyalkylperoxy Radicals. AB - Hydroperoxyalkylperoxy (OOQOOH) radical isomerization is an important low temperature chain branching reaction within the mechanism of hydrocarbon oxidation. This isomerization may proceed via the migration of the alpha-hydrogen to the hydroperoxide group. In this work, a combination of high level composite methods-CBS-QB3, G3, and G4-is used to determine the high-pressure-limit rate parameters for the title reaction. Rate rules for H-migration reactions proceeding through 5-, 6-, 7-, and 8-membered ring transitions states are determined. Migrations from primary, secondary and tertiary carbon sites to the peroxy group are considered. Chirality is also investigated by considering two diastereomers for reactants and transition states with two chiral centers. This is important since chirality may influence the energy barrier of the reaction as well as the rotational energy barriers of hindered rotors in chemical species and transition states. The effect of chirality and hydrogen bonding interactions in the investigated energies and rate constants is studied. The results show that while the energy difference between two diastereomers ranges from 0.1-3.2 kcal/mol, chirality hardly affects the kinetics, except at low temperatures (atmospheric conditions) or when two chiral centers are present in the reactant. Regarding the effect of the H-migration ring size, it is found that in most cases, the 1,5 and 1,6 H-migration reactions have similar rates at low temperatures (below ~830 K) since the 1,6 H-migration proceeds via a cyclohexane like transition state similar to that of the 1,5 H-migration. PMID- 29518340 TI - Improvement of the ReaxFF Description for Functionalized Hydrocarbon/Water Weak Interactions in the Condensed Phase. AB - The ReaxFF protein reactive force field (protein-2013) has been successfully employed to simulate the biomolecules and membrane fuel cells, but it inaccurately describes the weak interaction of functionalized hydrocarbon/water molecules in condensed phase, especially for the density. In this article, the development of a ReaxFF force field (CHON-2017_weak) on the basis of protein-2013 is presented that improves the weak interaction description for atom pairs of carbon, hydrogen, oxygen, and nitrogen. To examine the quality of the force field, we performed a series of molecular dynamics simulations with model systems. These simulations, describing density trends for pure and mixture compound systems, demonstrate that CHON-2017_weak force field predictions are in good agreement with experimental data. Furthermore, ReaxFF can also describe the phase separation in hexane-water mixture and dissolution of ethanol or tetramethylammonium (TMA) in liquid water. To validate it in the application of membrane fuel cells, we studied structural property and degradation mechanism of TMA in alkaline aqueous solution, as well as some typical chemical reactions for small compounds. On the basis of our results, an additional reaction pathway is proposed for the degradation of TMA, which seems to be more energetically favorable compared to the main mechanism predicted from quantum mechanics calculations. PMID- 29518342 TI - Effects of E-Cigarette Use on Human Lung Tissue. On Harm Reduction and Causing Harm. PMID- 29518341 TI - Impaired Tumor-Infiltrating T Cells in Patients with Chronic Obstructive Pulmonary Disease Impact Lung Cancer Response to PD-1 Blockade. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. OBJECTIVES: To study the impact of COPD on the immune contexture of non-small cell lung cancer. METHODS: We performed in depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status. MEASUREMENTS AND MAIN RESULTS: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD 1 antibody showed longer progression-free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. CONCLUSIONS: COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD. PMID- 29518343 TI - Dentoalveolar Cleft Treatment Outcome Using Modified Huddart-Bodenham Index and Regression Analysis of Associated Factors. AB - OBJECTIVES: The aim of this study is to assess the treatment outcome of complete unilateral cleft lip and palate (CUCLP) patients using modified Huddart/Bodenham scoring system (MHB). To determine whether there is an association of congenital and postnatal factors with the treatment outcome. DESIGN: Retrospective observational study. SETTING: Two regional cleft-referral centers. MAIN OUTCOME MEASURES: In the current study, 101 pairs of dental models of non-syndromic CUCLP patients were retrieved from hospital archives. Each occlusal relationship from central incisor till the first permanent molars were scored except the lateral incisor. Sum of 10 occlusal relationships in each study sample gave a total occlusion score. The primary outcome was the mean total occlusion score. RESULTS: According to MHB, a mean (standard deviation) total occlusion score of -8.92 (6.89) was determined. Based on treatment outcome, 66 cases were favorable (grades 1, 2, and 3) and 35 cases were unfavorable (grades 4 and 5). Chi-square tests indicated, difference of cheiloplasty ( P = .001) and palatoplasty ( P < .001) statistically significant. Five variables-gender, family history of cleft, cleft side, cheiloplasty, and palatoplasty-were analyzed with a logistic regression model. CONCLUSIONS: Final model indicated that cases treated with modified Millard technique (cheiloplasty) and Veau-Wardill-Kilner method (palatoplasty) had higher odds of unfavorable treatment outcome. PMID- 29518345 TI - Nasal Microbiota and Respiratory Tract Infections: The Role of Viral Detection. PMID- 29518344 TI - Prior treatment with the AMPK activator AICAR induces subsequently enhanced glucose uptake in isolated skeletal muscles from 24-month-old rats. AB - 5' AMP-activated protein kinase (AMPK) activation may be part of the exercise induced process that enhances insulin sensitivity. Independent of exercise, acute prior treatment of skeletal muscles isolated from young rats with a pharmacological AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-d ribofuranoside (AICAR), causes subsequently improved insulin-stimulated glucose uptake (GU). However, efficacy of a single prior AICAR exposure on insulin stimulated GU in muscles from old animals has not been studied. The purpose of this study was to determine whether brief, prior exposure to AICAR (3.5 h before GU assessment) leads to subsequently increased GU in insulin-stimulated skeletal muscles from old rats. Epitrochlearis muscles from 24-month-old male rats were isolated and initially incubated +/-AICAR (60 min), followed by incubation without AICAR (3 h), then incubation +/-insulin (50 min). Muscles were assessed for GU (via 3-O-methyl-[3H]-glucose accumulation) and site-specific phosphorylation of key proteins involved in enhanced GU, including AMPK, Akt, and Akt substrate of 160 kDa (AS160), via Western blotting. Prior ex vivo AICAR treatment resulted in greater GU by insulin-stimulated muscles from 24-month-old rats. Prior AICAR treatment also resulted in greater phosphorylation of AMPK (T172) and AS160 (S588, T642, and S704). Glucose transporter type 4 (GLUT4) protein abundance was unaffected by prior AICAR and/or insulin treatment. These findings demonstrate that skeletal muscles from older rats are susceptible to enhanced insulin-stimulated GU after brief activation of AMPK by prior AICAR. Consistent with earlier research using muscles from young rodents, increased phosphorylation of AS160 is implicated in this effect, which was not attributable to altered GLUT4 glucose transporter protein abundance. PMID- 29518346 TI - Metatranscriptome of the Oral Microbiome in Health and Disease. AB - The last few decades have witnessed an increasing interest in studying the human microbiome and its role in health and disease. The focus of those studies was mainly the characterization of changes in the composition of the microbial communities under different conditions. As a result of those studies, we now know that imbalance in the composition of the microbiome, also referred to as microbial dysbiosis, is directly linked to developing certain conditions. Dysbiosis of the oral microbiome is a prime example of how this imbalance leads to disease in the case of periodontal disease. However, there is considerable overlap in the phylogenetic profiles of microbial communities associated with active and inactive lesions, suggesting that the difference in periodontal status of those sites may not be explained solely by differences in the subgingival microbial composition. These findings suggest that differences in functional activities may be the essential elements that define the dysbiotic process. Researchers have recently begun to study gene expression of the oral microbiome in situ with the goal of identifying changes in functional activities that could explain the transition from health to disease. These initial results suggest that, rather than a specific composition, a better understanding of oral dysbiosis can be obtained from the study of functional activities of the microbial community. In this review, we give a summary of these initial studies, which have opened a new door to our understanding of the dynamics of the oral community during the dysbiotic process in the oral cavity. PMID- 29518347 TI - Dietary genistein supplementation in laying broiler breeder hens alters the development and metabolism of offspring embryos as revealed by hepatic transcriptome analysis. AB - Genistein (GEN) is a type of isoflavone mainly derived from soy products. In this experiment, we added 40 and 400 mg/kg GEN to the diet of laying broiler breeder hens to clarify the maternal effects of GEN on the development and metabolism of chick embryos. GEN treatment at 40 mg/kg increased embryonic length, weight, and liver index, as well as the width of the proliferative zone in the tibial growth plate of chick embryos. Gene ontology (GO) cluster analysis of the hepatic transcriptome showed that GEN treatment promoted embryonic development and cell proliferation. Low-dose GEN treatment increased insulin growth factor-binding protein (IGFBP)3 mRNA expression in the embryonic liver, whereas high-dose GEN treatment increased IGFBP5 expression and activated the apoptosis and protein tyrosine kinase signaling pathways. Furthermore, adding supplemental GEN to the diet of hens promoted the glycolysis process in the embryonic liver through the insulin-signaling pathway, upregulated target genes (phosphoglucomutase-2, hexokinase 1, dihydroxyacetone phosphate by aldolase, phosphofructokinase, platelet, and enolase 2), and enhanced the transport of carboxylic acids and cholesterol and the synthesis of unsaturated fatty acid (arachidonic acid) in the embryonic liver through upregulation of liver X receptor, sterol regulatory element-binding protein 1, and patatin-like phospholipase A. Additionally, GEN treatment increased fatty acid beta-oxidation and Na+/K+-ATPase activity in the embryonic liver through activation of peroxisome proliferator-activated receptors (PPARs; PPARalpha and PPARdelta) and the AMPK signaling pathway, which could provide energy for embryonic development. In addition, GEN treatment in hens increased superoxide dismutase activity and metallothionein expression in the chick embryonic liver and promoted lymphocyte proliferation through upregulation of mRNA expression of CDKN1A, IL12RB1, Sox11, PRKAR1A, PRKCQ, and TCF3. The improved immunity and antioxidant capacity, as a result of maternal GEN effects, was conducive to embryonic development. In summary, the addition of GEN to the diet of laying broiler breeder hens significantly promoted the development and metabolism of chick embryos.-Lv, Z., Fan, H., Zhang, B., Ning, C., Xing, K., Guo, Y. Dietary genistein supplementation in laying broiler breeder hens alters the development and metabolism of offspring embryos as revealed by hepatic transcriptome analysis. PMID- 29518348 TI - Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model. AB - Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin 1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ETB receptor antagonist), ONO-8711 (prostanoid receptor EP1 antagonist), and HC 030031 (TRPA1 antagonist). Prostaglandin E2 production in the ulcers was suppressed by BQ-788. Mechanical allodynia in the model was inhibited not only by BQ-788 and HC-030031 but also by BQ-123 (ETA receptor antagonist), SB-366791 (TRPV1 antagonist), and RN-1734 (TRPV4 antagonist). In naive rats, submucosal injection of endothelin-1 caused mechanical allodynia that was sensitive to HC 030031 and SB-366791 but not to RN-1734. These results suggest that endothelin-1 production following oral bacterial invasion via ulcerative regions elicits TRPA1 mediated spontaneous pain. This pain likely occurs through an indirect route that involves ETB receptor-accelerated prostanoid production. Endothelin-1 elicits directly TRPA1- and TRPV1-mediated mechanical allodynia via both ETA and ETB receptors on nociceptive fibers. The TRPV4-mediated allodynia component seems to be independent of endothelin signaling. These findings highlight the potential of endothelin signaling blockers as effective analgesic approaches for oral ulcer patients. PMID- 29518349 TI - Sperm motility in fish: technical applications and perspectives through CASA-Mot systems. AB - Although a relatively high number of sperm quality biomarkers have been reported over the years in several fish species, sperm motility is nowadays considered the best biomarker for fish spermatozoa. The first scientific reports focusing on fish sperm motility date from a century ago, but the objective assessment allowed by computer-aided sperm analysis (CASA-Mot) systems was not applied to fish species until the mid-1980s. Since then, a high number of sperm kinetic parameters from more than 170 fish species have been reported in more than 700 scientific articles, covering a wide range of topics, such as sperm physiology, sperm storage, broodstock management, the phenomenon of sperm competition, ecotoxicology and understanding the life cycle of the species. The sperm kinetic parameters provided by CASA-Mot systems can serve as powerful and useful tools for aquaculture and ecological purposes, and this review provides an overview of the major research areas in which fish sperm motility assessment by a CASA-Mot system has been used successfully. PMID- 29518350 TI - Single step, direct fluorescence immunoassays based on metal enhanced fluorescence (MEF-FIA) applicable as micro plate-, array-, multiplexing- or point of care-format. AB - Although Enzyme Linked Immuno Sorbent Assay (ELISA) technology is approaching it's 45th year of existence since first described in 1971, it is still the main diagnostic tool in clinical research and routine diagnostics. However, despite its broad usage it suffers from some drawbacks, limiting its use especially in more advanced assay formats like multiplexing platforms, point of care devices or protein arrays. Those limitations result from the need for an enzyme label, a soluble enzyme substrate, washing steps (multiplexing, point care, arrays) and in some cases also insufficient sensitivity, because the majority of circulating proteins and thus potential biomarkers may be found in lower sub-picomolar concentrations. We hereby present a new assay platform based on metal enhanced fluorescence (MEF), that remedies these problems since it eliminates the need for washing steps, for using enzyme labels and allows detection of analytes down to sub-picomolar concentrations. In addition this technology is fully compatible to standard fluorescence reader equipment as it is found in many laboratories nowadays. Since our present work is focused on single biomarker evaluation, we chose a 96 well plate format for convenience, but any other formate like antibody arrays, strip-like point of care devices etc. is feasible too. PMID- 29518352 TI - Loss of cone function without degeneration in a novel Gnat2 knock-out mouse. AB - Rods and cones mediate visual perception over 9 log units of light intensities, with both photoreceptor types contributing to a middle 3-log unit range that comprises most night-time conditions. Rod function in this mesopic range has been difficult to isolate and study in vivo because of the paucity of mutants that abolish cone signaling without causing photoreceptor degeneration. Here we describe a novel Gnat2 knockout mouse line (Gnat2-/-) ideal for dissecting rod and cone function. In this line, loss of Gnat2 expression abolished cone phototransduction, yet there was no loss of cones, disruption of the photoreceptor mosaic, nor change in general retinal morphology up to at least 9 months of age. Retinal microglia and Muller glia, which are highly sensitive to neuronal pathophysiology, were distributed normally with morphologies indistinguishable between Gnat2-/- and wildtype adult mice. ERG recordings demonstrated complete loss of cone-driven a-waves in Gnat2-/- mice; comparison to WT controls revealed that rods of both strains continue to function at light intensities exceeding 104 photoisomerizations rod-1 s-1. We conclude that the Gnat2-/- mouse is a preferred model for functional studies of rod pathways in the retina when degeneration could be an experimental confound. PMID- 29518351 TI - Genotypic and phenotypic signatures to predict immune checkpoint blockade therapy response in patients with colorectal cancer. AB - Immune checkpoint blockade therapy (ICBT) has resulted in extended overall survival for some patients with certain types of cancer, most prominently including colorectal cancer (CRC) associated with microsatellite instability (MSI). However, most patients with CRC whose phenotypes have microsatellite stability (MSS) are unresponsive to ICBT. In efforts to understand the responsiveness of CRC tumors to ICBT, genotypic and phenotypic signatures of CRC tumors are now being investigated. The MSI and MSS classification has been clinically validated as helpful in predicting response vs nonresponse to ICBT in patients with CRC. Other potential predictive markers include mutational and neoantigen loads, T-cell receptor diversity, and the immune score system, all of which have mechanistic connections to ICBT response. These novel predictive signatures could provide unprecedented insights into patients with CRC associated with MSS. Clinical trials or prospective cohort studies using standardized methodologies for biomarker quantification should be illuminating. Further validation of these novel predictive signatures will be essential to tailoring treatment of patients whose CRC is most likely to respond to ICBT. PMID- 29518354 TI - Augmenting the SMN Protein to Treat Infantile Spinal Muscular Atrophy. AB - Spinal muscular atrophy (SMA) is a common and oft-fatal pediatric neuromuscular disorder caused by insufficient SMN protein. Now, two clinical trials (Mendell et al., 2017; Finkel et al., 2017) demonstrate that restoring the protein is therapeutic, offering new treatment options and renewed hope to SMA patients. PMID- 29518353 TI - Nanoparticle-Fusion Protein Complexes Protect against Mycobacterium tuberculosis Infection. AB - Tuberculosis (TB) is the leading cause of death from infectious disease, and the current vaccine, Bacillus Calmette-Guerin (BCG), is inadequate. Nanoparticles (NPs) are an emerging vaccine technology, with recent successes in oncology and infectious diseases. NPs have been exploited as antigen delivery systems and also for their adjuvantic properties. However, the mechanisms underlying their immunological activity remain obscure. Here, we developed a novel mucosal TB vaccine (Nano-FP1) based upon yellow carnauba wax NPs (YC-NPs), coated with a fusion protein consisting of three Mycobacterium tuberculosis (Mtb) antigens: Acr, Ag85B, and HBHA. Mucosal immunization of BCG-primed mice with Nano-FP1 significantly enhanced protection in animals challenged with low-dose, aerosolized Mtb. Bacterial control by Nano-FP1 was associated with dramatically enhanced cellular immunity compared to BCG, including superior CD4+ and CD8+ T cell proliferation, tissue-resident memory T cell (Trm) seeding in the lungs, and cytokine polyfunctionality. Alongside these effects, we also observed potent humoral responses, such as the generation of Ag85B-specific serum IgG and respiratory IgA. Finally, we found that YC-NPs were able to activate antigen presenting cells via an unconventional IRF-3-associated activation signature, without the production of potentially harmful inflammatory mediators, providing a mechanistic framework for vaccine efficacy and future development. PMID- 29518355 TI - A Systems Neuroscience Approach to Migraine. AB - Migraine is an extremely common but poorly understood nervous system disorder. We conceptualize migraine as a disorder of sensory network gain and plasticity, and we propose that this framing makes it amenable to the tools of current systems neuroscience. PMID- 29518356 TI - TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function. AB - Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to beta-amyloid (Abeta) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Abeta binding. TREM2 deficiency impairs Abeta degradation in primary microglial culture and mouse brain. Abeta-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Abeta, regulating downstream phosphorylation of SYK and GSK3beta. Our data demonstrate TREM2 as a microglial Abeta receptor transducing physiological and AD-related pathological effects associated with Abeta. PMID- 29518357 TI - Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models. AB - Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models. PMID- 29518360 TI - TREM2 and Amyloid Beta: A Love-Hate Relationship. AB - Mutations in TREM2 increase risk for late-onset AD. In this issue of Neuron, Zhao et al. (2018) show that TREM2 binds Abeta to enhance its clearance and Lee et al. (2018) demonstrate that human TREM2 expression in AD mice ameliorates Abeta associated deficits. PMID- 29518358 TI - Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2 Dependent WAVE Complex Function. AB - The axons of retinal ganglion cells (RGCs) are topographically sorted before they arrive at the optic tectum. This pre-target sorting, typical of axon tracts throughout the brain, is poorly understood. Here, we show that cytoplasmic FMR1 interacting proteins (CYFIPs) fulfill non-redundant functions in RGCs, with CYFIP1 mediating axon growth and CYFIP2 specifically involved in axon sorting. We find that CYFIP2 mediates homotypic and heterotypic contact-triggered fasciculation and repulsion responses between dorsal and ventral axons. CYFIP2 associates with transporting ribonucleoprotein particles in axons and regulates translation. Axon-axon contact stimulates CYFIP2 to move into growth cones where it joins the actin nucleating WAVE regulatory complex (WRC) in the periphery and regulates actin remodeling and filopodial dynamics. CYFIP2's function in axon sorting is mediated by its binding to the WRC but not its translational regulation. Together, these findings uncover CYFIP2 as a key regulatory link between axon-axon interactions, filopodial dynamics, and optic tract sorting. PMID- 29518361 TI - Open Up to Make New Contacts: Caldendrin Senses Postsynaptic Calcium Influx to Dynamically Organize Dendritic Spines. AB - In this issue of Neuron, Mikhaylova et al. (2018) report how the Ca2+ sensor caldendrin interacts in dendritic spines with cortactin to control actin remodeling. Combining molecular and functional approaches, this work gains insights into postsynaptic dynamics relevant for synaptic plasticity. PMID- 29518359 TI - Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits. AB - The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer's disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans. PMID- 29518362 TI - The Drosophila Carbon Dioxide Receptor as Key Regulator of Odor Valence. AB - In this issue of Neuron, MacWilliam et al. (2018) show that the insect carbon dioxide receptor can also detect odorants from different chemical classes, the valence of which is determined by whether they excite or inhibit the sensory neuron. PMID- 29518363 TI - Shaping Reality through Mental Rehearsal. AB - Previous research has shown that mental rehearsal can improve performance. A new study by Vyas et al. (2018) reveals that direct modulation of neural dynamics using a brain-computer interface can also modify physical movements. The study further demonstrates that "mental practice" and physical movements share a common neural subspace. PMID- 29518365 TI - RACK1 upregulation induces neuroprotection by activating the IRE1-XBP1 signaling pathway following traumatic brain injury in rats. AB - Receptor for activated protein kinase C 1 (RACK1) is a multifaceted scaffolding protein known to be involved in the regulation of signaling events required for neuronal protection. In the present study, we investigated the role of RACK1 in secondary brain injury in a rat traumatic brain injury (TBI) model. A weight-drop TBI model was established in Sprague Dawley rats, and RACK1 in vivo knockdown and overexpression were performed 24 h before TBI insult. The IRE1 inhibitor 3,5 dibromosalicylaldehyde (DBSA) was administered by intracerebroventricular injection 1 h after TBI insult. Real-time PCR, Western blotting, immunofluorescence, neuronal apoptosis, brain water content, and neurological scores were evaluated. Our results revealed that TBI induced increased expression of endogenous RACK1, phosphorylated inositol-requiring enzyme 1 (p-IRE1), X-box binding protein-1 (XBP1) and glucose-regulated protein 78 (GRP78) in neurons. RACK1 overexpression significantly ameliorated neuronal apoptosis, blood-brain barrier disruption, brain edema and neurological deficits at 48 h after TBI, which was concomitant with upregulation of p-IRE1, XBP1 and GRP78 expression, while its knockdown induced the opposite effects. Furthermore, DBSA administration reversed the protective effects of RACK1 overexpression against brain injury and decreased the expression of p-IRE1, XBP1 and GRP78. In summary, the upregulation of RACK1 following brain contusion exerted neuroprotective effects against secondary brain injury, which were probably mediated by activation of the IRE1-XBP1 pathway. PMID- 29518364 TI - Subacute intranasal administration of tissue plasminogen activator improves stroke recovery by inducing axonal remodeling in mice. AB - In addition to thrombolysis, tissue plasminogen activator (tPA) can evoke neurorestorative processes. We therefore investigated the therapeutic effect of subacute intranasal administration of tPA post stroke on neurological recovery and on corticospinal innervation in mice. A transgenic mouse line, in which the pyramidal neurons and corticospinal tract (CST) axons are specifically labeled by yellow fluorescent protein (YFP) was employed. Adult CST-YFP mice were subjected to right unilateral middle cerebral artery occlusion (MCAo), and were randomly divided into groups treated with saline or tPA intranasally in the subacute phase. Pseudorabies virus (PRV)-614-monomeric red fluorescent protein (RFP) was injected into the left forelimb. The cervical spinal cord and brain were processed for fluorescent microscopy to detect YFP and RFP labeling. Primary embryonic neurons were cultured with tPA at different concentrations. Neurite length and branch numbers were then measured. In vivo, subacute tPA treatment significantly enhanced functional recovery (p < 0.05), and increased CST density in the denervated gray matter, and in the numbers of PRV-labeled neurons in bilateral cortices. The behavioral performance was significantly correlated with axonal density in the denervated spinal cord. In vitro, both neurite length and branch numbers significantly increased with concentration of tPA (p < 0.05). Our results demonstrate that tPA dose-dependently increases neurite outgrowth and branching of cultured cortical neurons. Subacute intranasal administration of tPA may provide enhance neurological recovery after stroke by promoting CST axonal remodeling. PMID- 29518366 TI - A Binge and a Breach: Cardiac Tamponade Caused by Haemophilus influenzae. PMID- 29518367 TI - A Worm Hole: Liver Abscess in Ascariasis. PMID- 29518368 TI - Importance of Genetic Testing in the Diagnosis of Transthyretin Cardiac Amyloidosis. PMID- 29518369 TI - Clinical Features and Prognosis of Type 2 Myocardial Infarction in Acutely Decompensated Diabetic Patients. AB - BACKGROUND: After the introduction of the universal definition of myocardial infarction, the incidence and diagnosis of type 2 myocardial infarction have risen dramatically, yet there are no clear guidelines on clinical management. Diabetic patients are at high risk for developing type 2 myocardial infarction when admitted in a decompensated state, and they are also at high risk for future cardiovascular events. METHODS: We performed a retrospective analysis of 1058 patients admitted with diabetic ketoacidosis or hyperosmolar hyperglycemic state between 2011 and 2016. Patients were included if they had cardiac troponin I measured within 24 hours of admission, were older than 18 years of age, and had no evidence of acute coronary syndrome on admission. Baseline characteristics, admission laboratory test results, major adverse cardiovascular events, cardiac stress testing, and coronary angiography data up to 1 year after admission were reviewed. Patients were categorized into 2 groups: those with and those without type 2 myocardial infarction. The study had 2 endpoints: mortality and major adverse cardiac events (MACE) at 1 year and an abnormal result on stress test or coronary angiography at 1 year. RESULTS: Of the 845 patients who met the inclusion criteria, 133 patients (15%) had type 2 myocardial infarction on admission. Patients with type 2 myocardial infarction were at a significantly higher risk for mortality and MACE at 1 year than those without. Patients with type 2 myocardial infarction were also at higher risk for developing an abnormal result on stress test or coronary angiography within 1 year of admission as compared with those without type 2 myocardial infarction (40% vs 24%; odds ratio 2; P = .0699). CONCLUSION: Acutely decompensated diabetic patients with type 2 myocardial infarction are at increased risk for death and MACE. These patients may also be at risk for undiagnosed coronary artery disease. PMID- 29518371 TI - Non-thermal atmospheric pressure plasma-induced IL-8 expression is regulated via intracellular K+ loss and subsequent ERK activation in human keratinocyte HaCaT cells. AB - Non-thermal atmospheric pressure plasma (NTAPP) has recently emerged as a novel medical therapy for skin wounds. Interleukin-8 (IL-8) is thought to play a critical role in wound healing. NTAPP irradiation has been reported to promote production of IL-8; however, the mechanism is not fully understood. The aim of this study was to elucidate the underlying mechanism of NTAPP-induced IL-8 expression in human keratinocyte HaCaT cells. NTAPP irradiation of HaCaT cells increased IL-8 mRNA expression in an irradiation time-dependent manner. Although hydrogen peroxide (H2O2) was generated in culture medium irradiated with NTAPP, treatment of HaCaT cells with H2O2 itself failed to induce the expression. In addition, we found that NTAPP irradiation of HaCaT cells decreased intracellular K+ levels. High intracellular K+ concentrations suppressed NTAPP-induced IL-8 mRNA expression, and the K+ ionophore valinomycin (Val) enhanced the induction of IL-8 mRNA. Moreover, NTAPP stimulated activation of ERK MAP kinase and the ERK inhibitor prevented NTAPP-induced IL-8 mRNA expression. NTAPP-induced ERK activation was inhibited in the presence of high concentrations of extracellular K+ and enhanced in the presence of Val. Taken together, these findings suggest that NTAPP irradiation stimulates intracellular K+ loss and subsequent ERK activation, leading to the induction of IL-8 expression. PMID- 29518370 TI - Visceral and Intrahepatic Fat Are Associated with Cardiometabolic Risk Factors Above Other Ectopic Fat Depots: The Framingham Heart Study. AB - BACKGROUND: We examined the associations among 8 different fat depots accumulated in various anatomic regions and the relationship between these fat depots and multiple cardiometabolic risk factors. METHODS: Participants were from the Framingham Heart Study Offspring and Third Generation who also participated in the multidetector computed tomography substudy in 2002-2005. Exposures were multidetector computed tomography-derived fat depots, including abdominal subcutaneous adipose tissue, abdominal visceral adipose tissue, intramuscular fat, intrathoracic fat, pericardial fat, thoracic periaortic fat, intrahepatic fat, and renal sinus fat. Multivariable-adjusted regression analyses with a forward selection procedure were performed to identify the most predictive fat depots. RESULTS: Of 2529 participants, 51.9% were women (mean age, 51.1 years). Visceral adipose tissue had the strongest correlations with each of the other fat measures (range, 0.26-0.77) and with various cardiometabolic risk factors (range, -0.34 to 0.39). As determined by the selection models, visceral adipose tissue was the only fat depot that was associated with all cardiometabolic risk factors evaluated in this study (all P<.05). Selection models also showed that subcutaneous adipose tissue and intrahepatic fat were associated with cardiometabolic risk factors related to the traits of dysglycemia, dyslipidemia, and hypertension (all P<.05). However, only associations with visceral adipose tissue and intrahepatic fat persisted after further adjustment for body mass index and waist circumference. CONCLUSIONS: Visceral adipose tissue and intrahepatic fat were consistent correlates of cardiometabolic risk factors, above and beyond standard anthropometric indices. Our data provide important insights for understanding the associations between variations in fat distribution and cardiometabolic abnormalities. PMID- 29518372 TI - Impact of polyphenols on extracellular vesicle levels and effects and their properties as tools for drug delivery for nutrition and health. AB - Polyphenols are found in plant-derived foods and beverages and display numerous protective effects against cancers, cardiovascular, metabolic and neurodegenerative diseases. Extracellular vesicles (EVs), microparticles, exosomes, and apoptotic bodies, originated by different cell types are emerging as a novel mean of cell-to-cell communication in physiology and pathology and represent a new way to convey fundamental information between cells. Polyphenols can act on signaling pathways that interfere with the biogenesis of EVs. Thus, they are able to control EV release from cells and their content and therefore their functional properties. Both EVs and polyphenols are therapeutic tools that can be used against several diseases. In this context, the combination of both tools can increase their therapeutic potential. Three types of strategies can be used: (i) plants are able to produce EVs that encapsulate natural components from vegetables, polyphenols for instance, (ii) mammalian cells can be treated with polyphenols and the subsequent EVs produced are enriched in these components, and (iii) EVs from mammalian cells can be uploaded with polyphenols. We review the novel aspects of the interplay between polyphenols and EVs that could trigger and improve the health benefits in cancer, cardiovascular, metabolic and neurodegenerative diseases. PMID- 29518373 TI - Ovarian tissue cryopreservation by stepped vitrification and monitored by X-ray computed tomography. AB - Ovarian tissue cryopreservation is, in most cases, the only fertility preservation option available for female patients soon to undergo gonadotoxic treatment. To date, cryopreservation of ovarian tissue has been carried out by both traditional slow freezing method and vitrification, but even with the best techniques, there is still a considerable loss of follicle viability. In this report, we investigated a stepped cryopreservation procedure which combines features of slow cooling and vitrification (hereafter called stepped vitrification). Bovine ovarian tissue was used as a tissue model. Stepwise increments of the Me2SO concentration coupled with stepwise drops-in temperature in a device specifically designed for this purpose and X-ray computed tomography were combined to investigate loading times at each step, by monitoring the attenuation of the radiation proportional to Me2SO permeation. Viability analysis was performed in warmed tissues by immunohistochemistry. Although further viability tests should be conducted after transplantation, preliminary results are very promising. Four protocols were explored. Two of them showed a poor permeation of the vitrification solution (P1 and P2). The other two (P3 and P4), with higher permeation, were studied in deeper detail. Out of these two protocols, P4, with a longer permeation time at -40 degrees C, showed the same histological integrity after warming as fresh controls. PMID- 29518374 TI - IAPP in type II diabetes: Basic research on structure, molecular interactions, and disease mechanisms suggests potential intervention strategies. AB - Islet amyloid polypeptide (a.k.a. IAPP, amylin) is a 37 amino acid hormone that has long been associated with the progression of type II diabetes mellitus (TIIDM) disease. The endocrine peptide hormone aggregatively misfolds to form amyloid deposits in and around the pancreatic islet beta-cells that synthesize both insulin and IAPP, leading to a decrease in beta-cell mass in patients with the disease. Extracellular IAPP amyloids induce beta-cell death through the formation of reactive oxygen species, mitochondrial dysfunction, chromatin condensation, and apoptotic mechanisms, although the precise roles of IAPP in TIIDM are yet to be established. Here we review aspects of the normal physiological function of IAPP in glucose regulation together with insulin, and its misfolding which contributes to TIIDM, and may also play roles in other pathologies such as Alzheimer's and heart disease. We summarize information on expression of the IAPP gene, the regulation of the hormone by post-translational modifications, the structural properties of the peptide in various states, the kinetics of misfolding to amyloid fibrils, and the interactions of the peptide with insulin, membranes, glycosaminoglycans, and nanoparticles. Finally, we describe how basic research is starting to have a positive impact on the development of approaches to circumvent IAPP amyloidogenesis. These include therapeutic strategies aimed at stabilizing non-amyloidogenic states, inhibition of amyloid growth or disruption of amyloid fibrils, antibodies directed towards amyloid structures, and inhibition of interactions with cofactors that facilitate aggregation or stabilize amyloids. PMID- 29518375 TI - Interdisciplinary Approaches to Facilitate Return to Driving and Return to Work in Mild Stroke: A Position Paper. AB - Adults with mild stroke face substantial challenges resuming valued roles in the community. The term "mild" provides false representation of the lived experience for many adults with mild stroke who may continue to experience persistent challenges and unmet needs. Rehabilitation practitioners can identify and consequently intervene to facilitate improved independence, participation, and quality of life by facilitating function and reducing the burden of lost abilities among adults with mild stroke. The Health and Wellness Task Force identified 2 important, and often interdependent, goals that frequently arise among adults living with mild stroke that must be addressed to facilitate improved community reintegration: (1) return to driving and (2) return to work. Adults with mild stroke may not be receiving adequate rehabilitative services to facilitate community reintegration for several reasons but primarily because current practice models are not designed to meet such needs of this specific population. Thus, the Health and Wellness Task Force convened to review current literature and practice trends to (1) identify opportunities based on the evidence of assessment and interventions, for return to driving and return to work; and (2) identify gaps in the literature that must be addressed to take advantage of the opportunities. Based on findings, the task force proposes a new interdisciplinary practice model for adults with mild stroke who are too often discharged from the hospital to the community without needed services to enable successful return to driving and work. PMID- 29518377 TI - Trynity models a tube valve in the Drosophila larval airway system. AB - Terminal differentiation of an organ is the last step in development that enables the organism to survive in the outside world after birth. Terminal differentiation of the insect tracheae that ends with filling the tubular network with gas is not fully understood at the tissue level. Here, we demonstrate that yet unidentified valves at the end of the tracheal system of the fruit fly Drosophila melanogaster embryo are important elements allowing terminal differentiation of this organ. Formation of these valves depends on the function of the zona pellucida protein Trynity (Tyn). The tracheae of tyn mutant embryos that lack these structures do not fill with gas. Additionally, external material penetrates into the tracheal tubes indicating that the tyn spiracles are permanently open. We conclude that the tracheal endings have to be closed to ensure gas-filling. We speculate that according to physical models closing of the tubular tracheal network provokes initial increase of the internal hydrostatic pressure necessary for gas generation through cavitation when the pressure is subsequently decreased. PMID- 29518378 TI - The crux of Cux genes in neuronal function and plasticity. AB - Cux1 and Cux2 are the vertebrate members of a family of homeodomain transcription factors (TF) containing Cut repeat DNA-binding sequences. Perturbation of their expression has been implicated in a wide variety of diseases and disorders, ranging from cancer to autism spectrum disorder (ASD). Within the nervous system, both genes are expressed during neurogenesis and in specific neuronal subpopulations. Their role during development and circuit specification is discussed here, with a particular focus on the cortex where their restricted expression in pyramidal neurons of the upper layers appears to be responsible for many of the specialized functions of these cells, and where their functions have been extensively investigated. Finally, we discuss how Cux TF represent a promising avenue for manipulating neuronal function and for reprogramming. PMID- 29518376 TI - C8orf46 homolog encodes a novel protein Vexin that is required for neurogenesis in Xenopus laevis. AB - Neural basic helix-loop helix (bHLH) transcription factors promote progenitor cell differentiation by activation of downstream target genes that coordinate neuronal differentiation. Here we characterize a neural bHLH target gene in Xenopus laevis, vexin (vxn; previously sbt1), that is homologous to human c8orf46 and is conserved across vertebrate species. C8orf46 has been implicated in cancer progression, but its function is unknown. Vxn is transiently expressed in differentiating progenitors in the developing central nervous system (CNS), and is required for neurogenesis in the neural plate and retina. Its function is conserved, since overexpression of either Xenopus or mouse vxn expands primary neurogenesis and promotes early retinal cell differentiation in cooperation with neural bHLH factors. Vxn protein is localized to the cell membrane and the nucleus, but functions in the nucleus to promote neural differentiation. Vxn inhibits cell proliferation, and works with the cyclin-dependent kinase inhibitor p27Xic1 (cdkn1b) to enhance neurogenesis and increase levels of the proneural protein Neurog2. We propose that vxn provides a key link between neural bHLH activity and execution of the neurogenic program. PMID- 29518379 TI - Cavitary Lung Diseases: A Clinical-Radiologic Algorithmic Approach. AB - Cavities occasionally are encountered on thoracic images. Their differential diagnosis is large and includes, among others, various infections, autoimmune conditions, and primary and metastatic malignancies. We offer an algorithmic approach to their evaluation by initially excluding mimics of cavities and then broadly classifying them according to the duration of clinical symptoms and radiographic abnormalities. An acute or subacute process (< 12 weeks) suggests common bacterial and uncommon nocardial and fungal causes of pulmonary abscesses, necrotizing pneumonias, and septic emboli. A chronic process (>= 12 weeks) suggests mycobacterial, fungal, viral, or parasitic infections; malignancy (primary lung cancer or metastases); or autoimmune disorders (rheumatoid arthritis and granulomatosis with polyangiitis). Although a number of radiographic features can suggest a diagnosis, their lack of specificity requires that imaging findings be combined with the clinical context to make a confident diagnosis. PMID- 29518380 TI - Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: A possible explanation as to why the clinical trials of antioxidants might have failed. AB - Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation. Probucol did not effectively inhibit the oxidation of LDL at lysosomal pH, as measured by conjugated dienes or oxidised cholesteryl esters or tryptophan residues in isolated LDL or by ceroid formation in the lysosomes of macrophage-like cells, in marked contrast to its highly effective inhibition of LDL oxidation at pH 7.4. LDL oxidation at lysosomal pH was inhibited very effectively for long periods by N,N'-diphenyl-1,4-phenylenediamine, which is more hydrophobic than probucol and has been shown by others to inhibit atherosclerosis in rabbits, and by cysteamine, which is a hydrophilic antioxidant that accumulates in lysosomes. Iron-induced LDL oxidation might be due to the formation of the superoxide radical, which protonates at lysosomal pH to form the much more reactive, hydrophobic hydroperoxyl radical, which can enter LDL and reach its core. Probucol resides mainly in the surface monolayer of LDL and would not effectively scavenge hydroperoxyl radicals in the core of LDL. This might explain why probucol failed to protect against atherosclerosis in various clinical trials. The oxidised LDL hypothesis of atherosclerosis now needs to be re-evaluated using different and more effective antioxidants that protect against the lysosomal oxidation of LDL. PMID- 29518381 TI - Levels of MMP-9 in patients with intracranial aneurysm: Relation with risk factors, size and clinical presentation. AB - BACKGROUND: Intracranial aneurysms are arterial anomalies affecting 2% to 3% of the general population in the world and these ruptures are associated with a high mortality. Some risk factors, such as age, gender, smoking, alcohol, hypertension and familial history are associated with the number of aneurysms and their size. In addition, inflammatory processes within the blood vessels of the brain can activate matrix metalloproteinase-9 (MMP-9), which degrades various components of the extracellular matrix, such as elastin. Thereby, this work has aimed at evaluating the relationship between plasma MMP-9 levels and the risk factors that are associated with intracranial aneurysm, as well as investigating the aneurysm statuses (ruptured and unruptured) and comparing them with the control volunteers. METHODS: Between August 2014 to June 2016, blood samples were collected from 282 patients (204 ruptured and 78 unruptured saccular intracranial aneurysms) and 286 control volunteers. The MMP-9 plasma levels were measured by ELISA. Statistical analyzes were performed with SPSS software when using parametric or nonparametric tests, after the normality tests. RESULTS: Higher levels of MMP-9 were found in the aneurysm groups as a whole and when they were stratified by rupture status, then compared with the control group (p < 0.0001). When stratifying them by diameter, those smaller than 7 mm presented high levels of MMP-9 (p < 0.0001), especially in the ruptured ones. As for risk factors, hypertension and smoking were the most important. However, hypertension was mostly associated with the ruptured aneurysms (p < 0.0001). CONCLUSIONS: High levels of MMP-9 were found in smaller ruptured and unruptured intracranial aneurysms (<7 mm) with strongest statistical associations than other sizes, especially when associated with smoking and hypertension. PMID- 29518382 TI - Development and evaluation of a rapid point-of-care test for detecting the hepatitis E virus antigen. AB - BACKGROUND: Hepatitis E virus (HEV)-caused acute viral hepatitis is a major threat to public health worldwide. Recently, an enzyme linked immunosorbent assay (ELISA) kit detecting the HEV antigen was reported to have good concordance with the HEV RNA load and showed good clinical performance. But the ELISA kits can barely satisfy the needs of community clinics. In this study, a fluorescent microbead-based immunoassay (FMIA) for detecting the HEV antigen was developed and evaluated. METHODS: A mouse anti-HEV monoclonal antibody (mAb) conjugated with fluorescent microbeads was used as capturing antibody and another mouse mAb was used as detection antibody. Overall, 150 serum samples were collected from HEV-infected patients (n = 50) and non-HEV cases (n = 100) to evaluate the performance of the FMIA. RESULTS: The FMIA results showed a strong linear correlation with the viral RNA load. The diagnostic sensitivity and specificity of the HEV antigen FMIA were 92.0% (46/50) and 100.0% (100/100), respectively, and the test was consistent (kappa = 0.937, p = 0.627) with the commercial HEV antigen ELISA. The FMIA also showed good consistency with the PCR results (kappa = 0.939, p = 0.134). CONCLUSIONS: As a rapid point-of-care (POC) test, a FMIA that is developed with acceptable performance is suitable for acute hepatitis E diagnosis, especially in developing countries and regions, because of its reduced time and simplified operation. PMID- 29518383 TI - Autoverification process improvement by Six Sigma approach: Clinical chemistry & immunoassay. AB - OBJECTIVE: This study examines effectiveness of a project to enhance an autoverification (AV) system through application of Six Sigma (DMAIC) process improvement strategies. DESIGN AND METHODS: Similar AV systems set up at three sites underwent examination and modification to produce improved systems while monitoring proportions of samples autoverified, the time required for manual review and verification, sample processing time, and examining characteristics of tests not autoverified. This information was used to identify areas for improvement and monitor the impact of changes. RESULTS: Use of reference range based criteria had the greatest impact on the proportion of tests autoverified. To improve AV process, reference range based criteria was replaced with extreme value limits based on a 99.5% test result interval, delta check criteria were broadened, and new specimen consistency rules were implemented. Decision guidance tools were also developed to assist staff using the AV system. The mean proportion of tests and samples autoverified improved from <62% for samples and <80% for tests, to >90% for samples and >95% for tests across all three sites. The new AV system significantly decreased turn-around time and total sample review time (to about a third), however, time spent for manual review of held samples almost tripled. There was no evidence of compromise to the quality of testing process and <1% of samples held for exceeding delta check or extreme limits required corrective action. CONCLUSIONS: The Six Sigma (DMAIC) process improvement methodology was successfully applied to AV systems resulting in an increase in overall test and sample AV by >90%, improved turn-around time, reduced time for manual verification, and with no obvious compromise to quality or error detection. PMID- 29518384 TI - Pulmonary Metastasectomy for Colorectal Cancer: Predictors of Survival in Routine Surgical Practice. AB - BACKGROUND: Resection of lung metastases is considered standard treatment for patients with metastatic colorectal cancer. We describe surgical management, prognostic factors, and outcomes in routine clinical practice. METHODS: All cases of colorectal cancer lung metastases in Ontario, Canada, resected during 2002 to 2009 were identified using the Ontario Cancer Registry and linked electronic records. Pathology reports were reviewed to identify extent of disease. RESULTS: The study population included 420 patients (60% male). Median age was 64 years. A solitary metastasis was present in 61% (256 of 420). Mean size of the largest metastasis was 2.4 cm. Lymph nodes were resected in 63% (263 of 420) of patients. The 5-year cancer-specific survival (CSS) and overall survival (OS) was 42% (95% confidence interval [CI], 37% to 47%) and 40% (95% CI, 35% to 45%), respectively. On adjusted analyses, greater number (p < 0.001) and size (p = 0.001) of lesions and lymph node involvement (p < 0.001) were associated with inferior CSS and OS. Lymph node positivity was strongly associated with survival (adjusted CSS hazard ratio, 2.19 [95% CI, 1.48 to 3.25]; adjusted OS hazard ratio, 2.08 [95% CI, 1.41 to 3.07]). Unadjusted 5-year CSS/OS was 49%/47% for node-negative disease and 19%/19% for node-positive disease. The negative prognostic effect of size (>2 cm) and number (>1) of lesions was additive: 5-year CSS/OS ranged from 57%/55% (single lesion <2 cm) to 24%/20% (multiple lesions, largest lesion>2 cm). CONCLUSIONS: Long-term survival of patients with resected colorectal cancer lung metastases in routine practice is comparable to outcomes reported in institutional case series. Lymph node positivity is strongly associated with reduced survival. Combining size and number of metastatic lesions in advance of the operation may facilitate treatment decision making. PMID- 29518385 TI - Cardiac Autonomic Nervous System Activity and Cardiac Function in Children After Coarctation Repair. AB - BACKGROUND: Coarctation of the aorta (CoA) is one of the most common congenital heart defects. Most patients live into adulthood as a result of improved surgical techniques; however, late complications, including hypertension, recoarctation, and arrhythmias, are common. The autonomic nervous system (ANS) might play a role in the pathology. This study evaluated cardiac ANS activity and cardiac function in children after CoA repair and investigated the relationship between the two. METHODS: The study participants were 31 children after CoA repair and 62 healthy controls aged between 8 and 18 years. Ambulatory impedance cardiography was used to measure cardiac ANS activity and cardiac output for 24 hours. Transthoracic echocardiography and cardiac magnetic resonance imaging were used to measure cardiac function. RESULTS: No group differences were found in ambulatory cardiac ANS activity. However, ambulatory cardiac output and left ventricular function were significantly decreased in patients compared with controls. CONCLUSIONS: Left ventricular function and ambulatory cardiac output are impaired in patients after CoA repair, despite unchanged cardiac ANS activity in this group. These results underscore the importance of clinical follow-up, even in patients without residual stenosis. PMID- 29518386 TI - The Society of Thoracic Surgeons General Thoracic Surgery Database 2018 Update on Outcomes and Quality. AB - For nearly 15 years The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD) has provided participating institutions with risk-adjusted feedback reports that allow outcome comparisons relative to national benchmarks. With more than 300 contributing centers across North America, the STS GTSD now includes more than 530,000 cases. In 2017 the STS GTSD Task Force revised the data collection form with the goal of collecting more detailed and accurate information for the most important thoracic surgical cases without increasing the workload of registrars. In addition, the learning curve for thoracoscopic lobectomy was examined, online public reporting was initiated, institutional feedback reports were made more user-friendly, and collaboration with the European Society of Thoracic Surgery continued. The STS GTSD Task Force continues to work to improve the quality of care and support research initiatives in general thoracic surgery. This report summarizes current aggregate national outcomes in general thoracic surgery and reviews related activities in the areas of quality measurement, performance improvement, and transparency from the STS GTSD during the past 12 months. PMID- 29518387 TI - Quadricuspid Aortic Valve With Sinus of Valsalva Aneurysm. PMID- 29518388 TI - Near-Infrared Lymphatic Mapping of the Recurrent Laryngeal Nerve Nodes in T1 Esophageal Cancer. AB - BACKGROUND: It is still unclear that dissection of recurrent laryngeal nerve nodes is mandatory in patients with cT1 middle or lower thoracic esophageal squamous cell carcinoma when the nodes are negative in preoperative staging workup. We aimed to evaluate the feasibility of near-infrared image-guided lymphatic mapping of bilateral recurrent laryngeal nerve nodes. METHODS: The day before operation, we injected indocyanine green (ICG) into the submucosal layer by endoscopy. At the time of upper mediastinal dissection, ICG-stained basins were identified along the bilateral recurrent laryngeal nerves and retrieved under guidance of the Firefly system. After the operation, remnant ICG-unstained basins were dissected from the specimen to assess the presence of metastasis. RESULTS: Of 29 patients enrolled, ICG-stained basins could be identified in 25 patients (86.2%), and 6 of them (24.0%) had nodal metastasis; 4 in the right recurrent laryngeal nerve chain, 1 in the left recurrent laryngeal nerve chain, and 1 in both recurrent laryngeal nerve chains. On pathologic examination of 345 recurrent laryngeal nerve nodes, two metastatic nodes were identified in ICG unstained basins along the left recurrent laryngeal nerve in a patient who had lymph node metastases in ICG-stained basins along both recurrent laryngeal nerves. Negative predictive value in detection of nodal metastasis was 100% for the right recurrent laryngeal nerve chain and 98.2% for the left recurrent laryngeal nerve chain. CONCLUSIONS: Real-time assessment of recurrent laryngeal nerve nodes with near-infrared image was technically feasible, and we could detect lymphatic basins that most likely have nodal metastasis. Our technique might be useful in determining the optimal extent of lymphadenectomy. PMID- 29518389 TI - Smurf1 restricts the antiviral function mediated by USP25 through promoting its ubiquitination and degradation. AB - Protein ubiquitination and deubiquitination enzymes are widely involved in innate immune responses. The ubiquitin specific protease 25 (USP25), a deubiquitinating enzyme, has been demonstrated to play an important role in virus infection and immunity. However, how USP25 is degraded and regulated by E3 ubiquitin ligases remains poorly understood. Here, we identified Smad ubiquitin regulatory factor 1(Smurf1) as a first novel E3 ubiquitin ligase of USP25. Smurf1 overexpression decreases USP25 protein turnover, and the E3 ligase enzymatic activity of Smurf1 is required for USP25 degradation. Additionally, Smurf1-mediated degradation of USP25 is via promoting the K48-linkage polyubiquitination of USP25 in an ubiquitin proteasome dependent pathway. Importantly, USP25 overexpression restricts vesicular stomatitis virus (VSV) replication and the restriction of VSV replication by USP25 is enhanced in Smurf1 stable knock down cells. Therefore, our study firstly identified that Smurf1 negatively regulated the antiviral function mediated by USP25. Our findings revealed a previously unrecognized role of Smurf1 acting on USP25 and also their roles in the regulation of VSV replications. PMID- 29518390 TI - Folate-modified PLGA nanoparticles for tumor-targeted delivery of pheophorbide a in vivo. AB - Targeted drug delivery has been an important issue for tumor therapy including photodynamic therapy (PDT). The purpose of our study is to increase the targeting efficiency of photosensitizer (PS) using folate-modified nanoparticles (NPs) to tumor site in vivo. Folate receptor is over-expressed on the surface of many human cancer cells. We prepared poly (lactic-co-glycolic acid) (PLGA) NPs containing pheophorbide a (Pba), a PS that is used in PDT and generates free radical for killing cancer cells. The surface of NPs was composed of phospholipids modified with polyethylene glycol (PEG) and folate (FA). The size of the resulting FA-PLGA-Pba NPs was about 200 nm in PBS at pH 7.4 and they were stable for long time. They showed faster cellular uptake to MKN28 human gastric cancer cell line than control PLGA-Pba NPs by high-affinity binding with folate receptors on cell surface. In MTT assay, FA-PLGA-Pba NPs also showed enhanced tumor cell killing compared to control PLGA-Pba NPs. In vivo and ex vivo imaging showed high accumulation of FA-PLGA-Pba NPs in tumor site during 24 h after intravenous injection to MKN28 tumor-bearing mice model. These results demonstrate that our FA-PLGA-Pba NPs are useful for tumor-targeted delivery of PS for cancer treatment by PDT. PMID- 29518391 TI - Regulation of keratin 5/14 intermediate filaments by CDK1, Aurora-B, and Rho kinase. AB - We previously reported that vimentin, GFAP, and desmin (type III intermediate filament [IF] proteins) are mitotically phosphorylated by CDK1, Aurora-B, and Rho kinase. This phosphorylation is critical for efficient separation of these IFs and completion of cytokinesis. Keratin 5 (K5) and K14 form a heterodimer, which constitutes IF network in basal layer cells of stratified squamous epithelia. Here, we report that the solubility of K5/K14 increased in mitosis. The in vitro assays revealed that three mitotic kinases phosphorylate K5 more than K14. We then identified Thr23/Thr144, Ser30, and Thr159 on murine K5 as major phosphorylation sites for CDK1, Aurora-B, and Rho-kinase, respectively. Using site- and phosphorylation-state-specific antibodies, we demonstrated that K5 Thr23 was phosphorylated in entire cytoplasm from prometaphase to metaphase, whereas K5-Ser30 phosphorylation occurred specifically at the cleavage furrow from anaphase to telophase. Efficient K5/K14-IF separation was impaired by K5 mutations at the sites phosphorylated by these mitotic kinases. K5-Thr23 phosphorylation was widely detected in dividing K5-positive cells of murine individuals. These results suggested that mitotic reorganization of K5/K14-IF network is governed largely through K5 phosphorylation by CDK1, Aurora-B, and Rho kinase. PMID- 29518392 TI - Identification of human Phosphatidyl Inositol 5-Phosphate 4-Kinase as an RNA binding protein that is imported into Plasmodium falciparum. AB - Plasmodium falciparum is a causative agent for malaria and has a complex life cycle in human and mosquito hosts. Translation repression of specific set of mRNA has been reported in gametocyte stages of this parasite. A conserved element present in the 3'UTR of some of these transcripts was identified. Biochemical studies have identified components of the RNA storage and/or translation inhibitor complex but it is not yet clear how the complex is specifically recruited on the RNA targeted for translation regulation. We used the 3'UTR region of translationally regulated transcripts to identify Phosphatidyl-inositol 5-phosphate 4-kinase (PIP4K2A) as the protein that associates with these RNAs. We further show that recombinant PIP4K2A has the RNA binding activity and can associate specifically with Plasmodium 3'UTR RNAs. Immunostainings show that hPIP4K2A is imported into the Plasmodium parasite from RBC. These results identify a novel RNA binding role for PIP4K2A that may play a role in Plasmodium propagation. PMID- 29518393 TI - Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat. AB - Systemic inflammation following infection is usually associated with long-term complications including cognitive deficit and dementia. Neuroinflammation and cognitive decline are also main hallmarks of several neurological conditions. Naringenin is a citrus flavanone with anti-inflammatory, neuroprotective, and antioxidant potential. In this study, the protective effect of naringenin against lipopolysaccharide (LPS)-induced cognitive decline was evaluated in the rat. LPS was daily injected at a dose of 167 MUg/kg for 1 week and naringenin was administered p.o. at doses of 25, 50, or 100 mg/kg/day. Treatment of LPS-injected rats with naringenin dose-dependently improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination task, and retention and recall capability in passive avoidance test. Furthermore, naringenin lowered hippocampal malondialdehyde (MDA) as an index of lipid peroxidation and improved antioxidant defensive system comprising superoxide dismutase (SOD), catalase, and glutathione (GSH) in addition to decreasing acetylcholinesterase (AChE) activity. Additionally, naringenin was able to lower hippocampal nuclear factor-kappaB (NF kappaB), toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNFalpha), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP) level and its immunoreactivity, and to elevate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Taken together, naringenin could alleviate LPS-induced cognitive deficits and neuroinflammation, as was evident from attenuation of oxidative stress and AChE and modulation of Nrf2/NF kappaB/TNFalpha/COX2/iNOS/TLR4/GFAP. PMID- 29518394 TI - Interferon-stimulated gene 15 promotes cholesterol efflux by activating autophagy via the miR-17-5p/Beclin-1 pathway in THP-1 macrophage-derived foam cells. AB - Macrophage autophagy contributes to the hydrolysis of cholesteryl ester into free cholesterol mainly for ATP-binding cassette transporter A1 (ABCA1)-dependent efflux. Interferon-stimulated gene 15 (ISG15) has been shown to regulate autophagy in multiple types of cells. The present study aimed to examine the effects of ISG15 on autophagy and cholesterol efflux in THP-1 macrophage-derived foam cells and to explore the underlying molecular mechanisms. Our results showed that overexpression of ISG15 promoted autophagy and cholesterol efflux and inhibited lipid accumulation without impact on ABCA1 expression. Inhibition of autophagy by 3-methyladenine (3-MA) abrogated the enhancing effects of ISG15 on cholesterol efflux. Both bioinformatics analysis and dual luciferase reporter assay identified Beclin-1 as a direct target of miR-17-5p. Moreover, ISG15 overexpression markedly decreased miR-17-5p levels and upregulated Beclin-1 expression. ISG15-induced enhancement of autophagy and cholesterol efflux was reversed by pretreatment with either miR-17-5p mimic or Beclin-1 siRNA. In conclusion, these findings suggest that ISG15 reduces miR-17-5p levels and thereby promotes Beclin-1-mediated autophagy, resulting in increased cholesterol efflux from THP-1 macrophage-derived foam cells. PMID- 29518395 TI - Oridonin inhibits vascular inflammation by blocking NF-kappaB and MAPK activation. AB - Oridonin, an active diterpenoid compound isolated from the plant Rabdosia Rrubescens, has various pharmacological activities, including antioxidant, anti tumor capacities and anti-inflammation. In the present study, we explore the role of oridonin in regulating endothelial inflammation and its underlying mechanism. Endothelial cell-monocyte interaction was detected by Leukocyte-endothelium Adhesion Assay. The protein expression was measured by Western blot. NF-kappaB p65 translocation was measured by immunofluorescence. Acute lung inflammation model was used to evaluate leukocyte infiltration in vivo. The endothelial leukocyte adhesion and the leukocyte transmigration were profoundly reduced by oridonin. Oridonin dramatically inhibited the expression of TNF-alpha-induced endothelial adhesion molecules (intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1) and E-selectin) and the pro inflammatory cytokine (IL-6, IL-8 and monocyte chemoattractant protein-1(MCP-1)). Oridonin suppressed the penetration of the leukocyte in the acute lung injury mice model. Furthermore, Oridonin also suppressed the TNF-alpha-activated MAPK and Nuclear factor kappa B (NF-kappaB) activation. Our results suggest that oridonin has the anti-inflammatory properties in endothelial cells, at least in part, through the suppression of MAPK and NF-kappaB activation, which may have a potential therapeutic use for inflammatory vascular diseases. PMID- 29518396 TI - Effects of AS2541019, a novel selective PI3Kdelta inhibitor, on antibody production and hamster to rat xenotransplantation. AB - B cell-mediated antibodies play a critical role in protecting the body from infections; however, excessive antibody production is involved in the pathogenesis of autoimmune diseases and transplanted organ rejection. Regulation of antibody production is therefore crucial for overcoming these complications. Phosphatidylinositol-3-kinase p110delta (PI3Kdelta), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation and proliferation, with a small molecule PI3Kdelta inhibitor having been approved for the treatment of B cell lymphoma. However, the effect of PI3Kdelta inhibitors on B cell mediated antibody production has not been clearly elucidated. In this study, we investigated the effect of the selective PI3Kdelta inhibitor, AS2541019, on B cell immunity and antibody production. Our results show that AS2541019 effectively prevented B cell activation and proliferation in vitro, and that oral administration of AS2541019 resulted in significant inhibition of both T dependent and T-independent de novo antibody production in peripheral blood. Further, in a hamster to rat concordant xenotransplant model, AS2541019 significantly prolonged graft survival time by inhibiting xenoreactive antibody production. Therefore, our study demonstrates that the selective PI3Kdelta inhibitor AS2541019 inhibits antibody production through potent inhibitory effects on B cell activation, and can protect against organ dysfunction. PMID- 29518397 TI - Levo-corydalmine alleviates vincristine-induced neuropathic pain in mice by inhibiting an NF-kappa B-dependent CXCL1/CXCR2 signaling pathway. AB - Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control in vivo experiments. The results revealed that both l-CDL and oxycodone attenuated vincristine-induced persistent pain hypersensitivity and proinflammatory factors release in mice. CXCL1 and CXCR2 were increased from 6 to 14 days after vincristine administration in the spinal cord. In addition, vincristine injection induced the phosphorylation of NFkappaB by activating p65/RelA. To confirm these results, we demonstrated that l-CDL controlled astrocytic-released CXCL1 by inhibiting p65/RelA activation, thus acting on the CXCR2 receptor in the spinal cord. In cultured astrocytes, TNF-alpha elicited marked release of the chemokine CXCL1; moreover, the release was blocked by NFkappaB p65 small interfering RNA, NFkappaB inhibitor, and was dose-dependently decreased by l-CDL. However, l-CDL had no effect on CXCL1 in response to NFkappaB p65-silenced. In primary neurons, l-CDL indirectly reduced an increase in CXCR2 by astrocyte-conditioned medium but did not act directly on the CXCR2 site. Taken together, our data first demonstrate that an NFkappaB-dependent CXCL1/CXCR2 signaling pathway is involved in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely attenuates this inflammation through down-regulation of this signaling pathway. PMID- 29518398 TI - Polycystin-2-dependent control of cardiomyocyte autophagy. AB - AIMS: Considerable evidence points to critical roles of intracellular Ca2+ homeostasis in the modulation and control of autophagic activity. Yet, underlying molecular mechanisms remain unknown. Mutations in the gene (pkd2) encoding polycystin-2 (PC2) are associated with autosomal dominant polycystic kidney disease (ADPKD), the most common inherited nephropathy. PC2 has been associated with impaired Ca2+ handling in cardiomyocytes and indirect evidence suggests that this protein may be involved in autophagic control. Here, we investigated the role for PC2 as an essential regulator of Ca2+ homeostasis and autophagy. METHODS AND RESULTS: Activation of autophagic flux triggered by mTOR inhibition either pharmacologically (rapamycin) or by means of nutrient depletion was suppressed in cells depleted of PC2. Moreover, cardiomyocyte-specific PC2 knockout mice (alphaMhc-cre;Pkd2F/F mice) manifested impaired autophagic flux in the setting of nutrient deprivation. Stress-induced autophagy was blunted by intracellular Ca2+ chelation using BAPTA-AM, whereas removal of extracellular Ca2+ had no effect, pointing to a role of intracellular Ca2+ homeostasis in stress-induced cardiomyocyte autophagy. To determine the link between stress-induced autophagy and PC2-induced Ca2+ mobilization, we over-expressed either wild-type PC2 (WT) or a Ca2+-channel deficient PC2 mutant (PC2-D509V). PC2 over-expression increased autophagic flux, whereas PC2-D509V expression did not. Importantly, autophagy induction triggered by PC2 over-expression was attenuated by BAPTA-AM, supporting a model of PC2-dependent control of autophagy through intracellular Ca2+. Furthermore, PC2 ablation was associated with impaired Ca2+ handling in cardiomyocytes marked by partial depletion of sarcoplasmic reticulum Ca2+ stores. Finally, we provide evidence that Ca2+-mediated autophagy elicited by PC2 is a mechanism conserved across multiple cell types. CONCLUSION: Together, this study unveils PC2 as a novel regulator of autophagy acting through control of intracellular Ca2+ homeostasis. PMID- 29518399 TI - Nicotine and caffeine alter the effects of the LPS- primed mesenchymal stem cells on the co-cultured neutrophils. AB - PURPOSE: Mesenchymal stem cells (MSCs) express some of the nicotinic receptor subunits and adenosine receptors. The communication between tissue MSCs with neutrophils has been shown in previous studies. The aim of the present study is to determine the role of nicotine or caffeine on MSCs and its effects on neutrophils. METHODS: After the isolation, MSCs were pulsed with LPS (10 ng/ml) for 1 h. Then, MSCs were incubated with different concentrations of caffeine (0.1, 0.5 and 1 mM) and or with different concentrations of nicotine (0.1, 0.5, and 1 MUM) for 48 h. Afterwards, the medium was aspirated and the cells were used for co-culture experiment with neutrophil. The obtained data showed that LPS primed MSCs could decrease neutrophil vitality, whereas the treatment of MSCs with nicotine and/or especially a treatment with caffeine reverse this effect. RESULTS: Obtained data showed that when the LPS-primed MSCs were treated with nicotine or caffeine, the vitality of co-cultured neutrophils was significantly increased. The rate of the respiratory burst of neutrophils after co-culture by LPS-primed MSCs was decreased compared to the respiratory burst of neutrophil alone. Nicotine and/or caffeine treatment could reverse this reduction. CONCLUSION: Generally, these findings provide a new insight into understanding the anti-inflammatory and immunomodulatory effects of nicotine and caffeine. PMID- 29518400 TI - Quantitative Estimation of Plasma Free Drug Fraction in Patients With Varying Degrees of Hepatic Impairment: A Methodological Evaluation. AB - Quantitative prediction of unbound drug fraction (fu) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of fu values under pathological conditions. The primary objective of this study was to predict fu values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and alpha1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling fu in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting fu in hepatic insufficiency, particularly for albumin-bound drugs. PMID- 29518401 TI - Effect of the Dispersion States of Azone in Hydroalcoholic Gels on Its Transdermal Permeation Enhancement Efficacy. AB - The objective of this study was to investigate the effect of dispersion states of azone in gels on the transdermal permeation of levamisole hydrochloride (LH). LH hydroalcoholic gels containing azone of different dispersion states were prepared by varying the contents of azone and Tween 80, and the in vitro transdermal permeation of LH across excised rat skin was evaluated. Depending on the content of azone, mixed solvents, and solubilizer used, azone presented as dissolved molecules, solubilized in micelles, and fine or coarse emulsion droplets in gels. Dramatically increased transdermal permeation of LH within the azone contents between 0.25% and 0.75% indicated high transdermal enhancement efficiency of the molecular or micellar azone, and extra azone that existed as oil droplets did not fully exert transdermal penetration enhancement of LH. Although solubilizer (Tween 80) can greatly increase the solubility of azone, only small amount of Tween 80 (0.5%) in the gel significantly increased the steady-state flux of LH. Addition of extra amount of Tween 80 (>0.5%) reduced the amount of azone distributed in the skin, and thus decreased the transdermal drug permeation. The results partly elucidated the versatile effects of the dispersion states of azone on the transdermal permeation of hydrophilic drug from semisolid gels. PMID- 29518402 TI - A Poincare map based analysis of stroke patients' walking after a rehabilitation by a robot. AB - Since the past decade, rehabilitation robots have become common technologies for recovering gait ability after a stroke. Nevertheless, it is believed that these robots can be further enhanced. Hence, several researches are making progress in optimizing gait rehabilitation robots. However, most of these researches have only assessed the robots and their controllers in improving spatiotemporal and kinetic features of walking. There are not many researchers have focused on the robots' controllers' effects on the central nervous or neuromuscular systems. On the other hand, recently computational methods have been utilized to investigate the rehabilitations of neural disorders, through developing neuromechanical models. However, these methods have neither studied the robot-assisted gait rehabilitation, nor have they theoretically proved why rehabilitation exercises enhance patients' walking ability. Therefore, this paper merged a theoretical approach into a computational method to investigate the effects of gait rehabilitation robots on post-stroke neuromuscular system. To this end, a neuromechanical model of gait has been developed and thereby, the Poincare maps of intact and stroke people have been obtained. Comparison of these maps revealed why a stroke reduces the stability of walking. Then, the effect of an impedance controller, which is used in a rehabilitative robot, is scrutinized in stabilizing a walking motion. Obtaining the Poincare map of this close-loop system, proved that this controller improves motion stability. Finally, the effect of this controller is investigated by simulations and experiments. The experimental tests are performed by Arman rehabilitative robot. Clinical Reference Number: IR.TMU.REC.1394.254. PMID- 29518403 TI - Use of the AHP methodology in system dynamics: Modelling and simulation for health technology assessments to determine the correct prosthesis choice for hernia diseases. AB - Health technology assessments (HTAs) are often difficult to conduct because of the decisive procedures of the HTA algorithm, which are often complex and not easy to apply. Thus, their use is not always convenient or possible for the assessment of technical requests requiring a multidisciplinary approach. This paper aims to address this issue through a multi-criteria analysis focusing on the analytic hierarchy process (AHP). This methodology allows the decision maker to analyse and evaluate different alternatives and monitor their impact on different actors during the decision-making process. However, the multi-criteria analysis is implemented through a simulation model to overcome the limitations of the AHP methodology. Simulations help decision-makers to make an appropriate decision and avoid unnecessary and costly attempts. Finally, a decision problem regarding the evaluation of two health technologies, namely, the evaluation of two biological prostheses for incisional infected hernias, will be analysed to assess the effectiveness of the model. PMID- 29518404 TI - MicroRNA signatures discriminate between uterine and ovarian serous carcinomas. AB - Synchronous endometrial and ovarian malignancies occur in 5% of women presenting with endometrial cancer and 10% of patients presenting with ovarian malignancy. When a high-grade serous carcinoma concurrently involves both ovary and endometrium, pathological determination of whether they are synchronous primaries or metastatic tumors from one primary site can be challenging. MicroRNAs (miRNA) are 22-nucleotide noncoding RNAs that are aberrantly expressed in cancer cells and may inherit their cellular lineage characteristics. We explored possible differential miRNA signatures that may separate high-grade ovarian serous carcinoma from primary endometrial serous carcinoma. Forty-seven samples of histologically pure high-grade serous carcinoma of both uterine (16 case) and ovarian primaries (31 cases) were included. Expression of 384 mature miRNAs was analyzed using ABI TaqMan Low-Density Arrays technology. A random forest model was used to identify miRNAs that together could differentiate between uterine and ovarian serous carcinomas. Among 150 miRNAs detectable at various levels in the study cases, a panel of 11-miRNA signatures was identified to significantly discriminate between ovarian and uterine serous carcinoma (P < .05). A nested cross-validated convergent forest plot using 6 of the 11 miRNA signature was eventually established to classify the tumors with 91.5% accuracy. In conclusion, we have characterized a miRNA signature panel in this exploratory study that shows significant discriminatory power in separating primary ovarian high-grade serous carcinoma from its endometrial counterpart. PMID- 29518405 TI - A DM9-containing protein from oyster Crassostrea gigas (CgDM9CP-2) serves as a multipotent pattern recognition receptor. AB - DM9 is a novel protein domain with unknown function originally discovered in Drosophila melanogaster. Recently, a protein harboring DM9 repeats was identified as mannose-specific lectin (CgCGL1, renamed as CgDM9CP-1) from the Pacific oyster Crassostrea gigas. In the present study, another DM9 containing protein was identified from oyster C. gigas (designated as CgDM9CP-2). The open reading frame of CgDM9CP-2 gene was of 432 bp, encoding a polypeptide of 143 amino acids with two tandem DM9 repeats. The deduced amino acid sequence of CgDM9CP-2 shared 60.8% identity with that of CgDM9CP-1. In the unrooted phylogenetic tree, CgDM9CP-2 was closely clustered with CgDM9CP-1, and then assigned into the branch of invertebrate DM9CPs. The mRNA transcripts of CgDM9CP-2 were expressed in all the tested tissues, including mantle, gonad, gills, adductor muscle, hemocytes, and hepatopancreas, with the highest expression level in gills. CgDM9CP-2 protein was mainly distributed on the cytomembrane of oyster hemocytes. After mannose stimulation, the mRNA expression of CgDM9CP-2 in gills was up-regulated to the peak level (5.90-fold of that in SSW group, p < 0.05) at 24 h, and kept at a significantly higher level compared with that in control group at 6-48 h. It significantly increased at 6 h (2.33-fold, p < 0.05), and 12 h (3.08-fold, p < 0.05) post Vibrio splendidus stimulation, and then gradually decreased from 48 to 72 h (p < 0.05) with significant difference comparing with that in control group. The recombinant CgDM9CP-2 protein (rCgDM9CP-2) displayed higher binding affinity to D-(+)-mannose while lower binding affinity to lipopolysaccharide and peptidoglycan. rCgDM9CP-2 also exhibited binding activity towards fungi (Pichia pastoris and Yarrowia lipolytica), gram-positive bacteria (Staphylococcus aureus and Micrococcus luteus), and gram-negative bacteria (Escherichia coli, Vibrio anguillarum, Aeromonas hydrophila and V. splendidus). It could agglutinate fungi P. pastoris and Y. lipolytica, and inhibit the growth of P. pastoris, S. aureus, V. anguillarum, and V. splendidus. These results collectively indicated that CgDM9CP-2 not only served as a pattern recognition receptor with a broad range of recognition spectrum, but also involved in inhibiting the growth of invading microbe in the innate immune response of oyster, which would provide further evidence for the function of DM9 domain in the innate immune system. PMID- 29518406 TI - Stimulatory function of peroxiredoxin 1 in activating adaptive humoral immunity in a zebrafish model. AB - Peroxiredoxin 1 (Prdx1/Prx1), a ubiquitous antioxidant enzyme involved in preventing oxidative damage and maintaining redox homeostasis, is essential for various cellular activities. Extracellular Prdx1 also plays important roles in innate immune responses. However, little is known about the regulatory functions of Prdx1 in adaptive immunity. In the present study, we report the stimulatory role of Prdx1 in the initiation of adaptive humoral immunity in a zebrafish model. Administration of Prdx1 protein to zebrafish significantly induced the expression of TNF-alpha, IL-1beta, and IL-6 by the Toll-like-receptor-4a-mediated NF-kappaB signaling pathway and enhanced the activation of MHC-II+ antigen presenting cells, CD4+ T cells, and mIgM+ B cells. Subsequently, increased production of antigen-specific IgM antibody was observed. Thus, Prdx1 can be used as a novel molecular adjuvant with great therapeutic value for the vaccination of fish diseases. Our study improved the understanding of the biology of Prdx1 family. PMID- 29518408 TI - Anti-Anisakis sp. antibodies in serum of patients with sepsis and their relationship with gammadelta T cells and disease severity. AB - Immunosuppression in sepsis reduces both alphabeta and gammadelta T cell subsets. Anisakis sp. is a parasitic nematode with a high prevalence in Spain. Previous contact with the parasite is related to a decrease in gammadelta T cells. Anti Anisakis antibodies were measured and related to alphabeta and gammadelta T cells in 114 septic patients versus 97 healthy controls. Significant differences were seen with respect to the groups with severe sepsis and septic shock where lower anti-Anisakis levels were observed. A similar decrease appeared in the case of specific IgM with significant differences between the groups of control/uncomplicated sepsis versus severe sepsis and septic shock. These differences were also apparent in the case of specific IgA. The lowest IgE levels were detected in the septic shock group. Anti-Anisakis IgG levels significantly increased in septic shock groups compared with the controls. We observed positive correlations among anti-Anisakis IgA levels and all gammadelta T cell subsets. There were negative correlations among IgA levels and APACHE and SOFA indices. Greater contact with the parasite (IgG) was directly related with septic shock, inflammation and markers of sepsis severity. A lack of protection in the mucosa (IgA and gammadelta T cells) was associated with the disease severity. PMID- 29518407 TI - Aging affects isoproterenol-induced water drinking, astrocyte density, and central neuronal activation in female Brown Norway rats. AB - Age-dependent impairments in the central control of compensatory responses to body fluid challenges have received scant experimental attention, especially in females. In the present study, we found that water drinking in response to beta adrenergic activation with isoproterenol (30 MUg/kg, s.c.) was reduced by more than half in aged (25 mo) vs. young (5 mo) ovariectomized female Brown Norway rats. To determine whether this age-related decrease in water intake was accompanied by changes in central nervous system areas associated with fluid balance, we assessed astrocyte density and neuronal activation in the SFO, OVLT, SON, AP and NTS of these rats using immunohistochemical labeling for GFAP and c fos, respectively. GFAP labeling intensity was increased in the SFO, AP, and NTS of aged females independent of treatment, and was increased in the OVLT of isoproterenol-treated rats independent of age. Fos immunolabeling in response to isoproterenol was reduced in both the SFO and the OVLT of aged females compared to young females, but was increased in the SON of female rats of both ages. Finally, fos labeling in the AP and caudal NTS of aged rats was elevated after vehicle control treatment and did not increase in response to isoproterenol as it did in young females. Thus, age-related declines in water drinking are accompanied by site-specific, age-related changes in astrocyte density and neuronal activation. We suggest that astrocyte density may alter the detection and/or processing of signals related to isoproterenol treatment, and thereby alter neuronal activation in areas associated with fluid balance. PMID- 29518409 TI - AbiEi Binds Cooperatively to the Type IV abiE Toxin-Antitoxin Operator Via a Positively-Charged Surface and Causes DNA Bending and Negative Autoregulation. AB - Bacteria resist phage infection using multiple strategies, including CRISPR-Cas and abortive infection (Abi) systems. Abi systems provide population-level protection from phage predation, via "altruistic" cell suicide. It has recently been shown that some Abi systems function via a toxin-antitoxin mechanism, such as the widespread AbiE family. The Streptococcus agalactiae AbiE system consists of a bicistronic operon encoding the AbiEi antitoxin and AbiEii toxin, which function as a Type IV toxin-antitoxin system. Here we examine the AbiEi antitoxin, which belongs to a large family of transcriptional regulators with a conserved N-terminal winged helix-turn-helix domain. This winged helix-turn-helix is essential for transcriptional repression of the abiE operon. The function of the AbiEi C-terminal domain is poorly characterized, but it contributes to transcriptional repression and is sufficient for toxin neutralization. We demonstrate that a conserved charged surface on one face of the C-terminal domain assists sequence-specific DNA binding and negative autoregulation, without influencing antitoxicity. Furthermore, AbiEi binds cooperatively to two inverted repeats within the abiE promoter and bends the DNA by 72 degrees . These findings demonstrate that the mechanism of DNA binding by the widespread family of AbiEi antitoxins and transcriptional regulators can contribute to negative autoregulation. PMID- 29518410 TI - Structurally Mapping Endogenous Heme in the CcmCDE Membrane Complex for Cytochrome c Biogenesis. AB - Although many putative heme transporters have been discovered, it has been challenging to prove that these proteins are directly involved with heme trafficking in vivo and to identify their heme binding domains. The prokaryotic pathways for cytochrome c biogenesis, Systems I and II, transport heme from inside the cell to outside for stereochemical attachment to cytochrome c, making them excellent models to study heme trafficking. System I is composed of eight integral membrane proteins (CcmA-H) and is proposed to transport heme via CcmC to an external "WWD" domain for presentation to the membrane-tethered heme chaperone, CcmE. Herein, we develop a new cysteine/heme crosslinking approach to trap and map endogenous heme in CcmC (WWD domain) and CcmE (defining "2-vinyl" and "4-vinyl" pockets for heme). Crosslinking occurs when either of the two vinyl groups of heme localize near a thiol of an engineered cysteine residue. Double crosslinking, whereby both vinyls crosslink to two engineered cysteines, facilitated a more detailed structural mapping of the heme binding sites, including stereospecificity. Using heme crosslinking results, heme ligand identification, and genomic coevolution data, we model the structure of the CcmCDE complex, including the WWD heme binding domain. We conclude that CcmC trafficks heme via its WWD domain and propose the structural basis for stereochemical attachment of heme. PMID- 29518412 TI - Electrophysiological determination of phosphodiesterase-6 inhibitor inhibition constants in intact mouse retina. AB - Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6. Here we introduce electroretinography-based methods for determining the inhibition constants of PDE inhibitors towards the naturally occurring light-activated and spontaneously activated forms of PDE6. We compare our results to earlier biochemical determinations with trypsin-activated PDE6 with disintegrated PDE6 gamma-subunit. The potencies of PDE inhibitors were determined by stimulating the photoreceptors of isolated mouse retinas with light and tracking the inhibitor-induced changes in their electrical responses. The methods were tested with three PDE inhibitors, 3-isobutyl-1-methylxanthine (IBMX), sildenafil, and zaprinast. The inhibition constants towards light activated, spontaneously activated, and trypsin-activated PDE6 differed significantly from each other for sildenafil and zaprinast but were closely similar for IBMX. We hypothesize that this is due to the ability of the PDE6 gamma-subunit to compete with sildenafil and zaprinast from the same binding sites near the catalytic domain of PDE6. The introduced methods are beneficial both for selecting potent molecules for PDE6 inhibition and for testing the drugs targeted at other PDE isoforms against adverse effects on visual function. PMID- 29518413 TI - Sentential negation modulates inhibition in a stop-signal task. Evidence from behavioral and ERP data. AB - Embodiment theories claim that language meaning involves sensory-motor simulation processes in the brain. A challenge for these theories, however, is to explain how abstract words, such as negations, are processed. In this article, we test the hypothesis that understanding sentential negation (e.g., You will not cut the bread) reuses the neural circuitry of response inhibition. Participants read manual action sentences with either affirmative or negative polarity, embedded in a Stop-Signal paradigm, while their EEG was recorded. The results showed that the inhibition-related N1 and P3 components were enhanced by successful inhibition. Most important, the early N1 amplitude was also modulated by sentence polarity, producing the largest values for successful inhibitions in the context of negative sentences, whereas no polarity effect was found for failing inhibition or go trials. The estimated neural sources for N1 effects revealed activations in the right inferior frontal gyrus, a typical inhibition-related area. Also, the estimated stop-signal reaction time was larger in trials with negative sentences. These results provide strong evidence that action-related negative sentences consume neural resources of response inhibition, resulting in less efficient processing in the Stop-Signal task. PMID- 29518411 TI - Efficacy and tolerability of AFPep, a cyclic peptide with anti-breast cancer properties. AB - PURPOSE: The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials. METHODS: AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts. RESULTS: AFPep arrests the growth of human MCF-7 breast cancer xenografts, inhibits the estrogen-induced growth of mouse uteri, and does not affect liver growth nor stimulate growth of human hepatocellular carcinoma cell lines when growing in vitro or as xenografts in vivo. AFPep is well tolerated in mice, rats, dogs, and primates. CONCLUSIONS: AFPep is effective for the treatment of ER-positive breast cancer and exhibits a therapeutic index that is substantially wider than that for drugs currently in clinical use. The data emphasize the importance of pursuing pre-clinical toxicology studies with the intent to enter clinical trials. PMID- 29518414 TI - Profiling the in vitro drug-resistance mechanism of influenza A viruses towards the AM2-S31N proton channel blockers. AB - The majority of human influenza A viruses currently in circulation carry the amantadine-resistant AM2-S31N channel mutation. We previously discovered a series of AM2-S31N inhibitors with potent antiviral activity against both oseltamivir sensitive and -resistant influenza A viruses. To understand the drug-resistance mechanism of AM2-S31N inhibitors, we performed serial viral passage experiments using the influenza virus A/California/07/2009 (H1N1) to select drug-resistant AM2 mutations against two representative AM2-S31N channel blockers (1 and 2). Unlike amantadine, which gives rise to resistance after a single passage, compounds 1 and 2 selected for partially resistant viruses at passages 05 and 04 with a V27I and L26I mutation, respectively. This appears to suggest compounds 1 and 2 have a higher genetic barrier to resistance than amantadine at least in cell culture. Passage with a higher drug concentration of compound 2 selected higher level resistant viruses with a double mutant L26I + A30T. The mechanism of resistance and replication fitness for mutant viruses were evaluated by electrophysiology, reverse genetics, growth kinetics, and competition assays. AM2 S31N/V27I and AM2-S31N/L26I channels achieved similar specific proton conductance as AM2-S31N, but the AM2-S31N/L26I/A30T triple mutant had drastically reduced specific proton conductance. Viral replication fitness of AM2-S31N/V27I and AM2 S31N/L26I double mutant viruses were similar to AM2-S31N containing viruses in cell culture. However, AM2-S31N/L26I/A30T viruses displayed attenuated growth as well as inability to compete with AM2-S31N viruses. The results herein offer insight regarding the resistance mechanism of AM2-S31N inhibitors, and may help guide the design of the next-generation of AM2-S31N inhibitors with a higher genetic barrier to drug resistance. PMID- 29518415 TI - Tackling muscle fibrosis: From molecular mechanisms to next generation engineered models to predict drug delivery. AB - Muscle fibrosis represents the end stage consequence of different diseases, among which muscular dystrophies, leading to severe impairment of muscle functions. Muscle fibrosis involves the production of several growth factors, cytokines and proteolytic enzymes and is strictly associated to inflammatory processes. Moreover, fibrosis causes profound changes in tissue properties, including increased stiffness and density, lower pH and oxygenation. Up to now, there is no therapeutic approach able to counteract the fibrotic process and treatments directed against muscle pathologies are severely impaired by the harsh conditions of the fibrotic environment. The design of new therapeutics thus need innovative tools mimicking the obstacles posed by the fibrotic environment to their delivery. This review will critically discuss the role of in vivo and 3D in vitro models in this context and the characteristics that an ideal model should possess to help the translation from bench to bedside of new candidate anti-fibrotic agents. PMID- 29518417 TI - Staphylococcus aureus enhances the tight junction barrier integrity in healthy nasal tissue, but not in nasal polyps. PMID- 29518416 TI - Allergen-induced activation of natural killer cells represents an early-life immune response in the development of allergic asthma. AB - BACKGROUND: Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and TH2-type inflammation; however, the early-life immune events that lead to TH2 skewing and disease development are unknown. OBJECTIVE: We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma. METHODS: In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years. RESULTS: PBMCs from the cases showed higher levels of expression of natural killer (NK) cell-related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key TH2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell-like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma. CONCLUSION: These findings provide important mechanistic insight into an early life immune pathway involved in TH2 polarization, leading to the development of allergic asthma. PMID- 29518420 TI - Basophil FcERI expression is linked to time to omalizumab response in chronic spontaneous urticaria. PMID- 29518419 TI - The nasal microbiome in asthma. AB - BACKGROUND: Nasal microbiota may influence asthma pathobiology. OBJECTIVE: We sought to characterize the nasal microbiome of subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls to identify nasal microbiota associated with asthma activity. METHODS: We performed 16S ribosomal RNA sequencing on nasal swabs obtained from 72 primarily adult subjects with exacerbated asthma (n = 20), nonexacerbated asthma (n = 31), and healthy controls (n = 21). Analyses were performed using Quantitative Insights into Microbial (QIIME); linear discriminant analysis effect size (LEfSe); Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; and Statistical Analysis of Metagenomic Profiles (PICRUSt); and Statistical Analysis of Metagenomic Profiles (STAMP). Species found to be associated with asthma activity were validated using quantitative PCR. Metabolic pathways associated with differentially abundant nasal taxa were inferred through metagenomic functional prediction. RESULTS: Nasal bacterial composition significantly differed among subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls (permutational multivariate ANOVA, P = 2.2 * 10-2). Relative to controls, the nasal microbiota of subjects with asthma were enriched with taxa from Bacteroidetes (Wilcoxon-Mann-Whitney, r = 0.33, P = 5.1 * 10-3) and Proteobacteria (r = 0.29, P = 1.4 * 10-2). Four species were differentially abundant based on asthma status after correction for multiple comparisons: Prevotella buccalis, Padj = 1.0 * 10-2; Dialister invisus, Padj = 9.1 * 10-3; Gardnerella vaginalis, Padj = 2.8 * 10-3; Alkanindiges hongkongensis, Padj = 2.6 * 10-3. These phyla and species were also differentially abundant based on asthma activity (exacerbated asthma vs nonexacerbated asthma vs controls). Quantitative PCR confirmed species overrepresentation in asthma relative to controls for Prevotella buccalis (fold change = 130, P = 2.1 * 10-4) and Gardnerella vaginalis (fold change = 160, P = 6.8 * 10-4). Metagenomic inference revealed differential glycerolipid metabolism (Kruskal-Wallis, P = 1.9 * 10-4) based on asthma activity. CONCLUSIONS: Nasal microbiome composition differs in subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls. The identified nasal taxa could be further investigated for potential mechanistic roles in asthma and as possible biomarkers of asthma activity. PMID- 29518421 TI - Mast cell activation test in the diagnosis of allergic disease and anaphylaxis. AB - BACKGROUND: Food allergy is an increasing public health issue and the most common cause of life-threatening anaphylactic reactions. Conventional allergy tests assess for the presence of allergen-specific IgE, significantly overestimating the rate of true clinical allergy and resulting in overdiagnosis and adverse effect on health-related quality of life. OBJECTIVE: To undertake initial validation and assessment of a novel diagnostic tool, we used the mast cell activation test (MAT). METHODS: Primary human blood-derived mast cells (MCs) were generated from peripheral blood precursors, sensitized with patients' sera, and then incubated with allergen. MC degranulation was assessed by means of flow cytometry and mediator release. We compared the diagnostic performance of MATs with that of existing diagnostic tools to assess in a cohort of peanut-sensitized subjects undergoing double-blind, placebo-controlled challenge. RESULTS: Human blood-derived MCs sensitized with sera from patients with peanut, grass pollen, and Hymenoptera (wasp venom) allergy demonstrated allergen-specific and dose dependent degranulation, as determined based on both expression of surface activation markers (CD63 and CD107a) and functional assays (prostaglandin D2 and beta-hexosaminidase release). In this cohort of peanut-sensitized subjects, the MAT was found to have superior discrimination performance compared with other testing modalities, including component-resolved diagnostics and basophil activation tests. Using functional principle component analysis, we identified 5 clusters or patterns of reactivity in the resulting dose-response curves, which at preliminary analysis corresponded to the reaction phenotypes seen at challenge. CONCLUSION: The MAT is a robust tool that can confer superior diagnostic performance compared with existing allergy diagnostics and might be useful to explore differences in effector cell function between basophils and MCs during allergic reactions. PMID- 29518423 TI - Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations. PMID- 29518418 TI - Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation? PMID- 29518422 TI - Egg-specific IgE and basophil activation but not egg-specific T-cell counts correlate with phenotypes of clinical egg allergy. AB - BACKGROUND: Egg allergy is phenotypically heterogeneous. A subset of patients with egg allergy can tolerate egg in an extensively heated form. Inclusion of baked egg (BE) into the diet accelerates resolution of egg allergy. Conversely, BE reactivity is associated with persistent disease. The immune basis of this clinical heterogeneity is unknown. OBJECTIVES: We sought to study egg-specific antibody, basophil, and T-cell responses in children with reactivity or tolerance to BE. METHODS: All participants underwent double-blind, placebo-controlled challenges to BE, and those who tolerated BE were challenged with unheated egg white protein to confirm clinical egg reactivity. Laboratory studies included serum antibody measurements, basophil activation tests, and CD154-based detection of egg-responsive T cells by using flow cytometry. RESULTS: Of the 129 children studied, BE-reactive participants had significantly greater levels of egg-, ovalbumin-, and ovomucoid-specific IgE; lower ratios of egg-specific IgG4/IgE; and increased basophil activation in response to egg. Among all participants, CD154-based profiling revealed egg-responsive T cells producing IL-4 and IL-13 but little IL-10 or IFN-gamma, as well as the presence of egg-responsive Foxp3+CD25+CD127low regulatory T cells. Egg-responsive T cells expressed CCR4, CCR6, and CXCR5, indicating capacity for homing to the skin, mucosa, and B-cell follicles. However, neither the frequency nor phenotype of egg-responsive T cells was different in those with tolerance or reactivity to BE. CONCLUSIONS: Egg specific antibody and basophil responses, but not T-cell responses, are greater in those with reactivity versus tolerance to BE. Egg-specific antibody and T-cell responses were highly heterogeneous in this cohort. The clinical implications of this immune heterogeneity will need to be studied longitudinally. PMID- 29518424 TI - Machine learning, natural language programming, and electronic health records: The next step in the artificial intelligence journey? PMID- 29518425 TI - Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor. AB - BACKGROUND: Leukotriene (LT) E4 is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE4 receptor, suggesting that current cysteinyl leukotriene type 1 (CysLT1) receptor antagonists can provide incomplete inhibition of CysLT responses. OBJECTIVE: We tested this hypothesis by assessing the influence of the CysLT1 antagonist montelukast on responses induced by means of inhalation of LTE4 in asthmatic patients. METHODS: Fourteen patients with mild intermittent asthma and 2 patients with aspirin-exacerbated respiratory disease received 20 mg of montelukast twice daily and placebo for 5 to 7 days in a randomized, double-blind, crossover study (NCT01841164). The PD20 value was determined at the end of each treatment period based on an increasing dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours after LTE4 challenge. RESULTS: Montelukast completely blocked LTE4-induced bronchoconstriction. Despite tolerating an at least 10 times higher dose of LTE4 after montelukast, there was no difference in the percentage of eosinophils in sputum. Urinary excretion of all major lipid mediators increased after LTE4 inhalation. Montelukast blocked release of the mast cell product prostaglandin (PG) D2, as well as release of PGF2alpha and thromboxane (Tx) A2, but not increased excretion of PGE2 and its metabolites or isoprostanes. CONCLUSION: LTE4 induces airflow obstruction and mast cell activation through the CysLT1 receptor. PMID- 29518427 TI - Hypersensitivity reactions to therapeutic monoclonal antibodies: Phenotypes and endotypes. AB - BACKGROUND: The increasing use of mAbs has led to a rise in hypersensitivity reactions (HSRs), which prevent their use as first-line therapy. HSRs' symptoms, diagnostic tools, and directed management approaches have not been standardized. OBJECTIVE: We propose a novel evidence-based classification of HSRs to mAbs, based on the clinical phenotypes, underlying endotypes and biomarkers, as well as their management with desensitization. METHODS: Phenotypes, endotypes, and biomarkers of HSRs to 16 mAbs for 104 patients were described and compared with the outcomes of 526 subcutaneous and intravenous desensitizations. RESULTS: Initial reactions presented with 4 patterns: type I-like reactions (63%), cytokine-release reactions (13%), mixed reactions (21%), and delayed type IV reactions (3%). In contrast, of the 23% breakthrough HSRs during desensitization, 52% were cytokine-release reactions, 32% were type 1, 12% were mixed, and 4% were type I with delayed type IV. Skin testing to 10 mAbs in 58 patients was positive in 41% of patients. Serum tryptase was elevated in 1 patient and IL-6 was elevated in 8 patients during desensitization and was associated with a cytokine release phenotype. CONCLUSIONS: HSRs to mAbs can be defined as type I, cytokine release, mixed (type I/cytokine-release), and type IV reactions, which are identified by biomarkers such as skin test, tryptase, and IL-6. These phenotypes can be used to improve personalized and precision medicine when diagnosing HSRs to mAbs and providing management recommendations with desensitization. Desensitization provides a safe and effective retreatment option to remain on culprit mAbs as first-line therapy. PMID- 29518428 TI - The classroom microbiome and asthma morbidity in children attending 3 inner-city schools. PMID- 29518429 TI - Transepithelial migration of mucosal hemocytes in Crassostrea virginica and potential role in Perkinsus marinus pathogenesis. AB - We have recently described the presence of hemocytes associated with mucus covering the pallial organs (mantle, gills, and body wall) 3 of the eastern oyster Crassostrea virginica. These hemocytes, hereby designated "pallial hemocytes" share common general characteristics with circulating hemocytes but also display significant differences particularly in their cell surface epitopes. The specific location of pallial hemocytes as peripheral cells exposed directly to the marine environment confers them a putative sentinel role. The purpose of this study was to gain a better understanding of the source of these pallial hemocytes by evaluating possible exchanges between circulatory and pallial hemocyte populations and whether these exchanges are regulated by pathogen exposure. Bi-directional transepithelial migrations of hemocytes between pallial surfaces and the circulatory system were monitored using standard cell tracking approaches after staining with the vital fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) in conjunction with fluorescent microscopy and flow cytometry. Results showed bi-directional migration of hemocytes between both compartments and suggest that hemocyte migration from the pallial mucus layer to the circulatory system may occur at a greater rate compared to migration from the circulatory system to the pallial mucus layer, further supporting the role of pallial hemocytes as sentinel cells. Subsequently, the effect of the obligate parasite Perkinsus marinus and the opportunistic pathogen Vibrio alginolyticus on transepithelial migration of oyster hemocytes was investigated. Results showed an increase in hemocyte migration in response to P. marinus exposure. Furthermore, P. marinus cells were acquired by pallial hemocytes before being visible in underlying tissues and the circulatory system suggesting that this parasite could use pallial hemocytes as a vehicle facilitating its access to oyster tissues. These results are discussed in light of new evidence highlighting the role of oyster pallial organs as a portal for the initiation of P. marinus infections in oysters. PMID- 29518426 TI - CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-gamma. AB - BACKGROUND: Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. OBJECTIVES: We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN gamma (rhIFN-gamma) on neutrophil function. METHODS: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. RESULTS: Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-gamma but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. CONCLUSION: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-gamma, indicating a potential novel therapeutic application for this cytokine. PMID- 29518430 TI - New insights into the entrance of Perkinsus olseni in the Manila clam, Ruditapes philippinarum. AB - In order to understand interactions between Perkinsus olseni and its host mollusk species Manila clam Ruditapes philippinarum, this study focused on invasion processes of the parasite, particularly the mechanisms of zoospore transformation to trophozoites in its portal entry into the host. We exposed Manila clam to P. olseni zoospores, then periodically quantified parasite intensity in various host organs and tissues. We detected large numbers of parasite cells within gills and labial palps of the host clam from the early to the final stages, moderately within mantle and digestive organs but low numbers within hemolymph, foot and adductor muscles. Our results suggest that P. olseni first invades the gills and labial palps of the host clam with limited translocation throughout the host body via the host's circulatory system until 12 days post exposure to zoospores. P. olseni zoospores exposed to extracts of gills and labial palps transformed into trophozoites more efficiently than they did when exposed to other tissues; this transformation was not observed when zoospores were exposed to heated organ extracts. Our results suggest the involvement of a host molecule in the transformation of P. olseni zoospores, leading to initial infection primarily within gills and labial palps of the host clam. PMID- 29518431 TI - Impact of Perkinsus olseni infection on a wild population of Manila clam Ruditapes philippinarum in Ariake Bay, Japan. AB - Many studies have addressed the production decline of Manila clam, Ruditapes philippinarum, in Japan, but infection of clams with Perkinsus olseni has received scarce attention. To evaluate the impact of P. olseni, infection levels and host density of a wild, unexploited clam population were monitored monthly or bimonthly on a tidal flat from June 2009 to January 2013. Real-time PCR analysis discriminating P. olseni and Perkinsus honshuensis detected only P. olseni in tested clams. The prevalence of P. olseni was 100% or nearly 100% in 7 cohorts throughout the study period, except in newly recruited clams. Infection intensity remained low and seldom reached 106 cells/g wet tissue in newly recruited clams until the month of September. Infection intensity reached 106 cells/g in autumn and remained high at 104-106 cells/g until each cohort of clams disappeared. Clam density began to decrease in the autumn when the infection intensities reached ca. 106 cells/g. Density was relatively stable in winter, increased in spring and decreased again in clams aged 1 year or older during summer and autumn in the following years. Survival of clams experimentally infected with P. olseni at ca. 106 cells/g and placed in a cage in the tidal flat for 1 or 2 months was significantly lower than survival of uninfected control clams. Our results suggested that heavy infection with P. olseni was a major cause of the clam density decrease, although other environmental and biological factors also may have contributed to the decline in density. In addition, uninfected clams were deployed in cages for 1-2 months from June 2010 to January 2013 and prevalence and infection intensity were monitored. Parasite transmission and infection progression increased in summer and autumn. PMID- 29518432 TI - Perioperative Immunonutrition Modulates Inflammatory Response after Radical Cystectomy: Results of a Pilot Randomized Controlled Clinical Trial. AB - PURPOSE: Poor preoperative nutritional status is associated with a higher complication rate after radical cystectomy in patients with bladder cancer. Given the short interval between diagnosis and radical cystectomy, we compared the effect of short-term specialized immunonutrition to that of a standard oral nutritional supplement on the acute inflammatory response and arginine status in patients treated with radical cystectomy. MATERIALS AND METHODS: In this prospective, randomized study in 29 men 14 received specialized immunonutrition and 15 received oral nutritional supplement. Each group drank 3 cartons per day for 5 days before and 5 days after radical cystectomy. The Th1-Th2 balance, plasma interleukin-6 and plasma amino acids were measured at baseline, intraoperatively and on postoperative days 2, 14 and 30. Body composition was measured by dual energy x-ray absorptiometry at baseline and on postoperative days 14 and 30. Differences in outcomes were assessed using the generalized linear mixed model. RESULTS: In the specialized immunonutrition group there was a 54.3% average increase in the Th1-Th2 balance according to the tumor necrosis factor-alpha-to-interleukin-13 ratio from baseline to intraoperative day, representing a shift toward a Th1 response. In the oral nutritional supplement group the Th1-Th2 balance decreased 4.8%. The change in the Th1-Th2 balance between the specialized immunonutrition and oral nutritional supplement groups significantly differed (p <0.027). Plasma interleukin-6 was 42.8% lower in the specialized immunonutrition group compared to the oral nutritional supplement group on postoperative day 2 (p = 0.020). In the specialized immunonutrition group plasma arginine was maintained from baseline to postoperative day 2 and yet the oral nutritional supplement group showed a 26.3% reduction from baseline to postoperative day 2 (p = 0.0003). The change in appendicular muscle loss between the groups was not statistically significant. CONCLUSIONS: Th1-to-Th2 ratios, peak interleukin-6 levels and plasma arginine suggest that consuming specialized immunonutrition counteracts the disrupted T-helper balance, lowers the inflammatory response and prevents arginine depletion due to radical cystectomy. PMID- 29518433 TI - Multiple Regions of Interest on Multiparametric Magnetic Resonance Imaging are Not Associated with Increased Detection of Clinically Significant Prostate Cancer on Fusion Biopsy. AB - PURPOSE: We sought to determine the association between multiple regions of interest on prebiopsy magnetic resonance imaging and the detection of clinically significant prostate cancer in men undergoing magnetic resonance imaging ultrasound fusion biopsy. MATERIALS AND METHODS: We performed a retrospective, single institution analysis of men who underwent fusion biopsy. Men with prior positive biopsies, magnetic resonance imaging performed elsewhere and/or magnetic resonance imaging prior to release of the PI-RADSTM (Prostate Imaging Reporting and Data System) version 2 were excluded from study, resulting in 381 participants. Modeled independent variables included patient age, number of regions of interest with a PI-RADS categorization of 3 or greater, body mass index, prostate specific antigen, prostate volume and PI-RADS categorization. Multivariable logistic regression was performed to determine factors associated with finding clinically significant prostate cancer (Gleason 7 or greater) on biopsy. RESULTS: Median age was 67.2 years (IQR (61.6-73.0) and median prostate specific antigen was 6.6 ng/ml (5.0-10.0). Adjusted analysis demonstrated that age (OR 1.10, 95% CI 1.06-1.15, p <=0.001), body mass index (OR 1.08, 95% CI 1.01 1.16, p = 0.038) and prostate specific antigen (OR 1.06, 95% CI 1.01-1.10, p = 0.015) were associated with detection of clinically significant prostate cancer. PI-RADS categories 4 (OR 4.62, 95% CI 2.23-9.33) and 5 (OR 6.75, 95% CI 2.72 16.71, each p <0.001) were associated with greater odds of clinically significant prostate cancer. Multiple regions of interest were not associated with the detection of clinically significant prostate cancer (OR 1.05, 95% CI 0.60-1.84, p = 0.857). CONCLUSIONS: Multiple regions of interest do not portend a greater likelihood of finding clinically significant prostate cancer. Physicians should recognize that multiple regions of interest should not influence the decision to perform fusion biopsy. Our findings may ease patient anxiety concerning these findings. PMID- 29518435 TI - Ziziphus spina-christi fruit extract suppresses oxidative stress and p38 MAPK expression in ulcerative colitis in rats via induction of Nrf2 and HO-1 expression. AB - In this study, we aimed to evaluate the anti-inflammatory and protective effects of Ziziphus spina-christi fruit extract (ZFE) against acetic acid (AcOH)-induced colitis in rats. Before a single AcOH instillation, ZFE (100, 200, and 400 mg/kg/day) was administered for 5 days by oral gavage. Pretreatment with ZFE at different doses suppressed the spread of inflammation and inhibited mucosal damage; in addition, it reduced ulcer size and mitigated colitis markers. Administration of ZFE (400 mg/kg) resulted in a greater reduction of inflammatory colonic injury than that after reference drug, mesalazine (MLZ), administration. In addition, ZFE not only histopathologically ameliorated AcOH-induced colitis but also restored the balance between the oxidants and antioxidants. Furthermore, ZFE effectively modulated the mRNA expression of redox-sensitive transcription factors, such as nuclear factor (erythroid-derived 2)-like 2 and heme oxygenase 1, downregulated the expression of p38 mitogen-activated protein kinase, and upregulated that of vascular endothelial growth factor A and interleukin-1beta in AcOH-induced colitis in rats. In conclusion, our results suggested that ZFE could prevent the development of chronic experimental colitis in rats; therefore, it could be considered as an alternative and/or additive therapeutic approach for the management of inflammatory bowel disease. PMID- 29518436 TI - Use of photoswitchable fluorescent proteins for droplet-based microfluidic screening. AB - Application of droplet-based microfluidics for the screening of microbial libraries is one of the important ongoing developments in functional genomics/metagenomics. In this article, we propose a new method that can be employed for high-throughput profiling of cell growth. It consists of light driven labelling droplets that contain growing cells directly in a microfluidics observation chamber, followed by recovery of the labelled cells. This method is based on intracellular expression of green-to-red switchable fluorescent proteins. The proof of concept is established here for two commonly used biological models, E. coli and S. cerevisiae. Growth of cells in droplets was monitored under a microscope and, depending on the targeted phenotype, the fluorescence of selected droplets was switched from a "green" to a "red" state. Red fluorescent cells from labelled droplets were then successfully detected, sorted with the Fluorescence Activated Cell Sorting machine and recovered. Finally, the application of this method for different kind of screenings, in particular of metagenomic libraries, is discussed and this idea is validated by the analysis of a model mini-library. PMID- 29518434 TI - Pharmacokinetics of [14C]-Benzo[a]pyrene (BaP) in humans: Impact of Co Administration of smoked salmon and BaP dietary restriction. AB - Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is a known human carcinogen. In non-smoking adults greater than 95% of BaP exposure is through diet. The carcinogenicity of BaP is utilized by the U.S. EPA to assess relative potency of complex PAH mixtures. PAH relative potency factors (RPFs, BaP = 1) are determined from high dose animal data. We employed accelerator mass spectrometry (AMS) to determine pharmacokinetics of [14C]-BaP in humans following dosing with 46 ng (an order of magnitude lower than human dietary daily exposure and million fold lower than animal cancer models). To assess the impact of co-administration of food with a complex PAH mixture, humans were dosed with 46 ng of [14C]-BaP with or without smoked salmon. Subjects were asked to avoid high BaP-containing diets and a 3-day dietary questionnaire given to assess dietary exposure prior to dosing and three days post-dosing with [14C]-BaP. Co-administration of smoked salmon, containing a complex mixture of PAHs with an RPF of 460 ng BaPeq, reduced and delayed absorption. Administration of canned commercial salmon, containing very low amounts of PAHs, showed the impacts on pharmacokinetics were not due to high amounts of PAHs but rather a food matrix effect. PMID- 29518437 TI - Spatial information is preferentially processed by the distal part of CA3: implication for memory retrieval. AB - For the past decades, CA3 was considered as a single functional entity. However, strong differences between the proximal (close to the dentate gyrus) and the distal (close to CA2) parts of CA3 in terms of connectivity patterns, gene expression and electrophysiological properties suggest that it is not the case. We recently showed that proximal CA3 (together with distal CA1) preferentially deals with non-spatial information [1]. In contrast to proximal CA3, distal CA3 mainly receives and predominantly projects to spatially tuned areas. Here, we tested if distal CA3 preferentially processes spatial information, which would suggest a segregation of the spatial information along the proximodistal axis of CA3. We used a high-resolution imaging technique based on the detection of the expression of the immediate-early gene Arc, commonly used to map activity in the medial temporal lobe. We showed that distal CA3 is strongly recruited in a newly designed delayed nonmatching-to-location task with high memory demands in rats, while proximal CA3 is not. These results indicate a functional segregation of CA3 that mirrors the one reported in CA1, and suggest the existence of a distal CA3- proximal CA1 spatial subnetwork. These findings bring further evidence for the existence of 'specialized' spatial and non-spatial subnetworks segregated along the proximodistal axis of the hippocampus and put forward the 'segregated' view of information processing in the hippocampus as a reasonable alternative to the well-accepted 'integrated' view, according to which spatial and non-spatial information are systematically integrated in the hippocampus to form episodic memory. PMID- 29518438 TI - Severity of chronic obstructive pulmonary disease and presenting rhythm in patients with out-of-hospital cardiac arrest. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with a non-shockable rhythm as presenting rhythm in out-of-hospital cardiac arrest (OHCA). Whether the severity of the underlying disease is related to presenting rhythm is unknown. We hypothesized that increased severity of COPD in OHCA patients is associated with an increased prevalence of non-shockable rhythm. METHODS: This study included OHCA patients >=40 years from the Danish Cardiac Arrest Registry (2001-2014). Population-based registries were used to identify chronic diseases and drug prescriptions. COPD was defined as a COPD diagnosis or pharmacological therapy for COPD. The severity of COPD was based on either 1) pharmacological therapy (mild/moderate/severe), 2) admission for exacerbation, 3) prescription for corticosteroids, or 4) forced expiratory volume in 1 s (FEV1). For each of these, a multivariable logistic regression model was used to estimate odds ratios (ORs) for a non-shockable rhythm. RESULTS: Of 33,228 patients with OHCA 7789 (23.4%) had COPD. Of these 6702 (86.0%) had a non-shockable rhythm. Compared to patients without COPD, mild COPD was associated with a non-shockable rhythm (OR = 1.46, 95%CI 1.29-1.65). This association was more pronounced for moderate (OR = 1.78, 95%CI 1.45-2.19) and severe COPD (OR = 2.01 95%CI 1.82 2.20). Recent admission for exacerbation (OR = 2.12, OR 95%CI 1.81-2.49) or prescription for corticosteroids (OR = 1.82, 95%CI 1.55-2.14) was also associated with a non-shockable rhythm. FEV1 <= 50% was associated with a non-shockable rhythm compared to FEV1 > 50% (OR = 1.74, 95%CI 1.07-2.82, n = 1122). CONCLUSION: Incremental severity of COPD is associated with increasing prevalence of a non shockable rhythm as presenting rhythm in OHCA patients. PMID- 29518439 TI - Sex, race, and insurance status differences in hospital treatment and outcomes following out-of-hospital cardiac arrest. AB - BACKGROUND: Sex, race, and insurance status are associated with treatment and outcomes in several cardiovascular diseases. These disparities, however, have not been well-studied in out-of-hospital cardiac arrest (OHCA). OBJECTIVE: Our objective was to evaluate the association of patient sex, race, and insurance status with hospital treatments and outcomes following OHCA. METHODS: We studied adult patients in the 2011-2015 California Office of Statewide Health Planning and Development (OSHPD) Patient Discharge Database with a "present on admission" diagnosis of cardiac arrest (ICD-9-CM 427.5). Insurance status was classified as private, Medicare, and Medi-Cal/government/self-pay. Our primary outcome was good neurologic recovery at hospital discharge, which was determined by discharge disposition. Secondary outcomes were survival to hospital discharge, treatment at a 24/7 percutaneous coronary intervention (PCI) center, "do not resuscitate" orders within 24 h of admission, and cardiac catheterization during hospitalization. Data were analyzed with hierarchical multiple logistic regression models. RESULTS: We studied 38,163 patients in the OSHPD database. Female sex, non-white race, and Medicare insurance status were independently associated with worse neurologic recovery [OR 0.94 (0.89-0.98), 0.93 (0.88-0.98), and 0.85 (0.79-0.91), respectively], lower rates of treatment at a 24/7 PCI center [OR 0.89 (0.85-0.93), 0.88 (0.85-0.93), and 0.87 (0.82-0.94), respectively], and lower rates of cardiac catheterization [OR 0.61 (0.57-0.65), 0.90 (0.84-0.97), and 0.44 (0.40-0.48), respectively]. Female sex, white race, and Medicare insurance were associated with DNR orders within 24 h of admission [OR 1.16 (1.10-1.23), 1.14 (1.07-1.21), and 1.25 (1.15-1.36), respectively]. CONCLUSIONS: Sex, race, and insurance status were independently associated with post-arrest care interventions, patient outcomes and treatment at a 24/7 PCI center. More studies are needed to fully understand the causes and implications of these disparities. PMID- 29518440 TI - Benefit of immediate coronary angiography after out-of-hospital cardiac arrest in France: A nationwide propensity score analysis from the ReAC Registry. AB - BACKGROUND: The survival rate of out-of-hospital cardiac arrest (OHCA) remains extremely low, generally under 10%. Post-resuscitation care, and particularly early coronary reperfusion, may improve this outcome. The main objective of the present study was to determine whether patients with immediate coronary angiography at hospital admission (CAA) had a better outcome than patients without immediate CAA. METHODS: This cohort analysis study was based on data extracted from the French National Cardiac Arrest registry (ReAC). To control for attribution bias, patients were matched using a propensity score, which included age clusters, low flow and no flow delays, initial rhythm and bystander cardiopulmonary resuscitation (CPR). The main endpoint was survival at day 30 (D30). Secondary endpoint was neurological recovery of survivors assessed by the Cerebral Performance Category (CPC) scale, with CPC 1 and 2 at D30 considered as a favorable outcome. RESULTS: From July 1st, 2011 to October 1st, 2016, 63394 OHCA were registered in the database, of which 39444 were of an unknown or suspected cardiac origin. After on-site resuscitation by a mobile medical team, 7584 patients were transported to a hospital facility. Among these patients, 4046 were retained in the analysis after matching for the aforementioned factors and constituted into 2 groups: immediate coronary angiography (iCAA) group (n = 2023) and non-immediate coronary angiography (niCAA) group (n = 2023). The survival rate at D30 after matching was 43.3% in the iCAA group versus 34.5% in the niCAA group (OD = 0.66 [0.58; 0.75], p < 0.001). In the iCAA group, (n = 707) 36% of the patients at D30 were CPC 1-2 comparatively to (n = 539) 27.3% in the niCAA group (p < 0.01). CONCLUSIONS: Both the survival and proportion of patients with favorable neurological recovery were significantly higher in patients who underwent an immediate coronary angiography after a resuscitated OHCA. These observational results warrant further exploration of the benefit of this invasive strategy in randomized studies. PMID- 29518441 TI - Physico-chemical evaluation of hydrophobically modified pectin derivatives: Step toward application. PMID- 29518442 TI - Coconut coir pith lignin: A physicochemical and thermal characterization. AB - The structural and thermal features of coconut coir pith lignin, isolated by three different extraction protocols incorporating two different energy supply sources, were characterized by different analytical tools. The three different chemical extraction protocols were alkaline - 7.5% (w/v) NaOH, organosolv - 85% (v/v) formic and acetic acids at 7:3 (v/v) ratio and polyethylene glycol (PEG): water ratio at 80:20wt%. The two sources of energy were thermal or microwave. Raw lignins were modified by epichlorohydrin to enhance reactivity, and the characteristics of raw and modified lignins were comparatively analysed. Using the thermal energy source, the alkaline and organosolv processes obtained the highest and lowest lignin yields of 26.4+/-1.5wt% and 3.4+/-0.2wt%, respectively, as shown by wet chemical analysis. Specific functional group analysis by Fourier transform infrared spectra (FTIR) revealed that significantly different amounts of hydroxyl and carbonyl groups exist in alkaline, organosolv and PEG lignins. Thermogravimetric analysis (TGA) illustrated that the lowest degradation onset temperature was recorded for organosolv lignin, and the overall order was organosolv3)-linked and (1->6)-linked Galp residues with an approximate molar ratio of 1:3. Approximately half of the (1->6) linked Galp residues were substituted at O-3, and small amounts of (1->6)-linked Galp were substituted at O-3 and O-4 by branches that mainly consisted of terminal and (1->5)-linked Araf residues. Bioactivity tests showed that SDNP-2 exhibited significant antagonistic effect against immunosuppression as shown by the cell viability of the culture supernatants of melanoma cells on RAW264.7 macrophages. However, SDNP-1 showed no effect. Thus, molecular weight and backbone chain may be the key factors for the antagonistic effects against immunosuppression. PMID- 29518444 TI - Biochemical characterization of a novel thermostable beta-glucosidase from Dictyoglomus turgidum. AB - Dtur_0462 gene from the hypertermophilic bacterium Dictyoglomus turgidum, encoding a beta-glucosidase, was synthetically produced and expressed in Escherichia coli BL21(DE3)-RIL. DturbetaGlu was purified to homogeneity by affinity chromatography and its homotetrameric structure was determined by gel filtration. The monomer is composed by 418 amino acidic residues and showed high sequence similarity with Glycoside Hydrolases (GHs) belonging to GH1 family. The maximum activity of DturbetaGlu was observed at 80 degrees C and at pH5.4. DturbetaGlu was stable in the range of pH5-8 and retained 70% of its activity after 2h of incubation at 70 degrees C. Metal ions and chemical reagents differently influenced the beta-glucosidase activity; furthermore, DturbetaGlu displays a good ethanol and glucose tolerance (Ki 750mM). The enzyme is active on p-nitrophenyl-beta-d-glucopyranoside (pNPGlu) (Km 0.84mM) and p-nitrophenyl-beta d-galactopyranoside (pNPGal) (Km 1.36mM) and shows a broad substrate specificity towards natural compounds as salicin, cellobiose and genistin. The ability to hydrolyze different substrates, the activation in the presence of surfactants, the good thermal resistance, and finally the high glucose and ethanol tolerance make this enzyme a good candidate for industrial applications. PMID- 29518446 TI - Inhibition of protein kinase A affects Paracoccidioides lutzii dimorphism. AB - A critical step in the lifecycle of many fungal pathogens is the ability to switch between filamentous and yeast growth, a process known as dimorphism. cAMP dependent protein kinase (PKA) controls morphological changes and the pathogenicity of several animal and plant pathogenic fungi. In this work, we report the analysis of PKA activity during the mycelium to yeast transition in the pathogenic fungus Paracoccidioides lutzii. This fungus, as well as the closely related species Paracoccidioides brasiliensis, causes paracoccidioidomycosis, a systemic mycosis that affects thousands of people in Latin America. Infection occurs when hypha fragments or spores released from mycelium are inhaled by the host, an event that triggers the morphological switch. We show here that PKA activity is regulated in the fungus phase, increasing during the mycelium to yeast transition. Also, morphological transition from mycelium to yeast is blocked by the compound H89, a specific PKA inhibitor. Nevertheless, the fungus recovers its ability to change morphology when H89 is removed from the culture media. This recovery is accompanied by a significant increase in PKA activity. Our results strongly indicate that PKA directly affects phase transition in P. lutzii. PMID- 29518445 TI - Quaternized gamma-Fe2O3@cellulose ionomer: An efficient recyclable catalyst for Michael-type addition reaction. AB - Owe to unique advantages of heterogeneous catalytic reactions, there is increasing interest to use this type of chemical transformations in organic synthesis. Among various heterogeneous catalytic systems, magnetic supported ionic liquids are emerging ones in the chemical synthesis. As a result, this research focuses on developing an efficient magnetically recyclable catalytic system for Michael-type addition reaction based on quaternized gamma Fe2O3@cellulose ionomer. Core-shell structured magnetite cellulose nanosphere was synthesized by one step precipitation route and further modified with epichlorohydrin and hexamethylenetetramine. Anion exchange reaction was performed with polytungstophosphate. Synthesized nanocatalyst was characterized with FESEM, FTIR, VSM, EDX and TEM techniques. Vinyl pyridine and three types of functional groups i.e., hydroxyl, thiol, and amine were employed to evaluate the catalyst performance. Results showed that the addition reaction promoted up to 95% within 2h reaction time at moderate temperature (50 degrees C) moreover the nanocatalyst showed good recyclability after three catalytic run as the reaction efficiency was >80% at the end of the third cycle which confirmed high efficiency of the presented system as a green heterogeneous catalyst to synthesis intermediate organic compounds. PMID- 29518447 TI - Structural characterization of a galactan from Ophiopogon japonicus and anti pancreatic cancer activity of its acetylated derivative. AB - A galactan ROH05 was isolated from the roots of Ophiopogon japonicus and further purified by DEAE SepharoseTM Fast Flow columns. The molecular weight of ROH05 was estimated to be 16.7kDa. ROH05 was composed of galactose only. According to the methylation analysis and the results of IR and NMR spectra, the backbone of ROH05 was composed of 1, 4-linked beta-D-galactose and 1, 4, 6-linked beta-D-galactose, while the branch of this polysaccharide was terminal-linked beta-D-galactose attached at C-6 position of 1, 4-linked beta-D-galactose directly. The acetylated galactan, ROH05A was prepared by the acetic anhydride-pyridine method. The acetylation modification mainly occurred at C-2, C-3 and C-6 positions of 1, 4 linked beta-D-galactose, and C-6 position of terminal-linked beta-D-galactose. Bioactivity test showed that ROH05A might inhibit both BxPC-3 and PANC-1 pancreatic cancer cells growth in a dose-dependent manner without significant toxicity to LO2 cells. In addition, the cells apoptosis was triggered since cleaved caspase-3 and FasL were activated while p53, p21, Bax expression were up regulated by ROH05A as well. PMID- 29518448 TI - Effects of nanoemulsions prepared with essential oils of copaiba- and andiroba against Leishmania infantum and Leishmania amazonensis infections. AB - Plant products are an important source of bioactive agents against parasitic diseases, including leishmaniasis. Among these products, vegetable oils have gained ground in the pharmaceutical field. Here we report the development of nanoemulsions as a delivery system for copaiba and andiroba oils (nanocopa and nanoandi) in order to test their effects on Leishmania infantum and L. amazonensis. The nanocopa and nanoandi had an average particle size of 76.1 and 88.1, respectively with polydispersity index 0.14 to 0.16 and potential zeta 2.54 to -3.9. The data indicated toxic activity of nanocopa and nanoandi against promastigotes of both Leishmania species ultrastructural analyses by scanning electron microscopy revealed that exposition to nanoemulsions induced oval cell shape and retracted flagella. The treatment with nanocopa and nanoandi led to a reduction in L. infantum and L. amazonensis infection levels in macrophage cultures. The nanoemulsions treatment have significant beneficial effects on all the parameters evaluated in lesions induced by L. amazonensis (lesion size, parasite burden and histopathology) on BALB/c mice. The treatment of L. infantum infected BALB/c mice with nanoemulsions also showed promising results reducing parasite burden in spleen and liver and improving histopathological features. PMID- 29518449 TI - Molecular characterization and epidemiological investigation of Cryptosporidium hominis IkA18G1 and C. hominis monkey genotype IiA17, two unusual subtypes diagnosed in Swedish patients. AB - Cryptosporidium hominis is considered a strictly human-adapted species, and it is only occasionally diagnosed in animals. However, two variants, C. hominis monkey genotype and C. hominis Ik, were originally described in non-human hosts, monkeys and horses, respectively. During a Swedish national Cryptosporidium study, where all samples were analyzed at the small subunit rRNA and the 60 kDa (gp60) glycoprotein loci, we identified two patients infected with C. hominis monkey genotype (subtype IiA17) and two infected with C. hominis subtype IkA18G1. The isolates were further analyzed at the actin and the 70 kDa heat shock protein loci, and these analyses showed that these two subtype families are closely related to each other and to human-adapted C. hominis as well as to Cryptosporidium cuniculus. The two patients with C. hominis monkey genotype infection (a father and son) had visited a monkey farm in Thailand prior to infection, while the two cases with C. hominis Ik were unrelated, both probably infected in Sweden. This is the first time that a monkey genotype infection in humans has been related to contact with monkeys and where the gp60 subtype was identified. It is also the first time that human infection caused by C. hominis subtype Ik is described. Even though we were not able to detect any parasites in the animal samples, zoonotic transmission cannot be ruled out in any of these cases because both subtype families are regarded as animal adapted. PMID- 29518450 TI - Comparison of in vitro viability methods for Cryptosporidium oocysts. AB - The water-borne protozoan parasite Cryptosporidium parvum forms oocysts that can persist for long periods of time in the environment, even though the sporozoites inside the oocysts may no longer be viable, making it difficult to assess the associated risk of infection. In this study, we compared the ability of various in vitro methods to discriminate viable from non-viable oocysts, including excystation, DAPI/PI staining, RNA FISH, PMA-qPCR and a novel polymer slide adhesion method. With the notable exception of our in vitro excystation protocol, all methods were found to be useful for identifying viable oocysts. PMID- 29518451 TI - Characterisation of susceptibility of chicken macrophages to infection with Toxoplasma gondii of type II and III strains. AB - Toxoplasma gondii is known to be able to infect any nucleated cell including immune cells like macrophages. In addition, it is assumed that macrophages serve as trojan horse during distribution in hosts. The underlying causes of parasite host interaction remain yet not fully understood. The aim of the present study was to investigate susceptibility of chicken macrophages to infection with T. gondii and the process of infection in avian cells in comparison to cells of mammalian origin. Primary avian blood monocyte-derived macrophages were infected with tachyzoites of type II (ME49) and III (NED) strains. Long term observations of parasite replication in primary macrophages were compared to data obtained in an avian macrophage cell line (HD11) and a standard cultivation mammalian cell line (VERO). Furthermore, we assessed the immune response of the primary macrophages by long-term investigation of gene expression of IL-1 beta, IL-12p40, Lipopolysaccharide induced TNF-alpha factor (LITAF) and inducible nitric oxide synthase (iNOS) comparing viable and heat-inactivated tachyzoites of the ME49 strain. Albeit, we found no differences between both strains, replication of tachyzoites in avian primary macrophages was significantly different from immortalized cell lines HD11 and VERO. The crucial period of parasite replication was between 8 and 24 h post-infection coinciding with the upregulation of gene expression of cytokines and iNOS revealing an active macrophage response at this period. Gene expression in macrophages was higher after infection with viable tachyzoites than by exposure of cells to heat-inactivated tachyzoites. Hence, we conclude that the process of penetration is pivotal for host cell response to the parasite both in avian as in mammalian cells. PMID- 29518452 TI - Positron emission tomography/computed tomography with 18F-fluorocholine improve tumor staging and treatment allocation in patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) staging according to the Barcelona Clinical Liver Cancer (BCLC) classification is based on conventional imaging. The aim of our study was to assess the impact of dual-tracer 18F fluorocholine and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on tumor staging and treatment allocation. METHODS: A total of 192 dual-tracer PET/CT scans (18F-fluorocholine and 18F-fluorodeoxyglucose PET/CT) were performed in 177 patients with HCC. BCLC staging and treatment proposal were retrospectively collected based on conventional imaging, along with any new lesions detected, and changes in BCLC classification or treatment allocation based on dual-tracer PET/CT. RESULTS: Patients were primarily men (87.5%) with cirrhosis (71%) due to alcohol +/- non-alcoholic steatohepatitis (26%), viral infection (62%) or unknown causes (12%). Among 122 patients with PET/CT performed for staging, BCLC stage based on conventional imaging was 0/A in 61 patients (50%), B in 32 patients (26%) and C in 29 patients (24%). Dual-tracer PET/CT detected new lesions in 26 patients (21%), upgraded BCLC staging in 14 (11%) and modified treatment strategy in 17 (14%). In addition, dual-tracer PET/CT modified the final treatment in 4/9 (44%) patients with unexplained elevation of alpha-fetoprotein (AFP), 10/25 patients (40%) with doubtful lesions on conventional imaging and 3/36 patients (8%) waiting for liver transplantation without active HCC after tumor response following bridging therapy. CONCLUSION: When used for HCC staging, dual-tracer PET/CT enabled BCLC upgrading and treatment modification in 11% and 14% of patients, respectively. Dual-tracer PET/CT might also be useful in specific situations (an unexplained rise in AFP, doubtful lesions or pre-transplant evaluation of patients without active HCC). LAY SUMMARY: Using a combination of tracers 18F-fluorocholine and 18F fluorodeoxyglucose when performing positron emission tomography/computed tomography (PET/CT), often called a PET scan, helps to identify new tumor lesions in patients with hepatocellular carcinoma. This technique enabled staging modification of patients' tumors and led to changes in treatment allocation in certain patients. PMID- 29518453 TI - Polyomavirus microRNA in saliva reveals persistent infectious status in the oral cavity. AB - Current evidence suggests that Polyomavirus (PyV) microRNAs (miRNAs) circulating in biological fluids may be relevant to understanding viral persistence. Here, the expression of polyomavirus BKPyV, JCPyV, MCPyV and SV40 miRNAs in saliva was investigated to evaluate PyV prevalence/persistence in the oral cavity. PyV-DNA status and PyV-miRNA expression was examined in paired saliva and plasma samples of 100 HIV-infected patients and of 50 healthy subjects using digital droplet PCR and PyV-miRNA-5p stem-loop RT-PCR. Overall, the PyV-miRNA in saliva samples showed higher positivity (65%) than PyV-DNA (24%). In particular, the PyV-miRNA prevalence in HIV-infected patients was 66% and that in healthy subjects was 64%. The PyV-DNA prevalence values in the HIV-infected and healthy subjects were 25% and 22%, respectively. The presence of a single type of PyV-miRNA in the saliva of HIV-infected patients ranged from 14% (MCPyV) to 61% (BKPyV) and in healthy subjects ranged from 14% (SV40) to 70% (BKPyV). Moreover, the PyV-miRNA in the saliva of both HIV-infected and healthy subjects exhibited higher prevalence than that in the paired plasma samples. Notably, the saliva of the HIV-infected and healthy subjects was more frequently positive for more than one PyV-miRNA than the paired plasma samples or the PyV-DNA in the paired saliva and plasma samples. Collectively, these data suggest that additional investigations of PyV-miRNA present in saliva may be useful to shed light on their utility as a surrogate for determining viral infection. PMID- 29518454 TI - Circulating CXCR5+CD4+ T cells participate in the IgE accumulation in allergic asthma. AB - The pathogenesis of allergic asthma is primarily characterized by abnormality in immunoglobin(Ig)E pathway, suggesting a possible role for follicular helper T cells (Tfh) in the genesis of excessive IgE accumulation. The blood chemokine (C X-C motif) receptor 5 (CXCR)5+CD4+ T cells, known as "circulating" Tfh, share common functional characteristics with Tfh cells from germinal centers. The aim of this study was to determine the phenotypes and functions of circulating CXCR5+CD4+ T cells in allergic asthmatics. Here we found the frequency of the circulating CXCR5+CD4+ T cells was raised in allergic asthma compared with healthy control (HC). Phenotypic assays showed that activated circulating CXCR5+CD4+ T cells display the key features of Tfh cells, including invariably coexpressed programmed cell death (PD)-1 and inducible costimulator (ICOS). The frequency of interleukin IL-4+-, IL-21+-producing CXCR5+CD4+ T cells was increased in allergic asthma patients compared with HC. Furthermore, sorted circulating CXCR5+CD4+ T cells from allergic asthma patients boosted IgE production in coculture assay which could be inhibited by IL-4 or IL-21 blockage. Interestingly, IL-4+-, IL-21+-CXCR5+CD4+ T cells positively correlated with total IgE in the blood. Our data indicated that circulating CXCR5+CD4+ T cells may have a significant role in facilitating IgE production in allergic asthma patients. PMID- 29518455 TI - Patient quality of life fluctuates before and after Mohs micrographic surgery: A longitudinal assessment of the patient experience. AB - BACKGROUND: Changes in patient perceptions of quality of life (QOL) after Mohs micrographic surgery (MMS) may benefit from different counseling or treatment. OBJECTIVE: To measure QOL before and after MMS and to identify risk factors associated with impaired QOL. METHODS: Prospective observational study of 727 patients with skin cancer who self-reported QOL via the Skin Cancer Index immediately before and at 1 to 2 weeks and 3 months after MMS. RESULTS: QOL fluctuated after MMS. At 1 to 2 weeks after surgery, overall QOL remained unchanged compared with before MMS. Patients reported reduced anxiety about skin cancer but had increased distress about social interactions and physical appearance. At 3 months after surgery, patients reported an overall improvement in QOL compared with before MMS (P = .0007). Age younger than 65 years (P = .0001), female sex (P = .0001), and tobacco use (P = .03) were associated with lower QOL scores at all assessment points. LIMITATIONS: Single-site observational study. Significant loss to follow-up at both time points after MMS. CONCLUSION: Patients with skin cancer had persistent concerns about social interactions and physical appearance 1 to 2 weeks after MMS, but all aspects of their QOL improved by 3 months after surgery. Patients who underwent MMS that were younger than 65 years, were female, or smoked were at increased risk for longitudinally impaired QOL. PMID- 29518456 TI - An effective game-based learning intervention for improving melanoma recognition. PMID- 29518457 TI - Assessing the safety of superficial chemical peels in darker skin: A retrospective study. AB - BACKGROUND: Chemical peels have shown efficacy in the treatment of acne, photoaging, and pigmentary dyschromias; however, studies evaluating side effects, particularly in patients with skin of color, are limited. OBJECTIVE: We sought to determine the frequency of side effects and complications associated with superficial chemical peels in patients with skin types III-VI. METHODS: A 5-year single center retrospective analysis was performed. RESULTS: Of 473 chemical peel treatments included in this study, 18 (3.8%) were associated with short-term (<=2 weeks) or long-term (>2 weeks) complications. The most frequent complications were crusting (2.3%), postinflammatory hyperpigmentation (1.9%), and erythema (1.9%). All side effects resolved within 8 months of treatment and were located on the face. When stratified by season, side effects were noted to be less common during the winter. In the adjusted model, Fitzpatrick skin type VI was associated with a higher odds of side effects (odds ratio 5.14, 95% confidence interval 1.21 21.8; P = .0118). LIMITATIONS: Single center retrospective design. CONCLUSION: In this study, superficial chemical peels performed on patients with skin types III VI had a relatively low complication rate, and skin type VI had higher odds of experiencing an adverse event. Side effects were noted to be less frequent during the winter months. PMID- 29518458 TI - The prognostic significance of tumor-infiltrating lymphocytes for primary melanoma varies by sex. AB - BACKGROUND: The immune response to melanoma is manifested locally by tumor infiltrating lymphocytes (TILs). Men and women are known to have varying patterns of immunity, yet sex-specific prognostic implications of TILs have not been explored. METHODS: Patients who had clinically localized primary melanoma with a Breslow thickness of 0.76 mm or more and underwent sentinel lymph node (SLN) biopsy at our institution were identified. The association between TILs (absent, nonbrisk, and brisk) and SLN positivity was evaluated by using logistic regression. Overall survival (OS) was evaluated by TIL status and sex. RESULTS: Among 1367 patients identified, 794 were men. TILs were brisk in 143 lesions, nonbrisk in 903, and absent in 321, which did not vary by sex (P = .71). SLN positivity was associated with TILs among men (brisk, 3.8%; nonbrisk, 16.9%; and absent, 26.6% [P < .001]). In contrast, there was no association between SLN positivity and TILs among women (P = .49). Interaction between brisk TILs and sex on SLN positivity was significant (P = .029). Among men, presence of brisk TILs was associated with prolonged OS (P = .038) but not after adjustment for SLN status (P = .42). There was no association between TIL status and OS among women. LIMITATIONS: Findings from this single-institution study have yet to be validated by other research groups. CONCLUSIONS: The implications of TILs in predicting SLN positivity appear to be more relevant for men than for women. PMID- 29518459 TI - Skin cancer prevention messages on Facebook: Likes, shares, and comments. PMID- 29518460 TI - Type I pityriasis rubra pilaris treated with tumor necrosis factor inhibitors, ustekinumab, or secukinumab: A review. PMID- 29518461 TI - Somatic and psychiatric comorbidities of hidradenitis suppurativa in children and adolescents. AB - BACKGROUND: Hidradenitis suppurativa (HS) is associated with various somatic and psychiatric comorbidities. Data regarding comorbidities in young patients with HS are sparse. OBJECTIVE: We analyzed both somatic and psychiatric comorbidities in young patients in a nationwide HS cohort. METHODS: In this retrospective case control study, data from cases of HS in young (age 5 to <18 years) patients and age-matched controls with benign melanocytic nevi were collected from the Finnish Care Register for Health Care. The prevalence of preselected comorbidities was compared between the HS and control groups. RESULTS: A total of 153 HS cases were found in the specified age group. Of these, 34.0% had at least 1 somatic comorbidity compared with 4.9% of the controls. At least 1 of the preselected psychiatric diagnoses was present before the age of 18 years in 15.7% of case patients with HS compared with in 5.6% of the controls. By the age of 23 years, 23.5% of the patients with HS and 8.7% of the controls had at least 1 identified psychiatric comorbidity. LIMITATIONS: Despite this being one of the largest HS cohorts ever studied, the number of young patients with HS was relatively low. Because this was a registry-based study, it was not possible to verify the accuracy of the International Classification of Diseases codes. CONCLUSION: Physicians should monitor young patients with HS for both somatic and psychiatric comorbidities. PMID- 29518462 TI - Degradation of cationic surfactants using immobilized bacteria: Its effect on adsorption to activated sludge. AB - Adsorption of cationic surfactants (QACs) Br-tetradecyltrimethylammonium (TTAB), Cl-tetradecylbenzyldimethylammonium (C14BDMA) and Cl hexadecylbenzyldimethylammonium (C16BDMA) to activated sludge from a wastewater treatment plant was tested. Adsorption equilibrium was reached after 2 h, and for initial 200 mg L-1 81%, 90% and 98% of TTAB, C14BDMA and C16BDMA were respectively adsorbed. After six successive desorption cycles, 21% of TTAB and 12.7% of C14BDMA were desorbed from the sludge. In agreement with the percentage of QACs pre-adsorbed, the more hydrophobic the compound, the lesser the extent of desorption. Wastewater samples with activated sludge were supplemented with TTAB 200 mg L-1 and Ca-alginate beads containing the QACs-degrading microorganisms Pseudomonas putida A (ATCC 12633) and Aeromonas hydrophila MFB03. After 24 h, 10 mg L-1 of TTAB were detected in the liquid phase and 6-8 mg L-1 adsorbed to the sludge. Since without Ca-alginate beads or with empty beads total TTAB amount (phase solid and liquid) did not change, the 90% reduction of the initial 200 mg L-1 after treatment with immobilized cells was attributed to the bacterial consortium's capacity to biodegrade QACs. The results show the advantages of using immobilized bacteria to achieve complete QACs elimination from wastewater systems, thus preventing them from reaching the environment. PMID- 29518463 TI - Sensitive and specific detection of ligands using engineered riboswitches. AB - Riboswitches are RNA elements found in non-coding regions of messenger RNAs that regulate gene expression through a ligand-triggered conformational change. Riboswitches typically bind tightly and specifically to their ligands, so they have the potential to serve as highly effective sensors in vitro. In B. subtilis and other gram-positive bacteria, purine nucleotide synthesis is regulated by riboswitches that bind to guanine. We modified the xpt-pbuX guanine riboswitch for use in a fluorescence quenching assay that allowed us to specifically detect and quantify guanine in vitro. Using this assay, we reproducibly detected as little as 5 nM guanine. We then produced sensors for 2'-deoxyguanosine and cyclic diguanylate (c-diGMP) by appending the P1 stem of the guanine riboswitch to the ligand-binding domains of a 2'-deoxyguanosine riboswitch and a c-diGMP riboswitch. These hybrid sensors could detect 15 nM 2'-deoxyguanosine and 3 nM c diGMP, respectively. Each sensor retained the ligand specificity of its corresponding natural riboswitch. In order to extend the utility of our approach, we developed a strategy for the in vitro selection of sensors with novel ligand specificity. Here we report a proof-of-principle experiment that demonstrated the feasibility of our selection strategy. PMID- 29518464 TI - Whole genome sequence analysis of Geitlerinema sp. FC II unveils competitive edge of the strain in marine cultivation system for biofuel production. AB - A filamentous cyanobacteria, Geitlerinema sp. FC II, was isolated from marine algae culture pond at Reliance Industries Limited (RIL), India. The 6.7 Mb draft genome of FC II encodes for 6697 protein coding genes. Analysis of the whole genome sequence revealed presence of nif gene cluster, supporting its capability to fix atmospheric nitrogen. FC II genome contains two variants of sulfide:quinone oxidoreductases (SQR), which is a crucial elector donor in cyanobacterial metabolic processes. FC II is characterized by the presence of multiple CRISPR- Cas (Clustered Regularly Interspaced Short Palindrome Repeats - CRISPR associated proteins) clusters, multiple variants of genes encoding photosystem reaction centres, biosynthetic gene clusters of alkane, polyketides and non-ribosomal peptides. Presence of these pathways will help FC II in gaining an ecological advantage over other strains for biomass production in large scale cultivation system. Hence, FC II may be used for production of biofuel and other industrially important metabolites. PMID- 29518465 TI - In vitro and ex vivo correlation of drug release from ophthalmic ointments. AB - In vitro drug release testing and ex vivo transcorneal drug permeation can provide valuable information on the performance of the Q1/Q2 equivalent ointments prior to any animal studies. Good correlation between in vitro and ex vivo drug release may be indicative of good in vitro and in vivo correlation. Accordingly, it is important to investigate in vitro as well as ex vivo drug release from Q1/Q2 equivalent ophthalmic ointments and evaluate whether a correlation between these release profiles can be established. Four Q1/Q2 equivalent loteprednol etabonate ointments were prepared using different processing methods and excipient sources. The rheological parameters (crossover modulus and K value) of the four formulations were determined. The in vitro drug release testing of the four ointment formulations were performed using three different apparati (Franz diffusion cells, USP apparatus 2 with enhancer cells and USP apparatus 4 with semisolid adapters). Three models (zero order, logarithmic and the Higuchi model) were used to study the release kinetics of the ointment formulations. The transcorneal (rabbit corneas) permeation studies were performed using spherical joint Franz diffusion cells. The USP apparatus 4 method demonstrated better discriminatory ability compared to the USP apparatus 2 and the Franz diffusion cell methods. The in vitro release profiles of the four Q1/Q2 equivalent ointments with manufacturing differences showed a better fit using the Higuchi model (R2 > 0.98) for all three release testing methods, compared to the other two models. Ex vivo drug release through the rabbit corneas displayed zero order release kinetics. A logarithmic correlation between rheological parameters (crossover and K value) and transcorneal flux were established. In addition, a plot of the in vitro release rate against the ex vivo release flux of the four ointment formulations, yielded a straight line (R2 > 0.98) for all three release methods. Accordingly, the rheological parameters may be useful in predicting in vitro as well as ex vivo release properties. PMID- 29518466 TI - PEG-PGA enveloped octaarginine-peptide nanocomplexes: An oral peptide delivery strategy. AB - The objective of this work was the development of a new drug nanocarrier intended to overcome the barriers associated to the oral modality of administration and to assess its value for the systemic or local delivery of peptides. The nanocarrier was rationally designed taking into account the nature of the intestinal barriers and was loaded with insulin, which was selected as a model peptide. The nanocarrier consisted of a complex between insulin and a hydrophobically-modified cell penetrating peptide (CPP), enveloped by a protecting polymer. The selected CPP was octaarginine (r8), chemically conjugated with cholesterol (Chol) or lauric acid (C12), whereas the protecting polymer was poly (glutamic acid)-poly (ethylene glycol) (PGA-PEG). This enveloping material was intended to preserve the stability of the nanocomplex in the intestinal medium and facilitate its diffusion across the intestinal mucus. The enveloped nanocomplexes (ENCPs) exhibited a number of key features, namely (i) a unimodal size distribution with a mean size of 200 nm and a neutral zeta potential, (ii) the capacity to associate insulin (~100% association efficiency) and protect it from degradation in simulated intestinal fluids, (iii) the ability to diffuse through intestinal mucus and, most importantly, (iv) the capacity to interact with the Caco-2 model epithelium, resulting in a massive insulin cell uptake (47.59 +/- 5.79%). This enhanced accumulation of insulin at the epithelial level was not translated into an enhanced insulin transport. In fact, only 2% of insulin was transported across the monolayer, and this was correlated with a moderate response of insulin following oral administration to healthy rats. Despite of this, the accumulation of the insulin-loaded nanocarriers in the intestinal mucosa could be verified in vivo upon their labeling with 99mTc. Overall, these data underline the capacity of the nanocarriers to overcome substantial barriers associated to the oral modality of administration and to facilitate the accumulation of the associated peptide at the intestinal level. PMID- 29518468 TI - Nutrient-specific system versus full fact panel: Testing the benefits of nutrient specific front-of-package labels in a student sample. AB - Current food labels include comprehensive nutritional information, but evaluations of their effects on judgments of nutritional quality and food choice are scarce. Building on previous empirical research that demonstrated that amount and complexity of information is negatively related to judgment accuracy, this study used an experimental design to evaluate nutritional information labels of varying complexity. Lens model analysis (Brunswik, 1952; Cooksey, 1996; Hammond, 1955; Stewart, 1976) was used to study the judgment process. Nutrition judgment accuracy was assessed by comparing nutrition judgments to a nutrition expert criterion (NuVal(r)) in three package labeling conditions. The conditions were: no nutritional information highlighted; nutrients highly related to nutritional quality highlighted using a front-of-package (FOP) label; and nutrients unrelated to nutritional quality highlighted using a FOP label. Findings indicate a limited role of FOP labeling in increasing judgment accuracy, consistency of nutritional information usage, and food choice. Implications for understanding labeling efforts to improve food choices are discussed. PMID- 29518467 TI - Cationic polymers for non-viral gene delivery to human T cells. AB - The clinical success of chimeric antigen receptor (CAR) T cell immunotherapy in treating multiple blood cancers has created a need for efficient methods of ex vivo gene delivery to primary human T cells for cell engineering. Here, we synthesize and evaluate a panel of cationic polymers for gene delivery to both cultured and primary human T cells. We show that a subset of comb- and sunflower shaped pHEMA-g-pDMAEMA polymers can mediate transfection with efficiencies up to 50% in the Jurkat human T cell line with minimal concomitant toxicity (>90% viability). We then optimize primary human T cell transfection conditions including activation time, cell density, DNA dose, culture media, and cytokine treatment. We demonstrate transfection of both CD4+ and CD8+ primary human T cells with messenger RNA and plasmid DNA at efficiencies up to 25 and 18%, respectively, with similarly high viability. PMID- 29518469 TI - Suppressing images of desire: Neural correlates of chocolate-related thoughts in high and low trait chocolate cravers. AB - Chocolate is the most often craved food in Western societies and many individuals try to resist its temptation due to weight concerns. Suppressing chocolate related thoughts might, however, lead to paradoxical enhancements of these thoughts and this effect might be more pronounced in individuals with frequent chocolate cravings. In the current study, neural and cognitive correlates of chocolate thought suppression were investigated as a function of trait chocolate craving. Specifically, 20 high and 20 low trait chocolate cravers followed suppression vs. free thinking instructions after being exposed to chocolate and neutral images. Enhanced cue reactivity was evident in high trait chocolate cravers in that they reported more chocolate-related thoughts selectively after chocolate images compared to their low trait craving counterparts. This cue reactivity was mirrored neurally by higher activation in the ventral and dorsal striatum, demonstrating enhanced reward system activity. Unexpectedly, high trait chocolate cravers successfully reduced their elevated chocolate thoughts in the suppression condition. This lends support for the use of thought suppression as a means of regulating unwanted thoughts, cravings and imagery. Whether this thought manipulation is able to curb the elevated cue reactivity and the underlying reward sensitivity in chocolate cravers in applied settings remains to be shown. PMID- 29518470 TI - When do healthiness and liking drive children's food choices? The influence of social context and weight status. AB - Children identify liking and healthiness of foods as factors influencing their food choices. However, the food decision making process is also influenced by both personal characteristics and food contexts. The present study explored the influence of liking and perceived healthiness of foods in normal- and overweight children's food choices intentions in a pleasure-oriented social eating context and a health-oriented social eating context. Children aged from 6 to 11 years old (n = 63; 34 children who were of normal weight and 29 who were overweight) were asked to select 5 foods among 10, based on food pictures, to make up a snack that would be suitable for their birthday party or a nutrition class. In addition, they rated their liking and healthiness perception of the foods. No significant difference in food choices was found between children who were of normal weight and children who were overweight. Both groups of children chose more healthy food items in a health-oriented social context (i.e., a fictive nutrition class) than in a pleasure-oriented social context (i.e., a fictive birthday party). Moreover, only liking significantly predicted food choices in the pleasure-oriented social context whereas both healthiness and liking significantly predicted food choices in the health-oriented social context. Overall these results advance our understanding on how children make food decisions and inform strategies that may help children to adopt a healthy diet. Because liking predicted children's food choices in both eating contexts, emphasizing the "good" taste of healthy foods and providing children with healthy foods they like could be efficient strategies to promote healthy eating habits in children. PMID- 29518471 TI - High Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression. AB - Cancer heterogeneity is one of the factors that constitute an obstacle towards an efficient targeting of this multifaceted disease. Molecular information can help in classifying cancer subtypes and in providing clinicians with novel targeted therapeutic opportunities. In this regard, classification of breast cancer into intrinsic subtypes based on molecular profiling represents a valuable prototype. The High Mobility Group A (HMGA) chromatin architectural factors (HMGA1a, HMGA1b, and HMGA2) have a relevant and causal role in breast cancer onset and development, by influencing virtually all cancer hallmarks. The regulation of HMGA expression is under the control of major pathways involved in cell proliferation and survival, as well as in other cancer-related processes, thereby suggesting, for the HMGA members, a high degree of homology and overlapping activities. Despite of this evidence, HMGA proteins display also specific functions. In this review, we provide an overview of (i) the pathways involved in HMGA transcriptional and post-transcriptional regulation, (ii) the utilization of HMGA as molecular markers, and (iii) the biological role of HMGA in the context of breast cancer. We focus on the potential significance of HMGA in governing the onset and development of this tumour, as well as on the potential of these factors as novel specific targets for preventing and treating strategies. The emerging picture is a highly interconnected triad of proteins that could mutually influence each other, either in a competitive or cooperative manner, and that, in our opinion, should be considered as a unified and integrated protein system. PMID- 29518472 TI - PCB28 and PCB52 induce hepatotoxicity by impairing the autophagic flux and stimulating cell apoptosis in vitro. AB - Hepatotoxicity is one of the adverse health effects induced by polychlorinated biphenyls (PCBs). Recently, autophagy was revealed to play an important role in PCBs-induced toxicology, however, its precise role in PCBs-induced hepatotoxicity is as yet unknown. In this study, treatment of PCB28/PCB52 for 48 h dose dependently induced hepatotoxicity at doses of 10, 20, 40 and 80 MUM in homo and rattus hepatocytes. Expressions of proteins of BECN1, LC3-II and ULK1 significantly increased in PCB28/PCB52-treated cells at a dose of 40 MUM, implying initiation of autophagy. Over-expression of p62 suggested deficient clearance of autophagosome. Consistently, accumulation of autophagosome was observed by transmission-electron microscopy and confocal fluorescence microscopy using adenovirus expressing mRFP-GFP-LC3, which may initiate apoptosis. Furthermore, increased reactive oxygen species levels might also induce autophagy and apoptosis. Consistently, cell apoptosis was evoked by the treatment of PCB28/PCB52 compared to the respective controls, which coincided with obvious hepatotoxicity. Subsequently, an inhibitor (3-methlyadenine) and an initiator (rapamycin) of autophagy were used. Compared to PCB28/PCB52 alone-treated cells, initiation of autophagy, blocked autophagic flux, cell apoptosis and hepatotoxicity were alleviated by 3-methlyadenine and aggravated by rapamycin, respectively. Taken together, PCB28 and PCB52 induced hepatotoxicity by impairing autophagic flux and stimulating cell apoptosis in vitro. PMID- 29518473 TI - Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. AB - Microcystin (MC) is a cyclic heptapeptide compound which could lead to the development of hepatocellular carcinoma. However, the underlying epigenetic regulation mechanism is largely unknown. In this study, microcystin-LR (L: lysine, R: arginine, MC-LR) was used to induce the malignant transformation of human hepatocyte L02 cell line. The profile of gene expression, microRNA (miRNA) and DNA methylation were detected through high-throughput sequencing. Compared with control group, the expression of 826 genes and 187 miRNAs changed significantly in MC-LR treated group. DNA methylation sequencing analysis showed that 2592 CpG sites differentially methylated in promoter or the coding DNA sequence (CDS) of genes, while DNA methyltransferase 3 alpha (DNMT3a) and DNA methyltransferase 3 beta (DNMT3b) were dramatically up-regulated. Functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that significantly changed mRNAs and microRNAs were mainly involved in the formation of cancer, proliferation, invasion, migration and metabolism. MiRNA mRNA network and mRNA-mRNA network analysis showed that hsa-miR-320a, hsa-miR-331 3p, hsa-miR-26a-5p, hsa-miR-196a-5p, hsa-miR-221-3p, coiled-coil domain containing 180 (CCDC180), melanoma antigen gene family member D1 (MAGED1), membrane spanning 4-domains A7 (MS4A7), hephaestin like 1 (HEPHL1), BH3 (Bcl-2 homology 3)-like motif containing, cell death inducer (BLID), matrix metallopeptidase 13 (MMP13), guanylate binding protein 5 (GBP5), adipogenesis regulatory factor (ADIRF), formin homology 2 domain containing 1 (FHDC1), protein kinase CAMP-dependent type II regulatory subunit beta (PRKAR2B), nodium leak channel, non-selective (NALCN), myosin light chain kinase 3 (MYLK3), epidermal growth factor receptor (EGFR) and zinc finger protein 704 (ZNF704) were key miRNAs and genes in the malignant transformation induced by MC-LR in L02 cells. Moreover, we found that expression of MYLK3, EGFR and ZNF704 were regulated by DNA methylation and miRNAs, and these genes affected the cell cycle and cell division. Our study suggested that characteristic gene alterations regulated by DNA methylation and miRNA could play an important role in environmental MC-LR induced hepatic carcinogenesis. PMID- 29518474 TI - Anti-allergy activities of Kuji amber extract and kujigamberol. AB - Amber is fossilized tree resin and several biologically active compounds were isolated from ambers using the growth-restoring activity of the mutant yeast [Saccharomyces cerevisiae (zds1? erg3? pdr1? pdr3?)] involving Ca2+-signal transduction. The aim of this study is to investigate the anti-allergic effect of both the methanol extract of Kuji amber (MEKA) and its main biologically active constituent, kujigamberol (15,20-dinor-5,7,9-labdatrien-18-ol) having activity against the mutant yeast. Both MEKA and kujigamberol inhibited the degranulation of RBL-2H3 cells by stimulation of thapsigargin (Tg) (IC50 = 15.0 MUg/ml and 29.1 MUM) and A23187 (IC50 = 19.6 MUg/ml and 24.9 MUM) without cytotoxicity, but not by stimulation of IgE + DNP-BSA (Ag) (IC50 > 50.0 MUg/ml and 50.0 MUM). However, both inhibited Ca2+-influx in RBL-2H3 cells by all three stimulations in a dose dependent manner. Leukotriene C4 production in RBL-2H3 cells stimulated by A23187 was also inhibited by both through the inhibition of ERK1/2 phosphorylation. In an ovalbumin-induced rhinitis model of guinea pigs, nasal administration of MEKA and kujigamberol inhibited nasal blockade in a dose-dependent manner and the effect was about 5 times potent than that of a steroid clinical drug, mometasone furoate. The growth-restoring activity of MEKA and kujigamberol against the mutant yeast is involved in the anti-allergic activities against cells and animals, and both are expected to be candidates for the development of new anti allergy agents. PMID- 29518475 TI - Most response-inducing strategies do not increase participation in observational studies: a systematic review and meta-analysis. AB - OBJECTIVES: To evaluate response-inducing strategies for observational studies using health-related questionnaires or interviews. STUDY DESIGN AND SETTING: We searched PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science up to December 28, 2017. Studies evaluating the effect of a response-inducing strategy on participation rates of observational studies were included. For each strategy, we estimated pooled response ratios with 95% confidence intervals (CIs) in a Hartung Knapp/Sidik-Jonkman random effects model with the final participation rate as outcome, stratified for type of participants and method of data collection. RESULTS: The search yielded 168 eligible studies involving 367,616 potential participants and 33 strategies. Among patients, response-inducing strategies for paper-based questionnaires included unconditional monetary incentives (response ratio 1.15; 95% CI 1.09-1.21) and shorter questionnaires (1.04; 1.02-1.06). Among nonpatients, a personalized mode of delivery (1.47; 1.24-1.74), more expensive mailing type (1.25; 1.00-1.56), unconditional monetary incentives (1.24; 1.12 1.38), prenotification (1.12; 1.03-1.22), unconditional scratch lottery tickets (1.09; 1.01-1.18), and shorter questionnaires (1.06; 1.02-1.11) increased response rates to paper-based questionnaires. For Web-based questionnaires and interviews among nonpatients, response rates were increased by conditional lottery tickets (1.17; 1.02-1.34) and conditional monetary incentives (1.39; 1.01 1.91), respectively. CONCLUSION: Although the majority of strategies evaluated were unsuccessful, some may increase response rates to observational studies, particularly among nonpatients. PMID- 29518476 TI - Letter to the editor in response to "No difference in knowledge obtained from infographic or plain language summary of a Cochrane systematic review: three randomized controlled trials" by Buljan et al. (2017). PMID- 29518477 TI - Response to letter to the editor by Mc Sween-Cadieux et al. (2017). PMID- 29518478 TI - Imbalance control in clinical trial subject randomization-from philosophy to strategy. PMID- 29518479 TI - The association between telomere length and frailty: A systematic review and meta analysis. AB - BACKGROUND: Several studies have examined the association between telomere length and frailty, but results from these studies are contradictory. Therefore, we conducted a systematic review and meta-analysis to examine the association between telomere length and frailty. METHODS: We searched the literature in Ovid (MEDLINE), Embase, PubMed, Web of Knowledge and Cochrane databases in July 2017 for studies evaluating the association of telomere length and the risk of frailty. RESULTS: A total of 5 studies (3268 participants) were eligible in our study. The prevalence of frailty ranged from 5.4% to 51.1%. The pooled mean difference of telomere length for the non-frail versus frail was 0.06 (95% CI: 0.01, 0.13), suggesting that no significant association was found between telomere length and frailty. In addition, the subgroup analysis indicated that telomere length was not significantly associated with the risk of frailty in all gender groups. Similar results were also found when frailty was defined by the Fried criteria (mean difference = 0.07, 95% CI: -0.03, 0.16) and frailty index (mean difference = -0.02, 95% CI: -0.05, 0.01), but not by the frailty scale (mean difference = 0.18, 95% CI: 0.04, 0.32). CONCLUSION: Telomere length is not associated with the risk of frailty. Well-designed prospective studies are needed to evaluate further whether telomere length is a meaningful biological marker for frailty. PMID- 29518480 TI - Longitudinal monitoring reveals dynamic changes in circulating tumor cells (CTCs) and CTC-associated miRNAs in response to chemotherapy in metastatic colorectal cancer patients. AB - We evaluated the changes in CTC count and CTC-associated miRNAs during the course of chemotherapy in patients with metastatic colorectal cancer. Blood samples were collected from 9 metastatic colorectal cancer patients prior to chemotherapy and at every other chemotherapy session during the course of treatment. CTCs were isolated and enumerated using a size-exclusion method (CellSievo, Singapore). CTC associated miRNAs were isolated using a paper-based, partitioning method, and analyzed using reverse transcription quantitative real-time PCR (MiRXES, Singapore). CTC count trends generally correlated with disease progression defined by radiological measurements and trends in carcinoembryonic antigen (CEA) levels; hence CTC counts may be useful in cases where CEA is not elevated. CTC associated miRNAs identified were miR-15b, miR-16, miR-19a, miR-21, miR-25, miR 30d, miR-126, miR-185, miR-221, miR-222, and miR-324-5p. The expression of CTC associated miRNAs did not appear to correlate with CTC count and exhibited inter individual heterogeneity. This pilot study suggests that analysis of CTC changes during the course of treatment may be useful in monitoring response to therapy in metastatic colorectal cancer. PMID- 29518481 TI - Epidermal growth factor receptor (EGFR) inhibitor PD153035 reverses ABCG2 mediated multidrug resistance in non-small cell lung cancer: In vitro and in vivo. AB - One of the major mediators of multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) is the overexpression of ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we conducted in vitro and in vivo experiments to determine whether PD153035, an inhibitor of EGFR, could reverse ABCG2-mediated MDR in human NSCLC and transfected cells overexpressing ABCG2. The efficacy of SN 38, topotecan, and mitoxantrone (MX) were significantly increased by PD153035, PD153035 significantly reversed ABCG2-mediated MDR by attenuating the efflux activity of this transporter. In addition, PD153035 significantly down-regulated the expression of the ABCG2 transporter protein. Furthermore, a combination of PD153035 and topotecan, exhibited significant synergistic anticancer activity against mice xenografted with human H460/MX20 cells. These results, provided that they can be extrapolated to humans, suggest that the combination of topotecan and PD153035 could be a promising therapeutic strategy to attenuate the resistance to topotecan, as well as other anticancer drugs, mediated by the overexpression of ABCG2. PMID- 29518482 TI - Antisense-mediated reduction of EphA4 in the adult CNS does not improve the function of mice with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult onset motor neuron disease characterized by progressive denervation and subsequent motor impairment. EphA4, a negative regulator of axonal growth, was recently identified as a genetic modifier in fish and rodent models of ALS. To evaluate the therapeutic potential of EphA4 for ALS, we examined the effect of CNS-directed EphA4 reduction in preclinical mouse models of ALS, and assessed if the levels of EPHA4 mRNA in blood correlate with disease onset and progression in human ALS patients. We developed antisense oligonucleotides (ASOs) to specifically reduce the expression of EphA4 in the central nervous system (CNS) of adult mice. Intracerebroventricular administration of an Epha4-ASO in wild-type mice inhibited Epha4 mRNA and protein in the brain and spinal cord, and promoted re innervation and functional recovery after sciatic nerve crush. In contrast, lowering of EphA4 in the CNS of two mouse models of ALS (SOD1G93A and PFN1G118V) did not improve their motor function or survival. Furthermore, the level of EPHA4 mRNA in human blood correlated weakly with age of disease onset, and it was not a significant predictor of disease progression as measured by ALS Functional Rating Scores (ALSFRS). Our data demonstrates that lowering EphA4 in the adult CNS may not be a stand-alone viable strategy for treating ALS. PMID- 29518484 TI - International regulatory requirements for skin sensitization testing. AB - Skin sensitization test data are required or considered by chemical regulation authorities around the world. These data are used to develop product hazard labeling for the protection of consumers or workers and to assess risks from exposure to skin-sensitizing chemicals. To identify opportunities for regulatory uses of non-animal replacements for skin sensitization tests, the needs and uses for skin sensitization test data must first be clarified. Thus, we reviewed skin sensitization testing requirements for seven countries or regions that are represented in the International Cooperation on Alternative Test Methods (ICATM). We noted the type of skin sensitization data required for each chemical sector and whether these data were used in a hazard classification, potency classification, or risk assessment context; the preferred tests; and whether alternative non-animal tests were acceptable. An understanding of national and regional regulatory requirements for skin sensitization testing will inform the development of ICATM's international strategy for the acceptance and implementation of non-animal alternatives to assess the health hazards and risks associated with potential skin sensitizers. PMID- 29518485 TI - Association of serum vitamin D levels and diabetic retinopathy in Asian Indians with type 2 diabetes. AB - BACKGROUND: Vitamin D deficiency (VDD) is a condition that has been associated with diabetic retinopathy (DR) in various populations, but has not been studied in Asian Indians. AIMS: To evaluate the association of serum 25-hydroxyvitamin D (25(OH)D) levels with presence and severity of DR among Asian Indians with type 2 diabetes. METHODS: We collected information on individuals with type 2 diabetes that received care at a tertiary diabetes centre in India, between 2012 and 2015. Patients were 18 years of age or older, underwent retinal examinations with DR severity grading and had serum 25(OH)D measurements. RESULTS: Serum 25(OH)D levels were lower in patients with retinopathy compared to those without (11.9 +/ 2.2 ng/ml vs. 13.7 +/- 2.1 ng/ml, p < 0.001). Stratifying patients by DR grade, reduced geometric means of 25(OH)D levels were associated with increased retinopathy severity. After adjusting for six key covariates, VDD was associated with increased rates of proliferative DR (OR 2.05; 95% CI 1.35-3.11; p = 0.001). CONCLUSIONS: In Asian Indians with type 2 diabetes, lower serum 25(OH)D was associated with increased severity of DR and the presence of VDD was associated with a two-fold increased risk for proliferative DR. PMID- 29518483 TI - Hypothalamic redox balance and leptin signaling - Emerging role of selenoproteins. AB - The hypothalamus is the central neural site governing food intake and energy expenditure. During the past 25 years, understanding of the hypothalamic cell types, hormones, and circuitry involved in the regulation of energy metabolism has dramatically increased. It is now well established that the adipocyte-derived hormone, leptin, acts upon two distinct groups of hypothalamic neurons that comprise opposing arms of the central melanocortin system. These two cell populations are anorexigenic neurons expressing proopiomelanocortin (POMC) and orexigenic neurons that express agouti-related peptide (AGRP). Several important studies have demonstrated that reactive oxygen species and endoplasmic reticulum stress significantly impact these hypothalamic neuronal populations that regulate global energy metabolism. Reactive oxygen species and redox homeostasis are influenced by selenoproteins, an essential class of proteins that incorporate selenium co-translationally in the form of the 21st amino acid, selenocysteine. Levels of these proteins are regulated by dietary selenium intake and they are widely expressed in the brain. Of additional relevance, selenium supplementation has been linked to metabolic alterations in both animal and human studies. Recent evidence also indicates that hypothalamic selenoproteins are significant modulators of energy metabolism in both neurons and tanycytes, a population of glial-like cells lining the floor of the 3rd ventricle within the hypothalamus. This review article will summarize current understanding of the regulatory influence of redox status on hypothalamic nutrient sensing and highlight recent work revealing the importance of selenoproteins in the hypothalamus. PMID- 29518486 TI - Postprandial microvascular reactivity is significantly modified by endogenous insulin in recently diagnosed Type 2 diabetic patients. PMID- 29518487 TI - Association of plasma vitamin D status with lifestyle patterns and ambulatory blood pressure monitoring parameters in patients with type 2 diabetes and hypertension. AB - AIMS: To evaluate nutritional and metabolic parameters associated with vitamin D status and blood pressure (BP) in type 2 diabetes and hypertensive patients. METHODS: BP evaluated by office and 24-h ambulatory BP monitoring (ABPM). Physical activity was evaluated by daily step count, body composition by DXA, and diet by a food frequency questionnaire. RESULTS: 116 patients were evaluated and median 25-hydroxyvitamin D level was 21 (16-27) ng/ml; 43% deficient (<20 ng/ml). Vitamin D deficiency was associated with higher systolic ABPM (136 +/- 10 vs. 130 +/- 13 mmHg; P = 0.01) and daytime ABPM (138 +/- 11 vs. 133 +/- 13 mmHg; P = 0.02), lower step counts (4400 [2700-6600] vs. 6400 [4700-8100] steps/day), lower urinary calcium (47 [32-141] vs. 89 [68-152] mEq), and higher fat mass (31 +/- 8 vs. 27 +/- 6.5 kg). Milk intake (37 vs. 64%; P = 0.009) and fish (31 vs. 69%; P < 0.001) were lower in deficients. On multivariate analysis, adjusted for fat mass and colder seasons, <5000 steps/day (OR = 3.30; 95%CI 1.34-8.12), no milk/fish intake (OR = 6.56; 95%CI 2.52-17.17), and both (OR = 7.24; 95%CI 2.19-23.90) remained associated with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency was highly prevalent in patients with hypertension and type 2 diabetes and associated with higher systolic ABPM (daytime and 24-h), less physical activity, and no milk or fish intake. PMID- 29518489 TI - Clinical and biochemical approach to predicting post-pregnancy metabolic decompensation. AB - The prevalence of gestational diabetes in the developed world is increased and parallels that of obesity. Apart from the maternal and fetal complications occurring during pregnancy, GDM is characterized by a high subsequent risk of type 2 diabetes, metabolic syndrome, and cardiovascular disease. In this paper, we outline the different factors to consider in assessing the future risk of diabetes developing in women with a history of GDM. Looking at the modifiable risk factors, it is worth noting that promoting a healthy diet and lifestyle before (physical activity), during and after pregnancy (breast feeding) in women of fertile age are fundamental to the success of efforts to reduce the burden of diabetes in these young people. PMID- 29518488 TI - Effects of polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CB2R) on metabolic and adiposity parameters after weight loss with two hypocaloric diets. AB - BACKGROUND: The role of CB2R gene variants on weight loss after a dietary intervention remained unclear. OBJECTIVE: Our aim was to analyze the effects of rs3123554 of CB2R receptor gene on metabolic and adiposity parameters after two different hypocaloric diets in obese subjects. DESIGN: A Caucasian population of 280 obese patients was enrolled. Patients were randomly allocated during 3 months to one of two diets (Diet I - moderate in carbohydrate. Vs Diet II - normal in carbohydrate). RESULTS: In both genotype groups (GG vs GA + AA), body weight, body mass index (BMI), fat mass, waist circumference and systolic blood pressure decreased after diet I and II. The decrease of these parameters was higher in non A allele carriers than A allele carriers. Pre- and post-dietary intervention, body weight, BMI, fat mass and waist circumference were higher in A allele carriers than non A allele carriers. In non A allele carriers, the decrease of glucose, insulin, HOMA-IR and Interleukin-6 levels was higher than A allele carriers after both diets. CONCLUSION: Carriers of the minor allele of rs3123554 variant of CB2R gene loose less body weight during two different hypocaloric diets. The improvement of metabolic parameters was better in no A allele carriers than A allele carriers. PMID- 29518490 TI - Association of 48 type 2 diabetes susceptibility loci with fasting plasma glucose and lipid levels in Chinese Hans. AB - AIM: Dozens of susceptibility loci have been identified by type 2 diabetes (T2D) genome wide association study (GWAS) in Europeans. In our previous studies, we systematically evaluated the association of 48 susceptibility loci with T2D risk in Chinese Hans. Because dyslipidemia and hyperglycemia are implicated in the pathogenic process of T2D, we further evaluated whether these 48 single nucleotide polymorphisms (SNPs) were related to fasting plasma glucose (FPG) or lipid levels in Chinese Hans. METHODS: The 48 SNPs were genotyped by using the Taqman OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform. Multiple linear regression was used to assess the relationship between genetic variants and FPG and lipid levels among 3281 non-diabetic, healthy Chinese Hans. RESULTS: After adjusting for age, gender, body mass index (BMI), smoking status and drinking status, the T allele of rs13266634 in the SLC30A8 gene was significantly associated with decreased glucose level (beta = -0.0119, P = 8.05 * 10-5), whereas the T allele of rs896854 in the TP53INP1 gene was associated with increased triglyceride (TG) level (beta = 0.0342, P = 9.61 * 10-4) and decreased high-density lipoprotein cholesterol (HDL-C) level (beta = -0.015, P = 3.24 * 10 3) after Bonferroni correction. We also conducted a meta-analysis consisted of 11 studies and confirmed that SNP rs896854 in the TP53INP1 gene was associated with T2D risk. CONCLUSION: Our findings indicated that SNP rs13266634 in SLC30A8 was associated with glucose level and SNP rs896854 in TP53INP1 was associated with lipid level. PMID- 29518491 TI - Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study). AB - AIMS: We conducted a nationwide educational initiative to determine the prevalence and risk factors of diagnosed and undiagnosed painful and painless distal sensory polyneuropathy (DSPN). METHODS: Among 1850 participants, 781 had no history of diabetes (ND), 126 had type 1 diabetes (T1D), and 943 had type 2 diabetes (T2D). Painful DSPN was defined as polyneuropathy detected by bedside tests with pain and/or burning in the feet, while painless DSPN was defined as polyneuropathy with paresthesias, numbness, or absence of symptoms. RESULTS: DSPN was detected in 48.2% of ND, 44.3% of T1D, and 55.3% of T2D subjects. DSPN was painful, painless, or atypical in 62.1, 24.8, and 13.1% of the participants. Painful DSPN was more severe than painless DSPN. Painful and painless DSPN were previously undiagnosed in 61.5 and 81.1% of the participants, respectively. In T2D subjects, painful and painless DSPN were associated with a higher and lower BMI, respectively. Among ND participants 39.2% had HbA1c levels indicating prediabetes/diabetes. CONCLUSIONS: Around half of participants in an educational initiative had DSPN, 62% of whom had the painful entity that correlated with BMI in T2D. Since many cases of neuropathy and diabetes remain undiagnosed, effective strategies to timely detect both conditions should be implemented. PMID- 29518492 TI - Lower mortality and cardiovascular event rates in patients with Latent Autoimmune Diabetes In Adults (LADA) as compared with type 2 diabetes and insulin deficient diabetes: A cohort study of 4368 patients. AB - BACKGROUND: Latent Autoimmune Diabetes in Adults (LADA) is the second most common form of diabetes, but data on its clinical course and prognosis are scarce. We compared long-term risk of mortality and cardiovascular outcomes in patients with LADA, type 2 diabetes mellitus (T2D), and insulin deficient diabetes (IDD). METHODS: We conducted a cohort study of 4368 adults with diabetes referred to the Department of Endocrinology, Odense University Hospital, Denmark, between 1997 and 2012. Data on comorbidity, cardiovascular outcomes and death were obtained from prospective medical databases. We compared adjusted hazard ratios (HRs) of mortality and cardiovascular outcomes for patients with LADA, T2D and IDD, respectively. RESULTS: We included 327 patients with LADA, 3539 with T2D and 502 with IDD. At diagnosis, patients with LADA were older (50 years (IQR 37-59)) than IDD patients (40 years (IQR 28-52)), but younger than patients with T2D (55 years (IQR 45-64)). During a median follow-up period of 6.6 years (IQR 3.4-9.4), patients with IDD had higher mortality than patients with LADA, age- and gender adjusted HR 2.2 (95% CI, 1.5-3.2). T2D also conferred higher mortality than LADA, HR 1.4 (95% CI, 1.0-1.9). Compared with LADA patients, cardiovascular outcome rates were increased both with IDD, HR 1.2 (95% CI, 0.7-2.0) and T2D, HR 1.2 (95% CI, 0.8-1.8), with the strongest association observed for T2D vs. LADA and acute myocardial infarction HR 1.7 (95% CI, 0.8-3.5). CONCLUSION: LADA seems to be associated with lower mortality and lower risk of cardiovascular events, compared with both T2D and IDD. PMID- 29518493 TI - Microbiota metabolites: Pivotal players of cardiovascular damage in chronic kidney disease. AB - In chronic kidney disease (CKD), cardiovascular (CV) damage is present in parallel which leads to an increased risk of CV disease. Both traditional and non traditional risk factors contribute to CV damage in CKD. The systemic role of the microbiota as a central player in the pathophysiology of many organs is progressively emerging in the literature: the microbiota is indeed involved in a complex, bi-directional network between many organs, including the kidney and heart connection, although many of these relationships still need to be elucidated through in-depth mechanistic studies. The aim of this review is to provide evidence that microbiota metabolites influence non-traditional risk factors, such as inflammation and endothelial dysfunction in CKD-associated CV damage. Here, we report our current understanding and hypotheses on the gut kidney and gut-heart axes and provide details on the potential mechanisms mediated by microbial metabolites. More specifically, we summarize some novel hypotheses linking the microbiota to blood pressure regulation and hypertension. We also emphasise the idea that the nutritional management of CKD should be redesigned and include the new findings from research on the intrinsic plasticity of the microbiota and its metabolites in response to food intake. The need is felt to integrate the classical salt and protein restriction approach for CKD patients with foods that enhance intestinal wellness. Finally, we discuss the new perspectives, especially the importance of taking care of the microbiota in order to prevent the risk of developing CKD and hypertension, as well as the still not tested but very promising CKD innovative treatments, such as postbiotic supplementation and bacteriotherapy. This interesting area of research offers potential complementary approaches to the management of CKD and CV damage assuming that the causal mechanisms underlying the gut-kidney and gut-heart axes are clarified. This will pave the way to the design of new personalized therapies targeting gut microbiota. PMID- 29518494 TI - Synaptic consolidation as a temporally variable process: Uncovering the parameters modulating its time-course. AB - Memories are not instantly created in the brain, requiring a gradual stabilization process called consolidation to be stored and persist in a long lasting manner. However, little is known whether this time-dependent process is dynamic or static, and the factors that might modulate it. Here, we hypothesized that the time-course of consolidation could be affected by specific learning parameters, changing the time window where memory is susceptible to retroactive interference. In the rodent contextual fear conditioning paradigm, we compared weak and strong training protocols and found that in the latter memory is susceptible to post-training hippocampal inactivation for a shorter period of time. The accelerated consolidation process triggered by the strong training was mediated by glucocorticoids, since this effect was blocked by pre-training administration of metyrapone. In addition, we found that pre-exposure to the training context also accelerates fear memory consolidation. Hence, our results demonstrate that the time window in which memory is susceptible to post-training interferences varies depending on fear conditioning intensity and contextual familiarity. We propose that the time-course of memory consolidation is dynamic, being directly affected by attributes of the learning experiences. PMID- 29518495 TI - The infralimbic cortex encodes inhibition irrespective of motivational significance. AB - Evidence indicates that the infralimbic cortex (IL) encodes and retrieves the inhibitory memory produced by fear extinction. Recently, we have shown that the IL is also involved in the inhibitory memory generated by stimulus pre-exposure that causes latent inhibition. These results are surprising because a stimulus undergoing fear extinction carries aversive motivational value, whereas a pre exposed stimulus is neutral. The present experiments tested the hypothesis that the IL encodes inhibition irrespective of the motivational information about the stimulus. Using rats, we first confirmed that IL activity during stimulus pre exposure is required for latent inhibition. Then, we found that pharmacological stimulation of the IL facilitated aversive extinction to a stimulus that had been trained and extinguished as an appetitive stimulus. This facilitation was stimulus specific and required appetitive extinction. The same facilitation was found when appetitive extinction was replaced with random presentations of the stimulus and an appetitive outcome. Together, these findings indicate that non reinforced stimulus presentations establish an inhibitory memory that is reactivated and strengthened in the IL during subsequent aversive extinction. This is consistent with the view that the IL encodes inhibition irrespective of motivational value, suggesting that this brain region plays a general role in inhibitory learning. PMID- 29518496 TI - Up-regulation of INSR/IGF1R by C-myc promotes TSCC tumorigenesis and metastasis through the NF-kappaB pathway. AB - The insulin receptor (INSR) and insulin-like growth factor 1 receptor (IGF1R) have been reported to be involved in the tumorigenesis and metastasis of various malignancies. The aim of our study was to investigate and compare the effects of INSR and IGF1R on the tumorigenesis and metastasis of tongue squamous cell carcinoma (TSCC) and explore the possible mechanism(s) involved. We found that INSR had the same up-regulated expression pattern as IGF1R in TSCC tissues. INSR and IGF1R up-regulation were correlated with each other and associated with lymph node metastasis and poor prognosis. Functional studies established that knocking down either INSR or IGF1R dramatically impeded TSCC cell proliferation, migration, and invasion in vitro and tumorigenesis and tumor metastasis in vivo, whereas ectopic overexpression of INSR or IGF1R enhanced these activities. Both INSR and IGF1R directly targeted p65 and activated the NF-kappaB pathway; furthermore, C-myc was observed to directly bind to the INSR and IGF1R promoters and up-regulates INSR and IGF1R expression in TSCC. Thus, our current data demonstrate that both INSR and IGF1R are directly targeted by C-myc and exert similar effects to promote the tumorigenesis and metastasis of TSCC through the NF-kappaB pathway. Therefore, INSR and IGF1R may be therapeutic target genes and potential prognostic factors for TSCC. PMID- 29518498 TI - Catch the live show: Visualizing damaged DNA in vivo. AB - The health of an organism is intimately linked to its ability to repair damaged DNA. Importantly, DNA repair processes are highly dynamic. This highlights the necessity of characterizing DNA repair in live cells. Advanced genome editing and imaging approaches allow us to visualize damaged DNA and its associated factors in real time. Here, we summarize both established and recent methods that are used to induce DNA damage and visualize damaged DNA and its repair in live cells. PMID- 29518497 TI - Bacterial pathogen spectrum of acute diarrheal outpatients in an urbanized rural district in Southwest China. AB - OBJECTIVES: To conduct a one-year pathogen surveillance of acute diarrheal disease based on outpatient clinics in township hospitals in rural Hongta District of Yunnan Province, China. METHODS: Fecal specimens of acute diarrhea cases and relevant epidemiological information were collected. Salmonella, Shigella, Vibrio, Aeromonas, Plesiomonas shigelloides and diarrheogenic Escherichia coli (DEC) were examined. RESULTS: Among the 797 stool specimens sampled, 198 samples (24.8%) were positive in pathogen isolation, and 223 strains were isolated. The order of isolation rates from high to low were DEC, Aeromonas, P. shigelloides, Salmonella, Shigella and Vibrio. The overall positive rate in middle school students and preschool children was relatively high; while the overall positive rate of less than 1-year-old infants and above 55 years olds was relatively low. The isolates were analyzed by pulsed-field gel electrophoresis (PFGE). Some cases had the same or very close onset time, and the isolates had similar PFGE patterns, suggesting a possible outbreak once occurred but was not detected by the current infectious disease reporting system. CONCLUSIONS: Pathogen infection and transmission in rapidly urbanized rural areas is a serious issue. There is a great need for a more sensitive and accurate mode of monitoring, reporting and outbreak identification of diarrheal disease. PMID- 29518499 TI - Construction of synthetic T7 RNA polymerase expression systems. AB - T7 RNA polymerase (T7 RNAP) is one of the preferred workhorses for recombinant gene expression, owing in part to its high transcriptional activity and the fact that it has a small (17 base-pair), easily manipulated promoter. Furthermore, the fact that T7 RNAP is largely orthogonal to most hosts enables its use in a wide variety of contexts. However, the high activity of the enzyme also often leads to an increased fitness burden on the host, limiting the predictability of its interactions and impact on host physiology, and potentially leading to mutations in the constructs. Here we use a synthetic biology approach to design and characterize a panel of T7 RNAP expression circuits with different modes of regulation that enable the reliable expression of downstream targets under a variety of conditions. First, we describe the construction of a minimal T7 RNAP expression system that is inducible by a small molecule anhydrotetracycline (aTc), and then characterize a self-limiting T7 RNAP expression circuit that provides better control over the amount of T7 RNAP produced upon induction. Finally, we characterize a so-called T7 RNAP homeostasis circuit that leads to constitutive, continuous, and sub-toxic levels of T7 RNAP. Coupled with previously characterized mutant T7 RNAP promoters in vitro, we demonstrate that this modular framework can be used to achieve precise and predictable levels of output (sfGFP) in vivo. This new framework should now allow modeling and construction of T7 RNAP expression constructs that expand the utility of this enzyme for driving a variety of synthetic circuits and constructs. PMID- 29518500 TI - Multiple Skip Incisions Versus Single Long Incision for Single-stage Basilic Transposition Arteriovenous Fistula: A Cohort Study. AB - BACKGROUND: Basilic vein transposition via single long incision is a renowned technique despite its known wound-related complications. Contrary to that, multiple skip incisions technique is thought to have relatively lower wound related complications. But to the best of our knowledge, these 2 techniques have never been formally compared. Therefore, we conducted this study to compare both. MATERIAL AND METHODS: This was a retrospective cohort study. Patients who underwent basilic vein transposition arteriovenous fistula (AVF) from January 2011 till May 2016 at Aga Khan University Hospital, Pakistan were eligible for inclusion in the study. Study population was divided into 2 groups; one group comprising of patients who underwent fistula formation through single long incision and the other group had the procedure carried out via multiple skip incisions. Wound-related complications including wound infection and dehiscence, fistula maturation time, duration of surgery, and primary patency at a follow-up of 12 months were recorded. RESULTS: Both the groups were comparable regarding baseline variables. Incidence proportion of wound infection, hematoma, and dehiscence was higher in long incision group; however, it was statistically insignificant. Primary patency at 12 months in skip versus long incision group was 73.0% vs. 69.7% (P-value: 0.62). The mean maturation time for fistula was 42.8 +/- 9.5 days and 44.3 +/- 10.4 days in skip and long incision group, respectively (P-value:0.31). Duration of surgery was comparable in both. CONCLUSIONS: Although skip technique does not have significant benefit over long incision technique based on these results, but it is a valid alternative. Randomized control trial is required to better differentiate between these two. PMID- 29518501 TI - Traumatic Knee Dislocation and Popliteal Artery Injury: A Case Series. AB - Popliteal artery injury is a potentially limb-threatening complication of traumatic knee dislocation. We describe 2 such cases that had been treated in our unit over the last decade. The first one was a 23-year-old woman who injured her right knee during a long jump competition, and the second was a 27-year-old man who had a motorbike accident. Both suffered traumatic knee dislocation along with significant ligament and neurovascular injuries. In the first patient, the popliteal artery was found thrombosed due to intimal rupture and required thrombectomy and vein patch repair, whereas in the second patient, the artery was completely transected and required end-to-end anastomosis. Both limbs were successfully revascularized and required subsequent orthopedic procedures to stabilize the knee joint. Traumatic knee dislocations are rare injuries that may be associated with potentially devastating vascular complications. A prompt diagnosis and timely arterial repair is of paramount importance if limb salvage is to be achieved. PMID- 29518502 TI - Polymer Embolization and Anaphylactic Reaction during Implantation of an Ovation Stent Graft for Abdominal Aortic Aneurysm Exclusion. AB - During implantation of an Ovation endograft for abdominal aortic aneurysm (AAA) correction, a patient experienced anaphylactic reaction after polymer leakage outside the device circuit. Procedure was completed after hemodynamic stabilization. Since postoperative day 2, patient complained of loss of legs strength. Medullar injury was excluded by electromyography test, and the clinical signs attributed to muscular necrosis and peripheral nerve involvement after arterial embolization. Furthermore, immediately after surgery, a wide erythematous area appeared in the lumbar region. During the next few days, the lesion developed from extensive blisters and necrosis to deep loss of substance. The wound needed to be medicated 2 or 3 times per week. One year after surgery, the patient still needs crutches for deambulation, and the back injury is currently under treatment. In conclusion, surgeons performing aortic endovascular repair with the Ovation endograft, as well as anesthesiologists participating in the procedure, should be aware of the possibility of embolization and ready to promptly treat possible complications. PMID- 29518503 TI - Early Outcomes following Endovascular, Open Surgical, and Hybrid Revascularization for Lower Extremity Acute Limb Ischemia. AB - BACKGROUND: Acute limb ischemia (ALI) of the lower extremity is a potentially devastating condition that requires urgent and definitive management. This challenging scenario is often treated with endovascular, open surgical, or hybrid revascularization (HyR) in an urgent basis, but the comparative effects of such therapies remain poorly defined. The purpose of this study was to compare the outcomes of endovascular, open surgical, and HyR for ALI in the contemporary era. METHODS: A large statewide cardiovascular consortium of 45 hospitals was queried for patients between January 2012 and June 2015 who underwent an endovascular, open surgical, or HyR for ALI deemed at high risk of limb loss if not treated within 24 hr (Rutherford class IIA or IIB). A propensity score weighted analysis was performed controlling for demographics, medical history, and procedure type for patients. The primary outcomes were 30-day morbidity and mortality. RESULTS: A total of 1,480 patients underwent endovascular revascularization (ER; n = 818), open surgical revascularization (OSR; n = 195), or hybrid revascularization (HyR; n = 467) for ALI. The mean age was similar across revascularization technique with an increased predominance of male gender in open surgery cohort. Comorbidities for all groups were consistent with peripheral arterial disease. The most common endovascular procedures were angioplasty (93%) and thrombolysis (49.8%), whereas the most common surgical revascularization was femoral to popliteal bypass (32.8%), femoral to tibial bypass (28.2%), and thrombectomy (19.0%); ER as compared with OSR and HyR procedures was associated with less transfusion (OSR versus ER, odds ratio [OR] 2.7; HyR versus ER, OR 2.8; P < 0.001) and major amputation (OSR versus ER, OR 3.4; HyR versus ER, OR 4.0; P < 0.001) within 30 days of intervention. There was no difference in 30-day freedom from reintervention, myocardial infarction (MI), or mortality. CONCLUSIONS: Among patients requiring urgent revascularization for Rutherford grade IIA and IIB ischemia, ER has lower 30-day morbidity but similar mortality and rates of reintervention. Although long-term patency rates were not compared, ER may offer superior short-term outcomes compared with open surgery and hybrid revascularization. PMID- 29518504 TI - Can Recognition of Spinal Ischemia Be Improved? Application of Motor-Evoked Potentials, Serum Markers, and Breath Gas Analysis in an Acutely Instrumented Pig Model. AB - BACKGROUND: Paraplegia due to spinal cord ischemia (SCI) is a serious complication after repair of thoracoabdominal aortic aneurysms. For prevention and early treatment of spinal ischemia, intraoperative monitoring of spinal cord integrity is essential. This study was intended to improve recognition of SCI through a combination of transcranial motor-evoked potentials (tc-MEPs), serum markers, and innovative breath analysis. METHODS: In 9 female German Landrace pigs, tc-MEPs were captured, markers of neuronal damage were determined in blood, and volatile organic compounds (VOCs) were analyzed in exhaled air. After thoraco phrenico-laparotomy, SCI was initiated through sequential clamping (n = 4) or permanently ligating (n = 5) SAs of the abdominal and thoracic aorta in caudocranial orientation until a drop in the tc-MEPs to at least 25% of the baseline was recorded. VOCs in breath were determined by means of solid-phase microextraction coupled with gas chromatography-mass spectrometry. After waking up, clinical and neurological status was evaluated (Tarlov score). Spinal cord histology was obtained in postmortem. RESULTS: Permanent vessel ligature induced a worse neurological outcome and a higher number of necrotic motor neurons compared to clamping. Changes of serum markers remained unspecific. After laparotomy, exhaled acetone and isopropanol showed highest concentrations, and pentane and hexane increased during ischemia-reperfusion injury. CONCLUSIONS: To mimic spinal ischemia occurring in humans during aortic aneurysm repair, animal models have to be meticulously evaluated concerning vascular anatomy and function. Volatiles from breath indicated metabolic stress during surgery and oxidative damage through ischemia reperfusion. Breath VOCs may provide complimentary information to conventional monitoring methods. PMID- 29518505 TI - Endovascular Treatment of Post-traumatic Superior Mesenteric Arteriovenous Fistula: A Case Report. AB - Superior mesenteric arteriovenous fistulae (SMAVFs) are extremely rare with no consensus about therapeutic indications and optimal approach. Here, we present a case of a symptomatic SMAVF found in a young patient a few years after a penetrating abdominal injury. Following a complex clinical management of the acute status, we successfully managed the fistula with 3 covered stents in 2 consecutive endovascular procedures. Technical details of the performed procedures, including the main pitfalls and chosen solutions, have been explored and discussed. PMID- 29518506 TI - Development of Angiosarcoma in a Saphenous Vein Graft after Femoral to Above-Knee Popliteal Artery Bypass. AB - Angiosarcoma is an exceedingly rare and aggressive neoplasm. Owing to early metastasis even in low-grade tumors, it is associated with poor survival. We report a late development of an angiosarcoma in a saphenous vein graft after a femoral artery to above-knee popliteal artery bypass performed for disabling claudication. Chronic inflammation, lymphatic disruption, and thrombosis of the graft may have contributed to the malignant transformation, similar to cases described as occurring after arteriovenous fistulae creation. This case illustrates that angiosarcoma may be a rare, late complication of autogenous vascular bypass. PMID- 29518507 TI - Early Treatment at a Referral Center Improves Outcomes for Patients with Acute Vascular Disease. AB - BACKGROUND: Patients with acute vascular disease frequently need specialized management that may require transfer to a vascular referral center. Although transfer may be medically necessary, it can delay definitive care and is an indicator of incorrect triage to the initial hospital. Regionalization of acute vascular care could improve patient triage and subsequent outcomes. To evaluate the potential benefit from regionalization, we analyzed outcomes of patients treated for acute vascular disease at vascular referral centers. METHODS: Using a statewide database capturing all inpatient admissions in Maryland during 2013 2015, patients undergoing noncardiac vascular procedures on an acute basis were identified. Patients admitted to a vascular referral center were stratified by admission status as direct or transfer. The primary outcome was inpatient mortality, and the secondary outcome was resource use. Patient groups were compared by univariable analyses, and the effect of admission status on mortality was assessed by multivariable logistic regression. RESULTS: Of 4,873 patients with acute vascular disease managed at vascular referral centers, 2,713 (56%) were admitted directly, whereas 2,160 (44%) were transferred. Transfers to referral centers accounted for 71% of all interhospital transfers. The transfer group patients were older, had more comorbidities, and higher illness severities. Patients who were transferred had higher mortality (14% vs. 9%, P < 0.0001), longer hospital lengths of stay, greater critical care-resource utilization, and higher costs. After adjusting for demographics, comorbidities, and illness severity, transfer status was independently associated with higher inpatient mortality. CONCLUSIONS: Primary treatment at a referral center is independently associated with improved outcomes for patients with acute vascular disease. Direct admission or earlier triage to a specialty center may improve patient and system outcomes and could be facilitated by standardization and regionalization of complex acute vascular care. PMID- 29518508 TI - Ilio-Iliac Arteriovenous Fistulae-An Unusual Diagnosis with an Even More Unusual Clinical Presentation. AB - BACKGROUND: Major pelvic ilio-iliac arteriovenous fistula (AVF) is an exceedingly rare diagnosis with only a few described cases in the literature, most of them related to congenital defects or trauma. In this case report, we aim to present a case of an ilio-iliac AVF with an atypical clinical presentation. METHODS: Relevant medical data were collected from hospital database. RESULTS: The patient is a 77-year-old woman, with a relevant medical history of a temporally remote hysterectomy. She developed an exuberant unilateral right leg edema and was diagnosed with a femoro-iliac deep vein thrombosis (DVT) and started on anticoagulation and daily use of elastic compression stockings. No improvement in leg edema was evident, and she reported painful complaints refractory to medication. She also progressively developed right foot numbness and foot drop. A computed tomography angiography (CTA) was performed to exclude any compressive or paraneoplastic syndrome, with no remarkable findings other than common iliac vein (CIV) occlusion. As the patient's symptoms continued to worsen, a new CTA was performed 5 months later, which revealed an ilio-iliac AVF that was confirmed by angiography. After 2 ineffective attempts to embolize AVF afferents, we chose to completely embolize the arterial component of the AVF with Helix EV3 coils and Onyx glue (Covidien, Irvine, CA, USA). CIV recanalization and deployment of a Venovo stent (Bard Inc, Tempe, AZ, USA) was also performed. The final angiograms showed exclusion of the AVF and rapid venous flow through the stent. There was progressive improvement of edema and pain but little improvement of foot drop. CONCLUSION: AVF etiology and mechanism of neurologic deficits are controversial, with multiple possible explanations. Endovascular treatment modalities are promising a safer and more efficient approach when compared with open surgery. Our experience in this case was encouraging, but long-term results are currently lacking. PMID- 29518509 TI - An Inferior Vena Cava Aneurysm in a Patient with Klippel-Trenaunay Syndrome. AB - Aneurysms of the inferior vena cava (IVC) are rare, with only 54 cases reported in the literature. They carry a significant morbidity and mortality risk. A case of an IVC aneurysm in a patient with Klippel-Trenaunay syndrome (KTS) is reported. Open aneurysmorrhaphy of the type III aneurysm was successfully performed. The patient's leg swelling, back pain, and exercise tolerance improved. IVC aneurysms are not known to be associated with KTS. However, clinicians should have a high index of suspicion for great vessel aneurysms in these patients as they are associated with greater thromboembolic risk. PMID- 29518511 TI - Surgical Thrombectomy and Simultaneous Stenting for Phlegmasia Cerulea Dolens Caused by Iliac Vein Occlusion. AB - BACKGROUND: Phlegmasia cerulea dolens (PCD) is a severe complication of deep veions thrombosis, and there are several treatment methods. This study aimed to investigate the clinical efficacy of surgical thrombectomy and simultaneous iliac vein stent implantation for the treatment of PCD caused by iliac vein occlusion. PURPOSE: This study aimed to investigate the clinical efficacy of surgical thrombectomy and simultaneous iliac vein stent implantation for the treatment of phlegmasia cerulea dolens (PCD) caused by iliac vein occlusion. METHODS: From February 2014 to December 2016, 5 patients with secondary PCD complicated with iliac vein occlusion were treated in our center. Thrombectomy by venous incision was performed with simultaneous iliac vein balloon dilatation and stents implantation. Efficacy and stents patency were assessed. Iliac vein occlusions were confirmed in all 5 patients by angiography after the thrombectomy. Stents implantation were performed after balloon dilatation. Three stents were implanted in 1 case of iliac vein and inferior vena cava (IVC) occlusion, whereas 1 stent was implanted in each of the other 4 cases. RESULTS: Symptoms were significantly relieved after surgery, with no complications. Patients were followed up for 6-24 months, and minor swelling of the affected limb was found in 1 case, with no thrombosis recurrence in all cases and vascular stent patency. CONCLUSIONS: Thrombectomy by venous incision and simultaneous iliac vein stent implantation for the treatment of PCD caused by iliac vein occlusion can quickly relieve symptoms, is easily implemented, is associated with fewer complications, and has good midterm efficacy and a high patency rate, making this technique a good treatment method. PMID- 29518510 TI - Expression in Whole Blood Samples of miRNA-191 and miRNA-455-3p in Patients with AAA and Their Relationship to Clinical Outcomes after Endovascular Repair. AB - BACKGROUND: The purpose of this study was to quantify and evaluate the expression response of miRNA-191 and miRNA-455-3p endovascular repair of abdominal aortic aneurysm (AAA) based in whole blood samples. METHODS: This report describes a prospective study of a single center of 30 patients with AAA who underwent endovascular repair. Blood samples were collected preoperatively and 6 months postoperatively. The differential expression of the miRNAs was performed by the real-time polymerase chain reaction method, after extraction of the RNA from the blood samples at the 2 moments. In addition, bioinformatic tools were used to determine pathophysiological pathways related to AAA. RESULTS: The miR-191 and miR-455-3p were overexpressed preoperatively. After 6 months postoperatively, miR 191 (median 0.98, IQR 0.5-2.1, P < 0.0001) and miR-455-3p (median 1.4, IQR 0.6 3.1, P = 0.0003) presented a significant reduction in their expressions. There was no correlation between the diameter of the aneurysm and the expression of the miRNAs studied. In addition, analysis of the influence of the various types of devices used for the endovascular treatment of AAA showed no significant differences in the expression of miR-191 and miR-455-3p. CONCLUSIONS: Exclusion of the aneurysmal sac after endovascular treatment induces a decrease in the expression of the studied miRNAs in whole blood samples, which suggests a possible use of them as biomarkers of therapeutic success. PMID- 29518512 TI - Septic Carotid Endarterectomy Patch as a Result of Preoperative Tooth Extraction. AB - Infected carotid patches are rare. We present a gentleman who had an elective carotid endarterectomy with Dacron patch closure for symptomatic carotid stenosis under regional anesthesia, and he presented 1 month later with a discharging sinus at the lower aspect of the neck wound. Computed tomography scan showed a rim-enhancing collection next to the carotid bifurcation. He subsequently underwent patch excision and repair with autologous saphenous vein graft, with good recovery. Of significance was that he had a dental extraction for a loose tooth 1 day before the index operation as advised by the anesthetist. Streptococcus viridans species, which are part of the normal flora of oral cavity, were isolated from the tissue culture. This is the first case in the world's literature of a patient who had S. viridans carotid patch infection that may be related to his preoperative tooth extraction. PMID- 29518513 TI - Rupture of Thrombosed Popliteal Aneurysm: A Case Report. AB - Asymptomatic rupture of a popliteal arterial aneurysm (AAP) is rare but has been previously reported in the literature. Here, we present the first case of a thrombosed AAP that ruptured and developed into an abscess. We present the case of an 83-year-old male patient who was admitted to the emergency room in an impaired general condition, with a 3-month history of a daily fever that mainly occurred in the evening (38 degrees C), a lack of appetite, and weight loss of 18 kg over 3 months. On initial physical examination in the emergency room, the patient presented with fever (37.8 degrees C), a heart rate of 105 bpm, a blood pressure of 110/70 mm Hg, and bulging in the posterior aspect of the right thigh that was hard, painless, without hyperemia, and without localized heat on palpation. The femoral pulses were normal bilaterally, but the popliteal and distal pulses in the right lower limb were absent. A magnetic resonance imaging demonstrated thrombosis of the right AAP associated with continuity contour loss and images compatible with collection with low degree on T1 and intermediate signal intensity on T2, which may correspond to the subacute bleeding areas that measured 10.6 * 5.9 * 4.0 cm and that were located between the muscle belly of the sartorius, semimembranosus, and vastus muscles inferiorly. There was another collection (with similar characteristics) that measured 5.4 * 4.2 * 2.4 cm and that was located medially from the biceps femoral muscle. The patient consented to the resection of the aneurysm and the ligation of the collateral arteries. First, we dissected down to the femoral artery proximal to the aneurysm and the popliteal artery at the P2 segment where there was no evidence of infection or rupture. The surgical wound was washed with 10 L of 0.9% saline solution, samples were sent to pathology for culture, and the surgical wound was drained with a closed drain. We decided not to revascularize the limb because there was good perfusion and a current infection. PMID- 29518514 TI - A Retrospective Study Comparing 2 Approaches to Catheter-Directed Thrombolysis for Acute Deep Venous Thrombosis. AB - BACKGROUND: To compare the clinical efficacy and safety of catheter-directed thrombolysis (CDT) using the anterior tibial vein approach (ATVA) and popliteal vein approach (PVA) for acute lower-extremity deep venous thrombosis (LEDVT). METHODS: From March 2014 to October 2015, 63 patients with unilateral acute extensive LEDVT were enrolled in this study: 36 patients received CDT via the PVA group, and 27 patients received CDT via the ATVA group. Limb circumference, thrombus score, complications, thrombolytic time, and the amount of thrombolytic agents administered were recorded. Postthrombotic syndrome (PTS) and venous insufficiency were assessed at 1 year after treatment. RESULTS: Thrombus scores were significantly decreased in both groups after CDT therapy (each P < 0.001). There was no significant difference in the detumescence and thrombolytic rates, thrombolytic times and administered amounts of thrombolytic agents between the 2 groups (each P > 0.050). The limb circumference difference below the knee in the ATVA group was lower than that in the PVA group (P = 0.029), and the ATVA resulted in fewer complications, especially sheath bleeding (P = 0.025). At the 1 year follow-up, popliteal venous insufficiency was present in 36.11% of the PVA group and 25.93% of the ATVA group (P = 0.390). In addition, PTS was observed in 13.89% of the PVA group compared with 7.41% of the ATVA group (P = 0.268). CONCLUSIONS: CDT is an effective and safe method for treating acute LEDVT. The ATVA is an effective and feasible approach for CDT with a lower incidence of complications than the PVA. PMID- 29518515 TI - Malignancy Does not Affect Outcomes of Pharmacomechanical Thrombolysis in Acute Symptomatic Iliofemoral Deep Vein Thrombosis. AB - BACKGROUND: Cancer patients demonstrate increased risk for venous thromboembolism (VTE), VTE recurrence, and anticoagulation-associated bleeding. Pharmacomechanical thrombolysis (PMT) aand thrombectomy improves venous patency, venous valve function, and quality of life in patients with acute iliofemoral deep vein thrombosis (DVT). It remains unknown whether pharmacomechanical thrombolysis can be used safely in patients with active cancer. We hypothesized that perioperative and short-term outcomes of pharmacomechanical iliofemoral DVT thrombolysis would not differ between patients with cancer and those without cancer. METHODS: A retrospective chart review of consecutive patients with symptomatic iliofemoral DVT undergoing PMT by AngioJet Power Pulse spray and thrombectomy at a single tertiary care university institution between December 2013 and December 2016 was performed. Outcomes between patients with cancer and without cancer were compared. RESULTS: We identified 22 limbs in 18 consecutive patients: 6 patients (7 limbs) with cancer and 12 patients (15 limbs) without cancer. Between these groups, the mean age was 60.5 +/- 4.3 vs. 53.8 +/- 26.8 years, respectively (P = 0.5593), and females comprised 66.7% vs. 25.0%, respectively (P = 0.0878). No significant difference in inferior vena cava (IVC) involvement between the groups (57.1% vs. 53.3%, P = 0.8676) was noted. Grade II (50-94% lysis) and III (95% complete lysis) thrombus lysis with restoration of venous patency was achieved in both the groups. Overnight catheter-directed thrombolysis (CDT) was rarely used. Notably, stenting was more frequently employed in cancer patients than in those without cancer (57.1% vs. 13.3%, P = 0.0316). The mean duration of follow-up was 3.42 +/- 4.41 months for the cancer group and 4.50 +/- 2.43 months for the noncancer group (P = 0.5060). Overall outcomes were excellent as no patient in both the groups experienced recurrent DVT, major bleeding, or postthrombotic syndrome. There was no mortality associated with the endovascular thrombolysis procedures. CONCLUSIONS: The results of our study suggest that the presence of malignancy does not affect short-term outcomes of endovascular thrombolytic therapy in symptomatic DVT. Further follow-up is needed to evaluate long-term outcomes. PMID- 29518516 TI - Paraplegia of Lower Limbs Caused by a Segmental Thrombosis of the Descending Thoracic Aorta Reversed with Endovascular Treatment-A Case Report and Literature Review. AB - BACKGROUND: Transient paraplegia of the lower limbs is a rare condition and, when has a vascular etiology, is usually associated with thromboembolic events, aortic dissection, aortic aneurysms, or as a complication of the surgical correction of those diseases. There is no case reported of acute paraplegia caused by a segmental thrombotic subocclusion of the descending thoracic aorta. CASE REPORT: We report a not yet described clinical situation of a young patient (51 years) admitted to the emergency care department for treatment of systemic arterial hypertension of difficult control with 4 antihypertensive medication classes. At the intensive care unit for treatment with intravenous antihypertensive medication, the patient evolved with acute paraplegia and a segmental thrombotic subocclusion of the descending thoracic aorta was diagnosed. He was submitted to endovascular treatment with total recovery of the deficits. CONCLUSIONS: The previously normal descending thoracic aorta may be a site of segmental thrombosis and may lead to paraplegia. Early endovascular treatment can reverse this type of situation. PMID- 29518517 TI - Spontaneous Deep Femoral Artery False Aneurysm Simulating a Neoplasm: A Rare Case and Literature Review. AB - A 70-year-old woman presented to our attention with a painless pulsating mass at the level of the upper left thigh without any previous history of trauma, arterial surgery, or puncture of the femoral artery. Duplex ultrasound showed a nodular angiomatous-like formation with deep venous compression; computed tomographic angiography and magnetic resonance imaging reported the presence of capsulated lesion vascularized by muscular branch of deep femoral artery (DFA). The patient underwent surgical excision of a very rare thrombized DFA branch false aneurysm. Spontaneous DFA false aneurysm, although rare, will be considered in absence of trauma or vascular catheterization or previous aneurysmal rupture. PMID- 29518518 TI - Right Subclavian Septic Pseudoaneurysm with Esophageal Fistula due to a Swallowed Fishbone. AB - Pseudoaneurysm due to a swallowed fishbone rarely involves subclavian arteries. A 46-year-old male with nonaberrant right subclavian artery (RSA) presented pseudoaneurysm and brachial plexus septic necrosis. Open surgery with sternotomy and right transverse supraclavicular cervicotomy was done in emergency to achieve revascularization using in situ cryopreserved arterial allograft. Infection severity led to septic allograft rupture that necessitated ligation without new arterial reconstruction. During follow-up, patient remained alive 8 months after surgery. Neurological deficit slowly regressed, and no upper arm ischemic sign appeared. PMID- 29518519 TI - Techniques for Infrapopliteal Arterial Bifurcation Stenting. AB - BACKGROUND: Endovascular treatment of infrapopliteal peripheral arterial disease (PAD) is an established and effective treatment strategy for patients with symptomatic PAD. Increasingly, complex infrapopliteal lesions are treated with an endovascular first approach, especially in the setting of critical limb ischemia (CLI) for limb salvage, avoiding major amputations which impact on mobility and quality of life. However, many complex infrapopliteal lesions involving the bifurcation of the tibial arteries remain challenging to treat because of recoil or acute dissection after angioplasty and may require stenting using specialized techniques. METHODS AND RESULTS: We illustrated techniques for infrapopliteal arterial bifurcation stenting using case-based examples. The techniques covered include the single-stent, culottes, kissing, crush, and T-stenting techniques, and each is considered based on individual strengths and limitations. CONCLUSIONS: Infrapopliteal bifurcation stenting allows complex bifurcation lesions to be treated effectively when flow-limiting complications are encountered after angioplasty. PMID- 29518520 TI - Repair of Delayed Type 1a Endoleak using Fenestrated and Parallel Endografts. AB - Endovascular aneurysm repair has become the first-line treatment modality for infrarenal aortic aneurysms. However, obtaining successful long-term results frequently requires reinterventions. Particularly, delayed type 1a endoleaks pose a challenging problem, as they are often associated with proximal extension of the aneurysmal process to juxtarenal or pararenal aortic segments. We describe 2 remedial techniques to repair delayed type 1a endoleak by extending the seal zone to the suprarenal aorta, while incorporating the renal arteries. In the first case, a commercially available fenestrated stent graft was used. Parallel grafting technique was used in the other case. Both cases were technically successful. Follow-up imaging revealed endoleak resolution with patent renal arteries for both patients. In addition, we describe the difference between the 2 techniques, as well as relevant anatomic and device-specific considerations. PMID- 29518521 TI - A Rare Surgical Case of Giant Jejunal Artery Aneurysm in a Young Patient. AB - Aneurysms of the abdominal visceral arteries are infrequently encountered. Jejunal artery aneurysm (JAA) is one of the rarest visceral aneurysms, especially in young patients. Endovascular surgery tends to be an effective treatment for visceral artery aneurysms. Here, we report a case of symptomatic JAA with a peripheral dilated vessel in a young patient. However, in consideration of the patient's anatomic suitability and young age, we chose open surgical intervention with intraoperative angiography. Thus, we could resect the aneurysm and the peripheral dilated vessel, preserve the bowel, and leave no devices that could cause further complication. The choice of the most appropriate treatment should depend on aneurysm characteristics and the background of the patient. PMID- 29518523 TI - Do not look away! Spontaneous frontal EEG theta/beta ratio as a marker for cognitive control over attention to mild and high threat. AB - BACKGROUND: Low spontaneous EEG theta/beta ratio (TBR) is associated with greater executive control. Their role in regulation of attentional bias for stimuli of different threat-levels is unknown. OBJECTIVES: To provide the first relations between frontal TBR, trait anxiety and attentional bias to mildly and highly threatening stimuli at different processing-stages. METHODS: Seventy-four healthy volunteers completed spontaneous EEG measurement, a self-report trait anxiety questionnaire and a dot-probe task with stimuli of different threat-level and 200 and 500 ms cue-target delays. RESULTS: Participants with high TBR directed attention towards mildly threatening and avoided highly threatening pictures. Moreover, the most resilient participants, (low TBR and low trait anxiety) showed attention towards highly threatening stimuli. There were no effects of delay. CONCLUSIONS: These data confirm that executive control is crucial for the study of threat-related attentional bias and further support the notion that TBR is a marker of cognitive control over emotional information. PMID- 29518524 TI - The impaired proteases and anti-proteases balance in Idiopathic Pulmonary Fibrosis. AB - Idiopathic Pulmonary Fibrosis (IPF) is a devastating chronic, progressive and irreversible disease that remains refractory to current therapies. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the development of pulmonary fibrosis since decades. Coagulation signalling deregulation, which influences several key inflammatory and fibro-proliferative responses, is also essential in IPF pathogenesis, and a growing body of evidence indicates that Protease-Activated Receptors (PARs) inhibition in IPF may be promising for future evaluation. Therefore, proteases and anti-proteases aroused great biomedical interest over the past years, owing to the identification of their potential roles in lung fibrosis. During these last decades, numerous other proteases and anti-proteases have been studied in lung fibrosis, such as matriptase, Human airway trypsin-like protease (HAT), Hepatocyte growth factor activator (HGFA)/HGFA activator inhibitor (HAI) system, Plasminogen activator inhibitor (PAI)-1, Protease nexine (PN)-1, cathepsins, calpains, and cystatin C. Herein, we provide a general overview of the proteases and anti-proteases unbalance during lung fibrogenesis and explore potential therapeutics for IPF. PMID- 29518525 TI - Morphological and electrophysiological differences in tarsal chemosensilla between the wild silkmoth Bombyx mandarina and the domesticated species Bombyx mori. AB - Gustatory and olfactory senses of phytophagous insects play important roles in the recognition of host plants. In the domestic silkmoth Bombyx mori and its wild species Bombyx mandarina, the morphologies and responses of adult olfactory organs (antennae) have been intensely investigated. However, little is known about these features of adult gustatory organs and the influence of domestication on the gustatory sense. Here we revealed that both species have two types of sensilla (thick [T] and slim [S] types) on the fifth tarsomeres of the adult legs. In both species, females have 3.6-6.9 times more T-sensilla than males. Therefore, T-sensilla seem to play more important roles in females than in males. Moreover, gustatory cells of T-sensilla of B. mandarina females responded intensely to mulberry leaf extract in electrophysiological experiments, while T sensilla of B. mori females (N4 strain) hardly responded to mulberry leaf extract. These results suggest that T-sensilla of B. mandarina females are involved in the recognition of oviposition sites. We also observed that, in three B. mori strains (N4, p50T, and Kinshu * Showa), the densities of sensilla on the fifth tarsomeres were much lower than in B. mandarina. These results indicate that domestication has influenced the tarsal gustatory system of B. mori. PMID- 29518522 TI - New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling. AB - RAS is the most frequently mutated gene across human cancers, but developing inhibitors of mutant RAS has proven to be challenging. Given the difficulties of targeting RAS directly, drugs that impact the other components of pathways where mutant RAS operates may potentially be effective. However, the system-level features, including different localizations of RAS isoforms, competition between downstream effectors, and interlocking feedback and feed-forward loops, must be understood to fully grasp the opportunities and limitations of inhibiting specific targets. Mathematical modeling can help us discern the system-level impacts of these features in normal and cancer cells. New technologies enable the acquisition of experimental data that will facilitate development of realistic models of oncogenic RAS behavior. In light of the wealth of empirical data accumulated over decades of study and the advancement of experimental methods for gathering new data, modelers now have the opportunity to advance progress toward realization of targeted treatment for mutant RAS-driven cancers. PMID- 29518526 TI - Laparoscopic Common Bile Duct Exploration for Choledocholithiasis: Analysis of Practice Patterns of Intermountain HealthCare. AB - BACKGROUND: The ideal management of common bile duct (CBD) stones remains controversial, whether with single-stage management using laparoscopic CBD exploration (LCBDE) during laparoscopic cholecystectomy, or with 2-stage management using preoperative or postoperative ERCP. We wished to elucidate the practice patterns within our health system, which includes both large urban referral centers and small rural critical access hospitals. STUDY DESIGN: We conducted a retrospective data analysis from our 22-hospital, not-for-profit, integrated healthcare system. All patients with a diagnosis of choledocholithiasis who underwent laparoscopic cholecystectomy (LC) and either ERCP or LCBDE for duct clearance between 2008 and 2013 were included. Demographic data, along with disease-specific characteristics and outcomes, were collected and compared. RESULTS: During the study period, 37,301 patients underwent LC. Of these, 1,961 (5.3%) met inclusion criteria. Single-stage management with LC+LCBDE was performed in 28% of patients, and the remaining 72% underwent 2-stage management with ERCP (73% postoperative ERCP, 27% preoperative). Mean total number of procedures was lowest in the LC+LCBDE group vs the post-cholecystectomy ERCP group vs the preoperative ERCP group (mean 1.4 vs 2.1 vs 2.3; p < 0.05). Hospital charges were also lower in the LC+LCBDE group vs post-cholecystectomy ERCP vs preoperative ERCP groups ($9,000 vs $10,800 vs $14,200; p < 0.05). Single stage vs two-stage management varied greatly between hospitals (from 0% to 93%). CONCLUSIONS: Single-stage management of CBD stones resulted in the fewest procedures and lower hospital charges without an increase in complications. Single-stage management (LC+LCBDE) of CBD stones is underused and can offer better value in today's cost-constrained environment. PMID- 29518527 TI - Systemic inflammation without gliosis mediates cognitive deficits through impaired BDNF expression in bile duct ligation model of hepatic encephalopathy. AB - Chronic liver disease per se induces neuroinflammation that contributes to cognitive deficits in hepatic encephalopathy (HE). However, the processes by which pro-inflammatory molecules result in cognitive impairment still remains unclear. In the present study, a significant increase in the activity of liver function enzymes viz. alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) was observed along with increase in plasma ammonia levels after four weeks of bile duct ligation (BDL) in rats suggesting hepatocellular damage. A significant increase was observed in mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) in brain regions and liver of BDL rats. Concomitantly, IL-6, TNF-alpha and MCP-1 protein levels were also increased in brain regions, liver and serum of BDL rats suggesting the involvement of blood brain-axis in inflammatory response. However, a significant decrease was observed in glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (Iba-1) expression at transcriptional and translation level in brain of BDL rats. Immunohistochemical and flowcytometric analysis revealed reduced number of GFAP-immunopositive astrocytes and Iba1-immunopositive microglia in the brain regions of BDL rats. Further, a significant decline was observed in cognitive functions in BDL rats assessed using Morris water maze and novel object recognition tests. Expression of pro and mature form of brain derived neurotrophic factor (BDNF) and its upstream transcription element showed significant reduction in brain of BDL rats. Taken together, the results of the present study suggest that systemic inflammation and reduced expression of BDNF and its upstream transcription factor plays a key role in cognitive decline in HE. PMID- 29518528 TI - Insight meditation and telomere biology: The effects of intensive retreat and the moderating role of personality. AB - A growing body of evidence suggests that meditation training may have a range of salubrious effects, including improved telomere regulation. Telomeres and the enzyme telomerase interact with a variety of molecular components to regulate cell-cycle signaling cascades, and are implicated in pathways linking psychological stress to disease. We investigated the effects of intensive meditation practice on these biomarkers by measuring changes in telomere length (TL), telomerase activity (TA), and telomere-related gene (TRG) expression during a 1-month residential Insight meditation retreat. Multilevel analyses revealed an apparent TL increase in the retreat group, compared to a group of experienced meditators, similarly comprised in age and gender, who were not on retreat. Moreover, personality traits predicted changes in TL, such that retreat participants highest in neuroticism and lowest in agreeableness demonstrated the greatest increases in TL. Changes observed in TRGs further suggest retreat related improvements in telomere maintenance, including increases in Gar1 and HnRNPA1, which encode proteins that bind telomerase RNA and telomeric DNA. Although no group-level changes were observed in TA, retreat participants' TA levels at post-assessment were inversely related to several indices of retreat engagement and prior meditation experience. Neuroticism also predicted variation in TA across retreat. These findings suggest that meditation training in a retreat setting may have positive effects on telomere regulation, which are moderated by individual differences in personality and meditation experience. (ClinicalTrials.gov #NCT03056105). PMID- 29518529 TI - The orphan nuclear receptor TLX regulates hippocampal transcriptome changes induced by IL-1beta. AB - TLX is an orphan nuclear receptor highly expressed within neural progenitor cells (NPCs) in the hippocampus where is regulates proliferation. Inflammation has been shown to have negative effects on hippocampal function as well as on NPC proliferation. Specifically, the pro-inflammatory cytokine IL-1beta suppresses NPC proliferation as well as TLX expression in the hippocampus. However, it is unknown whether TLX itself is involved in regulating the inflammatory response in the hippocampus. To explore the role of TLX in inflammation, we assessed changes in the transcriptional landscape of the hippocampus of TLX knockout mice (TLX-/-) compared to wildtype (WT) littermate controls with and without intrahippocampal injection of IL-1beta using a whole transcriptome RNA sequencing approach. We demonstrated that there is an increase in the transcription of genes involved in the promotion of inflammation and regulation of cell chemotaxis (Tnf, Il1b, Cxcr1, Cxcr2, Tlr4) and a decrease in the expression of genes relating to synaptic signalling (Lypd1, Syt4, Cplx2) in cannulated TLX-/- mice compared to WT controls. We demonstrate that mice lacking in TLX share a similar increase in 176 genes involved in regulating inflammation (e.g. Cxcl1, Tnf, Il1b) as WT mice injected with IL-1beta into the hippocampus. Moreover, TLX-/- mice injected with IL-1beta displayed a blunted transcriptional profile compared to WT mice injected with IL-1beta. Thus, TLX-/- mice, which already have an exaggerated inflammatory profile after cannulation surgery, are primed to respond differently to an inflammatory stimulus such as IL-1beta. Together, these results demonstrate that TLX regulates hippocampal inflammatory transcriptome response to brain injury (in this case cannulation surgery) and cytokine stimulation. PMID- 29518531 TI - Entrainment of the Circadian Clock in Neural Stem Cells by Epidermal Growth Factor is Closely Associated with ERK1/2-mediated Induction of Multiple Clock related Genes. AB - The mitotic activity of certain tissues in the body is closely associated with circadian clock function. However, the effects of growth factors on the molecular clockwork are not fully understood. Stimulation of neural stem cells (NSCs) with epidermal growth factor (EGF), a well-known mitogen, is known to cause synchronized cell cycle progression with a period of approximately 24 h, closely associated with the Per2 gene expression rhythm. Here, we examined the effects of EGF on the molecular clockwork of NSCs. Treatment of cultured NSCs derived from embryonic mouse forebrain with EGF (20 ng/mL) caused a phase shift in the PER2::LUCIFERASE bioluminescence rhythm in a stimulation time-dependent manner. The EGF phase-response curve differed from that of forskolin (FK)-a well-known chemical resetting stimulus-both in the advance/delay ratio and stimulation time dependency. PCR array analysis followed by quantitative PCR validation demonstrated that EGF treatment transiently induced multiple clock-related genes including Per1, Per2, Dec1, e4bp4, and Noct, whereas FK treatment induced a limited number of genes (Per1 and Dec1), suggesting that the mode of entrainment of NSC molecular clock was different for EGF and FK. EGF led to gene induction in the presence of cycloheximide, suggesting that de novo protein synthesis is unnecessary. Pretreatment with the MEK1/2 inhibitor U0126 significantly suppressed the acute induction of Per2, Dec1, and Noct by EGF and also abolished the EGF-induced phase shift of the PER2::LUCIFERASE rhythm in NSCs. These results suggest a unique effect of EGF on the molecular clockwork of NSCs. PMID- 29518530 TI - Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior. AB - Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1beta in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1beta in PFC, and depressive like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology. PMID- 29518532 TI - Somatotopic Organization and Temporal Characteristics of Cerebrocortical Excitation in Response to Nasal Mucosa Stimulation With and Without an Odor in the Rat: An Optical Imaging Study. AB - Nasal mucosa has roles in warming and humidifying inspired air and is highly sensitive to mechanical stimuli. Moreover, the upper part of the nasal mucosa expresses olfactory receptors processing olfactory information. Although the somatosensory map of the face in the primary (S1) and secondary (S2) somatosensory cortices is clearly documented, the map of the nasal mucosa and the effect of odors on their activities are largely unknown. This study aimed to identify the cortical regions in S1 and their temporal features in response to somatosensory stimulation of the nasal mucosa using an optical imaging technique in urethane-anesthetized rats. An air puff application response to nasal mucosa first occurred in a part of contralateral S1 and subsequently, spread toward the rostrally and ventrally adjacent sites. Upper pharynx stimulation initially activated this rostrally expanded site and the excitatory propagation from the initially activated region toward ventral region likely represented S2. Signal intensity and activated area increased dependent on air pressure. Nasal tip stimulation initially excited S1 region caudally adjacent to that of nasal mucosa. Moreover, the amplitude of S1 excitation was similar between air puff stimulation with and without an odor, amyl acetate. In contrast to contralateral S1, air puff stimulation with the odor showed a faint optical signal increase in the ipsilateral piriform cortex. These results suggest that somatosensory information from the nasal mucosa and skin, and upper pharynx are processed in spatially continuous regions of S1, and interaction between somatosensory and olfactory systems is relatively small in contralateral S1. PMID- 29518533 TI - Improving culture media for the isolation of Clostridium difficile from compost. AB - This study was to optimize the detection methods for Clostridium difficile from the animal manure-based composts. Both autoclaved and unautoclaved dairy composts were inoculated with a 12-h old suspension of a non-toxigenic C. difficile strain (ATCC 43593) and then plated on selected agar for vegetative cells and endospores. Six types of enrichment broths supplemented with taurocholate and l cysteine were assessed for detecting a low level of artificially inoculated C. difficile (ca. 5 spores/g) from dairy composts. The efficacy of selected enrichment broths was further evaluated by isolating C. difficile from 29 commercial compost samples. Our results revealed that using heat-shock was more effective than using ethanol-shock for inducing endospore germination, and the highest endospore count (p < 0.05) was yielded at 60 degrees C for 25 min. C. difficile agar base, supplemented with 0.1% l-cysteine, 7% defibrinated horse blood, and cycloserine-cefoxitin (CDA-CYS-H-CC agar) was the best medium (p < 0.05) for recovering vegetative cells from compost. C. difficile endospore populations from both types of composts enumerated on both CDA-CYS-H-CC agar supplemented with 0.1% sodium taurocholate (CDA-CYS-H-CC-T agar) and brain heart infusion agar supplemented with 0.5% yeast extract, 0.1% l-cysteine, cycloserine cefoxitin, and 0.1% sodium taurocholate (BHIA-YE-CYS-CC-T agar) media were not significantly different from each other (p > 0.05). Overall, enrichment of inoculated compost samples in broths containing moxalactam-norfloxacin (MN) produced significantly higher (p < 0.05) spore counts than in non-selective broths or broths supplemented with CC. Enrichment in BHIB-YE-CYS-MN-T broth followed by culturing on an agar containing 7% horse blood and 0.1% taurocholate provided a more sensitive and selective combination of media for detecting a low population of C. difficile from environmental samples with high background microflora. PMID- 29518534 TI - Tiara Valve Implantation in a Patient With Previously Implanted Mono-disk Mechanical Aortic Prosthesis. AB - Transcatheter mitral valve replacement with the Tiara valve can be performed in inoperable patients with severe functional regurgitation. Risk of left ventricular outflow tract obstruction can be prevented using preoperative 3D imaging and 3D-printed models. However, in the case of mono-disk mechanical prostheses previously implanted in aortic position (Bjork-Shiley), there is an additional risk of mechanical interference leading to reduced leaflet motion and aortic valve dysfunction. Hereafter, we describe the case of a patient with a 27 mm mono-disk mechanical aortic valve implanted in 1978, a EuroSCORE II of 18%, and a Society of Thoracic Surgeon score (mortality) of 16% who successfully underwent a transapical Tiara valve implantation. PMID- 29518535 TI - Successful Use of Aortic Homograft for Residual Tracheal Stenosis Following Slide Tracheoplasty. PMID- 29518536 TI - The Prevalence and Distribution of Occlusive Lesions of the Cerebral Arteries in Patients Undergoing Coronary Artery Bypass Graft Surgery. AB - Intracranial cerebral atherosclerosis is a significant predictor of stroke after coronary artery bypass grafting (CABG). However, there is limited information on intracranial occlusive lesions in patients undergoing CABG. The purpose of the study was to elucidate the precise prevalence and distribution of occlusive lesions of the extracranial and intracranial arteries in patients undergoing CABG. Between 2009 and 2016, 205 patients underwent preoperative magnetic resonance angiography and elective CABG. The prevalence and the distribution of occlusive lesions were retrospectively examined by preoperative magnetic resonance angiography. Association between postoperative central nervous system (CNS) complications and the occlusive lesions was analyzed. Fifty-six patients (27.3%) and 60 patients (29.3%) had occlusive lesions of the extracranial and intracranial arteries, respectively. Twenty-eight patients (13.7%) had both extracranial and intracranial occlusive lesions. Thirty-one (15.1%) and 45 (22.0%) patients had severe stenosis or occlusion of the extracranial and intracranial arteries, respectively. The intracranial internal carotid artery was the most commonly affected intracranial artery (60 vessels; 62.5%), followed by the middle cerebral arteries (20 vessels; 20.8%). Sixteen patients (7.8%) suffered from postoperative CNS complications, including 2 permanent strokes. The etiology of the stroke was attributable to a predefined intracranial lesion in 1 patient. In multivariate analysis, the presence of intracranial occlusive lesions was found to have an independent association with the development of CNS complications (odds ratio 4.05; 95% confidence interval 1.13-14.6). The prevalence of intracranial occlusive lesions was higher than that of extracranial lesions in patients undergoing CABG. There was a solid trend toward the anterior distribution of the intracranial occlusive lesions. PMID- 29518537 TI - High level expression and purification of recombinant human serum albumin in Pichia pastoris. AB - Human serum albumin (HSA) has been extensively used in a series of clinical care settings for nearly seven decades. However, the broad application of this protein is seriously limited by its short supply. In this work, the codon sequence of HSA was cloned under the control of the alcohol oxidase 1 promoter (AOX1) and expressed as a secretory protein in Pichia pastoris. A recombinant strain displaying the highest HSA yield was selected by screening for resistance to the highest concentration of antibiotic G418. After optimizing the induction conditions and additional supplements, the highest yield of HSA reached 1.6 g/L in a shake flask. Performing high density fermentation further improved the highest yield to 8.86 g/L in a fermenter after 96 h of methanol induction. This result is more promising than the previous reports of industrial applications, which reported the highest yield as 92.29 mg/L/h, considering that the space-time yield of rHSA was doubled. In addition, the desired protein was purified by filtration and Cibacron Blue affinity chromatography, which yielded a 58% recovery of a product that had over a 96% purity. This study reveals that Pichia pastoris is an excellent system for recombinant human serum albumin expression due to its outstanding expression capacity. In addition, the high efficiency level of rHSA production lays a solid foundation for its use in industrial production. PMID- 29518539 TI - Intravenous administration of retinoic acid-loaded polymeric nanoparticles prevents ischemic injury in the immature brain. AB - Perinatal stroke is often difficult to diagnose and an established treatment has not yet been validated, except for symptomatic measures. Herein, we propose to test the neuroprotective potential of the intravenous injection of retinoic acid loaded nanoparticles (RA-NP) upon ischemic injury to the immature brain. The role of RA-NP on endothelial cells and organotypic slice cultures exposed to oxygen and glucose deprivation was assessed by evaluating markers pertaining to survival, proliferation, oxidative stress (NO, ROS), neuronal damage (enolase), vascular oxidation (p47phox) and microglia activation (CD68). Data showed that RA NP (3 MUg/ml) increased endothelial proliferation and survival, and normalized NO and ROS levels. The intravenous administration of RA-NP (10 MUg/g) prevented ischemic injury in the hippocampus of 2-day-old mice by inhibiting cell death and normalizing markers of neurovascular function and inflammation. In sum, systemic administration of RA-NP protected neurovascular integrity and the inflammatory milieu from ischemia in the immature brain, highlighting its therapeutic value for perinatal stroke. PMID- 29518540 TI - Regulation of the voltage-gated Ca2+ channel CaValpha2delta-1 subunit expression by the transcription factor Egr-1. AB - It is well known that the CaValpha2delta auxiliary subunit regulates the density of high voltage-activated Ca2+ channels in the plasma membrane and that alterations in their functional expression might have implications in the pathophysiology of diverse human diseases such as neuropathic pain. However, little is known concerning the transcriptional regulation of this protein. We previously characterized the promoter of CaValpha2delta, and here we report its regulation by the transcription factor Egr-1. Using the neuroblastoma N1E-115 cells, we found that Egr-1 interacts specifically with its binding site in the promoter, affecting the transcriptional regulation of CaValpha2delta. Overexpression and knockdown analysis of Egr-1 showed significant changes in the transcriptional activity of the CaValpha2delta promoter. Egr-1 also regulated the expression of CaValpha2delta at the level of protein. Also, functional studies showed that Egr-1 knockdown significantly decreases Ca2+ currents in dorsal root ganglion (DRG) neurons, while overexpression of the transcription factor increased Ca2+ currents in the F11 cell line, a hybrid of DRG and N18TG2 neuroblastoma cells. Studying the effects of Egr-1 on the transcriptional expression of CaValpha2delta could help to understand the regulatory mechanisms of this protein in both health and disease. PMID- 29518538 TI - Selectivity of probes for PET imaging of dopamine D3 receptors. AB - Dopamine D3 receptors have key roles in behavioral reward, addiction, Parkinson's disease, and schizophrenia, and there is interest in studying their role in these disorders using PET. However, current PET radiotracers for studying D3 receptors in humans all bind to both D2 and D3 due to similarities between the two receptors. Selective D2 and D3 radioligands would aid investigation of the differences between D2 and D3 circuitry in the central nervous system. While there are currently in vitro measures of ligand D3/D2 selectivity, there is a need for an in vivo PET measure of D3/D2 selectivity. This review discusses current PET imaging of dopamine D2/D3 receptors and proposes methodology for quantitating in vivo selectivity of probes for PET imaging of dopamine D3 receptors. PMID- 29518541 TI - Computational methods to examine conformational changes and ligand-binding properties: Examples in neurobiology. AB - Many proteins that are central to key aspects of neurobiology undergo conformational changes as part of their function, usually in response to a stimulus. Often, these proteins are embedded within a membrane, which creates particular experimental challenges to surmount. This has resulted in computational methods providing a valuable complementary tool for some time now, especially in the development of working models at atomic resolution. Indeed, molecular dynamics (MD) simulations are now routinely applied to new structures, either as part of the initial analysis or as part of an automated pipeline. Such simulations have proven extremely useful in terms of characterizing the inherent underlying conformational dynamics or providing insight into the interactions with the surrounding lipid molecules. However, MD simulations are capable of providing much more sophisticated information, including fundamental kinetic and thermodynamic properties of transitions between states and a description of how those transitions are influenced by the presence of ligands. There is a very large array of advanced simulation methods that can provide this information, but in this short review we limit ourselves to some selected examples of techniques that have given particular insight into proteins associated with molecular neurobiology. In this review, we highlight the use of i) Markov State Modelling to examine sodium dynamics in the dopamine transporter, ii) Metadynamics to explore neurotransmitter binding to a ligand-gated ion channel and iii) Steered MD to investigate conformational change in ionotropic glutamate receptors. PMID- 29518542 TI - PET radioligands for the dopamine D1-receptor: Application in psychiatric disorders. AB - The dopamine (DA) system is considered to be centrally involved in the pathophysiology of several major psychiatric disorders. Using positron emission tomography (PET), aberrations in dopamine D2/D3-receptors (D2-R) levels and uptake of the DA precursor FDOPA have been shown for schizophrenia, substance abuse and depression. Radioligands for the dopamine D1-receptor (D1-R) have been available for more than three decades, however this receptor subtype has received much less attention in psychiatry research. Here, studies investigating D1-R in psychiatric patients in comparison to healthy control subjects are summarized. Although small sample sizes, medication effects and heterogeneous methods of quantification limit the conclusions that can be drawn, the data is suggestive of higher levels of cortical D1-R in drug naive patients with psychosis, and lower D1-R in patients with affective disorders. Data sharing and reanalysis using harmonized methodology are important next steps towards clarifying the role of D1 R in these disorders. PMID- 29518544 TI - Learning in a Web-Based World: An Innovative Approach to Teach Physical Examination Skills in Patients with Neurodisability. AB - Despite increasing numbers of patients with neurodisability, residents lack training to develop physical examination skills. Following a blended educational intervention combining online and bedside teaching, residents demonstrated desired patient-care behaviors on standardized clinical exam assessment. PMID- 29518543 TI - Nicotine exposure leads to deficits in differential cued fear conditioning in mice and humans: A potential role of the anterior cingulate cortex. AB - Stress and anxiety disorders such as posttraumatic stress disorder (PTSD) are characterized by disrupted safety learning. Tobacco smoking has been strongly implicated in stress and anxiety disorder symptomatology, both as a contributing factor and as a vulnerability factor. Rodent studies from our lab have recently shown that acute and chronic nicotine exposure disrupts safety learning. However, it is unknown if these effects of nicotine translate to humans. The present studies addressed this gap by administering a translational differential cued fear conditioning paradigm to both mice and humans. In mice, we found that chronic nicotine exposure reduced discrimination between a conditioned stimulus (CS) that signals for danger (CS+) and another CS that signals for safety (CS-) during both acquisition and testing. We then employed a similar differential cued fear conditioning paradigm in human smokers and non-smokers undergoing functional magnetic resonance imaging (fMRI). Smokers showed reduced CS+/CS- discrimination during fear conditioning compared to non-smokers. Furthermore, using fMRI, we found that subgenual and dorsal anterior cingulate cortex activations were lower in smokers than in non-smokers during differential cued fear conditioning. These results suggest a potential biological mechanism underlying a dysregulated ability to discriminate between danger and safety cues. Our results indicate a clear parallel between the effects of nicotine exposure on safety learning in mice and humans and therefore suggest that smoking might represent a risk factor for inability to process information related to danger and safety related cues. PMID- 29518545 TI - The study of the calpain and caspase-1 expression in ultrastructural dynamics of Ehrlich ascites carcinoma necrosis. AB - An expression of calpain and caspase-1 as well as the concomitant ultrastructural alterations were investigated during necrosis of the mouse Ehrlich ascites carcinoma. The calpain expression was registered at 0 h and 1 h although caspase 1 did not induce any signals during these time periods. The rise of the cytoplasmic lytic zones contacted by calpain antibodies was identified as a morphologic event corresponding to the expression of calpain. Lytic zone's distribution followed by the appearance of the calpain/caspase-1 clusters assigned for lysis of the Golgi vesicles and ER. Also, the microapocrine secretion of the vesicles containing the calpain/caspase-1 clusters was detected. Further, the lysis of the plasma membrane occurred due to progression of intracellular lysis. Rupture of the plasma membrane resulted in the termination of secretion and dissemination of cell contents. The nuclei still had their normal shape. Nuclear lysis continued to rise with intranuclear lytic zones, of which the progression was accompanied with the presence of calpain/caspase-1 clusters. The data contribute to the concept of the initial role of calpain for tumor cell destruction, provide first evidence of the calpain/caspase-1 pathway in tumor cells, and highlight microapocrine secretion as a possible tumor cell death signalling mechanism. PMID- 29518546 TI - Analysis of the miRNA-mRNA-lncRNA network in human estrogen receptor-positive and estrogen receptor-negative breast cancer based on TCGA data. AB - Estrogen receptor-positive (ER+) and ER-negative (ER-) subtypes of breast cancer have distinct clinical outcomes because they respond differentially to endocrine therapies. We aimed to comprehensively analyze differentially expressed microRNA (miRNAs), long non-coding RNAs (lncRNAs) and mRNAs in different ER subtypes as well as to identify prognosis-related RNAs. The expression levels of miRNAs, lncRNAs, and mRNAs between breast cancer and normal samples were compared using data from The Cancer Genome Atlas database. Differentially expressed miRNAs, lncRNAs and mRNAs between ER+ and ER- samples were also screened. An ER subtype related miRNA-lncRNA-mRNA network was constructed. lncRNAs and mRNAs in this network were further subjected to an analysis of their associations with patient prognosis. Sets of differentially expressed miRNAs, lncRNAs, and miRNAs between breast cancer and normal samples were identified among which 14 miRNAs, 78 lncRNAs, and 475 mRNAs were differentially expressed between ER subtypes. Relationships between these RNAs were analyzed. The resultant ER subtype-related miRNA-lncRNA-mRNA network consisted of 14 nodes, among which LINC0092 and chromosome 2 open reading frame 71 (C2orf71) were correlated with better prognosis of breast cancer. LINC0092 was co-expressed with SFRP1 and RGMA and regulated by hsa-miR-449a and hsa-miR-452-5p. C2orf71 was co-expressed with LINC00511 and regulated by hsa-miR-184. Cross-talk among differentially expressed miRNAs, lncRNAs, and miRNAs may be an important feature in ER+ and ER- subtypes of breast cancer. LINC0092 and C2orf71, two of these cross-talking RNAs, may serve as novel prognostic predictor of breast cancer because of their close associations with prognosis. PMID- 29518547 TI - MicroRNA-223-3p regulates cell chemo-sensitivity by targeting FOXO3 in prostatic cancer. AB - Prostate cancer (PCa) is one of the most common malignant cancers in male and docetaxel is commonly used as an effective chemotherapeutic drug for PCa patients. However, docetaxel resistance inhibits the therapeutic effect of this agent, thus investigating the mechanism of chemoresistance to docetaxel of PCa may help to improve the prognosis of PCa patients. In our present study, we found that miR-223-3p was up-regulated in PCa cell lines (C4-2, LNCap, PC3, DU-145). Transfection with miR-223-3p inhibitor increased chemo-sensitivity to docetaxel and cell apoptosis rate in PCa cells compared with docetaxel + miR-223-3p mock group, especially in DU-145 cells which were more resistant to docetaxel. Bioinformatics study and luciferase reporter assay indicated that FOXO3 was a target of miR-223-3p and the results from western blot suggested that FOXO3 was negatively regulated by miR-223-3p. Further study revealed that up-regulation of FOXO3 by transfection with pCMV-FOXO3 decreased the IC50 values of docetaxel and increased cell apoptosis rate compared with docetaxel + pCMV-vector group, suggesting that overexpressed FOXO3 suppressed cell survival and sensitized PCa cells to docetaxel. Moreover, siRNA-mediated knockdown of FOXO3 abolished the effects of miR-223-3p inhibitor on chemo-sensitivity and apoptosis in PCa cells by increasing chemoresistance and decreasing cell apoptosis rate. Finally, the in vivo experiments showed that miR-223-3p inhibitor sensitized prostatic cancer mouse model to docetaxel by increasing the expression of FOXO3. In conclusion, our present study indicated that miR-223-3p regulated cell chemo-sensitivity by targeting FOXO3 in prostatic cancer both in vitro and in vivo, providing new potential therapeutic strategy for PCa treatment. PMID- 29518548 TI - Identification of 'Xinlimei' radish candidate genes associated with anthocyanin biosynthesis based on a transcriptome analysis. AB - Radish is an economically important vegetable crop belonging to the family Brassicaceae. The high anthocyanin content of the 'Xinlimei' radish roots has been associated with diverse health benefits. However, there is a lack of transcript-level information regarding anthocyanin biosynthesis. In the present study, the 'Xinlimei' radish root transcriptome was analyzed by RNA sequencing at five developmental stages. A total of 222,384,034 clean reads were obtained and 32,253 unigenes were annotated. Expression profiles revealed 10,890 differentially expressed genes (DEGs) among the five analyzed libraries. The DEGs were predominantly involved in KEGG pathways related to the biosynthesis of phenylpropanoids, flavonoids, flavone, and flavonol. The transcriptome data revealed 44 structural and 182 transcription factor genes (TFs) associated with the anthocyanin biosynthetic pathway. Ten structural genes (i.e., 4CL3, CHSB2, CHS1, CHS3, F3H1, F3'H, DFR, DFR1, ANS, and UFGT) and two MYB genes, which were highly and differentially expressed during root development, may be critical for anthocyanin biosynthesis. Additionally, the co-expression of TFs and structural genes was analyzed. Three structural genes (i.e., DFR, ANS, and UFGT) were validated by molecular cloning. The qRT-PCR results indicated that the expression profiles of DEGs were generally consistent with the high-throughput sequencing results. These findings helped identify candidate genes involved in anthocyanin biosynthesis and may be useful for clarifying the molecular mechanism underlying the accumulation of anthocyanins in radish roots. PMID- 29518549 TI - SP1-mediated downregulation of ADAMTS3 gene expression in osteosarcoma models. AB - ADAMTS3 is a member of procollagen N-proteinase subfamily of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family. It has an important function in the procollagen maturation process. The removal of N peptidases is required for the accurate processing of fibrillar collagens. Otherwise, several disorders can occur that is related with the collagenous tissues. ADAMTS3 mainly maturates type II collagen molecule which is the main component of the bone and cartilage. There are several expression studies about ADAMTS3 gene however its transcriptional regulation has not been lightened up, yet. Here we first time cloned and functionally analyzed the promoter region of ADAMTS3 gene, approximately 1380 bp upstream of the transcription start site. Transient transfection experiments showed that all truncated promoter constructs are active and 171 bp fragment is sufficient to activate gene expression in both Saos-2 and MG63 cells. In silico analysis showed that ADAMTS3 has a TATA-less promoter and contains several SP1/GC box binding motifs and a CpG island. Therefore we mainly investigated the SP1 dependent regulation of ADAMTS3 promoter. SP1 downregulated ADAMTS3 transcriptional activity. As consistent with the transcriptional activity, mRNA, and protein expression levels were also decreased by SP1. On the other hand, functional binding of the SP1 on multiple regions of ADAMTS3 promoter was confirmed by EMSA studies. As ADAMTS3 is responsible for the collagen maturation and biosynthesis, further we investigated the effect of SP1 on type I-II and III collagen gene expressions. We point out that SP1 increased type II and III collagen expression and in contrast decreased type I collagen expression levels in Saos-2 cells. mRNA expression level was decreased for all collagen types in MG63 model. Decrease in the type II collagen expression was also demonstrated at the protein level by SP1. Collectively these results provide first findings for the SP1-related transcriptional regulation of ADAMTS3 and collagen genes in osteosarcoma cell lines. PMID- 29518550 TI - Regulation of trichome development in tobacco by JcZFP8, a C2H2 zinc finger protein gene from Jatropha curcas L. AB - Trichomes are epidermal outgrowths of plant tissues that can secrete or store large quantities of secondary metabolites, which contribute to plant defense responses against stress. The use of bioengineering methods for regulating the development of trichomes and metabolism is a widely researched topic. In the present study, we demonstrate that JcZFP8, a C2H2 zinc finger protein gene from Jatropha curcas L., can regulate trichome development in transgenic tobacco. To understand the underlying mechanisms, we performed transcriptome profiling of overexpression JcZFP8 transgenic plants and wild-type tobacco. Based on the analysis of differentially expressed genes, we determined that genes of the plant hormone signal transduction pathway was significantly enriched, suggesting that these pathways were modulated in the transgenic plants. In addition, the transcript levels of the known trichome-related genes in Arabidopsis were not significantly changed, whereas CycB2 and MYB genes were differentially expressed in the transgenic plants. Despite tobacco and Arabidopsis have different types of trichomes, all the pathways were associated with C2H2 zinc finger protein genes. Our findings help us to understand the regulation of multicellular trichome formation and suggest a new metabolic engineering method for the improvement of plants. PMID- 29518551 TI - Association between Activated Partial Thromboplastin Time and the Amount of Infused Heparin at Bone Marrow Transplantation. AB - The actual heparin concentration of harvested allogeneic bone marrow varies among harvest centers. We monitor the activated partial thromboplastin time (APTT) of the patient during bone marrow infusion and administer prophylactic protamine according to the APTT. We retrospectively reviewed the charts of consecutive patients who underwent bone marrow transplantation without bone marrow processing at our center between April 2007 and March 2016 (n = 94). APTT was monitored during marrow transfusion in 52 patients. We analyzed the relationship between the APTT ratio and several parameters related to heparin administration. As a result, the weight-based heparin administration rate (U/kg/hour) seemed to be more closely related to the APTT ratio (r = .38, P = .005) than to the total amount of heparin. There was no significant correlation between the APTT ratio and renal or liver function. Bleeding complications during and early after infusion were seen in 3 of 52 patients, and included intracranial, nasal, and punctured-skin bleeding. The APTT ratio during transfusion was over 5.88 in the former 2 patients and 2.14 in the latter. All of these patients recovered without sequelae. In conclusion, slow bone marrow infusion is recommended to decrease the weight-based heparin administration rate when the heparin concentration per patient body weight is high. PMID- 29518552 TI - Early Blood Stream Infections after BMT are Associated with Cytokine Dysregulation and Poor Overall Survival. AB - The key complications of allogeneic bone marrow transplantation (BMT) remain graft-versus-host disease (GVHD) and opportunistic infection. We have analyzed the blood stream infections (BSIs) occurring between day -7 and day 100 in a cohort of 184 adult patients undergoing allogeneic BMT in our center. A total of 167 of the 184 patients (91%) had blood cultures collected, and 69 (38%) patients had a confirmed BSI. Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp., and viridans Streptococcus spp. were the most commonly isolated organisms. Gender, conditioning (myeloablative versus reduced intensity), and donor type (sibling versus unrelated) did not differ significantly between those with and without confirmed BSI. Elevated temperature (>38 degrees C) at the time of culture collection was associated with an almost 2-fold increased likelihood of returning a positive blood culture. The absence of a BSI was associated with a significant improvement in overall survival at 2 years, due to a significant reduction in nonrelapse mortality predominantly unrelated to the primary BSI. The presence of a BSI before engraftment was associated with the dysregulation of IL 6 and IL-8. Our findings suggest that BSI early after BMT defines a group of high risk patients with enhanced cytokine dysregulation and poor transplant outcome. PMID- 29518553 TI - Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation - Positive Advanced Non-Small Cell Lung Cancer (CheckMate 370). AB - INTRODUCTION: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation-positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation-positive NSCLC. METHODS: Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation-positive NSCLC. The primary endpoint of safety would be met if <=20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. RESULTS: Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade >=3 hepatic toxicities. Five patients (38%) had a partial response. CONCLUSIONS: These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily. PMID- 29518554 TI - Brief Report on Radiological Changes following Stereotactic Ablative Radiotherapy (SABR) for Early-Stage Lung Tumors: A Pictorial Essay. AB - Distinctive patterns of early and late benign fibrosis are commonly observed after stereotactic ablative radiotherapy for lung malignancies. These changes on computed tomography scans need to be distinguished from so-called high-risk radiological features, which can be associated with a higher risk for tumor recurrence. This pictorial report illustrates the different radiological changes seen after stereotactic ablative radiotherapy delivered by using volumetric modulated radiotherapy, a technique that is being increasingly used in clinical care. PMID- 29518555 TI - Large eddy simulation of the flow pattern in an idealized mouth-throat under unsteady inspiration flow conditions. AB - An excellent understanding of the airflow properties is critical to improve the drug delivery efficiency via the extrathoracic airway. The present numerical study focuses on the investigation the characteristics of important airflow structures such as the secondary vortices, the impinging jet and the recirculation zone under unsteady inspiration flow conditions in a circular idealized mouth-throat model using large eddy simulation (LES). Five inhalation cycles are simulated, the last one of which is analyzed in detail at five different times. Two times are chosen during the accelerating branch, one at the peak and two within the decelerating inhalation wave. The flow exhibits an extinct process of the flow transiting from laminar to turbulent during the accelerating phase and transiting back from turbulent to laminar in the decelerating phase. It is found that the flow is much more turbulent during the decelerating phase compared to the accelerating phase of the inspiration wave, which is associated with more smaller secondary vortices, a shorter and more unsteady laryngeal jet, a smaller and more unsteady recirculation zone, as well as an enlarged mixing zone. These differences during the unsteady inspiration require more attention in particular if particle transport and deposition in the upper airway are to be investigated. PMID- 29518556 TI - Modulation of macrophage phenotype and protein secretion via heparin-IL-4 functionalized supramolecular elastomers. AB - : Hallmark of the in situ tissue engineering approach is the use of bioresorbable, synthetic, acellular scaffolds, which are designed to modulate the inflammatory response and actively trigger tissue regeneration by the body itself at the site of implantation. Much research is devoted to the design of synthetic materials modulating the polarization of macrophages, which are essential mediators of the early stages of the inflammatory response. Here, we present a novel method for the functionalization of elastomers based on synthetic peptide chemistry, supramolecular self-assembly, and immobilization of heparin and interleukin 4 (IL-4), which is known to skew the polarization of macrophages into the wound healing "M2" phenotype. Ureido-pyrimidinone (UPy)-modified chain extended polycaprolactone (CE-UPy-PCL) was mixed with a UPy-modified heparin binding peptide (UPy-HBP) to allow for immobilization of heparin, and further functionalization with IL-4 via its heparin binding domain. As a first proof of principle, CE-UPy-PCL and UPy-HBP were premixed in solution, dropcast and exposed to primary human monocyte-derived macrophages, in the presence or absence of IL-4 heparin functionalization. It was demonstrated that the supramolecular IL-4 heparin functionalization effectively promoted macrophage polarization into an anti-inflammatory phenotype, in terms of morphology, immunohistochemistry and cytokine secretion. Moreover, the supramolecular functionalization approach used was successfully translated to 3D electrospun scaffolds for in situ tissue engineering purposes, where UPy-HBP retention, and heparin and IL-4 attachment to the supramolecular scaffolds were proven over 7 days. Lastly, human monocyte derived macrophages were cultured on 3D scaffolds, which, in case of IL-4-heparin functionalization, were proven to promote of an anti-inflammatory environment on protein level. This study presents a novel method in designing a versatile class of functionalized elastomers that effectively harness the anti-inflammatory behavior of macrophages in vitro, and as such, may be instrumental for the development of a new class of synthetic materials for in situ tissue engineering purposes. STATEMENT OF SIGNIFICANCE: Macrophages and their phenotypic and functional plasticity play a pivotal role in metabolic homeostasis and tissue repair. Based on this notion, bioactivated materials modulating macrophage polarization were extensively investigated in the past. Here, we designed immunomodulating, synthetic materials based on supramolecular immobilization of a heparin binding peptide, and further bioactivation with heparin and IL-4, an anti inflammatory cytokine responsible for M2 activation and polarization. Human monocyte-derived macrophages cultured on heparin-IL-4 bioactivated materials displayed an elongated morphology and an anti-inflammatory phenotype, with downregulation of pro-inflammatory cytokines and promotion of anti-inflammatory cytokines over time. This study represents the first step in designing a novel class of synthetic, bioactivated materials that harness the regenerative behavior of host macrophages towards in situ tissue regeneration. PMID- 29518557 TI - Transcriptome analyses reveal Litopenaeus vannamei hemocytes response to lipopolysaccharide. AB - Although vertebrate immunity has been well studied for the past decades, invertebrate immunity was much less explored. One possible reason was that in vitro culture system was not well established. In this study, Litopenaeus vannamei was applied as an invertebrate study model. Primary culture conditions for L. vannamei hemocytes were optimized to get relatively quiescent state cells. LPS was used as an immune stimulator and the responses of primary cultured hemocytes were transcriptomically analyzed. Our results showed that around 1,600 genes were upregulated and 800 genes were downregulated from LPS treated hemocytes. The altered genes could be classified into three categories: upregulated, downregulated, upregulated and then downregulated. Further qPCR validation showed that ubiquitin, ubiquitin-conjugating enzyme E2 C, ubiquitin conjugating enzyme H1 and ubiquitin-conjugating enzyme H5b in ubiquitin proteasome pathway were upregulated, cytochrome c oxidase 1, NADH dehydrogenase 1, Inosine-5'-monophosphate dehydrogenase 1b and phospholipid-transporting ATPase IA in mitochondria oxidation phosphorylation were downregulated. Our results showed that L. vannamei hemocyte inflammation responses share a lot of similarities with mammalian macrophage inflammation responses. PMID- 29518558 TI - Leucaena leucocephala pod seed protein as an alternate to animal protein in fish feed and evaluation of its role to fight against infection caused by Vibrio harveyi and Pseudomonas aeruginosa. AB - The laboratory acclimatized Clarias gariepinus (80 +/- 10 g) were divided into six groups and five subgroups each containing 10 fish. A fish feed was reconstituted by adding 33% powder of Leucaena leucocephala seed in place of fish trash. Group B, C and E were fed on reconstituted feed and group A, D and F were fed on artificial feed containing animal protein for 7 days prior to start of experiments. Then Group B was challenged with BSA while other groups were challenged with Vibrio harveyi (Group C, D) and Pseudomonas aeruginosa (Group E, F). Group A was used as negative control (not challenged with antigen). The fish were challenged on weekly intervals till 28th day. Blood was collected from one subgroup of each group on day 7, 14, 21 & 28 and finally sacrificed on day 35. Change in body weight, liver function tests (SGOT, SGPT) and serum ALP levels were monitored. The phagocytic index, percentage phagocytosis and nitric oxide levels were measured in macrophages isolated from spleen and head kidney. The levels of total fish immunoglobulin were also measured following indirect ELISA. The results showed improved immune response in fish fed on 33% L. leucocephala pod seed reconstituted feed; however their specific growth rate was low. PMID- 29518560 TI - Pain, Please: An Investigation of Sampling Bias in Pain Research. AB - : Experimental pain research frequently relies on the recruitment of volunteers. However, because experimental pain research often involves unpleasant and painful sensations, it may be especially susceptible to sampling bias. That is, volunteers in experimental pain research might differ from nonvolunteers on several relevant variables that could affect the generalizability and external validity of the research. We conducted 2 studies to investigate potential sampling bias in experimental pain research. In study 1 we assessed participants' (N = 275; age = 17-30 years) perceived likelihood of participating in pain research. Pain catastrophizing, fear of pain, illness and injury sensitivity, depression, anxiety, sensation-seeking, gender identity, body appreciation, and social desirability were also assessed as potential predictors of the likelihood to participate. In study 2, participants (N = 87; Age = 18-31 years) could sign up for 2 nearly identical studies, with only one involving painful sensations. Thirty-six participants signed up for the pain study and 51 participants signed up for the no-pain study. Study 1 showed that lower levels of fear of pain, higher levels of sensation-seeking, and older age predicted the perceived likelihood of participating in pain research. Study 2 showed significantly higher levels of sensation-seeking in participants who signed up for the pain study compared with those who signed up for the no-pain study. The implications of these findings for future research, as well as the clinical conclusions on the basis of experimental pain research, are discussed. PERSPECTIVE: Intention to participate in experimental pain research was associated with less fear of pain, higher sensation-seeking, and older age. Actual participation in experimental pain research was associated with higher sensation-seeking. This potential sampling bias in studies involving painful stimuli could limit external validity and generalizability of pain research. PMID- 29518559 TI - Effect of beta-1, 3 glucan binding protein based zinc oxide nanoparticles supplemented diet on immune response and disease resistance in Oreochromis mossambicus against Aeromonas hydrophila. AB - Recently, several immunostimulants such as beta-glucan, microbial and plant products have been used as dietary supplements to combat disease outbreaks in aquaculture. The present study investigates the potential of Portunus pelagicus beta-1, 3 glucan binding protein based zinc oxide nanoparticles (Ppbeta-GBP-ZnO NPs) supplemented diet on growth, immune response and disease resistance in Mozambique tilapia, Oreochromis mossambicus. The immune-related protein beta-GBP was purified from the haemolymph of P. pelagicus using Sephadex G-100 affinity column chromatography. Ppbeta-GBP-ZnO NPs was physico- chemically characterized and experimental feed was formulated. Fish were separately fed with commercial diet (control-group I) and Ppbeta-GBP (group II, III, IV), Ppbeta-GBP-ZnO NPs (group V, VI, VII), chem-ZnO NPs (VIII, IX, X) mixed diet at the concentration of 0.001%, 0.002% and 0.004% respectively. Triplicate groups of O. mossambicus were fed with experimental diets twice a day for 30 days. Fish receiving Ppbeta-GBP ZnO NPs supplemented diet showed a significant increase (P < 0.05) in growth performance. Cellular immune responses (myeloperoxidase activity, lysozyme activity and reactive oxygen species activity) and humoral immune responses (complement activity, antiprotease activity and alkaline phosphatase activity) were evaluated at an interval of 15 days during the feeding trial. Results demonstrate that both cellular and humoral immune responses were substantially increased (P < 0.05) in fish fed with 0.004% of Ppbeta-GBP-ZnO NPs supplemented diet than others. Antibiofilm potential of Ppbeta-GBP-ZnO NPs against Aeromonas hydrophila was visualized through confocal laser scanning microscopy (CLSM), which reveals reduction in the preformed biofilm thickness to 10 MUm at the concentration of 50 MUg/ml. Furthermore, after 30 days of feeding trial, fish were challenged with aquatic fish pathogen A. hydrophila (1 * 107 cells ml-1) through intraperitoneal injection. Challenge study displayed a reduced mortality rate in fish fed with diet containing Ppbeta-GBP-ZnO NPs. Thus our study suggests that dietary supplementation of Ppbeta-GBP-ZnO NPs at 0.004% may have a potential effect to enhance the immune system and survival of O. mossambicus. PMID- 29518561 TI - Loss of metagenesis and evolution of a parasitic life style in a group of open ocean jellyfish. AB - Loss or stark reduction of the free-swimming medusa or jellyfish stage is common in the cnidarian class Hydrozoa. In the hydrozoan clade Trachylina, however, many species do not possess a sessile polyp or hydroid stage. Trachylines inhabiting freshwater and coastal ecosystems (i.e., Limnomedusae) possess a metagenetic life cycle involving benthic, sessile polyp and free-swimming medusa. In contrast, the paradigm is that open ocean inhabiting, oceanic trachylines (in the orders Narcomedusae and Trachymedusae) develop from zygote to medusa via a free-swimming larva, forgoing the polyp stage. In some open-ocean trachylines, development includes a sessile stage that is an ecto- or endoparasite of other oceanic organisms. We expand the molecular-based phylogenetic hypothesis of trachylines significantly, increasing taxon and molecular marker sampling. Using this comprehensive phylogenetic hypothesis in conjunction with character state reconstructions we enhance understanding of the evolution of life cycles in trachyline hydrozoans. We find that the polyp stage was lost at least twice independently, concurrent with a transition to an oceanic life style. Further, a sessile, polypoid parasitic stage arose once, rather than twice as current classification would imply, in the open ocean inhabiting Narcomedusae. Our results also support the hypothesis that interstitial species of the order Actinulida are directly descended from direct developing, oceanic trachylines. PMID- 29518562 TI - The performance of human papillomavirus DNA detection with type 16/18 genotyping by hybrid capture in primary test of cervical cancer screening: a cross-sectional study in 10,669 Chinese women. AB - OBJECTIVES: We aimed to assess the performance of DH3 human papillomavirus (HPV) assay, a newly developed hybrid capture technique that detects 14 high-risk HPVs with type 16/18 genotyping, as a primary test in cervical cancer screening. METHODS: In total 11,356 Chinese women aged 21-65 years participated in a cervical cancer screening programme using cytology (Thinprep, Hologic) and HPV testing (Cobas 4800 Test, Roche). Residual samples were used to detect HPV by DH3 HPV. RESULTS: In total 10,669 women with valid results were included in the study. Of those, 135 were diagnosed as CIN2+, and 83 were diagnosed as CIN3+; 1056 women (9.9%) were DH3 HPV-positive and 255 (2.4%) of those were 16/18 positive, while 990 (9.3%) women were Cobas HPV-positive and 243 (2.3%) of those were 16/18-positive. DH3 HPV was non-inferior to Cobas HPV in identifying CIN1- and CIN2+ using predetermined thresholds (both p < 0.001). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of DH3 HPV were 93.3% (95% confidence interval [CI] = 87.7-96.9), 91.2% (95%CI = 90.6-91.7), 12.0% (95%CI = 10.1-14.1) and 99.9% (95%CI = 99.8-100), respectively, similar to those of Cobas HPV (91.1%, 95%CI = 85.0-5.3; 91.8%, 95%CI = 91.2-92.3; 12.5%, 95%CI = 10.5-14.7; and 99.9%, 95%CI = 99.8-99.9, respectively), in identifying CIN2+ (all p > 0.05). When DH3 HPV and Cobas HPV were respectively used as primary testing in screening strategy, the performance of two strategies were similar in identifying CIN2+. The results were similar in identifying CIN3+. CONCLUSION: Our data suggest that DH3 HPV performs similarly to Cobas HPV in identifying high-grade CIN in cervical cancer screening. PMID- 29518563 TI - Distributed and opposing effects of incidental learning in the human brain. AB - Incidental learning affords a behavioural advantage when sensory information matches regularities that have previously been encountered. Previous studies have taken a focused approach by probing the involvement of specific candidate brain regions underlying incidentally acquired memory representations, as well as expectation effects on early sensory representations. Here, we investigated the broader extent of the brain's sensitivity to violations and fulfilments of expectations, using an incidental learning paradigm in which the contingencies between target locations and target identities were manipulated without participants' overt knowledge. Multivariate analysis of functional magnetic resonance imaging data was applied to compare the consistency of neural activity for visual events that the contingency manipulation rendered likely versus unlikely. We observed widespread sensitivity to expectations across frontal, temporal, occipital, and sub-cortical areas. These activation clusters showed distinct response profiles, such that some regions displayed more reliable activation patterns under fulfilled expectations, whereas others showed more reliable patterns when expectations were violated. These findings reveal that expectations affect multiple stages of information processing during visual decision making, rather than early sensory processing stages alone. PMID- 29518564 TI - Neural and genetic determinants of creativity. AB - Creative thinking plays a vital role in almost all aspects of human life. However, little is known about the neural and genetic mechanisms underlying creative thinking. Based on a cross-validation based predictive framework, we searched from the whole-brain connectome (34,716 functional connectivities) and whole genome data (309,996 SNPs) in two datasets (all collected by Southwest University, Chongqing) consisting of altogether 236 subjects, for a better understanding of the brain and genetic underpinning of creativity. Using the Torrance Tests of Creative Thinking score, we found that high figural creativity is mainly related to high functional connectivity between the executive control, attention, and memory retrieval networks (strong top-down effects); and to low functional connectivity between the default mode network, the ventral attention network, and the subcortical and primary sensory networks (weak bottom-up processing) in the first dataset (consisting of 138 subjects). High creativity also correlates significantly with mutations of genes coding for both excitatory and inhibitory neurotransmitters. Combining the brain connectome and the genomic data we can predict individuals' creativity scores with an accuracy of 78.4%, which is significantly better than prediction using single modality data (gene or functional connectivity), indicating the importance of combining multi-modality data. Our neuroimaging prediction model built upon the first dataset was cross validated by a completely new dataset of 98 subjects (r = 0.267, p = 0.0078) with an accuracy of 64.6%. In addition, the creativity-related functional connectivity network we identified in the first dataset was still significantly correlated with the creativity score in the new dataset (p<10-3). In summary, our research demonstrates that strong top-down control versus weak bottom-up processes underlie creativity, which is modulated by competition between the glutamate and GABA neurotransmitter systems. Our work provides the first insights into both the neural and the genetic bases of creativity. PMID- 29518565 TI - Distinct phase-amplitude couplings distinguish cognitive processes in human attention. AB - Spatial attention is the cognitive function that coordinates the selection of visual stimuli with appropriate behavioral responses. Recent studies have reported that phase-amplitude coupling (PAC) of low and high frequencies covaries with spatial attention, but differ on the direction of covariation and the frequency ranges involved. We hypothesized that distinct phase-amplitude frequency pairs have differentiable contributions during tasks that manipulate spatial attention. We investigated this hypothesis with electrocorticography (ECoG) recordings from participants who engaged in a cued spatial attention task. To understand the contribution of PAC to spatial attention we classified cortical sites by their relationship to spatial variables or behavioral performance. Local neural activity in spatial sites was sensitive to spatial variables in the task, while local neural activity in behavioral sites correlated with reaction time. We found two PAC frequency clusters that covaried with different aspects of the task. During a period of cued attention, delta-phase/high-gamma (DH) PAC was sensitive to cue direction in spatial sites. In contrast, theta-alpha-phase/beta low-gamma-amplitude (TABL) PAC robustly correlated with future reaction times in behavioral sites. Finally, we investigated the origins of TABL PAC and found it corresponded to behaviorally relevant, sharp waveforms, which were also coupled to a low frequency rhythm. We conclude that TABL and DH PAC correspond to distinct mechanisms during spatial attention tasks and that sharp waveforms are elements of a coupled dynamical process. PMID- 29518567 TI - Automatic skull segmentation from MR images for realistic volume conductor models of the head: Assessment of the state-of-the-art. AB - Anatomically realistic volume conductor models of the human head are important for accurate forward modeling of the electric field during transcranial brain stimulation (TBS), electro- (EEG) and magnetoencephalography (MEG). In particular, the skull compartment exerts a strong influence on the field distribution due to its low conductivity, suggesting the need to represent its geometry accurately. However, automatic skull reconstruction from structural magnetic resonance (MR) images is difficult, as compact bone has a very low signal in magnetic resonance imaging (MRI). Here, we evaluate three methods for skull segmentation, namely FSL BET2, the unified segmentation routine of SPM12 with extended spatial tissue priors, and the skullfinder tool of BrainSuite. To our knowledge, this study is the first to rigorously assess the accuracy of these state-of-the-art tools by comparison with CT-based skull segmentations on a group of ten subjects. We demonstrate several key factors that improve the segmentation quality, including the use of multi-contrast MRI data, the optimization of the MR sequences and the adaptation of the parameters of the segmentation methods. We conclude that FSL and SPM12 achieve better skull segmentations than BrainSuite. The former methods obtain reasonable results for the upper part of the skull when a combination of T1- and T2-weighted images is used as input. The SPM12-based results can be improved slightly further by means of simple morphological operations to fix local defects. In contrast to FSL BET2, the SPM12-based segmentation with extended spatial tissue priors and the BrainSuite-based segmentation provide coarse reconstructions of the vertebrae, enabling the construction of volume conductor models that include the neck. We exemplarily demonstrate that the extended models enable a more accurate estimation of the electric field distribution during transcranial direct current stimulation (tDCS) for montages that involve extraencephalic electrodes. The methods provided by FSL and SPM12 are integrated into pipelines for the automatic generation of realistic head models based on tetrahedral meshes, which are distributed as part of the open-source software package SimNIBS for field calculations for transcranial brain stimulation. PMID- 29518566 TI - Abstinence to chronic methamphetamine switches connectivity between striatal, hippocampal and sensorimotor regions and increases cerebral blood volume response. AB - Methamphetamine (meth), and other psychostimulants such as cocaine, present a persistent problem for society with chronic users being highly prone to relapse. We show, in a chronic methamphetamine administration model, that discontinuation of drug for more than a week produces much larger changes in overall meth-induced brain connectivity and cerebral blood volume (CBV) response than changes that occur immediately following meth administration. Areas showing the largest changes were hippocampal, limbic striatum and sensorimotor cortical regions as well as brain stem areas including the pedunculopontine tegmentum (PPTg) and pontine nuclei - regions known to be important in mediating reinstatement of drug taking after abstinence. These changes occur concomitantly with behavioral sensitization and appear to be mediated through increases in dopamine D1 and D3 and decreases in D2 receptor protein and mRNA expression. We further identify a novel region of dorsal caudate/putamen, with a low density of calbindin neurons, that has an opposite hemodynamic response to meth than the rest of the caudate/putamen and accumbens and shows very strong correlation with dorsal CA1 and CA3 hippocampus. This correlation switches following meth abstinence from CA1/CA3 to strong connections with ventral hippocampus (ventral subiculum) and nucleus accumbens. These data provide novel evidence for temporal alterations in brain connectivity where chronic meth can subvert hippocampal - striatal interactions from cognitive control regions to regions that mediate drug reinstatement. Our results also demonstrate that the signs and magnitudes of the induced CBV changes following challenge with meth or a D3-preferring agonist are a complementary read out of the relative changes that occur in D1, D2 and D3 receptors using protein or mRNA levels. PMID- 29518568 TI - Evolution of spatial and temporal features of functional brain networks across the lifespan. AB - Development and aging are associated with functional changes in the brain across the lifespan. These changes manifest in a variety of spatial and temporal features of resting state functional MRI (rs-fMRI) but have seldom been explored exhaustively. We present a comprehensive study assessing age-related changes in spatial and temporal features of blind-source separated components identified by independent vector analysis (IVA) in a cross-sectional lifespan sample (ages 6-85 years). We show that while large-scale network configurations remain consistent throughout the lifespan, changes persist in both local and global organization of these networks. We show that the spatial extent of the majority of functional networks exhibits linear decreases and both positive and negative quadratic trajectories across the lifespan. Network connectivity revealed nuanced patterns of linear and quadratic relationships with age, primarily in higher order cognitive networks. We also show divergent age-related patterns across the frequency spectrum in lower and higher frequencies. Taken together, these results point to the presence of sophisticated patterns of age-related changes that have previously not been considered collectively. We suggest that established patterns of lifespan changes in rs-fMRI features may be driven by changes in the spectral composition of BOLD signals. PMID- 29518569 TI - Acoustic and higher-level representations of naturalistic auditory scenes in human auditory and frontal cortex. AB - Often, in everyday life, we encounter auditory scenes comprising multiple simultaneous sounds and succeed to selectively attend to only one sound, typically the most relevant for ongoing behavior. Studies using basic sounds and two-talker stimuli have shown that auditory selective attention aids this by enhancing the neural representations of the attended sound in auditory cortex. It remains unknown, however, whether and how this selective attention mechanism operates on representations of auditory scenes containing natural sounds of different categories. In this high-field fMRI study we presented participants with simultaneous voices and musical instruments while manipulating their focus of attention. We found an attentional enhancement of neural sound representations in temporal cortex - as defined by spatial activation patterns - at locations that depended on the attended category (i.e., voices or instruments). In contrast, we found that in frontal cortex the site of enhancement was independent of the attended category and the same regions could flexibly represent any attended sound regardless of its category. These results are relevant to elucidate the interacting mechanisms of bottom-up and top-down processing when listening to real-life scenes comprised of multiple sound categories. PMID- 29518570 TI - Bayesian Optimisation of Large-Scale Biophysical Networks. AB - The relationship between structure and function in the human brain is well established, but not yet well characterised. Large-scale biophysical models allow us to investigate this relationship, by leveraging structural information (e.g. derived from diffusion tractography) in order to couple dynamical models of local neuronal activity into networks of interacting regions distributed across the cortex. In practice however, these models are difficult to parametrise, and their simulation is often delicate and computationally expensive. This undermines the experimental aspect of scientific modelling, and stands in the way of comparing different parametrisations, network architectures, or models in general, with confidence. Here, we advocate the use of Bayesian optimisation for assessing the capabilities of biophysical network models, given a set of desired properties (e.g. band-specific functional connectivity); and in turn the use of this assessment as a principled basis for incremental modelling and model comparison. We adapt an optimisation method designed to cope with costly, high-dimensional, non-convex problems, and demonstrate its use and effectiveness. Using five parameters controlling key aspects of our model, we find that this method is able to converge to regions of high functional similarity with real MEG data, with very few samples given the number of parameters, without getting stuck in local extrema, and while building and exploiting a map of uncertainty defined smoothly across the parameter space. We compare the results obtained using different methods of structural connectivity estimation from diffusion tractography, and find that one method leads to better simulations. PMID- 29518571 TI - Functional correlate and delineated connectivity pattern of human motion aftereffect responses substantiate a subjacent visual-vestibular interaction. AB - The visual motion aftereffect (MAE) is the most prominent aftereffect in the visual system. Regarding its function, psychophysical studies suggest its function to be a form of sensory error correction, possibly also triggered by incongruent visual-vestibular stimulation. Several observational imaging experiments have deducted an essential role for region MT+ in the perception of a visual MAE but not provided conclusive evidence. Potential confounders with the MAE such as ocular motor performance, attention, and vection sensations have also never been controlled for. Aim of this neuroimaging study was to delineate the neural correlates of MAE and its subjacent functional connectivity pattern. A rotational MAE (n = 22) was induced using differing visual stimuli whilst modulating ocular motor parameters in a 3T scanner. Data was analyzed with SPM12. Eye movements as a response to the same stimuli were studied by means of high resolution videooculography. Analysis for all stimuli gave bilateral activations along the dorsal visual stream with an emphasis on area MT. The onset of a visual MAE revealed an additional response in the right medial superior temporal area (MST) and a concurrent deactivation of vestibular hub region OP2. There was no correlation for the BOLD effects during the MAE with either ocular motor or attention parameters. The functional correlate of a visual MAE in humans may be represented in the interaction between region MT and area MST. This MAE representation is independent of a potential afternystagmus, attention and the presence of egomotion sensations. Connectivity analyses showed that in the event of conflicting visual-vestibular motion information (here MAE) area MST and area OP2 may act as the relevant mediating network hubs. PMID- 29518572 TI - Evaluation of non-negative matrix factorization of grey matter in age prediction. AB - The relationship between grey matter volume (GMV) patterns and age can be captured by multivariate pattern analysis, allowing prediction of individuals' age based on structural imaging. Raw data, voxel-wise GMV and non-sparse factorization (with Principal Component Analysis, PCA) show good performance but do not promote relatively localized brain components for post-hoc examinations. Here we evaluated a non-negative matrix factorization (NNMF) approach to provide a reduced, but also interpretable representation of GMV data in age prediction frameworks in healthy and clinical populations. This examination was performed using three datasets: a multi-site cohort of life-span healthy adults, a single site cohort of older adults and clinical samples from the ADNI dataset with healthy subjects, participants with Mild Cognitive Impairment and patients with Alzheimer's disease (AD) subsamples. T1-weighted images were preprocessed with VBM8 standard settings to compute GMV values after normalization, segmentation and modulation for non-linear transformations only. Non-negative matrix factorization was computed on the GM voxel-wise values for a range of granularities (50-690 components) and LASSO (Least Absolute Shrinkage and Selection Operator) regression were used for age prediction. First, we compared the performance of our data compression procedure (i.e., NNMF) to various other approaches (i.e., uncompressed VBM data, PCA-based factorization and parcellation based compression). We then investigated the impact of the granularity on the accuracy of age prediction, as well as the transferability of the factorization and model generalization across datasets. We finally validated our framework by examining age prediction in ADNI samples. Our results showed that our framework favorably compares with other approaches. They also demonstrated that the NNMF based factorization derived from one dataset could be efficiently applied to compress VBM data of another dataset and that granularities between 300 and 500 components give an optimal representation for age prediction. In addition to the good performance in healthy subjects our framework provided relatively localized brain regions as the features contributing to the prediction, thereby offering further insights into structural changes due to brain aging. Finally, our validation in clinical populations showed that our framework is sensitive to deviance from normal structural variations in pathological aging. PMID- 29518573 TI - Protracted hippocampal development is associated with age-related improvements in memory during early childhood. AB - The hippocampus is a structure that is critical for memory. Previous studies have shown that age-related differences in specialization along the longitudinal axis of this structure (i.e., subregions) and within its internal circuitry (i.e., subfields) relate to age-related improvements in memory in school-age children and adults. However, the influence of age on hippocampal development and its relations with memory ability earlier in life remains under-investigated. This study examined effects of age and sex on hippocampal subregion (i.e., head, body, tail) and subfield (i.e., subiculum, CA1, CA2-4/DG) volumes, and their relations with memory, using a large sample of 4- to 8-year-old children. Results examining hippocampal subregions suggest influences of both age and sex on the hippocampal head during early childhood. Results examining subfields within hippocampal head suggest these age effects may arise from CA1, whereas sex differences may arise from subiculum and CA2-4/DG. Memory ability was not associated with hippocampal subregion volume but was associated with subfield volume. Specifically, within the hippocampal head, relations between memory and CA1 were moderated by age; in younger children bigger was better, whereas in older children smaller was superior. Within the hippocampal body, smaller CA1 and larger CA2-4/DG contributed to better memory performance across all ages. Together, these results shed light on hippocampal development during early childhood and support claims that the prolonged developmental trajectory of the hippocampus contributes to memory development early in life. PMID- 29518574 TI - Proteomic profiling of rectal cancer reveals acid ceramidase is implicated in radiation response. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) is used in locally advanced rectal cancer when tumours threaten the circumferential resection margin, with varying response to treatment. This experimental study aimed to identify significantly differentially expressed proteins between patients responding and not responding to CRT, and to validate any proteins of interest. METHODS: Mass spectrometry (with isobaric tagging for relative quantification) analysis of rectal cancers pre- and post-CRT, and at resection. Validation of proteins of interest was performed by assessing tissue microarray (TMA) immunohistochemistry expression in a further 111 patients with rectal cancer. RESULTS: Proteomic data are available via ProteomeXchange with identifier PXD008436. Reduced abundance of contributing peptide ions for acid ceramidase (AC) (log fold change -1.526, p = 1.17E-02) was observed in CRT responders. Differential expression of AC was confirmed upon analysis of the TMAs. Cancer site expression of AC in stromal cells from post-CRT resection specimens was observed to be relatively low in pathological complete response (p = 0.003), and relatively high with no response to CRT (p = 0.017). CONCLUSION: AC may be implicated in the response of rectal cancer to CRT. We propose its further assessment as a novel potential biomarker and therapeutic target. SIGNIFICANCE: There is a need for biomarkers to guide the use of chemoradiotherapy in rectal cancer, as none are in routine clinical use. We have determined acid ceramidase may have a role in radiation response, based on novel proteomic profiling and validation in a wider dataset using tissue microarrays. The ability to predict or improve response would positively select those patients who will derive benefit, prevent delays in the local and systemic management of disease in non-responders, and reduce morbidity associated with chemoradiotherapy. PMID- 29518575 TI - Predictive biomarkers for type 2 of diabetes mellitus: Bridging the gap between systems research and personalized medicine. AB - : The global incidence of metabolic disorders like type 2 diabetes mellitus (DM2) has assumed epidemic proportions, leading to adverse health and socio-economic impacts. It is therefore of critical importance the early diagnosis of DM2 patients and the detection of those at increased risk of disease. In this respect, Precision Medicine (PM) is an emerging approach that includes practices, tests, decisions and treatments adapted to the characteristics of each patient. With regard to DM2, PM manages a wealth of "omics" data (genomic, metabolic, proteomic, environmental, clinical and paraclinical) to increase the number of clinically validated biomarkers in order to identify patients in early stage even before the prediabetic phase. SIGNIFICANCE: In this paper, we discuss the epidemic dimension of metabolic disorders like type 2 diabetes mellitus (DM2) and the urgent demand for novel biomarkers to reduce the incidence or even delay the onset of DM2. Recent research data produced by "multi-omics" technologies (genomics/epigenomics, transcriptomics, proteomics and metabolomics), suggest that many potential biomarkers might be helpful in the prediction and early diagnosis of DM2. Predictive, Preventive and Personalized Medicine (PPPM) manages and integrates these data to apply personalized, preventive, and therapeutic approaches. This is significant because there is an emerging need for establishing channels for communication and personalized consultation between systems research and precision medicine, as the medicine of the future. PMID- 29518576 TI - Identification of ethanol tolerant outer membrane proteome reveals OmpC-dependent mechanism in a manner of EnvZ/OmpR regulation in Escherichia coli. AB - : Ethanol is an efficient disinfectant, but long-term and wide usage of ethanol leads to microbial tolerance. Bacteria with the tolerance are widely identified. However, mechanisms of the tolerance are not elucidated. To explore the mechanisms of outer membrane (OM) proteins underlying ethanol tolerance in bacteria, functional proteomic methodologies were utilized to characterize OM proteins of E. coli suddenly exposed to 3.125% ethanol. Of eleven proteins altered significantly, seven were OM proteins, in which LamB, FadL and OmpC were up-regulated, and OmpT, OmpF, Tsx and OmpA were down-regulated. The alterations were validated using Western blot. Then, functional characterization of the altered abundance of OM proteins was investigated in gene-deleted and gene complemented mutants cultured in 1.56-6.25% ethanol. Higher inhibiting rate was detected in DeltaompC than DeltalamB and DeltaompA, but no difference was found between Deltatsx, DeltaompF, DeltafadL or DeltaompT and control. Furthermore, EnvZ/OmpR two-component signal transduction system, which regulates OmpC and OmpF expression, was determined to participate in the tolerance. Finally, our results show that absence of envZ, ompR or ompC and ompA led to elevated and reduced intracellular ethanol, respectively. These findings indicate EnvZ-dependent phosphotransfer signaling pathway of the OmpR-mediated expression of OmpC plays a crucial role in ethanol tolerance. BIOLOGICAL SIGNIFICANCE: Ethanol tolerance is an adaptation strategy of bacteria. In the present study, we used the proteomic approaches involving 2-DE and matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) to determined outer membrane (OM) protein changes in E. coli K 12 after 2 h of 1/2 MIC of ethanol exposure. Under ethanol stress, seven differential OM proteins were found, which were validated by Western blot. Functions of these seven OM proteins were compared using their genetically modified strains. Furthermore, the role of EnvZ/OmpR two-component signal transduction system was identified in ethanol tolerance of E. coli. Finally, Loss of ompC, envZ or ompR increases intracellular ethanol, while absence of ompA reduces reversal effect. This is the first report of OM proteomics in E. coli exposed to ethanol. Our findings reveal an unknown OmpC-dependent mechanism of ethanol tolerance in a manner of EnvZ/OmpR regulation. PMID- 29518578 TI - Principal component analysis of early alcohol, drug and tobacco use with major depressive disorder in US adults. AB - Early alcohol, tobacco and drug use prior to 18 years old are comorbid and correlated. This study included 6239 adults with major depressive disorder (MDD) in the past year and 72,010 controls from the combined data of 2013 and 2014 National Survey on Drug Use and Health (NSDUH). To deal with multicollinearity existing among 17 variables related to early alcohol, tobacco and drug use prior to 18 years old, we used principal component analysis (PCA) to infer PC scores and then use weighted multiple logistic regression analyses to estimate the associations of potential factors and PC scores with MDD. The odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. The overall prevalence of MDD was 6.7%. The first four PCs could explain 57% of the total variance. Weighted multiple logistic regression showed that PC1 (a measure of psychotherapeutic drugs and illicit drugs other than marijuana use), PC2 (a measure of cocaine and hallucinogens), PC3 (a measure of early alcohol, cigarettes, and marijuana use), and PC4 (a measure of cigar, smokeless tobacco use and illicit drugs use) revealed significant associations with MDD (OR = 1.12, 95% CI = 1.08-1.16, OR = 1.08, 95% CI = 1.04-1.12, OR = 1.13, 95% CI = 1.07-1.18, and OR = 1.15, 95% CI = 1.09-1.21, respectively). In conclusion, PCA can be used to reduce the indicators in complex survey data. Early alcohol, tobacco and drug use prior to 18 years old were found to be associated with increased odds of adult MDD. PMID- 29518577 TI - Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers. AB - This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naive and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naive CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non specific T-cell-mediated cytotoxicity and interferon (IFN)-gamma production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody dependent cellular cytotoxicity and IFN-gamma production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal. PMID- 29518579 TI - Understanding the HPV integration and its progression to cervical cancer. AB - Cervical cancer is one of the main causes of female cancer death worldwide, and human papilloma virus (HPV) its causal agent. To investigate viral oncogenesis several studies have focused on the effects of HPV oncoproteins E6 and E7 and the mechanisms by which these proteins stimulate the cellular transformation process. However, phenomena such as the physical state of the viral genome (episomal or integrated) and the effects of this integration on cell proliferation contribute new clues to understand how HPV infection causes carcinogenesis. New molecular technologies are currently facilitating these discoveries. This paper reviews the tumor development process initiated by HPV, recent findings on the process of viral integration into the host genome, new methods to detect HPV integration, and derived associated effects. PMID- 29518580 TI - Inequity in out-of-pocket payments for hospitalisation in India: Evidence from the National Sample Surveys, 1995-2014. AB - OBJECTIVE: We report inequity in out-of-pocket payments (OOPP) for hospitalisation in India between 1995 and 2014 contrasting older population (60 years or more) with a population under 60 years (younger population). METHODS: We used data from nationwide healthcare surveys conducted in India by the National Sample Survey Organisation in 1995-96, 2004 and 2014 with the sample sizes ranging from 333,104 to 629,888. We used generalised linear and fractional response models to study the determinants of OOPP and their burden (share of OOPP in household consumption expenditure) at a constant price. The relationship between predicted OOPP and its burden with monthly per capita consumption expenditure (MPCE) quintiles and selected socioeconomic characteristics were used to examine vertical and horizontal inequities in OOPP. RESULTS: The older population had higher OOPP for hospitalisation at all time points (range: 1.15 1.48 times) and a greater increase between 1995-96 and 2014 than the younger population (2.43 vs 1.88 times). Between 1995-96 and 2014, the increase in predicted mean OOPP for hospitalisation was higher for the poorest than the richest (3.38 vs 1.85 times) older population. The increase in predicted mean OOPP was higher for the poorest (2.32 vs 1.46 times) and poor (2.87 vs 1.05 times) older population between 1995-96 and 2004 than in the latter decade. In 2014, across all MPCE quintiles, the burden of OOPP was higher for the less developed states, females, private hospitals, and non-communicable disease and injuries, more so for the older than the younger population. In 2014, the predicted absolute OOPP for hospitalisation was positively associated with MPCE quintiles; however, the burden of OOPP was negatively associated with MPCE quintiles indicating a regressive system of healthcare financing. CONCLUSION: High OOPP for hospitalisation and greater inequity among older population calls for better risk pooling and prepayment mechanisms in India. PMID- 29518582 TI - Angioleiomyoma in the Ovarian Vessel Region. PMID- 29518581 TI - Transcriptome analysis identifies genes involved in sex determination and development of Xenopus laevis gonads. AB - Development of the gonads is a complex process, which starts with a period of undifferentiated, bipotential gonads. During this period the expression of sex determining genes is initiated. Sex determination is a process triggering differentiation of the gonads into the testis or ovary. Sex determination period is followed by sexual differentiation, i.e. appearance of the first testis- and ovary-specific features. In Xenopus laevis W-linked DM-domain gene (DM-W) had been described as a master determinant of the gonadal female sex. However, the data on the expression and function of other genes participating in gonad development in X. laevis, and in anurans, in general, are very limited. We applied microarray technique to analyze the expression pattern of a subset of X. laevis genes previously identified to be involved in gonad development in several vertebrate species. We also analyzed the localization and the expression level of proteins encoded by these genes in developing X. laevis gonads. These analyses pointed to the set of genes differentially expressed in developing testes and ovaries. Gata4, Sox9, Dmrt1, Amh, Fgf9, Ptgds, Pdgf, Fshr, and Cyp17a1 expression was upregulated in developing testes, while DM-W, Fst, Foxl2, and Cyp19a1 were upregulated in developing ovaries. We discuss the possible roles of these genes in development of X. laevis gonads. PMID- 29518583 TI - Total Laparoscopic Hysterectomy and Bilateral Salpingo-Oophorectomy for a 6095-g Myomatous Uterus in a Patient of the Jehovah's Witness Faith. AB - STUDY OBJECTIVE: To demonstrate techniques for addressing the unique challenges for a minimally invasive approach to hysterectomy presented by a massive myomatous uterus. DESIGN: Technical video of an operation demonstrating the methods used to perform hysterectomy in this setting, highlighting such aspects as port placement (Fig. 1), uterine manipulation (Fig. 2), exposure, and vascular control (Figs. 3 and 4) (Canadian Task Force classification III). SETTING: Academic tertiary care hospital. INTERVENTION: A 49-year-old woman elected to proceed with laparoscopic hysterectomy after years of suffering from bleeding and bulk symptoms from a massively enlarged myomatous uterus. A computed tomography scan estimated uterine dimensions of 32 * 27 * 24 cm, for a volume of >7000 mL (Fig. 5). Her surgical history included a ventral herniorrhaphy with mesh, and her body mass index was 43 kg/m2. She was a Jehovah's Witness, and thus blood transfusion was not an acceptable option for her due to a religious prohibition. Intraoperatively, the uterus extended deep into the pararectal and paravesical spaces on the right, from the caudad below the cervix (Fig. 6) to superiorly near the liver edge (Fig. 7). MEASUREMENTS AND MAIN RESULTS: Laparoscopic hysterectomy was successfully completed (Table), and the patient was discharged on the day after surgery. Final pathology revealed a 6095-g uterus with benign leiomyomata. She presented 9 days after surgery with nausea and vomiting, suspicious for an incarcerated hernia at the tissue extraction site. Her symptoms were ultimately determined to be due to either ileus or small bowel obstruction, which likely could have been managed nonoperatively with bowel rest and fluids. She stayed an additional 2 days after readmission and was then discharged, with no further complications. CONCLUSIONS: The size of the uterus was once considered a barrier to the use of laparoscopy for hysterectomy, but experience has shown that the benefits of minimally invasive surgery are particularly relevant for large myomas [1-4], given that a vaginal approach is not feasible and that other risks, such as wound complications and venous thromboembolism, would be greater with the large incision required to perform the procedure by laparotomy. This video uses a particularly challenging case to demonstrate a roadmap for addressing myomas in laparoscopic hysterectomy through exposure and vascular control. Although the presentation focused on the initial steps of the procedure and not on uterine extraction, this patient's readmission highlights potential complications associated with various methods of tissue removal for very large specimens. PMID- 29518584 TI - Temporal dynamics of halogenated organic compounds in Marcellus Shale flowback. AB - The chemistry of hydraulic fracturing fluids and wastewaters is complex and is known to vary by operator, geologic formation, and fluid age. A time series of hydraulic fracturing fluids, flowback fluids, and produced waters was collected from two adjacent Marcellus Shale gas wells for organic chemical composition analyses using ultrahigh resolution mass spectrometry. Hierarchical clustering was used to compare and extract ions related to different fluid ages and many halogenated organic molecular ions were identified in flowback fluids and early produced waters based on exact mass. Iodinated organic compounds were the dominant halogen class in these clusters and were nearly undetectable in hydraulic fracturing fluid prior to injection. The iodinated ions increased in flowback and remained elevated after ten months of well production. We suggest that these trends are mainly driven by dissolved organic matter reacting with reactive halogen species formed abiotically through oxidizing chemical additives applied to the well and biotically via iodide-oxidizing bacteria. Understanding the implications of these identified halogenated organic compounds will require future investigation in to their structures and environmental fate. PMID- 29518585 TI - Quaternary (triphenyl-) phosphonium compounds: Environmental behavior and toxicity. AB - An analytical method based on high resolution mass spectrometry coupled with liquid chromatography (LC-HRMS) for 25 quaternary phosphonium compounds (QPCs) and derived phosphine oxides (POs) was developed and validated. To investigate the occurrence and fate of QPCs in the aquatic environment, water, suspended solids and sediments from the rivers Rhine and Elbe (upper and middle Elbe as well as tidal Elbe) were analyzed, as well as samples from tributaries bearing significant loads of QPCs. For the first time, the quaternary phosphonium compound tetrabutylphosphonium (Bu4P+) was detected. In the river Elbe concentrations were determined of up to 4700 ng/L (surface water) and 1000 MUg/kg (sediment), respectively. Analysis of a time series of suspended solids (2005 2015) showed that QPCs have been present in the Elbe and Rhine catchment for at least one decade, with partly rising tendency. A degradation experiment with Rhine sediment revealed that triphenylphosphonium compounds (R-Ph3P+) and Bu4P+ are persistent in contact with sediment and suspended solids and tend to sorb onto sediment particles. Toxicological studies (reactive oxygen species (ROS) after substance exposure, Ames test, Micronucleus test, determination of cytotoxicity) with selected QPCs confirmed that all of them exhibit cytotoxicity and some even genotoxic potential at elevated concentrations, which emphasizes the need for an emission regulation of these compounds. PMID- 29518587 TI - Ultrasound-Guided Carpal Tunnel Release Using Dynamic Expansion of the Transverse Safe Zone in a Patient With Postpolio Syndrome: A Case Report. AB - The prevalence of carpal tunnel syndrome (CTS) in patients with postpolio syndrome occurs at a rate of 22%. Irrespective of those with CTS, 74% of postpolio patients weight bear through their arms for ambulation or transfers. As open carpal tunnel release is performed along the weight-bearing region of the wrist, their functional independence may be altered while recovering. This case demonstrates that ultrasound-guided carpal tunnel release was successfully performed in a patient with postpolio syndrome allowing him to immediately weight bear through his hands after the procedure so he could recover at home. LEVEL OF EVIDENCE: V. PMID- 29518586 TI - Chromatographic separation of similar post-translationally modified metallothioneins reveals the changing conformations of apo-MT upon cysteine alkylation by high resolution LC-ESI-MS. AB - Metallothioneins (MTs) are a class of small cysteine-rich proteins essential for Zn and Cu homeostasis, heavy metal detoxification, and cellular redox chemistry. Herein, we describe the separation and characterization of MTs differentially modified with N-ethylmaleimide (NEM) by liquid chromatography-mass spectrometry (LC-MS). The full-length recombinant MT isoform 1a as well as is isolated domain fragments were first alkylated, then separated on column with subsequent detection by ultra-high resolution ESI-MS. Different behavior was observed for the three peptides with the full-length protein and the isolated alpha-domain exhibiting similar separation characteristics. For the isolated beta-domain, the smallest peptide with 9 cysteines in the sequence, each alkylated species was well separated, indicating large changes in protein conformation. For the full length (20 cysteines in the sequence) and alpha-domain (11 cysteiens in the sequence) peptides, the apo- and lightly alkylated species co-eluted, indicating similar structural properties. However, the more extensively alkylated species were well separated from each other, indicating the sequential unfolding of the apo-MT peptides and providing evidence for the mechanistic explanation for the cooperative alkylation reaction observed for NEM and other bulky and hydrophobic alkylation reagents. We show for the first time clear separation of highly similar MTs, differing by only +125 Da, and can infer structural properties from the LC-MS data, analogous to more complicated and less ubiquitous ion-mobility experiments. The data suggest a compact globular structure for each of the apo MTs, but where the beta-domain is more easily unfolded. This differential folding stability may have biological implications in terms of domain-specific participation of MT in cellular redox chemistry and resulting metal release. PMID- 29518588 TI - Examination of Factors Related to the Effect of Improving Gait Speed With Functional Electrical Stimulation Intervention for Stroke Patients. AB - BACKGROUND: Functional electrical stimulation (FES) for patients with stroke and foot drop is an alternative to ankle foot orthoses. Characteristics of FES responders and nonresponders have not been clarified. OBJECTIVES: (1) To investigate the effects of treatment with FES on patients with stroke and foot drop and (2) to determine which factors may relate to responders and nonresponders. DESIGN: Multicenter, nonrandomized, prospective study. SETTING: Multicenter clinical trial. PARTICIPANTS: Participants included those who experienced foot drop resulting from stroke, were older than 20 years, and could provide consent to participate; they were enrolled from hospitals between January 2013 and September 2015 and performed rehabilitation with FES. METHODS: Stroke Impairment Assessment Set Foot-Pat Test (SIAS-FP), Fugl-Meyer Assessment for Lower Extremity (FMA-LE), Modified Ashworth scale (MAS) for ankle joint dorsiflexion and plantar flexion muscles, range of motion (ROM) for ankle joint, 10-m walking test (10mWT), Timed Up & Go test (TUG), and 6-minute walking test (6MWT) were evaluated pre- and postintervention. Age, gender, type of stroke, onset times of stroke, paretic side, Brunnstrom stage of the lower extremity (Br. stage-LE), Functional Independence Measure (FIM), Functional Ambulation Category (FAC), poststroke months, number of interventions, total hours of interventions, and whether a brace was used were extracted from patients' medical records and collected on the physiological examination day. MAIN OUTCOME MEASUREMENTS: The authors examined 10mWT and age, gender, type of stroke, onset times of stroke, paretic side, Br. stage-LE, FIM, FAC, poststroke months, number of interventions, total hours of interventions, whether a brace was used, SIAS-FP, FMA-LE, MAS, ROM, TUG, and 6MWT before intervention. Participants were divided into nonresponders and responders with a change in 10mWT of <0.1 and >=0.1 m/s, respectively. Single and multiple regression analyses were used for data analysis. Additionally, the changes between groups were compared. RESULTS: Fifty eight responders and 43 nonresponders were enrolled. The between-group differences, compared for changes between pre- and postintervention, were significant in terms of changes in SIAS-FP (P = .02), 10mWT (P < .001), 10-m gait steps (P < .001), TUG (P = .04), and 6MWT (P = .006). In the adjusted regression model, gender (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.426-12.25; P = .007), number of interventions (OR, 1.028; 95% CI, 1.003-1.070; P = .03), and active ankle joint dorsiflexion ROM (OR, 1.047; 95% CI, 1.014-1.088; P = .005) remained significant. CONCLUSION: The factors related to 10mWT showing changes beyond the minimal clinically important difference were found to be patient gender, number of interventions, and active ankle joint dorsiflexion ROM before intervention. When patients with stroke who have greater active ankle joint ROM, and are female, use FES positively, they may benefit more from using FES. LEVEL OF EVIDENCE: II. PMID- 29518589 TI - Sonographic Changes After Ultrasound-Guided Release of the Transverse Carpal Ligament: A Case Report. AB - Carpal tunnel syndrome is the most common entrapment neuropathy, resulting in 500,000 carpal tunnel release (CTR) surgeries and a total cost of more than 2 billion dollars annually in the United States. Although initially performed via a large (3-5 cm) palmar incision, CTR techniques have continually evolved to reduce incision size, recovery times, postoperative pain, and improve cosmesis and clinical outcomes. More recently, multiple authors have reported excellent results after ultrasound-guided carpal tunnel release (USCTR) using a variety of techniques, and one prospective randomized trial reported faster recovery after USCTR compared with traditional mini-open CTR. However, there is a paucity of data with respect to changes in the median nerve after USCTR. This case report presents the functional outcomes and pre- and postprocedure ultrasound images of a patient after USCTR with 3-month follow-up. LEVEL OF EVIDENCE: V. PMID- 29518590 TI - Predicting 1 Repetition Maximum Using Handheld Dynamometry. AB - BACKGROUND: Isometric assessment of muscular function using a handheld dynamometer (HHD) is frequently used in clinic environments. However, there is controversy in terms of the validity of isometric assessment to monitor changes in dynamic performance. One repetition maximum (1RM) is considered the gold standard for evaluating dynamic strength, though clinicians do not often use 1RM testing, preferring to be cautious with clients who have preexisting impairments. If strength testing using an HHD could be used to predict 1RM, this may have significant implications for the use of isometric testing to prescribe exercise in clinical environments. OBJECTIVE: To establish the relationship and agreement between 1RM and isometric strength scores measured using HHD for the biceps and quadriceps muscle groups and to determine if HHD measurements can be used to predict 1RM. DESIGN: Criterion standard comparison. SETTING: Tertiary institution gymnasium. PARTICIPANTS: Convenience sample of 50 healthy adults (26 women) aged 19-33 years (mean 23.38 +/- 3.11 years). METHODS: Muscle strength of the biceps and quadriceps muscle groups measured by 1RM and isometric maximal voluntary contraction measured using an HHD. MAIN OUTCOME MEASURES: Statistical analysis of the relation between the measures of strength was established using Pearson correlation and a Bland-Altman plot. A linear regression analysis with included covariates (gender, age, resistance training history, and body mass index) was used to derive the prediction equations. RESULTS: A significant correlation was found between 1RM and HHD scores for the biceps (r = .83, P < .001) and quadriceps muscle groups (r = .82, P < .001). However, strength scores were not in agreement. Linear regression analysis found significance in predicting 1RM from all HHD scores (P < .001). Gender as a covariate significantly influenced the prediction of 1RM for the biceps (P = .005) and quadriceps (P = .003) muscle groups. CONCLUSIONS: There is a significant relationship between 1RM and HHD measures of strength, and measures taken using an HHD can be used to predict 1RM in the biceps and quadriceps muscle groups. The use of an HHD may therefore provide a more accessible alternative to 1RM for muscle strength assessments. Further research is warranted to determine if results are applicable in clinical populations. LEVEL OF EVIDENCE: NA. PMID- 29518591 TI - Catch-and-release regulations and paddlefish angler preferences. AB - This paper presents research on recreational paddlefish anglers' preferences for catch-and-release fishing. We used stated preference (SP) data from a choice experiment to identify the effect of a hypothetical catch-and-release regulation on fishing preferences, and revealed preference (RP) data to measure the desirability of actual paddlefish fishing locations. We then modeled the effects of catch-and-release regulations on location choice and participation in the Oklahoma fishery. Our results indicate that although anglers dislike catch-and release, most directly affected by regulations will either continue fishing at their preferred site or switch to a site where harvesting is permitted. Our preferred model predicts two-thirds will continue to participate even if catch and-release fishing is required statewide. PMID- 29518592 TI - BTEX removal from aqueous solution with hydrophobic Zr metal organic frameworks. AB - The Zr based metal organic framework, UiO-66, has been synthesized along with its isostructural equivalence tetrafluorinated, the UiO-66-F4. The corresponding ligands to these MOFs are the widely used BDC (1,4-benzenedicarboxylic acid) and the TFBDC (2,3,5,6-Tetrafluoro-1,4-benzenedicarboxylic acid). These coordination materials have been tested towards the sorption of the organic pollutants (Benzene, Toluene, Ethylbenzene and Xylene) in aqueous phase and both materials showed capacities to adsorb all the pollutants. It has been possible to compare the efficiency in the adsorption of two iso-structural MOFs, which will behave differently due to the hydrophobic behavior of the UiO-66-F4 MOF. The addition of F in the structure of the ligand of the MOF allows to obtain a hydrophobic material by changing the nature of the interactions between the adsorbent and the adsorbate from pi-pi stacking in the pristine UiO-66 to hydrophobic interactions in the UiO-66-F4. However, size of the pores has also revealed an important effect, since steric impediments will decrease the capacity of the fluorinated MOF towards the sorption of bigger molecules. PMID- 29518593 TI - Aerobic granular sludge treating high strength citrus wastewater: Analysis of pH and organic loading rate effect on kinetics, performance and stability. AB - In the present paper, the feasibility of citrus wastewater treatment with aerobic granular sludge sequencing batch reactors (AGSBR) was investigated. Two AGSBRs (named R1 and R2, respectively) were operated for 90 days under different organic loading rates (OLR) and pH in two experimental periods. The OLR ranged approximately between 3.0 kg TCOD m-3d-1 and 7 kg TCOD m-3d-1 during Period I, whereas between 7 kg TCOD m-3d-1 and 15 kg TCOD m-3d-1 during Period II. pH was maintained at 7.0 and 5.5 in R1 and R2, respectively. The results revealed that under high OLR and unbalanced feast/famine regime (Period I), the development of fast-growing microorganisms (fungi and filamentous bacteria) was favoured in both reactors, resulting in granular sludge instability. An extended famine phase and a proper balancing between feast and famine periods (Period II) were favourable for the development of bacteria with low growth rates (0.05 d-1) thus enhancing the granules stability. To the benefit of granular sludge stability and effluent quality, the length of the feast period should not exceed 25% of cycle length. Moreover, under OLR lower than 7 kg TCOD m-3d-1 the removal efficiency of total chemical oxygen demand (TCOD) was approximately 90% in R1 and R2 and no side effects on the organic carbon removal performance related to the pH were observed. In contrast, at higher OLR a significant decrease in the removal efficiency (from 90% to less than 75%) was observed in R2. Results revealed also that under low pH, hydrolysis of proteins occurred and a decrease in the biological kinetic rates proportionally to the applied OLR was observed. PMID- 29518594 TI - Poultry manure and sugarcane straw biochars modified with MgCl2 for phosphorus adsorption. AB - Increases in agricultural productivity associated to the crescent use of finite reserves of phosphorus improved the demand for ways to recycle and reuse this nutrient. Biochars, after doping processes, seem to be an alternative to mitigate the large use of P reserves. Sugarcane straw and poultry manure were submerged in an MgCl2 solution in a 1:10 solid/liquid ratio and subsequently pyrolyzed at 350 and 650 degrees C producing biochar. Increasing concentrations of P were agitated with biochars in order to obtain the maximum adsorption capacity of P with the aid of Langmuir and Freudelich isotherm. MPAC was extracted, successively, with H2SO4 (0.5 mol L-1), NaHCO3 (0.5 mol l-1 a pH 8.5) and H2O, until no P was detected in the solution. Biochars without the addition of Mg did not have the ability to adsorb P but had this property developed after the doping process. The poultry manure biochar presented higher MPAC (250.8 and 163.6 mg g-1 of P at 350 and 650 degrees C, respectively) than that of sugarcane straw (17.7 and 17.6 mg g-1 of P at 350 and 650 degrees C, respectively). The pyrolysis temperature changed significantly the MPAC values for the poultry manure biochar, with an increase in the adsorbed P binding energy for both biochars. H2SO4 showed the best extraction power, desorbing, with a lower number of extractions, the greater amount of the adsorbed P. These materials doped with Mg and subjected to pyrolysis have characteristics that allow their use in P adsorption from eutrophic and wastewaters and therefore its use as a slow release phosphate fertilizer, indicating to be competitive in quality and quantity with available soluble chemical sources in the market. PMID- 29518595 TI - Assessing the effects of habitat patches ensuring propagule supply and different costs inclusion in marine spatial planning through multivariate analyses. AB - Marine Protected Areas are considered key tools for conservation of coastal ecosystems. However, many reserves are characterized by several problems mainly related to inadequate zonings that often do not protect high biodiversity and propagule supply areas precluding, at the same time, economic important zones for local interests. The Gulf of Naples is here employed as a study area to assess the effects of inclusion of different conservation features and costs in reserve design process. In particular eight scenarios are developed using graph theory to identify propagule source patches and fishing and exploitation activities as costs-in-use for local population. Scenarios elaborated by MARXAN, software commonly used for marine conservation planning, are compared using multivariate analyses (MDS, PERMANOVA and PERMDISP) in order to assess input data having greatest effects on protected areas selection. MARXAN is heuristic software able to give a number of different correct results, all of them near to the best solution. Its outputs show that the most important areas to be protected, in order to ensure long-term habitat life and adequate propagule supply, are mainly located around the Gulf islands. In addition through statistical analyses it allowed us to prove that different choices on conservation features lead to statistically different scenarios. The presence of propagule supply patches forces MARXAN to select almost the same areas to protect decreasingly different MARXAN results and, thus, choices for reserves area selection. The multivariate analyses applied here to marine spatial planning proved to be very helpful allowing to identify i) how different scenario input data affect MARXAN and ii) what features have to be taken into account in study areas characterized by peculiar biological and economic interests. PMID- 29518596 TI - Traditional and formal ecological knowledge to assess harvesting and conservation of a Mexican Tropical Dry Forest. AB - This research integrates Traditional and Formal Ecological Knowledge (TEK / FEK) of a Tropical Dry Forest in central Mexico, in order to assess harvesting and conservation of the non-timber forest species. We were interested in: knowing the structure and diversity of the forest community; identifying which are the tree resources of common interest to the users through participatory workshops. A further interest was to identify those resources which are important to local people in terms of preservation; explaining the relationship of the species with some environmental factors; and visualizing which management practices endanger or facilitate the conservation of species. Studied areas were defined and labelled on a map drawn by local informants, where they indicated those plant species of common interest for preservation. Ethnobotanical techniques were used to reveal the TEK and assess harvesting and conservation of the species. With the FEK through community and population ecology, we detected the importance of five environmental factors, obtained various ecological indicators of the vegetation, and studied the population structure of the relevant species. The FEK was analyzed using descriptive and multivariate statistics. As a result, low density and small basal area of trees were registered. Species richness and diversity index were similar to other natural protected areas in Mexico. Tree species harvested shown an asymmetric distribution of diameters. Harvesting, elevation, and accessibility were the most influential factors on tree density. FEK demonstrated that TEK is helpful for the assessment of forest harvesting. Ecological analysis complemented the local knowledge detecting that Lysiloma tergemina is a species non-identified for the people as interesting, although we discover that it is a threatened species by over-harvesting. Haematoxylum brasiletto was identified as important for conservation due to its scarcity and medicinal use. Our results advanced on how the traditional harvesting of tree community has contributed to preserve diversity, when comparing with protected areas. Discrepancies between both kinds of knowledge should be reconciled for contributing to the preservation of priority resources by the local society. PMID- 29518597 TI - Characterizing, monitoring, and simulating land cover dynamics using GlobeLand30: A case study from 2000 to 2030. AB - Land cover maps provide us with a unique opportunity to monitor our environmental and anthropogenic resources over space and time. Temporal land cover maps increase the efficiency of land monitoring process by providing a set of observations so that any changes in the landscape can be tracked. So far, many land change monitoring efforts have been limited to small regions and analysing local processes, because there has been a lack of fine resolution global land cover maps for regional and global studies. Recently, the availability of bi temporal GlobeLand30 product for years 2000 and 2010 has strengthened our land monitoring observations through a 10-year window at 30-meter resolution. The main objective of this study is to explore the land cover changes within 2000-2010 in one of the most dynamic regions in the Middle East. To do so, GlobeLand30 datasets were used for characterizing the regional landscapes and the distribution of the existing land cover types. Moreover, the study aims at predicting the future land cover patterns by 2030 based on the historical changes. The quantitative analysis reveals a high degree of changes from the majority of land types to barelands with the highest contribution from grasslands and shrublands. The vibrant spots of change are located on central Iran towards its eastern border while the persistent spots are located on its north and northwestern parts. The predictive measures using Markov chain analysis message forthcoming changes in favor of increasing barelands being taken from grasslands, cultivated lands, and shrublands. The findings are beneficial to a wide range of end users including academics, land managers, and environmentalists on a) which resources were available in the first decade of 21st century, and b) how they were treated within a decade, and c) how the resources will evolve within the following two decades. Further discussions on the achieved results and future directions of research are presented in the conclusions. PMID- 29518598 TI - Personal care products in surface, ground and wastewater of a complex aquifer system, a potential planning tool for contemporary urban settings. AB - The use and discharge of personal care products (PCPs) result in their presence in the aquatic environment. This study investigates the occurrence and fate of some PCPs in wastewater, surface and groundwater in an urbanized area in the North of Italy. We investigated four UV filters: phenylbenzimidazole sulfonic acid (PBSA), benzophenone-3 (BP3), benzophenone-4 (BP4) and 4 methyl-benzilidine camphor (4-MBC), and two antibacterial agents: triclosan (TCS) and triclocarban (TCC). BP3, BP4 and PBSA were detected in all WWTPs and concentrations ranged 27 822 ng/L (BP4 > PBSA > BP3). TCS was the only disinfectant detected in wastewater and ranged from <0.2 to 1690 ng/L. Removal efficiencies in WWTPs were good for BP3 and TCS (80-100%), but were quite low for PBSA and BP4 (0-40%). Consequently, PBSA and BP4 were the most abundant substances in surface water, detected up to 560.4 ng/L. TCS was also found in surface water (<0.2-161.0 ng/L). Only PBSA and TCS were found in untreated groundwater, and levels were higher in wells close to rivers, suggesting the contribution of surface water to this contamination, but not from the catchment and the sewer networks. These PCPs were confirmed to be ubiquitous in all the aquifers sampled, being reliable descriptors of human presence. The use of these data as direct indicators of pollutant's loads for the aquifers deriving from human presence could provide early warnings on chemicals that are continuously introduced into surface waters, identifying dynamic urban trends and suggesting paths for the planning in urban regions and for appropriate investment and rehabilitation strategies of infrastructure. PMID- 29518599 TI - Electrochemical treatment of cetrimonium chloride with boron-doped diamond anodes. A technical and economical approach. AB - This study presents the results of the electrochemical degradation of the emulsifier cetrimonium chloride (CTAC) on a boron-doped diamond (BDD) anode under different current densities and flow rates. Higher values of these parameters result in a more rapid removal. Nevertheless, operation at low current reduces the required applied charge and increases the chemical oxygen demand (COD) removal efficiency, as there is less development of ineffective parasitic reactions. On the other hand, high flow rates reduce the required volumetric applied charge and increase the COD removal current efficiency. In order to assist and enrich the study, an economic analysis has been performed. For short expected plant lifespans, operation at low current is advantageous due to the lower investment required, whereas for longer expected lifespans, the operational costs make the lower current densities less costly. High flow rates are always advantageous from a financial point of view. PMID- 29518600 TI - Potential for anaerobic treatment of polluted sediment. AB - Due to the anaerobic nature of aquatic sediments, the anaerobic treatment of sediments utilizing already present microflora represents an interesting treatment option. Contaminated sediment can contain a variety of organic contaminants, with easily degradable organics usually present in the higher amounts, along with traces of specific organic pollutants (total petroleum hydrocarbons and polycyclic aromatic hydrocarbons). This study applies a comprehensive approach to contaminated sediment treatment which covers all the organic contaminants present in the sediment. The aim of this study was to (1) evaluate the anaerobic treatment of aquatic sediment highly loaded with easily degradable organics via determination of potential biogas and methane production, and (2) assess possibilities of using anaerobic treatment for the degradation of specific organic pollutants in order to reduce the risks posed by the sediment. In order to promote the methanogenic conditions of the indigenous microflora in the sediment, the addition of co-substrates acetate and glucose was investigated. The results, expressed as mL biogas produced per volatile solids content in sediment (VSadded) indicate that the addition of the co-substrate has a significant impact on biogas production potential (58.7 and 55.1 mL/g VSadded for acetate and glucose co-substrate addition respectively, and 14.6 mL/g VSadded for the treatment without co-substrate addition). Theoretical biochemical methane potential was assessed by Gompertz model and Chemical oxygen demand model. The Gompertz model fit better for all the applied treatments, and was capable of predicting the final productivity of biogas and methane in the first 30 days with a relative error of less than 14%. From the aspects of specific organic pollutants, total petroleum hydrocarbon degradation was promoted by co-substrate addition (degradations of 75% and 60% achieved by acetate and glucose co substrate addition, compared to 45% for the treatment without co-substrate addition). Polycyclic aromatic hydrocarbons were reduced by significant amounts (84-87%) in all the applied treatments, but the addition of co-substrate did not further improve their degradation. PMID- 29518601 TI - Chemical pyrolysis of E-waste plastics: Char characterization. AB - This work studied the disposal of the non-metallic fraction from waste printed circuit board (NMF-WPCB) via the chemical pretreatments followed by pyrolysis. As a main heavy metal, the metallic Cu could be significantly removed by 92.4% using the HCl leaching process. Subsequently, the organic-Br in the brominated flame retardants (BFRs) plastics could be converted into HBr by pyrolysis. The alkali pretreatment was benefit for the Br fixation in the solid char. The Br fixation efficiency could reach up to 53.6% by the NaOH pretreatment followed by the pyrolysis process. The formed HBr could react with NaOH/KOH to generate the stabilized NaBr/KBr. Therefore, the integrated chemical pretreatment could be used for the eco-friendly disposal of the NMF-WPCB via pyrolysis. PMID- 29518602 TI - Sex-specific effects of prepubertal stress and high-fat diet on leptin signaling in rats. AB - OBJECTIVE: Both stress exposure and high-fat diet (HFD) are contributors to the alarming prevalence of obesity. Leptin is secreted from adipose tissue and regulates appetite and body weight via the JAK-STAT3 pathway in the hypothalamus; it also regulates the hypothalamic-pituitary-thyroid axis, modulating energy homeostasis. Leptin signaling may be impaired by HFD intake, and here we investigate whether social isolation during the prepubertal period, associated with chronic HFD, can exert long-term effects on metabolic parameters in a sex specific manner. METHODS: Wistar male and female rats were divided into two groups (receiving standard chow or standard chow and HFD), which were subdivided into (1) exposed to social isolation during the prepubertal period or (2) not exposed. RESULTS: HFD induced sex-specific effects on leptin signaling and on the hypothalamic-pituitary-thyroid axis; males receiving HFD presented increased T4 but a reduced T3:T4 ratio and higher caloric efficiency during development. A stress * diet interaction was noted for leptin signaling in males, where pSTAT3 was higher when these factors were applied together. On the other hand, females were more susceptible to early stress, which reduced pSTAT3 in the hypothalamus. CONCLUSION: Both stress during the prepubertal period and chronic consumption of HFD had long-term sex-specific effects on hormonal signaling related to energy balance. However, the effects of HFD were more pronounced in males, whereas prepubertal stress had greater effects on leptin signaling in females. PMID- 29518604 TI - MiR-410 inhibition induces HUVECs proliferation and represses ox-LDL-triggered apoptosis through activating STAT3. AB - Ox-LDL-induced endothelial cells injury has been reported to play an important role in the development of atherosclerosis (AS). MicroRNAs have been identified to regulate their target genes post-transcriptionally and they are able to participate in the various diseases, including AS. However, the role of miR-410 in ox-LDL-triggered abnormal function of endothelial cells remains to be elaborated. Hence, our current study was to find out the underlying mechanism of miR-410 in AS. Here, we observed that ox-LDL can inhibit HUVECs growth and lead to a great cell apoptosis both dose-dependently and time-dependently. Meanwhile, it was exhibited that miR-410 expression was remarkably elevated in ox-LDL indicated HUVECs. miR-410 knockdown was able to induce cell proliferation and alleviate HUVECs apoptosis subjected to ox-LDL. Reversely, signal transducer and activator of transcription 3 (STAT3) expression was greatly decreased in ox-LDL incubated HUVECs in a time and dose dependent manner. Additionally, these findings exhibited that STAT3 was a target of miR-410, which was validated by a dual-luciferase assay in our study. Additionally, we observed that overexpression of STAT3 rescued ox-LDL induced AS events in vitro. Taken these together, our current study implied that miR-410 silence can inhibit the ox-LDL-induced HUVECs proliferation and rescue cell apoptosis through activating STAT3 in vitro. PMID- 29518605 TI - Herb-drug interaction of Nisha Amalaki and Curcuminoids with metformin in normal and diabetic condition: A disease system approach. AB - Nisha Amalaki (NA), formulation with Curcuma longa Linn (Turmeric, Haridra, Nisha in Sanskrit; Family: Zingiberaceae) and Phyllanthus emblica Linn (Indian gooseberry, Amlaki in Sanskrit; Family: Phyllanthaceae) which is described for various diseases including diabetes in ayurvedic texts and Nighantus. The aim of the present study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of chemically standardized NA and Curcuminoids (CE) with metformin (MET) in normal and diabetic animals. Oral administration of NA (200 mg/kg) and CE (30 mg/kg) was carried out for seven days followed by co-administration of MET till fifteen days. MET plasma PK parameters including Cmax, AUC0-infinity, t1/2, CL and Vd were measured on the eighth day. PD parameters including plasma glucose AUC followed by oral glucose tolerance test, high-density lipoproteins (HDL), total cholesterol (TC) and triglycerides (TG) were measured on the fifteenth day. In normal animals, co-administration of NA + MET and CE + MET resulted in significant increase (p < 0.05) in Cmax, AUC0-infinity, t1/2, and reduction of CL and Vd. We report that co-administration of NA + MET and CE + MET significantly (p < 0.01, p < 0.001) reduced plasma glucose level, HDL level while a notable reduction in TG and TC level was observed. Interestingly, in diabetic condition, co-administration of NA + MET and CE + MET indicated a significant decrease (p < 0.05) in Cmax, AUC0-infinity, t1/2 and enhanced CL and Vd. Hence, to conclude, co administration of NA + MET and CE + MET resulted in beneficial PK and PD interactions leading to antihyperglycemic and antihyperlipidemic effects in both conditions. However, PK interaction was drastically different in diabetic and normal conditions. PMID- 29518606 TI - Curcumin protects against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis:A study in vitro and in vivo. AB - The C-X-C motif chemokine 12/C-X-C chemokine receptor type 4 (CXCL12/ CXCR4) biological axis plays an important role in the pathogenesis of liver fibrosis. Curcumin is known to have an anti-fibrosis effect, but the specific mechanism needs to be elucidated. There is currently no evidence illustrating a connection between curcumin and the CXCL12/CXCR4 axis in liver fibrosis. Here, we investigated the contribution of curcumin on CXCL12/ CXCR4 biological axis in liver fibrosis. Our results showed that curcumin remarkably improved hepatic function and liver fibrosis, and the effects are similar as silymarin. The alleviation of liver fibrosis with curcumin treatment was associated with a reduction of CXCL12, CXCR4, alpha-SMA and RhoA. In addition, curcumin markedly inhibited the proliferation and migration of HSC-T6 cells. This study indicates that curcumin could protect against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis. PMID- 29518607 TI - Pedunculoside, a novel triterpene saponin extracted from Ilex rotunda, ameliorates high-fat diet induced hyperlipidemia in rats. AB - Pedunculoside (PE) is a novel triterpene saponin extracted from the dried barks of Ilex rotunda Thunb. The present study aims to explore lipid-lowering effects of PE on hyperlipidemia rat induced by high-fat diet. The rats were fed with the high-fat diet and subjected to intragastric administration of PE at doses of 30, 15, or 5 mg/kg daily for 7 weeks. The results demonstrated that treatment with PE for 7-week dramatically decreased serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and reduced liver TC in hyperlipidemia rat induced by high-fat diet. Furthermore, the results also showed that PE modulated the expression of enzymes involved in lipid metabolism including peroxisome proliferator-activated receptor alpha (PPAR-alpha), sterol regulatory element binding protein 1 (SREBP-1), fatty acid synthase (FAS) and stearoyl CoA desaturase-1 (SCD-1) mRNA in liver. Besides, PE-treated group decreased weights and diameters of epididymal adipose hyperlipidemia rat. Mechanism study demonstrated that PE regulated PPAR-gamma, CCAAT/Enhancer-binding Protein alpha (C/EBPalpha),and SREBP-1 expression as well as inhibited phosphorylation of AMPK in MDI (methylisobutylxanthine, dexamethasone, insulin) induced-3T3L1 cells. Molecular Docking confirmed interaction between PE with proteins involving PPAR gamma, C/EBPalpha and SREBP-1. In summary, these findings may support that PE is a novel lipid-lowering drug candidate. PMID- 29518609 TI - Suppression of Nrf2 confers chemosensitizing effect through enhanced oxidant mediated mitochondrial dysfunction. AB - AIMS: Transcription factor Nrf2, which regulates the expression of cytoprotective and antioxidant enzymes, contributes to proliferation and resistance to chemotherapy in cancer. The inhibition of Nrf2 can sensitize cholangiocarcinoma (CCA) cells to the cytotoxicity of several chemotherapeutic agents. In this study, we investigated the mechanism of this chemosensitizing effect. MAIN METHODS: KKU-100 cells were used in the study. Nrf2 expression was knocked down by siRNA and expression was validated by reverse transcription and polymerase chain reaction. Cytotoxicity was assessed by sulforhodamine B method. Intracellular reactive oxygen species (ROS) was examined by fluorescent dye, dichlorofluorescin diacetate method and mitochondrial transmembrane potential was assessed by JC1 dye assay. KEY FINDINGS: Cytotoxicity of cisplatin (Cis) in KKU 100 cells was enhanced by knockdown of Nrf2 expression. The enhanced cytotoxic effect was abolished by treatment with N-acetylcysteine, TEMPOL and MnTBAP. Cells with Nrf2 knockdown or Cis treatment increased production of ROS, and ROS was markedly enhanced by a combination of Nrf2 knockdown and Cis. The increased ROS formation was associated with a decrease in mitochondrial transmembrane potential (Deltapsim), where this decrease was prevented by antioxidant compounds. The loss of Deltapsim and cell death were prevented by cyclosporine, an inhibitor of mitochondrial permeability transition pore (MPTP). Luteolin inhibited Nrf2 and markedly enhanced cytotoxicity in combination with Cis. SIGNIFICANCE: Inhibition of Nrf2 is a feasible strategy in enhancing antitumor activity of chemotherapeutic agents and improving efficacy of chemotherapy in CCA. PMID- 29518608 TI - RIP3-deficience attenuates potassium oxonate-induced hyperuricemia and kidney injury. AB - Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections. Additionally, RIP3-deletion reduced malondialdehyde (MDA), H2O2 and O2-, whereas enhanced superoxide dismutase (SOD), GSH and GSH-Px levels in potassium oxonate-induced mice. Potassium oxonate-treated mice showed significantly high mRNA levels of ATP binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), OAT3, organic cation transporter 1 (OCT1) and organic cation/carnitine transporter 1 (OCTN1) in renal tissue samples, which were reversed by RIP3 deficiency. Meanwhile, down-regulation of circulating and kidney pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-6) were observed in RIP3-knockout mice with hyperuricemia, associated with inactivation of toll-like receptor 4 (TLR4), inhibitor of NF-kappaB alpha (IkappaBalpha) and nuclear factor kappa B (NF kappaB). NLR family, pyrin domain-containing 3 (NLRP3) inflammasome was also suppressed by RIP3 knockout in potassium oxonate-treated mice. Importantly, RIP3 knockout mice exhibited the decrease of FAS-associated protein with a death domain (FADD), cleaved Caspase-8/-3 and Poly (ADP-ribose) polymerase (PARP) in renal samples, along with TUNEL reduction in mice with hyperuricemia. Similar results were observed in uric acid-incubated cells with RIP3 knockdown. Thus, we suggested that RIP3 played an important role in mice with hyperuricemia, which might be a novel signal pathway targeting for therapeutic strategies in future. PMID- 29518610 TI - Zhen-wu-tang protects against podocyte injury in rats with IgA nephropathy via PPARgamma/NF-kappaB pathway. AB - Zhen-wu-tang (ZWT) has been widely applied in chronic kidney diseases. However, the mechanism of ZWT remains unclear. Peroxisome proliferator-activated receptors gamma (PPARgamma) is known as a protective factor for podocyte and kidney function. This study is aimed to investigate the protective effects of ZWT on IgA nephropathy (IgAN) in rats against podocyte injury and the underlying mechanism related to PPARgamma. IgAN model rats were induced by administering bovine serum albumin, lipopolysaccharide, and carbon tetrachloride. ZWT at two doses and GW9662 (PPARgamma antagonist) was administered once daily for 4 weeks respectively. Cultured podocyte induced by LPS were used to evaluate the podocyte protective effect and related mechanism of ZWT in vitro. Results showed that ZWT observably reduced proteinuria and hematuria excretion, as well as the levels of blood urea nitrogen, serum creatinine, serum uric acid, low-density lipoprotein cholesterol, total cholesterol and triglycerides, but increased the contents of high-density lipoprotein cholesterol, ameliorating renal function and hyperlipidemia state in IgAN rats. Besides, both ZWT administration groups alleviated kidney pathological lesion, macrophage infiltration, IgA and C3 deposition in glomeruli. To further demonstrate the protective effects of ZWT, we found that podocyte damage was markedly ameliorated with ZWT treatments in IgAN rats and LPS-induced podocyte injury model by suppressing the expressions of desmin, reducing podocyte apoptosis and augmenting nephrin and podocin levels. Moreover, ZWT inhibited the phosphorylation of NF-kappaB and IkappaBalpha, simultaneously upregulated PPARgamma. However, GW9662 made no difference in all the above effects compared to the model group, and was reversed by ZWT in vitro study. In conclusion, these results demonstrated that ZWT ameliorated IgAN induced podocyte injury via upregulation PPARgamma and the underlying mechanism might involve the inhibition of NF-kappaB pathway. PMID- 29518611 TI - The tumor suppressive miR-26a regulation of FBXO11 inhibits proliferation, migration and invasion of hepatocellular carcinoma cells. AB - Accumulating researches identify microRNA-26a (miR-26a) as a tumor suppressor in hepatocellular carcinoma (HCC). F-box protein 11 (FBXO11), a predicted target gene of miR-26a, is an E3 ubiquitin ligase and a type II methyltransferase, and functions as a key regulator of tumor initiation and progression. This study was aimed to investigate the regulatory role of miR-26a in FBXO11 expression and explored the clinical significance as well as functional role of FBXO11 in HCC. The expression levels of miR-26a were prominently downregulated in HCC tissues compared to matched tumor-adjacent tissues. MiR-26a inversely regulated FBXO11 abundance in HCC cells. Hereby, miR-26a could directly target 3'UTR of FBXO11 mRNA to suppress its expression. Gene Expression Omnibus (GEO) database (GSE54236 and GSE45436) and our data demonstrated that the expression of FBXO11 was up regulated in HCC tissues. The level of FBXO11 mRNA was inversely correlated with miR-26a expression in HCC specimens. High FBXO11 expression was positively correlated with large tumor size, venous infiltration and advanced tumor stage of HCC patients. Clinical prognostic analysis illustrated that high FBXO11 expression predicted a poor survival of HCC patients. In vitro, FBXO11 knockdown inhibited cell proliferation, colony formation, migration and invasion of HCC cells. Additionally, miR-26a overexpression showed a consistent effect with FBXO11 knockdown on these malignant behaviors of HCC cells. Notably, FBXO11 restoration reversed the inhibitory effect of miR-26a on HCC cell proliferation, colony formation, migration and invasion. In summary, these results indicated that miR-26a regulation of FBXO11 exhibited an oncogenic role in HCC. Inhibition of FBXO11 might serve as a therapeutic target for HCC. PMID- 29518603 TI - Do dietary patterns determine levels of vitamin B6, folate, and vitamin B12 intake and corresponding biomarkers in European adolescents? The Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study. AB - OBJECTIVES: To determine dietary patterns (DPs) and explain the highest variance of vitamin B6, folate, and B12 intake and related concentrations among European adolescents. METHODS: A total of 2173 adolescents who participated in the Healthy Lifestyle in Europe by Nutrition in Adolescence study met the eligibility criteria for the vitamin B intake analysis (46% boys) and 586 adolescents for the biomarkers analysis (47% boys). Two non-consecutive, 24-h, dietary recalls were used to assess the mean intakes. Concentrations were measured by chromatography and immunoassay testing. A reduced rank regression was applied to elucidate the combined effect of food intake of vitamin B and related concentrations. RESULTS: The identified DPs (one per vitamin B intake and biomarker and by sex) explained a variability between 34.2% and 23.7% of the vitamin B intake and between 17.2% and 7% of the biomarkers. In the reduced rank regression models, fish, eggs, cheese, whole milk and buttermilk intakes were loaded positively for vitamin B intake in both sexes; however, soft drinks and chocolate were loaded negatively. For the biomarkers, a higher variability was observed in the patterns in terms of food loads such as alcoholic drinks, sugars, and soft drinks. Some food items were loaded differently between intakes and biomarkers such as fish products, which was loaded positively for intakes but negatively for plasma folate in girls. CONCLUSIONS: The identified DPs explained up to 34.2% and 17.2% of the variability of the vitamin B intake and plasma concentrations, respectively, in European adolescents. Further studies are needed to elucidate the factors that determine such patterns. PMID- 29518612 TI - Nicotine upregulates FGFR3 and RB1 expression and promotes non-small cell lung cancer cell proliferation and epithelial-to-mesenchymal transition via downregulation of miR-99b and miR-192. AB - BACKGROUND: Tobacco smoke is by far the greatest risk factor for non-small-cell lung cancer (NSCLC). Nicotine, an active alkaloid in tobacco, is unable to initiate tumorigenesis in humans and rodents, but can promote the growth and metastasis of various tumors, including NSCLC, initiated by tobacco carcinogens. Recently, cigarette smoke is reported to downregulate 24 miRNAs more than 3-fold in the lungs of rats, and most of these downregulated miRNAs are associated with NSCLC initiation and development. Nicotine as the major tobacco component might be associated with the expression changes of some miRNAs. METHODS: qRT-PCR was performed to determine the miRNA and mRNA expression, and western blot was conducted to measure protein expression. MTT assay was used to detect cell proliferation. RESULTS: The effects of nicotine on the expression of 24 miRNAs in NSCLC cell lines were determined, and the results showed that nicotine treatment decreased miR-99b and miR-192 expression. Cell proliferation and epithelial-to mesenchymal transition (EMT) detection showed that nicotine promoted NSCLC cell proliferation and EMT, and restoration of miR-99b or miR-192 expression relieved the effects of nicotine on NSCLC cell proliferation and EMT. Subsequently, fibroblast growth factor receptor 3 (FGFR3) and retinoblastoma 1 (RB1) were confirmed to be the targets of miR-99b and miR-192, respectively, and were upregulated by nicotine in NSCLC cells. In addition, FGFR3 or RB1 knockdown inhibited NSCLC cell proliferation and EMT. CONCLUSION: This study, for the first time, elucidates nicotine-miR-99b/miR-192-FGFR3/RB1 regulatory network that nicotine promotes NSCLC cell proliferation and EMT by downregulating miR-99b and miR-192, and upregulating their targets FGFR3 and RB1. These findings offer novel insights into the understanding of underlying molecular mechanisms of NSCLC related with the nicotine effects. PMID- 29518613 TI - Long non-coding RNA TUG1 inhibits apoptosis and inflammatory response in LPS treated H9c2 cells by down-regulation of miR-29b. AB - OBJECTIVE: Myocarditis is an important cause for cardiovascular morbidity and mortality in children and adults. The lncRNA taurine up-regulated gene 1 (TUG1) plays important roles in cell apoptosis and inflammation in tumor and liver injury. The present study aimed to investigate the role of TUG1 in LPS-injured H9c2 cells and explore the underlying molecular mechanism. METHODS: H9c2 cells were stimulated with LPS to induce inflammatory injury. The expression of TUG1 was altered by transient transfections. Cell viability and apoptotic cell rates were detected by CCK-8 assay and flow cytometry assay, respectively. Inflammatory response was determined by detecting levels of inflammatory cytokines using qRT PCR and ELISA. Furthermore, western blot analysis was conducted to assess the expression levels of core factors related with apoptosis and activations of NF kappaB and JAK/STAT signaling pathways. RESULTS: LPS exposure reduced cell viability but enhanced cell apoptosis and inflammation in H9c2 cells. Moreover, TUG1 expression was down-regulated in LPS-injured H9c2 cells. TUG1 overexpression attenuated LPS-induced injuries in H9c2 cells, evidenced by augmented cell viability, declined apoptotic cell rates and decreased levels of pro-apoptotic factors and inflammatory cytokines. Inversely, TUG1 inhibition exerted the opposite effects. More importantly, TUG1 negatively modulated the expression of miR-29b and miR-29b mimic blocked the effect of TUG1 overexpression on cell viability, apoptosis, inflammation and inactivation of NF-kappaB and JAK/STAT signaling pathways in LPS-stimulated H9c2 cells. CONCLUSION: This study demonstrated that TUG1 played the anti-apoptotic and anti-inflammatory roles in LPS-injured H9c2 cells via down-regulating miR-29b and inhibiting NF-kappaB and JAK/STAT pathways. PMID- 29518614 TI - Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. AB - Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-beta1 (TGF-beta1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF beta1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-beta1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-beta1. The Smad signaling system plays a central role in regulation of TGF-beta1 and TGF beta/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-beta/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF beta1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-beta-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF kappaB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-kappaB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-beta1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-beta/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD. PMID- 29518615 TI - Plasmid-based gene therapy with hepatocyte growth factor stimulates peripheral nerve regeneration after traumatic injury. AB - Peripheral nerve injury remains a common clinical problem with no satisfactory treatment options. Numerous studies have shown that hepatocyte growth factor (HGF) exerts neurotrophic effect in motor, sensory, and parasympathetic neurons in addition to mitogenic, morphogenic, angiogenic, antiapoptotic, antifibrotic, and anti-inflammatory effect on various tissues and cells. In our study we examined efficacy of gene therapy with HGF-bearing plasmid (pC4W-hHGF) to improve consequences of traumatic nerve injury in mice. Treatment by pC4W-hHGF led to restoration of nerve structure and functional recovery compared to similar parameters in control animals. Compound action potentials (CAP) in experimental groups treated with 100 or 200 MUg of pC4W-hHGF demonstrated increased amplitude and latency decrease compared to spontaneous recovery control group. In HGF treated mice histological analysis showed a three-fold increase in axon number in nerve portion located distal to the lesion site compared to control. Moreover, significant functional recovery of n. peroneus communis triggered by pC4W-hHGF gene therapy was observed using the footprints analysis. Obtained results provide evidence for plasmid-based HGF gene therapy as a potential treatment for traumatic injury of peripheral nerve. PMID- 29518616 TI - Inequality in utilization of cesarean delivery in Bangladesh: a decomposition analysis using nationally representative data. AB - OBJECTIVE: This study examined the inequality in cesarean section (CS) utilization and its socio-economic contributors. STUDY DESIGN: Retrospective two stage stratified sample design. METHODS: Data were extracted from two rounds of the Bangladesh Demographic and Health Survey conducted in 2004 and 2014. Concentration Index of CS utilization was calculated using the wealth quintile. Regression-based decomposition method was applied to assess the socio-economic contributors of inequality in CS utilization. RESULTS: The rate of CS utilization increased from 4.98% in 2004 to 24.21% in 2014. The utilization of CS was highly concentrated among the women of higher socio-economic status (SES) in both rounds of the survey. Results of the decomposition models revealed wealth quintile, higher education, higher number of antenatal visits, and being overweight or obese as the critical factors contributing to the inequalities of CS utilization. CONCLUSION: Bangladesh is now observing a rapid rise in CS utilization and women with higher SES are the main client group of this life saving procedure. There may have inadequate access for those who are relatively less advantaged, even when CS is necessary. Strong initiative from the government is necessary to ensure proper access to this service regardless of women's SES. PMID- 29518617 TI - Higher dietary diversity score is associated with obesity: a case-control study. AB - OBJECTIVE: The present study was carried out to compare dietary diversity score (DDS) among overweight, obese, and normal-weight adults. STUDY DESIGN: This case control study was conducted with a total of 200 cases (100 participants with obesity and 100 participants with overweight) and 300 controls (normal weight) matched by socio-economic status (SES), older than 18 years. METHODS: Dietary intakes were assessed using a self-administered Food Frequency Questionnaire. Data regarding physical activity and sociodemographic variables were gathered. DDS was computed based on the scoring of the five food groups emphasized in the United States Department of Agriculture Food Guide Pyramid. Anthropometric measurements were measured, and the body mass index and waist-to-hip ratio were calculated. RESULTS: The mean +/- standard deviation of DDS was higher in participants with obesity (5.65 +/- 1.32) than that in overweight participants (5.23 +/- 1.23), while the lowest score was reported among normal-weight individuals (4.97 +/- 1.42) (P < 0.001). The odds of obesity increased with each unit increase in DDS (odds ratio [OR]: 1.46; 95% confidence interval [CI]: 1.22, 1.74). However, the association became slightly weaker after adjusting for potential confounding factors (OR: 1.34; 95% CI: 1.07, 1.68). CONCLUSION: It was concluded that there was a significant positive association between DDS and obesity. However, additional investigations are warranted. PMID- 29518618 TI - The interplay of etiological knowledge and mental illness stigma on healthcare utilisation in the community: A structural equation model. AB - BACKGROUND: The stigma of mental illness, especially personal attitudes towards psychiatric patients and mental health help-seeking, is an important barrier in healthcare utilisation. These attitudes are not independent of each other and are also influenced by other factors, such as mental health literacy, especially the public's causal explanations for mental problems. We aimed to disentangle the interrelations between the different aspects of stigma and causal explanations with respect to their association with healthcare utilisation. METHODS: Stigma and causal explanations were assessed cross-sectional using established German questionnaires with two unlabelled vignettes (schizophrenia and depression) in a random-selection representative community sample (N = 1375, aged 16-40 years). They were interviewed through a prior telephone survey for current mental disorder (n = 192) and healthcare utilisation (n = 377). Structural equation modelling was conducted with healthcare utilisation as outcome and stigma and causal explanations as latent variables. The final model was additionally analysed based on the vignettes. RESULTS: We identified two pathways. One positive associated with healthcare utilisation, with high psychosocial stress and low constitution/personality related causal explanations, via positive perception of help-seeking and more help-seeking intentions. One negative associated with healthcare utilisation, with high biogenetic and constitution/personality, and low psychosocial stress related explanations, via negative perception of psychiatric patients and a strong wish for social distance. Sensitivity analysis generally supported both pathways with some differences in the role of biogenetic causal explanation. CONCLUSION: Our results indicate that campaigns promoting early healthcare utilisation should focus on different strategies to promote facilitation and reduce barriers to mental healthcare. PMID- 29518619 TI - Design of artificial enzymes by supramolecular strategies. AB - Enzymes are biomacromolecules with three-dimensional structures composed of peptide polymers via supramolecular interactions. Owing to the incredible catalytic efficiency and unique substrate selectivity, enzymes arouse considerable attention. To rival natural enzymes, various artificial enzymes have been developed over the last decades. Since supramolecular interactions play important roles in both substrate recognition and the process of enzymatic catalysis, designing artificial enzymes using supramolecular strategies is undoubtedly significant. Here we discuss the recent advances in constructing artificial enzymes using supramolecular platforms. PMID- 29518620 TI - Multi-Mode Elastic Peak Electron Microscopy (MM-EPEM): A new imaging technique with an ultimate in-depth resolution for surface analysis. AB - A non-destructive new imaging technique called Multi-Mode Elastic Peak Electron Microscopy (MM-EPEM), hypersensitive to surface chemistry and with an in-depth resolution of one atomic monolayer was developed. This method consists on performing several MM-EPEM images containing n * n pixels associated to an intensity of the elastic backscattered electrons by varying the incident electron energy in the range 200-2000 eV. This approach allows obtaining depth sampling information of the analyzed structures. Furthermore, MM-EPEM is associated with Monte-Carlo simulations describing the electron pathway in materials in order to obtain very precise quantitative information, for instance the growth mode and the organization of ultra-thin layers (2D materials) or nanoparticules. In this work, we used this new method to study the deposition of very small amount of gold down to one monolayer. Example of 3D reconstruction is also provided. PMID- 29518621 TI - Bacterial electroactivity and viability depends on the carbon nanotube-coated sponge anode used in a microbial fuel cell. AB - The anode material is vital to improve the power generation of a microbial fuel cell (MFC). In this study, a carbon nanotube (CNT)-coated sponge with macro porous structure, high surface area, and high conductivity was constructed as an anode to encapsulate Escherichia coli K12 (E. coli K12) cells. To achieve high power generation of the MFC, the optimal concentration of the CNT coating the sponge was found to be 30mgmL-1. At this concentration, a maximum power density of 787Wm-3 and a chemical oxygen demand (COD) removal of 80.9% were obtained with a long stable electricity generation process in batch mode. This indicates that the biofilm on the CNT (30mgmL-1)-coated sponge possessed excellent electroactivity and stability. Scanning electron microscope (SEM) images confirmed that the CNT-coated sponge provided a suitable microenvironment for E. coli K12 cells to maintain their attachment and colonization. Additionally, a CNT dependent viability phenomenon of the E. coli K12 cells was discovered after electricity generation. This CNT-dependent viability of the E. coli K12 cells was stable and sustainable after storage at -20 degrees C in a milk tube for one year. PMID- 29518622 TI - Cytocompatible tantalum films on Ti6Al4V substrate by filtered cathodic vacuum arc deposition. AB - Tantalum films were deposited on negatively biased Ti6Al4V substrates using filtered cathodic vacuum arc deposition to enhance the corrosion resistance of the Ti6Al4V alloy. The effect of substrate voltage bias on the microstructure, mechanical and corrosion properties was examined and the cytocompatibility of the deposited films was verified with mammalian cell culturing. The Ta films deposited with substrate bias of -100V and -200V show a mixture of predominantly beta phase and minority of alpha phase. The Ta/-100V film shows adhesive failure at the Ti/Ta interface and a cohesive fracture is observed in Ta/-200V film. The Ta/-100V showed a significant improvement in corrosion resistance, which is attributed to the stable oxide layer. The in-vitro cytocompatibility of the materials was investigated using rat bone mesenchymal stem cells, and the results show that the Ta films have no adverse effect on mammalian cell adhesion and spreading proliferation. PMID- 29518623 TI - Clinical and economic outcomes of nurse-led services in the ambulatory care setting: A systematic review. AB - BACKGROUND: With the increasing burden of chronic and age-related diseases, and the rapidly increasing number of patients receiving ambulatory or outpatient based care, nurse-led services have been suggested as one solution to manage increasing demand on the health system as they aim to reduce waiting times, resources, and costs while maintaining patient safety and enhancing satisfaction. OBJECTIVES: The aims of this review were to assess the clinical effectiveness, economic outcomes and key implementation characteristics of nurse-led services in the ambulatory care setting. DESIGN: A systematic review was conducted using the standard Cochrane Collaboration methodology and was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE EBSCO, CINAHL EBSCO, and PsycINFO Ovid (from inception to April 2016). REVIEW METHODS: Data were extracted and appraisal undertaken. We included randomised controlled trials; quasi randomised controlled trials; controlled and non-controlled before-and-after studies that compared the effects of nurse-led services in the ambulatory or community care setting with an alternative model of care or standard care. RESULTS: Twenty-five studies of 180,308 participants were included in this review. Of the 16 studies that measured and reported on health-related quality of life outcomes, the majority of studies (n = 13) reported equivocal outcomes; with three studies demonstrating superior outcomes and one demonstrating inferior outcomes in comparison with physician-led and standard care. Nurse-led care demonstrated either equivalent or better outcomes for a number of outcomes including symptom burden, self-management and behavioural outcomes, disease specific indicators, satisfaction and perception of quality of life, and health service use. Benefits of nurse-led services remain inconclusive in terms of economic outcomes. CONCLUSIONS: Nurse-led care is a safe and feasible model of care for consideration across a number of ambulatory care settings. With appropriate training and support provided, nurse-led care is able to produce at least equivocal outcomes or at times better outcomes in terms of health-related quality of life compared to physician-led care or standard care for managing chronic conditions. There is a lack of high quality economic evaluations for nurse-led services, which is essential for guiding the decision making of health policy makers. Key factors such as education and qualification of the nurse; self management support; resources available for the nurse; prescribing capabilities; and evaluation using appropriate outcome should be carefully considered for future planning of nurse-led services. PMID- 29518624 TI - Does self-compassion mitigate the relationship between burnout and barriers to compassion? A cross-sectional quantitative study of 799 nurses. AB - BACKGROUND: Burnout has numerous negative consequences for nurses, potentially impairing their ability to deliver compassionate patient care. However, the association between burnout and compassion and, more specifically, barriers to compassion in medicine is unclear. This article evaluates the associations between burnout and barriers to compassion and examines whether dispositional self-compassion might mitigate this association. HYPOTHESIS: Consistent with prior work, the authors expected greater burnout to predict greater barriers to compassion. We also expected self-compassion - the ability to be kind to the self during times of distress - to weaken the association between burnout and barriers to compassion among nurses. METHODS: Registered nurses working in New Zealand medical contexts were recruited using non-random convenience sampling. Following consent, 799 valid participants completed a cross-sectional survey including the Copenhagen Burnout Inventory, the Barriers to Physician Compassion scale, and a measure of dispositional self-compassion. RESULTS: As expected, greater burnout predicted greater barriers to compassion while self-compassion predicted fewer barriers. However, self-compassion mitigated the association between burnout and burnout related barriers to compassion (but not other barriers). The interaction suggested that suggested that the association was stronger (rather than weaker) among those with greater self-compassion. DISCUSSION: Understanding the lack of compassion and the effects of burnout in patient care are priorities in health. This report extends evidence on the association between burnout and compassion fatigue to show that burnout also predicts the experience of specific barriers to compassion. While self-compassion predicted lower burnout and barriers, it may not necessarily reduce the extent to which burnout contributes to the experience of barriers to compassion in medicine. Implications for understanding how burnout manifests in barriers to clinical compassion, interventions and professional training, and future directions in nursing are discussed. PMID- 29518625 TI - Functional competence in major depressive disorder: Objective performance and subjective perceptions. AB - BACKGROUND: Major depressive disorder (MDD) is increasingly recognized as a disorder of everyday functioning. Multi-level approaches to investigating functioning have been employed in other conditions whereby competence (ability to perform living skills) is distinguished from real-world functioning, but not yet in MDD. We used a multidimensional (adaptive and interpersonal), multi-level (competence and performance) approach to investigate differences between those with MDD and healthy comparisons (HC) on measures of competence, functional disability, and self-perceived competence. METHODS: Between-group analysis of variance identified differences between MDD (n = 42) and HC (n = 24). Moderation analysis determined whether the strength of the relationship between competence accuracy and self-perception of performance was related to group membership. RESULTS: In adaptive and interpersonal domains, the MDD group performed significantly lower on competence tasks, endorsed greater functional disability, and reported lower self-perception of competence. Group membership did not moderate the relationship between competence and self-perceived competence in the adaptive domain. Significant moderation was observed in the interpersonal domain such that competence and self-perception of abilities converged in the HC, but not MDD, group. LIMITATIONS: A cross-sectional design precluded the ability to interpret causality of results. Functional disability was measured by interview, thereby susceptible to biases in self-report. CONCLUSIONS: A multi-level approach to assessing functioning in MDD was supported. Performance-based measures of functional competence are sensitive to MDD and useful for research trials and clinical work to objectively track everyday living skills. Objective measurement is further supported, as those with depression are less likely to accurately evaluate their own abilities, even after demonstrating skills. PMID- 29518626 TI - Explaining the felt location of bodily sensations through body representations. AB - Why are bodily sensations felt on specific body parts? This paper discusses the view according to which we need body representations to account for the felt location of bodily sensations. My aim will be to consider whether or not some claims linked with that view are substantiated (namely, that all of our grasp of the spatiality of our bodies must come from bodily sensations, that the representation of the body can determine bodily sensations surmounting sensory input, that the content of body representations cannot be action-oriented). To do this, I first introduce and assess Brian O'Shaughnessy's seminal version of the representationalist approach to bodily sensations. Next, I will inquire into a purported objection to any version of the approach, showing its inadequacy. Finally, I will concentrate on Frederique de Vignemont's variant of the representationalist view, trying to pin down a few of her assertions. My conclusion will be that the scope and strength of the representationalist position in regard to the aforementioned claims is different from what it is usually thought to be. PMID- 29518627 TI - ZFP36L2, a novel AML1 target gene, induces AML cells apoptosis and inhibits cell proliferation. AB - The t(8;21)(q22;q22) translocation generated the fusion protein AML1-ETO. AML1 ETO recruits histone deacetylase (HDAC) complex via its ETO part to repress AML1 mediated transactivation. Our previous study demonstrated that HDAC inhibitor phenylbutyrate (PB) could induce AML1-ETO positive leukemia cell line Kasumi-1 cells to undergo differentiation and apoptosis accompanied by significant changes in gene expression profile. ZFP36L2 was one of the up-regulated genes in Kasumi-1 cells induced by PB treatment. In this study, ZFP36L2 was found to express at a lower level in acute myeloid leukemia (AML) patients with t(8;21) compared to AML patients without t(8;21). In order to investigate the correlation between the expression of ZFP36L2 and AML1 or AML1-ETO, the putative AML1 binding sites in the enhancer/promoter region of ZFP36L2 gene were predicted through the bioinformatics analysis. And the biological function of ZFP36L2 in leukemic cells was further investigated. The results demonstrated that AML1 could transactivate ZFP36L2 significantly by binding on specific site of the ZFP36L2 promoter sequence. And overexpression of ZFP36L2 in leukemia cells could inhibit the cell proliferation, promote cell-cycle arrest in G0/G1 phase and induce the cell apoptosis. In conclusion, ZFP36L2 could be transactivated by AML1, which subsequently induced cell-cycle arrest and apoptosis of leukemia cells. PMID- 29518628 TI - AML refractory to primary induction with Ida-FLAG has a poor clinical outcome. AB - We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group. PMID- 29518629 TI - Sucrose diester of aryldihydronaphthalene-type lignans from Echium angustifolium Mill. and their antitumor activity. AB - Four previously undescribed sucrose diester of aryldihydronaphthalene-type lignans, named echiumins A-D, were isolated from the butanol fraction of Echium angustifolium Mill, in addition to a known compound, trigonotin A, which is reported for the first time from the title plant. The structures of isolated compounds were elucidated using spectroscopic methods such as HRESIMS and 1D and 2D NMR spectroscopy. The isolated compounds displayed strong to weak antitumor activity against HepG2 and MCF7 cancer cell lines, with echiumins A and D showed the most potent activity. PMID- 29518630 TI - Design, synthesis and biological evaluation of novel thiazol-2-yl benzamide derivatives as glucokinase activators. AB - Glucokinase (GK) is the main enzyme which controls the blood glucose levels in a safe and narrow physiological range in humans. GK activators are the novel type of therapeutic agents which act on GK enzyme and show their anti-diabetic potential. The present work was planned to synthesize and evaluate the antidiabetic potential of a new series of thiazole-2-yl benzamide derivatives as potential GK activators. A series of thiazole-2-yl benzamide derivatives were synthesized from benzoic acid and evaluated by in vitro enzymatic assay for GK activation. In silico docking studies were carried out to determine the binding interactions for the best fit conformations in the allosteric site of GK enzyme. Based on the results of in vitro enzyme assay and in silico studies, the selected molecules were tested for their antidiabetic activity in the oral glucose tolerance test (OGTT). The results of the in vitro enzymatic assay were found to be in accordance to that of in silico studies. Amongst the synthesized molecules, compounds 1, 2, 5 and 8 displayed good in vitro GK activation (activation fold between 1.48 and 1.83). Compounds 2 and 8 exhibited highest antidiabetic activity in OGTT studies. The results of the in vivo antidiabetic studies were found to be in parallel to that of docking and in vitro studies. These newly synthesized thiazol-2-yl benzamide derivatives thus can be treated as the initial hits for the development of new, safe, effective and orally bioavailable GK activators as therapeutic agents for the treatment of type 2 diabetes. PMID- 29518631 TI - Natural compounds analysis using liquid and supercritical fluid chromatography hyphenated to mass spectrometry: Evaluation of a new design of atmospheric pressure ionization source. AB - The MS hyphenation performance of UniSpray(r), a new design of atmospheric pressure ionization source was evaluated in both SFC and RPLC modes. Sensitivity, stability, versatility and matrix effects offered by the UniSpray were assessed in positive and negative ionization modes and systematically compared to an electrospray source (ESI) using 120 natural compounds covering an extended chemical space. In a first instance, a multivariate approach was used to screen and optimize the UniSpray source settings to maximize detection sensitivity. The position of the source capillary against the fixed charged rod was highlighted as the major parameter affecting the detection sensitivity. The sensitivity improvement in Unispray vs. ESI strongly depends on the compounds chemical class and the chromatographic mode. For a few compounds (i.e. anabasine, theanine, caproic acid, fumaric acid and protopanaxatriol), up to a 10-fold increase in sensitivity was noticed with UniSpray. The signal stability over multiple injections was also found to be equivalent between both sources with RSD values on peak intensity lower than 14% on >100 injections, in both chromatographic modes. On complex plant extract, the matrix effects occurring from the secondary metabolites were also found to be comparable between ESI and UniSpray, at least in the positive ionization mode. However, a systematic decrease of MS signal intensity was observed in SFC mode when compounds were ionized using UniSpray in the negative ion mode. PMID- 29518632 TI - Stable isotope labeling - dispersive solid phase extraction - liquid chromatography - tandem mass spectrometry for quantitative analysis of transsulfuration pathway thiols in human serum. AB - Low-molecular-weight thiols play important roles in a variety of pathological processes and are closely associated with a wide range of diseases. In this study, a selective and sensitive method was developed for the simultaneous determination of all the 7 thiols occurring in the transsulfuration pathway (Cysteine (Cys), homocysteine (Hcys), glutathione (GSH), N-acetylcysteine (Nac), cysteinylglycine (CysGly), glutamylcysteine (GluCys) and cysteamine (CA)) in human serum by in-vitro stable isotope labeling - dispersive solid phase extraction - liquid chromatography - tandem mass spectrometry analysis (IL-DSPE LC-MS/MS). In the proposed method, a pair of stable isotope-labeling reagents, BQB (omega-bromoacetonylquinolinium bromide) and BQB-D7, were utilized to label thiols in human serum samples and thiol standards, respectively. The BQB labeled thiols which carry a positive charge were extracted and purified with C8-SO3H based DSPE followed by LC-MS/MS analysis. Good linearities for 7 thiols occurring in the transsulfuration pathway were obtained with the coefficient of determination (R2) >0.9901. The limits of detection (LODs) were in the range of 0.7-6.0 nmol/L. The method was further applied to investigate the contents change of 7 thiols in human serum samples of type 2 diabetes mellitus (T2DM) patients and breast cancer (BC) patients. The results showed that the contents of these thiols occurring in the transsulfuration pathway significantly changed and were highly diseases-related. In addition, partial least squares discriminant analysis (PLS-DA) suggested excellent classification performance between patients and healthy controls. The findings indicated that these significantly changed thiols occurring in the transsulfuration pathway in T2DM patients and BC patients might serve as the indicator for the diagnosis of T2DM and BC. Taken together, the developed IL-DSPE-LC-MS/MS method provides a promising tool for the sensitive analysis of thiols from complex biological samples, which may promote the in depth investigation of the functions of thiols. PMID- 29518633 TI - A comparison of the determination and speciation of inorganic arsenic using general HPLC methodology with UV, MS and MS/MS detection. AB - The determination and speciation of arsenic in natural resources such as drinking water and agricultural soils has been a growing concern in recent years due to its many toxicological effects [1-3]. To speciate and quantitate concentrations of <1 ppm of arsenic, typically an ion chromatograph (IC) interfaced to an inductively coupled plasma mass spectrometer (ICP-MS) is employed [4-9]. This methodology may be very robust and sensitive, but it is expensive and not as ubiquitous as high performance liquid chromatography (HPLC) with ultraviolet (UV) absorbance detection or electrospray ionization mass spectrometry (ESI-MS). Anion exchange chromatography is a well-documented means of speciating arsenite (As(III), As2O3) and arsenate (As(V), AsO4) using UV [10], conductivity [11], or ESI-MS detection [12,13]. This paper demonstrates the utilization of common liquid chromatographic instrumentation to speciate and determines inorganic Arsenic compounds using UV or MS via selected ion recording (SIR) or multiple reaction monitoring (MRM) detection. This paper describes the analysis of arsenite and arsenate samples prepared using both deionized and ground water. The limit of quantitation for the techniques described in this paper for samples spiked in ground water were 454 ppb (As(III)) and 562 ppb (As(V)) for UV detection, 45.4 ppb (As(III)) and 56.2 ppb (As(V)) for SIR detection, and 4.54 ppb (As(III)) and 5.62 ppb (As(V)) for MRM detection. PMID- 29518634 TI - Drosophila bendless catalyzes K63-linked polyubiquitination and is involved in the response to DNA damage. AB - In this study, we report the identification and functional characterization of the Drosophila ben/ubc13 gene, encoding a unique ubiquitin-conjugating enzyme (Ubc or E2), in DNA-damage response. Ben forms a heterodimer with DmUev1a, the only Ubc/E2 variant (Uev) in Drosophila. Ben and DmUev1a act together to catalyze K63-linked polyubiquitination in vitro. ben can functionally rescue the yeast ubc13 null mutant from killing by DNA-damaging agents. We also find that BenP97S, which was previously described to affect the connectivity between the giant fiber and the tergotrochanter motor neuron, fails to interact with the RING protein Chfr but retains interaction with DmUev1a as well as Uevs from other species. The corresponding yeast Ubc13P97S interacts with Mms2 but fails to bind Rad5. Consequently, neither benP97S nor ubc13P97S is able to complement the yeast ubc13 mutant defective in error-free DNA-damage tolerance. More importantly, the benP97S mutant flies are more sensitive to a DNA-damaging agent, suggesting that Ben functions in a manner similar to its yeast and mammalian counterparts. Collectively, our observations imply that Ben-DmUev1a-promoted K63-linked polyubiquitination and involvement in DNA-damage response are highly conserved in eukaryotes including flies. PMID- 29518635 TI - Is inflammation a direct response to dsDNA breaks? AB - Recent research shows that extra-nuclear cell-free chromatin (cfCh) released from dying cells can freely enter into healthy cells and integrate into their genomes. Genomic integration of cfCh leads to dsDNA breaks and activation of inflammatory cytokines both of which occur concurrently with similar kinetics and that induction of inflammation can be abrogated by preventing DNA breaks with the use of cfCh inactivating agents. The proposal is put forward that inflammatory cytokines are a new family of DDR proteins that are activated following dsDNA breaks inflicted by genomic integration of cfCh. PMID- 29518636 TI - The relationship between cigarette taxes and child maltreatment. AB - Prior research suggests that income and child maltreatment are related, but questions remain about the specific types of economic factors that affect the risk of maltreatment. The need to understand the role of economics in child welfare is critical, given the significant public health costs of child maltreatment. One factor that has been overlooked is regressive taxation. This study addresses this need by examining whether state-level changes in cigarette tax rates predict changes in state-level child maltreatment rates. The results of both a fixed effects (FE) and a fixed effects instrumental variables (FE-IV) estimator show that increases in state cigarette tax rates are followed by increases in child abuse and neglect. An additional test finds that increases in the sales tax (another tax deemed to be regressive) also predict increases in child maltreatment rates. Taken as a whole, the findings suggest that regressive taxes have a significant effect on the risk of child maltreatment. PMID- 29518637 TI - "Blood letting"-Self-phlebotomy in injecting anabolic-androgenic steroids within performance and image enhancing drug (PIED) culture. AB - BACKGROUND: New evidence with regard to a previously undocumented practice - self phlebotomy, known as 'bloodletting' - incontemporary injecting performance and image enhancing drug (PIED) culture is the subject of this paper. While self phlebotomy has been evidenced in psychiatric patients previously, it was performed here in people who inject AAS as a self directed health care procedure. METHODS: Data was collected from five publicly accessible internet discussion forums and coded using NVivo software. For the purposes of this study, posts in relation to bloodletting were extracted from the final set of records for analysis RESULTS: Motivation to perform bloodletting or to 'self - bleed' was largely grounded in experiencing symptoms of high blood pressure or a high red blood cell count (RBC).Instructions on how to perform bloodletting were found within discussion threads. CONCLUSION: This study is intended to provide the first snapshot of online communal activity around practice of self-phlebotomy or bloodletting amongst people who inject AAS. Further research in this area is warranted, and will be of benefit to healthcare workers, treatment providers and policy makers particularly as this relates to evidence informed and targeted harm reduction policies and effective public health interventions. PMID- 29518638 TI - Thrombophilia testing in children: What and when should be tested? AB - Venous thrombosis (VTE) in children is gaining increased awareness and apart from underlying medical conditions, recently reported systematic reviews on pediatric VTE (70% provoked) have shown significant associations between thrombosis and presence of inherited thrombophilic risk factors (IT), such as protein C-, protein S- and antithrombin deficiency, mutations of factor 5 (F5: rs6025) and factor 2 (F2: rs1799963), even more pronounced when combined IT were involved. Although we have learned more about the pathophysiology of VTE with the increased discovery of IT evidence is still lacking as to whether IT influence the clinical outcome in pediatric VTE. It still remains controversial as to whether children with VTE or offspring from thrombosis-prone families benefit from IT screening. Thus, IT testing in children should be individualized. If the decision "pro screening" is discussed as an appropriate option in adolescents with unprovoked VTE and in children with a positive family history for VTE screening should be performed in a specialized coagulation unit for acquired or inherited and prothrombotic defects based on the individual population background. Apart from the laboratory assessment for the presence/absence of lupus anticoagulants and antiphospholipid antibodies screening should be performed beyond the acute VTE onset and after withdrawal of anticoagulant medication possibly influencing laboratory results. PMID- 29518639 TI - Axillary lymph node metastases from unknown primary: A French multicentre study. AB - PURPOSE: The aim of the study was to investigate the management and prognosis of axillary cancers from unknown primaries (CUPax). METHODS: We included all patients with lesions described as axillary nodal metastases from an unknown primary referred to four French tertiary breast cancer centres between January 1988 and December 2012. The inclusion criteria comprised: no sign of primary breast cancer on clinical examination nor on imaging (mammography, ultrasonography and breast MRI) and no primary tumour identified elsewhere. RESULTS: CUPax represented 1.8% of all metastatic axillary lymphadenopathies in our institutions. The overall survival rate was 71%, and 16.7% of patients had secondary inflammatory breast cancer signalling a posteriori that CUPax originated from the breast. Factors that favourably affected survival according to univariate analysis were: histological type of non specific adenocarcinoma (versus other types, p = 0.02), only one lymph node involved (versus several, p = 0.04), a normal CA153 serum-level (p = 0.02), no distant metastasis at initial assessment (p = 0.02), no secondary distant metastasis (p = 0.005) and radiotherapy to the ipsilateral breast/chest wall/lymph nodes (p = 0.04). On multivariate analysis including these factors, a histological type of non specific adenocarcinoma (p = 0.03) and distant metastases (p = 0.03) were identified as independent factors affecting survival. CONCLUSION: We believe that these results will shed light on current investigations and treatment of this rare entity. PMID- 29518641 TI - Long-term experience of vaginal vault prolapse prevention at hysterectomy time by modified McCall culdoplasty or Shull suspension: Clinical, sexual and quality of life assessment after surgical intervention. AB - OBJECTIVES: The aim of this study was to evaluate the effectiveness of modified McCall culdoplasty or Shull suspension in preventing vaginal vault prolapse after vaginal hysterectomy and the long-term impact on quality of life and sexual function. STUDY DESIGN: Retrospective analysis in 414 patients underwent vaginal hysterectomy for pelvic organ prolapse (POP) and vaginal suspension through modified McCall culdoplasty (group A) or Shull suspension (group B) was evaluated. Clinical features and concomitant surgical procedures were assessed. Surgical data and perioperative and postoperative complications have also been analyzed. Clinical characteristics, urinary symptoms, POP-Q score classification, Quality of Life and Sexual Function were evaluated at baseline and at median follow up with P-QoL, ICIQ-UI-SF, PISQ-12, FSFI, FSDS questionnaires. RESULTS: The median follow up was 8.9 year (5.1-14.2 years). 200 women in group A and 214 in group B were evaluated. Vaginal vault prolapse occurred in 2 patients in group A and in 2 patients in group B. POP-Q score for all compartments showed a significant (p < 0.001) decrease for both groups without significant differences between the 2 groups. The total vaginal length (TVL) was reduced in greater proportion in McCall group (p < 0.001). P-QoL and ICIQ-UI-SF questionnaires documented an improvement for both groups (p < 0.001). The number of patients who regularly practice sexual activity increased in both groups, but patients in group B experienced a better quality of sexual life evaluated with PISQ-12 and FSFI. CONCLUSIONS: Both surgical techniques showed effectiveness and safety in preventing vaginal vault prolapse in women who underwent vaginal hysterectomy, with a significant improvement in quality of life and sexuality. Shull technique demonstrated greater improvement in sexual function. PMID- 29518640 TI - The prevalence of occult endometrial cancer in women undergoing hysterectomy for benign indications. AB - OBJECTIVE: To estimate the frequency of occult endometrial cancer in women undergoing hysterectomy for benign indications. STUDY DESIGN: We performed a retrospective review of all patients undergoing hysterectomies for benign indications at our institution from 2006 to 2014. A departmental database was used to identify all hysterectomies performed, and institutional tumor registry was used to identify cases of endometrial carcinoma. Occult carcinomas were defined as cases with no suspicion preoperatively and histopathologic diagnosis of endometrial cancer postoperatively. RESULTS: A total of 6981 hysterectomies were performed for benign indications. Among these, thirteen patients (0.19%) were found to have occult endometrial cancer, with an overall rate of 1 in 537 patients (95% confidence interval 1:314-1:1008). Twelve patients had stage IA and one had stage IB disease. Median age of women found to have endometrial cancer was 50 years (range 35-72 years). The median BMI was 29.8 kg/m2 (range 21.3-50.4 kg/m2). The most common indications for hysterectomy were abnormal bleeding (47%), postmenopausal bleeding (15%), adnexal mass (15%), prolapse (15%), and endometrial hyperplasia without atypia (8%). Of the postmenopausal women that had bleeding, all patients underwent evaluation of the endometrium, however 75% of samples did not have adequate amount of endometrium to be evaluated and 25% were found to have hyperplasia. CONCLUSION: This is one of the largest single institution cohorts to examine occult malignancy. Unexpected endometrial carcinomas were found to occur in 0.19% or 1:537 (95% confidence interval 1:314 1:1008) hysterectomies for benign indications in our population. PReCIS: Occult endometrial carcinomas are found to occur in 1:537 (0.19%) hysterectomies for benign indications. PMID- 29518642 TI - Seropositivity for the human heat shock protein (Hsp)60 accompanying seropositivity for Chlamydia trachomatis is less prevalent among tubal ectopic pregnancy cases than individuals with normal reproductive history. AB - OBJECTIVES: To investigate the role of anti-human heat shock protein 60 (hHsp60) antibody positivity in the pathogenesis of ectopic pregnancy, following Chlamydia trachomatis (CT) infection. STUDY DESIGN: In a case-control study, serological tests for anti-hHsp60 were performed in ectopic pregnancies (study group) and parturients with normal reproductive histories (control group). All participants in both groups were CT IgG(+). hHsp60 IgG(+) prevalences were compared between the two groups, by semiquantitative ELISA. Data were evaluated using nonparametric and parametric tests and multivariable regression. RESULTS: After an initial pilot study, two groups were formed: 63 ectopic gestations (study group) and 95 normal parturients (control group), all CT IgG(+). Blood samples from all cases were tested for anti-hHsp60 IgG. Age, gravidity, and practising contraception were higher in the control group, while a history of pelvic infections were more common in the study group. Hsp60 IgG(+) was found to be significantly higher in the control group (63/95, 66.3%) compared to study group (30/63, 47.6%). Regression analysis revealed anti-hHsp60 positivity was an independent factor delineating the two groups. CONCLUSION: Immunity to hHsp60 is less common in CT IgG(+) ectopic pregnancies than CT IgG(+) fertile subjects without a history of ectopic pregnancies. Hence, our findings suggest that hHsp60 seropositivity may decrease the probability of an ectopic gestation in subjects with previous CT infections. PMID- 29518643 TI - Duration of spontaneous labour in 'low-risk' women with 'normal' perinatal outcomes: A systematic review. AB - BACKGROUND: Despite decades of research, the concept of normality in labour in terms of its progression and duration is not universal or standardized. However, in clinical practice, it is important to define the boundaries that distinguish what is normal from what is abnormal to enable women and care providers have a shared understanding of what to expect and when labour interventions are justified. OBJECTIVES: To synthesise available evidence on the duration of latent and active first stage and the second stage of spontaneous labour in women at low risk of complications with 'normal' perinatal outcomes. SEARCH STRATEGY: PubMed, EMBASE, CINAHL, POPLINE, Global Health Library, and reference lists of eligible studies. SELECTION CRITERIA: Observational studies and other study designs. DATA COLLECTION AND ANALYSIS: Four authors extracted data on: maternal characteristics; labour interventions; duration of latent first stage, active first stage, and second stage of labour; and the definitions of onset of latent and active first stage, and second stage where reported. Heterogeneity in the included studies precluded meta-analysis and data were presented descriptively. MAIN RESULTS: Thirty-seven studies reporting the duration of first and/or second stages of labour for 208,000 women met our inclusion criteria. Among nulliparous women, the median duration of active first stage (when the starting reference point was 4 cm) ranged from 3.7-5.9 h (95th percentiles: 14.5-16.7 h). With active phase starting from 5 cm, the median duration was from 3.8-4.3 h (95th percentiles: 11.3-12.7 h). The median duration of second stage ranged from 14 to 66 min (95th percentiles: 65-138 min) and from 6 to 12 min (95th percentiles: 58 76 min) in nulliparous and parous women, respectively. Sensitivity analyses excluding first and second stage interventions did not significantly impact on these findings CONCLUSIONS: The duration of spontaneous labour in women with good perinatal outcomes varies from one woman to another. Some women may experience labour for longer than previously thought, and still achieve a vaginal birth without adverse perinatal outcomes. Our findings question the rigid limits currently applied in clinical practice for the assessment of prolonged first or second stage that warrant obstetric intervention. PMID- 29518644 TI - Simultaneous quantification of intracellular lamivudine and abacavir triphosphate metabolites by LC-MS/MS. AB - Nucleoside reverse transcriptase inhibitors (NRTIs) require intracellular phosphorylation to active triphosphate (TP) nucleotide metabolites before they can inhibit the HIV reverse transcriptase. However, monitoring these pharmacologically active TP metabolites is challenging due to their instability and their low concentrations at the pg/ml levels in blood and tissues. The combination of lamivudine (3TC) and abacavir (ABC) is one of the first lines for HIV therapy. Therefore, a sensitive, selective, accurate, and precise LC-MS/MS method was developed and validated for the simultaneous quantification of 3TC- and ABC-TP metabolites in mouse blood and tissues. Calibration curves were linear over the range of 10-100,000 pg/ml for 3TC-TP and 4-40,000 pg/ml for carbovir-TP (CBV-TP; phosphorylated metabolite of ABC). This corresponds to 2.1-21,322 fmol/106 cells for 3TC-TP and 0.8-8000 fmol/106 cells for CBV-TP. Accuracy and precision were less than 15% for all quality control sample (QCs), and absolute extraction recovery of were >65% for 3TC-TP and >90% for CBV-TP. The method was optimized to ensure stability of TP samples and standards during sample collection, preparation, analysis, and storage conditions. This method has enhanced sensitivity and requires smaller amounts of blood and tissue samples compared to previous LC-MS/MS methods for 3TC- and CBV-TP quantification. The developed method was successfully applied to characterize the pharmacokinetic profile of TP metabolites in mouse peripheral blood mononuclear cells (PBMCs), spleen, lymph nodes, and liver cells. In addition, another direct, simple, and high-throughput method for the quantification of TP standards was developed and used for the analysis of stability samples. PMID- 29518645 TI - Validation of an LC-ESI-MS/MS method for the determination of apalutamide, a novel non-steroidal anti-androgen in mice plasma and its application to a pharmacokinetic study in mice. AB - A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of apalutamide in mice plasma using apalutamide-d3 as an internal standard (I.S.). Sample preparation was accomplished through a simple protein precipitation process. Chromatography of apalutamide and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (20:80, v/v) delivered at a flow rate of 0.8 mL/min. LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique in positive ion mode and the transitions of m/z 478 -> 450 and m/z 481 > 453 were used to measure the derivative of apalutamide and the I.S, respectively. The total chromatographic run time was 2.5 min and the elution of apalutamide and I.S. occurred at 1.10 and 1.09 min, respectively. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. Linearity was established in the concentration range of 1.02 2030 ng/mL (r > 0.995) for apalutamide. The intra- and inter-day accuracy and precision for apalutamide in mice plasma were in the range of 2.11-8.44 and 2.51 6.09%, respectively. Apalutamide was found to be stable under various stability conditions. This novel method has been applied to a pharmacokinetic study in mice. PMID- 29518646 TI - Effect of delay in cord clamping 45 versus 60 s on very preterm singleton infants. AB - BACKGROUND: In the range of timing suggested by American College of Obstetricians and Gynecologists 30 to 60 s, preterm infants may potentially derive more short and long-term benefits with delayed cord clamping (DCC) for at least 60 s. However, there are concerns with longer resuscitation delay in this vulnerable population. OBJECTIVE: To compare the clinical consequences of 45 versus 60 s delay in umbilical cord clamping in singleton infants born between 230/7 to 316/7 weeks gestation. STUDY DESIGN: We implemented DCC process in very preterm singleton infants, initially for 45 s and later, modified the policy to increase the delay to 60 s. We compared the infants born and received DCC (n = 60) during the 45 s study period (DCC-45 cohort), from Aug.19, 2013, to Aug.18, 2014 to the infants born and received DCC (n = 63) during the 60 s study period (DCC-60 cohort), from Feb.1, 2015, to Jan.31, 2016. RESULTS: The incidence of necrotizing enterocolitis in DCC-60 cohort was 0% compared to 8% in the DCC-45 cohort (P = 0.02). Similarly, incidence of culture-positive sepsis was significantly lower in the DCC-60 cohort compared to DCC-45 cohort (8% versus 18%; P = 0.04). Incidence of mortality and other major morbidities were similar between both groups. Length of stay was significantly lower in DCC-60 cohort compared to DCC-45 cohort. CONCLUSION: DCC for 60 s in very preterm singleton infants was safe, feasible and not associated with any adverse maternal or neonatal short-term outcomes compared to DCC for 45 s. PMID- 29518647 TI - Vitamin D deficiency and respiratory morbidity among African American very low birth weight infants. AB - BACKGROUND: Very low birth weight infants (VLBWI) have unexplained variation in respiratory morbidity, including respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). We examined a potential association to serum 25 hydroxyvitamin D (s-25OHD) on day one. STUDY DESIGN: Prospective, observational study on 89 VLBWI (<=1250 g). S-25OHD (day one and 21) and respiratory severity score (RSS) (day one) were examined. Other respiratory morbidities including BPD were compared between infants with s-25OHD <= 10 ng/ml (deficient) versus >10 ng/ml (adequate). RESULTS: Eighty one neonates (91%) were African Americans. The mean (SD) birthweight was 868 (229) g, gestational age 27 (2) weeks. On day one, mean (SD) s-25OHD was 15.48 (8.31) ng/ml, with 32 (37%) being vitamin D deficient. The deficiency and adequate VLBWI groups had similar birthweight; 860 (262) vs 873 (210) g, and gestational age; 27 (2) vs 27 (2) weeks. In 78 survivors, s-25OHD rose from 15.48 (8.31) ng/ml day one to 52.36 (22.49) ng/ml day 21 after supplementation, p < 0.001. On day one, increasing RSS was inversely related to s-25OHD, trend p = 0.054. Compared to the adequate group, the deficiency group had higher RSS (5.0 +/- 2.7 vs 3.6 +/- 1.9), required surfactant therapy more frequently (91% vs 72%), and needed home oxygen therapy more often (48% vs 26%), p <= 0.05 for all. Among infants with BPD, the severity of disease was inversely related to s-25OHD, trend p < 0.09. CONCLUSION: Lower levels of s 25OHD were associated with increased severity of RDS and BPD among a cohort of mostly African American VLBWI. PMID- 29518648 TI - Polycyclic aromatic hydrocarbons in biochar amended soils: Long-term experiments in Brazilian tropical areas. AB - The interest in charcoal for agricultural use (biochar) has sharply increased in recent years. However, biochar can contain groups of compounds such as polycyclic aromatic hydrocarbons (PAHs) that are considered persistent pollutants, and are formed concomitantly with biochar during its production by pyrolysis. Soil samples were collected in three experimental areas at different intervals (1, 3, 5 or 6 years) after the application of 16 Mg ha-1 of biochar. The total concentrations of PAHs; benzo[a]pyrene; and the estimated total cancer risk in biochar treated plots were larger than found in the control ones, but they decreased over time, equaling the control values after three years in the high C content soil (11.2 g C kg-1 soil), or after six years in the low C content soil (6.8 g C kg-1 soil). Nevertheless, the sum of PAH concentrations found in the biochar amended plots, in the range of 15.80-39.40 ng g-1, were around two orders of magnitude below the limits of prevention established by Brazilian legislation (8100 ng g-1) and some European regulations for soils (3000 ng g-1) and also lower than the observed in previous studies about biochar amended soils. Our results indicate that, under the conditions evaluated, the application of biochar to soil in the studied proportion (16 Mg ha-1, every six years) is safe concerning soil contamination by PAHs. PMID- 29518649 TI - 1H-nuclear magnetic resonance metabolomics revealing the intrinsic relationships between neurochemical alterations and neurobehavioral and neuropathological abnormalities in rats exposed to tris(2-chloroethyl)phosphate. AB - Tris(2-chloroethyl)phosphate (TCEP) is a widely used environmental organic pollutant. Studies have revealed the presence of both TCEP and its metabolites in environmental media. The neurotoxicity of TCEP has been investigated in vitro but rarely in mammals. This study aimed to determine the neurotoxic effects of TCEP on rats and to explore the possible intrinsic relationships between neurochemical alterations and the neurotoxic effects. For this, 6-week-old female SD rats were administered 50, 100, or 250 mg/kg/d TCEP daily by oral gavage for 60 days. TCEP exposure produced neurotoxicity in the female SD rats. The Morris water maze results revealed a dose-dependent decline in spatial learning and memory functions of exposed rats. In addition, pathological examination of the brain showed apoptotic and necrotic lesions in the CA1 field pyramidal cells of the hippocampus; further, rats treated with the highest TCEP dose showed inflammatory cells and calcified/ossified foci in the cortex areas. Furthermore, 1H-nuclear magnetic resonance metabolomics results revealed that TCEP exposure interfered with normal biological processes, including amino acid and neurotransmitter metabolism, energy metabolism, and cell membrane function integrity by changing the concentrations of glutamate, gamma-aminobutyric acid, N-acetyl-d-aspartate, creatine, and lactic acid metabolites in the brain of treated rats. However, the changes in the concentrations of taurine, myo-inositol, creatine, and choline metabolites, which are associated with antioxidant physiological processes, might be a neuroprotective mechanism to prevent the neurotoxicity induced by TCEP. Thus, metabolomics combined with neuropathology and neurobehavioral analyses provided critical insights to investigate the TCEP-induced neurotoxic effects and mechanisms. PMID- 29518650 TI - Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target. AB - The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK). Cytosolic enzyme PanK, was selected for further biochemical, genetic, and phylogenetic characterization. Since E. histolytica PanK (EhPanK) is physiologically important and sufficiently divergent from its human orthologs, this enzyme represents an attractive target for the development of novel anti amebic chemotherapies. Epigenetic gene silencing of PanK resulted in a significant reduction of PanK activity, intracellular CoA concentrations, and growth retardation in vitro, reinforcing the importance of this gene in E. histolytica. Furthermore, we screened the Kitasato Natural Products Library for inhibitors of recombinant EhPanK, and identified 14 such compounds. One compound demonstrated moderate inhibition of PanK activity and cell growth at a low concentration, as well as differential toxicity towards E. histolytica and human cells. PMID- 29518651 TI - The relative associations of shape and weight over-evaluation, preoccupation, dissatisfaction, and fear of weight gain with measures of psychopathology: An extension study in individuals with anorexia nervosa. AB - Recent research has demonstrated that certain components of body image (i.e., shape and weight over-evaluation, preoccupation, and dissatisfaction) in secondary school students shared a distinct clinical significance because of their differential relation to measures of psychopathology. The present study aimed to replicate and extend on these findings by examining the distinctiveness of these body image constructs, in addition to a fear of weight gain, in individuals with anorexia nervosa (AN)-a disorder this is facilitated and maintained by extreme body image concerns. Treatment-seeking females with AN (n = 124) completed a questionnaire battery that measured these constructs. Findings demonstrated that once any shared variance between body image components was removed in regression analyses, fear of weight gain was the only unique predictor of eating disorder psychopathology (e.g., dietary restraint and compulsive exercise), while over-evaluation and preoccupation were the only unique predictors of general psychopathology (e.g., depressive and anxiety symptoms). Overall, these findings demonstrate certain components of body image may operate differently in AN, and reinforce previous calls to consider and assess for distinct facets of body image in this population. PMID- 29518652 TI - Subarachnoid hemorrhage in a Japanese cocaine abuser: Cocaine-related sudden death. AB - Based on a prospective case-control study of forensic autopsies, the causes of cocaine (COC)-related sudden death (SD) are cardiovascular events in 62.0% of cases, cerebrovascular events in 14.0%, and others. A forensic autopsy of a male in his early forties revealed subarachnoid hemorrhage (SAH) at the base of the brain. A cerebral arterial aneurysm was not detected even though hemorrhage was clearly observed in the anterior cerebral artery (ACA) bifurcation area. The brain weighed 1488 g and was edematous. We histopathologically examined the left ACA, right-ACA, and anterior communicating artery (Acom). Thickening of the internal vessel wall was observed as a pathological change. The internal elastic lamina of the right-ACA, near the peripheral part of Acom, was meandered with a jagged appearance. A toxicology examination detected COC and its metabolites, particularly benzoylecgonin, in blood and urine samples. Therefore, the present case was regarded as a non-fatal intoxication case, but also a COC-related death. Ethanol was also detected, indicating that COC was taken in combination with alcohol. The cause of COC-related death in the present case was SAH. COC use is known to induce aneurysmal SAH; however, whether an aneurysm had formed in the present case was unclear. Meander, extension, and degeneration of the internal elastic lamina of the right-ACA were observed near the bifurcation from the Acom. This area corresponded macroscopically with that considered to be the bleeding point from the blood vessel. Therefore, the present case was diagnosed as COC related SD. PMID- 29518653 TI - Liquid chromatography-tandem mass spectrometry detection of benzalkonium chloride (BZK) in a forensic autopsy case with survival for 18 days post BZK ingestion. AB - We report a forensic autopsy case of an elderly man who ingested unknown amount of germicidal disinfectant containing 50% benzalkonium chloride (BZK). He survived for 18 days after BZK ingestion and then died because of pneumonia. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to detect three BZK compounds (C12-BZK, C14-BZK and C16-BZK) in the blood. Extraction of BZK was carried out according to a modified QuEChERS method. Chromatographic separation was achieved on an ODS column and detection was performed in selected reaction monitoring mode. The accuracy and the precision were acceptable for quantitative analysis in the concentration range of 10-200 ng/mL for the three BZK compounds. BZK was detected in heart and femoral vein blood samples even 18 days after BZK ingestion. Taking into consideration clinical information during 18 days hospitalization and the autopsy findings, the cause of death was attributed to BZK poisoning. Several toxico-kinetic factors regarding absorption and excretion of BZK in the body were also discussed to elucidate the detection of BZK such a long time after ingestion. PMID- 29518654 TI - Phenol removal performance and microbial community shift during pH shock in a moving bed biofilm reactor (MBBR). AB - A moving bed biofilm reactor (MBBR) effectively removes pollutants and even runs under extreme conditions. However, the pH shock resistance of a biofilm in MBBRs has been rarely reported. In this study, simulated phenol wastewater with acidic shock (pH 7.5-3.0) was used. In the pH shock phase, the phenol and COD removal efficiencies initially decreased and gradually increased to more than 90%. Microscopic studies showed that the superficial biofilm was mainly composed of fungi (yeasts) in the acidic pH shock phase. The microbial community composition in the acidic pH shock phase was significantly different from those in other phases. Firmicutes and Ascomycota were the dominant bacterial and fungal phyla in this stage, respectively. 16S rRNA gene-based functional annotation indicated that functional profiles related to aromatic compound degradation existed in all of the stages. Therefore, MBBRs show potential for the treatment of phenolic wastewater exposed to pH shock. PMID- 29518655 TI - Label-free optical biosensor for real-time monitoring the cytotoxicity of xenobiotics: A proof of principle study on glyphosate. AB - Rapid and inexpensive biosensor technologies allowing real-time analysis of biomolecular and cellular events have become the basis of next-generation cell based screening techniques. Our work opens up novel opportunities in the application of the high-throughput label-free Epic BenchTop optical biosensor in cell toxicity studies. The Epic technology records integrated cellular responses about changes in cell morphology and dynamic mass redistribution of cellular contents at the 100-150 nm layer above the sensor surface. The aim of the present study was to apply this novel technology to identify the effect of the herbicide Roundup Classic, its co-formulant polyethoxylated tallow amine (POEA), and its active ingredient glyphosate, on MC3T3-E1 cells adhered on the biosensor surface. The half maximal inhibitory concentrations of Roundup Classic, POEA and glyphosate upon 1 h of exposure were found to be 0.024%, 0.021% and 0.163% in serum-containing medium and 0.028%, 0.019% and 0.538% in serum-free conditions, respectively (at concentrations equivalent to the diluted Roundup solution). These results showed a good correlation with parallel end-point assays, demonstrating the outstanding utility of the Epic technique in cytotoxicity screening, allowing not only high-throughput, real-time detection, but also reduced assay run time and cytotoxicity assessment at end-points far before cell death would occur. PMID- 29518656 TI - Copper-induced activation of TRP channels promotes extracellular calcium entry and activation of CaMK, PKA, PKC, PKG and CBLPK leading to increased expression of antioxidant enzymes in Ectocarpus siliculosus. AB - The existence of functional Transient Receptor Potential (TRP) channels was analyzed in Ectocarpus siliculosus using agonists of human TRPs and specific antagonists of TRPA1, TRPC5, TRPM8 and TRPV; intracellular calcium was detected for 60 min. Increases in intracellular calcium were observed at 13, 29, 39 and 50 52 min, which appeared to be mediated by the activation of TRPM8/V1 at 13 min, TRPV1 at 29 min, TRPA1/V1 at 39 min and TRPA1/C5 at 50-52 min. In addition, intracellular calcium increases appear to be due to extracellular calcium entry, not requiring protein kinase activation. On the other hand, 2.5 MUM copper exposure induced increased intracellular calcium at 13, 29, 39 and 51 min, likely due to the activation of a TRPA1/V1 at 13 min, TRPA1/C5/M8 at 29 min, TRPC5/M8 at 39 min, and a TRPC5/V1 at 51 min. The increases in intracellular calcium induced by copper were due to extracellular calcium entry and required protein kinase activation. Furthermore, from 3 to 24 h, copper exposure induced an increase in the level of transcripts encoding antioxidant enzymes such as superoxide dismutase, ascorbate peroxidase, glutathione reductase and peroxiredoxin. The described upregulation decreased with inhibitors of CaMK, PKA, PKC, PKG and CBLPK, as well as with a mixture of TRP inhibitors. Thus, copper induces the activation of TRP channels allowing extracellular calcium entry as well as the activation of CaMK, PKA, PKC, PKG and CBLPK leading to increased expression of genes encoding antioxidant enzymes in E. siliculosus. PMID- 29518657 TI - Magnesium and organic biostimulant integrative application induces physiological and biochemical changes in sunflower plants and its harvested progeny on sandy soil. AB - Magnesium (Mg) often leaches down in sandy soils due to high mobility and its foliar application proves to be beneficial. Organic biostimulants also prove to be helpful to affect plant physio-biochemistry and antioxidative defense system. The present study evaluated the beneficial effects of seed soaking in maize grain extract (MGE; 3%) in integration with or without foliar Mg (1 mM) in comparison to control (no treatment) on growth, yield performance, seed oil and fatty acid profile including physiological and biochemical basis of Hysun-336 sunflower hybrid grown on a sandy soil under greenhouse conditions. The integrative treatment (seed soaking in MGE + foliar spray with Mg) elevated growth traits, plant water status and membrane stability index, and reduced electrolyte leakage. Improved leaf contents of chlorophylls, carotenoids, total soluble sugars and proline, activities of non-enzymatic and enzymatic antioxidants were also observed. In addition, enhanced uptake of N, P, K including Mg and endogenous levels of plant hormones IAA, GA3 and zeatin were recorded with the integrative treatment. Seed yield and oil contents including oleic (mono-unsaturated) and linoleic (poly-unsaturated) fatty acids also increased; however, a decrease in other saturated, mono-unsaturated and poly-unsaturated fatty acids was noticed. Improved seed and seedling vigor traits were also observed in progeny of sunflower that harvested from the integrative treatment. In summary, improved plant performance by the integrative treatment may be attributed to improved activities of antioxidants contributing to improved plant water content, nutrient uptake and endogenous hormonal levels in sunflower plants grown under sandy soil conditions. PMID- 29518659 TI - The impacts of land reclamation on the accumulation of key elements in wetland ecosystems in the Sanjiang Plain, northeast China. AB - The Sanjiang Plain, which is located in northeastern China, given the distribution of temperate freshwater wetlands there and this region has considerable significance in ensuring food security in China. Two periods of farmland reclamation that occurred during the last 100 years led to the loss of nearly 80% of the area of the native wetlands, and the development of agriculture has also increased the potential environmental risks to the residual wetlands. To evaluate the effects of farmland reclamation on the accumulation of key elements within the residual wetland ecosystems, six wetland profiles in the Sanjiang Plain are selected in this study. Using age-depth models and the concentrations of key elements, the historical accumulation rates (ARs) of carbon (C), nutrient elements (N and P) and potentially toxic elements (Hg, As, Pb, Cu, and Zn) over the last 150 years are reconstructed. The results show that the ARs of the potentially toxic elements in two of the wetland profiles begin to increase during the first reclamation period (AD 1900-1930). The ARs of both of the key elements clearly increase in all of the wetland profiles during the second reclamation period (AD 1950-1980). After land reclamation had ceased, increases in population and the development of industry became major factors that caused the potential environmental risks to wetlands to continue to increase from AD 1980 to the present. During the last 100 years, reclamation has increased the potential environmental risks and has led to the storage of additional carbon in the residual wetlands of the Sanjiang Plain. PMID- 29518658 TI - In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion. AB - The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor alpha, glucocorticoid receptor or peroxisome proliferator-activated receptor gamma. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets. PMID- 29518660 TI - Accumulation of flame retardants in paired eggs and plasma of bald eagles. AB - In this study, we measured the concentrations of 58 flame retardants (and related compounds) in bald eagle (Haliaeetus leucocephalus) egg and plasma samples from the Michigan. These analytes include polybrominated diphenyl ethers (PBDEs), novel flame retardants (nFRs), Dechlorane-related compounds (Decs), and organophosphate esters (OPEs). A total of 24 paired eaglet plasma and egg samples were collected from inland (IN, N = 13) and the Great Lakes (GL, N = 11) breeding areas from 2000 to 2012. PBDEs were the most abundant chemical group with a geometric mean of 181 ng/g wet weight (ww) in egg and 5.31 ng/g ww in plasma. Decs were barely found in plasma samples, but they were frequently found in eggs (geometric mean 23.5 ng/g ww). OPE levels were comparable to those of PBDEs in the plasma but lower than those of PBDEs in eggs. Dec and PBDE concentrations were significantly higher in GL than in IN (p < 0.05). The ratio of egg to plasma concentrations (lipid normalized) varied with chemicals and correlated with the chemical's octanol-water partition coefficient. The lipid normalized bald eagle egg and plasma concentrations from Lake Superior and Huron were one to three orders of magnitude higher than concentrations measured in composite lake trout (Salvelinus namaycush) from the same lake, implying that they biomagnify in the environment. PMID- 29518661 TI - Environmental and public health related risk of veterinary zinc in pig production - Using Denmark as an example. AB - At great economic cost, important steps have been taken over the last many decades to reduce and control emissions of heavy metals in order to protect the environment and public health. Monitoring has confirmed the success of these policies with progressive declines of heavy metals in for example air, sewage sludge and environmental samples. For zinc, such improvements may nevertheless be counter-acted by its widely usage as a feed additive and veterinary medicinal product to piglets in the post-weaning period resulting in reduced occurrence of diarrhea and improvement of daily weight gain. This review therefore focuses on two major concerns associated with veterinary use of zinc, namely the quantifiable risks to the environment and promotion of (multi) resistant bacteria like LA-MRSA in pig farms. Denmark is used as an informed and realistic worst case scenario, representing the largest pig production per capita in Europe. It is furthermore, one of the countries where most recent information can be found regarding soil monitoring data and zinc consumption within the pig production. An average increase in soil concentration by >45% was recently reported within the period 1998-2014. In order to predict future risk, this review presents new and simplified model predictions using current soil concentrations, annual load rates and predicted accumulation rates. In conclusion, it is estimated that within 25 years, continued agricultural practice of current zinc loads may result in a situation where almost all soils receiving manure from intensive piglet production may be at risk, but also other pig production types may result in scenarios with predicted risk to soil dwelling species, especially in sandy soils. Besides the quantifiable risks to soil ecosystems, high levels of zinc furthermore co-select for the persistence of LA-MRSA CC398 and other resistant bacteria on pig farms. PMID- 29518662 TI - Road traffic noise, air pollution and incident cardiovascular disease: A joint analysis of the HUNT, EPIC-Oxford and UK Biobank cohorts. AB - BACKGROUND: This study aimed to investigate the effects of long-term exposure to road traffic noise and air pollution on incident cardiovascular disease (CVD) in three large cohorts: HUNT, EPIC-Oxford and UK Biobank. METHODS: In pooled complete-case sample of the three cohorts from Norway and the United Kingdom (N = 355,732), 21,081 incident all CVD cases including 5259 ischemic heart disease (IHD) and 2871 cerebrovascular cases were ascertained between baseline (1993 2010) and end of follow-up (2008-2013) through medical record linkage. Annual mean 24-hour weighted road traffic noise (Lden) and air pollution (particulate matter with aerodynamic diameter <= 10 MUm [PM10], <=2.5 MUm [PM2.5] and nitrogen dioxide [NO2]) exposure at baseline address was modelled using a simplified version of the Common Noise Assessment Methods in Europe (CNOSSOS-EU) and European-wide Land Use Regression models. Individual-level covariate data were harmonised and physically pooled across the three cohorts. Analysis was via Cox proportional hazard model with mutual adjustments for both noise and air pollution and potential confounders. RESULTS: No significant associations were found between annual mean Lden and incident CVD, IHD or cerebrovascular disease in the overall population except that the association with incident IHD was significant among current-smokers. In the fully adjusted models including adjustment for Lden, an interquartile range (IQR) higher PM10 (4.1 MUg/m3) or PM2.5 (1.4 MUg/m3) was associated with a 5.8% (95%CI: 2.5%-9.3%) and 3.7% (95%CI: 0.2%-7.4%) higher risk for all incident CVD respectively. No significant associations were found between NO2 and any of the CVD outcomes. CONCLUSIONS: We found suggestive evidence of a possible association between road traffic noise and incident IHD, consistent with current literature. Long-term particulate air pollution exposure, even at concentrations below current European air quality standards, was significantly associated with incident CVD. PMID- 29518663 TI - Aerosol exposure and risk assessment for green jobs involved in biomethanization. AB - Anaerobic digestion is a consolidated biotechnology able to produce renewable energy from biomasses. In the European countries, quick growth of biogas production from different organic matrices including wastes has been observed. In relation to the characteristics and quantity of the anaerobic digestion of feedstock, there are different technologies, advantages and criticisms. An accurate occupational risk assessment and development of management tools for green jobs involved in the anaerobic digestion plants are due. The aim of this work is to assess the aerosol exposure for such workers, focusing on the bioaerosol risk. Full scale plants for the treatment of organic municipal waste, waste water treatment sludge, agro zootechnical and food producing byproducts were involved for this purpose. The bioaerosol levels were monitored during activities through culturing and biomolecular methods; moreover, the sub fractionated PM10 and carried endotoxins were measured in different plant areas. Global microbial contamination is higher (>5000 UFC/m3) in the area where organic wastes are handled and pretreated, both for organic municipal waste plants - with a bacterial prevalence - and agro zootechnical plants - with a fungi prevalence. Moreover, the microbial contamination is higher where organic municipal waste is present in respect to other biomasses (ANOVA p < 0.01). Numerous pathogens are carried by the aerosol. HAdV-4 presence is lower than LOQ (50 gene copies/m3) in all the samples. Environmental PM10 reached the 280 MUg/m3 level including PM3 for 78%. Endotoxin pollution overtakes the 90 EU/m3 limit sporadically. Personal PM4.5 reached 10 mg/m3 only for maintenance technicians in the pretreatment area for organic municipal waste. The risk can be evaluated under a quantitative and qualitative point of view highlighting risk management improvement for anaerobic digestion plants. PMID- 29518664 TI - Adolescents' understanding and use of nicotine in e-cigarettes. AB - INTRODUCTION: Nicotine harms adolescent brain development and contributes to addiction. Some adolescents report using nicotine-free e-cigarettes, but the accuracy of their reporting is unclear. We explored adolescents' use of nicotine free e-cigarettes and understanding of chemicals in e-cigarettes, including nicotine. METHODS: Using social media, we recruited 1589 US adolescents (aged 15 17) who reported past 30-day use of e-cigarettes in 2016. We assessed perceptions of the nicotine source in e-liquid and whether e-cigarette aerosol is just "water vapor." We explored differences among adolescents who usually used e-cigarettes with nicotine (n = 473) and without nicotine (n = 452). We used weights to calibrate our sample to the Youth Risk Behavior Survey. RESULTS: Twenty-nine percent usually used e-cigarettes without nicotine, 28% with nicotine, 39% with "both," and 5% were "not sure." Few participants (17% of non-nicotine users vs. 34% of nicotine users, p < .001) understood the nicotine was derived from tobacco. Youth who thought e-cigarette aerosol was just water vapor were more likely to usually use without nicotine. Older adolescents and current tobacco users were less likely to usually use without nicotine. CONCLUSIONS: The adolescents who reported usually using e-cigarettes without nicotine had poorer knowledge of e-cigarettes. This lack of understanding could contribute to inaccurate reporting of nicotine use. Most youth thought the nicotine in e cigarettes was artificial, potentially indicating a belief that this nicotine is "safer." The US Food & Drug Administration will require nicotine warnings on e cigarettes in 2018; a complementary educational campaign could address youths' misperceptions about nicotine and other chemicals in e-cigarette aerosol. PMID- 29518665 TI - Sharp liver excision under hepatic vascular exclusion in case of liver transplant for large polycystic disease. Case report of a new surgical technique. AB - INTRODUCTION: Polycystic liver disease is observed in 75-90% of patients with autosomal dominant polycystic kidney disease (ADPKD). ADPKD has a high prevalence of 1/1000. Hepatomegaly severely reduces quality of life and liver transplantation seems to be method of choice for many patients. Because of the rarity of this disease and the small number of symptomatic patients with massive hepatomegaly indicated for the transplantation, there is no standard approach for explantation of the liver. CASE PRESENTATION: In our case, 57-year-old woman with massive hepatomegaly was treated with simultaneous split liver and kidney transplantation with bilateral nephrectomy. DISCUSSION: For the native liver excision we used unique surgical approach - sharp liver transection under hepatic vascular exclusion. Because we experienced some cases with massive bleeding during the polycystic liver explantation, we decided to change the surgical approach. The technique offers limited blood loss and comfortable operation field exposure. CONCLUSION: The giant polycystic liver could safely be explanted only using sharp transection hepatectomy under hepatic vascular exclusion. There is significant difference between blood loss in patients treated with or without hepatic vascular exclusion. PMID- 29518666 TI - Catastrophic intraoperative bleeding due to congenital extrahepatic porto systemic shunt anomaly: A surgical case report of two rare anomalies. AB - INTRODUCTION: Abernethy malformations are extremely rare congenital anomalous portosystemic shunts. We report the case of a patient with a rare variant Abernethy malformation between the superior mesenteric vein and left renal vein, associated with a massive jejunal diverticulum. PRESENTATION OF CASE: A 37-year old Caucasian female presented to our emergency department with severe abdominal pain and proceeded to laparotomy for a presumed small bowel obstruction. At laparotomy she was found to have a massive diverticulum at the duodeno-jejunal junction, which was intimately associated with a venous malformation and the anomalous portosystemic shunt. Whilst mobilising the diverticulum, the patient developed catastrophic haemorrhage from the malformation. The patient underwent a complicated post-operative course however was eventually stabilised. DISCUSSION: We discuss the anatomy and pathophysiology of anomalous portosystemic shunts and propose an embryological origin for our patients' anomalies. CONCLUSION: Abernethy malformations are rare however may be associated with other intra abdominal pathology and extreme caution is required when operating on these patients. PMID- 29518667 TI - Ultrasound guided low thoracic erector spinae plane block for postoperative analgesia in radical retropubic prostatectomy, a new indication. PMID- 29518668 TI - Advanced practice nurses leading the way: Interprofessional collaboration. AB - Healthcare delivery has become increasingly complex and fragmented. Leading healthcare organizations, such as the Institute of Medicine and the World Health Organization, have recognized that interprofessional collaboration is essential to improve healthcare delivery. The process of integrating interprofessional collaboration is complex and involves overcoming historical hierarchical factors and professional boundaries. The integration of interprofessional education in healthcare professions can help to alleviate these barriers. Furthermore, the inclusion of transformational leadership competencies in nursing education will help to prepare future nurses for leadership roles in collaborative practice. Nursing leaders must be prepared with foundational transformational leadership competencies in order to meet the challenges of leading collaboratively with other professions. The purpose of this manuscript is to explore the concept of interprofessional collaboration, its benefits, historical challenges, and barriers. In addition, interprofessional education and the role of nursing leadership in the implementation of interprofessional collaboration in healthcare practice are explored. PMID- 29518669 TI - Taking a step back: Self-distancing dynamics in adolescent writing about peer problems. AB - Can the retelling of an unpleasant experience help adolescents cope with that experience? This study answers that question by looking at the role of psychological self-distancing when adolescents write about recently untold stressful events with peers using either a traditional expressive writing (EW) intervention or a cognitively oriented expressive writing (CEW) intervention. Extent of self-distancing (i.e., low and high) as well as its variability (i.e., increasing or stable) were taken into account. Data, obtained from 292 written essays from 78 Italian adolescents (mean age was 12.9; 50% was female), were collected longitudinally on four occasions. Group-based trajectory modeling determined the extent and variability in self-distancing for the two writing interventions (i.e., EW and CEW) and two baseline peer problem conditions (i.e., low and high). Findings indicate that, for adolescents who experience high peer problems at baseline, CEW intervention fosters meaning-making through self distancing, resulting in being more beneficial than traditional EW. PMID- 29518670 TI - The relationship between semantic access and introspective awareness. AB - There have long been speculations about the relationship between consciousness and language. This study aimed to determine whether an individual's level of introspective awareness, based on self-report, relates to accessibility of their semantic system as evaluated by the N400. Thirty-five university students completed the study. All were right-handed, with normal or corrected-to-normal vision, without known neurological or psychological health issues. They first performed on a lexical decision task while their brain electrophysiological responses were recorded. Then, they provided assessment ratings about their levels of introspective awareness. Analysis revealed moderate to strong correlations (Pearson's rs = 0.49-0.62) between awareness self-ratings and ease of semantic access as indexed by the N400. Correlation between the self-report measure and the objective neurophysiological measure suggests that subjective assessment of awareness may deserve more credibility, which in addition to reflecting subjective perception and evaluation about one's own higher order mental functioning, may also interact with the neurophysiological processes contributive and subject to such awareness. Implications for future research on the role of semantic network in the mechanism of introspective awareness are discussed. PMID- 29518671 TI - Impact of group-singing on older adult health in senior living communities: A pilot study. AB - PURPOSE: Participating in a group-singing program may be beneficial to healthy aging through engaging in active music-making activities and breathing exercises. The purpose of this study was to assess the feasibility, acceptability, and impact of a 12-week group singing program on cognitive function, lung health and quality of life (QoL) of older adults. MATERIALS AND METHODS: A pre and post-test quasi-experimental design evaluated the impact of a group-singing program on older adult health. The intervention consisted of pre-singing exercises, song singing and learning, and socialization. Classes were 75 min/week for 12 weeks. Inclusion criteria were age >=60, no self-reported diagnosis of dementia, and able to hear conversations within 2 feet. Participants were recruited from 3 senior living communities. Outcome measures included cognition, lung function, QoL, and program feasibility and acceptability. A paired t-test with 2-sided alpha level at 0.05 was used to test the null hypotheses. RESULTS: We enrolled 49 participants (mean age 83.6). Forty-two (86%) completed the posttests and exit survey. At the 12th week there was significant improvement in phonological (p < 0.0001) and animal (p = 0.0004) semantic Verbal Fluency Tests, immediate Word Recall Test (p < 0.0001), Maximum Inspiratory Pressure (p = 0.0001), Maximum Expiratory Pressure (p < 0.0001), and in-session oxygen saturation (p = 0.03). Program satisfaction was rated, on average, 9 on a 10-point scale. CONCLUSION: A group-singing program with deep breathing training and song-learning may promote memory, language, speech information processing, executive function, and respiratory muscle strength in older adults. The program was feasible and well accepted. A clinical trial with a larger sample is indicated. PMID- 29518672 TI - Periodontal disease severity in subjects with dementia: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Despite clinical trials and reviews attempt to assess a possible relationship between dementia and periodontal disease, no meta-analysis has been performed and this issue remains undetermined. The aim of this study is to conduct a systematic review and meta-analysis to assess severity of periodontitis in subjects with dementia. METHODS: The search was conducted in Pubmed, Embase/MEDLINE. Two independent reviewers extracted data and assessed the risk bias (Newcastle-Ottawa scale). Meta-analyses were performed using the means of probing depth (PD) and clinical attachment loss (CAL) in patients with or without dementia. The mean difference were analyzed (P <= 0.05). RESULTS: Fourteen studies were included in the systematic review. In the qualitative analysis, most studies reported higher prevalence of periodontal disease in dementia patients. The studies had low risk of bias and two meta-analyses were performed for each parameter, including or not a cross-sectional study. The meta analyses including the cross-sectional study demonstrated significant association between dementia and periodontal disease (mean difference: PD = 1.41; CAL = 1.40, P < 0.05), however, it wasn't confirmed when the cross-sectional study was removed (1.25 mm, P < 0.22) and CAL (1.20 mm, P < 0.22). CONCLUSION: Although the qualitative analysis have suggested worse periodontal conditions in dementia patients, due to different study types and the high heterogeneity among them, the meta-analysis does not support the association between dementia and severity of periodontal disease. PMID- 29518674 TI - Mapping lexical-semantic networks and determining hemispheric language dominance: Do task design, sex, age, and language performance make a difference? AB - Blocked and event-related fMRI designs are both commonly used to localize language networks and determine hemispheric dominance in research and clinical settings. We compared activation profiles on a semantic monitoring task using one of the two designs in a total of 43 healthy individual to determine whether task design or subject-specific factors (i.e., age, sex, or language performance) influence activation patterns. We found high concordance between the two designs within core language regions, including the inferior frontal, posterior temporal, and basal temporal region. However, differences emerged within inferior parietal cortex. Subject-specific factors did not influence activation patterns, nor did they interact with task design. These results suggest that despite high concordance within perisylvian regions that are robust to subject-specific factors, methodological differences between blocked and event-related designs may contribute to parietal activations. These findings provide important information for researchers incorporating fMRI results into meta-analytic studies, as well as for clinicians using fMRI to guide pre-surgical planning. PMID- 29518675 TI - Multi-channel multi-scale fully convolutional network for 3D perivascular spaces segmentation in 7T MR images. AB - Accurate segmentation of perivascular spaces (PVSs) is an important step for quantitative study of PVS morphology. However, since PVSs are the thin tubular structures with relatively low contrast and also the number of PVSs is often large, it is challenging and time-consuming for manual delineation of PVSs. Although several automatic/semi-automatic methods, especially the traditional learning-based approaches, have been proposed for segmentation of 3D PVSs, their performance often depends on the hand-crafted image features, as well as sophisticated preprocessing operations prior to segmentation (e.g., specially defined regions-of-interest (ROIs)). In this paper, a novel fully convolutional neural network (FCN) with no requirement of any specified hand-crafted features and ROIs is proposed for efficient segmentation of PVSs. Particularly, the original T2-weighted 7T magnetic resonance (MR) images are first filtered via a non-local Haar-transform-based line singularity representation method to enhance the thin tubular structures. Both the original and enhanced MR images are used as multi-channel inputs to complementarily provide detailed image information and enhanced tubular structural information for the localization of PVSs. Multi-scale features are then automatically learned to characterize the spatial associations between PVSs and adjacent brain tissues. Finally, the produced PVS probability maps are recursively loaded into the network as an additional channel of inputs to provide the auxiliary contextual information for further refining the segmentation results. The proposed multi-channel multi-scale FCN has been evaluated on the 7T brain MR images scanned from 20 subjects. The experimental results show its superior performance compared with several state-of-the-art methods. PMID- 29518676 TI - Cerebrovascular network registration via an efficient attributed graph matching technique. AB - Registration of vascular networks is an indispensable element of prognostic and diagnostic studies that require structural analysis and comparison over time, among different samples, and to a gold standard. However, vascular networks manifest low spatial texture and sparse structural content so that even small variations in their location can make the intensity-based registration inefficient and prone to errors. Motivated by geometrical graph-based models developed in our prior work, we use the shape information in the graph topology sense to enhance the registration performance. An efficient feature-based registration is presented that seeks correspondence of the bifurcations and branches in a graph matching scheme. Since the graph matching is originally posed a NP-hard quadratic assignment problem (QAP) in the literature, we have designed a node signature that incorporates edge correspondences indirectly. This allows removing the quadratic term in the QAP to recast the problem as a linear assignment problem (LAP) to relieve the computational burden. The LAP is efficiently solvable and is scalable to data with graph representation of larger size. The performance is tested and validated using clinical 3-D angiography images of the human cerebrovasculature as well as synthetic datasets. This method proves to be robust in the face of different structural and algorithm's parameters. Quality of inter-subject and multimodal matching of clinical data has also been confirmed. PMID- 29518673 TI - Post-transcriptional regulation of gene expression and human disease. AB - A large number of mutations in genes that encode RNA binding proteins cause human disease. Many of these RNA binding proteins mediate key steps in post transcriptional regulation of gene expression from mRNA processing to eventual decay in the cytoplasm. Surprisingly, these RNA binding proteins, which are ubiquitously expressed and play fundamental roles in gene expression, are often altered in tissue-specific disease. Mutations linked to disease impact nearly every post-transcriptional processing step and cause diverse disease phenotypes in a variety of specific tissues. This review summarizes steps in post transcriptional regulation of gene expression that have been linked to disease providing specific examples of some of the many genes affected. Finally, recent advances that hold promise for treatment of some of these diseases are presented. PMID- 29518677 TI - Ultrasound-based prediction of pathologic response to neoadjuvant chemotherapy in breast cancer patients. AB - BACKGROUND: Accuracy in predicting pathologic response to neoadjuvant chemotherapy (NACT) in breast cancer is essential for the determination of therapeutic efficacy and surgical planning. This study aimed to assess the precision of ultrasound (US) for predicting pathologic complete response (pCR = ypT0) after NACT. METHODS: This retrospective mono-center study included 124 invasive breast cancer patients treated with NACT. Patients received US before and after NACT with documentation of clinical partial response (cPR) and clinical complete response (cCR). Post-operatively, the pathologic response was defined as absence of tumor cells (ypT0), presence of non-invasive tumor cells (ypTis) or invasive tumor cells (ypTinv). Sensitivity and specificity of US as well as false negative rate (FNR), negative predictive value (NPV) and positive predictive value (PPV) were analysed for receptor subtypes. A multivariable logistic regression model assessed the influence of patient- and tumor-associated covariates as predictors for pCR. RESULTS: 50 patients (40.3%) achieved pCR, 39 (78.0%) had a corresponding cCR. Overall sensitivity was 60.8% and specificity 78.0% for US-predicted remission. NPV and FNR differed substantially between subtypes. NPV was highest (75.0%) in triple negative (TN) subtype, while FNR was low (37.5%). Therefore, pathological response was most accurately predicted for TN cancers. NPV for human-epidermal-growth-factor-receptor-2-positive/hormone receptor-positive (HER2+/HR+) was 55.6%, for HER2+/HR- 64.3% and for HER2-/HR+ 16.7%, FNRs were 40.0%, 71.4% and 32.3%, respectively. Receptor subtypes impacted pCR significantly (p-value: 0.0033), cCR correlated positively with pCR (p-value: 0.0026). CONCLUSION: US imaging is insufficient to predict pCR with adequate accuracy. Receptor subtypes, however, affect diagnostic precision of US and pathologic outcome. PMID- 29518678 TI - Cytotoxic activity of fucoxanthin, alone and in combination with the cancer drugs imatinib and doxorubicin, in CML cell lines. AB - In the present study, we evaluate the in vitro cytotoxicity of fucoxanthin (Fx) on two human leukemia cell lines, K562 and TK6, alone and in combination with the conventional anticancer drugs imatinib (Imat) and doxorubicin (Dox). For the purpose, we assessed the cytotoxic and proliferation effects by cell count, induction of DNA damage by comet assay, and cell death by nuclear condensation, annexin V staining, coupled with propidium iodide uptake, and protein expression of Bax, caspase-3, and Bcl-2 (western blot). Our results show that Imat increased cytotoxicity in TK6 cells and inhibited proliferation in K562 cells, while Dox decreased cell viability and proliferation in both cell lines. Fx per se increased cytotoxicity against K562 cells and decreased cell proliferation of K562 and TK6 cells. The effects were confirmed by phase contrast microscopy. However, the antiproliferative effects are not explained by induction of DNA damage or cell death. In co-incubation, Fx increased antiproliferative effects of both drugs in the cell lines tested, however no differences where observed relative to Fx alone. This study unveiled in vitro cytotoxicity of Fx by inhibition of cell proliferation in both cell lines. Further studies are needed to elucidate the signal transduction pathways and molecular targets involved in that effect. PMID- 29518679 TI - Toxicity assessment of sediments from the Liaohe River Protected Area (China) under the influence of ammonia nitrogen, heavy metals and organic contaminants. AB - The aim of this study was to evaluate the toxicity of ammonia nitrogen, metals and organic contaminants in sediment collected from the Liaohe River Protected Areas. The TIE was applied to 16 samples. The zeolite, resin, and coconut charcoal were used to mask toxicity of the three kinds of pollutants, respectively. Then quantitative analyses together with a battery of bioassays were performed to evaluate toxic effects. At last, the spiking tests were used to confirm the major contributors to toxicity. The results of toxicity identification showed the ammonia nitrogen, gamma-HCHs, As and Cd may cause toxic hazards to benthic organisms. The significant correlation between the survival and volume ratio of the sediment and overlying water confirmed ammonia nitrogen and Cd were the major toxic pollutants that cause the biological toxicity. We confirmed bioassays combined with masking agent, spiking tests and quantitative analyses were suitable tools for detecting toxicity. PMID- 29518680 TI - New spectrophotometric/chemometric assisted methods for the simultaneous determination of imatinib, gemifloxacin, nalbuphine and naproxen in pharmaceutical formulations and human urine. AB - In this paper, novel univariate and multivariate regression methods along with model-updating technique were developed and validated for the simultaneous determination of quaternary mixture of imatinib (IMB), gemifloxacin (GMI), nalbuphine (NLP) and naproxen (NAP). The univariate method is extended derivative ratio (EDR) which depends on measuring every drug in the quaternary mixture by using a ternary mixture of the other three drugs as divisor. Peak amplitudes were measured at 294nm, 250nm, 283nm and 239nm within linear concentration ranges of 4.0-17.0, 3.0-15.0, 4.0-80.0 and 1.0-6.0MUgmL-1 for IMB, GMI, NLP and NAB, respectively. Multivariate methods adopted are partial least squares (PLS) in original and derivative mode. These models were constructed for simultaneous determination of the studied drugs in the ranges of 4.0-8.0, 3.0-11.0, 10.0-18.0 and 1.0-3.0MUgmL-1 for IMB, GMI, NLP and NAB, respectively, by using eighteen mixtures as a calibration set and seven mixtures as a validation set. The root mean square error of predication (RMSEP) were 0.09 and 0.06 for IMB, 0.14 and 0.13 for GMI, 0.07 and 0.02 for NLP and 0.64 and 0.27 for NAP by PLS in original and derivative mode, respectively. Both models were successfully applied for analysis of IMB, GMI, NLP and NAP in their dosage forms. Updated PLS in derivative mode and EDR were applied for determination of the studied drugs in spiked human urine. The obtained results were statistically compared with those obtained by the reported methods giving a conclusion that there is no significant difference regarding accuracy and precision. PMID- 29518681 TI - Experimental and theoretical elucidation of structural and antioxidant properties of vanillylmandelic acid and its carboxylate anion. AB - Vanillylmandelic acid (VMA), an important metabolite of catecholamines that is routinely screened as tumor marker, was investigated by the various spectroscopic techniques (IR, Raman, UV-Vis, antioxidant decolorization assay and NMR). Structures optimized by the employment of five common functionals (M05-2X, M06 2X, B3LYP, CAM-B3LYP, B3LYP-D3) were compared with the crystallographic data. The M05-2X functional reproduced the most reliable experimental bond lengths and angles (correlation coefficient >0.999). The importance of intramolecular hydrogen bonds for structural stability was discussed and quantified by the NBO analysis. The most prominent bands in vibrational spectrum were analyzed and compared to the experimental data. The positions of the carbon and hydrogen atoms in NMR spectra were well reproduced. The differences in UV-Vis spectrum were investigated by adding the explicit solvent and by performing NBO and QTAIM analyses. The discrepancy in the two spectra of about 50nm could be explained by the solvent effect on carboxyl group. The most probable antioxidant activity mechanism was discussed for VMA and its carboxylate anion. The Molecular Docking study with the C - reactive protein additionally proved that variety of functional groups present in VMA and its anion allowed strong hydrogen and hydrophobic interactions. PMID- 29518682 TI - A universal cue for grammatical categories in the input to children: Frequent frames. AB - How does a child map words to grammatical categories when words are not overtly marked either lexically or prosodically? Recent language acquisition theories have proposed that distributional information encoded in sequences of words or morphemes might play a central role in forming grammatical classes. To test this proposal, we analyze child-directed speech from seven typologically diverse languages to simulate maximum variation in the structures of the world's languages. We ask whether the input to children contains cues for assigning syntactic categories in frequent frames, which are frequently occurring nonadjacent sequences of words or morphemes. In accord with aggregated results from previous studies on individual languages, we find that frequent word frames do not provide a robust distributional pattern for accurately predicting grammatical categories. However, our results show that frames are extremely accurate cues cross-linguistically at the morpheme level. We theorize that the nonadjacent dependency pattern captured by frequent frames is a universal anchor point for learners on the morphological level to detect and categorize grammatical categories. Whether frames also play a role on higher linguistic levels such as words is determined by grammatical features of the individual language. PMID- 29518683 TI - Morphology control of self-deliverable nanodrug with enhanced anticancer efficiency. AB - The morphology of nanomedicines has a large influence on the anticancer efficiency of therapeutic agents in biological systems. In this study, camptothecin (CPT)-based nanodrugs with helical and spherical shapes were simply built without the need of any additional carriers. Self-deliverable spherical nanodrug represented a therapeutic advantage over the helical one, which was uncovered from the in vitro toxicity assay. Confocal imaging study indicated that the better outcome of spherical nanodrug was ascribed to the faster cellular uptake. With the aid of sonication treatment, helical nanodrugs with different lengths (HD-1, HD-2, HD-3, HD-4) were created. In comparing with the longest HD 1, the drug release kinetics indicated that the shortest HD-4 exhibited a 20% elevation in cumulative drug release at the first 10 h. The internalized drug amount of HD-4 was three-fold higher than that of HD-1 after the cultivation with 4T1 cells for 2 h. These results demonstrated that the anticancer efficacy of helical nanodrugs was inversely proportional to their lengths. The strategy demonstrated here presents great promise for the preparation of nanodrugs with suitable morphology for cancer therapy. PMID- 29518684 TI - Engineering an in vitro organotypic model for studying cardiac hypertrophy. AB - Neonatal cardiomyocytes cultured on flat surfaces are commonly used as a model to study cardiac failure of diverse origin. A major drawback of such a system is that the cardiomyocytes do not exhibit alignment, organization and calcium transients, similar to the native heart. Therefore, there is a need to develop in vitro platforms that recapitulate the cellular microenvironment of the murine heart as organotypic models to study cardiovascular diseases. In this study, we report an engineered platform that mimics cardiac cell organization and function of the heart. For this purpose, microscale ridges were fabricated on silicon using ultraviolet lithography and reactive ion etching techniques. Physical characterization of the microstructures was done using scanning electron microscopy and atomic force microscopy. Cardiomyocytes grown on these micro ridges showed global parallel alignment and elliptical nuclear morphology as observed in the heart. Interestingly, calcium currents traversed the engineered cardiomyocytes in a coordinated and directional manner. Moreover, the cardiomyocytes on the engineered substrates were found to be responsive to hypertrophic stimuli, as observed by the expression of a fetal gene, atrial natriuretic peptide and increase in calcium transients upon agonist treatment. Taken together, our work demonstrates that micro-ridges can be used to obtain cardiomyocyte response in vitro, which closely resembles mammalian heart. PMID- 29518685 TI - Fundamental understanding of distracted oxygen delignification efficiency by dissolved lignin during biorefinery process of eucalyptus. AB - In this work, a fundamental understanding of oxygen delignification distracted by dissolved lignin was investigated. In the new biorefinery model of shortening kraft pulping integrated with extended oxygen delignification process, increasing content of residual lignin in the original pulp could result in enhanced delignification efficiency, higher pulp viscosity and less carbonyl groups. However, the invalid oxygen consumption by dissolved lignin could be increased with the increase of process temperature and alkali dosage. The normalized ultraviolet absorbance (divided by absorbance at 280 nm) also showed that the content of chromophoric group in dissolved lignin decreased with oxygen delignification proceeded, both of which indicated that dissolved lignin could enhance the invalid oxygen consumption. Therefore, a conclusion that replacement of the liquor at the initial phase of oxygen delignification process would balance the enhancement of delignification efficiency and invalid oxygen consumption was achieved. PMID- 29518686 TI - Minimizing cellulase inhibition of whole slurry biomass hydrolysis through the addition of carbocation scavengers during acid-catalyzed pretreatment. AB - The aim of this work was to study how to minimize cellulase inhibition of whole slurry biomass hydrolysis through addition of carbocation scavengers during acid catalyzed pretreatment. Various potential carbocation scavengers were compared and their inhibition mitigating effects towards the hydrolytic performance of cellulase enzymes was assessed. The results indicated that the addition of carbocation scavengers during the pretreatment process could not only alleviate the inhibitory effect of the phenolics on the enzymatic hydrolysis but also increase the accessibility of cellulases to the pretreated substrates. It appeared that lignin-derived compounds such as 4-hydroxybenzoic acid, vanillic acid, syringic acid could all serve as efficient scavengers to alleviate the inhibitory effect of phenolics on cellulose hydrolysis where the syringic acid showed the best mitigating effect. By combining the carbocation scavengers in the pretreatment process, an improved cellulose hydrolysis of the pretreated whole slurry could be achieved without any post detoxification step. PMID- 29518687 TI - Integrated bioethanol production from mixtures of corn and corn stover. AB - Conversion of lignocellulosic biomass, such as corn stover (CS), to ethanol has encountered issues of inhibition from degradation products, low ethanol titer and low ethanol productivity. This work integrated CS into corn ethanol process for effective conversion. CS was pretreated using either dilute alkali or dilute acid pretreatment. The pretreated CS was enzymatically hydrolyzed and then mixed with liquefied corn for ethanol fermentation. Fermentation strains, substrate mixing ratios and fed-batch strategy were investigated. The mixture of alkali pretreated CS and corn at solids loadings of 10% and 20%, respectively, resulted in 92.30 g/L ethanol. Ethanol titer was further improved to 96.43 g/L with a fed-batch strategy. The mixture of dilute acid pretreated CS and corn achieved a better performance, leading to 104.9 g/L ethanol with 80.47% ethanol yield and a productivity as high as 2.19 g/L/h. This work demonstrated effective conversion of CS and corn together to ethanol. PMID- 29518688 TI - Combined effect of inorganic salts with calcium peroxide pretreatment for kenaf core biomass and their utilization for 2,3-butanediol production. AB - This study focuses on development of calcium peroxide (CaO2) pretreatment that removes major part of lignin but retaining most of sugar components of kenaf core powder (KCP) biomass. In chemical pretreatment, usually higher loss of biomass occurs which was less during this pretreatment strategy. Supplementation of inorganic salts; manganese sulfate (MnSO4) and cobalt chloride (COCl2) in CaO2 pretreatment resulted in maximum delignification of KCP relative to individual CaO2 pretreatment. Maximum glucose yield (98%) and hydrolysis yield (80.5%) was achieved after enzymatic hydrolysis (30 FPU/g of KCP) under optimized conditions. Analytical results proved effective lignin removal and significant destruction of KCP with this pretreatment strategy. Finally, utilization of KCP enzymatic hydrolysates by developed strain Klebsiella pneumoniae KMK05 resulted in maximum 2,3-butanediol (BDO) production (10.42 g/L) and BDO titer (0.385 g/g of sugar). BDO titer achieved with KCP derived sugars were found comparable with the mixture of standard sugars which is notable. PMID- 29518689 TI - Ultrasonic pretreatment effects on the co-pyrolysis of municipal solid waste and paper sludge through orthogonal test. AB - In this study, the influences of ultrasonic pretreatment factors (frequency, power, treatment time) on blends of municipal solid waste (MSW) and paper sludge (PS) with additive (MgO) was explored, through orthogonal experiments design. The optimum operating condition wanted to be acquired. However, for the ultimate (H/C) and ash analysis after pretreatment, solid residue mass and oxygenates compounds contents in products, the influences of factors were in different results. With adding PS unceasingly, the contents of hydrocarbon compounds decreased. And the ultrasonic pretreatment had the obvious influence with high PS percentage. Longer treatment time resulted to the lower content of oxygenates compounds. After adding MgO, the residue mass reduced, which meant MgO had the catalytic action, and the oxygenates compounds content reduced only with 100 kHz, which had the sonochemical effect. PMID- 29518690 TI - Other drug use does not impact cognitive impairments in chronic ketamine users. AB - BACKGROUND: Ketamine abuse causes cognitive impairments, which negatively impact on users' abstinence, prognosis, and quality of life. RESULTS: of cognitive impairments in chronic ketamine users have been inconsistent across studies, possibly due to the small sample sizes and the confounding effects of concomitant use of other illicit drugs. This study investigated the cognitive impairment and its related factors in chronic ketamine users with a large sample size and explored the impact of another drug use on cognitive functions. METHODS: Cognitive functions, including working, verbal and visual memory and executive functions were assessed in ketamine users: 286 non-heavy other drug users and 279 heavy other drug users, and 261 healthy controls. Correlations between cognitive impairment and patterns of ketamine use were analysed. RESULTS: Verbal and visual memory were impaired, but working memory and executive functions were intact for all ketamine users. No significant cognitive differences were found between the two ketamine groups. Greater number of days of ketamine use in the past month was associated with worse visual memory performance in non-heavy other drug users. Higher dose of ketamine use was associated with worse short-term verbal memory in heavy other drug users. CONCLUSION: Verbal and visual memory are impaired in chronic ketamine users. Other drug use appears to have no impact on ketamine users' cognitive performance. PMID- 29518691 TI - The Functional Movement Screen and modified Star Excursion Balance Test as predictors of T-test agility performance in university rugby union and netball players. AB - OBJECTIVES: Agility is a functional requirement of many sports, challenging stability, and commonly cited as a mechanism of injury. The Functional Movement Screen (FMS) and modified Star Excursion Balance Test (mSEBT) have equivocally been associated with agility performance. The aim of the current study was to establish a hierarchical ordering of FMS and mSEBT elements in predicting T-test agility performance. DESIGN: Cross-sectional study design. SETTING: University. PARTICIPANTS: Thirty-two female rugby players, 31 male rugby players and 39 female netballers MAIN OUTCOME MEASURES: FMS, mSEBT, T-test performance. RESULTS: The predictive potential of composite FMS and mSEBT scores were weaker than when discrete elements were considered. FMS elements were better predictors of T-test performance in rugby players, whilst mSEBT elements better predicted performance in netballers. Hierarchical modelling highlighted the in-line lunge (ILL) as the primary FMS predictor, whereas mSEBT ordering was limb and sport dependent. CONCLUSIONS: The relationship between musculoskeletal screening tools and agility performance was sport-specific. Discrete element scores are advocated over composite scores, and hierarchical ordering of tests might highlight redundancy in screening. The prominence of the ILL in hierarchical modelling might reflect the functional demands of the T-test. Sport-specificity and limb dominance influence hierarchical ordering of musculoskeletal screens. PMID- 29518692 TI - Fluctuations of estradiol during women's menstrual cycle: Influences on reactivity towards erotic stimuli in the late positive potential. AB - BACKGROUND: While several studies examined the reactivity towards negative emotional stimuli across women's menstrual cycle, only few investigated responses to positive emotional cues in association with sexual hormones on a neural level. Therefore, the aim of the current EEG-experiment was to study the differential reactivity towards positive (erotic) words during the menstrual cycle (i.e. with fluctuations in the steroids estradiol and progesterone) in the late positive potential (LPP). Regarding reactivity towards erotic stimuli, the LPP is seen as the most relevant ERP-component, as more positive amplitudes in the LPP reflect larger incentive salience and higher arousal. The LPP towards erotic words was expected to be more pronounced during fertile phases of the menstrual cycle (around ovulation). Furthermore, associations with hormonal concentrations of estradiol and progesterone were investigated. METHOD: 19 young, free cycling women were tested in an Erotic Stroop paradigm during the follicular phase, ovulation, and the luteal phase in a balanced cross-over design, while electroencephalogram (EEG) was recorded. RESULTS: LPPs in reaction to erotic compared to neutral words were larger in every phase. During the follicular phase and ovulation, higher estradiol-concentrations were associated with more positive LPP-amplitudes towards erotic- than to neutral words. No effects of progesterone, as well as no effects of cycle phase, were evident. Results are being discussed regarding implications for further research. PMID- 29518693 TI - Effects of paternal high-fat diet and rearing environment on maternal investment and development of defensive responses in the offspring. AB - Paternal preconception risk factors (e.g. stress, diet, drug use) correlate with metabolic dysfunction in offspring, which is often comorbid with depressive and anxiety-like phenotypes. Detection of these risk factors or deleterious phenotypes informs a female about prevailing ecological demands, in addition to potential adverse environment-induced phenotypes that may be disseminated to her offspring. We examined whether a F0 male rat's prior exposure to an obesogenic high-fat diet (HFD) influences a female's attraction towards a male, subsequent mother-infant interactions and the development of defensive (emotional) responses in the F1 offspring. Females displayed less interest in the HFD exposed F0 males relative to control diet-exposed F0 males. Dams that reared F1 offspring in larger, semi-naturalistic housing provided more licking and grooming and active arched-back-nursing behavior. However, some of these effects interacted with paternal experience. F0 HFD and maternal rearing environment revealed sex dependent, between group differences in F1 offspring wean weight, juvenile social interactions and anxiety-like behavior in adolescence. Our results show for the first time in mammals that male exposure to HFD may contribute to stable behavioral variation among females in courtship, maternal care, even when the females are not directly exposed to a HFD, and anxiety-like behavior in F1 offspring. Furthermore, when offspring were exposed to a predatory threat, hypothalamic Crf gene regulation was influenced by early housing. These results, together with our previous findings, suggest that paternal experience and maternal rearing conditions can influence maternal behavior and development of defensive responses of offspring. PMID- 29518694 TI - Diagnosis and monitoring of HCV infection using the cobas(r) HCV test for use on the cobas(r) 6800/8800 systems. AB - BACKGROUND AND OBJECTIVES: Accurate, sensitive, and specific tests for detection and monitoring of hepatitis C virus (HCV) RNA concentrations are essential for diagnosis and management of HCV infections. We evaluated the next-generation reverse-transcription real-time PCR test, cobas(r) HCV test for use with the cobas(r) 6800/8800 systems ("cobas HCV") by determining its analytical performance characteristics and clinical utility for the diagnosis and therapeutic monitoring of chronic HCV infections. METHODS: The limit of detection (LOD), linearity, precision, specificity, matrix equivalence of plasma and serum, and quantitative agreement with the COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HCV Test version 2.0 ("CAP/CTM HCV v2") were evaluated. Clinical utility for the diagnosis of chronic HCV infection was demonstrated by testing plasma from HCV seropositive individuals and comparing results to a nucleic acid amplification test (NAAT) approved for use in the diagnosis of chronic hepatitis C. Clinical specificity was investigated by testing plasma from HCV antibody negative subjects with non-HCV related liver diseases. Utility for monitoring treatment response was defined by testing plasma collected during treatment of HCV genotypes (GT) 1, 2, and 3 and determining positive predictive value (PPV), negative predictive value (NPV) and the odds ratio (OR) for predicting cure (sustained virologic response 12 weeks after treatment cessation, "SVR12"). RESULTS: The cobas HCV test demonstrated an LOD of at least 15 IU/mL and measurable range from 15 to at least 1.0E + 08 IU/mL (1.2-8.0 log10 IU/mL) for GT 1-6, with high accuracy (<=0.16 log10 difference) and precision (standard deviation 0.04-0.14 log10) throughout the linear range. Paired plasma and serum samples showed highly correlated performance (R2 = 0.97). Quantification was 100% specific for HCV in analytical studies. Correlation with CAP/CTM HCV v2 was high in patient samples (mean titer difference: 0.05 log10 with a 95% CI: 0.03-0.06 log10). For the diagnosis of chronic HCV, positive and negative percent agreement between cobas HCV and the comparator NAAT were 98.8-100% on the cobas 6800 and 8800 systems. Clinical specificity of cobas HCV using samples from HCV antibody negative subjects with non-HCV related liver diseases was 99.6% and 100% on cobas 6800 and 8800 systems. In therapeutic monitoring and SVR12 prediction during experimental treatment for chronic HCV GT 1 infections, undetectable HCV RNA by cobas HCV at different on-treatment weeks had a PPV 76.8%-79.4%, NPV 29.9%-100%, and OR 1.64-47.52. During therapy of HCV GT 2 and GT 3, treatment week 4 and 12 results were: PPV, 84.7% and 75.3%; NPV, 47.8% and 50.0%; OR, 5.09 and 3.05. CONCLUSIONS: The cobas HCV test is highly sensitive, specific, and accurate HCV RNA test for GT 1-6. It demonstrates excellent correlation with the FDA-approved CAP/CTM HCV v2 test. It is useful clinically for detection of active HCV infection in individuals that have had a positive anti-HCV antibody test result and in monitoring treatment response. PMID- 29518695 TI - BK polyomavirus microRNA expression and sequence variation in polyomavirus associated nephropathy. AB - BACKGROUND: BK polyomavirus (BKPyV) infection is a common asymptomatic viral infection in the general population. Severe complications are seen in immunocompromised individuals, such as polyomavirus-associated nephropathy (PyVAN) in renal transplant recipients. Information on BKPyV microRNA expressions is scarce, although polyomavirus-encoded microRNAs have been shown to control viral replication and assist in immune evasion. Whereas the pathogenic role of rearrangements in JC polyomavirus has been well established, little is known about BKPyV rearrangements in PyVAN. OBJECTIVES: To assess viral microRNA expression and transcriptional control region (TCR) sequence variation in PyVAN patients. STUDY DESIGN: bkv-miR-B1-3p and bkv-miR-B1-5p microRNA expression was quantified in 55 plasma samples from 9 PyVAN patients and 2 controls using specific miRNA assays. TCR architectures among the viral populations in each patient were characterized by massive parallel sequencing. RESULTS: bkv-miR-B1-3p and bkv-miR-B1-5p miRNA expression was established in 85.5% and 98.2% of samples, respectively. On average, an 8.9-fold (bkv-miR-B1-3p) and 8.7-fold (bkv-miR-B1 5p) higher expression levels were detected in PyVAN patients as compared to controls. Rearranged BKPyV strains with duplications and deletions were detected in 7/9 PyVAN patients, but 77.6-99.9% of all sequence reads in all samples represented archetype strains. CONCLUSIONS: The frequent detection and increased expression of miRNAs suggest involvement in PyVAN pathogenesis. Despite the predominance of archetype BKPyV strains, the frequent detection of minor rearranged viral populations urges further study on their role in severe kidney disease. Our results suggest that miRNA expression is increased in PyVAN patients, as well as in the presence of rearranged viral strains. PMID- 29518697 TI - Viscous dewetting of metastable liquid films on substrates with microgrooves. AB - We present a combined experimental and theoretical investigation of dewetting on substrates with parallel microgrooves. A thin, static liquid film has an equilibrium thickness so as to minimize the sum of the surface free energy and the gravitational potential energy. When the thickness of a liquid film is less than the equilibrium thickness, the film seeks the equilibrium through contraction of the wetted area, which is referred to as dewetting. We experimentally observed the dewetting of thin, metastable liquid films on substrates with parallel microgrooves. The experiments revealed that the films retract in the direction along the grooves and leaves liquid residues with various morphologies. We classify the residue morphologies into three modes and elucidate the dependence of the mode selection on the groove geometry and the equilibrium contact angle of the liquid. We also experimentally examined the dynamic motion of the receding contact lines of the dewetting films, and developed a mechanical model for the receding speed. Our results provide a basis for controlling liquid films using microstructures, which is useful for lubricant impregnated surface production, painting, spray cooling, and surface cleaning. PMID- 29518696 TI - EAF2 and p53 Co-Regulate STAT3 Activation in Prostate Cancer. AB - The tumor suppressor genes EAF2 and p53 are frequently dysregulated in prostate cancers. Recently, we reported that concurrent p53 nuclear staining and EAF2 downregulation were associated with high Gleason score. Combined loss of EAF2 and p53 in a murine model induced prostate tumors, and concurrent knockdown of EAF2 and p53 in prostate cancer cells enhanced proliferation and migration, further suggesting that EAF2 and p53 could functionally interact in the suppression of prostate tumorigenesis. Here, RNA-seq analyses identified differentially regulated genes in response to concurrent knockdown of p53 and EAF2. Several of these genes were associated with the STAT3 signaling pathway, and this was verified by significantly increased p-STAT3 immunostaining in the Eaf2-/-p53-/- mouse prostate. STAT3 knockdown abrogated the stimulation of C4-2 cell proliferation by concurrent knockdown of EAF2 and p53. Furthermore, immunostaining of p-STAT3 was increased in human prostate cancer specimens with EAF2 downregulation and/or p53 nuclear staining. Our findings suggest that simultaneous inactivation of EAF2 and p53 can act to activate STAT3 and drive prostate tumorigenesis. PMID- 29518699 TI - Learning rules for aversive associative memory formation. AB - For survival, organisms need the ability to flexibly modify their behavior. To achieve this, the brain is equipped with instructive brain circuits which trigger changes in neural connectivity and adaptive changes in behavior in response to environmental/internal challenges. Recent studies using a form of aversive associative learning termed fear conditioning have shed light on the neural mechanisms of instructive signaling. These studies demonstrate that fear learning is engaged through multiple, parallel aversive signaling pathways to the amygdala. Consistent with theoretical accounts of learning, activity in these circuits and behavioral learning is tightly regulated by the predictability of the aversive experience. However, in more complex learning conditions, these emotion circuits use a form of inference to approximate the appropriate reaction to danger. This suggests a revised view of how emotional learning systems represent aversive associations and how changes in these representations are instructed during learning. PMID- 29518698 TI - Sex differences in the regulation of social and anxiety-related behaviors: insights from vasopressin and oxytocin brain systems. AB - To understand how the brain regulates behavior, many variables must be taken into account, with sex as a prominent variable. In this review, we will discuss recent human and rodent studies showing the sex-specific involvement of the neuropeptides vasopressin and oxytocin in social and anxiety-related behaviors. We discuss that sex differences can be evident at pre-pubertal ages as seen in the sex-specific regulation of social recognition, social play, and anxiety by the vasopressin system in juvenile rats. We further discuss that the oxytocin system in humans and rodents alters brain activation, anxiety, and sociosexual motivation in sex-specific ways. Finally, we propose that knowledge of vasopressin and oxytocin mediated sex-specific brain mechanisms can provide essential insights into how these neuropeptide systems contribute to sex-specific vulnerability as well as resilience to perturbations, with subsequent relevance to social and emotional disorders. PMID- 29518700 TI - Healthy working days: The (positive) effect of work effort on occupational health from a human capital approach. AB - The neoclassic economic rationale has taken for granted that the effect of effort on health is negative. However, several studies in the field of occupational health and medicine claim that working is clearly better for health than non working or being unemployed, as some psychological and physical condition may improve with work effort. This paper analyzes the effect of work effort on occupational health. The proposed human capital approach builds upon the classic economic perspective, that assumes a negative effect of effort on health, and extends it by allowing positive effects, as suggested by occupational researchers. Using a sample from 2010 of 20,000 European workers we find that, under adequate working conditions, the level of effort (measured in working hours) at which health starts to deteriorate is very high (120 h per week). However, if working conditions are not adequate, even a moderate effort (35 h per week) can harm workers health. PMID- 29518702 TI - Governing the quality and safety of healthcare: A conceptual framework. AB - Recent research has advanced understanding of corporate governance of healthcare quality, highlighting the need for future empirical work to develop beyond a focus on board composition to a more detailed exploration of the internal workings of governance that influence board engagement and activities. This paper proposes a conceptual framework to guide empirical research examining the work of board and senior management in governing healthcare quality. To generate this framework, existing conceptual approaches and key constructs influencing effectiveness are identified in the governance literature. Commonalities between governance and team effectiveness literature are mapped and suggest a number of key constructs in the team effectiveness literature are applicable to, but not yet fully explored, within the governance literature. From these we develop a healthcare governance conceptual framework encompassing both literatures, that outlines input and mediating factors influencing governance. The mapping process highlights gaps in research related to board dynamics and external influences that require further investigation. Organizing the multiple complex factors that influence governance of healthcare quality in a conceptual framework brings a new perspective to structuring theory-led research and informing future policy initiatives. PMID- 29518701 TI - A geographically explicit ecological momentary assessment (GEMA) mixed method for understanding substance use. AB - Tobacco use is increasingly concentrated within marginalized groups, including LGBTQ+ young adults. Developing tailored interventions to reduce tobacco-related health disparities requires understanding the mechanisms linking individual and contextual factors associated with tobacco use to behavior. This paper presents an in-depth exploration of three cases from a novel mixed method study designed to identify the situational factors and place-based practices of substance use among high-risk individuals. We combined geographically explicit ecological momentary assessment (GEMA) with an adapted travel diary-interview method. Participants (young adult bisexual smokers, ages 18-26) reported on non-smoking and smoking situations for 30 days with a smartphone app. GEMA surveys captured internal and external situational factors (e.g., craving intensity, location type, seeing others smoking). Continuous locational data was collected via smartphone GPS. Subsequently, participants completed in-depth interviews reviewing maps of their own GEMA data. GEMA data and transcripts were analyzed separately and integrated at the case level in a matrix. Using GEMA maps to guide the interview grounded discussion in participants' everyday smoking situations and routines. Interviews clarified participant interpretation of GEMA measures and revealed experiences and meanings of smoking locations and practices. The GEMA method identified the most frequent smoking locations/times for each participant (e.g., afternoons at university). Interviews provided description of associated situational factors and perceptions of smoking contexts (e.g., peer rejection of bisexual identity) and the roles of smoking therein (e.g., physically escape uncomfortable environments). In conclusion, this mixed method contributes to advancing qualitative GIS and other hypothesis-generating approaches working to reveal the richness of individuals' experiences of the everyday contexts of health behavior, while also providing reliable measures of situational predictors of behaviors of interest, such as substance use. Limitations of and future directions for the method are discussed. PMID- 29518703 TI - Effect of tailored on-road driving lessons on driving safety in older adults: A randomised controlled trial. AB - AIM: We evaluated the effectiveness of individually tailored driving lessons compared with a road rules refresher course for improving older driver safety. METHODS: Two arm parallel randomised controlled trial, involving current drivers aged 65 and older (Mean age 72.0, 47.4% male) residing in Canberra, Australia. The intervention group (n = 28) received a two-hour class-based road rules refresher course, and two one-hour driving lessons tailored to improve poor driving skills and habits identified in a baseline on-road assessment. The control group (n = 29) received the road rules refresher course only. Tests of cognitive performance, and on-road driving were conducted at baseline and at 12 weeks. Main outcome measure was the Driver safety rating (DSR) on the on-road driving test. The number of Critical Errors made during the on-road was also recorded. RESULTS: 55 drivers completed the trial (intervention group: 27, control group: 28). Both groups showed reduction in dangerous/hazardous driver errors that required instructor intervention. From baseline to follow-up there was a greater reduction in the number of critical errors made by the intervention group relative to the control group (IRR = 0.53, SE = 0.1, p = .008). The intervention group improved on the DSR more than the control group (intervention mean change = 1.07 SD = 2.00, control group mean change = 0.32 SD = 1.61). The intervention group had 64% remediation of unsafe driving, where drivers who achieved a score of 'fail' at baseline, 'passed' at follow-up. The control group had 25% remediation. CONCLUSION: Tailored driving lessons reduced the critical driving errors made by older adults. Longer term follow-up and larger trials are required. PMID- 29518704 TI - Distraction by salient stimuli in adults with attention-deficit/hyperactivity disorder: Evidence for the role of task difficulty in bottom-up and top-down processing. AB - The cognitive mechanisms of increased distractibility in attention deficit/hyperactivity disorder (ADHD) are poorly understood. The current study investigated the influence of two major modulating factors (emotional saliency, task difficulty) on behavioral and electrophysiological parameters underlying distractibility in ADHD. In addition, the attentional focus (indirect and direct processing of distractors) was examined. Thirty-six adults with ADHD and 37 healthy controls completed two experimental tasks while electroencephalography (EEG) data was collected. Task 1 assessed indirect processing of emotional or neutral distractors during a perceptual judgment task with varying task difficulty. Task 2 measured direct processing of the emotional or neutral stimuli and required participants to rate the stimuli regarding valence and arousal. Results showed that adults with ADHD exhibited generally higher behavioral distractibility than healthy controls. Furthermore, the ADHD group exhibited an enhanced bottom-up processing [increased early posterior negativity (EPN) amplitudes] of distractors in trials with high task difficulty as well as enhanced top-down processing [increased late positive potential (LPP) amplitudes] in trials with low task difficulty. However, no group differences were evident in the neural processing of emotional content or between attentional focus conditions. These findings support the notion that distractibility in ADHD results from impairments to both top-down as well as bottom-up processes and underscore the importance of task difficulty as a modulating factor. PMID- 29518706 TI - Divergent assemblage patterns of abundant and rare microbial sub-communities in response to inorganic carbon stresses in a simultaneous anammox and denitrification (SAD) system. AB - Inorganic carbon has profound influence on anammox system and distinct microbial communities play pivotal roles in nitrogen removal, yet little is known about the ecological patterns of abundant and rare sub-communities in response to inorganic carbon stresses in simultaneous anammox and denitrification systems. Here the aspects of community ecology of abundant and rare taxa under abiotic constraints were explored. Results showed that different IC/NH4+-N ratios have significant influences on NH4+-N and TN removal. Co-occurrence networks revealed that abundant and rare taxa present contrasting assemblage patterns and ecological strategies. Spearman's correlation indicated that environmental filtering had discrepancy influences on these two bacterial sub-communities. Moreover, rare taxa were the key regulators for NH4+-N accumulation and NO2--N consumption. qPCR results indicated that nitrogen removal was mediated by multiple nitrogen transformation pathways. These findings collectively suggest that abundant and rare sub-communities have discrepant ecological patterns and provide insights into their structure-functional relationships. PMID- 29518705 TI - Cross domain self-monitoring in anosognosia for memory loss in Alzheimer's disease. AB - Anosognosia for memory loss is a common feature of Alzheimer's disease (AD). Recent theories have proposed that anosognosia, a disruption in awareness at a global level, may reflect specific deficits in self-monitoring, or local awareness. Though anosognosia for memory loss has been shown to relate to memory self-monitoring, it is not clear if it relates to self-monitoring deficits in other domains (i.e., motor). The current study examined this question by analyzing the relationship between anosognosia for memory loss, memory monitoring, and motor monitoring in 35 individuals with mild to moderate AD. Anosognosia was assessed via clinical interview before participants completed a metamemory task to measure memory monitoring, and a computerized agency task to measure motor monitoring. Cognitive and psychological measures included memory, executive functions, and mood. Memory monitoring was associated with motor monitoring; however, anosognosia was associated only with memory monitoring, and not motor monitoring. Cognition and mood related differently to each measure of self-awareness. Results are interpreted within a hierarchical model of awareness in which local self-monitoring processes are associated across domain, but appear to only contribute to a global level awareness in a domain-specific fashion. PMID- 29518707 TI - Characterization and application of size-sorted zonal chondrocytes for articular cartilage regeneration. AB - Current clinical approaches for articular cartilage repair have not been able to restore the tissue with zonal architecture, and its biomechanical and functional properties. Mimicking the zonal organization of articular cartilage in neo-tissue by implanting zonal chondrocyte subpopulations in multilayer construct could enhance the functionality of the graft, engineering of stratified tissue has not yet been realized due to lack of efficient and specific zonal chondrocyte isolation protocol. We show that by using a spiral microchannel device, the superficial, middle and deep zone chondrocytes can be separated based on cell size, and enriched from full thickness porcine cartilage in a high-throughput, label-free manner. The size-sorted cells show zone-specific characteristics in RT PCR analysis of zonal cartilage markers. Both freshly sorted and two-passage expanded zonal chondrocytes formed cartilage tissue in 3D hydrogel, bearing respective zonal characteristics, indicated by RT-PCR, histology, extracellular matrix proteins, and mechanical compression test. In the proof-of-concept in vivo study using a rodent cartilage defect model, the size-sorted zonal chondrocytes when delivered in bi-layered hydrogel construct, facilitated better cartilage repair with mechanically enhanced cartilage tissue, in comparison to conventional chondrocytes implantation. This study provides an effective approach to obtain large numbers of zonal chondrocytes, and demonstrates the translational potential of stratified zonal chondrocyte implantation for clinical repair of critical size cartilage defects. PMID- 29518708 TI - Changes in plasma 5-HT levels and equine leukocyte SERT expression in response to treadmill exercise. AB - Serotonin (5-HT) is a neurohormone transported from plasma into platelets and leukocytes by a specific transporter (SERT). While it is known that the brain 5 HT system is modulated by physical exercise, the peripheral serotoninergic response to exercise is not yet fully elucidated. In particular, this study aimed to evaluate changes in plasma 5-HT levels and equine leukocyte SERT expression in response to treadmill exercise in untrained horses. Analyses were carried out pre and post-treadmill exercise. 5-HT plasma levels were analysed by HPLC. Leukocytes and platelets were isolated to perform Real Time PCR for the evaluation of SERT mRNA levels. Western blot was conducted for the detection of SERT protein levels. The presence of SERT in leukocytes was analysed by flow cytometry. The functionality of SERT on leukocytes was investigated by using paroxetine as inhibitor of 5-HT reuptake. Results showed a significant decrease in SERT levels after exercise in both leukocytes and platelets and a significant increase in plasma 5-HT levels. Flow cytometry revealed that SERT is functional in one specific horse leukocyte subpopulation, still not identified, and paroxetine was able to block 5-HT reuptake into leukocytes. The exercise may have induced an increased mobilization of free-tryptophan and a release of 5-HT from the stores in the blood. High concentrations of plasma 5-HT could have caused a reduction in SERT expression affecting cellular 5-HT storage/uptake. The increase of cortisol levels after treadmill exercise was not significant. Exercise modulates the peripheral serotonin metabolism. More research is needed to assess its physiological implications. PMID- 29518709 TI - Metabolic predictors of peri-partum diseases and their association with parity in dairy cows. AB - The predictive values of plasma non-esterified fatty acid (NEFA), beta hydroxybutyrate (BHB), cholesterol, albumin and calcium to predict risk of peripartum diseases in primiparous (PP) and multiparous (MP) Holstein cows was investigated. Besides it was assessed if the health status interacted with parity on body condition score and metabolic profiles during the transition period. Dairy cows (126 PP and 182 MP) from a commercial dairy free stall herd (loose housing system) were weekly body condition scored and tail bled for metabolites determination from -3 to +4 weeks relative to calving. Peripartum diseases were diagnosed by a single trained veterinarian, while subclinical diseases (ketosis and hypocalcemia) were diagnosed at the laboratory. Cows were classified as healthy cows, cows with one event, or cows with two clinical events following a prospective observational cohort study, with only healthy cows enrolled at the beginning of the study. The largest incidence was for metritis (26.6%) followed by retained placenta (17.2%) and mastitis (15.2%) with no effect of parity, while subclinical hypocalcemia incidence was greater in MP than PP cows (43% vs 9.5%) respectively. In MP cows albumin concentrations were predictive for metritis at week -2 and for retained placenta at weeks -2 and -1, while cholesterol was predictive for mastitis at week -2, -1 and at calving. The interaction between health status and parity affected all metabolites during the transition period. This study showed a different evolution of metabolic profiles in healthy and sick cows during the transition according to parity, pointing out albumin and cholesterol as diseases predictors before calving. PMID- 29518710 TI - Porcine cluster of differentiation (CD) markers 2018 update. AB - Pigs are a major source of food worldwide; preventing and treating their infectious diseases is essential, requiring a thorough understanding of porcine immunity. The use of pigs as models for human physiology is a growing area; progress in this area has been limited because the immune toolkit is not robust. The international community has established cluster of differentiation (CD) markers for assessing cells involved in immunity as well as characterizing numerous other cells like stem cells. Overall, for humans 419 proteins have been designated as CD markers, each reacting with a defined set of antibodies (Abs). This paper summarizes current knowledge of swine CD markers and identifies 359 corresponding CD proteins in pigs. A broad-based literature and vendor search was conducted to identify defined sets of monoclonal (mAbs) and polyclonal Abs (pAbs) reacting with porcine CD markers along with other reagents (fusion proteins, ELISAs, PCR assays, and gene edited cell and pig models). This process identified over 800 reagents that are reportedly reactive with 266 pig CD markers. Despite this number, there is a great need to develop and characterize additional CD marker reagents, particularly mAbs, for pig research. There are numerous high priority targets: reagents for the characterization of porcine innate lymphoid cells, polarized macrophages and T regulatory cells and for the detection of porcine CD45 isoforms. Overall, improved technologies and genomics have contributed to dramatic increases in our knowledge of the pig, its immune system, disease and vaccine responses, and utility as a biomedical model. The development of more CD reagents will clearly advance these initiatives. PMID- 29518711 TI - Surgical treatment and outcome in patients over 80 years old with intracranial meningioma. AB - OBJECTIVE: Study of mortality rate and clinical outcomes in octogenarians patients operated for intracranial meningiomas. PATIENTS AND METHODS: Clinical, radiological and surgical data of 25 elderly patients aging over 80 years old operated at our Department from 2013 to 2016 for intracranial meningiomas have been recorded and analyzed. One-month mortality and clinical outcome at six months after surgery were evaluated. Logistic regression was used for detecting the risk factors influencing mortality and neurological functions. RESULTS: The median age at diagnosis was 8185 years (range 80-87). Meningiomas were gross total removed in 18 cases out of 25 (72%) and partially resected in 7 (28%). One month post-operative mortality occurred in 2 pts out of 25 (8%). A close correlation was found between operative duration over 240 min and mortality (p = 0,0421). There was a significantly lower mortality in patients with ASA II rather than in patients with ASA III (p = 0,038). The median pre-operative KPS value was 743 (range 50-90) while at six-month follow-up was 82. The surgical time (p = 00,006) and size of the lesion >4 cm (p = 002) were a significant prognostic factors for clinical improvement at six-month follow-up. CONCLUSIONS: The operative time and the ASA score are the most important prognostic factors for the mortality and neurological outcome of elderly patients over 80 years old operated for intracranial meningioma. Even if the number of patients is limited, our findings suggest that, after a careful preoperative stratification in elderly patients, it is possible to remove an intracranial meningioma with good results. PMID- 29518712 TI - Not just social sensitivity: Adolescent neural suppression of social feedback during risk taking. AB - Adolescence is a period of sensitivity to social stimuli. In particular, research has focused on the increased sensitivity to risks and social information seen during adolescence. However, recent evidence also suggests that adolescents can flexibly use information in service of their goals, raising an interesting question: are adolescents able to selectively discount social information if it conflicts with their goals? To test this question, fifty-five children and adolescents (ages 8-17 years) completed a social variant of the Balloon Analogue Risk Task during an fMRI session. Adolescents showed decreased tracking of negative social feedback in regions involved in salience-monitoring (e.g. insula) and social processing (e.g., TPJ, pSTS). Age-related changes in neural processing of risk and social feedback contributed to better performance for older participants. These results suggest that adolescents are able to suppress goal irrelevant social feedback, rather than being uniformly hyper-sensitive to social information. PMID- 29518713 TI - Field-based detection of biological samples for forensic analysis: Established techniques, novel tools, and future innovations. AB - Field based forensic tests commonly provide information on the presence and identity of biological stains and can also support the identification of species. Such information can support downstream processing of forensic samples and generate rapid intelligence. These approaches have traditionally used chemical and immunological techniques to elicit the result but some are known to suffer from a lack of specificity and sensitivity. The last 10 years has seen the development of field-based genetic profiling systems, with specific focus on moving the mainstay of forensic genetic analysis, namely STR profiling, out of the laboratory and into the hands of the non-laboratory user. In doing so it is now possible for enforcement officers to generate a crime scene DNA profile which can then be matched to a reference or database profile. The introduction of these novel genetic platforms also allows for further development of new molecular assays aimed at answering the more traditional questions relating to body fluid identity and species detection. The current drive for field-based molecular tools is in response to the needs of the criminal justice system and enforcement agencies, and promises a step-change in how forensic evidence is processed. However, the adoption of such systems by the law enforcement community does not represent a new strategy in the way forensic science has integrated previous novel approaches. Nor do they automatically represent a threat to the quality control and assurance practices that are central to the field. This review examines the historical need and subsequent research and developmental breakthroughs in field-based forensic analysis over the past two decades with particular focus on genetic methods Emerging technologies from a range of scientific fields that have potential applications in forensic analysis at the crime scene are identified and associated issues that arise from the shift from laboratory into operational field use are discussed. PMID- 29518714 TI - Individual and regional factors affecting stress and problem alcohol use: A representative nationwide study of China. AB - OBJECTIVES: The objective of this study was to examine the association between individual and environmental stressors and problem alcohol use among Chinese university students. METHODS: Participants were 11,942 students, who were identified through a multistage survey sampling process that included 50 universities. Individual information, including feelings of stress and perceptions of problem alcohol use, was obtained by self report. Urban and regional variables were retrieved from the National Bureau of Statistics database. Both unadjusted and adjusted methods were considered in the analyses. RESULTS: Almost one third (32.6%) of the students suffered from some form of severe stress while problem alcohol use prevalence was 7.3%, (95% CI: 4.1-10.4%). The multilevel logistic regression model found that uncertainty stress, gender, father's occupation and monthly expenses were associated with problem alcohol use. Of the contextual factors home region and the university city GDP and unemployment rate were important. When interactions were considered, the relationship between monthly expenses and financial uncertainty and problem drinking was most evident in high level universities. By contrast, the effects of uncertainty stress on problem drinking were most evident in middle and low level universities. CONCLUSIONS: The findings underscore that efforts to control problem alcohol use among students in China should pay greater attention to environmental determinants of stress and particularly to improvements in stress management in university settings. PMID- 29518715 TI - Perceived neighborhood walkability and physical exercise: An examination of casual communication in a social process. AB - Despite the accumulated evidence for the environmental correlates of physical activity, social processes underlying this association are not entirely clear. This study positions communication characterized by weak ties as a social mechanism linking neighborhood walkability with physical exercise. Data from a survey of Chicago residents show that perceived neighborhood walkability is positively related to frequency of weak-tie communication. Frequency of weak-tie communication is related positively to perceived social cohesion and negatively to anonymity, both of which are significantly related to frequency of physical exercise in the neighborhood. Data also show a sequential indirect relationship involving perceived neighborhood walkability, weak-tie communication, anonymity, and physical exercise. Implications are discussed in terms of the role of communication in promoting locality-based physical exercise. PMID- 29518716 TI - Neighborhood conditions and trajectories of alcohol use and misuse across the early life course. AB - While neighborhood conditions have been linked to alcohol misuse, less is known about the long-term consequences of exposure to adverse neighborhood conditions early in the life course. Using data from the National Longitudinal Survey of Adolescent to Adult Health, we examined how trajectories of alcohol behaviors from ages 12 to 32 varied according to neighborhood disorder, disadvantage, and advantage. Early exposure to adverse neighborhood conditions placed individuals at greater risk of being a current drinker and alcohol misuse, though these individuals never reached the same levels as those in more stable, advantaged neighborhoods. Early exposure appears to place individuals at risk for alcohol misuse across the early life course. PMID- 29518717 TI - Synthesis, molecular modeling and evaluation of alpha-glucosidase inhibition activity of 3,4-dihydroxy piperidines. AB - Biological evaluation of 3,4-dihydroxy piperidines as alpha-glucosidase inhibitors is being reported for the first time. Forty-five derivatives (amides, di-amides and sulfonamides) were made using cis and trans 3,4-dihydroxy piperidines to evaluate their alpha-glucosidase inhibition activity. Polar groups (-OH, -NH2) on phenyl ring having derivatives 5i, 5l, 7g, 7i &12j showed excellent activity compared to standard references. Acarbose, Voglibose and Miglitol were used as standard references. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of alpha-glucosidase. PMID- 29518718 TI - Potential biomarkers of Parkinson's disease revealed by plasma metabolic profiling. AB - The plasma of Parkinson's disease (PD) patients may contain various altered metabolites associated with the risk or progression of the disease. Characterization of the abnormal metabolic pattern in PD plasma is therefore critical for the search for potential PD biomarkers. We collected blood plasma samples from PD patients and used an LC-MS based metabolomics approach to identify 17 metabolites with significantly altered levels. Metabolic network analysis was performed to place the metabolites linked to different pathways. The metabolic pathways involved were associated with tyrosine biosynthesis, glycerol phospholipid metabolism, carnitine metabolism and bile acid biosynthesis, within which carnitine and bile acid metabolites as potential biomarkers are first time reported. These abnormal metabolic changes in the plasma of patients with PD were mainly related to lipid metabolism and mitochondrial function. PMID- 29518719 TI - Quantitative determination of metformin, saxagliptin and 5-hydroxy saxagliptin simultaneously by hydrophilic interaction liquid chromatography - electrospray ionization mass spectrometry and its application to a bioequivalence study with a single-pill combination in human. AB - A simple, sensitive and specific hydrophilic interaction liquid chromatography coupled to electrospray ionization mass spectrometric (HILIC-MS) method was developed and validated to determine the plasma concentrations of metformin, saxagliptin and 5-hydroxy saxagliptin simultaneously in clinical studies. Plasma samples were first acidified and then protein precipitated with acetonitrile. Chromatographic separation was achieved on a HILIC Chrom Matrix HP amide column (5 MUm, 3.0 * 100 mm I.D.). The mobile phase consisted of acetonitrile and 5 mM ammonium formate buffer containing 0.1% formic acid. Multiple reaction monitoring transitions were performed on triple quadrupole mass spectrometric detection in positive-ion mode with an electrospray ionization source. The calibration curves showed good linearity (r >= 0.999) over the established concentration range of 1.0-1000 ng/mL for metformin and 0.1-100 ng/mL for saxagliptin and its active metabolite 5-hydroxy saxagliptin. The extraction recovery for all of the analytes was >92% and the matrix effect ranged from 91.0 to 110.0%. After validation, the method was successfully applied to a bioequivalence study with a single-pill combination (SPC) consisting of 5 mg saxagliptin and 500 mg metformin in 10 healthy Chinese subjects. PMID- 29518720 TI - LC-MS/MS method for the simultaneous quantification of luteolin, wedelolactone and apigenin in mice plasma using hansen solubility parameters for liquid-liquid extraction: Application to pharmacokinetics of Eclipta alba chloroform fraction. AB - Eclipta alba (Bhringraj) in ayurveda has been widely used as a traditional medicine for its multi-therapeutic properties for ages. Luteolin (LTL), wedelolactone (WDL) and apigenin (APG) are the three main bioactive phytochemicals present in Eclipta alba extract. However there was a lack of sensitive bioanalytical method for the pharmacokinetics of these free compounds in plasma which majorly contributes for their activities after oral administration of Eclipta alba. The present study aims to develop a sensitive, rapid and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of mice plasma concentrations of LTL, WDL and APG using quercetin as an internal standard for the pharmacokinetic analysis. Analytes were separated on Phenomenex Luna C18 (150 * 4.6 mm, 3.0 MUm) column with mobile phase containing methanol: acetonitrile (90: 10, v/v) and 0.1% formic acid in 10 mM ammonium formate buffer in the ratio of 70: 30 (v/v) in isocratic mode. Liquid-liquid extraction was optimized using Hansen solubility parameters and diethyl ether finalized as an extraction solvent for the recovery ranging from 61 to 76% for all analytes in mice plasma. The validated method has an accuracy and precision over the linearity range of 0.1-200 ng/mL with a correlation coefficient (r2) of >=0.997. The intra and inter-day assay accuracy was between 98.17 and 107% and 95.83-107.89% respectively and the intra and inter day assay precision ranged from 0.37-6.05% and 1.85-10.76%, respectively for all the analytes. This validated method can be used for future clinical investigation studies of Eclipta alba extracts. PMID- 29518721 TI - Determination of the sulfate and glucuronide conjugates of levornidazole in human plasma and urine, and levornidazole and its five metabolites in human feces by high performance liquid chromatography-tandem mass spectrometry. AB - Levornidazole is a novel third-generation nitroimidazoles antibiotic which metabolism and disposition in human are not well known. We have previously developed two methods to quantify levornidazole and its phase I metabolites, Ml (Hydroxylation metabolite), M2 (N-dealkylation metabolite) and M4 (Oxidative dechlorination metabolite), in human plasma and urine. In this study, we developed three novel liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods and analyzed its phase II metabolites, sulfate conjugate (M6) and glucuronide conjugate (M16), in human plasma and urine, and the parent drug and above-mentioned five metabolites in human feces samples. Analytes and internal standard (IS) in human plasma were extracted by a solid-phase extraction procedure and separated on an ACQUITY UPLC CSH C18 column in gradient elution using acetonitrile and 0.1% formic acid aqueous solution as the mobile phase. The pretreatment procedures for urine and feces homogenate samples involved a protein precipitation followed by liquid-liquid extraction, and chromatographic separations were performed on the Atlantis T3 columns of different lengths and particle sizes (2.1 * 50 mm, 3 MUm and 2.1 * 150 mm, 5 MUm), respectively. The mobile phases consisted of formic acid and acetonitrile-methanol solution (v/v, 50:50) in gradient elution. The MS/MS analysis was conducted on TSQ Quantum triple quadrupole mass spectrometer using electrospray ionization with selected reaction monitoring (SRM) in the positive ion mode. The calibration curves for all analytes were linear and the validation ranges were as follows: 0.005-0.500 MUg/mL for M6 and 0.005-2.500 MUg/mL for M16 in plasma; 0.010-10.000 MUg/mL for M6 and M16 in urine; 0.005-1.000 MUg/mL for levornidazole, M2, M4 and M16, and 0.010-2.000 MUg/mL for M1 and M6 in human feces homogenate. Across these matrices, mean intra- and inter- batch accuracy values were in the ranges of 80.0%-120.0%, and intra- and inter-batch precision values did not exceed 20%. It was fully validated including selectivity, linearity, matrix effect, extraction recovery, stability, dilution integrity, carryover and incurred sample analysis (ISR). These newly developed methods were successfully applied in pharmacokinetics, metabolism and disposition study of levornidazole in 12 healthy Chinese subjects. PMID- 29518722 TI - Low black carbon concentration in agricultural soils of central and northern Ethiopia. AB - Soil carbon (C) represents the largest terrestrial carbon stock and is key for soil productivity. Major fractions of soil C consist of organic C, carbonates and black C. The turnover rate of black C is lower than that of organic C, and black C abundance decreases the vulnerablility of soil C stock to decomposition under climate change. The aim of this study was to determine the distribution of soil C in different pools and impact of agricultural management on the abundance of different species. Soil C fractions were quantified in the topsoils (0-15cm) of 23 sites in the tropical highlands of Ethiopia. The sites in central Ethiopia represented paired plots of agroforestry and adjacent control plots where cereal crops were traditionally grown in clayey soils. In the sandy loam and loam soils of northern Ethiopia, the pairs represented restrained grazing with adjacent control plots with free grazing, and terracing with cereal-based cropping with adjacent control plots without terracing. Soil C contained in carbonates, organic matter and black C along with total C was determined. The total C median was 1.5% (range 0.3-3.6%). The median proportion of organic C was 85% (range 53-94%), 6% (0-41%) for carbonate C and 6% (4-21%) for black C. An increase was observed in the organic C and black C fractions attributable to agroforestry and restrained grazing. The very low concentration of the relatively stable black C fraction and the dominance of organic C in these Ethiopian soils suggest vulnerability to degradation and the necessity for cultivation practices maintaining the C stock. PMID- 29518723 TI - Effects of forest-based bioenergy feedstock production on shallow groundwater quality of a drained forest soil. AB - Managed forests in southern U.S. are a potential source of lignocellulosic biomass for biofuel production. Changes in management practices to optimize biomass production may impact the quality of waters draining to nutrient sensitive waters in coastal plain regions. We investigated shallow groundwater quality effects of intercropping switchgrass (Panicum virgatum L.) with managed loblolly pine (Pinus taeda L.) to produce bioenergy feedstock and quality sawtimber in a poorly drained soil of eastern North Carolina, U.S.A. Treatments included PINE (traditional pine production), PSWITCH (pine-switchgrass intercropped), SWITCH (switchgrass monoculture) and REF (mature loblolly pine stand). Each treatment was replicated three times on 0.8ha plots drained by parallel-open ditches, 1.0-1.2m deep and 100m apart. Water samples were collected monthly or more frequently after fertilizer application. Water samples were analyzed for organic nitrogen (ON), ammonium N (NH4+- N), and nitrite+nitrate N (NO3-+ NO2-- N), ortohophosphate phosphorus (OP), and total organic carbon (TOC). Overall, PSWITCH did not significantly affect shallow groundwater quality relative to PINE and SWITCH. ON, NO3-+ NO2-- N, and TOC concentrations in PSWITCH, PINE and SWITCH were substantially elevated during the two years after tree harvest and site establishment. The elevated nutrient concentrations at the beginning of the study were likely caused by a combination of rapid organic matter decomposition of the abundant supply of post-harvest residues, warming of exposed soil surfaces and reduction of plant nutrient uptake that can occur after harvesting, and pre-plant fertilization. Nutrient concentrations returned to background levels observed in REF during the third year after harvest. PMID- 29518724 TI - Distribution of nitrous oxide emissions from managed organic soils under different land uses estimated by the peat C/N ratio to improve national GHG inventories. AB - Nitrous oxide (N2O) contributes substantially to greenhouse gas (GHG) emissions in the agricultural and land-use sectors. Owing to the high effort needed for measuring N2O emissions and the resulting lack of sufficient field measurements to apply at country-wide scale, soil-borne N2O emissions are often estimated by applying published IPCC default emission factors. To examine the data reported in the national GHG inventory, the current study utilizes a large data set of soil C/N ratios to predict N2O emissions and their distribution from drained organic soils in Switzerland. Calculated emission rates increase in the order of forest=15 years) from 15 countries grouped into 4 regions (Northern Europe: Norway; Central Europe: Austria, France, Germany, Switzerland, The Netherlands; Southern Europe: Croatia, Italy, Slovenia, and Spain; and Eastern Europe: Bulgaria, Estonia, Lithuania, Poland, and Slovakia), diagnosed with 7 malignant cancers in 2000-2007, and followed to end of 2008. A new variable (reconstructed stage) was created which used all available stage information. Age-standardised 5-year relative survival (RS) by reconstructed stage was estimated and compared between regions. Excess risks of cancer death in the 5 years after diagnosis were also estimated, taking age, sex and stage into account. RESULTS: Low proportions of Eastern European patients were diagnosed with local stage cancers and high proportions with metastatic stage cancers. Stage-specific RS (especially for non-metastatic disease) was generally lower for Eastern European patients. After adjusting for age, sex, and stage, excess risks of death remained higher for Eastern European patients than for European patients in general. CONCLUSIONS: Late diagnosis alone does not explain worse cancer survival in Eastern Europe: greater risk of cancer death together with worse stage-specific survival suggest less effective care, probably in part because fewer resources are allocated to health care than in the rest of Europe. We recommend that Eastern European cancer registries and other involved bodies to draw attention to poor cancer survival, so as to stimulate research and inform policies to improve outcomes. PMID- 29518727 TI - Onion quercetin monoglycosides alter microbial activity and increase antioxidant capacity. AB - The effects on fermentation processes in the digestive tract, the biochemical parameters and antioxidant capacity of blood in rats fed high-fat diets with quercetin (Q) and quercetin with quercetin monoglycosides (Q+MQ) preparations obtained from onion waste were evaluated. Four groups of eight animals were fed for 4 weeks with a control diet (C), a high-fat diet (HF) and high-fat diets with 0.15% addition of Q and Q+MQ preparations. HF caused an increase in alanine transaminase (ALT), non-high-density lipoprotein (non-HDL) and the atherogenic index AII vs. C and a decrease in the proportion of HDL in total cholesterol (TC). Q and Q+MQ showed a tendency to moderate the values aspartate transaminase (P=.087), ALT (P<.05), TC (P=.068), non-HDL cholesterol (P<.05), triglycerides (P=.064) and the atherogenic index AII (P<.05). Q+MQ significantly increased the activity of alpha-glucosidase (P<.05 vs. HF), beta-glucosidase (P<.05) and beta galactosidase (P<.05 vs. C and Q). Q increased activity of beta-glucosidase (P<.001 vs. C and HF). Both increased the activity of beta-glucuronidase (P<.05 vs. C and HF). Both increased the antioxidant capacity of the hydrophilic fraction in serum (P<.05 vs. C and HF), and Q enhanced that of the lipid fraction (P<.001). Q preparation contained 70% quercetin, and Q+MQ preparation contained 29% quercetin and 13% quercetin monoglycosides, mainly quercetin-4'-glucoside. Both exhibited high antioxidant capacity. Supplementation with Q and Q+MQ increased the enzymatic activity of the intestinal microbiota and the antioxidant capacity of blood and revealed a tendency to improve the blood lipid profile. MQ were particularly effective in stimulating the bacterial enzymatic activity. PMID- 29518728 TI - Hydrophobic modification of nanoscale zero-valent iron with excellent stability and floatability for efficient removal of floating oil on water. AB - Usually, nanoscale zero-valent iron (NZVI) cannot float on water because of high density and hydrophilic surface. Herein, alkyltrimethoxysilanes with different carbon chain lengths (C1, C8 and C16) were used as "water-repellent legs" to graft onto NZVI, enduing NZVI with hydrophobic and floatable characteristics like a water strider. The hydrophobic performance of as-modified NZVI materials was found to be better when NZVI was modified by alkyltrimethoxysilane with longer carbon chain, and a large contact angle of 151.2 degrees (>150 degrees ) was obtained in C16-NZVI, indicating the superhydrophobic characteristic of C16-NZVI. The oil-absorption experiments showed that the absorption capacity of C16-NZVI for lubricating oil reached 9.73 g/g within 30 s. After seven consecutive runs, the oil-absorption capacity of C16-NZVI still maintained at 9.26 g/g, indicating high reusability of C16-NZVI. Also, C16-NZVI exhibited excellent stability in NaCl solution without being oxidized for 32 d. Significantly, C16-NZVI possessed admirable chemical stability with high hydrophobic property in acid and alkaline solutions (pH 3-12). Considering the advantages of easy preparation, high stability and reusability, excellent oil-absorption capacity as well as magnetic recovery property, C16-NZVI is expected to have remarkable potential in the treatment of floating oil on water/seawater. PMID- 29518729 TI - Low-concentration exposure to BPA, BPF and BPAF induces oxidative DNA bases lesions in human peripheral blood mononuclear cells. AB - Because bisphenol A (BPA) and some of its analogs have been supposed to influence development of cancer, we have assessed the effect of BPA, bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF) on DNA bases oxidation, which is a key process in cancer initiation. The analysis was conducted on human peripheral blood mononuclear cells (PBMCs), which are very useful model to assess genotoxic potential of various toxicants in different cell types. In order to determine oxidative damage to DNA pyrimidines and purines, alkaline version of the comet assay with DNA glycosylases, i.e. endonuclease III (Nth) and human 8-oxoguanine DNA glycosylase (hOGG1) was used. PBMCs were exposed to BPA or its analogs in the concentrations of 0.01, 0.1 and 1 MUg/mL for 4 h and 0.001, 0.01 and 0.1 MUg/mL for 48 h. We have observed that BPA, BPS, BPF and particularly BPAF caused oxidative damage to DNA pyrimidines and more strongly to purines in human PBMCs. The results have also shown that BPS, which is the most commonly used as a substitute for BPA in the manufacture induced definitely the smallest oxidative DNA bases lesions in PBMCs. Moreover, we have noticed that BPA, BPF and BPAF caused DNA damage at very low concentration of 1 ng/mL. PMID- 29518730 TI - Umbilical cord blood PBDEs concentrations in relation to placental size at birth. AB - Previous studies have linked prenatal polybrominated diphenyl ether (PBDE) exposure to adverse birth outcomes. Reductions in placental size might mediate those adverse effects. We examined whether umbilical cord blood PBDEs concentrations were associated with placental size at birth. A total of 121 mother-newborn pairs residing in Wenzhou were enrolled in this study. Concentrations of 19 PBDEs in umbilical cord blood were determined by gas chromatography tandem mass spectrometry (GC-MS). Placental length, breadth and surface area was measured by medical professionals after delivery. BDE-206, 207, 208, 209 and the total of 19 PBDE congeners concentrations were negatively associated with placental length, breadth and surface area. Our results suggest that prenatal PBDEs exposure may suppress placental growth, resulting in reduced placental size. PMID- 29518731 TI - Evaluating death and activity decay of Anammox bacteria during anaerobic and aerobic starvation. AB - The decreased activity (i.e. decay) of anaerobic ammonium oxidation (Anammox) bacteria during starvation can be attributed to death (i.e. decrease in the amount of viable bacteria) and activity decay (i.e. decrease in the specific activity of viable bacteria). Although they are crucial for the operation of the Anammox process, they have never been comprehensively investigated. This study for the first time experimentally assessed death and activity decay of the Anammox bacteria during 84 days' starvation stress based on ammonium removal rate, Live/Dead staining and fluorescence in-situ hybridization. The anaerobic and aerobic decay rates of Anammox bacteria were determined as 0.015 +/- 0.001 d 1 and 0.028 +/- 0.001 d-1, respectively, indicating Anammox bacteria would lose their activity more quickly in the aerobic starvation than in the anaerobic starvation. The anaerobic and aerobic death rates of Anammox bacteria were measured at 0.011 +/- 0.001 d-1 and 0.025 +/- 0.001 d-1, respectively, while their anaerobic and aerobic activity decay rates were determined at 0.004 +/- 0.001 d-1 and 0.003 +/- 0.001 d-1, respectively. Further analysis revealed that death accounted for 73 +/- 4% and 89 +/- 5% of the decreased activity of Anammox bacteria during anaerobic and aerobic starvations, and activity decay was only responsible for 27 +/- 4% and 11 +/- 5% of the decreased Anammox activity, respectively, over the same starvation periods. These deeply shed light on the response of Anammox bacteria to the starvation stress, which would facilitate operation and optimization of the Anammox process. PMID- 29518732 TI - Preliminary evaluation of the application of carbon nanotubes as potential adsorbents for the elimination of selected anticancer drugs from water matrices. AB - The presence of anticancer drugs in the environment raises a major concern due to their potentially negative impact on living organisms, as they cause, inter alia, teratogenic, mutagenic, carcinogenic effects on growing cells. The main source of these pharmaceuticals in the environment is the ineffectively treated wastewaters, hence the efficient methods for their removal are required. In this study, we have evaluated for the first time the applicability of different Multi Walled Carbon Nanotubes (MWCNTs) as alternative adsorbents for the removal of three popular anticancer drugs from water matrices, which are detected in waste/hospital waters at the concentrations even up to MUg L-1: cyclophosphamide (CP), ifosfamide (IF) and 5-fluorouracil (5-FU). It was observed that adsorption equilibrium time was reached after 20 min for each compound and CNTs. Moreover, CP has the highest sorption potential (Kd up to 1597 L kg-1) for all CNTs and CNTs with the highest surface area have the greatest adsorption capacity. Isotherms were fitted best to the Freundlich model. Significant influence of pH in the range 4-9 and ionic strength was not observed what may indicate that adsorption is not dependent on fluctuation of basic environmental conditions. PMID- 29518733 TI - Trans-/multi-generational effects of deoxynivalenol on Caenorhabditis elegans. AB - Deoxynivalenol (DON, vomitoxin) is one of the most widely distributed trichothecene mycotoxins commonly found in cereal food and feeds. Significant acute and potential chronic toxic effects of DON have been observed in animals and human populations. However, potential adverse effects associated with DON exposure across multiple generations have not been extensively investigated. In this study, Caenorhabditis elegans (C. elegans) were used to evaluate the trans /multi-generational toxicities of DON via 3 physiological endpoints: growth, brood size, and feeding ability. DON concentration at higher than 100 MUg/mL significantly inhibited growth, decreased brood size, and reduced food intake in a concentration-dependent manner. Gradual decline in DON-induced impairments was observed in the filial generations when only the parental generation was exposed. However, greater damages in filial generations were found as compared to the parental generation (p < 0.01) with all generations continuously exposed to DON. Overall, the endpoints of brood size and food intake were more sensitive for both trans- and multi-generational toxic effects of DON. Additionally, the interactions between concentrations and generations significantly influence the response of C. elegans to DON exposure, based on a mixed-effect model with multi level analysis. Taken together, our results demonstrated that DON exposure produced significant trans-/multi-generational toxic effects on C. elegans, which may serve as a model organism to explore molecular mechanisms of long-term adverse health effects of DON. PMID- 29518734 TI - Oxidation of the beta-blocker propranolol by UV/persulfate: Effect, mechanism and toxicity investigation. AB - In this study, the degradation of propranolol (PRO) by UV/persulfate process was systematically investigated. Direct photolysis of PRO was limited due to its low quantum yield, while the PRO degradation efficiency can be greatly promoted by the combination of persulfate and UV irradiation. Radical scavenging tests showed that both SO4- and OH contributed to the removal of PRO, with SO4- playing a more important role. The degradation rate of PRO was improved by increasing the persulfate dose and initial solution pH consistent with pseudo-first-order reaction kinetics. The effects of common water constituents were species dependent. HCO3- and Cl- promoted PRO degradation. By contrast, NO3- and HA were found to inhibit PRO degradation. A total of nine degradation products were identified by LC/MS/MS, which mainly derived from the ring-opening attack on the naphthalene group or oxidation of the amino moiety by SO4- and OH. Finally, the toxicity of the reaction mixtures was also assessed using luminescent bacteria Vibrio fischeri, and the results indicated that UV/persulfate is capable of controlling the toxicity of PRO degradation. PMID- 29518735 TI - High-efficient energy recovery from organics degradation for neutral wastewater treatment based on radicals catalytic reaction of Fe2+/Fe3+-EDTA complexes. AB - A high-efficient photo-induced wastewater fuel cell (WFC) for neutral wastewater treatment was proposed in this paper based on radicals catalytic reaction of Fe3+/Fe2+- EDTA complexes in the system which has a lower redox potential than Fe3+/Fe2+ and can accelerate easily the conversion of slow catalytic step from Fe (III) to Fe (II). The results indicated that the WFC shows an excellent performance in a wide pH range of 5-9 and achieves optimal efficiency for organic degradation and electricity generation at pH 7.0. The removal ratio of organic pollutants (Rhodamine b, Phenol, and Methylene Blue) increased to 69.42%, 53.99% and 82.7% from 29.87%, 16.25% and 39% respectively after 3 h operation at an initial pH of 7.0. Meanwhile, the short-circuit current is up to 1.24-2.16 times that of the WFC without EDTA-ferrous complex. Furthermore, the system almost does not produce any sludge. The proposed WFC system can keep stable of Fe3+/Fe2+ in neutral solution and generate more intermediate active free radicals to treat neutral wastewater and recover the abundant chemical energy in organics. PMID- 29518736 TI - Solar photolysis of soluble microbial products as precursors of disinfection by products in surface water. AB - In the Pearl River Delta area, the upstream municipal wastewater is commonly discharged into rivers which are a pivotal source of downstream drinking water. Solar irradiation transforms some of the dissolved organic matter discharged from the wastewater, also affecting the formation of disinfection by-products in subsequent drinking water treatment plants. The effect of simulated solar radiation on soluble microbial products extracted from activated sludge was documented in laboratory experiments. Irradiation was found to degrade macromolecules in the effluent, yielding smaller, more reactive intermediate species which reacted with chlorine or chloramine to form higher levels of noxious disinfection by-products. The soluble microbial products were found to be more active in formation of disinfection by-products regard than naturally occurring organic matter. The results show that solar irradiation induced the formation of more trihalomethane (THMs), chloral hydrate (CH) and trichloronitromethane (TCNM), causing greater health risks for downstream drinking water. PMID- 29518737 TI - Fe0 catalyzed photo-Fenton process to detoxify the biodegraded products of azo dye Mordant Yellow 10. AB - Inspired by the efficiency of the photo-Fenton process on oxidation of organic pollutants, we herein present the feasibility of visible light driven photo Fenton process as a post treatment of biological method for the effective degradation and detoxification of monoazo dye Mordant Yellow 10 (MY10). Anaerobic degradation of MY10 by Pseudomonas aeroginosa formed aromatic amines which were further degraded in the subsequent Fe catalyzed photo-Fenton process carried out at pH 3.0, with iron shavings and H2O2 under blue LED light illumination. LC-MS and stoichiometric analysis confirmed that reductive azo bond cleavage was the major reaction in anaerobic bacterial degradation of MY10 producing 4-amino benzene sulfonic acid (4-ABS) and 5-amino salicylic acid (5-ASA) which were further degraded into hydroxyl amines, nitroso and di/tri carboxylic acids by the photo-Fenton process. Toxicity studies with human small cell lung cancer A549 cells provide evidence that incorporation of Fe0 catalyzed photo-Fenton step after anaerobic bacterial treatment improved the mineralization and detoxification of MY10 dye. PMID- 29518738 TI - Generation and characterization of DOM in wastewater treatment processes. AB - Wastewater reuse for resolving water shortage is increasingly emphasized. The presence of DOM in wastewater is a main consideration for wastewater reuse. Therefore, systematic understanding of characteristic changes of DOM in different wastewater treatment processes is needed. As biotechnology together with disinfection operation has been used widely by WWTPs to treat wastewater, this review aims to introduce the recent advances in the effects of wastewater biological treatment and disinfection on the characteristics of DOM. Firstly, the composition of DOM in WWTPs is introduced. Then, the effects of wastewater treatments on hydrophobicity, MW distribution and optical characteristics of DOM and their correlations are reviewed. Also, the influences of wastewater treatments on biodegradability and biotoxicity of DOM are discussed. Finally, the environmental impact of effluent DOM is summarized. Since the discharge of wastewater effluent DOM to the environment not only influences nutrient uptake by bacteria, plankton and algae, and phototransformation rate of micropollutants in natural water, but also changes DOM level and physicochemical properties of soil. PMID- 29518739 TI - Importance of homo-dimerization of Fanconi-associated nuclease 1 in DNA flap cleavage. AB - Fanconi-associated nuclease 1 (FAN1) removes interstrand DNA crosslinks (ICLs) through its DNA flap endonuclease and exonuclease activities. Crystal structures of human and bacterial FAN1 bound to a DNA flap have been solved. The Pseudomonas aeruginosa bacterial FAN1 and human FAN1 (hFAN1) missing a flexible loop are monomeric, while intact hFAN1 is homo-dimeric in structure. Importantly, the monomeric and dimeric forms of FAN1 exhibit very different DNA binding modes. Here, we interrogate the functional differences between monomeric and dimeric forms of FAN1 and provide an explanation for the discrepancy in oligomeric state between the two hFAN1 structures. Specifically, we show that the flexible loop in question is needed for hFAN1 dimerization. While monomeric and dimeric bacterial or human FAN1 proteins cleave a short 5' flap strand with similar efficiency, optimal cleavage of a long 5' flap strand is contingent upon protein dimerization. Our study therefore furnishes biochemical evidence for a role of hFAN1 homodimerization in biological processes that involve 5' DNA Flap cleavage. PMID- 29518740 TI - Sleep-endocrine effects of growth hormone-releasing hormone (GHRH) in patients with schizophrenia. AB - Changes in sleep-EEG after endocrine stimulation tests in patients with schizophrenia include reduced sleep efficiency, prolonged sleep latency and increased awaking after sleep onset Findings on sleep associated growth hormone (GH) secretion were ambiguous. The aim of this study was to elucidate the sleep endocrine activity especially in the GH system of patients with schizophrenia after repeated administration of GHRH. The effect of repetitive injections of 4 * 50 MUg GHRH between 22.00 and 01.00 h on sleep endocrine parameters was investigated in 9 patients diagnosed for schizophrenia. Patients did not receive any medication for one week. Concentrations of ACTH, cortisol, prolactin and GH were determined. Patients spent three consecutive nights in the sleep laboratory. Blood was taken every 20min. Results were compared with matched healthy controls. A non-significant prolonged sleep onset latency and increased time awake was found in patients compared to controls. Sleep stage 2 was significantly reduced in patients. No significant difference in ACTH and cortisol was detected, whereas the GH secretion in patients following GHRH stimulation was significantly elevated compared to controls. Our results in drug free patients confirm already known changes in sleep-EEG in these patients. The GH response to GHRH-stimulation indicates a different regulatory sensitivity of the system between daytime and night-time. PMID- 29518741 TI - Fatty acid profile and carcass traits of feedlot Nellore cattle fed crude glycerin and virginiamycin. AB - Forty-eight bulls with an initial body weight (BW) of 408.4 +/- 22.2 kg (age = 21 +/- 2 months) were used in a randomized complete block design arranged in a 2 * 2 factorial design. The treatments were diets without virginiamycin (VM-) or with virginiamycin, at 25 mg/kg of dry matter (DM, VM+), and diets without crude glycerin (CG-) or with crude glycerin, at 100 g/kg DM (CG+). The cold carcass weight and cold carcass dressing (P <= 0.05) was greater in bulls fed crude glycerin diets. Total unsaturated fatty acids (UFA) were 6.08% higher, and cooking weight loss was 10% lower in bulls fed CG+ diets, compared to bulls fed CG- diets (P = 0.0081). Crude glycerin at 100 g/kg DM could be a suitable replacement for VM, as it led to a slight increase in UFA deposition in meat. However, simultaneous administration of VM and CG did not positively affect performance and carcass traits of feedlot Nellore cattle. PMID- 29518742 TI - The utility of assessing for pain interference and psychological factors among emergency department patients who present with pain. PMID- 29518743 TI - Andrographolide suppresses TRIF-dependent signaling of toll-like receptors by targeting TBK1. AB - Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-kappaB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of andrographolide in TLR signaling pathways. Andrographolide suppressed NF kappaB activation as well as COX-2 expression induced by TLR3 or TLR4 agonists. Andrographolide also suppressed the activation of IRF3 and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Andrographolide attenuated ligand-independent activation of IRF3 following overexpression of TRIF, TBK1, or IRF3. Furthermore, andrographolide inhibited TBK1 kinase activity in vitro. These results indicate that andrographolide modulates the TRIF-dependent pathway of TLRs by targeting TBK1 and represents a potential new anti-inflammatory candidate. PMID- 29518745 TI - Risk of acute coronary syndrome in patients with cervical spondylosis. AB - BACKGROUND AND AIMS: Cervical spondylosis (CS) is reported to be associated with increased sympathetic activity and hypertension. However, the cardiovascular (CV) outcomes of patients with CS are largely unknown. METHODS: A national insurance claims dataset of 22 million enrollees in Taiwan during 1999-2010 was used as the research database. We identified 27,948 patients with CS and age-, sex-, and comorbidity-matched controls. By using multivariate logistic regression analysis after adjustment for potential cardiovascular (CV) confounders, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) to quantify the association between CS and acute coronary syndrome (ACS). RESULTS: A total of 744 ACS events were identified among the 27,948 patients with CS. The overall incidence of ACS was 4.27 per 1000 person-years in the CS cohort and 3.90 per 1000 person-years in the non-CS cohort, with an adjusted hazard ratio (aHR) of 1.13 (95% CI = 1.08 1.18). The aHRs of ACS were 1.08 (95% CI = 1.03-1.15) in the CS cohort without myelopathy and 1.20 (95% CI = 1.13-1.28) in the CS cohort with myelopathy, compared with the non-CS cohort. Compared with patients with CS without neurological signs, patients with CS receiving rehabilitation exhibited a 0.67 aHRs of ACS (95% CI = 0.59-0.76), whereas those with neurological signs receiving spinal decompression exhibited 0.73 aHRs of ACS (95% CI = 0.63-0.84). CONCLUSIONS: CS is associated with an increased risk of ACS. Receiving treatment for CS, either rehabilitation or spinal decompression, is associated with less risk of ACS. PMID- 29518744 TI - Circulating CD14+CD163+CD115+ M2 monocytes are associated with the severity of new onset severe acute pancreatitis in Chinese patients. AB - BACKGROUND: Despite the role of monocytes in the pathogenesis of severe acute pancreatitis (SAP), it remains unclear how different subtypes of monocytes regulate and contribute to this pathogenesis. METHODS: We examined the numbers of different subsets of monocytes by flow cytometry in 21 SAP, 15 mild acute pancreatitis (MAP) and 13 healthy controls (HC). The concentrations of plasma cytokines were assessed by cytometric bead array. Disease severity was evaluated based on the acute physiology and chronic health evaluation (APACHE) II score and plasma C-reactive proteins (CRP) levels. RESULTS: Compared with the numbers in MAP patients and HC, we observed that the numbers of CD14+CD163-, CD14+CD163 MAC387+, CD14+CD163-IL-12+ M1 monocytes, and CD115+, CD204+, IL-10+ M2 monocytes were significantly increased in SAP patients. In addition, these patients showed higher plasma levels of interleukin (IL)-12 and IL-10. Furthermore, the number of CD14+CD163-, CD14+CD163-MAC387+ M1 monocytes and the plasma IL-12 concentration showed a positive association with the CRP level, while the number of CD204+, IL 10+ M2 monocytes and the plasma IL-10 concentration showed a positive correlation with the APACHE II score. Importantly, the CD115+ M2 subset displayed a positive correlation with both the CRP level and APACHE II score, and treatment of SAP significantly reduced the number of this subset. CONCLUSIONS: The CD14+CD163+CD115+ M2 monocyte count appears to be important factor in determining the severity and prognosis of SAP. Both the pro- and anti-inflammatory monocytes appear to participate in the pathogenesis of SAP. PMID- 29518746 TI - Anthropometric measures of obesity and renal artery calcification: Results from the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND AND AIMS: Renal artery calcium (RAC) has been linked to several cardiovascular disease (CVD) risk factors, including age, male gender, and hypertension. The purpose of this study was to determine whether anthropometric measures of obesity are associated with presence of RAC. METHODS: We studied 1287 community-dwelling adults enrolled in the Multi-Ethnic Study of Atherosclerosis. Logistic regression models adjusted for CVD risk factors were used to examine body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) as primary predictors of RAC. RESULTS: Study participants had a mean age of 67.7 years, 55.7% were female, and 36.8% were non Hispanic White. Prevalence of RAC was 33.3%. WC and WHR as continuous variables were not significant with adjustment. Subjects with high WC, as defined by World Health Organization cut-offs, had significantly higher odds for RAC in the fully adjusted model. BMI and HC were not significantly associated with RAC in any models. CONCLUSIONS: In this community-based sample of older adults, higher levels of WC are significantly associated with RAC independently of CVD risk factors. Adults who meet World Health Organization criteria for high WC may be at higher risk for complications of calcified atherosclerosis in the renal arteries. PMID- 29518747 TI - Treatment with omega-3 polyunsaturated fatty acids does not improve endothelial function in patients with type 2 diabetes and very high cardiovascular risk: A randomized, double-blind, placebo-controlled study (Omega-FMD). AB - BACKGROUND AND AIMS: Numerous recent studies conducted in different clinical settings have focused on the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the prevention of cardiovascular diseases. There is limited evidence that patients with type 2 diabetes (T2D) and very high cardiovascular risk can also benefit from a high dose of n-3PUFAs, especially those on optimal medical therapy as recommended by the guidelines. The aim of the present study was to assess the impact of high-dose n-3 PUFA treatment on endothelial function in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD). METHODS: We conducted a prospective randomized double-blind, placebo-controlled, 2-center study, in which endothelial function was measured using flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). Serum fatty acids composition was measured by gas chromatography. All measurements were done at baseline and after 3 months of treatment with PUFAs at a dose of 2 g/d (n = 36) or placebo (n = 38). RESULTS: The majority of the study population was treated with optimal medical therapy. Despite significantly higher concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid in the n-3 PUFA group after 3-month treatment, we did not observe significant changes in endothelial function indices (FMD and NMD). However, in regression analysis, only baseline FMD was associated with EPA concentration before 3 months of n-3 PUFA treatment. CONCLUSIONS: Three months of high-dose n-3 PUFA treatment in very high-risk patients with ASCVD and T2D did not improve the endothelial function indices. PMID- 29518748 TI - Lipid phosphate phosphatase 3 in vascular pathophysiology. AB - LPP3 is an integral membrane protein belonging to a family of enzymes (LPPs) that display broad substrate specificity and catalyse dephosphorylation of several lipid substrates, including lysophosphatidic acid and sphingosine-1-phosphate. In mammals, the LPP family consists of three enzymes named LPP1, LPP2 and LPP3, which are encoded by three independent genes, PLPP1, PLPP2 and PLPP3, respectively (formerly known as PPAP2A, PPAP2C, PPAP2B). These three enzymes, in vitro, do not seem to differ for catalytic activities and substrate preferences. However, in vivo targeted inactivation of the individual genes has indicated that the enzymes do not have overlapping functions and that LPP3, specifically, plays a crucial role in vascular development. In 2011, two genome-wide association studies have identified PLPP3 as a novel locus associated with coronary artery disease susceptibility. Shortly after these reports, tissue specific inactivation of PLPP3 in mice highlighted a specific role for LPP3 in vascular pathophysiology and, more recently, in atherosclerosis development. This review is aimed at providing an updated overview on the function of LPP3 in embryonic cardiovascular development and on the experimental and clinical evidences relating this enzyme to vascular cell functions and cardiovascular disease. PMID- 29518749 TI - SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr-/- type 1 diabetic mice. AB - BACKGROUND AND AIMS: Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia. METHODS: Diabetes was induced using streptozotocin (STZ) in low density lipoprotein receptor (Ldlr) knockout (Ldlr-/-) mice after which they were fed a high-cholesterol diet for 4 weeks. Control and diabetic mice were treated with vehicle or sodium glucose cotransporter inhibitor (SGLT2i, Phlorizin or Dapagliflozin) for the duration of the diet. RESULTS: Induction of diabetes resulted in a dramatic increase in plasma cholesterol (TC) and triglyceride (TG) levels. These mice also exhibited an increased number of circulating monocytes and neutrophils. Monocytosis was driven by increased proliferation of progenitor cells in the bone marrow. Tighter glycemic control by SGLT2i treatment not only reduced monocytosis and atherosclerosis but also improved plasma lipoprotein profile. Interestingly, improved lipoprotein profile was not due to decreased TG synthesis or clearance via low density lipoprotein receptor-related protein (Lrp) 1 or scavenger receptor class B member (Scarb1) pathways, but likely mediated by heparin sulfate proteoglycans (HSPG)-dependent clearance mechanisms in the liver. Further examination of the liver revealed an important role for bile acid transporters (Abcg5, Abcg8) and cytochrome P450 enzymes in the clearance of hepatic cholesterol. CONCLUSIONS: These data suggest that tighter glycemic control in diabetes can improve lipoprotein clearance exclusive of Ldlr, likely via HSPG and bile acid pathways, and has an overall net positive effect on atherosclerosis. PMID- 29518750 TI - A YouTube video intervention as mHealth to promote first-episode psychosis education to Chinese. PMID- 29518751 TI - A cost analysis of the psychotropic medicines sold in the jan aushadhi generic drug stores in India. PMID- 29518753 TI - Does body mass index and adult height influence cancer incidence among Chinese living with incident type 2 diabetes? AB - BACKGROUND: We investigated the site-specific cancer incidence risks among participants living with newly diagnosed type 2 diabetes (T2D) in relation to body mass index (BMI) and height. METHODS: The sample consisted of 25,130 participants living in Ningbo (China) who were newly diagnosed with T2D between 01/01/2006 and 12/31/2007 but without cardiovascular disease or cancer diagnoses at baseline. Follow-up of the sample was from 01/01/2008 to 12/31/2014. Cancer incidence stratified by BMI categories and quartiles of height were analyzed using standardized incidence ratios (SIR; the ratio of observed to the expected number of diagnosed cases) with 95% confidence intervals (95%CI). RESULTS: Follow up included 22,795 participants, 155,845 person-years and 1063 cancer diagnoses. Compared with the general population of Ningbo, SIRs of all-cancer were 2.19 (95% CI: 2.01-2.37) for males and 1.80 (95% CI: 1.64-1.96) for females. The all-cancer SIRs for participants in the normal BMI category was 1.13 (95% CI: 1.00-1.38). By comparison, the SIRs for the overweight and obese groups were 0.62 (95% CI: 0.26 0.95) and 0.35 (95% CI: 0.03-0.71), respectively. Besides, higher participants had higher all-cancer SIRs. For males, SIRs were 1.08 (95% CI: 0.88-1.27) and 2.41 (95% CI: 2.05-2.78) in the lowest and highest quartiles of height, respectively. For females, SIRs were 1.03 (95% CI: 0.72-1.35) and 2.01 (95% CI: 1.66-2.58) in the lowest and highest quartiles of height, respectively. CONCLUSION: In this sample of participants living with newly diagnosed T2D, cancer incidence was higher among those who were taller, but also lower among those with higher BMI. PMID- 29518752 TI - Longitudinal and cross-sectional structural magnetic resonance imaging correlates of AV-1451 uptake. AB - We examined the relationship between in vivo estimates of tau deposition as measured by 18F-AV-1451 tau positron emission tomography imaging and cross sectional cortical thickness, as well as rates of antecedent cortical thinning measured from magnetic resonance imaging in individuals with and without evidence of cerebral amyloid in 63 participants from the Alzheimer's Disease Neuroimaging Initiative study, including 32 cognitively normal individuals (mean age 74 years), 27 patients with mild cognitive impairment (mean age 76.8 years), and 4 patients diagnosed with Alzheimer's disease (mean age 80 years). We hypothesized that structural measures would correlate with 18F-AV-1451 in a spatially local manner and that this correlation would be stronger for longitudinal compared to cross-sectional measures of cortical thickness and in those with cerebral amyloid versus those without. Cross-sectional and longitudinal estimates of voxelwise atrophy were made from whole brain maps of cortical thickness and rates of thickness change. In amyloid-beta-positive individuals, the correlation of voxelwise atrophy across the whole brain with a summary measure of medial temporal lobe (MTL) 18F-AV-1451 uptake demonstrated strong local correlations in the MTL with longitudinal atrophy that was weaker in cross-sectional analysis. Similar effects were seen in correlations between 31 bilateral cortical regions of interest. In addition, several nonlocal correlations between atrophy and 18F AV-1451 uptake were observed, including association between MTL atrophy and 18F AV-1451 uptake in parietal lobe regions of interest such as the precuneus. Amyloid-beta-negative individuals only showed weaker correlations in data uncorrected for multiple comparisons. While these data replicate previous reports of associations between 18F-AV-1451 uptake and cross-sectional structural measures, the current results demonstrate a strong relationship with longitudinal measures of atrophy. These data support the notion that in vivo measures of tau pathology are tightly linked to the rate of neurodegenerative change. PMID- 29518754 TI - Endocrine sequelae of immune checkpoint inhibitors. AB - Cancer immunotherapy has introduced a novel class of drugs known as immune checkpoint inhibitors (ICIs). They enhance antitumour immunity by blocking negative regulators (checkpoints) of T cell function that exist on both immune and tumour cells. ICIs targeting CTLA-4 and PD-1/PDL-1 have dramatically changed the outcome of patients with several advanced-stage malignancies but they may lead to a variety of inflammatory toxicities and autoimmune consequences. The main endocrine immune-related adverse events (IRAEs) include hypophysitis, primary thyroid dysfunction, adrenalitis and type 1 diabetes mellitus. In general, the management of endocrine IRAEs requires assessment of their severity, in moderate or severe cases interruption of the checkpoint inhibitor and use of corticosteroid or alternative immunosuppression and appropriate hormone replacement or treatment when necessary. PMID- 29518755 TI - Diabetic nephropathy: is it always there? Assumptions, weaknesses and pitfalls in the diagnosis. AB - Diabetic nephropathy is defined as a microvascular complication of the kidneys induced by diabetes mellitus and is characterized by albuminuria and progressive loss of kidney function. However, neither albuminuria nor glomerular filtration rate decline are diabetic nephropathy-specific markers, thus the diagnosis of diabetic nephropathy greatly depends on assumptions. Several factors should be taken into account when urinary albumin levels are assessed before establishing the diagnosis of diabetic nephropathy, while newer more specific markers for diabetic nephropathy are urgently needed. PMID- 29518756 TI - Detection rate of somatostatin receptor PET in patients with recurrent medullary thyroid carcinoma: a systematic review and a meta-analysis. AB - PURPOSE: Several articles have demonstrated the high diagnostic performance of somatostatin receptor positron emission tomography (PET) in patients with neuroendocrine tumours (NETs). On the other hand, only a few studies have evaluated the detection rate (DR) of this imaging method in recurrent medullary thyroid carcinoma (MTC). We aimed to perform a systematic review and a meta analysis of the DR of somatostatin receptor PET or PET/CT in patients with recurrent MTC to add evidence-based data to this setting. METHODS: A comprehensive computer literature search of studies published in PubMed/MEDLINE and the Cochrane Library Database through May 2017 and regarding somatostatin receptor PET or PET/CT in patients with recurrent MTC was carried out. DR was determined on a per patient-basis. A sub-analysis considering serum calcitonin (Ctn) values was also performed. RESULTS: Nine studies on the diagnostic performance of somatostatin receptor PET or PET/CT in detecting recurrent MTC were discussed in the systematic review. The meta-analysis of these selected studies provided the following DR on a per patient-based analysis: 63.5% [95% confidence interval (95%CI): 49-77]. Heterogeneity among the selected studies was found. DR of somatostatin receptor PET or PET/CT increased in patients with higher serum Ctn levels (83% for Ctn >500 ng/L). CONCLUSIONS: In patients with recurrent MTC, somatostatin receptor PET or PET/CT demonstrated a non-optimal DR which increased in patients with higher serum Ctn values. The diagnostic performance of somatostatin receptor PET or PET/CT in recurrent MTC is lower compared to that of the same imaging method in the majority of NETs. PMID- 29518757 TI - Prevalence, pathogenesis and management of prediabetes and type 2 diabetes mellitus in patients with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. PCOS is not only the leading cause of anovulatory infertility but is also associated with an array of metabolic disorders, among which impaired glucose metabolism has been a topic of intense research. The aim of the present narrative review is to summarize the findings of the studies that have evaluated the prevalence and incidence of prediabetes and type 2 diabetes mellitus (T2DM) in patients with PCOS, to analyze the factors underpinning the association between T2DM and PCOS and to discuss the current strategies for screening and management of impaired glucose metabolism in this population. Both prediabetes and T2DM are highly prevalent in patients with PCOS. Accordingly, regular screening is recommended in this population for the early identification of impaired glucose metabolism, particularly in overweight or obese patients and in those with a family history of T2DM. Prevention of T2DM in patients with prediabetes is primarily based on lifestyle changes, while metformin might be considered in selected cases. The treatment of T2DM is similar in patients with and without PCOS but appropriate contraceptive measures should be implemented in patients receiving treatments other than insulin, metformin or glyburide. PMID- 29518758 TI - Differentiated thyroid cancer in childhood: a literature update. AB - Differentiated thyroid cancer in childhood is rare. Apart from family history, radiation exposure is a major risk factor. Although its clinical course is quite aggressive with higher rates of lymph node and pulmonary metastases as compared to adults, the final outcome tends to be favorable with mortality rates less than 2%. We herein review the clinical picture, genetic background response to treatment and recurrence rates of differentiated thyroid cancer in children and young adolescents are thoroughly reviewed and the main differences with adult differentiated thyroid cancer are highlighted. PMID- 29518759 TI - Surgery for pheochromocytoma: A 20-year experience of a single institution. AB - OBJECTIVE: Resection of pheochromocytomas is a challenging procedure due to hemodynamic lability. Our aim was to evaluate surgical outcomes in 67 patients with pheochromocytoma and to validate the role of laparoscopic surgery in the treatment of these tumors. DESIGN: This study is a retrospective review. A total of 68 procedures for pheochromocytoma were performed between June 1997 and February 2017. All patients were investigated and operated on using an established departmental protocol. Relevant data were retrieved from the hospital records of 533 patients who underwent 541 adrenalectomies for benign and malignant adrenal tumors in the same period. RESULTS: Sixty-nine tumors were removed from 67 patients. One patient with/MEN2A underwent bilateral resection of pheochromocytomas in two stages. Tumor size in laparoscopic procedures ranged from 1.2 cm to 11.0 cm (mean 5.87 cm). Thirty-seven patients had benign disease, 31 potentially malignant (based on PASS) and 1 malignant with metastasis. Eight were in the context of a familial syndrome. Forty-nine patients underwent laparoscopic adrenalectomy, 8 patients had open approach from the start for recurrent pheochromocytoma or large benign tumor, 1 patient had open approach due to inoperable malignant pheochromocytoma and 10 patients had conversions from laparoscopic to open procedure. Nine patients received sodium nitroprusside intraoperatively to treat hypertension. One patient developed pulmonary embolism and succumbed 1 month later. There were no recurrences of the benign or potentially malignant tumors during the follow-up period. CONCLUSIONS: Laparoscopic resection of pheochromocytomas, despite its increased level of difficulty compared to that of other adrenal tumors, is a safe and effective procedure. PMID- 29518760 TI - Baseline glucose homeostasis predicts the new onset of diabetes during statin therapy: A retrospective study in real life. AB - OBJECTIVE: We evaluated the risk of altered glucose levels and new-onset diabetes (NOD) associated with statins according to glucose levels at baseline in a population treated for dyslipidemia on primary prevention for >5 years. DESIGN: The retrospective study included 308 subjects (265 on statins and 43 controls on diet) with a follow-up of 5-15 years. The cohort was classified according to glucose tolerance at both baseline and follow-up. RESULTS: The cumulative incidence of NOD was 13.6% (9.3% in controls and 13.5% in treated patients). NOD was diagnosed after 3.4+/-1.8 years. In the group with normal glucose levels at baseline, a family history of diabetes (OR: 3.4, 95% CI 1.3-8.9), BMI >30 kg/m2 (OR: 8.5, 95% CI 2.0-35.8), treatment with thiazide (OR: 21.9, 95% CI 1.2-384.2) and no alcohol consumption (OR: 0.3, 95% CI 0.1-0.8) reduced the risk of developing altered glucose levels or NOD. No effects of statins were seen. In the group with altered glucose levels at baseline, hypertension (OR: 5.0, 95% CI 1.0 25.3) and hypertriglyceridemia (OR: 3.5, 95% CI 1.0-11.8) increased the risk of remaining with altered glucose levels or developing NOD. Treatment with statins (OR: 7.5, 95% CI 1.5-37.4), in particular atorvastatin, was associated with an increased risk. In the whole population, statin therapy (OR: 4.0, 95% CI 1.1 14.1, p<0.020), and in particular simvastatin and atorvastatin, was associated with increased risk of altered glucose levels or NOD. Patients who developed or maintained altered glucose levels or NOD had a poor metabolic phenotype at baseline. CONCLUSIONS: Statins were associated with an increased risk of NOD or altered glucose levels, mainly in subjects with altered glucose levels before the beginning of therapy. Poor metabolic phenotype and unhealthy behaviors or family history of diabetes contributed to that risk. PMID- 29518761 TI - Hormonal responses following eccentric exercise in humans. AB - OBJECTIVE: Mechanically overloaded muscle and its subsequent damage are strong stimuli for eliciting acute hormonal changes, while the muscle adaptation which occurs following exercise-induced muscle damage may involve complex hormonal responses before the completion of muscle regeneration. The purpose of this study was to investigate systemic responses of various hormones, as well as secreted proteins that are exercise-regulated and associated with muscle adaptation, for several days after eccentric exercise-induced muscle damage in humans. DESIGN: Nine young male volunteers performed 50 maximal eccentric muscle actions using the knee extensor muscles of both legs. Blood samples were drawn before and at 6, 48 and 120 hours post exercise and serum levels of growth hormone (GH), insulin like growth factor binding protein-3 (IGFBP-3), cortisol, prolactin, thyroid stimulating hormone (TSH), free thyroxine (fT4), irisin, follistatin and sclerostin were measured. Myoglobin (Mb) concentration and lactate dehydrogenase (LDH) activity were also evaluated as indirect markers of muscle damage. RESULTS: Significant alterations in Mb and LDH were observed over time after eccentric exercise (p=0.039-0.001). A late serum increase in fT4 and decrease in irisin levels, along with an early and persistent decrease in IGFBP-3 levels, were observed following the muscle-damaging exercise (p=0.049-0.016). GH, cortisol, prolactin, TSH, follistatin and sclerostin exhibited moderate changes during the recovery period after exercise, though without reaching statistical significance (p>0.05), while correlational analyses revealed significant associationsbetween GH and IGFBP-3, prolactin and sclerostin over time (p=0.049-0.001). CONCLUSIONS: The significant hormonal responses observed in this study may indicate their involvement in the regenerative mechanisms following muscle damage, potentially as part of a regulatory network to support a normal adaptation process after muscle-damaging exercise. PMID- 29518762 TI - Diagnostic value of the water deprivation test in the polyuria-polydipsia syndrome. AB - OBJECTIVE: Diabetes insipidus (DI) and primary polydipsia (PP) are characterised by polyuria and polydipsia. It is crucial to differentiate between these two disorders since the treatment is different. The aim of this study was to evaluate the diagnostic value of the short and an extended variant of the water deprivation test (WDT) and of measuring urinary vasopressin (AVP) in patients with polyuria and polydipsia. DESIGN: A retrospective, single-centre study based on WDTs performed between 2004 and 2014 including 104 consecutive patients with the polyuria-polydipsia syndrome. During a strict water deprivation, weight, urinary osmolality, urinary vasopressin and specific gravity were collected until one of the following was reached: i) >3% weight reduction, ii) Urinary specific gravity >1.020 or, urinary osmolality >800 mOsm/L, iii) Intolerable adverse symptoms such as excessive thirst. RESULTS: Out of 104 patients (67 women, 37 men), 21 (20%) were diagnosed with DI and 83 (80%) with PP. The median (interquartile range; range) test duration was 14 hours (10-16; 3-36) in patients with DI and 18 hours (14-24; 7-48) in patients with PP (P=0.011). Of those diagnosed with PP, 22 (26%) did not reach urinary specific gravity >1.020 nor urine osmolality >800 mOsm/L. Urine AVP did not overlap between patients with PP and patients with central DI. CONCLUSIONS: The short WDT is of limited value in the diagnostic work-up of polydipsia and polyuria and a partial DI may have been missed in every fourth patient diagnosed with PP. Urinary AVP has excellent potential in discriminating PP from central DI. PMID- 29518763 TI - Medullary thyroid cancer, leukemia, mesothelioma and meningioma associated with germline APC and RASAL1 variants: a new syndrome? AB - Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor hereditary in 35% of cases. The most common syndromic form is in the context of the multiple endocrine neoplasia type 2 (MEN 2) syndromes in association with other tumors and due to germline RET mutations. We describe a 57-year-old female patient diagnosed with sporadic MTC. The patient had a history of other neoplasias, such as acute myeloid leukemia, for which she had received chemotherapy, and two other solid tumors, peritoneal mesothelioma and meningioma. Genetic analyses were carried out including whole exome and Sanger sequencing (WES and SS) and loss-of heterozygosity (LOH) testing for the respective loci. Immunohistochemistry (IHC) was used for the detection of proteins of interest. WES showed two germline variants in the APC and RASAL1 genes confirmed by SS. In MTC tissue only there was a RETvariant identified by SS; germline studies did not show any RETsequence changes. The pattern of tumors in this patient is unusual for either one of the APC- orRASAL1-associated neoplasms and her non-MEN 2-associated MTC contained a RET variant like other sporadic MTCs. As in other patients with more than one genetic variant predisposing to tumors, it is possible that this case represents a unique association. PMID- 29518764 TI - Sarcopenia: From definition to treatment. PMID- 29518765 TI - From Treating Childhood Malnutrition to Public Health Nutrition. AB - BACKGROUND: This analysis sets out an overview of an IUNS presentation of a European clinician's assessment of the challenges of coping with immediate critical clinical problems and how to use metabolic and a mechanistic understanding of disease when developing nutritional policies. SUMMARY: Critically ill malnourished children prove very sensitive to both mineral and general nutritional overload, but after careful metabolic control they can cope with a high-quality, energy-rich diet provided their initial lactase deficiency and intestinal atrophy are taken into account. Detailed intestinal perfusion studies also showed that gastroenteritis can be combatted by multiple frequent glucose/saline feeds, which has saved millions of lives. However, persisting pancreatic islet cell damage may explain our findings of pandemic rates of adult diabetes in Asia, the Middle East and Mexico and perhaps elsewhere including Africa and Latin America. These handicaps together with the magnitude of epigenetic changes emphasized the importance of a whole life course approach to nutritional policy making. Whole body calorimetric analyses of energy requirements allowed a complete revision of estimates for world food needs and detailed clinical experience showed the value of redefining stunting and wasting in childhood and the value of BMI for classifying appropriate adult weights, underweight and obesity. Lithium tracer studies of dietary salt sources should also dictate priorities in population salt-reduction strategies. Metabolic and clinical studies combined with meticulous measures of population dietary intakes now suggest the need for far more radical steps to lower the dietary goals for both free sugars and total dietary fat unencumbered by flawed cohort studies that neglect not only dietary errors but also the intrinsic inter-individual differences in metabolic responses to most nutrients. Key Messages: Detailed clinical and metabolic analyses of physiological responses combined with rigorous dietary and preferably biomarker of mechanistic pathways should underpin a new approach not only to clinical care but also to the development of more radical nutritional policies. PMID- 29518766 TI - Why Food System Transformation Is Essential and How Nutrition Scientists Can Contribute. AB - BACKGROUND: The International Union of Nutritional Sciences held its 21st International Congress of Nutrition in October 2017 in Buenos Aires, Argentina under the theme - From Sciences to Nutrition Security. In addition to multiple sessions on food systems and their links to diet, nutrition and health, the Congress closing lecture focused on the need to transform food systems so as to increase their capacity to provide healthy diets, making a call for greater involvement of nutrition scientists. SUMMARY: This article presents the main messages of that lecture, providing (i) an overview of global nutrition trends and their links to diets, food environments and food systems, (ii) a synopsis of the current global momentum for food system transformation and (iii) the need for nutrition scientists to leverage this momentum in terms of increased evidence generation and policy advocacy. Key Messages: Poor quality diets are increasingly leading to the compromising of human health as never before; the prevalence of undernutrition persists and remains acute in vulnerable regions, and hunger is increasing concomitantly with an unprecedented rise in overweight, obesity and nutrition-related non-communicable diseases. Increasing access to healthy diets through faster, stronger implementation of supply and demand-side strategies that address the underlying drivers of today's faulty food systems is imperative to solve these problems, as well as to address related environmental and economic costs. The global momentum for such action is increasing, but the evidence base needed to galvanize governments and hold stakeholders accountable remains yet a fledgling. To date, inputs from nutrition scientists to this reform agenda have been weak, especially given the unique contributions the field can make in terms of rigorous analysis and technical advice. Strengthened participation will require innovations in metrics and methodologies, combined with new thinking on what constitutes viable evidence and a greater willingness to engage with private sector agri-food actors. PMID- 29518768 TI - ISNN Society News. PMID- 29518767 TI - Vitamin D Levels, Body Composition, and Metabolic Factors in Asian Indians: Results from the Metabolic Syndrome and Atherosclerosis in South Asians Living in America Pilot Study. AB - BACKGROUND/AIMS: Asian Indians have a high prevalence of vitamin D deficiency and metabolic syndrome. Vitamin D deficiency is associated with an increased risk of cardiovascular disease and diabetes. METHODS: We performed a cross-sectional study of 150 Asian Indians (50% male) from the San Francisco Bay Area. We assessed the association between 25-OH vitamin D (25-OHD) levels and vitamin D deficiency with body composition (anthropometric and radiographic measures) and metabolic outcomes. RESULTS: In both men and women, the presence of vitamin D deficiency was associated with higher systolic (p = 0.004) and diastolic (p = 0.01) blood pressure, and fasting glucose (p = 0.01). Only in women, vitamin D deficiency status was associated with higher body mass index (BMI), waist-to-hip ratio, visceral fat area, and hepatic fat content after adjusting for age, income, and physical activity level. In women, 25-OHD was also associated with fasting glucose after adjusting for age, income, and physical activity and further adjusting for BMI and waist circumference (beta -2.1, 95% CI -0.86 to 0.01, p = 0.04). This association between vitamin D deficiency and metabolic parameters was not significant in men. CONCLUSIONS: A lower level of 25-OHD and vitamin D deficiency were associated with higher levels of metabolic factors among Asian Indians. Our findings suggest that 25-OHD metabolism may differ by the distribution of adipose tissue and involve previously unexplored pathways accounting for the variability in the role of vitamin D in cardiovascular disease. PMID- 29518769 TI - Knockdown of PRKAR2B Results in the Failure of Oocyte Maturation. AB - BACKGROUND/AIMS: Cyclic adenosine monophosphate (cAMP)-dependent type 2 regulatory subunit beta (Prkar2b) is a regulatory isoform of cAMP-dependent protein kinase (PKA), which is the primary target for cAMP actions. In oocytes, PKA and the pentose phosphate pathway (PPP) have important roles during the germinal vesicle (GV) stage arrest of development. Although the roles of the PKA signal pathway have been studied in the development of oocyte, there has been no report on the function of PRKAR2B, a key regulator of PKA. METHODS: Using reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR (qRT PCR), immunohistochemistry, and immunofluorescence, we determined the relative expression of Prkar2b in various tissues, including ovarian follicles, during oocyte maturation. Prkar2b-interfering RNA (RNAi) microinjection was conducted to confirm the effect of Prkar2b knockdown, and immunofluorescence, qRT-PCR, and time-lapse video microscopy were used to analyze Prkar2b-deficient oocytes. RESULTS: Prkar2b is strongly expressed in the ovarian tissues, particularly in the growing follicle. During oocyte maturation, the highest expression of Prkar2b was during metaphase I (MI), with a significant decrease at metaphase II (MII). RNAi-mediated Prkar2b suppression resulted in MI-stage arrest during oocyte development, and these oocytes exhibited abnormal spindle formation and chromosome aggregation. Expression of other members of the PKA family (except for Prkaca) were decreased, and the majority of the PPP factors were also reduced in Prkar2b-deficient oocytes. CONCLUSION: These results suggest that Prkar2b is closely involved in the maturation of oocytes by controlling spindle formation and PPP-mediated metabolism. PMID- 29518771 TI - Overexpression of Long Non-Coding RNA NNT-AS1 Correlates with Tumor Progression and Poor Prognosis in Osteosarcoma. AB - BACKGROUND/AIMS: Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) play critical regulatory roles in cancers, including osteosarcoma. A previous study showed that Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) was aberrantly expressed in several types of cancer. However, the potential biological roles and regulatory mechanisms of NNT-AS1 in osteosarcoma progression remain unknown. METHODS: Quantitative RT-PCR was performed to examine the expression of NNT-AS1 in human tissues and cells. The biological functions of NNT-AS1 were determined by CCK-8, colony formation, Flow cytometry and Transwell assays in vitro. A mouse xenograft model was performed to investigate the effect of NNT-AS1 on tumor growth in vivo. RESULTS: In this study, we found the expression of NNT-AS1 was significantly increased in tumor tissues compared to adjacent normal tissues. Furthermore, upregulated NNT-AS1 expression predicted poor prognosis and was an independent and significant risk factor for osteosarcoma patient survival. Further experiments revealed that NNT-AS1 knockdown significantly inhibited cell proliferation by inducing cell cycle arrest and promoting apoptosis in osteosarcoma cells. Moreover, NNT-AS1 silencing suppressed cell migration and invasion in vitro. In a tumor xenograft model, knockdown of NNT-AS1 suppressed tumor growth of OS-732 cells in vivo. CONCLUSIONS: Taken together, these findings indicate that NNT-AS1 functions as an oncogene in osteosarcoma and could be a novel diagnostic and therapeutic target for osteosarcoma. PMID- 29518772 TI - Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum. AB - Ring chromosome 13 is a rare genetic condition with an incidence of 1/58,000 in live births. Major clinical features of patients with ring chromosome 13 include growth and developmental retardation, microcephaly, facial dysmorphism, ambiguous genitalia, anal atresia, eye malformations, retinoblastoma, and hand, foot, and toe abnormalities. The severity of the phenotype depends on the amount of genetic material lost during ring chromosome formation. Here, we report 2 cases with ring chromosome 13 at either end of the phenotypic spectrum. PMID- 29518770 TI - Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy. AB - BACKGROUND/AIMS: Intervertebral disc degeneration (IDD) is a pathological process that is the primary cause of low back pain and is potentially mediated by compromised stress defense. Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. Here, we investigated the expression of Sesn in normal and degraded nucleus pulposus (NP) cells and its potential roles during IDD pathogenesis. METHODS: Sesn expression in normal and degraded NP cells was determined by quantitative polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. Sesn function was investigated by using Sesn knockdown and overexpression techniques with analysis of extracellular matrix (ECM), cell apoptosis, autophagy, AMPK, and mTOR activation. RESULTS: In human cultured NP cells, Sesn expression was significantly decreased in degraded NP cells at both the RNA and protein levels. The expression of Sesn1, 2, and 3 increased after stimulation by 2-deoxyglucose (2-DG), an endoplasmic reticulum stress inducer. 2-DG could also increase cell apoptosis, promote extracellular matrix (ECM) degradation, and positively regulate autophagy in NP cells. Sesn knockdown by small interfering RNA increased NP cell apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Conversely, Sesn overexpression mediated by plasmid transfection repressed IDD by enhancing autophagy, which was associated with changes in mTOR but not AMPK activation. CONCLUSIONS: Sesn expression is suppressed in degraded NP cells. In addition, Sesn inhibits stress-induced cell apoptosis and ECM degradation by enhancing autophagy, which is modulated though mTOR activity. Suppression of Sesn might therefore represent an important cellular dysfunction mechanism in the process of IDD. PMID- 29518773 TI - Comparative Proteomic Identification of Protein Disulphide Isomerase A6 Associated with Tert-Butylhydroperoxide-Induced Liver Injury in Rat Hepatocytes. AB - BACKGROUND/AIMS: Oxidants are important human toxicants. They have been implicated in the occurrence and development of liver diseases. Increased intracellular tert-butylhydroperoxide (t-BHP) may be critical for oxidant toxicity, and is commonly used for evaluating mechanisms involving oxidative stress, but the method remains controversial. METHODS: Primary cultures of hepatocytes as well as human Hep G2 and mouse FL83B liver cells were obtained. Cell viability was measured by annexin V-FITC/propidium iodide and DAPI staining to determine the effects of t-BHP treatment on acute liver injury. A proteomic assay provided information that was used to identify the differentially expressed proteins following t-BHP treatment; immunohistochemistry and western blotting were performed to detect the expression of PDIA6 activity in apoptotic and endoplasmic reticulum (ER) stress pathways. RESULTS: Our results demonstrate that t-BHP treatment of liver cells increased cell cytotoxicity and the generation of reactive oxygen species. This treatment also increased the level of PDIA6; this was validated in vitro and in vivo based on a comparison of t-BHP-treated and untreated groups. Treatment of mouse liver FL83B cells with t-BHP activated caspase 3, increased the expression of apoptotic molecules, caused cytochrome c release, and induced Bcl-2, Bax and IRE1alpha/TRAF2 complex formation. t-BHP dependent induction of apoptosis was accompanied by sustained phosphorylation of the IRE1alpha/ASK1/JNK1/2/p38 pathways and PDIA6 expression. Furthermore, t-BHP induced liver FL83B cell viability and apoptosis by upregulating the levels of PDIA6; this process could be involved in the activation of the IRE1alpha/ASK1/JNK1/2/p38 signalling pathways. CONCLUSIONS: We conclude that t BHP induced an apoptosis cascade and ER stress in hepatocytes by upregulation of PDIA6, providing a new mechanism underlying the effects of t-BHP on liver injury. PMID- 29518777 TI - Apparent Diffusion Coefficient of the Placenta in Twin versus Singleton Pregnancies. AB - : Previous studies in singleton pregnancies reported conflicting trends in apparent diffusion coefficient (ADC) values with gestational age (GA) and stable relative ADC (rADC; ADC placenta divided by ADC globe) throughout pregnancy. The purpose of our study was to compare the ADC and rADC of placentas of twin and singleton pregnancies. MATERIALS AND METHODS: Fetal MRI of 11 twin and 23 singleton pregnancies were retrospectively analyzed. Each group was further divided by GA (<=24 and >24 weeks). On ADC, 3 regions of interest were selected in the placenta and 1 in the globe. ADC and rADC measurements were compared between different GA and between singleton and twin placentas. RESULTS: No significant difference was shown between ADC and rADC values of singleton and twin placentas as well as between ADC and rADC values of singleton and twin placentas at different GA. No significant difference was shown when accounting for both GA and number of fetuses. CONCLUSION: The diffusion characteristics of twin placentas are similar to those of singleton placentas. ADC and rADC remain stable throughout pregnancy in twin and singleton placentas, reflecting stable extracellular water diffusion, despite changes associated with placental maturation. PMID- 29518774 TI - BMPER Enhances Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells. AB - BACKGROUND/AIMS: During bone repair and remodeling, osteogenesis is coupled with angiogenesis. Bone morphogenetic protein (BMP) antagonists are important modulators of BMP signaling and bone homeostasis. Several investigations have demonstrated that one 'BMP antagonist', BMP-binding endothelial cell precursor derived regulator (BMPER), participates in the regulation of BMP signaling. In this study, we examined the role of BMPER in the osteogenesis-angiogenesis coupling process. METHODS: Human bone mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs) were used in this experiment. After overexpressing or silencing BMPER with lentiviruses or siRNA, hBMSCs were stimulated by BMP-2, and osteogenic differentiation activity was detected by alkaline phosphatase and alizarin red staining. VEGF and endostatin release were assessed by ELISA. HUVEC migration was detected by the cell scratch test and transwell migration assay, and in vitro angiogenesis was determined by the tube formation assay. Bone formation was assessed using in vivo femoral monocortical defect and ectopic bone formation models. RESULTS: BMP-2 upregulated BMPER expression. Overexpression of BMPER remarkably enhanced BMP-2-induced osteogenic differentiation, while suppression of BMPER effectively inhibited this process both in vitro and in vivo. In addition, overexpression of BMPER promoted BMP-2 induced VEGF expression in vitro and vascularization in the ectopic bone formation model. CONCLUSION: BMPER functions as a positive regulator of the osteogenesis-angiogenesis coupling process in hBMSCs, suggesting a novel therapeutic role of BMPER in the regenerative capacity of bone repair. PMID- 29518776 TI - Dietary Docosahexaenoic Acid and Arachidonic Acid in Early Life: What Is the Best Evidence for Policymakers? AB - BACKGROUND: A wealth of information on the functional roles of docosahexaenoic acid (DHA) and arachidonic acid (ARA) from cellular, animal, and human studies is available. Yet, there remains a lack of cohesion in policymaking for recommended dietary intakes of DHA and ARA in early life. This is predominantly driven by inconsistent findings from a relatively small number of randomised clinical trials (RCTs), which vary in design, methodology, and outcome measures, all of which were conducted in high-income countries. It is proposed that this selective evidence base may not fully represent the biological importance of DHA and ARA during early and later life and the aim of this paper is to consider a more inclusive and pragmatic approach to evidence assessment of DHA and ARA requirements in infants and young children, which will allow policymaking to reflect the marked diversity of need worldwide. SUMMARY: Data from clinical RCTs is considered in the context of the extensive evidence from experimental, animal and human observational studies. Although the RCT data shows evidence of beneficial effects on visual function and in specific cognitive domains, early methodological approaches do not reflect current thinking and this undermines the strength of evidence. An outline of a framework for an inclusive and pragmatic approach to policy development on dietary DHA and ARA in early life is described. CONCLUSION: High-quality RCTs that will determine long-term health outcomes in appropriate real-world settings need to be undertaken. In the meantime, a collective pragmatic approach to evidence assessment, may allow public health policymakers to make comprehensive reasoned judgements on the merits, costs, and expediency of dietary DHA and ARA interventions. PMID- 29518778 TI - Does Age-Adjusted Charlson Comorbidity Score Impact Survival Endpoints in Women with Federation of Gynecology and Obstetrics-Stage III Endometrial Cancer? AB - OBJECTIVES: We sought to evaluate the impact of age-adjusted Charlson comorbidity index (AACCI) score on survival endpoints for women with advanced stage endometrial carcinoma (EC). METHODS AND MATERIALS: We identified 238 women with stage III EC. AACCI score was calculated and 3 groups were created accordingly; group 1 with a score of 0-2, group 2 with score 3-4, and group 3 with score >=5. Significant predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were analyzed. RESULTS: Median follow-up was 54 months and median age was 65 years. Stage IIIC was the most common stage (69%). The 3 groups were well-balanced except for less utilization of adjuvant chemotherapy in group 3 (p = 0.01). Five-year OS was significantly lower in group 3 compared to groups 1 and 2 (23 vs. 65 and 51%, respectively). Similarly, 5-year RFS was 54, 41, and 33% and DSS was 65, 54, and 35% for groups 1, 2, and 3 respectively. On multivariate analyses, AACCI group 3, cervical stromal involvement, positive peritoneal cytology, and higher tumor grade were predictors for shorter OS. Cervical stromal involvement and higher grade were independent predictors for worse RFS and DSS. Additionally, positive cytology, lymphovascular space invasion, and stage IIIC2 were significantly detrimental for RFS. CONCLUSIONS: Our study suggests that comorbidity burden is a strong predictor of worse OS in women with stage III EC. Women with higher AACCI are less likely to receive adjuvant chemotherapy. Comorbidity score can significantly impact survival endpoints for women with advanced EC. PMID- 29518779 TI - Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms. AB - BACKGROUND/AIMS: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. METHODS: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRbeta, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. RESULTS: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. CONCLUSION: Sunitinib showed evidence of activity in patients with GEPNEN G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3. PMID- 29518780 TI - Long-Time Course of Idiopathic Small Fiber Neuropathy. AB - BACKGROUND: Small fiber neuropathy (SFN) is a challenging subtype of peripheral neuropathies. Once the diagnosis has been established, there is an uncertainty how SFN may progress, whether larger fibers will become involved over time, whether quality of life may be compromised, or whether repeated diagnostic workup in patients with unknown underlying cause may increase the yield of treatable causes of SFN. METHODS: We evaluated 16 patients with documented long-time course of idiopathic SFN. RESULTS: Clinical and electrophysiological course remained stable in 75% of the patients, while 25% SFN-patients developed large fiber neuropathies. CONCLUSIONS: Our data suggest that SFN represents a benign disease course in the majority of patients without severely limiting the quality of life. PMID- 29518781 TI - Efficacy of Psychosocial Interventions for People with Multiple Sclerosis: A Meta Analysis of Specific Treatment Effects. AB - BACKGROUND: Psychosocial interventions are often used as an adjunct to the medical management of multiple sclerosis (MS). However, the efficacy of such approaches for a range of psychosocial indications remains unclear. OBJECTIVE: To determine the efficacy of psychosocial therapies for people with MS (PwMS). METHODS: We searched 6 electronic databases (Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, and Clinicaltrials.gov) until April 21, 2016, for randomized controlled trials reporting the effect of psychological interventions for depressive symptoms, anxiety, pain, fatigue, or health-related quality of life (HRQoL) in PwMS. RESULTS: The search yielded 356 articles with 13 included studies (n = 1,617). Benefits of psychological interventions were found for depressive symptoms (Cohen's d = 0.281), anxiety (d = 0.285), fatigue (d = 0.228), and mental (d = 0.398) and total HRQoL (d = 0.444), but not physical HRQoL. There were insufficient studies to meta-analyze posttreatment outcomes for pain. Interventions were more effective for HRQoL for patients with relapsing-remitting MS and when treatment doses were larger. Cognitive behavioral therapy (CBT) was not efficacious for PwMS when considered alone. CONCLUSION: Psychosocial interventions have a significant, positive impact across a range of outcomes for PwMS with small, yet consistent, effect sizes. There was some indication that CBT was less efficacious than other interventions. However, this may be due to smaller treatment doses in CBT studies. PMID- 29518782 TI - Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P Akt Signalling Pathways. AB - BACKGROUND/AIMS: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long term aspirin administration on pressure overload-induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. METHODS: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg.kg 1.day-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/beta-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. RESULTS: Aspirin significantly suppressed the expression of alpha-smooth muscle actin (alpha-SMA; 1.19+/-0.19-fold) and collagen I (0.95+/-0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 uM, also significantly suppressed angiotensin II-induced alpha-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49+/-0.19-fold; p-Erk2, 1.96+/-0.68-fold) was suppressed by aspirin (p-Erk1, 1.04+/-0.15-fold; p-Erk2, 0.87+/-0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36+/-0.12-fold for TAC; 1.06+/-0.07-fold for aspirin+TAC). The p-Akt and beta-catenin levels were also significantly inhibited in vivo and in vitro. CONCLUSIONS: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/beta-catenin signalling pathways. PMID- 29518784 TI - A Novel Concept of Amino Acid Supplementation to Improve the Growth of Young Malnourished Male Rats. AB - BACKGROUNDS/AIMS: This study was aimed at understanding the relationship between plasma amino acids and protein malnutrition and at determining whether amino acid supplementation associated with malnutrition and growth improves linear growth in growing rats. METHODS: Body length and plasma amino acids were measured in young male rats that were fed the following diet for 3 weeks, mimicking a low and imbalanced protein diets based on maize, a major staple consumed in developing countries: a 70% calorically restricted cornmeal-based diet (C), C + micronutrients (CM), CM + casein (CMC), CM + soy protein (CMS) or CMS + 0.3% lysine. RESULTS: A correlation analysis of linear growth and plasma amino acids indicated that lysine, tryptophan, branched-chain amino acids, methionine, and phenylalanine significantly correlated with body length. Supplementation with these 5 amino acids (AA1) significantly improved the body length in rats compared to CMC treatment whereas, nitrogen-balanced amino acid supplemented controls (AA2) did not (CM +1.2 +/- 0.2, CMC +2.7 +/- 0.3, CMS +2.1 +/- 0.3, AA1 +2.8 +/- 0.2, and AA2 +2.5 +/- 0.3 cm). CONCLUSION: With securing proper amino acid balance, supplementing growth-related amino acids is more effective in improving linear growth in malnourished growing male rats. Analysis of the correlation between plasma amino acids and growth represents a powerful tool to determine candidate amino acids for supplementation to prevent malnutrition. This technology is adaptable to children in developing countries. PMID- 29518783 TI - miR-194 Suppresses Proliferation and Migration and Promotes Apoptosis of Osteosarcoma Cells by Targeting CDH2. AB - BACKGROUND/AIMS: Studies have shown that miR-194 functions as a tumour suppressor and is associated with tumour growth and metastasis. This study intends to uncover the mechanism of tumour suppression by miR-194. The expression of miR-194 in osteosarcoma cell lines and tissues were monitored by real-time PCR. METHODS: The proliferation ability was examined by MTT assay. Migration and apoptosis of cells were monitored by migration assay and flow cytometry, respectively. The regulation of miR-194 on CDH2 was determined by luciferase assays and western blot assays. RESULTS: The results showed that miR-194 was significantly reduced in osteosarcoma compared with that in normal bone tissue. Overexpression of miR 194 significantly attenuated the proliferation and migration and induced the apoptosis of osteosarcoma cells. Furthermore, we demonstrated that miR-194 has inhibited the malignant behaviour of osteosarcoma by downregulating CDH2 expression. CONCLUSIONS: These findings suggested that miR-194 may act as a tumour suppressor in osteosarcoma. miR-194/CDH2 may be a novel therapeutic target in the treatment of osteosarcoma. PMID- 29518785 TI - Does Ramadan Fasting Affect Hydration Status and Kidney Function in CKD Patients? AB - BACKGROUND/AIMS: This study is the first of its kind to examine the impact of the Ramadan fasting on hydration status, plasma brain natriuretic peptide (BNP) levels, and kidney function in chronic kidney disease (CKD) patient. METHODS: This prospective cohort study included 2 groups of patients with CKD grades 2-4: thirty-one Muslim patients who fasted the month of Ramadan (fasting group) and 26 Muslim patients who did not fast (control group). One week before the Ramadan fast, in the last week of the month of Ramadan (4 weeks), and 4 weeks after the end of the Ramadan month (8 weeks), hydration status and blood analysis of urea, creatinine and BNP levels were measured. RESULTS: Among fasting patients, serum urea levels increased significantly (p = 0.024) during the last week of fasting and returned to basal levels at 4 weeks after the end of the Ramadan month, the estimated glomerular filtration rate did not change significantly at the end of fasting (p = 0.411), the hydration status indices and plasma BNP levels were significantly decreased after fasting (p <= 0.021) but returned to basal values 4 weeks thereafter. CONCLUSIONS: Patients with CKD grades 2-4 can fast throughout the month of Ramadan with no significant deterioration of renal functions and with a reasonable degree of safety. PMID- 29518787 TI - Elevated Plasma Haptoglobin Level as a Potential Marker for Poor Prognosis in Acute Cerebral Infarction. AB - BACKGROUND: Relationship between peripheral circulation concentration of haptoglobin (Hp) and risk of cerebrovascular disease has not been well investigated so far. The aim of the study was to reveal the prognostic significance of Hp on acute cerebral infarction. METHODS: A total of 200 patients with acute cerebral infarction and 200 controls were included. Research data were collected from their medical records. Blood samples were obtained on admission. Hp phenotyping was performed using a native polyacrylamide gel electrophoresis. Plasma Hp levels were determined using enzyme-linked immunosorbent assays. The patients were followed up yearly, and endpoint was overall death. RESULTS: Plasma levels of Hp were significantly elevated in the patients than in the controls (p < 0.001). Three-year overall death in the follow-up period was associated with the high plasma level of Hp (Hazard ratio [HR] 2.33, 95% CI 1.74-3.12). But, 3 year overall death was not related to Hp phenotyping (Hp 2-1 vs. 1-1: HR 1.07, 95% CI 0.66-1.73; Hp 2-2 vs. 1-1: HR 1.08, 95% CI 0.67-1.74). CONCLUSION: Peripheral circulation concentration of Hp might be an independent prognostic factor for acute cerebral infarction. But there was no relationship between Hp phenotyping and prognosis in this disease. PMID- 29518786 TI - Analysis of Long Noncoding RNA and mRNA Expression Profiles in IL-9-Activated Astrocytes and EAE Mice. AB - BACKGROUND/AIMS: Multiple sclerosis (MS) is an autoimmune disease in the central nervous system associated with demyelination and axonal injury. Astrocyte activation is involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This study was designed to find potential lncRNAs in EAE mice and activated astrocytes. METHODS: we performed microarray analysis of lncRNAs from the brain tissues of EAE mice and primary mouse astrocytes treated with IL-9(50 ng/ml). 12 lncRNAs were validated through real-time PCR. Gene ontology and KEGG pathway analysis were applied to explore the potential functions of lncRNAs. RESULTS: Differentially expressed 3300 lncRNAs and 3250 mRNAs were in the brain tissues of EAE mice, and 3748 lncRNAs and 3332 mRNAs were in activated astrocytes. Notably, there were 2 co-up regulated lncRNAs and 3 co-down-regulated lncRNAs both in the brain tissues of EAE mice and in activated astrocytes, including Gm14005, Gm12478, mouselincRNA1117, AK080435, and mouselincRNA0681, which regulate the ER calcium flux kinetics, zinc finger protein and cell apoptosis. Similarly, there were 7 mRNAs co-up-regulated and 2 mRNAs co-down-regulated both in vivo and in vitro. Gene ontology and KEGG pathway analysis showed that the biological functions of differentially expressed mRNAs were associated with metabolism, development and inflammation. The results of realtime PCR validation were consistent with the data from the microarrays. CONCLUSIONS: Our data uncovered the expression profiles of lncRNAs and mRNAs in vivo and in vitro, which may help delineate the mechanisms of astrocyte activation during MS/EAE process. PMID- 29518788 TI - The International Caries Detection and Assessment System - ICDAS: A Systematic Review. AB - The aims of this study were: (1) to evaluate the overall reproducibility and accuracy of the International Caries Detection and Assessment System (ICDAS) for assessing coronal caries lesions, and (2) to investigate the use of systems associated with the ICDAS for activity assessment of coronal caries lesions. Specific search strategies were adopted to identify studies published up to 2016. For the first objective, we selected studies that assessed primary coronal caries lesions using the ICDAS as a reference standard. A total of 54 studies were included. Meta-analyses summarized the results concerning reproducibility and accuracy (correlation with histology, summary ROC curves [SROC], and diagnostic odds ratio [DOR]). The latter 2 were expressed at D1/D3 levels. The heterogeneity of the studies was also assessed. Reproducibility values (pooled) were > 0.65. The ICDAS mostly presented a good overall performance as most areas under SROC were > 0.75 at D1 and > 0.90 at D3; DOR >=6. For the second objective, we selected studies investigating activity assessment associated with the ICDAS. The meta-analyses pooled results based on the same methodology and parameters as above. Longitudinal findings regarding caries progression were described to estimate the validity of these systems. On average, the systems for activity assessment of caries lesions showed moderate values concerning reproducibility and overall performance. Active caries lesions were more prone to progress than inactive ones after 2 years. In conclusion, the ICDAS presented a substantial level of reproducibility and accuracy for assessing primary coronal caries lesions. Additional systems associated with the ICDAS that classify caries lesion activity can be useful as they are moderately reproducible and accurate. PMID- 29518790 TI - Impact of Xenon on CLIC4 and Bcl-2 Expression in Lipopolysaccharide and Hypoxia Ischemia-Induced Periventricular White Matter Damage. AB - BACKGROUND: Premature birth is a significant health care burden. Xenon (Xe) is a general anesthetic with neuroprotective effects. OBJECTIVES: Here, we investigate the neuroprotective role of Xe in a lipopolysaccharide (LPS)- and hypoxia ischemia (HI)-induced white matter damage (WMD) model. METHODS: Three-day-old Sprague-Dawley rats were randomly divided into a sham group (group A, n = 24), an LPS + HI group (group B, n = 24), and an LPS + HI + Xe group (group C, n = 72). The onset of Xe inhalation started at 0, 2, and 5 h in subgroups C1, C2, and C3, respectively. Next, we performed TUNEL and hematoxylin and eosin (HE) staining; and examined the expression of CLIC4 and Bcl-2 in brain tissues. RESULTS: HE staining revealed distorted cytoarchitecture, tangled nerve fibers, and pyknosis in group B, while Xe treatment improved these histological alterations in the group C pups. Following LPS and HI insult, the number of apoptotic cells significantly increased in group B at 48 and 72 h (p < 0.05), and Xe significantly alleviated apoptosis (p < 0.001) at 24, 48, and 72 h, respectively. Similarly, CLIC4 mRNA expression was significantly increased in group B (p < 0.05), and Xe produced a marked reduction in CLIC4 mRNA expression in group C subgroups (p < 0.05). Western blotting demonstrated enhanced Bcl-2 expression in group C when compared to group B (p < 0.05). CONCLUSIONS: These results demonstrate that LPS and HI successfully induced WMD, and Xe decreased neuronal apoptosis via Bcl-2- and CLIC4-mediated pathways. Moreover, the therapeutic time window of Xe extended for up to 5 h. These findings suggest that Xe can be used as a protective treatment for WMD in premature infants. PMID- 29518789 TI - Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution. AB - BACKGROUND/AIMS: Metabolic diseases are leading health concerns in today's global society. In traditional Chinese medicine (TCM), one body type studied is the phlegm-dampness constitution (PC), which predisposes individuals to complex metabolic disorders. Genomic studies have revealed the potential metabolic disorders and the molecular features of PC. The role of epigenetics in the regulation of PC, however, is unknown. METHODS: We analyzed a genome-wide DNA methylation in 12 volunteers using Illumina Infinium Human Methylation450 BeadChip on peripheral blood mononuclear cells (PBMCs). Eight volunteers had PC and 4 had balanced constitutions. RESULTS: Methylation data indicated a genome scale hyper-methylation pattern in PC. We located 288 differentially methylated probes (DMPs). A total of 256 genes were mapped, and some of these were metabolic related. SQSTM1, DLGAP2 and DAB1 indicated diabetes mellitus; HOXC4 and SMPD3, obesity; and GRWD1 and ATP10A, insulin resistance. According to Ingenuity Pathway Analysis (IPA), differentially methylated genes were abundant in multiple metabolic pathways. CONCLUSION: Our results suggest the potential risk for metabolic disorders in individuals with PC. We also explain the clinical characteristics of PC with DNA methylation features. PMID- 29518792 TI - Predictive Factors of Contralateral Operation after Initial Pyeloplasty in Children with Antenatally Detected Bilateral Hydronephrosis Due to Ureteropelvic Junction Obstruction. AB - OBJECTIVES: This study was performed to analyze the predictive factors of a contralateral operation after initial pyeloplasty in patients with antenatally detected bilateral ureteropelvic junction obstruction. METHODS: Patients with prenatally diagnosed bilateral ureteropelvic junction obstruction who underwent initial pyeloplasty (aged <12 months at initial pyeloplasty) were offered to participate in the study. Patients were recruited from January 2012 to December 2015. The anteroposterior renal pelvic diameter, parenchymal thickness, and calyceal dilatation were evaluated. Predictive factors of contralateral pyeloplasty after initial unilateral pyeloplasty were also examined. RESULTS: In total, 82 patients were included in the study (mean age, 2.8 months). Among all patients who underwent initial pyeloplasty, additional contralateral pyeloplasty was required in 11 patients (13.4%). The outcome of contralateral hydronephrosis was assessed as resolution, persistence, or surgery. The median anteroposterior renal pelvic diameter and calyceal dilatation were significantly different among the groups (p < 0.001). Calyceal dilatation of >=10 mm and a calyceal dilatation/parenchymal thickness ratio of >=5 strongly suggested the likelihood of a contralateral operation. CONCLUSIONS: In most patients with bilateral ureteropelvic junction obstruction, improvement or resolution of contralateral hydronephrosis following initial unilateral pyeloplasty can be expected. Patients with contralateral calyceal dilatation >10 mm and the calyceal dilatation/parenchymal thickness ratio >5 are at higher risk of surgery. PMID- 29518791 TI - Effects of Haloperidol on Delirium in Adult Patients: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The aim of this systematic review and meta-analysis was to investigate whether or not the use of haloperidol could reduce the incidence of delirium in adult patients. SUBJECTS AND METHODS: PubMed, Embase, the Cochrane Library, Elsevier, Wiley, and Ovid were searched for randomized controlled trials and prospective interventional cohort studies that compared haloperidol with placebo for delirium prophylaxis or with second generation antipsychotics for delirium treatment. The primary end point was the incidence and severity of delirium. After reviewing 272 relevant articles, 10 studies with 1,861 patients were finally included (haloperidol vs. placebo in 8 studies [n = 1,734], and haloperidol vs. second-generation antipsychotics in 2 studies [n = 127]). Revman 5.3 was used for the data analysis. RESULTS: Compared with placebo, a high dose of prophylactic haloperidol (>=5 mg/day) may help reduce the incidence of delirium in surgical patients (risk ratio 0.50, 95% CI 0.32, 0.79). There were no differences in the duration of delirium, QTc interval prolongation, extrapyramidal symptoms, intensive care unit stay, hospital stay, or mortality between the haloperidol and placebo groups. For delirium treatment, haloperidol exhibited similar effects as the second-generation antipsychotics. CONCLUSIONS: In this study, the limited available data revealed that prophylaxis haloperidol at a dose of >=5 mg/day might help reduce delirium in adult surgical patients. Further outcome studies with larger sample sizes are required to confirm these findings. PMID- 29518793 TI - Cross-cultural adaptation and validation of the Portuguese version of the Oxford Shoulder Score (OSS). AB - OBJECTIVE: To translate and culturally adapt the Oxford Shoulder Score (OSS) to the European Portuguese language, and to test its reliability (internal consistency, reproducibility and measurement error) and validity (construct validity). METHODS: The OSS Portuguese version was obtained through translations, back-translations, consensus panels, clinical review and cognitive pre-test. Portuguese OSS, Disabilities of the Arm, Shoulder and Hand (DASH) questionnaires, and the visual analogue scales of pain at rest [VAS rest] and during movement [VAS movement] were applied to 111 subjects with shoulder pain (degenerative or inflammatory disorders) and recommended for physical therapy. A clinical and sociodemographic questionnaire was also applied. RESULTS: The reliability was good, with a Cronbach's alpha coefficient of 0.90, an intraclass correlation coefficient (ICC) of 0.92, a standard error of measurement (SEM) of 2.59 points and a smallest detectable change (SDC) of 7.18 points. Construct validity was supported by the confirmation of three initial hypotheses involving expected significant correlation between OSS and other measures (DASH, VAS rest and VAS movement) and between OSS and the number of days of work absenteeism. CONCLUSION: The Portuguese OSS version presented suitable psychometric properties, in terms of reliability (internal consistency, reproducibility and measurement error) and validity (construct validity). PMID- 29518794 TI - Climate change, human health and the CPTPP. PMID- 29518795 TI - Paediatric pelvic fractures: Starship Hospital experience. AB - AIM: Pelvic fractures constitute between 0.3% and 4% of all paediatric injuries, with a mortality rate up to 25%. This study aims to review the experience with pelvic fractures at Starship Children's Hospital and demonstrate its role as a marker of severe trauma. METHODS: A retrospective review of children with pelvic fractures managed at our institution in the 20-year period between July 1995 and May 2015 was performed. The search identified 179 consecutive children admitted with a pelvic fracture. Data fields collected included patient details, mechanisms of injury, investigations performed, length of hospital stay, management and complications. Data was also collected on Injury Severity Score (ISS), Glasgow coma scale (GCS), transfusion requirements and details of associated injuries (both orthopaedic and non-orthopaedic). RESULTS: Median age was eight years (IQR 5-12 years) with 65% boys. The median Injury Severity Score (ISS) was 9 (IQR 4-22). Pedestrian-motor vehicle injuries were most common at 46% of cases, followed by passengers injured in motor vehicle accidents accounting for 23% (n=41). Associated injuries were present in 68% (n=122) of patients, with other orthopaedic fractures (42%, n=75) and thoracic injuries (33%, n=59) most common. Management of pelvic fractures was primarily non-operative, with only 7% (n=13) requiring operative intervention. In comparison, operative procedures for associated injuries were much more common and were required in 38% (n=68) of cases. CONCLUSION: Pelvic fractures represent an important marker for severe trauma. Patterns of paediatric pelvic fractures reported by other studies around the world are very similar. Understanding the patterns in which pelvic fractures and their associated injuries occur and the outcome of treatment is fundamental to the establishment of effective preventative, diagnostic and therapeutic interventions. PMID- 29518796 TI - Seasonal variation in Takotsubo syndrome compared with myocardial infarction: ANZACS-QI 16. AB - BACKGROUND: The incidence of myocardial infarction (MI) is characterised by seasonal variation, with a winter peak and summer trough. Takotsubo syndrome (TS) mimics MI, but is thought to have a distinct aetiology and may exhibit a reversed pattern of seasonal variation. This study investigated the seasonal variation in the incidence of TS in comparison to MI. METHODS: Two hundred and sixty consecutive patients with TS (95% women, median age 66 years) admitted between March 2004 and December 2016 in the Auckland region of New Zealand were identified. The study population was grouped into three-month intervals (seasons) according to the date of admission to analyse for potential seasonal variations in the incidence. The TS cohort was compared with 36,376 patients who presented with acute MI in the Auckland region (40% women, median age 71 years) between March 2004 and December 2016. RESULTS: The onset of TS differed as a function of season (p=0.02), with the events most frequent in summer (n=77, 30%) and least so in winter (n=46, 18%). In contrast, incidence of MI also varied by season (p=0.0003), with highest events in winter and lowest in summer. CONCLUSION: The pattern of seasonal variation in TS is reversed compared with MI, with peaks during summer. PMID- 29518797 TI - Management of suspected acute coronary syndrome patients admitted to cardiology or non-cardiology services at Auckland City Hospital: implications for future national data collection. AB - AIMS: To review the number, characteristics and clinical management of suspected ACS patients admitted to cardiology and non-cardiology services at Auckland City Hospital, to assess differences between these services and to assess the number who would potentially be enrolled in the All New Zealand Acute Coronary Syndrome (ACS) Quality Improvement Programme (ANZACS-QI) database. METHODS: Auckland City Hospital patient data was extracted from the Australia and New Zealand ACS 'SNAPSHOT' audit, performed over 14 days in May 2012. RESULTS: There were 121 suspected ACS admissions to Auckland City hospital during the audit period, with 45 (37%) patients directly managed by the cardiology service, and 76 (63%) patients cared for by non-cardiology services. Based on the subsequent discharge diagnosis, the cardiology service had more patients with definite ACS than the non-cardiology services; 27/45 (60%) compared to 16/76 (21%), difference (95%CI) 39% (22-56), P<0.0001). Cardiology ACS patients were more likely to undergo echocardiography; 15/27 (56%) compared to 2/16 (13%), difference 42% (18-68), P=0.0089), coronary angiography; 21/27 (78%) compared to 3/16 (19%), difference (95%CI) 59% (34-84), P=0.0003), coronary revascularisation; 18/27 (67%) compared to 3/16 (19%), difference (95%CI) 48% (22-74), P=0.004, and be discharged on two antiplatelet agents; 18/26 (69%) compared to 3/15 (20%), difference (95%CI) 49% (22-76), P=0.0036, or an ACEI/ARB; 20/26 (77%) compared to 5/15 (33%), difference (95%CI) 44% (15-72), P=0.0088. CONCLUSIONS: In patients with a discharge diagnosis of definite ACS, those managed by non-cardiology services were less likely to receive guideline-recommended investigations, and management, in this relatively small cohort study. About one-third of all ACS patients are managed by non-cardiology services and would not be recorded by the ANZACS-QI database. PMID- 29518798 TI - Renal function monitoring in patients prescribed dabigatran in the Compass Health Primary Health Organisation: a quality improvement audit. AB - AIM: To assess annual renal function monitoring and clinical indications for use in patients prescribed dabigatran. METHOD: A quality improvement activity included all patients in the Compass Health Primary Health Organisation (PHO) prescribed dabigatran. Information recorded: demographics; indication for use; daily dose; height; weight; serum creatinine; and estimated glomerular filtration rate (eGFR). The first audit occurred during July 2013 - May 2014, the second during May 2014 - October 2016. RESULTS: Across the PHO, all patients prescribed dabigatran were reviewed: 941 patients and 1,564 respectively. At the time of the second pass audit, renal function monitoring improved from 88% to 90%, and 96% were prescribed dabigatran for an approved indication. CONCLUSION: Results showed a continuing high level of renal function monitoring across the PHO in 90% of patients prescribed dabigatran. Practitioners were reminded to use creatinine clearance as a marker of renal function. Dabigatran was prescribed for an approved indication in 96% of patients. Our results are in line with recommended best practice and clinical guidelines. PMID- 29518799 TI - Smoking prevalence among doctors and nurses-2013 New Zealand census data. AB - AIMS: To examine recent smoking trends among doctors and nurses in New Zealand. METHODS: Analysis of smoking prevalence in the 2013 New Zealand Census and comparison with previous census data. RESULTS: The 2013 census included 7,065 male and 5,619 female doctors, and 2,988 male and 36,138 female nurses. Non response to smoking questions was less than 3%. In 2013, 2% of male and female doctors and 9% of male and 8% of female nurses were regular cigarette smokers. This compared with 4% male and 3% female doctors, and 20% male and 13% female nurses in 2006. Psychiatric nurses had the highest smoking prevalence (15% male, 18% female). More Maori doctors (6.8%) and nurses (19.3%) smoked. Around 96% of young (<25 years) doctors and 87% of young nurses had never been regular smokers. CONCLUSIONS: By 2013, New Zealand doctors had achieved the Smokefree 2025 goal of minimal (<5%) smoking prevalence and all nurses except psychiatric nurses were on track to do so. This suggests smokefree cultures can be established among substantial occupational groups. However, smoking among Maori nurses was relatively high. Targeted workplace smoking cessation support may be an efficient means to reduce smoking among key occupational groups, and may help reduce population smoking prevalence. PMID- 29518800 TI - What do doctors know about assessing decision-making capacity? AB - AIMS: To survey hospital doctors (HDs) and general practitioners (GPs) on what they know about assessing capacity, and to determine their educational needs. METHOD: A mixed-methods, cross-sectional survey was administered to a convenience sample of HDs and GPs. Respondents were asked about their roles, the prevalence of older patients they had seen, specific questions about capacity assessment, difficulties encountered and their preferred format for further education. RESULTS: 152/980 (15%) HDs and 74/4,000 (2%) GPs responded. Most had been concerned about a patient's capacity in the past year, but had not received training in assessing capacity since graduation. The average responder scored below 70% on knowledge questions. Lack of legal knowledge and time pressures were among difficulties encountered. One-third of respondents lacked confidence to assess capacity to a standard high enough to present in court. Many doctors were willing to improve their skills, requesting tutorials or short courses. CONCLUSION: Respondents demonstrated gaps in their knowledge on assessing capacity, and a lack of confidence in their opinions. The findings of this survey suggest that further clinical and legal education of doctors in performing capacity assessments would be valuable. PMID- 29518801 TI - New atrial fibrillation diagnosed perioperatively-anticoagulation practices in a secondary hospital. AB - BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia encountered perioperatively in patients undergoing non-cardiac surgery. There is emerging evidence suggesting high risk of ischaemic stroke. There are no clear guidelines surrounding initiation of anticoagulation in this setting. This study evaluates current practice in anticoagulant management of new perioperative AF at Hutt Hospital. METHODS: We have undertaken a retrospective study of 3,558 patients aged 60 years and over admitted for non-cardiac surgery at Hutt Hospital in 2014, to assess incidence of new AF/flutter and review how they were managed in regards to anticoagulation. RESULTS: We identified 28 patients as having "new AF/flutter" with CHA2DS2-VASc scores between 1 and 8. Anticoagulation management was inconsistent, with only some patients receiving anticoagulation if using CHA2DS2 VASc score as a marker of indication for treatment. CONCLUSIONS: There is insufficient evidence and lack of clear guidelines in this area to enable consistent and evidence-based management of patients with new AF identified perioperatively. Until such guidelines are available we suggest all such patients are individually assessed and treated depending on their individual risk/benefit analysis. Multiple factors such as bleeding risk, CHA2DS2-VASc score and perhaps duration of AF need to be considered. PMID- 29518802 TI - Mahi a Atua: a pathway forward for Maori mental health? AB - Maori demand on New Zealand mental health services is out of proportion to the size of the Maori population, and the psychiatric service response is limited by lack of capacity. But there is also an inherent lack of capability, that is, the ability of a Western paradigm psychiatric service to meet the needs of an indigenous community. The Mahi a Atua narratives-based programme established in the primary mental healthcare services of the Tairawhiti/Gisborne area has created a new approach to psychiatric assessment, diagnosis and therapy that is appropriate, but not confined, to the Maori community. PMID- 29518803 TI - Cannabis-don't smoke it! Four cannabis-related pathologies in one radiograph. PMID- 29518804 TI - Children cycling on footpaths. PMID- 29518805 TI - Comparison of Accuracy Between a Conventional and Two Digital Intraoral Impression Techniques. AB - PURPOSE: To compare the accuracy (ie, precision and trueness) of full-arch impressions fabricated using either a conventional polyvinyl siloxane (PVS) material or one of two intraoral optical scanners. MATERIALS AND METHODS: Full arch impressions of a reference model were obtained using addition silicone impression material (Aquasil Ultra; Dentsply Caulk) and two optical scanners (Trios, 3Shape, and CEREC Omnicam, Sirona). Surface matching software (Geomagic Control, 3D Systems) was used to superimpose the scans within groups to determine the mean deviations in precision and trueness (MUm) between the scans, which were calculated for each group and compared statistically using one-way analysis of variance with post hoc Bonferroni (trueness) and Games-Howell (precision) tests (IBM SPSS ver 24, IBM UK). Qualitative analysis was also carried out from three dimensional maps of differences between scans. RESULTS: Means and standard deviations (SD) of deviations in precision for conventional, Trios, and Omnicam groups were 21.7 (+/- 5.4), 49.9 (+/- 18.3), and 36.5 (+/- 11.12) MUm, respectively. Means and SDs for deviations in trueness were 24.3 (+/- 5.7), 87.1 (+/- 7.9), and 80.3 (+/- 12.1) MUm, respectively. The conventional impression showed statistically significantly improved mean precision (P < .006) and mean trueness (P < .001) compared to both digital impression procedures. There were no statistically significant differences in precision (P = .153) or trueness (P = .757) between the digital impressions. The qualitative analysis revealed local deviations along the palatal surfaces of the molars and incisal edges of the anterior teeth of < 100 MUm. CONCLUSION: Conventional full-arch PVS impressions exhibited improved mean accuracy compared to two direct optical scanners. No significant differences were found between the two digital impression methods. PMID- 29518806 TI - Clinical Evaluation of Monolithic Zirconia Crowns: A Short-Term Pilot Report. AB - PURPOSE: This study aimed to prospectively evaluate the clinical performance of monolithic zirconia crowns made of yttria-stabilized tetragonal zirconia polycrystal. MATERIALS AND METHODS: A total of 26 crowns placed on premolar or molar teeth in 18 patients were evaluated at the time of crown placement and at 2 weeks, 6 months, 1 year, and 2 years after placement. RESULTS: Twenty-five crowns rated as satisfactory according to the California Dental Association quality evaluation system. Most of the abutment and antagonist teeth showed good periodontal condition. An enamel cracking occurred on one antagonist tooth 1 year after placement. CONCLUSION: Monolithic zirconia crowns can be a clinically acceptable prosthetic option. PMID- 29518807 TI - In Vitro Study of Bonding Strength of Zirconia on Dentin Using Different Adhesive Systems. AB - PURPOSE: To compare different dental bonding systems that are currently available on the market. MATERIALS AND METHODS: A total of 100 extracted, intact third molars were coated in resin, cut, and divided into 10 groups of 10 molars each. Molars were bonded to zirconia blocks with a different bonding system per group. Resistance to shear forces was tested using a universal traction machine. Samples were observed under scanning electron microscopy (SEM) to determine the type of fracture. RESULTS: Statistical analyses showed a significant influence of adhesive on the zirconia-dentin assembly's resistance to shear forces. SEM analysis showed mainly adhesive and mixed fractures. CONCLUSION: Dentin bonding systems without adhesive capability showed better results than self-etch systems. PMID- 29518808 TI - Prosthodontic Treatment of a Patient with Gnathodiaphyseal Dysplasia: 30-Year Follow-up. AB - This case history report describes the long-term prosthodontic treatment of a patient with gnathodiaphyseal dysplasia (GDD). The patient was initially diagnosed with osteomyelitis in the maxilla in 1986, followed by osteonecrosis spread throughout the mandible. GDD was genetically diagnosed in 2006. Despite the severe alveolar bone resorption, prosthodontic treatment improved the patient's satisfaction and ability to perform essential functions. Regular prosthesis adjustments and periodic follow-up should continue to avoid future complications. PMID- 29518809 TI - Guide-Plane Retention in Designing Removable Partial Dentures. AB - PURPOSE: To compare the influence of abutment teeth guide planes and guiding surfaces on retention of a removable partial denture (RPD). MATERIALS AND METHODS: Extracted teeth embedded into a maxillary cast in the first premolar and second molar positions simulated two bounded saddles. Acrylic resin RPDs were made with no guide planes, then with guide planes, then with guiding surfaces added to directly contact the guide planes. The maximum loads on removal from the cast were recorded. RESULTS: There was a significant increase in retention force of 1.6 times when only guide planes were present and of 10.2 times when guiding surfaces intimately contacted the guide planes. CONCLUSION: The retention of acrylic resin RPDs can be substantially increased by making their guiding surfaces intimately contact the guide planes of the teeth. PMID- 29518810 TI - Reuse of Implant Healing Abutments: Comparative Evaluation of the Efficacy of Two Cleaning Procedures. AB - PURPOSE: To compare the efficacy of two systems in cleaning used healing abutments (HAs). MATERIALS AND METHODS: A total of 60 used HAs were randomized into two groups: one treated with an automatic cleaning system, and the other with conventional decontamination procedures. After sterilization and staining, the HAs were microscopically analyzed and underwent a cellular adhesion in vitro assay. RESULTS: Contaminated areas were observed with different frequencies in the two groups (3.6% test; 78.2% control; P < .001). In vitro assay showed a uniform cell distribution in test HAs, while areas of debris without adhering cells were a common finding in the control HAs. CONCLUSION: Further studies investigating the chemical composition and clinical influence of biologic remnants are necessary before considering reusing HAs. PMID- 29518811 TI - Do Sealing Materials Influence Superstructure Attachment in Implants? AB - PURPOSE: This study aimed to evaluate the possible effect of sealing materials on superstructure attachment (ie, tightening/loosening torque and implant-abutment gap) in two different implant systems. MATERIALS AND METHODS: A silicone, a chlorhexidine gel, and an industrial lubricant were tested. A 3D microscope was used for assessment of the implant-abutment gap, and the abutment screw was tightened and loosened with a digital torque screwdriver. A total of 20 implants per test group (10 BEGO Semados RI and 10 Nobel Biocare Replace Select Straight) were evaluated. RESULTS: The tested sealing materials did not influence the gap between implant and abutment, but the force necessary for loosening the abutment screws decreased significantly. CONCLUSION: Sealing materials may be useful against bacteria, but probably influence torque negatively. PMID- 29518812 TI - Using Intraoral Scanning to Fabricate Complete Dentures: First Experiences. AB - The newest impression techniques use intraoral scanners to capture both the hard and soft tissues. However, with edentulous patients, the accuracy of an intraoral scanner to capture an acceptable impression for the fabrication of a complete denture needs to be evaluated. Therefore, the purpose of this report of two patient treatments is to describe a technique that used intraoral scanning to record mucosal morphology and fabricate computer-aided design/computer-assisted manufacture (CAD/CAM) complete dentures. PMID- 29518813 TI - Precision and Accuracy of a Digital Impression Scanner in Full-Arch Implant Rehabilitation. AB - PURPOSE: To evaluate the accuracy and precision of a digital scanner used to scan four implants positioned according to an immediate loading implant protocol and to assess the accuracy of an aluminum framework fabricated from a digital impression. MATERIALS AND METHODS: Five master casts reproducing different edentulous maxillae with four tilted implants were used. Four scan bodies were screwed onto the low-profile abutments, and a digital intraoral scanner was used to perform five digital impressions of each master cast. To assess trueness, a metal framework of the best digital impression was produced with computer-aided design/computer-assisted manufacture (CAD/CAM) technology and passive fit was assessed with the Sheffield test. Gaps between the frameworks and the implant analogs were measured with a stereomicroscope. To assess precision, three dimensional (3D) point cloud processing software was used to measure the deviations between the five digital impressions of each cast by producing a color map. The deviation values were grouped in three classes, and differences were assessed between class 2 (representing lower discrepancies) and the assembled classes 1 and 3 (representing the higher negative and positive discrepancies, respectively). RESULTS: The frameworks showed a mean gap of < 30 MUm (range: 2 to 47 MUm). A statistically significant difference was found between the two groups by the 3D point cloud software, with higher frequencies of points in class 2 than in grouped classes 1 and 3 (P < .001). CONCLUSION: Within the limits of this in vitro study, it appears that a digital impression may represent a reliable method for fabricating full-arch implant frameworks with good passive fit when tilted implants are present. PMID- 29518814 TI - Biotransformation of Cyclodextrine-Complexed Semisynthetic Betulin Derivatives by Plant Cells. AB - In this study, three semisynthetic betulonic acid-based compounds, 20(29) dihydrolup-2-en[2,3-d]isoxazol-28-oic acid, 1-betulonoylpyrrolidine, and lupa 2,20(29)-dieno[2,3-b]pyrazin-28-oic acid, were studied in biotransformation experiments using Nicotiana tabacum and Catharanthus roseus cell suspension cultures. Biotransformation was performed using cyclodextrin to aid dissolving poorly water-soluble substrates. Several new derivatives were found, consisting of oxidized and glycosylated (pentose- and hexose-conjugated) products. PMID- 29518815 TI - A Review of the Traditional Uses, Phytochemistry and Biological Activities of the Genus Santolina. AB - The genus Santolina is a taxonomically complex group of plant species widely distributed in the Mediterranean flora and used in traditional medicine since ancient times for their biological properties, including antimicrobial, anti inflammatory, antispasmodic, digestive, and analgesic activities. Phytochemical investigations of Santolina species have revealed the presence of terpenoids as the main bioactive constituents of the genus. Coumarins and flavonoids were also identified. This review deals, for the first time, with information on the traditional uses, chemical profile, and biological properties of plants of the genus Santolina in order to provide input for future research prospects. PMID- 29518816 TI - Pancreatoscopy-guided laser lithotripsy in a patient with difficult ductal stone. PMID- 29518817 TI - Precut fistulotomy - widening its limits. PMID- 29518818 TI - Spontaneous perforation of the subvesical bile duct. PMID- 29518819 TI - [Intra- and postoperative complications classified according to the Clavien-Dindo classification in patients > 80 years after transurethral resection of the urinary bladder]. AB - INTRODUCTION: Urothelial carcinoma of the urinary bladder is a tumour of advanced age. The demographic change increases the number of very old patients ( > 80 years) subjected to TUR-B. MATERIAL AND METHODS: In a retrospective analysis, perioperative complications in 89 patients (> 80 years), who underwent a transurethral resection of the bladder between 2013 and 2016 in our department, were recorded and evaluated using the Clavien-Dindo grading system. RESULTS: Mean patient age was 87 years (82 - 94). 81 patients (91 %) were treated with oral anticoagulants (32 * ASA, 24 * NOACs, 25 * Marcumar). A histological examination revealed no tumour in 25/89 (28 %) patients, pTa in 28/89 (31 %), pT1 in 22/89 (25 %) and pT2 or higher in 14/89 patients (16 %), respectively. A total of 36/89 (40 %) patients experienced complications according to the Clavien-Dindo classification. 21/89 (23 %) of patients had a prolonged bladder irrigation due to macrohaematuria, 5/89 (6 %) needed surgical reintervention. 14 (12.4 %) patients needed a blood transfusion, 6 (5.3 %) of them preoperatively. According to the Clavien-Dindo classification, 4/89 (4 %) patients were graded as I, 21/89 (24 %) as II, 5/89 (6 %) as IIb and 3/89 (3 %) as IVa, respectively. Three patients (3 %) died postoperatively (Clavien-Dindo V). One of them died as a result of aspiration pneumonia (86 y, ASA IV), one as a result of pulmonary embolism (90 y, ASA IV) and one as a result of multiorgan failure (84 y, ASA III). In multivariate analyses, a tumour stage > T2 was confirmed as a significant predictor of the occurrence of postoperative complications (odds ratio of 9.541 (95 % CI 1.14 - 84.67 p = 0.032). For oral anticoagulants the odds ratio was 4.10 (95 % CI, 41.00 - 1.23, p = 0.050). CONCLUSION: Overall, the data show that a TUR-B is feasible in patients > 80 years with an increased complication rate in comparison to younger patients. Prolonged macrohaematuria and a high transfusion rate are attributable to the high percentage of orally anticoagulated patients. PMID- 29518820 TI - Ampullary adenocarcinoma: Defining predictors of survival and the impact of adjuvant therapy following surgical resection for stage I disease. AB - BACKGROUND AND OBJECTIVES: Outcomes and recommendations regarding adjuvant therapy (AT) for stage I ampullary adenocarcinoma (AAC) are inadequately described. We sought to determine factors associated with survival and better define the impact of AT. METHODS: The NCDB was queried for stage I AAC patients undergoing resection. We evaluated variables influencing the administration of AT and affecting survival, including the receipt of AT. RESULTS: Five hundred thirty seven patients were identified. 1, 3, and 5-year OS were 91.3%, 78.8%, and 67.4%, respectively. 103 received AT: 101 chemotherapy, 31 radiation, and 29 a combination of both. AT was more commonly utilized in patients with poorly differentiated and T2 tumors. Comorbid disease was inversely associated with use of AT. Age >=65 was associated with decreased survival for stage IA and IB, while positive resection margins and sampling of <12 LNs were associated with decreased OS for stage IA and IB, respectively. After propensity matching key covariates, no significant difference in OS was observed between those receiving and not receiving AT (P = 0.449). CONCLUSION: This analysis revealed a modest 5-year OS for stage I AAC. Age, positive resection margins, and evaluation of <12 LNs negatively influenced OS and AT did not convey a survival benefit. PMID- 29518822 TI - Double vascularized omentum lymphatic transplant (VOLT) for the treatment of lymphedema. AB - BACKGROUND AND OBJECTIVES: Orthotopic vascularized lymph node transplant has been successfully used to treat lymphedema. A second, heterotopic lymph node transplant in the distal extremity may provide further improvement. The vascularized omentum lymphatic transplant (VOLT) provides adequate tissue for two simultaneous flap transfers to one limb. The purpose of this study was to review our experience with this technique. METHODS: We conducted a retrospective study of patients who underwent VOLT, with a subgroup analysis of patients who underwent double VOLT. Technical aspects of the procedure, complications, and early outcomes were reviewed. RESULTS: From May 2015 to August 2017, 54 VOLTs were performed in 38 patients, of whom 16 received double VOLT. Among patients in the double VOLT group with postoperative imaging at 1 year, uptake into the transplanted omentum was seen in three of six (50%) patients on lymphoscintigraphy and in one of five (20%) patients on indocyanine green lymphangiography. One patient (3.1%) in the double VOLT group required a return to the operating room. There were no donor site complications in the double VOLT group. The overall complication rate was 15.8%. CONCLUSIONS: Double VOLT to the mid-level and proximal extremity is a safe and viable option. PMID- 29518823 TI - [Rational use of glucocorticoids]. PMID- 29518821 TI - Cerebellar alpha6 -subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders. AB - BACKGROUND AND PURPOSE: The pathophysiological role of alpha6 -subunit-containing GABAA receptors, which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine-induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar alpha6 GABAA receptors. Here, using hispidulin and a selective alpha6 GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar alpha6 GABAA receptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders. EXPERIMENTAL APPROACH: PPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured in Xenopus oocytes expressing recombinant alpha6 beta3 gamma2S GABAA receptors. KEY RESULTS: Hispidulin given i.p. or by bilateral intracerebellar (i.cb.) injection rescued PPI disruptions induced by methamphetamine, ketamine, MK-801 and phencyclidine. Intracerebellar effects of hispidulin were mimicked by Ro15-4513 and loreclezole (two alpha6 GABAA receptor PAMs), but not by diazepam (an alpha6 GABAA receptor inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an alpha6 GABAA receptor antagonist. Importantly, Compound 6 (i.p.) also rescued methamphetamine-induced PPI disruption, an effect prevented by furosemide (i.cb.). Both hispidulin and Compound 6 potentiated alpha6 beta3 gamma2S GABAA receptor-mediated GABA currents. CONCLUSIONS AND IMPLICATIONS: Positive allosteric modulation of cerebellar alpha6 GABAA receptors rescued disrupted PPI by attenuating granule cell activity. alpha6 GABAA receptor-selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is based on evidence for cerebellar contributions to cognitive functioning including sensorimotor gating. PMID- 29518824 TI - [Current status and prospects of primary immunodeficiency management in China]. PMID- 29518825 TI - [Consensus on the application of glucocorticoid from relative experts in pediatric rheumatoid diseases(part 1)]. PMID- 29518826 TI - [The identification and treatment of common comorbidity in children with autism spectrum disorder]. PMID- 29518827 TI - [Stimulator of interferon genes-associated vasculopathy with onset in infancy: first case report in China]. AB - Objective: To summarize the clinical characteristics and treatment efficacy of the first reported case of a Chinese boy with stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI). Methods: Sanger sequencing of the gene TMEM173 was performed based on systemic evaluation and clinical analysis of a highly suspected SAVI child admitted to Peking Union Medical College Hospital. A literature search (search terms included 'STING''SAVI''autoinflammatory diseases' and 'interferonopathy') was conducted using Chinese literature database, EMBASE and PubMed to include recently published SAVI studies (searched from January 2010 to December 2017). Results: A 14-year-old boy who had a history of chronic dry cough along with decreased activity tolerance after birth presented with growth retardation, chilblain lesions on the ear, telangiectasia of multiple skin areas and long clubbed fingers. His C-reactive protein was 21 mg/L, erythrocyte sedimentation rate was 78 mm/1h, and IgG was 22.16 g/L. The high-resolution computed tomography (HRCT) revealed interstitial lung diseases and echocardiography showed pulmonary artery hypertension, with a level of 61 mmHg (1 mmHg=0.133 kPa). Genetic mutation of TMEM173 (c.463G>A, p.V155M) was confirmed by Sanger sequencing. His activity tolerance increased to some extent after treatment with tofacitinib at a dose of 5 mg twice a day. Our review yielded 8 publications (8 English and 0 Chinese) . To date 20 cases have been reported worldwide, who mostly presented with skin and lung involvement as well as growth retardation. Conclusions: SAVI has been included within the spectrum of interferonopathy, which is a kind of autoinflammatory diseases as well. Typical clinical features include chilblain skin lesions, interstitial lung disease, growth retardation, elevated IgG levels, and increased inflammation markers. Janus kinase (JAK) inhibitors may offer benefit for SAVI patients. PMID- 29518828 TI - [Clinical characteristics of human recombination activating gene 1 mutations in 8 immunodeficiency patients with diverse phenotypes]. AB - Objective: To investigate the clinical characteristics of 8 immunodeficiency cases caused by human recombination activating gene 1 (RAG1) mutations, and to explore the relationship among genotypes, clinical manifestations and immunophenotypes. Methods: Clinical data were collected and analyzed from patients with RAG1 mutations who visited the Department of Clinical Immunology, Children's Hospital of Fudan University between October 2013 and June 2017. The data included clinical manifestations, immunophenotypes and genotypes. Results: A total of 8 patients were diagnosed with RAG1 deficiency (6 boys and 2 girls). The minimum age of onset was 2 months, and the maximum age was 4 months. The minimum age of diagnosis was 2 months, and the maximum age was 13 years. Four patients had a family history of infant death due to severe infections. Two cases were born to the same consanguineous parents. All cases had recurrent infections, including involvement of respiratory tract (8 cases), digestive tract (6 cases), urinary tract (1 case), and central nervous system (1 case). The pathogens of infection included bacteria, viruses and fungi. Rotavirus was found in 3 cases, cytomegalovirus (CMV) in 5 cases, bacillus Calmette-Guerin adverse reaction in 2 cases (1 of whom had a positive acid-fast smear from lymph node puncture fluid), fungal infection in 3 cases. One case had multiple nodular space-occupying lesions in lungs and abdominal cavity complicated with multiple bone destruction. The peripheral blood lymphocyte counts of all patients ranged between 0.1 *10(9)/L and 3.3*10(9)/L (median, 0.65*10(9)/L). Eosinophilia was found in 3 cases (range, (0.48-1.69) *10(9)/L). The patients were classified according to immunophenotype as severe combined immunodeficiency phenotype (4 cases), leaky severe combined immunodeficiency (2 cases), Omenn syndrome (1 case) and combined immunodeficiency (1 case) . Decreased serum IgG levels were found in 3 cases, increased serum IgM levels in 3 cases, increased serum IgE levels in 5 cases. RAG1 homozygous mutations were detected in 5 cases and RAG1 compound heterozygous mutations in 3 cases. Two novel mutations and six previously reported mutations were identified. Three cases were successfully treated with hematopoietic stem cell transplantation. Four cases died due to infections, and the 13 year-old patient was still under follow-up in the outpatient clinic. Conclusions: Different RAG1 gene mutations can lead to diverse clinical presentations and immune phenotypes. Clinicians should pay attention to the family history of infant death with severe infection. In that situation, immunological evaluation and gene detection should be performed as early as possible. PMID- 29518829 TI - [A national survey on physical growth and development of children under seven years of age in nine cities of China in 2015]. AB - Objective: To investigate and analyze the status of physical growth and its change in children under 7 years of age in 9 cities of China, and to provide scientific data for renewing and developing the new growth reference of Chinese children. Methods: Data of healthy children under 7 years of age were collected by stratified cluster sampling method in Beijing, Harbin, Xi'an, Shanghai, Nanjing, Wuhan, Guangzhou, Fuzhou and Kunming during the period from June to November in 2015. They were divided into 22 age groups. The sample size of boys or girls, urban or suburban was 150-200 in each age group in each city, and the total sample size in the 9 cities was 161 774. Weight, length/height, head circumference, sitting height, chest circumference and waist circumference were measured by the trained investigators using standard methods. There were strict quality control measures during investigation process. The t test was used to compare the difference of physical growth between two groups and one-way ANOVA was used to compare the difference of physical growth among three groups. Results: (1) The level of physical growth of children under 7 years were different between boys and girls, urban and suburban, as well as different regions of China in 2015. The urban-suburban difference was more significant in children older than 8 months, that is, the weight and height of urban children were greater than those of suburban children (0.01-0.48 kg and 0.1-1.1 cm respectively). (2) Weight and height of children in the 9 cities, whether urban or suburban areas, had been greater than WHO growth standards, for example, the Z scores of height values of urban and suburban children were 0.43 +/-0.99 (t=130.551, P<0.05) and 0.30 +/-1.01 (t=87.407, P<0.05) higher than the WHO standards. (3) The physical growth of children in the 9 cities was improved in varying degrees during the past 10 years. For example, the changes of weight and height in urban children under 3 years were not significant, while there was significant improvement among children older than 3 years and the increasing trend became apparent along with the increasing of age (0.05-1.18 kg in weight and 0.5-1.8 cm in height). The urban-suburban difference of physical growth in each age group of boys and girls narrowed significantly during the past 10 years, which was clearly shown from the narrowing urban-suburban differences of weight and height in boys aged 5.5-<6.0 years (1.58 kg in 2005 vs. 0.44 kg in 2015 and 2.8 cm in 2005 vs. 0.9 cm in 2015) . (4) From the increments of each decade during 1975-2015, a rapid increments of physical growth during 1975-2005 were found, while the increments after 2005 had slowed comparing with that of the previous period in urban areas, for example, the increments of height in boys aged 5.5-<6.0 years were 1.5, 2.1, 2.7, 0.7 cm respectively in the 1(st), 2(nd), 3(rd) and 4(th) decade (1975-1985, 1985-1995, 1995-2005, 2005-2015) . In suburban areas, the trends of the previous 3 decades were similar with that of urban children, while the increments of the 4(th) decade were still bigger though they were slightly smaller than those of the 3(rd) decade, for example, the increments of height in boys aged 5.5-<6.0 years were 2.4, 2.3, 3.2, 2.6 cm in the 1(st), 2(nd), 3(rd) and 4(th) decade respectively. Conclusions: Physical growth of children under 7 years of age showed a slow positive secular trend during the last decade after a rapid increase. The increments of suburban children's physical growth were greater than those of urban children. The physical growth of children under 7 years in 9 Chinese cities exceeded the WHO standards. PMID- 29518830 TI - [A follow-up study of six years' outcome of children with asthma in urban area of Beijing]. AB - Objective: To understand the outcome of asthma in children from urban area of Beijing and the factors associated with the outcome. Methods: A total of 497 children with asthma diagnosed in the epidemiological survey of childhood asthma in urban area of Beijing in 2010 were selected in this study. Telephone follow-up was conducted in 2016 to obtain information about asthma attack, emergency visit, hospitalization, medication and disease control, and data of comorbidities of allergic diseases from 1 year earlier. Enumeration data were compared using chi square test, measurement data were compared by rank sum test. The multi-factor logistic regression analysis was employed for the relationship between the related factors and asthma, Kaplan-Meier survival analysis and COX regression was employed to understand the relationship between the related factors and the course of the disease. Results: Questionnaires were conducted in 366 children, of whom 66.7% (244/366) were male, and 33.3% (122/366) were female.Compared with 2010, the rate of asthma attack and emergency room visits in children in last 12 months were significantly lower (19.1%(70/366) vs. 57.1%(284/497), and 3.0% (11/366) vs.19.7% (98/497), chi(2)=125.910 and 53.352, both P<0.01). There was no significant change in the proportion of allergic rhinitis and atopic dermatitis in last 12 months compared with that 6 years ago (both P>0.05). The number of children with clinical remission (2 years and above) was 75.4% (276/366). The number of children without remission within 2 years was 24.6% (90/366). The majority of children without remission were less than 12 years old boys (52.4% (33/63) vs. 30.9% (56/181) , chi(2)=9.273, P<0.01) . The proportion of children without remission associated with allergic rhinitis (67.8%(61/90)), atopic dermatitis (30.0%(27/90)), first-degree relatives with asthma (68.9%(62/90)) was higher than that of children with remission (51.8%(143/276), 17.0%(47/276), and 54.7%(151/276), respectively, chi(2)=7.013, 7.079, 5.608, respectively, all P<0.05). The proportion of children without remission who used control drugs was (33.3%(30/90)), which was higher than that in children with remission (7.2%(20/276), chi(2)=39.158, P<0.01). Multiple logistic regression showed that boy (OR=2.402 (1.611-3.580), P<0.05), later onset (OR=4.339 (>3-6 years old vs. 0 3 years old), OR=2.630(>6 years old vs. 0-3 years old), chi(2)=18.512, 31.371, 6.510, all P<0.05) were independent risk factors for asthma remission. COX regression analysis showed that the use of control drugs (HR=0.705 (0.515-0.964), chi(2)=4.795, P<0.05) was the relevant factor in the course of the disease. Conclusions: With the increase of age, the incidence of asthma in children in Beijing city in recent 12 months reduced. Male and late onsets were independent risk factors for asthma remission. The use of control drugs was the relevant factor in the course of the disease. PMID- 29518831 TI - [Clinical features and expression of PLA(2)R in renal tissue with idiopathic membranous nephropathy in children]. AB - Objective: To explore the clinical features and expression of PLA(2)R in renal tissue of children with idiopathic membranous nephropathy. Methods: Retrospective study was performed in patients with membranous nephropathy diagnosed through renal biopsy and the follow-up time was at least half a year in Shanghai Children's Hospital from January 2010 to February 2017. We compared their clinicopathological and pathological findings of IMN. Indirect immunofluorescence assay was used to detect glomerular PLA(2)R expression. We analyzed the differences of clinical features between the PLA(2)R negative and positive groups. T test, rank-sum test and Fisher exact test were used. Results: Eleven cases had hematuria and proteinuria, 9 cases presented with nephrotic syndrome, and 2 cases showed isolated proteinuria. Of the 22 cases of children with IMN, 16 patients had complete remission (complete remission rate was 72.8%), and 22 patients had partial remission. The renal function of all cases was normal and in all cases the estimated glomerular filtration rate was > 90 ml/(min.1.73m(2)). Of 22 cases with IMN, 7 cases were PLA(2)R-positive in renal tissue and 15 cases were PLA(2)R-negative. The age of positive group (10 years old) was older than the negative group (6 years old)(Z=-2.483, P<0.05) and the time of positive group (6 months) for urine protein to return to negative was longer than the negative group (2.5 months) through treatment. These differences were significantly different (Z=-2.072, P<0.05). Conclusions: Hematuria and proteinuria can be found in most children with idiopathic primary membranous nephropathy. Prednisone combined with immunosuppressant was effective. The positive rate of PLA(2)R in renal tissue of children with IMN was about 32%. The age of PLA(2)R positive group was older than the negative group. And the time of urine protein turning to negative in positive group was longer than that in the negative group. PMID- 29518832 TI - [DARS mutations responsible for hypomyelination with brain stem and spinal cord involvement and leg spasticity: report of two cases and review of literature]. AB - Objective: To analyze the clinical and imaging features of hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) due to mutations in DARS, and to identify DARS mutations responsible for HBSL. Methods: Data on 2 HBSL patients who were admitted to the pediatric department of Peking University First Hospital from January 2009 through December 2016 were reviewed and the 2 patients were followed up. Targeted next generation sequencing, whole exome sequencing and Sanger sequencing were employed to identify potential genetic variations of the children and their parents. The clinical manifestations, MRI features and genotypic characteristics of two patients were reviewed, and the literature was reviewed. HBSL reported cases were searched with"leukoencephalopathies, DARS"on databases of PubMed, Wanfang, China National Knowledge Infrastructure and VIP from 1975 to 2017. The clinical manifestations and molecular features were analyzed. Results: Both patients showed delayed motor development, but had normal cognitive development. At the age of 8 years, case 1 reached the most significant motor development milestone of only standing with help during the last follow-up. At the age of 9, case 2 could walk independently during the last follow-up. On physical examination, both showed leg spastcity, active tendon reflex, positive Babinski sign. Both patients had brain MRI findings of high T2WI signal in bilateral deep cerebral white matter, slightly lower T1WI, and no abnormal DWI signal. Lesions of case 1 were relatively extensive and involved subcortical white matter, corpus callosum and internal capsule. Spinal MRI scans for both patients showed no abnormal signals. Novel mutations in DARS gene-namely, c.1498_1499insTCA (p.500_501insIle) and c.1210A>G (p.Met404Val) , c.1432A>G (p.Met478Val) and c.1210A>G (p.Met404Val) were identified in case 1 and case 2 respectively. On the database, 2 reports involving 13 foreign patients were retrieved. The age of disease onset was from 4 months to 18 years, and their initial symptoms were development delay or regression. Most of them presented with progressive lower extremity spasm, and the brain magnetic resonance imaging was characterized by hypomyelination in white matter. Clinical phenotypes of different age groups were significantly different. Conclusion: We have reported two patients with HBSL in China, and 3 novel mutations in DARS, which is helpful for the diagnosis and genetic counseling of HBSL. PMID- 29518834 TI - [A Case of Dent-2 disease]. PMID- 29518833 TI - [Clinical and genetic characteristics of congenital myasthenia syndrome with episodic apnea caused by CHAT gene mutation: a report of 2 cases]. AB - Objective: To investigate the clinical and genetic features of congenital myasthenia syndrome with episodic apnea (CMS-EA) caused by gene mutation of choline acetyltransferase (CHAT) Methods: The clinical data of 2 patients with congenital myasthenia syndrome were collected, and both were diagnosed from 2013 to 2015 in Beijing Children's Hospital, Capital Medical University. The clinical features and gene mutation characteristics were analyzed, and the patients were followed-up for therapeutic efficacy. Results: The two patients (case 1 and case 2) had the onset soon after birth and at 3 months after birth respectively. The two patients were admitted to the PICU due to dyspnea, cyanotic episodes that required intubation. The patients had repeated apnea and became ventilator dependent. Case 1 died due to refusal of any treatment. Case 2 had a tracheotomy, and gradually weaned from ventilator after using pyridostigmine. The hospitalization of case 2 lasted 162 days. Case 2 was followed up to the age of 3 years and 4 months, and was extubated and was maintained on oral neostigmine but still had fluctuating ptosis and minor physical and mental retardation. Both cases were negative for anti-AChR, anti-acetylcholinesterase, anti-MuSK antibodies. Neostigmine test was negative in case 1 and suspiciously positive in case 2. Low-frequency repetitive nerve stimulation testing of case 2 was negative. Cranial MRI scans of both cases showed brain atrophy-like change. Genetic testing showed compound heterozygous deletions (exon 4, 5, 6) and pathogenic variant c.914T>C (p.I305T) in CHAT in case 1, compound heterozygous variants c.1007T>C (p.I336T) and c.64C>T (p.Q22X) in CHAT in case 2. To our knowledge, compound heterozygous deletions (exon 4, 5, 6) and p.Q22X were novel, previously unreported variants. Conclusion: CMS-EA usually presents at birth or in the neonatal period with hypotonia, ptosis, dysphagia due to severe bulbar weakness, and respiratory insufficiency with cyanosis and apnea. Early treatment with pyridostigmine is helpful to the improvement of clinical symptoms and prognosis. PMID- 29518835 TI - [Intravenous ketogenic diet for super-refractory status epilepticus in a case]. PMID- 29518836 TI - [Lower digestive tract bleeding caused by whipworm and ascaris infection in a patient]. PMID- 29518838 TI - [NO.144: Myasthenia, rash, fever, and dyspnea]. PMID- 29518837 TI - [A case of Lewis-Summer syndrome]. PMID- 29518839 TI - [Recognition of systemic-onset juvenile idiopathic arthritis at the genetic level]. PMID- 29518840 TI - [Progress in Merosin deficient congenital muscular dystrophy]. PMID- 29518841 TI - [The impact of gene polymorphism on warfarin therapy in children]. PMID- 29518842 TI - [Minutes of work conference of editor-in-chief of Chinese Journal of Pediatrics in 2018]. PMID- 29518843 TI - [The promotion of Chinese asthma guidline to the grassroot level]. PMID- 29518844 TI - [The progress of asthma management in China]. PMID- 29518845 TI - [Comparison of Chinese guideline for asthma managment and prevention (2016 update) and global initiative for asthma (2017 update)]. PMID- 29518846 TI - [Dilemma and strategy of asthma management in West China]. PMID- 29518847 TI - [Trends of asthma control, disease management and perception in China]. AB - Objective: To evaluate the changes of asthma control, disease management and perception in recent years in China. Methods: We conducted 2 multi-center, cross sectional surveys. Outpatient asthmatic patients from 10 cities in mainland China (2007-2008) and 30 central cities from 30 provinces in China (except Tibet)(2015 2016) were recruited respectively. Data of asthma control, disease management and perception from the 2 surveys were compared for 10 cities which took part in both of the 2 surveys. Chi-square test was used for comparison between groups. Results: The asthma control level improved from 28.7%(839/2 928) in 2007-2008 to 39.2%(533/1 361) in 2015-2016(P<0.01). The rate of emergency visits was 18.2%(248/1 362) in 2015-2016, which was lower than that in 2007-2008(33.9%, 1 032/3 044)(P<0.01). The rate of peak flow meter (PFM) usage was 17.9%(244/1 360) in 2015-2016, which was slightly lower than the PFM usage rate in 2007 2008(21.8%, 660/3 030)(P=0.004). 56.0%(763/1 362) of the patients used inhaled corticosteroid (ICS) + formoterol to control asthma when asthma symptoms deteriorated in 2015-2016, which was higher than the result of 2007-2008(31.8%, 803/2 524)(P<0.01). 71.1%(968/1 361) of the patients in 2015-2016 had a right perception on disease nature, while the result in 2007-2008 was 63.3%(1 889/2 986)(P<0.01). 61.6%(839/1 362) of the patients in 2015-2016 had a right perception on medication choice on daily-use first-line medication for chronic asthma, while the result in 2007-2008 was 51.0%(1 500/2 942)(P<0.01). Conclusion: The current level of asthma control and disease perception in China improved significantly in recent years, while the rate of PFM usage showed no significant improvement. Asthma action plan including PFM monitoring and asthma self management should be further promoted nationwide. PMID- 29518848 TI - [Acute respiratory failure due to Pneumocystis pneumonia in connective tissue disease patients: clinical manifestation and prognostic factors related to hospital mortality]. AB - Objective: To investigate the clinical manifestations and prognostic factors of hospital death in connective tissue disease patients with acute respiratory failure caused by pneumocystis pneumonia (PCP) admitted to two medical intensive care units(MICU). Methods: A retrospective review was conducted for all connective tissue disease (CTD) patients with acute respiratory failure from PCP in MICU of 2 academic medical centers between 2010 and 2015. The patients were divided into survivors and non-survivors. Demographic and clinical data, including laboratory, radiological and microbiological findings, as well as therapy, clinical course, mortality and prognostic factors of hospital mortality were included in the analysis. Logistic regression models were used to determine the effect of prognostic factors on hospital death after adjusting for covariates of which the p values were less than 0.1. Results: A total of 41 patients with connective tissue disease were identified. The PaO(2)/FiO(2) ratio (PFR) on ICU admission was 120 mmHg(55-180 mmHg, 1 mmHg=0.133 kPa). Common clinical features included dyspnea (90.2%, 37/41), fever (87.8%, 36/41) and dry cough(65.9%, 30/41). 58.5%(24/41) and 17.1%(7/41) patients were co-infected by CMV and aspergillus, respectively. The overall mortality rate was 75.6%(31/41). Compared with survivors, the age, APACHEII score and incidence of barotrauma in non survivors were higher (39+/-17 vs 58+/-15, t=3.018, P=0.002), (15+/-6 vs 19+/-5, t=2.528, P=0.019), (0/10 vs 12/31, chi(2)=5.473, P=0.021), while PFR on ICU admission was lower in non-survivors (172+/-68 vs 116+/-49, t=-1.893, P=0.007). Logistic analysis showed that PFR on ICU admission was the independent risk factor for hospital death (OR=1.004, 95%CI: 1.002-1.006, P=0.048). Conclusions: Mortality rate among patients with acute respiratory failure secondary to CTD related PCP is still high, and the poor prognostic factors of hospital mortality included PFR on ICU admission and barotrauma. PMID- 29518849 TI - [Respiratory manifestations of yellow nail syndrome: report of two cases and literature review]. AB - Objective: To describe the clinical characteristics of respiratory manifestations of yellow nail syndrome. Methods: We conducted a retrospective analysis of 2 patients with respiratory diseases associated with yellow nail syndrome. Their clinical and chest radiological data were collected. We searched PubMed, Wanfang and CNKI databases with the keywords "yellow nail syndrome, yellow nail and lung" in Chinese and English. And the relevant literatures, including 6 articles in Chinese and 81 articles in English, were reviewed. Results: Our 2 patients were male, one 60 years old and the other 76. Typical yellow nails were present in their fingers, and one of them also showed toe yellow nails. One patient was admitted for refractory respiratory infection and he was diagnosed with diffuse bronchiectasis. The respiratory symptoms could be relieved with antibiotics according to the results of sputum microbiological analysis. The other patient was admitted for cough and exertional dyspnea, and refractory pleural effusions were revealed bilaterally. He received repeated effusion drainage by thoracentesis, and Octreotide was tried recently. A total of 373 cases were reviewed in Chinese and English literatures. Pleural effusions (152 cases) and diffuse bronchiectasis (121 cases) were the most common reported respiratory manifestations. Lymphoedema was present in almost all cases with pleural effusion associated with yellow nail syndrome, and the effusion was usually exudative and lymphocyte predominant. Pleurodesis and decortication were effective for them. But, somatostatin analogues had been tried effectively for these patients recently. On the other hand, literatures showed that diffuse bronchiectasis in yellow nail syndrome was less severe than idiopathic diffuse bronchiectasis, and might benefit from long-term macrolide antibiotics. Conclusions: Yellow nail syndrome is a very rare disorder. Besides yellow nail, respiratory manifestations are the main clinical presentations. Diffuse bronchiectasis and recurrent pleural effusions are the common manifestations. PMID- 29518850 TI - [Comprehensive identification of compensatory mutations in rifampicin-resistant Mycobacterium tuberculosis strains]. AB - Objective: To comprehensively identify compensatory mutations in rpoA, rpoB and rpoC genes of rifampicin-resistant Mycobacterium tuberculosis (RIF-r MTB) and to evaluate the effect of rifampicin-resistant mutation type and lineage background on occurrence of compensatory mutations. Methods: Published MTB whole genome sequencing data were searched and downloaded. RIF-r MTB was identified through known rifampicin-resistant mutations. Based on parallel evolutionary patterns, we identified putative compensatory mutations in the phylogenetic tree and calculated proportions of accumulating compensatory mutations in each rifampicin resistant mutations' type and lineage background of RIF-r MTB. Statistic significance was analyzed by chi-square test. Results: A total of 8 453 global MTB whole genome sequencing data were downloaded form ENA (covering 12 countries), including 1 749 RIF-r MTB. Based on phylogenetic analysis, we totally identified 60 putative compensatory mutations (6 in rpoA gene, 16 in rpoB gene and 38 in rpoC gene), 11 of which were newly reported. RIF-R strains carrying rpoB S450L (41.7%, 279/669) had a significant higher chance to accumulate compensatory mutations than strains with other rpoB mutations (8.0%, 31/388, chi(2)=378.5, P<0.000 1). In addition, RIF-R strains from lineage 2 (34.0%, 223/656) had a significant higher chance to accumulate compensatory mutations than strains from other lineages [lineage1: 4.7%(2/43), 2/43, lineage3: 12.5%(4/32), 4/32, lineage4: 15.1%(78/517), 78/517; chi(2)=238.5, P<0.000 1]. Conclusions: Our study comprehensively identified putative rifampicin-resistant compensatory mutations of rifampicin resistance. RIF-R strains carrying rpoB S450L mutation or from lineage 2 had a significantly higher chance to accumulate compensatory mutations than strains either with other rpoB mutations or from other lineages. PMID- 29518852 TI - [Advances and clinical application of drug the therapies in asthma]. PMID- 29518851 TI - [Comparison of the NoSAS score with four different questionnaires as screening tools for obstructive sleep apnea-hypopnea syndrome]. AB - Objective: To evaluate the clinical utility of the NoSAS score in the screening of patients with obstructive sleep apnea-hypopnea syndrome(OSAHS), and to compare the performance of the NoSAS score with other tools including Epworth Sleepiness Scale(ESS), STOP, STOP-Bang(SBQ) and Berlin questionnaires. Methods: A total of 444 consecutive patients(328 males and 116 females) with suspected OSAHS who underwent an overnight polysomnography(PSG) were recruited into this study. Five questionnaires including the NoSAS score, ESS, STOP, SBQ and Berlin were completed. Based on the severity of OSAHS which was determined by apnea-hypopnea index(AHI), the patients were classified into 4 groups: normal(<5 events/h), mild(5-15 events/h), moderate(15-30 events/h) and, severe (>=30 events/h) OSA.Sensitivity, specificity, positive predictive values, negative predictive values and the area under the receiver operating characteristics curve of 5 questionnaires were calculated. Results: With AHI>=5 events/h as the standard diagnosis of OSAHS, the NoSAS score and SBQ questionnaire showed a moderate performance, with the NoSAS score having the largest area under the ROC curve(0.753, P<0.001), followed by the SBQ questionnaire (0.727, P<0.001). The performance of the ESS, Berlin, and the STOP questionnaire was not high. Using mild moderate-severe(>=5 events/h), moderate-severe(>=15 events/h), and severe(>=30 events/h)OSAHS as cutoffs, NoSAS had the highest specificity and positive predictive values(80.2% and 88%, 72% and 69.8%, 66.3% and 50.5%), and the sensitivity and negative predictive values were (51.5% and 36.9%, 56.5% and 59.1%, 66.3% and 74.2%) .SBQ had the highest sensitivity and the negative predictive values(80.2% and 88%, 72% and 69.8%, 66.3% and 50.5%), and the specific and positive predictive values were (45.7% and 81.0%, 39.1% and 61.9%, 34.8% and 44.4%). The NoSAS score >= 7 had higher sensitivity and negative predictive value(75.0% and 47.1%, 78.1% and 66.5%, 82.7% and 81.9%)than the NoSAS socre >= 8. With AHI>=5 events/h as the standard diagnosis of OSAHS, the NoSAS score and the SBQ questionnaire had a higher accuracy than the other 3 questionnaires as screening questionnaires for diagnosing OSAHS, and the value of DOR were 4.298 and 3.758 respectively. Conclusions: The NoSAS score and the SBQ questionnaire have a moderate performance in diagnosing OSAHS. The NoSAS score is a new screening tool, and it is similar to the SBQ questionnaire, being also simple and effective. While the SBQ questionnaire is more widely used, it is necessary to further evaluate the diagnostic value of NoSAS score. PMID- 29518853 TI - [The literature review of city ambient fine particle on the effects of chronic obstrutive pulmonary diease]. PMID- 29518854 TI - [Innate immunity in the pathogenesis of asthma]. PMID- 29518855 TI - [Research progress in pulmonary microecology of idiopathic pulmonary fibrosis]. PMID- 29518856 TI - [Use of mobile health to improve real-world practice]. PMID- 29518857 TI - [The hemodynamic effects of analgesic and sedative therapies, you should know]. PMID- 29518858 TI - [Follow the reporting guidance to improve the quality of guidelines report]. PMID- 29518859 TI - [Management of extra-articular manifestations in ankylosing spondylitis]. PMID- 29518860 TI - [Current status of rheumatoid arthritis registries and prevalence of remission]. PMID- 29518861 TI - [Comparison of clinical manifestations according to HLA-B(27) genotype in ankylosing spondylitis patients: real-world evidence from smart management system for spondyloarthritis]. AB - Objective: The aim of this study was to set up a large, longitudinal and prospective database to compare the clinical manifestations in human leucocyte antigen (HLA)-B(27) positive and negative patients with ankylosing spondylitis(AS) based on real-world evidence in Chinese population. Methods: A total of 897 outpatients with confirmed AS were recruited consecutively by smart management system for spondyloarthritis (SMSP) from April 13, 2016 to June 6, 2017 in Chinese PLA General Hospital from 30 provinces and autonomous regions. 801 patients with HLA-B(27) data were included in the analysis. Demographic and clinical parameters including Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), ankylosing spondylitis disease activity score (ASDAS), arthritis, enthesitis, Bath ankylosing spondylitis metrology index (BASMI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were compared between HLA-B(27) positive and negative groups. Results: A total of 801 patients were included in the analysis with an average age of (30.7+/-8.8) years. There were 659 males and 142 females and HLA-B(27) was present in 88.0%(705/801). Males were significantly more in HLA B(27) positive patients [83.3%(587/705) vs. 75.0%(72/96); P=0.047].The average age at disease onset was (22.3+/-7.6)years in HLA-B(27) positive patients and (24.4+/-8.7) years in HLA-B(2)7 negative ones (P=0.028).There was significant difference in diagnose delay between two groups [14.3(2.5,43.6)months in HLA B(27) positive patients vs. 20.3(5.0,67.4) months in HLA-B(27) negative ones, P=0.041]. Anterior uveitis was found to be significantly more common in HLA-B(27) positive patients [18.9% (133/705)vs.7.3%(7/96),P=0.005], and knee involvement less common in HLA-B(27) positive patients [4.0%(27/682) vs.10.0%(9/90), P=0.010], conversely. CRP[6.5(3.0, 16.4)mg/L vs. 3.5(1.6, 12.3)mg/L] and ESR[11.0(4.0, 24.0)mm/1h vs. 7.0(3.0, 16.0)mm/1h] were significantly higher in HLA-B(27) positive patients(P=0.005,0.013, respectively).But no differences in BASDAI,ASDAS,BASFI and BASMI were obtained between two groups. Conclusions: HLA B(27) positive patients had a higher proportion of males, a younger age of onset and a greater risk for occurrence of anterior uveitis, suggesting a poorer prognosis. PMID- 29518862 TI - [Clinical characteristics and renal uric acid excretion in early-onset gout patients]. AB - Objective: To investigate clinical characteristics and renal uric acid excretion in early-onset gout patients. Methods: Consecutive inpatients with primary gout were recruited between 2013 and 2017. The patients with gout onset younger than 30 were defined as early-onset group while the others were enrolled as control group. Clinical characteristics and uric acid (UA) indicators were compared between two groups. Results: Among 202 recruited patients, the early-onset group included 36 patients (17.8%). Compared with control group, the early-onset group presented more patients with obesity [13 patients (36.1%) vs. 22 patients (13.3%), P<0.05], significantly higher serum UA level [(634+/-124)MUmol/L vs.(527+/-169)MUmol/L] and glomerular load of UA[(7.2+/-2.8)mg.min(-1).1.73m(-2) vs. (4.4+/-2.2)mg.min(-1).1.73m(-2)] and estimated glomerular filtration rate (GFR) [(83+/-21)ml.min(-1).1.73m(-2) vs. (67+/-21)ml.min(-1).1.73m(-2)] (all P<0.05), lower fractional excretion of UA [4.4% (3.4%,6.1%) vs. 7.2% (5.2%,9.6%),P<0.05], whereas 24h urinary UA excretion was comparable [(2 788+/ 882)MUmol/1.73m(2) vs. (2 645+/-1 140)MUmol/1.73m(2), P=0.274]. Subgroup analysis of patients without chronic kidney disease showed significantly lower fractional excretion of UA in the early-onset group [4.5%(3.3%,6.1%) vs. 6.7% (5.1%,8.7%),P<0.05]. Logistic regression analysis showed that obesity (OR=3.25) and fractional excretion of UA less than 7% (OR=9.01, all P<0.05) were risk factors of gout early onset. Conclusion: The gout patients with early-onset younger than 30 present high serum and glomerular load of uric acid which might be due to obesity and relative under-excretion of renal uric acid. PMID- 29518863 TI - [Clinical study of low cytomegalovirus viral load thresholds for preemptive antiviral therapy in hematopoietic cell transplant recipients]. AB - Objective: To investigate the threshold of cytomegalovirus (CMV) DNAemia for preemptive antiviral therapy in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Viral load between 1*10(3) copies/ml and 5*10(3) copies/ml was defined as low viral load by real time Q-PCR. Clinical data and outcome were collected. Results: A total of 95 allo-HSCT recipients with low viral load from September 2014 to February 2015 were recruited in this study. The control group included 37 patients who received preemptive initial antiviral therapy. The other 58 patients didn't received antiviral treatment after positive viremia was confirmed. During monitoring, CMV viremia was cleared spontaneously in 17 patients of study group. Among 41 patients with continuous positive viremia in study group, 26 patients received antiviral therapy after second positivity including 18 with viral load >5*10(3) copies/ml, 2 with fever but still low viral load, 2 with hemorrhagic cystitis and low viral load, 4 with continuous low viral load. Eleven patients received antiviral therapy after the third positivity including 5 with viral load >5*10(3) copies/ml, 1 low viral load patient with fever and diarrhea, 5 with continuous low viral load. Only 4 patients received antiviral therapy after the fourth positivity of >5*10(3) copies/ml. In the study group, 35 cases received ganciclovir and 6 cases received foscarnet. The incidence of neutropenia did not differ significantly between study and control groups [minimum of neutrophil count: (1.63+/-0.41)*10(9)/L vs. (1.58+/ 0.36)*10(9)/L]. The proportion of viral load greater than 5*10(3) copies/ml in the first week was comparable in two groups. Successful viral clearance rate was not statistically different (P=0.87). Of all 95 patients, no CMV diseases developed, neither did patient die of CMV infection. Conclusions: Spontaneous clearance of viremia occurs in some patients receiving allo-HSCT with low CMV viral load. Delayed antiviral treatment of continuous positive viremia does not prolong the whole treatment duration, neither contributes to the progression of CMV diseases. PMID- 29518864 TI - [Clinical features and risk factors of internal carotid artery stenosis coexisting with unruptured intracranial aneurysm]. AB - Objective: To analyze the incidence of intracranial unruptured aneurysms in patients with internal carotid artery (ICA) stenosis (>=30%), the characteristics of aneurysms and risk factors in patients with ICA stenosis and intracranial aneurysm. Methods: Clinical data of patients receiving digital subtraction angiography (DSA) at Peking University Third Hospital between January 2012 and June 2015 were retrospectively reviewed to identify patients with ICA stenosis and unruptured intracranial aneurysm. Results: Among 247 patients with ICA stenosis, 16 patients (6.5%) with intracranial unruptured aneurysms were found including 7 females and 9 males with age from 47 to 83 years old. The severity of ICA stenosis in aneurysm group was (85.3+/-13.2)%, whereas it was (77.7+/-17.9)% in non-aneurysm group. The incidence of aneurysms in male patients with ICA stenosis was 4.5%(9/202), and 15.6%(7/45) in female patients (P<0.05). The incidence of aneurysms in patients with only in cervical segment (C1 segment) of ICA was 4.4%(10/226), whereas that of other segment was 28.6%(6/21) (P<0.05). Logistic multivariate regression analysis showed that gender and stenosis location were independent risk factors of aneurysms in patients with ICA stenosis. Conclusions: In patients with ICA stenosis, the incidence of aneurysm is much higher than that in general population. Intracranial aneurysms are more likely to occur in women and patients with ICA stenosis other than C1 segment. PMID- 29518865 TI - [Clinical characteristics of central diabetes insipidus: a retrospective analysis of 230 cases]. AB - Objective: To evaluate the clinical characteristics and etiologies of central diabetes insipidus (CDI). Methods: The clinical data of 230 patients with CDI in the Department of Endocrinology of Chinese PLA General Hospital from 2008 June to 2014 December were collected and analyzed retrospectively. Results: The three most common causes of CDI were idiopathic CDI, lymphocytic hypophysitis and intracranial germ cell tumors. Among all the CDI, the idiopathic CDI accounted for 37.48%. There were significant differences in age onset and gender distribution among the different causes of CDI. The patients with intracranial germ cell tumors [age of onset(19.2+/-10.2) years] were younger than the other types of CDI. Germ cell tumors patients were more common in male, and lymphocytic hypophysitis patients were more common in female. The most frequent abnormality of anterior pituitary in patients with CDI was growth hormone deficiency, followed by hypogonadism, adrenal insufficiency and hypothyroidism. The dysfunction of thyroid axis and adrenal axis in patients with germ cell tumor was more common than those in patients with idiopathic and lymphocytic hypophysitis. Conclusions: The most common causes of central diabetes insipidus were idiopathic CDI, lymphocytic hypophysitis and intracranial germ cell tumors. There were differences in age of onset, gender distribution and abnormal production of anterior pituitary hormones among all causes of CDI patients. PMID- 29518866 TI - [The effect of DNA hydroxymethylase Tet2 on gamma globin activation in the treatment of beta-thalassemia]. AB - Objective: To study the function of ten-eleven translocation 2 (Tet2) in gamma globin gene expression in patients with beta- thalassemia. Methods: Gamma globin expression was induced by 5-azacytidine and Tet2 gene expression was knocked down by short hairpin RNA (shRNA) in a human immortalized myelogenous leukemia K562 cell line. The global 5-hydroxymethylcytosine (5hmC) level was measured by an ELISA kit. 5hmC level of gamma globin gene was quantified by sulfite sequencing. The mRNA level of Tet2, gamma globin, and related transcription factors Nfe4 and Klf1 were quantified by real-time PCR. Results: Tet2 knockdown resulted in a decreased global 5hmC level from 0.14% to 0.03% as of the control group in K562 cells. The expression of gamma globin was enhanced after 5-azacytidine treatment in vitro. However, gamma globin mRNA level in Tet2 knockdown cells was only 55% as that in control group. The CG sites on gamma globin gene were unmethylated. As Tet2 was down-regulated, the expression levels of Nfe4 and Klf1 decreased by about 80% and increased to 3.5 folds, respectively. Conclusions: Tet2 appears to maintain 5hmC level and facilitates gamma globin gene activation. Moreover, Tet2 more likely regulates gamma globin expression via affecting transcription factors rather than the gene itself. Thus, Tet2 could be a potential therapeutic target for beta thalassemias. PMID- 29518867 TI - [Sarcopenia and long-term prognosis of patients with chronic heart failure in patients aged 70 years and over]. AB - To explore the association between sarcopenia (SAR) and long-term prognosis of patients with chronic heart failure (CHF) aged 70 years and over, 182 CHF patients from January 1, 2012 to December 31, 2014 were included in the present study. The patients were divided into the SAR group and the non-SAR group. The median follow-up period was 36 (3, 57) months. The endpoint was any heart failure related event (HFRE). There were significant differences in age, body mass index, hemoglobin, B-type natriuretic peptide, hypersensitive troponin T (hs-TnT), left ventricular ejection fraction (LVEF) and cardiac function class between the two groups (all P<0.05). The Kaplan-Meier analysis showed that the survival time of the non-SAR patients was much longer than that of the SAR patients (P<0.05). The multivariate Cox regression analysis indicated that SAR was an independent risk factor for HFRE, suggesting a role of sarcopenia on long-term prognosis of patients with chronic heart failure. PMID- 29518868 TI - [Clinical outcome of allogeneic hematopoietic stem cell transplantation in the treatment of 9 myeloid leukemia patients with granulocytic sarcoma]. AB - To explore the efficacy and influencing factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myeloid leukemia and granulocytic sarcoma (GS). Clinical outcome including hematopoietic reconstitution, transplant-related complications, survival and relapse were collected and retrospectively analyzed in 9 patients with myeloid leukemia and GS after allo-HSCT. Hematopoiesis reconstitution was achieved in all the 9 recipients. Four cases developed acute graft-versus-host disease (GVHD), and 1 with chronic GVHD. The median follow-up time after transplantation was 10(4-81) months. Only 2 cases survived, the other 7 died of relapse. The median time of relapse after transplantation was 5(3-19) months. Allo-HSCT is relatively effective treatment for patients with myeloid leukemia and GS. Relapse after transplantation remains the major factor of mortality. PMID- 29518869 TI - [A disease that is easily overlooked in elderly patients with fever of unknown origin]. PMID- 29518870 TI - [The recurrence of Helicobacter pylori infection and its influencing factors]. PMID- 29518871 TI - [Advances in diagnosis and treatment of gastric ulcerative diseases]. PMID- 29518873 TI - [Prioritize the standardization of clinical diagnosis and treatment of glaucoma]. AB - The standardization of clinical diagnosis and treatment of glaucoma is crucial to ensuring the quality of medical treatment and yielding high quality results in clinical research. Based on the results of a questionnaire survey, this paper analyzes the reasons for the gap between the current situations of glaucoma diagnosis and treatment in China and the international and domestic guidelines and consensus, emphasizes the importance of standardization in clinical diagnosis and treatment, and discusses the feasible strategies for improving the standardization of diagnosis and treatment.The goal is to improve glaucoma diagnosis and treatment service capability, bridge the gap between reality and domestic and international guidelines and consensus, and further standardize the management of glaucoma as a chronic disease, through efforts in strengthening training and promoting standardization. (Chin J Ophthalmol, 2018, 54: 161-163). PMID- 29518872 TI - [The 461th case: fever, hematuria, and right lumbar pain]. AB - A 56-year-old female was admitted to the Department of Rheumatology, Peking Union Medical College Hospital with complaint of recurrent fever and acute lumbar pain. Fever was complicated with malaise, cough and occasional blood-streaked sputum. Lab tests showed elevated white blood cell count, increased serum creatinine, erythrocyte sedimentation rate and C-reactive protein. Other lab findings included severe anemia, hematuria, and proteinuria. Immunological examinations were positive for antinuclear antibodies, antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibody. Ultrasonography and CT scan detected a huge spontaneous perirenal hematoma at right side. Angiography revealed multiple microaneurysms on bilateral renal arteries and branches. A diagnosis of systemic vasculitis was suggested. Under the combination therapy of corticosteroids and cyclophosphamide, the patient presented sustained remission for one year. This case indicates that prompt and sufficient treatment of primary disease is essential to a promising outcome. PMID- 29518874 TI - [The association between corneal biomechanical parameters and visual field progression in patients with normal tension glaucoma]. AB - Objective: To evaluate the association between corneal biomechanical parameters and visual field (VF) progression in normal tension glaucoma (NTG) using the Corvis-ST device, and to evaluate the ability of corneal biomechanical parameters to predict the VF progression. Methods: Corneal biomechanical parameters of newly diagnosed NTG patients were obtained using Corvis-ST in the baseline follow-up visit. The VF progression was defined as a 4-point increase in the Advanced Glaucoma Intervention Study (AGIS) score compared to the baseline in three consecutive follow-up visits (per 3-6 months). Corneal biomechanical parameters were compared between progressive and nonprogressive VF loss eyes using the independent-sample t test and Mann-Whitney U test. Spearman correlation analysis was used to explore the relationship between the corneal biomechanical parameters and the VF progression. Receiver operating characteristic curves were studied for the parameters and the sensitivity and specificity for distinguishing between progressive and nonprogressive glaucomatous eyes. The areas under the receiver operating characteristic curves (AUC) were also evaluated. Results: Sixty patients with NTG were enrolled in this study. Among them, 12 were lost to follow up. A total of 48 patients completed all follow-up visits on schedule. Eleven of them were excluded due to one or more uncontrolled intraocular pressure (IOP) during the follow-up (less than 30% IOP reduction from the baseline). Thirty seven eyes of 37 diagnosed NTG patients were enrolled. Ten eyes reached a progression endpoint. There was no significant difference in age, central corneal thickness, axial length, baseline IOP or baseline VF between the two groups. There was significant difference in Time A1 [(7.10+/-0.17) ms vs. (7.37+/-0.28) ms, t=-3.357, P=0.002], Length A1 [1.74(1.61, 1.77) mm vs. 1.78(1.77, 1.79) mm, Z=-3.036, P=0.002], Velocity A1 [0.16(0.14, 0.16) m/s vs. 0.15(0.14, 0.15) m/s, Z=-2.627, P=0.009] and DefAmpl HC [(1.22+/-0.13) mm vs. (1.12+/-0.11) mm, t=2.601, P=0.013] between progressive and nonprogressive glaucomatous eyes. Correlation analysis showed that Time A1, Length A1, Velocity A1 and DefAmpl HC were correlated with VF progression (r=-0.521, -0.463, 0.401, 0.349, P<0.05) . Time A1 demonstrated the highest AUC (0.817, P=0.001), followed by Length A1 (0.780, P=0.003), Velocity A1 (0.734, P=0.012) and DefAmpl HC (0.713, P=0.022). The cut-off set of Time A1 was 7.2 ms, the sensitivity was 80.0%, and the specificity was 82.8%. Conclusions: There were differences in corneal biomechanical parameters between eyes with progressive and nonprogressive VF loss in patients with NTG. There were lower Time A1 and Length A1 values and higher Velocity A1 and DefAmpl HC values in progressive glaucomatous eyes. This indicates a quicker response to reach first degree applanation and a larger degree of corneal deformability in progressive eyes. It is predicted that the easier deforming of the cornea, the smaller tolerance of the sclera and lamina cribros on IOP, making the optic disc more vulnerably. This may be one of the causes of glaucomatous optic nerve damage. Time A1 was the best parameter to predict the progression of VF among the corneal biomechanical parameters obtained by Corvis-ST. (Chin J Ophthalmol, 2018, 54: 171-176). PMID- 29518875 TI - [The 8-year follow-up study for clinical diagnostic potentials of frequency doubling technology perimetry for perimetrically normal eyes of open-angle glaucoma patients with unilateral visual field loss]. AB - Objective: To analyze potentials of frequency-doubling technology perimetry (FDP) for diagnosing open-angle glaucoma (OAG) in perimetrically normal eyes of OAG patients diagnosed with standard automated perimetry (SAP) and relating factors from abnormalities on FDP to visual field loss on SAP. Methods: A prospective cohort study. Sixty-eight eyes of 68 OAG patients visiting the ophthalmic clinic of Peking University Third Hospital during November 2003 and October 2007 [32 primary open-angle glaucoma patients and 36 normal tension glaucoma patients, 32 males and 36 females, with an average age of (59+/-13) years] with unilateral field loss detected by SAP (Octopus101 tG2 program) were examined with the FDP N 30 threshold program (Humphrey Instruments) at baseline. Two groups, FDP positive group and FDP negative group, were divided based on the FDP results, and visual field examinations were followed by a series of SAP examinations for the perimetrically normal eyes over 8 years. During the follow-up, the difference of the converting rate of SAP tests between the two groups was analyzed. Differences between "convertors" and "non-convertors" of SAP tests in the FDP positive group, such as the cup-to-disk ratio and glaucomatous optic neuropathy rate, were also compared with the independent-sample t test or Wilcoxon two-sample test for continuous variable data and the chi(2) test or Fisher exact test for classified variable data and rates. Results: Forty-eight perimetrically normal eyes of 48 participants had complete data and a qualifying follow-up. Baseline FDP results were positive in 33 eyes and negative in 15 eyes. Of the eyes with positive FDP results, 22 eyes developed abnormal SAP results after 4.0 to 90.0 months (median 14.5 months) , whereas none of the eyes with negative FDP results developed abnormal SAP results. For perimetrically normal eyes in the FDP positive group, "converters" showed a greater cup-to-disk ratio (0.73+/-0.09 vs. 0.63+/-0.14, Wilcoxon two-sample test, P=0.011) and more eyes with glaucomatous optic neuropathy (19/22 vs. 4/11, Fisher exact test, P=0.006). Conclusions: In perimetrically normal eyes of OAG patients, FDP could detect visual field loss of these eyes and predict to some extent future visual field loss on SAP. Severity of glaucomatous optic neuropathy at baseline is related to converting from abnormalities on FDP to visual field loss on SAP. (Chin J Ophthalmol, 2018, 54: 177-183). PMID- 29518876 TI - [Changing patterns of surgical treatment for glaucoma in the Eye Hospital of Wenzhou Medical University during the past ten years]. AB - Objective: To investigate the patterns of surgical treatment for patients with glaucoma in the Eye Hospital of Wenzhou Medical University from 2005 to 2014. Methods: Retrospective case series about 6 781 glaucoma patients (7 751 eyes) who received surgical treatment from January 1, 2005 to December 31, 2014 in the Eye Hospital of Wenzhou Medical University. Among them, 2 869 were males and 3 912 were females, aged (62+/-14) years. The data of patients' demographic information, diagnosis and surgical procedures [trabeculectomy, aqueous shunts of ExPRESS and Ahmed for extraocular reservoir, cataract extraction with intraocular lens (IOL) implantation, and combined operations for glaucoma and cataract] were collected and the patterns of surgical treatment were evaluated. SPSS 21.0 statistical software was used, mainly for statistical description of the data. Results: The ratio of trabeculectomies increased between 2005 and 2009, from 48.2% (95/197) to 57.7% (488/846), but decreased to 21.1% (220/1 041) in 2014. The ratio of aqueous shunts of ExPRESS and Ahmed increased to 6.1% (63/1 041) and 7.6% (79/1 041) from 2005 to 2014, respectively. The ratio of cataract extraction with IOL implantation increased to 28.4% (294/1 036) in 2012, but decreased to 21.6% (225/1 041) in 2014. The ratio of combined operations for glaucoma and cataract decreased to 6.6% (47/717) from 2005 to 2010, and increased to 36.6% (381/1 041) in 2014. Over the decade, the ratio of cataract extraction with goniosynechialysis increased from 2.4% (15/623) to 17.7% (184/1 041). The rate of iridotectomy decreased to 0.2% (2/1041) in 2014. Conclusions: Trabeculectomy, cataract surgery and combined surgery for glaucoma with cataract were still the mainstream of glaucoma surgery in the Eye Hospital of Wenzhou Medical University from 2005 to 2014. And the ratio of cataract extraction with IOL implantation, aqueous shunts of ExPRESS and Ahmed, and combined operation for glaucoma and cataract rapidly increased, with cataract extraction with goniosynechialysis increasing most rapidly and becoming the mainstream procedure of treatment for glaucoma and cataract. Inversely, the rate of trabeculectomies and iridotectomies decreased dramatically over this period.(Chin J Ophthalmol, 2018, 54: 184-188). PMID- 29518877 TI - [Analysis on the medication of the outpatients diagnosed with glaucoma at West China Hospital of Sichuan University]. AB - Objective: To retrospectively investigate the medication structures and characteristics among the outpatients diagnosed with glaucoma at West China Hospital of Sichuan University in 2015. Methods: Based on retrospective study method, the data of glaucoma patients (6 236 people, and 13 693 person-times) who received medication at the outpatient department of West China Hospital in 2015 were collected from hospital information system, such data include date, doctor's advice date, doctor's advice ID, diagnosis, western medicine fee, Chinese medicine fee, etc. Excel 2011 software was used to analyze the drug use of glaucoma outpatients. Results: (1) The total of outpatients with glaucoma medication were 13 693 person-times, of which 4 247 persons-times patients who did not take intraocular pressure (IOP)-lowering drugs accounted for 31.02%. (2) There were 7 types of IOP-lowering drugs used, including 14 kinds of different drugs. The top three most frequently used drugs were prostaglandin analogs (PGA, 36.98%, 5 847 cases), beta-adrenergic receptor blockers (26.61%, 4 207 cases), and carbonic anhydrase inhibitor (CAI, 20.95%,3 312cases). (3) Among all the patients who have taken IOP-lowering drugs, the patients that received single drug treatment accounted for 62.41% (5 895/9 446), and the most frequently used single IOP-lowering drug is PGA(44.94%,2 649/5 895). Patients that received two drugs combined treatment accounted for 28.03% (2 648/9 446), and the most frequently used combined treatment is "beta-adrenergic receptor blockers+ PGA" (27.57%,730/2 648). Patients that received three-drugs combined treatment accounted for 7.88% (744/9 446), and the most frequently used combined treatment is "beta-adrenergic receptor blockers+ PGA+ CAI" (46.24%,344/744). Patients that received four-drugs combined treatment accounted for 1.57% (149/9 446), and the most frequently used combined treatment is "beta-adrenergic receptor blockers+alpha-adrenergic receptor agonist +PGA + CAI" (87.25%,130/149). And patients that received five-druges combined treatment accounted for 0.11% (10/9 446). Conclusions: The most frequently used single IOP-lowering drug for outpatients with glaucoma at West China Hospital of Sichuan University in 2015 is PGA. The most frequently used combined medications are "beta-adrenergic receptor blockers+ PGA" for two-drugs combined treatment and "beta-adrenergic receptor blockers+ PGA + CAI" for three-drugs combined treatment.(Chin J Ophthalmol, 2018, 54: 189-193). PMID- 29518878 TI - [Comparative analysis on the significances of contrast-enhanced ultrasound and dynamic contrast-enhanced magnetic resonance imaging in uveal melanoma diagnosis]. AB - Objective: To compare the significance of contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the diagnosis of uveal melanoma. Methods: It was a retrospective case series study. Sixty-three cases (63 eyes) of uveal melanoma patients (confirmed by histopathology) who underwent CEUS and DCE-MRI examination at Beijing Tongren Hospital during January 2010 and May 2014 were collected, including 30 males and 33 females, with average age of 47 years (ranged from 27 to 69 years). The data and images of CEUS and DCE MRI were analyzed and the findings were reviewed and compared to pathology results so as to evaluate the diagnosis coincidence rate of using CEUS, DCE-MRI and both (combined CEUS and DCE-MRI). Fisher's exact test method was used to explore the efficiency of diagnosing uveal melanoma with CEUS, DCE-MRI and the two combined. Results: Among the 63 cases of uveal melanoma, the coincidence rates of CEUS, DCE-MRI and combined diagnosis for uveal melanoma were 93.7% (59/63), 90.5% (57/63) and 100% (63/63) respectively. There was no significant difference between CEUS and DCE-MRI (P=0.663). Fifty-five cases showed fast wash in and fast wash out, and 8 cases showed fast wash in and slow wash out in time intensity curve of CEUS. Fifty-four cases showed rapid increase and rapid decrease, and 7 cases showed rapid increase and slow decrease, and 2 cases showed sustain enhancement in signal intensity-time curve of DCE-MRI. Conclusions: CEUS is an effective method in diagnosis of uveal melanoma. CEUS and DCE-MRI are of similar value in the diagnosis of uveal melanoma, physicians may be able to acquire more diagnostic information when using the two methods in combination.(Chin J Ophthalmol, 2018, 54: 194-198). PMID- 29518879 TI - [Computed tomography imaging parameters of 82 Chinese patients with congenital microphthalmia]. AB - Objective: To observe computed tomography (CT) imaging parameters of congenitally blind microphthalmia in Chinese patients and to provide clinical reference data for the Chinese population. Methods: It was a retrospective study for a consecutive case series of congenitally blind microphthalmia from July 2011 to July 2013. All of the patients were diagnosed in the Ocular Plastic Department, Tongren Eye Center, Beijing Tongren Hospital. We employed multi-section helical CT imaging with a computer-aided design system to observe and measure the imaging features in 82 Chinese patients (85 eyes). The paired T-test was applied for comparing the axial lengths, transverse diameters, and vertical diameters between the both sides in patients with congenital microphthalmia. The Pearson correlation was used for analyzing the relationship between the axial length and the age of the patients. Results: In the 82 patients, the age ranged from 1 month to 40 years old. Forty-one patients were male and 41 were female. The disease was unilateral in 96.34% of the patients. The orbital cysts were observed in 12.94% of them, and 76.47% of them presented basic structures on the CT scan. The abnormalities of the lens (62.35% of the eyes) and vitreous (82.35% of the eyes) were observed. The mean maximum axial length of the affected eyes (85 eyes) was (14.52+/-0.56) mm and the mean axial length of the unaffected eyes (79 eyes) was (22.79+/-0.36) mm. There was significantly statistical difference in the ocular size between the affected and unaffected eyes (t= 1.156, P<0.001) . Conclusions: Congenitally blind microphthalmia is usually complicated with the abnormalities of the lens and vitreous. The ocular size decreases significantly. The results of the present study provide a clinical reference for evaluating congenitally blind microphthalmia.(Chin J Ophthalmol, 2018, 54: 199-204). PMID- 29518880 TI - [Magnetic resonance imaging features of tear outflow and structural changes of the lacrimal sac and nasolacrimal duct in normal subjects with eyes closed]. AB - Objective: To investigate the static and dynamic features of the normal lacrimal sac (LS)-nasolacrimal duct (NLD), and find out if tear flows while the subject is in supine position with eyes closed. Methods: Cross-sectional study. Healthy volunteers and patients whose head were examined by MRI in Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine with normal LS NLD were recruited. The normal lacrimal ducts of the candidates were scanned, while candidates remained in supine position, by static or dynamic imaging procedures with a 1.5T MRI system, which adopted the thinnest slice thickness, consecutive sections (no spacing) and two scanning planes (axial and coronal planes of LS-NLD). The static and dynamic imaging procedures were done in June and July 2014 and October 2015, respectively. The static imaging was performed with conventional T(2)WI, contrast-enhanced 3D FIESTA-C, contrast-enhanced T(1)WI and heavy T(2)WI pulse sequences under normal physiological condition, and 104 eyes with normal LS-NLD from 39 patients and 13 healthy volunteers (21 male and 31 female) aged 10 to 75 years were scanned with the static procedure. The dynamic imaging was done with heavy T(2)WI pulse sequence. The coronal dynamic imaging was done only after 0.9% NaCl was instilled in the conjunctival sacs, and 20 eyes with normal LS-NLD of 10 volunteers (6 male and 4 female) aged 23 to 53 years were scanned with the coronal dynamic procedure. The axial dynamic imaging was done under normal physiological condition and after 0.9% NaCl was instilled in the conjunctival sacs respectively, and 20 eyes with normal LS-NLD of 10 volunteers (8 male and 2 female) aged 20 to 40 years were scanned with the axial dynamic procedure. The incidences on the axial dynamic imaging under the two conditions were compared with chi(2) test. Results: A total of 104 eyes with normal LS-NLD (52 candidates) were scanned with the static imaging sequences. In all LS-NLDs, an indentation located at the posterior-lateral side wall of the junction of LS-NLD was discovered, and its depth was variable. In 28.8% (30/104) of LS, 64.4% (67/104) of the junctions and 22.1% (23/104) of NLD, lumens were closed. As for the coronal dynamic imaging (20 eyes with normal LS-NLD in 10 subjects), segmental tear transit was observed in 15/20 of NLD. As for the axial dynamic imaging (20 eyes with normal LS-NLD in 10 subjects), after 0.9% NaCl was instilled, dynamic changing of their lumen size was revealed in 17/20 of LS-NL and the occurrence rate of the lumen size changing (29.3%, 94/321, the number of the axial slices with lumen changes/total number of the axial slices imaged) was higher than that (16.4%,52/317) under normal physiological condition. The difference between the two rates was statistically significant (chi(2)=14.993, P<0.001). LS contained more tear than NLD. Conclusion: While the candidates are in supine position with eyes closed (absolutely no blinking), an indentation is at the posterior-lateral side wall of the junction of LS-NLD, and there are autonomous, segmental lumen open-close actions in normal LS-NLD and tear transit in their lumens. (Chin J Ophthalmol, 2018, 54: 205-211). PMID- 29518881 TI - [A novel VSX1 gene mutation identified in a sporadic keratoconus patient from China]. AB - Objective: To investigate the possibility of the visual system homeobox 1 (VSX1) gene as a candidate susceptibility gene for Chinese patients with sporadic keratoconus, and to identify sequence variants of the VSX1 gene in such patients. Methods: Cross-sectional study. Genomic DNA was extracted from the leukocytes in the peripheral venous blood of 50 patients with sporadic keratoconus and 50 control subjects without this ocular disorder. Five exons and the intron-exon splicing of the VSX1 gene were amplified by polymerase chain reaction (PCR). The PCR products were directly sequenced and compared to the GeneBank database to find mutations. Bioinformatics analysis was done to predict the influence of these mutations on proteins. Results: One novel missense heterozygous mutation (p.R131P) was found in exon 1 of the VSX1 gene in one keratoconus patient. Another heterozygous mutation (p.G160V) in exon 2 was found in two keratoconus patients. These mutations were not detected in the control subjects. Bioinformatics analysis predicted that the p.R131P mutation may not cause a pathogenic change, but the p.G160V mutation might be functionally deleterious. In intron 3 of the VSX1 gene, the nucleotide substitution of g.8326G>A was detected to be heterozygous in 3 cases of sporadic keratoconus and 4 cases of control and homozygous in 2 cases of sporadic keratoconus and 1 case of control. The variation of g.8326G>A belonged to a single polymorphism change of the VSX1 gene. Conclusions: The p.R131P detected in this study is a novel mutation of the VSX1 gene. Sequence variants of the VSX1 gene were identified for the first time in Chinese patients with sporadic keratoconus, but their precise role in disease causation requires further investigations. (Chin J Ophthalmol, 2018, 54: 212 217). PMID- 29518882 TI - [Progress of clinical correlation research on migraine and glaucoma]. AB - Migraine is a common primary headache disorder. The estimated annual prevalence rate of migraine in China is 9.3%. Migraine is typically involved with a series of ocular symptoms including glaucoma, visual performance tests relevant to glaucoma exhibited correlation between glaucoma and migraine. Even though migraine patients exhibit no glaucoma-related signs during intermissions of migraine attacks, the results of visual function tests (visual field, electrophysiology, ocular imaging) relevant to glaucoma still indicate abnormalities. It is fairly typical that most of the patients may neglect their ocular problems when migraine breaks out. Epidemiological data suggests an increasing prevalence of migraine patients with glaucoma, particularly normal tension glaucoma. This paper reviews and discusses the effect of migraine on the clinical assessment and diagnosis of glaucoma. (Chin J Ophthalmol, 2018, 54: 224 228). PMID- 29518883 TI - [Research progress of Sturge-Weber syndrome induced glaucoma]. AB - Sturge-Weber Syndrome is a sporadic rare disease. Its characteristic feature of Port-wine Stain in patient's face has been an important indicator for screening secondary glaucoma, which further provides patients with possibility of early diagnosis and treatment of Sturge-Weber Syndrome induced glaucoma. This paper focuses on the pathogenesis, risk factors and treatment of Sturge-Weber Syndrome secondary glaucoma. (Chin J Ophthalmol, 2018, 54: 229-233). PMID- 29518884 TI - [The relationship between necroptosis and blinding eye diseases]. AB - As a programmed cell death manner which is distinguished from apoptosis and autophagy, necroptosis is a newly discovered pathway of regulated necrosis that requires the protein receptor interacting protein kinases 1 and 3 and mixed lineage kinase domain-like protein. Necroptosis is mediated by death receptors, toll-like receptors and probably other mediators. Emerging evidences have delineated that necroptosis plays an important role in the occurrence and development of various blinding eye diseases. In this review, the related mechanism of necroptosis, the relationship between necroptosis and multiple blinding eye diseases, such as age-related macular degeneration, retinitis pigmentosa and glaucoma, and the potential therapeutic targets of necroptosis are discussed. (Chin J Ophthalmol, 2018, 54: 234-240). PMID- 29518885 TI - A two-year progress report on medical education standards in the Western Pacific: Presidential address 2018. PMID- 29518886 TI - Curvas de fusion de regiones genomicas especificas: una herramienta prometedora para el diagnostico y tipificacion de las especies causantes de la leishmaniasis cutanea en Colombia. AB - Introduccion. La leishmaniasis cutanea es una enfermedad causada por parasitos del genero Leishmania que tiene gran incidencia en Colombia. El diagnostico y la identificacion de la especie infecciosa son factores criticos en el momento de escoger e iniciar el tratamiento. Actualmente, los metodos de diagnostico y tipificacion requieren procedimientos complejos, por lo que es necesario validar nuevos marcadores moleculares y metodos que simplifiquen el proceso.Objetivo. Desarrollar una herramienta basada en la reaccion en cadena de la polimerasa (PCR) con curvas de fusion (High Resolution Melting; PCR-HRM) para el diagnostico y tipificacion de las tres especies de Leishmania de importancia epidemiologica en casos de leishmaniasis cutanea en Colombia.Materiales y metodos. Los genomas de Leishmania panamensis, L. braziliensis y L. guyanensis se compararon mediante metodos bioinformaticos. Las regiones especificas de especie identificadas se validaron mediante PCR. Para los marcadores seleccionados se diseno una PCR-HRM y se estimaron algunos parametros de validez y seguridad usando aislamientos de pacientes colombianos caracterizados previamente mediante PCR y analisis de polimorfismos en la longitud de los fragmentos de restriccion (Restriction Fragment Length Polymorphism - RFLP; PCR-RFLP) del gen hsp70.Resultados. El analisis genomico comparativo mostro 24 regiones especificas de especie. Sin embargo, la validacion mediante PCR solo identifico un marcador especifico para cada especie de Leishmania. Los otros marcadores mostraron amplificacion cruzada. El limite de deteccion para los tres marcadores seleccionados fue de un parasito, mientras que la sensibilidad, la especificidad, el valor predictivo positivo y el negativo fueron de 91,4, 100, 100 y 75 %, respectivamente.Conclusiones. Las tres regiones seleccionadas pueden emplearse como marcadores moleculares en el diagnostico y tipificacion de las especies causantes de la leishmaniasis cutanea en Colombia. PMID- 29518887 TI - Cloning and Functional Characterization of Two 4-Coumarate: CoA Ligase Genes from Selaginella moellendorffii. AB - Selaginella is an extant lycopodiophyte genus, which is representative of an ancient lineage of tracheophytes. The important evolutionary status makes it a valuable resource for the study of metabolic evolution in vascular plants. 4 coumarate: CoA ligase (4CL) is the pivotal enzyme that controls the flow of carbon through the phenylpropanoid metabolic pathway into the specific lignin, flavonoid, and wall-bound phenolics biosynthesis pathways. Although 4CLs have been extensively characterized in other vascular plants, little is known of their functions in Selaginella. Here, we isolated two 4CL genes (Sm4CL1 and Sm4CL2) from Selaginella moellendorffii. Based on the enzymatic activities of the recombinant proteins, both of these genes encoded bona fide 4CLs. The 4CL isoforms in S. moellendorffii have different activities: Sm4CL2 was more active than Sm4CL1. The enzymatic properties and gene expression patterns indicated that the 4CL genes have been conserved in the evolution of vascular plants. PMID- 29518889 TI - Underwater Turbulence Detection Using Gated Wavefront Sensing Technique. AB - Laser sensing has been applied in various underwater applications, ranging from underwater detection to laser underwater communications. However, there are several great challenges when profiling underwater turbulence effects. Underwater detection is greatly affected by the turbulence effect, where the acquired image suffers excessive noise, blurring, and deformation. In this paper, we propose a novel underwater turbulence detection method based on a gated wavefront sensing technique. First, we elaborate on the operating principle of gated wavefront sensing and wavefront reconstruction. We then setup an experimental system in order to validate the feasibility of our proposed method. The effect of underwater turbulence on detection is examined at different distances, and under different turbulence levels. The experimental results obtained from our gated wavefront sensing system indicate that underwater turbulence can be detected and analyzed. The proposed gated wavefront sensing system has the advantage of a simple structure and high detection efficiency for underwater environments. PMID- 29518890 TI - Data Summarization in the Node by Parameters (DSNP): Local Data Fusion in an IoT Environment. AB - With the advent of the Internet of Things, billions of objects or devices are inserted into the global computer network, generating and processing data at a volume never imagined before. This paper proposes a way to collect and process local data through a data fusion technology called summarization. The main feature of the proposal is the local data fusion, through parameters provided by the application, ensuring the quality of data collected by the sensor node. In the evaluation, the sensor node was compared when performing the data summary with another that performed a continuous recording of the collected data. Two sets of nodes were created, one with a sensor node that analyzed the luminosity of the room, which in this case obtained a reduction of 97% in the volume of data generated, and another set that analyzed the temperature of the room, obtaining a reduction of 80% in the data volume. Through these tests, it has been proven that the local data fusion at the node can be used to reduce the volume of data generated, consequently decreasing the volume of messages generated by IoT environments. PMID- 29518891 TI - Erratum: Andreotti, S.; Franzoni, E.; Fabbri, P. Poly(hydroxyalkanoate)s-Based Hydrophobic Coatings for the Protection of Stone in Cultural Heritage. Materials 2018, 11, 165. PMID- 29518888 TI - Fungal Cytochrome P450s and the P450 Complement (CYPome) of Fusarium graminearum. AB - Cytochrome P450s (CYPs), heme-containing monooxygenases, play important roles in a wide variety of metabolic processes important for development as well as biotic/trophic interactions in most living organisms. Functions of some CYP enzymes are similar across organisms, but some are organism-specific; they are involved in the biosynthesis of structural components, signaling networks, secondary metabolisms, and xenobiotic/drug detoxification. Fungi possess more diverse CYP families than plants, animals, or bacteria. Various fungal CYPs are involved in not only ergosterol synthesis and virulence but also in the production of a wide array of secondary metabolites, which exert toxic effects on humans and other animals. Although few studies have investigated the functions of fungal CYPs, a recent systematic functional analysis of CYP genes in the plant pathogen Fusarium graminearum identified several novel CYPs specifically involved in virulence, asexual and sexual development, and degradation of xenobiotics. This review provides fundamental information on fungal CYPs and a new platform for further metabolomic and biochemical studies of CYPs in toxigenic fungi. PMID- 29518892 TI - The Microstructure Evolution of a Fe3Al Alloy during the LENS Process. AB - A Fe3Al intermetallic alloy has been successfully prepared by the laser engineered net shaping (LENS) process. The applied process parameters were selected to provide various cooling rates during the solidification of the laser melted material. The macro- and microstructure and the micro- and macrotexture of Fe3Al samples were investigated. The influence of the cooling rate on grain morphology and texture is discussed. For the applied cooling rate range of 0.64 * 104 K/s-2.6 * 104 K/s, the structure is characterized by the presence of columnar grains for which the growth is directed upwards from the substrate. The intensity of the microtexture varies with the height of the sample and the cooling rate. The intensity of the texture increases with the decrease in the cooling rate. The samples that were obtained with low and medium cooling rates are characterized by the well-developed <100> and <111> macrotextures. The Fe3Al alloy that was produced with a high cooling rate did not show a specific texture, which is reflected in the fairly uniform distribution of the normalized density intensity. Only a very weak texture with a <100> type component was observed. PMID- 29518893 TI - Antibacterial and Antifungal Activities of Poloxamer Micelles Containing Ceragenin CSA-131 on Ciliated Tissues. AB - Ceragenins were designed as non-peptide mimics of endogenous antimicrobial peptides, and they display broad-spectrum antibacterial and antifungal activities, including the ability to eradicate established biofilms. These features of ceragenins make them attractive potential therapeutics for persistent infections in the lung, including those associated with cystic fibrosis. A characteristic of an optimal therapeutic for use in the lungs and trachea is the exertion of potent antimicrobial activities without damaging the cilia that play a critical role in these tissues. In previous work, potent antimicrobial activities of ceragenin CSA-131 have been reported; however, we found in ex vivo studies that this ceragenin, at concentrations necessary to eradicate established biofilms, also causes loss of cilia function. By formulating CSA-131 in poloxamer micelles, cilia damage was eliminated and antimicrobial activity was unaffected. The ability of CSA-131, formulated with a poloxamer, to reduce the populations of fungal pathogens in tracheal and lung tissue was also observed in ex vivo studies. These findings suggest that CSA-131, formulated in micelles, may act as a potential therapeutic for polymicrobial and biofilm-related infections in the lung and trachea. PMID- 29518894 TI - Surface Treatment of PEOT/PBT (55/45) with a Dielectric Barrier Discharge in Air, Helium, Argon and Nitrogen at Medium Pressure. AB - This work describes the surface modification of 300PEO-PEOT/PBT 55/45 thin films using a medium pressure dielectric barrier discharge system operated in argon, helium, nitrogen or dry air to improve cell-surface interactions of this established biomaterial. The first part of the paper describes the optimization of the plasma processing parameters using water contact angle goniometry. The optimized samples are then characterized for changes in surface topography and surface chemical composition using atomic force microscopy (AFM) and X-ray fluorescence spectroscopy (XPS) respectively. For all plasma treatments, a pronounced increase in surface wettability was observed, of which the extent is dependent on the used plasma discharge gas. Except for dry air, only minor changes in surface topography were noted, while XPS confirmed that the changes in wettability were mainly chemical in nature with the incorporation of 5-10% of extra oxygen as a variety of polar groups. Similarly, for the nitrogen plasma, 3.8% of nitrogen polar groups were additionally incorporated. Human foreskin fibroblast (HFF) in vitro analysis showed that within the first 24 h after cell seeding, the effects on cell-surface interactivity were highly dependent on the used discharge gas, nitrogen plasma treatment being the most efficient. Differences between untreated and plasma-treated samples were less pronounced compared to other biodegradable materials, but a positive influence on cell adhesion and proliferation was still observed. PMID- 29518896 TI - Use of Metabolomics as a Complementary Omic Approach to Implement Risk Criteria for First-Degree Relatives of Gastric Cancer Patients. AB - A positive family history is a strong and consistently reported risk factor for gastric cancer (GC). So far, it has been demonstrated that serum pepsinogens (PGs), and gastrin 17 (G17) are useful for screening individuals at elevated risk to develop atrophic gastritis but they are suboptimal biomarkers to screen individuals for GC. The main purpose of this study was to investigate serum metabolomic profiles to find additional biomarkers that could be integrated with serum PGs and G17 to improve the diagnosis of GC and the selection of first degree relatives (FDR) at higher risk of GC development. Serum metabolomic profiles included 188 serum metabolites, covering amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexoses. Serum metabolomic profiles were performed with tandem mass spectrometry using the Biocrates AbsoluteIDQ p180 kit. The initial cohort (training set) consisted of n = 49 GC patients and n = 37 FDR. Differential metabolomic signatures among the two groups were investigated by univariate and multivariate partial least square differential analysis. The most significant metabolites were further selected and validated in an independent group of n = 22 GC patients and n = 17 FDR (validation set). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic power and the optimal cut-off for each of the discriminant markers. Multivariate analysis was applied to associate the selected serum metabolites, PGs, G17 and risk factors such as age, gender and Helicobacter pylori (H. pylori) infection with the GC and FDR has been performed and an integrative risk prediction algorithm was developed. In the training set, 40 metabolites mainly belonging to phospholipids and acylcarnitines classes were differentially expressed between GC and FDR. Out of these 40 metabolites, 9 were further confirmed in the validation set. Compared with FDR, GC patients were characterized by lower levels of hydroxylated sphingomyelins (SM(OH)22:1, SM(OH)22:2, SM(OH)24:1) and phosphatidylcholines (PC ae 40:1, PC ae 42:2, PC ae 42:3) and by higher levels of acylcarnitines derivatives (C2, C16, C18:1). The specificity and sensitivity of the integrative risk prediction analysis of metabolites for GC was 73.47% and 83.78% respectively with an area under the curve of the ROC curve of 0.811 that improves to 0.90 when metabolites were integrated with the serum PGs. The predictive risk algorithm composed of the C16, SM(OH)22:1 and PG-II serum levels according to the age of individuals, could be used to stratify FDR at high risk of GC development, and then this can be addressed with diagnostic gastroscopy. PMID- 29518895 TI - Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy. AB - The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG) channels. CNG channels are ligand gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and voltage-gated potassium channels (KCN). In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application. PMID- 29518897 TI - Factors Informing Outcomes for Older Cats and Dogs in Animal Shelters. AB - With advances in veterinary medicine that can increase the lifespan of cats and dogs and the effectiveness of spay/neuter programs in reducing the juvenile population of pets, animal shelters are experiencing an increasing population of older companion animals in their care. The purpose of this study was to assess the factors that inform the outcomes of these older cats and dogs. The sample consisted of 124 cats and 122 dogs that were over the age of 84 months (seven years) who were taken into a shelter over a one-year period. To assess the impact of condition at intake on the outcome for the senior animals, a multinomial logistic regression was performed. These findings indicate that preventative programming that can address the reasons these older animals are surrendered, as well as advancements in specialized medical or behavioral programs for ageing companion animals, may support an increase in live outcomes for older cats and dogs in shelters. Further study is needed to evaluate how the quality of life of older animals is impacted by remaining in the care of shelters rather than being euthanized. PMID- 29518898 TI - Caloric Restriction and Its Effect on Blood Pressure, Heart Rate Variability and Arterial Stiffness and Dilatation: A Review of the Evidence. AB - Essential hypertension, fast heart rate, low heart rate variability, sympathetic nervous system dominance over parasympathetic, arterial stiffness, endothelial dysfunction and poor flow-mediated arterial dilatation are all associated with cardiovascular mortality and morbidity. This review of randomised controlled trials and other studies demonstrates that caloric restriction (CR) is capable of significantly improving all these parameters, normalising blood pressure (BP) and allowing patients to discontinue antihypertensive medication, while never becoming hypotensive. CR appears to be effective regardless of age, gender, ethnicity, weight, body mass index (BMI) or a diagnosis of metabolic syndrome or type 2 diabetes, but the greatest benefit is usually observed in the sickest subjects and BP may continue to improve during the refeeding period. Exercise enhances the effects of CR only in hypertensive subjects. There is as yet no consensus on the mechanism of effect of CR and it may be multifactorial. Several studies have suggested that improvement in BP is related to improvement in insulin sensitivity, as well as increased nitric oxide production through improved endothelial function. In addition, CR is known to induce SIRT1, a nutrient sensor, which is linked to a number of beneficial effects in the body. PMID- 29518900 TI - Investigation on Selective Laser Melting AlSi10Mg Cellular Lattice Strut: Molten Pool Morphology, Surface Roughness and Dimensional Accuracy. AB - AlSi10Mg inclined struts with angle of 45 degrees were fabricated by selective laser melting (SLM) using different scanning speed and hatch spacing to gain insight into the evolution of the molten pool morphology, surface roughness, and dimensional accuracy. The results show that the average width and depth of the molten pool, the lower surface roughness and dimensional deviation decrease with the increase of scanning speed and hatch spacing. The upper surface roughness is found to be almost constant under different processing parameters. The width and depth of the molten pool on powder-supported zone are larger than that of the molten pool on the solid-supported zone, while the width changes more significantly than that of depth. However, if the scanning speed is high enough, the width and depth of the molten pool and the lower surface roughness almost keep constant as the density is still high. Therefore, high dimensional accuracy and density as well as good surface quality can be achieved simultaneously by using high scanning speed during SLMed cellular lattice strut. PMID- 29518899 TI - Halo-Substituted Chalcones and Azachalcones-Inhibited, Lipopolysaccharited Stimulated, Pro-Inflammatory Responses through the TLR4-Mediated Pathway. AB - A series of B-ring, halo-substituted chalcones and azachalcones were synthesized to evaluate and compare their anti-inflammatory activity. Mouse BALB/c macrophage RAW 264.7 were pre-treated with 10 MUg/mL of each compound for one hour before induction of inflammation by lipopolysaccharide (1 MUg/mL) for 6 h. Some halo chalcones and -azachalcones suppressed expression of pro-inflammatory factors toll-like receptor 4 (TLR4), IkappaB-alpha, transcription factor p65, interleukine 1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and cyclooxygenase 2 (COX-2). The present results showed that the synthetic halo azachalcones exhibited more significant inhibition than halo-chalcones. Therefore, the nitrogen atom in this series of azachalcones must play a more crucial role than the corresponding C-2 hydroxyl group of chalcones in biological activity. Our findings will lay the background for the future development of anti inflammatory nutraceuticals. PMID- 29518901 TI - Electrochemical Sensor for Bilirubin Detection Using Screen Printed Electrodes Functionalized with Carbon Nanotubes and Graphene. AB - Practice oriented point-of-care diagnostics require easy-to-handle, miniaturized, and low-cost analytical tools. In a novel approach, screen printed carbon electrodes (SPEs), which were functionalized with nanomaterials, are employed for selective measurements of bilirubin, which is an important biomarker for jaundice. Multi-walled carbon nanotubes (MWCNT) and graphene separately deposited on SPEs provide the core of an electrochemical sensor for bilirubin. The electrocatalytic activity towards bilirubin oxidation (bilirubin to biliverdin) was observed at +0.25 V. In addition, a further peak corresponding to the electrochemical conversion of biliverdin into purpurin appeared at +0.48 V. When compared to MWCNT, the graphene type shows a 3-fold lower detection limit (0.3 +/ 0.022 nM and 0.1 +/- 0.018 nM, respectively), moreover, the graphene type exhibits a larger linear range (0.1-600 uM) than MWCNT (0.5-500 uM) with a two fold better sensitivity, i.e., 30 nA uM-1 cm-2, and 15 nA uM-1 cm-2, respectively. The viability is validated through measurements of bilirubin in blood serum samples and the selectivity is ensured by inhibiting common interfering biological substrates using an ionic nafion membrane. The presented approach enables the design and implementation of low cost and miniaturized electrochemical sensors. PMID- 29518902 TI - Lightweight Active Object Retrieval with Weak Classifiers. AB - In the last few years, there has been a steadily growing interest in autonomous vehicles and robotic systems. While many of these agents are expected to have limited resources, these systems should be able to dynamically interact with other objects in their environment. We present an approach where lightweight sensory and processing techniques, requiring very limited memory and processing power, can be successfully applied to the task of object retrieval using sensors of different modalities. We use the Hough framework to fuse optical and orientation information of the different views of the objects. In the presented spatio-temporal perception technique, we apply active vision, where, based on the analysis of initial measurements, the direction of the next view is determined to increase the hit-rate of retrieval. The performance of the proposed methods is shown on three datasets loaded with heavy noise. PMID- 29518903 TI - Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma. AB - Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA) on type I NKT cells in polyoma middle T oncogene-driven (PyMT) murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1) were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity. PMID- 29518904 TI - Phase Transition-Driven Nanoparticle Assembly in Liquid Crystal Droplets. AB - When nanoparticle self-assembly takes place in an anisotropic liquid crystal environment, fascinating new effects can arise. The presence of elastic anisotropy and topological defects can direct spatial organization. An important goal in nanoscience is to direct the assembly of nanoparticles over large length scales to produce macroscopic composite materials; however, limitations on spatial ordering exist due to the inherent disorder of fluid-based methods. In this paper we demonstrate the formation of quantum dot clusters and spherical capsules suspended within spherical liquid crystal droplets as a method to position nanoparticle clusters at defined locations. Our experiments demonstrate that particle sorting at the isotropic-nematic phase front can dominate over topological defect-based assembly. Notably, we find that assembly at the nematic phase front can force nanoparticle clustering at energetically unfavorable locations in the droplets to form stable hollow capsules and fractal clusters at the droplet centers. PMID- 29518905 TI - Correction: Littink, K. W.; et al. Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome. Genes 2018, 9, 68. AB - The authors wish to make the following correction to this paper [1]. [...]. PMID- 29518907 TI - Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290. AB - Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290 associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant. PMID- 29518908 TI - Dietary Patterns Are Associated with Cardiovascular and Cancer Mortality among Swiss Adults in a Census-Linked Cohort. AB - Defining dietary guidelines requires a quantitative assessment of the influence of diet on the development of diseases. The aim of the study was to investigate how dietary patterns were associated with mortality in a general population sample of Switzerland. We included 15,936 participants from two population-based studies (National Research Program 1A (NRP1A) and Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)-1977 to 1993) who fully answered a simplified 24-h dietary recall. Mortality data were available through anonymous record linkage with the Swiss National Cohort (follow-up of up to 37.9 years). Multiple correspondence analysis and hierarchical clustering were used to define data-driven qualitative dietary patterns. Mortality hazard ratios were calculated for all-cause, cancer and cardiovascular mortality using Cox regression. Two patterns were characterized by a low dietary variety ("Sausage and Vegetables", "Meat and Salad"), two by a higher variety ("Traditional", "High-fiber foods") and one by a high fish intake ("Fish"). Males with unhealthy lifestyle (smokers, low physical activity and high alcohol intake) were overrepresented in the low variety patterns and underrepresented in the high-variety and "Fish" patterns. In multivariable-adjusted models, the "Fish" (hazard ratio = 0.82, 95% CI (0.68 0.99)) and "High-fiber foods" (0.85 (0.72-1.00)) patterns were associated with lower cancer mortality. In men, the "Fish" (0.73 (0.55-0.97)) and "Traditional" (0.76 (0.59-0.98)) patterns were associated with lower cardiovascular mortality. In summary, our results support the notion that dietary patterns affect mortality and that these patterns strongly cluster with other health determinants. PMID- 29518906 TI - Innate Immunity against Cryptococcus, from Recognition to Elimination. AB - Cryptococcus species, the etiological agents of cryptococcosis, are encapsulated fungal yeasts that predominantly cause disease in immunocompromised individuals, and are responsible for 15% of AIDS-related deaths worldwide. Exposure follows the inhalation of the yeast into the lung alveoli, making it incumbent upon the pattern recognition receptors (PRRs) of pulmonary phagocytes to recognize highly conserved pathogen-associated molecular patterns (PAMPS) of fungi. The main challenges impeding the ability of pulmonary phagocytes to effectively recognize Cryptococcus include the presence of the yeast's large polysaccharide capsule, as well as other cryptococcal virulence factors that mask fungal PAMPs and help Cryptococcus evade detection and subsequent activation of the immune system. This review will highlight key phagocyte cell populations and the arsenal of PRRs present on these cells, such as the Toll-like receptors (TLRs), C-type lectin receptors, NOD-like receptors (NLRs), and soluble receptors. Additionally, we will highlight critical cryptococcal PAMPs involved in the recognition of Cryptococcus. The question remains as to which PRR-ligand interaction is necessary for the recognition, phagocytosis, and subsequent killing of Cryptococcus. PMID- 29518909 TI - Individual and Combined Occurrence of Mycotoxins in Feed Ingredients and Complete Feeds in China. AB - The objective of this study was to investigate the individual and combined contamination of aflatoxin B1 (AFB1), zearalenone (ZEN) and deoxynivalenol (DON) in feedstuffs from different Provinces of China between 2016 and 2017. A total of 1569 samples, including 742 feed ingredients and 827 complete pig feed samples, were collected from various regions of China for mycotoxins analysis. The results showed that individual occurrence rates of AFB1, ZEN, and DON were more than 83.3%, 88%, and 74.5%, respectively, in all the tested samples. DON was the most prevalent contaminant, followed by ZEN and AFB1, with the average concentrations ranging from 450.0-4381.5 MUg/kg, 2.3-729.2 MUg/kg, and 1.3-10.0 MUg/kg, respectively. Notable, 38.2%, 10.8%, and 0.6% of complete pig feeds were contaminated with DON, ZEN, and AFB1 over China's regulatory limits, respectively. Moreover, over 75.0% analyzed samples were co-contaminated with two or three mycotoxins. In conclusion, the current study revealed that the feedstuffs in China were severely contaminated with DON, followed by ZEN and AFB1 during the past two years. These findings highlight the importance of monitoring mycotoxins in livestock feed and implementing feed management and bioremediation strategies to reduce mycotoxin exposure. PMID- 29518910 TI - Influence of Haem, Non-Haem, and Total Iron Intake on Metabolic Syndrome and Its Components: A Population-Based Study. AB - Studies suggest that haem, non-haem iron and total iron intake may be related to non-communicable diseases, especially metabolic syndrome. This study was undertaken to investigate the association of haem, non-haem iron and total iron intake with metabolic syndrome and its components. A cross-sectional population based survey was performed in 2008, enrolling 591 adults and elderly adults living in Sao Paulo, Brazil. Dietary intake was measured by two 24 h dietary recalls. Metabolic syndrome was defined as the presence of at least three of the following: hypertension, hyperglycaemia, dyslipidaemia and central obesity. The association between different types of dietary iron and metabolic syndrome was evaluated using multiple logistic regression. After adjustment for potential confounders, a higher haem iron intake was positively associated with metabolic syndrome and with elevated triglyceride levels. A higher total iron intake was positively associated with hyperglycaemia. Non-haem iron intake was positively associated with hyperglycaemia in the fourth quintile. In conclusion, this study suggests that the different types of dietary iron are associated with metabolic syndrome, elevated triglyceride levels and hyperglycaemia. In addition, it emphasises the importance of investigating the roles of dietary iron in health outcomes, since its consumption may have different impacts on health. PMID- 29518911 TI - Effects of an Intermittent Grape-Seed Proanthocyanidin (GSPE) Treatment on a Cafeteria Diet Obesogenic Challenge in Rats. AB - Obesity is highly associated with the pathologies included in the concept of the Metabolic Syndrome. Grape-seed proanthocyanins (GSPE) have showed very positive effects against all these metabolic disruptions; however, there is, as yet, no consensus about their effectiveness against an obesogenic challenge, such as a cafeteria diet. We determined the effectiveness of a dose of 500 mg GSPE/kg b.w. (body weight) against the obesogenic effects of a 17-week cafeteria diet, administered as a sub-chronic treatment, 10-15 days before, intermittently and at the end of the diet, in Wistar rats. Body weight, adiposity, indirect calorimetry and plasma parameters were analyzed. GSPE pre-treatment showed a long-lasting effect on body weight and adiposity that was maintained for seven weeks after the last dose. A corrective treatment was administered for the last two weeks of the cafeteria diet intervention; however, it did not effectively correct any of the parameters assessed. The most effective treatment was an intermittent GSPE dosage, administered every second week during the cafeteria diet. This limited body weight gain, adiposity and most lipotoxic effects. Our results support the administration of this GSPE dose, keeping an intermittent interval between dosages longer than every second week, to improve obesogenic disruptions produced by a cafeteria diet. PMID- 29518912 TI - Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self Renewal. AB - The cancer stem cell (CSC) hypothesis suggests that tumours are maintained by a subpopulation of cells with stem cell properties. Although the existence of CSCs was initially described in human leukaemia, less evidence exists for CSCs in solid tumours. Recently, a CD133+ cell subpopulation was isolated from human brain tumoursexhibiting stem cell properties in vitro as well as the capacity to initiate tumours in vivo. In the present work, we try to summarize the data showing that some elements of the Phosphoinositide 3-kinase Class I (PI3K)/ Thymoma viral oncogene protein kinase (Akt) pathway, such the activity of PI3K Class I or Akt2, are necessary to maintain the CSC-like phenotype as well as survival of CSCs (also denoted as tumour-initiating cells (TICs)). Our data and other laboratory data permit a working hypothesis in which each Akt isoform plays an important and specific role in CSC/TIC growth, self-renewal, maintaining survival, and epithelial-mesenchymal transition (EMT) phenotype, not only in breast cancer, but also in glioma. We suggest that a more complete understanding is needed of the possible roles of isoforms in human tumours (iso-signalling determination). Thus, a comprehensive analysis of how hierarchical signalling is assembled during oncogenesis, how cancer landmarks are interconnected to favour CSC and tumour growth, and how some protein isoforms play a specific role in CSCs to ensure that survival and proliferation must be done in order to propose/generate new therapeutic approaches (alone or in combination with existing ones) to use against cancer. PMID- 29518913 TI - Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation. AB - Radiation injury to the lung is the result of acute and chronic free radical formation, and there are currently few effective means of mitigating such injury. Studies in rodents indicate that superoxide dismutase mimetics may be effective in this regard; however, studies in humans or large animals are lacking. We hypothesized that post-exposure treatment with the lipophilic mitochondrial superoxide dismutase mimetic, MnTnHex-2-PyP5+ (hexyl), would reduce radiation induced pneumonitis and fibrosis in the lungs of nonhuman primates. Rhesus monkeys (Macaca mulatta) received 10 Gy whole thorax irradiation, 10 Gy + hexyl treatment, sham irradiation, or sham irradiation + hexyl. Hexyl was given twice daily, subcutaneously, at 0.05 mg/kg, for 2 months. Animals were monitored daily, and respiratory rates, pulse oximetry, hematology and serum chemistry panels were performed weekly. Computed tomography scans were performed at 0, 2, and 4 months after irradiation. Supportive fluid therapy, corticosteroids, analgesics, and antibiotics were given as needed. All animals were humanely euthanized 4.5 months after irradiation, and pathologic assessments were made. Multifocal, progressive lung lesions were seen at 2 and 4 months in both irradiated groups. Hexyl treatment delayed the onset of radiation-induced lung lesions, reduced elevations of respiratory rate, and reduced pathologic increases in lung weight. No adverse effects of hexyl treatment were found. These results demonstrate (1) development of a nonhuman primate model of radiation-induced lung injury, (2) a significant mitigating effect of hexyl treatment on lung pathology in this model, and (3) no evidence for toxicity of hexyl at the dose studied. PMID- 29518915 TI - Cis-Trans Configuration of Coumaric Acid Acylation Affects the Spectral and Colorimetric Properties of Anthocyanins. AB - The color expression of anthocyanins can be affected by a variety of environmental factors and structural characteristics. Anthocyanin acylation (type and number of acids) is known to be key, but the influence of acyl isomers (with unique stereochemistries) remains to be explored. The objective of this study was to investigate the effects of cis-trans configuration of the acylating group on the spectral and colorimetric properties of anthocyanins. Petunidin-3-rutinoside 5-glucoside (Pt-3-rut-5-glu) and Delphinidin-3-rutinoside-5-glucoside (Dp-3-rut-5 glu) and their cis and trans coumaroylated derivatives were isolated from black goji and eggplant, diluted in pH 1-9 buffers, and analyzed spectrophotometrically (380-700 nm) and colorimetrically (CIELAB) during 72 h of storage (25 degrees C, dark). The stereochemistry of the acylating group strongly impacted the spectra, color, and stability of the Dp and Pt anthocyanins. Cis acylated pigments exhibited the greatest lambdamax in all pH, as much as 66 nm greater than their trans counterparts, showing bluer hues. Cis acylation seemed to reduce hydration across pH, increasing color intensity, while trans acylation generally improved color retention over time. Dp-3-cis-p-cou-rut-5-glu exhibited blue hues even in pH 5 (C*ab = 10, hab = 256 degrees ) where anthocyanins are typically colorless. Cis or trans double bond configurations of the acylating group affected anthocyanin spectral and stability properties. PMID- 29518914 TI - Gold Nanoparticle-Induced Cell Death and Potential Applications in Nanomedicine. AB - Cell death is crucial to human health and is related to various serious diseases. Therefore, generation of new cell death regulators is urgently needed for disease treatment. Nanoparticles (NPs) are now routinely used in a variety of fields, including consumer products and medicine. Exhibiting stability and ease of decoration, gold nanoparticles (GNPs) could be used in diagnosis and disease treatment. Upon entering the human body, GNPs contact human cells in the blood, targeting organs and the immune system. This property results in the disturbance of cell function and even cell death. Therefore, GNPs may act as powerful cell death regulators. However, at present, we are far from establishing a structure activity relationship between the physicochemical properties of GNPs and cell death, and predicting GNP-induced cell death. In this review, GNPs' size, shape, and surface properties are observed to play key roles in regulating various cell death modalities and related signaling pathways. These results could guide the design of GNPs for nanomedicine. PMID- 29518916 TI - Modifying Thermal Switchability of Liquid Crystalline Nanoparticles by Alkyl Ligands Variation. AB - By coating plasmonic nanoparticles (NPs) with thermally responsive liquid crystals (LCs) it is possible to prepare reversibly reconfigurable plasmonic nanomaterials with prospective applications in optoelectronic devices. However, simple and versatile methods to precisely tailor properties of liquid-crystalline nanoparticles (LC NPs) are still required. Here, we report a new method for tuning structural properties of assemblies of nanoparticles grafted with a mixture of promesogenic and alkyl thiols, by varying design of the latter. As a model system, we used Ag and Au nanoparticles that were coated with three-ring promesogenic molecules and dodecanethiol ligand. These LC NPs self-assemble into switchable lamellar (Ag NPs) or tetragonal (Au NPs) aggregates, as determined with small angle X-ray diffraction and transmission electron microscopy. Reconfigurable assemblies of Au NPs with different unit cell symmetry (orthorombic) are formed if hexadecanethiol and 1H,1H,2H,2H-perfluorodecanethiol were used in the place of dodecanethiol; in the case of Ag NPs the use of 11 hydroxyundecanethiol promotes formation of a lamellar structure as in the reference system, although with substantially broader range of thermal stability (140 vs. 90 degrees C). Our results underline the importance of alkyl ligand functionalities in determining structural properties of liquid-crystalline nanoparticles, and, more generally, broaden the scope of synthetic tools available for tailoring properties of reversibly reconfigurable plasmonic nanomaterials. PMID- 29518917 TI - Electrospun Composite Liquid Crystal Elastomer Fibers. AB - We present a robust method to prepare thin oriented nematic liquid crystalline elastomer-polymer (LCE-polymer) core-sheath fibers. An electrospinning setup is utilized to spin a single solution of photo-crosslinkable low molecular weight reactive mesogens and a support polymer to form the coaxial LCE-polymer fibers, where the support polymer forms the sheath via in situ phase separation as the solvent evaporates. We discuss the effect of phase separation and compare two different sheath polymers (polyvinylpyrrolidone and polylactic acid), investigating optical and morphological properties of obtained fibers, as well as the shape changes upon heating. The current fibers show only irreversible contraction, the relaxation most likely being hindered by the presence of the passive sheath polymer, increasing in stiffness on cooling. If the sheath polymer can be removed while keeping the LCE core intact, we expect LCE fibers produced in this way to have potential to be used as actuators, for instance in soft robotics and responsive textiles. PMID- 29518918 TI - Protein Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: Progress and Challenges. AB - Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but interdisciplinary cooperation within the PDAC community is poised to confront it. PMID- 29518920 TI - Alloying and Properties of C14-NbCr2 and A15-Nb3X (X = Al, Ge, Si, Sn) in Nb Silicide-Based Alloys. AB - The oxidation of Nb-silicide-based alloys is improved with Al, Cr, Ge or Sn addition(s). Depending on addition(s) and its(their) concentration(s), alloyed C14-AB2 Laves and A15-A3X phases can be stable in the microstructures of the alloys. In both phases, A is the transition metal(s), and B and X respectively can be Cr, Al, Ge, Si or Sn, and Al, Ge, Si or Sn. The alloying, creep and hardness of these phases were studied using the composition weighted differences in electronegativity (?chi), average valence electron concentrations (VEC) and atomic sizes. For the Laves phase (i) the VEC and ?chi were in the ranges 4.976 < VEC < 5.358 and -0.503 < ?chi < -0.107; (ii) the concentration of B (=Al + Cr + Ge + Si + Sn) varied from 50.9 to 64.5 at %; and (iii) the Cr concentration was in the range of 35.8 < Cr < 51.6 at %. Maps of ?chi versus Cr, ?chi versus VEC, and VEC versus atomic size separated the alloying behaviours of the elements. Compared with unalloyed NbCr2, the VEC decreased and ?chi increased in Nb(Cr,Si)2, and the changes in both parameters increased when Nb was substituted by Ti, and Cr by Si and Al, or Si and Ge, or Si and Sn. For the A15 phase (i) the VEC and ?chi were in the ranges 4.38 < VEC < 4.89 and 0.857 < ?chi < 1.04, with no VEC values between 4.63 and 4.72 and (ii) the concentration of X (=Al + Ge + Si + Sn) varied from 16.3 to 22.7 at %. The VEC versus ?chi map separated the alloying behaviours of elements. The hardness of A15-Nb3X was correlated with the parameters ?chi and VEC. The hardness increased with increases in ?chi and VEC. Compared with Nb3Sn, the ?chi and hardness of Nb3(Si,Sn) increased. The substitution of Nb by Cr had the same effect on ?chi and hardness as Hf or Ti. The ?chi and hardness increased with Ti concentration. The addition of Al in Nb3(Si,Sn,Al) decreased the ?chi and increased the hardness. When Ti and Hf, or Ti, Hf and Cr, were simultaneously present with Al, the ?chi was decreased and the hardness was unchanged. The better creep of Nb(Cr,Si)2 compared with the unalloyed Laves phase was related to the decrease in the VEC and ?chi parameters. PMID- 29518919 TI - Protein-Based Nanoparticle Preparation via Nanoprecipitation Method. AB - Nanoparticles are nowadays largely investigated in the field of drug delivery. Among nanoparticles, protein-based particles are of paramount importance since they are natural, biodegradable, biocompatible, and nontoxic. There are several methods to prepare proteins containing nanoparticles, but only a few studies have been dedicated to the preparation of protein- based nanoparticles. Then, the aim of this work was to report on the preparation of bovine serum albumin (BSA)-based nanoparticles using a well-defined nanoprecipitation process. Special attention has been dedicated to a systematic study in order to understand separately the effect of each operating parameter of the method (such as protein concentration, solvent/non-solvent volume ratio, non-solvent injection rate, ionic strength of the buffer solution, pH, and cross-linking) on the colloidal properties of the obtained nanoparticles. In addition, the mixing processes (batch or drop-wise) were also investigated. Using a well-defined formulation, submicron protein-based nanoparticles have been obtained. All prepared particles have been characterized in terms of size, size distribution, morphology, and electrokinetic properties. In addition, the stability of nanoparticles was investigated using Ultraviolet (UV) scan and electrophoresis, and the optimal conditions for preparing BSA nanoparticles by the nanoprecipitation method were concluded. PMID- 29518921 TI - Analysis of Occupational Accidents in Underground and Surface Mining in Spain Using Data-Mining Techniques. AB - An analysis of occupational accidents in the mining sector was conducted using the data from the Spanish Ministry of Employment and Social Safety between 2005 and 2015, and data-mining techniques were applied. Data was processed with the software Weka. Two scenarios were chosen from the accidents database: surface and underground mining. The most important variables involved in occupational accidents and their association rules were determined. These rules are composed of several predictor variables that cause accidents, defining its characteristics and context. This study exposes the 20 most important association rules in the sector-either surface or underground mining-based on the statistical confidence levels of each rule as obtained by Weka. The outcomes display the most typical immediate causes, along with the percentage of accidents with a basis in each association rule. The most important immediate cause is body movement with physical effort or overexertion, and the type of accident is physical effort or overexertion. On the other hand, the second most important immediate cause and type of accident are different between the two scenarios. Data-mining techniques were chosen as a useful tool to find out the root cause of the accidents. PMID- 29518922 TI - Correction: Almeida-Dalmet, S.; et al. Differential Gene Expression in Response to Salinity and Temperature in a Haloarcula Strain from Great Salt Lake, Utah. Genes 2017, 9, 52. AB - The authors wish to make the following changes to their paper [1].[...]. PMID- 29518923 TI - Association between Frequency of Consumption of Fruit, Vegetables, Nuts and Pulses and BMI: Analyses of the International Study of Asthma and Allergies in Childhood (ISAAC). AB - Diets which emphasize intakes of plant-based foods are recommended to reduce disease risk and for promoting healthy weight. The aim of this study was to examine the association between fruit, vegetables, pulses and nut intake and body mass index (BMI) across countries in adolescents (13-14 years) and children (6-7 years). Data from the International Study of Asthma and Allergies in Childhood; 77,243 children's parents and 201,871 adolescents was used to examine the association between dietary intake (Food Frequency Questionnaire) and BMI using general linear models, adjusting for country gross national index. Adolescents who consumed fruit, vegetables, pulses and nuts three or more times a week had a lower BMI than the never or occasional group; eating nuts three or more times a week, was associated with a BMI value of 0.274 kg/m2 lower than the never group (p < 0.001). Compared to children who never or occasionally reported eating vegetables, those reporting that they ate vegetables three or more times per week had a lower BMI of -0.079 kg/m2. In this large global study, an inverse association was observed between BMI and the reported increasing intake of vegetables in 6-7 years old and fruit, vegetables, pulses and nuts in adolescents. This study supports current dietary recommendations which emphasize the consumption of vegetables, nut and pulses, although the effect sizes were small. PMID- 29518924 TI - Assessing the Association of Food Preferences and Self-Reported Psychological Well-Being among Middle-Aged and Older Adults in Contemporary China-Results from the China Health and Nutrition Survey. AB - China has undergone rapid social transitions within the last few decades. However, mental health issues, challenges to psychological well-being, and poor dietary choices have gradually surfaced. These health concerns are related to the rapid growth of the aging population and of the fast-paced industrialized society. Nevertheless, there is little knowledge about food preferences and psychological well-being measurements in contemporary China. Applying the 2011 China Health and Nutrition Survey (CHNS) with a cross-sectional study design (n = 7970), we conducted multinomial logistic regression models to investigate the associations of food preferences, including fast food, salty snacks, fruits, vegetables, and sweetened beverages, with psychological well-being among Chinese middle-aged and older adults (age >= 45). Food preferences are mostly associated with psychological well-being (p < 0.05). However, respondents' preferences regarding fast food, salty snacks, and sweetened beverages are associated not only with poorer psychological health status, but also with positive psychological well-being. We speculate that Chinese older adults may consume Westernized fast food and salty snacks as pleasure to the palate due to the recent Westernization in modern China. We also provide practical implications of results from this preliminary study. PMID- 29518925 TI - Effects of Chinese Cooking Methods on the Content and Speciation of Selenium in Selenium Bio-Fortified Cereals and Soybeans. AB - Cereals and soybeans are the main food sources for the majority of Chinese. This study evaluated the effects of four common cooking methods including steaming, boiling, frying, and milking on selenium (Se) content and speciation in seven selenium bio-fortified cereals and soybeans samples. The Se concentrations in the selected samples ranged from 0.91 to 110.8 mg/kg and selenomethionine (SeMet) was detected to be the main Se species. Total Se loss was less than 8.1% during the processes of cooking except milking, while 49.1% of the total Se was lost in milking soybean for soy milk due to high level of Se in residuals. It was estimated that about 13.5, 24.0, 3.1, and 46.9% of SeMet were lost during the processes of steaming, boiling, frying, and milking, respectively. Meanwhile, selenocystine (SeCys2) and methylselenocysteine (SeMeCys) were lost completely from the boiled cereals. Hence, steaming and frying were recommended to cook Se biofortified cereals in order to minimize the loss of Se. PMID- 29518926 TI - Facial Nerve Paralysis after Onyx Embolization of a Jugular Paraganglioma: A Case Report with a Long-Term Follow Up. AB - Jugular paragangliomas are slow growing highly vascular tumors arising from jugular paraganglia. The gold standard of treatment is complete surgical resection. Pre-operative embolization of these highly vascular tumors is essential to reduce intra-operative bleeding, allow safe dissection, and decrease operative time and post-operative complications. Onyx (ethylene-vinyl alcohol copolymer) has been widely used as permanent occluding material for vascular tumors of skull base because of its unique physical properties. We present the case of a 33-year-old woman who had left-sided facial nerve paralysis after Onyx embolization of jugular paraganglioma. The tumor was resected on the next day of embolization. The patient was followed up for 30 months with serial imaging studies and facial nerve assessment. The facial verve function improved from House-Brackmann grade V to grade II at the last visit. PMID- 29518927 TI - Smart Sound Processing for Defect Sizing in Pipelines Using EMAT Actuator Based Multi-Frequency Lamb Waves. AB - Pipeline inspection is a topic of particular interest to the companies. Especially important is the defect sizing, which allows them to avoid subsequent costly repairs in their equipment. A solution for this issue is using ultrasonic waves sensed through Electro-Magnetic Acoustic Transducer (EMAT) actuators. The main advantage of this technology is the absence of the need to have direct contact with the surface of the material under investigation, which must be a conductive one. Specifically interesting is the meander-line-coil based Lamb wave generation, since the directivity of the waves allows a study based in the circumferential wrap-around received signal. However, the variety of defect sizes changes the behavior of the signal when it passes through the pipeline. Because of that, it is necessary to apply advanced techniques based on Smart Sound Processing (SSP). These methods involve extracting useful information from the signals sensed with EMAT at different frequencies to obtain nonlinear estimations of the depth of the defect, and to select the features that better estimate the profile of the pipeline. The proposed technique has been tested using both simulated and real signals in steel pipelines, obtaining good results in terms of Root Mean Square Error (RMSE). PMID- 29518928 TI - Smart Winery: A Real-Time Monitoring System for Structural Health and Ullage in Fino Style Wine Casks. AB - The rapid development in low-cost sensor and wireless communication technology has made it possible for a large number of devices to coexist and exchange information autonomously. It has been predicted that a substantial number of devices will be able to exchange and provide information about an environment with the goal of improving our lives, under the well-known paradigm of the Internet of Things (IoT). One of the main applications of these kinds of devices is the monitoring of scenarios. In order to improve the current wine elaboration process, this paper presents a real-time monitoring system to supervise the status of wine casks. We have focused on a special kind of white wine, called Fino, principally produced in Andalusia (Southern Spain). The process by which this kind of wind is monitored is completely different from that of red wine, as the casks are not completely full and, due to the fact that they are not renewed very often, are more prone to breakage. A smart cork prototype monitors the structural health, the ullage, and the level of light inside the cask and the room temperature. The advantage of this smart cork is that it allows winemakers to monitor, in real time, the status of each wine cask so that, if an issue is detected (e.g., a crack appears in the cask), they can act immediately to resolve it. Moreover, abnormal parameters or incorrect environmental conditions can be detected in time before the wine loses its desired qualities. The system has been tested in "Bodegas San Acacio," a winery based in Montemayor, a town in the north of Andalusia. Results show that the use of such a system can provide a solution that tracks the evolution and assesses the suitability of the delicate wine elaboration process in real time, which is especially important for the kind of wine considered in this paper. PMID- 29518929 TI - Upregulation of Glucose Uptake and Hexokinase Activity of Primary Human CD4+ T Cells in Response to Infection with HIV-1. AB - Infection of primary CD4+ T cells with HIV-1 coincides with an increase in glycolysis. We investigated the expression of glucose transporters (GLUT) and glycolytic enzymes in human CD4+ T cells in response to infection with HIV-1. We demonstrate the co-expression of GLUT1, GLUT3, GLUT4, and GLUT6 in human CD4+ T cells after activation, and their concerted overexpression in HIV-1 infected cells. The investigation of glycolytic enzymes demonstrated activation-dependent expression of hexokinases HK1 and HK2 in human CD4+ T cells, and a highly significant increase in cellular hexokinase enzyme activity in response to infection with HIV-1. HIV-1 infected CD4+ T cells showed a marked increase in expression of HK1, as well as the functionally related voltage-dependent anion channel (VDAC) protein, but not HK2. The elevation of GLUT, HK1, and VDAC expression in HIV-1 infected cells mirrored replication kinetics and was dependent on virus replication, as evidenced by the use of reverse transcription inhibitors. Finally, we demonstrated that the upregulation of HK1 in HIV-1 infected CD4+ T cells is independent of the viral accessory proteins Vpu, Vif, Nef, and Vpr. Though these data are consistent with HIV-1 dependency on CD4+ T cell glucose metabolism, a cellular response mechanism to infection cannot be ruled out. PMID- 29518930 TI - Synthesis, Molecular Docking, and Antimycotic Evaluation of Some 3-Acyl Imidazo[1,2-a]pyrimidines. AB - A series of 3-benzoyl imidazo[1,2-a]pyrimidines, obtained from N heteroarylformamidines in good yields, was tested in silico and in vitro for binding and inhibition of seven Candida species (Candida albicans (ATCC 10231), Candida dubliniensis (CD36), Candida glabrata (CBS138), Candida guilliermondii (ATCC 6260), Candida kefyr, Candida krusei (ATCC 6358) and Candida tropicalis (MYA-3404)). To predict binding mode and energy, each compound was docked in the active site of the lanosterol 14alpha-demethylase enzyme (CYP51), essential for fungal growth of Candida species. Antimycotic activity was evaluated as the 50% minimum inhibitory concentration (MIC50) for the test compounds and two reference drugs, ketoconazole and fluconazole. All test compounds had a better binding energy (range: -6.11 to -9.43 kcal/mol) than that found for the reference drugs (range: 48.93 to -6.16 kcal/mol). In general, the test compounds showed greater inhibitory activity of yeast growth than the reference drugs. Compounds 4j and 4f were the most active, indicating an important role in biological activity for the benzene ring with electron-withdrawing substituents. These compounds show the best MIC50 against C. guilliermondii and C. glabrata, respectively. The current findings suggest that the 3-benzoyl imidazo[1,2-a]pyrimidine derivatives, herein synthesized by an accessible methodology, are potential antifungal drugs. PMID- 29518931 TI - Urinary Polyamine Biomarker Panels with Machine-Learning Differentiated Colorectal Cancers, Benign Disease, and Healthy Controls. AB - Colorectal cancer (CRC) is one of the most daunting diseases due to its increasing worldwide prevalence, which requires imperative development of minimally or non-invasive screening tests. Urinary polyamines have been reported as potential markers to detect CRC, and an accurate pattern recognition to differentiate CRC with early stage cases from healthy controls are needed. Here, we utilized liquid chromatography triple quadrupole mass spectrometry to profile seven kinds of polyamines, such as spermine and spermidine with their acetylated forms. Urinary samples from 201 CRCs and 31 non-CRCs revealed the N1,N12 diacetylspermine showing the highest area under the receiver operating characteristic curve (AUC), 0.794 (the 95% confidence interval (CI): 0.704-0.885, p < 0.0001), to differentiate CRC from the benign and healthy controls. Overall, 59 samples were analyzed to evaluate the reproducibility of quantified concentrations, acquired by collecting three times on three days each from each healthy control. We confirmed the stability of the observed quantified values. A machine learning method using combinations of polyamines showed a higher AUC value of 0.961 (95% CI: 0.937-0.984, p < 0.0001). Computational validations confirmed the generalization ability of the models. Taken together, polyamines and a machine-learning method showed potential as a screening tool of CRC. PMID- 29518933 TI - Mg-MOF-74/MgF2 Composite Coating for Improving the Properties of Magnesium Alloy Implants: Hydrophilicity and Corrosion Resistance. AB - Surface modification on Mg alloys is highly promising for their application in the field of bone repair. In this study, a new metal-organic framework/MgF2 (Mg MOF-74/MgF2) composite coating was prepared on the surface of AZ31B Mg alloy via pre-treatment of hydrofluoric acid and in situ hydrothermal synthesis methods. The surface topography of the composite coating is compact and homogeneous, and Mg-MOF-74 has good crystallinity. The corrosion resistance of this composite coating was investigated through Tafel polarization test and immersion test in simulated body fluid at 37 degrees C. It was found that Mg-MOF-74/MgF2 composite coating significantly slowed down the corrosion rate of Mg alloy. Additionally, Mg-MOF-74/MgF2 composite coating expresses super-hydrophilicity with the water contact angle of nearly 0 degrees . In conclusion, on the basis of MgF2 anticorrosive coating, the introduction of Mg-MOF-74 further improves the biological property of Mg alloys. At last, we propose that the hydrophilicity of the composite coating is mainly owing to the large number of hydroxyl groups, the high specific surface area of Mg-MOF-74, and the rough coating produced by Mg-MOF 74 particles. Hence, Mg-MOF-74 has a great advantage in enhancing the hydrophilicity of Mg alloy surface. PMID- 29518932 TI - Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity. AB - Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), a specific opener of mitochondrial KATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg/kg i.p.) was administered 30 min before DOXO (10 mg/kg i.p.) in C57BL/6j female mice for 1-3 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco/endoplasmic reticulum Ca2+-ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca2+-signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43. PMID- 29518934 TI - Electrode Coverage Optimization for Piezoelectric Energy Harvesting from Tip Excitation. AB - Piezoelectric energy harvesting using cantilever-type structures has been extensively investigated due to its potential application in providing power supplies for wireless sensor networks, but the low output power has been a bottleneck for its further commercialization. To improve the power conversion capability, a piezoelectric beam with different electrode coverage ratios is studied theoretically and experimentally in this paper. A distributed-parameter theoretical model is established for a bimorph piezoelectric beam with the consideration of the electrode coverage area. The impact of the electrode coverage on the capacitance, the output power and the optimal load resistance are analyzed, showing that the piezoelectric beam has the best performance with an electrode coverage of 66.1%. An experimental study was then carried out to validate the theoretical results using a piezoelectric beam fabricated with segmented electrodes. The experimental results fit well with the theoretical model. A 12% improvement on the Root-Mean-Square (RMS) output power was achieved with the optimized electrode converge ratio (66.1%). This work provides a simple approach to utilizing piezoelectric beams in a more efficient way. PMID- 29518935 TI - The Bacteriophage Lambda CII Phenotypes for Complementation, Cellular Toxicity and Replication Inhibition Are Suppressed in cII-oop Constructs Expressing the Small RNA OOP. AB - The temperate bacteriophage lambda (lambda) CII protein is a positive regulator of transcription from promoter pE, a component of the lysogenic response. The expression of cII was examined in vectors devoid of phage transcription modulating elements. Their removal enabled evaluating if the expression of the small RNA OOP, on its own, could suppress CII activities, including complementing for a lysogenic response, cell toxicity and causing rapid cellular loss of ColE1 plasmids. The results confirm that OOP RNA expression from the genetic element pO oop-to can prevent the ability of plasmid-encoded CII to complement for a lysogenic response, suggesting that it serves as a powerful regulatory pivot in lambda development. Plasmids with a pO promoter sequence of 45 nucleotides (pO45), containing the -10 and -35 regions for oop, were non-functional; whereas, plasmids with pO94 prevented CII complementation, CII-dependent plasmid loss and suppressed CII toxicity, suggesting the pO promoter has an extended DNA sequence. All three CII activities were eliminated by the deletion of the COOH-terminal 20 amino acids of CII. Host mutations in the hflA locus, in pcnB and in rpoB influenced CII activities. These studies suggest that the COOH-terminal end of CII likely interacts with the beta-subunit of RNA polymerase. PMID- 29518936 TI - Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy. AB - The evaluation of drug-polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening device based on their ability to predict drug-polymer miscibility, solid state properties (Tg value and width), and adequate polymer selection during the development of spray-dried amorphous solid dispersions (SDASDs). Binary ASDs of four drugs and seven polymers were produced at 20:80, 40:60, 60:40, and 80:20 (w/w). Samples were systematically analyzed using modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD). Principal component analysis (PCA) was used to qualitatively assess the predictability of screening methods with regards to SDASD development. Poor correlation was found between theoretical models and experimentally-obtained results. Additionally, the limited ability of usual screening methods to predict the miscibility of SDASDs did not guarantee the appropriate selection of lead excipient for the manufacturing of robust SDASDs. Contrary to standard approaches, our novel screening device allowed the selection of optimal polymer and drug loading and established insight into the final properties and performance of SDASDs at an early stage, therefore enabling the optimization of the scaled-up late-stage development. PMID- 29518938 TI - Mechanical Characteristics, In Vitro Degradation, Cytotoxicity, and Antibacterial Evaluation of Zn-4.0Ag Alloy as a Biodegradable Material. AB - Zn-based biodegradable metallic materials have been regarded as new potential biomaterials for use as biodegradable implants, mainly because of the ideal degradation rate compared with those of Mg-based alloys and Fe-based alloys. In this study, we developed and investigated a novel Zn-4 wt % Ag alloy as a potential biodegradable metal. A thermomechanical treatment was applied to refine the microstructure and, consequently, to improve the mechanical properties, compared to pure Zn. The yield strength (YS), ultimate tensile strength (UTS) and elongation of the Zn-4Ag alloy are 157 MPa, 261 MPa, and 37%, respectively. The corrosion rate of Zn-4Ag calculated from released Zn ions in DMEM extracts is approximately 0.75 +/- 0.16 MUg cm-2 day-1, which is higher than that of pure Zn. In vitro cytotoxicity tests showed that the Zn-4Ag alloy exhibits acceptable toxicity to L929 and Saos-2 cells, and could effectively inhibit initial bacteria adhesion. This study shows that the Zn-4Ag exhibits excellent mechanical properties, predictable degradation behavior, acceptable biocompatibility, and effective antibacterial properties, which make it a candidate biodegradable material. PMID- 29518937 TI - Generalized Unsafety Theory of Stress: Unsafe Environments and Conditions, and the Default Stress Response. AB - Prolonged physiological stress responses form an important risk factor for disease. According to neurobiological and evolution-theoretical insights the stress response is a default response that is always "on" but inhibited by the prefrontal cortex when safety is perceived. Based on these insights the Generalized Unsafety Theory of Stress (GUTS) states that prolonged stress responses are due to generalized and largely unconsciously perceived unsafety rather than stressors. This novel perspective necessitates a reconstruction of current stress theory, which we address in this paper. We discuss a variety of very common situations without stressors but with prolonged stress responses, that are not, or not likely to be caused by stressors, including loneliness, low social status, adult life after prenatal or early life adversity, lack of a natural environment, and less fit bodily states such as obesity or fatigue. We argue that in these situations the default stress response may be chronically disinhibited due to unconsciously perceived generalized unsafety. Also, in chronic stress situations such as work stress, the prolonged stress response may be mainly caused by perceived unsafety in stressor-free contexts. Thus, GUTS identifies and explains far more stress-related physiological activity that is responsible for disease and mortality than current stress theories. PMID- 29518939 TI - Quantitative Proteomic Approach Targeted to Fibrinogen beta Chain in Tissue Gastric Carcinoma. AB - Elevated plasma fibrinogen levels and tumor progression in patients with gastric cancer (GC) have been largely reported. However, distinct fibrinogen chains and domains have different effects on coagulation, inflammation, and angiogenesis. The aim of this study was to characterize fibrinogen beta chain (FGB) in GC tissues. Retrospectively we analyzed the data of matched pairs of normal (N) and malignant tissues (T) of 28 consecutive patients with GC at diagnosis by combining one- and two-dimensional electrophoresis (1DE and 2DE) with immunoblotting and mass spectrometry together with two-dimensional difference in gel electrophoresis (2D-DIGE). 1DE showed bands of the intact FGB at 50 kDa and the cleaved forms containing the fragment D at ~37-40 kDa, which corresponded to 19 spots in 2DE. In particular, spot 402 at ~50 kDa and spots 526 and 548 at ~37 kDa were of interest by showing an increased expression in tumor tissues. A higher content of spot 402 was associated with stomach antrum, while spots 526 and 548 amounts correlated with corpus and high platelet count (>208 * 108/L). The quantification of FGB and cleaved products may help to further characterize the interconnections between GC and platelet/coagulation pathways. PMID- 29518940 TI - A Three-MicroRNA Signature as a Potential Biomarker for the Early Detection of Oral Cancer. AB - Oral squamous cell carcinoma (OSCC) is often diagnosed at a late stage and may be malignantly transformed from oral leukoplakia (OL). This study aimed to identify potential plasma microRNAs (miRNAs) for the early detection of oral cancer. Plasma from normal, OL, and OSCC patients were evaluated. Small RNA sequencing was used to screen the differently expressed miRNAs among the groups. Next, these miRNAs were validated with individual samples by quantitative real-time polymerase chain reaction (qRT-PCR) assays in the training phase (n = 72) and validation phase (n = 178). The possible physiological roles of the identified miRNAs were further investigated using bioinformatics analysis. Three miRNAs (miR 222-3p, miR-150-5p, and miR-423-5p) were identified as differentially expressed among groups; miR-222-3p and miR-423-5p negatively correlated with T stage, lymph node metastasis status, and clinical stage. A high diagnostic accuracy (Area under curve = 0.88) was demonstrated for discriminating OL from OSCC. Bioinformatics analysis reveals that miR-423-5p and miR-222-3p are significantly over-expressed in oral cancer tissues and involved in various cancer pathways. The three-plasma miRNA panel may be useful to monitor malignant progression from OL to OSCC and as potential biomarkers for early detection of oral cancer. PMID- 29518941 TI - Effects of High Levels of Deoxynivalenol and Zearalenone on Growth Performance, and Hematological and Immunological Parameters in Pigs. AB - Background: Deoxynivalenol (DON) and zearalenone (ZEN) are common food contaminants produced by Fusarium sp. Mycotoxins are a potential health hazard because of their toxicological effects on both humans and farmed animals. Methods: We analyzed three groups of pigs: a control group (fed a standard diet), and the DON and ZEN groups, fed a diet containing 8 mg/kg DON and 0.8 mg/kg ZEN respectively, for four weeks. Results: DON and ZEN exposure decreased body weight (BW), average daily feed intake (ADFI), food conversion rate (FCR), and the serum levels of immunoglobulin (Ig)G and IgM. The total antioxidant levels significantly decreased in serum and increased in urine samples of both treatment groups. Additionally, DON and ZEN exposure increased serotonin levels in urine. Hematological parameters were not affected by the investigated toxins. Microscopic lesions were evident in sections of kidneys from either treatment group: we found sporadic interstitial nephritis in the DON group and renal glomerulus atrophy in the ZEN group. The expression levels of inflammatory cytokines and chemokine marker genes were reduced in tissues from DON- and ZEN exposed pigs. Conclusions: chronic ingestion of high doses of DON and ZEN alters the immune response and causes organs damage, and might be associated with various diseases in pigs. PMID- 29518942 TI - Gas Separation Properties of Polyimide Thin Films on Ceramic Supports for High Temperature Applications. AB - Novel selective ceramic-supported thin polyimide films produced in a single dip coating step are proposed for membrane applications at elevated temperatures. Layers of the polyimides P84(r), Matrimid 5218(r), and 6FDA-6FpDA were successfully deposited onto porous alumina supports. In order to tackle the poor compatibility between ceramic support and polymer, and to get defect-free thin films, the effect of the viscosity of the polymer solution was studied, giving the entanglement concentration (C*) for each polymer. The C* values were 3.09 wt. % for the 6FDA-6FpDA, 3.52 wt. % for Matrimid(r), and 4.30 wt. % for P84(r). A minimum polymer solution concentration necessary for defect-free film formation was found for each polymer, with the inverse order to the intrinsic viscosities (P84(r) >= Matrimid(r) >> 6FDA-6FpDA). The effect of the temperature on the permeance of prepared membranes was studied for H2, CH4, N2, O2, and CO2. As expected, activation energy of permeance for hydrogen was higher than for CO2, resulting in H2/CO2 selectivity increase with temperature. More densely packed polymers lead to materials that are more selective at elevated temperatures. PMID- 29518943 TI - Structural, Electronic, and Thermodynamic Properties of Tetragonal t-SixGe3-xN4. AB - The structural, mechanical, anisotropic, electronic, and thermal properties of t Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 in the tetragonal phase are systematically investigated in the present work. The mechanical stability is proved by the elastic constants of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4. Moreover, they all demonstrate brittleness, because B/G < 1.75, and v < 0.26. The elastic anisotropy of t-Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 is characterized by Poisson's ratio, Young's modulus, the percentage of elastic anisotropy for bulk modulus AB, the percentage of elastic anisotropy for shear modulus AG, and the universal anisotropic index AU. The electronic structures of t-Si3N4, t Si2GeN4, t-SiGe2N4, and t-Ge3N4 are all wide band gap semiconductor materials, with band gaps of 4.26 eV, 3.94 eV, 3.83 eV, and 3.25 eV, respectively, when using the Heyd-Scuseria-Ernzerhof (HSE06) hybrid functional. Moreover, t-Ge3N4 is a quasi-direct gap semiconductor material. The thermodynamic properties of t Si3N4, t-Si2GeN4, t-SiGe2N4, and t-Ge3N4 are investigated utilizing the quasi harmonic Debye model. The effects of temperature and pressure on the thermal expansion coefficient, heat capacity, Debye temperature, and Gruneisen parameters are discussed in detail. PMID- 29518945 TI - Selenium Accumulation, Antioxidant Enzyme Levels, and Amino Acids Composition in Chinese Mitten Crab (Eriocheir sinensis) Fed Selenium-Biofortified Corn. AB - The effects of selenium (Se)-biofortified corn on the total Se contents, the antioxidant enzyme levels, and the amino acids composition in Chinese mitten crab (Eriocheir sinensis) during the stage of the fifth shelling to maturity were investigated in the present study. The culture density of crabs was 600 per 667 m2, and they were continuously fed 120.4 mg Se from Se-biofortified corn per 667 m2 every two days for 90 days. The results showed that the total muscle Se levels in the crabs were significantly increased (p < 0.05). Activities of hemolymph supernatant enzymes including alkaline phosphatase (AKP), lysozyme (LZM), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were also enhanced (p < 0.05). The protein and crude fat levels at maturity were higher than those at the fourth molt. The levels of total essential amino acids (?EAAs) and total delicious amino acids (?DAAs) were significantly increased (p < 0.05). We demonstrate that the feeding of Se-biofortified corn could significantly improve total muscle Se concentrations and hemolymph supernatant antioxidant enzyme activities in Chinese mitten crab, and slow down the rapid decline of ?EAAs and ?DAAs at maturity, thus improving the nutritional quality of Chinese mitten crab. PMID- 29518944 TI - Tannic Acid Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Prostate Cancer. AB - Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via ER stress with natural compounds could be a novel therapeutic strategy for the management of prostate cancer. Tannic acid (a naturally occurring polyphenol) was used to examine the ER stress mediated UPR pathway in prostate cancer cells. Tannic acid treatment inhibited the growth, clonogenic, invasive, and migratory potential of prostate cancer cells. Tannic acid demonstrated activation of ER stress response (Protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme 1 (IRE1)) and altered its regulatory proteins (ATF4, Bip, and PDI) expression. Tannic acid treatment affirmed upregulation of apoptosis-associated markers (Bak, Bim, cleaved caspase 3, and cleaved PARP), while downregulation of pro-survival proteins (Bcl-2 and Bcl-xL). Tannic acid exhibited elevated G1 population, due to increase in p18INK4C and p21WAF1/CIP1 expression, while cyclin D1 expression was inhibited. Reduction of MMP2 and MMP9, and reinstated E-cadherin signifies the anti-metastatic potential of this compound. Altogether, these results demonstrate that tannic acid can promote apoptosis via the ER stress mediated UPR pathway, indicating a potential candidate for cancer treatment. PMID- 29518946 TI - Adherence to the Caffeine Intake Guideline during Pregnancy and Birth Outcomes: A Prospective Cohort Study. AB - The aims of this study were to identify: (i) the proportion of women exceeding the caffeine intake guideline (>200 mg/day) during each trimester, accounting for point of pregnancy awareness; (ii) guideline adherence trajectories across pregnancy; (iii) maternal characteristics associated with trajectories; and (iv) association between adherence and growth restriction birth outcomes. Typical and maximal intake per consumption day for the first trimester (T1; pre- and post pregnancy awareness), second (T2), and third trimester (T3) were recorded for a prospective cohort of pregnant Australian women with singleton births (n = 1232). Birth outcomes were birth weight, small for gestational age, and head circumference. For each period, participants were classified as abstinent, within (<=200 mg), or in excess (>200 mg). Latent class growth analyses identified guideline adherence trajectories; regression analyses identified associations between adherence in each trimester and birth outcomes. The percentage of participants who reported caffeine use declined between T1 pre- and post pregnancy awareness (89% to 68%), and increased in T2 and T3 (79% and 80%). Trajectories were: 'low consumption' (22%): low probability of any use; 'within guideline' (70%): high probability of guideline adherence; and 'decreasing heavy use' (8%): decreasing probability of excess use. The latter two groups were more likely to report alcohol and tobacco use, and less likely to report planning pregnancy and fertility problems. Exceeding the guideline T1 pre-pregnancy awareness was associated with lower birth weight after covariate control (b = 143.16, p = 0.011). Overall, high caffeine intake pre-pregnancy awareness occurs amongst a significant minority of women, and continued excess use post-pregnancy awareness is more common where pregnancy is unplanned. Excess caffeine consumption pre-pregnancy awareness may increase the risk for lower birth weight. Increasing awareness of the guideline in pregnancy and preconception health care may be warranted. PMID- 29518947 TI - Food Sources and Potential Determinants of Dietary Vitamin C Intake in Chinese Adults: A Cross-Sectional Study. AB - Vitamin C is essential for human health. It is important to estimate the dietary vitamin C intake in the Chinese population to examine the effects of the nutritional transition occurred in recent decades. The present study aimed to estimate the dietary vitamin C intake in Chinese adults by using cross-sectional data from the 2015 China Nutritional Transition Cohort Study and selecting those aged 18-65 years with complete records of sociodemographic characteristics and dietary measurements (n = 11,357). Wilcoxon rank-sum test, Kruskal-Wallis analysis, Chi-squared test, and multiple logistic regression were employed to analyze the daily dietary vitamin C intake on the basis of three-day 24 h dietary recalls and food sources in relation to demographic factors, to evaluate vitamin C intake status using the estimated average requirement cut-off point, and to explore underlying influencing factors. The mean (SD (standard deviation)) and median (interquartile range) levels of the dietary vitamin C intake in adults were 78.1 (54.6) and 65.4 (61.4) mg/day, respectively. Light vegetables, dark vegetables, fruits, and tubers were the top four food sources, contributing a combined 97.3% of total daily dietary vitamin C intake in the study population. The prevalence of risk of insufficient dietary vitamin C intake was 65.1%. Both the distribution of vitamin C intake and the prevalence of risk of insufficient dietary vitamin C intake differed by several demographic factors. Educational level, residence area, geographic location, vegetable consumption, and total energy intake were independent determinants of the risk of insufficient dietary vitamin C intake. In conclusion, dietary vitamin C intake is inadequate in Chinese adult population, and an increase in vitamin C intake should be recommended especially to the population at risk for vitamin C insufficiency. PMID- 29518949 TI - Interface Bond Improvement of Sisal Fibre Reinforced Polylactide Composites with Added Epoxy Oligomer. AB - To improve the interfacial bonding of sisal fiber-reinforced polylactide biocomposites, polylactide (PLA) and sisal fibers (SF) were melt-blended to fabricate bio-based composites via in situ reactive interfacial compatibilization with addition of a commercial grade epoxy-functionalized oligomer Joncryl ADR@ 4368 (ADR). The FTIR (Fourier Transform infrared spectroscopy) analysis and SEM (scanning electron microscope) characterization demonstrated that the PLA molecular chain was bonded to the fiber surface and the epoxy-functionalized oligomer played a hinge-like role between the sisal fibers and the PLA matrix, which resulted in improved interfacial adhesion between the fibers and the PLA matrix. The interfacial reaction and microstructures of composites were further investigated by thermal and rheological analyses, which indicated that the mobility of the PLA molecular chain in composites was restricted because of the introduction of the ADR oligomer, which in turn reflected the improved interfacial interaction between SF and the PLA matrix. These results were further justified with the calculation of activation energies of glass transition relaxation (?Ea) by dynamic mechanical analysis. The mechanical properties of PLA/SF composites were simultaneously reinforced and toughened with the addition of ADR oligomer. The interfacial interaction and structure-properties relationship of the composites are the key points of this study. PMID- 29518948 TI - ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion. AB - The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp mRNA and protein levels of Shp-/- mice were similar to those of wild-types; however, those of Chrebp-/-Shp-/- and Chrebp-/- mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp-/- mice were similar to wild-types but were much lower in Chrebp-/- and Chrebp-/-Shp-/- mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other. PMID- 29518950 TI - Highly Sensitive and Selective Potassium Ion Detection Based on Graphene Hall Effect Biosensors. AB - Potassium (K+) ion is an important biological substance in the human body and plays a critical role in the maintenance of transmembrane potential and hormone secretion. Several detection techniques, including fluorescent, electrochemical, and electrical methods, have been extensively investigated to selectively recognize K+ ions. In this work, a highly sensitive and selective biosensor based on single-layer graphene has been developed for K+ ion detection under Van der Pauw measurement configuration. With pre-immobilization of guanine-rich DNA on the graphene surface, the graphene devices exhibit a very low limit of detection (~1 nM) with a dynamic range of 1 nM-10 MUM and excellent K+ ion specificity against other alkali cations, such as Na+ ions. The origin of K+ ion selectivity can be attributed to the fact that the formation of guanine-quadruplexes from guanine-rich DNA has a strong affinity for capturing K+ ions. The graphene-based biosensors with improved sensing performance for K+ ion recognition can be applied to health monitoring and early disease diagnosis. PMID- 29518951 TI - Novel Trifluoromethylcoumarinyl Urea Derivatives: Synthesis, Characterization, Fluorescence, and Bioactivity. AB - A series of novel trifluoromethylcoumarinyl urea derivatives were designed, synthesized, and characterized by 1H-NMR, 13C-NMR, and HR-ESI-MS. The fluorescence spectra of the target compounds were recorded. The spectra show that most of the title compounds glow green with lambdamaxem of 500-517 nm, while compounds 5r, 5s, 5u, and 5l (compounds named by authors) glow violet with lambdamaxem of 381-443 nm. Moreover, the herbicidal and antifungal activities of the synthesized compounds were evaluated for their potential use as pesticides. The results indicate that compound 5f against the caulis of Amaranthusretroflexus and compounds 5j and 5l against the taproot of Digitariasanguinalis are equivalent to the commercial herbicide Acetochlor. Nine of the title compounds are more antifungal than commercial fungicide Carbendazim against Botrytis cinerea. PMID- 29518952 TI - Antimelanogenic Effect of an Oroxylum indicum Seed Extract by Suppression of MITF Expression through Activation of MAPK Signaling Protein. AB - In this study, the antimelanogenic effect of an ethyl acetate fraction of Oroxylum indicum Vent. seeds (OISEA) and its underlying mechanisms in melan-a cells were investigated. Antimelanogenesis activity was confirmed by assessing inhibition of tyrosinase activity and melanin content in the cells. Both transcriptional and translational expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase related protein-1 and 2 (TYRP-1 and TYRP-2), were also examined. The results depicted that pretreatment of OISEA significantly inhibits not only tyrosinase activity, but melanin production and intracellular tyrosinase activity. By repressing the expression of tyrosinase, TYRP-1, TYRP-2, and MITF, OISEA interrupted melanin production. Additionally, OISEA interfered with the phosphorylation of p38, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK), with the reversal of OISEA-induced melanogenesis inhibition after treatment with the specific inhibitors SB239063, U0126, and SP600125. Overall, these results suggest that OISEA can stimulate p38, ERK1/2, JNK phosphorylation, and subsequent suppression of melanin, leading to the inhibition of melanogenic enzymes and melanin production, possibly owing to the presence of polyphenolic compounds. PMID- 29518953 TI - A Neutrophil Proteomic Signature in Surgical Trauma Wounds. AB - Non-healing wounds continue to be a clinical challenge for patients and medical staff. These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is therefore important to decipher molecular signatures that reflect the macroscopic process of wound healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy after surgical trauma to generate wound-derived protein profiles via global mass spectrometry. We confidently identified 311 proteins in exudates. Among them were expected targets belonging to the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200 post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually collected exudates, we confirmed presence of neutrophils and their products, such as microparticles and fragments containing myeloperoxidase and DNA. These data confirmed known and identified less known wound proteins and their PTMs, which may serve as resource for future studies on human wound healing. PMID- 29518954 TI - RNA Trans-Splicing Modulation via Antisense Molecule Interference. AB - In recent years, RNA trans-splicing has emerged as a suitable RNA editing tool for the specific replacement of mutated gene regions at the pre-mRNA level. Although the technology has been successfully applied for the restoration of protein function in various genetic diseases, a higher trans-splicing efficiency is still desired to facilitate its clinical application. Here, we describe a modified, easily applicable, fluorescence-based screening system for the generation and analysis of antisense molecules specifically capable of improving the RNA reprogramming efficiency of a selected KRT14-specific RNA trans-splicing molecule. Using this screening procedure, we identified several antisense RNAs and short rationally designed oligonucleotides, which are able to increase the trans-splicing efficiency. Thus, we assume that besides the RNA trans-splicing molecule, short antisense molecules can act as splicing modulators, thereby increasing the trans-splicing efficiency to a level that may be sufficient to overcome the effects of certain genetic predispositions, particularly those associated with dominantly inherited diseases. PMID- 29518956 TI - Neighborhood Variation of Sustainable Urban Morphological Characteristics. AB - Compact cities and their urban forms have implications on sustainable city development because of high density urban settlement, increased accessibility, and a balanced land use mix. This paper uses quantitative means of understanding urban morphological characteristics with reference to the differing qualities of the urban form (i.e., street patterns, building volumes, land uses and greenery). The results, based on 89 neighborhood communities of Hong Kong, show varying degrees of regional differences in the urban built form supported by numerical statistics and graphical illustrations. This paper offers empirical evidence on some morphological characteristics that can be estimated objectively using modern geospatial technologies and applied universally to inform urban planning. However, more studies linking these quantifiable measures of the physical form with sustainable urban living are needed to account for human comfort in the totality of environmental, social, and economic responsibilities. PMID- 29518955 TI - From Content Knowledge to Community Change: A Review of Representations of Environmental Health Literacy. AB - Environmental health literacy (EHL) is a relatively new framework for conceptualizing how people understand and use information about potentially harmful environmental exposures and their influence on health. As such, information on the characterization and measurement of EHL is limited. This review provides an overview of EHL as presented in peer-reviewed literature and aggregates studies based on whether they represent individual level EHL or community level EHL or both. A range of assessment tools has been used to measure EHL, with many studies relying on pre-/post-assessment; however, a broader suite of assessment tools may be needed to capture community-wide outcomes. This review also suggests that the definition of EHL should explicitly include community change or collective action as an important longer-term outcome and proposes a refinement of previous representations of EHL as a theoretical framework, to include self-efficacy. PMID- 29518957 TI - Multi-Target Angle Tracking Algorithm for Bistatic Multiple-Input Multiple-Output (MIMO) Radar Based on the Elements of the Covariance Matrix. AB - In this paper, we consider the problem of tracking the direction of arrivals (DOA) and the direction of departure (DOD) of multiple targets for bistatic multiple-input multiple-output (MIMO) radar. A high-precision tracking algorithm for target angle is proposed. First, the linear relationship between the covariance matrix difference and the angle difference of the adjacent moment was obtained through three approximate relations. Then, the proposed algorithm obtained the relationship between the elements in the covariance matrix difference. On this basis, the performance of the algorithm was improved by averaging the covariance matrix element. Finally, the least square method was used to estimate the DOD and DOA. The algorithm realized the automatic correlation of the angle and provided better performance when compared with the adaptive asymmetric joint diagonalization (AAJD) algorithm. The simulation results demonstrated the effectiveness of the proposed algorithm. The algorithm provides the technical support for the practical application of MIMO radar. PMID- 29518958 TI - Automatic Non-Destructive Growth Measurement of Leafy Vegetables Based on Kinect. AB - Non-destructive plant growth measurement is essential for plant growth and health research. As a 3D sensor, Kinect v2 has huge potentials in agriculture applications, benefited from its low price and strong robustness. The paper proposes a Kinect-based automatic system for non-destructive growth measurement of leafy vegetables. The system used a turntable to acquire multi-view point clouds of the measured plant. Then a series of suitable algorithms were applied to obtain a fine 3D reconstruction for the plant, while measuring the key growth parameters including relative/absolute height, total/projected leaf area and volume. In experiment, 63 pots of lettuce in different growth stages were measured. The result shows that the Kinect-measured height and projected area have fine linear relationship with reference measurements. While the measured total area and volume both follow power law distributions with reference data. All these data have shown good fitting goodness (R2 = 0.9457-0.9914). In the study of biomass correlations, the Kinect-measured volume was found to have a good power law relationship (R2 = 0.9281) with fresh weight. In addition, the system practicality was validated by performance and robustness analysis. PMID- 29518959 TI - A Quality Assessment Method Based on Common Distributed Targets for GF-3 Polarimetric SAR Data. AB - The GaoFen-3 (GF-3) satellite, launched on 10 August 2016, is the first C-band polarimetric synthetic aperture radar (PolSAR) satellite in China. The PolSAR system of GF-3 can collect a significant wealth of information for geophysical research and applications. Being used for related applications, GF-3 PolSAR images must be of good quality. It is necessary to evaluate the quality of polarimetric data and achieve the normalized quality monitoring during 8-year designed life of GF-3. In this study, a new quality assessment method of PolSAR data based on common distributed targets is proposed, and the performance of the method is analyzed by simulations and GF-3 experiments. We evaluate the quality of GF-3 PolSAR data by this method. Results suggest that GF-3 antenna is highly isolated, and the quality of calibrated data satisfies the requests of quantitative applications. PMID- 29518960 TI - A Robust Adaptive Unscented Kalman Filter for Nonlinear Estimation with Uncertain Noise Covariance. AB - The Unscented Kalman filter (UKF) may suffer from performance degradation and even divergence while mismatch between the noise distribution assumed as a priori by users and the actual ones in a real nonlinear system. To resolve this problem, this paper proposes a robust adaptive UKF (RAUKF) to improve the accuracy and robustness of state estimation with uncertain noise covariance. More specifically, at each timestep, a standard UKF will be implemented first to obtain the state estimations using the new acquired measurement data. Then an online fault-detection mechanism is adopted to judge if it is necessary to update current noise covariance. If necessary, innovation-based method and residual based method are used to calculate the estimations of current noise covariance of process and measurement, respectively. By utilizing a weighting factor, the filter will combine the last noise covariance matrices with the estimations as the new noise covariance matrices. Finally, the state estimations will be corrected according to the new noise covariance matrices and previous state estimations. Compared with the standard UKF and other adaptive UKF algorithms, RAUKF converges faster to the actual noise covariance and thus achieves a better performance in terms of robustness, accuracy, and computation for nonlinear estimation with uncertain noise covariance, which is demonstrated by the simulation results. PMID- 29518961 TI - Phenotype- and SSR-Based Estimates of Genetic Variation between and within Two Important Elymus Species in Western and Northern China. AB - Elymus nutans and Elymus sibiricus are two important perennial forage grasses of the genus Elymus, widely distributed in high altitude regions of Western and Northern China, especially on the Qinghai-Tibetan Plateau. Information on phenotypic and genetic diversity is limited, but necessary for Elymus germplasm collection, conservation, and utilization. In the present study, the phenotypic and genetic differentiation of 73 accessions of the two species were evaluated using 15 phenotypic traits and 40 expressed sequence tag derived simple sequence repeat markers (EST-SSRs). The results showed that only 7.23% phenotypic differentiation (Pst) existed between the two Elymus species based on fifteen quantitative traits. Principal component analysis (PCA) revealed that leaf traits, spike traits, and some seed traits were dominant factors in phenotypic variation. Moreover, 396 (97.8%) and 331 (87.1%) polymorphic bands were generated from 40 EST-SSR primers, suggesting high levels of genetic diversity for the two species. The highest genetic diversity was found in the Northeastern Qinghai Tibetan Plateau groups. Clustering analysis based on molecular data showed that most accessions of each Elymus species tended to group together. Similar results were described by principal coordinates analysis (PCoA) and structure analysis. The molecular variance analysis (AMOVA) revealed that 81.47% and 89.32% variation existed within the geographical groups for the two species, respectively. Pearson's correlation analyses showed a strong positive correlation between Nei's genetic diversity and annual mean temperature. These results could facilitate Elymus germplasm collection, conservation, and future breeding. PMID- 29518963 TI - Optimization and Analysis of a U-Shaped Linear Piezoelectric Ultrasonic Motor Using Longitudinal Transducers. AB - A novel U-shaped piezoelectric ultrasonic motor that mainly focused on miniaturization and high power density was proposed, fabricated, and tested in this work. The longitudinal vibrations of the transducers were excited to form the elliptical movements on the driving feet. Finite element method (FEM) was used for design and analysis. The resonance frequencies of the selected vibration modes were tuned to be very close to each other with modal analysis and the movement trajectories of the driving feet were gained with transient simulation. The vibration modes and the mechanical output abilities were tested to evaluate the proposed motor further by a prototype. The maximum output speed was tested to be 416 mm/s, the maximum thrust force was 21 N, and the maximum output power was 5.453 W under frequency of 29.52 kHz and voltage of 100 Vrms. The maximum output power density of the prototype reached 7.59 W/kg, which was even greater than a previous similar motor under the exciting voltage of 200 Vrms. The proposed motor showed great potential for linear driving of large thrust force and high power density. PMID- 29518962 TI - Selection and Characterization of a DNA Aptamer Specifically Targeting Human HECT Ubiquitin Ligase WWP1. AB - Nucleic acid aptamers hold promise as therapeutic tools for specific, tailored inhibition of protein targets with several advantages when compared to small molecules or antibodies. Nuclear WW domain containing E3 ubiquitin ligase 1 (WWP1) ubiquitin ligase poly-ubiquitinates Runt-related transcription factor 2 (Runx2), a key transcription factor associated with osteoblast differentiation. Since WWP1 and an adapter known as Schnurri-3 are negative regulators of osteoblast function, the disruption of this complex has the potential to increase bone deposition for osteoporosis therapy. Here, we develop new DNA aptamers that bind and inhibit WWP1 then investigate efficacy in an osteoblastic cell culture. DNA aptamers were selected against three different truncations of the HECT domain of WWP1. Aptamers which bind specifically to a C-lobe HECT domain truncation were observed to enrich during the selection procedure. One particular DNA aptamer termed C3A was further evaluated for its ability to bind WWP1 and inhibit its ubiquitination activity. C3A showed a low uM binding affinity to WWP1 and was observed to be a non-competitive inhibitor of WWP1 HECT ubiquitin ligase activity. When SaOS-2 osteoblastic cells were treated with C3A, partial localization to the nucleus was observed. The C3A aptamer was also demonstrated to specifically promote extracellular mineralization in cell culture experiments. The C3A aptamer has potential for further development as a novel osteoporosis therapeutic strategy. Our results demonstrate that aptamer-mediated inhibition of protein ubiquitination can be a novel therapeutic strategy. PMID- 29518964 TI - A Quadruped Micro-Robot Based on Piezoelectric Driving. AB - Inspired by a way of rowing, a new piezoelectric driving quadruped micro-robot operating in bending-bending hybrid vibration modes was proposed and tested in this work. The robot consisted of a steel base, four steel connecting pins and four similar driving legs, and all legs were bonded by four piezoelectric ceramic plates. The driving principle is discussed, which is based on the hybrid of first order vertical bending and first order horizontal bending vibrations. The bending bending hybrid vibration modes motivated the driving foot to form an elliptical trajectory in space. The vibrations of four legs were used to provide the driving forces for robot motion. The proposed robot was fabricated and tested according to driving principle. The vibration characteristics and elliptical movements of the driving feet were simulated by FEM method. Experimental tests of vibration characteristics and mechanical output abilities were carried out. The tested resonance frequencies and vibration amplitudes agreed well with the FEM calculated results. The size of robot is 36 mm * 98 mm * 14 mm, its weight is only 49.8 g, but its maximum load capacity achieves 200 g. Furthermore, the robot can achieve a maximum speed of 33.45 mm/s. PMID- 29518966 TI - Blood Compatibility of Sulfonated Cladophora Nanocellulose Beads. AB - Sulfonated cellulose beads were prepared by oxidation of Cladophora nanocellulose to 2,3-dialdehyde cellulose followed by sulfonation using bisulfite. The physicochemical properties of the sulfonated beads, i.e., high surface area, high degree of oxidation, spherical shape, and the possibility of tailoring the porosity, make them interesting candidates for the development of immunosorbent platforms, including their application in extracorporeal blood treatments. A desired property for materials used in such applications is blood compatibility; therefore in the present work, we investigate the hemocompatibility of the sulfonated cellulose beads using an in vitro whole blood model. Complement system activation (C3a and sC5b-9 levels), coagulation activation (thrombin-antithrombin (TAT) levels) and hemolysis were evaluated after whole blood contact with the sulfonated beads and the results were compared with the values obtained with the unmodified Cladophora nanocellulose. Results showed that neither of the cellulosic materials presented hemolytic activity. A marked decrease in TAT levels was observed after blood contact with the sulfonated beads, compared with Cladophora nanocellulose. However, the chemical modification did not promote an improvement in Cladophora nanocellulose hemocompatibility in terms of complement system activation. Even though the sulfonated beads presented a significant reduction in pro-coagulant activity compared with the unmodified material, further modification strategies need to be investigated to control the complement activation by the cellulosic materials. PMID- 29518965 TI - Evaluating Human Intestinal Cell Lines for Studying Dietary Protein Absorption. AB - With the global population rising, the need for sustainable and resource efficiently produced proteins with nutritional and health promoting qualities has become urgent. Proteins are important macronutrients and are involved in most, if not all, biological processes in the human body. This review discusses these absorption mechanisms in the small intestine. To study intestinal transport and predict bioavailability, cell lines are widely applied as screening models and often concern Caco-2, HT-29, HT-29/MTX and T84 cells. Here, we provide an overview of the presence and activities of peptide- and amino acid transporters in these cell models. Further, inter-laboratory differences are discussed as well as the culture micro-environment, both of which may influence cell culture phenotype and performance. Finally, the value of new developments in the field, including culturing cells in 3-dimensional systems under shear stress (i.e., gut on-chips), is highlighted. In particular, their suitability in screening novel food proteins and prediction of the nutritional quality needed for inclusion in the human diet of the future is addressed. PMID- 29518967 TI - The Complete Chloroplast Genomes of Two Lancea Species with Comparative Analysis. AB - The genus Lancea is native to the Qinghai-Tibetan Plateau and consists of two species, Lancea tibetica Hook. f. et Thoms. and Lancea hirsuta Bonati. Here, we report the complete sequences of the chloroplast genomes of L. tibetica and L. hirsuta, which were 153,665 and 154,045 bp in length, respectively, and each included a pair of inverted repeated regions (25,624 and 25,838 bp in length, respectively) that were separated by a large single copy region (84,401 and 84,588 bp in length, respectively) and a smaller single copy region (18,016 and 17,781 bp in length, respectively). A total of 106 genes in L. tibetica and 105 in L. hirsuta comprised 79 protein-coding genes, and 4 ribosomal RNA (rRNA) genes, as well as 23 and 22 transfer RNA (tRNA) genes in L. tibetica and L. hirsuta, respectively. The gene order, content, and orientation of the two Lancea chloroplast genomes exhibited high similarity. A large number of informative repetitive sequences, including SSRs, were observed in both genomes. Comparisons of the genomes with those of three other Lamiales species revealed 12 highly divergent regions in the intergenic spacers and in the matK, rpoA, rps19, ndhF, ccsA, ndhD, and ycf1 coding regions. A phylogenomic analysis suggested that Lancea forms a monophyletic group that is closely related to the clade composed of the families Phrymaceae, Paulowniaceae, and Rehmanniaceae. PMID- 29518968 TI - Biocompatible Materials Based on Self-Assembling Peptides on Ti25Nb10Zr Alloy: Molecular Structure and Organization Investigated by Synchrotron Radiation Induced Techniques. AB - In this work, we applied advanced Synchrotron Radiation (SR) induced techniques to the study of the chemisorption of the Self Assembling Peptide EAbuK16, i.e., H Abu-Glu-Abu-Glu-Abu-Lys-Abu-Lys-Abu-Glu-Abu-Glu-Abu-Lys-Abu-Lys-NH2 that is able to spontaneously aggregate in anti-parallel beta-sheet conformation, onto annealed Ti25Nb10Zr alloy surfaces. This synthetic amphiphilic oligopeptide is a good candidate to mimic extracellular matrix for bone prosthesis, since its beta sheets stack onto each other in a multilayer oriented nanostructure with internal pores of 5-200 nm size. To prepare the biomimetic material, Ti25Nb10Zr discs were treated with aqueous solutions of EAbuK16 at different pH values. Here we present the results achieved by performing SR-induced X-ray Photoelectron Spectroscopy (SR-XPS), angle-dependent Near Edge X-ray Absorption Fine Structure (NEXAFS) spectroscopy, FESEM and AFM imaging on Ti25Nb10Zr discs after incubation with self-assembling peptide solution at five different pH values, selected deliberately to investigate the best conditions for peptide immobilization. PMID- 29518969 TI - Iron Oxide and Gold Based Magneto-Plasmonic Nanostructures for Medical Applications: A Review. AB - Iron oxide and gold-based magneto-plasmonic nanostructures exhibit remarkable optical and superparamagnetic properties originating from their two different components. As a consequence, they have improved and broadened the application potential of nanomaterials in medicine. They can be used as multifunctional nanoprobes for magneto-plasmonic heating as well as for magnetic and optical imaging. They can also be used for magnetically assisted optical biosensing, to detect extreme traces of targeted bioanalytes. This review introduces the previous work on magneto-plasmonic hetero-nanostructures including: (i) their synthesis from simple "one-step" to complex "multi-step" routes, including seed mediated and non-seed-mediated methods; and (ii) the characterization of their multifunctional features, with a special emphasis on the relationships between their synthesis conditions, their structures and their properties. It also focuses on the most important progress made with regard to their use in nanomedicine, keeping in mind the same aim, the correlation between their morphology-namely spherical and non-spherical, core-satellite and core-shell, and the desired applications. PMID- 29518970 TI - Unravelling the Effects of the Mutation m.3571insC/MT-ND1 on Respiratory Complexes Structural Organization. AB - Mammalian respiratory complex I (CI) biogenesis requires both nuclear and mitochondria-encoded proteins and is mostly organized in respiratory supercomplexes. Among the CI proteins encoded by the mitochondrial DNA, NADH ubiquinone oxidoreductase chain 1 (ND1) is a core subunit, evolutionary conserved from bacteria to mammals. Recently, ND1 has been recognized as a pivotal subunit in maintaining the structural and functional interaction among the hydrophilic and hydrophobic CI arms. A critical role of human ND1 both in CI biogenesis and in the dynamic organization of supercomplexes has been depicted, although the proof of concept is still missing and the critical amount of ND1 protein necessary for a proper assembly of both CI and supercomplexes is not defined. By exploiting a unique model in which human ND1 is allotopically re-expressed in cells lacking the endogenous protein, we demonstrated that the lack of this protein induces a stall in the multi-step process of CI biogenesis, as well as the alteration of supramolecular organization of respiratory complexes. We also defined a mutation threshold for the m.3571insC truncative mutation in mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1), below which CI and its supramolecular organization is recovered, strengthening the notion that a certain amount of human ND1 is required for CI and supercomplexes biogenesis. PMID- 29518972 TI - The ADAMTS5 Metzincin Regulates Zebrafish Somite Differentiation. AB - The ADAMTS5 metzincin, a secreted zinc-dependent metalloproteinase, modulates the extracellular matrix (ECM) during limb morphogenesis and other developmental processes. Here, the role of ADAMTS5 was investigated by knockdown of zebrafish adamts5 during embryogenesis. This revealed impaired Sonic Hedgehog (Shh) signaling during somite patterning and early myogenesis. Notably, synergistic regulation of myod expression by ADAMTS5 and Shh during somite differentiation was observed. These roles were not dependent upon the catalytic activity of ADAMTS5. These data identify a non-enzymatic function for ADAMTS5 in regulating an important cell signaling pathway that impacts on muscle development, with implications for musculoskeletal diseases in which ADAMTS5 and Shh have been associated. PMID- 29518971 TI - Dietary Plants for the Prevention and Management of Kidney Stones: Preclinical and Clinical Evidence and Molecular Mechanisms. AB - Kidney stones are one of the oldest known and common diseases in the urinary tract system. Various human studies have suggested that diets with a higher intake of vegetables and fruits play a role in the prevention of kidney stones. In this review, we have provided an overview of these dietary plants, their main chemical constituents, and their possible mechanisms of action. Camellia sinensis (green tea), Rubus idaeus (raspberry), Rubia cordifolia (common madder), Petroselinum crispum (parsley), Punica granatum (pomegranate), Pistacia lentiscus (mastic), Solanum xanthocarpum (yellow-fruit nightshade), Urtica dioica (stinging nettle), Dolichos biflorus (horse gram), Ammi visnaga (khella), Nigella sativa (black-cumin), Hibiscus sabdariffa (roselle), and Origanum vulgare (oregano) have received considerable interest based on scientific evidence. Beside these dietary plants, phytochemicals-such as catechin, epicatechin, epigallocatechin-3-gallate, diosmin, rutin, quercetin, hyperoside, and curcumin-as antioxidant dietary phyto phenols were found to be effective for the prevention of urolithiasis (the process of stone formation in the urinary tract). The main underlying mechanisms of these dietary plants and their isolated phytonutrients in the management of urolithiasis include diuretic, antispasmodic, and antioxidant activity, as well as an inhibitory effect on crystallization, nucleation, and aggregation of crystals. The results as presented in this review demonstrate the promising role of dietary plants and phytophenols in the prevention and management of kidney stones. Further investigations are required to confirm the safety and efficacy of these compounds. PMID- 29518973 TI - New Terpenoids from Chamaecyparis formosensis (Cupressaceae) Leaves with Modulatory Activity on Matrix Metalloproteases 2 and 9. AB - Chamaecyparis formosensis is Taiwan's most representative tree, and has high economic value. To date, only a few active chemical constituents have been reported for C. formosensis. In this study, 37 secondary metabolites, including three new compounds (1-3), were extracted from the leaves of C. formosensis. The compounds isolated from the ethyl acetate layer were used at different concentrations to treat HT-1080 human fibrosarcoma cells and to evaluate their effects on matrix metalloprotease 2 (MMP-2) and 9 (MMP-9) expression. Based on extensive analysis of data from high-resolution mass spectrometry (HR-MS) as well as nuclear magnetic resonance (NMR), infrared (IR), and ultraviolet (UV) spectroscopy, the new compounds were identified as 11,12-dihydroxyisodaucenoic acid (1), 12-hydroxyisodaucenoic acid (2), and 1-oxo-2alpha,3beta dihydroxytotarol (3). Known compounds 4-37 were identified by comparing their spectroscopic data with data reported in the literature. Biological activity tests by gelatin zymographic analysis revealed that seven compounds, including new compound 2, have no cytotoxic effect on HT-1080 cells and were found to increase MMP-2 or MMP-9 expression by 1.25- to 1.59-fold at lower concentrations of 10-50 uM. These naturally derived regulatory compounds could potentially serve as a novel pharmaceutical basis for medical purposes. PMID- 29518974 TI - One-Step Preparation of Phenyl Boron-Modified Magnetic Mesoporous Silica for Selective Enrichment of cis-Diol-Containing Substances. AB - For enrichment and separation of cis-diol-containing compounds from biomatrix, a new type of magnetic nanoparticles named MS-48-PBSC, whichwas facilely prepared in a one-step heterogeneous reaction. The morphology results demonstrated that the MS-48-PBSC was a spherical nanomaterial containing a core of silica-coated magnetic particle with a diameter of about 200 nm, and a cover layer of mesoporous silica with a thickness of approximate 50 nm. The characterization results showed that MS-48-PBSC presented a pore size of 4.2 nm, a surface area of 548 m2.g-1, and a pore volume of 0.30 cm3.g-1. The MS-48-PBSC also exhibited magnetism of 42 emu.g-1 that contributed to the easy separation of magnetic nanomaterial within 30 s from the matrix with the aid of the external magnetic field. In addition, the MS-48-PBSC exhibited high adsorption capacity for adenosine, xanthosine, uridine, sialic acid, and teicoplanin with 0.60, 0.51, 0.42, 0.75, and 1.26 mg/g, respectively, and showed a high selectivity for the cis-diol structure compounds, relative to interferences of bovine serum albumin, guanine, uric acid, and xanthine. The recoveries of adenosine, xanthosine, uridine, sialic acid, and teicoplanin were 71.8-114.1% with relative standard deviation (RSD) <= 8.6%, and the enrichment factors of them were 8-11. MS-48-PBSC exhibited quick separation capability from matrix, high adsorption capacity and size exclusion for bovine serum albumin, which could meet the requirements of separation and enrichment for substances with a cis-diol structure. PMID- 29518975 TI - Pharmacological Agents Targeting the Cellular Prion Protein. AB - Prion diseases are associated with the conversion of the cellular prion protein (PrPC), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc) that accumulates in brain tissues of affected individuals. PrPSc is a self-catalytic protein assembly capable of recruiting native conformers of PrPC, and causing their rearrangement into new PrPSc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrPSc, and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrPSc might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrPC, the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrPC in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrPC, discussing pharmacological properties and therapeutic potentials of each chemical class. PMID- 29518977 TI - Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach. AB - The major obstacle in the clinical use of the antitumor drug cisplatin is inherent and acquired resistance. Typically, cisplatin resistance is not restricted to a single mechanism demanding for a systems pharmacology approach to understand a whole cell's reaction to the drug. In this study, the cellular transcriptome of untreated and cisplatin-treated A549 non-small cell lung cancer cells and their cisplatin-resistant sub-line A549rCDDP2000 was screened with a whole genome array for relevant gene candidates. By combining statistical methods with available gene annotations and without a previously defined hypothesis HRas, MAPK14 (p38), CCL2, DOK1 and PTK2B were identified as genes possibly relevant for cisplatin resistance. These and related genes were further validated on transcriptome (qRT-PCR) and proteome (Western blot) level to select candidates contributing to resistance. HRas, p38, CCL2, DOK1, PTK2B and JNK3 were integrated into a model of resistance-associated signalling alterations describing differential gene and protein expression between cisplatin-sensitive and resistant cells in reaction to cisplatin exposure. PMID- 29518976 TI - EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non Immunocompromised Hosts. AB - The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored. PMID- 29518978 TI - Structural Biology of the TNFalpha Antagonists Used in the Treatment of Rheumatoid Arthritis. AB - The binding of the tumor necrosis factor alpha (TNFalpha) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel(r)), infliximab (Remicade(r)), adalimumab (Humira(r)), certolizumab-pegol (Cimzia(r)), and golimumab (Simponi(r)), are anti-TNFalpha agents. These drugs block TNFalpha from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFalpha-TNFalpha antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFalpha blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFalpha. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFalpha antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFalpha for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFalpha plays an important role in pathogenesis. PMID- 29518979 TI - Metabolic Reprogramming and the Recovery of Physiological Functionality in 3D Cultures in Micro-Bioreactors. AB - The recovery of physiological functionality, which is commonly seen in tissue mimetic three-dimensional (3D) cellular aggregates (organoids, spheroids, acini, etc.), has been observed in cells of many origins (primary tissues, embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and immortal cell lines). This plurality and plasticity suggest that probably several basic principles promote this recovery process. The aim of this study was to identify these basic principles and describe how they are regulated so that they can be taken in consideration when micro-bioreactors are designed. Here, we provide evidence that one of these basic principles is hypoxia, which is a natural consequence of multicellular structures grown in microgravity cultures. Hypoxia drives a partial metabolic reprogramming to aerobic glycolysis and an increased anabolic synthesis. A second principle is the activation of cytoplasmic glutaminolysis for lipogenesis. Glutaminolysis is activated in the presence of hypo- or normo-glycaemic conditions and in turn is geared to the hexosamine pathway. The reducing power needed is produced in the pentose phosphate pathway, a prime function of glucose metabolism. Cytoskeletal reconstruction, histone modification, and the recovery of the physiological phenotype can all be traced to adaptive changes in the underlying cellular metabolism. These changes are coordinated by mTOR/Akt, p53 and non-canonical Wnt signaling pathways, while myc and NF-kB appear to be relatively inactive. Partial metabolic reprogramming to aerobic glycolysis, originally described by Warburg, is independent of the cell's rate of proliferation, but is interwoven with the cells abilities to execute advanced functionality needed for replicating the tissues physiological performance. PMID- 29518980 TI - Rational Design, Synthesis and Evaluation of gamma-CD-Containing Cross-Linked Polyvinyl Alcohol Hydrogel as a Prednisone Delivery Platform. AB - This study describes the in-silico rational design, synthesis and evaluation of cross-linked polyvinyl alcohol hydrogels containing gamma-cyclodextrin (gamma CDHSAs) as platforms for the sustained release of prednisone (PDN). Through in silico studies using semi-empirical quantum mechanical calculations, the effectiveness of 20 dicarboxylic acids to generate a specific cross-linked hydrogel capable of supporting different amounts of gamma-cyclodextrin (gamma-CD) was evaluated. According to the interaction energies calculated with the in silico studies, the hydrogel made from PVA cross-linked with succinic acids (SA) was shown to be the best candidate for containing gamma-CD. Later, molecular dynamics simulation studies were performed in order to evaluate the intermolecular interactions between PDN and three cross-linked hydrogel formulations with different proportions of gamma-CD (2.44%, 4.76% and 9.1%). These three cross-linked hydrogels were synthesized and characterized. The loading and the subsequent release of PDN from the hydrogels were investigated. The in-silico and experimental results showed that the interaction between PDN and gamma-CDHSA was mainly produced with the gamma-CDs linked to the hydrogels. Thus, the unique structures and properties of gamma-CDHSA demonstrated an interesting multiphasic profile that could be utilized as a promising drug carrier for controlled, sustained and localized release of PDN. PMID- 29518981 TI - Simultaneous Detection of Two Chemicals Using a TE20-Mode Substrate-Integrated Waveguide Resonator. AB - Microwave resonators working as sensors can detect only a single analyte at a time. To address this issue, a TE20-mode substrate-integrated waveguide (SIW) resonator is exploited, owing to its two distinct regions of high-intensity electric fields, which can be manipulated by loading two chemicals. Two microfluidic channels with unequal fluid-carrying capacities, engraved in a polydimethylsiloxane (PDMS) sheet, can perturb the symmetric electric fields even if loaded with the two extreme cases of dielectric [ethanol (E), deionized water (DI)] and [deionized water, ethanol]. The four layers of the sandwiched structure considered in this study consisted of a top conductive pattern and a bottom ground, both realized on a Rogers RT/Duroid 5880. PDMS-based channels attached with an adhesive serve as the middle layers. The TE20-mode SIW with empty channels resonates at 8.26 GHz and exhibits a -25 dB return loss with an unloaded quality factor of Q ~ 28. We simultaneously load E and DI and demonstrate the detection of the four possible combinations: [E, DI], [DI, E], [E, E], and [DI, DI]. The performance of our proposed method showed increases in sensitivity (MHz/epsilonr) of 7.5%, 216%, and 1170% compared with three previously existing multichannel microwave chemical sensors. PMID- 29518982 TI - Transcriptome Profiling Reveals the EanI/R Quorum Sensing Regulon in Pantoea Ananatis LMG 2665T. AB - Pantoea ananatis LMG 2665T synthesizes and utilizes acyl homoserine lactones (AHLs) for signalling. The complete set of genes regulated by the EanI/R quorum sensing (QS) system in this strain is still not fully known. In this study, RNA sequencing (RNA-seq) was used to identify the EanI/R regulon in LMG 2665T. Pairwise comparisons of LMG 2665T in the absence of AHLs (Optical density (OD)600 = 0.2) and in the presence of AHLs (OD600 = 0.5) were performed. Additionally, pairwise comparisons of LMG 2665T and its QS mutant at OD600 = 0.5 were undertaken. In total, 608 genes were differentially expressed between LMG 2665T at OD600 = 0.5 versus the same strain at OD600 = 0.2 and 701 genes were differentially expressed between LMG 2665T versus its QS mutant at OD600 = 0.5. A total of 196 genes were commonly differentially expressed between the two approaches. These constituted approximately 4.5% of the whole transcriptome under the experimental conditions used in this study. The RNA-seq data was validated by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Genes found to be regulated by EanI/R QS were those coding for redox sensing, metabolism, flagella formation, flagella dependent motility, cell adhesion, biofilm formation, regulators, transport, chemotaxis, methyl accepting proteins, membrane proteins, cell wall synthesis, stress response and a large number of hypothetical proteins. The results of this study give insight into the genes that are regulated by the EanI/R system in LMG 2665T. Functional characterization of the QS regulated genes in LMG 2665T could assist in the formulation of control strategies for this plant pathogen. PMID- 29518983 TI - Interdisciplinary Pediatric Palliative Care Team Involvement in Compassionate Extubation at Home: From Shared Decision-Making to Bereavement. AB - Little is known about the role of pediatric palliative care (PPC) programs in providing support for home compassionate extubation (HCE) when families choose to spend their child's end of life at home. Two cases are presented that highlight the ways in which the involvement of PPC teams can help to make the option available, help ensure continuity of family-centered care between hospital and home, and promote the availability of psychosocial support for the child and their entire family, health care team members, and community. Though several challenges to realizing the option of HCE exist, early consultation with a PPC team in the hospital, the development of strategic community partnerships, early referral to home based care resources, and timely discussion of family preferences may help to make this option a realistic one for more families. The cases presented here demonstrate how families' wishes with respect to how and where their child dies can be offered, even in the face of challenges. By joining together when sustaining life support may not be in the child's best interest, PPC teams can pull together hospital and community resources to empower families to make decisions about when and where their child dies. PMID- 29518986 TI - A Hardware-Supported Algorithm for Self-Managed and Choreographed Task Execution in Sensor Networks. AB - Nowadays, sensor networks are composed of a great number of tiny resource constraint nodes, whose management is increasingly more complex. In fact, although collaborative or choreographic task execution schemes are which fit in the most perfect way with the nature of sensor networks, they are rarely implemented because of the high resource consumption of these algorithms (especially if networks include many resource-constrained devices). On the contrary, hierarchical networks are usually designed, in whose cusp it is included a heavy orchestrator with a remarkable processing power, being able to implement any necessary management solution. However, although this orchestration approach solves most practical management problems of sensor networks, a great amount of the operation time is wasted while nodes request the orchestrator to address a conflict and they obtain the required instructions to operate. Therefore, in this paper it is proposed a new mechanism for self-managed and choreographed task execution in sensor networks. The proposed solution considers only a lightweight gateway instead of traditional heavy orchestrators and a hardware-supported algorithm, which consume a negligible amount of resources in sensor nodes. The gateway avoids the congestion of the entire sensor network and the hardware-supported algorithm enables a choreographed task execution scheme, so no particular node is overloaded. The performance of the proposed solution is evaluated through numerical and electronic ModelSim-based simulations. PMID- 29518984 TI - Oxidative DNA Damage and Carotid Intima Media Thickness as Predictors of Cardiovascular Disease in Prediabetic Subjects. AB - Prediabetes is considered as a risk factor for the development of diabetes mellitus and cardiovascular disease. The present study was conducted with the aim of finding out the relationship between oxidative DNA damage and carotid intima media thickness for the prediction of cardiovascular disease in prediabetic subjects. The study included 100 prediabetic subjects and 100 normal individuals as controls. In both cases and controls, 8-OHdG was measured by ELISA, and CIMT was measured by B mode ultrasonography. Both 8-OHdG and CIMT were significantly higher in subjects with prediabetes as compared to controls (185.80 +/- 10.72 pg/mL vs. 126.13 +/- 16.01 pg/mL, p < 0.001 and 0.70 +/- 0.04 mm vs. 0.57 +/- 0.03 mm, p < 0.001, respectively). There was significant and positive correlation of IGT with 8-OHdG (r = 0.783; p < 0.001) and CIMT (r = 0.787; p < 0.001) in prediabetic subjects. Moreover, 8-OHdG showed significant positive correlation with CIMT (r = 0.704; p < 0.001) in prediabetic subjects. In conclusion, increased 8-OHdG and CIMT in prediabetic subjects indicate that biochemical changes of atherosclerosis start even before the onset of diabetes mellitus. Hence, 8-OHdG and CIMT could be used as indicators of cardiovascular disease risk in these subjects. PMID- 29518985 TI - The Repertoire of Adenovirus in Human Disease: The Innocuous to the Deadly. AB - Adenoviridae is a family of double-stranded DNA viruses that are a significant cause of upper respiratory tract infections in children and adults. Less commonly, the adenovirus family can cause a variety of gastrointestinal, ophthalmologic, genitourinary, and neurologic diseases. Most adenovirus infections are self-limited in the immunocompetent host and are treated with supportive measures. Fatal infections can occur in immunocompromised patients and less frequently in the healthy. Adenoviral vectors are being studied for novel biomedical applications including gene therapy and immunization. In this review we will focus on the spectrum of adenoviral infections in humans. PMID- 29518987 TI - Nationwide Drinking Water Sampling Campaign for Exposure Assessments in Denmark. AB - Nationwide sampling campaign of treated drinking water of groundwater origin was designed and implemented in Denmark in 2013. The main purpose of the sampling was to obtain data on the spatial variation of iodine concentration and speciation in treated drinking water, which was supplied to the majority of the Danish population. This data was to be used in future exposure and epidemiologic studies. The water supply sector (83 companies, owning 144 waterworks throughout Denmark) was involved actively in the planning and implementation process, which reduced significantly the cost and duration of data collection. The dataset resulting from this collaboration covers not only iodine species (I-, IO3-, TI), but also major elements and parameters (pH, electrical conductivity, DOC, TC, TN, F-, Cl-, NO3-, SO42-, Ca2+, Mg2+, K+, Na+) and a long list of trace elements (n = 66). The water samples represent 144 waterworks abstracting about 45% of the annual Danish groundwater abstraction for drinking water purposes, which supply about 2.5 million Danes (45% of all Danish residents). This technical note presents the design, implementation, and limitations of such a sampling design in detail in order (1) to facilitate the future use of this dataset, (2) to inform future replication studies, or (3) to provide an example for other researchers. PMID- 29518988 TI - Wetlands and Malaria in the Amazon: Guidelines for the Use of Synthetic Aperture Radar Remote-Sensing. AB - The prevention and control of mosquito-borne diseases, such as malaria, are important health issues in tropical areas. Malaria transmission is a multi-scale process strongly controlled by environmental factors, and the use of remote sensing data is suitable for the characterization of its spatial and temporal dynamics. Synthetic aperture radar (SAR) is well-adapted to tropical areas, since it is capable of imaging independent of light and weather conditions. In this study, we highlight the contribution of SAR sensors in the assessment of the relationship between vectors, malaria and the environment in the Amazon region. More specifically, we focus on the SAR-based characterization of potential breeding sites of mosquito larvae, such as man-made water collections and natural wetlands, providing guidelines for the use of SAR capabilities and techniques in order to optimize vector control and malaria surveillance. In light of these guidelines, we propose a framework for the production of spatialized indicators and malaria risk maps based on the combination of SAR, entomological and epidemiological data to support malaria risk prevention and control actions in the field. PMID- 29518989 TI - Water Bacterial and Fungal Community Compositions Associated with Urban Lakes, Xi'an, China. AB - Urban lakes play a vital role in the sustainable development of urbanized areas. In this freshwater ecosystem, massive microbial communities can drive the recycling of nutrients and regulate the water quality. However, water bacterial and fungal communities in the urban lakes are not well understood. In the present work, scanning electron microscopy (SEM) was combined with community level physiological profiles (CLPPs) and Illumina Miseq sequence techniques to determine the diversity and composition of the water bacterial and fungal community in three urban lakes, namely Xingqing lake (LX), Geming lake (LG) and Lianhu lake (LL), located in Xi'an City (Shaanxi Province, China). The results showed that these three lakes were eutrophic water bodies. The highest total nitrogen (TN) was observed in LL, with a value of 12.1 mg/L, which is 2 times higher than that of LG. The permanganate index (CODMn) concentrations were 21.6 mg/L, 35.4 mg/L and 28.8 mg/L in LG, LL and LX, respectively (p < 0.01). Based on the CLPPs test, the results demonstrated that water bacterial communities in the LL and LX urban lakes had higher carbon source utilization ability. A total of 62,742 and 55,346 high quality reads were grouped into 894 and 305 operational taxonomic units (OTUs) for bacterial and fungal communities, respectively. Water bacterial and fungal community was distributed across 14 and 6 phyla. The most common phyla were Proteobacteriaand Cyanobacteria. Cryptomycota was particularly dominant in LL, while Chytridiomycota and Entomophthormycota were the most abundant fungal phyla, accounting for 95% of the population in the LL and 56% in the LG. Heat map and redundancy analysis (RDA) highlighted the dramatic differences of water bacterial communities among three urban lakes. Meanwhile, the profiles of fungal communities were significantly correlated with the water quality parameters (e.g., CODMn and total nitrogen, TN). Several microbes (Legionella sp. and Streptococcus sp.) related to human diseases, such as infectious diseases, were also found. The results from this study provides useful information related to the water quality and microbial community compositions harbored in the aquatic ecosystems of urban lakes. PMID- 29518990 TI - Biosynthesis of Rishirilide B. AB - Rishirilide B was isolated from Streptomyces rishiriensis and Streptomyces bottropensis on the basis of its inhibitory activity towards alpha-2 macroglobulin. The biosynthesis of rishirilide B was investigated by feeding experiments with different 13C labelled precursors using the heterologous host Streptomyces albus J1074::cos4 containing a cosmid encoding of the gene cluster responsible for rishirilide B production. NMR spectroscopic analysis of labelled compounds demonstrate that the tricyclic backbone of rishirilide B is a polyketide synthesized from nine acetate units. One of the acetate units is decarboxylated to give a methyl group. The origin of the starter unit was determined to be isobutyrate. PMID- 29518991 TI - Revealed Preference Methods for Studying Bicycle Route Choice-A Systematic Review. AB - One fundamental aspect of promoting utilitarian bicycle use involves making modifications to the built environment to improve the safety, efficiency and enjoyability of cycling. Revealed preference data on bicycle route choice can assist greatly in understanding the actual behaviour of a highly heterogeneous group of users, which in turn assists the prioritisation of infrastructure or other built environment initiatives. This systematic review seeks to compare the relative strengths and weaknesses of the empirical approaches for evaluating whole journey route choices of bicyclists. Two electronic databases were systematically searched for a selection of keywords pertaining to bicycle and route choice. In total seven families of methods are identified: GPS devices, smartphone applications, crowdsourcing, participant-recalled routes, accompanied journeys, egocentric cameras and virtual reality. The study illustrates a trade off in the quality of data obtainable and the average number of participants. Future additional methods could include dockless bikeshare, multiple camera solutions using computer vision and immersive bicycle simulator environments. PMID- 29518992 TI - Dynamic regime of coherent population trapping and optimization of frequency modulation parameters in atomic clocks. AB - We theoretically investigate the dynamic regime of coherent population trapping (CPT) in the presence of frequency modulation (FM). We have formulated the criteria for quasi-stationary (adiabatic) and dynamic (non-adiabatic) responses of atomic system driven by this FM. Using the density matrix formalism for Lambda system, the error signal is exactly calculated and optimized. It is shown that the optimal FM parameters correspond to the dynamic regime of atomic-field interaction, which significantly differs from conventional description of CPT resonances in the frame of quasi-stationary approach (under small modulation frequency). Obtained theoretical results are in good qualitative agreement with different experiments. Also we have found CPT-analogue of Pound-Driver-Hall regime of frequency stabilization. PMID- 29518993 TI - Robust sub-millihertz-level offset locking for transferring optical frequency accuracy and for atomic two-photon spectroscopy. AB - Robust sub-millihertz-level offset locking was achieved with a simple scheme, by which we were able to transfer the laser frequency stability and accuracy from either cesium-stabilized diode laser or comb laser to the other diode lasers who had serious frequency jitter previously. The offset lock developed in this paper played an important role in atomic two-photon spectroscopy with which record resolution and new determination on the hyperfine constants of cesium atom were achieved. A quantum-interference experiment was performed to show the improvement of light coherence as an extended design was implemented. PMID- 29518994 TI - High performance and cost effective CO-OFDM system aided by polar code. AB - A novel polar coded coherent optical orthogonal frequency division multiplexing (CO-OFDM) system is proposed and demonstrated through experiment for the first time. The principle of a polar coded CO-OFDM signal is illustrated theoretically and the suitable polar decoding method is discussed. Results show that the polar coded CO-OFDM signal achieves a net coding gain (NCG) of more than 10 dB at bit error rate (BER) of 10-3 over 25-Gb/s 480-km transmission in comparison with conventional CO-OFDM. Also, compared to the 25-Gb/s low-density parity-check (LDPC) coded CO-OFDM 160-km system, the polar code provides a NCG of 0.88 dB @BER = 10-3. Moreover, the polar code can relieve the laser linewidth requirement massively to get a more cost-effective CO-OFDM system. PMID- 29518995 TI - Deconvolution based photoacoustic reconstruction with sparsity regularization. AB - In most photoacoustic tomography (PAT) reconstruction approaches, it is assumed that the receiving transducers have omnidirectional response and can fully surround the region of interest. These assumptions are not satisfied in practice. To deal with these limitations, we present a novel deconvolution based photoacoustic reconstruction with sparsity regularization (DPARS) technique. The DPARS algorithm is a semi-analytical reconstruction approach in which the projections of the absorber distribution derived from a deconvolution-based method are computed and used to generate a large linear system of equations. In these projections, computed over limited viewing angles, the directivity effect of the transducer is taken into account. The distribution of absorbers is computed using a sparse representation of absorber coefficients obtained from the discrete cosine transform. This sparse representation helps improve the numerical conditioning of the system of equations and reduces the computation time of the deconvolution-based approach by one order of magnitude relative to Tikhonov regularization. The algorithm has been tested in simulations, and using two dimensional and three-dimensional experimental data obtained with a conventional ultrasound transducer. The results show that DPARS, when evaluated using contrast to-noise ratio and root-mean-square errors, outperforms the conventional delay and-sum (DAS) reconstruction method. PMID- 29518996 TI - Superradiance of non-Dicke states. AB - In 1954, Dicke predicted that a system of quantum emitters confined to a subwavelength volume would produce a superradiant burst. For such a burst to occur, the emitters must be in the special Dicke state with zero dipole moment. We show that a superradiant burst may also arise for non-Dicke initial states with a nonzero dipole moment. Both for Dicke and non-Dicke initial states, superradiance arises due to a decrease in the dispersion of the quantum phase of the emitter state. For non-Dicke states, the quantum phase is related to the phase of long-period envelopes which modulate the oscillations of the dipole moments. A decrease in the dispersion of the quantum phase causes a decrease in the dispersion of envelope phases that results in constructive interference of the envelopes and the superradiant burst. PMID- 29518997 TI - Integral 3D display using multiple LCD panels and multi-image combining optical system. AB - We present a method to display an integral three-dimensional (3D) image without gaps between multiple display active areas by using multiple liquid crystal display (LCD) panels and multi-image combining optical systems (MICOS). We designed a MICOS to improve the resolution characteristics and decrease the luminance unevenness corresponding to the viewpoint. Furthermore, we developed a method for correcting the distortion of the integral 3D image by using image processing. We prototyped an integral 3D display using four 8K dual-green (8KDG) LCD panels and the improved MICOSs. The prototype display achieved to magnify the display area about 5.66 times more than when a single LCD panel was used. PMID- 29518998 TI - Proton radiation effect on InAs avalanche photodiodes. AB - : With increasing interest over the past decade in space-related remote sensing and communications using near-infrared (NIR) wavelengths, there is a need for radiation studies on NIR avalanche photodiodes (APDs), due to the high radiation environment in space. In this work, we present an experimental study of proton radiation effects on performance parameters of InAs APDs, whose sensitivity extends from visible light to ~3.5 MUm. Three irradiation energies (10.0, 31.4, and 58.8 MeV) and four fluences (109 to 1011 p/cm2) were used. At the harshest irradiation condition (10.0 MeV energy and 1011 p/cm2 fluence) the APDs' avalanche gain and leakage current showed a measurable degradation. However, the responsivity of the APDs was unaffected under all conditions tested. The data reported in this article are available from the figshare digital repository (DOI: https://dx.doi.org/10.15131/shef. DATA: 4560562). PMID- 29518999 TI - Transmitting more than 10 bit with a single photon. AB - Encoding information in the position of single photons has no known limits, given infinite resources. Using a heralded single-photon source and a spatial light modulator (SLM), we steer single photons to specific positions in a virtual grid on a large-area spatially resolving photon-counting detector (ICCD). We experimentally demonstrate selective addressing any location (symbol) in a 9072 size grid (alphabet) to achieve 10.5 bit of mutual information per detected photon between the sender and receiver. Our results can be useful for very-high dimensional quantum information processing. PMID- 29519001 TI - New approach to remote sensing of temperature and salinity in natural water samples. AB - Raman spectra for a natural water sample have been comprehensively investigated as a function of temperature and salinity, and we demonstrate that temperature and salinity can be determined from Raman spectra with RMS errors consistently below +/-0.2 degrees C and +/-0.6 PSU respectively where there is variation only in one parameter. Most significantly, we have applied multivariate methods to show that both temperature and salinity can be determined simultaneously from Raman spectra with RMS errors of +/-0.7 degrees C and +/-1.4 PSU respectively, and designed a three-channel Raman spectrometer that will be used for future studies. PMID- 29519000 TI - Generation of sub-20-fs pulses from a graphene mode-locked laser. AB - We demonstrate, what is to our knowledge, the shortest pulses directly generated to date from a solid-state laser, mode locked with a graphene saturable absorber (GSA). In the experiments, a low-threshold diode-pumped Cr3+:LiSAF laser was used near 850 nm. At a pump power of 275 mW provided by two pump diodes, the Cr3+:LiSAF laser produced nearly transform-limited, 19-fs pulses with an average output power of 8.5 mW. The repetition rate was around 107 MHz, corresponding to a pulse energy and peak power of 79 pJ and 4.2 kW, respectively. Once mode locking was initiated with the GSA, stable, uninterrupted femtosecond pulse generation could be obtained. In addition, the femtosecond output of the laser could be tuned from 836 nm to 897 nm with pulse durations in the range of 80-190 fs. We further performed detailed mode locking initiation tests across the full cavity stability range of the laser to verify that pulse generation was indeed started by the GSA and not by Kerr lens mode locking. PMID- 29519002 TI - X-ray spectrometer based on a bent diamond crystal for high repetition rate free electron laser applications. AB - A precise spectral characterization of every single pulse is required in many x ray free-electron laser (XFEL) experiments due to the fluctuating spectral content of self-amplified spontaneous emission (SASE) beams. Bent single-crystal spectrometers can provide sufficient spectral resolution to resolve the SASE spikes while also covering the full SASE bandwidth. To better withstand the high heat load induced by the 4.5 MHz repetition rate of pulses at the forthcoming European XFEL facility, a spectrometer based on single-crystal diamond has been developed. We report a direct comparison of the diamond spectrometer with its Si counterpart in experiments performed at the Linac Coherent Light Source. PMID- 29519003 TI - Coupling erbium dopants in yttrium orthosilicate to silicon photonic resonators and waveguides. AB - A scalable platform for on-chip optical quantum networks will rely on standard top-down nanofabrication techniques and solid-state emitters with long coherence times. We present a new hybrid platform that integrates amorphous silicon photonic waveguides and microresonators fabricated on top of a yttrium orthosilicate substrate doped with erbium ions. The quality factor of one such resonator was measured to exceed 100,000 and the ensemble cooperativity was measured to be 0.54. The resonator-coupled ions exhibited spontaneous emission rate enhancement and increased coupling to the input field, as required for further development of on-chip quantum light-matter interfaces. PMID- 29519004 TI - Lateral resolution enhancement of confocal microscopy based on structured detection method with spatial light modulator. AB - Lateral resolution in confocal microscope is limited by the size of pinhole. In this paper, we attempt to introduce a new method to achieve structured detection through using spatial light modulator (SLM) to improve it. SLM modulates the Airy disk amplitude distribution according to the detection function in collection arm. Instead of using CCD to capture spot images and modulate them with numerical analysis in virtual structured detection (VSD), this method uses SLM to accomplish these aims with higher imaging rates. Based on simulation and the experiment results, it can be found that coherent transfer function expands and the resolution is 1.6 times as large as that of conventional confocal microscope. PMID- 29519005 TI - Ultra-wide bandwidth photonic microwave phase shifter with amplitude control function. AB - This paper presents a new technique for realizing continuous 0 degrees -360 degrees RF signal phase shift over a very wide bandwidth. It is based on using single-sideband modulation together with optical filtering to largely suppress one of the RF modulation sidebands over a wide input RF frequency range, and controlling the phase of the optical carrier to shift an RF signal phase. The technique does not require expensive electrical or optical components to realize an RF signal phase shift over 2-40 GHz frequency range with a flat amplitude and phase response performance. This overcomes the current technology limitation in which no reported phase shifter structure has demonstrated the capability of operating in such a wide bandwidth. Experimental results demonstrate only +/- 1 dB amplitude variation and +/- 5 degrees phase deviation from the desired RF signal phase shift over 2-40 GHz bandwidth and the RF signal amplitude control function. The phase shifter wavelength insensitive performance is also demonstrated experimentally. PMID- 29519006 TI - Dynamic evolution of circular edge dislocations in free space and atmospheric turbulence. AB - Based on the extended Huygens-Fresnel principle, the analytical expressions for the cross-spectral density function of circular edge dislocation beams propagating through atmospheric turbulence and free space have been derived, and used to study the dynamic evolution of circular edge dislocations. It is shown that the number of circular edge dislocations on propagation equals that at the source plane when propagating through free space. The radius of circular edge dislocations increases with increasing propagation distance z. n-circular edge dislocations vanish and transform to n pairs of optical vortices with the opposite topological charge when propagating through atmospheric turbulence, and the position of each pair of optical vortices are symmetric about the slanted axis y = x. All the optical vortices will annihilate as soon as the propagation distance becomes large enough. The smaller radius of circular edge dislocation corresponds with the sooner annihilation of optical vortices. The structure constant affects the annihilation distance of the pairs of optical vortices, and the annihilation distance of the pairs of optical vortices will increase with the decrement of the structure constant. PMID- 29519007 TI - Interplay of mutual electric and magnetic couplings between three-dimensional split-ring resonators. AB - We experimentally and theoretically study the interplay between capacitive electric and inductive magnetic couplings in infrared metamaterials consisting of densely-packed three-dimensional (3D) meta-atoms. The meta-atom is made of metal stress-driven assembled 3D split-ring resonators to exhibit strong bi-anisotropy, where electric and magnetic resonances occur simultaneously. By varying the spatial arrangement of the arrayed meta-atoms, the mutual coupling between meta atoms dramatically modifies their mode profiles and resultant spectral responses. The corresponding numerical simulations evidently retrieved current densities and magnetic field strengths, as well as the transmittance, to reveal the important resonant behavior in the coupled meta-atom systems. We conclude that the mutual electric coupling between the neighboring meta-atoms plays a crucial role to the scattering behaviors of the bi-anisotropic metamaterials. PMID- 29519008 TI - Transmission of 2.86 Tb/s data stream in silicon subwavelength grating waveguides. AB - In this paper, we perform an investigation of terabit-scale data transmission in silicon subwavelength grating (SWG) waveguides for wavelength-division multiplexing (WDM) optical signals. Silicon SWG waveguide is capable of decreasing the light confinement in silicon core by engineering the geometry, leading to relatively lower optical nonlinearity compared to silicon wire waveguide. We demonstrate ultrahigh-bandwidth 2.86 Tb/s data transmission through the fabricated 2-mm-long silicon SWG waveguide over a wide range of launch powers. In the experiment, 75 WDM channels are utilized with each carrying 38.12 Gb/s orthogonal frequency-division multiplexing (OFDM) 16-ary quadrature amplitude modulation (16-QAM) signal. With the benefit of efficient reduction on optical nonlinearity, the optimum launch power is increased by 8 dB in SWG waveguide, indicating higher tolerance to the nonlinear impairments, compared to a silicon wire waveguide with identical length. With the optimum launch power, all 75 channels exhibit bit-error rate (BER) values less than 4e-5 after SWG waveguide transmission. We also evaluate the terabit-scale data transmission performance through four silicon SWG waveguides with different lengths (1 mm, 2 mm, 4 mm and 12 mm). The required optical signal-to-noise ratios (OSNRs) to achieve BER level of 1e-3 are around 15.27, 15.47, 16.66 and 20.38 dB, respectively. PMID- 29519009 TI - Intrinsic phasing of heterodyne-detected multidimensional infrared spectra. AB - We show that it is possible to phase multidimensional infrared spectra generated by a boxcars geometry four-wave mixing spectrometer directly from the signal generated by the molecular vibration of interest, without the need for auxiliary phasing measurements. For isolated vibrations, the phase profile of the 2D response smoothly varies between fixed phase limits, allowing for a general target for phasing independent of the degree of anharmonicity exhibited between the ground and excited state. As a proof of principle, the 2D response of the ~2155 cm-1 thiocyanate stretch vibration of MeSCN, a system exhibiting anharmonicity such that the 0-1 and 1-2 transitions are spectrally isolated, is successfuly phased directly from the experimental spectra. The methodology is also applied to correctly phase extremely weak signals of the unnatural amino acid azidohomoalanine following background subtraction. PMID- 29519010 TI - Passive photonic integrated ratiometric wavelength monitor with resolution better than 15 pm. AB - This paper presents a compact and low-loss photonic integrated device consisting of a Y-branch and a pair of multimode interferometers (MMI) for a ratiometric wavelength monitoring around 1550 nm on silicon-on-insulator (SOI) technique. Two MMIs are designed in terms of width and length to achieve overlapping but opposite slope spectral responses used as two edge filters over a wavelength measurement range from 1500 nm to 1600 nm. The developed integrated photonic ratiometric structure demonstrates a suitable discrimination range for a high speed passive wavelength measurement, with a high resolution better than 15 pm over a 100 nm wavelength range. PMID- 29519011 TI - Tungsten disulfide saturable absorbers for 67 fs mode-locked erbium-doped fiber lasers. AB - In this paper, we demonstrate 67 fs pulse emitting with tungsten disulfide (WS2) in mode-locked erbium-doped fiber (EDF) lasers. Using the pulsed laser deposition method, WS2 is deposited on the surface of the tapered fiber to form the evanescent field. The fiber-taper WS2 saturable absorber (SA) with the large modulation depth is fabricated to support the ultrashort pulse generation. The influences of the WS2 SA are analyzed through contrastive experiments on fiber lasers with or without the WS2 SA. The pulse duration is measured to be 67 fs, which is the shortest pulse duration obtained in the mode-locked fiber lasers with two dimensional (2D) material SAs. Compared to graphene, topological insulator, and other transition metal dichalcogenides (TMDs) SAs, results in this paper indicate that the fiber-taper WS2 SA with large modulation depth is a more promising photonic device in mode-locked fiber lasers with the wide spectrum and ultrashort pulse duration. PMID- 29519012 TI - High-harmonic terahertz Smith-Purcell free-electron-laser with two tandem cylindrical-gratings. AB - A modified Smith-Purcell free-electron-laser based on two tandem cylindrical gratings is proposed. The preset grating with larger size, operating in the slow wave condition, is to prebunch the initial continuous electron-beam, and the postpositive grating with smaller size, operating in the fast-wave condition, is used as the main radiator. Compared with traditional Smith-Purcell free-electron lasers operating at the second harmonic of the bunched-beam, the present scheme operates at much higher harmonics, fifth and sixth harmonics have been achieved, and the radiation frequency is greatly increased consequently. And also the radiation power is enhanced by tens of times. Thus it could be developed as an efficient terahertz source with frequency being over 0.5 THz in practice. PMID- 29519013 TI - Hyperentanglement purification using imperfect spatial entanglement. AB - As the interaction between the photons and the environment which will make the entangled photon pairs in less entangled states or even in mixed states, the security and the efficiency of quantum communication will decrease. We present an efficient hyperentanglement purification protocol that distills nonlocal high fidelity hyper-entangled Bell states in both polarization and spatial-mode degrees of freedom from ensembles of two-photon system in mixed states using linear optics. Here, we consider the influence of the photon loss in the channel which generally is ignored in the conventional entanglement purification and hyperentanglement purification (HEP) schemes. Compared with previous HEP schemes, our HEP scheme decreases the requirement for nonlocal resources by employing high dimensional mode-check measurement, and leads to a higher fidelity, especially in the range where the conventional HEP schemes become invalid but our scheme still can work. PMID- 29519014 TI - High-pressure cell for terahertz time-domain spectroscopy. AB - We introduce a sample cell that can be used for pressure-dependent terahertz time domain spectroscopy. Compared with traditional far-IR spectroscopy with a diamond anvil cell, the larger aperture permits measurements down to much lower frequencies as low as 3.3 cm-1 (0.1 THz), giving access to new spectroscopic results. The pressure tuning range reaches up to 34.4 MPa, while the temperature range is from 100 to 473 K. With this large range of tuning parameters, we are able to map out phase diagrams of materials based on their THz spectrum, as well as to track the changing of the THz spectrum within a single phase as a function of temperature and pressure. Pressure-dependent THz-TDS results for nitrogen and R-camphor are shown as an example. PMID- 29519015 TI - Editorial: 20 years of Optics Express. AB - Editor-in-Chief Andrew M. Weiner celebrates the 20th Anniversary of Optics Express, reflects on the history of the journal and the people who helped to make it a success, and describes special content that will be posted online throughout the year. PMID- 29519016 TI - Fiber nonlinearity mitigation of WDM-PDM QPSK/16-QAM signals using fiber-optic parametric amplifiers based multiple optical phase conjugations. AB - We demonstrate fiber nonlinearity mitigation by using multiple optical phase conjugations (OPCs) in the WDM transmission systems of both 8 * 32-Gbaud PDM QPSK channels and 8 * 32-Gbaud PDM 16-QAM channels, showing improved performance over a single mid-span OPC and no OPC in terms of nonlinear threshold and a best achievable Q2 factor after transmission. In addition, after an even number of OPCs, the signal wavelength can be preserved after transmission. The performance of multiple OPCs for fiber nonlinearity mitigation was evaluated independently for WDM PDM QPSK signals and WDM PDM 16-QAM signals. The technique of multiple OPCs is proved to be transparent to modulation formats and effective for different transmission links. In the WDM PDM QPSK transmission system over 3600 km, by using multiple OPCs the nonlinear threshold (i.e. optimal signal launched power) was increased by ~5 dB compared to the case of no OPC and increased by ~2 dB compared to the case of mid-span OPC. In the WDM PDM 16-QAM transmission system over 912 km, by using the multiple OPCs the nonlinear threshold was increased by ~7 dB compared to the case of no OPC and increased by ~1 dB compared to the case of mid-span OPC. The improvements in the best achievable Q2 factors were more modest, ranging from 0.2 dB to 1.1 dB for the results presented. PMID- 29519017 TI - Performance comparison between the InAs-based and GaSb-based type-II superlattice photodiodes for long wavelength infrared detection. AB - In this paper, we report on the characterization of InAs/GaAsSb type-II superlattice long wavelength infrared photodiodes grown on InAs substrates by molecular-beam epitaxy and also present the device performance comparison with the superlattice devices grown on GaSb substrates. These devices with PIN structures had a 100% cutoff wavelength of 10 MUm. The dark current density of InAs-based device at -30 mV reverse bias was 4.01 * 10-4 A/cm2 and the resistance-area product at zero bias (R0A) was 36.9 Omegacm2. The dark current density of GaSb-based device is higher more than one order of magnitude than that of InAs-based device. The temperature-dependence and bias-dependence of the dark current are studied experimentally and correlated to the theory. Good agreement was achieved between the measured I-V curves and the simulated ones, and between the experimental and theoretically predicted differential resistance values. Compared with InAs-based superlattice device, the generation-recombination current of GaSb-based device is larger and dominates in a wider temperature range due to shorter carrier lifetime and higher defect density. PMID- 29519018 TI - Dual-line fabrication method in direct laser lithography to reduce the manufacturing time of diffractive optics elements. AB - To reduce the manufacturing time of DOEs (Diffractive Optics Elements) and POEs (Periodical Optics Elements), a new fabrication method in direct laser lithography is proposed based on the laser ablation phenomenon and the thermochemical effect of chrome. The basic mechanism of the proposed method and experimental results are also presented. It was found that when a 3 * 3 rectangular pattern is fabricated, the proposed method can reduce the total lithographic length by approximately 33%. The manufacturing time is reduced by nearly 52%. When fabricating a 1,000 * 1,000 rectangular pattern, the manufacturing time was reduced by more than 90%. The time reduction rate is drastically improved when the number of patterns is increased. Various patterns including rectangular, triangular, parallelogram, and diamond shape were fabricated by using the proposed method. PMID- 29519019 TI - Spatial characterization of Bessel-like beams for strong-field physics. AB - We present a compact, simple design for the generation and tuning of both the spot size and effective focal length of Bessel-like beams. In particular, this setup provides an important tool for the use of Bessel-like beams with high power, femtosecond laser systems. Using a shallow angle axicon in conjunction with a spherical lens, we show that it is possible to focus Bessel-like modes to comparable focal spot sizes to sharp axicons while maintaining a long effective focal length. The resulting focal profiles are characterized in detail using an accurate high dynamic range imaging technique. Quantitatively, we introduce a metric (R0.8) which defines the spot-size containing 80% of the total energy. Our setup overcomes the typical compromise between long working distances and small spot sizes. This is particularly relevant for strong-field physics where most experiments must operate in vacuum. PMID- 29519020 TI - Single multimode fiber endoscope. AB - Multimode fibers can guide thousands of modes capable of delivering spatial information. Unfortunately, mode dispersion and coupling have so far prevented their use in endoscopic applications. To address this long-lasting challenge, we present a robust scanning fluorescence endoscope. A spatial light modulator shapes the input excitation wavefront to focus light on the distal tip of the fiber and to rapidly scan the focus over the region of interest. A detector array collects the fluorescence emission propagated back from the sample to the proximal tip of the fiber. We demonstrate that proper selection of the multimode fiber is critical for a robust calibration and for high signal-to-background ratio performance. We compare different types of multimode fibers and experimentally show that a focus created through a graded-index fiber can withstand a few millimeters of fiber distal tip translation. The resulting scanning endoscopic microscope images fluorescent samples over a field of view of 80um with a resolution of 2um. PMID- 29519021 TI - Metal clad waveguide (MCWG) based imaging using a high numerical aperture microscope objective. AB - Evanescent-field based methods such as surface plasmon resonance (SPR) have been used very effectively for label-free imaging of microscopic biological material in close proximity to a sensing surface. However, the shallow probing depth of SPR (typically less than ~200 nm) can be problematic when imaging relatively thick biological objects such as cells or bacteria. In this paper, we demonstrate how metal-clad waveguides (MCWG) can be used to achieve deeper probing depth compared to SPR while maintaining good imaging spatial resolution. Comparative numerical simulations of imaging spatial resolution versus probing depth are shown for a number of common SPR, long-range SPR, and MCWG configurations, demonstrating that MCWG offer the best compromise between resolution and depth for imaging thick biological objects. Experimental results of synthetic target and live cell imaging are shown that validate the numerical simulations and demonstrate the capabilities of the method. PMID- 29519022 TI - High resolution Shack-Hartmann sensor based on array of nanostructured GRIN lenses. AB - We present a novel method for the development of a micro lenslets hexagonal array. We use gradient index (GRIN) micro lenses where the variation of the refraction index is achieved with a structure of nanorods made of 2 types of glasses. To develop the GRIN micro lens array, we used a modified stack-and-draw technology which was originally applied for the fabrication of photonic crystal fibers. This approach results in a completely flat element that is easy to integrate with other optical components and can be effectively used in high refractive index medium as liquids. As a proof-of-concept of the method we present a hexagonal array of 469 GRIN micro lenses with a diameter of 20 um each and 100% fill factor. The GRIN lens array is further used to build a Shack Hartmann detector for measuring wavefront distortion. A 50 lens/mm sampling density is achieved. PMID- 29519023 TI - Compact integrated actively Q-switched waveguide laser. AB - A miniaturized deformed helix ferroelectric liquid crystal transducer cell was used in combination with a femtosecond laser inscribed active waveguide to realize a compact actively Q-switched laser source. The liquid crystal cell was controlled by a low-voltage frequency generator and laser pulse durations below 40 ns were demonstrated at repetition rates ranging from 0.1 kHz to 20 kHz and a maximum slope efficiency of up to 22%. This novel, integrated and low-cost laser source is a promising tool for a broad range of applications such as trace gas sensing, LIDAR, and nonlinear optics. To the best of our knowledge, this is the first demonstration of an actively Q-switched glass waveguide laser that has a user-variable repetition rate and can be fully integrated. PMID- 29519024 TI - Interface modification based ultrashort laser microwelding between SiC and fused silica. AB - It is a big challenge to weld two materials with large differences in coefficients of thermal expansion and melting points. Here we report that the welding between fused silica (softening point, 1720 degrees C) and SiC wafer (melting point, 3100 degrees C) is achieved with a near infrared femtosecond laser at 800 nm. Elements are observed to have a spatial distribution gradient within the cross section of welding line, revealing that mixing and inter diffusion of substances have occurred during laser irradiation. This is attributed to the femtosecond laser induced local phase transition and volume expansion. Through optimizing the welding parameters, pulse energy and interval of the welding lines, a shear joining strength as high as 15.1 MPa is achieved. In addition, the influence mechanism of the laser ablation on welding quality of the sample without pre-optical contact is carefully studied by measuring the laser induced interface modification. PMID- 29519025 TI - Modelling end-pumped passively Q-switched Nd-doped crystal lasers: manifestation by a Nd:YVO4/Cr4+:YAG system with a concave-convex resonator. AB - A theoretical model for the passively Q-switched (PQS) operation which includes the spatial overlapping between the pump and lasing modes under the thermal lensing effect is developed to give a transcendental equation that can directly determine the critical parameters such as pulse energy, pulse repetition rate, and pulse width for the PQS performance. More importantly, an analytical function which gives the approximate solution for the transcendental equation as well as a specific critical criterion for good PQS operation are derived for practical analyses and design. A Nd:YVO4/Cr4+:YAG system with a concave-convex resonator which can achieve fairly stable PQS pulse trains even at a high pump level is further exploited to manifest the proposed spatially dependent model. The good agreement between the experimental results and the theoretical predictions is verified to show the feasibility of the proposed model for designing high-power PQS lasers with high accuracy. PMID- 29519026 TI - Investigate the effects of EG doping PEDOT/PSS on transmission and anti reflection properties using terahertz pulsed spectroscopy. AB - The conductivity of poly(3,4-ethylene dioxythiophene)/poly(4-styrenesulfonate) (PEDOT/PSS) is significantly enhanced on adding some organic solvent such as ethylene glycol (EG). In this paper, the optoelectronic properties of EG doped PEDOT/PSS on transmission and anti-reflection effects are investigated in detail by terahertz time domain spectroscopy (THz-TDS). The transmission line circuit theory gives us an insight into the THz transmission mechanisms of the main and second pulses. In particular, we show that the conductivities of 10% EG doped PEDOT/PSS are nearly frequency independent from 0.3 to 1.5 THz. To demonstrate applications of this property, we design and fabricate broadband terahertz neutral density filters and anti-reflection coatings based on 10% EG doped PEDOT/PSS thin films with varying thickness. Our measurements highlight the capability of THz-TDS to characterize the conductivity of EG doped PEDOT/PSS, which is essential for broadband optoelectronic devices in THz region. PMID- 29519027 TI - Microfabricated devices for single objective single plane illumination microscopy (SoSPIM). AB - Light sheet microscopy is a relatively new form of fluorescence microscopy that has been receiving a lot of attention recently. The strong points of the technique, such as high signal to noise ratio and its reduced photodamage of fluorescently labelled samples, come from its unique feature to illuminate only a thin plane in the sample that coincides with the focal plane of the detection lens. Typically this requires two closely positioned perpendicular objective lenses, one for detection and one for illumination. Apart from the fact that this special configuration of objective lenses is incompatible with standard microscope bodies, it is particularly problematic for high-resolution lenses which typically have a short working distance. To address these issues we developed sample holders with an integrated micromirror to perform single lens light sheet microscopy, also known as single objective single plane illumination microscopy (SoSPIM). The first design is based on a wet-etched silicon substrate, the second on a microfabricated polished polymer plug. We achieved an on-chip light sheet thickness of 2.3 MUm (FWHM) at 638 nm with the polymer micromirror and of 1.7 MUm (FWHM) at 638 nm with the silicon micromirror, comparable to reported light sheet thicknesses obtained on dedicated light sheet microscopes. A marked contrast improvement was obtained with both sample holders as compared to classic epi-fluorescence microscopy. In order to evaluate whether this technology could be made available on a larger scale, in a next step we evaluated the optical quality of inexpensive replicas from both types of master molds. We found that replicas from the polished polymer based mold have an optical quality close to that of the master component, while replicas from the silicon based mold were of slightly lower but still acceptable quality. The suitability of the replicated polymer based sample holder for single-lens light sheet microscopy was finally demonstrated by imaging breast cancer spheroids. PMID- 29519028 TI - In situ calibration of position detection in an optical trap for active microrheology in viscous materials. AB - In optical trapping, accurate determination of forces requires calibration of the position sensitivity relating displacements to the detector readout via the V-nm conversion factor (beta). Inaccuracies in measured trap stiffness (k) and dependent calculations of forces and material properties occur if beta is assumed to be constant in optically heterogeneous materials such as tissue, necessitating calibration at each probe. For solid-like samples in which probes are securely positioned, calibration can be achieved by moving the sample with a nanopositioning stage and stepping the probe through the detection beam. However, this method may be applied to samples only under select circumstances. Here, we introduce a simple method to find beta in any material by steering the detection laser beam while the probe is trapped. We demonstrate the approach in the yolk of living Danio rerio (zebrafish) embryos and measure the viscoelastic properties over an order of magnitude of stress-strain amplitude. PMID- 29519029 TI - Plasmonic modulator with >170 GHz bandwidth demonstrated at 100 GBd NRZ. AB - We demonstrate a plasmonic Mach-Zehnder (MZ) modulator with a flat frequency response exceeding 170 GHz. The modulator comprises two phase modulators exploiting the Pockels effect of an organic electro-optic material in plasmonic slot waveguides. We further show modulation at 100 GBd NRZ and 60 GBd PAM-4. The electrical drive signals were generated using a 100 GSa/s digital to analog converter (DAC). The high-speed and small-scale devices are relevant for next generation optical interconnects. PMID- 29519030 TI - Photonic crystal nanocavity with a Q factor exceeding eleven million. AB - Photonic crystal nanocavities that simultaneously possess small modal volumes and high quality (Q) factors have opened up novel research areas in photonics during this decade. Here, we present an important key for the increase of Q factors to ranges beyond ten million. A systematic investigation on photon lifetimes of air bridge-type heterostructure nanocavities fabricated from silicon on insulator (SOI) substrates indicated the importance of cleaning the bottom side (buried oxide side) of the nanaocavites. Repeated thermal oxidation and an oxide removal process applied after the removal of the buried oxide layer underneath the nanocavities realized an experimental Q factor greater than eleven million, which is the highest experimental Q ever recorded. The results provide important information not only for Si PC nanocavities but also for general Si nanophotonic devices and photonic electronic convergence systems. PMID- 29519032 TI - Distributed photothermal spectroscopy in microstructured optical fibers: towards high-resolution mapping of gas presence over long distances. AB - Chemical sensing using optical fibers is often challenging, as it is generally difficult to achieve strong interaction between the guided light and the analyte at the wavelength of interest for performing the detection. Despite this difficulty, many schemes exist (and can be found in the literature) for point chemical fiber sensors. However, the challenge increases even further when it comes to performing fully distributed chemical sensing. In this case, the optical signal which interacts with the analyte is typically also the signal that has to travel to and from the interrogator: for a good sensitivity, the light should interact strongly with the analyte, leading inevitably to an increased loss and a reduced range. Few works in the literature actually provide demonstrations of truly distributed chemical sensing and, although there have been several attempts to realize these sensors (e.g. based on special fiber coatings), the vast majority of these attempts has failed to reach widespread use due to several reasons, among them: lack of sensitivity or selectivity, lack of range or resolution, cross sensitivity to temperature or strain, or need to work at specific wavelengths where fiber instrumentation becomes extremely expensive or unavailable. In this work we provide a preliminary demonstration of the possibility of achieving distributed detection of gas presence with spectroscopic selectivity, high spatial resolution, potential for long range measurements and feasibility of having most of the interrogator system working at conventional telecom wavelengths. For a full exploitation of this concept, new fibers (or more likely, fiber bundles) should be developed capable of guiding specific wavelengths in the IR (corresponding to gas absorption wavelengths) with good overlap with the analyte while also having a solid core with good transmission behavior at 1.55 MUm, and good thermal coupling between the two guiding structures. PMID- 29519031 TI - Measurement of the inhomogeneous broadening of a bi-exciton state in a quantum dot using Franson-type nonlocal interference. AB - The inhomogeneous broadening of the bi-exciton state in quantum dots, i.e., the inhomogeneous broadening of the upper level of the cascade process, is not only a fundamental problem in quantum dots, but also closely related with the coherent control of this complex system and the quality of the entangled photon pairs, especially the time-bin entangled photon pairs. This inhomogeneous broadening is inherently a two-photon correlated phenomenon. In this work, we construct a genuine Franson-type nonlocal interference process to measure the inhomogeneous broadening of the bi-exciton state. The results show that the inhomogeneous broadening of the bi-exciton state is considerably smaller than that of the exciton state, that is why the entangled photon pairs can be generated by the cascade process in the quantum dot. PMID- 29519033 TI - Photo-acoustic sensor for detection of oil contamination in compressed air systems. AB - We demonstrate an online (in-situ) sensor for continuous detection of oil contamination in compressed air systems complying with the ISO-8573 standard. The sensor is based on the photo-acoustic (PA) effect. The online and real-time PA sensor system has the potential to benefit a wide range of users that require high purity compressed air. Among these are hospitals, pharmaceutical industries, electronics manufacturers, and clean room facilities. The sensor was tested for sensitivity, repeatability, robustness to molecular cross-interference, and stability of calibration. Explicit measurements of hexane (C6H14) and decane (C10H22) vapors via excitation of molecular C-H vibrations at approx. 2950 cm-1 (3.38 MUm) were conducted with a custom made interband cascade laser (ICL). For the decane measurements a (1 sigma) standard deviation (STD) of 0.3 ppb was demonstrated, which corresponds to a normalized noise equivalent absorption (NNEA) coefficient for the prototype PA sensor of 2.8*10-9 W cm 1 Hz1/2. PMID- 29519034 TI - Stable passively harmonic mode-locking dissipative pulses in 2um solid-state laser. AB - We report on stable passively harmonic mode-locking dissipative pulses with high repetition rate and narrow bandwidth in 2um Tm: CaYAlO4 laser. At the large intracavity intensity, the laser generated 1st-order to 5th-order passively harmonic solitons with fundamental repetition rate of ~198 MHz and 5th-order repetition rate up to 0.98 GHz, which was mainly caused by the peak power clamp effect. The solitons yielded a tunable central wavelength from 1940nm to 1950 nm, and a narrow optical spectrum bandwidth of 60 pm without any active optical filter. At low intracavity intensity, the laser operated on the typical SESAM guided mode-locking mode, with the scaled output average power up to 1.15 W. To our knowledge, this is the first observation of passively harmonic mode locking in 2um solid laser system, and the first Watt-level output average power in Tm: CYA mode locking laser. PMID- 29519035 TI - Impact of spectral features of common LED lighting systems on TM-30 color indices. AB - We examine the difference between the newly developed IES TM-30 color indices and some of the most common previously established color indices for LED systems which are used for lighting purposes, focusing on the influence of realistic spectral variations among different system designs and manufacturing runs. We find a significantly stronger influence of the employed blue InGaN wavelength on TM-30 Rf and Rg than on CRI Ra and FCI. In addition, for the established combination of green converted InGaN chips with red InGaAlP chips, we observe large differences in the effect of the wavelength of the red emission of InGaAlP chips on Rf and Ra. PMID- 29519036 TI - Multislice does it all-calculating the performance of nanofocusing X-ray optics. AB - We describe an approach to calculating the optical performance of a wide range of nanofocusing X-ray optics using multislice scalar wave propagation with a complex X-ray refractive index. This approach produces results indistinguishable from methods such as coupled wave theory, and it allows one to reproduce other X-ray optical phenomena such as grazing incidence reflectivity where the direction of energy flow is changed significantly. Just as finite element analysis methods allow engineers to compute the thermal and mechanical responses of arbitrary structures too complex to model by analytical approaches, multislice propagation can be used to understand the properties of the real-world optics of finite extent and with local imperfections, allowing one to better understand the limits to nanoscale X-ray imaging. PMID- 29519037 TI - Mode stabilization in quantum cascade lasers via an intra-cavity cascaded nonlinearity. AB - We present self-stabilization of the inter-mode separation of a quantum cascade laser (QCL) emitting at 9 MUm via cascaded second order nonlinearity. This effect has been observed in lasers that have the optical cavity embedded into a microwave strip-line. The intermodal beat note spectra narrow with increasing laser output power, up to less than 100 kHz. A flat frequency response to direct modulation up to 14 GHz is reported for these microstrip QCLs. The laser inter mode spacing can be locked to an external RF signal and tuned by more than 1 MHz from the free-running spacing. A parallel study on the same laser material in a non-microstrip line waveguide shows superior performances of the microstrip QCL in terms of the intermodal spectral locking and stability. Finally by analyzing our results with the theory of the injection locking of coupled oscillators, we deduce that the microwave power injected in the microstrip QCL is 2 orders of magnitude higher than in the reference laser. PMID- 29519038 TI - Decelerating Airy pulse propagation in highly non-instantaneous cubic media. AB - The propagation of decelerating Airy pulses in non-instantaneous cubic medium is investigated both theoretically and numerically. In a Debye model, at variance with the case of accelerating Airy and Gaussian pulses, a decelerating Airy pulse evolves into a single soliton for weak and general non-instantaneous response. Airy pulses can hence be used to control soliton generation by temporal shaping. The effect is critically dependent on the response time, and could be used as a way to measure the Debye type response function. For highly non-instantaneous response, we theoretically find a decelerating Airy pulse is still transformed into Airy wave packet with deceleration. The theoretical predictions are confirmed by numerical simulations. PMID- 29519039 TI - Collective dynamics and entanglement of two distant atoms embedded into single negative index material. AB - We study the dynamics of two two-level atoms embedded near to the interface of paired meta-material slabs, one of negative permeability and the other of negative permittivity. This combination generates a strong surface plasmon field at the interface between the meta-materials. It is found that the symmetric and antisymmetric modes of the two-atom system couple to the plasmonic field with different Rabi frequencies. Including the Ohmic losses of the materials we find that the Rabi frequencies exhibit threshold behaviour which distinguish between the non-Markovian (memory preserving) and Markovian (memoryless) regimes of the evolution. Moreover, it is found that significantly different dynamics occur for the resonant and an off-resonant couplings of the plasmon field to the atoms. In the case of the resonant coupling, the field does not appear as a dissipative reservoir to the atoms. We adopt the image method and show that the dynamics of the two atoms coupled to the plasmon field are analogous to the dynamics of a four-atom system in a rectangular configuration. A large and long living entanglement mediated by the plasmonic field in both Markovian and non-Markovian regimes of the evolution is predicted. We also show that a simultaneous Markovian and non-Markovian regime of the evolution may occur in which the memory effects exist over a finite evolution time. In the case of an off-resonant coupling of the atoms to the plasmon field, the atoms interact with each other by exchanging virtual photons which results in the dynamics corresponding to those of two atoms coupled to a common reservoir. In addition, the entanglement is significantly enhanced. PMID- 29519040 TI - Slope-assisted BOTDA based on vector SBS and frequency-agile technique for wide strain-range dynamic measurements. AB - We present a slope-assisted BOTDA system based on the vector stimulated Brillouin scattering (SBS) and frequency-agile technique (FAT) for the wide-strain-range dynamic measurement. A dimensionless coefficient K defined as the ratio of Brillouin phase-shift to gain is employed to demodulate the strain of the fiber, and it is immune to the power fluctuation of pump pulse and has a linear relation of the frequency detuning for the continuous pump and Stokes waves. For a 30ns square pump pulse, the available frequency span of the K spectrum can reach up to 200MHz, which is larger than fourfold of 48MHz-linewidth of Brillouin gain spectrum. For a single-slope assisted BOTDA, dynamic strain measurement with the maximum strain of 2467.4MUepsilon and the vibration frequency components of 10.44Hz and 20.94Hz is obtained. For a multi-slope-assisted BOTDA, dynamic measurement with the strain variation up to 5372.9MUepsilon and the vibration frequency components of 5.58Hz and 11.14Hz is achieved by using FAT to extend the strain range. PMID- 29519042 TI - Digital signal processing for fiber nonlinearities [Invited]. AB - This paper reviews digital signal processing techniques that compensate, mitigate, and exploit fiber nonlinearities in coherent optical fiber transmission systems. PMID- 29519041 TI - Digital backpropagation accounting for polarization-mode dispersion. AB - Digital backpropagation (DBP) is a promising digital-domain technique to mitigate Kerr-induced nonlinear interference. While it successfully removes deterministic signal-signal interactions, the performance of ideal DBP is limited by stochastic effects, such as polarization-mode dispersion (PMD). In this paper, we consider an ideal full-field DBP implementation and modify it to additionally account for PMD; reversing the PMD effects in the backward propagation by passing the reverse propagated signal also through PMD sections, which concatenated equal the inverse of the PMD in the forward propagation. These PMD sections are calculated analytically at the receiver based on the total accumulated PMD of the link estimated from channel equalizers. Numerical simulations show that, accounting for nonlinear polarization-related interactions in the modified DBP algorithm, additional signal-to-noise ratio gains of 1.1 dB are obtained for transmission over 1000 km. PMID- 29519043 TI - Dispersion synthesis with multi-ordered metatronic filters. AB - We propose the synthesis of frequency dispersion of layered structures based on the design of multi-ordered optical filters using nanocircuit concepts. Following the well-known insertion loss method commonly employed in the design of electronic and microwave filters, here we theoretically show how we can tailor optical dispersion as we carry out the design of several low-pass, high-pass, band-pass and band-stop filters of different order with a (maximally flat) Butterworth response. We numerically demonstrate that these filters can be designed by combining metasurfaces made of one or two materials acting as optical lumped elements, and, hence, leading to simple, easy to apply, design rules. The theoretical results based on this circuital approach are validated with full-wave numerical simulations. The results presented here can be extended to virtually any frequency dispersion synthesis, filter design procedure and/or functionality, thus opening up exciting possibilities in the design of composite materials with on-demand dispersion and high-performance and compact optical filters using one or two materials. PMID- 29519044 TI - Probing effect of electric field on photocarrier transfer in graphene WS2 van der Waals heterostructures. AB - We report spatially and temporally resolved measurements of photocarrier transfer process in van der Waals heterostructures. Graphene-WS2 hetero bilayers were fabricated by manually stacking monolayers of graphene and WS2 obtained by mechanical exfoliation. Photocarriers were excited in WS2 by an ultrafast laser pulse. Their transfer to graphene was monitored by measuring the differential reflection signal as a function of both time and space. Surprisingly, we found that the width of the photocarrier profile in graphene decreases with time. This counter-intuitive phenomenon suggests that the Coulomb field of the holes transferred from WS2 to graphene can effectively drag the electrons to speed up their transfer. This effect illustrates that an externally applied electric field can be used to control the ambipolar photocarrier transfer in van der Waals heterostructures. PMID- 29519045 TI - Using X-ray spectroscopy of relativistic laser plasma interaction to reveal parametric decay instabilities: a modeling tool for astrophysics. AB - By analyzing profiles of experimental x-ray spectral lines of Si XIV and Al XIII, we found that both Langmuir and ion acoustic waves developed in plasmas produced via irradiation of thin Si foils by relativistic laser pulses (intensities ~1021 W/cm2). We prove that these waves are due to the parametric decay instability (PDI). This is the first time that the PDI-induced ion acoustic turbulence was discovered by the x-ray spectroscopy in laser produced plasmas. These conclusions are also supported by PIC simulations. Our results can be used for laboratory modeling of physical processes in astrophysical objects and a better understanding of intense laser-plasma interactions. PMID- 29519046 TI - Pixel-by-pixel local dimming for high-dynamic-range liquid crystal displays. AB - We propose a high dynamic range (HDR) liquid crystal display (LCD) with pixel level local dimming. The device structure consists of a pixelated LCD dimming panel to control the backlight intensity entering the master LCD panel. According to our analysis and test cell experiment, this dual-panel display system possesses exceedingly high contrast ratio (> 1,000,000:1) and high bit-depth (> 14 bits) at merely 5 volts. Meanwhile, to mitigate the Moire effect induced by the cascaded thin-film transistor (TFT) backplanes, we separate the two LCD panels with a polarization-dependent scattering film. The pros and cons of this HDR display are discussed. PMID- 29519047 TI - Quantitative characterization of endoscopic imaging fibers. AB - We describe a technique for the quantitative characterization of endoscopic imaging fibers using an interference pattern as the standard object to be imaged. The visibility of the pattern at the other end of the fiber is then analyzed as wavelength and fringe period are varied. We demonstrate the use of the technique by comparing three fibers: two fabricated in-house from the same preform, designed to minimize inter-core coupling at visible wavelengths less than 650 nm, and a commercial imaging fiber. The techniques discussed are currently being used to optimize fibers for fluorescence bronchoscopy to be used in intensive care clinics. PMID- 29519048 TI - Narrowband and tunable anomalous transmission filters for spectral monitoring in the extreme ultraviolet wavelength region. AB - We present the first experimental demonstration of a novel type of narrowband and wavelength-tunable multilayer transmission filter for the extreme ultraviolet (EUV) region. The operating principle of the filter is based on spatially overlapping the nodes of a standing wave field with the absorbing layers within the multilayer structure. For a wavelength with a matching node pattern, this increases the transmission as compared to neighboring wavelengths where anti nodes overlap with the absorbing layers. Using Ni/Si multilayers where Ni provides strong absorption, we demonstrate the proper working of such anomalous transmission filter. The demonstration is carried out at the example of 13.5 nm wavelength and at normal incidence, providing a 0.27 nm-wide transmission peak. We also demonstrate wavelength tunability by operating the same Ni/Si filter at different wavelengths by varying the angle of incidence. As the multilayer filter is directly deposited on the active area of an EUV-sensitive photodiode, this provides an extremely compact device for easy spectral monitoring in the EUV. The transmission spectrum of the filter is modeled and found to be in good agreement with the experimental data. The agreement proves that such filters and compact monitoring devices can be straightforwardly designed and fabricated, as desired, also for other EUV wavelengths, bandwidths and angles of incidence, thereby showing a high potential for applications. PMID- 29519049 TI - Ultra-high sensitive optical fiber hydrogen sensor using self-referenced demodulation method and WO3-Pd2Pt-Pt composite film. AB - A novel fiber optic hydrogen concentration detection platform with significantly enhanced performance is proposed and demonstrated in this paper. The hydrogen sensing probe was prepared by depositing WO3-Pd2Pt-Pt composite film on the fiber tip of two Bragg gratings paired with high-low reflectivity. At a room temperature of 25 degrees C, the hydrogen sensor has a significant response towards 10 ppm hydrogen in nitrogen atmosphere, and may detect tens of ppb hydrogen changes when the hydrogen concentration is between 10~60 ppm. Besides, the proposed system shows quick response when the hydrogen concentration is above 40 ppm. Moreover, the hydrogen sensor shows good repeatability during the hydrogen response. This work proposes a new concept to develop hydrogen sensing technology with ultra-high sensitivity, which can significantly promote its potential application in various fields, especially for ultra-low hydrogen detection in oxygen-free environment. PMID- 29519050 TI - Full-color large-scaled computer-generated holograms using RGB color filters. AB - A technique using RGB color filters is proposed for creating high-quality full color computer-generated holograms (CGHs). The fringe of these CGHs is composed of more than a billion pixels. The CGHs reconstruct full-parallax three dimensional color images with a deep sensation of depth caused by natural motion parallax. The simulation technique as well as the principle and challenges of high-quality full-color reconstruction are presented to address the design of filter properties suitable for large-scaled CGHs. Optical reconstructions of actual fabricated full-color CGHs are demonstrated in order to verify the proposed techniques. PMID- 29519051 TI - Optical sensors using chaotic correlation fiber loop ring down. AB - We have proposed a novel optical sensor scheme based on chaotic correlation fiber loop ring down (CCFLRD). In contrast to the well-known FLRD spectroscopy, where pulsed laser is injected to fiber loop and ring down time is measured, the proposed CCFLRD uses a chaotic laser to drive a fiber loop and measures autocorrelation coefficient ring down time of chaotic laser. The fundamental difference enables us to avoid using long fiber loop as required in pulsed FLRD, and thus generates higher sensitivity. A strain sensor has been developed to validate the CCFLRD concept. Theoretical and experiment results demonstrate that the proposed method is able to enhance sensitivity by more than two orders of magnitude comparing to the existing FLRD method. We believe the proposed method could find great potential applications for chemical, medical, and physical sensing. PMID- 29519052 TI - Stokes space modulation format classification based on non-iterative clustering algorithm for coherent optical receivers. AB - A Stokes-space modulation format classification (MFC) technique is proposed for coherent optical receivers by using a non-iterative clustering algorithm. In the clustering algorithm, two simple parameters are calculated to help find the density peaks of the data points in Stokes space and no iteration is required. Correct MFC can be realized in numerical simulations among PM-QPSK, PM-8QAM, PM 16QAM, PM-32QAM and PM-64QAM signals within practical optical signal-to-noise ratio (OSNR) ranges. The performance of the proposed MFC algorithm is also compared with those of other schemes based on clustering algorithms. The simulation results show that good classification performance can be achieved using the proposed MFC scheme with moderate time complexity. Proof-of-concept experiments are finally implemented to demonstrate MFC among PM-QPSK/16QAM/64QAM signals, which confirm the feasibility of our proposed MFC scheme. PMID- 29519053 TI - Machining approach of freeform optics on infrared materials via ultra-precision turning. AB - Optical freeform surfaces are of great advantage in excellent optical performance and integrated alignment features. It has wide applications in illumination, imaging and non-imaging, etc. Machining freeform surfaces on infrared (IR) materials with ultra-precision finish is difficult due to its brittle nature. Fast tool servo (FTS) assisted diamond turning is a powerful technique for the realization of freeform optics on brittle materials due to its features of high spindle speed and high cutting speed. However it has difficulties with large slope angles and large rise-and-falls in the sagittal direction. In order to overcome this defect, the balance of the machining quality on the freeform surface and the brittle nature in IR materials should be realized. This paper presents the design of a near-rotational freeform surface (NRFS) with a low non rotational degree (NRD) to constraint the variation of traditional freeform optics to solve this issue. In NRFS, the separation of the surface results in a rotational part and a residual part denoted as a non-rotational surface (NRS). Machining NRFS on germanium is operated by FTS diamond turning. Characteristics of the surface indicate that the optical finish of the freeform surface has been achieved. The modulation transfer function (MTF) of the freeform optics shows a good agreement to the design expectation. Images of the final optical system confirm that the fabricating strategy is of high efficiency and high quality. Challenges and prospects are discussed to provide guidance of future work. PMID- 29519054 TI - Enhancement of the localization and quantitative performance of fluorescence molecular tomography by using linear nBorn method. AB - The nonlinear normalized Born ratio (nBorn) method normalizes emission data with excitation data nonlinearly, which makes the relative distributions of the normalized measurements different from those of the emission data. When compared with the reconstruction using only emission data, what the nonlinear nBorn method does is equivalent to introducing the noisy excitation data to emission data. In our linear nBorn method, the emission data for each projection is linearly normalized with the average excitation data of all detectors. Phantom and in vivo mice studies indicate that the linear nBorn method provides better localization and quantitative performance than the nonlinear nBorn method. PMID- 29519055 TI - THz streak camera method for synchronous arrival time measurement of two-color hard X-ray FEL pulses. AB - The two-color operation of free electron laser (FEL) facilities allows the delivery of two FEL pulses with different energies, which opens new possibilities for user experiments. Measuring the arrival time of both FEL pulses relative to the external experimental laser and to each other improves the temporal resolution of the experiments using the two-color FEL beam and helps to monitor the performance of the machine itself. This work reports on the first simultaneous measurement of the arrival times of two hard X-ray FEL pulses with the THz streak camera. Measuring the arrival time of the two FEL pulses, the relative delay between them was calculated and compared to the set values. Furthermore, we present the first comparison of the THz streak camera method to the method of FEL induced transient transmission. The results indicate a good agreement between the two methods. PMID- 29519056 TI - Fundamental suppression of backscattering in silicon microrings. AB - In this paper we theoretically prove and experimentally demonstrate a novel approach to eliminate the effects of backscattering in silicon ring resonators. Not only the resonance-splitting can be completely suppressed, but also the unwanted light reflected to the in port and directed to the add port can be dramatically reduced. Ring resonators have become one of the most intensively used integrated optical components for various applications. However, in high index-contrast platforms like silicon photonics, sidewall roughness induced backscattering imposes limits on the performance of ring resonators. It frequently induces resonance-splitting in through and drop ports. At the same time, there will be unwanted light directed to the add port and reflected to the in port. We show that, by putting an intentional tunable reflector inside the ring to compete with the stochastic backscattering, the ring can work under a normal condition. All resonances can be tuned to be non-split with an improved extinction ratio and there will be significantly less light coming out from the in and the add ports. PMID- 29519057 TI - Red-green-blue plasmonic random laser. AB - A red-green-blue plasmonic random laser is achieved in a multilayer structure, which is fabricated by spin-coating three polymer solutions successively on a silica substrate. Under optical pumping, strong amplification of the polymer radiation can be observed due to the localized surface plasmon resonance of silver nanoparticles embedded in the multilayer structure. Red-green-blue random lasing is simultaneously obtained from the sample based on the enhanced scattering strength of silver nanoparticles. These results are useful for designing compact integrated random laser sources. PMID- 29519058 TI - Freestanding transparent terahertz half-wave plate using subwavelength cut-wire pairs. AB - We designed a cut-wire-pair metasurface that works as a transparent terahertz half-wave plate, by matching the electric and magnetic resonances of the structure. Due to the impedance matching nature of the resonances, a large transmission phase shift between the orthogonal polarizations was achieved, while permitting a high transmission. The electric and magnetic responses of the proposed structure were confirmed by evaluating the electric admittance and magnetic impedance. The structure was fabricated on a flexible film and its helicity-conversion function in the terahertz frequency range was experimentally demonstrated. The thickness of the device is less than 1/10 of the working vacuum wavelength, and a high amplitude helicity conversion rate over 80 % was achieved. Finally, using simulations, we demonstrate the feasibility of the gradually rotating cut-wire-pair array in terahertz wave-front control. PMID- 29519059 TI - 41-fs, 35-nJ, Green Pulse Generation from a Yb-doped Fiber Laser System. AB - We report ultrafast green pulse generation from a Yb-doped fiber laser system with gain-narrowing compensation. The chirped-pulse amplification system outputs repetitive 3 MHz pulses with an energy of 35 nJ and a reconstructed pulse duration of 41 fs. PMID- 29519060 TI - High-efficiency surface plasmonic polariton waveguides with enhanced low frequency performance in microwave frequencies. AB - In this paper, a planar waveguide based on spoof surface plasmon polaritons (SSPPs) with metals on both sides of the corrugated strip as grounds is firstly proposed in microwave region. Simple and efficient conversion between guided waves and SSPPs is realized by gradient corrugated strip with grounds on both sides. Compared with plasmonic waveguide with flaring ground [Laser Photonics Rev. 8, 146 (2014)], the addition of grounds suppresses the radiation loss effectively and improves the low-frequency performance with tighter field confinement, which leads to a wider operating bandwidth. Moreover, as the asymptotic frequency of SSPPs decreasing, the confinement of SSPPs is further enhanced by a defected ground structure (DGS), which is achieved by the periodic grooves symmetrical to those on the corrugated strip. Therefore, miniaturization of the proposed waveguide can be realized. Measured results validate both high efficiency of momentum and impedance matching and enhanced performance in the region of lower frequencies with the wave vectors close to those in free space. Such results have significant values in plasmonic functional devices and integrated circuits in microwave frequencies. PMID- 29519061 TI - See-through near-eye displays enabling vision correction. AB - We propose a see-through near-eye display, which is dedicated to the visually impaired users who suffer from refractive anomalies. Our solution is characterized by a pair of corrective lenses coated with multiplexed volume holograms. Its key performance including diffraction efficiency, field of view, modulation transfer function, and distortion has been studied. PMID- 29519062 TI - Angle-tolerant linear variable color filter based on a tapered etalon. AB - We propose and fabricate a linear variable color filter (LVCF) that possesses an enhanced angular tolerance in conjunction with a wide linear filtering range (LFR) by taking advantage of an Ag-TiO2-Ag configuration. The TiO2 cavity is tapered in thickness along the device so that the resonance wavelength can be continuously tuned according to the position. In addition, the metal-dielectric-metal structure is overlaid with a pre-designed graded anti-reflection coating in SiO2 to complete the etalon, thereby maximizing the transmission efficiency across the entire device. The tapered dielectric layers in the proposed filter were fabricated via glancing angle deposition without the help of any mask or moving parts. The center wavelength was scanned from 410 nm to 566 nm, resulting in an LFR of 156 nm, and the overall spectra exhibited an approximate peak transmission of 40% and spectral bandwidth of 68 nm. The angular tolerance was as large as 45 degrees , incurring a fractional wavelength shift below 4.2%. The resonance wavelength was verified to be linearly dependent on the position, providing a linearity beyond 99%. The proposed LVCF will thus be actively utilized in a portable micro-spectrometer and spectral scanning device. PMID- 29519063 TI - Polarization dependence of transverse photo-induced voltage in gold thin film with random nanoholes. AB - Transverse photo-induced voltage (TPIV) in 25 nm-thick Au film with random holes with 100 nm in diameter is measured for linearly, circularly and elliptically polarized light. By rotating the major axis of ellipse of the light, TPIV exhibits specific pattern depending on polarization. The experimental results are readily reproduced by assuming that the angular momentum transfer from the light beam to the film is responsible for TPIV. A novel ellipticity meter is proposed based on this mechanism. PMID- 29519064 TI - Resolution enhancement in confocal microscopy using Bessel-Gauss beams. AB - Laser scanning microscopy is limited in lateral resolution by the diffraction of light. We show that we can obtain twenty percent improvement in the resolution of confocal microscopy using Bessel-Gauss beams with the right pinhole size compared to conventional Gaussian beam based confocal microscopy. Advantages of this strategy include simplicity of installation and use, linear polarization compatibility, possibility to combine it with other resolution enhancement and superresolution strategies. We demonstrate the resolution enhancement capabilities of Bessel-Gauss beams both theoretically and experimentally on nano spheres and biological tissue samples without any residual artifacts coming from the Bessel-Gauss beam side lobes with a resolution of 0.39lambda. We also show that the resolution enhancement of Bessel-Gauss beams yields a better statistical colocalization analysis with fewer false positive results than when using Gaussian beams. We have also used Bessel-Gauss beams of different orders to further improve the resolution by combining them in SLAM microscopy (Switching LAser Modes : Dehez, Optics Express, 2013) achieving a resolution of 0.2lambda. PMID- 29519065 TI - Internal quantum efficiency and carrier dynamics in semipolar (2021) InGaN/GaN light-emitting diodes. AB - The internal quantum efficiencies (IQE) and carrier lifetimes of semipolar (202-1 ) InGaN/GaN LEDs with different active regions are measured using temperature dependent, carrier-density-dependent, and time-resolved photoluminescence. Three active regions are investigated: one 12-nm-thick single quantum well (SQW), two 6 nm-thick QWs, and three 4-nm-thick QWs. The IQE is highest for the 12-nm-thick SQW and decreases as the well width decreases. The radiative lifetimes are similar for all structures, while the nonradiative lifetimes decrease as the well width decreases. The superior IQE and longer nonradiative lifetime of the SQW structure suggests using thick SQW active regions for high brightness semipolar (202-1-) LEDs. PMID- 29519066 TI - Lifetime assessment of RbN3-filled MEMS atomic vapor cells with Al2O3 coating. AB - Micro-fabricated (MEMS) alkali vapor cells are at the heart of the miniaturization of atomic devices such as atomic magnetometers, atomic gyroscopes and atomic clocks. Among the different techniques used to fill microfabricated alkali vapor cell, UV decomposition of rubidium azide (RbN3) into metallic Rb and nitrogen in Al2O3 coated cells is a very promising approach for low-cost wafer-level fabrication. Here we present a detailed lifetime study of such cells. The rubidium consumption being the main identified cell failure mode, it is monitored with an novel image analysis technique and with high temperature long term aging tests. PMID- 29519068 TI - Broadband instantaneous frequency measurement based on stimulated Brillouin scattering. AB - A technique for the instantaneous frequency measurement (IFM) of broadband signals is proposed based on stimulated Brillouin scattering (SBS) in a single mode optical fiber. The instantaneous frequency and amplitude information is obtained by the narrowband filtering of the acoustic-optic interaction in the SBS process. Through sideband management of the optical-modulation, the IFM bandwidth can be far beyond the Brillouin frequency shift (i.e. ~11 GHz in 1550 nm). Proof of-concept experiments for both the linearly frequency modulated pulse and frequency Costas coded pulse are carried out to verify the feasibility of the IFM. PMID- 29519067 TI - Axial beam scanning in multiphoton microscopy with MEMS-based actuator. AB - We demonstrate a remotely located microelectromechanical systems (MEMS) actuator that can translate >400 MUm to perform axial beam scanning in a multiphoton microscope. We use a 2-dimensional MEMS mirror for lateral scanning, and collected multiphoton excited fluorescence images in either the horizontal or vertical plane with a field-of-view of either 270 * 270 or 270 * 200 MUm2, respectively, at 5 frames per second. Axial resolution varied from 4.5 to 7 MUm over the scan range. The compact size of the actuator and scanner allows for use in an endomicroscope to collect images in the vertical plane with >200 MUm depth. PMID- 29519069 TI - Repetition rate stabilization of an optical frequency comb based on solid-state laser technology with an intra-cavity electro-optic modulator. AB - The repetition rate stabilization of an optical frequency comb based on diode pumped solid-state laser technology is demonstrated using an intra-cavity electro optic modulator. The large feedback bandwidth of such modulators allows disciplining the comb repetition rate on a cavity-stabilized continuous-wave laser with a locking bandwidth up to 700 kHz. This surpasses what can be achieved with any other type of actuator reported so far. An in-loop integrated phase noise of 133 mrad has been measured and the PM-to-AM coupling of the electro optic modulator has been investigated as well. PMID- 29519070 TI - Orientation-dependent strong-field dissociative single ionization of CO. AB - The dissociative ionization of CO in orthogonally polarized femtosecond laser pulses are studied in a pump-probe scheme. The ionization of CO by the pump pulse and the dissociation of the created CO+ by the probe pulse can be fully disentangled by identifying the photoelectron momentum distributions. Different from the dissociative ionization by a single pulse in which the CO molecule mostly breaks along the field polarization, in this pump-probe strategy, the CO+ ion created from ionization by the pump pulse is favored to dissociate when it orients orthogonal to the polarization direction of the probe pulse. It is attributed to the laser-coupling of various electronic states of the molecular ion in the dissociation process, supported by the numerical simulation of a modeled time-dependent Schrodinger equation. PMID- 29519071 TI - Ripple distribution for nonlinear fiber-optic channels. AB - We demonstrate data rates above the threshold imposed by nonlinearity on conventional optical signals by applying novel probability distribution, which we call ripple distribution, adapted to the properties of the fiber channel. Our results offer a new direction for signal coding, modulation and practical nonlinear distortions compensation algorithms. PMID- 29519072 TI - Experimental study on depolarized GAWBS spectrum for optomechanical sensing of liquids outside standard fibers. AB - We report an experimental study on the spectral dependence of depolarized guided acoustic-wave Brillouin scattering (GAWBS) in a silica single-mode fiber (SMF) on acoustic impedance of external materials. The GAWBS spectrum was measured when the acoustic impedance was changed from 1.51 to 2.00 kg/s.mm2. With increasing acoustic impedance, the linewidth increased; the dependence was almost linear with an acoustic impedance dependence coefficient of 0.16 MHz/kg/s.mm2. Meanwhile, with increasing acoustic impedance, the central frequency linearly decreased with an acoustic impedance dependence coefficient of -0.07 MHz/kg/s.mm2. These characteristics are potentially applicable to acoustic impedance sensing. PMID- 29519073 TI - Dynamic mitigation of EDFA power excursions with machine learning. AB - Dynamic optical networking has promising potential to support the rapidly changing traffic demands in metro and long-haul networks. However, the improvement in dynamicity is hindered by wavelength-dependent power excursions in gain-controlled erbium doped fiber amplifiers (EDFA) when channels change rapidly. We introduce a general approach that leverages machine learning (ML) to characterize and mitigate the power excursions of EDFA systems with different equipment and scales. An ML engine is developed and experimentally validated to show accurate predictions of the power dynamics in cascaded EDFAs. Recommended channel provisioning based on the ML predictions achieves within 1% error of the lowest possible power excursion over 94% of the time. We also showcase significant mitigation of EDFA power excursions in super-channel provisioning when compared to the first-fit wavelength assignment algorithm. PMID- 29519074 TI - Enhancement of the performance of a fiber-based frequency comb by referencing to an acetylene-stabilized fiber laser. AB - We demonstrate a significant improvement in the performance of a fiber-based frequency comb when a GPS-disciplined Rb clock is replaced with an acetylene stabilized laser as the frequency reference. We have developed a compact, maintenance-free acetylene-stabilized fiber laser with a sub-kHz short-term linewidth and an Allan deviation below 3*10-13 for integration times above 1 s. Switching the comb reference from the Rb clock to the acetylene stabilized laser improves both comb tooth linewidth and Allan deviation by about two orders of magnitude. Furthermore, long-term measurements of the acetylene stabilized laser frequency with reference to the GPS-disciplined clock indicate a potential relative frequency uncertainty of 2 * 10-12. PMID- 29519075 TI - Compressive sensing and adaptive sampling applied to millimeter wave inverse synthetic aperture imaging. AB - In order to improve speed and efficiency over traditional scanning methods, a Bayesian compressive sensing algorithm using adaptive spatial sampling is developed for single detector millimeter wave synthetic aperture imaging. The application of this algorithm is compared to random sampling to demonstrate that the adaptive algorithm converges faster for simple targets and generates more reliable reconstructions for complex targets. PMID- 29519076 TI - Integration of polarization-multiplexing and phase-shifting in nanometric two dimensional self-mixing measurement. AB - Integration of phase manipulation and polarization multiplexing was introduced to self-mixing interferometry (SMI) for high-sensitive measurement. Light polarizations were used to increase measuring path number and predict manifold merits for potential applications. Laser source was studied as a microwave photonic resonator optically-injected by double reflected lights on a two feedback-factor analytical model. Independent external paths exploited magnesium oxide doped lithium niobate crystals at perpendicular polarizations to transfer interferometric phases into amplitudes of harmonics. Theoretical resolutions reached angstrom level. By integrating two techniques, this SMI outperformed the conventional single-path SMIs by simultaneous dual-targets measurement on single laser tube with high sensitivity and low speckle noise. In experimental demonstration, by nonlinear filtering method, a custom-made phase-resolved algorithm real-time figured out instantaneous two-dimensional displacements with nanometer resolution. Experimental comparisons to lock-in technique and a commercial Ploytec-5000 laser Doppler velocity meter validated this two-path SMI in micron range without optical cross-talk. Moreover, accuracy subjected to slewing rates of crystals could be flexibly adjusted. PMID- 29519077 TI - Influence of evanescent wave on birefringent microplates. AB - Mechanical action caused by the optical forces connected with the canonical momentum density associated with the local wavevector or Belinfante's spin angular momentum is experimentally verified. The helicity-dependent and the helicity-independent forces determined by spin momenta of different nature open attractive prospects for the use of optical structures for manipulating minute quantities of matter of importance in nanophysics, nanooptics and nanotechnologies, precision chemistry and pharmacology and in numerous other areas. Investigations in this area reveal new, extraordinary manifestations of optical forces, including the helicity-independent force caused by the transverse helicity-independent spin or vertical spin of a diagonally polarized wave, which was not observed and exploited up to recently. The main finding of our study consists in a direct experimental demonstration of the physical existence and mechanical action of this recently discovered extraordinary transverse component of the spin here arising in an evanescent light wave due to the total internal reflection of a linearly polarized probing beam with azimuthal angle 45 degrees at the interface between the birefringent plate and air, which is oriented perpendicularly to the wavevector of an evanescent wave and localized over the boundary of the transparent media with polarization-dependent refraction indices. PMID- 29519078 TI - High-resolution spectroscopy of laser ablation plumes using laser-induced fluorescence. AB - We report laser-induced fluorescence spectroscopy (LIF) of laser-produced plasmas under varying nitrogen pressure levels up to atmospheric pressure. The plasmas were generated on a glass target containing minor amounts of U and Al using 1064 nm, 6 ns pulses from a Nd:YAG laser. A frequency-doubled continuous-wave Ti:Sapphire laser was used as an ultra-narrowband tunable LIF excitation source to increase the magnitude and persistence of emission from selected U and Al atomic transitions in a laser-produced plasma. 2D-fluorescence spectroscopy (2D FS) absorption/emission images were recorded at various nitrogen pressure levels, showing both excitation and emission spectral features. At lower pressure levels (?100 Torr), fluorescence emission was found to be well separated in time from thermally-excited emission. However, as the ambient pressure increased, the thermally-excited emission persisted for longer times along with a reduction of LIF emission persistence and intensity. The excitation spectral features showed the inherent linewidths of various transitions in the plasma, which have significantly narrower spectral linewidths than observed in emission spectra. We evaluated two nearby transitions separated by only 18 pm to demonstrate the effectiveness of fluorescence spectra over thermally-excited spectra for high resolution studies. The present results highlight the importance of LIF as a diagnostic tool employing continuous-wave laser re-excitation, addressing some of the limitations of traditional emission and absorption spectroscopic methods. PMID- 29519079 TI - Multi-terahertz frequency sweeps for high-resolution, frequency-modulated continuous wave ladar using a distributed feedback laser array. AB - Swept-wavelength reflectometry is an absolute distance measurement technique with significant sensitivity and detector bandwidth advantages over normal pulsed, time-of-flight methods. Although several tunable laser sources exist, many exhibit short coherence lengths or require mechanical tuning components. Semiconductor distributed feedback laser diodes (DFBs) are advantageous as a swept source because they exhibit a narrow instantaneous linewidth and can be frequency-swept simply via a single injection current. Here, we present a novel bandwidth generation technique that uses a compact, monolithic, 12-element DFB array to create an effectively continuous, gap-free sweep. Each DFB is sequentially swept over 3.5 nm at 1,600 THz/s using a shaped current pulse, ensuring spectral overlap between each element. After combining the self heterodyned return signatures, the transform-limited resolution of the 43.6 nm sweep is demonstrated to be ~27.4 MUm in air with a precision of 0.18 MUm at a distance of 1.4 m. PMID- 29519080 TI - High-speed directly modulated widely tunable two-section InGaAlAs DBR lasers. AB - We report widely tunable two-section distributed Bragg reflector (DBR) lasers, which have InGaAlAs multiple quantum wells (MQWs) as the gain material. By butt jointing InGaAsP, which has a photoluminescence wavelength of 1.4 MUm as the material of the DBR section, a wavelength tuning range of 12 nm can be obtained by current injection into the DBR section. The direct modulation bandwidth of the lasers is greater than 10 GHz over the entire wavelength tuning range up to 40 degrees C. Compared with InGaAsP DBR lasers having the same structure, the InGaAlAs lasers have smaller variations in both the threshold current and slope efficiency with the temperature because of the better electron confinement in the InGaAlAs MQWs. Moreover, the DBR-current-induced decreases in the modulation bandwidth and side mode suppression ratio (SMSR) of the optical spectra are notably smaller for the InGaAlAs lasers than for the InGaAsP lasers. PMID- 29519081 TI - Loss enhanced spin Hall effect of transmitted light through anisotropic epsilon- and mu-near-zero metamaterial slab. AB - Spin Hall effect of light (SHEL) is prosperous in precision metrology and quantum information processing. In normal situations, the inevitable loss of material will greatly weaken SHEL, which is a major constraint to its potential applications. We first report the loss enhanced SHEL through epsilon and mu-near zero (EMNZ) metamaterial slab by anisotropic configuration of epsilon and mu tensors. It is verified that the loss of EMNZ metamaterial can effectively enlarge the splitting between right-circularly polarized (RCP) and left circularly polarized light (LCP) components of linear polarized light even when the incident angle is much larger than critical angle. Calculation results show that when the imaginary part of permeability's vertical component is equal to 0.1, a flat-top transverse shift peak can be observed which remains unchanged for different vertical component of permeability and thickness of EMNZ metamaterial. In this case the maximum transverse shift of left-circularly polarized light can be increased to 24.676 micrometers by EMNZ metamaterial loss without any amplification method. Meanwhile, the transverse shifts of RCP (LCP) light can be modulated flexibly by EMNZ metamaterial loss. Therefore the loss enhanced SHEL makes quantum devices applicable which paves the way towards on-chip and inter chip optical circuitry. PMID- 29519082 TI - Broadband high-resolution microwave frequency measurement based on low-speed photonic analog-to-digital converters. AB - An approach to microwave frequency measurement with a high resolution and a broad bandwidth is proposed based on three parallel low-speed photonic analog-to digital converters (ADCs) architecture. Through simultaneously bandpass sampling the input microwave signal with the three photonic ADCs, the input frequency can be calculated from the Fourier frequencies of the photonic ADCs using the proposed frequency recovery algorithm. Theoretical analysis and simulation results indicate that the proposed method is applicable for both single-tone and multi-tone microwave signals. By employing three ~1 GS/s@8 bits photonic ADCs, 0 100 GHz frequency measurement with an error of +/- 0.5 MHz and a spur-free dynamic range of 94 dB-Hz2/3 over the full band has been numerically demonstrated. Additionally, a proof-of-concept experiment is carried out to demonstrate the effectiveness of the proposed method, where a frequency measurement range of 0-20 GHz with a measurement error of +/- 8 kHz is realized by utilizing three photonic ADCs with sampling rates of 27.690 MS/s, 27.710 MS/s, and 27.730 MS/s. Larger frequency measurement range can be achieved by using an optical modulator with a larger bandwidth. PMID- 29519083 TI - Quasi phase-matched quartz for intense-laser pumped wavelength conversion. AB - Crystal quartz has excellent optical properties as short absorption edge and high laser-damage threshold, which are suitable for intense pulse-laser pumped wavelength conversion by artificial quasi-phase matching structures. We present on initial evaluation of second-harmonic green generation with 14.9 kW peak power using periodic laminar structured quartz, pumped by sub-nanosecond pulse with focused intensity > 100 GW/cm2. PMID- 29519084 TI - Theoretical study of gain-induced mode coupling and mode beating in few-mode optical fiber amplifiers. AB - We developed a generalized field-propagating model for active optical fibers that takes into account mode beating and mode coupling through the amplifying medium. We applied the model to the particular case of a few-mode erbium doped fiber amplifier. Results from the model predict that mode coupling mediated by the amplifying medium is very low. Furthermore, we applied the model to a typical amplifier configuration. In this particular configuration, the new model predicts much lower differential modal gain than that predicted by a classical intensity model. PMID- 29519085 TI - PCA-based denoising method for division of focal plane polarimeters. AB - Division of focal plane (DoFP) polarimeters are composed of interlaced linear polarizers overlaid upon a focal plane array sensor. The interpolation is essential to reconstruct polarization information. However, current interpolation methods are based on the unrealistic assumption of noise-free images. Thus, it is advantageous to carry out denoising before interpolation. In this paper, we propose a principle component analysis (PCA) based denoising method, which works directly on DoFP images. Both simulated and real DoFP images are used to evaluate the denoising performance. Experimental results show that the proposed method can effectively suppress noise while preserving edges. PMID- 29519086 TI - Conditions for reservoir computing performance using semiconductor lasers with delayed optical feedback. AB - Photonic implementations of reservoir computing (RC) have been receiving considerable attention due to their excellent performance, hardware, and energy efficiency as well as their speed. Here, we study a particularly attractive all optical system using optical information injection into a semiconductor laser with delayed feedback. We connect its injection locking, consistency, and memory properties to the RC performance in a non-linear prediction task. We find that for partial injection locking we achieve a good combination of consistency and memory. Therefore, we are able to provide a physical basis identifying operational parameters suitable for prediction. PMID- 29519087 TI - Sequential signal detection for high dynamic range time-resolved laser-induced incandescence. AB - A new method for collecting time-resolved laser-induced incandescence (TiRe-LII) signals with high dynamic range is presented. Gated photomultiplier tubes (PMT) are used to detect temporal sections of the LII signal. This helps to overcome the limitations of PMTs caused by restricted maximum signal current at the strong initial signal and poor signal-to-noise ratios when the signal intensity approaches the noise level. We present a simple method for increasing the accuracy of two-color pyrometry at later decay times and two advanced strategies for getting high accuracy over the complete temperature trace or even achieve single-shot capability with high dynamic range. Validation measurements in a standardized flame show that the method is sensitive enough to even resolve the local increase in gas temperature as a consequence of heating the soot particles with a laser pulse. PMID- 29519089 TI - Generation of phase edge singularities by coplanar three-beam interference and their detection. AB - In recent years singular optics has gained considerable attention in science and technology. Up to now optical vortices (phase point dislocations) have been of main interest. This paper presents the first general analysis of formation of phase edge singularities by coplanar three-beam interference. They can be generated, for example, by three-slit interference or self-imaging in the Fresnel diffraction field of a sinusoidal grating. We derive a general condition for the ratio of amplitudes of interfering beams resulting in phase edge dislocations, lateral separation of dislocations depends on this ratio as well. Analytically derived properties are corroborated by numerical and experimental studies. We develop a simple, robust, common path optical self-imaging configuration aided by a coherent tilted reference wave and spatial filtering. Finally, we propose an automatic fringe pattern analysis technique for detecting phase edge dislocations, based on the continuous wavelet transform. Presented studies open new possibilities for developing grating based sensing techniques for precision metrology of very small phase differences. PMID- 29519090 TI - Simplified high-order Volterra series transfer function for optical transmission links. AB - We develop a simplified high-order multi-span Volterra series transfer function (SH-MS-VSTF), basing our derivation on the well-known third-order Volterra series transfer function (VSTF). We notice that when applying an approach based on a recursive method and considering the phased-array factor, the order of the expression for the transfer function grows as 3 raised to the number of considered spans. By imposing a frequency-flat approximation to the higher-order terms that are usually neglected in the commonly used VSTF approach, we are able to reduce the overall expression order to the typical third-order plus a complex correction factor. We carry on performance comparisons between the purposed SH-MS VSTF, the well-known split-step Fourier method (SSFM), and the third-order VSTF. The SH-MS-VSTF exhibits a uniform improvement of about two orders of magnitude in the normalized mean squared deviation with respect to the other methods. This can be translated in a reduction of the overall number of steps required to fully analyze the transmission link up to 99.75% with respect to the SSFM, and 98.75% with respect to the third-order VSTF, respectively, for the same numerical accuracy. PMID- 29519088 TI - Fully integrated microwave frequency synthesizer on heterogeneous silicon-III/V. AB - We demonstrate a photonic microwave generator on the heterogeneous silicon-InP platform. Waveguide photodiodes with a 3 dB bandwidth of 65 GHz and 0.4 A/W responsivity are integrated with lasers that tune over 42 nm with less than 150 kHz linewidth. Microwave signal generation from 1 to 112 GHz is achieved. PMID- 29519091 TI - Metrology of nanoscale grating structures by UV scatterometry. AB - In this contribution we demonstrate goniometric scatterometry measurements of gratings with linewidths down to 25 nm on silicon wafers with an inspection wavelength of 266 nm. For each sample, measurements have been performed in four different configurations and the obtained data have been evaluated in parallel. As results we present the reconstruction of the complete cross-section profile. We introduce a novel geometry parameterization which overcomes some limitations of the default parameterization. A co-variance analysis of the parameters is offered to indicate the soundness of the results. A qualitative comparison with cross-section scanning electron microscope (SEM) images shows excellent agreement. PMID- 29519092 TI - Multi-color operation of tunable diffractive lenses. AB - Rotationally tunable diffractive optical elements (DOEs) consist of two stacked diffractive optical elements which are rotated with respect to each other around their central optical axis. The combined diffractive element acts as a highly efficient diffractive lens, which changes its optical power as a function of the mutual rotation angle. Here we show that the principle can be extended to produce polychromatic tunable lenses, i.e. lenses which have the same optical power, and the same diffraction efficiency within the full tuning range at three or more selectable wavelengths. The basic principle is to use higher order DOEs, which will be polychromatic at harmonics of a fundamental wavelength. The method can be applied to other types of optical elements which are tunable by rotation, like axicons, or generalized lenses with arbitrary radial phase profiles, or to elements tunable by a mutual translation, like diffractive Alvarez lenses. PMID- 29519093 TI - Oscillations of absorbing particles at the water-air interface induced by laser tweezers. AB - We present an experimental study on oscillation of absorbing particles at the water-air interface. The oscillation is induced by laser tweezers, which are generated with a high numerical aperture objective. When the laser beam is tightly focused at the water-air interface, the optical gradient force attracts the particles to the spot center, and the laser heating of particles results in a strong thermal gradient that drives the particles to leave the spot center. Under the action of thermal and optical gradient force together, the absorbing particles oscillate at the water-air interface. PMID- 29519095 TI - Practical guide to the realization of a convertible optical trapping system. AB - In this article, we provide a detailed guide to the construction of a convertible optical trapping system for either single-beam or counter-propagating trap. The single-beam trap maintains all the functionalities that a conventional optical tweezer has. While the counter-propagating trap allows for the trapping of particles that single-beam trap cannot handle. The counter-propagating trap can be easily switched to a single-beam trap, and vice versa. Therefore, this convertible optical trapping system allows for the trapping and manipulation of particles with a wide variety of sizes and materials. PMID- 29519094 TI - Fabrication of a vertically-stacked passive-matrix micro-LED array structure for a dual color display. AB - We report a color tunable display consisting of two passive-matrix micro-LED array chips. The device has combined vertically stacked blue and green passive matrix LED array chips sandwiched by a transparent bonding material. We demonstrate that vertically stacked blue and green micro-pixels are independently controllable with operation of four color modes. Moreover, the color of each pixel is tunable in the entire wavelength from the blue to green region (450 nm - 540 nm) by applying pulse-width-modulation bias voltage. This study is meaningful in that a dual color micro-LED array with a vertically stacked subpixel structure is realized. PMID- 29519096 TI - Sparse aperiodic arrays for optical beam forming and LIDAR. AB - We analyze optical phased arrays with aperiodic pitch and element-to-element spacing greater than one wavelength at channel counts exceeding hundreds of elements. We optimize the spacing between waveguides for highest side-mode suppression providing grating lobe free steering in full visible space while preserving the narrow beamwidth. Optimum waveguide placement strategies are derived and design guidelines for sparse (> 1.5 lambda and > 3 lambda average element spacing) optical phased arrays are given. Scaling to larger array areas by means of tiling is considered. PMID- 29519097 TI - Degeneracy-analogous femtosecond dual-wavelength optical parametric oscillator at non-degenerate wavelengths. AB - Synchronously pumped optical parametric oscillator (OPO) at degeneracy is ideal for generating ultrafast laser pulses. Normally, however, group velocity mismatch (GVM) is ubiquitous among the interacting pulses at widely separated wavelengths. A versatile quasi-phase-matching (QPM) technique is proposed for temporal synchronizing of the signal and idler pulses relied on a less common Type-II QPM (oe-o interaction). The proposed group-velocity regulation technology is advantageous to constructing a degeneracy-analogous femtosecond OPO for dual wavelength operation. Qualitative prediction for the proposed design is conducted based on a commercial femtosecond pump source at 1064 nm while the signal/idler wavelengths are 3.2 MUm and 1.59 MUm respectively. Compared with the conventional Type-0 QPM based counterpart (ee-e interaction), the uncompensated temporal distortion caused by temporal walk-off is strongly suppressed while the idler spectrum gets significantly broader. The versatility of the proposed scheme is also clearly demonstrated by its fairly stable performance within a broad tuning range of 2.9-3.5 MUm and 1.68-1.53 MUm. The demonstrated configuration might be promising for synchronously obtaining dual-wavelength ultrafast pulses with higher spectral and temporal qualities. PMID- 29519098 TI - Generation of a non-zero discord bipartite state with classical second-order interference. AB - We report an investigation on quantum discord in classical second-order interference. In particular, we theoretically show that a bipartite state with D = 0.311 of discord can be generated via classical second-order interference. We also experimentally verify the theory by obtaining D = 0.197 +/- 0.060 of non zero discord state. Together with the fact that the nonclassicalities originated from physical constraints and information theoretic perspectives are not equivalent, this result provides an insight to understand the nature of quantum discord. PMID- 29519099 TI - Digital waveguide adiabatic passage part 2: experiment. AB - Using a femtosecond laser writing technique, we fabricate and characterise three waveguide digital adiabatic passage devices, with the central waveguide digitised into five discrete waveguidelets. Strongly asymmetric behaviour was observed, devices operated with high fidelity in the counter-intuitive scheme while strongly suppressing transmission in the intuitive. The low differential loss of the digital adiabatic passage designs potentially offers additional functionality for adiabatic passage based devices. These devices operate with a high contrast (>90%) over a 60 nm bandwidth, centered at ~ 823 nm. PMID- 29519100 TI - Study of a Hi-Bi FOLM for tunable and dual-wavelength operation of a thulium doped fiber laser. AB - We report a study of an all-fiber Tm-doped fiber laser with tunable single wavelength emission and dual-wavelength generation operating in different laser wavelength ranges depending on the Tm-doped fiber (TDF) length. The wavelength selection and tuning for single wavelength laser operation and the adjustment of cavity losses for dual wavelength laser operation is obtained by temperature variations of the high birefringence fiber loop in a fiber optical loop mirror. Stable dual wavelength operation is achieved at the single wavelength tuning limits when cavity losses are balanced to generate two simultaneous laser lines with equal powers. A linear cavity fiber laser setup with TDF lengths of 2, 4, 8 and 12 m is used to obtain tunable single wavelength operation in a range of ~40 nm for each TDF length. A total tuning range of ~110 nm with the four different TDF lengths is achieved. At dual-wavelength laser operation the wavelength separation was ~48 nm. The maximal power efficiency of ~34.9% with a maximum output power of 274 mW was obtained with the use of TDF length of 4 m. PMID- 29519101 TI - Vectorial control of nonlinear emission via chiral butterfly nanoantennas: generation of pure high order nonlinear vortex beams. AB - We report on a chiral gap-nanostructure, which we term a "butterfly nanoantenna," that offers full vectorial control over nonlinear emission. The field enhancement in its gap occurs for only one circular polarization but for every incident linear polarization. As the polarization, phase and amplitude of the linear field in the gap are highly controlled, the linear field can drive nonlinear emitters within the gap, which behave as an idealized Huygens source. A general framework is thereby proposed wherein the butterfly nanoantennas can be arranged in a metasurface, and the nonlinear Huygens sources exploited to produce a highly structured far-field optical beam. Nonlinearity allows us to shape the light at shorter wavelengths, not accessible by linear plasmonics, and resulting in high purity beams. The chirality of the butterfly allows us to create orbital angular momentum states using a linearly polarized excitation. A third harmonic Laguerre Gauss beam carrying an optical orbital angular momentum of 41 is demonstrated as an example, through large-scale simulations on a high-performance computing platform of the full plasmonic metasurface with an area large enough to contain up to 3600 nanoantennas. PMID- 29519102 TI - Genetically optimized all-dielectric metasurfaces. AB - We present and study theoretically a new design approach for obtaining wide angle, highly efficient, all-dielectric metasurfaces. As a concrete example we focus on optimizing flat beam deflector for both the infra-red and visible spectral regions. Transmission efficiencies of up to 87.2% are obtained theoretically for deflection angle of 65 degrees in visible (580nm) spectrum and up to 82% for deflection angle of 30.5 degrees at telecom wavelength (1550nm). The enhanced efficiencies at wide deflection angles are obtained by genetic optimization of the nano-structures comprising the metasurface. Compared to previously employed design approaches, our approach enhances the transmission efficiency substantially without sacrificing rectangular grid arrangement and facilitates the realization of wide angle flat deflectors and holograms/lenses. PMID- 29519103 TI - Multicolor lasers using birefringent filters: experimental demonstration with Cr:Nd:GSGG and Cr:LiSAF. AB - In this study, we numerically and experimentally investigate application of birefringent filters (BRFs) as frequency selective elements in multicolor lasers. A BRF plate made out of crystalline quartz with an arbitrarily oriented optical axis has been explored. Simulation results have shown that compared to regular BRFs where the optical axis lies in the plane of the plates surface, a BRF with an optical axis pointing out of its surface enables design flexibility in filter parameters, providing access to a wider set of free spectral range and bandwidth values. As a result, multicolor operation could be obtained in many wavelength pairs using a single BRF plate. In the experiments a 3-mm thick quartz BRF with an optical axis 45 degrees to the surface plane has been used. With Cr:Nd:GSGG as a laser medium two-color and three-color cw laser operation has been demonstrated in 11 and 3 different transition combinations, respectively. Moreover, two-color laser operation has been demonstrated in 10 different wavelength pairs in Cr:LiSAF. To our knowledge, this study is the first detailed investigation and experimental demonstration of BRFs with tilted optical axis for multicolor operation of solid-state lasers. Compared to other methods, BRFs enable a rich selection of transition pairs and also the ratio of the power in each line could be regulated by fine adjustment of the rotation angle. Implementation of tilted-axis BRFs should boost development of efficient and low cost multicolor lasers in other gain media as well. PMID- 29519104 TI - Development of high resolution dual-energy KBA microscope with large field of view for RT-instability diagnostics at SG-III facility. AB - High resolution X-ray diagnosis is a significant method for obtaining ablation front and trajectory measurements targeting Rayleigh-Taylor (RT)-instability growth in initial confinement fusion (ICF) experiments. In this paper, a novel Kirkpatrick-Baez-type structure, as a kind of essential X-ray micro-imaging apparatus, has been developed that realizes a large field of view (FOV) and images with high resolution and energy response. Zoned multilayer coating technology is applied to the Kirkpatrick-Baez mirrors to transmit two specific quasi-monochromatic light through the same mirror and enables a compact dual channel structure. This microscope has been assembled in the laboratory and later implemented at the Chinese SG-III laser facility. The characterization results show that this imaging system can achieve a good spatial resolution of 5 um in a large FOV of 500 um, while maintaining a strong monochromatic performance with bandwidth of 0.5 keV at 2.5 keV and 4.3 keV respectively. PMID- 29519105 TI - Wavelength tuning of the spirally drawn whispering gallery mode microfiber lasers and the perspectives for sensing applications. AB - Facile and cost-efficient microcavities, as well as the tuning of the optical modes, especially for the application of top-grade optical devices, have been emerging as attractive research fields. In this work, controllable fabrication of the microfiber laser arrays in polymer matrix is achieved by employing the advanced spiral drawing technique. Besides the high-quality whispering gallery mode (WGM) lasing, wavelength tuning is also realized by applying external forces on the polymer matrix, which induce slightly enlarged cavity sizes. Furthermore, the perspectives of utilizing the microfiber arrays as force and strain sensors are discussed and demonstrated. PMID- 29519106 TI - Nonlinearities of organic electro-optic materials in nanoscale slots and implications for the optimum modulator design. AB - The performance of highly nonlinear organic electro-optic (EO) materials incorporated into nanoscale slots is examined. It is shown that EO coefficients as large as 190 pm/V can be obtained in 150 nm wide plasmonic slot waveguides but that the coefficients decrease for narrower slots. Possible mechanism that lead to such a decrease are discussed. Monte-Carlo computer simulations are performed, confirming that chromophore-surface interactions are one important factor influencing the EO coefficient in narrow plasmonic slots. These highly nonlinear materials are of particular interest for applications in optical modulators. However, in modulators the key parameters are the voltage-length product UpiL and the insertion loss rather than the linear EO coefficients. We show record-low voltage-length products of 70 Vum and 50 Vum for slot widths in the order of 50 nm for the materials JRD1 and DLD164, respectively. This is because the nonlinear interaction is enhanced in narrow slot and thereby compensates for the reduced EO coefficient. Likewise, it is found that lowest insertion losses are observed for slot widths in the range 60 to 100 nm. PMID- 29519107 TI - Two-mode contra-directional coupler based on superposed grating. AB - We propose and demonstrate a novel two-mode grating assisted contra-directional coupler (TGACC), which is capable of filtering two modes channels simultaneously by superposed grating with two superposed grating components. Finite-difference time-domain simulation is employed to study the structure. The influences of main structural parameters are analyzed, and apodization is employed to reduce the band sidelobes, crosstalk and back-reflections. We experimentally present a mode channel switchable TGACC for 2.54nm-wide wavelength band centered at 1548.0nm by 50K thermal-optic tuning. With two channels combined into one device, the TGACC can help to enrich the functionality and reduce the footprint of mode-division multiplexing (MDM) systems. PMID- 29519108 TI - Robust approach to reconstructing transparent objects using a time-of-flight depth camera. AB - This study presents a robust approach to reconstructing a three dimensional (3-D) translucent object using a single time-of-flight depth camera with simple user marks. Because the appearance of translucent objects depends on the light interaction with the surrounding environment, the measurement using depth cameras is considerably biased or invalid. Although several existing methods attempt to model the depth error of translucent objects, their model remains partial because of object assumptions and its sensitivity to noise. In this study, we introduce a ground plane and piece-wise linear surface model as priors and construct a robust 3-D reconstruction framework for translucent objects. These two depth priors are combined with the depth error model built on the time-of-flight principle. Extensive evaluation of various real data reveals that the proposed method substantially improves the accuracy and reliability of 3-D reconstruction for translucent objects. PMID- 29519109 TI - Counter-propagating parametric interaction with phonon-polaritons in periodically poled KTiOPO4. AB - Strongly enhanced backward stimulated polariton scattering (BSPS) is demonstrated in periodically-poled KTiOPO4 (KTP) crystals with a high power conversion efficiency up to 70%. We study the physical mechanism of such counter propagating parametric interaction with phonon-polaritons in chi(2) modulated structures. BSPS is a three-wave mixing that is distinguished from backward stimulated Raman scattering (BSRS), while a strong absorption at large polariton wave-vectors can still make BSPS display certain characteristics of BSRS such as self-compression of the Stokes pulse. We also compare BSPS with counter-propagating parametric oscillation in the near- and mid-infrared range, providing an estimation of the fabrication error margin to expect the outcome of their competition in the same device. PMID- 29519110 TI - Photo-switchable chiral liquid crystal with optical tristability enabled by a photoresponsive azo-chiral dopant. AB - A light-driven tristable chiral-tilted homeotropic nematic (TCHN) cell is demonstrated. The liquid-crystal cell is photo-switchable among the three stable states: the tilted-homeotropic, fingerprint, and the tilted-twist states. The inclusion of a photosensitive chiral bis(azobenzene) compound into a typical nematic liquid crystal makes the resulting material possible to switch from one to another stable state directly and reversibly owing to the photoinduced trans cis isomerization of the azo-chiral dopant and, hence, the configurational change of the liquid crystal via the guest-host effect. By further introducing dichroic dyes into the TCHN system, we devised a polarizer-free display and light modulators. The novel TCHN composite material opens up new possible applications in light-driven optical elements and devices. PMID- 29519111 TI - Computational imaging, relighting and depth sensing using flexible thin-film sensors. AB - We wrap a thin-film luminescent concentrator (LC) - a flexible and transparent plastic foil doped with fluorescent dye particles - around an object to obtain images of the object under varying synthetic lighting conditions and without lenses. These images can then be used for computational relighting and depth reconstruction. An LC is an efficient two-dimensional light guide that allows photons to be collected over a wide solid angle, and through multiple overlapping integration areas simultaneously. We show that conventional photodetectors achieve a higher signal-to-noise ratio when equipped with an LC than in direct measurements. Efficient light guidance in combination with computational imaging approaches, such as presented in this article, can lead to novel optical sensors that collect light in a structured way and within a wide solid angle rather than unstructured through narrow apertures. This enables flexible, scalable, transparent, and lens-less thin-film image and depth sensors. PMID- 29519112 TI - Multi-peak structure of generation spectrum of random distributed feedback fiber Raman lasers. AB - We study spectral features of the generation of random distributed feedback fiber Raman laser arising from two-peak shape of the Raman gain spectral profile realized in the germanosilicate fibers. We demonstrate that number of peaks can be calculated using power balance model considering different subcomponents within each Stokes component. PMID- 29519113 TI - Principal modes in multimode fibers: exploring the crossover from weak to strong mode coupling. AB - We present experimental and numerical studies on principal modes in a multimode fiber with mode coupling. By applying external stress to the fiber and gradually adjusting the stress, we have realized a transition from weak to strong mode coupling, which corresponds to the transition from single scattering to multiple scattering in mode space. Our experiments show that principal modes have distinct spatial and spectral characteristic in the weak and strong mode coupling regimes. We also investigate the bandwidth of the principal modes, in particular, the dependence of the bandwidth on the delay time, and the effects of the mode dependent loss. By analyzing the path-length distributions, we discover two distinct mechanisms that are responsible for the bandwidth of principal modes in weak and strong mode coupling regimes. Their interplay leads to a non-monotonic transition of the average principal mode bandwidth from weak to strong mode coupling. Taking into account the mode-dependent loss in the fiber, our numerical results are in qualitative agreement with our experimental observations. Our study paves the way for exploring potential applications of principal modes in communication, imaging and spectroscopy. PMID- 29519114 TI - Robust mapping of electrical properties of graphene from terahertz time-domain spectroscopy with timing jitter correction. AB - We demonstrate a method for reliably determining the electrical properties of graphene including the carrier scattering time and carrier drift mobility from terahertz time- domain spectroscopy measurements (THz-TDS). By comparing transients originating from directly transmitted pulses and the echoes from internal reflections in a substrate, we are able to extract electrical properties irrespective of random time delays between pulses emitted in a THz-TDS setup. If such time delays are not accounted for they can significantly influence the extracted properties of the material. The technique is useful for a robust determination of electrical properties from THz-TDS measurements and is compatible with substrate materials where transients from internal reflections are well-separated in time. PMID- 29519115 TI - Generation of cylindrical vector beams and optical vortex by two acoustically induced fiber gratings with orthogonal vibration directions. AB - Mode coupling from the fundamental vector mode (HE11x) to the cylindrical vector beams (CVBs) and optical vortex beams (OVBs) of a few-mode fiber excited by two acoustic flexural waves with orthogonal perturbations is achieved by using a composite acoustic transducer. The HE11x mode is converted to TM01 and TE01 modes, which have radial and azimuthal polarizations, by using the lowest-order acoustic flexural modes of F11x and F11y, respectively. Furthermore, HE11x mode can also be converted to the +/- 1-order OVBs of HE21even+/-iHE21odd through the combined acoustic modes of F11x+/-iF11y. This technique provides a useful way of generating CVBs and OVBs in optical fiber with conveniently electrically-controlled mode conversion characteristics. PMID- 29519116 TI - Evaluation of food storage racks available on the Polish market in the hygienic context AB - Background: Providing safe food products to the consumer depends on the material and technology used and adherence to hygienic practices, throughout the production process. The degree of microbial contamination of a surface is an important indicator of equipment cleanliness and effectiveness of cleaning and disinfection. Used material, construction solutions and quality of the applied devices also have an effect on hygienic status. Objective: The objective of the present study was to evaluate the influence of the design and construction material of selected food storage racks, available on the Polish market, on their hygienic status. Material and methods: The study was based on determination of the capability of microbial growth on the surface of the racks and the effectiveness of their cleaning. Microbiological cleanliness on the surface of the racks was monitored by the contact plates which are able to estimate the total number of icroorganisms. Examination of effectiveness of cleaning was conducted by the use of ATP bioluminescence method. Results: This experiment has proven a significant influence of adopted construction solutions on the hygienic status of the examined racks. Presence of antibacterial layer and a choice of the appropriate construction material characterized by a low surface roughness impedes the microbial growth and increases the effectiveness of cleaning. Conclusions: Design solutions have significant impact on the hygienic status of shelves. Selection of a suitable material for the construction of racks can greatly reduce the possibility of the development of microorganism, despite the low efficiency of the cleaning. The application of antimicrobial coatings inhibits microbial growth. PMID- 29519117 TI - Assessment of nutritional behaviours of children aged 7-12 attending to primary schools in Biala Podlaska, Poland AB - Background: Children and youth constitute a group that is particularly prone to the effects of improper diet. In the puberty period, numerous significant lifestyle choices are made, for instance regarding particular nutritional behaviours which may be repeated later in life and may determine the state of health. Objective: The aim of the study was to assess nutritional behaviours of children aged 7-12 attending to primary schools in Biala Podlaska county (Eastern Region of Poland). Material and methods: The study included 1643 children aged 7 12 from primary schools in Biala Podlaska county. The research was carried out in 2015. The questions included in the questionnaire prepared by the authors regarded the number and regularity of meals, the types of products (mainly fruit and vegetables, sweets, fizzy drinks, fast food, milk and dairy products) and the frequency of consuming them during these meals and between them. Differences between the responses to the questions in groups divided according to gender were analysed with the use of chi2 test (G function). Results: It was revealed that 672 girls (81.7%) and 633 boys (71.9%) had at least four meals a day, while as many as 23% of the girls and boys did not have breakfast before going to school and 33.5% of the girls and 37.4% of the boys did not take lunch to school. The main meal (dinner) was eaten every day by 652 girls (78.5%) and 605 boys (74.5%). Products most commonly eaten between the main meals were fruit and vegetables (51% of the girls and 42.4% of the boys), while sweets were consumed 2-3 times a week by 37.2% of the girls and 36.1% of the boys. The consumption of dairy products (milk, natural yoghurt and/or kefir) once a week or less frequently was declared by 53% of the girls and boys. Conclusions: Assessment of nutritional behaviours revealed numerous mistakes which may negatively affect the development of the study participants. In the light of the above findings, it seems necessary to provide children and their parents with nutritional education in order to develop proper nutritional behaviours and correct the mistakes. PMID- 29519118 TI - Comparison of diet and physical activity of children and adolescents with patients after cancer treatment AB - Background: Properly balanced diet and exercise are an essential element of healthy living for children and adolescents. Particular attention should be paid to nutrition and physical activity among juniors after cancer treatment, which is one of the most important elements of the convalescence period. Objective: The aim of the study was a comparative analysis of diet, physical activity of healthy children and adolescents with patients after cancer treatment. Material and methods: The study involved 60 children and adolescents; 30 healthy juniors and 30 patients after treatment for cancer. An analysis of diets based on a 3-day 24 hour nutrition diary. The questionnaire surveyed collected data about participation and physical activity preferences. Statistical program-Statistica 12.0, published by StatSoft, was used to develop the results. Results: Both groups were characterized by increased consumption of proteins and carbohydrates. Insufficient fat intake was shown in comparison with the recommended amounts in all study groups. It was observed that in the group of patients after treatment, vitamins B1, A, E and D intake was higher than in their healthy peers. Determinants of the choice of physical activity among children after cancer treatment was pleasure and fun, while among their healthy peers, aesthetic considerations (taking care of appearance). Conclusions: Children and adolescents after cancer treatmentin a much greater percentage covered of daily intake of nutrients than healthy children, and more willingly spent time on physical activity. Greater interest in physical activity in this group was probably due to previous restrictions related to illness and therapy. PMID- 29519119 TI - Quality of drinking water from the agricultural area treated with pitcher water filters AB - Background: Home methods of drinking water treatment through filtration have recently become quite popular. Objective: The aim of the study was to compare chemical composition of unfiltered water with water filtered in households with pitcher water filters. Obtained results were discussed in view of the effect of analysed chemical components of water on human health. Material and methods: Water samples were taken from water works supplies and from home dug wells from the agricultural area. Unfiltered water and water filtered through filters filled with active carbon and ion-exchanging resin and placed in a pitcher were analysed. Electrolytic conductivity, pH, hardness and the concentrations of calcium, magnesium, nitrate, phosphate and chloride ions were determined in water samples. Results of analyses were statistically processed. Results: As a result of water filtration, the concentration of phosphates significantly increased and the concentrations of calcium, magnesium, electrolytic conductivity and pH decreased. No changes were noted in the concentration of chloride ions. Filtering water decreased the concentration of nitrates in dug wells samples. Conclusions: Using water purification devices is justified in the case of water originating from home dug wells contaminated with nitrates when, at the same time, consumers' diet is supplemented with calcium and magnesium. Filtration of water from water works supplies, controlled by sanitary inspection seems aimless. PMID- 29519120 TI - The Acceptable Noise Level Benefit From Directionality for Listeners With Severe Hearing Loss. AB - OBJECTIVES: Directional microphone technology can enhance the speech intelligibility and listening comfort of listeners with hearing impairment. The main aim of this study is to investigate and compare the benefit derived by listeners with severe hearing loss from directional microphone technology with that derived by listeners with moderate hearing loss. METHODS: The acceptable noise levels (ANLs) of two groups of listeners with moderate or severe hearing impairment (17 subjects in each group) were measured under unaided, omnidirectional-baseline-aided, and directional-aided conditions. RESULTS: Although the absolute ANL of the listeners in the severe hearing loss group was significantly higher than that of the listeners in the moderate hearing loss group, their derived benefit was equivalent to that derived by the listeners in the moderate hearing loss group. ANL and hearing loss degree were significantly related. Specifically, the ANL increased with the severity of hearing loss. CONCLUSION: Directional microphone technology can provide the benefits of listening comfort to listeners with severe hearing loss. PMID- 29519121 TI - Body composition and fatty tissue distribution in women with various menstrual status AB - Background: Menopause, also referred to as climacterium, is a period of multiple changes in the structure and functions of a woman organism. Objective: Determination of differences in body composition and fatty tissue distribution in women from groups discriminated based on their menstrual status. Material and Methods: The survey covered 312 women aged 38-75 years. Menstrual status of the surveyed women was established according to WHO guidelines based on answers to a questionnaire, and three groups were discriminated: women in the premenopausal period (group 1), in the perimenopausal period (group 2), and in the postmenopausal period (group 3). The following anthropomological measurements were taken: body height, body mass, waist and hip circumference, and thickness of 6 skinfolds. Their results enabled evaluating the somatic built of women in the separated groups. Fatty tissue distribution was determined based on TER distribution index calculated as a ratio of the sum of trunk skinfolds (TSS) to the sum of extremity skinfolds (ESS). Body composition of the women, including percentage of body fat, lean body mass, soft tissue mass, and total body water, was assessed using an IOI 353 analyzer by JAWON MEDICAL. In addition, percentages of women with underweight, normal content of fatty tissue, and these with overweight and obesity were calculated. The WHR index was computed in the case of obese women. Results: The highest values of body mass, hip circumference and most of the skinfolds were determined in the perimenopausal group, whereas the postmenopausal women were characterized by the highest percentage of body fat (PBF) and by the lowest contents of lean tissue, soft tissue, and total water content in the body. The highest percentage of obese women was found in the postmenopausal group, including 40% of them having visceral type obesity. The occurrence of the menopause contributed to changes in fatty tissue distribution, causing its shift from extremities toward the trunk. Conclusions: The study showed differences in the somatic built and body composition in groups of women distinguished based on their menstrual status. PMID- 29519122 TI - Colorimetric Sensor Array for Discrimination of Heavy Metal Ions in Aqueous Solution Based on Three Kinds of Thiols as Receptors. AB - In the present work, we report a novel colorimetric sensor array for rapid identification of heavy metal ions. The sensing mechanism is based on the competition between thiols and urease for binding with the metal ions. Due to the different metal ion-binding abilities between the thiols and urea, different percentages of urease are free of metal ions and become catalytically active in the presence of varied metal ions. The metal ion-free urease catalyzes the decomposition of urea releasing ammonia and changing the pH of the analyte solution. Bromothymol blue, the pH indicator, changes its color in response to the metal-caused pH change. Three different thiols (l-glutathione reduced, l cysteine, and 2-mercaptoethanol) were used in our sensor array, leading to a unique colormetric repsonse pattern for each metal. Linear discriminant analysis (LDA) was employed to analyze the patterns and generate a clustering map for identifying 11 species of metal ions (Ni2+, Mn2+, Zn2+, Ag+, Cd2+, Fe3+, Hg2+, Cu2+, Sn4+, Co2+, and Pb2+) at 10 nM level in real samples. The method realizes the simple, fast (within 30 s), sensitive, and visual discrimination of metal ions, showing the potential applications in environmental monitoring. PMID- 29519123 TI - In Silico Investigations of Calcium Phosphate Mineralization in Extracellular Vesicles. AB - Calcification in bone, cartilage, and cardiovascular tissues involves the release of specialized extracellular vesicles (EVs) that promote mineral nucleation. The small size of the EVs, however, makes molecular level studies difficult, and consequently uncertainty exists on the role and function of these structures in directing mineralization. The lack of mechanistic understanding associated with the initiators of ectopic mineral deposition has severely hindered the development of potential therapeutic options. Here, we used multiscale molecular dynamics simulations to investigate the calcification within the EVs. Results show that Ca2+-HPO42- and phosphatidylserine complexes facilitate the early nucleation. Use of coarse-grained simulations allows investigations of Ca2+-PO43- nucleation and crystallization in the EVs. Systematic variation in the ion-to water ratio shows that the crystallization and growth strongly depend on the enrichment of the ions and dehydration inside the EVs. Our investigations provide insights into the role of EVs on calcium phosphate mineral nucleation and growth in both physiological and pathological mineralization. PMID- 29519124 TI - Selective Membrane Complexation and Uranium Isotopes Analysis in Tap Water and Seawater Samples. AB - The complexation of 238U and 234U in tap water and seawater after the use of a selective membrane was examined. At the first step, many ligands were used for original membranes preparation and their yields in uranium analysis were evaluated by X-ray fluorescence, in order to select the ligand with the highest uranium selectivity in water samples. At the second step the new prepared membrane was used for uranium analysis by alpha-spectrometry. Various factors were tested for a more effective uranium binding such as a membrane's active surface, water sample volume, equilibration time, and stirring during the process. After membrane complexation, uranium was separated by anion exchange and electroplated onto stainless steel plates in order to prepare suitable alpha-ray sources; these sources were measured by alpha-spectrometry and gave high chemical uranium recoveries and very good energy resolution spectra. The method can successfully be applied even for relatively small sample volumes and seawater samples. PMID- 29519125 TI - Computational Modeling of Stapled Peptides toward a Treatment Strategy for CML and Broader Implications in the Design of Lengthy Peptide Therapeutics. AB - The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia, and although several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed protein, known as CCmut3, is able to produce a dominant negative inactivating effect on Bcr-Abl kinase by preferentially oligomerizing with the N-terminal coiled-coil oligomerization domain of Bcr-Abl (Bcr-CC) to effectively reduce the oncogenic potential of Bcr-Abl. However, the sheer length of the CCmut3 peptide introduces a high degree of conformational variability and opportunity for targeting by intracellular proteolytic mechanisms. Here, we have examined the effects of introducing one or two molecular staples, or cross-links, spanning i, i + 7 backbone residues of the CCmut3 construct, which have been suggested to reinforce alpha-helical conformation, enhance cellular internalization, and increase resistance to proteolytic degradation, leading to enhanced pharmacokinetic properties. The importance of optimizing staple location along a highly tuned biological construct such as CCmut3 has been widely emphasized and, as such, we have employed in silico techniques to swiftly build, relax, and characterize a large number of candidates. This approach effectively allowed exploring each and every possible staple location along the peptide backbone so that every possible candidate is considered. Although many of the stapled candidate peptides displayed enhanced binding characteristics for Bcr-CC and improved conformational stability in the (Bcr-CC) bound form, simulations of the stapled peptides in the unbound form revealed widespread conformational variability among stapled candidates dependent on staple type and location, implicating the molecular replacement of helix-stabilizing residues with staple-containing residues in disrupting the native alpha-helical conformation of CCmut3, further highlighting a need for careful optimization of the CCmut3 construct. A candidate set has been assembled, which retains the native backbone alpha-helical integrity in both the bound and unbound forms while providing enhanced binding affinity for the Bcr-CC target, as research disseminated in this manuscript is intended to guide the development of a next-generation CCmut3 inhibitor peptide in an experimental setting. PMID- 29519126 TI - Design of New Bridge-Ring Energetic Compounds Obtained by Diels-Alder Reactions of Tetranitroethylene Dienophile. AB - The density functional theory method was employed to calculate three-dimensional structures for a series of novel explosophores. The design of new molecules (DA1 DA12) was based on the bridge-ring structures that could be formed via Diels Alder (DA) reaction of selected nitrogen-rich dienes and tetranitroethylene dienophile. The feasibility of the proposed DA reactions was predicted on the basis of the molecular orbital theory. The strong interactions between the HOMO of dienes, with electron-donating groups (Diene2, Diene6, and Diene8), and the LUMO of tetranitroethylene dienophile suggested thermodynamically favorable formation of the desired DA reaction products. In addition to molecular structures of the explored DA compounds, their physicochemical and energetic properties were also calculated in detail. Due to compact bridge-ring structures, new energetic molecules have highly positive heats of formation (up to 1124.90 kJ.mol-1) and high densities (up to 2.04 g.cm-3). Also, as a result of all-right ratios of nitrogen and oxygen, most of the new compounds possess high detonation velocities (8.28-10.02 km.s-1) and high detonation pressures (30.87-47.83 GPa). Energetic compounds DA1, DA4, and DA12 exhibit a superior detonation performance over widely used HMX explosive, and DA5, DA7, and DA10 could be comparable to the state-of-the-art CL-20 and ONC explosives. Our proposed designs and synthetic methodology should provide a platform for the development of novel energetic materials with superior performance. PMID- 29519127 TI - In Vivo Real-Time Monitoring System Using Probe Electrospray Ionization/Tandem Mass Spectrometry for Metabolites in Mouse Brain. AB - Recent improvements in ambient ionization techniques combined with mass spectrometry has enabled to achieve real-time monitoring of analytes of interest, even for biogenic molecules in living animals. Here, we demonstrate a newly developed system for in vivo real-time monitoring of metabolites in a living mouse brain. It consists of a semiautomated manipulation system and a unique probe electrospray ionization unit, which uses an extremely thin solid needle (tip dia.: 700 nm) for direct sampling and ionization, coupled to a conventional tandem mass spectrometer. The system successfully monitored 8 cerebrum metabolites related to central energy metabolism in an isoflurane-anesthetized mouse in real time with a 20 s interval. Moreover, our system succeeded in capturing dynamics of energy metabolism in a mouse administered with cannabinoid type-1 receptor agonist, which is known to disrupt cerebrum energy metabolism. The present system now opens the door to the next stage of cutting-edge technique in achieving in vivo real-time monitoring. PMID- 29519128 TI - Cumulative childhood interpersonal trauma is associated with reduced cortical differentiation between threat and non-threat faces in posttraumatic stress disorder adults. AB - OBJECTIVE: Posttraumatic stress disorder and childhood trauma frequently co occur. Both are associated with abnormal neural responses to salient emotion stimuli. As childhood trauma is a risk factor for posttraumatic stress disorder, differentiating between their neurophysiological effects is necessary to elucidate the neural pathways by which childhood trauma exposure contributes to increased posttraumatic stress disorder risks. METHODS: Face-specific N170 evoked response potentials for backward-masked (non-conscious) and conscious threat (fear, angry) and non-threat (happy) faces were measured in 77 adults (18-64 years old, 64% women, 78% right-handed) symptomatic for posttraumatic stress disorder. Differences in N170 peak amplitudes for fear-versus-happy and angry versus-happy faces at bilateral temporo-occipital (T5, T6) sites were computed. The effect of cumulative exposure to childhood interpersonal trauma, other childhood trauma, adult trauma, depression and posttraumatic stress disorder symptom severity on the N170 response was assessed using hierarchical multiple regression analyses. RESULTS: T5 N170 peak amplitudes for non-conscious fear versus-happy faces were inversely related to cumulative childhood interpersonal trauma after accounting for socio-demographic, clinical symptom and other trauma factors. Posttraumatic stress disorder Avoidance was positively associated with N170 peak amplitudes for non-conscious fear-versus-happy faces, primarily due to reduced N170 responsivity to happy faces. CONCLUSION: Childhood interpersonal trauma exposure is associated with reduced discrimination between fear and happy faces, while avoidance symptom severity is associated with dampened responsivity to automatically processed happy faces in posttraumatic stress disorder adults. Results are discussed in terms of the likely contributions of impaired threat discrimination and deficient reward processing during neural processing of salient emotion stimuli, to increased risks of posttraumatic stress disorder onset and chronicity in childhood interpersonal trauma-exposed adults. PMID- 29519129 TI - Quantitative Analysis of Directionality in Mammalian Karyotype Evolution. AB - The ancestral mammalian karyotype had been hypothesized to have had 2n ~ 80 (the "fusion hypothesis"), 2n = 6-14 (the "fission hypothesis") or a diploid number close to the present mode (the "modal hypothesis"). The fusion hypothesis has long been the dominant paradigm in the study of karyotype evolution, but recent evidence favors the fission hypothesis, and our analysis also strongly supports fission as the predominant rearrangement compared to fusion. To formalize our analysis, we first define $$?overline A$$ chromosomes as a group containing both acrocentrics and telocentrics, and $$?overline M$$ chromosomes as all the rest. Given this dichotomy, we then divide pericentric inversions into three types according to whether they convert $$?overline A$$ chromosomes to $$?overline M$$ , $$?overline M$$ to $$?overline A$$ or make no interchange. Only the first two types, denoted p.i. $$(?overline {AM})$$ and p.i. $$(?overline {MA})$$ , are important for the analysis. If fusion predominates, the direction of karyotype evolution is determined by the overall joint action of centric fusions and p.i. $$(?overline {MA})$$ (the "fusion cycle"), whereas, if fission predominates, the chief rearrangements are fission and p.i. $$(?overline {AM})$$ (the "fission cycle"). The necessary predominance of p.i. $$(?overline {MA})$$ over p.i. $$(?overline {AM})$$ in the fusion cycle makes it extremely unlikely on a priori grounds that this cycle has been very important in mammalian karyotype evolution, because a probabilistic analysis shows that p.i. $$(?overline {AM})$$ should occur many times more often than the reverse rearrangement, especially when the chromosome number is low. Chromosomes will therefore seldom be available for fusion. On the other hand, given duplication of both heterochromatic and centromeric material, there are no obstacles to the operation of the fission cycle. The modal hypothesis is also implausible on a priori grounds because of the many fusions required for most groups. We next define the karyograph as a graph on which karyotypes are plotted in terms of chromosome number (2n) versus arm number (2AN). We determine 2AN by counting one for each $$?overline A$$ and two for each $$?overline M$$ chromosome. Robertsonian changes each alter 2n by one while leaving 2AN constant while p.i. $$(?overline AM)$$ and p.i. $$(?overline MA)$$ do the reverse. An extensive karyograph analysis of the known mammalian karyotypes shows that there is little correlation between karyotypic and morphological level under any of the three hypotheses, and that there is a strong tendency for linear patterns to emerge when families are plotted separately. This linearity consists of either vertical or horizontal lines on the karyograph, or some combination of the two. Such linearity would be unexpected if the fusion cycle dominated mammalian karyotype evolution, but is readily understandable under the fission cycle as resulting from the development of synchrony between large sections of the genome. This synchrony can develop readily under the fission cycle in that fission produces two $$?overline A$$ chromosomes constrained to evolve by inversion for some time. The resulting $$?overline M$$ chromosomes would later become available for fission following duplication of centromeric material and give rise to four $$?overline A$$ chromosomes, again constrained to evolve by inversion for a while also. The frequently observed linearity of family karyograph distributions, and the above argument concerning the development of synchrony, suggests that mammalian karyotypes tend to follow an upwardly zig-zag course (with occasional "back eddies" by centric fusion) during evolution when plotted on the karyograph. PMID- 29519131 TI - Spatial Heterogeneity, Indirect Interactions, and the Coexistence of Prey Species. AB - Predation may generate patterns in the structure of communities similar to those produced by competition. The potential role of spatial heterogeneity in promoting the coexistence of prey species is explored with both analytical and graphical models. In these models, prey interact indirectly through their effect on predator numbers: an interaction that leads to "apparent competition" and a problem in species coexistence. A model of prey coexistence in a homogeneous habitat is explored. If prey grow logistically, prey abundance is measured by the effect prey have on predator growth, and the predator consumes prey in a finegrained manner, the criterion for species k to remain in the community takes a simple form: its sensitivity to predation (ak/rk) cannot exceed the average sensitivity to predation of the entire community, ( $$?overline {a/r}$$ ), divided by a measure of the intensity of predation on the community (Delta). At high Delta, species must have very similar values for ai/ri to coexist. This suggests that in spatially homogeneous environments, prey coexistence is difficult to achieve at high intensities of predation. There are two distinct ways in which spatial segregation may promote prey coexistence. First, habitat selection by the predator may provide each prey with an implicit refuge in the presence of the alternative prey, because predators will tend to leave a habitat in which their foraging yields are relatively low. If predators can select their habitats optimally without cost, and without interference from other predators, it is shown that at equilibrium no prey suffers a reduction in density because other prey are present in the diet. Nonoptimal habitat selection or interference between predators makes prey that have either low intrinsic growth rates (ri) or high rates of predator attack (ai) vulnerable to density reductions or extinction, as a result of predator "spillover" between patches. Second, if prey are spatially segregated, the predator population may be broken into two, partially independent subpopulations coupled by random predator movement. If each prey grows exponentially in the absence of predation, the permissible difference in their sensitivities to predation (ai/ri) is bounded by a measure of spatial coupling; the more tightly the two patches are linked by predator movement, the more similar the values for ai/ri must be if the prey are to continue to coexist. This model also provides a simple illustration of how spatial heterogeneity may stabilize an otherwise unstable predator-prey system. The evolutionary stability of segregation between prey is briefly discussed. Even if habitat partitioning relaxes apparent competition between prey occupying separate patches, the segregational pattern itself may persist because of apparent competition within each patch. Several examples from field studies suggest that habitat partitioning and the movement behavior of both predators and prey are important factors affecting coexistence in prey communities. PMID- 29519132 TI - mbtJ: an iron stress-induced acetyl hydrolase/esterase of Mycobacterium tuberculosis helps bacteria to survive during iron stress. AB - AIM: mbtJ from Mycobacterium tuberculosis H37Rv is a member of mbt A-J operon required for mycobactin biogenesis. MATERIALS & METHODS: The esterase/acetyl hydrolase activity of mbtJ was determined by pNP-esters/native-PAGE and expression under iron stress by quantitative-PCR. Effect of gene on growth/survival of Mycobacterium was studied using antisense. Its effect on morphology, growth/infection was studied in Mycobacterium smegmatis. RESULTS: It showed acetyl hydrolase/esterase activity at pH 8.0 and 50 degrees C with pNP butyrate. Its expression was upregulated under iron stress. The antisense inhibited the survival of bacterium during iron stress. Expression of mbtJ changed colony morphology and enhanced the growth/infection in M. smegmatis. CONCLUSION: mbtJ, an acetyl-hydrolase/esterase, enhanced the survival of M. tuberculosis under iron stress, affected the growth/infection efficiency in M. smegmatis, suggesting its pivotal role in the intracellular survival of bacterium. PMID- 29519133 TI - Effect of Fentanyl Nasal Packing Treatment on Patients With Acute Postoperative Pain After Nasal Operation: A Randomized Double-Blind Controlled Trial. AB - PURPOSE: Nasal packing is an option for bleeding control after endoscopic sinus surgery and septoplasty. Although new packing materials have been developed, patients still suffer from pain and require additional analgesics treatments. In this study, a prospective, randomized, and double-blind controlled trial was designed to evaluate the effect of fentanyl-soaked packing on pain after endoscopic sinus surgery and septoplasty. METHODS: One hundred fifty-two patients who underwent nasal surgeries due to chronic rhinosinusitis or nasal septal deviation were enrolled in this study. At the end of operation, 50 mcg fentanyl soaked biodegradable synthetic polyurethane foams packing Nasopore or Merocel were applied to a group of 79 patients, and saline-soaked ones were applied to another group of 73 patients. To evaluate the influence of fentanyl on postoperative nasal pain, patients' conditions were assessed via means of Numeric Rating Scale, patient satisfaction, and Ramsay Sedation Scale. In addition, symptoms of headache or sore throat and any signs of cardiopulmonary-relevant indicators were monitored. RESULTS: The fentanyl group had significantly decreased Numeric Rating Scale and increased patient satisfaction in every operation type for the majority of postoperative time periods ( P < .05) with reduced postoperative headache and sore throat compared to the control group. The fentanyl group showed a higher score on Ramsay Sedation Scale than the control group ( P < .05 in group including endoscopic sinus surgery). There were no significant differences in cardiopulmonary-relevant indicators between the 2 groups ( P > .05). CONCLUSION: Fentanyl group showed significantly reduced postoperative pain without serious adverse effects. We suggest that topical fentanyl application to nasal packs can be a useful method to reduce pain during the early postoperative period after endoscopic sinus surgery and septoplasty. PMID- 29519134 TI - High-Density Otologic Camps in Regions of Sparse Expertise. AB - : Aims/Purpose: When 2 models of otologic surgery instruction in Ethiopia are compared, high-density otologic surgery campaigns are more effective for accelerated skills transfer in areas of sparse expertise than the standard outpatient clinic/OR model. METHODS: A continuously operating otolaryngology/head and neck surgery department in a large public hospital is compared with a nonprofit specialty hospital where outpatients are selected for weeklong surgical campaigns. The number and variety of otologic visits and operations in each setting, presence of expert supervision, and resident-trainees' surgical progress were tallied. RESULTS: The public hospital saw 84 otologic operations in 1 full year. Meanwhile, the ear specialty surgical campaign site saw 185 otologic operations in 6 surgical campaign weeks. All operations at both sites were performed primarily by trainees. Experienced otologists supervised 40% of operations at the public hospital and 100% at the surgical campaign site. At the end of the year, none of the 10 resident-trainees in the public hospital were able to perform a simple underlay tympanoplasty, compared to 6 of 12 resident trainees in the campaign setting. CONCLUSIONS: Where otologic expertise is sparse, otologic surgical campaigns allow the most effective use of resources patient pathology, medical facilities, trainee attendance, and imported instructors. PMID- 29519140 TI - Risks of Population Extinction from Demographic and Environmental Stochasticity and Random Catastrophes. AB - Stochastic factors affecting the demography of a single population are analyzed to determine the relative risks of extinction from demographic stochasticity, environmental stochasticity, and random catastrophes. Relative risks are assessed by comparing asymptotic scaling relationships describing how the average time to extinction, T, increases with the carrying capacity of a population, K, under each stochastic factor alone. Stochastic factors are added to a simple model of exponential growth up to K. A critical parameter affecting the extinction dynamics is $$?tilde r,$$ the long-run growth rate of a population below K, including stochastic factors. If r is positive, with demographic stochasticity T increases asymptotically as a nearly exponential function of K, and with either environmental stochasticity or random catastrophes T increases asymptotically as a power of K. If r is negative, under any stochastic demographic factor, T increases asymptotically with the logarithm of K. Thus, for sufficiently large populations, the risk of extinction from demographic stochasticity is less important than that from either environmental stochasticity or random catastrophes. The relative risks of extinction from environmental stochasticity and random catastrophes depend on the mean and environmental variance of population growth rate, and the magnitude and frequency of catastrophes. Contrary to previous assertions in the literature, a population of modest size subject to environmental stochasticity or random catastrophes can persist for a long time, if r is substantially positive. PMID- 29519141 TI - Guide for Drug Selection During Pregnancy and Lactation: What Pharmacists Need to Know for Current Practice. AB - OBJECTIVE: To provide guidance for clinicians on risk assessment of medication use during pregnancy and lactation. DATA SOURCES: Authors completed PubMed searches to identify articles focused on the use of medications in pregnancy, including fetal development, drug transfer across the placenta, trimester exposure, chronic conditions in pregnancy, medications in lactation, and lactation and chronic disease. STUDY SELECTION AND DATA EXTRACTION: Articles were reviewed to provide overall guidance to medication selection during pregnancy. The following information was reviewed: medication use in pregnancy, including fetal development, drug transfer across the placenta, trimester exposure, chronic conditions in pregnancy, medications in lactation, and lactation and chronic disease. DATA SYNTHESIS: This article will provide an overview of medication safety considerations during pregnancy and lactation. Information was interpreted to help clinicians predict the potential risk and benefit in each patient to make an evidence-based decision. The article concludes with guidance on risk assessment and how pharmacists may support fellow health care providers and their patients when considering medication use. CONCLUSIONS: Information about the effects of medication use during reproductive periods is limited. With the removal of the Food and Drug Administration pregnancy categories, clinicians will be relying on pharmacists to aid in the appropriate selection of therapies for patients. It is critical that pharmacists keep abreast of resources available and be able to assess data to help prescribers and their patients. PMID- 29519142 TI - High burden of Aspergillus fumigatus infection among chronic respiratory diseases. AB - Aspergillus fumigatus (AF) is a ubiquitous fungus in our environment and causes severe airway disorders. Chronic respiratory diseases (CRDs) are a series of chronic airway and lung diseases. Although both are chronic disorders, however, the relationships between AF and CRDs are still unclear. Therefore, we examined 104 Aspergillus species (spp.) isolated samples in our hospital during three consecutive years to further elucidate the relationships between Aspergillus spp. and CRDs. Based on sample isolates, we then grouped these into two groups, AF and non-AF, to retrospectively analyse the clinical features and to clarify the relationships between AF and CRDs. Importantly, the manifestation of CRD was more frequent in the AF group than in the non-AF group ( p = 0.035). Among CRDs, lung fibrosis was more evident in the AF group ( p = 0.025). Moreover, diabetes mellitus was tended to be evident in AF group than non-AF group ( p = 0.035). In conclusion, CRDs, especially lung fibrosis, were highly prevalent in AF group than non-AF group. PMID- 29519145 TI - Changes in the Practice Patterns and Demographics of Ontario Dermatologists. AB - BACKGROUND: Changes in the practice patterns and demographics of Canadian dermatologists remain largely unknown and would be helpful in assessing the future practice of dermatology across Canada. OBJECTIVE: To assess changes in the population of Ontario dermatologists over time and the factors that influence their practice patterns, caseload, and the procedures they perform. METHODS: A retrospective population-based analysis was performed using comprehensive administrative data on Ontario Health Insurance Plan insured dermatology visits and procedures from April 1, 2009, to March 31, 2015. RESULTS: The number of dermatologists practicing in Ontario per 100 000 people increased from 1.52 (2009) to 1.62 (2014). During this period, the proportion of female dermatologists increased from 40% to 47%, and the proportion of male dermatologists decreased from 60% to 53%. The mean number of patient visits per dermatologist decreased from 6323 (2009) to 5877 (2014). Females saw a decrease from 4818 to 4181 visits, and males remained constant at 7274 to 7265 visits. Middle career dermatologists had more patient visits compared to those in their early or late career. A rural practice was associated with more patient visits compared to an urban one. The proportion of dermatologists providing nonemergency in-hospital patient services declined. The number of biopsies and malignant excisions performed increased. CONCLUSIONS: The number of dermatologists at the population level increased and the number of patient visits per dermatologist decreased. Career stage, physician sex, and practice location all affect the practice of dermatology. Future studies to assess underlying factors for these observations would be of value. PMID- 29519143 TI - Correlates of exchange sex among a population-based sample of low-income women who have heterosexual sex in Baltimore. AB - Sex exchange is associated with HIV and other morbidities yet has received little research, surveillance, and programmatic attention in the U.S. This study identified correlates of exchange sex and among low-income women in Baltimore, Maryland. Participants were recruited into the National HIV Behavioral Surveillance (NHBS) system in 2013 using respondent driven sampling (RDS) and completed a survey and HIV testing. The analytic sample (n = 253) consisted of women aged >=18 years who had recent (past year) heterosexual sex. Multivariable logistic regression identified correlates of recent exchange sex. Independently associated with recent exchange sex were history of injection drug use (adjusted odds ratio (AOR) = 3.4, 95% CI: 1.1-10.3), recent prescription painkiller use (AOR = 3.7, 95% CI: 1.4-9.9), recent crack/cocaine use (AOR = 6.6, 95% CI: 2.1 20.9), recent arrest (AOR = 4.1, 95% CI: 1.2-14.8), and recent consistent condom use (AOR 1.1; 95% CI: 1.0-1.3). Women who exchanged sex exhibited heightened social and structural vulnerability and substance use. These data demonstrate the need for further research examining the context of exchange sex among low-income women and synergies between substance use and HIV risk. PMID- 29519146 TI - The Successful Treatment of Elephantiasis Nostras Verrucosa With Ablative Carbon Dioxide Laser. AB - BACKGROUND AND OBJECTIVE: Elephantiasis nostras verrucosa (ENV) is a disfiguring skin condition that is difficult to treat. Existing treatment modalities serve to improve cosmesis or treat symptoms. Herein, we report a case of ENV with lymphocutaneous fistula successfully treated with ablative carbon dioxide laser. STUDY DESIGN/PATIENTS AND METHODS: A 57-year-old woman with biopsy-proven ENV with lymphocutaneous fistula was treated with ablative carbon dioxide laser to the symptomatic area of her right thigh in 3 treatment sessions over 6 months. RESULTS: The patient had resolution of lymphocutaneous drainage as well as 90% improvement in the appearance of ENV lesions at the 1-month follow-up visit. CONCLUSION: Ablative carbon dioxide laser may provide cosmetic, symptomatic, and medical benefit for patients with localized ENV. PMID- 29519147 TI - Biomechanical Cadaveric Evaluation of Partial Acute Peroneal Tendon Tears. AB - BACKGROUND: No clear guideline or solid evidence exists for peroneal tendon tears to determine when to repair, resect, or perform a tenodesis on the damaged tendon. The objective of this study was to analyze the mechanical behavior of cadaveric peroneal tendons artificially damaged and tested in a cyclic and failure mode. The hypothesis was that no failure would be observed in the cyclic phase. METHODS: Eight cadaveric long leg specimens were tested on a specially designed frame. A longitudinal full thickness tendon defect was created, 3 cm in length, behind the tip of the fibula, compromising 66% of the visible width of the peroneal tendons. Cyclic testing was initially performed between 50 and 200 N, followed by a load-to-failure test. Tendon elongation and load to rupture were measured. RESULTS: No tendon failed or lengthened during cyclic testing. The mean load to failure for peroneus brevis was 416 N (95% confidence interval, 351-481 N) and for the peroneus longus was 723 N (95% confidence interval, 578-868 N). All failures were at the level of the defect created. CONCLUSION: In a cadaveric model of peroneal tendon tears, 33% of remaining peroneal tendon could resist high tensile forces, above the physiologic threshold. CLINICAL RELEVANCE: Some peroneal tendon tears can be treated conservatively without risking spontaneous ruptures. When surgically treating a symptomatic peroneal tendon tear, increased efforts may be undertaken to repair tears previously considered irreparable. PMID- 29519148 TI - Tibialis Anterior Reconstruction With Hamstring Autograft Using a Minimally Invasive Approach. AB - BACKGROUND: Tibialis anterior tendon ruptures are rare and can cause significant dysfunction. Often, conservative measures are prescribed because of the morbidity of a tendon transfer as an operative solution. We present a novel reconstruction technique using hamstring autograft, which may obviate the need for local tendon transfer and long-term bracing. METHODS: Patients who underwent tibialis anterior reconstruction with hamstring autograft between 2011 and 2015 were screened for inclusion. Eight were included. Functional outcomes were assessed pre-and postoperatively using the Foot and Ankle Outcome Score (FAOS), Visual Analog Pain Scale (VAS), and Short-Form-12 (SF-12) general health questionnaire. Isokinetic testing using a dynamometer (Biodex System 4 Pro) was performed at 60 and 120 degrees/s, respectively, for inversion/eversion and plantarflexion/dorsiflexion on both ankles at a minimum of 6 months postoperatively to determine peak torque, average power, and total work. Range of motion (ROM) testing was also performed, using a goniometer, at a minimum of 6 months postoperatively. Average follow-up was 17.3 (6.0-40.0) months for strength testing and ROM testing, and 18.5 (12.0 26.0) months for functional outcome scores. RESULTS: Average postoperative functional scores improved for all tests. ROM was similar between the uninvolved and involved ankles for inversion/eversion and plantarflexion/dorsiflexion. Patients showed deficits in dorsiflexion strength in all measures tested and improvements in inversion strength. All patients were able to ambulate without a brace. CONCLUSION: Use of a hamstring autograft for tibialis anterior reconstruction resulted in good clinical outcomes. This procedure successfully restored ankle ROM postoperatively and tendon strength in inversion and dorsiflexion, with most patients showing little deficit when comparing their involved and uninvolved sides. LEVEL OF EVIDENCE: Level IV, Case series. PMID- 29519149 TI - Endoscopic Achilles Tendon Augmentation With Suture Anchors After Calcaneal Exostectomy in Haglund Syndrome. AB - BACKGROUND: Haglund syndrome is a common cause of heel pain. Risk for tendon detachment after calcaneoplasty can exist. Open Achilles tendon detachment, calcaneoplasty, bursectomy, pathologic tendon-tissue debridement, and tendon reattachment of the Achilles tendon is a common surgical management of Haglund syndrome combined with insertional Achilles tendinopathy. The aim of this study was to describe the endoscopic calcaneoplasty and anchor suture augmentation of the Achilles insertional area, and the results obtained in patients with an increased risk of Achilles tendon rupture after calcaneoplasty. METHODS: Between 2012 and 2015, endoscopic calcaneal ostectomy and suture anchor augmentation was performed in 12 patients. Mean age was 44.8 years (range, 35-52 years), and mean follow-up was of 33.5 months (range, 21-46 months). RESULTS: The mean AOFAS score increased from 70 preoperatively (range, 55-85) to 92 (range, 63-100) at final follow-up. The mean VISA-A questionnaire increased from 34 preoperatively (range, 15-63) to 92 (range, 30-100) at follow-up. No major complications were reported. All patients returned to their daily activities without limitations, but 2 described complaints with sports activity. CONCLUSION: Endoscopic calcaneoplasty and tendon augmentation with suture anchor for the treatment of Haglund syndrome was a reproducible and safe technique that offered the advantages of the endoscopic technique. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29519156 TI - The effect of attentional bias modification training on food intake in overweight and obese women. AB - This study modified food attentional biases via computerized attentional bias modification training and examined the effects on food intake. Overweight women were randomly allocated to (1) direct attention away from food ("attentional training"), (2) direct attention at random to food or neutral ("placebo"), or (3) no training ("control"). Individuals then completed a taste test. Those in the attentional-training consumed on average 600 kJ less of total food compared to the placebo. Those in the attentional-training had a reduction in food attentional bias compared to the placebo group, when controlling for executive function. Attentional-training seems to reduce high-calorie intake in overweight women. PMID- 29519157 TI - Cardioprotective effect of vitamin D2 on isoproterenol-induced myocardial infarction in diabetic rats. AB - OBJECTIVES: To assess the effect of vitamin D2 and to elucidate the underlying mechanisms on acute myocardial injury induced by isoproterenol (ISO) in diabetic rats. METHODS: Rats were divided into control rats, diabetic rats (DM), diabetic rats received ISO (DM-ISO), and diabetic rats pretreated with vitamin D2 and received ISO (DM-D2-ISO). RESULTS: Vitamin D2 pretreatment significantly decreased fasting glucose and myocardial malondialdehyde, associated with increased insulin, myocardial glutathione and superoxide dismutase in DM-D2-ISO versus DM-ISO. The serum triglycerides, total cholesterol, and LDL were significantly decreased, along with increased HDL and adiponectin. Poly-ADP ribose polymerase, cyclooxygenase-2, tumour necrosis factor alpha, interleukin-6, caspase-3, BAX, and p53 were significantly downregulated in myocardium of DM-D2 ISO versus DM-ISO. Histological studies showed diminished inflammatory cells infiltration in myocardium of DM-D2-ISO versus DM-ISO. CONCLUSION: Vitamin D2 ameliorates hyperglycaemia, dyslipidaemia, redox imbalance, inflammatory and apoptotic processes, protecting the myocardium of diabetic rats against acute myocardial infarction. PMID- 29519158 TI - CD133-targeted delivery of self-assembled PEGylated carboxymethylcellulose-SN38 nanoparticles to colorectal cancer. AB - Poor aqueous solubility of chemotherapeutics such as SN38 (7-ethyl-10 hydroxycamptothecin) and the associated systemic adverse effects are serious limitations of their clinical use. To improve the drug delivery efficiency of such compounds, they were covalently conjugated to hydrophilic macromolecular carriers that specifically deliver the drug moiety to the tumour cells. In the current study, we developed a PEGylated acetylated carboxymethylcellulose conjugate of SN38 which was covalently attached to an aptamer against a cancer stem cell marker, CD133. Then, the designed nanoplatform was used to specifically deliver SN38 to colorectal cancer cells. The results demonstrated that the synthesized conjugate was self-assembled to nanoparticles with 169 nm in size and poly dispersity index of 0.11. Besides, the targeted self-assembled nanoparticles could significantly enhance the cellular uptake by CD133-expressing HT29 cell line confirmed by fluorescent microscopy and flow cytometry. Moreover, our results revealed that the targeted self-assembled nanoconjugate exhibited significantly lower IC50 in HT29 cells overexpressing CD133 compared to non targeted self-assembled nanoconjugate. The promising data suggest that the prepared targeted self-assembled drug conjugate nanoparticles possess the potential to offer the desirable physicochemical properties thereby enhancing the solubility and the therapeutic index of poorly soluble cytotoxic agents. PMID- 29519159 TI - An evidence-based review of pregabalin for the treatment of fibromyalgia. AB - OBJECTIVES: Pregabalin, an alpha2-delta agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies and post-hoc analyses of clinical study data. METHODS: PubMed was searched using the term "pregabalin AND fibromyalgia" and the Cochrane Library with the term "pregabalin". Both searches were conducted on 2 March 2017 with no other date limits set. RESULTS: Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, two-way crossover and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1-2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics. CONCLUSIONS: Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated. PMID- 29519160 TI - Corrigendum for GNPL: 1402309. PMID- 29519161 TI - Repeating probability of authors with retracted scientific publications. AB - Both the scientific community and the general public have expressed concern over scientific misconduct. The number of retracted articles has increased dramatically over the past 20 years and now comprises about .02% of the 2 million articles published each year. Retraction of publications available in large public databases can be analyzed as an objective measure for scientific misconduct and errors. In this project, we analyzed retractions of scientific publications using the Web of Science (WoS) and PubMed databases. We found that a power law is applicable to distributions of retracting authors and retracted publications with exponents of about -.6 and -3.0, respectively. Application of a power-law model for retracted publications implies that retraction is not a random event. Analysis of the retraction distributions suggests that a small fraction (1-2%) of retracting authors with ?5 retractions are responsible for around 10% of retraction. The probabilities for their repeating retraction are calculated using a statistical model: 3-5% likelihood of repeat retraction for authors with a single retraction at five years after the latest retraction and 26 37% for authors with five retractions at five years after the latest retraction. By focusing on those with repeated retractions, this analysis could contribute to identification of measures to reduce such repetition of retractions. PMID- 29519162 TI - Does the graft-tunnel friction influence knee joint kinematics and biomechanics after anterior cruciate ligament reconstruction? A finite element study. AB - Graft tissues within bone tunnels remain mobile for a long time after anterior cruciate ligament (ACL) reconstruction. However, whether the graft-tunnel friction affects the finite element (FE) simulation of the ACL reconstruction is still unclear. Four friction coefficients (from 0 to 0.3) were simulated in the ACL-reconstructed joint model as well as two loading levels of anterior tibial drawer. The graft-tunnel friction did not affect joint kinematics and the maximal principal strain of the graft. By contrast, both the relative graft-tunnel motion and equivalent strain for the bone tunnels were altered, which corresponded to different processes of graft-tunnel integration and bone remodeling, respectively. It implies that the graft-tunnel friction should be defined properly for studying the graft-tunnel integration or bone remodeling after ACL reconstruction using numerical simulation. PMID- 29519163 TI - Ultrasonography and clinical examination of knee injuries in pre- and post- menarche dancers. AB - This study aimed at evaluating whether the prevalence of knee injuries and morphological features are different among pre-and-post menarche dancers; Sixty seven pre-and-post menarche dancers were screened for anthropometric parameters; knee laxity; patella femoral pain syndrome (PFPS), pathologies and anatomical structure of the knees. Both groups showed a high and similar prevalence of PFPS. The post-menarche dancers produced a significantly higher rate of Tanner stages 3 4 (p = .010), greater weight (p < .001) higher BMI (p = .003); and, higher prevalence of MCL pathology, pes planus, and scoliosis compared with pre-menarche dancers (p < .05). The pre-menarche dancers started dance practice earlier (p = .008); and, showed significantly higher prevalence of lateral laxity, patellar laxity, positive Lachman test and positive Drawer test compared with post menarche dancers (p < .05). Interactions (menarche yes/no by PFPS no/one leg/both legs) were found for BMI (p = .044; eta2 = .187), trochlear cartilage thickness (p = .020; eta2 = 0.121) and tip of patella - trochlear groove distance (p = .024; eta2 = .150). Pre-and-post-menarche female dancers demonstrated similar prevalence of knee injuries, with different body morphology. PMID- 29519164 TI - Development of functional docetaxel nanomicelles for treatment of brain glioma. AB - The efficacy of anticancer drugs is rather limited in the treatment of brain glioma due to the hindrance of the blood-brain barrier (BBB). Herein, we reported an easy formulation of functional docetaxel nanomicelles for the treatment of brain glioma using a graft copolymer soluplus as basic material through dual modifications with a glucose-lipid derivative and a dequalinium-lipid derivative. The studies were performed on brain glioma U87MG cells, in vitro BBB models and brain glioma-bearing nude mice. The functional docetaxel nanomicelles were approximately 100 nm. The results demonstrated that the functional docetaxel nanomicelles could transport across the BBB, enhance the cellular uptake, target to the mitochondria, induce the apoptosis, increase the cytotoxicity in the brain glioma cells, and extend survival span of the brain glioma-bearing mice. The action mechanisms were associated with dual-modifications by the glucose-lipid derivative and the dequalinium-lipid derivative, both of which are beneficial for the transport across the BBB. Furthermore, the modification with dequalinium lipid derivative was able to target to the brain glioma cells and to the mitochondria. In conclusion, the functional docetaxel nanomicelles would be a promising formulation for the treatment of brain glioma, deserving further development for clinical trials. PMID- 29519165 TI - Probing characteristics of cancer cells cultured on engineered platforms simulating different microenvironments. AB - In this study, we demonstrate cell culture platforms that can provide a microenvironment similar to in vivo conditions so that in vivo-compatible drug testing results can be obtained from the in vitro experiments. To realize such in vivo microenvironment-mimetic platforms, different culture platforms such as a three-dimensional (3D) cell aggregate film, fluidic environment within a microfluidic system or extracellular matrix (ECM) coating were established. The tumor cell growth rate and sensitivity to doxorubicin (DOX) were studied using the glioblastoma cell line T98G. When 3 D spheroids were cultured, they grew significantly slower than under other culture conditions. When the cells were treated with DOX, the anticancer drug could not efficiently penetrate the 3 D spheroids to inhibit cell growth. When cultured on the Matrigel-coated culture vessel, T98G cells grew even in the presence of DOX, demonstrating chemoresistance. Nonetheless, in the 2D culture plate and in the microfluidic chip, cell growth decreased with DOX treatment and the binding ability was lost. These results indicate that the cells reacted differently to the same anticancer drug depending on the culture microenvironment. We believe that the development of a more physiologically relevant tumor cell culture platform will lead to more reliable antitumor drug responses. PMID- 29519166 TI - Quantifying the clinical aspects of the cauda equina syndrome - The Cauda Scale (TCS). AB - AIM: To quantify the clinical findings in patients with potential cauda equina syndrome (CES). METHODS: Three domains were selected: bladder function (B), perianal sensation (S) and anal tone/squeeze (T). A quantified score was given to symptoms and signs in each domain. RESULTS: The lowest score in each domain and the lowest sum score (the most severe lesion) is 0. The best sum score is 9 (the normal patient). CONCLUSION: TCS can improve the clinical assessment and management of patients with possible CES and improve communication between the doctors who are called upon to assess and treat such patients. PMID- 29519167 TI - Social Support, Health, and Health Care Access Among Latino Immigrant Men in an Emerging Community. AB - OBJECTIVE: To determine the association of social support with alcohol abuse, depression, and health care access among Latino immigrant men in an emerging Latino community (an area with a small yet growing Latino population). METHODS: Cross-sectional baseline data of 140 men prior to a participatory male-to-male community health worker intervention among Latino immigrants were analyzed using logistic regression. Community health workers recruited community participants in Western Pennsylvania between 2011 and 2013. RESULTS: Participants constituted a vulnerable group: 47% had not finished high school, 36% had moderate to severe depression, and 30% reported binge drinking in the past month. Health care access was low (insurance = 6%, usual source = 20%). In multivariable logistic regression high social support was associated with less binge drinking (odds ratio [OR] = 0.44; 95% confidence interval [CI] [0.20, 0.98]) and lower depression (OR = 0.22; 95% CI [0.09-0.54]). Social support was associated with having a dentist visit but not with other health care access measures. CONCLUSIONS: Results indicate that the role of social support seems important for drinking and depression but remains controversial for health care access. It raises the hypothesis that low social support may be one of the mechanisms for the increase in drinking that happens after immigration. PMID- 29519168 TI - Acute carbon monoxide toxicity in a paediatric cohort: analysis of 10 boys poisoned during a scuba diving lesson. AB - BACKGROUND: Recent public health strategies have contributed towards a significant reduction in the incidence of carbon monoxide (CO) poisonings. When events do occur, symptoms can vary dramatically depending on the carboxyhaemoglobin level and individual factors. Most reports to date focus on individual cases or larger retrospective reviews of diverse cohorts. There are very few reports of CO exposure related to scuba diving activities. METHODS: We describe the clinical sequelae experienced by 10 children who were exposed to CO during a scuba diving lesson. We collate patient data in the context of a severely affected individual and employ exponential decay calculations to estimate half-life. RESULTS: Six of the patients exposed to CO were symptomatic. The most severely affected individual suffered multi-organ effects, including myocardial damage, and required intensive care unit admission. The remaining cohort demonstrated notable clinical variability. The half-life of carboxyhaemoglobin on high flow oxygen in this cohort was ~75 min, in line with previous estimates. CONCLUSION: This work described an uncommon clinical presentation, representing the largest single cohort of its kind. This work exemplifies the variable symptomatology of CO toxicity, of which clinicians should be alert to if patients fall ill after scuba diving. PMID- 29519169 TI - Bundling arrows: improving translational CNS drug development by integrated PK/PD metabolomics. AB - INTRODUCTION: Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species. PMID- 29519170 TI - DRESS syndrome: a detailed insight. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious and potentially fatal adverse effect to therapeutic medications. The incidence of this condition varies among different ethnicities because of the difference in the genetic makeup. Though fever, rash and eosinophilia are essential features for the diagnosis of this syndrome, these vary from patient to patient along with the involvement of various organs such as liver, kidney, lungs, pancreas, etc. Some of the atypical features are dysphagia, agranulocytosis, and chylous ascites. Phenytoin, phenobarbitone, carbamazepine, and allopurinol are the most common drugs responsible for developing this syndrome, although the list is fairly long. Among the criteria used for the diagnosis of DRESS syndrome, European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) criteria is the most commonly used one. The management of this syndrome involves early removal of the causative agent and treatment with anti-histamines and emollients in the mild form, corticosteroids in the moderate form and plasmapheresis in the severe form along with other alternatives drugs. Healthcare professionals should be more vigilant about the early manifestations of this syndrome, as early diagnosis and treatment improve outcomes considerably. PMID- 29519171 TI - Risks linked to accidental inoculation of humans with veterinary vaccines: a 7 year prospective study. AB - AIM: Accidental inoculation of humans with veterinary vaccines can lead to early and late complications. The aim of our study is to describe these complications and their risk factors. METHODS: Prospective observational study conducted from 2007 to 2014 at Angers University Hospital's Poison Control Centre. The endpoints examined were: early and late locoregional complications, surgical treatment, and absence from work. The statistical analysis was based on a multivariate analysis. DISCUSSION: The presence of mineral oil adjuvants, the injection of the vaccine under pressure and injection in joint and tendon of the hand significantly increased early locoregional complications and surgery but only the presence of mineral oil adjuvant increased significantly late locoregional complications at one month. Absence from work is significantly correlated to the site of injection and the presence of mineral oil adjuvant. CONCLUSION: It is important to know about the contents of the veterinary vaccine in order to anticipate early and late complications that may arise (particularly due to the presence of mineral oil adjuvants). Special attention must also be given do the site of injection. We think that any accidental injection of veterinary vaccine into humans, especially those containing mineral oils, must lead to an early medical consultation. This must also be indicated on the product. PMID- 29519172 TI - It was a very good year. PMID- 29519173 TI - Interprofessional training: Start with the youngest! A program for undergraduate healthcare students in Geneva, Switzerland. AB - AIMS: Demography of patients and complexity in the management of multimorbid conditions has made collaborative practice a necessity for the future, also in Switzerland. Since 2012, the University of Applied Sciences (UAS) and its Healthcare School as well as the University of Geneva (UG) with its Medical Faculty have joined forces to implement a training program in collaborative practice, using simulation as one of the main learning/teaching process. METHODS: The actual program consists of three sequential modules and totalizes 300 h of teaching and learning for approximately 1400-1500 students from six tracks (nutritionists, physiotherapists, midwives, nurses, technologists in medical radiology, physicians); in 2019 another hundred pharmacists will also be included. The main issues addressed by the modules are Module 1: the Swiss healthcare system and collaborative tools. Module 2: roles and responsibilities of the different health professionals, basic tools acquisition in team working (situation monitoring, mutual support, communication). Module 3: the axis of quality and safety of care through different contexts and cases. CONCLUSIONS: A very first evaluation of the teaching and learning and particularly on the aspects of acquisition of collaborative tools shows positive attitudes of students towards the implementation of this new training program. Furthermore, a pre-post questionnaire on teamwork aspects reveals significant modifications. PMID- 29519174 TI - Corrigendum. AB - Arenillas JF, Cortijo E, Garcia-Bermejo P, et al. Relative cerebral blood volume is associated with collateral status and infarct growth in stroke patients in SWIFT PRIME. J Cereb Blood Flow Metab. Epub ahead of print 1 January 2017. DOI: 10.1177/0271678X17740293 . This article was published online with the sixth author, David Liebeskind (Neurovascular Imaging Research Core, Department of Neurology, UCLA, USA), omitted. The full list and order of authors on the article is as follows: Juan F Arenillas, Elisa Cortijo, Pablo Garcia-Bermejo, Elad I Levy, Reza Jahan, David Liebeskind, Mayank Goyal, Jeffrey L Saver and Gregory W Albers Juan F Arenillas's affiliation should have read Neurovascular Research i3 Laboratory, Instituto de Biologia y Genetica Molecular, Consejo Superior de Investigaciones Cientificas (CSIC), Universidad de Valladolid, Valladolid, Spain. PMID- 29519175 TI - Universal 2 total wrist arthroplasty: high satisfaction but high complication rates. AB - : The Universal 2 total wrist arthroplasty is intended to alleviate wrist pain and restore function. There is limited evidence regarding its success and safety. We report outcomes in 48 wrists of 46 patients with Universal 2 arthroplasty between 2006 and 2014. We recorded range of motion of the operated wrist, patient satisfaction, complication and revision rates, and radiological appearances of the wrists with mean follow-up of 7 years (3.5 to 11 years). We found a significant improvement in DASH scores after surgery, with active range of wrist motion being 33 degrees flexion and 24 degrees extension. Thirty-nine patients would undergo the procedure again if he had similar wrist problems. Twenty-three patients had loosening of at least one component of the implant. Complications were found in 13 wrists; seven underwent revision. We conclude that the Universal 2 arthroplasty produces significant improvements in DASH scores and high levels of satisfaction of the patients. However, the surgery has a high complication rate. LEVEL OF EVIDENCE: IV. PMID- 29519176 TI - Stress response to ovariohysterectomy in rabbits: role of anaesthesia and surgery. AB - The aim of this study was to evaluate the neuroendocrine and inflammation response to laparoscopic total ovariohysterectomy (TOH) in rabbits, by comparing surgical stress markers of laparoscopic group with those of conventional open ovariohysterectomy and open ovariohysterectomy with pre-incisional local anaesthesia groups. Blood was sampled from 18 rabbits, of which six underwent laparoscopic TOH, six conventional open TOH and six conventional open TOH with pre-incisional local anaesthesia, 30 min before induction of anaesthesia (T0), immediately after skin incision (T1), 90 min postoperatively (T2), and 24 h postoperatively (T3). Cortisol and C-reactive protein serum, and adrenocorticothrophic hormone, tumour necrosis factor-a (TNF-a), adrenaline, noradrenaline and IL-6 plasma concentrations were evaluated. Laparoscopic TOH in rabbits has advantages over the open surgical technique because it causes less surgical stress response in terms of serum cortisol concentrations immediately after skin incision (p = .04), as well as plasma adrenaline (p = .035) and TNF-a (p = .047) concentrations 24 h postoperatively. Impact statement What is already known on this subject? Hysterectomy is the second most common surgery performed on women after caesarean section. Research has focussed on methods to modify the stress response associated with surgery. Various studies both in humans and animals, have demonstrated the less systemic, immunological and neurohormonal response of the laparoscopic technique, which is expressed by less elevated serum enzymes' and proteins' concentrations. However, other studies have documented that the systemic stress response after open hysterectomy is similar to that following laparoscopic surgery. What do the results of this study add? Laparoscopic total ovariohysterectomy in rabbits has advantages over the open surgical technique because it causes less surgical stress response in terms of serum cortisol concentrations, as well as plasma adrenaline and TNF-a concentrations during the first 24 h postoperatively. What are the implications are of these findings for clinical practice and/or further research? There were no significant differences between the groups in number of surgical stress markers (p > .05) perioperatively. We cannot exclude the possibility that a later increase of surgical stress response might take place after the first 24 h postoperatively. PMID- 29519177 TI - Knowledge, Attitudes, and Beliefs of Physicians and Other Health Care Providers Regarding Artificial Nutrition and Hydration at the End of Life. AB - OBJECTIVE: Despite the growing evidence against artificial nutrition and hydration (ANH) use among patients with advanced dementia, little is known about the perspectives of the health care team. This study examined the knowledge, attitudes, and beliefs of physicians and other health care providers regarding the use of ANH at the end of life (EOL). METHODS: A cross-sectional survey explored the provision of EOL care using a hypothetical case scenario of a patient with advanced dementia and dysphagia. Questionnaire items were analyzed using parametric and nonparametric approaches. RESULTS: In this sample of 323 respondents, statistical significance was found between physicians and other health care providers' views on ANH and its related beneficial effects or health outcomes in EOL care. DISCUSSION: Results indicate knowledge deficits in physicians and other health care professionals and highlight the need for comprehensive continuing education programs on EOL topics. CONCLUSION: Differences in knowledge, attitudes and beliefs regarding ANH in EOL among healthcare providers were observed and education regarding evidence based clinical guidelines are necessary. PMID- 29519178 TI - Trends of caesarean section rates in Turkey. AB - The aims of this study was to determine the trends in rates of caesarean sections in Turkey. The data source for this study was the Turkey Demographic and Health Survey (TDHS) 1993-1998-2003-2008-2013 conducted by Hacettepe University, Institute of Population Studies. Cross tables and binary logistic regression were used for analysis. It was found that the caesarean section rate, which was 14.3% in 1993, increased to 51.9% in 2013. The rate increased with maternal age and educational level at childbirth. The Caesarean section rate was higher in women who were under health insurance coverage, first time mothers, childbirth in the private health institutions, those staying in the Western region and urban areas, and having the highest level of wealth. This study aims to contribute to the literature of caesarean sections especially in developing countries, in which caesarean section has become a major healthcare issue. Impact Statement What is already known on this subject: Caesarean section is among the most widely practiced obstetric surgery worldwide. Previous studies have suggested that the rates of caesarean section were affected by the biological, genetic and medical factors. What the results of this study add: Besides the biological, genetic and medical factors, it is believed that social factors (income and social status, education, employment, etc.) play an important role on the caesarean section in developing countries. Although the laws on caesarean sections have been enforced since 2012 in Turkey, this study shows that there has been a significant increase in caesarean section between the 1993 and 2013 periods. The study also reveals that prohibiting caesarean sections, except in cases of medical necessity, is a problematic issue in the health system despite all efforts. What the implications are of these findings for clinical practice and/or further research: This study may be of interest for authorities and researchers in terms of showing the social factors associated with the caesarean section. PMID- 29519179 TI - The evolution of British neurosurgical selection and training over the past decade. AB - Selection of junior doctors into the British neurosurgical training program and subsequent speciality training have undergone several key changes over the past decade. Shift patterns in the era of the European Working Time Directive (EWTD) have had a major impact on surgical training. We discuss the national selection process, formalization of surgical simulation training and the need to encompass generic professional capabilities within the neurosurgical curriculum in order to create the "well-rounded surgeon". Future directions including hybrid cerebrovascular training, training in stereotactic radiosurgery, and dedicated training opportunities in spinal surgery. PMID- 29519180 TI - Intravenous lidocaine before caesarean section. PMID- 29519182 TI - Interactions among insulin resistance, inflammation factors, obesity-related gene polymorphisms, environmental risk factors, and diet in the development of gestational diabetes mellitus. AB - PURPOSE: The aim of this study was to investigate the correlations and interactions between the polymorphisms of insulin resistance-related genes (ADIPOQ rs2241766), inflammation factors (TNF-alpha rs1800629, IL-6 rs1800795), obesity-related genes (GNB3 rs5443, ADRB rs1042714), and risk factors for gestational diabetes mellitus (GDM) such as diet structure in the development of GDM. MATERIALS AND METHODS: This research was conducted among women who visited the third-affiliate hospital of Zhengzhou University for pregnancy checkups from 1 June 2014 to 30 December 2014. Based on the results of a 75-g glucose tolerance test (OGTT), 140 pregnant women with GDM were randomly selected as a part of the GDM group and140 healthy, pregnant women as part of the control group. Relevant clinical and laboratory data for the child and the mother including her pregnancy outcomes and the delivery mode were collected for the epidemiological survey. RESULTS: The results showed that risk factors for GDM are advanced age, the hepatitis B virus, family history of diabetes, high body mass index before pregnancy, and weight gain of >=10 kg before 24-week gestation. We found that diet structures were severely unbalanced. The polymorphisms rs2241766 and rs5443 were found to potentially be associated with GDM; moreover, a positive interaction was demonstrated between rs2241766 and age, and a negative interaction was demonstrated with weight gain of >=10 kg before 24-week gestation. CONCLUSION: Our findings demonstrate that both environmental risk factors and genetic background contribute to the development of GDM. PMID- 29519183 TI - Intracranial hemorrhage in the setting of posterior reversible encephalopathy syndrome: two case reports and a review. AB - Posterior reversible encephalopathy syndrome (PRES) is clinically characterized by seizures, changes in vision, altered mental status, and headache, with associated radiologic changes on brain imaging. Intraparenchymal hemorrhage is a rare complication of PRES and an atypical initial presentation of this condition. In this report, we discuss two patients who presented with multifocal cerebral hemorrhages that were later attributed to PRES. We further expand on the pathophysiology, management, and prognosis on patients with hemorrhagic PRES. Increased awareness of this complication of PRES is important in guiding prognostication and treatment. PMID- 29519181 TI - The protective effect of beta-casomorphin-7 via promoting Foxo1 activity and nuclear translocation in human lens epithelial cells. AB - PURPOSE: To investigate the protective effect of beta-casomorphin-7 (beta-CM-7) in oxidative stressed human lens epithelial cells (HLECs) and to explore the possible mechanism for oxidative stress in HLECs induced by high glucose. METHODS: We used HLECs to determine the effect of different concentrations of beta-CM-7 on cell viability by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H tetrazolimol/L bromide (MTT) assay. We used flow cytometry to determine the content of reactive oxygen species (ROS) induced by oxidative stress and a bioassay kit to determine the oxidant malondialdehyde (MDA) and antioxidant enzyme superoxide dismutase (SOD) levels. We used Western blotting and an immunofluorescence assay to determine the expression of Forkhead box o1 (Foxo1), SP1, and the related protein glutathione peroxidase (GSH-px) at the molecular biology level as well as their intracellular localization. RESULTS: The expression of Foxo1 and SP1 was weakly expressed when the glucose concentration was 40 mM/L, but was highly expressed when cells were pre-treated with an appropriate concentration of beta-CM-7. After pre-treatment with beta-CM-7, the cells treated with 40 mM/L glucose for 48 h showed Foxo1 was transferred to the nucleus, and the expression of SP1 was increased. The content of ROS and MDA in the HLECs that were pre-treated with beta-CM-7 was lower than in those that was not pre-treated (p <0.05). Accordingly, SOD was elevated in the cells pre-treated with beta-CM-7. The relative expression of GSH-px increased with increases of Foxo1 and SP1. CONCLUSION: beta-CM-7 protects HLECs from oxidative damage by upregulating the relative expression of Foxo1 and promoting Foxo1 nuclear translocation. PMID- 29519184 TI - Implementation of the Spanish ERAS program in bariatric surgery. AB - INTRODUCTION: The essence of Enhanced Recovery After Surgery (ERAS) programs is the multimodal approach, and many authors have demonstrated safety and feasibility in fast track bariatric surgery. According to this concept, a multidisciplinary ERAS program for bariatric surgery has been developed by the Spanish Fast Track Group (ERAS Spain). The aim of this study was to analyze the initial implementation of this Spanish National ERAS protocol in bariatric surgery, comparing it with a historical cohort receiving standard care. MATERIAL AND METHODS: A multi-centric prospective study was performed, including 233 consecutive patients undergoing bariatric surgery during 2015 and following ERAS protocol. It was compared with a historical cohort of 286 patients, who underwent bariatric surgery at the same institutions between 2013 and 2014 and following standard care. Compliance with the protocol, morbidity, mortality, hospital stay and readmission were evaluated. RESULTS: Bariatric techniques performed were Roux en-Y gastric bypass and sleeve gastrectomy. There were no significant differences in complications, mortality and readmission. Postoperative pain and hospital stay were significantly lower in the ERAS group. The total compliance to protocol was 80%. CONCLUSION: The Spanish National ERAS protocol is a safe issue, obtaining similar results to standard care in terms of complications, reoperations, mortality and readmissions. It is associated with less postoperative pain and earlier hospital discharge. PMID- 29519185 TI - Canal wall-down procedure with soft posterior meatal wall reconstruction in acquired cholesteatoma: focus on postoperative middle ear status. AB - OBJECTIVES: We reviewed surgical results of canal wall-down tympanoplasty (CWDT) with soft posterior meatal wall reconstruction (SWR) for acquired cholesteatoma (AC), and identified factors associated with surgical outcomes. METHODS: Results from 119 ears with AC (pars flaccida, n = 99; pars tensa, n = 20) that underwent CWDT with SWR were retrospectively reviewed. We defined postoperative balloon like retraction (PBR) with web formation, which needed reoperation to clean accumulated cerumen, as postoperative deep retraction pocket (PDRP). RESULTS: Residual cholesteatoma was found in 11 ears (9.2%). Seven residual cholesteatomas were treated with outpatient operation. Seven ears (5.9%) showed PDRP. A transcanal approach was applied to all PDRPs. Postoperative mastoid reaeration was observed in 57 ears (47.9%). No factors significantly associated with residual cholesteatoma or PDRP were identified. The frequency of postoperative mastoid reaeration was significantly higher among cases with young age (<50 years), stage I cholesteatoma, or type I ossiculoplasty. CONCLUSION: CWDT with SWR showed low rates of residual cholesteatoma or postoperative deep retraction pocket (PDRP). Most residual cholesteatomas and PDRPs could be dealt with using a minimally invasive procedure. Young age, stage I cholesteatoma, and type I ossiculoplasty were associated with postoperative mastoid reaeration. This procedure seems fully feasible for surgical treatment of AC. PMID- 29519186 TI - Vaginal reconstruction with the modified rectosigmoid colon: surgical technique, long-term results and sexual outcomes. AB - Although vaginal reconstructions with intestinal segments require particularly complex surgical procedures, this technique has become popular with respect to fairly good functional and esthetic outcomes. This study describes cases of vaginal reconstruction performed using a modified rectosigmoid colon held in an ischemic state in order to reduce secretion and denervated in order to prevent defecation problems. Vaginal reconstructions with rectosigmoid colon were performed on 43 patients. In this retrospective study, 34 patients had Mullerian agenesis, while nine had undergone male to female sex reassignment surgery in which adequate vaginal depth had not been achieved. A rectosigmoid colon with its vascular pedicle was used and left in an ischemic state. All nerve structures within the pedicle were excised intraoperatively. Follow-up period was between 12 and 60 months. Partial necrosis occurred in one patient which was reconstructed with local flap. Hematoma developed beneath the skin incision in two cases, but resolved with conservative treatment. A good esthetic outcome was achieved in all cases. Sexual function was assessed using the Female Sexual Function Index (FSFI) in 15 patients. Fourteen out of 15 patients scored above 26.5 on this scale and were determined as having no sexual dysfunction (FSFI score >=26.5). In conclusion, vaginal reconstruction with denervated rectosigmoid held in an ischemic state appears to be a reasonable option among several available reconstruction techniques. PMID- 29519187 TI - Molecular connectivity disruptions in males with major depressive disorder. AB - In most positron emission tomography (PET) molecular brain imaging studies, regions of interest have been defined anatomically and examined in isolation. However, by defining regions based on physiology and examining relationships between them, we may derive more sensitive measures of receptor abnormalities in conditions such as major depressive disorder (MDD). Using an average of 52 normalized binding potential maps, acquired using radiotracer [11C]-WAY100635 and full arterial input analysis, we identified two molecular volumes of interest (VOIs) with contiguously high serotonin 1A receptor (5-HT1A) binding sites: the olfactory sulcus (OLFS) and a band of tissue including piriform, olfactory, and entorhinal cortex (PRF). We applied these VOIs to a separate cohort of 25 healthy control males and 16 males with MDD who received [11C]-WAY100635 imaging. Patients with MDD had significantly higher binding than controls in both VOIs, ( p < 0.01). To identify potential homeostatic disruptions in MDD, we examined molecular connectivity, i.e. the correlation between binding of raphe nucleus (RN) 5-HT1A autoreceptors and post-synaptic receptors in molecular VOIs. Molecular connectivity was significant in healthy controls ( p < 0.01), but not in patients with MDD. This disruption in molecular connectivity allowed identification of MDD cases with high sensitivity (81%) and specificity (88%). PMID- 29519188 TI - Thiol/disulphide homeostasis in schizophrenia patients with positive symptoms. AB - INTRODUCTION: This study aims to investigate the dynamic thiol/disulphincide homeostasis in patients with schizophrenia who have positive psychotic indications. MATERIALS AND METHODS: Forty-four patients (26 males, 18 females; mean age = 34.40 +/- 8.98 years) accepted at the Department of Psychiatry of the Ankara Numune Training and Research Hospital and 33 healthy controls (15 males, 18 females; mean age of 30.30 +/- 8.48 years) were included in the study. Serum native thiol and total thiol were measured with a novel colorimetric, automated method. The disulfide levels and disulfide/native thiol ratios were also calculated from these measured parameters. RESULTS: Serum native thiol and the total thiol concentration were significantly lower in schizophrenia compared with the control group (p < .05). Disulphide levels and disulfide/native thiol ratios were significantly higher in schizophrenia compared with the control group (p < .05). When the patients were divided into two groups according to those who used medication and those who did not for the last two months, it was found to be significantly higher in those who used disulfide and disulfide/native thiol medication than those who did not use medication. CONCLUSION: The disulfide/native thiol ratio in patients with schizophrenia who have been using medication for the last 2 months has been found to be significantly higher than controls who have not been using medication, may be indicating that the level of native thiol does not increase in a correlation as high as the increase in disulfide levels. It demonstrates that thiol/disulfide equilibrium has shifted towards the disulfide. The excess disulfide amounts might associated with both disease itself and the using medication. PMID- 29519189 TI - Trusting early learners with critical professional activities through emergency medical technician certification. AB - BACKGROUND: Two dominant themes face medical education: developing integrated curricula and improving the undergraduate medical education (UME) to graduate medical education (GME) transition. An innovative solution to both of these challenges at the Zucker School of Medicine has been the application of the cognitive apprenticeship framework in requiring emergency medical technician (EMT) certification during the first course in medical school as the core on which to build an integrated curriculum and provide entrustable clinical skills. METHODS: Beginning with the Class of 2011, student feedback about the short-term impact of the experience was collected annually. In addition, perceptions of near graduates and alumni were surveyed in 2017 to explore the long-term impact of the experience. Theme analysis was conducted via inductive coding. RESULTS: Both first-year and more experienced learners report the value of the EMT curriculum as an integrated component of the first course of medical school. Reported positive long-term impacts included the first-hand observation of social determinants of health and interprofessionalism. Negative comments by early learners focused on course logistics, whereas older learners recalled the variability of clinical experiences during ambulance runs. CONCLUSIONS: The integration of the EMT curriculum as a core component of the first course serves multiple purposes: 1) it provides the foundation of a spiral learning approach; 2) it contextualizes the basic sciences within clinical practice; 3) it provides opportunities for students to engage in authentic clinical activities under the guidance of mentors; 4) it introduces students to the interdisciplinary nature of medicine; and 5) it serves as the first entrustable professional activity (EPA) for our students. PMID- 29519190 TI - Nursing Students' Attitudes and Use of Holistic Therapies for Stress Relief. AB - PURPOSE: The purpose of this study was to explore student nurses' openness to using or recommending holistic therapies, the strategies they use to manage stress from school or work, and their perceptions of the impact of holistic therapies on personal health. STUDY DESIGN: Qualitative component of a quasi experimental, mixed-methods study. METHODS: A convenience sample of undergraduate nursing students in a southeastern U.S. university completed baseline surveys, including demographics and three open-ended questions regarding attitudes toward holistic therapies and strategies used for stress management. Qualitative thematic analysis was undertaken to identify recurring themes in textual data. FINDINGS: Students are open to using or recommending holistic therapies but identify lack of knowledge and lack of time as barriers to their practice. Among strategies used by student nurses to manage stress from school or work were physical activity, prayer and meditation, time management, distraction, socialization, artistic pursuits, animal interactions, and other activities. Themes describing holistic therapies' impact on personal health were wholeness, self-empowerment, relaxation/restoration, and alternative/complement to traditional medicine. CONCLUSIONS: Findings indicate receptiveness by student nurses to the use of holistic therapies but point to the need for the inclusion of informational as well as experiential education on holistic therapies within nursing curricula. PMID- 29519191 TI - Spirituality, Spiritual Well-Being, and Spiritual Coping in Advanced Heart Failure: Review of the Literature. AB - : Heart failure is a chronic and terminal disease that affects a significant portion of the U.S. POPULATION: It is marked by considerable suffering, for which palliative care has been recommended. Palliative care standards require the inclusion of spiritual care, but there is a paucity of literature supporting effective spiritual interventions for the heart failure population. A literature search resulted in 30 articles meeting the criteria for review of spirituality and spiritual coping in the heart failure population. Findings within this body of literature include descriptive evidence of the uniqueness of spirituality in this population, quantitative and qualitative approaches to inquiry, theoretical models of spiritual coping, and proposed interventions. The article concludes with implications for future research and practice. PMID- 29519192 TI - Sound analysis of a left ventricular assist device: A technical evaluation of iOS devices. AB - INTRODUCTION: The use of left ventricular assist device (LVAD) has grown rapidly. Adverse events do continue to occur. In recent years, analysis of LVAD sound recordings emerged as a means to monitor pump function and detect pump thrombosis. The aim of this study was to characterize the sounds from HeartMate II and to evaluate the use of handheld iOS devices for sound recordings. METHOD: Signal analysis of LVAD sound recordings, with dedicated recording equipment and iOS devices, was performed. Two LVADs running in mock loop circuits were compared to an implanted LVAD. Spectral analysis and parametric signal models were explored to quantify the sound and potentially detect changes in it. RESULTS: The sound recordings of two LVADs in individual mock loop circuits and a third one implanted in a patient appeared to be similar. Qualitatively, sound characteristics were preserved following changes in pump speed. Recordings using dedicated equipment showed that HeartMate II sound comprises low-frequency components corresponding to pump impeller rotation, as well as high-frequency components due to a pulse width modulation of the electric power to the pump. These different signal components interact and result in a complicated frequency spectrum. The iPhone and iPod recordings could not reproduce the sounds as well as the dedicated equipment. In particular, lower frequencies were affected by outside disturbances. DISCUSSION: This article outlines a systematic approach to LVAD sound analysis using signal processing methods to quantify and potentially detect changes, and describes some of the challenges, for example, with the use of inexpensive recording devices. PMID- 29519194 TI - Corrigendum. PMID- 29519193 TI - Warwick Medical School: A four dimensional curriculum. AB - Medical curricula vary hugely across the world. Notions of horizontal and vertical integration and spiral curricula are present in many modern curricula although true integration happens to a varying degree. By seeing the development of a curriculum as fundamentally about integration, rather than as a process of seeking to integrate separate elements, we have developed a program that prepares students well for the complexities and rate of change of practice. The risks inherent in bringing forward the point at which learners need to deal with such substantive and fundamental complexity produces challenges. Such challenges are ones that our students have shown they can not only deal with, they are often better equipped than faculty to provide solutions for themselves, their peers and those who follow them. We present the three dimensions of integration in the Warwick Medical School curriculum and note the fourth dimension provided by our students, being student led teaching and support far beyond what is normally found in medical courses. PMID- 29519196 TI - Knowledge, time and change. PMID- 29519195 TI - Sport-specific and non-specific practice of strong and weak responders in junior and senior elite athletics - A matched-pairs analysis. AB - Elite track and field athletes with greater and lesser multi-year performance improvement were compared regarding their developmental sport-specific and non specific, organised (coach-led) and non-organised (peer-led) sporting activities. Athlete pairs were matched on gender, discipline and baseline performance in competitions (at 13/19 years). Their unequal subsequent performance development during junior (13-17 years; n = 138) and senior (19-23+ years; n = 80) age ranges defined "strong responders" and "weak responders". Analyses revealed that junior age strong responders accumulated more organised practice in athletics than weak responders, while the amounts of all other types of activities were indifferent. Senior-age strong responders did not accumulate a greater total sum of all kinds of sport activities or greater amounts of organised practice in athletics or non organised involvement in athletics or other sports than weak responders. But they engaged in more organised practice and competitions in other sports over more years (9 vs. 2 years) and specialised in athletics at a later age than weak responders (16 vs. 11 years). The results were also robust among senior international medallists vs. national medallists. The findings are reflected relative to the hypotheses of "multiple sampling and functional matching", "learning transfer as preparation for future learning" and "authenticity of variable learning experiences". PMID- 29519197 TI - What Constitutes Rape? The Effect of Marital Status and Type of Sexual Act on Perceptions of Rape Scenarios. AB - Many people believe that rape is always perpetrated by a stranger and involves vaginal intercourse. To clarify perceptions of rape that do not follow traditional beliefs, participants were presented with a vignette that described a rape in which the marital status and sexual act were manipulated. Participants were then asked to assess the incident's severity and the victim's responsibility. Results indicated that there was no difference in perceptions between vignettes based on marital status. However, rapes involving vaginal intercourse were associated with lesser degrees of victim blame and minimization than were rapes involving forced oral sex or digital sex. PMID- 29519198 TI - Microstructural and metabolic changes in the longitudinal progression of white matter hyperintensities. AB - Our purpose is to evaluate the microstructural and metabolism property in the white matter that later become white matter hyperintensity (WMH), and of WMH that later disappeared. Forty subjects with two-year follow-up were included. Each subject had 3DT1, T2FLAIR, DTI and FDG-PET scans. White matter was classified into: constant WMH, growing WMH, shrinking WMH and normal appearing white matter (NAWM). The average DTI (FA and MD) and FDG-PET (standardized FDG-PET rSUV) of each of the above-mentioned region were extracted and compared. At baseline, the growing WMH had lower FA and FDG-PET rSUV than NAWM, but had higher FA than the constant WMH. Longitudinally, in NAWM, there was a more rapid decline in metabolism compared to WMH areas, while in the growing WMH, a progression in diffusion was found. Finally, we discovered that the shrinking WMH had a similar microstructural and metabolism property and progression to the constant WMH. Our results suggest there are dynamic changes in microstructural and metabolism in WMH. The metabolic change was mainly found in NAWM, while the microstructural change was mainly found in WMH region. Besides, the reduced volume in WMH, to a larger extent, is irrelevant to the microstructural or metabolism recovery. PMID- 29519199 TI - Medical student perspectives of early general practice placements. PMID- 29519200 TI - Lead induced oxidative DNA damage in battery-recycling child workers from Bangladesh. AB - Lead exposure can damage cells directly by effecting DNA or indirectly by modifying proteins and enzymes. In Bangladesh, many working children are exposed to a very high level of lead during their early life due to their involvement with lead-oriented professions. This imposes a severe threat to the growth and development of the children. Therefore to study the effect of lead, we enrolled 60 age-matched male children, from an area of old Dhaka city, where battery recycling shops are located, depending on their blood lead concentration. If the children had a plasma lead concentration above the WHO recommended threshold level of 10 ug/dl, we grouped them as test subjects and others as control subjects to determine the effect of lead on different biochemical parameters of the body. Compared to the controls, acculumlation of the lipid peroxidation product, malondialdehyde, increased significantly in test subjects ( p < 0.01). Lead exposure also increased the protein carbonyl content ( p < 0.05) and significantly decreased the plasma glutathione levels of test subjects compared to the controls ( p < 0.05). While comparing the lead-exposed group against controls, it was found that the percentage of damaged DNA, as measured using the Comet assay, significantly increased in tail ( p < 0.01) and decreased in head regions. All of these results suggest that high-plasma lead content may induce an oxidative stress to the study population, which may lead to DNA damage. PMID- 29519201 TI - A comparative study of using free radical generators in the testing of chosen oxidative stress parameters in the different types of cells. AB - The aim of this study was to assess whether there are differences between the results of determining oxidative stress markers obtained from different origin cell lines after exposure to chemicals generating free radicals. The studies considered two markers of oxidative stress: the level of thiobarbituric acid reactive substances (TBARS) and superoxide dismutase activity. The evaluation was performed in five cell lines: Chinese hamster ovary (CHO-9) cells, lung adenocarcinoma A549, macrophages RAW264.7, skin carcinoma cells A431, and keratinocytes HaCaT. Three compounds generating free radicals were used as a source of reactive oxygen/nitrogen: 2,2'-azobis-2-methyl-propanimidamide dihydrochloride (AAPH), sodium persulfate (SP), and 3-morpholinosydnonimine hydrochloride (SIN-1). The most appropriate cell line to assess the level of TBARS proved to be the murine macrophage cell line RAW 264.7. Equally, good performance was observed in the lung cancer cell line A549, but only when tested with AAPH and SP. In the case of measuring superoxide dismutase activity, it appeared that the most suitable cell line was also the RAW 264.7 line, although dispersion increased significantly at the highest concentrations of AAPH and SP measurements. When choosing a cell line to determine oxidative stress, the specificity of the stress-inducing compound and the parameter determined should be taken into consideration. PMID- 29519202 TI - Carotid Pseudoaneurysm After Eversion Endarterectomy: A Case Report and Review of the Literature. AB - BACKGROUND: Pseudoaneurysm (PA) after carotid endarterectomy (CEA) is a rare and potentially life-threatening complication, with an incidence lower than 1%. Most of the cases described report PAs after carotid patch angioplasty and are associated with infection, often caused by Staphylococci. The management of PAs can be surgical, endovascular, or hybrid. METHODS: We herein present the case of an infected carotid PA 27 days after an eversion CEA. We performed a common to internal carotid bypass with the interposition of great saphenous vein (GSV) associated with specific polyantibiotic therapy for 4 weeks. We searched the PubMed database for reviews and cases reports for patients who developed carotid PA after primary repair CEA in the period between 1969 and 2017. RESULTS: We identified 21 cases of primary closure post-CEA PAs in the literature. In almost 60% of patients, infection was detected. Open surgery was performed in all the cases; in 1 case, an hybrid approach was preferred. In 52% of cases, a vein graft/patch or primary closure was chosen; in 3 cases, ligation was preferred, and in 1 case, a polyester graft was used. CONCLUSION: In our experience and with the evidence observed in the literature, open surgery with GSV interposition is the safest treatment in infected carotid PAs. The endovascular approach must be performed only in proven noninfectious cases. A bridge technique with the insertion of a stent followed by open surgery repair can be an option in emergency cases. PMID- 29519203 TI - Port-A-Cath Catheter Embolization to Distal Pulmonary Artery Branches: Two Tailored Percutaneous Retrieval Approaches. AB - Several types of intravascular devices and catheters are frequently used for long term drug therapy, especially for oncological patients. As a result, complications are becoming increasingly common, namely catheter embolization. Retrieving these devices is important, as embolized fragments may lead to serious consequences, such as arrhythmias, myocardial injury, thrombosis, infection, and even perforation and death. We describe 2 cases of long-term drug catheter (Port A-Cath) fracture, incidentally documented in a routine chest radiograph. In both cases, percutaneous extraction was attempted, yet the procedure was complicated by embolization of smaller fragments into the arterial pulmonary vasculature. We describe unusual approaches in successfully retrieving the remaining fragments. The ideal approaches for removal of foreign bodies from the cardiovascular system differ from case to case, but percutaneous extraction should be preferred in most of the cases. Less common techniques may be helpful in challenging cases. PMID- 29519205 TI - Impact of Serum Phosphate in Mechanically Ventilated Patients With Severe Sepsis and Septic Shock. AB - BACKGROUND: Hypo- and hyperphosphatemia are common in severe sepsis and septic shock. Published outcome data in patients with phosphate derangements primarily focus on hypophosphatemia and the general critically ill population. This study aimed to determine the impact of serum phosphate on clinical outcomes in patients with severe sepsis and septic shock. METHODS: A retrospective cohort analysis of adult mechanically ventilated patients with severe sepsis or septic shock was performed. Patients were randomly selected from an internal intensive care unit (ICU) database at an academic medical center in the United States and screened for inclusion and exclusion criteria. Time-weighted phosphate was calculated using all phosphate measurements obtained during ICU admission. The associations between time-weighted phosphate and duration of mechanical ventilation, 28-day mortality, and ICU and hospital length of stay were evaluated using linear or logistic regression as appropriate. RESULTS: One-hundred ninety-seven patients were evaluated: 33 were categorized as hypophosphatemia, 123 as normophosphatemia, and 41 as hyperphosphatemia. Patients with time-weighted hyperphosphatemia had a higher Simplified Acute Physiology Score III score and incidence of septic shock. Significantly higher rates of 28-day mortality were observed among those with time-weighted phosphate levels above 3.5 mg/dL. However, both time-weighted hypo- and hyperphosphatemia were associated with decreased duration of mechanical ventilation. For every 0.5 mg/dL increase in time-weighted phosphate referent values from 4.0 to 6.0, the duration of mechanical ventilation decreased by 8% to 26%. For every 0.5 mg/dL decrease in time-weighted phosphate referent values from 3.0 to 1.0, significant decreases in duration of mechanical ventilation ranged from 14% to 41%. CONCLUSION: Time weighted hyperphosphatemia may be associated with increased mortality in mechanically ventilated patients with severe sepsis or septic shock. However, time-weighted hypo- and hyperphosphatemia were associated with decreased duration of mechanical ventilation. Future studies should further describe the impact of hypo- and hyperphosphatemia on clinical outcomes among critically ill patients with severe sepsis or septic shock. PMID- 29519206 TI - The Top Ten Websites in Critical Care Medicine Education Today. AB - INTRODUCTION: The number of websites for the critical care provider is rapidly growing, including websites that are part of the Free Open Access Med(ical ed)ucation (FOAM) movement. With this rapidly expanding number of websites, critical appraisal is needed to identify quality websites. The last major review of critical care websites was published in 2011, and thus a new review of the websites relevant to the critical care clinician is necessary. METHODS: A new assessment tool for evaluating critical care medicine education websites, the Critical Care Medical Education Website Quality Evaluation Tool (CCMEWQET), was modified from existing tools. A PubMed and Startpage search from 2007 to 2017 was conducted to identify websites relevant to critical care medicine education. These websites were scored based on the CCMEWQET. RESULTS: Ninety-seven websites relevant for critical care medicine education were identified and scored, and the top ten websites were described in detail. Common types of resources available on these websites included blog posts, podcasts, videos, online journal clubs, and interactive components such as quizzes. Almost one quarter of websites (n = 22) classified themselves as FOAM websites. The top ten websites most often included an editorial process, high-quality and appropriately attributed graphics and multimedia, scored much higher for comprehensiveness and ease of access, and included opportunities for interactive learning. CONCLUSION: Many excellent online resources for critical care medicine education currently exist, and the number is likely to continue to increase. Opportunities for improvement in many websites include more active engagement of learners, upgrading navigation abilities, incorporating an editorial process, and providing appropriate attribution for graphics and media. PMID- 29519208 TI - Stimulant Use in the Management of Mild Traumatic Brain Injury: A Qualitative Literature Review. AB - OBJECTIVE: Mild traumatic brain injury (mTBI) often presents with cognitive complaints including difficulty with attention and concentration. As these symptoms resemble those of ADHD, stimulants may be a potential treatment for mTBI. This review evaluates the literature on the use of stimulants for the treatment of mTBI. METHOD: A systematic evaluation of the literature using six databases: Ovidmedline, Pubmed, psychINFO, CINAH, Embase, and Cochrane. Broad search terms were used and studies were included that evaluate the use of stimulant and stimulant-like medications in the mTBI population. Data extracted included stimulant type and dosing, symptoms targeted, outcomes, safety and tolerability, and if the study population had ADHD. RESULTS: Nine studies were identified that met the inclusion criteria. Immediate release methylphenidate and amantadine were used for treatment. Methylphenidate had some impact on attention, fatigue, and depression. However, due to the limited number of studies and heterogeneity of study populations, symptoms targeted, and outcome measures used, meaningful conclusions regarding the effect of stimulants in mTBI could not be made. No study evaluated for the presence of ADHD within the study population, despite stimulants being the mainstay treatment for ADHD. CONCLUSION: PProspective studies on the use of stimulants in mTBI, that evaluate participants for a diagnosis of ADHD, are needed. PMID- 29519207 TI - ADHD Medication Use During Pregnancy and Risk for Selected Birth Defects: National Birth Defects Prevention Study, 1998-2011. AB - OBJECTIVE: The objective of this study was to examine the prevalence of, and maternal characteristics associated with, ADHD medication use before and during pregnancy, and associations between early pregnancy ADHD medication use and risk for 12 selected birth defects. METHOD: We used data from the National Birth Defects Prevention Study (1998-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects. RESULTS: There was an increase in ADHD medication use from 1998-1999 (0.2%) to 2010-2011 (0.5%; p < .001). Early pregnancy ADHD medication use was more commonly reported by mothers of infants/fetuses with gastroschisis (crude odds ratio [cOR]: 2.9, 95% confidence interval [CI] = [1.2, 6.9]), omphalocele (cOR: 4.0, 95% CI = [1.2, 13.6]), and transverse limb deficiency (cOR: 3.3, 95% CI = [1.1, 9.6]). CONCLUSION: ADHD medication use before and during pregnancy was rare, but the prevalence of use has increased over time. In this analysis, early pregnancy ADHD medication use was associated with three of 12 selected birth defects. PMID- 29519209 TI - Adaptation, Resilience, and Secure Attachment States of Mind in Young South African Female Students Exposed to Intimate Partner Violence in Childhood. AB - Much research details the psychological risks to individuals exposed as children to intimate partner violence (IPV). However, resilience has been a neglected area of study within this population. This article details adaptive responses in six participants exposed to IPV in childhood. Adult attachment interviews (AAI) and follow-up semi-structured interviews analyzed using an interpretive thematic analysis revealed common themes relating to psychological defenses and adaptive strategies. Despite exposure to IPV in childhood, these six women were found to have secure attachment states of mind. Resilience was found not to be necessarily synonymous with the absence of distress. Despite the presence of suffering, it remained strongly associated with adaptive, robust defenses to manage distress and to retain caregiving relationships with parents. These defenses appeared to provide participants with ways to survive their traumatic environments and to remain connected to needed but frightening caregiving figures, and facilitated processing of trauma. Adaptation often entailed using compliance and caregiving responses in childhood in response to role reversal in parent-child relationships, but also the relinquishing of these roles in adulthood. Participants' abilities to coherently acknowledge and discuss their early experiences and retain compassion for their parents seemed linked to their abilities to attain some distance from troubling aspects of their pasts. In doing so, they separated from the unstable relationships of their parents, which fostered transitions to more integrated states of mind. PMID- 29519210 TI - Violence Against Children in Afghanistan: Community Perspectives. AB - Violence against children (VAC) is a significant international problem and, in Afghanistan, is particularly complex given the country has suffered armed conflict and extreme poverty for more than 30 years. The aim of this study was to examine the level of knowledge and observation of VAC by community leaders, professional groups, and business owners in three Afghan districts. A survey of community and religious leaders; health, socio-legal, and education professionals; and business owners from Kabul, Jalalabad, and Torkham ( n = 182) was conducted. Structured interviews included qualitative and quantitative components. Questions related to knowledge and experience of VAC, and to perceptions of consequences, causes, and strategies for preventing VAC. The statistical significance of differences between participant groups and measures of association were assessed by Pearson's chi-square test, the Mann-Whitney test, and the Kruskall-Wallis one-way ANOVA. Qualitative responses were analyzed thematically. VAC was reported to occur mostly in the home, community, and workplace. The scale of the problem varied, with religious and community leaders underreporting VAC by 30% to 40% compared with other participant groups ( p < .001). Business owners also significantly underreported VAC in the workplace, despite admitting to acts of discipline that included physical contact. There were some regional differences, with lower reporting of violence in Jalalabad compared with the two other locations ( p < .001). Causes of VAC were consistently attributed to poverty, lack of education, and the effects of war. The findings of this study indicate that VAC is a serious and complex problem in Afghanistan. Decades of armed conflict and entrenched poverty influence how violence is perceived and recognized. Consideration should be given to initiatives that build on the existing strengths within the community while raising awareness and recognition of the nature, extent, and burden of VAC in the community. PMID- 29519211 TI - Transitions in Loneliness Among Older Adults: A 5-Year Follow-Up in the National Social Life, Health, and Aging Project. AB - A substantial portion of the older adult population suffers from frequent feelings of loneliness, but a large proportion remains relatively unscathed by loneliness. To date, research examining both protective and risk factors for loneliness has not included data from the United States. The present study used the first two waves of data from the National Social Life, Health, and Aging Project to examine sociodemographic, structural, and functional factors thought to be associated with loneliness in older adults. Functional limitations and low family support were associated with an increase in loneliness frequency (as were more strained friendships) and with transitioning from nonlonely to lonely status. Better self-rated health, higher levels of socializing frequency, and lower family strain were associated with transitioning from lonely to nonlonely status. Interventions that target these factors may be effective in preventing and reducing loneliness and its effects on health and well-being in older adults. PMID- 29519212 TI - Surface-enhanced Raman spectroscopy study of red blood cells and platelets. PMID- 29519213 TI - Insight into the process of product expulsion in cellobiohydrolase Cel6A from Trichoderma reesei by computational modeling. AB - Glycoside hydrolase cellulase family 6 from Trichoderma reesei (TrCel6A) is an important cellobiohydrolase to hydrolyze cellooligosaccharide into cellobiose. The knowledge of enzymatic mechanisms is critical for improving the conversion efficiency of cellulose into ethanol or other chemicals. However, the process of product expulsion, a key component of enzymatic depolymerization, from TrCel6A has not yet been described in detail. Here, conventional molecular dynamics and steered molecular dynamics (SMD) were applied to study product expulsion from TrCel6A. Tyr103 may be a crucial residue in product expulsion given that it exhibits two different posthydrolytic conformations. In one conformation, Tyr103 rotates to open the -3 subsite. However, Tyr103 does not rotate in the other conformation. Three different routes for product expulsion were proposed on the basis of the two different conformations. The total energy barriers of the three routes were calculated through SMD simulations. The total energy barrier of product expulsion through Route 1, in which Tyr103 does not rotate, was 22.2 kcal.mol-1. The total energy barriers of product expulsion through Routes 2 and 3, in which Tyr103 rotates to open the -3 subsite, were 10.3 and 14.4 kcal.mol-1, respectively. Therefore, Routes 2 and 3 have lower energy barriers than Route 1, and Route 2 is the thermodynamically optimal route for product expulsion. Consequently, the rotation of Tyr103 may be crucial for product release from TrCel6A. Results of this work have potential applications in cellulase engineering. PMID- 29519215 TI - The introduction of synthetic colloids. PMID- 29519216 TI - The good, the bad, and the ugly: sodium-glucose cotransporter-2 inhibitors (gliflozins) and perioperative diabetes. PMID- 29519217 TI - Teaching airway management as part of continuing professional development in intensive care medicine. PMID- 29519218 TI - Recent advances and anaesthetic considerations in corneal transplantation. AB - Significant surgical advances have been made recently in corneal transplantation. Penetrating keratoplasty was the dominant method from 1905, until selective lamellar keratoplasty emerged as the preferred technique over the last 20 years. Advanced techniques such as corneal limbal stem cell transplant and keratoprosthesis are also available. The major surgical complications of corneal transplantation are extrusion of ocular content and expulsive choroidal haemorrhage. It is essential for an ophthalmic anaesthetist to have a good understanding of these new surgical procedures so as to provide optimal surgical conditions. This article aims to inform anaesthetists about the recent surgical advances in corneal transplantation and explore the anaesthetic considerations of these new techniques. General anaesthesia remains suitable for a wide range of these procedures especially in repeat surgery, difficult, or prolonged procedures. Regional ophthalmic blocks are ideal for endothelial keratoplasty but can be used in penetrating keratoplasty based on individual risk-benefit assessment, and as a supplement to general anaesthesia. Topical anaesthesia provides an alternative when general anaesthesia and ophthalmic regional blocks are less desirable but overall its use is limited. PMID- 29519219 TI - Morbid obesity impairs adequacy of thoracic compressions in a simulation-based model. AB - Adequate cardiopulmonary resuscitation is an important predictor of survival, however, obesity provides a significant physical barrier to thoracic compressions. This study explores the effect of morbid obesity on compression adequacy. We performed a prospective randomised controlled crossover study, assessing the adequacy of thoracic compressions on a manikin modified to emulate a morbidly obese patient. Participants recruited from critical care departments were randomised to perform continuous compressions for two minutes on each manikin. Accelerometers were used to measure thoracic wall movement. The primary endpoint was a composite measure of compression adequacy (rate, depth and recoil). Secondary endpoints were the individual components of the composite outcome and measures of perceived effectiveness, fatigue, and pain. One hundred and one participants were recruited. There was a significant difference between the obese and control groups in the composite endpoint (4% versus 30%, P <0.001), as well as the individual components of adequacy (P <0.01 for all). Quartile data showed significant deterioration in adequacy of depth and recoil in both groups, and this occurred significantly earlier in the obese group (P <=0.001). Participants' perception of effectiveness was significantly lower (P <=0.001) in the obese group, and levels of fatigue (P <=0.001) and pain (P <=0.001) significantly higher. Morbid obesity impairs the adequacy of thoracic compressions for trained rescuers in a simulation-based model. Participants were not fully aware of how ineffective compressions were. There is evidence of earlier fatigue further reducing effectiveness. These findings have significant implications for the training of rescuers in a clinically relevant population and the planning of future research. PMID- 29519220 TI - The effect of inhalational anaesthesia during deceased donor organ procurement on post-transplantation graft survival. AB - Many deceased by neurologic criteria donors are administered inhalational agents during organ recovery surgery-a process that is characterised by warm and cold ischaemia followed by warm reperfusion. In certain settings, volatile anaesthetics (VA) are known to precondition organs to protect them from subsequent ischaemia-reperfusion injury. As such, we hypothesised that exposure to VA during organ procurement would improve post-graft survival. Lifebanc (organ procurement organisation [OPO] for NE Ohio) provided the investigators with a list of death by neurologic criteria organ donors cared for at three large tertiary hospitals in Cleveland between 2006 and 2016-details about the surgical recovery phase were extracted from the organ donors' medical records. De identified data on graft survival were obtained from the United Network for Organ Sharing (UNOS). The collated data underwent comparative analysis based on whether or not VA were administered during procurement surgery. Records from 213 donors were obtained for analysis with 138 exposed and 75 not exposed. Demographics, medical histories, and organ procurement rates were similar between the two cohorts. For the primary endpoint, there were no significant differences observed in either early (30-day) or late (five-year) graft survival rates for kidney, liver, lung, or heart transplants. Our findings from this retrospective review of a relatively small cohort do not support the hypothesis that the use of VA during the surgical procurement phase improves graft survival. Reviews of larger datasets and/or a prospective study may be required to provide a definitive answer. PMID- 29519221 TI - The effect of a multifaceted postoperative nausea and vomiting reduction strategy on prophylaxis administration amongst higher-risk adult surgical patients. AB - Postoperative nausea and vomiting (PONV) is a common and distressing problem for patients and increases the burden of care in post-anaesthesia care units (PACU). As such it has been a recent focus for quality improvement. Evidence-based guidelines have demonstrated the benefit of PONV risk stratification and prophylaxis, but may be underutilised in clinical practice. This prospective pre /post-intervention study was conducted at an adult tertiary hospital in non cardiac adult surgical patients at higher-risk of PONV. The intervention included promotion of an evidence-based PONV guideline, and provision of individualised prescribing and patient outcome data to anaesthetists. Six hundred and twenty eight patients with >=2 risk factors for PONV following general anaesthesia for non-cardiac surgery were included (333 pre-intervention and 295 post intervention). Prior to the intervention, 9.0% (30/333) of moderate- and high risk patients received antiemetic prophylaxis consistent with our guideline. Post intervention, the rate of guideline adherence was 19.3% (57/295). In the high risk PONV group, the time in PACU was significantly reduced post-intervention, 66 minutes versus 83 minutes (P=0.032). This institution-specific PONV reduction strategy had a modest but significant effect on improving prophylaxis administration. However, our findings indicate that further efforts would be required to ensure fuller compliance with the current extensive evidence base for PONV management in higher-risk patients. PMID- 29519222 TI - Should ongoing airway education be a mandatory component of continuing professional development for College of Intensive Care Medicine Fellows? AB - This study aimed to determine whether airway education should be introduced to the continuing professional development (CPD) program for College of Intensive Care Medicine (CICM) Fellows. A random representative sample of 11 tertiary intensive care units (ICUs) was chosen from the list of 56 units accredited for 12 or 24 months of CICM training. All specialist intensive care Fellows (n=140) currently practising at the eleven ICUs were sent the questionnaire via email. Questionnaire data collection and post-collection data analysis was used to determine basic respondent demographics, frequency of certain airway procedures in the past 12 months, confidence with advanced airway practices in ICU, participation in airway education in the past three years, knowledge of can't intubate, can't oxygenate (CICO) algorithms, preference for certain airway equipment/techniques, and support for required airway education as a component of the CICM CPD program. All responses were tabled for comparison. Data was analysed to establish any significant effect of another specialty qualification and current co-practice in anaesthesia on volume of practice, confidence with multiple airway procedures, use of airway equipment, and support for airway education. In total, 112 responses (response rate 80%) to the questionnaire were received within four weeks; 107 were completed in full (compliance 96%). All results were tabled. There is currently widespread support amongst CICM Fellows for airway skills education as a CPD requirement for CICM Fellows. Volumes of practice and confidence levels with different airway procedures vary amongst Fellows and further support the need for education. PMID- 29519223 TI - Morbidity of cardiac arrest in the very elderly. AB - The objective of this retrospective cohort study was to assess mortality and morbidity after cardiac arrest in hospital inpatients aged 80 years or older, in an Australian tertiary hospital. We studied patients aged 80 years or older who suffered an in-hospital cardiac arrest from 1 January 2000 to 31 December 2016. The main outcome measures were one-year survival and narrative morbidity. Two hundred and eighty-five patients were identified. Absolute one-year survival after cardiac arrest was, at best, 12.6%. Narrative descriptions of morbidity demonstrate high healthcare utilisation, dependency or residential care, and significant impairments of physical and social function. In conclusion, one-year survival after cardiac arrest in the very elderly is poor. In those who survive, significant morbidity is present. PMID- 29519224 TI - Patients retrieved to intensive care via a dedicated retrieval service do not have increased hospital mortality compared with propensity-matched controls. AB - This study was performed to estimate the effect of the retrieval process on mortality for patients admitted to a mixed adult intensive care unit (ICU) compared with propensity-matched, non-retrieved controls. Patients retrieved to the Royal Adelaide Hospital (RAH) ICU between 2011 and 2015 were propensity-score matched for age, gender, Aboriginal and Torres Strait Islander status, Acute Physiology and Chronic Health Evaluation (APACHE) III score and diagnostic group with non-retrieved ICU patients to estimate the average treatment effect of retrieval on hospital mortality. Factors associated with mortality in those retrieved were assessed by multiple logistic regression. Retrieved patients comprised 1,597 (14%) of 11,641 index ICU admissions; this group were younger, mean (standard deviation) 53 (18.5) versus 59 (17.7) years, had higher APACHE III scores, 61 (30.3) versus 56 (27.5), were more likely to be Indigenous (5.1% versus 3.7%) and to have sustained trauma (34% versus 9%). The average treatment effect for retrieval on hospital mortality, risk difference (95% confidence interval), was -0.7% (-2.8% to 1.3%), P=0.50. Variables independently associated with hospital mortality in those retrieved included age, APACHE III score and diagnostic category. Time from retrieval team activation to arrival with the patient, rural location, radial distance from the RAH and population size at the retrieval location were not significantly associated with mortality. The hospital mortality for retrieved patients was not significantly different when compared with propensity-matched controls. Mortality in those retrieved was associated with increasing age, APACHE III score and diagnostic category; however, was independent of time from team activation to arrival with the patient. PMID- 29519225 TI - An observational study of perioperative risk associated with aortic stenosis in non-cardiac surgery. AB - This prospective multicentre observational study investigated the risk of non cardiac surgery in patients with moderate or severe aortic stenosis (AS). Patients with AS undergoing non-cardiac surgery in five New Zealand hospitals between August 2011 and September 2015 were studied. Preoperative variables were analysed for a significant association with postoperative major adverse cardiac events (MACE) and 30-day mortality. Of the 147 patients recruited, 13 (9%) died within 30 days and 33 (22%) had a MACE. Using univariate analysis, patients with severe AS had four times higher 30-day mortality than patients with moderate AS (16% versus 4%, P=0.007). Other factors associated with increased 30-day mortality included having a smaller aortic valve area, smaller dimensionless severity index, concomitant mitral regurgitation, and higher overall surgical risk. Patients with symptoms attributable to AS had a higher incidence of MACE compared to patients without symptoms (36% versus 16%, P=0.011). Variables significantly associated with both 30-day mortality and MACE were age, American Society of Anesthesiologists physical status, emergency surgery, New York Heart Association classification, preoperative albumin level, frailty, and history of congestive heart failure. Using multivariate analysis, emergency surgery, symptoms attributable to AS, preoperative albumin level, and AVA remained significantly associated with adverse outcome. While these findings should be interpreted with caution due to the observational nature of the study, limited power and multiple simultaneous comparisons, they suggest that patients with severe AS have a higher risk of adverse outcome after non-cardiac surgery than patients with moderate AS. PMID- 29519227 TI - Punctal dilator facilitates insertion of blunt cannula during sub-Tenon's block. PMID- 29519226 TI - Postoperative euglycaemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors (gliflozins): a report of two cases and review of the literature. AB - Sodium-glucose cotransporter 2 inhibitor (SGLT2i)-associated euglycaemic diabetic ketoacidosis (euDKA) is a serious and increasingly recognised complication of treatment with this class of oral hypoglycaemic agents and can present a diagnostic challenge, resulting in delayed recognition, inappropriate treatment and potentially life-threatening acidosis. We present two cases of patients developing SGLT2i-associated euDKA in the early postoperative period. We support ceasing SGLT2i for 72 hours preoperatively and would suggest continuing to withhold the medication until oral intake is restored, and recommend a wider awareness of SGLT2i-associated diabetic ketoacidosis (DKA) amongst patients and their healthcare providers with an emphasis on checking ketone levels irrespective of blood glucose levels in the postoperative setting. PMID- 29519228 TI - Airway education in intensive care medicine in Australia and New Zealand: what are we doing? PMID- 29519229 TI - A change to programmed intermittent epidural boluses from continuous local anaesthetic infusion for labour analgesia. PMID- 29519230 TI - Ultrasound-guided continuous erector spinae plane block for postoperative analgesia in video-assisted thoracotomy. PMID- 29519231 TI - The difficulty for clinicians in prescribing the correct nutrition in critically ill patients. PMID- 29519232 TI - Human-animal interaction as a social determinant of health: descriptive findings from the health and retirement study. AB - BACKGROUND: We focused on human-animal interaction (HAI) as an important aspect of social functioning at the individual level, framing this emerging field from a public health perspective. METHODS: Using data from the Health and Retirement Study (HRS) 2012 HAI module, we describe the characteristics of pet ownership in a population of older adults, and examine the relation between pet ownership and multiple mental and physical health indicators such as health status, depression, and physical activity. RESULTS: Of the 1657 participants in our subsample, approximately half (51.5%) reported being pet owners; the majority owned dogs or cats, and most had only one pet. Pet ownership was significantly associated with a higher likelihood of ever having had depression, with pet owners being 1.89 times more likely to have experienced depression. However, pet ownership was not associated with having experienced depression within the last week. CONCLUSIONS: The findings from this study could indicate a relationship between pet ownership and depression, but it is impossible to determine the directionality of that relationship. It is possible that owning a pet may put a person at an increased risk of developing depression, or individuals who are at risk, or who have already developed depression, may acquire a pet as a way of managing their depressive symptoms. The findings of this study provide an initial step in contributing to our understanding of the relationship between companion animals and the social, physical, and mental well-being of the HRS study population. Future research should include measures of HAI in longitudinal, population-based surveys. PMID- 29519233 TI - Treatment with oestrogen or manual separation for labial adhesions - initial outcome and long-term follow-up. AB - BACKGROUND: Topical oestrogen and manual separation are the main treatments for labial adhesions. The aim was to evaluate treatment of labial adhesions and compare the outcome of topical oestrogen treatment with that of manual separation. METHOD: All girls aged 0-12 years admitted to a tertiary centre for paediatric surgery for labial adhesions were included. The study design was dual: The first part was a retrospective chart review of the treatment success according to the medical charts. The second part was a cross-sectional parent reported long-term outcome study (> 6 months after last treatment finished). RESULTS: In total 71 patients were included and the median follow-up time for the chart study was 84 (6-162) months after treatment with oestrogen or manual separation. Oestrogen was the first treatment for 66 patients who had an initial successful rate of 62% but this was followed by recurrences in 44%. Five patients had manual treatment as their first treatment and they had a 100% initial success rate followed by recurrences in 20%. Therefore, for the first treatment course there was a final success rate of 35% for oestrogen and 80% for manual separation (p = 0.006). Corresponding final success rates including all consecutive treatments over the study period were 46/130 (35%) for oestrogen and 21/30 (70%) for manual separation (p = 0.001). The success rate for oestrogen did not differ if treatment was given in a course length of 0-4 weeks (39% success) or > 4 weeks (32% success) (p = 0.369). In the parent-reported long-term outcome study the response rate was 51% (36/71). Parents reported that recurrences of adhesions after last prescribed/performed treatment were frequent: in total 25% of patients still had adhesions corresponding to 8/29 (29%) of those whose last treatment was oestrogen and 1/9 (11%) of those whose last treatment was manual separation. CONCLUSION: Due to the results recurrences are common after both oestrogen and manual separations. However, the overall final outcome after manual separation seems to be more successful when compared to that of topical oestrogen treatment. PMID- 29519234 TI - Relationship of aging, skeletal muscle mass, and tooth loss with masseter muscle thickness. AB - BACKGROUND: Previous studies have reported a relationship between masseter muscle thickness and tooth loss or limb muscle thickness. However, it is not yet known whether masseter muscle thickness is related to appendicular skeletal muscle mass, and grip strength. The purpose of this study was to determine which of the two variables-tooth loss or appendicular skeletal muscle mass index-is more strongly related to masseter muscle thickness, and to identify a suitable indicator of decreasing masseter muscle thickness in healthy elderly individuals. METHODS: Grip strength, walking speed, body weight, skeletal muscle mass index, tooth loss, and masseter muscle thickness at rest and during contraction were determined in 97 community-dwelling elderly individuals aged >=65 years (men: 44, women: 53). Masseter muscle thickness was chosen as the dependent variable, while age, skeletal muscle mass index, body weight, grip strength, and tooth loss were chosen as the independent variables. Multiple regression analysis was conducted using the stepwise regression method. RESULTS: In men, grip strength was the only independent predictor of masseter muscle thickness at rest. Tooth loss and grip strength were independent predictor of masseter muscle thickness during contraction. In women, tooth loss was the independent predictor of masseter muscle thickness both at rest and during contraction, while grip strength and body weight were the independent predictor of masseter muscle thickness at rest only. CONCLUSIONS: We confirmed that in healthy elderly individuals, tooth loss has a stronger relationship with masseter muscle thickness than aging and skeletal muscle mass index do. Masseter muscle thickness in both elderly men and women is also associated with grip strength, suggesting that grip strength can be used as an indicator of masseter muscle thickness in this population. PMID- 29519235 TI - Before the ICU: does emergency room hyperoxia affect outcome? PMID- 29519237 TI - Correction to: Improving health promotion through central rating of interventions: the need for Responsive Guidance. AB - CORRECTION: It has been highlighted that the original manuscript [1] contains a typesetting error in the surname of Caspar David Roelofs. This was incorrectly captured as Caspar David Roelefs in the original manuscript which has since been updated. PMID- 29519236 TI - Progressive bladder remodeling due to bladder outlet obstruction: a systematic review of morphological and molecular evidences in humans. AB - BACKGROUND: Bladder outlet obstruction is a common urological condition. We aimed to summarize available evidences about bladder outlet obstruction-induced molecular and morphological alterations occurring in human bladder. METHODS: We performed a literature search up to December 2017 including clinical and preclinical basic research studies on humans. The following search terms were combined: angiogenesis, apoptosis, bladder outlet obstruction, collagen, electron microscopy, extracellular matrix, fibrosis, hypoxia, histology, inflammation, innervation, ischemia, pressure, proliferation, remodeling, suburothelium, smooth muscle cells, stretch, urothelium. RESULTS: We identified 36 relevant studies. A three-stages model of bladder wall remodeling can be hypothesized involving an initial hypertrophy phase, a subsequent compensation phase and a later decompensation. Histological and molecular alterations occur in the following compartments: urothelium, suburothelium, detrusor smooth muscle cells, detrusor extracellular matrix, nerves. Cyclic stretch, increased hydrostatic and cyclic hydrodynamic pressure and hypoxia are stimuli capable of modulating multiple signaling pathways involved in this remodeling process. CONCLUSIONS: Bladder outlet obstruction leads to progressive bladder tissue remodeling in humans. Multiple signaling pathways are involved. PMID- 29519238 TI - Glyphosate exposure in pregnancy and shortened gestational length: a prospective Indiana birth cohort study. AB - BACKGROUND: Glyphosate (GLY) is the most heavily used herbicide worldwide but the extent of exposure in human pregnancy remains unknown. Its residues are found in the environment, major crops, and food items that humans, including pregnant women, consume daily. Since GLY exposure in pregnancy may also increase fetal exposure risk, we designed a birth-cohort study to determine exposure frequency, potential exposure pathways, and associations with fetal growth indicators and pregnancy length. METHOD: Urine and residential drinking water samples were obtained from 71 women with singleton pregnancies living in Central Indiana while they received routine prenatal care. GLY measurements were performed using liquid chromatography-tandem mass spectrometry. Demographic and survey information relating to food and water consumption, stress, and residence were obtained by questionnaire. Maternal risk factors and neonatal outcomes were abstracted from medical records. Correlation analyses were used to assess relationships of urine GLY levels with fetal growth indicators and gestational length. RESULTS: The mean age of participants was 29 years, and the majority were Caucasian. Ninety three percent of the pregnant women had GLY levels above the limit of detection (0.1 ng/mL). Mean urinary GLY was 3.40 ng/mL (range 0.5-7.20 ng/mL). Higher GLY levels were found in women who lived in rural areas (p = 0.02), and in those who consumed > 24 oz. of caffeinated beverages per day (p = 0.004). None of the drinking water samples had detectable GLY levels. We observed no correlations with fetal growth indicators such as birth weight percentile and head circumference. However, higher GLY urine levels were significantly correlated with shortened gestational lengths (r = - 0.28, p = 0.02). CONCLUSIONS: This is the first study of GLY exposure in US pregnant women using urine specimens as a direct measure of exposure. We found that > 90% of pregnant women had detectable GLY levels and that these levels correlated significantly with shortened pregnancy lengths. Although our study cohort was small and regional and had limited racial/ethnic diversity, it provides direct evidence of maternal GLY exposure and a significant correlation with shortened pregnancy. Further investigations in a more geographically and racially diverse cohort would be necessary before these findings could be generalized. PMID- 29519239 TI - Usefulness of fetal magnetic resonance imaging for postnatal management of congenital lung cysts: prediction of probability for emergency surgery. AB - BACKGROUND: Emergency rescue lung resection is rarely performed to treat congenital lung cysts (CLCs) in neonates. Many reports have described fetal CLC treatment; however, prenatal predictors for postnatal respiratory failure have not been characterized. We hypothesized that fetal imaging findings are useful predictors of emergency surgery. METHODS: We retrospectively studied patients with CLC who underwent lung surgery during the neonatal period in our hospital between January 2001 and December 2015. The demographic data, fetal imaging findings, and intra- and postoperative courses of patients who underwent emergency surgery (Em group) were compared with those of patients who received elective surgery, i.e., non-emergency surgery (Ne group). RESULTS: The Em group and Ne group included 7 and 11 patients, respectively. No significant difference was noted in gestational age, time at prenatal diagnosis, birth weight, and body weight at surgery. The volumes of contralateral lung per thoracic volume were significantly smaller in the Em group than in the Ne group (p = 0.0188). Mediastinal compression was more common in the Em group (7/7) than in the Ne group (4/11) (p = 0.0128). CONCLUSIONS: This is the report describing neonatal emergency lobectomy in patients with CLC evaluated by fetal MRI using the lung volume ratio and mediastinal shift. In patients with CLC, mediastinal shift and significant decreases in contralateral lung volumes during the fetal stages are good prenatal predictors of postnatal emergency lung resection. PMID- 29519240 TI - Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa. AB - BACKGROUND: Hyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas. METHODS: In a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline >= 40% and/or lactate normalisation (lactate < 2.5 mmol/L). RESULTS: Of 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate >= 2.5 mmol/L), and 1179 (39%) had severe HL (>= 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L). At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h (OR 4.62; 95% CI 2.7, 8.0; p < 0.001). CONCLUSIONS: Independently of the underlying diagnosis, HL is a strong risk factor for death at 72 h in children admitted with severe febrile illnesses in Africa. Children able to clear lactate within 8 h had an improved chance of survival. These findings prompt the more widespread use of lactate and LC to identify children with severe disease and monitor response to treatment. TRIAL REGISTRATION: ISRCTN69856593 Registered 21 January 2009. PMID- 29519241 TI - Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. AB - BACKGROUND: Fatty acid oxidation disorders (FAODs) include more than 15 distinct disorders with variable clinical manifestations. After the introduction of newborn screening using tandem mass spectrometry, early identification of FAODs became feasible. This study describes the clinical, biochemical and molecular characteristics of FAODs patients detected by newborn screening (NBS) compared with those of 9 patients with symptomatic presentations. METHODS: Clinical and genetic features of FAODs patients diagnosed by NBS and by symptomatic presentations were reviewed. RESULTS: Fourteen patients were diagnosed with FAODs by NBS at the age of 54.8 +/- 4.8 days: 5 with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 5 with medium chain acyl-CoA dehydrogenase (MCAD) deficiency, 1 with primary carnitine deficiency, 1 with carnitine palmitoyltransferase 1A (CPT1A) deficiency, 1 with long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCAHD/MTP) deficiency, and 1 with short chain acyl-CoA dehydrogenase (SCAD) deficiency. Three patients with VLCAD or LCHAD/MTP deficiency developed recurrent rhabdomyolysis or cardiomyopathy, and one patient died of cardiomyopathy. The other 10 patients remained neurodevelopmentally normal and asymptomatic during the follow-up. In 8 patients with symptomatic presentation, FAODs manifested as LCHAD/MTP deficiencies by recurrent rhabdomyolysis or cadiomyopathy (6 patients), and VLCAD deficiency by cardiomyopathy (1 patient), and CPT1A deficiency by hepatic failure (1 patient). Two patients with LCHAD/MTP deficiencies died due to severe cardiomyopathy in the neonatal period, and developmental disability was noted in CPT1A deficiency (1 patient). CONCLUSIONS: NBS helped to identify the broad spectrum of FAODs and introduce early intervention to improve the clinical outcome of each patient. However, severe clinical manifestations developed in some patients, indicating that careful, life-long observation is warranted in all FAODs patients. PMID- 29519243 TI - Non-AIDS complexity amongst patients living with HIV in Sydney: risk factors and health outcomes. AB - OBJECTIVE: To assess the prevalence of non-AIDS co-morbidities (NACs) and predictors of adverse health outcomes amongst people living with HIV in order to identify health needs and potential gaps in patient management. DESIGN: Retrospective, non-consecutive medical record audit of patients attending a publicly funded HIV clinic in metropolitan Sydney analysed for predictors of adverse health outcomes. We developed a scoring system based on the validated Charlson score method for NACs, mental health and social issues and confounders were selected using directed acyclic graph theory under the principles of causal inference. RESULTS: 211 patient files were audited non-consecutively over 6 weeks. 89.5% were male; 41.8% culturally and linguistically diverse and 4.1% were of Aboriginal/Torres Strait Islander origin. Half of patients had no general practitioner and 25% were ineligible for Medicare subsidised care. The most common NACs were: cardiovascular disease (25%), hepatic disease (21%), and endocrinopathies (20%). One-third of patients had clinical anxiety, one-third major depression and almost half of patients had a lifetime history of tobacco smoking. Five predictors of poor health outcomes were identified: (1) co morbidity score was associated with hospitalisation (odds ratio, OR 1.58; 95% CI 1.01-2.46; p = 0.044); (2) mental health score was associated with hospitalisation (OR 1.79; 95% CI 1.22-2.62; p = 0.003) and poor adherence to ART (OR 2.34; 95% CI 1.52-3.59; p = 0.001); (3) social issues score was associated with genotypic resistance (OR 2.61; 95% CI 1.48-4.59; p = 0.001), co-morbidity score (OR 1.69; 95% CI 1.24-2.3; p = 0.001) and hospitalisation (OR 1.72; 95% CI 1.1-2.7; p = 0.018); (4) body mass index < 20 was associated with genotypic resistance (OR 6.25; 95% CI 1.49-26.24; p = 0.012); and (5) Medicare eligibility was associated with co-morbidity score (OR 2.21; 95% CI 1.24-3.95; p = 0.007). CONCLUSION: Most HIV patients are healthy due to effective antiretroviral therapy; however, NACs and social/mental health issues are adding to patient complexity. The current findings underpin the need for multidisciplinary management beyond routine viral load and CD4 count monitoring. PMID- 29519242 TI - FGF signaling controls Shh-dependent oligodendroglial fate specification in the ventral spinal cord. AB - BACKGROUND: Most oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig2. A minority of oligodendrocytes is also recognized to emerge from dorsal progenitors during fetal development. The prevailing view is that generation of ventral oligodendrocytes depends on Sonic hedgehog (Shh) while dorsal oligodendrocytes develop under the influence of Fibroblast Growth Factors (FGFs). RESULTS: Using the well-established model of the chicken embryo, we show that ventral spinal progenitor cells activate FGF signaling at the onset of oligodendrocyte precursor cell (OPC) generation. Inhibition of FGF receptors at that time appears sufficient to prevent generation of ventral OPCs, highlighting that, in addition to Shh, FGF signaling is required also for generation of ventral OPCs. We further reveal an unsuspected interplay between Shh and FGF signaling by showing that FGFs serve dual essential functions in ventral OPC specification. FGFs are responsible for timely induction of a secondary Shh signaling center, the lateral floor plate, a crucial step to create the burst of Shh required for OPC specification. At the same time, FGFs prevent down regulation of Olig2 in pMN progenitor cells as these cells receive higher threshold of the Shh signal. Finally, we bring arguments favoring a key role of newly differentiated neurons acting as providers of the FGF signal required to trigger OPC generation in the ventral spinal cord. CONCLUSION: Altogether our data reveal that the FGF signaling pathway is activated and required for OPC commitment in the ventral spinal cord. More generally, our data may prove important in defining strategies to produce large populations of determined oligodendrocyte precursor cells from undetermined neural progenitors, including stem cells. In the long run, these new data could be useful in attempts to stimulate the oligodendrocyte fate in residing neural stem cells. PMID- 29519244 TI - Acute liver failure complication of brucellosis infection: a case report and review of the literature. AB - BACKGROUND: Brucellosis is one of the most widespread zoonoses worldwide. It can affect any organ system, particularly the gastrointestinal system, but there is no report of acute liver failure as a brucellosis complication. CASE PRESENTATION: We present a case of acute liver failure secondary to brucellosis infection. A 75-year-old Hispanic man presented to a University Hospital in Chia, Colombia, with a complaint of 15 days of fatigue, weakness, decreased appetite, epigastric abdominal pain, jaundice, and 10 kg weight loss. On examination in an emergency room, abdomen palpation was normal with hepatosplenomegaly and the results of a liver function test were elevated. The diagnosis of brucellosis was confirmed by epidemiological contact and positive Rose Bengal agglutination with negative enzyme-linked immunosorbent assay immunoglobulin M for Brucella. He was then treated with doxycycline plus trimethoprim/sulfamethoxazole, with a favorable clinical outcome. CONCLUSIONS: The clinical presentation of brucellosis can be very imprecise because it can affect any organ system; however, there is no report of acute liver failure as a brucellosis complication. This is the first reported case in the Colombian literature of acute liver failure due to brucellosis. We found this case to be of interest because it could be taken into account for diagnosis in future appearances and we described adequate treatment and actions to be taken at presentation. PMID- 29519246 TI - Prostate cancer involving bilateral seminal vesicles along with bone and testicular metastases: a case report. AB - BACKGROUND: In the past 20 years, the incidence of prostate cancer has risen rapidly. It has been ranked as the third most common malignant tumor of the male genitourinary system. Testicular metastasis is uncommon in prostate cancer. Most cases are incidentally found in the treatment of prostate cancer with orchiectomy. Therefore, we believed it was necessary to report the case of our patient with this disease. CASE PRESENTATION: We present a case of a 69-year-old Han Chinese man with a high total prostate-specific antigen level. A transrectal ultrasound-guided prostate biopsy was performed. A pathology report showed prostate cancer tissue with a Gleason score of 4 + 4 = 8/10. Imaging findings suggested that the prostate cancer tissue involved bilateral seminal vesicles and multiple bones. Next, radioactive seed implantation was carried out, and endocrine therapy was continued after the operation. Then enlargement of the left scrotum was found along with a total prostate-specific antigen level of 19.21 ng/ml. Computed tomography of the middle abdomen and pelvic cavity revealed 2.0 * 1.3-cm lesions of the left testis. The patient underwent a left testicular high resection and right orchiectomy. The postoperative pathology report showed metastatic prostate cancer cells in the left testis. CONCLUSIONS: Testicular metastasis of prostate cancer is rare. Therefore, a testicular physical examination is necessary for patients without relapse to avoid a missed diagnosis. Testicular metastasis should be treated according to the principle of treatment for advanced prostate adenocarcinoma if testicular metastasis of prostate adenocarcinoma is detected. PMID- 29519245 TI - Molecular mechanisms underlying therapeutic potential of pericytes. AB - BACKGROUND: Pericytes are multipotent cells present in every vascularized tissue in the body. Despite the fact that they are well-known for more than a century, pericytes are still representing cells with intriguing properties. This is mainly because of their heterogeneity in terms of definition, tissue distribution, origin, phenotype and multi-functional properties. The body of knowledge illustrates importance of pericytes in the regulation of homeostatic and healing processes in the body. MAIN BODY: In this review, we summarized current knowledge regarding identification, isolation, ontogeny and functional characteristics of pericytes and described molecular mechanisms involved in the crosstalk between pericytes and endothelial or immune cells. We highlighted the role of pericytes in the pathogenesis of fibrosis, diabetes-related complications (retinopathy, nephropathy, neuropathy and erectile dysfunction), ischemic organ failure, pulmonary hypertension, Alzheimer disease, tumor growth and metastasis with the focus on their therapeutic potential in the regenerative medicine. The functions and capabilities of pericytes are impressive and, as yet, incompletely understood. Molecular mechanisms responsible for pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well described while their regenerative and immunomodulatory characteristics are still not completely revealed. Strong evidence for pericytes' participation in physiological, as well as in pathological conditions reveals a broad potential for their therapeutic use. Recently published results obtained in animal studies showed that transplantation of pericytes could positively influence the healing of bone, muscle and skin and could support revascularization. However, the differences in their phenotype and function as well as the lack of standardized procedure for their isolation and characterization limit their use in clinical trials. CONCLUSION: Critical to further progress in clinical application of pericytes will be identification of tissue specific pericyte phenotype and function, validation and standardization of the procedure for their isolation that will enable establishment of precise clinical settings in which pericyte-based therapy will be efficiently applied. PMID- 29519247 TI - Elevated Plasmodium infection rates and high pyrethroid resistance in major malaria vectors in a forested area of Cameroon highlight challenges of malaria control. AB - BACKGROUND: High coverage of long-lasting insecticidal nets (LLINs) is the cornerstone of the malaria control strategy of the national malaria control program (NMCP) in Cameroon, with a target of reducing malaria transmission to less than 10% by 2035. To this end, more than 20 million LLINs have been distributed to populations countrywide since 2011. The present study evaluated entomological indices and Anopheles susceptibility to pyrethroids in a rural forested area of south Cameroon with high coverage of LLINs. METHODS: The study was conducted between July 2014 and May 2016 in Obout, a village located in a rural forested area in south Cameroon. Resting mosquitoes were collected using electric aspirators and were identified to species using morphological criteria and PCR tools. Mosquito feeding preferences and infection status to Plasmodium falciparum were determined by ELISA and using TaqMan assays. The susceptibility of wild F1 adults to pyrethroids was monitored using WHO insecticide susceptibility bioassays. RESULTS: During the study period, 5,993 Anopheles mosquitoes were collected indoors both in rooms with and without nets. Two main vector species, namely An. funestus and An. gambiae, were identified in the locality, with An. funestus being by far the most abundant (89.68%). ELISA analysis revealed high percentage of blood meal taken exclusively on human (97.65 98.95%) supporting the high antropohilic behaviour of both species. Plasmodium falciparum infection rate detected by ELISA was high throughout the study period and varied between 3.28-14.04% (mean: 10.40%) in An. funestus, and between 5.55 22.22% (mean: 13.87%) in An. gambiae. This trend was confirmed by TaqMan assays, with P. falciparum infection prevalence of 23.33% in An. funestus. Significant decrease of mortality associated with high frequency of kdr mutation was observed in An. gambiae (deltamethrin: 36.6-56.45%; permethrin: 6-18.65%) indicating high level of resistance to pyrethroids. For An. funestus, resistance was marked for deltamethrin (mortality: 70.54-76.24%) than for permethrin (94.12-94.74%). CONCLUSIONS: Our study showed that despite LLINs, the population of Obout remains exposed to bites of highly infected An. funestus and An. gambiae mosquitoes, highlighting the challenges to controlling malaria in forested areas, especially in the presence of insecticide resistance. PMID- 29519248 TI - Correction to: Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM. AB - In the original publication of this article [1], published on 8 February 2018, it was noticed that the acknowledgement of the source of the drug ADI-PEG20 was missing. PMID- 29519249 TI - Cardiovascular disease in a nationwide population of Danish women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with obesity and low grade inflammation and the risk for cardiovascular disease (CVD) could be increased in PCOS. METHODS: National register-based study including women with PCOS and no previous diagnosis of CVD, hypertension, or dyslipidemia. PCOS Denmark (N = 18,112) included women with PCOS in the Danish National Patient Register. PCOS Odense University Hospital (OUH, N = 1165) was an embedded cohort including premenopausal women with PCOS and clinical and biochemical examination. Three age-matched controls were included per patient in PCOS Denmark (N = 52,769). The main study outcome was CVD events including hypertension and dyslipidemia defined according to nationwide in- and outpatient hospital contact diagnosis codes and/or inferred from filled medicine prescriptions. RESULTS: The age at inclusion was median (quartiles) 29 (23-35) years and follow up was 11.1 (6.9-16.0) years. The Hazard ratio (95% CI) for development of CVD in PCOS Denmark was 1.7 (1.7; 1.8) (P < 0.001) and the total event rate of CVD was 22.6 per 1000 patient years in PCOS Denmark vs. 13.2 per 1000 patient years in controls (P < 0.001). The median age at diagnosis of CVD was 35 (28-42) years in PCOS Denmark vs. 36 (30-43) years in controls (P < 0.001). Obesity, diabetes, and infertility, and previous use of oral contraceptives were associated with increased risk of development of CVD in PCOS Denmark (P < 0.001). Women in PCOS OUH resembled women in PCOS Denmark regarding risk of CVD. Age, BMI, blood pressure, lipid status, and glycemic status predicted development of CVD in PCOS OUH. CONCLUSION: The event rate of CVD including hypertension and dyslipidemia was higher in PCOS compared to controls. The risk of developing CVD must be considered even in young women with PCOS. PMID- 29519250 TI - Global impact of World Sepsis Day on digital awareness of sepsis: an evaluation using Google Trends. PMID- 29519251 TI - A synbio approach for selection of highly expressed gene variants in Gram positive bacteria. AB - BACKGROUND: The market for recombinant proteins is on the rise, and Gram-positive strains are widely exploited for this purpose. Bacillus subtilis is a profitable host for protein production thanks to its ability to secrete large amounts of proteins, and Lactococcus lactis is an attractive production organism with a long history in food fermentation. RESULTS: We have developed a synbio approach for increasing gene expression in two Gram-positive bacteria. First of all, the gene of interest was coupled to an antibiotic resistance gene to create a growth-based selection system. We then randomised the translation initiation region (TIR) preceding the gene of interest and selected clones that produced high protein titres, as judged by their ability to survive on high concentrations of antibiotic. Using this approach, we were able to significantly increase production of two industrially relevant proteins; sialidase in B. subtilis and tyrosine ammonia lyase in L. lactis. CONCLUSION: Gram-positive bacteria are widely used to produce industrial enzymes. High titres are necessary to make the production economically feasible. The synbio approach presented here is a simple and inexpensive way to increase protein titres, which can be carried out in any laboratory within a few days. It could also be implemented as a tool for applications beyond TIR libraries, such as screening of synthetic, homologous or domain-shuffled genes. PMID- 29519252 TI - A novel method of blind bedside placement of postpyloric tubes. PMID- 29519253 TI - The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor. AB - BACKGROUND: Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia. However, the mechanism of this protection has not been well established. CD44 is a receptor expressed on astrocytes that can bind GPNMB, and CD44 activation has been demonstrated to reduce NFkappaB activation and subsequent inflammatory responses in macrophages. GPNMB signaling has not been investigated in models of PD or specifically in astrocytes. More recently, genetic studies have linked polymorphisms in GPNMB with risk for PD. Therefore, it is important to understand the role this signaling protein plays in PD. METHODS: We used data mining techniques to evaluate mRNA expression of GPNMB and its receptor CD44 in the substantia nigra of PD and control brains. Immunofluorescence and qPCR techniques were used to assess GPNMB and CD44 levels in mice treated with MPTP. In vitro experiments utilized the immortalized mouse astrocyte cell line IMA2.1 and purified primary mouse astrocytes. The effects of recombinant GPNMB on cytokine-induced astrocyte activation was determined by qPCR, immunofluorescence, and measurement of nitric oxide and reactive oxygen production. RESULTS: Increased GPNMB and CD44 expression was observed in the substantia nigra of human PD brains and in GFAP-positive astrocytes in an animal model of PD. GPNMB treatment attenuated cytokine-induced levels of inducible nitric oxide synthase, nitric oxide, reactive oxygen species, and the inflammatory cytokine IL-6 in an astrocyte cell line and primary mouse astrocytes. Using primary mouse astrocytes from CD44 knockout mice, we found that the anti-inflammatory effects of GPNMB are CD44-mediated. CONCLUSIONS: These results demonstrate that GPNMB may exert its neuroprotective effect through reducing astrocyte-mediated neuroinflammation in a CD44-dependent manner, providing novel mechanistic insight into the neuroprotective properties of GPNMB. PMID- 29519255 TI - [Optic nerve infection caused by syphilis]. AB - BACKGROUND: Syphilis, 'the great imitator', can present with a variety of symptoms. CASE DESCRIPTION: A 54-year-old woman attended the hospital clinic for vision problems, preceded by mouth ulcers. Following extensive serological investigations, the diagnosis 'syphilitic optic neuritis' was made. CONCLUSION: It is important to be thoughtful of systemic causes, like syphilis, when patients present with local symptomatology. PMID- 29519254 TI - The preventive effect of antiplatelet therapy in acute respiratory distress syndrome: a meta-analysis. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality that imposes a serious medical burden. Antiplatelet therapy is a potential strategy for preventing ARDS in patients with a high risk of developing this condition. A meta-analysis was performed to investigate whether antiplatelet therapy could reduce the incidence of newly developed ARDS and its associated mortality in high-risk patients. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Medline, and the Web of Science were searched for published studies from inception to 26 October 2017. We included randomized clinical trials, cohort studies and case-control studies investigating antiplatelet therapy in adult patients presenting to the hospital or ICU with a high risk for ARDS. Baseline patient characteristics, interventions, controls and outcomes were extracted. Our primary outcome was the incidence of newly developed ARDS in high-risk patients. Secondary outcomes were hospital and ICU mortality. A random-effects or fixed-effects model was used for quantitative synthesis. RESULTS: We identified nine eligible studies including 7660 high-risk patients who received antiplatelet therapy. Based on seven observational studies, antiplatelet therapy was associated with a decreased incidence of ARDS (odds ratio (OR) 0.68, 95% confidence interval (CI) 0.52-0.88; I2 = 68.4%, p = 0.004). In two randomized studies, no significant difference was found in newly developed ARDS between the antiplatelet groups and placebo groups (OR 1.32, 95% CI 0.72-2.42; I 2 = 0.0%, p = 0.329). Antiplatelet therapy did not reduce hospital mortality in randomized studies (OR 1.15, 95% CI 0.58-2.27; I 2 = 0.0%; p = 0.440) or observational studies (OR 0.80, 95% CI 0.62-1.03; I2 = 31.9%, p = 0.221). CONCLUSIONS: Antiplatelet therapy did not significantly decrease hospital mortality in high-risk patients. However, whether antiplatelet therapy is associated with a decreased incidence of ARDS in patients at a high risk of developing the condition remains unclear. PMID- 29519256 TI - [Discuss the relationship between physicians and pharmacists in the context of euthanasia]. AB - Physicians are regularly confronted with pharmacists who refuse to provide euthanasia drugs. They do not always understand that the provision of euthanasia drugs is not a normal professional activity for pharmacists. It is a lot less clear that pharmacists are also allowed to have fundamental objections. In addition, professional standards lack clarity for pharmacists who do not have such objections to the provision of euthanasia drugs. The relationship between physicians and pharmacists in the context of euthanasia presents problems overlooked by researchers of the third evaluation of the Termination of Life on Request and Assisted Suicide (review procedures) Act (WTL). The professional bodies of physicians and pharmacists should address these as soon as possible. PMID- 29519257 TI - [Loss of kidney function caused by implanted gentamicin sponges]. AB - BACKGROUND: Infected joint replacements can be treated with gentamicin-containing materials for implantation. This may lead to side effects, especially in patients with impaired renal function. CASE DESCRIPTION: A 74-year-old woman underwent two surgeries for an acutely infected hip replacement. Gentamicin sponges (Garacol) were implanted during both interventions. The day after the second operation, her serum gentamicin levels had risen to toxic values. This confirmed the suspicion that she had a kidney impairment which was probably caused by the implanted gentamicin-containing sponges. In order to limit kidney damage, the patient received continuous venovenous haemodiafiltration (CVVHD). Outpatient check-up 3 months later found that the creatinine levels in the serum of the patient had normalised. CONCLUSION: Locally administered gentamicin sponges for implantation can cause therapeutic serum levels leading to systemic side effects. It is advisable to check kidney function before using the sponges. If this is reduced, it is recommended to be cautious when using these sponges for implantation. In case of toxic elevated values, CVVHD can limit kidney damage - which is reversible, given time - by accelerating gentamicin excretion. PMID- 29519258 TI - [Pharmacological treatment of asthma during pregnancy]. AB - - Asthma during pregnancy is associated with an increased risk of preterm delivery, low birth weight and pre-eclampsia.- This condition may be undertreated due to insufficient knowledge and, in particular, concerns about teratogenic effects of asthma medication among treating healthcare professionals and pregnant women.- The risk of teratogenic effects of inhaled medications (ICS, SABA and LABA) is small. These agents have been used by large groups of patients for many years.- Well-controlled asthma with pharmacological therapy during pregnancy is safer and leads to fewer complications then accepting asthma symptoms and exacerbations.- Preconception care for a woman with asthma who is treated with medication is recommended. PMID- 29519259 TI - ['Will I receive a liver transplant in time?'; chance of survival of patients on the liver transplant waiting list]. AB - OBJECTIVE: To calculate the chance of receiving a liver transplant for patients on the liver transplant waiting list in the Netherlands. DESIGN: Retrospective cohort research. METHOD: Data of all patients in the Netherlands on the waiting list for liver transplantation, from the introduction of the model of end-stage liver disease score on 16th December 2006 through to 31st December 2013 were collected. Survival analysis was computed with competing risk analyses. RESULTS: A total of 851 patients were listed, of whom 236 patients with hepatocellular carcinoma, 147 patients with primary sclerosing cholangitis, 142 patients with post-alcoholic liver disease, 93 patients with metabolic liver disease, 78 with viral hepatitis and 155 patients listed for other indications. The median waiting time till transplantation was 196 days. The chance to be transplanted at two years from listing was 65% and the risk of death was 17%. Patients with metabolic liver disease had the highest chance of undergoing liver transplantation. Patients with viral hepatitis were at highest risk of death while on the list, as well as having the lowest chance of undergoing liver transplantation. CONCLUSION: Our study shows a 65% chance of getting transplanted in time after a median waiting time of 6 months in the Netherlands. Sadly, 1 in 6 patients die before liver transplantation can be performed, with the highest risk of death occurring in patients with viral hepatitis. PMID- 29519260 TI - [Inguinal hernia repair: bringing order to variety]. AB - - With around 30,000 interventions a year, correction of an inguinal hernia is one of the most commonly performed surgeries in the Netherlands. One would therefore expect the same technique to be used all over the world by now. There are nevertheless different procedures, depending on a patient's age and history, the type of inguinal hernia and the expertise of the surgeon.- When the pathophysiology of an inguinal hernia became clear at the end of the 19th century, Bassini laid the foundation of modern inguinal hernia surgery: reinforcing the posterior wall of the inguinal canal after repositioning the hernial sac with its contents.- Although current surgical treatment still follows this principle, there are now many different techniques for this. Some are named after the 'inventor' of such an operation (Shouldice, Lichtenstein and Stoppa) while others are indicated with an abbreviation (TEP, TAPP, TIPP and TREPP).- In this review article, we describe the surgical techniques currently most common in the Netherlands and bring order to the chaos of proper names and abbreviations. PMID- 29519261 TI - [EndoBarrier as a treatment for obesity and diabetes]. AB - The EndoBarrier (duodenal-jejunal bypass liner) became available in 2009 as an endoscopic treatment method for obesity and type 2 diabetes mellitus (T2D). The treatment results in significant weight loss and improvement of the obesity related morbidities such as T2D, non-alcoholic steatohepatitis, hypertension and other cardiovascular diseases. However, unexpected complications such as liver abscesses can occur, in addition to expected adverse events such as bleeding, obstruction, and migration. The incidence of these complications is low however, and to date no treatment-related mortality has occurred with the use of EndoBarrier. After more than 3800 procedures, it can be concluded that the EndoBarrier is safe and effective. This treatment option can be applied in patients with a BMI over 30 kg/m2 and also obese patients with T2D who do not wish to undergo, or are not fit for, a surgical procedure. PMID- 29519262 TI - [National population screening for colorectal carcinoma in the Netherlands: results of the first years since the implementation in 2014]. AB - OBJECTIVE: To describe the effect of population screening for colorectal carcinoma (CRC) with the faecal immunochemical test, introduced in 2014, on the incidence of CRC in the Netherlands and to analyse differences between patient and tumour characteristics, stage distribution and treatment of carcinomas that were screening-detected and were not detected by screening (non-screening detected). DESIGN: Retrospective observational study. METHOD: We analysed data from the Netherlands Cancer Registry. We selected all CRCs diagnosed in the 2010 2016 period and calculated incidence rates standardised for the European population. For comparison between screening-detected and non-screening-detected carcinomas, we selected all CRCs diagnosed in 2015. RESULTS: The number of newly diagnosed CRCs rose from 13,028 in 2013 to 15,185 in 2014 and to 15,807 in 2015. This increase could only be seen for the birth years of people who had been invited for population screening during that particular year. The percentage of men was higher for screening-detected carcinomas than for non-screening-detected carcinomas (62% vs 55%). Screening-detected carcinomas were also more often in the left side of the colon (76% vs 64%). The percentage of patients with stage I CRC was higher in the group with screening-detected carcinomas (48% vs 16%). Patients with screening-detected carcinomas more often underwent local treatment or only resection without adjuvant or neoadjuvant treatment than the patients with non-screening-detected carcinomas. CONCLUSION: During the first years after the introduction of population screening, the incidence of CRC has increased as the result of earlier detection. Screening-detected carcinomas have a more favourable stage distribution and these patients are undergoing less-invasive treatment more often. PMID- 29519263 TI - [Handovers during anaesthetic care can be further improved]. AB - In 2005, the Dutch Society of Anaesthesiologists showed that handovers during anaesthetic care increase complication and mortality rates, an observation that has recently been confirmed by a Canadian study. In contrast to surgical care, handovers in anaesthetic care are quite common for various reasons including end of shift, tiredness after night duty, and activities outside the operating centre. The quality of handovers could be improved by training on an anaesthesia simulator, with emphasis on communication, reduction of information loss and using checklists. PMID- 29519264 TI - Validity of caregiver-report measures of language skill for Wolof-learning infants and toddlers living in rural African villages. AB - Valid indigenous language assessments are needed to further our understanding of how children learn language around the world. We assessed the psychometric properties and performance of two caregiver-report measures of Wolof language skill (language milestones achieved and vocabulary knowledge) for 500 children (ages 0;4 to 2;6) living in rural Senegal. Item response models (IRM) evaluated instrument- and item-level performance and differential function by gender. Both caregiver-report measures had good psychometric properties and displayed expected age and socioeconomic effects. Modest concurrent validity was found by comparing the caregiver-report scores to transcribed child language samples from a naturalistic play session. The caregiver-report method offers a valid alternative to more costly tools, such as direct behavioral assessments or language sampling, for measuring early language development in non-literate, rural African communities. Recommendations are made to further improve the performance of caregiver-report measures of child language skill in these settings. PMID- 29519266 TI - Recommendations for the configuration of a cardiac catheterisation laboratory for the treatment of children with CHD. AB - A modern catheter laboratory for the treatment of children with CHD should be in close proximity to the paediatric ICU, operating theatres, and imaging facilities. Space requirements and equipment for an up-to-date catheter laboratory are discussed. The document was endorsed by the council of the Association of European Paediatric and Congenital Cardiologists. PMID- 29519267 TI - The Comparison of Heterogeneous / Homogeneous Crystallization for 1 Phosphate Recovery from Biosolids. AB - In this study, a fluidized bed reactor was used to compare heterogeneous and homogeneous 15 crystallization for recovering magnesium ammonia phosphate (MAP) from the dewatering filtrate at a municipal wastewater treatment plant. PMID- 29519265 TI - Seasonality of helminth infection in wild red deer varies between individuals and between parasite taxa. AB - Parasitism in wild mammals can vary according to myriad intrinsic and extrinsic factors, many of which vary seasonally. However, seasonal variation in parasitism is rarely studied using repeated samples from known individuals. Here we used a wild population of individually recognized red deer (Cervus elaphus) on the Isle of Rum to quantify seasonality and intrinsic factors affecting gastrointestinal helminth parasitism over the course of a year. We collected 1020 non-invasive faecal samples from 328 known individuals which we then analysed for propagules of three helminth taxa: strongyle nematodes, the common liver fluke Fasciola hepatica and the tissue nematode Elaphostrongylus cervi. Zero-inflated Poisson models were used to investigate how season, age and sex were associated with parasite prevalence and count intensity, while Poisson models were used to quantify individual repeatability within and between sampling seasons. Parasite intensity and prevalence varied according to all investigated factors, with opposing seasonality, age profiles and sex biases between parasite taxa. Repeatability was moderate, decreased between seasons and varied between parasites; both F. hepatica and E. cervi showed significant between-season repeatability, while strongyle nematode counts were only repeatable within-season and showed no repeatability within individuals across the year. PMID- 29519268 TI - Hepatocyte Wnts Are Dispensable During Diethylnitrosamine and Carbon Tetrachloride-Induced Injury and Hepatocellular Cancer. AB - Activation of the Wnt/beta-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulation of Wnt genes is one contributing mechanism. In the current study, we sought to address the role of hepatocyte derived Wnts in a model of hepatic injury, fibrosis, and carcinogenesis. We subjected hepatocyte-specific Wntless knockout mice (HP-KO), unable to secrete Wnts from hepatocytes, and littermate controls (HP-CON) to diethylnitrosamine and carbon tetrachloride (DEN/CCl4) and harvested at 3, 5, and 6 months for histological and molecular analysis. Analysis at 5 months displayed increased hepatic expression of several Wnts and upregulation of some, but not all, beta catenin targets, without mutations in Ctnnb1. At 5 months, HP-CON and HP-KO had comparable tumor burden and injury; however, HP-KO uniquely showed small CK19+ foci within tumors. At 6 months, both groups were moribund with comparable tumor burden and CK19 positivity. While HCC histology was indistinguishable between the groups, HP-KO exhibited increased active beta-catenin and decreased c-Myc, Brd4, E-cadherin, and others. Hepatic injury, inflammation, and fibrosis were also indistinguishable at 3 months between both groups. Thus, lack of Wnt secretion from hepatocytes did not affect overall injury, fibrosis, or HCC burden, although there were protein expression differences in the tumors occurring in the two groups. PMID- 29519269 TI - Comparison of microbial removal between slow dead-end versus tangential sand filtration. AB - Both River-Bank Filtration and dead-end sand-filtration are becoming increasingly applied in rural areas to improve quality of fecally contaminated water. To evaluate the capacity of both treatments to remove E. coli, fecal streptococci, somatic and K13 phages, we have studied their concentrations in diluted wastewater after short-distance tangential sand-filtration and after dead-end sand-filtration.Bacteria were almost undetectable in both systems after sixty cm depth and at a pore water velocity of 1 m/d. Both phages underwent removal of 2.5 logs by tangential filtration, whereas dead-end filtration removed 5.1 logs and 3.9 logs of K13 and somatic phages, respectively. After discounting removal by the schmutzdecke, observed only in the dead-end filtration, both systems removed phages similarly.We conclude that short-distance river bank filtration alone does not meet WHO requirements for drinking water. However, the reduction of suspended solids renders the filtered water amenable to further treatment steps. PMID- 29519270 TI - Status, Challenges and Perspectives of Mainstream Nitritation-Anammox for Wastewater Treatment. AB - The nitritation-anammox process is an efficient and cost-effective approach for biological nitrogen removal, but its application in treating mainstream wastewater remains a great challenge. Mainstream nitritation-anammox processes could create opportunities for achieving energy self-sufficient or energy generating wastewater treatment plants. Significant advancements have been achieved via pilot- and full-scale trials to overcome the major obstacles under mainstream conditions, such as repression of nitrite-oxidizing bacteria, limiting the overgrowth of denitrifiers, and effective selection and retention of ammonia oxidizing bacteria and anammox bacteria. This review paper intends to provide a detailed update of research progress on mainstream nitritation-anammox processes, discuss metabolic interactions, and examine major challenges and possible solutions towards the future development of mainstream nitritation-anammox. PMID- 29519271 TI - Reduction of Turbidity and Chromium Content of Tannery Wastewater by Electrocoagulation Process. AB - The present study is carried out to remove chromium and turbidity from tannery wastewater using the electrocoagulation process with aluminum electrodes. This experimental study is carried out using a batch system. The applied pilot comprises a reactor containing two parallel metal electrodes (Al). The latter are connected as monopolar, and a different potential is applied between them. Several working parameters, such as applied potential difference, electrolysis time, active electrode surface, interelectrode distance, and the pH of the medium have been studied to achieve higher removal efficiency. The treatment reached a maximum reduction of 99% for turbidity and 93% for chromium under the following conditions: 15 V applied potential difference, 45 cm2 electrode surface, 1 cm interelectrode distance, pH 6.1 raw water, and a contact time of 90 min. Given the treatment efficiency obtained in this study, electrocoagulation process has the potential to be used for the cost-effective removal of wastewater pollutants. PMID- 29519272 TI - LED-Based UV Oxidation of Pharmaceuticals: Effects of Wavelength and Intensity, pH, and TiO2 Loading. AB - The presence of pharmaceuticals in water resources has alarmed water and health authorities. In this study, ultraviolet(UV)-based oxidation was evaluated to decompose sulfamethoxazole, ibuprofen, and triclosan in comparison. In particular, as an alternative UV source to problematic conventional mercury lamps, light emitting diode (LED), so-called UV-LED, was evaluated for the decomposition of the pharmaceuticals in water under various conditions varying UV wavelength, irradiation intensity, reaction pH, and TiO2 loading. Photolytic decomposition of the pharmaceuticals was also compared with their photocatalytic decomposition. Photolytic decomposition of the pharmaceuticals was solely determined by relation between their UV absorption characteristics and the UV emission spectra of LEDs. Both photolytic decomposition and photocatalytic decomposition were greatly affected by reaction pH. The presence of TiO2 in cases that significant photolysis was present, rather inhibited the overall decomposition process. However, in all cases, photocatalysis showed better mineralization than photolysis. PMID- 29519273 TI - A New Photocatalyst Bismuth Oxo Citrate: Synthesis, Characterization, and Photocatalytic Performance. AB - A new photocatalyst bismuth oxo citrate was synthesized by facile precipitation process with calcination at 200 degrees C. The photocatalyst was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, N2 sorptometry, and elemental analysis. Morphologically, it is composed of polyhedral particles with different, irregular shapes and sizes. The specific surface area (SSA) of the photocatalyst was 8.92 m2 g-1. It showed very good photocatalytic performance and reusability. Total decolorization of Reactive Blue 19 (RB19) was achieved in less than 10 minutes, which is much faster in comparison with TiO2 P25. Also, bismuth oxo citrate showed higher photocatalytic activity than other photocatalysts based on bismuth compounds reported by other authors. Optimal photocatalysis parameters were pH 2 and photocatalyst dose of 250 mg dm-3. The decolorization rate was found to decrease as initial dye concentration increased. The photocatalytic data best fitted to L-H kinetic model with pseudo-first order reaction rate. Chrastil diffusion model showed that diffusion has not influence on the process. PMID- 29519274 TI - [Expert consensus of Chinese and Western medicine emergency treatment for acute ischemic stroke in China]. PMID- 29519275 TI - [Effect of different concentrations of hypertonic sodium fluid resuscitation on intestine injury in rats at the early stage of severe burn]. AB - OBJECTIVE: To investigate the effect of different concentrations of hypertonic saline solution (HS) on intestine injury in rats at the early stage of severe burn. METHODS: 104 adult healthy female Sprague-Dawley (SD) rats were randomly divided into five groups: sham group (n = 8), lactated Ringer solution (LR) group (n = 24) and 200, 300, 400 mmol/L HS group (HS200 group, HS300 group, HS400 group, all n = 24). All the rats in LR group and different concentrations of HS groups were scalded for 30% total body surface area (TBSA) with III degree, after immediately, the rats were given burn resuscitation therapy by LR or corresponding concentrations of HS through the tail vein. Eight rats were sacrificed on the 2nd, 8th and 24th post-injury hour (PIH), respectively, to collect abdominal aorta blood and intestinal tissues. The rats in sham group were given simulation of burns without resuscitation, which were immediately sacrificed and the specimens were harvested. The serum Na+ concentration was determined by automatic biochemical analyzer. Tumor necrosis factor-alpha (TNF alpha) and interleukin-1beta (IL-1beta) contents in serum were determined by enzyme-linked immunosorbent assay (ELISA). The moisture content of intestine reflected by intestine wet/dry weight (W/D) ratio was determined. The content of malondialdehyde (MDA) and the activity of diamine oxidase (DAO) in intestinal tissue were determined by ultraviolet spectrophotometer. The activation of von Willebrand factor (vWF) was assessed by using immunohistochemistry. RESULTS: Compared with sham group, and the contents of TNF-alpha and IL-1beta in blood and W/D ratio and MDA contents in intestine at each time point after injury in LR group and three HS groups were significantly increased, and the activity of intestinal DAO was significantly decreased. The serum Na+ concentration was significantly reduced in the LR group as compared with that in the sham group, which was significantly higher in the three HS groups than that in the sham group, with the most obvious change on the 8th PIH. Compared with LR group, the serum Na+ concentration and the activity of intestine DAO at each time point after injury in different concentrations of HS groups were significantly increased, and the serum contents of TNF-alpha, IL-1beta and the W/D ratio, MDA contents in intestine were significantly lowered showing a dose dependent. The changes of HS400 group was the most significantly, and the difference on the 8th PIH was statistically significant as compared with LR group [blood Na+ (mmol/L): 145.51+/-0.72 vs. 131.52+/-0.85, intestinal DAO (U/g): 4.85+/-0.30 vs. 3.50+/ 0.45, blood TNF-alpha (ng/L): 88.47+/-4.91 vs. 153.21+/-13.45, blood IL-1beta (ng/L): 85.77+/-3.42 vs. 140.57+/-10.46, intestinal W/D ratio: 3.32+/-0.05 vs. 3.73+/-0.09, intestinal MDA (nmol/mg): 0.58+/-0.01 vs. 0.82+/-0.04, all P < 0.05]. The immunohistochemical results showed that the vWF activity in the LR group and different concentrations of HS groups was significantly reduced as compared with that of the sham group. Compared with LR group, the activity of intestinal vWF at each time point in different concentration of HS groups was increased to some extent with a dose dependent. The positive staining in HS400 group was the deepest, which showed that the activity of intestinal vWF was the strongest after treated by 400 mmol/L HS. CONCLUSIONS: Compared with LR, HS can attenuate intestinal tissue injury of rats at the early stage of severely burned, and of all, the curative effect of 400 mmol/L HS is the best. PMID- 29519276 TI - [Effects of acute respiratory distress syndrome induced by endotoxin on the right ventricular function in rats]. AB - OBJECTIVE: To explore the effect of acute respiratory distress syndrome (ARDS) induced by endotoxin on the right ventricular function in rats. METHODS: Sixty male Sprague-Dawley (SD) rats were randomly divided into normal saline (NS) control group and lipopolysaccharide (LPS) model group with 30 rats in each group. The rat model of ARDS was reproduced by intratracheal instillation of LPS 10 mg/kg after tracheotomy, and the rats in NS control group was intratracheally given the same volume of NS instead of LPS. The survival of rats in each group was observed. Right ventricular function was evaluated by echocardiography at 6 hours and 12 hours after instillation of LPS or NS respectively. Then the rats were sacrificed by bloodletting, and the right heart and lung tissue were harvested. The lung wet/dry weight (W/D) ratio was assessed. The pathological changes in cardiopulmonary tissue in rats were observed with hematoxylin and eosin (HE) strain, and the pathological score of lung injury was calculated. RESULTS: There was no animal death in NS control group. In LPS model group, there were 3 rats dead at 6 hours, and 4 dead at 12 hours. The pathological manifestations of lung injury were found at 6 hours after instillation of LPS, and the marked pathological changes of ARDS, such as atelectasis and hyaline membranes were observed at 12 hours. There was no obvious abnormality in the lung tissue of the NS control group. Compared with the NS control group, the 12-hour lung W/D ratio and the lung injury pathological score in the LPS model group were significantly increased (lung W/D ratio: 7.69+/-1.02 vs. 4.14+/-0.48, lung injury pathological score: 8.26+/-2.12 vs. 1.32+/-0.94, both P < 0.01). Echocardiography showed that the right heart function of rats was significantly abnormal with the prolongation of LPS induction time, which showed that pulmonary arterial diameter (PAD) and right ventricular diastolic diameter (RVDd) were increased, maximum blood flow velocity of pulmonary artery (PAVmax), maximum pulmonary artery pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT) and tricuspid annular plane systolic excursion (TAPSE) were decreased, with significant differences at 12 hours as compared with those of NS normal group [PAD (mm): 2.84+/-0.31 vs. 2.11+/-0.37, RVDd (mm): 4.18+/-0.71 vs. 3.17+/-0.40, PAVmax (mm/s): 704.00+/-145.13 vs. 809.59+/-120.48, PAmaxPG (mmHg, 1 mmHg = 0.133 kPa): 2.07+/-0.88 vs. 2.73+/-0.76, PAAT (ms): 23.80+/-4.87 vs. 30.01+/-3.02, TAPSE (mm): 2.48+/-0.45 vs. 3.56+/-0.40, all P < 0.01]. Pathological examination showed that the cardiac tissue in the LPS model group showed disorder of myocardial cells and scattered inflammatory cells at 6 hours, and cardiomyocyte degeneration, structural destruction and inflammatory cells were found at 12 hours. CONCLUSIONS: ARDS induced by instillation of LPS at 12 hours causes right ventricular dysfunction in rats. PMID- 29519277 TI - [Effects of heme oxygenase-1/carbon monoxide pathway on the mitochondrial fusion in rat alveolar epithelial type II cells stimulated by lipopolysaccharide]. AB - OBJECTIVE: To investigate the effects of heme oxygenase-1/carbon monoxide (HO 1/CO) pathway on mitochondrial fusion in rat alveolar epithelial type II cells (AEC II) stimulated by lipopolysaccharide (LPS). METHODS: Once the cultured in vitro rat AEC II cells line RLE-6TN reached confluency of 85%, they were subcultured and randomly divided into seven groups (n = 5 each). RLE-6TN cells were routinely cultured in control group. The cells in LPS group was stimulated with 10 mg/L LPS to reproduce the model of endotoxin challenge in AECII cells. The cells in carbon monoxide-releasing molecule-2 (CORM-2, in vitro CO release agent) + LPS group (CL group) and Hemin (HO-1 inducer) + LPS group (HL group) were pretreated with 100 MUmol/L CORM-2 or 20 MUmol/L Hemin for 1 hour, respectively, followed by 10 mg/L LPS stimulation. The cells in zinc protoporphyrin-IX (ZnPP-IX, HO-1 inhibitor) + LPS group (ZL group) was pretreated with 10 MUmol/L ZnPP-IX for 0.5 hour followed by 10 mg/L LPS stimulation. The cells in CORM-2 + ZnPP-IX + LPS group (CZL group) and Hemin + ZnPP-IX + LPS group (HZL group) were pretreated with 100 MUmol/L CORM-2 or 20 MUmol/L Hemin respectively for 1 hour, and other treatments were similar to those previously described in ZL group. At 24 hours after LPS stimulation, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the supernatant were determined by enzyme linked immunosorbent assay (ELISA), the protein expressions of HO-1, mitochondrial fusion related proteins 1 and 2 (Mfn1, Mfn2) and optic atrophy 1 (OPA1) were determined by Western Blot. RESULTS: Compared with control group, IL 6 and TNF-alpha contents in the supernatant were increased, HO-1 protein expression was up-regulated, Mfn1, Mfn2 and OPA1 protein expressions were down regulated in all treatment groups. Compared with LPS group, IL-6 and TNF-alpha contents were significantly decreased after CORM-2 or Hemin pretreatment [IL-6 (ng/L): 48.6+/-3.7, 48.4+/-3.1 vs. 58.7+/-2.5; TNF-alpha (ng/L): 40.7+/-5.3, 39.4+/-4.3 vs. 51.8+/-5.1], the protein expressions of HO-1, Mfn1, Mfn2 and OPA1 were significantly up-regulated (HO-1 protein: 0.873+/-0.051, 0.839+/-0.061 vs. 0.671+/-0.044; Mfn1 protein: 0.673+/-0.037, 0.654+/-0.025 vs. 0.568+/-0.021; Mfn2 protein: 0.676+/-0.044, 0.683+/-0.035 vs. 0.571+/-0.043; OPA1 protein: 0.648+/ 0.031, 0.632+/-0.031 vs. 0.554+/-0.032; all P < 0.05); while opposite effects were found after ZnPP-IX preincubation, and there were significant differences in IL-6 and TNF-alpha contents and protein expressions of HO-1, Mfn1, Mfn2 and OPA1 as compared with those of LPS group [IL-6 (ng/L): 69.8+/-5.1 vs. 58.7+/-2.5, TNF alpha (ng/L): 61.9+/-3.3 vs. 51.8+/-5.1, HO-1 protein: 0.545+/-0.023 vs. 0.671+/ 0.044, Mfn1 protein: 0.406+/-0.051 vs. 0.568+/-0.021, Mfn2 protein: 0.393+/-0.051 vs. 0.571+/-0.043, OPA1 protein: 0.372+/-0.050 vs. 0.554+/-0.032; all P < 0.05]. There were no significant differences in the parameters mentioned above between HL group and CL group, as well as among LPS, CZL and HZL groups. CONCLUSIONS: HO 1/CO pathway promotes mitochondrial fusion and alleviates inflammatory response in LPS-induced rat AEC II cells. PMID- 29519278 TI - [Effect of early intervention with heparin on function of coagulopathy, liver and kidney in rats with exertional heatstroke under the ambient air of high temperature and low humidity]. AB - OBJECTIVE: To explore the effects of early intervention with heparin on function of coagulopathy, liver and kidney as well as the prognosis in rats with exertional heatstroke (EHS) under the ambient air of high temperature and low humidity. METHODS: 108 healthy SPF male Sprague-Dawley (SD) rats were randomly divided into normal temperature control group, EHS + normal saline (NS) group and EHS + heparin group. Of which 54 rats were collected for survival analysis (18 rats in each group), the weight change and 8-hour survival rate were observed, and Kaplan-Meier survival curves were drawn. Other 54 rats were collected for intervention experiment, the rats in each group were subdivided into 0, 1, 2 hours subgroups according to the time points of intervention with heparin after model reproduction, with 6 rats in each subgroup. The rats were placed in an artificial experiment cabin with northwest special environment, and the temperature and the relative humidity were (25.0+/-1.0) centigrade and (35+/-5)%, respectively, in normal temperature control group, and the rats were not treated in the cabin. The rats in EHS + NS group and EHS + heparin group kept running in the cabin which temperature and relative humidity were set at (43.0+/-0.5) centigrade and (35+/-5)% until the anus temperature of rats reached 43.0 centigrade, and then the rats were placed in room temperature. The rats were injected with 1 mL/kg NS or 250 U/kg heparin sodium injection through their caudal veins at 0, 1, and 2 hours, respectively, and then the blood was collected after 1.5 hours to determine the biochemical parameters including coagulation, liver and kidney as well as platelet count (PLT). RESULTS: (1) The weight loss of EHS + NS group and EHS + heparin group was more significant than that of normal temperature control group (g: 8.28+/-1.41, 8.39+/-1.38 vs. 2.06+/-1.06, both P < 0.05), but there was no significant difference between EHS + NS group and EHS + heparin group. (2) As the time went on after modeling, serum creatinine (SCr), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), activated partial thromboplastin time (APTT), and D-dimer of EHS rats showed a tendency of increasing, but fibrinogen (FBG), antithrombin III (AT III) and PLT were decreased gradually, which were obviously abnormal as compared with those at corresponding time point of the normal temperature control group. Heparin intervention 0 hour after modeling could improve the function of liver and kidney, FBG, D-dimer, AT III and PLT, but APTT was prolonged further. The SCr, BUN, ALT, AST and CK in EHS 2 hours + heparin group were still better than EHS + NS group [SCr (MUmol/L): 93.33+/ 7.69 vs. 110.50+/-13.56, BUN (mmol/L): 20.55+/-1.35 vs. 24.88+/-2.41, ALT (U/L): 322.17+/-36.36 vs. 492.33+/-64.19, AST (U/L): 1 252.33+/-240.86 vs. 2 725.67+/ 461.17, CK (U/L): 1 4628.67+/-2 784.68 vs. 2 6843.00+/-2 637.16, all P < 0.01], APTT was significantly prolonged (s: 51.83+/-6.11 vs. 33.83+/-4.31, P < 0.01), and AT III and PLT were significantly increased [AT III: (78.03+/-9.15)% vs. (64.28+/-12.55)%, PLT (*109/L): 457.67+/-32.33 vs. 415.83+/-26.45, both P < 0.05], however, there was no obvious influence on FBG or D-dimer. (3) The rats in normal temperature control group were all survived within 8 hours, and all dead in EHS + NS group. The survival rate of rats given heparin intervention at 0, 1, 2 hours after successfully modeling was 50.0%, 33.3% and 0%, respectively. Kaplan Meier survival curve analysis showed that 8-hour cumulative survival rate in EHS 0 hour, 1 hour + heparin groups was higher than that in EHS 0 hour, 1 hour + NS groups (chi12 = 7.930, P1 = 0.005; chi 22 = 4.408, P2 = 0.036), however, there was no significant difference between EHS 2 hours + heparin group and EHS 2 hours + NS group (chi 2 = 2.660, P = 0.103). CONCLUSIONS: Early heparin intervention can improve the coagulation function and organ function of EHS rats, while improving the survival rate of rats, indicating the earlier intervention of heparin, the better prognosis of rats is. PMID- 29519279 TI - [Effect of sucralfate on cytokines in rat with paraquat poisoning]. AB - OBJECTIVE: To explore the effect of sucralfate on cytokines in rats with paraquat (PQ) poisoning. METHODS: Seventy-two healthy male Sprague-Dawley (SD) rats were randomly divided into PQ model group, sodium bicarbonate intervention group (SB group) and sucralfate suspension gel group (LTL group), with 24 rats in each group. The rat model of PQ poisoning was reproduced by one-time intragastric administration of PQ solution 25 mg/kg. The rats in SB group and LTL group were intragastricly administrated with 5 mL*kg-1*d-1 of 100 g/L sodium bicarbonate or 200 g/L sucralfate at 2 hours after exposing to PQ, and the rats in PQ model group were given the same amount of sterile saline. The abdominal aortic blood of rats was collected at 1, 3, 6, and 10 days after PQ poisoning, and the levels of serum tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1) were determined by enzyme-linked immunosorbent assay (ELISA). The left lung tissue was harvested, and lung wet/dry weight (W/D) ratio was assessed. RESULTS: With prolonged exposure, lung W/D ratios in all the groups were increased gradually, reached the peak at 10 days, but in the SB group and LTL group, the amplitude of increase was obviously reduced, the ratios were significantly decreased at 6 days and 10 days as compared with those in PQ model group (SB group vs. PQ model group: 4.99+/-0.79 vs. 6.98+/-0.86 at 6 days, 5.61+/-0.36 vs. 7.36+/-0.95 at 10 days; LTL group vs. PQ model group: 4.61+/-0.24 vs. 6.98+/-0.86 at 6 days, 4.24+/-0.20 vs. 7.36+/ 0.95 at 10 days, all P < 0.05), but there was no significant difference between SB group and LTL group (all P > 0.05). After PQ poisoning, the levels of TNF alpha, IL-10 and TGF-beta1 were elevated, and reached the peak at 3 days and then decreased gradually. Compared with the PQ model group, serum TNF-alpha, IL-10 and TGF-beta1 levels in SB group and LTL group were decreased significantly [SB group vs. PQ model group: 3-day TNF-alpha (ng/L) was 147.6+/-12.3 vs. 168.2+/-11.3, 3 day IL-10 (ng/L) was 65.4+/-3.2 vs. 115.1+/-9.2, 3-day TGF-beta1 (ng/L) was 356.3+/-50.3 vs. 415.6+/-68.3; LTL group vs. PQ model group: 3-day TNF-alpha (ng/L) was 82.2+/-7.4 vs. 168.2+/-11.3, 3-day IL-10 (ng/L) was 44.4+/-5.2 vs. 115.1+/-9.2, 3-day TGF-beta1 (ng/L) was 296.3+/-40.2 vs. 415.6+/-68.3, all P < 0.05], especially in LTL group (all P < 0.05). CONCLUSIONS: Early gastrointestinal lavage with sucralfate could effectively reduce the inflammatory exudation in lung tissue after PQ poisoning, and inhibit the cytokine secretion. PMID- 29519280 TI - [Variability of peripheral arterial peak velocity predicts fluid responsiveness in patients with septic shock]. AB - OBJECTIVE: To explore the accuracy of fluid responsiveness assessment by variability of peripheral arterial peak velocity and variability of inferior vena cava diameter (DeltaIVC) in patients with septic shock. METHODS: A prospective study was conducted. The patients with septic shock undergoing mechanical ventilation (MV) admitted to intensive care unit (ICU) of Beijing Electric Power Hospital from January 2016 to December 2017 were enrolled. According to sepsis bundles of septic shock, volume expansion (VE) was conducted. The increase in cardiac index (DeltaCI) after VE >= 10% was defined as liquid reaction positive (responsive group), DeltaCI < 10% was defined as the liquid reaction negative (non-responsive group). The hemodynamic parameters [central venous pressure (CVP), intrathoracic blood volume index (ITBVI), stroke volume variation (SVV), DeltaIVC, variability of carotid Doppler peak velocity (DeltaCDPV), and variability of brachial artery peak velocity (DeltaVpeak-BA)] before and after VE were monitored. The correlations between the hemodynamic parameters and DeltaCI were explored by Pearson correlation analysis. Receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of all hemodynamic parameters on fluid responsiveness. RESULTS: During the study, 74 patients with septic shock were included, of whom 9 were excluded because of peripheral artery stenosis, recurrent arrhythmia or abdominal distension influencing the ultrasound examination, and 65 patients were finally enrolled in the analysis. There were 31 patients in the responsive group and 34 in the non-responsive group. SVV, DeltaIVC, DeltaCDPV and DeltaVpeak-BA before VE in responsive group were significantly higher than those of the non-responsive group [SVV: (12.3+/-2.4)% vs. (9.2+/-2.1)%, DeltaIVC: (22.3+/-5.3)% vs. (15.5+/-3.7)%, DeltaCDPV: (15.3+/ 3.3)% vs. (10.3+/-2.4)%, DeltaVpeak-BA: (14.5+/-3.3)% vs. (9.6+/-2.3)%, all P < 0.05]. There was no significant difference in CVP [mmHg (1 mmHg = 0.133 kPa): 7.5+/-2.5 vs. 8.2+/-2.6] or ITBVI (mL/m2: 875.2+/-173.2 vs. 853.2+/-192.0) between the responsive group and non-responsive group (both P > 0.05). There was no significant difference in hemodynamic parameter after VE between the two groups. Correlation analysis showed that SVV, DeltaIVC, DeltaCDPV, and DeltaVpeak BA before VE showed significant linearity correlation with DeltaCI (r value was 0.832, 0.813, 0.854, and 0.814, respectively, all P < 0.05), but no correlation was found between CVP and DeltaCI (r = -0.342, P > 0.05) as well as ITBVI and DeltaCI (r = -0.338, P > 0.05). ROC curve analysis showed that the area under ROC curve (AUC) of SVV, DeltaIVC, DeltaCDPV, and DeltaVpeak-BA before VE for predicting fluid responsiveness was 0.857, 0.826, 0.906, and 0.866, respectively, which was significantly higher than that of CVP (AUC = 0.611) and ITBVI (AUC = 0.679). When the optimal cut-off value of SVV for predicting fluid responsiveness was 11.5%, the sensitivity was 70.4%, and the specificity was 94.7%. When the optimal cut-off value of DeltaIVC was 20.5%, the sensitivity was 60.3%, and the specificity was 89.7%. When the optimal cut-off value of DeltaCDPV was 13.0%, the sensitivity was 75.2%, and the specificity was 94.9%. When the optimal cut-off value of DeltaVpeak-BA was 12.7%, the sensitivity was 64.8%, and the specificity was 89.7%. CONCLUSIONS: Ultrasound assessment of DeltaIVC, DeltaCDPV, and DeltaVpeak-BA could predict fluid responsiveness in patients with septic shock receiving mechanical ventilation. DeltaCDPV had the highest predictive value among these parameters. PMID- 29519281 TI - [Predictive value of red cell distribution width on the prognosis of patients with abdominal sepsis]. AB - OBJECTIVE: To approach the value of red cell distribution width (RDW) on the prognostic assessment of patients with abdominal sepsis. METHODS: The clinical data of adult patients with abdominal sepsis admitted to intensive care unit (ICU) of Affiliated Hospital of Guizhou Medical University from January 2015 to September 2017 were retrospectively analyzed. The patients were divided into survival group and death group according to ICU prognosis. The levels of serum lactate (Lac), procalcitonin (PCT), RDW, and acute physiology and chronic health evaluation II (APACHE II) score within 24 hours were recorded. Receiver operating characteristic (ROC) curve was plotted to analyze the prognostic value of Lac, PCT, RDW and APACHE II score. RESULTS: 162 patients with abdominal sepsis were enrolled, 132 survived, and 30 died. Compared with survival group, the Lac, PCT, APACHE II score, and RDW in death group were significantly increased [Lac (mmol/L): 4.21+/-2.42 vs. 2.27+/-1.51, PCT (mg/L): 32.08+/-12.95 vs. 11.87+/ 8.81, APACHE II score: 30.13+/-6.42 vs. 23.36+/-5.29, RDW: (16.64+/-1.38)% vs. (13.49+/-2.03)%, all P < 0.01]. ROC curve analysis showed that all indicators could be used to predict the prognosis of abdominal sepsis, with the maximum predictive value of RDW. The area under the ROC curve (AUC) was 0.888, it was greater than that of APACHE II score (AUC = 0.787), Lac (AUC = 0.767) and PCT (AUC = 0.696). When threshold value of RDW was 15.40%, the sensitivity was 83.3%, and the specificity was 85.6%. CONCLUSIONS: RDW can evaluate the prognosis of patients with abdominal sepsis, and its predictive value is greater than traditional evaluation parameters such as APACHE II score, Lac, and PCT. PMID- 29519282 TI - [Profile and outcome of cardiopulmonary resuscitation after sudden cardiac arrests in the emergency department: a multicenter prospective observational study]. AB - OBJECTIVE: To investigate the status of cardiopulmonary resuscitation (CPR) in patients with sudden cardiac arrest (CA) in the emergency department. METHODS: A multicenter prospective observational study was conducted. The patients with CA admitted to 13 hospitals from 6 provinces in four different regions, including North China, Southern China, East China, Southwest China, from July 1st, 2015 to July 31st, 2017 were enrolled. A modified Utstein template was applied to collect clinical data, including general data, CA related data and prognosis, and primary outcome indicator was the return of spontaneous circulation (ROSC) rate, and the secondary outcome indicator was 28-day survival rate. The influence factors of ROSC were screened by Logistic regression analysis. RESULTS: The data of 613 patients with CA in 13 hospitals were enrolled. The ROSC rate in Beijing and Guangdong Province was higher, but there was no significant difference in 28-day survival rate among hospitals from different provinces. (1) In 613 patients with CA, there were 413 patients suffering from in-hospital cardiac arrest (IHCA, 67.4%), and 200 suffering from out-hospital cardiac arrest (OHCA, 32.6%). 208 patients had ROSC at least once (33.9%), only 20 patients survived within 28 days (3.3%). ROSC rate in IHCA patients was significantly higher than that in OHCA patients [37.3% (154/413) vs. 27.0% (54/200), P < 0.01]. There was no statistic difference in 28-day survival rate between patients with IHCA and OHCA. The patients received manual chest compression, electric defibrillation, or epinephrine <= 4 mg had higher ROSC rate, but 28-day survival rate showed no significant difference. Multivariate Logistic regression analysis showed that IHCA [odds ratio (OR) = 1.893, 95% confidence interval (95%CI) = 1.253-2.858, P = 0.002], manual chest compression (OR = 0.506, 95%CI = 0.348-0.736, P = 0.000), electric defibrillation (OR = 0.458, 95%CI = 0.300-0.699, P = 0.000), and total adrenalin <= 4 mg (OR = 0.317, 95%CI = 0.216-0.464, P = 0.000) were the protective factors of ROSC in CA patients. (2) In 200 OHCA patients, there were 49 patients had ROSC (24.5%), only 5 patients survived (2.5%). The patients aging < 65 years, with witnesses of CPR, received manual chest compression, electric defibrillation, or epinephrine <= 4 mg had higher ROSC rate, and the ROSC rate was higher in ambulances than that at home and in public sites, but 28-day survival rate showed no significant difference. Multivariable Logistic regression analysis showed that age < 65 years old (OR = 2.749, 95%CI = 1.192-6.336, P = 0.018), manual chest compressions (OR = 0.196, 95%CI = 0.072-0.535, P = 0.001), electric defibrillation (OR = 0.263, 95%CI = 0.108-0.641, P = 0.003), total adrenaline dose <= 4 mg (OR = 0.122, 95%CI = 0.049-0.303, P = 0.000) and the ambulance CA (OR = 2.441, 95%CI = 1.334-4.468, P = 0.004) were protective factors of ROSC in OHCA patients. CONCLUSIONS: The survival of sudden CA in emergency department was still poor. Early electric defibrillation, manual chest compression, CA occurred in hospital or in ambulance, and witness CPR can improve the ROSC rate of CA patients. Excessive use of adrenaline is not beneficial to patients with CA. Clinical Trials: NCT01987245. PMID- 29519283 TI - [Effect of lateral position ventilation combined with vibration sputum drainage on patients with acute respiratory distress syndrome: a prospective randomized controlled trial]. AB - OBJECTIVE: To investigate the curative effect of lateral position ventilation combined with vibration sputum drainage on the patients with acute respiratory distress syndrome (ARDS). METHODS: A prospective randomized controlled trial was conducted. The patients with ARDS undergoing mechanical ventilation (MV) admitted to intensive care unit (ICU) of Linyi Central Hospital from January 2013 to June 2017 were enrolled, and they were divided into simple ventilation group and combined treatment group according to random number table. The patients in both groups received etiological treatment, protective ventilation strategy, sensitive antibiotics for anti-infection, and calefacient and humidifying treatment. The patients in the simple ventilation group received bilateral discontinuous alternative lateral position ventilation [pressure controlled ventilation (PCV), tidal volume (VT) <= 6 mL/kg, the inhaled oxygen concentration (FiO2) and positive end expiratory pressure (PEEP) was adjusted to maintain the airway plateau pressure (Pplat) <= 30 cmH2O (1 cmH2O = 0.098 kPa)], and those in the combined treatment group received lateral position ventilation combined with vibration sputum drainage, twice a day, 15 minutes each time. The parameters of respiratory function and inflammation as well as excretion of sputum before and after treatment were compared between the two groups, and the complication and prognosis were recorded. RESULTS: A total of 200 patients with ARDS were included, 4 patients were excluded because of severe pneumothorax, massive hemorrhage of the digestive tract, or elevated intracranial pressure, so 196 patients were finally enrolled in the analysis. There were 98 patients in the simple ventilation group and the combined treatment group, respectively. There were no significant differences in parameters of respiratory function and inflammation as well as excretion of sputum before treatment between the two groups. After treatment, the above parameters in both groups were improved, and the effect of combined treatment was more significant. Compared with the simple ventilation group, white blood cell count (WBC), procalcitonin (PCT), C-reactive protein (CRP) at 24 hours of treatment in the combined treatment group were significantly decreased [WBC (*109/L): 9.1+/-1.6 vs. 11.8+/-3.6, PCT (MUg/L): 14.5+/-2.4 vs. 22.7+/-3.2, CRP (mg/L): 32.2+/-6.3 vs. 67.2+/-7.2, all P < 0.01], the quantity of sputum excretion was significantly increased (mL: 49.3+/-12.5 vs. 36.8+/-11.8, P < 0.01); 72 hours after treatment, the oxygenation index (PaO2/FiO2) in the combined treatment group was significantly increased [mmHg (1 mmHg = 0.133 kPa): 278+/-28 vs. 238+/-39, P < 0.01], and PEEP, FiO2, airway resistance (Raw) were significantly lowered [PEEP (cmH2O): 5+/-2 vs. 7+/-3, FiO2: 0.40+/-0.11 vs. 0.49+/-0.12, Raw (cmH2O): 12.8+/-0.7 vs. 16.2+/-0.8, all P < 0.01]. There was no significant difference in static lung compliance (Cst) or Pplat between the two groups. Compared with the simple ventilation group, the duration of MV (days: 5.5+/-3.0 vs. 8.6+/-2.1), the length of ICU stay (days: 7.5+/-5.4 vs. 11.3+/-4.6) and the extraction time of artificial airway (days: 6.6+/-2.8 vs. 9.4+/-3.3) in the combined treatment group were significantly shortened (all P < 0.01). However, there was no significant difference in the 28 day mortality rate [4.1% (4/98) vs. 3.1% (3/98)], the rate of tracheotomy [2.0% (2/98) vs. 3.1% (3/98)] or the incidence of I-II skin pressure sore [1.0% (1/98) vs. 2.0% (2/98)] between simple ventilation group and the combined treatment group (all P > 0.05). No artificial airway disappearance, pneumothorax, grade III or IV pressure sore was found in the two groups. CONCLUSIONS: Compared with lateral position ventilation alone, the treatment of combined with vibration sputum drainage is more effective for improving the respiratory function of patients with ARDS, reducing infection action, shortening the duration of MV and the length of ICU stay, and improve the recovery, promote the rehabitation of patients. PMID- 29519284 TI - [Application of early continuous renal replacement therapy in the bundle treatment of severe pneumonia]. AB - OBJECTIVE: To explore the role of early continuous renal replacement therapy (CRRT) in bundle treatment of severe pneumonia. METHODS: Seventy severe pneumonia patients admitted to respiratory intensive care unit (RICU) of Second Affiliated Hospital of Xuzhou Medical University from January 2013 to June 2017 were enrolled. The patients were randomly divided into routine treatment group and CRRT treatment group, with 35 patients in each group. All patients were treated with bundle therapy, and those in CRRT treatment group was treated with CRRT daily on the basis of conventional bundle therapy. The mode was continuous veno venous hemofiltration (CVVH), lasting 8-24 hours at a time. On the day of admission and the treatment of 1, 3, 5, 7 days, the fasting venous blood was collected. Inflammatory stress and immune parameters including procalcitonin (PCT), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), and CD4+ cells were determined by enzyme linked immunosorbent assay (ELISA) or flow cytometer. The incidence of acute respiratory distress syndrome (ARDS) and mortality within 7 days were observed in the two groups. RESULTS: Seventy patients with severe pneumonia were enrolled. There was no significant difference in the serum PCT, IL-6, TNF-alpha or CD4+ before treatment between the two groups. With the prolongation of treatment time, the PCT, IL-6 and TNF-alpha levels were gradually decreased, and the CD4+ was gradually increased. Compared with routine treatment group, PCT and TNF-alpha in CRRT treatment group were significantly decreased since the 3rd day [PCT (MUg/L): 3.11+/-1.28 vs. 3.76+/ 1.42, TNF-alpha (ng/L): 98.61+/-11.58 vs. 119.47+/-12.38], and CD4+ was significantly increased (0.39+/-0.03 vs. 0.35+/-0.03, all P < 0.05). The changes in IL-6 of CRRT treatment group was delayed, the statistical significance was found since the 5th day as compared with routine treatment group (ng/L: 35.43+/ 12.39 vs. 52.86+/-10.78, P < 0.05). Compared with routine treatment group, the incidence of ARDS [11.43% (4/35) vs. 31.43% (11/35)] and mortality [0% (0/35) vs. 11.43% (4/35)] within 7 days in CRRT treatment group were significantly lowered (both P < 0.05). CONCLUSIONS: CRRT in the early stage of bundle therapy for severe pneumonia is not only suggested to remove inflammatory mediators and improve immune function, but an opportunity and effective way to reduce complications and delay rapid progression of severe pneumonia. It provides the opportunity and condition for comprehensive treatment. PMID- 29519285 TI - [Use of somatosensory evoked potentials for preoperative assessment in patients with severe aneurysmal subarachnoid hemorrhage before surgical or interventional treatment: a prospective observational cohort study]. AB - OBJECTIVE: To explore the application value of short latency somatosensory evoked potentials (SLSEP) as a tool for preoperative assessment of surgical or interventional treatment in patients with severe aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A prospective observational cohort study was conducted. The patients with severe aSAH with a WFNS grade of IV or V admitted to intensive care unit (ICU) of Beijing Tiantan Hospital of Capital Medical University from November 2016 to April 2017 were enrolled. The patients received SLSEP monitoring within 12 hours after onset, and the monitoring results were classified according to the Judson scale. Meanwhile, the findings on cerebral CT scans at admission were evaluated by the modified Fisher classification. The follow-up was performed at 3 months after aSAH ictus based on the modified Rankin scale (mRS), and a mRS score 0-3 was defined as favorable outcome, 4-6 was defined as unfavorable outcome. For statistical evaluation, demographic, clinical, neuroimaging and SLSEP data were evaluated by univariate analysis to identify the risk factors associated with prognosis; afterwards, those factors were analyzed by multivariate Logistic regression; also the validity was assessed by calculating the respective sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: A total of 41 patients with aSAH were selected, of which 7 were excluded because of the interference of the SLSEP monitoring results, 34 patients with aSAH were enrolled finally. Among them, 21 were classified in the unfavorable outcome group, while the rest (n = 13) were allocated into the favorable outcome group. No significant difference was found in gender, age, body mass index (BMI), time delay from ictus to treatment or the options for therapeutic methods between the two groups. The findings of univariate analysis, however, showed statistically differences in WFNS grade, the modified Fisher scale and Judson scale of SLSEP between the two groups. Yet, the further validity evaluation for these predictors demonstrated that the sensitivity, specificity, PPV and NPV of WFNS grade of V and modified Fisher scale of IV were all less than 85%, whereas the results for SLSEP Judson scale of III were much better (sensitivity: 90.5% vs. 71.4% and 71.4%, specificity: 84.6% vs. 69.2% and 76.9%, PPV: 90.5% vs. 79.0% and 83.3%). In the following multivariate Logistic analysis, only Judson scale of III was identified to be the independent risk factor for poor outcome [odds ratio (OR) = 45.73, 95% confidence interval (95%CI) = 4.25-499.31, P = 0.002], while the WFNS grade of V (OR = 1.14, 95%CI = 0.12-13.06, P = 0.912) and the modified Fisher scale of IV (OR = 7.22, 95%CI = 0.51-113.20, P = 0.160) were merely associated with poor outcomes without significant independence. CONCLUSIONS: In comparison with WFNS grade and the modified Fisher scale, SLSEP seems more accurate in the prediction of long-term outcome of severe aSAH prior to surgical or interventional treatment, and thus may be applied as an effective aid in preoperative assessment. PMID- 29519286 TI - [Analysis of the difference between indirect calorimetry and predicted energy estimation in patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To analyze the difference between indirect calorimetry (IC) and predicted energy estimation in patients with chronic obstructive pulmonary disease (COPD), and its possible factors affecting the difference, to provide reasonable energy supply basis for COPD patients. METHODS: A prospective cohort study was conducted. Twenty-six patients with COPD undergoing mechanical ventilation (MV) admitted to intensive care unit (ICU) of Hangzhou City Fuyang District First People's Hospital in Zhejiang Province from January to December in 2016 were enrolled. The energy values of patients were calculated by IC and predicted energy estimation, respectively. According to the degree of IC values deviating from the predicted energy estimation, the patients were divided into energy approaching group (IC values deviating from the empirical energy estimation <=15%) and energy deviation group (IC values deviating from the empirical energy estimation > 15%). Bland-Altman diagram was drawn, and the consistency of the energy target values assessing by two methods was analyzed. The factors influencing the energy value deviation of the two measuring methods were screened by the multivariate Logistic regression and linear regression analysis. RESULTS: Twenty-six patients were enrolled in the final analysis. The energy target value of IC was significantly higher than that of predicted energy estimation (kJ: 7 079.3+/-1 213.4 vs. 6 527.0+/-949.8), and the difference between two values was statistically significant (P < 0.01). Bland-Altman heterogeneity analysis showed that the overall consistency of the energy values between the predicted energy estimation and IC was quite good. There were 14 patients in energy approaching group, and 12 in energy deviation group. There was no significant difference in gender, age, body mass index (BMI), type of COPD, or acute physiology and chronic health evaluation II (APACHE II) score between the two groups. In energy deviation group, the IC value of patients was significantly higher than predicted energy estimation (kJ: 7 711.1+/-1 125.5 vs. 6 556.3+/ 907.9, P < 0.01). However, in energy approaching group, there was no significant difference between the energy values of IC and predicted energy estimation (kJ: 6 539.6+/-1 037.6 vs. 6 501.9+/-1 016.7, P > 0.05). Multivariate Logistic regression analysis showed that APACHE II score was an independent risk factor inducing the deviation of energy evaluation between IC and predicted energy estimation [odds ratio (OR) = 1.403, 95% confidence interval (95%CI) = 1.019 1.932, P = 0.038]. Multivariate linear regression analysis showed that the APACHE II score increased by 1, and the energy deviation increased by 2.0 kJ (beta = 0.476, 95%CI = 0.004-0.956, P = 0.047). CONCLUSIONS: For patients with COPD, there was a good correlation between predicted energy estimation and the resting energy expenditure measured by IC. APACHE II score was an independent risk factor inducing the deviation of energy evaluation between IC and predicted energy estimation. It is suggested that the target value of energy should be determined by IC for patients with high APACHE II score. PMID- 29519287 TI - [Influence of clinical nutritional support on the effects of mechanical ventilation]. AB - OBJECTIVE: To study the influence of clinical nutritional support on the effects of mechanical ventilation (MV), and to find the factors affecting the outcome of patients undergoing MV. METHODS: A case-control study was conducted. The clinical data of 235 patients undergoing MV admitted to intensive care unit (ICU) of Tongde Hospital of Zhejiang Province from January 2015 to June 2017 were retrospectively analyzed. The patients were divided into two groups according to whether weaning successfully within 7 days. The clinical data of patients in the two groups were collected including gender, age, acute physiology and chronic health evaluation II (APACHE II) score, underlying disease, nutritional indicators, nutritional support, and complications. The outcome of withdrawal within 7 days was served as a dependent variable, all observed indicators were served as independent variables, and Logistic regression analysis was carried out to screen the influencing factors of the weaning results within 7 days. RESULTS: 235 patients undergoing MV were enrolled, 128 patients were successfully withdrawn within 7 days, and 107 were unsuccessfully withdrawn. Compared with the successful weaning group, the patients of weaning failure group were older, and had higher APACHE II score and lower albumin (Alb) and hemoglobin (Hb), more patients with internal medical underlying diseases and receiving parenteral nutrition (PN) and mixed nutrition, and the incidences of secondary infection, vomiting, abdominal distension, abnormal bowel sound, gastric retention, and diarrhea were higher. However, there was no statistical significance in gender between the two groups. The variables of statistical significance in univariate analysis were enrolled in the multifactor analysis model showing that age [odds ratio (OR) = 1.269, 95% confidence interval (95%CI) = 1.119-1.439, P < 0.001], APACHE II score (OR = 1.643, 95%CI = 1.423-1.897, P < 0.001), internal medical underlying diseases (OR = 6.298, 95%CI = 4.012-9.887, P < 0.001), secondary infection (OR = 8.323, 95%CI = 2.568-26.975, P < 0.001), abdominal distension (OR = 3.368, 95%CI = 1.586-7.152, P = 0.002), abnormal bowel sounds (OR = 2.856, 95%CI = 1.215-6.713, P = 0.017), gastric retention (OR = 1.996, 95%CI = 1.183 3.368, P = 0.010), diarrhea (OR = 3.035, 95%CI = 1.337-6.890, P = 0.008) were risk factors for unsuccessful weaning, and compared with PN, enteral nutrition (EN; OR = 0.191, 95%CI = 0.098-0.372, P < 0.001) and mixed nutrition (OR = 0.375, 95%CI = 0.150-0.938, P = 0.037) were protective factors of successful weaning. The gender, Alb and Hb before and after MV, vomiting, gastrointestinal hemorrhage were not associated with weaning outcome within 7 days. CONCLUSIONS: Elder, high APACHE II score, internal medical underlying diseases, or secondary infection, abdominal distension, abnormal bowel sounds, gastric retention, diarrhea were risk factors of weaning failure within 7 days in patients undergoing MV. Compared with PN, EN and mixed nutrition were protective factors for successful weaning. For patients undergoing MV, EN should be performed early in the case of full recovery, hemodynamic stability, and serious metabolic disorders. PMID- 29519288 TI - [Clinical analysis of 48 patients with acute mushroom poisoning]. AB - OBJECTIVE: To analyze the clinical manifestation and therapeutic method in patients with acute mushroom poisoning. METHODS: A retrospective study was conducted. The clinical data of 48 patients with acute mushroom poisoning admitted to Department of Poisoning Treatment of the 307th Hospital of PLA from January 2016 to May 2017 were analyzed. The clinical data including gender, age, clinical symptoms, onset season, initial symptoms, incubation time, the length of hospital stay, treatment, and prognosis. In addition to the conventional treatment, the patients with severe liver damage were treated with continuous blood purification (CBP). The changes in routine blood test, biochemical parameters, blood ammonia and coagulation function before and 1, 3 and 7 days after CBP were observed. RESULTS: There were 29 of male (60.4%) and 19 of female (39.6%) in 48 patients with acute mushroom poisoning, with an average age of (48.10+/-13.14) years. There were 9 patients suffering from gastroenteritis type, 26 suffering from liver damage type, 8 suffering from neuro-psychosis type, 2 suffering from hemolytic type, and 3 suffering from renal damage type. All of the poisoned patients had evident seasonal characteristic, mainly concentrated in the autumn, especially in August, according for 66.7% (32/48). The initial symptoms of poisoning patients were mainly manifested as nausea and vomiting (50.0%). In five kinds of poisoned patients, the incubation time [(1.44+/-1.15) hours] and the length of hospital stay [(3.50+/-2.33) days] of neuro-psychosis type was the shortest, and the incubation time of liver-damaged type [(10.63+/-3.50) hours] and the length of hospital stay of renal damage type [(20.67+/-0.58) days] was the longest. Patients received symptomatic treatment according to different types, among whom 12 patients with severe liver damage received additional treatment for CBP. After the treatment, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), and prothrombin activity (PTA) were significantly improved as compared with those before CBP treatment, with significant differences between 7 days after CBP and before CBP [ALT (U/L): 213.08+/-127.30 vs. 2 766.83+/-1 909.66, AST (U/L): 50.00 (41.00, 85.00) vs. 2 142.00 (1 225.00, 3 126.00), CK-MB (U/L): 24.09+/-8.87 vs. 44.75+/-22.09, LDH (MUmol*s-1*L-1): 3.70+/-1.46 vs. 13.03+/-12.77, PTA: (79.08+/-24.29)% vs. (35.25+/-19.85)%, all P < 0.01]. Among 48 patients, 47 were cured and discharged, and 1 patient with liver failure died due to aggravation of liver dysfunction, abnormal coagulation and bleeding, and massive hemorrhage of gastrointestinal tract. CONCLUSIONS: Acute mushroom poisoning patients demonstrated obvious seasonal characteristics, mostly liver damaged type, and its initial symptoms were mainly presented as nausea, vomiting and other gastrointestinal manifestations. Early clarification of diagnosis, timely treatment, as well as providence with CBP treatment in severe patients should be carried out as soon as possible. In such a way the curative effect can be enhanced, the mortality can be reduced, and the prognosis of the patients could be improved. PMID- 29519289 TI - [Research progress of nuclear factor-erythroid 2 related factor 2 in acute lung injury]. AB - OBJECTIVE: The anti-oxidant stress of the body is mainly mediated by the transcription factor nuclear factor-erythroid 2 related factor 2 (Nrf2). Nrf2 can promote cell protective gene expression. Nrf2 plays an important role in regulating the oxidative stress, the metabolism of toxic substances, the inflammation, the apoptosis, and the physiological functions of cells. Multiple studies have shown that the activation of Nrf2 alleviates oxidative stress and inflammation, plays an important role in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and is expected to be potential targets for the prevention and treatment of ALI/ARDS. In this article we review the importance of Nrf2 and its activation pathway in preventing and treating ALI/ARDS for the aim of understanding its functional mechanism in ALI/ARDS, and providing a reliable reference for the pathogenesis and treatment of ALI/ARDS. PMID- 29519291 TI - [Esophageal pressure and transpulmonary pressure monitoring]. AB - OBJECTIVE: Esophageal pressure monitoring provides a minimally invasive method to assess the pleural pressure, which can be used to differentiate the lung and chest wall mechanics. The information of transpulmonary pressure, work of breathing, intrinsic positive end-expiratory pressure and respiratory muscle performance can facilitate the proper setting of mechanical ventilation. Esophageal pressure monitoring is still not routinely used in the clinical setting because of difficulty in esophageal balloon catheter placement and data interpretation due to esophageal pressure monitoring has certain technical requirements, and the measurement results are influenced by many factors such as airbag volume, location, esophageal wall elasticity and mediastinal organ weight. In this review, we introduced technique for esophageal pressure measurement and calculation of transpulmonary pressure aiming to promote the clinical application of esophageal pressure monitoring. PMID- 29519290 TI - [Application of mesenchymal stem cell in the treatment of acute respiratory distress syndrome]. AB - OBJECTIVE: Acute respiratory distress syndrome (ARDS) is severe acute respiratory failure caused by severe infections, trauma or others, and with high mortality rate. The pathogenesis of ARDS is complicated, but the uncontrolled excessive inflammatory response is identified as one of the main causes. Mesenchymal stem cells (MSCs) have the ability to regulate immune responses, and many researches showed that MSCs had potential therapeutic effects on autoimmune diseases and graft versus host diseases. Recently, basic researches showed that MSCs could treat ARDS and many scientists paid attention to the therapeutic use of MSC in the treatment of ARDS. This paper summarized the basic and clinical results obtained in application of MSC in treatment of ARDS, and discussed the problems needed to be resolved in the further studies in order to provide new ideas for clinical treatment of ARDS. PMID- 29519292 TI - [Evaluation of platelet function in critically ill patients and its clinical significance]. AB - OBJECTIVE: Platelets play a pivotal role in the thromboembolic, inflammatory, and immunomodulatory process. The alteration of platelet quality often affects the treatment and prognosis of critically ill patients, and has a significant correlation with mortality. With the further research on the function of the platelet, it is found that the abnormal platelet quality can present during the early stage of the illness of the critically ill patients. In order to evaluate the alterations of the platelet quality more accurately, the further studies of platelet parameters, including platelet counts (PLT), platelet hematocrit (PCT), platelet large cell ratio (PLCR), mean platelet volume (MPV), platelet distribution width (PDW), immature platelet fraction (IPF) and so on, are still be the focus of current researches in the field of critical illness. At the same time, the application of thromboelastography/thrombelastography-platelet mapping (TEG/TEG MP) to the measurement of platelet function, especially the researches on the inhibitory rate of adenosine diphosphate (ADP) and the inhibitory rate of arachidonic acid (AA), is the hot spot of current researches. With regard to the diagnosis, prognosis and early goal-directed therapy (EGDT) of the critically ill patients, it is important to comprehensively apply the methods of platelet function evaluation. PMID- 29519294 TI - Hippo signaling: Special issue of BMB Reports in 2018. AB - Since the first component of Hippo signaling, Wts in Drosophila, was identified in 1995, the progress of Hippo signaling studies has been very slow initially. However, after the findings suggesting that the core kinase pathway established in Drosophila was evolutionarily conserved in metazoans for the determination of organ size around 2008, the number of publications related to Hippo signaling has grown exponentially. Identification of molecular mechanisms underlying Hippo signaling response to intrinsic cues, such as cell-cell contact and mechanotransduction, as well as extrinsic cues, such as nutrients and soluble factors, has been one of the key topics of Hippo signaling. In the beginning, the role of Hippo signaling in the regulation of cell proliferation, organ size determination and tumorigenesis was mainly studied. However, the study of Hippo signaling expanded recently to unexpected biological phenomena such as tissue regeneration, innate immunity and miRNA biogenesis. Editors of BMB reports thought that it was timely and informative to review the status of Hippo signaling to introduce the topic to researchers outside of this field. As an editor of BMB reports, I invited seven researchers, who are currently working in Korea on different aspects of Hippo signaling, to submit minireviews. [BMB Reports 2018; 51(3): 105]. PMID- 29519293 TI - Early potential effects of resveratrol supplementation on skeletal muscle adaptation involved in exercise-induced weight loss in obese mice. AB - Exercise and resveratrol supplementation exhibit anti-obesity functions in the long term but have not been fully investigated yet in terms of their early potential effectiveness. Mice fed with high-fat diet were categorized into control (Cont), exercise (Ex), resveratrol supplementation (Res), and exercise combined with resveratrol supplementation (Ex + Res) groups. In the four-week period of weight loss, exercise combined with resveratrol supplementation exerted no additional effects on body weight loss but significantly improved whole-body glucose and lipid homeostasis. The combined treatment significantly decreased intrahepatic lipid content but did not affect intramyocellular lipid content. Moreover, the treatment significantly increased the contents of mtDNA and cytochrome c, the expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and its downstream transcription factors, and the activities of ATPase and citrate synthase. However, exercise, resveratrol, and their combination did not promote myofiber specification toward slow-twitch type. The effects of exercise combined with resveratrol supplementation on weight loss could be partly due to enhanced mitochondrial biogenesis and not to fiber-type shift in skeletal muscle tissues. [BMB Reports 2018; 51(4): 200-205]. PMID- 29519296 TI - Imaging for the Management of Community-Acquired Pneumonia: What to Do if the Chest Radiograph Is Clear. PMID- 29519295 TI - Role of estrogen and RAS signaling in repeated implantation failure. AB - In humans, hormonal regulation is crucial for the preparation of uterine environment leading to either successful implantation or menstrual cycle. Estrogen is a pivotal female steroid hormone that regulates the uterine dynamics along with progesterone in the estrous and menstrual cycles in humans. Estrogen signals act via nuclear estrogen receptor or membrane-bound receptor. The membrane-bound estrogen receptor plays a crucial role in the rapid response of estrogen in the uterine epithelium. Recently, RASD1 has received attention as a novel signal transducer of estrogen in various systems including female reproductive organs. In this review, we discuss the regulation of estrogen and RASD1 signaling in the uterus and also provide insights into RAS as a novel signaling molecule in repeated implantation failure. [BMB Reports 2018; 51(5): 225-229]. PMID- 29519297 TI - Bariatric Surgery to Prevent COPD Exacerbations? PMID- 29519298 TI - Prehospital Antibiotics for Sepsis: An Open but Not Shut Case. PMID- 29519299 TI - CHLOROFORM, c. 1847. PMID- 29519300 TI - DIAGNOSIS. PMID- 29519301 TI - Community-Acquired Pneumonia: Now You See It, Now You Don't! PMID- 29519302 TI - Response. PMID- 29519303 TI - Efficacy of Hyperbaric Oxygen for Carbon Monoxide Poisoning. PMID- 29519304 TI - Response. PMID- 29519305 TI - Morphine Use in Acute Heart Failure and Limitation of Therapeutic Effort. PMID- 29519307 TI - Correction to Formulas in: Oxygenation Saturation Index Predicts Clinical Outcomes in ARDS. PMID- 29519306 TI - Response. PMID- 29519308 TI - Sjogren Syndrome With Associated Lymphocytic Interstitial Pneumonia Successfully Treated With Tacrolimus and Abatacept as an Alternative to Rituximab. AB - Interstitial lung disease (ILD) is a significant complication of Sjogren syndrome (SS) associated with increased morbidity and mortality. The mainstay of treatment remains corticosteroid administration, with or without additional immunosuppressive therapies. Preliminary studies in SS have shown benefit in glandular and serologic parameters following treatment with the CTLA4 immunoglobulin fusion protein abatacept. Topical tacrolimus has been effective for ocular symptoms in SS, but systemic therapy has not been reported. We describe the first case, to our knowledge, of the successful use of a combination of systemic tacrolimus and abatacept in severe refractory SS and related ILD. PMID- 29519309 TI - A Man in His 80s in Respiratory Distress With a History of COPD and Congestive Heart Failure. PMID- 29519310 TI - A Lung Cancer Patient With Respiratory Insufficiency and Hemodynamic Instability. PMID- 29519311 TI - A 24-Year-Old Woman With Precipitous Respiratory Failure After Lung Transplantation. AB - CASE PRESENTATION: A 24-year-old woman with DeltaF508/Y1092X cystic fibrosis (CF) complicated by severe obstructive lung disease (FEV1 of 30% predicted) was admitted for IV antibiotics for planned sinus surgery resulting from severe chronic sinusitis causing frequent exacerbations and declining lung function. She had persistent airway infection with multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and growth of a fungus presumed to be an airway colonizer, identified as Stephanoascus ciferrii 1 year before presentation. Two days after surgery, she developed acute respiratory failure requiring mechanical ventilation. On day 4 of mechanical ventilation, venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated for refractory respiratory failure. The following day, she was listed for bilateral lung transplant and was transplanted 4 days later. Following transplantation, she was decannulated from ECMO; however, over the next 12 hours, oxygenation deteriorated requiring reinstitution of VV-ECMO for presumed severe primary graft dysfunction. Despite treatment with broad spectrum antimicrobial coverage with piperacillin/tazobactam, ciprofloxacin, linezolid, micafungin, voriconazole, and ganciclovir, she failed to improve and developed complex bilateral pleural effusions. PMID- 29519312 TI - A 62-Year-Old Woman With Refractory Wheezing. AB - CASE PRESENTATION: A 62-year-old Hispanic woman, a resident of Puerto Rico, presented with symptoms of chronic cough and shortness of breath for the past 2 years that were slowly and progressively getting worse. She received a diagnosis of asthma on the basis of her history of symptomatic "wheezing" and had been on treatment with inhaled bronchodilators and corticosteroids with minimal symptomatic improvement. The peculiarity of her symptoms was that her dyspnea was worse when she was reclining in bed and she would often hear a "whistling" noise in her throat during those times. Additionally, she reported difficulty swallowing and would often drink water to aid in swallowing food. There was no prior history of endotracheal intubations or surgeries. She denied any history of joint pain, skin rashes, eye pain, hair loss, mouth ulcers, photosensitivity, diarrhea, blood-mixed stool, or blood in the urine. PMID- 29519313 TI - [We try hard, although it may not be enough]. PMID- 29519314 TI - Hypotensive and neurometabolic effects of intragastric Reishi (Ganoderma lucidum) administration in hypertensive ISIAH rat strain. AB - BACKGROUND: As the standard clinically used hypotensive medicines have many undesirable side effects, there is a need for new therapeutic agents, especially ones of a natural origin. PURPOSE: One possible candidate is extract from the mushroom Reishi (Ganoderma lucidum), which is used in the treatment and prevention of many chronic diseases. STUDY DESIGN AND METHODS: To study the effectiveness of Reishi, which grows in the Altai Mountains, as an antihypertensive agent, we intragastrically administered Reishi water extract to adult male hypertensive ISIAH (inherited stress-induced arterial hypertension) rats. RESULTS: After seven weeks, Reishi therapy reduced blood pressure in experimental animals at a level comparable to that of losartan. Unlike losartan, intragastric Reishi introduction significantly increases cerebral blood flow and affects cerebral cortex metabolic patterns, shifting the balance of inhibitory and excitatory neurotransmitters toward excitation. CONCLUSION: Changes in cerebral blood flow and ratios of neurometabolites suggests Reishi has a potential nootropic effect. PMID- 29519315 TI - The impact of regional locality on chemical composition, anti-oxidant and biological activities of Thymelaea hirsuta L. extracts. AB - BACKGROUND: Thymelaea hirsuta L. is a medicinal plant endemic to Tunisia, commonly used for its biological properties in traditional medicinal. PURPOSE: This study reports, to the best of our knowledge for the first time, the effect of regional location on the chemical composition, anti-oxidant and biological activities of organics extracts obtained from aerial parts of T. hirsuta. METHODS/STUDY DESIGN: The aerial parts collected from different locations were prepared by sequential method with solvents of increasing polarity namely hexane, ethyl acetate, ethanol and methanol. An assessment of the anti-oxidant properties of all extracts was performed using DPPH and ABTS+ assays. We also investigated the anti-cholinesterase, anti-xanthine oxidase and cytotoxic (against MCF-7 and OVCAR) activities. RESULTS: The study of the phytochemical composition showed that the extracts are rich in phenolics (5.38-315.65 mg GAE/g dw) and tannin (0.7 73.8 mg CE/g dw). Also, the results showed that the chemical composition as well as the biological activities varies considerably between regions. The DPPH and ABTS+ assays revealed that the highest important antioxidant activity was in the methanolic extract for all localities (IC50: 14.8-16.5 mg/l and 6.4-22.23 mg/l, respectively). However, the various extracts had moderate anti-cholinesterase activity (7.52-45.36%) at 50 mg/l. Regarding the xanthine oxidase inhibitory activity, ethyl acetate extract exhibited a moderate activity at a 50 mg/l. The highest cytotoxic activity against MCF-7 and OVCAR was recorded in the ethyl acetate extract of Fernana region (70.1% and 70.8% inhibition at 50 mg/l, respectively). The analysis of HPLC-UV indicates the presence of several phenolic compounds in different extracts of T. hirsuta, possibly accounting for its biological properties. CONCLUSION: The phenolic contents were highly correlated to anti-oxidant activity with very high correlation coefficient (R2) values. The findings show that the extracts are rich in antioxidant compounds and this plant may be used as a natural source of bioactive compounds with high anti-oxidant and potential anticancer activities. PMID- 29519316 TI - CGplus, a standardized herbal composition ameliorates non-alcoholic steatohepatitis in a tunicamycin-induced mouse model. AB - BACKGROUND: The prevalence of Non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) has increased by 15-39% worldwide, but no pharmaceutical therapeutics exists. HYPOTHESIS/PURPOSE: This study investigated anti-hepatosteatotic effect of CGplus (a standardized herbal composition of Artemisia iwayomogi, Amomum xanthioides, and Salvia miltiorrhiza) and its underlying mechanisms in a tunicamycin-induced NASH model. METHODS: C57/BL6J male mice were orally administrated CGplus (50, 100, or 200 mg/kg), dimethyl dimethoxy biphenyl dicarboxylate (DDB, 50 mg/kg) or distilled water daily for 5 days. 18 h after a single injection of tunicamycin (ip, 2 mg/kg), the parameters for hepatic steatosis and inflammation were measured. RESULTS: Pretreatment with CGplus significantly attenuated the accumulation of triglycerides and total cholesterol as well as lipid peroxidation, evidenced by quantitative and histopathological analyses in liver tissues. The elevations of serum aspartate transaminase, alanine transaminase and lactate dehydrogenase were significantly ameliorated by CGplus. Also, it normalized the altered activities of pro- (TNF-alpha, IL-1beta and IL-6), anti-inflammatory (IL-10) cytokines and lipid metabolism-related molecules in protein and gene expression analyses. CONCLUSION: Our data present experimental evidence for the potential of CGplus as an herbal therapeutic against NAFLD and NASH. Its underlying mechanisms may involve the modulations of pro- and anti-inflammatory cytokines, but further study is required especially for the actions of CGplus on lipid metabolisms. PMID- 29519317 TI - 16-O-caffeoyl-16-hydroxylhexadecanoic acid, a medicinal plant-derived phenylpropanoid, induces apoptosis in human hepatocarcinoma cells through ROS dependent endoplasmic reticulum stress. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer death, and novel chemotherapeutic drugs for treating HCC are urgently needed. 16-O caffeoyl-16-hydroxylhexadecanoic acid (CHHA) is a new phenylpropanoid isolated by our group from Euphorbia nematocypha which is commonly used to treat solid tumors. However, the underlying mechanisms responsible for the CHHA-induced apoptosis in cancer cells, particularly in HCC, remain unknown. PURPOSE: In the present work, we evaluated the growth inhibitory effect of CHHA on HCC cells and explored the underlying molecular mechanisms. METHODS/STUDY DESIGNS: The anti proliferative activity of CHHA was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. ER localization was performed by ER-tracker red staining. The effect of CHHA on the expression of mRNA in HCC cells was detected by RT-PCR. The potential mechanisms for proteins level in ER pathway and apoptosis were analyzed by Western blot. RESULTS: Our results showed that CHHA exerted strong anti proliferative activity against both HepG2 and Bel-7402 cells in a concentration- and time-dependent manner. Mechanistic studies demonstrated that CHHA induced apoptosis through mitochondrial apoptotic pathway, and arrested the cell cycle at G1 phase. CHHA was also found to induce endoplasmic reticulum (ER) stress, accompanied by ROS production, increase of intracellular calcium and up regulation of GRP78, CHOP, caspase-12 and p-PERK. Inhibition of endoplasmic reticulum stress by salubrinal pretreatment could suppress both apoptosis and ER stress, indicating that ER stress induction contributes to apoptosis and is required for the latter. Besides, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by CHHA and reversed CHHA-stimulated the expression of ER markers. CONCLUSION: In conclusion, CHHA inhibited HCC cell growth and induced apoptosis through mitochondria-mediated pathway and ROS mediated endoplasmic reticulum stress. This provides molecular bases for developing CHHA into a drug candidate for the treatment of HCC. PMID- 29519318 TI - Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome. AB - BACKGROUND: Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is acknowledged as an independent risk factor for cardiovascular disease, which underlines the urgent need for new medications to DN. Dihydroquercetin (DHQ), an important natural dihydroflavone, exerts significant antioxidant, anti-inflammatory, and antifibrotic properties, but its effects on DN have not been investigated yet. PURPOSE: We aimed to explore the kidney protection effects of DHQ on DN rats induced by high-fat diet/streptozotocin in vivo and the underlying mechanisms of DHQ on renal cells including HBZY-1 and HK2 exposed to high glucose in vitro. METHODS: Major biochemical indexes were measured including urine microalbumin, fasting serum glucose, serum levels of creatinine, total cholesterol and low density lipoprotein cholesterol. Renal histologic sections were stained with hematoxylin-eosin, periodic acid-Schiff and Masson. The cell proliferation was assessed by MTT assay. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay and laser scanning confocal microscope. Expression of all proteins was examined by western-blot. RESULTS: In high-fat diet/streptozotocin-induced DN rats, DHQ at the dose of 100 mg/kg/day significantly attenuated the increasing urine microalbumin excretion, hyperglycemia and lipid metabolism disorders, and mitigated renal histopathological lesions. In in vitro studies, DHQ significantly suppressed cell proliferation and the excessive ROS generation, and alleviated the activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the expression of renal fibrosis-associated proteins in renal cells exposed to high glucose. CONCLUSION: The results revealed that DHQ possesses kidney protection effects including attenuating urine microalbumin excretion, hyperglycemia and lipid metabolism disorders, and mitigating renal histopathological lesions on DN, and one of the possible renal protective mechanisms is suppressing ROS and NLRP3 inflammasome. PMID- 29519319 TI - Luteolin-4'-O-glucoside and its aglycone, two major flavones of Gnaphalium affine D. Don, resist hyperuricemia and acute gouty arthritis activity in animal models. AB - BACKGROUND: Gnaphalium affine D. Don is a folk medicine of China believed to be efficacious in the treatment of many ailments, including hyperuricemia and gout. PURPOSE: Based on a previous study, we isolated two flavones, luteolin and luteolin-4'-O-glucoside, from G. affine. Our aim was to assess the potential beneficial effects of treatment and mechanisms of these two flavones on hyperuricemia and acute gouty arthritis. METHODS: The model of potassium oxonate (PO)-induced hyperuricemia and monosodium urate (MSU) crystal-induced inflammation in mice has been established. We evaluated serum uric acid (Sur), xanthine oxidase (XO) activity, protein expression of urate transporter 1 (mURAT1) and glucose transporter 9 (mGLUT9) in renal and kidney protection in a hyperuricemia model. In addition, paw swelling and levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in serum were assessed in MSU crystal-induced mice. RESULTS: Luteolin and luteolin-4'-O-glucoside showed a potent clinical effect in treating hyperuricemia and gout. We observed that the two flavones possess potent effect in hyperuricemia mice by decreasing the level of mURAT1 and inhibiting XO activity, which contribute to enhancing uric acid (UA) excretion and improving hyperuricemia-induced renal dysfunction. In addition, luteolin and luteolin-4'-O-glucoside also alleviated paw swelling and inflammation induced by MSU crystals. Further investigation implied that luteolin and luteolin-4'-O-glucoside improved the symptoms of inflammation by decreasing the levels of IL-1beta and TNF-alpha. CONCLUSION: The present study suggests that luteolin and luteolin-4'-O-glucoside could be developed as therapeutics for treating hyperuricemia and gouty arthritis. PMID- 29519320 TI - Mechanism of action of cytotoxic compounds from the seeds of Euphorbia lathyris. AB - BACKGROUND: The seeds of Euphorbia lathyris are used in traditional Chinese medicines for the treatment of various medical conditions. E. lathyris contains many natural diterpenes with a lathyrane skeleton. PURPOSE AND STUDY DESIGN: Five lathyrane-type diterpenoids named Euphorbia factors L1, L2, L3, L8, and L9 (1-5), were investigated for cytotoxicity against A549, MDA-MB-231, KB, and MCF-7 cancer cell lines and the KB-VIN multidrug resistant (MDR) cancer cell line. Also, a tetraol derivative (6) of Euphorbia factor L2 (2) was synthesized to assess the effect of hydroxy moieties. METHODS: An ethanolic extract of seeds of Euphorbia lathyris was prepared and separated into petroleum ether, EtOAc, n-butanol, and n hexane extracts. The natural diterpenes were isolated by using silica gel and Sephadex LH-20 column chromatography as well as preparative thin-layer chromatography. Saponification of 2 gave tetraol derivative 6. Cytotoxic activity was determined by the sulforhodamine B (SRB) colorimetric assay. Mechanism of action studies focused on the impact of compounds on the cell cycle progression as well as cell morphology. RESULTS: Compound 5 exhibited the strongest cytotoxicity against all cell lines, while compound 2 showed selectivity against KB-VIN. In cells treated with 3 and 5, accumulation of G1 to early S phase cells was obvious, while no effect was seen on G2/M phase. CONCLUSION: Analysis of the screening data compared with compound structures suggested that the substitutions at C-3, C-5, C-7, and C-15 are critical for cytotoxicity, as well as cell type selectivity. Furthermore, results of cytotoxic mechanism analysis demonstrated for the first time that compounds 3 and 5 disrupted normal cell cycle progression, whereas compounds 2-5 induced obvious actin filament aggregation, as well as partial interference of the microtubule network. PMID- 29519321 TI - Parthenolide reduces metastasis by inhibition of vimentin expression and induces apoptosis by suppression elongation factor alpha - 1 expression. AB - BACKGROUND: Use of pharmaceutical agent for breast cancer chemotherapy is an interesting method that induces cells death by different way, such as apoptosis. Parthenolide is the main compound in feverfew that has been used to cure migraine and rheumatoid arthritis for long time. Parthenolide has been predominately investigated as inducer of apoptosis in human cancer cells. PURPOSE: We examined the expression of vimentin and Elongation factor alpha - 1 as breast cancer biomarkers in MCF7 cells exposure to Parthenolide. METHOD: In this study, we investigated the antitumor mechanism of Parthenolide on the human breast cancer cell line MCF7, using SEM, flow cytometry and proteomics techniques. RESULT: Comparative proteome analyses are shown Elongation factor1-alpha and vimentin was suppressed in response to Parthenolide treatment. PMID- 29519322 TI - Gastroprotective activity of a pectic polysaccharide fraction obtained from infusion of Sedum dendroideum leaves. AB - BACKGROUND: Sedum dendroideum, popularly known in Brazil as balsam, is traditionally used as a wound healing agent, to treat gastritis, and several other health problems. Some studies have shown that plant polysaccharides may have gastroprotective properties. PURPOSE: Considering the popular use of S. dendroideum and the gastroprotective activity of polysaccharides, the objective of this work was to obtain, to characterize, and to evaluate the gastroprotective activity of a polysaccharide fraction from this plant. METHODS: Polysaccharides of S. dendroideum were extracted with water by infusion, fractionated by freeze thawing process and dialyzed at a 100 kDa cut-off membrane, and characterized by monosaccharide composition and NMR analysis. The gastroprotective activity of the pectic polysaccharide fraction RSBAL was evaluated in the ethanol-induced ulcer model in rats, followed by determination of the mucus and glutathione levels in the gastric tissue. RESULTS: RSBAL was constituted by a homogalacturonan and a homogalacturonan branched by side chains of arabinans and type II arabinogalactans. It reduced ethanol-induced gastric ulcers in rats, preserving mucus and glutathione levels in the stomach. CONCLUSION: This study demonstrated that polysaccharides could be related to the pharmacological activity of S. dendroideum. PMID- 29519323 TI - Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats. AB - BACKGROUND: Excitotoxicity is extensively recognized as a major pathological process of neuronal death and has been proved to play a key role in Alzheimer's disease (AD). ICS II, a flavonoid compound from Herba Epimedii Maxim, is attracting great interests due to its neuroprotective properties. PURPOSE: The present study was aimed to explore the effects of ICS II on cognitive dysfunction and apoptotic response induced by excitatory neurotoxin ibotenic acid (IBO) injection in rats. METHODS: Rats subjected to bilateral hippocampal injection of IBO were intragastrically administered with 4, 8 and 16 mg/kg ICS II or 0.6 mg/kg donepezil once a day for continuous 20 days. Learning and memory functions were tested by Morris water maze. The neuronal morphology in hippocampus was examined by HE staining and Nissl staining, respectively. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The expression of apoptosis-related proteins and the activation of mitogen activated protein kinase (MAPK) pathway were detected by Western blot. RESULTS: It was uncovered that hippocampal injection of IBO caused learning and memory impairment, neuronal damage and loss, as well as pro-apoptotic response. ICS II administrated at doses of 8 and 16 mg/kg not only rescued behavioral performance, but also protected hippocampal neurons against neurotoxicity via suppressing the elevation of Bax/Bcl-2 ratio and the activation of caspase-3. Meanwhile, ICS II repressed the down-regulation of calbindin protein induced by IBO. Additionally, ICS II exerted an inhibitory effect on MAPK (p38, ERK1/2 and JNK) pathway phosphorylation. CONCLUSION: These results suggest that ICS II attenuates IBO induced cognitive deficits, possibly via the regulation of calbindin expression and the inhibition of apoptotic response. In addition, the MAPK signaling pathway is implicated in the potential mechanisms of ICS II against IBO-induced excitotoxicity, indicating that ICS II is a promising compound for treatment of excitotoxicity-related diseases, including AD. PMID- 29519325 TI - [Scientific communication and the social practice of writing]. PMID- 29519324 TI - Anti-inflammatory and anti-edematogenic action of the Croton campestris A. St. Hil (Euphorbiaceae) essential oil and the compound beta-caryophyllene in in vivo models. AB - BACKGROUND: Inflammation makes up a set of vascularized tissue reactions acting in the defense of the body against harmful stimuli. Natural products are a lower cost alternative with better benefit, often used in popular medicine in the treatment of inflammatory processes. Several species from the genus Croton have scientifically proven anti-inflammatory action. PURPOSE: This study aims to analyze the chemical composition of the Croton campestris A. St.-Hil essential oil (EOCC), derived from fresh leaves, as well as to evaluate the anti inflammatory potential and the possible mechanisms of action of the EOCC and its constituent beta-caryophyllene. METHODS: The assays were performed in in vivo models of acute and chronic inflammation. Initially, the chemical composition of the EOCC was determined and its oral toxicity was evaluated, followed by the evaluation of its topical antiedematogenic effect through acute and chronic ear edema induced by Croton oil. For the systemic verification of an anti inflammatory action, the abdominal contortions, formalin test, paw edema induced by carrageenan, dextran, histamine and arachidonic acid models, as well as a peritonitis test, vascular permeability and granuloma assays were performed. RESULTS: The evaluation of the essential oil chemical composition revealed the presence of beta-caryophyllene (15.91%), 1,8-cineol (16.98%) and germacrene-D (14.51%) as its main constituents. The EOCC had no relevant clinical toxicity on oral administration, with an LD50 of more than 5000 mg/kg. The tested substances showed anti-inflammatory action in the abdominal contortions, paw edema induced by carrageenan, dextran, histamine and arachidonic acid models, the formalin test, peritonitis test and vascular permeability; however, beta-caryophyllene had no significant effect on the granuloma assay. This suggests as a hypothesis that both substances tested showed significant influence on the arachidonic acid and histamine pathway reducing edema in these models. CONCLUSION: The tested substances have a clinically safe profile, additionally the EOCC and beta caryophyllene presented relevant anti-inflammatory activity. This study supports the hypothesis that beta-caryophyllene, in association with other constituents present in the EOCC such as 1,8-cineole, contributed to the anti-inflammatory effect observed, in addition to suggesting that one of the mechanisms of action probably involves the inhibition of cytokines with the involvement of the arachidonic acid and histamine pathways. PMID- 29519326 TI - Fluid Collections and Pseudocysts as a Complication of Acute Pancreatitis. AB - Pseudocysts evolve from fluid collections and/or disruptions of the pancreatic duct. They may occur secondary to acute pancreatitis, pancreatic trauma, or chronic pancreatitis. Lacking the clinical information, radiologists may inappropriately call a fluid collection or any cystic lesion a pseudocyst. With no clear history of acute pancreatitis or chronic pancreatitis, this is rare. Complications include infection, intracystic hemorrhage, or rupture. Pseudocysts can become painful, especially with chronic pancreatitis, and can cause early satiety and weight loss when their size affects the stomach and bowel. Symptomatic pseudocysts can successfully be drained with via surgical, radiologic, or endoscopic drainage. PMID- 29519327 TI - Surgical Management of Pancreatic Pseudocysts. AB - Open surgical intervention for treatment of simple pancreatic pseuodocyst (PP) has a high success rate and has been the historical gold standard. Open surgical intervention, however, confers significant morbidity and mortality, which has spurred the development of less invasive techniques. Laparoscopic approaches are feasible with the potential for lower complication rates and length of stay. The endoscopic approach has the appeal of potentially shorter hospitalization length of stays and does not require general anesthesia. Complicated PPs or those that arise in the setting of chronic pancreatitis warrant additional workup and special consideration. PMID- 29519328 TI - The Evolution of Endoscopic Cystgastrostomy. AB - The lumen-apposing metal stent is the first stent specifically designed for endoscopic ultrasound-guided transluminal drainage of extraintestinal fluid collections. With the "hot" electrocautery-enhanced delivery system, this platform marks the most recent evolutionary stage of endoscopic therapy of pancreatic fluid collections. The lumen-apposing metal stent platform has made endoscopic drainage of pancreatic fluid collections easier and safer, while serving as a port for safe entry into the cyst cavity to extend the reach of endoscopic diagnosis and therapy. Tools conceived for endoscopic ultrasound guided transluminal intervention have emerged and are opening the door to new frontiers of endoscopic transluminal therapy. PMID- 29519329 TI - Endoscopic Ultrasound-Guided Drainage of Pancreatic Fluid Collections. AB - Ultrasound-guided drainage is the first-line modality for drainage of symptomatic of pancreatic fluid collections. In the context of pancreatic cancer, use of multiple double-pigtail plastic stents suffice, with high treatment efficacy. This approach provides similar success rates with low complications and better quality of life compared with surgery. Lumen apposing metallic stents (LAMSs) permit more effective drainage with larger diameter; because of their higher costs than plastic stents, their main role is probably in the context of walled off necrosis, but the place and the use of LAMS should be studied to avoid and reduce the risks of complications. PMID- 29519330 TI - Endoscopic Ultrasound-Guided Biliary Drainage. AB - Endoscopic ultrasound (EUS)-guided biliary drainage is an emerging technique that combines the advantages of the endoscopic and percutaneous approaches, without the inconveniences and discomfort of an indwelling external catheter. There has been growing interest and experience in EUS-biliary drainage. Several different EUS-guided techniques have been developed to access the obstructed biliary tree from either the stomach or duodenum, according to the location of the stricture, the anatomy of the patient, and the experience of the endoscopist. PMID- 29519331 TI - Endoscopic Ultrasound-Guided Gallbladder Drainage. AB - Recent literature has demonstrated effectiveness and safety of endoscopic ultrasound-guided gallbladder drainage, both as a primary intervention in patients with cholecystitis who are unfit for urgent surgical intervention and as a secondary intervention to internalize biliary drainage after initial placement of a percutaneous cholecystostomy catheter. PMID- 29519332 TI - Novel Uses of Lumen-Apposing Metal Stents. AB - The lumen apposing metal stent (LAMS) has historically been used for drainage of pancreatic fluid collections. The unique design of this stent has allowed endoscopists to develop novel uses, including drainage of abscesses adjacent to gastrointestinal lumens, maintaining patency in gastrointestinal strictures, and creating a fistulous tract to bypass altered or compromised anatomy. These alternative uses for the LAMS take advantage of its ability to form a sealed, well-approximated anastomosis. Future applications of the LAMS are continuously being developed as clinicians provide minimally invasive approaches for management of these disease processes. PMID- 29519334 TI - Avoidance, Recognition, and Management of Complications Associated with Lumen Apposing Metal Stents. AB - The lumen-apposing metal stent has evolved endoscopic transluminal therapies, although it has potential complications, including maldeployment, bleeding, perforation, migration, and several risks specific to necrotizing pancreatitis. Careful planning and technique mitigate these inherent risks of lumen-apposing metal sent deployment; however, setbacks occur even in the most experienced of hands. Therefore, early recognition and management of these complications are critical to alleviating morbidity and avoiding mortality. Management frequently requires multidisciplinary effort, including advanced endoscopic technique and consultation of interventional radiologic and surgical colleagues. PMID- 29519333 TI - Lumen-Apposing Metal Stents: Which One and Why? AB - Numerous lumen-apposing metal stents (LAMS) have been designed for transluminal applications, including complex pancreatic fluid collections (PFCs) and difficult biliary access. Limited high-quality data exist directly comparing the various LAMS models, and their use remains largely dependent on availability and operator expertise. LAMS placement has been streamlined by the addition of electrocautery, allowing for single-step or modified "hot" approach, if desired. Therapeutic endoscopists continue to explore the application of this technology in a variety of clinical scenarios, and future innovations will be needed to meet these evolving clinical demands. PMID- 29519335 TI - Endoscopic Closure of Gastrointestinal Fistulae and Leaks. AB - The development of new endoscopic techniques, such as gastrointestinal (GI) stenting, full-thickness suturing, clip application, and use of tissue adhesives, has had a significant impact on management of GI fistulae. These techniques have shown promising results, but further study is needed to optimize the efficacy of long-term closure. The advancement of endoscopic techniques, including the use of the lumen apposing metal stent (LAMS), has allowed for the deliberate creation of fistula tracts to apply endoscopic therapy that previously could not be achieved. This article examines the rapidly evolving area of endoscopic fistula closure and its relationship to LAMS. PMID- 29519336 TI - How the Experts Do It: Step-by-Step Guide. AB - Lumen-apposing metal stents are integrated in a single-step delivery system for draining intra-abdominal fluid collections. The theoretic advantage of lumen apposing stents is the ability to approximate the wall of the drained cavity or organ to the gastrointestinal tract lumen. The use of lumen-apposing stents now includes drainage of organs adjacent to the stomach/duodenum and creation of anastomosis between the stomach and jejunum. The lumen-apposing stents may also serve as a conduit for accessing the remnant stomach for performing biliary tract interventions. This article outlines the approach to placement of lumen-apposing metal stents, technical challenges, and measures to counter adverse events. PMID- 29519337 TI - Lumen-Apposing Metal Stents: An Important New Tool for Interventional Endoscopy Comes of Age. PMID- 29519338 TI - Lumen-Apposing Stents: An Important Step Forward. PMID- 29519339 TI - Trials and Tribulations of Assessing New Imaging Protocols: Combining Vasodilator Stress With Exercise. AB - Among all patients referred for stress myocardial perfusion imaging (MPI), a substantial proportion in contemporary practice cannot exercise. Another group of patients are those who are thought to be able to achieve an adequate workload with treadmill (or bicycle) exercise but do not achieve at least 85% of maximum predicted heart rate without developing symptoms. There has been substantial interest and literature on the adjunctive use of vasodilator stress during the same visit to generate best-quality results for patients who do not exercise adequately. Current American Society of Nuclear Cardiology Guidelines recommend the possible use of vasodilator stress agents to supplement exercise in those patients who do not achieve target heart rate. However, optimal timing of administration is not clear. Herein, we summarize literature to date on the combination of vasodilator and exercise stress testing in light of the recently published Exercise to Regadenoson in Recovery Trial (EXERRT). PMID- 29519340 TI - Left Ventricular Hypertrophy Diagnosed on ECG Also Predicts Early Mortality After Stroke. PMID- 29519341 TI - The Authors Reply. PMID- 29519342 TI - Coronary Artery Calcium Progression: Increasing CAC Is Associated With Increased Events. PMID- 29519343 TI - The Authors Reply. PMID- 29519344 TI - What's Old Is New Again: A Reminder of the Importance of Left Ventricular Geometry and Function as Markers of Risk. PMID- 29519345 TI - Digoxin and Mortality in Patients With Atrial Fibrillation. AB - BACKGROUND: Digoxin is widely used in patients with atrial fibrillation (AF). OBJECTIVES: The goal of this paper was to explore whether digoxin use was independently associated with increased mortality in patients with AF and if the association was modified by heart failure and/or serum digoxin concentration. METHODS: The association between digoxin use and mortality was assessed in 17,897 patients by using a propensity score-adjusted analysis and in new digoxin users during the trial versus propensity score-matched control participants. The authors investigated the independent association between serum digoxin concentration and mortality after multivariable adjustment. RESULTS: At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 0.96 to 1.23; p = 0.19). However, patients with a serum digoxin concentration >=1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR: 1.56; 95% CI: 1.20 to 2.04) compared with those not on digoxin. When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score-matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users. CONCLUSIONS: In patients with AF taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations >=1.2 ng/ml. Initiating digoxin was independently associated with higher mortality in patients with AF, regardless of heart failure. PMID- 29519346 TI - Digoxin in Atrial Fibrillation?: Leave it Out of the Medicine Cabinet. PMID- 29519348 TI - Building the Economic Case for Investment in Cardiovascular Prevention. PMID- 29519347 TI - 10-Year Resource Utilization and Costs for Cardiovascular Care. AB - BACKGROUND: Cardiovascular disease (CVD) imparts a heavy economic burden on the U.S. health care system. Evidence regarding the long-term costs after comprehensive CVD screening is limited. OBJECTIVES: This study calculated 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi Ethnic Study of Atherosclerosis), a registry sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health. METHODS: Cumulative 10 year costs for CVD medications, office visits, diagnostic procedures, coronary revascularization, and hospitalizations were calculated from detailed follow-up data. Costs were derived by using Medicare nationwide and zip code-specific costs, inflation corrected, discounted at 3% per year, and presented in 2014 U.S. dollars. RESULTS: Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78%). Approximately $2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level >3 mg/l, or coronary artery calcium score (CACS) >=400. Costs varied widely from <$7,700 for low-risk (Framingham risk score <6%, 0 CACS, and normal glucose measurements at baseline) to >$35,800 for high-risk (persons with diabetes, Framingham risk score >=20%, or CACS >=400) subgroups. Among high-risk enrollees, CVD costs accounted for $74 million of the $155 million consumed by MESA participants. CONCLUSIONS: Longitudinal patterns of health care resource use after screening revealed new evidence on the economic burden of treatment and testing patterns not previously reported. Maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals. PMID- 29519349 TI - Sustained Physical Activity, Not Weight Loss, Associated With Improved Survival in Coronary Heart Disease. AB - BACKGROUND: Individuals with coronary heart disease (CHD) are recommended to be physically active and to maintain a healthy weight. There is a lack of data on how long-term changes in body mass index (BMI) and physical activity (PA) relate to mortality in this population. OBJECTIVES: This study sought to determine the associations among changes in BMI, PA, and mortality in individuals with CHD. METHODS: The authors studied 3,307 individuals (1,038 women) with CHD from the HUNT (Nord-Trondelag Health Study) with examinations in 1985, 1996, and 2007, followed until the end of 2014. They calculated the hazard ratio (HR) for all cause and cardiovascular disease (CVD) mortality according to changes in BMI and PA, and estimated using Cox proportional hazards regression models adjusted for age, smoking, blood pressure, diabetes, alcohol, and self-reported health. RESULTS: There were 1,493 deaths during 30 years of follow-up (55% from CVD, median 15.7 years). Weight loss, classified as change in BMI <-0.10 kg/m2/year, associated with increased all-cause mortality (adjusted HR: 1.30; 95% confidence interval [CI]: 1.12 to 1.50). Weight gain, classified as change in BMI >=0.10 kg/m2/year, was not associated with increased mortality (adjusted HR: 0.97; 95% CI: 0.87 to 1.09). Weight loss only associated with increased risk in those who were normal weight at baseline (adjusted HR: 1.38; 95% CI: 1.11 to 1.72). There was a lower risk for all-cause mortality in participants who maintained low PA (adjusted HR: 0.81; 95% CI: 0.67 to 0.97) or high PA (adjusted HR: 0.64; 95% CI: 0.50 to 0.83), compared with participants who were inactive over time. CVD mortality associations were similar as for all-cause mortality. CONCLUSIONS: The study observed no mortality risk reductions associated with weight loss in individuals with CHD, and reduced mortality risk associated with weight gain in individuals who were normal weight at baseline. Sustained PA, however, was associated with substantial risk reduction. PMID- 29519350 TI - Can Weight Control and Regular Physical Activity Increase Survival in CHD Patients? PMID- 29519351 TI - Non-Vitamin K Antagonist Oral Anticoagulants and Risk of Serious Liver Injury. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are relatively new drugs used for stroke prevention in nonvalvular atrial fibrillation (NVAF). However, there are concerns that their use may be associated with hepatotoxic effects. OBJECTIVES: The purpose of this study was to determine whether the use of NOACs is associated with an increased risk of serious liver injury compared with the use of vitamin K antagonists (VKAs) in NVAF patients with and without prior liver disease. METHODS: Using the administrative databases of the Canadian province of Quebec's health insurances, the authors conducted a cohort study among patients newly diagnosed with NVAF between January 2011 and December 2014. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious liver injury (defined as either a hospitalization or related death) were estimated using time-dependent Cox proportional hazards models, comparing current use of NOACs to current use of VKAs separately among patients with or without prior liver disease. RESULTS: The cohort comprised 51,887 patients, including 3,778 with prior liver disease. During 68,739 person-years of follow-up, 585 patients experienced a serious liver injury. Compared with current use of VKAs, current use of NOACs was not associated with an increased risk of serious liver injury in patients without or with prior liver disease (adjusted HR: 0.99; 95% CI: 0.68 to 1.45; and adjusted HR: 0.68; 95% CI: 0.33 to 1.37, respectively). CONCLUSIONS: Compared with VKAs, NOACs were not associated with an increased risk of serious liver injury irrespective of baseline liver status. Overall, these results provide reassurance regarding the hepatic safety of NOACs. PMID- 29519352 TI - Resolving Concerns With the Newer Oral Anticoagulant Medications: Is Hepatotoxicity a Real Concern? PMID- 29519354 TI - Vascular Mineralization in Pseudoxanthoma Elasticum: Etidronate to the Rescue? PMID- 29519353 TI - Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum. AB - BACKGROUND: In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease. OBJECTIVES: The authors hypothesized that etidronate, a pyrophosphate analog, might reduce ectopic mineralization in PXE. METHODS: In the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial, adults with PXE and leg arterial calcifications (n = 74) were randomly assigned to etidronate or placebo (cyclical 20 mg/kg for 2 weeks every 12 weeks). The primary outcome was ectopic mineralization, quantified with 18fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBRfemoral). Secondary outcomes were computed tomography arterial calcification and ophthalmological changes. Safety outcomes were bone density, serum calcium, and phosphate. RESULTS: During 12 months of follow-up, the TBRfemoral increased 6% (interquartile range [IQR]: -12% to 25%) in the etidronate group and 7% (IQR: -9% to 32%) in the placebo group (p = 0.465). Arterial calcification decreased 4% (IQR: -11% to 7%) in the etidronate group and increased 8% (IQR: -1% to 20%) in the placebo group (p = 0.001). Etidronate treatment was associated with significantly fewer subretinal neovascularization events (1 vs. 9, p = 0.007). Bone density decreased 4% +/- 12% in the etidronate group and 6% +/- 9% in the placebo group (p = 0.374). Hypocalcemia (<2.20 mmol/l) occurred in 3 versus 1 patient (8.1% vs. 2.7%, p = 0.304). Eighteen patients (48.6%) treated with etidronate, compared with 0 patients treated with placebo (p < 0.001), experienced hyperphosphatemia (>1.5 mmol/l) and recovered spontaneously. CONCLUSIONS: In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral 18fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180). PMID- 29519355 TI - Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 1 of a 2-Part Series. AB - Restrictive cardiomyopathies are the least common form of heart muscle disease. They are characterized as infiltrative and noninfiltrative, storage diseases, and endomyocardial disorders. Genetic diseases commonly present during childhood or adolescence. However, a growing percentage of elderly patients with heart failure with preserved ejection fraction are being recognized as having forms of restrictive cardiomyopathy, particularly cardiac amyloidosis. Noninvasive evaluation has replaced endomyocardial biopsy in the diagnostic evaluation of most suspected etiologies. The detection of infiltrative cardiomyopathies, including lysosomal and glycogen storage disorders, iron overload, and amyloidosis (both light chain amyloidosis and transthyretin amyloidosis variants), as well as inflammatory diseases such as sarcoidosis has slowly led to improved outcomes via disease-specific therapies. PMID- 29519356 TI - Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 2 of a 2-Part Series. AB - Restrictive cardiomyopathies are the least common form of heart muscle disease. They are characterized as infiltrative and noninfiltrative, storage diseases, and endomyocardial disorders. Genetic diseases commonly present during childhood or adolescence. However, a growing percentage of elderly patients with heart failure with preserved ejection fraction are being recognized as having forms of restrictive cardiomyopathy, particularly cardiac amyloidosis. Noninvasive evaluation has replaced endomyocardial biopsy in the diagnostic evaluation of most suspected etiologies. The detection of infiltrative cardiomyopathies, particularly primary and secondary forms of iron overload, as well as inflammatory diseases such as sarcoidosis has slowly led to improved outcomes via disease-specific therapies. PMID- 29519358 TI - The Perfect ECMO Candidate. PMID- 29519357 TI - The Radial Artery for Percutaneous Coronary Procedures or Surgery? AB - This article summarizes the current research on the benefits of using the transradial approach for percutaneous procedures and the radial artery as a conduit for coronary artery bypass surgery. Based on the available evidence, the authors provide recommendations for the use of the radial artery in patients undergoing percutaneous or surgical coronary procedures. PMID- 29519359 TI - Caval Valve Implantation for Treatment of Severe Tricuspid Regurgitation. PMID- 29519360 TI - Gut Microbiota Signature in Heart Failure Defined From Profiling of 2 Independent Cohorts. PMID- 29519361 TI - Lesion Complexity and Prolonged Antiplatelet Therapy: The Missing Variable to Complete the Puzzle. PMID- 29519362 TI - Time for an "Atrial-Watchful" Approach for Heart Failure Patients With a Cardiac Implantable Electronic Device. PMID- 29519363 TI - Reply: Time for an "Atrial-Watchful" Approach for Heart Failure Patients With a Cardiac Implantable Electronic Device. PMID- 29519364 TI - Special Issue of Physiology & Behavior: Sex Differences. PMID- 29519365 TI - Pyruvate kinase deficiency: novel mutations and a better understanding of the genotype-to-phenotype correlation in Brazilian patients. PMID- 29519366 TI - Platelet count response to Helicobacter pylori eradication for idiopathic thrombocytopenic purpura in northeastern Brazil. AB - BACKGROUND: Several studies have demonstrated that platelet counts in Helicobacter pylori-positive patients with chronic idiopathic thrombocytopenic purpura improved significantly after successful eradication of the infection. However, depending of the geographical region of the study the results have been highly divergent. OBJECTIVE: The purpose of this study was to evaluate the effect of H. pylori eradication therapy on platelet count in a cohort of chronic idiopathic thrombocytopenic purpura patients from northeastern Brazil. METHOD: H. pylori status was determined in 28 chronic idiopathic thrombocytopenic purpura patients using the rapid urease test and histology. H. pylori-positive patients received standard triple therapy for one week. The effect of the eradication therapy was evaluated using the 13C-urea breath test two to three months after treatment. RESULTS: The prevalence of H. pylori infection was similar to that found in the general population. Twenty-two patients (78.5%) were H. pylori positive. Fifteen were treated, 13 (86%) of whom successfully. At six months, 4/13 (30%) displayed increased platelet counts, which remained throughout follow up (12 months). Platelet response was not associated to mean baseline platelet count, duration of chronic idiopathic thrombocytopenic purpura, gender, age, previous use of medication, or splenectomy. CONCLUSIONS: H. pylori eradication therapy showed relatively low platelet recovery rates, comparable with previous studies from southeastern Brazil. The effect of H. pylori eradication on platelet counts remained after one year of follow-up suggesting that treating H. pylori infection might be worthwhile in a subset of chronic idiopathic thrombocytopenic purpura patients. PMID- 29519367 TI - Validation of the Brazilian version of the VERITAS-Pro scale to assess adherence to prophylactic regimens in hemophilia. AB - INTRODUCTION: Prophylaxis is the treatment of choice for patients with severe hemophilia. Low adherence may limit the effectiveness of the prophylactic regimen, thereby compromising outcomes. OBJECTIVE: The objective of this study was to validate the Brazilian version of the VERITAS-Pro prophylaxis adherence scale, originally an American questionnaire that can be answered by the individual responsible for prophylaxis as well as by an observer. METHODS: The scale has 24 questions divided into six subscales: Routine, Dosage, Plan, Remember, Skip and Communicate. Participants were recruited at a blood center in southeastern Brazil for validation and reliability analyses. Validation measures included the results obtained using analog visual scales of adherence, interval between medication dispensed by the treatment center pharmacy and the percentage of recommended doses administered and infusions registered in the patients' logs. RESULTS: The study included 32 individuals responsible for prophylaxis and five observers. The internal consistency was very good for the VERITAS-Pro total score, excellent for the Remember, Skip and Communicate subscales, good for the Dosage subscale, and acceptable for the Routine and Plan subscales. Twelve participants answered the questionnaire on more than one occasion to evaluate reproducibility. The intraclass correlation coefficient was excellent. Regarding convergent validity, the VERITAS-Pro scores were moderately correlated with the global adherence scale and with infusion log records, but showed a weak correlation with pharmacy dispensation records. CONCLUSION: The Brazilian version of VERITAS-Pro is a valid and reliable instrument, enabling the understanding of specific factors related to non-adherence and allowing targeted interventions for proper treatment. PMID- 29519368 TI - Transfusion management for patients taking an anti-CD38 monoclonal antibody. AB - INTRODUCTION: Pre-transfusion tests, essential for the release of blood components, may be affected by drugs. Monoclonal antibodies represent a class of medications increasingly used in the clinical practice, with anti-CD38 monoclonal antibodies (daratumumab) being a promising resource in the treatment of refractory myeloma. This monoclonal antibody recognizes CD38 in myeloma cells and interferes with pre-transfusion tests by causing panreactivity in indirect antiglobulin tests thereby clinically masking alloantibodies. Dithiothreitol is a reagent that breaks disulfide bonds and effectively destroys antigenic sites for CD38 on red blood cells. This study reports the immunohematological findings of pre-transfusion tests of patients with multiple myeloma receiving daratumumab and on solutions to prevent the interference of this monoclonal antibody. METHODS: Serum samples from five patients on anti-CD38 monoclonal antibody treatment were evaluated. Tests performed included ABO/RhD typing, indirect antiglobulin test, direct antiglobulin test and eluate test. A daily evaluation was performed to determine the shelf life of dithiothreitol-treated red blood cells when stored in Alsever's solution. RESULTS: No interference in the ABO/RhD typing results was noted but in all samples, a panreactivity was observed in indirect antiglobulin tests. Regarding the direct antiglobulin test, two samples presented positive results but negative eluates. In all samples, treatment of reagent red blood cells with 0.2M dithiothreitol offset interference by anti-CD38 monoclonal antibodies. Dithiothreitol-treated red blood cells stored in Alsever's solution were stable for up to 15 days. CONCLUSION: Treatment of reagent red blood cells with dithiothreitol can be efficient and accessible to offset the interference of the anti-CD38 drug in pre-transfusion tests. The number of costly serological workups can be reduced by having stored dithiothreitol red blood cells with this proving to be a useful reagent for investigating anti-CD38. PMID- 29519369 TI - The interpretation of rare or novel variants: damaging vs. disease-causing. PMID- 29519370 TI - Multiple myeloma and central nervous system involvement: experience of a Brazilian center. AB - INTRODUCTION: The estimated involvement of the central nervous system in patients with multiple myeloma is rare at about 1%. The infiltration can be identified at the time multiple myeloma is diagnosed or during its progression. However, it is more common in refractory disease or during relapse. METHODS: This retrospective cohort study reviewed data from medical records of patients followed up at the Gammopathy Outpatient Clinic of Santa Casa de Misericordia de Sao Paulo from January 2008 to December 2016. RESULTS: Twenty patients were included, with a median follow-up of 33.5 months after central nervous system infiltration. The prevalence was 7%. The median age at diagnosis of multiple myeloma was 56.1 years, with 70% of participants being female. Sixteen patients had central nervous system infiltration at diagnosis of multiple myeloma. Seventeen patients had exclusive osteodural lesions and three had infiltrations of the leptomeninge, of which one had exclusive involvement and two had associated osteodural lesions. The median overall survival was 40.3 months after central nervous system involvement. The median overall survival in the group with central nervous system infiltration at relapse was 7.4 months. The patients with leptomeningeal involvement had a median overall survival of 5.8 months. CONCLUSION: Central nervous system infiltration is a rare condition, but it should be considered as a possibility in patients with multiple myeloma and neurological symptoms. The best treatment regimen for this condition remains unknown and, in most cases, the prognosis is unfavorable. PMID- 29519371 TI - Mortality in children, adolescents and adults with sickle cell anemia in Rio de Janeiro, Brazil. AB - OBJECTIVE: To determine the mortality rate of children, adolescents and adults with sickle cell anemia in Rio de Janeiro, Brazil. METHODS: The number of deaths, the mortality rate and the causes of deaths in patients with sickle cell anemia who were treated and followed up at our institution for 15 years were determined and compared to data available for the Brazilian population. RESULTS: The overall number of deaths was 281 patients with a mortality rate of 16.77%. Survival probability was significantly higher in females. The number of deaths and the mortality rate were age-specific with a significant increase in the 19- to 29 year-old age group. The remaining life expectancy of the patients with sickle cell anemia was less than that of Brazilians at large. The gap between the two was about 20 years for ages between one and five years with this gap decreasing to ten years after the age of 65 years. The most common causes of death were infection, acute chest syndrome, overt stroke, organ damage and sudden death during painful crises. CONCLUSION: To the best of our knowledge, this is the first Brazilian study in a single institution in Rio de Janeiro; the mortality rate was 18.87% among adult patients with sickle cell anemia. The mortality rates in children and adults are higher than those reported in developed countries of the northern hemisphere. PMID- 29519372 TI - Can dentists detect multiple myeloma through oral manifestations? AB - OBJECTIVE: To review published data on oral manifestations of multiple myeloma. METHODS: An electronic database search was performed of articles published from 1971 to November 2016 in order to identify studies that reported oral manifestations of patients with multiple myeloma. Case reports and case series with oral manifestations of multiple myeloma in English were included in the study. An additional search was performed of the references of the selected articles. RESULTS: Thirty-seven articles that reported 81 patients with oral manifestations of multiple myeloma were selected: 30 case reports (82%) and seven case series (18%). The most common clinical features in the dental cavity were swelling (65.4%), bone pain (33.3%), paresthesia (27.1%) and amyloidosis lesions (11.1%). Osteolytic lesions detected on imaging exams were reported in the majority of the patients (90.1%) as plasmacytomas or 'punched-out' lesions. CONCLUSIONS: Swelling and osteolytic lesions represent the most common clinical and radiographic signs of the jaws relating to multiple myeloma, respectively. PMID- 29519373 TI - Novel mutations associated with pyruvate kinase deficiency in Brazil. AB - BACKGROUND: Pyruvate kinase deficiency is a hereditary disease that affects the glycolytic pathway of the red blood cell, causing nonspherocytic hemolytic anemia. The disease is transmitted as an autosomal recessive trait and shows a marked variability in clinical expression. This study reports on the molecular characterization of ten Brazilian pyruvate kinase-deficient patients and the genotype-phenotype correlations. METHOD: Sanger sequencing and in silico analysis were carried out to identify and characterize the genetic mutations. A non affected group of Brazilian individuals were also screened for the most commonly reported variants (c.1456C>T and c.1529G>A). RESULTS: Ten different variants were identified in the PKLR gene, of which three are reported here for the first time: p.Leu61Gln, p.Ala137Val and p.Ala428Thr. All the three missense variants involve conserved amino acids, providing a rationale for the observed enzyme deficiency. The allelic frequency of c.1456C>T was 0.1% and the 1529G>A variant was not found. CONCLUSION: This is the first comprehensive report on molecular characterization of pyruvate kinase deficiency from South America. The results allowed us to correlate the severity of the clinical phenotype with the identified variants. PMID- 29519374 TI - Compound heterozygote of Hb DIran [HBB: c.67G>C, beta 22(B4) Glu>Gln] with beta0 thalassemia [cds 41/42 (-CTTT)] from Eastern India. PMID- 29519375 TI - Bleomycin induced hyperpigmentation of skin. PMID- 29519376 TI - IRAK1 expression in bone marrow cells does not impact patient outcomes in myelodysplastic syndromes. PMID- 29519377 TI - A Multidisciplinary Approach on the Perioperative Antithrombotic Management of Patients With Coronary Stents Undergoing Surgery: Surgery After Stenting 2. AB - Perioperative management of antithrombotic therapy in patients treated with coronary stents undergoing surgery remains poorly defined. Importantly, surgery represents a common reason for premature treatment discontinuation, which is associated with an increased risk in mortality and major adverse cardiac events. However, maintaining antithrombotic therapy to minimize the incidence of perioperative ischemic complications may increase the risk of bleeding complications. Although guidelines provide some recommendations with respect to the perioperative management of antithrombotic therapy, these have been largely developed according to the thrombotic risk of the patient and a definition of the hemorrhagic risk specific to each surgical procedure, key to defining the trade off between ischemia and bleeding, is not provided. These observations underscore the need for a multidisciplinary collaboration among cardiologists, anesthesiologists, hematologists and surgeons to reach this goal. The present document is an update on practical recommendations for standardizing management of antithrombotic therapy management in patients treated with coronary stents (Surgery After Stenting 2) in various types of surgery according to the predicted individual risk of thrombotic complications against the anticipated risk of surgical bleeding complications. Cardiologists defined the thrombotic risk using a "combined ischemic risk" approach, while surgeons classified surgeries according to their inherent hemorrhagic risk. Finally, a multidisciplinary agreement on the most appropriate antithrombotic treatment regimen in the perioperative phase was reached for each surgical procedure. PMID- 29519379 TI - The Day After a Primary Endpoint. PMID- 29519378 TI - 5-Year Outcome Following Randomized Treatment of All-Comers With Zotarolimus Eluting Resolute Integrity and Everolimus-Eluting PROMUS Element Coronary Stents: Final Report of the DUTCH PEERS (TWENTE II) Trial. AB - OBJECTIVES: The study sought to evaluate for the first time the 5-year outcomes after treating an all-comers population with newer-generation cobalt chromium based Resolute Integrity zotarolimus-eluting stents (ZES) (Medtronic, Santa Rosa, California) versus platinum chromium-based PROMUS Element everolimus eluting stents (EES) (Boston Scientific, Natick, Massachusetts). BACKGROUND: The DUTCH PEERS (TWENTE II) (DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity: TWENTE II) trial is a randomized, multicenter, single blinded, investigator-initiated all-comers trial that found at its main analysis similar 1-year safety and efficacy for both drug-eluting stents. It is the first randomized trial ever to investigate the Resolute Integrity ZES and the first trial to compare both devices. METHODS: In total, 1,811 patients were 1:1 randomized to ZES versus EES. We performed a pre-specified assessment of the 5 year clinical outcomes in terms of safety and efficacy. The main endpoint target vessel failure (TVF) is a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization. Secondary endpoints included the individual components of TVF, and stent thrombosis. The study was independently monitored, and adverse clinical events were independently adjudicated. RESULTS: Five-year clinical follow-up data was available in 1,798 (99.3%) patients. The ZES and EES groups showed favorable outcomes, with similar 5-year incidence of TVF (13.2% vs. 14.2%; plog-rank = 0.62) and its individual components: cardiac death (4.5% vs. 4.9%; plog-rank = 0.69), target vessel related myocardial infarction (3.1% vs. 2.6%; plog-rank = 0.47), and target vessel revascularization (7.6% vs. 8.6%; plog-rank = 0.46). The 5-year incidence of definite or probable stent thrombosis was similar (1.5% vs. 1.3%; plog-rank = 0.83). CONCLUSIONS: At 5-year follow-up, the Resolute Integrity ZES and PROMUS Element EES showed similar and sustained results in terms of safety and efficacy for treating a broad population of all-comers. PMID- 29519381 TI - The Misinterpretation of Appropriate Use Criteria for Percutaneous Coronary Intervention in Patients With Stable Ischemic Heart Disease. PMID- 29519380 TI - 2017 Versus 2012 Appropriate Use Criteria for Percutaneous Coronary Interventions: Impact on Appropriateness Ratings. AB - OBJECTIVES: The purpose of this study is to revisit cases rated as "inappropriate" in the 2012 appropriate use criteria (AUC) using the 2017 AUC. BACKGROUND: AUC for coronary revascularization in patients with stable ischemic heart disease (SIHD) were released in January 2017. Earlier 2012 AUC identified a relatively high percentage of New York State patients for whom percutaneous coronary intervention (PCI) was rated as "inappropriate" versus optimal medical therapy alone. METHODS: New York State's PCI registry was used to rate inappropriateness of patients undergoing PCI in 2014 using the 2012 and 2017 AUC, and to examine patient characteristics for patients rated differently. RESULTS: A total of 911 of 9,261 (9.8%) patients who underwent PCI in New York State in 2014 with SIHD without prior coronary artery bypass grafting were rated as "inappropriate" using the 2012 AUC, but only 171 (1.8%) patients were rated as "rarely appropriate" ("inappropriate" in 2012 AUC terminology) using the 2017 AUC. A total of 26% of all 8,407 patients undergoing PCI in New York State with 1 to 2-vessel SIHD were without high-risk findings on noninvasive testing and were either asymptomatic or without antianginal therapy. No current or past randomized controlled trials have focused on these patients. CONCLUSIONS: The percentage of 2014 New York State PCI patients with SIHD who are rated "rarely appropriate" has decreased substantially using 2017 AUC in comparison with the older 2012 AUC. However, for many low-risk patients undergoing the procedure, the relative benefits of optimal medical therapy with and without PCI are unknown. Randomized controlled trials are needed to study these groups. PMID- 29519382 TI - Vascular Access Site and Outcomes in 58,870 Patients Undergoing Percutaneous Coronary Intervention With a Previous History of Coronary Bypass Surgery: Results From the British Cardiovascular Interventions Society National Database. AB - OBJECTIVES: Using the British Cardiovascular Intervention Society percutaneous coronary intervention (PCI) database, access site choice and outcomes of patients undergoing PCI with previous coronary artery bypass grafting (CABG) were studied. BACKGROUND: Given the influence of access site on outcomes, use of radial access in PCI-CABG warrants further investigation. METHODS: Data were analyzed from 58,870 PCI-CABG procedures performed between 2005 and 2014. Multivariate logistic regression was used to identify predictors of access site choice and its association with outcomes. RESULTS: The number of PCI-CABG cases and the percentage of total PCI increased significantly during the study period. Femoral artery (FA) utilization fell from 90.8% in 2005 to 57.6% in 2014 (p < 0.001), with no differences in the rate of change of left versus right radial use. In contemporary study years (2012 to 2014), female sex, acute coronary syndrome presentation, chronic total occlusion intervention, and lower operator volume were independently associated with FA access. Length of stay was shortened in the radial cohort. Unadjusted outcomes including an access site complication (1.10% vs. 0.30%; p < 0.001), blood transfusion (0.20% vs. 0.04%; p < 0.001), major bleeding (1.30% vs. 0.40%; p < 0.001), and in-hospital death (1.10% vs. 0.60%; p = 0.001) were more likely to occur with FA access compared with radial access. After adjustment, although arterial complications, transfusion, and major bleeding remained more common with FA use, short- and longer-term mortality and major adverse cardiac event rates were similar. CONCLUSIONS: In contemporary practice, FA access remains predominant during PCI-CABG with case complexity associated with it use. FA use was associated with longer length of stay, and higher rates of vascular complications, major bleeding, and transfusion. PMID- 29519383 TI - Radial Percutaneous Coronary Intervention and Coronary Artery Bypass Grafts: Buy, Hold, or Sell? PMID- 29519385 TI - Paclitaxel-Eluting Balloons or Everolimus-Eluting Stents for In-Stent Restenosis. PMID- 29519384 TI - Public Health Impact of the Centers for Medicare and Medicaid Services Decision on Pass-Through Add-On Payments for Drug-Coated Balloons: A Call to Action. AB - On Wednesday, November 1, 2017, the Centers for Medicare and Medicaid Services (CMS) made a public decision to end the transitional pass-through add-on payment for drug-coated balloons beginning January 1, 2018, without creating a new ambulatory payment classification rate for these devices. In this Viewpoint, the authors highlight the disconnect between the CMS's decision not to create a new ambulatory payment classification category for drug-coated balloons despite demonstrated clinical superiority. The authors believe this decision is more in line with a rigid fee-for-service payment system than a value-based system that encourages quality over quantity, and disadvantages both the elderly and the poor. They call on all who advocate for patients with peripheral artery disease to action, encouraging their engagement on CMS decisions regarding payment. PMID- 29519386 TI - Reply: Paclitaxel-Eluting Balloons or Everolimus-Eluting Stents for In-Stent Restenosis. PMID- 29519387 TI - De-Escalation of the P2Y12 Inhibitor After Acute Coronary Syndromes According to On-Treatment Platelet Reactivity: A Promising Step of Enormous Magnitude That Should Be Explored. PMID- 29519388 TI - Reply: De-Escalation of the P2Y12 Inhibitor After Acute Coronary Syndromes According to On-Treatment Platelet Reactivity: A Promising Step of Enormous Magnitude That Should Be Explored. PMID- 29519389 TI - Trends in Contrast Volume Use and Incidence of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention: Insights From Blue Cross Blue Shield of Michigan Cardiovascular Collaborative (BMC2). PMID- 29519390 TI - Collateral Quality Decay Several Days After Primary Percutaneous Coronary Intervention: A Unique Observation From the EXPLORE Trial. PMID- 29519391 TI - The Top Papers of 2017: Editor's Pick. PMID- 29519392 TI - Coronary Artery Kinking as a Rare Cause of Ischemia in a Young Woman: Harmonious Approach Using Intracoronary Imaging and Physiology. PMID- 29519394 TI - Improvement of VMAT plan quality for head and neck cancer with high resolution fluences generated by couch shift between arcs. AB - PURPOSE: To investigate the changes in quality of the volumetric modulated arc therapy (VMAT) plans with couch-shift between arcs by half of a multi-leaf collimator (MLC) leaf width. METHODS: A total of 22 patients with head-and-neck cancer were retrospectively selected. Since the smallest MLC leaf width was 5 mm in this study, the couch was shifted by 2.5 mm in the longitudinal-direction between arcs to increase the resolution of fluence map. A total of three types of VMAT plans were generated for each patient; the three types of plans were a two full-arc plan without couch-shift (NS plan), a two-half-arc-pair plan with couch shift (HAS plan), and a two-full-arc pair plan with couch-shift (FAS plan). Changes in the dose-volumetric parameters were investigated. RESULTS: The FAS plan showed the best plan quality for the target volumes and organs at risk compared to the NS and HAS plans. However, the magnitudes of differences among the three types of plans were minimal, and every plan was clinically acceptable. The average integral doses of the NS, HAS, and FAS plans were 160,549 +/- 37,600 Gy-cc, 147,828 +/- 33,343 Gy-cc, and 156,030 +/- 36,263 Gy-cc, respectively. The average monitor unit of the NS, HAS, and FAS plans were 717 +/- 120 MU, 648 +/- 100 MU, and 763 +/- 158 MU, respectively. CONCLUSIONS: The HAS plan was better than the others in terms of normal tissue sparing and plan efficiency. By shifting the couch by half of the MLC leaf width in the longitudinal direction between arcs, the VMAT plan quality could be improved. PMID- 29519395 TI - Participation of women medical Physicists in European scientific events: The European experience. AB - PURPOSE: Though the number of women scientists is increasing over the years, studies show that they are still under-represented in leadership roles. The purpose of this work is to establish the percentage of women Medical Physicists (wMPs) that have participated in European scientific events and evaluate it as an indication of the current position of women in the field of Medical Physics in Europe and to propose possible ways to encourage their participation. MATERIALS AND METHODS: Data regarding the participants in European scientific events of Medical Physics were collected. The participants were divided into categories according to the program of the events and their gender was identified. The percentage of wMPs in each category was evaluated. RESULTS: The participation of wMPs attending courses is greater than 50%. The categories with the greatest participation are "Organizing Committees", "Chairpersons-Moderators" and "Oral Presentations". The categories with the lower participation of wMPs are "Scientific Committee", "Symposiums" and "Invited Speakers". None of wMPs were represented as "Course Directors". CONCLUSIONS: The attendance of wMPs in courses is slightly greater than average. However, wMPs do not have an equally important recognition in special invited roles in conferences. They are still under represented in "Scientific Committees", "Invited Speakers", "Symposiums" and "Course directors". wMPs should be encouraged to participate even more actively in European conferences and the organizing committees should invite more wMPs in special roles. More studies concerning the status of female MPs in each country separately should be encouraged as they will help in understanding the position of wMPS in Europe. PMID- 29519396 TI - Air density dependence of the soft X-ray PTW 34013 ionization chamber. AB - PURPOSE: We studied the dependence on air density of the response of the PTW 34013 ionization chamber, recently upgraded for dosimetry control of low energy X ray beams. METHODS: Measurements were performed by changing the pressure conditions inside a pressure chamber. The behavior of the measurements against the air density inside this chamber was analyzed. X-ray beams generated with 50, 70, 100, 150 and 200 kVp and the two electrometer polarities were considered. RESULTS: For all beams studied, measurements corrected with the conventional temperature and pressure factor showed a residual dependence on the air density that was described with a linear function of the air density. For the 50 and 70 kVp beams, corrected measurements remained ~1% smaller than the value found at standard pressure/temperature conditions, for both electrometer polarities and for the air density range typical in clinical conditions. For air densities smaller than the standard one, measurements found for 100, 150 and 200 kVp beams were below or above the value found at standard pressure and temperature when the negative or positive electrometer polarities were used, respectively. The differences with the measurements at standard conditions were less than 1% for the 100 kVp beam and below 4% for the other two beams. CONCLUSIONS: The PTW 34013 ionization chamber showed a dependence on the air density that is not properly described with the usual temperature and pressure correction factor. This residual dependence is negligible for low energy beams, for which this chamber is recommended, but is more substantial for beams with energy above 80 kVp. PMID- 29519397 TI - Task-based phantom evaluation of cardiac catheterization imaging modes. AB - This study aimed to quantify the dose and quality of the preprogrammed imaging modes on two cardiac angiography devices (Philips Allura FD10 Clarity and Allura FD10) using a task-specific in-house phantom, and to discuss the appropriateness of the pre-programmed settings. A Figure of Merit (FOM), defined as the squared Signal Difference to Noise Ratio (SDNR) divided by Entrance Surface Air Kerma (ESAK), was calculated for phantom inserts with different sizes and concentrations of iodine, as well as tin foils. For the Allura FD10 Clarity device, the low dose fluoroscopic mode was found to be very dose efficient, while the available cine modes should only be used for cases with high demand for contrast and temporal resolutions. For both devices, the basic beam spectrum of the low dose fluoroscopic mode should be explored for use on other imaging modes. Cine modes for the Allura FD10 device differ only by their spatial resolution characteristics and have almost identical dose per frame. This study also found that tin may not be a suitable replacement for iodine for research purposes due to mismatching SDNR. The number of recommendations formulated for these two devices suggests that comparative dose and image quality tests of all routinely used imaging modes should be an obligatory part of the physicists' acceptance testing. PMID- 29519398 TI - Automatic detection of pulmonary nodules in CT images by incorporating 3D tensor filtering with local image feature analysis. AB - Computer-aided detection (CAD) technology has been developed and demonstrated its potential to assist radiologists in detecting pulmonary nodules especially at an early stage. In this paper, we present a novel scheme for automatic detection of pulmonary nodules in CT images based on a 3D tensor filtering algorithm and local image feature analysis. We first apply a series of preprocessing steps to segment the lung volume and generate the isotropic volumetric CT data. Next, a unique 3D tensor filtering approach and local image feature analysis are used to detect nodule candidates. A 3D level set segmentation method is used to correct and refine the boundaries of nodule candidates subsequently. Then, we extract the features of the detected candidates and select the optimal features by using a CFS (Correlation Feature Selection) subset evaluator attribute selection method. Finally, a random forest classifier is trained to classify the detected candidates. The performance of this CAD scheme is validated using two datasets namely, the LUNA16 (Lung Nodule Analysis 2016) database and the ANODE09 (Automatic Nodule Detection 2009) database. By applying a 10-fold cross validation method, the CAD scheme yielded a sensitivity of 79.3% at an average of 4 false positive detections per scan (FP/Scan) for the former dataset, and a sensitivity of 84.62% and 2.8 FP/Scan for the latter dataset, respectively. Our detection results show that the use of 3D tensor filtering algorithm combined with local image feature analysis constitutes an effective approach to detect pulmonary nodules. PMID- 29519399 TI - Significant dose reduction is feasible in FDG PET/CT protocols without compromising diagnostic quality. AB - PURPOSE: To reduce the radiation dose to patients by optimizing oncological FDG PET/CT protocols. METHODS: The baseline PET/CT protocol in our institution for oncological PET/CT examinations consisted of the administration of 5.18 MBq/kg of FDG and a CT acquisition with a reference current-time product of 120 mAs. In 2016, FDG activity was reduced to 4.44 and 3.70 MBq/kg and reference CT current time-product was reduced to 100 and 80 mAs. 322 patients scanned with different protocols were retrospectively evaluated. For each patient, effective dose was calculated. The overall image quality was subjectively rated by the referring physician on a 4-point scale (IQ score: 1 excellent, 2 good, 3 poor but interpretable, 4 poor not interpretable). Image quality was quantitatively evaluated measuring noise in the liver. RESULTS: CT Results: Effective dose was progressively reduced from 9.5 +/- 2.8 to 8.0 +/- 2.3 and 6.2 +/- 1.5 mSv (p < 0.001). A mean dose reduction of 34.9% was achieved. There was a significant degradation of IQ score (p < 0.05) and noise (p < 0.001). Nevertheless, the number of poor quality studies (IQ score >2) did not increase. PET Results: Effective dose was gradually reduced from 6.5 +/- 1.4 to 5.7 +/- 1.3 and 5.0 +/- 1.0 mSv (p < 0.001). Average dose reduction was 23.4%. IQ score (p < 0.05) and noise (p < 0.001) significantly degraded for lower activity protocols. However, all images with reduced activity were scored as interpretable (IQ score <= 3). CONCLUSIONS: A significant radiation dose reduction of 28.7% was reached. Despite a slight reduction in image quality, the new regime was successfully implemented with readers reporting unchanged clinical confidence. PMID- 29519400 TI - The impact of iodinated contrast media on intravascular and extravascular absorbed doses in X-ray imaging: A microdosimetric analysis. AB - : Studies suggest iodinated contrast media (ICM) may increase organ dose and blood cell DNA damage for a given X-ray exposure. The impact of ICM on dose/damage to extravascular cells and cancer risks is unclear. METHODS: We used Monte Carlo modelling to investigate the microscopic distribution of absorbed dose outside the lumen of arteries, capillaries and interstitial fluids containing blood and various concentrations of iodine. Models were irradiated with four X-ray spectra representing clinical procedures. RESULTS: For the artery model, The average dose enhancement factors (DEF) to blood were 1.70, 2.38, 7.38, and 12.34 for mass concentrations of iodine in blood (rhoiI) of 5, 10, 50 and 100 mg/ml, respectively, compared to 0 mg/ml. Average DEFs were reduced to 1.26, 1.51, 3.48 and 5.56, respectively, in the first micrometre of the vessel wall, falling to 1.01, 1.02, 1.06 and 1.09 at 40-50 MUm from the lumen edge. For the capillary models, DEF for extravascular tissues was on average 48% lower than DEF for the whole model, including capillaries. A similar situation was observed for the interstitial model, with DEF to the cell nucleus being 35% lower than DEF for the whole model. CONCLUSIONS: While ICM may modify the absorbed doses from diagnostic X-ray examinations, the effect is smaller than suggested by assays of circulating blood cells or blood dose enhancement. Conversely, the potentially large increase in dose to the endothelium of blood vessels means that macroscopic organ doses may underestimate the risk of radiation induced cardiovascular disease for ICM-enhanced exposures. PMID- 29519401 TI - Patient radiation doses in intraoral and panoramic X-ray examinations in Sudan. AB - Radiation doses were measured for the first time in intraoral and panoramic dental radiology at Sudanese hospitals. Doses were determined using various exposure settings for adults and children in 8 intraoral and 6 panoramic X-ray devices. The study sample was equally divided between devices using a digital image receptor (DR) and those using conventional screen film (SF). Radiation doses are reported in terms of incident air kerma (IAK) (intraoral radiology) and kerma area product (PKA) (panoramic radiology). IAK values in intraoral radiology were: 1.45 mGy (DR), 4.45 mGy (SF), and 3.01 mGy (combined). For panoramic radiology, PKA values ranged: from 35.8 to 103.2 mGy cm2 (average: 70.4 mGy cm2) for children and from 65.7 to 151.4 mGy cm2 (average: 103.4 mGy cm2) for adults. The results showed that the downward trend in patient doses can be achieved using digital imaging. The study revealed important concerns surrounding radiation protection, such as the lack of regular quality assurance programs and the use of circular collimators. PMID- 29519402 TI - Evaluation of a commercial automatic treatment planning system for liver stereotactic body radiation therapy treatments. AB - PURPOSE: Automated treatment planning is a new frontier in radiotherapy. The Auto Planning module of the Pinnacle3 treatment planning system (TPS) was evaluated for liver stereotactic body radiation therapy treatments. METHODS: Ten cases were included in the study. Six plans were generated for each case by four medical physics experts. The first two planned with Pinnacle TPS, both with manual module (MP) and Auto-Planning one (AP). The other two physicists generated two plans with Monaco TPS (VM). Treatment plan comparisons were then carried on the various dosimetric parameters of target and organs at risk, monitor units, number of segments, plan complexity metrics and human resource planning time. The user dependency of Auto-Planning was also tested and the plans were evaluated by a trained physician. RESULTS: Statistically significant differences (Anova test) were observed for spinal cord doses, plan average beam irregularity, number of segments, monitor units and human planning time. The Fisher-Hayter test applied to these parameters showed significant statistical differences between AP e MP for spinal cord doses and human planning time; between MP and VM for monitor units, number of segments and plan irregularity; for all those between AP and VM. The two plans created by different planners with AP were similar to each other. CONCLUSIONS: The plans created with Auto-Planning were comparable to the manually generated plans. The time saved in planning enables the planner to commit more resources to more complex cases. The independence of the planner enables to standardize plan quality. PMID- 29519403 TI - A novel Hemi-Body Irradiation technique using electron beams (HBIe-). AB - PURPOSE: Certain radiation responsive skin diseases may develop symptoms on the upper or the lower half of the body. The concept of a novel Hemi-Body Electron Irradiation (HBIe-) technique, described in this work, provides a low cost, LINAC based, intermediate treatment option in between extremely localized and Total Skin irradiation techniques. MATERIALS AND METHODS: The HBIe- technique, developed in our department, incorporates a custom crafted treatment chamber equipped with adjustable Pb shielding and a single electron beam in extended Source-Skin Distance (SSD) setup. The patient is positioned in 'Stanford' technique positions. The geometrical setup provides both optimal dose homogeneity and dose deposition up to a depth of 2 cm. To confirm this, the following characteristics were measured and evaluated: a) percentage depth dose (PDD) on the treatment plane produced by a single electron beam at perpendicular incidence for six fields at 'Stanford' angles, b) 2D profile of the entrance dose on the treatment plane produced by a single field and c) the total surface dose on an anthropomorphic phantom delivered by all 6 fields. RESULTS: The resulting homogeneity of the surface dose in the treatment plane for an average patient was 5-6%, while surface dose homogeneity on the anthropomorphic phantom was 7% for both the upper and the lower HBIe- variants. The total PDD exhibits an almost linear decrease to a practical range of 2 g/cm2. CONCLUSION: In conclusion, HBIe- was proven effective in delivering the prescribed dose to the target area, while protecting the healthy skin. PMID- 29519404 TI - Radiation protection from external exposure to radionuclides: A Monte Carlo data handbook. AB - The availability of a resource collecting dose factors for the evaluation of the absorbed doses from external exposure during the manipulation of radioactive substances is fundamental for radiological protection purposes. Monte Carlo simulations are useful for the accurate calculation of dose distributions in complex geometries, particularly in presence of extended spectra of multi radiation sources. We considered, as possible irradiation scenarios, a point source, a uniform planar source resembling a contaminated surface, several source volumes contained in plastic or glass receptacles, and the direct skin contamination case, implementing the corresponding Monte Carlo simulations in GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations). A set of 50 radionuclides was studied, focusing the attention on those ones mainly used in nuclear medicine, both for diagnostic and therapeutic purposes, in nuclear physics laboratories and for instrument calibration. Skin dose equivalents at 70 MUm of depth and deep dose equivalents at 10 mm of depth are reported for different configurations and organized in easy-to-read tables. PMID- 29519405 TI - Computational analysis of interfractional anisotropic shape variations of the rectum in prostate cancer radiation therapy. AB - PURPOSE: To analyze the uncertainties of the rectum due to anisotropic shape variations by using a statistical point distribution model (PDM). MATERIALS AND METHODS: The PDM was applied to the rectum contours that were delineated on planning computed tomography (CT) and cone-beam CT (CBCT) at 80 fractions of 11 patients. The standard deviations (SDs) of systematic and random errors of the shape variations of the whole rectum and the region in which the rectum overlapped with the PTV (ROP regions) were derived from the PDMs at all fractions of each patient. The systematic error was derived by using the PDMs of planning and average rectum surface determined from rectum surfaces at all fractions, while the random error was derived by using a PDM-based covariance matrix at all fractions of each patient. RESULTS: Regarding whole rectum, the population SDs were larger than 1.0 mm along all directions for random error, and along the anterior, superior, and inferior directions for systematic error. The deviation is largest along the superior and inferior directions for systematic and random errors, respectively. For ROP regions, the population SDs of systematic error were larger than 1.0 mm along the superior and inferior directions. The population SDs of random error for the ROP regions were larger than 1.0 mm except along the right and posterior directions. CONCLUSIONS: The anisotropic shape variations of the rectum, especially in the ROP regions, should be considered when determining a planning risk volume (PRV) margins for the rectum associated with the acute toxicities. PMID- 29519406 TI - High velocity pulse biopsy device enables controllable and precise needle insertion and high yield tissue acquisition. AB - Minimally invasive biopsies are a cornerstone of breast cancer management with ultrasound being the preferred guidance modality. New developments in breast cancer management and advances in imaging technologies bring new challenges to current biopsy methodologies. A new biopsy device (NeoNavia(r) biopsy system, 14 G) was developed. It incorporates a pneumatic needle insertion mechanism that is intended to provide better control of needle progression and enable stepwise insertion without noticeable deformation or displacement of surrounding tissue as visualized under ultrasound. A new method of tissue acquisition was designed to achieve a sampling yield higher than standard methodologies. Needle dynamics was assessed on a specifically designed test bed and sampling performance was compared to a Magnum(r) biopsy instrument (Bard, Covington, GA, USA) in representative tissue models. The histological quality of samples obtained ex vivo was evaluated. A pneumatic pulse was measured to accelerate the needle to a maximum velocity of 21.2 +/- 2.5 m/s on a stroke length of 2.5 mm, achieving significantly higher acceleration, maximum velocity and power than current biopsy devices. Mean weight of samples obtained by the NeoNavia device were 3.5, 4.6, and 4.3 times higher when sampling was performed in turkey breast, calf thymus and swine pancreas, respectively, as compared to samples obtained with the Magnum instrument. Ex-vivo analysis indicates that the method of tissue acquisition has no apparent negative impact on the histopathologic quality of obtained samples. PMID- 29519407 TI - Exploration of temporal stability and prognostic power of radiomic features based on electronic portal imaging device images. AB - PURPOSE: We aimed to explore the temporal stability of radiomic features in the presence of tumor motion and the prognostic powers of temporally stable features. METHODS: We selected single fraction dynamic electronic portal imaging device (EPID) (n = 275 frames) and static digitally reconstructed radiographs (DRRs) of 11 lung cancer patients, who received stereotactic body radiation therapy (SBRT) under free breathing. Forty-seven statistical radiomic features, which consisted of 14 histogram-based features and 33 texture features derived from the graylevel co-occurrence and graylevel run-length matrices, were computed. The temporal stability was assessed by using a multiplication of the intra-class correlation coefficients (ICCs) between features derived from the EPID and DRR images at three quantization levels. The prognostic powers of the features were investigated using a different database of lung cancer patients (n = 221) based on a Kaplan-Meier survival analysis. RESULTS: Fifteen radiomic features were found to be temporally stable for various quantization levels. Among these features, seven features have shown potentials for prognostic prediction in lung cancer patients. CONCLUSIONS: This study suggests a novel approach to select temporally stable radiomic features, which could hold prognostic powers in lung cancer patients. PMID- 29519408 TI - Evaluation of third treatment week as temporal window for assessing responsiveness on repeated FDG-PET-CT scans in Non-Small Cell Lung Cancer patients. AB - PURPOSE: Early assessment of tumour response to treatment with repeated FDG-PET CT imaging has potential for treatment adaptation but it is unclear what the optimal time window for this evaluation is. Previous studies indicate that changes in SUVmean and the effective radiosensitivity (alphaeff, accounting for uptake variations and accumulated dose until the second FDG-PET-CT scan) are predictive of 2-year overall survival (OS) when imaging is performed before radiotherapy and during the second week. This study aims to investigate if multiple FDG-PET-derived quantities determined during the third treatment week have stronger predictive power. METHODS: Twenty-eight lung cancer patients were imaged with FDG-PET-CT before radiotherapy (PET1) and during the third week (PET2). SUVmean, SUVmax, SUVpeak, MTV41%-50% (Metabolic Tumour Volume), TLG41% 50% (Total Lesion Glycolysis) in PET1 and PET2 and their change (), as well as average alphaeff (alpha-eff) and the negative fraction of alphaeff values [Formula: see text] ) were determined. Correlations were sought between FDG-PET derived quantities and OS with ROC analysis. RESULTS: Neither SUVmean, SUVmax, SUVpeak in PET1 and PET2 (AUC = 0.5-0.6), nor their changes (AUC = 0.5-0.6) were significant for outcome prediction purposes. Lack of correlation with OS was also found for alpha-eff (AUC = 0.5) and [Formula: see text] (AUC = 0.5). Threshold based quantities (MTV41%-50%, TLG41%-50%) and their changes had AUC = 0.5-0.7. P values were in all cases ?0.05. CONCLUSIONS: The poor OS predictive power of the quantities determined from repeated FDG-PET-CT images indicates that the third week of treatment might not be suitable for treatment response assessment. Comparatively, the second week during the treatment appears to be a better time window. PMID- 29519409 TI - Towards the definition of Institutional diagnostic reference levels in paediatric interventional cardiology procedures in Greece. AB - This study aimed to evaluate paediatric radiation doses in a dedicated cardiology hospital, with the objective of characterising patterns in dose variation. The ultimate purpose was to define Local (Institutional) Diagnostic Reference Levels (LDRLs) for different types of paediatric cardiac interventional procedures (IC), according to patient age. From a total of 710 cases performed during three consecutive years, by operators with more than 15 years of experience, the age was noted in only 477 IC procedures. The median values obtained for Fluoroscopy Time (FT), Number of Frames (N) and Kerma Area Product (PKA) by age range were 5.8 min, 1322 and 2.0 Gy.cm2 for <1 y; 6.5 min, 1403 and 3.0 Gy.cm2 for 1 to <5 y; 5.9 min, 950 and 7.0 Gy.cm2 for 5 to <10 y; 5.7 min, 940 and 14.0 Gy.cm2 for 10 to <16 y, respectively. A large range of patient dose data is observed, depending greatly on procedure type and patient age. In all age groups the range of median FT, N and PKA values was 3.1-15.8 min, 579-1779 and 1.0-20.8 Gy.cm2 respectively. Consequently, the definition of LDRLs presents challenges mainly due to the multiple clinical and technical factors affecting the outcome. On the other hand the lack of paediatric IC DRLs makes the identification of good practices more difficult. A consensus is needed on IC procedures nomenclature and grouping in order to allow a common assessment and comparison of doses. PMID- 29519410 TI - Cone-beam CT-based inter-fraction localization errors for tumors in the pelvic region. AB - PURPOSE: To evaluate inter-fraction tumor localization errors (TE) in the RapidArc(r) treatment of pelvic cancers based on CBCT. Appropriate CTV-to PTV margins in a non-IGRT scenario have been proposed. METHODS: Data of 928 patients with prostate, gynecological, and rectum/anal canal cancers were retrospectively analyzed to determine systematic and random localization errors. Two protocols were used: daily online IGRT (d-IGRT) and weekly IGRT. The latter consisted in acquiring a CBCT for the first 3 fractions and subsequently once a week. TE for patients who underwent d-IGRT protocol were calculated using either all CBCTs or the first 3. RESULTS: The systematic (and random) TE in the AP, LL, and SI direction were: for prostate bed 2.7(3.2), 2.3(2.8) and 1.9(2.2) mm; for prostate 4.2(3.1), 2.9(2.8) and 2.3(2.2) mm; for gynecological 3.0(3.6), 2.4(2.7) and 2.3(2.5) mm; for rectum 2.8(2.8), 2.4(2.8) and 2.3(2.5) mm; for anal canal 3.1(3.3), 2.1(2.5) and 2.2(2.7) mm. CTV-to-PTV margins determined from all CBCTs were 14 mm in the AP, 10 mm in the LL and 9-9.5 mm in the SI directions for the prostate and the gynecological groups and 9.5-10.5 mm in AP, 9 mm in LL and 8-10 mm in the SI direction for the prostate bed and the rectum/anal canal groups. If assessed on the basis of the first 3 CBCTs, the calculated CTV-to-PTV margins were slightly larger. CONCLUSIONS: without IGRT, large CTV-to-PTV margins up to 15 mm are required to account for inter-fraction tumor localization errors. Daily IGRT should be used for all hypo-fractionated treatments to reduce margins and avoid increased toxicity to critical organs. PMID- 29519411 TI - Feasibility of setting up generic alert levels for maximum skin dose in fluoroscopically guided procedures. AB - PURPOSE: The feasibility of setting-up generic, hospital-independent dose alert levels to initiate vigilance on possible skin injuries in interventional procedures was studied for three high-dose procedures (chemoembolization (TACE) of the liver, neuro-embolization (NE) and percutaneous coronary intervention (PCI)) in 9 European countries. METHODS: Gafchromic(r) films and thermoluminescent dosimeters (TLD) were used to determine the Maximum Skin Dose (MSD). Correlation of the online dose indicators (fluoroscopy time, kerma- or dose-area product (KAP or DAP) and cumulative air kerma at interventional reference point (Ka,r)) with MSD was evaluated and used to establish the alert levels corresponding to a MSD of 2 Gy and 5 Gy. The uncertainties of alert levels in terms of DAP and Ka,r, and uncertainty of MSD were calculated. RESULTS: About 20-30% of all MSD values exceeded 2 Gy while only 2-6% exceeded 5 Gy. The correlations suggest that both DAP and Ka,r can be used as a dose indicator for alert levels (Pearson correlation coefficient p mostly >0.8), while fluoroscopy time is not suitable (p mostly <0.6). Generic alert levels based on DAP (Gy cm2) were suggested for MSD of both 2 Gy and 5 Gy (for 5 Gy: TACE 750, PCI 250 and NE 400). The suggested levels are close to the lowest values published in several other studies. The uncertainty of the MSD was estimated to be around 10-15% and of hospital-specific skin dose alert levels about 20-30% (with coverage factor k = 1). CONCLUSIONS: The generic alert levels are feasible for some cases but should be used with caution, only as the first approximation, while hospital specific alert levels are preferred as the final approach. PMID- 29519412 TI - A constrained linear regression optimization algorithm for diaphragm motion tracking with cone beam CT projections. AB - PURPOSE: We presented a feasibility study to extract the diaphragm motion from the inferior contrast cone beam computed tomography (CBCT) projection images using a constrained linear regression optimization algorithm. METHODS: The shape of the diaphragm was fitted by a parabolic function which was initialized by five manually placed points on the diaphragm contour of a pre-selected projection. A constrained linear regression model by exploiting the spatial, algebraic, and temporal constraints of the diaphragm, approximated by a parabola, was employed to estimate the parameters. The algorithm was assessed by a fluoroscopic movie acquired at anterior-posterior (AP) fixed direction and kilovoltage CBCT projection image sets from four lung and two liver patients using the Varian 21iX Clinac. The automatic tracing by the proposed algorithm and manual tracking were compared in both space and frequency domains for the algorithm evaluations. RESULTS: The error between the results estimated by the proposed algorithm and those by manual tracking for the AP fluoroscopic movie was 0.54 mm with standard deviation (SD) of 0.45 mm. For the detected projections the average error was 0.79 mm with SD of 0.64 mm for all six enrolled patients and the maximum deviation was 2.5 mm. The mean sub-millimeter accuracy outcome exhibits the feasibility of the proposed constrained linear regression approach to track the diaphragm motion on rotational fluoroscopic images. CONCLUSION: The new algorithm will provide a potential solution to rendering diaphragm motion and possibly aiding the tumor target tracking in radiation therapy of thoracic/abdominal cancer patients. PMID- 29519413 TI - A collapsed-cone based transit EPID dosimetry method. AB - PURPOSE: To develop a transit-dose portal dosimetry method based on a commercial collapsed-cone algorithm. METHODS: A Varian Clinac21EX (Varian Medical Systems, USA), equipped with an amorphous-silicon EPID aS1000, was used. Dose calculations were performed with the collapsed-cone algorithm of Pinnacle3 v8.0 m (Philips Medical Systems, USA). A model for the energy of 6 MV was made in Pinnacle3 and afterwards validated for clinical use. A virtual phantom with different densities was contoured and superimposed on the patient images, simulating the presence of the EPID during the treatment. Corrections for photon spectral variations were introduced using Matlab (Mathworks, USA). Transit dosimetry was verified with an anthropomorphic phantom, on which different treatment fields were simulated in locations of skull, thorax and pelvis. In addition, a prostate treatment with IMRT was administered thereon. Dose distributions were compared with gamma index. RESULTS: The dose differences at the central point did not exceed 2%, except for the 20 x 20 cm2 field size centered in the skull. The model presented in this work, assumes that the dimensions of the solid water phantom, are infinite, except for the thickness. The mean values for the gamma index pass rates were 85.62% for (3%, 3 mm), 91.73% (4%, 3 mm) and 95.68% (5%, 3 mm). CONCLUSIONS: The value of 95% for gamma (5%, 3 mm) can be established as the value below which the origin of the discrepancies should be investigated. It should be considered that the proposed method is complementary and not a substitute for pre-treatment dosimetry. PMID- 29519414 TI - Image guidance in clinical practice - Influence of positioning inaccuracy on the dose distribution for prostate cancer. AB - BACKGROUND: In order to consider potential positioning errors there are different recipes for safety-margins for CTV-to-PTV expansion. The aim of this study is to simulate the effect of positioning inaccuracy with clinically realistic patient treatment plans. METHODS: For a collective of 40 prostate patients, the isocenter was shifted back appropriately to the applied table shifts after positioning verification, simulating that no positioning correction had been performed and the treatment plans were recalculated. All the treatment fractions with the appropriate isocenter-shifts were added to yield a new plan considering two scenarios:Afterwards all plans were analysed and compared with each other regarding target coverage, sparing of organs at risk (OAR) and normal tissue complication probability (NTCP). RESULTS: Dose distributions and especially DVH show a deterioration of the target-coverage caused by the positioning inaccuracy. Deviations in dose at a single point can reach values of over 10 Gy. In single cases minimum plan agreement only achieved 66% pass within 3% local dose for the realistic case. Organs at risk and NTCP analysis result in a slightly better sparing of the rectum. Measures of quality like homogeneity and conformity differ just minimally regarding the different scenarios. CONCLUSION: PTV-coverage suffers markedly by the positioning uncertainties, the shifted plans are in large parts clinically not acceptable. Surprisingly sparing of the OAR is not negatively affected by potential positioning errors for this prostate collective. PMID- 29519415 TI - Relative biological effectiveness study of Lipiodol based on microdosimetric kinetic model. AB - OBJECTIVES: We examine the contrast agent Lipiodol effect on the relative biological effectiveness (RBE) values for flattening filter free (FFF) and flattening filter (FF) beams of 6 MV-Xray (6 MVX) and 10 MVX. METHODS: Lipiodol was placed at 5 cm depth in water. According to the microdosimetric kinetic model, the RBE values for killing the human liver hepatocellular cells were calculated from dose and lineal energy (yd(y)) from Monte Carlo simulations. RBE200kVX and RBECo were defined as the ratios of dose using reference radiation (200 kVX, Co-?) to the dose of test radiation (FFF and FF beams for 6 MV and 10 MV) to produce the same biological effects. The dose enhancement RBE (RBEDE) was defined as the ratios of a dose without Lipiodol to with Lipiodol using to produce the same biological effects. The dose needed to achieve 10% (D10%) and 1% cell survival (D1%) was evaluated by cell surviving fraction (SF) formula. RESULTS: The deviation of mean y?D values with and without Lipiodol were 3.9-4.8% for 6 MVX and 3.5-3.6% for 10 MVX. The RBE200kVX and RBECo with Lipiodol were larger than that without Lipiodol. The RBEDE was larger for FFF beam than for FF beam. The deviation of RBEDE for FFF and FF beams of 6 MVX was larger than that of 10 MVX. CONCLUSION: The presence of Lipiodol seemed to locally increase the absorbed dose and to also cause an enhancement of the relative biological effectiveness. PMID- 29519416 TI - Real-time speech MRI: Commercial Cartesian and non-Cartesian sequences at 3T and feasibility of offline TGV reconstruction to visualise velopharyngeal motion. AB - PURPOSE: This study aims to improve clinical reliability of real-time Magnetic Resonance Imaging (rt-MRI) in the visualisation of velopharyngeal motion during speech. METHODS: Seven subjects were imaged at 3T during natural phonation. Speech rt-MRI methodologies were investigated with (i) a comparison of commercial Cartesian and non-Cartesian (radial and spiral) rt-MRI sequences and (ii) investigation of further improvement with accelerated radial acquisition and offline reconstruction methodology. RESULTS: Cartesian and non-Cartesian protocols were implemented with temporal resolutions between 10 frames per second (fps) and 27 fps and voxel sizes between 1.5 * 1.5 * 10 mm3 and 2.7 * 2.7 * 10 mm3. Commercial spiral acquisitions provided superior contrast-to-noise ratio (CNR) than otherwise equivalent Cartesian and radial. Spirals at 22 fps allowed for improved spatial resolution (1.9 * 1.9 mm2) when compared to similar Cartesian protocols (20 fps), limited to a lower spatial resolution (2.7 * 2.7 mm2). Cartesian protocols were on average scored higher than spiral protocols in visual quality. However, some variability was found on choice of recommended imaging protocol between subjects. Accelerated radial data reconstructed offline with a Total Generalized Variation (TGV) scheme showed improved visual sharpness of velum motion. DISCUSSION/CONCLUSION: Adequate visualisation of velopharyngeal motion with commercial rt-MRI at 3T was possible. Both Cartesian and spiral protocols demonstrated adequate temporal depiction and overall image quality. However, choice of optimal imaging protocol at 3T was more subject-dependent than in previously published 1.5T data and additional care should be taken when selecting an adequate protocol. Offline TGV reconstruction of radial data has shown potential to improve temporal sharpness. PMID- 29519417 TI - Regulation of macrophage polarization and promotion of endothelialization by NO generating and PEG-YIGSR modified vascular graft. AB - As an effective clinic treatment for cardiovascular disease, vascular transplantation gains much acceptance recently. However, due to the acute thrombosis and intimal hyperplasia, long-term failure of synthetic grafts after implanted in small diameter blood vessel decelerates its commercial use. The continued acute inflammation and delayed endothelialization have been considered as fundamental reasons. To enhance the adhesion and organization of endothelial cells (ECs) and improve the vascular remodeling process, we have constructed a vascular graft based on electrospun polycaprolactone (PCL) matrix, on which organoselenium-immobilized polyethyleneimine (SePEI) for in situ nitric oxide (NO) generation and hyaluronic acid (HA) grafted with poly (ethylene glycol) (PEG) modified Tyr-Ile-Gly-Ser-Arg (YIGSR) for antifouling and EC adhesion were deposited through electrostatic layer-by-layer assembly. The in vitro results showed that SePEI deposited on the grafts could catalyze stable generation of NO. After in situ implantation in rats for 4 and 8weeks, the graft promoted the transformation of macrophages into an anti-inflammatory phenotype (M2), which helped endothelium remodeling. YIGSR on the outmost layer facilitated more rapid and organized EC adhesion compared to PCL and non-modified grafts. PEG polymer chain on the outmost layer mitigated nonspecific adsorption of undesirable blood components. In our study, we first demonstrated the regulation of macrophage polarization by an NO-generating vascular graft. The results indicated that the approach of anti-inflammatory macrophage polarization and enhanced endothelialization through NO generation and PEG-modified YIGSR in our study may provide a new perspective for the clinic application of cell-free small-diameter vascular grafts. PMID- 29519418 TI - TPGS functionalized mesoporous silica nanoparticles for anticancer drug delivery to overcome multidrug resistance. AB - Multidrug resistance (MDR) has become a very serious problem in cancer therapy. To effectively reverse MDR in tumor treatments, a new pH-sensitive nano drug delivery system (NDDS) composed of mesoporous silica nanoparticles (MSNs) and d-a tocopheryl poly-ethylene glycol 1000 succinate (TPGS) copolymers was synthesized to deliver doxorubicin (DOX) into drug-resistant breast cancer cell line (MCF 7/ADR). DOX@MSNs-TPGS were characterized to have a single peak size distribution, high DOX loading efficiency and a pH-dependent drug release profile. MSNs-TPGS were internalized via caveolae, clathrin-mediated endocytosis and energy dependent cellular uptake. The DOX@MSNs-TPGS exhibited 10-fold enhanced cell killing potency compared to free DOX and DOX@MSNs. The enhanced MDR reversal effect was ascribed to the higher amount of cellular uptake of DOX@MSNs-TPGS in MCF-7/ADR cells than that of free DOX and DOX@MSNs, as a result of the inhibition of P-gp mediated drug efflux by TPGS. In vivo studies of NDDS in tumor-bearing mice showed that DOX@MSNs-TPGS displayed better efficacy against MDR tumors in mice and reached the tumor site more effectively than DOX and DOX@MSNs, with minimal toxicity. These results suggest DOX@MSNs-TPGS developed in this study have promising applications to overcome drug resistance in tumor treatments. PMID- 29519419 TI - Innovative material containing the natural product curcumin, with enhanced antimicrobial properties for active packaging. AB - Curcumin (Curc) reacts with zinc di-iodine (ZnI2) in 2:1molar ratio in the presence of an excess of a base triethylamine ((CH3CH2)3N) in methanol (CH3OH) solution towards the amorphous solid material of formula [ZnI2(Curc)2] (1). The complex was characterized by melting point (m.p.), Fourier Transform-Infra Red (FT-IR) and Nuclear Magnetic Resonance of hydrogen nucleus (1H NMR) spectroscopy. The formula of 1 was determined by X-ray fluorescence (XRF) analysis. The retention of the structure in solution was confirmed by 1H NMR spectroscopy. The antimicrobial activity of the complex has been studied against the bacteria Pseudomonas aeruginosa (PAO1). The Minimum Inhibitory Concentrations (MIC) of the compounds 1 and Curc against P. aeruginosa (PAO1) are: 71.3MUMU (75.3MUg/mL) for [ZnI2(Curc)2] and 339MUM (125MUg/mL) for Curc, respectively. Moreover, the antimicrobial activity of the new material which was diffused in polystyrene against biofilm formed by PAO1 was also calculated. PMID- 29519420 TI - Organic composite-mediated surface coating of human acellular bone matrix with strontium. AB - Acellular bone matrix (ACBM) provides an osteoconductive scaffold for bone repair, but its osteoinductivity is poor. Strontium (Sr) improves the osteoinductivity of bone implants. In this study, we developed an organic composite-mediated strontium coating strategy for ACBM scaffolds by using the ion chelating ability of carboxymethyl cellulose (CMC) and the surface adhesion ability of dopamine (DOPA). The organic coating composite, termed the CMC-DOPA-Sr composite, was synthesized under a mild condition, and its chemical structure and strontium ion chelating ability were then determined. After surface decoration, the physicochemical properties of the strontium-coated ACBM (ACBM-Sr) scaffolds were characterized, and their biocompatibility and osteoinductivity were determined in vitro and in vivo. The results showed that the CMC-DOPA-Sr composite facilitated strontium coating on the surface of ACBM scaffolds. The ACBM-Sr scaffolds possessed a sustained strontium ion release profile, exhibited good cytocompatibility, and enhanced the osteogenic differentiation of mesenchymal stem cells in vitro. Furthermore, the ACBM-Sr scaffolds showed good histocompatibility after subcutaneous implantation in nude mice. Taken together, this study provided a simple and mild strategy to realize strontium coating for ACBM scaffolds, which resulted in good biocompatibility and improved osteoinductivity. PMID- 29519421 TI - Fabrication, characterization and osteoblast responses of poly (octanediol citrate)/bioglass nanofiber composites. AB - In this study, a poly (octanediol citrate) (POC)/bioglass nanofiber composite was prepared by incorporating electrospun bioglass nanofiber (5, 10, and 15% w/w) into the POC matrix. The bioglass nanofiber interacted with POC via physical adsorption and carboxylate formation, and thus the addition of bioglass nanofiber increased the glass transition temperature, modulus and strength; however, decreased the elongation at break when the amount of bioglass nanofiber was up to 15% w/w. Compared to the pure POC elastomer, the POC/bioglass nanofiber composites exhibited accelerated stimulation to the mouse bone marrow mesenchymal stem cells (MSCs) on the cell growth and osteogenic differentiation. The level of alkaline phosphatase activity and cellular mineralization was higher for the POC/bioglass composites compared to the pure POC and increased with increasing amount of bioglass nanofiber within 14-day culture period. The gene expression of collagen type I and osteocalcin was also proportional to the bioglass nanofiber content of the composite. The results of this study showed that the composite of POC/bioglass nanofiber supported the osteogenic differentiation of MSCs and would be an excellent biomaterial candidate for applications in bone regeneration. PMID- 29519422 TI - Surface modification and characterization of GO/polymer thin coatings as excellent bio-active platforms for tissue regeneration. AB - Osteo-integration and tissue regeneration are vital for the longevity, durability, and unremitting functionality of medical implants/scaffolds implanted in vivo. It's essential for biomaterials used for in vivo implantation to induce the cellular secretion of growth factors, necessary for the desired tissue generation, since the administration of artificial growth factors, in vivo, is largely prohibited. Plasma functionalized (N2 and O2) and stabilized Graphene Oxide (GO) thin layers in a hybrid with amorphous carbon (aC) induced the expression of vascular endothelial growth factor (VEGF) and osteoprotegerin (OPG) growth factors in fibroblasts (hGF) and, more remarkably, in osteoblasts (hFOB) cells confirming the suitability for tissue regeneration and osteo-integration applications. We also observed a negative trend between hGF fibroblasts, but not hFOB osteoblasts, cellular viability and GO presence in the hybrid films that might indicate the phenomenon of oxidative stress. We traced that back to the presence of higher concentrations of carboxyl and the carbonyl groups on the surface of the GO rich coatings. The above described properties provided by GO coatings might be desirable for bio-selectivity applications and for the reduction of the undesired fibrosis process that is associated with medical implants in vivo environment. Moreover, novel plasma functionalized GO/polymer hybrid thin coating hybrid compositions are promising candidates for tissue engineering and bioengineering applications as excellent antimicrobial and anticancer platforms. PMID- 29519423 TI - Fabrication of micro/nanoporous collagen/dECM/silk-fibroin biocomposite scaffolds using a low temperature 3D printing process for bone tissue regeneration. AB - Biomaterials must be biocompatible, biodegradable, and mechanically stable to be used for tissue engineering applications. Among various biomaterials, a natural based biopolymer, collagen, has been widely applied in tissue engineering because of its outstanding biocompatibility. However, due to its low mechanical properties, collagen has been a challenge to build a desired/complex 3D porous structure with appropriate mechanical strength. To overcome this problem, in this study, we used a low temperature printing process to create a 3D porous scaffold consisting of collagen, decellularized extracellular matrix (dECM) to induce high cellular activities, and silk-fibroin (SF) to attain the proper mechanical strength. To show the feasibility of the scaffold, pre-osteoblast (MC3T3-E1) cells were grown on the fabricated scaffold. Various in vitro cellular activities (cell-viability, MTT assay, and osteogenic activity) for pure collagen, collagen/dECM, and collagen/SF/dECM scaffolds were compared. PMID- 29519424 TI - 3D-printed membrane for guided tissue regeneration. AB - Three-dimensional (3D) printing is currently being intensely studied for a diverse set of applications, including the development of bioengineered tissues, as well as the production of functional biomedical materials and devices for dental and orthopedic applications. The aim of this study was to develop and characterize a 3D-printed hybrid construct that can be potentially suitable for guided tissue regeneration (GTR). For this purpose, the rheology analyses have been performed on different bioinks and a specific solution comprising 8% gelatin, 2% elastin and 0.5% sodium hyaluronate has been selected as the most suitable composition for printing a structured membrane for GTR application. Each membrane is composed of 6 layers with strand angles from the first layer to the last layer of 45, 135, 0, 90, 0 and 90 degrees . Confirmed by 3D Laser Measuring imaging, the membrane has small pores on one side and large pores on the other to be able to accommodate different cells like osteoblasts, fibroblasts and keratinocytes on different sides. The ultimate cross-linked product is a 150MUm thick flexible and bendable membrane with easy surgical handling. Static and dynamic mechanical testing revealed static tensile modules of 1.95+/-0.55MPa and a dynamic tensile storage modulus of 314+/-50kPa. Through seeding the membranes with fibroblast and keratinocyte cells, the results of in vitro tests, including histological analysis, tissue viability examinations and DAPI staining, indicated that the membrane has desirable in vitro biocompatibility. The membrane has demonstrated the barrier function of a GTR membrane by thorough separation of the oral epithelial layer from the underlying tissues. In conclusion, we have characterized a biocompatible and bio-resorbable 3D-printed structured gelatin/elastin/sodium hyaluronate membrane with optimal biostability, mechanical strength and surgical handling characteristics in terms of suturability for potential application in GTR procedures. PMID- 29519425 TI - Strontium-modification of porous scaffolds from mineralized collagen for potential use in bone defect therapy. AB - The present study describes the development and characterization of strontium(II) modified biomimetic scaffolds based on mineralized collagen type I as potential biomaterial for the local treatment of defects in systemically impaired (e.g. osteoporotic) bone. In contrast to already described collagen/hydroxyapatite nanocomposites calcium was substituted with strontium to the extent of 25, 50, 75 and 100mol% by substituting the CaCl2-stock solution (0.1M) with SrCl2 (0.1M) during the scaffold synthesis. Simultaneous fibrillation and mineralization of collagen led to the formation of collagen-mineral nanocomposites with mineral phases shifting from nanocrystalline hydroxyapatite (Sr0) over poorly crystalline Sr-rich phases towards a mixed mineral phase (Sr100), consisting of an amorphous strontium phosphate (identified as Collin's salt, Sr6H3(PO4)5*2 H2O, CS) and highly crystalline strontium hydroxyapatite (Sr5(PO4)3OH, SrHA). The formed mineral phases were characterized by transmission electron microscopy (TEM) and RAMAN spectroscopy. All collagen/mineral nanocomposites with graded strontium content were processed to scaffolds exhibiting an interconnected porosity suitable for homogenous cell seeding in vitro. Strontium ions (Sr2+) were released in a sustained manner from the modified scaffolds, with a clear correlation between the released Sr2+ concentration and the degree of Sr substitution. The accumulated specific Sr2+ release over the course of 28days reached 141.2MUg (~27MUgmg-1) from Sr50 and 266.1MUg (~35MUgmg-1) from Sr100, respectively. Under cell culture conditions this led to maximum Sr2+ concentrations of 0.41mM (Sr50) and 0.73mM (Sr100) measured on day 1, which declined to 0.08mM and 0.16mM, respectively, at day 28. Since Sr2+ concentrations in this range are known to have an osteo-anabolic effect, these scaffolds are promising biomaterials for the clinical treatment of defects in systemically impaired bone. PMID- 29519426 TI - Biocompatible and mechanically robust nanocomposite hydrogels for potential applications in tissue engineering. AB - The synergistic contributions of nanofillers and polymer matrix induce remarkable properties in nanocomposite hydrogels. Present article reports the facile synthesis of biocompatible nanocomposite hydrogels using microporous multi wall carbon nanotubes (MWCNTs) dispersed chitosan (CH)-Acrylonitrile (AN), N,N' methylenebisacrylamide (MBAAm) and linseed polyol through solution blending method. Polyol and N,N'-methylenebisacrylamide (MBAAm) was used as the crosslinking agent. The structural characterization and formation of highly crosslinked network with dendrimer morphology was confirmed by FT-IR and scanning electron microscope (SEM) analysis. In addition, transmission electron microscope (TEM) was employed to visualize the size and proper dispersion of MWCNT in the polymer matrices. The strong mechanical strength exhibited by these hydrogel films was confirmed by the tensile strength analysis. The dispersion of the conductive nanofillers, like MWCNTs has significantly enhanced the strength, which revealed unique characteristics of these hydrogel films. The high swelling capacity and sustained expansion of hydrogel films were confirmed in the buffer solutions of pH4 and 7.4. The biodegradability of these films was estimated by hydrolytic and soil burial tests. The biocompatibility test was conducted on Human Embryonic Kidney (HEK-293) cell line, which confirmed the non-toxic and biocompatible nature of these films. Incorporation of carbon nanotubes (MWCNTs) in the polymer matrix enhanced the film forming properties, high modulus and tensile strength, swelling ability, biodegradable and biocompatibility. These properties can be finely tuned through the variation of MWCNT concentrations, as a result these nanostructure hydrogel films have potential scope for their diverse applications in the field of tissue engineering. PMID- 29519427 TI - Star-shaped polyester-based elastomers as an implantable delivery system for insulin: Development, pharmacokinetics, pharmacodynamics, and biocompatibility. AB - Elastomers are largely developed for biomedical applications; however, little is reported on them although they are an effective and controllable delivery system for proteins. In the present study, we investigated the pharmacokinetics, biosecurity, and hypoglycemic effect of an insulin-loaded elastomer formulation in diabetic rats. Cylindrical insulin-loaded elastomers were fabricated using a UV cross-linking process based on methyl-acrylic-star-poly(epsilon-caprolactone co-D,L-lactide) cyclic ester and methyl-bi-acrylic-poly(epsilon-caprolactone-b polyethylene glycol-b-epsilon-caprolactone) (CLPEGCLMA). The encapsulated insulin was well protected during the formulation. An in vitro pharmacokinetic study revealed that the rate of insulin release from the elastomers was affected by the hydrophilicity/hydrophobicity of the system and controlled by the CLPEGCLMA (hydrophilic prepolymer) composition. It was observed that insulin release followed the Higuchi model. In addition, the more hydrophilic elastomers showed higher degradation rates in vivo. Furthermore, in the pharmacodynamic study, all the elastomers, except those that contained star-poly(epsilon-caprolactone-co-D,L lactide) (number-average molecular weight, Mn), polyethylene glycol (PEG) (kMn), epsilon-caprolactone/PEG (mol/mol), and CLPEGCLMA (weight, %) at a ratio of 3432:10:20:30, respectively, decreased blood glucose concentration and maintained it at a stable level. It was observed that the hypoglycemic effect of the drug loaded elastomers was directly proportional to the rate of in vitro insulin release; however, emaciation was not observed. Moreover, elastomers play a positive role in biosecurity. Therefore, the elastomers might be effective carriers for the delivery of peptide drugs in the form of implants. PMID- 29519428 TI - Photocatalytic degradation of organic contaminants by g-C3N4/EPDM nanocomposite film: Viable, efficient and facile recoverable. AB - The original metal free graphitic carbon nitride/ethylene propylene diene monomer nanocomposite film (g-C3N4/EPDM NCF) was fabricated by facile solution cast method. g-C3N4/EPDM NCF with diameter (50mm) and thickness (4mm) was investigated towards the photocatalytic degradation of methylene blue (MB) and methyl orange (MO) dye solution under visible light irradiation. The as synthesized g-C3N4/EPDM NCF was exhibited high crystalline nature with the crystalline size of 21.53nm, the smooth surface nature and the particle size was observed from the TEM analysis is 20nm. Furthermore, the influence of operational parameters was carried out which demonstrated that 100mg photocatalyst and 25MUM of dye concentration were obtained as an optimized condition for the best photocatalytic degradation results. As a result of scavenger experiment, it was concluded that the hydroxyl radical (OH) was actively involved in the photocatalytic degradation. The g-C3N4/EPDM NCF were recoverable from the photocatalytic reaction system and the present find findings may open up a new platform for the simple handpicked photocatalyst. PMID- 29519429 TI - Biomineralized poly (l-lactic-co-glycolic acid)-tussah silk fibroin nanofiber fabric with hierarchical architecture as a scaffold for bone tissue engineering. AB - In bone tissue engineering, the fabrication of a scaffold with a hierarchical architecture, excellent mechanical properties, and good biocompatibility remains a challenge. Here, a solution of polylactic acid (PLA) and Tussah silk fibroin (TSF) was electrospun into nanofiber yarns and woven into multilayer fabrics. Then, composite scaffolds were obtained by mineralization in simulated body fluid (SBF) using the multilayer fabrics as a template. The structure and related properties of the composite scaffolds were characterized using different techniques. PLA/TSF (mass ratio, 9:1) nanofiber yarns with uniform diameters of 72+/-9MUm were obtained by conjugated electrospinning; the presence of 10wt% TSF accelerated the nucleation and growth of hydroxyapatite on the surface of the composite scaffolds in SBF. Furthermore, the compressive mechanical properties of the PLA/TSF multilayer nanofiber fabrics were improved after mineralization; the compressive modulus and stress of the mineralized composite scaffolds were 32.8 and 3.0 times higher than that of the composite scaffolds without mineralization, respectively. Interestingly, these values were higher than those of scaffolds containing random nanofibers. Biological assay results showed that the mineralization and multilayer fabric structure of the composite nanofiber scaffolds significantly increased cell adhesion and proliferation and enhanced the mesenchymal stem cell differentiation toward osteoblasts. Our results indicated that the mineralized nanofiber scaffolds with multilayer fabrics possessed excellent cytocompatibility and good osteogenic activity, making them versatile biocompatible scaffolds for bone tissue engineering. PMID- 29519430 TI - Gold-capped silicon for ultrasensitive SERS-biosensing: Towards human biofluids analysis. AB - Surface-enhanced Raman spectroscopy (SERS) has been widely used in a variety of biomedical, analytical, forensic and environmental investigations due to its chemical specificity, label-free nature combined with high sensitivity. Here, we report a simple method for the fabrication of reproducible and reliable, well defined, stable SERS substrates with uniform and giant Raman enhancement suitable for routine trace chemical analysis and detection of biological compounds in complex biological fluids. We prepared porous silicone (PS) surface by a galvanostatic anodic etch of crystalline silicon wafers. The electrochemical process generates a specific layer of PS: the thickness and porosity of a given layer is controlled by the current density, the duration of the etch cycle, and the composition of the etchant solution. These substrates presented high sensitivity to p-mercaptobenzoic acid (p-MBA) at a low concentration of 10-6M and the enhancement factor of over 108 was achieved. Such high enhancement is attributed to semiconducting silicon-induced and stabilized hot spots. The uniform distribution of SERS-active 'hot-spots' on the Au/Si surface results in high reproducibility towards detecting p-MBA at 40 different, randomly selected positions on a single substrate (RSD=6.7%) and on twenty different SERS substrates prepared under identical conditions (RSD=8%). Designed substrates allow the ultrahigh sensitive and specific detection of human such biofluids as blood, urine and cerebrospinal fluid (CSF) in a reliable, label-free, and reproducible manner. The SERS spectra of these fluids are rich in patient specific information and can be useful in many analytical and biomedical applications. We have shown that our developed SERS substrates allow the nanomolar detection of neopterin (bacterial infections' marker) in cerebrospinal fluid samples. In order to test the performance of our SERS method in term of low detection limit (LOD), the calibration curve i.e. plot of SERS intensity of the marker band at 695cm-1 versus the concentration of neopterin in CSF was constructed and used to calculate the neopterin concentration in clinical samples. The level of neopterin was significantly higher in CSF samples infected by Neisseria meningitidis, (54nmol/L), compared to normal (control) group, (4.3nmol/L). The high sensitivity, selectivity and stability of obtained SERS active substrates combined with simple, low-cost, and easy method of producing offer a promising tool for SERS-based analysis in clinical trials. PMID- 29519431 TI - Thermo-sensitively and magnetically ordered mesoporous carbon nanospheres for targeted controlled drug release and hyperthermia application. AB - A multifunctional nanoplatform based on thermo-sensitively and magnetically ordered mesoporous carbon nanospheres (TMOMCNs) is developed for effective targeted controlled release of doxorubicin hydrochloride (DOX) and hyperthermia in this work. The morphology, specific surface area, porosity, thermo-stability, thermo-sensitivity, as well as magnetism properties of TMOMCNs were verified by high resolution transmission electron microscopy, field emission scanning electron microscopy, thermo-gravimetric analysis, X-ray diffraction, Brunauer Emmeltt-Teller surface area analysis, dynamic light scattering and vibrating sample magnetometry measurement. The results indicate that TMOMCNs have an average diameter of ~146nm with a lower critical solution temperature at around 39.5 degrees C. They are superparamagnetic with a magnetization of 10.15emu/g at 20kOe. They generate heat when inductive magnetic field is applied to them and have a normalized specific absorption rate of 30.23W/g at 230kHz and 290Oe, showing good potential for hyperthermia. The DOX loading and release results illustrate that the loading capacity is 135.10mg/g and release performance could be regulated by changing pH and temperature. The good targeting, DOX loading and release and hyperthermia properties of TMOMCNs offer new probabilities for high effectiveness and low toxicity of cancer chemotherapy. PMID- 29519432 TI - 3D-micro-patterned fibrous dosage forms for immediate drug release. AB - At present, the most prevalent pharmaceutical dosage forms, the orally-delivered immediate-release tablets and capsules, are porous, granular solids. They disintegrate into their constituent particulates upon ingestion to release drug rapidly. The design, development, and manufacture of such granular solids, however, is inefficient due to difficulties associated with the unpredictable inter-particle interactions. Therefore, to achieve more predictable dosage form properties and processing, we have recently introduced melt-processed polymeric cellular dosage forms. The cellular forms disintegrated and released drug rapidly if the cells were predominantly interconnected. Preparation of interconnected cells, however, relies on the coalescence of gas bubbles in the melt, which is unpredictable. In the present work, therefore, new melt-processed fibrous dosage forms with contiguous void space are presented. The dosage forms are prepared by melt extrusion of the drug-excipient mixture followed by patterning the fibrous extrudate on a moving surface. It is demonstrated that the resulting fibrous structures are fully predictable by the extruder nozzle diameter and the motion of the surface. Furthermore, drug release experiments show that the disintegration time of the fibrous forms prepared in this work is of the order of that of the corresponding single fibers. The thin fibers of polyethylene glycol (excipient) and acetaminophen (drug) in turn disintegrate in a time proportional to the fiber radius and well within immediate-release specification. Finally, models of dosage form disintegration and drug release by single fibers and fibrous dosage forms are developed. It is found that drug release from fibrous forms is predictable by the physico-chemical properties of the excipient and such microstructural parameters as the fiber radius, the inter-fiber spacing, and the volume fraction of water-soluble excipient in the fibers. PMID- 29519433 TI - Tuning the structural and mechanical properties in ZrO2-SiO2 binary system through Y3+ inclusions. AB - The present investigation explores the influence of yttrium (Y3+) inclusions in ZrO2-SiO2 binary system (YSZ) on its structural and mechanical features. The powders were synthesized through sol-gel technique and an exclusive characterization were undertaken to investigate the structural and mechanical features influenced by Y3+ additions. Characterization techniques affirmed the crucial role of Y3+ on the resultant structural and thermal stability of the YZS system. Instrumented indentation inferred the enhanced mechanical properties demonstrated by YZS system in comparison with pure ZrO2-SiO2 binary system (ZS). PMID- 29519434 TI - 3D-printed biphasic calcium phosphate scaffolds coated with an oxygen generating system for enhancing engineered tissue survival. AB - Tissue engineering scaffolds with oxygen generating elements have shown to be able to increase the level of oxygen and cell survivability in specific conditions. In this study, biphasic calcium phosphate (BCP) scaffolds with the composition of 60% hydroxyapatite (HA) and 40% beta-tricalcium phosphate (beta TCP), which have shown a great potential for bone tissue engineering applications, were fabricated by a direct-write assembly (robocasting) technique. Then, the three-dimensional (3D)-printed scaffolds were coated with different ratios of an oxygen releasing agent, calcium peroxide (CPO), which encapsulated within a polycaprolactone (PCL) matrix through dip-coating, and used for in situ production of oxygen in the implanted sites. The structure, composition and morphology of the prepared scaffolds were characterized by different techniques. The oxygen release kinetics and biological investigations of the scaffolds were also studied in vitro. The results showed that oxygen release behaviour was sustained and dependant on the concentration of CPO encapsulated in the PCL coating matrix. It was also demonstrated that the coated scaffolds, having 3% CPO in the coating system, could provide a great potential for promoting bone ingrowth with improving osteoblast cells viability and proliferation under hypoxic conditions. The findings indicated that the prepared scaffolds could play a significant role in engineering of large bone tissue implants with limitations in oxygen diffusion. PMID- 29519435 TI - Development and mechanical characterisation of self-compressed collagen gels. AB - Collagen gels are considered a promising biomaterial for the manufacturing of tissue engineering scaffolds, however, their mechanical properties often need to be improved to enable them to provide enough mechanical support during the course of tissue regeneration process. In this paper, we present a simple self compression technique for the improvement of the mechanical properties of collagen gels, identified by the fitting of bespoke biphasic finite element models. Radially-confined highly hydrated gels were allowed to self-compress for 18h, expelling fluid, and which were subsequently subjected to unconfined ramp hold compression. Gels, initially of 0.2%, 0.3% and 0.4% (w/v) collagen and 13mm thickness, transformed to 2.9+/-0.2%, 3.2+/-0.3% and 3.6+/-0.1% (w/w) collagen and 0.45+/-0.06mm, 0.69+/-0.04mm and 0.99+/-0.07mm thickness. Young's moduli of the compressed gels did not increase with increasing collagen fibril density, whilst zero-strain hydraulic permeability significantly decreased from 51 to 21mm4/Ns. The work demonstrates that biphasic theory, applied to unconfined compression, is a highly appropriate paradigm to mechanically characterise concentrated collagen gels and that confined compression of highly hydrated gels should be further investigated to enhance gel mechanical performance. PMID- 29519436 TI - Free standing PEDOT films prepared by vapour phase polymerisation as electrically tuneable barriers to drug permeability. AB - We report the fabrication of PEDOT films using vapour phase polymerisation with Fe(III)tosylate as the oxidant and to provide the doping ion. Multiple polymerisation steps resulted in the formation of free-standing PEDOT films. The PEDOT films were highly conductive, a single layer was 1840+/-50S/cm with a small decrease in conductivity for the five layered films to 1550+/-60S/cm. The five layered films were flexible and freestanding in air with a thickness of 1.66+/ 0.06MUm. The ability of the freestanding PEDOT films to act as electrically tuneable rate controlling membranes was determined for nicotine (MW 162.2Da), dexamethasone phosphate (MW 516.4Da) and bovine lactoferrin (MW 80kDa), using a customised Franz cell. The membranes were highly permeable to nicotine and dexamethasone phosphate, however, the large lactoferrin molecules could not diffuse through the PEDOT membranes. The permeability of dexamethasone phosphate could be controlled electrically with an increase in flux observed when the membranes were maintained in the oxidised state compared to the reduce state. This is the first report where free standing PEDOT films were prepared by vapour phase polymerisation; these films were capable of electrically modifiable permeation of small drug molecules. The free standing and highly conductive PEDOT membranes are exciting materials to explore for molecular separation and drug delivery applications. PMID- 29519437 TI - Delivery of anticancer drug using pH-sensitive micelles from triblock copolymer MPEG-b-PBAE-b-PLA. AB - To improve the drug release rate in well-controlled manner, a new pH-sensitive triblock amphiphilic copolymer methyl poly(ethylene glycol) ether-b-poly(beta amino esters)-b-poly lactic acid (MPEG-b-PBAE-b-PLA) and its self-assembled micelles were developed for anticancer drug delivery. The average molecular weight and molecular structure of MPEG-b-PBAE-b-PLA were confirmed by gel permeation chromatography (GPC) and 1H NMR. The formation of self-assembled micelles, the microstructures at different pH values, and the distribution of doxorubicin (DOX) were investigated by dissipative particle dynamics (DPD) simulation combined with experimental techniques. The copolymers formed stable core-shell-type micelles in water. The critical micelle concentration (CMC) values, particle sizes and zeta potentials of the blank micelles increased along with globule-extended conformational transitions when the pH values decreased from 7.4 to 5.0, due to the protonation of amine groups of PBAE. Obvious increases in the particle sizes and the drug loading content of micelles were observed with increasing DOX. The in vitro release behavior of DOX from the micelles was pH-dependent. The DOX release rate was improved obviously as pH decreased from pH7.4 to pH5.0, with over 96% of DOX was released within 48h. The drug release mechanism under different conditions was also analyzed using theoretical formulas. All the results suggest that the pH-sensitive MPEG-b-PBAE-b PLA micelles might be a prospective candidate as anticancer drug delivery carrier with well-controlled release behavior. PMID- 29519438 TI - Degradation mechanism of magnesium alloy stent under simulated human micro-stress environment. AB - In this study, a vascular stent made of WE43 magnesium alloy was used as a research object and placed in a special physical simulation device constructed independently. This device provided a platform for the study of the degradation of the stent in a dynamic environment. The simulated body fluid of Hank's buffered salt solution flowing inside it would not only make the stent corroded but also apply cyclic shear stress to it, which get closer to the micro-stress environment in human blood vessels. In addition, by means of computer numerical simulation software, ANSYS Fluent 15.0, the fluid-structure interaction (FSI) model was established to simulate the wall shear stress (WSS) exerted by the flowing blood on stent in the blood vessel. Combined with the results of numerical simulation and physical simulation experiments, the degradation mechanism of magnesium alloy sent in an environment similar to the human blood vessels was studied. PMID- 29519439 TI - Collagen I derived recombinant protein microspheres as novel delivery vehicles for bone morphogenetic protein-2. AB - Bone morphogenetic protein-2 (BMP-2) is a powerful osteoinductive protein; however, there is a need for the development of a safe and efficient BMP-2 release system for bone regeneration therapies. Recombinant extracellular matrix proteins are promising next generation biomaterials since the proteins are well defined, reproducible and can be tailored for specific applications. In this study, we have developed a novel and versatile BMP-2 delivery system using microspheres from a recombinant protein based on human collagen I (RCP). In general, a two-phase release pattern was observed while the majority of BMP-2 was retained in the microspheres for at least two weeks. Among different parameters studied, the crosslinking and the size of the RCP microspheres changed the in vitro BMP-2 release kinetics significantly. Increasing the chemical crosslinking (hexamethylene diisocyanide) degree decreased the amount of initial burst release (24h) from 23% to 17%. Crosslinking by dehydrothermal treatment further decreased the burst release to 11%. Interestingly, the 50 and 72MUm-sized spheres showed a significant decrease in the burst release compared to 207-MUm sized spheres. Very importantly, using a reporter cell line, the released BMP-2 was shown to be bioactive. SPR data showed that N-terminal sequence of BMP-2 was important for the binding and retention of BMP-2 and suggested the presence of a specific binding epitope on RCP (KD: 1.2nM). This study demonstrated that the presented RCP microspheres are promising versatile BMP-2 delivery vehicles. PMID- 29519440 TI - Extended release of proteins following encapsulation in hydroxyapatite/chitosan composite scaffolds for bone tissue engineering applications. PMID- 29519441 TI - Biodegradable and electroconductive poly(3,4 ethylenedioxythiophene)/carboxymethyl chitosan hydrogels for neural tissue engineering. AB - Electroconductive hydrogels with excellent electromechanical properties have become crucial for biomedical applications. In this study, we developed a conductive composite hydrogel via in-situ chemical polymerization based on carboxymethyl chitosan (CMCS), as a biodegradable base macromolecular network, and poly(3,4-ethylenedioxythiophene) (PEDOT), as a conductive polymer layer. The physicochemical and electrochemical properties of conductive hydrogels (PEDOT/CMCS) with different contents of PEDOT polymer were analyzed. Cell viability and proliferation of neuron-like rat phaeochromocytoma (PC12) cells on these three-dimensional conductive hydrogels were evaluated in vitro. As results, the prepared semi-interpenetrating network hydrogels were shown to consist of up to 1825+/-135wt% of water with a compressive modulus of 9.59+/-0.49kPa, a porosity of 93.95+/-1.03% and an electrical conductivity of (4.68+/-0.28)*10 3S.cm-1. Cell experiments confirmed that PEDOT/CMCS hydrogels not only had no cytotoxicity, but also supported cell adhesion, viability and proliferation. These results demonstrated that the incorporation of conductive PEDOT component into CMCS hydrogels endowed the hydrogels with enhanced mechanical strength, conductivity and kept the biocompatibility. Thus, the attractive performances of these composite hydrogels would make them suitable for further neural tissue engineering application, such as nerve regeneration scaffold materials. PMID- 29519442 TI - Three-dimensional printing of shape memory hydrogels with internal structure for drug delivery. AB - Hydrogels with shape memory behavior and internal structure have wide applications in fields ranging from tissue engineering and medical instruments to drug delivery; however, creating the hydrogels has proven to be extremely challenging. This study presents a three-dimensional (3D) printing technology to fabricate the shape memory hydrogels with internal structure (SMHs) by combining sodium alginate (alginate) and pluronic F127 diacrylate macromer (F127DA). SMHs were constituted by a dual network structure. One is a stable network which is formed by F127DA photo-crosslinking; the other one is a reversible network which is formed by Ca2+ cross-linked alginate. SMHs recovery ratio was 98.15% in 10min after Ca2+ was removed in the Na2CO3 solution, and the elastic modulus remains essentially stable after the shape memory cycle. It showed that the drug releasing rate is more rapid compared with traditional drug-loaded hydrogels in in vitro experiments. The viability of 3T3 fibroblasts remained intact which revealed its excellent biocompatibility. Therefore, SMHs have a huge prospect for application in drug carriers and tissue engineering scaffold. PMID- 29519443 TI - Photo-responsive membrane surface: Switching from bactericidal to bacteria resistant property. AB - In this paper, a photo-responsive bactericidal and bacteria-resistant membrane was successfully prepared via the integration of atom transfer radical polymerization (ATRP) and click chemistry. Azide-functionalized polycationic poly (N, N-dimethyl-N-(2-(methacryloyloxy)ethyl)-N-((2-nitrobenzyl)oxy)-2 oxoethanaminium bromide) (PDMAEMA-NBE) was synthesized by ATRP. Then, the PDMAEMA NBE was clicked on alkynyl-functionalized polyethersulfone (PES) membrane surface, and proved by X-ray photoelectron spectrometer (XPS). Upon UV irradiation, the polycationic surface would switch to polyzwitterionic one. Before and after the irradiation, the zeta potentials of the surface altered from +14.7 to -3.8mV, and the water contact angle decreased from 64.0 degrees to 52.7 degrees . The polycationic surface exhibited excellent bactericidal property and the dead bacteria could detach from the polyzwitterionic surface induced by the subsequent UV irradiation. It demonstrated that the designing of photo-responsive membrane surface could be a new strategy for antibacterial adhesion. PMID- 29519444 TI - Bottom-up preparation of nitrogen doped carbon quantum dots with green emission under microwave-assisted hydrothermal treatment and their biological imaging. AB - Carbon quantum dots (CDs) have standout as one of the most important carbon nanomaterials owing to their small size, optical properties, biocompatibility and low toxicity. These CDs have been extensively explored for various applications especially in the biomedical fields. Although great efforts have been devoted to the fabrication of CDs through both top-down and bottom-up methods, most of these CDs exhibited blue emission under UV light irradiation. In this work, we reported a novel, green, economic approach for preparation of nitrogen doped CDs by directly microwave-assisted heating small organic molecules at 120 degrees C for 5min using Glu and amino group of MPD as the precursors and ethylene glycol as solvent. Thus prepared CDs emit green fluorescence when they were irradiated under 365nm UV light. Compared with other synthetic methods, this microwave assisted heating method does not require strict reaction conditions and is easy for operation. The CDs display unique luminescence properties, high water dispersibility and good biocompatibility. These remarkable features make CDs great potential for various biomedical applications. Taken together, a microwave assisted heating method has been developed for bottom-up preparation of green emission CDs in a rather mild route. Owing to the facile experimental procedure and outstanding features of CDs, this work will open up a new avenue for fabrication and biomedical applications of CDs. PMID- 29519446 TI - Peptide modified nanofibrous scaffold promotes human mesenchymal stem cell proliferation and long-term passaging. AB - Long-term culture, passage and proliferation of human mesenchymal stem cells (hMSCs) cause loss of their stemness properties including self-renewal and multipotency. By optimizing the MSCs environment in vitro, maintaining the stemness state and better controlling the cell fate might be possible. We have recently reported the significant effects of bioactive Tat protein-derived peptide named R-peptide on hMSC adhesion, morphology and proliferation, which has demonstrated R-peptide enhanced MSC early adhesion and proliferation in comparison to other bioactive molecules including RGD peptide, fibronectin and collagen. In this study, R-peptide was used to evaluate stemness properties of MSCs after long-term passaging. R-peptide conjugated poly caprolactone (PCL) nanofibrous scaffold and unmodified nanofibrous scaffold were used to study the impact of R-peptide modified PCL nanofibers and PCL nanofibers on cell behavior. The results showed early formation of focal adhesion (FA) complex on R-peptide modified scaffolds at 30min after cell seeding. The rate of cell proliferation was significantly increased due to presence of R-peptide, and the MSCs marker analyses using flow cytometry and immunocytochemistry staining proved the ability of R-peptide to maintain mesenchymal stem cell properties (high proliferation, expression of multipotent markers and differentiation capacity) even after long term passage culturing. Accordingly, our (The) results concluded that bioactive R peptide in combination with nanofibrous scaffold can mimic the native ECM comprising micro/nano architecture and biochemical molecules in a best way. The designed scaffold can link extracellular matrix (ECM) to nucleus via formation of FA and organization of cytoskeleton, causing fast and strong attachment of MSCs and allowing integrin-mediated signaling to start. PMID- 29519445 TI - Novel high-strength, low-alloys Zn-Mg (<0.1wt% Mg) and their arterial biodegradation. AB - It is still an open challenge to find a biodegradable metallic material exhibiting sufficient mechanical properties and degradation behavior to serve as an arterial stent. In this study, Zn-Mg alloys of 0.002 (Zn-002Mg), 0.005 (Zn 005Mg) and 0.08wt% Mg (Zn-08Mg) content were cast, extruded and drawn to 0.25mm diameter, and evaluated as potential biodegradable stent materials. Structural analysis confirmed formation of Mg2Zn11 intermetallic in all three alloys with the average grain size decreasing with increasing Mg content. Tensile testing, fractography analysis and micro hardness measurements showed the best integration of strength, ductility and hardness for the Zn-08Mg alloy. Yield strength, tensile strength, and elongation to failure values of >200-300MPa, >300-400MPa, and >30% respectively, were recorded for Zn-08Mg. This metal appears to be the first formulated biodegradable material that satisfies benchmark values desirable for endovascular stenting. Unfortunately, the alloy reveals signs of age hardening and strain rate sensitivity, which need to be addressed before using this metal for stenting. The explants of Zn-08Mg alloy residing in the abdominal aorta of adult male Sprague-Dawley rats for 1.5, 3, 4.5, 6 and 11months demonstrated similar, yet slightly elevated inflammation and neointimal activation for the alloy relative to what was recently reported for pure zinc. PMID- 29519447 TI - Therapeutic and technological potential of 7-chloro-4-phenylselanyl quinoline for the treatment of atopic dermatitis-like skin lesions in mice. AB - This study investigated the main effects of the oral treatment with 7-chloro-4 phenylselanyl quinoline (4-PSQ) on symptoms, inflammatory and oxidative parameters in an atopic dermatitis (AD) model in BALB/c mice. In addition, the possibility of antioxidant property of 4-PSQ improves the potential of a biofilm (based on chitosan/poly(vinyl alcohol) (PVA)/ bovine bone powder (BBP)) for the treatment of AD-like skin lesions was evaluated. 2,4-Dinitrochlorobenzene (DNCB) was applied to the dorsal skin on days 1-3 for sensitization. Mice were challenged with DNCB on the ear (on days 14-29) and dorsal skin (on days 14, 17, 20, 23, 26, and 29) and treated with 4-PSQ, dexamethasone, biofilm (biofilm sample without 4-PSQ) or 4-PSQ-loaded biofilms. On the day 30, skin severity scores and scratching behavior were determined. After that, animals were sacrificed, and ears and dorsal skin were removed for determination of inflammatory and oxidative parameters. DNCB induced the skin lesions, scratching behavior and ear swelling, increased myeloperoxidase (MPO) activity (ear and back) and reactive species (RS) levels (back). 4-PSQ, 4-PSQ-loaded biofilms and biofilm treatments ameliorated skin severity scores, scratching behavior and inflammatory response induced by DNCB. 4-PSQ and 4-PSQ-loaded biofilm treatments partially protected against the increase in the RS levels induced by DNCB. Our results revealed that the incorporation of 4-PSQ improved the therapeutic effect of the biofilm. The efficacy of 4-PSQ in treating AD-like lesions was similar or better than dexamethasone. In summary, 4-PSQ has a potential therapeutic advantage in the treatment and management of AD. PMID- 29519449 TI - Retraction notice. PMID- 29519448 TI - Influences of ionic liquid and temperature on the tailorable surface morphology of F-apatite nanocomposites for enhancing biological abilities for orthopedic implantation. AB - This report has approached for the green synthesis of morphological controlled novel metal-doped fluorinated apatite/polymeric nanocomposites. The synthesized nanocomposites have investigated for hard tissue engineering and bone substitute applications. The selected fluoro ionic liquid explored the dual performances as fluorine precursor and as a soft template for the morphological development of apatite nanocomposite synthesis. The structural and surface studies (XRD, FTIR, FE-SEM, EDS, AFM, HR-TEM & SAED) confirmed the crystalline and morphological changes of synthesized fluorohydroxyapatite nanostructures at two different reaction temperatures. The fluorinated apatite nanocomposites doped with silver for metal-doped composites, which have effective antibacterial efficacy and favorable biocompatibility. The silver-doped nanocomposites showed excellent antibacterial ability against Staphylococcus aureus and Escherichia coli bacterial pathogens with the uniform release of silver and fluorine ions. These antibacterial performances have systematically tested by the quantitative and qualitative methods. The rod-like fluorinated apatite nanocrystals promote cell adhesion and viability of human osteosarcoma (MG-63) cell lines and these studies compared with the sheet-like apatite nanocomposites. This type of biomedical apatite materials may be a promising material for orthopedic implant and regeneration applications. PMID- 29519450 TI - Inflammatory health effects of indoor and outdoor particulate matter. AB - Inflammation is a common and essential event in the pathogenesis of diverse diseases. Decades of research has converged on an understanding that all combustion-derived particulate matter (PM) is inflammatory to some extent in the lungs and also systemically, substantially explaining a significant portion of the massive cardiopulmonary disease burden associated with these exposures. In general, this means that efforts to do the following can all be beneficial: reduce particulates at the source, decrease the inflammatory potential of PM output, and, where PM inhalation is unavoidable, administer anti-inflammatory treatment. A range of research, including basic illumination of inflammatory pathways, assessment of disease burden in large cohorts, tailored treatment trials, and epidemiologic, animal, and in vitro studies, is highlighted in this review. However, meaningful translation of this research to decrease the burden of disease and deliver a clear and cohesive message to guide daily clinical practice remains rudimentary. Ongoing efforts to better understand substantial differences in the concentration and type of PM to which the global community is exposed and then distill how that influences inflammation promises to have real world benefit. This review addresses this complex topic in 3 sections, including ambient PM (typically associated with ground-level transportation), wildfire induced PM, and PM from indoor biomass burning. Recognizing the overlap between these domains, we also describe differences and suggest future directions to better inform clinical practice and public health. PMID- 29519451 TI - External exposome and allergic respiratory and skin diseases. AB - Allergies are complex diseases that result from interactions between multiple genetic and environmental factors. However, the increase in allergies observed in the past decades is explained exclusively by environmental changes occurring in the same period. Presently, the exposome, the totality of specific and nonspecific external environmental exposures (external exposome) to which a subject is exposed from preconception onward and their consequences at the organ and cell levels (internal exposome), is being considered to explain the inception, development, and exacerbations of allergic diseases. Among the best studied environmental factors of the specific external exposome, indoor and outdoor aeroallergens and air pollutants play a key role in the etiopathogenesis of the inflammatory response to allergens and in clinical manifestations of allergic disease. Climate change, urbanization, and loss of biodiversity affect sources, emissions, and concentrations of main aeroallergens and air pollutants and are among the most critical challenges facing the health and quality of life of the still increasing number of allergic patients today and in the coming decades. Thunderstorm-related asthma is a dramatic example of the effects of combined environmental factors and an in vivo model for understanding the mechanisms at work in respiratory allergy. Environment- or lifestyle-driven aberrancies in the gut and skin microbiome composition represent key mediators of allergic diseases. A better knowledge of the effect of the external exposome on allergy development is crucial for urging patients, health professionals, and policymakers to take actions to mitigate the effect of environmental changes and to adapt to them. PMID- 29519453 TI - Behavioral sensitization induced by dorsal periaqueductal gray electrical stimulation is counteracted by NK1 receptor antagonism in the ventral hippocampus and central nucleus of the amygdala. AB - A single threatening experience may change the behavior of an animal in a long lasting way and elicit generalized behavioral responses to a novel threatening situation that is unrelated to the original aversive experience. Electrical stimulation (ES) of the dorsal periaqueductal gray (dPAG) produces a range of defensive reactions, characterized by freezing, escape, and post-stimulation freezing (PSF). The latter reflects the processing of ascending aversive information to prosencephalic structures, including the central nucleus of the amygdala (CeA), which allows the animal to evaluate the consequences of the aversive situation. This process is modulated by substance P (SP) and its preferred receptor, neurokinin 1 (NK1). The ventral hippocampus (VH) has been associated with the processing of aversive information and expression of emotional reactions with negative valence, but the participation of the VH in the expression of these defensive responses has not been investigated. The VH is rich in NK1 receptor expression and has a high density of SP-containing fibers. The present study examined the role of NK1 receptors in the VH in the expression of defensive responses and behavioral sensitization that were induced by dPAG-ES. Rats were implanted with an electrode in the dPAG for ES, and a cannula was implanted in the VH or CeA for injections of vehicle (phosphate-buffered saline) or the NK1 receptor antagonist spantide (100 pmol/0.2 MUL. Spantide reduced the duration of PSF that was evoked by dPAG-ES, without changing the aversive freezing or escape thresholds. One and 7 days later, exploratory behavior was evaluated in independent groups of rats in the elevated plus maze (EPM). dPAG-ES in rats that received vehicle caused higher aversion to the open arms of the EPM compared with rats that did not receive dPAG stimulation at both time intervals. Injections of spantide in the VH or CeA prevented the proaversive effects of dPAG ES in the EPM only 1 day later. These findings suggest that NK1 receptors are activated in both the VH and CeA during the processing of aversive information that derives from dPAG-ES. As previously shown for the CeA, SP/NK1 receptors in the VH are recruited during PSF that is evoked by dPAG-ES, suggesting that a 24-h time window is susceptible to interventions with NK1 antagonists that block the passage of aversive information from the dPAG to higher brain areas. PMID- 29519454 TI - The parietal cortex and pain perception: a body protection system. AB - Pain is a very relevant function for our survival and its alteration leads to important consequences for people's lives. In the last decades, researchers have started to investigate pain from a neurocognitive and neuropsychologic perspective, showing some important similarities and differences with other cognitive and perceptual functions. The complexity of pain perception, due to its multicomponential nature, has led to the need to interpret pain within a multisensory frame of reference. That is, this function and its neural foundation cannot be fully understood without taking into consideration the processing of other information that is concurrently presented together with noxious stimuli. The extant research in this field has shown that the parietal cortex plays a major role in pain perception, due to its involvement in the integration of information coming from different sources, to the support of body ownership, and to its role in sustaining spatial attention and awareness. It is likely that this neurocognitive knowledge will lead to better treatments of chronic and acute pain in the future. PMID- 29519455 TI - The parietal lobe and the vestibular system. AB - The vestibular cortex differs in various ways from other sensory cortices. It consists of a network of several distinct and separate temporoparietal areas. Its core region, the parietoinsular vestibular cortex (PIVC), is located in the posterior insula and retroinsular region and includes the parietal operculum. The entire network is multisensory (in particular, vestibular, visual, and somatosensory). The peripheral and central vestibular systems are bilaterally organized; there are various pontomesencephalic brainstem crossings and at least two transcallosal connections of both hemispheres, between the PIVC and the motion-sensitive visual cortex areas, which also mediate vestibular input. Structural and functional vestibular dominance characterizes the right hemisphere in right-handers and the left hemisphere in left-handers. This explains why right hemispheric lesions in right-handers more often generally cause hemispatial neglect and the pusher syndrome, both of which involve vestibular function. Vestibular input also contributes to cognition and may determine individual lateralization of brain functions such as handedness. Bilateral organization is a major key to understanding cortical functions and disorders, for example, the visual-vestibular interaction that occurs in spatial orientation. Although the vestibular cortex is represented in both hemispheres, there is only one global percept of body position and motion. The chiefly vestibular aspects of the multiple functions and disorders of the parietal lobe dealt with in this chapter cannot be strictly separated from various multisensory vestibular functions within the entire brain. PMID- 29519456 TI - Multisensory and sensorimotor maps. AB - The parietal lobe plays a major role in sensorimotor integration and action. Recent neuroimaging studies have revealed more than 40 retinotopic areas distributed across five visual streams in the human brain, two of which enter the parietal lobe. A series of retinotopic areas occupy the length of the intraparietal sulcus and continue into the postcentral sulcus. On the medial wall, retinotopy extends across the parieto-occipital sulcus into the precuneus and reaches the cingulate sulcus. Full-body tactile stimulation revealed a multisensory homunculus lying along the postcentral sulcus just posterior to primary somatosensory cortical areas and overlapping with the anteriormost retinotopic maps. These topologically organized higher-level maps lay the foundation for actions in peripersonal space (e.g., reaching and grasping) as well as navigation through space. A preliminary yet comprehensive multilayer functional atlas was constructed to specify the relative locations of cortical unisensory, multisensory, and action representations. We expect that those areal and functional definitions will be refined by future studies using more sophisticated stimuli and tasks tailored to regions with different specificity. The long-term goal is to construct an online surface-based atlas containing layered maps of multiple modalities that can be used as a reference to understand the functions and disorders of the parietal lobe. PMID- 29519457 TI - Extinction as a deficit of the decision-making circuitry in the posterior parietal cortex. AB - Extinction is a common neurologic deficit that often occurs as one of a constellation of symptoms seen with lesions of the posterior parietal cortex (PPC). Although extinction has typically been considered a deficit in the allocation of attention, new findings, particularly from nonhuman primate studies, point to one potential and important source of extinction as damage to decision-making circuits for actions within the PPC. This new understanding provides clues to potential therapies for extinction. Also the finding that the PPC is important for action decisions and action planning has led to new neuroprosthetic applications using PPC recordings as control signals to assist paralyzed patients. PMID- 29519458 TI - Somatosensory deficits. AB - The analysis and interpretation of somatosensory information are performed by a complex network of brain areas located mainly in the parietal cortex. Somatosensory deficits are therefore a common impairment following lesions of the parietal lobe. This chapter summarizes the clinical presentation, examination, prognosis, and therapy of sensory deficits, along with current knowledge about the anatomy and function of the somatosensory system. We start by reviewing how somatosensory signals are transmitted to and processed by the parietal lobe, along with the anatomic and functional features of the somatosensory system. In this context, we highlight the importance of the thalamus for processing somatosensory information in the parietal lobe. We discuss typical patterns of somatosensory deficits, their clinical examination, and how they can be differentiated through a careful neurologic examination that allows the investigator to deduce the location and size of the underlying lesion. In the context of adaption and rehabilitation of somatosensory functions, we delineate the importance of somatosensory information for motor performance and the prognostic evaluation of somatosensory deficits. Finally, we review current rehabilitation approaches for directing cortical reorganization in the appropriate direction and highlight some challenging questions that are unexplored in the field. PMID- 29519459 TI - Pain syndromes and the parietal lobe. AB - Pain was considered to be integrated subcortically during most of the 20th century, and it was not until 1956 that focal injury to the parietal opercular insular cortex was shown to produce selective loss of pain senses. The parietal operculum and adjacent posterior insula are the main recipients of spinothalamic afferents in primates. The innermost operculum appears functionally associated with the posterior insula and can be segregated histologically, somatotopically and neurochemically from the more lateral S2 areas. The Posterior Insula and Medial Operculum (PIMO) encompass functional networks essential to initiate cortical nociceptive processing. Destruction of this region selectively abates pain sensations; direct stimulation generates acute pain, and epileptic foci trigger painful seizures. Lesions of the PIMO have also high potential to develop central pain with dissociated loss of pain and temperature. The PIMO region behaves as a somatosensory area on its own, which handles phylogenetically old somesthetic capabilities based on thinly myelinated or unmyelinated inputs. It integrates spinothalamic-driven information - not only nociceptive but also innocuous heat and cold, crude touch, itch, and possibly viscero-somatic interoception. Conversely, proprioception, graphesthesia or stereognosis are not processed in this area but in S1 cortices. Given its anatomo-functional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the region comprising the inner parietal operculum and posterior insula appears to contain a third somatosensory cortex contributing to the spinothalamic attributes of the final perceptual experience. PMID- 29519460 TI - Optic ataxia: beyond the dorsal stream cliche. AB - This chapter reviews clinical and scientific approaches to optic ataxia. This double historic track allows us to address important issues such as the link between Balint syndrome and optic ataxia, the alleged double dissociation between optic ataxia and visual agnosia, and the use of optic ataxia to argue for a specific vision-for-action occipitoposterior parietal stream. Clinical cases are described and reveal that perceptual deficits have been long shown to accompany ataxia. Importantly, the term ataxia appears to be misleading as patients exhibit a combination of visual and nonvisual perceptual, attentional, and visuomotor guidance deficits, which are confirmed by experimental approaches. Three major features of optic ataxia are described. The first is a spatial feature whereby the deficits exhibited by patients appear to be specific to peripheral vision, akin to the field effect. Visuomotor field examination allows us to quantify this deficit and reveals that it consists of a highly reliable retinocentric hypometria. The third is a temporal feature whereby these deficits are exacerbated under temporal constraints, i.e., when attending to dynamic stimuli. These two aspects combine in a situation where patients have to quickly respond to a target presented in peripheral vision that is experimentally displaced upon movement onset. In addition to the field effect, a hand effect can be described in conditions where the hand is not visible. Spatial and temporal aspects as well as field and hand effects may rely on several posterior parietal modules that remain to be precisely identified both anatomically and functionally. It is concluded that optic ataxia is not a visuomotor deficit and there is no dissociation between perception and action capacities in optic ataxia, hence a fortiori no double dissociation between optic ataxia and visual agnosia. Future directions for understanding the basic pathophysiology of optic ataxia are proposed. PMID- 29519461 TI - Bilateral parietal dysfunctions and disconnections in simultanagnosia and Balint syndrome. AB - In 1909 Rezso Balint published an extraordinary case study of a man with complex visuospatial deficits resulting from bilateral parietal lesions. Despite some controversies over the nature of reported symptoms, in 1954 Hecaen and Ajuriaguerra conceived the term "Balint syndrome," not only to honor Balint's influential work but to firmly conceptualize this striking neurologic disorder. Nowadays it is largely agreed that, while Balint syndrome may result from multiple etiologies, it is principally diagnosed based on the presence of three symptoms: simultanagnosia, optic ataxia, and ocular apraxia. One of the most striking characteristics of Balint syndrome, perfectly capturing the nature of this remarkable disorder, is that affected patients cannot perceive more than one object at a time or comprehend multiobject visual scenes due to a lack of ability to detect several objects concurrently and to grasp the spatial relationships between them. This chapter gives an overview of the cognitive mechanisms and neuroanatomy underlying Balint syndrome, which provides key insights into our understanding of the role of parietal cortex in human attention, visual perception, and visuomotor control. This chapter also pays homage to Glyn Humphreys (1954-2016), who pioneered contributions to the knowledge about complexity of visual and spatial deficits associated with Balint syndrome. PMID- 29519462 TI - Perceptual deficits of object identification: apperceptive agnosia. AB - It is argued here that apperceptive object agnosia (generally now known as visual form agnosia) is in reality not a kind of agnosia, but rather a form of "imperception" (to use the term coined by Hughlings Jackson). We further argue that its proximate cause is a bilateral loss (or functional loss) of the visual form processing systems embodied in the human lateral occipital cortex (area LO). According to the dual-system model of cortical visual processing elaborated by Milner and Goodale (2006), area LO constitutes a crucial component of the ventral stream, and indeed is essential for providing the figural qualities inherent in our normal visual perception of the world. According to this account, the functional loss of area LO would leave only spared visual areas within the occipito-parietal dorsal stream - dedicated to the control of visually-guided actions - potentially able to provide some aspects of visual shape processing in patients with apperceptive agnosia. We review the relevant evidence from such individuals, concentrating particularly on the well-researched patient D.F. We conclude that studies of this kind can provide useful pointers to an understanding of the processing characteristics of parietal-lobe visual mechanisms and their interactions with occipitotemporal perceptual systems in the guidance of action. PMID- 29519463 TI - Unilateral spatial neglect after posterior parietal damage. AB - Unilateral spatial neglect is a disabling neurologic deficit, most frequent and severe after right-hemispheric lesions. In most patients neglect involves the left side of space, contralateral to a right-hemispheric lesion. About 50% of stroke patients exhibit neglect in the acute phase. Patients fail to orient, respond to, and report sensory events occurring in the contralateral sides of space and of the body, to explore these portions of space through movements by action effectors (eye, limbs), and to move the contralateral limbs. Neglect is a multicomponent higher-level disorder of spatial awareness, cognition, and attention. Spatial neglect may occur independently of elementary sensory and motor neurologic deficits, but it can mimic and make them more severe. Diagnostic tests include: motor exploratory target cancellation; setting the midpoint of a horizontal line (bisection), that requires the estimation of lateral extent; drawing by copy and from memory; reading, assessing neglect dyslexia; and exploring the side of the body contralateral to the lesion. Activities of daily living scales are also used. Patients are typically not aware of neglect, although they may exhibit varying degrees of awareness toward different components of the deficit. The neural correlates include lesions to the inferior parietal lobule of the posterior parietal cortex, which was long considered the unique neuropathologic correlate of neglect, to the premotor and to the dorsolateral prefrontal cortices, to the posterior superior temporal gyrus, at the temporoparietal junction, to subcortical gray nuclei (thalamus, basal ganglia), and to parietofrontal white-matter fiber tracts, such as the superior longitudinal fascicle. Damage to the inferior parietal lobule of the posterior parietal cortex is specifically associated with the mainly egocentric, perceptual, and exploratory extrapersonal, and with the personal, bodily components of neglect. Productive manifestations, such as perseveration, are not a correlate of posterior parietal cortex damage. PMID- 29519464 TI - The history of the neurophysiology and neurology of the parietal lobe. AB - The development and change of knowledge on the function of the parietal lobe from the second half of the 19th century to the early 1970s are reviewed. Motor and somatosensory functions were initially localized in a broad frontoparietal region. At the beginning of the 20th century the motor cortex was restricted to the posterior frontal lobe. The separate attribution of somatosensory functions to the parietal lobe was initially based on anatomic considerations, but mostly on localized bodily sensations elicited by electric stimulation in awake patients. Patients and nonhuman primates with anterior parietal damage showed deficits in somatic sensation (tactile discrimination and position sense, less markedly pain and thermal sensitivity). Somatosensory evoked potentials demonstrated in all mammals that the body is orderly and multiply represented in the anterior parietal cortex. The parietal lobe was divided into an anterior and a posterior cortex (PPC). The PPC is particularly developed in primates, where it includes a superior and an inferior parietal lobule. The PPC was initially thought to be a higher-order region for somatosensory information processing, but its functional specialization proved soon to be greater and more complex. PPC damage in humans gives rise to a variety of neuropsychologic disorders: pain asymbolia, sensory extinction, spatial neglect, optic ataxia and limb apraxia, alexia and agraphia. Single-neuron recordings in freely behaving monkeys furnished the complementary information that the PPC is involved in body environment interactions, for visual exploration and hand use as a sensor and a tool. The PPC is now believed to underpin higher-order processes of sensory inputs, multisensory and sensorimotor integration, spatial attention, intention, and the conjoint representation of external space and the body. The symptoms in which disorders of these processes manifest after PPC damage are considerably different in humans and nonhuman primates. PMID- 29519465 TI - The evolution of parietal cortex in primates. AB - Many of the adaptive changes in the functional organization of parietal cortex of humans emerged in past in the early primates as they depended on visually guided forelimb use to grasp branches and food. Currently, human, apes and some monkeys have four well-defined subdivisions of anterior parietal cortex, areas 3a, 3b, 1 and 2 of Brodmann. In some of the smaller monkeys, and in stepsirrine primates (galagos, lemurs, and lorises), especially areas 1 and 2 are less developed, and the existence of an area 2 is questionable. In galagos, area 3b, the homologue of S1 in other mammals, has a more primitive somatotopy, is less devoted to representing the hand, and information from facial whiskers is more important. Humans and other primates also have more somatosensory areas in lateral parietal cortex than most mammals. While the regions of the second somatosensory area, S2 is divided into S2 and the parietal ventral area, PV in most mammals, primates have the additional caudal ad rostral ventral somatosensory areas, VSc and VSr. Posterior parietal cortex is another region of posterior cortex that has changed greatly from non-primate ancestors in having a more caudal half that is heavily devoted to further processing visual information for guiding different actions, such as running, reaching, looking, and grasping. All primates have at least 8 small subdivisions or domains in PPC, and have matching domains in premotor and motor cortex. In humans, domains for speech and tool use appear to have been added, and other parts of PPC have expanded. In addition, parts of PPC are differently specialized in the right and left cerebral hemispheres of humans more than in other primates. PMID- 29519466 TI - Bodily self-consciousness and its disorders. AB - Research in clinical and human neuroscience indicates that important brain mechanisms of self-consciousness are based on the integration of multisensory bodily signals (i.e., bodily self-consciousness: BSC), including signals coming from outside our body (i.e., exteroceptive signals, such as tactile, auditory, and visual information) and the inside of our body (i.e., interoceptive signals). In this chapter, we discuss selected behavioral and neuroimaging studies about how multisensory integration generates and modulates BSC in humans, with particular relevance to parietal mechanisms. We then review the neurology of disorders of BSC after acquired brain damage or dysfunction, ranging from body attentional disorders to delusional and illusory deficits about the patient's own body, associated with a breakdown of the link between the body and the self. PMID- 29519467 TI - Constructional apraxia. AB - Since the classic papers of Kleist, Mayer Gross, and Critchley, constructional apraxia (CA) has been considered to be a typical sign of a parietal lobe lesion, and as a precious tool to appreciate the spatial abilities subserved by this lobe. However, the development of more sophisticated neuropsychologic models and methods of investigation has revealed several problematic aspects. It has become increasingly clear that CA is a heterogeneous construct that can be examined with very different tasks, that are only mildly interconnected, and tap various kinds of visuospatial, perceptual, attentional, planning, and motor mechanisms. On the basis of these considerations, the relationships between parietal lobe functions and constructional activities must be considered, taking into account on the one hand the heterogeneity of the tasks and of the cognitive functions requested by different kinds of constructional activities and, on the other hand, the plurality of functions and of processing streams linking different parts of the parietal lobes to the occipital and frontal lobes. PMID- 29519468 TI - Limb apraxia and the left parietal lobe. AB - Limb apraxia is a heterogeneous disorder of skilled action and tool use that has long perplexed clinicians and researchers. It occurs after damage to various loci in a densely interconnected network of regions in the left temporal, parietal, and frontal lobes. Historically, a highly classificatory approach to the study of apraxia documented numerous patterns of performance related to two major apraxia subtypes: ideational and ideomotor apraxia. More recently, there have been advances in our understanding of the functional neuroanatomy and connectivity of the left-hemisphere "tool use network," and the patterns of performance that emerge from lesions to different loci within this network. This chapter focuses on the left inferior parietal lobe, and its role in tool and body representation, action prediction, and action selection, and how these functions relate to the deficits seen in patients with apraxia subsequent to parietal lesions. Finally, suggestions are offered for several future directions that will benefit the study of apraxia, including increased attention to research on rehabilitation of this disabling disorder. PMID- 29519469 TI - The parietal lobe and language. AB - Although the parietal lobe was considered by many of the earliest investigators of disordered language to be a major component of the neural systems instantiating language, most views of the anatomic substrate of language emphasize the role of temporal and frontal lobes in language processing. We review evidence from lesion studies as well as functional neuroimaging, demonstrating that the left parietal lobe is also crucial for several aspects of language. First, we argue that the parietal lobe plays a major role in semantic processing, particularly for "thematic" relationships in which information from multiple sensory and motor domains is integrated. Additionally, we review a number of accounts that emphasize the role of the left parietal lobe in phonologic processing. Although the accounts differ somewhat with respect to the nature of the linguistic computations subserved by the parietal lobe, they share the view that the parietal lobe is essential for the processes by which sound based representations are transcoded into a format that can drive action systems. We suggest that investigations of the linguistic capacities of the parietal lobe constrained by the understanding of the parietal lobe in action and multimodal sensory integration may serve to enhance not only our understanding of language, but also the relationship between language and more basic brain functions. PMID- 29519470 TI - Memory deficits. AB - In this chapter, the neuropsychologic literature concerning memory deficits following parietal lesions is reviewed. Left inferior parietal lobule lesions definitely cause verbal short-term memory impairments, while right parietal lesions disrupt visuospatial short-term memory. Episodic memory, as well as autobiographic memory, does not seem to be impaired after both unilateral and bilateral parietal lesions, in contrast with neuroimaging studies reporting activation of the lateral parietal cortex during memory tasks. The most substantiated hypothesis is that the parietal lobe is involved in the subjective experience of recollection. Indeed, patients with parietal lesions produce fewer false memories and show lower confidence in their source recollections, possibly due to a limited number of details that they are able to report. Finally, the parietal lobes contribute to semantic memory as far as abstract concepts are concerned; in addition some sparse evidence on traumatic brain injury suggests that the parietal lobe is part of the distributed network involved in prospective memory. PMID- 29519471 TI - Gerstmann syndrome: historic and current perspectives. AB - This chapter offers a perspective on the origin, operational definition, historic vicissitudes, and current status of Gerstmann syndrome. The main issues and controversy accompanying Gerstmann syndrome throughout the years are reviewed. The clinical picture of Gerstmann syndrome as it emerges from a series of modern day pure cases is described. In current clinical practice, a diagnosis of Gerstmann syndrome indicates the concomitant presence of four acquired symptoms: finger agnosia, acalculia, left-right disorientation, and agraphia. Finally, based on empiric work conducted in recent years, the chapter concludes with a new interpretation of Gerstmann syndrome. If seen as an instance of intraparietal disconnection, this classic parietal syndrome will acquire fresh clinical and theoretic significance. PMID- 29519472 TI - Parietal lobe epilepsy. AB - There are few reports of patients with parietal lobe epilepsy. One of the largest series, from the Montreal Neurological Institute (MNI), reported that patients with epileptogenic areas in the parietal cortex behind the postcentral gyrus comprised 6% of patients with refractory focal epilepsy treated surgically at the MNI between 1929 and 1988. Since then several other institutions have reported their experience with the evaluation and treatment of patients with parietal lobe epilepsy. This chapter reviews the functional anatomy of the parietal lobe, electroclinical manifestations and surgical outcome of parietal lobe epilepsy, and recent advances in the evaluation of patients with refractory focal epilepsy. PMID- 29519473 TI - Noninvasive brain stimulation of the parietal lobe for improving neurologic, neuropsychologic, and neuropsychiatric deficits. AB - Transcranial magnetic stimulation (TMS) and transcranial electric stimulation (tES) are noninvasive brain stimulation (NIBS) tools that are now widely used in neuroscientific research in humans. The fact that both TMS and tES are able to modulate brain plasticity and, in turn, affect behavior is opening up new horizons in the treatment of brain circuit and plasticity disorders. In the present chapter, we will first provide the reader with a brief background on the basic principles of NIBS, describing the electromagnetic and physical foundations of TMS and tES, as well as the current knowledge of the neurophysiologic basis of their effects on brain activity and plasticity. In the main part, we will outline studies aimed at improving persistent symptoms and deficits in patients suffering from neurologic and neuropsychiatric disorders featured by dysfunction of the parietal lobe. The emerging view is that NIBS of parietal areas holds the promise to overcome various sensory, motor, and cognitive disorders that are often refractory to standard medical or behavioral therapies. The chapter closes with an outlook on further developments in this realm, discussing novel therapeutic approaches that could lead to more effective rehabilitation procedures, better suited for the specific parietal lobe dysfunction. PMID- 29519474 TI - The dorsal "action" pathway. AB - In 1992, Goodale and Milner proposed a division of labor in the visual pathways of the primate cerebral cortex. According to their account, the ventral pathway, which projects to occipitotemporal cortex, constructs our visual percepts, while the dorsal pathway, which projects to posterior parietal cortex, mediates the visual control of action. Although the framing of the two-visual-system hypothesis has not been without controversy, it is clear that vision for action and vision for perception have distinct computational requirements, and significant support for the proposed neuroanatomic division has continued to emerge over the last two decades from human neuropsychology, neuroimaging, behavioral psychophysics, and monkey neurophysiology. In this chapter, we review much of this evidence, with a particular focus on recent findings from human neuroimaging and monkey neurophysiology, demonstrating a specialized role for parietal cortex in visually guided behavior. But even though the available evidence suggests that dedicated circuits mediate action and perception, in order to produce adaptive goal-directed behavior there must be a close coupling and seamless integration of information processing across these two systems. We discuss such ventral-dorsal-stream interactions and argue that the two pathways play different, yet complementary, roles in the production of skilled behavior. PMID- 29519475 TI - The role of the parietal cortex in sensorimotor transformations and action coding. AB - The picture of the human cortical motor system has fully changed in the last two decades. In the light of new data, the notion of a motor system devoted solely to action execution, strictly isolated from the sensory system, is not sustainable. There is evidence that parietal areas are strictly connected to frontal areas and these connections build up sensorimotor circuits aimed at interacting with objects in the environment, and at understanding actions. They are known as the canonic neuron system and mirror neuron system, respectively. These circuits are part of the classic dorsal stream. Recently, the dorsal stream has been further divided into a dorsodorsal and a ventrodorsal stream. The ventrodorsal stream is regarded as functionally linked to object awareness for action recognition/organization. The dorsodorsal stream is proposed to subserve online control of actions. Affordances indicate "action possibilities" as characterized by object properties the environment provides to interacting organisms. Affordances may be divided into stable and variable ones. According to this distinction, stable affordances emerge from slow offline processing of visual information based on object knowledge as well as previous experiences in object interaction. In contrast, variable affordances emerge from fast online processing of visual information during actual object interaction and refer to changing or temporary object characteristics, such as orientation in space, size changes, including the update of hand shape for grasping, defining overall the current state of the object. It has been proposed that the dorsodorsal stream codes for variable affordances, while the dorsoventral stream codes for stable affordances. PMID- 29519476 TI - The parietal lobe and tool use. AB - The ability to craft and use tools is a crucial skill of human beings, distinguishing humans from all other species. Humans show a unique capacity to create novel, technologically advanced devices and represent physical causality using tools. In the present chapter we review the effect of tool use in changing body-space multisensory integration and body representation and the fundamental contribution of the parietal lobe to the neural underpinnings of tool use. In the final section we briefly introduce the effect of parietal brain damage on tool use. At the beginning of 20th century, a crucial role for the left parietal lobe for a proper control of gestures, including the pantomimed and actual use of tools, was already clear. Actual available evidence supports a critical role of the parietal lobe for both the lower-level multisensory integration of somatosensory and visual input necessary for the interactions between body, tools, and external objects, and for the representation of the mechanical and conceptual dynamics of tool use. Parietal regions, rather than merely representing the prototypical use of a tool, would be critical to understand the general mechanical interactions of the tool with the environment. The increase of knowledge about such brain mechanisms is of utmost relevance in the present times, characterized by the development of more and more sophisticated technological tools, such as functional prostheses, robotic interfaces, and virtual-reality devices. PMID- 29519478 TI - Contributions of the ventral parietal cortex to declarative memory. AB - Our understanding of the role that ventral parietal cortex (VPC) plays in declarative memory processes has changed dramatically over the last two decades. The goal of this chapter is to provide a concise overview data concerning VPC involvement in episodic memory (EM), and to connect this data to several key theories of VPC function. We review evidence from five methodological domains in cognitive neuroscience: neuropsychological lesion evidence, univariate activation studies, multivoxel pattern analyses, functional connectivity studies, and brain stimulation experiments. We discuss how the body of empirical work bears on putative mnemonic functions of VPC related to attention and stimulus representation, and detail the strengths and weaknesses of related theories. Lastly, we identify several broad conceptual questions raised by recent investigations, and outline directions for future research. PMID- 29519477 TI - Parieto-frontal networks for eye-hand coordination and movements. AB - Eye-hand coordination lies at the core of our daily actions and interactions with objects and people around us, and is central to understanding how the brain creates internal models of the action space and generates movement within it. Eye hand coordination remains a very complex and elusive problem, which is further complicated by its distributed representation in the brain. In fact, evolution did not confine such a crucial function to a single area, but rather assigned it to several distributed cortical and subcortical systems, where encoding mechanisms can satisfy multiple demands and the consequences of lesions are less disruptive. We will discuss evidence suggesting that eye-hand coordination is, indeed, an emerging function of internal parietal operations and of their interplay with frontal cortex, where the cortical eye and hand motor output domains reside. Therefore, coordination of eye and hand movements requires an appropriate spatiotemporal activation of the subcortical structures which control the eyes and hand. In this distributed network, information transfer between different cortical areas and with subcortical structures is based on temporally dispersed communication patterns. PMID- 29519479 TI - Microarchitecture and connectivity of the parietal lobe. AB - This chapter summarizes current knowledge on the structural segregation of the parietal lobe based on cyto-, myelo-, and receptorarchitectonic studies, as well as the connectivity of this brain region with other cortical and subcortical structures. The anterior part of the human parietal cortex comprises the somatosensory areas 3a, 3b, 1, and 2, whereas the posterior part contains seven multimodal areas in both the superior and inferior parietal lobules. Available cytoarchitectonic maps of the human intraparietal sulcus do not provide a complete picture yet. Myelo- and receptorarchitectonic analyses largely confirm but also further differentiate the cytoarchitectonic maps. With the advent of diffusion imaging and functional connectivity studies, further insight into the structural and functional organization has been achieved. It shows that the posterior parietal cortex is a key node in anatomic networks connecting visual with (pre)frontal cortices, and temporal with parts of frontal cortices. Here, the superior longitudinal fascicle and its components play a major role, together with the arcuate and middle longitudinal fascicles. Major connections with subcortical structures, particularly the basal ganglia and thalamic nuclei, are discussed. Finally, the importance of precise maps of parietal areas for defining seed regions in structural and functional connectivity studies is emphasized. PMID- 29519480 TI - The mirror mechanism in the parietal lobe. AB - The mirror mechanism is a basic mechanism that transforms sensory representations of others' actions into motor representations of the same actions in the brain of the observer. The mirror mechanism plays an important role in understanding actions of others. In the present chapter we discuss first the basic organization of the posterior parietal lobe in the monkey, stressing that it is best characterized as a motor scaffold, on the top of which sensory information is organized. We then describe the location of the mirror mechanism in the posterior parietal cortex of the monkey, and its functional role in areas PFG, and anterior, ventral, and lateral intraparietal areas. We will then present evidence that a similar functional organization is present in humans. We will conclude by discussing the role of the mirror mechanism in the recognition of action performed with tools. PMID- 29519481 TI - Somatosensory maps. AB - Somatosensory areas containing topographic maps of the body surface are a major feature of parietal cortex. In primates, parietal cortex contains four somatosensory areas, each with its own map, with the primary cutaneous map in area 3b. Rodents have at least three parietal somatosensory areas. Maps are not isomorphic to the body surface, but magnify behaviorally important skin regions, which include the hands and face in primates, and the whiskers in rodents. Within each map, intracortical circuits process tactile information, mediate spatial integration, and support active sensation. Maps may also contain fine-scale representations of touch submodalities, or direction of tactile motion. Functional representations are more overlapping than suggested by textbook depictions of map topography. The whisker map in rodent somatosensory cortex is a canonic system for studying cortical microcircuits, sensory coding, and map plasticity. Somatosensory maps are plastic throughout life in response to altered use or injury. This chapter reviews basic principles and recent findings in primate, human, and rodent somatosensory maps. PMID- 29519482 TI - Preface. PMID- 29519483 TI - Foreword. PMID- 29519484 TI - Clinical Anatomy in Aesthetic Gluteal Contouring. AB - Despite the acceptance of gluteal augmentation procedures into today's mainstream of plastic surgery procedures, clinical anatomy continues to play a critical role in improving outcomes in aesthetic gluteal contouring. In this rapidly growing and evolving field, avoiding complications is imperative for the continuing advancement and acceptance of this group of procedures into the armamentarium of every plastic surgeon. This article highlights the clinically relevant anatomy important to improving patient satisfaction and avoiding complications. PMID- 29519485 TI - Classification System for Gluteal Evaluation: Revisited. AB - The buttock area has received much media attention in recent years, which has produced increased patient demand for buttock reshaping or contouring and augmentation. Increasing patient demand has necessitated a more structured approach to evaluation of gluteal anatomy and the development of surgical procedures to enhance its beauty. PMID- 29519486 TI - Complications in Gluteal Augmentation. AB - Gluteal augmentation is rapidly gaining in popularity and this is driving aesthetic surgeons to gain experience and develop techniques to meet patient expectations. Currently, the 2 main techniques - gluteal fat grafting and gluteal implant for augmentation have significant limitations. Autologous fat grafting seems to have a mortality rate significantly higher than other aesthetic procedures. Implant based gluteal augmentation is equally difficult. This is a broad review of all the complications associated with both types and autologous gluteal augmentation. Society and individual surgeons are developing guidelines for the procedure based on theoretic etiologies. Gluteal implant augmentation is also fraught with problems. PMID- 29519488 TI - Submuscular Gluteal Augmentation. AB - Submuscular gluteal augmentation is a very valid plane for buttocks implantation, even more so in North America, where surgeons can only use silicone elastomer implants. Irrespective of how soft elastomer implants are made, they are much firmer than the silicone gel implants that can be used in other countries. A deeper plane with more soft tissue coverage provides more natural results, as long as the anatomic boundaries are respected. Proper patient and implant selection is the key factor for satisfactory gluteal contours and outcomes. PMID- 29519487 TI - Practice-Based Patient Management Strategies in Gluteal Augmentation with Implants. AB - This article focuses on practice-based recommendations for surgeons performing gluteal augmentation with implants (GAI). Preoperative planning, including the indications, precautions, and contraindications to GAI, is discussed. Advantages and disadvantages of subfascial and intramuscular implantation are addressed along with recommendations for implant size, shape, and position. Recommendations for patient management before and after surgery along with operative and nonoperative strategies for postoperative complications, including wound dehiscence, infection, and seroma, are included. Aesthetic concerns and recommendations for the management of poor results are addressed. A comprehensive literature review is included along with illustrative preoperative and postoperative photos. PMID- 29519489 TI - Intramuscular Gluteal Augmentation with Implants Associated with Immediate Fat Grafting. AB - This article presents an overview of intramuscular gluteal augmentation involving primary and secondary augmentation with implants. Although gluteal augmentation is a well-studied procedure, few reports have described the intramuscular technique or this technique in association with lipofilling. This article presents experience with a combined technique; this recent innovation combines placement of an anatomic silicone gel implant underneath the gluteus maximus and immediate fat grafting. Primary and secondary gluteal augmentations using implants resulted in satisfactory outcomes. A majority of complications were minor, predictable, and did not affect aesthetic outcome or normal postoperative recovery. Success depends on patient selection and careful intraoperative and postoperative management. PMID- 29519490 TI - Intramuscular Gluteal Augmentation: The XYZ Method. AB - Although interest in buttocks implant procedures is growing around the world, it remains a technically demanding procedure. The intramuscular plane is thought to be superior to other planes of dissection. Asymmetry and visibility of the implants remain frequent complications when the surgeon works without any reference points to guide the procedure. The XYZ method helps the surgeon to obtain symmetry, to significantly reduce implant visibility and to decrease other complications associated with buttocks implants. The method uses the surface anatomy of the boney frame of the pelvis to perform a geometric plane to detach the muscle. PMID- 29519491 TI - Subfascial Gluteal Implant Augmentation. AB - Gluteal augmentation has gained popularity. It might be the only option to increase volume for lean patients without donor tissue for grafting. Subfascial augmentation is a safe treatment with low morbidity when performed in an appropriate setting with the right equipment. It is an anatomically based procedure. It is very important that pocket dissection is limited to the anatomic landmarks. Implants should be placed vertically to allow for proper contouring. The wound should never be closed with tension. One of the most important steps is postoperative care, which should avoid any pressure on the buttocks and stress on the wound. PMID- 29519492 TI - Improvement of the Gluteal Contour: Modern Concepts with Systematized Lipoinjection. AB - Buttock enlargement with lipoinjection is a procedure that has had a very high demand in the last 5 years. Changes in aesthetics have made more patients request greater volume in their buttocks and hips. The procedure requires not only liposuction, in which the fat is obtained, but also a systematization off the fat injection process in the buttock to obtain the appropriate aesthetic results according to the characteristics of each patient. The procedure achieves very satisfactory results because it can transform the patient's physical appearance significantly. PMID- 29519493 TI - Gluteal Augmentation and Contouring with Autologous Fat Transfer: Part I. AB - Gluteal augmentation with autologous fat transfer is an increasingly popular procedure that has the ability to transform a patient's entire body silhouette and gluteal appearance. Proper patient selection, preoperative evaluation, and planning are critical to the success of the procedure. Using the preoperative planning, surgical technique, and postoperative care described, the procedure can be performed safely with powerful and consistent results and avoidance of complications associated with gluteal fat transfer. PMID- 29519494 TI - Autologous Flap Gluteal Augmentation: Purse-String Technique. AB - The ideal patient for purse-string gluteoplasty has buttock deflation and ptosis, and wishes to improve projection. Key elements of the procedure are buttock lifting combined with auto-augmentation, no undermining of auto-augmentation tissue, and use of a purse-string suture to enhance projection of auto augmentation tissue. Purse-string gluteoplasty is a safe and effective technique to correct buttock ptosis and atrophy. PMID- 29519495 TI - Autologous Flap Gluteal Augmentation: Split Gluteal Flap Technique. AB - Postbariatric, cosmetic, and circumferential body lift patients seek to avoid a flattened buttock contour. Gluteal implants have been described with various rates of complications and difficulties. Lipografting moderately increases buttock volume; neither procedure directly addresses ptosis. The procedure described in this article addresses the volume deficit and ptosis. Most adipocutaneous flaps originate within the superior gluteal region and maintain volume in the top half of the buttocks, lacking the ability to reach the midportion of the buttocks. The ideal flap should be versatile, result in a superior gluteal concavity, and give the maximum projection at the midlevel of the buttocks. PMID- 29519497 TI - Preface. PMID- 29519496 TI - Autologous Gluteal Augmentation with the Moustache Transposition Flap Technique. AB - Massive weight loss patients and aesthetic patients can present with significant gluteal contour abnormalities. Gluteal ptosis, skeletal deformities, severe platypgia, and a paucity of donor fat for autologous transfer are common problems. Excisional procedures are used to treat massive-weight-loss contour abnormalities. These procedures present an opportunity to address severe gluteal deformities using autologous tissue augmentation. With a working knowledge of the relevant anatomy, sound surgical technique, and meticulous postoperative care, autologous gluteal autoaugmentation with circumferential body lift/excisional buttock lift using the "Moustache" flap technique will enhance massive weight loss body contouring outcomes and improve patient satisfaction. PMID- 29519498 TI - A study of laparoscopic instrument use during colorectal surgery. AB - The aim of this study was to quantify laparoscopic instrument use and actions of both limbs during a sample of common colorectal surgical procedures. A method was devised using Observer XT software to code video recordings. Anonymised HD video recordings of nine laparoscopic colorectal procedures performed by a single surgeon were analysed. We determined the percentage and frequency of instrument use and limb actions throughout the total laparoscopic surgical duration, as well as the duration of instrument inactivity. Seven instruments and seven actions were studied across nine surgical procedures. Manoeuvring, blunt dissection, and tenting up tissues accounted for the longest amount of total surgical time (non dominant hand (NDH) 29%, dominant hand (DH) 39%), followed by grasping (NDH 33%, DH 9%), and cauterising (NDH <0.2%, DH 8%). Least time was spent performing other actions such as suction/irrigation (NDH 0.01%, DH 3%) and stapling colorectal tissue (NDH 0.03%, DH 0.5%). The total duration of instrument use and hand actions by the dominant and non-dominant hands were similar overall. However, the frequency of actions performed was lower for the non-dominant hand. This indicates that the non-dominant hand spent more time holding actions than switching between actions, supporting the actions of the dominant hand. These findings highlight the lengthy durations of laparoscopic surgical procedures involved in navigating to anatomical planes and moving tissues. Further, the results detail the extent of secondary functions performed with the surgical instruments. PMID- 29519499 TI - Right ventricular end-systolic area as a simple first-line marker predicting right ventricular enlargement and decreased systolic function in children referred for cardiac magnetic resonance imaging. AB - AIM: To assess the accuracy of simple cardiovascular magnetic resonance imaging (CMR) parameters for first-line analysis of right ventricle (RV) dysfunction in children to identify those who require in-depth analysis and those in whom simple assessment is sufficient. MATERIALS AND METHODS: Sixty paediatric CMR studies were analysed. The following CMR parameters were measured: RV end-diastolic and end-systolic area (4CH EDA and 4CH ESA), fractional area change (FAC), RV diameter in end-diastole (RVD1), tricuspid annular plane systolic excursion (TAPSE), and RV outflow tract diameter in end-diastole (RVOT prox). They were correlated with RV end-diastolic volume (RVEDVI) and RV ejection fraction (RVEF). RESULTS: RVEDVI correlated best with 4CH ESA (r=0.85, <0.001) and EDA (r=0.82, <0.001). For RVEF only a moderate reverse correlation was found for 4CH ESA ( 0.56, <0.001), 4CH EDA (-0.49, 0.001) and positive correlation for FAC (0.49, <0.001). There was no correlation between TAPSE and RVEF and only weak between RVD1 and RVEDVI. A 4CH ESA cut-off value of 8.5 cm2/m2 had a very high diagnostic accuracy for predicting an enlarged RV (AUC=0.912, p<0.001, sensitivity 92.3%, specificity 79%) and a cut-off value of 10.5 cm2/m2 was also a good predictor of depressed RV systolic function (AUC=0.873, p<0.001, sensitivity 83%, specificity 89%). CONCLUSION: For routine screening in clinical practice, 4CH ESA seems a reliable and easy method to identify patients with RV dysfunction. PMID- 29519500 TI - Prediction and clinical implications of portal vein/superior mesenteric vein invasion in patients with resected pancreatic head cancer: the significance of preoperative CT parameters. AB - AIM: To determine the preoperative computed tomography (CT) parameters that predict portal vein/superior mesenteric vein (PV-SMV) invasion in patients with pancreatic head cancer, and to assess whether PV-SMV invasion affects patient survival. MATERIALS AND METHODS: Sixty patients with PV-SMV invasion, and 60 randomly selected patients without it, who had undergone preoperative CT and subsequent surgery for pancreatic head cancer were enrolled. The following CT parameters were evaluated using multivariate logistic regression and receiver operating characteristic analyses to predict vessel invasion (tumour size and margin, length of involved vessel, distance from the tumour to the vessel, vessel irregularity, the teardrop sign, and tumour-vein interface [TVI]). The Cox proportional hazard model was used to evaluate the effects of PV-SMV invasion on survival. RESULTS: In multivariate analysis, tumour size (odds ratio [OR]=1.99) and TVI (OR=3.79 [<=90 degrees ], 20.66 [>90 degrees , <=180 degrees ], and 47.24 [>180 degrees ]) were independent CT predictors of PV-SMV invasion (p<0.05); they achieved a sensitivity of 87%, a specificity of 75%, and an accuracy of 81%; however, PV-SMV invasion did not affect patient survival after surgery (p=0.374). CONCLUSION: In patients with pancreatic head cancer, preoperative CT parameters can predict PV-SMV invasion with high accuracy. PV-SMV invasion did not affect treatment outcome after surgery. PMID- 29519501 TI - FGF-19 agonism for NASH: a short study of a long disease. PMID- 29519502 TI - NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. AB - BACKGROUND: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Key eligibility criteria included a non alcoholic fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02443116. FINDINGS: Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content from baseline (relative risk 10.0 [95% CI 2.6-38.7] vs 11.4 [3.0-43.8], respectively; p<0.0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (>=10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life threatening events or patient deaths occurred during the study. INTERPRETATION: NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population. FUNDING: NGM Biopharmaceuticals. PMID- 29519503 TI - An ISMap02-like insertion sequence in Mycobacterium spp. interferes with specific detection of Mycobacterium avium subsp. paratuberculosis. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is a causative agent of Johne's disease or paratuberculosis (PTB), which is a chronic debilitating disease in ruminants, that is characterized by incurable enteritis and persistent diarrhea. ISMap02 is one of the major targets of PCR because it is present in multicopies (six copies) and known to be specific to MAP. However, in the present study, non MAP mycobacteria were shown to be positive by ISMap02 targeting PCR. Two bacterial isolates (Sample ID: BO-038 and BO-042) were cultured from bovine fecal samples that produced positive results in three of two ISMap02 targeting PCR analyses with negative results in IS900 real-time PCR. Species identification using 16S rRNA gene sequencing and hsp65 gene partial sequencing revealed that strains BO-038 and BO-042 were M. virginiense and M. nonchromogenicum, respectively, which both belong to the M. terrae complex (MTC). Moreover, the two isolates shared a novel insertion sequence (IS) with high similarity to some parts of nucleotide sequences of ISMap02, and IS was presumed to be identical to that present in M. heraklionense. Both the novel IS and ISMap02 were characterized as IS1182 family members, and several sequences similar to ISMap02 were identified by BLAST analysis. In addition, the DDE transposase of the novel IS showed great similarity in the N-terminal portion with the IS5/1182 DDE transposase of other mycobacteria. These results suggest that ISMap02 has a conserved region with similarity to other ISs, and that the diagnostic value of the primer sets targeting that region should be re-addressed. PMID- 29519504 TI - First four Oral Rabies Vaccination campaigns of the red foxes in Greece: Evaluating factors and assessment. AB - Following the last animal rabies outbreak in Greece in 2012, Oral Rabies Vaccination (ORV) campaigns of red foxes (Vulpes vulpes) were conducted in order to halt the spread of the disease, as widely and effectively have also been implemented in other countries. The present study aims to report the main outcomes following the first Greek ORV campaigns during autumn 2013, 2014, 2015 and spring 2016, to assess their effectiveness and to investigate factors potentially related to their success. Blood samples, mandible bones and teeth, derived by 452 foxes, were tested for rabies antibody titration, animal age determination and tetracycline (TTC) detection. The laboratory results obtained were statistically analyzed. High seroprevalence and TTC detection rates were obtained following the autumn campaigns studied, while these rates were significantly reduced following the spring campaign. The year or the season of the vaccination campaign, the estimated age group of the animal and the geographical Regional Unit (RU), where the animal was hunted, were identified as important factors. On the contrary, no significance could be ascertained for TTC detection based on exclusively previous uptake, use of filter paper, blood sample type and quality, as well as sex of animal. Based on the monitoring results achieved, the first ORV campaigns conducted in the country can be generally considered to be satisfactory. No positives cases were detected since May 2014. Seasonal, geographical parameters and factors related to fox ecology may interfere with monitoring results and should be always considered when planning future ORV programs. PMID- 29519505 TI - Bartonella henselae in small Indian mongooses (Herpestes auropunctatus) from Grenada, West Indies. AB - Many mammals are established hosts for the vector borne bacterial genus, Bartonella. Small Indian mongooses (Herpestes auropunctatus) have only been reported as a possible host for Bartonella henselae in southern Japan. Confirming Bartonella presence in mongooses from other regions in the world may support their role as potential reservoirs of this human pathogen. Specifically, documenting Bartonella in Caribbean mongooses would identify a potential source of zoonotic risk with mongoose-human contact in the New World. Using serological and molecular techniques, we investigated B. henselae DNA and specific antibody prevalence in 171 mongooses from all six parishes in Grenada, West Indies. Almost a third (32.3%, 54/167) of the tested mongooses were B. henselae seropositive and extracted DNA from 18/51 (35.3%) blood pellets were PCR positive for the citrate synthase (gltA) and/or the beta subunit of RNA polymerase (rpoB) genes. All sequences were identical to B. henselae genotype I, as previously reported from Japan. This study confirms the role of small Indian mongooses as a natural reservoir of B. henselae in the New World. PMID- 29519506 TI - Cleavage site of Newcastle disease virus determines viral fitness in persistent infection cells. AB - Newcastle disease, caused by infection with virulent strains of Newcastle disease virus (NDV), poses a risk for the poultry industry. The virulence of NDV is mainly determined by the cleavage site of F protein. Lentogenic NDV can become velogenic after passages in SPF chicken brain and air sac based on some strains isolated from water birds, because the proportion of virulent-related strains gradually increases. In contrast, this proportion remains unchanged if NDV is passaged via 10-day-old SPF chicken embryos. This information suggests that environmental conditions rather than mutation affect NDV fitness in quasispecies. However, it is unknown how the environment selects virulent-related strains from a viral population. In this study, velogenic and lentogenic NDV marked by green or red fluorescence were used to establish persistent infection (PI) in BHK-21 cells. Monitoring viruses by different methods, we found that, without competition, persistently infected cells harbored lentogenic and velogenic NDV strains similarly in terms of viral release, viral spread and the period of persistent viral infection. In contrast, under competitive co-infection, velogenic NDV became dominant in quasispecies from the fifth passage of PI cells, which resulted in the progressive disappearance of the lentogenic NDV strain. This domination was concomitant with a short-term reduction in the superinfection exclusion and supernatant interference in PI cells resulting in a velogenic virus rebound. We concluded that virulent-related F protein cleavage site facilitates the spread and replication of NDV in conditions under which cells do not secret trypsin-like proteases and do not inhibit free virus infection, resulting in a gradual increase in virulent strains in quasispecies with the number of passages. PMID- 29519507 TI - Induction of porcine reproductive and respiratory syndrome virus (PRRSV)-specific regulatory T lymphocytes (Treg) in the lungs and tracheobronchial lymph nodes of PRRSV-infected pigs. AB - Regulatory T lymphocytes (Treg) residing within the tissues, are known to possess immunosuppressive properties which contribute to immunomodulation within the organs. PRRSV infection usually weakens lung defense mechanisms, leading to porcine respiratory disease complex (PRDC). Induction of circulatory Treg is one of the reported mechanisms involved in PRRSV-induced immunomodulation. However, whether PRRSV can induce tissue-infiltrating Treg in the lungs and lymph nodes is still unclear. To investigate the effect of PRRSV on induction of porcine Treg in the tissues, we isolated mononuclear cells from the lungs and tracheobronchial lymph nodes, and identified the existence of Treg by flow cytometry. The results demonstrated that PRRSV could induce Treg proliferation in the cultured mononuclear cells derived from lungs and tracheobronchial lymph nodes, regardless of the pig's PRRSV infective status. Furthermore, PRRSV-infected pigs exhibited higher numbers of total tissue-infiltrating Treg and PRRSV-specific Treg in the lungs and tracheobronchial lymph nodes than the PRRSV-negative pigs. To determine if the lung Treg could produce an inhibitory cytokine, the numbers of IL-10 producing Treg were determined. Significantly higher numbers of IL-10-producing Treg in the lungs of PRRSV-infected pigs were observed. Altogether, our findings indicate the potent effect of PRRSV on induction of Treg in the lungs and tracheobronchial lymph nodes of the infected pigs. The findings expand our understanding in PRRSV immunopathogenesis within the target organs. PMID- 29519508 TI - Modulation of type I interferon signaling by African swine fever virus (ASFV) of different virulence L60 and NHV in macrophage host cells. AB - ASFV causes an important disease of domestic swine and wild boar. Currently no vaccine is available, highlighting the necessity to understand ASFV modulation of innate immune responses in natural host cells. With this aim, macrophage cultures enriched in SWC9 and CD163 differentiation markers were infected in parallel with high virulent ASFV/L60 and low virulent ASFV/NHV, the latter lacking MGF 360 and 505/530 genes associated with type I interferon (IFN I) control. IFN I production and signaling were studied after completion of the viral cycles. None of the viruses increased IFN I production in host cells, and accordingly, didn't cause activation of the central mediator of the pathway IRF3. However, upon stimulation by poly:IC treatment during infections, L60 and NHV similarly inhibited IFN I production. This didn't seem to depend on IRF3 modulation since its activation levels were not significantly decreased in L60 infection and were even increased in NHV's, in comparison to stimulated mock infections. The infections didn't evidently activate JAK-STAT pathway mediators STAT1 and STAT2, but did increase expression of interferon stimulated genes (ISGs), to higher levels in NHV than L60 infection. Interestingly, in presence of IFN-alpha, L60 but not NHV was able to decrease significantly the expression of some of the ISGs tested. Overall, both L60 and NHV were able to inhibit IFN I production in macrophages, through a mechanism not dependent on IRF3 modulation. The high virulent isolate showed however a more effective control of the downstream ISGs expression pathway. PMID- 29519509 TI - Maternally-derived antibodies do not inhibit swine influenza virus replication in piglets but decrease excreted virus infectivity and impair post-infectious immune responses. AB - Maternally-derived antibodies (MDA) reduce piglet susceptibility to swine influenza A virus, but interfere with post-infectious immune responses, raising questions about protection after waning of passive immunity. We therefore analysed the impact of different levels of residual MDA on virus excretion and immune responses in piglets born to vaccinated sows (MDA+) and infected with H1N1 at 5, 7 or 11 weeks of age, in comparison to piglets born to unvaccinated sows (MDA-). Subsequent protection against a second homologous infection occurring 4 weeks after the primo-infection was also investigated. MDA- pigs showed clinical signs, shed the virus, and developed specific immune responses despite some age dependent differences: 7-week-old pigs were less affected clinically, showed a 2 day delayed excretion peak and excreted less virus than younger pigs. In MDA+ animals, clinical signs increased together with the decrease of MDA levels related to the age at infection-time. Virus shedding was not prevented and genome quantification profiles were similar to those obtained in MDA- piglets. However, viral particles excreted by 5-week-old MDA+ piglets appeared to be less infectious than those shed by MDA- piglets at the same age. Humoral response was affected by MDA as illustrated by the absence of HI and neutralizing response regardless the infection age, but anti-NP/M responses were less affected. Proliferative T cell responses were slightly delayed by high MDA levels. Nevertheless, MDA+ animals were all protected from a second infection, like MDA- piglets. In conclusion, responses of pigs to H1N1 were affected by both the physiological development of animals at infection and the MDA level. PMID- 29519510 TI - Qac genes and biocide tolerance in clinical veterinary methicillin-resistant and methicillin-susceptible Staphylococcus aureus and Staphylococcus pseudintermedius. AB - Qac genes are associated with increased tolerance to quaternary ammonium compounds and other cationic biocides such as chlorhexidine. This study aimed to determine whether qac genes and increased biocide tolerance were present in 125 clinical methicillin-resistant and susceptible veterinary staphylococci. A total of 125 methicillin-resistant Staphylococcus aureus (MRSA) and methicillin resistant and -susceptible Staphylococcus pseudintermedius (MRSP and MSSP) from three archived Australian veterinary staphylococci collections underwent whole genome sequencing, multilocus sequence typing and qac gene screening. Two MRSA isolates (12%) harboured qacA/B genes; both isolates were ST8 from horses. QacJ, qacG and smr genes were identified in 28/90 (31%) MRSP and 1/18 (6%) MSSP isolates. ST71 MRSP was significantly more likely to harbour qac genes than other MRSP clones (p < 0.05). A random subset of 31 isolates underwent minimum bactericidal concentration (MBC) testing against F10SCTM (benzalkonium chloride and biguanide), and HexaconTM (chlorhexidine gluconate), with and without the addition of bovine serum albumin (BSA) as an in vitro substitute for organic matter contamination. Qac genes were not associated with increased phenotypic biocide tolerance but biocide efficacy was significantly affected by the presence of BSA. In the absence of BSA, all MBC values were well below the recommended usage concentration. When BSA was present, regardless of qac gene presence, 50% of MRSA and 43% of MRSP had an F10SCTM MBC above the recommended concentration for general disinfection. Qac genes did not confer increased in vitro biocide tolerance to veterinary staphylococci. Organic matter contamination must be minimized to ensure the efficacy of biocides against MRSA and MRSP. PMID- 29519511 TI - Characterization of quinolone resistance mechanisms in Enterobacteriaceae isolated from companion animals in Europe (ComPath II study). AB - ComPath is an ongoing European programme dedicated to monitor antibiotic susceptibility of bacterial pathogens from diseased dogs and cats. The objective was to characterize determinants associated with quinolone resistance among 160 enrofloxacin non-wild type strains (100 Escherichia coli, 45 Proteus mirabilis, 14 Klebsiella pneumoniae, 1 Enterobacter cloacae) selected among 843 non duplicate Enterobacteriaceae isolates collected in 12 European countries (2013 2014). These strains with non-wild type MICs of >=0.25 mg/L, for P. mirabilis >=0.5 mg/L, were screened for PMQR determinants (qnr, oqxAB, qepA and aac(6')-Ib cr), and for QRDR mutations in gyrA, gyrB, parC and parE genes. Among them, 20% (32/160) carried at least one PMQR (18/32 qnrB, qnrS or qnrD, 10/32 aac(6')-Ib-cr and 13/32 oqxAB), and 80% (128/160) no PMQR. qnrB was detected in 3 E. coli, 2 K. pneumoniae and 1 E. cloacae strains; qnrS in 6 E. coli and 1 P. mirabilis and aac(6')-Ib-cr in 4 E. coli, 5 K. pneumoniae and 1 E. cloacae strains. All qnrD1 were detected in P. mirabilis. oqxAB was detected in 12/14 K. pneumoniae and 1 E. cloacae. No qepA genes were detected. From the 32 PMQR-positive strains, 10 showed enrofloxacin MICs <=2 mg/L and 22 MICs >=8 mg/L, the latter carrying 1-4 mutations in QRDR. For the 128 non-PMQR strains, 37 showed enrofloxacin MICs <=2 mg/L with 0-2 QRDR mutations, and 91 MICs >=4 mg/L carrying 1-4 QRDR mutations. In conclusion, qnr was the major PMQR and qnrD only detected in Proteeae. Mutations in QRDR play a markedly greater role in mediating fluoroquinolone resistance than PMQR. PMID- 29519512 TI - Antimicrobial susceptibility of enterococci recovered from healthy cattle, pigs and chickens in nine EU countries (EASSA Study) to critically important antibiotics. AB - The European Antimicrobial Susceptibility Surveillance in Animals (EASSA) program collects zoonotic and commensal bacteria from food-producing animals at slaughter and tracks their susceptibility to medically important antibiotics. Results of commensal enterococci species (2013-2014) are presented here. Intestinal content from cattle, pigs and chickens were randomly sampled (5-6 countries/host; >=4 abattoirs/country; 1 sample/animal/farm) for isolation of enterococci, MICs of 9 antibiotics were assessed by CLSI agar dilution in a central laboratory. Clinical breakpoints (CLSI) and epidemiological cut-off values (EUCAST) were applied for data interpretation. In total 960 Enterococcus faecium and 779 Enterococcus faecalis strains were recovered. Seven porcine E. faecium/faecalis strains of Spanish origin were resistant to linezolid. One avian E. faecalis and one porcine E. faecium strain were non-wild type (MICs 8 mg/L) to daptomycin. Clinical vancomycin resistance was absent; 2 poultry E. faecium and 1 bovine E. faecalis strains were non-wild type, all with MICs of 8 mg/L. None of the strains tested were clinically resistant to tigecycline. Little clinical resistance to ampicillin or gentamicin was observed. Clinical resistance of E. faecium to quinupristin/dalfopristin was slightly higher (2.2-12.0%) but 61.9-83.2% of the strains were classified as non-wild type. Very high percentages resistance to tetracycline (67.4-78.3%) and to erythromycin (27.1-57.0%) were noted for both E. faecium and E. faecalis in pigs and chickens compared to cattle (5.2-30.4 and 9.0 10.4%, respectively). Similar non-wild type results were observed for E. hirae (n = 557), E. durans (n = 218) and E. casseliflavus (n = 55) including percentage non-wild type for daptomycin, linezolid, tigecycline being absent and for vancomycin low. For these species percentage non-wild type to erythromycin was lower as compared to E. faecalis/faecium. This pan-EU survey shows high variability in antibiotic susceptibility of commensal enterococci from healthy food animals. Clinical resistance to critically important antibiotics for human medicine was absent or low, except for erythromycin. PMID- 29519513 TI - Efficacy evaluation of two commercial modified-live virus vaccines against a novel recombinant type 2 porcine reproductive and respiratory syndrome virus. AB - NADC30-like porcine reproductive and respiratory syndrome virus (PRRSV) causing clinical disease outbreaks has been recently reported in China. The recombination occurring among PRRSV strains could lead to the emergence of novel and more virulent viruses. In our previous study, a novel recombinant type 2 PRRSV (TJnh1501) between NADC30-like and modified-live virus (MLV)-like derived from the Chinese highly pathogenic PRRSV was shown to have higher pathogenicity than NADC30-like PRRSV. It remains unknown whether the emergence of the novel recombinant PRRSV strain can lead to variable protection efficacy of the MLV vaccines. In this paper, two typical commercial MLV vaccines were used to evaluate their efficacy to block TJnh1501 infection and onset of clinical symptoms. Our results showed that both MLV vaccines could shorten the period of fever and reduce viral loads in sera, but were not able to reduce the clinical signs and lung lesions indicating that the two commercial MLV vaccines provide limited cross-protection efficacy against the novel recombinant type 2 PRRSV infection. This study gives valuable suggestions for the use of MLV vaccines to control PRRSV infection in the field. PMID- 29519514 TI - Prevalence of ESBL/AmpC genes and specific clones among the third-generation cephalosporin-resistant Enterobacteriaceae from canine and feline clinical specimens in Japan. AB - In recent years, besides the widespread occurrence of extended-spectrum beta lactamase (ESBL)- and/or plasmid-mediated AmpC (pAmpC)-producing Enterobacteriaceae in both healthcare and community settings of humans, the third generation cephalosporin (3GC)-resistant microbes have also been reported from companion animals worldwide. Here, we characterized ESBL- and/or pAmpC-producing Enterobacteriaceae clinical isolates from companion animals. Among the 487 clinical isolates mainly from urine of dogs and cats between May and September 2016, 104 non-repetitive isolates were resistant to the 3GC, and they consisted of 81 of 381 (21.3%) Escherichia coli, 21 of 50 (42.0%) Klebsiella pneumoniae, and 2 of 56 (3.6%) Proteus mirabilis isolates. In the 81 E. coli, the predominant bla genes were blaCTX-M-27 and blaCMY-2 (n = 15 each), followed by blaCTX-M-15 (n = 14), blaCTX-M-14 (n = 10), and blaCTX-M-55 (n = 5). In 21 K. pneumoniae, 10 bla gene types including blaCTX-M-15 (n = 4), blaCTX-M-2 (n = 4), and blaCTX-M-14 (n = 3) were found. The blaCTX-M-2 was identified in 2 P. mirabilis. Twenty-four of the 42 E. coli belonging to phylogroup B2 were O25b-ST131 clone, mostly associated with uropathogenic E. coli pathotype, and 22 isolates of this clone were identified as specific H30R subclone. High prevalence of the blaCTX-M-27 harboring isolates were noted among the H30R/non-Rx lineage (13/19, 68.4%) (p < 0.05). The genetic environment of blaCTX-M-27 of most isolates of this lineage was identical to that of human isolates, but unique flanking genetic structures were also identified. Newly emerging virulent lineage B2-non-O25b-ST1193 was also confirmed in 5 isolates. The fosA3 and/or armA genes were detected in E. coli and K. pneumoniae isolates. These data suggest that companion animals serve as a potential reservoir of antimicrobial resistant E. coli and K. pneumoniae. This also has considerable veterinary importance, since urinary tract infections are an important disease causing therapeutic challenges worldwide. PMID- 29519515 TI - Interaction of porcine monocyte-derived dendritic cells with African swine fever viruses of diverse virulence. AB - African swine fever (ASF) is a devastating disease for which there is no vaccine. The ASF virus (ASFV) can infect dendritic cell (DC), but despite the critical role these cells play in induction of adaptive immunity, few studies investigated their response to ASFV infection. We characterized the in vitro interactions of porcine monocyte-derived DCs (moDC) with a virulent (22653/14), a low virulent (NH/P68) and an avirulent (BA71V) ASFV strain. At a high multiplicity of infection (MOI = 1), all three strains infected immature moDC. Maturation of moDC, with IFN-alpha/TNF-alpha, increased susceptibility to infection with 22653/14 and other virulent strains, but reduced susceptibility to NH/P68 and BA71V. The reduced moDC susceptibility to BA71V/NH/P68 was IFN-alpha mediated, whereas increased susceptibility to 22653/14 was induced by TNF-alpha. Using an MOI of 0.01, we observed that BA71V replicated less efficiently in moDC compared to the other isolates and we detected increased replication of NH/P68 compared to 22653/14. We observed that BA71V and NH/P68, but not 22653/14, downregulated expression of MHC class I on infected cells. All three strains decreased CD16 expression on moDC, whereas ASFV infection resulted in CD80/86 down-regulation and MHC class II DR up-regulation on mature moDC. None of the tested strains induced a strong cytokine response to ASFV and only modest IL-1alpha was released after BA71V infection. Overall our results revealed differences between strains and suggest that ASFV has evolved mechanisms to replicate covertly in inflammatory DC, which likely impairs the induction of an effective immune response. PMID- 29519516 TI - Characterization and functional analysis of PnuC that is involved in the oxidative stress tolerance and virulence of Streptococcus suis serotype 2. AB - Streptococcus suis, an important swine pathogen and a major zoonotic agent, is responsible for severe financial losses in the global swine industry. Although a multitude of virulence factors have been reported, the pathogenesis of S. suis infections remains poorly understood. In our previous work, we identified a potential virulence-associated protein, named PnuC, unique to virulent strains of S. suis serotype 2 (S. suis 2). To investigate the functions of PnuC, the pnuC gene deletion mutant (DeltapnuC) was constructed in S. suis 2 strain ZY05719 to assess the phenotypic changes between DeltapnuC and the parental strain. The mutant strain DeltapnuC exhibited highly sensitive to H2O2 stress and reduced the growth ability under vigorous shaking, suggesting that PnuC contributes to the oxidative stress tolerance. Additionally, zebrafish infection model showed that the virulence of pnuC+ strains were significantly higher than pnuC- strains. Mouse infection experiments demonstrated that the abilities of DeltapnuC to colonize the tissues were significantly attenuated compared with the parental strain. Furthermore, the pnuC mutation decreased the virulence of S. suis 2 in both BALB/c mice and zebrafish infection models. Taken together, these results indicated for the first time that PnuC is involved in the oxidative stress tolerance and virulence of S. suis 2 during infection. PMID- 29519517 TI - Longitudinal study of Escherichia coli plasmid resistance to extended-spectrum cephalosporins in free-range broilers. AB - Resistance to extended-spectrum cephalosporins (ESCs) is mostly borne by conjugative plasmids. The aim of the present study was to evaluate the characteristics and diversity of ESC resistance plasmids in Escherichia coli from different free-range broiler flocks in France, and their persistence in flocks during rearing. Two hatcheries were selected. Faecal samples from 11 flocks were collected from before their arrival on the broiler production farm up to their slaughter at the end of the rearing period. A selection of 25 E. coli isolates obtained at different times from different flocks but all harbouring an ESC resistance gene was characterised. The plasmids coding for ESC resistance were sequenced using Mi-seq Illumina technology or the ion proton system (Ion Torrent). Ten IncI1 ST12 plasmids carried the blaCMY-2 gene, and most of them had no other resistance genes. All blaCMY-2 plasmids were obtained from day-old to 7 day-old chicks from four flocks hatched at the same hatchery and sent to three different farms. Sequence comparisons showed identity percentages higher than 99%. Fifteen IncI1 ST3 plasmids were obtained from day-old to 77-day-old broilers from seven flocks on six farms. These plasmids harboured the blaCTX-M-1 gene, and most also had the tet(A) and sul2 genes, with sequence identity higher than 99%. For both types of plasmid, very high identity percentages were also obtained with published sequences of plasmids isolated from broilers in other countries or from other animal species. Thus, unlike the IncI1 ST12 blaCMY-2 plasmids, the epidemic nature of the IncI1 ST3 blaCTX-M-1 plasmids in the French poultry production makes it difficult to determine the origin of a contamination which may persist for weeks in a flock. PMID- 29519518 TI - 23S rRNA and L22 ribosomal protein are involved in the acquisition of macrolide and lincosamide resistance in Mycoplasma capricolum subsp. capricolum. AB - Mycoplasma capricolum subsp. capricolum (Mcc) is one of the causative agents of contagious agalactia, and antimicrobial therapy is the most commonly applied measure to treat outbreaks of this disease. Macrolides and lincosamides bind specifically to nucleotides at domains II and V of the 23S rRNA. Furthermore, rplD and rplV genes encode ribosomal proteins L4 and L22, which are also implicated in the macrolide binding site. The aim of this work was to study the relationship between mutations in these genes and the acquisition of macrolide and lincosamide resistance in Mcc. For this purpose, in vitro selected resistant mutants and field isolates were studied. This study demonstrates the appearance of DNA point mutations at the 23S rRNA encoding genes (A2058G, A2059G and A2062C) and rplV gene (Ala89Asp) in association to high minimum inhibitory concentration values. Hence, it proves the importance of alterations in 23S rRNA domain V and ribosomal protein L22 as molecular mechanisms responsible for the acquisition of macrolide and lincosamide resistance in both field isolates and in vitro selected mutants. Moreover, these mutations enable us to provide an interpretative breakpoint of antimicrobial resistance for Mcc at MIC 0.8 MUg/ml. PMID- 29519519 TI - Factors associated with the bovine viral diarrhoea (BVD) status in cattle herds in Northwest Germany. AB - In Germany, all calves are tested for the presence of bovine viral diarrhoea/mucosal disease virus (BVDV) virus since January 1, 2011. The basis for this compulsory investigation is the BVDV Federal Regulation (BVDVV), which demands testing of calves before the age of six months and according to the new regulation of June 2016 within four weeks or before entering another stock. In 2012, a questionnaire was sent to 7250 Lower Saxony cattle farmers to identify potential factors associated with the presence of BVDV. Completed questionnaires were received from 2542 farms for further analysis. For BVD status determination of these farms, the diagnostic results of 425,911 ear notch samples of calves as part of the BVD eradication period from June 2010 to December 2013 were used. For the analysis of the completed questionnaires, a univariable analysis was performed by the chi-square or Wilcoxon test for each variable studied. In addition, a multivariable logistic model was performed. Four potential risk factors remained after a backward selection in the final logistic regression model: the dairy production compared to the suckling and other types of production, the herd size, the purchase of animals and the location in western region in comparison with the central and eastern regions. In summary, according to the results of this study, the farm with the highest probability of a BVDV infection in Lower Saxony is a large dairy farm that purchases cattle and is located in a cattle-dense region. When the complete eradication of the virus will be achieved, the results of the present study may help to conduct a risk-oriented monitoring programme. PMID- 29519520 TI - Mutual antagonism between Mannheimia haemolytica and Pasteurella multocida when forming a biofilm on bovine bronchial epithelial cells in vitro. AB - Mannheimia haemolytica and Pasteurella multocida are two bacterial species implicated in the bovine respiratory disease complex (BRDC) that is costly to the beef and dairy cattle industries. Both bacterial species are thought to occupy a similar niche as commensals in the upper respiratory tract. Many bacteria are thought to exist as biofilms in their hosts, perhaps in close proximity with other bacterial species. We previously showed that M. haemolytica forms biofilm on bovine respiratory epithelial cells in vitro. We are interested in the possibility that M. haemolytica and P. multocida co-exist as biofilms in the upper respiratory tract of cattle. In this study, we begin to explore this possibility by assessing the ability of M. haemolytica and P. multocida to form a biofilm on bovine respiratory epithelial cells in vitro. We found that M. haemolytica and P. multocida are separately able to form biofilms on bovine respiratory epithelial cells, but mutually inhibit one another when incubated together as a biofilm. Both the biofilm matrix (crystal violet stain) and bacterial numbers (CFU and PCR) were reduced when M. haemolytica and P. multocida were incubated together on fixed epithelial cells. This inhibition does not appear to result from a soluble factor, as neither conditioned medium nor separation of the two species by a transwell filter membrane reproduced the effect. We infer that when located in close proximity on the epithelial surface, M. haemolytica and P. multocida mutually regulate one another. PMID- 29519521 TI - Evaluation of selected phenotypic features among Campylobacter sp. strains of animal origin. AB - A total of 43 Campylobacter isolates from poultry, cattle and pigs were investigated for their ability to form biofilm. The studied strains were also screened for motility, adhesion and invasion of Caco-2 cells as well as extracellular DNase activity. The relation between biofilm formation and selected phenotypes was examined. Biofilm formation by the tested strains was found as irrespective from their motility and not associated with colonization abilities of human Caco-2 cells. Results of our study show that Campylobacter isolates from various animal sources are able to form biofilm and invade human Caco-2 cells in vitro. PMID- 29519522 TI - Pathogenicity and teratogenicity of Schmallenberg virus and Akabane virus in experimentally infected chicken embryos. AB - Schmallenberg virus (SBV) and Akabane virus (AKAV) are teratogenic Simbu serogroup Orthobunyaviruses. Embryonated chicken egg models (ECE) have been used to study the pathogenicity and teratogenicity of Simbu viruses previously, however to date no such studies have been reported for SBV. Hence, the aims of this study were to investigate if ECE are susceptible to experimental SBV infection, and to evaluate the pathogenicity and teratogenicity of SBV and AKAV in ECE models. Two studies were conducted. In Study A, SBV (106.4 TCID50) was inoculated into the yolk-sac of 6-day-old and 8-day-old ECEs. In Study B, SBV and AKAV were inoculated into 7-day-old ECEs at a range of doses (102.0-106.0 TCID50). ECE were incubated at 37 degrees C until day 19, when they were submitted for pathological and virological examination. SBV infection in ECE at 6, 7 and 8 days of incubation resulted in stunted growth and musculoskeletal malformations (arthrogryposis, skeletal muscle atrophy, contracted toes, distorted and twisted legs). Mortality was greater in embryos inoculated with SBV (31%) compared to AKAV (19%), (P < 0.01), suggesting that SBV was more embryo lethal. However, embryos infected with AKAV had a significantly higher prevalence of stunted growth (P < 0.05) and musculoskeletal malformations (P < 0.01), suggesting that AKAV was more teratogenic in this model. These studies demonstrate for the first time that the ECE model is a suitable in vivo small animal model to study SBV. Furthermore, these results are consistent with the clinico-pathological findings of natural SBV and AKAV infection in ruminants. PMID- 29519523 TI - The membrane transporter PotE is required for virulence in avian pathogenic Escherichia coli (APEC). AB - Over the last few years, polyamines have been described as key-signal of virulence in pathogenic bacteria. In the current study, we investigated whether the knockout of genes related to polyamine biosynthesis and putrescine transport affected the virulence of an avian pathogenic E. coli (APEC) strain. One-week-old White Leghorn chickens were infected intratracheally with mutants in polyamine biosynthesis (DeltaspeB/C and DeltaspeD/E) and transport genes (DeltapotE) of a well-characterized APEC strain of ST117 (O83: H4). All polyamine mutants and the wild-type strain were able to infect chicken; however, we observed significantly fewer lesions in the lungs of the chickens infected with the polyamine mutants in comparison with chicken infected with the wild-type. Results derived from histology of infected lungs detected significantly fewer lesions in the lung of birds infected within particular the putrescine transport mutant (DeltapotE). A decrease in colonization levels was observed in the liver and spleen of birds infected with the putrescine biosynthesis mutant DeltaspeB/C, and likewise, a decrease of the colonization levels of all organs from birds infected with the DeltapotE was detected. Together, our data demonstrate that the deletion of polyamine genes, and in particular the PotE membrane protein, attenuates the virulence of APEC during infection of chickens. PMID- 29519524 TI - Identification of Arcanobacterium phocae isolated from fur animals by phenotypic properties, by MALDI-TOF MS analysis and by detection of phocaelysin encoding gene phl as probable novel target. AB - In the present study 12 Arcanobacterium phocae strains isolated from fur animals in Finland, including foxes, minks and Finnraccoons, could successfully be identified phenotypically, by matrix-assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF MS) and genotypically by sequencing 16S rDNA and phocaelysin (PHL) encoding gene phl. The PHL of all 12 A. phocae strains in the present study and reference strains A. phocae DSM 10002T and A. phocae DSM 10003 displayed, as typical members of the cholesterol dependent cytolysin-group of toxins, the variant undecapeptide sequence EATGLAWDPWW which appeared to be most closely related to arcanolysin of Arcanobacterium haemolyticum and pyolysin of Trueperella pyogenes. In addition, gene phl could be determined with a newly designed loop-mediated isothermal amplification (LAMP) assay. The detection of mass spectra by MALDI-TOF MS and the LAMP assay based on gene phl might help to reliably identify A. phocae in future and also elucidate the role this species plays in infections of fur animals. PMID- 29519525 TI - Staphylococcus aureus in two municipal abattoirs in Nigeria: Risk perception, spread and public health implications. AB - Staphylococcus aureus is a zoonotic pathogen of significant public health concern. Information on the prevalence and risk factors facilitating bacterial colonization and spread under abattoir settings in Nigeria are scarce. This cross sectional study was designed to determine prevalence of S. aureus as well as risk factors on knowledge and practices facilitating pathogen carriage among workers and slaughter animals in two municipal abattoirs of Ilorin and Ibadan, Nigeria. Swab samples (n = 1671) from nostrils of cattle, goats, pigs and abattoir workers, and from meat tables and abattoir walls were collected for detection of S. aureus. A questionnaire was administered to 275 workers to elucidate risk factors of pathogen carriage applying a logistic regression model. S. aureus prevalence was 6.5%. In total, MSSA and MRSA were detected at a frequency of 5.4% and 1.1%. Molecular analysis of the isolates revealed 19 different spa types, including a novel spa type (t16751). Gender, marital status, occupation and abattoir location were factors influencing worker's practices in relation to pathogen carriage and spread in the abattoir setting. This present study detected not only low MSSA and MRSA prevalence, in both abattoirs but also low risk perception and hygiene practices employed by abattoir workers. Good practices among workers at Nigerian abattoirs are needed to mitigate S. aureus carriage. Further studies expounding the antibiotic resistance and relationships of MSSA and MRSA strains detected in this study are needed to complement understanding of the spread of S. aureus in the abattoir food chain. PMID- 29519526 TI - Semen as a source of Mycoplasma bovis mastitis in dairy herds. AB - Mycoplasma bovis infections are responsible for substantial economic losses in the cattle industry, have significant welfare effects and increase antibiotic use. The pathogen is often introduced into naive herds through healthy carrier animals. In countries with a low prevalence of M. bovis, transmission from less common sources can be better explored as the pathogen has limited circulation compared to high prevalence populations. In this study, we describe how M. bovis was introduced into two closed and adequately biosecure dairy herds through the use of contaminated semen during artificial insemination (AI), leading to mastitis outbreak in both herds. Epidemiological analysis did not reveal an infection source other than semen. In both farms the primary clinical cases were M. bovis mastitis in cows inseminated with the semen of the same bull four weeks before the onset of the disease. One semen straw derived from the semen tank on the farm and other semen lots of this bull were positive for M. bovis. In contrast, semen samples were negative from other bulls that had been used for insemination in previous or later oestrus to those cows with M. bovis mastitis. Furthermore, cgMLST of M. bovis isolates supported the epidemiological results. To our knowledge this is the first study describing the introduction of M. bovis infection into a naive dairy herd via processed semen. The antibiotics used in semen extenders should be re-evaluated in order to provide farms with M. bovis free semen or tested M. bovis-free semen should be available. PMID- 29519527 TI - First findings of duck circovirus in migrating wild ducks in China. AB - To probe the epidemiology of duck circovirus (DuCV) in migrating wild ducks in China, 189 samples collected from 11 species of wild ducks from 2013 to 2016 were analyzed by PCR. Four positive samples were obtained from Mallard (2), Green winged Teal (1), and Falcated Duck (1), and the positive rate was 2.12%. The homologous alignment of the complete genome shows that the homology of the wild duck strains is 81.6 to 95.1% to each other and 81.4 to 100% to the 32 strains from other origins. Amino acids alignment revealed that the mutable ORF2 gene has six major variable regions and many random mutation points. Phylogenetic analysis showed that the four sequences belong to two genotypes: wd2013017, wd2013046 and AY228555 (representative strain of genotype 1) belong to genotype 1, while wd2014012, wd2015028 and AY394721 (representative strain of genotype 2) belong to genotype 2. The results indicate that both genotypes of DuCV are distributed and common in migrating wild ducks. Further analysis shows that duck circovirus infection is mainly concentrated in the eastern coastal cities of China, which are part of the East Asian-Australian flyway. This suggests that wild ducks with circovirus may be an important factor in the epidemic and spread of DuCV. PMID- 29519528 TI - Emergence of novel canine parvovirus type 2 and its pathogenesis in raccoon dogs. AB - Three parvoviruses were isolated from the raccoon dogs experiencing severe enteritis, named RDPV-DP1, RDPV-DP2 and RDPV-DP3, respectively. The VP2 genes of the 3 isolates showed 99.9% identity at the nucleotide level, and shared 99.1% 99.5% identity with the reference CPVs. The RDPVs resembled original CPV-2, but with four mutations. The RDPVs displayed S297A of VP2 protein as CPV-2a or CPV-2b prevalent throughout most of the world. Residue N375D was found in the 3 isolates, resembling CPV-2a/2b/2c. And the 3 isolates had a natural mutation of VP2 residue V562L, which is adjacent to residue 564 and 568 and might be involved in host range. Interestingly, VP2 S27T was firstly found in the isolates. Phylogenetic analysis of VP2 genes revealed that the RDPVs were clustered into one small evolutionary branch and shared the identical branch with 7 CPV-2 isolates from raccoon dogs and one CPV-2 isolate from fox, not with CPV vaccine viruses. Phylogenetic analysis of NS1 genes demonstrated that the RDPVs shared the identical branch with the reference CPV-2a/2b/2c. Experimental infection showed that RDPV infection caused a high morbidity in raccoon dogs. It implied that the RDPV was virulent to raccoon dogs and continued to evolve in China. PMID- 29519530 TI - Antimicrobial resistance, multilocus sequence types and virulence profiles of ESBL producing and non-ESBL producing uropathogenic Escherichia coli isolated from cats and dogs in Switzerland. AB - Among 64 uropathogenic Escherichia coli (UPEC) isolated from 13 cats and 51 dogs, 35 were extended-spectrum beta-lactamase (ESBL) producers, and 29 were non-ESBL producers. Forty-six (71.9%) of the isolates were multidrug resistant (MDR). Among the ESBL producers, blaCTX-M-15 (n = 17/48.6% of the blaESBLs), blaCTX-M-1 (n = 10/28.6%), blaCTX-M-55 (n = 4/11.4%), blaCTX-M-14 (n = 3/8.6%), and blaCTX-M 27 (n = 1/2.9%) were identified. The plasmid-mediated fluoroquinolone resistance genes aac(6')-Ib-cr, qnrB and the azithromycin resistance gene mph(A) were detected in 17 (26.6% of all isolates), one (1.6%) and in 13 (20.3%) respectively. The most frequent phylogenetic groups were C (n = 19) and B2 (n = 15). Twenty-six different sequence types (STs) were identified, with two being novel. The most frequent STs were ST410 (n = 16/25%), ST131, and ST73 (both n = 5/7.8%), and ST361 (n = 4/6.3%). Ten (15.6%) of the STs have been associated with urinary tract infection (UTI) in humans, suggesting zoonotic potential. Among seven virulence-associated genes, fyuA was the most prevalent. The overall aggregate virulence factor (VF) score was highest for isolates belonging to phylogenetic group B2 (median aggregate VF score 6, mean score 5,5, range 3-7), and lowest for isolates belonging to phylogenetic group C (0/ 0.5/0-3). The most frequent ST in this study, ST410, harboured the lowest number of VF (0/0,3/0-2). VF scores were higher in NDR (4/3.8/3-4) than in MDR (1/1,9/0-7), and higher in non-ESBL producing isolates (3/3/0-7) than in ESBL producers (1/1,7/0-7). Our data advance our knowledge of the phenotypic and genotypic characteristics of UPEC in companion animals and their potential for infection, zoonotic transmission and dissemination of antimicrobial resistance determinants. PMID- 29519529 TI - Effective surveillance for early classical swine fever virus detection will utilize both virus and antibody detection capabilities. AB - Early recognition and rapid elimination of infected animals is key to controlling incursions of classical swine fever virus (CSFV). In this study, the diagnostic characteristics of 10 CSFV assays were evaluated using individual serum (n = 601) and/or oral fluid (n = 1417) samples collected from -14 to 28 days post inoculation (DPI). Serum samples were assayed by virus isolation (VI), 2 commercial antigen-capture enzyme-linked immunosorbent assays (ELISA), virus neutralization (VN), and 3 antibody ELISAs. Both serum and oral fluid samples were tested with 3 commercial real-time reverse transcription-polymerase chain reaction (rRT-PCR) assays. One or more serum samples was positive by VI from DPIs 3 to 21 and by antigen-capture ELISAs from DPIs 6 to 17. VN-positive serum samples were observed at DPIs >= 7 and by antibody ELISAs at DPIs >= 10. CSFV RNA was detected in serum samples from DPIs 2 to 28 and in oral fluid samples from DPIs 4 to 28. Significant differences in assay performance were detected, but most importantly, no single combination of sample and assay was able to dependably identify CSFV-inoculated pigs throughout the 4-week course of the study. The results show that effective surveillance for CSFV, especially low virulence strains, will require the use of PCR-based assays for the detection of early infections (<14 days) and antibody-based assays, thereafter. PMID- 29519531 TI - A highly pathogenic porcine reproductive and respiratory syndrome virus type 1 (PRRSV-1) strongly modulates cellular innate and adaptive immune subsets upon experimental infection. AB - Highly pathogenic (HP) PRRSV isolates have been discovered within both PRRSV-1 and PRRSV-2 genotypes and investigated in recent years especially for their ability to cause extremely severe disease in conventional pig herds. The exacerbation of general and respiratory clinical signs has been attributed not only to an efficient replication (virulence) but also to the ability to dysregulate viral recognition and induce mechanisms of immune evasion or immune enhancement of humoral and cellular anti-viral responses differently from non-HP PRRSV isolates in terms of intensity and temporal onset. Thus, the understanding of the immunopathogenesis of HP PRRSV is a major concern for the study of virus biology and development of efficacious vaccines. The present study aims at addressing the modulation of relevant immune cell subsets by flow cytometry in the blood of 4-week-old pigs experimentally infected with the recently discovered PR40/2014 HP PRRSV-1.1 strain phenotypically characterized in Canelli et al. (2017) compared to pigs infected with a non-HP PRRSV isolate (PR11/2014) and uninfected controls. PR40 infected animals showed an early and marked reduction of pro-inflammatory CD172alpha+ CD14+CD16+ and CD14+CD163+ monocytes and TCRgammadelta+CD8alpha+/CD8alpha- lymphocytes when pigs were most infected, possibly due to a recruitment sustaining an acute inflammatory response in target tissues. The prolonged increased CD3+CD16+ NKT cell levels may sustain peripheral inflammation and/or the anti-viral response. The late reduction (potential depletion) of gamma/delta T lymphocytes and CD3+CD4+CD8alpha- naive Th lymphocytes paralleled with the delayed increase of CD3+CD4+CD8alpha+ memory and CD3+CD4-CD8alpha/beta + cytotoxic T lymphocytes. In addition, PR40 infection showed an early depletion of activated CD4+CD25+ T lymphocytes and Tregs together with an intense and lasting depletion of CD21+ B lymphocytes. Overall, these features demonstrate that the more severe clinical signs observed upon infection with the HP PR40 strain are sustained by remarkable changes in the peripheral blood distribution of immune cells and provide further insights into the immune regulation/immunopathogenesis induced by PRRSV-1 subtype 1 European isolates. PMID- 29519532 TI - High diversity of genes and plasmids encoding resistance to third-generation cephalosporins and quinolones in clinical Escherichia coli from commercial poultry flocks in Italy. AB - The aim was to investigate occurrence and diversity of plasmid-mediated resistance to third-generation cephalosporins (3GC) and quinolones in clinical Escherichia coli from 200 industrial poultry farms across Italy. E. coli was isolated from colibacillosis lesions in turkeys (n = 109), broilers (n = 98) and layers (n = 22) between 2008 and 2012. 3GC-resistant isolates were screened for extended-spectrum and AmpC beta-lactamase (ESBL/AmpC), while all isolates were tested for plasmid-mediated quinolone resistance (PMQR) genes. ESBL/AmpC- and PMQR-positive isolates were typed by pulsed-field gel electrophoresis and antimicrobial susceptibility testing, and their plasmids were characterised by replicon typing, multilocus sequence typing, restriction fragment length polymorphism and conjugation. EBSL/AmpC genes (blaCTX-M-1, blaCTX-M-14, blaCTX-M 2, blaSHV-12 and blaCMY-2) were detected in 7%, 9% and 4% of isolates from turkeys, broilers and layers, respectively. We identified seven ESBL/AmpC encoding plasmid types, usually conjugative (78%), with a marked prevalence of IncI1/pST3 plasmids carrying blaCTX-M-1. PMQR occurred less frequently among isolates from turkeys (0.9%) compared to those from broilers (5%) and layers (4%). The PMQR genes qnrS, qnrB19 and oqxA/B were located on three plasmid types and two non-typeable plasmids, mostly (85%) conjugative. ESBL/AmpC- and PMQR positive isolates were genetically unrelated and 64% of them were additionally resistant to aminoglycosides, sulfonamides and tetracyclines. Our data show that 3GC- and quinolone-resistant clinical E. coli in Italian poultry production represent a highly diverse population often resistant to most antimicrobials available for poultry. These findings underline the crucial need to develop new strategies for prevention and control of colibacillosis. PMID- 29519534 TI - Importance of a making precocious diagnostic and implementing treatment of the ectopic pregnancy in the salpingectomy stump. PMID- 29519533 TI - A novel genotype VII Newcastle disease virus vaccine candidate generated by mutation in the L and F genes confers improved protection in chickens. AB - Administration of vaccines combined with the good management and strict biosecurity is an effective way for Newcastle disease (ND) control. However, vaccine failure is continuously reported in some countries mainly because the antigenic difference between the used vaccine and field strains even they are of one serotype. Therefore, development of antigen-matched ND vaccines is needed to improve the vaccine efficacy in birds. In this study, we introduced four site mutations, K1756A, D1881A, K1917A and E1954Q, respectively, into the large protein gene of the virulent genotype VII Newcastle disease virus (NDV) G7 strain using reverse genetics technology. Four rescued NDVs were sharply attenuated for the pathogenicity in chickens. One of these mutants, E1954Q, was further manipulated by replacing the F cleavage site sequence of typical velogenic strains with that of the LaSota vaccine, resulting in a new mutant, G7M. Biological characterization showed that G7M was safe and genetically stable after serial passages in embryos and chickens. Vaccination of chickens with G7M induced a progressive elevation of the homologous antibodies and markedly higher CD8+ T cell percentage, T cell proliferation and IFN-gamma than LaSota. G7M conferred full protection against genotype VII NDV challenge, and more importantly, it effectively reduced the challenge virus replication and shedding in chickens. Together, our data suggest that G7M is a promising genotype VII vaccine candidate, and the novel attenuation approach designed in this study could be used to develop new antigen-matched NDV vaccines. PMID- 29519535 TI - Macro-grazer herbivory regulates seagrass response to pulse and press nutrient loading. AB - Coastal ecosystems are exposed to multiple stressors. Predicting their outcomes is complicated by variations in their temporal regimes. Here, by means of a 16 month experiment, we investigated tolerance and resistance traits of Posidonia oceanica to herbivore damage under different regimes of nutrient loading. Chronic and pulse nutrient supply were combined with simulated fish herbivory, treated as a pulse stressor. At ambient nutrient levels, P. oceanica could cope with severe herbivory, likely through an increase in photosynthetic activity. Elevated nutrient levels, regardless of the temporal regime, negatively affected plant growth and increased leaf nutritional quality. This ultimately resulted in a reduction of plant biomass that was particularly severe under chronic fertilization. Our results suggest that both chronic and pulse nutrient loadings increase plant palatability to macro-grazers. Strategies for seagrass management should not be exclusively applied in areas exposed to chronic fertilization since even short-term nutrient pulses could alter seagrass meadows. PMID- 29519536 TI - Spatial distribution of juvenile fish along an artificialized seascape, insights from common coastal species in the Northwestern Mediterranean Sea. AB - Along the littoral, a growing number of anthropogenic structures have caused substantial habitat destruction. Despite their detrimental impact, these constructions could play a role in the functioning of coastal ecosystems. The objective of this work was to assess the distribution of juvenile coastal fish along a seascape composed of various natural and artificial habitats in order to determine the potential role of coastal infrastructures as juvenile habitat. We surveyed juvenile populations on various infrastructures and natural sites along a 100 km shoreline of the French Mediterranean coast. Juvenile densities varied according to the level of artificialization of the sites. Densities were the highest on coastal defense structures, intermediate in natural sites and lowest in harbors. Focusing inside harbors revealed highly variable densities depending on the type of habitat, with densities on ripraps or jetties that were equivalent to those of natural sites. Our results underline the importance of anthropogenic structures as potential juvenile habitats, which is too often not considered in management plans. PMID- 29519538 TI - Reply. PMID- 29519537 TI - Positioning document on incorporating point-of-care ultrasound in Internal Medicine departments. AB - This positioning document describes the most important aspects of clinical ultrasonography in the internal medicine setting, from its fundamental indications to the recommended training period. There is no question as to the considerable usefulness of this tool in the standard clinical practice of internists in numerous clinical scenarios and settings (emergencies, hospital ward, general and specific consultations and home care). Ultrasonography has a relevant impact on the practitioner's ability to resolve issues, increasing diagnostic reliability and safety and providing important information on the prognosis and progression. In recent years, ultrasonography has been incorporated as a tool in undergraduate teaching, with excellent results. The use of ultrasonography needs to be widespread. To accomplish this, we must encourage structured training and the acquisition of equipment. This document was developed by the Clinical Ultrasonography Workgroup and endorsed by the Spanish Society of Internal Medicine. PMID- 29519539 TI - Autonomic Dysfunction in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia Impairs Physiological Responses to Routine Care Events. AB - OBJECTIVE: To evaluate whether infants with hypoxic-ischemic encephalopathy and evidence of autonomic dysfunction have aberrant physiological responses to care events that could contribute to evolving brain injury. STUDY DESIGN: Continuous tracings of heart rate (HR), blood pressure (BP), cerebral near infrared spectroscopy, and video electroencephalogram data were recorded from newborn infants with hypoxic-ischemic encephalopathy who were treated with hypothermia. Videos between 16 and 24 hours of age identified 99 distinct care events, including stimulating events (diaper changes, painful procedures), and vagal stimuli (endotracheal tube manipulations, pupil examinations). Pre-event HR variability was used to stratify patients into groups with impaired versus intact autonomic nervous system (ANS) function. Postevent physiological responses were compared between groups with the nearest mean classification approach. RESULTS: Infants with intact ANS had increases in HR/BP after stimulating events, whereas those with impaired ANS showed no change or decreased HR/BP. With vagal stimuli, the HR decreased in infants with intact ANS but changed minimally in those with impaired ANS. A pupil examination in infants with an intact ANS led to a stable or increased BP, whereas the BP decreased in the group with an impaired ANS. Near infrared spectroscopy measures of cerebral blood flow/blood volume increased after diaper changes in infants with an impaired ANS, but were stable or decreased in those with an intact ANS. CONCLUSION: HR variability metrics identified infants with impaired ANS function at risk for maladaptive responses to care events. These data support the potential use of HR variability as a real time, continuous physiological biomarker to guide neuroprotective care in high risk newborns. PMID- 29519541 TI - Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial. AB - OBJECTIVE: To evaluate in a randomized, double-blind, placebo-controlled trial the effect of early caffeine on the age of first successful extubation in preterm infants. STUDY DESIGN: Preterm infants born at 23-30 weeks of gestation requiring mechanical ventilation in the first 5 postnatal days were randomized to receive a 20 mg/kg loading dose followed by 5 mg/kg/day of caffeine or placebo until considered ready for extubation. The placebo group received a blinded loading dose of caffeine before extubation. RESULTS: Infants were randomized to receive caffeine (n = 41) or placebo (n = 42). Age at first successful extubation did not differ between early caffeine (median, 24 days; IQR, 10-41 days) and control groups (median, 20 days; IQR, 9-43 days; P = .7). An interim analysis at 75% enrollment showed a trend toward higher mortality in 1 of the groups and the data safety and monitoring board recommended stopping the trial. Unblinded analysis revealed mortality did not differ significantly between the early caffeine (9 [22%]) and control groups (5 [12%]; P = .22). CONCLUSIONS: Early initiation of caffeine in this group of premature infants did not reduce the age of first successful extubation. A nonsignificant trend toward higher mortality in the early caffeine group led to a cautious decision to stop the trial. These findings suggest caution with early use of caffeine in mechanically ventilated preterm infants until more efficacy and safety data become available. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01751724. PMID- 29519542 TI - Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis. AB - OBJECTIVE: To establish baseline trends in fecal calprotectin, a protein excreted into the stool when there is neutrophilic inflammation in the bowel, in infants at risk for necrotizing enterocolitis (NEC). STUDY DESIGN: We performed a prospective observational cohort study in infants with a birth weight of <1500 g without existing bowel disease at a level IV neonatal intensive care unit from October 2015 to September 2016. Stools were collected once daily for 30 days or until 32 weeks postmenstrual age and processed using the Fecal Calprotectin High Range Quantitative Quantum Blue assay. RESULTS: In 64 preterm infants, during the first week after birth, 62% of infants had an initial stool sample with high baseline calprotectin levels (>=200 ug/g). In assessment of maternal and neonatal risk factors, maternal etiology for preterm birth (ie, eclamplsia or preeclampsia) was the only significant factor associated with high baseline calprotectin level. Two patients in the cohort developed NEC. Calprotectin levels for the entire cohort fluctuated during the observed period but generally increased in the third and fourth weeks after birth. CONCLUSIONS: At-risk infants had highly variable fecal calprotectin levels, with maternal causes for preterm birth associated with higher baseline levels. More longitudinal data in infants with NEC are necessary to determine whether acute rises in fecal calprotectin levels prior to clinical diagnosis can be confirmed as a diagnostic or prognostic biomarker. PMID- 29519543 TI - Defining the Severity and Duration of Health Status Decrements Due to Restenosis. PMID- 29519544 TI - Comparison of the Effect of Dual-Axis Rotational Coronary Angiography Versus Conventional Coronary Angiography on Frequency of Acute Kidney Injury, X-Ray Exposure Time, and Quantity of Contrast Medium Injected. AB - Dual-axis rotational coronary angiography (DARCA) has already been shown to reduce both the amount of contrast medium and radiation exposure compared with conventional coronary angiography (CCA). However, a clinical benefit of such imaging modality has never been demonstrated. The aim of this study was to evaluate the efficacy of DARCA to prevent acute kidney injury (AKI) compared with CCA. Consecutive patients who underwent coronary angiography were enrolled to DARCA (n = 80) or CCA (n = 80). Patients presenting with ST-segment elevation myocardial infarction or previously underwent coronary artery bypass graft were excluded. The 2 groups were homogeneous in terms of both clinical and procedural characteristics. Total x-ray time and total amount of contrast medium were significantly lower in the DARCA group compared with the CCA group (x-ray time 3.2 minutes [1.8 to 7.0] vs 5.1 minutes [2.6 to 9.9], p = 0.002; contrast medium amount 40 ml [31 to 116] vs 80 ml [50 to 150], p <0.001). AKI more often occurred in the CCA group compared with the DARCA group (16 [20%] vs 4 [5%], p = 0.007). Moreover, in patients presenting with acute coronary syndrome (ACS) or who underwent percutaneous coronary intervention (PCI), AKI more often occurred in the CCA group compared with the DARCA group (ACS patients, 6 [29%] vs 2 [6%], p = 0.04, and PCI patients, 11 [33%] vs 0 [0%], p <0.001). In addition, in patients with high pretest probability of coronary artery disease, AKI more often occurred in the CCA group compared with the DARCA group (11 [55%] vs 2 [6%], p <0.001). In conclusion, DARCA significantly reduces both x-ray exposure and amount of contrast medium usage, thereby reducing the occurrence of AKI compared with CCA. PMID- 29519540 TI - Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study. AB - OBJECTIVES: To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment. STUDY DESIGN: Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 +/- 15) were categorized as >=100, 85-99, and <85 for chi2 analysis. Risk for neurodevelopmental impairment (defined as >=1 score of <85 on the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition, scales) was analyzed using logistic regression. RESULTS: There were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P < .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P < .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age. CONCLUSION: Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are >4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00061828 and NCT00294684. PMID- 29519545 TI - Structural, rheological and dynamics insights of hydroxypropyl guar gel-like systems. AB - A dynamic, rheological, and structural characterization of aqueous gel-like systems containing hydroxypropyl guar gum (HPG), borax and glycerol is presented in this paper. The role of glycerol, which is introduced as a plasticizer in the formulation, is investigated by means of 11B NMR and 1H NMR PGSTE measurements in order to clarify its contribution to the gel network formation and its interaction with borax, with whom it forms a complex. The effect of gels components on the rheological behaviour and on the activation energy related to the relaxation process of the system was assessed by means of rheology. The results obtained suggest that the mechanical properties of these gels can be tuned and controlled by modulating the formulation in a wide range of compositions. Moreover, a structural characterisation has been also carried out by means of Small Angle X-ray Scattering (SAXS) to highlight the role of the various components on the mesh size of the network. The structural and mechanical characteristics of these systems suggest their potential use for applicative purposes. In this regard, one of the gel set up has been successfully tested as cleaning agent on the surface of a XIX stucco fragment coming from the La Fenice theatre (Venice, Italy) for the removal of a dirt layer composed by dust and particulated matter originated during a fire in 1996. PMID- 29519546 TI - Incidence of hospital-acquired hyponatremia by the dose and type of diuretics among patients with acute heart failure and its association with long-term outcomes. AB - BACKGROUND: Diuretics are the cornerstone therapy for acute heart failure (AHF) but can lead to various electrolyte disturbances and inversely affect the patients' outcome. We aimed to evaluate whether (1) the dose of loop diuretics could predict hospital-acquired hyponatremia (HAH) during AHF treatment, (2) addition of thiazide diuretics could affect development of HAH, and (3) assess their impact on long-term outcomes. METHODS: We analyzed the subjects enrolled in the multicenter AHF registry (WET-HF). Risk of HAH, defined as hyponatremia at discharge with normonatremia upon admission, was evaluated based on oral non potassium-sparing diuretics via multivariate logistic regression analysis. Additionally, we performed one-to-one matched analysis based on propensity scores for thiazide diuretics use and compared long-term mortality. RESULTS: Of total 1163 patients (mean age 72.6+/-13.6 years, male 62.6%), 92 (7.9%) had HAH. Compared with low-dose loop diuretics users (<40mg; without thiazide diuretics), risks for developing HAH were significantly higher in patients with thiazide diuretics, regardless of the dose of loop diuretics (OR 2.67, 95% CI 1.13-6.34 and OR 2.31, 95% CI 1.50-5.13 for low- and high-dose loop diuretics, respectively). The association was less apparent in patients without thiazide diuretics (OR 1.29, 95% CI 0.73-2.27 for high-dose loop diuretics alone). Among 206 matched patients, all-cause and cardiac mortality rate was 27% and 14% in non thiazide diuretics users and 50% and 30% in thiazide diuretics users, respectively (HR 2.46, 95% CI 1.29-4.69, p=0.006 and HR 2.50, 95% CI 1.10-5.67, p=0.028, respectively) during a mean 19.3 months of follow-up. CONCLUSIONS: Thiazide diuretics use, rather than loop diuretics dose, was independently associated with HAH; and mortality was higher in thiazide diuretics users even after statistical matching. PMID- 29519547 TI - Non-vitamin K antagonist oral anticoagulants have better efficacy and equivalent safety compared to warfarin in elderly patients with atrial fibrillation: A systematic review and meta-analysis. AB - BACKGROUND: To evaluate the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in elderly patients (aged >=75 years) with atrial fibrillation (AF), depending on dose and/or renal function. METHODS: After systematically searching the databases (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), 5 phase III randomized controlled trials and reported data according to subgroups of elderly/non-elderly AF patients, comparing any NOACs and warfarin were included. The primary efficacy and safety outcomes were stroke/systemic thromboembolism and major bleeding. RESULTS: (1) NOACs showed better efficacy than warfarin in elderly patients [RR 0.83 (0.69-1.00), p=0.04, I2=55%], but equivalent efficacy in non-elderly patients. (2) NOACs reduced major bleeding compared to warfarin in non-elderly (p<0.001) and had comparable safety to warfarin in elderly patients. (3) Even in elderly patients with moderately impaired renal function, NOACs had a safety profile comparable to that of warfarin for major bleeding if dose reduction was reached appropriately [pooled RR 0.82 (0.35-1.88), p=0.63, I2=63%]. (4) All-cause mortality was lower with NOACs in non-elderly patients [RR 0.89 (0.83-0.95), p=0.001, I2=0%], and with standard-dose NOAC group of elderly patients [RR 0.93 (0.86-1.00), p=0.04, I2=0%] compared to warfarin. CONCLUSIONS: For elderly patients (aged >=75 years), NOACs showed better efficacy and equivalent safety compared to warfarin even in those with moderately impaired renal function. All-cause mortality was lower with standard-dose NOACs compared to warfarin in the elderly patient group. SYSTEMATIC REVIEW REGISTRATION: The protocol of this meta-analysis was registered on PROSPERO under CRD42016047922 (https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016047922). PMID- 29519549 TI - Role of bile acids in the gut-liver axis. PMID- 29519548 TI - Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men. AB - BACKGROUND: Prostate-specific antigen (PSA) screening reduces prostate cancer deaths but leads to harm from overdiagnosis and overtreatment. OBJECTIVE: To determine the long-term risk of prostate cancer mortality using kallikrein blood markers measured at baseline in a large population of healthy men to identify men with low risk for prostate cancer death. DESIGN, SETTING, PARTICIPANTS: Study based on the Malmo Diet and Cancer cohort enrolling 11 506 unscreened men aged 45 73 yr during 1991-1996, providing cryopreserved blood at enrollment and followed without PSA screening to December 31, 2014. We measured four kallikrein markers in the blood of 1223 prostate cancer cases and 3028 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate cancer death (n=317) by PSA and a prespecified statistical model based on the levels of four kallikrein markers. RESULTS AND LIMITATIONS: Baseline PSA predicted prostate cancer death with a concordance index of 0.86. In men with elevated PSA (>=2.0ng/ml), predictive accuracy was enhanced by the four-kallikrein panel compared with PSA (0.80 vs 0.73; improvement 0.07; 95% confidence interval 0.04, 0.10). Nearly half of men aged 60+ yr with elevated PSA had a four-kallikrein panel score of <7.5%, translating into 1.7% risk of prostate cancer death at 15 yr-a similar estimate to that of a man with a PSA of 1.6ng/ml. Men with a four-kallikrein panel score of >=7.5% had a 13% risk of prostate cancer death at 15 yr. CONCLUSIONS: A prespecified statistical model based on four kallikrein markers (commercially available as the 4Kscore) reclassified many men with modestly elevated PSA, to have a low long-term risk of prostate cancer death. Men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy. PATIENT SUMMARY: Men with elevated prostate-specific antigen (PSA) are often referred for prostate biopsy. However, men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy. PMID- 29519550 TI - [45th Congress of the French society of neuroradiology]. PMID- 29519551 TI - Developing and validating a center-specific preoperative prediction calculator for risk of pancreaticoduodenectomy. AB - BACKGROUND: The American College of Surgeons (ACS) Surgical Risk Calculator predicts postoperative risk based on preoperative variables. The ACS model was compared to an institution-specific risk calculator for pancreaticoduodenectomy (PD). METHODS: Observed outcomes were compared with those predicted by the ACS and institutional models. Receiver operating characteristic (ROC) analysis evaluated the models' predictive ability. Institutional models were evaluated with retrospective and prospective internal validation. RESULTS: Brier scores indicate equivalent aggregate predictive ability. ROC values for the institutional model (ROC: 0.675-0.881, P < 0.01) indicate superior individual event occurrence prediction (ACS ROC: 0.404-0.749, P < 0.01-0.860). Institutional models' accuracy was upheld in retrospective (ROC: 0.765-0.912) and prospective (ROC: 0.882-0.974) internal validation. CONCLUSIONS: Identifying higher-risk patients allows for individualized care. While ACS and institutional models accurately predict average complication occurrence, the institutional models are superior at predicting individualized outcomes. Predictive metrics specific to PD center volume may more accurately predict outcomes. PMID- 29519552 TI - Discussion of "Risk management decisions in women with BRCA1 and BRCA2 mutations". PMID- 29519553 TI - Voices carry: Effects of verbal and physical aggression on injuries and accident reporting. AB - Recent years have witnessed a staggeringly high number of workplace aggressive behaviors as well as employee accidents and injuries. Exposure to workplace aggression is associated with a host of negative psychological, emotional, and physiological outcomes, yet research relating workplace aggression to employee safety outcomes is lacking. This study aims to examine the association between exposure to workplace physical and verbal aggression with workplace injuries and underreporting of accidents and near misses. Furthermore, deriving from social exchange theory, we attempt to reveal an underlying mechanism in the association between workplace aggression and underreporting of accidents and near misses. Finally, borrowing from aggression research on intimate relationships, we compare the relative importance of exposure to physical and verbal aggression on workplace injuries and underreporting. Using survey data from 364 public transportation personnel, we found that both verbal and physical aggression significantly predict workplace injuries as well as underreporting. Moreover, mediation analyses found that the relationship between verbal and physical aggression and underreporting was largely explained by an increase in negative reporting attitudes (rather than decreases in safety knowledge or motivation). Compared to exposure to physical aggression, exposure to verbal aggression best predicted employee underreporting of accidents and near misses. However, physical aggression was a better predictor of injuries than verbal aggression. Given these findings, organizational leaders should strive to foster a safe working environment by minimizing interpersonal mistreatment and increasing employee attitudes for reporting accidents. PMID- 29519554 TI - Analysing longitudinal data. PMID- 29519555 TI - Experience with NexoBrid(r) in enzymatic debridement of facial burns. PMID- 29519556 TI - Methylprednisolone and greater proteinuria predispose older adults with glomerulonephritis to new onset diabetes mellitus. PMID- 29519557 TI - Acute pancreatitis conditioned mesenteric lymph causes cardiac dysfunction in rats independent of hypotension. AB - BACKGROUND: Critical illness including severe acute pancreatitis is associated with the multiple organ dysfunction syndrome. The "gut-lymph" hypothesis states that multiple organ dysfunction syndrome is due to release of toxic factors from the intestine into the mesenteric lymph. The aims of this study were to determine the effect of normotensive acute pancreatitis conditioned mesenteric lymph on cardiac function and whether external drainage of mesenteric lymph would protect the heart. METHODS: Groups of normal rats and those with normotensive taurocholate induced acute pancreatitis, had either no lymphatic intervention or thoracic duct ligation and external drainage of mesenteric lymph. After 6 hours, the hearts were removed for ex vivo functional measurements, including cardiac output, ventricular contractility (+dP/dt), and relaxation (-dP/dt). In a second experiment, mesenteric lymph from normal rats and those with established acute pancreatitis was infused into ex vivo perfused normal working rat hearts to assess impact on cardiac function. Heart and lung tissues were collected for assessment of edema. RESULTS: Significant cardiac dysfunction, denoted by decreased cardiac output (21%), contractility (37%), relaxability (23%), and increased cardiac tissue edema (2-fold), developed in rats with established acute pancreatitis and no lymphatic intervention compared with the control group (all P < .05). Strikingly this cardiac dysfunction and edema was normalized in acute pancreatitis rats that had undergone prior thoracic duct ligation and external drainage of mesenteric lymph. In the second experiment, infusion of acute pancreatitis conditioned mesenteric lymph resulted in an immediate and significant similar magnitude decrease in of cardiac output (17%), contractility (22%), and relaxation (27%) compared with the infusion of normal lymph (all P <.05). CONCLUSION: Mesenteric lymph from normotensive acute pancreatitis animals caused significant cardiac dysfunction which could be prevented by thoracic duct ligation and external drainage of mesenteric lymph. PMID- 29519558 TI - Preoperative prediction of a pathologic complete response of esophageal squamous cell carcinoma to neoadjuvant chemoradiotherapy. AB - BACKGROUND: The accurate prediction of a pathologic complete response (ypT0N0M [LYM] 0 ypStage 0) before operation is essential for selecting appropriate strategies for treating esophageal cancer after neoadjuvant chemoradiotherapy. METHODS: We reviewed 130 consecutive patients with esophageal squamous cell carcinoma who were evaluated preoperatively using upper gastrointestinal endoscopy, computed tomography, and 18F-fluorodeoxyglucose-positron emission tomography after neoadjuvant chemoradiotherapy and subsequently underwent esophagectomy. Our aim was to determine the diagnostic abilities of computed tomography, 18F-fluorodeoxyglucose-positron emission tomography, and endoscopy to predict preoperatively a pathologic complete response of the primary site of the locally advanced esophageal squamous cell carcinoma and associated lymph nodes to trimodal neoadjuvant chemoradiotherapy. Associations between clinical complete response (ycT0N0M [LYM] 0 ycStage 0) and pathologic complete response were investigated preoperatively. RESULTS: Twenty-nine (22.3%) and 43 (33.1%) patients, respectively, achieved clinical complete response and pathologic complete response, which were associated (P=.001). The sensitivity and specificity, as well as the positive and negative predictive values of clinical complete response to define pathologic complete response were 39.5%, 86.2%, 58.6%, and 74.3%, respectively. Univariate and multivariate analyses selected clinical complete response as the sole independent preoperative predictor of pathologic complete response (clinical complete responses versus non-clinical complete responses: odds ratio: 0.26, 95% confidence interval, 0.10-0.65, P=.004). Recurrence-free and overall survival (OS) rates were better in patients with than in those without clinical complete response (5-year recurrence-free and overall survival: 69.0% vs 41.4% and 75.9% vs 45.0%, respectively, both P=.02). Furthermore, clinical complete response was an independent preoperative predictor of recurrence-free survival (clinical complete response versus nonclinical complete response: hazard ratio: 2.20, 95% confidence interval, 1.08-4.45, P=.03). CONCLUSION: Although pathologic complete response was predictable preoperatively to some extent, the accuracy was somewhat low. Considerable caution should be exercised when selecting the watch-and-wait approach with operation as needed and omitting planned operative intervention even for patients who achieve clinical complete response after neoadjuvant chemoradiotherapy. PMID- 29519559 TI - Eat healthy? Attitudes of the German population towards industrially produced cardioprotective food. AB - BACKGROUND AND AIM: Cardiovascular disease (CVD) is likely to increase in incidence. Foods with cardioprotective functions, e.g. specific functional food, could reduce CVD risk factors and hence CVD incidence. Little is known about industrially modified foods with cardioprotective functions. METHODS AND RESULTS: In a large German sample (n = 1007), attitudes of consumers in Germany towards industrially produced cardioprotective food were assessed using Cluster analyses. Consumers were contacted via telephone and interviewed using questionnaires. Overall, about 25% knew about industrially produced food with cardioprotective function. Our analysis revealed a small but determined group of consumers who think very skeptical about cardioprotective products, but we also identified a favorable group. These two groups only differed in age, with the skeptical group being ten years older. CONCLUSIONS: The rising number of industrially modified products with potential cardioprotective benefit is met by skepticism and a lack of knowledge by German costumers. If large scale studies show health benefits of these products, these will need to be better communicated to German customers in order to address possible doubts or concerns and to encourage healthy eating habits in consumer eating behavior. PMID- 29519560 TI - Mortality from infectious diseases in diabetes. AB - BACKGROUND AND AIMS: To investigate the risk of mortality from infections by comparing the underlying causes of death versus the multiple causes of death in known diabetic subjects living in the Veneto region of Northern Italy. METHODS AND RESULTS: A total of 185,341 subjects with diabetes aged 30-89 years were identified in the year 2010, and causes of death were assessed from 2010 to 2015. Standardized Mortality Ratios (SMRs) with 95% confidence intervals (CIs) were computed with regional mortality rates as reference. The underlying causes of death and all the diseases reported in the death certificates were scrutinized. At the end of the follow-up, 36,382 subjects had deceased. We observed an increased risk of death from infection-related causes in subjects with diabetes with a SMR of 1.83 (95% CI, 1.71-1.94). The SMR for death from septicemia was 1.91 (95% CI, 1.76-2.06) and from pneumonia was 1.47 (95% CI, 1.36-1.59). The use of the multiple causes of death approach emphasized the association of infectious diseases with mortality. CONCLUSION: The results of the present study demonstrate an excess mortality due to infection-related diseases in patients with diabetes; more interestingly, by routine mortality analyses, the results show a possible underestimation of the effect of these diseases on mortality. PMID- 29519561 TI - The role of neural precursor cell-expressed developmentally down-regulated protein 9 in predicting bacillus Calmette-Guerin response in nonmuscle invasive bladder cancer. AB - OBJECTIVE: To report the sensitivity and specificity of neural precursor cell expressed developmentally down-regulated protein 9 (NEDD9) protein high expression in predicting BCG response and its effect on recurrence or progression free survivals. PATIENTS AND METHODS: Between May 2014 and April 2017, a prospective cohort study was conducted on 105 patients with intermediate or high risk nonmuscle invasive bladder cancer. Immunohistochemical staining with mouse monoclonal anti-NEDD9 antibody was done. Examination of the slides was done to detect NEDD9 cytoplasmic expression. Intravesical induction bacillus Calmette Guerin (BCG) instillation therapy was started for all patients 2 to 4 weeks after endoscopy with once weekly instillation for 6 weeks. Intravesical maintenance BCG instillation was then continued every 3 months for at least 1 year. Follow up with cystoscopy every 3 months for 2 years and every 6 months after that. RESULTS: The mean age +/- SD of the patients was 57 +/- 4.5 years. The median follow-up period was 25 (12-36) months. NEDD9 protein was highly expressed in 61 (58.1%) patients, whereas low expression was in 44 (41.9%) patients. Sensitivity and specificity of NEDD9 high expression in predicting recurrence were 83.6% and 64.2%, respectively. Its sensitivity and specificity in predicting progression to muscle invasion or distant metastases were 91.3% and 51.2%, respectively. Its sensitivity and specificity in predicting complete response to BCG therapy were 84.1% and 80.9%. Kaplan-Meier test showed highly significant difference (P<0.0001) in survival without recurrence or progression between patients showing high expression and those showing low expression. CONCLUSION: NEDD9 protein tissue marker could be used as a predictive marker for BCG response in nonmuscle invasive bladder cancer with reasonable sensitivity and specificity. PMID- 29519562 TI - Early diagnosis of septic arthritis in immunocompromised patients. AB - OBJECTIVES: Septic arthritis results in rapid joint destruction if not properly diagnosed and treated. A work up for septic arthritis includes a peripheral white blood cell count, inflammatory markers, and a joint aspiration. In the general population, the interpretation of these labs has been well-defined by prior studies. To this point, no study has determined how immunosuppressive states affect this work up. METHODS: Patients with immunosuppressive conditions who received a joint aspiration for a painful joint were retrospectively identified. Laboratory results from their work up were gathered and analyzed. RESULTS: 216 patients were included in the study, 21 of whom were diagnosed with septic arthritis. The average aspiration WBC count was 74,190 with 88% PMNs. 81% had a positive gram stain. DISCUSSION: Laboratory values for immunosuppressed patients with septic arthritis were similar to those associated with septic arthritis in historical general population controls. PMID- 29519563 TI - Partial segmental thrombosis of the corpus cavernosum: imaging findings. AB - Partial segmental thrombosis of the corpus cavernosum is an unusual clinical condition of unknown origin that mainly affects young males, whose characteristic presentation is the appearance of unexplained perineal pain associated with a palpable perineal mass. This entity consists of thrombosis in the perineal portion of the corpus cavernosum, usually unilateral and it is associated with underlying malignant pathologies and predisposing factors such as microtrauma. After the adequate adherence to conservative treatment, the appearance of complications such as erectile dysfunction is very uncommon. PMID- 29519564 TI - Reply, Letter to the Editor - Clinical nutrition education in medical schools - Comment on the ESPEN survey. PMID- 29519565 TI - Genomic Analysis Reveals Distinct Subtypes in Two Rare Cases of Primary Ovarian Lymphoma. AB - Primary (localized) non-Hodgkin lymphoma (NHL) of the ovary is extremely rare; only a few cases have been reported in the literature. We report two cases of primary ovarian lymphoma (POL), one involving bilateral ovaries in a 15-year-old girl and other involving one ovary in a 5-year-old girl. This report describes detailed clinical, histopathological, and imaging findings, along with the review of literature of primary diffuse large B-cell lymphoma (DLBCL) arising from an ovary. In addition, we describe findings of targeted capture panel sequencing on both tumors and identify the major genetic mutations that are recurrently mutated in pan-cancers. Compared to the genomic mutation features of major subtypes of DLBCL, we distinguish that each POL belongs to distinctive subtypes, GCB (germinal center B-cell subtype) DLBCL and ABC (activated B-cell subtype) DLBCL, respectively. The findings from the genomic analysis may help to understand the pathogenesis of POL and to guide potential targeted therapy in the future. PMID- 29519566 TI - Evaluating the "cushion effect" among children in frontal motor vehicle crashes. AB - BACKGROUND: The "Cushion Effect," the phenomenon in which obesity protects against abdominal injury in adults in motor vehicle accidents, has not been evaluated among pediatric patients. This work evaluates the association between subcutaneous fat cross-sectional area, quantified using analytic morphomic techniques and abdominal injury. METHODS: This retrospective study includes 119 patients aged 1 to 18years involved in frontal impact motor vehicle accidents (2003-2015) with computed tomography scans. Subcutaneous fat cross-sectional area was measured and converted to age- and gender-adjusted percentiles from population-based normative data. Multivariable analysis determined the risk of the primary outcome, Maximum Abbreviated Injury Scale (MAIS) 2+ abdominal injury, after adjusting for age, weight, seatbelt status, and impact rating. RESULTS: MAIS 2+ abdominal injuries occurred in 20 (16.8%) of the patients. Subcutaneous fat area percentile was not significantly associated with MAIS 2+ abdominal injury on multivariable logistic regression (adjusted Odds Ratio, 0.86; 95% CI, 0.72-1.03; p=0.10). DISCUSSION: The "cushion effect" was not apparent among pediatric frontal motor vehicle crash victims in this study. Future work is needed to investigate other analytic morphomic measures. By understanding how body composition relates to injury patterns, there is a unique opportunity to improve vehicle safety design. LEVEL OF EVIDENCE: Prognosis Study, Level III. PMID- 29519567 TI - Prehospital education in triage for pediatric and pregnant patients in a regional trauma system without collocated pediatric and adult trauma centers. AB - PURPOSE: Patient triage to the appropriate destination is critical to prehospital trauma care. Triage decisions are challenging in a region without collocated pediatric and adult trauma centers. METHODS: A regional survey was administered to emergency medical response units identifying variability and confusion regarding factors influencing patient disposition. A course was developed to guide the triage of pediatric and pregnant trauma patients. Pre- and posttests were administered to address course principles, including decision making and triage. RESULTS: A total of 445 participants completed the course at 22 sites representing 88 different prehospital provider agencies. Pre- and posttests were administered to 62% of participants with an average score improvement of 53.4% (pretest range 30% to 56.6%; posttest range 85% to 100%). Improvements were seen in all categories including major and minor trauma in pregnancy, major trauma in adolescence, and knowledge of age limits and triage protocols. CONCLUSION: Education on triage guidelines and principles of pediatric resuscitation is essential for appropriate prehospital trauma management. Pre- and posttests may be used to demonstrate short term efficacy, while ongoing evaluations of practice patterns and follow-up surveys are needed to demonstrate longevity of acquired knowledge and identify areas of persistent confusion. LEVEL OF EVIDENCE: Level IV, Case Series without Standardized. PMID- 29519568 TI - Dressed for success? Silver impregnated nanocrystalline dressing for initial treatment of giant omphalocele. AB - OBJECTIVE: The purpose of this study was to describe outcomes and resource utilization in patients treated with twice-weekly silver impregnated (SI) nanocrystalline dressings for initial non-operative management of giant omphalocele (GO). METHODS: A retrospective review of patients with GO treated with SI dressings was undertaken. Clinical parameters, cost, and complications were recorded. RESULTS: Five patients with GO were treated with SI dressings between 2014 and 2016. Clinical characteristic (mean +/- SD) included gestational age 36 +/- 4 weeks, birth weight 2.6 +/- 0.63 kg, GO size 10.2 +/- 4.7 cm, ventilator days 7.5 +/- 8.7 d, days in NICU 41 +/- 20 d, days to full feeds, 30 +/- 15 d, and LOS 62 +/- 41 d. The average in-hospital cost of SI dressings was $110 CAD/week. This is comparable to daily silver sulfadiazine dressings ($109CAD/week) which were used historically. All patients were discharged with once- or twice-weekly dressing changes. No ruptures occurred. There was one mortality secondary to pulmonary sepsis. CONCLUSIONS: For initial non-operative management of GO, twice weekly SI nanocrystalline dressings is safe and effective. Use of SI dressings results in decreased handling of infants, reduced physician and nursing resource utilization, and favourable outcomes. LEVEL OF EVIDENCE: IV (Retrospective Case Series). PMID- 29519569 TI - Does size matter? Correlation of ultrasound findings in children without clinical evidence of acute appendicitis. AB - PURPOSE: The purpose of this study was to determine whether children with a positive ultrasound (US) for acute appendicitis but a negative clinical picture developed appendicitis requiring definitive management. METHODS: After obtaining IRB approval, we conducted a retrospective review of patients <=17years who presented with possible acute appendicitis between April 1st, 2014, and December 31st, 2015. We included patients with a US suggestive of acute appendicitis based on size criteria but without concerning clinical features. Patients were discharged from the emergency department (ED) or admitted for observation. Variables included demographic data, US characteristics, clinical findings, length of follow-up, and appendectomy. RESULTS: Of the 31 patients identified, 45% were male and average age was 11.3yrs. On US, the average maximal diameter of the appendix was 6.93mm. The median length of follow-up was 16.8 months, including 10 returns to the ED by 9 patients. Three of these underwent immediate laparoscopic appendectomy, while one had interval appendectomy. There were no cases of perforated appendicitis, and only 2 cases demonstrated pathology consistent with appendicitis. CONCLUSION: These findings demonstrate that it is safe to consider conservative measures such as observation or discharge in children with a positive US for appendicitis based on size criteria but a negative clinical picture. LEVEL OF EVIDENCE: 4. PMID- 29519570 TI - Intrathyroidal thymic tissue in children: Avoiding unnecessary surgery. AB - BACKGROUND/PURPOSE: Intrathyroidal thymic tissue may be misinterpreted as a thyroid lesion in children, leading to invasive tests or resection. We sought to describe the characteristic imaging features of these lesions and to evaluate the safety of non-operative management. METHODS: A retrospective review of all patients less than 18years old with intrathyroidal thymic tissue from 2000 to 2016 was performed. Data collection included patient demographics, imaging results, interventions, and outcomes. RESULTS: Eleven patients were identified using institutional radiology and pathology databases. Median patient age and lesion size at presentation were 5years old (range 2 to 8years old) and 0.9cm (range 0.4 to 9.2cm), respectively. Six lesions were incidentally identified, six were left-sided, and the most common location was the lower pole. Ultrasonographic features were reproducible and included well demarcated (10/11), hypoechoic lesions (11/11), containing punctate/linear internal echoes (11/11), and occasional mild hypervascularity (6/11). All cases demonstrated interval size and echotexture stability over a median surveillance period of 3years (range 1 to 8years). While 9 patients were simply observed, the first patient in this series underwent excision, while another had a fine needle aspiration to confirm pathology. LEVEL OF EVIDENCE: Study of diagnostic test, Level IV. CONCLUSION: Intrathyroidal thymic tissue has typical clinical and sonographic characteristics which allow for appropriate diagnosis and avoids thyroid resection. PMID- 29519571 TI - Sclerotherapy for intramuscular vascular malformations: A single-center experience. AB - BACKGROUND: Vascular malformations isolated to skeletal muscles are rare and often debilitating due to pain and very challenging to treat. Multi-modal management options include compression garments, medical therapy, sclerotherapy, and surgical resection. METHODS: A retrospective review of patients who underwent sclerotherapy for intramuscular venous malformations (IVM) between 2008 and 2016 was performed. Demographics, indications, and clinical follow-up were analyzed. RESULTS: Twenty patients underwent sclerotherapy for IVM. Six males and 14 females underwent 58 procedures. All patients presented with pain and were treated initially with compression garments. Median age at first treatment was 13years (+/- 5.06years). Initial protocol consisted of 2 sclerotherapy procedures with sodium tetradecyl sulfate (STS) within a 2-3month interval. Median volume of the lesion was 40cm3 (+/- 28.7), mostly located in the lower extremities (15/20). Median number of treatments was 2 (+/- 1.95). Treatment prior to puberty resulted in a median symptom-free time of 4years (+/- 2.18), while after puberty resulted in a symptom-free time of 2years (+/- 2.28). Two patients had an underlying coagulopathy and were admitted for observation and peri-procedural Lovenox. No procedure related complications were noted with a median follow-up of 4years (+/- 2.27). CONCLUSION: IVMs are rare but can be incapacitating secondary to pain. Sclerotherapy is a useful minimally invasive procedure generally requiring at least two consecutive treatments. Treatment of patients prior to puberty appears to provide a more durable result, and surgical resection may be avoided. TYPE OF STUDY: retrospective. LEVEL OF EVIDENCE: IV. PMID- 29519572 TI - Repair of congenital esophageal atresia with tracheoesophageal fistula repair in Ontario over the last 20years: Volume and outcomes. AB - BACKGROUND/PURPOSE: This study was designed to determine the volume, postoperative surgical outcomes and, if possible, the relationship between outcome and institutional / surgeon volume in neonates undergoing repair of esophageal atresia with tracheoesophageal fistula (EA-TEF) over the last 20years in Ontario. METHODS: Using administrative databases, a population based cohort study of patients undergoing EA-TEF repair in Ontario between 1993 and 2012 was conducted. RESULTS: 465 patients with the diagnosis of EA-TEF met inclusion criteria. The mean number of EA-TEF repairs per year per was 5.8. There was a significant difference in hospital annual volume between institutions (range 12.3 3.35: p<0.05). The average number of cases/surgeon for the last 10 study years ranged between 0.5 and 2 cases/year. Primary outcome revealed that repair of recurrent fistula or intestinal interposition was 5.3%, with no reportable difference between institutions. Secondary outcomes revealed that 45.6% underwent dilatation for esophageal strictures, and 19.8% underwent some type of drainage procedure of the chest. These rates were not significantly different between institutions. CONCLUSION: This study provides insight into the outcomes following EA-TEF repair in Ontario and the difficulty in determining surgeon or institution volume outcome relationships, as both primary and secondary outcome event rates are very low. LEVEL OF EVIDENCE: 2. PMID- 29519573 TI - The 49th annual meeting of the Canadian Association of Pediatric Surgeons. PMID- 29519574 TI - Malone appendicostomy versus cecostomy tube insertion for children with intractable constipation: A systematic review and meta-analysis. AB - PURPOSE: Children with intractable constipation are often treated with antegrade continence enemas. This requires the creation of a Malone appendicostomy in the operating room or insertion of a cecostomy tube using endoscopic, radiologic, or surgical techniques. The purpose of this study was to assess the evidence regarding these procedures. METHODS: We conducted a search of Embase, Medline, CINAHL, and Web of Science up to October 2016. We included comparative studies of children treated with Malone appendicostomy or cecostomy tube insertion. Two reviewers screened abstracts, reviewed studies, and extracted data. RESULTS: We identified 166 children from three retrospective studies who underwent Malone appendicostomy (n=82) or cecostomy tube insertion (n=84). There were no differences in the number of patients who achieved continence (80% versus 70%, p=0.76), but the need for additional surgery was higher in children treated with Malone appendicostomy (30% versus 12%, p=0.01). Studies reported a variety of tube and stoma-related complications, but quality of life was not assessed using validated measures. CONCLUSION: Malone appendicostomy and cecostomy tube insertion are comparable in terms of achieving continence. Children treated with Malone appendicostomy appear to be more likely to require additional surgery due to early or late complications. LEVEL OF EVIDENCE: Therapeutic, 1c. PMID- 29519575 TI - Oral feeding outcomes in infants with esophageal atresia and tracheoesophageal fistula. AB - PURPOSE: The purpose of this study was to explore oral feeding outcomes in infants born with type-C esophageal atresia and tracheoesophageal fistula (EA/TEF). METHODS: A retrospective cohort study of all infants born between January 2005 and December 2015 undergoing surgery for type-C EA/TEF at the University of Alberta Hospital was performed. RESULTS: Fifty-seven infants were identified, of which 61.4% were exclusively orally feeding at discharge home. Variables anticipated to predict oral feeding were explored. Only 46% of babies with a structural cardiac anomaly had exclusive oral feeding compared to 79% without cardiac anomaly, p=0.055. Logistic regression identified the presence of structural cardiac anomaly and corrected gestational age at discharge as significant negative predictor variables for exclusive oral feeding at discharge home. Additional regression analyses found early transanastomotic feeding to be a significant positive predictor for the discontinuation of PN. CONCLUSION: We report the rate of oral feeding at discharge for infants born with type-C EA/TEF and identify predictor variables. This information is important for health care professionals and the families of children born with EA/TEF, because a significant number will go home with supplemental nutrition by gavage tube or other routes. LEVEL OF EVIDENCE: Level 2. PMID- 29519577 TI - An improved technique for zygoma reduction malarplasty. AB - Zygoma reduction malarplasty is a standard procedure primarily performed in Asia on patients who prefer an oval facial shape. The technique is well established and standardized. However, the esthetic results are frequently unsatisfactory or accompanied by complications such as nonunion, malunion, and cheek drooping. These complications are generally attributed to postoperative bone fragment movement. In this study, we present an improvement to this standard procedure that involves modifying the surgical technique. With our suggested modification, the chance of displacement is decreased because of increased locking resulting from greater surface-to-surface contact between the posterior bone segments. Moreover, the prominence of the anterior zygoma is maintained, whereas posterior zygoma width is slightly decreased. In our technique, fixation is performed only in the zygoma body area, and posterior fixation can be avoided. In addition, in cases where fixation is not performed, the protrusion of the posterior aspect of the articular tubercle can be decreased by grinding. We believe that the modified technique has the potential to markedly improve the treatment outcomes of zygoma reduction malarplasty. PMID- 29519578 TI - Researching of tritium speciation in soils of "Balapan" site. AB - Speciation of tritium (3N) in soils from the "Balapan" site in Semipalatinsk are presented in this study. Three interrelated objects were chosen for further study: "Atomic" lake, the Shagan River and an external reservoir. The main speciation forms of 3N in soil were: 3N in surface-adsorbed water, 3N in interlayer water, hydroxylic 3N, organically bound 3N and crystalline-bound 3N. Results will allow an estimation of contamination mechanism to be made, and will also allow the potential for migration and bioavailability of 3N to be assessed. PMID- 29519576 TI - Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts. AB - INTRODUCTION: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. METHODS: We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. RESULTS: Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk. DISCUSSION: Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology. PMID- 29519580 TI - Association of obesity, sleep apnea and hypothalamic inflammation: Novel possibilities of research. PMID- 29519581 TI - Encrusted prostatitis by Corynebacterium urealyticum: The importance of clinical suspicion. PMID- 29519579 TI - A CCR4 antagonist enhances DC activation and homing to the regional lymph node and shows potent vaccine adjuvant activity through the inhibition of regulatory T cell recruitment. AB - CCR4 is a major chemokine receptor expressed by Treg cells that downregulate immune responses. Here, we investigated the role of CCR4-mediated Treg cell recruitment in antigen-specific immune responses. CCR4-deficient mice immunized intramuscularly with ovalbumin (OVA) showed enhanced OVA-specific IgG responses. Furthermore, intramuscular administration of OVA induced the expression of MDC/CCL22, a ligand for CCR4, in macrophages of the muscle tissues, and enhanced the recruitment of CCR4+ Treg cells in wild-type mice, whereas this recruitment of Treg cells was severely impaired in CCR4-deficient mice. Furthermore, OVA loaded dendritic cells (DCs) derived from the muscle injection site of CCR4 deficient mice had an upregulated expression of the DC activation marker CD40 and 86, and the lymphoid organ homing receptor CCR7 resulting in an increased number of migratory DCs in the regional lymph node. Compound 22, a CCR4 antagonist, also inhibited the recruitment of Treg cells to the muscle tissue, and further enhanced DC activation and homing to the regional lymph node. Consequently, Compound 22 enhanced OVA-specific IgG responses, and the expression levels of IL 4 and IFN-gamma in CD4+ T cells and the levels of IFN-gamma in CD8+ T cells. Finally, intramuscular administration of OVA and Compound 22 significantly inhibited the growth of OVA-expressing tumors. Collectively, CCR4 plays a pivotal role in Treg cell recruitment to the muscle tissue, and intramuscular administration of CCR4 antagonists may be a promising approach for enhancing vaccine efficacy. PMID- 29519582 TI - Vertical sleeve gastrectomy corrects metabolic perturbations in a low-exercise capacity rat model. AB - OBJECTIVE: Bariatric surgery is currently our most effective strategy at weight loss, yet the mechanisms for its success remain unknown. Low exercise capacity, in humans and rodents, predicts poor metabolic outcome. The objective of this manuscript was to determine if bariatric surgery could restore metabolic perturbations in rats with low intrinsic exercise capacity. METHODS: We performed vertical sleeve gastrectomy (VSG) or sham surgery in high fat-fed rats selectively bred for low running capacity. RESULTS: We found that VSG reduced body mass through a reduction in fat mass, caused early reductions in food intake, and shifted macronutrient preference away from fat and toward carbohydrates. VSG had no impact on basal glucose but did improve the return to baseline after an oral glucose load. As has been shown previously, VSG increased postprandial insulin, GLP-1, and bile acids. There was no significant impact of VSG on plasma triglycerides, hepatic triglycerides, or cholesterol. Interestingly, the brown adipose tissue to white adipose tissue ratio tended to be greater in VSG compared to sham surgery animals. While VSG positively impacted several aspects of metabolism, it did not enhance maximal oxygen capacity and seemed to lower metabolic efficiency as indicated by lower resting oxygen consumption and fat and carbohydrate oxidation. CONCLUSION: VSG can improve the metabolic status of animals with a low exercise capacity independently of exercise capacity. PMID- 29519583 TI - Customized headgear for the management of recurrent temporomandibular joint dislocations. AB - Chronic recurrent temporomandibular joint (TMJ) dislocation is both an uncommon and debilitating condition of the facial skeleton. Various conservative management strategies have been tried, but these have often been associated with poor and transient outcomes. The use of a simple, innovative, and non-invasive solution is presented herein. A co-ordinated multidisciplinary approach was used in which the oral and maxillofacial laboratory technicians produced a customized headgear appliance that utilizes a 'seat belt'-like technology. This headgear was used successfully to manage the condition. PMID- 29519584 TI - Involuntary, slow, rhythmic movements of the shoulder girdle after scapular surgery: Shoulder girdle dyskinesia. PMID- 29519585 TI - The effect of lower socioeconomic status insurance on outcomes after primary shoulder arthroplasty. AB - BACKGROUND: Patient-reported outcomes (PROs) are becoming increasingly important to define successful outcomes. With the potential transition toward quality-based reimbursement, identifying risk factors for poor surgical outcomes becomes increasingly important. This study compared functional and PROs of primary shoulder arthroplasty in patients aged younger than 65 years with lower socioeconomic insurance compared with those with private insurance. METHODS: A retrospective review of all primary shoulder arthroplasties in patients aged younger than 65 was performed at a single institution. Patients were stratified according to insurance type (private vs. Medicare/Medicaid) with 2-year minimum follow-up. Preoperative, postoperative, and improvements in range of motion, visual analog scale (VAS) pain, and PROs were compared. RESULTS: We evaluated 143 shoulders (64 Medicare/Medicaid, 79 private insurance). Age, race, diagnosis, and type of arthroplasty were similar between groups. Patients with Medicare/Medicaid insurance demonstrated worse PROs before and after surgery, despite similar range of motion at both assessments. Despite poorer PROs postoperatively, both groups demonstrated similar improvements after surgery. Complications and reoperation were more common in the socioeconomically disadvantaged group (14% vs. 9%, P = .3; 11% vs. 6%, P = .2, respectively). DISCUSSION: Medicaid and Medicare patients aged younger than 65 years undergoing shoulder arthroplasty demonstrate poorer preoperative and postoperative PRO measures compared with similar patients with private insurance. However, both groups demonstrate similar improvements in scores from baseline. PMID- 29519586 TI - Diagnosis and treatment of clavicular fractures in Belgium between 2006 and 2015. AB - BACKGROUND: Clavicular fractures are common fractures of the shoulder girdle. The debate about whether these fractures should be treated conservatively or surgically is ongoing. This study describes the incidence of clavicular fractures in Belgium between 2006 and 2015 and how the surgical treatment rates have evolved during this time span. METHODS: The study included all patients who were diagnosed with a clavicular fracture or surgically treated in Belgium. The Belgian National Institute for Health and Disability Insurance provided the data, which included the patients' age, sex, location, and time of injury for the entire Belgian population. The fracture incidences and surgical treatment rates for different population groups were assessed. RESULTS: The incidence of clavicular fractures in Belgium increased from 56.5/100,000 persons/year in 2006 to 70.6/100,000 persons/year in 2015. The age-related incidence was U-shaped, with high incidences seen in both men and women younger than 18 and older than 70. The rate of surgically treated clavicular fractures increased by 190% between 2006 and 2015. CONCLUSION: The incidence of clavicular fractures in Belgium increased between 2006 and 2015. In the male population, the fracture incidence increased among all age groups, but in the female population, the increase was most noted in elderly patients. Although the preferred treatment strategy of clavicular fractures continues to be debated, there is a high and increasing rate of surgical treatment in Belgium, with an increasing percentage of patients that are surgically treated as outpatients. PMID- 29519587 TI - On the Same Page: Nurse, Patient, and Family Perceptions of Change-of-shift Bedside Report. AB - PURPOSE: The purpose of this study was to explore nurse, patient, and family perceptions about change-of-shift bedside report in the pediatric setting and to describe specific safety concerns that were identified during change-of-shift handoff. DESIGN AND METHODS: An exploratory-descriptive qualitative study designed to elicit nurse, patient, and family experience with change-of-shift bedside report was utilized for this study. Interviews were conducted and reviewed to identify common themes. RESULTS: Data analysis revealed the emergence of the following themes: perceived barriers, patient safety, and impact on patient care. Study participants found that bedside report promotes patient safety and is the preferred form of change-of-shift handoff communication. Additionally, participants stated there is increased accountability and increased transparency as everyone involved in bedside report is "on the same page." CONCLUSION: The study results are consistent with current literature suggesting that bedside report contributes to effective communication and increases patient safety. PMID- 29519588 TI - Dietary interventions for adults with chronic kidney disease. PMID- 29519589 TI - Data integration through brain atlasing: Human Brain Project tools and strategies. AB - The Human Brain Project (HBP), an EU Flagship Initiative, is currently building an infrastructure that will allow integration of large amounts of heterogeneous neuroscience data. The ultimate goal of the project is to develop a unified multi level understanding of the brain and its diseases, and beyond this to emulate the computational capabilities of the brain. Reference atlases of the brain are one of the key components in this infrastructure. Based on a new generation of three dimensional (3D) reference atlases, new solutions for analyzing and integrating brain data are being developed. HBP will build services for spatial query and analysis of brain data comparable to current online services for geospatial data. The services will provide interactive access to a wide range of data types that have information about anatomical location tied to them. The 3D volumetric nature of the brain, however, introduces a new level of complexity that requires a range of tools for making use of and interacting with the atlases. With such new tools, neuroscience research groups will be able to connect their data to atlas space, share their data through online data systems, and search and find other relevant data through the same systems. This new approach partly replaces earlier attempts to organize research data based only on a set of semantic terminologies describing the brain and its subdivisions. PMID- 29519590 TI - Quercetin affecting gelatinases in rat aortas: Some comments. PMID- 29519591 TI - A safety and immunogenicity study of immunization with hVEGF26-104/RFASE in cynomolgus monkeys. AB - INTRODUCTION: Vascular endothelial growth factor (VEGF) is pivotal in tumor angiogenesis and therapies targeting the VEGF axis are widely used in the clinic for the treatment of cancer. We have developed a therapeutic vaccine targeting human (h)VEGF165. hVEGF26-104/RFASE is based on the truncated protein hVEGF26-104 as antigen formulated in an oil-in-water emulsion containing the sulpholipopolysaccharide RFASE as adjuvant. Here we describe the toxicity and immunogenicity of this therapeutic vaccine in cynomolgus monkeys. METHODS: In total 54 cynomolgus monkeys were used and divided in 7 groups. Groups 1-3 were control groups, either receiving PBS alone (group 1), RFASE alone (group 2) or hVEGF26-104 alone (group 3). Animals allocated to groups 4-7 received hVEGF26-104 together with RFASE, but with varying doses of the antigen or the adjuvant. All animals were immunized four times with 2-week intervals and safety and immunogenicity were monitored until 3 days after the final immunization. RESULTS: Immunization induced an RFASE adjuvant dependent acute phase response. High titers of antibodies against hVEGF26-104 and cross-reactive with hVEGF165, were found in monkey sera, 28 days after primer immunization. These antibodies were able to inhibit the binding of the monoclonal antibody bevacizumab with hVEGF165 in a competition ELISA. Moreover, the biological activity of hVEGF165 could be inhibited by the addition of immunized monkey serum in a VEGF specific bioassay. Importantly, no adverse events commonly observed with VEGF neutralization were observed throughout the study. CONCLUSION: These data show that hVEGF26-104/RFASE can be safely administered in cynomolgus monkeys, induces the desired immune response and therefore support the clinical development of this vaccine. PMID- 29519592 TI - Molecular epidemiology of rotaviruses in the south-east Asian region from 2009 to 2015. AB - BACKGROUND: In Asia, rotavirus accounts for approximately 45% of admissions due to acute gastroenteritis in children <5 years, and causes about 145,000 deaths every year. We studied the distribution of rotavirus strains from Myanmar, Sri Lanka, and Nepal during 2009-2015. METHODS: Stool samples collected from children <5 years of age hospitalized with acute diarrhea in the three sites and positive for rotavirus antigen by enzyme immunoassay (EIA) were sent to the Christian Medical College, Vellore from 2009 to 2015. G and P typing of rotavirus strains were performed using reverse-transcription polymerase chain reaction (RT-PCR). RESULT: Of the 2354 EIA positive samples tested, G12P[8] (36.8%), G1P[8] (30.1%), and G12P[6] (41.3%) were the most common strains isolated from Myanmar, Sri Lanka, and Nepal respectively. CONCLUSION: There was substantial diversity of rotavirus genotypes, and continued surveillance in developing countries of Asia will help in understanding the epidemiology of rotavirus before and after introduction of vaccines. PMID- 29519593 TI - "I wouldn't really believe statistics" - Challenges with influenza vaccine acceptance among healthcare workers in Singapore. AB - BACKGROUND: Influenza vaccine acceptance among healthcare workers (HCWs) is a worldwide problem, but relatively little research has focussed on Asia, including Singapore. Despite widespread access and recommendations from public health authorities, influenza vaccine uptake remains suboptimal among HCWs. METHODS: Our qualitative study used focus group discussions to identify and explain factors limiting influenza vaccine acceptance among HCWs in Singapore. A total of 73 doctors, nurses, allied health and ancillary staff across three public hospitals were included. RESULTS: Challenges identified include a fear of contracting influenza from vaccination exacerbated by negative anecdotes regarding vaccine safety and efficacy, distrust of published efficacy data, uncertainty regarding relevance of existing data for Singapore, reluctance to introduce chemicals or overmedicate, pain from injection, low risk attributed to influenza and limited awareness of influenza transmission with a preference for alternatives in patient protection. Differences in attitudes were observed across vocational groups. Lack of overt promotion by hospital leadership in some institutions, perceived vaccine hesitancy among doctors, access, and work culture that implicitly encourages working through illness were further barriers. CONCLUSION: Our findings highlight a combination of misperceptions about influenza vaccination and cognitive biases at the individual level, and challenges at the institutional level limiting uptake. Findings indicate an urgent need to provide targeted education and communication. Rather than providing more data, we recommend a widely disseminated, locally-compiled synthesis addressing specific concerns of hesitant HCWs. Tailoring interventions to specific vocational groups should be considered. Institutional norms and culture may have a powerful influence in setting default behaviours: more effort is needed in improving influenza vaccine promotion and priority at some institutions, integrating vaccine-related communication with other infection control communication and addressing influenza vaccine hesitancy among doctors as a priority. Finally, further study of strategies to address cognitive biases affecting influenza vaccine acceptance in Singapore is desirable. PMID- 29519594 TI - Molecular characteristics of Streptococcus agalactiae in a mother-baby prospective cohort study: Implication for vaccine development and insights into vertical transmission. AB - BACKGROUND: Streptococcus agalactiae (GBS) is a leading cause of neonatal sepsis and meningitis in many countries. This study aimed to determine the molecular characteristics of GBS colonized in mothers and their infants so as to provide implication for vaccine strategies and confirm vertical transmission. METHODS: A prospective cohort study was conducted to recruit 1815 mother-neonate pairs. All GBS isolates from pregnant women and her infants were tested for serotypes, multilocus sequence types and virulence genes. The relationship between multiple molecular characteristics of GBS isolates was tested by the correspondence analysis, and the agreement between mother-neonate paired data in molecular characteristics was analyzed using Kappa tests. RESULTS: The predominant serotypes were III, Ia and V, and the most prevalent sequence types (STs) were ST19, ST17, ST10, and ST12. All isolates carried at least one pilus island (PI). The most common combination of PIs was PI-2b alone, followed by PI-1+PI-2a and PI 2a alone, and the most prevalent alpha-like protein (alp) genes were rib, epsilon and alphaC. Moreover, a strong relationship was noted between STs, serotypes, alp genes and PIs, including ST17 associated with serotype-III/rib/PI-2b, ST19 with serotype-III/rib/PI-1+PI-2a, and ST485 with serotype-Ia/epsilon/PI-2b. The rate of GBS vertical transmission was 14.1%, and the kappa test revealed good agreement in multiple molecular characteristics among GBS-positive mother-neonate pairs. Notably, the switching of molecular characteristics was found during vertical transmission. CONCLUSIONS: Our findings underscore the value of monitoring multiple molecular characteristics so as to provide implication for multivalent strategies and gain insights into GBS vertical transmission and vertical characteristic switching. PMID- 29519595 TI - [Management of painful endometriosis in adolescents: CNGOF-HAS Endometriosis Guidelines]. AB - OBJECTIVE: To analyse the literature on the treatment of adolescent painful endometriosis. METHOD: This work is based on a Review of the literature between January 2006 and December 2017. The Medline (Pubmed) and Cochrane database were searched for meta-analyzes, randomized trials, literature reviews, controlled, not controlled and retrospective studies published on the subject. Studies concerning adolescent's dysmenorrhea without endometriosis were excluded. RESULTS: Study quality is heterogeneous. Dienogest and GnRH agonists (GnRHa) are the only treatments specifically evaluated for the treatment of adolescent endometriosis. They reduce the pain associated with endometriosis. Combined oral contraceptives have not been studied in the context of endometriosis but they are effective on dysmenorrhea. Add back therapy, containing estrogens improves bone mineral density and quality of life for young women treated with GnRHa. CONCLUSION: Medical treatment of endometriosis in adolescent is associated with risks related to the young age. The therapeutic strategy should take into account the adverse effects of each treatment. PMID- 29519596 TI - Constrained peptides and biological targets. PMID- 29519597 TI - Commentary on the paper: "Efficacy of a novel strategy for poststernotomy deep sternal infection after thoracic aorta replacement using a prosthetic graft". PMID- 29519598 TI - A prospective randomised comparison of fixation methods in Tamai's zone I amputation. AB - BACKGROUND: The treatment of choice for fingertip amputation is replantation to restore function and aesthetics. The purpose of this study was to compare the success rates and salvage periods between patients with Tamai's zone I amputation injuries treated with bony fixation and suture fixation. METHODS: Fifty-five patients with Tamai's zone I amputations with bony involvement were included in this study. The patients were allocated randomly to two groups treated by bony fixation with Kirschner (K-)wire and suture fixation, respectively. In the bony fixation group (n = 21), the distal phalangeal bone was fixed with K-wire; in the suture fixation group (n = 34), the amputated portion was fixed with sutures alone. The success rate was defined as the percentage of fully viable replanted cases, and the salvage period was defined as extending from the first postoperative day to the cessation of salvation. RESULTS: The success rates for the bony and suture fixation groups were 90.0% and 91.1%, respectively, with no significant difference. The average salvage period was longer in the bony fixation group than in the suture fixation group (8.7 +/- 1.25 vs. 6.4 +/- 0.98 days; P = 0.01). No case of non-union of the distal phalangeal bone, limitation of motion, or disfigurement was observed in either group. CONCLUSION: The average salvage period was significantly longer for the bony fixation group, but the success rates did not differ between groups. We suggest that bony fixation is not mandatory in the treatment of Tamai's zone I amputation. PMID- 29519599 TI - Hydrodynamics of high solids anaerobic reactor: Characterization of solid segregation and liquid mixing pattern in a pilot plant VALORGA facility under different reactor geometry. AB - One of the main problems of dry anaerobic digestion plants treating urban solid waste is the loss of useful volume by the sedimentation of solids (inerts) into the bottom of the digester, or by accumulation of floating materials in its upper part. This entails a periodic cost of emptying and cleaning the digesters, a decrease in biogas production and complications in maintenance. Usually the sedimentation is a consequence of the heterogeneity of waste that, in addition to organic matter, drags particles of high density that end up obstructing the digesters. To reduce this bottleneck, URBASER has designed a new configuration of VALORGA reactor. That is, the VALORGA central wall has been removed and an inclined bottom has been added. To test the sedimentability and the overall performance of both configurations (current and new design), hydrodynamic tests have been carried out in a pilot digester (digester of 95 m3 capacity). To simulate the liquid phase and the solid phase of the reactor, lithium tracers and tags of different densities with RFID (radio frequency identification reader) have been used respectively. The results of the study showed an improvement in the performance of the new reactor design at pilot level. PMID- 29519600 TI - Characterization of microplastic litter from oceans by an innovative approach based on hyperspectral imaging. AB - An innovative approach, based on HyperSpectral Imaging (HSI), was developed in order to set up an efficient method to analyze marine microplastic litter. HSI was applied to samples collected by surface-trawling plankton nets from several parts of the world (i.e. Arctic, Mediterranean, South Atlantic and North Pacific). Reliable information on abundance, size, shape and polymer type for the whole ensemble of plastic particles in each sample was retrieved from single hyperspectral images. The simultaneous characterization of the polymeric composition of the plastic debris represents an important analytical advantage considering that this information, and even the validation of the plastic nature of the small debris, is a common flaw in the analysis of marine microplastic pollution. HSI was revealed as a rapid, non-invasive, non-destructive and reliable technology for the characterization of the microplastic waste, opening a promising way for improving the plastic pollution monitoring. PMID- 29519601 TI - Advances in Left Ventricular Assist Devices and Mechanical Circulatory Support. AB - Recent technologic advances have resulted in the availability of percutaneous and minimally invasive surgical devices for temporary mechanical circulatory support. These may be deployed rapidly without the requirement for sternotomy or cardiopulmonary bypass. In addition, third generation implantable left ventricular assist devices have been compared with second generation devices in 2 recent randomized controlled trials. The aim of this article is to provide a current review of the recent literature relating to left ventricular assist devices and mechanical circulatory support. PMID- 29519602 TI - Acute Type A Aortic Dissection in Pregnancy-Diagnostic and Therapeutic Challenges in a Multidisciplinary Setting. PMID- 29519603 TI - Synthesis, antitumor activity and DNA binding features of benzothiazolyl and benzimidazolyl substituted isoindolines. AB - In this paper novel isoindolines substituted with cyano and amidino benzimidazoles and benzothiazoles were synthesized as new potential anti-cancer agents. The new structures were evaluated for antiproliferative activity, cell cycle changes, cell death, as well as DNA binding and topoisomerase inhibition properties on selected compounds. Results showed that all tested compounds exerted antitumor activity, especially amidinobenzothiazole and amidinobenzimidazole substituted isoindolin-1-ones and benzimidazole substituted 1-iminoisoindoline that showed antiproliferative effect in the submicromolar range. Moreover, the DNA-binding properties of selected compounds were evaluated by biophysical and biochemical approaches including thermal denaturation studies, circular dichroism spectra analyses and topoisomerase I/II inhibition assays and results identified some of them as strong DNA ligands, harboring or not additional topoisomerase II inhibition and able to locate in the nucleus as determined by fluorescence microscopy. In conclusion, we evidenced novel cyano- and amidino-substituted isoindolines coupled with benzimidazoles and benzothiazoles as topoisomerase inhibitors and/or DNA binding compounds with potent antitumor activities. PMID- 29519604 TI - Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors. AB - HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1. PMID- 29519605 TI - Time-driven activity-based cost comparison of prostate cancer brachytherapy and intensity-modulated radiation therapy. AB - PURPOSE: To evaluate the delivery cost of frequently used radiotherapy options offered to patients with intermediate- to high-risk prostate cancer using time driven activity-based costing and compare the results with Medicare reimbursement and relative value units (RVUs). METHODS AND MATERIALS: Process maps were created to represent each step of prostate radiotherapy treatment at our institution. Salary data, equipment purchase costs, and consumable costs were factored into the cost analysis. The capacity cost rate was determined for each resource and calculated for each treatment option from initial consultation to its completion. Treatment options included low-dose-rate brachytherapy (LDR-BT), combined high dose-rate brachytherapy single fraction boost with 25-fraction intensity modulated radiotherapy (HDR-BT-IMRT), moderately hypofractionated 28-fraction IMRT, conventionally fractionated 39-fraction IMRT, and conventionally fractionated (2 Gy/fraction) 23-fraction pelvis irradiation with 16-fraction prostate boost. RESULTS: The total cost to deliver LDR-BT, HDR-BT-IMRT, moderately hypofractionated 28-fraction IMRT, conventionally fractionated 39 fraction IMRT, conventionally fractionated 39-fraction IMRT, and conventionally fractionated (2 Gy/fraction) 23-fraction pelvis irradiation with 16-fraction prostate boost was $2719, $6517, $4173, $5507, and $5663, respectively. Total reimbursement for each course was $3123, $10,156, $7862, $9725, and $10,377, respectively. Radiation oncology attending time was 1.5-2 times higher for treatment courses incorporating BT. Attending radiation oncologist's time consumed per RVU was higher with BT (4.83 and 2.56 minutes per RVU generated for LDR-BT and HDR-BT-IMRT, respectively) compared to without BT (1.41-1.62 minutes per RVU). CONCLUSIONS: Time-driven activity-based costing analysis identified higher delivery costs associated with prostate BT compared with IMRT alone. In light of recent guidelines promoting BT for intermediate- to high-risk disease, re-evaluation of payment policies is warranted to encourage BT delivery. PMID- 29519606 TI - A new delivery system to resolve dosimetric issues in intravascular brachytherapy. AB - PURPOSE: Renewed interest is being expressed in intravascular brachytherapy (IVBT). A number of unresolved issues exist in the discipline. Providing a homogeneous and adequate dose to the target remains difficult in IVBT. The guidewire that delivers the device to the target, arterial plaques, and stent struts are all known to reduce the dose delivered to target. The viability and efficacy of a proposed IVBT delivery system designed to resolve the issue of guidewire attenuation is evaluated and compared to that of a popular and commercially available IVBT device. METHODS AND MATERIALS: Monte Carlo simulations are conducted to determine distributions of absorbed dose around an existing and proposed IVBT delivery system. RESULTS: For the Novoste Beta-Cath 3.5F (TeamBest(r)), dose in water varies by 10% as a function of angle in the plane perpendicular to the delivery catheter due to off-centering of seeds in the catheter. Dose is reduced by 52% behind a stainless steel guidewire and 64% behind a guidewire, arterial plaque, and stent strut for the Novoste Beta-Cath 3.5F. Dose is not perturbed by the presence of a guidewire for the proposed device and is reduced by 46% by an arterial plaque and stent strut. CONCLUSIONS: Dose attenuation by guidewire is likely the single greatest source of dose attenuation in IVBT in terms of absolute dose reduction and is greater than previously reported for the Novoste Beta-Cath 3.5F. The Novoste Beta-Cath 3.5F delivers an inhomogeneous dose to target. A delivery system is proposed, which resolves the issue of guidewire attenuation in IVBT and should reduce treatment times. PMID- 29519607 TI - Regarding: Revisiting the alerting effect of light; a systematic review. PMID- 29519608 TI - The impact of preoperative investigations on the management of bariatric patients; results of a cohort of more than 1200 cases. AB - BACKGROUND: Despite the increasing use of bariatric surgery as the most effective treatment of morbid obesity, there is still no consensus on its preoperative diagnostic workup. The aim of this study was to identify the pathologies of the endoscopic and radiologic investigations before performing bariatric surgery and to evaluate their impact on the patient management. METHODS: Retrospective analysis of prospectively collected data of 1225 consecutive patients who underwent laparoscopic Roux-en-Y gastric bypass (n = 834) or sleeve gastrectomy (n = 391) at our institution. An abdominal ultrasound was performed in 1188 patients, 1190 patients underwent upper gastrointestinal (GI) endoscopy, 1178 patients underwent upper GI series, and 610 patients underwent esophageal manometry. SETTING: Private hospital, Switzerland. RESULTS: Gallstones were detected in 222 (21.0%) patients, and a synchronous cholecystectomy was performed in 220 (18.0%) patients. The upper GI series indicated hiatal hernias in 325 (27.6%) patients. The most common findings of the upper GI endoscopy were type-C gastritis (224 patients, 18.8%), reflux esophagitis (229 patients, 19.2%), Helicobacter pylori-positive gastritis (158, 13.3%), and hiatal hernia (55 patients, 4.6%). Additionally, we detected 1 Barrett's high-grade dysplasia, 2 Barrett's carcinomas, and 1 stomach cancer in asymptomatic patients, who were scheduled to have a sleeve gastrectomy. Esophageal motility disorders were detected in 104 (17.0%) individuals, who underwent esophageal manometry. CONCLUSIONS: We recommend performing abdominal sonography and upper GI endoscopy before bariatric surgery as they reveal findings, which influence the therapeutic approach. Upper GI series and esophageal manometry help to define patients not suitable for sleeve gastrectomy. PMID- 29519609 TI - Chronic treatment with URB597 ameliorates post-stress symptoms in a rat model of PTSD. AB - Activating the endocannabinoid system has become a major focus in the search for novel therapeutics for anxiety and deficits in fear extinction, two defining features of PTSD. We examined whether chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.2, 0.3, 0.4 mg/kg, i.p.) or the CB1/2 receptor agonist WIN55,212-2 (0.25, 0.5 mg/kg, i.p.) injected for 3 weeks to rats exposed to the shock and reminders model of PTSD would attenuate post-stress symptoms and affect basolateral amygdala (BLA) and CA1 CB1 receptors. Exposure to shock and reminders enhanced acoustic startle response and impaired extinction. Rats exposed to shock and reminders and chronically treated with URB597 demonstrated normalized startle response and intact extinction kinetics. WIN55,212-2 only affected the startle response. The therapeutic effects of URB597 and WIN55,212-2 were found to be CB1 receptor dependent, as these effects were blocked when a low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg, i.p. for 3 weeks) was co-administered. Moreover, URB597, but not WIN55,212-2, normalized the shock/reminders-induced upregulation in CB1 receptor levels in the BLA and CA1. One hour after the shock, N-arachidonoylethanolamine (AEA) was increased in the BLA and decreased in the CA1. Circulating 2-arachidonoylglycerol (2-AG) concentrations were decreased in shocked rats, with no significant effect in the BLA or CA1. FAAH activity was increased in the CA1 of shocked rats. Chronic cannabinoid treatment with URB597 can ameliorate PTSD-like symptoms suggesting FAAH inhibitors as a potentially effective therapeutic strategy for the treatment of disorders associated with inefficient fear coping. PMID- 29519610 TI - A novel mechanism of depression: role for connexins. AB - Major depressive disorder (MDD) is a chronic and debilitating illness that affects over 350 million people worldwide; however, current treatments have failed to cure or prevent the progress of depression. Increasing evidence suggests a crucial role for connexins in MDD. In this review, we have summarised recent accomplishments regarding the role of connexins, gap junctions, and hemichannels in the aetiology of MDD, and discussed the limitations of current research. A blockage of gap junctions or hemichannels induces depressive behaviour. Possible underlying mechanisms include the regulation of neurosecretory functions and synaptic activity by gap junctions and hemichannels. Gap junctions are functionally inhibited under stress conditions. Conversely, hemichannel permeability is increased. Antidepressants inhibit hemichannel permeability; however, they have contrasting effects on the function of gap junctions under normal conditions and can protect them against stress. In conclusion, the blockage of hemichannels concurrent with improvements in gap junction functionality might be potential targets for depression treatment. PMID- 29519611 TI - Peptide Aptamers to Inhibit Protein Function in Plants. AB - Peptide aptamers - artificial short peptides with specific binding affinity for target molecules - can be used to interfere with protein functions and protein protein interactions in plant cells. Therefore, peptide aptamers have emerged as a new, powerful tool with high efficiency and specificity and wide applications in functional genomics and plant biotechnology. PMID- 29519612 TI - Shared goals for tuberculosis and HIV. PMID- 29519613 TI - Innovation challenge contests to enhance HIV responses. PMID- 29519614 TI - Posttreatment Immune Parameters Predict Cancer Control and Pneumonitis in Stage I Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Ablative Radiotherapy. AB - PURPOSE: Stereotactic ablative body radiotherapy (SABR) represents an exciting, tolerable, and highly effective form of radiotherapy. Ongoing investigations into the interactions between radiotherapy and the immune system have uncovered new mechanisms that can be exploited to improve efficacy. We determined whether baseline or posttreatment immune parameters could predict disease control and toxicity in stage I non-small-cell lung cancer (NSCLC) patients treated with SABR. PATIENTS AND METHODS: Peripheral blood samples were collected from 62 patients 24 hours before treatment and within 4 weeks after treatment for lymphocyte subset count analysis. All peripheral blood samples were analyzed by flow cytometry. Associated parameters were evaluated to determine their association with progression-free survival (PFS) and symptomatic radiation pneumonitis (grade 2 or higher). The survival rates were estimated with Kaplan Meier and multivariable analyses using binary logistic regression analysis or a Cox proportional hazards model. RESULTS: At a median follow-up time of 36.0 months, the PFS rates for years 1, 2, and 3 were 91.0%, 82.5%, and 48.9%, respectively. The multivariable logistic regression analysis showed that only proportion of lung receiving 20 Gy of radiotherapy (odds ratio = 1.41; 95% confidence interval, 1.05-1.87; P = .023) and mean lung dose (odds ratio = 2.02; 95% confidence interval, 1.16-3.53; P = .016) were associated with symptomatic radiation pneumonitis (grade 2 or higher). Moreover, the immune parameters had no predictive value. In the multivariable Cox regression analysis, an elevated posttreatment cytotoxic CD8+ T-cell level was an independent prognostic factor for longer PFS in stage I NSCLC (hazard ratio, 1.16; 95% confidence interval, 1.01-1.28; P = .01). CONCLUSION: A higher posttreatment cytotoxic CD8+ T-cell level was predictive of better PFS in stage I NSCLC patients receiving SABR. Thus, enhancing tumor antigen-specific cellular immunity by combining radiotherapy and immunotherapy might be a crucial strategy for improving survival in these patients. PMID- 29519615 TI - Elliptical Fourier descriptors of outline and morphological analysis in caudal view of foramen magnum of the tropical raccoon (Procyon cancrivorus) (Linnaeus, 1758). AB - OBJECTIVES: To evaluate sexual-size dimorphism and attempt at categorization of inter-individual shapes of foramen magnum outlines using Fourier descriptors which allow for shape outline evaluations with a resultant specimen character definition. MATERIALS AND METHODS: Individual characterization and quantification of foramen magnum shapes in direct caudal view based on elliptical Fourier technique was applied to 46 tropical raccoon skulls (26 females, 20 males). RESULTS: Incremental number of harmonics demonstrates morphological contributions of such descriptors with their relations to specific anatomical constructions established. The initial harmonics (1st to 3rd) described the general foramen shapes while the second (4th to 12th) demonstrated fine morphological details. Sexual-size dimorphism was observed in females (87.1%) and 91.7% in males, normalization of size produces 75% in females and 83% in males. With respect to foramen magnum dimorphism analysis, the result obtained through elliptic Fourier analysis was comparatively better in detail information of outline contours than earlier classical methods. The first four effective principal components defined 70.63% of its shape properties while the rest (22.51%) constituted fine details of morphology. CONCLUSION: Both size and shape seems important in sexual dimorphisms in this species, this investigation suggest clinical implications, taxonomic and anthropologic perspectives in foramen characterization magnum characterization and further postulates an increased possibility of volume reduction cerebellar protrusion, ontogenic magnum shape irregularities in the sample population with neurologic consequences especially among females. PMID- 29519616 TI - Erratum to 'Inhibition of human cytomegalovirus replication by tricin is associated with depressed CCL2 expression' [Antiviral Research (2017) 15-19]. PMID- 29519617 TI - Increased expression level of Hsp70 in the inner ears of mice by exposure to low frequency noise. AB - Previous studies showed that people in urban areas are possibly exposed to 60-110 dB of low frequency noise (LFN) defined as noise of <=100 Hz in their daily life. Previous studies also showed increased health risks by exposure to high levels (130-140 dB) of LFN in animals. However, little is known about the health effects of exposure to an ordinary level of LFN. We biochemically and immunohistochemically assessed the effects of exposure to inaudible LFN for mice (12 h/day of 100 Hz LFN at 95 dB for 5 days), at a level to which people are possibly exposed in daily life, on a murine inner ear by targeting 9 stress reactive molecules. There was more than a 5-fold increased transcript level of heat shock protein 70 (Hsp70) in the whole inner ear exposed to LFN. However, the transcript levels of the other 8 stress-reactive molecules including Hsp27 and Hsp90 were comparable in LFN-exposed and unexposed murine inner ears. Only the transcript level of Cebpbeta among the previously reported 4 transcriptional activators for Hsp70 expression was more than 3-fold increased by LFN exposure. Hsp70 transcript expression levels in the inner ears 3 days after LFN exposure were comparable to those in unexposed inner ears. The protein level of Hsp70, but not the levels of Hsp27 and Hsp90, was also increased in the vestibule by LFN exposure. However, hearing levels as well as expression levels of Hsp70 protein in the cochleae were comparable in LFN-exposed mice and unexposed mice. Our results demonstrated that the inner ear might be one of the organs that is negatively affected by stress from inaudible LFN exposure. Moreover, LFN exposure might increase Hsp70 expression level via Cebpbeta in the inner ear. Thus, Hsp70 and Cebpbeta levels could be candidates of biomarkers for response to LFN exposure. PMID- 29519618 TI - Prognostic Prediction Model for Second Allogeneic Stem-Cell Transplantation in Patients With Relapsed Acute Myeloid Leukemia: Single-Center Report. AB - PURPOSE: To identify factors affecting survival outcomes and to develop a prognostic model for second allogeneic stem-cell transplantation (allo-SCT2) for relapsed acute myeloid leukemia (AML) after the first autologous or allogeneic stem-cell transplantation. PATIENTS AND METHODS: Seventy-eight consecutive adult AML patients who received allo-SCT2 were analyzed in this retrospective study. RESULTS: The 4-year overall survival (OS) rate was 28.7%. In multivariate analysis, poor cytogenetic risk at diagnosis, circulating blast >= 20% at relapse, duration from first transplantation to relapse < 9 months, and failure to achieve morphologic complete remission after allo-SCT2 were factors associated with poor OS. A prognostic model was developed with the following score system: intermediate and poor cytogenetic risk at diagnosis (0.5 and 1 point), peripheral blast >= 20% at relapse (1 point), duration from the first transplantation to relapse < 9 months (1 point), and failure to achieve morphologic complete remission after allo-SCT2 (1 point). The model identified 2 subgroups according to the 4-year OS rate: 51.3% in the low-risk group (score < 2) and 2.8% in the high-risk group (score >= 2) (P < .001). CONCLUSION: This prognostic model might be useful to make an appropriate decision for allo-SCT2 in relapsed AML after the first autologous or allogeneic stem-cell transplantation. PMID- 29519619 TI - Efficacy of Ponatinib Versus Earlier Generation Tyrosine Kinase Inhibitors for Front-line Treatment of Newly Diagnosed Philadelphia-positive Acute Lymphoblastic Leukemia. AB - INTRODUCTION: Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) who had undergone front-line combination chemotherapy plus ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). PATIENTS AND METHODS: We identified 26 Ph+ ALL studies: 25 of earlier generation TKIs and 1 of ponatinib. The outcomes from studies of combination chemotherapy plus earlier generation TKIs were summarized using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the results from the single arm combination chemotherapy plus ponatinib trial. Adjusted logistic meta regression analyses were used to compare the outcomes between the TKI groups. RESULTS: The percentage of patients achieving a CMR was greater with combination chemotherapy plus ponatinib (79%) than the pooled percentage of patients achieving a CMR with combination chemotherapy plus earlier generation TKIs (34%). Greater OS was observed with ponatinib compared with the pooled OS for earlier generation TKIs (2-year, 83% vs. 58%; 3-year, 79% vs. 50%). Odds ratios for ponatinib versus earlier generation TKIs were 6.09 (95% CI, 1.16-31.90; P = .034) for CMR, 3.70 (95% CI, 0.93-14.73; P = .062) for 2-year OS, and 4.49 (95% CI, 1.00-20.13; P = .050) for 3-year OS. CONCLUSION: Ponatinib plus chemotherapy might be associated with better outcomes than chemotherapy with earlier generation TKIs in patients with newly diagnosed Ph+ ALL. PMID- 29519620 TI - Therapeutic Perspectives for Interferons and Plasmacytoid Dendritic Cells in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a multifactorial immune disease exhibiting diverse clinical responses to specific therapeutic agents. Such heterogeneity reflects variable activation of signaling pathways. Consequently, RA physiopathology has been linked to many immune cells and factors, with controversial observations for interferons (IFNs). In this opinion article, we review the roles of these cytokines and the cells that produce them in light of recent data: clinical observations showing that expression of IFN-dependent genes does not reflect RA activity and RA mouse models in which the stimulation of IFN-dependent pathways provided disease protection. We suggest that epicutaneous stimulation of the IFN network is an attractive possibility to limit neutrophil infiltration or activation, thus providing therapeutic benefits to RA patients refractory to current therapies. PMID- 29519621 TI - Nitric Oxide Signaling in T Cell-Mediated Immunity. AB - Nitric oxide (NO) is a key messenger in the pathogenesis of inflammation, linking innate and adaptive immunity. By targeting signaling molecules, NO from inducible NO synthase (iNOS) and endothelial (e)NOS affects T helper cell differentiation and the effector functions of T lymphocytes, and is a potential target for therapeutic manipulation. In this review we discuss the regulatory actions exerted by NO on T cell functions, focusing on S-nitrosylation as an important post-translational modification by which NO acts as a signaling molecule during T cell-mediated immunity. We also present recent findings showing novel mechanisms through which NO regulates the activation of human T cells, and consider their potential in strategies to treat tumoral, allergic, and autoimmune diseases. PMID- 29519622 TI - Alcohol mixed with energy drinks and arrhythmias. PMID- 29519623 TI - Demographic features of patients with concomitant facial fractures and closed head injuries in Maricopa, Arizona. AB - OBJECTIVE: The aim of this study was to investigate the demographic profile of Native American patients with concomitant facial fractures and closed head injuries (CHIs) and to explore the validation of the craniofacial crumple zone. STUDY DESIGN: This was a retrospective, observational, case-control study of 2131 maxillofacial fractures from 2010 to 2014, of which 173 (8%) had concomitant CHIs. RESULTS: Of the study patients, 133 (77%) were males (mean age 40.6 years). Only 2.1% of the local population was Native American, but this group represented 24% of the patients with CHIs and sustained 4.6 times more (P value < .001) assault injuries and 2.6 times more concussion (P value < .001) compared with other groups. Other trauma comparisons were not significant. Of the 173 study patients, 86 (50%), had blood alcohol levels which exceeded 80 mg/100 mL compared with 93% of the Native Americans. CONCLUSIONS: Native American patients had a highly significant predisposition to violence and road traffic accidents resulting in maxillofacial fractures and CHIs. The high blood alcohol levels found in this group also reflected longstanding serious sociologic problems. This study provides a useful model to investigate the relative ethnic/racial role of comminuted paranasal structures for the protection of the brain (i.e., the crumple zone). PMID- 29519624 TI - Evaluation of biofilm formation ability in different Candida strains and anti biofilm effects of Fe3O4-NPs compared with Fluconazole: an in vitro study. AB - OBJECTIVE: Biofilm formation ability is one of the major virulence factors contributing to the pathogenesis of Candida species. Biofilms produced by Candida spp. cause complicated treatments and contribute to increasing unpleasant mortality rates. Nanoparticles of Fe3O4 (Fe3O4-NPs) are considered due to their magnetic and biochemical properties, as well as their low costs. The purpose of present study was to determine biofilm formation ability in different Candida strains and evaluation of anti-biofilm effect of Fe3O4-NPs compared with FLC. MATERIALS AND METHODS: In this study, the biofilm-forming ability of Candida strains and the inhibitory effects of Fe3O4-NPs on Candida strains biofilms compared with FLC were measured by MTT assay. RESULTS: Our finding showed that the biofilm formation ability of C. lusitaniae was significantly higher than other tested Candida strains. However, all the studied Candida strains produced high degree of biofilms. The biofilm formation in different Candida strains was inhibited at concentrations >=1000MUg/mL to >=4000MUg/mL for Fe3O4-NPs and >=512MUg/mL to >=2048MUg/mL for FLC. After exposure to various concentrations of Fe3O4-NPs, biofilm formation reduction in C. albicans and C. parapsilosis were more than FLC. Although, this reduction was not significant. A significant reduction (P<0.05) was observed in biofilm formation in presence of FLC compared with Fe3O4-NPs in C. krusei, C. tropicalis, and C. lusitaniae. The inhibitory effects of Fe3O4-NPs and FLC on biofilm formation of C. glabrata were approximately equal. CONCLUSION: In accordance with the findings, the biofilm reduction effect of FLC for C. krusei, C. tropicalis, and C. lusitaniae were statistically higher than Fe3O4-NPs. PMID- 29519625 TI - Disseminated histoplasmosis diagnosed in the bone marrow of an HIV-infected patient: First case imported in Tunisia. AB - Histoplasmosis is a fungal infection caused by a dimorphic fungus, Histoplasma capsulatum. We report a first case of disseminated histoplasmosis in a 34-year old woman, infected with human immunodeficiency virus (HIV), originating from Ivory Coast and living in Tunisia for 4 years. She was complaining from fever, chronic diarrhoea and pancytopenia. The Histoplasma capsulatum var. capsulatum was identified by direct microscopic examination of the bone marrow. She was treated by Amphotericin B, relayed by itraconazole. Even though a regression of symptoms and normalization of blood cell count (BCC), the patient died in a respiratory distress related to CMV hypoxemic pneumonia. PMID- 29519626 TI - Prevalence of diabetes five years after having gestational diabetes during pregnancy - Croatian national study. AB - AIMS: The aim of this study was to determine the prevalence of diabetes among women 5 years after having gestational diabetes during pregnancy. Also, we sought to determine whether women who develop diabetes after GD during pregnancy differ from women who do not develop diabetes after GD during pregnancy. METHODS: This longitudinal study was performed using data from medical birth certificates and CroDiab diabetes registry. Women burdened with gestational diabetes in Croatia in 2011 were followed up until year 2016. Those registered in CroDiab registry were recognised as new patients with diabetes. RESULTS: Among 40,641 deliveries in 2011, gestational diabetes was reported in 1181 (2.9%) women. Among them 853 (72.23%) were followed up in CroDiab diabetes registry and 32 (3.75%) were identified as new patients with diabetes. Median time from childbirth to onset of diabetes was 29.12 months. The diabetes group did not significantly differ to the group without diabetes according to age (p=0.587), level of education (p=0.549) or marital status (p=0.849) except that the diabetes group was significantly more obese than the group without diabetes (p=0.002). CONCLUSIONS: Based on CroDiab diabetes registry data prevalence of diabetes 5 years after pregnancy complicated with gestational diabetes is 3.75% in Croatia. Women with gestational diabetes during pregnancy, and especially those with higher BMIs, are an important risk group for developing diabetes later in life so screening and preventive measures should be oriented toward them in primary care settings. PMID- 29519627 TI - Antitumor and radiosensitizing effects of SKLB-163, a novel benzothiazole-2-thiol derivative, on nasopharyngeal carcinoma by affecting the RhoGDI/JNK-1 signaling pathway. AB - BACKGROUND AND PURPOSE: SKLB-163 is a novel benzothiazole-2-thiol derivative with antitumor activities. This study investigated the effects of SKLB-163 on nasopharyngeal carcinoma (NPC) and its mechanisms. MATERIALS AND METHODS: Rho GDP dissociation inhibitor (RhoGDI) expression was examined in NPC cell lines by western blot. Effects of SKLB-163 on proliferation, migration and radiosensitivity were assessed by MTT, wound healing and colony formation assays in vitro. Anti-tumor and anti-metastatic effects, and radiosensitizing effects of SKLB-163 were evaluated in a NPC lung metastatic nude mouse model and a subcutaneous xenograft mouse model. Effects of SKLB-163 on proliferation and apoptosis were assessed by PCNA immunohistochemistry and TUNEL assay in vivo. Key molecules in RhoGDI/c-Jun N-terminal kinases-1 (JNK-1) pathway were examined by western blot. RESULTS: RhoGDI was up-regulated in NPC cell lines. SKLB-163 inhibited proliferation and migration, and increased radiosensitivity of NPC cells. SKLB-163 inhibited tumor growth and metastases, and sensitized tumor to irradiation. The radiosensitizing effects were correlated with induction of apoptosis and suppression of proliferation. The molecular mechanism was the down regulation of RhoGDI and activation of JNK-1 signaling, and the subsequent activation of caspase-3 and the decrease in phosphorylated AKT. CONCLUSIONS: SKLB 163 shows strong anti-tumor activities against NPC and sensitizes NPC to irradiation by affecting the RhoGDI/JNK-1 pathway. PMID- 29519629 TI - One year follow-up after treatment with CCH for Dupuytren's disease: A prospective view. AB - : Aim Clostridium histolyticum collagenase (CCH) is nowadays an alternative treatment for the contracture of Dupuytren. Our objective is to assess its effectiveness at one year in a series of consecutive patients. MATERIAL AND METHOD: Prospective study with minimum follow-up of one year. Evaluation of results and adverse effects. RESULTS: A total of 75 joints treated in 51 patients were included. The average age was 65.18years (SD: 7.288) and 82.7% were males. The initial mean contraction of the MCP was 34.0 degrees (SD: 27.37), PIP 41.5 degrees (SD: 31.33) and combined impairment (MCF+IFP) of 75.5 degrees (SD: 35.2). Efficacy was achieved in 68 patients (90.7%). Adverse effects were mild and self limiting. The mean correction for the MCP joint was 28.96 degrees (SD: 26.90) and for PIP it was 28.72 degrees (SD: 24.30). The recurrence rate was 18 (24.0%) joints in 14 patients, being more frequent in severe cases. QuickDASH score showed minimal differences measured before the intervention and once a year. DISCUSSION: Our results show a better outcome in mild cases; the outcome was more favourable and with a higher success rate in the MCP joint. QuickDASH score is not a useful tool for the assessment of Dupuytren's contracture. CONCLUSIONS: Treatment with CCH for Dupuytren's contracture is an effective treatment in the medium term. It has a poorer outcome in combined joint disorders, 5th finger, PIP and severe cases. PMID- 29519628 TI - 4pi plan optimization for cortical-sparing brain radiotherapy. AB - BACKGROUND AND PURPOSE: Incidental irradiation of normal brain tissue during radiotherapy is linked to cognitive decline, and may be mediated by damage to healthy cortex. Non-coplanar techniques may be used for cortical sparing. We compared normal brain sparing and probability of cortical atrophy using 4pi radiation therapy planning vs. standard fixed gantry intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: Plans from previously irradiated brain tumor patients ("original IMRT", n = 13) were re-planned to spare cortex using both 4pi optimization ("4pi") and IMRT optimization ("optimized IMRT"). Homogeneity index (HI), gradient measure, doses to cortex and white matter (excluding tumor), brainstem, optics, and hippocampus were compared with matching PTV coverage. Probability of three grades of post-treatment cortical atrophy was modeled based on previously established dose response curves. RESULTS: With matching PTV coverage, 4pi significantly improved HI by 27% (p = 0.005) and gradient measure by 8% (p = 0.001) compared with optimized IMRT. 4pi optimization reduced mean and equivalent uniform doses (EUD) to all standard OARs, with 14-15% reduction in hippocampal EUD (p <= 0.003) compared with the other two plans. 4pi significantly reduced dose to fractional cortical volumes (V50, V40 and V30) compared with the original IMRT plans, and reduced cortical V30 by 7% (p = 0.008) compared with optimized IMRT. White matter EUD, mean dose, and fractional volumes V50, V40 and V30 were also significantly lower with 4pi (p <= 0.001). With 4pi, probability of grade 1, 2 and 3 cortical atrophy decreased by 12%, 21% and 26% compared with original IMRT and by 8%, 14% and 3% compared with optimized IMRT, respectively (p <= 0.001). CONCLUSIONS: 4pi radiotherapy significantly improved cortical sparing and reduced doses to standard brain OARs, white matter, and the hippocampus. This was achieved with superior PTV dose homogeneity. Such sparing could reduce the probability of cortical atrophy that may lead to cognitive decline. PMID- 29519630 TI - Initial support with no immobilisation as therapy of choice for fractures of the fifth metatarsal. AB - AIM: To demonstrate the effectiveness of early weight bearing with no immobilisation (functional therapy) applied to fractures of the fifth metatarsal. MATERIAL AND METHOD: A retrospective case and control observational study was performed among 382 fractures on the fifth metatarsal comparing functional, conservative-orthopaedic and surgical treatments. Fractures were classified according to the settlement on the distal, diaphyseal or proximal part of the bone, the recommended therapy and the treatment performed. Influence of age, profession and characteristics of the injury were considered and results were measured using the parameters incapacity for work and number and intensity of complications. DISCUSSION: Fractures of the fifth metatarsal are the most common injuries of the foot. Whether conservative or surgical treatment is recommended depends on the sort of fracture, the trend nowadays is to use non-invasive methods. CONCLUSIONS: Functional treatment for metatarsal fractures provides earlier healing and fewer adverse effects than conventional therapies, and becomes first choice for non-displaced fractures and most displaced fractures of the fifth metatarsal. PMID- 29519631 TI - "Post-cut": An endoscopic technique for managing impacted biliary stone within an entrapped extraction basket. AB - BACKGROUND AND STUDY AIMS: Ampullary impaction of an entrapped stone-basket complex is not an infrequent yet challenging event during endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study is to evaluate the feasibility, safety, and efficacy of "post-cut" for the management of such scenarios. PATIENTS AND METHODS: Patients with impacted biliary stone with an entrapped basket during ERCP at West China Hospital, Chengdu, China, from October 2004 to August 2014 were included in this retrospective study. Adequate biliary sphincterotomy was performed in all cases before attempted stone basket removal. Using free hand needle knife techniques, the authors extended the sphincterotomy along the long axis of the distal common bile duct to manage the biliary stone basket impaction. In comparison with "pre-cut", the authors coined the term "post cut" referring to this technique. The feasibility, safety, and potential complications of post-cut were analysed. RESULTS: "Post-cut" was performed in consecutive 10 cases of impacted biliary stone within an entrapped extraction basket. The size of the removed stone ranged from 6 mm to 13 mm. The length of post-cut is 2 mm to 4 mm. The impacted basket was easily retrieved in all patients without complications, including bleeding, perforation, and pancreatitis. CONCLUSION: "Post-cut" is a feasible, effective, and safe endoscopic technique when impaction of a biliary stone with an entrapped extraction basket develops. PMID- 29519632 TI - Total antioxidant status in fresh and stored human milk from mothers of term and preterm neonates. AB - BACKGROUND: Antioxidant defense of the body is assured by both endogenous and exogenous factors comprising several enzymes, vitamins, protein components and derivates and oligoelements. Breast milk has been proven to have important and essential antioxidant composition to prevent and protect against diseases in infancy. The objective of this study was to determine the total antioxidant status (TAS) of human milk and to evaluate the differences between premature milk and term milk at different moments of lactation (colostrum, transitional milk and mature milk). A second objective was to evaluate how TAS varies whether the human milk is refrigerated or frozen. METHODS: Pumped human milk samples of the third, seven and 30th day were collected from women who had term deliveries (30 cases) and preterm deliveries (60 cases). Samples were refrigerated (+4 degrees C) or frozen in domestic conditions (-20 degrees C) for various durations and TAS was determined using the ABTS(r) technique with Randox(r) reagents and compared for the two groups. RESULTS: Higher values were found in term versus preterm fresh milk at 30 days of lactation. A slight reduction in TAS was found after 72 h of refrigeration, while 1 week freezing produced significant decrease of total antioxidants. Freezing for 12 weeks reduced more than 50% of TAS in fresh milk. CONCLUSION: Breastfeeding provides the optimal antioxidant for neonates, regardless of gestational age. Fresh milk has the higher antioxidant power. When it is not available, refrigerated milk for 24 h is better than for 72 h and preferable than frozen milk. Freezing human milk for 3 months in household conditions markedly diminishes TAS. PMID- 29519633 TI - Improvement of industrially important microbial strains by genome shuffling: Current status and future prospects. AB - The growing demand for biotechnological products against limited metabolic capacity of industrially used microorganisms has led to an increased interest on strain-improvement over the last several decades, which aimed to enhance metabolite yield, substrate uptake and tolerance of the strains. Among a few techniques of strain-improvement, genome shuffling is the most recent and promising approach used for rapid strain-improvement that can yield a new strain by combining whole genomes of multi-parental microorganisms using the principles of protoplast fusion. Genome shuffling has brought a major breakthrough in the strain-improvement concept as it is found to be effective and reliable for expressing complex phenotypes. This review will discuss the technical aspects and applications of genome shuffling for various industrial strains to present its current status and recent progress. In the concluding remarks, a summary will be presented focusing on the major challenges and future outlooks of this technology. PMID- 29519634 TI - Weak electricigens: A new avenue for bioelectrochemical research. AB - Electroactivity appears to be a phylogenetically diverse trait independent of cell wall classification, with both Gram-negative and Gram-positive electricigens reported. While numerous electricigens have been observed, the majority of research focuses on a select group of highly electroactive species. Under favorable conditions, many microorganisms can be considered electroactive, either through their own mechanisms or exogenously-added mediators, producing a weak current. Such microbes should not be dismissed based on their modest electroactivity. Rather, they may be key to understanding what drives extracellular electron transfer in response to transient limitations of electron acceptor or donor, with implications for the study of pathogens and industrial bioprocesses. Due to their low electroactivity, such populations are difficult to grow in bioelectrochemical systems and characterise with electrochemistry. Here, a critical review of recent research on weak electricigens is provided, with a focus on the methodology and the overall relevance to microbial ecology and bioelectrochemical systems. PMID- 29519635 TI - Alcohol and injury among attendees at a busy inner city New Zealand emergency department. AB - INTRODUCTION: We present a study that provides a contemporary view of alcohol related injury prevalence amongst patients presenting to a New Zealand (NZ) emergency department (ED). METHODS: Adult injury patients presenting to Auckland City Hospital ED within 6 h of injury were invited to participate during three recruitment periods (2015-2016). An interviewer-administered questionnaire obtained information on demographic, injury, general health, and lifestyle factors. Breath alcohol samples were obtained. Descriptive and logistic regression analyses were conducted. RESULTS: 501 patients participated (71% response rate), 21% had consumed alcohol within 6 h of their injury. The majority were male, and overall falls were the most common mechanism of injury among all patients. Alcohol-related injuries most commonly occurred at home, and were significantly more likely to occur during the weekend (Friday-Sunday) and night hours (23:00-06:59). After controlling for the effects of confounding; 'poor' general health, engaging in leisure activities at the time of injury, and injuries resulting from assaults were associated with increasing the odds of alcohol-related injury. CONCLUSIONS: Acute alcohol use continues to play a considerable role in ED injury presentations in NZ. Continued policy, health promotion, and injury prevention efforts are required to reduce the harms associated with alcohol use. PMID- 29519636 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria: Low Back Pain. PMID- 29519637 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria: Asymptomatic Patient at Risk for Coronary Artery Disease. PMID- 29519638 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria Acute Onset Flank Pain-Suspicion of Stone Disease (Urolithiasis). PMID- 29519639 TI - Heterogeneity of mismatch repair defect in colorectal cancer and its implications in clinical practice. PMID- 29519640 TI - Emotional orienting during interoceptive threat in orthostatic intolerance: Dysautonomic contributions to psychological symptomatology in the postural tachycardia syndrome and vasovagal syncope. AB - Cognitive and emotional processes are influenced by interoception (homeostatic somatic feedback), particularly when physiological arousal is unexpected and discrepancies between predicted and experienced interoceptive signals may engender anxiety. Due to the vulnerability for comorbid psychological symptoms in forms of orthostatic intolerance (OI), this study investigated psychophysiological contributions to emotional symptomatology in 20 healthy control participants (13 females, mean age 36 +/- 8 years), 20 postural tachycardia syndrome (PoTS) patients (18 females, mean age 38 +/- 13 years) and 20 vasovagal syncope (VVS) patients (15 females, mean age 39 +/- 12 years). We investigated indices of emotional orienting responses (OR) to randomly presented neutral, pleasant and unpleasant images in the supine position and during the induced interoceptive threat of symptom provocation of head-up tilt (HUT). PoTS and VVS patients produced greater indices of emotional responsivity to unpleasant images and, to a lesser degree, pleasant images, during interoceptive threat. Our findings are consistent with biased deployment of response-focused emotion regulation (ER) while patients are symptomatic, providing a mechanistic underpinning of how pathological autonomic overexcitation predisposes to anxiogenic traits in PoTS and VVS patients. This hypothesis may improve our understanding of why orthostasis exacerbates cognitive symptoms despite apparently normal cerebral autoregulation, and offer novel therapeutic targets for behavioural interventions aimed at reducing comorbid cognitive-affective symptoms in PoTS and VVS. PMID- 29519641 TI - Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome. AB - OBJECTIVE: To review the association between orthostatic intolerance syndromes and both joint hypermobility and Ehlers-Danlos syndrome, and to propose reasons for identifying hereditary connective tissue disorders in those with orthostatic intolerance in the context of both clinical care and research. METHODS: We searched the published peer-reviewed medical literature for papers reporting an association between joint hypermobility or Ehlers-Danlos syndrome and orthostatic intolerance. RESULTS: We identified 10 relevant papers. Although methodological variability between studies introduces some limitations, the published literature consistently identifies a significantly higher prevalence of orthostatic intolerance symptoms in patients with joint hypermobility or Ehlers-Danlos syndrome than in healthy controls, and a significantly higher prevalence of cardiovascular and autonomic abnormalities both at rest and during orthostatic challenge. Postural tachycardia syndrome is the most commonly recognized circulatory disorder. The severity of orthostatic symptoms in those with EDS correlates with impairments in quality of life. CONCLUSION: There is a strong association between several forms of cardiovascular dysfunction, most notably postural tachycardia syndrome, and joint hypermobility or Ehlers-Danlos syndrome. We propose that recognition of joint hypermobility and Ehlers-Danlos syndrome among those with orthostatic intolerance syndromes has the potential to improve clinical care and the validity of research findings. PMID- 29519642 TI - Universal characteristics of evolution and development are inherent in fetal autonomic brain maturation. AB - Adverse prenatal environmental influences to the developing fetus are associated with mental and cardiovascular disease in later life. Universal developmental characteristics such as self-organization, pattern formation, and adaptation in the growing information processing system have not yet been sufficiently analyzed with respect to description of normal fetal development and identification of developmental disturbances. Fetal heart rate patterns are the only non-invasive order parameter of the developing autonomic brain available with respect to the developing complex organ system. The objective of the present study was to investigate whether universal indices, known from evolution and phylogeny, describe the ontogenetic fetal development from 20 weeks of gestation onwards. By means of a 10-fold cross-validated data-driven multivariate regression modeling procedure, relevant indices of heart rate variability (HRV) were explored using 552 fetal heart rate recordings, each lasting over 30 min. We found that models which included HRV indices of increasing fluctuation amplitude, complexity and fractal long-range dependencies largely estimated the maturation age (coefficients of determination 0.61-0.66). Consideration of these characteristics in prenatal care may not only have implications for early identification of developmental disturbances, but also for the development of system-theory-based therapeutic strategies. PMID- 29519643 TI - Managing fatigue in postural tachycardia syndrome (PoTS): The Newcastle approach. AB - Fatigue is a significant symptom that is frequently reported by those with postural tachycardia syndrome (PoTS). There are a variety of reasons why those with PoTS might experience fatigue and as a consequence an individualised approach to management is most appropriate. In this chapter we will examine the prevalence of fatigue in those with PoTS, its overlap with conditions such as chronic fatigue syndrome and describe a clinical approach to the management of fatigue in those with PoTS. PMID- 29519644 TI - Myosteatosis predicts survival after surgery for periampullary cancer: a novel method using MRI. AB - BACKGROUND: Myosteatosis, characterized by inter- and intramyocellular fat deposition, is strongly related to poor overall survival after surgery for periampullary cancer. It is commonly assessed by calculating the muscle radiation attenuation on computed tomography (CT) scans. However, since magnetic resonance imaging (MRI) is replacing CT in routine diagnostic work-up, developing methods based on MRI is important. We developed a new method using MRI-muscle signal intensity to assess myosteatosis and compared it with CT-muscle radiation attenuation. METHODS: Patients were selected from a prospective cohort of 236 surgical patients with periampullary cancer. The MRI-muscle signal intensity and CT-muscle radiation attenuation were assessed at the level of the third lumbar vertebra and related to survival. RESULTS: Forty-seven patients were included in the study. Inter-observer variability for MRI assessment was low (R2 = 0.94). MRI muscle signal intensity was associated with short survival: median survival 9.8 (95%-CI: 1.5-18.1) vs. 18.2 (95%-CI: 10.7-25.8) months for high vs. low intensity, respectively (p = 0.038). Similar results were found for CT-muscle radiation attenuation (low vs. high radiation attenuation: 10.8 (95%-CI: 8.5 13.1) vs. 15.9 (95%-CI: 10.2-21.7) months, respectively; p = 0.046). MRI-signal intensity correlated negatively with CT-radiation attenuation (r=-0.614, p < 0.001). CONCLUSIONS: Myosteatosis may be adequately assessed using either MRI muscle signal intensity or CT-muscle radiation attenuation. PMID- 29519645 TI - A bibliometric analysis assessing temporal changes in publication and authorship characteristics in The Knee from 1996 to 2016. AB - BACKGROUND: Evidence-based practice is a foundation to clinical excellence. However there remains little evidence on the characteristics of authors who contribute to the evidence-base and whether these have changed over time. The purpose of this study was to explore these characteristics by undertaking a bibliometric analysis to explore publication and authorship characteristics in a leading sub-speciality orthopaedic journal (The Knee) over a 20-year period. METHODS: All articles published in The Knee in 1996, 2006 and 2016 were identified. For each article, data collected included: highest academic award; profession; gender; continent of first and last author; total number of authors; the level of evidence; and funding source. We analysed temporal changes in these variables using appropriate statistical models. RESULTS: A total of 413 papers were analysed. Between 1996 to 2016 there has been a significant increase in the overall number of authors, the number of paper submitted from Asia, the proportion of Level 1 or 2 tiered evidence, the proportion of people with Bachelor or Master-level degrees as their highest level of educational award and the proportion of non-medically qualified authors (P<0.001). From 2006 to 2016 there was a significant increase in the proportion of articles whose first author was female (P=0.03), but no significant change in the number of females as last author (P=0.43). CONCLUSION: The findings indicate that there have been changes in publication and authorship characteristics in this sub-speciality orthopaedic journal during the past 20years. This provides encouraging indication of greater diversification and internationalisation of orthopaedic research. PMID- 29519646 TI - Corrigendum to "Retropharyngeal abscess as a result of hyaluronic acid injection pharyngoplasy: A first of its kind" [Am J Otolaryngol 38(6) (Nov-Dec 2017) 718 719]. PMID- 29519647 TI - Transoral robotic surgery for the treatment of laryngeal chondrosarcoma: A case report. AB - IMPORTANCE: Transoral robotic surgery has revolutionized the practice of head and neck surgery over the past decade, with indications now expanding to include laryngeal pathology. Although laryngeal chondrosarcoma is a rare entity, trends in otolaryngology literature suggest that it can frequently be managed with conservative approaches. We hope to inspire other head and neck surgeons to consider transoral robotic surgery for the treatment of such tumors so that outcomes data can be collected and studied. OBSERVATION: An 87-year-old male presented with a left-sided supraglottic mass that was found incidentally on imaging performed for an unrelated reason. Flexible fiberoptic laryngoscopy revealed a cystic-appearing supraglottic mass with near complete obstruction of the glottis airway. Internal review of the imaging demonstrated a 3.5 by 2.3 by 2.8 cm centrally hypodense lesion with a rim of calcification in the left paraglottic space, with resultant narrowing of the laryngeal airway. INTERVENTION: The patient underwent awake tracheostomy and transoral robotic subtotal resection of the mass using the Da Vinci surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA). The vocal folds, ventricular mucosa, and arytenoid cartilage were grossly preserved. Final pathology revealed a low-grade cartilaginous neoplasm consistent with low-grade chondrosarcoma. CONCLUSIONS AND RELEVANCE: Chondrosarcoma of the larynx is a rare entity that accounts for roughly 1% of laryngeal neoplasms. Recent trends in otolaryngology literature and practice suggest that low-grade chondrosarcomas can be effectively treated with organ-preserving, conservative surgery. Transoral robotic surgery offers numerous advantages over both open and endoscopic approaches. To our knowledge, this is the first report in the literature describing the successful use of transoral robotic surgery for the resection of a laryngeal chondrosarcoma. PMID- 29519648 TI - Novel methods for capturing variation in unintended pregnancy across time and place. PMID- 29519649 TI - Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model. AB - BACKGROUND: Estimates of pregnancy incidence by intention status and outcome indicate how effectively women and couples are able to fulfil their childbearing aspirations, and can be used to monitor the impact of family-planning programmes. We estimate global, regional, and subregional pregnancy rates by intention status and outcome for 1990-2014. METHODS: We developed a Bayesian hierarchical time series model whereby the unintended pregnancy rate is a function of the distribution of women across subgroups defined by marital status and contraceptive need and use, and of the risk of unintended pregnancy in each subgroup. Data included numbers of births and of women estimated by the UN Population Division, recently published abortion incidence estimates, and findings from surveys of women on the percentage of births or pregnancies that were unintended. Some 298 datapoints on the intention status of births or pregnancies were obtained for 105 countries. FINDINGS: Worldwide, an estimated 44% (90% uncertainty interval [UI] 42-48) of pregnancies were unintended in 2010 14. The unintended pregnancy rate declined by 30% (90% UI 21-39) in developed regions, from 64 (59-81) per 1000 women aged 15-44 years in 1990-94 to 45 (42-56) in 2010-14. In developing regions, the unintended pregnancy rate fell 16% (90% UI 5-24), from 77 (74-88) per 1000 women aged 15-44 years to 65 (62-76). Whereas the decline in the unintended pregnancy rate in developed regions coincided with a declining abortion rate, the decline in developing regions coincided with a declining unintended birth rate. In 2010-14, 59% (90% UI 54-65) of unintended pregnancies ended in abortion in developed regions, as did 55% (52-60) of unintended pregnancies in developing regions. INTERPRETATION: The unintended pregnancy rate remains substantially higher in developing regions than in developed regions. Sexual and reproductive health services are needed to help women avoid unintended pregnancies, and to ensure healthy outcomes for those who do experience such pregnancies. FUNDING: Dutch Ministry of Foreign Affairs and UK Aid from the UK Government. PMID- 29519650 TI - Safe removal of gloves from contact precautions: The role of hand hygiene. AB - BACKGROUND: Routine hand hygiene effectively removes methicillin-resistant Staphylococcus aureus (MRSA) and/or vancomycin resistant Enterococcus (VRE) from the ungloved hands of healthcare workers (HCWs) who are caring for patients under contact precautions, when exposure to bodily fluids is not expected. METHODS: HCWs' ungloved hands were cultured after hand hygiene with alcohol-based hand rub (ABHR) or soap-and-water wash after routine clinical care of patients known to be colonized or infected with MRSA or VRE. RESULTS: Two hundred forty samples from 40 HCWs were tested and found to be culture negative for either MRSA or VRE after contact with patients when 3 pumps of ABHR (0/80) or plain soap-and-water wash (0/80) were used. No VRE was observed in any of the 120 samples collected. Two plates (2/40) grew 1 colony-forming unit of MRSA after 2 pumps of ABHR. Two HCWs with positive plates were cultured negative on retesting. CONCLUSION: We showed that appropriate hand hygiene was effective in removing MRSA and VRE even when gloves were not used for routine clinical care, despite contact with patients known to be colonized with MRSA or VRE. A modified approach to glove use for dry contact with patients on contact precautions might improve patient safety within healthcare settings. PMID- 29519651 TI - Determinants of urinary catheter removal practices in the pediatric intensive care unit: A survey. AB - BACKGROUND: Prolonged use of indwelling catheters is associated with hospital acquired urinary tract infections (UTIs). Literature is scarce about the factors influencing urinary catheter removal and maintenance in children. This study aims to describe the determinants of urinary catheter removal in pediatric intensive care unit (PICU) patients. METHODS: Cross-sectional survey of 171 physicians and nurses working at 2 tertiary PICUs in Montreal, Canada. We used focus groups and literature review to design the survey questions and 3 clinical scenarios. We analyzed our results using descriptive statistics and multivariate multinomial regression. RESULTS: There were 131 (77%) participants who answered the survey. Factors prompting urinary catheter removal (P < .01) included recent extubation, superficial sedation level, fever, and history of previous UTI. Presence of shock (P < .01) and fluid overload (P < .05) were associated with maintenance of catheters. Physicians were more likely to remove urinary catheters than nurses in all scenarios. CONCLUSIONS: We identified a consistent set of variables that drive the removal of indwelling catheters in PICUs. Studies are needed to determine whether incorporating these determinants into infection control interventions will reduce urinary catheter use and catheter-associated UTIs in critically ill children. PMID- 29519652 TI - Genetic manipulation to overexpress rpaA altered photosynthetic electron transport in Synechocystis sp. PCC 6803. AB - Cyanobacteria are a group of prokaryotic organisms that perform oxygenic photosynthesis using a similar photosynthetic apparatus as is used in higher plants and eukaryotic algae. Cyanobacteria are also known to have a circadian rhythm. Here, we evaluated the effects on photosynthesis caused by the genetic manipulation of RpaA, which is a response regulator of a two-component regulatory system responsible for the signal output from circadian clocks. Using the unicellular cyanobacterium Synechocystis sp. PCC 6803, photosynthetic activities and transcript levels of photosystem I and photosystems II in the rpaA overexpressing strain were measured, and it was found that the parameters, such as Fv/Fm, Fv'/Fm', qP, and phiII, obtained from chlorophyll fluorescence analysis were decreased by rpaA overexpression. These results suggest that rpaA overexpression modified photosynthetic electron transport under normal light conditions. Thus, we demonstrated that RpaA regulates photosynthesis in cyanobacteria and can be a potential target of photosynthetic engineering in this cyanobacterium. PMID- 29519653 TI - Controlled cell morphology and liver-specific function of engineered primary hepatocytes by fibroblast layer cell densities. AB - Engineered primary hepatocytes, including co-cultured hepatocyte sheets, are an attractive to basic scientific and clinical researchers because they maintain liver-specific functions, have reconstructed cell polarity, and have high transplantation efficiency. However, co-culture conditions regarding engineered primary hepatocytes were suboptimal in promoting these advantages. Here we report that the hepatocyte morphology and liver-specific function levels are controlled by the normal human diploid fibroblast (TIG-118 cell) layer cell density. Primary rat hepatocytes were plated onto TIG-118 cells, previously plated 3 days before at 1.04, 5.21, and 26.1*103 cells/cm2. Hepatocytes plated onto lower TIG-118 cell densities expanded better during the early culture period. The hepatocytes gathered as colonies and only exhibited small adhesion areas because of the pushing force from proliferating TIG-118 cells. The smaller areas of each hepatocyte result in the development of bile canaliculi. The highest density of TIG-118 cells downregulated albumin synthesis activity of hepatocytes. The hepatocytes may have undergone apoptosis associated with high TGF-beta1 concentration and necrosis due to a lack of oxygen. These occurrences were supported by apoptotic chromatin condensation and high expression of both proteins HIF-1a and HIF-1b. Three types of engineered hepatocyte/fibroblast sheets comprising different TIG-118 cell densities were harvested after 4 days of hepatocyte culture and showed a complete cell sheet format without any holes. Hepatocyte morphology and liver-specific function levels are controlled by TIG 118 cell density, which helps to design better engineered hepatocytes for future applications such as in vitro cell-based assays and transplantable hepatocyte tissues. PMID- 29519654 TI - Characterization and induction of phenolic acid decarboxylase from Aspergillus luchuensis. AB - Awamori is a traditional distilled liquor in the Ryukyu Islands, made from steamed rice by the action of the black-koji mold Aspergillus luchuensis and awamori yeast Saccharomyces cerevisiae. One of the specific flavors in aged awamori kusu is vanillin, which is derived from ferulic acid (FA) in rice grains. FA is released from the cell wall material in the rice grain by ferulic acid esterase produced by A. luchuensis. Through decarboxylation of FA, 4 vinylguaiacol (4-VG) is produced, which is transferred to the distilled liquor, and converted to vanillin by natural oxidization during the aging process. However, the actual mechanism for conversion of FA to 4-VG in the awamori brewing process is unknown. A genetic sequence having homology to the phenolic acid decarboxylase (PAD)-encoding region from bacteria and the yeast Candida guilliermondii has been identified in A. luchuensis mut. kawachii. In the present study, recombinant PAD from A. luchuensis, designated as AlPAD, expressed as a homodimer, catalyzed the conversion of FA to 4-VG, displayed optimal catalytic activity at pH 5.7 and 40 degrees C, and was stable up to 50 degrees C. Both rice bran and FA could induce the bioconversion of FA to 4-VG and the expression of AlPAD in A. luchuensis. The amount of AlPAD determined using western blotting correlated with the level of FA decarboxylase activity during koji production. In awamori brewing process, AlPAD might be responsible for a part of the conversion of FA to 4-VG. PMID- 29519655 TI - Psychological factors and demands for breast and cervical cancer screening. AB - OBJECTIVE: The study aims to investigate relationships between demands for breast and cervical cancer screening (BCS/CCS) and related health beliefs. METHODS: The study used cluster-randomized sampling and collected data about demands for BCS/CCS and constructs of health beliefs model (HBM). It calculated indices of perceived risk and seriousness of the cancers and perceived effectiveness, benefits and difficulties of the screening; and performed descriptive and multivariate regression analysis of the demands and the HBM constructs. RESULTS: Less than 23.7% of respondents (N = 805) had ever undertaken BCS/CCS but 62.7% reported willingness to receive the service. Demands for BCS/CCS illustrated negative associations (Beta = -0.11 and -0.10) with age but positive (Beta = 0.15 and 0.11) links with education. The absolute values of standardized regression coefficients between the demand and the HBM constructs added up to 0.69 for BCS and 0.64 for CCS respectively, being 4-40 times that of age and education. CONCLUSIONS: Models incorporating all HBM constructs have substantially greater power than commonly researched single factors in explaining BCS/CCS demands. PRACTICE IMPLICATIONS: Comprehensive BCS/CCS promotion addressing all HBM constructs in a synergetic way may prove to be more effective. PMID- 29519657 TI - 2017 American Society for Metabolic and Bariatric Surgery Presidential Address. PMID- 29519656 TI - Adaptation and delivery of a motivational interviewing-based counseling program for persons acutely infected with HIV in Malawi: Implementation and lessons learned. AB - OBJECTIVE: Individuals diagnosed with acute HIV infection (AHI) are highly infectious and require immediate HIV prevention efforts to minimize their likelihood of transmitting HIV to others. We sought to explore the relevance of Motivational Interviewing (MI), an evidence-based counseling method, for Malawians with AHI. METHODS: We designed a MI-based intervention called "Uphungu Wanga" to support risk reduction efforts immediately after AHI diagnosis. It was adapted from Options and SafeTalk interventions, and refined through formative research and input from Malawian team members and training participants. We conducted qualitative interviews with counselors and participants to explore the relevance of MI in this context. RESULTS: Intervention adaptation required careful consideration of Malawian cultural context and the needs of people with AHI. Uphungu Wanga's content was relevant and key MI techniques of topic selection and goal setting were viewed positively by counselors and participants. However, rating levels of importance and confidence did not appear to help participants to explore behavior change as intended. CONCLUSION: Uphungu Wanga may have provided some added benefits beyond "brief education" standard of care counseling for Malawians with AHI. PRACTICE IMPLICATIONS: MI techniques of topic selection and goal setting may enhance prevention education and counseling for Malawians with AHI. PMID- 29519658 TI - Is laparoscopic sleeve gastrectomy safer than laparoscopic gastric bypass? a comparison of 30-day complications using the MBSAQIP data registry. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become popular due to its technical ease and excellent short-term results. Understanding the risk profile of LSG compared with the gold standard laparoscopic Roux-en-Y gastric bypass (LRYGB) is critical for patient selection. OBJECTIVES: To use traditional regression techniques and random forest classification algorithms to compare LSG with LRYGB using the 2015 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Data Registry. SETTING: United States. METHODS: Outcomes were leak, morbidity, and mortality within 30 days. Variable importance was assessed using random forest algorithms. Multivariate models were created in a training set and evaluated on the testing set with receiver operating characteristic curves. The adjusted odds of each outcome were compared. RESULTS: Of 134,142 patients, 93,062 (69%) underwent LSG and 41,080 (31%) underwent LRYGB. One hundred seventy-eight deaths occurred in 96 (.1%) of LSG patients compared with 82 (.2%) of LRYGB patients (P<.001). Morbidity occurred in 8% (5.8% in LSG versus 11.7% in LRYGB, P<.001). Leaks occurred in 1% (.8% in LSG versus 1.6% in LRYGB, P<.001). The most important predictors of all outcomes were body mass index, albumin, and age. In the adjusted multivariate models, LRYGB had higher odds of all complications (leak: odds ratio 2.10, P<.001; morbidity: odds ratio 2.02, P<.001; death: odds ratio 1.64, P<.01). CONCLUSION: In the Metabolic and Bariatric Surgery Accreditation and Quality Improvements data registry for 2015, LSG had half the risk-adjusted odds of death, serious morbidity, and leak in the first 30 days compared with LRYGB. PMID- 29519659 TI - Comment on: is laparoscopic sleeve gastrectomy safer than laparoscopic gastric bypass? A comparison of 30-day complications using the MBSAQIP data registry. PMID- 29519660 TI - Comment on: portomesenteric vein thrombosis in sleeve gastrectomy: a 10 year review. PMID- 29519661 TI - Comment on: The safety and efficacy of the procedure-less intra-gastric balloon. PMID- 29519662 TI - Live surgery courses: retrospective safety analysis after 11 editions. AB - INTRODUCTION: Live surgery is a topic of interest at every meeting or course in the field of surgery. The potential of laparoscopy for live broadcasting makes it an excellent tool in continuing medical education. Surgeons who participate in live surgeries are usually experienced, but several conditions may influence the results and safety of a procedure. OBJECTIVES: To analyze safety and outcomes in a series of patients who underwent surgery in the last 10 years in a live surgery course at our institution. SETTING: University public hospital in Spain. METHODS: Retrospective review of patients who underwent surgery during these courses from 2006 to 2016. Morbidity, mortality, and long-term results were analyzed. RESULTS: Of 107 patients, 74 (68.5%) were women, and 38 (35.2%) had revision surgery. Five had surgery during previous editions. The most performed procedures were Roux-en Y gastric bypass (38.9%), sleeve gastrectomy (16.7%), and duodenal switch (14%). Ten cases were endoscopic procedures. Morbidity was 13% (14 cases), and 6 required early postoperative revision (5.6%). Most of the complications were Clavien types III and I. Bleeding was the most common (72.4%). There was no anastomotic leak, but 1 duodenal stump leak occurred. During follow-up, 6 patients had a surgical complication and 5 required revision surgery. There was no mortality. DISCUSSION: We found higher morbidity and reoperation rates. The conversion rate in long-term follow-up was higher. Despite the educational benefits, we should take into consideration the higher risk to our patients for future editions. PMID- 29519663 TI - Patients with clinically metabolically healthy obesity are not necessarily healthy subclinically: further support for bariatric surgery in patients without metabolic disease? AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) increases the risk of liver cirrhosis and hepatocellular carcinoma and is also strongly correlated with extrahepatic diseases, including cardiovascular disease and type 2 diabetes. This risk of NAFLD among obese individuals who are otherwise metabolically healthy is not well characterized. OBJECTIVES: To determine the prevalence and characteristics of NAFLD in individuals with metabolically healthy obesity. SETTING: A tertiary, academic, referral hospital. METHODS: All patients who underwent bariatric surgery with intraoperative liver biopsy from 2008 to 2015 were identified. Patients with preoperative hypertension, dyslipidemia, or prediabetes/diabetes were excluded to identify a cohort of metabolically healthy obesity patients. Liver biopsy reports were reviewed to determine the prevalence of NAFLD. RESULTS: A total of 270 patients (7.0% of the total bariatric surgery patients) met the strict inclusion criteria for metabolically healthy obesity. The average age was 38 +/- 10 years and the average body mass index was 47 +/- 7 kg/m2. Abnormal alanine aminotransferase (>45 U/L) and asparate aminotransferase levels (>40 U/L) were observed in 28 (10.4%) and 18 (6.7%) patients, respectively. A total of 96 (35.5%) patients had NAFLD with NALFD Activity Scores 0 to 2 (n = 61), 3 to 4 (n = 25), and 5 to 8 (n = 10). A total of 62 (23%) patients had lobular inflammation, 23 (8.5%) had hepatocyte ballooning, 22 (8.2%) had steatohepatitis, and 12 (4.4%) had liver fibrosis. CONCLUSION: Even with the use of strict criteria to eliminate all patients with any metabolic problems, a significant proportion of metabolically healthy patients had unsuspected NAFLD. The need and clinical utility of routine screening of obese patients for fatty liver disease and the role of bariatric surgery in the management of NAFLD warrants further investigation. PMID- 29519665 TI - SOARD Category 1 CME Credit Featured Articles, Volume 14, March 2018. PMID- 29519664 TI - Cost analysis and risk factors for interval cholecystectomy after bariatric surgery: a national study. AB - BACKGROUND: Besides rate and extent of weight loss, little is known regarding demographic factors predicting interval cholecystectomy (IC) after bariatric surgery and its incremental costs. OBJECTIVES: We aim to identify risk factors predicting IC after bariatric surgery and quantify its associated costs. SETTING: Nationally representative sampling of acute care hospitals across the United States. METHODS: A retrospective cohort study was performed using the National Readmission Database 2010 to 2014. Cox proportional hazard analyses were used to identify risk factors for IC. Linear regression models were constructed to examine associations between cholecystectomy timing and cumulative hospitalization costs. RESULTS: An estimated national total of 553,658 patients received bariatric surgery during the study period. Of these, 3.3% received concomitant cholecystectomy (CC). After adjusting for bariatric procedure type, age, sex, complication, and length of stay, CC was independently associated with a US$1589 increase in hospitalization cost (95% confidence interval US$1021-2158, P<.01). Of patients that received no CC, only .6% underwent IC during the up to 1 year follow-up. Age<35 (P<.01), female sex (P<.01), and high preoperative body mass index (P = .03) were all risk factors for IC. IC was independently associated with a US$1499 higher cumulative hospitalization cost than CC (P<.01, 95% confidence interval US$844-2154). CONCLUSIONS: Despite the higher absolute cost of IC, its low incidence does not financially justify a routine prophylactic CC approach. In addition, no significant reduction in cholecystectomy-related complications was achieved by performing CC. An individualized approach taking identified risk factors for IC into consideration is recommended when deciding whether to perform prophylactic CC. PMID- 29519666 TI - Rare Tongue Compromising of Mucocutaneous Leishmaniasis by Leishmania Subgenus Viannia. PMID- 29519667 TI - Comparison of rocuronium-induced neuromuscular blockade in second trimester pregnant women and non-pregnant women. AB - BACKGROUND: This study set out to compare the onset and duration of rocuronium induced neuromuscular blockade in second trimester pregnant women and non pregnant women receiving general anesthesia. METHODS: Forty-seven pregnant (Group P) and forty-seven non-pregnant (Group C) women were enrolled. Anesthesia was induced with propofol 2.0 mg/kg and rocuronium 0.6 mg/kg, and neuromuscular blockade was assessed with an accelerometric sensor using train-of-four stimulation (TOF-Watch(r) SX). Tracheal intubation was performed at maximum depression of the first twitch (T1) and anesthesia was maintained with sevoflurane 1.5-2.5% and 50% oxygen in air. We recorded the times to maximum T1 depression and 5% and 25% T1 recovery, as well as the mean arterial pressure and heart rate at baseline, injection of rocuronium, intubation, and 5% and 25% T1 recovery. RESULTS: The onset of rocuronium-induced neuromuscular blockade (time to maximum T1 depression) did not differ significantly between the groups. The duration (time to 25% T1 recovery) was significantly longer in Group P than in Group C (45.7 +/- 12.9 min vs 40.6 +/- 10.4 min, P <0.037). During the recovery period from the blockade, the mean arterial pressure was significantly lower in Group P than in Group C. CONCLUSION: Our data showed that the rocuronium-induced neuromuscular blockade did not significantly differ in onset but lasted significantly longer in second trimester pregnant women compared with non pregnant women. PMID- 29519668 TI - Ultrasonographic evaluation of gastric contents in term pregnant women fasted for six hours. AB - BACKGROUND: Current fasting guidelines suggest six hours are adequate to minimise the aspiration risk after a light meal consumed by pregnant women undergoing elective caesarean section. We assessed gastric contents in non-labouring pregnant women, using ultrasonographic analysis. METHODS: In a prospective study, pregnant women >=36 weeks' gestation, without conditions likely to influence gastric emptying, underwent ultrasonographic analysis of their gastric antrum, after six hours of fasting following a standardised light meal. The primary outcome was solid food content in the antrum. Other outcomes included fluid in the supine and right lateral positions, antral cross-sectional area and estimated residual gastric fluid volume. Antral grades were classified: grade 0 = absence of fluid in both supine and right lateral positions: grade 1 = fluid present in the right lateral position only: grade 2 = fluid in both positions. RESULTS: Complete data were available in 46/51 (90%) women. No woman had solid food visible. Antral grades 0, 1 and 2 were seen in 6 (13%), 36 (78%) and 4 (9%) women respectively. Eighteen of 48 women (37.5%) had a residual volume greater than 1.5 mL/kg. Of those with a grade 1 antrum, 13/36 (36%) had residual volumes in excess of 1.5 mL/kg. For grade 2, this was 4/4 (100%). CONCLUSIONS: Our cohort of pregnant women fasted for six hours had no solid food visible in the antrum, but many had both qualitative and quantitative ultrasonographic evidence of gastric volumes potentially associated with aspiration risk. This suggests that pregnancy specific fasting guidelines may be required. PMID- 29519669 TI - Primary hepatic marginal zone lymphoma: A rare coincidence. AB - Primary hepatic lymphoma (PHL) is an extremely rare disease and is often misdiagnosed. The optimal therapy is still unclear and the outcomes are uncertain. Among PHLs, a primary hepatic low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue is still rarer. The present study reports the case of an elderly female diagnosed with PHL (mucosa-associated lymphoid tissue) and treated with single agent rituximab. After 18 months, she had a progressive disease and developed Waldenstorms macroglobulinemia concomitantly. To date, the patient has received 2 cycles of the RCOP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen and patient's condition is presently stable. This case is reported for its rarity and to convey the importance of the meticulous examination of the tissue. Diagnosis of this condition is important, because the disease is treatable. PMID- 29519670 TI - Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults. AB - BACKGROUND: T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. METHODS: We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18-46years and 24 subjects aged 50years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18months. FINDINGS: Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold increase and peak immune responses after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1. In a mixed regression model, T cell responses over 18months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP+M1. INTERPRETATION: A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP+M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. FUNDING SOURCE: Medical Research Council UK, NIHR BMRC Oxford. PMID- 29519671 TI - Neuroparacoccidioidomycosis mimicking brain tumor in an immunocompetent patient. PMID- 29519672 TI - French clinical practice guidelines for Moyamoya angiopathy. PMID- 29519673 TI - Fatigue loading of tendon results in collagen kinking and denaturation but does not change local tissue mechanics. AB - Fatigue loading is a primary cause of tendon degeneration, which is characterized by the disruption of collagen fibers and the appearance of abnormal (e.g., cartilaginous, fatty, calcified) tissue deposits. The formation of such abnormal deposits, which further weakens the tissue, suggests that resident tendon cells acquire an aberrant phenotype in response to fatigue damage and the resulting altered mechanical microenvironment. While fatigue loading produces clear changes in collagen organization and molecular denaturation, no data exist regarding the effect of fatigue on the local tissue mechanical properties. Therefore, the objective of this study was to identify changes in the local tissue stiffness of tendons after fatigue loading. We hypothesized that fatigue damage would reduce local tissue stiffness, particularly in areas with significant structural damage (e.g., collagen denaturation). We tested this hypothesis by identifying regions of local fatigue damage (i.e., collagen fiber kinking and molecular denaturation) via histologic imaging and by measuring the local tissue modulus within these regions via atomic force microscopy (AFM). Counter to our initial hypothesis, we found no change in the local tissue modulus as a consequence of fatigue loading, despite widespread fiber kinking and collagen denaturation. These data suggest that immediate changes in topography and tissue structure - but not local tissue mechanics - initiate the early changes in tendon cell phenotype as a consequence of fatigue loading that ultimately culminate in tendon degeneration. PMID- 29519674 TI - Temporal-spatial reach parameters derived from inertial sensors correlate to neurodevelopment in toddlers born preterm. AB - Temporal-spatial reach parameters are revealing of upper-limb function in children with motor impairments, but have not been quantified in a toddler population. This work quantitatively characterizes temporal-spatial reach in typically-developing (TD) and very-low-birth-weight (VLBW) preterm toddlers, who are at increased risk of motor impairment. 47 children born VLBW (<1500 g birth weight; <=32 weeks gestation) and 22 TD children completed a reaching assessment at 18-22 months of age, adjusted for prematurity. Inertial sensors containing accelerometers, gyroscopes and magnetometers were fixed to toddlers' wrists while they reached for a cube. Reach time, path length, velocity at contact, peak velocity magnitude and timing, acceleration at contact, and peak acceleration were derived from inertial-sensor and high-speed video data. Preterm children also received the Bayley Scales of Infant Development-3rd Edition (BSID-III). Compared to TD toddlers, preterm toddlers had significantly different reach path length, velocity at contact, peak velocity magnitude and timing, acceleration at contact, and peak acceleration. Among preterm toddlers, decreased reach time (rho = -.346, p = .018), decreased time to peak velocity (r = -.390, p = .007), and increased peak acceleration (r = .298, p = .044) correlated to higher BSID-III fine motor scores. Toddlers with below-average fine motor scores had significantly higher peak and contact velocity. Preterm toddlers demonstrated substantial differences in temporal-spatial reach parameters compared to TD toddlers, and evidence indicated several reach parameters were revealing of function and may be useful as a clinical assessment. PMID- 29519675 TI - The Developing Infant Creates a Curriculum for Statistical Learning. AB - New efforts are using head cameras and eye-trackers worn by infants to capture everyday visual environments from the point of view of the infant learner. From this vantage point, the training sets for statistical learning develop as the sensorimotor abilities of the infant develop, yielding a series of ordered datasets for visual learning that differ in content and structure between timepoints but are highly selective at each timepoint. These changing environments may constitute a developmentally ordered curriculum that optimizes learning across many domains. Future advances in computational models will be necessary to connect the developmentally changing content and statistics of infant experience to the internal machinery that does the learning. PMID- 29519676 TI - Statin use is associated with carotid plaque composition: The Rotterdam Study. AB - BACKGROUND: Statins represent a key treatment for cardiovascular disease. Nevertheless, the direct effects of statin treatment on the composition of atherosclerotic plaques remain elusive. OBJECTIVES: We aimed to investigate the association of statin treatment with the presence of different plaque components located in the carotid arteries within a population-based setting. METHODS: From the population-based Rotterdam Study, 1740 participants with carotid atherosclerosis (mean age 72.9 years, 46% women) underwent MRI of the carotid arteries to determine the presence of calcification, lipid core, and intraplaque hemorrhage. Information for the duration and dosage of statin use was obtained from pharmacy records for all participants. We used logistic regression models to study the association of statin use with the presence of plaque components. RESULTS: Statin treatment was associated with a higher presence of calcification (OR: 1.73 [95% CI: 1.22-2.44]). Longer duration of use strengthened this association (OR: 1.82 [95% CI: 1.00-3.33] for 10 to 48 months, and OR 1.74 [95% CI: 1.09-2.77] for >48 months, compared to OR: 1.65 [95% CI: 0.94-2.89] for <=10 months). Current statin treatment was also associated with a lower presence of lipid core (OR: 0.66 [95% CI: 0.42-1.04]), but only when using statins for 10 months or less. Any dosage of statins was associated with a higher presence of calcification, whilst only high dosages (DDD > 1.33) were associated with a lower presence of lipid core. CONCLUSIONS: Active, high-dosage statin use seems to beneficially influence the composition of carotid atherosclerosis by shifting the composition from vulnerable plaque with a lipid core to more stable calcified plaque. PMID- 29519677 TI - Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy. AB - OBJECTIVE: High-fat diet-induced obesity leads to the development of hypertrophy and heart failure through poorly understood molecular mechanisms. We have recently shown that fibroblast growth factor-21 (FGF21) is produced by the heart and exerts protective effects that prevent cardiac hypertrophy development and oxidative stress. The aim of this study was to determine the effects of FGF21 on the cardiomyopathy associated with obesity development. RESULTS: Fgf21-/- mice showed an enhanced increase in the heart weight/tibia length (HW/TL) ratio in response to the high-fat diet. In keeping with this, echocardiographic measurements confirmed enhanced cardiac hypertrophy in Fgf21-/- mice. At the cellular level, the area of cardiomyocytes was increased in Fgf21-/- mice fed a high-fat diet. Furthermore, a high-fat diet induced fatty acid oxidation in the hearts of Fgf21-/- mice accompanied by an increase in cardiac oxidative stress. Oil-red O staining revealed the presence of higher amounts of lipid droplets in the hearts of Fgf21-/- mice fed a high-fat diet relative to wt mice fed this same diet. Finally, Fgf21-/- mice fed a high-fat diet showed impaired cardiac autophagy and signs of inactive cardiac lipophagy, suggesting that FGF21 promotes autophagy in cardiomyocytes. CONCLUSIONS: Our data indicate that a lack of FGF21 enhances the susceptibility of mice to the development of obesity-related cardiomyopathy. Furthermore, we demonstrate that this cardiac dysfunction is associated with deleterious lipid accumulation in the heart. An impaired ability of FGF21 to promote autophagy/lipophagy may contribute to lipid accumulation and cardiac derangements. PMID- 29519678 TI - Pyoderma gangrenosum and primary cutaneous cryptococcosis in an ulcerative colitis patient. PMID- 29519679 TI - Acute severe pulmonary toxicity due to biosimilar infliximab in a Crohn's disease patient. PMID- 29519680 TI - Cervicothoracic abscess secondary to transesophageal ultrasound-guided fine needle aspiration. PMID- 29519681 TI - A novel surgical technique for a rat subcutaneous implantation of a tissue engineered scaffold. AB - OBJECTIVES: Subcutaneous implantations in small animal models are currently required for preclinical studies of acellular tissue to evaluate biocompatibility, including host recellularization and immunogenic reactivity. METHODS: Three rat subcutaneous implantation methods were evaluated in six Sprague Dawley rats. An acellular xenograft made from porcine pericardium was used as the tissue-scaffold. Three implantation methods were performed; 1) Suture method is where a tissue-scaffold was implanted by suturing its border to the external oblique muscle, 2) Control method is where a tissue-scaffold was implanted without any suturing or support, 3) Frame method is where a tissue scaffold was attached to a circular frame composed of polycaprolactone (PCL) biomaterial and placed subcutaneously. After 1 and 4 weeks, tissue-scaffolds were explanted and evaluated by hematoxylin and eosin (H&E), Masson's trichrome,Picrosirius Red, transmission electron microscopy (TEM), immunohistochemistry, and mechanical testing. RESULTS: Macroscopically, tissue scaffold degradation with the suture method and tissue-scaffold folding with the control method were observed after 4 weeks. In comparison, the frame method demonstrated intact tissue scaffolds after 4 weeks. H&E staining showed progressive cell repopulation over the course of the experiment in all groups with acute and chronic inflammation observed in suture and control methods throughout the duration of the study. Immunohistochemistry quantification of CD3, CD 31, CD 34, CD 163, and alphaSMA showed a statistically significant differences between the suture, control and frame methods (P < 0.05) at both time points. The average tensile strength was 4.03 +/- 0.49, 7.45 +/- 0.49 and 5.72 +/- 1.34 (MPa) after 1 week and 0.55 +/- 0.26, 0.12 +/- 0.03 and 0.41 +/- 0.32 (MPa) after 4 weeks in the suture, control, and frame methods; respectively. TEM analysis showed an increase in inflammatory cells in both suture and control methods following implantation. CONCLUSION: Rat subcutaneous implantation with the frame method was performed with success and ease. The surgical approach used for the frame technique was found to be the best methodology for in vivo evaluation of tissue engineered acellular scaffolds, where the frame method did not compromise mechanical strength, but it reduced inflammation significantly. PMID- 29519682 TI - Left subclavian artery dissection associated with connective tissue abnormalities resembling Marfan-like syndrome in an English bulldog. AB - The unexpected demise of a 12-year-old male neutered English bulldog solicited a gross examination, which revealed a blood-filled space occurring in the proximal left subclavian artery (LSA). It originated about 1 cm from the branching point of the vessel and progressively dilated for 3 cm distal to this origin. Histopathological investigation showed that the tunica media of the LSA was more than 50% split, with the blood-filled space dissecting through the arterial wall. In the tunica media of the LSA, severe multifocal fragmentation and/or loss of the elastic fibers was observed. The retained disorganized elastic fibers were separated and disoriented due to accumulations of acid mucopolysaccharide. Marked, diffuse medial, and adventitial fibrous tissue deposition was also identified. The cause of death was attributed to acute hemorrhagic and necrotizing pancreatitis with pulmonary edema, suggesting that LSA dissection was an incidental finding. Subclavian artery dissection is extremely rare in humans, where the involvement of the LSA in cases of aortic dissection both with or without Marfan syndrome has been reported. Aortic and pulmonary artery dissection in bovines and aortic aneurysm and dissection in dogs have been reported to be associated with Marfan and Marfan-like syndromes, respectively. Histopathological findings suggestive of underlying connective tissue abnormalities resembling Marfan-like syndrome (i.e., the appearance of the elastic tissue and the degenerative changes of the tunica media) were detected in the first case of LSA dissection in dogs and veterinary medicine, herein described. PMID- 29519683 TI - The health of nurses: Political rhetoric or a valid concern? PMID- 29519684 TI - Nurses and physiotherapists' experience in mobilising postoperative orthopaedic patients with altered mental status: A phenomenological study. AB - BACKGROUND: A major goal of care for orthopaedic surgical patients is the achievement of their pre-morbid functional level or at least an improvement of their functional ability. However, patients with altered mental status can significantly impact this and other outcomes and influence the delivery of care. Patient mobilisation is a role shared by both nurses and physiotherapists. AIMS: To enhance the understanding of nurses and physiotherapists' experience in mobilising postoperative orthopaedic patients with altered mental status. METHOD: Three nurses and three physiotherapists were recruited using purposive sampling. Data was collected through interviews and analysed using Burnard's 14 stages of thematic content analysis. RESULTS: Four main categories emerged from the study: altruism, interprofessional specialist practice, patient dynamics and challenges. Nurses and physiotherapists' experience have more similarities than differences under the four categories. CONCLUSION: Nurses and physiotherapists experience numerous challenges from both patient and resources related factors such as environment, staffing and time limitations; safety risks to patient and staff; and communication barriers due to patient's altered mental state. While tensions and variations in priorities of care delivery exist between the two groups, interdisciplinary collaboration of both professional groups was clearly evident and enabled optimisation of mobilisation goals for this patient population and revealed more similarities than differences in their experience. Patient and staff safety takes precedence over mobilisation and safety risks in this patient group can be mitigated by adequate resources, competence, and teamwork. PMID- 29519685 TI - The use of patient reported outcome measures (PROMs) in clinical assessment. PMID- 29519687 TI - Reprint of: Clinical management of tardive dyskinesia: Five steps to success. AB - Tardive dyskinesia (TD) has long been thought to be a generally irreversible consequence of the use of dopamine receptor blocking agents. There is now an opportunity to successfully manage this condition with agents approved by the US Food and Drug Administration. This is important because TD has not been eliminated with the use of second-generation antipsychotics, and the expansion of antipsychotics to treat conditions other than schizophrenia has resulted in millions of additional individuals at risk for developing TD. Recognition of TD requires careful observation; a structured approach using the Abnormal Involuntary Movement Scale is encouraged. Harm reduction can be achieved by using antipsychotics judiciously when possible and by paying attention to other modifiable risk factors such as drug-induced parkinsonian symptoms and the use of anticholinergic medication. Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials. PMID- 29519686 TI - Nuciferine and paeoniflorin can be quality markers of Tangzhiqing tablet, a Chinese traditional patent medicine, based on the qualitative, quantitative and dose-exposure-response analysis. AB - BACKGROUND: Diabetes is a chronic disease associated with significant morbidity and mortality. Tangzhiqing tablet (TZQ), a Chinese traditional patent medicine, has been in phase 2 clinical trial for the treatment of diabetes mellitus. However, the current quality evaluation of TZQ still remains rather obscure. PURPOSE: The promising quality markers (Q-markers) of TZQ will be sought for its quality assessment and process control based on the qualitative, quantitative and dose-exposure-response analysis. METHODS: The fingerprint analysis of TZQ was carried out through ultra high performance liquid chromatography- quadrupole time of-flight/ mass spectrometry (UPLC-Q-TOF/MS) assay. Multicomponent quantitative analysis was implemented to the main ingredients of nuciferine, paeoniflorin, salvianolic acid B, hyperoside and rutin in TZQ by means of LC analysis. The dose exposure-response relationship of TZQ was revealed by a placebo-controlled, 5-way crossover study in healthy Chinese subjects. The potential Q-markers in plasma were determined by a liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method. The therapeutic effect of TZQ was expressed as the glucose lowering profile. The exposure-response relevance was developed between the concentration of Q-markers and the glucose-lowering effect of TZQ. RESULTS: 46 compounds were identified or tentatively characterized from TZQ. The contents of paeoniflorin, nuciferine, salvianolic acid B, hyperoside and rutin in TZQ were 6.40, 1.75, 1.70, 0.004, and 0.006 mg, respectively. However, salvianolic acid B, hyperoside and rutin could hardly be detected in human plasma under the current LC-MS/MS condition. The exposures of nuciferine and paeoniflorin (AUC0-3, Cmax) were dose-proportionality in human at the studied dosage ranges. The glucose lowering effect appeared to increase proportionally with increasing TZQ dose in healthy volunteers. A clockwise hysteresis was displayed between the exposure of nuciferine and paeoniflorin and the glucose-lowering effect of TZQ. CONCLUSION: Nuciferine and paeoniflorin were identified as the promising Q-markers of TZQ based on the fingerprint qualitative analysis, multicomponent quantitative analysis and dose-exposure-response analysis. The two Q-markers are meaningful to ensure the quality assessment and process control of TZQ. PMID- 29519688 TI - Exploring antibody-dependent adaptive immunity against aortic extracellular matrix components in experimental aortic aneurysms. AB - BACKGROUND: Recent evidence suggests that adaptive immunity develops during abdominal aortic aneurysm evolution. Uncertainties remain about the antigens implicated and their role in inducing rupture. Because antigens from the extracellular matrix (ECM) have been suspected, the aim of this experimental study was to characterize the role of adaptive immunity directed against antigens from the aortic ECM. METHODS: In a first step, an experimental model of abdominal aortic aneurysm rupture based on adaptive immunity against the ECM was developed and characterized. Forty 4-week-old male Lewis rats were divided into two groups. In the ECM group (n = 20), rats were presensitized against the guinea pig aortic ECM before implantation of a decellularized aortic xenograft (DAX). In the control group (n = 20), rats were not presensitized before DAX implantation. In each group, half the rats were sacrificed at day 3 to analyze early mechanisms involved after DAX implantation. In a second step, we aimed to assess which ECM component was most efficient in inducing rupture. For this purpose, the nonfibrillar and fibrillar ECM components were sequentially extracted from the guinea pig aortic wall. Forty Lewis rats were then divided into four groups. Each group was presensitized against one ECM component (structural glycoproteins and proteoglycans, collagen, elastin alone, and elastin-associated glycoproteins) before DAX implantation. Apart from those that experienced rupture, rats were sacrificed at day 21. Xenografts were harvested for histologic, immunofluorescence, and conditioned medium analyses. RESULTS: In total, early aortic rupture occurred in 80% of the ECM group vs 0% of the control group (P < .001). In the ECM group, major circumferential immunoglobulin deposits were observed in combination with the C3 complement fraction, without cell infiltration. Conditioned medium analysis revealed that matrix metalloproteinase 9 and myeloperoxidase levels and elastase activities were significantly increased in this group. Immunofluorescence analysis demonstrated that myeloperoxidase co localized with tissue-free DNA and histone H4, highlighting local neutrophil activation and formation of neutrophil extracellular traps. Following differential presensitization, it appeared that rats presensitized against structural glycoproteins and proteoglycans were significantly more susceptible to rupture after DAX implantation. CONCLUSIONS: Stimulating adaptive immunity against the aortic ECM, especially structural glycoproteins and proteoglycans, triggers rupture after DAX implantation. Further studies are needed to assess the precise proteins involved. PMID- 29519689 TI - Reliability and validity of the Japanese version of the Glasgow Edinburgh Throat Scale (GETS-J): Use for a symptom scale of globus sensation. AB - OBJECTIVE: Globus sensation, a feeling of lump or something stuck in the throat, could be caused by structural, functional, and psychogenic diseases. Due to a possible multifactorial nature of the disease, neither diagnosing test battery nor standard treatment for globus sensation has been established. Therefore, a questionnaire to accurately identify globus patients and evaluate the severity of the disease is desired. Glasgow Edinburgh Throat Scale (GETS) is a 10-item questionnaire about the throat symptoms consisting of three subscales relating to dysphagia, globus sensation, and pain/swelling in the throat. It was reported that globus patients marked high scores specifically for the globus scale among three scales, indicating that GETS can be used as a valid symptom scale for globus sensation. Aims of this study were to translate GETS into Japanese and to test its reliability and validity. METHODS: Fifty-five patients complaining of globus sensation without abnormal endoscopic and CT findings were enrolled into the study. They were asked to answer the questions of GETS translated into Japanese (GETS-J). Reliability (internal consistency) of the questionnaire was tested using Cronbach's coefficient alpha. To test the validity, principal components analysis was used to identify the factorial structure of the questionnaire and GETS-J data were compared with those reported in the original GETS. Contribution of psychiatric comorbidities to globus sensation was also investigated by examining the correlation between Hospital Anxiety and Depression Scale (HADS) and GETS-J. RESULTS: Reliability of the questionnaire examined by the Cronbach's coefficient alpha was satisfactory and all higher than 0.75. Principal components analysis identified following three questions as the globus scale: Q1, Feeling something stuck in the throat; Q5, Throat closing off; Q9, Want to swallow all the time. Somatic distress, i.e., patients' reaction to throat symptoms, was significantly correlated with globus scale (r=0.680). Anxiety component of HADS was significantly correlated with somatic distress but not with globus scale. These results were consistent with those of the original GETS except for the replacement of Q3 (discomfort/irritation in the throat) to Q5 (throat closing off) for globus scale in GETS-J. CONCLUSION: Translation of GETS into Japanese showed high reliability and validity, suggesting that translation and cross-cultural adaptation were not problematic. High correlation of globus scale of GETS-J with somatic distress indicated that GETS-J could be a useful questionnaire to identify the globus patients and evaluate the severity of the disease. Anxiety may complicate the somatic distress in patients with globus sensation. PMID- 29519690 TI - Music enjoyment with cochlear implantation. AB - Since the advent of cochlear implant (CI) surgery in the 1960s, there have been remarkable technological and surgical advances enabling excellent speech perception in quiet with many CI users able to use the telephone. However, many CI users struggle with music perception, particularly with the pitch-based and melodic elements of music. Yet remarkably, despite poor music perception, many CI users enjoy listening to music based on self-report questionnaires, and prospective studies have suggested a disassociation between music perception and enjoyment. Music enjoyment is arguably a more functional measure of one's listening experience, and thus enhancing one's listening experience is a worthy goal. Recent studies have shown that re-engineering music to reduce its complexity may enhance enjoyment in CI users and also delineate differences in musical preferences from normal hearing listeners. PMID- 29519691 TI - Mortality and Readmission Following Hospitalisation for Heart Failure in Australia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Heart failure (HF) is a common, costly condition with an increasing burden on Australian health care system resources. Knowledge of the burden of HF on patients and on the health system is important for resource allocation. This study is the first systematic review to estimate the mortality and readmission rates after hospitalisation for HF in the Australian population. METHODS: We searched for studies of HF hospitalisation in Australia published between January 1990 and May 2016, using a systematic search of PubMed, Medline, Scopus, Web of Science, EMBASE and Cochrane Library databases. Studies reporting 30-day and/or 1 year outcomes for mortality or readmission following hospitalisation were eligible and included in this study. RESULTS: Out of 2889 articles matching the initial search criteria, a total of 13 studies representing 67,255 patients were included in the final analysis. The pooled mean age of heart failure patients was 76.3 years and 51% were male (n=34,271). The pooled estimated 30-day and 1-year all-cause mortality were 8% and 25% respectively. The pooled estimated 30-day and 1-year all-cause readmission rates were 20% and 56% respectively. There is a high prevalence of comorbidities in heart failure patients. There were limited data on readmission and mortality in rural patients and Indigenous people. CONCLUSIONS: Heart failure hospitalisations in Australia are followed by substantial readmission and mortality rates. PMID- 29519692 TI - Development of Acute Decompensated Heart Failure Among Hospital Inpatients: Incidence, Causes and Outcomes. AB - BACKGROUND: We aimed to investigate the incidence, precipitants, and outcomes of acute decompensated heart failure (ADHF) that develops during the inpatient stay. METHODS: We undertook a case-control study in the medical, oncology, surgical, and orthopaedic wards of a tertiary referral hospital (February-May, 2016). Patients aged >=18 years who developed ADHF during their inpatient stay were enrolled as cases. One control patient was matched to each case by age, gender, presenting complaint/surgery performed and co-morbidities. Multivariate regression was employed to determine variables associated with ADHF. RESULTS: The incidence of ADHF was 1.0% of patients. Eighty cases were well-matched to 80 controls (p>0.05). ADHF precipitants comprised infection (30%), inappropriate intravenous (IV) fluid and medication management (23.8% and 8.8%, respectively), tachyarrhythmia (12.5%), ischaemic heart disease (8.8%), renal failure (1.3%), and other/unclear causes (15%). Three variables were associated with ADHF: not having English as the preferred language (OR 3.5, 95%CI 1.2-9.8), a history of ischaemic heart disease (OR 3.3, 95%CI 1.2-9.1), and the administration of >2000ml of IV fluid on the day before the ADHF (OR 8.3, 95%CI 1.5-48.0). The day before the ADHF, cases were administered significantly more IV fluids than controls (median 2,757.5 versus 975ml, p=0.001). Medication errors mostly related to failure to restart regular diuretics. Cases had significantly greater length of stay (median 15 versus 6 days, p<0.001) and mortality (12.5% versus 1.3%, p=0.01). CONCLUSIONS: New onset ADHF is common and a substantial proportion of cases are iatrogenic. Cases experience significantly increased length of hospital stay, morbidity, and mortality. PMID- 29519693 TI - Airway Obstruction Caused by Iron Pill Aspiration: An Interventional Pulmonology Approach to Prevent Surgery. AB - Iron Pill Aspiration (IPA) is a challenging medical condition that requires prompt management to prevent detrimental outcomes. One of the most serious complications of IPA is airway inflammation which commonly leads to severe obstruction. Airway complications may require surgical intervention including the resection of the affected lung. Prompt recognition and management of IPA can reduce the risk of airway complications and may prevent the need of a surgical intervention. Bronchoscopic management entails the use of flexible and rigid bronchoscopes along with balloon bronchoplasty, ablation of the inflammatory tissue causing obstruction and airway stenting. In this report, we describe a case of severe airway obstruction secondary to iron pill aspiration with favourable outcome following bronchoscopic multimodalities intervention including temporary airway stenting. PMID- 29519694 TI - Dismal Outcomes of Second-Run Extracorporeal Life Support in the Paediatric Population. AB - BACKGROUND: In 2011 we reported unfavourable outcomes of second-run extracorporeal life support (ECLS) in children. We wanted to investigate whether this previous report affected our strategy and modified our long-term outcomes. METHODS: Between 1988 and 2015, 31 patients underwent a second-run ECLS. Median age at the time of first support was 9days (0-16 years). Median length of support for the first and second runs were 4.7days (0.1-10) and 3.6days (0.5-8.7) respectively, with an interval of 1.8days (0.1-66) between supports. RESULTS: There was an increasing trend in the number of patients undergoing second-run ECLS after our report: 21 patients between 1988 and mid-2010 (0.9 patients/year) and 10 between mid-2010 and 2015 (two patients/year) (p=0.06). However, among all the patients who underwent ECLS, the proportion of second-run ECLS was not different before and after 2010 (4% vs. 4.2% respectively, p=0.92). While 58% of patients (18/31) survived weaning of support, only 23% (7/31) survived to hospital discharge and 14% (5/31) were still alive after hospital discharge at a median of 6.5 years (1.2-11.6). The three patients who had positive long-term outcomes had the second-run ECLS instituted to allow for major cardiac operations. CONCLUSIONS: Compassionate use of second-run ECLS is difficult to refuse but one should be aware that its outcomes are dismal. In our centre, benefits seem to be limited to cases where the second-run ECLS allows for a major cardiac intervention. PMID- 29519696 TI - Single fathers: neglected, growing, and important. PMID- 29519695 TI - Otoacoustic emissions in children treated with gentamicin in a secondary hospital. AB - INTRODUCTION: The National Commission for the Early Detection of Hearing Loss (CODEPEH) recommends the re-evaluation of hearing in children who have suffered any potentially harmful event, such as the prescription of ototoxic antibiotics such as gentamicin. The evoked otoacoustic emissions (EOAE) are a good method for assessing the integrity of cochlear functionality. MATERIAL AND METHOD: A prospective study is presented, including 92 children who were treated with intravenous gentamicin for septic risk/sepsis or urinary tract infection. The children underwent serial EOAE: on admission, at the end of treatment and one month later (if altered on discharge). RESULTS: In the end, none of the subjects were affected by the treatment. CONCLUSION: Gentamicin appears to be a safe antibiotic in treatments lasting <10days and at the doses described. EOAE are an inexpensive, fast, non-invasive and reliable method to check for gentamicin ototoxicity. This could save in the determination of drug levels. PMID- 29519697 TI - Gone or forgotten? The rise and fall of Zika virus. PMID- 29519698 TI - Road traffic injuries in shared bicycle riders in China. PMID- 29519699 TI - Protecting female migrants from forced sex and HIV infection. PMID- 29519700 TI - Non-attending patients in general practice. PMID- 29519701 TI - Translational overview of cytokine inhibition in acute myocardial infarction and chronic heart failure. AB - Many cytokines are currently under investigation as potential target to improve cardiac function and outcome in the setting of acute myocardial infarction (MI) or chronic heart failure (HF). Here we aim to provide a translational overview of cytokine inhibiting therapies tested in experimental models and clinical studies. In various experimental studies, inhibition of interleukin-1 (IL-1), -6 (IL-6), 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC chemokines, and tumor necrosis factor-alpha (TNF-alpha) had beneficial effects on cardiac function and outcome. On the other hand, neutral or even detrimental results have been reported for some (IL-1, IL-6, IL-8, and MCP-1). Ambivalence of cytokine function, differences in study designs, treatment regimens and chosen endpoints hamper the translation of experimental research into clinical practice. Human studies are currently limited to IL-1beta inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF inhibition. Despite favorable effects on cardiovascular events observed in retrospective cohort studies of rheumatoid arthritis patients treated with TNF inhibition or IL-1RA, most prospective studies reported disappointing and inconsistent results. Smaller studies (n < 100) generally reported favorable results of anticytokine therapy on cardiac function, but only one of the larger studies (n > 100) evaluating IL 1beta inhibition presented positive results on outcome. In conclusion, of the 10 anticytokine therapies tested in animals models beneficial effects have been reported in at least one setting. In larger clinical studies, findings were unsatisfactory in all but one. Many anticytokine therapies with promising animal experimental data continue to require further evaluation in humans. PMID- 29519702 TI - Letter in response to the article entitled "Recommendations for the implantation of leadless pacemakers from the French Working Group on Cardiac Pacing and Electrophysiology of the French Society of Cardiology" by Defaye et al. PMID- 29519703 TI - Reprint of Milk fever in dairy cows is preceded by activation of innate immunity and alterations in carbohydrate metabolism prior to disease occurrence. AB - The objective of this study was to search for potential alterations in innate immunity reactants and carbohydrate and lipid metabolism in the blood of transition dairy cows before, during, and after clinical occurrence of milk fever (MF) and identify potential predictive biomarkers of disease. One hundred pregnant multiparous Holstein dairy cows were involved in the study starting from -8wks before the expected day of parturition until +8wks postpartum as part of a large retrospective longitudinal study. Health status, DMI, milk yield, and milk composition were monitored during the whole experimental period. Six healthy cows (CON) and 6 cows that showed clinical signs of MF were selected for blood analyses. Serum concentrations of lactate, non-esterified fatty acids (NEFA), beta-hydroxybutyric acid (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA) were determined. Results indicated that concentrations of serum lactate, IL-6, TNF, SAA, and Hp were greater in cows with MF than those in the CON group at different time points. Moreover, serum lactate, TNF, SAA, and Hp were greater in cows with MF starting at -8 and -4wks prior to parturition. Both principal component analysis (PCA) and partial least squares - discriminant analysis (PLS-DA) showed separated clusters between MF and CON cows at -8, -4, and disease diagnosis weeks. Overall DMI and milk production were lower in MF-affected cows. Additionally milk fat and fat:protein ratio were greater in MF. In conclusion, cows affected by MF showed alterations in some of the innate immunity reactants and metabolites related to carbohydrate metabolism several weeks prior to appearance of clinical signs of MF. Variable importance in projection plots demonstrated that TNF and SAA in the serum were the strongest discriminators between MF cows and CON ones, which might be useful as predictive biomarkers of the disease. PMID- 29519704 TI - Introduction of the TERT and BMI1 genes into murine dermal papilla cells ameliorates hair inductive activity. PMID- 29519705 TI - Lymph stasis promotes tumor growth. PMID- 29519706 TI - [Congenital syngnathia]. PMID- 29519707 TI - Re: Letter to the Editor of Public Health in response to 'Physical functioning and risk for sleep disorders in US adults: results from the National Health and Nutrition Examination Survey 2005-2014'. PMID- 29519708 TI - Re: 'Physical functioning and risk for sleep disorders in US adults: results from the National Health and Nutrition Examination Survey 2005-2014'. PMID- 29519709 TI - Do surgeon interviewers have human factor-related issues during the long day UK National Trauma and Orthopaedic specialty recruitment process? AB - PURPOSE: The role that human factors (HF) play in contributing to medical error is increasingly being recognised by healthcare professionals. Surprisingly, much less is known about the possible effects of HF including boredom, fatigue and organisational influences, on performance outside of the clinical environment such as examining or assessing candidates in other high stakes situations. METHODS: The authors used a validated 38 response questionnaire based around the HF analysis and classification system (HFACS) to assess factors including stress and pressure, care and support and working within the rules for surgeon interviewers at the UK national trainee selection process in Trauma and Orthopaedic surgery. RESULTS: 121 completed questionnaires were analysed (86% response rate). No statistically significant differences were found between interviewer experience, grade or role at the interview and the mean scores obtained for all four factor items. Overall interviewers had a positive experience during national selection with mean factor scores ranging from 3.80 to 3.98 (out of a maximum satisfaction score of 5). CONCLUSIONS: Careful planning by organisations and recognising the importance of the human element are essential to ensure assessors are looked after properly during high stakes assessment processes. Our data suggests that a positive experience for examiners is likely to benefit candidate performance and contribute to a fair and reliable recruitment process. The relationship between examiner experience and candidate performance merits further investigation. PMID- 29519710 TI - Intensive care in cancer patients in the age of immunotherapy and molecular therapies: Commitment of the SEOM-SEMICYUC. AB - Cancer patients are a vulnerable group exposed to numerous and serious risks beyond cancer itself. In recent years, the prognosis of these individuals has improved substantially thanks to several advances such as immunotherapy, targeted molecular therapies, surgical techniques, or developments in support treatment. This coincides with the prolonged survival of oncological patients admitted to the ICU due to critical complications, and under the supervision of intensivists. The time has therefore come to revisit the intensive care support of these patients, which poses new professional as well as organizational challenges. An agreement was signed in 2017 between the SEOM and SEMICYUC with the aim of improving the quality of care of cancer patients with critical complications. The initiative seeks to aid in decision-making, standardize criteria, decrease subjectivity, generate channels of communication, and delve deeper into the ethical and scientific aspects of these situations. This document sets forth the most important reasons that have led us to undertake this initiative. PMID- 29519711 TI - Association of CDX2 Expression With Survival in Early Colorectal Cancer: A Systematic Review and Meta-analysis. AB - CDX2 is a homeobox gene encoding transcriptional factors for intestinal organogenesis and represents a specific marker of colorectal adenocarcinoma (CRC) differentiation. We have evaluated if CDX2 expression is associated with better overall and disease-free survival (OS and DFS) in patients with CRC. PubMed, SCOPUS, EMBASE, The Cochrane Library, and Web of Science (from inception to July 2017) were systematically reviewed for relevant studies on adult patients with CRC where OS and DFS were calculated according to CDX2 expression in uni- or multivariate analysis were included. Hazard ratio (HR) for mortality and/or disease progression was calculated. The search produced 16 studies suitable for inclusion (6291 individual patients). The meta-analysis showed a reduced risk of death for patients with CDX2-positive CRC in 14 studies (HR, 0.5; 95% confidence interval [CI], 0.38-0.66; P < .001 according to random effect model). In 6 studies where only DFS data was available, CDX2 expression led to a 52% lower risk of relapse or death (HR, 0.48; 95% CI, 0.39-0.59; P < .001 according to random effect model). The results did not change as a function of ethnicity, type of study, CDX2 detection modality, or stage. Interestingly, in stages II to III, CDX2 expression was associated with a 70% lower risk of death (HR, 0.3; 95% CI, 0.12-0.77; P = .01). CDX2 expression confirms to be a strong prognostic factor in stage II and III CRC. In this setting, along with other clinical and pathologic factors, the lack of expression of CDX2 may be considered an important variable when deciding for adjuvant chemotherapy. PMID- 29519712 TI - T300A variant of AT16L1 gene in a cohort of Algerian Crohn disease patients. AB - The T300A variant is among the most Crohn's disease (CD) associated genetic variants. The aim of our study is to bring a first insight about the contribution of the T300A variant in a cohort of Algerian CD. In a case/control design, 118 Algerian CD patients and 161 unrelated healthy subjects were genotyped for the T300A variant using the allelic discrimination test by Applied Biosystems Taqman(r) genotyping technology. A serological analysis was carried out using BiosystemsTM ELISA kit for the assessment of the anti-Saccharomyces cerevisiae antibodies and immunofluorimetry via Luminex(r) technology for the evaluation of cytokine levels (TNFalpha, IFNgamma, IL-6 and IL-17). The comparison between allelic and genotypic frequencies was performed using the chi2 test and the exact Fischer test. The odds ratio (OR) was noted adopting confidence interval of 95%. The comparison between the averages was carried out by the Mann-Whitney and Kruskal-Wallis tests. A factorial discriminant analysis and a binary logistic regression were performed as further analyses. The T300A variant showed an increased risk of CD within homozygous variant carriers (P=0.027). Moreover, the carriage of the G allele was associated with the early onset of CD (P=0.01) and a severe CD impairment (P=0.045). We were not able to comfort the association of the T300A variant and ASCA IgA, ASCA IgG and IFNgamma levels detected at the univariate analysis. Our results suggest a possible association between the T300A variant and CD in this cohort of Algerian CD patients. Moreover, this variant might be incriminated in the early onset of CD and a severe disease impairment. At the serological study, the univariate and the multivariate analyses yielded contradictory results. Further investigations of larger cohorts of Algerian CD are needed to better assess the suggested associations at the present study. PMID- 29519713 TI - Sinusoidal obstruction syndrome/veno-occlusive disease complication in lymphoma patients treated with oxaliplatin-based regimen: A case series report. AB - AIM: SOS/VOD is a relevant clinical syndrome that usually appears early after hematopoietic stem cell transplantation. The purpose of this article was to report a case series of SOS/VOD in non-susceptible patients and draw physicians' attention to the plausible relationship between liver injury and oxaliplatin based chemotherapy, preceding autologous transplantation. METHODS: In this study, we report a case series of SOS/VOD in 4 lymphoma patients following autologous transplantation. The data were collected between July 2013 and November 2015 by analyzing patient's characteristics and outcomes. RESULTS: We noticed 4 severe cases of SOS with unusual presentations in patients who did exhibit few classical risk factors. These patients received R-DHAO before transplantation. CONCLUSIONS: Physicians need to be aware that oxaliplatin-based regimen could contribute to SOS/VOD complications in hematological patients. PMID- 29519715 TI - Diagnosis and Management of Immune Checkpoint Inhibitor-related Toxicities in Ovarian Cancer: A Series of Case Vignettes. AB - Use of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1 have led to improved survival outcomes for advanced solid-tumor malignancies. This report helps the reader gain a better understanding of adverse events in patients with ovarian cancer on checkpoint inhibitor therapy. We describe 3 hypothetical case vignettes of patients with gynecologic cancer on checkpoint inhibitor immunotherapy and discuss common immune-related adverse events. The typical presentation and onset of immune-related events are different from those associated with conventional chemotherapy. This report highlights the importance of early recognition and management of these events. PMID- 29519714 TI - Impact of the Adalimumab Patient Support Program's Care Coach Calls on Persistence and Adherence in Canada: An Observational Retrospective Cohort Study. AB - PURPOSE: Adalimumab (ADA) is a tumor necrosis factor-alpha inhibitor indicated for use in various immune-mediated inflammatory diseases. Patients receiving ADA in Canada are eligible to enroll in the AbbVie Care's Patient Support Program (PSP), which provides personalized services, including tailored interventions in the form of nurse-provided care coach calls (CCCs), with the goal of improving patients' experiences and outcomes. The primary objective of this study was to evaluate the impact of PSP services, including CCCs and patient characteristics, on persistence with and adherence to ADA for those patients enrolled in the PSP. A secondary objective was to estimate the effect of initial CCCs on treatment initiation abandonment (ie, failure to initiate therapy after enrollment in the PSP). METHODS: An observational retrospective cohort study was conducted. A patient linkage algorithm based on probabilistic matching was developed to link the AbbVie Care PSP database to the QuintilesIMS longitudinal pharmacy transaction database. Patients who started ADA therapy between July 2010 and August 2014 were selected, and their prescriptions were evaluated for 12 months after the date of ADA start to calculate days until drug discontinuation, that is, the end of persistence, defined as >90 days without therapy. Cox proportional hazards modeling was used for estimating hazard ratios for the association between persistence and patient characteristics and each PSP service. Adherence, measured by medication possession ratio, was calculated, and multivariate logistic regression provided adjusted odds ratios for the relationship between being adherent (medication possession ratio >=80%) and patient characteristics and each PSP service. Treatment-initiation abandonment among patients who received an initial CCC compared with those who did not was analyzed using the chi2 test. FINDINGS: Analysis of 10,857 linked patients yielded statistically significant differences in the hazard ratio of discontinuation and the likelihood of being adherent across multiple variables between patients who received CCCs in comparison to patients who did not. Patients receiving CCCs were found to have a 72% decreased risk for therapy discontinuation (hazard ratio = 0.282; P < 0.0001), and a greater likelihood of being adherent (odds ratio = 1.483; P < 0.0001), when compared with those patients who did not receive CCCs. The rate of treatment-initiation abandonment was significantly higher in patients who did not receive initial CCCs (P < 0.0001). IMPLICATIONS: Ongoing CCCs, provided by AbbVie Care PSP, were associated with greater patient persistence and adherence over the first 12 months of treatment, while initial CCCs were associated with a lower rate of treatment-initiation abandonment. Results may inform the planning of interventions aimed at improving treatment adherence and patient outcomes. PMID- 29519716 TI - Short-course Regimen for Subsequent Treatment of Pulmonary Tuberculosis: A Prospective, Randomized, Controlled Multicenter Clinical Trial in China. AB - PURPOSE: We designed a prospective, multicenter, randomized, controlled study to assess a 5-month regimen compared with the standard regimen on previously treated patients with pulmonary tuberculosis (TB). METHODS: We enrolled 917 sputum smear positive patients undergoing additional treatment in 27 major tuberculosis hospitals in China. Patients were randomly assigned to a test group (n = 626)treated with a 5-month regimen of moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide or a reference group (n = 291) treated with an 8 month regimen of isoniazid, rifampicin, and streptomycin. All patients with a favorable response were followed up for 5 years after the end of treatment. FINDINGS: Of the study patients, 61 in the test group and 19 in the reference group had multidrug-resistant (MDR) TB. The treatment success rate in the study group was 74.12%, which was significantly higher than the 67.70% in the reference group (P = 0.04), whereas the treatment success rate of patients with MDR-TB was not significantly different between the test and reference groups (70.5% vs 63.1%, P =0.79). The adverse effects rates in the test and reference groups were 7.4% and 3.1%, respectively (P = .01). The difference in the TB recurrence rates between the group arm (9.6%) and the reference group (21.8%) was statistically significant (P < 0.001). IMPLICATIONS: The moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide test regimen yielded higher success and lower recurrence rates than the currently recommended isoniazid, rifampicin, and streptomycin regimen, but the rate of adverse effects was higher. ClinicalTrials.gov identifier: NCT02331823. PMID- 29519718 TI - Local Anesthetic-Induced Methemoglobinemia During Pregnancy: A Case Report and Evaluation of Treatment Options. AB - BACKGROUND: Methemoglobinemia is a well-recognized adverse drug reaction related to the use of certain local anesthetic agents. The mainstay of treatment for methemoglobinemia is i.v. methylene blue, along with provision of supplemental oxygen; however, methylene blue is listed as a category X teratogen. This poses an issue should methemoglobinemia develop during pregnancy. CASE REPORT: A 35 year-old, 20-week and 5-day gravid female was transferred from an outpatient oral surgeon's office for hypoxia. She was undergoing extraction of 28 teeth and was administered an unknown, but "large" quantity of prilocaine during the procedure. Given this exposure, the concern was for methemoglobinemia. This was confirmed with co-oximetry, which showed 34.7% methemoglobin. The initial treatment plan was methylene blue; however, this drug is a category X teratogen. Thus, an interdisciplinary team deliberated and decided on treatment with high-dose ascorbic acid and transfusion of a single unit of packed red blood cells. The patient was managed with noninvasive ventilation strategies and a total of 8 g ascorbic acid. She was discharged on hospital day 3 with no obstetric issues noted. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Intravenous ascorbic acid appears to be a potential alternative to methylene blue in this patient population. The data surrounding teratogenicity of methylene blue are mostly related to intra-amniotic or intra-uterine administration. In life-threatening cases of methemoglobinemia during pregnancy, the benefits of i.v. methylene blue may outweigh the risks. PMID- 29519717 TI - Mutation analysis of CHCHD2 and CHCHD10 in Italian patients with mitochondrial myopathy. AB - Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, for example, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas 1 sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10. Muscle biopsy of this patient showed intracellular glycogen accumulation with cytochrome c oxidase negative and ragged red fibers. Our study suggests that the homozygous Pro96Thr mutation in CHCHD10 might be pathogenic but does not support a major role for CHCHD2 in MM pathogenesis. PMID- 29519719 TI - Oral Nitroglycerin Solution May Be Effective for Esophageal Food Impaction. AB - BACKGROUND: Esophageal food impaction is a common illness presenting to emergency departments (ED), and is frequently resistant to pharmacologic therapy. Several medications have been promoted for this indication, but so far have not proven effective. Endoscopic removal is frequently required to resolve the impaction, resulting in risks from anesthesia and the physical procedure, and in prolonged hospital stay for recovery. Oral nitroglycerin solution was recently used in two such cases and may represent a new therapeutic option. CASE REPORTS: A 49-year old man presented to an ED with dysphagia 30 min after eating steak. He was given 0.4 mg nitroglycerin dissolved in 10 mL tap water orally, and obtained complete relief of symptoms within 2 min. A 43-year-old man with eosinophilic esophagitis and two prior food impaction episodes presented to a community ED with dysphagia and epigastric discomfort 110 min after eating steak. Five hours after symptom onset and after failure of intravenous glucagon, he was given 0.4 mg nitroglycerin sublingually, which resulted in headache but no relief in dysphagia. Twenty-nine minutes later he received 0.4 mg nitroglycerin solution, as above, with symptom resolution within 2 min. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The cases presented above demonstrate close temporal relationships between administration of oral nitroglycerin solution and symptom relief. Oral nitroglycerin solution for esophageal food impaction seemed effective in these cases, but further research on this therapeutic option is warranted. PMID- 29519720 TI - Mycobacterium avium subspecies paratuberculosis and myelin basic protein specific epitopes are highly recognized by sera from patients with Neuromyelitis optica spectrum disorder. AB - Epstein-Barr virus (EBV) is the main environmental agent associated to neuromyelitis optica spectrum disorder (NMOSD). Following to studies reporting an increased prevalence of antibodies against peptides derived from Mycobacterium avium subsp. paratuberculosis (MAP) homologous to EBV and human epitopes (MBP85 98, IRF5424-434) in multiple sclerosis (MS), we investigated whether seroreactivity to these antigens display a NMOSD-specific pattern. The sera of 34 NMOSD patients showed elevated levels of antibodies against MAP and MBP compared to healthy controls (44% vs. 5%, p < 0.0002 and 50% vs. 2%, p < 0.0001, respectively), while, unlike in MS, responsiveness to EBV was similar. PMID- 29519721 TI - Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat. AB - Neuroinflammation involving macrophages elevates Prostaglandin E2, associated with neuropathic pain. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) inhibits cyclooxygenase, reducing PGE2. However, NSAIDs cause physiological complications. We developed nanoemulsions incorporating celecoxib and near infrared dye. Intravenous injected nanoemulsion is incorporated into monocytes that accumulate at the injury; revealed in live animals by fluorescence. A single dose (celecoxib 0.24 mg/kg) provides targeted delivery in chronic constriction injury rats, resulting in significant reduction in the visualized inflammation, infiltration of macrophages, COX-2 and PGE2. Animals exhibit relief from hypersensitivity persisting at least four-days. The total body burden of drug is reduced by >2000 fold over oral drug delivery. PMID- 29519722 TI - Childhood trauma and increased peripheral cytokines in young adults with major depressive: Population-based study. AB - OBJECTIVE: The aim of this study was to evaluate the effect of childhood trauma in cytokine serum levels of individuals with MDD. METHODS: This was a cross sectional study population-based, with people aged 18 to 35. The Mini International Neuropsychiatric Interview (M.I.N.I) measured to current major depressive disorder (MDD). To evaluate traumatic experiences during childhood, the Childhood Trauma Questionnaire (CTQ) was applied. Serum TNF- alpha, IL-6 and IL-10 levels were measured by ELISA using a commercial kit. RESULTS: The total sample comprised 166 young adults, of these: 40.4% were subjects with MDD and childhood trauma and 59.6% were diagnosed with MDD without childhood trauma. In relation to serum interleukin levels, subjects with childhood trauma showed a significantly higher serum IL-6 (p = 0.013) and IL-10 levels (p = 0.022) to compare no childhood trauma. Subjects with childhood trauma was observed positive correlation between serum IL-6 and physical abuse (r = 0.232, p = 0.035) and emotional abuse (r = 0.460, p <= 0.001). Moreover, IL-10 were positive correlation with physical abuse (r = 0.258, p = 0.013). TNF- alpha was not associated with childhood trauma. CONCLUSION: Childhood maltreatment may result higher inflammation dysregulation in individuals with depression than individuals that no has childhood maltreatment. PMID- 29519723 TI - Effect of ensiling time on fermentation profile and ruminal in vitro starch digestibility in rehydrated corn with or without varied concentrations of wet brewers grains. AB - The objective of this study was to evaluate the effect of rehydrating and ensiling dry ground corn (DGC) with varying concentrations of wet brewers grain (WBG) on fermentation profile and ruminal in vitro starch digestibility (ivSD; 7 h incubations on dried and 4-mm ground samples). Samples of DGC and WBG were weighed separately and mixed into 100% WBG (WBG); mixture of DGC and WBG targeting 60 (RC60), 65 (RC65), or 70% (RC70) of dry matter (DM); and DGC rehydrated with distilled water targeting for 70% of DM (REH). Samples were ensiled in vacuum-sealed bags and allowed to ferment for 0, 1, 3, 7, 14, and 28 d. The experiment consisted of 30 treatments (5 mixtures of DGC and WGB * 6 ensiling time points) and 120 mini-silos (4 silos per treatment). All samples were analyzed for fermentation profile and water-soluble carbohydrates. Except for WBG, samples from 0 and 28 d were analyzed for ivSD. Content of DM was greater for REH (70.0%), followed by RC70 (69.2%), RC65 (63.9%), RC60 (58.4%), and WBG (17.5%) on d 0, with a slight decrease (1 to 2 percentage units) observed for all treatments until 28 d. Measurements of pH were highest for REH (6.19) and lowest for WBG (4.68) on 0 d, but all other treatments were lower than WBG on 14 and 28 d (3.83 vs. 4.14, on average). Except for WBG, all treatments had a gradual increase in lactic acid concentration from 0 to 28 d. In contrast, butyric acid gradually increased from 0 (0.25%) to 28 d (2.16% of DM) in WBG but not the other treatments. Fermentation patterns were related to water-soluble carbohydrates concentration, which was greater for all treatments except WBG from 0 (1.41% on average vs. 0.38% of DM, respectively) to 28 d (0.37% on average vs. 0.19% of DM, respectively). Except for RC60, greater ivSD was observed for all treatments on 28 than 0 d, but magnitude of the difference was greater for REH and RC70 (14.5 percentage units on average). Rehydration and ensiling of DGC with WBG resulted in adequate fermentation and enhanced starch digestibility. PMID- 29519724 TI - Public attitudes and literacy about posttraumatic stress disorder in U.S. adults. AB - There has been little study of public literacy regarding posttraumatic stress disorder (PTSD). Public knowledge and attitudes about PTSD are important for encouraging treatment, prevention, and informing policies. Using a national online survey of 541 adults across 47 U.S. states in November 2016, we assessed attitudes and knowledge about PTSD. Most notably with respect to attitudes, 76 94% of the sample endorsed more federal funding for research, training, and practice for PTSD; and 76% of the sample also believed people with PTSD should have restricted access to firearms. With respect to knowledge, participants demonstrated good general knowledge about PTSD, but tended to overestimate the rate of PTSD and trauma exposure, and demonstrated little knowledge about effective treatments. Sociodemographic characteristics and political affiliation were associated with PTSD knowledge and attitudes, but clinical characteristics did not explain much additional variance. Together, these findings suggest that there is strong public support for research and practice related to PTSD, but little public knowledge about evidence-based treatments for this disorder. PMID- 29519725 TI - Neuropeptide Y as a possible homeostatic element for changes in cortical excitability induced by repetitive transcranial magnetic stimulation. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is able to modify cortical excitability. Rat rTMS studies revealed a modulation of inhibitory systems, in particular that of the parvalbumin-expressing (PV+) interneurons, when using intermittent theta-burst stimulation (iTBS). OBJECTIVE: The potential disinhibitory action of iTBS raises the questions of how neocortical circuits stabilize excitatory-inhibitory balance within a physiological range. Neuropeptide Y (NPY) appears to be one candidate. METHODS: Analysis of cortical expression of PV, NPY and vesicular glutamate transporter type 1 (vGluT1) by immunohistochemical means at the level of cell counts, mean neuropil expression and single cell pre-/postsynaptic expression, with and without intraventricular NPY-injection. RESULTS: Our results show that iTBS not only reduced the number of neurons with high-PV expression in a dose-dependent fashion, but also increased the cortical expression of NPY, discussed to reduce glutamatergic transmission, and this was further associated with a reduced vGluT1 expression, an indicator of glutamateric presynaptic activity. Interneurons showing a low-PV expression exhibit less presynaptic vGluT1 expression compared to those with a high-PV expression. Intraventricular application of NPY prior to iTBS prevented the iTBS induced reduction in the number of high-PV neurons, the reduction in tissue vGluT1 level and that presynaptic to high-PV cells. CONCLUSIONS: We conclude that NPY, possibly via a global but also slow homeostatic control of glutamatergic transmission, modulates the strength and direction of the iTBS effects, likely preventing pathological imbalance of excitatory and inhibitory cortical activity but still allowing enough disinhibition beneficial for plastic changes as during learning. PMID- 29519726 TI - Combining cognitive training and multi-site rTMS to improve cognitive functions in Alzheimer's disease. PMID- 29519727 TI - Reduction of systemic inflammation after cardiac resynchronization therapy: A new form of response? PMID- 29519728 TI - Optimizing risk stratification in heart failure and the selection of candidates for heart transplantation. AB - INTRODUCTION AND AIMS: Selecting patients for heart transplantation is challenging. We aimed to identify the most important risk predictors in heart failure and an approach to optimize the selection of candidates for heart transplantation. METHODS: Ambulatory patients followed in our center with symptomatic heart failure and left ventricular ejection fraction <=40% prospectively underwent a comprehensive baseline assessment including clinical, laboratory, electrocardiographic, echocardiographic, and cardiopulmonary exercise testing parameters. All patients were followed for 60 months. The combined endpoint was cardiac death, urgent heart transplantation or need for mechanical circulatory support, up to 36 months. RESULTS: In the 263 enrolled patients (75% male, age 54+/-12 years), 54 events occurred. The independent predictors of adverse outcome were ventilatory efficiency (VE/VCO2) slope (HR 1.14, 95% CI 1.11 1.18), creatinine level (HR 2.23, 95% CI 1.14-4.36), and left ventricular ejection fraction (HR 0.96, 95% CI 0.93-0.99). VE/VCO2 slope was the most accurate risk predictor at any follow-up time analyzed (up to 60 months). The threshold of 39.0 yielded high specificity (97%), discriminated a worse or better prognosis than that reported for post-heart transplantation, and outperformed peak oxygen consumption thresholds of 10.0 or 12.0 ml/kg/min. For low-risk patients (VE/VCO2 slope <39.0), sodium and creatinine levels and variations in end-tidal carbon dioxide partial pressure on exercise identified those with excellent prognosis. CONCLUSIONS: VE/VCO2 slope was the most accurate parameter for risk stratification in patients with heart failure and reduced ejection fraction. Those with VE/VCO2 slope >=39.0 may benefit from heart transplantation. PMID- 29519729 TI - Lowering risk score profile during PCI in multiple vessel disease is associated with low adverse events: The ERACI risk score. AB - In recent years angiographic risk scores have been introduced in clinical practice to stratify different levels of risk after percutaneous coronary interventions (PCI). The SYNTAX score included all intermediate lesions in vessels >=1.5 mm, consequently, multiple stent implantation was required. Four years ago, we built a new angiographic score in order to guide PCI strategy avoiding stent deployment both in intermediate stenosis as in small vessels, therefore these were not scored (ERACI risk score). The purpose of this mini review is to validate the strategy of PCI guided by this scoring, taking into account long term follow up outcomes of two observational and prospective registries where this policy was used. With this new risk score we have modified risk profile of our patient's candidates for PCI or coronary artery bypass surgery lowering the risk and <20% of them are now included anatomically as high risk for PCI. The simple exclusion of small vessels and intermediate stenosis from the revascularization approach resulted in clinical outcome comparable with the one of fractional flow reserve guided revascularization. Low events rate at late follow up observed in both studies was also in agreement with guided PCI by functional lesion assessment observed by Syntax II registry, where investigators found lower events rate in spite of a few number of stents implanted per patient. In conclusion: use of ERACI risk scores may significantly reclassify patients into a lower risk category and be associated with low adverse events rate. PMID- 29519730 TI - Arteriotomy site complication during transcatheter aortic valve replacement: Ipsilateral wire protection and bailout. AB - Major vascular complications still occur in ~4.2% of transcatheter aortic valve replacement (TAVR) procedures. These complications are a major safety drawback of TAVR when compared to surgical aortic valve replacement (SAVR). Contemporary strategies designed to minimize and effectively treat vascular complications are of immense importance to a successful TAVR program. This review discusses strategies to optimize TAVR access and device choice along with TAVR access complication management. Iliac complications are less frequently encountered and can be managed effectively via the TAVR sheath over the TAVR wire employing ipsilateral proximal iliac balloon occlusion and endovascular repair. The more common arteriotomy site complications and access site closure failure require prophylactic or bail-out common femoral to superficial femoral artery wiring. Suggested is a novel method of ipsilateral arteriotomy site protection that is safe, simple and does not require additional resources. Ipsilateral wiring can also be done prophylactically or as a bailout in case of arteriotomy site complication. PMID- 29519731 TI - Non-pumping reactive wells filled with mixing nano and micro zero-valent iron for nitrate removal from groundwater: Vertical, horizontal, and slanted wells. AB - Non-pumping reactive wells (NPRWs) filled by zero-valent iron (ZVI) can be utilized for the remediation of groundwater contamination of deep aquifers. The efficiency of NPRWs mainly depends on the hydraulic contact time (HCT) of the pollutant with the reactive materials, the extent of the well capture zone (Wcz), and the relative hydraulic conductivity of aquifer and reactive material (Kr). We investigated nitrate removal from groundwater using NPRWs filled by ZVI (in nano and micro scales) and examined the effect of NPRWs orientations (i.e. vertical, slanted, and horizontal) on HCT and Wcz. The dependence of HCT on Wcz for different Kr values was derived theoretically for a homogeneous and isotropic aquifer, and verified using particle tracking simulations performed using the semi-analytical particle tracking and pathlines model (PMPATH). Nine batch experiments were then performed to investigate the impact of mixed nano-ZVI, NZVI (0 to 2 g l-1) and micro-ZVI, MZVI (0 to 4 g l-1) on the nitrate removal rate (with initial [Formula: see text] =132 mg l-1). The NPRWs system was tested in a bench-scale sand medium (60 cm length * 40 cm width * 25 cm height) for three orientations of NPRWs (vertical, horizontal, and slanted with inclination angle of 45 degrees ). A mixture of nano/micro ZVI, was used, applying constant conditions of pore water velocity (0.024 mm s-1) and initial nitrate concentration (128 mg l-1) for five pore volumes. The results of the batch tests showed that mixing nano and micro Fe0 outperforms these individual materials in nitrate removal rates. The final products of nitrate degradation in both batch and bench-scale experiments were [Formula: see text] , [Formula: see text] , and N2(gas). The results of sand-box experiments indicated that the slanted NPRWs have a higher nitrate reduction rate (57%) in comparison with vertical (38%) and horizontal (41%) configurations. The results also demonstrated that three factors have pivotal roles in expected HCT and Wcz, namely the contrast between the hydraulic conductivity of aquifer and reactive materials within the wells, the mass of Fe0 in the NPRWs, and the orientation of NPRWs adopted. A trade-off between these factors should be considered to increase the efficiency of remediation using the NPRWs system. PMID- 29519732 TI - Estimation of Knudsen diffusion coefficients from tracer experiments conducted with a binary gas system and a porous medium. AB - A previous study has reported that Knudsen diffusion coefficients obtained by tracer experiments conducted with a binary gas system and a porous medium are consistently smaller than those obtained by permeability experiments conducted with a single-gas system and a porous medium. To date, however, that study is the only one in which tracer experiments have been conducted with a binary gas system. Therefore, to confirm this difference in Knudsen diffusion coefficients, we used a method we had developed previously to conduct tracer experiments with a binary carbon dioxide-nitrogen gas system and five porous media with permeability coefficients ranging from 10-13 to 10-11 m2. The results showed that the Knudsen diffusion coefficient of N2 (DN2) (cm2/s) was related to the effective permeability coefficient ke (m2) as DN2 = 7.39 * 107ke0.767. Thus, the Knudsen diffusion coefficients of N2 obtained by our tracer experiments were consistently 1/27 of those obtained by permeability experiments conducted with many porous media and air by other researchers. By using an inversion simulation to fit the advection-diffusion equation to the distribution of concentrations at observation points calculated by mathematically solving the equation, we confirmed that the method used to obtain the Knudsen diffusion coefficient in this study yielded accurate values. Moreover, because the Knudsen diffusion coefficient did not differ when columns with two different lengths, 900 and 1500 mm, were used, this column property did not influence the flow of gas in the column. The equation of the dusty gas model already includes obstruction factors for Knudsen diffusion and molecular diffusion, which relate to medium heterogeneity and tortuosity and depend only on the structure of the porous medium. Furthermore, there is no need to take account of any additional correction factor for molecular diffusion except the obstruction factor because molecular diffusion is only treated in a multicomponent gas system. Thus, molecular diffusion considers only the obstruction factor related to tortuosity. Therefore, we introduced a correction factor for a multicomponent gas system into the DGM equation, multiplying the Knudsen diffusion coefficient, which includes the obstruction factor related to tortuosity, by this correction factor. From the present experimental results, the value of this correction factor was 1/27, and it depended only on the structure of the gas system in the porous medium. PMID- 29519733 TI - Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure. AB - Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 MUM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats. PMID- 29519734 TI - Attaching NorA efflux pump inhibitors to methylene blue enhances antimicrobial photodynamic inactivation of Escherichia coli and Acinetobacter baumannii in vitro and in vivo. AB - Resistance of bacteria to antibiotics is a public health concern worldwide due to the increasing failure of standard antibiotic therapies. Antimicrobial photodynamic inactivation (aPDI) is a promising non-antibiotic alternative for treating localized bacterial infections that uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species and kill microbes. Phenothiazinium photosensitizers like methylene blue (MB) and toluidine blue O are hydrophobic cations that are naturally expelled from bacterial cells by multidrug efflux pumps, which reduces their effectiveness. We recently reported the discovery of a NorA efflux pump inhibitor-methylene blue (EPI-MB) hybrid compound INF55-(Ac)en-MB that shows enhanced photodynamic inactivation of the Gram-positive bacterium methicillin-resistant Staphylococcus aureus (MRSA) relative to MB, both in vitro and in vivo. Here, we report the surprising observation that INF55-(Ac)en-MB and two related hybrids bearing the NorA efflux pump inhibitors INF55 and INF271 also show enhanced aPDI activity in vitro (relative to MB) against the Gram-negative bacteria Escherichia coli and Acinetobacter baumannii, despite neither species expressing the NorA pump. Two of the hybrids showed superior effects to MB in murine aPDI infection models. The findings motivate wider exploration of aPDI with EPI-MB hybrids against Gram negative pathogens and more detailed studies into the molecular mechanisms underpinning their activity. PMID- 29519735 TI - Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II). AB - Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin. PMID- 29519736 TI - Synthesis of new analogs of tetraiodothyroacetic acid (tetrac) as novel angiogenesis inhibitors for treatment of cancer. AB - In the angiogenesis process, integrins, which are members of a family of cell surface transmembrane receptors, play a critical role particularly in blood vessel formation and the local release of vascular growth factors. Thyroid hormones such as l-thyroxine (T4) and 3,5,3'-triiodo-l-thyronine (T3) promote angiogenesis and tumor cell proliferation via integrin alphavbeta3 receptor. At or near an arginine-glycine-aspartate (RGD) recognition site on the binding pocket of integrin alphavbeta3, tetraiodothyroacetic acid (tetrac, a deaminated derivative of T4) is a thyrointegrin receptor antagonist and blocks the actions of T3 and T4 as well as different growth factors-mediated angiogenesis. In this study, we synthesized novel tetrac analogs by modifying the phenolic moiety of tetrac and tested them for their anti-angiogenesis activity using a Matrigel plug model for angiogenesis in mice. Pharmacological activity results showed that tetrac can accommodate numerous modifications and maintain its anti-angiogenesis activity. PMID- 29519737 TI - The synthesis and evaluation of thymoquinone analogues as anti-ovarian cancer and antimalarial agents. AB - Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from Nigella sativa L., has previously been demonstrated to exhibit antiproliferative activity in vitro against a range of cancers as well as the human malarial parasite Plasmodium falciparum. We describe here the synthesis of a series of analogues of TQ that explore the potential for nitrogen-substitution to this scaffold, or reduction to a hydroquinone scaffold, in increasing the potency of this antiproliferative activity against ovarian cancer cell lines and P. falciparum. In addition, alkyl or halogen-substituted analogues were commercially sourced and tested in parallel. Several TQ analogues with improved potency against ovarian cancer cells and P. falciparum were found, although this increase is suggested to be moderate. Key aspects of the structure activity relationship that could be further explored are highlighted. PMID- 29519738 TI - Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran fused tricyclic benzo[d]imidazole series - Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2. AB - In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg). PMID- 29519739 TI - Small molecule modulators of PCSK9 - A literature and patent overview. AB - Proprotein convertase subtilisin kexin like type 9 (PCSK9) has since its discovery been a key protein target for the modulation of LDL cholesterol. The interest in PCSK9 has grown even more with the positive clinical trial outcomes in cardiovascular disease recently reported for two PCSK9 antibodies. Currently, there are no PCSK9 small molecule programs active in clinical development. However, there has been a steady increase in publications and patent applications within the PCSK9 small molecule field. This digest will provide a summary of small molecule and peptide PCSK9 modulators reported both in scientific journals and in patent applications, most of them originating from the last 3-4 years. As such, this digest will serve as an introduction to the field and assist further identification and discovery of small molecule PCSK9 modulators. PMID- 29519740 TI - Peri-operative desensitization-A promising strategy for overcoming the antibody barrier in heart transplantation. PMID- 29519741 TI - Hydralazine-associated vasculitis: Overlapping features of drug-induced lupus and vasculitis. AB - INTRODUCTION: Hydralazine is an antihypertensive medication that has been associated with drug-induced lupus erythematosus (DIL) as well as ANCA-associated vasculitis (AAV). Although rare, early diagnosis is critical since drug cessation is the mainstay of therapy. This retrospective study aims to characterize the clinical, laboratory, and histopathologic features of this disease. METHODS: Once approval was obtained from the Institutional Review Board at the University of Iowa, all patients carrying a diagnosis of vasculitis (ICD9 code: 447.6 or ICD10 code: I77.6, I80, L95, M30, or M31) and positive ANCA lab results over the past 15 years were identified. Age, gender, comorbid conditions, medications taken over the prior 6 months, laboratory data, including electrolytes, urine studies and serologies, chest x-rays, CT scans, and pathologic biopsy records were abstracted from the electronic medical record. RESULTS: 323 cases of AAV were identified, of which 12 were exposed to hydralazine, all at the time of diagnosis. The average duration of hydralazine therapy was 22 months and mean cumulative dose was 146g. Patients were typically older (70.3 years old) with slight female preponderance (7 females). Eleven patients presented with dyspnea, fatigue, and unintentional weight loss. Five had polyarthralgias and 8 had lower extremity petechiae. All 12 patients were both ANA and ANCA positive. ANA titers ranged from 1:160 and 1:2560. Ten were of diffuse pattern while 2 were nucleolar. ANCA titers ranged from 1:320 to 1:2560. Eleven had a pANCA pattern while one had cANCA. All 12 patients were positive for histone and 11 were positive for myeloperoxidase antibodies. Eleven also had dsDNA antibodies, and 4 had anti cardiolipin IgG or IgM antibodies. Nine patients were also hypocomplementemic (mean C3 level: 88.4mg/dL; mean C4 level: 16.5mg/dL). All patients had variable levels of proteinuria (1+ to 3+) and eleven had active urine sediment. Urine protein:creatinine ratios ranged from 0.2 to 1.7. Of the 6 patients who underwent kidney biopsy, all 6 showed pauci-immune crescentic glomerulonephritis. Seven patients had bilateral pulmonary interstitial infiltrates and four had pleural effusions on CT scan. Four had pericardial effusions as demonstrated by echocardiography. CONCLUSIONS: Hydralazine-associated vasculitis is a drug associated autoimmune syndrome that presents with interstitial lung disease, hypocomplementemia, and pauci-immune glomerulonephritis. Patients have elements of both DIL and DIV, as manifested by high ANA and ANCA titers as well as the presence of histone and MPO antibodies. Further research is needed to understand the etiopathogenesis of this condition. PMID- 29519742 TI - Reduction of Nicardipine-Related Phlebitis in Patients with Acute Stroke by Diluting Its Concentration. AB - BACKGROUND: Nicardipine is frequently used in the treatment of hypertension for patients with acute stroke; however, its dosing is complicated by a high risk of phlebitis. In the present study, we examined whether restricting nicardipine concentration under a specific value could reduce the incidence of nicardipine related phlebitis in patients with acute stroke. METHODS: Intravenous nicardipine related phlebitis was retrospectively analyzed. From July 2015, a simple proposition was made to dilute maximum intravenous nicardipine concentration to lower than 130 ug/mL. The maximum intravenous nicardipine concentration and the incidence of phlebitis were compared between patients treated from July 2014 to June 2015 (preproposition group) and patients treated from July 2015 to June 2016 (postproposition group). RESULTS: A total of 300 patients (preproposition group, 138; postproposition group, 162) were included. The postproposition group demonstrated significantly lower maximum intravenous nicardipine concentration (in ug/mL, 76.9, 47.6-104.5 versus 130.4, 69.8-230.8; P < .001) and incidence of phlebitis (9.9%, 16/162 vs. 30%, 42/138; P < .001) than the preproposition group. Multivariable logistic regression analysis revealed that the maximum intravenous nicardipine concentration lower than 130 ug/mL (odds ratio [OR] .15; 95% confidence interval [CI] .06-.35; P < .001) and National Institutes of Health Stroke Scale on admission (OR .95; 95% CI .91-.99; P = .007) were the statistically significant independent factors for phlebitis, which indicated the usefulness of the proposition to dilute maximum intravenous nicardipine concentration to lower than 130 ug/mL. CONCLUSIONS: The simple and appropriate proposition about nicardipine administration lowered maximum nicardipine concentration and reduced the incidence of nicardipine-related phlebitis in patients with acute stroke. PMID- 29519743 TI - A Response to Letter to the Editor by Dr. Mohammad Alwardat. PMID- 29519745 TI - Are light masks useful for early diabetic macular oedema? PMID- 29519746 TI - Analysis of the accuracy and reliability of the Short-Form Fonseca Anamnestic Index in the diagnosis of myogenous temporomandibular disorder in women. AB - BACKGROUND: The Fonseca Anamnestic Index is a questionnaire used to classify individuals with temporomandibular disorders. Previous studies have shown that the Fonseca Anamnestic Index provides a multidimensional measurement of the temporomandibular disorders construct and that the main dimension presents a good fit to the model according to the item response theory. OBJECTIVE: To evaluate the between-day reliability, accuracy, and best cut-off score of the Short-Form Fonseca Anamnestic Index for the diagnosis of myogenous temporomandibular disorders. METHODS: The sample consisted of 123 women (57 with myogenous temporomandibular disorders and 66 asymptomatic), evaluated by the Research Diagnostic Criteria for Temporomandibular Disorders. The participants answered the Short-Form Fonseca Anamnestic Index on two occasions with a seven-day interval between tests. For the analysis of between-day reliability, the intraclass correlation coefficient, the standard error of measurement and the minimum detectable change were used. The Receiver Operating Characteristic curve was used to determine the diagnostic accuracy and the best cut-off point. RESULTS: The Short-Form Fonseca Anamnestic Index demonstrated excellent reliability (intraclass correlation coefficient>=0.95) for all items and for the total Short-Form Fonseca Anamnestic Index score (intraclass correlation coefficient=0.98; standard error of measurement=3.28; minimum detectable change=9.09). The level of accuracy of the Short-Form Fonseca Anamnestic Index for the diagnosis of myogenous temporomandibular disorders was high (area under the curve of 0.97), with a better cut-off score of 17.5 points. CONCLUSION: The Fonseca Anamnestic Index should be used in its short form to classify the absence of myogenous temporomandibular disorders (scores between 0 and 15 points) or presence of myogenous temporomandibular disorders (scores between 20 and 50 points) in women. PMID- 29519744 TI - Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial. AB - BACKGROUND: We aimed to assess 24-month outcomes of wearing an organic light emitting sleep mask as an intervention to treat and prevent progression of non central diabetic macular oedema. METHODS: CLEOPATRA was a phase 3, single-blind, parallel-group, randomised controlled trial undertaken at 15 ophthalmic centres in the UK. Adults with non-centre-involving diabetic macular oedema were randomly assigned (1:1) to wearing either a light mask during sleep (Noctura 400 Sleep Mask, PolyPhotonix Medical, Sedgefield, UK) or a sham (non-light) mask, for 24 months. Randomisation was by minimisation generated by a central web-based computer system. Outcome assessors were masked technicians and optometrists. The primary outcome was the change in maximum retinal thickness on optical coherence tomography (OCT) at 24 months, analysed using a linear mixed-effects model incorporating 4-monthly measurements and baseline adjustment. Analysis was done using the intention-to-treat principle in all randomised patients with OCT data. Safety was assessed in all patients. This trial is registered with Controlled Trials.com, number ISRCTN85596558. FINDINGS: Between April 10, 2014, and June 15, 2015, 308 patients were randomly assigned to wearing the light mask (n=155) or a sham mask (n=153). 277 patients (144 assigned the light mask and 133 the sham mask) contributed to the mixed-effects model over time, including 246 patients with OCT data at 24 months. The change in maximum retinal thickness at 24 months did not differ between treatment groups (mean change -9.2 MUm [SE 2.5] for the light mask vs -12.9 MUm [SE 2.9] for the sham mask; adjusted mean difference 0.65 MUm, 95% CI -6.90 to 5.59; p=0.84). Median compliance with wearing the light mask at 24 months was 19.5% (IQR 1.9-51.6). No serious adverse events were related to either mask. The most frequent adverse events related to the assigned treatment were discomfort on the eyes (14 with the light mask vs seven with the sham mask), painful, sticky, or watery eyes (14 vs six), and sleep disturbance (seven vs one). INTERPRETATION: The light mask as used in this study did not confer long-term therapeutic benefit on non-centre-involving diabetic macular oedema and the study does not support its use for this indication. FUNDING: The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership. PMID- 29519747 TI - Calcified Alveolar Septal Pulmonary Amyloidosis as an Initial Manifestation of Multiple Myeloma. PMID- 29519748 TI - Giant Lung Herniation After Minimally Invasive Cardiac Surgery. PMID- 29519749 TI - Tracheobronchopathia Osteochondroplastica. PMID- 29519751 TI - Hypothesizing the potential implications of exposing known carcinogens on normal stem cells. PMID- 29519750 TI - De novo HDAC8 mutation causes Rett-related disorder with distinctive facial features and multiple congenital anomalies. AB - We present a unique 11-year-old girl showing clinical features of Rett-related disorder with distinctive facial features and multiple congenital anomalies including ocular hypertelorism, arched eyebrows, a broad nose, dental anomalies, congenital heart disease, truncal obesity, and epilepsy. A novel de novo mutation in histone deacetylase 8 (HDAC8) (c.652G > T, p.Gly218Cys) was confirmed by whole exome sequencing and Sanger sequencing. X-chromosome inactivation analysis on DNA isolated from peripheral blood lymphocytes revealed a completely skewed pattern associated with an inactive maternal allele. Late clinical loss of acquired purposeful hand movements and psychomotor deterioration may be a feature of Rett related disorder, while distinctive facial features and multiple congenital anomalies are reminiscent of Cornelia de Lange syndrome. PMID- 29519752 TI - Identification of T cell and B cell epitopes against Indian HCV-genotype-3a for vaccine development- An in silico analysis. AB - Hepatitis C virus (HCV) infects almost 150 million people and is a leading cause of liver disease worldwide. It has been classified into seven genotypes; the most common genotype affecting Indian population is genotype 3 (60-70%). Currently there is no vaccine for any genotype of HCV. In order to develop peptide based vaccine against HCV, it is important to identify the conservancy in the circulating genotypes, along with the Human Leucocyte Antigen (HLA) alleles in the target population. The present study aims to identify conserved CD4 and CD8 T cells and B cell epitopes against Indian HCV-genotype-3a using an in silico analysis. In the present study, 28 promiscuous CD4 T cell epitopes and some CD8 epitopes were identified. The NS4 region was predicted to be the most antigenic with maximum number of conserved and promiscuous CD4 T cell epitopes and CD8 T cell epitopes having strong and intermediate affinity towards a number of HLA alleles prevalent in Indian population. Additionally, some linear B cell epitopes were also identified, which could generate neutralizing antibodies. In order to ascertain the binding pattern of the identified epitopes with HLA alleles, molecular docking analysis was carried out. The authors suggest further experimental validation to investigate the immunogenicity of the identified epitopes. PMID- 29519753 TI - The Effect of Aromatherapy Massage on Knee Pain and Functional Status in Participants with Osteoarthritis. AB - This study was conducted to evaluate the effect of aromatherapy massage on knee pain and functional status in subjects with osteoarthritis. The study was designed as a non-randomized interventional study. The study was carried out on patients who referred to the outpatient clinics of the Department of Orthopedics, Physiotherapy and Rehabilitation at Bozok University Research and Application Hospital, and were diagnosed with osteoarthritis. A total number of 95 patients were included in the study, and of those, 33 were allocated to aromatherapy massage group, 30 were allocated to conventional massage group, and 32 were allocated to the control group. The study data were collected using the Patient Identification Form, visual analogue scale, the Western Ontario and McMaster University Osteoarthritis Index. Repeated measures analysis of variance test was used to analyze the outcomes in the aromatherapy, conventional massage and control groups, according to the weeks of follow-up. Bonferroni test was used for further analysis. Baseline mean visual analogue scale score and the Western Ontario and McMaster University Osteoarthritis Index were not significantly different between the groups (p > .05). Visual analogue scale (rest-activity) scores and the scores in the Western Ontario and McMaster University Osteoarthritis Index in the aromatherapy massage group were lower, and the difference compared to the control group was statistically significant (p < .001). Aromatherapy massage performed in patients with osteoarthritis reduced knee pain scores, decreased morning stiffness, and improved physical functioning status. Thus, as long as specific training is provided for aromatherapy massage, aromatherapy can be recommended for routine use in physical therapy units, hospitals and homes. PMID- 29519755 TI - Osteopontin-deficient progenitor cells display enhanced differentiation to adipocytes. AB - OBJECTIVE: Osteopontin (OPN, Spp1) is a protein upregulated in white adipose tissue (WAT) of obese subjects. Deletion of OPN protects mice from high-fat diet induced WAT inflammation and insulin resistance. However, the alterations mediated by loss of OPN in WAT before the obesogenic challenge have not yet been investigated. Therefore, we hypothesised that the lack of OPN might enhance the pro-adipogenic micro environment before obesity driven inflammation. METHODS: OPN deficiency was tested in visceral (V) and subcutaneous (SC) WAT from WT and Spp1 /- female mice. Gene expression for hypoxia, inflammation and adipogenesis was checked in WT vs. Spp1-/- mice (n=15). Adipocytes progenitor cells (APC) were isolated by fluorescence cell sorting and role of OPN deficiency in adipogenesis was investigated by cell images and RT-PCR. RESULTS: We show that Spp1-/- maintained normal body and fat-pad weights, although hypoxia and inflammation markers were significantly reduced. In contrast, expression of genes involved in adipogenesis was increased in WAT from Spp1-/- mice. Strikingly, APC from Spp1-/- were diminished but differentiated more efficiently to adipocytes than those from control mice. CONCLUSIONS: APC from SC-WAT of lean OPN-deficient mice display an enhanced capacity for differentiating to adipocytes. These alterations may explain the healthy expansion of WAT in the OPN-deficient model which is associated with reduced inflammation and insulin resistance. PMID- 29519756 TI - Effects of cannabis use on body mass, fasting glucose and lipids during the first 12 months of treatment in schizophrenia spectrum disorders. AB - While acute cannabis use stimulates appetite, general population studies suggest that chronic use is associated with reduced risk of obesity and other cardiometabolic risk factors. In this study we investigated changes in body mass index (BMI), fasting blood glucose and lipids, and rates of metabolic syndrome risk factors in cannabis users vs. non-users in 109 minimally treated patients with first-episode schizophrenia, schizophreniform or schizo-affective disorder who were treated according to a standardized treatment regime with depot antipsychotic medication over 12 months. Participants underwent repeated urine toxicology tests for cannabis and those testing positive at any time during the study (n = 40), were compared with those who tested negative at all time points (n = 69). There was a significant group*time interaction effect (p = 0.002) with the cannabis negative group showing a greater increase in BMI than the cannabis positive group, after adjusting for age, sex, methamphetamine use and modal dose of antipsychotic. There were no group*time interaction effects for fasting blood glucose or lipids. Post hoc tests indicated significant increases in fasting blood glucose and triglycerides and a decrease in high-density lipoprotein cholesterol for the cannabis negative group, with no significant changes in the cannabis positive group. Rates of metabolic syndrome did not differ significantly between groups, although more cannabis negative patients had elevated waist circumference at endpoint (p = 0.003). It may be that chronic cannabis use directly suppresses appetite, thereby preventing weight gain in users. However, other indirect effects such as dietary neglect and smoking may be contributory and could explain our findings. PMID- 29519754 TI - Aortic valve and left ventricular outflow tract calcium volume and distribution in transcatheter aortic valve replacement: Influence on the risk of significant paravalvular regurgitation. AB - OBJECTIVES: We sought to determine the impact of aortic root calcium on the risk of significant paravalvular regurgitation (sPAR) in transcatheter aortic valve replacement (TAVR). METHODS: In 302 consecutive patients from 3 centers, aortic root calcium was quantified volumetrically on pre-TAVR multidetector computed tomography (MDCT) in three regions: 1) the aortic valve region, 2) the overall left ventricular outflow tract (LVOT) and 3) the upper LVOT. Transcathether heart valve (THV) oversizing was calculated as (THV nominal area/MDCT annular area-1) * 100. The study endpoint sPAR was a composite of post-dilatation (PD) and PAR > mild. RESULTS: sPAR occurred in 15% (46/302) of patients. Upper LVOT calcium volume was more predictive of sPAR than overall LVOT calcium volume, with an area under the receiver operating curve (AUC) (95% confidence interval [CI]) of 0.80 (0.67-0.89) vs. 0.60 (0.51-0.70); p = 0.0001. The optimal cut-off calcium volume thresholds determined from receiver operating curves were 21 mm3 and 30 mm3 for upper LVOT and overall LVOT calcium, respectively. Upper LVOT calcium >= 21 mm3, but not overall LVOT calcium >= 30 mm3, independently predicted sPAR, odds ratio (95%CI): 9.5 (4.1-22.3) vs 1.6 (0.6-2.7). Upper LVOT calcium was more predictive of sPAR in patients with THV oversizing >= 13% compared to patients with THV oversizing <13%, AUC (95% CI): 0.83 (0.72-0.93) vs. 0.67 (0.51-0.74); p < 0.0001. CONCLUSIONS: Upper LVOT calcium predicts more-than-mild paravalvular regurgitation following TAVR or the need for postdilatation. Upper LVOT calcium is most predictive of paravalvular regurgitation in the event of THV oversizing >= 13%. PMID- 29519757 TI - Should the CRA Chain of Survival Be the Survival Cycle? PMID- 29519759 TI - Dynamic variations in platelet counts may reflect the severity and prognosis of stingray injuries in the early phase. AB - There is often a delay in offering quality and prompt treatment after a stingray sting. We present 3 cases of stings and discuss the Poisoning Severity Score (PSS) and a simple tool to assess the severity of such injuries. A 34-year-old man, who worked as an aquarium keeper, presented a wound on the left fifth digit caused by a stingray. Acute myocardial injury and rhabdomyolysis were detected. After 6weeks, the wound had almost healed. A 27-year-old man who experienced a stingray injury on the left second digit recovered without sequelae after 5weeks. A 45-year-old man with a history of diabetes, who was accidentally stung in the right palm by a stingray, experienced rhabdomyolysis and returned to work after 2months. We performed debridement, administered the tetanus toxoid and antibiotics, and immersed the wounded hand in warm water (about 43 degrees C) for all three cases. Meanwhile, patients with rhabdomyolysis were administered intravenous hydration. Upon presentation at the emergency department, we recorded the severity of the injury by using PSS. We found that relatively high PSSs were associated with lower platelet counts that happen due to various adverse events. We suggest that dynamic changes in platelet counts may be associated with the severity of the injury. Furthermore, lower platelet counts in the normal or abnormal range may indicate poor prognoses. PMID- 29519758 TI - Contribution of metabolic disease to bone fragility in MAGP1-deficient mice. AB - Microfibril-associated glycoprotein-1 (MAGP1) is an extracellular matrix protein that interacts with fibrillin and is involved in regulating the bioavailability of signaling molecules such as TGFbeta. Mice with germline MAGP1 deficiency (Mfap2-/-) develop increased adiposity, hyperglycemia, insulin resistance, bone marrow adipose tissue expansion, reduced cancellous bone mass, cortical bone thinning and bone fragility. The goal of this study was to assess whether the Mfap2-/- bone phenotypes were due to loss of MAGP1 locally or secondary to a change in whole body physiology (metabolic dysfunction). To do this, mice with conditional deletion of MAGP1 in the limb skeleton were generated by crossing MAGP1-flox mice (Mfap2lox/lox) with Prx1-Cre mice. Mfap2Prx-/- mice did not show any changes in peripheral adiposity, hyperglycemia or insulin sensitivity, but did have increased bone length and cancellous bone loss that was comparable to the germline Mfap2-/- knockout. Unlike the germline knockout, marrow adiposity, cortical bone thickness and bone strength in Mfap2Prx-/- mice were normal. These findings implicate systemic metabolic dysfunction in the development of bone fragility in germline Mfap2-/- mice. An unexpected finding of this study was the detection of MAGP1 protein in the Mfap2Prx-/- hematopoietic bone marrow, despite the absence of MAGP1 protein in osseous bone matrix and absent Mfap2 transcript expression at both sites. This suggests MAGP1 from a secondary site may accumulate in the bone marrow, but not be incorporated into the bone matrix, during times of regional MAGP1 depletion. PMID- 29519760 TI - Emergency medical technician-performed point-of-care blood analysis using the capillary blood obtained from skin puncture. AB - OBJECTIVE: Comparing a point-of-care (POC) test using the capillary blood obtained from skin puncture with conventional laboratory tests. METHODS: In this study, which was conducted at the emergency department of a tertiary care hospital in April-July 2017, 232 patients were enrolled, and three types of blood samples (capillary blood from skin puncture, arterial and venous blood from blood vessel puncture) were simultaneously collected. Each blood sample was analyzed using a POC analyzer (epoc(r) system, USA), an arterial blood gas analyzer (pHOx(r)Ultra, Nova biomedical, USA) and venous blood analyzers (AU5800, DxH2401, Beckman Coulter, USA). Twelve parameters were compared between the epoc and reference analyzers, with an equivalence test, Bland-Altman plot analysis and linear regression employed to show the agreement or correlation between the two methods. RESULTS: The pH, HCO3, Ca2+, Na+, K+, Cl-, glucose, Hb and Hct measured by the epoc were equivalent to the reference values (95% confidence interval of mean difference within the range of the agreement target) with clinically inconsequential mean differences and narrow limits of agreement. All of them, except pH, had clinically acceptable agreements between the two methods (results within target value >=80%). Of the remaining three parameters (pCO2, pO2 and lactate), the epoc pCO2 and lactate values were highly correlated with the reference device values, whereas pO2 was not. (pCO2: R2=0.824, y=-1.411+0.877.x; lactate: R2=0.902, y=-0.544+0.966.x; pO2: R2=0.037, y=61.6+0.431.x). CONCLUSION: Most parameters, except only pO2, measured by the epoc were equivalent to or correlated with those from the reference method. PMID- 29519761 TI - Prognostic value of D-dimer in patients with pulmonary embolism with and without deep vein thrombosis. PMID- 29519762 TI - iGEL vs laryngeal tube for airway management during a normal airway scenario. PMID- 29519763 TI - Anaphylaxis caused by a centipede bite: A "true" type-I allergic reaction. PMID- 29519765 TI - Cold steel might cure, but it takes a village to prevent surgical infections. PMID- 29519764 TI - Identifying the factors and root causes associated with the unintentional usage of an adrenaline auto-injector in Japanese children and their caregivers. AB - BACKGROUND: The unintentional usage of adrenaline auto-injectors may cause injury to caregivers or patients. To prevent such incidents, we assessed the causative factors of these incidents. METHODS: The Anaphylaxis Working Group of the Japanese Society of Pediatric Allergy and Clinical Immunology requested that society members register cases in which adrenaline auto-injectors were unintentionally used. One hundred cases were reported from June 2015 to March 2016. We identified the root causes of 70 child and 25 adult cases, separately. RESULTS: The incidents occurred with repeated prescriptions as well as the first prescription. Three cases resulted in a failure to administer an adrenaline auto injector to children with anaphylaxis. Four caregivers used it with improper application (epilepsy or enteritis). Among the child cases, the median age at the time of the incident was 5.5 years (range, 2-14 years). Five children injected the adrenaline auto-injector on their own body trunk. Twenty children were not the allergic patients themselves. Improper management protocol of the device and the child's development were concomitantly involved in most of the cases. A variety of human behaviors were identified as the root causes in the adult cases. At least 34 cases were associated with mix-ups between the actual and training device. CONCLUSIONS: Health workers should provide sufficient education regarding safety use of adrenaline auto-injector for caregivers tailored to their experience levels at both first and repeated prescriptions. Such education must cover anticipatory behavior based on normal child development. Devices should also be further improved to prevent such incidents. PMID- 29519766 TI - A multimodal infection control and patient safety intervention to reduce surgical site infections in Africa: a multicentre, before-after, cohort study. AB - BACKGROUND: Surgical site infections (SSIs) are the most frequent health-care associated infections in developing countries. Specific prevention measures are highly effective, but are often poorly implemented. We aimed to establish the effect of a multimodal intervention on SSIs in Africa. METHODS: We did a before after cohort study, between July 1, 2013, and Dec 31, 2015, at five African hospitals. The multimodal intervention consisted of the implementation or strengthening of multiple SSI prevention measures, combined with an adaptive approach aimed at the improvement of teamwork and the safety climate. The primary outcome was the first occurrence of SSI, and the secondary outcome was death within 30 days post surgery. Data on adherence to SSI prevention measures were prospectively collected. The intervention effect on SSI risk and death within 30 days post surgery was assessed in a mixed-effects logistic regression model, after adjustment for key confounders. FINDINGS: Four hospitals completed the baseline and follow-up; three provided suitable (ie, sufficient number and quality) data for the sustainability period. 4322 operations were followed up (1604 at baseline, 1827 at follow-up, and 891 in the sustainability period). SSI cumulative incidence significantly decreased post intervention, from 8.0% (95% CI 6.8-9.5; n=129) to 3.8% (3.0-4.8; n=70; p<0.0001), and this decrease persisted in the sustainability period (3.9%, 2.8-5.4; n=35). A substantial improvement in compliance with prevention measures was consistently observed in the follow-up and sustainability periods. The likelihood of SSI during follow-up was significantly lower than pre-intervention (odds ratio [OR] 0.40, 95% CI 0.29 0.54; p<0.0001), but the likelihood of death was not significantly reduced (0.72, 0.42-1.24; p=0.2360). INTERPRETATION: Implementation of our intervention is feasible in African hospitals. Improvement was observed across all perioperative prevention practices. A significant effect on the overall SSI risk was observed, but with some heterogeneity between sites. Further large-scale experimental studies are needed to confirm these results and to improve the sustainability and long-term effect of such complex programmes. FUNDING: US Agency for Healthcare Research and Quality, WHO. PMID- 29519768 TI - Charcot foot associated with chronic alcoholism in a non-diabetic patient: An unusual association. PMID- 29519767 TI - Clinical bacteriology in low-resource settings: today's solutions. AB - Low-resource settings are disproportionately burdened by infectious diseases and antimicrobial resistance. Good quality clinical bacteriology through a well functioning reference laboratory network is necessary for effective resistance control, but low-resource settings face infrastructural, technical, and behavioural challenges in the implementation of clinical bacteriology. In this Personal View, we explore what constitutes successful implementation of clinical bacteriology in low-resource settings and describe a framework for implementation that is suitable for general referral hospitals in low-income and middle-income countries with a moderate infrastructure. Most microbiological techniques and equipment are not developed for the specific needs of such settings. Pending the arrival of a new generation diagnostics for these settings, we suggest focus on improving, adapting, and implementing conventional, culture-based techniques. Priorities in low-resource settings include harmonised, quality assured, and tropicalised equipment, consumables, and techniques, and rationalised bacterial identification and testing for antimicrobial resistance. Diagnostics should be integrated into clinical care and patient management; clinically relevant specimens must be appropriately selected and prioritised. Open-access training materials and information management tools should be developed. Also important is the need for onsite validation and field adoption of diagnostics in low-resource settings, with considerable shortening of the time between development and implementation of diagnostics. We argue that the implementation of clinical bacteriology in low-resource settings improves patient management, provides valuable surveillance for local antibiotic treatment guidelines and national policies, and supports containment of antimicrobial resistance and the prevention and control of hospital-acquired infections. PMID- 29519769 TI - Rare association between Vogt-Koyanagi-Harada disease and rheumatoid arthritis: Report of a clinical case from the unit of multidisciplinary uveitis. PMID- 29519771 TI - Molecular features of Ixodes kazakstani: first results. AB - Ticks of the Ixodes ricinus group are important vectors of human pathogens in both Eurasia and North America; therefore, many studies have focused on their molecular systematics and evolutionary relationships. However, there are species that have not been characterized by molecular genetic methods so far. For the first time, we obtained nucleotide sequences of two nuclear and three mitochondrial genetic markers from four museum specimen of I. kazakstani Olenev et Sorokoumov, 1934, collected in Kyrgyzstan. The phylogenetic analysis showed that I. kazakstani undoubtedly belongs to the I. ricinus group but is not closely related to I. persulcatus, as was expected. Further studies of the genetic features of I. kazakstani, presumably an intermediate between Nearctic and Palearctic species, would elucidate the evolutionary relationships between tick species within the I. ricinus group. PMID- 29519772 TI - Natural infection of questing ixodid ticks with protozoa and bacteria in Chonburi Province, Thailand. AB - Ixodid ticks are important vectors of tick-borne disease agents affecting humans and animals, with wildlife often serving as important reservoirs. This study examined protozoal and bacterial infection in questing ticks in forest habitats in Chonburi Province, Thailand in 2015, using PCR and DNA sequencing techniques. A total of 12,184 ticks were morphologically identified to species and a subset of ticks were confirmed by PCR, targeting the tick mitochondrial 16S rRNA gene. Tick species collected included Haemaphysalis lagrangei (92.8%), H. wellingtoni (0.1%), and Rhipicephalus microplus (7.0%). In total, 419 tick pools [ELM(1] [ST2] were examined by PCR amplification of a fragment of the 18S rRNA gene of Babesia and Theileria species, and the 16S rRNA gene of bacteria in the family Anaplasmataceae. Results revealed a tick infection rate for the tick pools of 57.0% (239/419) including four pathogens and one bacterial symbiont. The highest infection rate in H. lagrangei, H. wellingtoni, and R. microplus pools was recorded for Anaplasma spp. at 55.6% (233/419) including three Anaplasma species genotype groups Anaplasma spp. closely related to A. bovis, A. platys, and unidentified Anaplasma spp. Theileria spp. showed a lower infection rate in H. lagrangei at 4.3% (18/419) with three Theileria species genotypes closely related to T. cervi, T. capreoli, and unidentified Theileria spp. Only 0.2% (1/419) of H. lagrangei pools contained Babesia spp., Ehrlichia spp., or Wolbachia spp. [ELM(3] [ST4] These findings provided information on tick species in wildlife habitats and detected protozoa and bacteria in the ticks. The results suggest that these tick species are possible vectors for transmitting tick-borne disease agents in Thailand wildlife habitats. PMID- 29519773 TI - Correction to Lancet Public Health 2018; 3: e115-23. PMID- 29519774 TI - Patient Centeredness in Electronic Communication: Evaluation of Patient-to-Health Care Team Secure Messaging. AB - BACKGROUND: As information and communication technology is becoming more widely implemented across health care organizations, patient-provider email or asynchronous electronic secure messaging has the potential to support patient centered communication. Within the medical home model of the Veterans Health Administration (VA), secure messaging is envisioned as a means to enhance access and strengthen the relationships between veterans and their health care team members. However, despite previous studies that have examined the content of electronic messages exchanged between patients and health care providers, less research has focused on the socioemotional aspects of the communication enacted through those messages. OBJECTIVE: Recognizing the potential of secure messaging to facilitate the goals of patient-centered care, the objectives of this analysis were to not only understand why patients and health care team members exchange secure messages but also to examine the socioemotional tone engendered in these messages. METHODS: We conducted a cross-sectional coding evaluation of a corpus of secure messages exchanged between patients and health care team members over 6 months at 8 VA facilities. We identified patients whose medical records showed secure messaging threads containing at least 2 messages and compiled a random sample of these threads. Drawing on previous literature regarding the analysis of asynchronous, patient-provider electronic communication, we developed a coding scheme comprising a series of a priori patient and health care team member codes. Three team members tested the scheme on a subset of the messages and then independently coded the sample of messaging threads. RESULTS: Of the 711 messages coded from the 384 messaging threads, 52.5% (373/711) were sent by patients and 47.5% (338/711) by health care team members. Patient and health care team member messages included logistical content (82.6%, 308/373 vs 89.1%, 301/338), were neutral in tone (70.2%, 262/373 vs 82.0%, 277/338), and respectful in nature (25.7%, 96/373 vs 33.4%, 113/338). Secure messages from health care team members sometimes appeared hurried (25.4%, 86/338) but also displayed friendliness or warmth (18.9%, 64/338) and reassurance or encouragement (18.6%, 63/338). Most patient messages involved either providing or seeking information; however, the majority of health care team member messages involved information provision in response to patient questions. CONCLUSIONS: This evaluation is an important step toward understanding the content and socioemotional tone that is part of the secure messaging exchanges between patients and health care team members. Our findings were encouraging; however, there are opportunities for improvement. As health care organizations seek to supplement traditional encounters with virtual care, they must reexamine their use of secure messaging, including the patient centeredness of the communication, and the potential for more proactive use by health care team members. PMID- 29519775 TI - Adolescents' Perspectives on a Mobile App for Relationships: Cross-Sectional Survey. AB - BACKGROUND: Adolescence can be a fertile time for relationship issues, with interpersonal conflict being a risk factor for poor mental health. Mobile app interventions may have a significant appeal to young people in assisting with relationship distress. However, currently available apps have not been formally evaluated. Youths' perspectives on engaging with mobile technology to assist with relationships are also unknown. OBJECTIVE: This study aimed to examine adolescents' attitudes toward the concept of a mobile phone app for relationship help and support, and whether they would be likely to use such an intervention. METHODS: A cross-sectional Web survey consisting of 42 questions, including 13 free responses, was delivered. The proposed app, including character vignettes, was presented, and participants were asked to indicate whether they had experienced the same relationship issues, whether their peers would relate to the issues, and how helpful they found the proposed advice. Participants were also asked to provide their own suggestions for help, which were analyzed using thematic analyses. RESULTS: A total of 150 adolescents (aged 15 to 18) participated. Overall, 60.7% (91/150) were likely to use an app for relationship problems, and this was not associated with demographics or social support (all P values >.05). Likelihood of app usage was found to be influenced by perceived need for help, personal beliefs about app effectiveness, and whether the app is engaging and easy to use. Overall, adolescents were receptive of the proposed content with an average of 99.3% (149/150), rating the strategies provided as somewhat to very helpful. CONCLUSIONS: Adolescents were likely to use a mobile phone app for relationship support, and use was not influenced by gender, age, social support, or any other background characteristic. Instead, likely use was influenced by need, personal beliefs, usability, and the appropriateness of app content. App developers must address these factors if the app is to have a wide scale uptake. PMID- 29519776 TI - Mobile Technology in E-Learning for Undergraduate Medical Education on Emergent Otorhinolaryngology-Head and Neck Surgery Disorders: Pilot Randomized Controlled Trial. AB - BACKGROUND: The use of mobile technology in e-learning (M-TEL) can add new levels of experience and significantly increase the attractiveness of e-learning in medical education. Whether an innovative interactive e-learning multimedia (IM) module or a conventional PowerPoint show (PPS) module using M-TEL to teach emergent otorhinolaryngology-head and neck surgery (ORL-HNS) disorders is feasible and efficient in undergraduate medical students is unknown. OBJECTIVE: The aim of this study was to compare the impact of a novel IM module with a conventional PPS module using M-TEL for emergent ORL-HNS disorders with regard to learning outcomes, satisfaction, and learning experience. METHODS: This pilot study was conducted at an academic teaching hospital and included 24 undergraduate medical students who were novices in ORL-HNS. The cognitive style was determined using the Group Embedded Figures Test. The participants were randomly allocated (1:1) to one of the two groups matched by age, sex, and cognitive style: the IM group and the PPS group. During the 100-min learning period, the participants were unblinded to use the IM or PPS courseware on a 7 inch tablet. Pretests and posttests using multiple-choice questions to evaluate knowledge and multimedia situational tests to evaluate competence were administered. Participants evaluated their satisfaction and learning experience by the AttrakDiff2 questionnaire, and provided feedback about the modules. RESULTS: Overall, the participants had significant gains in knowledge (median of percentage change 71, 95% CI 1-100, P<.001) and competence (median of percentage change 25, 95% CI 0-33, P=.007) after 100 min of learning. Although there was no significant difference in knowledge gain between the two groups (median of difference of percentage change 24, 95% CI -75 to 36; P=.55), competence gain was significantly lower in the IM group compared with the PPS group (median of difference of percentage change -41, 95% CI -67 to -20; P=.008). However, the IM group had significantly higher scores of satisfaction (difference 2, 95% CI 2-4; P=.01), pragmatic quality (difference 1.7, 95% CI 0.1-2.7; P=.03), and hedonic stimulation (difference 1.9, 95% CI 0.3-3.1; P=.01) compared with the PPS group. Qualitative feedback indicated that the various games in the IM module attracted the participants' attention but that the nonlinearly arranged materials affected their learning. CONCLUSIONS: Using M-TEL for undergraduate medical education on emergent ORL-HNS disorders, an IM module seems to be useful for gaining knowledge, but competency may need to occur elsewhere. While the small sample size reduces the statistical power of our results, its design seems to be appropriate to determine the effects of M-TEL using a larger group. TRIAL REGISTRATION: ClinicalTrials.gov NCT02971735; https://clinicaltrials.gov/ct2/show/NCT02971735 (Archived by WebCite at http://www.webcitation.org/6waoOpCEV). PMID- 29519778 TI - Outcome of Critically ill Patients Undergoing Mandatory Insulin Therapy Compared to Usual Care Insulin Therapy: Protocol for a Pilot Randomized Controlled Trial. AB - BACKGROUND: Observational and interventional studies in patients with both acute medical conditions and long-standing diabetes have shown that improved blood glucose control confers a survival advantage or reduces complication rates. Policies of "tight" glycaemic control were rapidly adopted by many general intensive care units (ICUs) worldwide in the mid 00's, even though the results of the studies were not generalizable to mixed medical/surgical ICUs with different intravenous feeding policies. OBJECTIVE: The primary objective of the study is to assess the safety of mandatory insulin infusion in critically ill patients in a general ICU setting. METHODS: This protocol summarizes the rationale and design of a randomized, controlled, single-center trial investigating the effect of mandatory insulin therapy versus usual care insulin therapy for those patients admitted for a stay of longer than 48 hours. In total, 109 critically ill adults predicted to stay in intensive care for longer than 48 hours consented. The primary outcome is to determine the safety of mandatory insulin therapy in critically ill patients using the number of episodes of hypoglycaemia and hypokalaemia per unit length of stay in intensive care. Secondary outcomes include the duration of mechanical ventilation, duration of ICU and hospital stay, hospital mortality, and measures of renal, hepatic, and haematological dysfunction. RESULTS: The project was funded in 2005 and enrolment was completed 2007. Data analysis is currently underway and the first results are expected to be submitted for publication in 2018. CONCLUSIONS: This protocol for a randomized controlled trial investigating the effect of mandatory insulin therapy should provide an answer to a key question for the management of patients in the ICU and ultimately improving outcome. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN00550641; http://www.isrctn.com/ISRCTN00550641 (Archived at WebCite: http://www.webcitation.org/6xk8NXxNv). PMID- 29519777 TI - Internet-Based Cognitive Behavioral Therapy for Symptoms of Depression and Anxiety Among Patients With a Recent Myocardial Infarction: The U-CARE Heart Randomized Controlled Trial. AB - BACKGROUND: Symptoms of depression and anxiety are common after a myocardial infarction (MI). Internet-based cognitive behavioral therapy (iCBT) has shown good results in other patient groups. OBJECTIVE: The aim of this study was to evaluate the effectiveness of an iCBT treatment to reduce self-reported symptoms of depression and anxiety among patients with a recent MI. METHODS: In total, 3928 patients were screened for eligibility in 25 Swedish hospitals. Of these, 239 patients (33.5%, 80/239 women, mean age 60 years) with a recent MI and symptoms of depression or anxiety were randomly allocated to a therapist-guided, 14-week iCBT treatment (n=117), or treatment as usual (TAU; n=122). The iCBT treatment was designed for post-MI patients. The primary outcome was the total score of the Hospital Anxiety and Depression Scale (HADS) 14 weeks post baseline, assessed over the internet. Treatment effect was evaluated according to the intention-to-treat principle, with multiple imputations. For the main analysis, a pooled treatment effect was estimated, controlling for age, sex, and baseline HADS. RESULTS: There was a reduction in HADS scores over time in the total study sample (mean delta=-5.1, P<.001) but no difference between the study groups at follow-up (beta=-0.47, 95% CI -1.95 to 1.00, P=.53). Treatment adherence was low. A total of 46.2% (54/117) of the iCBT group did not complete the introductory module. CONCLUSIONS: iCBT treatment for an MI population did not result in lower levels of symptoms of depression or anxiety compared with TAU. Low treatment adherence might have influenced the result. TRIAL REGISTRATION: ClinicalTrials.gov NCT01504191; https://clinicaltrials.gov/ct2/show/NCT01504191 (Archived at Webcite at http://www.webcitation.org/6xWWSEQ22). PMID- 29519779 TI - Effect of Using an Indoor Air Quality Sensor on Perceptions of and Behaviors Toward Air Pollution (Pittsburgh Empowerment Library Study): Online Survey and Interviews. AB - BACKGROUND: Air quality affects us all and is a rapidly growing concern in the 21st century. We spend the majority of our lives indoors and can be exposed to a number of pollutants smaller than 2.5 microns (particulate matter, PM2.5) resulting in detrimental health effects. Indoor air quality sensors have the potential to provide people with the information they need to understand their risk and take steps to reduce their exposure. One such sensor is the Speck sensor developed at the Community Robotics, Education and Technology Empowerment Lab at Carnegie Mellon University. This sensor provides users with continuous real-time and historical PM2.5 information, a Web-based platform where people can track their PM2.5 levels over time and learn about ways to reduce their exposure, and a venue (blog post) for the user community to exchange information. Little is known about how the use of such monitors affects people's knowledge, attitudes, and behaviors with respect to indoor air pollution. OBJECTIVE: The aim of this study was to assess whether using the sensor changes what people know and do about indoor air pollution. METHODS: We conducted 2 studies. In the first study, we recruited 276 Pittsburgh residents online and through local branches of the Carnegie Library of Pittsburgh, where the Speck sensor was made available by the researchers in the library catalog. Participants completed a 10- to 15-min survey on air pollution knowledge (its health impact, sources, and mitigation options), perceptions of indoor air quality, confidence in mitigation, current behaviors toward air quality, and personal empowerment and creativity in the spring and summer of 2016. In our second study, we surveyed 26 Pittsburgh residents in summer 2016 who checked out the Speck sensor for 3 weeks on the same measures assessed in the first study, with additional questions about the perception and use of the sensor. Follow-up interviews were conducted with a subset of those who used the Speck sensor. RESULTS: A series of paired t tests found participants were significantly more knowledgeable (t25=-2.61, P=.02), reported having significantly better indoor air quality (t25=-5.20, P<.001), and felt more confident about knowing how to mitigate their risk (t25=-1.87, P=.07) after using the Speck sensor than before. McNemar test showed participants tended to take more action to reduce indoor air pollution after using the sensor (chi225=2.7, P=.10). Qualitative analysis suggested possible ripple effects of use, including encouraging family and friends to learn about indoor air pollution. CONCLUSIONS: Providing people with low- or no-cost portable indoor air quality monitors, with a supporting Web-based platform that offers information about how to reduce risk, can help people better express perceptions and adopt behaviors commensurate with the risks they face. Thus, thoughtfully designed and deployed personal sensing devices can help empower people to take steps to reduce their risk. PMID- 29519781 TI - Cancelling routine surgery: creating more problems than it solves. PMID- 29519780 TI - Robotic Versus Open Renal Transplantation in Obese Patients: Protocol for a Cost Benefit Markov Model Analysis. AB - BACKGROUND: Recent studies have reported a significant decrease in wound problems and hospital stay in obese patients undergoing renal transplantation by robotic assisted minimally invasive techniques with no difference in graft function. OBJECTIVE: Due to the lack of cost-benefit studies on the use of robotic-assisted renal transplantation versus open surgical procedure, the primary aim of our study is to develop a Markov model to analyze the cost-benefit of robotic surgery versus open traditional surgery in obese patients in need of a renal transplant. METHODS: Electronic searches will be conducted to identify studies comparing open renal transplantation versus robotic-assisted renal transplantation. Costs associated with the two surgical techniques will incorporate the expenses of the resources used for the operations. A decision analysis model will be developed to simulate a randomized controlled trial comparing three interventional arms: (1) continuation of renal replacement therapy for patients who are considered non suitable candidates for renal transplantation due to obesity, (2) transplant recipients undergoing open transplant surgery, and (3) transplant patients undergoing robotic-assisted renal transplantation. TreeAge Pro 2017 R1 TreeAge Software, Williamstown, MA, USA) will be used to create a Markov model and microsimulation will be used to compare costs and benefits for the two competing surgical interventions. RESULTS: The model will simulate a randomized controlled trial of adult obese patients affected by end-stage renal disease undergoing renal transplantation. The absorbing state of the model will be patients' death from any cause. By choosing death as the absorbing state, we will be able simulate the population of renal transplant recipients from the day of their randomization to transplant surgery or continuation on renal replacement therapy to their death and perform sensitivity analysis around patients' age at the time of randomization to determine if age is a critical variable for cost-benefit analysis or cost-effectiveness analysis comparing renal replacement therapy, robotic-assisted surgery or open renal transplant surgery. After running the model, one of the three competing strategies will result as the most cost beneficial or cost-effective under common circumstances. To assess the robustness of the results of the model, a multivariable probabilistic sensitivity analysis will be performed by modifying the mean values and confidence intervals of key parameters with the main intent of assessing if the winning strategy is sensitive to rigorous and plausible variations of those values. CONCLUSIONS: After running the model, one of the three competing strategies will result as the most cost beneficial or cost-effective under common circumstances. To assess the robustness of the results of the model, a multivariable probabilistic sensitivity analysis will be performed by modifying the mean values and confidence intervals of key parameters with the main intent of assessing if the winning strategy is sensitive to rigorous and plausible variations of those values. PMID- 29519783 TI - Readers respond to the Hadiza Bawa-Garba case. PMID- 29519782 TI - Fluoroquinolones and the aorta. PMID- 29519784 TI - Barriers for mental health services for children and adolescents are too high, finds regulator. PMID- 29519785 TI - Plans to restrict access to drugs will put vulnerable patients at risk, BMA argues. PMID- 29519786 TI - MS drug is suspended after reports of inflammatory brain disorders. PMID- 29519787 TI - Quantitative Phase-Contrast MR Angiography to Measure Hemodynamic Changes in Idiopathic Intracranial Hypertension. AB - BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension is a syndrome of raised intracranial pressure of unknown etiology. Few MR imaging-based studies have investigated arterial and venous blood flow in these patients. Results are inconclusive, and to our knowledge, no comparison of the hemodynamic parameters before and after CSF pressure reduction has been published. The aim of this study was to assess the short-term effects of normalizing CSF pressure on intracranial flow to better understand the pathophysiology of idiopathic intracranial hypertension. MATERIALS AND METHODS: In this study, we performed quantitative MR imaging-derived flow measurements of brain-supplying arteries and draining veins/dural sinuses to visualize hemodynamic changes in patients with idiopathic intracranial hypertension before and after therapy by lumbar puncture in comparison with a healthy control group. RESULTS: We found differences in patients before and after lumbar puncture in the calculated resistance and pulsatility indices in the superior sagittal sinus. Venous pulsatility showed a negative correlation with CSF pressure in untreated patients. Additionally, there was a trend toward lower flow in the superior sagittal sinus in patients compared with healthy controls. Flow in the internal jugular veins was significantly reduced by lumbar puncture, and the resistance and pulsatility indices differed in patients and controls. The arterial flow was not influenced by pressure normalization. CONCLUSIONS: The results of the present study indicate that venous but not arterial blood flow differs in patients compared with controls and that calculating resistance and pulsatility indices may contribute to assessing short term hemodynamic changes in patients with diagnosed idiopathic intracranial hypertension before and after CSF diversion. PMID- 29519788 TI - Long-Term Outcomes of Patients with Stent Tips Embedded into Internal Carotid Artery Branches during Aneurysm Coiling. AB - BACKGROUND AND PURPOSE: During stent-assisted coiling of ICA aneurysms, stent tips are sometimes unintentionally embedded into ICA branches. Stent tips can be visualized because they have radiopaque markers. Concerns regarding stent tip misplacement include risks of artery perforation and occlusion. The aim of this study was to evaluate the long-term outcomes of ICA branches with embedded stent tips. MATERIALS AND METHODS: ICA branches with embedded stent tips were identified among 35 patients with unruptured ICA aneurysms treated with stent assisted coiling between November 2003 and November 2014. Patient clinical and angiographic outcomes associated with the embedded stent tip were analyzed. RESULTS: Most of the 35 studied aneurysms were paraclinoid ICA aneurysms (n = 30). The most commonly involved ICA branch was the posterior communicating artery (26 patients, 74.3%), followed by the anterior choroidal artery (8 patients, 22.9%) and ophthalmic artery (1 patient, 2.9%). During the follow-up period (38.6 +/- 17.9 months), no new neurologic deficits developed. Neither hemorrhagic nor thromboembolic events occurred. Angiography was performed during the final follow up evaluation at a mean of 32.7 +/- 18.0 months, and all ICA branches with embedded stent tips showed patent blood flow without severe luminal narrowing. CONCLUSIONS: In our experience, placement of a stent tip into ICA branches during stent-assisted coiling was not associated with any major adverse events. PMID- 29519790 TI - Targeting the Clot in Acute Stroke. PMID- 29519789 TI - Congenital Aqueductal Stenosis: Findings at Fetal MRI That Accurately Predict a Postnatal Diagnosis. AB - BACKGROUND AND PURPOSE: Congenital aqueductal stenosis is a common cause of prenatal ventriculomegaly. An accurate diagnosis provides prognostic information and may guide obstetric management. The purpose of this study was to identify specific anatomic findings on prenatal MR imaging that can be used as predictors of congenital aqueductal stenosis. MATERIALS AND METHODS: Prenatal and postnatal MRIs of fetuses referred to our institution for ventriculomegaly between June 2008 and August 2015 were reviewed. Imaging findings in postnatally confirmed congenital aqueductal stenosis (disease group) were compared with those of ventriculomegaly cases from other causes (control group). Univariate analysis was performed using the Fisher exact test and the Wilcoxon rank test, and multivariate analysis, via the random forest method. RESULTS: Forty-three cases of ventriculomegaly had a confirmed postnatal diagnosis of congenital aqueductal stenosis. Thirty-two ventriculomegaly cases negative for congenital aqueductal stenosis were included in the control group. Dominant findings associated with an accurate prenatal diagnosis of congenital aqueductal stenosis on multivariate analysis included the following: enlarged inferior third ventricular recesses, enlargement of the lateral ventricles and third ventricle, and an abnormal corpus callosum. Findings that significantly increase the probability of congenital aqueductal stenosis (high positive predictive value) included the following: enlarged third ventricular recesses, aqueduct funneling, hemorrhage in the cerebral aqueduct, ventricular diverticulum, rhombencephalosynapsis, and dystroglycanopathy-related cerebellar dysplasia. CONCLUSIONS: Our study identified specific characteristics on fetal MR imaging that can be used as predictors of the diagnosis of congenital aqueductal stenosis. Most of these findings are secondary to the obstructive nature of the resulting hydrocephalus. Common associated malformations such as rhombencephalosynapsis and dystroglycanopathies should also increase the suspicion of congenital aqueductal stenosis when present with ventriculomegaly. PMID- 29519791 TI - Fast and Robust Unsupervised Identification of MS Lesion Change Using the Statistical Detection of Changes Algorithm. AB - We developed a robust automated algorithm called statistical detection of changes for detecting morphologic changes of multiple sclerosis lesions between 2 T2 weighted FLAIR brain images. Results from 30 patients showed that statistical detection of changes achieved significantly higher sensitivity and specificity (0.964, 95% CI, 0.823-0.994; 0.691, 95% CI, 0.612-0.761) than with the lesion prediction algorithm (0.614, 95% CI, 0.410-0.784; 0.281, 95% CI, 0.228-0.314), while resulting in a 49% reduction in human review time (P = .007). PMID- 29519792 TI - Prenatal Brain MR Imaging: Reference Linear Biometric Centiles between 20 and 24 Gestational Weeks. AB - BACKGROUND AND PURPOSE: Evaluation of biometry is a fundamental step in prenatal brain MR imaging. While different studies have reported reference centiles for MR imaging biometric data of fetuses in the late second and third trimesters of gestation, no one has reported them in fetuses in the early second trimester. We report centiles of normal MR imaging linear biometric data of a large cohort of fetal brains within 24 weeks of gestation. MATERIALS AND METHODS: From the data bases of 2 referral centers of fetal medicine, accounting for 3850 examinations, we retrospectively collected 169 prenatal brain MR imaging examinations of singleton pregnancies, between 20 and 24 weeks of gestational age, with normal brain anatomy at MR imaging and normal postnatal neurologic development. To trace the reference centiles, we used the CG-LMS method. RESULTS: Reference biometric centiles for the developing structures of the cerebrum, cerebellum, brain stem, and theca were obtained. The overall interassessor agreement was adequate for all measurements. CONCLUSIONS: Reference biometric centiles of the brain structures in fetuses between 20 and 24 weeks of gestational age may be a reliable tool in assessing fetal brain development. PMID- 29519793 TI - MRI Features Can Predict 1p/19q Status in Intracranial Gliomas. AB - BACKGROUND AND PURPOSE: The 2016 revision of the World Health Organization Classification of Tumors of the Central Nervous System mandates codeletion of chromosomes 1p and 19q for the diagnosis of oligodendroglioma. We studied whether conventional MR imaging features could predict 1p/19q status. MATERIALS AND METHODS: Patients with previous 1p/19q testing were identified through pathology department records, typically performed on the basis of an oligodendroglial component on routine histology; 69 patients met the inclusion criteria. Preoperative imaging of patients with grade II or III gliomas was retrospectively assessed by 2 neuroradiologists, blinded to the 1p/19q status. Thirteen MR imaging features were first assessed in a small initial cohort (n = 10), after which the criteria were narrowed for the remaining patients as a validation cohort. RESULTS: There was 85% agreement between radiologists for the overall prediction of 1p/19q status in the validation cohort, with an accuracy of 84%. The presence of >50% T2-FLAIR mismatch and calcification was found to be the most useful for predicting 1p/19q status. The >50% T2-FLAIR mismatch variable was demonstrated in 14 tumors and had 100% specificity for identifying a noncodeleted tumor (P = .001), with 97% interobserver correlation. Calcification was visualized in 7 tumors, 6 of which were 1p/19q codeleted (specificity, 97%; P = .006), with 100% interobserver correlation. CONCLUSIONS: The presence of >50% T2 FLAIR mismatch is highly predictive of a noncodeleted tumor, while calcifications suggest a 1p/19q codeleted tumor. If formal 1p/19q testing is not possible, a combined MR imaging-histologic assessment may improve the diagnostic accuracy over histology alone. PMID- 29519794 TI - Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas. AB - BACKGROUND AND PURPOSE: Prediction of the isocitrate dehydrogenase 1 (IDH1) mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1 mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. MATERIALS AND METHODS: Ninety-three patients with World Health Organization grade II gliomas with known IDH1-mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1 mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1-mutant subgroups were evaluated using the least absolute shrinkage and selection operator. RESULTS: Various histogram and texture parameters differed significantly according to IDH1-mutation and 1p/19q codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. CONCLUSIONS: Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. PMID- 29519795 TI - Patients urged to lobby MPs over emergency department crisis. PMID- 29519796 TI - Mental health and well-being concerns of fly-in fly-out workers and their partners in Australia: a qualitative study. AB - OBJECTIVES: Fly-in fly-out (FIFO) work involves commuting long distances to the worksite and living in provided accommodation for 1-4 weeks while on shift. While the potentially detrimental impact of FIFO work on the health and well-being of workers has been documented, little attention has been paid to how workers, or their partners, cope with this impact. This study sought to investigate how workers and their partners negotiate the impact of FIFO on their mental health and well-being. DESIGN: The study design was qualitative. FIFO workers and partners responded to open-ended questions on concerns about the FIFO lifestyle and the support they use. SETTING: Australian FIFO workers and partners responded to the questions via email. PARTICIPANTS: Participants were 34 FIFO workers (25 men, M age=41 years) and 26 partners of FIFO workers (26 women, M age=40 years). RESULTS: Participant-validated thematic analysis generated three main themes: managing multiple roles, impact on mental health and well-being, and social support needs. Results revealed difficulties in adjusting between the responsibilities of perceptually distinct on-shift and off-shift lives, and managing potential psychological distance that develops while workers are on site. Participants emphasised the importance of maintaining quality communication and support from family members. Workers and partners attempted to maintain mental health and well-being by regularly engaging with support networks, although many felt organisational support was tokenistic, stigmatised or lacking. CONCLUSIONS: Recommendations for enhancing support provided by FIFO organisations are offered. In particular, organisations should emphasise the importance of good mental health and well-being, maintain transparency regarding potential challenges of FIFO lifestyles, and offer professional support for managing multiple social roles and effective communication. PMID- 29519797 TI - Authors' reply to Ryan, Menzies-Gow and Alexander, and Littlejohns. PMID- 29519799 TI - Diagnostic accuracy of three morning sputum versus standard sputum smears for pulmonary tuberculosis. PMID- 29519798 TI - Early activation of peripheral monocytes with hallmarks of M1 and M2 monocytic cells in excessive alcohol drinkers: a pilot study. AB - Excessive drinking can lead to the development of immune dysfunction. Our aim is to investigate the effect of alcohol on immune activation from circulating peripheral blood monocytes in excessive drinkers (EDs). Twenty-two EDs and healthy controls were enrolled. Time line follow-back was used to quantify the amount of alcohol consumed in the past 30 days before enrollment. Peripheral blood-derived CD14+ monocytes were isolated for gene expression analyses. Serum interleukin (IL)-6, IL-10 and lipopolysaccharides (LPS) were also measured. We found that serum LPS concentrations were significantly higher in EDs compared with controls (P<0.05). While no differences in the levels of circulating IL-6 and IL-10 were observed, the relative levels of gene transcripts (RQ) for Il6 (an M1-polarizing cytokine) and Il10 (an M2-polarizing cytokine) were significantly higher in peripheral blood-derived monocytes from EDs compared with controls (Il6: P<0.01. Il10: P<0.05). EDs exhibit early immune activation of peripheral blood monocyte mRNA transcripts, notably Il6 and Il10 Future studies are needed to explore the clinical implications of our findings and determine whether the levels of Il6 and Il10 mRNA expression can be used to identify those with excessive drinking and to monitor for alcohol abstinence. PMID- 29519800 TI - The Change in Living Kidney Donation in Women and Men in the United States (2005 2015): A Population-Based Analysis. AB - The factors underlying the decline in living kidney donation in the United States since 2005 must be understood to inform strategies to ensure access to this option for future patients. Population-based estimates provide a better assessment of donation activity than do trends in the number of living donor transplants. Using data from the Scientific Registry of Transplant Recipients and the United States Census, we determined longitudinal changes in living kidney donation between 2005 and 2015, focusing on the effect of sex and income. We used multilevel Poisson models to adjust for differences in age, race, the incidence of ESRD, and geographic factors (including population density, urbanization, and daily commuting). During the study period, the unadjusted rate of donation was 30.1 and 19.3 per million population in women and men, respectively, and the adjusted incidence of donation was 44% higher in women (incidence rate ratio [IRR], 1.44; 95% confidence interval [95% CI], 1.39 to 1.49). The incidence of donation was stable in women (IRR, 0.95; 95% CI, 0.84 to 1.07) but declined in men (IRR, 0.75; 95% CI, 0.68 to 0.83). Income was associated with longitudinal changes in donation in both sexes, yet donation was stable in the highest two population income quartiles in women but only in the highest income quartile in men. In both sexes, living related donations declined, irrespective of income. In conclusion, living donation declined in men but remained stable in women between 2005 and 2015, and income appeared to have a greater effect on living donation in men. PMID- 29519801 TI - Gender Disparities and Financial Barriers to Living Kidney Donation. PMID- 29519802 TI - Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation. AB - Mitochondria contain tens to thousands of copies of their own genome (mitochondrial DNA [mtDNA]), creating genetic redundancy capable of buffering mutations in mitochondrial genes essential for cellular function. However, the mechanisms regulating mtDNA copy number have been elusive. Here we found that DNA synthesis and degradation by mtDNA polymerase gamma (POLG) dynamically controlled mtDNA copy number in starving yeast cells dependent on metabolic homeostasis provided by autophagy. Specifically, the continuous mtDNA synthesis by POLG in starving wild-type cells was inhibited by nucleotide insufficiency and elevated mitochondria-derived reactive oxygen species in the presence of autophagy dysfunction. Moreover, after prolonged starvation, 3'-5' exonuclease-dependent mtDNA degradation by POLG adjusted the initially increasing mtDNA copy number in wild-type cells, but caused quantitative mtDNA instability and irreversible respiratory dysfunction in autophagy-deficient cells as a result of nucleotide limitations. In summary, our study reveals that mitochondria rely on the homeostatic functions of autophagy to balance synthetic and degradative modes of POLG, which control copy number dynamics and stability of the mitochondrial genome. PMID- 29519803 TI - Fast and furious . . . or not, Plk4 dictates the pace. AB - In each duplication cycle, daughter centrioles grow to the same length as their mothers. Which mechanisms regulate this fidelity to maintain centriole length is not known. In this issue, Aydogan et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201801014) report a novel role for Polo-like kinase 4 (Plk4). They found that Plk4 functions in a homeostatic manner to balance growth rate and growth period to set the final centriole size. PMID- 29519804 TI - Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms. AB - The transcription factor "nuclear factor erythroid 2" (NFE2) is overexpressed in the majority of patients with myeloproliferative neoplasms (MPNs). In murine models, elevated NFE2 levels cause an MPN phenotype with spontaneous leukemic transformation. However, both the molecular mechanisms leading to NFE2 overexpression and its downstream targets remain incompletely understood. Here, we show that the histone demethylase JMJD1C constitutes a novel NFE2 target gene. JMJD1C levels are significantly elevated in polycythemia vera (PV) and primary myelofibrosis patients; concomitantly, global H3K9me1 and H3K9me2 levels are significantly decreased. JMJD1C binding to the NFE2 promoter is increased in PV patients, decreasing both H3K9me2 levels and binding of the repressive heterochromatin protein-1alpha (HP1alpha). Hence, JMJD1C and NFE2 participate in a novel autoregulatory loop. Depleting JMJD1C expression significantly reduced cytokine-independent growth of an MPN cell line. Independently, NFE2 is regulated through the epigenetic JAK2 pathway by phosphorylation of H3Y41. This likewise inhibits HP1alpha binding. Treatment with decitabine lowered H3Y41ph and augmented H3K9me2 levels at the NFE2 locus in HEL cells, thereby increasing HP1alpha binding, which normalized NFE2 expression selectively in JAK2V617F positive cell lines. PMID- 29519805 TI - Active enhancer and chromatin accessibility landscapes chart the regulatory network of primary multiple myeloma. AB - Multiple myeloma (MM) is an aggressive cancer that originates from antibody secreting plasma cells. Although genetically and transcriptionally well characterized, the aberrant gene regulatory networks that underpin this disease remain poorly understood. Here, we mapped regulatory elements, open chromatin, and transcription factor (TF) footprints in primary MM cells. In comparison with normal antibody-secreting cells, MM cells displayed consistent changes in enhancer activity that are connected to superenhancer (SE)-mediated deregulation of TF genes. MM cells also displayed widespread decompaction of heterochromatin that was associated with activation of regulatory elements and in a major subset of patients' deregulation of the cyclic adenosine monophosphate pathway. Finally, building SE-associated TF-based regulatory networks allowed identification of several novel TFs that are central to MM biology. Taken together, these findings significantly add to our understanding of the aberrant gene regulatory network that underpins MM. PMID- 29519806 TI - Cancer and platelet crosstalk: opportunities and challenges for aspirin and other antiplatelet agents. AB - Platelets have long been recognized as key players in hemostasis and thrombosis; however, growing evidence suggests that they are also significantly involved in cancer, the second leading cause of mortality worldwide. Preclinical and clinical studies showed that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between platelets and cancer cells. For example, cancer changes platelet behavior by directly inducing tumor-platelet aggregates, triggering platelet granule and extracellular vesicle release, altering platelet phenotype and platelet RNA profiles, and enhancing thrombopoiesis. Reciprocally, platelets reinforce tumor growth with proliferation signals, antiapoptotic effect, and angiogenic factors. Platelets also activate tumor invasion and sustain metastasis via inducing an invasive epithelial mesenchymal transition phenotype of tumor cells, promoting tumor survival in circulation, tumor arrest at the endothelium, and extravasation. Furthermore, platelets assist tumors in evading immune destruction. Hence, cancer cells and platelets maintain a complex, bidirectional communication. Recently, aspirin (acetylsalicylic acid) has been recognized as a promising cancer-preventive agent. It is recommended at daily low dose by the US Preventive Services Task Force for primary prevention of colorectal cancer. The exact mechanisms of action of aspirin in chemoprevention are not very clear, but evidence has emerged that suggests a platelet-mediated effect. In this article, we will introduce how cancer changes platelets to be more cancer-friendly and highlight advances in the modes of action for aspirin in cancer prevention. We also discuss the opportunities, challenges, and opposing viewpoints on applying aspirin and other antiplatelet agents for cancer prevention and treatment. PMID- 29519807 TI - Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human beta-globin locus. AB - Naturally occurring, large deletions in the beta-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and beta-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the delta- and beta-globin genes and a putative gamma-delta intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in gamma-globin expression, whereas deletion or inversion of a 13.6-kb region causes a robust reactivation of HbF synthesis in adult erythroblasts that is associated with epigenetic modifications and changes in chromatin contacts within the beta-globin locus. In primary SCD patient derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of gamma-globin expression in erythroblasts, increased HbF synthesis, and amelioration of the sickling cell phenotype. Overall, this study provides clues for a potential CRISPR/Cas9 genome editing approach to the therapy of beta-hemoglobinopathies. PMID- 29519808 TI - Predictors of extubation readiness in preterm infants: a systematic review and meta-analysis. AB - CONTEXT: A variety of extubation readiness tests have already been incorporated into clinical practice in preterm infants. OBJECTIVE: To identify predictor tests of successful extubation and determine their accuracy compared with clinical judgement alone. METHODS: MEDLINE, Embase, PubMed, Cochrane Library and Web of Science were searched between 1984 and June 2016. Studies evaluating predictors of extubation success during a period free of mechanical inflations in infants less than 37 weeks' gestation were included. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. After identifying and describing all predictor tests, pooled sensitivity and specificity estimates for the different test categories were generated using a bivariate random-effects model. RESULTS: Thirty-five studies were included, showing wide heterogeneities in population characteristics, methodologies and definitions of extubation success. Assessments ranged from a few seconds to 24 hours, provided 0-6 cmH2O positive end-expiratory pressure and measured several clinical and/or physiological parameters. Thirty-one predictor tests were identified, showing good sensitivities but low and variable specificities. Given the high variation in test definitions across studies, pooling could only be performed on a subset. The commonly performed spontaneous breathing trials had pooled sensitivity of 95% (95% CI 87% to 99%) and specificity of 62% (95% CI 38% to 82%), while composite tests offered the best performance characteristics. CONCLUSIONS: There is a lack of strong evidence to support the use of extubation readiness tests in preterm infants. Although spontaneous breathing trials are attractive assessment tools, higher quality studies are needed for determining the optimal strategies for improving their accuracy. PMID- 29519809 TI - Many global health organisations fail to act on gender equality. PMID- 29519810 TI - Developing a novel international undergraduate surgical masterclass during a financial crisis: our 4-year experience. AB - BACKGROUND: Essential Skills in the Management of Surgical Cases (ESMSC) is a novel 3-day international undergraduate surgical masterclass. Its current curriculum (Cores integrated for Research-Ci4R) is built on a tetracore, multiclustered architecture combining high-fidelity and low-fidelity simulation based learning (SBL), with applied and basic science case-based workshops, and non-technical skills modules. We aimed to report our experience in setting up ESMSC during the global financial crisis. METHODS: We report the evolution of our curriculum's methodology and summarised the research outcomes related to the objective performance improvement of delegates, the educational environment of the course and the use of mixed-fidelity SBL. Feedback from the last three series of the course was prospectively collected and analysed using univariate statistics on IBM SPSS V.23. RESULTS: 311 medical students across the European Union (EU) were selected from a competitive pool of 1280 applicants during seven series of the course between 2014 and 2017. During this period, curriculum 14 s evolved to the final Ci4R version, which integrates a tetracore structure combining 32 stations of in vivo, ex vivo and dry lab SBL with small group teaching workshops. Ci4R was positively perceived across different educational background students (p>0.05 for any comparison). CONCLUSIONS: ESMSC is considered an innovative and effective multidisciplinary teaching model by delegates, where it improves delegates objective performance in basic surgical skills. Our experience demonstrates provision of high-quality and free surgical education during a financial crisis, which evolved through a dynamic feedback mechanism. The prospective recording and subsequent analysis of curriculum evolution provides a blueprint to direct development of effective surgical education courses that can be adapted to local needs. PMID- 29519811 TI - Single-Molecule Counting of High-Sensitivity Troponin I in Patients Referred for Diagnostic Angiography: Results From the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) Study. AB - BACKGROUND: The meaning of high-sensitivity troponin I (hsTnI) concentrations in patients without acute myocardial infarction (MI) requires clarity. We hypothesized that among patients referred for diagnostic coronary angiography without acute MI, hsTnI concentrations would correlate with prevalent coronary artery disease (CAD) and predict incident cardiovascular events and mortality. METHODS AND RESULTS: We measured hsTnI using a single-molecule counting assay (99th percentile, 6 ng/L) in samples from 991 patients obtained at the time of angiography. Concentrations of hsTnI were assessed relative to the severity of CAD and prognosis during mean follow-up of 3.7 years. Median hsTnI concentration was 4.19 ng/L; 38% of patients had hsTnI concentrations >=99th percentile. Across increasing hsTnI quartiles, patients had higher prevalence of angiographic CAD; in multivariate models, hsTnI >=99th percentile independently predicted obstructive CAD (odds ratio: 2.57; P<0.001) and incident MI (hazard ratio [HR]: 2.68; P<0.001), cardiovascular death (HR: 2.29; P=0.001), and all-cause death (HR: 1.84; P=0.004). In those with >70% coronary stenosis, hsTnI >=99th percentile independently predicted incident MI (HR: 1.87; P=0.01), cardiovascular mortality (HR: 2.74; P=0.001), and the composite end point of MI and all-cause death (HR: 2.06; P<0.001). In participants with coronary stenosis <70%, hsTnI >=99th percentile even more strongly predicted incident MI (HR: 8.41; P<0.001), cardiovascular mortality (HR: 3.60; P=0.03), and the composite end point of MI and all-cause death (HR: 3.62; P<0.001). CONCLUSIONS: In a large prospective cohort of patients who were free of prevalent MI and undergoing diagnostic coronary angiography, hsTnI concentrations were associated with higher prevalence of CAD and predicted incident MI, cardiovascular death, and all-cause death. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868. PMID- 29519812 TI - Impact of Ischemic and Valvular Heart Disease on Atrial Excitation:A High Resolution Epicardial Mapping Study. AB - BACKGROUND: The influence of underlying heart disease or presence of atrial fibrillation (AF) on atrial excitation during sinus rhythm (SR) is unknown. We investigated atrial activation patterns and total activation times of the entire atrial epicardial surface during SR in patients with ischemic and/or valvular heart disease with or without AF. METHODS AND RESULTS: Intraoperative epicardial mapping (N=128/192 electrodes, interelectrode distances: 2 mm) of the right atrium, Bachmann's bundle (BB), left atrioventricular groove, and pulmonary vein area was performed during SR in 253 patients (186 male [74%], age 66+/-11 years) with ischemic heart disease (N=132, 52%) or ischemic valvular heart disease (N=121, 48%). As expected, SR origin was located at the superior intercaval region of the right atrium in 232 patients (92%). BB activation occurred via 1 wavefront from right-to-left (N=163, 64%), from the central part (N=18, 7%), or via multiple wavefronts (N=72, 28%). Left atrioventricular groove activation occurred via (1) BB: N=108, 43%; (2) pulmonary vein area: N=9, 3%; or (3) BB and pulmonary vein area: N=136, 54%; depending on which route had the shortest interatrial conduction time (P<0.001). Ischemic valvular heart disease patients more often had central BB activation and left atrioventricular groove activation via pulmonary vein area compared with ischemic heart disease patients (N=16 [13%] versus N=2 [2%]; P=0.009 and N=86 [71%] versus N=59 [45%]; P<0.001, respectively). Total activation times were longer in patients with AF (AF: 136+/ 20 [92-186] ms; no AF: 114+/-17 [74-156] ms; P<0.001), because of prolongation of right atrium (P=0.018) and BB conduction times (P<0.001). CONCLUSIONS: Atrial excitation during SR is affected by underlying heart disease and AF, resulting in alternative routes for BB and left atrioventricular groove activation and prolongation of total activation times. Knowledge of atrial excitation patterns during SR and its electropathological variations, as demonstrated in this study, is essential to further unravel the pathogenesis of AF. PMID- 29519813 TI - Postsystolic Shortening by Speckle Tracking Echocardiography Is an Independent Predictor of Cardiovascular Events and Mortality in the General Population. AB - BACKGROUND: Postsystolic shortening (PSS) has been proposed as a novel marker of contractile dysfunction in the myocardium. Our objective was to assess the prognostic potential of PSS on cardiovascular events and death in the general population. METHODS AND RESULTS: The study design consisted of a prospective cohort study of 1296 low-risk participants from the general population, who were examined by speckle tracking echocardiography. The primary end point was the composite of heart failure, myocardial infarction, and cardiovascular death, defined as major adverse cardiovascular events (MACEs). The secondary end point was all-cause death. The postsystolic index (PSI) was defined as follows: [(maximum strain in cardiac cycle-peak systolic strain)/(maximum strain in cardiac cycle)]*100. PSS was regarded as present if PSI >20%. During a median follow-up of 11 years, 149 participants (12%) were diagnosed as having MACEs and 236 participants (18%) died. Increasing number of walls with PSS predicted both end points, an association that persisted after adjustment for age, sex, estimated glomerular filtration rate, global longitudinal strain, hypertension, heart rate, left ventricular ejection fraction, LV mass index, pro-B-type natriuretic peptide, previous ischemic heart disease, systolic blood pressure, average peak early diastolic longitudinal mitral annular velocity (e'), ratio between peak transmitral early and late diastolic inflow velocity (E/A), and left atrial volume index: MACEs (hazard ratio, 1.35; 95% confidence interval, 1.09 1.67; P=0.006 per 1 increase in walls displaying PSS) and death (hazard ratio, 1.30; 95% confidence interval, 1.08-1.57; P=0.006 per 1 increase in walls displaying PSS). The strongest predictor of end points was >=2 walls exhibiting PSS. The PSI also predicted increased risk of the end points, and the associations remained significant in multivariable models: MACEs (per 1% increase in PSI: hazard ratio, 1.18; 95% confidence interval, 1.02-1.36; P=0.024) and death (per 1% increase in PSI: hazard ratio, 1.18; 95% confidence interval, 1.05 1.33; P=0.005). CONCLUSIONS: Presence of PSS in the general population provides independent and long-term prognostic information on the occurrence of MACEs and death. PMID- 29519814 TI - Seven days in medicine: 28 February to 6 March. PMID- 29519815 TI - Structural and functional analyses reveal the contributions of the C- and N-lobes of Argonaute protein to selectivity of RNA target cleavage. AB - Some gene transcripts have cellular functions as regulatory noncoding RNAs. For example, ~23-nucleotide (nt)-long siRNAs are loaded into Argonaute proteins. The resultant ribonucleoprotein assembly, the RNA-induced silencing complex (RISC), cleaves RNAs that are extensively base-paired with the loaded siRNA. To date, base complementarity is recognized as the major determinant of specific target cleavage (or slicing), but little is known about how Argonaute inspects base pairing before cleavage. A hallmark of Argonaute proteins is their bilobal structure, but despite the significance of this structure for curtailing slicing activity against mismatched targets, the molecular mechanism remains elusive. Here, our structural and functional studies of a bilobed yeast Argonaute protein and its isolated catalytic C-terminal lobe (C-lobe) revealed that the C-lobe alone retains almost all properties of bilobed Argonaute: siRNA-duplex loading, passenger cleavage/ejection, and siRNA-dependent RNA cleavage. A 2.1 A-resolution crystal structure revealed that the catalytic C-lobe mirrors the bilobed Argonaute in terms of guide-RNA recognition and that all requirements for transitioning to the catalytically active conformation reside in the C-lobe. Nevertheless, we found that in the absence of the N-terminal lobe (N-lobe), target RNAs are scanned for complementarity only at positions 5-14 on a 23-nt guide RNA before endonucleolytic cleavage, thereby allowing for some off-target cleavage. Of note, acquisition of an N-lobe expanded the range of the guide RNA strand used for inspecting target complementarity to positions 2-23. These findings offer clues to the evolution of the bilobal structure of catalytically active Argonaute proteins. PMID- 29519816 TI - An auto-inhibitory helix in CTP:phosphocholine cytidylyltransferase hijacks the catalytic residue and constrains a pliable, domain-bridging helix pair. AB - The activity of CTP:phosphocholine cytidylyltransferase (CCT), a key enzyme in phosphatidylcholine synthesis, is regulated by reversible interactions of a lipid inducible amphipathic helix (domain M) with membrane phospholipids. When dissociated from membranes, a portion of the M domain functions as an auto inhibitory (AI) element to suppress catalysis. The AI helix from each subunit binds to a pair of alpha helices (alphaE) that extend from the base of the catalytic dimer to create a four-helix bundle. The bound AI helices make intimate contact with loop L2, housing a key catalytic residue, Lys122 The impacts of the AI helix on active-site dynamics and positioning of Lys122 are unknown. Extensive MD simulations with and without the AI helix revealed that backbone carbonyl oxygens at the point of contact between the AI helix and loop L2 can entrap the Lys122 side chain, effectively competing with the substrate, CTP. In silico, removal of the AI helices dramatically increased alphaE dynamics at a predicted break in the middle of these helices, enabling them to splay apart and forge new contacts with loop L2. In vitro cross-linking confirmed the reorganization of the alphaE element upon membrane binding of the AI helix. Moreover, when alphaE bending was prevented by disulfide engineering, CCT activation by membrane binding was thwarted. These findings suggest a novel two-part auto-inhibitory mechanism for CCT involving capture of Lys122 and restraint of the pliable alphaE helices. We propose that membrane binding enables bending of the alphaE helices, bringing the active site closer to the membrane surface. PMID- 29519817 TI - Salvador has an extended SARAH domain that mediates binding to Hippo kinase. AB - The Hippo pathway controls cell proliferation and differentiation through the precisely tuned activity of a core kinase cassette. The activity of Hippo kinase is modulated by interactions between its C-terminal coiled-coil, termed the SARAH domain, and the SARAH domains of either dRassF or Salvador. Here, we wanted to understand the molecular basis of SARAH domain-mediated interactions and their influence on Hippo kinase activity. We focused on Salvador, a positive effector of Hippo activity and the least well-characterized SARAH domain-containing protein. We determined the crystal structure of a complex between Salvador and Hippo SARAH domains from Drosophila This structure provided insight into the organization of the Salvador SARAH domain including a folded N-terminal extension that expands the binding interface with Hippo SARAH domain. We also found that this extension improves the solubility of the Salvador SARAH domain, enhances binding to Hippo, and is unique to Salvador. We therefore suggest expanding the definition of the Salvador SARAH domain to include this extended region. The heterodimeric assembly observed in the crystal was confirmed by cross-linked MS and provided a structural basis for the mutually exclusive interactions of Hippo with either dRassF or Salvador. Of note, Salvador influenced the kinase activity of Mst2, the mammalian Hippo homolog. In co-transfected HEK293T cells, human Salvador increased the levels of Mst2 autophosphorylation and Mst2-mediated phosphorylation of select substrates, whereas Salvador SARAH domain inhibited Mst2 autophosphorylation in vitro These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway. PMID- 29519819 TI - Draft Genome Sequences of Three Virulent Streptococcus thermophilus Bacteriophages Isolated from the Dairy Environment in the Veneto Region of Italy. AB - Streptococcus thermophilus, a very important dairy species, is constantly threatened by phage infection. We report the genome sequences of three S. thermophilus bacteriophages isolated from a dairy environment in the Veneto region of Italy. These sequences will be used for the development of new strategies to detect and control phages in dairy environments. PMID- 29519818 TI - Proteasome Activity Is Influenced by the HECT_2 Protein Ipa1 in Budding Yeast. AB - The ubiquitin-proteasome system (UPS) controls cellular functions by maintenance of a functional proteome and degradation of key regulatory proteins. Central to the UPS is the proteasome that adjusts the abundance of numerous proteins, thereby safeguarding their activity or initiating regulatory events. Here, we demonstrate that the essential Saccharomyces cerevisiae protein Yjr141w/Ipa1 (Important for cleavage and PolyAdenylation) belongs to the HECT_2 (homologous to E6-AP carboxyl terminus_2) family. We found that five cysteine residues within the HECT_2 family signature and the C-terminus are essential for Ipa1 activity. Furthermore, Ipa1 interacts with several ubiquitin-conjugating enzymes in vivo and localizes to the cytosol and nucleus. Importantly, Ipa1 has an impact on proteasome activity, which is indicated by the activation of the Rpn4 regulon as well as by decreased turnover of destabilized proteasome substrates in an IPA1 mutant. These changes in proteasome activity might be connected to reduced maturation or modification of proteasomal core particle proteins. Our results highlight the influence of Ipa1 on the UPS. The conservation within the HECT_2 family and the connection of the human HECT_2 family member to an age-related degeneration disease might suggest that HECT_2 family members share a conserved function linked to proteasome activity. PMID- 29519820 TI - Complete Genome Sequence of Streptococcus suis Serotype 2 Virulent Strain SS2-1. AB - Streptococcus suis is an important swine pathogen that can also cause severe diseases in humans. Herein, we describe the genome sequence of Streptococcus suis serotype 2 virulent strain SS2-1, which was isolated from a diseased dead pig amid the 1998 Streptococcus suis outbreak in Jiangsu Province in China. PMID- 29519821 TI - Complete Genome Sequence of an Enterovirus A71 Strain Isolated in 2006 from a Patient in Shenzhen, Southern China, with a Lethal Case of Enterovirus Infection. AB - The whole-genome sequence of an enterovirus A71 strain (EV71/SHENZHEN001/2006) isolated in 2006 from a patient with a fatal case of enterovirus infection was determined. Phylogenetic analysis based on the complete VP1 gene classified this strain as subgenotype C4a. PMID- 29519822 TI - Full-Genome Sequence of Infectious Laryngotracheitis Virus (Gallid Alphaherpesvirus 1) Strain VFAR-043, Isolated in Peru. AB - We report here the first genome sequence of infectious laryngotracheitis virus isolated in Peru from tracheal tissues of layer chickens. The genome showed 99.98% identity to the J2 strain genome sequence. Single nucleotide polymorphisms were detected in five gene-coding sequences related to vaccine development, virus attachment, and viral immune evasion. PMID- 29519823 TI - Whole-Genome Sequence of Brucella melitensis CIIMS-BH-2, a Biovar 2 Strain Isolated from Human Blood. AB - Brucella species are the etiological agent of brucellosis in humans and animals. Here, we report the whole-genome sequence of Brucella melitensis strain CIIMS-BH 2, belonging to biovar 2. The draft assembly of CIIMS-BH-2 is 3.31 Mb in size, with 57.2% G+C content. PMID- 29519824 TI - Draft Genome Sequences of Six Vibrio diazotrophicus Strains Isolated from Deep Subsurface Sediments of the Baltic Sea. AB - We present here the draft genome sequences of six Vibrio diazotrophicus strains, which were isolated from deep subseafloor sediments of the Baltic Sea. The genomic sequences contained several virulence and antibiotic resistance genes. These genome sequences provide insights into the genetic composition and evolution of the genus Vibrio in marine environments. PMID- 29519825 TI - Complete Genome Sequence of a Nontypeable GII Norovirus Detected in Peru. AB - Norovirus, a leading cause of acute gastroenteritis in humans, is a highly diverse virus. Here, we report the complete genome sequence of a nontypeable genogroup II (GII) norovirus that was detected in a symptomatic Peruvian child in 2008. This virus showed low nucleotide sequence identities (<=82%) against all known genotypes. PMID- 29519826 TI - Whole-Genome Sequence of Phage-Resistant Strain Escherichia coli DH5alpha. AB - The genomes of many strains of Escherichia coli have been sequenced, as this organism is a classic model bacterium. Here, we report the genome sequence of Escherichia coli DH5alpha, which is resistant to a T4 bacteriophage (CCTCC AB 2015375), while its other homologous E. coli strains, such as E. coli BL21, DH10B, and MG1655, are not resistant to phage invasions. Thus, understanding of the genome of the DH5alpha strain, along with comparative analysis of its genome sequence along with other sequences of E. coli strains, may help to reveal the bacteriophage resistance mechanism of E. coli. PMID- 29519827 TI - Draft Genome Sequence of a Multidrug- and Colistin-Resistant mcr-1-Producing Escherichia coli Isolate from a Swine Farm in Mexico. AB - A colistin-resistant mcr-1-carrying Escherichia coli strain, RC2-007, was isolated from a swine farm in Mexico. This extraintestinal and uropathogenic strain of E. coli belongs to serotype O89:H9 and sequence type 744. Assembly and annotation resulted in a 4.9-Mb draft genome that revealed the presence of plasmid-mediated mcr-1-ISApI1 genes as part of a prophage. PMID- 29519828 TI - Complete Genomic Characterization of Korean Porcine Epidemic Diarrhea Virus Strain KUPE21. AB - Nationwide porcine epidemic diarrhea virus (PEDV) outbreaks occurred in late 2013 in the Republic of Korea, resulting in an expansion of genomic data for Korean PEDVs. However, the data available for Korean PEDVs before 2013 are insufficient. Therefore, we sequenced and analyzed the complete genome of a Korean PEDV strain, KUPE21, which was isolated in the early 2000s. PMID- 29519829 TI - Draft Genome Sequence of Marinomonas fungiae Strain AN44T (JCM 18476T), Isolated from the Coral Fungia echinata from the Andaman Sea. AB - Marinomonas fungiae strain AN44T was isolated from mucus of the coral Fungia echinata Optimum growth occurs at 3 to 5% NaCl. The draft genome is 4.2 Mb, with 3,776 protein-coding genes. It harbors genes for the degradation of aromatic compounds, such as quinate, ferulate, p-coumarate, protocatechuate, and p hydroxyphenylacetate. PMID- 29519830 TI - Draft Genome Sequence of Bacillus licheniformis Heshi-B2, Isolated from Fermented Rice Bran in a Japanese Fermented Seafood Dish. AB - Bacillus licheniformis Heshi-B2 was isolated from fermented rice bran in Heshiko, a food produced by aging salted mackerel with fresh rice bran. Here, we report the draft genome sequence of B. licheniformis Heshi-B2, originating from a Heshiko sample from Fukui Prefecture, Japan. PMID- 29519831 TI - Complete Genome Sequence of the Biocontrol Agent Yeast Rhodotorula kratochvilovae Strain LS11. AB - Rhodotorula kratochvilovae strain LS11 is a biocontrol agent (BCA) selected for its antagonistic activity against several plant pathogens both in the field and postharvest. Genome assembly includes 62 contigs for a total of 22.56 Mbp and a G+C content of 66.6%. Genome annotation predicts 7,642 protein-encoding genes. PMID- 29519832 TI - Complete Genome Sequence of a Zika Virus Strain Isolated from the Serum of an Infected Patient in Thailand in 2006. AB - The complete genome of Zika virus (ZIKV) strain CVD_06-274 was isolated from the serum of an infected patient in Thailand in 2006. Phylogenetic analysis showed that this strain belongs to the Asian lineage and also high titers in Vero cells (RCB 10-87). It has potential for development as an inactivated ZIKV vaccine. PMID- 29519833 TI - Genome Sequence of Enterococcus faecium Strain ICIS 96 Demonstrating Intermicrobial Antagonism Associated with Bacteriocin Production. AB - We report here the complete genome sequence of Enterococcus faecium strain ICIS 96, which was isolated from the feces of a horse. Bacteriological characterization of strain ICIS 96 revealed the absence of pathogenicity factors, while its spectrum of antagonistic activity was found to be broad, having activities associated with both Gram-positive and Gram-negative bacteria. Analysis of the E. faecium ICIS 96 genome revealed five genes associated with antimicrobial activity (enterocin [ent] A, ent B, lactobin A/cerein 7b, and ent L50 A/B). No genes that correlate with human pathogenicity were identified. PMID- 29519834 TI - Draft Genome Sequence and Annotation of the Phytopathogenic Ralstonia pickettii (Previously Burkholderia glumae) Strain ICMP-8657. AB - Strain ICMP-8657 was formerly taxonomically classified as Burkholderia glumae and reported to be the producer of an antibacterial pyrazole derivative. Here, we report the draft genome sequence of ICMP-8657, which failed to demonstrate the biosynthetic capacity to produce the stated antibacterial compound, leading to its taxonomic reclassification as Ralstonia pickettii ICMP-8657. PMID- 29519835 TI - Complete Genome Sequence of a Mammarenavirus Harbored by Rodents on Hainan Island, China. AB - Wenzhou virus (WENV) is a rodent-borne mammarenavirus that was recently found to infect humans. In this study, we sequenced and analyzed the complete genome of a genetic variant of WENV, HMU (Hainan Medical University) virus. The virus was harbored by a Rattus norvegicus individual in the residential areas of Hainan Province in southern China. PMID- 29519836 TI - Draft Genome Sequence of Labrenzia sp. Strain EL143, a Coral-Associated Alphaproteobacterium with Versatile Symbiotic Living Capability and Strong Halogen Degradation Potential. AB - We report here the genome sequence of Labrenzia sp. EL143, an alphaproteobacterium isolated from the gorgonian coral Eunicella labiata that possesses various genes involved in halogen and aromatic compound degradation, as well as polyketide synthesis. The strain also maintains multiple genes that confer resistance to toxic compounds such as heavy metals and antibiotics. PMID- 29519837 TI - Genome Sequence of Bacillus halotolerans Strain MS50-18A with Antifungal Activity against Phytopathogens, Isolated from Saline Soil in San Luis Potosi, Mexico. AB - Bacillus halotolerans strain MS50-18A, isolated from saline soil, possesses antifungal activity toward root rot causal phytopathogens and has friendly interactions with the chili pepper plant. The draft genome sequence is 4.06 Mb in length and contains 4,215 genes. Genes related to glycine/betaine uptake and bacilysin biosynthesis are present, supporting its saline stress tolerance and antifungal activity. PMID- 29519838 TI - Draft Genome Sequence of Lactobacillus helveticus Strain Lh 12 Isolated from Natural Whey Starter. AB - Lactobacillus helveticus is a lactic acid bacterium widely used in cheese-making and for the production of bioactive peptides from milk proteins. Here, we describe the draft genome sequence and annotation of L. helveticus strain Lh 12 isolated from natural whey starter used in the production of Grana Padano cheese. PMID- 29519839 TI - Draft Genome Sequence of Methylobacterium sp. Strain V23, Isolated from Accretion Ice of the Antarctic Subglacial Lake Vostok. AB - Here, we report the draft genome sequence of Methylobacterium sp. strain V23, a bacterium isolated from accretion ice of the subglacial Lake Vostok (3,592 meters below the surface). This genome makes possible the study of ancient and psychrophilic genes and proteins from a subglacial environment isolated from the surface for at least 15 million years. PMID- 29519840 TI - Complete Genome Sequence of the Symbiotic Strain Bradyrhizobium icense LMTR 13T, Isolated from Lima Bean (Phaseolus lunatus) in Peru. AB - The complete genome sequence of Bradyrhizobium icense LMTR 13T, a root nodule bacterium isolated from the legume Phaseolus lunatus, is reported here. The genome consists of a circular 8,322,773-bp chromosome which codes for a large and novel symbiotic island as well as genes putatively involved in soil and root colonization. PMID- 29519841 TI - Complete Genome Sequence of a Renamed Isolate, Trichoplusia ni Ascovirus 6b, from the United States. AB - The complete genome of Trichoplusia ni ascovirus 6b (TnAV-6b) was sequenced for the first time. The TnAV-6b isolate, which has its closest phylogenetic relationship with the TnAV-6a isolate, has a circular genome of 185,664 bp, with a G+C content of 46.0% and 178 predicted open reading frames. PMID- 29519842 TI - Complete Genome Sequences of 13 Human Respiratory Syncytial Virus Subgroup A Strains of Genotypes NA1 and ON1 Isolated in the Philippines. AB - Complete genome sequences of 13 human respiratory syncytial virus strains were determined from samples obtained from children hospitalized in the Philippines between 2012 and 2013 because of acute respiratory infection. We identified amino acid polymorphisms between the NA1 and ON1 genotypes in the P, G, F, and L proteins. PMID- 29519843 TI - Draft Genome Sequence of Byssochlamys sp. Isolate BYSS01, a Filamentous Fungus Adapted to the Fuel Environment. AB - Byssochlamys sp. isolate BYSS01 (anamorph, Paecilomyces sp.), which was isolated from jet fuel, is highly adapted to grow in hydrocarbons, having predicted genes involved in degradation of n-alkanes, branched alkanes, and aromatic compounds. The draft genome size is estimated at 29 Mb, containing 8,509 proteins. PMID- 29519844 TI - Draft Genome Sequences of Four Parasaccharibacter apium Strains Isolated from Honey Bees. AB - Parasaccharibacter apium displays multiple ecological strategies in its honey bee host. We sequenced the genomes of four strains found in larvae and the adult gut in order to better understand its ecology and relationship to other Acetobacteraceae The P. apium genome consists of 2,009,892 bp and 1,830 protein coding genes. PMID- 29519845 TI - Correction for Pinto et al., "Draft Genome Sequences of Novel Pseudomonas, Flavobacterium, and Sediminibacterium Strains from a Freshwater Ecosystem". PMID- 29519846 TI - Complete Genome Sequence of Listeria monocytogenes Strain MR310, Isolated from a Pastured-Flock Poultry Farm System. AB - Investigation of Listeria monocytogenes transmission from environmental sources associated with pasture-raised chickens to poultry products is needed to determine ways to prevent potential foodborne illness. Here, we report the complete genome sequence of Listeria monocytogenes MR310, one of the isolates from a pastured-flock poultry management system. PMID- 29519847 TI - Virulence-Related Genes Identified from the Genome Sequence of the Non-O1/Non O139 Vibrio cholerae Strain VcN1, Isolated from Dhaka, Bangladesh. AB - We report here the first draft genome sequence of the non-O1/non-O139 Vibrio cholerae strain VcN1, isolated from Dhaka, Bangladesh. The data submitted to GenBank for this strain will contribute to advancing our understanding of this environmentally disseminated bacterium, including its virulence and its evolution as an important pathogen. PMID- 29519848 TI - Complete Genome Sequences of Three Staphylococcus pseudintermedius Strains Isolated from Botswana. AB - We report here the first whole-genome sequences for 3 strains of Staphylococcus pseudintermedius (112N, 113N, and 114N) isolated in Africa. Samples of this opportunistic pathogen were collected from nasal swabs obtained from healthy carrier dogs in Botswana. The sequence information will facilitate spatial phylogenetic comparisons of staphylococcal species and other bacteria at the genome level. PMID- 29519849 TI - Trends in Hospitalizations and Survival of Acute Decompensated Heart Failure in Four US Communities (2005-2014): ARIC Study Community Surveillance. AB - BACKGROUND: Community trends of acute decompensated heart failure (ADHF) in diverse populations may differ by race and sex. METHODS: The ARIC study (Atherosclerosis Risk in Communities) sampled heart failure-related hospitalizations (>=55 years of age) in 4 US communities from 2005 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification codes. ADHF hospitalizations were validated by standardized physician review and computer algorithm, yielding 40 173 events after accounting for sampling design (unweighted n=8746). RESULTS: Of the ADHF hospitalizations, 50% had reduced ejection fraction, and 39% had preserved EF (HFpEF). HF with reduced ejection fraction was more common in black men and white men, whereas HFpEF was most common in white women. Average age-adjusted rates of ADHF were highest in blacks (38.1 per 1000 black men, 30.5 per 1000 black women), with rates differing by HF type and sex. ADHF rates increased over the 10 years (average annual percentage change: black women +4.3%, black men +3.7%, white women +1.9%, white men +2.6%), mostly reflecting more acute HFpEF. Age-adjusted 28-day and 1-year case fatality proportions were ~10% and 30%, respectively, similar across race-sex groups and HF types. Only blacks showed decreased 1-year mortality over time (average annual percentage change: black women -5.4%, black men -4.6%), with rates differing by HF type (average annual percentage change: black women HFpEF -7.1%, black men HF with reduced ejection fraction -4.7%). CONCLUSIONS: Between 2005 and 2014, trends in ADHF hospitalizations increased in 4 US communities, primarily driven by acute HFpEF. Survival at 1 year was poor regardless of EF but improved over time for black women and black men. PMID- 29519852 TI - Human V4 Activity Patterns Predict Behavioral Performance in Imagery of Object Color. AB - Color is special among basic visual features in that it can form a defining part of objects that are engrained in our memory. Whereas most neuroimaging research on human color vision has focused on responses related to external stimulation, the present study investigated how sensory-driven color vision is linked to subjective color perception induced by object imagery. We recorded fMRI activity in male and female volunteers during viewing of abstract color stimuli that were red, green, or yellow in half of the runs. In the other half we asked them to produce mental images of colored, meaningful objects (such as tomato, grapes, banana) corresponding to the same three color categories. Although physically presented color could be decoded from all retinotopically mapped visual areas, only hV4 allowed predicting colors of imagined objects when classifiers were trained on responses to physical colors. Importantly, only neural signal in hV4 was predictive of behavioral performance in the color judgment task on a trial-by trial basis. The commonality between neural representations of sensory-driven and imagined object color and the behavioral link to neural representations in hV4 identifies area hV4 as a perceptual hub linking externally triggered color vision with color in self-generated object imagery.SIGNIFICANCE STATEMENT Humans experience color not only when visually exploring the outside world, but also in the absence of visual input, for example when remembering, dreaming, and during imagery. It is not known where neural codes for sensory-driven and internally generated hue converge. In the current study we evoked matching subjective color percepts, one driven by physically presented color stimuli, the other by internally generated color imagery. This allowed us to identify area hV4 as the only site where neural codes of corresponding subjective color perception converged regardless of its origin. Color codes in hV4 also predicted behavioral performance in an imagery task, suggesting it forms a perceptual hub for color perception. PMID- 29519850 TI - Excreted Steroids in Vertebrate Social Communication. AB - Steroids play vital roles in animal physiology across species, and the production of specific steroids is associated with particular internal biological functions. The internal functions of steroids are, in most cases, quite clear. However, an important feature of many steroids (their chemical stability) allows these molecules to play secondary, external roles as chemical messengers after their excretion via urine, feces, or other shed substances. The presence of steroids in animal excretions has long been appreciated, but their capacity to serve as chemosignals has not received as much attention. In theory, the blend of steroids excreted by an animal contains a readout of its own biological state. Initial mechanistic evidence for external steroid chemosensation arose from studies of many species of fish. In sea lampreys and ray-finned fishes, bile salts were identified as potent olfactory cues and later found to serve as pheromones. Recently, we and others have discovered that neurons in amphibian and mammalian olfactory systems are also highly sensitive to excreted glucocorticoids, sex steroids, and bile acids, and some of these molecules have been confirmed as mammalian pheromones. Steroid chemosensation in olfactory systems, unlike steroid detection in most tissues, is performed by plasma membrane receptors, but the details remain largely unclear. In this review, we present a broad view of steroid detection by vertebrate olfactory systems, focusing on recent research in fishes, amphibians, and mammals. We review confirmed and hypothesized mechanisms of steroid chemosensation in each group and discuss potential impacts on vertebrate social communication. PMID- 29519851 TI - Domain-General and Domain-Specific Patterns of Activity Supporting Metacognition in Human Prefrontal Cortex. AB - Metacognition is the capacity to evaluate the success of one's own cognitive processes in various domains; for example, memory and perception. It remains controversial whether metacognition relies on a domain-general resource that is applied to different tasks or if self-evaluative processes are domain specific. Here, we investigated this issue directly by examining the neural substrates engaged when metacognitive judgments were made by human participants of both sexes during perceptual and memory tasks matched for stimulus and performance characteristics. By comparing patterns of fMRI activity while subjects evaluated their performance, we revealed both domain-specific and domain-general metacognitive representations. Multivoxel activity patterns in anterior prefrontal cortex predicted levels of confidence in a domain-specific fashion, whereas domain-general signals predicting confidence and accuracy were found in a widespread network in the frontal and posterior midline. The demonstration of domain-specific metacognitive representations suggests the presence of a content rich mechanism available to introspection and cognitive control.SIGNIFICANCE STATEMENT We used human neuroimaging to investigate processes supporting memory and perceptual metacognition. It remains controversial whether metacognition relies on a global resource that is applied to different tasks or if self evaluative processes are specific to particular tasks. Using multivariate decoding methods, we provide evidence that perceptual- and memory-specific metacognitive representations coexist with generic confidence signals. Our findings reconcile previously conflicting results on the domain specificity/generality of metacognition and lay the groundwork for a mechanistic understanding of metacognitive judgments. PMID- 29519853 TI - Cooperative Regulation of Intestinal UDP-Glucuronosyltransferases 1A8, -1A9, and 1A10 by CDX2 and HNF4alpha Is Mediated by a Novel Composite Regulatory Element. AB - The gastrointestinal tract expresses several UDP-glucuronosyltransferases (UGTs) that act as a first line of defense against dietary toxins and contribute to the metabolism of orally administered drugs. The expression of UGT1A8, UGT1A9, and UGT1A10 in gastrointestinal tissues is known to be at least partly directed by the caudal homeodomain transcription factor, CDX2. We sought to further define the factors involved in regulation of the UGT1A8-1A10 genes and identified a novel composite element located within the proximal promoters of these three genes that binds to both CDX2 and the hepatocyte nuclear factor (HNF) 4alpha, and mediates synergistic activation by these factors. We also show that HNF4alpha and CDX2 are required for the expression of these UGT genes in colon cancer cell lines, and show robust correlation of UGT expression with CDX2 and HNF4alpha levels in normal human colon. Finally, we show that these factors are involved in the differential expression pattern of UGT1A8 and UGT1A10, which are intestinal specific, and that of UGT1A9, which is expressed in both intestine and liver. These studies lead to a model for the developmental patterning of UGT1A8, UGT1A9, and UGT1A10 in hepatic and/or extrahepatic tissues involving discrete regulatory modules that may function (independently and cooperatively) in a context dependent manner. PMID- 29519854 TI - Erysipelothrix rhusiopathiae serotype 15 associated with recurring pig erysipelas outbreaks. PMID- 29519855 TI - Evaluation of radiography as a screening method for detection and characterisation of congenital vertebral malformations in dogs. AB - Congenital vertebral malformations (CVM) are common in brachycephalic 'screw tailed' dogs; they can be associated with neurological deficits and a genetic predisposition has been suggested. The purpose of this study was to evaluate radiography as a screening method for congenital thoracic vertebral malformations in brachycephalic 'screw-tailed' dogs by comparing it with CT. Forty-nine dogs that had both radiographic and CT evaluations of the thoracic vertebral column were included. Three observers retrospectively reviewed the images independently to detect CVMs. When identified, they were classified according to a previously published radiographic classification scheme. A CT consensus was then reached. All observers identified significantly more affected vertebrae when evaluating orthogonal radiographic views compared with lateral views alone; and more affected vertebrae with the CT consensus compared with orthogonal radiographic views. Given the high number of CVMs per dog, the number of dogs classified as being CVM free was not significantly different between CT and radiography. Significantly more midline closure defects were also identified with CT compared with radiography. Malformations classified as symmetrical or ventral hypoplasias on radiography were frequently classified as ventral and medial aplasias on CT images. Our results support that CT is better than radiography for the classification of CVMs and this will be important when further evidence of which are the most clinically relevant CVMs is identified. These findings are of particular importance for designing screening schemes of CVMs that could help selective breeding programmes based on phenotype and future studies. PMID- 29519856 TI - Substantial numerical decline in South Australian rabbit populations following the detection of rabbit haemorrhagic disease virus 2. AB - Lagovirus europaeus GI.2, also commonly known as rabbit haemorrhagic disease virus 2, was first detected at two long-term monitoring sites for European rabbits, Oryctolagus cuniculus, in South Australia, in mid-2016. Numbers of rabbits in the following 12-18 months were reduced to approximately 20 per cent of average numbers in the preceding 10 years. The impact recorded at the two South Australian sites, if widespread in Australia and persistent for several years, is likely to be of enormous economic and environmental benefit. PMID- 29519857 TI - Clinical presentation and pathology of suspected vector transmitted African horse sickness in South African domestic dogs from 2006 to 2017. AB - African horse sickness (AHS) is a fatal vector transmitted viral disease of horses caused by the African horse sickness virus (AHSV). This disease is characterised by circulatory and respiratory failure, resulting from vascular endothelial injury affecting many organs. The susceptibility of dogs to AHS has been demonstrated in the past following experimental infection through consumption of infected horse meat. Thirty three clinical cases of AHS in dogs (cAHS) have been documented, without a history of ingesting infected horse meat, over a period of 12 years. The clinical cases included in this study presented with a history of acute respiratory distress syndrome or sudden death. The macroscopic and histological changes were mostly characterised by acute interstitial pneumonia, serofibrinous pleuritis and mediastinal oedema. Confirmation of cAHS was obtained by AHS specific NS4 antibody immunohistochemistry and/or AHSV specific duplex real time RT-quantitative PCR. Here, we document the clinical and postmortem diagnostic features of confirmed cAHS cases with no history of ingestion of AHS infected horse meat. PMID- 29519858 TI - Thrombectomy for late occlusion of high flow extracranial-intracranial saphenous vein bypass graft after 27 years of patency. AB - High flow extracranial-intracranial (EC-IC) bypass with a saphenous vein graft (SVG) has been used for more than 40 years in patients with giant aneurysms of the posterior circulation refractory to medical management, and has demonstrated high long term patency rates. We report the case of a patient treated with external carotid artery (ECA)-posterior cerebral artery SVG bypass in 1989 who presented 27 years later with paresthesias and confusion, and was found to have partial occlusion of her SVG bypass graft and a basilar occlusion. She was treated with mechanical thrombectomy of the basilar occlusion via the partially thrombosed graft, the first report of such a procedure through a high flow posterior circulation EC-IC SVG, resulting in improvement of the patient's neurologic examination. At 27 years, this is the longest reported delay in thrombosis of a high flow SVG bypass graft, highlighting the long term patency of these grafts and the feasibility of thrombectomy through occluded bypass grafts. PMID- 29519859 TI - Treating people with arthritis with traditional Chinese medicine (TCM): an examination of the perception of TCM practitioners. AB - INTRODUCTION: Emerging evidence has shown that traditional Chinese medicine (TCM) has a positive effect on arthritis. This research provides the first critical, systematic examination of TCM practitioners' perceptions of TCM use for people with arthritis. METHODS: An online survey was distributed to all TCM professionals including acupuncturists and Chinese herbal medicine practitioners registered with the Practitioner Research and Collaborate Initiative (PRACI) practitioner database. The survey questions focus on practitioner characteristics, practice characteristics and clinical management approaches regarding arthritis care. RESULTS: The survey attracted a response rate of 53% (n=52). The average age of the respondents was 49.9 years, more than half were female, and the majority held a bachelor degree or higher qualification. More than two thirds of TCM practitioners in our study worked with other health professionals, while they had a high level of referral relationships with a wide range of conventional, allied health and complementary and alternative medicine (CAM) providers. Most of the TCM practitioners reported that their patients with arthritis used other treatments alongside TCM and a large number of the TCM practitioners who participated believed that TCM was effective for treating arthritis. CONCLUSIONS: The TCM profession represents a substantial component of the healthcare field in Australia, and treating patients with arthritis appears to be an important area of TCM practice, among others. Further detailed research is needed to help ensure effective, safe patient care for those with arthritis who may be utilising TCM alongside a broader range of conventional medicine, allied health, and other CAM treatments. PMID- 29519860 TI - Effects of electroacupuncture combined with stem cell transplantation on anal sphincter injury-induced faecal incontinence in a rat model. AB - BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) and acupuncture are known to mitigate tissue damage. This study aimed to investigate the therapeutic effects of combined electroacupuncture (EA) stimulation and BMSC injection in a rat model of anal sphincter injury-induced faecal incontinence (FI). METHODS: 60 Sprague-Dawley rats were randomly divided into five groups: sham-operated control, FI, FI+EA, FI+BMSC, and FI+BMSC+EA. The anorectal tissues were collected on days 1, 3, 7 and 14. Repair of the injured anal sphincter was compared using haematoxylin and eosin (HE) and immunocytochemiscal analyses with sarcomeric alpha actinin. The expression of stromal cell derived factor-1 (SDF-1) and monocyte chemoattractant protein-3 (MCP-3) was detected by quantitative reverse transcription PCR to evaluate the effects of EA on the homing of BMSCs. RESULTS: The therapeutic effect of combined EA+BMSCs on damaged tissue was the strongest among all the groups as indicated by HE and immunohistochemical staining. The expression of SDF-1 and MCP-3 was significantly increased by combined EA and BMSC treatment when compared with the other groups (P=0.01 to P<0.05), suggesting promotive effects of EA on the homing of BMSCs. CONCLUSION: The combination of EA and BMSC transplantation effectively repaired the impaired anal sphincters. The underlying mechanism might be associated with apparent promotive effects of EA on the homing of BMSCs. Our study provides a theoretical basis for the development of a non-surgical treatment method for FI secondary to muscle impairment. PMID- 29519861 TI - Recurrent thrombosis in patients with antiphospholipid antibodies treated with vitamin K antagonists or rivaroxaban. PMID- 29519862 TI - and predictors of infection among patients prior to treatment of chronic lymphocytic leukemia: a Danish nationwide cohort study. PMID- 29519863 TI - Improved erythroid differentiation of multiple human pluripotent stem cell lines in microcarrier culture by modulation of Wnt/beta-Catenin signaling. PMID- 29519864 TI - Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. PMID- 29519865 TI - Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia. PMID- 29519866 TI - Increased rituximab exposure does not improve response and outcome of patients with chronic lymphocytic leukemia after fludarabine, cyclophosphamide, rituximab. A French Innovative Leukemia Organization (FILO) study. PMID- 29519867 TI - Prognostic impact of the absence of biallelic deletion at the TRG locus for pediatric patients with T-cell acute lymphoblastic leukemia treated on the Medical Research Council UK Acute Lymphoblastic Leukemia 2003 trial. PMID- 29519868 TI - RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice. AB - Sickle cell disease patients are at increased risk of developing a chronic kidney disease. Endothelial dysfunction and inflammation associated with hemolysis lead to vasculopathy and contribute to the development of renal disease. Here we used a Townes sickle cell disease mouse model to examine renal endothelial injury. Renal disease in Townes mice was associated with glomerular hypertrophy, capillary dilation and congestion, and significant endothelial injury. We also detected substantial renal macrophage infiltration, and accumulation of macrophage stimulating protein 1 in glomerular capillary. Treatment of human cultured macrophages with hemin or red blood cell lysates significantly increased expression of macrophage membrane-associated protease that might cleave and activate circulating macrophage stimulating protein 1 precursor. Macrophage stimulating protein 1 binds to and activates RON kinase, a cell surface receptor tyrosine kinase. In cultured human renal glomerular endothelial cells, macrophage stimulating protein 1 induced RON downstream signaling, resulting in increased phosphorylation of ERK and AKT kinases, expression of Von Willebrand factor, increased cell motility, and re-organization of F-actin. Specificity of macrophage stimulating protein 1 function was confirmed by treatment with RON kinase inhibitor BMS-777607 that significantly reduced downstream signaling. Moreover, treatment of sickle cell mice with BMS-777607 significantly reduced glomerular hypertrophy, capillary dilation and congestion, and endothelial injury. Taken together, our findings demonstrated that RON kinase is involved in the induction of renal endothelial injury in sickle cell mice. Inhibition of RON kinase activation may provide a novel approach for prevention of the development of renal disease in sickle cell disease. PMID- 29519869 TI - Dexamethasone in hyperleukocytic acute myeloid leukemia. AB - Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50*109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; P<0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; P=0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in NPM1-mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with NPM1 mutation. PMID- 29519870 TI - Leukemia reconstitution in vivo is driven by cells in early cell cycle and low metabolic state. AB - In contrast to well-established hierarchical concepts of tumor stem cells, leukemia-initiating cells in B-cell precursor acute lymphoblastic leukemia have not yet been phenotypically identified. Different subpopulations, as defined by surface markers, have shown equal abilities to reconstitute leukemia upon transplantation into immunodeficient mice. Using a non-obese diabetes/severe combined immunodeficiency human acute lymphoblastic leukemia mouse model and cell cycle analysis annotating cells to distinct cycle phases, we functionally characterized leukemia-initiating cells and found that cells in all stages of the cell cycle are able to reconstitute leukemia in vivo, with early cycling cells (G1blow population) exhibiting the highest leukemia-initiating potential. Interestingly, cells of the G2/M compartment, i.e. dividing cells, were less effective in leukemia reconstitution. Moreover, G1blow cells were more resistant to spontaneous or drug-induced cell death in vitro, were enriched for stem cell signatures and were less metabolically active, as determined by lower levels of reactive oxygen species, compared to G2/M stage cells. Our data provide new information on the biological properties of leukemia-initiating cells in B-cell precursor acute lymphoblastic leukemia and underline the concept of a stochastic model of leukemogenesis. PMID- 29519871 TI - The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia. AB - Transcription factor IKZF1 (IKAROS) acts as a critical regulator of lymphoid differentiation and is frequently deleted or mutated in B-cell precursor acute lymphoblastic leukemia. IKZF1 gene defects are associated with inferior treatment outcome in both childhood and adult B-cell precursor acute lymphoblastic leukemia and occur in more than 70% of BCR-ABL1-positive and BCR-ABL1-like cases of acute lymphoblastic leukemia. Over the past few years, much has been learned about the tumor suppressive function of IKZF1 during leukemia development and the molecular pathways that relate to its impact on treatment outcome. In this review, we provide a concise overview on the role of IKZF1 during normal lymphopoiesis and the pathways that contribute to leukemia pathogenesis as a consequence of altered IKZF1 function. Furthermore, we discuss different mechanisms by which IKZF1 alterations impose therapy resistance on leukemic cells, including enhanced cell adhesion and modulation of glucocorticoid response. PMID- 29519873 TI - Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection? AB - Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias. Underpinning these actions are complex but increasingly understood cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the vasculature. In clinical trials, PDE5 inhibitors improve symptoms and ventricular function in systolic HF, and accumulating epidemiological data indicate a reduction in cardiovascular events and mortality in PDE5 inhibitor users at high cardiovascular risk. Here, we focus on the translation of underpinning basic science to clinical studies and report that PDE5 inhibitors act through a number of cardioprotective mechanisms, including a direct myocardial action independent of the vasculature. We conclude that future clinical trials should be designed with these mechanisms in mind to identify patient subsets that derive greatest treatment benefit from these novel cardioprotective agents. PMID- 29519872 TI - Adipocyte Long-Noncoding RNA Transcriptome Analysis of Obese Mice Identified Lnc Leptin, Which Regulates Leptin. AB - Obesity induces profound transcriptome changes in adipocytes, and recent evidence suggests that long-noncoding RNAs (lncRNAs) play key roles in this process. We performed a comprehensive transcriptome study by RNA sequencing in adipocytes isolated from interscapular brown, inguinal, and epididymal white adipose tissue in diet-induced obese mice. The analysis revealed a set of obesity-dysregulated lncRNAs, many of which exhibit dynamic changes in the fed versus fasted state, potentially serving as novel molecular markers of adipose energy status. Among the most prominent lncRNAs is Lnc-leptin, which is transcribed from an enhancer region upstream of leptin (Lep). Expression of Lnc-leptin is sensitive to insulin and closely correlates to Lep expression across diverse pathophysiological conditions. Functionally, induction of Lnc-leptin is essential for adipogenesis, and its presence is required for the maintenance of Lep expression in vitro and in vivo. Direct interaction was detected between DNA loci of Lnc-leptin and Lep in mature adipocytes, which diminished upon Lnc-leptin knockdown. Our study establishes Lnc-leptin as a new regulator of Lep. PMID- 29519875 TI - Metastability and avalanche dynamics in strongly correlated gases with long-range interactions. AB - We experimentally study the stability of a bosonic Mott insulator against the formation of a density wave induced by long-range interactions and characterize the intrinsic dynamics between these two states. The Mott insulator is created in a quantum degenerate gas of 87-Rubidium atoms, trapped in a 3D optical lattice. The gas is located inside and globally coupled to an optical cavity. This causes interactions of global range, mediated by photons dispersively scattered between a transverse lattice and the cavity. The scattering comes with an atomic density modulation, which is measured by the photon flux leaking from the cavity. We initialize the system in a Mott-insulating state and then rapidly increase the global coupling strength. We observe that the system falls into either of two distinct final states. One is characterized by a low photon flux, signaling a Mott insulator, and the other is characterized by a high photon flux, which we associate with a density wave. Ramping the global coupling slowly, we observe a hysteresis loop between the two states-a further signature of metastability. A comparison with a theoretical model confirms that the metastability originates in the competition between short- and global-range interactions. From the increasing photon flux monitored during the switching process, we find that several thousand atoms tunnel to a neighboring site on the timescale of the single-particle dynamics. We argue that a density modulation, initially forming in the compressible surface of the trapped gas, triggers an avalanche tunneling process in the Mott-insulating region. PMID- 29519874 TI - How to prove without randomised controlled trials that automated external defibrillators used by the public save lives? PMID- 29519877 TI - Type 3 neovascularisation: long-term analysis of visual acuity and optical coherence tomography anatomical outcomes. AB - BACKGROUND: To investigate the long-term visual and optical coherence tomography (OCT) anatomical outcomes of type 3 neovascularisation (NV) and to identify any baseline predictors of poor outcomes. METHODS: In this retrospective study, patients diagnosed with treatment naive type 3 NV were identified and categorised into two groups: good or poor vision based on final vision at 1 year. Baseline demographic features and visual acuity (VA) and baseline and 1-year spectral domain OCT (SD-OCT) anatomical findings were studied and correlated with good versus poor visual outcomes. RESULTS: Ten of 25 eyes were classified as having a poor visual outcome (20/50 or worse) at 1 year. Increased age (P=0.049), male gender (p=0.041) and worse baseline VA (rhos=0.61, p=0.001) were associated with poor vision at 1 year. Greater foveal atrophy was noted at 1 year in the poor visual outcome group (p=0.030). Subretinal hyper-reflective material and choroidal thinning were additional features noted more commonly in this group. CONCLUSION: Increased age, male gender and lower baseline vision may be important baseline predictors of poor visual outcomes in eyes with type 3 NV. The development of central outer retinal atrophy and fibrosis, as identified with SD OCT, may limit long-term vision in eyes with type 3 NV. PMID- 29519878 TI - Posterior scleral reinforcement using genipin-cross-linked sclera for macular hole retinal detachment in highly myopic eyes. AB - BACKGROUND/AIMS: To investigate the surgical outcomes of posterior scleral reinforcement (PSR) using genipin-cross-linked sclera to treat macular hole retinal detachment (MHRD) in highly myopic eyes. METHODS: Nineteen patients with high myopia (19 eyes) with MHRD were treated sequentially with genipin-cross linked PSR and were followed at least for 1 year after the surgery. The best corrected visual acuity (BCVA), axial length (AL), optical coherence tomography (OCT) outcomes and the complications were evaluated. RESULTS: Macular hole was closed in 73.7% of the eyes, foveal reattachment rate was 100%. The mean logMAR BCVA improved from 1.27+/-0.55 preoperatively to 0.88+/-0.55 postoperatively. The preoperative AL (29.88+/-1.97 mm) was decreased (27.73+/-1.84 mm) after the operation (p<0.001). CONCLUSIONS: For at least a 1-year period of follow-up, PSR with genipin-cross-linked sclera should be considered as a preferred surgical approach to treat MHRD in highly myopic eyes, especially when foveal retinoschisis is also documented. PMID- 29519876 TI - Conserved in situ arrangement of complex I and III2 in mitochondrial respiratory chain supercomplexes of mammals, yeast, and plants. AB - We used electron cryo-tomography and subtomogram averaging to investigate the structure of complex I and its supramolecular assemblies in the inner mitochondrial membrane of mammals, fungi, and plants. Tomographic volumes containing complex I were averaged at ~4 nm resolution. Principal component analysis indicated that ~60% of complex I formed a supercomplex with dimeric complex III, while ~40% were not associated with other respiratory chain complexes. The mutual arrangement of complex I and III2 was essentially conserved in all supercomplexes investigated. In addition, up to two copies of monomeric complex IV were associated with the complex I1III2 assembly in bovine heart and the yeast Yarrowia lipolytica, but their positions varied. No complex IV was detected in the respiratory supercomplex of the plant Asparagus officinalis Instead, an ~4.5-nm globular protein density was observed on the matrix side of the complex I membrane arm, which we assign to gamma-carbonic anhydrase. Our results demonstrate that respiratory chain supercomplexes in situ have a conserved core of complex I and III2, but otherwise their stoichiometry and structure varies. The conserved features of supercomplex assemblies indicate an important role in respiratory electron transfer. PMID- 29519880 TI - Meibomian gland dysfunction and keratopathy are associated with dry eye disease in aniridia. AB - AIMS: To investigate the aetiology and characteristics of dry eye disease (DED) in a Nordic cohort of patients with congenital aniridia. METHODS: Thirty-four Norwegian and one Danish subject with congenital aniridia and 21 healthy controls were examined. All subjects underwent an extensive dry eye examination, including evaluation of meibomian glands (MGs) by meibography, measurement of tear production and tear film osmolarity and grading of vital staining of the ocular surface. Moreover, slit-lamp biomicroscopy was undertaken, including grading of aniridia-associated keratopathy (AAK). RESULTS: Mean tear film osmolarity was significantly higher (314+/-11 mOsmol/L) in patients with aniridia compared with the healthy control group (303+/-11 mOsmol/L, p=0.002). Vital staining score was higher in the aniridia group (4.3+/-3.0) compared with healthy controls (2.4+/ 1.6, p=0.02). The degree of staining correlated positively with the stage of AAK (r=0.44, p=0.008) and negatively with corneal sensitivity (r=-0.45, p=0.012). Number of expressible MGs was lower in aniridia subjects (2.9+/-1.6) than in controls (4.0+/-1.3, p=0.007). MG loss, staged from 0 to 3, was higher in the aniridia group than in the control group, both in upper eyelid (0.86+/-0.89 vs 0.10+/-0.31, p=0.001) and lower eyelid (0.94+/-0.73 vs 0.30+/-0.47, p=0.003). Computerised analyses showed thinning (p=0.004) and lower density (p<0.001) of the MGs compared with the healthy population. CONCLUSIONS: Patients with congenital aniridia demonstrate increased tear film osmolarity, ocular surface staining, loss of MGs and lower MG expressibility. We conclude that meibomian gland dysfunction and keratopathy are related to development of DED in aniridia. PMID- 29519882 TI - Social tenants' health: evaluating the effectiveness of landlord interventions. AB - BACKGROUND: The National Health Service (NHS) scores well internationally on access to healthcare. But access has been measured on methods likely to undersample the more disadvantaged. Social landlords have access to more disadvantaged groups and may be able to improve health outcomes for their tenants and reduce their NHS usage by simple interventions. METHODS: This is a randomised controlled trial of 547 London social housing 'general needs' tenants over 50 years of age. Participants were given a health assessment, then split into a control group or one of two treated groups. Following early assessment 25 participants had to be withdrawn to receive intensive treatment because of currently untreated major health problems. Participants were followed up over 18 months and changes in health outcomes and NHS usage measured. RESULTS: Compared with the control the most intensively treated group showed non-significant improvements on health outcomes but a significant reduction in NHS resource use, on conventional costings worth some L760 per person. All 25 participants transferred to the most intensively treated group after their early health assessments showed improvement on all health outcomes at final assessment, but these improvements were not statistically significant. CONCLUSIONS: Drawing a sample from disadvantaged but not the most seriously disadvantaged groups in London revealed 4.5% of the population to have very serious untreated health problems. The reason for lack of treatment was mainly non-registration with a general practitioner or psychiatric issues. Simple interventions to a targeted group were found to produce significant reductions in NHS usage and other, although non-significant, health benefits. TRIAL REGISTRATION NUMBER: ID ISRCTN96259142. PMID- 29519881 TI - Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. AB - OBJECTIVE: To investigate whether oral fluoroquinolone use is associated with an increased risk of aortic aneurysm or dissection. DESIGN: Nationwide historical cohort study using linked register data on patient characteristics, filled prescriptions, and cases of aortic aneurysm or dissection. SETTING: Sweden, July 2006 to December 2013. PARTICIPANTS: 360 088 treatment episodes of fluoroquinolone use (78%ciprofloxacin) and propensity score matched comparator episodes of amoxicillin use (n=360 088). MAIN OUTCOME MEASURES: Cox regression was used to estimate hazard ratios for a first diagnosis of aortic aneurysm or dissection, defined as admission to hospital or emergency department for, or death due to, aortic aneurysm or dissection, within 60 days from start of treatment. RESULTS: Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1000 person years among fluoroquinolone users and 0.7 cases per 1000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection. CONCLUSIONS: In a propensity score matched cohort, fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. This association appeared to be largely driven by aortic aneurysm. PMID- 29519879 TI - Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR ROP study): a prospective, multicentre study in 69 neonatal intensive care units. AB - BACKGROUND: To evaluate the prevalence, risk factors and treatment of retinopathy of prematurity (ROP) in Turkey and to establish screening criteria for this condition. METHODS: A prospective cohort study (TR-ROP) was performed between 1 April 2016 and 30 April 2017 in 69 neonatal intensive care units (NICUs). Infants with a birth weight (BW)<=1500 g or gestational age (GA)<=32 weeks and those with a BW>1500 g or GA>32 weeks with an unstable clinical course were included in the study. Predictors for the development of ROP were determined by logistic regression analyses. RESULTS: The TR-ROP study included 6115 infants: 4964 (81%) with a GA<=32 weeks and 1151 (19%) with a GA>32 weeks. Overall, 27% had any stage of ROP and 6.7% had severe ROP. A lower BW, smaller GA, total days on oxygen, late-onset sepsis, frequency of red blood cell transfusions and relative weight gain were identified as independent risk factors for severe ROP in infants with a BW<=1500 g. Of all infants, 414 needed treatment and 395 (95.4%) of the treated infants had a BW<=1500 g. Sixty-six (16%) of the treated infants did not fulfil the Early Treatment for Retinopathy of Prematurity requirements for treatment. CONCLUSIONS: Screening of infants with a GA<=34 weeks or a BW<1700 g appears to be appropriate in Turkey. Monitoring standards of neonatal care and conducting quality improvement projects across the country are recommended to improve neonatal outcomes in Turkish NICUs. TRIAL REGISTRATION NUMBER: NCT02814929, Results. PMID- 29519883 TI - Intimate partner violence against young women: prevalence and associated factors in Europe. AB - BACKGROUND: The magnitude of intimate partner violence (IPV) in young women is a source of increasing concern. The prevalence of IPV has not been analysed in Europe as a whole. The objective was to assess the prevalence and main characteristics of experiencing physical and/or sexual and psychological-only IPV among young women in the European Union and to identify individual and contextual associated risk factors. METHODS: We analysed a cross-sectional subsample of 5976 ever-partnered women aged 18-29 years from the European Union Agency for Fundamental Rights Violence Against Women Survey, 2012. The main outcomes were current physical and/or sexual IPV and lifetime psychological-only IPV. Risk factors were assessed by the prevalence ratio (PR) from multilevel Poisson regression models. RESULTS: Current prevalence of physical and/or sexual IPV was 6.1%, lifetime prevalence of psychological-only IPV was 28.7%. Having suffered physical and/or sexual abuse by an adult before age 15 was the strongest risk factor for IPV (PR: 2.9 for physical and/or sexual IPV, PR: 1.5 for psychological only IPV). Other individual risk factors were: perceived major difficulties in living within their household income (PR: 2.6), having children (PR: 1.8) and age 18-24 years (PR: 1.5) for physical/sexual IPV and immigration background for psychological-only IPV (PR: 1.4). Living in countries with a higher prevalence of binge drinking or early school dropout was positively associated with IPV. CONCLUSIONS: Findings show that the fight against violence in young women should consider individual characteristics, childhood experiences of abuse and also structural interventions including reduction of alcohol consumption and improvement in the education-related indicators. PMID- 29519884 TI - Budget cuts force local councils into "narrow" focus on social care, warns watchdog. PMID- 29519885 TI - Accelerating the Pace of Cancer Prevention- Right Now. AB - As a nation, we underinvest in prevention and fail to implement strategies that ensure all population groups equitably share in the return on investment in prevention research and the benefits of prevention effectiveness. There is significant evidence indicating that by applying knowledge that we already have to reduce tobacco, inactivity, and obesity (known modifiable causes of cancer), we can prevent more than 50% of cancers. Vaccination against HPV, aspirin and selective estrogen receptor modulators, and screening programs further reduce risk. Evidence-based prevention strategies are inconsistently implemented across the United States. Substantial variation across States indicates that there is much room for improvement in implementation of prevention. Implementation science applies innovative approaches to identifying, understanding, and developing strategies for overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions, tools, policies, and guidelines that will prevent cancer through application of evidence-based interventions. When we get implementation of prevention programs right and at scale, we achieve substantial population benefits. Although many efforts are underway to maximize our knowledge about the causes and treatments of cancer, we can achieve reductions in the cancer burden right now by doing what we already know. The time to start is now. Cancer Prev Res; 11(4); 171-84. (c)2018 AACR. PMID- 29519886 TI - ACL rupture is a single leg injury but a double leg problem: too much focus on 'symmetry' alone and that's not enough! AB - The authors present their thoughts on the focus on targeting asymmetry in rehabilitation after ACL reconstruction, which they think may not be rich enough to identify deficits. PMID- 29519887 TI - How should clinicians integrate the findings of The Lancet's 2018 placebo controlled subacromial decompression trial into clinical practice? PMID- 29519888 TI - Nesprins and opposing microtubule motors generate a point force that drives directional nuclear motion in migrating neurons. AB - Nuclear migration of newly born neurons is essential for cortex formation in the brain. The nucleus is translocated by actin and microtubules, yet the actual force generated by the interplay of these cytoskeletons remains elusive. High resolution time-lapse observation of migrating murine cerebellar granule cells revealed that the nucleus actively rotates along the direction of its translocation, independently of centrosome motion. Pharmacological and molecular perturbation indicated that spin torque is primarily generated by microtubule motors through the LINC complex in the absence of actomyosin contractility. In contrast to the prevailing view that microtubules are uniformly oriented around the nucleus, we observed that the perinuclear microtubule arrays are of mixed polarity and both cytoplasmic dynein complex and kinesin-1 are required for nuclear rotation. Kinesin-1 can exert a point force on the nuclear envelope via association with nesprins, and loss of kinesin-1 causes failure in neuronal migration in vivo Thus, microtubules steer the nucleus and drive its rotation and translocation via a dynamic, focal interaction of nesprins with kinesin-1 and dynein, and this is necessary for neuronal migration during brain development. PMID- 29519890 TI - Microtubules spin the nucleus during neuronal migration. PMID- 29519892 TI - Medical textbook authors received L11m in undisclosed payments from drug and device makers. PMID- 29519889 TI - Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. AB - The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease modeling platform, as well as recent advancements in the development of human iPSC models that mimic in vivo tissues and organs at the three-dimensional (3D) level. Recent bioengineering approaches have begun to combine different 3D organoid types into a single '4D multi-organ system'. We summarize the advantages of this approach and speculate on the future role of 4D multi-organ systems in human disease modeling. PMID- 29519893 TI - Correction of Persistent Errors in Arabidopsis Reference Mitochondrial Genomes. PMID- 29519894 TI - Autophagy: Both Friend and Foe in Pseudomonas syringae Infection. PMID- 29519895 TI - Trust but Verify: A Lesson in Technology Limitations and Error Propagation. PMID- 29519896 TI - Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases. AB - Toxoplasma gondii aspartyl protease 3 (TgASP3) phylogenetically clusters with Plasmodium falciparum Plasmepsins IX and X (PfPMIX, PfPMX). These proteases are essential for parasite survival, acting as key maturases for secreted proteins implicated in invasion and egress. A potent antimalarial peptidomimetic inhibitor (49c) originally developed against Plasmepsin II selectively targets TgASP3, PfPMIX, and PfPMX To unravel the molecular basis for the selectivity of 49c, we constructed homology models of PfPMIX, PfPMX, and TgASP3 that were first validated by identifying the determinants of microneme and rhoptry substrate recognition. The flap and flap-like structures of several reported Plasmepsins are highly flexible and critically modulate the access to the binding cavity. Molecular docking of 49c to TgASP3, PfPMIX, and PfPMX models predicted that the conserved phenylalanine residues in the flap, F344, F291, and F305, respectively, account for the sensitivity toward 49c. Concordantly, phenylalanine mutations in the flap of the three proteases increase twofold to 15-fold the IC50 values of 49c. Compellingly the selection of mutagenized T. gondii resistant strains to 49c reproducibly converted F344 to a cysteine residue. PMID- 29519897 TI - MARCH6 and TRC8 facilitate the quality control of cytosolic and tail-anchored proteins. AB - Misfolded or damaged proteins are typically targeted for destruction by proteasome-mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome-mediated degradation of the soluble misfolded reporter, mCherry-CL1, involves two ER-resident E3 ligases, MARCH6 and TRC8. mCherry-CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells. To identify a more physiological correlate, we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail-anchored protein heme oxygenase-1 (HO-1). These E3 ligases associate with the intramembrane cleaving signal peptide peptidase (SPP) and facilitate the degradation of HO-1 following intramembrane proteolysis. Our results highlight how ER-resident ligases may target the same substrates, but work independently of each other, to optimise the protein quality control of selected soluble and tail-anchored proteins. PMID- 29519898 TI - Structures of human plasma beta-factor XIIa cocrystallized with potent inhibitors. AB - Activated factor XIIa (FXIIa) is a serine protease that has received a great deal of interest in recent years as a potential target for the development of new antithrombotics. Despite the strong interest in obtaining structural information, only the structure of the FXIIa catalytic domain in its zymogen conformation is available. In this work, reproducible experimental conditions found for the crystallization of human plasma beta-FXIIa and crystal growth optimization have led to determination of the first structure of the active form of the enzyme. Two crystal structures of human plasma beta-FXIIa complexed with small molecule inhibitors are presented herein. The first is the noncovalent inhibitor benzamidine. The second is an aminoisoquinoline containing a boronic acid reactive group that targets the catalytic serine. Both benzamidine and the aminoisoquinoline bind in a canonical fashion typical of synthetic serine protease inhibitors, and the protease domain adopts a typical chymotrypsin-like serine protease active conformation. This novel structural data explains the basis of the FXII activation, provides insights into the enzymatic properties of beta-FXIIa, and is a great aid toward the further design of protease inhibitors for human FXIIa. PMID- 29519899 TI - Systematic review and meta-analysis on outcome differences among patients with TICI2b versus TICI3 reperfusions: success revisited. AB - OBJECTIVE: A reperfusion quality of thrombolysis in cerebral infarction (TICI)>=2b has been set as the therapeutic angiography target for interventions in patients with acute ischaemic stroke. This study addresses whether the distinction between TICI2b and TICI3 reperfusions shows a clinically relevant difference on functional outcome. METHODS: A systematic literature review and meta-analysis was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria to test the primary hypothesis that TICI2b and TICI3 reperfusions are associated with different rates of modified Rankin Scale (mRS) <=2 at day 90. Secondary endpoints included rates of haemorrhagic transformations, mortality and excellent functional outcome (mRS <=1). Summary estimates of ORs (sOR) with 95% CI were calculated using the inverse variance heterogeneity model accounting for multiple true effect sizes. RESULTS: Fourteen studies on 2379 successfully reperfused patients were included (1131 TICI3, 1248 TICI2b). TICI3 reperfusions were associated with higher rates of functional independence (1.74, 95% CI 1.44 to 2.10) and excellent functional outcomes (2.01, 95% CI 1.60 to 2.53), also after including adjusted estimates. The safety profile of patients with TICI3 was superior, as demonstrated by lower rates of mortality (sOR 0.59, 95% CI 0.37 to 0.92) and symptomatic intracranial haemorrhages (sOR 0.42, 95% CI 0.25 to 0.71). CONCLUSION: TICI3 reperfusions are associated with superior outcome and better safety profiles than TICI2b reperfusions. This effect seems to be independent of time and collaterals. As reperfusion quality is the most important modifiable predictor of patients' outcome, a more conservative definition of successful therapy and further evaluation of treatment approaches geared towards achieving TICI3 reperfusions are desirable. PMID- 29519901 TI - Robotically Guided Left Ventricular Biopsy to Diagnose Cardiac Sarcoidosis: A Multidisciplinary Innovation Leading to First-in-Human Case. PMID- 29519902 TI - Thirty-Day Readmissions After Left Ventricular Assist Device Implantation in the United States: Insights From the Nationwide Readmissions Database. AB - BACKGROUND: Early readmissions contribute significantly to heart failure-related morbidity and negatively affect quality of life. Data on left ventricular assist device (LVAD)-related 30-day readmissions are scarce and limited to small studies. METHODS AND RESULTS: Patients undergoing LVAD implantation between January 2013 and November 2014 who survived the index hospitalization were identified in the Nationwide Readmissions Database. We analyzed the incidence, predictors, causes, and costs of 30-day readmissions. Of 2510 LVAD recipients, 788 (31%) were readmitted within 30 days. Length of index hospitalization >=31 days (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.07-1.50) and female sex (HR, 1.19; 95% CI, 1.01-1.42) were associated with a higher risk of 30 day readmission, whereas private insurance (HR, 0.83; 95% CI, 0.70-0.99), pre LVAD use of short-term mechanical circulatory support (HR, 0.53; 95% CI, 0.29 0.98), and discharge to a short-term hospital facility (HR, 0.41; CI, 0.21-0.78) were associated with a lower risk. Cardiac causes accounted for 23.8% of readmissions: heart failure (13.4%) and arrhythmias (8.1%). Noncardiovascular causes accounted for 76.2% of readmissions: infection (30.2%), bleeding (17.6%), and device-related causes (8.2%). Mean length of stay for readmission was 10.7 days (median, 6 days), and average hospital cost per readmission was $34 948+/ 2457. CONCLUSIONS: Early readmissions are frequent after LVAD implantation even in contemporary times. Preimplant identification of high-risk patients, and a protocol-driven follow-up using a multidisciplinary approach will be needed to reduce readmissions and improve outcomes. PMID- 29519900 TI - Collateral status affects the onset-to-reperfusion time window for good outcome. AB - OBJECTIVE: To characterise the time window in which endovascular thrombectomy (EVT) is associated with good outcome, and to test the differential relationship between functional outcome and onset-to-reperfusion time (ORT), depending on collateral status. METHODS: This was a retrospective analysis of clinical and imaging data of 554 consecutive patients, who had recanalisation success by EVT for anterior circulation large artery occlusion, from the prospectively maintained registries of 16 comprehensive stroke centres between September 2010 and December 2015. The patients were dichotomised into good and poor collateral groups, based on CT angiography. We tested whether the likelihood of good outcome (modified Rankin Scale, 0-2) by ORT was different between two groups. RESULTS: ORT was 298 min+/-113 min (range, 81-665 min), and 84.5% of patients had good collaterals. Age, diabetes mellitus, previous infarction, National Institutes of Health Stroke Scale, good collaterals (OR 40.766; 95% CI 10.668 to 155.78; p<0.001) and ORT (OR 0.926 every 30 min delay; 95% CI 0.862 to 0.995; p=0.037) were independently associated with good outcome. The drop in likelihood of good outcome associated with longer ORT was significantly faster in poor collateral group (OR 0.305 for every 30 min; 95% CI 0.113 to 0.822) than in good collateral group (OR 0.926 for every 30 min; 95% CI 0.875 to 0.980). CONCLUSIONS: Earlier successful recanalisation was strongly associated with good outcome in poor collateral group; however, this association was weak during the tested time window in good collateral group. This suggests that the ORT window for good outcome can be adjusted according to collateral status. PMID- 29519903 TI - Asbestos-related lung cancers are rarely associated with ALK, ROS1 and RET rearrangements. PMID- 29519904 TI - A well-designed/conducted study on alpha-1 antitrypsin epidemiology not quoted. PMID- 29519905 TI - New era for European Respiratory Society clinical practice guidelines: joining efficiency and high methodological standards. PMID- 29519906 TI - Contrary to popular belief, ventilator-associated lower respiratory tract infections are less common in immunocompromised patients. PMID- 29519907 TI - The ROS controversy in hypoxic pulmonary hypertension revisited. PMID- 29519909 TI - Principles for designing and delivering psychosocial and mental healthcare. AB - The development of the UK's military policy includes the potential for military organisations to deploy in support of humanitarian aid operations. This paper offers an overview of the risks to people's mental health of their exposure to emergencies, major incidents, disasters, terrorism, displacement, postconflict environments in which humanitarian aid is delivered, and deployments to conflict zones. It summarises the psychosocial approach recommended by many contemporary researchers and practitioners. It differentiates the extremely common experience of distress from the mental disorders that people who are affected may develop and introduces the construct of psychosocial resilience. The authors recognise the importance of trajectories of response in separating people who are distressed and require psychosocial care from those who require mental healthcare. Finally, this paper summarises a strategic approach to designing, planning and providing psychosocial and mental healthcare, provides a model of care and outlines the principles for early psychosocial interventions that do not require training in mental healthcare to deliver them. PMID- 29519908 TI - Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma. AB - Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1 a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7*10-16) and serum IL1RL1-a levels (p=2.8*10-56). IL1RL1 methylation was not associated with asthma or IL1RL1 a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma. PMID- 29519910 TI - Syphilis the great pretender: when is cancer not cancer? AB - The number of cases of syphilis continues to rise in the UK, USA and elsewhere and may present to a variety of clinical specialties. We report a complex case of early acquired disseminated syphilis causing an ulceronodular rash (lues maligna), orchitis, osteitis and lung nodules in an immunocompetent man who has sex with men who presented to the genitourinary medicine clinic. Syphilis should be considered in the differential diagnoses of multiple clinical presentations and optimal management should involve multidisciplinary care. PMID- 29519912 TI - Correction: Discoidin domain receptor 2 deficiency predisposes hepatic tissue to colon carcinoma metastasis. PMID- 29519911 TI - Ethnicity and sexual risk in heterosexual people attending sexual health clinics in England: a cross-sectional, self-administered questionnaire study. AB - OBJECTIVES: In the UK, people of black ethnicity experience a disproportionate burden of HIV and STI. We aimed to assess the association of ethnicity with sexual behaviour and sexual health among women and heterosexual men attending genitourinary medicine (GUM) clinics in England. METHODS: The Attitudes to and Understanding of Risk of Acquisition of HIV is a cross-sectional, self administered questionnaire study of HIV negative people recruited from 20 GUM clinics in England, 2013-2014. Modified Poisson regression with robust SEs was used to calculate adjusted prevalence ratios (aPR) for the association between ethnicity and various sexual risk behaviours, adjusted for age, study region, education and relationship status. RESULTS: Questionnaires were completed by 1146 individuals, 676 women and 470 heterosexual men. Ethnicity was recorded for 1131 (98.8%) participants: 550 (48.6%) black/mixed African, 168 (14.9%) black/mixed Caribbean, 308 (27.2%) white ethnic groups, 105 (9.3%) other ethnicity. Compared with women from white ethnic groups, black/mixed African women were less likely to report condomless sex with a non-regular partner (aPR (95% CI) 0.67 (0.51 to 0.88)), black/mixed African and black/mixed Caribbean women were less likely to report two or more new partners (0.42 (0.32 to 0.55) and 0.44 (0.29 to 0.65), respectively), and black/mixed Caribbean women were more likely to report an STI diagnosis (1.56 (1.00 to 2.42)). Compared with men from white ethnic groups, black/mixed Caribbean men were more likely to report an STI diagnosis (1.91 (1.20 to 3.04)), but did not report risk behaviours more frequently. Men and women of black/mixed Caribbean ethnicity remained more likely to report STI history after adjustment for sexual risk behaviours. DISCUSSION: Risk behaviours were reported less frequently by women of black ethnicity; however, history of STI was more prevalent among black/mixed Caribbean women. In black/mixed Caribbean men, higher STI history was not explained by ethnic variation in reported risk behaviours. The association between STI and black/mixed Caribbean ethnicity remained after adjustment for risk behaviours. PMID- 29519913 TI - As we continue to delay death, total system breakdown is inevitable. PMID- 29519914 TI - Structural basis for coupling protein transport and N-glycosylation at the mammalian endoplasmic reticulum. AB - Protein synthesis, transport, and N-glycosylation are coupled at the mammalian endoplasmic reticulum by complex formation of a ribosome, the Sec61 protein conducting channel, and oligosaccharyltransferase (OST). Here we used different cryo-electron microscopy approaches to determine structures of native and solubilized ribosome-Sec61-OST complexes. A molecular model for the catalytic OST subunit STT3A (staurosporine and temperature sensitive 3A) revealed how it is integrated into the OST and how STT3-paralog specificity for translocon associated OST is achieved. The OST subunit DC2 was placed at the interface between Sec61 and STT3A, where it acts as a versatile module for recruitment of STT3A-containing OST to the ribosome-Sec61 complex. This detailed structural view on the molecular architecture of the cotranslational machinery for N glycosylation provides the basis for a mechanistic understanding of glycoprotein biogenesis at the endoplasmic reticulum. PMID- 29519915 TI - Structure of the nuclear exosome captured on a maturing preribosome. AB - The RNA exosome complex processes and degrades a wide range of transcripts, including ribosomal RNAs (rRNAs). We used cryo-electron microscopy to visualize the yeast nuclear exosome holocomplex captured on a precursor large ribosomal subunit (pre-60S) during 7S-to-5.8S rRNA processing. The cofactors of the nuclear exosome are sandwiched between the ribonuclease core complex (Exo-10) and the remodeled "foot" structure of the pre-60S particle, which harbors the 5.8S rRNA precursor. The exosome-associated helicase Mtr4 recognizes the preribosomal substrate by docking to specific sites on the 25S rRNA, captures the 3' extension of the 5.8S rRNA, and channels it toward Exo-10. The structure elucidates how the exosome forms a structural and functional unit together with its massive pre-60S substrate to process rRNA during ribosome maturation. PMID- 29519916 TI - Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. AB - Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes. PMID- 29519917 TI - Observation of topological superconductivity on the surface of an iron-based superconductor. AB - Topological superconductors are predicted to host exotic Majorana states that obey non-Abelian statistics and can be used to implement a topological quantum computer. Most of the proposed topological superconductors are realized in difficult-to-fabricate heterostructures at very low temperatures. By using high resolution spin-resolved and angle-resolved photoelectron spectroscopy, we find that the iron-based superconductor FeTe1-x Se x (x = 0.45; superconducting transition temperature Tc = 14.5 kelvin) hosts Dirac-cone-type spin-helical surface states at the Fermi level; the surface states exhibit an s-wave superconducting gap below Tc Our study shows that the surface states of FeTe0.55Se0.45 are topologically superconducting, providing a simple and possibly high-temperature platform for realizing Majorana states. PMID- 29519918 TI - Multidimensional quantum entanglement with large-scale integrated optics. AB - The ability to control multidimensional quantum systems is central to the development of advanced quantum technologies. We demonstrate a multidimensional integrated quantum photonic platform able to generate, control, and analyze high dimensional entanglement. A programmable bipartite entangled system is realized with dimensions up to 15 * 15 on a large-scale silicon photonics quantum circuit. The device integrates more than 550 photonic components on a single chip, including 16 identical photon-pair sources. We verify the high precision, generality, and controllability of our multidimensional technology, and further exploit these abilities to demonstrate previously unexplored quantum applications, such as quantum randomness expansion and self-testing on multidimensional states. Our work provides an experimental platform for the development of multidimensional quantum technologies. PMID- 29519920 TI - Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis. AB - Human mesenchymal stem/stromal cells (MSCs) have been reported to produce an M2 like, alternatively activated phenotype in macrophages. In addition, MSCs mediate effective bacterial clearance in pre-clinical sepsis models. Thus, MSCs have a paradoxical antimicrobial and anti-inflammatory response that is not understood.Here, we studied the phenotypic and functional response of monocyte derived human macrophages to MSC exposure in vitroMSCs induced two distinct, coexistent phenotypes: M2-like macrophages (generally elongated morphology, CD163+, acute phagosomal acidification, low NOX2 expression and limited phagosomal superoxide production) and M1-like macrophages characterised by high levels of phagosomal superoxide production. Enhanced phagosomal reactive oxygen species production was also observed in alveolar macrophages from a rodent model of pneumonia-induced sepsis. The production of M1-like macrophages was dependent on prostaglandin E2 and phosphatidylinositol 3-kinase. MSCs enhanced human macrophage phagocytosis of unopsonised bacteria and enhanced bacterial killing compared with untreated macrophages. Bacterial killing was significantly reduced by blockade of NOX2 using diphenyleneiodonium, suggesting that M1-like cells are primarily responsible for this effect. MSCs also enhanced phagocytosis and polarisation of M1-like macrophages derived from patients with severe sepsis.The enhanced antimicrobial capacity (M1-like) and inflammation resolving phenotype (M2-like) may account for the paradoxical effect of these cells in sepsis in vivo. PMID- 29519919 TI - Photoperiodic control of seasonal growth is mediated by ABA acting on cell-cell communication. AB - In temperate and boreal ecosystems, seasonal cycles of growth and dormancy allow perennial plants to adapt to winter conditions. We show, in hybrid aspen trees, that photoperiodic regulation of dormancy is mechanistically distinct from autumnal growth cessation. Dormancy sets in when symplastic intercellular communication through plasmodesmata is blocked by a process dependent on the phytohormone abscisic acid. The communication blockage prevents growth-promoting signals from accessing the meristem. Thus, precocious growth is disallowed during dormancy. The dormant period, which supports robust survival of the aspen tree in winter, is due to loss of access to growth-promoting signals. PMID- 29519921 TI - Markers of neutrophil extracellular traps predict adverse outcome in community acquired pneumonia: secondary analysis of a randomised controlled trial. AB - Neutrophil extracellular traps (NETs) are a hallmark of the immune response in inflammatory diseases. However, the role of NETs in community-acquired pneumonia (CAP) is unknown. This study aims to characterise the impact of NETs on clinical outcomes in pneumonia.This is a secondary analysis of a randomised controlled, multicentre trial. Patients with CAP were randomly assigned to either 50 mg prednisone or placebo for 7 days. The primary end-point was time to clinical stability; main secondary end-points were length of hospital stay and mortality.In total, 310 patients were included in the analysis. Levels of cell free nucleosomes as surrogate markers of NETosis were significantly increased at admission and declined over 7 days. NETs were significantly associated with reduced hazards of clinical stability and hospital discharge in multivariate adjusted analyses. Moreover, NETs were associated with a 3.8-fold increased adjusted odds ratio of 30-day mortality. Prednisone treatment modified circulatory NET levels and was associated with beneficial outcome.CAP is accompanied by pronounced NET formation. Patients with elevated serum NET markers were at higher risk for clinical instability, prolonged length of hospital stay and 30-day all-cause mortality. NETs represent a novel marker for outcome and a possible target for adjunct treatments of pneumonia. PMID- 29519922 TI - Nonadherence in the era of severe asthma biologics and thermoplasty. AB - Nonadherence to inhaled preventers impairs asthma control. Electronic monitoring devices (EMDs) can objectively measure adherence. Their use has not been reported in difficult asthma patients potentially suitable for novel therapies, i.e. biologics and bronchial thermoplasty.Consecutive patients with difficult asthma were assessed for eligibility for novel therapies. Medication adherence, defined as taking >75% of prescribed doses, was assessed by EMD and compared with standardised clinician assessment over an 8-week period.Among 69 difficult asthma patients, adherence could not be analysed in 13, due to device incompatibility or malfunction. Nonadherence was confirmed in 20 out of 45 (44.4%) patients. Clinical assessment of nonadherence was insensitive (physician 15%, nurse 28%). Serum eosinophils were higher in nonadherent patients. Including 11 patients with possible nonadherence (device refused or not returned) increased the nonadherence rate to 31 out of 56 (55%) patients. Severe asthma criteria were fulfilled by 59 out of 69 patients. 47 were eligible for novel therapies, with confirmed nonadherence in 16 out of 32 (50%) patients with EMD data; including seven patients with possible nonadherence increased the nonadherence rate to 23 out of 39 (59%).At least half the patients eligible for novel therapies were nonadherent to preventers. Nonadherence was often undetectable by clinical assessments. Preventer adherence must be confirmed objectively before employing novel severe asthma therapies. PMID- 29519924 TI - Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma. AB - Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO 211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO 211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression. PMID- 29519925 TI - Impact of sleep alterations on weaning duration in mechanically ventilated patients: a prospective study. AB - Sleep is markedly altered in intensive care unit (ICU) patients and may alter respiratory performance. Our objective was to assess the impact of sleep alterations on weaning duration.We conducted a prospective physiological study at a French teaching hospital. ICU patients intubated for at least 24 h and difficult to wean were included. Complete polysomnography (PSG) was performed after the first spontaneous breathing trial failure. Presence of atypical sleep, duration of sleep stages, particularly rapid eye movement (REM) sleep, and electroencephalogram (EEG) reactivity at eyes opening were assessed by a neurologist.20 out of 45 patients studied (44%) had atypical sleep that could not be classified according to the standard criteria. Duration of weaning between PSG and extubation was significantly longer in patients with atypical sleep (median (interquartile range) 5 (2-8) versus 2 (1-2) days; p=0.001) and in those with no REM sleep compared with the others. Using multivariate logistic regression analysis, atypical sleep remained independently associated with prolonged weaning (>48 h after PSG). Altered EEG reactivity at eyes opening was a good predictor of atypical sleep.Our results suggest for the first time that brain dysfunction may have an influence on the ability to breathe spontaneously. PMID- 29519923 TI - Biomarkers of carcinogenesis and tumour growth in patients with cutaneous melanoma and obstructive sleep apnoea. AB - The goal of this study was to assess the relationship between the severity of obstructive sleep apnoea (OSA) and the levels of carcinogenesis- and tumour growth-related biomarkers in patients with cutaneous melanoma.This multicentre observational study included patients who were newly diagnosed with melanoma. The patients were classified as non-OSA (apnoea-hypopnoea index (AHI) 0-5 events.h 1), mild OSA (AHI 5-15 events.h-1) and moderate-severe OSA (AHI >15 events.h-1). ELISAs were performed to analyse the serum levels of hypoxia- and tumour adhesion related biomarkers (vascular endothelial growth factor (VEGF), interleukin (IL) 8, intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM)-1) and markers of tumour aggressiveness (S100 calcium-binding protein B (S100B) and melanoma inhibitory activity (MIA)). A logistic model adjusted for age, sex and body mass index was fitted to each biomarker, and the AHI served as the dependent variable.360 patients were included (52.2% male, median (interquartile range) age 55.5 (43.8-68.0) years and AHI 8.55 (2.8-19.5) events.h 1). The levels of VEGF, IL-8, ICAM-1, S100B and MIA were not related to the severity of OSA. The levels of VCAM-1 were higher in patients with OSA than those without OSA (mild OSA: odds ratio (OR) 2.07, p=0.021; moderate-severe OSA: OR 2.35, p=0.013).In patients with cutaneous melanoma, OSA was associated with elevated circulating levels of VCAM-1 that could indicate the contribution of OSA in tumorigenesis via integrin-based adhesion. PMID- 29519926 TI - Rates of change in FEV1 and DLCO as potential indicators for mTOR inhibitor therapy in premenopausal lymphangioleiomyomatosis patients. AB - The value of rates of change in forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) to predict disease progression, and initiation of mTOR (mechanistic target of rapamycin) inhibitor therapy has not been evaluated.In 84 premenopausal lymphangioleiomyomatosis patients, individual rates of change in FEV1 and DLCO and their 95% confidence intervals were used to derive subsequent lowest values of FEV1 and DLCO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with a criterion based on FEV1 or DLCO <=70% predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated.27 and 35 patients who experienced greater than expected rates of change in FEV1 and DLCO, respectively, would have been excluded from therapy based on an FEV1 or DLCO >70% pred. 25 of the 84 patients were eventually treated, but only when FEV1 or DLCO were <=70% pred. Applying such treatment criteria to 12 patients undergoing sirolimus therapy would have delayed treatment for many years.Premenopausal females in whom FEV1 or DLCO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV1 or DLCO falls to <=70% pred. PMID- 29519927 TI - Asthma health services utilisation before, during and after pregnancy: a population-based cohort study. AB - During pregnancy, females with asthma may be at higher risk of exacerbation. The objective of this study was to determine whether females with asthma in Ontario, Canada have increased health services utilisation (HSU) during pregnancy.Rates of asthma-specific, asthma-related and non-pregnancy-related HSU were calculated in a population-based cohort of pregnant females with asthma. Poisson regression with repeated measures was used to determine adjusted rate ratios and 95% confidence intervals of HSU during and 1 year after pregnancy, compared to the year before pregnancy.The cohort consisted of 103 976 pregnant females with asthma. Compared to the year prior to pregnancy, hospitalisation rates per 100 person-months during pregnancy increased 30% for asthma (from 0.016 to 0.020), 24% for asthma-related conditions (from 0.012 to 0.015) and decreased 37% for non pregnancy-related conditions (from 0.24 to 0.15). Emergency department visits for asthma and asthma-related conditions did not increase significantly during pregnancy. During pregnancy, physician office visits decreased 19% for asthma (from 2.20 to 1.79), 10% for asthma-related conditions (from 9.44 to 8.47) and increased 74% for non-pregnancy-related conditions (from 56.4 to 98.2).Hospitalisations for asthma and asthma-related conditions increased during pregnancy, demonstrating that the overall increase in non-pregnancy-related physician office visits may not meet the primary care needs of pregnant females with asthma. PMID- 29519929 TI - An exit strategy for new platelets. PMID- 29519931 TI - Unusual cause of infant pancytopenia: granulomatous bone marrow lesion with disseminated histoplasmosis. PMID- 29519930 TI - Csk/CD148 and platelet SFK activation: a balancing act! PMID- 29519932 TI - Key design considerations for adaptive clinical trials: a primer for clinicians. PMID- 29519933 TI - Tuning dCas9's ability to block transcription enables robust, noiseless knockdown of bacterial genes. AB - Over the past few years, tools that make use of the Cas9 nuclease have led to many breakthroughs, including in the control of gene expression. The catalytically dead variant of Cas9 known as dCas9 can be guided by small RNAs to block transcription of target genes, in a strategy also known as CRISPRi. Here, we reveal that the level of complementarity between the guide RNA and the target controls the rate at which RNA polymerase "kicks out" dCas9 from the target and completes transcription. We use this mechanism to precisely and robustly reduce gene expression by defined relative amounts. Alternatively, tuning repression by changing dCas9 concentration is noisy and promoter-strength dependent. We demonstrate broad applicability of this method to the study of genetic regulation and cellular physiology. First, we characterize feedback strength of a model auto repressor. Second, we study the impact of amount variations of cell-wall synthesizing enzymes on cell morphology. Finally, we multiplex the system to obtain any combination of fractional repression of two genes. PMID- 29519934 TI - Tobacco outlet density and adolescents' cigarette smoking: a meta-analysis. AB - OBJECTIVE: We conducted meta-analyses of studies that investigated the associations between tobacco outlet density around homes and schools and adolescents' past-month cigarette smoking. DATA SOURCES: Systematic literature searches of eight databases were carried out in February 2017. Searches were not limited by date, language, country or peer-reviewed status. STUDY SELECTION: After screening for quality, studies that examined the relationship between tobacco outlet density and adolescents' past-month smoking were selected for inclusion. DATA EXTRACTION: Two investigators screened study abstracts and full texts and independently extracted data. Consensus was reached at each stage. DATA SYNTHESIS: Random-effects meta-analyses were conducted on 11 studies that provided 13 effect sizes. Results showed that there was a significant association between tobacco outlet density around homes and adolescents' past-month smoking behaviour, with an overall effect size of OR=1.08 (95% CI 1.04 to 1.13; P<0.001; I2=0%). For density around schools, the association was not statistically significant (OR=1.01, 95% CI 0.98 to 1.03; P=0.53; I2=39%). CONCLUSIONS: These findings suggest that exposure to tobacco outlets near home environments may be important for understanding adolescents' past-month smoking. Restricting access to tobacco outlets and controlling the number of outlets in residential areas may be an effective preventive strategy to help reduce adolescents' smoking. PMID- 29519935 TI - Disentangling the roles of point-of-sale ban, tobacco retailer density and proximity on cessation and relapse among a cohort of smokers: findings from ITC Canada Survey. AB - OBJECTIVE: To examine how point-of-sale (POS) display bans, tobacco retailer density and tobacco retailer proximity were associated with smoking cessation and relapse in a cohort of smokers in Canada, where provincial POS bans were implemented differentially over time from 2004 to 2010. METHODS: Data from the 2005 to 2011 administrations of the International Tobacco Control (ITC) Canada Survey, a nationally representative cohort of adult smokers, were linked via residential geocoding with tobacco retailer data to derive for each smoker a measure of retailer density and proximity. An indicator variable identified whether the smoker's province banned POS displays at the time of the interview. Outcomes included cessation for at least 1 month at follow-up among smokers from the previous wave and relapse at follow-up among smokers who had quit at the previous wave. Logistic generalised estimating equation models were used to determine the relationship between living in a province with a POS display ban, tobacco retailer density and tobacco retailer proximity with cessation (n=4388) and relapse (n=866). RESULTS: Provincial POS display bans were not associated with cessation. In adjusted models, POS display bans were associated with lower odds of relapse which strengthened after adjusting for retailer density and proximity, although results were not statistically significant (OR 0.66, 95% CI 0.41 to 1.07, p=0.089). Neither tobacco retailer density nor proximity was associated with cessation or relapse. CONCLUSIONS: Banning POS retail displays shows promise as an additional tool to prevent relapse, although these results need to be confirmed in larger longitudinal studies. PMID- 29519936 TI - Inducible Genome Editing with Conditional CRISPR/Cas9 Mice. AB - Genetically engineered mouse models (GEMMs) are powerful tools by which to probe gene function in vivo, obtain insight into disease etiology, and identify modifiers of drug response. Increased sophistication of GEMMs has led to the design of tissue-specific and inducible models in which genes of interest are expressed or ablated in defined tissues or cellular subtypes. Here we describe the generation of a transgenic mouse harboring a doxycycline-regulated Cas9 allele for inducible genome engineering. This model provides a flexible platform for genome engineering since editing is achieved by exogenous delivery of sgRNAs and should allow for the modeling of a range of biological and pathological processes. PMID- 29519937 TI - Functional Validation of Candidate Genes Detected by Genomic Feature Models. AB - Understanding the genetic underpinnings of complex traits requires knowledge of the genetic variants that contribute to phenotypic variability. Reliable statistical approaches are needed to obtain such knowledge. In genome-wide association studies, variants are tested for association with trait variability to pinpoint loci that contribute to the quantitative trait. Because stringent genome-wide significance thresholds are applied to control the false positive rate, many true causal variants can remain undetected. To ameliorate this problem, many alternative approaches have been developed, such as genomic feature models (GFM). The GFM approach tests for association of set of genomic markers, and predicts genomic values from genomic data utilizing prior biological knowledge. We investigated to what degree the findings from GFM have biological relevance. We used the Drosophila Genetic Reference Panel to investigate locomotor activity, and applied genomic feature prediction models to identify gene ontology (GO) categories predictive of this phenotype. Next, we applied the covariance association test to partition the genomic variance of the predictive GO terms to the genes within these terms. We then functionally assessed whether the identified candidate genes affected locomotor activity by reducing gene expression using RNA interference. In five of the seven candidate genes tested, reduced gene expression altered the phenotype. The ranking of genes within the predictive GO term was highly correlated with the magnitude of the phenotypic consequence of gene knockdown. This study provides evidence for five new candidate genes for locomotor activity, and provides support for the reliability of the GFM approach. PMID- 29519940 TI - CD40L Deficiency Protects Against Aneurysm Formation. AB - OBJECTIVE: The mechanisms underlying formation of arterial aneurysms remain incompletely understood. Because inflammation is a common feature during the progressive degeneration of the aortic wall, we studied the role of the costimulatory molecule CD40L, a major driver of inflammation, in aneurysm formation. APPROACH AND RESULTS: Transcriptomics data obtained from human abdominal aortic aneurysms and normal aortas revealed increased abundance of both CD40L and CD40 in media of thrombus-free and thrombus-covered human abdominal aortic aneurysms samples. To further unravel the role of CD40L in aneurysm formation, apolipoprotein E-deficient (Apoe-/-) and Cd40l-/-Apoe-/- mice were infused with angiotensin II for 7 and 28 days. Only a minority of Cd40l-/-Apoe-/- mice (33% and 17%) developed (dissecting) aneurysms compared with 75% and 67% of Apoe-/- littermates after 7 and 28 days of infusion, respectively. Total vessel area of the aorta at the suprarenal level was 52% smaller in angiotensin II infused Cd40l-/-Apoe-/- mice compared with that in angiotensin II-infused Apoe-/- mice. Chimeric Apoe-/- mice repopulated with Cd40l-/-Apoe-/- bone marrow afforded a similar protection against dissecting aneurysm formation. Moreover, lack of CD40L protected mice from fatal aneurysm rupture. T helper cell and macrophage accumulation in aneurysmal tissue was reduced in Cd40l-/-Apoe-/- mice with a concomitant decrease in expression of proinflammatory chemo- and cytokines. In addition, aneurysms of Cd40l-/-Apoe-/- mice displayed reduced abundance of matrix metalloproteinase-13 and an increase in tissue inhibitor of metalloproteinase-3 while activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 was diminished. CONCLUSIONS: Deficiency of (hematopoietic) CD40L protects against dissecting aneurysm formation and reduces the incidence of fatal rupture. This is associated with a decreased accumulation and activation of inflammatory cells and a dampened protease activity in the arterial wall. PMID- 29519938 TI - Rapid Nuclear Exclusion of Hcm1 in Aging Saccharomyces cerevisiae Leads to Vacuolar Alkalization and Replicative Senescence. AB - The yeast, Saccharomyces cerevisiae, like other higher eukaryotes, undergo a finite number of cell divisions before exiting the cell cycle due to the effects of aging. Here, we show that yeast aging begins with the nuclear exclusion of Hcm1 in young cells, resulting in loss of acidic vacuoles. Autophagy is required for healthy aging in yeast, with proteins targeted for turnover by autophagy directed to the vacuole. Consistent with this, vacuolar acidity is necessary for vacuolar function and yeast longevity. Using yeast genetics and immunofluorescence microscopy, we confirm that vacuolar acidity plays a critical role in cell health and lifespan, and is potentially maintained by a series of Forkhead Box (Fox) transcription factors. An interconnected transcriptional network involving the Fox proteins (Fkh1, Fkh2 and Hcm1) are required for transcription of v-ATPase subunits and vacuolar acidity. As cells age, Hcm1 is rapidly excluded from the nucleus in young cells, blocking the expression of Hcm1 targets (Fkh1 and Fkh2), leading to loss of v-ATPase gene expression, reduced vacuolar acidification, increased alpha-syn-GFP vacuolar accumulation, and finally, diminished replicative lifespan (RLS). Loss of vacuolar acidity occurs about the same time as Hcm1 nuclear exclusion and is conserved; we have recently demonstrated that lysosomal alkalization similarly contributes to aging in C. elegans following a transition from progeny producing to post-reproductive life. Our data points to a molecular mechanism regulating vacuolar acidity that signals the end of RLS when acidification is lost. PMID- 29519941 TI - Kinesin-1 Is a New Actor Involved in Platelet Secretion and Thrombus Stability. AB - OBJECTIVE: Platelet secretion is crucial for many physiological platelet responses. Even though several regulators of the fusion machinery for secretory granule exocytosis have been identified in platelets, the underlying mechanisms are not yet fully characterized. APPROACH AND RESULTS: By studying a mouse model (cKO [conditional knockout]Kif5b) lacking Kif5b (kinesin-1 heavy chain) in its megakaryocytes and platelets, we evidenced unstable hemostasis characterized by an increase of blood loss associated to a marked tendency to rebleed in a tail clip assay and thrombus instability in an in vivo thrombosis model. This instability was confirmed in vitro in a whole-blood perfusion assay under blood flow conditions. Aggregations induced by thrombin and collagen were also impaired in cKOKif5b platelets. Furthermore, P-selectin exposure, PF4 (platelet factor 4) secretion, and ATP release after thrombin stimulation were impaired in cKOKif5b platelets, highlighting the role of kinesin-1 in alpha-granule and dense granule secretion. Importantly, exogenous ADP rescued normal thrombin induced-aggregation in cKOKif5b platelets, which indicates that impaired aggregation was because of defective release of ADP and dense granules. Last, we demonstrated that kinesin-1 interacts with the molecular machinery comprising the granule-associated Rab27 (Ras-related protein Rab-27) protein and the Slp4 (synaptotagmin-like protein 4/SYTL4) adaptor protein. CONCLUSIONS: Our results indicate that a kinesin-1 dependent process plays a role for platelet function by acting into the mechanism underlying alpha-granule and dense granule secretion. PMID- 29519939 TI - Improved Genome Assembly and Annotation for the Rock Pigeon (Columba livia). AB - The domestic rock pigeon (Columba livia) is among the most widely distributed and phenotypically diverse avian species. C. livia is broadly studied in ecology, genetics, physiology, behavior, and evolutionary biology, and has recently emerged as a model for understanding the molecular basis of anatomical diversity, the magnetic sense, and other key aspects of avian biology. Here we report an update to the C. livia genome reference assembly and gene annotation dataset. Greatly increased scaffold lengths in the updated reference assembly, along with an updated annotation set, provide improved tools for evolutionary and functional genetic studies of the pigeon, and for comparative avian genomics in general. PMID- 29519942 TI - MicroRNA-21 Knockout Exacerbates Angiotensin II-Induced Thoracic Aortic Aneurysm and Dissection in Mice With Abnormal Transforming Growth Factor-beta-SMAD3 Signaling. AB - OBJECTIVE: Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-beta (TGF-beta) signaling in vascular smooth muscle cells and elevated angiotensin II (AngII) levels are implicated in the development of TAAD. In this study, we investigated whether these 2 factors lead to TAAD in a mouse model and explored the possibility of using microRNA-21 (miR-21) for the treatment of TAAD. APPROACH AND RESULTS: TAAD was developed in Smad3 (mothers against decapentaplegic homolog 3) heterozygous (S3+/-) mice infused with AngII. We found that p-ERK (phosphorylated extracellular regulated protein kinases)- and p-JNK (phosphorylated c-Jun N terminal kinase)-associated miR-21 was higher in TAAD lesions. We hypothesize that downregulation of miR-21 mitigate TAAD formation. However, Smad3+/-:miR-21-/ (S3+/-21-/-) mice exhibited conspicuous TAAD formation after AngII infusion. The vascular wall was dilated, and aortic rupture occurred within 23 days during AngII infusion. We then examined canonical and noncanonical TGF-beta signaling and found that miR-21 knockout in S3+/- mice increased SMAD7 and suppressed canonical TGF-beta signaling. Vascular smooth muscle cells lacking TGF-beta signals tended to switch from a contractile to a synthetic phenotype. The silencing of Smad7 with lentivirus prevented AngII-induced TAAD formation in S3+/ 21-/- mice. CONCLUSIONS: Our study demonstrated that miR-21 knockout exacerbated AngII-induced TAAD formation in mice, which was associated with TGF-beta signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-beta signaling. PMID- 29519944 TI - Health-related quality of life and its determinants in paediatric arterial ischaemic stroke survivors. AB - OBJECTIVE: Health-related quality of life (HRQL) instruments are patient or proxy reported outcome measures that provide a comprehensive and subjective assessment of patient's well-being and hence vital for health outcomes evaluation. A clear and thorough understanding of HRQL and its determinants is especially important to appropriately guide health-improving interventions. In this study, HRQL of paediatric arterial ischaemic stroke survivors was assessed using guidelines recommended for interpretation and reporting of the patient-reported outcome data. Determinants of HRQL were also explored. METHODS: Children diagnosed with arterial ischaemic stroke between 2003 and 2012 were assessed at least 1 year poststroke using the parent-proxy report versions of the Pediatric Quality of Life Inventory 4.0 and Pediatric Stroke Recurrence and Recovery Questionnaire. HRQL data were compared with population norms and used as outcome in multiple linear regression analysis. RESULTS: 59 children were evaluated. Mean age at diagnosis of stroke was 2.2 years. Mean age at assessment and time elapsed since stroke was 7 years and 5 years, respectively. A total of 41% children had normal global outcome, whereas 51% had moderate to severe deficits. A lower overall HRQL was observed in both self and proxy reports. Parents reported the maximum impairment in emotional domain, whereas children indicated physical functioning to be the most affected. Neurological outcome, site of stroke and socioeconomic status were independently associated with overall HRQL. CONCLUSIONS: Lower HRQL was demonstrated in children who survived arterial ischaemic stroke. Socioeconomic status of families was an important determinant of HRQL, over and above clinical parameters. PMID- 29519945 TI - Is the incidence of paediatric inflammatory bowel disease still increasing? PMID- 29519943 TI - What factors influence recruitment to a birth cohort of infants with Down's syndrome? AB - OBJECTIVE: To understand how to maximise recruitment of young infants with Down's syndrome (DS) into research through qualitative interviews with parents and care providers. In complex neonatal and genetic conditions such as DS, frequently diagnosed after birth, parents may go through a period of adaptation. These factors need consideration when overcoming barriers to recruitment. PARTICIPANTS AND DESIGN: Participants, who were drawn from health professionals and volunteers working with families experiencing DS, were recruited using a purposive sampling strategy. Semistructured telephone interviews were completed with nine paediatricians, three research nurses and six family support workers. Five of those interviewed had a child with DS. The interviews were transcribed and analysed thematically. RESULTS: A positive decision to take part in a 'from birth' cohort study depends on factors such as the child's overall health, parent demographics (educational background and ethnicity), medical interactions that take place with the families (communication) and study logistics. The data suggest that recruitment methods need to take all these factors into consideration. Multiple recruitment methods should be considered including face to face, through parent and support groups, websites and social media. There also needs to be flexibility in the research timings to fit around the needs of the child and parents. CONCLUSION: Researchers need to be aware of the variable responses elicited by families to a diagnosis of DS for their baby and be sensitive to the child's current medical status. This does not preclude recruitment into studies, but to maximise uptake good communication and flexibility is essential. PMID- 29519946 TI - Air pollution and asthma. PMID- 29519948 TI - ? Daclizumab withdrawn from the market worldwide. PMID- 29519949 TI - Do hypertension guidelines put the person first? PMID- 29519947 TI - Acute hyperkinetic movement disorders in Italian paediatric emergency departments. AB - INTRODUCTION: Limited data exist on epidemiology, clinical presentation and management of acute hyperkinetic movement disorders (AHMD) in paediatric emergency departments (pED). METHODS: We retrospectively analysed a case series of 256 children (aged 2 months to 17 years) presenting with AHMD to the pEDs of six Italian tertiary care hospitals over a 2-year period (January 2012 to December 2013). RESULTS: The most common type of AHMD was tics (44.5%), followed by tremors (21.1%), chorea (13.7%), dystonia (10.2%), myoclonus (6.3%) and stereotypies (4.3%). Neuropsychiatric disorders (including tic disorders, psychogenic movement disorders and idiopathic stereotypies) were the most represented cause (51.2%). Inflammatory conditions (infectious and immune mediated neurological disorders) accounted for 17.6% of the cases whereas non inflammatory disorders (including drug-induced AHMDs, genetic/metabolic diseases, paroxysmal non-epileptic movements and idiopathic AHMDs) accounted for 31.2%. Neuropsychiatric disorders prevailed among preschoolers and schoolers (51.9% and 25.2%, respectively), non-inflammatory disorders were more frequent in infants and toddlers (63.8%), whereas inflammatory conditions were more often encountered among schoolers (73.3%). In 5 out of 36 Sydenham's chorea (SC) cases, tics were the presentation symptom on admission to emergency department (ED), highlighting the difficulties in early diagnosis of SC. Inflammatory disorders were associated with a longer hospital stay and a greater need of neuroimaging test compared with other disorders. CONCLUSIONS: This study provides the first large sample of paediatric patients presenting to the ED for AHMDs, helping to elucidate the epidemiology, aetiology and clinical presentation of these disorders. PMID- 29519951 TI - Correlation of Urine Ammonium and Urine Osmolal Gap in Kidney Transplant Recipients. PMID- 29519950 TI - Associations of Plasma Amino Acid and Acylcarnitine Profiles with Incident Reduced Glomerular Filtration Rate. AB - BACKGROUND AND OBJECTIVES: Metabolomics is instrumental in identifying novel biomarkers of kidney function to aid in the prevention and management of CKD. However, data linking the metabolome to incident eGFR are sparse, particularly in Asian populations with different genetic backgrounds and environmental exposures. Therefore, we aimed to investigate the associations of amino acid and acylcarnitine profiles with change in eGFR in a Chinese cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included 1765 community-living Chinese adults aged 50-70 years with baseline eGFR>=60 ml/min per 1.73 m2. At baseline, 22 amino acids and 34 acylcarnitines in plasma were quantified by gas or liquid chromatography coupled with mass spectrometry. Annual rate of change in eGFR was calculated, and incident eGFR decline was defined as eGFR<60 ml/min per 1.73 m2 by the end of 6 years of follow-up. RESULTS: The mean (SD) unadjusted annual change in eGFR was 2.2+/-2.0 ml/min per 1.73 m2 and the incidence of reduced eGFR was 16%. After Bonferroni correction, 13 of 56 metabolites were significantly associated with annual eGFR change. After multivariable adjustment of baseline covariates, including baseline eGFR, seven of the 13 metabolites, including cysteine, long-chain acylcarnitines (C14:1OH, C18, C18:2, and C20:4), and other acylcarnitines (C3DC and C10), were significantly associated with incident reduced eGFR (relative risks ranged from 1.16 to 1.25 per SD increment of metabolites; P<3.8E-03 after Bonferroni correction of multiple testing of the 13 metabolites). Moreover, principal component analysis identified two factors, consisting of cysteine and long-chain acylcarnitines, respectively, that were associated with incident reduced eGFR. CONCLUSIONS: Elevated plasma levels of cysteine and a panel of acylcarnitines were associated with a higher incidence of reduced eGFR in Chinese adults, independent of baseline eGFR and other conventional risk factors. PMID- 29519952 TI - Association of FGF-2 Concentrations with Atheroma Progression in Chronic Kidney Disease Patients. AB - BACKGROUND AND OBJECTIVES: Atherosclerosis is highly prevalent in CKD. The rate of progression of atherosclerosis is associated with cardiovascular events. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family with potentially both protective and deleterious effects in the development of atherosclerosis. The role of circulating FGF-2 levels in the progression of atherosclerosis in CKD is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used a multicenter, prospective, observational cohorts study of 481 patients with CKD. We determined the presence of atheroma plaque in ten arterial territories by carotid and femoral ultrasounds. Progression of atheromatosis was defined as an increase in the number of territories with plaque after 24 months. Plasma levels of FGF-2 were measured by multiplex analysis. A multivariable logistic regression analysis was performed to determine whether plasma FGF-2 levels were associated with atheromatosis progression. RESULTS: Average age of the population was 61 years. The percentage of patients in each CKD stage was 51% in stage 3, 41% in stages 4 5, and 8% in dialysis. A total of 335 patients (70%) showed plaque at baseline. Atheromatosis progressed in 289 patients (67%). FGF-2 levels were similar between patients with or without plaque at baseline (79 versus 88 pg/ml), but lower in patients with atheromatosis progression after 2 years (78 versus 98 pg/ml; P<0.01). In adjusted analyses, higher plasma FGF-2 was associated with lower risk of atheromatosis progression (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.76 to 0.96; per 50 pg/ml increment). Analysis of FGF-2 in tertiles showed that atheroma progression was observed for 102 participants in the lowest tertile of FGF-2 (reference group), 86 participants in the middle tertile of FGF-2 (adjusted OR, 0.70; 95% CI, 0.40 to 1.20), and 74 participants in the lowest tertile of FGF-2 (adjusted OR, 0.48; 95% CI, 0.28 to 0.82). CONCLUSIONS: Low FGF 2 levels are independently associated with atheromatosis progression in CKD. PMID- 29519953 TI - beta-Blocker Dialyzability in Maintenance Hemodialysis Patients: A Randomized Clinical Trial. AB - BACKGROUND AND OBJECTIVES: There is a paucity of data available to describe drug dialyzability. Of the available information, most was obtained before implementation of modern hemodialysis membranes. Our study characterized dialyzability of the most commonly prescribed beta-blockers in patients undergoing high-flux hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis (n=8) were recruited to an open label, pharmacokinetic, four-way crossover trial. Single doses of atenolol, metoprolol, bisoprolol, and carvedilol were administered on separate days in random order to each patient. Plasma and dialysate drug concentrations were measured, and dialyzability was determined by the recovery clearance and arterial venous difference methods. RESULTS: Using the recovery clearance method, the dialytic clearance values for atenolol, metoprolol, bisoprolol, and carvedilol were 72, 87, 44, and 0.2 ml/min, respectively (P<0.001). Applying the arterial venous difference method, the dialytic clearance values of atenolol, metoprolol, bisoprolol, and carvedilol were 167, 114, 96, and 24 ml/min, respectively (P<0.001). CONCLUSIONS: Atenolol and metoprolol are extensively cleared by hemodialysis compared with the negligible dialytic clearance of carvedilol. Contrary to estimates of dialyzability on the basis of previous literature, our data indicate that bisoprolol is also dialyzable. This finding highlights the importance of conducting dialyzability studies to definitively characterize drug dialytic clearance. PMID- 29519954 TI - Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients. AB - BACKGROUND AND OBJECTIVES: Dysregulated mineral metabolism is a common and potentially maladaptive feature of critical illness, especially in patients with AKI, but its association with death has not been comprehensively investigated. We sought to determine whether elevated plasma levels of the osteocyte-derived, vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23), are prospectively associated with death in critically ill patients with AKI requiring RRT, and in a general cohort of critically ill patients with and without AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured plasma FGF23 and other mineral metabolite levels in two cohorts of critically ill patients (n=1527). We included 817 patients with AKI requiring RRT who enrolled in the ARF Trial Network (ATN) study, and 710 patients with and without AKI who enrolled in the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study. We hypothesized that higher FGF23 levels at enrollment are independently associated with higher 60-day mortality. RESULTS: In the ATN study, patients in the highest compared with lowest quartiles of C-terminal (cFGF23) and intact FGF23 (iFGF23) had 3.84 (95% confidence interval, 2.31 to 6.41) and 2.08 (95% confidence interval, 1.03 to 4.21) fold higher odds of death, respectively, after adjustment for demographics, comorbidities, and severity of illness. In contrast, plasma/serum levels of parathyroid hormone, vitamin D metabolites, calcium, and phosphate were not associated with 60-day mortality. In the VALID study, patients in the highest compared with lowest quartiles of cFGF23 and iFGF23 had 3.52 (95% confidence interval, 1.96 to 6.33) and 1.93 (95% confidence interval, 1.12 to 3.33) fold higher adjusted odds of death. CONCLUSIONS: Higher FGF23 levels are independently associated with greater mortality in critically ill patients. PMID- 29519956 TI - Enhancing Health IT Functionality for Children: The 2015 Children's EHR Format. AB - Electronic health record (EHR) use throughout the United States has advanced considerably, but functionality to support the optimal care of children has been slower to develop and deploy. A previous team of experts systematically identified gaps in EHR functionality during collaborative work from 2010 to 2013 that produced the Children's EHR Format (Format), funded under the Children's Health Insurance Program Reauthorization Act of 2009, Public Law 111-3. After that, a team of practitioners, software developers, health policy leaders, and other stakeholders examined the Format's exhaustive list of 547 EHR functional requirements in 26 topic areas and found them to be valuable but in need of further refinement and prioritization. Work began in 2014 to develop a shortened high priority list of requirements and provide guidance to improve their use. Through a modified Delphi process that included key document review, selection criteria, multiple rounds of voting, and small group discussion, a multistakeholder work group identified and refined 47 items on the basis of earlier requirements to form the 2015 Children's EHR Format Priority List and developed 16 recommended uses of the Format. The full report of the Format enhancement activities is publicly available. In this article, we aim to promote awareness of these high priority EHR functional requirements for the care of children, sharpen industry focus on adopting these changes, and align all stakeholders in prioritizing specific health information technology functionalities including those essential for well-child preventive care, medication management, immunization tracking, and growth data for specific pediatric subgroups. PMID- 29519955 TI - The Role of the Microbiome in the Developmental Origins of Health and Disease. AB - Although the prominent role of the microbiome in human health has been established, the early-life microbiome is now being recognized as a major influence on long-term human health and development. Variations in the composition and functional potential of the early-life microbiome are the result of lifestyle factors, such as mode of birth, breastfeeding, diet, and antibiotic usage. In addition, variations in the composition of the early-life microbiome have been associated with specific disease outcomes, such as asthma, obesity, and neurodevelopmental disorders. This points toward this bacterial consortium as a mediator between early lifestyle factors and health and disease. In addition, variations in the microbial intrauterine environment may predispose neonates to specific health outcomes later in life. A role of the microbiome in the Developmental Origins of Health and Disease is supported in this collective research. Highlighting the early-life critical window of susceptibility associated with microbiome development, we discuss infant microbial colonization, beginning with the maternal-to-fetal exchange of microbes in utero and up through the influence of breastfeeding in the first year of life. In addition, we review the available disease-specific evidence pointing toward the microbiome as a mechanistic mediator in the Developmental Origins of Health and Disease. PMID- 29519957 TI - Analysis of chronic aortic regurgitation by 2D and 3D echocardiography and cardiac MRI. AB - PURPOSE: The study compares the feasibility of the quantitative volumetric and semi-quantitative approach for quantification of chronic aortic regurgitation (AR) using different imaging modalities. METHODS: left ventricular (LV) volumes, regurgitant volumes (RVol) and regurgitant fractions (RF) were assessed retrospectively by 2D, 3D echocardiography and cMRI in 55 chronic AR patients. Semi-quantitative parameters were assessed by 2D echocardiography. RESULTS: 22 (40%) patients had mild, 25 (46%) moderate and 8 (14%) severe AR. The quantitative volumetric approach was feasible using 2D, 3D echocardiography and cMRI, whereas the feasibility of semi-quantitative parameters varied considerably. LV volume (LVEDV, LVESV, SVtot) analyses showed good correlations between the different imaging modalities, although significantly increased LV volumes were assessed by cMRI. RVol was significantly different between 2D/3D echocardiography and 2D echocardiography/cMRI but was not significantly different between 3D echocardiography/cMRI. RF was not statistically different between 2D echocardiography/cMRI and 3D echocardiography/cMRI showing poor correlations (r<0.5) between the different imaging modalities. For AR grading by RF moderate agreement was observed between 2D/3D echocardiography and 2D echocardiography/cMRI and good agreement was observed between 3D echocardiography/cMRI. CONCLUSION: Semi-quantitative parameters are difficult to determine by 2D echocardiography in clinical routine. The quantitative volumetric RF assessment seems to be feasible and can be discussed as an alternative approach in chronic AR. However, RVol and RF did not correlate well between the different imaging modalities. The best agreement for grading of AR severity by RF was observed between 3D echocardiography and cMRI. LV volumes can be verified by different approaches and different imaging modalities. PMID- 29519958 TI - Role of the potassium/lysine cationic center in catalysis and functional asymmetry in membrane-bound pyrophosphatases. AB - Membrane-bound pyrophosphatases (mPPases), which couple pyrophosphate hydrolysis to transmembrane transport of H+ and/or Na+ ions, are divided into K+,Na+ independent, Na+-regulated, and K+-dependent families. The first two families include H+-transporting mPPases (H+-PPases), whereas the last family comprises one Na+-transporting, two Na+- and H+-transporting subfamilies (Na+-PPases and Na+,H+-PPases, respectively), and three H+-transporting subfamilies. Earlier studies of the few available model mPPases suggested that K+ binds to a site located adjacent to the pyrophosphate-binding site, but is substituted by the epsilon-amino group of an evolutionarily acquired lysine residue in the K+ independent mPPases. Here, we performed a systematic analysis of the K+/Lys cationic center across all mPPase subfamilies. An Ala -> Lys replacement in K+ dependent mPPases abolished the K+ dependence of hydrolysis and transport activities and decreased these activities close to the level (4-7%) observed for wild-type enzymes in the absence of monovalent cations. In contrast, a Lys -> Ala replacement in K+,Na+-independent mPPases conferred partial K+ dependence on the enzyme by unmasking an otherwise conserved K+-binding site. Na+ could partially replace K+ as an activator of K+-dependent mPPases and the Lys -> Ala variants of K+,Na+-independent mPPases. Finally, we found that all mPPases were inhibited by excess substrate, suggesting strong negative co-operativity of active site functioning in these homodimeric enzymes; moreover, the K+/Lys center was identified as part of the mechanism underlying this effect. These findings suggest that the mPPase homodimer possesses an asymmetry of active site performance that may be an ancient prototype of the rotational binding-change mechanism of F-type ATPases. PMID- 29519959 TI - P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity. AB - Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 (LRRK2) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations (N1437H, R1441C/G/H, Y1699C, G2019S), implicating hyperphosphorylation of a substrate in the pathogenesis of the disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in the disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and a substrate of LRRK2. Using mass spectrometry and phospho-specific antibodies, we found that LRRK2 phosphorylates p62 on Thr138 in vitro and in cells. We found that the pathogenic LRRK2 PD-associated mutations (N1437H, R1441C/G/H, Y1699C, G2019S) increase phosphorylation of p62 similar to previously reported substrate Rab proteins. Notably, we found that the pathogenic I2020T mutation and the risk factor mutation G2385R displayed decreased phosphorylation of p62. p62 phosphorylation by LRRK2 is blocked by treatment with selective LRRK2 inhibitors in cells. We also found that the amino-terminus of LRRK2 is crucial for optimal phosphorylation of Rab7L1 and p62 in cells. LRRK2 phosphorylation of Thr138 is dependent on a p62 functional ubiquitin-binding domain at its carboxy-terminus. Co-expression of p62 with LRRK2 G2019S increases the neurotoxicity of this mutation in a manner dependent on Thr138. p62 is an additional novel substrate of LRRK2 that regulates its toxic biology, reveals novel signaling nodes and can be used as a pharmacodynamic marker for LRRK2 kinase activity. PMID- 29519960 TI - Association between serum copper levels and cervical cancer risk: a meta analysis. AB - Whether serum copper levels were higher in patients with cervical cancer than that in controls was controversial. Hence, we conducted the present study to explore the relationship between serum copper levels and cervical cancer. We searched PubMed, WanFang, and China National Knowledge Internet (CNKI) for relevant studies before November 30, 2017. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to combine results across studies using the random-effect model. A total of 14 publications involving 747 patients with cervical cancer and 1014 controls were eligible through inclusion criteria. In comparison with controls, serum copper levels were significantly higher in patients with cervical cancer [summary SMD = 1.35; 95%CI: 0.10-2.59], with significant heterogeneity (I2 = 98.8%; P<0.001) was found. Significant association was also found among Asian populations [summary SMD = 1.39; 95%CI: 0.06-2.71]. The association was positive in subgroup analysis of population-based case-control studies (PBCC) [summary SMD = 1.64; 95%CI: 0.02-3.34], but not in hospital-based case-control studies (HBCC). Through a sensitivity analysis, we did not identify any single study to strongly influence the results of our serum copper levels and cervical cancer risk. No publication bias was found in our analysis. In conclusion, our study provided significant evidence of higher serum copper levels in patients with cervical cancer than in controls, suggesting that serum copper exposure was a risk factor on cervical cancer. PMID- 29519961 TI - [Practice Guideline for Dementia 2017; Critical Point of Revision]. AB - A revised version of guideline for dementia has been published in 2017 by the guideline committee under the supervision of Japanese Society of Neurology. This guideline was elaborated for 3 years, and introduces recent understanding of Alzheimer's pathoetiology and major diagnostic guidelines on dementia, being reported later than 2010. Furthermore, this guideline covers new diagnostic tests for dementia, therapeutic algorism for the use of anti-dementia drugs, and full description on the medical resource and social system for dementia care. We believe this new guideline can be a useful tool in daily clinical practice for dementia patients. PMID- 29519962 TI - [Prevention of Dementia-with Special Reference to Lifestyle and Vascular Risk Factors]. AB - There is a wide range of potentially modifiable risk factors for Alzheimer's disease and dementia, including cardiovascular risk factors (e.g. hypertension, diabetes, dyslipidemia, obesity, sleep-apnea syndrome), psychosocial factors (e.g., depression), health behaviors (e.g., low level of physical or mental activity, smoking status), and head trauma. In the elderly, weight loss associated with frailty and sarcopenia is another risk factor for dementia. Recent epidemiological studies have shown that the prevalence of dementia has declined in the US and European countries during the last 20 years. In addition to an increase in educational attainment, treatment and prevention of vascular risk factors may contribute to some extent of the decline in dementia prevalence. PMID- 29519963 TI - [Non-pharmacological Interventions to Treat Clinical Symptoms in Patients with Dementia]. AB - Previous systematic reviews of non-pharmacological interventions for clinical symptoms in dementia patients have confirmed the effectiveness of cognitive stimulation therapy (CST) for cognitive impairment, exercise therapy for activities of daily living, and music therapy and behavior management techniques for behavioral and psychological symptoms of dementia (BPSD). A Japanese version of CST has been developed and is available, but standardized exercise therapy and music therapy have not been developed. It is also important for informal and formal caregivers to learn behavior management techniques. Thus, attempts are being made to promote the use of behavior management techniques in Japan. It is further important to incorporate non-pharmacological interventions into the daily life of dementia patients and to prevent the development of BPSD. In Japan, these interventions are usually provided in care services for elderly people and are covered by the Japanese long-term insurance system. Thus, it is advisable for dementia patients to start using these care services before they develop BPSD. The effectiveness of non-pharmacological interventions in patients with diseases causing dementia other than Alzheimer's disease has not yet been assessed. PMID- 29519964 TI - [Pharmacologic Therapies for Different Types of Dementia]. AB - We provide a general overview of pharmacologic treatments for different types of dementia in light of the Guidelines on the Clinical Management of Dementia in Japan 2017, clinical data not addressed in those guidelines, and the results of observational studies, focusing mainly on the treatment of Alzheimer-type dementia. In everyday clinical practice, patients must be provided with personalized treatment that strikes a balance between evidence-based treatment, as described in the guidelines and actual clinical circumstances. PMID- 29519965 TI - [Social Systems and Resources for People with Dementia]. AB - In the Clinical Guidelines for Dementia 2017, the strategies to support persons with dementia and their families have increased significantly. This article provides a comprehensive and concise explanation of the importance of the newly launched systems and social resources. A new Five-Year Plan for promotion of Dementia Measures ("New Orange Plan") supports the realization of a society where persons with dementia are able to live with dignity as long as possible. New Medical Centers for Dementia provide specialized medical services and integrate community resources for building a comprehensive support network for persons with dementia. Dementia Support Doctors provide support and advice to the primary care doctors, who are able to facilitate multi-disciplinary collaboration in the community. General Support Centers in the community provide comprehensive support for the improvement of health and medical care, and promotion of education among the general public. Initial-phase intensive support team for dementia is a multi disciplinary team that organizes a support system for early detection and diagnosis of dementia, law against elderly abuse, and measures for younger-onset dementia. Demonstrating evidence on the significance and usefulness of these systems and social resources is an important issue for the future. PMID- 29519966 TI - [Use of Clinical Practice Guidelines in Daily Practice]. AB - Clinical practice guidelines aim to improve patients' outcomes by providing recommendations for key clinical issues with alternative care options. Improvement in healthcare quality can be expected by applying clinical practice guidelines to daily practice for appropriate decision-making by patients and practitioners. Integration of clinical practice guidelines with the original articles, textbooks, and experiences, together with the patient's personal situation, is essential for the appropriate use of clinical practice guidelines. PMID- 29519967 TI - [Medical Needs Survey on Neurological Disorders]. AB - The Japanese Society of Neurological Therapeutics and Japan Human Science Foundation jointly conducted the "Medical Needs Survey on Neurological Disorders" in 2013. This was the first survey focusing on the field of neurology, and provided important information such as an overview of unmet medical needs in neurological disorders for administrative agencies, industry, and academia. Follow-up surveillance will be conducted on summer or autumn in 2018. PMID- 29519968 TI - [Cortical Midline Structures: "Self" and "Pain"]. AB - Emerging evidence indicates that cortical midline structures (CMS) (which consist of the orbitomedial prefrontal cortex (OMPFC), dorsomedial prefrontal cortex (DMPFC), anterior cingulate cortex (ACC), and precuneus/posterior cingulate cortex (pC/PCC)) have a critical role in generating a model of the self. These regions also serve as hub regions for the default mode network (DMN) or salience network (SN). Furthermore, regions of the CMS overlap with pain-related regions such as the so-called "pain matrix," suggesting that pain has unique attributes compared to other sensations like vision. Previous studies have reported that disturbances of the CMS relate to chronic pain, as well as neurological and psychiatric diseases. The considerable overlap between regions involved in pain and those involved in self-cognition may provide important insights not only into the pathology of chronic pain and cognitive aspects of pain, but also for understanding self-representation in the brain. PMID- 29519969 TI - [An Autopsy Case of Meningoencephalitis and Cerebral Infarction that Developed with Ramsay Hunt Syndrome and Disseminated Herpes Zoster]. AB - We report here the clinical presentation and subsequent autopsy of a 90-year-old man who developed small papules with pain and swelling in his right ear. On admission, he exhibited right facial nerve paralysis, neck stiffness and Kernig's sign. The cell count was elevated and the varicella-zoster virus-PCR was positive in the CSF. Brain magnetic resonance imaging showed hyperintense lesions in the left pons and left temporal lobe, in FLAIR images. We diagnosed the patient with Ramsay Hunt syndrome and meningoencephalitis due to varicella-zoster virus. Although the symptoms of meningitis improved following treatment with intravenous acyclovir (750 mg/day initially, raised to 1,125 mg/day), 16 days after admission, he died suddenly due to gastrointestinal hemorrhage. The autopsy findings included lymphocytic infiltration of the leptomeninges and perivascular space of the cerebrum, and slight parenchyma in the left temporal lobe and insula, as the main histological features. Encephalitis due to varicella zoster virus has been recognized as a vasculopathy affecting large and small vessels. Pathological confirmation is rare in varicella zoster virus meningoencephalitis. PMID- 29519970 TI - Accuracy of the demirjian, willems and cameriere methods of estimating dental age on turkish children. AB - Background and Aim: Age estimation plays a significant role in forensic science, archeology, pediatric endocrinology and clinical dentistry. Tooth development is a reliable pathway for age estimation, especially in children. The aim of this study was to evaluate the accuracy of the Demirjian method (DM), Willems method (WM) and Cameriere method (CM). Materials and Methods: This study included panaramic radiographs of 330 individuals (165 girls, 165 boys) aged between 5 and 15.90 years. The differences between chronological age (CA) and the estimated dental age (DA) were statistically tested using a paired sample t-test and the Wilcoxon signed rank test. Results: The mean prediction error showed that; the DM overestimated the DA by 0.304 years, the WM underestimated the DA by -0.060 years and the CM underestimated the DA by -0.580 years. The difference between CA and estimated DA was not statistically significant according to WM (p = 0.074) and statistically significant according to DM and CM (p < 0.001). Conclusion: In conclusion, this study indicated that WM determines DA satisfactorily in a Turkish subpopulation. PMID- 29519972 TI - Relationship between salivary calprotectin levels and recurrent aphthous stomatitis: A preliminary study. AB - Aim: Recurrent aphthous stomatitis (RAS) is an inflammatory condition of the oral mucosa. The etiology of RAS remains unclear. Calprotectin is a major cytoplasmic protein contained in granulocytes, monocytes/macrophages and epithelial cells, and its level is increased body fluids in some inflammatory diseases. The aim is to determine the relationship between salivary calprotectin and RAS. Material and Methods: In the cross-sectional study, 67 patients with active lesions of RAS (F/M: 43/24, mean age: 30.27 +/- 9.14 years) and 42 healthy controls (HC, F/M: 30/12, 30.54 +/- 9.49 years) were included. Calprotectin levels were evaluated in unstimulated whole saliva samples by using the ELISA method in both groups. Results: Salivary calprotectin levels were significantly higher in RAS group (23.72 +/- 4.28 mg/L) compared to the HC group (21.59 +/- 4.27 mg/L) (P = 0.013). No significant relationship was found between calprotectin levels and age or gender in both groups (P >0.05). Conclusion: RAS is a very common inflammatory ulcerative condition of the oral cavity and its etiology is uncertain. Regarded as an inflammatory mechanism, releasing a high level of calprotectin in saliva has been suggested that it may play a role in pathogenesis of RAS. PMID- 29519971 TI - Turkish health field periodical editors' Views on publication process and ethical problems. AB - Objective: We aimed in this study to investigate views and suggestions of health field editors about the publication process and ethical problems. Materials and Methods: The study involved 42 journal editors who accepted to participate in the study. The data were collected through 70-item "Editor Views Questionnaire" which was developed by the researchers in line with the related literature. Results: The editors who participated in the study were asked about their views about the most common problems they encountered related to publication ethics; the top three problems indicated by the editors included unjustified authorship (40.5%), duplicate publication (33.3%), and falsification (26.2%). An analysis of the problems encountered in the initial evaluation stage revealed the top three issues as articles that did not follow the writing rules of the journal (33.3%), unqualified articles (30.1%), and negligence of the author(s) (14.3%). Views in relation to the problems about the referee evaluation stage included evaluations that were not completed within the time given (28.6%), insufficient importance attached to the evaluation (23.9%), and inability to find sufficient number of referees (16.7%). Conclusion: some editors were found to encounter violation of publication ethics, to experience problems in the revision stage, and not to feel fully independent in their contribution to article publication and thus the improvement of the journal quality. Identification of journal editors' views and problems is an important step for the solution to these problems; it could thus contribute to improving the quality of publication process and journal quality. PMID- 29519973 TI - Are roadside petrol dispensers at risk of oxidative stress? a study from gombe, North East Nigeria. AB - Background: Gasoline is one of the most frequently utilized chemicals whose use is on the increase. Exposure to the volatile constituents of gasoline generates free radicals leading to oxidative stress. This is associated with nucleic acid, lipids, and protein damages leading to chronic diseases including cancers. Occupational exposure to this product is of public health concern, especially in the developing countries where the awareness and enforcement of safety measures are not adequate. Materials and Methods: Plasma level of total antioxidant status (TAS) was compared between 90 roadside dispensers of gasoline and 90 age- and sex matched controls. TAS was measured using standard colorimetric method. Results: The mean age of the exposed and control groups is 29.03 +/- 3.7 and 29.24 +/- 3.5 years, respectively. The mean plasma TAS level of the exposed (0.60 +/- 0.33 mmol/L) was significantly (P < 0.001) lower than that of the controls (1.29 +/- 0.25 mmol/L). Conclusion: Our data have demonstrated higher level of oxidative stress in roadside dispensers of gasoline compared to the controls. This is an indication that roadside gasoline dispensers are probably at greater risk of developing chronic diseases associated with increased oxidative stress. Antioxidant supplementation may be of benefit to the roadside gasoline dispensers. Legislation on roadside gasoline dispensing should be enforced to reduce the incidence of long-term complications from repeated exposures. PMID- 29519974 TI - The effect of endodontic irrigants on the microtensile bond strength of different dentin adhesives. AB - Objectives: The aim of this study was to determine the influence of irrigants on bond strength of adhesive systems. Materials and Methods: Superficial dentin surfaces of 60 extracted molars were divided into 15 groups, according to irrigants and adhesives. In the control groups, surfaces were irrigated with distilled water. In experimental groups, sodium hypochlorite (NaOCl), ethylenediaminetetraacetic acid (EDTA) + NaOCl, chlorhexidine (CHX), and NaOCl + sodium ascorbate were used as irrigants. Resin composites were then built up using Single Bond, Clearfil SE Bond, and Xeno 3 as adhesives. The microtensile bond strength of groups was determined. Data were statistically analyzed by two way analysis of variance (ANOVA), one-way ANOVA, and the Bonferroni test. Results: NaOCl reduced bond strength of Single Bond and Clearfil SE Bond (P < 0.01). For all adhesive systems, EDTA + NaOCl-treated groups exhibited lower bond strength than control groups (P < 0.01). CHX decreased bond strength of Single Bond (P < 0.01). Application of sodium ascorbate improved compromised bond strength to NaOCl-treated dentin (P < 0.01). Conclusion: Different irrigants had several effects on bonding of different adhesives. Sodium ascorbate after NaOCl could restore compromised bond strengths. PMID- 29519975 TI - The efficiency of different irrigation solutions and techniques for the removal of triple antibiotic paste from simulated immature root canals. AB - Introduction: The purpose of this study was to evaluate the efficiencies of different irrigation protocols in the removal of triple antibiotic paste (TAP) from root canals. Materials and Methods: A total of 127 extracted human maxillary incisor teeth were prepared. Then, root-end resection of 3 mm was accomplished to simulate immature apex model. The root canals were filled with TAP, after 21 days, randomly divided into nine groups according to irrigation systems and solutions (n = 13). Conventional irrigation (CI) groups - Group 1: Root canal irrigation was performed with CI by Peracetic acid (PAA) solution, Group 2: Root canal irrigation was performed with CI by etidronic acid 1-hydroxyethylidene-1, 1 bisphosphonate (HEBP) + sodium hypochlorite (NaOCl) solution, Group 3: Root canal irrigation was performed with CI by ethylenediaminetetraacetic acid (EDTA)/NaOCl solutions. Vibringe system groups - Group 4: Root canal irrigation was performed with Vibringe system by PAA solution, Group 5: Root canal irrigation was performed with Vibringe system by HEBP + NaOCl solution, Group 6: Root canal irrigation was performed with Vibringe system by EDTA/NaOCl solution. EndoVac system groups - Group 7: Root canal irrigation was performed with EndoVac system by PAA solution, Group 8: Root canal irrigation was performed with EndoVac system by HEBP + NaOCl solution, Group 9: Root canal irrigation was performed with EndoVac system by EDTA/NaOCl solution. Control Group: (n = 0). Samples were sectioned vertically, and the amount of remaining medicament was scored for each root half and data were statistically analyzed. Results: Among the irrigation systems, CI groups showed the highest scores at both apical and coronal parts (P < 0.05). In comparisons among the solutions, at the apical part, PAA groups showed the highest scores (P < 0.05). At the coronal part, EDTA + NaOCl groups showed the lowest score values (P < 0.05). Conclusion: The use of irrigation systems improved the removal of TAP from the simulated immature root canals. Also, as an irrigation solution EDTA gives more promising results than PAA and HEBP solutions. PMID- 29519976 TI - E-learning readiness from perspectives of medical students: A survey in Nigeria. AB - Context: Learning in the medical school of the study university is still by the traditional face-to-face approach with minimal e-communication. Aim: This paper assesses student's perspectives of E-learning readiness, its predictors and presents a model for assessing them. Settings and Design: A descriptive cross sectional study of medical students. Subjects and Methods: By proportional quota sampling 284 students responded to a semi-structured self-administered questionnaire adapted from literature. Ethical issues were given full consideration. Statistical Analysis Used: Analysis was with SPSS version 20, using descriptive statistics, ANOVA, Spearman's correlation, and multiple regression. Statistical significance was considered at P < 0.05. Results: Medical students are ready for E-learning (Mlr = 3.8 > Melr = 3.4), beyond reliance on the face-to-face approach (69.7%), expecting effective (51.1%), and quality improvement in their learning (73.1%). Having basic information and communications technology skills (68.9%) (Mict = 3.7 > Melr = 3.4), access to laptops (76.1%), ability to use web browsers confidently (91.8%) (Mwb = 4.3 > Melr = 3.4), with only few able to use asynchronous tools (45.5%), they consider content design important to attract users (75.6%), and agree they need training on E-learning content (71.4%). They however do not believe the university has enough information technology infrastructure (62.4%) (Mi = 2.7 < Melr = 3.4) nor sufficient professionals to train them (M = 2.9). Predictors are attitude, content readiness, technological readiness, and culture readiness. The model however only explains 37.1% of readiness in the population. Conclusions: Medical students in this environment are ready to advance to E-learning. Predicted by their attitude, content, technological and cultural readiness. Further study with qualitative methodology will help in preparing for this evolution in learning. PMID- 29519977 TI - Health of periodontal tissues and resorption status after orthodontic treatment of impacted maxillary canines. AB - Objective: The aim of the present study was to evaluate the changes of incisor root resorption associated with impacted maxillary canines and health of periodontal tissues around maxillary canines erupted with orthodontic treatment. Materials and Methods: Twenty patients with a unilateral palatally impacted maxillary canine were included in the study. Cone-beam computed tomography images taken before and after orthodontic treatment were compared with the contralateral canines serving as control teeth. Results: Root resorption was present in 10% of central and 40% of lateral incisors before treatment. After treatment, the incidence of resorption decreased. The thickness of the buccal bone surrounding the impacted canines was similar to that surrounding the contralateral canines, except in the apical area. Periodontal pocket depth and alveolar bone loss were greater for the impacted canine teeth than for the contralateral canines. Conclusions: Incisor root resorption associated with impacted canine teeth showed signs of repair after orthodontic treatment. Slight differences related to periodontal health were found between the previously impacted teeth and contralateral canine teeth. PMID- 29519978 TI - The In vitro Evaluation of the effect of xyliwhite, probiotic, and the conventional toothpastes on the enamel roughness and microhardness. AB - Aim: The aim of this study was to evaluate the effect of fluoride, Xylitol, Probiotic, and Whitening toothpastes on the permanent teeth enamel roughness and microhardness. Materials and Methods: One hundred and twenty teeth were randomly divided into 2 groups, each group having 60 samples. G1: The group in which enamel roughness was examined (n = 60). G2: The group in which enamel microhardness was examined (n = 60). Then, these groups were randomly divided into 4 groups among themselves (n = 15). Each group was brushed using four different toothpastes for 1 week with a battery-powered toothbrush in the morning and evening for 2 min. Vicker's hardness tester was used to measure the changes in microhardness, and the profilometer was used to measure the changes in surface roughness. Results: No statistically significant differences were found on surface roughness and microhardness values measured after tooth brushing process in group brushed with Colgate MaxFresh toothpaste (P > 0.01). Statistically significant decrease was observed on Vicker's hardness values measured after tooth brushing process in groups brushed with Ipana White Power Carbonate toothpaste, Xyliwhite Toothpaste Gel, and Periobiotic Probiotic Toothpaste (P < 0.01). Statistically significant increase was observed on surface roughness values in groups brushed with Ipana White Power Carbonate toothpaste, Xyliwhite Toothpaste Gel, Periobiotic Probiotic Toothpaste (P < 0.01). Conclusions: As a result, Colgate MaxFresh abrasive-free toothpaste with fluoride has no effect on permanent tooth enamel surface roughness and microhardness. Xyliwhite, Periobiotic, and Ipana White Power Carbonate-containing abrasive toothpastes led to changes negatively on permanent tooth enamel surface roughness and microhardness. PMID- 29519979 TI - Is there A Relationship between route of delivery, perinatal characteristics, and neonatal outcome in preterm birth? AB - Background: Preterm birth is one of the most challenging problems in obstetric care and it is closely related to perinatal mortality and morbidity. The aim of the current study was to document our experience with preterm births and to analyze the association between perinatal variables and clinical outcomes. Methodology: In this retrospective study, data were derived from the medical records of 785 singleton preterm births delivered in the obstetrics and gynecology department of our institution. Variables under investigation were maternal and gestational ages, fetal gender, route of delivery (vaginal vs. cesarean section [C/S]), causes of preterm birth, birth weight, placental weight, umbilical cord length, and Apgar scores at the 1st and 5th min. Results: Pregnant women with advanced age (>=35 years) were more likely to undergo C/S (P < 0.001). Apgar score at the 1st and 5th min was influenced significantly by gestational age (P < 0.001), newborn birth weight (P < 0.001), placental weight (P < 0.001), and umbilical cord length (P < 0.001). Infants delivered due to antepartum fetal distress indication had remarkably lower Apgar scores at the 1st min and the birth weight seemed to be positively correlated with Apgar scores at both 1st (P < 0.001) and 5th min (P < 0.001). Apgar scores both at the 1st and 5th min were positively correlated with placental weight (R: 0.239 and 0.231, respectively, and P < 0.001 for both) and length of umbilical cord (R:0.228 and 0.211, respectively, and P < 0.001 for both). Conclusion: Advanced age pregnancies have higher C/S rates, but Apgar scores are significantly correlated with infant characteristics. Umbilical cord length and placental weight might be the new add on predictors of postpartum well-being in premature infants. PMID- 29519980 TI - Dentists' Attitudes and perceptions toward protective mouthguards. AB - Objectives (Background): Risk of dental injury from contact sports can be prevented by the use of mouthguards. Dentists provide excellent information regarding mouthguards. Thus, the aim was to assess the awareness among dentists regarding the same, the level of training in fabricating a mouthguard and whether they regularly recommend one for their athletically active patients. Materials and Methods: This institutional cross-sectional survey was conducted in the Department of Orthodontics, Government Dental College, Kottayam, and Kerala, India. An online form was sent out to 1500 offices and departments in dental institutions through email with a time period of 1 month given to fill responses and was analyzed using descriptive statistics. Results: A response from 640 was recorded; most of them had not received or had fabricated a mouthguard during their dental training or private practice, even though one-third recommended one to their athletically active patients with a lack of formal training being the reason for not routinely advocating mouthguard usage. Most were aware of more than one type of mouthguards and recommended customized one for the same, however, more than half were not aware of a different type intended for orthodontic patients. Conclusion: It is not a routine practice currently, among general dentists and specialists alike, in our country, to prescribe a mouthguard. It is time that the dental fraternity spread awareness for the prevention of injuries. A relook into the academic curriculum while advocating the use of customized mouthguards to patients due to contact sports is required. PMID- 29519981 TI - Dentists knowledge of lipid treatment of local anaesthetic systemic toxicity. AB - Context: : Local anesthetics (LAs) are in widespread use by dental practitioners, and erroneous administration, such as intravenously or exceeding the maximum dose, can cause the life-threatening condition of local anesthetic systemic toxicity (LAST). Aims: The objective of the present study was evaluate the ability of dentists to recognize signs of LAST and quantify how often they have used lipids to treat LAST in dentistry patients. Materials and Methods: The study administered 600 questionnaires that asked about the frequency with which dentists encountered LAST and the symptoms of LAST and its treatment, especially with lipids. Results: The results showed that 520 (86.66%) respondents had never seen LAST, and 404 (67.3%) had no idea about lipid treatment. In addition, 128 (21.3%) had heard about lipid treatment but had inadequate knowledge of it and 59 (9.8%) had read an article about lipid treatment, but only 9 (1.5%) knew how to use lipid treatment. Finally, 80 (13.33%) participants had seen LAST but had used a treatment other than lipids. Conclusion: Dentists and all facilities using LA must be aware of LAST, and knowledge of lipid treatment must be increased by education. Twenty percent lipid solutions must be kept handy in their offices by dentists. PMID- 29519982 TI - Nonspecific abdominal pain: A follow-up survey. AB - Introduction: Little data have been published on the outcome of patients discharged from the emergency department (ED) after being diagnosed with nonspecific abdominal pain (NSAP). This study aimed to investigate short-term follow-up of patients discharged with a diagnosis of NSAP from the ED. Materials and Methods: This prospective, observational study was conducted in the University-based ED and enrolled all consecutive adult patients who were diagnosed as NSAP out of patients presented with abdominal pain (AP). The main outcome measure was the presence of recurrent AP resulting in referral to the ED and specific diagnoses within the first 3- and 90-day postdischarge. On the 3rd and 90th days, all patients discharged with NSAP from the ED were asked questions, and their response entered into a questionnaire. Results: A total of 684 patients presented with AP, of which 299 (46%) had a diagnosis of NSAP within the 4-month period. Fifty cases (16%) could not be included due to inability to access. Eighty-one out of 249 patients (32.5%) complained of recurrent AP within the first 3 days. Twenty-two cases (8.8%) were readmitted to ED once again in the meantime, and ten received specific diagnoses including three with acute abdomen. Within 90 days, additional nine patients out of 20 (45%) with recurrent AP received specific diagnoses including two with acute abdomen. Conclusions: Certain specific underlying entities can be missed in patients considered to have NSAP and discharged from the ED. Adherence to timely follow-up and repeated examinations are of vital importance in these patients. PMID- 29519983 TI - The evaluation of stress patterns in porcelain laminate veneers with different restoration designs and loading angles induced by functional loads: A three dimensional finite element analysis study. AB - Background: Fractures in porcelain laminate veneers (PLVs) are a significant clinical problem. Preparation designs can affect stress distribution, which leads to fractures in PLVs. Therefore, identification of the most favorable preparation design in terms of stress distribution is required. Objective: The purpose of this study is to examine the functional stress patterns of PLVs with featheredge, incisal bevel, and overlapped preparation designs under 0 degrees , 60 degrees , and 120 degrees functional loads using finite element analysis. Materials and Methods: Porcelain veneers with three different preparation designs (incisal overlap, incisal bevel, and featheredge) were modeled. A cement layer of 100 MUm of luting composite resin was assumed, and a thickness of 0.5 mm of porcelain veneers was used. All models were loaded at 0 degrees , 60 degrees , and 120 degrees to the long axis of the tooth to determine the stresses that may occur during mastication under different load angulations. A total force of 200 N was applied from the incisal edge of the models. Results: Maximum stresses were recorded in the incisal overlapped design (53.3 MPa) under 120 degrees of functional load. Minimum stresses were recorded in the incisal bevel preparation design (22.37 MPa) under 0 degrees of functional load. Conclusion: Both the preparation design and load angle affected the stress distribution on the PLVs. The incisal bevel preparation design provided a more appropriate geometry for stress distribution compared with the other techniques. Lateral forces produced more stress on the tooth and laminate material than vertical forces. PMID- 29519984 TI - Patient Self-reported quality of life assessment in Type 2 diabetes mellitus: A pilot study. AB - Background: Quality of life (QoL) is an important outcome measure to assess the diabetic care and is increasingly replacing the traditional indicators of health. Aim: The aim is to evaluate the QoL in patients with type 2 diabetes mellitus (DM) using a third generation individualized QoL instrument like an audit of diabetes-dependent QoL (ADDQoL) questionnaire and to determine the predictors. Materials and Methods: Patients who met the inclusion and exclusion criteria were recruited from a tertiary care hospital by convenience sampling. Sociodemographic and other relevant details were collected from the study patients, and ADDQoL questionnaire were administered to them. Results: A total of 200 patients were included in the study among which 66% of patients had uncontrolled type 2 DM as suggested by their glycated hemoglobin (HbA1c) values. The mean QoL score was 0.07 (0.91) and diabetes-dependent QoL was -1.33 (0.58). Approximately 38% were associated with poor health-related QoL with a mean average weighted impact score of -0.51 (0.51). Most frequently affected life domain was the freedom to eat. A positive correlation was observed between QoL and gender, age, domicile, education status, occupation, family structure, duration of type 2 DM, HbA1c, insulin treatment, and the presence of comorbidities. Conclusion: The study highlights the impact of type 2 DM on QoL. Improving QoL of type 2 diabetic patients is important and knowledge of these preventable risk factors help to implement strategies to better management of type 2 DM and ultimately improve therapeutic outcome. PMID- 29519985 TI - Effects of Postsurface Treatments Including Femtosecond Laser and Aluminum-oxide Airborne-particle Abrasion on the Bond Strength of the Fiber Posts. AB - Context: Bond strength of fiber posts. Aims: The purpose of this study was to evaluate the effect of different Post Surface treatment techniques on the push out bond strength of the quartz fiber posts. Subjects and Methods: A total of 30 maxillary central incisors were decoronated at cementoenamel junction. Root canals were filled and postspaces were prepared. The specimens were classified into three groups according to the surface treatment performed to the postsurface (n = 10) as no surface treatment (control group) (Group 1), A 50-MUm aluminum oxide airborne-particle abrasion group (Group 2), femtosecond laser (FS) group (Group 3). A self-curing adhesive cement was used for cementation of posts. Six sections (two coronal, two middle, and two apical) of 1-mm thickness specimens were prepared with a slow speed diamond saw. Specimens were stored in distilled water at 37 degrees C for 24 h. Then, push-out test was performed on a universal testing machine. Results: The data were analyzed by one-way ANOVA (alpha = 0.05). The test results indicated that push-out test values significantly different according to surface treatments among groups (P < 0.05). There were no significant differences between root sections of each group for bond strength (P > 0.05). All dislodged Group 3 posts were free of cement, indicating adhesive failure, Group 1 and 2 were partially coated with cement, indicating a mixed failure at the cement/postsurface. Conclusions: Based on the results, aluminum oxide airborne-particle abrasion group showed higher and FS irradiation group showed lower bond strength values. Push-out bond strength values of the root segments were the same in all groups. PMID- 29519986 TI - A study on shotgun injuries to the craniomaxillofacial Region in a Nigerian Tertiary Health Center. AB - Context: Short-range shotgun wounds of the craniomaxillofacial region are life threatening and are as devastating as military rifle wounds. Aims: This study aimed to evaluate the pattern of presentation of craniomaxillofacial shotgun injuries, types of shotgun injuries, and the outcome of treatments in our environment. Setting and Design: This is a prospective observational study. Materials and Methods: This is a prospective observational study conducted from February 2006 to March 2012. All patients with shotgun wounds to the craniomaxillofacial region were included in the study by convenient sampling method. Glezer's shotgun classification scheme was used to categorize the patients into short-, intermediate-, and long-range shotgun wounds. Data collected were analyzed using SPSS version 16. Statistical Analysis Used: Descriptive statistics were used to calculate the data. Mean and standard deviation (SD) were calculated for all quantitative variables such as age. Frequency and percentages were presented for qualitative variables. Results: A total number of 28 patients were seen. Ages ranged from 19 to 64 years with a mean (+/-SD) of 32.7 (+/-11.4) years. The two most commonly used shotguns were locally made pistol (25, 42.9%) and the cut-size gun (10, 35.7%) and the least commonly used was Dane gun (1, 3.6%). Close-range injury to the face was 17 (60.7%) while that of intermediate- and long-range injuries were 6 (21.1%) and 5 (17.9%), respectively. Conclusion: Wounds sustained from close-range shotguns to the face were the most common in this environment. The outcome of treatment was satisfactory when treated with conservative debridement and early reconstruction. PMID- 29519987 TI - Is medial calcar continuity necessary in plate osteosynthesis for proximal humerus fractures? AB - Objective: To evaluate the functional and radiological results of patients with and without medial calcar continuity in plate osteosynthesis applied for a proximal humerus fracture retrospectively. Methods: The study included 27 patients to whom plate osteosynthesis was applied because of a proximal humerus fracture between January 2, 2010, and December 30, 2013, at Okmeydani Research and Training Hospital. Patients were separated into Group A with medial calcar continuity and Group B without medial calcar continuity. On the radiographs taken postoperatively and at the final follow-up examination, measurements were taken of the humeral head height and the humeral neck-shaft angle. The presence of avascular necrosis was recorded. Results: The functional and radiological results of the patients were evaluated after a mean follow-up of 39.1 months. No statistically significant difference was determined between Groups A and B in respect of the postoperative and the final follow-up humeral head height (P > 0.05). No statistically significant difference was determined between Groups A and B in respect of the postoperative and the final follow-up humeral neck-shaft angle (P > 0.05). Plate breakage was seen in one patient without medial calcar continuity. Penetration of the screw into the joint was determined in one patient in Group A and three patients in Group B. No avascular necrosis or infection was seen in any patient. Conclusion: When the surgical process has not damaged the soft tissue and sufficient stability has been achieved, providing calcar continuity is not an absolute condition. PMID- 29519988 TI - Effect of adhesive resin cements on bond strength of ceramic core materials to dentin. AB - Objectives: The aim of the present study was to evaluate the effects of self-etch and self-adhesive resin cements on the shear bond strength of ceramic core materials bonded to dentin. Materials and Methods: Extracted, caries-free, human central maxillary incisor teeth were selected, and the vestibule surfaces were cut flat to obtain dentin surfaces. Ceramic core materials (IPS e.max Press and Prettau Zirconia) were luted to the dentin surfaces using three self-etch adhesive systems (Duo-Link, Panavia F 2.0, and RelyX Ultimate Clicker) and two self-adhesive resin systems (RelyX U200 Automix and Maxcem Elite). A shear bond strength test was performed using a universal testing machine. Failure modes were observed under a stereomicroscope, and bonding interfaces between the adhesive resin cements and the teeth were evaluated with a scanning electron microscope. Data were analyzed with Student's t-test and one-way analysis of variance followed by Tukey's test (alpha = 0.05). Results: The type of adhesive resin cement significantly affected the shear bond strengths of ceramic core materials bonded to dentin (P < 0.05). Significant differences were noted between the ceramic core materials when the specimens were luted with self-adhesive resin cements (P < 0.05). The specimens luted with RelyX Ultimate Clicker had the highest shear bond strengths. Conclusion: The self-etch adhesive resin cements exhibited better shear bond strength than the self-adhesive resin cements, except for Panavia cement in the IPS e.max Press group. However, shear bond strengths of the self-adhesive resin cements were dependent on the nature of the ceramic core materials. PMID- 29519989 TI - Helicobacter pylori and precancerous lesions of the stomach in a Nigerian Metropolis: A Cohort Study. AB - Introduction: Helicobacter pylori (H. pylori)-related atrophic gastritis transits through a sequential pathway of intestinal metaplasia, dysplasia to gastric cancer. Gastroscopy offers early detection, treatment and surveillance of gastric cancer. Aims: This study aims to study the prevalence of H. pylori infection and evaluate precancerous lesions (PCLs) of the stomach. Patients and Methods: This is a case controlled study of patients with dyspepsia undergoing gastroscopy at a referral endoscopy facility in Port Harcourt metropolis of Nigeria. The variables studied included demographics, clinical, endoscopic, and histopathologic findings. Statistical analysis of data was done using IBM SPSS Statistics for Windows, Version 20.0. (Armonk, NY, USA). Results: A total of 104 patients were included in the study. Age ranged from 20 to 80 years (mean 47.1 +/- 14.4 years); 56 were males and 48 were females. H. pylori were detected in 40 (38.5%) mucosal biopsies. The prevalence of PCLs was: chronic atrophic gastritis 6.7% (7 cases); intestinal metaplasia 2.9% (3 cases); and dysplasia 5.8% (6 cases). There was no statistical significance in sex distribution of PCLs (P = 0.245). Conclusion: There is a low prevalence of H. pylori in this metropolitan population. Mandatory multiple topographically targeted biopsies, even with normal mucosal appearance, at gastroscopy in addition to surveillance of PCL are recommended for early detection of gastric cancer. PMID- 29519990 TI - In vitro Fracture strength and hardness of different computer-aided design/computer-aided manufacturing inlays. AB - Objective: The purpose of this study was to examine the fracture strength and surface microhardness of computer-aided design/computer-aided manufacturing (CAD/CAM) materials in vitro. Materials and Methods: Mesial-occlusal-distal inlays were made from five different CAD/CAM materials (feldspathic ceramic, CEREC blocs; leucite-reinforced ceramic, IPS Empress CAD; resin nano ceramic, 3M ESPE Lava Ultimate; hybrid ceramic, VITA Enamic; and lithium disilicate ceramic, IPS e.max CAD) using CEREC 4 CAD/CAM system. Samples were adhesively cemented to metal analogs with a resin cement (3M ESPE, U200). The fracture tests were carried out with a universal testing machine. Furthermore, five samples were prepared from each CAD/CAM material for micro-Vickers hardness test. Data were analyzed with statistics software SPSS 20 (IBM Corp., New York, USA). Results: Fracture strength of lithium disilicate inlays (3949 N) was found to be higher than other ceramic inlays (P < 0.05). There was no difference between other inlays statistically (P > 0.05). The highest micro-Vickers hardness was measured in lithium disilicate samples, and the lowest was in resin nano ceramic samples. Conclusion: Fracture strength results demonstrate that inlays can withstand the forces in the mouth. Statistical results showed that fracture strength and micro Vickers hardness of feldspathic ceramic, leucite-reinforced ceramic, and lithium disilicate ceramic materials had a positive correlation. PMID- 29519991 TI - Volar percutaneous screw fixation for scaphoid nonunion. AB - Background: Percutaneous screw fixation is widely used in acute fractures of the scaphoid. In this study, we aimed to present our results with volar percutaneous screw fixation in patients with scaphoid nonunions. Methodology: A total of 12 patients with scaphoid nonunion (>=13 weeks) that underwent volar percutaneous screw fixation were evaluated retrospectively. Two of the patients were female, and 10 were male. Mean age was 27 years (range = 19-41). The mean time that elapsed between the fracture and surgical procedure was 7.5 months (range = 4 12). According to the anatomic location, 33.3% were proximal pole, and 67.7% were waist fractures. All of the patients underwent percutaneous fixation with a headless cannulated screw from volar part under fluoroscopic guidance. Clinical evaluation was performed according to the modified mayo wrist scoring system (MMWS). The absence of a radiolucent fracture line on the radiographs was considered "union" on radiological evaluation. Results: The mean follow-up time was 18 weeks (range = 8-36). Union was achieved in all patients (91.6%), except one. The mean time to union was 15.5 weeks (range = 8-30). Based on MMWS system, 8 patients were interpreted as excellent, 3 patients as good. Conclusion: Percutaneous fixation in appropriate patients provides satisfactory results with high union and minimal complication rates in scaphoid nonunions. PMID- 29519992 TI - Pulmonary extranodal marginal zone B-cell lymphoma of mucosa-associated lymph tissue: A case report and literature review. AB - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymph tissue (MALT lymphoma) is a rare subtype of marginal zone B-cell lymphoma. Most primary MALT lymphoma occurs in the stomach, while lung is an uncommon site of MALT lymphoma. We herein report a case of MALT lymphoma in a 44-year-old female who underwent a pulmonary lobectomy and received rituximab plus CHOP chemotherapy regimen. The patient had an uneventful postoperative course and a good prognosis without tumor recurrence for 3 years. PMID- 29519993 TI - Idiopathic multiple eruptive milia: Report of a case in a nigerian woman. AB - Milia are multiple, small, benign keratin-filled superficial epidermoid cysts which are classified as primary when they occur spontaneously or secondary when they result from skin trauma or disease. Multiple eruptive milia (MEM) refer to a condition characterized by a sudden eruption of a large number of milia. MEM may be familial, occur as part of a genodermatosis, or occur spontaneously when they are termed idiopathic. Idiopathic MEM are an exceedingly rare disease. We present the case of a 70-year-old Nigerian woman with idiopathic MEM. PMID- 29519994 TI - Laparoscopy in the management of lumboperitoneal shunt catheter in obese patients with pseudotumor cerebri. AB - Lumboperitoneal shunts are widely used for the treatment of patients diagnosed with pseudotumor cerebri (PTC). Obesity is a risk factor for PTC. In particular, catheter migration out of the abdominal cavity is more commonly observed in morbidly obese patients. The aim of this study was to discuss the underlying mechanisms of catheter migration and treatment modalities in morbidly obese patients with PTC. The present study included four morbidly obese patients. All cases had undergone the previous laparotomy for insertion of a distal catheter into the abdominal cavity. In three cases, migration of the distal catheter out of the abdominal cavity was observed. Migration of the proximal tip of the catheter out of the spinal canal was observed in the fourth case. In all cases, laparoscopic revision surgeries were performed. During revision surgery, a catheter tunnel was prepared immediately over the external oblique fascia to obtain the shortest and deepest tunnel, and a distal catheter was inserted by laparoscopic guidance posterolaterally, i.e., through the postaxillary line. None of the patients developed any complications during the follow-up period of 4 years. We recommend laparoscopic insertion of distal catheters through the postaxillary line into the abdominal cavity using as short a catheter route as possible. Thus, tension and traction on the catheter due to abdominal movements can be decreased in morbidly obese patients to prevent catheter migration. PMID- 29519995 TI - Clinical Features, Treatment and Prognostic Factors of Post-Transplant Immunoglobulin A Nephropathy. AB - BACKGROUND Initially described as a relatively benign condition, recent studies report graft loss in up to 50% of the patients with post-transplant IgA nephropathy. There is no evidence for the best therapeutic approach, and prognostic factors remain to be elucidated. MATERIAL AND METHODS Single center retrospective analysis of patients >12 years old, with clinically relevant post transplant IgA nephropathy (proteinuria >=1.0 g/g and/or graft dysfunction) and >=6 months follow-up after diagnosis (n=47). RESULTS Living donor transplants represented 85% of cases. Dysmorphic hematuria (100%), blood pressure elevation (95.7%), renal dysfunction (70.2%) and subnephrotic proteinuria (60.6%) predominated at presentation. Using the Oxford Classification, mesangial proliferation was the main histological lesion (91%). Treatment consisted mostly of blockade of the renin angiotensin system (89.4%) and modification of immunosuppression (85.1%), mainly by increasing oral steroids dose (83%), with venous pulse therapy in 63.8% of cases. Partial and complete remission occurred in 48.9% and 17% of cases, respectively. One patient died (sepsis) and 15 patients (31.9%) lost their grafts due to nephropathy. The percentage of decrease in glomerular filtration rate at diagnosis was independently associated with partial remission (HR 0.97, 95% CI 0.94-0.99, p=0.01) and graft loss (HR 1.13, 95% CI 1.06-1.20, p<0.001). Deceased donor (HR 28.04, 95% CI 4.41-178.39, p<0.001) and donor age (HR 1.1, 95% CI 1.04-1.16, p=0.001) were also risk factors for graft loss. CONCLUSIONS Despite treatment, most patients with post-transplant IgA nephropathy in this cohort study presented unfavorable outcomes, and graft dysfunction at diagnosis appeared to be the main prognostic marker. PMID- 29519996 TI - Sterile Bronchopleural Fistula Following Surgical Removal of Primary Lung Leiomyoma Inducing Secondary Hypertrophic Osteoarthropathy. AB - BACKGROUND Leiomyomas are benign neoplasms of the smooth muscle. When found in the pulmonary system, a rare occurrence, leiomyomas can result in hypertrophic osteoarthropathy, or significant clubbing, associated with proliferation of long bone periosteum. Bronchopulmonary fistulas, or communications between the bronchial tree and pleural space, are an uncommon postoperative complication of pneumonectomies. Even more infrequent is the presence of a bronchopulmonary fistula that is determined to be sterile. CASE REPORT The patient presented in the current case report is a 40-year-old previously healthy woman who presented with a 5-year history of chronic cough, right-sided chest discomfort, and dyspnea associated with back pain, and lower leg pain. The CT scan performed on the patient revealed a mass originating from the right lower lobe. Activity at the site of the lesion, in the long bones of the upper and lower limbs, rib cage, and vertebral bones was demonstrated by a bone scan. A CT-guided biopsy was performed, and the pathology report confirmed the presence of a leiomyoma. Following a right-sided lobectomy, the resected tumor was sent for histopathology, with the results confirming the biopsy. The patient subsequently presented with a history of persistent cough associated with increased watery secretions. The CT scan revealed the presence of a bronchopleural fistula, after which the patient underwent surgical correction. All symptoms resolved, and the patient was discharged in stable condition. CONCLUSIONS Here, we report on a patient who presented with 3 rare clinical findings: pulmonary leiomyoma, hypertrophic osteoarthropathy, and sterile bronchopulmonary fistula. PMID- 29519997 TI - Overexpression of Nitrogen Permease Regulator Like-2 (NPRL2) Enhances Sensitivity to Irinotecan (CPT-11) in Colon Cancer Cells by Activating the DNA Damage Checkpoint Pathway. AB - BACKGROUND Colorectal cancer (CRC) is the third most common cancer worldwide, making it is a serious threat to human health. It is imperative to develop new therapeutics to improve the CRC treatment efficiency. The aim of this study was to investigate the role of NPRL2 in improving sensitivity to CPT-11 in colon cancer cells. MATERIAL AND METHODS NPRL2 overexpression was established by transfecting the recombinant lentivirus-encoding NPRL2 gene into HCT116 colon cancer cells. Cell proliferation was identified using Cell Counting Kit-8 (CCK8) assay. Cell cycle and apoptosis were examined by flow cytometry. An immunofluorescence staining assay was conducted to examine the expression of gamma-H2AX. Wound-healing and Transwell assays were utilized to show cell migration and invasion capability. The expression of apoptosis-related proteins (cleaved caspase-3, caspase-9, cleaved PARP, BAX, and Bcl-2), invasion-related proteins (MMP2, MMP9, p-PI3K, and p-AKT), and DNA damage checkpoint pathway proteins (p-ATM, p-Chk2, Cdc25C, Cdc2, and Cyclin B1) were quantified by Western blotting. RESULTS A CCK8 assay revealed that the overexpression of NPRL2 improved the sensitivity of CPT-11 in HCT116 cells (P<0.05). Functionally, NPRL2 overexpression elevated the sensitivity of CPT-11 by preventing colon cancer cell proliferation, cell movement, and invasion, and promoting cell apoptosis and G2/M cell cycle arrest. Mechanistically, NPRL2 overexpression enhanced CPT-11 sensitivity by activating the DNA damage checkpoint pathway. CONCLUSIONS NPRL2 overexpression enhances sensitivity to CPT-11 treatment in colon cancer cells, and it may serve as a molecular therapeutic agent to treat patients with CRC. PMID- 29519999 TI - Oscillating modes of driven colloids in overdamped systems. AB - Microscopic colloidal particles suspended in liquids are a prominent example of an overdamped system where viscous forces dominate over inertial effects. Frequently, colloids are used as sensitive probes, e.g., in biophysical applications from which molecular forces are inferred. The interpretation of such experiments rests on the assumption that, even when the particles are driven, the liquid remains in equilibrium. Here we experimentally demonstrate that this is not valid for particles in viscoelastic fluids. Even at small driving forces, we observe particle oscillations with several tens of seconds. They are attributed to non-equilibrium fluctuations of the fluid being excited by the particle's motion. The oscillatory dynamics is in quantitative agreement with an overdamped Langevin equation with negative friction-memory term being equivalent to a stochastically driven underdamped oscillator. Such oscillatory modes are expected to widen the use of colloids as model systems but must also be considered in colloidal probe experiments. PMID- 29519998 TI - HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns. AB - Endogenous bioelectrical signaling coordinates cell behaviors toward correct anatomical outcomes. Lack of a model explaining spatialized dynamics of bioelectric states has hindered the understanding of the etiology of some birth defects and the development of predictive interventions. Nicotine, a known neuroteratogen, induces serious defects in brain patterning and learning. Our bio realistic computational model explains nicotine's effects via the disruption of endogenous bioelectrical gradients and predicts that exogenous HCN2 ion channels would restore the endogenous bioelectric prepatterns necessary for brain patterning. Voltage mapping in vivo confirms these predictions, and exogenous expression of the HCN2 ion channel rescues nicotine-exposed embryos, resulting in normal brain morphology and molecular marker expression, with near-normal learning capacity. By combining molecular embryology, electrophysiology, and computational modeling, we delineate a biophysical mechanism of developmental brain damage and its functional rescue. PMID- 29520001 TI - Fostering the exchange of real world data across different countries to answer primary care research questions: an UNLOCK study from the IPCRG. AB - There is growing awareness amongst healthcare planners, providers and researchers of the need to make better use of routinely collected health data by translating it into actionable information that improves efficiency of healthcare and patient outcomes. There is also increased acceptance of the importance of real world research that recruits patients representative of primary care populations and evaluates interventions realistically delivered by primary care professionals. The UNLOCK Group is an international collaboration of primary care researchers and practitioners from 15 countries. It has coordinated and shared datasets of diagnostic and prognostic variables for COPD and asthma to answer research questions meaningful to professionals working in primary care over a 6-year period. Over this time the UNLOCK Group has undertaken several studies using data from unselected primary care populations from diverse contexts to evaluate the burden of disease, multiple morbidities, treatment and follow-up. However, practical and structural constraints have hampered the UNLOCK Group's ability to translate research ideas into studies. This study explored the constraints, challenges and successes experienced by the UNLOCK Group and its participants' learning as researchers and primary care practitioners collaborating to answer primary care research questions. The study identified lessons for future studies and collaborations that require data sharing across borders. It also explored specific challenges to fostering the exchange of primary care data in comparison to other datasets such as public health, prescribing or hospital data and mechanisms that may be used to overcome these. PMID- 29520000 TI - Activation of serotonin neurons promotes active persistence in a probabilistic foraging task. AB - The neuromodulator serotonin (5-HT) has been implicated in a variety of functions that involve patience or impulse control. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, we studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next. Critically, mice were required to actively nose-poke in order to exploit a given site. We show that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increases the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function. PMID- 29520002 TI - Stimulated left DLPFC-nucleus accumbens functional connectivity predicts the anti depression and anti-anxiety effects of rTMS for depression. AB - Not all depression patients effectively respond to repeated transcranial magnetic stimulation (rTMS). We tested whether the intrinsic functional connectivity (FC) strength between the stimulated left dorsolateral prefrontal cortex (DLPFC) and left nucleus accumbens (NAcc) might predict effects of rTMS. Twenty-two medication-naive depression patients received rTMS on left DLPFC for 2 weeks and underwent baseline functional magnetic resonance imaging (fMRI). We compared the amplitude of the low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) in the stimulated target (the cortex region directly stimulated by rTMS) located in the left DLPFC, and the left NAcc, as well as the intrinsic FC of the DLPFC NAcc between early improvers and non-improvers. We evaluated the association between the baseline brain imaging features (ALFF, ReHo, and FC) and improvements in depression and anxiety symptoms. We found that the pretreatment ALFF and ReHo in the stimulated DLPFC and left NAcc did not significantly differ between the subgroups. The early improvers displayed increased negative FC strength between the stimulated DLPFC and left NAcc with respect to non-improvers. The stimulated DLPFC-NAcc FC strength negatively correlated with improved depressive and anxious symptoms. This study is the first to demonstrate that the resting-state FC of the stimulated DLPFC-NAcc, rather than regional brain activity or local synchronization in the stimulated target, might predict the anti-depression and anti-anxiety effects of rTMS for depression. PMID- 29520003 TI - Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting. AB - Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket. This "PIP-stop" releases endosomal SNX3 to the cytosol, and reveals how protein kinases control membrane assemblies. It constitutes a widespread regulatory element found across the PX superfamily and throughout evolution including of fungi and plants. This illuminates the mechanism of a biological switch whereby structured PIP sites are phosphorylated to liberate protein machines from organelle surfaces. PMID- 29520004 TI - Mechanical dyssynchrony and diastolic dysfunction are common in LVH: a pilot correlation study using Doppler echocardiography and CZT gated-SPECT MPI. AB - Hypertrophic cardiomyopathy (HCM) is an often under-diagnosed cause of left ventricular hypertrophy (LVH). It affects 1/500 of the population, is the most commonly inherited cardiovascular disorder, and can present in apical, concentric, or septal forms. Although most patients are asymptomatic, sudden cardiac death can be the initial presentation of HCM. By retrospectively enrolling patients suspected of having three different types of HCM in the absence of epicardial coronary stenosis, we aimed to examine systolic and diastolic dysfunction and perfusion abnormalities using both Doppler echocardiography and state-of-the-art gated single-photon emission computerized tomography (SPECT) myocardial perfusion imaging (MPI) with a cadmium-zinc telluride camera and thallium-201. Both regional perfusion and gated SPECT parameters were collected in addition to diastolic parameters from Doppler echocardiography. The results showed that mild ischemia was common in patients suspected of having HCM, with a mean summed stress score of 4.7 +/- 4.9 (score 0 4 in 17-segment model). The patients with HCM were associated with discernible left ventricular mechanical dyssynchrony, especially those with the apical form. In addition, diastolic dysfunction was prevalent and early to late ventricular filling velocity ratios were significantly different between groups. By combining gated-MPI and Doppler data, the trivial functional changes in HCM may be identified. PMID- 29520005 TI - Left Atrium Wall-mapping Application for Wall Thickness Visualisation. AB - The measurement method for the LA wall thickness (WT) using cardiac computed tomography (CT) is observer dependent and cannot provide a rapid and comprehensive visualisation of the global LA WT. We aim to develop a LA wall mapping application to display the global LA WT on a coplanar plane. The accuracy, intra-observer, and inter-observer reproducibility of the application were validated using digital/physical phantoms, and CT images of eight patients. This application on CT-based LA WT measures were further validated by testing six pig cardiac specimens. To evaluate its accuracy, the expanded maps of the physical phantom and pig LA were generated from the CT images and compared with the expanded map of the digital phantom and LA wall of pig heart. No significant differences (p > 0.05) were found between physical phantom and digital phantom as well as pig heart specimen and CT images using our application. Moreover, the analysis was based on the LA physical phantom or images of clinical patients; the results consistently demonstrated high intra-observer reproducibility (ICC > 0.9) and inter-observer reproducibility (ICC > 0.8) and showed good correlation between measures of pig heart specimen and CT data (r = 0.96, p < 0.001). The application can process and analyse the LA architecture for further visualisation and quantification. PMID- 29520006 TI - Design and validation of a foldable and photovoltaic wide-field epiretinal prosthesis. AB - Retinal prostheses have been developed to fight blindness in people affected by outer retinal layer dystrophies. To date, few hundred patients have received a retinal implant. Inspired by intraocular lenses, we have designed a foldable and photovoltaic wide-field epiretinal prosthesis (named POLYRETINA) capable of stimulating wireless retinal ganglion cells. Here we show that within a visual angle of 46.3 degrees, POLYRETINA embeds 2215 stimulating pixels, of which 967 are in the central area of 5 mm, it is foldable to allow implantation through a small scleral incision, and it has a hemispherical shape to match the curvature of the eye. We demonstrate that it is not cytotoxic and respects optical and thermal safety standards; accelerated ageing shows a lifetime of at least 2 years. POLYRETINA represents significant progress towards the improvement of both visual acuity and visual field with the same device, a current challenging issue in the field. PMID- 29520007 TI - Spatiotemporal Airy Ince-Gaussian wave packets in strongly nonlocal nonlinear media. AB - The self-accelerating Airy Ince-Gaussian (AiIG) and Airy helical Ince-Gaussian (AihIG) wave packets in strongly nonlocal nonlinear media (SNNM) are obtained by solving the strongly nonlocal nonlinear Schrodinger equation. For the first time, the propagation properties of three dimensional localized AiIG and AihIG breathers and solitons in the SNNM are demonstrated, these spatiotemporal wave packets maintain the self-accelerating and approximately non-dispersion properties in temporal dimension, periodically oscillating (breather state) or steady (soliton state) in spatial dimension. In particular, their numerical experiments of spatial intensity distribution, numerical simulations of spatiotemporal distribution, as well as the transverse energy flow and the angular momentum in SNNM are presented. Typical examples of the obtained solutions are based on the ratio between the input power and the critical power, the ellipticity and the strong nonlocality parameter. The comparisons of analytical solutions with numerical simulations and numerical experiments of the AiIG and AihIG optical solitons show that the numerical results agree well with the analytical solutions in the case of strong nonlocality. PMID- 29520009 TI - Transient Radiation Imaging Based on a ZnO:Ga Single-Crystal Image Converter. AB - A ZnO:Ga single crystal with an applicable size of phi40 * 1 mm was prepared using the hydro-thermal method. The crystal exhibits good crystallinity and scintillation properties with a 63.94-arcsec full-width at half-maximum (FWHM) in the X-ray rocking curve (XRC) spectrum, 8% luminous non-uniformity, emission at 389 nm in the X-ray excited luminescence spectrum, fast response and 5.5% BGO luminous intensity. Furthermore, an X-ray pinhole imaging system of nanosecond temporal resolution with a ZnO:Ga single-crystal image converter was established to diagnose the cathode electron emission spatial distribution of an intense current diode. Results for shutter times of 4 MUs and 5 ns were obtained, which directly represent the cathode electron spatial distribution throughout the entire pulse duration and during a certain moment of the pulse, respectively. The results demonstrate that the large ZnO:Ga single crystal can diagnose the spatial distribution of cathode electron emission in an intense current diode with high temporal resolution and provide new solutions for high-temporal-resolution diagnosis of a pulse radiation field. PMID- 29520008 TI - Social Contact Enhances Bodily Self-Awareness. AB - Human self-awareness is arguably the most important and revealing question of modern sciences. Converging theoretical perspectives link self-awareness and social abilities in human beings. In particular, mutual engagement during social interactions-or social contact-would boost self-awareness. Yet, empirical evidence for this effect is scarce. We recently showed that the perception of eye contact induces enhanced bodily self-awareness. Here, we aimed at extending these findings by testing the influence of social contact in auditory and tactile modalities, in order to demonstrate that social contact enhances bodily self awareness irrespective of sensory modality. In a first experiment, participants were exposed to hearing their own first name (as compared to another unfamiliar name and noise). In a second experiment, human touch (as compared to brush touch and no-touch) was used as the social contact cue. In both experiments, participants demonstrated more accurate rating of their bodily reactions in response to emotional pictures following the social contact condition-a proxy of bodily self-awareness. Further analyses indicated that the effect of social contact was comparable across tactile, auditory and visual modalities. These results provide the first direct empirical evidence in support of the essential social nature of human self-awareness. PMID- 29520010 TI - Dna is a New Target of Parp3. AB - Most members of the poly(ADP-ribose)polymerase family, PARP family, have a catalytic activity that involves the transfer of ADP-ribose from a beta-NAD+ molecule to protein acceptors. It was recently discovered by Talhaoui et al. that DNA-dependent PARP1 and PARP2 can also modify DNA. Here, we demonstrate that DNA dependent PARP3 can modify DNA and form a specific primed structure for further use by the repair proteins. We demonstrated that gapped DNA that was ADP ribosylated by PARP3 could be ligated to double-stranded DNA by DNA ligases. Moreover, this ADP-ribosylated DNA could serve as a primed DNA substrate for PAR chain elongation by the purified proteins PARP1 and PARP2 as well as by cell-free extracts. We suggest that this ADP-ribose modification can be involved in cellular pathways that are important for cell survival in the process of double strand break formation. PMID- 29520011 TI - Modulating the water channel AQP4 alters miRNA expression, astrocyte connectivity and water diffusion in the rodent brain. AB - Aquaporins (AQPs) facilitate water diffusion through the plasma membrane. Brain aquaporin-4 (AQP4) is present in astrocytes and has critical roles in normal and disease physiology. We previously showed that a 24.9% decrease in AQP4 expression after in vivo silencing resulted in a 45.8% decrease in tissue water mobility as interpreted from magnetic resonance imaging apparent diffusion coefficients (ADC). Similar to previous in vitro studies we show decreased expression of the gap junction protein connexin 43 (Cx43) in vivo after intracortical injection of siAQP4 in the rat. Moreover, siAQP4 induced a loss of dye-coupling between astrocytes in vitro, further demonstrating its effect on gap junctions. In contrast, silencing of Cx43 did not alter the level of AQP4 or water mobility (ADC) in the brain. We hypothesized that siAQP4 has off-target effects on Cx43 expression via modification of miRNA expression. The decreased expression of Cx43 in siAQP4-treated animals was associated with up-regulation of miR224, which is known to target AQP4 and Cx43 expression. This could be one potential molecular mechanism responsible for the effect of siAQP4 on Cx43 expression, and the resultant decrease in astrocyte connectivity and dramatic effects on ADC values and water mobility. PMID- 29520013 TI - Publisher Correction: Tamm plasmon modes on semi-infinite metallodielectric superlattices. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29520012 TI - Assisted delivery of antisense therapeutics in animal models of heritable neurodegenerative and neuromuscular disorders: a systematic review and meta analysis. AB - Antisense oligonucleotide (AON)-based therapies hold promise for a range of neurodegenerative and neuromuscular diseases and have shown benefit in animal models and patients. Success in the clinic is nevertheless still limited, due to unfavourable biodistribution and poor cellular uptake of AONs. Extensive research is currently being conducted into the formulation of AONs to improve delivery, but thus far there is no consensus on which of those strategies will be the most effective. This systematic review was designed to answer in an unbiased manner which delivery strategies most strongly enhance the efficacy of AONs in animal models of heritable neurodegenerative and neuromuscular diseases. In total, 95 primary studies met the predefined inclusion criteria. Study characteristics and data on biodistribution and toxicity were extracted and reporting quality and risk of bias were assessed. Twenty studies were eligible for meta-analysis. We found that even though the use of delivery systems provides an advantage over naked AONs, it is not yet possible to select the most promising strategies. Importantly, standardisation of experimental procedures is warranted in order to reach conclusions about the most efficient delivery strategies. Our best practice guidelines for future experiments serve as a step in that direction. PMID- 29520014 TI - Single molecule real time sequencing in ADTKD-MUC1 allows complete assembly of the VNTR and exact positioning of causative mutations. AB - Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubulointerstitial kidney disease (ADTKD). Most causative mutations are buried within a GC-rich 60 basepair variable number of tandem repeat (VNTR), which escapes identification by massive parallel sequencing methods due to the complexity of the VNTR. We established long read single molecule real time sequencing (SMRT) targeted to the MUC1-VNTR as an alternative strategy to the snapshot assay. Our approach allows complete VNTR assembly, thereby enabling the detection of all variants residing within the VNTR and simultaneous determination of VNTR length. We present high resolution data on the VNTR architecture for a cohort of snapshot positive (n = 9) and negative (n = 7) ADTKD families. By SMRT sequencing we could confirm the diagnosis in all previously tested cases, reconstruct both VNTR alleles and determine the exact position of the causative variant in eight of nine families. This study demonstrates that precise positioning of the causative mutation(s) and identification of other coding and noncoding sequence variants in ADTKD-MUC1 is feasible. SMRT sequencing could provide a powerful tool to uncover potential factors encoded within the VNTR that associate with intra- and interfamilial phenotype variability of MUC1 related kidney disease. PMID- 29520016 TI - The effect of decreasing permafrost stability on ecosystem carbon in the northeastern margin of the Qinghai-Tibet Plateau. AB - The objective of this study is to investigate the effect of decreased permafrost stability on carbon storage of the alpine ecosystems in the northeastern margin of the Qinghai-Tibet Plateau. During July and August 2013, we selected 18 sites in five types of permafrost (stable, substable, transitional, unstable, and extremely unstable) regions. We measured aboveground phytomass carbon (APC) and soil respiration (SR), soil inorganic carbon (SIC), soil organic carbon (SOC), belowground phytomass carbon, and soil properties down to 50 cm at same types of soils and grasslands. The results indicated that ecosystem carbon in cold calcic soils first decreased and then increased as the permafrost stability declined. Overall, decreasing permafrost stability was expected to reduce ecosystem carbon in meadows, but it was not obvious in swamp meadows and steppes. APC decreased significantly, but SIC and SOC in steppes first decreased and then increased with declining permafrost stability. Soil clay fraction and soil moisture were the controls for site variations of ecosystem carbon. The spatial variations in SR were possibly controlled by soil moisture and precipitation. This meant that alpine ecosystems carbon reduction was strongly affected by permafrost degradation in meadows, but the effects were complex in swamp meadows and steppes. PMID- 29520015 TI - Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot Marie-Tooth neuropathy. AB - Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on alpha-tubulin. A decrease in alpha tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore alpha-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D. PMID- 29520017 TI - Critical test of isotropic periodic sum techniques with group-based cut-off schemes. AB - Truncation is still chosen for many long-range intermolecular interaction calculations to efficiently compute free-boundary systems, macromolecular systems and net-charge molecular systems, for example. Advanced truncation methods have been developed for long-range intermolecular interactions. Every truncation method can be implemented as one of two basic cut-off schemes, namely either an atom-based or a group-based cut-off scheme. The former computes interactions of "atoms" inside the cut-off radius, whereas the latter computes interactions of "molecules" inside the cut-off radius. In this work, the effect of group-based cut-off is investigated for isotropic periodic sum (IPS) techniques, which are promising cut-off treatments to attain advanced accuracy for many types of molecular system. The effect of group-based cut-off is clearly different from that of atom-based cut-off, and severe artefacts are observed in some cases. However, no severe discrepancy from the Ewald sum is observed with the extended IPS techniques. PMID- 29520018 TI - Lower cognitive control network connectivity in stroke participants with depressive features. AB - Around one-third of people develop depression following ischaemic stroke, yet the underlying mechanisms are poorly understood. Post-stroke depression has been linked to frontal infarcts, mainly lesions in the left dorsolateral prefrontal cortex (DLPFC). But depression is a network disorder that cannot be fully characterised through lesion-symptom mapping. Researchers of depression in non stroke populations have successfully tapped into the cognitive control network (CCN) using the bilateral DLPFC as a seed, and found that CCN resting-state connectivity is reduced in even mildly depressed subjects, compared to healthy controls. Hence, we aimed to investigate the association between post-stroke depressive features and the CCN resting-state connectivity in a stroke population. We analysed DLPFC resting-state connectivity in 64 stroke participants, 20 of whom showed depressive features assessed with the Patient Health Questionnaire (PHQ-9) at 3 months after stroke. We directly compared groups showing symptoms of depression with those who did not, and performed a regression with PHQ-9 scores in all participants, controlling for age, gender, lesion volume and stroke severity. Post-stroke depression was associated with lower connectivity between the left DLPFC and the right supramarginal gyrus (SMG) in both group and regression analyses. Neither the seed nor the results overlapped with stroke lesions. These findings confirm an important role of the left DLPFC in post-stroke depression, but now show that large-scale network disruptions following stroke associated with depressive features occur without lesions in the DLPFC. PMID- 29520019 TI - Hypofractionated simultaneous integrated boost (IMRT-SIB) with pelvic nodal irradiation and concurrent androgen deprivation therapy for high-risk prostate cancer: results of a prospective phase II trial. AB - OBJECTIVE: The approach for treating high-risk prostate cancer still presents different unresolved issues. We report the safety and efficacy of a radiation therapy strategy based on the combination of moderate hypofractioned simultaneous integrated boost (SIB) and Image Guidance. MATERIALS AND METHODS: In this phase II trial of patients with high-risk prostate cancer, Image Guided SIB-IMRT plans (Simultaneous Intensity Modulated - Intensity Modulated Radiotherapy) were delivered between 2009 and 2012. All patients enrolled (41) received in 25 fractions a total dose of 67.5 Gy (2.7 Gy/fraction) to the prostatic volume, 56.25 Gy (2.25 Gy/fraction) to the seminal vescicles, and 50 Gy (2.0 Gy/fraction) to the pelvic lymph nodes (LN) chains with concurrent androgen deprivation therapy (ADT). The image-guided radiotherapy (IGRT) procedure was performed using three gold seeds. RTOG late gastrointestinal and genitourinary toxicities and 6 year biochemical relapse-free survival (BRFS) were assessed in combination of their statistical correlation with clinical factors and dosimetric parameters. RESULTS: Rate of late genitourinary toxicity grade 2 was 9.8%, while rates of late gastrointestinal toxicity were 14.6% and 2.4%, for grade 1 and 2, respectively. Diabetes and maximum doses to rectum appeared to be statistically relevant risk factors for late rectal toxicity. Five-year BRFS was 95.1%. CONCLUSIONS: In our study, we observed positive results in terms of toxicity and good efficacy in a cohort of high-risk prostate cancer patients treated with a multimodality therapy approach comprising hypofractionation, irradiation of pelvic nodes (common iliac nodes included), and concurrent ADT. These favorable results may merit further investigation in a phase III randomized trial to confirm that whole pelvic radiation therapy (WPRT) combined with moderate hypofractionation and ADT could be performed safely and effectively. PMID- 29520020 TI - Rapid and transient oxygen consumption increase following acute HDAC/KDAC inhibition in Drosophila tissue. AB - Epigenetic deregulation, such as the reduction of histone acetylation levels, is thought to be causally linked to various maladies associated with aging. Consequently, histone deacetylase inhibitors are suggested to serve as epigenetic therapy by increasing histone acetylation. However, previous work suggests that many non-histone proteins, including metabolic enzymes, are also acetylated and that post transitional modifications may impact their activity. Furthermore, deacetylase inhibitors were recently shown to impact the acetylation of a variety of proteins. By utilizing a novel technique to measure oxygen consumption rate from whole living tissue, we demonstrate that treatment of whole living fly heads by the HDAC/KDAC inhibitors sodium butyrate and Trichostatin A, induces a rapid and transient increase of oxygen consumption rate. In addition, our study indicates that the rate increase is markedly attenuated in midlife fly head tissue. Overall, our data suggest that HDAC/KDAC inhibitors may induce enhanced mitochondrial activity in a rapid manner. This observed metabolic boost provides further, but novel evidence, that treating various maladies with deacetylase inhibitors may be beneficial. PMID- 29520021 TI - Cation vacancy stabilization of single-atomic-site Pt1/Ni(OH)x catalyst for diboration of alkynes and alkenes. AB - Development of single-atomic-site catalysts with high metal loading is highly desirable but proved to be very challenging. Although utilizing defects on supports to stabilize independent metal atoms has become a powerful method to fabricate single-atomic-site catalysts, little attention has been devoted to cation vacancy defects. Here we report a nickel hydroxide nanoboard with abundant Ni2+ vacancy defects serving as the practical support to achieve a single-atomic site Pt catalyst (Pt1/Ni(OH)x) containing Pt up to 2.3 wt% just by a simple wet impregnation method. The Ni2+ vacancies are found to have strong stabilizing effect of single-atomic Pt species, which is determined by X-ray absorption spectrometry analyses and density functional theory calculations. This Pt1/Ni(OH)x catalyst shows a high catalytic efficiency in diboration of a variety of alkynes and alkenes, yielding an overall turnover frequency value upon reaction completion for phenylacetylene of ~3000 h-1, which is much higher than other reported heterogeneous catalysts. PMID- 29520022 TI - High-speed photon-counting laser ranging for broad range of distances. AB - We demonstrate a high-speed photon-counting laser ranging system with laser pulses of multiple repetition rates to extend the unambiguous range. In the experiment, the laser pulses of three different repetition rates around 10 MHz were employed to enlarge the maximum unambiguous range from 15 m to 165 km. Moreover, the range of distances was increased as well, enabling the measurement on different targets of large separation distance with high depth resolution. An outdoor photon-counting laser ranging up to 21 km was realized with high repetition rate, which is beneficial for the airborne and satellite-based topographic mapping. PMID- 29520023 TI - Volcanic ash as a driver of enhanced organic carbon burial in the Cretaceous. AB - On greater than million year timescales, carbon in the ocean-atmosphere-biosphere system is controlled by geologic inputs of CO2 through volcanic and metamorphic degassing. High atmospheric CO2 and warm climates in the Cretaceous have been attributed to enhanced volcanic emissions of CO2 through more rapid spreading at mid-ocean ridges and, in particular, to a global flare-up in continental arc volcanism. Here, we show that global flare-ups in continental arc magmatism also enhance the global flux of nutrients into the ocean through production of windblown ash. We show that up to 75% of Si, Fe and P is leached from windblown ash during and shortly after deposition, with soluble Si, Fe and P inputs from ash alone in the Cretaceous being higher than the combined input of dust and rivers today. Ash-derived nutrient inputs may have increased the efficiency of biological productivity and organic carbon preservation in the Cretaceous, possibly explaining why the carbon isotopic signature of Cretaceous seawater was high. Variations in volcanic activity, particularly continental arcs, have the potential of profoundly altering carbon cycling at the Earth's surface by increasing inputs of CO2 and ash-borne nutrients, which together enhance biological productivity and burial of organic carbon, generating an abundance of hydrocarbon source rocks. PMID- 29520024 TI - A systematic classification of death causes in multiple myeloma. PMID- 29520026 TI - Intestinal epithelial Caspase-8 signaling is essential to prevent necroptosis during Salmonella Typhimurium induced enteritis. AB - Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8?IEC mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8?IEC mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8?IECTnfr1-/- mice showed improved survival after infection, tissue destruction was similar to Casp8?IEC mice, indicating that necroptosis partially depends on TNF-alpha signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization. PMID- 29520025 TI - Disease-induced assemblage of a plant-beneficial bacterial consortium. AB - Disease suppressive soils typically develop after a disease outbreak due to the subsequent assembly of protective microbiota in the rhizosphere. The role of the plant immune system in the assemblage of a protective rhizosphere microbiome is largely unknown. In this study, we demonstrate that Arabidopsis thaliana specifically promotes three bacterial species in the rhizosphere upon foliar defense activation by the downy mildew pathogen Hyaloperonospora arabidopsidis. The promoted bacteria were isolated and found to interact synergistically in biofilm formation in vitro. Although separately these bacteria did not affect the plant significantly, together they induced systemic resistance against downy mildew and promoted growth of the plant. Moreover, we show that the soil-mediated legacy of a primary population of downy mildew infected plants confers enhanced protection against this pathogen in a second population of plants growing in the same soil. Together our results indicate that plants can adjust their root microbiome upon pathogen infection and specifically recruit a group of disease resistance-inducing and growth-promoting beneficial microbes, therewith potentially maximizing the chance of survival of their offspring that will grow in the same soil. PMID- 29520028 TI - Author Correction: nr3c1 null mutant zebrafish are viable and reveal DNA-binding independent activities of the glucocorticoid receptor. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29520029 TI - Estimating wildlife activity curves: comparison of methods and sample size. AB - Camera traps and radiotags commonly are used to estimate animal activity curves. However, little empirical evidence has been provided to validate whether they produce similar results. We compared activity curves from two common camera trapping techniques to those from radiotags with four species that varied substantially in size (~1 kg-~50 kg), diet (herbivore, omnivore, carnivore), and mode of activity (diurnal and crepuscular). Also, we sub-sampled photographs of each species with each camera trapping technique to determine the minimum sample size needed to maintain accuracy and precision of estimates. Camera trapping estimated greater activity during feeding times than radiotags in all but the carnivore, likely reflective of the close proximity of foods readily consumed by all species except the carnivore (i.e., corn bait or acorns). However, additional analyses still indicated both camera trapping methods produced relatively high overlap and correlation to radiotags. Regardless of species or camera trapping method, mean overlap increased and overlap error decreased rapidly as sample sizes increased until an asymptote near 100 detections which we therefore recommend as a minimum sample size. Researchers should acknowledge that camera traps and radiotags may estimate the same mode of activity but differ in their estimation of magnitude in activity peaks. PMID- 29520027 TI - The oxidized phospholipid oxPAPC protects from septic shock by targeting the non canonical inflammasome in macrophages. AB - Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1 palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL 1beta release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram negative bacterial sepsis. PMID- 29520030 TI - Ti12C68: A stable T h -symmetry hollow cage. AB - A stable T h -symmetry Ti12C68 cage was systemically investigated using density functional theory. The structure of Ti12C68 is a hollow cage with twelve TiC13 subunit of three pentagons and one hexagon. The calculated frequencies are in the range 95.1 cm-1-1423.9 cm-1. There are no imaginary frequencies, showing its kinetic stability. Ab initio molecular dynamics simulations demonstrate that the topological structure of cage-like Ti12C68 cluster was well maintained when the effective temperature is up to 1139 K. The natural bond orbitals analysis shows that the d orbit of Ti atoms form four sigma bonds with the neighboring four carbon atoms in each TiC13 subunit playing an important role in the cluster stability. The molecular frontier orbitals analysis indicates that Ti12C68 cage has a narrow HOMO-LUMO gap with metal-like property. It would be expected to enrich the species of hollow metal carbide clusters. PMID- 29520032 TI - Design of broadband graphene-metamaterial absorbers for permittivity sensing at mid-infrared regions. AB - In this paper, a tunable broadband metamaterial absorber (MA) based on graphene is investigated theoretically and numerically at mid-infrared regions. Compared with the previously reported multiband graphene-based MAs, a broad bandwidth of 11.7 THz with the absorption over 90% is obtained in the proposed MA, which is composed of a Jerusalem cross (JC) metal encrusting into the slot graphene layer in the top layer. The results show that the origin of broadband absorption is caused by coupling effect between metal and graphene, and this effect is explained by the two-mode waveguide coupling theory. The tunability of MA is achieved via changing the external gate voltage to modify the Fermi energy of graphene. Further results show that the proposed MA can be used as the permittivity sensor with a high absorption. This work indicates that the proposed MA has the potential applications with respect to sensors and infrared absorbers. PMID- 29520034 TI - Oxygenation index has better predictive ability than oxygenation ventilation index in CDH patients. PMID- 29520033 TI - Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro. AB - Low molecular weight heparin (LMWH) is widely used in recurrent miscarriage treatment. The anti-coagulant effects are established, while immunological effects are not fully known. Our aim was to assess LMWH effects on activation and polarization of central regulatory immune cells from healthy women, and on placenta tissues from women undergoing elective abortions. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured with or without LMWH. Flow cytometry showed that LMWH exposure induced increased expression of HLA-DR and CD206 in macrophages. This phenotype was associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory T-cells, intensified IFN-gamma secretion and showed a tendency to increase the lymphoblast proportions. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells. Although the biological significancies of these in vitro findings are uncertain and need to be confirmed in vivo, they suggest the possibility that immunological effects of LMWH may be beneficial mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage. PMID- 29520035 TI - A novel standardized deep sequencing-based assay for hepatitis C virus genotype determination. AB - Hepatitis C virus (HCV) genotype and subtype (1a/1b) identification is needed to tailor anti-HCV therapy. Currently available methods accurately identify the genotype and differentiate subtypes 1a from 1b. However, these assays have not been designed to identify other HCV subtypes, nor to recognize mixed genotype/subtype infections, emphasizing the need for a high-resolution system based on phylogenetic analysis of reads obtained by deep sequencing of a relevant genome region. The aim of this study was to evaluate the performance of the Sentosa SQ HCV Genotyping Assay, a novel deep sequencing-based assay targeting the HCV nonstructural 5B (NS5B) region, in clinical samples from patients with an indication for anti-HCV therapy. A high concordance rate with Sanger sequencing of the NS5B region, the reference method, was found for genotype 1 to 6 determination, 1a/1b subtype identification, and genotype 4, 5 and 6 subtyping. Discrepancies were seen essentially for HCV genotype 2 subtyping. Overall, the performance of the deep sequencing-based assay in generating the genotypes/subtype information needed to tailor anti-HCV treatment was adequate in this study. Further improvements, such as a longer NS5B fragment analyzed and enriching the database of reference prototype strains used for subtype assignment would make it a method of choice for HCV genotyping and subtyping for future clinical practice and research. PMID- 29520031 TI - A proteomic landscape of diffuse-type gastric cancer. AB - The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with the worst prognosis and few treatment options. Here we present a dataset from 84 DGC patients, composed of a proteome of 11,340 gene products and mutation information of 274 cancer driver genes covering paired tumor and nearby tissue. DGC can be classified into three subtypes (PX1-3) based on the altered proteome alone. PX1 and PX2 exhibit dysregulation in the cell cycle and PX2 features an additional EMT process; PX3 is enriched in immune response proteins, has the worst survival, and is insensitive to chemotherapy. Data analysis revealed four major vulnerabilities in DGC that may be targeted for treatment, and allowed the nomination of potential immunotherapy targets for DGC patients, particularly for those in PX3. This dataset provides a rich resource for information and knowledge mining toward altered signaling pathways in DGC and demonstrates the benefit of proteomic analysis in cancer molecular subtyping. PMID- 29520037 TI - Correction to: The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI. AB - The author list was presented as last name, first name. The names should have been listed as:Christoph Kraus, Manfred Klobl, Martin Tik, Bastian Auer, Thomas Vanicek, Nicole Geissberger, Daniela M. Pfabigan, Andreas Hahn, Michael Woletz, Katharina Paul, Arkadiusz Komorowski, Siegfried Kasper, Christian Windischberger, Claus Lamm, Rupert Lanzenberger. PMID- 29520036 TI - Genome-wide analysis of insomnia disorder. AB - Insomnia is a worldwide problem with substantial deleterious health effects. Twin studies have shown a heritable basis for various sleep-related traits, including insomnia, but robust genetic risk variants have just recently begun to be identified. We conducted genome-wide association studies (GWAS) of soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). GWAS were carried out separately for each ancestral group (EUR, AFR, LAT) using logistic regression for each of the STARRS component studies (including 3,237 cases and 14,414 controls), and then meta-analysis was conducted across studies and ancestral groups. Heritability (SNP-based) for lifetime insomnia disorder was significant (h2g = 0.115, p = 1.78 * 10-4 in EUR). A meta-analysis including three ancestral groups and three study cohorts revealed a genome-wide significant locus on Chr 7 (q11.22) (top SNP rs186736700, OR = 0.607, p = 4.88 * 10-9) and a genome-wide significant gene-based association (p = 7.61 * 10-7) in EUR for RFX3 on Chr 9. Polygenic risk for sleeplessness/insomnia severity in UK Biobank was significantly positively associated with likelihood of insomnia disorder in STARRS. Genetic contributions to insomnia disorder in STARRS were significantly positively correlated with major depressive disorder (rg = 0.44, se = 0.22, p = 0.047) and type 2 diabetes (rg = 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (rg = -0.34, se = 0.17, p = 0.039) and subjective well being (rg = -0.59, se = 0.23, p = 0.009) in external datasets. Insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease. PMID- 29520038 TI - Problems in interpreting and using GWAS of conditional phenotypes illustrated by 'alcohol GWAS'. PMID- 29520039 TI - Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders. AB - In recent years, striking new evidence has demonstrated non-genetic inheritance of acquired traits associated with parental environmental exposures. In particular, this transgenerational modulation of phenotypic traits is of direct relevance to psychiatric disorders, including depression, post-traumatic stress disorder, and other anxiety disorders. Here we review the recent progress in this field, with an emphasis on acquired traits of psychiatric illnesses transmitted epigenetically via the male lineage. We discuss the transgenerational effects of paternal exposure to stress vs. positive stimuli, such as exercise, and discuss their impact on the behavioral, affective and cognitive characteristics of their progeny. Furthermore, we review the recent evidence suggesting that these transgenerational effects are mediated by epigenetic mechanisms, including changes in DNA methylation and small non-coding RNAs in the sperm. We discuss the urgent need for more research exploring transgenerational epigenetic effects in animal models and human populations. These future studies may identify epigenetic mechanisms as potential contributors to the 'missing heritability' observed in genome-wide association studies of psychiatric illnesses and other human disorders. This exciting new field of transgenerational epigenomics will facilitate the development of novel strategies to predict, prevent and treat negative epigenetic consequences on offspring health, and psychiatric disorders in particular. PMID- 29520040 TI - Biological annotation of genetic loci associated with intelligence in a meta analysis of 87,740 individuals. AB - Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems. PMID- 29520043 TI - Publisher Correction: Oxidative demethylation of algal carbohydrates by cytochrome P450 monooxygenases. AB - In the version of this article originally published, the line of conditions shown for NADH in Figure 2b was shifted out of place. The error has been corrected in the HTML and PDF versions of the article. PMID- 29520042 TI - Publisher Correction: A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters. AB - In the version of this article originally published, the bottom of Figure 4f,g was partially truncated in the PDF. The error has been corrected in the PDF version of this article. PMID- 29520044 TI - The full spectrum of human naive T cells. AB - Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation. PMID- 29520041 TI - Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project. AB - BACKGROUND: While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type. METHODS: The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. RESULTS: Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57-2.20) and ICC (HR = 1.47, 95% CI: 1.07-2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74-1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR>=7 drinks/day = 1.87, 95% CI: 1.41-2.47) and a 68% increased ICC risk (HR>=5 drinks/day = 1.68, 95% CI: 0.99-2.86). However, light to-moderate alcohol consumption of <3 drinks/day appeared to be inversely associated with HCC risk (HR>0-<0.5 drinks/day = 0.77, 95% CI: 0.67-0.89; HR>0.5 <1 drinks/day = 0.57, 95% CI: 0.44-0.73; HR1-<3 drinks/day = 0.71, 95% CI: 0.58 0.87), but not ICC. CONCLUSIONS: These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC. PMID- 29520045 TI - Comparison of long-term decentration and tilt in two types of multifocal intraocular lenses with OPD-Scan III aberrometer. AB - PURPOSE: To compare the long-term decentration and tilt in two multifocal intraocular lenses (MfIOLs) with an OPD-Scan III aberrometer. METHODS: Eighty cataract patients who underwent uneventful MfIOL implantation (42 with AcrySof(r) IQ ReSTOR(r) SN6AD1 and 38 with AMO Tecnis(r) ZMB00) were enrolled. At 1 year after surgery, a postoperative visual acuity evaluation included the measurement of uncorrected distance visual acuity, corrected distance visual acuity, distance corrected near visual acuity, and distance-corrected intermediate visual acuity. OPD-Scan III aberrometer was used to collect the decentration, tilt, and high order aberration (HOA) data. Significance was tested with Student's t test, Mann Whitney U test, paired t test, and chi2 test RESULTS: The average intraocular tilt was lower in the SN6AD1 group than in the ZMB00 group, whereas the average decentration of the two groups did not differ significantly. The mean total ocular HOAs, ocular trefoil, total internal HOAs, and spherical aberrations were significantly lower in the SN6AD1 group than in the ZMB00 group. In both the SN6AD1 and ZMB00 groups, the intraocular tilt was directly proportional to the total ocular HOAs, coma, and spherical aberration. However, there was no significant correlation between decentration and any type of HOA in SN6AD1 group, whereas decentration correlated positively with total ocular HOAs, coma, and spherical aberration in ZMB00 group. CONCLUSION: Both MfIOLs significantly improve the visual acuity of the patients. However, tilt was lower in the SN6AD1 group than in the ZMB00 group 1 year after surgery, which provide fewer HOAs and better visual quality. PMID- 29520047 TI - Optimisation of intravitreal injection technique using a Barraquer speculum with solid flat blade and finger stabilisation. PMID- 29520046 TI - Diabetic retinopathy and endothelin system: microangiopathy versus endothelial dysfunction. AB - In the face of the global epidemic of diabetes, it is critical that we update our knowledge about the pathogenesis of diabetes and the related micro alterations on the vascular network in the body. This may ultimately lead to early diagnosis and novel treatment options for delaying the progression of diabetic complications. Research has recently revealed the pivotal role of endothelin in the pathogenesis of diabetic complications, particularly in the regulation of the capillary flow, which is affected in the course of retinopathy. Although there are several reviews on various approaches to the treatment of diabetes, including normalization of glucose and fat metabolism, no reviews in literature have focused on the endothelin system as a therapeutic target or early indicator of diabetic microangiopathy. In this review, we summarize some of the experimental and clinical evidence suggesting that current therapeutic approaches to diabetes may include the modulation of the blood concentration of compounds of the endothelin system. In addition, we will briefly discuss the beneficial effects produced by the inhibition of the production of high levels of endothelin in vasculopathy, with focus on diabetic retinopathy. The cutting-edge technology currently widely used in opththalmology, such as the OCT angiography, allows us to detect very early retinal morphological changes alongside alterations in choroidal and retinal vascular network. Combination of such changes with highly sensitive measurements of alterations in serum concentrations of endothelin may lead to more efficient early detection and treatment of diabetes and related macro/microvascular complications. PMID- 29520048 TI - Response to: 'Comment on: 'Immediate IOP elevation after transscleral cyclophotocoagulation'. PMID- 29520049 TI - Prophylactic laser in age-related macular degeneration: the past, the present and the future. AB - The presence of drusen in the posterior eye is a hallmark feature of the early stages of age-related macular degeneration and their size is an indicator of risk of progression to vision-threatening forms of the disease. Since the initial observations that laser treatment can resolve drusen, there has been great interest in whether laser treatment can be used to reduce the progression of age related macular degeneration. In this article, we review the development of lasers for the treatment of those with age-related macular degeneration. We provide an overview of the clinical trial results that demonstrated drusen resolution but that had mixed effects on progression of disease. In addition, we provide a summary of the recent developments in pulsed lasers that are designed to reduce the energy applied to the posterior eye to provide the therapeutic effects of conventional continuous wave lasers while reducing the secondary tissue effects. PMID- 29520050 TI - Automated diabetic retinopathy detection in smartphone-based fundus photography using artificial intelligence. AB - OBJECTIVES: To assess the role of artificial intelligence (AI)-based automated software for detection of diabetic retinopathy (DR) and sight-threatening DR (STDR) by fundus photography taken using a smartphone-based device and validate it against ophthalmologist's grading. METHODS: Three hundred and one patients with type 2 diabetes underwent retinal photography with Remidio 'Fundus on phone' (FOP), a smartphone-based device, at a tertiary care diabetes centre in India. Grading of DR was performed by the ophthalmologists using International Clinical DR (ICDR) classification scale. STDR was defined by the presence of severe non proliferative DR, proliferative DR or diabetic macular oedema (DME). The retinal photographs were graded using a validated AI DR screening software (EyeArtTM) designed to identify DR, referable DR (moderate non-proliferative DR or worse and/or DME) or STDR. The sensitivity and specificity of automated grading were assessed and validated against the ophthalmologists' grading. RESULTS: Retinal images of 296 patients were graded. DR was detected by the ophthalmologists in 191 (64.5%) and by the AI software in 203 (68.6%) patients while STDR was detected in 112 (37.8%) and 146 (49.3%) patients, respectively. The AI software showed 95.8% (95% CI 92.9-98.7) sensitivity and 80.2% (95% CI 72.6-87.8) specificity for detecting any DR and 99.1% (95% CI 95.1-99.9) sensitivity and 80.4% (95% CI 73.9-85.9) specificity in detecting STDR with a kappa agreement of k = 0.78 (p < 0.001) and k = 0.75 (p < 0.001), respectively. CONCLUSIONS: Automated AI analysis of FOP smartphone retinal imaging has very high sensitivity for detecting DR and STDR and thus can be an initial tool for mass retinal screening in people with diabetes. PMID- 29520051 TI - Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment. AB - Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor kappaB (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment. PMID- 29520053 TI - Correction to: Use of multicolor fluorescence in situ hybridization to detect deletions in clinical tissue sections. AB - Figure 2 is incorrect in the original version of this article. The correct figure 2 is provided below. PMID- 29520052 TI - Expansion of functional personalized cells with specific transgene combinations. AB - Fundamental research and drug development for personalized medicine necessitates cell cultures from defined genetic backgrounds. However, providing sufficient numbers of authentic cells from individuals poses a challenge. Here, we present a new strategy for rapid cell expansion that overcomes current limitations. Using a small gene library, we expanded primary cells from different tissues, donors, and species. Cell-type-specific regimens that allow the reproducible creation of cell lines were identified. In depth characterization of a series of endothelial and hepatocytic cell lines confirmed phenotypic stability and functionality. Applying this technology enables rapid, efficient, and reliable production of unlimited numbers of personalized cells. As such, these cell systems support mechanistic studies, epidemiological research, and tailored drug development. PMID- 29520054 TI - Patient-derived xenograft cryopreservation and reanimation outcomes are dependent on cryoprotectant type. AB - Patient-derived xenografts (PDX) are being increasingly utilized in preclinical oncologic research. Maintaining large colonies of early generation tumor-bearing mice is impractical and cost-prohibitive. Optimal methods for efficient long-term cryopreservation and subsequent reanimation of PDX tumors are critical to any viable PDX program. We sought to compare the performance of "Standard" and "Specialized" cryoprotectant media on various cryopreservation and reanimation outcomes in PDX tumors. Standard (10% DMSO media) and Specialized (Cryostor(r)) media were compared between overall and matched PDX tumors. Primary outcome was reanimation engraftment efficiency (REE). Secondary outcomes included time to tumor formation (TTF), time to harvest (TTH), and potential loss of unique PDX lines. Overall 57 unique PDX tumors underwent 484 reanimation engraftment attempts after previous cryopreservation. There were 10 unique PDX tumors cryopreserved with Standard (71 attempts), 40 with Specialized (272 attempts), and 7 with both (141 attempts). Median frozen time of reanimated tumors was 29 weeks (max. 177). Tumor pathology, original primary PDX growth rates, frozen storage times, and number of implantations per PDX model were similar between cryoprotectant groups. Specialized media resulted in superior REE (overall: 82 vs. 39%, p < 0.0001; matched: 97 vs. 36%, p < 0.0001; >52 weeks cryostorage: 59 vs. 9%, p < 0.0001), shorter TTF (overall 24 vs. 54 days, p = 0.0051; matched 18 vs. 53 days, p = 0.0013) and shorter TTH (overall: 64 vs. 89 days, p = 0.009; matched: 47 vs. 88 days, p = 0.0005) compared to Standard. Specialized media demonstrated improved REE with extended duration cryostorage (p = 0.048) compared to Standard. Potential loss of unique PDX lines was lower with Specialized media (9 vs. 35%, p = 0.017). In conclusion, cryopreservation with a specialized cryoprotectant appears superior to traditional laboratory-based media and can be performed with reliable reanimation even after extended cryostorage. PMID- 29520055 TI - Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study. AB - Spaceflight introduces a combination of environmental stressors, including microgravity, ionizing radiation, changes in diet and altered atmospheric gas composition. In order to understand the impact of each environmental component on astronauts it is important to investigate potential influences in isolation. Rodent spaceflight experiments involve both standard vivarium cages and animal enclosure modules (AEMs), which are cages used to house rodents in spaceflight. Ground control AEMs are engineered to match the spaceflight environment. There are limited studies examining the biological response invariably due to the configuration of AEM and vivarium housing. To investigate the innate global transcriptomic patterns of rodents housed in spaceflight-matched AEM compared to standard vivarium cages we utilized publicly available data from the NASA GeneLab repository. Using a systems biology approach, we observed that AEM housing was associated with significant transcriptomic differences, including reduced metabolism, altered immune responses, and activation of possible tumorigenic pathways. Although we did not perform any functional studies, our findings revealed a mild hypoxic phenotype in AEM, possibly due to atmospheric carbon dioxide that was increased to match conditions in spaceflight. Our investigation illustrates the process of generating new hypotheses and informing future experimental research by repurposing multiple space-flown datasets. PMID- 29520057 TI - What a relief! A role for dopamine in positive (but not negative) valence. AB - We have long known that dopamine encodes the predictive relationship between cues and rewards. But what about relief learning? In this issue of Neuropsychopharmacology, Mayer et al. show that the same circuits encoding rewarding events also encode relief from aversive events. And this appears to be in a manner distinct from encoding of the aversive event itself. So does dopamine only contribute to learning about positive events? And are these events encoded in the same way regardless of how that positive experience came about? Not quite. Turns out, the devil is in the details. PMID- 29520056 TI - Nanoscale kinetics of asymmetrical corrosion in core-shell nanoparticles. AB - Designing new materials and structure to sustain the corrosion during operation requires better understanding on the corrosion dynamics. Observation on how the corrosion proceeds in atomic scale is thus critical. Here, using a liquid cell, we studied the real-time corrosion process of palladium@platinum (Pd@Pt) core shell nanocubes via transmission electron microscopy (TEM). The results revealed that multiple etching pathways operatively contribute to the morphology evolution during corrosion, including galvanic etching on non-defected sites with slow kinetics and halogen-induced etching at defected sites at faster rates. Corners are the preferential corrosion sites; both etching pathways are mutually restricted during corrosion. Those insights on the interaction of nanostructures with reactive liquid environments can help better engineer the surface structure to improve the stability of electrocatalysts as well as design a new porous structure that may provide more active sites for catalysis. PMID- 29520058 TI - Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence. AB - Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAAR) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAAR hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still unknown. We found that chronic ethanol exposure using either ethanol gavage or two-bottle choice voluntary access paradigms decreased Gabra1 expression and increased Hdac2 and Hdac3 expression. Administration of the HDAC inhibitor trichostatin A (TSA) after chronic ethanol exposure prevents the decrease in Gabra1 expression and function as well as the increase in Hdac2 and Hdac3 expression in both the cortex and the medial prefrontal cortex (mPFC). Chronic ethanol exposure and withdrawal, but not acute ethanol exposure or acute withdrawal, cause a selective upregulation of HDAC2 and HDAC3 associated with the Gabra1 promoter that accompanies a decrease in H3 acetylation of the Gabra1 promoter and the reduction in GABAAR alpha1 subunit expression. TSA administration prevented each of these molecular events as well as behavioral manifestations of ethanol dependence, including tolerance to zolpidem-induced loss of righting reflex, reduced open-arm time in the elevated plus maze, reduced center-time and locomotor activity in the open-field assay, and TSA reduced voluntary ethanol consumption. The results show how chronic ethanol exposure regulates the highly prominent GABAAR alpha1 subunit by an epigenetic mechanism that represents a potential treatment modality for alcohol dependence. PMID- 29520059 TI - Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder. AB - Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states. PMID- 29520060 TI - Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia. AB - Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants. In contrast to the replicable findings of elevation of KYNA in the central nervous system in SZ, plasma levels of KYNA were significantly lower in SZ compared to controls (p = .004). Kynurenine levels were significantly correlated with levels of interferon-gamma (p < .001), which is involved in the regulation of IDO, in both patients and controls. However, although patients had higher levels of interleukin-6 (IL-6) compared to controls (p = .012), IL-6 levels were not correlated with kynurenine or KYNA, and did not explain group differences in KYNA. Based on the lack of evidence that pro inflammatory cytokines were significantly related to the KP abnormality in SZ despite an adequate sample size, further studies must consider alternative hypotheses to identify the origins of the KP abnormalities in SZ. PMID- 29520061 TI - Strong phenotypic plasticity limits potential for evolutionary responses to climate change. AB - Phenotypic plasticity, the expression of multiple phenotypes from one genome, is a widespread adaptation to short-term environmental fluctuations, but whether it facilitates evolutionary adaptation to climate change remains contentious. Here, we investigate seasonal plasticity and adaptive potential in an Afrotropical butterfly expressing distinct phenotypes in dry and wet seasons. We assess the transcriptional architecture of plasticity in a full-factorial analysis of heritable and environmental effects across 72 individuals, and reveal pervasive gene expression differences between the seasonal phenotypes. Strikingly, intra population genetic variation for plasticity is largely absent, consistent with specialisation to a particular environmental cue reliably predicting seasonal transitions. Under climate change, deteriorating accuracy of predictive cues will likely aggravate maladaptive phenotype-environment mismatches and increase selective pressures on reaction norms. However, the observed paucity of genetic variation for plasticity limits evolutionary responses, potentially weakening prospects for population persistence. Thus, seasonally plastic species may be especially vulnerable to climate change. PMID- 29520063 TI - ProBDNF/p75NTR/sortilin pathway is activated in peripheral blood of patients with alcohol dependence. AB - Alcohol dependence is a worldwide problem with a great social and economic burden in many countries. A number of studies have suggested that BDNF (mature BDNF) and its precursor (proBDNF) play important roles in the alcohol dependence. However, what roles of the mBDNF/proBDNF pathways play during the pathological process of alcohol dependence are not clearly understood. In our clinical study, peripheral blood was sampled from 30 male patients with alcohol dependence and 50 healthy males (as control). The protein levels of proBDNF, p75NTR, sortilin, mBDNF, TrkB and mRNA levels of BDNF, p75NTR, sortilin, and TrkB were detected in the peripheral blood in our study. We found that the protein levels of proBDNF and p75NTR were increased, but not the sortilin protein level; while the TrkB protein level was decreased in the alcohol dependence patients compared with healthy controls. Moreover, the mRNA levels of p75NTR and sortilin from the lymphocytes were slightly increased; while BDNF and TrkB were significantly decreased. The ELISA results of mBDNF and TrkB were declined in the alcohol dependence group. The levels of mBDNF and TrkB were negatively correlated with the average amount of daily ethanol consumption, and the levels of proBDNF, p75NTR and sortilin were positively correlated with the average amount of ethanol consumption per day. The ratio of proBDNF to mBDNF was altered in alcohol dependence patients. The balance between the proBDNF/p75NTR and mBDNF/TrkB signalling pathways appeared dysregulated in alcohol dependence. Our results suggested that both pathways may participate in the complex processes of alcohol dependence. PMID- 29520062 TI - The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non-homologous end joining. AB - Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. Here we show the role of Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, in the repair of programmed DNA breaks in vivo. Ablation of Usp22 in primary B cells results in defects in gammaH2AX and impairs the classical non-homologous end joining (c NHEJ), affecting both V(D)J recombination and CSR. Surprisingly, Usp22 depletion causes defects in CSR to various Ig isotypes, but not IgA. We further demonstrate that IgG CSR primarily relies on c-NHEJ, whereas CSR to IgA is more reliant on the alternative end joining pathway, indicating that CSR to different isotypes involves distinct DNA repair pathways. Hence, Usp22 is the first deubiquitinase reported to regulate both V(D)J recombination and CSR in vivo by facilitating c NHEJ. PMID- 29520064 TI - Sedimentary noise and sea levels linked to land-ocean water exchange and obliquity forcing. AB - In ancient hothouses lacking ice sheets, the origins of large, million-year (myr) scale sea-level oscillations remain a mystery, challenging current models of sea level change. To address this mystery, we develop a sedimentary noise model for sea-level changes that simultaneously estimates geologic time and sea level from astronomically forced marginal marine stratigraphy. The noise model involves two complementary approaches: dynamic noise after orbital tuning (DYNOT) and lag-1 autocorrelation coefficient (rho1). Noise modeling of Lower Triassic marine slope stratigraphy in South China reveal evidence for global sea-level variations in the Early Triassic hothouse that are anti-phased with continental water storage variations in the Germanic Basin. This supports the hypothesis that long-period (1-2 myr) astronomically forced water mass exchange between land and ocean reservoirs is a missing link for reconciling geological records and models for sea-level change during non-glacial periods. PMID- 29520065 TI - Publisher Correction: A Multi-Institutional Comparison of Dynamic Contrast Enhanced Magnetic Resonance Imaging Parameter Calculations. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29520066 TI - Author Correction: Interactions count: plant origin, herbivory and disturbance jointly explain seedling recruitment and community structure. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29520067 TI - Vector species-specific association between natural Wolbachia infections and avian malaria in black fly populations. AB - Artificial infection of mosquitoes with the endosymbiont bacteria Wolbachia can interfere with malaria parasite development. Therefore, the release of Wolbachia infected mosquitoes has been proposed as a malaria control strategy. However, Wolbachia effects on vector competence are only partly understood, as indicated by inconsistent effects on malaria infection reported under laboratory conditions. Studies of naturally-occurring Wolbachia infections in wild vector populations could be useful to identify the ecological and evolutionary conditions under which these endosymbionts can block malaria transmission. Here we demonstrate the occurrence of natural Wolbachia infections in three species of black fly (genus Simulium), which is a main vector of the avian malaria parasite Leucocytozoon. Prevalence of Leucocytozoon was high (25%), but the nature and magnitude of its association with Wolbachia differed between black fly species. Wolbachia infection was positively associated with avian malaria infection in S. cryophilum, negatively associated in S. aureum, and unrelated in S. vernum. These differences suggest that Wolbachia interacts with the parasite in a vector host species-specific manner. This provides a useful model system for further study of how Wolbachia influences vector competence. Such knowledge, including the possibility of undesirable positive association, is required to guide endosymbiont based control methods. PMID- 29520068 TI - Author Correction: Myeloperoxidase is not a good biomarker for preeclampsia prediction. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29520070 TI - The effect of texture and grain size on improving the mechanical properties of Mg Al-Zn alloys by friction stir processing. AB - Friction stir processing (FSP) was used to achieve grain refinement on Mg-Al-Zn alloys, which also brought in significant texture modification. The different micro-texture characteristics were found to cause irregular micro-hardness distribution in FSPed region. The effects of texture and grain size were investigated by comparative analyses with strongly textured rolling sheet. Grain refinement improved both strength and elongation in condition of a basal texture while such led to an increment in yield stress and a drop in elongation and ultimate stress when the basal texture was modified by FSP. PMID- 29520071 TI - HSP27 inhibitor attenuates radiation-induced pulmonary inflammation. AB - Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the radioprotective effects of HSP27 inhibitor (J2) on radiation induced lung inflammation in comparison to amifostine. In gross and histological findings, J2 treatment significantly inhibited immune cell infiltration in lung tissue, revealing anti-inflammatory potential of J2. Normal lung volume, evaluated by micro-CT analysis, in J2-treated mice was higher compared to that in irradiated mice. J2-treated mice reversed radiation-induced respiratory distress. However, amifostine did not show significant radioprotective effects in comparison to that of J2. In HSP27 transgenic mice, we observed increased immune cells recruitment and decreased volume of normal lung compared to wild type mice. Increased ROS production and oxidative stress after IR were down-regulated by J2 treatment, demonstrating antioxidant property of J2. The entire data of this study collectively showed that J2 may be an effective therapeutic agent for radiation-induced lung injury. PMID- 29520072 TI - Author Correction: Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29520069 TI - An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. AB - Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-beta signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-beta signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases. PMID- 29520073 TI - Author Correction: Energy use and life cycle greenhouse gas emissions of drones for commercial package delivery. AB - In the original version of this Article, the first sentence of the sixth paragraph of the "Comparing emissions" section, the Results originally incorrectly read as 'In the base case, delivery of a small (0.5 kg) package with the small quadrotor drone has lower impacts than delivery by diesel truck, ranging from a 59% reduction in GHGs in California, to a 17% reduction in Missouri'. The correct version states '54%' instead of '59%' and '23%' instead of '17%'.The fourth sentence of the same paragraph originally incorrectly read as 'In the base case, delivery of a medium-sized (8 kg) package has 17% lower GHGs than delivery by truck in California, is about equivalent to delivery trucks for the U.S. average electricity mix, but has 77% higher GHGs than truck delivery in Missouri, which has a carbon-intensive electricity grid'. The correct version states 'In the base case, delivery of a medium-sized (8 kg) package has 9% lower GHGs than delivery by truck in California, is about 24% higher than delivery trucks for the U.S. average electricity mix, and has 50% higher GHGs than truck delivery in Missouri, which has a carbon-intensive electricity grid.The last sentence of the seventh paragraph of the same section originally incorrectly read as 'Because of the importance of electricity used to power the octocopter, charging with low-carbon electricity of 200 g GHG/kWh can reduce delivered package GHGs by 34% compared to diesel trucks'. The correct version states '37%' instead of '34%'.These errors have been corrected in both the PDF and HTML versions of the Article. PMID- 29520074 TI - Publisher Correction: Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29520075 TI - Association between pro- and anti-inflammatory cytokines and depressive symptoms in patients with diabetes-potential differences by diabetes type and depression scores. AB - Subclinical inflammation has been implicated in the development of depression, a common comorbidity of type 1 diabetes (T1D) and type 2 diabetes (T2D). This study aimed to characterise the relationships between biomarkers of inflammation and depressive symptoms in T1D and T2D. Biomarkers of inflammation were measured in serum of participants with elevated depressive symptoms and T1D (n = 389, mean age 38 years, diabetes duration 15 +/- 11 years) or T2D (n = 204, mean age 56 years, diabetes duration 13 +/- 8 years). Subclinical depression was examined using three questionnaires (Center for Epidemiologic Studies Depression [CES-D], Patient Health Questionnaire-9 [PHQ-9], 5-item World Health Organization Well Being Index [WHO-5]). In T1D, levels of interleukin-1 receptor antagonist (IL 1RA) were positively associated with two depression scores (CES-D, PHQ-9), and high-sensitivity C-reactive protein (hsCRP) was positively associated with depression for one score (WHO-5) after adjustment for age, sex, body mass index, diabetes duration, metabolic variables, medication and comorbidities (P = 0.008 0.042). In T2D, IL-18 and IL-1RA were positively associated with depression for two scores (IL-18: PHQ-9, WHO-5; IL-1RA: CES-D, WHO-5), hsCRP was associated with one depression score (PHQ-9), and adiponectin showed an inverse association with one depression score (PHQ-9) after adjustment (P = 0.006-0.048). No associations were found for IL-6 and CC-chemokine ligand 2 (CCL2). In conclusion, we observed associations between hsCRP, IL-1RA and depressive symptoms in patients with diabetes. In T2D, there was additional evidence for associations of IL-18 and (inversely) adiponectin with depressive symptoms. The strength of the associations appeared to depend on diabetes type and the method used to asssess depressive symptoms. PMID- 29520076 TI - GABAa excitation and synaptogenesis after Status Epilepticus - A computational study. AB - The role of GABAergic neurotransmission on epileptogenesis has been the subject of speculation according to different approaches. However, it is a very complex task to specifically consider the action of the GABAa neurotransmitter, which, in its dependence on the intracellular level of Cl-, can change its effect from inhibitory to excitatory. We have developed a computational model that represents the dentate gyrus and is composed of three different populations of neurons (granule cells, interneurons and mossy cells) that are mutually interconnected. The interconnections of the neurons were based on compensation theory with Hebbian and anti-Hebbian rules. The model also incorporates non-synaptic mechanisms to control the ionic homeostasis and was able to reproduce ictal discharges. The goal of the work was to investigate the hypothesis that the observed aberrant sprouting is promoted by GABAa excitatory action. Conjointly with the abnormal sprouting of the mossy fibres, the simulations show a reduction of the mossy cells connections in the network and an increased inhibition of the interneurons as a response of the neuronal network to control the activity. This finding contributes to increasing the changes in the connectivity of the neuronal circuitry and to increasing the epileptiform activity occurrences. PMID- 29520077 TI - MHC diversity and female age underpin reproductive success in an Australian icon; the Tasmanian Devil. AB - Devil Facial Tumour Disease (DFTD), a highly contagious cancer, has decimated Tasmanian devil (Sarcophilus harrisii) numbers in the wild. To ensure its long term survival, a captive breeding program was implemented but has not been as successful as envisaged at its launch in 2005. We therefore investigated the reproductive success of 65 captive devil pair combinations, of which 35 produced offspring (successful pairs) whereas the remaining 30 pairs, despite being observed mating, produced no offspring (unsuccessful pairs). The devils were screened at six MHC Class I-linked microsatellite loci. Our analyses revealed that younger females had a higher probability of being successful than older females. In the successful pairs we also observed a higher difference in total number of heterozygous loci, i.e. when one devil had a high total number of heterozygous loci, its partner had low numbers. Our results therefore suggest that devil reproductive success is subject to disruptive MHC selection, which to our knowledge has never been recorded in any vertebrate. In order to enhance the success of the captive breeding program the results from the present study show the importance of using young (2-year old) females as well as subjecting the devils to MHC genotyping. PMID- 29520078 TI - Microscopic diffusion processes measured in living planarians. AB - Living planarian flatworms were probed using quasielastic neutron scattering to measure, on the pico-to-nanosecond time scale and nanometer length scale, microscopic diffusion of water and cell constituents in the planarians. Measurable microscopic diffusivities were surprisingly well defined in such a complex system as living animals. The overall variation in the microscopic diffusivity of cell constituents was found to be far lower than the variation in the microscopic diffusivity of water in planarians in a temperature range of 284.5 to 304.1 K. PMID- 29520079 TI - A 6-week laboratory research rotation in pharmacogenomics: a model for preparing pharmacy students to practice precision medicine. AB - Comparison of human genome sequences from different individuals has unraveled that genes involved in the drug efficacy and metabolism are polymorphic, harboring mutations, splicing variations and other alterations. These data provide a reasonable explanation for the inter-individual variations observed in drug therapy. Thus, a detailed molecular analysis and an in-depth knowledge of these genes is a prerequisite to practice pharmacogenomics-based medicine. We have introduced a 6-week laboratory research rotation to train students in the expression analysis of different pharmacogenes combined with bioinformatics tools. Students were first introduced to the bioinformatics tools to identify appropriate DNA primers to amplify specific pharmacogenes from the laboratory cancer cell lines. The amplified DNA fragments were sequenced. Finally, students were trained in bioinformatics tools to establish the identity of these DNA sequences. The possible implications of this laboratory training in developing problem-solving skills needed in the implementation of pharmacogenomics knowledge in the clinic, are discussed. PMID- 29520080 TI - Impact of CYP2C19 polymorphism in prognosis of minor stroke or TIA patients with declined eGFR on dual antiplatelet therapy: CHANCE substudy. AB - Clopidogrel resistance is prevalent in chronic kidney disease (CKD) patients. Genetic polymorphism is considered to be the most important factor that influences clopidogrel resistance. Limited data exist as to the role of pharmacogenetics in prognosis of stroke patients with impaired renal function on clopidogrel. We sought to explore whether decreased kidney function alters the association between CYP2C19 genetic variants and clinical outcome in patients with minor stroke or transient ischemic attack (TIA) receiving clopidogrel therapy. A total of 1476 participants on clopidogrel-aspirin treatment with genotyping results in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were categorized by quintiles of renal function estimated by estimated glomerular filtration rate (eGFR), and were stratified according to the possession of CYP2C19 loss-of-function (LOF) alleles: carriers and non carriers. Patients were followed up and clinical outcomes were evaluated. The primary efficacy outcome was new stroke. The secondary efficacy outcome was combined vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death). The safety outcome was bleeding event. CYP2C19 LOF carriers had higher odds of new stroke than non-carriers (10.4% versus 2.4 %, hazard ratio [HR], 5.30; 95% CI, 1.51-18.3, P = 0.009) in the lowest quintile of renal function group with eGFR < 75 ml/min/1.73 m2 but not in the other four higher quintiles. Similar results were observed for the ischemic stroke and combined vascular events. There was no significant difference in the individual outcomes of bleeding in carriers compared with non-carriers in any renal function group. Among patients with minor stroke or TIA taking clopidogrel-aspirin treatment, CYP2C19 LOF carrier state was associated with higher risk of new stroke in those with eGFR < 75 ml/min/1.73 m2. This observation supports that the evaluation of CYP2C19 LOF carrier state may be useful for identification of the patients with kidney impairment with greater likelihood of having worse outcomes. PMID- 29520081 TI - Evaluation of a clinical pharmacogenetics model to predict methotrexate response in patients with rheumatoid arthritis. AB - Variability of response to treatment hinders successful management of rheumatoid arthritis (RA). Consequently, a clinical pharmacogenetics model for predicting response to methotrexate (CP-MTX) has been previously proposed that includes four clinical variables (disease activity, sex, the presence of rheumatoid factor and smoking status) and four SNPs (rs2236225, rs17602729, rs1127354, and rs2372536) in genes of the folate pathway. It showed good performance, but failed to attract attention, likely, in relation with lack of clear clinical benefit. Here, we have revised the value of the CP-MTX model directly addressing its clinical benefit by focusing on the expected benefit-cost of the predictions. In addition, our study included a much larger number of RA patients (n = 720) in MTX monotherapy than previous studies. Benefit of CP-MTX prediction was defined as the patients that would have received combination therapy as first treatment because they were correctly predicted as non-responders to MTX monotherapy. In contrast, cost of CP MTX prediction was defined as the responder patients that were wrongly predicted as non-responders. Application of CP-MTX predictions to our patients showed a good benefit-cost relationship, with half of the 66.7% non-responders to MTX monotherapy rightly directed to alternative treatments (a benefit of 33.3%) at the cost of 8.5% wrongly predicted non-responders. These benefits-costs were consistent with reanalysis of the previously published studies. Therefore, predictions of CP-MTX showed a good benefit-cost relationship for informing MTX prescription. PMID- 29520082 TI - The impact of malnutrition on quality of life in patients with systemic sclerosis. AB - BACKGROUND/OBJECTIVES: Our objective was to investigate the prevalence of malnutrition in patients with systemic sclerosis (SSc) and its impact on their quality of life (QoL). SUBJECTS/METHODS: One hundred and twenty-nine patients with SSc underwent clinical evaluation and were screened with the Malnutrition Universal Screening Tool (MUST). Malnutrition was defined as MUST score >=2.To investigate QoL, all patients completed the Short Form 36 Questionnaire and the Scleroderma Health Assessment Questionnaire. The data were analyzed with IBM SPSS(r) Statistics by using chi2/Fisher's test, Mann-Whitney U test, correlation, and linear regression analysis. RESULTS: One hundred and twenty-nine patients were included in this study (mean age was 59.1 +/- 13.8 years, 90.7% women). The prevalence of malnutrition was 10.9%. Age and disease duration were not significantly different between malnourished and well-nourished patients. All QoL scores (except bodily pain and self-reported health) were significantly impaired in malnourished patients. Furthermore, the Scleroderma Health Assessment Score score which assesses disease-specific QoL was significantly higher in the malnourished patients (1.6 +/- 0.73 compared to 0.91 +/- 0.61 in well-nourished patients; p = 0.001), reflecting a lower QoL due to disease-specific impairments. CONCLUSIONS: Severe malnutrition in SSc patients is associated with reduced QoL. Standardized nutritional screening should routinely be conducted to identify the risk of malnutrition in order to enable an intervention with multimodal treatment and avoid the serious consequences associated with severe malnutrition. PMID- 29520083 TI - The effect of vitamin B12 and folic acid supplementation on routine haematological parameters in older people: an individual participant data meta analysis. AB - BACKGROUND/OBJECTIVES: Low vitamin B12 and folate levels in community-dwelling older people are usually corrected with supplements. However, the effect of this supplementation on haematological parameters in older persons is not known. Therefore, we executed a systematic review and individual participant data meta analysis of randomised placebo-controlled trials (RCTs). SUBJECTS/METHODS: We performed a systematic search in PubMed, EMBASE, Web of Science, Cochrane and CENTRAL for RCTs published between January 1950 and April 2016, where community dwelling elderly (60+ years) who were treated with vitamin B12 or folic acid or placebo. The presence of anaemia was not required. We analysed the data on haematological parameters with a two-stage IPD meta-analysis. RESULTS: We found 494 full papers covering 14 studies. Data were shared by the authors of four RCTs comparing vitamin B12 with placebo (n = 343) and of three RCTs comparing folic acid with placebo (n = 929). We found no effect of vitamin B12 supplementation on haemoglobin (change 0.00 g/dL, 95% CI: -0.19;0.18), and no effect of folic acid supplementation (change -0.09 g/dL, 95% CI: -0.19;0.01). The effects of supplementation on other haematological parameters were similar. The effects did not differ by sex or by age group. Also, no effect was found in a subgroup of patients with anaemia and a subgroup of patients who were treated >4 weeks. CONCLUSIONS: Evidence on the effects of supplementation of low concentrations of vitamin B12 and folate on haematological parameters in community-dwelling older people is inconclusive. Further research is needed before firm recommendations can be made concerning the supplementation of vitamin B12 and folate. PMID- 29520084 TI - Publisher Correction: Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. AB - In the version of this Article originally published, the affiliations for Roland A. Fleck and Jose Antonio Del Rio were incorrect due to a technical error that resulted in affiliations 8 and 9 being switched. The correct affiliations are: Roland A. Fleck: 8Centre for Ultrastructural Imaging, Kings College London, London, UK. Jose Antonio Del Rio: 2Cellular and Molecular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain; 9Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 10Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. This has now been amended in all online versions of the Article. PMID- 29520085 TI - Author Correction: Effects of biochar, waste water irrigation and fertilization on soil properties in West African urban agriculture. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29520086 TI - Turning microplastics into nanoplastics through digestive fragmentation by Antarctic krill. AB - Microplastics (plastics <5 mm diameter) are at the forefront of current environmental pollution research, however, little is known about the degradation of microplastics through ingestion. Here, by exposing Antarctic krill (Euphausia superba) to microplastics under acute static renewal conditions, we present evidence of physical size alteration of microplastics ingested by a planktonic crustacean. Ingested microplastics (31.5 um) are fragmented into pieces less than 1 um in diameter. Previous feeding studies have shown spherical microplastics either; pass unaffected through an organism and are excreted, or are sufficiently small for translocation to occur. We identify a new pathway; microplastics are fragmented into sizes small enough to cross physical barriers, or are egested as a mixture of triturated particles. These findings suggest that current laboratory based feeding studies may be oversimplifying interactions between zooplankton and microplastics but also introduces a new role of Antarctic krill, and potentially other species, in the biogeochemical cycling and fate of plastic. PMID- 29520088 TI - Epigenetics: Methylating patterns. PMID- 29520087 TI - Genetic and metabolic regulation of Mycobacterium tuberculosis acid growth arrest. AB - Mycobacterium tuberculosis (Mtb) senses and adapts to acidic environments during the course of infection. Acidic pH-dependent adaptations include the induction of metabolic genes associated with anaplerosis and growth arrest on specific carbon sources. Here we report that deletion of isocitrate lyase or phosphoenolpyruvate carboxykinase results in reduced growth at acidic pH and altered metabolite profiles, supporting that remodeling of anaplerotic metabolism is required for pH dependent adaptation. Mtb cultured at pH 5.7 in minimal medium containing glycerol as a single carbon source exhibits an acid growth arrest phenotype, where the bacterium is non-replicating but viable and metabolically active. The bacterium assimilates and metabolizes glycerol and maintains ATP pools during acid growth arrest and becomes tolerant to detergent stress and the antibiotics isoniazid and rifampin. A forward genetic screen identified mutants that do not arrest their growth at acidic pH, including four enhanced acid growth (eag) mutants with three distinct mutations in the proline-proline-glutamate (PPE) gene MT3221 (also named ppe51). Overexpression of the MT3221(S211R) variant protein in wild type Mtb results in enhanced acid growth and reduced drug tolerance. These findings support that acid growth arrest is a genetically controlled, adaptive process and not simply a physiological limitation associated with acidic pH. PMID- 29520089 TI - Immunotherapy: Tear down this wall. PMID- 29520091 TI - Author Correction: A Robust Method for Inferring Network Structures. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29520090 TI - Non-angiogenic tumours and their influence on cancer biology. AB - Solid tumours need a blood supply, and a large body of evidence has previously suggested that they can grow only if they induce the development of new blood vessels, a process known as tumour angiogenesis. On the basis of this hypothesis, it was proposed that anti-angiogenic drugs should be able to suppress the growth of all solid tumours. However, clinical experience with anti-angiogenic agents has shown that this is not always the case. Reports of tumours growing without the formation of new vessels can be found in the literature dating back to the 1800s, yet no formal recognition, description and demonstration of their special biological status was made until recently. In 1996, we formally recognized and described non-angiogenic tumours in lungs where the only blood vessels present were those originating from normal lung tissue. This is far from an isolated scenario, as non-angiogenic tumour growth has now been observed in tumours of many different organs in both humans and preclinical animal models. In this Opinion article, we summarize how these tumours were discovered and discuss what we know so far about their biology and the potential implications of this knowledge for cancer treatment. PMID- 29520093 TI - Tissue-agnostic cancer drug pipeline grows, despite doubts. PMID- 29520092 TI - An immunoproteomic approach revealing peptides from Sporothrix brasiliensis that induce a cellular immune response in subcutaneous sporotrichosis. AB - Sporothrix brasiliensis is the most virulent fungus of the Sporothrix complex and is the main species recovered in the sporotrichosis zoonotic hyperendemic area in Rio de Janeiro. A vaccine against S. brasiliensis could improve the current sporotrichosis situation. Here, we show 3 peptides from S. brasiliensis immunogenic proteins that have a higher likelihood for engaging MHC-class II molecules. We investigated the efficiency of the peptides as vaccines for preventing subcutaneous sporotrichosis. In this study, we observed a decrease in lesion diameters in peptide-immunized mice, showing that the peptides could induce a protective immune response against subcutaneous sporotrichosis. ZR8 peptide is from the GP70 protein, the main antigen of the Sporothrix complex, and was the best potential vaccine candidate by increasing CD4+ T cells and higher levels of IFN-gamma, IL-17A and IL-1beta characterizing a strong cellular immune response. This immune environment induced a higher number of neutrophils in lesions that are associated with fungus clearance. These results indicated that the ZR8 peptide induces a protective immune response against subcutaneous sporotrichosis and is a vaccine candidate against S. brasiliensis infection. PMID- 29520094 TI - Vaccines take a shot at antimicrobial resistance. PMID- 29520095 TI - Transient rheology of the Sumatran mantle wedge revealed by a decade of great earthquakes. AB - Understanding the rheological properties of the upper mantle is essential to develop a consistent model of mantle dynamics and plate tectonics. However, the spatial distribution and temporal evolution of these properties remain unclear. Here, we infer the rheological properties of the asthenosphere across multiple great megathrust earthquakes between 2004 and 2014 along the Sumatran subduction zone, taking advantage of decade-long continuous GPS and tide-gauge measurements. We observe transient mantle wedge flow following these earthquakes, and infer the temporal evolution of the effective viscosity. We show that the evolution of stress and strain rate following these earthquakes is better matched by a bi viscous than by a power-law rheology model, and we estimate laterally heterogeneous transient and background viscosities on the order of ~1017 and ~1019 Pa s, respectively. Our results constitute a preliminary rheological model to explain stress evolution within earthquake cycles and the development of seismic hazard in the region. PMID- 29520096 TI - Surgical Anatomy of the Superior Mesenteric Vessels Related to Colon and Pancreatic Surgery: A Systematic Review and Meta-Analysis. AB - The surgeon dissecting the base of the mesenterium, around the superior mesenteric vein (SMV) and artery, is facing a complex tridimensional vascular anatomy and should be aware of the anatomical variants in this area. The aim of this systematic review is to propose a standardized terminology of the superior mesenteric vessels, with impact in colon and pancreatic resections. We conducted a systematic search in PubMed/MEDLINE and Google Scholar databases up to March 2017. Forty-five studies, involving a total of 6090 specimens were included in the present meta-analysis. The pooled prevalence of the ileocolic, right colic and middle colic arteries was 99.8%, 60.1%, and 94.6%, respectively. The superior right colic vein and Henle trunk were present in 73.9%, and 89.7% of specimens, respectively. In conclusion, the infra-pancreatic anatomy of the superior mesenteric vessels is widely variable. We propose the term Henle trunk to be used for any venous confluence between gastric, pancreatic and colic veins, which drains between the inferior border of the pancreas and up to 20 mm downward on the right-anterior aspect of the SMV. The term gastrocolic trunk should not be synonymous, but a subgroup of the Henle trunk, together with to gastropancreatocolic, gastropancreatic, or colopancreatic trunk. PMID- 29520097 TI - An accurate and robust imputation method scImpute for single-cell RNA-seq data. AB - The emerging single-cell RNA sequencing (scRNA-seq) technologies enable the investigation of transcriptomic landscapes at the single-cell resolution. ScRNA seq data analysis is complicated by excess zero counts, the so-called dropouts due to low amounts of mRNA sequenced within individual cells. We introduce scImpute, a statistical method to accurately and robustly impute the dropouts in scRNA-seq data. scImpute automatically identifies likely dropouts, and only perform imputation on these values without introducing new biases to the rest data. scImpute also detects outlier cells and excludes them from imputation. Evaluation based on both simulated and real human and mouse scRNA-seq data suggests that scImpute is an effective tool to recover transcriptome dynamics masked by dropouts. scImpute is shown to identify likely dropouts, enhance the clustering of cell subpopulations, improve the accuracy of differential expression analysis, and aid the study of gene expression dynamics. PMID- 29520099 TI - Comparative Proteomic Profiling and Biomarker Identification of Traditional Chinese Medicine-Based HIV/AIDS Syndromes. AB - Given the challenges in exploring lifelong therapy with little side effect for human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) cases, there is increasing interest in developing traditional Chinese medicine (TCM) treatments based on specific TCM syndrome. However, there are few objective and biological evidences for classification and diagnosis of HIV/AIDS TCM syndromes to date. In this study, iTRAQ-2DLC-MS/MS coupled with bioinformatics were firstly employed for comparative proteomic profiling of top popular TCM syndromes of HIV/AIDS: accumulation of heat-toxicity (AHT) and Yang deficiency of spleen and kidney (YDSK). It was found that for the two TCM syndromes, the identified differential expressed proteins (DEPs) as well as their biological function distributions and participation in signaling pathways were significantly different, providing biological evidence for the classification of HIV/AIDS TCM syndromes. Furthermore, the TCM syndrome-specific DEPs were confirmed as biomarkers based on western blot analyses, including FN1, GPX3, KRT10 for AHT and RBP4, ApoE, KNG1 for YDSK. These biomarkers also biologically linked with the specific TCM syndrome closely. Thus the clinical and biological basis for differentiation and diagnosis of HIV/AIDs TCM syndromes were provided for the first time, providing more opportunities for stable exertion and better application of TCM efficacy and superiority in HIV/AIDS treatment. PMID- 29520098 TI - Metaboloptics: Visualization of the tumor functional landscape via metabolic and vascular imaging. AB - Many cancers adeptly modulate metabolism to thrive in fluctuating oxygen conditions; however, current tools fail to image metabolic and vascular endpoints at spatial resolutions needed to visualize these adaptations in vivo. We demonstrate a high-resolution intravital microscopy technique to quantify glucose uptake, mitochondrial membrane potential (MMP), and SO2 to characterize the in vivo phentoypes of three distinct murine breast cancer lines. Tetramethyl rhodamine, ethyl ester (TMRE) was thoroughly validated to report on MMP in normal and tumor-bearing mice. Imaging MMP or glucose uptake together with vascular endpoints revealed that metastatic 4T1 tumors maintained increased glucose uptake across all SO2 ("Warburg effect"), and also showed increased MMP relative to normal tissue. Non-metastatic 67NR and 4T07 tumor lines both displayed increased MMP, but comparable glucose uptake, relative to normal tissue. The 4T1 peritumoral areas also showed a significant glycolytic shift relative to the tumor regions. During a hypoxic stress test, 4T1 tumors showed significant increases in MMP with corresponding significant drops in SO2, indicative of intensified mitochondrial metabolism. Conversely, 4T07 and 67NR tumors shifted toward glycolysis during hypoxia. Our findings underscore the importance of imaging metabolic endpoints within the context of a living microenvironment to gain insight into a tumor's adaptive behavior. PMID- 29520100 TI - Surface plasmon resonance extension through two-block metal-conducting polymer nanorods. AB - Research on surface plasmon resonance coupling of metallic nanostructures is an important area in the field of plasmonics because distinctive collective optical properties can be realized that are different from the individual constituents. Here we report the localized surface plasmon resonance of hybrid metal-organic nanorods. Colloidal-dispersed Au-PPy nanorods were synthesized as a representative material using a modified electrochemical method, and the collective oscillation properties were systematically investigated by comparing these materials with pure Au nanorods. We observed the extended surface plasmon resonance of a hybrid system. The presence of doped-PPy segments on Au segments induced an enhanced coherent electric field due to the partial contribution of pi electrons on the PPy segment, which led to a red-shifted plasmon feature. Additionally, we demonstrated that surface plasmon resonance extension can be tuned by dopant anions, which demonstrates a way of tuning a dopant-induced plasmonic system. PMID- 29520101 TI - Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole. AB - Trimethoprim (TMP)-sulfamethoxazole (SMX) is a widely used synergistic antimicrobial combination to treat a variety of bacterial and certain fungal infections. These drugs act by targeting sequential steps in the biosynthetic pathway for tetrahydrofolate (THF), where SMX inhibits production of the THF precursor dihydropteroate, and TMP inhibits conversion of dihydrofolate (DHF) to THF. Consequently, SMX potentiates TMP by limiting de novo DHF production and this mono-potentiation mechanism is the current explanation for their synergistic action. Here, we demonstrate that this model is insufficient to explain the potent synergy of TMP-SMX. Using genetic and biochemical approaches, we characterize a metabolic feedback loop in which THF is critical for production of the folate precursor dihydropterin pyrophosphate (DHPPP). We reveal that TMP potentiates SMX activity through inhibition of DHPPP synthesis. Our study demonstrates that the TMP-SMX synergy is driven by mutual potentiation of the action of each drug on the other. PMID- 29520102 TI - KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response mediated apoptosis in glioblastoma cells. AB - The nuclear import receptor karyopherin beta1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest. KPNB1 inhibition upregulated Puma and Noxa and freed Mcl-1-sequestered Bax and Bak, leading to mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Moreover, combination of Bcl-xL inhibitors and KPNB1 inhibition enhanced apoptosis in glioblastoma cells. KPNB1 inhibition promoted cytosolic retention of its cargo and impaired cellular proteostasis, resulting in elevated polyubiquitination, formation of aggresome-like-induced structure (ALIS), and unfolded protein response (UPR). Ubiquitination elevation and UPR activation in KPNB1-deficient cells were reversed by KPNB1 overexpression or inhibitors of protein synthesis but aggravated by inhibitors of autophagy-lysosome or proteasome, indicating that rebalance of cytosolic/nuclear protein distribution and alleviation of protein overload favor proteostasis and cell survival. Chronic activation of eIF2alpha/ATF4 cascade of UPR was responsible for the upregulation of Puma and Noxa, apoptosis and ABT-263 sensitivity. Taken together, our findings demonstrate that KPNB1 is required for proteostasis maintenance and its inhibition induces apoptosis in glioblastoma cells through UPR-mediated deregulation of Bcl-2 family members. PMID- 29520103 TI - Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression. AB - Metformin has beneficial effects of preventing and treating cancers on type 2 diabetic patients. However, the role of metformin in non-diabetic cancer patients and the precise molecular mechanisms against cancer have not yet been sufficiently elucidated. We recently reported that the pseudokinase protein TRIB3 acts as a stress sensor linking metabolic stressors to cancer promotion by inhibiting autophagy and ubiquitin-proteasomal degradation systems; genetically abrogating of TRIB3 expression reduces tumourigenesis and cancer progression. Thus, TRIB3 is a potential therapeutic target for diverse cancers. In this study, we found that metformin attenuates melanoma growth and metastasis by reducing TRIB3 expression in non-diabetic C57BL/6 mice and diabetic KK-Ay mice; overexpression of TRIB3 protects metformin from the activation of autophagic flux, the clearance of accumulated tumour-promoting factors and the attenuation of tumour progression. We further elucidated that TRIB3 acts as an adaptor to recruit lysine acetyltransferase 5 (KAT5) to SMAD3 and induce a phosphorylation dependent K333 acetylation of SMAD3, which sustains transcriptional activity of SMAD3 and subsequently enhances TRIB3 transcription. Metformin suppresses SMAD3 phosphorylation and decreases the KAT5/SMAD3 interaction, to attenuate the KAT5 mediated K333 acetylation of SMAD3, reduce the SMAD3 transcriptional activity and subsequent TRIB3 expression, thereby antagonizes melanoma progression. Together, our study not only defines a molecular mechanism by which metformin protects against melanoma progression by disturbing the KAT5/TRIB3/SMAD3 positive feedback loop in diabetes and non-diabetes mice, but also suggests a candidate diverse utility of metformin in tumour prevention and therapy because of suppressing stress protein TRIB3 expression. PMID- 29520104 TI - The Rbm38-p63 feedback loop is critical for tumor suppression and longevity. AB - The RNA-binding protein Rbm38 is a target of p63 tumor suppressor and can in-turn repress p63 expression via mRNA stability. Thus, Rbm38 and p63 form a negative feedback loop. To investigate the biological significance of the Rbm38-p63 loop in vivo, a cohort of WT, Rbm38-/-, TAp63+/-, and Rbm38-/-;TAp63+/- mice were generated and monitored throughout their lifespan. While mice deficient in Rbm38 or TAp63 alone died mostly from spontaneous tumors, compound Rbm38-/-;TAp63+/- mice had an extended lifespan along with reduced tumor incidence. We also found that loss-of-Rbm38 markedly decreased the percentage of liver steatosis in TAp63+/- mice. Moreover, we found that Rbm38 deficiency extends the lifespan of tumor-free TAp63+/- mice along with reduced expression of senescence-associated biomarkers. Consistent with this, Rbm38-/-;TAp63+/- MEFs were resistant, whereas Rbm38-/- or TAp63+/- MEFs were prone, to cellular senescence. Importantly, we showed that the levels of inflammatory cytokines (IL17D and Tnfsf15) were significantly reduced by Rbm38 deficiency in senescence-resistant Rbm38-/ ;TAp63+/- mouse livers and MEFs. Together, our data suggest that Rbm38 and p63 function as intergenic suppressors in aging and tumorigenesis and that the Rbm38 p63 loop may be explored for enhancing longevity and cancer management. PMID- 29520105 TI - Metastasis-associated miR-23a from nasopharyngeal carcinoma-derived exosomes mediates angiogenesis by repressing a novel target gene TSGA10. AB - Benefiting from more precise imaging and radiotherapy, patients with locoregionally nasopharyngeal carcinoma (NPC) have a significantly higher survival rate. Nonetheless, distant metastasis is still the predominant mode of failure. Advances in cancer research have highlighted that pathological angiogenesis is necessary for tumor metastasis by offering oxygen, nutrients, or cell metastatic conduits. MicroRNAs (miRNAs), a class of small noncoding RNAs, are increasingly implicated in modulation of angiogenesis in physiological and pathological conditions. Currently, we detected that miR-23a was highly enriched in NPC tissues at the metastatic or premetastatic stage, and its levels in NPC were associated with microvessel density. Subsequently, we proved that alteration of miR-23a expression modulated the growth, migration, and tube formation of HUVECs in vitro and affected the blood vessel outgrowth in the zebrafish model. Considering the possibility that extracellular miR-23a was horizontally transferred from CNE2 cells to HUVECs, we analyzed miR-23a encapsulated in exosomes, showing that overexpression of exosomal miR-23a in NPC promoted angiogenesis both in vitro and in vivo. Moreover, we provided evidences that miR 23a regulated angiogenesis by directly targeting testis-specific gene antigen (TSGA10). Taken together, our findings revealed that metastasis-associated miR 23a from NPC-derived exosomes plays an important role in mediating angiogenesis by targeting TSGA10. PMID- 29520106 TI - microRNA-200a downregulation in human glioma leads to Galphai1 over-expression, Akt activation, and cell proliferation. AB - We previously identified a pivotal role for G protein alpha inhibitory subunit 1 (Galphai1) in mediating PI3K-Akt signaling by receptor tyrosine kinases (RTKs). Here, we examined the expression and biological function of Galphai1 in human glioma. Galphai1 mRNA and protein expression were significantly upregulated in human glioma tissues, which correlated with downregulation of an anti-Galphai1 miRNA: microRNA-200a ("miR-200a"). Forced-expression of miR-200a in established (A172/U251MG lines) and primary (patient-derived) human glioma cells resulted in Galphai1 downregulation, Akt inactivation and proliferation inhibition. Reduction of Galphai1 expression by shRNA, dominant negative mutant interference, or complete Galphai1 depletion inhibited Akt activation and cell proliferation. Notably, miR-200a was unable to inhibit glioma cell proliferation when Galphai1 was silenced or mutated. Co-immunoprecipitation studies, in human glioma cells and tissues, show that Galphai1 forms a complex with multiple RTKs (EGFR, PDGFRalpha, and FGFR) and the adapter protein Gab1. In vivo, the growth of subcutaneous and orthotopic glioma xenografts in nude mice was largely inhibited by expression of Galphai1 shRNA or miRNA-200a. Collectively, miR-200a downregulation in human glioma leads to Galphai1 over-expression, Akt activation and glioma cell proliferation. PMID- 29520107 TI - Sacrificial-template-free synthesis of core-shell C@Bi2S3 heterostructures for efficient supercapacitor and H2 production applications. AB - Core-shell heterostructures have attracted considerable attention owing to their unique properties and broad range of applications in lithium ion batteries, supercapacitors, and catalysis. Conversely, the effective synthesis of Bi2S3 nanorod core@ amorphous carbon shell heterostructure remains an important challenge. In this study, C@Bi2S3 core-shell heterostructures with enhanced supercapacitor performance were synthesized via sacrificial- template-free one pot-synthesis method. The highest specific capacities of the C@Bi2S3 core shell was 333.43 F g-1 at a current density of 1 A g-1. Core-shell-structured C@Bi2S3 exhibits 1.86 times higher photocatalytic H2 production than the pristine Bi2S3 under simulated solar light irradiation. This core-shell feature of C@Bi2S3 provides efficient charge separation and transfer owing to the formed heterojunction and a short radial transfer path, thus efficiently diminishing the charge recombination; it also facilitates plenty of active sites for the hydrogen evolution reaction owing to its mesoporous nature. These outcomes will open opportunities for developing low-cost and noble-metal-free efficient electrode materials for water splitting and supercapacitor applications. PMID- 29520108 TI - Low-temperature synthesis and investigation into the formation mechanism of high quality Ni-Fe layered double hydroxides hexagonal platelets. AB - This paper describes the wet-chemistry synthesis of highly crystalline hexagonal flakes of Ni-Fe layered double hydroxide (LDH) produced at temperature as low as 100 degrees C. The flakes with diameter in the range of 0.5-1.5 MUm and the thickness between 15 and 20 nm were obtained by homogeneous precipitation method with the use of triethanolamine (TEA) and urea. By analyzing the intermediate products, it is suggested that, differently from previous reports, a thermodynamically metastable iron oxyhydroxide and Ni-TEA complex are firstly formed at room temperature. Subsequently, when the mixture is heated to 100 degrees C and the pH increases due to the thermal decomposition of urea, Ni2+ and Fe3+ are slowly released and then recombine, thus leading to formation of pure, highly-crystalline Ni-Fe LDH flakes. This material showed promising results as an electrocatalyst in oxygen evolution reaction (OER) providing an overpotential value of 0.36 V. PMID- 29520109 TI - Physical activity, sedentary behaviour and colorectal cancer risk in the UK Biobank. AB - This corrects the article DOI: 10.1038/bjc.2017.85. PMID- 29520110 TI - Capsaicin upregulates HDAC2 via TRPV1 and impairs neuronal maturation in mice. AB - Transient receptor potential vanilloid 1 (TRPV1) affects mood and neuroplasticity in the brain, where its role is poorly understood. In the present study we investigated whether capsaicin (8-methyl-N-vanillyl-trans-6-nonenamide), an agonist of TRPV1, induced chromatin remodeling and thereby altered gene expression related to synaptic plasticity. We found that capsaicin treatment resulted in upregulation of histone deacetylase 2 (HDAC2) in the mouse hippocampus and HDAC2 was enriched at Psd95, synaptophysin, GLUR1, GLUR2 promoters. Viral-mediated hippocampal knockdown of HDAC2 induced expression of Synapsin I and prevented the detrimental effects of capsaicin on Synapsin I expression in mice, supporting the role of HDAC2 in regulation of capsaicin induced Synapsin I expression. Taken together, our findings implicate HDAC2 in capsaicin-induced transcriptional regulation of synaptic molecules and support the view that HDAC2 is a molecular link between TRPV1 activity and synaptic plasticity. PMID- 29520111 TI - Evaluation of several methodological challenges in circulating miRNA qPCR studies in patients with head and neck cancer. AB - Circulating microRNAs (ci-miRNAs) in blood have emerged as promising diagnostic, prognostic and predictive biomarkers in cancer. Many clinical studies currently incorporate studies that assess ci-miRNAs. Validation of the clinical significance of candidate biomarker miRNAs has proven to be difficult, potentially resulting from vast discrepancies in the detection methodology as well as biological variability. In the current study, the influence of several methodological factors on ci-miRNA detection was evaluated as well as short-term biological variability in patients with head and neck cancer. RNA was isolated from 124 serum and plasma samples originating from patients with head and neck cancer and healthy volunteers. The miRNA levels were measured using RT-qPCR and the influence of pre-analytical factors, different normalization strategies and temporal reproducibility was assessed. RNA carriers improved ci-miRNA detection in serum and plasma specimens. A prolonged pre-processing time correlated with an increased hemolytic index in serum samples only. Hemolysis differentially affected the detection of individual miRNAs. Optimal normalization was achieved using the averaged detection values of spike-in cel-miR-39-3p and endogenous miR 16-5p. Comparing biological replicates from patients with head and neck cancer, the intra-individual miRNA levels were relatively stable (average interval 7 days). Differences in the ci-miRNA detection methodology and limitations of currently used technologies can greatly affect the results and may explain inconsistent outcomes between studies. Prior to the implementation of ci-miRNAs as useful clinical biomarkers, further advances in the standardization of the detection methodology and reduction of technical variability are needed. PMID- 29520113 TI - The factorial structure of job-related affective well-being: Polish adaptation of the Warr's measure. AB - OBJECTIVES: The first aim of the study reported in this article was to test the factorial structure of job-related affect in a Polish sample. The second aim was to develop the Polish adaptation of the Warr's job-related affective well-being measure published in 1990, which is designed to assess 4 types of affect at work: anxiety, comfort, depression, enthusiasm. MATERIAL AND METHODS: A longitudinal study design with 2 measurement times was used for verifying the psychometric properties of the Polish version of the measure. The final sample consisted of 254 Polish employees from different professions. Participants were asked to fill in a set of questionnaires consisting of measures capturing job-related affective well-being, mood, and turnover intention. RESULTS: The first step of analysis was to test the theoretically-based structure of the job-related affective well-being measure in a Polish sample. The confirmatory factor analysis revealed that a 4 factor model best describes the structure of the measure in comparison to 5 alternative models. Next, reliability of this measure was assessed. All scales achieved good internal consistency and acceptable test-retest reliability after 2 weeks. Finally, the convergent and discriminant validity as well as the criterion and predictive validity of all job-related affective well-being scales was confirmed, based on correlations between job-related affect and mood as well as turnover intention. CONCLUSIONS: The results suggest that the Polish adaptation of Warr's job-related affective well-being measure can be used by scientists as well as by practitioners who aim at assessing 4 types of affective well-being at a work context. Int J Occup Med Environ Health 2018;31(4):429-443. PMID- 29520114 TI - Letter to the Editor (November 15, 2017) concerning the paper "Screening commercial drivers for obstructive sleep apnea: Validation of STOP-Bang questionnaire". PMID- 29520112 TI - Transcriptional regulation and development of regulatory T cells. AB - Regulatory T (Treg) cells are a distinct subset of CD4+ T cells. Instead of triggering adaptive immunity, they suppress immune responses. Small numbers of Treg cells reside within lymphoid organs and peripheral tissues, but their contribution to immune tolerance is so significant that defects in Treg cell function cause catastrophic immune disorders. Since they were first discovered 20 years ago, efforts have been made to understand the differences in developmental processes between Treg cells and conventional T cells that determine the ultimate fate of the overall T-cell population. Transcription factor Foxp3 is crucial for Treg cell differentiation, but it is not the whole story. Owing to recent advances in Treg cell research, we are now on the verge of appreciating the comprehensive mechanisms underlying Treg cell generation. Here, we discuss major discoveries, active study topics and remaining questions regarding Treg cell development. PMID- 29520115 TI - Authors' response (November 28, 2017) to the letter to the Editor concerning the paper "Screening commercial drivers for obstructive sleep apnea: Validation of STOP-Bang questionnaire". PMID- 29520116 TI - POLYCYCLIC AROMATIC HYDROCARBONS WITH STRAIGHT EDGES AND THE 7.6/6.2 AND 8.6/6.2 INTENSITY RATIOS IN REFLECTION NEBULAE. AB - We have investigated the mid-infrared spectral characteristics of a series of polycyclic aromatic hydrocarbons (PAHs) with straight edges and containing an even or odd number of carbons using density functional theory (DFT). For several even and odd-carbon PAHs, the 8.6/6.2 and 7.6/6.2 intensity ratios computed in emission after the absorption of a 8 eV photon match the observed ratios obtained for three reflection nebulae (RNe), namely NGC 1333, NGC 7023, and NGC 2023. Odd carbon PAHs are favored, particularly for NGC 1333. Both cations and anions are present with the cations being predominant. Relevant PAHs span sizes ranging from 46 to 103-113 carbons for NGC 7023 and NGC 2023 and from 38 to 127 carbons for NGC 1333 and have symmetries ranging from D2h to C s . Our work suggests that even and odd-carbon PAHs with straight edges are viable candidates for the PAH emission seen towards irradiated Photo-Dissociation Regions (PDRs). PMID- 29520117 TI - International Intercomparison of Specific Absorption Rates in a Flat Absorbing Phantom in the Near-Field of Dipole Antennas. AB - This paper reports the results of an international intercomparison of the specific absorption rates (SARs) measured in a flat-bottomed container (flat phantom), filled with human head tissue simulant fluid, placed in the near-field of custom-built dipole antennas operating at 900 and 1800 MHz, respectively. These tests of the reliability of experimental SAR measurements have been conducted as part of a verification of the ways in which wireless phones are tested and certified for compliance with safety standards. The measurements are made using small electric-field probes scanned in the simulant fluid in the phantom to record the spatial SAR distribution. The intercomparison involved a standard flat phantom, antennas, power meters, and RF components being circulated among 15 different governmental and industrial laboratories. At the conclusion of each laboratory's measurements, the following results were communicated to the coordinators: Spatial SAR scans at 900 and 1800 MHz and 1 and 10 g maximum spatial SAR averages for cubic volumes at 900 and 1800 MHz. The overall results, given as meanstandard deviation, are the following: at 900 MHz, 1 g average 7.850.76; 10 g average 5.160.45; at 1800 MHz, 1 g average 18.44 +/- 1.65; 10 g average 10.14 +/- 0.85, all measured in units of watt per kilogram, per watt of radiated power. PMID- 29520118 TI - Survey of Pest Management Practices on Washington Dairy Farms. AB - Washington state dairy producers were surveyed to determine pest and parasite prevalence and range of current pest management strategies. Nearly all respondents reported treating their cattle or premises for flies, while 62% reported treating their animals for external parasites. Use of pyrethroid and pyrethrins insecticides was common throughout the state. Results indicated that use of non-chemical options to control flies are commonly used by Washington dairy producers and may have become more widespread since the late 1990s. Extension professionals could improve outreach education to dairies by partnering with farm supply stores, veterinarians, and feed distributors. PMID- 29520119 TI - Stroke Literature Synopses: Basic Science (2017/Aug). PMID- 29520120 TI - A Semiparametric Single-Index Risk Score Across Populations. AB - We consider a problem motivated by issues in nutritional epidemiology, across diseases and populations. In this area, it is becoming increasingly common for diseases to be modeled by a single diet score, such as the Healthy Eating Index, the Mediterranean Diet Score, etc. For each disease and for each population, a partially linear single-index model is fit. The partially linear aspect of the problem is allowed to differ in each population and disease. However, and crucially, the single-index itself, having to do with the diet score, is common to all diseases and populations, and the nonparametrically estimated functions of the single-index are the same up to a scale parameter. Using B-splines with an increasing number of knots, we develop a method to solve the problem, and display its asymptotic theory. An application to the NIH-AARP Study of Diet and Health is described, where we show the advantages of using multiple diseases and populations simultaneously rather than one at a time in understanding the effect of increased Milk consumption. Simulations illustrate the properties of the methods. PMID- 29520121 TI - Avoided climate impacts of urban and rural heat and cold waves over the U.S. using large climate model ensembles for RCP8.5 and RCP4.5. AB - Previous studies examining future changes in heat/cold waves using climate model ensembles have been limited to grid cell-average quantities. Here, we make use of an urban parameterization in the Community Earth System Model (CESM) that represents the urban heat island effect, which can exacerbate extreme heat but may ameliorate extreme cold in urban relative to rural areas. Heat/cold wave characteristics are derived for U.S. regions from a bias-corrected CESM 30-member ensemble for climate outcomes driven by the RCP8.5 forcing scenario and a 15 member ensemble driven by RCP4.5. Significant differences are found between urban and grid cell-average heat/cold wave characteristics. Most notably, urban heat waves for 1981-2005 are more intense than grid cell-average by 2.1 degrees C (southeast) to 4.6 degrees C (southwest), while cold waves are less intense. We assess the avoided climate impacts of urban heat/cold waves in 2061-2080 when following the lower forcing scenario. Urban heat wave days per year increase from 6 in 1981-2005 to up to 92 (southeast) in RCP8.5. Following RCP4.5 reduces heat wave days by about 50%. Large avoided impacts are demonstrated for individual communities; e.g., the longest heat wave for Houston in RCP4.5 is 38 days while in RCP8.5 there is one heat wave per year that is longer than a month with some lasting the entire summer. Heat waves also start later in the season in RCP4.5 (earliest are in early May) than RCP8.5 (mid-April), compared to 1981-2005 (late May). In some communities, cold wave events decrease from 2 per year for 1981 2005 to one-in-five year events in RCP4.5 and one-in-ten year events in RCP8.5. PMID- 29520123 TI - Testing the reciprocal associations among co-worker incivility, organisational inefficiency, and work-related exhaustion: A one-year, cross-lagged study. AB - In spite of the considerable number of studies on co-worker incivility, knowledge on this topic needs to be further enhanced. In particular, no studies have focused on the reciprocal nature of the relationship of incivility with other important aspects of working life, i.e. employee well-being and the quality of the working process. The aim of the present study was to examine the cross-lagged associations among co-worker incivility, work-related exhaustion, and organisational efficiency in a sample of healthcare workers. Based on the conservation of resource theory, we hypothesised that those three variables affect each other reciprocally over the time. Data from a two-wave study design (with a one-year time lag) were utilised, and cross-lagged structural equation models were performed. Results confirmed that incivility and efficiency affected each other reciprocally over time. On the other hand, whereas incivility positively predicted exhaustion and exhaustion at inversely predicted organisational efficiency, the opposite paths were found to be not significant. The study suggests that efficiency is crucial for understanding incivility because it operates both as its cause and as its outcome. Interventions aimed at promoting civility and respect in the workplace may help prevent co-worker incivility, work-related exhaustion, and enhance organisational efficiency. PMID- 29520124 TI - Bandit strategies evaluated in the context of clinical trials in rare life threatening diseases. AB - In a rare life-threatening disease setting the number of patients in the trial is a high proportion of all patients with the condition (if not all of them). Further, this number is usually not enough to guarantee the required statistical power to detect a treatment effect of a meaningful size. In such a context, the idea of prioritizing patient benefit over hypothesis testing as the goal of the trial can lead to a trial design that produces useful information to guide treatment, even if it does not do so with the standard levels of statistical confidence. The idealised model to consider such an optimal design of a clinical trial is known as a classic multi-armed bandit problem with a finite patient horizon and a patient benefit objective function. Such a design maximises patient benefit by balancing the learning and earning goals as data accumulates and given the patient horizon. On the other hand, optimally solving such a model has a very high computational cost (many times prohibitive) and more importantly, a cumbersome implementation, even for populations as small as a hundred patients. Several computationally feasible heuristic rules to address this problem have been proposed over the last 40 years in the literature. In this article we study a novel heuristic approach to solve it based on the reformulation of the problem as a Restless bandit problem and the derivation of its corresponding Whittle index rule. Such rule was recently proposed in the context of a clinical trial in Villar et al (2015). We perform extensive computational studies to compare through both exact value calculations and simulated values the performance of this rule, other index rules and simpler heuristics previously proposed in the literature. Our results suggest that for the two and three-armed case and a patient horizon less or equal than a hundred patients, all index rules are a priori practically identical in terms of the expected proportion of success attained when all arms start with a uniform prior. However, we find that a posteriori, for specific values of the parameters of interest, the index policies outperform the simpler rules in every instance and specially so in the case of many arms and a larger, though still relatively small, total number of patients with the diseases. The very good performance of bandit rules in terms of patient benefit (i.e. expected number of successes and mean number of patients allocated to the best arm, if it exists) makes them very appealing in context of the challenge posed by drug development for rare life threatening diseases. PMID- 29520122 TI - Geometric Detection Algorithms for Cavities on Protein Surfaces in Molecular Graphics: A Survey. AB - Detecting and analyzing protein cavities provides significant information about active sites for biological processes (e.g., protein-protein or protein-ligand binding) in molecular graphics and modeling. Using the three-dimensional structure of a given protein (i.e., atom types and their locations in 3D) as retrieved from a PDB (Protein Data Bank) file, it is now computationally viable to determine a description of these cavities. Such cavities correspond to pockets, clefts, invaginations, voids, tunnels, channels, and grooves on the surface of a given protein. In this work, we survey the literature on protein cavity computation and classify algorithmic approaches into three categories: evolution-based, energy-based, and geometry-based. Our survey focuses on geometric algorithms, whose taxonomy is extended to include not only sphere-, grid-, and tessellation-based methods, but also surface-based, hybrid geometric, consensus, and time-varying methods. Finally, we detail those techniques that have been customized for GPU (Graphics Processing Unit) computing. PMID- 29520125 TI - Realizable algorithm for approximating Hilbert-Schmidt operators via Gabor Multipliers. AB - In this work, we consider new computational aspects to improve the approximation of Hilbert-Schmidt operators via generalized Gabor multipliers. One aspect is to consider the approximation of the symbol of an Hilbert-Schmidt operator as L2 projection in the spline-type space associated to a Gabor multiplier. This gives the possibility to employ a selection procedure of the analysis and synthesis function, interpreted as time-frequency lag; hence, with the related algorithm it is possible to handle both underspread and overspread operators. In the numerical section, we exploit the case of approximating overspread operators having compact and smooth spreading function and discontinuous time-varying systems. For the latter, the approximation of discontinuities in the symbol is not straightforward achievable in the generalized Gabor multipliers setting. For this reason, another aspect is to further process the symbol through a Hough transform, to detect discontinuities and to smooth them using a new class of approximants. This procedure creates a bridge between features detections techniques and harmonic analysis methods and in specific cases it almost doubles the accuracy of approximation. PMID- 29520126 TI - Optimum allocation for a dual-frame telephone survey. AB - Careful design of a dual-frame random digit dial (RDD) telephone survey requires selecting from among many options that have varying impacts on cost, precision, and coverage in order to obtain the best possible implementation of the study goals. One such consideration is whether to screen cell-phone households in order to interview cell-phone only (CPO) households and exclude dual-user household, or to take all interviews obtained via the cell-phone sample. We present a framework in which to consider the tradeoffs between these two options and a method to select the optimal design. We derive and discuss the optimum allocation of sample size between the two sampling frames and explore the choice of optimum p, the mixing parameter for the dual-user domain. We illustrate our methods using the National Immunization Survey, sponsored by the Centers for Disease Control and Prevention. PMID- 29520127 TI - GENDER CONFORMITY, PERCEPTIONS OF SHARED POWER, AND MARITAL QUALITY IN SAME- AND DIFFERENT-SEX MARRIAGES. AB - Research on gender inequality within different-sex marriages shows that women do more unpaid labor than men, and that the perception of inequality influences perceptions of marital quality. Yet research on same-sex couples suggests the importance of considering how gender is relational. Past studies show that same sex partners share unpaid labor more equally and perceive greater equity than do different-sex partners, and that lesbian, gay, and bisexual people are less gender conforming than heterosexuals. However, studies have not considered how gender conformity might shape inequalities and marital quality within same- and different-sex unions. In this study, we analyze dyadic data from both spouses in same- and different-sex marriages to explore how sex of spouse and gender conformity influence perceptions of shared power within the relationship, which, in turn, influences marital quality. Results show that greater gender conformity is related to stronger perceptions of shared power in different-sex and male same sex couples but not in female same-sex couples. Perceptions of shared power are positively associated with marital quality in all union types. Our findings suggest that maintaining hegemonic masculinity and power inequalities may be salient to marriages with men. In female same-sex couples, gender and its relation to power inequalities may carry less meaning. PMID- 29520128 TI - A study of long-term static load on degradation and mechanical integrity of Mg alloys-based biodegradable metals. AB - Predicting degradation behavior of biodegradable metals in vivo is crucial for the clinical success of medical devices. This paper reports on the effect of long term static stress on degradation of magnesium alloys and further changes in mechanical integrity. AZ31B (H24) and ZE41A (T5) alloys were tested to evaluate stress corrosion cracking (SCC) in a physiological solution for 30 days and 90 days (ASTM G39 testing standard). Scanning electron microscopy (SEM) with energy dispersive X-ray spectroscopy (EDX) and micro-computed tomography (micro-CT) were used to characterize surface morphology and micro-structure of degraded alloys. The results show the different mechanisms of stress corrosion cracking for AZ31B (transgranular stress corrosion cracking, TGSCC) and ZE41A (intergranular stress corrosion cracking, IGSCC). AZ31B was more susceptible to stress corrosion cracking under a long term static load than ZE41A. In conclusion, we observed that long-term static loading accelerated crack propagation, leading to the loss of mechanical integrity. PMID- 29520129 TI - Precise dielectric property measurements and E-field probe calibration for specific absorption rate measurements using a rectangular waveguide. AB - Specific absorption rate (SAR) measurements require accurate calculations of the dielectric properties of tissue-equivalent liquids and associated calibration of E-field probes. We developed a precise tissue-equivalent dielectric measurement and E-field probe calibration system. The system consists of a rectangular waveguide, electric field probe, and data control and acquisition system. Dielectric properties are calculated using the field attenuation factor inside the tissue-equivalent liquid and power reflectance inside the waveguide at the air/dielectric-slab interface. Calibration factors were calculated using isotropicity measurements of the E-field probe. The frequencies used are 900 MHz and 1800 MHz. The uncertainties of the measured values are within +/-3%, at the 95% confidence level. Using the same waveguide for dielectric measurements as well as calibrating E-field probes used in SAR assessments eliminates a source of uncertainty. Moreover, we clearly identified the system parameters that affect the overall uncertainty of the measurement system. PMID- 29520130 TI - Age-related changes in the peripheral retinal nerve fiber layer thickness. AB - Purpose: This pilot cross-sectional study aimed to determine age-related changes of the retinal nerve fiber layer (RNFL) thickness in retinal periphery by swept source optical coherence tomography-based analysis. Methods: Forty eyes of 40 healthy subjects were studied in three age groups, group 1 (20-40 years, n=15), group 2 (41-60 years, n=14), and group 3 (>=61 years, n=11). Wide-angle swept source optical coherence tomography scans, including the optic disc and macula, were montaged with the nasal peripheral optical coherence tomography images acquired with a contralateral gaze. The peripapillary and peripheral RNFL thickness values were obtained for nasal and temporal sides. The ratio of peripheral-to-peripapillary RNFL thickness was also calculated for these sectors. Results: We detected a significantly thinner RNFL in older than younger subjects at a distance of 6 mm from the optic disc on nasal and temporal sides (P<0.001). An age-related reduction in peripheral-to-peripapillary RNFL thickness ratios (P<0.001 and P<0.02 for nasal and temporal sides, respectively) was also detected. Conclusion: The age-related decline should be taken into consideration when determining the glaucoma-related alterations in peripheral RNFL thickness. Continued analysis in patients with ocular hypertension and glaucoma should help determine whether RNFL in the periphery with lower nerve tissue reserve might be more susceptible to injury, whether injury to the peripheral RNFL might be easier to detect, and/or whether analysis of the peripheral RNFL thickness could improve clinical diagnosis and follow-up of glaucoma. PMID- 29520131 TI - The conundrum of indeterminate QuantiFERON-TB Gold results before anti-tumor necrosis factor initiation. AB - Background: Tumor necrosis factor alpha (TNFalpha) is a key cytokine in both the pathogenesis of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) and the host defense against tuberculosis (TB). Consequently, anti-TNFalpha medications result in an increased risk of latent TB infection (LTBI) reactivation. Here, we sought to evaluate the factors affecting the results of QuantiFERON-TB Gold In-Tube (QFT-GIT) assay as a screening tool for LTBI. Methods: We conducted an observational, retrospective study in patients with IBD and RA who underwent LTBI screening using QFT-GIT at UMass Memorial Medical Center between 2008 and 2016 prior to initiation of anti-TNF medications. Results: We included 107 and 89 patients with IBD and RA, respectively. We found that a higher proportion of IBD patients had indeterminate QFT-GIT result compared to RA patients. Furthermore, we found that the majority of patients with indeterminate results were tested during an acute flare of IBD (88%) and while taking corticosteroids. Of all patients receiving >=20 mg equivalent prednisone dose (n=32), 63% resulted in indeterminate QFT-GIT, compared to only 6% indeterminate testing in patients receiving <20 mg of equivalent prednisone dose (n=164, P<0.001). There was no correlation between indeterminate results and age, gender, disease duration, or distribution, or smoking status within each population. Conclusion: We observed that high-dose corticosteroids may affect QFT GIT outcomes leading to a high proportion of indeterminate results. We propose that IBD patients should be tested prior to initiation of corticosteroids to avoid equivocal results and prevent potential delays in initiation of anti-TNF medications. PMID- 29520132 TI - Effects of frailty and chronic diseases on quality of life in Dutch community dwelling older adults: a cross-sectional study. AB - Objective: The aim of this cross-sectional study was to determine the associations between frailty and multimorbidity on the one hand and quality of life on the other in community-dwelling older people. Methods: A questionnaire was sent to all people aged 70 years and older belonging to a general practice in the Netherlands; 241 persons completed the questionnaire (response rate 47.5%). For determining multimorbidity, nine chronic diseases were examined by self report. Frailty was assessed by the Tilburg Frailty Indicator, and quality of life was assessed by the World Health Organization Quality of Life Instrument Older Adults Module. Results: Multimorbidity, physical, psychological, as well as social frailty components were negatively associated with quality of life. Multimorbidity and all 15 frailty components together explained 11.6% and 36.5% of the variance of the score on quality of life, respectively. Conclusion: Health care professionals should focus their interventions on the physical, psychological, and social domains of human functioning. Interprofessional cooperation between health care professionals and welfare professionals seems necessary to be able to meet the needs of frail older people. PMID- 29520133 TI - Bone mineral density in patients with chronic heart failure: a meta-analysis. AB - Objective: This study aimed to verify the existing relationship between bone mineral density (BMD) and chronic heart failure (CHF) by meta-analysis. Methods: Databases, including PubMed, Web of Science, and Chinese National Knowledge Infrastructure, published in English or Chinese up to February 28, 2017, were searched for studies on the association between CHF and BMD. Two independent reviewers collected the relevant articles. The standard mean deviation (SMD) and 95% confidence interval were calculated for BMD with fixed- and random-effect models. Subgroup and sensitivity analyses were also conducted. Results: A total of six studies (552 CHF and 243 non-CHF patients) were included. The results indicated that the patients with CHF had a lower total BMD compared with the non CHF patients. Similar effects were also observed for femoral neck, arm, leg, and trunk BMD. However, no difference was observed in the lumbar spine BMD. The SMD of total BMD in New York Heart Association classes I or II (NYHA I or II) patients was -0.62, while that in NYHA III or IV patients was -0.87, and the SMD of femoral bone mineral density in NYHA I or II patients was -0.47, while that in NYHA III or IV patients was -1.07. Moreover, vitamin D and parathyroid hormone (PTH) were also found to be associated with CHF. Conclusion: Patients with CHF had a lower total BMD and femoral neck, arm, leg, or trochanter BMD than patients with non-CHF. Vitamin D reduced, whereas PTH increased, with the severity of CHF. The clinical significance of the present findings remains uncertain and should be confirmed by future studies. PMID- 29520134 TI - Obstructive sleep apnea, COPD, the overlap syndrome, and mortality: results from the 2005-2008 National Health and Nutrition Examination Survey. AB - Objective: The aim of this study was to investigate the role of obstructive sleep apnea (OSA) on all-cause mortality in patients with COPD. Methods: Data for this cross-sectional study were obtained from the National Health and Nutrition Examination Survey (NHANES) data (year 2005-2008). Eligible subjects were >=20 years who had no COPD or OSA (n=9,237), had only OSA (n=366), had only COPD (n=695), and had OSA/COPD overlap syndrome (n=90). Univariate and multivariate analyses were used to evaluate factors associated with overall mortality. Results: Multivariate analysis found that the COPD and OSA/COPD overlap syndrome groups had significantly higher chance of all-cause mortality than the group of subjects who did not have OSA or COPD (adjusted hazard ratio [HR] =1.5 for the COPD group and 2.4 for the overlap syndrome group) (P<=0.007). Although not significant, having OSA/COPD overlap syndrome was associated with higher likelihood of death than COPD alone (HR =1.5; P=0.160). Other factors associated with higher overall mortality were aging, poorer family status, current smoker, serum vitamin D deficiency, cardiovascular disease, history of cancer, diabetes, and impaired renal function. Conclusion: The present study found that COPD and OSA/COPD overlap syndrome were associated with higher all-cause mortality compared with patients without either disease and that OSA did not significantly increase mortality in patients with COPD. PMID- 29520135 TI - Co-existence of COPD and bronchiectasis: a risk factor for a high ratio of main pulmonary artery to aorta diameter (PA:A) from computed tomography in COPD patients. AB - Background: Pulmonary vascular disease, especially pulmonary hypertension, is an important complication of COPD. Bronchiectasis is considered not only a comorbidity of COPD, but also a risk factor for vascular diseases. The main pulmonary artery to aorta diameter ratio (PA:A ratio) has been found to be a reliable indicator of pulmonary vascular disease. It is hypothesized that the co existence of COPD and bronchiectasis may be associated with relative pulmonary artery enlargement (PA:A ratio >1). Methods: This retrospective study enrolled COPD patients from 2012 through 2016. Demographic and clinical data were collected. Bhalla score was used to determine the severity of bronchiectasis. Patient characteristics were analyzed in two ways: the high (PA:A >1) and low (PA:A <=1) ratio groups; and COPD with and without bronchiectasis groups. Logistic regression analysis was used to assess risk factors for high PA:A ratios. Results: In this study, 480 COPD patients were included, of whom 168 had radiographic bronchiectasis. Patients with pulmonary artery enlargement presented with poorer nutrition (albumin, 35.6+/-5.1 vs 38.3+/-4.9, P<0.001), lower oxygen partial pressure (74.4+/-34.5 vs 81.3+/-25.4, P<0.001), more severe airflow obstruction (FEV1.0, 0.9+/-0.5 vs 1.1+/-0.6, P=0.004), and a higher frequency of bronchiectasis (60% vs 28.8%, P<0.001) than patients in the low ratio group. Patients with both COPD and bronchiectasis had higher levels of systemic inflammation (erythrocyte sedimentation rate, P<0.001 and fibrinogen, P=0.006) and PA:A ratios (P<0.001). A higher PA:A ratio was significantly closely correlated with a higher Bhalla score (r=0.412, P<0.001). Patients with both COPD and bronchiectasis with high ratios presented higher levels of NT-proBNP (P<0.001) and systolic pulmonary artery pressure (P<0.001). Multiple logistic analyses have indicated that bronchiectasis is an independent risk factor for high PA:A ratios in COPD patients (OR =3.707; 95% CI =1.888-7.278; P<0.001). Conclusion: Bronchiectasis in COPD has been demonstrated to be independently associated with relative pulmonary artery enlargement. PMID- 29520136 TI - Early life insults as determinants of chronic obstructive pulmonary disease in adult life. AB - Background: Early life events may predispose to the development of chronic lung disease in adulthood. Aim: To provide an update on current knowledge of early nongenetic origins of COPD. Materials and methods: Systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: A total of 16 studies, comprising 69,365 individuals, met the predefined criteria and were included in the present review. Studies have shown that in utero tobacco exposure, low birth weight, preterm birth, and respiratory diseases, primarily asthma and pneumonia, in early childhood are associated with lung function impairment later in childhood, and by that predispose to subsequent development of COPD, although the causal association between childhood respiratory diseases and COPD has been questioned in one study. Environmental tobacco exposure has also been shown to have negative impact on lung function in childhood possibly leading to COPD in adulthood, although it is at present not possible to clearly distinguish between the impact of active and the environmental tobacco exposure on subsequent development of COPD. Conclusion: Tobacco exposure in utero and early life is a risk factor for subsequent development of COPD. Furthermore, low birth weight, lower respiratory tract infections and asthma, including wheezy bronchitis, in childhood also seem to be important determinants for later development of COPD. Early life insults may, therefore, be crucial to COPD development. PMID- 29520138 TI - Pharmacokinetics, distribution and anti-tumor efficacy of liposomal mitoxantrone modified with a luteinizing hormone-releasing hormone receptor-specific peptide. AB - Background: A previous study developed a novel luteinizing hormone-releasing hormone (LHRH) receptor-targeted liposome. The aim of this study was to further assess the pharmacokinetics, biodistribution, and anti-tumor efficacy of LHRH receptor-targeted liposomes loaded with the anticancer drug mitoxantrone (MTO). Methods: Plasma and tissue distribution profiles of LHRH receptor-targeted MTO loaded liposomes (LHRH-MTO-LIPs) were quantified in healthy mice or a xenograft tumor nude mouse model of MCF-7 breast cancer, and were compared with non targeted liposomes and a free-drug solution. Results: The LHRH-MTO-LIPs demonstrated a superior pharmacokinetic profile relative to free MTO. The first target site of accumulation is the kidney, followed by the liver, and then the tumor; maximal tumor accumulation occurs at 4 h post-administration. Moreover, the LHRH-MTO-LIPs exhibited enhanced inhibition of MCF-7 breast cancer cell growth in vivo compared with non-targeted MTO-loaded liposomes (MTO-LIPs) and free MTO. Conclusion: The novel LHRH receptor-targeted liposome may become a viable platform for the future targeted treatment of cancer. PMID- 29520137 TI - Factors associated with appropriate inhaler use in patients with COPD - lessons from the REAL survey. AB - Background: Nonadherence to medication and incorrect use of inhalers represent significant barriers to optimal disease management of patients with chronic obstructive pulmonary disease (COPD). Thus, health care professionals (HCPs) play a critical role in educating their patients on appropriate inhaler use and in ensuring medication adherence. However, many patients do not receive appropriate inhaler training or have not had their inhaler technique checked. Methods: The Real-life Experience and Accuracy of inhaLer use (REAL) survey was a computer assisted, telephonic survey consisting of 23 questions gathering real-world information on correct inhaler use, inhalation technique, device attributes, adherence, dosing accuracy, training, correct device use, ease of use, and factors that influence patient adherence in commercially available inhalers delivering COPD maintenance therapy. All results are based on patient-reported data. Results: The survey was conducted between January 4, 2016 and February 2, 2016. A total of 764 patients using various inhalers (Breezhaler(r) =186; Ellipta(r) =191; Genuair(r) =194; Respimat(r) =201) with mild to very severe COPD, with a mean +/- SD age 56+/-9.8 years, completed the survey. Patient self reported adherence was significantly lower in younger patients compared to older patients (p=0.020). Eighty-three percent of patients indicated that a demonstration (in-person) was "very helpful" versus 58% for video. Patient preferences for training methods were as follows: demonstration of inhaler use (83%), video (58%), instructions for use (51%), and leaflet (34%). Twenty-nine percent of patients had not been checked to see if they were using their device correctly by a HCP within the last two years. Patients who were checked were significantly more adherent than unchecked patients (p=0.020). The majority of the patients using Breezhaler reported either being very confident or confident of having taken a full dose, which was higher than those using Genuair, Ellipta (alpha=0.05), and Respimat (alpha=0.05). Treatment adherence in the last 30 days was highest with Breezhaler followed by Respimat, Ellipta, and Genuair. Conclusion: The REAL survey identified attributes that influenced patient adherence and optimal inhaler use. Predictive attributes that influence patient adherence which HCPs should be aware of include age and disease severity. Modifiable attributes which the HCP can influence include correct inhaler use training, choice of training methods, checking patient inhaler technique at subsequent visits, and device selection. Inhalers are integral in the effective management of patients with COPD; it is therefore important that patients use the inhaler correctly and have full confidence in the dosage. PMID- 29520139 TI - Enhanced biocompatibility and osteogenic potential of mesoporous magnesium silicate/polycaprolactone/wheat protein composite scaffolds. AB - Background: Successful bone tissue engineering using scaffolds is primarily dependent on the properties of the scaffold, including biocompatibility, highly interconnected porosity, and mechanical integrity. Methods: In this study, we propose new composite scaffolds consisting of mesoporous magnesium silicate (m_MS), polycaprolactone (PCL), and wheat protein (WP) manufactured by a rapid prototyping technique to provide a micro/macro porous structure. Experimental groups were set based on the component ratio: (1) WP0% (m_MS:PCL:WP =30:70:0 weight per weight; w/w); (2) WP15% (m_MS:PCL:WP =30:55:15 w/w); (3) WP30% (m_MS:PCL:WP =30:40:30 w/w). Results: Evaluation of the properties of fabricated scaffolds indicated that increasing the amount of WP improved the surface hydrophilicity and biodegradability of m_MS/PCL/WP composites, while reducing the mechanical strength. Moreover, experiments were performed to confirm the biocompatibility and osteogenic differentiation of human mesenchymal stem cells (MSCs) according to the component ratio of the scaffold. The results confirmed that the content of WP affects proliferation and osteogenic differentiation of MSCs. Based on the last day of the experiment, ie, the 14th day, the proliferation based on the amount of DNA was the best in the WP30% group, but all of the markers measured by PCR were the most expressed in the WP15% group. Conclusion: These results suggest that the m_MS/PCL/WP composite is a promising candidate for use as a scaffold in cell-based bone regeneration. PMID- 29520140 TI - Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment. AB - A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(beta thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR) overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical (1H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer. PMID- 29520141 TI - Design and synthesis of nanoscaled IQCA-TAVV as a delivery system capable of antiplatelet activation, targeting arterial thrombus and releasing IQCA. AB - Background: Arterial thrombosis has been associated with a series of pathological conditions, and the discovery of arterial thrombosis inhibitor is of clinical importance. Methods: By analyzing the pharmacophores of anti-platelet agents, thrombus targeting peptide and anti-thrombotic nano-systems 3S-1,2,3,4 tetrahydroisoquino-line-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) was designed and prepared as a nano-scaled arterial thrombosis inhibitor. Results: In vitro the nanoparticles of IQCA-TAVV were able to adhere onto the surface of activated platelets, attenuate activated platelets to extend pseudopodia and inhibit activated platelets to form aggregators. In vivo IQCA-TAVV targeted arterial thrombus, dose dependently inhibited arterial thrombosis with a 1 nmol/kg of minimal effective dose, and the activity was1670 folds of that of aspirin. Conclusion: IQCA-TAVV represented the design, preparation and application of nanomedicine capable of adhering on the surface of activated platelets, attenuating platelet activation, targeting arterial thrombus and inhibiting arterial thrombosis. PMID- 29520142 TI - Combined use of vancomycin-modified Ag-coated magnetic nanoparticles and secondary enhanced nanoparticles for rapid surface-enhanced Raman scattering detection of bacteria. AB - Background: Pathogenic bacteria have always been a significant threat to human health. The detection of pathogens needs to be rapid, accurate, and convenient. Methods: We present a sensitive surface-enhanced Raman scattering (SERS) biosensor based on the combination of vancomycin-modified Ag-coated magnetic nanoparticles (Fe3O4@Ag-Van MNPs) and Au@Ag nanoparticles (NPs) that can effectively capture and discriminate bacterial pathogens from solution. The high performance Fe3O4@Ag MNPs were modified with vancomycin and used as bacteria capturer for magnetic separation and enrichment. The modified MNPS were found to exhibit strong affinity with a broad range of Gram-positive and Gram-negative bacteria. After separating and rinsing bacteria, Fe3O4@Ag-Van MNPs and Au@Ag NPs were synergistically used to construct a very large number of hot spots on bacteria cells, leading to ultrasensitive SERS detection. Results: The dominant merits of our dual enhanced strategy included high bacterial-capture efficiency (>65%) within a wide pH range (pH 3.0-11.0), a short assay time (<30 min), and a low detection limit (5*102 cells/mL). Moreover, the spiked tests show that this method is still valid in milk and blood samples. Owing to these capabilities, the combined system enabled the sensitive and specific discrimination of different pathogens in complex solution, as verified by its detection of Gram-positive bacterium Escherichia coli, Gram-positive bacterium Staphylococcus aureus, and methicillin-resistant S. aureus. Conclusion: This method has great potential for field applications in food safety, environmental monitoring, and infectious disease diagnosis. PMID- 29520144 TI - Sex differences in gut microbiota in patients with major depressive disorder. AB - Objective: Our previous studies found that disturbances in gut microbiota might have a causative role in the onset of major depressive disorder (MDD). The aim of this study was to investigate whether there were sex differences in gut microbiota in patients with MDD. Patients and methods: First-episode drug-naive MDD patients and healthy controls were included. 16S rRNA gene sequences extracted from the fecal samples of the included subjects were analyzed. Principal-coordinate analysis and partial least squares-discriminant analysis were used to assess whether there were sex-specific gut microbiota. A random forest algorithm was used to identify the differential operational taxonomic units. Linear discriminant-analysis effect size was further used to identify the dominant sex-specific phylotypes responsible for the differences between MDD patients and healthy controls. Results: In total, 57 and 74 differential operational taxonomic units responsible for separating female and male MDD patients from their healthy counterparts were identified. Compared with their healthy counterparts, increased Actinobacteria and decreased Bacteroidetes levels were found in female and male MDD patients, respectively. The most differentially abundant bacterial taxa in female and male MDD patients belonged to phyla Actinobacteria and Bacteroidia, respectively. Meanwhile, female and male MDD patients had different dominant phylotypes. Conclusion: These results demonstrated that there were sex differences in gut microbiota in patients with MDD. The suitability of Actinobacteria and Bacteroidia as the sex-specific biomarkers for diagnosing MDD should be further explored. PMID- 29520145 TI - Manic behavior and asymmetric right frontotemporal dementia from a novel progranulin mutation. AB - Studies suggest a relationship of manic behavior and bipolar disorder (BD) with behavioral variant frontotemporal dementia (bvFTD). The nature of this relationship is unclear. This report presents a patient with initial manic behavior as the main manifestation of familial bvFTD from a novel progranulin (GRN) mutation. In contrast, there are other reports of a long background of BD preceding a diagnosis of bvFTD. A review of the literature and this patient suggest that manic symptoms result from damage to right frontotemporal neural structures from longstanding BD, as well as from bvFTD and other focal neurological disorders. In addition, there is a subgroup of patients with a probable genetic predisposition to both BD and bvFTD. PMID- 29520146 TI - Prevalence, risk factors and microorganisms of urinary tract infections in patients with type 2 diabetes mellitus: a retrospective study in China. AB - Background: Urinary tract infections (UTIs) occur more frequently in diabetic patients. This study was conducted to investigate the prevalence, risk factors and microorganisms of UTIs in Chinese patients with type 2 diabetes (T2D). Patients and methods: A total of 3,652 Chinese inpatients with T2D were reviewed and data on their clinical characteristics, symptoms of UTIs, random blood glucose, HbA1c, glutamic acid decarboxylase antibody, insulin autoantibody, albumin excretion rate in 24-hour urine, urine culture and susceptibility to antibiotics, and so on were collected. Binary logistic analysis was performed to look for risk factors of UTIs. Results: There were 409 (11.2%) patients suffering from UTIs. Gender, age, random blood glucose, insulin autoantibody and albumin excretion rate in 24-hour urine were the risk factors of UTIs in diabetic patients. The percentage of positive urine cultures was higher in the asymptomatic bacteriuria patients than in symptomatic patients (P<0.001). The incidence of septicemia was considerable in the UTIs and asymptomatic bacteriuria groups. Escherichia coli was the most common pathogenic microorganism isolated in diabetic patients with UTIs, and one-half of the E. coli infections were multidrug resistant. Furthermore, meropenem was the most effective antibiotic on E. coli. Conclusion: We suggest that a routine urine analysis or urine culture should be conducted in patients with T2D diabetes who have the identified risk factors. The UTIs might affect the islet function or blood glucose control in patients with T2D. Before a doctor decides to prescribe antibiotics to a diabetic patient with UTIs, the drug sensitivity test should be performed. PMID- 29520147 TI - A 10-year retrospective study of alterative aeroallergens sensitization spectrum in urban children with allergic rhinitis. AB - Objective: To investigate the alterative spectrum and trends of aeroallergens sensitization in children with allergic rhinitis (AR) in Guangzhou, China in the past 10 years. Participants and methods: In this retrospective study, 4,111 children with complaints of nasal hyper-reactivity who visited the Pediatric Department and/or Otolaryngology Department from January 2007 to November 2016 were enrolled. Serum specific immunoglobulin E was measured and positive detection was made in 3,328 patients, who were, therefore, diagnosed with AR. Positive rates and trends of different aeroallergens sensitization were assessed. The tendency of positive rates changing over the years, and the difference and trends in positive rate of aeroallergen sensitization that occurred in subgroups of gender, age, and season were determined and analyzed with logistic regression. Results: The percentage of detected common aeroallergens in AR children was (from high to low) 81.07%, 34.44%, 14.72%, 11.81%, 6.04%, and 3.70% for house dust mites (HDMs), cat-dog dander, cockroach, mold mixture, tree pollen mixture, and herb pollen mixture, respectively. An ascending trend of aeroallergens sensitization or AR (odds ratio [OR] =1.116, 95% CI: 1.086-1.146) was found. Interestingly, an increasing trend of cat-dog dander and mold sensitization was found in AR children (OR =1.164, 95% CI: 1.133-1.196; OR =1.169, 95% CI: 1.120 1.223) in this retrospective study, while HDMs sensitization held a steady trend (OR =0.983, 95% CI: 0.961-1.007). Conclusion: In the increasing trend of aeroallergens sensitization or AR, HDMs sensitization still held the majority. But emphasis should be made on pet allergy for young children with AR in the context of ascending trend of sensitization to cat-dog dander. PMID- 29520143 TI - Nanotechnology-based drug delivery systems for control of microbial biofilms: a review. AB - Since the dawn of civilization, it has been understood that pathogenic microorganisms cause infectious conditions in humans, which at times, may prove fatal. Among the different virulent properties of microorganisms is their ability to form biofilms, which has been directly related to the development of chronic infections with increased disease severity. A problem in the elimination of such complex structures (biofilms) is resistance to the drugs that are currently used in clinical practice, and therefore, it becomes imperative to search for new compounds that have anti-biofilm activity. In this context, nanotechnology provides secure platforms for targeted delivery of drugs to treat numerous microbial infections that are caused by biofilms. Among the many applications of such nanotechnology-based drug delivery systems is their ability to enhance the bioactive potential of therapeutic agents. The present study reports the use of important nanoparticles, such as liposomes, microemulsions, cyclodextrins, solid lipid nanoparticles, polymeric nanoparticles, and metallic nanoparticles, in controlling microbial biofilms by targeted drug delivery. Such utilization of these nanosystems has led to a better understanding of their applications and their role in combating biofilms. PMID- 29520148 TI - Umbilical cord blood stem cells transplantation as an adjunctive treatment strategy for liver cirrhosis in Chinese population: a meta-analysis of effectiveness and safety. AB - Objective: The aim of the study was to evaluate the efficacy and safety of umbilical cord blood stem cells (USCs) transplantation combined with routine supportive therapy (RST) for liver cirrhosis (LC). Materials and methods: Clinical trials involved in this research were searched from Web of Science, PubMed, EMBASE, Cochrane Library, Wanfang and CNKI database. Treatment effects, quality of life (QoL), adverse events and other outcome measures were extracted and evaluated. Results: A total of 10 trials including 616 LC patients were involved in this study. Based on our analysis, the liver function of LC patients was significantly improved after USCs transplantation and RST combined therapy, indicated by decreased total bilirubin, alanine aminotransferase, aspartate aminotransferase levels and prothrombin time and increased serum albumin level and prothrombin activity. Compared to those treated by RST alone, patients treated by combined therapy showed more satisfied treatment effects, improved QoL reflected by improved appetite (odds ratio [OR]=5.43, 95% CI=2.84 to 10.38, P<0.00001) and relieved fatigue (OR=4.33, 95% CI=0.87 to 21.60, P=0.07), ascetic fluid (OR=4.56, 95% CI=2.69 to 7.74, P<0.00001), abdominal distension (OR=4.01, 95% CI=1.34 to 12.02, P=0.01) and edema (OR=2.69, 95% CI=0.23 to 31.72, P=0.43). No serious adverse events occurred during USCs therapy. Conclusion: USCs transplantation is a safe and effective adjuvant therapy for RST-treated LC, possibly through improving patients' liver function. PMID- 29520149 TI - Kanglaite reverses multidrug resistance of HCC by inducing apoptosis and cell cycle arrest via PI3K/AKT pathway. AB - Background: Multidrug resistance (MDR) frequently contributes to the failure of chemotherapeutic treatments in patients diagnosed with hepatocellular carcinoma (HCC). Revealing the molecular mechanism of MDR is indispensable for the development of effective chemotherapeutic drugs. Purpose: Due to the low-toxicity modulators to inhibit MDR, we considered that Kanglaite (KLT) is a potential agent for reversing MDR in HCC. Materials and Methods: BEL-7402/5-fluorouracil (5 FU) and HepG2/adriamycin (ADM) were analyzed for cell viability, colony formation assay, cell scratch assay, and cell cycle analysis and apoptosis assay by flow cytometry. The expression of PARP, caspase-3, Bax, Bcl-2, CDC25C, Cyclin B1 and phosphorylation of PTEN, PI3K, and AKT in HepG2/ADM cells were detected by western blotting. Results: The proliferation of drug-resistant cell lines BEL 7402/5-FU and HepG2/ADM pretreated with KLT was significantly inhibited when compared with drug alone. KLT could increase the accumulation of ADM in HepG2/ADM cells. In this study, we found that KLT treatment notably reduced cell viability, induced apoptosis and cell cycle arrest in human HepG2/ADM and BEL-7402/5-FU cells, and effectively reversed the MDR by p-glycoprotein (P-gp) inhibition. Moreover, KLT decreased the phosphorylation of AKT and PI3K in KLT-treated HepG2/ADM cells. These data together implied that KLT might reverse drug resistance in HCC by blocking the PI3K/AKT signaling. Conclusion: We demonstrated that KLT reversed MDR of human HCC by inducing apoptosis and cell cycle arrest via the PI3K/AKT signaling pathway. PMID- 29520150 TI - Prognostic significance of Epstein-Barr virus DNA in NK/T-cell lymphoma: a meta analysis. AB - Extranodal NK/T-cell lymphoma is closely associated with Epstein-Barr virus (EBV) infection. However, the prognostic value of EBV-DNA in extranodal NK/T-cell lymphoma remains unclear. Thus, we conducted a meta-analysis to estimate its prognostic significance. PubMed, EMBASE, and Web of Science were used to search for studies conducted until June 12, 2017. The pooled hazard ratio (HR) and its 95% confidence interval (CI) were calculated to evaluate the prognostic value of pretreatment EBV-DNA on the overall survival of extranodal NK/T-cell lymphoma. Seven eligible studies on 356 patients with extranodal NK/T-cell lymphoma were pooled for this meta-analysis. Results suggested that the pretreatment EBV-DNA positivity was significantly correlated with the overall survival of extranodal NK/T-cell lymphoma (pooled HR =3.78, 95% CI: 1.52-9.40, p=0.004; heterogeneity test: I2=52%, p=0.05). Subgroup analyses stratified by sample type, survival analysis mode, and HR origin showed that patients with positive pretreatment EBV DNA had poorer prognosis than those with negative pretreatment EBV-DNA. Moreover, the cut-off value (HR =1.66; 95% CI: 0.73-3.73; p=0.22) might account for the heterogeneity. No significant publication bias was observed. Pretreatment EBV-DNA positivity can predict poor prognosis for patients with extranodal NK/T-cell lymphoma. Future large-scale studies based on prognostic significance of EBV-DNA for patients with extranodal NK/T-cell lymphoma are necessary. PMID- 29520151 TI - How many ELNs are optimal for breast cancer patients with more than three PLNs who underwent MRM? A large population-based study. AB - Background: Few studies have focused on the optimal threshold of examed lymph nodes (ELNs) for breast cancer patients with more than three positive lymph nodes after modified radical mastectomy. Materials and methods: The X-tile and the minimum P-value models were applied to determine the optimal threshold. Cox proportional hazard analysis was used to analyze the cancer-specific survival and perform subgroup analysis. Results: The results showed that 12 ELNs was the optimal threshold for these patients, and the patients with >12 ELNs had a better cancer-specific survival benefit compared with the patients with <12 ELNs (P<0.001). Conclusion: The number 12 can be selected as the optimal threshold of ELNs for breast cancer patients with >3 positive lymph nodes after modified radical mastectomy. PMID- 29520152 TI - Prognostic value of circulating tumor cells detected with the CellSearch System in patients with gastric cancer: evidence from a meta-analysis. AB - Background: Circulating tumor cells (CTCs) have been proposed as a marker for predicting the prognosis of cancer. However, the prognostic value of CTCs detected with the CellSearch System in patients with gastric cancer (GC) remains controversial. We performed a meta-analysis of available studies to investigate this topic. Methods: Two authors systematically searched the studies independently in PubMed, Science Citation Index, Cochrane Database, Embase, and the references in relevant studies (up to September 2017) using keywords. Our meta-analysis was performed in Stata software, version 12.0 (2011; Stata Corp, College Station, TX, USA), with the risk ratio (RR), hazard ratio (HR), and 95% CI as the effect measures. Subgroup analyses and meta-regression were also conducted. Results: Seven studies (including eight sets of data) containing 579 patients with GC from four countries were included in this meta-analysis. The pooled results showed CTC-positive status detected by the CellSearch System was significantly associated with poor overall survival (HR =2.09, 95% CI [1.71, 2.55], P<0.001, I2=31.5%) and progression-free survival (HR =2.11, 95% CI [1.25, 3.57], P=0.005, I2=75.6%) of patients with GC, regardless of sampling time. The disease control rate of CTC-positive group was lower than that of CTC-negative group for both baseline and intra-therapy, although no statistical difference existed at both sampling time points (baseline: 69.5% versus 81.8%, RR=0.79, 95% CI [0.54, 1.16], P=0.23, I2=68.0%; intra-therapy: 50.0% versus 85.9%, RR=0.24, 95% CI [0.02, 3.13], P=0.28, I2=87.4%). Conclusion: Our meta-analysis demonstrated that CTCs detected with the CellSearch System from the peripheral blood had significant prognostic value and might predict poor response to chemotherapy for patients with GC. PMID- 29520153 TI - Reversine, a substituted purine, exerts an inhibitive effect on human renal carcinoma cells via induction of cell apoptosis and polyploidy. AB - Background: Human renal cell carcinoma (RCC) is the most common type of kidney cancer that arises from the renal epithelium. Up to 33.3% of RCC patients treated with local tumor resections will subsequently develop recurrence or metastases. Thus, optimized therapeutic regimes are urgently needed to improve the prognosis of RCC. Reversine was recently reported to exert critical roles in cancer therapy. Materials and methods: This study evaluated the anti-tumor effects of reversine on cell viability, colony formation, apoptosis, and cell cycle in 786-O and ACHN cell lines. Results: It was demonstrated that reversine significantly inhibited the proliferation of both cell lines in time- and dose-dependent manners. Polyploidy formation was observed under high-concentration reversine treatment. In addition, reversine induced cell death via caspase-dependent apoptotic pathways, which could be partially inhibited by Z-VAD-FMK, a pan caspase inhibitor. Conclusion: Reversine could effectively suppress the proliferation of human RCC cells, and may serve as a novel therapeutic regimen for RCC in clinical practice. PMID- 29520154 TI - Clinicopathologic characteristics and prognosis of proximal and distal gastric cancer. AB - Background and objectives: The dismal prognosis of gastric cancer patients is a global problem. We aim to evaluate the clinicopathologic features and prognostic factors of proximal and distal gastric cancer. Materials and methods: Gastric cancer cases diagnosed and treated at the same surgical unit between 2007 and 2010 were reviewed. Follow-up data from all patients were collected for at least 5 years until 2015. A total of 964 patients were studied (distal gastric cancer [DG], n=777 and proximal gastric cancer [PG], n=187). Results: DG patients had a relatively higher percentage of females, more thorough therapy (R0 [D0/D1/D2]), fewer combined organ resections, younger age, smaller tumors (<5 cm), shorter surgery durations, less blood loss during surgery, and a relatively lower percentage of nodal metastases and a TNM stage of 4 (p<0.05). A significantly higher 5-year survival rate was observed in DG patients compared to PG patients (DG: 51%, PG: 28%; p<0.001). A multivariate analysis demonstrated that tumor size, blood loss during surgery, surgery approach of lymph node dissection, treatment with palliative surgery, histopathologic type, TNM stage, and tumor location were independent predictors of poor outcome. Conclusion: The different characteristics and prognosis of DG and PG cases have implications for the development of guiding strategies for a surgical program and assessment of prognosis of gastric cancer patients based on tumor location. PMID- 29520155 TI - CXCR3 is a prognostic marker and a potential target for patients with solid tumors: a meta-analysis. AB - Objective: To deeply verify the clinical significance of CXCR3 in prediction of cancer patients' prognosis. Data sources: We performed a meta-analysis including 12 studies searched from PubMed, Web of Science, Embase, and Cochrane databases. A total of 1,751 patients were used to analyze the association between CXCR3 and patients' prognosis, based on either overall survival or time to tumor progression. Study selection: Studies evaluating CXCR3 expression for predicting prognosis in human solid tumors were included. Results: It showed that patients with higher expression of CXCR3 had significantly shorter OS (pooled hazard ratio =2.315, 95% CI: 1.162-4.611, P=0.017). In addition, higher CXCR3 expression was associated with distant metastasis (yes vs no: pooled relative ratio [RR] =1.828, 95% CI: 1.140-2.931, P=0.012) in solid tumors and indicated advanced tumor stage (III/IV vs I/II, RR =2.656, 95% CI: 1.809-3.900, P<0.001) and lymph node metastasis (yes vs no: RR =2.28, 95% CI: 1.61-3.25, P<0.001) in colorectal cancer. Conclusion: Our study highlights the role of CXCR3 as a potential prognostic marker and a promising therapeutic target in solid tumors. PMID- 29520156 TI - Forkhead box K2 inhibits the proliferation, migration, and invasion of human glioma cells and predicts a favorable prognosis. AB - Purpose: Forkhead box K2 (FOXK2) is a member of the forkhead box family of transcription factors. Recently, researchers discovered that overexpression of FOXK2 inhibits the proliferation and metastasis of breast cancer, non-small cell lung cancer, and colorectal cancer, and is related to the clinical prognosis. However, in hepatocellular carcinoma, FOXK2 results in the opposite phenotypes. Currently, the contribution of FOXK2 to glioma pathogenesis is not clear. Patients and methods: We evaluated the expression of FOXK2 in 151 glioma patients using immunohistochemistry assays. The associations among the expression of FOXK2, clinicopathological parameters, and the prognosis of glioma patients were statistically analyzed. We downregulated and upregulated the level of FOXK2 in glioma cells by transfections with small interfering RNA and plasmids. Then, we investigated the effects on tumor cell behavior in vitro by Cell Counting Kit-8 assays, colony-formation assay, transwell assay, and the epithelial-to mesenchymal transition (EMT) biomarker levels. Results: The clinical data showed that expression of FOXK2 gradually decreased with increasing World Health Organization (WHO) grades and a low level of FOXK2 indicates a poor prognosis. FOXK2 expression is negatively correlated with Ki67 expression and the WHO degree but is not correlated with other clinicopathological parameters, including sex, age, Karnofsky Performance Status, tumor diameter, O-6-methylguanine-DNA methyltransferase, and glutathione S-transferase pi. FOXK2 knockdown enhances glioma cell proliferation, migration, invasion, and EMT process, and, in contrast, FOXK2 overexpression inhibits glioma cell proliferation, migration, invasion, and the EMT process. Conclusion: Expression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process. PMID- 29520157 TI - Overview of the development of quinolone resistance in Salmonella species in China, 2005-2016. AB - Purpose: Several factors contribute to the complexity of quinolone resistance in Salmonella, including >2000 different Salmonella serotypes, a variety of hosts for Salmonella, and wide use of quinolones in human beings and animals. We thus aimed to obtain an overview of the development of quinolone resistance and relevant molecular mechanisms of such a resistance in Salmonella species. Materials and methods: A total of 1,776 Salmonella isolates were collected in Ningbo, China, between 2005 and 2016. Antimicrobial susceptibility to quinolone and relevant genetic mechanisms in these isolates were retrospectively analyzed. Results: The ratio for ciprofloxacin (CIP) resistant:reduced CIP susceptible:CIP susceptible was 26:522:1,228. CIP resistance was found in nine of 51 serotypes: Derby, London, Kentucky, Indiana, Corvallis, Rissen, Hadar, Typhimurium, and Agona. Of 26 CIP-resistant isolates, all were concurrently resistant to ampicillin and 21 were also concurrently resistant to cefotaxime and produced extended-spectrum beta-lactamase (ESBL). The minimal inhibitory concentration values were at three levels: 2-4 MUg/mL (serotypes except for Kentucky and Indiana), 16 MUg/mL (one Kentucky isolate), and >32 MUg/mL (Indiana isolates). As with the three most common serotypes, Salmonella Typhi showed quickly increased prevalence of reduced CIP susceptibility in recent years, Salmonella Enteritidis remained at a high prevalence of reduced CIP susceptibility throughout the study period, and several isolates of Salmonella Typhimurium were resistant to CIP. Transferable plasmid-mediated quinolone resistance gene qnrB was only found in all CIP-resistant isolates. In contrast, gyrA mutations were often found in reduced CIP-susceptible isolates and were not necessarily found in all CIP resistant isolates. Conclusion: We conclude that in Salmonella, there exists a high prevalence of reduced CIP susceptibility and a low prevalence of CIP resistance, which focuses on several serotypes. Our study also demonstrates that, rather than gyrA mutations, qnrB is the most common indicator for CIP resistance. PMID- 29520158 TI - Randomized trial of amino acid mixture combined with physical activity promotion for abdominal fat reduction in overweight adults. AB - Purpose: The purpose of this study was to test the efficacy of arginine, alanine, and phenylalanine mixture (A-mix) ingestion at 1,500 mg/day in combination with the promotion of physical activity for abdominal fat reduction in overweight adults. Methods: A placebo-controlled, double-blind, parallel-group, randomized trial for 12 weeks combined with a 4-week follow-up period was conducted at a single center in Minato-ku, Tokyo, Japan, between December 2016 and May 2017. Data were analyzed between June and August 2017. The study participants were 200 overweight adults within the age range of 20-64 years. The participants were randomly assigned to the A-mix group (n=100) or a placebo group (n=100) and were administered 500 mL of test beverage containing 1,500 or 0 mg of A-mix, respectively, for 12 weeks. All participants maintained a physically active lifestyle between week 0 and week 12 through monthly sessions of physical activity. The primary outcomes were the 12-week changes in the abdominal total, subcutaneous, and visceral fat areas, as assessed by computed tomography. Results: Of the 200 enrolled participants, 199 (99%) accomplished the 12-week intervention and 4-week follow-up period. The per-protocol-based analysis for 194 participants demonstrated that the abdominal total fat area decreased significantly in the A-mix group compared with that in the placebo group (difference, 10.0 cm2; 95% confidence interval [CI]: 0.4-19.6 cm2; P=0.041). Comparable outcomes were obtained for the abdominal subcutaneous fat area (difference, 7.4 cm2; 95% CI: 0.1-14.7 cm2; P=0.047). No study-related unfavorable events occurred. Conclusion: A-mix supplementation in combination with physical activity promotion facilitated abdominal fat reduction in overweight adults. PMID- 29520159 TI - Therapeutic management of classic lichen planopilaris: a systematic review. AB - Several treatment strategies have been proposed in classic lichen planopilaris (LPP), although no gold standard therapeutic approach has been recognized so far due to the variable and, sometimes, contradictory results reported in the literature, as well as due to the lack of guidelines and randomized controlled trials. In the present review, we sought to provide an updated overview on the treatment of classic LPP by analyzing the level of evidence of published studies, also proposing a possible therapeutic strategy according to the findings highlighted in this systematic review. PMID- 29520160 TI - Cyclic vomiting syndrome: diagnostic approach and current management strategies. AB - Cyclic vomiting syndrome (CVS) is a disorder characterized by episodes of nausea and vomiting lasting for 1-5 days followed by asymptomatic periods. The etiology of CVS is unknown, but it shares similar characteristics to migraine headaches. CVS is generally classified as having four phases: prodromal, acute/vomiting/hyperemesis, recovery, and remission/interepisodic. Current management strategies include trigger avoidance, abortive and prophylactic medication therapies, and supportive care. The goal of therapy for the remission phase is prophylaxis of further episodes. Antidepressant, antiepileptic, and antimigraine medications show an overall reduction or remission of CVS symptoms in more than 70% of patients. This article provides a summary of diagnostic strategies and reviews current management strategies for CVS. PMID- 29520161 TI - Knowledge on self-management and levels of asthma control among adult patients in Ho Chi Minh City, Vietnam. AB - Background: Most asthma patients in Vietnam have poorly controlled asthma. Besides reasons related to the health care system and health care providers, knowledge on the self-management of patients has also contributed to this situation. Purpose: To assess knowledge on asthma self-management among adult asthma patients in Ho Chi Minh City. Patients and methods: A cross-sectional study with convenience sampling was conducted among 322 ambulatory patients using questionnaires filled in via a face-to-face interview. The questionnaires enquired about: 1) sociodemographic details, 2) the Global Initiative for Asthma 2017 criteria of asthma control, 3) the Asthma Control Test, and 4) the Asthma Self-Management Questionnaire (ASMQ). Knowledge on asthma self-management was determined by the ASMQ score. The relationship between this knowledge and demographic factors and asthma control levels was determined. Results: The knowledge on asthma self-management was low, with a mean raw ASMQ score of 4.3 (maximum 14); this is equivalent to 30 in a transformed score (maximum 100). Only 0.3% of these patients had good knowledge, 16.2% had adequate knowledge, and 83.5% had poor knowledge. Of all participants, 52% stated erroneously that asthma can be cured, 30% were confused about control and rescue medications, 68% failed to correctly describe the inhalation technique, and only 15.5% could answer correctly about the management of an exacerbation. Although most participants had poor asthma control, the higher the patient's level of control, the better the ASMQ score. Conversely, patients with better knowledge of asthma self-management (ASMQ score >=50) had better asthma control based on the Asthma Control Test score. Also, a higher education level was associated with more knowledge on asthma self-management. Conclusion: In these patients, the level of knowledge on asthma self-management was low and significantly correlated with the level of asthma control. There is a clear need to improve knowledge in order to improve asthma control in Vietnam. PMID- 29520163 TI - Pustular psoriasis of pregnancy: current perspectives. AB - Pustular psoriasis of pregnancy (PPP) is a life-threatening condition for both the pregnant mother and fetus, and must be efficiently and accurately diagnosed and treated. This condition has historically been classified as a unique, separate dermatosis of pregnancy. However, current opinion and data suggest that it may be a variant of generalized pustular psoriasis. PPP typically occurs in the third trimester and is characterized by widespread coalescent pustules, desquamation, and systemic symptoms. Clinical features and histopathologic evaluation aid in diagnosis. Treatments during pregnancy include high-dose corticosteroids, cyclosporine, narrow-band ultraviolet B radiation, infliximab, granulocyte and monocyte adsorptive apheresis, and systemic antibiotics. Both the mother and fetus should be closely monitored with appropriate laboratory studies for the duration of the pregnancy and postpartum. PMID- 29520162 TI - Influence of implant location on the clinical outcomes of implant abutments: a systematic review and meta-analysis. AB - Purpose: To compare the failure events and incidence of complications of different abutment materials in anterior and posterior regions. Failure was defined as complete loss of the abutment requiring replacement by a new abutment. Materials and methods: Electronic searches using PubMed/Medline and Google Scholar complemented with manual searches were performed with specific search terms. Searches were restricted to publications in English between January 2006 and March 2016. Results: A total of 863 and 1,264 implants were inserted in the anterior and posterior regions, respectively, in a total of 1,529 patients. No titanium abutments failed in anterior or posterior regions. On the other hand, 1.6% of zirconia abutments failed in the anterior region and 1.5% failed in the posterior region. Technical complications occurred mostly in the posterior region and mostly involved zirconia abutment. Meta-analysis was possible only for zirconia-abutment failure, due to considerable heterogeneity of studies and outcome variables. No significant difference in failure rate was found between anterior and posterior zirconia abutments (risk ratio 1.53, 95% CI 0.49-4.77; P=0.47). Conclusion: This systematic review and meta-analysis showed similar outcomes of different abutment materials when used in anterior and posterior regions in terms of failure events and biological and aesthetic complications. The only significant finding was the increased incidence of technical complications in the posterior region, mostly involving zirconia abutments. Abutment-screw loosening was the most common technical complication. PMID- 29520165 TI - Silencing MR-1 attenuates atherosclerosis in ApoE-/- mice induced by angiotensin II through FAK-Akt-mTOR-NF-kappaB signaling pathway. AB - Myofibrillogenesis regulator-1 (MR-1) is a novel protein involved in cellular proliferation, migration, inflammatory reaction and signal transduction. However, little information is available on the relationship between MR-1 expression and the progression of atherosclerosis. Here we report atheroprotective effects of silencing MR-1 in a model of Ang II-accelerated atherosclerosis, characterized by suppression focal adhesion kinase (FAK) and nuclear factor kappaB (NF-kappaB) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the siRNA-MR-1 substantially attenuated Ang II-accelerated atherosclerosis with stabilization of atherosclerotic plaques and inhibited FAK, Akt, mammalian target of rapamycin (mTOR) and NF-kB activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in Ang II treated vascular smooth muscle cells (VSMCs) and macrophages: siRNA-MR-1 inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of Ang II and highlight actions of silencing MR-1 to inhibit Ang II signaling, which is atheroprotective. PMID- 29520166 TI - Tumor necrosis factor alpha-converting enzyme inhibitor attenuates lipopolysaccharide-induced reactive oxygen species and mitogen-activated protein kinase expression in human renal proximal tubule epithelial cells. AB - Tumor necrosis factor-alpha (TNFalpha) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which TNFalpha-converting enzyme (TACE) contributes to lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2 cells were cultured with or without LPS (10 ug/ml) in the presence or absence of a type 1 TACE inhibitor (1 uM) or type 2 TACE inhibitor (10 uM). LPS treatment induced increased serum creatinine, TNFalpha, and urinary neutrophil gelatinase associated lipocalin. Angiotensin II type 1 receptor, mitogen activated protein kinase (MAPK), and TACE increased, while angiotensin-converting enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and LPS-treated HK-2 cells. LPS induced reactive oxygen species and the down-regulation of ACE2, and these responses were prevented by TACE inhibitors in HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells and attenuated oxidative stress and inflammatory cytokines. Our findings indicate that LPS activates renin angiotensin system components via the activation of TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney injury. PMID- 29520164 TI - The potential theragnostic (diagnostic+therapeutic) application of exosomes in diverse biomedical fields. AB - Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now. PMID- 29520167 TI - Toll-like receptor 2 promotes neurogenesis from the dentate gyrus after photothrombotic cerebral ischemia in mice. AB - The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain. PMID- 29520168 TI - The antidepressant action of 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid is mediated by phosphorylation of histone deacetylase 5. AB - 3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive N-methyl D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant-like effects in animal models of depression. However, the molecular mechanisms underlying these behavioral actions remain unknown. Here, we demonstrate that CPP rapidly stimulates histone deacetylase (HDAC) 5 phosphorylation and nuclear export in rat hippocampal neurons. These effects are accompanied by calcium/calmodulin kinase II (CaMKII) and protein kinase D (PKD) phosphorylation. Behavioral experiments revealed that viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant effects of CPP in stressed animals. Taken together, our results imply that CPP acts via HDAC5 and suggest that HDAC5 is a common regulator contributing to the antidepressant actions of NMDA receptor antagonists such as CPP. PMID- 29520169 TI - Effects of salmon DNA fraction in vitro and in a monosodium iodoacetate-induced osteoarthritis rat model. AB - PRF001 is a fragmented DNA polymer extracted from the testes of salmon. The purpose of this study was to assess the anti-inflammatory effect of PRF001 in vitro as well as the protective effect of PRF001 intake against arthritis in a rat model. In vitro, cell survival and inflammatory markers after H2O2 treatment to induce cell damage were investigated in CHON-001 cells treated with different concentrations of PRF001. In vivo, osteoarthritis was induced by intra-articular injection of monosodium iodoacetate (MIA) into the knee joints of rats. After consumption of PRF001 (10, 50, or 100 mg/kg) for 4 weeks, inflammatory mediators and cytokines in articular cartilage were investigated. In vitro, the levels of inflammatory markers, IL-1beta, TNF-alpha, COX-2, iNOS, and PGE2, were significantly suppressed by PRF001 treatment. In vivo, the inflammatory mediators and cytokines, IL-1beta, p-Erk1/2, NF-kappaB, TNF-alpha, COX-2, and PGE2, as well as MMP3 and MMP7, which have catabolic activity in chondrocytes, were decreased in the MIA-induced osteoarthritic rats following intake of PRF001. Histological analysis revealed that PRF001 had a protective effect on the articular cartilage. Altogether, these results demonstrated that the anti-inflammatory property of PRF001 contributes to its protective effects in osteoarthritis through deregulating IL-1beta, TNF-alpha, and subsequent signals, such as p-Erk1/2, NF kappaB, COX-2, PGE2, and MMPs. PMID- 29520170 TI - Oxytocin produces thermal analgesia via vasopressin-1a receptor by modulating TRPV1 and potassium conductance in the dorsal root ganglion neurons. AB - Recent studies have provided several lines of evidence that peripheral administration of oxytocin induces analgesia in human and rodents. However, the exact underlying mechanism of analgesia still remains elusive. In the present study, we aimed to identify which receptor could mediate the analgesic effect of intraperitoneal injection of oxytocin and its cellular mechanisms in thermal pain behavior. We found that oxytocin-induced analgesia could be reversed by d(CH2)5[Tyr(Me)2,Dab5] AVP, a vasopressin-1a (V1a) receptor antagonist, but not by desGly-NH2-d(CH2)5[DTyr2, Thr4]OVT, an oxytocin receptor antagonist. Single cell RT-PCR analysis revealed that V1a receptor, compared to oxytocin, vasopressin-1b and vasopressin-2 receptors, was more profoundly expressed in dorsal root ganglion (DRG) neurons and the expression of V1a receptor was predominant in transient receptor potential vanilloid 1 (TRPV1)-expressing DRG neurons. Fura-2 based calcium imaging experiments showed that capsaicin-induced calcium transient was significantly inhibited by oxytocin and that such inhibition was reversed by V1a receptor antagonist. Additionally, whole cell patch clamp recording demonstrated that oxytocin significantly increased potassium conductance via V1a receptor in DRG neurons. Taken together, our findings suggest that analgesic effects produced by peripheral administration of oxytocin were attributable to the activation of V1a receptor, resulting in reduction of TRPV1 activity and enhancement of potassium conductance in DRG neurons. PMID- 29520171 TI - Berberine alleviates symptoms of anxiety by enhancing dopamine expression in rats with post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a trauma-induced psychiatric disorder characterized by impaired fear extermination, hyperarousal, anxiety, depression, and amnesic symptoms that may involve the release of monoamines in the fear circuit. The present study measured several anxiety-related behavioral responses to examine the effects of berberine (BER) on symptoms of anxiety in rats after single prolonged stress (SPS) exposure, and to determine if BER reversed the dopamine (DA) dysfunction. Rats received BER (10, 20, or 30 mg/kg, intraperitoneally, once daily) for 14 days after SPS exposure. BER administration significantly increased the time spent in the open arms and reduced grooming behavior during the elevated plus maze test, and increased the time spent in the central zone and the number of central zone crossings in the open field test. BER restored neurochemical abnormalities and the SPS-induced decrease in DA tissue levels in the hippocampus and striatum. The increased DA concentration during BER treatment may partly be attributed to mRNA expression of tyrosine hydroxylase and the DA transporter in the hippocampus, while BER exerted no significant effects on vesicular monoamine transporter mRNA expression in the hippocampus of rats with PTSD. These results suggest that BER had anxiolytic-like effects on behavioral and biochemical measures associated with anxiety. These findings support a role for reduced anxiety altered DAergic transmission and reduced anxiety in rats with PTSD. Thus, BER may be a useful agent to treat or alleviate psychiatric disorders like those observed in patients with PTSD. PMID- 29520172 TI - Fluvastatin inhibits advanced glycation end products-induced proliferation, migration, and extracellular matrix accumulation in vascular smooth muscle cells by targeting connective tissue growth factor. AB - Connective tissue growth factor (CTGF) is a novel fibrotic mediator, which is considered to mediate fibrosis through extracellular matrix (ECM) synthesis in diabetic cardiovascular complications. Statins have significant immunomodulatory effects and reduce vascular injury. We therefore examined whether fluvastatin has anti-fibrotic effects in vascular smooth muscle cells (VSMCs) and elucidated its putative transduction signals. We show that advanced glycation end products (AGEs) stimulated CTGF mRNA and protein expression in a time-dependent manner. AGE-induced CTGF expression was mediated via ERK1/2, JNK, and Egr-1 pathways, but not p38; consequently, cell proliferation and migration and ECM accumulation were regulated by CTGF signaling pathway. AGE-stimulated VSMC proliferation, migration, and ECM accumulation were blocked by fluvastatin. However, the inhibitory effect of fluvastatin was restored by administration of CTGF recombinant protein. AGE-induced VSMC proliferation was dependent on cell cycle arrest, thereby increasing G1/G0 phase. Fluvastatin repressed cell cycle regulatory genes cyclin D1 and Cdk4 and augmented cyclin-dependent kinase inhibitors p27 and p21 in AGE-induced VSMCs. Taken together, fluvastatin suppressed AGE-induced VSMC proliferation, migration, and ECM accumulation by targeting CTGF signaling mechanism. These findings might be evidence for CTGF as a potential therapeutic target in diabetic vasculature complication. PMID- 29520173 TI - Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation. AB - Tumor undergo uncontrolled, excessive proliferation leads to hypoxic microenvironment. To fulfill their demand for nutrient, and oxygen, tumor angiogenesis is required. Endothelial progenitor cells (EPCs) have been known to the main source of angiogenesis because of their potential to differentiation into endothelial cells. Therefore, understanding the mechanism of EPC-mediated angiogenesis in hypoxia is critical for development of cancer therapy. Recently, mitochondrial dynamics has emerged as a critical mechanism for cellular function and differentiation under hypoxic conditions. However, the role of mitochondrial dynamics in hypoxia-induced angiogenesis remains to be elucidated. In this study, we demonstrated that hypoxia-induced mitochondrial fission accelerates EPCs bioactivities. We first investigated the effect of hypoxia on EPC-mediated angiogenesis. Cell migration, invasion, and tube formation was significantly increased under hypoxic conditions; expression of EPC surface markers was unchanged. And mitochondrial fission was induced by hypoxia time-dependent manner. We found that hypoxia-induced mitochondrial fission was triggered by dynamin-related protein Drp1, specifically, phosphorylated DRP1 at Ser637, a suppression marker for mitochondrial fission, was impaired in hypoxia time dependent manner. To confirm the role of DRP1 in EPC-mediated angiogenesis, we analyzed cell bioactivities using Mdivi-1, a selective DRP1 inhibitor, and DRP1 siRNA. DRP1 silencing or Mdivi-1 treatment dramatically reduced cell migration, invasion, and tube formation in EPCs, but the expression of EPC surface markers was unchanged. In conclusion, we uncovered a novel role of mitochondrial fission in hypoxia-induced angiogenesis. Therefore, we suggest that specific modulation of DRP1-mediated mitochondrial dynamics may be a potential therapeutic strategy in EPC-mediated tumor angiogenesis. PMID- 29520175 TI - Asian Radiology Forum 2016 for Promoting Radiology Together in the Asian-Oceanian Region: Roles of the Asian-Oceanian Society of Radiology and Its Member Societies. AB - According to the reports presented at the second Asian Radiology Forum (ARF) 2016, organized by the Korean Society of Radiology (KSR) during the Korean Congress of Radiology (KCR) in September 2016 in Seoul, there is an increasing need for the Asian-Oceanian Society of Radiology (AOSR) and its member societies to promote radiology together in the Asian-Oceanian region. In ARF 2016, the national delegates of the Asian-Oceanian radiological partner societies primarily discussed their societies' activities and contributions in international and regional societies including AOSR, expectations for AOSR, recommendations and suggestions for AOSR, and their societies' support of AOSR. PMID- 29520174 TI - Hydrogen peroxide inhibits Ca2+ efflux through plasma membrane Ca2+-ATPase in mouse parotid acinar cells. AB - Intracellular Ca2+ mobilization is closely linked with the initiation of salivary secretion in parotid acinar cells. Reactive oxygen species (ROS) are known to be related to a variety of oxidative stress-induced cellular disorders and believed to be involved in salivary impairments. In this study, we investigated the underlying mechanism of hydrogen peroxide (H2O2) on cytosolic Ca2+ accumulation in mouse parotid acinar cells. Intracellular Ca2+ levels were slowly elevated when 1 mM H2O2 was perfused in the presence of normal extracellular Ca2+. In a Ca2+-free medium, 1 mM H2O2 still enhanced the intracellular Ca2+ level. Ca2+ entry tested using manganese quenching technique was not affected by perfusion of 1 mM H2O2. On the other hand, 10 mM H2O2 induced more rapid Ca2+ accumulation and facilitated Ca2+ entry from extracellular fluid. Ca2+ refill into intracellular Ca2+ store and inositol 1,4,5-trisphosphate (1 uM)-induced Ca2+ release from Ca2+ store was not affected by 1 mM H2O2 in permeabilized cells. Ca2+ efflux through plasma membrane Ca2+-ATPase (PMCA) was markedly blocked by 1 mM H2O2 in thapsigargin-treated intact acinar cells. Antioxidants, either catalase or dithiothreitol, completely protected H2O2-induced Ca2+ accumulation through PMCA inactivation. From the above results, we suggest that excessive production of H2O2 under pathological conditions may lead to cytosolic Ca2+ accumulation and that the primary mechanism of H2O2-induced Ca2+ accumulation is likely to inhibit Ca2+ efflux through PMCA rather than mobilize Ca2+ ions from extracellular medium or intracellular stores in mouse parotid acinar cells. PMID- 29520176 TI - Prostate Imaging-Reporting and Data System Version 2: Beyond Prostate Cancer Detection. AB - The main purpose of Prostate Imaging-Reporting and Data System Version 2 (PI RADSv2) is to effectively detect clinically significant prostate cancers (csPCa) using multiparametric magnetic resonance imaging. Since the first introduction of PI-RADSv2, researchers have validated its diagnostic performance in identifying csPCa, and these promising data have influenced biopsy and treatment schemes. However, in this article, we focused on the potential of PI-RADSv2 in relation to various aspects of PCa such as Gleason score, tumor volume, extraprostatic extension, lymph node metastasis, and postoperative biochemical recurrence, beyond prostate cancer detection. PMID- 29520177 TI - Functional Evaluation of Transplanted Kidneys with Reduced Field-of-View Diffusion-Weighted Imaging at 3T. AB - Objective: To determine the feasibility of reduced field-of-view diffusion weighted imaging (rFOV DWI) with multi-b values to detect functional variability in transplanted kidneys. Materials and Methods: Using a 3T MRI scanner, multi-b rFOV DWI of transplanted kidney or native kidney was performed in 40 renal transplantation recipients and 18 healthy volunteers. The patients were stratified, according to an estimated glomerular filtration rate (eGFR): Group 1, eGFR >= 60 mL/min/1.73 m2; Group 2, eGFR >= 30 mL/min/1.73 m2 and < 60 mL/min/1.73 m2; Group 3, eGFR < 30 mL/min/1.73 m2. Total apparent diffusion coefficient (ADCT), perfusion-free ADC (ADCD) and perfusion fraction (FP) of kidneys were calculated and compared among the four groups. Correlations between the imaging results and eGFR were assessed. Results: All volunteers had eGFR >= 60 mL/min/1.73 m2, while 16, 16, and 8 patients were included in Groups 1, 2, and 3, respectively. In the renal cortex, ADCT was higher in Group 1 ([1.65 +/- 0.13] * 10-3 mm2/s) than Group 3 ([1.44 +/- 0.11] * 10-3 mm2/s) (p < 0.05), and the inter-group differences of FP values were significant (all p < 0.05) (0.330 +/- 0.024, 0.309 +/- 0.019, 0.278 +/- 0.033, and 0.250 +/- 0.028 for control group, Groups 1, 2, and 3, respectively). Renal cortical ADCT, ADCD, FP, and renal medullary ADCT and FP correlated positively with eGFR (r = 0.596, 0.403, 0.711, 0.341, and 0.323, respectively; all p < 0.05). When using 0.278 as the cutoff value, renal cortical FP had a sensitivity of 97.1% and a specificity of 66.7% for predicting decreased renal function. Conclusion: Multi-b rFOV DWI presents transplanted kidneys with high resolution, which is a promising functional tool for non-invasively monitoring function of transplanted kidneys. PMID- 29520179 TI - Plug-Assisted Retrograde Transvenous Obliteration for the Treatment of Gastric Varices: The Role of Intra-Procedural Cone-Beam Computed Tomography. AB - Objective: To investigate the technical and clinical outcomes of plug-assisted retrograde transvenous obliteration (PARTO) for the treatment of gastric varices (GV) and to evaluate the role of intra-procedural cone-beam computed tomography (CBCT) performed during PARTO to confirm its technical success. Materials and Methods: From January 2016 to December 2016, 17 patients with GV who had undergone PARTO were retrospectively evaluated. When the proximal part of the afferent vein was identified on a fluoroscopy, non-contrast CBCT images were obtained. In patients with incomplete embolization of GV, an additional injection of gelatin sponges was performed. Follow-up data from contrast-enhanced CT and upper intestinal endoscopy, as well as clinical and laboratory data were collected. Results: Plug-assisted retrograde transvenous obliteration procedures were technically successful in all 17 patients. Complete embolization of GV was detected on CBCT images in 15 patients; whereas, incomplete embolization was detected in two. Complete embolization of GV was then achieved after an additional injection of gelatin sponges in these two patients as demonstrated on the 2nd CBCT image. The mean follow-up period after PARTO was 193 days (range, 73 383 days). A follow-up CT obtained 2-4 months after PARTO demonstrated marked shrinkage or complete obliteration of GV and portosystemic shunts in all 17 patients. There were no cases of variceal bleeding during the follow-up. Conclusion: Plug-assisted retrograde transvenous obliteration is technically and clinically effective for the treatment of GV. In addition, intra-procedural CBCT can be an adjunct tool to fluoroscopy, because it can provide an immediate and accurate evaluation of the technical success of PARTO. PMID- 29520178 TI - Imaging Evaluation Following 90Y Radioembolization of Liver Tumors: What Radiologists Should Know. AB - Radioembolization using beta-emitting yttrium-90 microspheres is being increasingly used for the treatment of primary and metastatic liver cancers. It is a form of intra-arterial brachytherapy which delivers intense radiation to liver tumors with little embolic effect; this mode of action results in unique post-treatment imaging findings. It is important to understand these imaging findings to avoid misinterpretation of tumor response and to determine further management of the disease. Herein, we discuss the current concepts for assessing tumor response, common post-treatment imaging features, and associated complications following radioembolization. PMID- 29520180 TI - Double-Stent System with Long Duodenal Extension for Palliative Treatment of Malignant Extrahepatic Biliary Obstructions: A Prospective Study. AB - Objective: To investigate the technical safety and clinical efficacy of a double stent system with long duodenal extension in patients with malignant extrahepatic biliary obstruction. Materials and Methods: This prospective study enrolled 48 consecutive patients (31 men, 17 women; mean age, 61 years; age range, 31-77 years) with malignant extrahepatic biliary obstructions from May 2013 to December 2015. All patients were treated with a double-stent system with long duodenal covered extension (16 cm or 21 cm). Results: The stents were successfully placed in all 48 patients. There were five (10.4%) procedure-related complications. Minor complications were self-limiting hemobilia (n = 2). Major complications included acute pancreatitis (n = 1) and acute cholecystitis (n = 2). Successful internal drainage was achieved in 42 (87.5%) patients. Median patient survival and stent patency times were 92 days (95% confidence interval [CI], 61-123 days) and 83 days (95% CI, 46-120 days), respectively. Ten (23.8%) of the 42 patients presented with stent occlusion due to food impaction with biliary sludge, and required repeat intervention. Stent occlusion was more frequent in metastatic gastric cancer patients with pervious gastrectomy, but did not reach statistical significance (p = 0.069). Conclusion: Percutaneous placement of a double-stent system with long duodenal extension is feasible and safe. However, this stent system does not completely prevent stent occlusion caused by food reflux. PMID- 29520181 TI - Comparison of the Efficacy and Prognostic Factors of Transarterial Chemoembolization Plus Microwave Ablation versus Transarterial Chemoembolization Alone in Patients with a Large Solitary or Multinodular Hepatocellular Carcinomas. AB - Objective: To evaluate the efficacy and prognostic factors associated with transcatheter arterial chemoembolization (TACE) combined with microwave ablation (MWA) versus TACE alone for a large solitary or multinodular hepatocellular carcinomas (HCCs). Materials and Methods: This retrospective study involved 258 patients with a large solitary or multinodular HCCs (not more than 10 tumors) who underwent TACE + MWA (n = 92) or TACE alone (n = 166) between July 2011 and April 2015. Local tumor control, survival outcomes, and complications were compared between the two groups. Prognostic factors for time to progression (TTP) and overall survival (OS) were evaluated by univariate and multivariate analyses. Results: The median duration of follow-up was 21.2 months (range, 4-45 months). The median TTP and OS were 12.5 months and 26.6 months, respectively, for the TACE + MWA group and 6.7 months and 17.1 months, respectively, for the TACE group (p < 0.001). The 1-, 2-, and 3-year OS rates were 85.9, 59.8, and 32.6%, respectively, for the TACE + MWA group and 59.0, 40.4, and 11.4%, respectively, for the TACE group (p < 0.001). The corresponding recurrence rates were 47.8, 78.3, and 94.6% for the TACE + MWA group, respectively, and 74.7, 96.4, and 97.6%, respectively, for the TACE group (p < 0.001). Logistic regression analyses showed that the treatment method, tumor size, and tumor number were significant prognostic factors for TTP and OS. Conclusion: TACE + MWA appears to have more advantages compared to TACE in prolonging OS, with a satisfactory TTP, for inpatients with solitary large or multinodular HCCs. Treatment method, tumor size, and tumor number are significant prognostic factors for TTP and OS. Further randomized, multi-center, prospective trials are required to confirm the findings of this study. PMID- 29520182 TI - Self-Gated Late Gadolinium Enhancement at 7T to Image Rats with Reperfused Acute Myocardial Infarction. AB - Objective: A failed electrocardiography (ECG)-trigger often leads to a long acquisition time (TA) and deterioration in image quality. The purpose of this study was to evaluate and optimize the technique of self-gated (SG) cardiovascular magnetic resonance (CMR) for cardiac late gadolinium enhancement (LGE) imaging of rats with myocardial infarction/reperfusion. Materials and Methods: Cardiovascular magnetic resonance images of 10 rats were obtained using SG-LGE or ECG with respiration double-gating (ECG-RESP-gating) method at 7T to compare differences in image interference and TA between the two methods. A variety of flip angles (FA: 10 degrees -80 degrees ) and the number of repetitions (NR: 40, 80, 150, and 300) were investigated to determine optimal scan parameters of SG-LGE technique based on image quality score and contrast-to noise ratio (CNR). Results: Self-gated late gadolinium enhancement allowed successful scan in 10 (100%) rats. However, only 4 (40%) rats were successfully scanned with the ECG-RESP-gating method. TAs with SG-LGE varied depending on NR used (TA: 41, 82, 154, and 307 seconds, corresponding to NR of 40, 80, 150, and 300, respectively). For the ECG-RESP-gating method, the average TA was 220 seconds. For SG-LGE images, CNR (42.5 +/- 5.5, 43.5 +/- 7.5, 54 +/- 9, 59.5 +/- 8.5, 56 +/- 13, 54 +/- 8, and 41 +/- 9) and image quality score (1.85 +/- 0.75, 2.20 +/- 0.83, 2.85 +/- 0.37, 3.85 +/- 0.52, 2.8 +/- 0.51, 2.45 +/- 0.76, and 1.95 +/- 0.60) were achieved with different FAs (10 degrees , 15 degrees , 20 degrees , 25 degrees , 30 degrees , 35 degrees , and 40 degrees , respectively). Optimal FAs of 20 degrees -30 degrees and NR of 80 were recommended. Conclusion: Self-gated technique can improve image quality of LGE without irregular ECG or respiration gating. Therefore, SG-LGE can be used an alternative method of ECG RESP-gating. PMID- 29520183 TI - Natural History of Untreated Coronary Total Occlusions Revealed with Follow-Up Semi-Automated Quantitative Coronary CT Angiography: The Morphological Characteristics of Initial CT Predict Occlusion Shortening. AB - Objective: To investigate the morphological changes of coronary chronic total occlusion (CTO) as determined by coronary computed tomography angiography (CCTA) follow-up using semi-automated quantitative analysis. Materials and Methods: Thirty patients with 31 CTO lesions confirmed by invasive coronary angiography and baseline/follow-up CCTA were retrospectively included. CTOs were quantitatively analyzed by a semi-automated coronary plaque analysis software (Coronary Plaque Analysis, version 2.0, Siemens) after manually determining the lesion border. Recanalized lumen was defined as the linear-like enhanced opacity traversing the non-opacified occluded segment. Other parameters, such as total occlusion length, total occlusion volume, volume with low attenuation component (< 30 Hounsfield unit [HU]), volume with middle to high attenuation component (30 190 HU) as well as the calcification volume, were also recorded. Results: Recanalized lumen was found within 48.4% (15/31) occlusions on the follow-up CCTA, compared to 45.2% (14/31) occlusions on the baseline CCTA. Eleven of 14 lesions (78.6%) with CT-visible recanalized lumen within CTOs had a shorter occlusion length on follow-up compared to only 3 of 17 lesions (17.6%) without CT visible recanalized lumen (odds ratio, 17.1, p < 0.001). The percentage of low attenuation component of occlusions was smaller on follow-up CCTA compared to baseline value (18.1 +/- 20.1% vs. 22.6 +/- 19.6%, p = 0.033). Conclusion: Coronary computed tomography angiography enables non-invasive characterization of natural progression of untreated CTO lesions. Recanalized lumen within CTOs observed at baseline CCTA was associated with shortening of occlusion length on follow-up. Compared to their earlier stage, occlusions of later stage were presented with higher density of non-calcified components. PMID- 29520184 TI - Effect of Patient Characteristics on Vessel Enhancement at Lower Extremity CT Angiography. AB - Objective: To evaluate the effect of patient characteristics on popliteal aortic contrast enhancement at lower extremity CT angiography (LE-CTA) scanning. Materials and Methods: Prior informed consent to participate was obtained from all 158 patients. All were examined using a routine protocol; the scanning parameters were tube voltage 100 kVp, tube current 100 mA to 770 mA (noise index 12), 0.5-second rotation, 1.25-mm detector row width, 0.516 beam pitch, and 41.2 mm table movement, and the contrast material was 85.0 mL. Cardiac output (CO) was measured with a portable electrical velocimeter within 5 minutes of starting the CT scan. To evaluate the effects of age, sex, body size, CO, and scan delay on the CT number of popliteal artery, the researchers used multivariate regression analysis. Results: A significant positive correlation was seen between the CT number of the popliteal artery and the patient age (r = 0.39, p < 0.01). A significant inverse correlation was observed between the CT number of the popliteal artery and the height (r = -0.48), total body weight (r = -0.52), body mass index (r = -0.33), body surface area (BSA) (r = -0.56), lean body weight (r = -0.56), and CO (r = -0.35) (p < 0.001 for all). There was no significant correlation between the enhancement and the scan delay (r = 0.06, p = 0.47). The BSA, CO, and age had significant effects on the CT number (standardized regression: BSA -0.42, CO -0.22, age 0.15; p < 0.05, respectively). Conclusion: The BSA, CO, and age are significantly correlated with the CT number of the popliteal artery on LE-CTA. PMID- 29520185 TI - Multimodality Imaging in Patients with Secondary Hypertension: With a Focus on Appropriate Imaging Approaches Depending on the Etiologies. AB - Although the causes of hypertension are usually unknown, about 10% of the cases occur secondary to specific etiologies, which are often treatable. Common categories of secondary hypertension include renal parenchymal disease, renovascular stenosis, vascular and endocrinologic disorders. For diseases involving the renal parenchyma and adrenal glands, ultrasonography (US), computed tomography (CT) or magnetic resonance (MR) imaging is recommended. For renovascular stenosis and vascular disorders, Doppler US, conventional or noninvasive (CT or MR) angiography is an appropriate modality. Nuclear imaging can be useful in the differential diagnosis of endocrine causes. Radiologists should understand the role of each imaging modality and its typical findings in various causes of secondary hypertension. This article focuses on appropriate imaging approaches in accordance with the categorized etiologies leading to hypertension. PMID- 29520186 TI - Prediction of Late Postoperative Hemorrhage after Whipple Procedure Using Computed Tomography Performed During Early Postoperative Period. AB - Objective: Postpancreatectomy hemorrhage (PPH) is an uncommon but serious complication of Whipple surgery. To evaluate the radiologic features associated with late PPH at the first postoperative follow up CT, before bleeding. Materials and Methods: To evaluate the radiological features associated with late PPH at the first follow-up CT, two radiologists retrospectively reviewed the initial postoperative follow-up CT images of 151 patients, who had undergone Whipple surgery. Twenty patients showed PPH due to vascular problem or anastomotic ulcer. The research compared CT and clinical findings of 20 patients with late PPH and 131 patients without late PPH, including presence of suggestive feature of pancreatic fistula (presence of air at fluid along pancreaticojejunostomy [PJ]), abscess (fluid collection with an enhancing rim or gas), fluid along hepaticojejunostomy or PJ, the density of ascites, and the size of visible gastroduodenal artery (GDA) stump. Results: CT findings including pancreatic fistula, abscess, and large GDA stump were associated with PPH on univariate analysis (p <= 0.009). On multivariate analysis, radiological features suggestive of a pancreatic fistula, abscess, and a GDA stump > 4.45 mm were associated with PPH (p <= 0.031). Conclusion: Early postoperative CT findings including GDA stump size larger than 4.45 mm, fluid collection with an enhancing rim or gas, and air at fluid along PJ, could predict late PPH. PMID- 29520187 TI - The Correlation between the Injury Patterns of the Medial Patellofemoral Ligament in an Acute First-Time Lateral Patellar Dislocation on MR Imaging and the Incidence of a Second-Time Lateral Patellar Dislocation. AB - Objective: To evaluate the correlation between the injury patterns of the medial patellofemoral ligament (MPFL) on magnetic resonance imaging in an acute first time lateral patellar dislocation (LPD) and incidence of a second-time LPD. Materials and Methods: Magnetic resonance images were prospectively analyzed in 147 patients after an acute first-time LPD with identical nonoperative management. The injury patterns of MPFL in acute first-time LPDs were grouped by location and severity for the analysis of the incidence of second-time LPD in a 5 year follow-up. Independent t tests, chi-square tests and Kruskal-Wallis tests were performed as appropriate. Results: Forty-six cases (46/147, 31.3%) of second time LPD were present at the 5-year follow-up. Fourteen (14/62, 22.6%) and 31 cases (31/80, 38.8%) were present in the partial and complete MPFL tear subgroups, respectively. Twenty-five cases (25/65, 38.5%), 11 cases (11/26, 42.3%), and 8 cases (8/47, 17%) were present in the isolated femoral-side MPFL tear (FEM), combined MPFL tear (COM), and isolated patellar-side MPFL tear (PAT) subgroups, respectively. Compared with the partial MPFL tears, complete tears showed higher incidence of a second-time LPD (p = 0.04). The time interval between the two LPDs was shorter in the complete MPFL tear subgroup (24.2 months) than in the partial tear subgroup (36.9 months, p = 0.001). Compared with the PAT subgroup, the FEM and COM subgroups showed a higher incidence of a second-time LPD (p = 0.025). The time intervals between the two LPDs were shorter in the FEM and COM subgroups (20.8 months and 19.2 months) than in the PAT subgroup (32.5 months, p = 0.049). Conclusion: A complete MPFL tear, isolated femoral-side tear and combined tear in a first-time LPD predispose a second-time LPD. PMID- 29520188 TI - The Incidence of Various Types of Systemic Reactions Related to Epidural Steroid Injections: A Prospective Observational Study. AB - Objective: To evaluate the incidence, types and association of systemic reactions after an epidural steroid injection (ESI) with patient demographics, ESI factors and repeated occurrence of an ESI. Materials and Methods: This prospective observational study was approved by the Institutional Review Board of our hospital, and written informed consent was obtained from all the participants. From October to December 2011, systemic reactions at 2 weeks after 960 ESIs among 885 patients were measured. Patients were evaluated by phone interviews to obtain the patients' demographics, history of previous ESI, ESI factors, and ESI reoccurrence. Statistical analyses were performed using the chi-square tests, Fisher's exact tests and a binary logistic regression analysis. Results: Overall, 557 types of systemic reactions occurred after 292 injections (30.4%) of a total of 960 ESIs in which facial flushing was most common (131/557, 23.5%) and 144 ESIs were followed by a mixed form of systemic reactions (49.3%). Age of 62 years or younger (odds ratio [OR], 2.361), female sex (OR, 1.674), and history of diabetes mellitus (OR, 1.681) were significant risk factors in the occurrence of systemic reactions after an ESI. In 73 patients with repeated ESI, 14 patients re experienced systemic reactions (19.2%), of which twelve re-experienced the same systemic reaction as the previous one. Conclusion: Systemic reactions followed about 30% of ESIs, and more commonly occurred in patients 62 years of age or younger, women, and diabetic patients. Half of the patients experienced a mixed form of systemic reactions. Patients with recurring systemic reactions tend to re experience the same systemic reaction as the prior one after an ESI. PMID- 29520189 TI - Clinical Feasibility of Synthetic Magnetic Resonance Imaging in the Diagnosis of Internal Derangements of the Knee. AB - Objective: To evaluate the feasibility of synthetic magnetic resonance imaging (MRI) compared to conventional MRI for the diagnosis of internal derangements of the knee at 3T. Materials and Methods: Following Institutional Review Board approval, image sets of conventional and synthetic MRI in 39 patients were included. Two musculoskeletal radiologists compared the image sets and qualitatively analyzed the images. Subjective image quality was assessed using a four-grade scale. Interobserver agreement and intersequence agreement between conventional and synthetic images for cartilage lesions, tears of the cruciate ligament, and tears of the meniscus were independently assessed using Kappa statistics. In patients who underwent arthroscopy (n = 8), the sensitivity, specificity, and accuracy for evaluated internal structures were calculated using arthroscopic findings as the gold standard. Results: There was no statistically significant difference in image quality (p = 0.90). Interobserver agreement (kappa = 0.649- 0.981) and intersequence agreement (kappa = 0.794-0.938) were nearly perfect for all evaluated structures. The sensitivity, specificity, and accuracy for detecting cartilage lesions (sensitivity, 63.6% vs. 54.6-63.6%; specificity, 91.9% vs. 91.9%; accuracy, 83.3-85.4% vs. 83.3-85.4%) and tears of the cruciate ligament (sensitivity, specificity, accuracy, 100% vs. 100%) and meniscus (sensitivity, 50.0-62.5% vs. 62.5%; specificity, 100% vs. 87.5-100%; accuracy, 83.3-85.4% vs. 83.3-85.4%) were similar between the two MRI methods. Conclusion: Conventional and synthetic MRI showed substantial to almost perfect degree of agreement for the assessment of internal derangement of knee joints. Synthetic MRI may be feasible in the diagnosis of internal derangements of the knee. PMID- 29520190 TI - Evaluation of the Subscapularis Tendon Tears on 3T Magnetic Resonance Arthrography: Comparison of Diagnostic Performance of T1-Weighted Spectral Presaturation with Inversion-Recovery and T2-Weighted Turbo Spin-Echo Sequences. AB - Objective: To compare the T1-weighted spectral presaturation with inversion recovery sequences (T1 SPIR) with T2-weighted turbo spin-echo sequences (T2 TSE) on 3T magnetic resonance arthrography (MRA) in the evaluation of the subscapularis (SSC) tendon tear with arthroscopic findings as the reference standard. Materials and Methods: This retrospective study included 120 consecutive patients who had undergone MRA within 3 months between April and December 2015. Two musculoskeletal radiologists blinded to the arthroscopic results evaluated T1 SPIR and T2 TSE images in separate sessions for the integrity of the SSC tendon, examining normal/articular-surface partial-thickness tear (PTTa)/full-thickness tear (FTT). Diagnostic performance of T1 SPIR and T2 TSE was calculated with arthroscopic results as the reference standard, and sensitivity, specificity, and accuracy were compared using the McNemar test. Interobserver agreement was measured with kappa (kappa) statistics. Results: There were 74 SSC tendon tears (36 PTTa and 38 FTT) confirmed by arthroscopy. Significant differences were found in the sensitivity and accuracy between T1 SPIR and T2 TSE using the McNemar test, with respective rates of 95.9-94.6% vs. 71.6-75.7% and 90.8-91.7% vs. 79.2-83.3% for detecting tear; 55.3% vs. 31.6-34.2% and 85.8% vs. 78.3-79.2%, respectively, for FTT; and 91.7-97.2% vs. 58.3-61.1% and 89% vs. 78-79.3%, respectively, for PTTa. Interobserver agreement for T1 SPIR was almost perfect for T1 SPIR (kappa = 0.839) and substantial for T2 TSE (kappa = 0.769). Conclusion: T1-weighted spectral presaturation with inversion-recovery sequences is more sensitive and accurate compared to T2 TSE in detecting SSC tendon tear on 3T MRA. PMID- 29520191 TI - Early Changes in Apparent Diffusion Coefficient for Salivary Glands during Radiotherapy for Nasopharyngeal Carcinoma Associated with Xerostomia. AB - Objective: To evaluate the early changes in the apparent diffusion coefficient (ADC) of the salivary glands during radiotherapy (RT) and their association with the degree of xerostomia at 6 months after RT in patients with nasopharyngeal carcinoma (NPC). Materials and Methods: We enrolled 26 patients with NPC who underwent RT. Each patient underwent diffusion-weighted MRI of the salivary glands at rest and with gustatory stimulation within 1 week before RT and 2 weeks after the beginning of RT. The ADC at rest (ADCR) and increase and increase rate with stimulation (ADCI, ADCIR) of the submandibular and parotid glands were calculated. The differences in the variables' values between 2 weeks after the beginning of RT and baseline (DeltaADCR, DeltaADCI, and DeltaADCIR) were compared to the degree of xerostomia at 6 months after RT. Results: The ADCR of the submandibular and parotid glands were both significantly higher at 2 weeks after the beginning of RT than found at baseline (both p < 0.01). The ADCI and ADCIR for the parotid glands were both significantly lower at 2 weeks after the beginning of RT than found at baseline (both p < 0.01). DeltaADCI and DeltaADCIR of the parotid glands were associated with the degree of xerostomia at 6 months after RT (r = -0.61 and -0.72, both p < 0.01). Conclusion: The ADCs of the salivary glands change early during RT. The differences in the ADC increase and increase rate of the parotid glands between 2 weeks after the beginning of RT and baseline were associated with the degree of xerostomia at 6 months after RT. PMID- 29520192 TI - Endovascular Treatment of Bilateral Cavernous Sinus Dural Arteriovenous Fistula: Therapeutic Strategy and Follow-Up Outcomes. AB - Objective: Bilateral cavernous sinus dural arteriovenous fistula (CSdAVF) is very rare, even in Asian countries. The research intended to present clinical and radiologic outcomes of treating such fistulas through endovascular embolization. Materials and Methods: Data was obtained from 220 consecutive patients, with CSdAVF, who were treated from January 2004 to December 2015. Bilateral CSdAVF was identified in 17 patients (7.7%). The clinical and radiologic outcomes of the fistulas were assessed with an emphasis on the technical aspects of treatment. Results: At the time of treatment, 7 and 10 patients presented with bilateral and unilateral symptoms, respectively. In the former cases, 4 patients had progressed from unilateral to bilateral symptoms. Bilateral fistulas were treated with a single-stage transvenous embolization (TVE) in 15 patients, via bilateral inferior petrosal sinuses (IPS) (n = 9) and unilateral IPS (n = 6). In the other 2 patients with one-sided dominance of shunting, only dominant fistula was treated. Two untreated lesions were found on follow-up to have spontaneously resolved after treatment of the dominant contralateral fistula. Of the 34 CSdAVF lesions, complete occlusion was achieved in 32 lesions after TVE. Seven patients (41.2%) developed worsening of cranial nerve palsy after TVE. During the follow up period, 4 patients obtained complete recovery, whereas the other 3 remained with deficits. Conclusion: With adjustments of endovascular procedures to accommodate distinct anatomical configurations, endovascular treatment for bilateral CSdAVF can achieve excellent angiographic occlusion results. However, aggravation of symptoms after TVE may occur frequently in bilateral CSdAVF. In the patients with one-sided dominance of shunt, treatment of only dominant fistula might be an alternative option. PMID- 29520193 TI - Diagnostic Value of Volume-Based Fluorine-18-Fluorodeoxyglucose PET/CT Parameters for Characterizing Thyroid Incidentaloma. AB - Objective: To assess clinical value of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for differentiation of malignant from benign focal thyroid incidentaloma. Materials and Methods: This retrospective study included 99 patients with focal thyroid incidentaloma of 5216 non-thyroid cancer patients that had undergone PET/CT. PET/CT semi-quantitative parameters, volume-based functional parameters, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of thyroid incidentaloma were assessed. Receiver operating characteristic (ROC) analysis was conducted and areas under the curve (AUC) were compared by Hanley and McNeil test to evaluate usefulness of maximum standardized uptake value (SUVmax), MTV and TLG, as markers for differentiating malignant from benign thyroid incidentalomas. Results: Of 99 thyroid incidentalomas, 64 (64.6%) were malignant and 35 (35.4%) were benign. Malignant thyroid incidentalomas were larger (1.8 cm vs. 1.3 cm, p = 0.006), and had higher SUVmax (11.3 vs. 4.8, p < 0.001), MTV (all p < 0.001) and TLG (all p < 0.001) than benign. TLG 4.0 had the highest performance for differentiation of malignant from benign thyroid incidentaloma in all semi-quantitative parameters with AUC 0.895 by ROC curve analysis. AUC (TLG 4.0) was significantly larger than AUC (SUVmean), AUC (MTV 2.5), AUC (MTV 3.0), AUC (MTV 3.5), AUC (TLG 2.5), and AUC (TLG 3.0), respectively (all, p < 0.05). There was no statistical difference between AUC (TLG 4.0) and AUC (SUVmax) (p > 0.05). A threshold TLG 4.0 of 2.475 had 81.3% sensitivity and 94.3% specificity for identifying malignant thyroid incidentalomas. Conclusion: Volume-based PET/CT parameters could potentially have clinical value in differential diagnosis of thyroid incidentaloma along with SUVmax. PMID- 29520194 TI - Incidence of Breakthrough Reaction in Patients with Prior Acute Allergic-Like Reactions to Iodinated Contrast Media according to the Administration Route. AB - Objective: This study assessed the risk of acute allergic-like reactions (AARs) after extravascular administration of iodinated contrast media (ICM) in at-risk patients compared with that after intravascular ICM administration. Materials and Methods: From July 2012 to January 2016, 264 patients with a history of moderate or severe reactions to ICM, with re-exposure to ICM intravascularly or extravascularly were included. The incidence of recurrent AARs after ICM re exposure were assessed according to the administration routes by reviewing electronic medical records and comparison between the two routes. Results: Among 264 patients, 244 patients had been subsequently exposed to ICM intravascularly, 7 patients via an extravascular route and 13 patients with dual re-exposure. Of 257 patients with intravascular ICM re-exposure, 87 (33.9%) had mild to severe recurrent AARs and 143 (19.5%) cases of recurrent AARs occurred among 733 cases of intravascular ICM re-exposure on a case-by-case basis. However, there was no case of recurrent ARR after extravascular administration of ICM in 20 patients (45 cases) with ICM administrated extravascularly. Conclusion: For high-risk patients with a history of moderate or severe reactions to ICM, AARs upon extravascular administration of ICM are significantly infrequent compared with intravascular ICM administration. PMID- 29520196 TI - RE: Multi-Parameter CMR Approach in Acute Myocarditis to Improve Diagnosis and Prognostic Stratification. PMID- 29520197 TI - Exponential bounds for the hypergeometric distribution. AB - We establish exponential bounds for the hypergeometric distribution which include a finite sampling correction factor, but are otherwise analogous to bounds for the binomial distribution due to Leon and Perron (Statist. Probab. Lett.62 (2003) 345-354) and Talagrand (Ann. Probab.22 (1994) 28-76). We also extend a convex ordering of Kemperman's (Nederl. Akad. Wetensch. Proc. Ser. A76 = Indag. Math.35 (1973) 149-164) for sampling without replacement from populations of real numbers between zero and one: a population of all zeros or ones (and hence yielding a hypergeometric distribution in the upper bound) gives the extreme case. PMID- 29520195 TI - A Whole-Tumor Histogram Analysis of Apparent Diffusion Coefficient Maps for Differentiating Thymic Carcinoma from Lymphoma. AB - Objective: To assess the performance of a whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating thymic carcinoma from lymphoma, and compare it with that of a commonly used hot-spot region-of interest (ROI)-based ADC measurement. Materials and Methods: Diffusion weighted imaging data of 15 patients with thymic carcinoma and 13 patients with lymphoma were retrospectively collected and processed with a mono-exponential model. ADC measurements were performed by using a histogram-based and hot-spot-ROI-based approach. In the histogram-based approach, the following parameters were generated: mean ADC (ADCmean), median ADC (ADCmedian), 10th and 90th percentile of ADC (ADC10 and ADC90), kurtosis, and skewness. The difference in ADCs between thymic carcinoma and lymphoma was compared using a t test. Receiver operating characteristic analyses were conducted to determine and compare the differentiating performance of ADCs. Results: Lymphoma demonstrated significantly lower ADCmean, ADCmedian, ADC10, ADC90, and hot-spot-ROI-based mean ADC than those found in thymic carcinoma (all p values < 0.05). There were no differences found in the kurtosis (p = 0.412) and skewness (p = 0.273). The ADC10 demonstrated optimal differentiating performance (cut-off value, 0.403 * 10-3 mm2/s; area under the receiver operating characteristic curve [AUC], 0.977; sensitivity, 92.3%; specificity, 93.3%), followed by the ADCmean, ADCmedian, ADC90, and hot-spot-ROI-based mean ADC. The AUC of ADC10 was significantly higher than that of the hot spot ROI based ADC (0.977 vs. 0.797, p = 0.036). Conclusion: Compared with the commonly used hot spot ROI based ADC measurement, a histogram analysis of ADC maps can improve the differentiating performance between thymic carcinoma and lymphoma. PMID- 29520199 TI - Helicobacter Pylori Treatment Results in Slovenia in the Period 2013-2015 as a Part of European Registry on Helicobacter Pylori Management. AB - Background: Helicobacter pylori (H. pylori) is the most common chronic bacterial infection in the world affecting over 50% of the world's population. H. pylori is a grade I carcinogen, responsible for the development of 89 % of noncardia gastric cancers. In the present study we analyzed the data for H. pylori eradication treatments in Slovenia. Patients and methods: Slovenia is a part of the European Registry on Helicobacter pylori Management from the beginning. In seven medical institutions data for H. pylori eradication treatments was collected for 1774 patients from April 16th 2013 to May 15th 2016. For further modified intention to treat (mITT) analysis 1519 patients were eligible and for per protocol (PP) analysis 1346 patients. Results: Patients' dropout was 11.4%. Eradication rate for 7 day triple therapy with proton pump inhibitor (PPI) + Clarithromycin (C) + Amoxicillin (A) was 88.7% PP and 72.0% mITT; for PPI + C + Metronidazole (M) 85.2% PP and 84.4% mITT. Second line 14 day therapy PPI + A + Levofloxacin had 92.3% eradication rate PP and 87.1% mITT. Ten to fourteen day Bismuth quadruple therapy was the therapy in difficult to treat patients. At the end all patients that adhered to prescribed regimens were cured of their H. pylori infection. Conclusions: High dropout rate deserves further analysis. Slovenia is still a country with < 15% H. pylori resistance to clarithromycin, triple therapy with PPI plus two antibiotics reaches PP eradication rate > 85%, but mITT eradication rates are suboptimal. PMID- 29520198 TI - Men's Perpetration of Partner Violence in Bangladesh: Community Gender Norms and Violence in Childhood. AB - Men's perpetration of intimate partner violence (IPV) is common, but its multilevel determinants are understudied. We leveraged novel data from a probability sample of 570 junior men (married, 18-34 years) from 50 urban and 62 rural communities who took part in the Bangladesh survey of the 2011 UN Multi Country Study of Men and Violence. We tested whether more equitable community gender norms among senior men (N=938; married, 35-49 years) was negatively associated, and a junior man's greater exposure to childhood violence was positively associated, with his lifetime count (or scope) of physical IPV acts perpetrated. We also tested whether more equitable community gender norms mitigated the association of more violence in childhood with the lifetime scope of physical IPV acts perpetrated. Among younger married men, 50% reportedly ever perpetrated physical IPV, the mean lifetime scope of physical IPV types perpetrated was 1.1 (SD 1.3) out of 5.0 listed. A majority (64%) reported childhood exposure to violence. In multilevel Poisson models, a man with more childhood exposure to violence had a higher log scope (Est. 0.31, SE 0.04, p<.001) and a man living amidst the most equitable gender norms had a lower log scope (Est. -0.52, SE 0.19, p<.01) of physical IPV acts perpetrated; however, no significant cross-level interaction was observed. Interventions that address the trauma of childhood violence and that promote more equitable community gender norms may be needed to mitigate IPV perpetration by younger men. PMID- 29520200 TI - Premalignant Gastric Lesions in Patients Included in National Colorectal Cancer Screening. AB - Background: Gastric cancer is the fifth most common malignancy in the world with almost one million new cases annually. Helicobacter pylori infection causes 89% of all gastric cancers. Premalignant lesions (atrophy and intestinal metaplasia) develop after several decades of inflammation. Secondary prevention with gastroscopy is possible, but it is costly and has a low compliance rate. Alternative procedures like serology testing for pepsinogen I and II and pepsinogen I/II ratio are available to select patients for surveillance gastroscopies. Patients and methods: In seven outpatient endoscopic units, 288 patients (154 men; 53.5%), average age 60.68 years, tested positive in National colorectal cancer screening programme SVIT, were included in the study. Gastropanel (BioHit, Finland) was used as a serologic biopsy method. Results: We found 24 patients (12 men, mean age 63.7 years) with pepsinogen (pepsinogen I/II < 3 and/or pepsinogen I < 30 MUg/L). Premalignant changes were found on gastric biopsies in 21 patients (7.3% incidence). Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) >= 1 was found in 20 patients; Operative Link for Gastritis Assessment (OLGA) >= 1 was found in 19 patients. Combined accuracy for preneoplastic lesions in Gastropanel positive patients was 87.5%. H. pylori seropositivity was found in 219 patients (76%). Only 24% of our population had normal results. Conclusions: Gastropanel test has proven to be a reliable non invasive test for advanced gastric preneoplastic lesions that can select patients for further gastroscopy. We found high H. pylori seropositivity in older age groups in Slovenia. PMID- 29520201 TI - Computed Tomographic Perfusion Imaging for the Prediction of Response and Survival to Transarterial Chemoembolization of Hepatocellular Carcinoma. AB - Background: The purpose of this retrospective cohort study was to evaluate the clinical value of computed tomographic perfusion imaging (CTPI) parameters in predicting the response to treatment and overall survival in patients with hepatocellular carcinoma (HCC) treated with drug-eluting beads transarterial chemoembolization (DEBTACE). Patients and methods: Between December 2010 and January 2013 eighteen patients (17 men, 1 woman; mean age 69 +/- 5.8 years) with intermediate stage HCC underwent CTPI of the liver prior to treatment with DEBTACE. Treatment response was evaluated on follow-up imaging according to modified Response Evaluation Criteria in Solid Tumors. Pre-treatment CTPI parameters were compared between patients with complete response and partial response with a Student t-test. We compared survival times with Kaplan-Meier method. Results: CTPI parameters of patients with complete response and others did not show statistical significant difference. The mean survival time was 25.4 +/- 3.2 months (95%; CI: 18.7-32.1). Survival was statistically significantly longer in patients with hepatic blood flow (BF) lower than 50.44 ml/100 ml/min (p = 0.033), hepatic blood volume (BV) lower than 13.32 ml/100 ml (p = 0.028) and time to peak (TTP) longer than 19.035 s (p = 0.015). Conclusions: CTPI enables prediction of survival in patients with intermediate stage HCC, treated with DEBTACE based on the pre-treatment values of BF, BV and TTP perfusion parameters. CT perfusion imaging can't be used to predict treatment response to DEBTACE. PMID- 29520202 TI - Preoperative Intensity-modulated Chemoradiation Therapy with Simultaneous Integrated Boost in Rectal Cancer: 2-year Follow-up Results of Phase II Study. AB - Background: The aim of the study was to investigate the feasibility and safety of experimental fractionation using intensity modulated radiation therapy with a simultaneous integrated boost (IMRT-SIB) to shorten the overall treatment time without dose escalation in preoperative radiochemotherapy of locally advanced rectal cancer. Patients and methods: Between January 2014 and November 2015, a total of 51 patients with operable stage II-III rectal adenocarcinoma were treated. The preoperative treatment with intensity modulated radiation therapy (IMRT) and a pelvic dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/3 and 48.4 Gy to T4 tumour in 22 fractions, with standard concomitant capecitabine, was completed in 50 patients out of whom 47 were operated. The median follow-up was 35 months. Results: The rate of acute toxicity G >= 3 was 2.4%. The total downstaging rate was 89% and radical resection was achieved in 98% of patients. Pathologic complete response (pCR) was observed in 25.5% of patients, with 2-year local control (LC), disease free survival (DFS), and overall survival (OS) of 100% for this patient group. An intention-to-treat analysis revealed pN to be a significant prognostic factor for DFS and OS (P = 0.005 and 0.030, respectively). LC for the entire group was 100%, and 2-year DFS and OS were 90% (95 % CI 98.4 81.6) and 92.2% (95% CI 99.6-84.7), respectively. Conclusions: The experimental regime in this study resulted in a high rate of pCR with a low acute toxicity profile. Excellent early results translated into encouraging 2-year LC, DFS, and OS. PMID- 29520203 TI - Prognostic Significance of Tumor Regression in Locally Advanced Rectal Cancer after Preoperative Radiochemotherapy. AB - Background: The majority of rectal cancers are discovered in locally advanced forms (UICC stage II, III). Treatment consists of preoperative radiochemotherapy, followed by surgery 6-8 weeks later and finally by postoperative chemotherapy. The aim of this study was to find out if tumor regression affected long-term survival in patients with localy advanced rectal cancer, treated with neoadjuvant radiochemotherapy. Patients and methods: Patients with rectal cancer stage II or III, treated between 2006 and 2010, were included in a retrospective study. Clinical and pathohistologic data were acquired from computer databases and information about survival from Cancer Registry. Survival was estimated according to Kaplan-Meier method. Significance of prognostic factors was evaluated in univariate analysis; comparison was carried out with log-rank test. The multivariate analysis was performed according to the Cox regression model; statistically significant variables from univariate analysis were included. Results: Two hundred and two patients met inclusion criteria. Median follow-up was 53.2 months. Stage ypT0N0 (pathologic complete response, pCR) was observed in 14.8% of patients. Pathohistologic stage had statistically significant impact on survival (p = 0.001). 5-year survival in patients with pCR was>90%. Postoperative T and N status were also found to be statistically significant (p = 0.011 for ypT and p < 0.001 for ypN). According to multivariate analysis, tumor response to neoadjuvant therapy was the only independent prognostic factor (p = 0.003). Conclusions: Pathologic response of tumor to preoperative radiochemotherapy is an important prognostic factor for prediction of long-term survival of patients with locally advanced rectal cancer. PMID- 29520204 TI - Laparoscopic Parenchyma-sparing Liver Resection for Colorectal Metastases. AB - Background: Laparoscopic liver resection (LLR) of colorectal liver metastases (CLM) is increasingly performed in specialized centers. While there is a trend towards a parenchyma-sparing strategy in multimodal treatment for CLM, its role is yet unclear. In this study we present short- and long-term outcomes of laparoscopic parenchyma-sparing liver resection (LPSLR) at a single center. Patients and methods: LLR were performed in 951 procedures between August 1998 and March 2017 at Oslo University Hospital, Oslo, Norway. Patients who primarily underwent LPSLR for CLM were included in the study. LPSLR was defined as non anatomic hence the patients who underwent hemihepatectomy and sectionectomy were excluded. Perioperative and oncologic outcomes were analyzed. The Accordion classification was used to grade postoperative complications. The median follow up was 40 months. Results: 296 patients underwent primary LPSLR for CLM. A single specimen was resected in 204 cases, multiple resections were performed in 92 cases. 5 laparoscopic operations were converted to open. The median operative time was 134 minutes, blood loss was 200 ml and hospital stay was 3 days. There was no 90-day mortality in this study. The postoperative complication rate was 14.5%. 189 patients developed disease recurrence. Recurrence in the liver occurred in 146 patients (49%), of whom 85 patients underwent repeated surgical treatment (liver resection [n = 69], ablation [n = 14] and liver transplantation [n = 2]). Five-year overall survival was 48%, median overall survival was 56 months. Conclusions: LPSLR of CLM can be performed safely with the good surgical and oncological results. The technique facilitates repeated surgical treatment, which may improve survival for patients with CLM. PMID- 29520205 TI - Simultaneous Pure Laparoscopic Resection of Primary Colorectal Cancer and Synchronous Liver Metastases: A Single Institution Experience with Propensity Score Matching Analysis. AB - Background: The aim of the study was to compare the outcome of pure laparoscopic and open simultaneous resection of both the primary colorectal cancer and synchronous colorectal liver metastases (SCLM). Patients and methods: From 2000 to 2016 all patients treated by simultaneous resection were assessed for entry in this single center, clinically nonrandomized trial. A propensity score matching was used to compare the laparoscopic group (LAP) to open surgery group (OPEN). Primary endpoints were perioperative and oncologic outcomes. Secondary endpoints were overall survival (OS) and disease-free survival (DFS). Results: Of the 82 patients identified who underwent simultaneous liver resection for SCLM, 10 patients underwent LAP. All these consecutive patients from LAP were matched to 10 comparable OPEN. LAP reduced the length of hospital stay (P = 0.044) and solid food oral intake was faster (P = 0.006) in this group. No patient undergoing the laparoscopic procedure experienced conversion to the open technique. No difference was observed in operative time, blood loss, transfusion rate, narcotics requirement, clinical risk score, resection margin, R0 resections rate, morbidity, mortality and incisional hernias rate. The two groups did not differ significantly in terms of the 3-year OS rate (90 vs. 75%; P = 0.842) and DFS rate (60 vs. 57%; P = 0.724). Conclusions: LAP reduced the length of hospital stay and offers faster solid food oral intake. Comparable oncologic and survival outcomes can be achieved. LAP is beneficial for well selected patients in high volume centers with appropriate expertise. PMID- 29520207 TI - Outcomes of the Surgical Treatment for Adenocarcinoma of the Cardia - Single Institution Experience. AB - Background: Adenocarcinomas at the cardia are biologically aggressive tumors with poor long-term survival following curative resection. For resectable adenocarcinoma of the cardia, mostly esophagus extended total gastrectomy or esophagus extended proximal gastric resection is performed; however, the surgical approach, transhiatal or transthoracic, is still under discussion. Postoperative morbidity, mortality and long-term survival were analyzed to evaluate the potential differences in clinically relevant outcomes. Patients and methods: Of altogether 844 gastrectomies performed between January 2000 and December 2016, 166 were done for the adenocarcinoma of the gastric cardia, which we analyzed with using the Cox proportional hazards model. Results: 136 were esophagus extended total gastrectomy and 125 esophagus extended proximal gastric resection. A D2 lymphadenectomy was performed in 88.2%, splenectomy in 47.2%, and multivisceral resections in 12.4% of patients. R0 resection rate was 95.7%. The mean proximal resection margin on the esophagus was 42.45 mm. It was less than 21 mm in 9 patients. Overall morbidity regarding Clavien-Dindo classification (> 1) was altogether 28.6%. 15.5% were noted as surgical and 21.1% as medical complications. The 30-day mortality was 2.2%. The 5-year survival for R0 resections was 33.4%. Multivisceral resection, depth of tumor infiltration, nodal stage, and curability of the resection were identified as independent prognostic factors. Conclusions: Transhiatal approach for resection of adenocarcinoma of the cardia is a safe procedure for patients with Siewert II and III regarding the postoperative morbidity and mortality; moreover, long-term survival is comparable to transthoracic approach. The complications associated with thoracoabdominal approach can therefore be avoided with no impact on the rate of local recurrence. PMID- 29520206 TI - Impact Factors for Perioperative Morbidity and Mortality and Repercussion of Perioperative Morbidity and Long-term Survival in Pancreatic Head Resection. AB - Background: The focus of the present study was to reveal any impact factors for perioperative morbidity and mortality as well as repercussion of perioperative morbidity on long-term survival in pancreatic head resection. Patients and methods: In a retrospective study, clinic-pathological factors of 240 patients after pancreatic head (PD) or total resection were analyzed for correlations with morbidity, 30- and 90-day mortality, and long-term survival. According to Clavien Dindo classification, all complications with grade II and more were defined as overall complications (OAC). OAC, all surgical (ASC), general (AGC) and some specific types of complications like leaks from the pancreatoenteric anastomosis (PEA) or pancreatic fistula (PF, type A, B and C), leaks from other anastomoses (OL), bleeding (BC) and abscesses (AA) were studied for correlation with clinic pathological factors. Results: In the 9-year period, altogether 240 patients had pancreatic resection. The incidence of OAC was 37.1%, ASC 29.2% and AGC 15.8%. ASC presented themselves as PL, OL, BC and AA in 19% (of 208 PD), 5.8%, 5.8%, and 2.5% respectively. Age, ASA score, amylase on drains, and pancreatic fistulas B and C correlated significantly with different types of complications. Overall 30- and 90-day mortalities were 5 and 7.9% and decreased to 3.5 and 5% in P2. Conclusions: High amylase on drains and higher mean age were independent indicators of morbidity, whereas PL and BC revealed as independent predictor for 30-day mortality, and physical status, OAC and PF C for 90-day mortality. PMID- 29520208 TI - The Impact of Outpatient Clinical Care on the Survival and Hospitalisation Rate in Patients with Alcoholic Liver Cirrhosis. AB - Background: In the study, we aimed to determine whether regular outpatient controls in patients with alcoholic liver cirrhosis have an impact on their survival and hospitalisation rates. Patients and methods: We included patients with liver cirrhosis and regular outpatient controls as a prospective study group and patients with liver cirrhosis who were admitted to hospital only in cases of complications as a retrospective control group. The study was conducted between 2006 and 2011. Results: We included 98 patients in the study group and 101 patients in the control group. There were more outpatient controls in the study group than in the control group (5.54 examinations vs. 2.27 examinations, p = 0.000). Patients in the study group had 25 fewer hospitalisations (10.2%; p = 0.612). The median survival rate was 4.6 years in the study group and 2.9 years in the control group (p = 0.021). Patients with Child A classification had an average survival of one year longer in the study group (p = 0.035). No significant difference was found for Child B patients. Patients with Child C classification had longer survival by 1.6 years in the study group (p = 0.006). Alcohol consumption was lower in the study group than in the control group (p = 0.018). Conclusions: We confirmed that patients with regular outpatient controls had lower alcohol consumption, a lower hospitalisation rate and significantly prolonged survival time. We confirmed the necessity for the establishment of regular outpatient controls in patients with alcoholic liver cirrhosis. PMID- 29520209 TI - Nutrition of Patients with Severe Neurologic Impairment. AB - Background: Commercial enteral formulas are generally recommended for gastrostomy feeding in patients with severe neurologic impairment. However, pureed food diets are still widely used and even gaining popularity among certain groups. We tried to compare the effectiveness of gastrostomy feeding for treatment of severe malnutrition with either enteral formulas or pureed feeds. Patients and methods: A 6-month nutritional intervention was made with 37 malnourished children, adolescents and young adults (2-26 years old) with severe neurologic impairment (Gross Motor Function Classification system [GMFCS] grade V). The individual needs were calculated. Participants were fed by gastrostomy with either enteral formulas (n = 17) or pureed food (n = 20). Measurements to assess nutritional status were made at the beginning and at the end of intervention. Results: The Z scores for weight-for-age and for the body-mass index increased more in enteral formula than in pureed food group (2.07 vs. 0.70, p = 0.0012; and 3.75 vs. 0.63, p = 0.0014, respectively). Fat mass index increased more in enteral formula than in pureed food group (1.12 kg/m2vs. 0.38 kg/m2; p = 0.0012). Patients in the enteral formula group showed increase in lean body mass expressed as fat-free mass index (0.70 kg/m2), while those in pureed food group did not (-0.06 kg/m2) (p = 0.0487). Conclusions: The results suggest that even professionally planned pureed food diet is less effective than commercial enteral formula for nutritional rehabilitation of malnourished patients with severe neurologic impairment. However, larger and if possible randomised clinical studies should be made to confirm our findings. PMID- 29520211 TI - Electrochemotherapy with Bleomycin of Different types of Cutaneous Tumours in a Ferret (Mustela Putorius Furo). AB - Background: Mast cell tumour, sebaceous gland adenoma, and less common squamous papilloma are skin tumours in ferrets (Mustela putorius furo), and early excisional surgery is usually the treatment of choice. The aim of our study was to investigate the effectiveness of electrochemotherapy (ECT), a new, minimally invasive non-surgical method, as first treatment option of different types of ferret skin tumours located on surgically difficult sites. Materials and methods: A 5-year-old castrated male ferret with two cutaneous masses, presenting 4 months apart and a 7-year-old spayed female ferret with two cutaneous masses, that appeared simultaneously on two locations are presented. In the first patient, both masses were diagnosed as mast cell tumours, and in the second patient, squamous papilloma and sebaceous adenoma were diagnosed. One session of ECT with bleomycin injected intratumourally was applied in all tumours. Results: Complete response (CR) of all tumours was obtained, without recurrence during observation period of 15 months after ECT for first tumour and 11 months after ECT of the tumour located on the right hock in first patient, and 8 months after treatment for the second patient. Conclusions: In present study, ECT with bleomycin proved to be safe and effective against different cutaneous tumours in ferrets. Due of good results, low cost and relatively easy procedure, ECT could be the treatment of choice instead of surgery for the selected skin tumours in ferrets. PMID- 29520210 TI - MRI and 11C Acetate PET/CT for Prediction of Regional Lymph Node Metastasis in Newly Diagnosed Prostate Cancer. AB - Background: The aim of the study was to examine the value of quantitative and qualitative MRI and 11C acetate PET/CT parameters in predicting regional lymph node (LN) metastasis of newly diagnosed prostate cancer (PCa). Patients and methods: Patients with intermediate (n = 6) and high risk (n = 47) PCa underwent 3T MRI (40 patients) and 11C acetate PET/CT (53 patients) before extended pelvic LN dissection. For each patient the visually most suspicious LN was assessed for mean apparent diffusion coefficient (ADCmean), maximal standardized uptake value (SUVmax), size and shape and the primary tumour for T stage on MRI and ADCmean and SUVmax in the index lesion. The variables were analysed in simple and multiple logistic regression analysis. Results: All variables, except ADCmean and SUVmax of the primary tumor, were independent predictors of LN metastasis. In multiple logistic regression analysis the best model was ADCmean in combintion with MRI T-stage where both were independent predictors of LN metastasis, this combination had an AUC of 0.81 which was higher than the AUC of 0.65 for LN ADCmean alone and the AUC of 0.69 for MRI T-stage alone. Conclusions: Several quantitative and qualitative imaging parameters are predictive of regional LN metastasis in PCa. The combination of ADCmean in lymph nodes and T-stage on MRI was the best model in multiple logistic regression with increased predictive value compared to lymph node ADCmean and T-stage on MRI alone. PMID- 29520212 TI - The Influence of Genetic Variability on the Risk of Developing Malignant Mesothelioma. AB - Background: Malignant mesothelioma is a rare cancer with poor outcome, associated with asbestos exposure. Reactive oxygen species may play an important role in the mechanism of carcinogenesis; therefore, genetic variability in antioxidative defence may modify an individual's susceptibility to this cancer. This study investigated the influence of functional polymorphisms of NQO1, CAT, SOD2 and hOGG1 genes, gene-gene interactions and gene-environment interactions on malignant mesothelioma risk. Patients and methods: In total, 150 cases with malignant mesothelioma and 122 controls with no asbestos-related disease were genotyped for NQO1, CAT, SOD2 and hOGG1 polymorphisms. Results: The risk of malignant mesothelioma increased with smoking, odds ratio (OR) 9.30 [95% confidence interval (CI): 4.83-17.98] and slightly with age, OR 1.10 (95% CI: 1.08-1.14). Medium and high asbestos exposures represented 7-times higher risk of malignant mesothelioma compared to low exposure, OR 7.05 (95% CI 3.59-13.83). NQO1 rs1800566 was significantly associated with increased malignant mesothelioma risk, OR 1.73 (95% CI 1.02-2.96). Although there was no independent association between either CAT rs1001179 or hOGG1 rs1052133 polymorphism and malignant mesothelioma, interaction between both polymorphisms showed a protective effect, ORint 0.27 (95% CI 0.10-0.77). Conclusions: Our findings suggest a role of both genetic variability in antioxidative defence and repair as well as the impact of gene-gene interactions in the development of malignant mesothelioma. The results of this study could add to our understanding of pathogenesis of malignant mesothelioma and contribute to prevention and earlier diagnosis of this aggressive cancer. PMID- 29520213 TI - Voluntary Deep Inspiration Breath-hold Reduces the Heart Dose Without Compromising the Target Volume Coverage During Radiotherapy for Left-sided Breast Cancer. AB - Background: During radiotherapy of left-sided breast cancer, parts of the heart are irradiated, which may lead to late toxicity. We report on the experience of single institution with cardiac-sparing radiotherapy using voluntary deep inspiration breath hold (V-DIBH) and compare its dosimetric outcome with free breathing (FB) technique. Patients and methods: Left-sided breast cancer patients, treated at our department with postoperative radiotherapy of breast/chest wall +/- regional lymph nodes between May 2015 and January 2017, were considered for inclusion. FB-computed tomography (CT) was obtained and dose planning performed. Cases with cardiac V25Gy >= 5% or risk factors for heart disease were coached for V-DIBH. Compliant patients were included. They underwent additional CT in V-DIBH for planning, followed by V-DIBH radiotherapy. Dose volume histogram parameters for heart, lung and optimized planning target volume (OPTV) were compared between FB and BH. Treatment setup shifts and systematic and random errors for V-DIBH technique were compared with FB historic control. Results: Sixty-three patients were considered for V-DIBH. Nine (14.3%) were non compliant at coaching, leaving 54 cases for analysis. When compared with FB, V DIBH resulted in a significant reduction of mean cardiac dose from 6.1 +/- 2.5 to 3.2 +/- 1.4 Gy (p < 0.001), maximum cardiac dose from 51.1 +/- 1.4 to 48.5 +/- 6.8 Gy (p = 0.005) and cardiac V25Gy from 8.5 +/- 4.2 to 3.2 +/- 2.5% (p < 0.001). Heart volumes receiving low (10-20 Gy) and high (30-50 Gy) doses were also significantly reduced. Mean dose to the left anterior coronary artery was 23.0 (+/- 6.7) Gy and 14.8 (+/- 7.6) Gy on FB and V-DIBH, respectively (p < 0.001). Differences between FB- and V-DIBH-derived mean lung dose (11.3 +/- 3.2 vs. 10.6 +/- 2.6 Gy), lung V20Gy (20.5 +/- 7 vs. 19.5 +/- 5.1 Gy) and V95% for the OPTV (95.6 +/- 4.1 vs. 95.2 +/- 6.3%) were non-significant. V-DIBH-derived mean shifts for initial patient setup were <= 2.7 mm. Random and systematic errors were <= 2.1 mm. These results did not differ significantly from historic FB controls. Conclusions: When compared with FB, V-DIBH demonstrated high setup accuracy and enabled significant reduction of cardiac doses without compromising the target volume coverage. Differences in lung doses were non-significant. PMID- 29520214 TI - [125 I]IodoDPA-713 Binding to 18 kDa Translocator Protein (TSPO) in a Mouse Model of Intracerebral Hemorrhage: Implications for Neuroimaging. AB - Intracerebral hemorrhage (ICH) is a fatal stroke subtype with significant public health impact. Although neuroinflammation is a leading cause of neurological deficits after ICH, no imaging tool is currently available to monitor brain inflammation in ICH patients. Given the role of TSPO in neuroinflammation, herein we investigate whether a second-generation TSPO ligand, [125 I]IodoDPA-713 can be used to monitor the changes in TSPO expression in a preclinical model of intracerebral hemorrhage. Male CD1 mice were subjected to ICH/Sham. The brain sections, collected at different time points were incubated with [125 I]IodoDPA 713 and the brain uptake of [125 I]IodoDPA-713 was estimated using autoradiography. The specificity of [125 I]IodoDPA-713 binding was confirmed by a competitive displacement study with an unlabeled TSPO ligand, PK11195. [125 I]IodoDPA-713 binding was higher in the ipsilateral striatum with an enhanced binding observed in the peri-hematomal brain region after ICH, whereas the brain sections from sham as well as contralateral brain areas of ICH exhibited marginal binding of [125 I]IodoDPA-713. PK11195 completely reversed the [125 I] IodoDPA 713 binding to brain sections suggesting a specific TSPO-dependent binding of [125 I]IodoDPA-713 after ICH. This was further confirmed with immunohistochemistry analysis of adjacent sections, which revealed a remarkable expression of TSPO in the areas of high [125 I]IodoDPA-713 binding after ICH. The specific as well as enhanced binding of [125 I]IodoDPA-713 to the ipsilateral brain areas after ICH as assessed by autoradiography analysis provides a strong rationale for testing the applicability of [125 I]IodoDPA-713 for non-invasive neuroimaging in preclinical models of ICH. PMID- 29520215 TI - Does 10-Hz Cathodal Oscillating Current of the Parieto-Occipital Lobe Modulate Target Detection? AB - The phase of alpha (8-12 Hz) brain oscillations have been associated with moment to moment changes in visual attention and awareness. Previous work has demonstrated that endogenous oscillations and subsequent behavior can be modulated by oscillating transcranial current stimulation (otCS). The purpose of the current study is to establish the efficacy of cathodal otCS for modulation of the ongoing alpha brain oscillations, allowing for modulation of individual's visual perception. Thirty-six participants performed a target detection with sham and 10-Hz cathodal otCS. Each participant had two practice and two experimental sets composed of three blocks of 128 trials per block. Stimulating electrodes were placed on the participant's head with the anode electrode at Cz and the cathode electrode at Oz. A 0.5 mA current was applied every 100 ms (10 Hz frequency) during the otCS condition. The same current and frequency was applied for the first 10-20 s of the sham condition, after which the current was turned off. Target detection rates were compared between the sham and otCS experimental conditions in order to test for effects of otCS phase on target detection. We found no significant difference in target detection rates between the sham and otCS conditions, and discuss potential reasons for the apparent inability of cathodal otCS to effectively modulate visual perception. PMID- 29520216 TI - A Nogo-Like Signaling Perspective from Birth to Adulthood and in Old Age: Brain Expression Patterns of Ligands, Receptors and Modulators. AB - An appropriate strength of Nogo-like signaling is important to maintain synaptic homeostasis in the CNS. Disturbances have been associated with schizophrenia, MS and other diseases. Blocking Nogo-like signaling may improve recovery after spinal cord injury, stroke and traumatic brain injury. To understand the interacting roles of an increasing number of ligands, receptors and modulators engaged in Nogo-like signaling, the transcriptional activity of these genes in the same brain areas from birth to old age in the normal brain is needed. Thus, we have quantitatively mapped the innate expression of 11 important genes engaged in Nogo-like signaling. Using in situ hybridization, we located and measured the amount of mRNA encoding Nogo-A, OMgp, NgR1, NgR2, NgR3, Lingo-1, Troy, Olfactomedin, LgI1, ADAM22, and MAG, in 18 different brain areas at six different ages (P0, 1, 2, 4, 14, and 104 weeks). We show gene- and area-specific activities and how the genes undergo dynamic regulation during postnatal development and become stable during adulthood. Hippocampal areas underwent the largest changes over time. We only found differences between individual cortical areas in Troy and MAG. Subcortical areas presented the largest inter-regional differences; lateral and basolateral amygdala had markedly higher expression than other subcortical areas. The widespread differences and unique expression patterns of the different genes involved in Nogo-like signaling suggest that the functional complexes could look vastly different in different areas. PMID- 29520217 TI - Acute Down-regulation of BDNF Signaling Does Not Replicate Exacerbated Amyloid beta Levels and Cognitive Impairment Induced by Cholinergic Basal Forebrain Lesion. AB - Degeneration of basal forebrain cholinergic neurons (BFCNs) precedes hippocampal degeneration and pathological amyloid-beta (Abeta) accumulation, and underpins the development of cognitive dysfunction in sporadic Alzheimer's disease (AD). We hypothesized that degeneration of BFCNs causes a decrease in neurotrophin levels in innervated brain areas, which in turn promotes the development of Abeta pathology and cognitive impairment. Here we show that lesion of septo-hippocampal BFCNs in a pre-symptomatic transgenic amyloid AD mouse model (APP/PS1 mice) increases soluble Abeta levels in the hippocampus, and induces cognitive deficits in a spatial memory task that are not seen in either unlesioned APP/PS1 or non transgenic littermate control mice. Furthermore, the BFCN lesion results in decreased levels of brain-derived neurotrophic factor (BDNF). However, viral knockdown of neuronal BDNF in the hippocampus of APP/PS1 mice (in the absence of BFCN loss) neither increased the level of Abeta nor caused cognitive deficits. These results suggest that the cognitive decline and Abeta pathology induced by BFCN loss occur independent of dysfunctional neuronal BDNF signaling, and may therefore be directly underpinned by reduced cholinergic neurotransmission. PMID- 29520218 TI - alpha-Synuclein Heterocomplexes with beta-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity. AB - Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily alpha-synuclein (alpha syn), beta-amyloid1-42 (Abeta1-42) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of alpha-syn with Abeta or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging related pathologies. Herein, a small cohort (N = 28) of patients affected by Parkinson's disease (PD) and age-matched controls were enrolled to detect the content of alpha-syn (total and oligomeric), Abeta1-42 and tau (total and phosphorylated) in RBCs. Moreover, the presence of alpha-syn association with tau and Abeta1-42 was explored by co-immunoprecipitation/western blotting in the same cells, and quantitatively confirmed by immunoenzymatic assays. For the first time, PD patients were demonstrated to exhibit alpha-syn heterocomplexes with Abeta1-42 and tau in peripheral tissues; interestingly, alpha-syn-Abeta1-42 concentrations were increased in PD subjects with respect to healthy controls (HC), and directly correlated with disease severity and motor deficits. Moreover, total-alpha-syn levels were decreased in PD subjects and inversely related to their motor deficits. Finally, an increase of oligomeric-alpha-syn and phosphorylated-tau was observed in RBCs of the enrolled patients. The combination of three parameters (total-alpha-syn, phosphorylated-tau and alpha-syn-Abeta1-42 concentrations) provided the best fitting predictive index for discriminating PD patients from controls. Nevertheless further investigations should be required, overall, these data suggest alpha-syn hetero-aggregates in RBCs as a putative tool for the diagnosis of PD. PMID- 29520219 TI - Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in a Drosophila Model of Peripheral Neuropathy. AB - Dominant mutations in GARS, encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ). In this Drosophila model for CMT2D, we have previously shown that mutant gars expression decreases viability and larval motor function, and causes a concurrent build-up of mutant GlyRS at the larval neuromuscular presynapse. Here, we report additional phenotypes that closely mimic the axonal branching defects of Drosophila plexin transmembrane receptor mutants, implying interference of plexin signaling in gars mutants. Individual dosage reduction of two Drosophila Plexins, plexin A (plexA) and B (plexB) enhances and represses the viability and larval motor defects caused by mutant GlyRS, respectively. However, we find plexB levels, but not plexA levels, modify mutant GlyRS association with the presynaptic membrane. Furthermore, increasing availability of the plexB ligand, Semaphorin-2a (Sema2a), alleviates the pathology and the build-up of mutant GlyRS, suggesting competition for plexB binding may be occurring between these two ligands. This toxic gain-of-function and subversion of neurodevelopmental processes indicate that signaling pathways governing axonal guidance could be integral to neuropathology and may underlie the non-cell autonomous CMT2D mechanism. PMID- 29520220 TI - Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation. AB - Neuron-glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron-glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation. PMID- 29520221 TI - Topographic Organization of Hippocampal Inputs to the Anterior Olfactory Nucleus. AB - Top-down processes conveying contextual information play a major role in shaping odor representations within the olfactory system, yet the underlying mechanisms are poorly understood. The hippocampus (HPC) is a major source of olfactory top down modulation, providing direct excitatory inputs to the anterior olfactory nucleus (AON). However, HPC-AON projections remain uncharacterized. In an effort to understand how hippocampal inputs are distributed within the AON, we systematically outlined their organization using anterograde and retrograde tracing methods. We found that AON-projecting hippocampal pyramidal neurons are located mostly in the ventral two-thirds of the HPC and are organized topographically such that cells with a ventral to intermediate hippocampal point of origin terminate, respectively, at the medial to lateral AON. Our neuroanatomical findings suggest a potential role for the HPC in the early processing and contextualization of odors which merits further investigation. PMID- 29520223 TI - Anxiolytic Effect of Exogenous Ketone Supplementation Is Abolished by Adenosine A1 Receptor Inhibition in Wistar Albino Glaxo/Rijswijk Rats. AB - Anxiety disorders are one of the most common mental health problems worldwide, but the exact pathophysiology remains largely unknown. It has been demonstrated previously that administration of exogenous ketone supplement KSMCT (ketone salt/KS + medium chain triglyceride/MCT oil) by intragastric gavage for 7 days decreased the anxiety level in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. To investigate the potential role of the adenosinergic system in the pathomechanism of anxiety we tested whether the inhibition of adenosine A1 receptors (A1Rs) influence the anxiolytic effect of the exogenous ketone supplement. As A1Rs may mediate such an effect, in the present study we used a specific A1R antagonist, DPCPX (1,3-dipropyl-8 cyclopentylxanthine) to test whether it modulates the anxiolytic effect of sub chronically (7 days) applied KSMCT in the previously tested animal model by using elevated plus maze (EPM) test. We administered KSMCT (2.5 g/kg/day) alone by intragastric gavage and in combination with intraperitoneally (i.p.) injected of DPCPX in two doses (lower: 0.15 mg/kg, higher: 0.25 mg/kg). Control groups represented i.p saline and water gavage with or without i.p. DPCPX administration (2.5 g/kg/day). After treatments, the level of blood glucose and beta hydroxybutyrate (betaHB), as well as body weight were recorded. KSMCT alone significantly increased the time spent in the open arms and decreased the time spent in the closed arms, supporting our previous results. Injection of lower dose of DPCPX decreased, while higher dose of DPCPX abolished the effect of KSMCT administration on EPM. Blood betaHB levels were significantly increased after administration of KSMCT, while DPCPX did not change the KSMCT induced increase in blood betaHB levels. These results demonstrate that A1R inhibition modified (decreased) the anti-anxiety effect of KSMCT administration implying that the adenosinergic system, likely via A1Rs, may modulate the exogenous ketone supplement induced anxiolytic influence. PMID- 29520224 TI - Young Adults with Autism Spectrum Disorder Show Early Atypical Neural Activity during Emotional Face Processing. AB - Social cognition is impaired in autism spectrum disorder (ASD). The ability to perceive and interpret affect is integral to successful social functioning and has an extended developmental course. However, the neural mechanisms underlying emotional face processing in ASD are unclear. Using magnetoencephalography (MEG), the present study explored neural activation during implicit emotional face processing in young adults with and without ASD. Twenty-six young adults with ASD and 26 healthy controls were recruited. Participants indicated the location of a scrambled pattern (target) that was presented alongside a happy or angry face. Emotion-related activation sources for each emotion were estimated using the Empirical Bayes Beamformer (pcorr <= 0.001) in Statistical Parametric Mapping 12 (SPM12). Emotional faces elicited elevated fusiform, amygdala and anterior insula and reduced anterior cingulate cortex (ACC) activity in adults with ASD relative to controls. Within group comparisons revealed that angry vs. happy faces elicited distinct neural activity in typically developing adults; there was no distinction in young adults with ASD. Our data suggest difficulties in affect processing in ASD reflect atypical recruitment of traditional emotional processing areas. These early differences may contribute to difficulties in deriving social reward from faces, ascribing salience to faces, and an immature threat processing system, which collectively could result in deficits in emotional face processing. PMID- 29520225 TI - Broca's Area as a Pre-articulatory Phonetic Encoder: Gating the Motor Program. AB - The exact nature of the role of Broca's area in control of speech and whether it is exerted at the cognitive or at the motor level is still debated. Intraoperative evidence of a lack of motor responses to direct electrical stimulation (DES) of Broca's area and the observation that its stimulation induces a "speech arrest" without an apparent effect on the ongoing activity of phono-articulatory muscles, raises the argument. Essentially, attribution of direct involvement of Broca's area in motor control of speech, requires evidence of a functional connection of this area with the phono-articulatory muscles' motoneurons. With a quantitative approach we investigated, in 20 patients undergoing surgery for brain tumors, whether DES delivered on Broca's area affects the recruitment of the phono-articulatory muscles' motor units. The electromyography (EMG) of the muscles active during two speech tasks (object picture naming and counting) was recorded during and in absence of DES on Broca's area. Offline, the EMG of each muscle was analyzed in frequency (power spectrum, PS) and time domain (root mean square, RMS) and the two conditions compared. Results show that DES on Broca's area induces an intensity-dependent "speech arrest." The intensity of DES needed to induce "speech arrest" when applied on Broca's area was higher when compared to the intensity effective on the neighboring pre-motor/motor cortices. Notably, PS and RMS measured on the EMG recorded during "speech arrest" were superimposable to those recorded at baseline. Partial interruptions of speech were not observed. Speech arrest was an "all-or-none" effect: muscle activation started only by removing DES, as if DES prevented speech onset. The same effect was observed when stimulating directly the subcortical fibers running below Broca's area. Intraoperative data point to Broca's area as a functional gate authorizing the phonetic translation to be executed by the motor areas. Given the absence of a direct effect on motor units recruitment, a direct control of Broca's area on the phono-articulatory apparatus seems unlikely. Moreover, the strict correlation between DES-intensity and speech prevention, might attribute this effect to the inactivation of the subcortical fibers rather than to Broca's cortical neurons. PMID- 29520226 TI - Does the Relation between Rapid Automatized Naming and Reading Depend on Age or on Reading Level? A Behavioral and ERP Study. AB - Reading predictors evolve through age: phonological awareness is the best predictor of reading abilities at the beginning of reading acquisition while Rapid Automatized Naming (RAN) becomes the best reading predictor in more experienced readers (around 9-10 years old). Those developmental changes in the relationship between RAN and reading have so far been explained in term of participants' age. However, it should be noted that in the previous experiments age always co-vary with participants reading level. It is thus not clear whether RAN-reading relationship is developmental in nature or related to the reading system itself. This study investigates whether the behavioral changes in the relationship between RAN and reading and their electrophysiological correlates are related to the chronological age or to the reading level of the participants. Thirty two French-speaking children aged 7-10 years took part to the experiment: they were divided into groups contrasted on age but with similar reading levels and the other way round. Participants performed two reading tasks and four RAN tasks. EEG/ERP was recorded during discrete letter and picture RAN. Behavioral results revealed that alphanumeric RAN is more sensitive to age variations than reading level differences. The inverse profile was revealed for picture RAN, which discriminate poor and good readers among typically developed children within the same age-group. ERPs of both letter and picture RAN differed across age groups whereas only for the picture RAN ERPs differed across reading levels. Taken together, these results suggest that picture RAN is a particularly good indicator of reading level variance independently of age. PMID- 29520222 TI - Immediate Early Genes Anchor a Biological Pathway of Proteins Required for Memory Formation, Long-Term Depression and Risk for Schizophrenia. AB - While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR) hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD). Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3), early growth response 1 (EGR1) and NGFI-A Binding Protein 2 (NAB2); each of which contains the "Index single nucleotide polymorphism (SNP)" (most SNP) at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may result in insufficient electrophysiologic, immunologic, and neuroprotective, processes that these genes normally mediate. Continued adverse environmental experiences, over time, may thereby result in neuropathology that gives rise to the symptoms of schizophrenia. By combining multiple genes associated with schizophrenia susceptibility, in a functional cascade triggered by neuronal activity, the proposed biological pathway provides an explanation for both the polygenic and environmental influences that determine the complex etiology of this mental illness. PMID- 29520227 TI - Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity. AB - Background: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated (FTO) gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers. Methods: We have tested WM integrity in 21 male participants genotyped on the FTO risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: "risk tracts", "obesity-associated tracts", and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the "risk-tracts" (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire. Results: An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the "risk tracts". Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks. Conclusions: A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the FTO AA risk-allele, and possibly act as a predisposing factor to the development of obesity. PMID- 29520229 TI - Tacrolimus Reverses UVB Irradiation-Induced Epidermal Langerhans Cell Reduction by Inhibiting TNF-alpha Secretion in Keratinocytes via Regulation of NF kappaB/p65. AB - Background: Topical calcineurin inhibitors including tacrolimus and pimecrolimus are used in the treatment of many inflammatory skin diseases mainly via blocking T-cell proliferation. Our previous studies found that pimecrolimus 1% cream could reverse high-dose ultraviolet B (UVB) irradiation-induced epidermal Langerhans cell (LC) reduction via inhibition of LC migration. We conducted this study to investigate the effects of topical tacrolimus 0.03% ointment on high-dose UVB irradiated human epidermal LCs. Methods: Twenty fresh human foreskin tissues were randomly divided into four groups as follows: Control, Tacrolimus (0.03%), UVB (180 mJ/cm2), and UVB (180 mJ/cm2) + Tacrolimus (0.03%). Four time points were set as follows: 0, 18, 24, and 48 h. We collected culture medium and tissues at each time point. The percentage of CD1a+ cells in the medium was detected by means of flow cytometry. Each tissue was prepared for immunohistochemistry, real time quantitative PCR, and western blot. HaCaT cells were cultured and divided into four groups: Control, Tacrolimus (1 MUg/ml), UVB (30 mJ/cm2), and UVB (30 mJ/cm2) + Tacrolimus (1 MUg/ml). The cells were incubated for 24 h and prepared for real-time quantitative PCR and western blot. Results: Topical tacrolimus significantly reversed high-dose UVB irradiation-induced epidermal LC reduction and CD1a+ cell increment in culture medium. Tacrolimus significantly inhibited UVB irradiation-induced tumor necrosis factor-alpha (TNF-alpha) and nuclear factor kappa B (NF-kappaB)/p65 mRNA and protein expression in HaCaT cells. Tacrolimus also significantly inhibited high-dose UVB irradiation-induced TNF alpha expression in cultured tissues. Finally, TNF-alpha antagonist (recombinant human TNF-alpha receptor II: IgG Fc fusion protein) could significantly reverse UVB irradiation-induced epidermal LC reduction. Conclusion: Topical tacrolimus 0.03% could reverse UVB irradiation-induced epidermal LC reduction by inhibiting TNF-alpha secretion in keratinocytes via regulation of NF-kappaB/p65. PMID- 29520228 TI - Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer's Disease Brain: A Review. AB - This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram negative bacteria) could play a role in causing sporadic Alzheimer's disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with beta amyloid (Abeta) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Abeta levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Abeta1-42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram negative bacteria might be treatment or prevention targets for sporadic AD. PMID- 29520230 TI - Convenience versus Biological Significance: Are PMA-Differentiated THP-1 Cells a Reliable Substitute for Blood-Derived Macrophages When Studying in Vitro Polarization? AB - Human peripheral-blood monocytes are used as an established in vitro system for generating macrophages. For several reasons, monocytic cell lines such as THP-1 have been considered as a possible alternative. In view of their distinct developmental origins and phenotypic attributes, we set out to assess the extent to which human monocyte-derived macrophages (MDMs) and phorbol-12-myristate-13 acetate (PMA)-differentiated THP-1 cells were overlapping across a variety of responses to activating stimuli. Resting (M0) macrophages were polarized toward M1 or M2 phenotypes by 48-h incubation with LPS (1 MUg/ml) and IFN-gamma (10 ng/ml) or with IL-4 (20 ng/ml) and IL-13 (5 ng/ml), respectively. At the end of stimulation, MDMs displayed more pronounced changes in marker gene expression than THP-1. Upon assaying an array of 41 cytokines, chemokines and growth factors in conditioned media (CM) using the Luminex technology, secretion of 29 out of the 41 proteins was affected by polarized activation. While in 12 of them THP-1 and MDM showed comparable trends, for the remaining 17 proteins their responses to activating stimuli did markedly differ. Quantitative comparison for selected analytes confirmed this pattern. In terms of phenotypic activation markers, measured by flow cytometry, M1 response was similar but the established MDM M2 marker CD163 was undetectable in THP-1 cells. In a beads-based assay, MDM activation did not induce significant changes, whereas M2 activation of THP-1 decreased phagocytic activity compared to M0 and M1. In further biological activity tests, both MDM and THP-1 CM failed to affect proliferation of mouse myogenic progenitors, whereas they both reduced adipogenic differentiation of mouse fibro-adipogenic progenitor cells (M2 to a lesser extent than M1 and M0). Finally, migration of human umbilical vein endothelial cells was enhanced by CM irrespective of cell type and activation state except for M0 CM from MDMs. In summary, PMA-differentiated THP-1 macrophages did not entirely reproduce the response spectrum of primary MDMs to activating stimuli. We suggest that THP-1 be regarded as a simplified model of human macrophages when investigating relatively straightforward biological processes, such as polarization and its functional implications, but not as an alternative source in more comprehensive immunopharmacology and drug screening programs. PMID- 29520231 TI - Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells. AB - Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic cancer cells, which was shown previously to be synergistic. A total of 4069 drug-responsive proteins were identified and quantified in a time-series proteome analysis. This rich dataset provides broad views and accurate quantification of signaling pathways. Pathways relating to DNA damage response regulations, DNA repair, anti-apoptosis, pro-migration/invasion were implicated as underlying mechanisms for gemcitabine resistance and for the beneficial effects of the drug combination. Promising drug targets were identified for future investigation. This study also provides a database for systems mathematical modeling to relate drug effects and interactions in various signaling pathways in pancreatic cancer cells. PMID- 29520232 TI - Triphenylphosphonium Moiety Modulates Proteolytic Stability and Potentiates Neuroprotective Activity of Antioxidant Tetrapeptides in Vitro. AB - Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant tetrapeptides based on the model opioid YRFK motif was studied. Two tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP 6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties. PMID- 29520233 TI - Cyclophilin J PPIase Inhibitors Derived from 2,3-Quinoxaline-6 Amine Exhibit Antitumor Activity. AB - Cyclophilin J (CyPJ), also called peptidylprolyl isomerase like 3, has been identified as a novel member of the cyclophilin family. Our previous research has resolved the three-dimensional structure of CyPJ and demonstrated the peptidylprolyl cis-trans isomerase (PPIase) activity of CyPJ, which can be inhibited by the common immunosuppressive drug cyclosporine A (CsA). Importantly, CyPJ is upregulated in hepatocellular carcinoma (HCC) and promotes tumor growth; CyPJ inhibition by CsA- or siRNA-based knockdown results in a remarkable suppression of HCC. These findings suggest that CyPJ may be a potential therapeutic target for HCC, and discovery of relevant inhibitors may facilitate development of a novel CyPJ-based targeting therapy. However, apart from the common inhibitor CsA, CyPJ has yet to be investigated as a target for cancer therapy. Here, we report structure-based identification of novel small molecule non-peptidic CyPJ inhibitors and their potential as antitumor lead compounds. Based on computer-aided virtual screening, in silico, and subsequently surface plasmon resonance analysis, 19 potential inhibitors of CyPJ were identified and selected for further evaluation of PPIase CyPJ inhibition in vitro. Thirteen out of 19 compounds exhibited notable inhibition against PPIase activity. Among them, the compound ZX-J-19, with a quinoxaline nucleus, showed potential for tumor inhibition; thus, we selected it for further structure-activity optimization. A total of 22 chemical derivatives with 2,3-substituted quinoxaline-6-amine modifications were designed and successfully synthesized. At least 2 out of the 22 derivatives, such as ZX-J-19j and ZX-J-19l, demonstrated remarkable inhibition of tumor cell growth, comparable to CsA but much stronger than 5-fluorouracil. These results indicate that these two small molecules represent novel potential lead compounds for CyPJ-based antitumor drug development. PMID- 29520234 TI - Characterization of the in Vitro Metabolic Profile of Evodiamine in Human Liver Microsomes and Hepatocytes by UHPLC-Q Exactive Mass Spectrometer. AB - Evodiamine is an indoloquinazoline alkaloid isolated from the fruit of Evodia rutaecarpa, which has a wide range of pharmacological effects like anti-tumor and anti-inflammatory effects. This study was intended to investigate the metabolic characteristics of evodiamine in human liver microsomes and hepatocytes by ultra high performance liquid chromatography coupled with a Q Exactive mass spectrometer. A total of 12 phase I metabolites were detected in human liver microsomes; whereas in human hepatocytes 19 metabolites, including seven phase II metabolites were detected. The structures of the metabolites were characterized based on their accurate masses, fragment ions, and chromatographic retention times. Four metabolites (M1, M2, M5, and M7) were further unambiguously confirmed by matching their retention times, accurate masses, and fragment ions with those of their reference standards. Among these metabolites, 12 metabolites are first identified (M2, M5-M8, M10-M13, and M17-M19). The current study revealed that oxygenation, N-demethylation, dehydrogenation, glucuronidation, and GSH conjugation were the major metabolic pathways for evodiamine. This study elucidated the detailed metabolite profiles of evodiamine, which is helpful in predicting in vivo metabolism of evodiamine in human and in understanding the elimination mechanism of evodiamine and in turn, the effectiveness and toxicity. PMID- 29520235 TI - Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver. AB - Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition. MALDI mass spectra of thin-sections of freeze-clamped rat liver perfused with metformin showed a peak at 130.16 m/z which was unambiguously assigned to metformin. The mass spectrometric detection limit was at a tissue concentration of about 250 nM, and uptake of metformin from the perfusion medium to the liver occurred with a Km of 0.44 mM. Metformin was evenly distributed in the liver irrespective of its concentration in the perfusion medium and the duration of a perfusion. At a parenchymal concentration of 30 MUM, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that matrix-assisted laser desorption/ionization mass spectrometry imaging can be applied to estimate the tissue concentration and distribution of metformin in a therapeutically relevant micromolar concentration range. Our findings challenge the view that metformin causes an inhibition of glucose release from the liver by an acute inhibition of mitochondrial glycerol 3 phosphate dehydrogenase (EC 1.1.5.3). PMID- 29520236 TI - Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome. AB - Damage to the endothelial glycocalyx is a critical factor in increased pulmonary vascular permeability, which is the basic pathological feature of acute respiratory distress syndrome (ARDS). Neferine (Nef), a bisbenzylisoquinoline alkaloid isolated from green seed embryos of Nelumbo nucifera Gaertn, has extensive pharmacological activity. In this study, we showed that Nef reduced lung-capillary permeability, down-regulated the production of cytokines (IL 1beta, IL-6, TNF-alpha, and IL-10) and inhibited the activation of the NF-kappaB signaling pathway in mice with lipopolysaccharide (LPS)-induced ARDS. Further analysis indicated that Nef provided protection against endothelial glycocalyx degradation in LPS-induced ARDS mice (in vivo) and in LPS-stimulated human umbilical vein endothelial cells (in vitro). The glycocalyx-protective effect of Nef may be initiated by suppressing the production of mitochondrial ROS (mtROS) and decreasing oxidative damage. Nef was also found to promote glycocalyx restoration by accelerating the removal of mtROS in endothelial cells in LPS induced ARDS. These results suggested the potential of Nef as a therapeutic agent for ARDS associated with Gram-negative bacterial infections and elucidated the mechanisms underlying the protection and restoration of the endothelial glycocalyx. PMID- 29520237 TI - Expression of Proinflammatory Cytokines Is Upregulated in the Hypothalamic Paraventricular Nucleus of Dahl Salt-Sensitive Hypertensive Rats. AB - Accumulating evidence indicates that inflammation is implicated in hypertension. However, the role of brain proinflammatory cytokines (PICs) in salt sensitive hypertension remains to be determined. Thus, the objective of this study was to test the hypothesis that high salt (HS) diet increases PICs expression in the paraventricular nucleus (PVN) and leads to PVN neuronal activation. Eight-week old male Dahl salt sensitive (Dahl S) rats, and age and sex matched normal Sprague Dawley (SD) rats were divided into two groups and fed with either a HS (4% NaCl) or normal salt (NS, 0.4% NaCl) diet for 5 consecutive weeks. HS diet induced hypertension and significantly increased cerebrospinal fluid (CSF) sodium concentration ([Na+]) in Dahl S rats, but not in normal SD rats. In addition, HS diet intake triggered increases in mRNA levels and immunoreactivities of PVN PICs including TNF-alpha, IL-6, and IL-1beta, as well as Fra1, a chronic marker of neuronal activation, in Dahl S rats, but not in SD rats. Next, we investigated whether this increase in the expression of PVN PICs and Fra1 was induced by increased CSF [Na+]. Adult male SD rats were intracerebroventricular (ICV) infused with 8 MUl of either hypertonic salt (4 MUmol NaCl), mannitol (8 MUmol, as osmolarity control), or isotonic salt (0.9% NaCl as vehicle control). Three hours following the ICV infusion, rats were euthanized and their PVN PICs expression was measured. The results showed that central administration of hypertonic saline in SD rats significantly increased the expression of PICs including TNF-alpha, IL-6, and IL-1beta, as well as neuronal activation marker Fra1, compared to isotonic NaCl controls and osmolarity controls. Finally, we tested whether the increase in PICs expression occurred in neurons. Incubation of hypothalamic neurons with 10 mM NaCl in a culture medium for 6 h elicited significant increases in TNF-alpha, IL-6, and Fra1 mRNA levels. These observations, coupled with the important role of PICs in modulating neuronal activity and stimulating vasopressin release, suggest that HS intake induces an inflammatory state in the PVN, which, may in turn, augments sympathetic nerve activity and vasopressin secretion, contributing to the development of salt sensitive hypertension. PMID- 29520238 TI - Erythrocytes and Vascular Function: Oxygen and Nitric Oxide. AB - Erythrocytes regulate vascular function through the modulation of oxygen delivery and the scavenging and generation of nitric oxide (NO). First, hemoglobin inside the red blood cell binds oxygen in the lungs and delivers it to tissues throughout the body in an allosterically regulated process, modulated by oxygen, carbon dioxide and proton concentrations. The vasculature responds to low oxygen tensions through vasodilation, further recruiting blood flow and oxygen carrying erythrocytes. Research has shown multiple mechanisms are at play in this classical hypoxic vasodilatory response, with a potential role of red cell derived vasodilatory molecules, such as nitrite derived nitric oxide and red blood cell ATP, considered in the last 20 years. According to these hypotheses, red blood cells release vasodilatory molecules under low oxygen pressures. Candidate molecules released by erythrocytes and responsible for hypoxic vasodilation are nitric oxide, adenosine triphosphate and S-nitrosothiols. Our research group has characterized the biochemistry and physiological effects of the electron and proton transfer reactions from hemoglobin and other ferrous heme globins with nitrite to form NO. In addition to NO generation from nitrite during deoxygenation, hemoglobin has a high affinity for NO. Scavenging of NO by hemoglobin can cause vasoconstriction, which is greatly enhanced by cell free hemoglobin outside of the red cell. Therefore, compartmentalization of hemoglobin inside red blood cells and localization of red blood cells in the blood stream are important for healthy vascular function. Conditions where erythrocyte lysis leads to cell free hemoglobin or where erythrocytes adhere to the endothelium can result in hypertension and vaso constriction. These studies support a model where hemoglobin serves as an oxido-reductase, inhibiting NO and promoting higher vessel tone when oxygenated and reducing nitrite to form NO and vasodilate when deoxygenated. PMID- 29520239 TI - Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia. AB - Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research. PMID- 29520240 TI - A Computational Assessment of Target Engagement in the Treatment of Auditory Hallucinations with Transcranial Direct Current Stimulation. AB - We use auditory verbal hallucinations (AVH) to illustrate the challenges in defining and assessing target engagement in the context of transcranial direct current stimulation (tDCS) for psychiatric disorders. We defined the target network as the cluster of regions of interest (ROIs) that are consistently implicated in AVH based on the conjunction of multimodal meta-analytic neuroimaging data. These were prescribed in the New York Head (a population derived model) and head models of four single individuals. We appraised two potential measures of target engagement, tDCS-induced peak electric field strength and tDCS-modulated volume defined as the percentage of the volume of the AVH network exposed to electric field magnitude stronger than the postulated threshold for neuronal excitability. We examined a left unilateral (LUL) montage targeting the prefrontal cortex (PFC) and temporoparietal junction (TPJ), a bilateral (BL) prefrontal montage, and a 2 * 1 montage targeting the left PFC and the TPJ bilaterally. Using computational modeling, we estimated the peak electric field strength and modulated volume induced by each montage for current amplitudes ranging 1-4 mA. We found that the LUL montage was inferior to both other montages in terms of peak electric field strength in right-sided AVH-ROIs. The BL montage was inferior to both other montages in terms of modulated volume of the left-sided AVH-ROIs. As the modulated volume is non-linear, its variability between montages reduced for current amplitudes above 3 mA. These findings illustrate how computational target engagement for tDCS can be tailored to specific networks and provide a principled approach for future study design. PMID- 29520241 TI - Establishing a Longitudinal Comparable Scale of Chinese Children's Cognitive Development through Calibrated Projection Linking. AB - In the past decades, the longitudinal approach has been remarkably and increasingly used in the investigations of children's cognitive development. Recently, many researchers have started to realize the importance and necessity of examining measurement invariance for any further longitudinal analysis. However, there are few empirical studies demonstrating how to conduct further analysis when the assumption of measurement invariance of an instrument is violated. The primary purpose of this study is to explore how a newly-developed calibrated projection method can be applied to reduce the impact of lack of parameter invariance in a longitudinal study of preschool children's cognitive development. The sample consisted of 882 children from China who participated in two waves of the cognitive tests when they were 4 and 5 years old. Before this study was conducted, the IRT method was used to examine the measurement invariance of the instrument. The results showed that five items presented difficulty parameter drift and three items presented discrimination/slope parameter drift. In the study, the invariant items were treated as "common items" and calibrated projection linking was used to establish a comparable scale across two time points. Then the linking method was evaluated by three properties: grade to-grade growth, grade-to-grade variability, and the separation of distributions. The results showed that the grade-to-grade growth across two waves was larger and exhibited a larger effect size; the grade-to-grade variability showed less scale shrinkage, which indicated a smaller measurement error; the separation of distributions showed a larger growth as well. PMID- 29520242 TI - Evaluation of Analysis Approaches for Latent Class Analysis with Auxiliary Linear Growth Model. AB - This study investigated the performance of three selected approaches to estimating a two-phase mixture model, where the first phase was a two-class latent class analysis model and the second phase was a linear growth model with four time points. The three evaluated methods were (a) one-step approach, (b) three-step approach, and (c) case-weight approach. As a result, some important results were demonstrated. First, the case-weight and three-step approaches demonstrated higher convergence rate than the one-step approach. Second, it was revealed that case-weight and three-step approaches generally did better in correct model selection than the one-step approach. Third, it was revealed that parameters were similarly recovered well by all three approaches for the larger class. However, parameter recovery for the smaller class differed between the three approaches. For example, the case-weight approach produced constantly lower empirical standard errors. However, the estimated standard errors were substantially underestimated by the case-weight and three-step approaches when class separation was low. Also, bias was substantially higher for the case-weight approach than the other two approaches. PMID- 29520243 TI - Structured Semantic Knowledge Can Emerge Automatically from Predicting Word Sequences in Child-Directed Speech. AB - Previous research has suggested that distributional learning mechanisms may contribute to the acquisition of semantic knowledge. However, distributional learning mechanisms, statistical learning, and contemporary "deep learning" approaches have been criticized for being incapable of learning the kind of abstract and structured knowledge that many think is required for acquisition of semantic knowledge. In this paper, we show that recurrent neural networks, trained on noisy naturalistic speech to children, do in fact learn what appears to be abstract and structured knowledge. We trained two types of recurrent neural networks (Simple Recurrent Network, and Long Short-Term Memory) to predict word sequences in a 5-million-word corpus of speech directed to children ages 0-3 years old, and assessed what semantic knowledge they acquired. We found that learned internal representations are encoding various abstract grammatical and semantic features that are useful for predicting word sequences. Assessing the organization of semantic knowledge in terms of the similarity structure, we found evidence of emergent categorical and hierarchical structure in both models. We found that the Long Short-term Memory (LSTM) and SRN are both learning very similar kinds of representations, but the LSTM achieved higher levels of performance on a quantitative evaluation. We also trained a non-recurrent neural network, Skip-gram, on the same input to compare our results to the state-of-the art in machine learning. We found that Skip-gram achieves relatively similar performance to the LSTM, but is representing words more in terms of thematic compared to taxonomic relations, and we provide reasons why this might be the case. Our findings show that a learning system that derives abstract, distributed representations for the purpose of predicting sequential dependencies in naturalistic language may provide insight into emergence of many properties of the developing semantic system. PMID- 29520244 TI - Does Allocation of Attention Influence Relative Velocity and Strength of Illusory Line Motion? AB - In illusory line motion, presentation of a cue is followed by presentation of a nearby stationary line, and the line is perceived to "unfold," "expand," or "extend" away from the cue. Effects of the allocation of attention regarding where the cue or the line would be presented were measured in three experiments, and ratings of relative velocity and relative strength of illusory motion were collected. Findings included (a) relative velocity and relative strength decreased with increases in SOA from 50 to 450 ms, (b) relative velocity and relative strength were not influenced by whether illusory motion moved from one end of the line to the other or from both ends toward the middle of the line, (c) increased uncertainty regarding where the line would appear did not influence relative velocity or relative strength, and (d) valid pre-cues regarding the location of a cue resulted in faster relative velocity than did invalid pre-cues, but pre-cue validity did not influence relative strength. Implications of these findings for the relationship of such illusory motion and attention (e.g., divided attention, shifts in attended location) are considered. PMID- 29520245 TI - Response: Commentary: Facial Width-to-Height Ratio (fWHR) Is Not Associated with Adolescent Testosterone Levels. PMID- 29520246 TI - The Benefit of Attention-to-Memory Depends on the Interplay of Memory Capacity and Memory Load. AB - Humans can be cued to attend to an item in memory, which facilitates and enhances the perceptual precision in recalling this item. Here, we demonstrate that this facilitating effect of attention-to-memory hinges on the overall degree of memory load. The benefit an individual draws from attention-to-memory depends on her overall working memory performance, measured as sensitivity (d') in a retroactive cue (retro-cue) pitch discrimination task. While listeners maintained 2, 4, or 6 auditory syllables in memory, we provided valid or neutral retro-cues to direct listeners' attention to one, to-be-probed syllable in memory. Participants' overall memory performance (i.e., perceptual sensitivity d') was relatively unaffected by the presence of valid retro-cues across memory loads. However, a more fine-grained analysis using psychophysical modeling shows that valid retro cues elicited faster pitch-change judgments and improved perceptual precision. Importantly, as memory load increased, listeners' overall working memory performance correlated with inter-individual differences in the degree to which precision improved (r = 0.39, p = 0.029). Under high load, individuals with low working memory profited least from attention-to-memory. Our results demonstrate that retrospective attention enhances perceptual precision of attended items in memory but listeners' optimal use of informative cues depends on their overall memory abilities. PMID- 29520247 TI - Psychopathy and Pride: Testing Lykken's Hypothesis Regarding the Implications of Fearlessness for Prosocial and Antisocial Behavior. AB - Despite widespread assumptions that psychopathy is associated with serious and repeated law-breaking, individuals with psychopathic personality traits do not invariably become chronic criminal offenders. As a partial explanation for this finding, Lykken (1995) ventured that a fearless temperament underlies both psychopathic traits and heroic behavior, and that heroic individuals' early exposure to effective socializing forces such as warm parenting or healthy self esteem often fosters a characteristic adaption that tends to beget "successful" behaviors, thereby differentiating heroes from convicts. In this study, we investigate relations between psychopathy, principally its fearless dominance dimension, pride, and prosocial and antisocial behavior in a community sample (N = 339). Fearless dominance and self-centered impulsivity components of psychopathy yielded differential relations with authentic and hubristic pride (Tracy and Robins, 2004), such that fearless dominance was significantly positively correlated with both facets of pride while self-centered Impulsivity was significantly negatively correlated with authentic pride and significantly positively correlated with hubristic pride. Further, authentic pride moderated (potentiated) the relation between fearless dominance and transformational leadership, one of the two outcome measures for prosocial behavior employed in our investigation. Authentic pride did not moderate the relations between fearless dominance and either our other measure of prosocial behavior (heroism) or antisocial behavior, nor did positive parenting moderate the relations between psychopathy components and social behavior. Unexpectedly, hubristic pride significantly moderated the relation between impulsive-antisocial features and antisocial behavior in a protective manner. PMID- 29520248 TI - Development and Initial Validation of a Rock Climbing Craving Questionnaire (RCCQ). AB - Conceptual similarities have been identified between experiences of extreme sports athletes and those with drug and behavioral addictions. Evidence suggests rock climbers experience craving and other withdrawal-like states when abstinent from their sport. However, no studies have attempted to quantitatively measure the craving experienced by participants of any extreme sports. Such a measure could allow a greater understanding of the craving experienced by extreme sports athletes and a comparison of these across sports (e.g., surfing) and activities (e.g., drug-use). Therefore, using validated craving measures as a template, the aim of the two studies outlined here was to design and preliminarily validate a subjective multidimensional inventory that could be used to measure craving in the sports of rock-climbing and mountaineering ("RCCQ"). The aim of the first study was to investigate the factor structure of a preliminary measure of craving. Climbers (n = 407) completed the RCCQ. A 3-factor model explained 53.65% of the total variance in item scores. All three factors comprised five items each, which were conceptually labeled as "urge to climb" "negative reinforcement" and "positive reinforcement." The aim of the second study was to validate the 15 item 3-factor RCCQ resulting from Study 1 using confirmatory factor analysis (CFA). Climbers (n = 254) completed the questionnaire under a climbing-related cue condition or a cue-neutral condition. CFA revealed a good model fit and that all individual parameter estimates were significant and standard errors were within reasonable limits once item 13 was removed from Factor 1. Study 1 supports the multi-dimensional nature of rock climbing craving and shows parallels with substance-related craving in reflecting intention and positive (desire) and negative (withdrawal) reinforcement. Study 2 confirms this factor structure and gives initial validation to the measure with evidence that these factors are sensitive to cue exposure. Given the preliminary nature of the data, any practical implications are tentative. However, if as shown here, craving for climbing (and potentially other extreme sports) is similar to that experienced by drug-users and addicts, there is the potential that climbing and other extreme sports could be used as a replacement therapy for drug users. PMID- 29520249 TI - Integration of World Knowledge and Temporary Information about Changes in an Object's Environmental Location during Different Stages of Sentence Comprehension. AB - Recent findings have shown that information about changes in an object's environmental location in the context of discourse is stored in working memory during sentence comprehension. However, in these studies, changes in the object's location were always consistent with world knowledge (e.g., in "The writer picked up the pen from the floor and moved it to the desk," the floor and the desk are both common locations for a pen). How do people accomplish comprehension when the object-location information in working memory is inconsistent with world knowledge (e.g., a pen being moved from the floor to the bathtub)? In two visual world experiments, with a "look-and-listen" task, we used eye-tracking data to investigate comprehension of sentences that described location changes under different conditions of appropriateness (i.e., the object and its location were typically vs. unusually coexistent, based on world knowledge) and antecedent context (i.e., contextual information that did vs. did not temporarily normalize unusual coexistence between object and location). Results showed that listeners' retrieval of the critical location was affected by both world knowledge and working memory, and the effect of world knowledge was reduced when the antecedent context normalized unusual coexistence of object and location. More importantly, activation of world knowledge and working memory seemed to change during the comprehension process. These results are important because they demonstrate that interference between world knowledge and information in working memory, appears to be activated dynamically during sentence comprehension. PMID- 29520250 TI - Characteristics of Epileptiform Discharge Duration and Interdischarge Interval in Genetic Generalized Epilepsies. AB - We sought to investigate (1) the characteristics of epileptiform discharge (ED) duration and interdischarge interval (IDI) and (2) the influence of vigilance state on the ED duration and IDI in genetic generalized epilepsy (GGE). In a cohort of patients diagnosed with GGE, 24-h ambulatory EEG recordings were performed prospectively. We then tabulated durations, IDI, and vigilance state in relation to all EDs captured on EEGs. We used K-means cluster analysis and finite mixture modeling to quantify and characterize the groups of ED duration and IDI. To investigate the influence of sleep, we calculated the mean, median, and SEM in each population from all subjects for sleep state and wakefulness separately, followed by the Kruskal-Wallis test to compare the groups. We analyzed 4,679 EDs and corresponding IDI from 23 abnormal 24-h ambulatory EEGs. Our analysis defined two populations of ED durations and IDI: short and long. In all populations, both ED durations and IDI were significantly longer in wakefulness. Our results highlight different characteristics of ED populations in GGE and the influence by the sleep-wake cycle. PMID- 29520252 TI - Management of Refractory Orofacial Dyskinesia Caused by Anti-N-methyl-d-aspartate Receptor Encephalitis Using Botulinum Toxin. AB - The use of botulinum neurotoxin serotype A (BoNT-A) injections for the treatment of orofacial dyskinesia secondary to anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is rarely reported. Here, we report a case of an urgent, successful management of severe orofacial dyskinesia in an 8-year-old girl with anti-NMDAR encephalitis using BoNT-A injection. The patient presented with de novo unilateral paroxysmal movement disorder progressing to generalized dystonia and repetitive orofacial dyskinesia. Diagnosis was confirmed by the presence of NMDAR antibodies in serum and cerebrospinal fluid. The orofacial dyskinesia worsened despite the aggressive use of first-line immunotherapy and second-line immunotherapy (rituximab), and resulted in a potentially fatal self-inflicted oral injury. We urgently attempted symptomatic management using BoNT-A injections in the masseter, and induced muscle paralysis using vecuronium. The patient's severe orofacial dyskinesia was controlled. We observed the effects of the BoNT-A injections and a tapering off of the effects of vecuronium 10 days after the treatment. The movement disorder had improved significantly 4 weeks after the first administration of rituximab. The injection of BoNT-A into the masseter may be an effective treatment for medically refractory orofacial dyskinesia in pediatric patients with anti-NMDAR encephalitis. We propose that the use of BoNT A injections should be considered early to avoid self-inflicted oral injury due to severe refractory orofacial dyskinesia in patients with anti-NMDAR encephalitis. PMID- 29520251 TI - Obstructive Sleep Apnea Syndrome, Objectively Measured Physical Activity and Exercise Training Interventions: A Systematic Review and Meta-Analysis. AB - A systematic review of English and French articles using Pubmed/Medline and Embase included studies assessing objective physical activity levels of obstructive sleep apnea (OSA) patients and exploring the effects of exercise training on OSA severity, body mass index (BMI), sleepiness, and cardiorespiratory fitness [peak oxygen consumption (VO2peak)]. Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of evidence. For objective physical activity levels, eight studies were included. The mean number of steps per day across studies was 5,388 (95% CI: 3,831-6,945; p < 0.001), which was by far lower than the recommended threshold of 10,000 steps per day. For exercise training, six randomized trials were included. There was a significant decrease in apnea-hypopnea-index following exercise training (mean decrease of 8.9 events/h; 95% CI: -13.4 to -4.3; p < 0.01), which was accompanied by a reduction in subjective sleepiness, an increase in VO2peak and no change in BMI. OSA patients present low levels of physical activity and exercise training is associated with improved outcomes. Future interventions (including exercise training) focusing on increasing physical activity levels may have important clinical impacts on both OSA severity and the burden of associated co morbidities. Objective measurement of physical activity in routine OSA management and well-designed clinical trials are recommended. Registration # CRD42017057319 (Prospero). PMID- 29520253 TI - TCF21/POD-1, a Transcritional Regulator of SF-1/NR5A1, as a Potential Prognosis Marker in Adult and Pediatric Adrenocortical Tumors. AB - With recent progress in understanding the pathogenesis of adrenocortical tumors (ACTs), identification of molecular markers to predict their prognosis has become possible. Transcription factor 21 (TCF21)/podocyte-expressed 1 (POD1) is a transcriptional regulatory protein expressed in mesenchymal cells at sites of epithelial-mesenchymal transition during the development of different systems. Adult carcinomas express less TCF21 than adenomas, in addition, the KEGG pathway analysis has shown that BUB1B, among others genes, is negatively correlated with TCF21 expression. The difference between BUB1B and PTEN-induced putative kinase 1 (PINK1) expression has been described previously to be associated with survival in adult but not in pediatric carcinomas. Here, we analyzed the gene expression of TCF21, BUB1B, PINK1, and NR5A1 in adult and pediatric ACTs. We found a negative correlation between the relative expression levels of TCF21 and BUB1B in adult ACTs, but the relative expression levels of TCF21, BUB1B, PINK1, and NR5A1 were similar in childhood ACTs. In addition, we propose using the subtracted expression levels of the TCF21/POD-1 genes as a predictor of overall survival (OS) in adult carcinomas and TCF21-NR5A1 as a predictor of malignancy for pediatric tumors in patients aged <5 years. These results require further validation in different cohorts of both adult and pediatric samples. Finally, we observed that the OS for patients aged <5 years was markedly favorable compared with that for patients >5 years as well as adult patients with carcinoma. In summary, we propose TCF21/POD-1 as a new prognostic marker in adult and pediatric ACTs. PMID- 29520254 TI - Acclimation of Culturable Bacterial Communities under the Stresses of Different Organic Compounds. AB - The phylogenetic diversity of bacterial communities in response to environmental disturbances such as organic pollution has been well studied, but little is known about the way in which organic contaminants influence the acclimation of functional bacteria. In the present study, tolerance assays for bacterial communities from the sediment in the Pearl River Estuary were conducted with the isolation of functional bacteria using pyrene and different estrogens as environmental stressors. Molecular ecological networks and phylogenetic trees were constructed using both 16S rRNA gene sequences of cultured bacterial strains and 16S rRNA gene-based pyrosequencing data to illustrate the successions of bacterial communities and their acclimations to the different organic compounds. A total of 111 bacterial strains exhibiting degradation and endurance capabilities in response to the pyrene estrogen-induced stress were successfully isolated and were mainly affiliated with three orders, Pseudomonadales, Vibrionales, and Rhodobacterales. Molecular ecological networks and phylogenetic trees showed various adaptive abilities of bacteria to the different organic compounds. For instance, some bacterial OTUs could be found only in particular organic compound-treated groups while some other OTUs could tolerate stresses from different organic compounds. Furthermore, the results indicated that some new phylotypes were emerged under stresses of different organic pollutions and these new phylotypes could adapt to the contaminated environments and contribute significantly to the microbial community shifts. Overall, this study demonstrated a crucial role of the community succession and the acclimation of functional bacteria in the adaptive responses to various environmental disturbances. PMID- 29520255 TI - Benthic Bacterial Community Composition in the Oligohaline-Marine Transition of Surface Sediments in the Baltic Sea Based on rRNA Analysis. AB - Salinity has a strong impact on bacterial community composition such that freshwater bacterial communities are very different from those in seawater. By contrast, little is known about the composition and diversity of the bacterial community in the sediments (bacteriobenthos) at the freshwater-seawater transition (mesohaline conditions). In this study, partial 16S-rRNA sequences were used to investigate the bacterial community at five stations, representing almost freshwater (oligohaline) to marine conditions, in the Baltic Sea. Samples were obtained from the silty, top-layer (0-2.5 cm) sediments with mostly oxygenated conditions. The long water residence time characteristic of the Baltic Sea, was predicted to enable the development of autochthonous bacteriobenthos at mesohaline conditions. Our results showed that, similar to the water column, salinity is a major factor in structuring the bacteriobenthos and that there is no loss of bacterial richness at intermediate salinities. The bacterial communities of marine, mesohaline, and oligohaline sediments differed in terms of the relative rRNA abundances of the major bacterial phyla/classes. At mesohaline conditions typical marine and oligohaline operational taxonomic units (OTUs) were abundant. Putative unique OTUs in mesohaline sediments were present only at low abundances, suggesting that the mesohaline environment consists mainly of marine and oligohaline bacteria with a broad salinity tolerance. Our study provides a first overview of the diversity patterns and composition of bacteria in the sediments along the Baltic Sea salinity gradient as well as new insights into the bacteriobenthos at mesohaline conditions. PMID- 29520256 TI - Contrasting the Genetic Patterns of Microbial Communities in Soda Lakes with and without Cyanobacterial Bloom. AB - Soda lakes have high levels of sodium carbonates and are characterized by salinity and elevated pH. These ecosystems are found across Africa, Europe, Asia, Australia, North, Central, and South America. Particularly in Brazil, the Pantanal region has a series of hundreds of shallow soda lakes (ca. 600) potentially colonized by a diverse haloalkaliphilic microbial community. Biological information of these systems is still elusive, in particular data on the description of the main taxa involved in the biogeochemical cycling of life important elements. Here, we used metagenomic sequencing to contrast the composition and functional patterns of the microbial communities of two distinct soda lakes from the sub-region Nhecolandia, state of Mato Grosso do Sul, Brazil. These two lakes differ by permanent cyanobacterial blooms (Salina Verde, green water lake) and by no record of cyanobacterial blooms (Salina Preta, black-water lake). The dominant bacterial species in the Salina Verde bloom was Anabaenopsis elenkinii. This cyanobacterium altered local abiotic parameters such as pH, turbidity, and dissolved oxygen and consequently the overall structure of the microbial community. In Salina Preta, the microbial community had a more structured taxonomic profile. Therefore, the distribution of metabolic functions in Salina Preta community encompassed a large number of taxa, whereas, in Salina Verde, the functional potential was restrained across a specific set of taxa. Distinct signatures in the abundance of genes associated with the cycling of carbon, nitrogen, and sulfur were found. Interestingly, genes linked to arsenic resistance metabolism were present at higher abundance in Salina Verde and they were associated with the cyanobacterial bloom. Collectively, this study advances fundamental knowledge on the composition and genetic potential of microbial communities inhabiting tropical soda lakes. PMID- 29520257 TI - Vaccine Development against Zoonotic Hepatitis E Virus: Open Questions and Remaining Challenges. AB - Hepatitis E virus (HEV) is a fecal-orally transmitted foodborne viral pathogen that causes acute hepatitis in humans and is responsible for hepatitis E outbreaks worldwide. Since the discovery of HEV as a zoonotic agent, this virus has been isolated from a variety of hosts with an ever-expanding host range. Recently, a subunit HEV vaccine developed for the prevention of human disease was approved in China, but is not yet available to the rest of the world. Meanwhile, notable progress and knowledge has been made and revealed in recent years to better understand HEV biology and infection, including discoveries of quasi enveloped HEV virions and of a new function of the HEV-ORF3 product. However, the impact of these new findings on the development of a protective vaccine against zoonotic HEV infection requires further discussion. In this review, hallmark characteristics of HEV zoonosis, the history of HEV vaccine development, and recent discoveries in HEV virology are described. Moreover, special attention is focused on quasi-enveloped HEV virions and the potential role of the HEV-ORF3 product as antibody-neutralization target on the surface of quasi-enveloped HEV virions to provide new insights for the future development of improved vaccines against zoonotic HEV infection. PMID- 29520258 TI - Protection of Pepper Plants from Drought by Microbacterium sp. 3J1 by Modulation of the Plant's Glutamine and alpha-ketoglutarate Content: A Comparative Metabolomics Approach. AB - Drought tolerance of plants such as tomato or pepper can be improved by their inoculation with rhizobacteria such as Microbacterium sp. 3J1. This interaction depends on the production of trehalose by the microorganisms that in turn modulate the phyto-hormone profile of the plant. In this work we describe the characterization of metabolic changes during the interaction of pepper plants with Microbacterium sp. 3J1 and of the microorganism alone over a period of drought. Our main findings include the observation that the plant responds to the presence of the microorganism by changing the C and N metabolism based on its glutamine and alpha-ketoglutarate content, these changes contribute to major changes in the concentration of molecules involved in the balance of the osmotic pressure. These include sugars and amino-acids; the concentration of antioxidant molecules, of metabolites involved in the production of phytohormones like ethylene, and of substrates used for lignin production such as ferulic and sinapic acids. Most of the altered metabolites of the plant when inoculated with Microbacterium sp. 3J1 in response to drought coincided with the profile of altered metabolites in the microorganism alone when subjected to drought, pointing to a response by which the plant relies on the microbe for the production of such metabolites. To our knowledge this is the first comparative study of the microbe colonized-plant and microbe alone metabolomes under drought stress. PMID- 29520259 TI - Copy Number Variation in Fungi and Its Implications for Wine Yeast Genetic Diversity and Adaptation. AB - In recent years, copy number (CN) variation has emerged as a new and significant source of genetic polymorphisms contributing to the phenotypic diversity of populations. CN variants are defined as genetic loci that, due to duplication and deletion, vary in their number of copies across individuals in a population. CN variants range in size from 50 base pairs to whole chromosomes, can influence gene activity, and are associated with a wide range of phenotypes in diverse organisms, including the budding yeast Saccharomyces cerevisiae. In this review, we introduce CN variation, discuss the genetic and molecular mechanisms implicated in its generation, how they can contribute to genetic and phenotypic diversity in fungal populations, and consider how CN variants may influence wine yeast adaptation in fermentation-related processes. In particular, we focus on reviewing recent work investigating the contribution of changes in CN of fermentation-related genes in yeast wine strains and offer notable illustrations of such changes, including the high levels of CN variation among the CUP genes, which confer resistance to copper, a metal with fungicidal properties, and the preferential deletion and duplication of the MAL1 and MAL3 loci, respectively, which are responsible for metabolizing maltose and sucrose. Based on the available data, we propose that CN variation is a substantial dimension of yeast genetic diversity that occurs largely independent of single nucleotide polymorphisms. As such, CN variation harbors considerable potential for understanding and manipulating yeast strains in the wine fermentation environment and beyond. PMID- 29520260 TI - Environmental and Host Effects on Skin Bacterial Community Composition in Panamanian Frogs. AB - Research on the amphibian skin microbiota has focused on identifying bacterial taxa that deter a pathogenic chytrid fungus, and on describing patterns of microbiota variation. However, it remains unclear how environmental variation affects amphibian skin bacterial communities, and whether the overall functional diversity of the amphibian skin microbiota is associated to such variation. We sampled skin microbial communities from one dendrobatoid frog species across an environmental gradient along the Panama Canal, and from three dendrobatoid frog species before and after the onset of the wet season in one site. We found frog skin microbial alpha diversity to be highest in frogs from sites with low soil pH, but no clear effect of the onset of the wet season. However, we found frog skin microbial community structure to be affected by soil pH and the onset of the wet season, which also resulted in a decrease in between-sample variation. Across the sampled frog species, bacterial functional groups changed with the onset of the wet season, with certain bacterial functional groups entirely disappearing and others differing in their relative abundances. In particular, we found the proportion of Bd-inhibitory bacteria to correlate with mean soil pH, and to increase in two of the frog species with the onset of the wet season. Taken together, our results suggest that structure and predicted function of amphibian bacterial skin communities may be influenced by environmental variables such as pH and precipitation, site effects, and host effects. PMID- 29520261 TI - Transcriptional Activator GmrA, Encoded in Genomic Island OI-29, Controls the Motility of Enterohemorrhagic Escherichia coli O157:H7. AB - Enterohemorrhagic Escherichia coli O157:H7 is a major human enteric pathogen capable of causing large outbreaks of severe infections that induce bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Its genome contains 177 unique O islands (OIs) including those carrying the main virulence elements, Shiga toxin-converting phages (OI-45 and OI-93) and locus for enterocyte effacement (OI-148). However, many of these islands harbor only genes of unknown function. Here, we demonstrate that OI-29 encodes a newly discovered transcriptional activator, Z0639 (named GmrA), that is required for motility and flagellar synthesis in O157:H7. GmrA directly binds to the promoter of fliA, an RNA polymerase sigma factor, and thereby regulates flagellar genes controlled by FliA. Expression of gmrA is maximal under host conditions (37 degrees C, neutral pH, and physiological osmolarity), and in the presence of host epithelial cells, indicative of a role of this gene in infection by promoting motility. Finally, GmrA was found to be a widespread regulator of bacterial motility and flagellar synthesis in different pathotypes of E. coli. Our work largely enriches our understanding of bacterial motility control, and provides another example of regulators acquired laterally that mediate flagellar synthesis. PMID- 29520263 TI - Editorial: Cell Signaling in Host-Pathogen Interactions: The Host Point of View. PMID- 29520262 TI - Hypoxia, Hypoxia-Inducible Factor-1alpha, and Innate Antileishmanial Immune Responses. AB - Low oxygen environments and accumulation of hypoxia-inducible factors (HIFs) are features of infected and inflamed tissues. Here, we summarize our current knowledge on oxygen levels found in Leishmania-infected tissues and discuss which mechanisms potentially contribute to local tissue oxygenation in leishmanial lesions. Moreover, we review the role of hypoxia and HIF-1 on innate antileishmanial immune responses. PMID- 29520264 TI - Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF kappaB Ligand-Induced Osteoclast Differentiation. AB - C-reactive protein (CRP) is an established marker of rheumatoid arthritis (RA) but with ill-defined actions in the pathogenesis. Here, we show that CRP regulates the differentiation of osteoclasts, a central mediator of joint inflammation and bone erosion in RA, in a conformation- and receptor activator of NF-kappaB ligand (RANKL)-dependent manner. CRP in the native conformation is ineffective, whereas the monomeric conformation (mCRP) actively modulates osteoclast differentiation through NF-kappaB and phospholipase C signaling. Moreover, mCRP can bind RANKL, the major driver of osteoclast differentiation, and abrogate its activities. The binding and inhibition of RANKL are mediated by the cholesterol binding sequence (CBS) of mCRP. Corroborating the in vitro results, CRP knockout exacerbates LPS-induced bone resorption in mice. These results suggest that mCRP may be protective in joint inflammation by inhibiting pathological osteoclast differentiation and that the CBS peptide could be exploited as a potential RANKL inhibitor. PMID- 29520265 TI - Protein SIC Secreted from Streptococcus pyogenes Forms Complexes with Extracellular Histones That Boost Cytokine Production. AB - Innate immunity relies on an effective recognition of the pathogenic microorganism as well as on endogenous danger signals. While bacteria in concert with their secreted virulence factors can cause a number of inflammatory reactions, danger signals released at the site of infection may in addition determine the amplitude of such responses and influence the outcome of the disease. Here, we report that protein SIC, Streptococcal Inhibitor of Complement, an abundant secreted protein from Streptococcus pyogenes, binds to extracellular histones, a group of danger signals released during necrotizing tissue damage. This interaction leads to the formation of large aggregates in vitro. Extracellular histones and SIC are abundantly expressed and seen colocalized in biopsies from patients with necrotizing soft-tissue infections caused by S. pyogenes. In addition, binding of SIC to histones neutralized their antimicrobial activity. Likewise, the ability of histones to induce hemolysis was inhibited in the presence of SIC. However, when added to whole blood, SIC was not able to block the pro-inflammatory effect of histones. Instead SIC boosted the histone triggered release of a broad range of cytokines and chemokines, including IL-6, TNF-alpha, IL-8, IL-1beta, IL-1ra, G-CSF, and IFN-gamma. These results demonstrate that the interaction between SIC and histones has multiple effects on the host response to S. pyogenes infection. PMID- 29520266 TI - Effectiveness and Safety of Rituximab in Recalcitrant Pemphigoid Diseases. AB - Introduction: Rituximab (RTX) is a monoclonal antibody targeting CD20, a transmembrane protein expressed on B cells, causing B cell depletion. RTX has shown great efficacy in studies of pemphigus vulgaris, but data of pemphigoid diseases are limited. Objective: To assess the effectiveness and safety of RTX in pemphigoid diseases. Methods: The medical records of 28 patients with pemphigoid diseases that were treated with RTX were reviewed retrospectively. Early and late endpoints, defined according to international consensus, were disease control (DC), partial remission (PR), complete remission (CR), and relapses. Safety was measured by reported adverse events. Results: Patients with bullous pemphigoid (n = 8), mucous membrane pemphigoid (n = 14), epidermolysis bullosa acquisita (n = 5), and linear IgA disease (n = 1) were included. Treatment with 500 mg RTX (n = 6) or 1,000 mg RTX (n = 22) was administered on days 1 and 15. Eight patients received additional 500 mg RTX at months 6 and 12. Overall, DC was achieved in 67.9%, PR in 57.1%, and CR in 21.4% of the cases. During follow-up, 66.7% patients relapsed. Repeated treatment with RTX led to remission (PR or CR) in 85.7% of the retreated cases. No significant difference in response between pemphigoid subtypes was found. IgA-dominant cases (n = 5) achieved less DC (20 vs. 81.3%; p = 0.007), less PR (20 vs. 62.5%; p = 0.149), and less CR (0 vs. 18.8%; p = 0.549) compared to IgG-dominant cases (n = 16). Five severe adverse events and three deaths were reported. One death was possibly related to RTX and one death was disease related. Conclusion: RTX can be effective in recalcitrant IgG-dominant pemphigoid diseases, however not in those where IgA is dominant. PMID- 29520267 TI - Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade. AB - Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4+ T cells in DCreg infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4+ T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4+CTLA4hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4+CTLA4hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade. PMID- 29520268 TI - Targeting IgE Antibodies by Immunoadsorption in Atopic Dermatitis. AB - One major hallmark of atopic dermatitis (AD) is the elevated level of total serum IgE, which has been reported to be partly of the autoreactive type in a subset of patients. Immunoadsorption (IA) has been successfully applied in various classical autoantibody-mediated diseases such as pemphigus. Recent reports proposed the use of IA also for patients with severe AD and high total serum IgE levels. In this mini-review, we summarize the current knowledge about this novel treatment approach for AD and briefly discuss the so far incompletely known role of autoreactive IgE as potential target of IA therapy in this common inflammatory skin disorder. PMID- 29520269 TI - Functional and Phenotypic Changes of Natural Killer Cells in Whole Blood during Mycobacterium tuberculosis Infection and Disease. AB - Tuberculosis (TB) is still a global health concern, especially in resource-poor countries such as The Gambia. Defining protective immunity to TB is challenging: its pathogenesis is complex and involves several cellular components of the immune system. Recent works in vaccine development suggest important roles of the innate immunity in natural protection to TB, including natural killer (NK) cells. NK cells mediate cellular cytotoxicity and cytokine signaling in response to Mycobacterium tuberculosis (Mtb). NK cells can display specific memory-type markers to previous antigen exposure; thus, bridging innate and adaptive immunity. However, major knowledge gaps exist on the contribution of NK cells in protection against Mtb infection or TB. We performed a cross-sectional assessment of NK cells phenotype and function in four distinct groups of individuals: TB cases pre-treatment (n = 20) and post-treatment (n = 19), and household contacts with positive (n = 9) or negative (n = 18) tuberculin skin test (TST). While NK cells frequencies were similar between all groups, significant decreases in interferon-gamma expression and degranulation were observed in NK cells from TB cases pre-treatment compared to post-treatment. Conversely, CD57 expression, a marker of advanced NK cells differentiation, was significantly lower in cases post-treatment compared to pre-treatment. Finally, NKG2C, an activation and imprinted-NK memory marker, was significantly increased in TST+ (latently infected) compared to TB cases pre-treatment and TST- (uninfected) individuals. The results of this study provide valuable insights into the role of NK cells in Mtb infection and TB disease, demonstrating potential markers for distinguishing between infection states and monitoring of TB treatment response. PMID- 29520270 TI - A Novel Role for C5a in B-1 Cell Homeostasis. AB - B-1 cells constitute a unique subpopulation of lymphocytes residing mainly in body cavities like the peritoneal cavity (PerC) but are also found in spleen and bone marrow (BM). As innate-like B cells, they mediate first line immune defense through low-affinity natural IgM (nIgM) antibodies. PerC B-1 cells can egress to the spleen and differentiate into nIgM antibody-secreting plasma cells that recognize conserved exogenous and endogenous cellular structures. Homing to and homeostasis within the PerC are regulated by the chemokine CXCL13 released by PerC macrophages and stroma cells. However, the exact mechanisms underlying the regulation of CXCL13 and B-1 homeostasis are not fully explored. B-1 cells play important roles in the inflammatory response to infection, autoimmunity, ischemia/reperfusion injury, obesity, and atherosclerosis. Remarkably, this list of inflammatory entities has a strong overlap with diseases that are regulated by complement suggesting a link between B-1 cells and the complement system. Interestingly, up to now, no data exist regarding the role of complement in B-1 cell biology. Here, we demonstrate for the first time that C5a regulates B-1 cell steady-state dynamics within the peritoneum, the spleen, and the BM. We found decreased B-1a cell numbers in the peritoneum and the spleen of C5aR1-/- mice associated with increased B1-a and B1-b numbers in the spleen and high serum titers of nIgM antibodies directed against phosphorylcholine and several pneumococcal polysaccharides. Similarly, peritoneal B-1a cells were decreased in the peritoneum and splenic B-1a and B-1b cells were increased in C5aR2-/- mice. The decrease in peritoneal B-1 cell numbers was associated with decreased peritoneal CXCL13 levels in C5aR1-/- and C5aR2-/- mice. In search for mechanisms, we found that combined TLR2 and IL-10 receptor activation in PerC macrophages induced strong CXCL13 production, which was significantly reduced in cells from C5aR1- and C5aR2-deficient mice and after combined C5aR-targeting. Such stimulation also induced marked local C5 production by PerC macrophages and C5a generation. Importantly, peritoneal in vivo administration of C5a increased CXCL13 production. Taken together, our findings suggest that local non-canonical C5 activation in PerC macrophages fuels CXCL13 production as a novel mechanism to control B-1 cell homeostasis. PMID- 29520271 TI - Glutathione S-Transferase Pi Prevents Sepsis-Related High Mobility Group Box-1 Protein Translocation and Release. AB - Glutathione S-transferase Pi (GSTP) was originally identified as one of cytosolic phase II detoxification enzymes and also was considered to function via its non catalytic, ligand-binding activity. We have reported that GSTP played an anti inflammatory role in macrophages, suggesting that GSTP may have a protective role in inflammation. In this study, we deleted the murine Gstp gene cluster and found that GSTP significantly decreased the mortality of experimental sepsis and reduced related serum level of high mobility group box-1 protein (HMGB1). As HMGB1 is the key cytokine involved in septic death, we further studied the effect of GSTP on HMGB1 release. The results demonstrated that a classic protein kinase C (cPKC) dependent phosphorylation of cytoplasmic GSTP at Ser184 occurred in macrophages in response to lipopolysaccharide (LPS) stimulation. Phosphorylated GSTP was then translocated to the nucleus. In the nucleus, GSTP bound to HMGB1 and suppressed LPS-triggered and cPKC-mediated HMGB1 phosphorylation. Consequently, GSTP prevented the translocation of HMGB1 to cytoplasm and release. Our findings provide the new evidence that GSTP inhibited HMGB1 release via binding to HMGB1 in the nucleus independent of its transferase activity. cPKC mediated GSTP phosphorylation was essential for GSTP to translocate from cytoplasm to nucleus. To our knowledge, we are the first to report that nuclear GSTP functions as a negative regulator to control HMGB1 release from macrophages and decreases the mortality of sepsis. PMID- 29520273 TI - Extracellular Vesicles Released from Mycobacterium tuberculosis-Infected Neutrophils Promote Macrophage Autophagy and Decrease Intracellular Mycobacterial Survival. AB - Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the lungs, macrophages and neutrophils are the first immune cells that have contact with the infecting mycobacteria. Neutrophils are phagocytic cells that kill microorganisms through several mechanisms, which include the lytic enzymes and antimicrobial peptides that are found in their lysosomes, and the production of reactive oxygen species. Neutrophils also release extracellular vesicles (EVs) (100-1,000 nm in diameter) to the extracellular milieu; these EVs consist of a lipid bilayer surrounding a hydrophilic core and participate in intercellular communication. We previously demonstrated that human neutrophils infected in vitro with Mtb H37Rv release EVs (EV-TB), but the effect of these EVs on other cells relevant for the control of Mtb infection, such as macrophages, has not been completely analyzed. In this study, we characterized the EVs produced by non stimulated human neutrophils (EV-NS), and the EVs produced by neutrophils stimulated with an activator (PMA), a peptide derived from bacterial proteins (fMLF) or Mtb, and observed that the four EVs differed in their size. Ligands for toll-like receptor (TLR) 2/6 were detected in EV-TB, and these EVs favored a modest increase in the expression of the co-stimulatory molecules CD80, a higher expression of CD86, and the production of higher amounts of TNF-alpha and IL-6, and of lower amounts of TGF-beta, in autologous human macrophages, compared with the other EVs. EV-TB reduced the amount of intracellular Mtb in macrophages, and increased superoxide anion production in these cells. TLR2/6 ligation and superoxide anion production are known inducers of autophagy; accordingly, we found that EV-TB induced higher expression of the autophagy-related marker LC3-II in macrophages, and the co-localization of LC3-II with Mtb inside infected macrophages. The intracellular mycobacterial load increased when autophagy was inhibited with wortmannin in these cells. In conclusion, our results demonstrate that neutrophils produce different EVs in response to diverse activators, and that EV-TB activate macrophages and promote the clearance of intracellular Mtb through early superoxide anion production and autophagy induction, which is a novel role for neutrophil-derived EVs in the immune response to Mtb. PMID- 29520272 TI - Metabolic Modulation in Macrophage Effector Function. AB - Traditionally cellular respiration or metabolism has been viewed as catabolic and anabolic pathways generating energy and biosynthetic precursors required for growth and general cellular maintenance. However, growing literature provides evidence of a much broader role for metabolic reactions and processes in controlling immunological effector functions. Much of this research into immunometabolism has focused on macrophages, cells that are central in pro- as well as anti-inflammatory responses-responses that in turn are a direct result of metabolic reprogramming. As we learn more about the precise role of metabolic pathways and pathway intermediates in immune function, a novel opportunity to target immunometabolism therapeutically has emerged. Here, we review the current understanding of the regulation of macrophage function through metabolic remodeling. PMID- 29520274 TI - Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment. AB - Monoclonal antibodies and their fragments have significantly changed the outcome of cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibody-dependent immune effector cell activation and complement mediated cell death. Along with a continued expansion in number, diversity, and complexity of validated tumor targets there is an increasing focus on engineering recombinant antibody fragments for lead development. Single-domain antibodies (sdAbs), in particular those engineered from the variable heavy-chain fragment (VHH gene) found in Camelidae heavy-chain antibodies (or IgG2 and IgG3), are the smallest fragments that retain the full antigen-binding capacity of the antibody with advantageous properties as drugs. For similar reasons, growing attention is being paid to the yet smaller variable heavy chain new antigen receptor (VNAR) fragments found in Squalidae. sdAbs have been selected, mostly from immune VHH libraries, to inhibit or modulate enzyme activity, bind soluble factors, internalize cell membrane receptors, or block cytoplasmic targets. This succinct review is a compilation of recent data documenting the application of engineered, recombinant sdAb in the clinic as epitope recognition "modules" to build monomeric, dimeric and multimeric ligands that target, tag and stall solid tumor growth in vivo. Size, affinity, specificity, and the development profile of sdAbs drugs are seemingly consistent with desirable clinical efficacy and safety requirements. But the hepatotoxicity of the tetrameric anti-DR5-VHH drug in patients with pre-existing anti-drug antibodies halted the phase I clinical trial and called for a thorough pre-screening of the immune and poly-specific reactivities of the sdAb leads. PMID- 29520276 TI - Alloreactive T Cell Receptor Diversity against Structurally Similar or Dissimilar HLA-DP Antigens Assessed by Deep Sequencing. AB - T cell alloreactivity is mediated by a self-human leukocyte antigen (HLA) restricted T cell receptor (TCR) repertoire able to recognize both structurally similar and dissimilar allogeneic HLA molecules (i.e., differing by a single or several amino acids in their peptide-binding groove). We hypothesized that thymic selection on self-HLA molecules could have an indirect impact on the size and diversity of the alloreactive response. To test this possibility, we used TCR Vbeta immunophenotyping and immunosequencing technology in a model of alloreactivity between self-HLA selected T cells and allogeneic HLA-DPB1 (DPB1) differing from self-DPB1*04:02 by a single (DPB1*02:01) or several (DPB1*09:01) amino acids in the peptide-binding groove. CD4+ T cells from three different self DPB1*04:01,*04:02 individuals were stimulated with HeLa cells stably transduced with the relevant peptide processing machinery, co-stimulatory molecules, and HLA DP. Flow cytometric quantification of the DPB1-specific T cell response measured as upregulation of the activation marker CD137 revealed significantly lower levels of alloreactivity against DPB1*02:01 compared with DPB1*09:01 (mean CD4+CD137+ frequency 35.2 +/- 9.9 vs. 61.5 +/- 7.7%, respectively, p < 0.0001). These quantitative differences were, however, not reflected by differences in the breadth of the alloreactive response at the Vbeta level, with both alloantigens eliciting specific responses from all TCR-Vbeta specificities tested by flow cytometry, albeit with higher levels of reactivity from most Vbeta specificities against DPB1*09:01. In line with these observations, TCRB-CDR3 immunosequencing showed no significant differences in mean clonality of sorted CD137+CD4+ cells alloreactive against DPB1*02:01 or DPB1*09:01 [0.39 (0.36-0.45) and 0.39 (0.30 0.46), respectively], or in the cumulative frequencies of the 10 most frequent responding clones (55-67 and 58-62%, respectively). Most of the clones alloreactive against DPB1*02:01 (68.3%) or DPB1*09:01 (75.3%) were characterized by low-abundance (i.e., they were not appreciable among the pre-culture T cells). Interestingly, however, their cumulative frequency was lower against DPB1*02:01 compared with DPB1*09:01 (mean cumulative frequency 35.3 vs. 50.6%, respectively). Our data show that, despite lower levels of alloreactivity, a similar clonal diversity can be elicited by structurally similar compared with structurally dissimilar HLA-DPB1 alloantigens and demonstrate the power of TCRB immunosequencing in unraveling subtle qualitative changes not appreciable by conventional methods. PMID- 29520275 TI - Tolerogenic Dendritic Cells in Solid Organ Transplantation: Where Do We Stand? AB - Over the past century, solid organ transplantation has been improved both at a surgical and postoperative level. However, despite the improvement in efficiency, safety, and survival, we are still far from obtaining full acceptance of all kinds of allograft in the absence of concomitant treatments. Today, transplanted patients are treated with immunosuppressive drugs (IS) to minimize immunological response in order to prevent graft rejection. Nevertheless, the lack of specificity of IS leads to an increase in the risk of cancer and infections. At this point, cell therapies have been shown as a novel promising resource to minimize the use of IS in transplantation. The main strength of cell therapy is the opportunity to generate allograft-specific tolerance, promoting in this way long-term allograft survival. Among several other regulatory cell types, tolerogenic monocyte-derived dendritic cells (Tol-MoDCs) appear to be an interesting candidate for cell therapy due to their ability to perform specific antigen presentation and to polarize immune response to immunotolerance. In this review, we describe the characteristics and the mechanisms of action of both human Tol-MoDCs and rodent tolerogenic bone marrow-derived DCs (Tol-BMDCs). Furthermore, studies performed in transplantation models in rodents and non-human primates corroborate the potential of Tol-BMDCs for immunoregulation. In consequence, Tol-MoDCs have been recently evaluated in sundry clinical trials in autoimmune diseases and shown to be safe. In addition to autoimmune diseases clinical trials, Tol-MoDC is currently used in the first phase I/II clinical trials in transplantation. Translation of Tol-MoDCs to clinical application in transplantation will also be discussed in this review. PMID- 29520277 TI - Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis. AB - Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted. PMID- 29520278 TI - Interferon-alpha Subtypes As an Adjunct Therapeutic Approach for Human Immunodeficiency Virus Functional Cure. AB - Human immunodeficiency virus (HIV) establishes life-long latency in infected individuals. Although highly active antiretroviral therapy (HAART) has had a significant impact on the course of HIV infection leading to a better long-term outcome, the pool of latent reservoir remains substantial even under HAART. Numerous approaches have been under development with the goal of eradicating the latent HIV reservoir though with limited success. Approaches that combine immune mediated control of HIV to activate both the innate and the adaptive immune system under suppressive therapy along with "shock and kill" drugs may lead to a better control of the reactivated virus. Interferon-alpha (IFN-alpha) is an innate cytokine that has been shown to activate intracellular defenses capable of restricting and controlling HIV. IFN-alpha, however, harbors numerous functional subtypes that have been reported to display different binding affinities and potency. Recent studies have suggested that certain subtypes such as IFN-alpha8 and IFN-alpha14 have potent anti-HIV activity with little or no immune activation, whereas other subtypes such as IFN-alpha4, IFN-alpha5, and IFN alpha14 activate NK cells. Could these subtypes be used in combination with other strategies to reduce the latent viral reservoir? Here, we review the role of IFN alpha subtypes in HIV infection and discuss the possibility that certain subtypes could be potential adjuncts to a "shock and kill" or therapeutic vaccination strategy leading to better control of the latent reservoir and subsequent functional cure. PMID- 29520279 TI - Human Langerhans Cells with Pro-inflammatory Features Relocate within Psoriasis Lesions. AB - Psoriasis is a common skin disease that presents with well-demarcated patches of inflammation. Recurrent disease in fixed areas of the skin indicates a localized disease memory that is preserved in resolved lesions. In line with such concept, the involvement of tissue-resident immune cells in psoriasis pathology is increasingly appreciated. Langerhans cells (LCs) are perfectly placed to steer resident T cells and local tissue responses in psoriasis. Here, we present an overview of the current knowledge of LCs in human psoriasis, including findings that highlight pro-inflammatory features of LCs in psoriasis lesions. We also review the literature on conflicting data regarding LC localization and functionality in psoriasis. Our review highlights that further studies are needed to elucidate the molecular mechanisms that drive LCs functionality in inflammatory diseases. PMID- 29520280 TI - The Influence of Invariant Natural Killer T Cells on Humoral Immunity to T Dependent and -Independent Antigens. AB - Vaccination with CD1d-binding glycolipid adjuvants and co-administered protein, lipid, and carbohydrate antigens leads to invariant natural killer T (NKT) cell dependent enhancement of protective B cell responses. NKT cell activation boosts the establishment of protein antigen-specific B cell memory and long-lived plasma cell (LLPC) compartments. NKT cells may exert a similar effect on some carbohydrate-specific B cells, but not lipid-specific B cells. The mechanisms of action of NKT cells on B cell responsiveness and subsequent differentiation into memory B cells and LLPC is dependent on CD1d expression by dendritic cells and B cells that can co-present glycolipids on CD1d and antigen-derived peptide on MHCII. CD1d/glycolipid-activated NKT cells are able to provide help to B cells in a manner dependent on cognate and non-cognate interactions. More recently, a glycolipid-expanded subset of IL-21-secreting NKT cells known as NKT follicular helper cells has been suggested to be a driver of NKT-enhanced humoral immunity. This review summarizes established and recent findings on how NKT cells impact humoral immunity and suggests possible areas of investigation that may allow the incorporation of NKT-activating agents into vaccine adjuvant platforms. PMID- 29520281 TI - Possible Therapeutic Application of Targeting Type II Natural Killer T Cell Mediated Suppression of Tumor Immunity. AB - Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies. PMID- 29520282 TI - Checks and Balances in Autoimmune Vasculitis. AB - Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system. PMID- 29520284 TI - Closing the Yield Gap of Sugar Beet in the Netherlands-A Joint Effort. AB - The reform of the European Union's sugar regime caused potential decreasing beet prices. Therefore, the Speeding Up Sugar Yield (SUSY) project was initiated. At the start, a 3 * 15 target was formulated: in 2015 the national average sugar yield in the Netherlands equals 15 t/ha (60% of the sugar beet potential) and the total variable costs 15 euro/t sugar beet, aspiring a saving on total variable costs and a strong increase in sugar yield. Based on their average sugar yield in 2000-2004, 26 pairs of "type top" (high yielding) and "type average" (average yielding) growers were selected from all sugar beet growing regions in the Netherlands. On the fields of those farmers, all measures of sugar beet cultivation were investigated, including cost calculation and recording phytopathological, agronomical and soil characteristics in 2006 and 2007. Although there was no significant difference in total variable costs, the "type top" growers yielded significantly 20% more sugar in each year compared to the "type average" growers. Therefore, the most profitable strategy for the growers is maximizing sugar yield and optimizing costs. The difference in sugar yield between growers could be explained by pests and diseases (50%), weed control (30%), soil structure (25%) and sowing date (14%), all interacting with each other. The SUSY-project revealed the effect of the grower's management on sugar yield. As a follow up for the SUSY-project, a growers' guide "Suikerbietsignalen" was published, Best Practice study groups of growers were formed and trainings and workshops were given and field days organized. Further, the benchmarking and feedback on the crop management recordings and the extension on variety choice, sowing performance, foliar fungi control and harvest losses were intensified. On the research part, a resistance breaking strain of the Beet Necrotic Yellow Vein Virus (BNYVV) and a new foliar fungus, Stemphylium beticola, were identified and options for control were tested, and implemented in growers practices. The joint efforts of sugar industry, sugar beet research and growers resulted in a raise in sugar yield from 10.6 t/ha in 2002-2006 to 13.8 t/ha in 2012-2016. PMID- 29520285 TI - Chloroplast Glutamine Synthetase, the Key Regulator of Nitrogen Metabolism in Wheat, Performs Its Role by Fine Regulation of Enzyme Activity via Negative Cooperativity of Its Subunits. AB - Glutamine synthetase (GS) is of central interest as the main route of ammonia assimilation in plants, and as a connection point between the organic and inorganic worlds. Even though GS activity is critical for producing high yields of crop plants, the autoregulation of substrate consumption of wheat GS remained unknown until now. Here we show kinetic evidence, that the chloroplast localized GS isoform (GS2) of wheat (Triticum aestivum L. cv. Jubilejnaja-50) takes place at the carbon-nitrogen metabolic branch point, where it is a mediator, and its enzymatic activity is regulated in a negatively cooperative allosteric manner. We have discovered that GS2 activity is described by a tetraphasic kinetic curve in response to increasing levels of glutamate supply. We constructed a model that explains the kinetic properties of glutamate consumption and this unique allosteric behavior. We also studied the subunit composition of both wheat leaf GS isoenzymes by a combination of two dimensional gel electrophoresis and protein blotting. Both leaf isozymes have homogeneous subunit composition. Glutamate is both a substrate, and an allosteric regulator of the biosynthetic reaction. We have concluded on the basis of our results and previous reports, that wheat GS2 is probably a homooctamer, and that it processes its substrate in a well regulated, concentration dependent way, as a result of its negatively cooperative, allosteric activity. Thus, GS2 has a central role as a regulator between the nitrogen and the carbon cycles via maintaining glutamine-glutamate pool in the chloroplast on the level of substrates, in addition to its function in ammonia assimilation. PMID- 29520283 TI - Ethylene and 1-Aminocyclopropane-1-carboxylate (ACC) in Plant-Bacterial Interactions. AB - Ethylene and its precursor 1-aminocyclopropane-1-carboxylate (ACC) actively participate in plant developmental, defense and symbiotic programs. In this sense, ethylene and ACC play a central role in the regulation of bacterial colonization (rhizospheric, endophytic, and phyllospheric) by the modulation of plant immune responses and symbiotic programs, as well as by modulating several developmental processes, such as root elongation. Plant-associated bacterial communities impact plant growth and development, both negatively (pathogens) and positively (plant-growth promoting and symbiotic bacteria). Some members of the plant-associated bacterial community possess the ability to modulate plant ACC and ethylene levels and, subsequently, modify plant defense responses, symbiotic programs and overall plant development. In this work, we review and discuss the role of ethylene and ACC in several aspects of plant-bacterial interactions. Understanding the impact of ethylene and ACC in both the plant host and its associated bacterial community is key to the development of new strategies aimed at increased plant growth and protection. PMID- 29520286 TI - Foxtail Millet [Setaria italica (L.) Beauv.] Grown under Low Nitrogen Shows a Smaller Root System, Enhanced Biomass Accumulation, and Nitrate Transporter Expression. AB - Foxtail millet (FM) [Setaria italica (L.) Beauv.] is a grain and forage crop well adapted to nutrient-poor soils. To date little is known how FM adapts to low nitrogen (LN) at the morphological, physiological, and molecular levels. Using the FM variety Yugu1, we found that LN led to lower chlorophyll contents and N concentrations, and higher root/shoot and C/N ratios and N utilization efficiencies under hydroponic culture. Importantly, enhanced biomass accumulation in the root under LN was in contrast to a smaller root system, as indicated by significant decreases in total root length; crown root number and length; and lateral root number, length, and density. Enhanced carbon allocation toward the root was rather for significant increases in average diameter of the LN root, potentially favorable for wider xylem vessels or other anatomical alterations facilitating nutrient transport. Lower levels of IAA and CKs were consistent with a smaller root system and higher levels of GA may promote root thickening under LN. Further, up-regulation of SiNRT1.1, SiNRT2.1, and SiNAR2.1 expression and nitrate influx in the root and that of SiNRT1.11 and SiNRT1.12 expression in the shoot probably favored nitrate uptake and remobilization as a whole. Lastly, more soluble proteins accumulated in the N-deficient root likely as a result of increases of N utilization efficiencies. Such "excessive" protein-N was possibly available for shoot delivery. Thus, FM may preferentially transport carbon toward the root facilitating root thickening/nutrient transport and allocate N toward the shoot maximizing photosynthesis/carbon fixation as a primary adaptive strategy to N limitation. PMID- 29520288 TI - TBC2target: A Resource of Predicted Target Genes of Tea Bioactive Compounds. AB - Tea is one of the most popular non-alcoholic beverages consumed worldwide. Numerous bioactive constituents of tea were confirmed to possess healthy benefits via the mechanisms of regulating gene expressions or protein activities. However, a complete interacting profile between tea bioactive compounds (TBCs) and their target genes is lacking, which put an obstacle in the study of healthy function of tea. To fill this gap, we developed a database of target genes of TBCs (TBC2target, http://camellia.ahau.edu.cn/TBC2target) based on a pharmacophore mapping approach. In TBC2target, 6,226 interactions between 240 TBCs and 673 target genes were documented. TBC2target contains detailed information about each interacting entry, such as TBC, CAS number, PubChem CID, source of compound (e.g., green, black), compound type, target gene(s) of TBC, gene symbol, gene ID, ENSEMBL ID, PDB ID, TBC bioactivity and the reference. Using the TBC-target associations, we constructed a bipartite network and provided users the global network and local sub-network visualization and topological analyses. The entire database is free for online browsing, searching and downloading. In addition, TBC2target provides a BLAST search function to facilitate use of the database. The particular strengths of TBC2target are the inclusion of the comprehensive TBC target interactions, and the capacity to visualize and analyze the interacting networks, which may help uncovering the beneficial effects of tea on human health as a central resource in tea health community. PMID- 29520287 TI - Dynamin-Like Proteins Are Potentially Involved in Membrane Dynamics within Chloroplasts and Cyanobacteria. AB - Dynamin-like proteins (DLPs) are a family of membrane-active proteins with low sequence identity. The proteins operate in different organelles in eukaryotic cells, where they trigger vesicle formation, membrane fusion, or organelle division. As discussed here, representatives of this protein family have also been identified in chloroplasts and DLPs are very common in cyanobacteria. Since cyanobacteria and chloroplasts, an organelle of bacterial origin, have similar internal membrane systems, we suggest that DLPs are involved in membrane dynamics in cyanobacteria and chloroplasts. Here, we discuss the features and activities of DLPs with a focus on their potential presence and activity in chloroplasts and cyanobacteria. PMID- 29520289 TI - Identification of Metabolites and Transcripts Involved in Salt Stress and Recovery in Peanut. AB - HIGHLIGHTS Metabolites and transcripts related to plant physiology in salt stress conditions, especially to the recovery process were disclosed in peanut. Peanut (Arachis hypogaea L.) is considered as a moderately salt-sensitive species and thus soil salinity can be a limiting factor for peanut cultivation. To gain insights into peanut plant physiology in response to salt stress and alleviation, we comprehensively characterized leaf relative electrolyte leakage (REC), photosynthesis, leaf transpiration, and metabolism of plants under salt stress and plants that were subjected to salt stress followed by salt alleviation period. As expected, we found that REC levels were higher when plants were subjected to salt stress compared with the untreated plants. However, in contrast to expectations, REC was even higher compared with salt treated plants when plants were transferred from salt stress to standard conditions. To decipher REC variation in response to salt stress, especial during the recovery, metabolite, and transcript variations were analyzed by GC/MS and RNA-seq method, respectively. Ninety two metabolites, among total 391 metabolites identified, varied in response to salt and 42 metabolites responded to recovery specially. Transcriptomics data showed 1,742 in shoots and 3,281 in roots transcript varied in response to salt stress and 372 in shoots and 1,386 transcripts in roots responded specifically to recovery, but not salt stress. Finally, 95 transcripts and 1 metabolite are indicated as candidates involved in REC, photosynthesis, transpiration, and Na+ accumulation variation were revealed by using the principal component analysis (PCA) and correlation analysis. This study provides valuable information on peanut response to salt stress and recovery and may inspire further study to improve salt tolerance in peanut germplasm innovation. PMID- 29520290 TI - PlantSize Offers an Affordable, Non-destructive Method to Measure Plant Size and Color in Vitro. AB - Plant size, shape and color are important parameters of plants, which have traditionally been measured by destructive and time-consuming methods. Non destructive image analysis is an increasingly popular technology to characterize plant development in time. High throughput automatic phenotyping platforms can simultaneously analyze multiple morphological and physiological parameters of hundreds or thousands of plants. Such platforms are, however, expensive and are not affordable for many laboratories. Moreover, determination of basic parameters is sufficient for most studies. Here we describe a non-invasive method, which simultaneously measures basic morphological and physiological parameters of in vitro cultured plants. Changes of plant size, shape and color is monitored by repeated photography with a commercial digital camera using neutral white background. Images are analyzed with the MatLab-based computer application PlantSize, which simultaneously calculates several parameters including rosette size, convex area, convex ratio, chlorophyll and anthocyanin contents of all plants identified on the image. Numerical data are exported in MS Excel compatible format. Subsequent data processing provides information on growth rates, chlorophyll and anthocyanin contents. Proof-of-concept validation of the imaging technology was demonstrated by revealing small but significant differences between wild type and transgenic Arabidopsis plants overexpressing the HSFA4A transcription factor or the hsfa4a knockout mutant, subjected to different stress conditions. While HSFA4A overexpression was associated with better growth, higher chlorophyll and lower anthocyanin content in saline conditions, the knockout hsfa4a mutant showed hypersensitivity to various stresses. Morphological differences were revealed by comparing rosette size, shape and color of wild type plants with phytochrome B (phyB-9) mutant. While the technology was developed with Arabidopsis plants, it is suitable to characterize plants of other species including crops, in a simple, affordable and fast way. PlantSize is publicly available (http://www.brc.hu/pub/psize/index.html). PMID- 29520291 TI - Ectopic Expression of GsSRK in Medicago sativa Reveals Its Involvement in Plant Architecture and Salt Stress Responses. AB - Receptor-like kinases (RLK) play fundamental roles in plant growth and stress responses. Compared with other RLKs, little information is provided concerning the S-locus LecRLK subfamily, which is characterized by an extracellular G-type lectin domain and an S-locus-glycop domain. Until now, the function of the G-type lectin domain is still unknown. In a previous research, we identified a Glycine soja S-locus LecRLK gene GsSRK, which conferred increased salt stress tolerance in transgenic Arabidopsis. In this study, to investigate the role of the G-type lectin domain and to breed transgenic alfalfa with superior salt stress tolerance, we transformed the full-length GsSRK (GsSRK-f) and a truncated version of GsSRK (GsSRK-t) deleting the G-type lectin domain into alfalfa. Our results showed that overexpression of GsSRK-t, but not GsSRK-f, resulted in changes of plant architecture, as evidenced by more branches but shorter shoots of GsSRK-t transgenic alfalfa, indicating a potential role of the extracellular G-type lectin domain in regulating plant architecture. Furthermore, we also found that transgenic alfalfa overexpressing either GsSRK-f or GsSRK-t showed increased salt stress tolerance, and GsSRK-t transgenic alfalfa displayed better growth (more branches and higher fresh weight) than GsSRK-f lines under salt stress. In addition, our results suggested that both GsSRK-f and GsSRK-t were involved in ion homeostasis, ROS scavenging, and osmotic regulation. Under salt stress, the Na+ content in the transgenic lines was significantly lower, while the K+ content was slightly higher than that in WT. Moreover, the transgenic lines displayed reduced ion leakage and MDA content, but increased SOD activity and proline content than WT. Notably, no obvious difference in these physiological indices was observed between GsSRK-f and GsSRK-t transgenic lines, implying that deletion of the GsSRK G-type lectin domain does not affect its physiological function in salt stress responses. In conclusion, results in this research reveal the dual role of GsSRK in regulating both plant architecture and salt stress responses. PMID- 29520292 TI - SLFL Genes Participate in the Ubiquitination and Degradation Reaction of S-RNase in Self-compatible Peach. AB - It has been proved that the gametophytic self-incompatibility (GSI), mainly exists in Rosaceae and Solanaceae, is controlled by S genes, which are two tightly linked genes located at highly polymorphic S-locus: the S-RNase for pistil specificity and the F-box gene (SFB/SLF) for pollen specificity, respectively. However, the roles of those genes in SI of peach are still a subject of extensive debate. In our study, we selected 37 representative varieties according to the evolution route of peach and identified their S genotypes. We cloned pollen determinant genes mutated PperSFB1m, PperSFB2m, PperSFB4m, and normal PperSFB2, and style determinant genes PperS1-RNase, PperS2 RNase, PperS2m-RNase, and PperS4-RNase. The mutated PperSFBs encode truncated SFB proteins due to a fragment insertion. The truncated PperSFBs and normal PperSFB2 interacted with PperS-RNases demonstrated by Y2H. Normal PperSFB2 was divided into four parts: box, box-V1, V1-V2, and HVa-HVb. The box domain of PperSFB2 did not interact with PperS-RNases, both of the box-V1 and V1-V2 had interactions with PperS-RNases, while the hypervariable region of PperSFB2 HVa-HVb only interacted with PperS2-RNase showed by Y2H and BiFC assay. Bioinformatics analysis of peach genome revealed that there were other F-box genes located at S locus, and of which three F-box genes were specifically expressed in pollen, named as PperSLFL1, PperSLFL2, and PperSLFL3, respectively. In phylogenetic analysis PperSLFLs clustered with Maloideae SFBB genes, and PperSFB genes were clustered into the other group with other SFB genes of Prunus. Protein interaction analysis revealed that the three PperSLFLs interacted with PperSSK1 and PperS-RNases with no allelic specificity. In vitro ubiquitination assay showed that PperSLFLs could tag ubiquitin molecules onto PperS-RNases. The above results suggest that three PperSLFLs are the appropriate candidates for the "general inhibitor," which would inactivate the S-RNases in pollen tubes, involved in the self-incompatibility of peach. PMID- 29520293 TI - Analysis of Parent-of-Origin Effects on the X Chromosome in Asian and European Orofacial Cleft Triads Identifies Associations with DMD, FGF13, EGFL6, and Additional Loci at Xp22.2. AB - Background: Although both the mother's and father's alleles are present in the offspring, they may not operate at the same level. These parent-of-origin (PoO) effects have not yet been explored on the X chromosome, which motivated us to develop new methods for detecting such effects. Orofacial clefts (OFCs) exhibit sex-specific differences in prevalence and are examples of traits where a search for various types of effects on the X chromosome might be relevant. Materials and Methods: We upgraded our R-package Haplin to enable genome-wide analyses of PoO effects, as well as power simulations for different statistical models. 14,486 X chromosome SNPs in 1,291 Asian and 1,118 European case-parent triads of isolated OFCs were available from a previous GWAS. For each ethnicity, cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) were analyzed separately using two X-inactivation models and a sliding-window approach to haplotype analysis. In addition, we performed analyses restricted to female offspring. Results: Associations were identified in "Dystrophin" (DMD, Xp21.2-p21.1), "Fibroblast growth factor 13" (FGF13, Xq26.3-q27.1) and "EGF-like domain multiple 6" (EGFL6, Xp22.2), with biologically plausible links to OFCs. Unlike EGFL6, the other associations on chromosomal region Xp22.2 had no apparent connections to OFCs. However, the Xp22.2 region itself is of potential interest because it contains genes for clefting syndromes [for example, "Oral-facial-digital syndrome 1" (OFD1) and "Midline 1" (MID1)]. Overall, the identified associations were highly specific for ethnicity, cleft subtype and X-inactivation model, except for DMD in which associations were identified in both CPO and CL/P, in the model with X-inactivation and in Europeans only. Discussion/Conclusion: The specificity of the associations for ethnicity, cleft subtype and X-inactivation model underscores the utility of conducting subanalyses, despite the ensuing need to adjust for additional multiple testing. Further investigations are needed to confirm the associations with DMD, EGF16, and FGF13. Furthermore, chromosomal region Xp22.2 appears to be a hotspot for genes implicated in clefting syndromes and thus constitutes an exciting direction to pursue in future OFCs research. More generally, the new methods presented here are readily adaptable to the study of X-linked PoO effects in other outcomes that use a family-based design. PMID- 29520295 TI - Genetic Variation of the Endangered Neotropical Catfish Steindachneridion scriptum (Siluriformes: Pimelodidae). AB - Steindachneridion scriptum is an important species as a resource for fisheries and aquaculture; it is currently threatened and has a reduced occurrence in South America. The damming of rivers, overfishing, and contamination of freshwater environments are the main impacts on the maintenance of this species. We accessed the genetic diversity and structure of S. scriptum using the DNA barcode and control region (D-loop) sequences of 43 individuals from the Upper Uruguay River Basin (UUR) and 10 sequences from the Upper Parana River Basin (UPR), which were obtained from GenBank. S. scriptum from the UUR and the UPR were assigned in two distinct molecular operational taxonomic units (MOTUs) with higher inter-specific K2P distance than the optimum threshold (OT = 0.0079). The COI Intra-MOTU distances of S. scriptum specimens from the UUR ranged from 0.0000 to 0.0100. The control region indicated a high number of haplotypes and low nucleotide diversity, compatible with a new population in recent expansion process. Genetic structure was observed, with high differentiation between UUR and UPR basins, identified by BAPS, haplotype network, AMOVA (FST = 0.78, p < 0.05) and Mantel test. S. scriptum from the UUR showed a slight differentiation (FST = 0.068, p < 0.05), but not isolation-by-distance. Negative values of Tajima's D and Fu's Fs suggest recent demographic oscillations. The Bayesian skyline plot analysis indicated possible population expansion from beginning 2,500 years ago and a recent reduction in the population size. Low nucleotide diversity, spatial population structure, and the reduction of effective population size should be considered for the planning of strategies aimed at the conservation and rehabilitation of this important fisheries resource. PMID- 29520294 TI - Genetic Characterization of the Fish Piaractus brachypomus by Microsatellites Derived from Transcriptome Sequencing. AB - The pirapitinga, Piaractus brachypomus (Characiformes, Serrasalmidae), is a fish from the Amazon basin and is considered to be one of the main native species used in aquaculture production in South America. The objectives of this study were: (1) to perform liver transcriptome sequencing of pirapitinga through NGS and then validate a set of microsatellite markers for this species; and (2) to use polymorphic microsatellites for analysis of genetic variability in farmed stocks. The transcriptome sequencing was carried out through the Roche/454 technology, which resulted in 3,696 non-redundant contigs. Of this total, 2,568 contigs had similarity in the non-redundant (nr) protein database (Genbank) and 2,075 sequences were characterized in the categories of Gene Ontology (GO). After the validation process of 30 microsatellite loci, eight markers showed polymorphism. The analysis of these polymorphic markers in farmed stocks revealed that fish farms from North Brazil had a higher genetic diversity than fish farms from Southeast Brazil. AMOVA demonstrated that the highest proportion of variation was presented within the populations. However, when comparing different groups (1: Wild; 2: North fish farms; 3: Southeast fish farms), a considerable variation between the groups was observed. The FST values showed the occurrence of genetic structure among the broodstocks from different regions of Brazil. The transcriptome sequencing in pirapitinga provided important genetic resources for biological studies in this non-model species, and microsatellite data can be used as the framework for the genetic management of breeding stocks in Brazil, which might provide a basis for a genetic pre-breeding programme. PMID- 29520296 TI - Rathke's Cleft Cyst as Origin of a Pediatric Papillary Craniopharyngioma. AB - A 6-year old patient presented with an intra and suprasellar cystic lesion accompanied with impairment of the hypothalamic-pituitary axis and partial hypopituitarism. The most likely cause of sellar lesions in this age group are adamantinomatous craniopharyngioma (adaCP) or Rathke's cleft cysts (RCCs). AdaCP are characterized by CTNNB1 mutations accompanied with aberrant nuclear beta catenin expression. RCC show neither nuclear beta-catenin expression nor BRAF mutation. The latter is a hallmark of papillary craniopharyngiomas (papCP) that exhibit remarkable histological similarity with metaplasia of RCC. Diagnosis of the patient was elucidated by CTNNB1 and BRAF mutation screening, utilizing different approaches, as well as histological examination of markers, e.g., beta catenin, claudin-1, EpCAM and the mutated BRAFV600E protein, which are known to be differentially expressed in sellar lesions. The case presented reveals extraordinary aspects for two reasons. Firstly, the lesion appeared clinically, on MRI, intraoperatively and histologically as RCC with prominent squamous metaplasia, but showing an expression pattern of markers also found in papCP, whilst exhibiting a hitherto undescribed BRAFV600E mutation. This important result documents a supposable transition of RCC metaplasia into a papillary craniopharyngioma (papCP). Secondly, this intriguing case shows unexpectedly that although papCP usually occurs almost exclusively in adults, it can also arise in childhood. PMID- 29520298 TI - Association of MU-Calpain and Calpastatin Polymorphisms with Meat Tenderness in a Brahman-Angus Population. AB - Autogenous proteolytic enzymes of the calpain family are implicated in myofibrillar protein degradation. As a result, the MU-calpain gene and its specific inhibitor, calpastatin, have been repeatedly investigated for their association with meat quality traits in cattle; however, no functional mutation has been identified for these two genes. The objectives of this study were: (1) to assess breed composition effect on tenderness; (2) to perform a linkage disequilibrium (LD) analysis in MU-calpain and calpastatin genes as well as an association analyses with tenderness; and (3) to analyze putative functional SNPs inside the significant LD block for an effect on tenderness. Tenderness measurements and genotypes for 16 SNPs in MU-calpain gene and 28 SNPs in calpastatin gene from 673 steers were analyzed. A bioinformatic analysis identified "putative functional SNPs" inside the associated LD block - polymorphisms able to produce a physical and/or chemical change in the DNA, mRNA, or translated protein in silico. Breed composition had a significant (P < 0.0001) effect on tenderness where animals with more than 80% Angus composition had the most tender meat. One 11-kb LD-block and three LD-blocks of 37, 17, and 14 kb in length were identified in the MU-calpain and calpastatin genes, respectively. Out of these, the LD-block 3 in calpastatin, tagged by SNPs located at 7-98566391 and 7-98581038, had a significant effect on tenderness with the TG-CG diplotype being approximately 1 kg more tender than the toughest diplotype, TG-CG. A total of 768 SNPs in the LD-block 3 of calpastatin were included in the bioinformatic analysis, and 28 markers were selected as putative functional SNPs inside the LD block 3 of calpastatin; however, none of them were polymorphic in this population. Out of 15 initial polymorphisms segregating inside the LD-block 3 of calpastatin in this population, markers ARSUSMARC116, Cast5, rs730723459, and rs210861835 were found to be significantly associated with tenderness. PMID- 29520297 TI - Genomic Characterisation of the Indigenous Irish Kerry Cattle Breed. AB - Kerry cattle are an endangered landrace heritage breed of cultural importance to Ireland. In the present study we have used genome-wide SNP array data to evaluate genomic diversity within the Kerry population and between Kerry cattle and other European breeds. Patterns of genetic differentiation and gene flow among breeds using phylogenetic trees with ancestry graphs highlighted historical gene flow from the British Shorthorn breed into the ancestral population of modern Kerry cattle. Principal component analysis (PCA) and genetic clustering emphasised the genetic distinctiveness of Kerry cattle relative to comparator British and European cattle breeds. Modelling of genetic effective population size (Ne) revealed a demographic trend of diminishing Ne over time and that recent estimated Ne values for the Kerry breed may be less than the threshold for sustainable genetic conservation. In addition, analysis of genome-wide autozygosity (FROH) showed that genomic inbreeding has increased significantly during the 20 years between 1992 and 2012. Finally, signatures of selection revealed genomic regions subject to natural and artificial selection as Kerry cattle adapted to the climate, physical geography and agro-ecology of southwest Ireland. PMID- 29520299 TI - A BAYESIAN SPATIAL AND TEMPORAL MODELING APPROACH TO MAPPING GEOGRAPHIC VARIATION IN MORTALITY RATES FOR SUBNATIONAL AREAS WITH R-INLA. AB - Hierarchical Bayes models have been used in disease mapping to examine small scale geographic variation. State level geographic variation for less common causes of mortality outcomes have been reported however county level variation is rarely examined. Due to concerns about statistical reliability and confidentiality, county-level mortality rates based on fewer than 20 deaths are suppressed based on Division of Vital Statistics, National Center for Health Statistics (NCHS) statistical reliability criteria, precluding an examination of spatio-temporal variation in less common causes of mortality outcomes such as suicide rates (SRs) at the county level using direct estimates. Existing Bayesian spatio-temporal modeling strategies can be applied via Integrated Nested Laplace Approximation (INLA) in R to a large number of rare causes of mortality outcomes to enable examination of spatio-temporal variations on smaller geographic scales such as counties. This method allows examination of spatiotemporal variation across the entire U.S., even where the data are sparse. We used mortality data from 2005-2015 to explore spatiotemporal variation in SRs, as one particular application of the Bayesian spatio-temporal modeling strategy in R-INLA to predict year and county-specific SRs. Specifically, hierarchical Bayesian spatio temporal models were implemented with spatially structured and unstructured random effects, correlated time effects, time varying confounders and space-time interaction terms in the software R-INLA, borrowing strength across both counties and years to produce smoothed county level SRs. Model-based estimates of SRs were mapped to explore geographic variation. PMID- 29520301 TI - Teaching and learning guide for audiovisual speech perception: A new approach and implications for clinical populations. PMID- 29520302 TI - Widespread distribution of OH/H2O on the lunar surface inferred from spectral data. AB - Remote sensing data from lunar orbiters have revealed spectral features consistent with the presence of OH or H2O on the lunar surface. Analyses of data from the Moon Mineralogy Mapper spectrometer onboard the Chandryaan-1 spacecraft have suggested that OH/H2O is recycled on diurnal timescales and persists only at high latitudes. However, the spatial distribution and temporal variability of the OH/H2O, as well as its source, remain uncertain. Here we incorporate a physics based thermal correction into analysis of reflectance spectra from the Moon Mineralogy Mapper and find that prominent absorption features consistent with OH/H2O can be present at all latitudes, local times, and surface types examined. This suggests the widespread presence of OH/H2O on the lunar surface without significant diurnal migration. We suggest that the spectra are consistent with the production of OH in space weathered materials by the solar wind implantation of H+ and formation of OH at crystal defect sites, as opposed to H2O sourced from the lunar interior. Regardless of the specific composition or formation mechanism, we conclude that OH/H2O can be present on the Moon under thermal conditions more wide-ranging than previously recognized. PMID- 29520303 TI - The selective electrochemical fluorination of S-alkyl benzothioate and its derivatives. AB - We herein report that the regioselective anodic fluorination of S-alkyl benzothioate and its derivatives in various aprotic solvents using Et3N.nHF (n = 3-5) and Et4NF.nHF (n = 3-5) as supporting electrolyte and a fluorine source successfully provided the corresponding alpha-fluorinated products in moderate yields. Dichloromethane containing Et4NF.4HF was found to be the most suitable combination as electrolytic solvent and supporting salt as well as fluorine source for the anodic fluorination. The electrochemical fluorination of cyclic benzothioates such as benzothiophenone was also achieved. PMID- 29520300 TI - Audiovisual speech perception: A new approach and implications for clinical populations. AB - This selected overview of audiovisual (AV) speech perception examines the influence of visible articulatory information on what is heard. Thought to be a cross-cultural phenomenon that emerges early in typical language development, variables that influence AV speech perception include properties of the visual and the auditory signal, attentional demands, and individual differences. A brief review of the existing neurobiological evidence on how visual information influences heard speech indicates potential loci, timing, and facilitatory effects of AV over auditory only speech. The current literature on AV speech in certain clinical populations (individuals with an autism spectrum disorder, developmental language disorder, or hearing loss) reveals differences in processing that may inform interventions. Finally, a new method of assessing AV speech that does not require obvious cross-category mismatch or auditory noise was presented as a novel approach for investigators. PMID- 29520304 TI - Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries. AB - The preparation of protein libraries is a key issue in protein engineering and biotechnology. Such libraries can be prepared by a variety of methods, starting from the respective gene library. The challenge in gene library preparation is to achieve controlled total or partial randomization at any predefined number and position of codons of a given gene, in order to obtain a library with a maximum number of potentially successful candidates. This purpose is best achieved by the usage of trinucleotide synthons for codon-based gene synthesis. We here review the strategies for the preparation of fully protected trinucleotides, emphasizing more recent developments for their synthesis on solid phase and on soluble polymers, and their use as synthons in standard DNA synthesis. PMID- 29520305 TI - Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-alpha amanitin conjugates for tumor-targeting. AB - RGD-alpha-amanitin and isoDGR-alpha-amanitin conjugates were synthesized by joining integrin ligands to alpha-amanitin via various linkers and spacers. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the purified alphaVbeta3 receptor, retaining good binding affinity, in the same nanomolar range as the free ligands. The antiproliferative activity of the conjugates was evaluated in three cell lines possessing different levels of alphaVbeta3 integrin expression: human glioblastoma U87 (alphaVbeta3+), human lung carcinoma A549 (alphaVbeta3-) and breast adenocarcinoma MDA-MB-468 (alphaVbeta3-). In the U87, in the MDA-MB-468, and partly in the A549 cancer cell lines, the cyclo[DKP-isoDGR]-alpha-amanitin conjugates bearing the lysosomally cleavable Val-Ala linker were found to be slightly more potent than alpha amanitin. Apparently, for all these alpha-amanitin conjugates there is no correlation between the cytotoxicity and the expression of alphaVbeta3 integrin. To determine whether the increased cytotoxicity of the cyclo[DKP-isoDGR]-alpha amanitin conjugates is governed by an integrin-mediated binding and internalization process, competition experiments were carried out in which the conjugates were tested with U87 (alphaVbeta3+, alphaVbeta5+, alphaVbeta6-, alpha5beta1+) and MDA-MB-468 (alphaVbeta3-, alphaVbeta5+, alphaVbeta6+, alpha5beta1-) cells in the presence of excess cilengitide, with the aim of blocking integrins on the cell surface. Using the MDA-MB-468 cell line, a fivefold increase of the IC50 was observed for the conjugates in the presence of excess cilengitide, which is known to strongly bind not only alphaVbeta3, but also alphaVbeta5, alphaVbeta6, and alpha5beta1. These data indicate that in this case the cyclo[DKP-isoDGR]-alpha-amanitin conjugates are possibly internalized by a process mediated by integrins different from alphaVbeta3 (e.g., alphaVbeta5). PMID- 29520306 TI - Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines. AB - N-Glycan oxazolines have found widespread use as activated donor substrates for endo-beta-N-acetylglucosaminidase (ENGase) enzymes, an important application that has correspondingly stimulated interest in their production, both by total synthesis and by semi-synthesis using oligosaccharides isolated from natural sources. Amongst the many synthetic approaches reported, the majority rely on the fabrication (either by total synthesis, or semi-synthesis from locust bean gum) of a key Manbeta(1-4)GlcNAc disaccharide, which can then be elaborated at the 3- and 6-positions of the mannose unit using standard glycosylation chemistry. Early approaches subsequently relied on the Lewis acid catalysed conversion of peracetylated N-glycan oligosaccharides produced in this manner into their corresponding oxazolines, followed by global deprotection. However, a key breakthrough in the field has been the development by Shoda of 2-chloro-1,3 dimethylimidazolinium chloride (DMC), and related reagents, which can direct convert an oligosaccharide with a 2-acetamido sugar at the reducing terminus directly into the corresponding oxazoline in water. Therefore, oxazoline formation can now be achieved in water as the final step of any synthetic sequence, obviating the need for any further protecting group manipulations, and simplifying synthetic strategies. As an alternative to total synthesis, significant quantities of several structurally complicated N-glycans can be isolated from natural sources, such as egg yolks and soy bean flour. Enzymatic transformations of these materials, in concert with DMC-mediated oxazoline formation as a final step, allow access to a selection of N-glycan oxazoline structures both in larger quantities and in a more expedient fashion than is achievable by total synthesis. PMID- 29520307 TI - Palladium-catalyzed ortho-halogenations of acetanilides with N-halosuccinimides via direct sp2 C-H bond activation in ball mills. AB - A solvent-free palladium-catalyzed ortho-iodination of acetanilides using N iodosuccinimide as the iodine source has been developed under ball-milling conditions. This present method avoids the use of hazardous organic solvents, high reaction temperature, and long reaction time and provides a highly efficient methodology to realize the regioselective functionalization of acetanilides in yields up to 94% in a ball mill. Furthermore, the current methodology can be extended to the synthesis of ortho-brominated and ortho-chlorinated products in good yields by using the corresponding N-halosuccinimides. PMID- 29520308 TI - Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing. AB - Oligonucleotides (ONs) have been envisaged for therapeutic applications for more than thirty years. However, their broad use requires overcoming several hurdles such as instability in biological fluids, low cell penetration, limited tissue distribution, and off-target effects. With this aim, many chemical modifications have been introduced into ONs definitively as a means of modifying and better improving their properties as gene silencing agents and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug under different stimuli. The interest in stimuli responsive ONs for gene silencing functions has been notable in recent years. The ON prodrug strategies usually help to overcome limitations of natural ONs due to their low metabolic stability and poor delivery. Nevertheless, compared to permanent ON modifications, transient modifications in prodrugs offer the opportunity to regulate ON activity as a function of stimuli acting as switches. Generally, the ON prodrug is not active until it is triggered to release an unmodified ON. However, as it will be described in some examples, the opposite effect can be sought. This review examines ON modifications in response to various stimuli. These stimuli may be internal or external to the cell, chemical (glutathione), biochemical (enzymes), or physical (heat, light). For each stimulus, the discussion has been separated into sections corresponding to the site of the modification in the nucleotide: the internucleosidic phosphate, the nucleobase, the sugar or the extremities of ONs. Moreover, the review provides a current and detailed account of stimuli-responsive ONs with the main goal of gene silencing. However, for some stimuli-responsive ONs reported in this review, no application for controlling gene expression has been shown, but a certain potential in this field could be demonstrated. Additionally, other applications in different domains have been mentioned to extend the interest in such molecules. PMID- 29520309 TI - Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review. AB - Ursodeoxycholic acid (UDCA) is a pharmaceutical ingredient widely used in clinics. As bile acid it solubilizes cholesterol gallstones and improves the liver function in case of cholestatic diseases. UDCA can be obtained from cholic acid (CA), which is the most abundant and least expensive bile acid available. The now available chemical routes for the obtainment of UDCA yield about 30% of final product. For these syntheses several protection and deprotection steps requiring toxic and dangerous reagents have to be performed, leading to the production of a series of waste products. In many cases the cholic acid itself first needs to be prepared from its taurinated and glycilated derivatives in the bile, thus adding to the complexity and multitude of steps involved of the synthetic process. For these reasons, several studies have been performed towards the development of microbial transformations or chemoenzymatic procedures for the synthesis of UDCA starting from CA or chenodeoxycholic acid (CDCA). This promising approach led several research groups to focus their attention on the development of biotransformations with non-pathogenic, easy-to-manage microorganisms, and their enzymes. In particular, the enzymatic reactions involved are selective hydrolysis, epimerization of the hydroxy functions (by oxidation and subsequent reduction) and the specific hydroxylation and dehydroxylation of suitable positions in the steroid rings. In this minireview, we critically analyze the state of the art of the production of UDCA by several chemical, chemoenzymatic and enzymatic routes reported, highlighting the bottlenecks of each production step. Particular attention is placed on the precursors availability as well as the substrate loading in the process. Potential new routes and recent developments are discussed, in particular on the employment of flow-reactors. The latter technology allows to develop processes with shorter reaction times and lower costs for the chemical and enzymatic reactions involved. PMID- 29520310 TI - Carbohydrate inhibitors of cholera toxin. AB - Cholera is a diarrheal disease caused by a protein toxin released by Vibrio cholera in the host's intestine. The toxin enters intestinal epithelial cells after binding to specific carbohydrates on the cell surface. Over recent years, considerable effort has been invested in developing inhibitors of toxin adhesion that mimic the carbohydrate ligand, with particular emphasis on exploiting the multivalency of the toxin to enhance activity. In this review we introduce the structural features of the toxin that have guided the design of diverse inhibitors and summarise recent developments in the field. PMID- 29520312 TI - Continuous multistep synthesis of 2-(azidomethyl)oxazoles. AB - An efficient three-step protocol was developed to produce 2-(azidomethyl)oxazoles from vinyl azides in a continuous-flow process. The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl bromide to provide 2-(bromomethyl)oxazoles. The latter compounds are versatile building blocks for nucleophilic displacement reactions as demonstrated by their subsequent treatment with NaN3 in aqueous medium to give azido oxazoles in good selectivity. Process integration enabled the synthesis of this useful moiety in short overall residence times (7 to 9 min) and in good overall yields. PMID- 29520311 TI - Functionalization of N-arylglycine esters: electrocatalytic access to C-C bonds mediated by n-Bu4NI. AB - An efficient electrocatalytic functionalization of N-arylglycine esters is reported. The protocol proceeds in an undivided cell under constant current conditions employing the simple, cheap and readily available n-Bu4NI as the mediator. In addition, it is demonstrated that the mediated process is superior to the direct electrochemical functionalization. PMID- 29520313 TI - Statistical Methods in Organ Failure and Transplantation. PMID- 29520314 TI - Exploring transgender legal name change as a potential structural intervention for mitigating social determinants of health among transgender women of color. AB - The purpose of this exploratory study was to examine the effects of legal name change on socioeconomic factors, general and transgender-related healthcare access and utilization, and transgender-related victimization in a sample of young transgender women (transwomen) of color. A cross-sectional group comparison approach was used to assess the potential effects of legal name change. A convenience sample of young transwomen enrolled in a no-cost legal name change clinic were recruited to complete a 30-minute interviewer-guided telephone survey including sociodemographic and socioeconomic factors, health and well-being, health care utilization, transgender transition-related health care, and transgender-related victimization. Sixty-five transgender women of color (37 = pre-name change group; 28 = post-name change group) completed the survey. Results indicated that the transwomen in the post-name change group were significantly older than the pre-name change group. In age-adjusted analyses, the post-name change group was significantly more likely to have a higher monthly income and stable housing than the pre-name change group. No significant differences were observed for general healthcare utilization; however, a significantly greater percentage of transwomen in the pre-name change group reported postponing medical care due to their gender identity. In addition, a significantly larger proportion of transwomen in the pre-name change group reported using non-prescribed hormones injected by friends and experiencing verbal harassment by family and friends compared to transwomen in the post-name change group. Findings suggest that legal name change may be an important structural intervention for low-income transwomen of color, providing increased socioeconomic stability and improved access to primary and transition-related health care. PMID- 29520315 TI - Spatially Resolved Sensitivity of Single-Particle Plasmon Sensors. AB - The high sensitivity of localized surface plasmon resonance sensors to the local refractive index allows for the detection of single-molecule binding events. Though binding events of single objects can be detected by their induced plasmon shift, the broad distribution of observed shifts remains poorly understood. Here, we perform a single-particle study wherein single nanospheres bind to a gold nanorod, and relate the observed plasmon shift to the binding location using correlative microscopy. To achieve this we combine atomic force microscopy to determine the binding location, and single-particle spectroscopy to determine the corresponding plasmon shift. As expected, we find a larger plasmon shift for nanospheres binding at the tip of a rod compared to its sides, in good agreement with numerical calculations. However, we also find a broad distribution of shifts even for spheres that were bound at a similar location to the nanorod. Our correlative approach allows us to disentangle effects of nanoparticle dimensions and binding location, and by comparison to numerical calculations we find that the biggest contributor to this observed spread is the dispersion in nanosphere diameter. These experiments provide insight into the spatial sensitivity and signal-heterogeneity of single-particle plasmon sensors and provides a framework for signal interpretation in sensing applications. PMID- 29520316 TI - Blood Perfusion in a Full-Thickness Eyelid Flap, Investigated by Laser Doppler Velocimetry, Laser Speckle Contrast Imaging, and Thermography. AB - Purpose: The eyelid is commonly dissected and divided in the process of, for example, blepharotomy, entropion repair, or when preparing a full-thickness eyelid flap to reconstruct a tumor defect. No study has yet been conducted to examine how perfusion in an eyelid is affected by dissection, using modern imaging techniques. Methods: The eyelid was divided with a 10-mm vertical incision, 5 mm from the medial canthus, and the incision was extended horizontally by 30 mm to provide a full-thickness eyelid. Blood perfusion was measured along the length of the free dissected eyelid using both laser Doppler velocimetry and laser speckle contrast imaging. Tissue temperature was visualized using a high-resolution infrared camera (thermography). Results: Measurements using laser speckle contrast imaging showed that blood flow decreased gradually from the pedicel base to the tip of the free dissected eyelid: 83% at 10 mm, stabilizing at 80% at 20 mm from the pedicel base. These results were supported by laser Doppler velocimetry, showing a reduction in perfusion to 67%, 15 mm from the pedicel base. Thermographic imaging showed a corresponding decrease in temperature from the tip to the pedicel base compared with nondissected eyelids. Conclusions: Dissection of an eyelid, to provide a full-thickness eyelid flap, results in only a slight decrease in blood flow. The results support the view that plastic surgery of the eyelids is permissive, and the rich vascularization of the eyelid due to the anastomotic network of vessels in the tarsal plate may increase the likelihood of flap survival and surgical success. PMID- 29520317 TI - Levamisole-Induced Vasculitis. PMID- 29520318 TI - Cholesterol enhances influenza binding avidity by controlling nanoscale receptor clustering. AB - Influenza virus infects cells by binding to sialylated glycans on the cell surface. While the chemical structure of these glycans determines hemagglutinin glycan binding affinity, bimolecular affinities are weak, so binding is avidity dominated and driven by multivalent interactions. Here, we show that membrane spatial organization can control viral binding. Using single-virus fluorescence microscopy, we demonstrate that the sterol composition of the target membrane enhances viral binding avidity in a dose-dependent manner. Binding shows a cooperative dependence on concentration of receptors for influenza virus, as would be expected for a multivalent interaction. Surprisingly, the ability of sterols to promote viral binding is independent of their ability to support liquid-liquid phase separation in model systems. We develop a molecular explanation for this observation via molecular dynamics simulations, where we find that cholesterol promotes small-scale clusters of glycosphingolipid receptors. We propose a model whereby cholesterol orders the monomeric state of glycosphingolipid receptors, reducing the entropic penalty of receptor association and thus favoring multimeric complexes without phase separation. This model explains how cholesterol and other sterols control the spatial organization of membrane receptors for influenza and increase viral binding avidity. A natural consequence of this finding is that local cholesterol concentration in the plasma membrane of cells may alter the binding avidity of influenza virions. Furthermore, our results demonstrate a form of cholesterol-dependent membrane organization that does not involve lipid rafts, suggesting that cholesterol's effect on cell membrane heterogeneity is likely the interplay of several different factors. PMID- 29511529 TI - In silico analysis of single nucleotide polymorphisms (SNPs) in human FOXC2 gene. AB - Introduction: Lymphedema is an abnormal accumulation of interstitial fluid, due to inefficient uptake and reduced flow, leading to swelling and disability, mostly in the extremities. Hereditary lymphedema usually occurs as an autosomal dominant trait with allelic heterogeneity. Methods: We identified single nucleotide polymorphisms (SNPs) in the FOXC2 gene using dbSNP, analyzed their effect on the resulting protein using VEP and Biomart, modelled the resulting protein using Project HOPE, identified gene - gene interactions using GeneMANIA and predicted miRNAs affected and the resulting effects of SNPs in the 5' and 3' regions using PolymiRTS. Results: We identified 473 SNPs - 429 were nsSNPs and 44 SNPs were in the 5' and 3' UTRs. In total, 2 SNPs - rs121909106 and rs121909107 - have deleterious effects on the resulting protein, and a 3D model confirmed those effects. The gene - gene interaction network showed the involvement of FOXC2 protein in the development of the lymphatic system. hsa-miR-6886-5p, hsa-miRS 6886-5p, hsa-miR-6720-3p, which were affected by the SNPs rs201118690, rs6413505, rs201914560, respectively, were the most important miRNAs affected, due to their high conservation score. Conclusions: rs121909106 and rs121909107 were predicted to have the most harmful effects, while hsa-miR-6886-5p, hsa-miR-6886-5p and hsa miR-6720-3p were predicted to be the most important miRNAs affected. Computational biology tools have advantages and disadvantages, and the results they provide are predictions that require confirmation using methods such as functional studies. PMID- 28928948 TI - Virtual-screening workflow tutorials and prospective results from the Teach Discover-Treat competition 2014 against malaria. AB - The first challenge in the 2014 competition launched by the Teach-Discover-Treat (TDT) initiative asked for the development of a tutorial for ligand-based virtual screening, based on data from a primary phenotypic high-throughput screen (HTS) against malaria. The resulting Workflows were applied to select compounds from a commercial database, and a subset of those were purchased and tested experimentally for anti-malaria activity. Here, we present the two most successful Workflows, both using machine-learning approaches, and report the results for the 114 compounds tested in the follow-up screen. Excluding the two known anti-malarials quinidine and amodiaquine and 31 compounds already present in the primary HTS, a high hit rate of 57% was found. PMID- 29333250 TI - Retract p < 0.005 and propose using JASP, instead. AB - Seeking to address the lack of research reproducibility in science, including psychology and the life sciences, a pragmatic solution has been raised recently: to use a stricter p < 0.005 standard for statistical significance when claiming evidence of new discoveries. Notwithstanding its potential impact, the proposal has motivated a large mass of authors to dispute it from different philosophical and methodological angles. This article reflects on the original argument and the consequent counterarguments, and concludes with a simpler and better-suited alternative that the authors of the proposal knew about and, perhaps, should have made from their Jeffresian perspective: to use a Bayes factors analysis in parallel (e.g., via JASP) in order to learn more about frequentist error statistics and about Bayesian prior and posterior beliefs without having to mix inconsistent research philosophies. PMID- 29511530 TI - Two center experience of capsule endoscopy in Iran: Report on 101 cases. AB - Background: Capsule endoscopy (CE) is a minimally invasive method for the visual examination of the small intestine, which may be for the evaluation and follow-up of patients with Crohn's disease. It can also be used to look at mucosal inflammation. Methods: This cross sectional study was used to determine the diagnostic efficacy of the CE system by performing a cross-sectional study of cases from 2011-2014. This study involved a total of 101 Iranian patients who were referred to the gastrointestinal and liver diseases outpatient clinics in Guilan (northern Iran) and in Isfahan (central Iran) for complaints of gastrointestinal problems. For all patients, definitive diagnosis had failed with the use of other diagnostic tools and CE was performed. Descriptive analysis was used. The patient population was represented by men and women equally, and the mean age of the patients was 42.3 +/- 17.2 years (range: 16-89 years). Results: The final diagnoses were: non-specific enteritis (30.6%), Crohn's disease (20.7%), ulcers caused by aspirin or non-steroidal anti-inflammatory drugs (8.9%), mucosal erosion (5.9%) and angioectasia (4.9%); nearly 10% of the patients had normal findings. Analysis of the distribution of chief presenting complaints with patients stratified by the final diagnosis of Crohn's disease showed that the most frequently presented chief complaint was abdominal pain 42.9% and the least frequently presented chief complaint was diarrhea (4.8%). Conclusions: Small bowel evaluation by CE was well tolerated and capable of diagnosing Crohn's disease and gastrointestinal bleeding in patients who failed other diagnostic tests. PMID- 29511531 TI - netSmooth: Network-smoothing based imputation for single cell RNA-seq. AB - Single cell RNA-seq (scRNA-seq) experiments suffer from a range of characteristic technical biases, such as dropouts (zero or near zero counts) and high variance. Current analysis methods rely on imputing missing values by various means of local averaging or regression, often amplifying biases inherent in the data. We present netSmooth, a network-diffusion based method that uses priors for the covariance structure of gene expression profiles on scRNA-seq experiments in order to smooth expression values. We demonstrate that netSmooth improves clustering results of scRNA-seq experiments from distinct cell populations, time course experiments, and cancer genomics. We provide an R package for our method, available at: https://github.com/BIMSBbioinfo/netSmooth. PMID- 29479425 TI - Positive Mental Health from the perspective of Iranian society: A qualitative study. AB - Background: According to the World Health Organization, mental health relates, not only to the absence of mental disorder, but also to Positive Mental Health. Studies have shown that promoting positive mental health, not only reduces the prevalence and incidence of mental disorders, but also affects the process of treatment and reduces related burden. However, this concept has different interpretations in different cultures, and in many societies, mental health is still considered the absence of mental illness. Thus, the present study was conducted to provide an in-depth understanding of Iranian adults' perspective towards the concept of positive mental health. Materials and Methods: In the present qualitative study, eight focus group discussions (6 to 8 adults in each session) were held consisting of 30 to 60 year-old men and women from Tehran. Data were analyzed in "DeDoose" qualitative software using content analysis. Results: According to the data obtained, participants found no difference between positive mental health and mental health, mostly equating it to the absence of mental disorders and having positive energy, peace in and satisfaction with life. According to the results, positive mental health has four domains of emotional/psychological, spiritual, social, and life skills. Conclusion: Understanding an individual's positive mental health concepts culturally and providing appropriate community based programs can significantly promote the mental health of the community. PMID- 29520325 TI - Olfactory and Imaging Features in Atypical Alzheimer's Disease. AB - Objectives: Cognition and speech disorders are the most common symptoms of dementia in neurodegenerative disease. Here, we present a detailed clinical evaluation of a case of logopenic variant of primary progressive aphasia (lv PPA), an atypical form of Alzheimer disease (AD), including cognitive testing over time, brain imaging, electrophysiology, and tests of olfactory function. Case report: We present the case of a 58-year-old man suffering from progressive language difficulties who was finally diagnosed with lv-PPA. Clinical data included neuropsychological examinations, electrophysiology tests, neuroimaging, biomarkers, olfactory tests, and olfactory functional magnetic resonance imaging (fMRI). Results and Discussion: The patient suffered from language disorders, including stumbling speech and forgetting appropriate words and how to pronounce some words. This had started 2 years earlier, and he had begun to deteriorate in recent months. In addition to his speech disorder, scores on the Mini Mental State Examination and Montreal cognitive assessment indicated that his cognition was affected. Structural imaging revealed no obvious hippocampal atrophy (score of 1), and molecular imaging showed hypometabolism and amyloid deposits in the temporal parietal region. The patient also presented with olfactory impairment. Although his odour detection threshold was normal, his cognitive threshold for scent recognition was significantly increased. Olfactory fMRI showed that activation of the whole brain and primary olfactory cortex was rare. Conclusion: This case provides evidence suggesting that lv-PPA is an atypical form of AD, with symptoms including speech disorders and impaired cognition. This patient with lv-PPA presented with olfactory impairment. PMID- 29520326 TI - Enantio- and Diastereoselective Synthesis of Hydroxy Bis(boronates) via Cu Catalyzed Tandem Borylation/1,2-Addition. AB - Catalytic enantioselective synthesis of 1-hydroxy-2,3-bisboronate esters through multicomponent borylation/1,2-addition is reported. Catalyst and substrates are readily available, form both a C-B and C-C bond, and generate up to three contiguous stereocenters. The reaction is tolerant of aryl, vinyl, and alkyl aldehydes and ketones in up to 95% yield, >20:1 dr, and 99:1 er. Intramolecular additions to aldehydes and ketones result in stereodivergent processes. The hydroxy bis(boronate) ester products are amenable to site-selective chemical elaboration. PMID- 29520327 TI - Re-fracture of Distal Radius and Hardware Repair in the Setting of Trauma. AB - Distal radius fractures are one of the most common fractures in the elderly. Falls and motor vehicle collisions lead to increased risk for this type of fracture. A seventy-three year-old female had a previous history of distal radius fracture with repair by open reduction and internal fixation. She was involved in a motor vehicle collision that re-fractured the distal radius. The plate was bent and required removal, which is a very rare but potentially serious complication. Surgery was done to fix the open reduction and internal fixation with volar locking plates while removing damaged hardware. Only a select few cases have reported hardware failure as a cause of complications. Among those cases, high energy activities and maintained stress on the hardware were likely causes. Distal radius fractures are the most common upper extremity fracture in the elderly. We highlight a unique case of re-fracture in the setting of trauma with prior hardware failure and describe the strategy for hardware repair. PMID- 29520328 TI - Influence of Iron Deficiency on Olfactory Behavior in Weanling Rats. AB - Chronically high occupational exposure to airborne metals like iron can impair olfactory function, but little is known about how low iron status modifies olfactory behavior. To investigate the influence of body iron status, weanling rats were fed a diet with low iron content (4 - 7 ppm) to induce iron deficiency anemia and olfactory behavior was compared to control rats fed an isocaloric diet sufficient in iron (210 - 220 ppm). Iron-deficient rats had prolonged exploratory time for attractive odorants in behavioral olfactory habituation/dis-habituation tests, olfactory preference tests and olfactory sensitivity tests compared with control rats. No significant differences were observed for aversive odorants between the two groups. These findings suggest that iron-dependent functions may be involved in controlling and processing of olfactory signal transduction via self and lateral inhibition such that odorant signal remains stronger for longer times prolonging exploratory activity on attractive odorants in the behavioral tests. These findings establish that iron deficiency can modify olfactory behavior. PMID- 29520329 TI - Probable REM-Sleep Behavior Disorder and Dysautonomic Symptoms in Essential Tremor. AB - Background: Non-motor symptoms can be present in essential tremor (ET). We intend to assess the frequency of rapid eye movement (REM) sleep behavior disorder (RBD) and dysautonomic symptoms in ET patients and evaluate the differences between patients with ET and RBD (ET-RBD and ET without RBD [ET-nonRBD]). Methods: All ET patients were contacted by telephone. Autonomic symptoms were assessed using the Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) questionnaire, and RBD symptoms with the RBD screening questionnaire (RBDSQ) using >=5 as a cut off for probable RBD (pRBD). Results: From 92 ET patients contacted, 53 (55% female) were included. The mean age at assessment was 73.6+/-19 years, and the average disease duration was 19.9+/-17.3 years. Fourteen patients (26.4%) had pRBD and 52 (98.1%) reported at least one autonomic symptom, the most prevalent being urinary symptoms (96%). The ET-RBD group had higher SCOPA-total and thermoregulatory scores than ET-nonRBD patients (13.9+/-9.6 vs. 7.7+/-5.1, p=0.017 and 2.5+/-2.0 vs. 0.9+/-1.6, p=0.001). There were no other differences between groups. Discussion: Our results suggest that pRBD is common in ET, and its presence is associated with dysautonomic symptoms. As these symptoms are known to be prodromal symptoms of Parkinson's disease (PD), we question if this patient subgroup has a higher risk of developing a synucleinopathy. PMID- 29520332 TI - RF Interference in Hearing Aids from Cellphones Part 1: Near-field cellphone emissions measurements and the effects of hands. AB - Cellular telephones (cellphones) are currently categorized for hearing aid compatibility based on a calculated value (metric) obtained from the measurement of near-field, radio-frequency emissions according to a procedure described in ANSI Standard C63.19 "Measurement of Compatibility between Wireless Communications Devices and Hearing Aids". There has been a lack of documentation, however, that relates this metric to a cellphone's potential for interference in actual use, that is, when it is held at the ear in a normal-use position by a hearing aid wearer. In Part 1 of this two-part series, we compare the ANSI C63.19 metric to simpler metrics, still based on the near-field test procedure of the standard, and to near-field measurements made when the cellphones are hand-held. The results justify employing a simpler no-hand metric than the exclusion area procedure presently specified by the standard, but not the addition of a test hand to the procedure. The further effect of the head and interaction with the hearing aid is examined in Part 2 of the series. PMID- 29520331 TI - Reversal of Status Dystonicus after Relocation of Pallidal Electrodes in DYT6 Generalized Dystonia. AB - Background: DYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available. Case Report: A pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved. Discussion: This case study demonstrates that medication resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS. PMID- 29520330 TI - Advances in Treatment of Wilson Disease. AB - Background: Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults. Without treatment the disease is invariably fatal. Though treatments for WD have been available since the 1950s, the disease continues to be associated with considerable morbidity and mortality because of missed diagnosis, and delayed or inadequate treatment. In this paper we survey WD related literature in order to review recent advances in WD treatment. Methods: We performed a literature search using the PubMed database for articles relating to WD and its medical treatment. We reviewed the articles, and cross-references of relevant articles, to summarize the current practices for treatment of WD. Results: The survey shows that if WD is properly treated, in most patients the liver can be stabilized, even severe neurological disability reversed, and patients can resume normal lives. Discussion: Medical treatment for WD includes use of copper chelators (penicillamine, trientine, dimercaprol, dimercaptopropane sulfonate, and ammonium tetrathiomolybdate) and drugs that decrease gastrointestinal copper absorption. Our knowledge of the treatment approaches has benefited from the large systematic clinical studies that have been conducted over the last decade. For each drug used to treat WD, we surveyed its development, indication for use, dosing, efficacy, and adverse effects. PMID- 29520333 TI - How Many Subjects are Needed for a Visual Field Normative Database? A Comparison of Ground Truth and Bootstrapped Statistics. AB - Purpose: The number of subjects needed to establish the normative limits for visual field (VF) testing is not known. Using bootstrap resampling, we determined whether the ground truth mean, distribution limits, and standard deviation (SD) could be approximated using different set size (x) levels, in order to provide guidance for the number of healthy subjects required to obtain robust VF normative data. Methods: We analyzed the 500 Humphrey Field Analyzer (HFA) SITA Standard results of 116 healthy subjects and 100 HFA full threshold results of 100 psychophysically experienced healthy subjects. These VFs were resampled (bootstrapped) to determine mean sensitivity, distribution limits (5th and 95th percentiles), and SD for different 'x' and numbers of resamples. We also used the VF results of 122 glaucoma patients to determine the performance of ground truth and bootstrapped results in identifying and quantifying VF defects. Results: An x of 150 (for SITA-Standard) and 60 (for full threshold) produced bootstrapped descriptive statistics that were no longer different to the original distribution limits and SD. Removing outliers produced similar results. Differences between original and bootstrapped limits in detecting glaucomatous defects were minimized at x = 250. Conclusions: Ground truth statistics of VF sensitivities could be approximated using set sizes that are significantly smaller than the original cohort. Outlier removal facilitates the use of Gaussian statistics and does not significantly affect the distribution limits. Translational Relevance: We provide guidance for choosing the cohort size for different levels of error when performing normative comparisons with glaucoma patients. PMID- 29520334 TI - A Tablet-Based Retinal Function Test in Neovascular Age-Related Macular Degeneration Eyes and At-Risk Fellow Eye. AB - Purpose: To determine the feasibility of a tablet-based application to detect changes in retinal sensitivity and correlations with underlying pathology in neovascular age-related macular degeneration (nAMD) eyes undergoing treatment and in at-risk fellow eyes. Method: Participants with nAMD in at least one eye were recruited, examined, and imaged using spectral-domain optical coherence tomography (SD-OCT). Retinal sensitivity was measured within the central 5 degrees at 12 locations using a customized test delivered on an iPad. Test points were superimposed on SD-OCT locations to investigate structure/function relationships. Results: Included in the study were 53 nAMD eyes and 21 at-risk fellow eyes. In nAMD eyes, the mean retinal sensitivity was 24.1 +/- 1.8 dB with reduced retinal sensitivity associated with the presence of atrophy (P < 0.01), retinal pigment epithelium (RPE) disruption (P < 0.01), and absent ellipsoid zone (EZ) (P < 0.01), but not with the presence of subretinal fluid (P = 0.94) nor intraretinal fluid (P = 0.52). In at-risk eyes, the average retinal sensitivity was 28.8 +/- 0.6 dB, with reduced sensitivity significantly associated with the presence of drusen, atrophy, RPE disruption, and absent EZ (P < 0.01). Conclusion: The tablet-based test of retinal sensitivity was able to be performed by an elderly cohort with nAMD. The ability to correlate differences in sensitivity with pathology is encouraging when considering using the tablet devices as a home monitoring tool with remote surveillance. Dual pathology often present with retinal fluid confounded our ability to correlate fluid with sensitivity. Translational Relevance: These findings highlight the potential of tablet-based devices in performing visual function measures as a home monitoring tool with remote surveillance for the earlier detection of nAMD. PMID- 29520335 TI - The mechanistic implications of gene expression studies in SSc: Insights from Systems Biology. PMID- 29520336 TI - No-cost gym visits are associated with lower weight and blood pressure among non Latino black and Latino participants with a diagnosis of hypertension in a multi site demonstration project. AB - Well documented, persistent racial/ethnic health disparities in obesity and hypertension in the US demonstrate the continued need for interventions that focus on people of color who may be at higher risk. We evaluated a demonstration project funded by the CDC's Racial/Ethnic Approaches to Community Health (REACH) program at four federally qualified health centers (FQHC) and YMCA fitness and wellness centers in Boston. No-cost YMCA memberships were offered from June 2014 to June 2015 to non-Latino black and Latino adults with a diagnosis of hypertension. YMCA visit data were merged with health data for 224 participants (n = 1265 health center visits). We assessed associations between gym visit frequency and weight, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) using longitudinal time-varying linear fixed effects models. The total number of gym visits over the entire program duration was 5.5, while the conditional total number of visits (after the first gym visit has been made) was 17.3. Having visited the gym at least 10 times before an FQHC exam was, on average, associated with lower weight (1.19 kg, p = 0.01), lower BMI (0.43 kg/m2, p = 0.01) and reductions in SBP (-3.20 mm Hg, p = 0.01) and DBP ( 2.06 mm Hg p = 0.01). Having visited the gym an average of 1.4 times per month (study average) was associated with reductions in weight, BMI, and DBP. No-cost gym visits were associated with improved weight and blood pressure in hypertensive non-Latino black and Latino adults in this program. Additional evaluation is necessary to assess the sustainability of these effects. PMID- 29520337 TI - Long non-coding RNA ANRIL is associated with a poor prognosis of osteosarcoma and promotes tumorigenesis via PI3K/Akt pathway. AB - Aim: Increasing evidence has shown that long noncoding RNAs (lncRNAs) ANRIL may function as oncogenes in various types of malignancies. However, there is still a lack of knowledge concerning its role in osteosarcoma (OS). In this study, we aimed to investigate the influence of ANRIL on cell proliferation and invasion of OS and to determine its association with clinicopathological features of the patients. Methods: The tumor specimens and the adjacent normal tissues were collected from 57 OS patients and the expression level of ANRIL was quantified by RT-qPCR. High expression of ANRIL was defined as a relative mRNA expression of > 1.5 fold (tumor/normal). Knockdown of ANRIL was performed in human OS cell lines to investigate its influence on cell proliferation, apoptosis and invasion. In addition, expression of downstream genes in the transfected cells were determined by Western blot. Results: The expression level of ANRIL was significantly increased in OS tissues than in the adjacent normal tissues. 33 patients were included in the high expression group and the other 24 patients were included in the normal expression group. ANRIL expression was significantly associated with tumor size (5.7 cm +/- 2.4 cm vs. 4.3 cm +/- 1.7 cm, p = 0.02) and the 5-year survival rate (51.5% vs. 79.1%, p = 0.03). Knockdown of ANRIL could significantly induce cell apoptosis and inhibit cell proliferation and invasion. Moreover, knockdown of ANRIL could significantly decrease the expression level of phosphorylated PI3K and AKT in OS cells. Conclusions: Upregulated expression of ANRIL is associated with the tumor development and prognosis of OS. ANRIL may regulate the function of OS cells through the AKT pathway. PMID- 29520338 TI - Gynecologic oncologists involvement on ovarian cancer standard of care receipt and survival. AB - AIM: To examine the influence of gynecologic oncologists (GO) in the United States on surgical/chemotherapeutic standard of care (SOC), and how this translates into improved survival among women with ovarian cancer (OC). METHODS: Surveillance, Epidemiology, and End Result (SEER)-Medicare data were used to identify 11688 OC patients (1992-2006). Only Medicare recipients with an initial surgical procedure code (n = 6714) were included. Physician specialty was identified by linking SEER-Medicare to the American Medical Association Masterfile. SOC was defined by a panel of GOs. Multivariate logistic regression was used to determine predictors of receiving surgical/chemotherapeutic SOC and proportional hazards modeling to estimate the effect of SOC treatment and physician specialty on survival. RESULTS: About 34% received surgery from a GO and 25% received the overall SOC. One-third of women had a GO involved sometime during their care. Women receiving surgery from a GO vs non-GO had 2.35 times the odds of receiving the surgical SOC and 1.25 times the odds of receiving chemotherapeutic SOC (P < 0.01). Risk of mortality was greater among women not receiving surgical SOC compared to those who did [hazard ratio = 1.22 (95%CI: 1.12-1.33), P < 0.01], and also was higher among women seen by non-GOs vs GOs (for surgical treatment) after adjusting for covariates. Median survival time was 14 mo longer for women receiving combined SOC. CONCLUSION: A survival advantage associated with receiving surgical SOC and overall treatment by a GO is supported. Persistent survival differences, particularly among those not receiving the SOC, require further investigation. PMID- 29520339 TI - Targeted Therapy and Immunotherapy Response Assessment with F-18 Fluorothymidine Positron-Emission Tomography/Magnetic Resonance Imaging in Melanoma Brain Metastasis: A Pilot Study. AB - Introduction: This pilot study aimed at exploring the utility of the proliferation tracer F-18 fluorothymidine (FLT) and positron-emission tomography (PET)/magnetic resonance imaging (MRI) (FLT-PET/MRI) for early treatment monitoring in patients with melanoma brain metastasis (MBM) who undergo targeted therapy or immunotherapy. Material and Methods: Patients with newly diagnosed MBM underwent baseline and follow-up FLT-PET/MRI scans at 3-4 weeks of targeted therapy or immunotherapy. Up to six measurable brain lesions >=1.0 cm per subject, as identified on T1-weighted post-gadolinium images, were included for quantitative analyses. The maximum SUV of each lesion was divided by the mean SUV of the pons to obtain the SUV ratio (SUVR). Results: Five enrolled subjects underwent the baseline FLT-PET/MRI study in which the MBM showed a median size of 1.7 cm (range 1.0-2.9) and increased metabolic activity with SUVR of 9.9 (range 3.2-18.4). However, only two subjects (cases #1 and #2) returned for a follow-up scan. At baseline, a total of 22 lesions were analyzed in all five subjects, which showed a median size of 1.7 cm (range 1.0-2.9) and median SUVR of 9.9 (range 3.2-18.4). At follow-up, case #1 was a 55-year-old man who received targeted BRAF inhibitor and MEK inhibitor therapy with dabrafenib and trametinib. Fused PET/MRI data of six measured lesions demonstrated a significant reduction in MBM proliferative activity (median -68%; range -38 to -77%) and size (median 23%; range -4 to -55%) at three weeks of therapy. Nevertheless, the subject eventually progressed and died 13 months after therapy initiation. Case #2 was a 36-year-old man who received immunotherapy with nivolumab and ipilimumab. The five measured MBM lesions showed a mixed response at both proliferative and morphologic imaging at 1-month follow-up. Some lesions demonstrated interval decrease while others interval increase in proliferative activity with a median 44% (range -77 to +68%). On MRI, the size change was +7% (range -64 to +50%). The therapy was switched to dabrafenib and trametinib, which led to a partial response. The patient is still alive 16 months following therapy initiation. Conclusion: The five cases presented show the potential benefit of hybrid FLT PET/MRI for the diagnosis of MBM and treatment monitoring of targeted therapy and immunotherapy. However, further studies are required to assess their complementary role in distinguishing true progression from pseudoprogression. PMID- 29520341 TI - Influence of Novel Highly Pathogenic Avian Influenza A (H5N1) Virus Infection on Migrating Whooper Swans Fecal Microbiota. AB - The migration of wild birds plays an important role in the transmission and spread of H5 highly pathogenic avian influenza (HPAI) virus, posing a severe risk to animal and human health. Substantial evidence suggests that altered gut microbial community is implicated in the infection of respiratory influenza virus. However, the influence of H5N1 infection in gut microbiota of migratory birds remains unknown. In January 2015, a novel recombinant H5N1 virus emerged and killed about 100 migratory birds, mainly including whooper swans in Sanmenxia Reservoir Area of China. Here, we describe the first fecal microbiome diversity study of H5N1-infected migratory birds. By investigating the influence of H5N1 infection on fecal bacterial communities in infected and uninfected individuals, we found that H5N1 infection shaped the gut microbiota composition by a difference in the dominance of some genera, such as Aeromonas and Lactobacillus. We also found a decreased alpha diversity and increased beta diversity in infectious individuals. Our results highlight that increases in changes in pathogen-containing gut communities occur when individuals become infected with H5N1. Our study may provide the first evidence that there are statistical association among H5N1 presence and fecal microbiota compositional shifts, and properties of the fecal microbiota may serve as the risk of gut-linked disease in migrates with H5N1 and further aggravate the disease transmission. PMID- 29520340 TI - Molecular Mechanisms and Emerging Therapeutic Targets of Triple-Negative Breast Cancer Metastasis. AB - Breast cancer represents a highly heterogeneous disease comprised by several subtypes with distinct histological features, underlying molecular etiology and clinical behaviors. It is widely accepted that triple-negative breast cancer (TNBC) is one of the most aggressive subtypes, often associated with poor patient outcome due to the development of metastases in secondary organs, such as the lungs, brain, and bone. The molecular complexity of the metastatic process in combination with the lack of effective targeted therapies for TNBC metastasis have fostered significant research efforts during the past few years to identify molecular "drivers" of this lethal cascade. In this review, the most current and important findings on TNBC metastasis, as well as its closely associated basal like subtype, including metastasis-promoting or suppressor genes and aberrantly regulated signaling pathways at specific stages of the metastatic cascade are being discussed. Finally, the most promising therapeutic approaches and novel strategies emerging from these molecular targets that could potentially be clinically applied in the near future are being highlighted. PMID- 29520342 TI - Control of hmu Heme Uptake Genes in Yersinia pseudotuberculosis in Response to Iron Sources. AB - Despite the mammalian host actively sequestering iron to limit pathogenicity, heme (or hemin when oxidized) and hemoproteins serve as important sources of iron for many bloodborne pathogens. The HmuRSTUV hemin uptake system allows Yersinia species to uptake and utilize hemin and hemoproteins as iron sources. HmuR is a TonB-dependent outer membrane receptor for hemin and hemoproteins. HmuTUV comprise a inner membrane ABC transporter that transports hemin and hemoproteins from the periplasmic space into the bacterial cytoplasm, where it is degraded by HmuS. Here we show that hmuSTUV but not hmuR are expressed under iron replete conditions, whereas hmuR as well as hmuSTUV are expressed under iron limiting conditions, suggesting complex transcriptional control. Indeed, expression of hmuSTUV in the presence of inorganic iron, but not in the presence of hemin, requires the global regulator IscR acting from a promoter in the intergenic region between hmuR and hmuS. This effect of IscR appears to be direct by binding a site mapped by DNaseI footprinting. In contrast, expression of hmuR under iron limiting conditions requires derepression of the ferric uptake regulator Fur acting from the hmuR promoter, as Fur binding upstream of hmuR was demonstrated biochemically. Differential expression by both Fur and IscR would facilitate maximal hemin uptake and utilization when iron and heme availability is low while maintaining the capacity for periplasmic removal and cytosolic detoxification of heme under a wider variety of conditions. We also demonstrate that a Y. pseudotuberculosis DeltaiscR mutant has a survival defect when incubated in whole blood, in which iron is sequestered by heme-containing proteins. Surprisingly, this phenotype was independent of the Hmu system, the type III secretion system, complement, and the ability of Yersinia to replicate intracellularly. These results suggest that IscR regulates multiple virulence factors important for Yersinia survival and growth in mammalian tissues and reveal a surprising complexity of heme uptake expression and function under differing conditions of iron. PMID- 29520343 TI - Efficacy of loco-regional treatment for hepatocellular carcinoma prior to living donor liver transplantation: a report from a single center in Egypt. AB - Background and aim: The number of loco-regional therapies (LRTs) for hepatocellular carcinoma (HCC) has increased dramatically during the past decade, bridging or downstaging patients on the waiting list for liver transplantation. This study aimed to analyze the outcomes of LRTs prior to living donor liver transplantation in patients with HCC. Methods: Sixty-two HCC patients received living donor liver transplantation at Ain Shams Center for Organ Transplantation over a 2-year period. Data from 29 HCC patients were analyzed. Twenty patients (68.97%) met the Milan Criteria and 4 patients (13.8%) exceeded the Milan Criteria, but met the University of California, San Francisco Criteria. Five patients (17.2%) exceeded the University of California, San Francisco Criteria. All patients underwent preoperative LRTs. The protocol of bridging/downstaging, methods, duration of follow-up, the number of patients who were successfully downstaged before liver transplantation (LT), and their outcomes after LT were recorded. Results: There was a decrease in the mean overall size of focal lesions (from mean 5.46 to 4.11 cm) in the last abdominal computed tomography (CT) scan after LRT (p=0.0018). Discrepancies between the radiological findings and histopathology were as follows: in 16 patients (55.17%) the CT findings were consistent with the histopathological examination of the explanted liver. Underestimated tumor stage was documented in 10 patients (34.48%), and was overestimated by CT scan findings in 3 patients (10.34%). The 1-year survival rate was 93%. No patient had HCC recurrence after median follow-up of 21 months (range 1-46 months). Conclusion: These results encouraged tumor bridging/downstaging as a potential treatment option among carefully selected patients with HCC beyond conventional criteria for LT. Further studies on a large number of patients are necessary. PMID- 29520344 TI - Analysis of lawsuit cases in the Department of Surgery in Korea. AB - Purpose: The aim of this study is to prepare medical staff in order to prevent medical malpractice litigation through analysis of litigation cases related to the department of surgery in Korea. Methods: A total of 94 litigation cases related to the department of surgery, where a certain amount of payment was ordered to the defendant between 2005 through 2010, were analyzed. We examined time of occurrence, amount claimed and awarded in damages, plaintiff claims, and court opinion. Results: An average of 3.2 years was spent from the date of the incident occurring to the end of the litigation procedures. The average amount awarded in judgments for damages was 59,708,983 +/- 67,307,264 (range, 1,700,000 365,201,482) Korean won. Cases were found involving the following opinion of the court: violation of duty of care (49 cases), violation of informed consent (7 cases), violation of duty of care and informed consent (5 cases), and settlement, reconciliation, and others (32 cases). By analyzing defendants' negligence in court opinions, diagnosis (30.8%) was the most common, followed by post-operation management (27.7%). Conclusion: Physicians have to conduct treatment and surgery based on exact diagnosis and be careful to observe patients' conditions and symptoms after surgery. It is essential to identify the current status and characteristics of medical litigation for reducing further litigation and improving patient safety. In order to create a safe medical environment, national efforts should be made not only by individuals but also at the national level. PMID- 29520345 TI - Effects of splanchnic vasoconstrictors on liver regeneration and survival after 90% rat hepatectomy. AB - Purpose: Posthepatectomy liver failure is a serious complication and considered to be caused by increased portal pressure and flow. Splanchnic vasoactive agents and propranolol are known to decrease portal pressure. The aim of this study was to identify optimal candidates with potential for clinical use among somatostatin, terlipressin, and propranolol using rats with 90% hepatectomy. Methods: Rats were divided into 5 groups: sham operation (n = 6), control (n = 20), propranolol (n = 20), somatostatin (n = 20), and terlipressin group (n = 20). Seven-day survival rates and portal pressure change were measured, and biochemical, histologic, and molecular analyses were performed. Results: Portal pressure was significantly decreased in all 3 treatment groups compared to control. All treatment groups showed a tendency of decreased liver injury markers, and somatostatin showed the most prominent effect at 24 hours postoperatively. Histologic liver injury at 24 hours was significantly decreased in propranolol and terlipressin groups (P = 0.016, respectively) and somatostatin group showed borderline significance (P = 0.056). Hepatocyte proliferation was significantly increased after 24 hours in all treatment groups. Median survival was significantly increased in terlipressin group compared to control group (P < 0.01). Conclusion: Terlipressin is considered as the best candidate, while somatostatin has good potential for clinical use, considering their effects on portal pressure and subsequent decrease in liver injury and increase in liver regeneration. PMID- 29520346 TI - Early disseminated recurrence after liver resection in solitary hepatocellular carcinoma. AB - Purpose: Although few hepatectomy patients develop unexpected early diffuse and multinodular recurrence in the remnant liver, the prognosis in such cases is often dismal. The aim of this study was to evaluate the risk factors of early disseminated multinodular hepatocellular carcinoma (HCC) recurrence within 3 months after liver resection for solitary HCC. Methods: Eighty-four patients who were diagnosed with recurrent HCC within 3 months after hepatectomy for solitary HCC were retrospectively reviewed. Disseminated HCC recurrence was defined as more than 10 tumors in both lobes and total tumor size >10 cm. Results: Preoperative alpha-FP level, incidence of poor tumor grade, and presence of portal vein tumor thrombosis were higher in the patients with disseminated HCC recurrence than in those without disseminated HCC recurrence (P < 0.05). Multivariate analysis showed that alpha-FP >1,000 ng/dL was a predisposing factor of disseminated HCC recurrence within 3 months after liver resection. The overall survival rate for patients without disseminated HCC recurrence was higher than that for patients with disseminated HCC recurrence (P < 0.001). Conclusion: Early disseminated multinodular HCC recurrence in hepatectomy patients was associated with preoperative alpha-FP >1,000 ng/dL. Such patients should be frequently evaluated for the early detection of recurrent HCC for early intervention. PMID- 29520347 TI - The optimal surgical resection approach for T2 gallbladder carcinoma: evaluating the role of surgical extent according to the tumor location. AB - Purpose: The clinical behavior of T2 gallbladder cancer varies among patients. The aims of this study were to identify prognostic factors for survival and recurrence, and to determine the optimal surgical strategy for T2 gallbladder cancer. Methods: We conducted a retrospective analysis of 78 patients with T2 gallbladder cancer who underwent surgical resection for gallbladder cancer. Results: Twenty-eight patients (35.9%) underwent simple cholecystectomy and 50 (64.1%) underwent extended cholecystectomy. Among 56 patients without LN metastasis (n = 20) or unknown LN status (no LN dissection, n = 36), the 5-year disease-free survival rates were 81.6%, and 69.8% (P = 0.080). In an analysis according to tumor location, patients with tumors located on the hepatic side (n = 36) had a higher recurrence rate than patients with tumors located on the peritoneal side only (n = 35) (P = 0.043). On multivariate analysis, R1 resection and lymph node metastasis were significant, independent prognostic factors for poor disease-free and overall survival. Conclusion: R0 resection and LN dissection are an appropriate curative surgical strategy in patients with T2 gallbladder cancer. Tumors located on the hepatic side show worse prognosis than tumors located on the peritoneal side only, hepatic resection should be considered. PMID- 29520348 TI - In vivo porcine training model of laparoscopic common bile duct repair with T tube insertion under the situation of iatrogenic common bile duct injury. AB - Purpose: We introduce a training porcine model for laparoscopic common bile duct (CBD) repair with T-tube insertion. The model could be the feasible training tool for a surgeon learning hepatobiliary surgery. Methods: Totally laparoscopic CBD repair with T-tube insertion was performed on 9 pigs by 9 trainees naive in hepatobiliary surgery. Similar to the situation of iatrogenic injury, CBD was transected by laparoscopic scissors at the middle part about 1 cm in length, and the transected CBD was repaired through end-to-end anastomosis with T-tube insertion. A secureness of anastomosis was confirmed by saline leakage test and all animals were sacrificed after the surgery. Results: All novice surgeons completed operations successfully without complications. Total mean operative time was 85 +/- 1.7 minutes and the mean time spent performing the CBD repair with T-tube insertion was 71 +/- 3 minutes. There was no bile leakage after primary anastomosis in all animals. Conclusion: This porcine training model for laparoscopic CBD repair with T-tube insertion could be a feasible and effective training tool for surgeons with little experience in laparoscopic hepatobiliary surgery. PMID- 29520349 TI - Comparison of the short-term outcomes of reduced-port laparoscopic surgery and conventional multiport surgery in colon cancer: a propensity score matching analysis. AB - Purpose: The feasibility of reduced-port laparoscopic surgery (RPS) in colon cancer remains uncertain. This study aimed to compare the short-term outcomes of RPS and multiport surgery (MPS) in colon cancer using propensity score matching analysis. Methods: A total of 302 patients with colon cancer who underwent laparoscopic anterior resection (AR) (n = 184) or right hemicolectomy (RHC) (n = 118) by a single surgeon between January 2011 and January 2017 were included. Short-term outcomes were compared between RPS and MPS. Results: Seventy-three patients in the AR group and 23 in the RHC group underwent RPS. After propensity score matching, the RPS and MPS groups showed similar baseline characteristics. In the AR group, patients who underwent RPS (n = 72) showed a shorter operation time (114.4 +/- 28.7 minutes vs. 126.7 +/- 34.5 minutes, P = 0.021) and a longer time to gas passage (3.6 +/- 1.7 days vs. 2.6 +/- 1.5 days, P = 0.005) than MPS (n = 72). Similarly, in the RHC group, the operation time was shorter (112.6 +/- 26.0 minutes vs. 146.5 +/- 31.2 minutes, P = 0.005), and the time to first flatus was longer (2.7 +/-1.1 days vs. 3.8 +/- 1.3 days, P = 0.004) in the RPS group (n = 23) than in the MPS group (n = 23). Other short-term outcomes were similar for RPS and MPS in both the AR and RHC groups. Conclusion: The short-term outcomes of RPS were found to be acceptable compared to those of MPS in colon cancer surgery. PMID- 29520350 TI - Bacterial infection monitoring in the early period after liver transplantation. AB - Purpose: Infection remains the main cause of morbidity and mortality in liver transplantation (LT) recipients; however infection is notoriously difficult to diagnose because its usual signs and symptoms of infection may be masked or absent. This study comprises an analysis of bacterial infections in the early period after LT. Methods: This is a study of 129 adults who underwent LT from January 2013 to December 2013, and it includes patients who were followed daily from the day of transplantation to 1-week posttransplantation using bacteriological cultures of blood, urine, sputum, and drained ascites. Results: The following factors were significantly different between the positive and negative culture groups: living donor LT vs. deceased donor LT (odds ratio [OR], 3.269; P = 0.003), model for end-stage liver disease score (OR, 4.364; P < 0.001), and Child-Pugh classification (P = 0.007). Neither positive culture nor negative culture was associated with infection within 4 weeks of surgery (P = 0.03), and most events were due to surgical complications (75%). Conclusion: Since the full effect of immunosuppression is not yet present during the first month after LT, we suggest that the number of bacterial culture test could be reduced such that they are performed every other day depending on patient's situation. PMID- 29520351 TI - Silent invasion of Hem-O-Lok clip. AB - A 58-year-old man underwent laparoscopy-assisted distal gastrectomy (LADG) with Billroth I gastroduodenostomy due to early gastric cancer. During surgery, the perigastric vessels were ligated with Hem-o-Lok clips. Esophagogastroduodenoscopy (EGD) 6 months later showed a fungating mass at the anastomosis site. Repeat EGD 1 year after LADG showed a Hem-o-Lok clip at the fungating mass lesion. Because the patient was asymptomatic, with no major abnormalities on clinical examination, and endoscopic removal of the clip would have been difficult due to the presence of adhesions and inflammation, no attempt was made to remove the clip. The patient remained well after the exposed Hem-o-Lok clip was identified. A third EGD 6 months later showed that the clip had disappeared from the anastomosis site, and that this site was covered with normal mucosa surrounding the scar. PMID- 29520352 TI - Laparoscopic hepatectomy for the treatment of Caroli's disease: a case report. AB - Caroli disease is a rare congenital disorder characterized by nonobstructive dilatation of intrahepatic ducts. In cases with symptomatic intrahepatic manifestations, treatment should correspond to the type with hepatic resection for localized disease and transplantation for diffuse forms. If possible, complete resection of the cysts can cure the symptoms and avoid the risk of malignancy. A 66-year-old woman presented to Wuxi Xishan People's Hospital with recurrent intermittent upper quadrant abdominal pain. Further examinations suggested the diagnosis of Caroli disease limited to the left hepatic lobe. She underwent laparoscopic hepatectomy. Pathological examination confirmed the diagnosis of Caroli disease, and no malignancy was found. There were no immediate complications and no long-term complications after one and one-half years of follow-up. Laparoscopic hepatectomy could be a feasible, safe treatment option for localized Caroli disease. PMID- 29520353 TI - Introduction and Goals for the National Children's Study. AB - The National Children's Study (NCS) evolved in concept and planning to become an integrated systems based initiative to assess a full spectrum of health and capture the environmental factors and other influences that shape the trajectory of child development. The NCS built on prior work in health assessment, epidemiology, logistics, and methodology in order to address the broad goals of its mandate. To develop the specific methods and tools to conduct a study in multiple environments outside conventional health care delivery clinics the NCS invested in new approaches such as informatics, study operations, and the establishment of a Health Measurements Network to provide accurate, cost effective, and scientifically valid data that would be interoperable with data collected by other longitudinal studies around the world as well as with major national and international health improvement initiatives. PMID- 29520355 TI - The Epidemic of Neonatal Abstinence Syndrome, Historical References of Its' Origins, Assessment, and Management. AB - Neonatal abstinence syndrome (NAS) refers to a constellation of signs that are present in some newborn infants resulting from the abrupt cessation of passive transfer of maternal opioids used during pregnancy. The classic NAS refers to infants born to mothers who used opioids during pregnancy, but the term has broadened to include infants whose mothers have used or abused other psychoactive substances during pregnancy that contribute to the expression of the syndrome. Pregnant women who use opioids do so illicitly, and/or as medically prescribed for pain relief, and/or as medication assisted treatment for opioid dependence. The first case of NAS in infants and the subsequent treatment (or lack thereof) was reported in 1875 and was called Congenital Morphinism. By 2012, the incidence of NAS increased to more than 30 per 1,000 hospital live births, along with an increase in the number of infants being treated pharmacologically for NAS, resulting in an increase in the length of stay and healthcare expenses. We present historical references on NAS, the various factors and events that led to its increasing prevalence and today's current epidemic. We also review the current tools to assess infants with NAS and treatment options in its management. PMID- 29520356 TI - Rotational Spectrum and Conformational Analysis of N-Methyl-2-Aminoethanol: Insights into the Shape of Adrenergic Neurotransmitters. AB - We describe an experimental and quantum chemical study for the accurate determination of the conformational space of small molecular systems governed by intramolecular non-covalent interactions. The model systems investigated belong to the biological relevant aminoalcohol's family, and include 2-amino-1 phenylethanol, 2-methylamino-1-phenylethanol, noradrenaline, adrenaline 2 aminoethanol, and N-methyl-2-aminoethanol. For the latter molecule, the rotational spectrum in the 6-18 and 59.6-74.4 GHz ranges was recorded in the isolated conditions of a free jet expansion. Based on the analysis of the rotational spectra, two different conformational species and 11 isotopologues were observed and their spectroscopic constants, including 14N-nuclear hyperfine coupling constants and methyl internal rotation barriers, were determined. From the experimental data a structural determination was performed, which was also used to benchmark accurate quantum chemical calculations on the whole conformational space. Atom in molecules and non-covalent interactions theories allowed the characterization of the position of the intramolecular non-covalent interactions and the energies involved, highlighting the subtle balance responsible of the stabilization of all the molecular systems. PMID- 29520358 TI - Usage of FT-ICR-MS Metabolomics for Characterizing the Chemical Signatures of Barrel-Aged Whisky. AB - Whisky can be described as a complex matrix integrating the chemical history from the fermented cereals, the wooden barrels, the specific distillery processes, aging, and environmental factors. In this study, using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), we analyzed 150 whisky samples from 49 different distilleries, 7 countries, and ranging from 1 day new make spirit to 43 years of maturation with different types of barrel. Chemometrics revealed the unexpected impact of the wood history on the distillate's composition during barrel aging, regardless of the whisky origin. Flavonols, oligolignols, and fatty acids are examples of important chemical signatures for Bourbon casks, whereas a high number of polyphenol glycosides, including for instance quercetin-glucuronide or myricetin-glucoside as potential candidates, and carbohydrates would discriminate Sherry casks. However, the comparison of barrel aged rums and whiskies revealed specific signatures, highlighting the importance of the initial composition of the distillate and the distillery processes. PMID- 29520357 TI - Heat and Drought Stresses in Crops and Approaches for Their Mitigation. AB - Drought and heat are major abiotic stresses that reduce crop productivity and weaken global food security, especially given the current and growing impacts of climate change and increases in the occurrence and severity of both stress factors. Plants have developed dynamic responses at the morphological, physiological and biochemical levels allowing them to escape and/or adapt to unfavorable environmental conditions. Nevertheless, even the mildest heat and drought stress negatively affects crop yield. Further, several independent studies have shown that increased temperature and drought can reduce crop yields by as much as 50%. Response to stress is complex and involves several factors including signaling, transcription factors, hormones, and secondary metabolites. The reproductive phase of development, leading to the grain production is shown to be more sensitive to heat stress in several crops. Advances coming from biotechnology including progress in genomics and information technology may mitigate the detrimental effects of heat and drought through the use of agronomic management practices and the development of crop varieties with increased productivity under stress. This review presents recent progress in key areas relevant to plant drought and heat tolerance. Furthermore, an overview and implications of physiological, biochemical and genetic aspects in the context of heat and drought are presented. Potential strategies to improve crop productivity are discussed. PMID- 29520354 TI - Group B Streptococcal Maternal Colonization and Neonatal Disease: Molecular Mechanisms and Preventative Approaches. AB - Group B Streptococcus (GBS) colonizes the gastrointestinal and vaginal epithelium of a significant percentage of healthy women, with potential for ascending intrauterine infection or transmission during parturition, creating a risk of serious disease in the vulnerable newborn. This review highlights new insights on the bacterial virulence determinants, host immune responses, and microbiome interactions that underpin GBS vaginal colonization, the proximal step in newborn infectious disease pathogenesis. From the pathogen perspective, the function GBS adhesins and biofilms, beta-hemolysin/cytolysin toxin, immune resistance factors, sialic acid mimicry, and two-component transcriptional regulatory systems are reviewed. From the host standpoint, pathogen recognition, cytokine responses, and the vaginal mucosal and placental immunity to the pathogen are detailed. Finally, the rationale, efficacy, and potential unintended consequences of current universal recommended intrapartum antibiotic prophylaxis are considered, with updates on new developments toward a GBS vaccine or alternative approaches to reducing vaginal colonization. PMID- 29520359 TI - Supramolecular Organization of Nonstoichiometric Drug Hydrates: Dapsone. AB - The observed moisture- and temperature dependent transformations of the dapsone (4,4'-diaminodiphenyl sulfone, DDS) 0. 33-hydrate were correlated to its structure and the number and strength of the water-DDS intermolecular interactions. A combination of characterization techniques was used, including thermal analysis (hot-stage microscopy, differential scanning calorimetry and thermogravimetric analysis), gravimetric moisture sorption/desorption studies and variable humidity powder X-ray diffraction, along with computational modeling (crystal structure prediction and pair-wise intermolecular energy calculations). Depending on the relative humidity the hydrate contains between 0 and 0.33 molecules of water per molecule DDS. The crystal structure is retained upon dehydration indicating that DDS hydrate shows a non-stoichiometric (de)hydration behavior. Unexpectedly, the water molecules are not located in structural channels but at isolated-sites of the host framework, which is counterintuitively for a hydrate with non-stoichiometric behavior. The water-DDS interactions were estimated to be weaker than water-host interactions that are commonly observed in stoichiometric hydrates and the lattice energies of the isomorphic dehydration product (hydrate structure without water molecules) and (form III) differ only by ~1 kJ mol-1. The computational generation of hypothetical monohydrates confirms that the hydrate with the unusual DDS:water ratio of 3:1 is more stable than a feasible monohydrate structure. Overall, this study highlights that a deeper understanding of the formation of hydrates with non-stoichiometric behavior requires a multidisciplinary approach including suitable experimental and computational methods providing a firm basis for the development and manufacturing of high quality drug products. PMID- 29520360 TI - Evidence Synthesis in Harm Assessment of Medicines Using the Example of Rosiglitazone and Myocardial Infarction. AB - The current system of harm assessment of medicines has been criticized for relying on intuitive expert judgment. There is a call for more quantitative approaches and transparency in decision-making. Illustrated with the case of cardiovascular safety concerns for rosiglitazone, we aimed to explore a structured procedure for the collection, quality assessment, and statistical modeling of safety data from observational and randomized studies. We distinguished five stages in the synthesis process. In Stage I, the general research question, population and outcome, and general inclusion and exclusion criteria are defined and a systematic search is performed. Stage II focusses on the identification of sub-questions examined in the included studies and the classification of the studies into the different categories of sub-questions. In Stage III, the quality of the identified studies is assessed. Coding and data extraction are performed in Stage IV. Finally, meta-analyses on the study results per sub-question are performed in Stage V. A Pubmed search identified 30 randomized and 14 observational studies meeting our search criteria. From these studies, we identified 4 higher level sub-questions and 4 lower level sub questions. We were able to categorize 29 individual treatment comparisons into one or more of the sub-question categories, and selected study duration as an important covariate. We extracted covariate, outcome, and sample size information at the treatment arm level of the studies. We extracted absolute numbers of myocardial infarctions from the randomized study, and adjusted risk estimates with 95% confidence intervals from the observational studies. Overall, few events were observed in the randomized studies that were frequently of relatively short duration. The large observational studies provided more information since these were often of longer duration. A Bayesian random effects meta-analysis on these data showed no significant increase in risk of rosiglitazone for any of the sub questions. The proposed procedure can be of additional value for drug safety assessment because it provides a stepwise approach that guides the decision making in increasing process transparency. The procedure allows for the inclusion of results from both randomized an observational studies, which is especially relevant for this type of research. PMID- 29520361 TI - Beyond Enumeration: Functional and Computational Analysis of Circulating Tumor Cells to Investigate Cancer Metastasis. AB - Circulating tumor cells (CTCs) are defined as those cells that detach from a cancerous lesion and enter the bloodstream. While generally most CTCs are subjected to high shear stress, anoikis signals, and immune attack in the circulatory system, few are able to survive and reach a distant organ in a viable state, possibly leading to metastasis formation. A large number of studies, both prospective and retrospective, have highlighted the association between CTC abundance and bad prognosis in patients with various cancer types. Yet, beyond CTC enumeration, much less is known about the distinction between metastatic and nonmetastatic CTCs, namely those features that enable only some CTCs to survive and seed a cancerous lesion at a distant site. In addition, critical aspects such as CTC heterogeneity, mechanisms that trigger CTC intravasation and extravasation, as well as vulnerabilities of metastatic CTCs subpopulations are poorly understood. In this short review, we highlight recent studies that successfully adopted functional and computational analysis to gain insights into CTC biology. We also discuss approaches to overcome challenges that are associated with CTC isolation, molecular and computational analysis, and speculate regarding few open questions that currently frame the CTC research field. PMID- 29520362 TI - Posttransplant Intramuscular Injection of PLX-R18 Mesenchymal-Like Adherent Stromal Cells Improves Human Hematopoietic Engraftment in A Murine Transplant Model. AB - Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45+ cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p < 0.001) and 8 (7.3 vs. 13.1%, p < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19+ cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX R18 may have a therapeutic role in improving incomplete engraftment after HCT. PMID- 29520363 TI - Pattern Formation over Multigraphs. AB - Two of the most common pattern formation mechanisms are Turing-patterning in reaction-diffusion systems and lateral inhibition of neighboring cells. In this paper, we introduce a broad dynamical model of interconnected modules to study the emergence of patterns, with the above mentioned two mechanisms as special cases. Our results do not restrict the number of modules or their complexity, allow multiple layers of communication channels with possibly different interconnection structure, and do not assume symmetric connections between two connected modules. Leveraging only the static input/output properties of the subsystems and the spectral properties of the interconnection matrices, we characterize the stability of the homogeneous fixed points as well as sufficient conditions for the emergence of spatially non-homogeneous patterns. To obtain these results, we rely on properties of the graphs together with tools from monotone systems theory. As application examples, we consider patterning in neural networks, in reaction-diffusion systems, and contagion processes over random graphs. PMID- 29520364 TI - State Level Point-of-Sale Policy Priority as a Result of the FSPTCA. AB - The Family Smoking Prevention and Tobacco Control Act (FSPTCA) give the U.S. Food and Drug Administration (FDA) unprecedented power to regulate tobacco products. One of the most significant provisions of the law allows state and local governments to adopt and enforce tobacco control legislation restricting the time, place, and manner (but not the content) of tobacco advertising. However, there is still reluctance among states and localities for mass adoption of laws due to challenges associated with legal feasibility and lack of U.S.-based evidence in effectiveness. The Center for Public Health Systems Science conducted interviews with key tobacco control contacts in 48 states at two time points (2012 and 2014) since the passage of the FSPTCA to assess the influence of the law on point-of-sale policy development in their state tobacco programs. Logistic regression results show that point-of-sale policy importance is growing post FSPTCA, and that key influencers of this importance are states' tobacco control histories and environments, including that related to excise taxes and smoke free air policies. The adoption of smokefree and tax policies has become commonplace across the U.S., and the quality and extent of these laws and prevailing political will increasingly impact the ability of states to work in emerging tobacco control policy areas including those directed at the point of sale. PMID- 29520365 TI - Platelet-Targeted Gene Therapy for Hemophilia. AB - Gene therapy is an attractive approach for disease treatment. Since platelets are abundant cells circulating in blood with the distinctive abilities of storage and delivery and fundamental roles in hemostasis and immunity, they could be a unique target for gene therapy of diseases. Recent studies have demonstrated that ectopic expression of factor VIII (FVIII) in platelets under control of the platelet-specific promoter results in FVIII storage together with its carrier protein von Willebrand factor (VWF) in alpha-granules and the phenotypic correction of hemophilia A. Importantly, the storage and sequestration of FVIII in platelets appears to effectively restore hemostasis even in the presence of functional-blocking inhibitory antibodies. This review summarizes studies on platelet-specific gene therapy of hemophilia A as well as hemophilia B. PMID- 29520366 TI - Microglial activation, white matter tract damage, and disability in MS. AB - Objective: To investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS. Methods: Patients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [11C](R)-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison. Results: [11C](R)-PK11195 binding was significantly higher in the normal appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls. Conclusions: PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters. PMID- 29520367 TI - Architectural B-cell organization in skeletal muscle identifies subtypes of dermatomyositis. AB - Objective: To study the B-cell content, organization, and existence of distinct B cell subpopulations in relation to the expression of type 1 interferon signature related genes in dermatomyositis (DM). Methods: Evaluation of skeletal muscle biopsies from patients with adult DM (aDM) and juvenile DM (jDM) by histology, immunohistochemistry, electron microscopy, and quantitative reverse-transcription PCR. Results: We defined 3 aDM subgroups-classic (containing occasional B cells without clusters), B-cell-rich, and follicle-like aDM-further elucidating IM B lymphocyte maturation and immunity. The quantity of B cells and formation of ectopic lymphoid structures in a subset of patients with aDM were associated with a specific profile of cytokines and chemokines involved in lymphoid neogenesis. Levels of type 1 interferon signature related gene expression paralleled B-cell content and architectural organization and link B-cell immunity to the interferon type I signature. Conclusion: These data corroborate the important role of B cells in DM, highlighting the direct link between humoral mechanisms as key players in B-cell immunity and the role of type I interferon-related immunity. PMID- 29520368 TI - Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice. AB - Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3 dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO) mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway. PMID- 29520369 TI - Two models of inescapable stress increase tph2 mRNA expression in the anxiety related dorsomedial part of the dorsal raphe nucleus. AB - Expression of TPH2, the rate-limiting enzyme for brain serotonin synthesis, is elevated in the dorsal raphe nucleus (DR) of depressed suicide victims. One hypothesis is that this increase in TPH2 expression is stress-induced. Here, we used an established animal model to address whether exposure to an acute stressor, inescapable tail shock (IS), increases tph2 mRNA and Tph2 protein expression, and if IS sensitizes the DR to a subsequent, heterotypic stressor. In Experiment 1, we measured tph2 mRNA expression 4 h after IS or home cage (HC) control conditions in male rats, using in situ hybridization histochemistry. In Experiment 2, we measured Tph2 protein expression 12 h or 24 h after IS using western blot. In Experiment 3, we measured tph2 mRNA expression following IS on Day 1, and cold swim stress (10 min, 15 degrees C) on Day 2. Inescapable tail shock was sufficient to increase tph2 mRNA expression 4 h and 28 h later, selectively in the dorsomedial DR (caudal aspect of the dorsal DR, cDRD; an area just rostral to the caudal DR, DRC) and increased Tph2 protein expression in the DRD (rostral and caudal aspects of the dorsal DR combined) 24 h later. Cold swim increased tph2 mRNA expression in the dorsomedial DR (cDRD) 4 h later. These effects were associated with increased immobility during cold swim, elevated plasma corticosterone, and a proinflammatory plasma cytokine milieu (increased interleukin (IL)-6, decreased IL-10). Our data demonstrate that two models of inescapable stress, IS and cold swim, increase tph2 mRNA expression selectively in the anxiety-related dorsomedial DR (cDRD). PMID- 29520370 TI - Nitric Oxide Release for Improving Performance of Implantable Chemical Sensors - A Review. AB - Over the last three decades, there has been extensive interest in developing in vivo chemical sensors that can provide real-time measurements of blood gases (oxygen, carbon dioxide, and pH), glucose/lactate, and potentially other critical care analytes in the blood of hospitalized patients. However, clot formation with intravascular sensors and foreign body response toward sensors implanted subcutaneously can cause inaccurate analytical results. Further, the risk of bacterial infection from any sensor implanted in the human body is another major concern. To solve these issues, the release of an endogenous gas molecule, nitric oxide (NO), from the surface of such sensors has been investigated owing to NO's ability to inhibit platelet activation/adhesion, foreign body response and bacterial growth. This paper summarizes the importance of NO's therapeutic potential for this application and reviews the publications to date that report on the analytical performance of NO release sensors in laboratory testing and/or during in vivo testing. PMID- 29520371 TI - Interest Matters: The Importance of Promoting Interest in Education. AB - Interest is a powerful motivational process that energizes learning, guides academic and career trajectories, and is essential to academic success. Interest is both a psychological state of attention and affect toward a particular object or topic, and an enduring predisposition to reengage over time. Integrating these two definitions, the four-phase model of interest development guides interventions that promote interest and capitalize on existing interests. Four interest-enhancing interventions seem useful: attention-getting settings, contexts evoking prior individual interest, problem-based learning, and enhancing utility value. Promoting interest can contribute to a more engaged, motivated, learning experience for students. PMID- 29520372 TI - Highly Accelerated SSFP Imaging with Controlled Aliasing in Parallel Imaging and integrated-SSFP (CAIPI-iSSFP). AB - Purpose: To develop a novel combination of controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) with integrated SSFP (CAIPI iSSFP) for accelerated SSFP imaging without banding artifacts at 3T. Materials and Methods: CAIPI-iSSFP was developed by adding a dephasing gradient to the balanced SSFP (bSSFP) pulse sequence with a gradient area that results in 2pi dephasing across a single pixel. Extended phase graph (EPG) simulations were performed to show the signal behaviors of iSSFP, bSSFP, and RF-spoiled gradient echo (SPGR) sequences. In vivo experiments were performed for brain and abdominal imaging at 3T with simultaneous multi-slice (SMS) acceleration factors of 2, 3 and 4 with CAIPI-iSSFP and CAIPI-bSSFP. The image quality was evaluated by measuring the relative contrast-to-noise ratio (CNR) and by qualitatively assessing banding artifact removal in the brain. Results: Banding artifacts were removed using CAIPI-iSSFP compared to CAIPI-bSSFP up to an SMS factor of 4 and 3 on brain and liver imaging, respectively. The relative CNRs between gray and white matter were on average 18% lower in CAIPI-iSSFP compared to that of CAIPI bSSFP. Conclusion: This study demonstrated that CAIPI-iSSFP provides up to a factor of four acceleration, while minimizing the banding artifacts with up to a 20% decrease in the relative CNR. PMID- 29520373 TI - Pattern of Alcohol Consumption by Young People from North Eastern Portugal. AB - Alcohol is the most used psychoactive substance among adolescents, is an important public health problem and a major risk factor for the health of this group. This study is regarding to the pattern of alcohol consumption by adolescents. Descriptive, correlational and cross-sectional study, with a sample of 378 adolescents, which are attending three high schools, in north-eastern Portugal. In the data collection we used a questionnaire. Data was analysed using SPSS. The prevalence of alcohol is 86.8%. The mean score of Alcohol Use Disorders Identification Test (AUDIT) was 3.53+/-4.525 points. The vast majority of participants were located in the non-excessive alcohol consumption area (91.3%). The pattern of alcohol consumption differs significantly between gender (Wald: p <= 0,004) and the religious practice (Wald: p <= 0,027), with greater percentage of boys and students who did not practice any religion in excessive consumers. The prevalence of alcohol consumers is high. The proportion of young people with excessive consumption in our sample is lower than in other studies, but shows that there is a group of adolescents in excessive consumption. It found a relationship between consumption pattern, gender and religious practice. These results justify the development of public health interventions. PMID- 29520374 TI - Cleidocranial Dysplasia-dental Disorder Treatment and Audiology Diagnosis. AB - A review of numerous case reports was made, in order to demonstrate the possibilities for treatment of dental disorders in patients with Cleidocranial dysplasia (CCD). In this paper, our own report, including a diagnosis of the effect on the auditory system, is presented. In addition to the triad of CCD symptoms that include hypoplastic or aplastic clavicles, impacted and supernumerary teeth, delayed closure of fontanelles and cranial sutures, impairment of the hearing system resulting in conductive hearing loss also occurs. Our own report is based on the case of a 12-year-old CCD patient, in whom Cone Beam Computed Tomography (CBCT) revealed the presence of 12 supernumerary teeth. Furthermore, a clinical examination pointed to the presence of retained deciduous teeth and a delayed eruption of permanent teeth. Orthodontic-surgical procedures were implemented, in accordance with the literature. During the course of the orthodontic treatment, a decrease in auditory sensitivity was observed, for which reason hearing tests were also performed. Conductive hearing loss was detected. As such, it is important to remember that in such cases, auditory check ups need to be performed between the many surgical and orthodontic interventions, which usually last a few years. PMID- 29520375 TI - Dual enhancement mechanisms for overnight motor memory consolidation. AB - Our brains are constantly processing past events [1]. These off-line processes consolidate memories, leading in the case of motor skill memories to an enhancement in performance between training sessions. A similar magnitude of enhancement develops over a night of sleep following an implicit task, when a sequence of movements is acquired unintentionally, or following an explicit task, when the same sequence is acquired intentionally [2]. What remains poorly understood, however, is whether these similar offline improvements are supported by similar circuits, or through distinct circuits. We set out to distinguish between these possibilities by applying Transcranial Magnetic Stimulation (TMS), over the primary motor cortex (M1) or the inferior parietal lobule (IPL) immediately after learning in either the explicit or implicit task. These brain areas have both been implicated in encoding aspects of a motor sequence, and subsequently supporting offline improvements over sleep [3-5]. Here we show that offline improvements following the explicit task are dependent upon a circuit that includes M1 but not IPL. By contrast, offline improvements following the implicit task are dependent upon a circuit that includes IPL but not M1. Our work establishes the critical contribution made by M1 and IPL circuits to offline memory processing, and reveals that distinct circuits support similar offline improvements. PMID- 29520376 TI - Multimodal Examination of Atrial Fibrillation Substrate: Correlation of Left Atrial Bipolar Voltage Using Multi-Electrode Fast Automated Mapping, Point-by Point Mapping, and Magnetic Resonance Image Intensity Ratio. AB - Background: Bipolar voltage mapping, as part of atrial fibrillation (AF) ablation, is traditionally performed in a point-by-point (PBP) approach using single-tip ablation catheters. Alternative techniques for fibrosis-delineation include fast-anatomical mapping (FAM) with multi-electrode circular catheters, and late gadolinium-enhanced magnetic-resonance imaging (LGE-MRI). The correlation between PBP, FAM, and LGE-MRI fibrosis assessment is unknown. Objective: In this study, we examined AF substrate using different modalities (PBP, FAM, and LGE-MRI mapping) in patients presenting for an AF ablation. Methods: LGE-MRI was performed pre-ablation in 26 patients (73% males, age 63+/ 8years). Local image-intensity ratio (IIR) was used to normalize myocardial intensities. PBP- and FAM-voltage maps were acquired, in sinus rhythm, prior to ablation and co-registered to LGE-MRI. Results: Mean bipolar voltage for all 19,087 FAM voltage points was 0.88+/-1.27mV and average IIR was 1.08+/-0.18. In an adjusted mixed-effects model, each unit increase in local IIR was associated with 57% decrease in bipolar voltage (p<0.0001). IIR of >0.74 corresponded to bipolar voltage <0.5 mV. A total of 1554 PBP-mapping points were matched to the nearest FAM-point. In an adjusted mixed-effects model, log-FAM bipolar voltage was significantly associated with log-PBP bipolar voltage (beta=0.36, p<0.0001). At low-voltages, FAM-mapping distribution was shifted to the left compared to PBP mapping; at intermediate voltages, FAM and PBP voltages were overlapping; and at high voltages, FAM exceeded PBP-voltages. Conclusion: LGE-MRI, FAM and PBP mapping show good correlation in delineating electro-anatomical AF substrate. Each approach has fundamental technical characteristics, the awareness of which allows proper assessment of atrial fibrosis. PMID- 29520377 TI - Use of Nd:YAG laser to recanalize occluded Cypass Micro-Stent in the early post operative period. AB - Purpose: To report the first case of Neodymium Yttrium Aluminum Garnet (Nd:YAG) laser use to recanalize a CyPass occluded with a clot in the early postoperative follow-up. Observations: A 66 year-old woman with primary open angle glaucoma and cataract received combined cataract surgery plus CyPass in the right eye. Surgery was uneventful, however, there was a small amount of hyphema related to bleeding around the site of Cypass insertion. Intraocular pressure (IOP) was between 6 and 7 mmHg in the first week on no glaucoma medications. At the second postoperative week, IOP jumped to 30 mmHg and a clot was observed obstructing the CyPass lumen. We disrupted the clot with a single shot from a Nd:YAG laser. Twenty minutes after the laser, the IOP was 8 mmHg. CyPass was recanalized without complications. IOP was 11 mmHg at 1 month postoperatively with timolol 0.5% twice a day. Conclusions and importance: It is important to perform gonioscopy to evaluate for CyPass obstruction in cases of IOP spike. Nd:YAG laser may be a useful approach to recanalize the CyPass in the early postoperative follow-up. PMID- 29520378 TI - Cardiosphere-Derived Cells Demonstrate Metabolic Flexibility That Is Influenced by Adhesion Status. AB - Adult stem cells demonstrate metabolic flexibility that is regulated by cell adhesion status. The authors demonstrate that adherent cells primarily utilize glycolysis, whereas suspended cells rely on oxidative phosphorylation for their ATP needs. Akt phosphorylation transduces adhesion-mediated regulation of energy metabolism, by regulating translocation of glucose transporters (GLUT1) to the cell membrane and thus, cellular glucose uptake and glycolysis. Cell dissociation, a pre-requisite for cell transplantation, leads to energetic stress, which is mediated by Akt dephosphorylation, downregulation of glucose uptake, and glycolysis. They designed hydrogels that promote rapid cell adhesion of encapsulated cells, Akt phosphorylation, restore glycolysis, and cellular ATP levels. PMID- 29520379 TI - Evaluation of Apolipoprotein E Fragmentation as a Biomarker for Alzheimer's Disease. AB - Recent studies have supported a role for the proteolytic cleavage of apolipoprotein E4 (APOE4) as a potential mechanism for the enhanced dementia risk associated with Alzheimer's disease. To determine whether APOE4 fragmentation is correlated with AD, ELISA assays were performed with cerebral spinal fluid (CSF) and plasma samples utilizing an antibody that specifically detects a 17 kDa amino terminal fragment (p17) of APOE (nApoECF antibody). In CSF samples, levels of APOE fragmentation were minimal in both neuropathological normals (NPNs) and AD cases and there were no significant differences between the two cohorts across APOE genotypes. Similar results were found in plasma samples where the p17 APOE fragment comprised only 8.4% of the total level of identified APOE. As with CSF, there were no significant differences found between NPNs and AD cases in terms of the amount of nApoECF quantified. Taken together, these results suggest that the p17 amino-terminal fragment of APOE is not correlated with AD or APOE genotype in the plasma or CSF. PMID- 29520380 TI - Factors Associated with Self-Reported 14 or More Activity Limitation Days among Adults in the United States. AB - Objective: It is estimated that 41 million American adults 18 and older experience poor physical or mental health which limits their ability to engage in their daily activities. The objective of this study was to assess the prevalence of and factors associated with >=14activity limitation days (ALD) due to poor physical or mental health as self-reported by persons aged 18 years and over in the United States (U.S). Methods: Using the 2012 Behavioral Risk Factors Surveillance System (BRFSS), persons over the age of 18 in the U.S. were examined to assess the prevalence of and factors associated with >= 14ALD due to poor physical or mental health. The BRFSS is administered on a continuous basis by telephone using random-digit dial sampling methods. A clustering sample design was used to account for differences in the probability of selection and non response in order to accurately derive US and state-based population estimates. The design consists of a probability sample of all households with telephones in the state. Analyses were conducted using SAS 9.2. Results: Of the 104,257 participants included in the analyses, 40% reported having >=14 ALD due to poor physical or mental health. After adjusting for demographic and socioeconomic factors, males (AOR1.17, 95% CI: 1.14-1.21), those with high school or less education (AOR: 1.42, 95% CI: 1.37-1.21), those who were separated (AOR: 1.23; 95% CI=1.14-1.32), divorced (AOR: 1.10; 95% CI=1.06-1.15), those from the Southern Black Belt States (AOR1.14, 95% CI: 1.10-1.20), and those from the remainder of the Southern region of the U.S. (AOR1.14, 95% CI: 1.08-1.21) were significantly more likely to report >=14ALD due to poor physical or mental health. Conclusion: The prevalence of >=14ALD due to poor physical or mental health among the study population was associated with sociodemographic and region of residence factors. These findings highlight the need for prevention strategies specifically for populations who might be more at risk for ALD due to social determinants of health. PMID- 29520381 TI - Knowledge-based diagnosis and prediction using big data and deep learning in precision medicine. PMID- 29520383 TI - Can pelvic node dissection at radical prostatectomy influence the nodal recurrence at salvage lymphadenectomy for prostate cancer? AB - Purpose: To verify the quality of pelvic lymph node dissection (PLND) performed at radical prostatectomy (RP) and its impact on nodal recurrence in patients undergoing salvage lymph node dissection (sLND). Materials and Methods: Retrospective review of 48 patients who underwent sLND for presumed nodal recurrence, to describe the PLND characteristics at RP and correlate the anatomical sites and number of suspicious nodes reported in radiological imaging and final pathology of sLND. Results: Overall, at RP, 8 (16.7%) did not undergo PLND, 32 (66.7%) and 8 (16.7%) received a "limited" (between external iliac vein and obturator nerve) and an "extended" (external iliac, hypogastric, and obturator) dissection, respectively. Median nodes removed during limited and extended dissection were 2 and 24, respectively. At sLND, the mean age was 61.3 years and median prostate specific antigen (PSA) was 1.07 ng/mL. Median nodes removed at sLND were 17 with a median of 2 positive nodes. Recurrent nodes were identified within the template of an extended PLND in 62.5%, 50.0% and 12.5% patients, respectively, following prior no, limited and extended dissection at RP. Recurrence outside the expected lymphatic drainage pathway was noted in 37.5% patients with prior extended dissection at RP. There was a correlation between imaging and pathology specimen in 83% for node location and 58.3% for number of anatomical sites involved. Conclusions: In prostate cancer patients undergoing sLND, most had inadequate PLND at the original RP. Pattern of nodal recurrence may be influenced by the prior dissection and pre sLND imaging appears to underestimate the nodal recurrence. PMID- 29520382 TI - Unmasking molecular profiles of bladder cancer. AB - Precision medicine is designed to tailor treatments for individual patients by factoring in each person's specific biology and mechanism of disease. This paradigm shifted from a "one size fits all" approach to "personalized and precision care" requires multiple layers of molecular profiling of biomarkers for accurate diagnosis and prediction of treatment responses. Intensive studies are also being performed to understand the complex and dynamic molecular profiles of bladder cancer. These efforts involve looking bladder cancer mechanism at the multiple levels of the genome, epigenome, transcriptome, proteome, lipidome, metabolome etc. The aim of this short review is to outline the current technologies being used to investigate molecular profiles and discuss biomarker candidates that have been investigated as possible diagnostic and prognostic indicators of bladder cancer. PMID- 29520384 TI - What do patients with urothelial cancer know about the association of their tumor disease with smoking habits? Results of a German survey study. AB - Purpose: Smoking represents a primary risk factor for the development of urothelial carcinoma (UC) and a relevant factor impacting UC-specific prognosis. Data on the accordant knowledge of UC-patients in this regard and the significance of physicians in the education of UC-patients is limited. Materials and Methods: Eighty-eight UC-patients were enrolled in a 23-items-survey-study aimed to analyse patient knowledge and awareness of their tumor disease with smoking along with physician smoking cessation counselling. Results: The median age of the study patients was 69 years; 26.1% (n=23), 46.6% (n=41), and 27.3% (n=24), respectively, were non-smokers, previous, and active smokers. Exactly 50% of active smokers reported a previous communication with a physician about the association of smoking and their tumor disease; however, only 25.0% were aware of smoking as main risk factor for UC development. Merely 33% of the active smokers had been prompted directly by their physicians to quit smoking. About 42% of active smokers had received the information that maintaining smoking could result in a tumor-specific impairment of their prognosis. Closely 29% of active and about 5% of previous smokers (during the time-period of active smoking) had been offered support from physicians for smoking cessation. No association was found between smoking anamnesis (p=0.574) and pack-years (p=0.912), respectively, and tumor stage of UC. Conclusions: The results of this study suggest that the medical conversation of physicians with UC-patients about the adverse significance of smoking is limited. Implementation of structured educational programs for smoking cessation may be an opportunity to further enhance comprehensive cancer care. PMID- 29520385 TI - Detection and recurrence rate of transurethral resection of bladder tumors by narrow-band imaging: Prospective, randomized comparison with white light cystoscopy. AB - Purpose: The purpose of this study was to evaluate the efficacy of narrow-band imaging (NBI) as a diagnostic tool for detecting bladder tumors during cystoscopy compared with white light cystoscopy (WLC). Materials and Methods: From December 2013 to June 2017, a randomized prospective study was conducted on 198 patients underwent transurethral resection of bladder tumor by a single surgeon. The patients were divided into two groups according to diagnostic method. In Group I, WLC only was performed. In Group II, NBI was additionally performed after WLC. We analyzed the rate of detection of bladder tumors as a primary endpoint. In addition, we evaluated rates of recurrence in each group. Results: There were no significant differences between the two groups in characteristics except hypertension. In the analysis of rates of detection, the probability of diagnosing cancer was 80.9% (114/141) in the WLC group, and the probability of diagnosing cancer using WLC in the NBI group was 85.5% (159/186). After switching from WLC to NBI for second-look cystoscopy in the NBI group, NBI was shown to detect additional tumors with a detection rate of 35.1% (13/37) from the perspective of the patients and 42.2% (27/64) from the perspective of the tumors. The 1-year recurrence-free rate was 72.2% in the WLC group and 85.2% in the NBI group (p=0.3). Conclusions: NBI had benefits for detecting tumors overlooked by WLC. Although the difference in the 1-year recurrence-free rate was not statistically significant, our results showed a trend for higher recurrence in the NBI group. PMID- 29520386 TI - Dietary risk factors for urolithiasis in Korea: A case-control pilot study. AB - Purpose: Dietary factors are one of the main causes of urolithiasis. However, little research has evaluated dietary factors related to urolithiasis in Korea. We investigated the various dietary risk factors for urinary stone formation in Korean people. Materials and Methods: We conducted a prospective case-control pilot study. A total of 27 patients newly diagnosed with urolithiasis and 20 applicants without urolithiasis were designated as the patients and the control group, respectively. A face-to-face survey was carried out using a food-frequency questionnaire. After adjustment for physical activity level and total energy intake, multivariate logistic regression models were applied to search for risk factors for urolithiasis. Results: There were no significant differences between the two groups in gender, age, body mass index, family history, or total energy intake. The physical activity level of the control group was significantly higher than that of the patients (p=0.012). The results of the multivariate logistic regression model demonstrated that intake of carbohydrate (odds ratio [OR], 1.055; 95% confidence interval [CI], 1.012-1.099), protein (OR, 1.101; 95% CI, 1.001-1.211), and cereals (OR, 1.012; 95% CI, 1.002-1.023) could increase the risk for urolithiasis. Conclusions: A higher intake of carbohydrate, protein, and cereal may increase the risk of urinary stone formation among Korean people. PMID- 29520387 TI - Predictive factors and treatment outcomes of Steinstrasse following shock wave lithotripsy for ureteral calculi: A Bayesian regression model analysis. AB - Purpose: This study aims to assess the predictive factors and treatment outcomes of Steinstrasse formation following shock wave lithotripsy (SWL) for ureter stone. Materials and Methods: The medical records of 1,418 ureter stone patients who underwent one-session SWL from November 2005 to May 2013 at our medical institute were retrospectively reviewed. Finally, 551 patients met inclusion criteria. Maximal length and location of stone, stone attenuation (Hounsfield units), and skin-to-stone distance (SSD) were determined on pretreatment non contrast computed tomography. Results: Of 551 patients, 12 patients (2.2% of total cohort) developed Steinstrasse after one-session SWL. The Steinstrasse incidence was significantly associated with stone size, stone attenuation value, and SSD. Prophylactic ureter stenting was not a statistically significant predictor of Steinstrasse formation. After propensity-score matching, Steinstrasse group showed a significant shorter SSD compare to non-Steinstrasse group. Multivariate logistic regression and Bayesian analysis revealed that stone size, stone attenuation and SSD were significant predictor of Steinstrasse formation following SWL for ureter stone. The Steinstrasse resolved spontaneously in six patients and remaining six patients were treated by additional SWL. None of patients with Steinstrasse required ureteral stenting, percutaneous drainage, or consequent surgical intervention. Conclusions: Steinstrasse formation following SWL for ureter stone was rare event but nonnegligible. Large stone size, high stone attenuation and short SSD were significant predictors of Steinstrasse formation following SWL for ureter stone. Majority of patients with Steinstrasse formation could be treated conservatively in this clinical scenario. PMID- 29520388 TI - Ureteral catheters for colorectal surgery: Influence on operative times and complication outcomes: An observational study. AB - Purpose: Placement of pre-operative ureteral catheters for colorectal surgery can aid in the identification of ureteral injuries. This study investigates whether simultaneous ureteral catheterization with surgery skin preparation can minimize operating room times without increasing post-operative complications. Materials and Methods: Patients undergoing simultaneous colorectal surgery skin preparation and placement of pre-operative ureteral catheters (n=21) were compared to those who underwent these events sequentially (n=28). Operative time-points of anesthesia ready (AR), surgery procedure start (PS), dorsal lithotomy and catheter insertion (CI) times were compared to assess for differences between groups. Complications were compared between groups. Results: There were no differences in age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA), comorbidities, current procedure terminology (CPT) or International Classification of Diseases, 9th revision (ICD-9) codes between groups. Simultaneous catheterization saved 11.82 minutes of operative time between CI to PS (p=0.005, t-test). There was a significant difference in mean time between CI to PS (11.82 minutes, p=0.008) between simultaneous and sequential ureteral catheterization groups in a linear regression multivariate analysis controlling for age, BMI, CPT and ICD-9 codes. There were 4 complications in the simultaneous (19%) and 3 in the sequential group (11%) (p=0.68). Conclusions: Ureteral catheterization and colorectal surgery skin preparation in a simultaneous fashion decreases the time between CI and PS without significant increase in complications. Mean time saved with simultaneous ureteral catheterization was 11.82 minutes per case. Simultaneous ureteral catheterization may be an option in colorectal surgery and may result in cost savings without additional complications. PMID- 29520389 TI - An evaluation of the Manufacturer And User Facility Device Experience database that inspired the United States Food and Drug Administration's Reclassification of transvaginal mesh. AB - Purpose: To assess the utility of the Manufacturer And User Facility Device Experience (MAUDE) database in objectively capturing adverse events for transvaginal mesh in the United States. Materials and Methods: We reviewed 1,103 individual medical device reports submitted to the MAUDE database that inspired the United States (US) Food and Drug Administration's 2008 Public Health Notification. Entries were compiled into a categorical database that reported manufacturer, brand, reporter type, report source, and type of adverse event. Results: There were numerous examples of missing, duplicated, and non standardized entries. Analysis revealed 64 reports with duplicated information, and six reports representing multiple patients. Forty-seven percent of medical device reports did not identify a reporter source. At least 28% of reported devices are no longer on the US market. There was wide variability in the quality and completeness of submitted reports and true adverse event rates could not be accurately calculated because the number of total cases was unknown. Conclusions: The MAUDE database was limited in its ability to collect, quantify, and standardize real-life adverse events related to transvaginal mesh. While it functions to collect information related to isolated adverse events, systematic limitations of the MAUDE database, that no doubt extend to other medical devices, necessitate the development of new reporting systems. Alternatives are under development, which may allow regulators to more accurately scrutinize the safety profiles of specific medical devices. PMID- 29520390 TI - Short-term outcomes of the transvaginal minimal mesh procedure for pelvic organ prolapse. AB - Purpose: This study aimed to evaluate the clinical outcomes and complications of transvaginal minimal mesh repair without using commercially available kits for treatment of pelvic organ prolapse (POP). Materials and Methods: This retrospective cohort study involved 91 women who underwent surgical management of POP with originally designed small mesh between July 2014 and August 2015. This mesh is 56% smaller than the mesh widely used in Japan, and it has only two arms delivered into each right and left sacrospinous ligament. The main study outcome was the anatomic cure rate defined as recurrence of POP quantification (POP-Q) stage II or more. We also assessed changes in the overactive bladder symptom score (OABSS) and prolapse quality of life questionnaire (P-QOL) and evaluated adverse events. Finally, we compared patient backgrounds between the patients with and without recurrence. Results: Prolapse recurred in 10 of 91 patients (11.0%), and all patients with recurrence were diagnosed as POP-Q stage II. As adverse events, only mesh erosion occurred in two (2.2%) and pelvic pain in one (1.1%) of the 91 patients. The OABSS and P-QOL were significantly improved by the operation. When we compared patient backgrounds between the patients with and without recurrence, body mass index was the only factor influencing affecting recurrence. Conclusions: Transvaginal minimal mesh repair resulted in successful outcomes with low mesh-related complications and anatomic recurrence at one year. Furthermore, significant improvement in QOL was offered by this procedure. Our minimal mesh technique should be considered as one treatment option for the management of POP. PMID- 29520391 TI - The safety of a mixture of bupivacaine and lidocaine in children after urologic inguinal and scrotal surgery. AB - Purpose: Local anesthetic agents such as bupivacaine and lidocaine are commonly used after surgery for pain control. The aim of this prospective study was to evaluate the safety of a mixture of bupivacaine and lidocaine in children who underwent urologic inguinal and scrotal surgery. Materials and Methods: Fifty five patients who underwent pediatric urologic outpatient surgeries, were prospectively enrolled in this study. The patients were divided into three groups according to age (group I: under 2 years, group II: between 3-4 years, and group III: 5 years and above). Patients were further sub-divided into unilateral and bilateral groups. All patients were injected with a mixture of 0.5% bupivacaine and 2% lidocaine (2:1 volume ratio) at the surgical site, just before the surgery ended. Hemodynamic and electrocardiographic parameters were measured before local anesthesia, 30 minutes after administration of local anesthesia, and 60 minutes after administration. Results: The patients' mean age was 40.5+/-39.9 months. All patients had normal hemodynamic and electrocardiographic parameters before local anesthesia, after 30 minutes, and after 60 minutes. Also, results of all intervals were within normal values, when analyzed by age and laterality. No mixture related adverse events (nausea, vomiting, pruritus, sedation, respiratory depression) or those related to electrocardiographic parameters (arrhythmias and asystole) were reported in any patients. Conclusions: A mixture of bupivacaine and lidocaine can be safely used in children undergoing urologic inguinal and scrotal surgery. An appropriate dose has no clinically significant hemodynamic or cardiac changes and adverse effects. PMID- 29520392 TI - Current themes in myocardial and coronary vascular aging. AB - Advancing age will affect every individual and its impact on cardiac health deserves significant attention. The age-related physiological changes occurring in the coronary vasculature, myocardium, and valves set the stage upon which cardiovascular disease can escalate in the elderly population. The overall focus of this review is to highlight new and noteworthy studies and to incorporate reviews related to cardiac senescence in the context of the current state of the field. Lastly, future directions in the field of cardiac aging and the development of novel therapeutics to treat pathophysiological conditions typically associated with advancing age will be discussed. PMID- 29520393 TI - Evaluation of an Evidence-Based Weight Loss Trial for Urban African American Adolescents and Caregivers. AB - Rates of obesity are among the highest for African American adolescents in the US. However, African American adolescents benefit the least from evidence-based weight loss interventions, often experiencing poor treatment retention and low motivation. Participant evaluations provide key information for future development of family-based weight loss interventions able to address these barriers. The purpose of this study was to examine the experiences of African American adolescent and caregivers participating in the FIT Families trial for program satisfaction and content palatability. Content analysis was used to analyze semi-structured exit interviews from 136 African American adolescents [median age 14 years, 69% female] and caregiver pairs [primarily mothers] participating in a family-based 6-month behavioral weight loss intervention that was delivered either in the home or in an office setting. Participants reported most program practices [location, parent involvement, interpersonal relationship with weight loss counselors] and intervention content [cognitive behavioral skills training, motivational interviewing, contingency management] were helpful. Many adolescents [49%] and their caregivers [47%] reported that the program was acceptable overall, however noted that areas for refinement did exist. Participants reported that managing the logistics of weekly sessions was hard. Families expressed a desire for more engaging skills-based learning and the inclusion of exercise sessions and additional tailoring to needs and interests. Individualization, active learning, and support around parenting continues to be beneficial when designing interventions. PMID- 29520394 TI - Development and Validation of a High-Pressure Liquid Chromatography Method for the Determination of Chemical Purity and Radiochemical Purity of a [68Ga]-Labeled Glu-Urea-Lys(Ahx)-HBED-CC (Positron Emission Tomography) Tracer. AB - Background: Prostate-specific membrane antigen (PSMA) has gained high attention as a useful biomarker in the imaging evaluation of prostate cancer with positron emission tomography (PET) during recent years. [68Ga]-labeled Glu-urea-Lys(Ahx) HBED-CC ([68Ga]-PSMA-HBED-CC) is a novel PSMA inhibitor radiotracer which has demonstrated its suitability in detecting prostate cancer. Preparation conditions may influence the quality and in vivo behavior of this tracer, and no standard procedure for the quality control (QC) is available. The aim of this study was to develop a new rapid and simple high-pressure liquid chromatography method of analysis for the routine QCs of [68Ga]-PSMA-HBED-CC to guarantee the high quality of the radiopharmaceutical product before release. Methods: A stepwise approach was used based on the quality by design concept of the International Conference of Harmonisation Q2 (R1) and Q8 (Pharmaceutical Development) guidelines in accordance with the regulations and requirements of European Association of Nuclear Medicine, Society of Nuclear Medicine, International Atomic Energy Agency, World Health Organization, and Italian Association of Nuclear Medicine and Molecular Imaging. The developed analytical test method was validated because a specific monograph in the pharmacopoeia is not available for [68Ga]-PSMA-HBED CC. Results: The purity and quality of the radiopharmaceutical obtained according to the proposed method resulted high enough to safely administrate it to patients. An excellent linearity was found between 0.8 and 5 MUg/mL, with a detection limit of 0.2 MUg/mL. Assay imprecision (% CV) was <2%. Conclusions: The developed method to assess the radiochemical and chemical purity of [68Ga]-PSMA HBED-CC is rapid, accurate, and reproducible, allowing routinely the use of this PET tracer as a diagnostic tool for imaging prostate cancer and also assuring patient safety. PMID- 29520396 TI - Discovery of Causal Models that Contain Latent Variables through Bayesian Scoring of Independence Constraints. AB - Discovering causal structure from observational data in the presence of latent variables remains an active research area. Constraint-based causal discovery algorithms are relatively efficient at discovering such causal models from data using independence tests. Typically, however, they derive and output only one such model. In contrast, Bayesian methods can generate and probabilistically score multiple models, outputting the most probable one; however, they are often computationally infeasible to apply when modeling latent variables. We introduce a hybrid method that derives a Bayesian probability that the set of independence tests associated with a given causal model are jointly correct. Using this constraint-based scoring method, we are able to score multiple causal models, which possibly contain latent variables, and output the most probable one. The structure-discovery performance of the proposed method is compared to an existing constraint-based method (RFCI) using data generated from several previously published Bayesian networks. The structural Hamming distances of the output models improved when using the proposed method compared to RFCI, especially for small sample sizes. PMID- 29520397 TI - A Practical Approach for Recognizing Eating Moments with Wrist-Mounted Inertial Sensing. AB - Recognizing when eating activities take place is one of the key challenges in automated food intake monitoring. Despite progress over the years, most proposed approaches have been largely impractical for everyday usage, requiring multiple on-body sensors or specialized devices such as neck collars for swallow detection. In this paper, we describe the implementation and evaluation of an approach for inferring eating moments based on 3-axis accelerometry collected with a popular off-the-shelf smartwatch. Trained with data collected in a semi controlled laboratory setting with 20 subjects, our system recognized eating moments in two free-living condition studies (7 participants, 1 day; 1 participant, 31 days), with F-scores of 76.1% (66.7% Precision, 88.8% Recall), and 71.3% (65.2% Precision, 78.6% Recall). This work represents a contribution towards the implementation of a practical, automated system for everyday food intake monitoring, with applicability in areas ranging from health research and food journaling. PMID- 29520395 TI - Posttraumatic Stress Disorder and Depression Symptom Severities Are Differentially Associated With Hippocampal Subfield Volume Loss in Combat Veterans. AB - Background: Two decades of human neuroimaging research have associated volume reductions in the hippocampus with posttraumatic stress disorder. However, little is known about the distribution of volume loss across hippocampal subfields. Recent advances in neuroimaging methods have made it possible to accurately delineate 10 gray matter hippocampal subfields. Here, we apply a volumetric analysis of hippocampal subfields to data from a group of combat-exposed Veterans. Method: Veterans (total, n = 68, posttraumatic stress disorder, n = 36; combat control, n = 32) completed high-resolution structural magnetic resonance imaging. Based on previously validated methods, hippocampal subfield volume measurements were conducted using FreeSurfer 6.0. The Clinician-Administered PTSD Scale assessed posttraumatic stress disorder symptom severity; Beck Depression Inventory assessed depressive symptom severity. Controlling for age and intracranial volume, partial correlation analysis examined the relationship between hippocampal subfields and symptom severity. Correction for multiple comparisons was performed using false discovery rate. Gender, intelligence, combat severity, comorbid anxiety, alcohol/substance use disorder, and medication status were investigated as potential confounds. Results: In the whole sample, total hippocampal volume negatively correlated with Clinician-Administered PTSD Scale and Beck Depression Inventory scores. Of the 10 hippocampal subfields, Clinician-Administered PTSD Scale symptom severity negatively correlated with the hippocampus-amygdala transition area (HATA). Beck Depression Inventory scores negatively correlated with dentate gyrus, cornu ammonis 4 (CA4), HATA, CA2/3, molecular layer, and CA1. Follow-up analysis limited to the posttraumatic stress disorder group showed a negative correlation between Clinician-Administered PTSD Scale symptom severity and each of HATA, CA2/3, molecular layer, and CA4. Conclusion: This study provides the first evidence relating posttraumatic stress disorder and depression symptoms to abnormalities in the HATA, an anterior hippocampal region highly connected to prefrontal-amygdala circuitry. Notably, dentate gyrus abnormalities were associated with depression severity but not posttraumatic stress disorder symptoms. Future confirmatory studies should determine the extent to which dentate gyrus volume can differentiate between posttraumatic stress disorder- and depression-related pathophysiology. PMID- 29520398 TI - Enhanced vapour sensing using silicon nanowire devices coated with Pt nanoparticle functionalized porous organic frameworks. AB - Recently various porous organic frameworks (POFs, crystalline or amorphous materials) have been discovered, and used for a wide range of applications, including molecular separations and catalysis. Silicon nanowires (SiNWs) have been extensively studied for diverse applications, including as transistors, solar cells, lithium ion batteries and sensors. Here we demonstrate the functionalization of SiNW surfaces with POFs and explore its effect on the electrical sensing properties of SiNW-based devices. The surface modification by POFs was easily achieved by polycondensation on amine-modified SiNWs. Platinum nanoparticles were formed in these POFs by impregnation with chloroplatinic acid followed by chemical reduction. The final hybrid system showed highly enhanced sensitivity for methanol vapour detection. We envisage that the integration of SiNWs with POF selector layers, loaded with different metal nanoparticles will open up new avenues, not only in chemical and biosensing, but also in separations and catalysis. PMID- 29520399 TI - Hg isotopes reveal in-stream processing and legacy inputs in East Fork Poplar Creek, Oak Ridge, Tennessee, USA. AB - Natural abundance stable Hg isotope measurements were used to place new constraints on sources, transport, and transformations of Hg along the flow path of East Fork Poplar Creek (EFPC), a point-source contaminated headwater stream in Oak Ridge, Tennessee. Particulate-bound Hg in the water column of EFPC within the Y-12 National Security Complex, was isotopically similar to average metallic Hg(0) used in industry, having a mean delta202Hg value of -0.42 +/- 0.090/00 (1SD) and near-zero Delta199Hg. On average, particulate fraction delta202Hg values increased downstream by 0.530/00, while Delta199Hg decreased by -0.100/00, converging with the Hg isotopic composition of the fine fraction of streambed sediment along the 26 km flow path. The dissolved fraction behaved differently. Although initial Delta199Hg values of the dissolved fraction were also near-zero, these values increased transiently along the flow path. Initial delta202Hg values of the dissolved fraction were more variable than in the particulate fraction, ranging from -0.44 to 0.180/00 among three seasonal sampling campaigns, but converged to an average delta202Hg value of 0.01 +/- 0.100/00 (1SD) downstream. Dissolved Hg in the hyporheic and riparian pore water had higher and lower delta202Hg values, respectively, compared to dissolved Hg in stream water. Variations in Hg isotopic composition of the dissolved and suspended fractions along the flow path suggest that: (1) physical processes such as dilution and sedimentation do not fully explain decreases in total mercury concentrations along the flow path; (2) in-stream processes include photochemical reduction, but microbial reduction is likely more dominant; and (3) additional sources of dissolved mercury inputs to EFPC at baseflow during this study predominantly arise from the hyporheic zone. PMID- 29520400 TI - Role of the (H2O)n (n = 1-3) cluster in the HO2 + HO ->3O2 + H2O reaction: mechanistic and kinetic studies. AB - To study the catalytic effects of (H2O)n (n = 1-3), the mechanisms of the reaction HO2 + HO ->3O2 + H2O without and with (H2O)n (n = 1-3) have been investigated theoretically at the CCSD(T)/aug-cc-pVTZ//M06-2X/aug-cc-pVTZ level of theory, coupled with rate constant calculations using the conventional transition state theory. Our results show that upon incorporation of (H2O)n (n = 1-3) into the channel of H2O + 3O2 formation, two different reactions, i.e. HO + HO2(H2O)n (n = 1-3) and HO2 + HO(H2O)n (n = 1-3), have been observed, and these two reactions are competitive with each other. The catalytic effects of (H2O)n (n = 1-3) mainly arise from the contribution of a single water vapor molecule; this is because the effective rate constants with water are respectively larger by 2-3 and 3-4 orders of magnitude than those of the reactions with (H2O)2 and (H2O)3. Furthermore, the catalytic effects of the water monomer mainly arise from the H2OHO2 + HO reaction, and the enhancement factor of this reaction is obvious within the temperature range of 240.0-425.0 K, with the branching ratio (k'(RW)/ktot) of 17.27-80.77%. Overall, the present results provide a new example of how water and water clusters catalyze gas phase reactions under atmospheric conditions. PMID- 29520401 TI - N- and S-donor leaving groups in triazole-based ruthena(ii)cycles: potent anticancer activity, selective activation, and mode of action studies. AB - A series of 11 novel ruthenium(ii) arene complexes [Ru(p-cym)(trzC^N)L]NO3 based on the cycloruthenated 1,2,3-triazole scaffold (trzC^N) bearing different N- or S donor leaving groups (L) were prepared. These complexes exhibited strongly diverging pH-dependent stability profiles, but consistently exerted antiproliferative effects in the low micromolar range in three cancer cell lines (A549, SW480, CH1/PA-1). The interaction with biomolecules was correlated to dissociation of the monodentate leaving group. Under oxidative conditions, the stably bound dimethylsulfide ligand (3a) undergoes oxidation, while metal coordination is maintained, affording the labile DMSO complex (3b). Rationalization of the homogenous antiproliferative activities was attempted by determination of the cellular accumulation and lipophilicity indices (phi0). Investigations on their mechanism of action revealed that these metalacycles are inducers of apoptosis, exert a slight antioxidative effect in cell culture studies, but have no DNA intercalatory activity. PMID- 29520402 TI - Chemoenzymatic synthesis of cytokinins from nucleosides: ribose as a blocking group. AB - Nucleoside phosphorylases are involved in the salvage pathways of nucleoside biosynthesis and catalyze the reversible reaction of a nucleobase with alpha-d ribose-1-phosphate to yield a corresponding nucleoside and an inorganic phosphate. The equilibrium of these reactions is shifted towards nucleosides, especially in the case of purines. Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is widely used in labs and industry for the synthesis of nucleosides of practical importance. Bacterial PNPs have relatively broad substrate specificity utilizing a wide range of purines with different substituents to form the corresponding nucleosides. To shift the reaction in the opposite direction we have used arsenolysis instead of phosphorolysis. This reaction is irreversible due to the hydrolysis of the resulting alpha-d-ribose-1-arsenate. As a result, heterocyclic bases are formed in quantitative yields and can be easily isolated. We have developed a novel method for the preparation of cytokinins based on the enzymatic cleavage of the N-glycosidic bond of N6-substituted adenosines in the presence of PNP and Na2HAsO4. According to the HPLC analysis the conversion proceeds in quantitative yields. In the proposed strategy the ribose residue acts as a protective group. No contamination of the final products with AsO43- has been detected via HPLC-HRMS; simple analytical arsenate detection via ESI-MS has been proposed. PMID- 29520413 TI - [The new TNM classification for thyroid cancer]. PMID- 29520403 TI - The alkyne-tag Raman imaging of coronatine, a plant pathogen virulence factor, in Commelina communis and its possible mode of action. AB - We previously reported that coronatine, a virulence factor of plant bacteria, facilitates bacterial infection through an ER (endoplasmic reticulum)-mediated, non-canonical mechanism in the model dicot plant, Arabidopsis thaliana. Here, we report that this same ER-mechanism is ubiquitous among dicots and monocots, and works by affecting the ethylene signaling pathway widely found in plants. The subcellular localization of coronatine by the alkyne-tag Raman imaging (ATRI) approach provided a convincing clue. PMID- 29520414 TI - [Treatment of achalasia : Laparoscopic Heller myotomy or peroral endoscopic myotomy?] PMID- 29520416 TI - Assessment of sensitivity of whole body CT for major trauma. AB - INTRODUCTION: Whole body computed tomography has become standard practice in many centres in the management of severely injured trauma patients, however, the evidence for it's diagnostic accuracy is limited. AIM: To assess the sensitivity of whole body CT in major trauma. METHOD: Retrospective review of all patients with injury severity score (ISS) > 15 presenting with blunt trauma to a UK Major Trauma Centre between May 2012 and April 2014. Injuries were classified as per ISS score-1 = head and neck 2 = face 3 = chest 4 = abdomen. The authors reviewed patient's electronic charts, radiological results; interventional procedure records, discharge letters and outpatient follow up documentation and referenced this with Trauma Audit and Research Network data. RESULTS: 407 patients with ISS > 15 presented to the Trauma centre during May 2012 and April 2014. Of these, 337 (82.8%) had a whole body CT scan. 246 pts were male, 91 were female. 74 (21.9%) were due to a fall from > 2 m, 41 (12.2%) due to a fall from < 2 m, 208 (61.7%) were due to motor vehicle crashes, 1 (0.3%) due to a blast injury, 5 (1.5%) due to blows, and 8 (2.4%) due to crush injuries. Sensitivity for Region 1 was 0.98, Region 2 = 0.98, Region 3 = 0.98 and Region 4 was 0.95. Overall sensitivity was 0.98. 15 injuries (2.4%) were not identified on initial CT (false -ve). These injuries were: colonic perforation = 1, splenic contusion = 1, pneumothorax = 1, liver laceration = 1, intracranial haemorrhage = 1, cerebral contusions = 1, spinal injuries = 7, canal haemorrhage = 1, maxilla fracture = 1. CONCLUSION: These results show that whole body CT in trauma has a high sensitivity and a low rate of missed injuries (2.4%). However, our study only evaluated a subgroup of patients with ISS > 15 and further work is required to assess the use of this investigation for all major trauma patients. PMID- 29520415 TI - Recurrent multiple neurofibromatosis type 1 of the right lower limb. AB - Neurofibromatosis type 1 is an autosomal dominant inherited disease, which is characterized by the presence of multiple neurofibromas. We encountered a case in which a sporadic dispersed neurofibroma recurred locally on numerous occasions extending over 16 years. The patient developed multiple masses with a focus of neurofibroma on the right lower limb, which were excised. The patient was initially diagnosed with inflammatory changes via computed tomography and magnetic resonance imaging; however, subsequently, pathological and immunohistochemical examinations revealed an intraneural neurofibroma. The patient underwent a comprehensive and complete local resection several times. After a continuous postoperative follow-up strategy, the patient recovered well. This report describes a case of primary manifestations of multiple and recurrent neurofibromas. We aim to emphasize the possibility of a unique, recurrent, non healing neurofibroma and review the diagnostic techniques utilized to reach a definitive diagnosis. Early and complete surgical resection is an effective method to treat and prevent this type of neurofibroma. PMID- 29520417 TI - Heavy Metal Pollution Monitoring in Vulnerable Ecosystems: A Case Study of the Lagos Lagoon, Nigeria. AB - This comparative analysis was carried out to monitor heavy metal concentrations in the Lagos Lagoon over the last 2 decades. Surface water and sediment samples were collected from stations on the Lagos Lagoon based on their suitability for comparative analysis and future monitoring. Heavy metal content in samples was determined using Flame atomic absorption spectrophotometry (FAAS). The concentrations in the samples were compared to those obtained by Don-Pedro et al. (West African Journal of Applied Ecology 5:103-114, 2004) in previous studies from the same sampling zones. Results show that concentration of most heavy metals analysed has reduced significantly (p < 0.05) in the past 2 decades. However, the concentration of Cadmium (Cd) was found to have increased significantly (p < 0.05) over the same period. Increased concentration of Cadmium poses a threat to ecosystem health thus, it is imperative that safe limits for heavy metal discharge in waste streams should be revised and implemented. PMID- 29520418 TI - [Uniform remuneration in the dual health insurance system?] PMID- 29520420 TI - [Innovations and globalization in surgery]. PMID- 29520419 TI - [Extracorporeal shock wave lithotripsy]. AB - Interventional treatment of stones essentially consists of three treatment modalities. Extracorporeal shockwave lithotripsy (ESWL), in addition to uterorenoscopy (URS) and percutaneous nephrolitholapaxy (PCNL) is an essential treatment pillar and is the only noninvasive therapy option for the treatment of urinary stones. After a long period of ESWL being the leading choice in stone treatment, the number of SWL interventions diminished in recent years in favor of the other two treatment modalities (URS and PCNL). This article describes the indications, surgical technique and management of complications of SWL. PMID- 29520421 TI - Regulatory functions of gammadelta T cells. AB - gammadelta T cells share characteristics of innate and adaptive immune cells and are involved in a broad spectrum of pro-inflammatory functions. Nonetheless, there is accumulating evidence that gammadelta T cells also exhibit regulatory functions. In this review, we describe the different phenotypes of regulatory gammadelta T cells in correlation with the identified mechanisms of suppression. PMID- 29520424 TI - [Torsion errors after fractures of long bones]. PMID- 29520422 TI - In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15. AB - A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10. Cell-based overexpression experiments revealed that this binding affected the maturation process and surface expression of the protease. Our current study shows that Tspan15 is abundantly expressed in mouse brain, where it specifically interacts with endogenous ADAM10. Tspan15 knockout mice did not reveal an overt phenotype but showed a pronounced decrease of the active and mature form of ADAM10, an effect which augmented with aging. The decreased expression of active ADAM10 correlated with an age-dependent reduced shedding of neuronal (N)-cadherin and the cellular prion protein. APP alpha-secretase cleavage and the expression of Notch-dependent genes were not affected by the loss of Tspan15, which is consistent with the hypothesis that different TspanC8s cause ADAM10 to preferentially cleave particular substrates. Analyzing spine morphology revealed no obvious differences between Tspan15 knockout and wild-type mice. However, Tspan15 expression was elevated in brains of an Alzheimer's disease mouse model and of patients, suggesting that upregulation of Tspan15 expression reflects a cellular response in a disease state. In conclusion, our data show that Tspan15 and most likely also other members of the TspanC8 family are central modulators of ADAM10-mediated ectodomain shedding in vivo. PMID- 29520425 TI - Differentiating papillary type I RCC from clear cell RCC and oncocytoma: application of whole-lesion volumetric ADC measurement. AB - PURPOSE: To determine whether objective volumetric whole-lesion apparent diffusion coefficient (ADC) distribution analysis improves upon the capabilities of conventional subjective small region-of-interest (ROI) ADC measurements for prediction of renal cell carcinoma (RCC) subtype. METHODS: This IRB-approved study retrospectively enrolled 55 patients (152 tumors). Diffusion-weighted imaging DWI was acquired at b values of 0, 250, and 800 s/mm2 on a 1.5T system (Aera, Siemens Healthcare). Whole-lesion measurements were performed by a research fellow and reviewed by a fellowship-trained radiologist. Mean, median, skewness, kurtosis, and every 5th percentile ADCs were determined from the whole lesion histogram. Linear mixed models that accounted for within-subject correlation of lesions were used to compare ADCs among RCC subtypes. Receiver operating characteristic (ROC) curve analysis with optimal cutoff points from the Youden index was used to test the ability of ADCs to differentiate clear cell RCC (ccRCC), papillary RCC (pRCC), and oncocytoma subtypes. RESULTS: Whole-lesion ADC values were significantly different between pRCC and ccRCC, and between pRCC and oncocytoma, demonstrating strong ability to differentiate subtypes across the quantiles (both P < 0.001). Best percentile ROC analysis demonstrated AUC values of 95.2 for ccRCC vs. pRCC; 67.6 for oncocytoma vs. ccRCC; and 95.8 for oncocytoma vs. pRCC. Best percentile ROC analysis further indicated model sensitivities/specificities of 84.5%/93.1% for ccRCC vs. pRCC; 100.0%/10.3% for oncocytoma vs. ccRCC; and 88.5%/93.1% for oncocytoma vs. pRCC. CONCLUSION: The objective methodology of whole-lesion volumetric ADC measurements maintains the sensitivity/specificity of conventional expert-based ROI analysis, provides information on lesion heterogeneity, and reduces observer bias. PMID- 29520426 TI - Utility of multiphasic multidetector computed tomography in discriminating between clear cell renal cell carcinomas with high and low carbonic anhydrase-IX expression. AB - PURPOSE: To investigate if multiphasic multidetector computed tomography (MDCT) enhancement profiles can distinguish clear cell renal cell carcinomas (ccRCCs) with high carbonic anhydrase-IX (CA-IX) expression from ccRCCs with low CA-IX expression. METHODS: With IRB approval for this retrospective study, we derived a cohort of 105 histologically proven ccRCCs with preoperative 4-phase renal mass MDCT from 2001 to 2013. Following manual segmentation, the computer-assisted detection algorithm selected a 0.5-cm-diameter region of maximal attenuation within each lesion in each phase. CA-IX expression level was determined by immunohistochemical staining of tumor specimens. In the high and low CA-IX expression subgroups, the magnitude of enhancement and washout were compared using t tests; the performance of contrast washout in differentiating between subgroups was assessed with logistic regression analysis. RESULTS: ccRCCs with high and low CA-IX expression both exhibited peak enhancement in the corticomedullary phase. ccRCCs with high CA-IX expression demonstrated significantly greater relative nephrographic washout than those with low CA-IX expression (18.4% vs. 7.8%, p = 0.03). ccRCCs with high CA-IX expression had greater relative excretory washout than ccRCCs with low CA-IX expression with a trend toward significance (33.4% vs. 25.2%, p = 0.05). After controlling for tumor size and stage, for distinguishing ccRCCs with high and low CA-IX expression, relative excretory washout had a sensitivity, negative predictive value, accuracy, and positive predictive value of 99% (65/66), 88% (7/8), 69% (72/105), and 67% (65/97), respectively. CONCLUSION: Relative nephrographic and excretory washout may have the potential to help distinguish ccRCCs with high and low CA-IX expression, but this requires further validation. PMID- 29520423 TI - Challenges and approaches to understand cholesterol-binding impact on membrane protein function: an NMR view. AB - Experimental evidence for a direct role of lipids in determining the structure, dynamics, and function of membrane proteins leads to the term 'functional lipids'. In particular, the sterol molecule cholesterol modulates the activity of many membrane proteins. The precise nature of cholesterol-binding sites and the consequences of modulation of local membrane micro-viscosity by cholesterol, however, is often unknown. Here, we review the current knowledge of the interaction of cholesterol with transmembrane proteins, with a special focus on structural aspects of the interaction derived from nuclear magnetic resonance approaches. We highlight examples of the importance of cholesterol modulation of membrane protein function, discuss the specificity of cholesterol binding, and review the proposed binding motifs from a molecular perspective. We conclude with a short perspective on what could be future trends in research efforts targeted towards a better understanding of cholesterol/membrane protein interactions. PMID- 29520428 TI - XXIst Symposium Neuroradiologicum. PMID- 29520427 TI - The role of FDG-PET/CT in gynecologic imaging: an updated guide to interpretation and challenges. AB - All women, during their lifetime, are at risk of developing some form of gynecologic malignancy. The role of FDG-PET/CT has become more established in the management of gynecologic malignancies in the last decade. In this article, we will review the role of FDG-PET/CT in endometrial, cervical, ovarian, and vaginal cancer, by highlighting its strengths and limitations. While the role in initial or pre-operative staging for FDG-PET/CT is controversial, it allows noninvasive detection of equivocal or distant metastases, may alter stage and prognosis, and can guide or help eliminate unnecessary interventions that may not be beneficial. FDG-PET/CT is a useful adjunct to traditional staging with MR and CT. PMID- 29520430 TI - Prostatic Fragment Requiring Endoscopic Management After Prostatic Artery Embolization for Indwelling Bladder Catheter. PMID- 29520429 TI - Robustness versus disease differentiation when varying parameter settings in radiomics features: application to nasopharyngeal PET/CT. AB - OBJECTIVES: To investigate the impact of parameter settings as used for the generation of radiomics features on their robustness and disease differentiation (nasopharyngeal carcinoma (NPC) versus chronic nasopharyngitis (CN) in FDG PET/CT imaging). METHODS: We studied 106 patients (69/37 NPC/CN, pathology confirmed), and extracted 57 radiomics features under different parameter settings. Robustness was assessed by the intra-class correlation coefficient (ICC). Logistic regression with leave-one-out cross validation was used to generate classification probabilities, and diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: Varying averaging strategies and symmetry, 4/26 GLCM features showed poor range of pairwise ICCs of 0.02-0.98, while depicting good AUCs of 0.82-0.91. Varying distances, 5/26 GLCM features showed ICCs of 0.82-0.99 while corresponding AUCs were 0.52-0.91. 6/13 GLRLM features showed both high AUC (0.81-0.89) and high ICC (0.85-0.99) regarding to averaging strategies. 7/13 GLSZM features showed AUCs of 0.81-0.90 while having ICCs of 0.01-0.99 under different neighbourhoods. 2/5 NGTDM features showed AUCs of 0.81-0.85 while having ICCs of 0.19-0.89 for different window sizes. Differentiating a subset of NPC (stages I-II) form CN, both SumEntropy and SZLGE achieved significantly higher AUCs than metabolically active tumour volume (AUC: 0.91 vs. 0.72, p<0.01). CONCLUSIONS: Radiomics features depicting poor absolute-scale robustness regarding to parameter settings can still lead to good diagnostic performance. As such, robustness of radiomics features should not be overemphasized for removal of features towards assessment of clinical tasks. For differentiating NPC from CN, some radiomics features (e.g. SumEntropy, SZLGE, LGZE) outperformed conventional metrics. KEY POINTS: * Poor robustness did not necessarily translate into poor differentiation performance. * Absolute-scale robustness of radiomics features should not be overemphasized. * Radiomics features SumEntropy, SZLGE and LGZE outperformed conventional metrics. PMID- 29520432 TI - The Arsenic Contamination of Drinking and Groundwaters in Bangladesh: Featuring Biogeochemical Aspects and Implications on Public Health. AB - Arsenic is a widespread contaminant of drinking and groundwaters in the world. Even if these contaminations have a geogenic origin, they often are exacerbated by anthropogenic activities. This is particularly true for the Bengal delta. Millions of people in Bangladesh are consuming drinking water with arsenic concentrations >= 50 ug/L. Their drinking water supply is based on groundwaters extracted by pumping wells, which were part of a well-drilling program by the United Nations. The intention was to provide the people with groundwater instead of surface water due to its critical hygienic conditions. Unfortunately, many wells extract the groundwater at depths where arsenic concentrations are highest. Arsenic is being dissolved from the aquifer by biogeochemical processes that are fueled by the presence of high amounts of organics in the Bengal delta sediments. This problem was not encountered at the time due to a lack of chemical analyses of the waters. PMID- 29520431 TI - Primary Stenting of the Superficial Femoral Artery in Patients with Intermittent Claudication Has Durable Effects on Health-Related Quality of Life at 24 Months: Results of a Randomized Controlled Trial. AB - BACKGROUND: Intermittent claudication (IC) is commonly caused by lesions in the superficial femoral artery (SFA), yet invasive treatment is still controversial and longer term patient-reported outcomes are lacking. This prospective randomized trial assessed the 24-month impact of primary stenting with nitinol self-expanding stents compared to best medical treatment (BMT) alone in patients with stable IC due to SFA disease on health-related quality of life (HRQoL). METHODS: One hundred patients with stable IC due to SFA disease treated with BMT were randomized to either stent (n = 48) or control (n = 52) group. HRQoL assessed by Short Form 36 Health Survey (SF-36) and EuroQoL 5-dimensions (EQ5D) 24 months after treatment were primary outcome measures. Walking Impairment Questionnaire, ankle-brachial index (ABI), and walking distance were secondary outcomes. RESULTS: Significantly better SF-36 Physical Component Summary (P = 0.024) and physical domain scores such as Physical Function (P = 0.012), Bodily Pain (P = 0.002), General Health (P = 0.037), and EQ5D (P = 0.010) were reported in intergroup comparison between the stent and the control group. Both ABI (from 0.58 +/- 0.11 to 0.85 +/- 0.18; P < 0.001 in the stent group and from 0.63 +/- 0.17 to 0.69 +/- 0.18; P = 0.036 in the control group) and walking distance (from 170 +/- 90 m to 616 +/- 375 m; P < 0.001 in the stent group and from 209 +/- 111 m to 331 +/- 304 m; P = 0.006 in the control group) improved significantly in intragroup comparisons. CONCLUSIONS: In patients with IC caused by lesions in the SFA, primary stenting compared to BMT alone was associated with significant improvements in HRQoL, ABI, and walking distance durable up to 24 months of follow-up. Clinical Trial Registration http://www.clinicaltrials.gov . Unique Identifier: NCT01230229. PMID- 29520433 TI - Connecting criminal justice, mental health, and family support for better delivery of human services. PMID- 29520434 TI - A patient with B-cell acute lymphoblastic leukemia with PAX5-ETV6 rearrangement with dic(9;12)(p13;p13) identified by chromosomal microarray. PMID- 29520435 TI - A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma. AB - PURPOSE: The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC). METHODS: Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design. Dose limiting toxicity (DLT) was defined as treatment related grade 3 or 4 non-hematologic toxicity (except for a subset of manageable toxicities) or any grade 4 hematologic toxicities. RESULTS: In 21 patients enrolled, there were 3 DLTs; grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis. The maximum tolerated dose of cixutumumab was 4 mg/kg IV weekly with standard dose sorafenib. Eighteen of 21 (86%) patients had grade 3 or above toxicities attributed to treatment. One patient also experienced grade 4 colonic perforation and grade 5 peritonitis. The median number of cycles completed was 4 (0-26). Of 16 patients evaluable for response, 81% achieved stable disease. The median progression free survival was 6.0 months (95% CI 3.6 undefined) and the median overall survival was 10.5 months (95% CI 7.1 undefined). CONCLUSIONS: While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC. PMID- 29520436 TI - History and current state of pediatric neurosurgery at Beijing Tiantan Hospital Neurosurgery Center. PMID- 29520437 TI - Central nervous system (CNS) neuroblastoma. A case-based update. AB - BACKGROUND: Primary central nervous system (CNS) neuroblastoma is a rare intracranial tumor affecting children mainly in the first years of life. It is usually a supratentorial tumor with a wide spectrum of clinical presentation, seizures, and focal neurological deficits being the most common presenting signs. CASE DESCRIPTION: A 2-year-old child was admitted to our ward after a generalized seizure. Neurological examination was normal. Radiological studies showed a small DWI hyperintense lesion of the right rectus gyrus. Follow-up brain MRI 8 months later showed a huge growth of the tumor (90 * 80 * 65 mm) with polycyclic and apparently defined margins, cystic components, and diffuse contrast enhancement. Complete tumor removal was performed in two planned surgical steps. Histological diagnosis was CNS neuroblastoma. At a follow-up of 8 months, the child is in good clinical and neurological condition and is completing chemotherapy treatment according to the SIOP PNET 4 protocol. DISCUSSION AND CONCLUSION: A thorough review of the literature confirms that primary CNS neuroblastoma has to be considered a distinct entity. The disease related mortality is 12.5%, lower than the one usually reported for other previously described as PNETs tumors. The most relevant factors influencing prognosis are the possibility of obtaining a complete tumor removal and age more than 3 years, which allows to include radiotherapy among treatment options. PMID- 29520438 TI - African Forest Honey: an Overlooked NTFP with Potential to Support Livelihoods and Forests. AB - In parts of the developing world, deforestation rates are high and poverty is chronic and pervasive. Addressing these issues through the commercialization of non-timber forest products (NTFPs) has been widely researched, tested, and discussed. While the evidence is inconclusive, there is growing understanding of what works and why, and this paper examines the acknowledged success and failure factors. African forest honey has been relatively overlooked as an NTFP, an oversight this paper addresses. Drawing on evidence from a long-established forest conservation, livelihoods, and trade development initiative in SW Ethiopia, forest honey is benchmarked against accepted success and failure factors and is found to be a near-perfect NTFP. The criteria are primarily focused on livelihood impacts and consequently this paper makes recommendations for additional criteria directly related to forest maintenance. PMID- 29520439 TI - Validation of Davson's equation in patients suffering from idiopathic normal pressure hydrocephalus. AB - INTRODUCTION: The so-called Davson's equation relates baseline intracranial pressure (ICP) to resistance to cerebrospinal fluid outflow (Rout), formation of cerebrospinal fluid (If) and sagittal sinus pressure (PSS) There is a controversy over whether this fundamental equation is applicable in patients with normal pressure hydrocephalus (NPH). We investigated the relationship between Rout and ICP and also other compensatory, clinical and demographic parameters in NPH patients. METHOD: We carried out a retrospective study of 229 patients with primary NPH who had undergone constant-rate infusion studies in our hospital. Data was recorded and processed using ICM+ software. Relationships between variables were sought by calculating Pearson product correlation coefficients and p values. RESULTS: We found a significant, albeit weak, relationship between ICP and Rout (R = 0.17, p = 0.0049), Rout and peak-to-peak amplitude of ICP (AMP) (R = 0.27, p = 3.577e-05) and Rout and age (R = 0.16, p = 0.01306). CONCLUSIONS: The relationship found between ICP and Rout provides indirect evidence to support disturbed Cerebrospinal fluid circulation as a key factor in disturbed CSF dynamics in NPH. Weak correlation may indicate that other factors-variable PSS and formation of CSF outflow-contribute heavily to linear model expressed by Davson's equation. PMID- 29520440 TI - Procalcitonin and C-reactive protein as early markers of anastomotic leak after laparoscopic colorectal surgery within an enhanced recovery after surgery (ERAS) program. AB - BACKGROUND: C-reactive protein (CRP) and procalcitonin (PCT) have been described as good predictors of anastomotic leak after colorectal surgery, obtaining the highest diagnostic accuracy on the 5th postoperative day. However, if an enhanced recovery after surgery (ERAS) program is performed, early predictors are needed in order to ensure a safe and early discharge. The aim of this study was to investigate the efficacy of CRP, PCT, and white blood cell (WBC) count determined on first postoperative days, in predicting septic complications, especially anastomotic leak, after laparoscopic colorectal surgery performed within an ERAS program. METHODS: We conducted a prospective study including 134 patients who underwent laparoscopic colorectal surgery within an ERAS program between 2015 and 2017. The primary endpoint investigated was anastomotic leak. CRP, PCT, and WBC count were determined in the blood sample extracted on postoperative day 1 (POD 1), POD 2 and POD 3. RESULTS: Anastomotic leak (AL) was detected in 6 patients (4.5%). Serum levels of CRP and PCT, but not WBC, determined on POD 1, POD 2, and POD 3 were significantly higher in patients who had AL in the postoperative course. Using ROC analysis, the best AUC of the CRP and PCT levels was on POD 3 (0.837 and 0.947, respectively). A CRP cutoff level at 163 mg/l yielded 85% sensitivity, 80% specificity, and 99% negative predictive value (NPV). A PCT cutoff level at 2.5 ng/ml achieved 85% sensitivity, 95% specificity, 44% positive predictive value, and 99% NPV. CONCLUSIONS: CRP and PCT are relevant markers for detecting postoperative AL after laparoscopic colorectal surgery. Furthermore, they can ensure an early discharge with a low probability of AL when an ERAS program is performed. PMID- 29520441 TI - Optimal cancer care: what essential elements of care would help haematological cancer patients obtain and understand information about their disease and its treatment and impact? AB - PURPOSE: To describe the perceptions of haematological cancer patients about the components of care deemed essential to supporting them to obtain and understand information about their cancer, its treatment and its impact on their life. METHODS: A cross-sectional survey was conducted with individuals diagnosed with haematological cancer. Eligible patients presenting for a scheduled outpatient appointment were invited to complete a pen-and-paper survey in the clinic waiting room while waiting for their appointment. Those who completed the survey were mailed a second survey approximately 4 weeks later. Participants provided data about their demographic and disease characteristics and perceptions of optimal care for haematological cancer patients. RESULTS: A total of 170 patients completed both surveys and were included in the analysis. The items endorsed as essential components of care by the highest number of participants were being able to share accurate information about their disease, treatment and ongoing care with their GP/family doctor (49%); being able to obtain up-to-date information specific to their circumstances (43%); being able to obtain information in the amount of detail that they want (34%); being able to call a health care professional at the treatment centre where they are receiving care (34%) and being able to call an experienced health care professional who has knowledge of their disease and its treatment (34%). CONCLUSIONS: Further research is needed to determine ways of meeting the preferences of haematological cancer patients and determining the associated impact on patient outcomes. PMID- 29520442 TI - CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. AB - PURPOSE: This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. MATERIALS AND METHODS: The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2'3'-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC). RESULTS: Among the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. Meanwhile, CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. During the median follow-up duration of 39 months, 14 (15.7%) patients experienced disease recurrence. Among the five immune checkpoint proteins, CD274, LAG3, and IDO1 expressions in TIICs were significantly associated with a better disease-free survival (DFS) in a univariate analysis (P = 0.028, 0.037, and 0.030 respectively). Moreover, co-expression of CD274, LAG3, and IDO1 in TIICs showed an even better survival for DFS (P = 0.010). In a multivariate survival analysis, CD274, LAG3, and IDO1 expressions in TIICs remained as independent prognostic factors for a better DFS. CONCLUSION: CD274, LAG3, and IDO1 expressions in TIICs showed a better prognosis for patients with MSI-H colon cancer. Thus, the potential therapeutic implications of these immune checkpoint molecules should be further investigated. PMID- 29520443 TI - Face sensorimotor cortex undergoes neuroplastic changes in a rat model of trigeminal neuropathic pain. AB - Trigeminal nerve injury can result in neuropathic pain behavior and alterations in motor function, but it is unclear if such injury produces neuroplastic alterations in face sensorimotor cortex that could contribute to the alterations in motor function. Therefore, this study aimed to determine if trigeminal nerve injury in a rat neuropathic pain model induces neuroplastic changes in jaw and tongue motor representations in face sensorimotor cortex in association with facial nociceptive behavior. Right infraorbital nerve transection was performed in adult male Sprague-Dawley rats; sham-operated rats served as controls. Nociceptive behavior was assessed by testing facial mechanical sensitivity pre operatively and post-operatively (1-28 days). Intracortical microstimulation was also applied post-operatively in a series of microelectrode penetrations to map jaw and tongue motor representations in the face sensorimotor cortex by analyzing anterior digastric and genioglossus electromyographic activities evoked by microstimulation at histologically verified sites in face primary somatosensory cortex (face-SI) as well as face primary motor cortex (face-MI). Compared to sham, infraorbital nerve injury induced a significant (2-way repeated-measures analysis of variance, P < 0.001) bilateral decrease in facial mechanical threshold that lasted up to 28 days post-operatively. Nerve injury also induced a significant bilateral decrease compared to sham (P < 0.05) in the number of anterior digastric and/or genioglossus sites in face-MI and in face-SI. These findings indicate that trigeminal nerve injury induces neuroplastic alterations in jaw and tongue motor representations in face sensorimotor cortex that are associated with facial nociceptive behavior and that may contribute to sensorimotor changes following trigeminal nerve injury. PMID- 29520444 TI - Sensory adaptation and inhibition of return: dissociating multiple inhibitory cueing effects. AB - Inhibition of return (IOR) refers to an increase in reaction times to targets that appeared at a previously cued location relative to an uncued location, often investigated using a spatial cueing paradigm. Despite numerous studies that have examined many aspects of IOR, the neurophysiological mechanisms underlying IOR are still in dispute. The objective of the current research is to investigate the plausible mechanisms by manipulating the cue and target types between central and peripheral stimuli in a traditional cue-target paradigm with saccadic responses to targets. In peripheral-cueing conditions, we observed inhibitory cueing effects across all cue-target onset asynchronies (CTOAs) with peripheral targets, but IOR was smaller and arose later with central targets. No inhibition was observed in central-cueing conditions at any CTOAs. Empirical data were simulated using a two-dimensional dynamic neural field model. Our results and simulations support previous work demonstrating that, at short CTOAs, behavioral inhibition is only observed with repeated stimulation-an effect of sensory adaptation. With longer CTOAs, IOR is observed regardless of target type when peripheral cueing is used. Our findings suggest that behaviorally exhibited inhibitory cueing effects can be attributed to multiple mechanisms, including both attenuation of visual stimulation and local inhibition in the superior colliculus. PMID- 29520445 TI - The power law as behavioral illusion: reappraising the reappraisals. AB - Marken and Shaffer (Exp Brain Res 235:1835-1842, 2017) have argued that the power law of movement, which is generally thought to reflect the mechanisms that produce movement, is actually an example of what Powers (Psychol Rev 85:417-435, 1978) dubbed a behavioral illusion, where an observed relationship between variables is seen as revealing something about the mechanisms that produce a behavior when, in fact, it does not. Zago et al. (Exp Brain Res. https://doi.org/10.1007/s0022-017-5108-z , 2017) and Taylor (Exp Brain Res, https://doi.org/10.1007/s00221-018-5192-8 , 2018) have "reappraised" this argument, claiming that it is based on logical, mathematical, statistical and theoretical errors. In the present paper we answer these claims and show that the power law of movement is, indeed, an example of a behavioral illusion. However, we also explain how this apparently negative finding can point the study of movement in a new and more productive direction, with research aimed at understanding movement in terms of its purposes rather than its causes. PMID- 29520446 TI - When to Stop Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. AB - OPINION STATEMENT: Strict criteria for when to stop tyrosine kinase inhibitor (TKI) therapy in clinical practice are not easily defined without an agreement on what probability of achieving a treatment-free remission (TFR) constitutes a medically acceptable standard and consideration of the potential medical risks of continued TKI therapy and/or patient preferences. Patients in sustained deep molecular response (DMR) have no significant chronic myelogenous leukemia-related risk of progression and death, and thus, safety is of paramount importance. Patients with prior history of advanced disease, additional chromosomal abnormalities (ACA), atypical transcripts, TKI resistance, high Sokal score, or who cannot be relied upon to come for regular molecular monitoring should generally be excluded from TKI cessation in clinical practice. Similarly, stopping TKIs should not be attempted without the availability of standardized BCR-ABL1 testing with a sensitivity of at least MR4.5 and a turnaround time of less than 4 weeks. Prior TKI therapy of 5 years and stable MR4.0 of 2 years or more constitutes reasonable minimal criteria for stopping TKIs with approximately a 50% chance of success. The risk of morbidity with continued TKI therapy and patient preferences need to be considered to determine to what extent these minimal criteria should be exceeded and at what threshold to re-initiate therapy whether on the loss of major molecular response or at a lower molecular endpoint. PMID- 29520447 TI - Current and Future Directions for Angiosarcoma Therapy. AB - OPINION STATEMENT: Angiosarcomas are rare vascular neoplasms that are among the most aggressive subtypes of soft tissue sarcomas. Surgical resection is often challenging even in localized disease, as the infiltrative nature of these cancers leads to frequent local and metastatic recurrences. Cytotoxic chemotherapy, including anthracycline-based regimens and taxanes can produce significant responses in a subset of patients but durability is limited with most patients ultimately succumbing to metastatic disease. Targeted therapy with tyrosine kinase inhibitors is usually well-tolerated but prone to development of resistance. Few head-to-head trials have addressed the optimal sequence of therapies, or demonstrated conclusive benefits of one therapy over another based on clinical and etiologic factors. Novel therapies in clinical trials, including antibodies to endoglin and checkpoint inhibitors have demonstrated exciting early activity in patients with angiosarcoma. Improved understanding of the genetic heterogeneity within various angiosarcoma subtypes may identify predictive biomarkers to match patients to effective existing and future therapies. Overall, angiosarcoma patients with optimal performance status are best served in clinical trials that incorporate novel combinations of cytotoxic chemotherapy, targeted therapies, and immunotherapies. PMID- 29520448 TI - Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies. AB - OPINION STATEMENT: Bacillus Calmette-Guerin in urothelial carcinoma, high-dose interleukin-2 in renal cell carcinoma, and sipuleucel-T in prostate cancer serve as enduring examples that the host immune response can be harnessed to promote effective anti-tumor immunity in genitourinary malignancies. Recently, cancer immunotherapy with immune checkpoint inhibitors has transformed the prognostic landscape leading to durable responses in a subset of urothelial carcinoma and renal cell carcinoma patients with traditionally poor prognosis. Despite this success, many patients fail to respond to immune checkpoint inhibitors and progression/relapse remains common. Furthermore, modest clinical activity has been observed with ICIs as a monotherapy in advanced PCa. As such, novel treatment approaches are warranted and improved biomarkers for patient selection and treatment response are desperately needed. Future efforts should focus on exploring synergistic and rational combinations that safely and effectively boost response rates and survival in genitourinary malignancies. Specific areas of interest include (1) evaluating the optimal sequencing, disease burden, and timing of immuno-oncology agents with other anti-cancer therapeutics and (2) validating novel biomarkers of response to immunotherapy to optimize patient selection and to identify individuals most likely to benefit from immunotherapy across the heterogenous spectrum of genitourinary malignancies. PMID- 29520449 TI - Cardiac CT in the Emergency Department: Contrasting Evidence from Registries and Randomized Controlled Trials. AB - PURPOSE OF REVIEW: To compare outcomes between registries and randomized controlled trials of coronary computed tomographic angiography (CCTA)-based versus standard of care approaches to the initial evaluation of patients with acute chest pain. RECENT FINDINGS: Randomized trials have demonstrated CCTA to be a safe and efficient tool for triage of low- to intermediate-risk patients presenting to the emergency department with chest pain. Recent studies demonstrate heterogeneous result using different standard of care approaches for evaluation of hard endpoints in comparison with standard evaluation. Also, there has been continued concern for increase in subsequent testing after coronary CTA. Although CCTA improves detection of coronary artery disease, it is uncertain if it will bring improvement of long-term health outcomes at this point of time. Careful analysis of the previous results and further investigation will be required to validate evaluation of hard endpoints. PMID- 29520450 TI - Haloarchaea from the Andean Puna: Biological Role in the Energy Metabolism of Arsenic. AB - Biofilms, microbial mats, and microbialites dwell under highly limiting conditions (high salinity, extreme aridity, pH, and elevated arsenic concentration) in the Andean Puna. Only recent pioneering studies have described the microbial diversity of different Altiplano lakes and revealed their unexpectedly diverse microbial communities. Arsenic metabolism is proposed to be an ancient mechanism to obtain energy by microorganisms. Members of Bacteria and Archaea are able to exploit arsenic as a bioenergetic substrate in either anaerobic arsenate respiration or chemolithotrophic growth on arsenite. Only six aioAB sequences coding for arsenite oxidase and three arrA sequences coding for arsenate reductase from haloarchaea were previously deposited in the NCBI database. However, no experimental data on their expression and function has been reported. Recently, our working group revealed the prevalence of haloarchaea in a red biofilm from Diamante Lake and microbial mat from Tebenquiche Lake using a metagenomics approach. Also, a surprisingly high abundance of genes used for anaerobic arsenate respiration (arr) and arsenite oxidation (aio) was detected in the Diamante's metagenome. In order to study in depth the role of arsenic in these haloarchaeal communities, in this work, we obtained 18 haloarchaea belonging to the Halorubrum genus, tolerant to arsenic. Furthermore, the identification and expression analysis of genes involved in obtaining energy from arsenic compounds (aio and arr) showed that aio and arr partial genes were detected in 11 isolates, and their expression was verified in two selected strains. Better growth of two isolates was obtained in presence of arsenic compared to control. Moreover, one of the isolates was able to oxidize As[III]. The confirmation of the oxidation of arsenic and the transcriptional expression of these genes by RT-PCR strongly support the hypothesis that the arsenic can be used in bioenergetics processes by the microorganisms flourishing in these environments. PMID- 29520451 TI - Physiological and Ecological Aspects of Chlorella sorokiniana (Trebouxiophyceae) Under Photoautotrophic and Mixotrophic Conditions. AB - Mixotrophy is a metabolic strategy in which an organism is autotrophic and heterotrophic simultaneously. Considering that the aquatic environment provides several organic sources of carbon, it is probably common for microalgae to perform mixotrophy and not only photoautotrophy, but little is known about microalgae mixotrophy. The present work aimed at investigating the growth, photosynthetic activity, morphology, and biochemical composition of the microalga Chlorella sorokiniana in mixotrophic and photo-mixotrophic conditions, comparing it with photoautotrophy. The results showed pH changes after glucose addition, reaching pH 11.62 in mixotrophic and 10.47 in sequential photo-mixotrophic cultures, which limited the microalgal growth. Highest biomass was obtained in the mixotrophic culture in comparison with the sequential photo-mixotrophic one. Rapid light saturation curves showed that alpha (photosynthetic efficiency, 1.69) and relative electron transport rate (rETR; 565.61) were higher in the mixotrophic cultures, whereas the highest Ik (irradiance saturation, 386.68) was obtained in the photoautotrophic ones. In the sequential photo-mixotrophic cultures, photosynthetic activity varied during glucose consumption, decreasing the maximum quantum yield Fv/Fm after glucose addition, indicating change in metabolism, from photoautotrophy to mixotrophy by the microalga. The results showed that the mixotrophic cultures had higher production of chlorophyll a (6.26 mg mL-1), cell density (6.62 * 107 cell mL-1), and lipids (0.06 pg MUm-3). Sequential photo-mixotrophic cultures showed the highest biovolume (360.5 MUm3 cell-1) and total carbohydrates (0.026 pg MUm-3). The protein concentration was 3.2 and 2.4 times higher in photoautotrophy and photo-mixotrophic growth, respectively, than in mixotrophy, but lipids were three times higher under mixotrophy. The biochemical changes we observed indicate that the microalga's plasticity in face of new environmental characteristics, such as the presence of organic carbon, can change the flow of energy through natural ecosystems. PMID- 29520452 TI - Egalitarianism in Biofilms. AB - Microbial biofilms are multicellular communities of sessile microorganisms encased by the hydrated polymeric matrix. They have significant influences on both aquatic/terrestrial ecosystem and anthropogenic activities. Taking advantage of the governing features of selective stress (Tan and Ng in Water Res 42:1122 1132, 2008; Wei in Water Res 45:863-871, 2011; Dereli in Water Res 59C:11-22, 2014), the evenness of microbial communities in a membrane-centered mesocosm was successfully manipulated. By measuring the biofilm growing rates under different evenness levels of communities, an evenly distributed community favors the formation of biofilms was observed. This finding is not only a new evidence linking biofilm diversity to its functionality but also a clear suggestion on controlling a biofilm-based process via a simple and smart way. PMID- 29520453 TI - Detection and Characterization of Streptomycin Resistance (strA-strB) in a Honeybee Gut Symbiont (Snodgrassella alvi) and the Associated Risk of Antibiotic Resistance Transfer. AB - Use of antibiotics in medicine and farming contributes to increasing numbers of antibiotic-resistant bacteria in diverse environments. The ability of antibiotic resistance genes (ARG) to transfer between bacteria genera contributes to this spread. It is difficult to directly link antibiotic exposure to the spread of ARG in a natural environment where environmental settings and study populations cannot be fully controlled. We used managed honeybees in environments with contrasting streptomycin exposure (USA: high exposure, Norway: low exposure) and mapped the prevalence and spread of transferrable streptomycin resistance genes. We found a high prevalence of strA-strB genes in the USA compared to Norway with 17/90 and 1/90 positive samples, respectively (p < 0.00007). We identified strA strB genes on a transferrable transposon Tn5393 in the honeybee gut symbiont Snodgrassella alvi. Such transfer of resistance genes increases the risk of the spread to new environments as honeybees are moved to new pollination sites. PMID- 29520454 TI - Extra nodular metastasis is a poor prognostic factor for overall survival in node positive patients with colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the second leading cause for cancer related death in industrialized nations. Nodal involvement has been identified as a relevant prognostic feature in CRC. Extra nodal metastasis (ENM) describes the spread of malignant cells beyond the nodal capsule. ENM is thought to be an independent risk factor for poor survival. This study examined ENM as an independent risk factor for poor overall survival in patients with node-positive CRC. MATERIALS AND METHODS: Data from a prospectively maintained CRC database was retrospectively analyzed. Blinded slides of patients with stage III and IV CRC following radical surgical resection were re-examined for the presence of ENM. The effect of ENM on overall survival was examined using Kaplan-Meier curves. RESULTS: One hundred forty-seven cases with node-positive CRC (UICC stages III and IV) including 78 cases with ENM were included for analysis. ENM was seen in 60 patients with colon cancer (58.8%) and in 18 patients with rectal cancer (40%), p = 0.033. ENM-positive patients had a significantly higher odd for cancer related death compared to ENM-negative patients ratio of [OR 0.44: 0.22-0.88, CI 95%, p = 0.021], p = 0.02. The median overall survival was significantly longer in patients without ENM, 51.0 +/- 33 vs. 30.5 +/- 42 months, p = 0.02. CONCLUSION: Extra nodal metastasis is an independent prognostic factor in patients with node-positive colorectal cancer. Extra nodal metastasis is associated with high odds of tumor-related mortality and poor overall survival. PMID- 29520455 TI - A novel summary report of colonoscopy: timeline visualization providing meaningful colonoscopy video information. AB - PURPOSE: The colonoscopy adenoma detection rate depends largely on physician experience and skill, and overlooked colorectal adenomas could develop into cancer. This study assessed a system that detects polyps and summarizes meaningful information from colonoscopy videos. METHODS: One hundred thirteen consecutive patients had colonoscopy videos prospectively recorded at the Seoul National University Hospital. Informative video frames were extracted using a MATLAB support vector machine (SVM) model and classified as bleeding, polypectomy, tool, residue, thin wrinkle, folded wrinkle, or common. Thin wrinkle, folded wrinkle, and common frames were reanalyzed using SVM for polyp detection. The SVM model was applied hierarchically for effective classification and optimization of the SVM. RESULTS: The mean classification accuracy according to type was over 93%; sensitivity was over 87%. The mean sensitivity for polyp detection was 82.1%, and the positive predicted value (PPV) was 39.3%. Polyps detected using the system were larger (6.3 +/- 6.4 vs. 4.9 +/- 2.5 mm; P = 0.003) with a more pedunculated morphology (Yamada type III, 10.2 vs. 0%; P < 0.001; Yamada type IV, 2.8 vs. 0%; P < 0.001) than polyps missed by the system. There were no statistically significant differences in polyp distribution or histology between the groups. Informative frames and suspected polyps were presented on a timeline. This summary was evaluated using the system usability scale questionnaire; 89.3% of participants expressed positive opinions. CONCLUSIONS: We developed and verified a system to extract meaningful information from colonoscopy videos. Although further improvement and validation of the system is needed, the proposed system is useful for physicians and patients. PMID- 29520456 TI - MRI defecography of the ileal pouch-anal anastomosis-contributes little to the understanding of functional outcome. AB - PURPOSE: Variability in functional outcome after ileal pouch-anal anastomosis (IPAA) is to a large extent unexplained. The aim of this study was to use MRI to evaluate the morphology, emptying pattern and other pathology that may explain differences in functional outcome between well-functioning and poorly functioning pouch patients. A secondary aim was to establish a reference of normal MRI findings in pelvic pouch patients. METHODS: From a previous study, the best and worst functioning patients undergoing IPAA surgery between 2000 and 2013 had been identified and examined with manovolumetric tests (N = 47). The patients were invited to do a pelvic MRI investigating pouch morphology and emptying patterns, followed by a pouch endoscopy. RESULTS: Forty-three patients underwent MRI examination. We found no significant morphological or dynamic differences between the well-functioning and poorly functioning pouch patients. There was no correlation between urge volume and the volume of the bony pelvis, and no correlation between emptying difficulties or leakage and dynamic MRI findings. Morphological MRI signs of inflammation were present in the majority of patients and were not correlated to histological signs of inflammation. Of the radiological signs of inflammation, only pouch wall thickness correlated to endoscopic pouchitis disease activity index scores. CONCLUSION: It seems MRI does not increase the understanding of factors contributing to functional outcome after ileal pouch-anal anastomosis. Unless there is a clinical suspicion of perianal/peripouch disease or pelvic sepsis, MRI does not add value as a diagnostic tool for pelvic pouch patients. Endoscopy remains the golden standard for diagnosing pouch inflammation. PMID- 29520457 TI - Risk factors associated with longer cecal intubation time: a systematic review and meta-analysis. AB - PURPOSE: Cecal intubation time (CIT) is an indicator for difficult colonoscopy which is associated with patients' unpleasant experience as well as increased risk of complications. Several studies have attempted to identify predictors for prolonged CIT but those studies tended to be small which gave rise to inconsistent and underpowered results. This systematic review and meta-analysis was conducted to summarize all available data. METHODS: MEDLINE and EMBASE databases were searched through November 2017 for studies that investigated the factors for prolonged CIT. Only factors that were reported by at least three studies were included in the meta-analyses. Pooled mean difference (MD) and 95% confidence interval (CI) were calculated using random effects model. The between study heterogeneity of effect size was quantified using the Q statistic and I2. RESULTS: A total of nine studies involving 7131 patients were included. A total of six factors were analyzed. Patients with older age (>= 65 versus < 65), female sex (versus male), low body mass index (BMI) (< 25 versus >= 25 kg/m2), and poor bowel preparation (versus fair to good) had significantly longer CIT. The presence of diverticulosis and prior abdominal surgery were not significantly associated with prolonged CIT. CONCLUSIONS: The current meta-analyses have demonstrated that old age, female sex, low BMI, and poor bowel preparation were the predictors for prolonged CIT. PMID- 29520458 TI - Heterologous expression of kiwifruit (Actinidia chinensis) GOLDEN2-LIKE homolog elevates chloroplast level and nutritional quality in tomato (Solanum lycopersicum). AB - MAIN CONCLUSION: Constitutive expression of AchGLK from A. chinensis in transgenic tomato (S. lycopersicum) confers fruits an elevated plastid biogenesis with intensified granule thylakoid stacks and increased content of nutritional compounds. Plastid development is regulated by multiple environmental and genetic factors. Golden2-like (GLK) genes, members from GARP subfamily of the MYB transcription factors, have been shown to regulate plastid biogenesis and development in several species. In tomato (S. lycopersicum), SlGLK2 gene is expressed in the fruit in a manner of latitudinal gradient and determines the green shoulder phenotype. Here, we report the isolation and characterization of a kiwifruit (A. chinensis) GLK homolog (AchGLK). Transcription analysis showed that AchGLK is highly expressed in mature leaves and in fruits 60-day post-anthesis. Overexpression of AchGLK in transgenic tomato resulted in dark green immature fruit with higher concentration of chlorophyll and overall increased chloroplast compartment, both number and size. The ripened fruit had higher levels of carotenoids and sugars as well. Nevertheless, no phenotypic changes were observed in the transgenic leaves, similar to the previously described overexpression of SlGLK2 in tomato. Our study suggests that AchGLK is functionally homologous to tomato GLK2 with a potential in regulating plastid level in fruit that could contribute to improvement of fruit quality. PMID- 29520459 TI - Isolation, purification, and characterization of AgUCGalT1, a galactosyltransferase involved in anthocyanin galactosylation in purple celery (Apium graveolens L.). AB - MAIN CONCLUSION: This study showed that a galactosyltransferase, AgUCGalT1, is involved in anthocyanin galactosylation in purple celery. Celery is a well-known vegetable because of its rich nutrients, low calories, and medicinal values. Its petioles and leaf blades are the main organs acting as nutrient sources. UDP galactose: cyanidin 3-O-galactosyltransferase can transfer the galactosyl moiety from UDP-galactose to the 3-O-position of cyanidin through glycosylation. This process enhances the stability and water solubility of anthocyanins. In the present study, LC-MS data indicated that abundant cyanidin-based anthocyanins accumulated in the petioles of purple celery ('Nanxuan liuhe purple celery'). A gene encoding UDP-galactose: cyanidin 3-O-galactosyltransferase, namely AgUCGalT1, was isolated from purple celery and expressed in Escherichia coli BL21 (DE3). Sequence alignments revealed that the AgUCGalT1 protein contained a highly conserved putative secondary plant glycosyltransferase (PSPG) motif. The glycosylation product catalyzed by AgUCGalT1 was detected using UPLC equipment. The recombinant AgUCGalT1 had an optimal enzyme activity at 35 degrees C and pH 8.0, and showed highest enzyme activity toward cyanidin among the enzyme activities involving other substances, namely, peonidin, quercetin, and kaempferol. The expression levels of AgUCGalT1 were positively correlated with the total anthocyanin contents in purple and non-purple celery varieties. Crude enzymes extracted from purple celery exhibited glycosylation ability, whereas crude enzymes obtained from non-purple celery did not have this ability. This work provided evidence as a basis for investigations on the function of AgUCGalT1 in anthocyanin glycosylation in purple celery. PMID- 29520460 TI - Gateway-compatible inducible vector set for the functional analysis of transcription factors in plants. AB - MAIN CONCLUSION: The inducible vectors pER8-Gateway-3Flag and pER8-Gateway-3Flag SRDX have been subjected to considerable research in terms of the function of transcription factors (TFs) via transcription activity and repression, respectively. Approximately 1500 TFs have been identified in Arabidopsis thaliana genome. To identify their functions, loss-of-function and gain-of-function mutants were generated to analyze the phenotype. However, many loss-of-function mutants did not show any evident phenotype because of the functional redundancy within the TF family. The constitutive misexpression of some TFs may result in lethality or sterility. To overcome these problems, we produced a Gateway compatible inducible binary vector system that facilitates fast and reliable DNA cloning and biological function identification. The vector can be used for the inducible expression of protein fusions to a polypeptide protein tag named 3xFLAG tag. This vector system can also be used to generate an inducible transcription inhibition of protein fusion to an Ethylene-Responsive Factor-associated amphiphilic repression (EAR) motif. The EAR motif makes it possible to get rid of redundancy within a TF family, thereby facilitating studies on loss of function. With these Gateway vectors, conventional subcloning technology that depends on restriction digestion and ligation is avoided. Thus, these Gateway vectors should be useful not only for the rapid analysis of the functions of redundant plant TFs, but also for the manipulation of TF overexpression, resulting in plant lethality or sterility, via an inducible promoter. PMID- 29520461 TI - A reversible light- and genotype-dependent acquired thermotolerance response protects the potato plant from damage due to excessive temperature. AB - MAIN CONCLUSION: A powerful acquired thermotolerance response in potato was demonstrated and characterised in detail, showing the time course required for tolerance, the reversibility of the process and requirement for light. Potato is particularly vulnerable to increased temperature, considered to be the most important uncontrollable factor affecting growth and yield of this globally significant crop. Here, we describe an acquired thermotolerance response in potato, whereby treatment at a mildly elevated temperature primes the plant for more severe heat stress. We define the time course for acquiring thermotolerance and demonstrate that light is essential for the process. In all four commercial tetraploid cultivars that were tested, acquisition of thermotolerance by priming was required for tolerance at elevated temperature. Accessions from several wild type species and diploid genotypes did not require priming for heat tolerance under the test conditions employed, suggesting that useful variation for this trait exists. Physiological, transcriptomic and metabolomic approaches were employed to elucidate potential mechanisms that underpin the acquisition of heat tolerance. This analysis indicated a role for cell wall modification, auxin and ethylene signalling, and chromatin remodelling in acclimatory priming resulting in reduced metabolic perturbation and delayed stress responses in acclimated plants following transfer to 40 degrees C. PMID- 29520462 TI - Cardiac Magnetic Resonance Assessment of the Structural and Functional Cardiac Adaptations to Soccer Training in School-Aged Male Children. AB - Physical training is associated with changes in cardiac morphology called the "athlete's heart", which has not been sufficiently studied in children. The aim of the study was to analyze cardiac adaptation to exercise in pre-adolescent soccer players. Thirty-six soccer players (mean age 10.1 +/- 1.4 years) and 24 non-athlete male controls (10.4 +/- 1.7 years) underwent cardiac magnetic resonance. Measurements of myocardial mass, end-diastolic and end-systolic volume, stroke volume and ejection fraction for left and right ventricle (LV, RV) were performed. Additionally, left and right atrial (LA, RA) areas and volumes were analysed. Relative wall thickness (RWT) was calculated to describe the pattern of cardiac remodeling. Interventricular wall thickness and LV mass were significantly higher in athletes, but remained within the reference (6.9 +/- 0.8 vs. 6.2 +/- 0.9 mm/?m2, p = 0.003 and 57.1 +/- 7.4 vs. 50.0 +/- 7.1 g/m2, p = 0.0006, respectively) with no changes in LV size and function between groups. The RWT tended to be higher among athletes (p = 0.09) indicating LV concentric remodeling geometry. Soccer players had significantly larger RV size (p < 0.04) with similar function and mass. Also, the LA volume (p = 0.01), LA area (p = 0.03) and LA diameter (p = 0.009) were significantly greater in players than in controls. Cardiac adaptations in pre-adolescent soccer players are characterized by an increased LV mass without any changes in LV size and systolic function, which is typical of resistance training with tendency to concentric remodeling. This is accompanied by increase of LA and RV size. It should be taken into account during annual pre-participation evaluation. PMID- 29520463 TI - 22q11.2 Deletion Status and Perioperative Outcomes for Tetralogy of Fallot with Pulmonary Atresia and Multiple Aortopulmonary Collateral Vessels. AB - Deletion of 22q11.2 (del22q11) is associated with adverse outcomes in patients with tetralogy of Fallot (TOF). We sought to investigate its contribution to perioperative outcome in patients with a severe form of TOF characterized by pulmonary atresia (PA) or severe pulmonary stenosis (PS) and major aortopulmonary collateral arteries (MAPCAS). We conducted a retrospective review of patients with TOF/MAPCAS who underwent staged surgical reconstruction between 1995 and 2006. Groups were compared according to 22q11.2 deletion status using t-tests or the Wilcoxon Rank sum test. We included 26 subjects, 24 of whom survived the initial operation. Of those, 21 subjects had known deletion status and constitute the group for this analysis [15 with no deletion present (ND) and 6 del22q11 subjects]. There was no difference with respect to occurrence of palliative procedure prior to initial operation, or to timing of closure of the ventricular septal defect (VSD). Other than higher prevalence of prematurity (50%) in the del22q11 group versus no prematurity in the ND, the groups were comparable in terms of pre-operative characteristics. The intra- and post-operative course outcomes (length of cardiopulmonary bypass, use of vasopressors, duration of intensive care and length of hospital stay, tube-feeding) were also comparable. Although the del22q11 had longer mechanical ventilation than the ND, this difference was not significant [68 h (range 4-251) vs. 45 h (range 3-1005), p = 0.81]. In this detailed comparison of a small patient cohort, 22q11.2 deletion syndrome was not associated with adverse perioperative outcomes in patients with TOF, PA, and MAPCAS when compared to those without 22q11.2 deletion syndrome. These results are relevant to prenatal and neonatal pre-operative counseling and planning. PMID- 29520464 TI - Tissue Motion Annular Displacement of the Mitral Valve Can Be a Useful Index for the Evaluation of Left Ventricular Systolic Function by Echocardiography in Normal Children. AB - As the important role of longitudinal shortening in ventricular function has been well recognized over the past decade, evaluation of longitudinal systolic function of the left ventricle has become a subject of growing interest. Tissue motion annular displacement of the mitral valve (TMAD) is a new parameter of longitudinal systolic function. Although some studies have reported that this new parameter correlates with left ventricular ejection fraction (LVEF) in adults, little is known about TMAD in normal children. In this work, we investigated 94 children with no history of cardiovascular disease. TMAD was measured in the apical four-chamber view using the two-dimensional speckle tracking technique. Three points for tracking were selected in a diastolic frame: the lateral mitral valve annulus, medial mitral valve annulus, and left ventricular apex. The value was expressed as the percentage of displacement of the midpoint of the mitral valve annulus, using software to correct for left ventricular length at end diastole. Pearson's coefficient was used to estimate the correlation between TMAD and left ventricular systolic function parameters including the biplane modified Simpson method-derived ejection fraction and global longitudinal strain (GLS). We also analyzed the correlation between TMAD and heart rate (HR), height, age, and body surface area (BSA). TMAD was found to correlate significantly with LVEF (r = 0.71, p < 0.01) and GLS (r = -0.77, p < 0.01). However, no correlation was revealed for HR (r = -0.14, p = 0.19), height (r = -0.17, p = 0.10), age (r = 0.19, p = 0.09), or BSA (r = -0.19, p = 0.08). These results indicate that TMAD is useful for assessing LVEF and longitudinal systolic function in normal children, and is not influenced by changes in HR, height, age, or BSA. PMID- 29520465 TI - Survival to Stage II with Ventricular Dysfunction: Secondary Analysis of the Single Ventricle Reconstruction Trial. AB - Ventricular dysfunction affects survival in patients with single right ventricle (RV), and remains one of the primary indications for heart transplantation. Since it is challenging to predict the capacity of patients with ventricular dysfunction to proceed to the stage II procedure, we sought to identify factors that would be associated with death or heart transplantation without achieving stage II for single RV patients with ventricular dysfunction after Norwood procedure. The Single Ventricle Reconstruction (SVR) trial public-use database was used. Patients with a RV ejection fraction less than 44% or a RV fractional area of change less than 35% on the post-Norwood echocardiogram were included. Parametric risk hazard analysis was used to identify risk factors for death or transplantation without achieving stage II. Of 365 patients with ventricular function measurements on the post-Norwood echocardiogram, 123 (34%) patients had RV dysfunction. The transplantation-free survival was significantly lower for those with ventricular dysfunction compared to those with normal function (log rank Chi-square = 4.23, p = 0.04). Furthermore, having a Blalock-Taussig (BT) shunt, a large RV, a post-Norwood infectious complication, and a surgeon who performs five or less Norwood per year were independent risk factors for death or transplantation without achieving stage II. The predicted 6-month transplantation free survival for patients with all four identified risk factors was 1% (70% CI 0 13%). Early heart transplantation referral might be considered for post-Norwood patients with BT shunt and RV dysfunction, especially if other high-risk features are present. PMID- 29520466 TI - Leadless Pacemaker Implantation in a Pediatric Patient with Prolonged Sinus Pauses. AB - Permanent cardiac pacing is the only effective solution for patients with symptomatic bradycardia and heart block. About 10% of patients undergoing implantation of the conventional pacing system develop complications related to the subcutaneous pocket or the leads and in pediatric patients lead problems may rise in up to 30% of the patients. The leadless pacemaker devices were developed in order to minimize some of those complications. We present a case of an 11-year old patient who presented after the sudden death of his older brother, with recurrent episodes of syncope and documented prolonged sinus pauses. The patient underwent percutaneous implantation of a leadless MicraTM pacemaker device with optimal results. PMID- 29520467 TI - Outcomes after revision of metal on metal hip resurfacing to total arthroplasty using the direct anterior approach. AB - BACKGROUND: Function after revision total hip arthroplasty (THA) in failed metal on-metal (MoM) hip resurfacing arthroplasty (HRA) is variable, but post-operative complication rates are reportedly high. We hypothesized HRA conversion to THA using the direct anterior approach (DAA) would be associated with optimal outcome. METHODS: Seventeen MoM-HRAs in 15 patients (seven males, eight females) were revised through the DAA. The mean age was 45 years (28-59 yrs). The most common indications for revision were aseptic loosening of the acetabular component or of the femoral component and femoral neck fracture. In 16 hips, a conversion to a ceramic-on-ceramic (CoC) (13 hips) or to a metal-on polyethylene (MOP) (2), or to a large-head MoM (1) THA was done. An isolated femoral revision was done in one hip. RESULTS: After 6.7 +/- 3 years, no hip had required a re revision. The Postel-Merle d'Aubigne (PMA) functional score improved from 9 (4 14) to 16 (12-18) (p < 0.001). An intra-operative fracture of the greater trochanter (one hip) and dysesthesia of the lateral femoral cutaneous nerve (four hips) were reported. Mean serum chromium concentration decreased from 33.2 MUg/L (11.8-62 MUg/L) pre-operatively to 5.8 MUg/L (0.4-35.5 MUg/L) post-operatively (p < 0.001), and mean serum cobalt concentration decreased from 35.8 MUg/L (6.3-85.5 MUg/L) to 4.7 MUg/L (0.26-25.7 MUg/L) (p = 0.003). CONCLUSION: Revision of failed MoM-HRA using the DAA resulted in an acceptable clinical outcome, no specific complication and no further surgery. A consistent decline in serum ion levels may be expected following HRA conversion to THA. PMID- 29520468 TI - Ten-year survival and chipping rates and clinical quality grading of zirconia based fixed dental prostheses. AB - OBJECTIVES: To prospectively evaluate the clinical long-term outcome of 3- to 6 unit fixed dental prostheses (FDPs) made of hot isostatic pressed (HIP) zirconia frameworks, veneered with a synthetic sintering glass-ceramic. MATERIALS AND METHODS: A total of 27 different restorations were cemented in 21 patients. FDPs were examined with regard to biological and technical complications/failures. Additionally, clinical quality was assessed based on (i) the California Dental Association (CDA) criteria, (ii) the patient's viewpoint according to Hickel, and (iii) periodontal parameters. Descriptive statistics were computed. The Kaplan Meier estimator was used for the survival and chipping-free rates. Wilcoxon signed ranks test (ordinal/continuous data) or the McNemar test (binary data) was used to describe the periodontal outcome of abutment teeth versus that of the respective control teeth. RESULTS: After a mean observation period of 10.0 +/- 2.1 years, the dataset comprised 15 patients with 20 (mainly posterior) FDPs. The 10-year survival rate and 10-year chipping-free rate were 95.0% (CI 86.0-100%) and 78.8% (CI 62.2-99.7%), respectively. Evaluation based on the CDA criteria yielded satisfactory (excellent or acceptable) results for all categories. This was also confirmed by the high level of patient satisfaction. The periodontal health of tissues adjacent to the study teeth was clinically acceptable, but inferior to the ones of control teeth. CONCLUSIONS: FDPs made from CAD/CAM fabricated HIP zirconia ceramic frameworks have a favorable survival rate. However, because damage to the surface texture showed a disproportionate increase after long-term usage, additional long-term studies are required. CLINICAL RELEVANCE: The outstanding mechanical properties of zirconia-based systems have contributed to the belief that all-ceramics are a reliable material for prosthetic restorations. However, only long-term reports (such as this one) provide more detailed information on actual clinical efficacy. PMID- 29520469 TI - Reduced salivary amylase activity in metabolic syndrome patients with obesity could be improved by treatment with a dipeptidyl peptidase IV inhibitor. AB - OBJECTIVES: The present study is to investigate the salivary gland function of metabolic syndrome (MetS) patients, as indicated by salivary flow rate, amylase activity, and salivary oxidative stress, by measuring MDA level. MATERIALS AND METHODS: One hundred and eighty-one MetS patients from Maharaj Nakorn Chiang Mai Hospital were enrolled onto this study. The metabolic parameters of each patient were collected and evaluated. Unstimulated saliva was also collected for 5 min. Salivary gland functions, including salivary flow rate, amylase activity, and salivary MDA levels, were investigated. RESULTS: High levels of triglycerides, high-density lipoprotein, blood pressure, and waist circumference in MetS patients did not show a correlation with altered salivary gland function. However, a decrease in salivary flow rate was observed in MetS patients with hyperglycemia. In addition, decreased amylase activity was found in MetS patients with obesity (BMI >= 23 kg/m2). Salivary amylase activity of MetS patients treated with dipeptidyl peptidase IV (DPP-IV) inhibitor was significantly greater than that observed in MetS patients without a DPP-IV inhibitor. Moreover, the salivary amylase activity in MetS patients was found to be independently positively correlated with DPP-IV inhibitor therapy (r = 0.708, p < 0.01). CONCLUSION: These findings suggest that obesity and hyperglycemia in MetS patients were associated with the impairment of salivary glands. Treatment with a DPP-IV inhibitor was found to exert beneficial effects on the salivary gland. CLINICAL RELEVANCE: This study demonstrated the impairment of salivary glands of MetS patients and the beneficial effect of DPP-IV inhibitor treatment in the salivary glands. PMID- 29520470 TI - Relationship among perceived stress, xerostomia, and salivary flow rate in patients visiting a saliva clinic. AB - OBJECTIVE: This aimed to assess the potential role of chronic stress in saliva secretion, xerostomia, and oral health in a population attending a saliva clinic. MATERIALS AND METHODS: Data of 114 patients who met the inclusion criteria and completed all questionnaires were analyzed in this study. Participants completed several validated questionnaires, including the Perceived Stress Scale, the Oral Health Impact Profile (OHIP-14), Xerostomia Inventory (XI), and Bother xerostomia Index (BI). Subsequently, the unstimulated, chewing-stimulated, and citric acid stimulated saliva secretion rates were determined gravimetrically. Data were evaluated using Spearman's correlation analysis and the Mann-Whitney U test. RESULTS: A significant correlation was observed between perceived stress and XI score (r = 0.312, p = 0.001), as well as between perceived stress and BI score (r = 0.334, p = 0.001). Stress levels also were significantly associated with OHIP 14 scores (r = 0.420, p < 0.001), but an association between experienced stress and salivary flow rate could not be established. CONCLUSION: In this population, perceived chronic stress seems to be related to several aspects of dry mouth, including the perception of dry mouth, suffering from dry mouth, and the impact on quality of life. These effects were independent of the use of psychotropic medication. No actual reduction in salivary flow was found. Further studies to explore the causal linkage of stress with xerostomia seem warranted. CLINICAL RELEVANCE: Perceived chronic stress seems to be related with several aspects of dry mouth. This finding might be relevant in future prevention and treatment of xerostomia. PMID- 29520471 TI - First-trial protective step performance before and after short-term perturbation practice in people with Parkinson's disease. AB - BACKGROUND: Protective steps are critical for fall prevention and are altered in people with Parkinson's disease (PD). Previous work suggests that perturbation training, in which patients are exposed to repeated slips, may improve protective postural responses. However, these studies typically take the average performance of several postural responses before and after training. To reduce falls in the community, training must improve protective stepping after the first perturbation exposure. To date, no investigations have examined whether first-trial protective stepping is improved after training in people with PD. METHODS: First-trial protective stepping was measured in 14 people with PD and 9 healthy adults before and 24 h after 1 day of perturbation training. The primary outcome was margin of stability after a perturbation, a measure of protective stepping effectiveness. RESULTS: Margin of stability for the first perturbation was significantly (p = 0.001) improved on day 2 compared to before perturbation practice (day 1) in both groups. Furthermore, improvement in margin of stability was correlated with age and baseline stepping performance, such that older individuals and people with worse baseline performance showed the most pronounced improvement. CONCLUSIONS: Improving the first loss of balance after training is critical if such training is to reduce falls in people with PD. The observed improvement in first-trial protective stepping provides further support for perturbation training as a potential tool to improve protective steps and reduce falls in people with PD. PMID- 29520472 TI - Residential traffic noise and mammographic breast density in the Diet, Cancer, and Health cohort. AB - OBJECTIVES: Traffic is the most important source of community noise, and it has been proposed to be associated with a range of disease outcomes, including breast cancer. As mammographic breast density (MD) is one of the strongest risk factors for developing breast cancer, the present study investigated whether there is an association between residential exposure to traffic noise and MD in a Danish cohort. METHODS: We included women with reproductive and lifestyle information available from the Diet, Cancer, and Health cohort, who also participated in the Copenhagen Mammography Screening Programme (n = 5,260). Present and historical addresses from 1987 to 2011 were found in national registries, and traffic noise was modeled 5 years before mammogram. Analyses between residential traffic noise and MD were performed using logistic regression. RESULTS: We found no association between residential road and railway noise exposure 5 years before mammogram, and having a mixed/dense versus a fatty mammogram, and no interaction with menopausal status, BMI, HRT use, and railway noise exposure, for analyses on road traffic noise. CONCLUSION: The present study does not suggest an association between residential traffic noise exposure and subsequent MD in a cohort of middle-aged Danish women. PMID- 29520474 TI - Cancer immunotherapy in patients with brain metastases. AB - The exclusion of "real-world" patients from registration clinical trials of cancer immunotherapy represents a significant emerging issue. For instance, a large fraction of cancer patients develops brain metastases during the course of the disease, but results from large prospective clinical trials investigating this considerable proportion of the cancer patient population are currently lacking. To provide a useful tool for the clinician in a "real-world" setting, we have reviewed the available literature regarding the safety and efficacy of immune check-point inhibitors in patients with cancer metastatic to the brain. Overall, these data provide encouraging evidence that these therapeutic agents can induce intracranial objective responses, particularly in patients with asymptomatic and previously untreated brain metastases. Larger prospective studies are needed to confirm these initial results. PMID- 29520473 TI - Study of the validity of a job-exposure matrix for the job strain model factors: an update and a study of changes over time. AB - OBJECTIVES: The objectives of the study were to construct a job-exposure matrix (JEM) for psychosocial work factors of the job strain model, to evaluate its validity, and to compare the results over time. METHODS: The study was based on national representative data of the French working population with samples of 46,962 employees (2010 SUMER survey) and 24,486 employees (2003 SUMER survey). Psychosocial work factors included the job strain model factors (Job Content Questionnaire): psychological demands, decision latitude, social support, job strain and iso-strain. Job title was defined by three variables: occupation and economic activity coded using standard classifications, and company size. A JEM was constructed using a segmentation method (Classification and Regression Tree CART) and cross-validation. RESULTS: The best quality JEM was found using occupation and company size for social support. For decision latitude and psychological demands, there was not much difference using occupation and company size with or without economic activity. The validity of the JEM estimates was higher for decision latitude, job strain and iso-strain, and lower for social support and psychological demands. Differential changes over time were observed for psychosocial work factors according to occupation, economic activity and company size. CONCLUSIONS: This study demonstrated that company size in addition to occupation may improve the validity of JEMs for psychosocial work factors. These matrices may be time-dependent and may need to be updated over time. More research is needed to assess the validity of JEMs given that these matrices may be able to provide exposure assessments to study a range of health outcomes. PMID- 29520475 TI - Reductive dissolution and sequestration of arsenic by microbial iron and thiosulfate reduction. AB - Iron oxide and oxy-hydroxide are commonly used for remediation and rehabilitation of arsenic (As)-contaminated soil and water. However, the stability of As sequestered by iron oxide and oxy-hydroxide under anaerobic conditions is still uncertain. Geochemical properties influence the behavior of As; in addition, microbial activities affect the mobility of sequestered As in soil and water. Microbial-mediated iron reduction can increase the mobility of As by reductive dissolution of Fe oxide; however, microbial-mediated sulfate reduction can decrease the mobility of As by sulfide mineral precipitation. This study investigated the geomicrobial impact on the behavior of As and stability of sequestered As in iron-rich sediment under anaerobic conditions. Increase in Fe(II) concentrations in water was evidence of microbial-mediated iron reduction. Arsenic concentrations increased with Fe(II) concentration; however, the thiosulfate reduction process also induced immobilization of As through the precipitation of AsFeS. Therefore, microbial-mediated iron reduction and thiosulfate reduction have opposite influences on the mobility of As under anaerobic condition. PMID- 29520476 TI - Correction to: Potentially traumatic events have negative and positive effects on loneliness, depending on PTSD-symptom levels: evidence from a population-based prospective comparative study. AB - In the original article, Tables 2 and 3 have published with incorrect alignment. The correct tables are given below. The original article was corrected. PMID- 29520477 TI - Biodistribution and Pharmacokinetic Evaluations of a Novel Taxoid DHA-SBT-1214 in an Oil-in-Water Nanoemulsion Formulation in Naive and Tumor-Bearing Mice. AB - PURPOSE: The main purpose of this study was to formulate an oil-in-water nanoemulsion of a next generation taxoid DHA-SBT-1214 and evaluate its biodistribution and pharmacokinetics. METHODS: DHA-SBT-1214 was encapsulated in a fish oil containing nanoemulsion using a high pressure homogenization method. Following morphological characterization of the nanoemulsions, qualitative and quantitative biodistribution was evaluated in naive and cancer stem cell-enriched PPT-2 human prostate tumor bearing mice. RESULTS: DHA-SBT-1214 was successfully encapsulated up to 20 mg/ml in the nanoemulsion formulation and had an average oil droplet size of 200 nm. Using a DiR near infra-red dye encapsulated nanoemulsion, we have shown the delivery of nanoemulsion to mouse tumor region. By quantitative analysis, DHA-SBT-1214 encapsulated nanoemulsion demonstrated improved pharmacokinetic properties in plasma and different tissues as compared to its solution form. Furthermore, the nanoemulsions were stable and had slower in vitro drug release compared to its solution form. CONCLUSIONS: The results from this study demonstrated effective encapsulation of the drug in a nanoemulsion and this nanoemulsion showed sustained plasma levels and enhanced tumor delivery relative to the solution form. PMID- 29520478 TI - Increase in the OCT angiographic peripapillary vessel density by ROCK inhibitor ripasudil instillation: a comparison with brimonidine. AB - PURPOSE: To assess the responses of the superficial peripapillary retinal vessel density (VD) and prelaminar flow index (PLFI) to topical Rho-assisted coiled-coil forming protein kinase (ROCK) inhibitor ripasudil and alpha-2 agonist brimonidine using optical coherence tomography angiography. METHODS: This is a prospective, non-randomized, comparative cohort study. We studied the response of optical coherence tomography angiography (OCTA) parameters to drugs in 24 eyes treated with ripasudil and 23 eyes treated with brimonidine at the Sensho-kai Eye Institute. After division by the signal strength (SS), we compared the responses of peripapillary VD/SS and PLFI/unit area (UA)/SS to topical eye drops in eyes with primary open-angle glaucoma (POAG) and ocular hypertension (OH). RESULTS: In the superficial peripapillary retina, VD/SS increased significantly in the ripasudil-treated eyes (12.5 +/- 21.7%, P = 0.018), but not in the brimonidine treated eyes (- 2.0 +/- 13.8%, P = 0.484). In the deeper area of the optic disc, the changes in the PLFI/UA/SS in the brimonidine-treated eyes (+ 0.9 +/- 8.9%, P = 1.00) and ripasudil-treated eyes (- 1.3 +/- 8.5%, P = 0.241) were not significant. Multivariate discriminant analysis showed that the change in the peripapillary VD/SS was the most important parameter (P = 0.0186) for differentiating ripasudil- and brimonidine-treated eyes. CONCLUSIONS: The topical ROCK inhibitor ripasudil enhanced the peripapillary VD in POAG and OH, whereas the alpha-2 agonist brimonidine did not. The PLFI did not respond to either drug. PMID- 29520479 TI - Features of choroidal naevi on swept source optical coherence tomography angiography and structural reverse flow optical coherence tomography. AB - PURPOSE: The purpose of our study was to describe features of choroidal naevi as seen on swept source optical coherence tomography angiography (OCTA) and also on en face images derived from structural data from OCTA. METHODS: A prospective observational cohort study was carried out. Patients attending a specialised choroidal naevomelanocytic with known naevi were imaged with swept source OCTA. RESULTS: Seventy-one eyes of 70 patients were imaged. Forty-three patients and 44 eyes were included. Mean age was 57.7 years (SD 14.9), range 29-81 years. Male to female ratio was 20:23. On OCTA after manual segmentation, naevi could be seen in 47.6% of cases, whereas in the en face images, naevi could be clearly visualised in 79.5% of cases. In OCTA, the superficial and deep capillary plexuses appeared undisturbed as did the outer retinal layer appeared in all cases of flat naevi. In choroidal naevi with mild elevation, the outer retinal layer appeared more susceptible to projection artefacts from overlying retinal vasculature. The choriocapillaris layer showed a fading of the normal homogenous vascular mosaic corresponding to the area of the naevus. In the en face images, even the faintest and thinnest naevi could be visualised in striking detail, and naevi greater than 120 MUm thickness appeared darker (p = 0.0034). CONCLUSIONS: OCTA presents characteristic changes in the choriocapillaris layers in cases of choroidal naevi. The association of naevus substance appearing darker with increasing thickness may offer a novel prognostic clue. En face structural OCT may allow accurate, detailed measurement of lateral dimensions which could be of value in the monitoring of suspicious naevi. PMID- 29520480 TI - Clinical Phenotyping of Transthyretin Cardiac Amyloidosis with Bone-Seeking Radiotracers in Heart Failure with Preserved Ejection Fraction. AB - PURPOSE OF REVIEW: The two most common types of cardiac amyloidosis are caused by fibril deposits of immunoglobulin light chains (AL) and transthyretin (TTR), each with distinct prognosis and clinical management. Cardiac amyloidosis is under recognized among heart failure patients with preserved ejection fraction (HFpEF). Bone-seeking tracers like 99mTc-PYP and 99mTc-DPD have long been used to identify cardiac amyloidosis, and more recently, to differentiate TTR from AL cardiac amyloidosis in symptomatic patients. However, results are mainly derived from single-center retrospective studies, with comparable but not standardized imaging protocols and interpretation criteria. RECENT FINDINGS: The clinical scope of cardiac amyloidosis among HFpEF patients and current literature supporting the use of bone-seeking tracers for TTR cardiac amyloidosis are presented. The differences of imaging techniques for cardiac amyloid and bone disease evaluation, bone tracer pharmacodynamics, and imaging interpretation criteria for cardiac amyloidosis diagnosis are discussed. Finally, a diagnostic algorithm to use bone scintigraphy in cardiac amyloidosis diagnosis among HFpEF patients is proposed. Bone scintigraphy with 99mTc-PYP or 99mTc-DPD can be a useful tool with high sensitivity and specificity for detecting TTR-related cardiac amyloidosis in patients with HFpEF. It is needed to standardize the imaging protocol and interpretation criteria and to perform prospective clinical studies. PMID- 29520481 TI - Connectivity profiles of the insular network for speech control in healthy individuals and patients with spasmodic dysphonia. AB - The importance of insula in speech control is acknowledged but poorly understood, partly due to a variety of clinical symptoms resulting from insults to this structure. To clarify its structural organization within the speech network in healthy subjects, we used probabilistic diffusion tractography to examine insular connectivity with three cortical regions responsible for sound processing [Brodmann area (BA) 22], motor preparation (BA 44) and motor execution (laryngeal/orofacial primary motor cortex, BA 4). To assess insular reorganization in a speech disorder, we examined its structural connectivity in patients with spasmodic dysphonia (SD), a neurological condition that selectively affects speech production. We demonstrated structural segregation of insula into three non-overlapping regions, which receive distinct connections from BA 44 (anterior insula), BA 4 (mid-insula) and BA 22 (dorsal and posterior insula). There were no significant differences either in the number of streamlines connecting each insular subdivision to the cortical target or hemispheric lateralization of insular clusters and their projections between healthy subjects and SD patients. However, spatial distribution of the insular subdivisions connected to BA 4 and BA 44 was distinctly organized in healthy controls and SD patients, extending ventro-posteriorly in the former group and anterio-dorsally in the latter group. Our findings point to structural segregation of the insular sub-regions, which may be associated with the different aspects of sensorimotor and cognitive control of speech production. We suggest that distinct insular involvement may lead to different clinical manifestations when one or the other insular region and/or its connections undergo spatial reorganization. PMID- 29520482 TI - Leptin alters somatosensory thalamic networks by decreasing gaba release from reticular thalamic nucleus and action potential frequency at ventrobasal neurons. AB - Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca2+-dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity. PMID- 29520483 TI - Immune cell landscape in therapy-naive squamous cell and adenocarcinomas of the lung. AB - Squamous cell and adenocarcinomas of the lung develop different mechanisms during carcinogenesis to evade attacks of the immune system. Besides the well-known check-point control programmed death 1 and its ligand, many more mechanisms, acting either tumoricidal or in favor of tumor progression, exist. Analysis of the immune cell profiles in resected tissues and bronchoalveolar lavage samples and correlation between them and with overall survival data was performed. In all tumor samples in this study, cells of the immune system expressed a tumor cooperating phenotype. High numbers of regulatory T cells, or alternatively expression of Vista on lymphocytes was present. Tumoricidal dendritic cells were absent in tumor tissue, and barely present in bronchoalveolar lavage, whereas tumor-friendly monocytoid and plasmocytoid dendritic cells were seen in both. Alveolar macrophages were predominantly differentiated into tumor-cooperating M2 types, whereas tumoricidal M1 macrophages were absent or rare. The expression of PDL1 on tumor cells did not correlate with any other immune cells. Expression of PD1 on lymphocytes was frequently encountered. None of analyzed immune cells showed correlation with overall survival. Immune cells in bronchoalveolar lavage and tissue did not correlate. For the first time, a tissue-based analysis of different immune cells in squamous cell and adenocarcinomas of the lung is provided, trying to explain their potential role in tumor development and progression. Discordant numbers of cells with bronchoalveolar lavage are most probably due to the fact that bronchoalveolar lavage reflects the situation in the whole lung, where chronic obstructive lung disease and other conditions are present. PMID- 29520484 TI - Totally Laparoscopic Radical Resection of Gallbladder Cancer: Technical Aspects and Long-Term Results. AB - INTRODUCTION: Gallbladder cancer (GBC) is a rare tumor in developed countries. Chile has one of the highest incidences worldwide. For patients affected by resectable T1b or more advanced GBC, radical cholecystectomy (RC) is considered the standard therapy. Our aim is to describe the surgical technique and clinical pathological results of patients undergoing totally laparoscopic radical resection of GBC. METHODS: Patients undergo laparoscopic radical resection for primary and incidental GBC, between the years 2009 and 2016 in two centers from Chile. Patients in whom suspected bile duct invasion, frozen biopsy did not confirm cancer and para-aortic lymph node sampling was positive were excluded. RESULTS: Eighteen patients were operated, 77.8% were female with median age of 60.5 year, and 16 patients had previous cholecystectomy with incidental cancer finding. The median operative time was 490 min (400-550). No conversion to open surgery occurred. All patients achieved a R0 resection. Postoperative complications occurred in 2 patients (11.1%), and there was not mortality. After a median follow-up of 59 months, the 5-year survival was 80.7%. CONCLUSION: This study shows the technical feasibility of the totally laparoscopic approach for radical resection of GBC with the same principles of classical open surgery. It appears that long-term oncological findings would also be similar at least in less advanced lesions. PMID- 29520485 TI - Quality of Life in Patients with Background of Iatrogenic Bile Duct Injury. AB - BACKGROUND: There are only a few reports regarding the quality of life of patients who underwent a complicated cholecystectomy with an iatrogenic bile duct injury (IBDI); the results have been heterogeneous and realized with unspecific measures. METHODS: The objective was to determine whether the quality of life of the subjects with a history of IBDI repaired with bilioenteric derivation is modified in the long term with respect to a control group, for which a group of patients with a history of IBDI (group A) was compared with a group of patients with a history of uncomplicated cholecystectomy (group B). Two different measures were used: on the one hand, the SF-12 questionnaire and on the other hand, a questionnaire was implemented where the patient could determine by himself which variables define his quality of life. RESULTS: A total of 46 patients were included in group A and 51 in group B. The analysis of the SF-12 questionnaire showed a statistical significant reduction in 4 of 8 of the evaluated parameters (general health, physical functioning, physical role and social functioning) in group A in comparison with group B. If a more specific questionnaire is used, the results are similar, with a statistically significant reduction in the quality of life within the group A (0.03). CONCLUSIONS: We conclude that the quality of life of patients with a history of bilioenteric derivation due to an IBDI decreases significantly compared to patients with uncomplicated cholecystectomy. PMID- 29520487 TI - Growth, reproductive, and productive performance of Begait cattle under different herd management systems in northern Ethiopia. AB - The performance of indigenous Begait cattle (498 cows, 284 calves, and 48 heifers) in northern Ethiopia was studied. System of herd management significantly (P < 0.01) influenced all production traits. Calves in medium-input herds (MIHM) grew faster than those in low-input herds (LIHM), by 232 g/d from birth to 9 months (Gain1) and by 385 g/d from 9 to 12 months (Gain2). Cow's dry period, calving interval (CI), and age at first calving (AFC) were 234, 222, and 343 days shorter for MIHM than for LIHM. Compared with LIHM, cows from MIHM had 74% higher daily milk yield (DMY) and 91% higher lactation milk yield (LMY). Calves born at wet season grew faster by 14 and 10% than those calves born in the dry season at Gain1 and Gain2. The subsequent CI of cows calved in the wet season had 77 days shorter, 0.45 kg DMY, and 93 kg LMY increment. The differences between production systems can be attributed to differences in management skills and access to better quality feeds. Technical intervention is needed to ensure provision of balanced rations to exploit the potential productivity of Begait cattle. PMID- 29520486 TI - Third molar maturity index (I3M) for assessing age of majority: study of a black South African sample. AB - AIMS: The evaluation of the cutoff value of I3M = 0.08 for discriminating black South African minors from adults, and its relationship with chronological age. MATERIAL AND METHODS: A sample of 833 panoramic radiographs of healthy black South African subjects (500 females and 333 males), in the age range of 14 to 24 years (mean age 17.67 years in females and 17.42 years in males), was retrospectively evaluated. RESULTS: ICC values were 99.10% (95% CI 97.70 to 99.70%) and 99.20% (95% CI 98.00 to 99.60%), for the intra- and inter-observer reliability, respectively. I3M decreased as the real age gradually increased in both sexes. According to the logistic regression model, the variable sex was not significant when the probability that an individual is 18 years or older was calculated. The I3M = 0.08 was valuable in discriminating between adults and minors. The overall accuracy (ACC = fraction of accurately classified subjects) is 0.90 (95% CI 0.87-0.91); the proportion of correctly classified subjects (Se = sensitivity) is 0.80 (95% CI 0.76-0.84), and specificity (Sp) is 0.95 (95% CI 0.93-0.97). The PPV (predictive positive value) is 0.96 (95% CI 0.95-0.97), and the negative predictive value is 0.76 (95% CI 0.72-0.80). CONCLUSION: The results show that I3M is a valuable method to distinguish subjects who are around legal adult age in South Africa. PMID- 29520488 TI - Determination of carbonyl compounds in electronic cigarette refill solutions and aerosols through liquid-phase dinitrophenyl hydrazine derivatization. AB - In this study, we report a 2,4-dinitrophenylhydrazine (DNPH) derivatization HPLC/UV method to quantify carbonyl compounds (CCs) either in electronic cigarette (EC) refill solutions or in vaped aerosols. Vaped aerosol samples were entrained in a 1 L atm min-1 ambient lab air stream and pulled through an impinger containing a DNPH solution for derivatization. The mass change tracking (MCT) approach was used to check mass balance. Refill solution samples were diluted (2, 4, and 10 times) in a DNPH/acetonitrile solution for derivatization. EC vaping samples were collected for 5, 10, or 15 puffs (2-s puff duration) with a 10-s interpuff interval. The DNPH derivatization method was used successfully for the estimation of both EC liquid CCs concentrations and vaping emission factors. The results for formaldehyde (FA), acetaldehyde (AA), and butyraldehyde (BA) were determined as 10.4 +/- 3.10 MUg mL-1 (27.6 +/- 7.43 ng puff-1), 1.9 +/- 0.83 MUg mL-1 (4.4 +/- 1.98 ng puff-1), and 4.4 +/- 2.82 MUg mL-1 (12.0 +/- 7.43 ng puff-1), respectively. PMID- 29520489 TI - Monitoring of metallic contaminants in energy drinks using ICP-MS. AB - In this study, an improved method was validated for the determination of some metallic contaminants (arsenic (As), chromium (Cr), cadmium (Cd), lead (Pb), iron (Fe), nickel (Ni), copper (Cu), Mn, and antimony (Sb)) in energy drinks using inductive coupled plasma mass spectrometry (ICP-MS). The validation procedure was applied for the evaluation of linearity, repeatability, recovery, limit of detection, and quantification. In addition, to verify the trueness of the method, it was participated in an interlaboratory proficiency test for heavy metals in soft drink organized by the LGC (Laboratory of the Government Chemist) Standard. Validated method was used to monitor for the determination of metallic contaminants in commercial energy drink samples. Concentrations of As, Cr, Cd, Pb, Fe, Ni, Cu, Mn, and Sb in the samples were found in the ranges of 0.76-6.73, 13.25-100.96, 0.16-2.11, 9.33-28.96, 334.77-937.12, 35.98-303.97, 23.67-60.48, 5.45-489.93, and 0.01-0.42 MUg L-1, respectively. The results were compared with the provisional guideline or parametric values of the elements for drinking waters set by the WHO (World Health Organization) and EC (European Commission). As, Cd, Cu, and Sb did not exceed the WHO and EC provisional guideline or parametric values. However, the other elements (Cr, Pb, Fe, Ni, and Mn) were found to be higher than their relevant limits at various levels. PMID- 29520490 TI - Attentional bias on motor control: is motor inhibition influenced by attentional reorienting? AB - Motor inhibition and attentional processing are tightly linked. Recent neurophysiological studies have shown that both processes might rely on similar cognitive and neural mechanisms (Wessel and Aron, Neuron 93:259-280, 2017). However, it remains unclear whether attentional reorientation influences inhibition of a subsequent action. Therefore, we combined two tasks that are commonly used in the motor inhibition and visual attention reorientation field [respectively: the stop-signal task (Logan and Cowan, Psychol Rev 91:295-327, 1984) and the Posner endogenous cueing paradigm (Posner, Q J Exp Psychol 32(1):3 25, 1980)] to investigate how different aspects of visual attention modulate subsequent voluntary inhibition. Our results showed an increase in stopping reaction time after a reorientation of attention only. This suggests a specific impairment of inhibitory control when a reorientation of visual attention is needed. These findings support the idea of a selective influence of attention reorientation on subsequent motor inhibition (stop signal). This may be linked to the "circuit breaker" hypothesis, proposing that attention reorientation toward an unexpected event "resets" the ongoing processes to allow the analysis of the potentially behaviorally relevant visual events (Corbetta et al., Neuron 58(3):306-324, 2008). PMID- 29520491 TI - [Correction to: Abstracts volume DOG 2017, abstract PDo02-02]. PMID- 29520492 TI - [Statement from the BVA, the DOG, and the RG on treatment of choroidal neovascularization in diseases other than neovascular age-related macular degeneration : October 2017]. PMID- 29520493 TI - The reverse Sauve-Kapandji procedure for the treatment of (posttraumatic) proximal radioulnar synostosis. AB - Proximal radioulnar synostosis is a rare but highly disabling posttraumatic complication in periarticular elbow injuries. Surgical treatment is an option for functionally limiting proximal radioulnar synostosis; however, the approach can endanger local neurovascular structures, especially if the synostosis affects the level of the bicipital tuberosity. We report two cases of proximal radioulnar synostosis with a preoperative prono-supination range of motion of 0 degrees and 15 degrees treated by a reverse Sauve-Kapandji procedure resecting a 1-cm section of the radial shaft distal to the bicipital tuberosity and leaving the synostosis in place. An improvement in prono-supination arc of motion of 82.5 degrees was achieved at 2 years of follow-up with no complications associated with the technique. The reverse Sauve-Kapandji procedure could be an option in the treatment of proximal radioulnar synostosis in selected cases. PMID- 29520494 TI - The occurrences of heavy metals in farmland soils and their propagation into paddy plants. AB - In this research, heavy metal accumulation pattern was investigated using the data measured from the soil, paddy plants, and irrigation water samples in Jessore district in Bangladesh with the aid of principal component analysis. A total of 28 samples representing farmland soil and irrigation water along with paddy plant were collected from 28 locations in the Jessore district in November 2016. In agricultural soil, arsenic (As) and nickel (Ni) were found 2.78 and 1.11 times more concentrated than their background values. In addition, 89% of the sample sites exhibited enhanced As concentrations relative to the background value. Principal component analysis (PCA) of soil data showed strong homogeneity in many species (e.g., Ni, Cu, Fe, and As) to reflect intense agricultural activities. In contrast, Pb showed no such homogeneity in soil accumulation pattern. In plant samples, Cu, Fe, and As were strongly correlated and homologous. This homology of pollution was in agreement with the pollution homology in the agricultural soil in which the plants were grown. In irrigation water, Cu and Ni were homologous. Observation of spatial distribution and other variables indicated that the accumulation of any particular metal in paddy plants was correlated with its content in soil and irrigation water, which was influenced by the soil organic matter, soil/water pH, and other metals present in that environment. PMID- 29520495 TI - Rational Design of Cholesterol Derivative for Improved Stability of Paclitaxel Cationic Liposomes. AB - PURPOSE: This work explores synthesis of novel cholesterol derivative for the preparation of cationic liposomes and its interaction with Paclitaxel (PTX) within liposome membrane using molecular dynamic (MD) simulation and in-vitro studies. METHODS: Cholesteryl Arginine Ethylester (CAE) was synthesized and characterized. Cationic liposomes were prepared using Soy PC (SPC) at a molar ratio of 77.5:15:7.5 of SPC/CAE/PTX. Conventional liposomes were composed of SPC/cholesterol/PTX (92:5:3 M ratio). The interaction between paclitaxel, ligand and the membrane was studied using 10 ns MD simulation. The interactions were studied using Differential Scanning Calorimetry (DSC) and Small Angle Neutron Scattering analysis. The efficacy of liposomes was evaluated by MTT assay and endothelial cell migration assay on different cell lines. The safety of the ligand was determined using the Comet Assay. RESULTS: The cationic liposomes improved loading efficiency and stability compared to conventional liposomes. The increased PTX loading could be attributed to the hydrogen bond between CAE and PTX and deeper penetration of PTX in the bilayer. The DSC study suggested that inclusion of CAE in the DPPC bilayer eliminates Tg. SANS data showed that CAE has more pronounced membrane thickening effect as compared to cholesterol. The cationic liposomes showed slightly improved cytotoxicity in three different cell lines and improved endothelial cell migration inhibition compared to conventional liposomes. Furthermore, the COMET assay showed that CAE alone does not show any genotoxicity. CONCLUSIONS: The novel cationic ligand (CAE) retains paclitaxel within the phospholipid bilayer and helps in improved drug loading and physical stability. Graphical Abstract ?. PMID- 29520496 TI - Endoscopic transnasal surgery of clival lesions: our experience. AB - BACKGROUND: The clivus is a region characterized by complex anatomy, with vascular and neural structures that are located in close proximity. Different pathologies can affect this area, and traditional surgical approaches were open approaches. Recently, the endoscopic transnasal technique has been introduced, and currently represents a good alternative for the surgical management of these lesions. This is a preliminary report on patients treated endoscopically for clival lesions by the authors' Skull Base Team. PATIENTS AND METHODS: This was a retrospective chart review of patients who underwent an endoscopic exclusive transnasal approach (EEA) or a transoral one (TO) for clival lesions between June 2015 and November 2017 at our Skull Base Referral Center. Patient characteristics and symptoms, preoperative neuroradiological evaluation, surgical approach, complications, and postoperative results were evaluated. RESULTS: Nine patients (6 females and 3 males; age range 6-82 years, mean 50.8 years) underwent EEA or TO. From histological analysis, we found chordomas (6/9 subjects), chondrosarcoma (1/9), craniopharyngioma (1/9), and eosinophilic granuloma (1/9). Three patients had previously been operated for a parasellar chondrosarcoma (1/9), a pituitary macroadenoma (1/9), or a chondroid chordoma (1/9). The lesions were totally (2/9) or sub-totally (5/9) resected, debulked (1/9), or analyzed with a biopsy (1/9). Reconstruction was accomplished with a multilayer technique (7/9), or with a gasket-seal (1/9), using a mucoperichondrial graft, a single/double nasoseptal flap, a middle turbinate flap, a fascia lata, or a synthetic fascia. One patient (11.1%) was re-operated on due to cerebrospinal leakage, without further complications. Two patients (22.2%) were re-operated on due to chordoma regrowth. Adjuvant chemotherapy was administered to 1/9 patient with progressive healing. All of the other patients underwent proton-beam radiotherapy with no documented tumor growth (median follow-up: 20 months; range 5.1-29.9 months). CONCLUSIONS: Clival lesions represent a heterogeneous group of lesions located in a very complex and difficult area. EEA and TO approaches are safe and mini-invasive, with lower morbidity and with postoperative complications when compared to the traditional open approaches, according to the extent and type of pathology. PMID- 29520497 TI - Improved overall survival in head and neck cancer patients after specific therapy of distant metastases. AB - PURPOSE: While metastases directed therapy for oligometastatic disease is recommended in different cancer entities, the treatment of solitary metastases in head and neck squamous cell carcinoma (HNSCC) patients is not clearly defined. METHODS: A retrospective analysis was performed on data from 143 HNSCC patients treated between 2001 and 2016 in a tertiary university hospital. Clinical factors and outcome were measured using the median survival of patients receiving metastases specific therapy in comparison with matched control patients. RESULTS: In 37 patients, distant metastases were treated specifically with either surgery and/or stereotactic ablative radiotherapy and had with 23.97 months a more than three times higher median survival than 10 untreated matched controls with potentially treatable distant metastases (7.07 months). CONCLUSIONS: Our retrospective analysis demonstrates a significant survival benefit for HNSCC patients who received a specific therapy regarding distant metastasis irrespective of localization as compared to a matched control cohort. PMID- 29520498 TI - Does microbial colonisation of a neck drain predispose to surgical site infection: clean vs clean-contaminated procedures. AB - PURPOSE: The study was designed to assess the difference in microbiological colonisation and growth that may occur in drains, in the setting of clean contaminated compared to clean head and neck surgery. METHODS: A prospective observational cohort study was performed. Surgical drain tips upon removal were sent for bacterial culture and the culture results were compared between clean contaminated and clean procedures using mixed effects logistic regression. In all statistical analyses, a priori, p < 0.05 (two-tailed) was calculated to indicate statistical significance. RESULTS: One hundred and ten drains were examined in both clean-contaminated and clean procedures. Drains from clean-contaminated procedures had a significantly longer time in situ (11 vs 5 days, p < 0.001). Overall, significant evidence was seen for an association between procedure type and drain growth rates: 68% of clean-contaminated procedures; and 45% of clean procedures. Although not statistically significant, there was an increase in normal skin flora contaminated drains in clean-contaminated procedures (41 vs 25%). Rates of pathogenic skin organisms (15 vs 16%) and pathogenic oropharyngeal organisms (2.9 vs 0%) were similar for clean-contaminated vs clean procedure patients. CONCLUSION: This preliminary study demonstrated a higher rate of microbial contamination of neck drains that were placed during procedures that involved continuity with the upper aero-digestive tract and neck. Retrograde migration of skin flora along the drain is common but of no clinical significance. Similar rates of pathogenic microbial growth have been demonstrated thus far. However, selection of nosocomial pathogens due to extended antibiotic prophylaxis may pose a risk for infection. LEVEL OF EVIDENCE: 1b. PMID- 29520499 TI - Towards an in vitro fibrogenesis model of human vocal fold scarring. AB - BACKGROUND: Vocal fold (VF) scarring remains a therapeutic dilemma and challenge in modern laryngology. To facilitate corresponding research, we aimed to establish an in vitro fibrogenesis model employing human VF fibroblasts (hVFF) and the principles of macromolecular crowding (MMC). METHODS: Fibrogenesis was promoted by addition of transforming growth factor-beta1 to standard medium and medium containing inert macromolecules (MMC). Hepatocyte growth factor (HGF) and Botox type A were tested for their antifibrotic properties in various doses. Experiments were analyzed with respect to the biosynthesis of collagen, fibronectin, and alpha-smooth muscle actin using immunofluorescence, silver stain and western blot. RESULTS: MMC led to favourable enhanced deposition of collagen and other extracellular matrix components, reflecting fibrotic conditions. Low doses of HGF were able to dampen profibrotic effects. This could not be observed for higher HGF concentrations. Botox type A did not show any effects. CONCLUSION: Based on the principles of MMC we could successfully establish a laryngeal fibrogenesis model employing hVFF. Our finding of dose-dependent HGF effects is important before going into clinical trials in humans and has never been shown before. Our model provides a novel option to screen various potential antifibrotic compounds under standardized conditions in a short time. PMID- 29520500 TI - Spatial distribution, bioavailability, and toxicity of metals in surface sediments of tropical reservoirs, Brazil. AB - Depending on the environmental conditions, surface sediments can retain all the contaminants present and provide a record of the anthropic activities affecting the aquatic environment. In order to analyze the impacts on reservoirs, surface sediments were collected in three characteristic regions (riverine, transitional, and limnetic zones) of seven reservoirs in Sao Paulo State, Brazil. Analyses were made of grain size, organic matter (OM), total phosphorus (TP), and total nitrogen (TN). Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) was used to determine pseudo-total and bioavailable metals (Cu, Cd, Cr, Ni, Pb, Zn, Mn, Fe, and Al). A Horiba probe was used to measure dissolved oxygen (DO), pH, redox potential (ORP), and temperature (Temp) in the bottom water. The data were analyzed using multivariate statistics. Enrichment factors (EF), pollution load index values (PLI), and background values (BG) were also determined in order to evaluate the potential toxicity. Intra-reservoir and inter-reservoir spatial heterogeneity (p < 0.05) were observed using two-way analysis of similarities. Principal component analysis indicated greater influence of metals in the Barra Bonita, Salto Grande, and Rio Grande reservoirs, corroborating the PLI, EF, and BG data. Bioavailable Cu was found in the Rio Grande reservoir, possibly associated with copper sulfate used to control algal blooms, while bioavailable Ni in the Barra Bonita reservoir was attributed to the presence of industrial wastes and natural geology. The bottom water conditions indicated that the metals remained in insoluble forms. PMID- 29520501 TI - Feasibility study of contralateral risk-reducing mastectomy with breast reconstruction for breast cancer patients with BRCA mutations in Japan. AB - BACKGROUND: Contralateral risk-reducing mastectomy (CRRM) for breast cancer patients with BRCA mutations has been reported to not only reduce breast cancer incidence but also to improve survival. The National Comprehensive Cancer Network guidelines recommend providing CRRM to women with BRCA mutations who desire CRRM after risk-reduction counseling. However, in Japan, CRRM cannot be performed generally because it is not covered by health insurance. Thus, we conducted a feasibility study to confirm the safety of CRRM. METHODS: CRRM with bilateral breast reconstructions were performed for breast cancer patients with BRCA mutations. The primary endpoint was early adverse events within 3 months, and secondary endpoints were late adverse events. RESULTS: Between August 2014 and November 2016, ten patients were enrolled. The median age was 37.5 years, and five of the patients had the BRCA1 mutation while five had the BRCA2 mutation. Six patients received neoadjuvant chemotherapy. Eight patients selected silicone breast implants, and two patients selected transverse rectus abdominis myocutaneous flap reconstruction. Pathological findings showed no evidence of occult breast cancers in any of the patients. At a median of 25.5 months follow up time, CRRM-related early adverse events were hematoma (subsequently removed by re-operation; grade 2, n = 1), wound infection (grade 2, n = 1), skin ulceration (grade 1, n = 2) and wound pain (grade 1, n = 1). Overall, there were no grade 3 or more severe adverse events. CONCLUSION: Our results confirm that CRRM with reconstruction could be performed safely. PMID- 29520502 TI - [Acute hypersensitivity reactions associated with monoclonal antibodies for targeted therapy]. AB - The application of biologics such as monoclonal antibodies for targeted therapy may lead to immediate adverse drug reactions with different pathophysiological mechanisms. Some of them are due to the immunogenicity of these drugs and are truly allergic, some of them are non-allergic, some are on-target, and some are off-target. The main example of non-allergic reactions are infusion reactions, mainly induced by cytokine release. They generally occur already at the first application and symptoms may decrease in subsequent applications. Allergic reactions need a preceding sensitization phase and therefore may not occur at first application. However, if the IgE-mediated reaction is due to cross reactivity, they may occur at the first application of the monoclonal antibody. The management of these reactions depends on their severity and the ultimate need to treat the patient with these drugs. PMID- 29520503 TI - Comparing Mechanistic and Preclinical Predictions of Volume of Distribution on a Large Set of Drugs. AB - PURPOSE: Volume of distribution at steady state (Vdss) is a fundamental pharmacokinetic (PK) parameter driven predominantly by passive processes and physicochemical properties of the compound. Human Vdss can be estimated using in silico mechanistic methods or empirically scaled from Vdss values obtained from preclinical species. In this study the accuracy and the complementarity of these two approaches are analyzed leveraging a large data set (over 150 marketed drugs). METHODS: For all the drugs analyzed in this study experimental in vitro measurements of LogP, plasma protein binding and pKa are used as input for the mechanistic in silico model to predict human Vdss. The software used for predicting human tissue partition coefficients and Vdss based on the method described by Rodgers and Rowland is made available as supporting information. RESULTS: This assessment indicates that overall the in silico mechanistic model presented by Rodgers and Rowland is comparably accurate or superior to empirical approaches based on the extrapolation of in vivo data from preclinical species. CONCLUSIONS: These results illustrate the great potential of mechanistic in silico models to accurately predict Vdss in humans. This in silico method does not rely on in vivo data and is, consequently, significantly time and resource sparing. The success of this in silico model further suggests that reasonable predictability of Vdss in preclinical species could be obtained by a similar process. PMID- 29520504 TI - Fern-shaped patch as a hallmark of blue rubber bleb nevus syndrome in neonatal venous malformations. AB - : Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital vascular disease associated with important morbidity and non-insignificant risk of mortality in cases of severe gastrointestinal or neurological involvement. Early diagnosis in the neonatal period can be difficult as very often skin lesions appear progressively during childhood having no correlation with gastrointestinal lesion development. The appearance of one large venous malformation (VM) in the neonatal period has suggested a characteristic finding of this syndrome. The objective of the study was to identify a specific clinical sign in the congenital venous malformations (VMs) of the BRBNS to distinguish them from the conventional VMs. Clinical histories of all patients diagnosed with BRBNS were reviewed, including those who presented a large VM at birth. Clinical characteristics of congenital VM associated with BRBNS were recorded. Five patients with BRBNS were found to have a large VM since birth. All of them presented a fern-shaped patch over the surface of the VM. CONCLUSION: The finding of this macroscopic sign in the evaluation of the newborn with a VM could be considered as a guiding syndromic herald which should raise suspicion for BRBNS and allow for more accurate evaluation and surveillance for complications. What is Known: * BRBNS is a rare vascular disease associated with important morbidity and non-insignificant risk of mortality in cases of severe gastrointestinal or neurological involvement. * Early diagnosis in the neonatal period can be difficult as very often skin lesions appear progressively during childhood having no correlation with gastrointestinal lesion development. What is New: * Recognition of a fern-shaped patch in neonates with a VM should raise suspicion for BRBNS and allow for more accurate evaluation and surveillance for complications. PMID- 29520505 TI - Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut Restricted Polymer. AB - PURPOSE: Polymeric drugs, including patiromer (Veltassa(r)), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R 2 = 0.7, Q 2 = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs. PMID- 29520506 TI - Effects of denosumab on bone mineral density in Japanese women with osteoporosis treated with aromatase inhibitors for breast cancer. AB - Adjuvant aromatase inhibitor (AI) therapy, for hormone receptor-positive breast cancer, in postmenopausal women is associated with bone loss, leading to an increased risk of fractures. Denosumab, an antibody raised against the receptor activator of nuclear factor-kappaB ligand, has been proven to protect against AI induced bone loss. Hence, we aimed to determine whether denosumab is effective in postmenopausal Japanese women with osteoporosis, treated with AI. We prospectively evaluated the bone mineral density (BMD) in the lumbar spine and the bilateral femoral neck in 102 postmenopausal women with clinical hormone receptor-positive breast cancer, stages I-IIIA, during a postoperative period of 12 months. The other inclusion criteria for this study were: women that should receive AIs as adjuvant therapy and those with evidence of osteoporosis (lumbar spine or bilateral femoral neck BMD, equivalent to T-score classification of <= - 2.5) upon enrollment. The patients received supplemental calcium, vitamin D, and 60 mg of subcutaneous denosumab every 6 months. The BMD of the lumber spine increased by 4.9 and 6.6% at 6 and 12 months, respectively. An increase in BMD was observed at the femoral neck, bilaterally. Hypocalcemia >= grade 2, osteonecrosis of the jaw, and non-traumatic clinical fracture were not observed in this study. Our findings revealed that biannual treatment with denosumab is associated with a great increase of BMD in Japanese women receiving adjuvant AI therapy, irrespective of their previous history of AI therapy. PMID- 29520507 TI - PCOS and risk of fractures. PMID- 29520508 TI - Disease burden of fractures among patients with osteoporosis in Japan: health related quality of life, work productivity and activity impairment, healthcare resource utilization, and economic costs. AB - Osteoporosis remains undertreated in Japan, and bone fractures are the most frequent complications imposing heavy burden on individuals and the community. This paper investigates the clinical and economic burden of fractures among osteoporosis patients in Japan. The Japan National Health and Wellness Survey 2012-2014 database was used for analysis. Respondents aged >= 50 years and indicated a physician diagnosis of osteoporosis (N = 1107) were categorized into three subgroups: no prior fracture (N = 693), single fracture (N = 242), and multiple (>= 2) fractures (N = 172). Health-related quality of life (HRQoL), work productivity and activity impairment, healthcare resource utilization and associated direct and indirect costs were compared across three fracture subgroups adjusting for respondents' sociodemographic and clinical characteristics using generalized linear regression models. The estimated fracture prevalence among respondents with osteoporosis who were >= 50 years was 37.4%, of whom 41.5% had multiple fractures. Relative to osteoporosis respondents with no fracture and with single fracture, those with multiple fractures reported significant higher disability in HRQoL, more healthcare resource utilization, and were associated with higher direct costs. Improved treatment of fractures among osteoporosis patients is necessary and may help reduce the clinical and economic burden in this osteoporosis population. PMID- 29520509 TI - Correction to: Association of Cannabis, Stimulant, and Alcohol use with Mortality Prognosis Among HIV-Infected Men. AB - In the original publication of the article, the given and family name of the third author was not correct. The name has been corrected with this erratum. PMID- 29520510 TI - Variant Angina and Aborted Sudden Cardiac Death. AB - PURPOSE OF REVIEW: Variant angina, which is characterized by recurrent chest pain and transient ECG changes along with angiographic evidence of coronary artery spasm, generally has a favorable prognosis. However, episodes of ischemia caused by vasospasm may lead to potentially life-threatening ventricular arrhythmias and cardiac arrest, even in patients with no history of prior cardiac disease. This review describes the epidemiology, pathogenesis, clinical spectrum, and management of variant angina, as well as outcomes in patients who present with aborted sudden cardiac death (ASCD). RECENT FINDINGS: Contrary to prior opinions, evidence from recent observational studies indicate that patients with variant angina presenting with ASCD face a worse prognosis than those without this type of presentation. Predictors of ASCD include age, hypertension, hyperlipidemia, family history of sudden cardiac death, multi-vessel spasm, and left anterior descending artery spasm. Medical therapy alone with calcium channel blockers and nitrates may not be sufficiently protective in these patients and there is lack of concrete data on the optimal management strategy. Current guidelines recommend implantable cardiac defibrillator (ICD) therapy in patients who are survivors of cardiac arrest caused by ventricular fibrillation or unstable ventricular tachycardia after reversible causes are excluded, and should strongly be considered in these patients. Although medical therapy is absolutely imperative for patients with variant angina and a history of ASCD, ICD therapy in these patients is justified. Further large-scale studies are required to determine whether ICD therapy can improve survival in this high-risk group of patients. PMID- 29520511 TI - Social inequalities in oral health in a group of older people in a Middle Eastern country: a cross-sectional survey. AB - BACKGROUND AND OBJECTIVE: The percentage of Lebanese older people has increased considerably. Given that Lebanese seniors are marginalized in the health policy making process, we suggest a high social inequality in oral health that has not been studied so far. The purpose of our study was to describe and compare oral health status in a group of Lebanese older people according to their socioeconomic status (SES) MATERIALS AND METHODS: Participants were recruited from three different primary health care clinics in Beirut, Lebanon. Data were collected from an administered questionnaire that included sociodemographic variables, perception of oral health, and regular dental visits. Oral examination included the number of missing and decayed teeth, the prosthetic status, and the number of functional dental units (FUs). The SES of the participants was determined by educational level, previous or actual work, and neighborhood level. RESULTS: 264 participants aged 71.4 +/- 6.27 years (64.7% female) were included in the study. Regular dental visit, dental status, FU, and oral health perception were significantly related to the participants' place of residence, educational level, and work. Moreover, the mean number of missing teeth (p = 0.048) and decayed teeth (p = 0.018) was significantly elevated in the low SES. CONCLUSION: There is a clear socioeconomic inequality in oral health among the Lebanese older people. Further researches should explore the potential contribution of psychosocial and behavioral factors in explaining these disparities. PMID- 29520512 TI - Comparative Analysis of the Gut Bacterial Community of Four Anastrepha Fruit Flies (Diptera: Tephritidae) Based on Pyrosequencing. AB - Fruit flies are the most economically important group of phytophagous flies worldwide. Whereas the ecological role of bacteria associated with tephritid fruit fly species of the genera Bactrocera and Ceratitis has been demonstrated, the diversity of the bacterial community in Anastrepha has been poorly characterized. This study represents the first comprehensive analysis of the bacterial community in the gut of larvae and adults of Anastrepha ludens, A. obliqua, A. serpentina, and A. striata using 454 pyrosequencing. A total of four phyla, seven classes, 11 families, and 27 bacterial genera were identified. Proteobacteria was the most represented phylum, followed by Firmicutes, Actinobacteria, and Deinococcus-Thermus. The genera Citrobacter, Enterobacter, Escherichia, Klebsiella, and Raoultella were dominant in all samples analyzed. In general, the bacterial community diversity in adult flies was higher in species with a broader diet breadth than species with a restricted number of hosts, whereas it was also higher in adults versus larvae. Differences in bacterial communities in adults might be determined by the number of fruit species infested. Lastly, the predictive functional profile analysis suggested that community members may participate in metabolic pathways related to membrane transport and metabolism of carbohydrates, amino acids, cofactors, and lipids. These results provide the basis for the study of unexplored functional roles of bacteria in this insect group. PMID- 29520513 TI - Production and Identification of Inthomycin B Produced by a Deep-Sea Sediment Derived Streptomyces sp. YB104 Based on Cultivation-Dependent Approach. AB - The natural products discovery program in our group utilizes deep-sea sediment derived microorganisms and employs a bio-active guided isolation procedure and one strain many compounds (OSMAC) approach to screen bio-active natural products for practical applications in the medicinal and agricultural industry. OSMAC strategy is employed to stimulate secondary metabolite production through changing culture conditions. In this paper, we applied cultivation-dependent procedure, changing media type, leading to the discovery of a bio-active compound named inthomycin B (1) from a marine-derived Streptomyces sp. YB104. The compound was characterized based on extensive spectroscopic analyses and comparison to that in the reported literature. The quantification of inthomycin B demonstrated that Streptomyces sp. YB104 produced moderate yield of inthomycin B with a yield around 25 mg/l after 14 days. Thus, Streptomyces sp. YB104 was considered to be a useful potential as a first industrial-producing strain of inthomycins. PMID- 29520514 TI - Determinants of inappropriate hospitalization in cataract surgery in the south of Italy: a retrospective study. AB - PURPOSE: To analyze the frequency of inappropriate hospitalization in cataract surgery and the type of related determinants. METHODS: A nested retrospective case-control study was carried out on 2708 consecutive cataract surgery patients operated between January 2013 and December 2015. All cases with inappropriate hospitalization (day surgery or ordinary hospitalization) were compared with a control group of cases treated in an appropriate (day service) regimen. The predictive value for inappropriate admissions to the hospital was assessed using a logistic regression model. Significant variables from the univariate analysis were included in a multivariate model. RESULTS: Forty-five cases (< 2%) of inappropriate hospital admissions were recorded. Residence, heart disease, tremors, anticoagulants, intraoperative floppy iris syndrome were not related to appropriateness, while psychotic disorder (OR 12.571, p = 0.018), anxiety depressive syndrome (OR 7.818, p = 0.010) and use of antipsychotropic drugs (OR 7.724, p = 0.002) were related to the inappropriateness of admission by univariate and multivariate analysis. Previous systemic surgeries were predictors of ordinary hospitalization by logistic regression analysis. A greater presence of hypertension, diabetes mellitus and fellow eye pseudophakia was noticed in appropriate hospitalization cases. CONCLUSIONS: This study detects the predictive role of psychiatric disorders as determinants of hospitalization inappropriateness in cataract surgery. The negative correlation between inappropriate hospitalization and conditions such as hypertension and diabetes points out that in the elderly population common diseases are effectively addressed, in contrast to the difficult management of psychiatric patients. Prior systemic interventions represent factors inducing transfer from day service to ordinary hospitalization, highlighting communication problems related to difficult coping with an outpatient surgery setting. PMID- 29520516 TI - Abstracts of the 1st meeting of the Austrian Autonomic Society - Otto Loewi Gesellschaft. PMID- 29520517 TI - Initial treatment with pulse methylprednisolone followed by short-term prednisolone and tonsillectomy for childhood IgA nephropathy. AB - BACKGROUND: Although a combination therapy, comprising 2-year high-dose oral prednisolone (PSL), is effective for treating childhood immunoglobulin A nephropathy (IgAN), severe adverse effects and residual proteinuria occur in some patients after the therapy. METHODS: To clarify the efficacy of intravenous pulse methylprednisolone (IVMP; 15-20 mg/kg; maximum 600 mg/day; for 3 consecutive days/week for 3 weeks) followed by short-term reduced-dose PSL (initially 1 mg/kg; maximum 30 mg on alternate days; tapered off within approximately 12 months) and tonsillectomy as an initial treatment, we retrospectively reviewed the clinical courses of 54 consecutive children with IgAN (32 boys; mean age at onset, 12.2 years; follow-up period of > 2 years) after initiating the treatment. According to the Japanese pediatric IgAN guidelines, we divided the 54 patients into the following two groups: group 1, comprising 24 patients with severe IgAN, and group 2, comprising 30 patients with mild IgAN. RESULTS: After the treatment, proteinuria disappeared in all patients at a median of 1.6 months (group 1, 2.8 months; group 2, 0.4 months) and hematuria disappeared in 47 patients (87%) at a median of 13.2 months (group 1, 15.9 months; group 2, 13.2 months). During the follow-up period (median 5 years), no severe adverse effects were observed in any patient. At the last visit, although two patients (4%) had mild proteinuria, none developed hypertension or renal insufficiency. CONCLUSIONS: As an initial treatment, IVMP followed by short-term PSL and tonsillectomy appears to be effective for treating childhood IgAN. PMID- 29520518 TI - Scanning electron microscopy of polycystic liver disease. AB - Resected specimens of PCLD by laparoscopic fenestration surgery were evaluated by scanning electron microscopy. Epithelium lining the largest cyst (26 cm in size) showed prominent villous proliferation with positivity of Ki-67, while the epithelium of the small cyst (3 cm in size) showed slight proliferation (smooth) with small positivity of Ki-67. PMID- 29520515 TI - OPERA models for predicting physicochemical properties and environmental fate endpoints. AB - The collection of chemical structure information and associated experimental data for quantitative structure-activity/property relationship (QSAR/QSPR) modeling is facilitated by an increasing number of public databases containing large amounts of useful data. However, the performance of QSAR models highly depends on the quality of the data and modeling methodology used. This study aims to develop robust QSAR/QSPR models for chemical properties of environmental interest that can be used for regulatory purposes. This study primarily uses data from the publicly available PHYSPROP database consisting of a set of 13 common physicochemical and environmental fate properties. These datasets have undergone extensive curation using an automated workflow to select only high-quality data, and the chemical structures were standardized prior to calculation of the molecular descriptors. The modeling procedure was developed based on the five Organization for Economic Cooperation and Development (OECD) principles for QSAR models. A weighted k-nearest neighbor approach was adopted using a minimum number of required descriptors calculated using PaDEL, an open-source software. The genetic algorithms selected only the most pertinent and mechanistically interpretable descriptors (2-15, with an average of 11 descriptors). The sizes of the modeled datasets varied from 150 chemicals for biodegradability half-life to 14,050 chemicals for logP, with an average of 3222 chemicals across all endpoints. The optimal models were built on randomly selected training sets (75%) and validated using fivefold cross-validation (CV) and test sets (25%). The CV Q2 of the models varied from 0.72 to 0.95, with an average of 0.86 and an R2 test value from 0.71 to 0.96, with an average of 0.82. Modeling and performance details are described in QSAR model reporting format and were validated by the European Commission's Joint Research Center to be OECD compliant. All models are freely available as an open-source, command-line application called OPEn structure-activity/property Relationship App (OPERA). OPERA models were applied to more than 750,000 chemicals to produce freely available predicted data on the U.S. Environmental Protection Agency's CompTox Chemistry Dashboard. PMID- 29520519 TI - A cytosol derived factor of Group B streptococcus prevent its invasion into human epithelial cells. AB - Group B streptococcus (GBS) or Streptococcus agalactiae, is an opportunistic pathogen causing a wide range of infections like pneumonia, sepsis, and meningitis in newborn, pregnant women and adults. While this bacterium has adapted well to asymptomatic colonization of adult humans, it still remains a potentially devastating pathogen to susceptible infants. Advances in molecular techniques and refinement of in vitro and in vivo model systems have elucidated key elements of the pathogenic process, from initial attachment to the maternal vaginal epithelium to penetration of the newborn blood-brain barrier. Still, the formidable array of GBS virulence factors makes this bacterium at the forefront of neonatal pathogens. The involvement of bacterial components in the host pathogen interaction of GBS pathogenesis and its related diseases is not clearly understood. In this study we demonstrated the role of a 39 kDa factor from GBS which plays an important role in the process of its invasion. We found a homogeneous 39 kDa factor from the cytosol of GBS after following a combination of sequential purification steps involving molecular sieving and ion exchange chromatography using ACTA-FPLC system. Its N-terminal sequence showed a homology with xenobiotic response element type transcriptional regulator protein, a 40 kDa protein of Streptococcus. This factor leads to inhibition of GBS invasion in HeLa and A549 cells. This protein also showed sensitivity and specific cross reactivity with the antibodies raised against it in New Zealand white rabbits by western immunoblotting. This inhibitory factor was further confirmed tolerant for its cytotoxicity. These results add a novel aspect to bacterial pathogenesis where bacteria's own intracellular protein component can act as a potential therapeutic candidate by decreasing the severity of disease thus promoting its invasion inhibition. PMID- 29520520 TI - Large-Scale Genomic Biobanks and Cardiovascular Disease. AB - PURPOSE OF REVIEW: Cardiovascular disease is a leading cause of morbidity and mortality worldwide and is the focus of extensive biomedical research. Large genetic consortia combining data from many traditional prospective cohort and ascertained case-control study designs have facilitated the discovery of genetic associations for a variety of cardiovascular diseases including diabetes, coronary artery disease, and hypertension. Biobank-based genetic studies offer an alternative whereby large populations are genotyped and linked to electronic health records. RECENT FINDINGS: Biobank sample sizes worldwide have surpassed even the largest genetic consortia and have yielded key insights into the genetic determinants of both common and rare cardiovascular phenotypes. Herein, we provide an overview of the largest genomic biobanks and discuss the relevant advantages and challenges inherent to the biobank model of cohort generation and genomic study design. PMID- 29520521 TI - Patient empowerment in Europe: is no further research needed? PMID- 29520522 TI - The role of sciatic nerve block to complement femoral nerve block in total knee arthroplasty: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Femoral nerve block (FNB) appears to have higher postoperative analgesic benefits compared with the patient-controlled analgesia (PCA) in total knee arthroplasty (TKA). However, the role of sciatic nerve block (SNB) as a complement to FNB remains controversial. We performed a meta-analysis assessing the benefits of the SNB as a complement to FNB, as well as comparing the efficacy of single-injection versus continuous SNB in TKA. METHODS: Our group conducted a systematic literature search in PubMed, EMBASE and Google Scholar. We retrieved randomized trials comparing either SNB versus placebo or continuous versus single injection SNB. The intervention group was the use of SNB as a complement to FNB, while the control group was FNB alone. Pain score at rest and movement (at 4, 12, 24, 48 and 72 h), patient-controlled intravenous opioid consumption, length of hospital stay, and incidence of nausea were extracted from each study. Random effects model was used for meta-analysis and standardized mean difference (SMD) was used as the effect size. RESULTS: Ten articles comprising 514 patients were included to compare the effects of SNB combined with FNB versus FNB alone. Interventional group was found to significantly reduce pain score at for 4 h (SMD = - 0.94, 95% CI - 1.42 to - 0.47, P < 0.001, I2 = 76.5%) compared with the control group. Pain score at rest was significantly reduced at movement for 12 h (SMD = - 0.29, 95% CI - 0.54 to - 0.04, P = 0.02, I2 = 0%). Opioid consumption was significantly reduced at 24 (SMD = - 0.60, 95% CI - 1.01 to - 0.17, P = 0.01, I2 = 69.1%) and 48 h (SMD = - 1.04, 95% CI - 1.46 to - 0.61, P < 0.001, I2 = 43.4%) after TKA using SNB as a complement to FNB. Three articles were additionally meta-analyzed to compare the efficacy of single-injection (n = 79) versus continuous SNB (n = 79), being the latter one significantly associated with less pain score at 24 (SMD = -0.77, 95% CI - 1.10 to - 0.45, P < 0.001, I2 = 0%) and 48 h (SMD = - 0.69, 95% CI - 1.01 to - 0.36, P < 0.001, I2 = 0%), but not at 12 h (SMD = - 0.34, 95% CI - 0.73 to - 0.06, P = 0.10, I2 = 0%). CONCLUSIONS: This meta-analysis provides evidence-based supports to the benefits of SNB as a complement to FNB in TKA. The combination sciatic-femoral nerve block appears to be the optimal choice for patients in high risk of postoperative opioids consumption or acute pain after TKA. PMID- 29520524 TI - Time has come for proton and carbon beam therapy. PMID- 29520523 TI - Type of second primary malignancy after achieving complete response by definitive chemoradiation therapy in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: While the standard treatment for stage II-III (non-T4) esophageal squamous cell carcinoma (ESCC) is neoadjuvant therapy followed by esophagectomy, definitive chemoradiation therapy (dCRT) is an option to treat ESCC patients who reject or may not tolerate surgical treatment. Second primary malignancy (SPM) is a problem for long-term survivors after achieving complete response (CR) by dCRT. METHODS: The source of the subjects in this study was the patients with stage II/III (excluding T4 disease) ESCC (UICC6th) who underwent dCRT from 2000 to 2011 at the National Cancer Center Hospital, Japan. SPM, defined as malignancy newly detected at different site from the initial disease, was checked in patients who achieved CR by the initial dCRT. RESULTS: Among the 285 patients with stage II/III (excluding T4 disease) ESCC who underwent dCRT, 185 patients achieved CR. SPM was detected in 49 patients (median time to developing SPM, 41.5 months), accounting for 19.3% (95% CI 0.137-0.257) as the 5-year cumulative risk of SPM. SPMs were head and neck cancer (n = 12), gastric cancer (n = 12), esophageal cancer (n = 7), lung cancer (n = 5), colon cancer (n = 4), diffuse large B-cell lymphoma (n = 3), bladder cancer (n = 2), small intestinal cancer (n = 1), cholangiocarcinoma (n = 1), malignant melanoma (n = 1), and breast cancer (n = 1). There were no significant differences in baseline characteristics between the patients who developed SPM (n = 49) and others (n = 136). CONCLUSIONS: Because second primary malignancy developed often after achieving CR by dCRT for ESCC, it should be followed carefully. PMID- 29520525 TI - A linear stepping endovascular intervention robot with variable stiffness and force sensing. AB - BACKGROUND/PURPOSE: Robotic-assisted endovascular intervention surgery has attracted significant attention and interest in recent years. However, limited designs have focused on the variable stiffness mechanism of the catheter shaft. Flexible catheter needs to be partially switched to a rigid state that can hold its shape against external force to achieve a stable and effective insertion procedure. Furthermore, driving catheter in a similar way with manual procedures has the potential to make full use of the extensive experience from conventional catheter navigation. Besides driving method, force sensing is another significant factor for endovascular intervention. METHODS: This paper presents a variable stiffness catheterization system that can provide stable and accurate endovascular intervention procedure with a linear stepping mechanism that has a similar operation mode to the conventional catheter navigation. A specially designed shape-memory polymer tube with water cooling structure is used to achieve variable stiffness of the catheter. Hence, four FBG sensors are attached to the catheter tip in order to monitor the tip contact force situation with temperature compensation. RESULTS: Experimental results show that the actuation unit is able to deliver linear and rotational motions. We have shown the feasibility of FBG force sensing to reduce the effect of temperature and detect the tip contact force. The designed catheter can change its stiffness partially, and the stiffness of the catheter can be remarkably increased in rigid state. Hence, in the rigid state, the catheter can hold its shape against a [Formula: see text] load. The prototype has also been validated with a vascular phantom, demonstrating the potential clinical value of the system. CONCLUSION: The proposed system provides important insights into the design of compact robotic assisted catheter incorporating effective variable stiffness mechanism and real time force sensing for intraoperative endovascular intervention. PMID- 29520526 TI - Motion-invariant SRT treatment detection from direct M-scan OCT imaging. AB - PURPOSE: Selective retina therapy (SRT) is a laser treatment targeting specific posterior retinal layers. It is focused on inducing damage to the retinal pigment epithelium (RPE), while sparing other retinal tissue compared to traditional photocoagulation. However, the targeted RPE layer is invisible with most imaging modalities and induced SRT lesions cannot be monitored. In this work, imaging scans acquired from an experimental setup that couples the SRT laser beam with an optical coherence tomography (OCT) beam are analyzed in order to evaluate the treatment as they occur. METHODS: We isolated a small part of the time-resolved scan corresponding to the end of the treatment, for which we have microscopic evidence of the SRT outcome. We then use a convolutional neural network to correspond each scan to the treatment result. We explore which aspects of the scan convey more valuable information for a robust therapy evaluation. By only using this adequately small part, we can achieve an online estimation, while being resilient to eye movement. RESULTS: The available dataset consists of time- resolved OCT scans of 98 ex vivo porcine eyes, treated with different energy levels. The proposed method yields high performance in the task of predicting whether the applied energy was adequate for SRT treatment, by focusing on the immediate OCT signal acquired during treatment time. CONCLUSIONS: We propose a strategy toward online noninvasive SRT treatment assessment, able to provide a satisfying evaluation of a treatment status, that therefore could be used for the planning of the treatment continuation. PMID- 29520527 TI - Sublethal effects of spirodiclofen, abamectin and pyridaben on life-history traits and life-table parameters of two-spotted spider mite, Tetranychus urticae (Acari: Tetranychidae). AB - Two-spotted spider mite, Tetranychus urticae Koch, is one of the economically most important pests on a wide range of crops in greenhouses and orchards worldwide. Control of T. urticae has been largely based on the use of acaricides. Sublethal effects of spirodiclofen, pyridaben and abamectin were studied on life table parameters of T. urticae females treated with the acaricides. LC25 values of spirodiclofen, abamectin and pyridaben (3.84, 0.04 and 136.96 ug a.i./ml, respectively) were used for sublethal studies. All acaricides showed significant effects on T. urticae biological parameters including developmental time, survival rate, and fecundity. The females treated with spirodiclofen, abamectin and pyridaben at LC25 exhibited significantly reduced net reproductive rate (R0), finite rate of increase (lambda) and intrinsic rate of increase (r). The intrinsic rate of increase in spirodiclofen, abamectin and pyridaben treated groups and control were 0.0138, 0.0273, 0.039 and 0.2481 female offspring per female per day, respectively. The results indicated that sublethal concentrations of tested pesticides strongly affected the life characteristics of spider mite and consequently may influence mite population growth in future generations. PMID- 29520528 TI - Distribution of 1-aminocyclopropane-1-carboxylate deaminase and D-cysteine desulfhydrase genes among type species of the genus Methylobacterium. AB - The presence of 1-aminocyclopropane-1-carboxylate (ACC) deaminase determines the ability of bacteria to increase the resistance of plants to various types of stress. The genes of ACC deaminase (acdS) and the closely related enzyme D cysteine desulfhydrase (dcyD) were searched in type strains of various representatives of the genus Methylobacterium. Using PCR screening and in silico searching in the available complete genome sequences of type strains, the genes were found in 28 of 48 species of the genus. Phylogenetic analysis of amino acid sequences of proteins revealed two large groups of sequences of the AcdS protein and one of the DcyD protein. The distribution of these groups correlates well with the phylogenetic tree based on the sequences of the 16S rRNA genes, which apparently indicates a different evolutionary adaptation to association with plants in the representatives of these groups. For the first time for aerobic methylotrophs it was demonstrated that the gene dcyD encodes D-cysteine desulfhydrase by cloning and recombinant protein characterization. PMID- 29520532 TI - Factors influencing survival among patients with HER2-positive metastatic breast cancer treated with trastuzumab. AB - PURPOSE: We have limited capability to predict survival among patients treated for metastatic HER2-positive breast cancer. Further research is warranted to identify significant prognostic and predictive factors. METHODS: We identified all HER2-positive metastatic breast cancer patients receiving trastuzumab at the Sunnybrook Odette Cancer Centre (SOCC) from 1999 to 2013 through the Cancer Care Ontario (CCO) Registry (n = 256) and selected patients with available pathology reports (n = 154). A retrospective review was completed documenting clinical, pathologic, and laboratory characteristics at the time of first trastuzumab therapy and survival outcomes. Cox proportional hazards regression models were used to identify prognostic factors for overall survival (OS) (primary endpoint) and failure-free survival (FFS), adjusted for the known prognostic factors of the presence of CNS metastases and the presence of >= 2 distant metastatic sites. RESULTS: A multivariable model identified older age [hazard ratio (HR) 1.18/decade, 95% confidence interval (CI) 1.02-1.37)], increased platelet-to lymphocyte ratio (PLR) (HR 1.75/log-unit, 95% CI 1.25-2.46), increased serum alkaline phosphatase (ALP) (HR 1.87/log-unit, 95% CI 1.41-2.49), and ER positivity (HR 0.63, 95% CI 0.42-0.96) as significant prognostic factors for OS after adjusting for the presence of CNS metastasis (HR 3.19, 95% CI 1.59-6.38) and the presence of >= 2 distant metastatic sites (HR 2.10, 95% CI 1.19-3.70). PLR (HR 1.54/log-unit, 95% CI 1.12-2.12) was the only prognostic factor associated with FFS after adjusting for CNS and >= 2 distant metastatic sites. CONCLUSION: Older age, increased PLR, and ALP were identified as poor prognostic factors and ER positivity as a favorable prognostic factor for OS after adjusting for the presence of CNS metastasis and the presence of number of >= 2 distant metastatic sites. Increased PLR was a poor prognostic factor for both OS and FFS, and warrants further investigation into its prognostic ability amongst patients with HER2-positive metastatic breast cancer. PMID- 29520533 TI - Acupuncture for breast cancer-related lymphedema: a randomized controlled trial. AB - PURPOSE: Approximately 20% of breast cancer survivors develop breast cancer related lymphedema (BCRL), and current therapies are limited. We compared acupuncture (AC) to usual care wait-list control (WL) for treatment of persistent BCRL. METHODS: Women with moderate BCRL lasting greater than six months were randomized to AC or WL. AC included twice weekly manual acupuncture over six weeks. We evaluated the difference in circumference and bioimpedance between affected and unaffected arms. Responders were defined as having a decrease in arm circumference difference greater than 30% from baseline. We used analysis of covariance for circumference and bioimpedance measurements and Fisher's exact to determine the proportion of responders. RESULTS: Among 82 patients, 73 (89%) were evaluable for the primary endpoint (36 in AC, 37 in WL). 79 (96%) patients received lymphedema treatment before enrolling in our study; 67 (82%) underwent ongoing treatment during the trial. We found no significant difference between groups for arm circumference difference (0.38 cm greater reduction in AC vs. WL, 95% CI - 0.12 to 0.89, p = 0.14) or bioimpedance difference (1.06 greater reduction in AC vs. WL, 95% CI - 5.72 to 7.85, p = 0.8). There was also no difference in the proportion of responders: 17% AC versus 11% WL (6% difference, 95% CI - 10 to 22%, p = 0.5). No severe adverse events were reported. CONCLUSIONS: Our acupuncture protocol appeared to be safe and well tolerated. However, it did not significantly reduce BCRL in pretreated patients receiving concurrent lymphedema treatment. This regimen does not improve upon conventional lymphedema treatment for breast cancer survivors with persistent BCRL. PMID- 29520534 TI - Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development. AB - Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data. PMID- 29520535 TI - Attitudes of Austrian Psychotherapists Towards Process and Outcome Monitoring. AB - While monitoring systems in psychotherapy have become more common, little is known about the attitudes that mental health practitioners have towards these systems. In an online survey among 111 Austrian psychotherapists and trainees, attitudes towards therapy monitoring were measured. A well-validated questionnaire measuring attitudes towards outcome monitoring, the Outcome Measurement Questionnaire, was used. Clinicians' theoretical orientations as well as previous knowledge and experience with monitoring systems were associated with positive attitudes towards monitoring. Possible factors that may have led to these findings, like the views of different theoretical orientations or obstacles in Austrian public health care, are discussed. PMID- 29520536 TI - MDCT arthrography assessment of scaphoid nonunion advanced collapse: distribution of cartilage damage and relationship with scaphoid nonunion features. AB - OBJECTIVES: Our primary aim was to evaluate the distribution and severity of cartilage damage in a sample of patients with scaphoid nonunion advanced collapse (SNAC), assessed on MDCT arthrography, with regard to two well-known SNAC staging systems. Secondarily, we wanted to see if the degree of cartilage damage varied with the location of the nonunion. METHODS: We retrospectively included 35 patients with a history of SNAC who had undergone MDCT arthrography. The location of the fracture was defined as the proximal, middle, or distal third of the scaphoid. Cartilage damage was assessed in 14 distinct regions of the wrist using a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Staging of SNAC for each patient was based on the distribution of cartilage damage seen on MDCT arthrography. The one-way ANOVA test was used to evaluate whether global cartilage damage scores differed between patients with proximal vs middle and distal nonunion. RESULTS: The radial styloid-scaphoid (85.7%), the scaphoid trapezium-trapezoid (60%), the scapho-capitate (57.1%), and the proximal radio scaphoid joints (42.9%) were most commonly affected by degenerative cartilage damage. A substantial number of patients could not be classified according to the two SNAC staging systems. Patients with proximal nonunion exhibited a higher mean score of global cartilage damage than patients with middle or distal nonunion: 14.3 +/- 9.5 (95% CI 9.8, 18.7) vs 8.6 +/- 6.9 (95% CI 4.7, 12.4); p < 0.0001. CONCLUSION: The distribution of cartilage damage does not always follow the pattern of progressive osteoarthritis widely described in SNAC. Proximal scaphoid nonunion is related to greater severity of global cartilage damage. PMID- 29520537 TI - Radiological glenohumeral osteoarthritis in long-term type 1 diabetes. Prevalence and reliability of three classification systems. The Dialong shoulder study. AB - OBJECTIVE: In the present study, we evaluate the intra- and interrater agreement of radiological glenohumeral OA using three different classification systems and estimate the prevalence of radiological and clinical glenohumeral OA in patients with type 1 diabetes mellitus (DM1), for over 45 years and controls (The Dialong study). MATERIALS AND METHODS: We included 102 patients with DM1 (49% women, mean age, 61.9 years) and 73 controls (57% women, mean age, 62.6 years). Anterior posterior shoulder radiographs were interpreted by two observers applying the Kellgren-Lawrence (K-L), Samilson-Prieto (S-P) and Samilson-Prieto Allain (S-PA) classifications. RESULTS: The interrater agreement was moderate (weighted kappa, 0.46 to 0.48) for all classifications and the intrarater agreement mainly substantial (0.48-0.86) for both observers. The agreed prevalence of radiological OA was 26 and 18% (OR 1.6 (0.8 to 3.3), p = 0.22, 44 and 26% (OR 2.2 (1.2 to 4.2), p = 0.02) and 30 and 17% (OR 2.1 (1.0 to 4.5), p = 0.05) for the K-L, S-P and S-PA classifications respectively in the diabetes and control groups. The prevalence of moderate or severe radiological OA was 1 to 6% and clinical OA 1 to 2% with no difference between the groups. CONCLUSION: The prevalence of radiological glenohumeral OA was higher in the diabetes group with the Samilson Prieto classification systems, but not associated with clinical OA. The interrater agreement was moderate. We recommend the Samilson-Prieto Allain classification for glenohumeral OA to avoid interpretation of osteophytes < 1 mm as OA in patient groups with a low pre-test likelihood of glenohumeral OA. PMID- 29520538 TI - Body Language in Relational Family Therapy. AB - The mechanism of projective and introjective identification has been re-evaluated in modern analysis. It is no longer just about the transference of mental content to an other, rather it addresses also the deepest psycho-organic sensations and vibrations, which in turn become the basis for interpersonal and family dialogues. The goal of this article is also to lay out the fundamental dynamics of body language as understood by the relational family paradigm. It is a novel analytical perspective on the individual, who is always part of any relational family configuration. PMID- 29520539 TI - Temperament in child and adolescent offspring of patients with schizophrenia and bipolar disorder. AB - Shared vulnerability in offspring of individuals with schizophrenia (SzO) and bipolar disorder (BpO) might manifest early during development through common temperament traits. Temperament dimensions in child and adolescent BpO (N = 80), SzO (N = 34) and the offspring of community controls (CcO) (N = 101) were assessed using the Revised Dimensions of Temperament Survey. The association between temperament dimensions and lifetime psychopathology (including threshold and subthreshold DSM-IV-TR diagnoses) and current socio-academic adjustment was assessed using logistic regression. Fully adjusted models showed that both BpO and SzO scored significantly lower in the positive mood dimension and in the adaptability factor than CcO, with small-medium effect sizes (Cohen's d ~ 0.3 0.5). BpO also scored lower in the activity factor and the activity dimensions than CcO (Cohen's d ~ 0.3). Lower scores in the positive mood dimension were associated with increased risk of impaired adjustment both in BpO [OR 2.30, 95% CI (1.18-4.46)] and in SzO [OR 2.87, 95% CI (1.07-7.66)]. In BpO, lower scores in positive mood were also associated with increased likelihood of internalizing [OR 1.84, 95% CI (1.28-2.64)] and externalizing disorders [OR 1.48, 95% CI (1.01 2.18)]; in SzO, higher scores in activity and flexibility were associated with increased likelihood of internalizing [OR 2.31, 95% CI (1.22-4.38)] and externalizing disorders [OR 3.28, 95% CI (1.2-9)], respectively. Early difficulties in emotion regulation might represent a shared vulnerability phenotype in BpO and SzO. The identification of extreme temperament traits could help to characterize subgroups at greater risk of psychopathology and impaired adjustment, in which targeted interventions are warranted. PMID- 29520540 TI - Co-occurring internalizing and externalizing psychopathology in childhood and adolescence: a network approach. AB - The network approach suggests that psychopathology arises from complex associations between symptoms and may offer insight into the mechanisms that underpin psychiatric comorbidities. The transition from childhood to adolescence is a key period in the development of psychopathology, yet has rarely been considered from a network perspective. As such, the present study examined the network structure of internalizing and externalizing psychopathology from middle childhood through adolescence using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4405). Eight DSM-IV disorders were assessed using maternal reports when children were aged 7.5, 10.5 and 14 years. Weighted, undirected networks were estimated and the relative importance of each node was assessed using three common measures of node centrality; strength, betweenness, and closeness. A consistent network structure emerged at all three time points; nodes clustered together in two regions of space broadly reflecting the internalizing and externalizing spectra. Permutation tests supported structural invariance across this developmental period. These spectra were bridged by numerous disorder-level interactions, the most consistent of which was between depression and oppositional defiant disorder (ODD). Furthermore, inspection of the centrality indices indicated that generalised anxiety disorder and ODD were the most central disorders in the networks. These findings demonstrate that symptom/disorder-level interplay and reciprocal influence are plausible mechanisms for the association between internalizing and externalizing psychopathology in childhood/adolescence. PMID- 29520541 TI - Effect of Alcohol Consumption on Cardiovascular Health. AB - PURPOSE OF REVIEW: This review aims to discuss the effect of alcohol consumption on various cardiovascular (CV) diseases and CV mortality. RECENT FINDINGS: Alcohol intake has consistently shown a J- or U-shaped relationship with several cardiovascular diseases. Light to moderate alcohol intake has been associated with lower risk of coronary artery disease, heart failure (HF), as well as CV mortality. On the other hand, heavy consumption has been associated with deleterious CV outcomes including increased mortality. However, the evidence is based from observational and population-based studies where risk of confounding cannot be excluded even after meticulous methodological approaches. This is compounded by conflicting data such as higher risk of certain CV diseases like HF in former drinkers compared to abstainers. Further, Mendelian randomization studies using genetic polymorphisms in enzymes have recently questioned the beneficial association of low-moderate drinking with CV system. There has been substantial and consistent evidence that light to moderate alcohol consumption have beneficial effect on overall cardiovascular profile and mortality. However, there are considerable limitations in the reported literature to determine a strong causality of a protective effect of moderate alcohol consumption by itself. Further robust studies or possibly a well-structured randomized controlled could bring an end to this debate. PMID- 29520542 TI - Enhanced adsorption of Cd(II) from aqueous solution by a magnesium oxide-rice husk biochar composite. AB - In this study, a magnesium oxide-rice husk biochar composite (MgO-BCR) was successfully prepared by a MgO impregnation method, and its adsorption performance was investigated in Cd(II) aqueous solution. A pseudo-second-order kinetic model described the Cd(II) adsorption behaviour on BCR and MgO-BCR well, while a Langmuir adsorption isotherm was more suitable for Cd(II) adsorption on the adsorbent. The fitting results of the monolayer model indicated that the number of ions captured by per site varied between 0.97 and 1.09. The calculated thermodynamic parameters indicated that Cd(II) adsorption onto MgO-BCR was spontaneous and endothermic. Characterisation of the adsorbent revealed that in situ precipitation, surface complexation, and electrostatic attraction contributed to the Cd(II) adsorption. The adsorption capacities of rice husk biochar (BCR) and MgO-BCR for Cd(II) reached 6.36 and 18.1 mg/g, respectively. The results demonstrated that MgO-BCR composite could be used as an effective and eco-friendly adsorbent to enhance the removal of Cd(II) from aqueous solution. PMID- 29520543 TI - EDTA-functionalized clinoptilolite nanoparticles as an effective adsorbent for Pb(II) removal. AB - An efficient Pb(II) adsorbent was prepared by the modification of clinoptilolite nanoparticles (CpN) with ethylenediaminetetraacetic acid (EDTA). Samples were characterized by XRD, FT-IR, SEM, BET, TG-DTG, CHNS analyzer, and energy dispersive analysis X-ray spectroscopy (EDX). The experiments were designed by response surface methodology (RSM) based on central composite design (CCD) that suggested a quadratic model to predict the conditions and the interactions between the variables including adsorbent dosage, removal time, CPb, and its solution pH. Adequacy of the suggested quadratic model was judged by ANOVA. The maximum Pb(II) removal of 0.27 mmolPb(II)/gads was achieved in optimal run including adsorbent dosage 2 g L-1, removal time 271 min, CPb 22.51 mmol L-1, and Pb(II) solution pH 5.88. In binary metal cation systems including 1000 mg L-1 with respect to both Pb(II) and interfering cations, good selectivity of CpN-EDTA adsorbent was observed towards Pb(II) among the tested cations except Fe(III). Adsorption isotherm of lead removal by the adsorbent was well modeled by Langmuir equation, indicating a monolayer sorption of Pb(II) onto the adsorbent. The pseudo-second-order rate equation, indicating chemical reaction rate limiting step for the process, well modeled the kinetic of the process. An exothermic and spontaneous process was confirmed by the negative ?H and ?G. PMID- 29520544 TI - Variations of the nirS-, nirK-, and nosZ-denitrifying bacterial communities in a northern Chinese soil as affected by different long-term irrigation regimes. AB - Denitrification causes nitrogen loss from agricultural soils and emission of nitrous oxide (N2O). Water addition leads to an increase in soil moisture which greatly influenced soil denitrification. However, it is unclear how irrigation management affected the denitrifying bacterial communities in agricultural systems. In the present study, we investigated the abundance, diversity, and composition of the nirS-, nirK-, and nosZ-denitrifying bacterial communities in the soil under different long-term irrigation regimes by using real-time PCR (qPCR) and Illumina MiSeq sequencing approaches. Results showed that the abundance of nosZ gene was 3.94-6.01 and 35.09-60.21 times more than that of nirS and nirK genes, and the abundance of nirS gene was 5.84-15.30 times higher than that of nirK gene, respectively, in different irrigation treatments. However, the Alpha diversity indices of the nirK-denitrifying bacterial community were higher than those of the nirS- and nosZ-denitrifying bacterial communities. Proteobacteria was the predominant phylum for all the denitrifying bacterial communities, and significant differences were observed in relative abundance of Alphaproteobacteria and Betaproteobacteria in predominant class between different irrigation treatments for the nirS- and nosZ-denitrifying bacterial communities, respectively. Irrigation significantly affected the abundance, Shannon and Invsimpson indices, and structure of the nirS- and nosZ-denitrifying bacterial communities, whereas it only minor influenced the structure of the nirK denitrifying bacterial community. Furthermore, the shifts in abundance, diversity, and structure of the nirS- and nosZ-denitrifying bacterial communities correlated significantly with the soil property variations; however, no soil property was significantly correlated with the abundance and Alpha diversity index of the nirK-denitrifying bacterial community. Our results demonstrate that different long-term irrigation regimes greatly altered the abundance, diversity, and structure of the nirS- and nosZ- rather than the nirK-denitrifying bacterial communities. PMID- 29520545 TI - Agricultural solid waste for sorption of metal ions: part I-characterization and use of lettuce roots and sugarcane bagasse for Cu(II), Fe(II), Zn(II), and Mn(II) sorption from aqueous medium. AB - Sugarcane bagasse and hydroponic lettuce roots were used as biosorbents for Cu(II), Fe(II), Zn(II), and Mn(II) removal from monoelemental solutions in aqueous medium, at pH 5.5, using batch procedures. These biomasses were studied in natura (lettuce roots, NLR, and sugarcane bagasse, NSB) and modified with HNO3 (lettuce roots, MLR, and sugarcane bagasse, MSB). Langmuir, Freundlich, and Dubinin-Radushkevich non-linear isotherm models were used to evaluate the data from the metal ion adsorption assessment. The maximum adsorption capacities (qmax) in monoelemental solution, calculated using the Langmuir isothermal model for Cu(II), Fe(II), Zn(II), and Mn(II), were respectively 24.61, 2.64, 23.04, and 5.92 mg/g for NLR; 2.29, 16.89, 1.97, and 2.88 mg/g for MLR; 0.81, 0.06, 0.83, and 0.46 mg/g for NSB; and 1.35, 2.89, 20.76, and 1.56 mg/g for MSB. The Freundlich n parameter indicated that the adsorption process was favorable for Cu(II) uptake by NLR; Fe(II) retention by MLR and MSB; and Zn(II) sorption by NSB, MLR, and NSB and favorable for all biomasses in the accumulation of Mn(II). The Dubinin-Radushkevich isotherm was applied to estimate the energy (E) and type of adsorption process involved, which was found to be a physical one between analytes and adsorbents. Organic groups such as O-H, C-O-C, CH, and C=O were found in the characterization of the biomass by FTIR. In the determination of the biomass surface charges by using blue methylene and red amaranth dyes, there was a predominance of negative charges. PMID- 29520546 TI - Study on embodied CO2 transfer between the Jing-Jin-Ji region and other regions in China: a quantification using an interregional input-output model. AB - Jing-Jin-Ji region (i.e., Beijing, Tianjin, and Hebei) is China's key development region, but it is also the leading and most serious air pollution region in China. High fossil fuel consumption is the major source of both carbon dioxide (CO2) emissions and air pollutants. Therefore, it is important to reveal the source of CO2 emissions to control the air pollution in the Jing-Jin-Ji region. In this study, an interregional input-output model was applied to quantitatively estimate the embodied CO2 transfer between Jing-Jin-Ji region and other region in China using China's interregional input-output data in 2010. The results indicated that there was a significant difference in the production-based CO2 emissions in China, and furthermore, the Jing-Jin-Ji region and its surrounding regions were the main regions of the production-based CO2 emissions in China. Hebei Province exported a large amount of embodied CO2 to meet the investment, consumption, and export demands of Beijing and Tianjin. The Jing-Jin-Ji regions exported a great deal of embodied CO2 to the coastal provinces of southeast China and imported it from neighboring provinces. PMID- 29520547 TI - NO3-/NH4+ ratios affect nutritional homeostasis and production of Tanzania guinea grass under Cu toxicity. AB - Nitrogen (N) can alleviate metal toxicity. However, as of yet, there have been no studies showing the efficacy of NO3-/NH4+ in mitigating Cu toxicity. The objective of this study was to evaluate the Cu toxicity on the nutritional and productive attributes of Panicum maximum cv. Tanzania as well as the role of NO3- and NH4+ ratios in nutritional homeostasis. The experiment was conducted using 3 * 4 factorial treatments arranged in a randomized complete block design with three replicates. The treatments were three NO3-/NH4+ ratios (100/0, 70/30, and 50/50) and four Cu rates (0.3, 250, 500, and 1000 MUmol L-1) in nutrient solution. Copper concentrations in the diagnostic leaves (DL) were highest in plants grown under 70/30 NO3-/NH4+ ratios and a Cu rate of 1000 MUmol L-1. In this combination, it was observed that DL had higher concentrations of NH4+, greater glutamine synthetase activity, lower chlorophyll concentration (SPAD value), and lower shoot dry mass, suggesting high disorders of nutritional homeostasis. Plants receiving N in the form of NO3- and 1000 Cu MUmol L-1 showed that DL had lower concentrations of Cu, higher concentration of chlorophyll, higher NO3- concentration, higher nitrate reductase activity, and higher NO3- accumulation in the roots, suggesting a reduction in disorders of nutritional homeostasis. The disorders on mineral uptake, N assimilation, and biomass production caused by Cu toxicity are shown to be affected by NO3-/NH4+ ratios, and N supply via NO3- allowed for better homeostasis of the forage grass. PMID- 29520548 TI - Detoxification, oxidative stress, and cytogenotoxicity of crack cocaine in the brown mussel Perna perna. AB - The presence of cocaine and its metabolites and by-products has been identified in different aquatic matrices, making crack cocaine the target of recent studies. The aim of this study was to evaluate the sublethal effects of crack on the brown mussel Perna perna. Mussels were exposed to three concentrations of crack cocaine (0.5, 5.0, and 50.0 MUg L-1) for 168 h. Gills, digestive glands, and hemolymph were extracted and analyzed after three different exposure times using a suite of biomarkers (EROD, DBF, GST, GPX, LPO, DNA damage, ChE, and lysosomal membrane stability [LMS]). After 48 and 96 h of exposure, EROD, DBF, GST, GPX activities and DNA strand breaks in the gills increased significantly after 48 and 96 h of exposure. Alterations in LMS were also observed in the mussels exposed to all crack concentrations after 96 and 168 h. Our results demonstrated that crack cocaine is metabolized by CYP-like and GST activities in the gills. GPX was not able to prevent primary genetic damage, and cytotoxic effects in the hemocytes were also observed in a dose- and time-dependent response. Our study shows that the introduction of illicit drugs into coastal ecosystems must be considered a threat to marine organisms. PMID- 29520549 TI - Levels of urinary metabolites of four PAHs and cotinine determined in 1016 volunteers living in Central Italy. AB - Polycyclic aromatic hydrocarbons (PAH) are products of the incomplete combustion of organic materials, and exposure of the general population to PAH is ubiquitous. They are also present in tobacco smoke. Some PAH are classified as carcinogens. Urine samples from 747 non-smoking and 269 smoking subjects living in the same area of Central Italy were analyzed in order to determine reference values for PAHs exposure of a general population. The concentration of cotinine, urinary metabolite of nicotine was also measured in these samples in order to classify the subjects as smokers or not. The median concentration and 50th percentile in females was higher than in males for all metabolites; 1- and 2 hydroxynaphtalene (1-OHNAP and 2-OHNAP) and 1-hydroxypyrene (1-OHPy), are significantly higher in smokers; on the other side 3-hydroxybenzo[a]pyrene (3 OHBaPy) and 6-hydroxynitropyrene (6-OHNPy) do not correlate with the cotinine concentration. PMID- 29520550 TI - Bleaching of biofilm-forming algae induced by UV-C treatment: a preliminary study on chlorophyll degradation and its optimization for an application on cultural heritage. AB - Green microalgae colonizing stone surfaces represent a major problem for the conservation of heritage monuments, since they lead to biodegradation and aesthetic issues. Previous studies in La Glaciere show cave (France) have demonstrated that UV-C may have a strong effect on microalgae, thus leading to chlorophyll bleaching, which was increased when biofilms were maintained under VIS-light condition unlike to those maintained in the dark. To understand the physiological mechanisms underlying this response and in order to optimize in situ treatment, 30 kJ m-2 UV-C exposure times were applied to Chlorophyta Chlorella sp. and chlorophyll degradation kinetics were then monitored. UV-C irradiation was enough to inhibit photosynthesis and to directly kill all algal cells. Results also showed that chlorophyll a was degraded faster than chlorophyll b and that 14 h were necessary for complete degradation of all the present chlorophyll. In addition, our results highlighted the importance of visible light exposition after UV-C treatment which leading to chlorophyll bleaching. Irradiated algae cultivated in the dark were still green 5 days after treatment while cultivated samples in the light lost their green color after 14 h. An efficient UV-C treatment applicable to show caves and other heritage monuments was proposed. PMID- 29520551 TI - Effects of export concentration on CO2 emissions in developed countries: an empirical analysis. AB - This paper provides the evidence on the short- and the long-run effects of the export product concentration on the level of CO2 emissions in 19 developed (high income) economies, spanning the period 1962-2010. To this end, the paper makes use of the nonlinear panel unit root and cointegration tests with multiple endogenous structural breaks. It also considers the mean group estimations, the autoregressive distributed lag model, and the panel quantile regression estimations. The findings illustrate that the environmental Kuznets curve (EKC) hypothesis is valid in the panel dataset of 19 developed economies. In addition, it documents that a higher level of the product concentration of exports leads to lower CO2 emissions. The results from the panel quantile regressions also indicate that the effect of the export product concentration upon the per capita CO2 emissions is relatively high at the higher quantiles. PMID- 29520552 TI - Biochar application increases sorption of nitrification inhibitor 3,4 dimethylpyrazole phosphate in soil. AB - Biochar (BC) application to soils is of growing interest as a strategy to improve soil fertility and mitigate climate change. However, BC-induced alterations in the soil N cycle are currently under debate. BC has recently been shown to accelerate the emissions of N2O via the biotic ammonium oxidation pathway, which results in lower nitrogen use efficiency and environmentally harmful losses of NO3 and/ or N2O. To avoid these potential losses, the use of nitrification inhibitor (NI) could provide a useful mitigation strategy for BC-amended agricultural fields. Here, we tested the sorption behavior of a model NI, the synthetic 3,4-dimethylpyrazole phosphate (DMPP) on 15-month-aged soil-BC mixtures. We saw that BC additions increased DMPP sorption to varying extents depending on BC feedstock type and pyrolysis temperature. The highest sorption was found for BC pyrolyzed at a lower temperature. BC effects on soil physico chemical characteristics (i.e., hydrophobicity) seem to be important factors. PMID- 29520553 TI - Mapping for the management of diffuse pollution risks related to agricultural plant protection practices: case of the Etang de l'Or catchment area in France. AB - Faced with health, environmental, and socio-economic issues related to the heavy use of pesticides, diffuse phytosanitary pollution becomes a major concern shared by all the field actors. These actors, namely the farmers and territorial managers, have expressed the need to implement decision support tools for the territorial management of diffuse pollution resulting from the plant protection practices and their impacts. To meet these steadily increasing requests, a cartographic analysis approach was implemented based on GIS which allows the spatialization of the diffuse pollution impacts related to plant protection practices on the Etang de l'Or catchment area in the South of France. Risk mapping represents a support-decision tool that enables the different field actors to identify and locate vulnerable areas, so as to determine action plans and agri-environmental measures depending on the context of the natural environment. This work shows that mapping is helpful for managing risks related to the use of pesticides in agriculture by employing indicators of pressure (TFI) and risk on the applicator's health (IRSA) and on the environment (IRTE). These indicators were designed to assess the impact of plant protection practices at various spatial scales (field, farm, etc.). The cartographic analysis of risks related to plant protection practices shows that diffuse pollution is unequally located in the North (known for its abundant garrigues and vineyards) and in the South of the Etang de l'Or catchment area (the Mauguio-Lunel agricultural plain known for its diversified cropping systems). This spatial inequity is essentially related to land use and agricultural production system. Indeed, the agricultural lands cover about 60% of the total catchment area. Consequently, this cartographic analysis helps the territorial actors with the implementation of strategies for managing risks of diffuse pollution related to pesticides use in agriculture, based on environmental and socio-economic issues and the characteristics of the natural environment. PMID- 29520554 TI - Effects of a novel neonicotinoid insecticide cycloxaprid on earthworm, Eisenia fetida. AB - Cycloxaprid (CYC) is a novel neonicotinoid insecticide with high activity against resistant pests but is safe for mammals. The toxic effects of CYC on earthworms (Eisenia fetida) were studied in this paper. The 14-day exposure results showed that CYC is potentially toxic to earthworms, with a 14d-LC50 of 10.21 mg/kg dry soil, and that it induced tissue damage to the epidermis, gut, and neurochord at sublethal doses. During a 21-day exposure, CYC induced oxidative stress in earthworms, and both enzyme activities of catalase (CAT) and superoxide dismutase (SOD) were impacted. In addition, expression of the genes Cat and Sod were down- and upregulated, respectively. The activity of the enzyme acetylcholinesterase (AChE) was increased at day 7 but decreased at day 21 after CYC exposure, while expression of the signal transduction-related genes was significantly regulated. Our study shows for the first time that negative impacts could be induced by CYC on earthworms under both acute and chronic exposure through oxidative stress and gene regulation. The present study provides a database for assessing the environmental risk to non-target organisms resulting from the use of CYC. PMID- 29520555 TI - Financial impact of intravenous iron treatments on the management of anaemia inpatients: a 1 year observational study. AB - Background Intravenous (IV) iron preparations bypass the difficulties (malabsorption and side effects) associated with oral iron for the treatment of iron deficiency anaemia (IDA). Ferric carboxymaltose (FCM) can be administered as a single infusion over short periods of time but is more expensive than iron sucrose (IS) when the patients are hospitalized. Objectives To evaluate the appropriateness of FCM prescriptions and to establish the economic impact of this management (including disease coding) compared to the use of IV IS. Setting This study was conducted for inpatients in all departments (orthopaedic department, gastroenterology department and two units of the internal medicine department) where FCM was widely prescribed. Method We retrospectively identified 224 patients, diagnosed with IDA using laboratory parameters and/or disease coding, who received FCM between January and December 2014. Main outcome measure The primary outcome was the rate of appropriateness of FCM prescriptions and the financial impact compared to IV IS. Results 89 Patients were included. The total additional cost for an inappropriate prescription of IV FCM (68% of cases) was of 6053 ?. The total incremental cost of unsuitable disease coding was estimated at 31,688 ?. Indications for IV FCM were categorized: intestinal bleeding (31%), malabsorption (17%), intolerance (9%) and refractory to oral iron (7%). The majority of patients (62%) received 1000 mg of FCM per week. The average length of hospital stay was of 10 days. Conclusion The prescription of IV iron was appropriate in most cases but did not necessarily require FCM. The use of IV IS, in many cases, could present a cost-saving option for inpatients with IDA. The lack of an IDA coding generated incremental costs. PMID- 29520556 TI - Using Community-Driven, Participatory Qualitative Inquiry to Discern Nuanced Community Health Needs and Assets of Chicago's La Villita, a Mexican Immigrant Neighborhood. AB - In predominately immigrant neighborhoods, the nuances of immigrant life in the ethnic enclave have important, yet underappreciated impact on community health. The complexities of immigrant experiences are essential to unpacking and addressing the impact of acculturative processes on observed racial, ethnic, and class-based health disparities in the United States. These insights because they are largely unexplored are best captured qualitatively through academic-community research partnership. We established the participatory mixed method Little Village participatory community health assessment (CHA) to explore community health in an ethnic enclave. In this paper, we share findings from our qualitative component exploring: how do Residents in a Predominately Immigrant Neighborhood Perceive Community Health Needs and Assets in Little Village. Three major themes emerged: rich, health promoting community assets inherent in the ethnic enclave; cumulative chronic stress impacting the mental health of families and intra-familial strain; and, work and occupation as important but underappreciated community health determinants in an immigrant neighborhood. These nuanced findings enhanced our community health assessment and contributed to the development of two additional tailored CHA methods, a community member administered Community Health Survey, and an oral history component that provided deeper insight on the community's health needs and assets, and a focus for action on work as a social determinant of health at the community level. Conducting trusted community-driven health assessments that are adaptive and flexible to capture authentic needs and assets are critical, given health consequences of the new anti-immigrant rhetoric and growing socio-political tensions and fear in immigrant neighborhoods in the United States. PMID- 29520557 TI - Feishu Acupuncture Inhibits Acetylcholine Synthesis and Restores Muscarinic Acetylcholine Receptor M2 Expression in the Lung When Treating Allergic Asthma. AB - Acupuncture was proven beneficial in treating allergic inflammation. We aimed to explore the regulation underlying the effects of acupuncture on Feishu, an acupoint most commonly used in the acupuncture therapy for respiratory diseases, with respect to the system of sympathetic nerve neurotransmitter acetylcholine (Ach). Male Wistar rats were randomly grouping. No treatment was taken in the normal group. Allergic asthma was induced using ovalbumin on the model, Feishu acupuncture, and sham acupuncture groups; then control or acupuncture treatment lasting for 3 weeks was performed. Bronchoalveolar lavage fluid (BALF) from the four groups was examined. And pulmonary tissues were subjected to histological analysis with H&E staining; besides, immunofluorescent staining, quantitative PCR, and western blot were used to detect synthetase (ChAT) and Ach hydrolase (AchE), and its muscarinic receptors (mAchRs) M1-M3. There was inflammatory infiltration in the lung upon allergic asthma, which was alleviated by the Feishu acupuncture. The eosinophilic granulocytes, neutrophils, and lymphocytes in BALF from the Feishu acupuncture group were all significantly decreased compared with those of the model and sham acupuncture groups. The specific acupuncture on Feishu upon allergic asthma put down the pulmonary expression of ChAT, repaired at the level of gene expression the pulmonary expression of mAchR M1, and restored the pulmonary expression of mAchR M2 (especially in the bronchiolar epithelium) which has a role in inhibiting Ach release; while sham acupuncture had no effect. These results confirmed the therapeutic effects of Feishu acupuncture on allergic asthma, suggesting that the mechanisms may involve suppression of the Ach signal both from its synthesis and during its release. PMID- 29520558 TI - The role of heavy metals and polychlorinated biphenyls (PCBs) in the oncogenesis of head and neck tumors and thyroid diseases: a pilot study. AB - Previous literature has highlighted the mechanisms of molecular toxicity induced by substances such as arsenic, cadmium, chromium, nickel, lead, barium and PCBs. The research was carried out on 20 volunteers, all the patients gave their consent to the research: the aim of the study was to evaluate the presence of metals and PCBs in these different matrices (blood and hair), correlating the biochemical data to pathological conditions present, and also to the area in which patients resided. Various quantitative determinations were carried out on samples of blood and hair for 14 heavy metals and on blood samples for 12 PCBs. For the 11 patients the results indicated that blood levels for half of the 14 displayed heavy metals measured considerably higher compared to the reference values, whilst the levels measured in hair evidenced some positive values significantly higher than the maximum reference. Of the 12 PCBs assayed in blood some showed higher positive values compared to the maximum tabular reference (although there is no clear reference quantified in the WHO-2005 report). In the 9 healthy patients heavy metals in the blood were within the expected target range, with those showing positive results (<= 3 out of 14 heavy metals for each patient) having values only slightly higher than the reference maximum. The levels of 14 heavy metals measured in hair were below thresholds, and levels for the 12 PCBs measured in blood showed negativity or positivity with values close to the minimum benchmarks. The analyses carried out on biological matrices have uncovered important and significant differences between healthy and unhealthy subjects, both qualitative and quantitative differences with respect to heavy metals and PCBs. All patients with head and neck cancer enlisted for the study had heavy metal and PCB blood levels at least twice the maximum reference level. The levels of heavy metals in hair were at least double the maximum reference. In contrast, all healthy volunteers enrolled showed no significant levels for either metals or PCBs. PMID- 29520559 TI - Life for patients with myelofibrosis: the physical, emotional and financial impact, collected using narrative medicine-Results from the Italian 'Back to Life' project. AB - PURPOSE: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterised by an aggressive clinical course, with disabling symptoms and reduced survival. Patients experience a severely impaired quality of life and their families face the upheaval of daily routines and high disease-related financial costs. The aim of this study was to investigate the perceptions of Italian patients and their caregivers about living with MF and the burden of illness associated with MF. METHODS: A quali-quantitative questionnaire and a prompted written narrative survey were administered to patients affected by primary or post-essential thrombocythemia/post-polycythaemia vera MF and their primary caregiver in 35 Italian haematological centres. RESULTS: In total, 287 questionnaires were returned by patients and 98 by caregivers, with 215 and 62, respectively, including the narrative. At the time of diagnosis, the most commonly expressed emotional states of patients were fear, distress and anger, confirming the difficulty of this phase. A high level of emotional distress was also reported by caregivers. Along the pathway of care, the ability to cope with the disease differed according to the quality of care received. The mean cost to each patient attributable to MF was estimated as ?12,466 per year, with an estimated average annual cost of loss of income of ?7774 per patient and ?4692 per caregiver. CONCLUSIONS: Better understanding of the personal life of MF patients and their families could improve the relationships between health workers and patients, resulting in better focused healthcare pathways and more effective financial support to maintain patients in their social roles. PMID- 29520560 TI - Effects of combined treatment of tadalafil and tamsulosin on bladder dysfunction via the inhibition of afferent nerve activities in a rat model of bladder outlet obstruction. AB - PURPOSE: To investigate the effects of combined treatment of tadalafil (a phosphodiesterase-5 inhibitor) and tamsulosin (an alpha1-adrenoceptor antagonist) on bladder dysfunction in a rat model of bladder outlet obstruction (BOO). METHODS: Cystometry was performed in conscious female BOO rats 6 weeks after partially ligation of the urethra. Either tadalafil (0.03, 0.1 and 0.3 mg/kg) or tamsulosin (0.001, 0.003 and 0.01 mg/kg) was cumulatively applied intravenously at 30-min intervals to examine changes in cystometric parameters and blood pressures. Changes in cystometric parameters and blood pressures were also checked when tadalafil (0.3 mg/kg), tamsulosin (0.003 mg/kg) or both were intravenously applied. RESULTS: In BOO rats, application of either tadalafil (0.3 mg/kg) or tamsulosin (0.003, 0.01 mg/kg) alone significantly increased threshold pressures and intercontraction intervals whereas there were no significant changes in other cystometric parameters. In addition, because a significant reduction in blood pressures was detected after the administration of tamsulosin (0.01 mg/kg), tamsulosin at a lower dose (0.003 mg/kg) was used for the combined treatment. The combination therapy of tadalafil and tamsulosin induced a significantly larger rate of increase in intercontraction intervals (1.7 times) compared with monotherapy of either drug (1.3 times each) although the combined therapy did not affect blood pressures. CONCLUSIONS: These results suggest that the combination therapy of tadalafil and tamsulosin can induce the additive inhibitory effects on urinary frequency compared with monotherapy, more likely via inhibition of the afferent limb of micturition reflex rather than the efferent function as evidenced by the increases in threshold pressures and intercontraction intervals without affecting bladder contractile function. PMID- 29520561 TI - Liquid Biopsy in Primary Brain Tumors: Looking for Stardust! AB - PURPOSE OF REVIEW: Personalized medicine is a challenge to improve survival and quality of life of patients suffering from primary malignant brain tumor. Molecular biology is integrated in initial diagnosis and relapse, and, in the nearest future, over treatment schedule and monitoring. Liquid biopsy is a minimally invasive way to obtain tumor material. RECENT FINDINGS: Over the past years, three fluids have been explored to provide tumor information in primary malignant brain tumor: blood, cerebrospinal fluid, and vitreous liquid. Different tumor components were identified: (1) circulating tumor cells, (2) circulating tumor DNA, (3) RNA and non-coding miRNA, and (4) extracellular vesicles. The performance of the liquid biopsy depends on the tumor type and on the method of detection. Liquid biopsy could be a valuable tool to improve patient care in primary malignant brain tumor. Improvement of its sensitivity is the major challenge to generalize its use in daily practice. PMID- 29520562 TI - Regarding the editorial "The autopsy evaluation of 'straightforward' fire deaths". PMID- 29520564 TI - Fluid intake restores retinal blood flow early after exhaustive exercise in healthy subjects. AB - PURPOSE: It remains unclear whether rehydration restores retinal blood flow reduced by exhaustive exercise. We investigated the effect of fluid intake on retinal blood flow after exhaustive exercise. METHODS: Blood flow in the inferior (ITRA) and superior temporal retinal arterioles (STRA) was measured before and after incremental cycling exercise until exhaustion in 13 healthy males. After the exercise, the subjects rested without drinking (control condition: CON) or with drinking an electrolyte containing water (rehydrate condition: REH) and were followed up for a period of 120 min. To assess the hydration state, the body mass was measured, and venous blood samples were collected and plasma volume (PV) was calculated. RESULTS: Body mass decreased in CON after the trial [- 1.1 +/- 0.1% (mean +/- SE), p < 0.05]. PV was lower in CON than in REH during recovery. The ITRA and STRA blood flows decreased immediately after exercise from the resting baseline (ITRA; - 23 +/- 4% in REH and - 30 +/- 4% in CON, p < 0.05). The ITRA blood flow recovered baseline level at 15 min of recovery in REH (- 9 +/- 3%, p = 0.5), but it remained reduced in CON (-14 +/- 3%, p < 0.05). The STRA blood flow was higher in REH than in CON at 15 min (2 +/- 3 vs. - 5 +/- 3%, p < 0.05). CONCLUSIONS: The results of this study suggest that the reduction in retinal blood flow induced by exhaustive exercise can be recovered early by rehydration. PMID- 29520563 TI - Immunohistochemical Biomarkers of Gastrointestinal, Pancreatic, Pulmonary, and Thymic Neuroendocrine Neoplasms. AB - Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations that irrespective of their primary site share features of neural and endocrine differentiation including the presence of secretory granules, synaptic-like vesicles, and the ability to produce amine and/or peptide hormones. NENs encompass a wide spectrum of neoplasms ranging from well differentiated indolent tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. Most cases arise in the digestive system and in thoracic organs, i.e., the lung and thymus. A correct diagnostic approach is crucial for the management of patients with both digestive and thoracic NENs, because their high clinical and biological heterogeneity is related to their prognosis and response to therapy. In this context, immunohistochemistry represents an indispensable diagnostic tool that pathologists need to use for the correct diagnosis and classification of such neoplasms. In addition, immunohistochemistry is also useful in identifying prognostic and theranostic markers. In the present article, the authors will review the role of immunohistochemistry in the routine workup of digestive and thoracic NENs. PMID- 29520565 TI - The sag response in human muscle contraction. AB - PURPOSE: We examined how muscle length and time between stimuli (inter-pulse interval, IPI) influence declines in force (sag) seen during unfused tetani in the human adductor pollicis muscle. METHODS: A series of 16-pulse contractions were evoked with IPIs between 1 * and 5 * the twitch time to peak tension (TPT) at large (long muscle length) and small (short muscle length) thumb adduction angles. Unfused tetani were mathematically deconstructed into a series of overlapping twitch contractions to examine why sag exhibits length- and IPI dependencies. RESULTS: Across all IPIs tested, sag was 62% greater at short than long muscle length, and sag increased as IPI was increased at both muscle lengths. Force attributable to the second stimulus increased as IPI was decreased. Twitch force declined from maximal values across all IPI tested, with the greatest reductions seen at short muscle length and long IPI. At IPI below 2 * TPT, the twitch with highest force occurred earlier than the peak force of the corresponding unfused tetani. Contraction-induced declines in twitch duration (TPT + half relaxation time) were only observed at IPI longer than 1.75 * TPT, and were unaffected by muscle length. CONCLUSIONS: Sag is an intrinsic feature of healthy human adductor pollicis muscle. The length-dependence of sag is related to greater diminution of twitch force at short relative to long muscle length. The dependence of sag on IPI is related to IPI-dependent changes in twitch duration and twitch force, and the timing of peak twitch force relative to the peak force of the associated unfused tetanus. PMID- 29520566 TI - Effective-dose estimation in interventional radiological procedures. AB - Interventional radiology is based on minimally invasive procedures that allow diagnosis and percutaneous treatment of diseases in almost all organ systems. Such procedures have many benefits, but they also contribute significantly to collective radiation dose. In this regard, effective dose (E) is a convenient quantity to estimate patients' stochastic radiation risk. However, E cannot be accurately evaluated immediately. In the present study, we aimed to estimate the E value in 15 selected interventional procedures. The estimation was based on dose area product (DAP) measurements and used case-specific conversion coefficients. The E values ranged from 3.3 to 69.9 mSv, depending on the kind of procedure. This wide range was mainly due to the broad variation in DAP values, which in turn depend on the details of how the procedures are performed. This suggests that to ensure valid comparative studies and universal reference levels, all interventional procedures should be well classified. PMID- 29520567 TI - Optimization of Synthetic mRNA for Highly Efficient Translation and its Application in the Generation of Endothelial and Hematopoietic Cells from Human and Primate Pluripotent Stem Cells. AB - Identification of transcription factors that directly convert pluripotent stem cells (PSCs) into endothelial and blood cells and advances in the chemical modifications of messenger RNA (mRNA) offer alternative nucleic acid-based transgene-free approach for scalable production of these cells for drug screening and therapeutic purposes. Here we evaluated the effect of 5' and 3' RNA untranslated regions (UTRs) on translational efficiency of chemically-modified synthetic mRNA (modRNA) in human PSCs and showed that an addition of 5'UTR indeed enhanced protein expression. With the optimized modRNAs expressing ETV2 or ETV2 and GATA2, we are able to produce VE-cadherin+ endothelial cells and CD34+CD43+ hematopoietic progenitors, respectively, from human PSCs as well as non-human primate (NHP) PSCs. Overall, our findings provide valuable information on the design of in vitro transcription templates being used in PSCs and its broad applicability for basic research, disease modeling, and regenerative medicine. PMID- 29520568 TI - Gene expression of A6-like subgroup of ATP-binding cassette transporters in mouse brain parenchyma and microvessels. AB - The A-subclass of ATP-binding cassette (ABC) transporters is a highly conserved superfamily of potent lipid transporters. Although the ABCA1-like subgroup of ABCA1-4, and A7 have been shown to mediate the transport of endogenous lipids, the roles of the ABCA6-like subgroup transporters, which have been identified as a unique gene cluster on human chromosome 17q24 (ABCA5, A6, A8, A9, and A10) and mouse chromosome 11 (Abca5, a6, a8a, a8b, and a9), remains largely unknown. The purpose of the present study was to clarify the spatial and temporal expression profiles of Abca6-like subgroup transporters in embryonic and postnatal mouse brains by a combination of in situ hybridization and quantitative polymerase chain reaction (PCR) using magnetically isolated brain vascular endothelial cells. In embryonic brains, the transcripts of Abca5, a8a and a8b were detected predominantly in the mantle zone, where postmitotic neurons differentiate. At the postnatal stages, they were expressed in various nuclei and neuronal layers. Abca9 mRNA was detected diffusely in the embryonic and postnatal brains and sequential and/or strong spotted signals were detected in the leptomeninges on the brain surface. PCR detected expression of Abca8a and Abca9 mRNAs in isolated vascular endothelial cells. Expression signals for Abca6 mRNA were hardly observed at any stages examined. These distinct spatio-temporal expression patterns of Abca6-like subgroup transporters may reflect their functional significance and diversity to regulate lipid transport, particularly in neurons, leptomeningeal cells, and vascular endothelial cells. PMID- 29520569 TI - Mathematical Model for Glucose Dependence of the Local Renin-Angiotensin System in Podocytes. AB - Diabetic kidney disease (DKD) is the primary cause of kidney failure. Diabetic hyperglycemia primarily damages podocyte cells. Podocytes express a local renin angiotensin system (RAS) that produces angiotensin II (ANG II). ANG II levels are elevated by hyperglycemia, triggering podocyte injury. Quantitative descriptions of glucose dose dependency of ANG II are scarce in the literature. For better understanding of the mechanism of glycemic injury in DKD, a mathematical model is developed to describe the glucose-stimulated local RAS in podocytes. The model of the RAS signaling pathway in podocytes tracks peptides and enzymes without explicit glucose dependence. Local and global sensitivity analyses are used to identify the key parameters to be estimated in the model. Three approaches are explored to incorporate glucose dependency through linear ramp functions for the sensitive parameters. The first approach uses inferences from literature data to estimate the parameter values, while the other approaches reduce the number of assumptions by using least-squares regression to estimate all or a subset of the parameters. Physiological parameter values and RAS peptide concentrations ranges are used to discriminate between plausible models for the glucose dose dependency. This is the first model of the theory of the local RAS mechanism specific to podocyte cells to track ANG II levels in a range of glycemic conditions that may contribute to podocyte damage in DKD. The ability to track ANG II behavior could enable prediction of its downstream effects on podocytes and provide opportunities to better characterize pathophysiological features of DKD progression. PMID- 29520571 TI - Could FDG-PET imaging play a role in the detection of progressing atherosclerosis in HIV-infected patients? AB - Important progresses in the management of patients with human immunodeficiency virus, in particular the advent of new anti-retroviral therapies (ART), have turned this rapidly fatal condition into a controllable chronic disease with a life expectancy that approaches the one from the general population. Cardiovascular diseases have now become one of the leading causes of non-HIV related mortality in this population. Several factors including the presence of HIV in the vascular wall and the development of dyslipidemia and alteration in body fat distribution under ART might play a role the progression of atherosclerosis in HIV-infected patients. The use of imaging biomarkers may help to identify the factors associated with an increased risk of cardiovascular events and select high-risk patients who will benefit the most from the early implementation of preventive treatments. PMID- 29520570 TI - Diagnostic Model of Serum miR-193a-5p, HE4 and CA125 Improves the Diagnostic Efficacy of Epithelium Ovarian Cancer. AB - Epithelium ovarian cancer (EOC) is currently the prevalent malignant cancer worldwide. However, there is a lack of efficient biomarkers for EOC screening. Accumulating evidence reveals that serum miRNA detectable in various types of cancer. Therefore, we explore the diagnostic value of combined detection of plasma miR-193a-5p, HE4 and CA125 for EOC. Serum samples were collected from 45 patients with primary EOC, 30 patients with benign ovarian tumor patients and 40 healthy controls. The expression of serum miR-193a-5p was detected by real-time quantitative PCR, and serum HE4 and CA125 were detected by chemiluminescent immunoassay. Moreover, a diagnostic model combining miR-193a-5p, HE4 and CA125 or alone in EOC patients was evaluated by ROC curve analysis. The relative expression quantity (RQ) of serum miR-193a-5p in EOC patients, benign ovarian tumor patients and healthy control groups were 0.419 (0.093, 2.215), 3.667 (1.633, 6.691) and 1.130 (1.000, 7.087), respectively. The RQ of serum miR-193a 5p in EOC patients was significantly lower than that in benign ovarian tumor patients and healthy controls (both P < 0.001), and there was no significant difference between benign ovarian tumor patients and healthy controls (both P > 0.05). There was no significant correlation between serum miR-193-5p, HE4 and CA125 levels (both P > 0.05). Additionally a risk model for miR-193a-5p, HE4 and CA125 was correlated with Grading and Lymph node metastasis (P = 0.016, P = 0.029). The area under the receiver operating characteristic curve of a risk model for distinguishing EOC patients from healthy individuals was 0.996, which higher than any single biomarker. Combined detection of miR-193-5p, HE4 and CA125 by logistic regression analysis could greatly improved the diagnostic ability of EOC and may prove to be a candidate biomarker, providing new directions for further investigation. PMID- 29520572 TI - Assessment of left ventricular ejection fraction with cardiofocal collimators: Comparison between IQ-SPECT, planar equilibrium radionuclide angiography, and cardiac magnetic resonance. AB - BACKGROUND: IQ-SPECT has been shown to significantly reduce acquisition time and administered dose while preserving image quality in myocardial perfusion imaging. Whether IQ-SPECT provides accurate left ventricular ejection fractions (LVEF) with gated blood pool SPECT (GBPS) remains unknown. METHODS: Sixty patients underwent IQ-SPECT GBPS and planar imaging. Among those patients, 11 underwent both cMRI and GBPS. GBPS LVEF, LVEDV, and LVESV were calculated using 2 validated software; QBS (Cedars-Sinai Medical Center, Los Angeles, USA) and MHI (Montreal Heart Institute, Montreal, Canada). LVEF, LVEDV, and LVESV obtained with the different modalities were compared. RESULTS: Average planar LVEF was 48 +/- 11% (mean +/- SD), average LVEDV was 177 +/- 59 mL (range 63 to 342 mL), and average LVESV was 96 +/- 46 mL (range 16 to 234 mL). GBPS LVEF and their correlation coefficient with planar LVEF were 40 +/- 12% (r = 0.70) and 44 +/- 12% (r = 0.83) with QBS and MHI, respectively. Correlation coefficient between cMRI and planar LVEF was 0.65 and were 0.69 and 0.52 between cMRI and GBPS using QBS and MHI, respectively. CONCLUSIONS: LVEF calculated with GBPS using IQ-SPECT correlates with planar measurements. Correlation is best using the MHI method and variation is independent of LVEDV. PMID- 29520573 TI - Correction to: Exosomes in Cardiovascular Medicine. AB - This article was originally published under a [CC BY-NC-SA 4.0/CC BY-NC-ND 4.0] license, but has now been made available under a CC BY 4.0 license. PMID- 29520575 TI - First Record of Culex (Microculex) daumastocampa (Diptera: Culicidae) in Mexico, with Notes on Cx. rejector and Cx. imitator. AB - Culex (Microculex) daumastocampa Dyar & Knab was originally described by Dyar and Knab (Proc US Nat Mus 35:53-70, 1908) from larvae collected at axils of bromeliads in Port San Felipe, Panama. Culex daumastocampa is found in Colombia, Venezuela, Panama, Suriname, Costa Rica, Nicaragua, Guatemala, and Mexico, although its presence had not been reported suggesting its northernmost distribution. In Mexico, the subgenus Microculex had included Cx. rejector Dyar and Knab, and Cx. imitator Theobald. However, after that collection specimens were re-examined along with other specimens collected during 2016 in Chiapas (all specimens are available in the Culicidae Collection of the Universidad Autonoma Agraria Antonio Narro Unidad Laguna [UAAAN-UL], Mexico). Culex daumastocampa is now reported for the first time in Mexico, Cx. rejector for Chiapas, and Cx. imitator removed from the checklist of previous reports as to be present in Mexico. PMID- 29520574 TI - Respiratory terminal oxidases alleviate photo-oxidative damage in photosystem I during repetitive short-pulse illumination in Synechocystis sp. PCC 6803. AB - Oxygenic phototrophs are vulnerable to damage by reactive oxygen species (ROS) that are produced in photosystem I (PSI) by excess photon energy over the demand of photosynthetic CO2 assimilation. In plant leaves, repetitive short-pulse (rSP) illumination produces ROS to inactivate PSI. The production of ROS is alleviated by oxidation of the reaction center chlorophyll in PSI, P700, during the illumination with the short-pulse light, which is supported by flavodiiron protein (FLV). In this study, we found that in the cyanobacterium Synechocystis sp. PCC 6803 P700 was oxidized and PSI was not inactivated during rSP illumination even in the absence of FLV. Conversely, the mutant deficient in respiratory terminal oxidases was impaired in P700 oxidation during the illumination with the short-pulse light to suffer from photo-oxidative damage in PSI. Interestingly, the other cyanobacterium Synechococcus sp. PCC 7002 could not oxidize P700 without FLV during rSP illumination. These data indicate that respiratory terminal oxidases are critical to protect PSI from ROS damage during rSP illumination in Synechocystis sp. PCC 6803 but not Synechococcus sp. PCC 7002. PMID- 29520576 TI - The Impact of Designated Behavioral Health Services on Resource Utilization and Quality of Care in Patients Requiring Constant Observation in a General Hospital Setting: A Quality Improvement Project. AB - Constant observation (CO) is a common economic burden on general hospitals. A quality improvement (QI) project focusing on behavioral health (BH) management of this population was piloted using a novel BH protocol for the proactive assessment and management of all patients requiring CO. The impact on CO-cost and length of stay (LOS) was assessed. Data on demographics, diagnoses, psychopharmacologic treatment, complications and clinical setting were collected and analyzed for all CO-patients over a 6-month period. Cost and LOS data were compared with a similar sequential group prior to project implementation. Out of the 533 patients requiring CO during the study period, 491 underwent the protocol. This QI-project resulted in a significant reduction in the average monthly CO-cost by 33.06% and a 15% reduction in LOS without any increase in complications. PMID- 29520577 TI - The Use of Magnetic Resonance Imaging for Non-Invasive Assessment of Venofer(r) Biodistribution in Rats. AB - PURPOSE: The aim of this study was to determine the potential of magnetic resonance imaging to evaluate the biodistribution of exogenous iron within 24 h after one single injection of Venofer(r) (iron sucrose). METHODS: Venofer(r) was evaluated in vitro for its ability to generate contrast in MR images. Subsequently, iron disposition was assessed in rats with MRI, in vivo up to 3 h and post mortem at 24 h after injection of Venofer(r), at doses of 10- and 40 mg/kg body weight (n = 2 * 4), or saline (n = 4). RESULTS: Within 10-20 min after injection of Venofer(r), transverse relaxation rates (R2) clearly increased, representative of a local increase in iron concentration, in liver, spleen and kidney, including the kidney medulla and cortex. In liver and spleen R2 values remained elevated up to 3 h post injection, while the initial R2 increase in the kidney was followed by gradual decrease towards baseline levels. Bone marrow and muscle tissue did not show significant increases in R2 values. Whole-body post mortem MRI showed most prominent iron accumulation in the liver and spleen at 24 h post injection, which corroborated the in vivo results. CONCLUSIONS: MR imaging is a powerful imaging modality for non-invasive assessment of iron distribution in organs. It is recommended to use this whole-body imaging approach complementary to other techniques that allow quantification of iron disposition at a (sub)cellular level. PMID- 29520578 TI - ? PMID- 29520579 TI - ? PMID- 29520580 TI - Spousal cardiometabolic risk factors and incidence of type 2 diabetes: a prospective analysis from the English Longitudinal Study of Ageing. AB - AIMS/HYPOTHESIS: In the UK, more than one million people have undiagnosed diabetes and an additional five million are at high risk of developing the disease. Given that early identification of these people is key for both primary and secondary prevention, new screening approaches are needed. Since spouses resemble each other in cardiometabolic risk factors related to type 2 diabetes, we aimed to investigate whether diabetes and cardiometabolic risk factors in one spouse can be used as an indicator of incident type 2 diabetes in the other spouse. METHODS: We analysed data from 3649 men and 3478 women from the English Longitudinal Study of Ageing with information on their own and their spouse's diabetes status and cardiometabolic risk factors. We modelled incidence rates and incidence rate ratios with Poisson regression, using spousal diabetes status or cardiometabolic risk factors (i.e. BMI, waist circumference, systolic and diastolic BP, HDL- and LDL-cholesterol and triacylglycerols) as exposures and type 2 diabetes incidence in the index individual as the outcome. Models were adjusted for two nested sets of covariates. RESULTS: Spousal BMI and waist circumference were associated with incident type 2 diabetes, but with different patterns for men and women. A man's risk of type 2 diabetes increased more steeply with his wife's obesity level, and the association remained statistically significant even after adjustment for the man's own obesity level. Having a wife with a 5 kg/m2 higher BMI (30 kg/m2 vs 25 kg/m2) was associated with a 21% (95% CI 11%, 33%) increased risk of type 2 diabetes. In contrast, the association between incident type 2 diabetes in a woman and her husband's BMI was attenuated after adjusting for the woman's own obesity level. Findings for waist circumference were similar to those for BMI. Regarding other risk factors, we found a statistically significant association only between the risk of type 2 diabetes in women and their husbands' triacylglycerol levels. CONCLUSIONS/INTERPRETATION: The main finding of this study is the sex-specific effect of spousal obesity on the risk of type 2 diabetes. Having an obese spouse increases an individual's risk of type 2 diabetes over and above the effect of the individual's own obesity level among men, but not among women. Our results suggest that a couples-focused approach may be beneficial for the early detection of type 2 diabetes and individuals at high risk of developing type 2 diabetes, especially in men, who are less likely than women to attend health checks. DATA AVAILABILITY: Data were accessed via the UK Data Service under the data-sharing agreement no. 91400 ( https://discover.ukdataservice.ac.uk/catalogue/?sn=5050&type=Data%20catalogue ). PMID- 29520583 TI - Integrated Care Training for Psychiatrists: Lessons from a Changing Healthcare Landscape. PMID- 29520582 TI - No increased risk of perforation during colonoscopy in patients undergoing propofol versus traditional sedation: A meta-analysis. AB - BACKGROUND AND AIMS: The safety of propofol sedation during colonoscopy remains unclear, and we performed a meta-analysis to assess the risk of perforation in patients undergoing propofol vs. traditional sedation. METHODS: MEDLINE, CBM, VIP, CNKI, and Wanfang databases were searched up to December 2016. Two reviewers independently assessed abstract of those searched articles. Data about perforation condition in propofol and traditional sedation groups were extracted and combined using the random effects model. RESULTS: A total of 19 studies were included in the current meta-analysis. Compared to traditional sedation, propofol sedation did not increase the risk of perforation (RD = - 0.00, 95% CI - 0.00~0.00, p = 0.98; subgroup analysis: OR = 1.30, 95% CI 0.83~2.05, p = 0.25). CONCLUSION: This meta-analysis suggested that propofol sedation did not increase the risk of perforation compared to traditional sedation during colonoscopy. PMID- 29520581 TI - Biomarkers of diabetic kidney disease. AB - Diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in diabetes. The quest for both prognostic and surrogate endpoint biomarkers for advanced DKD and end-stage renal disease has received major investment and interest in recent years. However, at present no novel biomarkers are in routine use in the clinic or in trials. This review focuses on the current status of prognostic biomarkers. First, we emphasise that albuminuria and eGFR, with other routine clinical data, show at least modest prediction of future renal status if properly used. Indeed, a major limitation of many current biomarker studies is that they do not properly evaluate the marginal increase in prediction on top of these routinely available clinical data. Second, we emphasise that many of the candidate biomarkers for which there are numerous sporadic reports in the literature are tightly correlated with each other. Despite this, few studies have attempted to evaluate a wide range of biomarkers simultaneously to define the most useful among these correlated biomarkers. We also review the potential of high-dimensional panels of lipids, metabolites and proteins to advance the field, and point to some of the analytical and post-analytical challenges of taking initial studies using these and candidate approaches through to actual clinical biomarker use. PMID- 29520584 TI - Research Tracks During Psychiatry Residency Training. PMID- 29520586 TI - Consistency of Limited Prosocial Emotions Across Occasions, Sources, and Settings: Trait- or State-Like Construct in a Young Community Sample? AB - Limited prosocial emotions (LPE, also referred to as callous-unemotional [CU] traits) are considered to reflect a more trait- than state-like construct. Our first objective was to determine the amount true score variance in CU/LPE that was consistent (trait consistency) over two occasions (12-month interval) of measurement versus specific (occasion-specificity) to each occasion. Our second objective was to determine the convergent validity of the consistent (trait) and occasion-specific (state) variance in CU/LPE symptom ratings within and across settings. Mothers, fathers, primary teachers, and ancillary teachers rated the CU/LPE symptoms in sample of 811 Spanish children (55% boys) on two occasions (i.e., end of first and second grades). CU/LPE symptom ratings showed more trait consistency than occasion-specificity for mothers and fathers, slightly more occasion-specificity than trait consistency for primary teachers, and much more occasion-specificity than trait consistency for ancillary teachers. Convergent validity for trait consistency was strong for fathers with mothers but weaker for primary with ancillary teachers. There was essentially no convergent validity for either trait consistency or occasion-specificity across home and school settings. CU/LPE symptom ratings within this age range represented a more trait-like construct for mothers and fathers and more state-like construct for primary teachers and ancillary teachers. In contrast, earlier studies showed ADHD and ODD ratings to be trait-like within and across home and school. The study of CU/LPE in young children should therefore include multiple sources in multiple settings across occasions to better understand the consistent and occasion-specific nature of the CU/LPE construct. PMID- 29520585 TI - Body satisfaction and body weight in under- and healthy-weight adolescents: mediating effects of restrictive dieting, healthy and unhealthy food intake. AB - PURPOSE: Theoretical models, such as the transdiagnostic model of eating disorders highlight the role of cognitive factors (e.g., the way people perceive their bodies) and their associations with maladaptive weight management behaviors resulting in underweight. This paper aims at testing the indirect association of adolescent's body satisfaction and body mass index (BMI) through restrictive dieting, healthy eating or unhealthy eating as well as moderating role of adolescent's weight status. METHODS: The study was conducted in 16 public middle and high schools in Central and Eastern Poland. A sample of 1042 under- and healthy-weight white adolescents aged 13-20 (BMI: 12.63-24.89) completed two self reported questionnaires (fruit, vegetable, and energy-dense food intake) with a 11-month interval. Weight and height were measured objectively. Multiple mediation analysis and moderated multiple mediation analysis were conducted to test the study hypotheses. RESULTS: Adolescents less satisfied with their bodies were more likely to diet restrictively and at the same time ate more unhealthy energy-dense food rather than healthy food, which in turn predicted lower BMI. No moderating effects of weight status were found. CONCLUSIONS: Low body satisfaction is a risk for restrictive diet and unhealthy food intake. Prevention programs may target under- and healthy-weight adolescents who are highly dissatisfied with their bodies, have a high intake of energy-dense food and apply a restrictive diet at the same time. LEVEL OF EVIDENCE: Level III: longitudinal cohort study. PMID- 29520587 TI - P-glycoprotein Restricts Ocular Penetration of Loperamide across the Blood-Ocular Barriers: a Comparative Study in Mdr1a Knock-out and Wild Type Sprague Dawley Rats. AB - The current research was undertaken to determine the existence and magnitude of P glycoprotein (P-gp) expression on the blood-ocular barriers by studying the ocular penetration of loperamide, a specific P-gp substrate, in P-gp (Mdr1a) knock-out (KO) and wild type (WT) Sprague Dawley rats. A clear, stable, sterile solution of loperamide (1 mg/mL), for intravenous administration, was formulated and evaluated. Ocular distribution was studied in P-gp KO and WT rats following intravenous administration of loperamide (at two doses). The drug levels in plasma, aqueous humor (AH), and vitreous humor (VH) samples were determined with the aid of UHPLC-Q-TOF-MS/MS, and the AH/plasma (D AH ) and VH/plasma (D VH ) distribution ratios were estimated. Electroretinography (ERG), ultrastructural analyses, and histology studies were carried out, in both KO and WT rats, to detect any drug-induced functional and/or structural alterations in the retina. Dose-related loperamide levels were observed in the plasma of both WT and KO rats. The loperamide concentrations in the AH and VH of KO rats were significantly higher compared to that observed in the WT rats, at the lower dose. However, a marked increase in the D AH and D VH was noted in the KO rats. ERG, ultrastructure, and histology studies did not indicate any drug-induced toxic effects in the retina under the test conditions. The results from these studies demonstrate that P-gp blocks the penetration of loperamide into the ocular tissues from the systemic circulation and that the effect is more pronounced at lower plasma loperamide concentrations. PMID- 29520588 TI - Nanoparticles for Protein Sensing in Primary Containers: Interaction Analysis and Application. AB - Silver nanoparticles (AgNPs) are known to interact with proteins, leading to modifications of the plasmonic absorption that can be used to monitor this interaction, entailing a promising application for sensing adsorption of therapeutic proteins in primary containers. First, transmission electron microscopy in combination with plasmonic absorption and light scattering responses were used to characterize AgNPs and protein-AgNP complexes, including its concentration dependence, using two therapeutic molecules as models: a monoclonal antibody (mAb) and a synthetic copolymer (SC). Upon interaction, a protein corona was formed around AgNPs with the consequent shifting and broadening of their characteristic surface plasmon resonance (SPR) band (400 nm) to 410 nm and longer wavelenghts. Additional studies revealed secondary and three dimensional structure modifications of model proteins upon interaction with AgNPs by circular dichroism and fluorescence techniques, respectively. Based on the modification of the SPR condition of AgNPs upon interaction with proteins, we developed a novel protein-sensing application of AgNPs in primary containers. This strategy was used to conduct a compatibility assessment of model proteins towards five commercially available prefillable glass syringe (PFS) models. mAb- and SC-exposed PFSs showed that 74 and 94% of cases were positive for protein adsorption, respectively. Interestingly, protein adsorption on 15% of total tested PFSs was negligible (below the nanogram level). Our results highlight the need of a case-by-case compatibility assessment of therapeutic proteins and their primary containers. This strategy has the potential to be easily applied on other containers and implemented during early-stage product development by pharmaceutical companies and for routine use during batch release by packaging manufacturers. PMID- 29520589 TI - Expression of Colocasia esculenta tuber agglutinin in Indian mustard provides resistance against Lipaphis erysimi and the expressed protein is non-allergenic. AB - KEY MESSAGE: Transgenic Brassica juncea plants expressing Colocasia esculenta tuber agglutinin (CEA) shows the non-allergenic nature of the expressed protein leading to enhanced mortality and reduced fecundity of mustard aphid-Lipaphis erysimi. Lipaphis erysimi (common name: mustard aphid) is the most devastating sucking insect pest of Indian mustard (Brassica juncea L.). Colocasia esculenta tuber agglutinin (CEA), a GNA (Galanthus nivalis agglutinin)-related lectin has previously been reported by the present group to be effective against a wide array of hemipteran insects in artificial diet-based bioassays. In the present study, efficacy of CEA in controlling L. erysimi has been established through the development of transgenic B. juncea expressing this novel lectin. Southern hybridization of the transgenic plants confirmed stable integration of cea gene. Expression of CEA in T0, T1 and T2 transgenic plants was confirmed through western blot analysis. Level of expression of CEA in the T2 transgenic B. juncea ranged from 0.2 to 0.47% of the total soluble protein. In the in planta insect bioassays, the CEA expressing B. juncea lines exhibited enhanced insect mortality of 70-81.67%, whereas fecundity of L. erysimi was reduced by 49.35-62.11% compared to the control plants. Biosafety assessment of the transgenic B. juncea protein containing CEA was carried out by weight of evidence approach following the recommendations by FAO/WHO (Evaluation of the allergenicity of genetically modified foods: report of a joint FAO/WHO expert consultation, 22-25 Jan, Rome, http://www.fao.org/docrep/007/y0820e/y0820e00.HTM , 2001), Codex (Codex principles and guidelines on foods derived from biotechnology, Food and Agriculture Organization of the United Nations, Rome; Codex, Codex principles and guidelines on foods derived from biotechnology, Food and Agriculture Organization of the United Nations, Rome, 2003) and ICMR (Indian Council of Medical Research, guidelines for safety assessment of food derived from genetically engineered plants, http://www.icmr.nic.in/guide/Guidelines%20for%20Genetically%20Engineered%20Plants pdf , 2008). Bioinformatics analysis, pepsin digestibility, thermal stability assay, immuno-screening and allergenicity assessment in BALB/c mice model demonstrated that the expressed CEA protein from transgenic B. juncea does not incite any allergenic response. The present study establishes CEA as an efficient insecticidal and non-allergenic protein to be utilized for controlling mustard aphid and similar hemipteran insects through the development of genetically modified plants. PMID- 29520590 TI - Role of urinary tract infection in bladder cancer: a systematic review and meta analysis. AB - PURPOSE: We sought to examine the literature reporting the effect of urinary tract infection (UTI) on non-schistosomiasis-related UBC (UBCNS) through a systematic review and meta-analysis. METHODS: A predefined study protocol was developed according to PRISMA. Medline and Scopus were searched for all studies investigating exposure to UTI with UBCNS as the primary outcome. Potential studies were screened against eligibility criteria. Clinical heterogeneity was assessed and groups with more than two studies were evaluated by random effect meta-analysis. Study-level bias was assessed with the Newcastle-Ottawa Scale (NOS). In cases of substantial between study heterogeneity (I2 > 50%), predefined sensitivity and subgroup analyses were performed. RESULTS: Of 16 eligible studies, eight case-control studies spanning four decades and five countries were suitable for quantitative analysis. Main analysis favored exposure to UTI increasing risk of subsequent UBCNS (RR 1.33 [95% CI 1.14-1.55]). This effect was no longer statistically significant after excluding studies published prior to year 2000 and at high risk of bias. Between study heterogeneity was considerable for nearly all analyses and not reduced by predefined sensitivity or subgroup analyses. CONCLUSION: Exposure to UTI favors increased risk for UBCNS, particularly in men, but these effects were statistically insignificant when pooling data from the most recent and highest quality studies. These data do not support findings of previously published studies, that report on heterogenous populations with poor definitions of UTI and minimal control for important confounders. Results from previous studies should be viewed as hypothesis generating. This review highlights the need for higher quality investigation. PMID- 29520591 TI - Sarcopenia predicts 90-day mortality and postoperative complications after radical cystectomy for bladder cancer. AB - PURPOSE: A single-center study was conducted to investigate the impact of sarcopenia as a predictor for 90-day mortality (90 dM) and complications within 90 days after radical cystectomy for bladder cancer. METHODS: In total, 327 patients with preoperative available digital computed tomography (CT) scans of the abdomen and pelvis were identified. The lumbar skeletal muscle index was measured using preoperative abdominal CT to assess sarcopenia. Complications were recorded and graded according to Clavien-Dindo (CD). Predictors of 90 dM and complications within 90 days were analyzed by uni- and multivariable logistic regression. RESULTS: Of the 327 patients, 262 (80%) were male and 108 (33%) patients were classified as sarcopenic. Within 90 days, 28 (7.8%) patients died, of whom 15 patients were sarcopenic and 13 were not. In multivariable logistic regression analysis, sarcopenia (OR 2.59; 95% CI 1.13-5.95; p = 0.025), ASA 3-4 (OR 2.53; 95% CI 1.10-5.82; p = 0.029) and cM + (OR 7.43; 95% CI 2.34-23.64; p = 0.001) were independent predictors of 90-day mortality. Sarcopenic patients experienced significantly more complications, i.e., CD 4a-5 (p = 0.003), compared to non-sarcopenic patients. In multivariable logistic regression analysis, sarcopenia was independently associated with CD >= 3b complications corrected for age, BMI, ASA-Score and type of urinary diversion. CONCLUSIONS: We reported that sarcopenia proved an independent predictor for 90 dM and complications in patients undergoing RC for bladder cancer. PMID- 29520594 TI - ? PMID- 29520598 TI - Community composition, diversity, and metabolism of intestinal microbiota in cultivated European eel (Anguilla anguilla). AB - The intestinal tract, which harbours tremendous numbers of bacteria, plays a pivotal role in the digestion and absorption of nutrients. Here, high-throughput sequencing technology was used to determine the community composition and complexity of the intestinal microbiota in cultivated European eels during three stages of their lifecycle, after which the metabolic potentials of their intestinal microbial communities were assessed. The results demonstrated that European eel intestinal microbiota were dominated by bacteria in the phyla Proteobacteria and Fusobacteria. Statistical analyses revealed that the three cultured European eel life stages (elver, yellow eel, and silver eel) shared core microbiota dominated by Aeromonas. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) predictions of metagenome function revealed that the European eel intestinal microbiota might play significant roles in host nutrient metabolism. Biolog AN MicroPlateTM analysis and extracellular enzyme assays of culturable intestinal bacteria showed that the intestinal microbiota have a marked advantage in the metabolism of starch, which is the main carbohydrate component in European eel formulated feed. Understanding the ecology and functions of the intestinal microbiota during different developmental stages will help us improve the effects of fish-based bacteria on the composition and metabolic capacity of nutrients in European eels. PMID- 29520592 TI - Decrease of cocaine, but not heroin, self-administration and relapse by the tyrosine kinase inhibitor masitinib in male Sprague Dawley rats. AB - RATIONALE: Accumulating evidence shows that cocaine, and also heroin, influence several tyrosine kinases, expressed in neurons and in non-neuronal populations such as microglia, astrocytes and mast-cells. Drug-induced activation of mast cells both triggers inflammatory processes in the brain mediated by the glial cells they activate, and facilitates histamine release which may directly influence the dopamine system. Thus, by triggering the activation and degranulation of mast cells dependent on the tyrosine kinase c-kit and Fyn, the latter being also involved in NMDA-dependent synaptic plasticity, cocaine and heroin may indirectly influence the neural mechanisms that mediate their reinforcing properties. Masitinib, a novel tyrosine kinase inhibitor with high selectivity for c-Kit, Fyn and Lyn, may alter the aberrant consequences of the activation of these tyrosine kinases by cocaine and heroin. OBJECTIVE: We investigated in rats the effect of a chronic oral treatment with masitinib (20 mg/kg) on the reinforcing and motivational properties of self-administered cocaine (250 MUg/infusion) and heroin (40 MUg/infusion). METHODS: Three different cohorts of rats were trained instrumentally to respond for cocaine, heroin or food under continuous reinforcement. In each group, we assessed the influence of chronic daily treatment with masitinib on the maintenance of instrumental responding and intake and the motivation for the reinforcer. Thus, masitinib and vehicle-treated rats were challenged to adapt to high behavioural demand, to respond under a progressive ratio schedule of reinforcement and to reinstate instrumental responding after extinction and/or abstinence. RESULTS: Masitinib selectively decreased cocaine intake, the motivation for cocaine and the subsequent propensity to respond for cocaine under extinction, while having no effect on instrumental responding for heroin or food. CONCLUSION: The present findings suggest masitinib, a drug with proven efficacy in CNS disorders, could represent a novel treatment for cocaine addiction provided its influence on the reinforcing and incentive properties of the drug is confirmed. PMID- 29520599 TI - Biolubricant potential of exopolysaccharides from the cyanobacterium Cyanothece epiphytica. AB - Exopolysaccaharides (EPS) are carbohydrate polymers secreted by microbial cells, as a protective layer termed sheath or capsule. Their composition is variable. Optimisation of nutrient factors and the effect of some simple stresses on the ability of Cyanothece epiphytica to produce EPS were tested. Of the tested stresses, exposure to ozone for 50 s at 0.06 mg/L resulted in a relatively high EPS yield, without any damage to cell structure. EPS was characterised physicochemically. Chemically, it was found to be composed of pentoses arabinose and xylose; hexoses glucose, galactose and mannose; and the deoxyhexose fucose sugars which were sulphated and with different functional groups. EPS from C. epiphytica was found to be a good hydrophobic dispersant, an excellent emulsifier as well as a flocculant. Its potential as a biolubricant with characteristics better than the conventional lubricant 'grease' was revealed through analysis. This study gave the clue for developing a commercial technology to produce a less expensive and more environment-friendly natural lubricant from the cyanobacterium C. epiphytica for tribological applications. PMID- 29520600 TI - A strong promoter of a non-cry gene directs expression of the cry1Ac gene in Bacillus thuringiensis. AB - Bacillus thuringiensis bacteria show insecticidal activities that rely upon the production of insecticidal crystal proteins, which are encoded by cry or cyt genes and can target a variety of insect pests. It has been shown that cry1Ac is the only cry gene in B. thuringiensis subsp. kurstaki HD73 (B. thuringiensis HD73) and its expression is controlled by both sigmaE and sigmaK. Here, we report a novel sigmaE-dependent strong promoter of a non-cry gene (HD73_5014), which can direct strong cry1Ac gene expression in B. thuringiensis HD73. We constructed an E. coli-B. thuringiensis shuttle vector (pHT315-P 5014 -1Ac) for cry1Ac gene expression, using the HD73_5014 gene promoter. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot analysis showed that expression of the cry1Ac gene directed by the HD73_5014 gene promoter was at the same level as that directed by the previously known strongest cry promoter, P cry8E . However, this strain did not form typical bipyramidal crystals in mother cells, as observed by transmission electron microscopy and atomic force microscope. The strain with Cry1Ac protein expression under the control of the HD73_5014 gene promoter (P 5014 -cry1Ac) showed insecticidal activity against Plutella xylostella similar to that under the control of the orf1cry8E gene promoter (P cry8E -cry1Ac). Collectively, these results suggest that the HD73_5014 gene promoter, as a non-cry gene promoter, would be an efficient transcriptional element for cry gene expression. These data also show the possibility for improving Cry production by searching for transcriptional elements in not only cry genes, but also non-cry genes. PMID- 29520601 TI - Biotechnological production of mono- and diamines using bacteria: recent progress, applications, and perspectives. AB - Common plastics such as polyamides are derived typically from petroleum or natural gas. Fossil-based polyamide production often involves toxic precursors or intermediates. By contrast, bio-based polyamides offer a realistic alternative. Bio-based routes to monomeric precursors of polyamides such as diamines, dicarboxylic acids, and omega-amino acids have been developed. Recent advances in the metabolic engineering of the biotechnologically relevant Escherichia coli and Corynebacterium glutamicum for the production of monoalkylamines such as omega amino acids as well as diamines are presented. PMID- 29520603 TI - New Medicines in Wales: The All Wales Medicines Strategy Group (AWMSG) Appraisal Process and Outcomes. AB - BACKGROUND: The All Wales Medicines Strategy Group (AWMSG) develops prescribing advice and is responsible for appraising new medicines for use in Wales. In this article, we examine the medicines appraisal process in Wales, its timeliness and its impact on medicines availability in Wales, and compare its processes and recommendations with the two other UK health technology appraisal bodies [the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC)]. METHODS: We reviewed the medicines appraisals conducted by AWMSG between October 2010 and September 2015. The duration of the process and the recommendations made by AWMSG were compared with those of NICE and SMC. Only publicly available data were considered in this review. RESULTS: AWMSG conducted 171 single technology appraisals for 137 medicines during the study period (34 were for medicines previously appraised by AWMSG but these were for new indications). Of these, 152 appraisals were supported for use in NHS Wales (33 with restrictions) and 19 were not supported. Recommendations broadly concurred with SMC and NICE for the majority of appraisals. Compared with NICE recommendations, the median time advantage gained in Wales for those medicines that received a positive AWMSG recommendation and which were subsequently superseded by NICE advice was 10.6 months (range 3.5-48.3 months; n = 17). CONCLUSION: This review highlights the work carried out by AWMSG over a 5-year period, and provides evidence to support the effectiveness of the appraisal process in terms of patients in Wales gaining earlier access to medicines and efficiency through reduced duplication with NICE. PMID- 29520602 TI - (Bio)electrochemical ammonia recovery: progress and perspectives. AB - In recent years, (bio)electrochemical systems (B)ES have emerged as an energy efficient alternative for the recovery of TAN (total ammonia nitrogen, including ammonia and ammonium) from wastewater. In these systems, TAN is removed or concentrated from the wastewater under the influence of an electrical current and transported to the cathode. Subsequently, it can be removed or recovered through stripping, chemisorption, or forward osmosis. A crucial parameter that determines the energy required to recover TAN is the load ratio: the ratio between TAN loading and applied current. For electrochemical TAN recovery, an energy input is required, while in bioelectrochemical recovery, electric energy can be recovered together with TAN. Bioelectrochemical recovery relies on the microbial oxidation of COD for the production of electrons, which drives TAN transport. Here, the state-of-the-art of (bio)electrochemical TAN recovery is described, the performance of (B)ES for TAN recovery is analyzed, the potential of different wastewaters for BES-based TAN recovery is evaluated, the microorganisms found on bioanodes that treat wastewater high in TAN are reported, and the toxic effect of the typical conditions in such systems (e.g., high pH, TAN, and salt concentrations) are described. For future application, toxicity effects for electrochemically active bacteria need better understanding, and the technologies need to be demonstrated on larger scale. PMID- 29520604 TI - Estrogen therapy for osteoporosis in the modern era. AB - Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal women to receive appropriate guidance for the prevention and management of osteoporosis. The Women's Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone, leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once "lowest dose for shortest period of time" concept should no longer be used. This review will focus on the prior and current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT. PMID- 29520605 TI - Opportunistic screening for bone disease using abdominal CT scans obtained for other reasons in newly diagnosed IBD patients. AB - : Bone disease is prevalent among patients with inflammatory bowel disease (IBD), though bone density screening remains underutilized. We used CT scans performed for other indications in IBD patients to identify and monitor osteopenia using CT attenuation values at the lumbar spine. Significant rates of bone disease were detected which would have otherwise gone undiagnosed. INTRODUCTION: Osteoporosis affects about 14-42% of patients with IBD. Though screening is recommended in IBD patients with risk factors, it remains underutilized. In patients with newly diagnosed IBD, we used CT scans performed for other indications to identify and monitor progression of osteopenia. METHODS: Using the Ocean State Crohn's and Colitis Area Registry, we identified adult patients with one or more abdominal CT scans. Each patient had two age- and gender-matched controls. Radiologists measured attenuation through trabecular bone in the L1 vertebral body recorded in Hounsfield units (HU). Generalized estimating equations were used to measure how HU varied as a function of gender, type of IBD, and age. RESULTS: One hundred five IBD patients were included, and 72.4% were classified as "normal" bone mineral density (BMD) and 27.6% as potentially osteopenic: 8.6% with ulcerative colitis and 19.0% with Crohn's disease. We found a decrease in bone density over time (p < 0.001) and that BMD decreases more in Crohn's disease than in ulcerative colitis (p < 0.004). Sixty patients had two CT scans, and mean loss of 9.3 HU was noted. There was a non-significant decrease in BMD over time in patients exposed to > 31 days of steroids and BMD was stable with < 30 days of steroid exposure (p < 0.09). CONCLUSION: Using CT scans obtained for other indications, we found low rates of osteopenia and osteoporosis that may otherwise have gone undiagnosed. Refinement of opportunistic screening may have advantages in terms of cost-savings and earlier detection of bone loss. PMID- 29520606 TI - Low peak jump power is associated with elevated odds of dysmobility syndrome in community-dwelling elderly individuals: the Korean Urban Rural Elderly (KURE) study. AB - : In a community-dwelling elderly cohort (Korean Urban Rural Elderly), low peak jump power was associated with elevated odds of dysmobility syndrome and its components, independent of age and comorbidities. Jump power measurement improved discrimination of individuals with dysmobility syndrome when added to conventional risk factors. INTRODUCTION: Dysmobility syndrome was proposed to encompass the risks affecting musculoskeletal outcomes. Jump power measurement is a safe, reproducible high-intensity test for physical function in elderly. However, the relationship between jump power and dysmobility syndrome remains unknown. METHODS: A total of 1369 subjects (mean 71.6 years; women, 66%) were analyzed from a community-based cohort. Dysmobility syndrome was defined as the presence of >= 3 factors among falls in the preceding year, low lean mass, high fat mass, osteoporosis, low grip strength, and low timed get-up-and-go (TUG) performance. Subjects were grouped into tertiles of jump power relative to weight based on sex-stratified cutoffs (32.4 and 27.6 W/kg in men; 23.9 and 19.9 W/kg in women) or into the failed-to-jump group. RESULTS: The prevalence of dysmobility syndrome was 20% overall, increasing from the highest (T1) to lowest (T3) jump power tertile (1, 11, 15% in men; 11, 16, 39% in women) and the failed-to-jump group (39% in men; 48% in women). Low jump power or failed-to-jump was associated with elevated odds of dysmobility syndrome (T3 vs. T1, adjusted odds ratio [aOR] 4.35, p < 0.001; failed-to-jump vs. T1, aOR 7.60, p < 0.001) and its components including falls, low lean mass, high fat mass, and poor TUG performance but not osteoporosis after adjustment for covariates. Jump power modestly discriminated dysmobility syndrome (area under the curve [AUC], 0.71, p < 0.001), which improved discriminatory performance when added to conventional risk factors (AUC, from 0.75 to 0.79, p < 0.001). CONCLUSIONS: Low peak jump power was associated with elevated odds of dysmobility syndrome and its components, independent of age and comorbidities. PMID- 29520607 TI - Teriparatide treatment exerts differential effects on the central and peripheral skeleton: results from the MOAT study. AB - : The central and peripheral skeleton was characterised using imaging techniques during 104 weeks of teriparatide treatment. Teriparatide exerts differential effects on the central and the peripheral skeleton. Overall, we did not observe a change in total body bone mineral. Our conclusions are constrained by the study limitations. INTRODUCTION: Teriparatide stimulates bone formation and resorption and therefore can cause bone gain and loss. We simultaneously characterised the central and peripheral skeleton using imaging techniques to better understand the mechanism of action of teriparatide. METHODS: Postmenopausal, osteoporotic women (n = 20, 65.4 +/- 5.5 years) were recruited into a 104-week study of teriparatide. Imaging techniques included DXA, quantitative computed tomography (QCT), and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Total lumbar spine areal bone mineral content (aBMC) (+ 11.2%), total lumbar spine areal bone mineral density (aBMD) (+ 8.1%), subregional thoracic spine aBMD (+ 7.5%), lumbar spine aBMC (+ 23.5%), lumbar spine aBMD (+ 11.9%), pelvis aBMC (+ 9.3%), and pelvis aBMD (+ 4.3%) increased. However, skull aBMC (- 5.0%), arms aBMC (- 5.1%), legs aBMC (- 2.9%), and legs aBMD (- 2.5%) decreased. Overall, we did not observe a change in total body bone mineral. Increases in L1 L3 volumetric BMD (vBMD) (+ 28.5%) occurred but there was no change in total proximal femur vBMD. Radius and tibia cortical vBMD (- 3.3 and - 3.4%) and tissue mineral density (- 3.2 and - 3.8%) decreased and there was an increase in porosity (+ 21.2 and + 10.3%). Tibia, but not radius, trabecular inhomogeneity (+ 3.2%), and failure load (+ 0.2%) increased, but cortical thickness (- 3.1%), area (- 2.9%), and pore volume (- 1.6%) decreased. CONCLUSIONS: Teriparatide exerts differential effects on the central and the peripheral skeleton. Central trabecular vBMD (L1-L3) is improved, but there is a concomitant decrease in peripheral cortical vBMD and an increase in porosity. Overall, we did not observe a change in total body bone mineral. We acknowledge that our conclusions may be speculative and are constrained by the technical limitations of the imaging techniques used, the lack of a control group, and the small sample size studied. PMID- 29520608 TI - Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X. AB - : We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression. INTRODUCTION: Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non consanguineous Chinese family. METHODS: We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long term bisphosphonate treatment in this patient was evaluated. RESULTS: The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient. CONCLUSION: We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X. PMID- 29520609 TI - Timing of re-irradiation in recurrent high-grade gliomas: a single institution study. AB - There is no standard treatment available for recurrent high-grade gliomas. This monoinstitutional retrospective analysis evaluates the differences in overall survival and progression-free survival in patients according to the timing of re irradiation. Patients suffering from a glioblastoma who received re-irradiation for recurrence were evaluated retrospectively. The median overall survival (OS) and the median progression-free survival were compared with different treatment options and within various time periods. From January 2007 until March 2015, 41 patients suffering from recurrent high-grade gliomas received re-irradiation [median dose of 30.6 Gy (range 20-40 Gy) in median 4 Gy fractions (range 1.8-5 Gy)] in our institution after initial postoperative irradiation or combined radiochemotherapy. The OS in this population was 34 months, and the OS after recurrence (OS-R) was 13 months. After diagnosis of recurrence, patients underwent additional surgical resection after a median of 1.2 months, received a second-line systemic therapy after 2.2 months with or without re-irradiation after 5.7 months. Growth of the tumour was assessed 4.3 months after the start of re-irradiation. The OS after the second surgical resection was 12.2 months, 11.7 months after the start of the second-line systemic therapy, and 6.7 months after the start of re-irradiation. The OS-R was not significantly correlated with the start of re-irradiation after a diagnosis of recurrence or the time period after the previous surgery. At this institution, re-irradiation was performed later compared to other treatment options. However, select patients could benefit from irradiation at an earlier time point. A precise time point should still be evaluated on an individual basis due to the patient's diverse conditions. PMID- 29520610 TI - ATP binding cassette (ABC) transporters: expression and clinical value in glioblastoma. AB - ATP-binding cassette transporters (ABC transporters) regulate traffic of multiple compounds, including chemotherapeutic agents, through biological membranes. They are expressed by multiple cell types and have been implicated in the drug resistance of some cancer cells. Despite significant research in ABC transporters in the context of many diseases, little is known about their expression and clinical value in glioblastoma (GBM). We analyzed expression of 49 ABC transporters in both commercial and patient-derived GBM cell lines as well as from 51 human GBM tumor biopsies. Using The Cancer Genome Atlas (TCGA) cohort as a training dataset and our cohort as a validation dataset, we also investigated the prognostic value of these ABC transporters in newly diagnosed GBM patients, treated with the standard of care. In contrast to commercial GBM cell lines, GBM patient derived cell lines (PDCL), grown as neurospheres in a serum-free medium, express ABC transporters similarly to parental tumors. Serum appeared to slightly increase resistance to temozolomide correlating with a tendency for an increased expression of ABCB1. Some differences were observed mainly due to expression of ABC transporters by microenvironmental cells. Together, our data suggest that the efficacy of chemotherapeutic agents may be misestimated in vitro if they are the targets of efflux pumps whose expression can be modulated by serum. Interestingly, several ABC transporters have prognostic value in the TCGA dataset. In our cohort of 51 GBM patients treated with radiation therapy with concurrent and adjuvant temozolomide, ABCA13 overexpression is associated with a decreased progression free survival in univariate (p < 0.01) and multivariate analyses including MGMT promoter methylation (p = 0.05) suggesting reduced sensitivity to temozolomide in ABCA13 overexpressing GBM. Expression of ABC transporters is: (i) detected in GBM and microenvironmental cells and (ii) better reproduced in GBM-PDCL. ABCA13 expression is an independent prognostic factor in newly diagnosed GBM patients. Further prospective studies are warranted to investigate whether ABCA13 expression can be used to further personalize treatments for GBM. PMID- 29520611 TI - AnnexinA5 promote glioma cell invasion and migration via the PI3K/Akt/NF-kappaB signaling pathway. AB - As an important member of the Annexins, AnnexinA5 has been attributed important functions in trophoblast membrane repair, anticoagulation and cellular signal transduction. Accumulated studies show that AnnexinA5 is closely associated with various types of carcinomas. However, the potential contribution of AnnexinA5 to glioma cancer progression remains unclear. In this study, we report that AnnexinA5 is significantly upregulated in both high-grade glioma samples and glioma cell lines. Moreover, overexpression of AnnexinA5 promotes cell migration and invasion in vitro and tumorigenicity of glioma cells in nude mice, while knockdown of AnnexinA5 manifests a repressive function during these cellular processes. Importantly, mechanistic studies further reveal that AnnexinA5 is an essential transcriptional target of Snail via activating the PI3K/Akt/NF-kappaB signaling pathway. Taken together, these findings suggest that AnnexinA5 or the PI3K/Akt/NF-kappaB pathway may be promising therapeutic molecules to eradicate glioma metastases. PMID- 29520612 TI - Pediatric versus adult meningioma: comparison of epidemiology, treatments, and outcomes using the Surveillance, Epidemiology, and End Results database. AB - Pediatric meningiomas, which account for < 1% of all meningiomas, are thought to have unique features, including being more aggressive than their adult counterparts. The goal of this investigation was to compare pediatric and adult meningiomas in a large head-to-head comparison. We used the Surveillance, Epidemiology, and End Result (SEER) datasets to compare meningioma demographics, first treatments, and outcomes among children/adolescents (0-21 years), young adults (22-45 years), and older adults (> 45 years). During 2004-2012, SEER contained 59148 patients age 0-107 years diagnosed with meningioma, with children/adolescents accounting for 381 (0.64%) patients. Unlike older and young adults, children/adolescents with meningioma did not demonstrate female predominance, and had an equal 1:1 male-to-female ratio. Children/adolescents also had almost three-times as many spinal tumors (13.1%) than young adults (4.2%) and older adults (4.4%). Both children/adolescents and young adults had undergone more gross total resections (both 43%) versus older adults (25%), and were treated more with radiation (14.6%, and 12.0% respectively) than their older counterparts (8.5%). In addition, both children/adolescents and young adults had significantly lower all-cause mortality (4.5% in both) than older adults (24.6%), during median 35-month follow-up. Inherent limitations of the SEER datasets restrict our ability to answer important questions regarding comparisons of tumor grading, histological diagnosis, cause-specific mortality, and neurofibromatosis status. Pediatric meningiomas appear distinct from their adult counterparts as they do not display the typical female predominance and include more clinically relevant spinal tumors. More extensive surgeries, greater use of radiation therapy, and lower all-cause mortality were seen in both children/adolescents and young adults, which raises questions regarding the perceived uniquely aggressive nature of pediatric meningiomas. However, due to the significant limitations of the SEER datasets, our results must be interpreted cautiously and stand only to foster novel questions, which would be better answered in well-designed, prospective studies. PMID- 29520613 TI - In vivo exploration of retinal nerve fiber layer morphology in Parkinson's disease patients. AB - Thinning of the retinal nerve fiber layer (RNFL) is a recently discovered feature of Parkinson's disease (PD). Its exact pathological mechanism is yet unknown. We aimed to determine whether morphological changes of the RNFL are limited to RNFL thinning or also comprise an altered internal structure of this layer. Therefore, we investigated RNFL thickness and applied the RNFL attenuation coefficient (RNFL AC), a novel method derived from optical coherence tomography, in PD patients and healthy controls (HCs). In this pilot study, we included 20 PD patients and 20 HCs matched for age, sex, and ethnicity. An ophthalmologist investigated all participants thoroughly, and we acquired retinal images from both eyes of each participant with a Spectralis optical coherence tomography system. We obtained both the RNFL-AC and RNFL thickness from peripapillary RNFL scans for the entire RNFL, as well as for each quadrant separately. We found no significant differences in the average RNFL-AC or the RNFL-AC of the separate retinal quadrants between PD patients and the HC group. However, compared to the HC group, PD patients had a significantly thinner RNFL in the temporal retinal quadrant. RNFL thinning was found in the temporal quadrant in PD patients without a corresponding change in the RNFL-AC. These findings suggest a reduction in the number of RNFL axons (atrophy) without other major changes in the structural integrity of the remaining RNFL. PMID- 29520614 TI - Attentional functioning in individuals with 22q11 deletion syndrome: insight from ERPs. AB - The 22q11 deletion syndrome (22q11DS), or DiGeorge syndrome (DG), is one of the most common genetic deletion syndromes. DG also carries a high risk for psychiatric disorders, with learning disabilities frequently being reported. Impairments in specific cognitive domains, such as executive functioning and attention, have also been described. The aim of this study was to investigate attentional functioning in a group of subjects with DG using ERPs, and in particular the P300 and CNV components. We studied ten patients with DG and ten healthy subjects that performed a P300 Novelty task and a CNV motor task. P3b amplitude was significantly lower in patients than in controls, while P3b latency was comparable in patients and controls. The P3a parameters were similar in both groups. All CNV amplitudes were significantly lower in DG patients than in controls. DG patients displayed slower reaction times in the CNV motor task than healthy subjects. These results point to a cognitive dysfunction related above all to executive attentional processing in DG patients. In particular, a specific difficulty emerged in selective attention and in the ability to orient and to sustain the anticipatory attention required for an executive motor response. PMID- 29520616 TI - Reply to the letter from Damman et al.: Heart transplantation in the Netherlands: a national achievement. PMID- 29520615 TI - Customization of home closed-loop insulin delivery in adult patients with type 1 diabetes, assisted with structured remote monitoring: the pilot WP7 Diabeloop study. AB - AIMS: Improvement in closed-loop insulin delivery systems could result from customization of settings to individual needs and remote monitoring. This pilot home study evaluated the efficacy and relevance of this approach. METHODS: A bicentric clinical trial was conducted for 3 weeks, using an MPC-based algorithm (Diabeloop Artificial Pancreas system) featuring five settings designed to modulate the reactivity of regulation. Remote monitoring was ensured by expert nurses with a web platform generating automatic Secured Information Messages (SIMs) and with a structured procedure. Endpoints were glucose metrics and description of impact of monitoring on regulation parameters. RESULTS: Eight patients with type 1 diabetes (six men, age 41.8 +/- 11.4 years, HbA1c 7.7 +/- 1.0%) were included. Time spent in the 70-180 mg/dl range was 70.2% [67.5; 76.9]. Time in hypoglycemia < 70 mg/dl was 2.9% [2.1; 3.4]. Eleven SIMs led to phone intervention. Original default settings were modified in all patients by the intervention of the nurses. CONCLUSION: This pilot trial suggests that the Diabeloop closed-loop system could be efficient regarding metabolic outcomes, whereas its telemedical monitoring feature could contribute to enhanced efficacy and safety. This study is registered at ClinicalTrials.gov with trial registration number NCT02987556. PMID- 29520617 TI - Heart transplantation in the Netherlands : A national achievement. PMID- 29520618 TI - Criss-cross. PMID- 29520619 TI - Criss-cross. PMID- 29520620 TI - Cardiac arrest during sports activity is difficult to recognise? Let the AED do the job! PMID- 29520621 TI - Reply to the letter from A. Zorzi and D. Corrado. Rhythm analysis with an AED in an unconscious athlete. PMID- 29520622 TI - Resuscitating athletes. PMID- 29520623 TI - Study of Vesicular Monoamine Transporter 2 in Myopic Retina Using [18F]FP-(+) DTBZ. AB - PURPOSE: To investigate the relationship between expression level of vesicular monoamine transporter 2 (VMAT2) and myopia, as well as the feasibility of noninvasive myopia diagnosis through imaging VMAT2 in retina by using [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ). PROCEDURES: The right eyes of ten guinea pigs were deprived of vision to establish form-deprived (FD) myopia and the left eyes were untreated as the self-control eyes. The location and expression level of VMAT2 in the eyes were detected by micro positron emission tomography (PET)/X-ray computed tomography (CT) imaging through using [18F]FP-(+)-DTBZ. Immunofluorescence staining and Western blot were used to confirm the location and expression level of VMAT2 in the eyes. The concentrations of dopamine (DA) and its metabolites including 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also investigated by high-performance liquid chromatography. RESULTS: The right eyes deprived of vision were obviously myopic (- 3.17 +/- 1.33 D) after procedure, while the left eyes were hyperopic (4.60 +/- 0.83 D, P < 0.0001). The main expressions of VMAT2 in the eyes were located in retina. VMAT2 was significantly reduced in the myopic retina compared to the normal one from PET/CT results (P = 0.0008), which could also be verified by Western blots (P = 0.029). The concentrations of DA, DOPAC, and HVA in the FD eyes were all significantly less than those in the control eyes (P = 0.024, P = 0.018, P = 0.008). As a role of storing and releasing DA in vesicles, VMAT2 was demonstrated positively correlating with the amounts of DA (P = 0.030), DOPAC (P = 0.038), and HVA (P = 0.025) through Pearson's correlation coefficient test. CONCLUSIONS: We demonstrate that [18F]FP-(+)-DTBZ can be used to noninvasively image VMAT2 in retina. The expression level of VMAT2 in retina may act as a new biomarker for myopia diagnosis. The decreasing of VMAT2 expression level may play an important role in the development of myopia through correspondingly reducing the amount of DA in retina. PMID- 29520624 TI - Maternal soybean diet during lactation alters breast milk composition and programs the lipid profile in adult male rat offspring. AB - PURPOSE: To evaluate the effects of maternal dietary soybean during lactation on the milk composition, body composition, lipid profile and glucose homeostasis of dams and offspring at weaning (21 days) and adulthood (150 days). METHODS: Lactating rats were divided into: casein control (C): casein diet; soy (S): soybean diet; soy oil control (SOC): casein diet, but with fat content similar to the S group. RESULTS: At 21 days, S mothers showed lower estradiol, total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and triglycerides (TG) in serum; and lower TC and TG in milk. The S offspring had lower body weight, body fat mass, TC, LDL, hyperleptinemia and hypertriglyceridemia. At 150 days, S offspring presented higher total mineral content and lower TC (v. SOC) and LDL (v. C and SOC), and hyperinsulinemia with lower glycemia v. SOC group, which had lower insulinemia with higher glycemia, TC and LDL. CONCLUSIONS: Maternal intake of soybeans in lactation changes the lipid content of breast milk and programmed offspring for phenotype of the lower metabolic risk, with lower serum TC and LDL, and seems to protect the progeny of alterations in glucose metabolism despite the higher lipid content. The difference in fat content of breast milk and the higher isoflavones content of soy diet are possible imprinting factors that could program the offspring. PMID- 29520625 TI - Oro-dental pathologies in acromegaly. AB - PURPOSE: Oro-dental pathologies (ODP) such as enlargement of the tongue, mandibular prognathism, and spaced teeth are characteristic features of acromegaly. Their frequency of occurrence during the course of the disease is largely unresolved. Purpose of this study was to assess ODP and oro-dental treatments in patients with acromegaly with regard to the length of the diagnostic process, tumor histology, and quality of life (QoL). METHODS: Single center retrospective survey study using questionnaires on dental symptoms, diagnostic process, and treatment in patients with acromegaly operated on a growth hormone-secreting pituitary adenoma. The association between ODP and QoL was assessed using the Short-Form 36 (SF-36) Health Survey. RESULTS: 145/314 patients completed the questionnaires. 80.7% were affected by any ODP, most frequently enlargement of the tongue (57.9%), spaced teeth (42.8%), mandibular growth (24.1%), and mandibular prognathism (22.1%). ODP were significantly more frequent in patients with sparsely vs. densely granulated adenomas (p = 0.045). Early diagnosis within 2 years was associated with significantly fewer ODP than later diagnosis (68.5 vs. 87.2%, p = 0.009). Treatments included dental crowns (16.6%), dental bridges (12.4%), dental implants (9.7%), dental prostheses (3.4%), orthodontal (i.e., braces, 6.9%), and surgical correction of the teeth (2.1%). Physical QoL was significantly lower in patients with ODP than in those without (p = 0.014). CONCLUSION: In our large series of patients, four of five patients were affected by ODP at any time during the course of the disease. The results highlight the importance of early identification and treatment of oro dental problems in patients with acromegaly as hallmarks of the disease. PMID- 29520626 TI - The influence of the N-terminal region proximal to the core domain on the assembly and chaperone activity of alphaB-crystallin. AB - alphaB-Crystallin (HSPB5) is a small heat-shock protein that is composed of dimers that then assemble into a polydisperse ensemble of oligomers. Oligomerisation is mediated by heterologous interactions between the C-terminal tail of one dimer and the core "alpha-crystallin" domain of another and stabilised by interactions made by the N-terminal region. Comparatively little is known about the latter contribution, but previous studies have suggested that residues in the region 54-60 form contacts that stabilise the assembly. We have generated mutations in this region (P58A, S59A, S59K, R56S/S59R and an inversion of residues 54-60) to examine their impact on oligomerisation and chaperone activity in vitro. By using native mass spectrometry, we found that all the alphaB-crystallin mutants were assembly competent, populating similar oligomeric distributions to wild-type, ranging from 16-mers to 30-mers. However, circular dichroism spectroscopy, intrinsic tryptophan and bis-ANS fluorescence studies demonstrated that the secondary structure differs to wild type, the 54-60 inversion mutation having the greatest impact. All the mutants exhibited a dramatic decrease in exposed hydrophobicity. We also found that the mutants in general were equally active as the wild-type protein in inhibiting the amorphous aggregation of insulin and seeded amyloid fibrillation of alpha-synuclein in vitro, except for the 54-60 inversion mutant, which was significantly less effective at inhibiting insulin aggregation. Our data indicate that alterations in the part of the N-terminal region proximal to the core domain do not drastically affect the oligomerisation of alphaB-crystallin, reinforcing the robustness of alphaB-crystallin in functioning as a molecular chaperone. PMID- 29520627 TI - Gene expression profile following an oral unsaturated fat load in abdominal obese subjects. AB - PURPOSE: Our aim was to evaluate the postprandial effect of an oral fat load test (OFLT) rich in unsaturated fatty acids on gene expression profile in peripheral blood mononuclear cells (PBMC) from subjects with abdominal obesity as an insulin resistance model and controls. METHODS: A total of 20 controls and 20 abdominal obese patients were studied. Metabolic parameters and oxidative stress markers were measured with standardized protocols. The whole gene expression at fasting state and after the OFLT (0, 4 and 8 h) was analysed using human HT-12-v4 expression beadchips, from Illumina. RESULTS: We found a significant decrease in plasma glucose, insulin and oxidative stress markers in abdominal obese patients and controls. We found beneficial metabolic postprandial gene expression in three genes: FKBP5, DDIT4 and DHRS9. Following an OFLT, the postprandial mRNA expression of FKBP5, and DDIT4 was downregulated while that of DHRS9 was overexpressed, both in nondiabetic normolipidemic subjects and in insulin resistant subjects with abdominal obesity. CONCLUSIONS: Our results suggest that an OFLT rich in unsaturated fatty acids downregulates the expression of FKBP5, coding for the glucocorticoid receptor pathway, and that of DDIT4, involved in the oxidative stress response. These changes could favourably influence the insulin resistance and oxidative stress status in the postprandial state. PMID- 29520628 TI - Computed Free Energies of Peptide Insertion into Bilayers are Independent of Computational Method. AB - We show that the free energy of inserting hydrophobic peptides into lipid bilayer membranes from surface-aligned to transmembrane inserted states can be reliably calculated using atomistic models. We use two entirely different computational methods: high temperature spontaneous peptide insertion calculations as well as umbrella sampling potential-of-mean-force (PMF) calculations, both yielding the same energetic profiles. The insertion free energies were calculated using two different protein and lipid force fields (OPLS protein/united-atom lipids and CHARMM36 protein/all-atom lipids) and found to be independent of the simulation parameters. In addition, the free energy of insertion is found to be independent of temperature for both force fields. However, we find major difference in the partitioning kinetics between OPLS and CHARMM36, likely due to the difference in roughness of the underlying free energy surfaces. Our results demonstrate not only a reliable method to calculate insertion free energies for peptides, but also represent a rare case where equilibrium simulations and PMF calculations can be directly compared. PMID- 29520630 TI - White Coat Hypertension and Cardiovascular Diseases: Innocent or Guilty. AB - PURPOSE OF REVIEW: This review aims to clarify the cardiovascular risk of white coat hypertension (WCH). RECENT FINDINGS: Cardiovascular risk of WCH has been evaluated in multiple meta-analyses and population-based studies. International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes study evaluated the cardiovascular risk in 653 patients with WCH and 5137 normotensive patients. The patients were age-matched and were followed for 10.6 years. The results revealed no increased cardiovascular risk except in older high-risk WCH patients. A recent meta-analysis evaluated the cardiovascular risk in WCH subjects without any antihypertensive treatment (23 cohorts, 20 445 individuals), WCH subjects with antihypertensive treatment (11 cohorts, 8656 individuals), and mixed population including both treated and untreated subjects (12 cohorts, 21 336 individuals). This study revealed increased cardiovascular risk in untreated and mixed population WCH subjects but not in treated WCH subjects. WCH might have prognostic impact on cardiovascular outcomes; however, this is not true in all WCH subjects. Further studies should identify the subgroups of WCH that are at increased risk and evaluate the effect of therapeutic measures on cardiovascular outcomes. PMID- 29520631 TI - Network structure of the Wisconsin Schizotypy Scales-Short Forms: Examining psychometric network filtering approaches. AB - Schizotypy is a multidimensional construct that provides a useful framework for understanding the etiology, development, and risk for schizophrenia-spectrum disorders. Past research has applied traditional methods, such as factor analysis, to uncovering common dimensions of schizotypy. In the present study, we aimed to advance the construct of schizotypy, measured by the Wisconsin Schizotypy Scales-Short Forms (WSS-SF), beyond this general scope by applying two different psychometric network filtering approaches-the state-of-the-art approach (lasso), which has been employed in previous studies, and an alternative approach (information-filtering networks; IFNs). First, we applied both filtering approaches to two large, independent samples of WSS-SF data (ns = 5,831 and 2,171) and assessed each approach's representation of the WSS-SF's schizotypy construct. Both filtering approaches produced results similar to those from traditional methods, with the IFN approach producing results more consistent with previous theoretical interpretations of schizotypy. Then we evaluated how well both filtering approaches reproduced the global and local network characteristics of the two samples. We found that the IFN approach produced more consistent results for both global and local network characteristics. Finally, we sought to evaluate the predictability of the network centrality measures for each filtering approach, by determining the core, intermediate, and peripheral items on the WSS SF and using them to predict interview reports of schizophrenia-spectrum symptoms. We found some similarities and differences in their effectiveness, with the IFN approach's network structure providing better overall predictive distinctions. We discuss the implications of our findings for schizotypy and for psychometric network analysis more generally. PMID- 29520629 TI - Left Ventricular Dysfunction and Chemotherapeutic Agents. AB - PURPOSE OF REVIEW: We aim to summarize the effect of cancer therapy-related cardiotoxicity on the development of left ventricular (LV) dysfunction. RECENT FINDINGS: We discuss commonly used cancer therapeutics that have the potential for both acute and delayed cardiotoxicity. LV dysfunction from cancer therapies may be found by routine cardiac imaging prior to clinical manifestations of heart failure (HF) and we discuss the current multi-modality approaches for early detection of toxicity with the use of advanced echocardiographic parameters including strain techniques. Further, we discuss the role of biomarkers for detection of LV dysfunction from cancer therapies. Current approaches monitoring and treating LV dysfunction related to cancer therapy-related cardiotoxicity include addressing modifiable cardiovascular risk factors especially hypertension and early initiation of neurohormonal blockade (NHB) with disease-modifying beta blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. Once LV dysfunction is identified, traditional ACC/AHA guideline-directed therapy is employed. Further, we highlight the use of advanced heart failure therapies including mechanical resynchronization devices, the use of durable ventricular assist devices, and cardiac transplantation as increasingly employed modalities for treatment of severe LV dysfunction and advanced heart failure in the cardio oncology population. This review seeks to highlight the importance of early detection, treatment, and prevention of LV dysfunction from cancer therapy related cardiotoxicity. PMID- 29520632 TI - Affective auditory stimulus database: An expanded version of the International Affective Digitized Sounds (IADS-E). AB - Using appropriate stimuli to evoke emotions is especially important for researching emotion. Psychologists have provided several standardized affective stimulus databases-such as the International Affective Picture System (IAPS) and the Nencki Affective Picture System (NAPS) as visual stimulus databases, as well as the International Affective Digitized Sounds (IADS) and the Montreal Affective Voices as auditory stimulus databases for emotional experiments. However, considering the limitations of the existing auditory stimulus database studies, research using auditory stimuli is relatively limited compared with the studies using visual stimuli. First, the number of sample sounds is limited, making it difficult to equate across emotional conditions and semantic categories. Second, some artificially created materials (music or human voice) may fail to accurately drive the intended emotional processes. Our principal aim was to expand existing auditory affective sample database to sufficiently cover natural sounds. We asked 207 participants to rate 935 sounds (including the sounds from the IADS-2) using the Self-Assessment Manikin (SAM) and three basic-emotion rating scales. The results showed that emotions in sounds can be distinguished on the affective rating scales, and the stability of the evaluations of sounds revealed that we have successfully provided a larger corpus of natural, emotionally evocative auditory stimuli, covering a wide range of semantic categories. Our expanded, standardized sound sample database may promote a wide range of research in auditory systems and the possible interactions with other sensory modalities, encouraging direct reliable comparisons of outcomes from different researchers in the field of psychology. PMID- 29520633 TI - A low-cost touchscreen operant chamber using a Raspberry PiTM. AB - The development of a touchscreen platform for rodent testing has allowed new methods for cognitive testing that have been back-translated from clinical assessment tools to preclinical animal models. This platform for cognitive assessment in animals is comparable to human neuropsychological tests such as those employed by the Cambridge Neuropsychological Test Automated Battery, and thus has several advantages compared to the standard maze apparatuses typically employed in rodent behavioral testing, such as the Morris water maze. These include improved translation of preclinical models, as well as high throughput and the automation of animal testing. However, these systems are relatively expensive, which can impede progress for researchers with limited resources. Here we describe a low-cost touchscreen operant chamber based on the single-board computer, Raspberry PiTM, which is capable of performing tasks similar to those supported by current state-of-the-art systems. This system provides an affordable alternative for cognitive testing in a touchscreen operant paradigm for researchers with limited funding. PMID- 29520634 TI - Picture perfect: A stimulus set of 225 pairs of matched clipart and photographic images normed by Mechanical Turk and laboratory participants. AB - The present study provides normative measures for a new stimulus set of images consisting of 225 everyday objects, each depicted both as a photograph and a matched clipart image generated directly from the photograph (450 images total). The clipart images preserve the same scale, shape, orientation, and general color features as the corresponding photographs. Various norms (modal name and verb agreement measures, picture-name agreement, familiarity, visual complexity, and image agreement) were collected separately for each image type and in two different contexts: online (using Mechanical Turk) and in the laboratory. We discuss similarities and differences in the normative measures according to both image type and experimental context. The full set of norms is provided in the supplemental materials. PMID- 29520635 TI - Computational Analysis of High-Risk SNPs in Human DBY Gene Responsible for Male Infertility: A Functional and Structural Impact. AB - BACKGROUND: DEAD-box helicase 3, Y-linked (DBY) is a candidate gene of the AZF region which is involved in spermatogenesis process. Mutations in the DBY gene may disrupt the spermatogenesis and lead to infertility in men. Identification of functionally neutral mutation from the disease-causing mutation is the biggest challenge in human genetic variation analysis. Owing to the importance of DBY in male infertility, functional analysis was carried out to reveal the association between genetic mutation and phenotypic variation through various in silico approaches. METHODS: The present study analyzed the functional consequences of the nsSNPs in human DBY gene using SIFT, PolyPhen 2, PROVEAN, SNAP2, PMut, nsSNPAnalyzer, PhD-SNP and SNPs&GO along with stability analysis through I Mutant2.0, MuPro and iPTREE-STAB. The conservational analysis of amino acid residues, biophysical properties and conserved domains of the DBY protein was analyzed using various computational tools. The 3D structure of the protein was generated using SPARKS-X and validated using RAMPAGE. RESULTS: Out of 1130 SNPs reported in dbSNP, only one nsSNP (G300D) was found to have a functional effect on stability as well as the function of the DBY protein. The results showed the presence of G300 in the putative structure of DBY domain. CONCLUSION: To the best of our knowledge, this is the first study to detect pathologically significant nsSNPs (G300D) through a computational approach in the DBY which can be useful for development in potent drug discovery studies. PMID- 29520636 TI - The Future of Personality Theory: a Processual Approach. AB - The perpetual discussion of approaches and principles in the study of personality has been one of the notable trends of development of psychological science over many decades. The structural approach, based on the delineation of a person's traits and characteristics, made an important contribution to various branches of psychology, but now the scientific community has recognized the limitations of a structural understanding of personality. Its inadequacy becomes particularly obvious in today's conditions, when fundamental changes pose a challenge to man's ability to respond flexibly to changing conditions of everyday existence, as well as to larger-scale changes. At the beginning of the twenty-first century, it is obvious that there is a need for new ways to understand and describe the personality: Scholars are calling for study of the dynamic personality, of the personality as an open system. At the foundational level, modern personality psychology should incorporate classical ideas about its structure; secondly, it should consider personality in the context of the individual's lifetime; and - at the highest level - it should describe personality as the subject of Being. We submit our own description of personality psychology's problem field. PMID- 29520637 TI - Maternity Leave and Mothers' Long-Term Sickness Absence: Evidence From West Germany. AB - Exploiting unique German administrative data, we estimate the association between an expansion in maternity leave duration from two to six months in 1979 and mothers' postbirth long-term sickness absence over a period of three decades after childbirth. Adopting a difference-in-difference approach, we first assess the reform's labor market effects and, subsequently, prebirth and postbirth maternal long-term sickness absence, accounting for the potential role of the reform in mothers' selection into employment. Consistent with previous research, our estimates show that the leave extension caused mothers to significantly delay their return to work within the first year after childbirth. We then provide difference-in-difference estimates for the number and length of spells of long term sickness absence among returned mothers. Our findings suggest that among those returned, mothers subject to the leave extension exhibit a higher incidence of long-term sickness absence compared with mothers who gave birth before the reform. This also holds true after we control for observable differences in prebirth illness histories. At the same time, we find no pronounced effects on mothers' medium-run labor market attachment following the short-run delay in return to work, which might rationalize a negative causal health effect. Breaking down the results by mothers' prebirth health status suggests that the higher incidence of long-term sickness absence among mothers subject to the reform may be explained by the fact that the reform facilitated the reentry of a negative health selection into the labor market. PMID- 29520638 TI - If My Blood Pressure Is High, Do I Take It to Heart? Behavioral Effects of Biomarker Collection in the Health and Retirement Study. AB - Starting in 2006, respondents in the biennial U.S. Health and Retirement Study were asked to submit biomarkers every other wave and were notified of several results. Rates of undiagnosed high blood pressure and diabetes according to these biomarkers were 1.5 % and 0.7 %, respectively. An intent-to-treat analysis suggests that collection and notification had small effects on the average respondent and may have reduced health care utilization. Among respondents who received notification of potentially dangerous biomarker levels, subsequent rates of new diagnosis and associated pharmaceutical usage increased by 20 to 40 percentage points, an order of magnitude above baseline. High blood glucose A1C was associated with a 2.2 % drop in weight and an increase in exercise among respondents without a previous diagnosis of diabetes. Notifications appear also to have altered health behaviors by spouses, suggesting household responses to health maintenance. Biomarker collection seems to have altered circumstances for an interesting minority of HRS respondents. PMID- 29520639 TI - Correction to: Outcomes Associated with Generic Drugs Approved Using Product Specific Determinations of Therapeutic Equivalence. AB - Page 432, Fig. 2 Plots of model-based outcome incidence rates (per 100 person years of exposure) before and after introduction of first generic versions of study and control drugs. PMID- 29520640 TI - Obsessive-compulsive symptoms in psychotic disorders: longitudinal associations of symptom clusters on between- and within-subject levels. AB - Obsessive-compulsive symptoms (OCS) are frequently reported in patients with schizophrenia and have been associated with subjective distress and higher impairment. Recent studies suggest fluctuation in co-occurring OCS and associations with the course of psychotic symptoms. Current evidence is limited by few studies with long assessments intervals and a sole focus on between subject comparisons. The aim of this study was to specifically investigate co variation of symptom domains over time within individuals. Patients with a psychotic disorder (n = 56) and un-affected siblings (n = 49) completed monthly assessments of clinical and subclinical symptoms over 6 months. Mixed-model multilevel analyses examined the variability and relationship between OCS and positive, negative, and depressive symptoms on the between- and within-subject level. Symptom domains were associated across subjects and assessment times, in patients and siblings, with the strongest association between OCS and (subclinical) positive symptoms. Within-subjects, substantial variability and co variation of all symptom domains was found. Particularly, between-subject differences in positive symptoms and within-subject change in depressive symptoms predicted subsequent OCS in patients 1 months later. This is the first prospective study disaggregating between and within-subject associations between co-occurring OCS and symptom cluster of psychosis. Differences on these two levels suggest different underlying mechanisms. The association between depressive symptoms and subsequent increase/decrease of OCS within patients may have important treatment implications. PMID- 29520641 TI - Structural connectome with high angular resolution diffusion imaging MRI: assessing the impact of diffusion weighting and sampling on graph-theoretic measures. AB - PURPOSE: Advances in computational network analysis have enabled the characterization of topological properties of human brain networks (connectomics) from high angular resolution diffusion imaging (HARDI) MRI structural measurements. In this study, the effect of changing the diffusion weighting (b value) and sampling (number of gradient directions) was investigated in ten healthy volunteers, with specific focus on graph theoretical network metrics used to characterize the human connectome. METHODS: Probabilistic tractography based on the Q-ball reconstruction of HARDI MRI measurements was performed and structural connections between all pairs of regions from the automated anatomical labeling (AAL) atlas were estimated, to compare two HARDI schemes: low b value (b = 1000) and low direction number (n = 32) (LBLD); high b value (b = 3000) and high number (n = 54) of directions (HBHD). RESULTS: LBLD and HBHD data sets produced connectome images with highly overlapping hub structure. Overall, the HBHD scheme yielded significantly higher connection probabilities between cortical and subcortical sites and allowed detecting more connections. Small worldness and modularity were reduced in HBHD data. The clustering coefficient was significantly higher in HBHD data indicating a higher level of segregation in the resulting connectome for the HBHD scheme. CONCLUSION: Our results demonstrate that the HARDI scheme as an impact on structural connectome measures which is not automatically implied by the tractography outcome. As the number of gradient directions and b values applied may introduce a bias in the assessment of network properties, the choice of a given HARDI protocol must be carefully considered when comparing results across connectomic studies. PMID- 29520642 TI - Hemodynamic vascular biomarkers for initiation of paraclinoid internal carotid artery aneurysms using patient-specific computational fluid dynamic simulation based on magnetic resonance imaging. AB - PURPOSE: We performed computational fluid dynamics (CFD) for patients with and without paraclinoid internal carotid artery (ICA) aneurysms to evaluate the distribution of vascular biomarkers at the aneurysm initiation sites of the paraclinoid ICA. METHODS: This study included 35 patients who were followed up for aneurysms using 3D time of flight (TOF) magnetic resonance angiography (MRA) and 3D cine phase-contrast MR imaging. Fifteen affected ICAs were included in group A with the 15 unaffected contralateral ICAs in group B. Thirty-three out of 40 paraclinoid ICAs free of aneurysms and arteriosclerotic lesions were included in group C. We deleted the aneurysms in group A based on the 3D TOF MRA dataset. We performed CFD based on MR data set and obtained wall shear stress (WSS), its derivatives, and streamlines. We qualitatively evaluated their distributions at and near the intracranial aneurysm initiation site among three groups. We also calculated and compared the normalized highest (nh-) WSS and nh-spatial WSS gradient (SWSSG) around the paraclinoid ICA among three groups. RESULTS: High WSS and SWSSG distribution were observed at and near the aneurysm initiation site in group A. High WSS and SWSSG were also observed at similar locations in group B and group C. However, nh-WSS and nh-SWSSG were significantly higher in group A than in group C, and nh-SWSSG was significantly higher in group A than in group B. CONCLUSION: Our findings indicated that nh-WSS and nh-SWSSG were good biomarkers for aneurysm initiation in the paraclinoid ICA. PMID- 29520644 TI - In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study. AB - INTRODUCTION: In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. MATERIAL AND METHODS: This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. RESULTS: Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). CONCLUSION: During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose. PMID- 29520643 TI - Quantitative evaluation of facial hypoplasia and airway obstruction in infants with syndromic craniosynostosis: relationship with skull base and splanchnocranium sutural pattern. AB - PURPOSE: Craniosynostostic syndromes are due to multisuture synostoses and affect the entire craniofacial skeleton. This study analyzed the facial complex and airways to quantify the relationship between insufficient facial growth, airways obstruction, and the sutural pattern of the splanchnocranium and cranial fossae. METHODS: Preoperative high-resolution CT images in 19 infants with syndromic craniosynostosis were quantitatively analyzed. Because all children showed involvement of minor sutures/synchondroses coursing in the posterior cranial fossa, they were divided into three groups according to the synostotic involvement of "minor" sutures/synchondroses coursing in anterior (ACF) and middle (MCF) cranial fossae: group 1 (ACF), group 2 (MCF), and group 3 (ACF-MCF). Analysis of the facial complex and airway was performed. Each group was compared with age-matched healthy subjects. RESULTS: Premature closure of skull base synchondroses of ACF and MCF was found only in groups MCF and ACF-MCF. Group MCF showed synostosis in the posterior branch of the coronal ring and reduced anterior hemifossae lengths while group ACF-MCF showed synostosis in the anterior branch of the coronal ring and reduced middle hemifossae lengths. No group showed reduced maxillary or mandibular volumes but group MCF showed synostosis of the zygomaticomaxillary sutures and maxillary retrusion. All groups showed reduced airway volume but group 2 had a higher degree of airway hypoplasia. CONCLUSION: The skull base synostotic process drives the changes in facial complex growth and airway obstruction. Premature closure of synchondroses/sutures in the posterior branch of the coronal ring causes insufficient facial growth, maxillary retrusion, and more severe airway reduction. PMID- 29520645 TI - EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection. AB - The analysis of safety data from spontaneous reporting systems has a proven value for the detection and analysis of the risks of medicines following their placement on the market and use in medical practice. EudraVigilance is the pharmacovigilance database to manage the collection and analysis of suspected adverse reactions to medicines authorised in the European Economic Area. EudraVigilance first operated in December 2001, with access to the database being governed by the EudraVigilance access policy. We performed a literature search including data up to December 2016 to demonstrate how the data from EudraVigilance has been used in scientific publications. We describe the results, including by type of publication, research topics and drugs involved. In 50% of the publications, the data are used to describe safety issues, in 44% to analyse methodologies used in pharmacovigilance activities and in 6% to support clinical perspectives. We also outline a description of the use of the database by the European Union regulatory network. Driven by the full implementation of the 2010 pharmacovigilance legislation, EudraVigilance has undergone further enhancements together with a major revision of its access policy, taking into account the use of the new individual case safety report standard developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and the International Organization for Standardization. The aim of the broadened access is to facilitate more effective safety monitoring of authorised medicines, to make more data available for research and to provide better access to information on suspected adverse reactions for healthcare professionals and patients. In November 2017, the new full functionalities of EudraVigilance were launched, including the extensive web access to data on suspected adverse drug reactions and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research. The main objective of this article is to describe the new access to the database together with the opportunities that this new access can bring for research. It is intended to promote an appropriate use of the data to support the safe and effective use of medicines. PMID- 29520646 TI - Surgical Outcomes of Pancreaticoduodenectomy for Pancreatic Cancer with Proximal Dorsal Jejunal Vein Involvement. AB - BACKGROUND/PURPOSE: The proximal jejunal vein which branches from the dorsal side of the superior mesenteric vein (SMV) usually drains the inferior pancreatoduodenal veins (IPDVs) and contacts the uncinate process of the pancreas. We focused on this vein, termed the proximal dorsal jejunal vein (PDJV), and evaluated the anatomical classification of the PDJV and surgical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) with PDJV involvement (PDJVI). METHODS: The jejunal veins that branch from the dorsal side of the SMV above the inferior border of the duodenum are defined as PDJVs. We investigated 121 patients who underwent upfront pancreaticoduodenectomy for PDAC between 2011 and 2017; PDJVs were resected in all patients. The anatomical classification of PDJV was evaluated using multidetector computed tomography. Surgical and prognostic outcomes of pancreticoduodenectomy for PDAC with PDJVI were evaluated. RESULTS: The PDJVs were classified into seven types depending on the position of the first and second jejunal veins relative to the superior mesenteric artery. In all patients, the morbidity and mortality rates were 15.7 and 0.8%, respectively. The rates for parameters including SMV resection, presence of pathological T3-4, R0 resection, and 3-year survival were 46.2, 92.3, 92.3, and 61.1%, respectively, when there was PDJVI (n = 13). When there was no PDJVI (n = 108), the rates were 60.2, 93.5, 86.1, and 58.3%, respectively. Overall, there were no significant differences. CONCLUSIONS: Pancreaticoduodenectomy with PDJV resection is feasible for PDAC with PDJVI and satisfactory overall survival rates are achievable. It may be necessary to reconsider the resectability of PDAC with PDJVI. PMID- 29520647 TI - Colonic Interposition After Adult Oesophagectomy: Systematic Review and Meta analysis of Conduit Choice and Outcome. AB - BACKGROUND: Colonic interposition is a second-line option after oesophagectomy when a gastric neo-oesophagus is not viable. There is no consensus on the optimum anatomical colonic conduit (right or left), or route of placement (posterior mediastinal, retrosternal or subcutaneous). The aim of this review was to determine the optimum site and route of neo-oesophageal conduit after adult oesophagectomy. METHODS: PubMed, MEDLINE, and the Cochrane Library (January 1985 to January 2017) were systematically searched for studies which reported outcomes following colonic interposition in adults. The outcome measures were overall morbidity and mortality. RESULTS: Twenty-seven observational studies involving 1849 patients [1177 males; median age (range) 60.5 (18-84) years] undergoing colonic interposition for malignant (n = 697) and benign (n = 1152) pathology were analysed. Overall pooled morbidity of left vs. right colonic conduit was 15.7% [95% CI (11.93-19.46), p < 0.001] and 18.7% [95% CI (15.58-21.82), p < 0.001] respectively. Overall pooled mortality of left vs. right colonic conduit was 6.5% [95% CI (4.55-8.51), p < 0.001] and 10.1% [95% CI (7.35-12.82), p < 0.001] respectively. Retrosternal route placement was associated with the lowest overall pooled morbidity and mortality of 9.2% [95% CI (6.48-11.99), p < 0.001] and 4.8% [95% CI (3.74-5.89), p < 0.001] respectively. CONCLUSION: Left colonic conduits placed retrosternally were safest. PMID- 29520648 TI - Time to Surgery: a Misguided Quality Metric in Early Stage Pancreatic Cancer. AB - BACKGROUND: Longer time to surgery is associated with worse outcomes in several cancers. We sought to identify disparities in time from diagnosis to surgery in pancreatic cancer and whether delays to surgery correlated with worse survival. METHODS: The US National Cancer Database (2003-2011) was reviewed for patients with clinical stages I-II pancreatic adenocarcinoma who underwent surgical resection. Patients who received neoadjuvant therapy were excluded. Linear regression, Kaplan-Meier analyses, and Cox regression were performed as 3-month landmark analyses. RESULTS: Of the 14,807 patients included, 37.8% underwent resection <= 1 week, 13.7% 1-2 weeks, 25.4% 2-4 weeks, 19.5% 4-8 weeks, and 3.7% 8-12 weeks. Older age, Medicare coverage, greater distance from hospital, treatment at an academic center, and greater comorbidities were associated with increased time. After excluding patients treated within 1 week of diagnosis and controlling for patient, disease, and treatment characteristics, greater time was not associated with worse survival (2-4, HR 1.03, P = 0.399; 4-8, HR 0.98, P = 0.529; 8-12, P = 0.123). CONCLUSIONS: For patients with stages I-II pancreatic adenocarcinoma, there are disparities in surgical wait times. However, earlier initiation of surgical resection within 12 weeks of diagnosis is not associated with a survival benefit. This suggests that allowing time for confirmatory testing and optimization in preparation for surgery may not negatively impact survival. PMID- 29520649 TI - The effects of environmentally relevant concentrations of aldrin and methoxychlor on the testes and sperm of male Clarias gariepinus (Burchell, 1822) after short term exposure. AB - The organochlorine pesticides aldrin (0.14 MUg/L) and methoxychlor (0.23 MUg/L) were both present in the Albasini Dam, Limpopo Province, South Africa, during a field survey in 2014. The use of aldrin has been banned in the USA since 1987 and restricted in South Africa since 1992. The use of methoxychlor, however, remains undefined with little information available about its registration in South Africa despite being banned in Europe (2002) and USA (2003). The aim of this study was to determine the potential effects of environmentally relevant concentrations of aldrin and methoxychlor on the reproductive system of male catfish, Clarias gariepinus. Males were exposed for 96 h to the two pesticides under controlled laboratory conditions. Following exposure, each fish was weighed and measured, and a necropsy performed to determine any macroscopic abnormalities and the general health of the fish. The fish were killed and dissected and the testes removed, weighed and measured to determine the gonadosomatic index (GSI). The right testis of each fish was sectioned for histopathological assessment and to calculate the testes index (I T ). The left testis was used for computer assisted sperm analysis (CASA). The histopathological assessment of the testes showed histopathological changes such as of melano-macrophage centres (MMCs) and vacuolation of spermatogonia and spermatocytes. However, the classification of these changes indicated that the testes tissue structure was normal with slight histological changes. No statistically significant differences (p > 0.05) were found in the CASA parameters between exposure groups. The results of this study showed that the environmentally relevant concentrations of aldrin and methoxychlor did not have a negative effect on the motility of the mature sperm, but adverse effects were noted in the early stages of spermatogenesis, indicating possible effects over longer exposure periods. PMID- 29520650 TI - Chromosome painting and comparative physical mapping of the sex chromosomes in Populus tomentosa and Populus deltoides. AB - Dioecious species accounted for 6% of all plant species, including a number of crops and economically important species, such as poplar. However, sex determination and sex chromosome evolution have been studied only in few dioecious species. In poplar, the sex-determining locus was mapped to chromosome 19. Interestingly, this locus was mapped to either a peritelomeric or a centromeric region among different poplar species. We developed an oligonucleotide (oligo)-based chromosome painting probe based on the sequence of chromosome 19 from Populus trichocarpa. We performed chromosome painting in P. tomentosa and P. deltoides. Surprisingly, the distal end on the short arm of chromosome 19, which corresponds to the location of the sex-determining locus reported in several species, was not painted in both species. Thus, the DNA sequences associated with this region have not been anchored to the current chromosome 19 pseudomolecule, which was confirmed by painting of somatic metaphase chromosome 19 of P. trichocarpa. Interestingly, the unpainted distal ends of the two chromosome 19 did not pair at the pachytene stage in 22-24% of the meiotic cells in the two species, suggest that these regions from the sex chromosomes have structurally diverged from each other, resulting in the reduced pairing frequency. These results shed light on divergence of a pair of young sex chromosomes in poplar. PMID- 29520651 TI - Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy. AB - Background The objective of this study was to assess the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics, and anti-tumor efficacy of CKD-581, a novel pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma (MM) refractory to standard therapy. Methods In this phase I study, CKD-581 was intravenously administered on days 1, 8, and 15 of a 28-day cycle. A standard 3 + 3 cohort design was used to determine the MTD. Acetylated histones H3 and H4 in peripheral blood mononuclear cells were measured for pharmacodynamic assessment in a subpopulation of patients. Results Thirty nine patients were treated with CKD-581 at 9 dose levels from 10 mg/m2 to 210 mg/m2. The DLTs were grade 3 neutropenia that delayed the treatment for >2 weeks (one patient at a dose of 50 mg/m2) and grade 4 thrombocytopenia (two patients at a dose of 210 mg/m2). The MTD of CKD-581 was 160 mg/m2. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (n = 5, 12.8%) and neutropenia (n = 2, 5.1%). The peak concentration and area under the curve values for CKD-581 increased in proportion to the dose, indicating linear pharmacokinetics. A partial response was observed in 2 patients (5.6%), and stable disease was observed in 16 (44.4%) patients. In the pharmacodynamic evaluation, acetylation of H3 and H4 was observed at all doses of >=50 mg/m2. Conclusion CKD-581 was well tolerated by the patients with lymphoma or MM refractory to standard therapy. It exhibited dose-proportional pharmacokinetics and modest anti-tumor efficacy. PMID- 29520652 TI - Salvage Surgery for Recurrent Retroperitoneal Well-Differentiated Liposarcoma: Early Reoperation may not Provide Benefit. AB - PURPOSE: Current evidence regarding salvage resection for recurrent retroperitoneal (RP) sarcomas generally lacks detailed histology-specific analyses, but the aggressiveness of these tumors varies widely by histology. We investigated associations between timing and extent of salvage surgery and survival outcomes in patients with recurrent RP well-differentiated liposarcoma (WDLPS). METHODS: The University of Texas MD Anderson Cancer Center Surgical Oncology sarcoma database was reviewed to identify patients with RP WDLPS who underwent surgical resection for first recurrent disease (salvage surgery) in 1995-2015. Medical records were retrospectively reviewed to identify factors associated with overall survival and disease-free survival. RESULTS: We identified 52 patients who underwent salvage surgery for RP WDLPS for first local recurrence; 28 (54%) underwent salvage surgery within 6 months after recurrence. Concomitant organ resections were performed in 32 (62%) patients, 4 (13%) of whom had pathologic invasion of resected organs. After R0/R1 resections (n = 45), 38 (84%) experienced a second local recurrence. Multivariable analyses revealed that organ invasion at the primary surgery [hazard ratio (HR) 13.08; p = 0.005] and disease-free interval < 1 year (HR 3.64; p = 0.044) were associated with shorter overall survival. Recurrence-to-salvage interval < 6 months was associated with shorter disease-free survival (HR 2.18; p = 0.025). Concomitant organ resection was associated with a longer hospital stay: >= 14 days (odds ratio 21.58; p = 0.007). CONCLUSIONS: Early salvage surgery may not always be the best approach for recurrent RP WDLPS patients. Because organ invasion is rare among recurrent RP WDLPS patients and concomitant organ resection is associated with a longer hospital stay, preservation of uninvolved organs should be considered. PMID- 29520653 TI - Precision Hilar Cholangiocarcinoma Surgery. PMID- 29520655 TI - Centralization of Upper Gastrointestinal Cancer Care Should be Dictated by Quality of Care. PMID- 29520654 TI - The 21-Gene Recurrence Score in Male Breast Cancer. AB - BACKGROUND: Given the limited data, systemic treatment of male breast cancer has been extrapolated from female patients. The 21-gene recurrence score (RS) assay estimates the risk of distant recurrence and chemotherapy benefit in early-stage, ER+/HER2- female breast cancer. We assessed the association between RS and type of treatment in male breast cancer. METHODS: We identified male patients with ER+/HER2- breast cancer and available RS results treated at our institution in 2006-2016. We collected data on clinicopathologic features, treatment, and outcome. The Institutional Review Board approved the study. RESULTS: The study cohort consists of 38 male breast cancer patients with a median age of 70 years. Median tumor size was 1.6 cm, and 81.6% (31) were node-negative. RS was low (<= 17) in 26 (68.4%) cases, intermediate (18-30) in 9 (23.7%) cases, and high (>= 31) in 3 (7.9%) cases, comparable to that in female patients at our institution. All patients underwent total mastectomy, and one received radiotherapy. Thirty four (89.5%) patients received adjuvant endocrine therapy, mostly tamoxifen (81.6%; 31). Five (13.2%) patients with intermediate or high RS were treated with adjuvant chemotherapy. No locoregional recurrence was observed, and one patient developed distant recurrence (median follow-up 34 months). CONCLUSIONS: The RS distribution in male breast cancers was similar to that in females treated at our institution. With limited follow-up, patients with low RS were spared chemotherapy and did not develop recurrence. Our results suggest that the RS may have a clinical utility in male breast cancer patients. PMID- 29520656 TI - Reasons Associated with Total Thyroidectomy as Initial Surgical Management of an Indeterminate Thyroid Nodule. AB - BACKGROUND: Diagnostic hemithyroidectomy (HT) is the most widely recommended surgical procedure for a nodule with indeterminate cytology; however, additional details may make initial total thyroidectomy (TT) preferable. We sought to identify patient-specific factors (PSFs) associated with initial TT in patients with indeterminate thyroid nodules. METHODS: Retrospective analysis of all patients with a thyroid nodule >= 1 cm and initial cytology of atypia of undetermined significance or suspicious for follicular neoplasm between 2012 and 2015 who underwent thyroidectomy. Medical records were reviewed for patient demographics, neck symptoms, nodule size, cytology, molecular test results, final histopathology, and additional PSFs influencing surgical management. Variables were analyzed to determine associations with the use of initial TT. Logistic regression analyses were performed to identify independent associations. RESULTS: Of 325 included patients, 182/325 (56.0%) had HT and 143/325 (44.0%) had TT. While patient age and sex, nodule size, and cytology result were not associated with initial treatment, five PSFs were associated with initial TT (p < 0.0001). These included contralateral nodules, hypothyroidism, fluorodeoxyglucose avidity on positron emission tomography scan, family history of thyroid cancer, and increased surgical risk. At least one PSF was present in 126/143 (88.1%) TT patients versus 47/182 (25.8%) HT patients (p < 0.0001). Multivariate logistic regression analysis demonstrated that these variables were the strongest independent predictor of TT (odds ratio 45.93, 95% confidence interval 18.80 112.23, p < 0.001). CONCLUSIONS: When surgical management of an indeterminate cytology thyroid nodule was performed, several PSFs were associated with a preference by surgeons and patients for initial TT, which may be useful to consider in making decisions on initial operative extent. PMID- 29520657 TI - SOX11 expression as a MRD molecular marker for MCL in comparison with t(11;14) and IGH rearrangement. AB - The main cause of death in mantle cell lymphoma (MCL) patients is relapse due to undetermined minimal residual disease (MRD) and therefore monitoring MRD is crucial for making the best treatment decisions. The gold standard method for MRD analysis is the quantitative polymerase chain reaction. The most commonly used molecular markers for measuring MRD in MCL are: t(11;14)(q13;p32) translocation or CCND1 expression and IGH rearrangement. Such markers can, however, be found in other B cell non-Hodgkin lymphomas. Recent studies demonstrate that SOX11 expression is highly specific for MCL and could be used as a marker for measuring MRD. Moreover, evidence shows that SOX11 level could be predictive for overall survival (OS) and progression-free survival (PFS). We have measured MRD level in follow-up samples from 27 patients diagnosed with MCL using the molecular markers: t(11;14), IGH rearrangement and SOX11 expression. We compared all markers by their sensitivity, utility and quantitative range. We also examined the predictive value of SOX11 expression for OS and PFS. SOX11 expression was found to have better specificity, quantitative range and utility than the t(11;14). The predictive value of SOX11 expression was confirmed. At diagnosis, patients with high SOX11 expression had shorter PFS than patients with low SOX11 expression (p = 0.04*); differences between OS being statistically insignificant. To our best knowledge this is a first study comparing SOX11 with t(11;14) and IGH rearrangement as markers of MRD level. Moreover, in this study we confirmed that SOX11 is useful in cases when other molecular markers cannot be used. PMID- 29520658 TI - Lung point in the absence of pneumothorax. PMID- 29520659 TI - Critical care research in Morocco and Tunisia. PMID- 29520660 TI - Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D. PMID- 29520662 TI - A Sustainable Alternative to the Gold Standard EBP: Validating Existing Programs. AB - Increasingly, jurisdictions are requiring the adoption of certified evidence based programs (EBPs) for behavioral health and human services for children, youth, and their families. Often, such adoption of proven, prepackaged programs is done without regard to existing, yet effective, locally developed program models. This study presents a replicable six-step process that identifies key researched elements from within existing programs and creates program-specific fidelity scoring and tracking tools for routine use during clinical supervision to assure that these elements are implemented well. A case study is used to demonstrate that a locally developed program model, when implemented with high fidelity, can serve clients with outcomes comparable to its EBP counterpart at a much lower cost. The results underscore the importance of one common element among EBPs and effective services in general: measuring key elements of the service and client outcomes and feeding these data back to clinicians for continuous improvement. PMID- 29520661 TI - Sceletium tortuosum may delay chronic disease progression via alkaloid-dependent antioxidant or anti-inflammatory action. AB - The link between obesity-induced systemic inflammation and decreased insulin signalling is well-known. It is also known that peripherally produced inflammatory cytokines can cross the blood-brain barrier, resulting in the release of neurotoxins that can ultimately lead to the demise of central nervous system integrity. A high-mesembrine Sceletium tortuosum extract was recently shown to possess cytoprotective and mild anti-inflammatory properties in monocytes and to target specific p450 enzymes to reduce adrenal glucocorticoid synthesis. This is significant since the aetiology of both obesity and diabetes is linked to inflammation and excess glucocorticoid production. Given the interlinked nature of glucocorticoid action and inflammation, central immunomodulatory effects of two Sceletium tortuosum extracts prepared by different extraction methods were investigated. Human astrocytes were pre-treated for 30 min, before exposure to Escherichia coli lipopolysaccharide for 23.5 h (in the presence of treatment). Cytotoxicity, mitotoxicity and cytokine responses (basally and in response to inflammatory stimulus) were assessed. In addition, total polyphenol content, antioxidant capacity and selected neural enzyme inhibition capacity were assessed for both extracts. The high-mesembrine Sceletium extract exerted cytoprotective and anti-inflammatory effects. In contrast, the high delta7-mesembrenone extract, rich in polyphenols, exhibited potent antioxidant effect, although with relatively higher risk of adverse effects with overdose. We conclude that both Sceletium tortuosum extracts may be employed as either a preventative supplement or complimentary treatment in the context of obesity and diabetes; however, current data also highlights the impact that extraction methods can have on plant product mechanism of action. PMID- 29520664 TI - Association between genital mycoplasmas infection and human papillomavirus infection, abnormal cervical cytopathology, and cervical cancer: a systematic review and meta-analysis. AB - BACKGROUND: Some studies demonstrated that female genital mycoplasmas play important roles in human papillomavirus (HPV) infection, abnormal cervical cytopathology, and cervical cancer. However, those results remained inconclusive. We aimed to perform a systematic review and meta-analysis to investigate the association between female genital mycoplasmas and those disorders. METHODS: Computerized databases were comprehensively searched before 26 January 2017. Pooled odd radios (ORs) and correlative 95% confidence intervals (CIs) were adopted to evaluate the strength of association. RESULTS: Our meta-analysis included 22 studies with 16,181 participants. Ureaplasma urealyticum and Ureaplasma parvum were associated with a significantly increased risk of overall HPV infection (OR 1.57, 95% CI 1.05-2.34; OR 3.02, 95% CI 2.10-4.33, respectively), and U. urealyticum and Mycoplasma genitalium were associated with a significantly increased risk of high-risk HPV infection (OR 1.37, 95% CI 1.05 1.80; OR 1.50, 95% CI 1.11-2.02, respectively). In addition, U. urealyticum, U. parvum, and Mycoplasma hominis were associated with a significantly increased risk of abnormal cervical cytopathology (OR 1.51, 95% CI 1.23-1.85; OR 1.41, 95% CI 1.10-1.80; OR 1.48, 95% CI 1.10-1.99, respectively). CONCLUSION: We found that U. urealyticum and M. genitalium may increase the risk of high-risk HPV infection, while U. urealyticum, U. parvum, and M. hominis may increase the risk of abnormal cervical cytopathology. PMID- 29520663 TI - Engaging Caregivers in the Treatment of Youth with Complex Developmental and Mental Health Needs. AB - Caregivers of youth with coexisting cognitive and mental health problems face difficult treatment decisions for their child and have unique challenges engaging in shared decision-making. Many stakeholders can influence care management decisions, and the child's cognitive impairment often prohibits their inclusion in the shared decision-making process. In-depth interviews and focus groups with 37 caregivers elicited their experiences with care management related to their child's educational, mental health, and other care needs. Four themes that describe the process of engagement were awareness, activation, formulating a strategy, and action. Findings show psychoeducation, and peer-to-peer support could enhance caregivers' awareness of the condition and encourage activation, which would help in navigating complex service sectors. Coordinated services could enhance capabilities for formulating a strategy jointly with multiple providers and stakeholders. Ultimately, this would contribute to shared decision making around a common treatment goal that hopefully leads to better quality of care in the least restrictive setting. PMID- 29520665 TI - Report of the survey on current opinions and practice of German Society for Gynecologic Endoscopy (AGE) members regarding the laparoscopic treatment of ovarian malignancies. AB - PURPOSE: The purpose of this survey was to assess the opinions of members of the German Society of Gynecologic Endoscopy (AGE) regarding the laparoscopic treatment of ovarian malignancies and current practice at their institutions. METHODS: Between February and October 2015, the AGE sent an anonymous online survey via mail to its members. The questionnaire solicited participants' opinions about the laparoscopic treatment of ovarian cancers according to T stage and borderline tumors, and information about current practice at their institutions. Participants were also asked their opinions on currently available data on this issue. RESULTS: Of 228 AGE members who completed the survey, 132 (58%) were fellows or attending physicians and 156 (68%) worked at university hospitals or tertiary referral centers. Most [212 (93%)] respondents stated that < 10% of all ovarian cancer cases were currently treated laparoscopically at their institutions. Most participants indicated that T1 (a, b, c) tumors [145 (64%)] and ovarian borderline tumors [206 (90%)], but not T2 [48 (21%)] or T3/4 [9 (4%) ovarian tumors] should or could be treated laparoscopically. One hundred seventy-two (75%) participants considered currently available data on this topic to be insufficient and 152 (66%) stated that they would take part in a clinical trial assessing a laparoscopic approach to T1/2 ovarian cancer. CONCLUSION: According to this survey, to the opinion of the majority of AGE members, laparoscopy might be a considerable option for the treatment of early ovarian malignancies and borderline tumors and should be evaluated further in future studies. PMID- 29520666 TI - Endoscopy-assisted inguinal lymphadenectomy in vulvar cancer. AB - OBJECTIVE: To explore the feasibility and efficiency of video endoscopic inguinal lymphadenectomy (VEIL) for vulvar cancer. METHODS: We evaluated 46 patients with vulvar cancer. Treatment included VEIL using the hypogastric subcutaneous approach (VEIL-H, 17 patients), VEIL with the limb subcutaneous surgical approach (VEIL-L, 8 patients), and open inguinal lymphadenectomy (OIL, 21 patients). All patients underwent radical vulvectomy; we evaluated operative time, the amount of bleeding, SF score, recurrence rate, etc. RESULTS: The durations of VEIL-H and VEIL-L were 170.79 +/- 18.92 and 180.12 +/- 17.88 min, respectively, which were longer than that of OIL (100.68 +/- 11.37 min; P = 0.028). Bleeding volumes in the VEIL-H and VEIL-L groups were 15.23 +/- 2.17 and 17.16 +/- 2.35 ml, respectively; there were significantly lower than that of the OIL group (36.68 +/ 3.48 ml; P = 0.021). The numbers of unilateral lymph nodes harvested were similar in all groups. The duration of hospitalization in VEIL group was shorter than that of the OIL group. There were less skin and lymphatic complications after VEIL than after OIL. Total SF-36 scores were significantly higher in the VEIL group than that in the OIL group (P = 0.032). There were no statistically significant differences in local recurrence, distant metastasis, and mortality among the three groups. CONCLUSION: VEIL for vulvar cancer treatment is effective, with the advantages of short hospitalization stay, less bleeding, and reduced postoperative complications comparing the OIL. PMID- 29520667 TI - Stability of matrix metalloproteinase-9 as biological marker in colorectal cancer. AB - Matrix metalloproteinases (MMPs) are believed to be of importance in the growth and spread of colorectal cancer (CRC). MMP-9 level has been suggested as a biological predictor of prognosis in CRC as well as in other types of cancer such as breast and cervical cancer. The purpose of this study was to investigate the stability over time of MMP-9 in cryopreserved plasma, colorectal tumor tissue extract and macroscopically tumor-free colon mucosa tissue extract samples. Plasma and tissue samples were taken from patients at primary CRC surgery and analyzed for MMP-9. Aliquots of samples from the same patients were stored at - 80 degrees C pending analysis. These aliquots were analyzed using identical methods after storage periods of nine (plasma) and twelve (tissue) years. No significant difference in plasma MMP-9 concentration was seen between baseline samples and those after 9 years of cryopreservation (median values 9.9 and 9.7 ng/mL, respectively; p > 0.05). MMP-9 levels in the tumor-free tissue extracts had increased to baseline (median values 7.1 and 8.1 ng/mL, respectively; p < 0.01). MMP-9 levels in the tumor tissue extracts had also increased significantly (median values 89.9 and 133.5 ng/mL, respectively; p < 0.01). We have demonstrated that MMP-9 levels in frozen citrated plasma are stable if stored at 80 degrees C, whereas MMP-9 levels in extracts from tumor tissue and tumor-free intestinal mucosa appear to increase with time. We conclude that MMP-9 levels in cryopreserved plasma may be considered stable over time and are thus suitable for comparison purposes in consecutive series. PMID- 29520668 TI - 3D patient imaging and retrieval analysis help understand the clinical importance of rotation in knee replacements. AB - PURPOSE: The purpose of the present study was to correlate highly accurate CT measurements of pre-revision total knee arthroplasty (TKA) implant position with findings of retrieval analysis post-revision, to understand the clinical relevance of TKA orientation. METHODS: This study involved 53 retrieved TKA implants with pre-revision 3D-CT scans used to determine coronal (varus-valgus), sagittal (tibial slope) and rotational (internal rotation-external rotation) TKA orientation as well as tibiofemoral leg axis. Differences between femoral and tibial angles to describe the "relative rotational mismatch" were also calculated. All tibial inserts were forensically analyzed using the Hood score. Statistical analysis was performed to investigate correlations between TKA component orientation and surface damage (p < 0.05). RESULTS: Femoral components were found to have axial rotations mainly within +/- 3 degrees (68%), whilst 45% of the tibial components and 66% of the relative rotational mismatches were > 3 degrees and < - 3 degrees , respectively. The majority of femoral and tibial components (87% in both cases), as well as the femorotibial angle (70%), showed coronal orientations within +/- 3 degrees . The 64% of the tibial components showed posterior tibial slopes out of both the 0 degrees -3 degrees and 5 degrees -7 degrees ranges. There was a significant correlation between tibial slope and damage score on polyethylene tibial inserts (r = 0.2856; p = 0.0382) as well as a significant correlation between implants' position in the axial plane and damage score on polyethylene tibial inserts (r = 0.6537, p = 0.0240). CONCLUSIONS: This is the first study to use accurate measurements from pre revision 3DCT to compare tibial and femoral orientation in all three planes with retrieval findings in total knee replacements. A significant correlation between implant position and polyethylene surface damage was found. These results showed the importance of optimizing component position to minimize polyethylene damage. Further analysis involving more accurate polyethylene wear measurements are fundamental to fully understand the role of components' orientation in TKAs. PMID- 29520669 TI - The use of oral appliances in obstructive sleep apnea: a retrospective cohort study spanning 14 years of private practice experience. AB - PURPOSE: In 2005, the American Academy of Sleep Medicine stated, "Oral appliances are indicated for use in patients with mild to moderate obstructive sleep apnea (OSA) who prefer them to CPAP therapy, or who do not respond to, are not appropriate candidates for, or who fail treatment attempts with CPAP." However, this recommendation is based upon variable results from only six studies with more than 100 participants. These studies have assessed the effectiveness of mandibular advancement devices (MADs) in specific groups (military populations, academic institutions, or hospital settings) with no large study conducted in a fee-for-service private practice where the majority of patients receive MADs for OSA. The purpose of this study is to report outcomes of a board-certified dental sleep practitioner managing mild, moderate, and severe OSA using customized titratable MADs. We hypothesize that patients will demonstrate a significant reduction in apnea-hypopnea index (AHI) scores after adjusting their customized titratable MADs. METHODS: This is a 14-year retrospective study design with pre- and post-treatment sleep studies. An AHI score < 10 respiratory events per hour with therapy is defined as treatment success. This study was performed by a single private practitioner. RESULTS: Of 2419 patient records analyzed, 544 (22%) had pre- and post-treatment sleep studies (89% polysomnograms). Of 510 patients with complete data, 459 (90%) revealed a decrease in AHI score < 10 respiratory events per hour indicating treatment success. Only 51 of these patients (10%) had a final AHI >= 10 and were considered treatment failures. Among the patients who lacked post overnight polysomnogram, 66/1921 (3%) discontinued the MAD due to adverse effects. Considering these patients as treatment failures as well, and therefore adding their number to the patients with complete sleep study data, the total treatment failures were 117/576 or 20%. Of the treatment successes, OSA was categorized by AHI at baseline as mild in 170 (34%), moderate in 181 (36%), and severe in 138 (28%). CONCLUSIONS: In patients with evaluable data, there was an 80% success rate for treatment of OSA using a custom-fabricated adjustable MAD including substantial numbers of patients with moderate and severe disease. PMID- 29520670 TI - 3D powder printed tetracalcium phosphate scaffold with phytic acid binder: fabrication, microstructure and in situ X-Ray tomography analysis of compressive failure. AB - One of the important aspects in 3D powder printing (3DPP) is the selection of binder for a specific material composition to produce scaffolds with desired microstructure and physico-chemical properties. To this end, a new powder-binder combination, namely tetracalcium phosphate (TTCP) and phytic acid (IP6) was investigated at ambient temperature, for low load bearing application. A minimal deviation (<200 um, w.r.t. computer aided design) was observed in the final sample through optimization of 3DPP process, along with minimum strut and macro pore size of 200 and 750 um, respectively. Importantly, the printed scaffolds exhibited compressive strength of 4-8.5 MPa (in the range of cancellous bone) and in vitro dissolution experiments in phosphate buffered saline (PBS) upto one month revealed gradual degradation in strength property. The TTCP scaffolds are characterized to be moderately porous (~40%) with high interconnectivity, which is essential for vascularization and good osteoconductivity. Another major aim of this study was to demonstrate the failure mechanism of 3D powder-printed scaffolds using monotonic and intermittent compression coupled with micro computed tomography (uCT) imaging. Analyzing these results, we have demonstrated the origin of crack generation and propagation under compressive loading in relation to the unique microstructure, obtained through 3DPP. These findings enable us to acquire a deeper insight of the relationship between structural attributes and failure behavior, to further tailor the 3D powder printing process for ceramic biomaterials. PMID- 29520672 TI - Features associated with pulmonary arterial hypertension in Chinese hospitalized systemic lupus erythematosus patients. AB - Pulmonary arterial hypertension (PAH) is an increasingly recognized complication of systemic lupus erythematosus (SLE). This study aims to estimate the point prevalence of PAH and identify risk factors for PAH in a large cohort of hospitalized SLE patients. We have collected the medical records of patients hospitalized with SLE at the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital. Resting transthoracic echocardiography (TTE) was used to estimate pulmonary artery pressure (PAP) and PAH was defined as systolic PAP (PASP) > 30 mmHg. Patients with other connective tissue diseases, aPL syndrome, left heart disease, valvular heart disease, congenital heart disease, HIV, and portal hypertension were excluded because of diseases affecting the PAP. We assessed potential risk factors for PAH such as thrombogenic factors, SLE clinical manifestations, laboratory abnormalities and disease activity. Ninety-five were diagnosed with PAH of 1639 patients with SLE. The presence of high fibrinogen, serositis, and thrombocytopenia were significantly higher in patients with PAH than in those without PAH (all P < 0.05). Multivariate logistic regression found the associations between high fibrinogen (OR = 1.629), serositis (OR = 2.866), and thrombocytopenia (OR = 1.825) with PAH. The point prevalence of PAH was 5.8% in our cohort of patients with SLE. The significant association of high fibrinogen, serositis, and thrombocytopenia with PAH suggested that hypercoagulable state, organ damage, and hematological abnormality may all contribute to the development of PAH in SLE. This is important, as it is treatable. PMID- 29520671 TI - Receptor Occupancy Imaging Studies in Oncology Drug Development. AB - The selection of therapeutic dose for the most effective treatment of tumours is an intricate interplay of factors. Molecular imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT) can address questions central to this selection: Does the drug reach its target? Does the drug engage with the target of interest? Is the drug dose sufficient to elicit the desired pharmacological effect? Does the dose saturate available target sites? Combining functional PET and SPECT imaging with anatomical imaging technologies such as magnetic resonance imaging (MRI) or computed tomography (CT) allows drug occupancy at the target to be related directly to anatomical or physiological changes in a tissue resulting from therapy. In vivo competition studies, using a tracer amount of radioligand that binds to the tumour receptor with high specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Including imaging studies in early drug development can aid with dose selection and suggest improvements for patient stratification to obtain higher effective utility from a drug after approval. In this review, the potential value of including translational receptor occupancy studies and molecular imaging strategies early on in drug development is addressed. PMID- 29520673 TI - Determinants of renal and patient outcomes in a Spanish cohort of patients with ANCA-associated vasculitis and renal involvement. AB - The classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains controversial. The main objective of this study was to define the respective values of ANCA serotype-based classification, clinicopathological classification, and histopathological classification in predicting patient and renal outcomes in a Spanish cohort of patients with ANCA with specificity for myeloperoxidase, MPO-ANCA, versus ANCA with specificity for proteinase 3, PR3-ANCA. Two hundred and forty-five patients with ANCA-AAV and biopsy-proven renal involvement diagnosed between 2000 and 2104 were recruited in 12 nephrology services. Clinical and histologic data, renal outcomes, and mortality were analyzed. We applied the Chapel Hill Consensus Conference definition with categories for granulomatosis with the polyangiitis (GPA) and microscopic polyangiitis (MPA), the classification based on ANCA specificity, and the histopathological classification proposed in 2010. Eighty-two percent were MPO-ANCA positive and 18.0% PR3-ANCA positive. Altogether, 82.9% had MPA and 17.1% GPA. The median follow-up was 43.2 months (0.1-169.3). Neither ANCA-based serological nor clinical classification was predictive of renal outcomes or patient survival on bivariate or multivariate Cox regression analysis. Histopathological classification was found to predict development of end-stage renal disease (p = 0.005) in Kaplan-Meier analysis. ANCA specificity was more predictive of relapse than clinicopathological classification in multivariate analysis (HR 2.086; 95% CI 1.046-4.158; p = 0.037). In our Spanish cohort, a majority of patients had an MPO-ANCA-AAV. A classification based on ANCA specificity has a higher predictive value for relapse occurrence and could be used for decision-making with respect to induction treatment and maintenance therapies. PMID- 29520675 TI - Gut Microbiota Alteration After Long-Term Consumption of Probiotics in the Elderly. AB - Gut microbiota has been proven to be of crucial importance in maintaining human health. However, the microbiota profile changes with aging, while the loss of microbiota diversity and the alterations in the optimal composition and quantity of beneficial microbes are believed to increase the risk of many diseases. Although the short-term modulatory impact of probiotics on gut microbiota has been revealed in various studies, no studies focused on longer time consumption of probiotics have been demonstrated. In this study, we found that microbial diversity in the probiotic group was similar to that in the control. We identified a panel of microbiota changes, such as Blautia (10.24 vs. 3.76%, P = 0.006), Streptococcus (7.38 vs. 1.16%, P = 0.004), and Enterococcus (0.13 vs. 0.00%, P = 0.030) were more abundant in the probiotic group. Faecalibacterium, a genus containing anti-inflammatory property, also had a higher abundance in the probiotic group in the gut. The microbiota architecture in the different probiotic dose groups was also revealed. No statistical difference was observed in regard to the short-chain fatty acid concentration between the groups. High dose intake of probiotics resulted in lower microbial richness. The profile of inflammatory factors indicated that only the level of IL-1beta was higher in the probiotic population. Taken together, our study demonstrated that the long-time intake of probiotics caused significant changes in the gut microbiota structure, including an increase in the composition of beneficial microorganisms, which might contribute to the maintenance of host health and homeostasis of microenvironment. More prospective cohorts were needed to illustrate the influences of probiotics on the gut microbiota. PMID- 29520674 TI - The association between serum vitamin B12 deficiency and tension-type headache in Turkish children. AB - This study aimed to determine the relationship between serum vitamin B12 level and tension-type headache. The study groups consisted of 75 patients (40 females, 35 males) with headache and a control group of 49 healthy children (25 females, 24 males). Serum vitamin B12 level < 200 pg/ml was defined as deficient, and < 160 pg/ml as severely deficient. The serum vitamin B12 level was measured by the electrochemiluminescence (ECLIA) method. The serum vitamin B12 levels in the headache and control groups were 273.01 +/- 76.77 and 316.22 +/- 74.53 pg/ml, with the difference determined as statistically significant (p = 0.003). In the case group, 18/75 patients (24%) had a serum vitamin B12 level below the normal of 200 pg/ml, and in the control group 4/49 (8%) patients were also below the normal range (p = 0.021). The serum vitamin B12 level in the children with tension-type headache was significantly lower than that in the control group. From the results of the study, it was concluded that there may be an association between vitamin B12 level and tension-type headache. However, further clinical studies are needed. PMID- 29520677 TI - Ionic liquid-induced aggregate formation and their applications. AB - In the last two decades, researchers have extensively studied highly stable and ordered supramolecular assembly formation using oppositely charged surfactants. Thereafter, surface-active ionic liquids (SAILs), a special class of room temperature ionic liquids (RTILs), replace the surfactants to form various supramolecular aggregates. Therefore, in the last decade, the building blocks of the supramolecular aggregates (micelle, mixed micelle, and vesicular assemblies) have changed from oppositely charged surfactant/surfactant pair to surfactant/SAIL and SAIL/SAIL pair. It is also found that various biomolecules can also interact with SAILs to construct biologically important supramolecular assemblies. The very latest addition to this combination of ion pairs is the dye molecules having a long hydrophobic chain part along with a hydrophilic ionic head group. Thus, dye/surfactant or dye/SAIL pair also produces different assemblies through electrostatic, hydrophobic, and pi-pi stacking interactions. Vesicles are one of the important self-assemblies which mimic cellular membranes, and thus have biological application as a drug carrier. Moreover, vesicles can act as a suitable microreactor for nanoparticle synthesis. PMID- 29520676 TI - Recent Advances in Exosomal Protein Detection Via Liquid Biopsy Biosensors for Cancer Screening, Diagnosis, and Prognosis. AB - Current cancer diagnostic methods are challenged by low sensitivity, high false positive rate, limited tumor information, uncomfortable or invasive procedures, and high cost. Liquid biopsy that analyzes circulating biomarkers in body fluids represents a promising solution to these challenges. Exosomes are one of the promising cancer biomarkers for liquid biopsy because they are cell-secreted, nano-sized, extracellular vesicles that stably exist in all types of body fluids. Exosomes transfer DNAs, RNAs, proteins, and lipids from parent cells to recipient cells for intercellular communication and play important roles in cancer initiation, progression, and metastasis. Many liquid biopsy biosensors have been developed to offer non- or minimally-invasive, highly sensitive, simple, rapid, and cost-effective cancer diagnostics. This review summarized recent advances of liquid biopsy biosensors with a focus on the detection of exosomal proteins as biomarkers for cancer screening, diagnosis, and prognosis. We reviewed six major types of liquid biopsy biosensors including immunofluorescence biosensor, colorimetric biosensor, surface plasmon resonance (SPR) biosensor, surface enhanced Raman scattering (SERS) biosensor, electrochemical biosensor, and nuclear magnetic resonance (NMR) biosensor. We shared our perspectives on future improvement of exosome-based liquid biopsy biosensors to accelerate their clinical translation. PMID- 29520678 TI - Intraoperative feasibility of bulbocavernosus reflex monitoring during untethering surgery in infants and children. AB - Bulbocavernosus reflex (BCR) monitoring is used to assess the integrity of urinary and bowel function. In this study, we evaluated the feasibility of BCR monitoring during untethering surgery in infants and children to predict postoperative urinary and bowel dysfunction. The records of 22 patients ranging from 4 days to 10 years old (mean 2.7 +/- 3.3 years) were reviewed. Anesthesia was maintained by propofol or sevoflurane/opioid without neuromuscular blockade. BCR waveforms induced by electrical stimulation (20-40 mA, train-of-four pulses with 500 Hz) to the penis or clitoris were recorded from bilateral external anal sphincters. To assess the sensitivity and specificity of BCR monitoring, we investigated the association between a significant continuous decrease in BCR amplitude at the end of surgery and postoperative urinary and bowel dysfunction after surgery. Reproducible baseline BCR waveforms were successfully recorded in 20 of 22 patients (90.9%). A significant continuous decrease in BCR amplitude was observed in 8 patients. The results of intraoperative BCR monitoring included three true-positives, twelve true-negatives, five false-positives, and zero false negatives. Therefore, the sensitivity and specificity of BCR monitoring used to predict postoperative urinary and bowel dysfunction were 100 and 70.6%, respectively. BCR monitoring during untethering surgery in infants and children under general anesthesia was found to be a feasible method to prevent postoperative urinary and bowel dysfunction. PMID- 29520679 TI - [Rheumatology in Austria]. PMID- 29520680 TI - [Relevance of big data for molecular diagnostics]. AB - Big data analysis raises the expectation that computerized algorithms may extract new knowledge from otherwise unmanageable vast data sets. What are the algorithms behind the big data discussion? In principle, high throughput technologies in molecular research already introduced big data and the development and application of analysis tools into the field of rheumatology some 15 years ago. This includes especially omics technologies, such as genomics, transcriptomics and cytomics. Some basic methods of data analysis are provided along with the technology, however, functional analysis and interpretation requires adaptation of existing or development of new software tools. For these steps, structuring and evaluating according to the biological context is extremely important and not only a mathematical problem. This aspect has to be considered much more for molecular big data than for those analyzed in health economy or epidemiology. Molecular data are structured in a first order determined by the applied technology and present quantitative characteristics that follow the principles of their biological nature. These biological dependencies have to be integrated into software solutions, which may require networks of molecular big data of the same or even different technologies in order to achieve cross-technology confirmation. More and more extensive recording of molecular processes also in individual patients are generating personal big data and require new strategies for management in order to develop data-driven individualized interpretation concepts. With this perspective in mind, translation of information derived from molecular big data will also require new specifications for education and professional competence. PMID- 29520681 TI - Predictive markers for efficacy of everolimus plus exemestane in patients with luminal HER2-negative metastatic breast cancer. AB - Metastatic breast cancer (MBC) is essentially incurable despite recent improvements in systemic therapies. We often encounter difficulties in choosing the most appropriate treatments, with optimal timing, for individual patients. Everolimus, one of the mTOR inhibitors, is usually used with endocrine therapy for MBC. Identification of predictive markers for everolimus-based treatment remains a major issue, but to date, no predictive markers have been established. We retrospectively investigated predictive markers for treatments with everolimus plus exemestane in patients with ER-positive and HER2-negative breast cancer. Clinicopathological features of 18 patients, with locally advanced disease or MBC given everolimus plus exemestane treatments, were examined in relation to treatment effects. Also, primary breast cancer specimens, all ER positive and HER2 negative, were immunohistochemically investigated for phospho-S6 (pS6) and PTEN, to evaluate the mTOR and PIK3CA/Akt pathways. Those showing a good clinical response had a significantly lower Ki67 labeling index than the poor responders. A similar trend was observed in pS6 level but without statistical significance. Interestingly, there was no correlation between the Ki67 labeling index and pS6, and when both indexes were low, the good clinical response rate was high. The median progression-free survival was longer in the group showing a low Ki67 labeling index (109 weeks) than in that with high Ki67 (19 weeks). There was no trend between PTEN expression and treatment effects. Our results suggest that the primary tumor in luminal HER2-negative breast cancer patients with a low Ki67 labeling index and pS6 level has the potential to respond well to everolimus plus exemestane. PMID- 29520683 TI - Correction to: Characterization of fibril dynamics on three timescales by solid state NMR. AB - In our recent publication (Smith et al., J Biomol NMR 65:171-191, 2016) on the dynamics of HET-s(218-289), we reported on page 176, that calculation of solid state NMR R1rho rate constants using analytical equations based on Redfield theory (Kurbanov et al., J Chem Phys 135:184104:184101-184109, 2011) failed when the correlation time of motion becomes too long. PMID- 29520682 TI - Deuteration and selective labeling of alanine methyl groups of beta2-adrenergic receptor expressed in a baculovirus-insect cell expression system. AB - G protein-coupled receptors (GPCRs) exist in equilibrium between multiple conformations, and their populations and exchange rates determine their functions. However, analyses of the conformational dynamics of GPCRs in lipid bilayers are still challenging, because methods for observations of NMR signals of large proteins expressed in a baculovirus-insect cell expression system (BVES) are limited. Here, we report a method to incorporate methyl-13C1H3-labeled alanine with > 45% efficiency in highly deuterated proteins expressed in BVES. Application of the method to the NMR observations of beta2-adrenergic receptor in micelles and in nanodiscs revealed the ligand-induced conformational differences throughout the transmembrane region of the GPCR. PMID- 29520684 TI - Identification of key genes of papillary thyroid cancer using integrated bioinformatics analysis. AB - OBJECTIVE: To identify novel clinically relevant genes in papillary thyroid carcinoma from public databases. METHODS: Four original microarray datasets, GSE3678, GSE3467, GSE33630 and GSE58545, were downloaded. Differentially expressed genes (DEGs) were filtered from integrated data. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, followed by protein-protein interaction (PPI) network construction. The CentiScape pug-in was performed to scale degree. The genes at the top of the degree distribution (>= 95% percentile) in the significantly perturbed networks were defined as central genes. UALCAN and The Cancer Genome Atlas Clinical Explorer were used to verify clinically relevant genes and perform survival analysis. RESULT: 225 commonly changed DEGs (111 up-regulated and 114 down regulated) were identified. The DEGs were classified into three groups by GO terms. KEGG pathway enrichment analysis showed DEGs mainly enriched in the PI3K Akt signaling pathway, pathways in cancer, focal adhesion and proteoglycans in cancer. DEGs' protein-protein interaction (PPI) network complex was developed; six central genes (BCL2, CCND1, FN1, IRS1, COL1A1, CXCL12) were identified. Among them, BCL2, CCND1 and COL1A1 were identified as clinically relevant genes. CONCLUSION: BCL2, CCND1 and COL1A1 may be key genes for papillary thyroid carcinoma. Further molecular biological experiments are required to confirm the function of the identified genes. PMID- 29520685 TI - Daniel Lambert, a protagonist of real life with monstrous obesity in eighteenth century in England. PMID- 29520686 TI - Can photobiomodulation associated with implantation of mesenchymal adipose derived stem cells attenuate the expression of MMPs and decrease degradation of type II collagen in an experimental model of osteoarthritis? AB - This study aimed to determine whether photobiomodulation therapy (PBMT) could improve the bioavailability and chondroprotective benefits of mesenchymal stem cells injected into the knees of rats used as an experimental model of osteoarthritis (OA) as well as reduce the expression of matrix metalloproteinases (MMPs) and degradation of type II collagen (COL2-1) in the cartilage. Adipose derived stem/stromal cells (ADSCs) were collected from three male Fischer 344 rats and characterized by flow cytometry. Fifty female Fischer 344 rats were distributed into five groups of 10 animals each. These groups were as follows: control, OA, OA PBMT, OA ADSC, and OA ADSC PBMT. OA was induced in the animals using a 4% papain solution. Animals from the OA ADSC and OA ADSC PBMT groups received an intra-articular injection of 10 * 106 ADSCs and were treated with PBMT by irradiation (wavelength: 808 nm, power: 50 mW, energy: 42 J, energy density: 71.2 J/cm2, spot size: 0.028). Euthanasia was performed 7 days after the first treatment. The use of PBMT alone and the injection of ADSCs resulted in downregulation of pro-inflammatory cytokines and MPs in cartilage compared to the OA group. PBMT and ADSCs caused upregulation of tissue inhibitors of MPs 1 and 2 and mRNA and protein expression of COL2-1 in cartilage compared to the OA group. The intra-articular injection of ADSCs and PBMT prevented joint degeneration resulting from COL2-1 degradation and modulated inflammation by downregulating cytokines and MMPs in the OA group. PMID- 29520688 TI - Experimental in vitro and in vivo systems for studying the innate immune response during dengue virus infections. AB - Dengue is the most prevalent arboviral disease in humans and leads to significant morbidity and socioeconomic burden in tropical and subtropical areas. Dengue is caused by infection with any of the four closely related serotypes of dengue virus (DENV1-4) and usually manifests as a mild febrile illness, but may develop into fatal dengue hemorrhagic fever and shock syndrome. There are no specific antiviral therapies against dengue because understanding of DENV biology is limited. A tetravalent chimeric dengue vaccine, Dengvaxia, has finally been licensed for use, but its efficacy was significantly lower against DENV-2 infections and in dengue-naive individuals. The identification of mechanisms underlying the interactions between DENV and immune responses will help to determine efficient therapeutic and preventive options. It has been well established how the innate immune system responds to DENV infection and how DENV overcomes innate antiviral defenses, however further progress in this field remains hampered by the absence of appropriate experimental dengue models. Herein, we review the available in vitro and in vivo approaches to study the innate immune responses to DENV. PMID- 29520687 TI - Effect of 660 nm visible red light on cell proliferation and viability in diabetic models in vitro under stressed conditions. AB - The current study evaluated the photobiomodulatory effect of visible red light on cell proliferation and viability in various fibroblast diabetic models in vitro, namely, unstressed normal (N) and stressed normal wounded (NW), diabetic wounded (DW), hypoxic wounded (HW) and diabetic hypoxic wounded (DHW). Cells were irradiated at a wavelength of 660 nm with a fluence of 5 J/cm2 (11.23 mW/cm2), which related to an irradiation time of 7 min and 25 s. Control cells were not irradiated (0 J/cm2). Cells were incubated for 48 h and cellular proliferation was determined by measuring 5-bromo-2'-deoxyuridine (BrdU) in the S-phase (flow cytometry), while viability was assessed by the Trypan blue exclusion test and Apoptox-glo triplex assay. In comparison with the respective controls, PBM increased viability in N- (P <= 0.001), HW- (P <= 0.01) and DHW-cells (P <= 0.05). HW-cells showed a significant progression in the S-phase (P <= 0.05). Also, there was a decrease in the G2M phase in HW- and DHW-cells (P <= 0.05 and P <= 0.05, respectively). This study concludes that hypoxic wounded and diabetic hypoxic wounded models responded positively to PBM, and PBM does not damage stressed cells but has a stimulatory effect on cell viability and proliferation to promote repair and wound healing. This suggests that the more stressed the cells are the better they responded to photobiomodulation (PBM). PMID- 29520689 TI - Development and validation of an epitope-blocking ELISA using an anti haemagglutinin monoclonal antibody for specific detection of antibodies in sheep and goat sera directed against peste des petits ruminants virus. AB - Peste des petits ruminants (PPR) is a contagious and economically important disease affecting production of small ruminants (i.e., sheep and goats). Taking into consideration the lessons learnt from the Global Rinderpest Eradication Programme (GREP), PPR is now targeted by the international veterinary community as the next animal disease to be eradicated. To support the African continental programme for the control of PPR, the Pan African Veterinary Vaccine Centre of the African Union (AU-PANVAC) is developing diagnostics tools. Here, we describe the development of a blocking enzyme-linked immunosorbent assay (bELISA) that allows testing of a large number of samples for specific detection of antibodies directed against PPR virus in sheep and goat sera. The PPR bELISA uses an anti haemagglutinin (H) monoclonal antibody (MAb) as a competitor antibody, and tests results are interpreted using the percentage of inhibition (PI) of MAb binding generated by the serum sample. PI values below or equal to 18% (PI <= 18%) are negative, PI values greater than or equal to 25% (PI >= 25%) are positive, and PI values greater than 18% and below 25% are doubtful. The diagnostic specificity (DSp) and diagnostic sensitivity (DSe) were found to be 100% and 93.74%, respectively. The H-based PPR-bELISA showed good correlation with the virus neutralization test (VNT), the gold standard test, with a kappa value of 0.947. The H-based PPR-bELISA is more specific than the commercial kit ID Screen(r) PPR Competition (N-based PPR-cELISA) from IDvet (France), but the commercial kit is slightly more sensitive than the H-based PPR-bELISA. The validation process also indicated good repeatability and reproducibility of the H-based PPR-bELISA, making this new test a suitable tool for the surveillance and sero-monitoring of the vaccination campaign. PMID- 29520690 TI - Structural Elucidation of Metabolites of Synthetic Cannabinoid UR-144 by Cunninghamella elegans Using Nuclear Magnetic Resonance (NMR) Spectroscopy. AB - The number of new psychoactive substances keeps on rising despite the controlling efforts by law enforcement. Although metabolism of the newly emerging drugs is continuously studied to keep up with the new additions, the exact structures of the metabolites are often not identified due to the insufficient sample quantities for techniques such as nuclear magnetic resonance (NMR) spectroscopy. The aim of the study was to characterise several metabolites of the synthetic cannabinoid (1-pentyl-1H-indol-3-yl) (2,2,3,3-tetramethylcyclopropyl) methanone (UR-144) by NMR spectroscopy after the incubation with the fungus Cunninghamella elegans. UR-144 was incubated with C. elegans for 72 h, and the resulting metabolites were chromatographically separated. Six fractions were collected and analysed by NMR spectroscopy. UR-144 was also incubated with human liver microsomes (HLM), and the liquid chromatography-high resolution mass spectrometry analysis was performed on the HLM metabolites with the characterised fungal metabolites as reference standards. Ten metabolites were characterised by NMR analysis including dihydroxy metabolites, carboxy and hydroxy metabolites, a hydroxy and ketone metabolite, and a carboxy and ketone metabolite. Of these metabolites, dihydroxy metabolite, carboxy and hydroxy metabolites, and a hydroxy and ketone metabolite were identified in HLM incubation. The results indicate that the fungus is capable of producing human-relevant metabolites including the exact isomers. The capacity of the fungus C. elegans to allow for NMR structural characterisation by enabling production of large amounts of metabolites makes it an ideal model to complement metabolism studies. PMID- 29520691 TI - Invitation to Speak at a Conference: The Tempting Technique Adopted by Predatory Conferences' Organizers. AB - In recent years, predatory journals, conferences, and publishers have turned to an inevitable threat in scientific publishing. Researchers, regardless of their disciplines, should be aware of these predators and have to be able to recognize them. The main aim of the present paper is to raise awareness about the growing menace of fake invitations to speak at a scientific conference organized by predatory organizers and publishers. Some subtle signs to identify the fake invitations from the authentic ones have been introduced and discussed. PMID- 29520692 TI - Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants with Bartter-syndrome-like hypokalemia alkalosis. AB - Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G > C and c.3062C > T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF. PMID- 29520693 TI - Alteration of heat shock protein 20 expression in preeclamptic patients and its effect in vascular and coagulation function. AB - Preeclampsia (PE) is a pregnancy-specific, multi-system disorder and the leading cause of maternal and perinatal morbidity and mortality in obstetrics worldwide. Excessive vasoconstriction and dysregulated coagulation function are closely associated with PE. Heat shock protein 20 (HSP20) is ubiquitously expressed under normal physiological conditions and has important roles in vascular dilatation and suppression of platelet aggregation. However, the role of HSP20 in the pathogenesis of PE remains unclear. In this study, we collected chorionic plate resistance arteries (CPAs) and serum from 118 healthy pregnant women and 80 women with PE and detected the levels of HSP20 and its phosphorylated form. Both HSP20 and phosphorylated HSP20 were downregulated in CPAs from women with PE. Comparison of the vasodilative ability of CPAs from the two groups showed impaired relaxation responses to acetyl choline in preeclamptic vessels. In addition to the reduced HSP20 in serum from women with PE, the platelet distribution width and mean platelet volume were also decreased, and the activated partial thromboplastin time and thromboplastin time were elevated.With regard to the vital roles of HSP20 in mediating vasorelaxation and coagulation function, the decreased HSP20 might contribute to the pathogenesis of PE. PMID- 29520696 TI - Epitrochlear lymph node basin in melanoma: an extension of the axillary station or an independent basin? PMID- 29520695 TI - AKIP1 promotes angiogenesis and tumor growth by upregulating CXC-chemokines in cervical cancer cells. AB - Upregulation of A-kinase-interacting protein 1 (AKIP1) has been observed in breast and esophageal cancers, indicating that AKIP1 may be a potent oncogenic protein. However, the role of AKIP1 in cervical cancer still remains unknown. This study aimed to explore the role of AKIP1 in cervical cancer and to investigate the underlying mechanism of AKIP1 in tumor growth. Expression of AKIP1 in cervical cancer cells was determined by qRT-PCR and western blotting. Cell-Light EdU and colony formation assays were used to determine cell proliferation. CXCL1 and CXCL8 proteins were quantified by ELISA kits. Western blotting and qRT-PCR were used to examine the alterations in signaling-related proteins and mRNA, respectively. Endothelial cell tube formation assay was performed to evaluate the effect of AKIP1 on angiogenesis. A BALB/c nude mouse xenograft model was used to evaluate the role of AKIP1 in vivo. Cancer cell proliferation was inhibited and tumor growth and angiogenesis restrained in BALB/c nude mice by suppressing AKIP1 expression in cervical cancer cell lines. In addition, overexpression of AKIP1 in cervical cancer cells elevated the levels of CXCL1, CXCL2, and CXCL8. These three chemokines were not only involved in endothelial tube formation by binding to the endothelial receptor CXCR2, but also in cervical cancer cell proliferation and clone formation, which were induced by overexpression of AKIP1. Furthermore, we found that AKIP1-induced chemokine expression was decreased by an inhibitor of nuclear factor kappa-B kinase subunit beta. These results show that AKIP1 is crucial in cervical cancer angiogenesis and growth by elevating the levels of the NF-kappaB-dependent chemokines CXCL1, CXCL2, and CXCL8. PMID- 29520694 TI - Calcific Aortic Valve Disease: a Developmental Biology Perspective. AB - PURPOSE OF REVIEW: This review aims to highlight the past and more current literature related to the multifaceted pathogenic programs that contribute to calcific aortic valve disease (CAVD) with a focus on the contribution of developmental programs. RECENT FINDINGS: Calcification of the aortic valve is an active process characterized by calcific nodule formation on the aortic surface leading to a less supple and more stiffened cusp, thereby limiting movement and causing clinical stenosis. The mechanisms underlying these pathogenic changes are largely unknown, but emerging studies have suggested that signaling pathways common to valvulogenesis and bone development play significant roles and include Transforming Growth Factor-beta (TGF-beta), bone morphogenetic protein (BMP), Wnt, Notch, and Sox9. This comprehensive review of the literature highlights the complex nature of CAVD but concurrently identifies key regulators that can be targeted in the development of mechanistic-based therapies beyond surgical intervention to improve patient outcome. PMID- 29520697 TI - The cytotoxic, apoptotic and oxidative effects of carbonic anhydrase IX inhibitor on colorectal cancer cells. AB - Colorectal cancer (CRC) is the third most common tumor, malignant and has developed one of the main reasons of cancer mortality. According to studies conducted recently; carbonic anhydrase 9 (CAIX) is an especially attractive target for cancer therapy, in part since it is limited way expressed in normal tissues on the other hand in a wide variety of solid neoplasia are overexpressed. The aim of this study was to appreciate the effects of CAIX inhibitor, namely novel synthesized sulfonamide derivative (H-4i) with high affinity for CAIX, in CAIX-positive human colorectal cancer cell (HT-29) and CAIX-negative human normal embryonic kidney cell line (HEK-293). For this reason, we planned to investigate apoptotic, cytotoxic and oxidative stress activity of H-4i on HT-29 and HEK-293 cell lines. Cell viability determined by WST-1 assay afterwards IC50 values, apoptosis and cell cycle induction measured by flow cytometric analysis, intracellular free radical induction performed by reactive oxygen species (ROS) analyses. The IC50 value of the sulfonamide derivative compound was found to be very low, especially in HT-29 cells, when compared to human normal cells. This research found that H-4i significantly increased cytotoxicity and ROS production, caused significant signs of apoptosis level. High level of ROS and apoptosis lead to arrest the cell cycle and reduce cell survival. The most obvious finding to emerge from the analysis that novel synthesized sulfonamide derivative H-4i is effective on HT-29 more than HEK-293. Therefore, novel derivative H-4i might be used as an anti-cancer potential compound on CRC. PMID- 29520698 TI - Renal sympathetic denervation restores aortic distensibility in patients with resistant hypertension: data from a multi-center trial. AB - Renal sympathetic denervation (RDN) is under investigation as a treatment option in patients with resistant hypertension (RH). Determinants of arterial compliance may, however, help to predict the BP response to therapy. Aortic distensibility (AD) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR. This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes. We analyzed data of 65 patients with RH included in a multicenter trial. RDN was performed in all participants. A standardized CMR protocol was utilized at baseline and at 6 month follow-up. AD was determined as the change in cross-sectional aortic area per unit change in BP. Office BP decreased significantly from 173/92 +/- 24/16 mmHg at baseline to 151/85 +/- 24/17 mmHg (p < 0.001) 6 months after RDN. Maximum aortic areas increased from 604.7 +/- 157.7 to 621.1 +/- 157.3 mm2 (p = 0.011). AD improved significantly by 33% from 1.52 +/- 0.82 to 2.02 +/- 0.93 * 10-3 mmHg 1 (p < 0.001). Increase of AD at follow-up was significantly more pronounced in younger patients (p = 0.005) and responders to RDN (p = 0.002). Patients with high-baseline AD were significantly younger (61.4 +/- 10.1 vs. 67.1 +/- 8.4 years, p = 0.022). However, there was no significant correlation of baseline AD to response to RDN. AD is improved after RDN across all age groups. Importantly, these improvements appear to be unrelated to observed BP changes, suggesting that RDN may have direct effects on the central vasculature. PMID- 29520699 TI - Indication and short-term clinical outcomes of high-risk percutaneous coronary intervention with microaxial Impella(r) pump: results from the German Impella(r) registry. AB - BACKGROUND: Percutaneous coronary intervention (PCI) is an alternative strategy to coronary artery bypass grafting (CABG) in patients with high perioperative risk. The microaxial Impella(r) pump (Abiomed, Danvers, MA, USA), used as prophylactic and temporary support, is currently the most common device for "protected high-risk PCI" to ensure hemodynamic stability during complex coronary intervention. METHODS: The study is an observational, retrospective multi-center registry. Patients from nine tertiary hospitals in Germany, who have undergone protected high-risk PCI, are included in the present study. RESULTS: A total of 154 patients (mean age 72.6-10.8 years, 75.3% male) were enrolled. The majority were at a high operative risk illustrated by a logistic EuroSCORE of 14.7-17.4. The initial SYNTAX score was 32.0-13.3, indicating very complex CAD and could be reduced to 14.1-14.3 (p < 0.0001) after PCI. The main reasons for protected PCI were complex coronary anatomy (70.8%), personal impression (56.5%), reduced ventricular ejection fraction (49.4%), comorbidities (47.4%), and surgical turndown (30.5%). Four patients (2.6%) experienced an intrahospital death. CONCLUSIONS: Data from the study show that protected PCI is a safe and effective approach to revascularize high-risk patients with complex coronary anatomy and comorbidities. PMID- 29520700 TI - Multidisciplinary approach to the management of patients with pulmonary embolism and deep vein thrombosis: a consensus on diagnosis, traditional therapy and therapy with rivaroxaban. AB - Despite the availability of updated guidelines for the diagnosis and treatment of venous thromboembolism (VTE), the management of this disorder in clinical practice is often not standardized, given the different degree of compliance with official recommendations by the various involved specialists. The aim of this consensus paper, as a result of a board of experts in thromboembolism, is to define strategies to improve the quality of patients' care and the efficiency of healthcare resources utilization, by means of: (a) analysis of the guidelines for diagnosis and treatment of VTE; (b) analysis of diagnostic and therapeutic algorithms currently used in clinical practice by different specialists; (c) agreement on a common algorithm for diagnosis and treatment of VTE in different clinical settings; (d) definition of the possible role of the new oral anticoagulant agents (NOAC), such as rivaroxaban, based on their potential benefits for both acute and chronic therapy. The so-called "single drug approach" (as opposed to the traditional heparin/VKA combination), which can be adopted with these drugs, makes anticoagulation more convenient for both patients and healthcare providers, without the need for a close monitoring of the hemocoagulative status, and with a concomitant reduction of length of hospitalization and treatment costs. Among NOACs, in this paper we focused on rivaroxaban only because it was the unique available NOAC in Italy for the treatment of VTE at the time the manuscript was written. Concerning rivaroxaban, the results of two phase III, randomized and controlled trials confirm the non inferiority of this drug compared to standard therapy (enoxaparin/warfarin) for the treatment of patients with pulmonary embolism (EINSTEIN PE Study) or deep vein thrombosis (EINSTEIN DVT Study) in terms of both efficacy and safety, supporting its use as an effective therapeutic option for these disorders. PMID- 29520702 TI - The Just War Tradition: A Model for Healthcare Ethics. AB - Healthcare ethics committees, physicians, surgeons, nurses, families, and patients themselves are constantly under pressure to make appropriate medically ethical decisions concerning patient care. Various models for healthcare ethics decisions have been proposed throughout the years, but by and large they are focused on making the initial ethical decision. What follows is a proposed model for healthcare ethics that considers the most appropriate decisions before, during, and after any intervention. The Just War Tradition is a model that is thorough in its exploration of the ethics guiding a nation to either engage in or refuse to engage in combatant actions. In recent years, the Just War Tradition has expanded beyond the simple consideration of going to war or not to include how the war is conducted and what the post-war phase would look like ethically. This paper is an exploration of a healthcare ethics decision making model using the tenets of the Just War Tradition as a framework. It discusses the initial consult level of decision making prior to any medical intervention, then goes further in considering the ongoing ethical paradigm during medical intervention and post intervention. Thus, this proposal is a more holistic approach to healthcare ethics decision making that encourages healthcare ethics committees to consider alternate models and ways of processing so that ultimately what is best for patient, family, staff, and the environment is all taken into consideration. PMID- 29520701 TI - Intracranial hemorrhage in anticoagulated patients with mild traumatic brain injury: significant differences between direct oral anticoagulants and vitamin K antagonists. AB - Prognosis after mild traumatic brain injury (MTBI) on oral anticoagulant therapy (OAT) is uncertain. We evaluated the rate of immediate and delayed traumatic intracranial hemorrhage (ICH) comparing vitamin K antagonists (VKAs) to direct oral anticoagulants (DOACs) and the safety of a clinical management protocol. In this single-center prospective observational study, we enrolled 220 patients on OAT with MTBI. After a first negative CT scan, asymptomatic patients underwent a close neurological observation; if neurologically stable, they were discharged without a second CT scan and followed up for 1 month. Out of the 220 patients, 206 met the inclusion criteria. 23 of them (11.2%) had a positive first CT scan for ICH. Only 1 (0.5%, 95% CI 0.0-1.4%) died because of ICH; no one required neurosurgical intervention. The observed prevalence rate of immediate ICH resulted statistically higher in VKAs-treated patients compared to those treated with DOACs (15.7 vs. 4.7%, RR 3.34, 95% CI 1.18-9.46, P < 0.05). In the 1-month follow-up, 5 out of the 183 patients with a negative CT scan were lost. Out of the remaining 178 patients, only 3 showed a delayed ICH (1.7%, 95% CI 0.0-3.6%), 1 of them died (0.6%, 95% CI 0.5-1.7%) and the others did not require neurosurgical intervention. DOACs resulted safer than VKAs also in the setting of MTBI. In our observation, the rate of delayed hemorrhage was relatively low. Patients presenting with a negative first CT scan and without neurological deterioration could be safely discharged after a short period of in-ward observation with a low rate of complications and without a second CT scan. PMID- 29520703 TI - Short-Term Results of Revisional Single-Anastomosis Gastric Bypass After Sleeve Gastrectomy for Weight Regain. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) has become the most performed bariatric procedure as of 2015. However, inadequate weight loss may present the need for revisional procedures. OBJECTIVES: The objective of this study was to analyze the efficacy of single-anastomosis gastric bypass (SAGB) in attaining successful weight loss following an initial LSG. METHODS: A retrospective analysis was performed on all patients who underwent LSG at Amiri Hospital, Kuwait from 2008 to 2017. A list was obtained of those who underwent revisional SAGB surgery after initial LSG, and their demographics were analyzed. RESULTS: A total of 31 patients underwent revisional SAGB bariatric surgery after initial LSG, of which 87.1% were female. Prior to LSG, the mean weight of the patients was 127.5 kg and the mean BMI was 49.0 kg/m2. The mean weight loss after initial LSG was 43.8 kg, while the average duration until patients underwent revisional SAGB was 5.1 years. The cause for revision was weight regain (86.2%), inadequate weight loss (10.3%), or the development of a complication (reflux) (6.5%). Prior to undergoing revisional SAGB, the weight and BMI of the patients were 110.9 kg and 42.6 kg/m2, respectively. This demonstrated a %excess weight loss of 14.5, 31.9, 48.0, and 58.9% 2 weeks, 3 months, 6 months, and 1-year post-SAGB, respectively. Three (10.3%) morbidities were reported and thereafter successfully resolved. CONCLUSION: Revisional SAGB bariatric surgery is a safe and effective method in the short-term basis for the management of inadequate primary LSG. PMID- 29520704 TI - Prevalence of Micronutrient Deficiencies Prior to Bariatric Surgery: Tehran Obesity Treatment Study (TOTS). AB - BACKGROUND: Micronutrient deficiencies are major concerns after bariatric surgery, although these conditions often go undiagnosed pre-surgery. OBJECTIVE: To assess pre-surgery micronutrient status of an Iranian population of morbidly obese candidates of bariatric surgery in a cross-sectional study. METHODS: A cross-sectional analysis of 2008 candidates for bariatric surgery, aged 15-65 years, with either body mass index (BMI) >= 40 kg/m2 or 30 < BMI < 35 kg/m2 with a medical comorbidity was conducted. In order to determine the micronutrient status of participants, blood samples were collected to assess serum concentrations of vitamins (B12 and D), minerals (copper, calcium, phosphate, and zinc), and iron profiles (total iron binding capacity, iron concentration, ferritin, and iron saturation), according to standard protocol. RESULTS: The mean age and BMI of patients (79.3% female) were 37.8 years and 44.8 kg/m2, respectively. Deficiencies were found for 25(OH) D (53.6%), vitamin B12 (34.4%), serum iron (10.2%), and low levels of hemoglobin (16.6%). The prevalence of other deficiencies were all below 10%. Body mass index had a negative correlation with iron, calcium, vitamin B12, and 25(OH) D and was positively correlated with copper. CONCLUSION: Micronutrient deficiencies, including vitamin D, vitamin B12, and iron, are commonly found among morbidly obese subjects who are potential candidates of bariatric surgery. PMID- 29520705 TI - Targeting BCL-2 in Hematologic Malignancies. AB - Resistance to apoptosis is one of the hallmarks of cancer and members of the B cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL 2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma. PMID- 29520706 TI - The Evolving Role of Cardiorespiratory Fitness and Exercise in Prevention and Management of Heart Failure. AB - PURPOSE OF REVIEW: This paper highlights the dynamic relationship between cardiorespiratory fitness (CRF) and heart failure (HF). As heart failure with preserved ejection fraction (HFpEF) surpasses heart failure with reduced ejection fraction (HFrEF) in prevalence, our void in understanding how to treat this syndrome becomes less justifiable. As such, significant attention has been given to the role that obesity and physical inactivity play, as both risk factors for heart failure, and therapeutic targets for its treatment. RECENT FINDINGS: Previous findings have shown that low CRF, obesity, and physical inactivity are all risk factors for HF. More recently, it has been discovered that these factors are even more significant when applied to HFpEF, even after accounting for traditional cardiovascular risk factors. As such, new investigations have attempted to discover whether improvements in CRF could be utilized as a tool for prevention of HF. In addition, small studies have shown that interventions to improve CRF in patients with HF could improve both quality of life and fitness. The role of CRF, PA, and obesity in the development of HF is now well established; however, our ability to attenuate that risk is yet to be determined. Observational data have signaled a correlation between improvements in PA, CRF and lower risk of HF however, large randomized controlled trials are still required to truly determine whether exercise training could be used in the prevention and treatment of HF, particularly HFpEF. PMID- 29520707 TI - Biomarkers of Cardiac Stress and Injury in Athletes: What Do They Mean? AB - PURPOSE OF THE REVIEW: Markers of myocardial stress, including troponin, creatine kinase, and brain natriuretic peptide are frequently elevated after endurance athletic pursuits. Here, we summarize the current literature pertaining to the potential mechanism of cardiac enzyme release in athletes and seek to determine the clinical implications of these findings. RECENT FINDINGS: Recent studies have highlighted the potential adverse cardiac effects of long-term extreme endurance exercise. While troponin release occurs in a pattern distinct from ischemic damage, BNP release has been correlated with right ventricular dysfunction and is likely related to wall stress from prolonged increases in cardiac output. Higher intensity pre-race training regimes are associated with lower race-day enzyme release. While the holistic benefits of regular moderate exercise are indisputable, recent studies have raised concerns about the potential risks of extreme endurance exercise. Release of serum biomarkers suggesting myocardial damage was first described in the 1970s, yet our understanding of the implications of these findings remains incomplete. The mechanisms of release are complex but appear to be primarily physiological phenomena rather than pathologic. PMID- 29520708 TI - Association study between copy number variation and beef fatty acid profile of Nellore cattle. AB - The aim of this study was to analyze the association between the copy number variation regions (CNVRs) and fatty acid profile phenotypes for saturated (SFA), monosaturated (MUFA), polyunsaturated (PUFA), omega6 and omega3 fatty acids, PUFA/SFA and omega6/omega3 ratios, as well as for their sums, in Nellore cattle (Bos primigenius indicus). A total of 963 males were finished in feedlot and slaughtered with approximately 2 years of age. Animals were genotyped with the BovineHD BeadChip (Illumina Inc., San Diego, CA, USA). The copy number variation (CNV) detection was performed using the PennCNV algorithm. Log R ratio (LRR) and allele B frequency (BAF) were used to estimate the CNVs. The association analyses were done using the CNVRuler software and applying a logistic regression model. The phenotype was adjusted using a linear model considering the fixed effects of contemporary group and the animal age at slaughter. The fatty acid profile was analyzed on samples of longissimus thoracis muscle using gas chromatography with a 100-m capillary column. For the association analysis, the adjusted phenotypic values were considered for the traits, while the data was adjusted for the effects of the farm and year of birth, management groups at birth, weaning, and superannuation. A total of 186 CNVRs were significant for SFA (43), MUFA (42), PUFA (66), and omega fatty acid (35) groups, totaling 278 known genes. On the basis of the results, several genes were associated with several fatty acids of different saturations. Olfactory receptor genes were associated with C12:0, C14:0, and C18:0 fatty acids. The SAMD8 and BSCL2 genes, both related to lipid metabolic process, were associated with C12:0. The RAPGEF6 gene was found to be associated with C18:2 cis-9 cis-12 n-6, and its function is related to regulation of GTPase activity. Among the results, we highlighted the olfactory receptor activity (GO:0004984), G-protein-coupled receptor activity (GO:0004930), potassium:proton antiporter activity (GO:0015386), sodium:proton antiporter activity (GO:0015385), and odorant-binding (GO:0005549) molecular functions. A large number of genes associated with fatty acid profile within the CNVRs were identified in this study. These findings must contribute to better elucidate the genetic mechanism underlying the fatty acid profile of intramuscular fat in Nellore cattle. PMID- 29520709 TI - Direct Analysis of Proteins from Solutions with High Salt Concentration Using Laser Electrospray Mass Spectrometry. AB - The detection of lysozyme, or a mixture of lysozyme, cytochrome c, and myoglobin, from solutions with varying salt concentrations (0.1 to 250 mM NaCl) is compared using laser electrospray mass spectrometry (LEMS) and electrospray ionization mass spectrometry (ESI-MS). Protonated protein peaks were observed up to a concentration of 250 mM NaCl in the case of LEMS. In the case of ESI-MS, a protein solution with salt concentration > 0.5 mM resulted in predominantly salt adducted features, with suppression of the protonated protein ions. The constituents in the mixture of proteins were assignable up to 250 mM NaCl for LEMS and were not assignable above a NaCl concentration of 0.5 mM for ESI. The average sodium adducts (< n >) bound to the 7+ charge state of lysozyme for LEMS measurements from salt concentrations of 2.5, 25, 50, and 100 mM NaCl are 1.71, 5.23, 5.26, and 5.11, respectively. The conventional electrospray measurements for lysozyme solution containing salt concentrations of 0.1, 1, 2, and 5 mM NaCl resulted in < n > of 2.65, 6.44, 7.57, and 8.48, respectively. LEMS displays an approximately two orders of magnitude higher salt tolerance in comparison with conventional ESI-MS. The non-equilibrium partitioning of proteins on the surface of the charged droplets is proposed as the mechanism for the high salt tolerance phenomena observed in the LEMS measurements. Graphical Abstract ?. PMID- 29520710 TI - A Traveling Wave Ion Mobility Spectrometry (TWIMS) Study of the Robo1-Heparan Sulfate Interaction. AB - Roundabout 1 (Robo1) interacts with its receptor Slit to regulate axon guidance, axon branching, and dendritic development in the nervous system and to regulate morphogenesis and many cell functions in the nonneuronal tissues. This interaction is known to be critically regulated by heparan sulfate (HS). Previous studies suggest that HS is required to promote the binding of Robo1 to Slit to form the minimal signaling complex, but the molecular details and the structural requirements of HS for this interaction are still unclear. Here, we describe the application of traveling wave ion mobility spectrometry (TWIMS) to study the conformational details of the Robo1-HS interaction. The results suggest that Robo1 exists in two conformations that differ by their compactness and capability to interact with HS. The results also suggest that the highly flexible interdomain hinge region connecting the Ig1 and Ig2 domains of Robo1 plays an important functional role in promoting the Robo1-Slit interaction. Moreover, variations in the sulfation pattern and size of HS were found to affect its binding affinity and selectivity to interact with different conformations of Robo1. Both MS measurements and CIU experiments show that the Robo1-HS interaction requires the presence of a specific size and pattern of modification of HS. Furthermore, the effect of N-glycosylation on the conformation of Robo1 and its binding modes with HS is reported. Graphical Abstract ?. PMID- 29520711 TI - Cross-modal attentional entrainment: Insights from magicians. AB - Recently, performance magic has become a source of insight into the processes underlying awareness. Magicians have highlighted a set of variables that can create moments of visual attentional suppression, which they call "off-beats." One of these variables is akin to the phenomenon psychologists know as attentional entrainment. The current experiments, inspired by performance magic, explore the extent to which entrainment can occur across sensory modalities. Across two experiments using a difficult dot probe detection task, we find that the mere presence of an auditory rhythm can bias when visual attention is deployed, speeding responses to stimuli appearing in phase with the rhythm. However, the extent of this cross-modal influence is moderated by factors such as the speed of the entrainers and whether their frequency is increasing or decreasing. In Experiment 1, entrainment occurred for rhythms presented at .67 Hz, but not at 1.5 Hz. In Experiment 2, entrainment only occurred for rhythms that were slowing from 1.5 Hz to .67 Hz, not speeding. The results of these experiments challenge current models of temporal attention. PMID- 29520712 TI - The contribution of forward masking to saccadic inhibition of return. AB - : Inhibition of return is the name typically given to the prolonged latency of motor responses directed to a previously cued target location. There is intense debate about the origins of this effect and its function, but most take for granted (despite lack of evidence) that it depends little on forward masking. Therefore, we re-examined the role of forward masking in inhibition of return. Forward masking was indexed by slower saccadic reaction times (SRTs) when the target orientation repeated the cue orientation at the same location. We confirmed effects of orientation repetition in the absence of an attentional bias when cues were presented on both sides of fixation (bilateral presentation). The effect of orientation repetition was reduced with high target contrast, consistent with a low-level origin such as contrast gain control in early visual areas. When presenting cues on only one side of fixation (unilateral presentation), we obtained inhibition of return with longer cue-target intervals and facilitation with targets presented shortly after the cue. The effect of orientation repetition was reduced when facilitation was observed, but was as strong as with bilateral cues when inhibition of return was observed. Therefore, forward masking may contribute to the inhibition of return effect by delaying reaction times to repeated features at the same location, but is not a principal cause of inhibition of return; in agreement with previous views. SIGNIFICANCE STATEMENT: The saccadic inhibition of return effect is a reaction-time cost when responding to a pre-cued location. Additional object updating costs are typically invoked to explain reaction-time costs observed when cue and target have the same shape. Yet, lower-level, forward masking of the target by the cue can not be ruled out. Importantly, we show an effect of orientation repetition that is consistent with low-level forward masking rather than object updating costs and that does not interact with inhibition of return. PMID- 29520713 TI - May I have your attention please: Binding of attended but response-irrelevant features. AB - The feature codes of stimuli and responses can be integrated, and if a stimulus is repeated it can retrieve the previously integrated response. Furthermore, even irrelevant features can be integrated and, upon repetition, retrieve the response. Yet the role of attention in feature integration and retrieval is not clearly understood. Some theories assume a central role of attention (e.g., Logan, 1988; Treisman & Gelade, 1980), but other studies have shown no influence of attention on feature binding (e.g., Hommel, 2005). In the present experiments the effect of attention on the integration of two different response-irrelevant features of the same stimulus was examined. In two experiments, participants responded to the color (response feature) of word stimuli, while two irrelevant features of the words (word type and valence) were systematically varied. Participants' attention was directed to either one or the other of the response irrelevant features by asking participants to report that feature at the end of the trial. Feature-response binding effects in the color task were observed to be stronger for the attended response-irrelevant feature. These results indicate that feature binding is not only very flexible but also sensitive to the distribution of attention. It is also automatic, in the sense that as long as attention is available, feature binding occurs irrespective of the task-specific demands. PMID- 29520714 TI - Losing control: Mostly incongruent lists postpone, but do not eliminate, the Stroop effect. AB - Identifying the color (e.g., red) of a color word that is incongruent (e.g., "BLUE") can be remarkably difficult. The Stroop effect is a measure of the interference between activity from word and color pathways. The efficacy of these pathways is thought to be highly contingent on the frequency of incongruent trials within a block. A block of trials with mostly incongruent (MI) trials typically results in a smaller Stroop effect than a block with mostly congruent (MC) trials. This reduction of the Stroop effect has been largely attributed to the strategic list-wide control of the word pathway. Here, the time course of the Stroop effect was explored using speed-accuracy tradeoff functions (SATfs) in tasks with 50 % congruent, MC, and MI trials. In the MC and 50 % congruent condition, color-word congruency affected the rate parameter of the SATf. In the MI condition, however, congruency affected the asymptote. This evidence is consistent with the idea that the strategic control of the word pathway is an effortful, temporary phenomenon, prone to buckle if responding is held in check. PMID- 29520715 TI - Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan. AB - Glycosylation fine-tunes signal transduction of adhesion molecules during neural development and supports synaptic plasticity and repair after injury in the adult nervous system. One abundantly expressed neural glycan is LewisX (LeX). Although it is known that its expression starts at the formation of the neural tube during the second embryonic week in the mouse and peaks during the first postnatal week, its functional relevance is only rudimentarily understood. To gain better insights into the functions of this glycan, we identified small organic compounds that mimic structurally and functionally this glycan glycosidically linked to several neural adhesion molecules. Mimetic compounds were identified by competitive enzyme-linked immunosorbent assay (ELISA) using the LeX-specific monoclonal antibodies L5 and SSEA-1 for screening a library of small organic molecules. In this assay, antibody binding to substrate-coated LeX glycomimetic peptide is measured in the presence of compounds, allowing identification of molecules that inhibit antibody binding and thereby mimic LeX. Gossypol, orlistat, ursolic acid, folic acid, and tosufloxacin inhibited antibody binding in a concentration-dependent manner. With the aim to functionally characterize the molecular consequences of the compounds' actions, we here present evidence that, at nM concentrations, the mimetic compounds enhance neurite outgrowth and promote neuronal survival of cultured mouse cerebellar granule cells via, notably, distinct signal transduction pathways. These findings raise hopes that these LeX mimetics will be powerful tools for further studying the functions of LeX and its effects in acute and chronic nervous system disease models. It is worth mentioning in this context that the LeX compounds investigated in the present study have been clinically approved for different therapies. PMID- 29520716 TI - Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and Its Action to Rapidly Downregulate ERK Phosphorylation. AB - Vitamin A is important for the circadian timing system; deficiency disrupts daily rhythms in activity and clock gene expression, and reduces the nocturnal peak in melatonin in the pineal gland. However, it is currently unknown how these effects are mediated. Vitamin A primarily acts via the active metabolite, retinoic acid (RA), a transcriptional regulator with emerging non-genomic activities. We investigated whether RA is subject to diurnal variation in synthesis and signaling in the rat pineal gland. Its involvement in two key molecular rhythms in this gland was also examined: kinase activation and induction of Aanat, which encodes the rhythm-generating melatonin synthetic enzyme. We found diurnal changes in expression of several genes required for RA signaling, including a RA receptor and synthetic enzymes. The RA-responsive gene Cyp26a1 was found to change between day and night, suggesting diurnal changes in RA activity. This corresponded to changes in RA synthesis, suggesting rhythmic production of RA. Long-term RA treatment in vitro upregulated Aanat transcription, while short-term treatment had no effect. RA was also found to rapidly downregulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, suggesting a rapid non-genomic action which may be involved in driving the molecular rhythm in ERK1/2 activation in this gland. These results demonstrate that there are diurnal changes in RA synthesis and activity in the rat pineal gland which are partially under circadian control. These may be key to the effects of vitamin A on circadian rhythms, therefore providing insight into the molecular link between this nutrient and the circadian system. PMID- 29520718 TI - Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60) 63-tris Malonic Acid [C3] in Mice and Primates. AB - BACKGROUND AND OBJECTIVES: Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C3), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys. The aim of this study was to characterize its toxicity and pharmacokinetics in mice and monkeys. METHODS: To assess pharmacokinetics in mice, we synthesized and administered 14C-C3 to mice using various routes of delivery, including orally. To assess potential toxicity in primates, serial blood studies and electrocardiograms (ECGs) were obtained from monkeys treated with C3 (3 or 7 mg/kg/day) for 2 months. RESULTS AND CONCLUSIONS: The plasma half-life of C3 was 8.2 +/- 0.2 h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C3 was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD50 in mice was 80 mg/kg for a single intraperitoneal injection, and was > 30 mg/kg/day for sustained administration; therapeutic doses are 1-5 mg/kg/day. For primates, no evidence of renal, hepatic, electrolyte, or hematologic abnormalities were noted, and serial ECGs demonstrated no alteration in cardiac electrical activity. Thus, doses of C3 that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment. PMID- 29520717 TI - Presentation and Neurobiology of Anhedonia in Mood Disorders: Commonalities and Distinctions. AB - PURPOSE OF REVIEW: To focus on the clinical and behavioral presentation of anhedonia in mood disorders, as well as the differences and commonalities in the underlying neurocircuitry. RECENT FINDINGS: Evidence suggests that depression is characterized by hypofunction of the reward system, while bipolar disorder manifests dysregulation of the behavioral activation system that increases goal directed reward behavior. Importantly, strong evidence does not exist to suggest significant differences in anhedonia severity between depressed unipolar and bipolar patients, suggesting that there are more nuanced fluctuations in reward processing deficits in bipolar patients depending on their state. Both euthymic unipolar and bipolar patients frequently report residual reward dysfunction, which highlights the potential of reward processing deficits that give rise to the clinical symptom of anhedonia to be trait factors of mood disorders; however, the possibility that therapies are not adequately treating anhedonia could also explain the presence of residual symptoms. Reward processing represents a potential diagnostic and treatment marker for mood disorders. Further research should systematically explore the facets of reward processing in at-risk, affected, and remitted patients. PMID- 29520719 TI - Determination of Puquitinib in Human Plasma by HPLC-ESI MS/MS: Application to Pharmacokinetic Study. AB - BACKGROUND AND OBJECTIVE: Puquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients. METHODS: The analytes of human plasma were prepared by liquid-liquid extraction using methyl-t-butyl ether (MTBE). The plasma analytes were separated by HPLC on Thermo ODS Hypersil column (2.1 * 150 mm; 3 MUm) at 25 degrees C with 5 mmol/L ammonium acetate (A) acetonitrile (B) (30:70, v/v) as the mobile phase. RESULTS: The total run time was 3.5 min and the elution of puquitinib was at 1.38 min. The detection were analyzed by multiple reaction monitoring (MRM) mode with positive-ion electrospray ionization (ESI) interface using the respective [M + H]+ ions: m/z 318.2 -> 261.1 for puquitinib and m/z 258.2 -> 121.0 for the internal standard (etofesalamide). The optimized method provided a good linear relation over the concentration range of 1.00-500.00 ng/mL (r = 0.9944) for puquitinib. The intra day and inter-day precision (relative standard deviation [RSD%]) were within 9.83%, and the intra-day and inter-day accuracy ranged from 91.05 to 103.26%. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. The absolute extraction recovery was on an average of 50.43% for puquitinib and 49.3% for internal standard. In addition, the maximum plasma concentration (Cmax) of puquitinib in dosage from 50 to 800 mg/m2 in the human study showed an increased linearly (57.1 1289.2 ng/mL), which displayed that the concentrations had reached effective levels. CONCLUSIONS: The optimized method was successfully applied to the pharmacokinetic profile study in human cancer patient plasma after the oral administration of puquitinib. PMID- 29520720 TI - Microbial community and physicochemical dynamics during the production of 'Chicha', a traditional beverage of Indigenous people of Brazil. AB - The microbial community of artisanal corn fermentation called Chicha were isolated, purified and then identified using protein profile by Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF) and confirmed by partial ribosomal gene sequencing. Samples from Chicha beverage were chemically characterized by gas and liquid chromatography (HPLC and GC-MS). Aerobic mesophilic bacteria (AMB) (35.8% of total of isolated microorganisms), lactic acid bacteria (LAB) (21.6%) and yeast (42.6%) were identified. Species of the genera Klebsiella, Bacillus, Staphylococcus, Micrococcus, Enterobacter, and Weissella were identified. Rhodotorula mucilaginosa, Lodderomyces elongisporus, Candida metapsilosis, and C. bohicensis were the yeasts found. The LAB isolates detected were responsible for the high concentrations of lactic acid found during the fermentation process (1.2 g L- 1), which is directly related to the decrease in pH values (from 6.95 to 3.70). Maltose was the main carbohydrate detected during corn fermentation (7.02 g L- 1 with 36 h of fermentation). Ethanol was found in low concentrations (average 0.181 g L- 1), making it possible to characterize the beverage as non-alcoholic. Twelve volatile compounds were identified by gas chromatography; belonging to the groups acids, alcohols aldehydes, acetate and others. MALDI-TOF was successfully used for identification of microbiota. Weissella confusa and W. cibaria were detected in the final product (after 36 h of fermentation), W. confusa is often classified as probiotic and deserve further application studies. PMID- 29520721 TI - Anacardic Acids from Cashew Nuts Prevent Behavioral Changes and Oxidative Stress Induced by Rotenone in a Rat Model of Parkinson's Disease. AB - Anacardic acids (AAs) are alkyl phenols mainly presenting in cashew nuts. The antioxidant effects of these compounds have been an area of interest in recent research, with findings suggesting potential therapeutic use for certain diseases. Nevertheless, none of these studies were performed in order to test the hypothesis of whether anacardic acids are capable of preventing behavioral changes and oxidative stress induced by the pesticide rotenone in experimental model of Parkinson's disease. In our research, adult male rats were treated orally with AAs (1, 3, 10, 25, 50, or 100 mg/kg/day) 1 h before rotenone (3 mg/kg; s.c.) for five consecutive days. The behavioral testing strategies, including tests for general locomotor activity (open field), motor coordination (rotarod), and spatial memory performance (elevated T-maze), were carried out. Lipoperoxidation levels and total superoxide dismutase (t-SOD) activity, as well as cytoplasmic and mitochondrial SOD gene expression, were assessed in the substantia nigra (SN), striatum, and cerebral cortex. The results showed that AAs dose-dependently prevented the rotenone-induced learning and motor impairment from 10 mg/kg/day. AAs also precluded rotenone-induced lipoperoxidation in all doses, acting directly on the mitochondria, and improved the t-SOD activity in the doses 25-100 mg/kg/day. AAs per se (100 mg/kg/day) increased SOD gene expression and t-SOD activity. Our findings indicate that the oral administration of AAs prevents rotenone-induced behavioral changes and oxidative stress, in part due to a modulatory action on the mitochondria and SOD gene expression. These data suggest that AAs have promising neuroprotective action against degenerative changes in Parkinson's disease. PMID- 29520722 TI - Human Umbilical Cord Matrix Stem Cells Reverse Oxidative Stress-Induced Cell Death and Ameliorate Motor Function and Striatal Atrophy in Rat Model of Huntington Disease. AB - Huntington disease (HD) is an inherited disorder hallmarked by progressive deterioration of specific neurons, followed by movement and cognitive anomalies. Cell therapy approaches in neurodegenerative conditions have concentrated on the replenishment of lost/dying neurons with functional ones. Multipotent mesenchymal stem cells (MSCs) have been represented as a potential remedy for HD. In this study, we evaluated the in vitro and in vivo efficacy of umbilical cord matrix stem cells (UCMSCs) and their paracrine effect against oxidative stress with a specific focus on HD. To this end, UCMSCs were isolated, immunophenotypically characterized by the positive expression of MSC markers, and exhibited multilineage potentiality. Besides, synthesis of neurotrophic factors of GDNF and VEGF by UCMSC was confirmed. Initially, PC12 cells were exposed to superoxide in the presence of conditioned media (CM) collected from UCMSC (UCMSC-CM) and cell viability plus neuritogenesis were measured. Next, bilateral striatal transplantation of UCMSC in 3-nitropropionic acid (3-NP) lesioned rat models was conducted, and 1 month later, post-graft analysis was performed. According to our in vitro results, CM of UCMSC protected PC12 cells against oxidative stress and considerably enhanced cell viability and neurite outgrowth. On the other hand, transplanted UCMSC survived, decreased gliosis, and ameliorated motor coordination and muscle activity, along with an increase in striatal volume as well as in dendritic length of the striatum in HD rats. Collectively, our findings imply that UCMSCs provide an enriched platform by largely their paracrine factors, which downgrades the unfavorable effects of oxidative stress. PMID- 29520723 TI - High Doses of Boron Have No Protective Effect Against Nephrolithiasis or Oxidative Stress in a Rat Model. AB - Boron plays roles in the metabolism of calcium, vitamin D, steroid hormones, healthy bone development, and maintenance of cell membranes. The biological effects of boron are dose-dependent but follow a U-shaped pattern, rendering it important to define the active range. The studies of Bahadoran et al. on rats and Naghii et al. on humans showed that low doses of boron (3 and 10 mg/day) prevented kidney stone formation. The aim of this study was to determine whether high doses of boron have an anti-urolithiatic or antioxidant effect on nephrolithiasis in an experimental rat model. The study was conducted on 50 adult male Wistar rats randomized to five groups. Nephrolithiasis was induced with water containing 0.75% ethylene glycol (EG) and 2% ammonium chloride (AC). This treatment was given to animals in all groups for 10 days, except the positive and negative controls. Simultaneously, groups 2, 3, and 4 were given boric acid via gavage at doses of 25, 50, and 100 mg/kg/day (equivalent to 4/8/16 mg boron respectively) as the source of boron. Animals in the negative and positive control groups were given 6 MUL/g distilled water without boric acid. At day 10, intra-cardiac blood samples were drawn from all animals. The right and left kidneys were removed for biochemical and histopathological examinations, respectively. The groups were compared with respect to serum urea, creatinine, calcium, phosphorous, total antioxidant status (TAS), total oxidant status (TOS), serum paraoxonase (PON1) activity, tissue calcium and oxalate levels, and stone burden as determined by histopathological examination. Serum urea and creatinine levels were significantly higher (p < 0.001 and p < 0.05, respectively), while serum calcium and phosphorous levels were significantly lower (p < 0.001 and p < 0.001, respectively), in animals given EG/AC compared to negative controls. No significant differences were detected in serum calcium, phosphorous, urea, or creatinine levels between animals treated with boron and positive controls (p > 0.05). Serum PON1 activity was significantly lower in animals given EG/AC than in negative controls (p < 0.001), while no significant difference in serum PON1 level was detected between rats treated with boron and positive controls. No significant differences were detected in vitamin D, TAS, TOS, tissue calcium, or tissue oxalate levels among groups. No stone formation was detected on histopathological examination in negative controls. No significant differences were found in stone formation between rats treated with boron and positive controls. Based on this study, high doses of boron had no protective effect against nephrolithiasis and oxidative stress. PMID- 29520724 TI - Autophagy Protects MC3T3-E1 Cells upon Aluminum-Induced Apoptosis. AB - Aluminum (Al) exposure has adverse effects on osteoblasts, and the effect might be through autophagy-associated apoptosis. In this study, we showed that aluminum trichloride (AlCl3) could induce autophagy in MC3T3-E1 cells, as demonstrated by monodansylcadaverine (MDC) staining and the expressions of the ATG3, ATG5, and ATG9 genes. We found AlCl3 inhibited MC3T3-E1 cell survival rate and caused apoptosis, as evidenced by CCK-8 assay, Annexin V/PI double staining, and increased expressions of Bcl-2, Bax, and Caspase-3 genes. In addition, increased autophagy induced by rapamycin further attenuated the MC3T3-E1 cell apoptosis rate after AlCl3 exposure. These results support the hypothesis that autophagy plays a protective role in impeding apoptosis caused by AlCl3. Activating autophagy may be a strategy for treatment of Al-induced bone disease. PMID- 29520725 TI - Antimony-Induced Neurobehavioral and Biochemical Perturbations in Mice. AB - Groundwater used for drinking has been contaminated with naturally occurring inorganic arsenic and other metals, and metal-contaminated drinking water is the biggest threat to public health in Bangladesh. Toxic metals present in the drinking water have a strong relationship with chronic diseases in humans. Antimony (Sb), a naturally occurring metal, has been reported to be present in the drinking water along with other heavy metals in Bangladesh. Although Sb is present in the environment, very little attention has been given to the toxic effects of Sb. The present study was designed to investigate the in vivo effects of Sb on neurobehavioral changes like anxiety, learning and memory impairment, and blood indices related to organ dysfunction. Mice exposed to antimony potassium-tartrate hydrate (Sb) (10 mg/kg body weight) significantly (p < 0.05) decreased the time spent in open arms while increased the time spent in closed arms compared to the control mice in elevated plus maze. The mean latency time of control group to find the platform decreased (p < 0.05) significantly during 7 days learning as compared to Sb-treated group in Morris water maze test, and Sb exposed group spent significantly (p < 0.05) less time in the desired quadrant as compared to the control group in probe trial. Sb treatment also significantly altered blood indices related to liver and kidney dysfunction. Additionally, Sb induced biochemical alterations were associated with significant perturbations in histological architecture of liver and kidney of Sb-exposed mice. These data suggest that Sb has a toxic effect on neurobehavioral and biochemical changes in mice. PMID- 29520726 TI - Refining Suicide Prevention: a Narrative Review on Advances in Psychotherapeutic Tools. AB - PURPOSE OF REVIEW: Since psychotherapies for suicide prevention are receiving increasing attention, our purpose was to evaluate the related literature [meta analyses and reviews on their effect on suicidal outcomes (A), perspective reviews concerning specific socio-demographic and clinical features (B), original studies with particular interest (C)] published over the last 3 years. RECENT FINDINGS: (A) Across different diagnoses, particularly, efficacious psychotherapies were cognitive behavioral therapy-based ones and interventions directly addressing suicidal thoughts and behaviors during the treatment. When the focus was restricted to specific diagnoses, results were different: for example, in borderline patients, dialectical behavior therapy and psychodynamic psychotherapies were the only efficacious interventions. (B) Family therapies for adolescents and treatments for elderly depressed patients with disability/cognitive impairment should be further developed. (C) General long term effects seem to be present, but specific interventions and treatment duration should be considered. Results indicated the presence of a number of promising interventions. PMID- 29520727 TI - Constructing a Culturally Informed Spanish Decision-Aid to Counsel Latino Parents Facing Imminent Extreme Premature Delivery. AB - Objective How Latino parents perceive and understand antenatal counseling for extreme prematurity, < 26 weeks of gestational age (GA), is not clear. We aim to characterize Latino parental perceptions of antenatal counseling in order to construct and validate a Spanish decision-aid (SDA) to improve parental knowledge of prematurity after antenatal consults. Methods This is a three-phased, prospective, multicenter study. First, interviews of 22 Latino parents with a history of birth < 26 weeks GA were conducted. Thematic analysis identified themes valued during antenatal counseling for decisions regarding neonatal resuscitation. Next, we incorporated these themes into the SDA. Finally, improvement in knowledge of prematurity in two Spanish-speaking groups, 'experienced' parents with a history of extremely premature birth and 'naive' adult Latino volunteers, was measured using a multiple choice test before and after simulated counseling with the SDA. Result Twenty-two interviews generated seven unique themes. An SDA was constructed that preserved six themes paralleled by those found in a previously studied English population, and addressed a novel theme of "intercultural linguistic barriers" unique to our population. Knowledge scores rose in "naive" volunteers, 41 +/- 12% to 71 +/- 15% (P < 0.001), after simulated counseling with the SDA. 'Experienced' parents had a ceiling effect in knowledge scores, 62 +/- 9% to 65 +/- 11% (P = 0.22). The SDA was well received by participants. Conclusions for Practice Interviews of Latino parents with a history of premature birth generated similar themes to English-speaking parents, with intercultural linguistic barriers as a novel theme. An SDA for Latino parents facing extremely premature birth may improve comprehension of antenatal counseling. PMID- 29520728 TI - Completing the Maternal Care Team: OB/GYN Expertise at Rural District Hospitals in Ghana, a Qualitative Study. AB - Introduction To provide a qualitative perspective on the changes that occurred after newly placed OB/GYNs began working at district hospitals in Ashanti, Ghana. Methods Structured interviews of healthcare professionals were conducted at eight district hospitals located throughout the Ashanti district of Ghana, four with and four without a full-time OB/GYN on staff. Individuals interviewed include: medical superintendents, medical officers, district hospital administrators, OB/GYNs (where applicable), and nurse-midwives. Interviews were transcribed verbatim and content analysis was performed to identify common themes. Characteristics quotes were identified to illustrate principal interview themes. Quotes were verified in context by researchers for accuracy. Results Interviews with providers revealed four areas most impacted by an OB/GYN's leadership and expertise at district hospitals: patient referral patterns, obstetric protocol and training, facility management and organization, and hospital reputation. Discussion OB/GYNs are uniquely positioned to add clinical capacity and care quality to established maternal care teams at district hospitals-empowering district hospitals as reliable care centers throughout rural Ghana for women's health. Coordinated efforts between government, donors and OBGYN training institutions to provide complete obstetric teams is the next step to achieve the global goal of eliminating preventable maternal mortality by 2030. PMID- 29520729 TI - Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment. AB - BACKGROUND: The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients. METHODS: In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir +/- ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh Turcotte Class A) cirrhosis]. RESULTS: In the phase I study, plasma exposures (area under the concentration-time curve) were similar in subjects with Child Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration-time curve over the 24-h dosing interval; AUCtau) was similar and sofosbuvir exposures were higher (~ 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant. CONCLUSIONS: No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment. PMID- 29520730 TI - A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women. AB - BACKGROUND: Reducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400 mg daily dose is adequate during pregnancy. METHODS: We developed a mechanistic population pharmacokinetic model using pooled data from women included in seven studies (1968 samples, 774 collected during pregnancy). Total and free efavirenz exposure (AUC24 and C12) were predicted for 400 (reduced) and 600 mg (standard) doses in both pregnant and non-pregnant women. RESULTS: Using a 400 mg dose, the median efavirenz total AUC24 and C12 during the third trimester of pregnancy were 91 and 87% of values among non-pregnant women, respectively. Furthermore, the median free efavirenz C12 and AUC24 were predicted to increase during pregnancy by 11 and 15%, respectively. CONCLUSIONS: It was predicted that reduced-dose efavirenz provides adequate exposure during pregnancy. These findings warrant prospective confirmation. PMID- 29520732 TI - The effects of pool shape manipulations on rat spatial memory acquired in the Morris water maze. AB - The Morris water maze is a popular task for examining spatial navigation and memory in rats. Historically, emphasis has been put on extramaze cues as the primary environmental feature guiding navigation and spatial memory formation. However, other features of the environment may also be involved. In this experiment, we trained rats on the spatial version of the Morris water maze over four days. A probe test was given 24 h after training, in which the shape of the pool either remained the same as during training or was changed to a different shape. Mass training of a new platform position in one training session was performed in a pool of one of these two shapes, with a second probe test being done 24 h afterward. The results showed that spatial training produces a spatial preference for the trained location in the probe test when the pool shape remains the same. However, changing the shape of the pool eliminates this preference. All groups learned the new platform position during mass training and also expressed a spatial preference for the mass-trained quadrant when tested 24 h later. The results from these experiments implicate the use of pool shape in guiding spatial navigation in the water maze and as a critical environmental feature represented in spatial memory. PMID- 29520733 TI - Dosimetric Analysis of Unflattened (FFFB) and Flattened (FB) Photon Beam Energy for Gastric Cancers Using IMRT and VMAT-a Comparative Study. AB - PURPOSE: To evaluate the feasibility of flattening filter free beam (FFFB) for the treatment of gastric tumors and to review their benefits over 6MV flatten beam (6MV_FFB). METHODS: Fifteen patients with histologically proven gastric carcinoma were selected. CT scans with slice thickness of 0.3 cm were acquired and planning target volume (PTV) and organ at risk (OAR) were delineated. Plans were made retrospectively for each patient for the prescription dose of 45 Gy/25 fractions to the PTV. Four isocentric plans were compared in the present study on Varian TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA, USA). RESULTS: PTV D98% was 44.41 +/- 0.12, 44.38 +/- 0.13, 44.59 +/- 0.14, and 44.49 +/- 0.19 Gy for IMRT 6MV_FFB, IMRT 6MV_FFFB, VMAT 6MV_FFB, and VMAT 6MV_FFFB respectively. 6MV_FFFB beam minimizes the mean heart dose Dmean (P = 0.001). VMAT dominates over IMRT when it came to kidney doses V12Gy (P = 0.02), V23Gy (P = 0.015), V28Gy (P = 0.011), and Dmax (P < 0.01). VMAT has significantly reduced the doses to kidneys. It was analyzed that 6MV_FFFB significantly reduces the dose to normal tissues (P = 0.006 and P = 0.018). VMAT significantly reduces the TMU, which is required to deliver the similar dose by IMRT (P < 0.01). CONCLUSIONS: Unflattened beam spares the organs at risk significantly to avoid the chances of secondary malignancies and reduces the intra-fraction motion during treatment due to provision of higher dose rate. Hence, we conclude that 6MV unflattened beam can be used to treat gastric carcinoma. PMID- 29520734 TI - The effect of 12-month dehydroepiandrosterone supplementation on the menstrual pattern, ovarian reserve markers, and safety profile in women with premature ovarian insufficiency. AB - PURPOSE: To evaluate the effect of 12-month DHEA supplementation on menstrual pattern and ovarian reserve markers in women with premature ovarian insufficiency (POI) METHODS: This is a prospective observational study. Women with POI were given DHEA supplements (25 mg three times daily) for 12 months. Sonographic assessment for ovarian volume and antral follicle count (AFC) and serum measurement for anti-Mullerian hormone (AMH), follicle stimulating hormone (FSH), estradiol, testosterone, liver function, and hemoglobin level were performed at baseline and monthly for 13 months after the supplementation. Menstrual pattern, ovarian reserve markers, and side-effects were recorded. RESULTS: Between August 2011 and July 2014, 38 women with POI were recruited and 31 completed the study. The median age of women was 36 years, and the median baseline FSH and AMH concentrations were 82.2 IU/L and 0.01 ng/ml, respectively. No women had resumption of regular menstruation after DHEA supplementation. AMH, FSH, and AFC did not change significantly. No serious side effects were reported. CONCLUSIONS: Our results do not support any significant improvement in ovarian function by 12 month DHEA supplementation in women with POI. PMID- 29520735 TI - Neonatal outcomes among twins stratified by method of conception: secondary analysis of maternal fetal medicine (MFMU) network database. AB - PURPOSE: To investigate whether twin pregnancies conceived by different forms of fertility treatments are associated with adverse neonatal outcomes and to examine the difference in maternal and obstetrical characteristics between patients. METHODS: Our study was a retrospective analysis of twin pregnancies conceived by fertility treatments from a prospectively collected database. Treatments were stratified into two groups: group 1 (ART) consisted of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and group 2 (non-ART) included intrauterine insemination (IUI) and ovulation induction (OI). Composite neonatal morbidity included respiratory distress syndrome, intraventricular hemorrhage, leukomalacia, chronic lung disease, and death prior to discharge. RESULTS: There were 460 neonates in our study; among them, 67% (n = 310) were in group 1, and 33% (n = 150) in group 2. Group 1 patients were more likely to be older (p = 0.004), nulliparous (p = 0.01), delivered twins with lower birth weights (2278 g +/- 605 vs. 2427 +/- 519, p = 0.009), and had more deliveries < 32 weeks gestation (p = 0.001). In multivariable Poisson regression model, only neonatal intensive care unit admission rate was increased for group 1 twins (aRR = 1.27, 95% CI 1.003-1.60). CONCLUSIONS: After adjusting for confounders, twins conceived via ART compared to non-ART had similar neonatal outcomes. These data can help when counseling this patient population and assist in planning larger prospective cohorts. PMID- 29520736 TI - Family Resemblances: Human Reproductive Cloning as an Example for Reconsidering the Mutual Relationships between Bioethics and Science Fiction. AB - In the traditions of narrative ethics and casuistry, stories have a well established role. Specifically, illness narratives provide insight into patients' perspectives and histories. However, because they tend to see fiction as an aesthetic endeavour, practitioners in these traditions often do not realize that fictional stories are valuable moral sources of their own. In this paper I employ two arguments to show the mutual relationship between bioethics and fiction, specifically, science fiction. First, both discourses use imagination to set a scene and determine a perspective. Second, bioethics and science fiction share the family resemblance of expressing moral beliefs. I then consider how understanding bioethics and science fiction as interrelated discourses can be the basis of a methodology for inquiry into relational autonomy in the context of biotechnologies and medicine. As an example of this methodology, I analyse Fay Weldon's novel The Cloning of Joanna May (1989). PMID- 29520731 TI - Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. AB - Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today's literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics. PMID- 29520737 TI - MPS-IIIA mice acquire autistic behaviours with age. AB - Mucopolysaccharidosis (MPS) type IIIA is an inherited, neurodegenerative lysosomal storage disorder resulting from mutations in the SGSH gene. Consequently, N-sulphoglucosamine sulphohydrolase enzyme activity is reduced resulting in impaired catabolism of heparan sulphate. After an asymptomatic period, patients typically show a progressive loss of cognitive and motor skills, with death often during the second decade of life. The diagnostic criteria of autism spectrum disorders (ASD) include impaired communication and social interactions, as well as displays of repetitive behaviours and fixed interests. Children with MPS-IIIA have been shown to exhibit decreased social communicative behaviours from approximately 3-4 years of age but behavioural stereotypies are mostly absent. In this study, we investigated whether a mouse model of MPS-IIIA exhibited ASD-like symptoms. The BTBR T+Itpr3tf/J inbred mouse model of autism was used as a positive control. Male MPS-IIIA and BTBR mice were less sociable compared with unaffected C57BL/6 male mice in the reciprocal social approach test administered at 20 weeks of age. Alternations in the frequency of social interactions was not evident at earlier stages of the disease course, suggesting an acquisition of ASD-like social behaviours. Stereotypical behaviours were not evident in male MPS-IIIA mice in the marble-burying test nor was the quality of nest constructed by mice affected. Collectively, these data suggest that MPS-IIIA mice acquire autistic social behaviours similar to the human condition, and thus they may be useful for elucidating symptom generating mechanisms and novel treatments for ASD. PMID- 29520738 TI - Tetrahydrobiopterin treatment reduces brain L-Phe but only partially improves serotonin in hyperphenylalaninemic ENU1/2 mice. AB - Hyperphenylalaninemia (HPA) caused by hepatic phenylalanine hydroxylase (PAH) deficiency has severe consequences on brain monoamine neurotransmitter metabolism. We have studied monoamine neurotransmitter status and the effect of tetrahydrobiopterin (BH4) treatment in Pahenu1/enu2 (ENU1/2) mice, a model of partial PAH deficiency. These mice exhibit elevated blood L-phenylalanine (L-Phe) concentrations similar to that of mild hyperphenylalaninemia (HPA), but brain levels of L-Phe are still ~5-fold elevated compared to wild-type. We found that brain L-tyrosine, L-tryptophan, BH4 cofactor and catecholamine concentrations, and brain tyrosine hydroxylase (TH) activity were normal in these mice but that brain serotonin, 5-hydroxyindolacetic acid (5HIAA) and 3-methoxy-4 hydroxyphenylglycol (MHPG) content, and brain TH protein, as well as tryptophan hydroxylase type 2 (TPH2) protein levels and activity were reduced in comparison to wild-type mice. Parenteral L-Phe loading conditions did not lead to significant changes in brain neurometabolite concentrations. Remarkably, enteral BH4 treatment, which normalized brain L-Phe levels in ENU1/2 mice, lead to only partial recovery of brain serotonin and 5HIAA concentrations. Furthermore, indirect evidence indicated that the GTP cyclohydrolase I (GTPCH) feedback regulatory protein (GFRP) complex may be a sensor for brain L-Phe elevation to ameliorate the toxic effects of HPA. We conclude that BH4 treatment of HPA toward systemic L-Phe lowering reverses elevated brain L-Phe content but the recovery of TPH2 protein and activity as well as serotonin levels is suboptimal, indicating that patients with mild HPA and mood problems (depression or anxiety) treated with the current diet may benefit from supplementation with BH4 and 5-OH tryptophan. PMID- 29520739 TI - The impact of ammonia levels and dialysis on outcome in 202 patients with neonatal onset urea cycle disorders. AB - Neonatal onset hyperammonemia in patients with urea cycle disorders (UCDs) is still associated with high morbidity and mortality. Current protocols consistently recommend emergency medical and dietary management. In case of increasing or persistent hyperammonemia, with continuous or progressive neurological signs, dialysis is performed, mostly as ultima ratio. It is presently unknown whether the currently defined ammonia threshold (e.g., at 500 MUmol/L) to start dialysis is useful to improve clinical outcome. A systematic review of clinical and biochemical data from published neonatal onset UCD patients was performed to identify factors determining clinical outcome and to investigate in which clinical and biochemical setting dialysis was most effective. A total of 202 patients (118 proximal and 84 distal UCDs) described in 90 case reports or case series were included according to predefined inclusion/exclusion criteria. Median age at onset was three days and mean ammonia that triggered start of dialysis was 1199 MUmol/L. Seventy-one percent of all patients received any form of dialysis. Total mortality was 25% and only 20% of all patients had a "normal" outcome. In general, patients with higher ammonia levels were more likely to receive dialysis, but this had for most patients no influence on outcome. In conclusion, in severe neonatal onset hyperammonemia, the current practice of dialysis, which effectively clears ammonia, had no impact on outcome. It may be essential for improving outcome to initiate all available treatment options, including dialysis, as early as possible. PMID- 29520740 TI - The Relationship Between Severe Mental Disorders and Recidivism in a Sample of Women Released from Prison. AB - Women are one of the fastest growing sectors of the prison population, and have different pathways into prison and differing needs during the reentry process when compared to men (Cloyes et al. J Forensic Nurs; 6:3-14, 2010b; Herrschaft et al. J Offender Rehabil; 48:463-482, 2009). Women report higher levels of mental health problems overall, and report more severe symptomatology (Cloyes et al. J Forensic Nurs; 6:3-14, 2010a; Hyde 2012; Lynch et al. 2014). The current study focuses on the role of severe mental disorders for women released from prison. Data collected from the North Carolina Division of Adult Correction and Juvenile Justice were used to analyze the specific role of severe mental disorders in women's recidivism at eight years post-release (n = 2311). Approximately 20% of women in this sample met the criteria for diagnosis with a severe mental disorder (SMD). Logistic regression analysis indicated that there was an association between SMDs and recidivism for this sample only (p = .11). Cox regression analyses indicated that women diagnosed with SMDs were 16% more likely to have recidivated at eight years post-release compared with women who were not diagnosed with an SMD (p < .05). Implications for the recognition, role, and treatment of SMDs during reentry are discussed. PMID- 29520741 TI - Adherence to Insulin, Emotional Distress, and Trust in Physician Among Patients with Diabetes: A Cross-Sectional Study. AB - INTRODUCTION: Type 2 diabetes represents a significant public health issue, with increasing prevalence in developing countries while adherence to insulin treatment remains a challenge. No studies have evaluated the relationship between adherence to insulin, diabetes-related distress, and trust in physician among persons with diabetes. Our objectives were to evaluate treatment adherence to insulin, emotional distress (using the Problem Areas in Diabetes Questionnaire, PAID), trust in physician, and to examine associations between them among Lebanese patients with diabetes. METHODS: This cross-sectional study, conducted in all districts of Lebanon between August 2016 and April 2017, enrolled 135 adult patients. RESULTS: The mean percentage score of adherence to insulin was 79.7 +/- 19.94. A significantly higher mean adherence score was found in non sedentary (81.96) compared to sedentary patients (67.41) (p = 0.017), with no difference between gender, employment, rural vs non-rural residence, or familial history of diabetes. In addition, no significant relationship was seen between adherence score and education level, smoking, or alcohol intake. A significant positive association was found between trust in physician and adherence scores, whereas a significant but negative one was found between PAID and adherence scores. The results of linear regressions showed that a secondary level of education (beta = - 13.48) significantly decreased the trust in physician score, whereas the total number of oral antidiabetics (beta = 0.93) increased it. Having a sedentary lifestyle (beta = - 12.73) and smoking < 3 waterpipes/week compared to no smoking (beta = - 16.82) significantly decreased the adherence score. Female gender (beta = 10.46), smoking < 3 waterpipes (beta = 27.42) and 3 + waterpipes/week (beta = 17.95) significantly increased the PAID score. CONCLUSION: Trust in physician is associated with an increased adherence and with decreased diabetes-related distress. This distress was also associated with poor adherence in our study. PMID- 29520742 TI - Effects of Insulin Lispro Mix 25 and Insulin Lispro Mix 50 on Postprandial Glucose Excursion in Patients with Type 2 Diabetes: A Prospective, Open-Label, Randomized Clinical Trial. AB - INTRODUCTION: We compared the effects of insulin lispro mix 25 (LM25) and insulin lispro mix 50 (LM50) on postprandial glucose excursion in patients with type 2 diabetes mellitus (T2DM). METHODS: In this randomized, open-label, investigator initiated trial, 81 T2DM patients treated with premixed human insulin 70/30 (PHI70/30) for more than 90 days were randomly divided into two groups and received a crossover protocol of either LM25 or LM50 twice daily for 16 weeks. Continuous glucose monitoring (CGM) was performed for 72 h at baseline and at the end of each treatment phase to evaluate glycemic excursions in the subjects. RESULTS: The LM50 regimen resulted in significantly smaller postprandial glycemic excursions than the LM25 regimen after breakfast (1.3 +/- 2.5 vs. 2.4 +/- 2.6 mmol/L, P = 0.046) and dinner (1.5 +/- 2.8 vs. 2.8 +/- 2.4 mmol/L, P = 0.036). Glycosylated hemoglobin levels were similar for the patients on the three regimens. The percentage of patients who achieved their glycosylated hemoglobin target was significantly higher for the LM25 and LM50 regimens than for the PHI70/30 regimen, regardless of whether the target was set at 7.0% or 6.5%. The proportion of the patients who were hypoglycemic for a high percentage (> 10%) of the time was lower for the LM50 regimen than for the LM25 and PHI70/30 regimens. CONCLUSIONS: LM50 may provide better glycemic excursion control after breakfast and dinner than LM25 in T2DM patients. TRIAL REGISTRATION: http://www.chictr.org.cn # ChiCTR-TTRCC-12002516. FUNDING: Lilly Suzhou Pharmaceutical Co., Ltd. (Shanghai Branch, China) and National Key Program of Clinical Science of China (WBYZ 2011-873). PMID- 29520743 TI - Herpes Zoster and Diabetes Mellitus: A Review. AB - Accumulating evidence suggests that diabetes mellitus (DM) represents an important risk factor for both herpes zoster and post-herpetic neuralgia. Moreover, post-herpetic neuralgia appears to be more severe and persistent in diabetic patients. On the other hand, a novel vaccine against varicella-zoster virus (VZV) was recently introduced in clinical practice. Given the increased risk and severity of herpes zoster infection in patients with DM, this vaccine might be useful in this population. However, there are limited data regarding the efficacy and safety of vaccination against herpes zoster in the diabetic population. The aim of the present review is to discuss the incidence and consequences of herpes zoster infection in DM and to comment on the role of vaccination against VZV in these patients. PMID- 29520744 TI - Investigation of Viral Pathogen Profiles in Some Natural Hosts and Vectors in China. PMID- 29520746 TI - Application and Impact of Run-In Studies for the Evaluation of Statin Efficacy and Safety. PMID- 29520745 TI - Isolation, Characterization, and Phylogenetic Analysis of Two New Crimean-Congo Hemorrhagic Fever Virus Strains from the Northern Region of Xinjiang Province, China. AB - Crimean-Congo hemorrhagic fever (CCHF) caused by the CCHF virus (CCHFV) is a tick borne natural focal disease with a mortality rate of approximately 50%. CCHFV is widely prevalent in Africa, southern Asia, the Middle East, and southeast Europe. CCHF outbreaks have been reported previously in Xinjiang province, China, especially in its southern region. Epidemiological surveys conducted on ticks and animals have revealed the presence of CCHFV strains in ticks, rodents, and infected individuals from cities and counties in southern Xinjiang. Phylogenetic analyses revealed that the Chinese CCHFV strains belong to one genotype, based on complete sequences of the S segments of its negative-stranded RNA genome. The present study reports two new CCHFV strains isolated from Hyalomma asiaticum asiaticum ticks collected from Fukang City and Wujiaqu City in the northern region of Xinjiang. Viral characteristics and their evolutionary relationships were analyzed through metagenomic and reverse-transcription PCR analyses; these analyses indicated that the genotype of both strains was different from that of other Chinese strains. Furthermore, previous reports of CCHFV in Xinjiang were reviewed and phylogenetic analyses were performed. CCHFV was found to prevail in Fukang City in Junggar Basin for more than 20 years, and that Fukang City and Wujiaqu City are considered natural reservoirs of different genotypes of CCHFV strains. Our findings facilitate the understanding of CCHFV distribution in Xinjiang province and provide insights into the evolutionary relationships among Chinese CCHFV strains. PMID- 29520747 TI - Physicians' Perspectives Regarding Prescription Drug Monitoring Program Use Within the Department of Veterans Affairs: a Multi-State Qualitative Study. AB - BACKGROUND: The Department of Veterans Affairs (VA) has implemented robust strategies to monitor prescription opioid dispensing, but these strategies have not accounted for opioids prescribed by non-VA providers. State-based prescription drug monitoring programs (PDMPs) are a potential tool to identify VA patients' receipt of opioids from non-VA prescribers, and recent legislation requires their use within VA. OBJECTIVE: To evaluate VA physicians' perspectives and experiences regarding use of PDMPs to monitor Veterans' receipt of opioids from non-VA prescribers. DESIGN: Qualitative study using semi-structured interviews. PARTICIPANTS: Forty-two VA primary care physicians who prescribed opioids to 15 or more Veterans in 2015. We sampled physicians from two states with PDMPs (Massachusetts and Illinois) and one without prescriber access to a PDMP at the time of the interviews (Pennsylvania). APPROACH: From February to August 2016, we conducted semi-structured telephone interviews that addressed the following topics regarding PDMPs: overall experiences, barriers to optimal use, and facilitators to improve use. KEY RESULTS: VA physicians broadly supported use of PDMPs or desired access to one, while exhibiting varying patterns of PDMP use dictated by state laws and their clinical judgment. Physicians noted administrative burdens and incomplete or unavailable prescribing data as key barriers to PDMP use. To facilitate use, physicians endorsed (1) linking PDMPs with the VA electronic health record, (2) using templated notes to document PDMP use, and (3) delegating routine PDMP queries to ancillary staff. CONCLUSIONS: Despite the time and administrative burdens associated with their use, VA physicians in our study broadly supported PDMPs. The application of our findings to ongoing PDMP implementation efforts may strengthen PDMP use both within and outside VA and improve the safe prescribing of opioids. PMID- 29520748 TI - Do Changes in Post-acute Care Use at Hospitals Participating in an Accountable Care Organization Spillover to All Medicare Beneficiaries? AB - BACKGROUND: While early evidence suggests that Medicare accountable care organizations (ACOs) may reduce post-acute care (PAC) utilization for attributed beneficiaries, whether these effects spill over to all beneficiaries admitted to hospitals participating in ACOs stray is unknown. OBJECTIVE: The objective of this study was to evaluate whether changes in PAC use and Medicare spending spill over to all beneficiaries admitted to hospitals participating in the Medicare Shared Savings Program (MSSP). DESIGN: Observational study using a difference-in differences design comparing changes in PAC utilization and spending among beneficiaries admitted to ACO-participating hospitals before and after the start of the ACO contracts, compared to those admitted to non-ACO hospitals. SETTING: A total of 233 hospitals participate in MSSP ACOs and 3103 non-ACO hospitals. PARTICIPANTS: A national sample of 11,683,573 Medicare beneficiaries experiencing 26,503,086 hospital admissions from 2010 to 2013. EXPOSURE: Admission to a hospital participating in an MSSP ACO. MAIN MEASURES: The probability of discharge and Medicare payments to inpatient rehabilitation facilities (IRF), skilled nursing facilities (SNF), and home health agencies (HHA). KEY RESULTS: For beneficiaries admitted to hospitals that joined an ACO, the likelihood of being discharged to PAC did not change after the hospital joined the ACO compared with non-ACO hospitals over the same period (differential change in probability of discharge to any PAC was 0.000 (P = 0.89), SNF was 0.000 (P = 0.73), IRF was 0.000 (P = 0.96), and HHA was 0.001 (P = 0.57)). Payments reduced significantly for PAC overall (- $130.41, P = 0.03), but not for any individual PAC type alone. These results were consistent in samples that were conditional on discharge to any PAC, across conditions with high PAC use nationally, and among ACO participating hospitals that also had a PAC participant. CONCLUSIONS: Hospital participation in an ACO did not result in spillovers in PAC utilization or payments to all beneficiaries, even when considering high PAC-use conditions and ACO hospitals that also have an ACO-participating PAC. PMID- 29520749 TI - Living in an oasis: Rapid transformations, resilience, and resistance in the North Water Area societies and ecosystems. AB - Based on lake sediment data, archaeological findings, and historical records, we describe rapid transformations, resilience and resistance in societies and ecosystems, and their interactions in the past in the North Water area related to changes in climate and historical events. Examples are the formation of the polynya itself and the early arrival of people, ca. 4500 years ago, and later major human immigrations (different societies, cultural encounters, or abandonment) from other regions in the Arctic. While the early immigrations had relatively modest and localised effect on the ecosystem, the later-incoming culture in the early thirteenth century was marked by extensive migrations into and out of the area and abrupt shifts in hunting technologies. This has had long lasting consequences for the local lake ecosystems. Large natural transformations in the ecosystems have also occurred over relatively short time periods related to changes in the polynya. Finally, we discuss the future perspectives for the North Water area given the many threats, but also opportunities. PMID- 29520750 TI - Life around the North Water ecosystem: Natural and social drivers of change over a millennium. AB - The formation of the North Water in Smith Sound about 4500 years ago, as evidenced by the establishment of bird colonies and human presence, also initiated a long-term anthropogenic agent as part of this High Arctic ecosystem. Different epochs have influenced the human occupation in the area: immigration pulses from Canada and Alaska, trade with meteorite iron throughout the Arctic, introduction of new technologies by whalers and explorers, exploitation of resources by foreigners, political sequestration, export of fox and seal skins and later narwhal products, and recently fishing. Physical drivers in terms of weather and climate affecting the northern hemisphere also impact accessibility and productivity of the ecosystem, with cascading effects on social drivers, again acting back on the natural ecologies. Despite its apparent isolation, the ecosystem had and still has wide ranging spatial ramifications that extend beyond the High Arctic, and include human activity. The challenge is to determine what is internal and what is external to an ecosystem. PMID- 29520751 TI - Present and past dynamics of Inughuit resource spaces. AB - Information from a collaborative GPS tracking project, Piniariarneq, involving 17 occupational hunters from Qaanaaq and Savissivik, Northwest Greenland, is used to explore the resource spaces of hunters in Avanersuaq today. By comparison with historical records from the time of the Thule Trading Station and the decades following its closure, we reveal a marked variability in resource spaces over time. It is argued that the dynamics of resources and resource spaces in Thule are not underlain by animal distribution and migration patterns, or changes in weather and sea ice conditions alone; but also by economic opportunities, human mobility, settlement patterns, particular historical events and trajectories, and not least by economic and political interests developed outside the region. PMID- 29520752 TI - Evaluation of Bevacizumab for the Treatment of Epidural Fibrosis by Immunohistochemical Staining for CD105 and Osteopontin. AB - AIM: To evaluate bevacizumab for epidural fibrosis (EF) treatment in an experimental rat model using histopathology as well as immunohistochemical staining for CD105 and osteopontin (OPN). MATERIAL AND METHODS: Sixteen Wistar Albino rats underwent either laminectomy alone to induce EF (group I, control) or laminectomy plus local bevacizumab treatment (group II). The degree of EF was compared between groups using the current histopathological grading method as well as immunohistochemistry for CD105 and OPN. In addition, the consistency of EF staging using CD105 and OPN expression was compared to that using histopathology. RESULTS: The grade of EF was significantly lower in group II than in group I based on the fibroblast count and fibrosis density determined using histopathology, as well as by CD105 expression determined using immunohistochemistry. In contrast, OPN expression was not a reliable marker for EF evaluation because it did not show a significant difference between the two groups. CONCLUSION: Bevacizumab prevents EF development as assessed using both histopathology and CD105 expression. CD105 is a potentially reliable marker for the immunohistochemical grading of EF, in contrast to OPN. PMID- 29520753 TI - The Partners for Change Outcome Management System: A Both/And System for Collaborative Practice. AB - Systematic client feedback (SCF) is increasingly employed in mental health services worldwide. While research supports its efficacy over treatment as usual, clinicians, especially those who highly value relational practices, may be concerned that routine data collection detracts from clinical process. This article describes one SCF system, the Partners for Change Outcome Management System (PCOMS), along a normative (standardized measurement) to communicative (conversational) continuum, highlighting PCOMS' origins in everyday clinical practice. The authors contend that PCOMS represents "both/and," providing a valid signal of client progress while facilitating communicative process particularly prized by family therapists steeped in relational traditions. The article discusses application of PCOMS in systemic practice and describes how it actualizes time-honored family therapy approaches. The importance of giving voice to individualized client experience is emphasized. PMID- 29520754 TI - Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease. AB - Distinguishing autosomal-dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture-based next-generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD. Through our analysis, 32 patients had PKD1 or PKD2 mutations. Additionally, 3 patients with disease-causing mutations in NPHP4, PKHD1, and OFD1 were diagnosed with an inherited renal cystic disease other than ADPKD. In patients with PKD1 or PKD2 mutations, the prevalence of polycystic liver disease, defined as more than 20 liver cysts, was significantly higher (71.9% vs 33.3%, P = .006), total kidney volume was significantly increased (median, 1580.7 mL vs 791.0 mL, P = .027) and mean arterial pressure was significantly higher (median, 98 mm Hg vs 91 mm Hg, P = .012). The genetic screening approach and clinical features described here are potentially beneficial for optimal management of adult sporadic polycystic kidney disease patients. PMID- 29520755 TI - A Typology of Interactional Patterns Between Youth and Their Stepfathers: Associations with Family Relationship Quality and Youth Well-Being. AB - Stepfamilies are an increasingly common family form, many of which are headed by a resident mother and stepfather. Stepfather-child relationships exert notable influence on stepfamily stability and individual well-being. Although various stepfather roles have been observed, more research is warranted by which stepfather-child interactions are explored holistically and across a variety of life domains (e.g., recreational, personal, academic, and disciplinary). Thus, the primary purpose of the current study is to explore varying interactional patterns between youth and their stepfathers. A latent class analysis is conducted using a representative sample of 1,183 youth (53% female; mean age = 15.64 years, SD = 1.70 years; 62% non-Hispanic White) residing in mother stepfather families from Wave I of the National Longitudinal Study of Adolescent to Adult Health. Latent-class enumeration processes support a four-class solution, with latent classes representing inactive, academically oriented, casually connected, and versatile and involved patterns of youth-stepparent interaction. Notable differences and similarities are evident across patterns with respect to family relationship quality, youth well-being, and socio demographic characteristics. Differences are most stark between the inactive and versatile and involved patterns. Ultimately, the results showcase notable variation in youth-stepparent interactional patterns, and one size does not necessarily fit all stepfamilies. Family practitioners should be mindful of variation in youth-stepparent interactional patterns and assist stepfamilies in seeking out stepparent-child dynamics that are most compatible with the needs and dynamics of the larger family system. PMID- 29520756 TI - Pressure- and heat-induced protein unfolding in bacterial cells: crowding vs. sticking. AB - In-cell protein stability is increased by crowding, but can be reduced by destabilizing surface interactions. Will different denaturation techniques yield similar trends? Here, we apply pressure and thermal denaturation to green fluorescent protein/ReAsH-labeled yeast phosphoglycerate kinase (PGK) in Escherichia coli cells. Pressure denaturation is more two state-like in E. coli than in vitro, stabilizing the native state. Thermal denaturation destabilizes PGK in E. coli, unlike in mammalian cells. Results in wild-type MG1655 strain are corroborated in pressure-resistant J1 strain, where PGK is less prone to aggregation. Thus, destabilizing surface interactions overcome stabilizing crowding in the E. coli cytoplasm under thermal denaturation, but not under pressure denaturation. PMID- 29520757 TI - Proton pump inhibitor medication is associated with colonisation of gut flora in the oropharynx. AB - BACKGROUND: The normal body exists in mutualistic balance with a large range of microbiota. The primary goal of this study was to establish whether there is an imbalance in the oropharyngeal flora early after hospital or ICU admittance, and whether flora differs between control, ward and critically ill patients. The secondary goal was to explore whether there are patient characteristics that can be associated with a disturbed oropharyngeal flora. METHODS: Oropharyngeal cultures were obtained from three different study groups: (1) controls from the community, (2) ward patients and (3) critically ill patients, the two latter within 24 h after admittance. RESULTS: Cultures were obtained from 487 individuals: 77 controls, 193 ward patients and 217 critically ill patients. Abnormal pharyngeal flora was more frequent in critically ill and ward patients compared with controls (62.2% and 10.4% vs. 1.3%, P < 0.001 and P = 0.010, respectively). Colonisation of gut flora in the oropharynx was more frequent in critically ill patients compared with ward patients or controls (26.3% vs. 4.7% and 1.3%, P < 0.001 and P < 0.001, respectively). Proton pump inhibitor medication was the strongest independent factor associated with the presence of gut flora in the oropharynx in both ward and critically ill patients (P = 0.030 and P = 0.044, respectively). CONCLUSION: This study indicates that abnormal oropharyngeal flora is an early and frequent event in hospitalised patients and more so in the critically ill, compared to controls. Proton pump inhibitor medication is associated with colonisation of gut flora in the oropharynx. PMID- 29520758 TI - Digest: Effects of spatially-spreading adaptive mutations on genome-wide diversity. PMID- 29520759 TI - Empirical metronidazole for patients with severe bacterial infection: protocol for a systematic review. AB - INTRODUCTION: Anaerobic bacteria are believed to be common pathogens in severe infections. Yet, they are difficult to culture and consequently often unrecognised in clinical infections. Metronidazole is often used empirically for potential anaerobic infections, as the resistance to metronidazole is low. However, disadvantages of metronidazole use exist, including drug interactions, side effects and economical expenses. Currently, the balance between the benefits and harms of empirical metronidazole for severe bacterial infections is unknown. We aim to assess patient-important benefits and harms of empirical metronidazole vs. placebo or no treatment in adult patients with severe bacterial infection of any origin in a systematic review of randomised clinical trials with meta analysis and trial sequential analysis. METHODS AND ANALYSIS: This protocol provides details on the planned systematic review, which will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA) statement, the Cochrane Handbook, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. The primary outcome is all-cause mortality. Secondary outcomes include adverse events, secondary infections, use of life support, antibiotic resistance and hospital length of stay. We will conduct conventional meta-analyses, including predefined subgroup- and sensitivity analyses. Additionally, we will assess the risk of random errors by trial sequential analysis. ETHICS AND DISSEMINATION: Ethical approval is not needed, as the outlined review exclusively will include previously published data. We aim to publish in an international, peer-reviewed journal. PMID- 29520760 TI - Miscarriage induced by adoptive transfer of dendritic cells and invariant natural killer T cells into mice. AB - Unexpected fetal loss is one of the common complications of pregnancy; however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC-205+ dendritic cells (DCs) and NK1.1+ invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of alpha-galactosylceramide (alpha-GalCer). Here we demonstrate that the adoptive transfer of DEC-205+ bone marrow-derived DCs cocultured with alpha-GalCer (DEC-205+ BMDCs-c/w-alpha-GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (?) * BALB/c (?)), which was accompanied by the accumulation of activated iNKT cells in the myometrium. Further, the adoptive transfer of NK1.1+ iNKT cells obtained from B6 mice injected with alpha-GalCer facilitated miscarriages in syngeneic Jalpha18(-/ ) (iNKT cell-deficient) mice. These results suggest that DEC-205+ DCs and NK1.1+ iNKT cells play crucial roles required for the initiation of fetal loss associated with stimulation by glycolipid antigens and sterile inflammation. PMID- 29520761 TI - Mapping Aquifer Systems with Airborne Electromagnetics in the Central Valley of California. AB - The passage of the Sustainable Groundwater Management Act in California has highlighted a need for cost-effective ways to acquire the data used in building conceptual models of the aquifer systems in the Central Valley of California. One approach would be the regional implementation of the airborne electromagnetic (AEM) method. We acquired 104 line-kilometers of data in the Tulare Irrigation District, in the Central Valley, to determine the depth of investigation (DOI) of the AEM method, given the abundance of electrically conductive clays, and to assess the usefulness of the method for mapping the hydrostratigraphy. The data were high quality providing, through inversion of the data, models displaying the variation in electrical resistivity to a depth of approximately 500 m. In order to transform the resistivity models to interpreted sections displaying lithology, we established the relationship between resistivity and lithology using collocated lithology logs (from drillers' logs) and AEM data. We modeled the AEM response and employed a bootstrapping approach to solve for the range of values in the resistivity model corresponding to sand and gravel, mixed coarse and fine, and clay in the unsaturated and saturated regions. The comparison between the resulting interpretation and an existing cross section demonstrates that AEM can be an effective method for mapping the large-scale hydrostratigraphy of aquifer systems in the Central Valley. The methods employed and developed in this study have widespread application in the use of the AEM method for groundwater management in similar geologic settings. PMID- 29520762 TI - Cooperation of Sall4 and Sox8 transcription factors in the regulation of the chicken Sox3 gene during otic placode development. AB - To elucidate the transcriptional regulation that underlies specification of the otic placode, we investigated the Sox3 downstream enhancer Otic1 of the chicken, the activity of which is restricted to and distributed across the entire otic placode. The 181-bp Otic1 enhancer sequence was dissected into a 68-bp minimal activating sequence, which exhibited dimer enhancer activity in the otic placode and cephalic neural crest, and this was further reduced to a 25-bp Otic1 core sequence, which also showed octamer enhancer activity in the same regions. The Otic1 core octamer was activated by the combined action of Sall4 and the SoxE transcription factors (TFs) Sox8 or Sox9. Binding of Sall4, Sox8 and Sox9 to the Otic1 sequence in embryonic tissues was confirmed by ChIP-qPCR analysis. The core adjoining 3' side sequences of Otic1 augmented its enhancer activity, while inclusion of the CAGGTG sequence in the immediate 3' end of the 68-bp sequence repressed its enhancer activity outside the otic placode. The CAGGTG sequence likely serves as the binding sites of the repressor TFs deltaEF1 (Zeb1), Sip1 (Zeb2), and Snail2, all of which are expressed in the cephalic neural crest but not in the otic placode. Therefore, the combination of Sall4-Sox8-dependent activation and CAGGTG sequence-dependent repression determines otic placode development. Although the Otic1 sequence is not conserved in mammals or fishes, the activation mechanism is, as Otic1 was also activated in otic placode tissues developed from mouse embryonic stem cells and transient transgenic zebrafish embryos. PMID- 29520763 TI - The challenge of ambulance missions to patients not in need of emergency medical care. PMID- 29520764 TI - Systematic Review and Meta-analysis of Stepping Stones Triple P for Parents of Children with Disabilities. AB - The aim of this systematic review and meta-analysis was to examine the effectiveness of Stepping Stones Triple P (SSTP) parent training programs on child behavior problems and parenting outcomes in families of children with developmental disabilities. Sixteen suitable studies including data from over 900 families were identified in a search for English language published and unpublished controlled outcome studies. SSTP has five levels on a graded continuum of increasing intensity targeting families with differing degrees of treatment need from low intensity media-based parenting information campaigns at level 1, through brief interventions at levels 2 and 3, to more intensive parent training and family therapy interventions at levels 4 and 5. Analyses were conducted on the combination of all levels of SSTP and separately for each level. For combined levels, significant overall effect sizes were found for parent reported child problems (d = 0.46), researcher observed child behavior (d = 0.51), parenting style (d = 0.70), parenting satisfaction/self-efficacy (d = 0.44), parental adjustment (d = 0.27), and coparental relationship (d = 0.26), but not researcher-observed parent behavior. Strong support was found for level 4 SSTP as an effective intervention for improving child and parent outcomes in families of children with disabilities who have clinically significant problems. Less intensive SSTP interventions for cases with circumscribed difficulties yielded fewer significant treatment effects, and there were relatively few studies of such interventions. PMID- 29520765 TI - Factors Associated With Medication-Overuse Headache in Patients Seeking Treatment for Primary Headache. AB - BACKGROUND: Although risk factors for medication-overuse headache have been identified within the general population, most studies have neglected clinical samples. The present study examined the relative and combined associations of these factors with medication-overuse headache in a sample of US adults seeking treatment for primary headache disorders. METHODS: Treatment-seeking headache patients provided data on demographics, headache variables, psychiatric variables, use of headache medications, and use of other prescription medications and substances. A classification tree selection strategy was utilized within this cross-sectional study to differentiate between those with and without medication overuse headache, and a final multivariable model assessed their combined utility. RESULTS: Forty-three of 164 participants (26.2%) met diagnostic criteria for medication-overuse headache. Relative to non-medication-overuse headache participants, participants with medication-overuse headache reported greater headache-related disability (odds ratio = 1.09, 95% confidence interval = 1.01 1.18), escape and avoidance responses indicative of fear of pain (odds ratio = 1.07, 95% confidence interval = 1.00-1.15), and use of combination medications for headache (odds ratio = 3.10, 95% confidence interval = 1.51-6.36). The final multivariable model differentiated well between the 2 groups (area under the receiver operating characteristic curve = .78; 95% confidence interval = .71 .86). CONCLUSIONS: Items that assess headache-related disability, use of combination medications, and fear of pain help identify patients who are currently overusing acute headache medications and may serve as indicators of treatment progress. Future studies should apply similar analytic approaches longitudinally to identify headache sufferers at risk for medication-overuse headache prior to headache progression. PMID- 29520766 TI - A novel IKBKG mutation in a patient with incontinentia pigmenti and features of hepatic ciliopathy. AB - We describe a new mutation in exon 4 of IKBKG, encoding nuclear factor-kappa B in a patient with incontinentia pigmenti. The patient had a severe cholestatic liver disease with features of a ciliopathy and underwent liver transplantation. We cannot establish a link between incontinentia pigmenti, a very rare disease, and hepatic ciliopathy, but we suggest that hepatic evaluation should be considered in patients with incontinentia pigmenti. PMID- 29520767 TI - High mobility group box transcription factor 1 (HBP1) from Lampetra japonica affects cell cycle regulation. AB - High mobility group (HMG) box-containing protein 1 (HBP1) is a member of the HMG family of chromosomal proteins. Previous studies have shown that human HBP1 exhibits tumor-suppressor activity. Here, we identified a homologue of HBP1, L hbp1, in Lampetra japonica. The L-hbp1 gene shared high sequence similarity with its homologues in jawed vertebrates, as shown by bioinformatics analyses. L-hbp1 contains a 1,584-bp open reading frame that encodes 527 amino acids. A pAdenox-L HBP1 plasmid was constructed and transfected successfully in Raji cells, as revealed by real-time PCR. The overexpression of L-HBP1 reduced cell growth rates, inhibited G1 phase progression, decreased cyclin D1 and c-Myc protein expression, and increased p53 protein expression. Western blot and immunohistochemical assays showed that L-HBP1 was primarily distributed in the heart, kidney, gill and liver of lamprey. Cell cycle analysis revealed that decreased L-HBP1 expression in HBP1 morpholino oligonucleotide-transfected lamprey cells resulted in a decreased fraction of cells in the G1 phase and corresponding increases in the S and G2/M phases. Additionally, treatment of lamprey cardiac cells with pharmacological inhibitors of p38 MAP kinase released the cells from G1 arrest. Together, these results indicated that HBP1 expression in lamprey was correlated with the onset of mitotic arrest in these cells, which have implications for cell cycle regulation. PMID- 29520768 TI - Tailor-made computational protocols for precise characterization of small biological building blocks using QM and MM approaches. AB - Computational modeling involving Quantum Mechanics (QM) and Molecular Mechanics (MM) calculations are widely utilized to unveil the atomic-molecular properties that underpin their inherent characteristic features. The choice over the either of the QM and MM methods or a multiscale composite approach is driven by the target property of interest, and of course, the molecular size. Often, tailor made schemes need to be devised to match the specific study purpose. Herein, we provide a perspective of these approaches addressing their effectiveness in terms of the delicate balance between the accuracy and computational feasibility. We focus on representative examples to highlight how different approaches can be fruitfully exploited for modeling the conformational landscape, and possibly, the spectroscopic behavior of biochemical molecules, especially amino acids building blocks. PMID- 29520769 TI - The role of menopause on the relationship between metabolic risk factors and periodontal disease via salivary oxidative parameters. AB - BACKGROUND: Periodontal disease is shown to be aggravated by an increase in the count of metabolic risk factors. This study aims to evaluate the effects of metabolic risk factors on periodontal parameters and salivary oxidative stress markers related to menopausal status. METHODS: One hundred and seventy-six women were categorized according to menopausal status, either premenopause (Pre/M) (n = 86) or postmenopause (Post/M) (n = 90). The count of metabolic risk factors was evaluated. Sociodemographics and systemic status were determined via questionnaire and medical records. After clinical periodontal measurements and saliva collection, myeloperoxidase (MPO), total oxidant status (TOS) and total antioxidant capacity (TAOC) were determined by enzyme-linked immunosorbent assay and automatic colorimetric method. Oxidative stress index (OSI) was also calculated. RESULTS: The count of metabolic risk factors was higher in the Post/M group than the Pre/M group. Periodontal parameters and TOS levels were elevated by an increase in the count of metabolic risk factors. Multivariate regression analyses revealed that periodontal (clinical attachment level and missed teeth) and oxidative (MPO and OSI) parameters increased and TAOC levels decreased due to menopause. Additionally, positive relationships between periodontal and oxidative parameters were determined. CONCLUSION: These findings suggest that salivary oxidative stress level may be an indicator of worsened periodontal status related to menopause and the count of metabolic risk factors. PMID- 29520770 TI - A three-phase excess post-exercise oxygen consumption in Atlantic salmon Salmo salar and its response to exercise training. AB - The recovery of oxygen uptake to the standard metabolic rate (SMR) following exhaustive chasing exercise in Atlantic salmon Salmo salar parr occurred in three phases (rapid, plateau and slow). The initial recovery phase lasted 0.7 h and contributed 16% to the total excess post-exercise oxygen consumption (EPOC). It was followed by a longer plateau phase that contributed 53% to the total EPOC. The slow recovery phase that completed recovery of SMR, which has not been reported previously, made a 31% contribution to the total EPOC. The plasticity of EPOC was demonstrated in exercise-trained fish. Exercise training increased EPOC by 39% when compared with control fish (mean +/- S.E., 877.7 +/- 73.1 v. 629.2 +/ 53.4 mg O2 kg-1 , d.f. = 9, P < 0.05), with the duration of the plateau phase increasing by 38% (4.7 +/- 0.58 v. 3.4 +/- 0.16 h, d.f. = 9, P < 0.05) and the contribution of the slow phase to the total EPOC increasing by 80% (173.9 +/- 23.9 v. 312.5 +/- 50.4 mg O2 kg-1 , d.f. = 9, P < 0.05). As a result, the combination of the plateau and slow phases of exercise-trained fish increased by 47% compared with control fish (756.6 +/- 71.4 v. 513.6 +/- 43.1 mg O2 kg-1 ; d.f. = 9, P = 0.01). To substantiate the hypothesis that the plateau and slow recovery phase of EPOC was related to general metabolic recovery following exhaustive exercise, the time-course for recovery of SMR was compared with previously published metabolite recovery profiles. The final phase of metabolic recovery was temporally associated with the final phases of gluconeogenesis, lactate oxidation and muscle intracellular pH regulation. Therefore, the plasticity of the latter phase of EPOC agreed with the known effects of exercise training in fishes. PMID- 29520772 TI - The effect of twice daily kiwifruit consumption on periodontal and systemic conditions before and after treatment: A randomized clinical trial. AB - BACKGROUND: To assess the nutraceutical effects of twice/daily intake of kiwifruit on periodontal parameters and systemic health before and after initial periodontal treatment (IPT). METHODS: At baseline, participants were randomly assigned to test and control group, and either consumed two kiwifruits/day for 5 months or no kiwifruit. In the first 2 months, no periodontal treatment was delivered (2 M). Subsequently, a session of full-mouth IPT within 24 hours was performed. Participants were then re-assessed after 3 months (5 M). Blood samples, evaluating systemic biomarkers and vital signs, were also collected atbaseline, 2 M, and 5 M. RESULTS: Groups were balanced at baseline. At 2 M no within-groups differences could be detected for any parameter but the bleeding score, which decreased significantly in the kiwifruit group by 6.67% +/- 11.90% (P < 0.01). Comparison of test and control group showed that 2 months of kiwifruit consumption resulted in significant lower values of bleeding, plaque, and attachment loss. After IPT both groups demonstrated substantial significant clinical benefits however the control group showed significant greater reductions of bleeding, plaque and attachment loss than the test group. Systemic biomarkers and vital signs did not show clinically relevant differences between test and control group. CONCLUSIONS: Kiwifruit consumption reduces gingival inflammation despite the lack of any periodontal instrumentation or patient's behavioral changes. No adjunctive effect to periodontal treatment of dietary intake of kiwifruit was noted. (NCT NCT03084484). PMID- 29520773 TI - Phylogenetic patterns and correlation of key structures for jumping: bone crests and cross-sectional areas of muscles in Leptodactylus (Anura, Leptodactylidae). AB - Anurans are characterized by their saltatory mode of locomotion, which is associated with a specific morphology. The coordinated action of the muscles and bones of the pelvic girdle is key to the transmission of the force of the hindlimbs to the axial skeleton during jumping. Two features are critical for optimal locomotory performance: the cross-sectional area of muscle and the bone crest attachment sites. The first character is a proxy of the force exerted by the muscle, whereas the crests are muscle attachments sites related to muscle force. The provisory relationship between these features has previously been identified and bone crest size can be used to infer the magnitude and, therefore, muscle force in fossils records. In this work, we explore the correlation between the cross-sectional area of essential muscles to the jumping mechanism (longissimus dorsi, extensor iliotibialis B, tenuissimus, puboischiofemoralis internus B, coccygeo-sacralis and coccygeo-iliacus) and the bone crests where these muscles are inserted (dorsal tubercle, dorsal crest and urostylar crest) in species of the genus Leptodactylus. This genus, along with other leptodactylids, exhibits a diversity of locomotor modes, including jumping, hopping, swimming and burrowing. We therefore analyzed the morphometric variation in the two features, cross-sectional area and bone crest area, expecting a correlation with different locomotor types. Our results showed: (i) a correlation between the urostylar crest and the cross-sectional area of the related muscles; (ii) that the bone crest surface area of urostyle and ilium and the cross-sectional area of the corresponding muscles can be utilized to infer locomotor faculties in leptodactylid frogs; and (iii) that the evolution of both characters demonstrates a general tendency from lower values in leptodactylid ancestors to higher values in the Leptodactylus genus. The results attest to the importance of the comparison of current ecological and phylogenetic analogues as they allow us to infer functionality and behavior in fossil and extant groups based on skeletal evidence. Phylogenetic patterns in character evolution and their correlation with locomotory types could imply that functional restrictions are also inherited in leptodactylid. PMID- 29520771 TI - Thalamostriatal and cerebellothalamic pathways in a songbird, the Bengalese finch. AB - The thalamostriatal system is a major network in the mammalian brain, originating principally from the intralaminar nuclei of thalamus. Its functions remain unclear, but a subset of these projections provides a pathway through which the cerebellum communicates with the basal ganglia. Both the cerebellum and basal ganglia play crucial roles in motor control. Although songbirds have yielded key insights into the neural basis of vocal learning, it is unknown whether a thalamostriatal system exists in the songbird brain. Thalamic nucleus DLM is an important part of the song system, the network of nuclei required for learning and producing song. DLM receives output from song system basal ganglia nucleus Area X and sits within dorsal thalamus, the proposed avian homolog of the mammalian intralaminar nuclei that also receives projections from the cerebellar nuclei. Using a viral vector that specifically labels presynaptic axon segments, we show in Bengalese finches that dorsal thalamus projects to Area X, the basal ganglia nucleus of the song system, and to surrounding medial striatum. To identify the sources of thalamic input to Area X, we map DLM and cerebellar recipient dorsal thalamus (DTCbN ). Surprisingly, we find both DLM and dorsal anterior DTCbN adjacent to DLM project to Area X. In contrast, the ventral medial subregion of DTCbN projects to medial striatum outside Area X. Our results suggest the basal ganglia in the song system, like the mammalian basal ganglia, integrate feedback from the thalamic region to which they project as well as thalamic regions that receive cerebellar output. PMID- 29520774 TI - Serum, salivary, and tissue levels of plasminogen in familial Mediterranean fever, amyloidosis, and chronic periodontitis. AB - BACKGROUND: There are no published studies regarding the role of the plasminogen (PLG) system in familial Mediterranean fever (FMF), FMF-associated secondary amyloidosis, or chronic periodontitis (CP), although recent limited data have focused on the association between FMF and chronic periodontitis. Therefore, the aim of this study was to evaluate the serum, salivary, and gingival tissue levels of PLG in patients with CP, FMF, and amyloidosis. METHODS: The study population included 122 patients with FMF (only FMF, and FMF and amyloidosis and 128 individuals who were systemically healthy controls. Blood and salivary samples were obtained from the cases and controls, and clinical periodontal parameters were recorded. Serum and salivary PLG levels were assessed. The gingival tissue samples of the case and control groups were analyzed histopathologically and immunohistochemically for amyloid deposition and PLG. RESULTS: The amyloidosis group had significantly more severe clinical periodontal parameters than those of the FMF and systemically healthy groups (P < 0.05). Salivary levels of PLG were significantly higher in the FMF and amyloidosis groups compared with those in the control group (P < 0.001). The FMF with periodontitis and amyloidosis with periodontitis groups had higher salivary PLG levels compared with those in the CP group. Serum and salivary PLG levels were significantly associated with the clinical periodontal parameters in the FMF group. The amyloidosis cases had hyperplasia, severe inflammation, and activation of the gingiva. CONCLUSION: The PLG system could play an important role in inflammatory diseases, such as chronic periodontitis, FMF, and FMF-associated secondary amyloidosis. PMID- 29520775 TI - The koniocellular whiteboard. AB - In 1994 Vivien Casagrande published a review paper in which she summarized evidence for a koniocellular pathway to visual cortex. Here we try to explain how that review moved the field forward, and summarize some key unanswered questions about koniocellular pathways. PMID- 29520777 TI - Association between the number of teeth and hypertension in a study based on 13,561 participants. AB - BACKGROUND: No studies have reported the association between the number of teeth and hypertension in the Korean national data. The purpose of this study was to investigate whether the number of teeth is associated with blood pressure and hypertension in a representative sample of the Korean population. METHODS: A cross-sectional study was conducted on 13,561 participants aged >=19 years using the 2012 to 2014 Korea National Health and Nutrition Examination Survey data. The number of teeth was divided into four groups: 0, 1 to 19, 20 to -27, and 28. The definition of hypertension was systolic blood pressure >=140 mm Hg or diastolic blood pressure >=90 mm Hg or being medicated for hypertension. Multivariate logistic regression analyses were performed after controlling for age, sex, income, education, smoking, drinking, diabetes mellitus, obesity, and hypercholesterolemia. Age- and sex-stratified analyses were performed. RESULTS: The fully adjusted odds ratios (AOR) of the number of teeth group for hypertension were as follows: AOR: 1.25, 95% CI: 1.11 to 1.43 for 20 to 27 teeth; AOR: 1.46, 95% CI: 1.22 to 1.76; 1 to 19 teeth; and AOR: 1.63, 95% CI: 1.22 to 2.18 for edentulism. The strength of the association was highest in women aged >=60 years across all age and sex groups (OR = 1.81, 95% CI = 1.15 to 2.86). CONCLUSION: Findings suggest that a decrease in the number of teeth may be independently associated with hypertension in the Korean population. PMID- 29520776 TI - Interpreting the three-dimensional orientation of vascular canals and cross sectional geometry of cortical bone in birds and bats. AB - Cortical bone porosity and specifically the orientation of vascular canals is an area of growing interest in biomedical research and comparative/paleontological anatomy. The potential to explain microstructural adaptation is of great interest. However, the determinants of the development of canal orientation remain unclear. Previous studies of birds have shown higher proportions of circumferential canals (called laminarity) in flight bones than in hindlimb bones, and interpreted this as a sign that circumferential canals are a feature for resistance to the torsional loading created by flight. We defined the laminarity index as the percentage of circumferential canal length out of the total canal length. In this study we examined the vascular canal network in the humerus and femur of a sample of 31 bird and 24 bat species using synchrotron micro-computed tomography (micro-CT) to look for a connection between canal orientation and functional loading. The use of micro-CT provides a full three dimensional (3D) map of the vascular canal network and provides measurements of the 3D orientation of each canal in the whole cross-section of the bone cortex. We measured several cross-sectional geometric parameters and strength indices including principal and polar area moments of inertia, principal and polar section moduli, circularity, buckling ratio, and a weighted cortical thickness index. We found that bat cortices are relatively thicker and poorly vascularized, whereas those of birds are thinner and more highly vascularized, and that according to our cross-sectional geometric parameters, bird bones have a greater resistance to torsional stress than the bats; in particular, the humerus in birds is more adapted to resist torsional stresses than the femur. Our results show that birds have a significantly (P = 0.031) higher laminarity index than bats, with birds having a mean laminarity index of 0.183 in the humerus and 0.232 in the femur, and bats having a mean laminarity index of 0.118 in the humerus and 0.119 in the femur. Counter to our expectation, the birds had a significantly higher laminarity index in the femur than in the humerus (P = 0.035). To evaluate whether this discrepancy was a consequence of methodology we conducted a comparison between our 3D method and an analogue to two-dimensional (2D) histological measurements. This comparison revealed that 2D methods significantly underestimate (P < 0.001) the amount of longitudinal canals by an average of 20% and significantly overestimate (P < 0.001) the laminarity index by an average of 7.7%, systematically mis-estimating indices of vascular canal orientations. In comparison with our 3D results, our approximated 2D measurement had the same results for comparisons between the birds and bats but found significant differences only in the longitudinal index between the humerus and the femur for both groups. The differences between our 3D and pseudo-2D results indicate that differences between our findings and the literature may be partially based in methodology. Overall, our results do not support the hypothesis that the bones of flight are more laminar, suggesting a complex relation between functional loading and microstructural adaptation. PMID- 29520778 TI - Chronic periodontitis and oral health-related quality of life in Chinese adults: A population-based, cross-sectional study. AB - BACKGROUND: This population-based, cross-sectional study explored the association between chronic periodontitis and oral health-related quality of life (OHRQoL) in Chinese adults, independently of sociodemographic factors and other common oral conditions. METHODS: The present study was carried out in a sample population of 480 adults aged 35 to 74 years from Chongqing municipality. A multi-stage stratified random sampling approach was adopted to select participants. The Chinese version of the short-form oral health impact profile (OHIP-14) was used to assess OHRQoL. Chronic periodontitis was trichotomized into mild, moderate, and severe periodontitis. Logistic regression models were adopted to explore the association between the severity of chronic periodontitis and OHIP-14 scores. RESULTS: After adjustment for sociodemographic factors and other common clinical conditions, participants with severe and moderate chronic periodontitis, respectively, had 1.63- (95% CI: 1.41 to 1.98) and 1.42-fold (95% CI: 1.29 to 1.63) higher odds for the OHIP-14 scores being above the median compared with participants without chronic periodontitis. However, participants with mild periodontitis did not have significantly higher odds for the OHIP-14 scores being above the median than participants without chronic periodontitis. Certain sociodemographic variables, including higher age, lower education level, number of missing teeth, and current smoker, had negative associations with OHRQoL. CONCLUSIONS: Chronic periodontitis was associated with poorer OHRQoL in Chinese adults. In addition, the impairment in OHRQoL showed a significant correlation with the severity of chronic periodontitis. PMID- 29520779 TI - Influence of periodontitis and scaling and root planing on insulin resistance and hepatic CD36 in obese rats. AB - BACKGROUND: The aim of the study was to explore the influence of periodontitis and scaling and root planing (SRP) on insulin resistance and hepatic CD36 in obese rats with periodontitis. METHODS: Thirty-two specific pathogen free Sprague Dawley rats were randomly divided into four groups of eight animals each as follows: healthy rats (healthy group), obese rats (obesity group), obese rats with periodontitis (non-therapy group), and obese rats with periodontitis who underwent periodontal SRP (therapy group). Rats were fed with a high-fat diet for 16 weeks to build an obesity model. Periodontal inflammation was induced by performing periodontal ligation with Porphyromonas gingivalis. The tissue around the maxillary second molars, bilaterally, were collected. The periodontal attachment level (from the cemento-enamel junction to the bottom of the periodontal pocket) of the second molars was measured in all groups. All rats were subjected to fasting blood glucose, insulin, and serum C-reactive protein tests (CRP). Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR), oral glucose tolerance test (OGTT), and area under the curve (AUC). The liver was excised to detect intrahepatic free fatty acid (FFA) levels and pathologic observation. Real-time quantification PCR, western blot, and immunohistochemistry were applied to detect hepatic CD36 expression. RESULTS: Compared with the obesity group, HOMA-IR, AUC, intrahepatic FFA, and protein expression, and mRNA levels of hepatic CD36 in the non-therapy group were significantly increased (P < 0.05). HOMA-IR, AUC, CRP, protein expression, and mRNA levels of hepatic CD36 were all significantly decreased (P < 0.05) 2-weeks after SRP. CONCLUSIONS: Periodontitis increases insulin resistance while scaling and root planning could improve insulin resistance. Hepatic CD36 regulation may be considered a potential mechanism for this phenomenon. PMID- 29520781 TI - Effects of d-valine on periodontal or peri-implant pathogens: Porphyromonas gingivalis biofilm. AB - BACKGROUND: When presented with a surface or an interface, bacteria often grow as biofilms in which cells are held together by an extracellular matrix. Biofilm formation on implants is an initiating factor for their failure. Porphyromonas gingivalis is the primary etiologic bacteria of initiation and progression of periodontal disease. This microorganism is also the risk factor of many systemic diseases, such as cardiovascular disease, diabetes, and pulmonary infection. To date, no medication that can remove such biofilm has been accepted for clinical use. D-valine (D-val) can reportedly inhibit the formation of biofilm and/or trigger the scattering of mature biofilm. Accordingly, this study investigated the effects of d-val on single-species P. gingivalis biofilms in vitro. METHODS: P. gingivalis grown in brain heart infusion culture with or without d-val was inoculated in 24- or 96-well plates. After incubation for 72 hours, biomass via crystal violet staining, extracellular polysaccharide production by biofilms, and scanning electron microscopy (SEM) were used to determine the d-val concentration that can effectively prevent P. gingivalis biofilm formation. RESULTS: Experimental results showed that d-val effectively inhibited biofilm formation at concentrations >=50 mM (mMol/L), and that d-val inhibition increased with increased concentration. Moreover, at high concentrations, the bacterial form changed from the normal baseball form into a rodlike shape. d-val also notably affected extracellular polysaccharide production by P. gingivalis. CONCLUSIONS: d val can inhibit P. gingivalis biofilm formation, and high concentrations can affect bacterial morphology. PMID- 29520780 TI - Molecular anatomy of the alligator dorsal telencephalon. AB - The evolutionary relationships of the mammalian neocortex and avian dorsal telencephalon (DT) nuclei have been debated for more than a century. Despite their central importance to this debate, nonavian reptiles remain underexplored with modern molecular techniques. Reptile studies harbor great potential for understanding the changes in DT organization that occurred in the early evolution of amniotes. They may also help clarify the specializations in the avian DT, which comprises a massive, cell-dense dorsal ventricular ridge (DVR) and a nuclear dorsal-most structure, the Wulst. Crocodilians are phylogenetically and anatomically attractive for DT comparative studies: they are the closest living relatives of birds and have a strikingly bird-like DVR, but they also possess a highly differentiated reptile cerebral cortex. We studied the DT of the American alligator, Alligator mississippiensis, at late embryonic stages with a panel of molecular marker genes. Gene expression and cytoarchitectonic analyses identified clear homologs of all major avian DVR subdivisions including a mesopallium, an extensive nidopallium with primary sensory input territories, and an arcopallium. The alligator medial cortex is divided into three components that resemble the mammalian dentate gyrus, CA fields, and subiculum in gene expression and topography. The alligator dorsal cortex contains putative homologs of neocortical input, output, and intratelencephalic projection neurons and, most notably, these are organized into sublayers similar to mammalian neocortical layers. Our findings on the molecular anatomy of the crocodilian DT are summarized in an atlas of the alligator telencephalon. PMID- 29520782 TI - A novel method to visualise the three-dimensional organisation of the human cerebral cortical vasculature. AB - Current tissue-clearing protocols for imaging in three dimensions (3D) are typically applied to optimally fixed, small-volume rodent brain tissue - which is not representative of the tissue found in diagnostic neuropathology laboratories. We present a method to visualise the cerebral cortical vasculature in 3D in human post-mortem brain tissue which had been preserved in formalin for many years. Tissue blocks of cerebral cortex from two control cases, two Alzheimer's brains and two cases from Alzheimer's patients immunised against Abeta42 were stained with fluorescent Lycopersicon esculentum agglutinin (Tomato lectin), dehydrated and cleared using an adapted three-dimensional imaging of solvent cleared organs (3DISCO) protocol to visualise the vascular endothelium. Tissue was imaged using light sheet and confocal microscopy and reconstructed in 3D using amira software. The method permits visualisation of the arrangement of the parallel penetrating cortical vasculature in the human brain. The presence of four vascular features including anastomosis, U-shaped vessels, spiralling and loops were revealed. In summary, we present a low cost and simple method to visualise the human cerebral vasculature in 3D compatible with prolonged fixation times (years), allowing study of vascular involvement in a range of normative and pathological states. PMID- 29520783 TI - The KCNQ1 gene polymorphism as a shared genetic risk for rheumatoid arthritis and chronic periodontitis in Japanese adults: A pilot case-control study. AB - BACKGROUND: A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. METHODS: We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. RESULTS: Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. CONCLUSION: The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults. PMID- 29520784 TI - Asiaticoside induces osteogenic differentiation of human periodontal ligament cells through the Wnt pathway. AB - BACKGROUND: Asiaticoside is a compound isolated from Herb Centella asiatica, which has been shown to promote osteogenic differentiation of human periodontal ligament (hPDL) cells. This study investigated the molecular mechanism underlying the asiaticoside-induced osteogenic differentiation of hPDL cells. METHODS: hPDL cells were incubated with various concentrations of asiaticoside to test cell viability by MTT assay. The mRNA expression levels were analyzed by using quantitative real-time polymerase chain reaction (PCR). Osteogenic differentiation was determined by alkaline phosphatase activity assay and alizarin red staining. The subcellular localization of beta-catenin was analyzed by both immunofluorescence and western blot. RESULTS: The results showed that asiaticoside had no effect on the cell viability at any of the tested concentrations. Real-time PCR revealed that osterix (OSX) and dentin matrix protein1 (DMP1) mRNA were significantly enhanced by asiaticoside treatment. Alkaline phosphatase activity and in vitro mineralization were also significantly induced. Interestingly, asiaticoside dose-dependently increased WNT3A mRNA expression, but not WNT5A and WNT10B. The activation of Wnt signaling was shown to result in nuclear accumulation of beta-catenin as evaluated by immunofluorescence staining and western blot analysis. Pre-treatment with recombinant human Dickkopf1 (rhDKK1) inhibited asiaticoside-induced beta-catenin nuclear translocation and osteoblast marker gene expression. Moreover, rhDKK1 attenuated asiaticoside-induced DMP1 protein expression. CONCLUSION: The data demonstrate that asiaticoside induces osteogenic differentiation of hPDL cells by activating the Wnt/beta-catenin signaling pathway. The findings suggest that asiaticoside could be used as a novel therapeutic drug for periodontal tissue regeneration. PMID- 29520785 TI - Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers. AB - This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, it is directed towards authors, reviewers and editors. Explanations for many of the requirements were outlined previously and are not restated here. The new guidelines are intended to replace those published previously. The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards. PMID- 29520786 TI - Preliminary investigation of the vitamin D pathway in periodontal connective tissue cells. AB - BACKGROUND: The vitamin D pathway, from toll-like receptor activation to human cationic antimicrobial protein (hCAP-18/LL-37) generation, has been identified in monocytes and keratinocytes. This study aimed to investigate the vitamin D pathway in human gingival fibroblasts (hGFs) and human periodontal ligament cells (hPDLCs) and to provide preliminary evidence of its role in periodontal immune defense. METHODS: Primary cultures of hGFs and hPDLCs were stimulated with 1,25 dihydroxy vitamin D3 and 25-hydroxy vitamin D3 , with or without Porphyromonas gingivalis lipopolysaccharide. CYP27B1 RNA interference and vitamin D receptor (VDR) antagonism were also used for reverse proof. The mRNA expression of hCAP 18/LL-37, VDR, interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 were detected using real-time polymerase chain reaction. The LL-37 concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: In hGFs and hPDLCs, 25 hydroxy vitamin D3 and 1,25-dihydroxy vitamin D3 induced hCAP-18/LL-37 expression, which was further increased by Porphyromonas gingivalis lipopolysaccharide. If the function of CYP27B1 or VDR was blocked, the induction was significantly weakened. IL-8 and monocyte chemotactic protein-1 mRNA expression could be suppressed by the vitamin D pathway. CONCLUSION: These findings suggest that the vitamin D pathway exists in hGFs and hPDLCs and plays an important role in immune defense in periodontal soft tissues. PMID- 29520787 TI - Periodontal response to orthodontic tooth movement in diabetes-induced rats with or without periodontal disease. AB - BACKGROUND: Systemic conditions can influence orthodontic tooth movement. This study evaluates histologic periodontal responses to orthodontic tooth movement in diabetes-induced rats with or without periodontal disease. METHODS: Forty Wistar rats were divided according their systemic condition (SC) into diabetic (D) and non-diabetic (ND) groups. Each group was subdivided into control (C), orthodontic tooth movement (OM), ligature-induced periodontitis (P) and ligature-induced periodontitis with orthodontic movement (P+OM) groups. Diabetes mellitus (DM) was induced with alloxan monohydrate, and after 30 days, the P group received a cotton ligature around their first lower molar crown. An orthodontic device was placed in OM and P+OM groups for 7 days, and the animals were then euthanized. RESULTS: Differences in OM between D and ND groups were not significant (6.87+/- 3.55 mm and 6.81 +/- 3.28 mm, respectively), but intragroup analysis revealed statistically significant differences between the P+OM groups for both SCs. Bone loss was greater in the D group (0.16 +/- 0.07 mm2 ) than in the ND group (0.10 +/- 0.03 mm2 ). In intragroup analysis of the D condition, the P+OM group differed statistically from the other groups, while in the ND condition, the P+OM group was different from the C and OM groups. There was a statistically significant difference in bone density between D and ND conditions (18.03 +/- 8.09% and 22.53 +/- 7.72%) in the C, P, and P+OM groups. CONCLUSION: DM has deleterious effects on bone density and bone loss in the furcation region. These effects are maximized when associated with ligature-induced periodontitis with orthodontic movement. PMID- 29520788 TI - A case of CD8+ and CD56+ cytotoxic variant of poikilodermatous mycosis fungoides: Dermoscopic features of reticular pigmentation and vascular structures. PMID- 29520789 TI - The molecular control of tendril development in angiosperms. AB - The climbing habit has evolved multiple times during the evolutionary history of angiosperms. Plants evolved various strategies for climbing, such as twining stems, tendrils and hooks. Tendrils are threadlike organs with the ability to twine around other structures through helical growth; they may be derived from a variety of structures, such as branches, leaflets and inflorescences. The genetic capacity to grow as a tendrilled climber existed in some of the earliest land plants; however, the underlying molecular basis of tendril development has been studied in only a few taxa. Here, we summarize what is known about the molecular basis of tendril development in model and candidate model species from key tendrilled families, that is, Fabaceae, Vitaceae, Cucurbitaceae, Passifloraceae and Bignoniaceae. Studies on tendril molecular genetics and development show the molecular basis of tendril formation and ontogenesis is diverse, even when tendrils have the same ontogenetic origin, for example leaflet-derived tendrils in Fabaceae and Bignoniaceae. Interestingly, all tendrils perform helical growth during contact-induced coiling, indicating that such ability is not correlated with their ontogenetic origin or phylogenetic history. Whether the same genetic networks are involved during helical growth in diverse tendrils still remains to be investigated. PMID- 29520790 TI - The anticancer activity of antisense microRNA (fRNA) in combination with the lectin from Bacillus subtilis B-7025. AB - OBJECTIVES: Many adenocarcinomas have the ability to capture from an extracellular matrix the oligonucleotides and nanoparticles by pinocytosis, when the non-cancerous cells are not capable to capture the oligonucleotides and small liposomes. This provides selective accumulation of proposed protected oligonucleotides (fRNA) in cancer cells and also provides the absence toxicity in the fRNA. METHODS: For the immunotherapy, we used immunotropic 70 kDa lectin Bacillus subtilis B-7025. In vivo experiments were carried out in C57BL line mice in Lewis lung carcinoma. The cytotoxic activity, lymphocytes and macrophages were determined in vitro using the MTT assay. KEY FINDINGS: Animal survival rate in groups receiving either the fRNA or lectine was 70 and 40%, respectively. CONCLUSIONS: Combined use of fRNA and lectine has the advantage compared with the use of these drugs in monotherapy, as the anticancer efficacy of the scheme is much higher, which is manifested in the primary tumour node and metastasis inhibition. PMID- 29520791 TI - Self-perceived oral symptoms and periodontal status among young intravenous heroin addicts: A cross-sectional case-control study. AB - BACKGROUND: It is hypothesized that (a) self-perceived oral symptoms (OSs) are worse in intravenous heroin addicts (IHA) than controls; and (b) clinical periodontal inflammatory parameters (plaque index [PI], bleeding on probing [BOP], PD and clinical attachment loss [AL]), number of missing teeth (MT), and radiographic marginal bone loss (MBL) are higher in IHA compared with controls. The aim was to compare the self-perceived OSs and periodontal parameters among young IHA and controls. METHODS: Sociodemographic data, self-perceived OSs and duration and daily frequency of intravenous heroin use was gathered using a structured questionnaire. Full-mouth PI, BOP, PD, and clinical AL were measured, and number of MT were recorded. Mesial and distal MBL on all teeth was measured on digital radiographs. Odds ratios (OR) with 95% confidence intervals (CI) were computed for self-perceived OSs and periodontal parameters were assessed using the Mann Whitney U-test and logistic regression analysis. Sample-size was estimated, and level of significance was set at P < 0.05. RESULTS: OR (95% CI) for self-perceived loose teeth (P < 0.001), pain in teeth (P < 0.001), dry mouth (P < 0.001), burning sensation in mouth (P < 0.001), bleeding gums (P < 0.001) and pain during chewing (P < 0.001) were significantly higher in the test than control group. Number of MT (P < 0.05), PI (P < 0.05), clinical AL (P < 0.05), and mesial (P < 0.05) and distal (P < 0.05) MBL were statistically significantly higher among individuals in the test group compared with the control group. CONCLUSION: Self-perceived OSs and periodontal inflammatory parameters were worse in IHA than controls. PMID- 29520792 TI - Chemical Synthesis of Rare Natural Bile Acids: 11alpha-Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids. AB - A method for the preparation of 11alpha-hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12alpha mesyloxy group of the methyl esters of 3alpha-acetate-12alpha-mesylate and 3alpha,7alpha-diacetate-12alpha-mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting ?11 -3alpha-acetoxy and ?11 -3alpha,7alpha diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11alpha-hydroxylation of the ?11 -3alpha,24-diol and ?11 -3alpha,7alpha,24-triol intermediates with B2 H6 /tetrahydrofuran (THF); and (4) selective oxidation at C 24 of the resulting 3alpha,11alpha,24-triol and 3alpha,7alpha,11alpha,24-tetrol to the corresponding C-24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6 tetramethylpiperidine 1-oxyl free radical (TEMPO) and NaClO. In summary, 3alpha,11alpha-dihydroxy-5beta-cholan-24-oic acid and 3alpha,7alpha,11alpha trihydroxy-5beta-cholan-24-oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis. PMID- 29520793 TI - High serum procalcitonin levels in patients with periodontitis and chronic migraine. AB - BACKGROUND: To evaluate the contribution of chronic periodontitis (CP) to serum procalcitonin (proCT) levels in chronic migraine (CM) patients in a cross sectional study. METHODS: We included 138 subjects divided into 4 groups based on clinical features of CM and periodontal parameters: systemically and periodontally healthy individuals (n = 37), systemically healthy and CP patients (n = 19), CM and periodontally healthy patients (n = 34), and CM+CP patients (n = 48). Demographic, neurological, clinical data as well as full-mouth periodontal records were obtained. ProCT and high sensitive C-reactive protein (hs-CRP) serum levels were determined from blood samples taken during migraine interictal period. RESULTS: Patients from the CP+CM group (0.056+/-0.006 ng/mL) had significantly higher serum proCT levels in comparison with the systemically and periodontally healthy group (0.029+/-0.019 ng/mL), CM group (0.041+/-0.002 ng/mL), or CP group (0.034+/-0.014 ng/mL) (p < 0.001). There were no significant differences in hs-CRP between groups (p = 0.081). Multiple linear regression analysis showed that CP was associated with increased proCT levels in CM patients (R2 = 0.293, p < 0.001). CONCLUSIONS: CP independently contributes to elevated serum proCT levels in CM patients. These findings suggest that CP could play a role in migraine chronification. PMID- 29520794 TI - Critical developments of 2017: a review of the literature from selected topics in transfusion. A committee report from the AABB Clinical Transfusion Medicine Committee. AB - BACKGROUND: The AABB compiles an annual synopsis of the published literature covering important developments in the field of Transfusion Medicine. For the first time, an abridged version of this work is being made available in TRANSFUSION, with the full-length report available as an Appendix S1 (available as supporting information in the online version of this paper). STUDY DESIGN AND METHODS: Papers published in 2016 and early 2017 are included, as well as earlier papers cited for background. Although this synopsis is comprehensive, it is not exhaustive, and some papers may have been excluded or missed. RESULTS: The following topics are covered: duration of red blood cell storage and clinical outcomes, blood donor characteristics and patient outcomes, reversal of bleeding in hemophilia and for patients on direct oral anticoagulants, transfusion approach to hemorrhagic shock, pathogen inactivation, pediatric transfusion medicine, therapeutic apheresis, and extracorporeal support. CONCLUSION: This synopsis may be a useful educational tool. PMID- 29520795 TI - Insulin resistance predicts the risk of gingival/periodontal inflammation. AB - OBJECTIVES: Evaluate whether insulin resistance (IR) predicts the risk of oral inflammation, assessed as the number of sites with bleeding on probing (BOP) and number of teeth with probing pocket depths (PPD) >= 4 mm and BOP. METHODS: Data on 870 overweight/obese diabetes free adults, aged 40-65 years from the San Juan Overweight Adults Longitudinal Study over a three-year period, was analyzed. Baseline IR, assessed using the Homeostasis Model Assessment of IR (HOMA-IR) index, was divided into tertiles. BOP was assessed at buccal and lingual sites, and PPD at six sites per tooth. Negative binomial regression was used to estimate the risk ratios (RRs) for oral inflammation adjusted for baseline age, gender, smoking status, alcohol intake, education, physical activity, waist circumference, mean plaque index, and baseline number of sites with BOP, or number of teeth with PPD>=4 mm and BOP. The potential impact of tertiles of serum TNF-alpha and adiponectin on the IR-oral inflammation association was also assessed in a subsample of 597 participants. RESULTS: Participants in the highest HOMA-IR tertile at baseline had significantly higher numbers of sites with BOP [RR = 1.19, 95% confidence interval (CI): 1.03-1.36] and number of teeth with PPD >= 4 mm and BOP (RR = 1.39, 95% CI: 1.09-1.78) at follow-up, compared with individuals in the lower two HOMA-IR tertiles. Neither TNF-alpha nor adiponectin confounded the associations. CONCLUSION: IR significantly predicts gingival/periodontal inflammation in this population. PMID- 29520796 TI - Application of statistical and computational methodology to predict brainstem dosimetry for trigeminal neuralgia stereotactic radiosurgery. AB - OBJECTIVES: To apply advanced statistical and computational methodology in evaluating the impact of anatomical and technical variables on normal tissue dosimetry of trigeminal neuralgia (TN) stereotactic radiosurgery (SRS). METHODS: Forty patients treated with LINAC-based TN SRS with 90 Gy maximum dose were randomly selected for the study. Parameters extracted from the treatment plans for the study included three dosimetric output variables: the maximum dose to the brainstem (BSmax), the volume of brainstem that received at least 10 Gy (V10BS), and the volume of normal brain that received at least 12 Gy (V12). We analyzed five anatomical variables: the incidence angle of the nerve with the brainstem surface (A), the nerve length (L), the nerve width as measured both axially (WA) and sagittally (WS), the distance measured along the nerve between the isocenter and the brainstem surface (D), and one technical variable: the utilized cone size (CS). Univariate correlation was calculated for each pair among all parameters. Multivariate regression models were fitted for the output parameters using the optimal input parameters selected by the Gaussian graphic model LASSO. Repeated twofold cross-validations were used to evaluate the models. RESULTS: Median BSmax, V10BS, and V12 for the 40 patients were 35.7 Gy, 0.14 cc, and 1.28 cc, respectively. Median A, L, WA, WS, D, and CS were 43.7 degrees , 8.8 mm, 2.8 mm, 2.7 mm, 4.8 mm, and 6 mm, respectively. Of the three output variables, BSmax most strongly correlated with the input variables. Specifically, it had strong, negative correlations with the input anatomical variables and a positive correlation with CS. The correlation between D and BSmax at -0.51 was the strongest correlation between single input and output parameters, followed by that between CS and V10BS at 0.45, and that between A and BSmax at -0.44. V12 was most correlated with cone size alone, rather than anatomy. LASSO identified an optimal 3-feature combination of A, D, and CS for BSmax and V10BS prediction. Using cross-validation, the multivariate regression models with the three selected features yielded stronger correlations than the correlation between the BSmax and V10BS themselves. CONCLUSIONS: For the first time, an advanced statistical and computational methodology was applied to study the impact of anatomical and technical variables on TN SRS. The variables were found to impact brainstem doses, and reasonably strong correlation models were established using an optimized 3-feature combination including the nerve incidence angle, cone size, and isocenter-brainstem distance. PMID- 29520797 TI - An internally validated prognostic model for success in revision stapes surgery for otosclerosis. AB - OBJECTIVES/HYPOTHESIS: To develop a prediction model that can accurately predict the chance of success following revision stapes surgery in patients with recurrent or persistent otosclerosis at 2- to 6-months follow-up and to validate this model internally. STUDY DESIGN: A retrospective cohort study of prospectively gathered data in a tertiary referral center. METHODS: The associations of 11 prognostic factors with treatment success were tested in 705 cases using multivariable logistic regression analysis with backward selection. Success was defined as a mean air-bone gap closure to 10 dB or less. The most relevant predictors were used to derive a clinical prediction rule to determine the probability of success. Internal validation by means of bootstrapping was performed. Model performance indices, including the Hosmer-Lemeshow test, the area under the receiver operating characteristics curve (AUC), and the explained variance were calculated. RESULTS: Success was achieved in 57.7% of cases at 2- to 6-months follow-up. Certain previous surgical techniques, primary causes of failure leading up to revision stapes surgery, and positions of the prosthesis placed during revision surgery were associated with higher success percentages. The clinical prediction rule performed moderately well in the original dataset (Hosmer-Lemeshow P = .78; AUC = 0.73; explained variance = 22%), which slightly decreased following internal validation by means of bootstrapping (AUC = 0.69; explained variance = 13%). CONCLUSIONS: Our study established the importance of previous surgical technique, primary cause of failure, and type of the prosthesis placed during the revision surgery in predicting the probability of success following stapes surgery at 2- to 6-months follow-up. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:2390-2396, 2018. PMID- 29520798 TI - Influence of periodontal treatment on subgingival and salivary microbiotas. AB - BACKGROUND: The purpose of this study was to characterize and compare subgingival and salivary microbiotas before and after periodontal treatment to learn if any changes of the subgingival microbiota were reflected in saliva. We tested the hypothesis that salivary levels of specific periopathogens correlate with corresponding subgingival levels before and after periodontal treatment. METHODS: Twenty-five patients with generalized chronic periodontitis completed the study. Stimulated saliva samples and subgingival plaque samples were collected at baseline and 2, 6, and 12 weeks after nonsurgical periodontal therapy. Subgingival and salivary microbiotas were processed by means of the Human Oral Microbe Next Generation Sequencing (HOMINGS) technique and characterized based on relative abundance. Spearman signed rank test was used to test correlation of periopathogens in subgingival and saliva samples. RESULTS: Periodontal treatment resulted in significantly higher relative abundance of Streptococcus, Rothia and Actinomyces in combination with a significant decrease in Porphyromonas and Treponema in subgingival plaque samples. Relative abundance of the overall predominant genera in saliva was not influenced by periodontal treatment. However, there was a positive correlation between samples of subgingival plaque and saliva before and after periodontal treatment (p < 0.0001) with respect to relative abundance of specific periopathogens, such as Porphyromonas gingivalis (r = 0.68), Prevotella intermedia (r = 0.72), Filifactor alocis (r = 0.58), Treponema denticola (r = 0.51), Tannerella forsythia (r = 0.45) and Parvimonas micra (r = 0.45). CONCLUSIONS: Subgingival and salivary abundance of periodontal pathogens correlated before and after treatment. Thus, data from this study suggest that periopathogens identified in saliva may be spill-over from the subgingival microbiota. PMID- 29520799 TI - Frequent source plasma donors are not at risk of iron depletion: the Ferritin Levels in Plasma Donor (FLIPD) study. AB - BACKGROUND: Whole blood and red blood cell (RBC) donors are at risk of iron deficiency. Since Source plasma (SP) donors have RBCs returned during apheresis, risk of iron depletion appears low. However, SP donors can donate frequently and assessment of frequent donor iron status is needed. STUDY DESIGN AND METHODS: A total of 1254 SP donors were enrolled in four frequency groups determined by donations in the prior 12 months: no donations and 1 to 24, 25 to 69, and 70 or more donations. Ferritin was determined for each donor. Donors with ferritin levels of less than 12 ng/mL were classified as having absent iron stores (AIS). RESULTS: Compared to new donors, ferritin for females was higher in each successive frequency group. For 70 or more donations, ferritin was 13 ng/mL higher than in new donors (p = 0.02). For males, 1 to 24 donations had the highest ferritin levels. Compared to new donors, highest-frequency donors had lower ferritin levels, 114 ng/mL versus 100 ng/mL (p = 0.14). Age for females and males increased with each successive frequency group. Age adjustment resulted in smaller ferritin differences for females and larger differences for males in the high-frequency groups; AIS for females was highest in new donors (7%) and lowest in the highest-frequency group (1%). In aggregate, AIS occurred in less than 1% of all male donors. Male new and highest-frequency donors had 1% AIS with none in the other groups. CONCLUSION: Few SP donors have iron depletion and it is not higher in frequent donors. Frequent SP donation does not adversely impact iron stores. Thus, monitoring donor iron status or iron supplementation is not necessary. PMID- 29520800 TI - Disparities in detection of antibodies against hepatitis E virus in US blood donor samples using commercial assays. AB - BACKGROUND: Reported hepatitis E virus (HEV) antibody assay performance characteristics are variable. Using a subset of surplus US blood donation samples, we compared assays for detecting anti-HEV immunoglobulin M (Ig)M and IgG or total anti-HEV antibodies. STUDY DESIGN AND METHODS: Samples from 5040 random blood donations, all HEV-RNA negative, collected primarily in the midwestern United States in 2015 were tested for anti-HEV IgM and IgG or total anti-HEV using assays manufactured by Diagnostic Systems, Wantai, and MP Biomedicals. RESULTS: Overall, the percentage of detection for anti-HEV IgG and total anti-HEV was 11.4%, and for anti-HEV IgM was 1.8%. Nine samples were reactive for anti-HEV IgM by all assays, giving a recent infection rate of 0.18%. Anti-HEV IgG/total anti-HEV detection rates increased with age. Interassay agreement was higher among the IgG anti-HEV/total anti-HEV assays (84%) than the IgM assays (22%). Regression analyses of signal-to-cutoff ratios from IgG/total antibody assay were heteroskedastic, indicating no constant variance among these assays, suggesting they may detect different epitopes or were affected by waning or less avid antibodies in the US donor population. CONCLUSIONS: Although similar percentages of IgG anti-HEV/total anti-HEV detection were observed across the three commercial assays, each assay detected a unique sample subpopulation and was heteroskedastic when compared pairwise. Discordance was higher among anti-HEV IgM assays, but a recent HEV infection rate of at least 0.18% was estimated based on assay concordance. PMID- 29520801 TI - Peri-implant soft tissue inflammatory parameters and crestal bone loss among waterpipe (narghile) smokers and never-smokers with and without type 2 diabetes mellitus. AB - BACKGROUND: Peri-implant soft tissue inflammatory parameters and crestal bone loss (CBL) among waterpipe smokers (WS) with and without type 2 diabetes mellitus (T2DM) remains uninvestigated. The aim of the present study was to assess peri implant soft tissue inflammatory parameters and CBL among WS and never smokers (NS) with and without T2DM. METHODS: Demographic data and information regarding duration of implants in function, daily frequency of smoking, duration and treatment of T2DM, and daily toothbrushing was collected using a questionnaire. Peri-implant plaque index (PI), bleeding on probing (BOP), probing depth (PD) >=4 mm, CBL, and hemoglobin A1c (HbA1c) levels were assessed in all individuals. Level of significance was set at 5%. RESULTS: Seventy-nine male individuals (39 patients with T2DM [20 WS and 19 NS] and 40 systemically healthy individuals [21 WS smokers and 19 NS]) were included. The mean age was comparable among individuals in all groups. The mean HbA1c levels were significantly higher among patients with T2DM compared to controls (P < 0.01). Peri-implant PI, BOP, PD, and CBL were comparable among WS and NS with T2DM. Among patients without T2DM, PI (P < 0.05), PD >=4 mm (P < 0.05) and mesial and distal CBL (P < 0.05) were significantly higher in WS than NS. Among individuals without T2DM, BOP was significantly higher among NS (P < 0.05) than WS. In patients with T2DM, BOP was comparable among WS and NS. CONCLUSIONS: Peri-implant soft tissue inflammatory parameters and CBL were comparable among WS and NS with T2DM. Among individuals without T2DM, these parameters were worse among WS than NS. PMID- 29520802 TI - Association of marijuana use with oral HPV infection and periodontitis among Hispanic adults: Implications for oral cancer prevention. AB - BACKGROUND: Despite limited data, research suggests that marijuana use is associated with oral HPV infection and periodontitis, two potential oropharyngeal cancer risk factors. We assessed these associations in a Hispanic adult population in Puerto Rico. METHODS: A cross-sectional study of 735 adults assessed marijuana use, determined through an audio computer-assisted self interview, and periodontitis and self-collection of oral HPV samples following the National Health and Nutrition Examination Survey methodology. The Centers of Disease Control and Prevention/American Academy of Periodontology definition was used for periodontitis. HPV typing was performed using polymerase chain reaction with modified L1 consensus primers (MY09/MY11). RESULTS: 26.5% of adults reported lifetime use of marijuana, 2.7% were frequent users (lifetime use >= 26 times, past year use >= 6 times, and past 30-day use >=2 times), 5.7% had oral HPV infection, and 20.1% had severe periodontitis. The multivariate logistic regression analysis showed that frequent marijuana users were more likely to have severe periodontitis (OR = (2.93, 95%: 1.08-7.96)) than never/once lifetime users after adjusting for age, sex, healthcare coverage, smoking, binge drinking, number of oral sex partners, and oral HPV infection. However, frequent marijuana use was not associated with oral HPV infection. CONCLUSION: Marijuana use was associated with periodontitis, but not with oral HPV infection. Further evaluation of the role of marijuana use in oral HPV infection and periodontitis may inform novel preventive public health strategies, as marijuana users could be at increased risk of oral cancer. PMID- 29520803 TI - Association between bilateral segmental vitiligo and lichen striatus: an expression of mosaicism? PMID- 29520804 TI - Hashimoto's thyroiditis with elevated serum IgG4 concentrations is not equivalent to IgG4 Hashimoto's thyroiditis. AB - BACKGROUND: Hashimoto's thyroiditis (HT) with serum IgG4 concentrations greater than 135 mg/dL can be diagnosed as elevated serum IgG4 HT. HT can also be classified into IgG4 HT and non-IgG4 HT based on an immunohistochemistry analysis of IgG4. The aim of our study was to determine the relationship between elevated serum IgG4 HT and IgG4 HT. METHOD: Both thyroid tissues and serum samples stored before pathological examination from 93 patients with HT were collected. The serum levels of IgG, IgG4, TgAb IgG, TgAb IgG4, TPOAb IgG and TPOAb IgG4 were measured by ELISAs. The expression levels of IgG4, IgG and TGF-beta1 in thyroid tissues were detected by immunohistochemistry. RESULTS: Patients with HT were divided into two groups: elevated serum IgG4 HT (n = 12) and nonelevated serum IgG4 HT (n = 81). Hypothyroidism was found in 5 of 12 cases (41.7%) in the elevated serum IgG4 HT group and 10 of 81 cases (12.3%) in the nonelevated serum IgG4 HT group (P = .023). Serologically, there were no significant differences in the levels of TgAb IgG, TPOAb IgG, TgAb IgG4 and TPOAb IgG4 between the two groups, and the expression of TGF-beta1 in thyroid tissues was not significantly different between the groups. Most importantly, the frequency of patients who satisfied the criteria for IgG4 HT diagnosis was comparable (25% vs 20.9%, P = .756). CONCLUSIONS: The measurement of serum IgG4 allows the identification of patients with HT closely associated with hypothyroidism. However, our study demonstrated that elevated serum IgG4 HT is not equivalent to IgG4 HT. PMID- 29520805 TI - Treatment escape reduces the effectiveness of cabergoline during long-term treatment of acromegaly in monotherapy or in association with first-generation somatostatin receptor ligands. AB - BACKGROUND: Few studies evaluated the use of cabergoline (CAB) for acromegaly treatment in monotherapy or in combination with first-generation somatostatin receptor ligands (SRLs). AIM: To evaluate the efficacy, predictors of response and safety of CAB treatment in acromegaly both in monotherapy and in combination with SRLs. METHODS: We retrospectively collected demographic, biochemical, tumour and treatment data. Short-term disease control was defined as random GH level < 1.0 MUg/L and normal age-matched IGF-I level after 3-6 months of treatment with the higher dose used. Long-term disease control was defined as maintenance of normal GH and IGF-I levels at the last visit (at least 9 months of treatment). RESULTS: Eighty-two patients were studied. The median total time of treatment in monotherapy or in combination with SRLs was 14 months (3-124) and 34 months (3 88), respectively. Short-term disease control was observed in 6 (21%) patients in the monotherapy group and in 20 (32%) in the combination group. Treatment escape was observed in 1 patient after 16 months of CAB monotherapy and in 6 (30%) patients with combination therapy (after a median of 38 months), resulting in long-term disease control of 18% and 23%, respectively. Hyperprolactinemia was a predictor of response to monotherapy and pretreatment GH level to combination treatment. CONCLUSION: We presented the results of the largest single-centre study with CAB in monotherapy and in combination with SRL. The efficacy of CAB in acromegaly seems to be lower than that of other drugs, and treatment escape may occur after a long-term follow-up. PMID- 29520806 TI - Microbiome at sites of gingival recession in children with Hutchinson-Gilford progeria syndrome. AB - BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder with significant oral and dental abnormalities. Clinical symptoms include various features of accelerated aging such as alopecia, loss of subcutaneous fat, bone abnormalities, and premature cardiovascular disease. In addition, children with HGPS have been observed to suffer from generalized gingival recession. Whether periodontal manifestations associated with this syndrome are the results of changes in the oral flora is unknown. The present study aimed to identify the microbial composition of subgingival sites with gingival recession in children with HGPS. METHODS: Nine children with HGPS were enrolled in this study. Plaque samples were collected from teeth with gingival recession. DNA samples were analyzed using the Human Oral Microbe Identification Microarray (HOMIM). Microbial profiles from HGPS children were compared with microbial profiles of controls from healthy individuals (n = 9) and patients with periodontal disease (n = 9). RESULTS: Comparison of microbial compositions of HGPS samples with periodontal health samples demonstrated significant differences for two bacterial taxa; Porphyromonas catoniae and Prevotella oulora were present in children with HGPS, but not normal controls. There were statistically significant differences of 20 bacterial taxa between HGPS and periodontal disease groups. CONCLUSIONS: Typical periodontal pathogens were not present at sites with gingival recession in HGPS children. The microbial compositions of sites of gingival recession and attachment loss in HGPS were generally more similar to those of periodontal health than periodontal disease. Species other than typical periodontal pathogens may be involved in this recession. PMID- 29520808 TI - Impacts of perianal disease and faecal incontinence on quality of life and employment in 1092 patients with inflammatory bowel disease. AB - BACKGROUND: Patient reported outcomes regarding perianal disease and faecal incontinence in the community-based inflammatory bowel disease population are poorly described. AIMS: To determine the impacts of perianal disease and faecal incontinence on quality of life and employment in inflammatory bowel disease patients. METHODS: For this cross-sectional study, a comprehensive survey was sent out to members of the Dutch National Crohn's and Colitis patient organisation. Validated questionnaires regarding faecal incontinence and active perianal disease were used to estimate its prevalence's. The effect on the quality of life (36-Item Short Form Survey) and on employment status (multivariate binary regression analysis) was assessed in this inflammatory bowel disease population. RESULTS: A total number of 1092 returned questionnaires (58% responders) were used for analysis; 750 respondents (69%) were female; mean age was 47 years (IQR 35-59). In 621 patients (57%) Crohn's disease, in 422 (39%) ulcerative colitis and in 49 (4%) patients unclassifiable inflammatory bowel disease was self-reported. The 114 patients (10%) with a stoma were excluded for continence related analyses. Faecal incontinence was reported in 555 patients (57%), was comparable between the different inflammatory bowel disease diagnoses and affected all 36-Item Short Form Survey subscales adversely (incontinence vs continence: Physical functioning 75 vs 84, P < 0.0001; Limitations due to physical health 49 vs 63, P < 0.0001; Limitations due to emotional problems 49 vs 64, P < 0.0001; Energy/fatigue 47 vs 53, P < 0.0001; Emotional well-being 71 vs 74, P = 0.005; Social functioning 63 vs 73, P < 0.0001; Pain 66 vs 75, P < 0.0001; General health 41 vs 48, P < 0.0001). Active perianal disease was reported in 39% Crohn's disease, 16% ulcerative colitis (84% fissures) and 20% unclassifiable inflammatory bowel disease patients. Faecal incontinence was more common in patients with perianal disease (67% vs 53%, P = 0.003). When correcting for age, disease duration, inflammatory bowel disease-related surgery and faecal incontinence, active perianal disease was independently affecting employment (OR 0.67; 95% CI 0.50-0.91; P = 0.01). CONCLUSIONS: Faecal incontinence and perianal disease are quality of life determining factors. Faecal incontinence needs more attention among clinicians, and development of new (drug) therapies needs to be focussed on perianal disease. PMID- 29520807 TI - Global spatial analysis of Arabidopsis natural variants implicates 5'UTR splicing of LATE ELONGATED HYPOCOTYL in responses to temperature. AB - How plants perceive and respond to temperature remains an important question in the plant sciences. Temperature perception and signal transduction may occur through temperature-sensitive intramolecular folding of primary mRNA transcripts. Recent studies suggested a role for retention of the first intron in the 5'UTR of the clock component LATE ELONGATED HYPOCOTYL (LHY) in response to changes in temperature. Here, we identified a set of haplotypes in the LHY 5'UTR, examined their global spatial distribution, and obtained evidence that haplotype can affect temperature-dependent splicing of LHY transcripts. Correlations of haplotype spatial distributions with global bioclimatic variables and altitude point to associations with annual mean temperature and temperature fluctuation. Relatively rare relict type accessions correlate with lower mean temperature and greater temperature fluctuation and the spatial distribution of other haplotypes may be informative of evolutionary processes driving colonization of ecosystems. We propose that haplotypes may possess distinct 5'UTR pre-mRNA folding thermodynamics and/or specific biological stabilities based around the binding of trans-acting RNA splicing factors, a consequence of which is scalable splicing sensitivity of a central clock component that is likely tuned to specific temperature environments. PMID- 29520809 TI - Genome-wide signatures of flowering adaptation to climate temperature: Regional analyses in a highly diverse native range of Arabidopsis thaliana. AB - Current global change is fueling an interest to understand the genetic and molecular mechanisms of plant adaptation to climate. In particular, altered flowering time is a common strategy for escape from unfavourable climate temperature. In order to determine the genomic bases underlying flowering time adaptation to this climatic factor, we have systematically analysed a collection of 174 highly diverse Arabidopsis thaliana accessions from the Iberian Peninsula. Analyses of 1.88 million single nucleotide polymorphisms provide evidence for a spatially heterogeneous contribution of demographic and adaptive processes to geographic patterns of genetic variation. Mountains appear to be allele dispersal barriers, whereas the relationship between flowering time and temperature depended on the precise temperature range. Environmental genome-wide associations supported an overall genome adaptation to temperature, with 9.4% of the genes showing significant associations. Furthermore, phenotypic genome-wide associations provided a catalogue of candidate genes underlying flowering time variation. Finally, comparison of environmental and phenotypic genome-wide associations identified known (Twin Sister of FT, FRIGIDA-like 1, and Casein Kinase II Beta chain 1) and new (Epithiospecifer Modifier 1 and Voltage-Dependent Anion Channel 5) genes as candidates for adaptation to climate temperature by altered flowering time. Thus, this regional collection provides an excellent resource to address the spatial complexity of climate adaptation in annual plants. PMID- 29520810 TI - Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism. AB - OBJECTIVE: Nonsurgical hypoparathyroidism (NS-HypoPT) and pseudohypoparathyroidism (PHP) are rare diseases, with a prevalence of 2/100.000 and 1/100.000, respectively. Only few studies on Quality of Life (QoL) among patients with Ns-HypoPT and PHP are available. We aimed to investigate the QoL among patients with Ns-HypoPT and PHP including information about education. DESIGN: A cohort study with patients identified from a previously epidemiological study. PATIENTS: Fifty seven patients with Ns-HypoPT and 30 patients with PHP. MEASUREMENTS: The well-validated questionnaires SF-36v2 and WHO-5 Well Being Index. Results compared to norm-based material, disease-specific norm-based material and patients with postsurgical HypoPT RESULTS: SF36v2 showed a significantly reduced score in all eight subdomains in patients with NS-HypoPT compared with a norm-based population. PHP patients scored lower in five subdomains. Females were more affected than males. Compared with postsurgical HypoPT, Ns-HypoPT and PHP are compatible at most domains. At the domains Physical Function, Social Function and Mental Health, Ns-HypoPT and PHP patients scored significantly lower (Pall < .05). At the Mental Component Score, patients with Ns-HypoPT had a lower score compared with postsurgical HypoPT (P < .01). The overall WHO-5 Well Being Index score was comparable between groups (P = .45). No differences were seen comparing patients with postsurgical HypoPT and Ns-HypoPT (P = .68) or postsurgical HypoPT and PHP (P = .67). A WHO-5 score below 28 indicates depression (NS-HypoPT=7; PHP=3, P = .71), whereas a score between 28-50 suggesting poor emotional well-being (NS-HypoPT=19; PHP=5, P = .13). The remaining patients scored above 50 suggesting well-being. CONCLUSION: QoL is impaired equally among patients with Ns-HypoPT and PHP. PMID- 29520811 TI - A major natural genetic variation associated with root system architecture and plasticity improves waterlogging tolerance and yield in soybean. AB - Natural genetic variations in waterlogging tolerance are controlled by multiple genes mapped as quantitative trait loci (QTLs) in major crops, including soybean (Glycine max L.). In this research, 2 novel QTLs associated with waterlogging tolerance were mapped from an elite/exotic soybean cross. The subsequent research was focused on a major QTL (qWT_Gm03) with the tolerant allele from the exotic parent. This QTL was isolated into near-isogenic backgrounds, and its effects on waterlogging tolerance were validated in multiple environments. Fine mapping narrowed qWT_Gm03 into a genomic region of <380 Kbp excluding Rps1 gene for Phytophthora sojae resistance. The tolerant allele of qWT_Gm03 promotes root growth under nonstress conditions and favourable root plasticity under waterlogging, resulting in improved waterlogging tolerance, yield, and drought tolerance-related traits, possibly through more efficient water/nutrient uptakes. Meanwhile, involvement of auxin pathways was also identified in the regulation of waterlogging tolerance, as the genotypic differences of qWT_Gm03 in waterlogging tolerance and formation of adventitious/aerial roots can be complemented by an exogenous auxin-biosynthesis inhibitor. These findings provided genetic resources to address the urgent demand of improving waterlogging tolerance in soybean and revealed the determinant roles of root architecture and plasticity in the plant adaptation to waterlogging. PMID- 29520812 TI - Nature's first "atypical opioids": Kratom and mitragynines. AB - WHAT IS KNOWN AND OBJECTIVE: Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (ie, they are "multimechanistic") and that better pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multimechanistic. At least two of the more-modern analgesics combine opioid and non-opioid mechanisms, and have become known as "atypical opioids." Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery efforts. COMMENT: Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant. They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two most recent analgesics were developed to have both an opioid mechanism and, a second, non opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties. WHAT IS NEW AND CONCLUSION: As debate about the use and abuse potential of kratom swirls, conflicting, often contradicting, opinions are expressed. A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non-opioid properties. Fascinatingly, just as the poppy plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines-Nature's "atypical opioids." PMID- 29520813 TI - A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. AB - BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men. PMID- 29520814 TI - Reply to "anaesthesia technique and outcomes: the search for causality". PMID- 29520815 TI - Anesthesia technique and outcomes: the search for causality. PMID- 29520816 TI - Self-assembling peptide matrix for treatment of dentin hypersensitivity: A randomized controlled clinical trial. AB - BACKGROUND: Patient-reported dentin hypersensitivity [DHS] pain is a common finding linked with periodontal disease. This pilot clinical study investigates a novel therapeutic regimen using self-assembling peptide matrix [SAPM] gel (test) compared with use of an 8% arginine and calcium carbonate [ACC] toothpaste (control) for treatment of DHS. METHODS: A total of 50 patients with history of supportive periodontal therapy were enrolled in this prospective, randomized monocentric clinical study, of which 45 (test: n = 22; control: n = 23) fulfilled all the study visits. Test group patients performed ex-office application of SAPM gel over 1 week, while control group patients performed ex-office application of ACC toothpaste over 90 days. DHS was assessed in office by Visual Analog Scale [VAS], and patient's perception of pain relief was evaluated by questionnaire. In support of the clinical data, scanning electron microscopy images were recorded to investigate tubule occlusion of both control and test product. RESULTS: Both SAPM and ACC significantly reduced DHS in patients throughout the study, with the patient questionnaire indicating higher patient satisfaction at the earlier time points for the test group. CONCLUSIONS: Both SAPM gel and ACC toothpaste were successful in providing relief from DHS and showed similar outcomes on VAS and verbal response scale (VRS) throughout the study period of 90 days. The new therapeutic regimen using SAPM resulted in higher patient satisfaction at day 7, as indicated by the patient questionnaire and the higher number of pain-free patients at day 7 and day 90. This is a pilot study describing a novel therapy for DHS. PMID- 29520817 TI - Regional chemoarchitecture of the brain of lungfishes based on calbindin D-28K and calretinin immunohistochemistry. AB - Lungfishes are the closest living relatives of land vertebrates, and their neuroanatomical organization is particularly relevant for deducing the neural traits that have been conserved, modified, or lost with the transition from fishes to land vertebrates. The immunohistochemical localization of calbindin (CB) and calretinin (CR) provides a powerful method for discerning segregated neuronal populations, fiber tracts, and neuropils and is here applied to the brains of Neoceratodus and Protopterus, representing the two extant orders of lungfishes. The results showed abundant cells containing these proteins in pallial and subpallial telencephalic regions, with particular distinct distribution in the basal ganglia, amygdaloid complex, and septum. Similarly, the distribution of CB and CR containing cells supports the division of the hypothalamus of lungfishes into neuromeric regions, as in tetrapods. The dense concentrations of CB and CR positive cells and fibers highlight the extent of the thalamus. As in other vertebrates, the optic tectum is characterized by numerous CB positive cells and fibers and smaller numbers of CR cells. The so-called cerebellar nucleus contains abundant CB and CR cells with long ascending axons, which raises the possibility that it could be homologized to the secondary gustatory nucleus of other vertebrates. The corpus of the cerebellum is devoid of CB and CR and cells positive for both proteins are found in the cerebellar auricles and the octavolateralis nuclei. Comparison with other vertebrates reveals that lungfishes share most of their features of calcium binding protein distribution with amphibians, particularly with salamanders. PMID- 29520818 TI - Effects of colchicine on gingival inflammation, apoptosis, and alveolar bone loss in experimental periodontitis. AB - BACKGROUND: The aim of the study was to investigate the effects of colchicine on cytokine production, apoptosis, alveolar bone loss, and oxidative stress in an experimental model of periodontitis in rats. METHODS: Forty-eight rats were divided equally into four groups: healthy (H); periodontitis (P); periodontitis+colchicine low dose (CL, 30 MUg/kg/day), and periodontitis+colchicine high dose (CH, 100 MUg/kg/day). After 11 days, interleukin (IL) -1beta, IL-8, and IL-10 were analyzed in gingival samples using Enzyme-Linked ImmunoSorbent Assay. Receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), total oxidative stress (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were measured in gingiva and serum. Alveolar bone volume was evaluated via micro-CT. Apoptotic cells were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in histological sections. RESULTS: Colchicine treatment significantly reduced IL-1beta, IL-8, RANKL, RANKL/OPG, TOS, OSI, and bone volume ratio levels, and increased TAS levels compared to group P (p < 0.05). High dose colchicine treatment (CH) significantly decreased TUNEL+ cell counts compared to group P (p < 0.05). CONCLUSIONS: These finding suggest that colchicine has a prophylactic potential for the prevention of periodontal tissue destruction through anti-inflammatory, anti-oxidative, anti-apoptotic, and bone-protective effects. PMID- 29520819 TI - Virtual reality applications for diagnosis, risk assessment and therapy of child abusers. AB - Despite the successful application of virtual reality (VR) in a wide variety of mental disorders and the obvious potentials that VR provides, the use of VR in the context of criminology and forensic psychology is sparse. For forensic mental health professionals, VR provides some advantages that outrun general advantages of VR, e.g., ecological validity and controllability of social situations. Most important seems to be the unique possibility to expose offenders and to train coping skills in virtual situations, which are able to elicit disorder-relevant behavior-without endangering others. VR has already been used for the assessment of deviant sexual interests, for testing the ability to transfer learned coping skills communicated during treatment to behavior, and for risk assessment of child abusers. This article reviews and discusses these innovative research projects with regard to their impact on current clinical practice regarding risk assessment and treatment as well as other implementations of VR applications in forensic mental health. Finally, ethical guidelines for VR research in forensic mental health are provided. PMID- 29520820 TI - Childhood death rates declined in Sweden from 2000 to 2014 but deaths from external causes were not always investigated. AB - AIM: Countries that conduct systematic child death reviews report a high proportion of modifiable characteristics among deaths from external causes, and this study examined the trends in Sweden. METHODS: We analysed individual-level data on external, ill-defined and unknown causes from the Swedish cause of death register from 2000 to 2014, and mortality rates were estimated for children under the age of one and for those aged 1-14 and 15-17 years. RESULTS: Child deaths from all causes were 7914, and 2006 (25%) were from external, ill-defined and unknown causes: 610 (30%) were infants, 692 (34%) were 1-14 and 704 (35%) were 15 17. The annual average was 134 cases (range 99-156) during the study period. Mortality rates from external, ill-defined and unknown causes in children under 18 fell 19%, from 7.4 to 6.0 per 100 000 population. A sizeable number of infant deaths (8.0%) were registered without a death certificate during the study period, but these counts were lower in children aged 1-14 (1.3%) and 15-17 (0.9%). CONCLUSION: Childhood deaths showed a sustained decline from 2000 to 2014 in Sweden and a quarter were from external, ill-defined or unknown causes. Systematic, interagency death reviews could yield information that could prevent future deaths. PMID- 29520821 TI - Practical microscale one-pot radiosynthesis of 18 F-labeled probes. AB - High specific activity is often a significant requirement for radiopharmaceuticals. To achieve that with fluorine-18 (18 F)-labeled probes, it is mandatory to start from no-carrier-added fluoride and to reduce to a minimum the amount of precursor in order to decrease the presence of any pseudocarrier. In the present study, a feasible and efficient method for microscale one-pot radiosynthesis of 18 F-labeled probes is described. It allows a substantial reduction in precursor, solvent, and reagents, thus reducing also possible side reaction in the case of base-sensitive precursors. The method is based on the use of a small amount of Kryptofix 2.2.2/potassium [18 F]fluoride in MeOH (K.222/K[18 F]F-MeOH) obtained using Oasis MAX and MCX cartridges. Five methods, differing in terms of MeOH evaporation and precursor addition, for the radiosynthesis of [18 F]fallypride and [18 F]FET in <=50-MUL scale, were examined and evaluated. The method using the addition of DMSO to the K.222/K[18 F]F-MeOH solution prior to MeOH evaporation is proposed as a versatile procedure for feasible one-pot 10- to 20-MUL scale radiosyntheses. This method was successfully applied also to the radiosynthesis of [18 F]FES, [18 F]FLT, and [18 F]FMISO, with radiochemical yields comparable with those reported in the literature. Purification of a crude product by an analytical HPLC column was also demonstrated. PMID- 29520822 TI - Periodontal profile classes predict periodontal disease progression and tooth loss. AB - BACKGROUND: Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. METHODS: The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). RESULTS: Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. CONCLUSIONS: These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived personalized propensity scores provide clinical periodontal definitions that reflect disease patterns in the population and offer a useful system for patient stratification that is predictive for disease progression and tooth loss. PMID- 29520823 TI - Periodontal profile class is associated with prevalent diabetes, coronary heart disease, stroke, and systemic markers of C-reactive protein and interleukin-6. AB - BACKGROUND: This paper focuses on the Periodontal Profile Class (PPC) System that may be more informative and representative of periodontitis phenotypes than current case definitions of periodontitis. This study illustrates the unique aspects of the PPC compared with other periodontal indices for studying associations between periodontal disease and prevalent systemic conditions. METHODS: We computed odds ratios and 95% confidence intervals to compare associations between periodontal disease and prevalent systemic conditions using our new PPC and two traditional indices. We used the Bayesian Information Criterion (BIC) to determine the fit of the model and the magnitude of the contribution attributable to periodontal disease beyond traditional risk factors. The Atherosclerosis Risk in Communities (ARIC) Study (1996-1998) results were compared with results from the combined National Health and Nutrition Examination Survey 2009-2014 datasets. RESULTS: In the ARIC Study, high gingival inflammation, tooth loss, severe tooth loss, and severe disease PPC components were significantly associated with diabetes, coronary heart disease (CHD), high sensitivity C-reactive protein, and interleukin (IL)-6, while only severe disease was associated with stroke. Severe disease was associated with CHD using the Centers for Disease Control/American Academy of Periodontology index, and the European Periodontal index was associated with CHD and IL-6. CONCLUSIONS: The addition of the PPC to traditional variables associated with prevalent diabetes, stroke, CHD, and systemic measures of inflammation resulted in very strong improvement of the overall models, while the traditional indices were less likely to be associated and, if present, the associations were weaker. The PPC system provides specific insight into the individuals and periodontal characteristics of the phenotype that are associated with systemic conditions that may be useful in designing treatment interventions. PMID- 29520824 TI - Eosinophil cationic protein and histamine production by neutrophils from patients with periodontitis. AB - BACKGROUND: Periodontitis develops through an inflammatory process caused by an infection at the microbial biofilm, followed by tissue destruction mediated by leukocytes, which cause clinically significant destruction of connective tissue and bone. Several elements derived from the bacteria cause the inflammatory response and the release of mediators involved in destruction of the periodontium. There are number of inflammatory mediators released by leukocytes, mainly neutrophils, upon bacterial challenge. Neutrophils produce and release eosinophil cationic protein (ECP) and histamine, two important inflammatory mediators; however, their role has not been characterized in periodontal inflammation. Thus, the purpose of this study is to investigate whether neutrophils from patients with periodontitis can produce ECP and histamine in response to lipopolysaccharides (LPSs). METHODS: ECP and histamine production in response to LPSs was analyzed by enzyme-linked immunosorbent assay. Expression of the histidine decarboxylase and ECP was also analyzed by flow cytometry and fluorescence microscopy in neutrophils from patients with periodontitis in response to LPS. RESULTS: It was found that neutrophils from patients with periodontitis express higher levels of histidine decarboxylase and ECP than those from healthy volunteers, and they also release higher levels of histamine. CONCLUSION: Findings described could represent new knowledge indicating neutrophils as a source of histamine and ECP in the progression of periodontitis. PMID- 29520825 TI - Subgingival microbial profile of obese women with periodontal disease. AB - BACKGROUND: This study compared the composition of subgingival microbiota between obese and non-obese women with or without periodontal disease. METHODS: Full mouth periodontal clinical assessments were carried out in 76 obese women (17 periodontally healthy and 59 with periodontal disease), and 34 non-obese women (12 periodontally healthy, 22 with periodontal disease). Subgingival biofilm samples were individually obtained from seven sites of each individual, and the prevalence and counts of 40 bacterial taxa were determined by the checkerboard method. The frequency and counts of each species were computed for each individual and across the groups. Differences among and between groups were sought by the Kruskal-Wallis and Mann-Whitney tests, respectively. Possible correlations between obesity and clinical and microbiologic parameters were tested with Spearman correlation coefficient. RESULTS: Streptococcus sanguinis, Streptococcus oralis, and Capnocytophaga ochracea were found in significantly higher levels in obese compared with non-obese women (P < 0.01). In patients with periodontal health, Porphyromonas gingivalis and Leptotrichia buccalis were detected in higher mean frequency and/or counts in obese women than in non-obese women, whereas in patients with periodontal disease, obese women harbored greater levels of C. ochracea than non-obese women (P < 0.01). Moreover, obese women with periodontal disease presented significantly greater mean counts of P. gingivalis and Tannerella forsythia than non-obese women with periodontal health (P < 0.01). When the conditions obesity and periodontal disease are present at the same time, significant positive correlations were detected with C. ocharcea, P. gingivalis, S. sanguinis, and T. forsythia. CONCLUSION: Few differences in the composition of the subgingival microbiota of obese and non-obese women with periodontal health or disease were found. However, a high prevalence of P. gingivalis in obese women with periodontal health was observed. PMID- 29520826 TI - Impact of a triclosan-containing toothpaste during the progression of experimental peri-implant mucositis: Clinical parameters and local pattern of osteo-immunoinflammatory mediators in peri-implant fluid. AB - BACKGROUND: This study evaluated the influence of a triclosan-containing toothpaste in the profile of osteo-immunoinflammatory mediators in peri-implant crevicular fluid (PICF) and in clinical parameters during progression of peri implant mucositis. METHODS: Twenty-two clinically healthy patients with an implant-supported single-unit crown were enrolled in this double-blind, randomized, crossover study carried out in two phases of 21 days each. During an experimental 3-week period of undisturbed plaque accumulation in the implants, patients were randomly assigned to use three times/day: triclosan (n = 11), triclosan/copolymer/fluoride toothpaste; or placebo (n = 11), fluoride toothpaste. After a professional prophylaxis, a washout period of 30 days was established. Clinical parameters and 15 osteo-immunoinflammatory mediators in the PICF were evaluated at baseline and at 3, 7, 14, and 21 days. RESULTS: Both groups showed increase in plaque index at implant sites from the 3rd until the 21st day (P < 0.05). Only triclosan treatment was able to avoid an increase in bleeding on probing (BOP) throughout the follow-ups (P > 0.05), whereas a significant intensification in BOP was observed from the 14th day in the placebo treated sites (P < 0.05). Lower interleukin (IL)-10 concentrations were detected in the placebo group at the 21st day when compared with triclosan-treated implant sites (P < 0.05). IL-10 levels were reduced and IL-1beta concentrations were increased at 21 days when compared with baseline only in placebo-treated sites (P < 0.05). Osteoprotegerin levels significantly increased from the 14th until the 21st day only in triclosan-treated sites (P < 0.05). CONCLUSION: Triclosan containing toothpaste controls clinical inflammation and interferes positively in the profile of osteo-immunoinflammatory mediators during progression of experimental peri-implant mucositis. PMID- 29520827 TI - In search of appropriate measures of periodontal status: The Periodontal Profile Phenotype (P3 ) system. AB - BACKGROUND: This paper focuses on Periodontal Profile Class (PPC), a component of the Periodontal Profile Phenotype (P3 ) System that may be more representative of the periodontitis phenotype than current case definitions of periodontitis. Data illustrate the unique aspects of the PPC compared with other commonly used periodontal classification indices. METHODS: Latent Class Analysis (LCA) identified discrete classes of individuals grouped by tooth-level clinical parameters. The analysis defined seven distinct periodontal profile classes (PPC A through G) and seven distinct tooth profile classes (TPC A through G). This LCA classification was an entirely data-derived agnostic process without any preconceived presumptions of what constituted disease. RESULTS: Comparing the PPC with the Centers for Disease Control/American Academy of Periodontology (CDC/AAP) and European indices, the PPC is unique in that it contains four disease classes not traditionally used. Less than half of individuals classified as Healthy by both the CDC/AAP and European indices were Healthy using the PPC. About 25% of those classified as Severe by CDC/AAP and European indices were PPC-Severe. The remainder spread out over the High Gingival Index, Posterior Disease, Tooth Loss, and Severe Tooth Loss phenotypes. CONCLUSIONS: The PPC classification provides a significant departure from the traditional clinical case status indices that have been used, but has resulted in clinical phenotypes that are quite familiar to most clinicians who take notice of the distribution of missing teeth, areas of recession, diminished periodontal support, and other aspects of the dentition while conducting a periodontal examination. The mutually exclusive categories provided by the PPC system provide periodontal clinical summaries that can be an important component of precision dentistry. PMID- 29520828 TI - Periodontal disease and its connection to systemic biomarkers of cardiovascular disease in young American Indian/Alaskan natives. AB - BACKGROUND: Periodontal disease has been shown to be associated with cardiovascular disease (CVD). No known studies evaluate the relationship between periodontal disease status and biomarkers of CVD risk in the American Indian/Alaskan Native (AI/AN) population despite their disproportionately high rates of poor oral health and cardiovascular disease-related outcomes. This study compared levels of interleukin (IL)-6 and C-reactive protein (CRP) across increasing severity of periodontal disease status among younger adults between the ages of 21 and 43 years. METHODS: Plasma levels of IL-6 and CRP were measured in adult participants (ages 21 to 43 years) as part of a study of periodontal disease and CVD risk among an AI/AN population in southern California (n = 59). Periodontal evaluations were performed and disease status was classified into three categories based on highest probing depth (none/mild: < 3 mm; moderate: 4 to 5 mm; severe: >=6 mm). Participants with known systemic disease or active infection were excluded. RESULTS: Severe periodontitis was significantly associated with increased levels of IL-6 compared with those with none or mild periodontitis before controlling for other variables (P = 0.02), but lacked significance after controlling for sex, BMI, smoking status, and high-density lipoprotein (P = 0.09). Moderate periodontal disease was positively associated with IL-6 levels after controlling for potential confounders (P = 0.01). Periodontal status was not associated with CRP, before or after adjusting for covariates. CONCLUSIONS: In this otherwise healthy AI/AN adult sample, moderate periodontal disease compared with none or mild periodontal disease was associated with increased levels of IL-6. High levels of CRP found in this population warrant further research. PMID- 29520829 TI - Cell Phones ? Self and Other Problems with Big Data Detection and Containment during Epidemics. AB - Evidence from Sierra Leone reveals the significant limitations of big data in disease detection and containment efforts. Early in the 2014-2016 Ebola epidemic in West Africa, media heralded HealthMap's ability to detect the outbreak from newsfeeds. Later, big data-specifically, call detail record data collected from millions of cell phones-was hyped as useful for stopping the disease by tracking contagious people. It did not work. In this article, I trace the causes of big data's containment failures. During epidemics, big data experiments can have opportunity costs: namely, forestalling urgent response. Finally, what counts as data during epidemics must include that coming from anthropological technologies because they are so useful for detection and containment. PMID- 29520830 TI - Separating the coherence transfer from chemical shift evolution in high resolution pure shift COSY NMR. AB - Recent developments in data sampling and processing techniques have made it possible to acquire 2-dimensional NMR spectra of small molecules at digital resolutions in both dimensions approaching the intrinsic limitations of the equipment and sample on a realistic timescale. These developments offer the possibility of enormously increased effective resolution (peak dispersion) and the ability to effectively study samples where peak overlap was previously a limiting factor. Examples of such spectra have been produced for a number of 2 dimensional techniques including TOCSY and HSQC. In this paper, we investigate some of the problems in applying such techniques to COSY spectra and suggest a modification to the classic experiment that alleviates some of these problems. PMID- 29520832 TI - Suicidality Among Gay and Bisexual Men in Taiwan: Its Relationships with Sexuality and Gender Role Characteristics, Homophobic Bullying Victimization, and Social Support. AB - This study aimed to examine the associations of suicidality in emerging adulthood with time of coming out, gender role nonconformity, sexual orientation, traditional and cyber homophobic bullying victimization, and family and peer support during childhood in gay and bisexual men in Taiwan. The frequency of "experiencing suicide ideation" and "attempting suicide" in the past year among 500 gay or bisexual men was examined. The participants' time of coming out, level of subjective masculinity, sexual orientation, experiences of traditional and cyber homophobic bullying victimization, and levels of family and peer support during childhood were also evaluated. In total, 31% (n = 155) of participants reported experiencing suicide ideation (n = 82) or attempting suicide (n = 73). Early coming out, traditional homophobic bullying victimization, and low family support during childhood increased the risk of suicidality in emerging adulthood; by contrast, family support did not moderate the association of early coming out or traditional bullying victimization with current suicidality. A high proportion of participants reported experiencing suicide ideation and attempt in emerging adulthood. Hence, effective suicide prevention is required for gay and bisexual men. Suicide prevention programs should consider time of coming out, traditional homophobic bullying victimization, and level of family support. PMID- 29520831 TI - A convolutional neural network to filter artifacts in spectroscopic MRI. AB - PURPOSE: Proton MRSI is a noninvasive modality capable of generating volumetric maps of in vivo tissue metabolism without the need for ionizing radiation or injected contrast agent. Magnetic resonance spectroscopic imaging has been shown to be a viable imaging modality for studying several neuropathologies. However, a key hurdle in the routine clinical adoption of MRSI is the presence of spectral artifacts that can arise from a number of sources, possibly leading to false information. METHODS: A deep learning model was developed that was capable of identifying and filtering out poor quality spectra. The core of the model used a tiled convolutional neural network that analyzed frequency-domain spectra to detect artifacts. RESULTS: When compared with a panel of MRS experts, our convolutional neural network achieved high sensitivity and specificity with an area under the curve of 0.95. A visualization scheme was implemented to better understand how the convolutional neural network made its judgement on single voxel or multivoxel MRSI, and the convolutional neural network was embedded into a pipeline capable of producing whole-brain spectroscopic MRI volumes in real time. CONCLUSION: The fully automated method for assessment of spectral quality provides a valuable tool to support clinical MRSI or spectroscopic MRI studies for use in fields such as adaptive radiation therapy planning. PMID- 29520833 TI - Bone heat generated using conventional implant drills versus piezosurgery unit during apical cortical plate perforation. AB - BACKGROUND: The apical portion of the implant osteotomy receives less irrigation and cooling during surgical preparation. High bone temperature, above the critical 10 degrees C threshold, may impair osseointegration, particularly around dense cortical bone. The aim of this study was to evaluate the apical cortical plate temperature increase with two different devices and pressure loads in a porcine rib ex vivo model. METHODS: A total of 24 implant sites were prepared on porcine ribs, divided into 4 groups of 6 samples each, according to the device used (conventional drill system or piezosurgery) and pressure load applied (1,000 g or 1,500 g). A rubber dam was used to isolate the apical cortical plate from the cooling effect of irrigation. Temperature variation measurements were taken using an infrared thermometer. RESULTS: The piezosurgery unit was two times more likely to increase the osteotomy temperature by 10 degrees C (OR = 2; 95% CI 1.136, 3.522; P < 0.05). The average temperature increase was 0.07 degrees C (SD = 0.10) for group 1 (drill system 1,000 g); 0.22 degrees C (SD = 0.26) for group 2 (drill system 1,500 g); 9.18 degrees C (SD = 4.51) for group 3 (piezosurgery 1,000 g); and 8.17 degrees C (SD = 6.12) for group 4 (piezosurgery 1,500 g). The piezosurgery site preparation had significantly higher temperature increase than did the conventional drill site preparation (P < 0.05). There was no statistically significant difference in temperature change between the two pressure loads applied (P = 0.78). Temperature increases exceeded the critical 10 degrees C threshold in half of the samples prepared with the piezoelectric device. CONCLUSIONS: Bone overheating using a piezosurgery unit is a potential risk during implant site preparation. The piezosurgical device resulted in significantly higher temperatures than did conventional drilling at the apical cortical portion of the osteotomy. The temperature increase was often higher than the critical 10 degrees C threshold. PMID- 29520834 TI - Microanatomy of the digestive tract, hooves and some visceral organs of addax antelope (Addax nasomaculatus) following a concentrate or forage feeding regime. AB - Subacute ruminal acidosis is a common disease in captive non-domesticated ruminants and is mainly diagnosed by rumen fluid pH and rumen histology. Furthermore, differences in ruminant gastrointestinal histology have been hypothesized to correlate with the browser-grazer continuum. Twelve surplus addax antelope (Addax nasomaculatus) were divided into two groups, fed either their usual diet, consisting of a concentrate feed with a limited amount of hay, or a diet of unlimited hay only, for 3 months. After culling, descriptive and morphometric histology and pH measurements were compared between groups. Significant variations in cellular subpopulations were noted between groups, with roughage-fed individuals presenting primarily with balloon cells of the Stratum corneum and living layer cell vacuolization, whereas parakeratosis and intermediate-type cells were more frequent in the concentrate-fed group. Lesions typical of subacute ruminal acidosis were significantly more pronounced in concentrate-fed individuals. Ruminal pH measurements did not differ significantly, but were more consistent in forage-fed individuals, indicating a more stable reticuloruminal environment. The results indicate that ruminal histology may be more appropriate in assessing ruminal health compared to a single post-mortem pH measurement. It is proposed that Stratum corneum balloon cells may indicate cell maturation and not, as previously assumed, hyperfunction. Concentrate-fed individuals scored higher on the presence of inflammatory cells on hoof corium histology. The study further emphasizes the adaptability of ruminant digestive tract microanatomy in adult animals even after a short period of time and the positive effects an increased roughage diet may have in populations of captive grazing ruminants. PMID- 29520835 TI - Sensory gating in the ipsilateral somatosensory cortex during voluntary activity: what might this mean for chronic limb pain? PMID- 29520836 TI - The Impact of Computing Interpregnancy Intervals Without Accounting for Intervening Pregnancy Events. AB - BACKGROUND: Short interpregnancy intervals (IPI) are associated with poor birth outcomes. Often, only livebirths are considered to estimate IPI. The objective of our work is to explore whether the associations between demographic, behavioural, and pregnancy variables and IPI change when events other than livebirth are included. METHODS: We used data from the 2006-10 and 2011-13 period of the National Survey of Family Growth (NSFG). We defined IPI using the conception date of the index pregnancy and the event date of the previous one ending in (i) livebirth; (ii) stillbirth; (iii) miscarriage; (iv) abortion; or (v) any of these events. Risk ratios (RR) were estimated for short IPI (<18 months), and demographic, pregnancy, and behavioural variables using log-linear models. RESULTS: When intervening events are included, the association between short IPI and its predictors vary by definition, especially for unintended versus intended pregnancies (only livebirth risk ratio [RR] 1.34, 95% confidence interval [CI] 1.2, 1.5) versus livebirth and miscarriage RR 1.14, 95% CI 1.0, 1.3) and women older than 30 vs. younger than 20 at resolution of the previous pregnancy (only livebirth RR 1.22, 95% CI 1.0, 1.5 versus livebirth and miscarriage RR 1.36, 95% CI 1.2, 1.6). CONCLUSIONS: Including miscarriage as an intervening event in the calculation of IPI changes the association between several risk factors and short IPI. However, the association between short IPI and preterm birth does not vary when different IPI calculations are used. PMID- 29520837 TI - Health-promoting leadership: An integrative review and future research agenda. AB - AIM: To provide a synthesis of the evidence of health-promoting leadership related to nursing by exploring definitions, core attributes and critical conditions. BACKGROUND: Increasing pressure in healthcare settings due to efficiency requirements, population ageing with complex illnesses and projected global shortage of nurses, is a potential threat to nurses' health and job satisfaction, and patient quality of care and safety. New ways of thinking about nursing leadership and evidence-based human resource management are required to improve nursing environments. DESIGN: Integrative literature review. DATA SOURCES: Eight databases were searched: Academic Search Premier, CINAHL, Emerald, ERIC, Web of Science, MEDLINE, Psychinfo and Science Direct. Included papers were published between 2000-2016. REVIEW METHODS: Of 339 papers, 13 were eligible for inclusion: eight qualitative and five quantitative. Studies were assessed for quality using standardized checklists. Framework-based synthesis was used, allowing for themes identified a priori to be specified as coding categories. This method also allows new themes to emerge de novo. RESULTS: Four themes were identified. There are multiple definitions of health-promoting leadership, along with description of the non-health-promoting leader. The health-promoting nurse leader engages in employees' health promotion, and takes responsibility for actions and maintains open communication, accommodating nurses' participation in change processes. Through competence development, the health-promoting organization builds capacity. CONCLUSION: Health-promoting leadership may be a promising path to optimizing nursing outcomes through holistic thinking, which emphasizes the importance of context. Accumulated research is required to build a stronger line of international research, with attention to underlying mechanisms, limiting conditions and behaviours known to health-promoting leadership. PMID- 29520838 TI - Editorial Comment from Dr Castelli to Thulium laser ablation facilitates retrograde intra-renal surgery for upper urinary tract urothelial carcinoma. PMID- 29520839 TI - Directed Assembly of Hybrid Nanomaterials and Nanocomposites. AB - Hybrid nanomaterials are molecular or colloidal-level combinations of organic and inorganic materials, or otherwise strongly dissimilar materials. They are often, though not exclusively, anisotropic in shape. A canonical example is an inorganic nanorod or nanosheet sheathed in, or decorated by, a polymeric or other organic material, where both the inorganic and organic components are important for the properties of the system. Hybrid nanomaterials and nanocomposites have generated strong interest for a broad range of applications due to their functional properties. Generating macroscopic assemblies of hybrid nanomaterials and nanomaterials in nanocomposites with controlled orientation and placement by directed assembly is important for realizing such applications. Here, a survey of critical issues and themes in directed assembly of hybrid nanomaterials and nanocomposites is provided, highlighting recent efforts in this field with particular emphasis on scalable methods. PMID- 29520840 TI - Photoinduced Self-Assembled Nanostructures and Permanent Polaron Formation in Regioregular Poly(3-hexylthiophene). AB - Solution processing of conjugated polymers into ordered self-assembled precursors has attracted great interest in the past years owing to the ability to manipulate their structural and physical properties. Regioregular poly(3-hexylthiophene) (P3HT) has become the benchmark polymer in this scenario, where ordered lamellar structures significantly improve carrier mobility of the thin films due to increased crystallinity, extended intrachain conjugation, and ordered interchain pi-stacking. Here, a new photoinduced approach is presented for the generation of highly ordered P3HT aggregate structures that is amenable to the use of visible light to control the aggregate formation. Strong intra- and interchain interactions in the solution precursors allow for permanent formation of localized and delocalized polarons that are stable for months. Spin-coated thin films are found to preserve, in part, the morphological and physical properties of the aggregated P3HT solution precursors with high degree of crystallinity and short pi-stack interchain distances. PMID- 29520841 TI - Adductor magnus: An EMG investigation into proximal and distal portions and direction specific action. AB - Cadaveric studies indicate that adductor magnus is structurally partitioned into at least two regions. The aim of this study was to investigate the direction specific actions of proximal and distal portions of adductor magnus, and in doing so determine if these segments have distinct functional roles. Fine-wire EMG electrodes were inserted into two portions of adductor magnus of 12 healthy young adults. Muscle activity was recorded during maximum voluntary isometric contractions (MVICs) across eight tests (hip flexion/extension, internal/external rotation, abduction, and adduction at 0 degrees , 45 degrees , and 90 degrees hip flexion). Median activity within each action (normalized to peak) was compared between segments using repeated measures nonparametric tests (alpha = 0.05). An effect size (ES = z-score/?sample size) was calculated to determine the magnitude of difference between muscle segments. The relative contribution of each muscle segment differed significantly during internal rotation (P < 0.001; ES = 0.88) and external rotation (P = 0.003, ES = 0.79). The distal portion was most active during extension [median (interquartile range); 100(0)% MVIC)] and internal rotation [58(34)% MVIC]. The proximal portion was most active during extension [100(49)% MVIC] and adduction [59(64)%MVIC], with low level activity during external rotation [15(41)%MVIC]. This study suggests that adductor magnus has at least two functionally unique regions. Differences were most evident during rotation. The different direction-specific actions may imply that each segment performs separate roles in hip stability and movement. These findings may have implications on injury prevention and rehabilitation for adductor-related groin injuries, hamstring strain injury, and hip pathology. Clin. Anat. 31:535 543, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29520842 TI - Mapping the landscape of urology: A new media-based cross-sectional analysis of public versus academic interest. AB - OBJECTIVES: To quantify public and academic interest in the urological field using a novel new media-based methodology. METHODS: We systematically measured public and academic interest in 56 urological keywords and combined in nine subspecialties. Public interest was quantified as video views on YouTube. Academic interest was quantified as article citations using Microsoft Academic Search. The public-to-academic interest ratio was calculated for a comparison of subspecialties as well as for diseases and treatments. RESULTS: For the selected 56 urological keywords, we found 226 617 591 video views on YouTube and 2 146 287 citations in the academic literature. The public-to-academic interest ratio was highest for the subspecialties robotic urology (ratio 6.3) and andrological urology (ratio 4.6). Prostate cancer was the central urological disease combining both a high public (20% of all video views) and academic interest (26% of all citations, ratio 0.8). Further diseases/treatments of high public interest were premature ejaculation (ratio 54.4), testicular cancer (ratio 11.4), erectile dysfunction (ratio 5.5) and kidney transplant (ratio 3.7). Urological treatments had a higher public-to-academic interest ratio (median ratio 0.25) than diseases (median ratio 0.05; P = 0.029). CONCLUSIONS: A quantification of academic and public interest in the urological field is feasible using a novel new media-based methodology. We found several mismatches in public versus academic interest in urological diseases and treatments, which has implications for research strategies, conference planning and patient information projects. Regular re assessments of the public and academic interest landscape can contribute to detecting and proving trends in the field of urology. PMID- 29520843 TI - Lymphatic growth factors are expressed in human gingiva and upregulated in gingival fibroblasts after stimulation. AB - BACKGROUND: The lymphatic growth factors vascular endothelial growth factor (VEGF)-C and -D are important for maintenance and growth of lymphatic vessels (lymphangiogenesis), but their localization in human gingiva is unknown. This study investigated the expression of VEGF-C and -D in human gingiva and isolated human gingival fibroblasts (HGFs). In addition, the localization of their main receptor VEGFR-3 was explored. METHODS: Non-inflamed gingiva from six donors was used for immunohistochemistry or isolation of HGFs. HGFs were stimulated with either E.coli lipopolysaccharide (LPS) or IL-6/soluble IL-6 receptor (sIL-6R) complex for 1, 6, and 24 hours. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to quantify the relative changes in gene expression of VEGF-A, -C, and -D and enzyme-linked immunosorbent assay (ELISA) for quantification of protein levels. RESULTS: VEGF-C, -D and VEGFR-3 were seen in keratinocytes, blood vessels and in scattered single cells in gingiva. VEGFR-3 was also found in lymphatic vessels and VEGF-C in cells with fibroblastic appearance. Gene analysis showed no expression of VEGF-D in the HGFs, but showed constitutive expression of VEGF-C and -A. Stimulation of HGFs with LPS or IL-6/sIL-6R complex was followed by gene upregulation of VEGF-C and -A and increased protein levels in cell culture supernatant (P <=0.05). CONCLUSIONS: The localization of VEGF-C, -D, and VEGFR-3 expression imply that signaling via VEGFR-3 is linked to vascular homeostasis and keratinocyte function under normal conditions in gingiva. Inflammatory stimulation of HGFs upregulates VEGF-C and -A expression and may contribute to angiogenesis and lymphangiogenesis. PMID- 29520844 TI - Children with sickle cell anemia with normal transcranial Doppler ultrasounds and without silent infarcts have a low incidence of new strokes. AB - In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow-up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow-up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow-up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062-0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification. PMID- 29520845 TI - Draper-mediated JNK signaling is required for glial phagocytosis of apoptotic neurons during Drosophila metamorphosis. AB - Development of the central nervous system involves elimination of superfluous neurons through apoptosis and subsequent phagocytosis. In Drosophila, this occurs mainly during three developmental stages: embryogenesis, metamorphosis and emerging adult. Two transmembrane glial phagocytic receptors, SIMU (homolog of the mammalian Stabilin-2) and Draper (homolog of the mammalian MEGF10 and Jedi), mediate glial phagocytosis of apoptotic neurons during embryogenesis. However, less is known about the removal of apoptotic neurons during later stages of development. Here we show that during metamorphosis, Draper plays a critical role in apoptotic cell clearance by glia, whereas SIMU, which is mostly expressed in pupal macrophages outside the brain, is not involved in glial phagocytosis. We found that Draper activates Drosophila c-Jun N-terminal kinase (dJNK) signaling predominantly in the ensheathing glia and astrocytes, where it is required for efficient removal of apoptotic neurons. Our data suggest that besides the dJNK pathway, Draper also triggers an additional signaling pathway capable of removing apoptotic neurons in the pupal brain. This study thus reveals that SIMU unexpectedly is not involved in glial phagocytosis of apoptotic neurons during metamorphosis and highlights the novel role of dJNK signaling in developmental apoptotic cell clearance downstream of Draper. PMID- 29520846 TI - Dissipative Self-Assembly Driven by the Consumption of Chemical Fuels. AB - Dissipative self-assembly leads to structures and materials that exist away from equilibrium by continuously exchanging energy and materials with the external environment. Although this mode of self-assembly is ubiquitous in nature, where it gives rise to functions such as signal processing, motility, self-healing, self-replication, and ultimately life, examples of dissipative self-assembly processes in man-made systems are few and far between. Herein, recent progress in developing diverse synthetic dissipative self-assembly systems is discussed. The systems reported thus far can be categorized into three classes, in which: i) the fuel chemically modifies the building blocks, thus triggering their self assembly, ii) the fuel acts as a template interacting with the building blocks noncovalently, and iii) transient states are induced by the addition of two mutually exclusive stimuli. These early studies give rise to materials that would be difficult to obtain otherwise, including hydrogels with programmable lifetimes, vesicular nanoreactors, and membranes exhibiting transient conductivity. PMID- 29520847 TI - Detectable end of radiation prostate specific antigen assists in identifying men with unfavorable intermediate-risk prostate cancer at high risk of distant recurrence and cancer-specific mortality. AB - BACKGROUND: Undetectable End of Radiation PSA (EOR-PSA) has been shown to predict improved survival in prostate cancer (PCa). While validating the unfavorable intermediate-risk (UIR) and favorable intermediate-risk (FIR) stratifications among Johns Hopkins PCa patients treated with radiotherapy, we examined whether EOR-PSA could further risk stratify UIR men for survival. METHODS: A total of 302 IR patients were identified in the Johns Hopkins PCa database (178 UIR, 124 FIR). Kaplan-Meier curves and multivariable analysis was performed via Cox regression for biochemical recurrence free survival (bRFS), distant metastasis free survival (DMFS), and overall survival (OS), while a competing risks model was used for PCa specific survival (PCSS). Among the 235 patients with known EOR-PSA values, we then stratified by EOR-PSA and performed the aforementioned analysis. RESULTS: The median follow-up time was 11.5 years (138 months). UIR was predictive of worse DMFS and PCSS (P = 0.008 and P = 0.023) on multivariable analysis (MVA). Increased radiation dose was significant for improved DMFS (P = 0.016) on MVA. EOR-PSA was excluded from the models because it did not trend towards significance as a continuous or binary variable due to interaction with UIR, and we were unable to converge a multivariable model with a variable to control for this interaction. However, when stratifying by detectable versus undetectable EOR PSA, UIR had worse DMFS and PCSS among detectable EOR-PSA patients, but not undetectable patients. UIR was significant on MVA among detectable EOR-PSA patients for DMFS (P = 0.021) and PCSS (P = 0.033), while RT dose also predicted PCSS (P = 0.013). CONCLUSIONS: EOR-PSA can assist in predicting DMFS and PCSS among UIR patients, suggesting a clinically meaningful time point for considering intensification of treatment in clinical trials of intermediate-risk men. PMID- 29520849 TI - LncRNA H19 targets miR-22 to modulate H2 O2 -induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling. AB - Intervertebral disc (IVD) degeneration (IDD) is a major contributor to low back pain. During IDD progression, ROS can be produced in the form of H2 O2 in nucleus pulposus cells (NPCs) in response to elevated cytokines, leading to subsequent alternations of cell fate and metabolic processes. Genetic factors are considered as main contributors to IDD pathopoiesis. Herein, we investigated the detailed function and mechanism of H19, one of the most up-regulated lncRNAs in IDD specimens, in H2 O2 -induced cell senescence model in NPCs. H19 could accelerate H2 O2 -induced degenerative changes by promoting cell senescence, increasing ADAMTS-5 and MMPs protein levels and Collagen I content, as well as suppressing NPC proliferation through activating Wnt/beta-catenin signaling. Moreover, miR 22, a direct target of H19, could bind to the 3'UTR of LEF1 to inhibit its expression and reverse the effect of H19 on NPCs, thus inhibiting Wnt/beta catenin signaling. Taken together, H19 acts as a ceRNA to compete with LEF1 for miR-22, thus modulating downstream Wnt/beta-catenin signaling in NPCs; H19/miR 22/LEF1 might be a novel target for improving H2 O2 -induced NPC senescence and treatment for IDD. PMID- 29520850 TI - Exploring the oncoproteomic response of human prostate cancer to therapeutic radiation using data-independent acquisition (DIA) mass spectrometry. AB - INTRODUCTION: The development of radioresistance in prostate cancer (PCa) is an important clinical issue and is still largely uninformed by personalized molecular characteristics. The aim of this study was to establish a platform that describes the early oncoproteomic response of human prostate tissue to radiation therapy (RT) using a prospective human tissue cohort. METHODS: Fresh and fixed transperineal biopsies from eight men with clinically localized tumors were taken prior to and 14 days following a single fraction of high-dose-rate brachytherapy. Quantitative protein analysis was achieved using an optimized protein extraction pipeline and subsequent data-independent acquisition mass spectroscopy (DIA-MS). Ontology analyses were used to identify enriched functional pathways, with the candidates further interrogated in formalin-fixed paraffin-embedded tissue biopsies from five additional patients. RESULTS: We obtained a mean coverage of 5660 proteins from fresh tissue biopsies; with the principal post-radiation change observed being an increase in levels amongst a total of 49 proteins exhibiting abundance changes. Many of these changes in abundance varied between patients and, typically to prostate cancer tissue, exhibited a high level of heterogeneity. Ontological analysis revealed the enrichment of the protein activation cascades of three immunological pathways: humoral immune response, leukocyte mediated immunity and complement activation. These were predominantly associated with the extracellular space. We validated significant expression differences in between 20% and 61% of these candidates using the separate fixed tissue cohort and established their feasibility as an experimental tissue resource by acquiring quantitative data for a mean of 5152 proteins per patient. DISCUSSION: In this prospective study, we have established a sensitive and reliable oncoproteomic pipeline for the analysis of both fresh and formalin-fixed human PCa tissue. We identified multiple pathways known to be radiation responsive and have established a powerful database of candidates and pathways with no current association with RT. This information may be beneficial in the advancement of personalized therapies and potentially, predictive biomarkers. PMID- 29520848 TI - Core outcome domains in incontinence-associated dermatitis research. AB - AIM: To report the development of a core set of outcome domains for clinical research involving adults with incontinence-associated dermatitis or at risk, independently from any geographical location or skin colour. BACKGROUND: The management of incontinence-associated dermatitis is important in caring for incontinent patients. The lack of comparability of clinical trial outcomes is a major challenge in the field of evidence-based incontinence-associated dermatitis prevention and treatment. Core outcome sets may therefore be helpful to improve the value of clinical incontinence-associated dermatitis research. DESIGN: Systematic literature review, patient interviews and consensus study using Delphi procedure. METHODS: A list of outcome domains was generated through a systematic literature review (no date restrictions-April 2016), consultation of an international steering committee and three patient interviews. The project team reviewed and refined the outcome domains prior to starting a three-round Delphi procedure conducted between April-September 2017. The panellists, including healthcare providers, researchers and industry were invited to rate the importance of the outcome domains. RESULTS: We extracted 1,852 outcomes from 244 articles. Experts proposed 56 and patients 32 outcome domains. After refinement, 57 panellists from 17 countries rated a list of 58 outcome domains. The final list of outcome domains includes erythema, erosion, maceration, IAD-related pain and patient satisfaction. CONCLUSION: Erythema, erosion, maceration, incontinence associated dermatitis -related pain and patient satisfaction are the most important outcome domains to be measured in incontinence-associated dermatitis trials. Based on this international consensus on what to measure, the question of how to measure these domains now requires consideration. Registration: This project has been registered in the Core Outcome Measures in Effectiveness Trials (COMET Initiative) database and is part of the Cochrane Skin Group-Core Outcomes Set Initiative (CSG-COUSIN). PMID- 29520851 TI - Adrenaline and cortisol levels are lower during nighttime than daytime hypoglycaemia in children with type 1 diabetes. AB - AIM: We investigated children's counter regulatory hormone profiles during a hyperinsulinaemic hypoglycaemic clamp procedure at day and night. METHODS: In 2013, we assessed the counter regulatory response to hypoglycaemia in eight outpatients with type 1 diabetes, recruited from the Herlev Hospital, Denmark, at a mean age of 9.6 +/- 2.3 years. Hyperinsulinaemic 80 mU/m2 /min clamps were performed with a stepwise reduction in plasma glucose from euglycaemia (7-9 mmol/L) to hypoglycaemia (<3.5 mmol/L) and the glucose nadir (<=2.2 mmol/L) during the day and night. Adrenaline, cortisol, glucagon and growth hormone levels were assessed. RESULTS: Adrenaline and growth hormone levels were higher during the day versus the night (p = 0.04 and p = 0.01, respectively). However, at the glucose nadir, the level of adrenaline was lower during the night than the day (0.6 +/- 0.2 versus 1.9 +/- 0.5 nmol/L, p = 0.016) and cortisol was lower during the day than the night (42 +/- 15 versus 319 +/- 81 nmol/L, p = 0.016). No differences were demonstrated for glucagon and growth hormone levels based on the same criteria. CONCLUSION: The adrenaline response was blunted during nocturnal iatrogenic hypoglycaemia in our study cohort, and no increase in cortisol levels was demonstrated. PMID- 29520854 TI - CORRIGENDUM. PMID- 29520852 TI - Satellite glial cells represent a population of developmentally arrested Schwann cells. AB - Satellite glial cells (SGCs) are glial cells in the peripheral nervous system that form sheaths around the neuronal cell body. This unique arrangement of SGCs allows it to exert a highly regulated control over the neuronal microenvironment. Not much is known about the origin of SGCs. In this study, we examine the development of SGCs. We show that rat SGCs develop postnatally and these cells express a number of markers associated with Schwann cell precursors, in particular cadherin-19 (CDH19) even in adult DRGs. We developed a method for the purification of SGCs and showed that they are transcriptionally and morphologically very similar to adult rat Schwann cells (SCs). Finally, we demonstrate that purified SGCs are capable of myelinating embryonic axons when cocultured with those axons. Based on these observations we hypothesize that SGCs represent a population of cells in the SC lineage, whose further differentiation appears to be arrested through contact with DRG neuronal soma. PMID- 29520855 TI - The composition of prostate core matrisome in vivo and in vitro unveiled by mass spectrometric analysis. AB - BACKGROUND: The composition and organization of extracellular matrix (ECM) are important regulators of cell behavior. In particular in the prostate, this central role of the ECM is further stressed by the fact that several potential markers of prostate stem cells are matrix receptors. METHODS: We established 12 fibroblastic cell lines from cancerous and non-cancerous areas of six prostates and allowed the cells to produce ECM under cell culture conditions. We also performed a proteome wide analysis of the ECM components by mass spectrometry. To study the in vitro activation of fibroblastic cells we compared the differences between the ECM produced in cell culture by six non-cancerous-tissue-derived fibroblasts and the in vivo matrisome from the corresponding non-cancerous tissue of prostate. RESULTS: Our results suggest that at tissue level the ECM is mainly produced by fibroblastic cells and that it contains standard collagen I fibrils and fibril-associated proteins. Beaded-filament forming collagen VI is also abundant and basement membranes potentially contain five laminin subtypes and collagens XV and XVIII. As the main finding, we also detected differences when in vivo and in vitro matrisomes were compared. Only 65 out of 206 proteins were found to be common for both in vivo and in vitro samples. Majority of the 55 proteins, which were solely detected in in vivo samples, were considered to be plasma derived. Eighty-six proteins were solely found from in vitro fibroblast derived ECM, and most of them were related to matrix remodeling or growth factor action, proposing that the activation of fibroblasts in cell culture may remarkably modify their gene expression profile. Finally, in comparison to traditional 2D in vitro cell culture, the ECM composition of 3D spheroid culture was analyzed. The matrisome in spheroid culture did not resemble the in vivo ECM more closely than in monolayer culture. CONCLUSIONS: Artificial activation of ECM remodeling seems to be a distinctive feature in in vitro models. In conclusion the constitution of ECM produced by prostate derived fibroblasts in vitro is similar, but not identical to the prostate ECM in vivo as shown here by mass spectrometric analysis. PMID- 29520856 TI - Synchronization in the prefrontal-striatal circuit tracks behavioural choice in a go-no-go task in rats. AB - Rodent striatum is involved in sensory-motor transformations and reward-related learning. Lesion studies suggest dorsolateral striatum, dorsomedial striatum and nucleus accumbens underlie stimulus-response transformations, goal-directed behaviour and reward expectation, respectively. In addition, prefrontal inputs likely control these functions. Here, we set out to study how reward-driven behaviour is mediated by the coordinated activity of these structures in the intact brain. We implemented a discrimination task requiring rats to either respond or suppress responding on a lever after the presentation of auditory cues in order to obtain rewards. Single unit activity in the striatal subregions and pre-limbic cortex was recorded using tetrode arrays. Striatal units showed strong onset responses to auditory cues paired with an opportunity to obtain reward. Cue onset responses in both striatum and cortex were significantly modulated by previous errors suggesting a role of these structures in maintaining appropriate motivation or action selection during ongoing behaviour. Furthermore, failure to respond to the reward-paired tones was associated with higher pre-trial coherence among striatal subregions and between cortex and striatum suggesting a task negative corticostriatal network whose activity may be suppressed to enable processing of reward-predictive cues. Our findings highlight that coordinated activity in a distributed network including both pre-limbic cortex and multiple striatal regions underlies reward-related decisions. PMID- 29520857 TI - Pityriasis rosea-like eruption associated with ondansetron use in pregnancy. AB - A 30-year-old pregnant female presented with a 2-week history of pityriasis rosea like eruption. The rash started 2 days after the patient had started taking ondansetron 8 mg for alleviation of moderate-to-severe nausea and vomiting of pregnancy. Physical examination revealed erythematous papulosquamous lesions characterized by annular scaly margins and a dusky centre over the arms, chest, abdomen, lower back and legs. The rash did not involve the palms, sole or mucous membranes, and no lesions were observed on the lymph nodes. Ondansetron was discontinued. The rash ceased to spread and started to disappear within 2 weeks with full resolution noted after 1 month. Analysis of the case using the Naranjo adverse drug reaction probability scale indicated that ondansetron was the probable cause of the pityriasis rosea-like eruption. This is the first case report of pityriasis rosea related to ondansetron therapy. PMID- 29520858 TI - Principal component analysis of normalized full spectrum mass spectrometry data in multiMS-toolbox: An effective tool to identify important factors for classification of different metabolic patterns and bacterial strains. AB - RATIONALE: Explorative statistical analysis of mass spectrometry data is still a time-consuming step. We analyzed critical factors for application of principal component analysis (PCA) in mass spectrometry and focused on two whole spectrum based normalization techniques and their application in the analysis of registered peak data and, in comparison, in full spectrum data analysis. We used this technique to identify different metabolic patterns in the bacterial culture of Cronobacter sakazakii, an important foodborne pathogen. METHODS: Two software utilities, the ms-alone, a python-based utility for mass spectrometry data preprocessing and peak extraction, and the multiMS-toolbox, an R software tool for advanced peak registration and detailed explorative statistical analysis, were implemented. The bacterial culture of Cronobacter sakazakii was cultivated on Enterobacter sakazakii Isolation Agar, Blood Agar Base and Tryptone Soya Agar for 24 h and 48 h and applied by the smear method on an Autoflex speed MALDI-TOF mass spectrometer. RESULTS: For three tested cultivation media only two different metabolic patterns of Cronobacter sakazakii were identified using PCA applied on data normalized by two different normalization techniques. Results from matched peak data and subsequent detailed full spectrum analysis identified only two different metabolic patterns - a cultivation on Enterobacter sakazakii Isolation Agar showed significant differences to the cultivation on the other two tested media. The metabolic patterns for all tested cultivation media also proved the dependence on cultivation time. CONCLUSIONS: Both whole spectrum based normalization techniques together with the full spectrum PCA allow identification of important discriminative factors in experiments with several variable condition factors avoiding any problems with improper identification of peaks or emphasis on bellow threshold peak data. The amounts of processed data remain still manageable. Both implemented software utilities are available free of charge from http://uprt.vscht.cz/ms. PMID- 29520859 TI - Contrast gain control and retinogeniculate communication. AB - Visual information processed in the retina is transmitted to primary visual cortex via relay cells in the lateral geniculate nucleus (LGN) of the dorsal thalamus. Although retinal ganglion cells are the primary source of driving input to LGN neurons, not all retinal spikes are transmitted to the cortex. Here, we investigate the relationship between stimulus contrast and retinogeniculate communication and test the hypothesis that both the time course and strength of retinogeniculate interactions are dynamic and dependent on stimulus contrast. By simultaneously recording the spiking activity of synaptically connected retinal ganglion cells and LGN neurons in the cat, we show that the temporal window for retinogeniculate integration and the effectiveness of individual retinal spikes are inversely proportional to stimulus contrast. This finding provides a mechanistic understanding for the phenomenon of augmented contrast gain control in the LGN-a nonlinear receptive field property of LGN neurons whereby response gain during low-contrast stimulation is enhanced relative to response gain during high-contrast stimulation. In addition, these results support the view that network interactions beyond the retina play an essential role in transforming visual signals en route from retina to cortex. PMID- 29520860 TI - Antiadipogenic effects of a standardized quassinoids-enriched fraction and eurycomanone from Eurycoma longifolia. AB - Bioactive compounds of Eurycoma longifolia (EL) jack were previously shown to reduce omentum fat mass and oestradiol-induced fatty uterine adhesion in rats. However, the exact role of EL on adipogenesis remains unknown. This study sought to investigate the effects of an EL standardized quassinoids-enriched fraction (SQEL) and the pure compound, eurycomanone, on adipogenesis in 3T3-L1 preadipocyte cells. 3T3-L1 cells were induced to differentiate and treated for 8 days. The treatment reduced intracellular accumulation of lipid droplets and triglycerides in the differentiating adipocytes and induced lipolysis in matured adipocytes. The expressions of adipogenic transcription factors and markers were also significantly downregulated during the early stage of differentiation. Furthermore, SQEL also suppressed body weight gain, decreased epididymal and perirenal fat pad mass and size, and reduced the accumulation of fat in the livers of C57BL/6J mice fed with normal or high-fat diet that were concurrently given 5 mg/kg and 10 mg/kg (i.p) of SQEL for 12 weeks. SQEL also improved glucose intolerance and decreased the elevated total cholesterol and triglyceride levels in these mice groups. These findings suggest that SQEL could be explored as an alternative pharmacologic agent inhibiting adipogenesis for the prevention of obesity. PMID- 29520861 TI - Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk. AB - INTRODUCTION: Venous thromboembolism (VTE) is highly heritable. Physical activity, physical inactivity and body mass index (BMI) are also risk factors, but evidence of interaction between genetic and environmental risk factors is limited. METHODS: Data on 2,134 VTE cases and 3,890 matched controls were obtained from the Nurses' Health Study (NHS), Nurses' Health Study II (NHS II), and Health Professionals Follow-up Study (HPFS). We calculated a weighted genetic risk score (wGRS) using 16 single nucleotide polymorphisms associated with VTE risk in published genome-wide association studies (GWAS). Data on three risk factors, physical activity (metabolic equivalent [MET] hours per week), physical inactivity (sitting hours per week) and BMI, were obtained from biennial questionnaires. VTE cases were incident since cohort inception; controls were matched to cases on age, cohort, and genotype array. Using conditional logistic regression, we assessed joint effects and interaction effects on both additive and multiplicative scales. We also ran models using continuous wGRS stratified by risk-factor categories. RESULTS: We observed a supra-additive interaction between wGRS and BMI. Having both high wGRS and high BMI was associated with a 3.4-fold greater risk of VTE (relative excess risk due to interaction = 0.69, p = 0.046). However, we did not find evidence for a multiplicative interaction with BMI. No interactions were observed for physical activity or inactivity. CONCLUSION: We found a synergetic effect between a genetic risk score and high BMI on the risk of VTE. Intervention efforts lowering BMI to decrease VTE risk may have particularly large beneficial effects among individuals with high genetic risk. PMID- 29520863 TI - Density Functional Theory Simulations of Water Adsorption and Activation on the ( 201) beta-Ga2 O3 Surface. AB - Density functional theory calculations are used to study the molecular and dissociative adsorption of water on the (-201) beta-Ga2 O3 surface. The effect of adsorption of different water-like species on the geometry, binding energies, vibrational spectra and the electronic structure of the surface are discussed. The study shows that although the hydrogen evolution reaction requires a small amount of energy to become energetically favourable, the over potential for activating the oxygen evolution reaction is quite high. The results of our calculations provide insight as to why a high voltage is required in experiments to activate the water-splitting reaction, whereas previous studies of gallium oxide predicted very low activation energies for other energetically more favourable facets. Application of this work to studies of GaN-based chemical sensors with gallium oxide surfaces shows that it is possible to select the gate bias so that the sensors are not influenced by water-splitting reactions. It was also found that in the region where water splitting does not occur, the surface can exist in two states, that is, water or hydroxyl terminated. PMID- 29520862 TI - Circadian clock components control daily growth activities by modulating cytokinin levels and cell division-associated gene expression in Populus trees. AB - Trees are carbon dioxide sinks and major producers of terrestrial biomass with distinct seasonal growth patterns. Circadian clocks enable the coordination of physiological and biochemical temporal activities, optimally regulating multiple traits including growth. To dissect the clock's role in growth, we analysed Populus tremula * P. tremuloides trees with impaired clock function due to down regulation of central clock components. late elongated hypocotyl (lhy-10) trees, in which expression of LHY1 and LHY2 is reduced by RNAi, have a short free running period and show disrupted temporal regulation of gene expression and reduced growth, producing 30-40% less biomass than wild-type trees. Genes important in growth regulation were expressed with an earlier phase in lhy-10, and CYCLIN D3 expression was misaligned and arrhythmic. Levels of cytokinins were lower in lhy-10 trees, which also showed a change in the time of peak expression of genes associated with cell division and growth. However, auxin levels were not altered in lhy-10 trees, and the size of the lignification zone in the stem showed a relative increase. The reduced growth rate and anatomical features of lhy-10 trees were mainly caused by misregulation of cell division, which may have resulted from impaired clock function. PMID- 29520864 TI - Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma. AB - BACKGROUND: The release of various inflammatory mediators into the bronchial lumen is thought to reflect both the type and degree of airway inflammation, eosinophilic Th2, and Th9, or neutrophilic Th1, and Th17, in patients with asthma. AIMS: We investigated whether cytokines and chemokines differed in sputum from subjects with more severe compared with milder asthma and whether unbiased factor analysis of cytokine and chemokine groupings indicates specific inflammatory pathways. METHODS: Cell-free supernatants from induced sputum were obtained from subjects with a broad range of asthma severity (n = 158) and assessed using Milliplex(r) Cytokines/Chemokine kits I, II and III, measuring 75 individual proteins. Each cytokine, chemokine or growth factor concentration was examined for differences between asthma severity groups, for association with leucocyte counts, and by factor analysis. RESULTS: Severe asthma subjects had 9 increased and 4 decreased proteins compared to mild asthma subjects and fewer differences compared to moderate asthma. Twenty-six mediators were significantly associated with an increasing single leucocyte type: 16 with neutrophils (3 interleukins [IL], 3 CC chemokines, 4 CXC chemokines, 4 growth factors, TNF-alpha and CX3CL1/Fractalkine); 5 with lymphocytes (IL-7, IL-16, IL-23, IFN-alpha2 and CCL4/MIP1beta); IL-15 and CCL15/MIP1delta with macrophages; IL-5 with eosinophils; and IL-4 and TNFSF10/TRAIL with airway epithelial cells. Factor analysis grouped 43 cytokines, chemokines and growth factors which had no missing data onto the first 10 factors, containing mixes of Th1, Th2, Th9 and Th17 inflammatory and anti-inflammatory proteins. CONCLUSIONS: Sputum cytokines, chemokines and growth factors were increased in severe asthma, primarily with increased neutrophils. Factor analysis identified complex inflammatory protein interactions, suggesting airway inflammation in asthma is characterized by overlapping immune pathways. Thus, focus on a single specific inflammatory mediator or pathway may limit understanding the complexity of inflammation underlying airway changes in asthma and selection of appropriate therapy. PMID- 29520865 TI - Schwann cells regulate sensory neuron gene expression before and after peripheral nerve injury. AB - Sensory neurons in the PNS demonstrate substantial capacity for regeneration following injury. Recent studies have identified changes in the transcriptome of sensory neurons, which are instrumental for axon regeneration. The role of Schwann cells (SCs) in mediating these changes remains undefined. We tested the hypothesis that SCs regulate expression of genes in sensory neurons before and after PNS injury by comparing mice in which LDL Receptor-related Protein-1 (LRP1) is deleted in SCs (scLRP1-/- mice) with wild-type (scLRP1+/+ ) littermates. LRP1 is an endocytic and cell-signaling receptor that is necessary for normal SC function and the SC response to nerve injury. scLRP1-/- mice represent a characterized model in which the SC response to nerve injury is abnormal. Adult DRG neurons, isolated from scLRP1-/- mice, with or without a conditioning nerve lesion, demonstrated increased neurite outgrowth when cultured ex vivo, compared with neurons from wild-type mice. Following sciatic nerve crush injury, nerve regeneration was accelerated in vivo in scLRP1-/- mice. These results were explained by transcriptional activation of RAGs in DRG neurons in scLRP1-/- mice prior to nerve injury. Although the presence of abnormal SCs in scLRP1-/- mice primed DRG neurons for repair, nerve regeneration in scLRP1-/- mice resulted in abnormalities in ultrastructure, principally in Remak bundles, and with the onset of neuropathic pain. These results demonstrate the importance of SCs in controlling RAG expression by neurons and the potential for this process to cause chronic pain when abnormal. The SC may represent an important target for preventing pain following PNS injury. PMID- 29520867 TI - Randomised double-blind comparison of bolus phenylephrine or ephedrine for treatment of hypotension in women with pre-eclampsia undergoing caesarean section. AB - Treatment of post-spinal hypotension during caesarean section assumes special concern in pre-eclamptic patients due to a compromised fetoplacental circulation and increased risk of placental hypoperfusion. Phenylephrine and ephedrine are the most commonly used vasopressors, although the best choice is still not clear. We studied 80 pre-eclamptic women with a singleton pregnancy who underwent caesarean section with spinal anaesthesia, and who developed hypotension defined as a decrease in systolic arterial pressure >= 20% from baseline or absolute value < 100 mmHg. Women were randomly allocated to receive phenylephrine 50 MUg or ephedrine 4 mg boluses for treatment of hypotension. Blood pressure changes following vasopressor administration were similar in both groups, but heart rate remained higher after ephedrine at all time-points. The primary outcome measure of umbilical artery pH was 7.26 (0.11) in the phenylephrine group and 7.25 (0.09) in the ephedrine group (p = 0.86). The incidence of neonatal acidosis (umbilical artery pH < 7.20) was 9 (22.5%) in the phenylephrine group and 11 (27.5%) in the ephedrine group (p = 0.80). Other secondary outcome measures were comparable. In conclusion, phenylephrine 50 MUg and ephedrine 4 mg, administered as intravenous boluses to treat post-spinal hypotension during caesarean section in pre eclamptic patients, resulted in similar fetal acid-base values, were equally effective in treating hypotension and were associated with good maternal and neonatal outcome. PMID- 29520868 TI - Systemic nocardiosis in a lepromatous leprosy patient with type 2 reaction. PMID- 29520866 TI - Hypothalamic epigenetics driving female puberty. AB - Puberty involves a series of morphological, physiological and behavioural changes during the last part of the juvenile period that culminates in the attainment of fertility. The activation of the pituitary-gonadal axis by increased hypothalamic secretion of gonadotrophin-releasing hormone (GnRH) is an essential step in the process. The current hypothesis postulates that a loss of transsynaptic inhibition and a rise in excitatory inputs are responsible for the activation of GnRH release. Similarly, a shift in the balance in the expression of puberty activating and puberty inhibitory genes exists during the pubertal transition. In addition, recent evidence suggests that the epigenetic machinery controls this genetic balance, giving rise to the tantalising possibility that epigenetics serves as a relay of environmental signals known for many years to modulate pubertal development. Here, we review the contribution of epigenetics as a regulatory mechanism in the hypothalamic control of female puberty. PMID- 29520869 TI - Circularly polarized luminescence of helically assembled pyrene pi-stacks on RNA and DNA duplexes. AB - In this report, we describe the circularly polarized luminescence (CPL) of the RNA duplexes having one to four 2'-O-pyrene modified uridines (Upy) and the DNA duplexes having two, four, and six pyrene modified non-nucleosidic linkers (Py). Both the pyrene pi-stack arrays formed on the RNA and DNA double helical structures exhibited pyrene excimer fluorescence. In the pyrene-modified RNA systems, the RNA duplex having four Upys gives CPL emission with glum value of <0.01 at 480 nm. The structure of pyrene stacks on the RNA duplex may be rigidly regulated with increase in the Upy domains, which resulted in the CPL emission. In the DNA systems, the pyrene-modified duplexes containing two and four Pys exhibited CPL emission with glum values of <0.001 at 505 nm. The pyrene pi-stack arrays presented here show CPL emission. However, the glum values are relatively small when compared with our previous system consisting of the pyrene-zipper arrays on RNA. PMID- 29520870 TI - Effects of anesthesia on renal function and metabolism in rats assessed by hyperpolarized MRI. AB - PURPOSE: Anesthesia is necessary for most animal studies requiring invasive procedures. It is well documented that various types of anesthesia modulate a wide variety of important metabolic and functional processes in the body, and as such, represent a potential limitation in the study design. In the present study, we aimed to investigate the renal functional and metabolic consequences of 3 typical rodent anesthetics used in preclinical MRI: sevoflurane, inaction, and a mixture of fentanyl, fluanisone, and midazolam (FFM). METHODS: The renal effects of 3 different classes of anesthetics (inactin, servoflurane, and FFM) were investigated using functional and metabolic MRI. The renal glucose metabolism and hemodynamics was characterized with hyperpolarized [1-13 C]pyruvate MRI and by DCE imaging. RESULTS: Rats receiving sevoflurane or FFM had blood glucose levels that were 1.3-fold to 1.4-fold higher than rats receiving inactin. A 2.9-fold and 4.8-fold increased 13 C-lactate/13 C-pyruvate ratio was found in the FFM mixture anesthetized group compared with the sevoflurane and the inactin anesthetized groups. The FFM anesthesia resulted in a 50% lower renal plasma flow compared with the sevoflurane and the inactin anesthetized groups. CONCLUSION: This study demonstrates different renal metabolic and hemodynamic changes under 3 different anesthetics, using hyperpolarized MR in rats. Inactin and sevoflurane were found to affect the renal hemodynamic and metabolic status to a lesser degree than FFM. Sevoflurane anesthesia is particularly easy to induce and maintain during the whole anesthesia procedure, and as such, represents a good alternative to inaction, although it alters the blood glucose level. PMID- 29520871 TI - Effects of intra-yolk-sac injection of dextrose and albumin on performance, jejunum morphology, liver and pectoral muscle glycogen and some serum metabolites of broilers. AB - This study carried out to investigate the effects of intra-yolk-sac injection (IYSI) of some solutions including 1 ml of distilled water, dextrose 20% and albumin 20% on hatch percentage, performance traits, jejunum morphology, glycogen content of liver and breast and serum metabolites in broilers (Ross 308). Fertile eggs were injected into the yolk sac at day 8 of incubation period. Results showed that hatchability, absolute body weight (BW), feed intake (FI) and feed conversion ratio (FCR) at day 7 and 14 of growing period were not different among treatments, but in comparison with control group, BW and FCR were numerally better by IYSI of albumin. In addition, IYSI of albumin increased jejunum villus height at hatch day, but crypt depth was not affected by any injection treatments. Also, the glycogen concentrations of liver and pectoral muscle in albumin injected group were significantly higher than control at hatch and 7th day respectively. At hatch day, serum glucose and cholesterol concentrations were, respectively, maximum and minimum statistically by IYSI of albumin which continued numerally up to 7th day of rearing period. Furthermore, liver glycogen and serum glucose concentrations were directly correlated on the day of hatch. In conclusion, the IYSI of albumin could increase performance traits, jejunum villus height, liver and breast glycogen and serum glucose in broiler chicks. PMID- 29520872 TI - Responses are durable for up to 5 years after completion of peginterferon alfa-2a treatment in hepatitis B e antigen-positive patients. AB - BACKGROUND: In the large randomised NEPTUNE study, peginterferon alfa-2a 180 MUg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post-treatment (36%) than a lower dose (90 MUg/wk) and/or shorter duration (24 weeks) (range 14%-26%). AIM: To determine seroconversion rates 5 years after completion of treatment in NEPTUNE. METHODS: HBeAg-positive patients who completed 24 weeks' follow-up in NEPTUNE (with peginterferon alfa-2a 90 MUg/wk * 24 weeks [group 1]; 180 MUg/wk * 24 weeks [2]; 90 MUg/wk * 48 weeks [3] or 180 MUg/wk * 48 weeks [4]) were followed up. RESULTS: Three hundred and eighty three of the 544 patients in the original study were enrolled in the long-term follow-up study. Many patients (196 overall; more in groups 1-3 than 4) received nucleos(t)ide analogues or immunomodulators during follow-up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per-protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1-3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements. CONCLUSION: Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa-2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 MUg * 48 weeks) is more efficacious for HBeAg-positive patients than a lower dose and/or shorter treatment duration. PMID- 29520873 TI - Beyond the physico-chemical barrier: Glycerol and xylitol markedly yet differentially alter gene expression profiles and modify signalling pathways in human epidermal keratinocytes. AB - Polyols (e.g. glycerol, xylitol) are implicated as moisturizers of the skin and other epithelial tissues. However, we lack information about their exact cellular mechanisms and their effects on the gene expression profiles. Therefore, in this study, we aimed at investigating the effects of glycerol and xylitol on human epidermal keratinocytes. The polyols (identical osmolarities; xylitol: 0.0045% 0.45%; glycerol: 0.0027%-0.27%) did not alter cellular viability or intracellular calcium concentration. However, they exerted differential effects on the expression of certain genes and signalling pathways. Indeed, both polyols up regulated the expression of filaggrin, loricrin, involucrin and occludin; yet, xylitol exerted somewhat more profound effects. Moreover, while both polyols stimulated the MAPK pathway, only xylitol induced the activation-dependent translocation of protein kinase Cdelta, a key promoter of epidermal differentiation. Finally, in various keratinocyte inflammation models, both polyols (albeit with different efficacies) exerted anti-inflammatory effects. Taken together, these data strongly suggest that glycerol and xylitol differentially modulate expressions of multiple genes and activities of signalling pathways in epidermal keratinocytes. Thus, our findings invite clinical trials to explore the applicability and the impact of a combined glycerol-xylitol therapy in the management of various skin conditions. PMID- 29520876 TI - Severe cognitive impairment in a patient with CMT2A. PMID- 29520877 TI - The genetic heterogeneity of hereditary transthyretin amyloidosis in a sample of the Brazilian population. AB - To present the genetic heterogeneity of a sample of the Brazilian population with transthyretin (TTR) mutations. This cohort study was descriptive and retrospective, and enrolled patients with peripheral neuropathy of unknown cause that were found to have a mutation in the TTR gene during the process of etiological investigation, between July 1997 to January 2016. Over the study period, 129 point mutations were identified in 448 tested patients, of whom 128 were of Brazilian origin. The TTR Val30Met mutation was identified in 116 patients (90.6%); while 7 (4.7%) patients had a pathogenic non-TTR mutation and 7 (4.7%) carried non-pathogenic mutations (4.7%). The four non-TTRMet30 pathogenic mutations were TTR Aps38Tyr; TTR Ile107Val; TTR Val71Ala; and TTR Val122Ile. In the non-pathogenic group, we only found two mutations, including TTR Gly6Ser and TTR Thr119Thr. Our study depicts a scenario of greater genetic heterogeneity among Brazilian hereditary transthyretin amyloidosis (hATTR) patients with familial amyloidotic polyneuropathy (FAP). We expect that this number will grow fast over a short period of time, due to increasing availability of genetic tests, increasing knowledge of the disease and the multivariate origin of our population. PMID- 29520878 TI - Analysis of the impact of race on blood transfusion in pediatric scoliosis surgery. AB - INTRODUCTION: Surgical correction of pediatric scoliosis is associated with significant blood loss. Minimizing estimated blood loss and blood transfusion is beneficial as transfusions have been associated with increased morbidity, including risk of surgical site infections, longer hospitalizations, and increased cost. Although there is evidence that African-American or Black adults are more likely to require intraoperative blood transfusion compared with Caucasian or White adults, the reasons for this difference are unclear. METHODS: The electronic records for all patients <18 y/o undergoing primary corrective scoliosis surgery by a single pediatric orthopedic surgeon at a single academic medical center between 2013 and 2015 were collected and reviewed. Multivariate models were performed to assess the association between Black race and blood loss/transfusion in primary pediatric scoliosis surgery. RESULTS: In a multivariate model, Black race was independently associated with 1.61 times higher estimated blood loss than White race (P < .01; 95% CI = 1.16-2.23). Additionally, compared to a White patient, the odds a Black patient received blood transfusion was 6.25 times higher (P = .03; 95% CI = 1.56-25.06) and among the patients who received blood transfusion, Black race was independently associated with 2.61 times greater volume of blood transfusion than White race (P < .01; 95% CI = 1.54-4.41). CONCLUSION: Black race was independently associated with increased estimated blood loss, increased rate of blood transfusion, and increased amount of blood transfused during surgical correction of pediatric scoliosis. Further investigation is needed to better understand the etiology of the disparity and assess opportunities for improving outcomes. PMID- 29520879 TI - Who stays in addiction treatment groups? Anxiety and avoidant attachment styles predict treatment retention and relapse. AB - Attachment styles have been shown to be an important predictor of relationship quality and well-being. They have also been linked with ability to function well in groups. Insecure attachment styles are thought to be an underlying cause of addiction and represent a target for change in one-to-one therapy. How attachment styles themselves affect group therapy for addiction is understudied. The current study addresses this gap by examining the effects of attachment styles on relapse and treatment retention amongst a population of people attending addiction therapy groups. Fifty-eight individuals in such groups completed measures of attachment anxiety and avoidance. Participants were followed up 4 weeks later, and their continued treatment attendance and relapse status were recorded. In terms of treatment retention, high anxiety/high avoidant participants had the highest retention. In terms of relapse, low anxiety/high avoidant participants had the lowest rates. These results are discussed in terms of the potentially protective effects of avoidant attachment styles during group therapy and the role of anxiety attachment in the continued maintenance of both protective and risky personal relationships. PMID- 29520880 TI - Dry-air drying at room temperature - a practical pre-treatment method of tree leaves for quantitative analyses of phenolics? AB - INTRODUCTION: In ecological experiments, storage of plant material is often needed between harvesting and laboratory analyses when the number of samples is too large for immediate, fresh analyses. Thus, accuracy and comparability of the results call for pre-treatment methods where the chemical composition remains unaltered and large number of samples can be treated efficiently. OBJECTIVE: To study if a fast dry-air drying provides an efficient pre-treatment method for quantitative analyses of phenolics. METHODOLOGY: Dry-air drying of mature leaves was done in a drying room equipped with dehumifier (10% relative humidity, room temperature) and results were compared to freeze-drying or freeze-drying after pre-freezing in liquid nitrogen. The quantities of methanol-soluble phenolics of Betula pendula Roth, Betula pubescens Ehrh., Salix myrsinifolia Salisb., Picea abies L. Karsten and Pinus sylvestris L. were analysed with HPLC and condensed tannins were analysed using the acid-butanol test. RESULTS: In deciduous tree leaves (Betula, Salix), the yield of most of the phenolic compounds was equal or higher in samples dried in dry-air room than the yield from freeze-dried samples. In Picea abies needles, however, dry-air drying caused severe reductions in picein, stilbenes, condensed tannin and (+)-catechin concentrations compared to freeze-drying. In Pinus sylvestris highest yields of neolignans but lowest yields of acetylated flavonoids were obtained from samples freeze-dried after pre freezing. CONCLUSION: Results show that dry-air drying provides effective pre treatment method for quantifying the soluble phenolics for deciduous tree leaves, but when analysing coniferous species, the different responses between structural classes of phenolics should be taken into account. PMID- 29520881 TI - Beneficial effect of Burdock complex on asymptomatic Helicobacter pylori-infected subjects: A randomized, double-blind placebo-controlled clinical trial. AB - BACKGROUND: Burdock complex (BC) constitutes of burdock (Arctium lappa), angelica (Angelica sinensis), gromwell (Lithospermum erythrorhizon), and sesame (Sesamum indicum) oil, which are commonly used in traditional Chinese medicine (TCM) for treating various disorders. This study intended to examine the anti-H. pylori activity of BC on AGS cell model as well as in asymptomatic H. pylori-infected subjects. MATERIALS AND METHODS: AGS cell incubated with H. pylori and treated with BC to evaluate the minimum inhibition concentration (MIC), cell viability (MTT) anti-adhesion activity, and inflammatory markers. In case of clinical trial, H. pylori-positive subjects (urea breath test [UBT] >10%, n = 36) were enrolled and requested to intake BC (n = 19) or placebo (n = 17) for 8 weeks. Antioxidant capacity, total phenol, UBT, inflammatory markers were analyzed at the initial, 4th, 8th, and 10th weeks. Moreover, the endoscopic examination was carried out on baseline and 10th week. RESULTS: In vitro studies showed that BC treatment significantly inhibited (P < .05) the inflammatory markers and adhesion of H. pylori to AGS cell. However, H. pylori-infected subject ingested with BC for 8 weeks significantly decreased (P < .05) the UBT value, inflammatory markers with improved antioxidant activity, and phenolic levels as compared to placebo. Also, consumption of BC considerably healed the ulcer wound. CONCLUSION: Overall, the BC could attenuate H. pylori infection by inhibiting H. pylori adhesion and subsequent inflammatory response on the gastric epithelial cell (AGS) as well as clinically ameliorated UBT, antioxidant capacity, and alleviated inflammation to display its anti-H. pylori activity. PMID- 29520882 TI - Sex-related differences in behavioral and amygdalar responses to compound facial threat cues. AB - During face perception, we integrate facial expression and eye gaze to take advantage of their shared signals. For example, fear with averted gaze provides a congruent avoidance cue, signaling both threat presence and its location, whereas fear with direct gaze sends an incongruent cue, leaving threat location ambiguous. It has been proposed that the processing of different combinations of threat cues is mediated by dual processing routes: reflexive processing via magnocellular (M) pathway and reflective processing via parvocellular (P) pathway. Because growing evidence has identified a variety of sex differences in emotional perception, here we also investigated how M and P processing of fear and eye gaze might be modulated by observer's sex, focusing on the amygdala, a structure important to threat perception and affective appraisal. We adjusted luminance and color of face stimuli to selectively engage M or P processing and asked observers to identify emotion of the face. Female observers showed more accurate behavioral responses to faces with averted gaze and greater left amygdala reactivity both to fearful and neutral faces. Conversely, males showed greater right amygdala activation only for M-biased averted-gaze fear faces. In addition to functional reactivity differences, females had proportionately greater bilateral amygdala volumes, which positively correlated with behavioral accuracy for M-biased fear. Conversely, in males only the right amygdala volume was positively correlated with accuracy for M-biased fear faces. Our findings suggest that M and P processing of facial threat cues is modulated by functional and structural differences in the amygdalae associated with observer's sex. PMID- 29520883 TI - The nucleotide-bound/substrate-bound conformation of the Mycoplasma genitalium DnaK chaperone. AB - Hsp70 chaperones keep protein homeostasis facilitating the response of organisms to changes in external and internal conditions. Hsp70s have two domains nucleotide binding domain (NBD) and substrate binding domain (SBD)-connected by a conserved hydrophobic linker. Functioning of Hsp70s depend on tightly regulated cycles of ATP hydrolysis allosterically coupled, often together with cochaperones, to the binding/release of peptide substrates. Here we describe the crystal structure of the Mycoplasma genitalium DnaK (MgDnaK) protein, an Hsp70 homolog, in the noncompact, nucleotide-bound/substrate-bound conformation. The MgDnaK structure resembles the one from the thermophilic eubacteria DnaK trapped in the same state. However, in MgDnaK the NBD and SBD domains remain close to each other despite the lack of direct interaction between them and with the linker contacting the two subdomains of SBD. These observations suggest that the structures might represent an intermediate of the protein where the conserved linker binds to the SBD to favor the noncompact state of the protein by stabilizing the SBDbeta-SBDalpha subdomains interaction, promoting the capacity of the protein to sample different conformations, which is critical for proper functioning of the molecular chaperone allosteric mechanism. Comparison of the solved structures indicates that the NBD remains essentially invariant in presence or absence of nucleotide. PMID- 29520884 TI - The histologic detection of Helicobacter pylori in seropositive subjects is affected by pathology and secretory ability of the stomach. AB - BACKGROUND: Helicobacter pylori is unevenly distributed in hypochlorhydric environments. The study aim was to elucidate the risk factors for a negative Giemsa staining finding in seropositive subjects by measuring the secretory ability of the stomach. METHODS: Subjects aged over 18 years were included consecutively after endoscopic biopsy at gastric lesions with color or structural changes. Blood was sampled for the serum pepsinogen (PG) assay and H. pylori serology test. After excluding the subjects with past H. pylori eradication, the risk factors for a negative Giemsa staining finding in seropositive subjects were analyzed. RESULTS: Among 872 included subjects, a discrepancy between the serum anti-H. pylori IgG and Giemsa staining findings was found in 158 (18.1%) subjects, including 145 Giemsa-negative, seropositive subjects. Gastric adenocarcinoma/adenoma (OR = 11.090, 95% CI = 3.490-35.236) and low serum PG II level (OR = 0.931, 95% CI = 0.899-0.963) were the independent risk factors for a negative Giemsa staining finding in seropositive subjects. The cutoff value of serum PG II level was 7.45 ng/mL (area under curve [AUC] = 0.904, 95% CI = 0.881 0.927). Follow-up studies of Giemsa staining at different sites of the stomach revealed that 75% of the Giemsa-negative seropositive subjects with adenocarcinoma are positive, whereas none of those with low serum PG II level of <7.45 ng/mL revealed positive findings. CONCLUSIONS: The risk of a negative Giemsa staining finding in seropositive subjects is increased in gastric adenocarcinoma/adenoma specimens and in subjects with a diminished gastric secretory ability with low serum PG II level of <7.45 ng/mL. A false-negative Giemsa staining finding is common in subjects with adenocarcinoma, and therefore, additional biopsies at different sites should be performed in these subjects. PMID- 29520886 TI - Caesarean section among immigrants with different obstetrical risks. AB - AIM: To determine the variation in caesarean section rates among immigrant populations. BACKGROUND: Australia is one of the most multicultural in the world and is also among those with the highest caesarean section rates. DESIGN: Secondary data analysis. METHODS: Routinely collected data from a Local Heath District between 2011 and 2015 were analysed. Women were categorized into regional groups based on country of birth. Obstetrical risk was classified using the Robson classification. RESULTS/FINDINGS: In total 48 711 women gave birth, of whom 64.0% were born overseas; 13 966 had a caesarean section (28.7%). South and Central Asia women had a high number of caesarean sections (n = 4139; 29.6% of all caesarean sections), a high overall adjusted caesarean section rate (31.4%; 95% CI, 30.5%-32.3%), and consistently high caesarean section rates among women with single cephalic term pregnancy without a previous caesarean section. High adjusted caesarean section rates were seen among South East Asia women with nulliparous, single cephalic, term pregnancy, and spontaneous labour. Demographic and clinical characteristics explained 83.5% of the variation in overall caesarean section rates between country of birth and 21.8% to 100% depending on Robson group. CONCLUSIONS: Caesarean section rates varied by country of birth and within some Robson groups. The studied factors had various effects on the variation in caesarean section rates between country of birth and Robson groups. PMID- 29520885 TI - Maternal cytomegalovirus sero-positivity and autism symptoms in children. AB - PROBLEM: Autism spectrum disorder (ASD) is one of the most commonly diagnosed neurodevelopmental disorders in the United States. While ASD can be significantly influenced by genetics, prenatal exposure to maternal infections has also been implicated in conferring risk. Despite this, the effects of several important maternal pathogens, such as cytomegalovirus (CMV) and herpes simplex virus 2 (HSV2), remain unknown. METHOD OF STUDY: We tested whether maternal CMV and/or HSV2 sero-positivity was associated with ASD symptoms in children. ELISA was used to assay for CMV IgG and HSV2 IgG in serum from the mothers of 82 children whose ASD symptoms were assessed at 3-6 years of age using the Social Responsiveness Scale version 2 (SRS-2). RESULTS: Associations between maternal viral serostatus and SRS-2 scores were estimated using linear regression with covariate adjustments. The children of mothers sero-positive for CMV, but not for HSV2, had SRS-2 scores 3.6-4.2 points higher, depending on the adjustment model, than sero negative women, a significant finding, robust to several statistical adjustments. CONCLUSION: Our results suggest that maternal CMV infections may influence ASD symptoms. These findings are being further evaluated in ongoing prospective studies with larger population samples. PMID- 29520887 TI - Evaluation of a patient with classical Ehlers-Danlos syndrome due to a 9q34 duplication affecting COL5A1. AB - Ehlers-Danlos syndrome classical type is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and joint hypermobility. The condition typically results from mutations in COL5A1 or COL5A2 leading to the functional haploinsufficiency. Here, we report of a 24-year-old male with mild intellectual disability, dysmorphic features, and a phenotype consistent with Ehlers-Danlos syndrome classical type. A copy number variant calling algorithm from panel sequencing data identified the deletions exons 2-11 and duplications of exons 12-67 within COL5A1. Array comparative genomic hybridization confirmed a 94 kb deletion at 9q34.3 involving exons 2-11 of COL5A1, and a 3.4 Mb duplication at 9q34.3 involving exons 12-67 of COL5A1. PMID- 29520888 TI - One-Dimensional Porphyrin-Fullerene (C60 ) Assemblies: Role of Central Metal Ion in Enhancing Ambipolar Mobility. AB - One-dimensional (1D) nanostructures of pi-conjugated molecules exhibiting excellent charge carrier mobilities have attracted much interest for use in organic electronic devices. Although it is tedious to form such structures, the availability of highly delocalized electron and hole carriers in these donor (D) acceptor (A) coassemblies realize ambipolar charge transport. Here we demonstrate the use of a simple solution casting method to create an ambipolar donor-acceptor single-crystalline assembly. 1D assemblies of 5,10,15,20-tetraphenylporphyrins (H2 TPP, ZnTPP) and fullerene (C60 ) exhibit high ambipolar mobility in the range of 0.8-3.4 cm2 Vs-1 for electrons and holes with high ON/OFF ratio and low threshold voltage. A direct experimental proof for the pivotal role of the central Zn2+ in tetraphenyl porphyrin, which enables a strong D-A charge transfer interaction in the cocrystal and thereby induces electron (1.35 cm2 Vs-1 ), hole (3.42 cm2 Vs-1 ) mobilities, the highest reported for two component D-A assemblies using solution casting, is demonstrated. PMID- 29520889 TI - Efficacy of artichoke leaf extract in non-alcoholic fatty liver disease: A pilot double-blind randomized controlled trial. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is potentially treatable, though there are few therapeutic agents available. Artichoke leaf extract (ALE) has shown potential as a hepatoprotective agent. This study sought to determine if ALE had therapeutic utility in patients with established NAFLD. In this randomized double-blind placebo-controlled parallel-group trial, 100 subjects with ultrasound-diagnosed NAFLD were randomized to either ALE 600 mg daily or placebo for a 2-month period. NAFLD response was assessed by liver ultrasound and serological markers including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and AST to platelet ratio index (APRI) score. Ninety patients completed the study (49 ALE and 41 placebo) with no side effects reported. ALE treatment compared with placebo: Doppler sonography showed increased hepatic vein flow (p < .001), reduced portal vein diameter (p < .001) and liver size (p < .001), reduction in serum ALT (p < .001) and AST (p < .001) levels, improvement in AST/ALT ratio and APRI scores (p < .01), and reduction in total bilirubin. ALE supplementation reduced total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and triglyceride concentrations (p = .01). This study has shown beneficial effects of ALE supplementation on both ultrasound liver parameters and liver serum parameters (ALT, AST, APRI ratio, and total bilirubin) in patients with NAFLD. PMID- 29520891 TI - My prolonged collaboration with Ray Guillery. AB - My active collaboration with Ray Guillery started in 1968, when he was a Full Professor at the University of Wisconsin and I was a graduate student at the University of Pennsylvania. The collaboration lasted almost 50 years with virtually no breaks. Among the ideas we proposed are that glutamatergic pathways in thalamus and cortex can be classified into drivers and modulators; that many thalamic nuclei could be classified as higher order, meaning that they receive driving input from layer 5 of cortex and participate in cortico-thalamocortical circuits; and that much of the information relayed by thalamus serves as an efference copy for motor commands initiated by cortex. PMID- 29520890 TI - Protein kinase C zeta suppresses low- or high-grade colorectal cancer (CRC) phenotypes by interphase centrosome anchoring. AB - Histological grading provides prognostic stratification of colorectal cancer (CRC) by scoring heterogeneous phenotypes. Features of aggressiveness include aberrant mitotic spindle configurations, chromosomal breakage, and bizarre multicellular morphology, but pathobiology is poorly understood. Protein kinase C zeta (PKCz) controls mitotic spindle dynamics, chromosome segregation, and multicellular patterns, but its role in CRC phenotype evolution remains unclear. Here, we show that PKCz couples genome segregation to multicellular morphology through control of interphase centrosome anchoring. PKCz regulates interdependent processes that control centrosome positioning. Among these, interaction between the cytoskeletal linker protein ezrin and its binding partner NHERF1 promotes the formation of a localized cue for anchoring interphase centrosomes to the cell cortex. Perturbation of these phenomena induced different outcomes in cells with single or extra centrosomes. Defective anchoring of a single centrosome promoted bipolar spindle misorientation, multi-lumen formation, and aberrant epithelial stratification. Collectively, these disturbances induce cribriform multicellular morphology that is typical of some categories of low-grade CRC. By contrast, defective anchoring of extra centrosomes promoted multipolar spindle formation, chromosomal instability (CIN), disruption of glandular morphology, and cell outgrowth across the extracellular matrix interface characteristic of aggressive, high-grade CRC. Because PKCz enhances apical NHERF1 intensity in 3D epithelial cultures, we used an immunohistochemical (IHC) assay of apical NHERF1 intensity as an indirect readout of PKCz activity in translational studies. We show that apical NHERF1 IHC intensity is inversely associated with multipolar spindle frequency and high-grade morphology in formalin-fixed human CRC samples. To conclude, defective PKCz control of interphase centrosome anchoring may underlie distinct categories of mitotic slippage that shape the development of low- or high-grade CRC phenotypes. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29520892 TI - Deconvolution in mass spectrometry based proteomics. AB - Mass spectrometry (MS) has played a vital role across a broad range of fields and applications in proteomics. The development of high-resolution MS has significantly advanced biology in areas such as protein structure, function, post translational modification and global protein dynamics. The two most widely used MS ionization techniques in proteomics are electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). ESI typically yields multiple charge values for each molecular mass and an isotopic cluster for each nominal mass-to-charge (m/z) value. Although MALDI mass spectra typically contain only singly charged ions, overlapping isotope patterns can be problematic for accurate mass measurement. To overcome these challenges of overlapping isotope patterns associated with complex samples in MS-based proteomics research, deconvolution strategies are being used. This manuscript describes a wide variety of deconvolution strategies, including de-isotoping and de-charging processes, deconvolution of co-eluting isomers or peptides with different sequences in data dependent acquisition (DDA) and data-independent acquisition (DIA) modes, and data analysis in intact protein mass determination, ion mobility MS, native MS, and hydrogen/deuterium exchange MS. It concludes with a discussion of future prospects in the development of bioinformatics and potential new applications in proteomics. PMID- 29520893 TI - Morphology of the core fibrous layer of the cetacean tail fluke. AB - The cetacean tail fluke blades are not supported by any vertebral elements. Instead, the majority of the blades are composed of a densely packed collagenous fiber matrix known as the core layer. Fluke blades from six species of odontocete cetaceans were examined to compare the morphology and orientation of fibers at different locations along the spanwise and chordwise fluke blade axes. The general fiber morphology was consistent with a three-dimensional structure comprised of two-dimensional sheets of fibers aligned tightly in a laminated configuration along the spanwise axis. The laminated configuration of the fluke blades helps to maintain spanwise rigidity while allowing partial flexibility during swimming. When viewing the chordwise sectional face at the leading edge and mid-chord regions, fibers displayed a crossing pattern. This configuration relates to bending and structural support of the fluke blade. The trailing edge core was found to have parallel fibers arranged more dorso-ventrally. The fiber morphology of the fluke blades was dorso-ventrally symmetrical and similar in all species except the pygmy sperm whale (Kogia breviceps), which was found to have additional core layer fiber bundles running along the span of the fluke blade. These additional fibers may increase stiffness of the structure by resisting tension along their long spanwise axis. PMID- 29520894 TI - Evaluation of MLH1 variants of unclear significance. AB - Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient. PMID- 29520895 TI - Electron transfer dissociation of synthetic and natural peptides containing lanthionine/methyllanthionine bridges. AB - RATIONALE: The modes of cleavage of lanthionine/methyllanthionine bridges under electron transfer dissociation (ETD) were investigated using synthetic and natural lantipeptides. Knowledge of the mass spectrometric fragmentation of lanthionine/methyllanthionine bridges may assist in the development of analytical methods for the rapid discovery of new lantibiotics. The present study strengthens the advantage of ETD in the characterization of posttranslational modifications of peptides and proteins. METHODS: Synthetic and natural lantipeptides were obtained by desulfurization of peptide disulfides and cyanogen bromide digestion of the lantibiotic nisin, respectively. These peptides were subjected to electrospray ionization collision-induced dissociation tandem mass spectrometry (CID-MS/MS) and ETD-MS/MS using an HCT ultra ETDII ion trap mass spectrometer. MS3 CID was performed on the desired product ions to prove cleavage of the lanthionine/methyllanthionine bridge during ETD-MS/MS. RESULTS: ETD has advantages over CID in the cleavage of the side chain of lanthionine/methyllanthionine bridges. The cleavage of the N-Calpha backbone peptide bond followed by C-terminal side chain of the lanthionine bridge results in formation of c*+ and z+ ions. Cleavage at the preceding peptide bond to the C terminal side chain of lanthionine/methyllanthionine bridges yields specific fragments with the cysteine/methylcysteine thiyl radical and dehydroalanine. CONCLUSIONS: ETD successfully cleaves the lanthionine/methyllanthionine bridges of synthetic and natural lantipeptides. Diagnostic fragment ions of ETD cleavage of lanthionine/methyllanthionine bridges are the N-terminal cysteine/methylcysteine thiyl radical and C-terminal dehydroalanine. Detection of the cysteine/methylcysteine thiyl radical and dehydroalanine in combined ETD-CID MS may be used for the rapid identification of lantipeptide natural products. PMID- 29520896 TI - Eater and draper are involved in the periostial haemocyte immune response in the mosquito Anopheles gambiae. AB - Haemocytes respond to infection by phagocytosing pathogens, producing the enzymes that drive the phenoloxidase-based melanization cascade, secreting lytic factors, and producing other humoral proteins. A subset of haemocytes, called periostial haemocytes, aggregate on the surface of the heart of mosquitoes and kill pathogens in areas of high haemolymph flow. Periostial haemocytes are always present, but an infection induces the recruitment of additional haemocytes to these regions. Here, we tested whether members of the Nimrod gene family are involved in the periostial immune response of the African malaria mosquito, Anopheles gambiae. Using organismal manipulations, RNA interference (RNAi) and microscopy, we show that, following an infection with Escherichia coli, nimrod - the orthologue of Drosophila NimB2 - is not involved in periostial responses. At 4 h postinfection, however, RNAi-based knockdown of draper results in a marginal increase in the number of periostial haemocytes and a doubling of E. coli accumulation at the periostial regions. Finally, at 24 h postinfection, knockdown of eater decreases the number of periostial haemocytes and decreases the phagocytosis of E. coli on the surface of the heart. Phagocytosis of bacteria is more prevalent in the periostial regions of the mid abdominal segments, and knockdown of draper, nimrod or eater does not alter this distribution. Finally, knockdown of Nimrod family genes did not have a meaningful effect on the accumulation of melanin at the periostial regions. This study identifies roles for eater and draper in the functional integration of the mosquito immune and circulatory systems. PMID- 29520897 TI - What do self-efficacy items measure? Examining the discriminant content validity of self-efficacy items. AB - OBJECTIVES: Self-efficacy - an individual's judgement of their ability to successfully perform a behaviour - is commonly used to explain and predict behaviour. It is measured through self-report questionnaires. These scales require good content validity, that is must measure the full scope and content of the construct without contamination from similar constructs. This study uses a systematic, transparent quantitative method (discriminant content validation, DCV) to assess the content validity of a variety of self-efficacy items and qualitatively explores participant interpretations of these items. DESIGN: A quantitative DCV and qualitative think-aloud study of self-efficacy item interpretation. METHODS: Participants (n = 21) were presented with items designed to measure self-efficacy and related constructs following standard DCV methodology. Items were rated against construct definitions to determine whether they measured a particular construct (yes/no). Judges' confidence in each assessment was also assessed (%) and used to establish quantitative estimates of content validity for each item. A qualitative think-aloud study explored the judgements made in a subset of participants. RESULTS: 8/8 self-efficacy items were found to measure self-efficacy; however, 2/8 of these also measured motivation. 6/8 items displayed discriminant content validity and thus can be considered 'pure' measures of self-efficacy. The think-aloud study indicated that item wording is a likely cause of item misinterpretation. CONCLUSIONS: Self efficacy items vary in terms of their content validity with only some of the items assessed providing 'pure' measures of the self-efficacy construct. Item wording should be considered during study design to avoid misinterpretation. Statement of contribution What is already known on this subject? For decades, questions have been raised relating to the content validity of self-efficacy scales, with suggestions of possible construct contamination. Previous studies have shown that manipulation of the wording of self-efficacy scale items results in varied participant interpretations. While self-efficacy items have been found to be distinguishable from other similar constructs, it is equally important to ensure that they are uncontaminated by different constructs within the same theory. Otherwise, when the theory is used to investigate behaviour, variance attributable to self-efficacy may be attributed to a different construct or vice versa. The present study uses discriminant content validation to test this and a think-aloud study to explore participants' interpretation of classic self efficacy items. What does this study add? The study uses discriminant content validity methodology to assess the content validity of self-efficacy scales. Self efficacy items which are contaminated with content from other constructs are identified. Information is presented on 'pure' self-efficacy items which can be used to guide item selection in future studies. PMID- 29520898 TI - CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis. AB - CD169+ macrophages are suggested to play a pivotal role in establishing anti tumor immunity. They capture dead tumor cell-associated antigens and transfer their information to lymphocsytes, including CD8+ T cells, which is important for successful tumor suppression. This study aimed to determine the prognostic significance of CD169+ macrophages residing in the tumor-draining lymph nodes from cases of bladder cancer. In this retrospective study, 44 bladder cancer patients who received radical cystectomy were examined. The abundance of CD169+ macrophages in the regional lymph nodes and the number of CD8+ T cells in the primary tumor were investigated by immunohistochemistry. A CD169 score was calculated based on the intensity of CD169 staining and the proportion of CD169+ macrophages, and the scores were compared to the patients' clinicopathological parameters. A high CD169 score was significantly associated with low T stage and with a high number of CD8+ T cells infiltrating into the tumor. The group with high CD169 expression had significantly longer cancer-specific survival than the group with low CD169 expression (5-year cancer-specific survival rate: 83.3% vs 31.3%). In a multivariate analysis, the CD169 score was identified as a strong and independent favorable prognostic factor for cancer-specific survival. Our findings suggest that CD169+ macrophages in the lymph nodes enhance anti-tumor immunity by expanding CD8+ T cells in bladder cancer. The CD169 score may serve as a novel marker for the evaluation of bladder cancer prognosis. PMID- 29520899 TI - Pain in Parkinson's disease: facts and uncertainties. AB - Pain is one of the most common and troublesome non-motor symptoms of Parkinson's disease (PD). It can appear at any time during the disease and is often present before diagnosis. However, there is little or no consensus on its definition. An expert group of clinicians with relevant research experience met to review the existing evidence and to identify gaps in our understanding leading towards AUTHOR: 'understanding towards' has been changed to 'understanding leading towards'. Please check and confirm that this is appropriate an optimized therapy of pain in PD. Key findings from epidemiologic, neurophysiologic, neuroimaging and clinical studies are reviewed. In each case, the evidence base is limited by wide variations in the definitions of pain applied, study methodologies and populations evaluated. Disease-related and medical conditions trigger spontaneous pain in patients with PD, which is then abnormally processed and results in painful manifestations in specific body parts. Dopaminergic medications, such as rotigotine, as well as opiate analgesics, such as oxycodone, have shown positive results but future studies with more detailed pain characterization at inclusion are warranted. PMID- 29520900 TI - Neuromelanin-sensitive magnetic resonance imaging features of the substantia nigra and locus coeruleus in de novo Parkinson's disease and its phenotypes. AB - BACKGROUND AND PURPOSE: Neuromelanin of the brainstem, which is considered a marker of neurodegeneration in Parkinson's disease (PD), can be detected by T1 weighted neuromelanin-sensitive magnetic resonance imaging (NM-MRI). Our aim was to investigate the NM-MRI features of de novo PD and to determine whether these features are associated with motor and non-motor symptoms in de novo PD patients. METHODS: Fifty-one patients with de novo PD (Hoehn and Yahr stage 1-2) and 28 healthy controls were recruited. All subjects underwent clinical and MRI examinations including an NM-MRI sequence. The width and contrast-to-noise ratio (CNR) of the substantia nigra pars compacta (SNc) and the CNR of the locus coeruleus (LC) were measured on NM-MRI images. RESULTS: Both the width and CNR values of the high intensity signals in the SNc were significantly decreased in the lateral, central and medial SNc parts in de novo PD patients compared to control subjects. The changes in the SNc on NM-MRI were not significantly different between the motor subgroups. The CNR values of the left LC were significantly lower in the PD group than in the control group. Specifically, the subtype of PD patients with depressive symptoms exhibited a significantly lower CNR in the left LC than the control group and PD patients without depressive symptoms. CONCLUSIONS: Substantia nigra pars compacta neuromelanin changes occur across both motor and non-motor (with and without depressive symptoms) subtypes, whilst LC changes are more notable in PD patients with depressive symptoms. Our results may provide new evidence to understand the pathophysiology of non-motor symptoms in PD. PMID- 29520902 TI - Convergence for Translation: Drug-Delivery Research in Multidisciplinary Teams. AB - The void between drug discovery and successful translation to humans is vast. In order to develop effective solutions, convergence of a multidisciplinary team with a range of expertise is required. In this Essay, examples of successful sustained delivery systems for antimalarials and antiretrovirals, as well as to the gastrointestinal tract are discussed. PMID- 29520903 TI - Investigation of ultrahigh-performance liquid chromatography/travelling-wave ion mobility/time-of-flight mass spectrometry for fast profiling of fatty acids in the high Arctic sea surface microlayer. AB - RATIONALE: Fatty acids are enriched in the ocean surface microlayer (SML) and have as a consequence been detected worldwide in sea spray aerosols. In searching for a relationship between the properties of the atmospheric aerosol and its ability to form cloud condensation nuclei and to promote cloud droplet formation over remote marine areas, the role of surface active fatty acids sourced from the SML is of interest to be investigated. Here we present a fast method for profiling of major fatty acids in SML samples collected in the high Arctic (89 degrees N, 1 degrees W) in the summer of 2001. METHODS: Ultrahigh-performance liquid chromatography (UHPLC)/travelling-wave ion mobility spectrometry (TWIMS)/time-of-flight (TOF) mass spectrometry (MS) for profiling was evaluated and compared with UHPLC/TOFMS. Except for evaporation and centrifugation, no sample preparation was necessary prior to the analysis. RESULTS: TOFMS data on accurate mass, isotopic ratios and fragmentation patterns enabled identification of the fatty acids. The TWIMS dimension added to the selectivity by extensive reduction of the noise level and the entire UHPLC/TWIMS/TOFMS method provided a fast profiling of the acids, ranging from C8 to C24 . Hexadecanoic and octadecanoic acids were shown to yield the highest signals among the FAs detected in a high Arctic SML sample, followed by the unsaturated octadecenoic and octadecadienoic acids. The predominance of signal from even-numbered carbon chains indicates a mainly biogenic origin of the detected FAs. CONCLUSIONS: This study presents a fast alternative method for screening and profiling of FAs, which has the advantage of not requiring any complicated sample preparation, thus limiting the loss of analytes. Almost no manual handling, together with the very small sample volumes needed, is certainly beneficial for the determination of trace amounts and should open up the field of applications to also include atmospheric aerosol and fog. PMID- 29520901 TI - Novel method for DNA methylation analysis using high-performance liquid chromatography and its clinical application. AB - The aim of this study was to develop a new methodology that is suitable for DNA methylation diagnostics and to demonstrate its clinical applicability. We developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions. The DNA methylation levels of synthetic DNA were quantified accurately and reproducibly within 10 minutes without time-consuming pretreatment of PCR products, and the measured values were unaffected by the distribution of methylated CpG within the synthetic DNA fragments. When the DNA methylation status of the FAM150A gene, a marker of the CpG island methylator phenotype specific to clear cell renal cell carcinoma (ccRCC), was examined in 98 patients with ccRCC, bulk specimens of tumorous tissue including cancer cells showing DNA methylation of the FAM150A gene were easily identifiable by simply viewing the differentiated chromatograms, even when the cancer cell content was low. Sixteen ccRCC showing DNA methylation more frequently exhibited clinicopathological parameters reflecting tumor aggressiveness (ie, a larger diameter, higher histological grade, vascular involvement, renal vein tumor thrombi, infiltrating growth, tumor necrosis, renal pelvis invasion and higher pathological TNM stage), and had significantly lower recurrence-free and overall survival rates. These data indicate that HPLC analysis using this newly developed anion-exchange column could be a powerful tool for DNA methylation diagnostics, including prognostication of patients with cancers, in a clinical setting. PMID- 29520904 TI - Renal thrombotic microangiopathy caused by bevacizumab. PMID- 29520905 TI - Successful treatment of HCV-related glomerulonephritis with sofosbuvir and daclatasvir. PMID- 29520906 TI - Acute aortoiliac thrombosis due to minimal change disease. PMID- 29520907 TI - Lysozyme Nephropathy in Haematologically Stable Chronic Myelomonocytic Leukaemia. PMID- 29520908 TI - Electrocardiogram failure in the operating room - bench testing to prevent bed side disaster. AB - Electrocardiogram (ECG) false alarms are common in electrically-hostile peri operative environments. Newer integrated monitoring, with sophisticated hardware and software, has the potential to minimise artefacts. However, monitoring issues continue to occur, with the potential for critical incidents and unnecessary and harmful interventions. We describe the root cause analysis of a series of apparent ECG flatline asystolic events that appeared in the operating room shortly after the introduction of new intra-operative monitoring systems. Clinical events and biomedical laboratory testing revealed complete loss of ECG signal with increasing resistance. The new ECG systems had incorporated both software and hardware changes to improve the fidelity of signal acquisition and display, but had become much more sensitive to impedance changes. After we alerted the manufacturer, they added software and hardware updates that resulted in resolution of all incidents of ECG loss-of-signal. PMID- 29520909 TI - Rheum palmatum root extract inhibits hepatocellular carcinoma in rats treated with diethylnitrosamine. AB - OBJECTIVES: The aim of this study was to investigate the potential anticancer properties of a methanol extract of Rheum palmatum roots against diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC) in rats and to characterize its phytoconstituents. METHODS: HPLC-PDA-MS/MS was used to profile the secondary metabolites in R. palmatum root extract. HCC was induced using diethylnitrosamine (DENA). The activity of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP), total proteins, serum albumin and serum globulin was determined. DNA fragmentation and histopathological examination and GST-P immunostaining were also studied. KEY FINDINGS: LC-MS/MS analysis identified 16 compounds belonging to anthraquinones, flavonoids and tannins. The root extract significantly reduced the elevated liver enzymes ALT and AST and increased total proteins, albumin and globulin in HCC-rats. Also, the tumour markers AFP and GGT levels were significantly reduced in HCC-rats treated with the extract. In addition, the extract significantly reduced elevated DNA fragmentation and decreased the numbers and areas of GST-P positive putative foci in HCC-rats. CONCLUSIONS: Rheum palmatum is a potential candidate to be explored for the treatment of hepatocellular carcinoma. PMID- 29520911 TI - Functional segregation loss over time is moderated by APOE genotype in healthy elderly. AB - We investigated the influence of the apolipoprotein E-E4 allele (APOE-E4) on longitudinal age-related changes in brain functional connectivity (FC) and cognition, in view of mixed cross-sectional findings. One hundred and twenty-two healthy older adults (aged 58-79; 25 APOE-E4 carriers) underwent task-free fMRI scans at baseline. Seventy-eight (16 carriers) had at least one follow-up (every 2 years). Changes in intra- and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross-sectionally, APOE-E4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age-dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter-ECN-DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE-E4 genotype, but the brain-cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE E4 may alter aging by accelerating the change in segregation between high-level cognitive systems. Its modulation on the longitudinal brain-cognition relationship was age-dependent. PMID- 29520910 TI - A network meta-analysis of interproximal oral hygiene methods in the reduction of clinical indices of inflammation. AB - BACKGROUND: A wide selection of Interdental Oral Hygiene (IOH) aids is available to consumers. Recommendations for selection are, however, limited by the lack of direct comparisons in available studies. We aimed to assess the comparative efficacy of IOH aids using Bayesian Network Meta-Analysis (BNMA). METHODS: Two independent reviewers performed a systematic literature review of randomized clinical trials assessing IOH aids, based on a focused question. Gingival inflammation (Gingival Index (GI), Bleeding-on-probing (BOP)) was the primary outcome and plaque and probing depth were secondary outcomes A random-effects arm based BNMA model was run for each outcome; posterior medians and 95% credible intervals (CIs) summarized marginal distributions of parameters. RESULTS: A two phase selection process identified 22 trials assessing 10 IOH aids as brushing adjuncts. Interdental brushes (IB) yielded the largest reduction in GI (0.23 [95% CI: 0.09, 0.37]) as toothbrushing adjuncts, followed by water-jet (WJ) (0.19 [95% CI: 0.14, 0.24]). Rankings based on posterior probabilities revealed that IB and WJ had the highest probability of being "best" (64.7% and 27.4%, respectively) for GI reduction, whereas the probability for toothpick and floss being the "best" IOH aids was near zero. Notably, except for toothpicks, all IOH aids were better at reducing GI as compared with control. CONCLUSIONS: BNMA enabled us to quantitatively evaluate IOH aids and provide a global ranking of their efficacy. Interdental brushes and water-jets ranked high for reducing gingival bleeding, whereas toothpicks and floss ranked last. The patient-perceived benefit of IOH aids is not clear because gingival inflammation measures are physical indicators of periodontal health. PMID- 29520912 TI - Laser ablation synthesis of arsenic-phosphide Asm Pn clusters from As-P mixtures. Laser desorption ionisation with quadrupole ion trap time-of-flight mass spectrometry: The mass spectrometer as a synthesizer. AB - RATIONALE: Only a few arsenic phosphides are known. A high potential for the generation of new compounds is offered by Laser Ablation Synthesis (LAS) and when Laser Desorption Ionization (LDI) is coupled with simultaneous Time-Of-Flight Mass Spectrometry (TOFMS), immediate identification of the clusters can be achieved. METHODS: LAS was used for the generation of arsenic phosphides via laser ablation of phosphorus-arsenic mixtures while quadrupole ion trap time-of flight mass spectrometry (QIT-TOFMS) was used to acquire the mass spectra. RESULTS: Many new Asm Pn+/- clusters (479 binary and 369 mono-elemental) not yet described in the literature were generated in the gas phase and their stoichiometry determined. The likely structures for some of the observed clusters arbitrary selected (20) were computed by density functional theory (DFT) optimization. CONCLUSIONS: LAS is an advantageous approach for the generation of new Asm Pn clusters, while mass spectrometry was found to be an efficient technique for the determination of cluster stoichiometry. The results achieved might inspire the synthesis of new materials. PMID- 29520913 TI - Delineation between different components of chronic pain using dimension reduction - an ASL fMRI study in hand osteoarthritis. AB - BACKGROUND: Traditional psychometric measures aimed at characterizing the pain experience often show considerable overlap, due to interlinked affective and modulatory processes under central nervous system control. Neuroimaging studies have been employed to investigate this complexity of pain processing, in an attempt to provide a quantifiable, adjunctive description of pain perception. In this exploratory study, we examine psychometric and neuroimaging data from 38 patients with painful osteoarthritis of the carpometacarpal joint. We had two aims: first, to utilize principal component analysis (PCA) as a dimension reduction strategy across multiple self-reported endpoints of pain, cognitive and affective functioning; second, to investigate the relationship between identified dimensions and regional cerebral blood flow (rCBF) as an indirect measure of brain activity underpinning their ongoing pain experiences. METHODS: Psychometric data were collected using validated questionnaires. Quantitative estimates of rCBF were acquired using pseudo-continuous arterial spin-labelled functional magnetic resonance imaging. RESULTS: Two principal components were identified that accounted for 73% of data variance; one related to pain scores and a second to psychological traits. Voxel-wise multiple regression analysis revealed a significant negative association between the 'pain score' component and rCBF to a right temporal lobe cluster, including the amygdala and the parahippocampal cortex. CONCLUSION: We suggest this association may represent a coping mechanism that aims to reduce fear-related pain-anxiety. Further investigation of central brain processing mechanisms in osteoarthritis-related pain may offer insights into more effective therapeutic strategies. SIGNIFICANCE: This study demonstrates that dimension reduction using PCA allows insight into pain perception and its affective components in relation to brain activation patterns in patients with painful hand osteoarthritis. PMID- 29520914 TI - The persistent 'memory effect' of triethylamine in atmospheric pressure ionization sources can be effectively controlled by decontamination with a iPrOH/AcOH mixture. PMID- 29520915 TI - A new method for calibrating the current gain of 1013 Omega amplifiers in thermal ionization mass spectrometry. AB - We report a new method for calibrating the current gain of 1013 Omega amplifiers in both positive and negative mode used in thermal ionisation mass spectrometry (TIMS). This method uses any isotopic standard or sample to calibrate the gain factor as long as it can produce a stable current signal. It is simpler and more flexible than that recommended by Thermo-Fisher (the manufacture of the TIMS). In these analyses, the gains of five 1013 Omega amplifiers were assessed. The precision of gain factors was better than 100 ppm (2 RSD) in a day, and the long term reproducibility was better than 300 ppm (2 RSD) within 2 to 8 months. After a gain was calibrated, the ratio accuracy and precision in the positive mode for 87 Sr/88 Sr of NIST 987 Sr and 143 Nd/144 Nd of La Jolla Nd were 0.710242 +/- 60 (2 SD, n = 14) and 0.511842 +/- 10 (2 SD, n = 22), respectively, at intensities of 88 Sr 0.3 V and 142 Nd 0.4 V, while in the negative mode for 187 Os/188 Os of Merck Os was 0.120229 +/- 34 (2 SD, n = 23) at an intensity of 187 OsO3 0.01 mV. In addition, a difference in the gain factors between the negative mode TIMS (NTIMS) and positive mode TIMS (PTIMS) has been recognized. The values of the gain factor for NTIMS and PTIMS show a deviation of 0.54% on the Triton and 0.31% on the Triton Plus TIMS in this study; therefore, gain calibration should be carried out on both NTIMS and PTIMS. Moreover, a bias of ~ 1.5 * 10-5 between H and L Faraday cups for the same 1013 Omega amplifier has been detected, hinting that the efficiency of different Faraday cups may affect the gain factors, which can be eliminated through the new method of "cross-calibration" discribed in this study. PMID- 29520917 TI - The use of hyaluronic acid subdermal filler for entropion in canines and felines: 40 cases. AB - PURPOSE: To evaluate the use of hyaluronic acid (HA) subdermal filler in canines and felines for entropion. METHODS: Complete ophthalmologic examination was performed by a board-certified veterinary ophthalmologist or ABVO-approved resident. Each case was characterized as primary, secondary, spastic or cicatricial entropion. HA subdermal filler, specifically Restylane(r) and Restylane Silk(r) , were utilized in dogs and cats, respectively. Subdermal injection was performed 1-2 mm from the eyelid margin in the affected area until normal eyelid conformation was achieved. All patients did not require sedation or general anesthesia. RESULTS: Forty animals (28 dogs and 12 cats) were included in the study. No local reaction to the HA dermal filler or any other complications other than minor skin bleeding at the injection sites were noted in all patients. Resolution of entropion and secondary complications including corneal ulceration, epiphora, and blepharospasm were noted by the first week after injection in the majority of cases. Three canines and one feline case failed to resolve the entropion, necessitating additional permanent surgical intervention. Two cases were submitted for histopathological analysis. Median follow-up time for all cases was 152.5 days (mean: 194.6 +/- 142.7 days; range 9-419 days). Five patients died or were euthanized during the study for unrelated causes. CONCLUSIONS: Hyaluronic acid (HA) subdermal filler appears to be a safe, easy, reliable method for mild to moderate eyelid entropion not requiring general anesthesia. This procedure may be especially appropriate for geriatric patients and those with high anesthetic risk with entropion. PMID- 29520916 TI - Identification and characterisation of a Theileria annulata proline-rich microtubule and SH3 domain-interacting protein (TaMISHIP) that forms a complex with CLASP1, EB1, and CD2AP at the schizont surface. AB - Theileria annulata is an apicomplexan parasite that modifies the phenotype of its host cell completely, inducing uncontrolled proliferation, resistance to apoptosis, and increased invasiveness. The infected cell thus resembles a cancer cell, and changes to various host cell signalling pathways accompany transformation. Most of the molecular mechanisms leading to Theileria-induced immortalization of leukocytes remain unknown. The parasite dissolves the surrounding host cell membrane soon after invasion and starts interacting with host proteins, ensuring its propagation by stably associating with the host cell microtubule network. By using BioID technology together with fluorescence microscopy and co-immunoprecipitation, we identified a CLASP1/CD2AP/EB1 containing protein complex that surrounds the schizont throughout the host cell cycle and integrates bovine adaptor proteins (CIN85, 14-3-3 epsilon, and ASAP1). This complex also includes the schizont membrane protein Ta-p104 together with a novel secreted T. annulata protein (encoded by TA20980), which we term microtubule and SH3 domain-interacting protein (TaMISHIP). TaMISHIP localises to the schizont surface and contains a functional EB1-binding SxIP motif, as well as functional SH3 domain-binding Px(P/A)xPR motifs that mediate its interaction with CD2AP. Upon overexpression in non-infected bovine macrophages, TaMISHIP causes binucleation, potentially indicative of a role in cytokinesis. PMID- 29520918 TI - Systematic review: Disease-specific instruments to assess gastrointestinal symptoms in functional dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal disorder with incompletely understood pathophysiology and heterogeneous symptom presentation. Assessment of treatment efficacy in FD is a methodological challenge as response to treatment must be assessed primarily by measuring subjective symptoms. Therefore, the use of patient-reported outcome measures (PROMs) is recommended by regulatory authorities to assess gastrointestinal symptoms in clinical trials for FD. In the last decades, a multitude of outcome measures has been developed. However, currently no PROM has been approved by the regulatory authorities, and no consensus has been reached with regard to the most relevant outcome measure in FD. PURPOSE: This systematic review discusses the available disease-specific outcome measures for assessment of FD symptoms with psychometric validation properties, strengths, and limitations. Moreover, recommendations for use of current available outcome measures are provided, and potential areas of future research are discussed. PMID- 29520919 TI - Predictors of weight reduction and maintenance in a large cohort of overweight and obese adults in a community setting. AB - AIM: In overweight/obese individuals, modest 5% weight loss and its maintenance promotes health; however, it is challenging and typically unachievable, especially in community settings. Established predictors of weight loss outcome in a community setting are lacking, hindering the development of practical interventions and prevention tools. Our aim was to identify predictors associated with 5% weight reduction (initial 6 months) and maintenance (1 year) in overweight and obese adults undergoing weight reduction treatment, free of charge, in a community setting. METHODS: Computerised medical files of 11 842 adults aged 50.6 +/- 16.3 years, attending 162 primary clinics, were analysed retrospectively. Thirty medical, biochemical and demographic independent variables were tested as potential predictors using multiple logistic regression models. RESULTS: Significant predictors of high successful weight reduction were: not being treated with insulin (odds ratio (OR) = 0.53), higher baseline body mass index (OR = 1.05) and younger age (OR = 0.98). Weight maintenance predictors were: successful initial weight reduction (OR = 1.26), short time intervals between weighings (OR = 0.88) and frequent weighing (OR = 0.95). Visits to a dietitian were significantly associated with success during both periods: each visit raised the probability of success by 13.4 and 7.6%, respectively. Type 2 diabetes or use of hypoglycaemic drugs were not significant predictors. CONCLUSIONS: In a community-based setting, number of visits to a dietitian is a strong predictor of successful weight reduction and maintenance. Initial success is a critical predictor of weight loss maintenance. Subgroup of older, diabetic patients treated with insulin has a dramatically lower probability of weight reduction success. PMID- 29520920 TI - Nuclear protein in testis (NUT) carcinoma diagnosed using only FNA material in the absence of a histological sample. PMID- 29520921 TI - Radical amino acid mutations persist longer in the absence of sex. AB - Harmful mutations are ubiquitous and inevitable, and the rate at which these mutations are removed from populations is a critical determinant of evolutionary fate. Closely related sexual and asexual taxa provide a particularly powerful setting to study deleterious mutation elimination because sexual reproduction should facilitate mutational clearance by reducing selective interference between sites and by allowing the production of offspring with different mutational complements than their parents. Here, we compared the rate of removal of conservative (i.e., similar biochemical properties) and radical (i.e., distinct biochemical properties) nonsynonymous mutations from mitochondrial genomes of sexual versus asexual Potamopyrgus antipodarum, a New Zealand freshwater snail characterized by coexisting and ecologically similar sexual and asexual lineages. Our analyses revealed that radical nonsynonymous mutations are cleared at higher rates than conservative changes and that sexual lineages eliminate radical changes more rapidly than asexual counterparts. These results are consistent with reduced efficacy of purifying selection in asexual lineages allowing harmful mutations to remain polymorphic longer than in sexual lineages. Together, these data illuminate some of the population-level processes contributing to mitochondrial mutation accumulation and suggest that mutation accumulation could influence the outcome of competition between sexual and asexual lineages. PMID- 29520923 TI - Silica-Protection-Assisted Encapsulation of Cu2 O Nanocubes into a Metal-Organic Framework (ZIF-8) To Provide a Composite Catalyst. AB - The integration of metal/metal oxide nanoparticles (NPs) into metal-organic frameworks (MOFs) to form composite materials has attracted great interest due to the broad range of applications. However, to date, it has not been possible to encapsulate metastable NPs with high catalytic activity into MOFs, due to their instability during the preparation process. For the first time, we have successfully developed a template protection-sacrifice (TPS) method to encapsulate metastable NPs such as Cu2 O into MOFs. SiO2 was used as both a protective shell for Cu2 O nanocubes and a sacrificial template for forming a yolk-shell structure. The obtained Cu2 O@ZIF-8 composite exhibits excellent cycle stability in the catalytic hydrogenation of 4-nitrophenol with high activity. This is the first report of a Cu2 O@MOF-type composite material. The TPS method provides an efficient strategy for encapsulating unstable active metal/metal oxide NPs into MOFs or maybe other porous materials. PMID- 29520922 TI - Fused dimerization increases expression, solubility, and activity of bacterial dehydratase enzymes. AB - FabA and FabZ are the two dehydratase enzymes in Escherichia coli that catalyze the dehydration of acyl intermediates in the biosynthesis of fatty acids. Both enzymes form obligate dimers in which the active site contains key amino acids from both subunits. While FabA is a soluble protein that has been relatively straightforward to express and to purify from cultured E. coli, FabZ has shown to be mostly insoluble and only partially active. In an effort to increase the solubility and activity of both dehydratases, we made constructs consisting of two identical subunits of FabA or FabZ fused with a naturally occurring peptide linker, so as to force their dimerization. The fused dimer of FabZ (FabZ-FabZ) was expressed as a soluble enzyme with an ninefold higher activity in vitro than the unfused FabZ. This construct exemplifies a strategy for the improvement of enzymes from the fatty acid biosynthesis pathways, many of which function as dimers, catalyzing critical steps for the production of fatty acids. PMID- 29520924 TI - Reproductive organ-sparing cystectomy significantly improves continence in women after orthotopic bladder substitution without affecting oncological outcome. AB - OBJECTIVES: To compare functional and oncological outcomes of reproductive organ sparing cystectomy (ROSC) compared with standard cystectomy (SC) in women undergoing orthotopic bladder substitution (OBS). PATIENTS AND METHODS: Between 1995 and 2016, 121 consecutive women undergoing OBS were prospectively included in this single-centre non-randomized clinical follow-up study comprising an ROSC and an SC group. Urinary continence, the need for intermittent self catheterization (ISC), lateral standing micturition cystourethrogram (MCUG), urethral pressure profile findings, if available, and oncological outcomes were assessed and compared between ROSC and SC. RESULTS: After 12 months, patients who had undergone ROSC with OBS had significantly higher daytime and nighttime continence rates than patients who had undergone SC with OBS (87.5% vs 63.5%; P = 0.027 and 87.5% vs 57.7%; P = 0.008), whereas no significant differences were found between groups in ISC rates (12.5% vs 12.94%; P > 0.99). The degree of attempted nerve-sparing (none, unilateral, bilateral) positively affected continence rates in both groups. No significant differences were found in local recurrence rates (0% vs 9.4%; P = 0.126), 5- and 10-year overall survival rates (80.9% and 80.9% vs 64.9% and 55.7%; P = 0.443) or 5- and 10-year cancer-specific survival rates (84.3% and 84.3% vs 73% and 66.2%; P = 0.431). CONCLUSION: Superior continence rates were found for ROSC with an OBS compared with SC, without a negative impact on oncological outcome. ROSC should, therefore, be offered to women receiving an OBS whenever justifiable. PMID- 29520925 TI - Intermediate detection in real time using reactive surface desorption dielectric barrier discharge ionization mass spectrometry. AB - Reactive intermediates play key roles for reaction mechanism elucidation. A suitable tool for identifying the key intermediates is crucial and highly desirable. In this study, surface desorption dielectric-barrier discharge ionization (reactive SDDBDI) was developed for characterization of the reactive intermediates. In reactive SDDBDI, the plasma is doped with a reagent before the plasma ions are directed at a cover slip surface bearing another analyte. Different from SDDBDI, reactive SDDBDI can be used both as an ambient ionization source and as a means to produce reagent ions for ambient ion/molecule reactions. The online derivation of 4-aminophenol with trifluoroacetic anhydride demonstrated that reactive SDDBDI can be used for chemical analysis where improved specificity or sensitivity is required. The utility of this approach for real-time detection of reactive intermediate was demonstrated by the Schiff-base and Eberlin reactions. The formed intermediates and products could be readily detected and identified by tandem mass spectrometry. These results indicate that reactive SDDBDI can be used to generate reagent ions that undergo ion/molecule reactions in the open air with an analyte at condensed phase on a surface. Reactive SDDBDI has high-efficiency ion transmission and high MS sensitivity. It is thus a potential tool to perform ambient ion/molecule reactions and detect reactive intermediates. PMID- 29520927 TI - Pressure exposure and catheter impingement affect the recorded pressure in the Manoscan 360TM system. AB - BACKGROUND: The accuracy of pressure measurements by Manoscan high-resolution manometry (HRM) system is affected by pressure drift (PD). The PD is partly related to temperature and study duration, but other factors that contribute to errant pressure recording have not been systematically evaluated. The aim of this study was to investigate and quantify contributing factors to pressure recording error. METHODS: In total, 660 in vitro experiments were conducted on seven HRM catheters to determine the effects of sustained pressure exposure, catheter impingement, temperature, duration of study, and immersion in saline or acid on recorded pressure and PD. KEY RESULTS: At room temperature and without application of pressure, the PD was negligible. Application of sustained pressure significantly increased PD and catheter impingement of even 15 degrees produced remarkable increases in the recorded pressure as well as post-recording PD. There was significant variability across sensors in their propensity to develop PD with temperature. Body (37 degrees C) and freezing (0 degrees C) temperatures resulted in significantly higher absolute value of PD in the opposite algebraic direction, respectively (for individual sensors). Although the overall trend was for higher PD with increasing temperature, some of the pressure sensors demonstrated inherently negative PD at body temperature. CONCLUSIONS AND INFERENCES: In addition to the known effects of temperature, both sustained pressure exposure and catheter impingement significantly affect the recorded pressure and the magnitude of the PD observed at the end of the recording. These effects can be substantial enough to result in erroneous manometric diagnoses. PMID- 29520926 TI - The impact of treatment delivery format on response to cognitive behaviour therapy for preadolescent children with anxiety disorders. AB - BACKGROUND: Several delivery formats of cognitive behaviour therapy (CBT) for child anxiety have been proposed, however, there is little consensus on the optimal delivery format. The primary goal of this study was to investigate the impact of the child's primary anxiety diagnosis on changes in clinical severity (of the primary problem) during individual CBT, group CBT and guided parent-led CBT. The secondary goal was to investigate the impact of the child's primary anxiety diagnosis on rates of remission for the three treatment formats. METHODS: A sample of 1,253 children (5-12 years; Mage = 9.3, SD = 1.7) was pooled from CBT trials carried out at 10 sites. Children had a primary diagnosis of generalised anxiety disorder (GAD), social anxiety disorder (SoAD), specific phobia (SP) or separation anxiety disorder (SAD). Children and parents completed a semistructured clinical interview to assess the presence and severity of DSM-IV psychiatric disorders at preintervention, postintervention and follow-up. Linear mixture modelling was used to evaluate the primary research question and logistic modelling was used to investigate the secondary research question. RESULTS: In children with primary GAD, SAD or SoAD, there were no significant differences between delivery formats. However, children with primary SP showed significantly larger reductions in clinical severity following individual CBT compared to group CBT and guided parent-led CBT. The results were mirrored in the analysis of remission responses with the exception that individual CBT was no longer superior to group CBT for children with a primary SP. The difference between individual and group was not significant when follow-up data were examined separately. CONCLUSIONS: Data show there may be greater clinical benefit by allocating children with a primary SP to individual CBT, although future research on cost effectiveness is needed to determine whether the additional clinical benefits justify the additional resources required. PMID- 29520928 TI - PBOV1 as a potential biomarker for more advanced prostate cancer based on protein and digital histomorphometric analysis. AB - BACKGROUND: There are few tissue-based biomarkers that can accurately predict prostate cancer (PCa) progression and aggressiveness. We sought to evaluate the clinical utility of prostate and breast overexpressed 1 (PBOV1) as a potential PCa biomarker. METHODS: Patient tumor samples were designated by Grade Groups using the 2014 Gleason grading system. Primary radical prostatectomy tumors were obtained from 48 patients and evaluated for PBOV1 levels using Western blot analysis in matched cancer and benign cancer-adjacent regions. Immunohistochemical evaluation of PBOV1 was subsequently performed in 80 cancer and 80 benign cancer-adjacent patient samples across two tissue microarrays (TMAs) to verify protein levels in epithelial tissue and to assess correlation between PBOV1 proteins and nuclear architectural changes in PCa cells. Digital histomorphometric analysis was used to track 22 parameters that characterized nuclear changes in PBOV1-stained cells. Using a training and test set for validation, multivariate logistic regression (MLR) models were used to identify significant nuclear parameters that distinguish Grade Group 3 and above PCa from Grade Group 1 and 2 PCa regions. RESULTS: PBOV1 protein levels were increased in tumors from Grade Group 3 and above (GS 4 + 3 and >= 8) regions versus Grade Groups 1 and 2 (GS 3 + 3 and 3 + 4) regions (P = 0.005) as assessed by densitometry of immunoblots. Additionally, by immunoblotting, PBOV1 protein levels differed significantly between Grade Group 2 (GS 3 + 4) and Grade Group 3 (GS 4 + 3) PCa samples (P = 0.028). In the immunohistochemical analysis, measures of PBOV1 staining intensity strongly correlated with nuclear alterations in cancer cells. An MLR model retaining eight parameters describing PBOV1 staining intensity and nuclear architecture discriminated Grade Group 3 and above PCa from Grade Group 1 and 2 PCa and benign cancer-adjacent regions with a ROC-AUC of 0.90 and 0.80, respectively, in training and test sets. CONCLUSIONS: Our study demonstrates that the PBOV1 protein could be used to discriminate Grade Group 3 and above PCa. Additionally, the PBOV1 protein could be involved in modulating changes to the nuclear architecture of PCa cells. Confirmatory studies are warranted in an independent population for further validation. PMID- 29520930 TI - Love Transcends Disease. PMID- 29520929 TI - Changes in iron availability in Arabidopsis are rapidly sensed in the leaf vasculature and impaired sensing leads to opposite transcriptional programs in leaves and roots. AB - The OLIGOPEPTIDE TRANSPORTER 3 (OPT3) has recently been identified as a component of the systemic network mediating iron (Fe) deficiency responses in Arabidopsis. Reduced expression of OPT3 induces an over accumulation of Fe in roots and leaves, due in part by an elevated expression of the IRON-REGULATED TRANSPORTER 1. Here we show however, that opt3 leaves display a transcriptional program consistent with an Fe overload, suggesting that Fe excess is properly sensed in opt3 leaves and that the OPT3-mediated shoot-to-root signaling is critical to prevent a systemic Fe overload. We also took advantage of the tissue-specific localization of OPT3, together with other Fe-responsive genes, to determine the timing and location of early transcriptional events during Fe limitation and resupply. Our results show that the leaf vasculature responds more rapidly than roots to both Fe deprivation and resupply, suggesting that the leaf vasculature is within the first tissues that sense and respond to changes in Fe availability. Our data highlight the importance of the leaf vasculature in Fe homeostasis by sensing changes in apoplastic levels of Fe coming through the xylem and relaying this information back to roots via the phloem to regulate Fe uptake at the root level. PMID- 29520931 TI - Quantifying climate-growth relationships at the stand level in a mature mixed species conifer forest. AB - A range of environmental factors regulate tree growth; however, climate is generally thought to most strongly influence year-to-year variability in growth. Numerous dendrochronological (tree-ring) studies have identified climate factors that influence year-to-year variability in growth for given tree species and location. However, traditional dendrochronology methods have limitations that prevent them from adequately assessing stand-level (as opposed to species-level) growth. We argue that stand-level growth analyses provide a more meaningful assessment of forest response to climate fluctuations, as well as the management options that may be employed to sustain forest productivity. Working in a mature, mixed-species stand at the Howland Research Forest of central Maine, USA, we used two alternatives to traditional dendrochronological analyses by (1) selecting trees for coring using a stratified (by size and species), random sampling method that ensures a representative sample of the stand, and (2) converting ring widths to biomass increments, which once summed, produced a representation of stand level growth, while maintaining species identities or canopy position if needed. We then tested the relative influence of seasonal climate variables on year-to year variability in the biomass increment using generalized least squares regression, while accounting for temporal autocorrelation. Our results indicate that stand-level growth responded most strongly to previous summer and current spring climate variables, resulting from a combination of individualistic climate responses occurring at the species- and canopy-position level. Our climate models were better fit to stand-level biomass increment than to species-level or canopy position summaries. The relative growth responses (i.e., percent change) predicted from the most influential climate variables indicate stand-level growth varies less from to year-to-year than species-level or canopy-position growth responses. By assessing stand-level growth response to climate, we provide an alternative perspective on climate-growth relationships of forests, improving our understanding of forest growth dynamics under a fluctuating climate. PMID- 29520932 TI - Bimetallic Chromium Catalysts with Chain Transfer Agents: A Route to Isotactic Poly(propylene oxide)s with Narrow Dispersities. AB - Bimetallic chromium catalysts are investigated for the enantioselective polymerization of propylene oxide. The catalyst is composed of two salen chromium species linked by an alkyl chain, the length of which significantly impacts the rate of polymerization. While the use of a chloride initiator on the catalyst resulted in bimodal molecular weight distributions, switching to a trifluoroacetate initiating group and adding a diol chain transfer agent afforded polymers of controllable molecular weight with low, unimodal dispersities. PMID- 29520933 TI - Evaluating the risk of underlying malignancy in patients with pathologic nipple discharge. AB - Most pathologic nipple discharge (PND) is benign, but duct excision has been advised to exclude malignancy. To identify factors associated with malignancy, we reviewed 280 patients with PND at our institution from 2004 to 2014. In 49 cases, malignancy was found. These patients more often had palpable masses (39% vs 11%, P < .001) and abnormal imaging (94% vs 75%, P = .004). On multivariable analysis, age, palpable mass, and abnormal imaging were independently associated with malignancy. Among 48 patients with PND but no other clinical/imaging abnormalities, only 1 malignancy, a small ductal carcinoma in situ, was identified. Observation may be reasonable for these select patients. PMID- 29520934 TI - Recent Advances in Multicomponent Particle Assembly. AB - Particle assembly and co-assembly have been research frontiers in chemistry and material science in the past few decades. To achieve a large variety of intricate structures and functional materials, remarkable progress has been made in particle assembly principles and strategies. Essentially, particle assembly is driven by intrinsic interparticle interactions or the external control. In this article, we focus on binary or ternary particle co-assembly and review the principles and feasible strategies. These advances have led to new disciplines of microfabrication technology and material engineering. Although significant achievement on particle-based structures has been made, it is still challenging to fully develop general and facile strategies to precisely control the one dimensional (1D) co-assembly. This article reviews the recent development on multicomponent particle co-assembly, which significantly increases structural complexity and functional diversity. In particular, we highlight the advances in the particle co-assembly of well-ordered 1D binary superstructures by liquid soft confinement. Finally, prospective outlook for future trends in this field is proposed. PMID- 29520935 TI - Living with multiple sclerosis: A Jordanian perspective. AB - BACKGROUND: Multiple sclerosis (MS) symptoms are very heterogeneous and may lead to reduced physical, cognitive, and psychosocial functioning that can consequently impair aspects of individual's life. Many studies have examined the living experiences of individuals with MS and its impact on their daily lives. In developing countries and particularly in Jordan, there has been little attempt to conduct studies exploring the experiences of people living with MS. Such knowledge will provide a background to hidden aspects of human concepts, such as culture, perception, and attitudes about chronic diseases. OBJECTIVE: The purpose of this qualitative study was to explore and describe the daily living experiences and challenges of Jordanian individuals with MS. METHODS: A qualitative design was utilized. Sixteen individuals with MS took part in the study; they were interviewed and divided into 4 focus groups. Conversations were digitally recorded followed by a verbatim transcription. Transcripts were analysed using thematic analysis and validated via researcher triangulation and peer checking. RESULTS: Experiences of 16 Jordanian individuals with MS who participated in this study were categorized into the following major themes: (a) experiences related to the disease itself and (b) experiences related to the healthcare system. Disease-related experiences include physical decline, psychosocial withdrawal, and fear of the future. Participants' experiences with the healthcare system include difficulty of diagnosis, poor communication and rapport with healthcare providers, and lack of awareness about MS and its rehabilitation. CONCLUSIONS: Findings of this study suggests that more attention should be given to the people with MS in Jordan. In particular, awareness about the disease should be improved among healthcare providers and the general public. Furthermore, rehabilitation services should be emphasized during the management of MS disease. PMID- 29520936 TI - Effects of the hierarchical macro/mesoporous structure on the osteoblast-like cell response. AB - To improve the success of medical devices, implants with strong surface bioactivity are urgently required. Coatings with a macroporous structure produced by micro-arc oxidation possess advantages, such as strong adhesion to substrate and excellent resistance to wear and corrosion. Mesoporous structures contain pores with sizes of 2-50 nm, which can endow the biomaterials with the ability to enhance osteogenesis and to be loaded with diverse drugs. Thus, in this study, we aimed to evaluate the effects of both macroporous and mesoporous structures using a hierarchical macro/mesoporous structure to modify the titanium implant surface. The behaviors of SaOS-2 human osteosarcoma cells on the macro/mesoporous structure, including initial adhesion, proliferation, alkaline phosphatase (ALP) activity, and collagen secretion, were investigated. Cells that attached on the macro/mesoporous surface showed the highest cell numbers and greatest spreading area after incubation for 1, 2, and 4 h compared with the polished smooth substrate and macroporous surface in the presence of fetal bovine serum (FBS). However, in the absence of FBS, cell adhesion on the polished substrate, macroporous structure, and macro/mesoporous structure did not differ significantly. Cell proliferation on the macroporous and macro/mesoporous surfaces increased compared with that on the smooth substrate surface. Furthermore, ALP activity and collagen secretion were enhanced on the macro/mesoporous structure. Our findings provided important insights into the cellular responses to macro/mesoporous structures in the field of implant surface modification. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1896-1902, 2018. PMID- 29520937 TI - Osteogenic stimulation of human dental pulp stem cells with a novel gelatin hydroxyapatite-tricalcium phosphate scaffold. AB - The aim of the present study was to construct and compare gelatin-HA-TCP scaffolds with a gelatin-only scaffold and to investigate the effect of the scaffold on osteogenic differentiation of human dental pulp stem cells. We developed a novel scaffold for bone tissue engineering via a solution casting/particle washing method, and the physical and mechanical properties of the scaffolds were examined using scanning electron microscopy and a universal testing machine, respectively. Scaffold cytotoxicity toward human dental pulp stem cells (hDPSCs) was evaluated with the CCK8 method, and hDPSC differentiation was evaluated with an alkaline phosphatase activity assay, alizarin red S staining, and reverse transcription-polymerase chain reaction (RT-PCR). Our results indicate that the gelatin-HA-TCP scaffolds exhibited good homogeneity, interconnected pores, and relatively high mechanical strength and water absorption rates. A significant increase in hDPSC proliferation and ALP activity that stimulated mineralization of the hDPSC-generated matrix was also seen on gelatin-HA-TCP scaffolds compared with the gelatin-only scaffolds. In addition, RT-PCR revealed that the gelatin-HA-TCP scaffold upregulated gene expression of the osteogenic markers Runx2, bone sialoprotein, and OSX. In conclusion, gelatin HA-TCP scaffolds presented better mechanical properties, cytocompatibility and differentiation-inducing characteristics than gelatin scaffolds. These results indicate that the novel hydrogel gelatin-HA-TCP scaffolds may be a promising biomaterial for bone tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1851-1861, 2018. PMID- 29520938 TI - An evaluation of the stability of image quality parameters of Elekta X-ray volume imager and iViewGT imaging systems. AB - INTRODUCTION: A robust image quality assurance and analysis methodology for image guided localization systems is crucial to ensure the accurate localization and visualization of target tumors. In this study, the long-term stability of selected image parameters was assessed and evaluated for the cone-beam computed tomography (CBCT) mode, planar radiographic kV mode, and the radiographic MV mode of an Elekta VersaHD. MATERIALS AND METHODS: The CATPHAN, QckV-1, and QC-3 phantoms were used to evaluate the image quality parameters. The planar radiographic images were analyzed in PIPSproTM with spatial resolution (f30, f40, f50), contrast to noise ratio (CNR) and noise being recorded. For XVI CBCT, Head and Neck Small20 (S20) and Pelvis Medium20 (M20) standard acquisition modes were evaluated for uniformity, noise, spatial resolution, and HU constancy. Dose and kVp for the XVI were recorded using the Unfors RaySafe Xi system with the R/F low detector for the kV planar radiographic mode. For each metric, values were normalized to the mean and the standard deviations were recorded. RESULTS: A total of 30 measurements were performed on a single Elekta VersaHD linear accelerator over an 18-month period without significant adjustment or recalibration to the XVI or iViewGT systems during the evaluated time frame. For the planar radiographic spatial resolution, the normalized standard deviation values of the f30, f40, and f50 were 0.004, 0.003, and 0.003 and 0.015, 0.009, and 0.017 for kV and MV, respectively. The average recorded dose for kV was 67.96 MUGy. The standard deviations of the evaluated metrics for the S20 acquisition were 0.083(f30), 0.058(f40), 0.056(f50), 0.021(Water/poly-HU constancy), 0.029(uniformity) and 0.028(noise). The standard deviations for the M20 acquisition were 0.093(f30), 0.043(f40), 0.037(f50), 0.016(Water/poly-HU constancy), 0.010(uniformity) and 0.011(Noise). CONCLUSION: A study was performed to assess the stability of the basic image quality parameters recommended by TG 142 for the Elekta XVI and iViewGT imaging systems. The two systems show consistent imaging and dosimetric properties over the evaluated time frame. PMID- 29520939 TI - A proposed clinical research support career pathway for noninvestigators. AB - AIM: To discuss the international experience of clinical research support for noninvestigator roles and to propose a new pathway for Australia, to promote a sustainable research support workforce capable of delivering high-quality clinical research. BACKGROUND: Noninvestigator research support roles are currently characterized by an ad hoc approach to training, with limited role delineation and perceived professional isolation with implications for study completion rates and participant safety. A focused approach to developing and implementing research support pathways has improved patient recruitment, study completion, job satisfaction, and research governance. DATA SOURCES: The Queensland and New South Wales state-based Nurses' Awards, the Australian Qualifications Framework, and a University Professional (Research) Staff Award. Research nurses in the clinical environment improve study coordination, adherence to study protocol, patient safety, and clinical care. CONCLUSION: A career pathway that guides education and outlines position descriptions and skill sets would enhance development of the research support workforce. This pathway could contribute to changing the patient outcomes through coordination and study completion of high-quality research. A wide consultative approach is required to determine a cost-effective and feasible approach to implementation and evaluation of the proposed pathway. PMID- 29520940 TI - Synthesis of an Iron(IV) Aqua-Oxido Complex Using Ozone as an Oxidant. AB - The iron(IV) oxido complex [(tmc)Fe=O(OTf)]OTf with the macrocyclic ligand 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclo-tetradecane (tmc) has been synthesized using ozone as an oxidant. By adding water to this compound the complex [(H2 O)(tmc)Fe=O)](OTf)2 could be prepared. This complex is important in regard to a better understanding of the reactivity of FeIV oxido complexes. Mossbauer measurements using the solid compound showed an isomer shift of delta=0.19 mm s-1 and a quadrupole splitting DeltaEQ =1.38 mm s-1 , confirming the high-valent FeIV state. DFT calculations were performed and led to an assignment of triplet spin multiplicity. Crystallographic characterization of [(H2 O)(tmc)Fe=O)](OTf)2 as well as of starting materials [(tmc)Fe(CH3 CN)](OTf)2 and [(tmc)Fe(OTf)]OTf together with previous results strongly suggest that [(H2 O)(tmc)Fe=O)](OTf)2 was formed similar to the oxido-hydroxido tautomerism analogous to heme systems. PMID- 29520941 TI - In vitro evaluation of controlled-release 14% doxycycline gel for decontamination of machined and sandblasted acid-etched implants. AB - BACKGROUND: Peri-implant infections are associated with the establishment and maturation of a bacterial biofilm characterized by a predominance of Gram negative fusiform anaerobic species. The decontamination of implant surfaces is then crucial for a successful peri-implant therapy. METHODS: Twenty-one smooth and 21 rough implants, divided into four groups according to surface and treatment modality, were contaminated with Streptococcus sanguinis and then placed in an incubator with the atmosphere of 5% CO2 at 37 degrees C for 24 hours to allow the bacteria to grow. After 24 hours, the test groups were treated with controlled release 14% doxycycline gel injecting the gel circumferentially over the surface of the implant for 3 minutes, while the control groups were irrigated with sterile saline for 1 minute. The implants were then vortexed into triptych soy broth to allow the bacteria to detach from the surface, diluted 1:100 and plated. Colony forming units (CFU) were counted 48 hours after incubation. RESULTS: The use of a 14% doxycycline gel minimized CFU counts compared to control groups, with the difference being statistically significant (P < 0.05). The reduction of CFUs in the smooth test group is more marked than in the rough test group, but the difference doesn't reach statistically significance (P = 0.215). CONCLUSIONS: The use of 14% doxycycline gel in implant surface decontamination was efficacious in this in-vitro study. Adjunctive use of locally delivered 14% doxycycline gel might be a viable option in the management of peri implantitis and peri-implant mucositis considering its efficacy in reducing bacterial colonization. PMID- 29520942 TI - Detection of metronidazole in honey and metronidazole tablets using carbon dots based sensor via the inner filter effect. AB - In this work, carbon dots (CDs) with a high quantum yield (22.3%) were easily prepared by hydrothermal pyrolysis of acid fuchsin 6B and hydrogen peroxide at 180 degrees C for 10 h. The resultant CDs possess a narrow size distribution in the range of 2.6 to 3.2 nm and emit blue fluorescence. Interestingly, the absorption band of metronidazole (MTZ) centered at 318 nm can complementary overlap with the excitation band of the as-prepared CDs centered at 320 nm, resulting in an inner filter effect (IFE) in high efficiency. In fact, the fluorescence quenching of the CDs depends on the concentration of MTZ. Therefore, a simple method for the detection of MTZ can be established using the CDs-based sensor via the IFE. The linear range of the proposed method was 0-10 MUg mL-1 with the limit of detection as low as 0.257 MUg mL-1 . This CDs-based sensor had been applied for the detection of MTZ in honey and MTZ tablets with the recoveries in the range of 98.0% to 105.1% and 95.7% to 106.5%, respectively. Therefore, the as-prepared CDs have a potential to be developed as a MTZ sensor with high selectivity, sensitivity and accuracy. PMID- 29520943 TI - Pre admission treatment with Beta-blockers in hypertensive patients with acute stroke and 3-month outcome-Data from a national stroke registry. AB - The impact of beta-blockers (BB) treatment on stroke outcome is unclear. We used data from a prospective national stroke registry to assess the associations between use of BB and poor outcome 3 months after stroke. Using the National Acute Stroke Israeli (NASIS) registry, we identified 1126 patients with ischemic stroke and intracerebral hemorrhage with pre-stroke hypertension treatment, who were followed for 3-months. Functional outcome and mortality at 3-month were compared by use of BB, adjusting for demographics and clinical factors. Pre stroke use of BB was reported by 615 (54.6%) patients. Users of BB showed higher rates of atrial fibrillation, heart disease, statin use, cancer, and severe stroke. Adjusted odds-ratios (ORs, 95% CI) for BB users compared with non-users 3 months after stroke were 0.86 (0.49-1.52) for mortality and 1.07 (0.76-1.50) for Barthel Index <=60. In conclusion, treatment with BB is not associated with 3 month poor outcome in hypertensive patients. PMID- 29520944 TI - Novel treatment of in-office tooth bleaching sensitivity: A randomized, placebo controlled clinical study. AB - OBJECTIVES: Aim of this clinical trial was to investigate the effect of a calcium phosphate based desensitizer paste applied prior to in-office tooth whitening on bleaching sensitivity (BS). METHODS: This crossover study was designed as randomized double-blinded, placebo-controlled trial. The desensitizer paste Teethmate AP (TAP) contains tetracalcium phosphate and dicalcium phosphate anhydrous in glycerol and polyethylene glycol, whereas placebo (PLA) is a calcium phosphate free analog. Fifty patients with sound maxillary incisors and canines were enrolled. Tooth shades were determined with a Vitapan Classic Shade guide. Randomly, TAP and PLA were applied to the left or to the right anterior teeth. After rinsing and air-drying the bleaching gel (Opalescence Boost PF 40%) was applied and left on the labial surfaces for 15 minutes. Sensitivity was recorded using a 10 cm visual analog scale (VAS) before, at 5, 10, and 15 minutes during, and at 1 hour, 1, 2, and 7 days after bleaching. Tooth whitening was determined with the shade guide after 1 day and 1 week. RESULTS: Prebleaching desensitization with TAP reduced BS significantly when compared with PLA. Between 1 and 7 days the average sensitivity scores were close to zero, whereas the average scores for PLA were significantly higher during this time interval. Independent from the desensitizing treatment after 1 and 7 days the medians of the shades were between 5 and 3.5 units brighter. CONCLUSIONS: Prebleaching desensitization with TAP was effective in reducing BS during and after tooth whitening treatment and had no adverse effect on the bleaching result. CLINICAL SIGNIFICANCE: Prebleaching topical application of a calcium phosphate containing compound reduced significantly bleaching sensitivity during a single 15 minutes treatment and up to one week with a 40% hydrogen peroxide containing gel without compromising tooth whitening. PMID- 29520946 TI - Links between the organization of the family home environment and child obesity: a systematic review. AB - Due to increasingly high rates of child overweight and obesity, it is important to identify risk and protective factors that may inform more effective prevention and intervention. The degree of organization in the family home environment is a studied, but not well-specified, factor that may impact child weight. Prior research on household organization has examined an array of constructs, including family routines, limit setting, household chaos, crowding and the broad home environment. This study systematically reviews literature on organization within the family home environment and weight among children ages 2-12. Six hundred thirty-seven studies were reviewed by four coders for eligibility, and 32 studies were included in the final synthesis. Overall, 84% of studies provided evidence for relations between at least one indicator of organization within the family home environment and child weight. Studies provided compelling evidence across several constructs, suggesting that the relevance of household organization to child weight extends beyond a single indicator. Directions for future work include (i) examining the mediating role of health behaviours, (ii) examining the moderating role of socioeconomic factors, (iii) broadening this evidence base across cultures and nationalities and (iv) integrating constructs to develop a comprehensive model of organization within the home environment. PMID- 29520945 TI - A Vitis vinifera basic helix-loop-helix transcription factor enhances plant cell size, vegetative biomass and reproductive yield. AB - Strategies for improving plant size are critical targets for plant biotechnology to increase vegetative biomass or reproductive yield. To improve biomass production, a codon-optimized helix-loop-helix transcription factor (VvCEB1opt ) from wine grape was overexpressed in Arabidopsis thaliana resulting in significantly increased leaf number, leaf and rosette area, fresh weight and dry weight. Cell size, but typically not cell number, was increased in all tissues resulting in increased vegetative biomass and reproductive organ size, number and seed yield. Ionomic analysis of leaves revealed the VvCEB1opt -overexpressing plants had significantly elevated, K, S and Mo contents relative to control lines. Increased K content likely drives increased osmotic potential within cells leading to greater cellular growth and expansion. To understand the mechanistic basis of VvCEB1opt action, one transgenic line was genotyped using RNA-Seq mRNA expression profiling and revealed a novel transcriptional reprogramming network with significant changes in mRNA abundance for genes with functions in delayed flowering, pathogen-defence responses, iron homeostasis, vesicle-mediated cell wall formation and auxin-mediated signalling and responses. Direct testing of VvCEB1opt -overexpressing plants showed that they had significantly elevated auxin content and a significantly increased number of lateral leaf primordia within meristems relative to controls, confirming that cell expansion and organ number proliferation were likely an auxin-mediated process. VvCEB1opt overexpression in Nicotiana sylvestris also showed larger cells, organ size and biomass demonstrating the potential applicability of this innovative strategy for improving plant biomass and reproductive yield in crops. PMID- 29520947 TI - Inter-relations among negative social control, self-efficacy, and physical activity in healthy couples. AB - OBJECTIVES: In romantic relationships, partners can influence each other's health relevant behaviour by exerting negative social control (e.g., pressuring), however, with mixed success. To elucidate this phenomenon, we examined couples motivated to increase their physical activity and investigated the degree to which both partners exerted negative control on each other, their self-efficacy, reciprocal associations among the two behaviour-specific constructs, and their relationship with moderate-to-vigorous physical activity (MVPA). DESIGN: This was a longitudinal study with three assessment periods (T0, T2, T3) spanning 7 weeks. METHODS: We performed secondary analyses with data from the control condition (N = 113 heterosexual couples) of a published randomized controlled trial. Dyadic mediator models specified either both partners' self-efficacy as predictors and provided negative partner control to each other as mediators or vice versa. The outcomes comprised both partners' accelerometer-assessed MVPA. Mediators and outcomes were controlled for their T0 values. RESULTS: The first model showed that women's and men's provided negative partner control (T0) was positively related to the other partners' self-efficacy (T2). Testing the alternative predictive direction, the second model showed that only women's self-efficacy (T0) was associated with more provided negative partner control (T2) by men. Women and men showed less MVPA (T3) when their partners had provided them with more negative control at T2. CONCLUSIONS: As negative control provided to partners may be detrimental to their behaviour change, interventionists should advise couples to avoid it. However, active ingredients of negative control that may benefit recipients' self-efficacy beliefs should be investigated in future work. Statement of contribution What is already known on this subject? Couples often try to change each other's health behaviour not just using supportive tactics, but also controlling ones. Negative partner control (e.g., rebuking and nagging) was found to have adverse or no effects on control recipients' health behaviour change. To understand underlying mechanisms of this relationship, reactance and negative affect of recipients have been investigated, but only rarely their self-efficacy, a consistent individual predictor of behaviour change that is likely to share reciprocal relations with social exchange processes, including negative social control. What does this study add? Although harmful for behaviour change, negative partner control may increase control recipients' self efficacy. Higher self-efficacy of one partner may also increase provided negative partner control by the other. PMID- 29520948 TI - Influence of macroporosity on NIH/3T3 adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 over bio-functionalized highly porous titanium implant material. AB - Highly porous Ti implant materials are being used in order to overcome the stress shielding effect on orthopedic implants. However, the lack of bioactivity on Ti surfaces is still a major concern regarding the osseointegration process. It is known that the rapid recruitment of osteoblasts in bone defects is an essential prerequisite for efficient bone repair. Conventionally, osteoblast recruitment to bone defects and subsequent bone repair has been achieved using growth factors. Thus, in this study highly porous Ti samples were processed by powder metallurgy using space holder technique followed by the bio-functionalization through microarc oxidation using a Ca- and P-rich electrolyte. The biological response in terms of early cell response, namely, adhesion, spreading, viability, and proliferation of the novel biofunctionalized highly porous Ti was carried out with NIH/3T3 fibroblasts and MC3T3-E1 preosteoblasts in terms of viability, adhesion, proliferation, and alkaline phosphatase activity. Results showed that bio-functionalization did not affect the cell viability. However, bio functionalized highly porous Ti (22% porosity) enhanced the cell proliferation and activity. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29520949 TI - Predictive modelling of 2-year potency outcomes using a novel 90-day erection fullness scale after robot-assisted radical prostatectomy. AB - OBJECTIVE: To introduce a patient-reported erection fullness scale (%fullness) after robot-assisted radical prostatectomy (RARP) as a qualitative adjunct to the five-item version of the International Index of Erectile Function (IIEF-5) and as a 90-day predictor of 2-year potency outcomes. PATIENTS AND METHODS: Prospective data were collected from 540 men with preoperative IIEF-5 scores of 22-25 who underwent RARP by a single surgeon, and of whom 299 had complete data at all time points up to 2 years. In addition to standard assessment tools (IIEF-5 and erections sufficient for intercourse [ESI]), the men were asked to 'indicate the fullness you are able to achieve in erections compared to before surgery?' (range: 0-100%). The primary outcome was prediction of potency (defined as ESI) at 24 months, based on 90-day %fullness tertile (0-24%, 25-74% and 75-100%). RESULTS: A total of 299 men with complete follow-up were included in the study. Significant predictors of 24-month potency included age, body mass index, pathological stage, nerve-sparing status and %fullness tertiles. When the men (preoperative IIEF-5 score 22-25) were assessed at 90 days after RARP, 181/299 (61%) had erections inadequate for intercourse. If IIEF-5 scores of 1-6 were used, 142/181 men (78%) would be targeted for early intervention. By contrast, if 0-24% fullness was used, 88/181 men (49%) would be targeted. If both the IIEF-5 score and %fullness were used, this would be reduced to 77/181 men (43%). CONCLUSIONS: We introduce %fullness as a qualitative adjunct to the IIEF-5 score, and separately as a 90-day predictor of 2-year potency recovery. This initial report is hypothesis-generating, such that the use of %fullness enables the identification of men who are most likely to benefit from early, secondary intervention. PMID- 29520950 TI - Early intervention of peri-implantitis and periodontitis using a mouse model. AB - BACKGROUND: Peri-implantitis is an inflammatory response to bacterial biofilm resulting in bone loss and can ultimately lead to implant failure. Because of the lack of predictable treatments available, a thorough understanding of peri implantitis's pathogenesis is essential. The objective of this study is to evaluate and compare the response of acute induced peri-implantitis and periodontitis lesions after insult removal. METHODS: Implants were placed in one month-old C57BL/6J male mice eight weeks post extraction of their left maxillary molars. Once osseointegrated, ligatures were placed around the implants and contralateral second molars of the experimental groups. Controls did not receive ligatures. After one week, half of the ligatures were removed, creating the ligature-retained and ligature-removed groups. Mice were sacrificed at two time points, 5 and 14 days, from ligature removal. The specimens were analyzed via micro-computed tomography and histology. RESULTS: By 5 and 14 days after ligature removal, the periodontitis group experienced significant bone gain, whereas the peri-implantitis group did not. Histologically, all implant groups exhibited higher levels of cellular infiltrate than any of the tooth groups. Osteoclast numbers increased in peri-implantitis and periodontitis ligature-retained groups and decreased following insult removal. Collagen was overall more disorganized in peri-implantitis than periodontitis for all groups. Peri-implantitis experimental groups revealed greater matrix metalloproteinase-8 and NF-kB levels than periodontitis. CONCLUSIONS: Implants respond slower and less favorably to insult removal than teeth. Future research is needed to characterize detailed peri implantitis disease pathophysiology. PMID- 29520951 TI - Decreasing ALT donor site morbidity with the keystone flap. AB - BACKGROUND: The anterolateral thigh (ALT) flap is a workhorse flap for a variety of wounds. The primary disadvantage of ALT flaps is donor site morbidity associated with large skin paddle defects. We present a strategy of managing the donor site with the Keystone flap to avoid skin grafts in cases where primary closure is not possible. METHODS: A retrospective, multi-institutional review from December 2015 to March 2017 based on a single surgeon's experience was performed. Inclusion criteria were harvest of an ALT flap and closure of the thigh donor site with a keystone flap. RESULTS: Six patients underwent reconstruction of the ALT donor site with a keystone flap. The average width of the ALT skin paddle was 7.8 cm (range 7-8 cm) and the defects could not be closed primarily or with wide undermining. Surface area of the ALT flaps averaged 96.8 cm2 (range 64-152 cm2 ). Mean patient BMI was 24.6 (range 16-37). Keystone flap dimensions averaged 9.5 * 17.8 cm. There were no major donor or recipient site complications, and one *minor complication of delayed wound healing. No patients exhibited decreased range of motion at the hip or knee. CONCLUSIONS: Primary closure of the ALT donor site is preferred, but becomes difficult as skin paddle width approaches 8 cm. Managing the ALT flap donor site with a keystone flap is safe, does not appear to have significant morbidity, and can allow the surgeon to avoid the morbidity and secondary donor site associated with skin grafting. PMID- 29520952 TI - LaSr3 NiRuO4 H4 : A 4d Transition-Metal Oxide-Hydride Containing Metal Hydride Sheets. AB - The synthesis of the first 4d transition metal oxide-hydride, LaSr3 NiRuO4 H4 , is prepared via topochemical anion exchange. Neutron diffraction data show that the hydride ions occupy the equatorial anion sites in the host lattice and as a result the Ru and Ni cations are located in a plane containing only hydride ligands, a unique structural feature with obvious parallels to the CuO2 sheets present in the superconducting cuprates. DFT calculations confirm the presence of S=1/2 Ni+ and S=0, Ru2+ centers, but neutron diffraction and MUSR data show no evidence for long-range magnetic order between the Ni centers down to 1.8 K. The observed weak inter-cation magnetic coupling can be attributed to poor overlap between Ni 3dz2 and H 1s in the super-exchange pathways. PMID- 29520953 TI - Class IV laser therapy for trapeziometacarpal joint osteoarthritis: Study protocol for a randomized placebo-controlled trial. AB - OBJECTIVE: Osteoarthritis (OA) is a chronic and prevalent joint disorder with great impact on quality of life and high economic burden. Although a number of conservative therapies have proven to be effective for the management of hand OA, only modest treatment effects were reported for most individual interventions. The aim of the proposed study is to assess the effect of Class IV laser therapy (LT) on pain and pinch strength in patients with thumb carpometacarpal (TCMC) OA. METHODS: A randomized, controlled, single-centre, double-blind, clinical trial, with 1:1 allocation ratio, will be carried out involving patients presenting TCMC OA Grades 1-2 (aged >18 years). Both assessor and statistician will remain blinded. Patients with TCMC-OA will be randomly assigned to the experimental group (will receive LT) and control group (will receive a placebo treatment). Outcome measures will be pain scores at the base of the thumb measured with visual analogue scale (0-10: 0, no pain and 10, worst pain) and changes in pinch strength, both collected at baseline, 4, and 12 weeks. Statistical analyses will be based on an intention-to-treat analysis using the last value forward method. A two-tailed independent Student's t test for the continuous variable of age and baseline scores will be used for comparison of baseline characteristics and outcome variables. Paired Student's t tests will be used to determine the level of significance of the differences between the pretreatment and posttreatment measurements of the individual groups. Repeated measures analysis of variance will be used to determine the differences in time as the within-subjects factor and group as the between-subjects factor. DISCUSSION: To our knowledge, the results of this study will provide the first double-blinded evidence for Class IV LT in patients with TCMC-OA. PMID- 29520954 TI - Large-scale purification of unstable, water-soluble secologanic acid using centrifugal partition chromatography. AB - INTRODUCTION: Secologanic acid, a major secoiridoid in the flower buds of Lonicera japonica, is a fragile, highly polar compound that readily changes to epivogeloside or vogeloside after being dissolved in methanol. Thus, it is very difficult to obtain secologanic acid on a large-scale. OBJECTIVE: To develop a centrifugal partition chromatography (CPC) method for large-scale purification of secologanic acid with high purity from the flower buds of L. japonica. METHODS: After fractionation with Diaion HP-20 macroporous resin, 30% methanol eluent was purified by CPC with a ternary biphasic solvent system with ethyl acetate/isopropanol/water (6:4:10, v/v/v). CPC was performed separately twice with the same solvent system, first in descending mode and second in ascending mode. RESULTS: After the first CPC operation, a secologanic acid enriched fraction (586 mg) was obtained from 3 g of crude extract, and secologanic acid (206 mg) was isolated with a purity over 93% in the subsequent ascending mode with the same solvent system from a 586 mg enriched fraction. In addition, it was confirmed that epivogeloside and vogeloside were reversely converted to secologanic acid in an aqueous acidic solution. CONCLUSION: These results demonstrate that CPC is a simple, effective, and rapid method for the purification of secologanic acid in the flower buds of L. japonica. PMID- 29520955 TI - Counterfeit esthetic devices and patient safety in dermatology. AB - This study addresses the dilemma concerned with meeting patients who may have encountered counterfeit esthetic devices in the marketplace. Over the past several years, we have witnessed a rise in counterfeit injectables and medical devices in our field. Often times, the procedures are marketed to patients at significantly reduced prices compared to competitors. Patients may be unaware that counterfeit devices exist and may unknowingly have procedures completed using untested and uncertified devices. It is important for clinicians to recognize when their patients may be encountering counterfeit devices, know what to do in this situation, and offer the best recommendations. PMID- 29520956 TI - Effect of Chemical Disinfectants on the Color Stability of Maxillofacial Silicones: An In Vitro Study. AB - PURPOSE: To evaluate the effect of chemical disinfection on the color stability of room temperature vulcanizing (RTV) maxillofacial silicone elastomer with and without pigment addition. MATERIALS AND METHODS: Sixty specimens were obtained from a RTV maxillofacial silicone. The specimens were randomly divided into 6 groups according to pigments and disinfectant to be used (n = 10). NP-DW nonpigmented silicone specimens to be immersed in distilled water (control). NP-S nonpigmented silicone specimens to be rubbed with an anti-bacterial soap. NP-CHX nonpigmented silicone specimens to be immersed in chlorhexidine gluconate solution (2%). P-DW-pigmented silicone specimens to be immersed in distilled water (control). P-S-pigmented silicone specimens to be rubbed with antibacterial soap. P-CHX-pigmented silicone specimens to be immersed in chlorhexidine gluconate solution (2%). Disinfection was conducted 6 times a day for 60 days simulating 1 year of usage. Color was evaluated after 60 days (disinfection period) using a reflectance spectrophotometer. Color alterations were calculated by the CIE L* a* b* system. Data were analyzed by t-test, one-way ANOVA, and Tukey test (alpha = 0.05). RESULTS: NP-S and P-S exhibited the highest color alterations, whereas NP-DW and P-DW the lowest color alterations. CONCLUSION: Disinfection procedures affect the color stability of maxillofacial silicone. Chlorhexidine gluconate solution (2%) can be effectively used as a chemical disinfectant for maxillofacial prostheses. Antibacterial soap produced clinically unacceptable color changes in the silicone, hence is not advisable as a disinfectant. PMID- 29520957 TI - Quantification of NETs-associated markers by flow cytometry and serum assays in patients with thrombosis and sepsis. AB - INTRODUCTION: Neutrophil extracellular traps (NETs) are networks of extracellular fibres produced from neutrophil DNA with a pathogenic role in infection, thrombosis and other conditions. Reliable assays for measuring NETs are desirable as novel treatments targeting NETs are being explored for the treatment of these conditions. We compare a whole blood flow cytometry method with serum assays to measure NETs-associated markers in patients with sepsis and thrombosis. METHODS: Patients with deep venous thrombosis (n = 25), sepsis (n = 21) and healthy controls (n = 23) were included in the study. Neutrophil surface NETs markers were determined by flow cytometry on whole blood samples by gating of neutrophils stained for surface citrullinated histone (H3cit) and myeloperoxidase (MPO). Serum double-stranded (ds) DNA, MPO, myeloid-related protein, nucleosomes, DNAse, elastase, human high-mobility group box 1 and MPO-DNA complexes were quantified as circulating markers of NETs. RESULTS: Neutrophil NETs markers by flow cytometry and serum NETs markers were significantly higher in patients with thrombosis and sepsis compared with healthy controls. Neutrophil NETs markers significantly correlated with the serum marker dsDNA. CONCLUSION: Flow cytometry detection of neutrophil NETs markers is feasible in whole blood and correlates with serum markers of NETs. We propose the flow cytometry detection of MPO/H3cit positive neutrophils and serum dsDNA as simple methods to quantify cellular and extracellular NET markers in patients with thrombosis and sepsis. PMID- 29520958 TI - Predictors of inadequate initial echocardiography in suspected Kawasaki disease: Criteria for sedation. AB - OBJECTIVE: Kawasaki disease is the primary cause of acquired pediatric heart disease in developed nations. Timely diagnosis of Kawasaki disease incorporates transthoracic echocardiography for visualization of the coronary arteries. Sedation improves this visualization, but not without risks and resource utilization. To identify potential sedation criteria for suspected Kawasaki disease, we analyzed factors associated with diagnostically inadequate initial transthoracic echocardiography performed without sedation. DESIGN: This retrospective review of patients < 18 years old undergoing initial transthoracic echocardiography for the inpatient evaluation of suspected Kawasaki disease from 2009 to 2015 occurred at a medium-sized urban children's hospital. The primary outcome was diagnostically inadequate transthoracic echocardiography without sedation due to poor visualization of the coronary arteries, determined by review of clinical records. The associations of the primary outcome with demographics, Kawasaki disease type, laboratory data, fever, and antipyretic or intravenous immunoglobulin treatment prior to transthoracic echocardiography were analyzed. RESULTS: In total, 112 patients (44% female, median age 2.1 years, median BSA 0.54 m2 ) underwent initial transthoracic echocardiography for suspected Kawasaki disease, and 99 were not sedated. Transthoracic echocardiography was diagnostically inadequate in 19 out of these 99 patients (19.2%) and was associated with age <= 2.0 years, weight <= 10.0 kg, and antipyretic use <= 6 hours before transthoracic echocardiography (all P < .05). These variables did not reach statistical significance on multivariable analysis. CONCLUSIONS: Patients <= 2.0 years or <= 10.0 kg or those recently receiving antipyretics, potentially a surrogate for irritability, were associated with diagnostically inadequate transthoracic echocardiography during the inpatient workup of Kawasaki disease. These factors should be considered when deciding which patients to sedate for initial Kawasaki disease transthoracic echocardiography. PMID- 29520959 TI - The energy budget in C4 photosynthesis: insights from a cell-type-specific electron transport model. AB - Extra ATP required in C4 photosynthesis for the CO2 -concentrating mechanism probably comes from cyclic electron transport (CET). As metabolic ATP : NADPH requirements in mesophyll (M) and bundle-sheath (BS) cells differ among C4 subtypes, the subtypes may differ in the extent to which CET operates in these cells. We present an analytical model for cell-type-specific CET and linear electron transport. Modelled NADPH and ATP production were compared with requirements. For malic-enzyme (ME) subtypes, c. 50% of electron flux is CET, occurring predominantly in BS cells for standard NADP-ME species, but in a ratio of c. 6 : 4 in BS : M cells for NAD-ME species. Some C4 acids follow a secondary decarboxylation route, which is obligatory, in the form of 'aspartate-malate', for the NADP-ME subtype, but facultative, in the form of phosphoenolpyruvate carboxykinase (PEP-CK), for the NAD-ME subtype. The percentage for secondary decarboxylation is c. 25% and that for 3-phosphoglycerate reduction in BS cells is c. 40%; but these values vary with species. The 'pure' PEP-CK type is unrealistic because its is impossible to fulfil ATP : NADPH requirements in BS cells. The standard PEP-CK subtype requires negligible CET, and thus has the highest intrinsic quantum yields and deserves further studies in the context of improving canopy productivity. PMID- 29520960 TI - Visual complaints of patients with glaucoma and controls under optimal and extreme luminance conditions. AB - PURPOSE: To determine (i) whether, compared to controls, visual complaints of glaucoma patients are more pronounced under extreme luminance conditions than in the optimal luminance condition and (ii) whether complaints belonging to different extreme luminance conditions are associated. METHODS: We developed a luminance-specific questionnaire and sent it to 221 glaucoma patients (response rate 81%); controls (182) were primarily their spouses. Median (interquartile range) mean deviation of the visual field of the patients' better eye was -4.5 ( 10.7 to -1.9) dB. Questions were addressing visual performance under five luminance conditions: presumed optimal (outdoor on a cloudy day), low, high, sudden decrease and sudden increase. We compared percentages of patients and controls who reported visual complaints while performing activities under different luminance conditions. RESULTS: Percentages of patients and controls with visual complaints were 4 versus 0% (p = 0.02) for optimal luminance and 48 versus 6% (p < 0.001), 22 versus 1% (p < 0.001), 32 versus 1% (p < 0.001) and 25 versus 3% (p < 0.001) for low, high, sudden decrease and sudden increase in luminance. Within the group of glaucoma patients, the frequency of complaints increased significantly with increasing disease severity at a Bonferroni corrected p value of 0.003 for all but one (p = 0.005) luminance-specific questions that addressed extreme luminance conditions. CONCLUSION: The concept of (early stage) glaucoma as an asymptomatic disease is only valid with optimal luminance. Differences in visual complaints between glaucoma patients and controls are greater under extreme luminance conditions, especially in the dark. The fact that the cases were aware of their diagnosis could have induced bias. PMID- 29520962 TI - In response to 'Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials'. PMID- 29520961 TI - Increased circulating microparticles in women with preeclampsia. AB - INTRODUCTION: Preeclampsia (PE) is associated with hypercoagulability, endothelial dysfunction and inflammation, which generate microparticles (MPs). Therefore, MPs may be important for PE. METHODS: We established a verified MP measurement procedure to detect MPs in nonpregnant women (n = 25), healthy pregnant women (n = 29) and PE women (n = 73) and compared their MP levels. RESULTS: Microparticles prepared from platelets (PMPs), endothelial cells (EMPs) and leucocytes (LMPs) were confirmed by transmission electron microscopy and were analysed by our established flow cytofluorimetric approach, which showed good specificity for determining the cell origin and level of MPs. The levels of total MPs (tMPs) and PMPs in the healthy pregnant group were significantly higher than those in the nonpregnant group (158.78 vs 93.00 and 45.04 vs 17.41, P = .004 and P = .007, respectively) but were not significantly different from those of the PE group. However, EMPs and LMPs were significantly higher in the PE group than in the healthy pregnant group (14.62 vs 11.48 and 8.94 vs 5.03, P = .015 and P < .001, respectively). Furthermore, the area under the receiver operating characteristic curves (AUC) for EMPs, LMPs and the combined sum of EMPs and LMPs were 0.661, 0.746 and 0.718, respectively (P < . 05); at their optimal cut-off values, the sensitivities were 50.68%, 87.67% and 46.58%, respectively, and the specificities were 80.77%, 58.33% and 95.65%, respectively. CONCLUSION: Determining the MP level, especially that of EMPs and LMPs, by a specificity verified method may reflect the endothelial dysfunction and inflammation involved in PE pathogenesis. PMID- 29520963 TI - Site-Specific Systematic Analysis of Lysine Modification Crosstalk. AB - Research has revealed that post-translational modifications (PTMs) that occur at lysine (PLMs) can cooperatively regulate various biological processes by crosstalk. However, the trend of the crosstalk between multiple PLMs and the properties of PLM crosstalk require additional investigation. Here, the crosstalk among acetylation, succinylation, and SUMOylation is systematically studied in a site-specific waz. First, crosstalk between SUMOylation is detected and succinylation is found to be underexpressed, whereas succinylation tends to crosstalk with acetylation and SUMOylation on the same lysine residue while PLM crosstalk is tissue-specific across different species. Further analysis reveals that different PLMs tend to occur crosstalk at diverse subcellular compartments and structural regions, and they participate in distinct biological processes and functions. Additionally, short-term evolutionary analysis shows that there is no additional evolutionary pressure on PLMs crosstalk sites, as found by comparison with singly modified sites. Finally, phylogenetic classification reveals that genes with co-occupied lysine crosstalk are more likely to have higher evolutionary similarity and possess a tendency to cluster in the specific branch. The integrated approach reported here has the potential for large-scale prioritization of in situ crosstalk of PLM candidates and provides a profound understanding of the underlying relationship between different lysine modifications. PMID- 29520965 TI - Development of a mixed-species biofilm model and its virulence implications in device related infections. AB - It is becoming increasingly accepted that to understand and model the bacterial colonization and infection of abiotic surfaces requires the use of a biofilm model. There are many bacterial colonizations by at least two primary species, however this is difficult to model in vitro. This study reports the development of a simple mixed-species biofilm model using strains of two clinically significant bacteria: Staphylococcus aureus and Pseudomonas aeruginosa grown on nanoporous polycarbonate membranes on nutrient agar support. Scanning electron microscopy revealed the complex biofilm characteristics of two bacteria blending in extensive extracellular matrices. Using a prototype wound dressing which detects cytolytic virulence factors, the virulence secretion of 30 single and 40 mixed-species biofilms was tested. P. aeruginosa was seen to out-compete S. aureus, resulting in a biofilm with P. aeruginosa dominating. In situ growth of mixed-species biofilm under prototype dressings showed a real-time correlation between the viable biofilm population and their associated virulence factors, as seen by dressing fluorescent assay. This paper aims to provide a protocol for scientists working in the field of device related infection to create mixed species biofilms and demonstrate that such biofilms are persistently more virulent in real infections. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29520964 TI - Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. AB - The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30-40% of patients) and associated with a higher risk of HF hospitalization, all-cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first-line choice. Sulphonylureas and insulin have been the traditional second- and third-line therapies although their safety in HF is equivocal. Neither glucagon-like preptide-1 (GLP-1) receptor agonists, nor dipeptidyl peptidase-4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium glucose co-transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM. PMID- 29520966 TI - Laser tattoo removal: do we already have picosecond lasers? PMID- 29520967 TI - Surgical versus non-surgical management of type B ankle fractures with minimal talar shift in adults: a systematic review. AB - BACKGROUND: This systematic review aims to determine the effectiveness of surgical and non-surgical management for the type B ankle fracture with minimal talar shift. METHODS: Two authors independently systematically searched the following databases: MEDLINE, EMBASE and CENTRAL. Only randomized controlled trials were included that evaluated surgical versus non-surgical management of type B ankle fracture with minimal talar shift in adults. Two authors independently performed study selection, risk of bias assessment and data extraction. Main outcomes extracted were general health and ankle function. Heterogeneity was assessed using I2 and chi-squared statistic. Data were pooled using fixed effect where appropriate. RESULTS: Two studies were included involving 241 patients. The pooled mean difference for the physical component score was 0.60 (95% confidence interval (CI): -1.62 to 2.82) non-significantly favouring surgical management. One study reported no significant difference in ankle function (mean difference: 3.20; 95% CI: -6.56 to 12.96) whilst the other reported a significant difference favouring non-surgical management (mean difference: 3.20; 95% CI: 0.44-5.96). Ankle function scores were not pooled due to heterogeneity. Meta-analysis showed that the surgical group was more likely to develop a minor infection (odds ratio: 12.46; 95% CI: 2.29-67.78) or undergo hardware removal (odds ratio: 4.40; 95% CI: 1.09-17.84). There was no significant difference in major infection between the two groups (odds ratio: 4.03; 95% CI: 0.44-36.65; favouring non-surgical management). CONCLUSION: There was no significant difference in the general health outcome or ankle function for patients treated surgically versus non-surgically at 12 months. Further follow-up is needed to evaluate longer-term ankle function. PMID- 29520968 TI - Post-operative arterio-venous fistula blood flow influences primary and secondary patency following access surgery. AB - PURPOSE: Primary arteriovenous fistula arterio venous fistula (AVF) formation has proven to be the best and optimal vascular access for the majority of haemodialysis patients. At present there are limited data to suggest which haemodynamic parameters most correlate with the likelihood of early failure. The aim of this study is to identify the haemodynamic predictors of early failure, hence identify which fistulae may benefit from timely pre-emptive intervention. MATERIAL AND METHODS: Retrospective analysis of data was performed of 201 patients undergoing native AVF creation over a one year period. Demographic details, co-morbidity, preoperative vessel calibre were collected. Flow was measured by duplex ultrasound post operatively. RESULTS: Preoperative vein calibre (p = 0.01) and fistula flow (p < 0.001) positively affected primary patency. Age, gender, ethnicity, type of fistula, hypertension and preoperative arterial calibre did not influence outcome. Regression analysis showed that the strength of correlation between early postoperative fistula flow and patency decreased progressively with time. Six week flow predicts early, but not late, failure. ROC analysis identified 300 ml/min flow as the best predictor of patency. Fistulae with flow above 300 ml/min were more likely to remain patent over the next 12 months (p < 0.001, HR = 7.4). CONCLUSION: Postoperative fistula flow of less than 300 ml/min identifies AVFs at high risk of early failure. These may be candidates for early intervention with balloon assisted maturation. The findings of this retrospective cohort study strongly support the need for a more robust prospectively designed trial identifying haemodynamic factors that can predict mid and long-term AVF patency. PMID- 29520969 TI - Molecular mechanisms underpinning phosphorus-use efficiency in rice. AB - Orthophosphate (H2 PO4- , Pi) is an essential macronutrient integral to energy metabolism as well as a component of membrane lipids, nucleic acids, including ribosomal RNA, and therefore essential for protein synthesis. The Pi concentration in the solution of most soils worldwide is usually far too low for maximum growth of crops, including rice. This has prompted the massive use of inefficient, polluting, and nonrenewable phosphorus (P) fertilizers in agriculture. We urgently need alternative and more sustainable approaches to decrease agriculture's dependence on Pi fertilizers. These include manipulating crops by (a) enhancing the ability of their roots to acquire limiting Pi from the soil (i.e. increased P-acquisition efficiency) and/or (b) increasing the total biomass/yield produced per molecule of Pi acquired from the soil (i.e. increased P-use efficiency). Improved P-use efficiency may be achieved by producing high yielding plants with lower P concentrations or by improving the remobilization of acquired P within the plant so as to maximize growth and biomass allocation to developing organs. Membrane lipid remodelling coupled with hydrolysis of RNA and smaller P-esters in senescing organs fuels P remobilization in rice, the world's most important cereal crop. PMID- 29520970 TI - Determinants of success and hemodynamic impact of balloon postdilatation of self expanding transcatheter aortic valves. AB - OBJECTIVES: To explore the rate, the determinants of success, and the hemodynamic impact of balloon postdilatation (BPD) of self-expanding transcatheter heart valves (SE-THVs) BACKGROUND: BPD is commonly used to optimize valve expansion and reduce paravalvular leakage (PVL) after transcatheter aortic valve implantation (TAVI) without clearly knowing its hemodynamic benefits. METHODS: Patients (n = 307) who received a SE-THV were stratified according to whether a BPD was performed or not. Patients who received BPD were stratified according to the severity of PVL remaining after BPD into two groups: Successful BPD (<=mild PVL + BPD) and Failed BPD (moderate-severe PVL + BPD). RESULTS: BPD was performed in 121 patients (39.4%) and was successful in 106 patients (87.6% of attempts). A ratio of the postdilatation balloon diameter to the annulus diameter <=0.95 was an independent predictor of BPD failure (OR: 10.72 [2.02-56.76], P = .005). Peak transvalvular pressure gradient (PG) was lower in the Successful BPD group (14[12 22] mm Hg) than in the Failed BPD group (18[16-23] mm Hg, P = .029), and did not rise in either group during follow-up (median [IQR], 364[161-739] days). CONCLUSION: BPD was performed in 39% of patients who received a SE-THV, and was successful in the majority of attempts. BPD failure was more likely in patients with a small postdilatation balloon-to-annulus diameter ratio. Effective BPD improved THV hemodynamic performance, and this was maintained in the intermediate term post-TAVI. PMID- 29520972 TI - Cervical dilatation over time is a poor predictor of severe adverse birth outcomes: a call for higher level evidence. PMID- 29520971 TI - Electrochemical deposition of conductive polymers onto magnesium microwires for neural electrode applications. AB - Metals are widely used in electrode design for recording neural activities because of their excellent electrical conductivity and mechanical strength. However, there are still serious problems related to these currently used metallic electrodes, including tissue damage due to the mechanical mismatch between metals and neural tissues, fibrosis, and electrode fouling and encapsulation that lead to the loss of signal and eventual failure. In this study, a biocompatible, biodegradable, and conductive electrode was created. Specifically, pure magnesium (Mg) microwire with a diameter of 127 um was used as the electrode substrate and the conductive polymer, that is, poly(3,4 ethylenedioxythiophene) (PEDOT), was electrochemically deposited onto Mg microwires to decrease corrosion rate and improve biocompatibility of the electrodes for potential neural electrode applications. Both chronopotentiometry and cyclic voltammetry (CV) methods and the associated parameters for electrochemical deposition of PEDOT onto Mg microwires were investigated, such as deposition current, deposition temperature, voltage, sweep rate, cycle number, and duration. The CV method from -2.0 to 1.25 V for 1 cycle at a cycle duration of 600 s with a sweep rate of 5 mV/s at 65 degrees C led to a consistent, uniform, and complete PEDOT coating on Mg microwires. The surface conditions of Mg microwires also affected the quality of PEDOT coating. The corrosion rate of PEDOT-coated Mg microwire was 0.75 mm/year, much slower than the noncoated Mg microwire that showed a corrosion rate of 1.78 mm/year. The optimal Mg microwires with PEDOT coating could potentially serve as biodegradable electrodes for neural recording and stimulation applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1887-1895, 2018. PMID- 29520974 TI - Web-Like Interconnected Carbon Networks from NaCl-Assisted Pyrolysis of ZIF-8 for Highly Efficient Oxygen Reduction Catalysis. AB - The oxygen reduction reaction (ORR) is under intense research due to its significance in energy storage and conversion processes. Recent studies show that interconnected and hierarchically porous structures can further enhance ORR kinetics as well as catalyst durability, but their preparation can be quite time and/or chemical consuming. Here, a simple approach is reported to prepare such complex structures by pyrolyzing composites containing NaCl and ZIF-8. The templating effect of molten NaCl connects ZIF-8 particles into web-like carbon networks. During ORR activity measurements, it achieves a 0.964 V onset potential and a 38 mV dec-1 Tafel slope, which are comparable to those of the benchmark Pt/C (0.979 V and 40 mV dec-1 ). Due to the metal-free feature, this catalyst exhibits a 16 mV shift in half-wave potential after a 10 000-cycle durability test, which is only 60% of that of Pt/C. The catalyst is also tested in Zn-air batteries and the assemblies are able to work at above 1.2 V for 140 h, which triples the life held by those with Pt/C. This study demonstrates a facile strategy to prepare metal-free ORR catalysts with interconnectivity and hierarchical porosity, and proves their great potentials in ORR catalysis and Zn air batteries. PMID- 29520973 TI - Fluorescence tumor imaging by i.v. administered indocyanine green in a mouse model of colitis-associated colon cancer. AB - Fluorescence tumor imaging using exogenous fluorescent tumor-targeting agents has potential to improve early tumor detection. The fluorescent contrast agent indocyanine green (ICG) is used in medical diagnostics. The aim of the present study is to investigate the tumor imaging capability and the imaging mechanism of i.v. administered ICG in a mouse model of colitis-associated colon cancer. To do this, an azoxymethane/dextran sodium sulfate-induced colon cancer mouse model was used. Ex vivo imaging experiments were carried out 1 hour after i.v. injection of ICG. The ICG fluorescence was observed in the colon tumor tissues, with sufficient tumor to normal tissue ratio, correlating with tumor malignancy. In the tumor tissues, ICG fluorescence was localized in the vascular interstitial tissue. Immunofluorescence microscopy revealed that tumor cells formed tight junctions normally, suggesting an inability of tumor cellular uptake of ICG. In contrast, tumor tissues increased the CD31-immunoreactive endothelial cell area, and accumulated stromal cells immunoreactive for COX-2 and tumor cell population immunoreactive for inducible nitric oxide synthase. In vivo vascular permeability assay revealed that prostaglandin E2 promoted the endothelial cell permeability of ICG. In conclusion, our data indicated that fluorescence contrast-enhanced imaging following i.v. administered ICG can be applied to the detection of colon tumors in a mouse colitis-associated colon cancer model. The tumor tissue preference of ICG in the present model can be attributed to the enhanced vascular leakage of ICG involving inflammatory mediators, such as COX-2 and inducible nitric oxide synthase, in conjunction with increased tumor vascularity. PMID- 29520975 TI - Enteric motor dysfunctions in experimental chronic pancreatitis: Alterations of myenteric neurons regulating colonic motility in rats. AB - BACKGROUND: The mechanism underlying gastrointestinal (GI) dysmotility associated with chronic pancreatitis (CP) has not been fully elucidated, and enteric nervous system (ENS) has an important regulatory role in gastrointestinal motor function. The aim of this study is to investigate the effect of ENS in the colonic hypomotility induced by trinitrobenzene sulfonic acid (TNBS) infusion which mimics CP. METHODS: Male Sprague-Dawley rats were submitted to CP which was induced by pancreatic infusion of 2% TNBS, or sham group with treatment of equal saline. Three weeks after induction of CP, we pathologically examined the inflammation of pancreas and counted the number of withdrawal events stimulated by Von Frey filaments to evaluate hyperalgesia. The gastrointestinal transit rate was measured using Carbon inkl driving test, and the contraction activities of colonic muscle strip were studied in an organ bath system. The expression of choline acetyltransferase (ChAT) and nitric oxide synthase (NOS) in colonic myenteric plexus (MP) of ENS were investigated by Western blotting and double immunofluorescence staining. KEY RESULTS: In TNBS-treated group, rats had the signs of chronic pancreatitis 3 weeks after intraductal infusion and had increased sensitivity to mechanical stimulation of the abdomen. For rats with CP, the gastrointestinal transit rate was reduced; in addition, the contractile activities of longitudinal muscle (LM) and circular muscle (CM) strips of distal colon in TNBS group were lower than those in sham group. Immunofluorescence demonstrated that the percentage of ChAT-immunoreactive (IR) neurons in the MP was decreased, but the proportion of NOS-IR neurons in the MP was increased when compared with sham-operated group. Western blotting proved that TNBS infusion down-regulated ChAT but up-regulated NOS expression in the colon MP. CONCLUSIONS & INFERENCES: Decreased ChAT-IR neurons and increased NOS-IR in the MP of colon ENS may contribute to the pathogenesis of colonic dysmotility in CP. PMID- 29520976 TI - Comparative study among Spanish students of health sciences degrees: Facing death. AB - The purpose of this study was to explore the perceptions and attitudes of students of health sciences faculties (medicine, nursing, and physiotherapy) regarding specific issues related to death and end of life in both professional and personal realms. A descriptive, cross-sectional, and multi-center approach was used. The modified Bugen Scale for facing death was used. The study population (411 students) encompassed three distinct groups: students from the degrees of medicine, nursing, and physiotherapy. In total, 12 items showed significant differences between the three groups. The sample presented a moderate level of perceived competency in the ability to face death. We found significant differences in the scores obtained by the three groups regarding their ability to face the death of people who are emotionally close. Furthermore, the sample demonstrated a good level of self-efficacy when facing death, with nursing students displaying the greatest emotional involvement when compared to their colleagues studying medicine and physiotherapy. It is therefore recommended that study curricula of future health professionals contain specific training in end of-life care. PMID- 29520977 TI - The role of primary lymph node sites in survival and mortality prediction in Hodgkin lymphoma: a SEER population-based retrospective study. AB - As diagnostic and therapeutic modalities for Hodgkin's Lymphoma (HL) continue to improve, patient-related factors affecting survival become more difficult to identify. Very little is known about the relationship between the primary site of lymph node (LN) involvement and survival of HL patients. We retrospectively analyzed the United States Surveillance, Epidemiology and End Results (SEER) database for 12,658 HL patients reported between 1973 and 2010 using survival analysis and time-interval multiple logistic regression (MLR) to disclose that relationship. The effect of all primary LN sites on the survival of HL patients was supported. The intra-abdominal (IAB) primary LN site was significantly associated with the worst survival. The pelvic (P) LN sites were significantly and independently associated with nearly 2 times and 2.5 times the probability of having 1-year overall mortality (OM) and 1-year cancer-specific mortality (CSM), respectively. Head, face and neck (HFN) primary LN sites were significant and independent predictors of better overall and HL-specific survival. A worse survival with the intra-abdominal primary LN site was probably related to their association with higher age, or advanced stages of HL. The biological basis behind the aggressiveness of intra-abdominal and pelvic LN sites is yet to be investigated. PMID- 29520979 TI - A novel treatment for height growth in patients with growth hormone insensitivity syndrome by cyproheptadine hydrochloride. AB - BACKGROUND: Cyproheptadine HCl (CyproH) is an appetite-stimulating drug and while it was prescribed for a patient with growth hormone insensitivity syndrome (GHIS) for increasing appetite, his height growth was surprisingly increased. Therefore, the aim of this study was to investigate the effect of CyproH on growth parameters of the patients with GHIS. PATIENTS AND DESIGN: Twenty patients were enrolled in two prospective cohorts at two different times. Fifteen cases were observed for 1.17 +/- 1.3 years without treatment (observation period, OP). Then, CyproH was administered for 2.2 +/- 2.7 years (treatment period, TP), and growth parameters were compared within these two periods. Five patients who did not receive any treatment for 1-8.24 years (4 +/- 2.9) were the control group. RESULTS: Height velocity (HV) increased from 1.88 +/- 0.7 to 6.1 +/- 0.8 cm/year and HV-SDS reached from -4.5 +/- 0.74 to -0.21 +/- 1.2 in OP and TP, respectively (P < .001), whereas HV and HV-SDS were 2.2 +/- 1.1 cm/yr and -4.2 +/- 1.2, respectively, in controls (P < .001). Height SDS was -7.0 +/- 1.7 and increased to -6 +/- 2.2 after treatment (P = .002). Gain in height was 2.3 +/- 0.6 SDS in 5 patients who were treated for 5.4 +/- 2.8 years. BMI-SDS was not significantly changed within two time periods and also in cases and controls. CONCLUSION: CyproH caused height growth in the patients with GHIS, and therefore, this treatment can be considered as an alternative option to IGF-I injection. PMID- 29520978 TI - Performance of the MAGGIC heart failure risk score and its modification with the addition of discharge natriuretic peptides. AB - AIMS: Predictive models for heart failure patients are widely used in the clinical practice to stratify patients' mortality and enable clinicians to tailor and intensify their approach. However, such models have not been validated internationally. In addition, biomarkers are now frequently measured to obtain prognostic information, and the implications of this practice are not known. In this study, we aimed to validate the model performance of the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) score in a Japanese acute heart failure registry and further explore the incremental prognostic value of discharge B-type natriuretic peptide (BNP) level. METHODS AND RESULTS: In this study, we evaluated the registered data of 2215 consecutive acute HF patients (with 694 119 person-years follow-up) from a prospective multicentre registry (the West Tokyo Heart Failure) conducted in Japan from April 2006 to August 2016. The mean age was 73.0 +/- 13.0, and 61.2% were male. The MAGGIC score demonstrated modest discrimination (c-index = 0.71, 95% confidence interval 0.67 0.74) and good calibration (R2 value = 0.97); there was constant overestimation for 1 year mortality. However, when the BNP level was added to the original MAGGIC variables, the model demonstrated good discrimination (c-index = 0.74, 95% confidence interval 0.70-0.78) with adequate calibration (R2 value = 0.91). The modified MAGGIC BNP score was externally validated in a separate Japanese registry (NaDEF) and demonstrated moderate discrimination (c-index = 0.69, 95% confidence interval 0.65-0.73) and calibration (R2 value = 0.85). CONCLUSION: The original MAGGIC score performed modestly in Japanese patients, but the addition of discharge BNP level enhanced model performance. The addition of objective biomarkers may result in effective modification of preexisting internationally recognized risk models and aid in multinational comparisons of heart failure patients' outcomes. PMID- 29520980 TI - Detection of a novel HLA allele, HLA-B*50:01:09, identified by next generation sequencing. AB - HLA-B*50:01:09 differs by a synonymous nucleotide exchange in codon 17 from B*50:01:01. PMID- 29520981 TI - Metabolic effects of Tofogliflozin are efficiently enhanced with appropriate dietary carbohydrate ratio and are distinct from carbohydrate restriction. AB - Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert their antidiabetic effects by promoting urinary glucose excretion. Nutrition therapy is obviously important, but little is known about the interactions between SGLT2i agents and carbohydrate restriction. Therefore, we studied these interactions using an obese diabetic animal model. KK-Ay mice were pair-fed normal chow [NC; carbohydrate: fat: protein = 65:15:20], low carbohydrate [LC; 43:42:15] or severely carbohydrate restricted diets [SR; 12:45:43] for 12 weeks. Tofogliflozin (Tofo) was administered as the SGLT2i in the NC and LC diet groups. Blood glucose levels were significantly increased in the SR group. Tofo reduced blood glucose levels significantly in the NC group during the experiment and in the LC group at 2-6 weeks. Plasma triglycerides were markedly elevated in the SR group without Tofo, but decreased in response to Tofo administration. Hepatic triglyceride contents were not changed by the LC or the SR diet alone. However, Tofo ameliorated hepatosteatosis in NC-fed animals. Consistent with the downregulation of stearoyl CoA desaturase 1, the ratio of plasma monounsaturated to saturated fatty acids was significantly reduced in the LC with Tofo and in the SR alone groups, but was not altered in the NC with Tofo group. In summary, metabolism of glucose and lipids was improved by Tofo but not by the SR diet. Furthermore, Tofo improved these parameters more effectively in the NC than in the LC diet group. These data suggest that the effects of SGLT2i are distinct from those of carbohydrate restriction and that a nonrestricted dietary carbohydrate composition is essential for SGLT2i treatment to be effective. PMID- 29520982 TI - Using the Mus musculus hybrid zone to assess covariation and genetic architecture of limb bone lengths. AB - Two subspecies of the house mouse, Mus musculus domesticus and Mus musculus musculus, meet in a narrow contact zone across Europe. Mice in the hybrid zone are highly admixed, representing the full range of mixed ancestry from the two subspecies. Given the distinct morphologies of these subspecies, these natural hybrids can be used for genomewide association mapping at sufficiently high resolution to directly infer candidate genes. We focus here on limb bone length differences, which is of special interest for understanding the evolution of developmentally correlated traits. We used 172 first-generation descendants of wild-caught mice from the hybrid zone to measure the length of stylopod (humerus/femur), zeugopod (ulna/tibia) and autopod (metacarpal/metatarsal) elements in skeletal CT scans. We find phenotypic covariation between limb elements in the hybrids similar to patterns previously described in Mus musculus domesticus inbred strains, suggesting that the hybrid genotypes do not influence the covariation pattern in a major way. Mapping was performed using 143,592 SNPs and identified several genomic regions associated with length differences in each bone. Bone length was found to be highly polygenic. None of the candidate regions include the canonical genes known to control embryonic limb development. Instead, we are able to identify candidate genes with known roles in osteoblast differentiation and bone structure determination, as well as recently evolved genes of, as yet, unknown function. PMID- 29520983 TI - Prospective analysis of hydrogel spacer for patients with prostate cancer undergoing radiotherapy. AB - OBJECTIVE: To report on the dosimetric benefits and late toxicity outcomes after injection of hydrogel spacer (HS) between the prostate and rectum for patients treated with prostate radiotherapy (RT). PATIENTS AND METHODS: In all, 76 patients with a clinical stage of T1-T3a prostate cancer underwent general anaesthesia for fiducial marker insertion plus injection of the HS into the perirectal space before intensity-modulated RT (IMRT) or volumetric-modulated arc RT (VMAT). HS safety, dosimetric benefits, and the immediate- to long-term effects of gastrointestinal (GI) toxicity were assessed. RESULTS: There were no postoperative complications reported. The mean (range) prostate size was 66.0 (25.0-187.0) mm. Rectal dose volume parameters were observed and the volume of rectum receiving 70 Gy (rV70 ), 75 Gy (rV75 ) and 78 Gy (rV78 ) was 7.8%, 3.6% and 0.4%, respectively. In all, 21% of patients (16/76) developed acute Grade 1 GI toxicities, but all were resolved completely by 3 months after treatment; whilst, 3% of patients (2/76) developed late Grade 1 GI toxicities. No patients had acute or late Grade >=2 GI toxicities. CONCLUSION: Injection of HS resulted in a reduction of irradiated rectal dose volumes along with minimal GI toxicities, irrespective of prostate size. PMID- 29520984 TI - Genetic factors contributing to hypertension in African-based populations: A systematic review and meta-analysis. AB - In a systematic review, the authors explored genetic association studies of essential hypertension in African populations. Studies reporting on the association of polymorphism(s) with hypertension in African populations were included. Appropriate studies were pooled using random effects model meta analysis, under six potential inheritance models. In all, 46 polymorphisms in 33 genes were investigated for their association with hypertension or blood pressure levels. Meta-analysis was possible for three single nucleotide polymorphisms: rs4340, rs699, and rs5186. An association was found between rs5186, rs699, and hypertension under allele contrast and homozygous codominant models (odds ratio, 1.63 [95% confidence interval, 1.04-2.54] and 4.01 [95% confidence interval, 1.17 13.80] for rs5186, respectively; and 1.80 [95% confidence interval, 1.13-2.87] for rs699). Findings were mostly robust in sensitivity analyses. According to the systematic review, there is currently insufficient evidence on the specific polymorphisms that pose the risk of hypertension in African populations. Large scale genetic studies are warranted to better understand susceptibility polymorphisms that may be specific to African populations. PMID- 29520985 TI - Seroprevalence of Mycobacterium bovis infection in warthogs (Phacochoerus africanus) in bovine tuberculosis-endemic regions of South Africa. AB - Bovine tuberculosis (bTB), caused by Mycobacterium bovis (M. bovis), has been reported in many species including suids. Wild boar are important maintenance hosts of the infection with other suids, that is domestic and feral pigs, being important spillover hosts in the Eurasian ecosystem and in South Africa, warthogs (Phacochoerus africanus) may play a similar role in M. bovis-endemic areas. However, novel diagnostic tests for warthogs are required to investigate the epidemiology of bTB in this species. Recent studies have demonstrated that serological assays are capable of discriminating between M. bovis-infected and uninfected warthogs (Roos et al., ). In this study, an indirect ELISA utilizing M. bovis purified protein derivative (PPD) as a test antigen was used to measure the prevalence and investigate risk factors associated with infection in warthogs from uMhkuze Nature Reserve and the southern region of the Greater Kruger National Park (GKNP). There was a high overall seroprevalence of 38%, with adult warthogs having a higher risk of infection (46%). Seroprevalence also varied by geographic location with warthogs from Marloth Park in the GKNP having the greatest percentage of positive animals (63%). This study indicates that warthogs in M. bovis-endemic areas are at high risk of becoming infected with mycobacteria. Warthogs might present an under-recognized disease threat in multi species systems. They might also serve as convenient sentinels for M. bovis in endemic areas. These findings highlight the importance of epidemiological studies in wildlife to understand the role each species plays in disease ecology. PMID- 29520986 TI - Assessment of Electrolytes and Metals Profile of the Faro Lake (Capo Peloro Lagoon, Sicily, Italy) and Its Impact on Mytilus galloprovincialis. AB - Faro Lake is a coastal meromictic lagoon with singular characteristics in the Mediterranean (Messina, Sicily - Italy). It is part of the Natural Oriented Reserve of Capo Peloro (38 degrees 15' 57" N; 15 degrees 37' 50" E). In this area, traditional mollusc farming activity persists, producing 'autochthonous' mussels. This study reports of the Mytilus galloprovincialis haemolymph chemical profile and water variables determination of 1 year-lasted survey (April 2016 - March 2017). The determinations of electrolytes (Na+ , Cl- , K+ , Ca2+ , Mg2+ , P inorganic) and heavy metals in both Faro lake water and haemolymph have been carried out. Heavy metals are elements with high density and are quite toxic in low concentrations, such as Aluminum (Al), Arsenic (As), Cobalt (Co), Chrome (Cr), Copper (Cu), Iron (Fe), Magnesium (Mg), Manganese (Mn), Lead (Pb), Tin (Sn), Zinc (Zn). Heavy metals toxicity depends, principally, on bioaccumulation processes. M. galloprovincialis is a good bio-indicator, ideal for assess levels of environmental pollution thanks to its biological, ecological and physiological characteristics. The results of this study showed a typical fluctuation range in haemolymph and water parameters, related to the water ones; chemical-physical parameters affected the ions (electrolytes and metals) levels in some period of the year. The study reports the interactions between biotic (Mytilus galloprovincialis) and abiotic (water parameters) components of Faro Lake, and creates reference data for further future study on the same area or on similar ones. PMID- 29520987 TI - Effect of mesalazine on recurrence of diverticulitis in patients with symptomatic uncomplicated diverticular disease: a meta-analysis with trial sequential analysis of randomized controlled trials. AB - AIM: he aim was to investigate the effect of mesalazine on the recurrence of diverticulitis in patients with symptomatic uncomplicated diverticular disease (SUDD). METHODS: We performed a systematic review and conducted a search of electronic information sources to identify all randomized controlled trials (RCTs) investigating the effect of mesalazine on the recurrence of diverticulitis in patients with SUDD. We used the Cochrane tool to assess the quality of included studies. Random effects models were applied to calculate pooled outcome data. Trial sequential analysis was performed to assess the possibility of type I or II errors and to compute the information size required for conclusive meta analysis. RESULTS: We identified six RCTs which enrolled a total of 1918 patients. There was no difference in the recurrence of diverticulitis between the mesalazine and placebo groups (OR 1.20, 95% CI 0.96-1.50, P = 0.11). A low level of heterogeneity among the studies existed (I2 = 9%, P = 0.36). When the mesalazine dose was <= 2 g/day, there was no difference in recurrence rate between the two groups (OR 1.10, 95% CI 0.79-1.54, P = 0.58). When the mesalazine dose was > 2 g/day, the risk of recurrence was higher in the mesalazine group (OR 1.28, 95% CI 1.02-1.62, P = 0.04). The information size was calculated as 2461 patients. Trial sequential analysis showed that the meta-analysis was conclusive and the risk of type II error was minimal. CONCLUSIONS: Mesalazine does not prevent the recurrence of diverticulitis in patients with SUDD. Further studies are required to investigate the role of mesalazine as an adjunct to other medical agents in the prevention of diverticulitis in patients with SUDD. PMID- 29520988 TI - A natural recombinant PRRSV between HP-PRRSV JXA1-like and NADC30-like strains. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically significant pathogen that has adversely affected China's swine industry. Currently, a novel type 2 PRRSV, called the NADC30-like strain, is epidemic in numerous provinces of China, and commercial vaccines provide limited protection for infected animals. The extensive recombination phenomenon among NADC30-like PRRSVs is identified as a unique molecular characteristic of the virus. However, our understanding of how recombination influences NADC30-like PRRSVs is largely inadequate. In this study, we analysed the genetic characteristics of a recombinant NADC30-like PRRSV (SC-d) and examined its pathogenicity compared with a non-recombinant NADC30-like PRRSV (SD-A19) and a highly pathogenic PRRSV (HuN4). SC-d has three discontinuous deletions in nsp2, consistent with NADC30 isolated from the United States in 2008. Furthermore, we identified four recombination breakpoints in the SC-d genome, which separated the SC-d genome into four regions (regions A, B, C and D). Regions A and C are closely related to the JXA1-like strain, one of the earliest Chinese HP-PRRSV strains, and regions B and D are closely related to the NADC30 strain. Moreover, SC-d inoculated piglets exhibited a persistent fever, moderate weight loss, mild thymus atrophy and obvious microscopic lung lesions. In summary, the recombinant NADC30-like PRRSV SC-d strain displayed a higher pathogenicity than the non recombinant NADC30-like PRRSV SD-A19 strain; however, the pathogenicity of the NADC30-like PRRSV SC-d was lower compared with the HP-PRRSV HuN4 strain in piglets. Our findings demonstrate that recombination is responsible for the enormous genetic diversity and pathogenicity variance of the NADC30-like PRRSV in China. This study provides a theoretical basis for developing a more reasonable PRRSV control and prevention strategy. PMID- 29520989 TI - Nano Trek Beyond: Driving Nanocars/Molecular Machines at Interfaces. AB - In 2016, the Nobel Prize in Chemistry was awarded for pioneering work on molecular machines. Half a year later, in Toulouse, the first molecular car race, a "nanocar race", was held by using the tip of a scanning tunneling microscope as an electrical remote control. In this Focus Review, we discuss the current state of-the-art in research on molecular machines at interfaces. In the first section, we briefly explain the science behind the nanocar race, followed by a selection of recent examples of controlling molecules on surfaces. Finally, motion synchronization and the functions of molecular machines at liquid interfaces are discussed. This new concept of molecular tuning at interfaces is also introduced as a method for the continuous modification and optimization of molecular structure for target functions. PMID- 29520990 TI - Preoperative echocardiographic measures in interrupted aortic arch: Which ones best predict surgical approach and outcome? AB - OBJECTIVE: It is unclear whether neonates with interrupted aortic arch (IAA) and a smaller left ventricular outflow tract may have improved outcomes with a Yasui operation (ventricular outflow bypass procedure) over a primary complete repair. This study sought to identify preoperative echocardiographic parameters to differentiate which neonates may have improved outcomes with a primary vs Yasui operation. DESIGN: Patient demographics, cardiac surgery type, complications, need for reoperation and/or interventional catheterization, and date of last follow-up were collected on neonates who underwent a biventricular repair for IAA from 2003 to 2014. Preoperative echocardiograms were analyzed for: IAA type, valve annulus size, aortic valve morphology, ventricular size and aortic arch anatomy. RESULTS: Seventy-seven neonates underwent IAA repair between 2003 and 2013. 60 neonates had a primary repair and 17 a Yasui operation. Neonates that underwent a Yasui operation had significantly smaller mitral and aortic valves with aortic arch hypoplasia. Within the primary repair group, a decreasing aortic root z-score on univariate analysis increased the odds of reoperation by twofold [OR = 1.98, 95% CI: (1.15-3.42), P = .014]. A significant interaction between repair type and aortic root z-score was identified on multivariable analysis (P = .039), for neonates with aortic root z-scores less than -2.5, the probability of reoperation during the follow up time period [mean 4.5 years (3.3 months-10 year)] was significantly higher in the primary repair group compared to the Yasui group (64.3% vs 37.5%). CONCLUSIONS: Neonates with IAA and an aortic root z-score less than -2.5 have lower odds of subsequent reoperations with a Yasui operation compared to a primary repair over the follow up period. These findings suggest a Yasui operation should be considered if the preoperative aortic root z-score is less than -2.5. Careful evaluation of these morphologic predictors on preoperative echocardiograms can be helpful in surgical planning in neonates with IAA. PMID- 29520991 TI - Magnesium-Based Micromotors: Water-Powered Propulsion, Multifunctionality, and Biomedical and Environmental Applications. AB - The new capabilities and functionalities of synthetic micro/nanomotors open up considerable opportunities for diverse environmental and biomedical applications. Water-powered micromachines are particularly attractive for realizing many of these applications. Magnesium-based motors directly use water as fuel to generate hydrogen bubbles for their propulsion, eliminating the requirement of common toxic fuels. This Review highlights the development of new Mg-based micromotors and discusses the chemistry that makes it extremely attractive for micromotor applications. Understanding these Mg properties and its transient nature is essential for controlling the propulsion efficiency, lifetime, and overall performance. The unique and attractive behavior of Mg offers significant advantages, including efficient water-powered movement, remarkable biocompatibility, controlled degradation, convenient functionalization, and built in acid neutralization ability, and has paved the way for multifunctional micromachines for diverse real-life applications, including operation in living animals. A wide range of such Mg motor-based applications, including the detection and destruction of environmental threats, effective in-vivo cargo delivery, and autonomous release, have been demonstrated. In conclusion, the current challenges, future opportunities, and performance improvements of the Mg based micromotors are discussed. With continuous innovation and attention to key challenges, it is expected that Mg-based motors will have a profound impact on diverse biomedical and environmental applications. PMID- 29520992 TI - A comparative study on different Descemet membrane endothelial keratoplasty graft preparation techniques. AB - PURPOSE: To compare different Descemet membrane endothelial keratoplasty (DMEK) graft preparation methods. METHODS: Stripping from the trabecular meshwork (M1) using epithelial spatula; stripping by scoring the peripheral endothelium (M2) using Sinskey hook; stripping by punch method (M3) using donor trephine; Submerged hydro-separation (M4); and pneumatic dissection method (M5) were evaluated. Preparation time, costs, endothelial cell loss (ECL) postpreparation, cell death and morphology were compared. Hoechst/Ethidium/Calcien AM (HEC) staining and Zonula Occludens-1 (ZO-1) expression were analysed. Statistical analysis was performed using one-way anova and; Tukey as post hoc test. RESULTS: A total of 35 corneas (seven per group) were used. Endothelial cell loss (ECL) represented as Mean (SD), in M1, M2, M3, M4 and M5 was 2.7 (5.0), 3.0 (7.4), 1.2 (7.4), 3.3 (7.3) and 4.1 (7.1)%, respectively not showing any difference between the groups (p = 0.96). A significantly higher cell death (p < 0.05) was observed in M4 and M5 compared with M1, M2 and M3. Graft preparation time was significantly shorter in M4 and M5 and longest in M3 (p < 0.05). M3 was the most expensive preparation technique. Minimum pleomorphic cells were observed in M1, M2 and M3, whereas moderate pleomorphism was seen in M4 and M5. Hoechst, Ethidium homodimer and Calcein AM (HEC) staining showed high Ethidium positivity (dead cells) in M4 and M5 with minimum positivity in M1, M2 and M3. Zonula Occludens-1 (ZO-1) was expressed in all the conditions except the denuded areas. CONCLUSION: Graft preparation using Sinskey hook (M2) and donor punch (M3) are reliable methods in terms of efficiency and quality with acceptable range of ECL. The preparation time and associated costs could be a limitation for M3. PMID- 29520993 TI - Ultraviolet-visible phototransformation of dehydroacetic acid - Structural characterization of photoproducts and global ecotoxicity. AB - RATIONALE: The present work is devoted to the structural elucidation of by products issued from the direct ultraviolet-visible (UV-vis) irradiation of dehydroacetic acid (DHA) in solution and in cosmetic emulsion. METHODS: Analyses were carried out using gas chromatography coupled with ion trap mass spectrometry and by high-performance liquid chromatography coupled with ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (LC/UHRMS). The potential toxicities of by-products were estimated by in silico calculations based on a QSAR (Quantitative Structure-Activity Relationship) approach and by in vitro bioassays conducted on Vibrio fischeri bacteria. RESULTS: Three photoproducts were detected by LC/MS while one photoproduct was detected by GC/MS. The first photoproduct (PP1) corresponds to an isomer of DHA while two isomeric compounds correspond to dimeric structures. The oral rat LD50 of PP1 was evaluated to be 4.5 times lower than that of the parent molecule which classes it in the category 'moderately toxic' on the Hodge and Sterne toxicity classification. In vitro assays on Vibrio fischeri bacteria showed that the global ecotoxicity of the DHA solution increases with irradiation time. CONCLUSIONS: With the exception of one photoproduct, the structures proposed for the photoproducts on the basis of mass spectral interpretation have not been reported in previous studies. All photoproducts, with the exception of dimers, were detected after irradiation in the cosmetic emulsion. This result shows that personal care products containing DHA must be protected from direct sunlight to prevent photodegradation. PMID- 29520995 TI - Genetics of hypertension: Implications of single nucleotide polymorphism(s) in African populations and beyond. PMID- 29520994 TI - Self-Formed Channel Devices Based on Vertically Grown 2D Materials with Large Surface-Area and Their Potential for Chemical Sensor Applications. AB - 2D layered materials with sensitive surfaces are promising materials for use in chemical sensing devices, owing to their extremely large surface-to-volume ratios. However, most chemical sensors based on 2D materials are used in the form of laterally defined active channels, in which the active area is limited to the actual device dimensions. Therefore, a novel approach for fabricating self-formed active-channel devices is proposed based on 2D semiconductor materials with very large surface areas, and their potential gas sensing ability is examined. First, the vertical growth phenomenon of SnS2 nanocrystals is investigated with large surface area via metal-assisted growth using prepatterned metal electrodes, and then self-formed active-channel devices are suggested without additional pattering through the selective synthesis of SnS2 nanosheets on prepatterned metal electrodes. The self-formed active-channel device exhibits extremely high response values (>2000% at 10 ppm) for NO2 along with excellent NO2 selectivity. Moreover, the NO2 gas response of the gas sensing device with vertically self formed SnS2 nanosheets is more than two orders of magnitude higher than that of a similar exfoliated SnS2 -based device. These results indicate that the facile device fabrication method would be applicable to various systems in which surface area plays an important role. PMID- 29520996 TI - A Hybrid Mineral Battery: Energy Storage and Dissolution Behavior of CuFeS2 in a Fixed Bed Flow Cell. AB - The development of a hybrid system capable of storing energy and the additional benefit of Cu extraction is discussed in this work. A fixed bed flow cell (FBFC) was used in which a composite negative electrode containing CuFeS2 (80 wt %) and carbon black (20 wt %) in graphite felt was separated from a positive (graphite felt) electrode by a proton-exchange membrane. The anolyte (0.2 m H2 SO4 ) and catholyte (0.5 m Fe2+ in 0.2 m H2 SO4 with or without 0.1 m Cu2+ ) were circulated in the cell. The electrochemical activity of the Fe2+ /Fe3+ redox couple over graphite felt significantly improved after the addition of Cu2+ in the catholyte. Ultimately, in the CuFeS2 ?Fe2+ /Cu2+ (CFeCu) FBFC system, the specific capacity increased continuously to 26.4 mAh g-1 in 500 galvanostatic charge-discharge (GCD) cycles, compared to the CuFeS2 ?Fe2+ (CFe) system (13.9 mAh g-1 ). Interestingly, the specific discharge energy gradually increased to 3.6 Wh kg-1 in 500 GCD cycles for the CFeCu system compared to 3.29 Wh kg-1 for the CFe system in 150 cycles. In addition to energy storage, 10.75 % Cu was also extracted from the mineral, which is an important feature of the CFeCu system as it would allow Cu extraction and recovery through hydrometallurgical methods. PMID- 29520997 TI - The presence of duck Tembusu virus in Thailand since 2007: A retrospective study. AB - Duck Tembusu virus (DTMUV), a newly emerging virus in ducks, was first reported in China in 2010. However, an unknown severe contagious disease associated with severe neurological signs and egg production losses in ducks, resembling to DTMUV infection, was observed in Thailand since 2007. To determine the presence of DTMUV in 2007, the clinical samples from affected ducks collected in 2007 were tested for DTMUV using pathological and virological analyses. Gross and histopathological lesions of affected ducks were mostly restricted to the ovary, brain and spinal cord, and correlated with the presence of flavivirus antigen in the brain and spinal cord samples. Subsequently, DTMUV was identified by RT-PCR and nucleotide sequencing of the polyprotein gene. Phylogenetic analysis of the polyprotein gene sequence revealed that the 2007 Thai DTMUV was a unique virus, belonged within DTMUV cluster 1, but distinctively separated from the Malaysian DTMUV, which was the most closely related DTMUV. It is interesting to note that the 2007 Thai DTMUV was genetically different from the currently circulating Thai and Chinese DTMUVs, which belonged to cluster 2. Our findings indicated that the 2007 Thai DTMUV emerged earlier from a common ancestor with the recently reported DTMUVs; however, it was genetically distinctive to any of the currently circulating DTMUVs. In conclusion, our data demonstrated the presence of DTMUV in the Thai ducks since 2007, prior to the first report of DTMUV in China in 2010. This study indicates that DTMUV may have circulated in the region long before 2010 and highlights high genetic diversity of DTMUVs in Asia. PMID- 29520998 TI - Does respiratory variation of inferior vena cava diameter predict fluid responsiveness in spontaneously ventilating children with sepsis. AB - OBJECTIVE: The intent of fluid bolus therapy (FBT) is to increase cardiac output and tissue perfusion, yet only 50% of septic children are fluid responsive. We evaluated respiratory variation of inferior vena cava (IVC) diameter as a predictor of fluid responsiveness. METHODS: A prospective observational study in the ED of The Royal Children's Hospital, Melbourne, Australia. Patients were spontaneously ventilating children treated with FBT for sepsis-induced acute circulatory failure. IVC ultrasound was performed prior to FBT. Trans-thoracic echocardiography was performed prior to, 5 and 60 min after FBT. IVC collapsibility index and stroke distance were calculated by a blinded Paediatric Emergency Physician and blinded Paediatric Cardiologist, respectively. RESULTS: Thirty-nine fluid boluses were recorded in 33 children, 28/39 (72%) of which met criteria for fluid responsiveness at 5 min, which was sustained in 2/28 (7%) of initial fluid responders at 60 min. Sensitivity and specificity (95% confidence interval) of IVC collapsibility index were 0.44 (0.25-0.65) and 0.33 (0.10-0.65) with an area under the receiver operator characteristics curve (95% confidence interval) of 0.38 (0.23-0.55) at 5 min. Test characteristics 60 min after fluid bolus administration were not meaningful because of the infrequency of sustained fluid responsiveness in this patient group. There was no significant correlation between IVC collapsibility and fluid responsiveness at 5 or 60 min. CONCLUSIONS: IVC collapsibility has poor test characteristics for predicting fluid responsiveness in spontaneously ventilating children with sepsis. PMID- 29520999 TI - Silica coating followed by heat-treatment of MDP-primer for resin bond stability to yttria-stabilized zirconia polycrystals. AB - This study evaluated the influence of silica coating, primer type and its heat treatment on bond strength durability between resin cement and an yttrium stabilized polycrystalline tetragonal zirconia (Y-TZP). Eighty (80) Y-TZP blocks were allocated into 16 groups considering four factors: silica coating (without and with); type of primer (RelyX Ceramic Primer, a silane-based primer; Single Bond Universal, a universal MDP-based primer); heat treatment of the primer (without and with); aging (without and with). After zirconia treatments, resin cement cylinders (RelyX ARC) (n = 20; N = 320) were built. Half of the samples were tested after 24 h, and another half were subjected to aging (thermocycling 5 55 degrees C/5.000, and storage in water for 6 months). Shear bond strength test and failure analysis were performed. Bond strength data were submitted to four way ANOVA and Tukey test (p = 0.05). All factors were statistically significant (p < 0.001) for bond strength (MPa): silica coating (7.3 +/- 5.9) > no-treatment (3.6 +/- 4.3); universal primer (6.7 +/- 4.8) > silane (4.2 +/- 5.8); heat treatment (6.5 +/- 6.3) > no-heating (4.4 +/- 4.3); no-aging (8.2 +/- 5) > aging (2.7 +/- 4.4). Tukey test revealed that the association of silica coating + universal primer + heat-treatment promoted higher and stable resin bond strength. Silica coating, universal adhesive application and heat treatment improve/increase durability and bond strength of zirconia. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29521000 TI - Detection of an HLA-B*15 variant, HLA-B*15:192, in a Taiwanese individual. AB - One nucleotide replacement at codon 145 of HLA-B*15:01:01:01 results in a new allele, HLA-B*15:192. PMID- 29521001 TI - Manipulating multifaceted microbubble shell composition to target both TRAIL sensitive and resistant cells. AB - This study represents the first attempt to combine surface TRAIL expression and doxorubicin co-encapsulation in a single drug delivery agent in the form of ultrasound-responsive microbubbles that shatter into fragments, or nanoshards, in an ultrasound beam. We compare customized microbubbles of different polymeric shell compositions, and investigate the effect of both shell composition and incorporation of doxorubicin on action against TRAIL-sensitive MDA-MB-231 and TRAIL-resistant MCF7 human breast adenocarcinoma cells. Ligation of TRAIL only significantly impacted MDA-MB-231 cells predominantly by apoptosis, and had minimal effect on MCF12A (normal control) cells. For all shell types, nanoshards had a greater effect (apoptotic death ranging from approximately 25% for 1 wt % LipidPEG to 50% for 100% PLA), reflecting the greater surface area and larger number of particles that ultrasound generates. Encapsulation of doxorubicin generated necrosis in all cell lines, but PEGylation produced less effective necrosis in all cell lines. Co-encapsulation of doxorubicin within the contrast agent shell increased MDA-MB-231 cell death to approximately 40-80%, representing a marked increase over TRAIL alone, reflecting the dramatic effect of shell composition. Additionally, shells that co-encapsulated TRAIL and doxorubicin resulted in approximately 30-60% death in TRAIL-resistant MCF7 human breast adenocarcinoma cells, compared with little apoptotic response in these cells from shells encapsulating TRAIL alone, demonstrating the sensitization effect of the drug. This work has resulted in production of a library of effective ultrasound triggered, minimally immunogenic, targeted drug delivery agents for potential use in cancer therapy, and represents a promising multifaceted treatment to better serve the population with solid tumors. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1903-1915, 2018. PMID- 29521003 TI - Daily sodium intake influences the relationship between angiotensin-converting enzyme gene insertion/deletion polymorphism and hypertension in older adults. AB - The angiotensin-converting enzyme insertion/deletion (I/D) gene polymorphism has been widely reported as being associated with hypertension; however, most studies do not consider environmental/behavioral factors. This study aimed to investigate the relationship among angiotensin-converting enzyme insertion/deletion gene polymorphism, environmental/behavioral factors, and hypertension in community dwelling elderly individuals. All community-dwelling older adults from Aiquara, Bahia, Brazil, were invited to take part in this study. After exclusions, 234 elderly participants were submitted to a data collection, which included sociodemographics, lifestyle and health status questionnaires, clinical assessment, and blood withdrawal. From the blood samples, the gene polymorphism was identified through polymerase chain reaction and patients grouped as II or D allele carriers (ID and DD genotypes). Hypertension was defined by self-report of the condition and confirmed by antihypertensive drug treatment. Chi-square test was used to identify differences in the proportions distributed between groups of each dependent variable (ie, genotype, diagnosis of hypertension, and blood pressure state from medicated patients with hypertension). The prevalence of hypertension was 59.3% and was associated with diabetes mellitus and obesity, but not with angiotensin-converting enzyme insertion/deletion gene polymorphism. However, carriers of the II genotype, a salt-sensitivity genotype, exhibited a significantly greater estimated sodium intake. In addition, among medicated elderly patients with hypertension, II genotype carriers exhibited poor blood pressure control, despite similar antihypertensive drug treatment in D allele carriers, while exhibiting a greater estimated sodium intake. Our results provide new evidence regarding the interaction of genetic and environmental/behavioral factors in the genesis of hypertension among elderly patients, as well as in blood pressure control in medicated elderly patients with hypertension. PMID- 29521002 TI - In vivo metabolic imaging and monitoring of brown and beige fat. AB - Activation of the thermogenic brown and beige fat is an effective means to increasing whole-body energy expenditure. In this work, a unique label-free method was developed to quantitatively assess the metabolism and thermogenesis of mouse adipose tissues in vivo. Specifically, an optical redox ratio (ORR) based on the endogenous fluorescence of mitochondrial metabolic coenzymes (nicotinamide adenine dinucleotide and flavin adenine dinucleotide) was used to measure the metabolic state of adipocytes. Our findings demonstrate that the ORR provides a label-free and real-time biomarker to determine the thermogenic response of brown, beige and white adipose tissues to a variety of physiological stimulations. In addition, the redox ratio also can be used to evaluate the degree of browning in the white fat of cold-acclimated mice. This technique is important to understand the recruitment and activation of thermogenic adipocytes in mammals and thus can help to develop therapeutic strategies against obesity. PMID- 29521005 TI - PGC1beta Organizes the Osteoclast Cytoskeleton by Mitochondrial Biogenesis and Activation. AB - Osteoclasts are mitochondria-rich cells, but the role of these energy-producing organelles in bone resorption is poorly defined. To this end, we conditionally deleted the mitochondria-inducing co-activator, PGC1beta, in myeloid lineage cells to generate PGC1betaLysM mice. In contrast to previous reports, PGC1beta deficient macrophages differentiate normally into osteoclasts albeit with impaired resorptive function due to cytoskeletal disorganization. Consequently, bone mass of PGC1betaLysM mice is double that of wild type. Mitochondrial biogenesis and function are diminished in PGC1betaLysM osteoclasts. All abnormalities are normalized by PGC1beta transduction. Furthermore, OXPHOS inhibitors reproduce the phenotype of PGC1beta deletion. PGC1beta's organization of the osteoclast cytoskeleton is mediated by expression of GIT1, which also promotes mitochondrial biogenesis. Thus, osteoclast mitochondria regulate the cell's resorptive activity by promoting cytoskeletal organization. (c) 2018 American Society for Bone and Mineral Research. PMID- 29521004 TI - Delayed puberty and abnormal anthropometry and its associations with quality of life in young Fontan survivors: A multicenter cross-sectional study. AB - INTRODUCTION: We sought to evaluate the prevalence of delayed puberty and abnormal anthropometry and its association with quality of life (QoL) in young Fontan survivors. METHODS: This was a cross-sectional study at 11 Pediatric Heart Network centers. Demographic and clinical data, anthropomety, and Tanner stage were collected. Anthropometric measurements and pubertal stage were compared to US norms. QoL was assessed using Pediatric Quality of Life inventory (PedsQL). Mixed effects regression modeling adjusting for clustering by center was used to evaluate factors associated with abnormal anthropometry and delayed puberty and associations with QoL. RESULTS: Of the 299 subjects, 42% were female. The median enrollment age was 13.9 years, and the median age at Fontan was 3 years. Fontan survivors had a higher prevalence of short stature relative to normative data (20% vs 5%, P < .0001) and an increased prevalence of abnormal BMI (16% vs 10%, P < .0001) (low [43%] and high [57%]). Fontan subjects, both males (58%) and females (58%), had a delay of 1.5-2 years in >=1 Tanner stage parameter compared to normal population. There was no association between delayed puberty and QoL. Abnormal anthropometry was associated with lower overall (62.3 +/- 17.3 vs 72.5 +/- 16.6; P < .001) and physical appearance scores (72.2 +/- 27.4 vs 79.8 +/- 21.5; P < .01). Lower exercise capacity was associated with abnormal anthropometry and >2 surgeries before Fontan was associated with delayed puberty. Lower family income (<$25 000) and hypoplastic left heart syndrome were associated with lower QoL. CONCLUSION: Compared to the normal population, Fontan survivors have high prevalence of short stature, abnormal BMI and delayed puberty. Abnormal anthropometry, but not delayed puberty, was associated with lower overall QoL and perceived physical appearance scores. Routine screening for abnormal anthropometry, especially in HLHS and in lower socioeconomic status families, should be considered to allow interventions, which might ameliorate the negative psychosocial impact. PMID- 29521006 TI - Effects of nutrient loading on sediment bacterial and pathogen communities within seagrass meadows. AB - Eutrophication can play a significant role in seagrass decline and habitat loss. Microorganisms in seagrass sediments are essential to many important ecosystem processes, including nutrient cycling and seagrass ecosystem health. However, current knowledge of the bacterial communities, both beneficial and detrimental, within seagrass meadows in response to nutrient loading is limited. We studied the response of sediment bacterial and pathogen communities to nutrient enrichment on a tropical seagrass meadow in Xincun Bay, South China Sea. The bacterial taxonomic groups across all sites were dominated by the Gammaproteobacteria and Firmicutes. Sites nearest to the nutrient source and with the highest NH4 + and PO4 3- content had approximately double the relative abundance of putative denitrifiers Vibrionales, Alteromonadales, and Pseudomonadales. Additionally, the relative abundance of potential pathogen groups, especially Vibrio spp. and Pseudoalteromonas spp., was approximately 2 fold greater at the sites with the highest nutrient loads compared to sites further from the source. These results suggest that proximity to sources of nutrient pollution increases the occurrence of potential bacterial pathogens that could affect fishes, invertebrates and humans. This study shows that nutrient enrichment does elicit shifts in bacterial community diversity and likely their function in local biogeochemical cycling and as a potential source of infectious diseases within seagrass meadows. PMID- 29521007 TI - Retrospective study of porcine circovirus 3 infection in China. AB - PCV3 is an emerging swine virus associated with porcine dermatitis and nephropathy syndrome (PDNS), reproductive failure, respiratory diseases and systematic inflammation. Although first identified in 2015, the earliest case has been traced back to 2009 in the United States. In China, PCV3 infection was first detected in 2015, but little information has been available about its occurrence and prevalence there before 2015. In this study, 200 porcine clinical samples collected from 20 provinces, five autonomous regions and four municipalities between 1990 and 1999 were analysed for PCV3 infection by PCR. Results showed that 6.5% of the porcine samples collected from eight provinces and one autonomous region were PCV3 positive, with the earliest cases occurring in 1996. Nucleotide sequence analysis showed that PCV3 strains obtained in this study shared 96.6%-99.7% and 97.1%-99.4% sequence identity at the ORF2 gene and genome levels with all available reference strains from China and other countries, indicating the high genetic stability of PCV3 over the past 20 years. PMID- 29521008 TI - Biomaterial Scaffolds as Pre-metastatic Niche Mimics Systemically Alter the Primary Tumor and Tumor Microenvironment. AB - Primary tumor (PT) immune cells and pre-metastatic niche (PMN) sites are critical to metastasis. Recently, synthetic biomaterial scaffolds used as PMN mimics are shown to capture both immune and metastatic tumor cells. Herein, studies are performed to investigate whether the scaffold-mediated redirection of immune and tumor cells would alter the primary tumor microenvironment (TME). Transcriptomic analysis of PT cells from scaffold-implanted and mock-surgery mice identifies differentially regulated pathways relevant to invasion and metastasis progression. Transcriptomic differences are hypothesized to result from scaffold mediated modulations of immune cell trafficking and phenotype in the TME. Culturing tumor cells with conditioned media generated from PT immune cells of scaffold-implanted mice decrease invasion in vitro more than two-fold relative to mock surgery controls and reduce activity of invasion-promoting transcription factors. Secretomic characterization of the conditioned media delineates interactions between immune cells in the TME and tumor cells, showing an increase in the pan-metastasis inhibitor decorin and a concomitant decrease in invasion promoting chemokine (C-C motif) ligand 2 (CCL2) in scaffold-implanted mice. Flow cytometric and transcriptomic profiling of PT immune cells identify phenotypically distinct tumor-associated macrophages (TAMs) in scaffold-implanted mice, which may contribute to an invasion-suppressive TME. Taken together, this study demonstrates biomaterial scaffolds systemically influence metastatic progression through manipulation of the TME. PMID- 29521010 TI - Medication adherence in first-episode psychosis patients in Singapore. AB - AIM: Early intervention programmes for first episode psychosis (FEP) aim to reduce the duration of untreated psychosis (DUP) and improve functional outcomes. The sustained maintenance of improved outcomes depends largely on patients' adherence to prescribed treatment. This paper examines the prevalence of non adherence in a cohort of patients with FEP and the sociodemographic and clinical factors associated with non-adherent behaviour. METHODS: The sample included consecutive patients accepted from 2007 to 2012 into the Early Psychosis Intervention Programme (EPIP) in Singapore. Sociodemographic variables as well as DUP, insight, severity of psychopathology and clinical diagnoses were collected. Patients were assessed at baseline and 1 year with the PANSS and Global Assessment of Functioning Scale (GAF). Medication adherence was grouped into 3 categories: no-adherence, partial adherence and regular adherence. RESULTS: Of the 445 patients included, 51% were male with a mean age of 26.3 years, 74.6% had schizophrenia spectrum and delusional disorders, 14% had affective psychosis and 11.3% had brief psychotic disorder or psychotic disorder not otherwise specified. At 1 year follow up, 65.5% reported regular adherence, 18.7% were partially adherent and 15.8% were non-adherent. Non-adherence was correlated with male gender, living alone and having poorer judgement and insight. Partial adherence was associated with Malay ethnicity and having undergone national service. CONCLUSION: Medication adherence is prevalent in FEP and associated with a variety of factors. This study supports the use of culturally appropriate interventions in addressing barriers to adherence. Further studies would need to be done to address specific factors affecting adherence outcomes. PMID- 29521009 TI - Obese patients with castration-resistant prostate cancer may be at a lower risk of all-cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. AB - OBJECTIVE: To assess whether obesity is associated with progression to metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM), in patients with non-metastatic castration-resistant prostate cancer (non mCRPC). At the population level, obesity is associated with prostate cancer mortality; however, some studies have found that higher body mass index (BMI) is associated with better long-term prostate cancer outcomes amongst men with mCRPC. PATIENTS AND METHODS: We identified 1 192 patients with non-mCRPC from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BMI was calculated from height and weight abstracted from the medical records at the time closest to but prior to CRPC diagnosis and categorised as underweight (<21 kg/m2 ), normal weight (21-24.9 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (>=30 kg/m2 ). Competing risks regression and Cox models were used to test associations between obesity and progression to metastasis, PCSM, and ACM, accounting for confounders. RESULTS: Overall, 51 (4%) men were underweight, 239 (25%) were normal weight, 464 (39%) were overweight, and 438 (37%) were obese. In adjusted analysis, higher BMI was significantly associated with reduced ACM (hazard ratio [HR] 0.98, P = 0.012) but not PCSM (HR 1.00, P = 0.737) or metastases (HR 0.99, P = 0.225). Likewise, when BMI was treated as a categorical variable in adjusted models, obesity was not associated with PCSM (HR 1.11, P = 0.436) or metastases (HR 1.06, P = 0.647), but was associated with decreased ACM (HR 0.79, P = 0.016) compared to normal weight. No data were available on treatments received after CRPC diagnosis. CONCLUSIONS: Amongst patients with non-mCRPC obesity was associated with better overall survival. Although this result mirrors evidence from men with mCRPC, obesity was not associated with prostate cancer outcomes. Larger studies are needed to confirm these findings. PMID- 29521011 TI - Influence of prior oral ethinylestradiol use on the efficacy of enzalutamide for the treatment of castration-resistant prostate cancer in men. AB - OBJECTIVE: To elucidate the effect of prior use of ethinylestradiol on enzalutamide treatment for men with castration-resistant prostate cancer. METHODS: We retrospectively analyzed data from 99 consecutive patients (median age 72 years, range 50-88 years) treated with enzalutamide for castration resistant prostate cancer between May 2014 and November 2015 after receiving several lines of hormonal therapy. RESULTS: A total of 45 patients were given ethinylestradiol before enzalutamide. The prostate-specific antigen response rate (decline in prostate-specific antigen >50% from baseline) of patients receiving ethinylestradiol and enzalutamide were 51.1% and 41.4%, respectively. Cross resistance between ethinylestradiol and enzalutamide was clearly observed in the setting of pre-docetaxel. In multivariate analysis, the T stage and number of therapies before enzalutamide were the only significant predictors of prostate specific antigen response to enzalutamide. However, in patients treated pre docetaxel use, prior use of ethinylestradiol was a significant predictor of prostate-specific antigen response to enzalutamide, whereas ethinylestradiol did not affect the overall survival of these patients. CONCLUSIONS: Cross-resistance between ethinylestradiol and enzalutamide in the setting of pre-docetaxel therapy seems to be evident. Therefore, ethinylestradiol should be used prudently before enzalutamide in this setting. PMID- 29521012 TI - A computational modeling of blood flow in asymmetrically bifurcating microvessels and its experimental validation. AB - Microvascular transport is complex due to its heterogeneity. Many researchers have been developing mathematical and computational models in predicting microvascular geometries and blood transport. However, previous works were focused on developing simulation models, not on validating suggested models with microvascular geometry and blood flow in the real microvasculature. In this paper, we suggest a computational model for microvascular transport with experimental validation in its geometry and blood flow. The geometry is generated by controlling asymmetric conditions of microvascular network. Also, the blood flow in microvascular networks is predicted by considering in vivo viscosity, Poiseuille flow model, and hematocrit redistribution by plasma skimming. The suggested model is validated by the measured data in rat mesentery. Also, the microvascular transport in a case of mouse cortex is predicted and compared against experimental data to check applicability of the suggested model. PMID- 29521013 TI - Long-term clinical and quality of life outcomes after stenting of femoropopliteal artery stenosis: 3-year results from the STROLL study. AB - OBJECTIVES: To evaluate the clinical and health status outcomes of patients undergoing superficial femoral artery (SFA) revascularization using the Shape Memory Alloy Recoverable Technology (S.M.A.R.T.(r)) nitinol self-expanding stent through 3 years of follow-up. BACKGROUND: Limited long-term data are available describing the durability of benefits after femoropopliteal revascularization. METHODS: In a multicenter, prospective, core-lab adjudicated study, 250 subjects with de novo or restenotic femoropopliteal arterial lesions were treated with the S.M.A.R.T.(r) stent. The primary endpoint of target vessel patency, a composite of ultrasound-assessed patency and freedom from clinically driven target lesion revascularization (TLR), was evaluated through 3 years. Secondary endpoints included stent fracture and health status. Health status was measured using generic and disease-specific instruments, including the Peripheral Artery Questionnaire (PAQ). RESULTS: At 3-year follow-up, Kaplan-Meier estimated target vessel patency was 72.7%, freedom from clinically driven TLR was 78.5%, and the incidence of stent fracture was 3.6%. The PAQ summary score was markedly impaired at baseline (mean 37.3 +/- 19.6 points) and improved substantially at 1 month (mean change from baseline of 31.4 points, 95% CI: 28.5-34.3; P < 0.001). Disease specific health status benefits assessed by the PAQ were largely preserved through 3 years of follow-up (mean change from baseline, 28.0 points, 95% CI: 24.3-31.7; P < 0.0001). CONCLUSIONS: In patients undergoing revascularization for moderately complex SFA disease, use of the self-expanding S.M.A.R.T(r) stent was associated with a high rate of target vessel patency through 3 years and led to substantial and sustained health status benefits. PMID- 29521014 TI - Quetiapine-induced pancreatitis in a case of juvenile bipolar disorder. PMID- 29521016 TI - Dullard deficiency causes hemorrhage in the adult ovarian follicles. AB - In mammals, the ovarian follicles are regulated at least in part by bone morphogenetic protein (BMP) family members. Dullard (also known as Ctdnep1) gene encodes a phosphatase that suppresses BMP signaling by inactivating or degrading BMP receptors. Here we report that the Col1a1-Cre-induced Dullard mutant mice displayed hemorrhagic ovarian cysts, with red blood cells accumulated in the follicles, resulting in infertility. Cells expressing Cre driven by Col1a1 2.3-kb promoter and their descendants were found in granulosa cells in the ovary and in Sertoli cells in the testis. DullardmRNA was localized to granulosa cells in the ovary. Genes involved in steroid hormone genesis including Cyp11a1, Hsd3b1 and Star were reduced, whereas expression of Smad6 and Smad7, BMP-inducible inhibitory Smads, was up-regulated in the Dullard mutant ovaries. Tamoxifen inducible Dullard deletion in the whole body using Rosa26-CreER mice also resulted in hemorrhagic ovarian cysts in 2 weeks, which was rescued by administration of LDN-193189, a chemical inhibitor of BMP receptor kinase, suggesting that the hemorrhage in the Dullard-deficient ovarian follicles might be caused by increased BMP signaling. Thus, we conclude that Dullard is essential for ovarian homeostasis at least in part via suppression of BMP signaling. PMID- 29521017 TI - Diabetes-induced colonic slow transit mediated by the up-regulation of PDGFRalpha+ cells/SK3 in streptozotocin-induced diabetic mice. AB - BACKGROUND: A major complication related to gastrointestinal (GI) symptoms in diabetic patients is chronic constipation. Constipation has serious negative impacts on quality of life; however, without a comprehensive understanding of the disease, currently available treatments cannot provide a cure. Platelet-derived growth factor receptor alpha-positive cells (PDGFRalpha+ cells), which form the SIP syncytium with interstitial cells of Cajal and smooth muscle cells, play important roles in GI motility. In the present study, the contributions of PDGFRalpha+ cells to diabetes-induced colonic slow transit were investigated in streptozotocin (STZ)-induced diabetic mice. METHODS: Western blotting, quantitative PCR, contractile experiments, and intracellular recording were used in the present study. KEY RESULTS: The results demonstrated that the colon length was increased in STZ-treated mice. The colonic transit of artificial fecal pellets in vitro was significantly delayed in STZ-treated mice. The mRNA and protein expression of PDGFRalpha, small-conductance Ca2+ -activated K channels (SK3), and P2Y1 receptors were increased in the colons of STZ-treated mice. In contractile experiments, the colonic smooth muscles were more sensitive to the SK3 agonist and antagonist (CyPPA and apamin) and the P2Y1 agonist and antagonist (MRS2365 and MRS2500) in STZ-treated mice. Intracellular recordings showed the responses of membrane potentials in colonic smooth muscle cells to CyPPA, apamin, MRS2365, and MRS2500 were more sensitive in STZ-treated mice. The electric field stimulation-induced P2Y1/SK3-dependent fast inhibitory junctional potentials (fIJPs) of colonic smooth muscles were more significantly hyperpolarized in STZ treated mice. CONCLUSIONS AND INFERENCES: These results suggest that the purinergic neurotransmitters/P2Y1/SK3 signaling pathway is up-regulated in the diabetic colons, thereby mediating diabetes-induced colonic slow transit. PMID- 29521015 TI - Efficient estimation of personalized biventricular mechanical function employing gradient-based optimization. AB - Individually personalized computational models of heart mechanics can be used to estimate important physiological and clinically-relevant quantities that are difficult, if not impossible, to directly measure in the beating heart. Here, we present a novel and efficient framework for creating patient-specific biventricular models using a gradient-based data assimilation method for evaluating regional myocardial contractility and estimating myofiber stress. These simulations can be performed on a regular laptop in less than 2 h and produce excellent fit between measured and simulated volume and strain data through the entire cardiac cycle. By applying the framework using data obtained from 3 healthy human biventricles, we extracted clinically important quantities as well as explored the role of fiber angles on heart function. Our results show that steep fiber angles at the endocardium and epicardium are required to produce simulated motion compatible with measured strain and volume data. We also find that the contraction and subsequent systolic stresses in the right ventricle are significantly lower than that in the left ventricle. Variability of the estimated quantities with respect to both patient data and modeling choices are also found to be low. Because of its high efficiency, this framework may be applicable to modeling of patient specific cardiac mechanics for diagnostic purposes. PMID- 29521018 TI - Cutaneous pseudolymphoma following quadrivalent human papillomavirus vaccination a rare adverse event. PMID- 29521019 TI - Degradation rate of DNA scaffolds and bone regeneration. AB - Scaffolds implanted into bone defect sites must achieve optimal biodegradation rates while appropriately filling the void as new bone formation progresses. We recently developed a unique biomaterial consisting of salmon deoxyribose nucleic acid (DNA) and protamine, which can be used as an osteoconductive scaffold for tissue engineering. The aim of the present study was to elucidate how the degradation rate of the scaffold affects bone regeneration. We examined the relationships between the degradation rate of salmon DNA scaffolds and new bone formation using a rat skin flank subcutaneous model and rat calvarial defect model. The degradation rates of the scaffolds were proportional to the durations of pretreatment with ultraviolet (UV) light irradiation. The biodegradation rates of the scaffolds were also dependent on the duration of UV irradiation, as tested a subcutaneous tissue implantation. Scaffolds irradiated with UV light for 0.5 h maintained gradual biodegradation of phosphate compared with scaffolds irradiated for 0 or 3 h. In the calvarial defect model, we found that new bone formation was higher in rats treated with scaffolds irradiated with UV light for 0.5 h compared with those irradiated with UV light for 0 or 3.0 h. The present results suggest that bioengineering of scaffolds for biodegradation is important to regenerate bone. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29521020 TI - Frequency-dependent anisotropic modeling and analysis using mfEIT: A computer simulation study. AB - Electrical properties of human tissues are usually linked with structure of thin insulating membranes and thereby reflect physiological function of the tissues or organs. It is clinically important to characterize electrical properties of tissues in vivo. Electrical impedance tomography is a recently developed medical imaging technique, which has been exploited to characterize electrical properties (conductivity and permittivity) of human tissues by injecting currents and measuring the resulting voltages at boundary electrodes. The electrical characteristic of a majority of human tissues, such as bones, muscles, and brain white matter, exhibits an anisotropic property. The anisotropic phenomenon of human tissues is frequency dependent that vanishes at high frequencies. Previous electrical impedance tomography studies that aimed at the reconstruction of anisotropic subject tissues have been focused on the theoretical analysis of uniqueness up to a diffeomorphism or the establishment of an accurate forward model by using an anisotropic conductivity tensor. However, effects of the current frequency on the accuracy of the reconstructions of anisotropic subjects remain poorly studied. The goal of this study is to examine the feasibility of multifrequency electrical impedance tomography by using it in a simulation study to recover the frequency-dependent anisotropic properties of a phantom subject composed of alternating insulating and conductive layers. The anisotropic properties of the subject were analyzed by an effective admittivity tensor, and the responses of the current flow pathways and voltages were investigated at various applied current frequencies in the forward model. The linear reconstruction was performed following the sensitivity matrix approach at multiple frequencies. Simulation results achieved at various frequencies revealed that the anisotropy of the model was effectively reconstructed at low frequencies and disappeared at high frequencies, from which we validated the feasibility of multifrequency electrical impedance tomography method in reconstructing the anisotropic directions of the considered object. PMID- 29521021 TI - NKG2D-ligands: Putting everything under the same umbrella can be misleading. AB - NKG2D is a key receptor for the activation of immune effector cells, mainly Natural Killer cells and T lymphocytes, in infection, cancer and autoimmune diseases. Since the detection of ligands for NKG2D in sera of cancer patients is, in many human models, indicative of prognosis, a large number of studies have been undertaken to improve understanding of the biology regulating this receptor and its ligands, with the aim of translating this knowledge into clinical practice. Although it is becoming clear that the NKG2D system can be used as a tool for diagnosis and manipulated for therapy, some questions remain open due to the complexity associated with the existence of a large number of ligands, each one of them displaying distinct biological properties. In this review, we have highlighted some key aspects of this system that differ between humans and mice, including the properties of NKG2D, as well as the genetic and biochemical complexity of NKG2D-ligands. All of these features affect the characteristics of the immune response exerted by NKG2D-expressing cells and are likely to be important factors in the clearance of a tumour or the development of autoimmunity. Implementation of more global analyses, including information on genotype, transcription and protein properties (cellular vs released to the blood stream) of NKG2D-ligands expressed in patients will be necessary to fully understand the links between this system and disease progression. PMID- 29521022 TI - Microfluidic Contact Lenses. AB - Contact lens is a ubiquitous technology used for vision correction and cosmetics. Sensing in contact lenses has emerged as a potential platform for minimally invasive point-of-care diagnostics. Here, a microlithography method is developed to fabricate microconcavities and microchannels in a hydrogel-based contact lens via a combination of laser patterning and embedded templating. Optical microlithography parameters influencing the formation of microconcavities including ablation power (4.3 W) and beam speed (50 mm s-1 ) are optimized to control the microconcavity depth (100 um) and diameter (1.5 mm). The fiber templating method allows the production of microchannels having a diameter range of 100-150 um. Leak-proof microchannel and microconcavity connections in contact lenses are validated through flow testing of artificial tear containing fluorescent microbeads (O = 1-2 um). The microconcavities of contact lenses are functionalized with multiplexed fluorophores (2 uL) to demonstrate optical excitation and emission capability within the visible spectrum. The fabricated microfluidic contact lenses may have applications in ophthalmic monitoring of metabolic disorders at point-of-care settings and controlled drug release for therapeutics. PMID- 29521023 TI - Sex ratio rather than population size affects genetic diversity in Antennaria dioica. AB - Habitat fragmentation and small population size can lead to genetic erosion in threatened plant populations. Classical theory implies that dioecy can counteract genetic erosion as it decreases the magnitude of inbreeding and genetic drift due to obligate outcrossing. However, in small populations, sex ratios may be strongly male- or female-biased, leading to substantial reductions in effective population size. This may theoretically result in a unimodal relationship between sex ratios and genetic diversity; yet, empirical studies on this relationship are scarce. Using AFLP markers, we studied genetic diversity, structure and differentiation in 14 highly fragmented Antennaria dioica populations from the Central European lowlands. Our analyses focused on the relationship between sex ratio, population size and genetic diversity. Although most populations were small (mean: 35.5 patches), genetic diversity was moderately high. We found evidence for isolation-by-distance, but overall differentiation of the populations was rather weak. Females dominated 11 populations, which overall resulted in a slightly female-biased sex ratio (61.5%). There was no significant relationship between population size and genetic diversity. The proportion of females was not unimodally but positively linearly related to genetic diversity. The high genetic diversity and low genetic differentiation suggest that A. dioica has been widely distributed in the Central European lowlands in the past, while fragmentation occurred only in the last decades. Sex ratio has more immediate consequences on genetic diversity than population size. An increasing proportion of females can increase genetic diversity in dioecious plants, probably due to a higher amount of sexual reproduction. PMID- 29521024 TI - Design of Conjugated Molecules Presenting Short-Wavelength Luminescence by Utilizing Heavier Atoms of the Same Element Group. AB - The introduction of heavy atoms into conjugated molecules often induces a redshift in the emission spectra. Conversely, we report here a blueshifting effect in the absorption and emission bands of a conjugated organic dye by employing a heavier atom from the same element group. Boron complexes having oxygen- and sulfur-bridged structures in the ligand moiety were synthesized, and their optical properties were compared. Significant optical bands in the absorption and luminescence spectra of the sulfur-bridged complex were observed in a shorter wavelength region than those of the oxygen-bridged complex. Theoretical calculations suggest that replacement of the bridging atom by a heavier one should reduce molecular planarity because of the larger atom size. As a result, the degree of electronic conjugation decreases, and this is followed by a blueshift in the optical bands. Finally, a blue-emissive crystal is demonstrated. PMID- 29521025 TI - Functional outcome measures for infantile Charcot-Marie-Tooth disease: a systematic review. AB - A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions. PMID- 29521026 TI - Cross cultural comparison of constipation profiles at tertiary care centers between India and USA. AB - BACKGROUND: Despite potential differences in patient perception of chronic constipation (CC) in geographically and culturally distinct regions, head-to-head studies comparing the clinical profile, constipation severity, impact on quality of life (QOL) and economic impact are lacking. METHODS: We conducted a cross sectional cohort study of patients presenting with CC to tertiary care centers in the USA and India. Standardized instruments were used to assess constipation subtype, disease severity, disease-specific QOL, somatization, and psychiatric comorbidities. We used multivariable linear regression to determine the predictors of QOL and number of healthcare visits. KEY RESULTS: Sixty-six and 98 patients with CC were enrolled in the USA and India, respectively. Indian patients with CC had significantly more frequent bowel movements/week compared to their USA counterparts (Median 5 vs 3, P < .0001). The proportion of patients with Bristol stool form scale type 1 and 2 was significantly higher in the USA compared to India (65.5% vs 48%, P = .04). Higher depression score (P = .001), more severe constipation symptoms (P = .001) and site of the study being USA (P = .008) independently predicted worse QOL. Indian patients (P < .001) and worse QOL (P = .02) were independent predictors of number of healthcare visits in the last 12 months. CONCLUSIONS AND INFERENCES: Indian patients with CC have more frequent and softer bowel movements compared to those in the USA suggesting significant differences in perception of CC in different geographic and cultural settings. QOL and economic impact related to constipation varies with geographic/cultural setting irrespective of other clinical and psychosomatic features. PMID- 29521027 TI - Detection of a novel porcine circovirus-like agent in aborted pig foetuses. AB - A large outbreak of swine abortion, which began in January 2017, is ongoing in Jiangsu and Anhui provinces, China. We identified a new porcine circovirus-like agent, designated P4, in the aborted foetuses from several of these cases of swine reproductive failure. PCR and qRT-PCR analyses confirmed that other common abortogenic agents were not present in these animals. P4 contains a 710 nucleotide circular viral genome, and all strains examined in this study were closely related to the dominant genotype of porcine circovirus type 2. Further studies, such as in vivo analyses, are needed to confirm P4 as the aetiological agent. PMID- 29521028 TI - Beta-blockers, hypertension, and stroke outcomes. PMID- 29521029 TI - Insight into the development of obesity: functional alterations of adipose derived mesenchymal stem cells. AB - Obesity is associated with a variety of disorders including cardiovascular diseases, diabetes mellitus and cancer. Obesity changes the composition and structure of adipose tissue, linked to pro-inflammatory environment, endocrine/metabolic dysfunction, insulin resistance and oxidative stress. Adipose derived mesenchymal stem cells (ASCs) have multiple functions like cell renewal, spontaneous repair and homeostasis in adipose tissue. In this review article, we have summarized the recent data highlighting that ASCs in obesity are defective in various functionalities and properties including differentiation, angiogenesis, motility, multipotent state, metabolism and immunomodulation. Inflammatory milieu, hypoxia and abnormal metabolites in obese tissue are crucial for impairing the functions of ASCs. Further work is required to explore the precise molecular mechanisms underlying its alterations and impairments. Based on these data, we suggest that deregulated ASCs, possibly also other mesenchymal stem cells, are important in promoting the development of obesity. Restoration of ASCs/mesenchymal stem cells might be an additional strategy to combat obesity and its associated diseases. PMID- 29521031 TI - The impact of junk food marketing regulations on food sales: an ecological study. AB - OBJECTIVE: To evaluate the impact of junk food broadcast marketing policies on nationwide junk food sales and identify policy characteristics effective in reducing sales. METHODS: Country policy data (n = 79) were categorized in a thorough literature review and analysed using a repeated measures design against data on food sales per capita. Study conducted in United States, 2017. RESULTS: Countries with junk food broadcast marketing policies saw a decrease in junk food sales per capita after implementation, while those without said policies saw an increase (p = 0.013). Countries with statutory policies saw a decrease in sales per capita, while those with only self-regulation saw an increase (p = 0.004). Audience restrictions (p = 0.024) and standardized nutrition criteria (p = 0.008) were policy characteristics significantly associated with a decrease in sales per capita. CONCLUSIONS: Utilizing a novel approach to evaluate junk food broadcast marketing policies, the study demonstrated that countries with statutory policies saw a significant decrease in junk food sales per capita not seen in countries with no or only self-regulatory policies. To effectively reduce exposure to child targeted junk food marketing, governments should establish strong, comprehensive statutory regulations. Additionally, countries that implement junk food marketing policies can use food sales data to track policy effectiveness. PMID- 29521030 TI - Tyrosinase Inhibitors from the Aerial Parts of Wulfenia carinthiaca Jacq. AB - Activity guided isolation of a MeOH extract of the aerial plant parts of Wulfenia carinthiaca Jacq. (Plantaginaceae), using a mushroom tyrosinase assay, resulted in the isolation of five phenylethanoid glucosides and four iridoid glycosides. Two of them, 2'-O-acetylisoplantamajoside and 2',6"-O-diacetylisoplantamajoside, represent new natural products. Evaluation of the inhibitory activity of all isolated compounds revealed that the observed activity is not related to the isolated phenylethanoid glycosides but mainly due to the presence of the iridoid glycoside globularin (IC50 41.94 MUm; CI95% +/- 16.61/11.89 MUm). Interestingly, structurally close related compounds (globularicisin, baldaccioside, and isoscrophularioside) showed no or only a weak tyrosinase inhibitory activity. PMID- 29521032 TI - Collagen from Marine Biological Sources and Medical Applications. AB - Collagen is the most studied protein with a wide range of applications including pharmaceutical, biomedical, cosmetics, leather, and film industries due to its special characteristics that are high biocompatibility, good bioactivity, and weak antigenicity. Although collagen sources are abundant, the outbreak of varied diseases among land animals posed threat to its utilization in our daily life. Thus, a probe for an alternative source began, which in turn revealed the immense untapped marine sources, such as fish, jellyfish, and some marine Mammals. The present article deals with a brief description of collagen, its characteristics, marine sources, extraction, collagen peptides and their biological activities, potential use and application in various field. PMID- 29521033 TI - Erratum. PMID- 29521034 TI - Bioactivity tests of calcium phosphates with variant molar ratios of main components. AB - Calcium phosphates constitute attractive materials of biomedical applications. Among them particular attention is devoted to bioactive hydroxyapatite (HAp) and bioresorbable tricalcium phosphate (TCP) that possess ability to bind to living bones and can be used clinically as important bone substitutes. Notably, in vivo bone bioactivity can be predicted from apatite formation of bone immersed in SBF fluids. Thus, analyses of behavior of calcium phosphates immersed in various bio fluids are of great importance. Recently, stoichiometric HAp and TCP structures have been widely studied, whereas only limited number of publications have been devoted to analyses of nonstoichiometric calcium phosphates. Here, we report physicochemical analysis of natural and synthetic phosphates with variable Ca/P molar ratios. Subsequently attained structures were subjected to incubation in either artificial saliva or Ringer's fluids. Both pH and conductivity of such fluids were determined before and after incubation. Furthermore, the influence of the Ca/P values on such parameters was exemplified. Physicochemical analysis of received materials was performed by XRD and FT-IR characterization techniques. Their potential antibacterial activity and behavior in the presence of infectious microorganisms as Escherichia coli and Staphylococcus aureus was also evaluated. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1941-1950, 2018. PMID- 29521035 TI - The Special Issue: Clinical Proteomics for Precision Medicine. PMID- 29521036 TI - Multi-Pronged Proteomic Analysis to Study the Glioma Pathobiology using Cerebrospinal Fluid Samples. PMID- 29521038 TI - The protective action of tocopherol and acetylsalicylic acid on the behavior of rats treated with dioxins. AB - BACKGROUND: Dioxins contribute to neurological disorders in humans and animals, causing also neurological disorders in offspring during prenatal and postnatal periods. These compounds significantly affect the development of the central nervous system (CNS) structures, which results in behavioral changes. Tocopherol (TCP) and acetylsalicylic acid (ASA) may provide protective measures to reduce the inflammatory effects in the CNS associated with free radicals generated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), thus contributing to the reduction of the negative effects of dioxin. OBJECTIVES: The main objective of this study was to determine the influence of dioxin on rats and their behavioral functions, and to ascertain whether a combined administration of TCP and ASA to rats treated with TCDD shows the possibility of potential protective effect on the functioning of the CNS. MATERIAL AND METHODS: Experiments were performed on 75 female and 12 male Buffalo strain rats, which are offspring of females from particular study groups. TCDD was used in the experiments, TCP and ASA were administered orally every day for 3 weeks. Animals were subjected to behavioral testing: the tail and swimming tests. RESULTS: During the observation of the offspring of both sexes born to females exposed to TCDD, males did not demonstrate any attempt to swim, whereas in females, the immobility time was significantly extended. Assessing the response times from the tail test in the animals treated with dioxins in relation to the control group, it was demonstrated that the response time was extended in the 3rd measurement in both females and males. CONCLUSIONS: Dioxin is characterized by neurotoxic effect causing behavioral disorders associated with prolonged response times. The use of TCP after the administration of dioxins causes a significant reduction and improvement of reflex response times. In contrast, ASA reduces the reflex response times also in the offspring of females exposed to TCDD and ASA. PMID- 29521037 TI - Human physiological and metabolic responses to an attempted winter crossing of Antarctica: the effects of prolonged hypobaric hypoxia. AB - An insufficient supply of oxygen to the tissues (hypoxia), as is experienced upon high-altitude exposure, elicits physiological acclimatization mechanisms alongside metabolic remodeling. Details of the integrative adaptive processes in response to chronic hypobaric hypoxic exposure remain to be sufficiently investigated. In this small applied field study, subjects (n = 5, male, age 28-54 years) undertook a 40 week Antarctica expedition in the winter months, which included 24 weeks residing above 2500 m. Measurements taken pre- and postexpedition revealed alterations to glucose and fatty acid resonances within the serum metabolic profile, a 7.8 (+/-3.6)% increase in respiratory exchange ratio measured during incremental exercise (area under curve, P > 0.01, mean +/- SD) and a 2.1(+/-0.8) % decrease in fat tissue (P < 0.05) postexpedition. This was accompanied by an 11.6 (+/-1.9) % increase (P > 0.001) in VO2 max corrected to % lean mass postexpedition. In addition, spine bone mineral density and lung function measures were identified as novel parameters of interest. This study provides, an in-depth characterization of the responses to chronic hypobaric hypoxic exposure in one of the most hostile environments on Earth. PMID- 29521039 TI - Comparison of polypropylene and silicone Ahmed(r) glaucoma valves in the treatment of neovascular glaucoma: A 2-year follow-up. AB - BACKGROUND: Inflammation associated with biomaterials of Ahmed(r) glaucoma drainage devices may cause the formation of a capsule around the device and can thus have a significant influence on the level of intraocular pressure reduction. OBJECTIVES: The objective of this study was to compare the clinical outcomes after the implantation of a polypropylene or silicone Ahmed(r) glaucoma valve in patients with neovascular glaucoma. MATERIAL AND METHODS: In the study, 27 eyes with neovascular glaucoma (group 1) received silicon Ahmed(r) valves and 23 eyes (group 2) received polypropylene valves. The best corrected distance visual acuity (BCDVA), intraocular pressure (IOP) and number of anti-glaucomatous drugs were recorded preoperatively and during a follow-up period of 24 months after surgery. Success was defined by the following criteria: 1) intraocular pressure in the rage of 6-21 mm Hg; 2) IOP reduction of at least 30% relative to preoperative values. All complications were registered. RESULTS: One month postoperatively, the mean BCDVA increased significantly in both groups compared to preoperative values (p < 0.001). These values did not change during the 24 months of follow-up examinations. The probability of success defined by criterion 1 at 24 months of observation was 66.7% for silicone and 27.3% for propylene valves group (p < 0.007). According to criterion 2, the difference in success between the groups was not statistically significant. The total number of complications that occurred in both groups during the 24 months of follow-up examinations was similar, except for a higher occurrence of Tenon's cyst formation in the group with a polypropylene valve (18% vs 35%; p < 0.04). CONCLUSIONS: In patients with neovascular glaucoma, the implantation of a silicone valve is associated with a significantly higher probability of long-term reduction of IOP below 21 mm Hg and with a lower risk of valve encapsulation in comparison to polypropylene valves. The obtained results suggest that silicone Ahmed(r) valves are more effective in the treatment of patients with neovascular glaucoma. PMID- 29521040 TI - Methodological exploration of bone marrow stem cell therapy in acute myocardial infarction - how to achieve greater benefit on cardiac outcomes: A systematic review and meta-analysis. AB - BACKGROUND: Clinical trials of intracoronary injection of bone marrow-derived stem cells (BMCs) in patients with acute myocardial infarction (AMI) have revealed promising but variable and modest results. One of the reasons underlying this situation may be the unstandardized preparation of BMCs. OBJECTIVES: The aim of this study was to explore whether methodological differences affect the prognosis of acute myocardial infarction patients who received BMCs transplantation. MATERIAL AND METHODS: MEDLINE was searched for randomized controlled trials providing AMI patients with intracoronary BMCs injection or a standard therapy. Changes in cardiac parameters and clinical outcomes were analyzed. Subgroup analyses were conducted according to different methodologies for cell preparation, including supplement for serum or plasma, use of heparin and cell washout. RESULTS: Non-use of serum or plasma in the cell suspension is associated with more reduction in infarct size (IS) and a lower risk of all-cause mortality. Heparin usage could diminish the benefit in reducing IS. All-cause mortality rose significantly without the cell washout procedure when heparin was used. CONCLUSIONS: Methodological differences in BMCs preparation as well as the use of heparin and serum/ plasma impact on the prognosis of AMI patients. PMID- 29521041 TI - Computerized planimetry evaluation of hyperbaric oxygen therapy in the treatment of diabetic foot. AB - BACKGROUND: Diabetic foot ulcer is one of the major complications of diabetes mellitus in adults. OBJECTIVES: The aim of the study was to conduct a planimetry evaluation of the effectiveness of hyperbaric oxygen therapy (HBOT) in the treatment of patients with vascular disorders caused by diabetic foot. MATERIAL AND METHODS: The study included 94 patients, 30 females (32%) and 64 males (68%), aged 33-76 years, with diabetes lasting 1.5-32 years, who underwent HBOT due to diabetic foot. All patients from that group underwent vascular procedures prior to HBOT. In qualifying patients for hyperbaric oxygen therapy, transcutaneous oximetry method was applied (30-60 exposures in hyperbaric oxygen at pressure of 2.5 ATA). Progress in wound healing was evaluated by computerized planimetry system IRIS 4. RESULTS: In 26 patients the wounds were completely closed and in 37 patients the topical state was significantly improved - the wound surface decreased by 34% in average. During the treatment, in 11 patients amputation of fingers and metatarsal necrotic bones was performed, while in 9 patients amputation was prevented. CONCLUSIONS: A planimetry evaluation showed that the application of HBOT in the treatment of diabetic foot enhances foot ulcer healing, reduces tissue damage, contributes to the reduction of complications related to soft tissue and bone infections. PMID- 29521042 TI - IL-6, IL-1beta, and TNF-alpha only in combination influence the osteoporotic phenotype in Crohn's patients via bone formation and bone resorption. AB - BACKGROUND: Crohn's disease (CD) is associated with a higher prevalence of osteoporosis. The pathogenesis of bone affliction remains controversial, especially if inflammatory cytokines or glucocorticoid therapy are the main contributors. In postmenopausal osteoporosis, bone resorption is induced by IL-6, IL-1beta and TNF-alpha. In contrast, in children with CD, IL-6 exclusively decreased bone formation without affecting bone resorption. OBJECTIVES: The objective of this study was to further clarify the pathophysiology of bone affliction in adult patients with CD with the use of an osteoblast and osteoclast cell model. MATERIAL AND METHODS: Inflammatory cytokines IL-6, IL-1beta, and TNF alpha were measured in adult CD patients' serum. Mean values of these cytokines were applied with or without dexamethasone to the human cell line SCP-1 (osteoblastic cell model). Also, the effect of cytokines on primary human osteoclast differentiation and activity was determined. RESULTS: The combined cytokine application increased the receptor activator of NF-kappaB ligand/osteoprotegerin (RANKL/OPG) ratio 2-fold after 2 and 14 days. Additional application of dexamethasone to SCP-1 cells further increased the RANKL/OPG ratio 3-fold, but decreased IL-6 and IL-1beta expression to 10% and 50%, respectively. TNF-alpha expression was maximally suppressed to 16% by dexamethasone in the presence of cytokines. In osteoclasts, the combined cytokine treatment decreased expression of characteristic genes to approx. 30%, while increasing osteoclast resorption activity to 148%. In addition, a cytokine stimulated osteoblast cell culture-generated supernatant stimulated osteoclast resorption activity by 170%. CONCLUSIONS: Our results suggest that IL-6, IL-1beta, and TNF-alpha only in combination induced osteoclaststimulating activity represented by the RANKL/OPG ratio in osteoblasts. Dexamethasone further increased this effect in osteoblasts, while decreasing cytokine expression. The results in osteoclasts support a direct and osteoblast-mediated effect on bone resorption. Our in vitro results differentiate for the first time the effect of cytokines on bone turnover as measured in adult CD patients from the additional dexamethasone effect on osteoblasts as part of the pathophysiology of osteoporosis. PMID- 29521043 TI - Clinical and immunological characteristics of Polish patients with systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with varied clinical manifestations, which creates difficulties and delays in establishing a diagnosis. OBJECTIVES: The aim of this study was to evaluate the prevalence and nature of the clinical symptoms of SLE, both at the onset of the disease and in its further course. An attempt to assess the immunological characteristics of the patients and to analyze autoantibodies variability over time was also made. MATERIAL AND METHODS: This retrospective study included 71 Caucasian patients, 63 women and 8 men, meeting the criteria for diagnosis of SLE according to ACR. RESULTS: The ratio of women to men was approximately 7.9:1. The average age of the onset of SLE was 31.5 years. The average time from the onset of symptoms to diagnosis was 5 years. The most common first manifestation of SLE were joint and muscles symptoms - 71.8%, skin lesions - 69.0%, fever - 57.7%. The main symptoms in the further course of the disease were neurological disorders - 69.0%, joint and muscle changes - 67.7%, and general symptoms - 59.2%. There was an increase in the incidence of renal involvement and neurological symptoms throughout the disease course. The most commonly detected antibodies were anti dsDNA - 47.9%, anti-Ro/SSA - 40.8%, anti-nucleosomal antibodies - 29.6%, and lupus anticoagulant - 22.5%. A panel of antibodies typically did not change. CONCLUSIONS: There is no typical clinical picture of SLE, the population suffering from this disease is very various. Therefore, early and accurate diagnosis can be a big challenge for any clinician, which justifies the need for this type of study to better characterize the disease. PMID- 29521044 TI - Heart infarct as the major cause of death of hematological patients as identified by autopsy. AB - BACKGROUND: Despite progress in diagnostic procedures, clinical diagnosis is not always confirmed by an autopsy. An autopsy is a valuable tool in evaluating diagnostic accuracy. OBJECTIVES: The aim of the study was to compare clinical diagnoses of immediate causes of death with autopsy findings in patients with hematological malignancies or aplastic anemia. MATERIAL AND METHODS: In this study, the results of 154 autopsies (1993-2004) of patients with hematological diseases were reviewed and compared with clinical data. The most probable causes of death in the case of particular hematological diseases as well as the discordances between clinical and autopsy diagnoses and their relation to the clinical characteristic were identified in the studied cohort, which primarily included patients whose death at that particular time was not explained by the clinical course, and in 50% of cases was sudden. RESULTS: Although various combined infections have been found to be responsible for the largest number of deaths (26.6%), the most common single cause was myocardial infarction (29 patients, 18.8%). The discordance between clinical and post-mortem diagnoses of immediate causes of death was found in 55 patients (35.7%; 95% CI 28.2-42.8%), with 50.9% of cases considered class I discrepancies according to Goldman's criteria. The myocardial infarction was found to be clinically undiagnosed in 69% of cases. In 41% of cases, it was a class I discrepant diagnosis. CONCLUSIONS: This data suggests that hematological patients require special attention and probably preventive measures concerning coronary heart disease, particularly during the initiation of antineoplastic therapy. PMID- 29521045 TI - The relationship between QDASH scale and clinical, electrophysiological findings in carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome (CTS) occurs as a result of compression of the median nerve at the wrist. The Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire is a selfadministered region-specific outcome instrument which measures symptom severity and functional status. OBJECTIVES: The aim of this study was to evaluate the clinical and electrophysiological relationship with QDASH scale in CTS. MATERIAL AND METHODS: The study included 99 females and 22 males in total out of 121 idiopathic CTS patients with the mean age of 47.9 +/-9.5 years. Patients were divided clinically and electrophysiologically into 2 groups as severe and mild based on modified criteria defined by Italian CTS working group. Pain severity was evaluated by visual analog scale (VAS). Patients were evaluated functionally by QDASH scale and the relationship between clinical and electrophysiological effect intensity (degree) was examined. RESULTS: QDASH scores were found significantly high in female patients, in patients with long disease duration (6 years and more), patients with clinically severe symptoms, and the ones with positive phalen test in both hands. Statistically significant positive relationship was found between QDASH scores, disease duration and clinical severity. However, no relationship was found between electrophysiological severity and QDASH. A mild and positive correlation was observed among disease duration, clinical severity and VAS. A small and positive correlation was detected between VAS and QDASH. CONCLUSIONS: Although electrophysiological findings were prioritized in the follow-up and treatment strategies of CTS patients, clinical and patient-oriented assessment scales should be dealt together. Despite the electrophysiological findings, we believe that individual differences are effective in clinical and functional capacity. We conclude that since QDASH scale has a simple applicability in a short time, it can be used for assessing the symptom severity and disability of patients with CTS. PMID- 29521046 TI - Oxidative stress in colonic adenocarcinoma: An impact on the body's antioxidative status and oxidative protein damage. AB - BACKGROUND: Thus far, the pathogenesis of these intestinal tumors has not been fully explained. However, the analysis of risk factors and research regarding their formation that have continued for 3 decades have allowed us to demonstrate a significant role of oxidative stress in the processes leading to the development of cancer in the large intestine as well as in some other organs. OBJECTIVES: The aim of the study was to examine the level of anti-oxidative status and the degree of oxidative protein damage in patients with varying severity of colonic adenocarcinoma (CAC) in relation to healthy individuals. MATERIAL AND METHODS: The study involved 4 groups (A-D) of patients with increasing severity of CAC stages according to Dukes' classification and a control group of healthy volunteers. Total antioxidant capacity (TAC) of blood plasma, as well as carbonyl (C=O) group contents in blood plasma proteins as a product of their oxidative damage, were estimated in all participants. Both parameters were determined by spectrophotometric methods using commercial kit to test TAC and 2,4-dinitrophenylhydrazine to assay the contents of C=O groups. RESULTS: In each of the studied groups, A-D, a statistically significant reduction in the TAC values was noted relative to the control group, which progressed with increased severity of CAC stages: 1.783 mmol/L vs 1.191 mmol/L (group A), 1.07 mmol/L (group B), 0.931 mmol/L (group C), and 0.899 mmol/L (group D). At the same time, significantly increased contents of protein C=O groups were observed compared to the controls, also progressive in the course of growing CAC severity: 0.496 nmol/mg protein vs 0.57 nmol/mg protein (group A), 0.689 nmol/mg protein (group B), 0.804 nmol/mg protein (group C), and 1.054 nmol/mg protein (group D). CONCLUSIONS: The CAC-related oxidative stress considerably reduces the systemic anti-oxidative status and increases the protein damage; both those changes become worse in parallel with the progression of this cancer. PMID- 29521047 TI - Expression of VEGF165b, VEGFR1, VEGFR2 and CD34 in benign and malignant tumors of parotid glands. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is an angiogenic factor and could be involved in the pathogenesis of salivary gland tumors. VEGF exerts its biological function by binding to its receptors, VEGFR1 and VEGFR2. An alternative splice variant of VEGF (VEGFxxxb) is an anti-angiogenic factor. Binding VEGF165b with VEGFR2 results in an impaired angiogenic response. The imbalance of VEGFxxx and VEGFxxxb isoforms can underpin pathological angiogenesis. OBJECTIVES: The purpose of this study was to evaluate and compare the expression of VEGF165b, VEGFR1, VEGFR2, and CD34 in benign and malignant parotid gland tumors and to explore the possible correlations between their expression and clinicopathological features of tumors. MATERIAL AND METHODS: The study was performed on archived paraffin-embedded tissue samples derived from 70 patients with benign and malignant parotid gland tumors (25 with malignant tumors, 23 with pleomorphic adenoma and 22 with Warthin's tumor). Immunohistochemical staining of selected tissue sections was performed using monoclonal antibodies. Immunohistochemical staining of selected molecules was used for evaluation of their expression in tissue sections. RESULTS: There were no statistically significant differences in the expression of the selected proteins localized in the tumor and surgical margin taken from the same patient. Expression of VEGFR2 correlated with VEGF165b in mixed tumors. There was a statistically significant difference in the expression of VEGFR1 in malignant tumors between females and males, and between the expression of VEGFR1 and the score of T classification in malignant tumors. CONCLUSIONS: VEGF165b cannot be treated as a prognostic factor. VEGF receptors correlated with selected clinicopathological data of malignant tumors, indicating their possible role as a prognostic marker. The balance of VEGF isoforms have a limited influence on the development of parotid glands tumors. The correlation between VEGF165b and VEGFR2 in mixed tumors suggests the existence of an additional antiangiogenic pathway in poorly vascularized mixed tumors. PMID- 29521048 TI - Imatinib in the treatment of chronic myeloid leukemia in children and adolescents is effective and well tolerated: Report of the Polish Pediatric Study Group for the Treatment of Leukemias and Lymphomas. AB - BACKGROUND: Chronic myeloid leukemia (CML) constitutes only 2-3% of all leukemias in pediatric patients. Philapelphia chromosome and BCR-ABL fusion are genetic hallmarks of CML, and their presence is crucial for targeted molecular therapy with tyrosine kinase inhibitors (TKIs), which replaced hematopoietic stem cell transplantation (HSCT) as a standard first-line therapy. The disease in pediatric population is rare, and despite molecular and clinical similarities to CML in adults, different approach is needed, due to the long lifetime expectancy and distinct developmental characteristics of affected children. OBJECTIVES: The objective of this study is to evaluate treatment with imatinib in Polish pediatric patients with CML. MATERIAL AND METHODS: We analyzed the results of treatment with imatinib in 57 pediatric patients (June 2006 - January 2016) from 14 Polish pediatric hematology and oncology centers. RESULTS: In the study group, 40 patients continued imatinib (median follow-up: 23.4 months), while in 17 the treatment was terminated (median follow-up: 15.1 months) due to therapy failure. In the latter group, 13 patients underwent HSCT, while 4 switched to second generation TKIs. The 5-year overall survival rate (OS) in the study group was 96%, and the 5-year event-free survival (EFS) was 81%. CONCLUSIONS: Our results confirm that the introduction of TKI therapy has revolutionized the treatment of CML in the pediatric population by replacing the previous method of treatment with HSCT and allowing a high percentage of OS and EFS. PMID- 29521049 TI - Elevated serum concentrations of metalloproteinases (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2) in patients with Graves' orbitopathy. AB - BACKGROUND: Graves' orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is characterized by dramatic tissue reactivity. Both inflammation and tissue remodeling characterize the clinical course of GO. Some data has been found regarding the association of MMPs and TIMPs in GO. MATERIAL AND METHODS: Serum concentrations of MMP-9, MMP-2, TIMP-1, and TIMP-2 were determined by ELISA method. OBJECTIVES: Forty-eight patients (34 females, 14 males, with median age 51.5 years) with GD and hyperthyroidism were enrolled in the study. In 28 patients, active, moderate-to-severe grade orbitopathy was diagnosed. The aim of this study was to assess the serum concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 in patients with Graves' disease (GD), with and without GO, and their relationship with disease severity, as well as to evaluate how these concentrations change after successful treatment. RESULTS: Median serum concentrations of MMP-2 and MMP-9 were significantly higher in all patients with GD as well as in the subgroup with GO than in the control group. Median serum concentrations of TIMP-1 and TIMP-2 were significantly higher in all patients with GD than in controls. The same significant differences were observed in the subgroups with and without GO in comparison with controls. The GO subgroup showed a significant positive correlation between the MMP-9 concentration and the serum level of TSHRAb antibodies, and a clinical activity score >=4 according to EUGOGO. CONCLUSIONS: In our study we found that only MMP-9 differentiates the patients with and without GO, and may be used as a marker of the disease severity in patients with this manifestation of GD. PMID- 29521050 TI - The effect of hemodialysis on intraocular pressure. AB - BACKGROUND: The effect of hemodialysis (HD) on intraocular pressure (IOP) has been investigated before, but there is a lack of consensus. Clinicians dealing with renal failure patients are interested in the potential negative effects of HD on IOP and the course of glaucoma. OBJECTIVES: The aim of this study was to investigate the effects of HD on IOP in patients with end-stage renal disease. MATERIAL AND METHODS: This prospective study included 106 patients who were receiving outpatient hemodialysis. Patient history of systemic and ophthalmologic conditions was recorded. Serum osmolality (mOsm), blood urea nitrogen (BUN), blood glucose (BG), bicarbonate (BC), and hematocrit (Hct) levels at the start of HD (pre-HD), at the end of HD (end-HD), and 30 min after HD (post-HD) were measured. Systolic and diastolic blood pressures (SBP and DBP) and IOP were measured at pre-HD, 1-hour intervals during HD, end-HD, and post-HD. RESULTS: A significant decrease in mOsm and BUN and a significant increase in BG, BC, and Hct levels were observed at end-HD (p < 0.05). Mean IOP was 16.71 +/-2.51 mm Hg at pre-HD, 15.52 +/-3.18 mm Hg at endHD, and 15.23 +/-2.73 mm Hg at post-HD (p = 0.001; F = 4.439). Post-HD SBP and DBP were significantly lower than at pre-HD (p < 0.001). There was a positive correlation between the change in IOP and the change in mOsm and the change in BUN at end-HD (r = 0.315, p = 0.004; and r = 0.279, p = 0.012, respectively). CONCLUSIONS: IOP decreased significantly during HD in this study. Additional research on the effects of the change in blood parameters and ocular perfusion pressure on IOP and optic nerve perfusion during HD is recommended. PMID- 29521051 TI - Typing of Enterococcus spp. strains in 4 hospitals in the Malopolska region in Poland. AB - BACKGROUND: In the Malopolska province, the first case of vancomycin resistant enterococci (VRE) occurrence was an outbreak in 2001 caused by strains of the genus E. faecium carrying the vanA operon. OBJECTIVES: The aim of this study is to determine the antimicrobial resistance and the occurrence of virulence determinants among Enterococcus spp. in patients hospitalized in the Malopolska region in 2015. MATERIAL AND METHODS: Antimicrobial susceptibility was determined by disc diffusion and the E test. The presence of aminoglycoside and glycopeptide resistance genes and virulence genes (asa1, gelE, cylA, esp, hyl) was investigated using multiplex polymerase chain reaction (PCR). Also, the presence of IS16 was investigated. The activity of gelatinase, cytolysin (hemolysin), and DNase was tested. RESULTS: All E. faecalis were susceptible to ampicillin, vancomycin, teicoplanin, linezolid and tigecycline. All E. faecium strains were susceptible to quinupristin-dalfopristin. Resistance to ampicillin and vancomycin was detected among all E. faecium isolates from hospitals C and D. 87.32% of E. faecium presented high-level aminoglycoside-resistant (HLAR) phenotype, including 78.33% of strains from hospital C and 100% from hospital D. In hospital C (98.3%) and D (96%), resistance to ciprofloxacin, levofloxacin and norfloxacin was observed. Gene esp was detected in all E. faecium isolates and the majority of E. faecium isolates carried hyl (97%). In E. faecalis, different combinations of virulence genes were detected. All analyzed E. faecium strains showed the presence of IS16 insertion element. CONCLUSIONS: E. faecalis isolates were more susceptible to antimicrobials than E. faecium, which were largely multidrug resistant. E. faecalis strains have diverse virulence factors. E. faecium showed a high percentage of hyl and esp genes and the presence of IS16. PMID- 29521052 TI - Probiotics: Myths or facts about their role in allergy prevention. AB - BACKGROUND: The hygiene hypothesis proposed by Strachan in the 1980s clearly emphasized the role of microorganisms in atopy prevention. OBJECTIVES: The study objective was to assess the preventive role of probiotics in patients with allergic rhinitis, bronchial asthma, atopic dermatitis, and/or food allergy. MATERIAL AND METHODS: The methods used in the study were the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires for 6-7- and 13-14 year-olds and the European Community Respiratory Health Survey II (ECRHS II) questionnaire targeted for the 20-44 age group. The study was conducted as part of the cross-sectional Epidemiology of Allergic Diseases in Poland study conducted in 9 Polish regions (8 urban: Warszawa, Lublin, Bialystok, Gdansk, Poznan, Wroclaw, Katowice, Krakow, and the rural regions of Zamojski and Krasnostawski counties). The study material was a group of patients diagnosed with food allergy (n = 407), atopic dermatitis (n = 311), allergic rhinitis (n = 1.353), bronchial asthma (n = 505), and healthy volunteers (n = 2,403). RESULTS: Genetic factors play an important role in the allergy development. A family history positive for chronic skin disorders increased the risk of atopic dermatitis and food allergies (OR = 1.456, CI = 1.14-1.85, p = 0.002; and OR = 1.378, CI = 1.05-1.81, p = 0.02, respectively). The consumption of products containing live bacterial cultures showed no preventive effects in any of the evaluated disorders in early childhood. Conversely, over the age of 14 years, probiotic formulations exhibit health-promoting effects and may lower the risk of allergic diseases. CONCLUSIONS: The use of probiotics in the Polish population showed no protective effect in the first years of life. The changes in dietary habits introduced during late adolescence demonstrated significantly greater preventive effects of live bacterial cultures against the development of allergic diseases. PMID- 29521053 TI - Genetic polymorphisms and their involvement in the regulation of the inflammatory response in asthma and COPD. AB - Asthma and chronic obstructive pulmonary disease (COPD) are widely documented diseases with an inflammatory component. Asthma is a heterogeneous disorder of the airways that involves chronic inflammation, decline of the airway function and tissue remodeling. Chronic obstructive pulmonary disease is a preventable and treatable disease, which is characterized by persistent limited airflow, and is usually progressive with an increased inflammatory response in the airways. The inflammatory response is evoked by the stimulus of noxious particles and gases. Inflammation is a natural process in response to injury, but in asthma and COPD patients it occurs as an abnormal immune response to pathogenic stimuli which induce chronic inflammation, a key process in the pathogenesis of both diseases. However, the inflammatory process is different in both diseases, and is involved in several release patterns of inflammation mediators. It is not entirely clear whether these proteins are simply markers of the inflammatory process that accompanies a chronic disease or if they play a major role in the pathogenesis of the disease. The main proteins which have been described in these illnesses are: IL-4, IL-6, IL-8, and TNF-alpha. In addition, polymorphisms have been described in genes encoding these proteins that alter the transcription and susceptibility associated with these diseases. In this review, we will focus on asthma and COPD, and the involvement of these proteins and their genetic polymorphisms. PMID- 29521054 TI - The significance of anthocyanins in the prevention and treatment of type 2 diabetes. AB - Anthocyanins are food compounds which belong to polyphenols and can mainly be found in dark fruits (e.g., blueberries, black currants, cranberries) and vegetables (e.g., red cabbage, radish, eggplant). The results of large research have shown that these compounds play an important role in the prevention of type 2 diabetes (T2D). In rodent studies and in studies with isolated omental adipocytes, it was observed that anthocyanins regulated the carbohydrate metabolism in the body due to the upregulation of GLUT4 (insulinregulated glucose transporter) translocation, increased activation of PPARgamma (peroxisome proliferator-activated receptor-gamma) in adipose tissue and skeletal muscles as well as increased secretion of adiponectin and leptin. Moreover, these compounds reduced the inflammation status in the body. Studies conducted on humans and experimental animals showed that anthocyanins decrease insulin resistance. This effect may be achieved by the upregulation of GLUT4 gene expression, activation of AMP-activated protein kinase and downregulation of retinol binding protein 4 (RBP4) expression. Anthocyanins also increased the uptake and utilization of glucose by tissues in streptozotocin-induced diabetic rats and mice, and they also protected pancreatic cells against necrosis induced by streptozotocin. Another mechanism that might explain the lower glucose level in the blood after a meal with anthocyanins compared to a meal without them is the inhibition of intestinal alpha-glucosidase and pancreatic alpha-amylase by these compounds. Moreover, anthocyanins improve insulin secretion, which can have a special meaning for people with T2D. The evidence from the presented studies suggests that foods rich in anthocyanins may be one of the diet elements supporting the prevention and treatment of T2D. PMID- 29521055 TI - Post-ERCP pancreatitis: Pathophysiology, early identification and risk stratification. AB - Acute pancreatitis is the most common and feared complication of endoscopic retrograde cholangiopancreatography (ERCP). The aim of the study was to review the current knowledge on the nomenclature, etiology, pathophysiology, clinical presentation, diagnostic workup, and risk stratification of post-ERCP pancreatitis (PEP). A structured search in PubMed and Scopus databases was performed using search terms related to the subject of diagnosis, pathophysiology, risk stratification of post-ERCP pancreatitis, including full text articles and abstracts in the English language. Several causes, operating both at a local and systemic level, might play an important role in the pathogenesis of PEP. Different patient-related risk factors can help predict post ERCP pancreatitis; diagnosis depends on clinical presentation, imaging and laboratory investigations. As an outpatient procedure, post-ERCP pancreatitis may be safe in a selected group of low-risk patients. Further investigation of the etio-pathogenesis of post-ERCP pancreatitis is required in order to improve diagnosis and treatment. Early identification and severity stratification of post ERCP pancreatitis greatly affects the patient's outcome. There is still controversy concerning the risk factors related to PEP. More studies are needed to clarify early and definite diagnosis, risk and severity stratification, as well as treatment of post-ERCP pancreatitis. PMID- 29521056 TI - Blocking MET receptor signaling in multiple myeloma cells in vitro and in vivo. AB - BACKGROUND: Numerous studies have shown a role of the hepatocyte growth factor (HGF) as a ligand for the MET receptor in promoting aggressiveness in myeloma cells. OBJECTIVES: The aim of this study was to confirm the presence of the MET receptor in myeloma cell lines, to establish a stable lentiviral construct directed against MET receptor mRNA and then to evaluate the effect of blocking MET receptor expression both in vitro and in vivo. MATERIAL AND METHODS: The U266 and INA6 cells were transduced using a lentiviral vector carrying siRNA to achieve the reduction of MET receptor expression. The ocular sinus of NOD/SCID mice was injected with wt-U266, shMET-U266 and shLacZ-U266 cells. RESULTS: MET receptor expression was demonstrated in all tested myeloma cell lines. Blocking the HGF/MET axis did not affect the growth of transduced U266 and INA6 cell lines. The inoculation of NOD/SCID mice with myeloma cells with reduced expression of MET led to increased survival of the animals. CONCLUSIONS: MET receptor expression was constituently expressed in all tested myeloma cell lines. A lentiviral construct can effectively reduce the expression of the MET receptor in myeloma cells. Further studies are necessary to evaluate the effect of the reduction of MET receptor expression in multiple myeloma, focusing on animal models with a larger test group size. PMID- 29521057 TI - Urine nerve growth factor (NGF) level, bladder nerve staining and symptom/problem scores in patients with interstitial cystitis. AB - BACKGROUND: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a challenging disease, affecting thousands of people all around the world, especially women. Although there have been numerous theories regarding IC/BPS etiology, the physiopathology of the disease still remains unclear and there is a lack of certain treatment. OBJECTIVES: The aim of the study was to assess the role of nerve fibers and nerve growth factor (NGF) in the etiopathogenesis of IC/BPS symptoms by demonstrating if there is a correlation between urine NGF levels, amount of peripheral nerves in bladder mucosa and symptom severity. MATERIAL AND METHODS: A prospective clinical study was conducted with 15 IC/BPS patients and 18 controls. Urine NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Bladder punch biopsies were obtained from 15 IC/BPS patients and 9 controls. Immunohistochemistry was performed for S-100 to highlight peripheral nerve twigs in bladder mucosa. The O'Leary-Sant Interstitial Cystitis Symptom and Problem Index (OSICSPI) was used to assess symptom severity and effects of the disease on the patients' life. RESULTS: NGF normalized to urine creatinine (NGF/Cr) levels in IC/BPS patients were significantly higher than in controls, 0.34 +/-0.22 and 0.09 +/-0.08 pg/mL: mg/dL, respectively (p < 0.001). The mean symptom score in IC patients was 12.27 +/-2.4 (median: 12) and the mean problem score was 10.9 +/-2.3 (median: 12). The mean mucosal nerve (S 100 stained) area in the IC/BPS group was significantly higher than in the controls, 2.53 +/-1.90 vs 1.0 +/-0.70, respectively (p = 0.018). In correlation analyses, the NGF/Cr level in IC/BPS patients was found significantly correlated with the O'Leary-Sant IC Symptom and Problem Index scores independently (p = 0.001 and p = 0.028, respectively). CONCLUSIONS: NGF seems to be a promising biomarker in IC/BPS. It may help clinicians in diagnoses and patient follow-up. Thus, unnecessary, expensive and invasive tests, interventions and treatments might be avoided. PMID- 29521058 TI - Splenectomy delays fracture healing by affecting the level of tumor necrosis factor alpha, interleukin 6 and bone morphogenetic protein. AB - BACKGROUND: Abdominal injuries combined with bone fractures are increasing. Splenectomies are often required, but have prolonged healing time for bone fracture. OBJECTIVES: The aim of the study was to explore the molecular mechanism for splenectomy delaying fracture healing. MATERIAL AND METHODS: Eighty-four patients (42 received splenectomy) who received hip fractures operations were recruited in our hospital. One-year follow-up analysis was performed. To ensure the results, an animal model was established. Sprague-Dawley (SD) rats were randomly divided into 5 groups: group A: experimental group, femoral fractures + splenectomy; group B: femoral fractures; group C: splenectomy; group D: femoral fracture + sham splenectomy; group E: sham fracture. After the femoral fracture surgery, the callus status was evaluated by X-ray. RESULTS: After 1-year follow up, the healing index and bone quality was higher in the fracture-operatedonly group than in the splenectomy group. In contrast, the rate of healing complications was lower in the fracture-operated-only group than in the splenectomy group. Biomarker analysis showed that the serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and bone morphogenetic protein (BMP) were higher in the fracture-operated-only group than in the splenectomy group. No difference of the callus status was found among the rats in groups B, D and E (p > 0.05), while there were significant differences of the callus status of the rats in groups A and C at different stages (p < 0.05). On the other hand, the levels of TNF-alpha, IL-6 and BMP increased, reached peak after 7-day splenectomy surgery, and then decreased significantly in groups A and C (p > 0.05). CONCLUSIONS: Splenectomy delays fracture healing by affecting the levels of TNF-alpha, IL-6 and BMP. PMID- 29521059 TI - IL-4RA gene expression in PBMC with regard to place of living and atopy status. AB - BACKGROUND: IL-4 and IL-4RA are key factors in allergic inflammation. IL-4 stimulates both IgE production and Th2 lymphocyte differentiation. Increased levels of IL-4 and IL-4RA have been shown in allergic patients. Genetic analyses have confirmed that polymorphisms within the IL-4RA gene influence the risk of allergy and can change the expression of the protein. Due to gene-environment interactions, this process is also likely to be modified by environmental exposure. OBJECTIVES: The aim of the study was to evaluate the IL-4RA gene expression in peripheral blood mononuclear cells (PBMC) from atopic and non atopic subjects with regard to place of living (urban vs rural). MATERIAL AND METHODS: We enrolled 38 subjects into the study, 18 of whom were atopic. Atopy was estimated according to the results of a skin prick test. PBMC were isolated from whole blood, total RNA was extracted and reverse transcribed into cDNA. We performed real-time PCR to measure gene expression, the ACTB gene was chosen as a reference and the delta-delta Ct (DeltaDeltaCT) method was applied for relative quantification. The Mann-Whitney U test was used for statistics. RESULTS: We did not observe any statistically significant differences in the gene expression profile between atopic and non-atopic subjects regardless of their place of living. However, a trend was observed for atopic rural inhabitants to have lower levels of IL-4RA gene expression than atopic subjects living in the town. CONCLUSIONS: The regulation of IL-4RA gene expression is complex and probably influenced by both genetic and environmental factors, such as farming exposures, which could provide the counterbalance to atopy. PMID- 29521060 TI - Analysis of prevalence of selected anamnestic factors among women with pelvic organ prolapse. AB - BACKGROUND: Pelvic organ prolapse is the most frequent medical condition in women in the postmenopausal age. The pathophysiology is multifactorial. OBJECTIVES: The purpose of this paper was to analyze the prevalence of selected anamnestic factors in the population of women treated due to pelvic organ prolapse in the 2nd Department and Clinic of Obstetrics and Gynecology Wroclaw Medical University (Poland). MATERIAL AND METHODS: A total of 104 medical histories of women treated in the 2nd Department and Clinic of Obstetrics and Gynecology in the years 2012 2013 due to pelvic organ prolapse were analyzed. RESULTS: The most frequent type of defect was the complex defect concerning both cystocele and rectocele. Intensity of dysfunctions was determined by age, obstetric history (parity, newborn's body mass and process of labor), and woman's constitutional characteristic (her BMI and height). A comparison based on the type of defect revealed no differences between the groups except for BMI, which was the highest in the rectocele group (31.15 +/-5.84; p = 0.0069). CONCLUSIONS: The multifactorial ethology and differential clinical presentation including several types of this defect make this disorder difficult to prevent and treat. The obtained results confirm that there exists a relation between the data from the medical history and the prevalence of pelvic organ prolapse. Anamnesis can be useful when predicting prevalence and, in the future, may even help to decrease the prevalence of this type of disorder. PMID- 29521061 TI - Oxidative stress markers predict early left ventricular systolic dysfunction after acute myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: Despite successful primary percutaneous coronary intervention (PCI) after ST-segment elevation myocardial infarction (STEMI), some patients develop left ventricular systolic dysfunction (LVSD) and acute heart failure (HF). Identifying patients with an increased risk of developing LVSD by means of biomarkers may help select patients requiring more aggressive therapy. OBJECTIVES: The aim of this study was to evaluate the relationship between the levels of oxidative stress markers and development of LVSD and acute HF early after STEMI. MATERIAL AND METHODS: The study enrolled 148 patients with the first STEMI, who were treated by primary PCI < 12 h from the onset of symptoms. We assessed the impact of different biomarkers for developing LVSD and acute HF (Killip >= 2) including: markers of necrosis - peak creatine kinase (CK), markers of myocardial stretch - B-type natriuretic peptide (BNP), inflammatory markers - C-reactive protein (CRP), leucocyte and neutrophil count, as well as oxidative stress markers - total thiol groups, catalase, superoxide dismutase (SOD) and glutathione reductase (GR). RESULTS: In multivariate analysis, thiol groups, peak CK, anterior wall infarction, and age were predictors of LVEF <= 40%. Out of 16 variables significantly associated with the Killip >= 2 in univariate logistic regression analysis, 5 appeared to be independently associated with acute HF in multivariate analysis: catalase, BNP, leucocytes, neutrophil count, and size of left atrium. CONCLUSIONS: In this study, we have shown for the first time that thiol groups and catalase are independent predictors of STEMI complication - LVSD and acute HF, respectively. Beside routine used biomarkers of necrosis and myocardial stretch, thiol groups and catalase may provide additional information regarding the risk stratification. PMID- 29521062 TI - Temporomandibular disorders in adolescents with headache. AB - BACKGROUND: Headache is a common complaint in all age groups and is a frequent cause of medical consultations and hospitalization. OBJECTIVES: The aim of this study was to evaluate the prevalence of bite and non-bite parafunctions as well as the signs and symptoms of temporomandibular disorder (TMD) in adolescents presenting with primary headaches. MATERIAL AND METHODS: Parents of adolescents presented with headaches to the Department of Developmental Neurology within a 12 month period were asked to complete a questionnaire developed by the authors of this study. Of the 1000 patients evaluated, 19 females and 21 males, aged 13 to 17 years, met the inclusion criterion - a confirmed clinical diagnosis of migraine or a tension headache according to the International Classification of Headache Disorders, 2nd edition. The diagnostic algorithm of the study group consisted of a full medical history, an assessment of the occurrence of bite habits and a physical examination based on the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). RESULTS: Bite and non-bite parafunctions were found in 36 of the study group patients. A significant difference (p = 0.0003) between the number of bite parafunctions and non-bite parafunctions was found in females but not in males. However, bite parafunctions were more frequent in boys compared to girls (p = 0.01). CONCLUSIONS: Our findings suggest that it may be useful for pediatricians and neurologists to include TMD dysfunctions as a part of a standard examination of adolescents presenting with persistent headaches. PMID- 29521063 TI - Morphometric study of the triangle of Petit in human fetuses. AB - BACKGROUND: The inferior lumbar triangle of Petit is bounded by the iliac crest, lateral border of the latissimus dorsi and the medial border of the external oblique. OBJECTIVES: In the present study, we aimed to quantitatively examine the base, sides, area, and interior angles of the inferior lumbar triangle in the human fetus so as to provide their growth dynamics. MATERIAL AND METHODS: Using anatomical dissection, digital image analysis (NIS-Elements AR 3.0), and statistics (Student's t-test, regression analysis), we measured the base, 2 sides, area and interior angles of Petit's triangle in 35 fetuses of both sexes (16 male, 19 female) aged 14-24 weeks. RESULTS: Neither sex nor laterality differences were found. All the parameters studied increased commensurately with age. The linear functions were computed as follows: y = -0.427 + 0.302 * age for base, y = 1.386 + 0.278 * age for medial side, y = 0.871 + 0.323 * age for lateral side, and y = -13.230 + 1.590 * age for area of the Petit triangle. CONCLUSIONS: In terms of geometry, Petit triangle reveals neither male-female nor right-left differences. An increase in both lengths and area of the inferior lumbar triangle follows proportionately. The Petit triangle is an acute one in the human fetus. PMID- 29521064 TI - The effect of high intensity physical exercise and hypoxia on glycemia, angiogenic biomarkers and cardiorespiratory function in patients with type 1 diabetes. AB - BACKGROUND: An integral part of the treatment of diabetes is physical activity. Scientific reports have shown the beneficial effects of hypoxia and exercise on cardiovascular and metabolic variables in patients with diabetes. OBJECTIVES: The aim of the study was to assess the effect of normobaric hypoxia and exercise on the serum concentrations of proangiogenic factors and glycemia in patients with type 1 diabetes. MATERIAL AND METHODS: A total of 28 adults (aged 30.4 years +/ 9.7 years), suffering from diabetes for 12.1 years +/-6.0 years and healthy individuals, participated in the following trials: normoxic (Nor) and hypoxic (Hy) rest and Nor and Hy incremental exercise test (Ex) (FIO2 = 15.2%). The Altitude Trainer Hypoxico System (HYP-123 Hypoxic Generator, LOWOXYGEN Technology GmbH, Berlin, Germany) corresponding to a height of about 2500 m above sea level was used in the study. Exercise tests were performed on a cycle ergometer Excalibur Sport (Lode B.V., Groningen, The Netherlands). Cardiorespiratory variables, glycemia, angiogenic and hematological indices were measured at rest and in response to both exercise protocols. RESULTS: The present data confirmed that the patients with type 1 diabetes demonstrated a good level of aerobic capacity and fitness. NorEx and HyEx resulted in a significant decrease in serum glucose concentration (p < 0.05 vs p < 0.01). Patients with diabetes had higher baseline hypoxia induced factor-1alpha levels compared to healthy adults (p < 0.05), which increased after exposure to hypoxia and hypoxia with exercise (p < 0.001). Hypoxia significantly decreased baseline transforming growth factor-beta (TGF-beta) (p < 0.05) and had a significant effect on tumor necrosis factor-alpha level (TNF-alpha) (F = 4.9; p < 0.05). CONCLUSIONS: Our study demonstrated that hypoxia combined with exercise reduces glycemia and may induce significant benefits in the prevention of diabetes cardiovascular complications. PMID- 29521065 TI - Nutrient intake assessed with Diet History Questionnaire II, in relation to long term calcium-phosphate control in hemodialysis patients with end-stage renal failure. AB - BACKGROUND: Diet is a key factor that determines proper alignment of calcium phosphate and nutritional status among hemodialysis (HD) patients. OBJECTIVES: To assess the nutrient intake in relation to long-term calcium-phosphate control in HD patients with end-stage renal failure. MATERIAL AND METHODS: The study included 107 patients (66 men, 41 women) from 10 dialysis centers in the Upper Silesia region of Poland. To analyze the diet composition during the previous year, a portion-sized version of the Diet History Questionnaire II (DHQ-II) from National Institutes of Health was used. The nutrient intake was assessed in accordance with the most complex recommendations on HD patients' nutrition - K/DOQI Clinical Practice Guidelines for nutrition in chronic renal failure. Poor long-term alignment of calcium-phosphate homeostasis was defined as the presence of over 50% monthly phosphorus concentrations exceeding 5 mg/dL, and for calcium 10.2 mg/dL, during the last 6-month period. RESULTS: Lower than recommended protein intake was found in 63% of HD patients (average consumption: 0.9 +/-0.5 g/kg/day). Most of the patients consumed too much fat (33.5 +/-6.7% of daily energy intake) and sodium (2912 +/-1542 mg/day). In 42% of patients, dietary phosphorus intake was consistent with the recommendations (13.3 +/-7.5 mg/kg/day). Protein intake over 1.2 g/kg/day resulted in an increased consumption of phosphorous, but did not increase the risk of misalignment of phosphorus concentrations (OR = 1.15 [0.40-3.27]); p = 0.8). Poor control of serum phosphorus concentrations was observed in 69% of patients (they were on average 8 years younger). The average intake of protein and phosphate in the groups with good or not satisfactory serum phosphorus alignment did not differ significantly. CONCLUSIONS: Adequate control of protein intake is not sufficient to obtain phosphorus alignment, especially in younger HD patients. PMID- 29521066 TI - New predictor of acute necrotizing pancreatitis: Red cell distribution width. AB - BACKGROUND: Acute pancreatitis (AP) is inflammation of the pancreas of various severity ranging from mild abdominal pain to mortality. AP may be classified as acute interstitial edematous pancreatitis (AEP) or acute necrotizing pancreatitis (ANP), according to the revised Atlanta criteria. Most of the patients with AP are AEP (75-85% of patients), while 15-25% of patients have ANP. The mortality rate is 3% in AEP and 15% in ANP. Thus, it is important to predict the severity of AP to decrease the morbidity and mortality. OBJECTIVES: The aim of the study was to evaluate the relationship between red cell distribution width (RDW) and the severity of AP on admission to hospital. MATERIAL AND METHODS: Patients admitted to Adana Numune Research and Educational Hospital with a diagnosis of AP through the time frame of January 2014-May 2016 were included in our study. Diagnosis of AP was made according to the revised Atlanta classification. Patients' age, sex, etiology of AP, and RDW values were recorded on admission to the hospital. RESULTS: A total of 180 patients were included in the study. Eighty patients (44%) were male and 100 patients were female. Mean age was 56.25 +/-18.3 years (52.66 +/-14.4 in males; 59.84 +/-20.2 in females). There was no statistically significant difference between patients' age. The most frequently observed etiologic factor was gallstone disease followed by alcohol intake and the use of pharmaceuticals. Drug-related AP was associated with azathioprine, furosemide, and thiazide diuretics. One hundred forty-four (80%) patients had AEP and 36 (20%) patients had ANP. RDW values showed a statistically significant difference between patients with AEP and ANP (p = 0.011). The cut-off value of RDW was 16.4 and the area under curve (AUC) value was 0.591 (p = 0.0227) with a sensitivity of 29.2% and specificity of 89.83%. CONCLUSIONS: Red cell distribution width could be used to evaluate the prognosis of acute pancreatitis. PMID- 29521067 TI - Social and medical determinants of quality of life and life satisfaction in women with Turner syndrome. AB - BACKGROUND: Turner syndrome (TS) appears in women as a result of the lack of part or the whole of one of the X chromosomes. It is characterized by the occurrence of low height, hypogonadism, numerous developmental defects, and is often accompanied by psychological disturbances. OBJECTIVES: Although the phenotype characteristics of women with TS are quite well documented, the knowledge of the impact of Turner syndrome on the satisfaction with life is still insufficient. The aim of our study was to assess the impact of TS on selected variables of quality of life, and hence also life satisfaction in women with this syndrome. MATERIAL AND METHODS: The research was carried out in a group of 176 women with TS starting March 1995. The patients underwent anthropological and medical examinations, and their medical histories were taken using a questionnaire that included demographic and psychosocial items as well as issues related to selected variables of quality of life. In our research model, general life satisfaction was a dependent variable. The statistical analysis was conducted using the eta and Cramer's V correlation coefficients as well as a multidimensional logistic regression model. RESULTS: The main determinants of dissatisfaction with life in women with TS were short stature and feelings of loneliness and being handicapped. CONCLUSIONS: The determinants of life satisfaction in women with Turner syndrome were closely related to the private life of the study participants, in particular self-perception and feelings concerning their health status. PMID- 29521068 TI - Real-life use of thromboprophylaxis in patients hospitalized for pulmonary disorders: A single-center retrospective study. AB - BACKGROUND: Underuse of thromboprophylaxis in hospitalized medical patients is still common worldwide. Little is known about the use of thromboprophylaxis in patients with pulmonary diseases in everyday hospital practice. OBJECTIVES: The aim of this study was to assess the use of pharmacological prophylaxis of venous thromboembolism (VTE) in real-life patients with pulmonary diseases. MATERIAL AND METHODS: In this retrospective study, 2 validated scoring systems, i.e., the Padua prediction score and Caprini VTE risk assessment, were used to assess the VTE risk in 2011 patients (1133 men and 878 women), aged 18 years or more, hospitalized for pulmonary diseases (median 6 days) in a single tertiary pulmonary medical center from January to December 2014. RESULTS: Using the Padua prediction score, we identified 428 (21.28%) patients at a high risk for VTE, including 167 (39.01%) who received thromboprophylaxis with low-molecular-weight heparin, and 261 (60.98%) individuals at a high risk without thromboprophylaxis (p < 0.001). A total of 888 (44.16%) patients who scored 5 points or more using the Caprini VTE risk assessment were identified as subjects at a high risk for VTE, including 34.79% of patients receiving thromboprophylaxis. From among patients at a high risk for VTE, 579 (65.20%) did not receive appropriate thromboprophylaxis (p < 0.001). Underuse of thromboprophylaxis was observed more commonly among patients hospitalized for lung cancer or pneumonia (50.60% and 24.87% of patients at a high risk for VTE without prophylaxis, respectively). CONCLUSIONS: Thromboprophylaxis is underutilized in hospitalized patients with pulmonary diseases regardless of the scoring system used. Implementation of thromboprophylaxis should be markedly improved in this patient group. PMID- 29521069 TI - Selenium - a fascinating antioxidant of protective properties. AB - Selenium is a trace element which fulfils important functions in the organism. Its deficit may cause acute disorders, but an overdose can also lead to severe consequences. The functions of selenium in the organism are mainly connected with its antioxidant properties, as it is an essential part of important antioxidant enzymes. Disturbances of oxidant balance have been found to be involved in the activity of numerous harmful factors as well as in the pathogenesis of diverse illnesses. Selenium administration has proved to be effective against the toxicity of many agents and the side effects of drugs. However, the narrow range between therapeutic and toxic doses of selenium, as well as the dependence of its effect on the applied form, dose and method of treatment, makes the choice of the most effective supplement a very complex issue. Divergent forms of selenium are still being studied, including both inorganic and organic compounds as well as Se enriched natural products. The newest research has also involved selenium nanoparticles. The aim of this review is to present the great potential of selenium for protecting the organism against a wide variety of environmental pollutants, drugs and physical factors. PMID- 29521070 TI - Non-suicidal self-injury (NSSI) and suicidal: Criteria differentiation. AB - There are 2 types of basic self-destructive behavior: suicide and non-suicidal self-injury (NSSI). Currently, more and more researchers point out significant disorders which are NSSI behavior. This phenomenon is not new; NSSI seemingly has always been present in society, and certainly in approx. 10% of the population worldwide in recent times. Despite the enormous scale of the phenomenon, so far it has been overlooked and marginalized. They were considered transient behavior, typical of adolescence, a part of youthful rebellion. Current research indicates that the disorder affects the adult population in almost equal measure. It is only in the latest diagnostic classification - Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) by American Psychiatric Association - that has considered NSSI a separate class of behavior. Up to now, it was classified as a prelude to suicide or an element of personality disorders. NSSI is more commonly associated with disturbing behavior and suicide attempts. PMID- 29521071 TI - Role of miR-181a in the process of apoptosis of multiple malignant tumors: A literature review. AB - It has been recognized that miR-181a expression is dysregulated and intimately associated with clinical prognosis in a variety of human cancers. However, the direct role of miR-181a in tumor progression has been elusive. Moreover, mounting evidence has demonstrated that cellular apoptosis, a physiological process of programmed cell death, is disrupted in various categories of human malignancies. Multiple apoptosisrelated genes have been proven to act as the target genes of miR-181a. In this study, we hypothesize that miR-181a probably plays a potential role in modulating the procession and apoptosis of cancer cells. We performed a literature review and elucidated how miR-181a modulated cellular apoptosis, especially the malignant neoplasm cells. We also unraveled the potential role of miR-181a in the diagnosis, treatment and clinical prognosis of multiple human malignancies - miR-181a plays a pivotal role in the development, treatment and prognosis of patients suffering from malignant tumors. It also participates in the development of cancer partially by modulating cellular apoptosis. PMID- 29521072 TI - The role of hypoxia-inducible factors in leukemias. AB - Hypoxia, understood as low partial oxygen pressure, has become one of the most explored fields in recent years. Cellular response to hypoxia is mediated by hypoxia-inducible factors (HIFs) - potent transcription regulators, and their downstream pathways. In general, HIFs modify energy metabolism, inflammation and immune response, enhance cancer invasion, metastasis, resistance to treatment, and relapse. The influence of HIFs on the progression of leukemia is still under investigation in various studies, but in mice and some human models HIFs have been recognized as leukemia immortalizers by promoting leukemic stem cell quiescence and inhibiting their cell cycle. This makes leukemic stem cells resistant to most known treatment approaches. The role of HIFs in solid tumors and leukemia makes them almost ideal targets for an anticancer treatment. Although the first attempts with new molecules are encouraging, there is a need to investigate the ambiguous role of HIFs to develop a modern antileukemic treatment. PMID- 29521073 TI - Telemedicine and eHealth in Poland from 1995 to 2015. AB - The aim of this study is to present a review based on the literature and proceedings from selected telemedicine conferences. The review was developed using the PRISMA framework. The Embase and PubMed (updated until July 13, 2015) literature databases were searched for telemedicine-related terms and Poland. The literature search identified 129 eligible articles in the databases and 85 in conference proceedings until July 2015. Articles measured as a number of contributions per year presented a similar rising, fluctuating and almost parallel pattern. Fifty-nine percent of the reviewed papers were published in impacted journals. Almost half of all publications presented original papers. The published articles concerned mostly cardiology (16%), family medicine (15%) and pathology (11%). Conference proceedings papers concerned orthopedics (29%, significantly more frequent; p < 0.001) and cardiology (14%). Scientific activity of researchers and practitioners in Poland in the field of telemedicine is not high, but it is increasing over time. There is a tendency to present the research rather in high-quality journals instead of conferences before publication. The occurrence of individual medical specialty telemedicine in Poland may reflect country-specific needs. PMID- 29521074 TI - Thromboprophylaxis in cancer patients in hospice. AB - Advanced cancer patients in hospice are at notably increased risk of venous thromboembolism (VTE) due to age, local and distal advancement of the malignancy and bed confinement, among other factors. Asymptomatic VTE prevalence among palliative care patients has been found to reach 50%, whereas the clinically overt form occurs in 10%. Hospice patients are frequently given medications increasing VTE risk, for instance megestrol which is a drug commonly used in cancer cachexia. Many of the available guidelines encourage the implementation of thromboprophylaxis (TPX) in cancer patients, e.g., in the perioperative period or over the course of chemotherapy. However, concerning patients remaining under hospice care where the priority goal is not life extension but assurance of the best possible quality of life (QoL), the main benefit from the TPX would be a decrease in the risk of symptom burden associated with VTE, i.e., pain, edema or dyspnea. Nevertheless, studies performed on a sufficiently large study group, which could unequivocally determine the influence of anticoagulation on VTE symptom burden in hospice patients, are still lacking. VTE prophylaxis is challenging for many reasons: its unknown effect on QoL, vague risk of its discontinuation, and risk of bleeding complications which is additionally increased in conditions prevalent in hospice population, i.e., malnutrition, renal or liver insufficiency. So far, most of the guidelines issued by oncological societies do not precisely refer to the problem of TPX in hospice patients. Therefore, the decisions on the implementation of anticoagulation should be taken individually, with previous assessment of VTE risk, comorbidities and possible hemorrhagic complications. PMID- 29521075 TI - The importance of antiangiogenic effect in multiple myeloma treatment. AB - Angiogenesis plays a significant role in oncogenesis, and thus it has become an attractive target for cancer treatment. It is the formation of new blood vessels that occurs physiologically as well as under pathological conditions, and may influence cancer proliferation and survival. The current therapeutic approach in oncology includes conventional chemotherapy in combination with biologically based treatment in various perspectives, targeting not only the malignant cells, but also its microenvironment. Target treatment might be less toxic than conventional chemotherapy. In multiple myeloma, there is a close connection between bone marrow stroma, myeloma cell growth and their ability to survive. It has been reported in many clinical observations that the more advanced the multiple myeloma, the more increased the angiogenesis, and this might correlate with the treatment response. There are several angiogenesis inhibitors already registered or in clinical trials in cancer treatment. Despite the continuous research on the development of prognostic factors and introduction of new agents in the treatment, multiple myeloma still remains an incurable and debilitating disease. Some antiangiogenic agents have already been introduced in multiple myeloma treatment, but there is still a need to search for new antiangiogenic drugs and the exploitation of angiogenesis in a clinical approach. PMID- 29521076 TI - Special Section on Selected Topics in Biophotonics: Optogenetics and Label-Free Optical Spectroscopy (Publisher's Note). AB - This publisher's note explains the change in citation data for 3 articles. PMID- 29521077 TI - Prudent healthcare in emergency departments: a case study in Wales. AB - To deliver a patient-centred service, emergency departments (EDs) must be efficient, effective and meet the needs of the local population. This article describes a service redesign of unscheduled care in a hospital in Wales, which followed the principles of prudent healthcare to improve patient experiences. Extending the roles of nurse specialist practitioners was a major component of the redesign. Six working groups were established to guide the process, one of which was responsible for working cooperatively with the local community, which was concerned about perceived 'downgrading' of the ED. The service redesign was completed in 2016 and evaluation shows the target for patients being seen in under four hours improved from 88% to 96%, significantly more acute medical admission patients were discharged in less than 24 hours, and patient satisfaction increased overall. PMID- 29521079 TI - Advanced nurse practitioner scheduled return clinic: a clinical audit of a quality initiative. AB - Emergency care settings in Ireland have struggled with a high volume of service users in recent years. This nationwide crisis led to the establishment of the National Emergency Medicine Programme Strategy in 2012, which identified two key performance indicators for efficiency in emergency care: the patient experience time, which should not exceed six hours from the time of registration to the time of discharge; and patients who do not wait for treatment (DNW) should make up less than 5% of those attending emergency care services. This article explores a quality initiative to improve DNW rates using scheduled return clinics, implemented by a group of advanced nurse practitioners in an emergency department in a Dublin hospital. It reviews the literature on scheduled return clinics and discusses the rationale for the initiative, its implementation, barriers to its introduction and an audit of its effectiveness. PMID- 29521078 TI - Recognition and nursing management of children with non-traumatic limp. AB - Children with acute onset non-traumatic limp often present to emergency departments (EDs). The limp can occasionally be associated with medical emergencies such as septic arthritis and slipped upper femoral epiphysis but is often due to less severe conditions. This article discusses the common and self limiting causes of acute onset of non-traumatic limp in children, such as transient synovitis, reactive arthritis, and benign acute childhood myositis. It also discusses more severe conditions, including septic arthritis, osteomyelitis, slipped upper femoral epiphysis, Perthes disease, malignancies and non-accidental injury. Management and prognosis of these conditions are discussed in the context of guidance from the National Institute for Health and Care Excellence. The article includes two case studies that illustrate different presentations and the challenges that nurses who manage children in EDs are likely to come across in clinical practice. PMID- 29521080 TI - Concussion in sport: the importance of accurate and reliable discharge advice. AB - Concussion in sport is a common presentation in urgent and emergency care settings, so it is essential that nurses have a full understanding of the condition. Most patients who attend an emergency department with concussion are discharged and discharge advice must be well-informed and evidence based. This article outlines the normal anatomy of the brain and the pathophysiology of concussion, and discusses the guidelines on returning to sport following this injury. PMID- 29521081 TI - Delivering at the country level: the International Coordinating Group on Vaccine Provision and its impact in 2016 and 2017. PMID- 29521082 TI - Above-Band Gap Photoinduced Stabilization of Engineered Ferroelectric Domains. AB - The effect of above-band gap photons on the domains of the BiFeO3 (BFO) thin film was investigated via piezoresponse force microscopy and Kelvin probe force microscopy. It is found that under above-band gap illumination, the relaxation time of the polarization state was significantly extended, while the effective polarizing voltage for the pristine domains was reduced. We propose that this photoinduced domain stabilization can be attributed to the interaction between photogenerated surface charges and domains. Importantly, a similar phenomenon is observed in other ferroelectric (FE) materials with an internal electric field once they are illuminated by above-band gap light, indicating that this photoinduced stabilization is potentially universal rather than specific to BFO. Thus, this study will not only contribute to the knowledge of photovoltaic (PV) phenomena but also provide a new route to promote the stability of PV and FE materials. PMID- 29521083 TI - Quinoxaline-Containing Nonfullerene Small-Molecule Acceptors with a Linear A2-A1 D-A1-A2 Skeleton for Poly(3-hexylthiophene)-Based Organic Solar Cells. AB - We used the quinoxaline (Qx) unit to design and synthesize two nonfullerene small molecule acceptors of Qx1 and Qx1b with an A2-A1-D-A1-A2 skeleton, where indacenodithiophene (IDT), Qx, and rhodanine (R) were adopted as the central donor (D), bridge acceptors (A1), and terminal acceptors (A2), respectively. Qx1 and Qx1b contain different side chains of 4-hexylphenyl and octyl in the central IDT segment to modulate the properties of final small molecules. Both small molecules show good thermal stability, high solubility, and strong and broad absorption spectra with optical band gaps of 1.74 and 1.68 eV, respectively. Qx1 and Qx1b exhibit the complementary absorption spectra with the classic poly(3 hexylthiophene) (P3HT) and the high-lying lowest unoccupied molecular orbital energy levels of -3.60 and -3.66 eV, respectively. Polymer solar cells based on P3HT:Qx1 showed a high open-circuit voltage ( Voc) of 1.00 V and a power conversion efficiency (PCE) of 4.03%, whereas P3HT:Qx1b achieved a Voc of 0.95 V and a PCE of 4.81%. These results demonstrate that the Qx unit is also an effective building block to construct promising n-type nonfullerene small molecules to realize a relatively high Voc and PCE for P3HT-based solar cells. PMID- 29521084 TI - Novel Engineered Microgels with Amphipathic Network Structures for Simultaneous Tumor and Inflammation Depression. AB - Novel engineered microgels with amphipathic network structures were designed and synthesized by copolymerizing N-isopropylacrylamide, 1-vinylimidazole, and 2 (cinnamoyloxy)ethyl methacrylate in the presence of 1,6-dibromohexane. The engineered microgels possess hydrophilic quaternization cross-linking structures and hydrophobic cross-linking inner nanodomains, which are suitable for loading and simultaneous release of hydrophilic nonsteroidal anti-inflammatory drug diclofenac sodium (DS) and hydrophobic antic cancer drug doxorubicin (DOX), respectively. The engineered microgels exhibited excellent stability, low cytotoxicity, and long blood circulation time and could be uptaken into the cytoplasm of cells, metabolized, and excreted from the living body by the kidney and the liver. In vivo experiments showed that with injection of DS and DOX dual drug-loaded microgels, simultaneous antitumor treatment and inflammation depression were achieved along with high antitumor efficacy and low drug-related toxicity. Such microgels with amphipathic network structures have promising applications for combination therapy. PMID- 29521085 TI - Impact of Sampling and Cellular Separation on Amino Acid Determinations in Drosophila Hemolymph. AB - The fruit fly is a frequently used model system with a high degree of human disease-related genetic homology. The quantitative chemical analysis of fruit fly tissues and hemolymph uniquely brings chemical signaling and compositional information to fly experimentation. The work here explores the impact of measured chemical content of hemolymph with three aspects of sample collection and preparation. Cellular content of hemolymph was quantitated and removed to determine hemolymph composition changes for seven primary amine analytes. Hemolymph sampling methods were adapted to determine differences in primary amine composition of hemolymph collected from the head, antenna, and abdomen. Also, three types of anesthesia were employed with hemolymph collection to quantitate effects on measured amino acid content. Cell content was found to be 45.4 +/- 22.1 cells/nL of hemolymph collected from both adult and larvae flies. Cell concentrated fractions of adult, but not larvae, hemolymph were found to have higher and more variable amine content. There were amino acid content differences found between all three areas indicating a robust method to characterize chemical markers from specific regions of a fly, and these appear related to physiological activity. Methods of anesthesia have an impact on hemolymph amino acid composition related to overall physiological impact to fly including higher amino acid content variability and oxygen deprivation effects. Together, these analyses identify potential complications with Drosophila hemolymph analysis and opportunities for future studies to relate hemolymph content with model physiological activity. PMID- 29521086 TI - From Broadband to Electrochromic Notch Filters with Printed Monochiral Carbon Nanotubes. AB - Dense layers of semiconducting single-walled carbon nanotubes (SWNTs) serve as electrochromic (EC) materials in the near-infrared with high optical density and high conductivity. EC cells with tunable notch filter properties instead of broadband absorption are created via highly selective dispersion of specific semiconducting SWNTs through polymer-wrapping followed by deposition of thick films by aerosol-jet printing. A simple planar geometry with spray-coated mixed SWNTs as the counter electrode renders transparent metal oxides redundant and facilitates complete bleaching within a few seconds through iongel electrolytes with high ionic conductivities. Monochiral (6,5) SWNT films as working electrodes exhibit a narrow absorption band at 997 nm (full width at half-maximum of 55-73 nm) with voltage-dependent optical densities between 0.2 and 4.5 and a modulation depth of up to 43 dB. These (6,5) SWNT notch filters can retain more than 95% of maximum bleaching for several hours under open-circuit conditions. In addition, different levels of transmission can be set by applying constant low voltage (1.5 V) pulses with modulated width or by a given number of fixed short pulses. PMID- 29521087 TI - Magnetic Submicron Mullite Coatings with Oriented SiC Whiskers. AB - Addressing the challenge of making ceramic thin films with the in-plane-oriented nanorods, we propose to decorate the nanorods with magnetic nanoparticles and orient them using the external magnetic field. As an illustration, the mullite thin films with embedded and oriented SiC nanorods were synthesized. The SiC nanorods were decorated with the Fe3O4 nanoparticles. A two-step processing route was developed when the nanorods are first oriented in a sacrificial polymer layer. Then, the polymer film with the aligned nanorods was removed by heat treatment. In the second step, a sol-gel/dip-coating method was applied to produce the mullite composite film. The main challenge was to guarantee that all of the nanorods that were initially randomly distributed in the polymer would have time to rotate toward the field direction before complete solidification of the sacrificial layer. Theoretical and experimental analyses of the orientational distribution of the nanorod axes were conducted to identify a relationship between the polymer viscosity and processing parameters of the system. In contrast to the ferromagnetic nanorods, the rate of rotation of paramagnetic nanorods and their time of alignment are more sensitive to the magnetic field. This methodology allows manufacturing of different ceramic films with aligned nanorods and making nonmagnetic ceramic coating magnetic. PMID- 29521088 TI - Direct Detection of the Terminal Hydride Intermediate in [FeFe] Hydrogenase by NMR Spectroscopy. AB - Hydride state intermediates are known to occur in various hydrogen conversion enzymes, including the highly efficient [FeFe] hydrogenases. The intermediate state involving a terminal iron-bound hydride has been recognized as crucial for the catalytic mechanism, but its occurrence has up to now eluded unequivocal proof under (near) physiological conditions. Here we show that the terminal hydride in the [FeFe] hydrogenase from Chlamydomonas reinhardtii can be directly detected using solution 1H NMR spectroscopy at room temperature, opening new avenues for detailed in situ investigations under catalytic conditions. PMID- 29521089 TI - Fungal Spores Promote the Glycerol Production of Saccharomyces cerevisiae by Upregulating the Oxidative Balance Pathway. AB - Fungal contamination is prevalent in grape berries and unavoidable during the winemaking process. In botrytized wine, Botrytis cinerea contamination of grape berries beneficially promotes the wine flavor, which is desirable especially with high glycerol content. To investigate the underlying mechanism, Aspergillus carbonarius and B. cinerea spores were separately cocultured with two different Saccharomyces cerevisiae strains in both grape juice and synthetic nutrient media. The results showed that both A. carbonarius and B. cinerea promoted glycerol accumulation and the consumption of sugars in the coculture systems but could not synthesize glycerol by themselves. The metabolites produced by fungal spores triggered these reactions. Reverse transcription-polymerase chain reaction analysis showed that the presence of A. carbonarius spores regulated the expression of GPP1 and GPD2, indicating that the reaction was triggered by regulating the oxidative balance pathway. The study revealed the beneficial impact of fungal contamination on wine quality by influencing yeast metabolism. PMID- 29521090 TI - Quantitative Structure-Activity Relationship Modeling Coupled with Molecular Docking Analysis in Screening of Angiotensin I-Converting Enzyme Inhibitory Peptides from Qula Casein Hydrolysates Obtained by Two-Enzyme Combination Hydrolysis. AB - In this study, Qula casein derived from yak milk casein was hydrolyzed using a two-enzyme combination approach, and high angiotensin I-converting enzyme (ACE) inhibitory activity peptides were screened by quantitative structure-activity relationship (QSAR) modeling integrated with molecular docking analysis. Hydrolysates (<3 kDa) derived from combinations of thermolysin + alcalase and thermolysin + proteinase K demonstrated high ACE inhibitory activities. Peptide sequences in hydrolysates derived from these two combinations were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). On the basis of the QSAR modeling prediction, a total of 16 peptides were selected for molecular docking analysis. The docking study revealed that four of the peptides (KFPQY, MPFPKYP, MFPPQ, and QWQVL) bound the active site of ACE. These four novel peptides were chemically synthesized, and their IC50 was determined. Among these peptides, KFPQY showed the highest ACE inhibitory activity (IC50 = 12.37 +/- 0.43 MUM). Our study indicated that Qula casein presents an excellent source to produce ACE inhibitory peptides. PMID- 29521091 TI - Diboryne Nanostructures Stabilized by Multitopic N-Heterocyclic Carbenes: A Computational Study. AB - Different families of nanomaterials produced from the stabilization of diboryne (B=B) units by multitopic N-heterocyclic carbenes (NHCs), such as nanowires, nanorings, and nanotents, were studied by computational methods. Density functional theory calculations with and without periodic boundary conditions were applied to estimate the dependence of the electronic and thermochemical properties of different diboryne macromolecules with respect to the nature of the bridging ligand. Our results show that all diboryne nanostructures studied herein are viable candidates for synthesis. The Janus-type multitopic naphthobis(imidazolylidene) (5), anthrobis(imidazolylidene) (10), and pyracenetetrakis(imidazolylidene) (16) compounds are the best candidates for generating diboryne nanowires. A path to covalent organic frameworks, nanocages, and nanotubes from the optimized diboryne nanostructures is also described. Rather than just scientific curiosity, diboryne nanostructures emerge as interesting targets for the synthesis of main-group nanomaterials. PMID- 29521092 TI - Designed Synthesis of Mesoporous Solid-Supported Lewis Acid-Base Pairs and Their CO2 Adsorption Behaviors. AB - Conventional amines and phosphines, such as diethylenetriamine, diphenylpropylphosphine, triethylamine, and tetramethylpiperidine, were grafted or impregnated on the surface of metalated SBA-15 materials, such as Ti-, Al-, and Zr-SBA-15, to generate air-stable solid-supported Lewis acid-base pairs. The Lewis acidity of the metalated materials before and after the introduction of Lewis bases was verified by means of pyridine adsorption-Fourier transform infrared spectroscopy. Detailed characterization of the materials was achieved by solid-state 13C and 31P MAS NMR spectroscopy, low-temperature N2 physisorption, X ray photoelectron spectroscopy, and energy-dispersive X-ray mapping analyses. Study of their potential interactions with CO2 was performed using CO2 adsorption isotherm experiments, which provided new insights into their applicability as solid CO2 adsorbents. A correlation between solid-supported Lewis acid-base pair strength and the resulting affinity to CO2 is discussed based on the calculation of isosteric enthalpy of adsorption. PMID- 29521093 TI - Au-Se-Bond-Based Nanoprobe for Imaging MMP-2 in Tumor Cells under a High-Thiol Environment. AB - The gold nanosensors based on the Au-S bond have been widely applied to biochemical detections. However, signal distortion caused by biothiols has been seldom mentioned and urgently needs to be solved. Herein, we designed a novel but easily assembled gold nanoprobe by coupling a selenol-modified peptide with FITC onto the gold nanoparticle's surface via an Au-Se bond for fluorescence imaging of a tumor marker matrix, metalloproteinases 2 (MMP-2). Compared to the Au-S probes, the Au-Se probes display high thermal stability and a very good anti interference ability toward glutathione under simulated physiological conditions. More importantly, the Au-Se nanoprobe exhibits a high-fidelity fluorescent signal toward MMP-2, effectively avoiding interference caused by high levels of thiol compounds in vivo. In addition, in vivo experiments further proved that no significant signal intensity change for the tumor cells treated by the Au-Se probes was observed before and after eliminating glutathione. Hence, we believe such Au-Se probes with in vivo glutathione interfering resistance offer new routes and perspectives in biology and medicine in the future. PMID- 29521094 TI - Electrophoretic Mechanism of Au25(SR)18 Heating in Radiofrequency Fields. AB - Gold nanoparticles in radiofrequency (RF) fields have been observed to heat. There is some debate over the mechanism of heating. Au25(SR)18 in RF is studied for the mechanistic insights obtainable from precise synthetic control over exact charge, size, and spin for this nanoparticle. An electrophoretic mechanism can adequately account for the observed heat. This study adds a new level of understanding to gold particle heating experiments, allowing for the first time a conclusive connection between theoretical and experimentally observed heating rates. PMID- 29521095 TI - Miniaturized Reverse Electrodialysis-Powered Biosensor Using Electrochemiluminescence on Bipolar Electrode. AB - We suggest an electrochemiluminescence (ECL)-sensing platform driven by ecofriendly, disposable, and miniaturized reverse electrodialysis (RED) patches as an electric power source. The flexible RED patches composed of ion-exchange membranes (IEMs) can produce voltage required for ECL sensing by simply choosing the appropriate number of IEMs and the ratio of salt concentrations. We integrate the RED patch with a bipolar electrode on the microfluidic chip to demonstrate the proof-of-concept, i.e., glucose detection in the range of 0.5-10 mM by observing ECL emissions with naked eyes. The miniaturized RED-powered biosensing system is widely applicable for electrochemical-sensing platforms. This is expected to be a solution for practical availability of battery-free electrochemical sensors for disease diagnosis in developing countries. PMID- 29521096 TI - Plant Sterols: Chemical and Enzymatic Structural Modifications and Effects on Their Cholesterol-Lowering Activity. AB - Plant sterols have attracted increasing attention due to their excellent cholesterol-lowering activity. However, free plant sterols have some characteristics of low oil solubility, water insolubility, high melting point, and low bioavailability, which greatly limit their application in foods. Numerous studies have been undertaken to modify their chemical structures to improve their chemical and physical properties in meeting the needs of various applications. The present review is to summarize the literature and update the progress on structural modifications of plant sterols in the following aspects: (i) synthesis of plant sterol esters by esterification and transesterification with hydrophobic fatty acids and triacylglycerols to improve their oil solubility, (ii) synthesis of plant sterol derivatives by coupling with various hydrophilic moieties to enhance their water solubility, and (iii) mechanisms by which plant sterols reduce plasma cholesterol and the effect of structural modifications on plasma cholesterol-lowering activity of plant sterols. PMID- 29521098 TI - Status updates of Newcastle disease and amelioration effects of medicinal plants against Newcastle disease virus: A review. AB - Recently, medicinal plants are achieving great interest because of their use in ethno medicine treatment of different common diseases and also other medicinal assertions are now reinforced by comprehensive scientific evidence. Almost 82 research articles and abstracts published, so far, were screened for evaluating antiviral efficiency of various plant samples and 23 different plants were found to be traditionally used against Newcastle disease (ND). ND is a most transmissible viral disease of avian species caused by virulent strain of Avula virus from the Paramyxoviridae family. The first epidemic of ND was perceived in Java, Indonesia and England in year 1926. ND causes great economic loses to the commercial poultry farmers around the world. Medicinal plants are traditionally used in the control of viral or other diseases and infections. Plants have been found useful in treating many microbial diseases in man and animals caused by bacteria and viruses. The ability to synthesize compounds retaining antiviral potential by secondary metabolism makes plants a vital source of pharmaceutical and therapeutic products, which can reduce chemotherapeutic load in birds. Current studies signify that the natural products posses a rich potential source of new antiviral compounds. Further ethnobotanical studies and laboratory investigations are established to identify species having potential to improve ND control. PMID- 29521097 TI - Characterization of an A-Site Selective Protein Disulfide Isomerase A1 Inhibitor. AB - Protein disulfide isomerase A1 (PDIA1) is an endoplasmic reticulum (ER)-localized thiol-disulfide oxidoreductase that is an important folding catalyst for secretory pathway proteins. PDIA1 contains two active-site domains (a and a'), each containing a Cys-Gly-His-Cys (CGHC) active-site motif. The two active-site domains share 37% sequence identity and function independently to perform disulfide-bond reduction, oxidation, and isomerization. Numerous inhibitors for PDIA1 have been reported, yet the selectivity of these inhibitors toward the a and a' sites is poorly characterized. Here, we identify a potent and selective PDIA1 inhibitor, KSC-34, with 30-fold selectivity for the a site over the a' site. KSC-34 displays time-dependent inhibition of PDIA1 reductase activity in vitro with a kinact/ KI of 9.66 * 103 M-1 s-1 and is selective for PDIA1 over other members of the PDI family, and other cellular cysteine-containing proteins. We provide the first cellular characterization of an a-site selective PDIA1 inhibitor and demonstrate that KSC-34 has minimal sustained effects on the cellular unfolded protein response, indicating that a-site inhibition does not induce global protein folding-associated ER stress. KSC-34 treatment significantly decreases the rate of secretion of a destabilized, amyloidogenic antibody light chain, thereby minimizing pathogenic amyloidogenic extracellular proteins that rely on high PDIA1 activity for proper folding and secretion. Given the poor understanding of the contribution of each PDIA1 active site to the (patho)physiological functions of PDIA1, site selective inhibitors like KSC-34 provide useful tools for delineating the pathological role and therapeutic potential of PDIA1. PMID- 29521099 TI - Disruption of the blood brain barrier is vital property of neurotropic viral infection of the central nervous system. AB - The blood brain barrier consisting of astrocytes, pericytes and brain microvascular endothelial cells plays a vital role in the pathogenesis of neurotropic viruses by controlling the access of circulating molecules, immune cells or viruses into the central nervous system (CNS). However, this barrier is not impenetrable and neuroviruses have evolved to disrupt and evade it. This review aims to describe the underlying entry mechanisms of several neuroviruses such as (Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), Nipah virus (NiV), Rabies virus (RABV), Herpes simplex virus (HSV) and Human immunodeficiency virus (HIV)) into the CNS through BBB disruption. The mechanisms, through which neurotropic viruses enter the BBB, are being studied and are becoming clearer, however, some aspects still remain unknown. Some of these viruses are able to invade the brain parenchyma by a 'Trojan horse' mechanism, through diapedesis of infected immune cells that either cross the BBB paracellularly or transcellularly. Important mechanisms of BBB disruption associated with paracellular entry of viruses include alterations in expression or phosphorylation of tight junction proteins, disruption of the basal lamina and disruption of the actin cytoskeleton. In the absence of such mechanisms, indirect effects of viruses on the immune system are likely causes of barrier disruption. PMID- 29521100 TI - Highlighting the 'blood-nerve barrier' in virology research. AB - The blood-nerve barrier (BNB) shields peripheral nerves from the blood in order to maintain the homeostasis of the nervous system. In the field of infectious diseases, little information is currently available concerning the BNB. Recently documented evidence in virology suggests that elevated permeability of the BNB by immune cells and the natural absence of the BNB in the olfactory mucosa play significant roles in neuroprotection as well as neuropathogenesis. Importantly, the BNB can behave more flexibly than previously thought. In the near future, drug delivery via manipulation of the BNB will shed light on new therapeutic and prophylactic strategies for serious and intractable nervous system infections. PMID- 29521101 TI - Functional role of Hsp60 as a positive regulator of human viral infection progression. AB - Heat shock proteins (Hsps) are a family of proteins highly conserved in evolution. Members of the Hsp family are mainly responsible for proper protein folding, however they perform many other functions in living organisms. Hsp60 is a molecular chaperone that is present in mitochondria and cytosol of eukaryotic cells, as well as on their surface. It is also found in the extracellular space and in the peripheral blood. Apart from its role in assisting protein folding in cooperation with Hsp10, Hsp60 contributes to regulation of apoptosis, as well as participates in modulation of the immune system activity. Hsp60 may favor oncogenesis by promoting survival or growth of some tumor cell types. Hsp60 is a subject of medical research due to its role in pathogenesis of certain tumors and infectious diseases. In this review we discuss mechanisms by which Hsp60 promotes development and progression of infections caused by three human viruses: hepatitis B virus (HBV), human immunodeficiency virus (HIV) and influenza A virus. PMID- 29521102 TI - Transmissible gastroenteritis virus nsp7 protein localized in the cytoplasm down regulates interleukin 8 expression in porcine intestinal epithelial cell. AB - Transmissible gastroenteritis virus (TGEV) is an important pathogen in swine that is responsible for substantial economic losses. Previous studies suggest that the TGEV non-structural protein 7 (nsp7) plays an important role in the viral assembly process. However, the subcellular localization and other functions of the TGEV nsp7 protein are still unclear. In this study we have examined the subcellular localization and other functions of TGEV nsp7 protein through analysis of its effects on cell growth, cell cycle progression, interleukin 8 (IL 8) expression, and NF-kappaB activation. Our results showed that the nsp7 protein is localized in the cytoplasm and has no effect on intestinal epithelial cells (IECs) growth, cell cycle, and cyclin A expression. Further studies showed that TGEV nsp7 protein had no effect on GRP78 expression, could not induce endoplasmic reticulum (ER) stress and activate NF-kappaB activity. Interestingly, the IECs expressing nsp7 protein secreted lower levels of IL-8 than control cells. This is the first report to demonstrate the subcellular localization and novel functions of TGEV nsp7 protein. These findings provide novel information about the function of the poorly characterized TGEV non-structural protein 7. PMID- 29521103 TI - Prokaryotic expression and identification of scavenger receptor B2. AB - There is still no effective clinical antiviral drug against human enterovirus 71 (EV71) infection, which causes hand, foot and mouth disease (HFMD) in children. Scavenger receptor class B member 2 (SCARB2) is an important receptor of EV71 as it plays a vital role in the early steps of viral infection. In this study, recombinant SCARB2 protein was expressed and purified in a prokaryotic expression system, and was identified by western blot with a monoclonal antibody and mass spectrometry analysis. Detection of the sera from mice immunized with the recombinant SCARB2 protein using ELISA and western blot showed good immunogenicity of the recombinant protein. Furthermore, in the neutralization test cytopathic effect was significantly decreased when EV71 was incubated with the immune sera before infection. In summary, the SCARB2 protein was expressed successfully, and the immune sera showed obvious antiviral effect against EV71. This study provides useful information about the interaction mechanism between SCARB2 and EV71, and is also helpful for further clinical treatment research of HFMD. PMID- 29521104 TI - Association of Toll-like receptor 4 with hepatitis A virus infection in Assam. AB - Hepatitis A virus (HAV) which causes liver disease is recognized by Toll-like receptors (TLRs) through the viral nucleic acid, initiating the host defense response. The study aims to analyze the role of TLR4 rs11536889 polymorphism in the pathogenesis of hepatitis A cases from Assam. There was significant correlation between TLR4 SNP G/C (rs11536889) and between acute viral hepatitis (AVH) A cases and controls. The correlation of the 3 different genotypes GG, GC and CC of TLR4 rs11536889 with the TLR4 mRNA expression level in all the HAV cases groups have been found to be statistically significant (p <0.001). TLR4 expression was most significantly upregulated in the acute HAV cases, HAV with cholestasis cases and even the HAV caused fulminant hepatitis failure (FHF) cases with the CC genotype of TLR4 rs11536889. The upregulation is mostly seen in the cases with the CC genotype of TLR4 rs11536889 and thus indicates that the mutant variant of TLR4 rs11536899 (CC) may have an effect on the expression of TLR4 at the transcription level. Our study did not show any significant association between AVH and HAV caused FHF (p = 0.32, OR = 0; p = 0.59, OR = 2.06 at 95% CI) among the genotypes GG, GC and CC. Our data suggest that TLR4 gene polymorphism rs11536889 may play a prominent role in HAV disease susceptibility and TLR4 expression in population from Assam. PMID- 29521105 TI - A novel point mutation (L70P) inactivates poliovirus 3C protease. AB - Poliovirus (PV) contains a single-stranded positive-sense RNA genome, which is translated into a single polyprotein. Viral proteases process this polyprotein to produce several individual as well as fused proteins. The major viral protease 3C cleaves at nine of the eleven cleavage sites. During the process of expressing PV 3ABC protein in Escherichia coli, we identified a 3C mutant (L70P), which lost its protease activity. This loss of function was confirmed by generating recombinant adenoviruses expressing mutant and wild-type 3C. Further, infectious PV could not be recovered from PV full-length cDNA containing the L70P mutation. However, 3C L70P mutant cDNA could complement a PV cDNA containing a 1AB deletion, producing a viable virus population containing defective complementing genomes. Structural analysis of the mutant protein indicated that the L70P mutation resulted in the loss of a hydrogen bond between two residues located within a loop between two beta-sheets, potentially leading to strain on the catalytic site. We conclude that L70P inactivates 3C protease because of its close proximity to the 3C catalytic site. PMID- 29521106 TI - Wogonin, a flavonoid isolated from Scutellaria baicalensis, has anti-viral activities against influenza infection via modulation of AMPK pathways. AB - Wogonin, a flavonoid isolated from Scutellaria baicalensis, has attracted increasing scientific attention in recent years because of its potent anti-tumor activity. Its role during viral infection has largely been unexplored. Wogonin treatment effectively suppressed both influenza A and B virus replication in Madin-Darby Canine Kidney (MDCK) cells and human lung epithelial (A549) cells. In contrast, wogonin treatment following influenza A virus infection led to up regulation of interferon (IFN)-induced antiviral signaling. Additionally, influenza A virus infection in A549 cells induced 5' adenosine monophosphate activated protein kinase (AMPK) phosphorylation and activation in a time dependent manner and wogonin treatment led to the suppression of AMPK phosphorylation. Furthermore, the treatment with AMPK-specific inhibitor (compound C; CC) attenuated influenza A virus replication. These data suggest that wogonin possesses a potent anti-influenza activity mediated by regulation of AMPK activation, suggesting that wogonin has the potential to be developed as an anti-influenza drug. PMID- 29521107 TI - Sequence analysis of VP2 hypervariable region of the field isolates of infectious bursal disease viruses from southern region of India. AB - Infectious bursal disease virus isolates obtained from southern parts of India were subjected to comparative sequencing and phylogenetic analysis of 743bp hypervariable region of VP2. The sequence analysis showed that among eight isolates, only HY12 showed the characteristic conserved amino acid residues at 256I, 294I, and 299S of vvIBDV. Six isolates BGE14, PY12, NKL14, VCN14, RPM14 and EDE14 had conserved amino acid residues at 256I and 299S, whereas at residue 294, isoleucine was substituted by valine. The remaining isolate MB11 had leucine at residue 294 and asparagine at residue 299 similar to classical strain 52/70. The serine-rich heptapeptide sequence SWSASGS adjacent to the second hydrophilic region was conserved in all seven Indian IBDV isolates except isolate MB11. Conservation of this sequence was earlier reported to be an indication of a virus isolate being pathogenic in nature. The reported heptapeptide sequence of the classical strain is 'SWSARGS'. In the present study, 'SWSARGS' heptapeptide sequence was observed in MB11 isolate. The pathogenicity trials conducted with these isolates further confirmed the genome analysis in classification. This study further reveals that the circulating IBDV strains in India could be diverse in nature. PMID- 29521108 TI - A survey on murine gammaherpesvirus 68 in ticks collected in Slovakia. AB - Murine gammaherpesvirus 68 (MHV-68) is a natural pathogen that infects murid rodents which serve as hosts for Dermacentor reticulatus and Ixodes ricinus ticks. For the first time, MHV-68 was detected in immature I. ricinus ticks feeding on lizards trapped in Slovakia. Later on, MHV-68 infection was detected in D. reticulatus and Haemaphysalis concinna ticks collected on vegetation, which supported the idea that ticks can acquire the virus from feeding on infected hosts. Here, we report MHV-68 infection, which was detected by nested PCR, in D. reticulatus and I. ricinus adult ticks and I. ricinus nymphs collected in five geographically isolated localities, in west, southwest, south and central Slovakia. Viral incidence in ticks was 46.7% (121/259) without considering the season, site of collection and tick species and their life stage. MHV-68 infection was detected in all five localities investigated and in both tick species. Here, for the first time, we report MHV-68 infection in I. ricinus nymphs collected from the vegetation. The finding of virus in ticks from five separated localities suggested that ticks became infected with MHV-68 via feeding on infected rodents; thus, this virus might be a newfound natural pathogen in ticks. PMID- 29521109 TI - An isothermal based recombinase polymerase amplification assay for rapid, sensitive and robust indexing of citrus yellow mosaic virus. AB - Management of viral diseases relies on definite and sensitive detection methods. Citrus yellow mosaic virus (CYMV), a double stranded DNA virus of the genus Badnavirus, causes yellow mosaic disease in citrus plants. CYMV is transmitted through budwood and requires a robust and simplified indexing protocol for budwood certification programme. The present study reports development and standardization of an isothermal based recombinase polymerase amplification (RPA) assay for a sensitive, rapid, easy, and cost-effective method for detection and diagnosis of CYMV. Two different oligonucleotide primer sets were designed from ORF III (coding for polyprotein) and ORF II (coding for virion associated protein) regions of CYMV to perform amplification assays. Comparative evaluation of RPA, PCR and immuno-capture recombinase polymerase amplification (IC-RPA) based assays were done using purified DNA and plant crude sap. CYMV infection was efficiently detected from the crude sap in RPA and IC-RPA assays. The primer set used in RPA was specific and did not show any cross-amplification with banana streak MY virus (BSMYV), another Badnavirus species. The results from the present study indicated that RPA assay can be used easily in routine indexing of citrus planting material. To the best of our knowledge, this is the first report on development of a rapid and simplified isothermal detection assay for CYMV and can be utilized as an effective technique in quarantine and budwood certification process. PMID- 29521110 TI - In vitro micrografting of different Prunus species by cherry-adapted Plum pox virus isolate. PMID- 29521111 TI - Microsampling Collection Methods for Measurement of C-peptide in Whole Blood. AB - BACKGROUND: Microsampling techniques are alternative methods to venous sampling for obtaining blood for measurement of circulating biomarkers, offering the convenience of reduced sample volume and elimination of the need for phlebotomists. Dried blood spot (DBS) microsampling methods have been used for many years while more recently a volumetric absorptive microsampling device (VAMSTM) has been introduced. In diabetes mellitus, circulating C-peptide is commonly used as an indicator of endogenous insulin secretion and clinical measurement can aid in diagnosis as well as informing on therapy. This pilot study investigated the effectiveness of microsampling collection of capillary blood for measurement of C-peptide. METHODS: Capillary blood was collected into capillary tubes and centrifuged for plasma samples. Simultaneous samples were also collected using both microsampling methods (DBS and VAMS). Blood from both microsamplers was extracted prior to assaying for C-peptide alongside the corresponding plasma samples, using specific immunoassays and results obtained from microsampling compared to the reference plasma concentrations. Stability was determined by collecting duplicate DBS and VAMS and assaying both in a single assay after storing one at -20 degrees C immediately and one at room temperature for 48 hours post-collection. RESULTS: Good agreement was observed between C peptide concentrations in plasma and equivalent DBS and VAMS samples ( R2 = .929 and .9231, DBS and VAMS, respectively), with mean differences of 75.7 and 8.4 pmol/L observed for DBS and VAMS. Small decreases in C-peptide of 11.6% and 0.1% were observed after 48 hours storage for DBS and VAMS, respectively. CONCLUSIONS: C-peptide collected using DBS and VAMS showed good agreement with reference plasma concentrations, suggesting both would be an effective microsampling method for collection and measurement of C-peptide. PMID- 29521112 TI - Evaluation of the right ventricle by echocardiography: particularities and major challenges. AB - INTRODUCTION: Compared with the left ventricle (LV), the right ventricle (RV) is less suited for evaluation by echocardiography (ECHO). Nevertheless, RV ECHO assessment has currently emerged as an important diagnostic tool with meaningful prognostic value and essential contribution to therapeutic decisions. Although significant progress has been made, including generation of higher-quality normative data, validation of several two-dimensional measurements and improvements in three-dimensional ECHO-techniques, many challenges in RV ECHO assessment still persist. Areas covered: This review discusses the particular challenges and limits in obtaining accurate measurements of RV anatomical and functional parameters and focuses primarily on the difficulties in proper interpretation of the highly load dependent RV ECHO-parameters which complicates the use of this valuable diagnostic and surveillance technique. Expert commentary: There is increasing evidence that RV assessment in relation with its actual loading conditions by ECHO-derived composite variables, which either incorporate a certain functional parameter and load, or incorporate measures which reflect the relationship between RV dilation and RV load, considering also the right atrial pressure (i.e. 'load adaptation index'), is particularly suited for clinical decision-making. Load dependency of RV ECHO-parameters must be taken into consideration especially in patients with advanced RV dysfunction scheduled for LV assist device implantation or lung transplantation. PMID- 29521113 TI - Lateral switch to IFN beta-1a 44 mcg may be effective as escalation switch to fingolimod in selected persons with relapsing remitting multiple sclerosis: a real-world setting experience. AB - BACKGROUND: The efficacy of lateral and escalation switch is a challenge in MS. We compared in a real-world setting the efficacy of switching to IFN beta-1a 44 mcg or to fingolimod in persons with relapsing remitting MS (pwRRMS) who failed with others injectable IFNs or glatiramer acetate. RESEARCH DESIGN AND METHODS: retrospective analysis of 24 months prospectively-collected data at the MS center of the University of Catania, Italy was performed. Patients who were switched to IFN-beta 1a 44 mcg or fingolimod were analyzed using propensity-score covariate adjustment model within demographic (e.g. age and gender) and disease (e.g. timing of pre-switch relapse) characteristics. Switching-time was considered the starting-time of the observation. RESULTS: 43 pwRRMS on IFN beta-1a 44 mcg and 49 pwRRMS on fingolimod were included. Baseline characteristics differed for EDSS score and number of T2 lesions (higher in group on fingolimod). At 24 months of follow up, both groups showed no differences in the survival curves of reaching a first new relapse, new T2 and Gd+ MRI brain lesions, even corrected for the propensity score covariate adjustment. CONCLUSIONS: lateral switch to IFN beta-1a 44 mcg and escalation switch to fingolimod showed same ability in influencing RRMS disease activity at 24 months. PMID- 29521114 TI - Changes of human movement complexity during maturation: quantitative assessment using multiscale entropy. AB - Movement complexity can be defined as the capability of using different strategies to accomplish a specific task and is expected to increase with maturation, reaching its highest level in adulthood.Multiscale Entropy (MSE) has been proposed to estimate complexity on different kinematic signals, at different time scales. When applied on trunk acceleration data during natural walking (NW) at different ages, MSE decreased from childhood to adulthood, apparently contradicting the premises. On the contrary, authors hypothesised that this decrease was dependent on the specific task analysed and resulted from the concurrent increase in gait automaticity.This work aims to test this hypothesis, applying MSE on a non-paradigmatic task (tandem walking, TW), in order to exclude aspects related to automaticity.MSE was estimated on trunk acceleration data, collected on children, adolescents, and young adults during TW and NW. As hypothesized, MSE increased significantly with age in TW and decreased in NW on the sagittal plane. Assuming the development of complexity in TW as reference, MSE in NW showed a reduction to half of the complexity of TW with maturation on the sagittal plane. These results indicate MSE as sensitive to differences in performance due to maturation and to expected changes in complexity related to the specific performed task. PMID- 29521116 TI - Two new sesquineolignans from the seeds of Crataegus pinnatifida and their beta amyloid aggregation inhibitory activitiy. AB - Two new sesquineolignans, hawthornsesquinins K and L (1 and 2), were isolated from the seeds of Crataegus pinnatifida. Their structures were determined by spectroscopic analyses, including 1D, 2D NMR and HRESIMS data. All isolated compounds were tested for their beta-amyloid aggregation inhibitory activity and neuroprotective effects against H2O2-induced damage in SH-SY5Y cells. The results indicated that compound 1 showed prominent inhibition of Abeta1-42 aggregation and significant neuroprotective effect on H2O2-induced cellular damage in SH-SY5Y cells. PMID- 29521115 TI - Enhanced anti-proliferative efficacy of epothilone B loaded with Escherichia coli Nissle 1917 bacterial ghosts on the HeLa cells by mitochondrial pathway of apoptosis. AB - Epothilones constitute a new class of microtubule-stabilizing anti-cancer agents with promising preclinical and clinical activity. However, its systemic application still causes some toxic side effects. To reduce these undesired effects, advanced drug delivery systems based on cell targeting carriers are needed currently. In this study, the high quality bacterial ghosts of the probiotic Escherichia coli Nissle 1917 (EcN) were prepared in a large scale and retained fully intact surface structures for specific attachment to mammalian cells. The EcN ghosts could be efficiently loaded with the low hydrophilic drug Epothilone B (Epo B) and the maximal load efficiency was approximately 2.5% (w/w). Cytotoxicity assays revealed that Epo B-ghosts exhibited enhanced anti proliferative properties on the HeLa cells. The Epo B associated with EcN ghosts was more cytotoxic at least 10 times than the free Epo B at the same concentrations. Apoptosis assays showed that both Epo B-ghosts and free Epo B induced time course-dependent apoptosis and necrosis in HeLa cells, respectively. While the former induced more apoptosis and necrosis than the latter. Furthermore, the cytochrome C release and the activation of caspase-3 were more remarkable after treatment with the Epo B-ghosts compared to the free Epo B, which implied that Epo B-ghosts might more effectively induce the apoptosis mediated by mitochondrial pathway in HeLa cells. Therefore, the higher anti proliferative effects of the Epo B-ghosts on the HeLa cells were mediated by mitochondrial pathway of apoptosis. The EcN ghosts may provide a useful drug delivery carrier for drug candidates in cancer therapy. PMID- 29521117 TI - Neurocysticercosis: the good, the bad, and the missing. AB - INTRODUCTION: Neurocysticercosis (NC) is a neglected disease that contributes substantially to neurological morbidity/mortality in lower-income countries and increasingly among high-income countries due to migration. Many advances have been made in understanding NC, but unanswered questions remain Areas covered: This review discusses the epidemiology, pathophysiology, immunology, diagnosis, treatment, and eradication of NC. Expert commentary: The global NC prevalence remains unknown and needs proper ascertainment. Further understanding of the pathophysiology of extraparenchymally located cysts is needed to improve management. The role of inflammation, which is required for parasite death and reabsorption, but may lead to severe complications, must be better understood. Valid screening tools including immunological and molecular tests need to be developed to reduce the reliance on neuroimaging which is not usually accessible in endemic areas. Prognosis for people with parenchymal NC is generally good after treatment, but there are no sufficiently powered randomized trials evaluating antiparasitic treatment for extraparenchymal NC. Most people with seizures do not develop epilepsy. Overemphasizing NC as the main cause of epilepsy could increase stigmatization with potential medico/social implications. Several tools for prevention and control of taeniasis/cysticercosis are available, but strategies to eradicate NC must be created with the involvement of all stakeholders. PMID- 29521118 TI - A new tremulane sesquiterpenoid from the fungus Irpex lacteus. AB - A new tremulane sesquiterpenoid, named irlactam A (1), was isolated from cultures of the fungus Irpex lacteus. The new structure was elucidated by spectroscopic data analysis. The compound was tested for its cytotoxicities on HL-60, SMMC 7721, A-549, MCF-7, and SW480 cells and for its inhibitory activity against isozymes of 11beta-hydroxysteroid dehydrogenases (11beta-HSD). PMID- 29521119 TI - Soft tissue calcifications secondary to Hymenoptera stings: a potential prognostic CT imaging sign in pediatric patients. AB - CONTEXT: Soft tissue calcifications (STCs) were incidentally found in some of the Hymenoptera-stung (HS) children when they underwent computed tomography (CT) scans for evaluating complications of vital organs. Afterwards, a predilection of STCs to the children with severe complications was clinically noticed. A hypothesis was then developed that STCs secondary to HS may correlate with poor outcomes. OBJECTIVE: This study aims to firstly characterize the CT findings of STCs in HS children and to confirm our hypothesis that the occurrence of STCs may act as an indicator of poor outcomes in HS children. MATERIALS AND METHODS: Children who received CT scanning after Hymenoptera sting from January 2011 to October 2016 in our hospital were analyzed retrospectively. Shape, location, and distribution of the STCs were described according to the CT findings. Then the enrolled cases were classified into Soft Tissue Calcification Group (STCG) and non-Soft tissue Calcification Group (non-STCG) to conduct prognostic comparisons of Sequential Organ Failure Assessment (SOFA) scores, incidence of main complications (acute liver failure (ALF), acute kidney injury stage III (AKI-III) and multiple organ failure (MOF)), length of hospital days, and in-hospital death, respectively. Pearson correlation was also utilized between the cumulative volume of STCs and the SOFA score. RESULTS: Sixteen cases were enrolled, and STCs' incidence was 56.25% (9/16). Two STCG cases had diffuse nodular calcifications in their swollen subcutaneous tissue, and another seven had symmetrically stripy or patchy calcifications within or along local muscles. The SOFA scores during the first 3 days were all higher in STCG, and rose to the greatest difference at the third day (9.78 +/- 2.17 vs. 2.29 +/- 2.06, t = 7.009, p < .001); the incidence of ALF, AKI-III and MOF were significantly higher in STCG (66.67% vs. 0, p = .011), (77.78% vs. 0, p = .003) and (77.78% vs. 14.29%, p = .041); and children in STCG were treated with longer hospital durations (26.33 +/- 8.41 days vs. 12.29 +/- 7.36 days, t = 3.493, p = .004). One child in STCG died of cardiopulmonary failure, and no deaths occurred in non-STCG. No significant correlations presented between STCs cumulative volumes and SOFA score (rDay1 = 0.096, p = .806; rDay2 = 0.067, p = .863; rDay3 = 0.024, p = .950). CONCLUSION: Soft tissue calcifications detected on CT imaging following multiple Hymenoptera stings in pediatric patients may be a potential prognostic indicator of more severe complications and poorer outcomes. PMID- 29521120 TI - Better than a pound of cure: preventing the development of multidrug-resistant tuberculosis. AB - Diagnostic and treatment delays contribute to increased death and disability among the 490,000 adults and children who develop multidrug-resistant (MDR) tuberculosis every year. Since the treatment of MDR tuberculosis is complex, costly and often toxic, tuberculosis control programs should prioritize strategies to prevent drug-resistant tuberculosis. Opportunities to limit transmission and prevent disease progression in close contacts of MDR tuberculosis cases are often neglected. Effective MDR tuberculosis preventive strategies could minimize the costs for patients and healthcare systems. This review characterizes the biological basis for the development of MDR tuberculosis, outlines the evidence for strategies to reduce transmission and highlights programmatic approaches to the management of patients infected with drug-resistant strains of Mycobacterium tuberculosis. PMID- 29521121 TI - Evaluation of reference values for phenotypic tests to detect oxacillin resistance in coagulase-negative staphylococci. AB - AIM: To evaluate the adequacy of the disc-diffusion test and E-test(r) compared with detection of mecA for coagulase-negative staphylococci isolated from blood cultures, nasal swabs and wounds. RESULTS: Agreement between all techniques was observed in 65.7% of cases. The greatest discrepancy between mecA/susceptible E test was observed for non-epidermidis species. A resistance breakpoint <=19 mm using the oxacillin disc was found to best classify all coagulase-negative staphylococci isolates; Staphylococcus epidermidis, <=19 mm (oxacillin) and <=27 mm (cefoxitin); Staphylococcus haemolyticus and Staphylococcus capitis, <=21 mm (oxacillin) and <=18 mm (cefoxitin); Staphylococcus warneri, MICs >=0.75 mg/l. CONCLUSION: Although no longer recommended by the Clinical Laboratory Standards Institute, we observed some cases in which only the oxacillin disc-diffusion test detected resistance. The discrepancy between phenotypic tests and mecA is probably due to heterogeneity and borderline resistance. PMID- 29521122 TI - Do checkpoint inhibitors provide new hope for management of metastatic penile carcinoma? PMID- 29521123 TI - Adherence of physical therapy with clinical practice guidelines for the rehabilitation of stroke in an active inpatient setting. AB - BACKGROUND: Clinical guidelines are systematically developed statements designed to help practitioners and patients to make decisions about appropriate health care. Clinical practice guideline adherence analysis is the best way to fine tune the best practices in a health care industry with international benchmarks. OBJECTIVE: To assess the physical therapist's adherence to structured stroke clinical practice guidelines in an active inpatient rehabilitation center in Qatar. SETTING: Department of Physical therapy in the stroke rehabilitation tertiary referral hospital in Qatar. METHOD: A retrospective chart audit was performed on the clinical records of 216 stroke patients discharged from the active inpatient stroke rehabilitation unit with a diagnosis of stroke in 2016. The audit check list was structured to record the adherence of the assessment, goal settings and the management domains as per the "Physical Therapy After Acute Stroke" (PAAS) guideline. RESULT: Of the 216 case files identified during the initial search, 127 files were ultimately included in the audit. Overall adherence to the clinical practice guideline was 71%, a comparable rate with the studies analyzing the same in various international health care facilities. Domains which were shared by interdisciplinary teams than managed by physical therapy alone and treatments utilizing sophisticated technology had lower adherence with the guideline. A detailed strength and weakness breakdown were then conducted. CONCLUSION: This audit provides an initial picture of the current adherence of physical therapy assessment and management with the stroke physical therapy guideline at a tertiary rehabilitation hospital in the state of Qatar. An evaluation of the guideline adherence and practice variations helps to fine tune the physical therapy care to a highest possible standard of practice. Implications for Rehabilitation * An evaluation of the guideline adherence and practice variations helps to fine tune the rehabilitation care to the highest possible standard of practice. * Proper assessments of the relationship between the process of rehabilitation care and outcomes with a comprehensive set of process indicators will improve the quality of the care. * An agreement needs to be established between rehabilitation teams engage in interdisciplinary stroke care regarding the shared responsibilities and team functioning. * It is recommendable to develop a specialty based clinical practice guidelines that can be aligned at a higher 'comprehensive rehabilitation level' to provide the best possible and evidence based stroke care. PMID- 29521124 TI - Comment on "Antivenom for European Vipera species envenoming". PMID- 29521125 TI - The potential of a microneedle patch for reducing obesity. PMID- 29521126 TI - Lapatinib nano-delivery systems: a promising future for breast cancer treatment. AB - INTRODUCTION: Breast cancer stands the second prominent cause of death among women. For its efficient treatment, Lapatinib (LAPA) was developed as a selective tyrosine kinase inhibitor of receptors, overexpressed by breast cancer cells. Various explored delivery strategies for LAPA indicated its controlled release with enhanced aqueous solubility, improved bioavailability, decreased plasma protein binding, reduced dose and toxicity to the other organs with maximized clinical efficacy, compared to its marketed tablet formulation. Areas covered: This comprehensive review deals with the survey, performed through different electronic databases, regarding various challenges and their solutions attained by fabricating delivery systems like nanoparticles, micelle, nanocapsules, nanochannels, and liposomes. It also covers the synthesis of novel LAPA conjugates for diagnostic purpose. Expert opinion: Unfortunately, clinical use of LAPA is restricted because of its extensive albumin binding capacity, poor oral bioavailability, and poor aqueous solubility. LAPA is marketed as the oral tablet only. Therefore, it becomes imperative to formulate alternate efficient multiparticulate or nano-delivery systems for administration through non-oral routes, for active/passive targeting, and to scale-up by pharmaceutical scientists followed by their clinical trials by clinical experts. LAPA combinations with capecitabine and letrozole should also be tried for breast cancer treatment. PMID- 29521127 TI - BAG-S53P4 as bone graft extender and antimicrobial activity against gentamicin- and vancomycin-resistant bacteria. AB - AIM: To evaluate the suitability of bioactive glass (BAG)-S53P4 as a bone-graft extender for large bony defect filling in bone and joint infection. MATERIALS & METHODS: Antimicrobial activity of BAG-S53P4 against clinically relevant strains isolated from bone and joint infections was evaluated by means of time-kill curves in presence of bone graft. Furthermore, the susceptibility to BAG of strains resistant to vancomycin and gentamicin was assessed. RESULTS: Though attenuated, BAG maintains a good in vitro antimicrobial activity in presence of human body fluids and tissues contained in bone graft, with the exception of Enterococcus faecalis. CONCLUSION: BAG-S53P4 is a suitable bone substitute that can be used as an extender with autologous bone graft to promote better fusion and healing. PMID- 29521128 TI - Calprotectin: a biomarker for both infant/childhood and adult disease. PMID- 29521129 TI - Intracellular sequestration of HER2 via targeted subcellular peptide delivery. AB - The use of peptides in drug development has been hampered by their poor pharmaceutical properties, most notably their inability to reliably permeate biological membranes and lack of targeting. To overcome these disadvantages, the AMino acid Intracellular Delivery SysTem (AMIDST) was developed. This modular peptide-based delivery system confers cellular permeability and organelle specific targeting for therapeutic peptides. As demonstrated in this study, the delivery of a HER2-binding peptide to the secretory organelles of breast cancer cells resulted in intracellular sequestration, a reduction in downstream signalling, and reduced viability compared to the delivery of a control peptide. Given its modular design and ease of production, AMIDST has the potential to enhance the use of peptides as therapeutic agents. PMID- 29521130 TI - Carotid intima-media thickness and osteoporosis in postmenopausal women: a cross sectional study. AB - OBJECTIVES: To explore the difference in carotid intima-media thickness (CIMT) between postmenopausal women with and without osteoporosis and the risk of elevated CIMT and plaque presentation. METHOD: A cross-sectional study was conducted including 46 postmenopausal women with osteoporosis and 45 non osteoporotic postmenopausal women. CIMT was measured using B-mode ultrasound. RESULTS: There was no statistically significant difference in mean CIMT between postmenopausal women with osteoporosis and those without osteoporosis (p > 0.05). Risk for elevated CIMT in the osteoporosis group was comparable to that of the non-osteoporosis group (adjusted odds ratio = 0.844; 95% confidence interval 0.11 6.45). The risk for the presence of plaque was three times higher in osteoporotic women than in normal individuals. However, after adjusting for age and underlying diseases that would predispose the women to cardiovascular disease, there was no significant difference in terms of presence of plaque between the two groups (adjusted odds ratio = 0.844; 95% confidence interval 0.11-6.45). CONCLUSION: There was no difference in mean CIMT between postmenopausal women with and without osteoporosis. Risk of elevated CIMT in postmenopausal women with osteoporosis was comparable to that of postmenopausal women without osteoporosis. There was no significant difference between the two groups in terms of the presence of plaque. PMID- 29521131 TI - Water-soluble porphyrin-PAMAM-conjugates of melphalan and their anticancer activity. AB - p-[bis(chloro-2-ethyl)amino]-L-phenylalanine (melphalan) is an approved anti cancer agent with a broad spectrum of antitumor activity. However, it has some disadvantages, such as poor water-solubility followed by rapid elimination, which reduce the target specificity. To solve these problems, porphyrin- poly(amidoamine) or PAMAM-conjugates of melphalan were synthesized and characterized. The dendrimeric conjugates showed satisfactory water solubility. It was found that the size of the dendrimer played a crucial role in controlling the drug content and diameter of the melphalan-conjugates. The in vitro studies of cell cytotoxicity revealed that by employing the dendrimeric conjugation strategy and using the PAMAM dendritic arms as spacers, the conjugates had good anti-cancer activity and lower toxicity than free melphalan. PMID- 29521132 TI - A novel and discriminative method of in vitro disintegration time for preparation and optimization of taste-masked orally disintegrating tablets of carbinoxamine maleate. AB - The primary objective of this study was to mask bitter taste and decrease the disintegration time of carbinoxamine maleate (CAM) orally disintegrating tablets (ODTs). In order to screen the prescription of ODTs, a novel modified in vitro disintegration method (MIVDM) was developed to measure the in vitro disintegration time. In this method, different concentrations of ethanol served as disintegration medium in order to delay the in vitro water absorption and disintegration process of tablets. The MIVDM demonstrated good in vitro and in vivo correlation and proved more precise and discriminative than other reported methods. In this research, ion exchange resins (IERs) were used to mask bitter taste for improving mouthfeel. The drug-resin ratio and reaction temperature were investigated to obtain the optimum carbinoxamine resin complexes (CRCs). The characterization of CRCs revealed an amorphous state. ODTs were prepared by direct compression. Superdisintegrants and diluents of ODTs were screened first. Further optimization was carried out by using Box-Behnken design. The effect of (X1) mannitol/microcrystalline cellulose ratio, (X2) the amount of low substituted hydroxypropylcellulose and (X3) the hardness was investigated for achieving the lowest (Y) in vitro disintegration time. Technological characterization, wetting time, water absorption ratio, and roughness degree were evaluated. The CRCs and ODTs proved successful taste-masking efficiency. The end product improved patients' compliance. The developed MIVDM was practical for commercial use. PMID- 29521133 TI - Cavopulmonary mechanical circulatory support in Fontan patients and the need for physiologic control: A computational study with a closed-loop exercise model. AB - PURPOSE: Rotary blood pumps are a promising treatment approach for patients with a total cavopulmonary connection and a failing cardiovascular system. The aim of this study was to investigate the hemodynamic effects of cavopulmonary support using a numerical model with closed-loop baroreflex and exercise mechanisms. METHODS: A numerical model of the univentricular cardiovascular system was developed, mimicking the hemodynamics during rest and exercise. Rotary blood pumps with different hydraulic pump characteristics (flat vs steep pressure-flow relationships) were investigated in the cavopulmonary position. Furthermore, two support modes-a constant speed setting and a physiologically controlled speed were examined. RESULTS: Hemodynamics without rotary blood pumps were achieved with less than 10% deviation from reported values during rest and exercise. Rotary blood pumps at constant speed improve the hemodynamics at rest, however, they constitute a hydraulic resistance during light (steep characteristics) or moderate (flat characteristics) exercise. In contrast, physiologic control increases cardiac output (moderate exercise: 8.2 vs 7.4 L/min) and reduces sympathetic activation (heart rate at moderate exercise: 111 vs 123 bpm). CONCLUSION: In this simulation study, the necessity of an automatically controlled rotary blood pump in the cavopulmonary position was shown. A pump at constant speed might constitute an additional resistance to venous return during physical activity. Therefore, a physiologic control algorithm based on the pressure difference between the caval veins and the atrial pressure is proposed to improve hemodynamics, especially during physical activity. PMID- 29521134 TI - Effects of CYP3A4*1G and CYP3A5*3 polymorphisms on pharmacokinetics of tylerdipine hydrochloride in healthy Chinese subjects. AB - The aim of this analysis was to explore the influence of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of tylerdipine in healthy Chinese subjects. A total of 64 and 63 healthy Chinese subjects were included and identified as the genotypes of CYP3A4*1G and CYP3A5*3, respectively. Plasma samples were collected for up to 120 h post-dose to characterize the pharmacokinetic profile following single oral dose of the drug (5, 15, 20, 25 and 30 mg). Plasma levels were measured by a high-performance liquid chromatography-mass spectrometry (LC MS/MS). The pharmacokinetic parameters were calculated using non-compartmental method. The maximum concentration (Cmax) and the area under the curve (AUC0-24 h) were all corrected by the dose given. In the wild-type group, the mean dose corrected AUC0-24 h was 1.35-fold larger than in CYP3A4*1G carriers (p = .018). Among the three CYP3A5 genotypes, there showed significantly difference (p = .008) in the t1/2, but no significant difference was observed for the AUC0-24 h and Cmax. In subjects with the CYP3A5*3/*3 genotype, the mean t1/2 was 1.35-fold higher than in CYP3A5*1/*1 group (p = .007). And the t1/2 in CYP3A5*3 carriers also was 1.32-fold higher than in the wild-type group (p = .004). CYP3A4*1G and CYP3A5*3 polymorphisms may influence tylerdipine pharmacokinetic in healthy Chinese subjects. PMID- 29521135 TI - Determination of low intrinsic clearance in vitro: the benefit of a novel internal standard in human hepatocyte incubations. AB - 1. A novel method utilizing an internal standard in hepatocytes incubations has been developed and demonstrated to decrease the variability in the determination of intrinsic clearance (CLint) in this system. The reduced variability was shown to allow differentiation of lower elimination rate constants from noise. 2. The suggested method was able to compensate for a small but systematic error (0.5 uL/min/106 cells) caused by an evaporation of approximately 15% of the volume during the incubation time. 3. The approach was validated using six commercial drugs (ketoprofen, tolbutamide, phenacetin, etodolac and quinidine) which were metabolized by different pathways. 4. The suggested internal standard, MSC1815677, was extensively characterized and the acquired data suggest that it fulfills the requirements of an internal standard present during the incubation. The proposed internal standard was stable during the incubation and showed a low potential to inhibit drug metabolizing enzymes and transporters. With MSC1815677 we propose a novel simple, robust and cost-effective method to address the challenges in the estimation of low clearance in hepatocyte incubations. PMID- 29521136 TI - Prophylactic antibiotics to prevent surgical site infections in Botswana: findings and implications. AB - OBJECTIVES: Antibiotic prophylaxis in surgery is known to reduce the rate of surgical site infections (SSI) as well as shorten hospital stay. However, there is currently a scarcity of data on antibiotic prophylaxis and SSIs among African countries including Botswana. Consequently, this study aimed to address this. METHODS: A prospective study involving 400 patients was carried out at a leading tertiary hospital in Botswana from 2014-2015. Patients' demographic information, type of surgery performed and peri-operative use of antibiotics were documented. All enrolled patients were followed-up for 30 days post discharge to fully document the incidence of SSIs. RESULTS: Median age of patients was 35.5 (25 - 50) years, with 52% female. There were 35.8% emergency and 64.2% elective surgeries. The most common operations were exploratory laparotomy (25%), appendectomy (18.3%), excision, and mastectomy (8%). Antibiotics were given in 73.3% of patients, mainly postoperatively (58.3%). The most commonly prescribed antibiotics were cefotaxime (80.7%), metronidazole (63.5%), cefradine (13.6%) and amoxicillin/clavulanate (11.6%). The incidence of SSI was 9%. The most common organisms were Pseudomonas aeruginosa, Staphylococcus aureus, and coagulase negative staphylococci. CONCLUSION: The rate of SSI is a concern, and may be related to inappropriate antibiotic prophylaxis given post operatively. Interventions are in place to decrease SSI rates to acceptable levels in this leading hospital by improving for instance infection prevention practices including the timing of antibiotic prophylaxis. Research is also ongoing among other hospitals in Botswana to reduce SSI rates building on these findings. PMID- 29521137 TI - Psychological Factors Associated with Episodic Chelation Adherence in Thalassemia. AB - beta-Thalassemia major (beta-TM) is a life-long genetic hemoglobin (Hb) disorder requiring intensive treatment regimens, including frequent blood transfusions and daily chelation therapy. Understanding psychosocial correlates of chelation adherence is important for developing interventions to improve adherence. This study investigated within-participant correlates of oral chelation adherence on a daily (episodic) basis. Thirty-seven adult participants with beta-TM were recruited from clinics at two hospitals (22 males, 9 females, mean age 34.5 years, range 19-54 years). A structured interview was used to assess behavioral and psychological situational variables related to an adherent and a nonadherent episode for each participant. Positive outcome expectancies and higher self efficacy were both significantly associated with adherent episodes. Behavioral variables, including difficulty in accessing medication, location, and whether alone or with others, were also associated with nonadherent episodes. Findings suggested that situational psychological factors are important for chelation adherence. Adherence interventions should consider focusing on potentially modifiable situational variables (psychological and behavioral). PMID- 29521138 TI - Longitudinal monitoring of mesoscopic cortical activity in a mouse model of microinfarcts reveals dissociations with behavioral and motor function. AB - Small vessel disease is characterized by sporadic obstruction of small vessels leading to neuronal cell death. These microinfarcts often escape detection by conventional magnetic resonance imaging and are identified only upon postmortem examination. Our work explores a brain-wide microinfarct model in awake head fixed mice, where occlusions of small penetrating arterioles are reproduced by endovascular injection of fluorescent microspheres. Mesoscopic functional connectivity was mapped longitudinally in awake GCaMP6 mice using genetically encoded calcium indicators for transcranial wide-field calcium imaging. Microsphere occlusions were quantified and changes in cerebral blood flow were measured with laser speckle imaging. The neurodeficit score in microinfarct mice was significantly higher than in sham, indicating impairment in motor function. The novel object recognition test showed a reduction in the discrimination index in microinfarct mice compared to sham. Graph-theoretic analysis of functional connectivity did not reveal significant differences in functional connectivity between sham and microinfarct mice. While behavioral tasks revealed impairments following microinfarct induction, the absence of measurable functional alterations in cortical activity has a less straightforward interpretation. The behavioral alterations produced by this model are consistent with alterations observed in human patients suffering from microinfarcts and support the validity of microsphere injection as a microinfarct model. PMID- 29521139 TI - Emerging roles of bexarotene in the prevention, treatment and anti-drug resistance of cancers. AB - INTRODUCTION: Retinoic acid X receptors play key roles in tumor cell proliferation, differentiation, apoptosis and angiogenesis via transcriptional regulation. Bexarotene is a specific RXRs agonist which has been granted by FDA approval for the clinical treatment of cutaneous T cell lymphoma (CTCL). Its cancer prevention and treatment potentials in various tumors have been under investigation over the past decade. Areas covered: This review summarizes the efficacy and underlying mechanisms of bexarotene for the treatment of multiple cancers based on the launched clinical trials as well as the basic studies. Expert commentary: In general, bexarotene is an active and reasonable chemoprevention and treatment for various cancers and its combination regimen with other cytotoxic agents or targeted drugs may significantly enhance efficacy and at the same time reduce toxicity due to their nonoverlapping side effects. However, only a subpopulation of bexarotene treated patients benefited from bexarotene administration in most cases. The level of RXRs may serve as a preliminary indicator for the bexarotene response in cancers such as non-small cell lung cancer, acute myeloid leukemia, breast cancer, thyroid cancer and melanoma. Further identification and verification of bexarotene response biomarkers may finally lead to the personalized clinical application of bexarotene on cancers beyond CTCL. PMID- 29521140 TI - Current and emerging treatment options for a patient with a second relapse of Hodgkin's lymphoma. AB - INTRODUCTION: Hodgkin's lymphoma (HL) is largely a curable disease with excellent prognosis. The standard of care in patients with relapsed disease has been to try salvage chemotherapy followed by an autologous stem cell transplantation (ASCT). Managing the patients who relapse after ASCT, is challenging. With the approval of targeted therapies such as PD-1 inhibitors, brentuximab vedotin, the outcomes have improved greatly. Areas covered: This review summarizes the current data available on the newer therapies as well as the present strategies used to treat patients with relapsed HL after an autologous stem cell transplantation. Expert commentary: The approval of brentuximab vedotin and PD-L1 inhibitors has ushered in a new era of targeted therapy in HL. There are currently several targeted therapies under investigation, particularly in the setting of relapsed disease. The current challenges faced are how best to integrate these newer therapies into the existing treatment regimens, finding a right combination with minimal toxicities, role of allogenic transplant in the era of targeted therapy. PMID- 29521142 TI - Therapeutic potential of melatonin for breast cancer radiation therapy patients. AB - Melatonin is an endogenous hormone primarily known for its action on the circadian rhythms. But pre-clinical studies are reporting both its radioprotective and radiosensitizing properties, possibly mediated through an interaction between melatonin and the regulation of estrogens. Melatonin pre treatment prior to ionizing radiation was associated with a decrease in cell proliferation and an increase in p53 mRNA expression, leading to an increase in the radiosensitivity of breast cancer cells. At the same time, a decrease in radiation-induced side effects was described in breast cancer patients and in rodent models. This review examines the potential for melatonin to improve the therapeutic outcomes of breast radiation therapy, specifically estrogen receptor positive patients. Evidence suggests that melatonin may offer a novel, non-toxic and cheap adjuvant therapy to improve the existing treatment modalities. But further research is required in the clinical setting before a clear understanding of its therapeutic benefits is determined. PMID- 29521141 TI - Anti-neuroinflammatory effects of cudraflavanone A isolated from the chloroform fraction of Cudrania tricuspidata root bark. AB - CONTEXT: Cudrania tricuspidata Bureau (Moraceae) is an important source of traditional Korean and Chinese medicines used to treat neuritis and inflammation. OBJECTIVE: The anti-neuroinflammatory effects of cudraflavanone A isolated from a chloroform fraction of C. tricuspidata were investigated in LPS-induced BV2 cells. MATERIALS AND METHODS: Cudraflavanone A was isolated from the root of C. tricuspidata, and its structure was determined by MS and NMR data. Cytotoxicity of the compound was examined by MTT assay, indicating no cytotoxicity at 5-40 MUM of cudraflavanone A. NO concentration was measured by the Griess reaction, and the levels of PGE2, cytokines and COX-2 enzyme activity were measured by each ELISA kit. The mRNA levels of cytokines were analysed by quantitative-PCR. The expression of iNOS, COX-2, HO-1, NF-kappaB, MAPKs and Nrf2 was detected by Western blot. RESULTS: Cudraflavanone A had no major effect on cell viability at 40 MUM indicating 91.5% viability. It reduced the production of NO (IC50 = 22.2 MUM), PGE2 (IC50 = 20.6 MUM), IL-1beta (IC50 = 24.7 MUM) and TNF-alpha (IC50 = 33.0 MUM) in LPS-stimulated BV2 cells. It also suppressed iNOS protein, IL-1beta and TNF-alpha mRNA expression. These effects were associated with the inactivation of NF-kappaB, JNK and p38 MAPK pathways. This compound mediated its anti-neuroinflammatory effects by inducing HO-1 protein expression via increased nuclear translocation of Nrf2. DISCUSSION AND CONCLUSIONS: The present study suggests a potent effect of cudraflavanone A to prevent neuroinflammatory diseases. Further investigation is necessary to elucidate specific molecular mechanism of cudraflavanone A. PMID- 29521143 TI - Human disease glycomics: technology advances enabling protein glycosylation analysis - part 2. AB - INTRODUCTION: The changes in glycan structures have been attributed to disease states for several decades. The surface glycosylation pattern is a signature of physiological state of a cell. In this review we provide a link between observed substructural glycan changes and a range of diseases. Areas covered: We highlight biologically relevant glycan substructure expression in cancer, inflammation, neuronal diseases and diabetes. Furthermore, the alterations in antibody glycosylation in a disease context are described. Expert commentary: Advances in technologies, as described in Part 1 of this review have now enabled the characterization of specific glycan structural markers of a range of disease states. The requirement of including glycomics in cross-disciplinary omics studies, such as genomics, proteomics, epigenomics, transcriptomics and metabolomics towards a systems glycobiology approach to understanding disease mechanisms and management are highlighted. PMID- 29521144 TI - In vitro marker gene expression analyses in human peripheral blood mononuclear cells: A tool to assess safety of influenza vaccines in humans. AB - Vaccines are inoculated in healthy individuals from children to the elderly, and thus high levels of safety and consistency of vaccine quality in each lot must meet the required specifications by using preclinical and lot release testing. Because vaccines are inoculated into humans, recapitulation of biological reactions in humans should be considered for test methods. We have developed a new method to evaluate the safety of influenza vaccines using biomarker gene expression in mouse and rat models. Some biomarker genes are already known to be expressed in human lymphocytes, macrophages and dendritic cells; therefore, we considered some of these genes might be common biomarkers for human and mice to evaluate influenza vaccine safety. In this study, we used human peripheral blood mononuclear cells (PBMC) as a primary assessment tool to confirm the usefulness of potential marker genes in humans. Analysis of marker gene expression in PBMC revealed biomarker gene expressions were dose-relatedly increased in toxic reference influenza vaccine (RE)-stimulated PBMC. Although some marker genes showed increased expression in hemagglutinin split vaccine-stimulated PBMC, their expression levels were lower than that of RE in PBMC from two different donors. Many marker gene expressions correlated with chemokine production. Marker genes such as IRF7 were associated with other Type 1 interferon (IFN)-associated signals and were highly expressed in the CD304+ plasmacytoid dendritic cell (pDC) population. These results suggest PBMC and their marker genes may be useful for vaccine safety evaluation in humans. PMID- 29521145 TI - Extensive sharing of mitochondrial COI and CYB haplotypes among reef-building staghorn corals (Acropora spp.) in Sabah, North Borneo. AB - This study is aimed at establishing a baseline on the genetic diversity of the Acropora corals of Sabah, North Borneo based on variations in the partial COI and CYB nucleotide sequences. Comparison across 50 shallow-water Acropora morphospecies indicated that the low substitution rates in the two genes were due to negative selection and that rate heterogeneity between them was asymmetric. CYB appeared to have evolved faster than COI in the Acropora as indicated by differences in the rate of pairwise genetic distance, degrees of transition bias (Ts/Tv), synonymous-to-nonsynonymous rate ratio (dN/dS), and substitution patterns at the three codon positions. Despite the relatively high haplotype diversity (Hd), nucleotide diversity (pi) of the haplotype datasets was low due to stringent purifying selection operating on the genes. Subsequently, we identified individual COI and CYB haplotypes that were each extensively shared across sympatrically and allopatrically distributed Indo-Pacific Acropora. These reciprocally common mtDNA types were suspected to be ancestral forms of the genes whereas other haplotypes have mostly evolved from autoapomorphic mutations which have not been fixed within the species even though they are selectively neutral. To our knowledge, this is the first report on DNA barcodes of Acropora species in North Borneo and this understanding will play an important role in the management and conservation of these important reef-building corals. PMID- 29521146 TI - Desalted Salicornia europaea powder and its active constituent, trans-ferulic acid, exert anti-obesity effects by suppressing adipogenic-related factors. AB - CONTEXT: Salicornia europaea (Amaranthaceae) (SE) has been shown to reduce obesity, but it remains a problem as a food supplement because of its high salt content (25-35% NaCl). OBJECTIVES: This study investigated the anti-obesity effects and mechanism of action of desalted SE powder (DSP). MATERIALS AND METHODS: Sprague-Dawley rats (n = 50) were divided into a normal control group (NC), a high-fat diet (HFD)-induced obesity control group (HFD), and HFD groups co-administered DSP (250 and 500 mg/kg) or Garcinia cambogia (Clusiaceae) extract (GE, 200 mg/kg, standard control) orally each day for 12 weeks. RESULTS: The body weight was significantly reduced by co-administration of DSP (596.51 +/- 19.84 kg, 4.60% and 562.08 +/- 9.74 kg, 10.10%, respectively) and GE (576.00 +/- 11.29 kg, 7.88%) relative to the HFD group (625.25 +/- 14.02 kg) and was accompanied by reduced abdominal fat mass, and serum lipid levels, with no effects on feed intake. To find the underlying mechanism of the anti-obesity effects, trans ferulic acid (TFA) was identified as the main ingredient and investigated with regard to whether it attenuated adipogenesity in 3T3L-1 cells. DSP-derived TFA suppressed adipocyte differentiation and accumulation of intracellular lipids. TFA also down-regulated the adipogenesis-related gene expression of sterol regulatory element-binding protein 1, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein-alpha and fatty acid synthase. CONCLUSIONS: These findings suggest that DSP may be considered for use as a food supplement intent of controlling obesity through its antiobesity and antiadipogenic properties. PMID- 29521147 TI - Optimizing skin and skin structure infection outcomes: considerations of cost of care. AB - INTRODUCTION: Skin and skin structure infections (SSSIs) refer to a collection of clinical infectious syndromes involving layers of skin and associated soft tissues. Although associated with less morbidity and mortality than other common skin infections, SSSIs represent a significant increasing source of healthcare expense, with a prevalence of 500 episodes per 10,000 patient-years in the United States resulting in burdening health care systems, of approximately $6 billion annually. Areas covered: Opportunities to reduce costs of care associated with SSSI are highlighted, including transitions of care and avoiding unnecessary hospital admissions. Moreover, we reviewed new antibiotics (e.g. single dose glycopeptides), and the impact of consulting specialists in the emergency department on SSSI treatment outcomes. Expert commentary: New healthcare models and payment strategies combined with new therapeutics are challenging norms of care. Newer drugs to treat skin infections can move a substantive percent of patients previously admitted to hospital care to the outpatient setting. Additionally, patients can be managed with oral or one time intravenous regimens, improving the likelihood of patient adherence and satisfaction. These variables need to be weighed against added acquisition costs and the development of thoughtful algorithms is needed to direct care and optimize treatment, cost, and patient satisfaction. PMID- 29521148 TI - Does maintenance therapy have a role in mantle cell lymphoma treatment? AB - INTRODUCTION: Mantle cell lymphoma (MCL) is a rare but often aggressive B-cell non-Hodgkin lymphoma (NHL). Initial therapy can achieve high response rates but invariably patients relapse and die from their disease. Incorporating a maintenance phase into the treatment strategy may prolong remission duration and ultimately prolong survival. Areas covered: The current literature incorporating a maintenance phase into treatment strategies for newly diagnosed and pre-treated MCL patients has been summarized. A literature search was performed using search terms 'mantle cell lymphoma', 'indolent NHL', 'maintenance', 'interferon', 'rituximab', 'lenalidomide', 'bortezomib' and 'ibrutinib'. Relevant conference proceedings and on-going clinical trial databases were also searched. Expert commentary: There have been few significant trials evaluating the use of maintenance therapy in the context of MCL. Of those performed only rituximab has a significant body of evidence to support it's use and it's benefit is confined to use after certain specific therapies. Of the newer drugs ibrutinib is the most active of the single agents being used in this condition and it is given as continuous therapy to patients who respond to it. How it will be used precisely in a maintenance approach needs to be better defined and is the subject of on going clinical trials. PMID- 29521150 TI - The difference is more than floating: factors affecting breast cancer survivors' decisions to join and maintain participation in dragon boat teams and support groups. AB - PURPOSE: Peer support can be helpful in rehabilitation from breast cancer, but participation in peer support groups is low. Groups that provide support opportunities in physical activity contexts are an attractive alternative for some survivors. This study examined survivors' reasons for joining and maintaining participation on a dragon boat team, along with perceptions of barriers and attractions to traditional peer support groups. MATERIALS AND METHODS: Seventeen breast cancer survivors were interviewed on five occasions over their first two seasons of a newly formed dragon boating team to explore their perceptions of peer support groups and dragon boating. Data were inductively analyzed using thematic analysis. RESULTS: Categories surrounding physical, psychological, social and community features were identified with several themes emerging within each. Advantages of dragon boating included opportunities to get a combination of physical, psychosocial and community benefits; health improvement and behavior change; and obtaining social support without the focus being on cancer. Peer support groups were identified as having advantages for forming relationships and avoiding barriers associated with physical activity. CONCLUSIONS: While neither type of program meets all needs, practical considerations are identified for incorporating advantages of both programs to improve participation. Implications for rehabilitation Further understanding of perceptions, and attractions and challenges to taking part in group programs will inform development of accessible programs that target multiple rehabilitation needs. Physical activity can provide a positive, alternative focus that takes the emphasis off of cancer, which is more accessible to some survivors. Physical activity also provides opportunities to build relationships around a common, positive goal, which can be a foundation for providing support for coping with cancer. PMID- 29521149 TI - Protective properties of geniposide against UV-B-induced photooxidative stress in human dermal fibroblasts. AB - CONTEXT: Geniposide (genipin-1-O-beta-d-glucoside) is a major bioactive ingredient in the fruits of gardenia [Gardenia jasminoides J. Ellis (Rubiaceae)], a traditional herbal medicine in Asian countries. OBJECTIVE: This work assesses the skin anti-photoaging potential of geniposide in human dermal fibroblasts under UV-B irradiation. MATERIALS AND METHODS: The anti-photoaging property of geniposide, at varying concentrations (5, 12 and 30 MUM) treated for 30 min prior to UV-B irradiation, was evaluated by analysing reactive oxygen species (ROS), promatrix metalloproteinase-2 (proMMP-2), glutathione (GSH), superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2) and cellular viability. RESULTS: Geniposide suppressed the ROS elevation under UV-B irradiation, which was revealed using three ROS-sensitive fluorescent dyes. The use of 2',7' dichlorodihydrofluorescein diacetate (DCFH-DA), dihydroethidium (DHE) and dihydrorhodamine 123 (DHR-123) elicited the IC50 values of 10.5, 9.8 and 21.0 MUM, respectively. Geniposide attenuated proMMP-2 at activity and protein levels that were elevated under UV-B-irradiation. Geniposide at 5, 12 and 30 MUM augmented the UV-B-reduced total GSH content to 1.9 +/- 0.1-, 2.2 +/- 0.2- and 4.1 +/- 0.2-fold, respectively. Geniposide at 5, 12 and 30 MUM upregulated total SOD activity to 2.3 +/- 0.1-, 2.5 +/- 0.3- and 3.3 +/- 0.3-fold, respectively, under UV-B irradiation. The UV-B-reduced Nrf2 levels were also upregulated by geniposide treatment. Geniposide, at the concentrations used, was unable to interfere with cellular viabilities under UV-B irradiation. DISCUSSION AND CONCLUSIONS: After the skin anti-photoaging potential of geniposide may be further verified, it can be utilized as a safer resource in the manufacture of effective anti-aging cosmetics. PMID- 29521151 TI - Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database. AB - INTRODUCTION: As both anti-tumour effects and toxicity are thought to be dose dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored. METHODS: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0-2 vs. 3 4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression. RESULTS: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender. CONCLUSION: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under treatment. PMID- 29521152 TI - Are competing risks models appropriate to describe implant failure? AB - Background and purpose - The use of competing risks models is widely advocated in the arthroplasty literature due to a perceived bias in comparison of simple Kaplan-Meier estimates. Proponents of competing risk models in the arthroplasty literature appear to be unaware of the subtle but important differences in interpretation of net and crude failure estimated by competing risk and Kaplan Meier methods respectively. Methods - Using a simple simulation we illustrate the differences between competing risks and Kaplan-Meier methods. Results - Competing risk and Kaplan-Meier methods estimate different survival quantities, i.e., crude and net failure respectively. Estimates of crude failure estimated using competing risk methods will be less than net failure as estimated using Kaplan Meier methods. Interpretation - Kaplan-Meier methods are appropriate for describing implant failure, whereas crude survival estimated using competing risk methods estimates the risk of surgical revision as it depends on both implant failure and mortality. Both competing risk models and Kaplan-Meier methods are useful in arthroplasty, and both provide unbiased estimates of crude and net failure in the absence of any confounding or selection respectively. Surgeons and researchers should carefully consider whether the use of competing risks is always justified. Lower estimates of failure from competing risk models may be misleading to surgeons who are attempting to select the best implants with the lowest failure rates for their patients. PMID- 29521153 TI - E-Cigarettes: Implications for Health Promotion in the Asian Pacific Region. AB - Since their introduction to the United States in 2007, electronic cigarettes (e cigarettes) use has grown exponentially. This rapid growth in e-cigarette use has been heralded by some as a potential important public health measure that could ultimately replace tobacco cigarettes, while others recommend a cautionary approach until there is clear evidence they will not become "new tobacco" bringing a possible myriad of other problems. E-cigarettes may have real benefits, however they do expose users and those nearby to organic compounds, solvents and particulate matter, with there being limited data relating to their health impact. It is unclear as to whether this relatively new device has the potential to exacerbate nicotine addictions, or play a part in reducing harm and smoking cessation. The fundamental requirement of public health practice is to do no harm and from the inconclusive evidence we have to date on e-cigarettes, it appears a cautious approach is warranted. This commentary reviews evidence that supports a cautious approach to e-cigarette availability in Australia and the Asian Pacific region. PMID- 29521154 TI - Recent Trends in Blood Pressure According to Economic Status: Korean National Health and Nutrition Examination Survey From 2005 to 2015. AB - Our study assessed recent blood pressure (BP) trends according to economic status based on data from 2005 to 2015. In total, 56 873 participants were included and were defined as low, middle-low, middle-high, and high according to their house income quartile. In men, the mean systolic BP ( P < .001, beta = -1.95; P = .01, beta = -0.61; P = .35, beta = -0.19; and P = .04, beta = -0.47, from the low to the high group, respectively) and diastolic BP were decreased significantly in all groups ( P < .001, beta = -2.18; P < .001, beta = -0.77; P = .02, beta = 0.40; and P < .001, beta = -0.69, from the low to the high group, respectively). In women, the decreasing trends in systolic BP and diastolic BP were statistically significant except in the high-income group. In addition, the percentages of less-than-normotensive and less-than-hypertensive BP in both sexes and the control rate of hypertension on antihypertensive medications increased in all groups. Decreasing BP trends were observed in the recent decade and the gap in health inequities has been decreased, particularly in men in Korea. PMID- 29521155 TI - Migraine, hormones and the menopausal transition. AB - Migraine is a common, disabling and incapacitating headache disorder that may be triggered by many factors, such as hormones especially during the perimenopausal period, where large alterations in estradiol levels can occur. The evidence implies that hormonal fluctuations are one of the important triggers of migraine. During reproductive life and during hormonal contraception, the course of migraine can be impacted. Different types of migraine with and without aura can be variously influenced by hormones. Migraine can constitute a risk factor for stroke and this must be taken in account for menopause hormone therapy. Hormone therapy is a possible approach to prevent migraine that happens during the menopause transition. Scarce data on the various regimens and types of hormone therapy are available. Transdermal estradiol displays a more favorable profile on migraine than oral estrogens because it may provide more constant levels of estrogens. PMID- 29521156 TI - Nurse evaluation of the redesigned fertility pen injector: a questionnaire-based observational survey. AB - BACKGROUND: Owing to the wide-ranging role nurses have in supporting patients undergoing fertility treatment, we recorded the learning/teaching expectations and experiences of nurses using a redesigned fertility pen injector. METHODS: This was a multicentre, simulated-use study, using unbranded placebo-filled pens. Before teaching patients, nurses were given free choice to rank the importance of the device attributes and predict the level of patient anxiety. Nurses taught 2-5 patients how to prepare the device, inject the dose and complete an incomplete dose. They rated the teaching experience on a 5-point scale during a questionnaire interview. RESULTS: Thirty nurses were enrolled across four countries. All nurses found the redesigned fertility pen injector easy to use and teach. 90% found the overall administration process easy to learn and teach. More than 80% (range 83%-100%) found each of the steps easy (score 4 or 5), and most found the steps easier to teach than expected (score 4 or 5; range 57%-90%). 97% would recommend the redesigned fertility pen injector to a colleague. CONCLUSIONS: Nurses rated the redesigned fertility pen injector easy to learn and use and easier to teach than expected. Most would recommend the device to a colleague. PMID- 29521157 TI - Reflections on the theoretical contributions and clinical applications of parental insightfulness. AB - This paper outlines the theoretical antecedents that contextualize parental insightfulness and examines this concept's value in assessing parental functioning and in monitoring treatment progress with parents and young children who experience mental health and relationship problems. As a concept, parental insightfulness provides a much-needed bridge linking important aspects of attachment theory with their psychoanalytic origins, including early contributions that conceptualize parenting as a developmental process that furthers the unfolding capacities of the adult self. The paper examines the compatibility between the dimensions of parental insightfulness and the criteria for a healthy adult sense of self. The empirical body of knowledge generated by the concept of parental insightfulness is briefly reviewed as the basis for using the concept as a valuable tool for the empirical exploration of intrapsychic, interpersonal, and clinical processes in parents and their children. PMID- 29521158 TI - Calreticulin mutation analysis in non-mutated Janus kinase 2 essential thrombocythemia patients in Chiang Mai University: analysis of three methods and clinical correlations. AB - OBJECTIVES: The primary objective was to determine the prevalence of calreticulin (CALR) mutation in patients with non-JAK2V617F mutated essential thrombocythemia (ET). The secondary objectives were to evaluate the accuracy of CALR mutation analysis by high-resolution melting (HRM) analysis and real-time polymerase chain reaction (PCR) compared with DNA sequencing and to compare clinical characteristics of CALR mutated and JAK2V617F mutated ET. METHODS: This was a prospective cohort study involving ET patients registered at Chiang Mai University in the period September 2015-September 2017 who were aged more than 2 years, and did not harbor JAK2V617F mutation. The presence of CALR mutation was established by DNA sequencing, HRM, and real-time PCR for type 1 and type 2 mutation. Clinical data were compared with that from ET patients with mutated JAK2V617F. RESULTS: Twenty-eight patients were enrolled onto the study. CALR mutations were found in 10 patients (35.7%). Three patients had type 1 mutation, 5 patients had type 2 mutation, 1 patient had type 18 mutation, and 1 patients had novel mutations (c.1093 C-G, c.1098_1131 del, c.1135 G-A). HRM could differentiate between the types of mutation in complete agreement with DNA sequencing. Patients with a CALR mutation showed a significantly greater male predominance and had a higher platelet count when compared with 42 JAK2V617F patients. DISCUSSION AND CONCLUSIONS: The prevalence of CALR mutation in JAK2V617F-negative ET in this study is 35.7%. HRM is an effective method of detecting CALR mutation and is a more advantageous method of screening for CALR mutation. PMID- 29521159 TI - Twofold trauma exposure - the dual function of attachment avoidance. AB - Spouses of traumatized war veterans might suffer from distress following indirect exposure to combat and direct exposure to domestic abuse. Yet the effect of this twofold trauma exposure is far from being fully understood. Theory views attachment security as a personal resource mitigating adversity, whereas attachment insecurities intensify distress. Nevertheless, there are mixed results concerning the effects of attachment in the aftermath of trauma. Furthermore, the role of trauma exposure levels regarding the effects of attachment remains largely uninvestigated. Filling these gaps, this study assessed female military spouses 30 (T1) and 38 (T2) years after the 1973 Yom Kippur War. Direct (domestic abuse) and indirect (veteran partners' posttraumatic stress symptoms) trauma exposure, attachment, depression, and anxiety were assessed. Findings indicated an interaction between the trauma types in predicting spouses' anxiety. Domestic abuse moderated the relations between attachment and distress. Although attachment anxiety had nonsignificant effects on anxiety among low-level domestic abuse sufferers, it predicted elevated anxiety among high-level domestic abuse sufferers. Furthermore, while attachment avoidance predicted elevated distress among low-level domestic abuse sufferers, its effects dissolved or became positive in nature among high-level domestic abuse sufferers. Discussion focuses on evolutionary explanations of the functions of attachment under different conditions of threat. PMID- 29521160 TI - A multi-level, multi-jurisdictional strategy: Transnational tobacco companies' attempts to obstruct tobacco packaging restrictions. AB - Despite the extensive literature on the tobacco industry, there has been little attempt to study how transnational tobacco companies (TTCs) coordinate their political activities globally, or to theorise TTC strategies within the context of global governance structures and policy processes. This article draws on three concepts from political science - policy transfer, multi-level governance and venue shifting - to analyse TTCs' integrated, global strategies to oppose augmented packaging requirements across multiple jurisdictions. Following Uruguay's introduction of extended labelling requirements, Australia became the first country in the world to require tobacco products to be sold in standardised ('plain') packaging in 2012. Governments in the European Union, including in the United Kingdom and Ireland, adopted similar laws, with other member states due to follow. TTCs vehemently opposed these measures and developed coordinated, global strategies to oppose their implementation, exploiting the complexity of contemporary global governance arrangements. These included a series of legal challenges in various jurisdictions, alongside political lobbying and public relations campaigns. This article draws on analysis of public documents and 32 semi-structured interviews with key policy actors. It finds that TTCs developed coordinated and highly integrated strategies to oppose packaging restrictions across multiple jurisdictions and levels of governance. PMID- 29521161 TI - Neural networks supporting social evaluation of bodies based on body shape. AB - Body shape cues inferences regarding personality and health, but the neural processes underpinning such inferences remain poorly understood. Across two fMRI experiments, we test the extent to which neural networks associated with body perception and theory-of-mind (ToM) support social inferences based on body shape. Participants observed obese, muscular, and slim bodies that cued distinct social inferences as revealed in behavioural pilot experiments. To investigate judgment intentionality, the first fMRI experiment required participants to detect repeat presentations of bodies, whereas in fMRI Experiment 2 participants intentionally formed an impression. Body and ToM networks were localized using independent functional localisers. Experiment 1 revealed no differential network engagement for muscular or obese compared to slim bodies. By contrast, in Experiment 2, compared to slim bodies, forming impressions of muscular bodies engaged the body-network more, whereas the ToM-network was engaged more when forming impressions of obese bodies. These results demonstrate that social judgments based on body shape do not rely on a single neural mechanism, but rather on multiple mechanisms that are separately sensitive to body fat and muscularity. Moreover, dissociable responses are only apparent when intentionally forming an impression. Thus, these experiments show how segregated networks operate to extract socially-relevant information cued by body shape. PMID- 29521162 TI - Sociotechnical factors influencing unsafe use of hospital information systems: A qualitative study in Malaysian government hospitals. AB - The objective of this study is to identify factors influencing unsafe use of hospital information systems in Malaysian government hospitals. Semi-structured interviews with 31 medical doctors in three Malaysian government hospitals implementing total hospital information systems were conducted between March and May 2015. A thematic qualitative analysis was performed on the resultant data to deduce the relevant themes. A total of five themes emerged as the factors influencing unsafe use of a hospital information system: (1) knowledge, (2) system quality, (3) task stressor, (4) organization resources, and (5) teamwork. These qualitative findings highlight that factors influencing unsafe use of a hospital information system originate from multidimensional sociotechnical aspects. Unsafe use of a hospital information system could possibly lead to the incidence of errors and thus raises safety risks to the patients. Hence, multiple interventions (e.g. technology systems and teamwork) are required in shaping high quality hospital information system use. PMID- 29521163 TI - Polygamy, piousness, and the practice of medicine: Understanding Brigham Young and the predominance of female medical providers in early Utah. AB - The nineteenth century Mormon Prophet, Brigham Young, has long been lauded as progressive for sending dozens of Mormon women from the Utah territory to receive a formal medical education at The Women's Medical College of Pennsylvania. This manuscript comes to a contrary conclusion through close reading of diaries and journals created by these same women and the public speeches of the Prophet himself. These texts have historically been held up as evidence of Prophet Young's encouragement of women as physicians. This new interpretation of historical texts includes stringent study of his speeches, as they were originally reported, alongside later citations by historians from within the faith that decontextualized his words to fit the Church's predominant narrative. This manuscript concludes that, contrary to Church tradition, the historical record provides evidence of Young's desire to enforce limits and separations along traditional gender lines rather than showing an intent to change those cultural norms. PMID- 29521164 TI - Causes of microcytic anaemia and evaluation of conventional laboratory parameters in the differentiation of erythrocytic microcytosis in blood donors candidates. AB - CONTEXT AND OBJECTIVE: Microcytic anaemia results from defective synthesis of haemoglobin in the erythroid precursors, causing a reduction in its mean corpuscular volume (MCV). The most common causes of microcytosis, without the increase in HbA2 levels, are iron deficiency anaemia (IDA) and alpha-thalassemia. The aim of this study was to identify the causes of microcytic anaemia and evaluate the haematological parameters from blood donors deemed ineligible (due to the low haematocrit level) that would differentiate the IDA and alpha-thal, whether isolated or in association. METHODS: Genomic DNA was submitted to the polymerase chain reaction multiplex for the diagnosis of the most common allele deletions of alpha-thal and erythrogram and in order to verify haematological parameters. Iron deficiency (ID) was determined through the measurement of serum ferritin. RESULTS: Of the 204 samples, 82 (40.2%) were identified with ID, 24 (17.8%) with alpha-thal and 10 (4.9%) with ID associated with alpha-thal. In the alpha-thal with ID group haemoglobin (Hb), MCV, mean corpuscular Hb concentration (MCHC) and mean corpuscular Hb (MCH) values were significantly lower compared to the isolated alpha-thal. In the group with ID Hb, MCV, MCHC and MCH values were significantly lower compared to those with isolated alpha-thal. The alpha-thal with ID group, showed Hb, MCV, MCHC and MCH significantly reduced when compared to those with IDA. CONCLUSIONS: This study showed that the values of haematological parameters, especially haematocrit, Hb, MCV, MCH, MCHC and red blood cell distribution width (RDW), are lower in patients with IDA, especially when associated with alpha-thal and therefore it may be useful to discriminate between the different types of microcytic anaemia. PMID- 29521165 TI - A novel synthetic compound, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2 iminothiazolidin-4-one (MHY773) inhibits mushroom tyrosinase. AB - As part of continued efforts for the development of new tyrosinase inhibitors, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one derivatives (1a - 1l) were rationally synthesized and evaluated for their inhibitory potential in vitro. These compounds were designed and synthesized based on the structural attributes of a beta-phenyl-alpha,beta-unsaturated carbonyl scaffold template. Among these compounds, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin 4-one (1e, MHY773) exhibited the greatest tyrosinase inhibition (IC50 = 2.87 MUM and 8.06 MUM for monophenolase and diphenolase), and outperformed the positive control, kojic acid (IC50 = 15.59 and 31.61 MUM). The kinetic and docking studies demonstrated that MHY773 interacted with active site of tyrosinase. Moreover, a melanin quantification assay demonstrated that MHY773 attenuates alpha-melanocyte stimulating hormone (alpha-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-induced melanin contents in B16F10 melanoma cells. Taken together, these data suggest that MHY773 suppressed the melanin production via the inhibition of tyrosinase activity. MHY773 is a promising for the development of effective pharmacological and cosmetic agents for skin-whitening. PMID- 29521166 TI - Establishment of plasmid vector and allelic exchange mutagenesis systems in a mycobacterial strain that is able to degrade polycyclic aromatic hydrocarbon. AB - Plasmid vector and allelic exchange mutagenesis systems were established for the genetic analysis of a phenanthrene-degrading mycobacterial strain, Mycobacterium sp. EPa45. Successful application of these systems revealed the necessity of the EPa45 phdI gene for the degradation of 1-hydroxy-2-naphthoate, which has been proposed to be an intermediate product in the degradation pathway of phenanthrene. PMID- 29521167 TI - Mechanosensing Piezo channels in tissue homeostasis including their role in lungs. AB - Piezo channels are deemed to constitute one of the most important family of mechanosensing ion channels since their discovery in 2010. With recent advances in identifying their topological structure and the discovery of the agonist Yoda1 as well as the specific inhibitor GsMTx4, it is now possible to study the mechanisms by which Piezo channels are involved in physiological and pathophysiological processes. During embryonic cardiovascular development, Piezo1 senses shear stress and promotes vasculature growth. In adult mice, Piezo1 mediates the release of nitric oxide and ATP from endothelial cells to regulate blood pressure. Piezo channels also play a crucial role in cell differentiation and tissue homeostasis by exquisite mechanical force sensing. Piezo channels are also abundantly expressed in lung tissues. As the lung is exposed to complex pulmonary hemodynamics and respiratory mechanics, cells in the lung, such as microvascular endothelial cells, bear mechanical forces from blood flow shear, pulsatile strain, static pressure, and cyclic stretch due to respiratory movement. These mechanical stimuli are involved in a serial of physiological function and pathophysiological processes of the lung, many of which Piezo channels may be the key player. Mutation of genes encoding Piezo channels are also associated with hereditary human diseases, thus highlighting the critical role of Piezo channels in both tissue homeostasis and disease. PMID- 29521168 TI - Influence of ankle joint plantarflexion and dorsiflexion on lateral ankle sprain: A computational study. AB - Understanding the mechanism of injury involved in lateral ankle sprain is essential to prevent injury, to establish surgical repair and reconstruction, and to plan reliable rehabilitation protocols. Most studies for lateral ankle sprain posit that ankle inversion, internal rotation, and plantarflexion are involved in the mechanism of injury. However, recent studies indicated that ankle dorsiflexion also plays an important role in the lateral ankle sprain mechanism. In this study, the contributions of ankle plantarflexion and dorsiflexion on the ankle joint were evaluated under complex combinations of internal and inversion moments. A multibody ankle joint model including 24 ligaments was developed and validated against two experimental cadaveric studies. The effects of ankle plantarflexion (up to 60 degrees ) and dorsiflexion (up to 30 degrees ) on the lateral ankle sprain mechanism under ankle inversion moment coupled with internal rotational moment were investigated using the validated model. Lateral ankle sprain injuries can occur during ankle dorsiflexion, in which the calcaneofibular ligament and anterior talofibular ligament tears may occur associated with excessive inversion and internal rotational moment, respectively. Various combinations of inversion and internal moment may lead to anterior talofibular ligament injuries at early ankle plantarflexion, while the inversion moment acts as a primary factor to tear the anterior talofibular ligament in early plantarflexion. It is better to consider inversion and internal rotation as primary factors of the lateral ankle sprain mechanism, while plantarflexion or dorsiflexion can be secondary factor. This information will help to clarify the lateral ankle sprain mechanism of injury. PMID- 29521169 TI - Re-design of a uniplanar, monolateral external fixator. AB - This work deals with the structural analysis of screw clamps for external fixator devices. Screw clamps are widely used in external fixators as a means to connect the half-pins to the fixator body. The analysis is carried out by both numerical and experimental techniques, based on the case study of a clamp produced by Citieffe (Bologna, Italy). As a preliminary activity, the tribological parameters involved in the screw-clamp interaction have been characterized by means of a mixed finite element analysis and experimental procedure. Then, an assessment of the current design of the clamp has been carried out. A re-design has been proposed, which, based on some targeted geometrical modifications, allows achieving higher strength requirements with the same overall dimensions and type of materials. A higher load-bearing capability for a given size may allow the fixator to be used on a broader population. Finally, a list of good practices for the design of this kind of clamps has been proposed. PMID- 29521170 TI - The relationship of systemic markers of haemostasis with retinal blood vessel responses in cardiovascular disease and/or diabetes. AB - Background Hypercoagulability is a leading factor in diabetes and cardiovascular disease. Retinal vessel responses to flickering light are an important tool for assessing ocular function. We hypothesised a significant relationship between systemic markers of haemostasis and retinal vessel function. Methods Intra-ocular pressure and retinal microcirculation function were measured in 116 patients with diabetes and/or cardiovascular disease using unstimulated and stimulated arterial and venous retinal vessel responses to flickering light. Haemostasis was evaluated by platelet microparticles, soluble P selectin, and five functional markers of fibrin clot formation and lysis, hyperglycaemia by HbA1c. Results Intra-ocular pressure was linked to the rates of clot formation (p = 0.006) and clot dissolution (p = 0.013) whilst central retinal vein equivalent was linked to HbA1c (p = 0.017). In the first of three flickering light cycles only, arterial baseline diameter fluctuation was linked to the lag time to clot formation (p = 0.017), whilst maximum venous dilatation was linked to HbA1c (p = 0.001) and clot density (p = 0.011). HbA1c was linked to venous dilatation amplitude (p = 0.003). There were no significant links between any ocular index and any platelet index. Conclusions In addition to glycaemia, several haemostasis measures, but no measures of platelet activity, are linked to ocular and retinal blood vessel indices in patients with diabetes and/or cardiovascular disease. These associations may have pathophysiological significance. PMID- 29521171 TI - Motor performance, body fatness and environmental factors in preschool children. AB - The first aim of this study was to investigate the relationship between motor performance and body fatness among 3- to 5-year-old children. The second aim was to assess whether this relationship works similarly for boys and girls. We also investigated whether socioeconomic status (SES) and geographical area when children are aged 3 years old predicts the motor performance of 4 and 5-yr-old children. Motor performance was assessed through the Preschool Test Battery, while body fatness was estimated through body mass index (BMI). SES and geographical area were assessed via parent proxy-report questionnaires. BMI was negatively associated with standing long jump. The association of BMI and motor performance was not statistically different for boys and girls. Children from low SES performed better than high SES peers in tennis ball throw for distance. Rural children were better performers than urban peers in standing long jump. Rural area at baseline was also predictor of standing long jump and tennis ball throw for distance at time 1 and 2. In conclusion, BMI had a negative association with standing long jump and the relationship of BMI with all motor tests was similar for boys and girls. SES and rural area were predictors of motor performance. PMID- 29521172 TI - Hans Enoch and vivicillin. AB - Hans Emmanuel Enoch (1896-1991) was born in Hamburg, the son of a manufacturer of sera and vaccines. Upon his father's death, he took charge of the Hamburg Serum Werke. Following the rise of Hitler, he came to be pilloried in the Nazi press for allegedly having poisoned the population of Hamburg and was imprisoned for a time. He immigrated to England in 1935 where he had secured a position with the International Serum Company in Norwich. Following the outbreak of war, he was interned as an enemy alien, eventually ending up in Canada. In 1941, he was permitted to return to England, but wartime conditions prevented him from continuing to manufacture sera. At about this time, penicillin was making the headlines, and coupled with accounts of its miraculous properties, was the news that all production was reserved exclusively for the armed forces. Enoch decided to meet the public clamour for penicillin by producing a crude version which he termed 'vivicillin.' News of this spread globally, and he came to incur the disdain of Howard Florey for the attendant publicity. Notwithstanding this, vivicillin was to prove itself effective and its use led to the saving of lives. PMID- 29521173 TI - Fixed-ratio combination therapy for type 2 diabetes: the top ten things you should know about insulin and glucagon-like peptide-1 receptor agonist combinations. AB - Many individuals with type 2 diabetes (T2D) will eventually require insulin therapy to help achieve and maintain adequate glycemic control. However, the use of insulin can be associated with adverse effects such as hypoglycemia and weight gain, and in some patients the addition of insulin to treatment regimens is often still insufficient to achieve target glycemic control. Combining basal insulin with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) for the treatment of patients with T2D has been demonstrated to be effective and well tolerated, while mitigating many of the adverse events associated with giving either of these drug classes alone. Two titratable, fixed-ratio combination therapies, iGlarLixi and IDegLira, that combine basal insulin and a GLP-1 RA in a once-daily subcutaneous injection are currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with T2D. The fixed-ratio combination iGlarLixi combines insulin glargine 100 Units/mL with lixisenatide, while IDegLira combines insulin degludec 100 Units/mL with liraglutide. While these new fixed-ratio combinations contain antihyperglycemic medications that are familiar to most health care providers, there are many questions relating to their use when formulated as a fixed-ratio combination therapy. This article discusses the 'top 10' considerations that health care providers should know about these novel combination therapies as these agents begin to gain an increasing presence in clinical practice. PMID- 29521174 TI - Difficulties in modelling ARDS (2017 Grover Conference Series). AB - Fifty years after the first description of acute respiratory distress syndrome (ARDS), none of the many positive drug studies in animal models have been confirmed in clinical trials and translated into clinical practice. This bleak outcome of so many animal experiments shows how difficult it is to model ARDS. Lungs from patients are characterized by hyperinflammation, permeability edema, and hypoxemia; accordingly, this is what most models aim to reproduce. However, in animal models it is very easy to cause inflammation in the lungs, but difficult to cause hypoxemia. Often - and not unlike in patients - models with hypoxemia are accompanied by cardiovascular failure that necessitates fluid support and ventilation, raising the question as to the role of intensive care measures in models of ARDS. In our opinion, there are two major arguments in favor of modelling intensive care medicine in models of ARDS: (1) preventing death from shock; and (2) modelling ventilation and other ICU measures as a second hit. The preferable predictive endpoints in any model of ARDS remain unclear. At present, the best recommendation is to use endpoints that can be compared across studies (i.e. PaO2/FiO2 ratio, compliance, wet-to-dry weight ratio) rather than percentage data. Another important and often overlooked issue is the fact that the thermoneutral environmental temperatures for mice and rats are 30C and 28C, respectively; thus, at room temperature (20-22C) they suffer from cold stress with the associated significant metabolic changes. While, by definition, any model is an abstraction, we suggest that clinically relevant models of ARDS will have to closer recapitulate important properties of the disease while taking into account species-specific confounders. PMID- 29521175 TI - Back to the Future - in support of a renewed emphasis on generic agility training within sports-specific developmental pathways. AB - Perhaps as a consequence of increased specialism in training and support, the focus on engendering and maintaining agility as a generic quality has diminished within many contemporary sports performance programmes. Reflecting this, we outline a rationale suggesting that such a decreased focus represents an oversight which may be detrimental to maximising the potential of performers. We present an evidence-based argument that both generic and specific elements of agility performance should be consistently emphasised within long-term performance-training programmes. We contend that prematurely early specialisation in athlete development models can diminish focus on generic movement skill development with a subsequent detriment in adult performance. Especially when this is coupled with poor primary physical education and limited movement experiences. More speculatively, we propose that generic agility can play a role in operationalising movement development through facilitating skill transfer: thereby enabling the learning of new skills, reduce incidence of injury and facilitating re-learning of old skills during rehabilitation and Return-to-Play processes. PMID- 29521176 TI - What was it like to suffer from obsessional disorder in the United States, 1840 1950? AB - The time period from 1840 to 1950 was one of rapid, dramatic change in the experience of suffering from and receiving treatment for obsessional disorder in the United States. Several patient case histories are discussed in detail, including those of a theology professor's acquaintance (1844), a wealthy gentleman (1880), a hosiery shop proprietor (1938), and a former college student (1949). Although the focus here is on the patients' experience, many broader aspects of the history of obsessional disorder are also explored. PMID- 29521177 TI - Adaptive evidence of mitochondrial genomes in Dolycoris baccarum (Hemiptera: Pentatomidae) to divergent altitude environments. AB - Given mitochondrion is the 'energy and oxygen usage factories', adaptive signatures of mitochondrial genes have been extensively investigated in vertebrates from different altitudes, but few studies focus on insects. Here, we sequenced the complete mitochondrial genome (mitogenome) of Dolycoris. baccarum living in the Tibetan Plateau (DBHC, ~3200 m above sea level (asl)) and conducted a detailed comparative analysis with another D. baccarum mitogenome (DBQY) from relatively low altitude (~1300 m asl). All the 37 mitochondrial genes were highly conserved and under purifying selection, except for two mitochondrial protein coding genes (MPCGs) (atp6 and nad5) that showed positively selected signatures. We therefore further examined non-synonymous substitutions in atp6 and nad5, by sequencing more individuals from three populations with different altitudes. We found that these non-synonymous substitutions were polymorphic in these populations, likely due to relaxed selection constraints in different altitudes. Purifying selection in all mitochondrial genes may be due to their functional importance for the precision of ATP production usually. Length difference in mitochondrial control regions between DBHC and DBQY was also conversed at the population level, indicating that sequence size adjustments in control region may be associated with adaptation to divergent altitudes. Quantitatively real-time PCR analysis for 12 MPCGs showed that gene expression patterns had a significant change between the two populations, suggesting that expression levels of MPCGs could be modulated by divergent environmental pressures (e.g. oxygen content and ambient temperature). These results provided an important guide for further uncovering genetic mechanisms of ecological adaptation in insects. PMID- 29521178 TI - Frequency and impact of midlife stressors among men and women with physical disability. AB - PURPOSE: Middle-age may be a challenging time for people with physical disabilities as life demands, secondary symptoms such as fatigue, and risk for depression increase, yet little is known about types, levels, and impact of life stressors in individuals aging with disability. Our aims were to describe aging- and disability-associated life stressors, explore gender differences, and evaluate effects of resilience on adjustment to these stressors. MATERIALS AND METHODS: Longitudinal data analysis of self-report surveys completed by 541 middle-aged community-dwelling participants with long-term physical disability from baseline to 5-year follow-up. RESULTS: 97% of participants endorsed one or more stressful life events (M = 8.2, SD = 4.9), all of whom endorsed at least one life stressor with a negative impact. Reporting more life stressors and having lower resilience were significantly associated with developing more depressive symptoms. Interaction analyses indicated that women developed more depressive symptoms as negative impact increased than men. CONCLUSIONS: Findings suggest that middle-aged individuals with physical disability experience a range of life stressors, many with negative impact. Women are at higher risk of depressive symptoms than men. Resilience may buffer against negative impact of life stressors on development of depressive symptoms. Targeted intervention to increase resilience, especially in women, may decrease risk of depression in persons aging with disability. Implications for Rehabilitation Middle-age adults living with physical disability experience a number of aging- and disability associated stressors that can have a negative impact and contribute to depression. Women aging with disability who experience more negative impact from life stressors may be more vulnerable to developing depression. Providing interventions that enhance resilience when faced with life stressors could prevent development of depression. PMID- 29521179 TI - Familial abnormalities of endocannabinoid signaling in schizophrenia. AB - OBJECTIVES: Epidemiological and experimental evidence suggests that the endocannabinoid system plays a pathophysiological role in schizophrenia. This is reflected by elevated cerebrospinal levels of the endocannabinoid anandamide in schizophrenia and its initial prodromal states. METHODS: We analyzed plasma concentrations of anandamide, 2-arachidonoyl-sn-glycerol, palmitoylethanolamide and oleoylethanolamide from 25 twin pairs discordant for schizophrenia, six discordant for bipolar disorder and eight healthy twin pairs to determine hereditary traits. RESULTS: Twin pairs discordant for schizophrenia or bipolar disorder had significantly higher levels of anandamide and palmitoylethanolamide compared to healthy twins (both P < 0.002). Non-affected twins discordant for schizophrenia, who developed a psychotic disorder within 5 years follow-up showed lower anandamide (P = 0.042) and 2-arachidonoyl-sn-glycerol levels (P = 0.049) than twins who remained healthy. CONCLUSIONS: We suggest that the protective upregulation of endocannabinoid signalling reflects either a hereditary trait or mirrors a modulating response to genetically influenced cerebral function involving, e.g., other neurotransmitters or energy metabolism. PMID- 29521180 TI - Childhood football play and practice in relation to self-regulation and national team selection; a study of Norwegian elite youth players. AB - Childhood sport participation is argued to be important to understand differences in self-regulation and performance level in adolescence. This study sought to investigate if football-specific activities in childhood (6-12 years of age) is related to self-regulatory skills and national under 14- and 15-team selection in Norwegian elite youth football. Data of practice histories and self-regulatory skills of 515 youth football players selected at Norwegian regional level were collected and further analysed using multilevel analyses. The results revealed that high self-regulated players were more likely to be selected for national initiatives, and increased their involvement in peer-led football practice and adult-led football practice during childhood, compared to players with lower levels of self-regulation. While national level players reported higher levels of peer-led football play in childhood, the interaction effect suggest that the regional level players increased their involvement in peer-led play during childhood compared to national level players. In conclusion, the findings indicate that childhood sport participation may contribute to later differences in self-regulation, and highlights the importance of childhood engagement in football-specific play and practice in the development of Norwegian youth football players. PMID- 29521181 TI - Obesity-related metabolic and endocrine disorders diagnosed during postoperative follow-up of slipped capital femoral epiphysis. AB - Background and purpose - Patients with slipped capital femoral epiphysis (SCFE) are phenotypically overweight or obese and may therefore require clinical follow up of obesity-related disorders. We evaluated obesity-related disorders such as dyslipidemia, type 2 diabetes mellitus (DM), and vitamin-D deficiency during the postoperative period in patients with SCFE. Patients and methods - 51 patients who were operated and followed-up for SCFE and 62 healthy adolescents without SCFE (control group) were included in this retrospective study. Patients' BMI, serum lipid profile (total cholesterol, LDL-C, HDL-C, triglyceride), fasting blood glucose, HbA1c, and serum vitamin D levels were evaluated. Results - At the time of surgery, 45 patients in the SCFE group were overweight or obese (BMI >25). At the latest follow-up, 42 patients in the SCFE group and 53 patients in the control group were overweight/obese. Abnormal serum lipid profile and ratio of total dyslipidemia were similar between the groups. 8 patients had abnormal HbA1c levels in the SCFE group and mean HbA1c levels were significantly higher in the SCFE group (p = 0.03). All patients and controls had low levels of vitamin D. Interpretation - Although serum lipid profile and vitamin D levels were detected as similar in SCFE and control groups, the potential risk of type 2 DM identified via abnormal HbA1c levels was significantly higher in patients with SCFE. We recommend that patients diagnosed with SCFE should be considered as potential candidates for type 2 DM; thus follow-up after surgical treatment should include not only orthopedic outcomes but also evaluation of future risk for DM. PMID- 29521182 TI - Effects of miR-27a, miR-196a2 and miR-146a polymorphisms on the risk of breast cancer. AB - Background microRNAs (miRNAs) are potentially involved in many physiopathological processes, including regulation of cell growth, differentiation, apoptosis and cancer. Single nucleotide polymorphisms of the genes encoding miRNAs can alter their expression and may influence cancer risks. This case-control study explored the relationship between three microRNA polymorphisms (miR-27a, miR-196a2 and miR -146a) and breast cancer (BC). Methods A total of 353 breast cancer cases and 353 controls were genotyped for miR-27a (rs895819), miR-196a2 (rs11614913) and miR 146a (rs2910164). The miR-27a and miR-146a variants were discriminated using a PCR-restriction fragment length polymorphism method, while miR-196a2 were analysed by tetra-primers amplification refractory mutation system PCR. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to estimate associations. Results The CC homozygous genotype of miR-146a (rs2910164) was seen in 45(12.7%) patients with breast cancer and 18(5.1%) controls (OR 4.09 [95%CI 2.19-7.67] p < 0.001). The minor allele G of miR-27a was associated with a decreased risk of breast cancer (OR 0.24 [95% CI 0.14-0.42] p < 0.001). The miR 196a2 (rs11614913) was not related to breast cancer (p > 0.05). Conclusion Our data indicate that miR-146a (rs2910164) and miR-27a (rs895819) variants contribute to breast cancer. Further studies in larger populations including other genetic and environmental factors are required to achieve a definitive conclusion. PMID- 29521183 TI - Short- and long-term mortality after pulmonary embolism in patients with and without cancer. AB - Pulmonary embolism (PE) is a major cause of mortality and morbidity. It is known that the risk of death varies by provoking factors; however, it is unknown if the risk of death persists beyond the initial diagnosis among patients with cancer associated and non-cancer provoked patients. In this study, we aimed to investigate the effect of cancer on overall, short- and long-term mortality in a cohort of consecutive incident PE patients. Using administrative databases, we identified all incident cases of PE between 2004 and 2012 in Alberta, Canada. Cases were stratified by provoking factors (i.e. unprovoked, provoked, and cancer associated). A multivariate Cox survival model was used to estimate the hazard ratios of short- and long-term death. We identified 8641 patients with PE, among which 42.2% were unprovoked, 37.9% were provoked and 19.9% were cancer associated. The 1-year and 5-year survival probabilities were 60% (95% CI: 57 64%) and 39% (95% CI: 36-43%) in patients with cancer-associated PE, 93% (95% CI: 92-94%) and 80% (95% CI: 78-81%) in provoked PE, and 94% (95% CI: 93-95%) and 85% (95% CI: 83-87%) in unprovoked PE, respectively. Compared to patients with unprovoked events, both short-term and long-term survival in patients with cancer associated PE have a higher observed risk of all-cause mortality in all age groups ( p<0.001). In contrast, patients with provoked events had a similar short and long-term all-cause mortality. While PE has a significant mortality in all risk groups, patients with cancer have a higher risk of short-term mortality compared to patients with unprovoked PE. PMID- 29521184 TI - [Review]. PMID- 29521185 TI - ? PMID- 29521186 TI - ? PMID- 29521187 TI - ? PMID- 29521188 TI - [Self-optimization - a topic for child and adolescent psychiatry?]. PMID- 29521189 TI - [Martin Schmidt and Helmut Remschmidt - 80th birthday]. PMID- 29521190 TI - BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series). AB - Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH. PMID- 29521192 TI - The impact of 'gay cure' in the mental health. PMID- 29521193 TI - Reporting Maltreatment to Child Protective Services in the Context of Intimate Partner Violence Research. AB - Given the overlap between intimate partner violence (IPV) and child maltreatment, IPV-exposed child participants in research might disclose instances of child maltreatment. Such disclosures might require researchers to report the maltreatment to child protective services (CPS). However, the literature provides minimal guidance on how to navigate the complex challenges and ethical dilemmas around reporting in the context of research. To help address this gap and stimulate discussion regarding protocols and policies for reporting child maltreatment, this article presents a CPS reporting protocol developed as part of a community-engaged research project evaluating a parenting intervention for system-involved mothers experiencing IPV. PMID- 29521191 TI - Public attitude towards restrictions on persons with mental illness in greater Hanoi area, Vietnam. AB - BACKGROUND AND AIMS: In recent years, there has been a growing awareness of the need to protect human rights in psychiatry. Within the last years, considerable effort has been made to reduce restrictive measures in mental health settings. Reducing restrictive measures within mental health care has also moved increasingly into the focus of public debate. This study aims, for the first time in a Southeast Asian sample, to explore whether socio-demographic factors affect public attitudes toward restrictions on mentally ill people in Hanoi, Vietnam. METHODS: A general population-based survey (self-report questionnaire) was carried out in 2013 in the greater Hanoi area. The survey sample ( N = 813) was recruited according to the latest published census (2009) and micro-census (2013) in Vietnam and Hanoi with regard to the socio-demographic factors gender, age, urbanity, household size and marital status. Multinomial logistic regressions for odds ratios with 95% confidence intervals were calculated to examine the influence of epidemiological variables, like gender and age, on the public attitude toward restrictions imposed on mentally ill people in Vietnam. RESULTS: This study found, for the first time in a large Vietnamese sample, that gender and age were associated with public attitudes toward restrictions on mentally ill people. In detail, significantly fewer men endorsed compulsory admission to a hospital and abortion than Vietnamese women. In addition, endorsement of abortion was significantly higher in older people. CONCLUSION: The results offer some insight into roles of women in the Vietnamese society and might reflect the traditional gender expectations in Vietnamese families. Moreover, the results emphasize the need for supporting female psychiatric patients and their families within their communities and in the Vietnamese society. PMID- 29521194 TI - Synthesis of a Tyr-Tyr Dipeptide Library and Evaluation Against Tumor Cells. AB - BACKGROUND: Structural component of proteins and peptides, amino acids have been used as building blocks in the synthesis of more complex molecules with antitumor activity against several types of cancer. OBJECTIVE: The search for new anticancer compounds is ongoing, especially for cancers that are very aggressive and have poor prognoses, such as leukemia. METHOD: Here, we report a method to synthesize Tyr-Tyr dipeptides via sonochemistry reactions followed by functionalization of these Tyr-Tyr dipeptides with Suzuki-Miyaura and Sonogashira crosscoupling reactions in good yields. Twelve different Tyr-Tyr dipeptides were investigated against three cell lines: HaCaT; Jurkat-E6; and A2058. RESULTS: Some of the Tyr-Tyr dipeptides showed activity against Jurkat-E6 leukaemia cells at low concentration, decreasing their viability, but not against non-tumor HaCaT cells, suggesting a cytotoxicity specific to tumor cells. CONCLUSION: All dipeptides were able to decrease the viability of Jurkat cell line, however the A2058 cell line did not respond well to treatment with the peptides. Some of the modified Tyr-Tyr dipeptides presented selective activity on leukemic tumor cells. PMID- 29521195 TI - Neuropharmacological Properties of the Essential Oil of Bergamot for the Clinical Management of Pain-Related BPSDs. AB - : 1.1. BACKGROUND: Alzheimer's Disease (AD) accounts for approximately 50% of all cases of dementia and, in spite of the great effort for the development of disease-modifying drugs, a definitive treatment of cognitive impairment is not available yet. A perfect adherence to the current therapy of cognitive decline is needed for a better control of the disease and this is proven to reduce, though not completely abolish, the associated Behavioural and Psychological Symptoms of Dementia (BPSDs) from occurring. This cluster of symptoms, remarkably affecting patients' health-related quality of life (HRQL), is tightly associated to pain states. Antipsychotics are the only treatment for BPSDs. However, these drugs are more effective and safer in the short-term (6-12 weeks), they are able to manage aggression but not agitation and they cannot control pain. Aromatherapy with Melissa officinalis and Lavandula officinalis has been employed to handle BPSDs, but it has not provided strong evidence to offer relief from pain. 1.2. OBJECTIVE: Bergamot Essential Oil (BEO) exerts antinociceptive activity through several pharmacological mechanisms: in particular, it is able to enhance autophagy, a process undergoing derangement in chronic pain. Thus, the sound pharmacological basis for clinical translation of aromatherapy with BEO in the treatment of BPSDs has been pointed out. 1.3. CONCLUSION: The antinociceptive effects elicited by BEO in experimental pain models make of it a possible candidate for the pharmacological management of pain-related BPSDs. PMID- 29521196 TI - Significance of oxidized low-density lipoprotein in body fluids as a marker related to diseased conditions. AB - Oxidatively modified low-density lipoprotein (oxLDL) is known to be involved in various diseases, including cardiovascular diseases. The presence of oxLDL in the human circulatory system and in atherosclerotic lesions has been demonstrated using monoclonal antibodies. Studies have shown the significance of circulating oxLDL in various systemic diseases, including acute myocardial infarction and diabetic mellitus. Several different enzyme-linked immunosorbent assay (ELISA) procedures to measure oxLDL were utilized. Evidence has been accumulating that reveals changes in oxLDL levels under certain pathological conditions. Since oxLDL concentration tends to correlate with low-density lipoprotein (LDL) cholesterol, the ratio of oxLDL and LDL rather than oxLDL concentration alone has been focused attention. In addition to circulating plasma, LDL and oxLDL are found in gingival crevicular fluid (GCF), where the ratio of oxLDL to LDL in GCF is much higher than in plasma. LDL and oxLDL levels in GCF show an increase in diabetic patients and periodontal patients, suggesting that GCF might be useful in examining systemic conditions. GCF oxLDL increased when the teeth were affected by periodontitis. It is likely that oxLDL levels in plasma and GCF could reflect oxidative stress and transfer efficacy in circulatory system. PMID- 29521197 TI - Neurodegenerative Process Linking the Eye and the Brain. AB - Recent literature agrees that neurodegenerative processes involve both the retina and the central nervous system, which are two strictly related anatomical structures. However, the causal mechanisms of this dual involvement are still uncertain. To date, anterograde transynaptic neurodegeneration, triggered by retinal ganglion cells' death, and retrograde transynaptic neurodegeneration, induced by neurodegenerative processes of the central nervous system, have been considered the major possible causal mechanisms. The development of novel neuroimaging techniques has recently supported both the study of the central stations of the visual pathway as well as the study of the retina which is a possible open window to the central nervous system. PMID- 29521198 TI - Speciation of metal complexes of medicinal interest: relationship between solution equilibria and pharmaceutical properties. AB - Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids. PMID- 29521199 TI - Exercise-Induced Cardioprotection via eNOS: a Putative Role of Red Blood Cell Signaling. AB - Moderate exercise training is a key aspect of primary and secondary prevention strategies. Shear-induced upregulation of eNOS activity and function in the vascular endothelium is considered as one of the main molecular mechanisms of exercise-induced protection against myocardial ischemia/reperfusion (I/R) injury. It has been reported that levels of plasma nitrite, which are largely dependent on eNOS activity, were increased in healthy subjects after acute exercise, while this increase was abolished in coronary artery disease (CAD) patients. Our group and others demonstrated that RBCs contain a functional eNOS, which contributes to systemic nitrite homeostasis and to cardioprotection; moreover, expression and activity of red cell eNOS is decreased in CAD patients and significantly correlated with flow-mediated dilation, a diagnostic marker of endothelial function. Therefore, in addition to vascular eNOS, also red cell eNOS (or in more general terms NO metabolic activity of RBCs) may play a role in exercise dependent changes of NO-bioavailability. In this review we will focus on what is known and what is unknown about the role of RBCs in exercise-dependent cardioprotection with emphasis on RBC signaling and red cell eNOS. In details, we will discuss the effects and molecular mechanisms of shear stress and exercise training on RBC signaling and function, review how these changes may influence blood rheology and systemic hemodynamics and highlight the potential role of red cell eNOS-mediated cardiovascular protection induced by physical activity against myocardial injury in animal and human studies and in clinical settings. PMID- 29521200 TI - Mitochondria-targeting Anticancer Metal Complexes. AB - Since the serendipitous discovery of the antitumor activity of cisplatin, there has been a continuous surge in studies aimed at the development of new cytotoxic metal complexes. While the majority of these complexes have been designed to interact with nuclear DNA, other targets for anticancer metallodrugs attract increasing interest. In cancer cells the mitochondrial metabolism is deregulated. Impaired apoptosis, insensitivity to anti-growth signals and unlimited proliferation have been linked to mitochondrial dysfunction. It is therefore not surprising that mitochondria have emerged as a major target for cancer therapy. Mitochondria-targeting agents are able to bypass resistance mechanisms and to (re )activate cell-death programs. This review discusses cytotoxic metal complexes that are taken up by the mitochondria and interact with mitochondrial DNA or mitochondrial proteins, disrupt the mitochondrial membrane potential, facilitate mitochondrial membrane permeabilization or activate mitochondria-dependent cell death signaling by unbalancing the cellular redox state. Strategies to selectively accumulate metallodrugs in the mitochondria, such as the use of mitochondria-targeting carrier ligands and the formation of lipophilic cationic complexes are described. Recent developments in the design, cytotoxic potency, and mechanistic understanding of antimitochondrial metal complexes, in particular of cyclometalated Au, Ru, Ir and Pt complexes, Ru polypyridine complexes and Au-N heterocyclic carbene and phosphine complexes are summarized and discussed. PMID- 29521201 TI - Chronic Kidney Disease and the Search for New Biomarkers for Early Diagnosis. AB - Chronic kidney disease (CKD) is a progressive condition characterized by a permanent and irreversible loss of renal function. In accordance to international guidelines, CKD clinical diagnosis methods are based on creatinine and albumin levels and glomerular filtration rate. Unfortunately, these parameters are scarcely affected in early stages, and its inherent intrinsic variability only allows for the identification of intermediate and advanced stages, when life expectancy has become shorter and treatment poses a significant financial investment. In this context, several targeted strategies have been designed for searching novel markers. Among them, "omics" techniques have emerged, mainly based on proteomics and metabolomics research. Urine and serum samples have been selected as starting material to conduct the identification of new CKD biomarkers, capable of differentiating between stages and predicting progression outcomes. In many cases, the principal objective is to develop a fast and reliable clinical method for non-invasive analysis in the early progression stages of the disease. On the other hand, significant efforts have been directed to identify molecules related to the CKD end stage in order to adequate therapies, reduce impairments, and have a positive impact on survival rate. In this article, the state of the art of novel proposed biomarkers for CKD identification is reviewed, with the aim of underlining its molecular diversity, emphasizing chemical structure differences and correlating its biological relevance. Efforts directed in this line could provide evidence of metabolic pathways imbalance, and lead to the development of new integral strategies for CKD evaluation and management. PMID- 29521202 TI - Biotechnological Production of Pharmaceuticals and Biopharmaceuticals in Plant Cell and Organ Cultures. AB - BACKGROUND: Plant biofactories are biotechnological platforms based on plant cell and organ cultures used for the production of pharmaceuticals and biopharmaceuticals, although to date only a few of these systems have successfully been implemented at an industrial level. Metabolic engineering is possibly the most straightforward strategy to boost pharmaceutical production in plant biofactories, but social opposition to the use of GMOs means empirical approaches are still being used. Plant secondary metabolism involves thousands of different enzymes, some of which catalyze specific reactions, giving one product from a particular substrate, whereas others can yield multiple products from the same substrate. This trait opens plant cell biofactories to new applications, in which the natural metabolic machinery of plants can be harnessed for the bioconversion of phytochemicals or even the production of new bioactive compounds. Synthetic biological pipelines involving the bioconversion of natural substrates into products with a high market value may be established by the heterologous expression of target metabolic genes in model plants. OBJECTIVE: To summarize the state of the art of plant biofactories and their applications for the pipeline production of cosme-, pharma- and biopharmaceuticals. RESULTS: In order to demonstrate the great potential of plant biofactories for multiple applications in the biotechnological production of pharmaceuticals and biopharmaceuticals, this review broadly covers the following: plant biofactories based on cell and hairy root cultures; secondary metabolite production; biotransformation reactions; metabolic engineering tools applied in plant biofactories; and biopharmaceutical production. PMID- 29521203 TI - Involvement of Breast Cancer-Associated Fibroblasts in Tumor Development, Therapy Resistance and Evaluation of Potential Therapeutic Strategies. AB - Breast cancer is the most common cancer in women, which incidence has increased in recent years. It is constituted by very heterogeneous tissue characterized by an abnormal microenvironment regulating tumor progression and providing evasion from cancer therapies. Breast cancer-associated fibroblasts (BCAFs) are the main cell type of breast cancer microenvironment and can represent up to 80% of the tumor mass. In particular, BCAFs induce cancer initiation, proliferation, invasion and metastasis by undergoing an activation process associated with the secretion of growth factors, cytokines, and paracrine interactions. Therapy resistance is the main cause of poor therapeutic results or even failure in breast cancer patients. Despite recent advances in breast cancer management, there is a need for new prognostic markers and novel agents for targeting key signalling pathways to either improve the efficacy of the current therapies, or reduce toxicity. In this view, BCAFs represent markers useful to clinical diagnosis, therapy, and prognosis of breast cancer. This review focuses on the role of BCAFs in cancer, and describes the processes of endocrine/chemotherapy resistance linked to BCAFs action. Moreover, it points to molecules and pathways regulating therapy resistance induced by BCAFs. Finally, potential therapeutic strategies targeting BCAFs and offering new tools in breast cancer therapy are highlighted. PMID- 29521204 TI - In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases. AB - Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, is emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls. PMID- 29521205 TI - Bile Acid Derivatives: From Old Molecules to a New Potent Therapeutic Use: An Overview. AB - Bile acids or bile salts, belong to a large family of biological steroid derivatives found predominantly in the bile of mammals and other vertebrates. These amphipathic molecules possess numerous functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites, emulsifying fat-soluble vitamins to enable their absorption, aiding in motility and in reducing the bacteria flora found in the small intestine and biliary tract. In this review, we investigate progress towards synthetic bile acid derivatives, with special emphasis on how they might be used for various biological applications and the challenges that remain in developing these compounds as potent drugs of the future especially in the field of microbiology (antimicrobial activities) and cancer (anticancer agents). We will emphasize the fact that even few researches are devoted around these peculiar structures. All the researches pointed out the important potential of such derivatives for the design of new classes of drugs. PMID- 29521206 TI - Biological Activity of Trans-Membrane Anion Carriers. AB - Natural and synthetic anionophores promote the trans-membrane transport of anions such as chloride and bicarbonate. This process may alter cellular homeostasis with possible effects on internal ions concentration and pH levels triggering several and diverse biological effects. In this article, an overview of the recent results on the study of aniontransporters, mainly acting with a carrier type mechanism, is given with emphasis on the structure/activity relationship and on their biological activity as antibiotic and anticancer agents and in the development of new drugs for treating conditions derived from dysregulation of natural anion channels. PMID- 29521207 TI - Grid-Based Technologies for In Silico Screening and Drug Design. AB - Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained from an SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and the bioactive probability have been described. The design methods are implemented at www.chemosophia.com web-site for online computational services. PMID- 29521208 TI - Apoptin, A Versatile Protein with Selective Antitumor Activity. AB - BACKGROUND: Research in the field of antitumor chemotherapeutics pursues a key issue, drug selectivity for cancer cells. In the last 20 years, a group of proteins has attracted scientific interest as cancer chemotherapeutics due to their ability to specifically kill cancer cells while leaving normal cells undamaged. One of these proteins is apoptin. METHODS: In this study, the recent available literature regarding cell death mechanisms induced by apoptin has been reviewed. Delivering this drug to tumor cells is a challenge because it spontaneously forms soluble non-covalent aggregates. This led us to include in this review the different approaches for obtaining the maximum efficiency of apoptin entry to cancer cells. RESULTS: This review provides an up-to-date summary of the mechanisms by which apoptin induces selective apoptosis in tumor cells while leaving normal cells undamaged. It highlights the relationship between the apoptosis mechanism induced by this protein and its functional motifs. Apoptin has been described as an intrinsically disordered protein, which explains its ability to interact with multiple partners and affect multiple pathways inside the cell. Characterization of the different partners and pathways induced by apoptin has begun to shed light on the molecular basis of apoptin's tumor-selective cytotoxicity. CONCLUSION: The findings confirm the interest in apoptin as a potentially safe antitumor drug. Research still needed to be conducted to find an effective way to deliver apoptin for use in clinics. PMID- 29521209 TI - Hybrid Molecules: Promising Compounds for the Development of New Treatments Against Leishmaniasis and Chagas Disease. AB - Leishmaniasis and Chagas disease are endemic pathologies in tropical countries. These cause high morbidity and a public health problem. Current chemotherapies are based on conventional drugs with variable efficacy and toxicity related with the length of therapeutic schemes and high doses. When two pharmacological agents are combined into a single molecule, the result is the so-called hybrid molecule. In the search for new treatments against Chagas disease and leishmaniasis, several studies have shown that hybrid molecules display high antiprotozoal activity and this emerging strategy is quite promising in the field of new drug discovery and development. This review focuses on the antiprotozoal activity of different hybrids obtained from the hybridization of pharmacophores, showing that the most of the efforts have been concentrated in the molecular hybridization of quinoline, chalcone and hydrazone moieties. PMID- 29521210 TI - Phosphodiesterase 10 Inhibitors - Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery. AB - BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP 10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson's, Huntington's, and Alzheimer's diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors. PMID- 29521211 TI - Acyclovir in the Treatment of Herpes Viruses - a Review. AB - BACKGROUND: Herpes simplex (HSV) viruses are widely spread, highly contagious human pathogens. The statistics indicate that 50-90% of adults worldwide are seropositive for these viruses, mainly HSV-1 and HSV-2. The primary infection results in the appearance of watery blisters (cold sores) on the skin, lips, tongue, buccal mucosa or genitals. The ocular infection is the major cause of corneal blindness in the Western World. Once the HSV virus enters human body it cannot be completely eradicated because HSV viruses are able to change into their latent form which can survive the treatment. The viron reside in trigeminal ganglia of the host, who becomes vulnerable to reoccurrence of the disease during the whole lifespan. The neurotropic and neuro-invasive properties of HSV are considered as responsible for neurodegenerative illnesses, such as Alzheimer's disease. Acyclovir and its analogues, being the inhibitors of the viral DNA replication, are the only approved medicines for HSV infection therapies. OBJECTIVE: The current paper presents the up-to-date overview of the important pharmacological features of acyclovir, its analogues and their delivery systems including the mechanism of action, routes of administration, absorption and metabolism, as well as side effects of the therapy. CONCLUSION: Acyclovir remains the gold standard in the treatment of herpes virus infections, mainly due to the emerging of the new delivery systems improving considerably its bioavailability. The analogues of acyclovir, especially their esters, characterized by significantly higher bioavailability and safety, may gradually replace acyclovir in selected applications. PMID- 29521212 TI - Linking Antimicrobial Potential of Natural Products Derived from Aquatic Organisms and Microbes Involved in Alzheimer's Disease - A Review. AB - The following review is oriented towards microbes linked to Alzheimer's disease (AD) and antimicrobial effect of compounds and extracts derived from aquatic organisms against specific bacteria, fungi and viruses which were found previously in patients suffering from AD. Major group of microbes linked to AD include bacteria: Chlamydia pneumoniae, Helicobacter pylori, Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, Actinomyces naeslundii, spirochete group; fungi: Candida sp., Cryptococcus sp., Saccharomyces sp., Malassezia sp., Botrytis sp., and viruses: herpes simplex virus type 1 (HSV 1), Human cytomegalovirus (CMV), hepatitis C virus (HCV). In the light of that fact, this review is the first to link antimicrobial potential of aquatic organisms against these sorts of microbes. This literature review might serve as a starting platform to develop novel supportive therapy for patients suffering from AD and to possibly prevent escalation of the disease in patients already having high risk factors for AD occurrence. PMID- 29521213 TI - Advances in Spirocyclic Hybrids: Chemistry and Medicinal Actions. AB - The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the antihypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century. Actually, there has been a growing interest in the synthesis of heterocyclic hybrids gathered via a spiro carbon. Most of these combinations are two moieties in one scaffold being able to interfere with biological systems through sequential mechanisms. Spirocyclic hybrids containing indole or oxindole units are compounds exhibiting higher interaction with biological receptors by protein inhibition or enzymatic pathways and their recognition as promising anticancer agents in targeted chemotherapy is foreseen. These specific, low-weight and noncomplex spirocyclic hybrids are potent inhibitors of SIRT1, Mdm2-p53 and PLK4, showing affinity for anaplastic lymphoma kinase (ALK) receptor. They are also known as excellent DNA binders, acting on cellular division by arresting the cell cycle at different phases and inducing apoptotic cell death. A structural diversity of spirocyclic hybrids has proved neuroprotective effects, anti-HIV, antiviral and antibacterial activities. Hundred of papers are mentioned in this review underlying chemical issues and pharmacological potencies of spiro compounds, which render them impressive synthetic hits for innovative drug conception. PMID- 29521214 TI - Formulation of Herbal Fast Disintegrating Tablets and its ex-vivo Study for Anti histaminic Activity in Guinea Pig Ileum. AB - OBJECTIVE: The aim of present research work was to develop a herbal fast disintegrating tablet containing Fagonia schweinfurthii Hadidi dried extract and determining its antihistaminic activity using guinea pig ileum. METHOD: The tablets were formulated by wet granulation technique using three different superdisintegrants (croscarmillose, crospovidone and sodium starch glycolate) at three different levels. The tablets were evaluated for various physical properties like hardness, friability weight variation etc. and various mechanical properties like disintegration time, wetting time to select the best superdisintegrant. The selected superdisintegrant was further used as intra as well as extra granulating agent to develop fast disintegrating tablets of Fagonia schweinfurthii Hadidi dried extract. The optimized formulation was subjected to stability study as per the ICH guidelines. Finally, Ex-vivo antihistaminic study was conducted on guinea pig ileum for optimized formulation and compared with marketed tablet containing cetrizine HCl as API (Stanhist-10, Ranbaxy, Pvt. Ltd). RESULTS: Physical properties of all tablet batches were found to be acceptable and comply with various official specifications. The disintegration time and wetting time of optimized formulation (F'3) were found to be 1.15+/-0.08 and 0.56+/-0.04 min respectively. Results of Ex-vivo study showed a comparable histamine inhibition between optimized tablet (15%) and marketed tablet formulation (18.8%) in a dose of 5 ug/ml. CONCLUSION: On the basis of in-vitro and Ex-vivo studies, it was concluded that prepared herbal fast disintegrating tablets were stable and had potent antihistaminic activity. PMID- 29521215 TI - LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound. AB - BACKGROUND: Nitroproston is a novel prostaglandin-based compound modified by NOdonating groups with potential application in obstructive respiratory diseases such as asthma and obstructive bronchitis. Nitroproston has been extensively studied using various pharmacological models. Its biological stability is still uncertain. OBJECTIVE: The aim of the present study was to evaluate Nitroproston stability in vitro, as well as to identify and characterize its major biodegradation products. METHODS: The principal biodegradation products of Nitroproston were identified in vitro using liquid chromatography/ion trap - time of-flight mass-spectrometry. The postulated structure of metabolites was confirmed using authentic reference standards. Rat, rabbit and human plasma and human whole blood samples were used for comparative in vitro degradation study. Nitroproston and its biodegradation products in biological samples were measured by liquid chromatography/triple -stage quadrupole mass spectrometry. RESULTS: Nitroproston is rapidly hydrolyzed in rat plasma to generate glycerol-1,3 dinitrate and prostaglandin E2. The latter can undergo conversion to cyclopentenone prostaglandins A2 and B2. Thereby less than 5% of the parent compound was observed in rat plasma at the first moment of incubation. A similar pattern was observed for rabbit plasma where half-life (T1/2) of Nitroproston was about 2.0 minutes. Nitroproston biodegradation rate for human plasma was the slowest (T1/2 = 2.1 h) among tested species, occurred more rapidly in whole blood (T1/2 = 14.8 min). CONCLUSION: It was found that Nitroproston is rapidly hydrolyzed in rodent compared to human plasma incubations. Whereas Nitroproston is relatively stable in human plasma an enhanced hydrolytic activity was observed in whole human blood incubations. Extensive metabolism of Nitroproston in human whole blood was mainly associated with red blood cells. The observed interspecies variability highlights the need of suitable animal model selection for Nitroproston follow-up PK/PD studies. PMID- 29521216 TI - Development of the Biomaterials Technology for the Infection Resistance. AB - Infections caused by microbial proliferation are one of the common issues and serious threats to the medical care, and they usually result in disease spread. Therefore, it is a significant issue for developing the antiinfective biomaterials to control this problem, according to the specific clinical application. Meanwhile, all their properties, the best anti-infective performance, the safe biocompatibility and the appropriate tissue interactions must be conformed to each other. At present, technologies are developing novel biomaterials and surfaces endowed with anti-infective properties, relying either on bactericidal or anti-biofilm activities. This review focuses on thoroughly summarizing numerous kinds of antibacterial biomaterials, including the antibacterial matrix biomaterials, antibacterial coatings and films, nanostructured materials and antibacterial fibers. Among these strategies, the utilization of bio-glass base and graphene base antibacterial matrix, and their effects on the antibiosis mechanism were emphatically discussed. Simultaneously, the effects and mechanisms of nano-coated metallic ions are also mentioned. Overall, there is a wealth of technical solutions to contrast the establishment of an implant infection. The lack of well-structured prospective multicenter clinical trials hinders the achievement of conclusive data on the efficacy and comparative performance of antibacterial biomaterials. PMID- 29521217 TI - Plant-produced Recombinant Influenza A Vaccines Based on the M2e Peptide. AB - BACKGROUND: Influenza is a widely distributed infection that almost annually causes seasonal epidemics. The current egg-based platforms for influenza vaccine production are facing a number of challenges and are failing to satisfy the global demand in the case of pandemics due to the long production time. Recombinant vaccines are an alternative that can be quickly produced in high quantities in standard expression systems. METHODS: Plants may become a promising biofactory for the large-scale production of recombinant proteins due to low cost, scalability, and safety. Plant-based expression systems have been used to produce recombinant vaccines against influenza based on two targets; the major surface antigen hemagglutinin and the transmembrane protein M2. RESULTS: Different forms of recombinant hemagglutinin were successfully expressed in plants, and some plantproduced vaccines based on hemagglutinin were successfully tested in clinical trials. However, these vaccines remain strain specific, while the highly conserved extracellular domain of the M2 protein (M2e) could be used for the development of a universal influenza vaccine. In this review, the state of the art in developing plant-produced influenza vaccines based on M2e is presented and placed in perspective. A number of strategies to produce M2e in an immunogenic form in plants have been reported, including its presentation on the surface of plant viruses or virus-like particles formed by capsid proteins, linkage to bacterial flagellin, and targeting to protein bodies. CONCLUSION: Some M2e-based vaccine candidates were produced at high levels (up to 1 mg/g of fresh plant tissue) and were shown to be capable of stimulating broad-range protective immunity. PMID- 29521218 TI - Regulation of Mammalian UDP-Glucuronosyltransferases. AB - BACKGROUND: UDP-glucuronosyltransferases (UGTs) are a class of important phase II drug metabolizing enzymes (DMEs), playing essential roles in the homeostasis of endobiotics as well as the dispositional behavior of exogenous compounds. The expression and enzyme activity of UGTs are regulated by multiple dimensions of mechanisms and can be influenced by diverse factors. Thus, the intensive research of its regulatory network is pivotal for better understanding about the physiological, pathological, and therapeutic significance of UGTs. Despite the lag to the research in cytochrome P450s, extensive efforts have been made to advance the understanding of the regulatory network of UGTs in recent years. METHOD: This review presents a comprehensive summary and intensive discussion about the recent advancement on the regulatory network of UGTs. RESULTS: UGTs can be regulated at the epigenetic level via DNA methylation and histone modification. Various nuclear receptors can influence the mRNA levels of UGTs in a ligand dependent manner. Some general transcriptional factors such as AP-1, NF kappaB, and p53, and some tissue specific transcriptional factors including HFN1alpha and HNF4alpha can also regulate UGTs at the transcriptional level. Multiple miRNAs have been found to be involved in the regulation of UGTs at post transcriptional level. UGT proteins can be directly regulated via various post translational modifications, protein-protein interactions, and protein-chemicals interactions, leading to the alternation of enzyme activities. CONCLUSION: In addition to the well-defined genetic polymorphism that induce individual variation of UGTs, this review reinforces the importance of other mechanisms that are critical for the regulation of UGTs. PMID- 29521219 TI - Therapeutic Uses of HSP90 Inhibitors in Non-Small Cell Lung Carcinoma (NSCLC). AB - BACKGROUND: Non-Small Cell Lung Carcinoma is one of the major cause of morbidity and mortality worldwide with an incidence rate of 1.3 million cases per year. Heat shock protein 90 (HSP90) is a promising drug target in cancer treatment. HSP90 is required to activate numerous eukaryotic proto-oncogenic protein kinases, hence play a prominent role in cancer. METHOD: We reviewed fifty-five articles to highlight the importance of HSP90 in NSCLC and the recent developments of its inhibitors. RESULTS: This review showed that HSP90 inhibitors i.e. Ganestespib have shown great potential in the treatment of non-small cell lung carcinoma (NSCLC). Different HSP90 inhibitors has been designed till date that acts as effective drugs in tumour suppression. However, the utility of these drugs has been limited due to several drawbacks including hepato-toxicity, poor solubility, and poorly tolerated formulations. CONCLUSION: The goal of this review is to present the data in support of use of HSP90 inhibitors in NSCLC and to provide an overview of the on-going clinical trials involving new-generation HSP90 inhibitors. PMID- 29521220 TI - Kidney-on-a-Chip: A New Technology for Predicting Drug Efficacy, Interactions, and Drug-induced Nephrotoxicity. AB - BACKGROUND: Kidney dysfunction resulting from various drugs is an important issue during the drug development process. Traditional in vivo animal experiments are limited with respect to evaluating drug efficacy and nephrotoxicity due to discrepancies in drug pharmacokinetics and pharmacodynamics between humans and animals, and static cell culture experiments cannot fully reflect the actual microphysiological environment in humans. METHOD: In this review article, authors collected manually relevant bibliographic databases including journal articles and textbooks related to microfluidics, kidney-on-a-chip, and drug screening and interaction. In this review, we discuss recent developments in microfluidic culturing technique and describe current and future kidney-on-a-chip applications. RESULTS: The pharmacodynamic and pathophysiological responses of cells are more realistic in microfluidic or 3D culture systems than in conventional 2D culture systems. Recently, several types of kidney-on-a-chip have been developed that reflect the microenvironment of the kidney tubule and have been shown to better reflect actual in-vivo results of drug nephrotoxicity. Using kidney-on-a-chip, investigators can measure various drug-induced biological responses. In the future, it is expected that a multi-organ chip will be utilized to examine the interaction between kidney and other organs, and kidney-on-a-chip can be used in disease modeling and the development of new renal replacement therapy. CONCLUSIONS: Using kidney-on-a-chip, researchers can create experimental environments resembling the physiological environments in human organs and obtain experimental results that better reflect human physiology. Kidney-ona- chip can be used to overcome the drawbacks of traditional animal models and to more effectively identify drug effects, interactions, and drug-induced nephrotoxicity. PMID- 29521221 TI - Non-invasive Qualitative Urinary Metabolomic Profiling Discriminates Gut Microbiota Derived Metabolites in the Moderate and Chronic Alcoholic Cohorts. AB - BACKGROUND: Excessive alcohol consumption damages the intestine and liver cells directly as well as through unbalancing the gut microbiota. OBJECTIVE: The current study was undertaken to correlate the alcohol consumption and change in urinary metabolites profile linked with gut microbiota. METHOD: Non-alcoholic (control) healthy (n=22) and moderate alcoholic (n=26) males with an average age of 39.3+/-1.83 years subjected to alcohol use disorders identification test (AUDIT) were considered for study. First pass urine and blood samples were collected in the morning. RESULTS: Liver function test showed the increased levels of gammaGT, AST and ALT to 40.3 +/- 2.3, 53.3 +/- 0.7, and 38.9 +/- 0.5 U/L, respectively. Urine samples were processed and subjected to HPLC-Q-TOFMS analysis in positive and negative ion polarity modes. Mass data were processed to align and filter out insignificant entities and subjected to One-way ANOVA with Bonferroni multiple testing corrections analysis. The analysis provided list of 211gut microbes specific metabolites with p>0.05 and fold change >1.5. All metabolites were identified using standards and referring to METALIN library of standard metabolites. Further analyses showed that alcohol intake disturbed more than ten metabolic pathways. Tryptophan, tyrosine, branched chain amino acids and short-chain fatty acids metabolism were the significantly disturbed pathways in alcoholics. CONCLUSION: Correlation of various metabolites with gut microbiota showed that chronic and moderate dose intake of alcohol decreased the level of Bifidobacterium, Lactobacillus Ruminococcus and Faecalibacterium spp. and increased the levels of Proteobacteria, Alcaligenes and Clostridium. PMID- 29521222 TI - Evaluation of Drug Transport in MDCKII-Wild Type, MDCKII-MDR1, MDCKII-BCRP and Caco-2 Cell Lines. AB - BACKGROUND: Drug transporters function as gatekeepers and modulate drug access into body and various tissues. Thus, a thorough and precise understanding of transporter liability for compound uptake and efflux is critical during drug development. METHODS: In the present study, we assessed the apparent permeability (Papp) and compared efflux ratio of various compounds in stably transfected Madin Darby Canine Kidney (MDCKII) cells overexpressing human P-gp (MDCKII-MDR1), human BCRP (MDCKII-BCRP), wild-type (MDCKII-WT), and Caco-2 cell monolayers. RESULTS: We observed that quinidine, a substrate for MDR1 transporter, showed efflux ratio (Papp B-A/ Papp A-B) of 838 in MDCKII-MDR1 cells which plummeted to 14 in presence of verapamil, a known inhibitor of MDR1. With MDCKII-WT cells, Papp of quinidine dropped from 2 to 1, in the presence of verapamil. Caco-2 cells showed a diminutive decrease in efflux ratio of quinidine from 2.5 to 1.6 by verapamil. Prazosin and dantrolene were evaluated in MDCKII-BCRP cells and were found to have 80-fold higher efflux ratio compared to MDCKII-WT cells. In Caco-2 cells, prazosin and dantrolene showed efflux ratio of 4 and 2, respectively. Rhodamine 123, a fluorogenic probe substrate of MDR1 showed an efflux ratio of 4 in Caco-2 cells and BCRP substrate estrone-3-sulphate showed an efflux ratio of 7. In presence of BCRP inhibitor fumitremorgin-c, the efflux ratio of estrone-3-sulfate dropped to 1 in Caco-2 cells. CONCLUSION: The very high efflux ratios of MDR1 and BCRP substrates in transfected MDCKII cells clearly demonstrate the potential usefulness of these models to provide more definitive data to evaluate the transporter involvement compared to Caco-2 or MDCKII-WT cells. PMID- 29521223 TI - Effects of a Series of Acidic Drugs on L-Lactic Acid Transport by the Monocarboxylate Transporters MCT1 and MCT4. AB - BACKGROUND: Drug-induced myopathy is a serious side effect that often requires removal of a medication from a drug regimen. For most drugs, the underlying mechanism of drug-induced myopathy remains unclear. Monocarboxylate transporters (MCTs) mediate L-lactic acid transport, and inhibition of MCTs may potentially lead to perturbation of L-lactic acid accumulation and muscular disorders. Therefore, we hypothesized that L-lactic acid transport may be involved in the development of drug-induced myopathy. The aim of this study was to assess the inhibitory potential of 24 acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 and MCT4, respectively. METHODS: The influx transport of L-lactic acid was minimally inhibited by all drugs tested. The efflux transport was next examined: loratadine (IC50: 10 and 61 uM) and atorvastatin (IC50: 78 and 41 uM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively. Acidic drugs including fluvastatin, cerivastatin, simvastatin acid, lovastatin acid, irbesartan and losartan exhibited weak inhibitory potency on L lactic acid efflux. RESULTS: Our results suggest that some acidic drugs, such as loratadine and atorvastatin, can inhibit the efflux transport of L-lactic acid. CONCLUSION: This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders. PMID- 29521224 TI - Recent Progress in Clinical Development of Therapeutic Antibodies Targeting Glycan-Binding Proteins. AB - BACKGROUND: Glycan-binding proteins are widely distributed in human and play an essential role in biological processes. Their involvements in inflammatory and immune responses make it increasingly likely that the glycan-binding proteins may represent valuable therapeutic targets. OBJECTIVE: The current review aims to provide information on recent advancements in clinical developments of antibodies against glycan-binding proteins as potential targets. RESULTS AND CONCLUSION: There are several therapeutic antibodies being developed targeting glycanbinding proteins, including CD22, CD33, DEC-205, and CD62P, for different diseases. The clinical investigations demonstrated benefits of treatments with one antibody drug conjugate against CD22 being approved by the regulatory agencies. The recent progresses in clinical developments of these antibodies have provided great promises in therapeutic targeting of more glycan-binding proteins for treating multiple diseases, including inflammation, autoimmune diseases, and hematological malignancies. PMID- 29521225 TI - Withdrawn: Role of Haematopoietic Stem Cell Transplantation in management of Severe Chronic Neutropenia. AB - Withdrawn by the publisher. PMID- 29521227 TI - VCP/p97/Cdc48, A Linking of Protein Homeostasis and Cancer Therapy. AB - VCP/p97/Cdc48, a member of the ATPases associated with diverse cellular activities (AAA) family, is necessary for the endoplasmic-reticulum-associated protein degradation (ERAD) pathway to maintain protein homeostasis. Overwhelming proteotoxic stress drove cancer cells to enhance VCP/p97/Cdc48-associated ERAD to maintain protein homeostasis for survival, demonstrating that VCP/p97/Cdc48 expression was positively correlated with cancer prognosis. More studies revealed that targeting VCP/p97/Cdc48 could be a potential target in cancer therapy. CB 5083, a novel inhibitor of VCP/p97/Cdc48, is in clinical trials as the first VCP/p97/Cdc48- inhibiting drug for cancer therapy. Here, we discuss the relationship between VCP/p97/Cdc48, ERAD, protein homeostasis and cancer therapy. PMID- 29521226 TI - Graphene Oxide as Scaffolds for Stem Cells: An Overview. AB - Graphene and graphene oxide topography have an effect on the fate of stem cells such as adhesion, differentiation, and proliferation. This overview clearly shows that a new design and manipulation of associated graphene oxide stem cell culture platforms are of paramount importance as a focus in stem cell to tissue engineering applications. This overview also proposes that a film of graphene oxide is an efficient platform to modulate structure and function of multipotent mesenchymal stem/stromal cells (MSCs) and in special human adipose tissue derived mesenchymal stromal/stem cells (AT-MSCs). The implication of graphene oxide on osteogenesis, neurogenesis, oligodendrogenesis, adipogenic and epithelial differentiation is also discussed. Graphene oxide toxicity on stem cells and the importance of GO application on ATMSCs differentiation and proliferation are final topics that are being discussed. PMID- 29521228 TI - Uncoupling Protein Overexpression in Metabolic Disease and the Risk of Uncontrolled Cell Proliferation and Tumorigenesis. AB - In metabolic diseases such as obesity, metabolic syndrome and type II diabetes, the over-expression of uncoupling proteins (UCPs) in a response to increased reactive oxygen species (ROS) generation by mitochondrial respiratory complexes, and to the excess of free fatty acid (FFA) supply from adipose tissue, may protect cells from oxidative stress, lipotoxicity and in turn from death. UCPs by reducing superoxide anion and H2O2 generation trigger several signals to cell for their adaptation to the lipotoxic microenvironment. In mitochondria, a decrease of cytochrome c (cyt c) and proapoptotic protein release promotes cell survival and proliferation. The altered lipid metabolism also affects cardiolipin susceptibility to the peroxidation, a process involved in the dissociation of cyt c from mitochondrial inner membrane and its release, a key step of apoptosis. Therefore, UCPs by attenuating ROS generation and lipotoxicity may downregulate programmed cell death, a well-known physiological process controlling cell proliferation contributing to uncontrolled cell proliferation and tumorigenesis. In addition, tumor cells over-expressed UCPs, by inhibiting ROS generation acquire resistance to death during pharmacological treatment with oxidative stress drug inducers. Therefore, the aim of this review is to discuss recent findings regarding the role that UCPs play in cell survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote cell proliferation. PMID- 29521229 TI - The Mitochondrial Unfolded Protein Response: Role in Cellular Homeostasis and Disease. AB - Mitochondria are the sole semiautonomous organelles of the human cell and play a very important role in not only energy production but also in apoptosis, metabolism and cell signaling. They are also known to be major producers of ROS and RNS free radicals during ATP production. These free radicals in excessive amount may damage the mitochondrial DNA as well as proteome resulting in accumulation of misfolded proteins which may prove deleterious to their functioning and are known to be involved in disease pathology. To maintain healthy proteome, mitochondria have developed as quality control machinery in semiautonomous manner, where cellular proteins such as proteases and heat shock proteins are used for quality control. The present review discusses various aspects of mitochondrial protein quality control operating at outer or inner membrane as well as intermembranal space. The various pathways involved in mitochondrial unfolded protein response have been discussed along with their implications in cancer and various neurodegenerative diseases. PMID- 29521231 TI - Intraepithelial Attack Rather than Intratumorally Infiltration of CD8+T Lymphocytes is a Favorable Prognostic Indicator in Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are one of the major participants in the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of interaction between TILs and tumors is complex and remains unclear. OBJECTIVE: To evaluate the state of immunoreactions in PDAC tissues, and explore the prognostic value of these markers in a large sample, to provide a new theoretical basis for PDAC immunotherapy. METHOD: Immunohistochemical staining of CD4+ and CD8+T cells was performed in a tissue microarray (TMA) of 143 cases of PDAC. Two major variables for the spatial distributions of CD4+T and CD8+T cells in PDAC tissues, intraepithelial attack and intratumoral infiltration, were used to evaluate the state of immunoreactions, and the interrelationships with the clinicopathological variables were analyzed. RESULTS: Our data showed that both the intraepithelial CD4+T and CD8+T attack were less frequent than the intratumoral infiltration. CD8+T intraepithelial attack and intratumoral infiltration were more intense than CD4+T. CD8+T intraepithelial attack was an independent favorable prognostic factor for overall survival, correlating negatively with vascular invasion and positively with CD4+T and CD8+T high intratumoral infiltration. CD8+T high intratumoral infiltration without CD8+T intraepithelial attack was a poor prognostic factor. CD8+T high intratumoral infiltration was accompanied by T stage progression. Conclusively, in PDAC progression, imbalances of T cells occurred in CD4+ and CD8+ immunoreactions. The CD8+T intraepithelial attack was an independent favorable prognostic indicator, however the intraepithelial attack of CD4+T and the both intratumoral infiltration of CD8+T and CD4+T played an ambiguous role. CONCLUSION: Our data suggested that it is a potential approach to increasing the number of intraepithelial attacking CD8+T cells for tumor immunotherapy, and exploring a new mechanism for immunosuppression in a tumor microenvironment with high T cell infiltration without attack. PMID- 29521230 TI - Role of Zebrafish fhl1A in Satellite Cell and Skeletal Muscle Development. AB - BACKGROUND: Four-and-a-half LIM domains protein 1 (FHL1) mutations are associated with human myopathies. However, the function of this protein in skeletal development remains unclear. METHODS: Whole-mount in situ hybridization and embryo immunostaining were performed. RESULTS: Zebrafish Fhl1A is the homologue of human FHL1. We showed that fhl1A knockdown causes defective skeletal muscle development, while injection with fhl1A mRNA largely recovered the muscle development in these fhl1A morphants. We also demonstrated that fhl1A knockdown decreases the number of satellite cells. This decrease in satellite cells and the emergence of skeletal muscle abnormalities were associated with alterations in the gene expression of myoD, pax7, mef2ca and skMLCK. We also demonstrated that fhl1A expression and retinoic acid (RA) signalling caused similar skeletal muscle development phenotypes. Moreover, when treated with exogenous RA, endogenous fhl1A expression in skeletal muscles was robust. When treated with DEAB, an RA signalling inhibitor which inhibits the activity of retinaldehyde dehydrogenase, fhl1A was downregulated. CONCLUSION: fhl1A functions as an activator in regulating the number of satellite cells and in skeletal muscle development. The role of fhl1A in skeletal myogenesis is regulated by RA signaling. PMID- 29521232 TI - Role of miR-193a in Cancer: Complexity and Factors Control the Pattern of its Expression. AB - BACKGROUND: There is emerging data suggesting that the non-coding RNA (microRNA 193a or miR-193a) plays key roles in different types of cancers. OBJECTIVE: This review aims to investigate the functional significance of miR-193a in different cancers according to the information of literature. METHOD: All the literature concerning miR-193a in cancer in PubMed are analysed. RESULTS: Several studies proved the association of miR-193a expression patterns with cancer's stages, grades, response to the chemotherapy and even patient survival. Also, miR-193a can be used to differentiate some types of cancer. In cancer, miR-193a can act as a tumour suppressor gene or as an oncogene. Till now, several genetic factors (MAX, RXR alpha, XB130, P63, P73, AEG-1, HIFs, EGFR, Drosha, DGCR8, Dicer) and epigenetic factors (DNA methylation and long non-coding RNAs) were predicted to control miR-193a expression. They have fundamental effects on its biological behaviour in different types of cancers. CONCLUSION: miR-193a has significant roles in cancer and can be targeted in the future for cancer therapy by better understanding of the factors that control its biological behaviour. PMID- 29521233 TI - PARP Inhibitors for the Treatment of Ovarian Cancer. AB - The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologousrecombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCAmutation carriers leads to the persistence of DNA damage usually repaired by the homologousrecombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in "BRCAness" ovarian tumors, and in BRCA related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice. PMID- 29521234 TI - Noxa: Role in Cancer Pathogenesis and Treatment. AB - The B-cell lymphoma 2 (Bcl-2) family proteins play an important role in regulating apoptosis, or programmed cell death, in response to several extracellular and intracellular signals. These proteins are either pro-apoptotic or anti-apoptotic. The pro-apoptotic Noxa is a Bcl-2 family protein that belongs to a subclass of BH3-only proteins. Noxa induces apoptosis via p53-dependent and/or p53-independent mechanisms. While Noxa may play a limited role in apoptosis, it is a crucial player that interacts with several proteins in the apoptosis pathway, highlighting its importance in the pathogenesis and treatment of certain cancers. In this review, we will elucidate the mechanisms by which Noxa regulates apoptosis and review the roles of chemotherapeutic drugs in relation to Noxa. PMID- 29521235 TI - Metastatic Site Location Influences the Diagnostic Accuracy of ctDNA EGFR- Mutation Testing in NSCLC Patients: a Pooled Analysis. AB - BACKGROUND: Recent studies evaluated the diagnostic accuracy of circulating tumor DNA (ctDNA) analysis in the detection of epidermal growth factor receptor (EGFR) mutations from plasma of NSCLC patients, overall showing a high concordance as compared to standard tissue genotyping. However it is less clear if the location of metastatic site may influence the ability to identify EGFR mutations. OBJECTIVE: This pooled analysis aims to evaluate the association between the metastatic site location and the sensitivity of ctDNA analysis in detecting EGFR mutations in NSCLC patients. METHODS: Data from all published studies, evaluating the sensitivity of plasma-based EGFRmutation testing, stratified by metastatic site location (extrathoracic (M1b) vs intrathoracic (M1a)) were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the ctDNA analysis sensitivity, according to metastatic site location. RESULTS: A total of ten studies, with 1425 patients, were eligible. Pooled analysis showed that the sensitivity of ctDNA-based EGFR-mutation testing is significantly higher in patients with M1b vs M1a disease (OR: 5.09; 95% CIs: 2.93 - 8.84). A significant association was observed for both EGFR-activating (OR: 4.30, 95% CI: 2.35-7.88) and resistant T790M mutations (OR: 11.89, 95% CI: 1.45-97.22), regardless of the use of digital-PCR (OR: 5.85, 95% CI: 3.56-9.60) or non-digital PCR technologies (OR: 2.96, 95% CI: 2.24-3.91). CONCLUSIONS: These data suggest that the location of metastatic sites significantly influences the diagnostic accuracy of ctDNA analysis in detecting EGFR mutations in NSCLC patients. PMID- 29521237 TI - Closed-Loop Neuropharmacology For Epilepsy: Distant Dream Or Future Reality? AB - Epilepsy is considered the most frequent severe neurological condition but most patients treated with medication become seizure free. The management of treatment however is highly empirical, mainly relying on observation. A closed-loop therapy for epilepsy would be very valuable for more efficient treatment regimens. Here we discuss monitoring treatment (therapeutic drug monitoring) and the potential developments in this field, as well as providing a review of potential biomarkers that could be used to monitor the disease activity. Finally, we consider the pharmacogenetic input in epilepsy treatment. PMID- 29521238 TI - Quality By Design: Concept To Applications. AB - BACKGROUND: Quality by Design is associated to the modern, systematic, scientific and novel approach which is concerned with pre-distinct objectives that not only focus on product, process understanding but also leads to process control. It predominantly signifies the design and product improvement and the manufacturing process in order to fulfill the predefined manufactured goods or final products quality characteristics. It is quite essential to identify desire and required product performance report such as Target Product Profile, typical Quality Target Product Profile (QTPP) and Critical Quality attributes (CQA). METHODS: This review highlighted about the concepts of QbD design space, for critical material attributes (CMAs) as well as the critical process parameters that can totally affect the CQAs within which the process shall be unaffected and consistently manufacture the required product. Risk assessment tools and design of experiments are its prime components. RESULTS: This paper outlines the basic knowledge of QbD, the key elements; steps as well as various tools for QbD implementation in pharmaceutics field are presented briefly. In addition to this, quite a lot of applications of QbD in numerous pharmaceutical related unit operations are discussed and summarized. CONCLUSION: This article provides a complete data as well as the road map for universal implementation and application of QbD for pharmaceutical products. PMID- 29521239 TI - Hypnotic Effect of Portulaca oleracea L on Pentobarbital-Induced Sleep in Mice. AB - OBJECTIVE: In Iranian Traditional Medicine, the herbs with cold and wet temperament can help to improve insomnia. Portulaca oleracea has cold and wet temperament, so the present study was carried out to investigate the sleep prolonging effect of Portulaca oleracea. METHODS: This work was an experimental study on mice which were randomly divided into these groups: saline (control); Diazepam:) positive control); hydro-alcoholic extract of Portulaca oleracea (12.5, 25, 50, 75 and 100 mg/kg) by Soxhlet apparatus and maceration; in the effective (dose25 mg/kg), different fractions of extract were tested. Ethyl acetate fraction (EAF:); n-Hexane fraction (n-HF); water fraction (WF). All the test compounds were injected intraperitoneally (IP) 30 minutes before pentobarbital administration (30 mg/kg). Duration and latency of pentobarbital induced sleep were recorded. Also, LD50 of Portulaca oleracea extract was determined and the possible neurotoxicity of the extract was tested on neural PC12 cells. Besides, 30 min after administration of hydro alcoholic extract (HAE) motor coordination (rota-rod test) were assessed. RESULTS: HAE increased the duration of pentobarbital-induced sleep at doses of 25, 50, 75 and 100 mg/kg The hypnotic effect of HAE was comparable to that induced by diazepam. Similarly, WF, EAF, and n-HF at 25 mg/kg could increase sleep duration. The sleep latency was decreased by HAE and NHF but not by WF and EAF. The LD50 value for HAE was found to be 4.8 g/Kg. HAE and its fractions did not show neurotoxic effect in cultured PC12-cell line, also HAE did not affect the animals' performance on the rotarod test. CONCLUSIONS: The present data demonstrated that Portulaca oleracea potentiates sleeping behaviors. The main component (s) responsible for the hypnotic effects of this plant is most likely a non-polar agent (s) which is found in n-HF. Isolation of the active constituents may yield a novel sedative drug. PMID- 29521240 TI - Brassica Nigra: Ethopharmacological Review Of A Routinely Used Condiment. AB - Brassica nigra belonging to the family Brassicaceae (syn - black mustard) comprises of dried seeds and is widely cultivated in Mediterranean region and various other countries like India and Europe. B. nigra contains glycosinolates which undergoes hydrolysis in the presence of myrosinase enzyme yields allyl isothiocyante. The bitter taste and pungent odor is due to the isothiocyanates. B. Nigra shows various activities that are medically important such as anticancer, anti-bacterial, anti-fungal, anti-helminthic, protection against renal and hepatic toxicity and can also be used in diabetes treatment. Black mustards are also used in cardiovascular and neurological disorders. The present review explores the historical background including the macroscopic and microscopic characteristics, chemical constituents, pharmacological action, various evaluation parameters, formulations and uses of black mustard. PMID- 29521241 TI - Beta vulgaris - A mini review of traditional uses in Iran, phytochemistry and pharmacology. AB - BACKGROUND: Beta vulgaris (family: Chenopodiacea) is now much used in the food industry as a rich source of sugar but it is much less considered in medicine. Beet has been used in traditional medicine for hundreds of years to treat a variety of diseases such as constipation, decreased libido, gut and joint pain and dandruff. METHODS: This study introduced the benefits of Beta vulgaris by reviewing of Iranian traditional documents from 10th century until now and also compared modern phytotherapy of plant beet from the electronic data banks such as ISI, Pub Med and Scopus with findings that extracted from traditional literature. RESULTS: This plant is known in Iranian traditional medicine (ITM) as Selgh (Arabic) or Choghondar (Farsi) and its leaves are used to develop treatments. Results confirmed that the plant referred to as Selgh in traditional books is that the plant Beta vulgaris in contemporary studies. Treatments that have not been evaluated in modern phytotherapy but do appear in traditional treatments include fever, as well as psychological and psychiatric issues. This article tells the history of beet in ITM and can confirm use of plant Beta vulgaris in medicinal practice. The report can be applied for certification of plant Beta vulgaris for researchers and experts. CONCLUSION: The findings of this study can help the researchers in producing therapeutic products and new application. PMID- 29521242 TI - Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Novel Therapy for Multidrug Resistant Gram Negative Infections in Children. AB - The rise in Multidrug-resistant (MDR) infections has become a significant problem in both the developing countries and in the United States (U.S.). Specifically, MDR gram-negative infections are emerging, affecting not only adults but children as well. The specific gram-negative organisms that have been most concerning within the pediatric population include MDR P. aeruginosa, Enterobacteriaceae, and Acinetobacter spp. The increase in antimicrobial resistance rates is associated with various mechanisms with one of the most common being the production of beta-lactamases. Both Ceftazidime/Avibactam (CZA) and Ceftolozane/Tazobactam (C/T) are two recently approved antibiotics in the U.S. While both of these agents are inhibitors of beta-lactamase enzymes, there are differences between them that are important to understand. At this time, the data in children for these agents are extremely limited. The aim of this review is to describe the characteristics of these agents and their potential uses in pediatric patients. PMID- 29521243 TI - Hypertensive Versus HIV-infected Patients: Who Has the Greatest Target Organ Damage? Comparison of Carotid Plaque Prevalence, Intima Media Thickness and Renal Resistive Index in the Two Groups of Patients. AB - OBJECTIVES: to compare the prevalence of target-organ damage (TOD), defined as carotid plaque, or intima media thickness, cIMT, >0.9 mm, and that of increased renal resistive index (RRI), among HIV-1-infected patients and uninfected hypertensive patients (HT-non HIV). METHODS: HIV-infected patients aged >= 18 years and virologically suppressed were matched with pair-age, sex and BMI HT-non HIV. Patients on antihypertensive treatment were excluded. All patients' cIMT and RRI were evaluated with ultrasonography. Data were analysed throughout Chi2 test, analysis of variance and logistic regression. RESULTS: Fifty-nine HIV-infected patients were enrolled (71% men) and matched with 59 HT-non HIV. No differences were found in cIMT values (p=0.827) and in the prevalence of TOD between HIV infected patients and HT-non HIV (36% vs 38%, p= 0.79). Among HIV-infected patients, those hypertensive had significantly higher prevalence of TOD (46% vs 21%, P< 0.05) and higher cIMT (0.747 +/- 0.104 vs 0.654 +/-0.100 mm, p = 0.0185). Patients with TOD were older (p= 0.004) and more frequently current smokers (p= 0.022). At the logistic regression analysis, TOD was significantly related to age (p=0.04, 95%CI 1.0-1.1) and smoke, current (p=0.178, 95%CI1.2-12.8) or previous (p=0.04, 95%CI 1.0-7.2). Mean RRI were identical for both HIV-1 infected and uninfected patients (0.60, SD+/- 0.05 and 0.60, SD+/- 0.04, respectively, p=0.996). CONCLUSIONS: In our study TOD was associated to hypertension, older age and smoke, but not to HIV serostatus itself, confirming the major importance of traditional risk factors and the need of risk assessment and cardiovascular prevention measures in HIV-infected patients. PMID- 29521245 TI - Designing Ligands for Leishmania, Plasmodium, and Aspergillus N-Myristoyl Transferase with Specificity and Anti-Target-Safe Virtual Libraries. AB - BACKGROUND: Leishmaniasis, malaria, and fungal diseases are burdens on individuals and populations and can present severe complications. Easily accessible chemical treatments for these diseases are increasingly sought-after. Targeting the parasite N-myristoyl transferase while avoiding the human enzyme and other anti-targets may allow the prospect of compounds with pan-activity against these diseases, which would simplify treatments and costs. Developing chemical libraries, both virtual and physical, that have been filtered and flagged early on in the drug discovery process (before virtual screening) could reduce attrition rates of compounds being developed and failing late in development stages due to problems of side-effects or toxicity. METHODS: Chemical libraries have been screened against the anti-targets pregnane-X-receptor, sulfotransferase, cytochrome P450 2a6, 2c9, and 3a4 with three different docking programs. Statistically significant differences are observed in their interactions with these enzymes as compared to small molecule drugs and bioactive non-drug datasets. RESULTS AND CONCLUSION: A series of compounds are proposed with the best predicted profiles for inhibition of all parasite targets while sparing the human form and anti-targets. Some of the topranked compounds have confirmed experimental activity against Leishmania, and highlighted are those compounds with best properties for further development. PMID- 29521246 TI - Knowledge, Attitudes, and Practices of Pharmacovigilance and ADRs Spontaneous Reporting Among Pediatricians and Pediatric Residents in Jordan. AB - INTRODUCTION: Pharmacovigilance (PV) is the science responsible for ADRs reporting and accordingly medication safety. Pediatrics age group is a special concern as they have a higher risk of developing ADRs; this put more burden on pediatricians for early detection and reporting of ADRs. The present study aims to explore pediatricians' knowledge, attitude, and practices of pharmacovigilance. METHOD: A structured validated questionnaire was designed to achieve the study goals. A convenient sample of 142 pediatricians took part in the study. RESULTS: The majority of pediatricians had a poor knowledge score about pharmacovigiliance and ADRs reporting. On the other hand, 71% of respondents had a good attitude score towards reporting ADRs. When exploring their own practice, pediatricians have a low reporting rate. CONCLUSION: The results of the present study reveal that pediatricians lack knowledge of PV and ADRs reporting. However, they have a good attitude towards ADRs reporting and enhancing their PV practice. This is still not reflected in their own practice. Further training and education about ADRs reporting are very important to move toward safer medications in children. PMID- 29521244 TI - Synthesis, Structural Characterization and Docking Studies of Sulfamoyl- Phenyl Acid Esters as Dipeptidyl Peptidase-IV Inhibitors. AB - BACKGROUND: Diabetes mellitus is a major worldwide health concern that has several serious complications including retinopathy, neuropathy, nephropathy and macrovascular diseases. OBJECTIVE: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, gliptins, are a new class of antidiabetic agents that potentiate the action of incretins in decreasing the blood glucose levels. METHODS: In the present study, synthesis and characterization of a series of ten N4-sulfonamido-acrylic and phthalamic acid methyl esters (3a-e and 5a-e) were achieved. RESULTS: In vitro anti-DPP-IV activity of the synthesized compounds was evaluated, where compound 3b demonstrated the best activity with a % inhibition of 41.7 at 10 uM concentration and an IC50 of 23.9 uM. Moreover, Glide docking experiments revealed that our targeted compounds accommodate the binding site of DPP-IV and tend to form H-bonding with the backbones of R125, E206, S209, D545, K554, W629, Y631, and G632. CONCLUSION: Modeling findings recommend the attachment of bulky hydrophobic group on the ester side of the structure in addition to harboring extra aromatic rings that might be beneficial for better binding interaction and biological activity. PMID- 29521247 TI - Evaluating the Effect of Oral N-acetylcysteine as an Adjuvant Treatment on Clinical Outcomes of Patients with Rheumatoid Arthritis: A Randomized, Double Blind Clinical Trial. AB - OBJECTIVE: Oxidative stress and Overproduction of pro-inflammatory cytokines are contributed in Rheumatoid Arthritis (RA) pathogenesis. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent which demonstrated analgesic effects in some studies. This study is designed to assess the effects of oral NAC as an adjuvant therapy on the clinical outcomes of patients with active RA. METHODS: In this randomized clinical trial, 51 RA patients with active RA were studied in 2 groups: NAC group (27 patients) received standard treatment of RA and 600 mg NAC twice a day for 12 weeks, and placebo group (24 patients) received the standard treatment of RA and placebo. Disease activity score (DAS28) was used to assess the activity of RA, Visual Analog Scale (VAS) for the severity of pain, Health Assessment Questionnaire (HAQ) for the patients' physical performance, and Global Health (GH) parameter for the patients' assessment of their disease activity. The number of tender and swollen joints and Erythrocyte Sedimentation Rate (ESR) were also determined for each patient. Data were analyzed using SPSS version 16.0 (Chicago, IL, USA). RESULTS: After 12 weeks of intervention, there were no significant differences between two groups in DAS28 score and ESR (P values were 0.4 and 0.6, respectively). However, GH, VAS, and HAQ scores were improved significantly in the NAC group compared to the placebo group. CONCLUSION: Our findings indicate that oral administration of NAC may be associated with improving health status in RA patients and considered as an adjuvant therapy in these patients. Further studies with larger sample size, longer study duration and higher doses of NAC are needed to confirm the effects of oral NAC in RA patients. PMID- 29521236 TI - In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease. AB - Parkinson's Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel antiparkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated with dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused on a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5 hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure- and ligand-based in silico approaches for the development of small molecules to target these receptors. PMID- 29521248 TI - 99mTc-(tricine)-HYNIC-Lys-FROP Peptide for Breast Tumor Targeting. AB - BACKGROUND: Breast cancer is malignant disease with high mortality rate among women in the world. It is necessary to diagnose breast cancer at the early stage before it metastasizes in patients. OBJECTIVE: The aim of this is the evaluation of 99mTc-(tricine)-HYNIC-Lys-FROP for breast tumor imaging. METHOD: Lys-FROP peptide was labeled with 99mTc using HYNIC as chelator and tricine as co-ligand. Specific binging of this radiolabeled peptide on breast cancerous cell was assessed in different cell lines as well as in tumor bearing mice. RESULTS: HYNIC Lys-FROP peptide was labeled with 99mTc at radiochemical purity more than 99%. It was observed high stability in normal saline and serum about 95%. A highest cellular uptake was observed in MCF-7 breast tumor cells treated with 99mTc (tricine)-HYNIC-Lys-FROP as compared to other cell lines (lung, ovarian, T47D breast cancer cell lines). Biodistribution results in female MCF-7 tumor bearing mice showed the relatively high tumor uptake and tumor-muscle ratio as 3.82 +/- 0.66 after 15 min post-injection of 99mTc-(tricine)-HYNIC-Lys-FROP. Tumor uptake was reduced in mice that were co-injected with excess of unlabeled peptide to be 0.91 +/- 0.08. Conclusion Findings showed this radiolabeled peptide is a promising candidate for tumor targeting and molecular imaging of breast cancer. PMID- 29521249 TI - Parallel Solid-Phase Synthesis Using a New Diethylsilylacetylenic Linker and Leading to Mestranol Derivatives with Potent Antiproliferative Activities on Multiple Cancer Cell Lines. AB - RM-133 belongs to a new family of aminosteroid derivatives demonstrating interesting anticancer properties, as confirmed in vivo in four mouse cancer xenograft models. However, the metabolic stability of RM-133 needs to be improved. After investigation, the replacement of its androstane scaffold by a more stable estrane scaffold led to the development of the mestranol derivative RM-581. Using solid-phase strategy involving five steps, we quickly synthesized a series of RM-581 analogs using the recently-developed diethylsilyl acetylenic linker. To establish structure-activity relationships, we then investigated their antiproliferative potency on a panel of cancer cell lines from various cancers (breast, prostate, ovarian and pancreatic). Some of the mestranol derivatives have shown in vitro anticancer activities that are close to, or better than those observed for RM-581. Compound 23, a mestranol derivative having a ((3,5 dimethylbenzoyl)-L-prolyl)piperazine side chain at position C2, was found to be active as an antiproliferative agent (IC50 = 0.38 +/- 0.34 to 3.17 +/- 0.10 uM) and to be twice as active as RM-581 on LNCaP, PC-3, MCF-7, PANC-1 and OVCAR-3 cancer cells (IC50 = 0.56 +/- 0.30, 0.89 +/- 0.63, 1.36 +/- 0.31, 2.47 +/- 0.91 and 3.17 +/- 0.10 uM, respectively). Easily synthesized in good yields by both solid-phase organic synthesis and classic solution-phase chemistry, this promising candidate could be used as an antiproliferative agent on a variety of cancers, notably pancreatic and ovarian cancers, both having very bad prognoses. PMID- 29521250 TI - Sorafenib as a Salvage Therapy in FLT3-ITD Negative Relapse/Refractory Acute Myeloid Leukemia. AB - Multi-kinase inhibitor sorafenib showed dramatic effects in acute myeloid leukemia (AML) cells harboring fms-related tyrosine kinase 3-internal tandem duplication(FLT3-ITD) mutation. However, little is known about its therapeutic effects and underlying mechanisms on AML without this mutation. In this report, sorafenib monotherapy was utilized as a salvage treatment in two relapse/refractory AML patients without FLT3-ITD mutation. A central nervous system(CNS) relapsed patient exhibited significant shrink of tumor volume, the other patient with refractory AML, arising from chronic myelomonocytic leukemia, achieved hematological improvements. These two cases suggested that sorafenib might be utilized as a potent salvage therapy for some refractory/relapsed AML patients without the FLT3-ITD mutation. PMID- 29521251 TI - Suppression of the Viability and Proliferation of HepG2 Hepatocellular Carcinoma Cell Line by Konjac Glucomannan. AB - BACKGROUND: Konjac glucomannan (KGM) is a water-soluble dietary fibre extracted from Amorphophallus konjac K. Koch (Araceae). Konjac fibre has been clinically proven as an effective antioxidant agent in weight control but its traditionally known tumour suppression property remains to be explored. OBJECTIVE: The main objective of this study is to determine the potential anti-proliferative effect of KGM on cancer and normal human liver cell lines, HepG2 and WRL68, respectively. METHOD: HepG2 and WRL68 cells were treated with KGM, D-mannose, KGM D-mannose and 5-fluorouracil. The morphological changes in those treated cells were observed. Cytotoxic effect of the treatments on cell viability and proliferation, and apoptosis genes expression were assessed by cytotoxicity assay, flow cytometry and RT-PCR analyses. RESULTS: The results show that KGM treatment resulted in reduced viability of HepG2 cells significantly, in line with the apoptosis-like morphological changes. Up-regulation of BAX and down regulation of BCL2 genes as reflected by high Bax to Bcl 2 ratio suggests that the inhibitory effect of KGM on HepG2 cells most likely via Bcl2/Bax protein pathway. Despite the effectiveness of standard drug 5-FU in suppressing the viability and proliferation of HepG2 cells, it is however, exhibited no selective inhibition of cancer cells as compared to KGM. CONCLUSION: Current findings suggested that KGM is a potential anti-cancer compound/drug entity, which could be an alternative preventive agent against liver cancer. PMID- 29521252 TI - New Quinoline Based Sulfonamide Derivatives : Cytotoxic and Apoptotic Activity Evaluation Against Pancreas Cancer Cells. AB - BACKGROUND: Quinoline is a privileged scaffold especially known with antimalarial and antibacterial drugs before, presently followed anticancer efficiency with a new group of protein kinase inhibitors. OBJECTIVE: In this work, combining quinoline ring, hydrazone and sulphonamide groups, we have synthesized N' arylidene-2-[4-(quinolin-8-ylsulfonyl)piperazin-1-yl]acetohydrazide derivatives (3a-o) and evaluated their in vitro anticancer activity against cancerous cell lines PANC-1, CAPAN-1 and healthy cell line hTERT-HPNE. METHOD: Fifteen compounds were synthesized a simple, well-known three-step synthetic procedure starting from 8-quinolinesulfonylchloride. Cytotoxicity studies were performed according to conventional MTT method. As a second stage, flow cytometric analysis was done to the most cytotoxic nine compounds for determining mechanism of action which could be apoptosis and/or necrosis. RESULTS/CONCLUSION: According to anticancer activity evaluation, compound 3b bearing 4-methyl phenyl moiety exhibited significant cytotoxicity which has an IC50 value nearly four fold lower than cisplatin displayed whereas compound 3f bearing 4-trifloromethyl phenyl moiety showed two fold potency of standard drug against PANC-1 cell line. Compounds 3h, 3k and 3n against CAPAN-1 have also showed significant cytotoxicity, selectively. The most active compounds 3b, 3c, 3d, 3f, 3g, 3h, 3k and 3n against PANC-1 and compounds 3f, 3g, 3h, 3k and 3n against CAPAN-1 were selected to be studied in flow cytometry. Compound 3b induced apoptosis of PANC-1 cells with a percentage of 16.0% whereas compound 3h induced apoptosis of CAPAN-1 cells with a value of 20.6%. PMID- 29521253 TI - Ameliorative Effect of Trans-Sinapic Acid and its Protective Role in Cerebral Hypoxia in Aluminium Chloride Induced Dementia of Alzheimer's Type. AB - BACKGROUND: Trans-Sinapic Acid is a bioactive compound. Recent studies showed that it has a significant potential to attenuate various chemically induced Neurodegenerative toxicities. AIM: The present study investigates the potential of trans-Sinapic Acid as neuromodulator and its effect on release of Monoamine Oxidase (MAO-A, MAO-B), TNF-alpha, Acetylcholine esterase Enzyme, in cognitive dysfunctions associated with experimental dementia. Experiment: Aluminium chloride was administered at a dose of 175mg/kg, p.o. for a period of 25 days in rats and then divided into different groups, i.e. Treatment group, negative control and two groups of trans- Sinapic Acid, (at a dose of 30 and 60mg/kg, p.o.), where these groups treated and observed until the 35th day of experimental trial. Morris water Maze (MWM) and Photoactometer was used to access learning, memory and ambulatory movements on 5th, 16th, 26th and 36th day of experiment. Later, the animals were sacrificed for biochemical and histopahological studies. The oxidative stress was measured by estimating the levels of Glutathion (GSH), Superoxide dismutase (SOD), Nitrite, Catalase. Brain acetylcholine esterase (Ache) activity and Monoamine oxidase (MAO-A, MAO-B) were also estimated. The Brain level of TNF-alpha was measured as a marker of inflammation. RESULTS: Aluminium chloride (AlCl3) produced a marked decline in MWM performance and ambulatory movements' of animals, reflecting impairment of memory and learning. Trans-Sinapic Acid treatment significantly modulates AlCl3 induced memory deficits, biochemical and pathological alterations. The findings demonstrate that the memory restorative ability of trans-Sinapic Acid may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential. PMID- 29521254 TI - Mechanism by which Regulatory Rheumatoid Factor Prevents Experimental Autoimmune Encephalomyelitis. AB - BACKGROUND: One mechanism that underlies protection from autoimmunity and avoidance of uncontrolled inflammation is the controlled contraction of lymphocyte expansion during the immune response. We identified regulatory rheumatoid factor (regRF), the production of which is associated with resistance to and remission of experimental autoimmune diseases. RegRF is anti-idiotypic antibodies to lymphocyte receptors against autoimmune disease-inducing antigens; at the same time, it is specific to epitopes in the hinge Fc fragments of IgG. OBJECTIVE: The aim of this study is to test the hypothesis that regRF prevents autoimmunity by limiting the expansion of lymphocytes. METHODS: To test this hypothesis, we used a model of experimental autoimmune encephalitis. RESULTS: We found that in the lymph nodes that drain the injection site in rats producing regRF in response to immunization with myelin basic protein (MBP) the proportion of CD4+lymphocytes was lower than in rats in which MBP-immunization did not induce higher regRF levels. RegRF-containing plasma obtained from MBP-immunized rats induces complement-dependent killing of MBP-activated lymphocytes. Activated MBP-specific lymphocytes are not sensitive to the regRF-containing plasma of intact rats. CONCLUSION: The regRF produced during the immune response is a specific control factor for the expansion of antigen-activated CD4+lymphocytes. PMID- 29521255 TI - An Overview on Various Approaches and Recent Patents on Gastroretentive Drug Delivery Systems. AB - BACKGROUND: Drugs having absorption window in the stomach or upper small intestine have restricted bioavailability with conventional dosage forms. The gastric residence time of these dosage forms is usually short and they do not show drug release for prolonged period of time. OBJECTIVE: To avoid these problems and to enhance the bioavailability and gastric retention time of these drugs, controlled drug delivery systems with prolonged gastric retention time are currently being developed. METHODS: This review highlights the various pharmaceutical approaches for gastroretention such as floating drug delivery systems, mucoadhesive systems, high-density systems, expandable and swelling systems, super porous hydrogels systems, magnetic systems, ion exchange resin system and recent patents filed or granted for these approaches. RESULTS: Recently, some patents are also reported where a combination of various approaches is being employed to achieve very effective gastroretention. The various patent search sites were used to collect and analyze the information on gastroretentive drug delivery systems. CONCLUSION: The present study provides valuable information, advantages, limitations and future outlook of various gastroretentive drug delivery systems. PMID- 29521256 TI - Definitions and Historical Perspectives in Environmental Forensics. AB - Environmental forensics is a tool that uses chemical, physical, and statistical techniques to investigate contaminants in the environment as a means to determine attribution for legal purposes. Environmental microbiology is a branch of science that has benefited from the use of metagenomics. The term microbial forensics, which includes nucleic acid sequencing methods, is now used to investigate the sources of microorganisms for attribution purposes as well. Environmental microbial forensics can fully address the questions that must be answered for attribution of causation and subsequent remedial actions within a reasonably short time frame. Although sensu stricto forensics refers to obtaining scientific evidence to be presented during legal proceedings, the term sensu lato is used as a description of the procedures used to reconstruct previous events, such as contamination. The term microbial forensics was first used to describe a forensic science approach for attribution purposes, specifically for bioterror as a purposeful release of pathogen microorganisms, but it also especially refers to investigations on the inadvertent or accidental release of pathogenic agents. However, microbial forensics can be used to determine the source of a microorganism or a group of microorganisms, regardless of whether they are pathogenic or not. Microbial forensics has limitations, but it should be used as part of a toolbox of methods to be relied upon when doing forensic studies. Environmental microbial forensics can only benefit from the development of new methods, and we already are experiencing a paradigm change in terms of approaches to the forensic sciences. PMID- 29521257 TI - Future Technologies. AB - Microbiome analysis of environmental samples may represent the next frontier in environmental microbial forensics. Next-generation sequencing technologies significantly increased the available genetic data that could be used as evidentiary material. It is not clear, however, whether the microbiome can scale across institutions using forensic-based evidence due to the data resource requirements and the associated costs of maintaining these databases. A successful microbiome study is impacted by the quality of the information gathered and the steps in sample processing and data analysis. To ascertain the validity of methods and the results obtained, there needs to be a stringent procedure to validate the methods and ensure that the results are comparable and reproducible, not only within the laboratory but also between laboratories conducting similar research. Of primary importance for meaningful microbiome studies is an experimental design that leads to carefully executed, controlled, and reproducible studies. The microbiome literature contains a fair share of anecdotal descriptions of microbial community composition and "diagnostic" relative abundance of the taxa therein. These studies are now being supplemented by experimental designs that feature repeated measurements, error estimates, correlations of microbiota with covariates, and increasingly sophisticated statistical tests that enhance the robustness of data analysis and study conclusions. It is imperative to be careful, especially when carrying out attribution studies, to be fully aware of the possible biases included in a specific sample being analyzed. PMID- 29521259 TI - Seroprevalence of Toxoplasma gondii and Encephalitozoon cuniculi among domestic rabbits in central China. AB - Rabbits (Oryctolagus cuniculus) are frequently reared for meat production in China. The aim of this study was to assess the seroprevalence of Toxoplasma gondii and Encephalitozoon cuniculi, and risk factors of infection in domestic rabbits raised in Henan province, central China. 1,213 serum samples of domestic rabbits were collected and tested for anti-T. gondii and anti-E. cuniculi antibodies using a modified agglutination test (MAT) and an enzyme-linked immunosorbent assay (ELISA), respectively. The serum positive rates of T. gondii and E. cuniculi were 128/1,213 (10.55%) and 235/1,213 (19.37%), respectively. Co infection of T. gondii and E. cuniculi was demonstrated in 84 specimens; 44 rabbits were seropositive for T. gondii alone, while 151 rabbits were seropositive for E. cuniculi alone. The main risk factors simultaneously associated with T. gondii and E. cuniculi infection were the age of the rabbit, the type of food, and the rabbit rearing system. Serum positive rates of T. gondii and E. cuniculi among domestic rabbits were high, indicating the possibility of public health issues. PMID- 29521258 TI - Do drowning and anoxia kill head lice? AB - Chemical, physical, and mechanical methods are used to control human lice. Attempts have been made to eradicate head lice Pediculus humanus capitis by hot air, soaking in various fluids or asphyxiation using occlusive treatments. In this study, we assessed the maximum time that head lice can survive anoxia (oxygen deprivation) and their ability to survive prolonged water immersion. We also observed the ingress of fluids across louse tracheae and spiracle characteristics contrasting with those described in the literature. We showed that 100% of lice can withstand 8 h of anoxia and 12.2% survived 14 h of anoxia; survival was 48.9% in the untreated control group at 14 h. However, all lice had died following 16 h of anoxia. In contrast, the survival rate of water-immersed lice was significantly higher when compared with non-immersed lice after 6 h (100% vs. 76.6%, p = 0.0037), and 24 h (50.9% vs. 15.9%, p = 0.0003). Although water-immersed lice did not close their spiracles, water did not penetrate into the respiratory system. In contrast, immersion in colored dimeticone/cyclomethicone or colored ethanol resulted in penetration through the spiracles and spreading to the entire respiratory system within 30 min, leading to death in 100% of the lice. PMID- 29521260 TI - Tuberculous lumbar spinal epidural abscess in a young adult (case report). AB - INTRODUCTION: Spinal Epidural abscess (SEA) is an uncommon pathology that needs an urgent intervention to decompress the pressure on the spinal epidural sac, cord, and roots. The authors report a rare case of a young adult with lumbar spinal epidural tuberculous abscess occupying the spinal canal from L2-L5 vertebrae with extesion to the posterior paraspinal muscles and presenting with bilateral progressive lower limb weakness. Case report: A 42 years old male teacher presented with a 15-day history of progressive difficulty to walking and bilateral lower limb weakness associated with fever, malaise and later on urinary incontinence. A magnetic resonance imaging (MRI) scan revealed a paraspinal intermuscular abscess and an abscess occupying the spinal canal compressing the dural sac from L2-L4/5, without any signs of vertebral involvement. Surgery was done by a posterior midline incision. Pus was evacuated from multiple pockets through the paraspinal muscle layers. Laminectomy for L3/4, and hemilaminectomy for L2/3, and L4/5 were performed. Pus and bone specimens were negative for acid fast bacilli. However, both histopathological studies and Polymerase Chain Reaction (PCR) testing confirmed the presence of tuberculosis (TB). The patient received TB antibiotics, and a follow-up MRI scan at 2 months showed complete evacuation of the abscess. However, signs of L5 spondylitis were evident. No further surgery was needed as there was no vertebral collapse or neural compression and the patient's clinical condition was improving. He had normal right lower limb power and sensation and grade 4+ motor power of the left lower limb. Bowels and bladder function was normal. CONCLUSION: Isolated tuberculous spinal epidural abscess is a rare disease and should be treated urgently with evacuation and decompression. Signs of spondylitis or spondylodiscitis may appear later and therefore long follow up is recommended in tuberculous cases presenting with an isolated epidural abscess. PMID- 29521262 TI - [Rectovesical fistula after laparoscopic radical prostatectomy secondary to the use of hem-o-lock clips.] PMID- 29521261 TI - Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2 mediated mechanotransduction in peripheral sensory neurons. AB - Piezo2 ion channels are critical determinants of the sense of light touch in vertebrates. Yet, their regulation is only incompletely understood. We recently identified myotubularin related protein-2 (Mtmr2), a phosphoinositide (PI) phosphatase, in the native Piezo2 interactome of murine dorsal root ganglia (DRG). Here, we demonstrate that Mtmr2 attenuates Piezo2-mediated rapidly adapting mechanically activated (RA-MA) currents. Interestingly, heterologous Piezo1 and other known MA current subtypes in DRG appeared largely unaffected by Mtmr2. Experiments with catalytically inactive Mtmr2, pharmacological blockers of PI(3,5)P2 synthesis, and osmotic stress suggest that Mtmr2-dependent Piezo2 inhibition involves depletion of PI(3,5)P2. Further, we identified a PI(3,5)P2 binding region in Piezo2, but not Piezo1, that confers sensitivity to Mtmr2 as indicated by functional analysis of a domain-swapped Piezo2 mutant. Altogether, our results propose local PI(3,5)P2 modulation via Mtmr2 in the vicinity of Piezo2 as a novel mechanism to dynamically control Piezo2-dependent mechanotransduction in peripheral sensory neurons. PMID- 29521263 TI - [Efficacy and safety of D-mannose (2 g), 24h prolonged release, associated with Proanthocyanidin (PAC), versus isolate PAC, in the management of a series of women with recurrent urinary infections.] AB - OBJECTIVE: To compare the efficacy and safety of dietary supplement "Manosar(r)" composed of D-mannose (2 g), 24 h prolonged release, associated with Proanthocyanidin (PAC) (140 mg), ursolic acid (7.98 mg), A, C, and D vitamins and the oligoelement zinc, versus 240 mg of PAC in recurrent urinary tract infections (UTI), for a designed follow-up of 24 weeks, in women. METHODS: A multicenter randomized experimental double-blind study was carried out. The study was approved by review board of "Complejo Hospitalario de Toledo" (Spain), and all patients gave informed consent. A total of 150 women with non complicated UTI were screened for participation. Valid data was obtained from 93, with mean age of 48 years. Fortyfour patients were assigned to the Manosar(r) group and 51 patients to the PAC group. Patients were followed during six months. A previous UTI was defined based on a combination of symptoms and a positive reactive urine trip. Confirmation of a new UTI was based on symptoms, reactive urine strip and urine culture. RESULTS: Thirty-three patients (35%) had an UTI during the six months follow-up. The percentage of UTI of the Manosar(r) group during this period was 24%, while the percentage of the PAC group was 45% (p<0.05). The disease-free time for the Manosar(r) group was 95 days, while this time was 79 days for the PAC group. The incidence of side effects was low. Diarrhea was the most frequent side-effect in both groups. CONCLUSION: Manosar(r) (oral once a day) is more effective than single dose PAC (240 mg daily orally) to prevent recurrent UTI in women. PMID- 29521264 TI - Application of ERAS (Enhanced Recovery After Surgery) and laparoscopic surgery in the management of patients with bladder cancer. AB - OBJECTIVE: The enhanced recovery after surgery program (ERAS) has become the base of perioperative management in various surgical specialties. However, limited data are available for radical cystectomy. METHODS: We have analyzed 124 patients undergoing radical cystectomy. For retrospective analysis, the patients were divided into two groups:Group A (n=72) included patients whose surgery was performed before the introduction of the ERAS protocol; and Group B (n=52) included patients who were treated following the items included in the ERAS protocol. The main objective was to assess the length of hospital stay and the permanence in intensive care units (ICU). Other variables were the use of intraoperative blood products, fluid-therapy and medical and surgical complications. RESULTS: Hospital and ICU stay were significantly shorter (p<0.001) in Group B for patients following the ERAS protocol, which led to reduce 7 hospitalization days and 25.7 hours of overall ICU stay. Regarding fluid replacement following the ERAS protocol, our study showed a statistically significant reduction in the total amount of fluid administered, both crystalloids and colloids, in Group B (p<0.001). The need of blood transfusion was also lower in Group B with a statistically significant difference (p<0.001). No statistical differences were observed regarding the incidence of surgical complications. CONCLUSIONS: Introduction of ERAS protocol in radical cystectomy decreases the length of hospital stay, permanence in critical care units, and the need for fluidtherapy and blood product transfusion. However, more and larger studies are needed to prove the efficacy of ERAS for patients undergoing radical cystectomy. PMID- 29521265 TI - [Efficacy of lycopene intake in primary prevention of prostate cancer: a systematic review of the literature and meta-analysis.] AB - OBJECTIVE: To evaluate the efficacy of lycopene intake in primary prevention of prostate cancer (PCa). METHODS: A systematic search of the literature was conducted in March 2015 and the articles published between the years 1990-2015 were reviewed. The following search terms were used: prostate cancer, prostatic neoplasm, lycopene, prevention, effectiveness and efficacy (MeSH). Publications including research in humans, written in English and whose texts were accessible were reviewed. The types of studies included were: clinical trials, cohort and case-control studies. We found 343 articles; of these, 27 were included in the systematic review. After the latter were rigorously analyzed, 23 were included in the meta-analysis using the pooled odds ratios (OR) and risk ratios (RR) of case control and cohort studies, respectively, and their confidence intervals (95% CI), using random-effects models with Review Manager 5.2. RESULTS: Out of the 27 articles included in the systematic review, 22 were case-control and 5 were cohort studies. For the case-control studies, the total number of patients with PCa was 13,999 and the total number of controls 22,028. Cohort studies included 187,417 patients and PCa was diagnosed in 8,619 of these. The metaanalysis determined an OR = 0.94 (IC 95% 0.89-1.00) and RR = 0.9 (IC 95% 0.85-0.95) of PCa related with lycopene and/or raw or cooked tomatoes intake. CONCLUSIONS: Although our study found that there is a statistically significant inverse association between lycopene intake and PCa, the magnitude of this association is weak and comes solely from observational studies, which do not allow recommending its use as a standard of practice. High-quality randomized clinical trials are required to clarify current evidence. PMID- 29521266 TI - Laparoscopic partial nephrectomy using the Simon clamp: our experience in 18 cases. AB - OBJECTIVE: Kidney tumors represent 2- 3% of adult tumors. Partial nephrectomy is the standard of care for the treatment of localized tumors. Minimizing ischemia time is critical for postoperative renal function. The aim of this paper is to present our experience in laparoscopic partial nephrectomy with selective renal parenchymal compression using the Simon clamp. METHODS: We analyzed the record of patients that underwent surgery for renal tumors between January 2011 and June 2016 at our institution. Cases treated conwith this technique were selected. Demographic variables, operative, and postoperative outcomes were analyzed. RESULTS: 323 nephrectomies were performed and 18 cases treated with this technique were analyzed. Average age was 56.27 years (34- 75) with 10 female cases. BMI was 25.01 kg/m2 (21.2- 34.3). 17 cases were lower pole and one upper pole with 11 right and 7 left. Average surgical time was 83.25 minutes (43- 120); renal ischemia time was 21.36 minutes (12- 40) with an estimated blood loss of 91 ml (0- 400). Average tumor diameter was 2.6 cm (1.8 to 5.3). Glomerular filtration rate preoperative and immediate postoperative was 83 ml/min and 87 ml/min (p=0.42) respectively. Average length of stay was 2.75 days (1- 7). All cases had negative margins. With a mean follow up of 23.1 months (1- 58) no recurrences were observed. CONCLUSIONS: Laparoscopic partial nephrectomy using the Simon clamp for vascular control is a feasible technique for selected cases with polar exophytic tumors. Immediate postoperative glomerular filtration rate showed no significant changes and oncological control in our experience was satisfactory. PMID- 29521267 TI - [Small cell bladder carcinoma in age extremes: Report of two cases.] AB - OBJECTIVE: We report 2 cases of small cell neuroendocrine carcinomas (CCP) of the urinary bladder in patients aged 37 and 80 years. CCP is a malignancy with poor prognosis. We review the literature, under the current WHO classification (2016). METHODS: Paraffin blocks were cut for HE staining and immunohistochemistry to analyze the expression of neuroendocrine differentiation. RESULTS: The main diagnosis was based on histopathologic features, which revealed a diffuse growth pattern of small cells with scant cytoplasm and hyperchromatic nuclei. The result of the additional technical immunoreaction was positive for synaptophysin and CD56. CONCLUSIONS: Our cases have been reviewed with the literature to discuss the evolution and differential diagnosis of small cell carcinoma of the urinary bladder. This is a rare tumor with very aggressive behavior and its diagnosis lies in its morphology, and immunohistochemical profile. PMID- 29521268 TI - Pseudomyxoma peritonei: A case report and review of the literature. AB - OBJECTIVE: We present the case of a patient incidentally diagnosed with a pelvic mass next to the bladder. After surgical excision, definitive diagnosis was pseudomyxoma peritonei. We provide a concise review of the literature of this pathology. METHODS: A 55 year-old male patient, was found to have, in annual routine ultrasound, a pelvic retrovesical mass. CT guided needle aspirate showed a tumor with myxoid changes and low aggressive cytology. Surgical excision was performed. RESULTS: The excised mass contained the cecal appendix and ileal serosa. Pathology report was: mucinous cystadenoma of the appendix and pseudomyxoma peritonei. CONCLUSIONS: PMP is a local-regional disease within the abdomen, characterized by a mucinous tumor (mucocele) that produces a progressive amount of mucinous ascites, which eventually blows-out, and tumor cells are spread through the peritoneal cavity. Treatment options differ significantly, depending the stage of the disease. PMID- 29521269 TI - The effect of darbepoetin alfa on renal fibrosis in rats with acute unilateral ureteral obstruction. AB - OBJECTIVES: The most important treatment strategy for obstructive nephropathy is to protect renal tissue from the deleterious effects of fibrosis. Therefore, we sought to investigate the renoprotective effects of darbepoetin alfa on unilateral ureteral obstructions. METHODS: We used 12 female and 12 male 3 monthold Wistar rats weighing between 250 and 350 g. The rats were divided equally into sham, darbepoetin and control groups. With the exception of the sham group, left unilateral obstructions were applied to all of the rats. The darbepoetin group received perioperative darbepoetin alfa at a dose of 10 mg/kg. The rats were sacrificed on postoperative day 7, and 3-cc blood samples and bilateral renal specimens were collected from each rat. RESULTS: Renal ectasia was observed significantly less frequently in the darbepoetin group than the obstruction group (p<0.001). Additionally, the uptake rates of cortical TNF and medullary SMA in the darbepoetin group were comparable to those in the sham group but lower than those in the ureteral obstruction group (p<0.001 and p<0.008, respectively). When biomarkers of renal injury, including cystatin-C, malondialdehyde, and B2 microglobulin, were evaluated in combination, B2 microglobulin was found at higher levels in the ureteral obstruction group (p<0.004). CONCLUSION: As we know pelvicalyceal ectasia reflects intrapelvic pressure into renal tubular system via renal reflux. Therefore pelvicalyceal ectasia can be used as an indicator of renal tubular pressure. Although as a limitation of our study, renal tubular pressure was not quantitatively evaluated, parallelism between levels of renal ectasia detected in the rats of the sham, and DPO groups can predict that this drug (darbepoetin-a) can decrease renal tubular pressure in acute ureteral obstruction. Moreover, B2 microglobulin levels in the sham, and DPO groups differed from those of ureteral obstruction group, which suggested that DPO does not impair renal perfusion in addition to its decreasing effects on renal tubular pressure. We think that in countries with higher incidence rates of stone disease similar to our country, DPO may be used among medical treatment alternatives, which aim to preserve renal reserve. PMID- 29521270 TI - Supernumerary lump pelvic kidney: The first case of the literature. PMID- 29521271 TI - Bladder foreign body. PMID- 29521272 TI - Depth resolved grazing incidence neutron scattering experiments from semi infinite interfaces: a statistical analysis of the scattering contributions. AB - Grazing incidence neutron scattering experiments offer surface sensitivity by reflecting from an interface at momentum transfers close to total external reflection. Under these conditions the penetration depth is strongly non-linear and may change by many orders of magnitude. This fact imposes severe challenges for depth resolved experiments, since the brilliance of neutron beams is relatively low in comparison to e.g. synchrotron radiation. In this article we use probability density functions to calculate the contribution of scattering at different distances from an interface to the intensities registered on the detector. Our method has the particular advantage that the depth sensitivity is directly extracted from the scattering pattern itself. Hence for perfectly known samples exact resolution functions can be calculated and visa versa. We show that any tails in the resolution function, e.g. Gaussian shaped, hinders depth resolved experiments. More importantly we provide means for a descriptive statistical analysis of detector images with respect to the scattering contributions and show that even for perfect resolution near surface scattering is hardly accessible. PMID- 29521273 TI - Spectral characterization of plastic scintillation detector response as a function of magnetic field strength. AB - The purpose of this work was to characterize intensity and spectral response changes in a plastic scintillation detector (PSD) as a function of magnetic field strength. Spectra measurements as a function of magnetic field strength were performed using an optical spectrometer. The response of both a PSD and PMMA fiber were investigated to isolate the changes in response from the scintillator and the noise signal as a function of magnetic field strength. All irradiations were performed in water at a photon beam energy of 6 MV. Magnetic field strengths of (0, +/-0.35, +/-0.70, +/-1.05, and +/-1.40) T were investigated. Four noise subtraction techniques were investigated to evaluate the impact on the resulting noise-subtracted scintillator response with magnetic field strength. The noise subtraction methods included direct spectral subtraction, the spectral method, and variants thereof. The PMMA fiber exhibited changes in response of up to 50% with magnetic field strength due to the directional light emission from [Formula: see text]erenkov radiation. The PSD showed increases in response of up to 10% when not corrected for the noise signal, which agrees with previous investigations of scintillator response in magnetic fields. Decreases in the [Formula: see text]erenkov light ratio with negative field strength were observed with a maximum change at -1.40 T of 3.2% compared to 0 T. The change in the noise-subtracted PSD response as a function of magnetic field strength varied with the noise subtraction technique used. Even after noise subtraction, the PSD exhibited changes in response of up to 5.5% over the four noise subtraction methods investigated. PMID- 29521274 TI - Pressure-induced superconductivity in palladium sulfide. AB - An extended study on PdS is carried out with the measurements of the resistivity, Hall coefficient, Raman scattering, and x-ray diffraction at high pressures up to 42.3 GPa. With increasing pressure, superconductivity is observed accompanying with a structural phase transition at around 19.5 GPa. The coexistence of semiconducting and metallic phases observed at normal state is examined by the Raman scattering and x-ray diffraction between 19.5 and 29.5 GPa. After that, only the metallic normal state maintains with an almost constant superconducting transition temperature. The similar evolution between the superconducting transition temperature and carrier concentration with pressure supports the phonon-mediated superconductivity in this material. These results highlight the important role of pressure played in inducing superconductivity from these narrow band-gap semiconductors. PMID- 29521275 TI - Spin current and second harmonic generation in non-collinear magnetic systems: the hydrodynamic model. AB - We report a theoretical study of the second harmonic generation in a noncollinearly magnetized conductive medium with equilibrium spin current. The hydrodynamic model is used to unravel the mechanism of a novel effect of the double frequency signal generation that is attributed to the spin current. According to our calculations, this second harmonic response appears due to the 'non-adiabatic' spin polarization of the conduction electrons induced by the oscillations in the non-uniform magnetization forced by the electric field of the electromagnetic wave. Together with the linear velocity response this leads to the generation of the double frequency spin current. This spin current is converted to the electric current via the inverse spin Hall effect, and the double-frequency electric current emits the second harmonic radiation. Possible experiment for detection of the new second harmonic effect is proposed. PMID- 29521276 TI - Mesoporous TiO2 nanosheets anchored on graphene for ultra long life Na-ion batteries. AB - Sodium-ion batteries, which have a similar electrochemical reaction mechanism to lithium-ion batteries, have been considered as one of the most potential lithium ion battery alternatives due to the rich reserves of sodium. However, it is very hard to find appropriate electrode materials imputing the large radius of sodium ion. TiO2 is particularly interesting as anodes for sodium-ion batteries due to their reasonable operation voltage, cost, and nontoxicity. To obtain a better electrochemical property, mesoporous TiO2 nanosheets (NSs)/reduced graphene oxide (rGO) composites have been synthesized via a scalable hydrothermal-solvothermal method with a subsequent calcination process. Benefitting from unique structure design, TiO2 NSs@rGO exhibits a superior cycle stability (90 mAh g-1 after 10 000 cycles at a high current rate of 20 C) and satisfactory rate performance (97.3 mAh g-1 at 25 C). To our knowledge, such ultra long cycle life has not previously been reported. PMID- 29521277 TI - Corrigendum to "Analysis of dose heterogeneity using subvolume-DVH". AB - The dose-volume histogram (DVH) is universally used in radiation therapy for its highly efficient way of summarizing three-dimensional dose distributions. An apparent limitation that is inherent to standard histograms is the loss of spatial information, e.g. it is no longer possible to tell where low- and highdose regions are, and whether they are connected or disjoint. Two methods for overcoming the spatial fragmentation of low- and high-dose regions are presented, both based on the gray-level size zone matrix, which is a two-dimensional histogram describing the frequencies of connected regions of similar intensities. The first approach is a quantitative metric which can be likened to a homogeneity index. The large cold spot metric (LCS) is here defined to emphasize large contiguous regions receiving too low a dose; emphasis is put on both size, and deviation from the prescribed dose. In contrast, the subvolume-DVH (sDVH) is an extension to the standard DVH and allows for a qualitative evaluation of the degree of dose heterogeneity. The information retained from the two-dimensional histogram is overlaid on top of the DVH and the two are presented simultaneously. Both methods gauge the underlying heterogeneity in ways that the DVH alone cannot, and both have their own merits-the sDVH being more intuitive and the LCS being quantitative. PMID- 29521278 TI - Potassium ions intercalated into g-C3N4-modified TiO2 nanobelts for the enhancement of photocatalytic hydrogen evolution activity under visible-light irradiation. AB - Solar-to-chemical energy conversion is a challenging photochemical reaction for renewable energy storage. In recent decades, photocatalytic H2 evolution has been studied extensively. TiO2 is a well-established semiconductor in the field of photocatalytic H2 production; however, its low efficiency for solar energy utilization, and high photocarrier recombination rate, restrict its photocatalytic efficiency. Here, a series of K-intercalated g-C3N4-modified TiO2 nanobelts (TCN-Kx) with different dosages of K atoms were fabricated using a hydrothermal method followed by a calcination process. XRD, TEM and XPS tests indicate that a tight interfacial connection is formed between K-g-C3N4 and the TiO2 nanobelts. DFT calculations indicated that K dopants prefer to be at the interlayer sites of g-C3N4, suggesting increased charge transfer efficiency. The H2 production efficiency of the TCN-Kx composite materials from water splitting under visible-light irradiation was clearly improved. Steady fluorescence spectroscopy and photocurrent measurements confirmed that the improvement in photocatalytic H2 production activity was due to the superior charge separation and electron transfer efficiency of TCN-Kx composite materials. PMID- 29521280 TI - Beam characterisation of the 1.5 T MRI-linac. AB - As a prerequisite for clinical treatments it was necessary to characterize the Elekta 1.5 T MRI-linac 7 MV FFF radiation beam. Following acceptance testing, beam characterization data were acquired with Semiflex 3D (PTW 31021), microDiamond (PTW 60019), and Farmer-type (PTW 30013 and IBA FC65-G) detectors in an Elekta 3D scanning water phantom and a PTW 1D water phantom. EBT3 Gafchromic film and ion chamber measurements in a buildup cap were also used. Special consideration was given to scan offsets, detector effective points of measurement and avoiding air gaps. Machine performance has been verified and the system satisfied the relevant beam requirements of IEC60976. Beam data were acquired for field sizes between 1 * 1 and 57 * 22 cm2. New techniques were developed to measure percentage depth dose (PDD) curves including the electron return effect at beam exit, which exhibits an electron-type practical range of [Formula: see text] cm. The Lorentz force acting on the secondary charged particles creates an asymmetry in the crossline profiles with an average shift of +0.24 cm. For a 10 * 10 cm2 beam, scatter from the cryostat contributes 1% of the dose at isocentre. This affects the relative output factors, scatter factors and beam profiles, both in-field and out-of-field. The average 20%-80% penumbral width measured for small fields with a microDiamond detector at 10 cm depth is 0.50 cm. MRI-linac penumbral widths are very similar to that of the Elekta Agility linac MLC, as is the near-surface dose PDD(0.2 cm) = 57%. The entrance surface dose is ~36% of [Formula: see text]. Cryostat transmission is quantified for inclusion within the treatment planning system. As a result, the 1.5 T MRI-linac 7 MV FFF beam has been characterised for the first time and is suitable for clinical use. This was a key step towards the first clinical treatments with the MRI-linac, which were delivered at University Medical Center Utrecht in May 2017 (Raaymakers et al 2017 Phys. Med. Biol. 62 L41-50). PMID- 29521279 TI - Flexible microelectrode array for interfacing with the surface of neural ganglia. AB - OBJECTIVE: The dorsal root ganglia (DRG) are promising nerve structures for sensory neural interfaces because they provide centralized access to primary afferent cell bodies and spinal reflex circuitry. In order to harness this potential, new electrode technologies are needed which take advantage of the unique properties of DRG, specifically the high density of neural cell bodies at the dorsal surface. Here we report initial in vivo results from the development of a flexible non-penetrating polyimide electrode array interfacing with the surface of ganglia. APPROACH: Multiple layouts of a 64-channel iridium electrode (420 um2) array were tested, with pitch as small as 25 um. The buccal ganglia of invertebrate sea slug Aplysia californica were used to develop handling and recording techniques with ganglionic surface electrode arrays (GSEAs). We also demonstrated the GSEA's capability to record single- and multi-unit activity from feline lumbosacral DRG related to a variety of sensory inputs, including cutaneous brushing, joint flexion, and bladder pressure. MAIN RESULTS: We recorded action potentials from a variety of Aplysia neurons activated by nerve stimulation, and units were observed firing simultaneously on closely spaced electrode sites. We also recorded single- and multi-unit activity associated with sensory inputs from feline DRG. We utilized spatial oversampling of action potentials on closely-spaced electrode sites to estimate the location of neural sources at between 25 um and 107 um below the DRG surface. We also used the high spatial sampling to demonstrate a possible spatial sensory map of one feline's DRG. We obtained activation of sensory fibers with low-amplitude stimulation through individual or groups of GSEA electrode sites. SIGNIFICANCE: Overall, the GSEA has been shown to provide a variety of information types from ganglia neurons and to have significant potential as a tool for neural mapping and interfacing. PMID- 29521281 TI - Spin-orbit coupling induced three-dimensional topological objects in attractive Bose-Einstein condensates. AB - Attractive Bose-Einstein condensates of dilute alkali gases are unstable against collapse in two- and three-dimensional free space. Nevertheless, we demonstrate that the spin-orbit coupling of the two-component condensates counteracts the tendency of collapse and makes the system preferable to an extended spatial distribution in the three-dimensional case. Furthermore, stable topological objects can be formed in the condensates, which are shown to be the lowest energy states. Two configurations of the density profiles, called three-dimensional skyrmion and three-dimensional dimeron, respectively, are identified depending on the strength of the spin-orbit coupling. PMID- 29521282 TI - Electron energy-loss spectroscopy of single nanocrystals: mapping of tin allotropes. AB - Using monochromated electron energy-loss spectroscopy (EELS), we are able to map different allotropes in Sn-nanocrystals embedded in Si. It is demonstrated that alpha-Sn and beta-Sn, as well as an interface related plasmon, can be distinguished in embedded Sn-nanostructures. The EELS data is interpreted by standard non-negative matrix factorization followed by a manual Lorentzian decomposition. The decomposition allows for a more physical understanding of the EELS mapping without reducing the level of information. Extending the analysis from a reference system to smaller nanocrystals demonstrates that allotrope determination in nanoscale systems down below 5 nm is possible. Such local information proves the use of monochromated EELS mapping as a powerful technique to study nanoscale systems. This possibility enables investigation of small nanostructures that cannot be investigated through other means, allowing for a better understanding and thus leading to realizations that can result in nanomaterials with improved properties. PMID- 29521284 TI - Additional Dose of Intravenous Tranexamic Acid after Primary Total Knee Arthroplasty Further Reduces Hidden Blood Loss. AB - Background: Total knee arthroplasty (TKA) is the most frequently performed procedure in treating advanced knee osteoarthritis. Excessive perioperative blood loss can sometimes lead to postoperative anemia. Tranexamic acid (TXA) is a potent fibrinolysis inhibitor which has been extensively used at the surgical incision and closure to lower overall blood loss in adult reconstruction surgery. Our previous study suggested that about two-thirds of the total blood loss (TBL) came from hidden blood loss (HBL) on postoperative days 1 and 2. The role of reducing HBL with TXA administration in postoperative TKA patients is unknown. The current study was designed to evaluate the efficiency and safety of supplemental intravenous (IV) TXA in further reducing HBL after primary TKA. Methods: A prospective pilot study was conducted at a single institution on 43 consecutive patients who underwent unilateral TKA from September 2014 to February 2015. All patients were given 1 g of IV TXA 10-15 min before operation and another 1 g of IV TXA at the time of wound closure on the day of surgery. On postoperative days 1 and 2, the supplemental group (n = 21) was given additional 1 g of TXA intravenously twice a day, whereas the control group (n = 22) received an equal volume of saline. Drain output, hemoglobin (Hb), and hematocrit (HCT) were recorded preoperatively and 5 consecutive days postoperatively in both groups. HBL was calculated with the Gross formula. Pre- and post-operative lower extremity Doppler venous ultrasound was performed in all patients to detect deep vein thrombosis (DVT). The indexes were compared using the Mann-Whitney test, whereas the results of Hb and HCT were analyzed by repeated-measures analysis of variance. The difference was considered statistically significant if P < 0.05. Results: The demographics and surgical characteristics of the two groups were comparable. Supplemental group had higher Hb level on postoperative days 1-5 compared to the control; however, the difference was not significant (F = 2.732, P = 0.106). The HCT of the supplemental group was significantly higher than that of the control group on postoperative day 5 (F = 5.254, P = 0.027). No significant difference was found in drainage volume and TBL, but the HBL was reduced in the supplemental group (supplemental 133.1 [71.8, 287.3] ml and control 296.0 [185.3, 421.4] ml, Z = 2.478, P = 0.013, median [interquartile range]). There was one DVT in the control group and none in the supplemental group. All patients were followed at 1 year after surgery, and no further complications were reported. Conclusion: Based on the current study, additional doses of IV TXA could potentially further reduce HBL after primary TKA without increasing the risk of venous thromboembolism. PMID- 29521283 TI - Effectiveness and Safety of a Novel Approach for Management of Patients with Potential Difficult Mask Ventilation and Tracheal Intubation: A Multi-center Randomized Trial. AB - Background:: Patients with potential difficult mask ventilation (DV) and difficult intubation (DI) are often managed with awake intubation, which can be stressful for patients and anesthesiologists. This prospective randomized study evaluated a new approach, fast difficult airway evaluation (FDAE). We hypothesized that the FDAE approach would reduce the need for awake intubation. Methods:: After obtaining informed consent, 302 patients with potential DV/DI undergoing elective surgeries were randomly assigned to the FDAE group (Group E) and the control group (Group C). In Group E, patients were gradually sedated, and adequacy of manual mask ventilation during spontaneous breathing was assessed at various sedation levels. Awake intubation was applied in those with inadequate mask ventilation. In Group C, DI was evaluated under local anesthesia. However, the care team could intubate under general anesthesia if the vocal cords were visible. The primary outcome was the rate of awake intubations in both groups and the induction efficiency assessed by the induction time. The secondary outcome was the incidence of serious complications. Results: The rate of awake intubation was significantly lower in Group E than that in Group C (5.81% vs. 36.05%, chi2 = 42.3, P < 0.001). The induction time was much shorter in Group E than in Group C (11.85 +/- 4.82 min vs. 18.71 +/- 7.85 min, t = 5.39, P < 0.001). There was no significant difference in the incidence of intubation related complications between the two groups. Patients in Group E had a much lower incidence of recall (9.68% vs. 44.90%, chi2 = 47.68, P < 0.001) of the induction process and higher satisfaction levels than patients in Group C (t = 15.36, P < 0.001). Conclusions: The FDAE significantly reduces the need for awake intubation and improves the efficiency of the intubation process without comprising safety in patients with potential difficult mask ventilation and DI. Trial Registration:: No. ChiCTR-TRC 11001418; http://www.gctr.org/cn/proj/show.aspx?proj=1562. PMID- 29521285 TI - Variant of EOMES Associated with Increasing Risk in Chinese Patients with Relapsing-remitting Multiple Sclerosis. AB - Background: Multiple sclerosis (MS) is a common central nervous system autoimmune disorder. Increasing number of genome-wide association study (GWAS) analyses hint that MS is strongly associated with genetics. Unfortunately, almost all the GWAS analyses were Caucasian population based. Numbers of risk loci might not be replicated in Chinese MS patients. Hence, we performed a MassArray Assay to genotype the previously reported variants located in the transcription regulation genes in order to elucidate their role in the Chinese MS patients. Methods: One hundred and forty-two relapsing-remitting MS (RRMS) patients and 301 healthy controls were consecutively collected from September 2, 2008, to June 7, 2013, as stage 1 subjects. Eight reported transcription regulation-related single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom MassArray system. In stage 2, another 44 RRMS patients and 200 healthy controls were consecutively collected and Sanger sequenced from April 7, 2015, to June 29, 2017, for the validation of positive results in stage 1. Differences in allele and genotype frequencies between patients and healthy controls, odds ratios, and 95% confidence intervals were calculated with the Chi-square test or Fisher's exact test. Hardy-Weinberg equilibrium was tested also using the Chi-square test. Results: In stage 1 analysis, we confirmed only one previously reported risk variant, rs11129295 in EOMES gene. We found that the frequency of T/T genotype was much higher in MS group (chi2 = 10.251, P = 0.005) and the T allele of rs11129295 increased the risk of MS (chi2 = 10.022, P = 0.002). In stage 2 and combined analyses, the T allele of rs11129295 still increased the risk of MS (chi2 = 4.586, P = 0.030 and chi2 = 16.378, P = 5.19 * 10-5, respectively). Conclusions: This study enhances the knowledge that the variant of EOMES is associated with increasing risk in Chinese RRMS patients and provides a potential therapeutic target in RRMS. PMID- 29521286 TI - Neuropsychological Profile Related with Executive Function of Chinese Preschoolers with Attention-Deficit/Hyperactivity Disorder: Neuropsychological Measures and Behavior Rating Scale of Executive Function-Preschool Version. AB - Background:: Previous studies have found that schoolchildren with attention deficit/hyperactivity disorder (ADHD) showed difficulties in neuropsychological function. This study aimed to assess neuropsychological function in Chinese preschoolers with ADHD using broad neuropsychological measures and rating scales and to test whether the pattern and severity of neuropsychological weakness differed among ADHD presentations in preschool children. Methods:: The 226 preschoolers (163 with ADHD and 63 controls) with the age of 4-5 years were included and assessed using the Behavior Rating Scale of Executive Function Preschool Version (BRIEF-P) and a series of tests to investigate neuropsychological function. Results: Preschoolers with ADHD showed higher scores in all domains of the BRIEF-P (inhibition: 30.64 +/- 5.78 vs.20.69 +/- 3.86, P < 0.001; shift: 13.40 +/- 3.03 vs.12.41 +/- 2.79, P = 0.039; emotional control:15.10 +/- 3.53 vs.12.20 +/- 2.46, P < 0.001; working memory: 28.41 +/- 4.99 vs.20.95 +/- 4.60, P < 0.001; plan/organize: 17.04 +/- 3.30 vs.13.29 +/- 2.40, P < 0.001) and lower scores of Statue (23.18 +/- 7.84 vs.28.27 +/- 3.18, P = 0.001), Word Generation (15.22 +/- 6.52 vs.19.53 +/- 7.69, P = 0.025), Comprehension of Instructions (14.00 +/- 4.44 vs.17.02 +/- 3.39, P = 0.016), Visuomotor Precision (P < 0.050), Toy delay (P = 0.048), and Matrices tasks (P = 0.011), compared with normal control. In terms of the differences among ADHD subtypes, all ADHD presentations had higher scores in several domains of the BRIEF-P (P < 0.001), and the ADHD-combined symptoms (ADHD-C) group had the poorest ratings on inhibition and the ability to Plan/Organize. For neuropsychological measures, the results suggested that the ADHD-C group had poorer performances than the ADHD-predominantly inattentive symptoms (ADHD-I) group on Statue tasks (F = 7.34, eta2 = 0.12, P < 0.001). Furthermore, the ADHD hyperactive/impulsive symptoms group had significantly poorer performances compared to the ADHD-C group in the Block Construction task (F = 4.89, eta2 = 0.067, P = 0.003). However, no significant group differences were found between the ADHD-I group and normal control. Conclusion:: Based on the combined evaluation of performance-based neuropsychological tests and the BRIEF-P, preschoolers with ADHD show difficulties of neuropsychological function in many aspects. PMID- 29521287 TI - Blood Pressure Variability and Outcome in Patients with Acute Nonlobar Intracerebral Hemorrhage following Intensive Antihypertensive Treatment. AB - Background:: Blood pressure (BP) variability has been associated with stroke risk. We elucidated the association between systolic BP (SBP) variation and outcomes in patients with nonlobar intracerebral hemorrhage (ICH) following intensive antihypertensive treatment upfront. Methods: We screened consecutive patients with spontaneous ICH who underwent intensive antihypertensive treatments targeting BP <140 mmHg between 2008 and 2016. SBPs were monitored hourly during the acute period (<=7 days after symptom onset) in the intensive care unit. SBP variability was determined in terms of range, standard deviation (SD), coefficient of variation (CoV), and mean absolute change (MAC). The primary outcomes included hematoma growth and poor clinical outcome at 3 months (modified Rankin Scale [mRS] score >=3. The secondary outcome was an ordinal shift in mRS at 3 months. Results: A total of 104 individuals (mean age, 63.0 +/- 13.5 years; male, 57.7%) were included in this study. In multivariable model, MAC (adjusted odds ratio [OR], 1.11; 95% confidence interval [CI]: 1.02-1.21; P = 0.012) rather than the range of SD or CoV, was significantly associated with hematoma growth even after adjusting for mean SBP level. Sixty-eight out of 104 patients (65.4%) had a poor clinical outcome at 3 months. SD and CoV of SBP were significantly associated with a 3-month poor clinical outcome even after adjusting for mean SBP. In addition, in multivariable ordinal logistic models, the MAC of SBP was significantly associated with higher shift of mRS at 3 months (adjusted OR, 1.08; 95% CI: 1.02-1.15; P = 0.008). Conclusions:: The MAC of SBP is associated with hematoma growth, and SD and COV are correlated with 3-month poor outcome in patients with supratentorial nonlobar ICH. Therefore, sustained SBP control, with a reduction in SBP variability is essential to reinforce the beneficial effect of intensive antihypertensive treatment. PMID- 29521288 TI - Clinical and Radiological Features of Wallerian Degeneration of the Middle Cerebellar Peduncles Secondary to Pontine Infarction. AB - Background: Wallerian degeneration (WD) of bilateral middle cerebellar peduncles (MCPs) can occur following pontine infarction, but its characteristics have not yet been clarified because of the low incidence. Thus, the present study discussed the clinical and radiological features to improve the awareness of this disease. Methods: Clinical and radiological information from consecutive individuals diagnosed with WD of bilateral MCPs following pontine infarction in three hospitals over the past 4 years between October 2012 and October 2016 were retrospectively investigated and compared with a control group (patients with pontine infarction had no secondary WD). Results:: This study involved 30 patients with WD of MCPs, with a detection rate of only 4.9%. The primary infarctions (chi2 =24.791, P = 0.001, vs. control group) were located in the paramedian pons in 21 cases (70.0%), and ventrolateral pons in nine cases (30.0%). WD of the MCPs was detected 8-24 weeks after pons infarction using conventional magnetic resonance imaging (MRI); all secondary WDs were asymptomatic and detected incidentally. All WD lesions exhibited bilateral, symmetrical, and boundary blurring on MRI. The signal features were hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging and fluid-attenuated inversion recovery, and slightly hyperintense or isointense on diffusion-weighted imaging and apparent diffusion coefficient maps. Secondary brainstem atrophy was found in six (20.0%) cases. A Modified Rankin Scale score 0-2 was found in 10 (33.3%) cases and score >2 in 20 (66.7%) cases at 90 days after discharge, and the short-term prognosis was worse than that in control group (chi2 =12.814, P = 0.001). Conclusions: Despite the rarity of bilateral and symmetrical lesions of MCPs, secondary WD should be highly suspected if these lesions occur within 6 months after pontine infarction, particularly paramedian pons. Conventional MRI appears to be a relatively sensitive method for detecting WD of MCPs, which might affect the short-term prognosis. PMID- 29521289 TI - Effect of Primary Elective Cesarean Delivery on Placenta Accreta: A Case-Control Study. AB - Background: Cesarean section (CS) is an independent risk factor for placenta accreta. Some researchers think that the timing of primary cesarean delivery is associated with placenta accreta in subsequent pregnancies. The aim of this study was to investigate the risk of placenta accreta following primary CS without labor, also called primary elective CS, in a pregnancy complicated with placenta previa. Methods:: A retrospective, single-center, case-control study was conducted at Peking University Third Hospital. Relevant clinical data of singleton pregnancies between January 2010 and September 2017 were recorded. The case group included women with placenta accreta who had placenta previa and one previous CS. Control group included women with one previous CS that was complicated with placenta previa. Maternal age, body mass index, gestational age, fetal birth weight, gravity, parity, induced abortion, the rate of women received assisted reproductive technology, other uterine surgery, and primary elective CS were analyzed between the two groups. Results:: The rate of primary elective CS (90.1% vs. 69.9%, P < 0.001) was higher, and maternal age was younger (32.7 +/- 4.7 years vs. 34.6 +/- 4.0 years, P < 0.001) in case group, compared with control group. Case group also had higher gravity and induced abortions compared with the control group (both P < 0.05). Primary CS without labor was associated with significantly increased risk of placenta accreta in a subsequent pregnancy complicated with placenta previa (odds ratio: 3.32; 95% confidential interval: 1.68-6.58). Conclusion:: Women with a primary elective CS without labor have a higher chance of developing an accreta in a subsequent pregnancy that is complicated with placenta previa. PMID- 29521290 TI - Outcomes of Liver Transplantation Using Pediatric Deceased Donor Livers: A Single Center Analysis of 102 Donors. AB - Background: The outcome of pediatric deceased donor liver transplantation (LT) has not been well studied, especially pediatric deceased donor livers used in adult transplantation. This study aimed to evaluate the efficacy of LT using pediatric deceased donor livers and compare the outcomes between pediatric-to pediatric LT and pediatric-to-adult LT. Methods: A retrospective review of LT using pediatric deceased donor livers from June 2013 to August 2016 was performed. The patients were divided into the pediatric-to-pediatric LT group and pediatric-to-adult LT group based on the ages of the recipients. The survival and incidence of early vascular complications (VCs) were observed between the two groups. We also analyzed the risk factors of early VCs in pediatric LT and the effect of donor hypernatremia on the prognosis of recipients. Results: There were 102 cases of LT using pediatric deceased donor livers in our hospital from June 2013 to August 2016, 83 pediatric-to-pediatric LT (recipients' age <=13 years) and 19 pediatric-to-adult LT (recipients' age >=19 years). The ratio of early VC was similar in the two groups (19.3% vs. 10.6%, P = 0.514). Low body weight of recipient was an independent risk factor of early VC in pediatric LT (odds ratio: 0.856, 95% confidence interval: 0.752-0.975, P = 0.019). The 1-year cumulative survival rates of grafts and patients were 89.16% and 91.57% in pediatric-to pediatric LT and 89.47% and 94.74% in pediatric-to-adult LT, respectively (all P > 0.05). In all cases, patients using donors with hypernatremia (serum sodium levels >=150 mmol/L) had worse graft survival (chi2=4.330, P = 0.037). Conclusions: Pediatric-to-pediatric LT group has similar graft and patient survival rates with those of pediatric-to-adult LT group. Low body weight of recipients is an independent risk factor of early VC in pediatric LT. Patients using donors with hypernatremia have worse graft survival. PMID- 29521291 TI - Associations of Polymorphism of rs9944155, rs1051052, and rs1243166 Locus Allele in Alpha-1-antitrypsin with Chronic Obstructive Pulmonary Disease in Uygur Population of Kashgar Region. AB - Background: Previous studies conducted in various geographical and ethnical populations have shown that Alpha-1-antitrypsin (Alpha-1-AT) expression affects the occurrence and progression of chronic obstructive pulmonary disease (COPD). We aimed to explore the associations of rs9944155AG, rs1051052AG, and rs1243166AG polymorphisms in the Alpha-1-AT gene with the risk of COPD in Uygur population in the Kashgar region. Methods: From March 2013 to December 2015, a total of 225 Uygur COPD patients and 198 healthy people were recruited as cases and controls, respectively, in Kashgar region. DNA was extracted according to the protocol of the DNA genome kit, and Sequenom MassARRAY single-nucleotide polymorphism technology was used for genotype determination. Serum concentration of Alpha-1-AT was detected by enzyme-linked immunosorbent assay. A logistic regression model was used to estimate the associations of polymorphisms with COPD. Results: The rs1243166-G allele was associated with a higher risk of COPD (odds ratio [OR] = 2.039, 95% confidence interval [CI]: 1.116-3.725, P = 0.019). In cases, Alpha-1 AT levels were the highest among participants carrying rs1243166 AG genotype, followed by AA and GG genotype (chi2 = 11.89, P = 0.003). Similarly, the rs1051052-G allele was associated with a higher risk of COPD (OR = 19.433, 95% CI: 8.783-43.00, P < 0.001). The highest Alpha-1-AT levels were observed in cases carrying rs1051052 AA genotype, followed by cases with AG and GG genotypes (chi2 = 122.45, P < 0.001). However, individuals with rs9944155-G allele exhibited a lower risk of COPD than those carrying the rs9944155-A allele (OR = 0.121, 95% CI: 0.070-0.209, P < 0.001). In both cases and controls, no significant difference in Alpha-1-AT levels was observed among various rs9944115 genotypes. Conclusions: rs1243166, rs9944155, and rs1051052 sites of Alpha-1-AT may be associated with the COPD morbidity in Uygur population. While rs1243166-G allele and rs1051052-G allele are associated with an increased risk of developing COPD, rs9944155-G allele is a protect locus in Uygur population. Alpha-1-AT levels in Uygur COPD patients were lower than those in healthy people and differed among patients with different rs1051052 AG and rs1243166 AG genotypes. PMID- 29521292 TI - Glehnia littoralis Extract Promotes Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Mouse through Increasing Expressions of Brain-Derived Neurotrophic Factor and Tropomyosin-Related Kinase B. AB - Background: Glehnia littoralis has been used for traditional Asian medicine, which has diverse therapeutic activities. However, studies regarding neurogenic effects of G. littoralis have not yet been considered. Therefore, in this study, we examined effects of G. littoralis extract on cell proliferation, neuroblast differentiation, and the maturation of newborn neurons in the hippocampus of adult mice. Methods: A total of 39 male ICR mice (12 weeks old) were randomly assigned to vehicle-treated and 100 and 200 mg/kg G. littoralis extract-treated groups (n = 13 in each group). Vehicle and G. littoralis extract were orally administrated for 28 days. To examine neurogenic effects of G. littoralis extract, we performed immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU, an indicator for cell proliferation) and doublecortin (DCX, an immature neuronal marker) and double immunofluorescence staining for BrdU and neuronal nuclear antigen (NeuN, a mature neuronal marker). In addition, we examined expressional changes of brain-derived neurotrophic factor (BDNF) and its major receptor tropomyosin-related kinase B (TrkB) using Western blotting analysis. Results: Treatment with 200 mg/kg, not 100 mg/kg, significantly increased number of BrdU immunoreactive (+) and DCX+ cells (48.0 +/- 3.1 and 72.0 +/- 3.8 cells/section, respectively) in the subgranular zone (SGZ) of the dentate gyrus (DG) and BrdU+/NeuN+ cells (17.0 +/- 1.5 cells/section) in the granule cell layer as well as in the SGZ. In addition, protein levels of BDNF and TrkB (about 232% and 244% of the vehicle-treated group, respectively) were significantly increased in the DG of the mice treated with 200 mg/kg of G. littoralis extract. Conclusion: G. littoralis extract promots cell proliferation, neuroblast differentiation, and neuronal maturation in the hippocampal DG, and neurogenic effects might be closely related to increases of BDNF and TrkB proteins by G. littoralis extract treatment. PMID- 29521293 TI - Effects of Paclitaxel-conjugated N-Succinyl-Hydroxyethyl Chitosan Film for Proliferative Cholangitis in Rabbit Biliary Stricture Model. AB - Background: Paclitaxel (PTX) could inhibit the growth of fibroblasts, which occurs in proliferative cholangitis and leads to biliary stricture. However, its use has been limited due to poor bioavailability and local administration for short time. This study designed and synthesized a new PTX-conjugated chitosan film (N-succinyl-hydroxyethyl chitosan containing PTX [PTX-SHEC]) and evaluated its safety and efficiency using in vivo and in vitro experiments. Methods:: The SHEC conjugated with PTX was confirmed by nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FT-IR) measurements. Drug releases in vitro and in vivo were determined using high-performance liquid chromatography. Cell viability in vitro was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide. Rabbit biliary stricture model was constructed. All rabbits randomly divided into five groups (n = 8 in each group): the sham operated rabbits were used as control (Group A), Groups B received laparotomies and suture, Group C received laparotomies and covered SHEC suture without the PTX coating, Group D received laparotomies and covered PTX-SHEC suture, and Group E received laparotomies and 1000 MUmol/L PTX administration. Liver function tests and residual dosage of PTX from each group were measured by enzyme-linked immunosorbent assay. Histological data and alpha-smooth muscle actin (SMA) immunohistochemical staining of common bile duct were examined. Results:: NMR and FT-IR indicated that PTX was successfully introduced, based on the appearance of signals at 7.41-7.99 ppm, 1.50 ppm, and 1.03 ppm, due to the presence of aromatic protons, methylene protons, and methyl protons of PTX, respectively. No bile leak was observed. The PTX-conjugated film could slowly release PTX for 4 weeks (8.89 +/- 0.03 MUg at day 30). The in vitro cell viability test revealed significantly different levels of toxicity between films with and without PTX (111.7 +/- 4.0% vs. 68.1 +/- 6.0%, P < 0.001), whereas no statistically significant difference was observed among the three sets of PTX-contained films (67.7 +/- 5.4%, 67.2 +/- 3.4%, and 59.1 +/- 6.0%, P > 0.05). Histological examinations revealed that after 28 days of implantment, Groups D and E (but not Group C) had less granulation tissue and glandular hyperplasia in the site of biliary duct injury than Group B. The pattern was more obvious in Group D than Group E. Less alpha-SMA-positive cells were found in tissue from Groups D and E. Comparing with Group E, the liver function was improved significantly in Group D, including total bilirubin (2.69 +/- 1.03 MUmol/L vs. 0.81 +/- 0.54 MUmol/L, P = 0.014), alanine aminotransferase (87.13 +/- 17.51 U/L vs. 42.12 +/- 15.76 U/L, P = 0.012), and alkaline phosphatase (60.61 +/- 12.31 U/L vs. 40.59 +/- 8.78 U/L, P < 0.001). Conclusions: PTX-SHEC film effectively inhibites the myofibroblast proliferation and extracellular matrix over-deposition during the healing process of biliary reconstruction. This original film might offer a new way for reducing the occurrence of the benign biliary stricture. PMID- 29521294 TI - Effects of Adipose-derived Mesenchymal Stem Cell Exosomes on Corneal Stromal Fibroblast Viability and Extracellular Matrix Synthesis. AB - Background: Corneal stromal cells (CSCs) are components of the corneal endothelial microenvironment that can be induced to form a functional tissue engineered corneal endothelium. Adipose-derived mesenchymal stem cells (ADSCs) have been reported as an important component of regenerative medicine and cell therapy for corneal stromal damage. We have demonstrated that the treatment with ADSCs leads to phenotypic changes in CSCs in vitro. However, the underlying mechanisms of such ADSC-induced changes in CSCs remain unclear. Methods: ADSCs and CSCs were isolated from New Zealand white rabbits and cultured in vitro. An Exosome Isolation Kit, Western blotting, and nanoparticle tracking analysis (NTA) were used to isolate and confirm the exosomes from ADSC culture medium. Meanwhile, the optimal exosome concentration and treatment time were selected. Cell Counting Kit-8 and annexin V-fluorescein isothiocyanate/propidium iodide assays were used to assess the effect of ADSC- derived exosomes on the proliferation and apoptosis of CSCs. To evaluate the effects of ADSC- derived exosomes on CSC invasion activity, Western blotting was used to detect the expression of matrix metalloproteinases (MMPs) and collagens. Results:: ADSCs and CSCs were successfully isolated from New Zealand rabbits. The optimal concentration and treatment time of exosomes for the following study were 100 MUg/ml and 96 h, respectively. NTA revealed that the ADSC-derived exosomes appeared as nanoparticles (40-200 nm), and Western blotting confirmed positive expression of CD9, CD81, flotillin-1, and HSP70 versus ADSC cytoplasmic proteins (all P < 0.01). ADSC-derived exosomes (50 MUg/ml and 100 MUg/ml) significantly promoted proliferation and inhibited apoptosis (mainly early apoptosis) of CSCs versus non-exosome-treated CSCs (all P < 0.05). Interestingly, MMPs were downregulated and extracellular matrix (ECM)-related proteins including collagens and fibronectin were upregulated in the exosome-treated CSCs versus non-exosome treated CSCs (MMP1: t = 80.103, P < 0.01; MMP2: t = 114.778, P < 0.01; MMP3: t = 56.208, P < 0.01; and MMP9: t = 60.617, P < 0.01; collagen I: t = -82.742, P < 0.01; collagen II: t = -72.818, P < 0.01; collagen III: t = -104.452, P < 0.01; collagen IV: t = -133.426, P < 0.01, and collagen V: t = -294.019, P < 0.01; and fibronectin: t = -92.491, P < 0.01, respectively). Conclusion:: The findings indicate that ADSCs might play an important role in CSC viability regulation and ECM remodeling, partially through the secretion of exosomes. PMID- 29521295 TI - Comparison of Intracorporeal and Extracorporeal Esophagojejunostomy after Laparoscopic Total Gastrectomy for Gastric Cancer: A Meta-Analysis Based on Short Term Outcomes. AB - Background:: Laparoscopic total gastrectomy (LTG) is increasingly performed in patients with gastric cancer. However, the usage of intracorporeal esophagojejunostomy (IEJ) following LTG is limited, as the safety and efficacy remain unclear. The present meta-analysis aimed to evaluate the feasibility and safety of IEJ following LTG. Methods:: Studies published from January 1994 to January 2017 comparing the outcomes of IEJ and extracorporeal esophagojejunostomy (EEJ) following LTG were reviewed and collected from the PubMed, EBSCO, Cochrane Library, Embase, and China National Knowledge Internet (CNKI). Operative results, postoperative recovery, and postoperative complications were compared and analyzed. The weighted mean difference (WMD) and odds ratio (OR) with a 95% confidence interval (CI) were calculated using the Review Manager 5.3. Results:: Seven nonrandomized studies with 785 patients were included. Compared with EEJ, IEJ has less blood loss (WMD: -13.52 ml; 95% CI: -24.82--2.22; P = 0.02), earlier time to first oral intake (WMD: -0.49 day; 95% CI: -0.83--0.14; P < 0.01), and shorter length of hospitalization (WMD: -0.62 day; 95% CI: -1.08--0.16; P < 0.01). There was no significant difference between IEJ and EEJ regarding the operation time, anastomotic time, number of retrieved lymph nodes, time to first flatus, anastomosis leakage rate, anastomosis stenosis rate, and proximal resections (all P > 0.05). Conclusions: Compared with EEJ, IEJ has better cosmesis, milder surgical trauma, and a faster postoperative recovery. IEJ can be performed as safely as EEJ. IEJ should be encouraged to surgeons with sufficient expertise. PMID- 29521297 TI - The Spectrum of Biopsy-Proven Glomerular Disease in China: A Systematic Review. AB - Background: Chronic kidney disease has become a leading public health concern in China, as it is associated with increased morbidity, mortality, and costs. However, the overall situation regarding common glomerular diseases in China remains unclear. Hence, the aim of this study was to assess the national profile of the common types of glomerulonephritis in China. Methods: We searched Medline, Embase, Cochrane Library, CNKI, SinoMed, VIP, and Wanfang databases for English and Chinese language articles from inception to September 2017. We also collected potentially relevant studies and reviews using a manual search. The following words in combinations are as keywords: "renal biopsy", "kidney pathological diagnosis", and "spectrum of pathological types". Results: We identified 23 studies involving 176,355 patients from 15 provinces/cities in China. The detection rates of primary glomerulonephritis (PGN) and secondary glomerulonephritis (SGN) were 0.740 and 0.221, respectively. Over the past 30 years, the top five types of PGN were immunoglobulin A nephropathy (IgAN; 24.3%), mesangial proliferative glomerulonephritis (MsPGN; 10.5%), membranous nephropathy (MN; 12.6%), minimal change disease (MCD; 9.8%), and focal segmental glomerulosclerosis (FSGS; 4.6%), and the top four types of SGN were lupus nephritis (LN; 8.6%), Henoch-Schonlein purpura glomerulonephritis (4.1%), hepatitis B virus-associated glomerulonephritis (HBV-GN; 2.6%), and diabetic nephropathy (DN; 1.6%). The proportion of MN, MCD, HBV-GN, and DN tended to increase, while those of IgAN, MsPGN, FSGS, and LN tended to drop. Conclusions: Although the incidence of SGN is increasing gradually, PGN is still the leading form of kidney disease in patients undergoing renal biopsies in China. IgAN and LN are the most common types of PGN and SGN, respectively. Differences between regions are related to various factors such as nationality, environment, and diet. Furthermore, unified standards and norms for evaluating renal biopsies are urgently needed. PMID- 29521298 TI - Aberrant Functional Connectivity Patterns of Default Mode Network May Play a Key Role in the Interaction between Auditory Verbal Hallucinations and Insight. PMID- 29521299 TI - Inhalation of Sevoflurane and Desflurane Can Not Affect QT Interval, Corrected QT, Tp-Te/QT or Tp-Te/JT in Children. PMID- 29521296 TI - Imaging Gliomas with Nanoparticle-Labeled Stem Cells. AB - Objective:: Gliomas are the most common neoplasm of the central nervous system (CNS); however, traditional imaging techniques do not show the boundaries of tumors well. Some researchers have found a new therapeutic mode to combine nanoparticles, which are nanosized particles with various properties for specific therapeutic purposes, and stem cells for tracing gliomas. This review provides an introduction of the basic understanding and clinical applications of the combination of stem cells and nanoparticles as a contrast agent for glioma imaging. Data Sources: Studies published in English up to and including 2017 were extracted from the PubMed database with the selected key words of "stem cell," "glioma," "nanoparticles," "MRI," "nuclear imaging," and "Fluorescence imaging." Study Selection:: The selection of studies focused on both preclinical studies and basic studies of tracking glioma with nanoparticle-labeled stem cells. Results:: Studies have demonstrated successful labeling of stem cells with multiple types of nanoparticles. These labeled stem cells efficiently migrated to gliomas of varies models and produced signals sensitively captured by different imaging modalities. Conclusion: The use of nanoparticle-labeled stem cells is a promising imaging platform for the tracking and treatment of gliomas. PMID- 29521300 TI - Intact Canal Wall Mastoidectomy Combined with Balloon Dilation Eustachian Tuboplasty in the Treatment of Middle Ear Cholesterol Granuloma. PMID- 29521301 TI - Isolated Unilateral Horizontal Semicircular Canal Malformation. PMID- 29521302 TI - ST-Segment Elevation Myocardial Infarction Patients Complicated by Out-of Hospital Cardiac Arrest May Not Benefit from Emergency Percutaneous Intervention. PMID- 29521303 TI - Cerebral Venous Sinus Thrombosis as the First Manifestation of JAK2V617F-positive Essential Thrombocythemia. PMID- 29521304 TI - Pulmonary Metastasis of a Gigantic Cystosarcoma Phyllodes of the Breast. PMID- 29521305 TI - Tracheal Intubation Awake or Under Anesthesia for Potential Difficult Airway: Look Before You Leap. PMID- 29521306 TI - Corrigendum: Downregulation of Na+/Ca2+ Exchanger Isoform 1 Protects Isolated Hearts by Sevoflurane Postconditioning but Not by Delayed Remote Ischemic Preconditioning in Rats. AB - [This corrects the article DOI: 10.4103/0366-6999.213967]. PMID- 29521307 TI - Corrigendum: Proportion of Uterine Malignant Tumors in Patients with Laparoscopic Myomectomy: A National Multicenter Study in China. AB - [This corrects the article DOI: 10.4103/0366-6999.218008]. PMID- 29521308 TI - Case Image: A rare coincidence of hypoplasia of the posterior mitral leaflet and the bicuspid aortic valve. PMID- 29521309 TI - When sweet becomes too sweet: Left ventricular longitudinal strain in focus. PMID- 29521310 TI - Pulmonary vein remodeling in hypertension: Mechanistic insight into primary prevention of atrial fibrillation. PMID- 29521311 TI - Serial assessment of endothelial vasomotor function using optimal medical therapy predicts clinical outcomes in patients after complete coronary revascularization. AB - OBJECTIVE: Previous studies have demonstrated the importance of intensive optimal medical therapy (OMT) in patients with coronary artery disease (CAD). To investigate our hypothesis that patients with and without OMT achievement differed with respect to the risk of future cardiac events, we investigated the endothelial function in patients with CAD who underwent percutaneous coronary intervention (PCI) and contemporary medical therapy. METHODS: We conducted a prospective longitudinal cohort study to evaluate the endothelial function in 96 consecutive patients at 12 h after admission and 3 months at <12 h after admission and at 3 months after discharge by measuring the brachial artery dilatation after 5 min of forearm ischemia flow-mediated dilation (FMD). OMT achievement was defined as systolic blood pressure of <=130 mm Hg, low-density lipoprotein cholesterol of <=100 mg/dl, and hemoglobin A1c level of <=7.0%. The primary endpoint was the incidence of composite major adverse cardiac or cerebrovascular events (MACCE) at 36 months. RESULTS: Forty-nine (51%) patients achieved all three risk factor targets at 3 months. Although baseline FMD values did not differ between the OMT achievement and non-achievement groups, the 3 month FMD significantly improved in the OMT achievement group (6.6+/-3.5 vs. 5.2+/-2.9, p=0.03). Patients with improved FMD at 3 months had a lower rate of 36 month MACCE than those with persistently impaired FMD. A multiple Cox hazards analysis showed that OMT was a protective predictor of MACCE (hazard ratio, 0.19; 95% confidence interval, 0.04-0.88, p=0.03). CONCLUSION: This study demonstrated a significant association between the serial measurement of endothelial function with OMT and the clinical outcome in patients after PCI. PMID- 29521312 TI - Surface electrogram-guided left ventricular lead placement improves response to cardiac resynchronization therapy. AB - OBJECTIVE: Failure to select the optimal left ventricular (LV) segment for lead implantation is one of the most important causes of unresponsiveness to the cardiac resynchronization therapy (CRT). In our study, we aimed to investigate the echocardiographic and clinical benefits of LV lead implantation guided by an intraoperative 12-lead surface electrocardiogram (ECG) in patients with multiple target veins. METHODS: We included 80 [42 (62.5%) male] heart failure patients who successfully underwent CRT defibrillator (CRT-D) implantation. Patients were divided into two groups. In group 1, LV lead was positioned at the site with the shortest biventricular-paced (BiV-paced) QRS duration (QRSd), as intraprocedurally measured using surface ECG. In group 2 (control), we included patients who underwent the standard unguided CRT. ECG, echocardiogram, and functional status were evaluated before and 6 months after CRT implantation in all patients. RESULTS: In group 1, BiV-paced QRSd measurements were successfully performed in 112 of 120 coronary sinus branches during CRT and an LV lead was successfully placed at the optimal site in all patients. Compared with group 2, group 1 had a significantly higher rate (85% vs. 50%, p=0.02) of response (>15% reduction in LV end-systolic volume) to CRT as well as a shorter QRSd (p<0.001) and a greater QRS shortening (DeltaQRS) associated with CRT compared with baseline (p<0.001). The mean New York Heart Association functional class was significantly improved in both groups, and no significant differences were found in clinical response to CRT (85% vs. 70%, p=0.181). CONCLUSION: Surface ECG can be used to guide LV lead placement in patients with multiple target veins for improving response to CRT. Thus, it is a safe, feasible, and economic approach for CRT-D implantation. PMID- 29521313 TI - Identification of differentially expressed circular RNAs during TGF-beta1-induced endothelial-to-mesenchymal transition in rat coronary artery endothelial cells. AB - OBJECTIVE: Although differentially expressed circRNAs have been proposed to be closely associated with epithelial-mesenchymal transition (EMT), the roles of circRNAs remain unclear in endothelial-to-mesenchymal transition (EndMT), which is a subcategory of EMT. Herein, we characterized the expression and potential function of circRNAs during TGF-beta1-induced EndMT in rat coronary artery endothelial cells (CAEC). METHODS: High-throughput RNA sequencing was performed for unbiasedly profiling the expression of circRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis were performed using online forecasting databases. Real-time quantitative polymerase chain reaction (RT-qPCR) was used for confirming the circRNA expression obtained from the sequencing data. RESULTS: Among the candidated circRNAs, 102 circRNAs were differentially expressed, among which 66 circRNAs and 36 circRNAs were up regulated and down-regulated, respectively, in TGF-beta1-treated rat CAEC. GO analysis findings revealed that numerous differentially expressed circRNAs were closely associated with the biological process. KEGG signaling pathway analysis suggested that the abnormal expression of circRNAs had been implicated in regulating the dynamics endothelial cell junctions. Furthermore, we also found that three EndMT-related circRNAs, chr5:90817794|90827570, chr8:71336875|71337745, and chr6:22033342|22038870, were significantly up regulated in TGF-beta1-treated rat CAEC. CONCLUSION: The findings of this study reveal a comprehensive expression and potential functions of differentially expressed circRNAs during TGF-beta1-induced EndMT. These findings provide mechanistic insights into the role of circRNAs in EndMT-related cardiovascular diseases (CVDs). PMID- 29521314 TI - (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one reduces lipoteichoic acid-induced damage in rat cardiomyoblast cells. AB - OBJECTIVE: Infective endocarditis is usually caused by Streptococcus sanguinis and characterized by inflammatory responses in the endocardium. This study aimed to investigate if the new compound (3R)-5,6,7-trihydroxy-3-isopropyl-3 methylisochroman-1-one (TIM) isolated from Alpinia katsumadai Hayata could provide protection against lipoteichoic acid (LTA)-induced cell damage in embryonic rat heart cells (H9c2). METHODS: LTA-induced cell damage was established in H9c2, and the protective effects of TIM against the cell damage were examined at different concentrations (0.1-2.5 uM). The inflammatory response and oxidative stress in H9c2 cells were also measured. RESULTS: Treatment with TIM (0.1-2.5 uM) significantly decreased LTA-induced toxicity in H9c2 cells, which was indicated by increase in cell viability, elevation in the mitochondrial membrane potential, decrease in the release of cytochrome-c and DNA damage, inhibition of caspase-3/9 activities, and change in apoptosis-related protein expression in LTA-treated H9c2 cells. TIM treatment also significantly attenuated the redox imbalance in H9c2 cells by decreasing malondialdehyde and intracellular reactive oxygen species levels as well as by enhancing superoxide dismutase activities and glutathione levels by increasing nuclear factor (erythroid-derived 2)-like 2 protein expression. Moreover, TIM treatment decreased interleukin 1 beta, interleukin 12, and tumor necrosis factor alpha levels by inhibiting nuclear factor kappa B protein expression. CONCLUSION: Our data indicated that TIM protected H9c2 cells against LTA-induced toxicity, at least partially through inhibiting the inflammatory response and oxidative stress, providing scientific rational to develop TIM to treat infective endocarditis. PMID- 29521315 TI - Relationship between intrarenal renin-angiotensin activity and re-hospitalization in patients with heart failure with reduced ejection fraction. AB - OBJECTIVE: Heart failure (HF) is a clinical syndrome resulting from structural or functional damages. Although clinical trials have shown that the plasma renin angiotensin system (RAS) activation decreases HF functional status and increases hospitalization for HF patients, the effect of intrarenal RAS activity is still unknown. In this study, we investigated the relationship between the New York Heart Association (NYHA) class, duration, and number of hospitalizations in the previous year and urinary angiotensinogen (UAGT) in patients with HF with reduced ejection fraction (HFrEF). METHODS: This study included 85 patients who had an ejection fraction of <40% and were receiving optimal medical treatment. Among these, 22 were excluded from the study for various reasons. Demographically and biochemically, the remaining 63 patients were compared according to the NYHA functional classes and re-hospitalization status. RESULTS: When the groups were compared in terms of N-terminal pro-B-type natriuretic peptide (NT-proBNP), UAGT, and high-sensitivity C-reactive protein (Hs-CRP), it was found that these parameters were significantly higher in patients who were hospitalized more than two times in the previous year [p<0.001; p=0.007; p<0.001, respectively]. There was a significant correlation between number of hospitalizations and NT-proBNP (r=0.507, p<0.001), Hs-CRP (r=0.511, p<0.001), hemoglobin (r=-0.419, p=0.001), serum sodium (r=-0.26, p=0.04), and systolic blood pressure (r=-0.283, p=0.02). When the independence of multiple correlations was assessed using multiple linear regression analysis, NT-proBNP, Hs-CRP, and hemoglobin levels were independent predictors of re-hospitalization, but this was not the same for UAGT. CONCLUSION: Although UAGT levels are high in patients with poor NYHA functional class and repeated hospitalizations, this marker is not valuable for predicting repeated hospitalization in patients with HFrEF. PMID- 29521316 TI - Protective effects of curcumin and beta-carotene on cisplatin-induced cardiotoxicity: An experimental rat model. AB - OBJECTIVE: Cisplatin (CDDP) has been known to be an effective antineoplastic drug; however, it has a cardiotoxic effect. Curcumin (CMN) and beta-carotene (BC) have been suggested to protect biological systems against CDDP-induced damage. The current study was conducted to evaluate the possible protective roles of CMN and BC on CDDP-induced cardiotoxicity in rat cardiac tissues. METHODS: A total of 49 adult female Wistar albino rats were equally divided into seven groups as follows: control (no medication), sesame oil (1 mg/kg), CDDP (single dose injection two times as once a week, 5 mg/kg/week), BC (100 mg/kg), CDDP+BC (pretreated BC for 30 min before CDDP injection), CMN (200 mg/kg), and CDDP+CMN (pretreated CMN for 30 min before CDDP injection). These treatments were applied intraperitoneally for CDDP and with gavage for CMN and BC. The oxidative/antioxidant indicators, inflammatory cytokines, and histopathological alterations were examined. RESULTS: These alterations included a marked increase in malondialdehyde (MDA) level, significant decrease in catalase (CAT) and superoxide dismutase (SOD) activities, and significant elevation of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interleukin (IL)-6 in the CDDP group compared with the other groups. Histopathologically, CDDP-induced severe myocardial degenerative changes were observed. However, the CDDP-induced disturbances in the above-mentioned parameters significantly improved by treatment with BC and particularly CMN. CONCLUSION: This study indicated that CDDP treatment markedly caused cardiotoxicity; however, treatment with CMN or BC ameliorated this cardiotoxicity in rats. Furthermore, these findings revealed that treatment with CMN has a higher cardioprotective effect than that with BC against CDDP-induced cardiotoxicity in rat cardiac tissues. PMID- 29521317 TI - Lessons from the current European Heart Rhythm Association consensus document on screening for atrial fibrillation. AB - In this paper, we reviewed the atrial fibrillation screening strategies in a stepwise manner and discussed the uncertainties in the assessment of the need for anticoagulation in light of the recently published European Heart Rhythm Association consensus document. We reviewed not only the methods and tools but also the role of health care professionals and patient organizations in addition to cost-effectiveness issues. PMID- 29521318 TI - Ticagrelor-induced acute kidney injury can increase serum concentration of statin and lead to concurrence of rhabdomyolysis. PMID- 29521319 TI - Worth listening to the kidney: An uncommon cause of congestive heart failure. PMID- 29521320 TI - Soluble suppression of tumorigenicity-2 for risk stratification in outpatients with heart failure. PMID- 29521321 TI - Author's Reply. PMID- 29521322 TI - Interleukin-1 gene cluster polymorphisms associated with coronary slow flow phenomenon. PMID- 29521323 TI - Author's Reply. PMID- 29521324 TI - Lack of accurate evidence on non-statin medication in patients receiving highintensity statin therapy: Re-evaluation of recommendations is needed. PMID- 29521325 TI - Excessive movement of the coronary sinus lead of CRT-D and severe tricuspid regurgitation. PMID- 29521326 TI - Cardiac calcified amorphous tumor originating from the aortic valve: A rare case report. PMID- 29521327 TI - Identifying patients who may benefit from treatment. PMID- 29521328 TI - Arterial excess-reservoir pressure integral as a predictor of cardiovascular complications in patients with acute coronary syndrome. AB - INTRODUCTION The excess pressure-time integral (excess PTI) and reservoir pressure-time integral(reservoir PTI) are new measures derived from blood pressure (BP) waveform decomposition. Thesemarkers predict cardiovascular (CV) complications and are associated with target organ damage inpa tients on antihypertensive treatment or those with chronic and acute heart failure. OBJECTIVES We investigated whether reservoir PTI or excess PTI predict future CV events (death, stroke, myocardial infarction [MI]) in patients with acute coronary syndrome (ACS) and reduced ejection fraction (EF). PATIENTS AND METHODS BP waveforms were obtained by radial tonometry in 251 patients with ACS (median age, 64 years) and reduced EF (median, 40%). Left ventricular EF was assessed by transthoracic echocardiography. Reservoir PTI and excess PTI were derived by decomposition of the BP waveform RESULTS A total of 78 CV events occurred during the follow-up (median, 1245 days). A Kaplan-Meier analysis showed that the highest tertile of excess PTI was a significant predictor of adverse outcome. A multivariate Cox regression analysis demonstrated that excess PTI was a predictor of CV events after adjustment for EF, age, history of stroke, MI, and coronary artery bypass grafting (hazard ratio, 1.9; 95% confidence interval, 1.1-3.3; P = 0.02). CONCLUSIONS In conclusion, excess PTI, a new measure derived from reservoir-pressure analysis, predicts outcome in survivors of ACS with reduced EF. PMID- 29521329 TI - [Clinical profile of patients diagnosed with type 2 Diabetes Mellitus]. AB - OBJECTIVE: Type 2 Diabetes Mellitus is a chronic disease that represent an important problem of public health. The objective of this study was to describe the sociodemographic, anthropometric, metabolic control, comorbidity and cardiovascular risk characteristics of patients diagnosed with Diabetes Mellitus type 2 in the health area of Vigo. METHODS: Retrospective observational descriptive study. Between March and September 2016, it did telephone interview and an audit of electronic medical records to 195 patients >= 18 years old from the health area of Vigo diagnosed with type 2 Diabetes Mellitus. It selected by random sampling with replacement. It evaluated the cardiovascular risk using the method "United Kingdom Prospective Diabetes Study", the metabolic control with the recommendations of the "American Diabetes Association" 2016, and the comorbidity using the Charlson index. It performed a descriptive and bivariate analysis with R statistical package. RESULTS: The glycemic control was adequate (HbA1c less than 7.0%) in the 61.03% of the patients. The 58.46% had a blood pressure under 140/90mmHg, 52.82% had a total cholesterol under 185mg/dl and 66.15% had a triglyceride level under 150mg/dl. The 49.74% presented a high comorbidity (Charlson larger or the same as 3 points). The risk of suffering and/or dying of heart disease was 37.81%, and 23.50% of suffering and/or dying of a stroke in the next 10 years. CONCLUSIONS: Most diabetic patients of the health area of Vigo have a good control of their disease but they present a high index of comorbidity and high cardiovascular risk. PMID- 29521330 TI - Obesity: ERAD linked to obesity. PMID- 29521331 TI - Diabetes: LRP1 - a key modulator of beta-cell function in T2DM. PMID- 29521332 TI - Metabolism: DRP1 links mitochondrial dynamics to the clock. PMID- 29521333 TI - Bone: Microarchitecture of bone predicts fractures in older women. PMID- 29521334 TI - Traumatic brain injury: Evidence of blood-brain barrier disruption after concussion. PMID- 29521336 TI - Motor neuron disease: Reactive microglia protect neurons in ALS. PMID- 29521335 TI - Nontraumatic intracerebral haemorrhage in young adults. AB - Nontraumatic intracerebral haemorrhage (ICH) is a common subtype of stroke with a poor prognosis, high mortality and long-term morbidity. The incidence of ICH increases with age. ICH has not been widely investigated in young adults (herein defined as aged ~18-50 years) despite an annual incidence of ~5 per 100,000 individuals. Furthermore, ICH characteristics differ between young and elderly patients. Risk factors for ICH are surprisingly common in young adults, in whom ICH is often caused by structural lesions or hypertension, and only rarely by anticoagulation therapy and cerebral amyloid angiopathy (which are common predisposing factors in elderly patients). High short-term mortality (17% at 3 months) and long-term mortality (>25% at 10 years) persist even in contemporary series from high-income countries, and long-term disability is very common. Thus, an aggressive approach to identifying treatable underlying conditions and preventing ICH recurrence is indicated in young patients, although treatment strategies have generally not been investigated specifically in this age group. This narrative Review summarizes existing knowledge on the epidemiology, risk factors, causes, diagnosis, treatment and outcomes of ICH in young adults. We provide comparisons with the population of elderly patients with ICH and discuss challenges for future research. PMID- 29521341 TI - The ethical way to treat patients. PMID- 29521339 TI - OMFS: Severe mandibular bone destruction. PMID- 29521342 TI - Universal adhesive with active moisture control. PMID- 29521343 TI - Sub-mucosal swelling. PMID- 29521344 TI - A harmonious interplay between aesthetics. PMID- 29521345 TI - Non-traumatic dislocation. PMID- 29521337 TI - The current role of MRI in differentiating multiple sclerosis from its imaging mimics. AB - MRI red flags proposed over a decade ago by the European Magnetic Resonance Network in MS (MAGNIMS) have guided clinicians in the diagnosis of multiple sclerosis (MS). However, the past 10 years have seen increased recognition that vascular disease can coexist and possibly interact with MS, improvements in the reliability of ways to differentiate MS from novel antibody-mediated CNS disorders (such as anti-aquaporin-4 antibody and myelin-oligodendrocyte glycoprotein antibody-associated diseases) and advances in MRI techniques. In this Review, MAGNIMS updates the imaging features that differentiate the most common mimics of MS, particularly age-related cerebrovascular disease and neuromyelitis optica, from MS itself. We also provide a pragmatic summary of the clinically useful MRI features that distinguish MS from its mimics and discuss the future of nonconventional techniques that have identified promising disease specific features. PMID- 29521347 TI - Beating bruxism. PMID- 29521346 TI - Tooth wear. PMID- 29521350 TI - Conference report: Shaping the future of restorative dentistry service delivery in the UK. PMID- 29521351 TI - Dental practices encouraged to contribute to national survey. PMID- 29521352 TI - Childhood socioeconomic conditions and teeth in older adulthood: Evidence from SHARE wave 5. AB - Poor social conditions in childhood may have implications for dental health throughout life. PMID- 29521353 TI - Campaign launched to challenge unacceptable behaviour and promote best practice. PMID- 29521354 TI - True genius. PMID- 29521355 TI - Probe with precision. PMID- 29521356 TI - A new immediate-loading concept. PMID- 29521357 TI - Making a tangible difference to your practice. PMID- 29521358 TI - For restorations short and long. PMID- 29521359 TI - New toothwear website launched. PMID- 29521360 TI - Economic evaluation of dental sealants: A systematic literature review. AB - Caries risk assessment and the venue for placement may be relevant. PMID- 29521362 TI - Help kick off a summer of smiles. PMID- 29521361 TI - An intelligent implant system. PMID- 29521363 TI - Here today, there tomorrow. PMID- 29521365 TI - Confidential professional advice for dentists. PMID- 29521364 TI - Effectiveness of oral health education on oral hygiene and dental caries in schoolchildren: Systematic review and meta-analysis. AB - Analysis of recently published research appears to show only short-term improvements in plaque indices. PMID- 29521366 TI - The class-leading, speed-increasing handpiece. PMID- 29521368 TI - Exhibition to focus on our evolving relationship with our teeth. PMID- 29521367 TI - Swallowed partial denture. PMID- 29521369 TI - The power of regeneration. PMID- 29521371 TI - Leave your forceps in the drawer. PMID- 29521370 TI - Dentists on film: Three Billboards Outside Ebbing, Missouri. PMID- 29521374 TI - Reverse osmosis - a simple way to achieve compliance. PMID- 29521373 TI - James Hooper. PMID- 29521375 TI - Cost-effectiveness of caries-preventive fluoride varnish applications in clinic settings among patients of low, moderate and high risk. AB - Application of fluoride varnish targeted at high risk individuals may be more cost effective. PMID- 29521376 TI - Oral cancer: B-cell lymphoma. PMID- 29521377 TI - [Acoustic conditions in open plan office - Application of technical measures in a typical room]. AB - BACKGROUND: Noise in open plan offices should not exceed acceptable levels for the hearing protection. Its major negative effects on employees are nuisance and impediment in execution of work. Specific technical solutions should be introduced to provide proper acoustic conditions for work performance. MATERIAL AND METHODS: Acoustic evaluation of a typical open plan office was presented in the article published in "Medycyna Pracy" 5/2016. None of the rooms meets all the criteria, therefore, in this article one of the rooms was chosen to apply different technical solutions to check the possibility of reaching proper acoustic conditions. Acoustic effectiveness of those solutions was verified by means of digital simulation. The model was checked by comparing the results of measurements and calculations before using simulation. RESULTS: The analyzis revealed that open plan offices supplemented with signals for masking speech signals can meet all the required criteria. It is relatively easy to reach proper reverberation time (i.e., sound absorption). It is more difficult to reach proper values of evaluation parameters determined from A-weighted sound pressure level (SPLA) of speech. The most difficult is to provide proper values of evaluation parameters determined from speech transmission index (STI). Finally, it is necessary (besides acoustic treatment) to use devices for speech masking. The study proved that it is technically possible to reach proper acoustic condition. CONCLUSIONS: Main causes of employees complaints in open plan office are inadequate acoustic work conditions. Therefore, it is necessary to apply specific technical solutions - not only sound absorbing suspended ceiling and high acoustic barriers, but also devices for speech masking. Med Pr 2018;69(2):153 165. PMID- 29521379 TI - The role of maintenance therapy in the treatment of elderly non-small-cell lung cancer patients: a meta-analysis of randomized controlled trials [Corrigendum]. AB - [This corrects the article on p. 3435 in vol. 11.]. PMID- 29521378 TI - Treatment expectations but not preference affect outcome in a trial of CBT and exercise for pain. AB - Background: Patients' beliefs and attitudes toward a treatment can affect treatment response. In unblinded trials this can affect outcomes. Aims: The aim of this analysis was to examine the association between treatment preference and expectation and outcome in a trial of pain treatments. Methods: In a randomized trial (ISRCTN67013851) of four treatments for chronic widespread pain, participants were asked which they would prefer and what improvement they expect from each. The proportion of participants reporting positive health outcomes at three time points after treatment were compared between those matched or unmatched with their preference and between those with and without expectation for improvement. Odds ratios were calculated adjusted for baseline characteristics associated with preference and expectation. Results: Four hundred forty-two participants were recruited to the trial (69.5% female). The proportion reporting positive outcomes among participants matched to their preference compared to those unmatched was 33.3% vs. 34.4% at the end of treatment (adjusted odds ratio [aOR] = 0.80, 95% confidence interval [CI], 0.44-1.46), 34.4% vs. 29.0% at 3 months (aOR = 1.23, 95% CI, 0.67-2.26), and 34.8% vs. 30.3% at 2 years (aOR = 1.31, 95% CI, 0.70-2.46). The proportion of participants reporting positive outcomes among those expecting improvement compared to those not expecting improvement was 36.6% vs. 15.0% at the end of treatment (aOR = 2.03, 95% CI, 1.07-3.85), 34.1% vs. 13.2% at 3 months (aOR = 2.31, 95% CI, 1.22-4.38), and 32.8% vs. 19.1% at 2 years (aOR = 1.16, 95% CI, 0.67-2.36). Conclusions: Treatment preference had no clear effect on outcomes, but expectation did. These results could inform future approaches to management, and researchers assessing treatments should take into account this expectation effect. PMID- 29521380 TI - "I'm Not Sure We Had A Choice": Decision Quality and The Use of Cardiac Implantable Electronic Devices In Older Adults With Cognitive Impairment. AB - Background: The decision to implant a cardiac device in a person with Alzheimer's disease or related dementia requires considering the possible trade-offs of quality of life (QOL) and quantity of life. This study measured the decision making experience of patients with and without cognitive impairment (CI) who received a cardiac device and their family members who were involved in the decision. Methods and Results: Semi-structured interviews and questionnaires were administered with 15 patient-family member dyads. Interviews revealed few conversations between physicians, patients and family members about the patient's cognitive status or about the benefits, risks, and long-term implications of the device for someone with CI. Participants largely stated that the decision to get the device was based on the patient's functional status at the time of the implant, and not on expectations about future functioning. Patients with CI had more regret, measured with the Decision Regret Scale (DRS), (p=0.037) and family members of patients without CI reported more decisional conflict, measured with the Decisional Conflict Scale (p=0.057). Conclusions: Although CI impacts life expectancy and QOL, cognitive status was largely not discussed prior to device implant. Few differences were found between the experiences of dyads that included patients with or without CI. PMID- 29521381 TI - Knowledge and Use of Folic Acid among Women Attending the high-Risk Prenatal Clinics at the Adults University Hospital in Puerto Rico. AB - Introduction: Pregnancies affected with neural tube defects (NTDs) are mostly associated to maternal deficiency of folic acid (FA). Although supplementation is recommended for all women of childbearing age, the incidence of NTDs in Puerto Rico has not shown a significant decrease. Objective: The goal of this study was to assess the awareness and level of knowledge of FA supplementation among women attending prenatal clinics, and correlate this knowledge with the source ofinformation and the actual use of FA. A secondary objective was to corroborate or abrogatethe association of the lack of FA supplementation with the occurrence of unplanned pregnancies. Methods: This descriptive study was conducted at the High-Risk Prenatal Care Clinicsof the Adults University Hospital from August 2015 to November 2015. The answers to a non-validated self-administered questionnaire were assessed and then analyzed with Epi Info 7. Results: From a total of 200 Hispanic female participants, 87.0% were Puerto Rican, most (69.0%) had an education above high school level and 54.5% had a low-income status. Overall, 66.5% were taking FA at the time of the interview, 77% understood that the best time to start FA supplementation was prior to conception, but only 23% of the participants actually began preconceptional FA intake. Unplanned pregnancies were reported in 70.5%. Most referred to have received information about FA benefits from a healthcare professional, yet many could not identify all of FA benefits. Conclusion: Although most participants were aware of the best time to begin FA supplementation, the majority began intake once pregnancy was discovered; timing related to the 70.5% unplanned pregnancies. Information received is not sufficient sincemost women are not entirely clear about the benefits of FA supplementation, despite their source of information. In caring for women of childbearing age, further investigation is required to optimize educational strategies and methodologies. PMID- 29521382 TI - CORRIGENDUM: Correction of funding statement in ACKNOWLEDGEMENTS section: Epigenetic inactivation of RUNX3 in colorectal cancer. AB - [This corrects the article on p. 19 in vol. 94, PMID: 29333422.]. PMID- 29521384 TI - Commentary: The Nature of Unsymbolized Thinking. PMID- 29521383 TI - Erratum: Application of Deconvolution Algorithm of Point Spread Function in Improving Image Quality: An Observer Preference Study on Chest Radiography. AB - [This corrects the article on p. 147 in vol. 19, PMID: 29354011.]. PMID- 29521385 TI - Ternary nanocomposites of Au/CuS/TiO2 for an ultrasensitive photoelectrochemical non-enzymatic glucose sensor. AB - A novel and highly sensitive photoelectrochemical biosensor for the detection of glucose based on ternary nanocomposites of Au/CuS/TiO2 (Au/CuS/TiO2) has been fabricated. Highly ordered TiO2 nanotube arrays (TiO2 NTs) were prepared by anodization of Ti foils, and CuS nanoparticles (NPs) and Au NPs were deposited on TiO2 NTs by the successive ionic layer adsorption and reaction (SILAR) method. The resultant Au/CuS/TiO2 exhibited excellent photoelectrochemical behavior as a glucose sensor under white light illumination due to the remarkable photocatalytic capabilities of TiO2 and CuS, and the surface plasmonic resonance (SPR) effect of Au NPs. The fabricated Au/CuS/TiO2 non-enzymatic photoelectrochemical sensor showed brilliant catalytic activity, favourable selectivity, good reproducibility and long-term stability for glucose detection under optimized conditions. The linear range was 0.1-3 MUM (R = 0.9942) with a detection limit of 0.03 MUM (S/N = 3). Moreover, the proposed sensor detected glucose in human serum samples. Thus, Au/CuS/TiO2 appears to be a promising photocatalyst for a non-enzymatic glucose sensor. PMID- 29521386 TI - Impact of magnetization and hyperfine field distribution on high magnetoelectric coupling strength in BaTiO3-BiFeO3 multilayers. AB - Correlations were established between the hyperfine field distribution around the Fe atoms, the multiferroic properties, and the high magnetoelectric coefficient in BaTiO3-BiFeO3 multilayer stacks with variable BiFeO3 single layer thickness, down to 5 nm. Of key importance in this study was the deposition of 57Fe - enriched BiFeO3, which enhances the sensitivity of conversion electron Mossbauer spectroscopy by orders of magnitude. The magnetoelectric coefficient alphaME reaches a maximum of 60.2 V cm-1 Oe-1 at 300 K and at a DC bias field of 2 Tesla for a sample of 15 * (10 nm BaTiO3-5 nm BiFeO3) and is one of the highest values reported so far. Interestingly, the highest alphaME is connected to a high asymmetry of the hyperfine field distribution of the multilayer composite samples. The possible mechanisms responsible for the strong magnetoelectric coupling are discussed. PMID- 29521387 TI - Geometrically defined spin structures in ultrathin Fe3O4 with bulk like magnetic properties. AB - We have grown high quality magnetite microcrystals free from antiphase boundaries on Ru(0001) by reactive molecular beam epitaxy, conserving bulk magnetic properties below 20 nm thickness. Magnetization vector maps are obtained by X-ray spectromicroscopy and compared with micromagnetic simulations. The observed domain configurations are dictated purely by shape anisotropy, overcoming the possible influences of (magneto)crystalline anisotropy and defects, thus demonstrating the possibility of designing spin structures in ultrathin, magnetically soft magnetite at will. PMID- 29521388 TI - Ultrafast growth of horizontal GaN nanowires by HVPE through flipping the substrate. AB - Recently, horizontal nanowires (NWs) have attracted much attention due to their increased compatibility with NW-based integrated nanoelectronic and nanophotonic systems. However, it still remains challenging to synthesize horizontal NWs efficiently. Here we introduce a novel method towards controllable growth of horizontal GaN NWs using HVPE with an Au/Ni thin film as the catalyst. By simply flipping the substrate, horizontal GaN NWs with various growth directions and cross sections have been obtained on a sapphire substrate with various facet orientations. Benefiting from the high decomposition frequency of GaCl precursors, the growth rate for the horizontal NWs is as fast as 400 MU h-1. Our results show that the facing orientation of the loaded substrate affects the flow of the local precursor, which determines the growth mode of the GaN NWs, i.e., no matter whether the substrate is facing downward or upwards. Photoluminescence measurements of the horizontal NWs show a finite blue shift of the band edge related emission. It indicates the presence of compressed stress and is confirmed by the geometrical phase analysis (GPA) further. Our work opens up a new route and sheds light on the horizontal GaN NWs and will advance the development of horizontal NW-based nanoelectronic and nanophotonic devices and systems. PMID- 29521389 TI - Greener synthesis of Cu-MOF-74 and its catalytic use for the generation of vanillin. AB - A greener synthesis of Cu-MOF-74 was obtained, for the first time, in methanol as the unique solvent and at room temperature. Full characterisation of the MOF material showed its purity and also its nanocrystalline nature. Complete activation (150 degrees C for 1 h and 10-3 bar) of Cu-MOF-74 afforded unsaturated Cu metal sites and this was corroborated by in situ DRIFT spectroscopy. The access to these Cu open metal sites was tested for the catalytic transformation of trans-ferulic acid to vanillin (yield of 71% and 97% selectivity) and a plausible catalytic reaction mechanism was postulated based on quantum chemical calculations. PMID- 29521390 TI - Efficient structural elucidation of microhydrated biomolecules through the interrogation of hydrogen bond networks. AB - Microhydration of biomolecules is an important structural factor associated with their biological processes. However, there is no general way to elucidate stable hydrated structures even for simple amino acids because of the high complexity of chemical space increasing rapidly with the number of water molecules. Here, we propose a very efficient computational method to selectively sample the most stable structures of microhydrated molecules. The key idea is to utilize the unique structural patterns of H-bond networks obtained from their energetic features, i.e. their tendency to form more H-bonds. As a proof of concept, we could identify the new global minima of glycine.10(H2O) and for the first time, we found the minimum number of water molecules required to stabilize the zwitterionic form of tyrosine. Furthermore, the most stable structures of hydrated glycine and tyrosine indeed had common features, which were consistent with the X-ray data of proteins in water. PMID- 29521391 TI - Colloidal nanocrystals as LEGO(r) bricks for building electronic band structure models. AB - The synthesis of self-assembled semiconductor nanocrystal (NC) superlattices using oriented attachment recently became a flourishing research topic. This technique already produced remarkable forms of NC superlattices, such as linear chains, mono and multilayer square lattices, and silicene-like honeycomb lattices. In the case of lead chalcogenide semiconductors where NCs are in the form of truncated nanocubes, the attachment mostly occurs via (100) facets. In this work, we show that all these structures can be seen as sub-structures of a simple cubic lattice. From this, we investigate a rich variety of one-dimensional or two-dimensional superlattices that could be built as few lines or few layers taken from the same cubic system following different crystallographic orientations. Each NC can be therefore considered as a LEGO(r) brick, and any superlattice can be obtained from another one by rearranging the bricks. Moreover, we show that this concept of LEGO(r) bricks can be extended to the calculation of the electronic band structure of the superlattices. This leads to a simple yet powerful way to build analytical Hamiltonians that present band structures in excellent agreement with more elaborate atomistic tight-binding calculations. This LEGO(r) concept could guide the synthesis of superlattices and LEGO(r) Hamiltonians should greatly simplify further studies on the (opto )electronic properties of such structures. PMID- 29521392 TI - Electrochemical nitrogen reduction to ammonia under mild conditions enabled by a polymer gel electrolyte. AB - A novel gel electrolyte approach has been implemented to enable the electrochemical reduction of nitrogen to ammonia at low temperature and pressure. PMID- 29521393 TI - The effect of probiotics and polysaccharides on the gut microbiota composition and function of weaned rats. AB - Weaning is an essential and important event for infants and rodent animals, and the dietary supplementation plays a crucial role in regulating the composition and function of gut microbiota in the initial period after weaning. In this study, we investigated the potential effects of two probiotics along with three polysaccharides (PP) in weaned rats. Male SD rats, 21 days of age, were divided into two groups: one group was administered with PP for four weeks and the other was not. Body weight, food intake, gut epithelial barrier function, digestive enzyme activities, and the composition and function of gut microbiota were analyzed. The dietary PP increased the body weight and food intake, promoted gut epithelial barrier integrity, and elevated the activities of digestive enzymes. Moreover, the microbial community structure was different between the two groups. At the genus level, Bifidobacterium, Lactobacillus, and Allobaculum were significantly increased, whereas Anaerostipes, Enterococcus, and Parabacteroides were observably reduced. Furthermore, PP significantly increased amino acid metabolism, energy metabolism, and SCFA-related metabolism. This study shows that synbiotics containing probiotics (L. acidophilus NCFM and B. lactis Bi-07) in combination with polysaccharides (LBP, PCPs, and Lentinan) can modulate the composition of gut microbiota, stimulate the maturation of gut microbiota biological function, and promote the growth performance in weaned rats. PMID- 29521394 TI - L-edge sum rule analysis on 3d transition metal sites: from d10 to d0 and towards application to extremely dilute metallo-enzymes. AB - According to L-edge sum rules, the number of 3d vacancies at a transition metal site is directly proportional to the integrated intensity of the L-edge X-ray absorption spectrum (XAS) for the corresponding metal complex. In this study, the numbers of 3d holes are characterized quantitatively or semi-quantitatively for a series of manganese (Mn) and nickel (Ni) complexes, including the electron configurations 3d10-> 3d0. In addition, extremely dilute (<0.1% wt/wt) Ni enzymes were examined by two different approaches: (1) by using a high resolution superconducting tunnel junction X-ray detector to obtain XAS spectra with a very high signal-to-noise ratio, especially in the non-variant edge jump region; and (2) by adding an inert tracer to the sample that provides a prominent spectral feature to replace the weak edge jump for intensity normalization. In this publication, we present for the first time: (1) L-edge sum rule analysis for a series of Mn and Ni complexes that include electron configurations from an open shell 3d0 to a closed shell 3d10; (2) a systematic analysis on the uncertainties, especially on that from the edge jump, which was missing in all previous reports; (3) a clearly-resolved edge jump between pre-L3 and post-L2 regions from an extremely dilute sample; (4) an evaluation of an alternative normalization standard for L-edge sum rule analysis. XAS from two copper (Cu) proteins measured using a conventional semiconductor X-ray detector are also repeated as bridges between Ni complexes and dilute Ni enzymes. The differences between measuring 1% Cu enzymes and measuring <0.1% Ni enzymes are compared and discussed. This study extends L-edge sum rule analysis to virtually any 3d metal complex and any dilute biological samples that contain 3d metals. PMID- 29521395 TI - Fast, irreversible modification of cysteines through strain releasing conjugate additions of cyclopropenyl ketones. AB - A method of cysteine alkylation using cyclopropenyl ketones is described. Due to the significant release of cyclopropene strain energy, reactions of thiols with cyclopropenyl ketones are both fast and irreversible and give rise to stable conjugate addition adducts. The resulting cyclopropenyl ketones have a low molecular weight and allow for simple attachment of amides via N hydroxysuccinimide (NHS)-esters. While cyclopropenyl ketones do display slow background reactivity toward water, labeling by thiols is much more rapid. The reaction of a cyclopropenyl ketone with glutathione (GSH) proceeds with a rate of 595 M-1 s-1 in PBS at pH 7.4, which is considerably faster than alpha halocarbonyl labeling reagents, and competitive with maleimide/thiol couplings. The method has been demonstrated in protein conjugation, and an arylthiolate conjugate was shown to be stable upon prolonged incubation in either GSH or human plasma. Finally, cyclopropenyl ketones were used to create PEG-based hydrogels that are stable to prolonged incubation in a reducing environment. PMID- 29521396 TI - Mussel-inspired fabrication of porous anodic alumina nanochannels and a graphene oxide interfacial ionic rectification device. AB - A mussel-inspired new interfacial ionic rectification device is fabricated using porous anodic alumina nanochannels and graphene oxide via dopamine polymerization. In addition, the rectification mechanism is elucidated based on the principles of physics and thermodynamics via finite element simulation and the results show that the interface distance and surface charge play a vital role in ion transport. PMID- 29521397 TI - A bio-inspired homogeneous graphene oxide actuator driven by moisture gradients. AB - An actuator driven by moisture gradients has been developed from a homogeneous graphene oxide film, relying on the in situ formation of a bilayer structure induced by water adsorption. This actuator shows efficient and controllable bending motions, coupled with the capability of lifting objects 8 times heavier than itself. PMID- 29521398 TI - [Personalised medicine: a beckoning perspective for psychiatry?] PMID- 29521399 TI - ? PMID- 29521400 TI - [Personalised medicine in rheumatology]. AB - BACKGROUND: An important goal in medicine is to provide patients with individualised and personalised treatment. Personalised medicine is making an important contribution. AIM: To summarise developments in the field of personalised medicine in rheumatology. METHOD: We review the results so far and discuss what developments we can expect in the future. RESULTS: In rheumatology there have been advances in three main areas: 1. therapeutic drug monitoring (measuring medication levels and using the results as a guide for further treatment); 2. the use of biomarkers to determine which drugs should be selected or which should be stopped; 3. involvement of the patient's own observations concerning treatment options. CONCLUSION: Personalised medicine is being used increasingly in rheumatology. PMID- 29521401 TI - [Psychiatric diagnosis: personalised by definition]. AB - BACKGROUND: Personalised psychiatry requires a psychiatric diagnosis which aims to determine the causes of the mental disorder and the context within which it has developed, including the factors of most importance for the choice of an appropriate treatment. AIM: To show that psychiatric diagnosis is personalised by definition. METHOD: Description of the differences between psychiatric classification and psychiatric diagnosis, including a discussion of symptom network diagnosis and diagnosis of meaningful connections. RESULTS: It appears from references from classical and recent psychiatric textbooks and from the recent Dutch Guideline for psychiatric evaluation that psychiatric diagnosis, different from classification, has always been aimed at determining both biological and psychosocial etiological and pathogenic factors and factors influencing the course and the treatment of the disorder. CONCLUSION: A personalised approach in psychiatry may lead to a direly necessary reappraisal of psychiatric diagnosis that is not limited to the classification of symptoms, but that aims specifically towards explaning and understanding mental illness. PMID- 29521402 TI - [Personalised diagnosis and treatment of depression]. AB - BACKGROUND: It is often said that a patient with depression can derive considerable benefit from personalised diagnostics and treatment.
AIM: To find out whether we have enough data to demonstrate that personalised diagnostics and personalised treatment of depression are better than what we do now and, if so, what specific action we should take.
METHOD: We review the literature on the foregoing topic.
RESULTS: There is ample evidence to support the view that the efficacy of treatment may improve quite dramatically if we are able to diagnose with much greater precision and select a treatment that is best suited to an individual person. Although there is less empirical evidence available with regard to a system that makes use of short regular feedback of unique personal data of patients and of the personal input of the professionals involved, these factors may nevertheless improve efficacy still further.
CONCLUSION: Although no hard evidence is available so far, for instance as a result of trials, there is sufficient evidence to support the further development of personalised diagnostics and personalised treatment of depression. PMID- 29521403 TI - [Personalised medicine for psychosis]. AB - BACKGROUND: Personalised medicine (pm) means treatment that specifically targets the needs of individual patients on the basis of genetic, biomarker, phenotypic or psychosocial characteristics.
AIM: To update our knowledge about the current use of pm in the treatment of psychotic disorders.
METHOD: Review of the literature on pm for psychoses.
RESULTS: At the moment, genetic and other biological characteristics cannot be used for the diagnosis and treatment of psychotic disorders because they are not sensitive enough and their specificity is too low. We investigated immunulogical, oxidative, metabolic, hormonal and dopaminergic aspects that could lead to the use of pm. pm is already being used on the basis of phenotypical, cognitive and psychosocial characteristics; those characteristics include substance abuse, cognitive dysfunction, ethnicity and childhood trauma.
CONCLUSION: In the next years there may be more opportunities for using for pm in psychosis. The increase may results from large genetic network studies and treatment studies involving stratification based on hypothetical specific mechanisms instead of on the categorical diagnosis of illnesses such as schizophrenia. PMID- 29521404 TI - [Personalised treatment of disorders in the use of alcohol and nicotine]. AB - BACKGROUND: There is an increasing interest in personalised treatment based on the individual characteristics of the patient in the field of addiction care. AIM: To summarise the present state of staging and profiling possibilities within addiction care. METHOD: A literature review highlighting the current scientific findings and proposing a theoretical model. RESULTS: There are currently an insufficient number of studies to allow for a fully data driven model. However, research identifying biomarkers is growing and some clinically implementable findings can be put forward. CONCLUSION: a personalised approach in addiction care holds promise. There is an urgent need for better and larger datasets to empirically support models aimed for clinical use. PMID- 29521405 TI - [Is a personalised approach of the borderline personality disorder useful?] AB - BACKGROUND: Borderline personality disorder (bpd) seems to have a progressive course, starting during adolescence. It's prevalence peaks during early adulthood, after which it declines. The symptom profile changes during its course. Consequently, a personalised approach based on staging and profiling appears suitable for bpd. AIM: To describe a useful model for clinical staging and profiling of bpd. METHOD: A literature analysis, reviewing the evidence of clinical stages and risk factors. RESULTS: bpd can be described in different stages, ranging from a preliminary stage associated with a higher risk of developing bpd to a chronic, therapy resistant stage. Although there are no specific predictors, there are several factors that increase the risk of developing bpd. CONCLUSION: Clinical staging and profiling can contribute to a more personalised approach and treatment selection. More research is needed to develop this model further. PMID- 29521407 TI - [Personalised prevention of mental disorder]. AB - BACKGROUND: The prevention of mental disorders is feasible, but a broader implementation requires a more precise application of available interventions to target populations.
AIM: A literature review of the different approaches where preventive measures are applied more precisely and personally.
METHOD: A narrative review of existing literature.
RESULTS: Several promising strategies to improve precision and personalisation of prevention are indeed available, but there is insufficient research to substantiate them.
CONCLUSION: Prevention of mental health disorders is possible, and there are interventions proven to be effective. In order to have an actual impact at population level, we require a mix of universal, selective and indication-based preventive measures. The universal campaigns, aimed at the entire population, would hereby create conditions enabling the other strategies, aimed at risk groups, to succeed. PMID- 29521406 TI - [Personalised medicine in forensic psychiatry: an example for other domains of psychiatry?] AB - BACKGROUND: Personalised medicine promises to provide us with a diagnostic predictive system of stratification that is based on a wide variety of tests; these can include biological, cognitive, demographic, psychopathological tests and other clearly defined tests. The purpose of forensic psychiatry is not only to take care of and treat mentally impaired patients but also to engage in risk assessment and risk management.
AIM: To explain risk assessment in forensic psychiatry as a nomothetic approach to personalised medicine, and also to demonstrate the link with offence paralleling behaviour, which is an illustration of the ideographic approach.
METHOD: A discussion of recent literature and insights into risk assessment, risk management and offence paralleling behaviour.
RESULTS: Risk assessment helps us to divide patients into groups according to the risk of recidivism. The nomothetic concept is the basis of most risk assessment instruments. One of the most important tasks in risk management in forensic psychiatry is to reduce the risk factors and strengthen the influence of protective factors. The model of offence paralleling behaviour resembles in many respects the concept of integrating risk management and treatment, but shows more precisely how hypotheses can be tested in a clinical context.
CONCLUSION: In view of the great importance to society of preventing offences, forensic psychiatry is leading the way in the application of personalised medicine in psychiatry. PMID- 29521408 TI - [Transdiagnostic psychiatry: work in progress]. AB - BACKGROUND: There is an increasing awareness that the current approach to clinical thought and work in psychiatry in relation to psychiatric diagnosis, treatment and research has its limitations. This necessitates a process to reform both the clinical practice and future scientific research. One way to reform this is the transdiagnostic approach. AIM: To clarify the psychological, biological and therapeutic aspects of a transdiagnostic approach in psychiatry. METHOD: An analysis of new approaches based on recent findings from the recent literature. RESULTS: Transdiagnostic psychiatry is a relatively new concept which is still under development. The examples extracted from the reviewed literature on developmental psychology, neurobiology and treatment demonstrate that this approach may lead to improvements in clinical care and generate new etiological insights. CONCLUSION: A transdiagnostic approach in psychiatry may lead to new insights that are relevant for clinical practice and future scientific research. PMID- 29521409 TI - [Personalised psychiatry: no substitute for personal care]. AB - BACKGROUND: Personalised psychiatry is the promise that biological stratification and analysis of 'big' data will enable clinical prediction.
AIM: To analyse promises and problems regarding personalised medicine in the psychiatry.
METHOD: Analysis of current challenges.
RESULTS: Essential challenges are: 1. Biological psychiatry yields weak findings and clinically negligible diagnostic likelihood ratios. 2. The impact of biological stratification in medicine is relatively small yet may result in explosive health care costs. 3. Equivalent investment in public mental health may result in considerably higher health gains. 4. Data quality may be more important than data density. 5. The promise of biological stratification detracts from a hermeneutic approach and a focus on connectedness, meaning and identity.
CONCLUSION: Personal care with a focus on the unique narrative development and the non-linear process of enhancing resilience, in combination with within-person (n=1) predictive measurements (emotional, biological or other), may represent the best way to link the practice of psychiatry with the promise of personalised medicine. PMID- 29521410 TI - [Data science in psychiatry]. AB - BACKGROUND: The information society is digitalising at a fast pace. New technology enables the collection of real life and real time information from sources that were inaccessible before. This creates an inordinate amount of dynamic data and, consequently, opportunities to introduce new insights and improvement of treatment in the field of psychiatry.
AIM: To clarify the definition of big data and how a big data approach can reform care into a data driven, patient oriented dynamic system which is constantly learning.
METHOD: Brief description of a pilot effected at the UMC Utrecht where the Cross Industry Standard Process for Interactive Data Mining (CRISP-IDM) was performed and description of applications in the future.
RESULTS: The described approach and examples from literature show that there are possibilities to realise quick improvements in practice and implement new insights from existing data sources.
CONCLUSION: Introduction of data science in psychiatric practice offers new prospects. PMID- 29521411 TI - [Personalised medicine: from a scientific perspective]. AB - BACKGROUND: The goal of personalised medicine is to adapt the therapy precisely to an individual's specific needs. But how can we practise personalised medicine from a scientific perspective?
AIM: To discuss how we can progress from a science based on group findings to a science based on individual cases.
METHOD: We will outline various research designs that may be helpful for investigating an approach to personalised medicine.
RESULTS: One approach is to focus on more homogenous groups, e.g. using symptom dimensions or by dividing the groups on the basis of biomarkers, sociomarkers or psychomarkers. Another approach is to study variations within an individual, adjusting the intervention precisely to the individual, both in terms of content and timing.
CONCLUSION: Designs that allow for a scientific approach to personalised medicine should improve our understanding of what is happening to a specific individual and enable us to select the most suitable intervention for a specific individual. PMID- 29521412 TI - Genetic relatedness of indigenous ethnic groups in northern Borneo to neighboring populations from Southeast Asia, as inferred from genome-wide SNP data. AB - The region of northern Borneo is home to the current state of Sabah, Malaysia. It is located closest to the southern Philippine islands and may have served as a viaduct for ancient human migration onto or off of Borneo Island. In this study, five indigenous ethnic groups from Sabah were subjected to genome-wide SNP genotyping. These individuals represent the "North Borneo"-speaking group of the great Austronesian family. They have traditionally resided in the inland region of Sabah. The dataset was merged with public datasets, and the genetic relatedness of these groups to neighboring populations from the islands of Southeast Asia, mainland Southeast Asia and southern China was inferred. Genetic structure analysis revealed that these groups formed a genetic cluster that was independent of the clusters of neighboring populations. Additionally, these groups exhibited near-absolute proportions of a genetic component that is also common among Austronesians from Taiwan and the Philippines. They showed no genetic admixture with Austro-Melanesian populations. Furthermore, phylogenetic analysis showed that they are closely related to non-Austro-Melansian Filipinos as well as to Taiwan natives but are distantly related to populations from mainland Southeast Asia. Relatively lower heterozygosity and higher pairwise genetic differentiation index (FST ) values than those of nearby populations indicate that these groups might have experienced genetic drift in the past, resulting in their differentiation from other Austronesians. Subsequent formal testing suggested that these populations have received no gene flow from neighboring populations. Taken together, these results imply that the indigenous ethnic groups of northern Borneo shared a common ancestor with Taiwan natives and non-Austro-Melanesian Filipinos and then isolated themselves on the inland of Sabah. This isolation presumably led to no admixture with other populations, and these individuals therefore underwent strong genetic differentiation. This report contributes to addressing the paucity of genetic data on representatives from this strategic region of ancient human migration event(s). PMID- 29521413 TI - Extracellular matrix proteins as diagnostic markers of breast carcinoma. AB - Changes in amount and composition of extracellular matrix (ECM) are considered a hallmark of tumor development. We tested the hypothesis that abnormal production of ECM components leads to blood-released ECM molecules representing tumor circulating biomarkers. Candidate genes were selected through class comparison in two publicly available datasets and confirmed in paired normal and tumor associated fibroblasts from breast carcinoma (BC) specimens. Production and release of ECM molecules were evaluated in normal human dermal fibroblasts (NHDFs) treated with conditioned media from three BC cell lines. Plasma samples from healthy donors and from patients with malignant or benign breast disease were tested by ELISA for the presence of collagen 11a1 (COL11A1), collagen oligomeric matrix protein (COMP), and collagen 10a1 (COL10A1). Selected ECM molecules were investigated by IHC in malignant and benign specimens. In silico analysis of gene expression profiles identified 11 ECM genes significantly up regulated in tumor versus normal tissue. Western blot analyses revealed increased levels of molecules encoded by three of these genes, COL11A1, COMP, and COL10A1, in cell lysates and supernatants of conditioned NHDFs. Class comparison and class prediction analyses of two independent series of human plasma samples identified the combination of COL11A1, COMP, and COL10A1 as potentially informative in discriminating BC patients from those with benign disease. The three molecules resulted expressed in the stroma of BC tissue samples. Our results indicate that circulating COL11A1, COMP, and COL10A1 may be useful in diagnostic assessment of suspicious breast nodules and ECM molecules could represent an avenue to biomarker identification. PMID- 29521414 TI - Diabetes, Heart Disease, and Dementia: National Estimates of Functional Disability Trajectories. AB - OBJECTIVES: To estimate the associations between diabetes, heart disease, and dementia, which may increase the difficulty of self-care; model functional disability trajectories jointly with attrition (death or dropout) over 5 years. DESIGN: Population-based complex survey design. SETTING: National Health and Aging Trends Study. PARTICIPANTS: Community-dwelling Medicare beneficiaries aged 65 and older (N=7,609). MEASUREMENTS: National estimates were generated using sampling weights. Sociodemographic characteristics, self-reported physician diagnosed chronic conditions, six activities of daily living (ADL), and cognitive status were ascertained in annual in-person interviews. A joint model using group based trajectory modeling was used to estimate the number of ADL disabilities and attrition probability. Multinomial logistic regression with survey weights was used to estimate the association between diabetes, heart disease, and dementia and resultant trajectories of disability, with the least disabled trajectory used as a reference. RESULTS: Three functional disability trajectories were identified: 26.9 million (76.3%) individuals with no disability and a constant study attrition of 14.3%, 4.9 million (13.9%) with mild and increasing disability and 12% attrition in 2012 and 27.2% in 2015, and 3.4 million (9.7%) with severe and increasing disability and 25.4% attrition in 2012 and 35% in 2015. Persons with possible dementia, possible dementia and diabetes, or possible dementia with diabetes and heart disease had significantly greater odds of being on the mild disability trajectory than those with no disability. Persons with probable dementia, representing more than 1.5 million persons, regardless of concurrent conditions, had significantly greater odds of being on the severe disability trajectory than on the no disability trajectory. CONCLUSIONS: Methods that generate national estimates and account for attrition and for multiple chronic conditions and cognitive status may be useful for health policy-makers to make decisions on care provisions and services. PMID- 29521415 TI - WITHDRAWN: Angioplasty (versus non surgical management) for intermittent claudication. AB - BACKGROUND: Intermittent claudication is pain in the legs due to muscle ischaemia associated with arterial stenosis or occlusion. Angioplasty is a technique that involves dilatation and recanalisation of a stenosed or occluded artery. OBJECTIVES: The objective of this review was to determine the effects of angioplasty of arteries in the leg when compared with non surgical therapy, or no therapy, for people with mild to moderate intermittent claudication. SEARCH METHODS: Sources searched include the Cochrane Peripheral Vascular Diseases Group's Specialized Trials Register (August 2006), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2006) and reference lists of relevant articles. The review authors also contacted investigators in the field and handsearched relevant conference proceedings (August 2006). SELECTION CRITERIA: Randomised trials of angioplasty for mild or moderate intermittent claudication. DATA COLLECTION AND ANALYSIS: The contact author selected suitable trials and this was checked by the other review author. Both review authors assessed trial quality independently. The contact author extracted data and this was cross checked by the other review author. MAIN RESULTS: Two trials with a total of 98 participants were included. The average age was 62 years old with 20 women and 78 men. Participants were followed for two years in one trial and six years in the other.At six months follow up, mean ankle brachial pressure indices were higher in the angioplasty groups than control groups (mean difference 0.17; 95% confidence interval (CI) 0.11 to 0.24). In one trial, walking distances were greater in the angioplasty group, but in the other trial, in which controls underwent an exercise programme, walking distances did not show a greater improvement in the angioplasty group. At two years follow up in one trial, the angioplasty group were more likely to have a patent artery (odds ratio 5.5; 95% CI 1.8 to 17.0) but not a significantly better walking distance or quality of life. In the other trial, long term follow up at six years demonstrated no significant differences in outcome between the angioplasty and control groups. AUTHORS' CONCLUSIONS: These limited results suggest that angioplasty may have had a short term benefit, but this may not have been sustained. PMID- 29521416 TI - Effects of neonatal handling on play and anxiety in F344 and Lewis rats. AB - Play is an important part of normal childhood development and seen in many mammals, including rats. To better understand the interplay between genotype and postnatal experiences, the effects of neonatal handling on play were assessed in Lewis (LEW) and Fischer 344 (F344) rats. Handled litters experienced brief periods of separation during the first two postnatal weeks. F344 rats were less likely to direct nape contacts toward an untreated Sprague-Dawley (SD) partner and less likely to rotate to a supine position in response to a nape contact. When compared to rats from control litters, handled LEW, and F344 rats were more likely to respond to nape contacts with complete rotations, suggesting that handling increased playful responsiveness to a comparable extent in both strains. SD rats paired with handled inbred rats had more nape contacts than those paired with non-handled rats. While handled LEW rats also tended to direct more nape contacts to the SD partner than non-handled LEW rats there was no difference between handled and non-handled F344 rats. These results could not be readily explained by handling-induced changes in either maternal care or anxiety. These data suggest that the behavioral consequences of neonatal handling may not depend to a great extent on the genetic platform that these manipulations are acting on. These data also suggest that the ability to maintain the ebb and flow between playful solicitation and playful responsiveness may be compromised in F344 rats and may contribute to the lower levels of play in this strain. PMID- 29521417 TI - Teaching help-seeking when lost to individuals with autism spectrum disorder. AB - Deficits in safety skills and communication deficits place individuals with autism spectrum disorder (ASD) at an increased risk of danger. We used a multiple probe across-participants design to evaluate the effects of video modeling and programming common stimuli to teach low- and high-tech help-seeking responses to children with ASD when lost. Participants acquired answering or making a FaceTime(r) call and exchanging an identification card in contrived and natural settings. Responses generalized to novel community settings and maintained during a one- and two-week follow-up. Social validity measures showed that the procedures and outcomes of the study were acceptable to indirect and direct consumers, and immediate and extended community members. Implications are that children with ASD can effectively be taught both low- and high-tech help-seeking responses when lost. PMID- 29521418 TI - Teach the teacher: Training otolaryngology fellows to become academic educators. AB - OBJECTIVES/HYPOTHESIS: Fellowship is the capstone of academic training and serves as preparation for an academic career. Fellows are expected to educate medical students and residents during and long after fellowship. However, little time is typically spent teaching fellows to become effective educators. We investigate a formal curriculum addressing teaching skills among fellows in otolaryngology-head and neck surgery (OHNS). STUDY DESIGN: E-mail survey. METHODS: We developed and implemented an educational program called Teach the Teacher to build skills as educators for fellows in OHNS. We conducted a survey of fellows from 2014 to 2017 in OHNS who participated in the course. The survey evaluated demographics, teaching experiences, and teaching limitations structured as yes/no and Likert style questions (1 = strongly disagree, 5 = strongly agree). RESULTS: Thirty fellows were surveyed with a response rate was 80%. Fellowship was rated highly as an experience that will make fellows a better academic educator (mean +/- standard deviation: 4.54 +/- 0.64). The most important components of teaching during fellowship were role modeling (4.67 +/- 0.62), followed by teaching psychomotor skills in the operating room (4.29 +/- 0.89), diagnostic reasoning (4.25 +/- 0.66), and evidence-based medicine (4.25 +/- 0.83). The Teach the Teacher course specifically was rated as a helpful experience (4.00 +/- 0.90). The primary limitations to developing teaching skills during fellowship identified were lack of time, patient safety, and inexperience with hospital culture. CONCLUSIONS: Fellowship is a key time to improve skills as academic educators. Fellows value formal efforts to teach academic skills. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:2034-2048, 2018. PMID- 29521419 TI - Cochlear implant provider awareness of vaccination guidelines. AB - OBJECTIVE: Guidelines for vaccination of cochlear implant (CI) recipients have been promulgated and updated by the Center for Disease Control and Prevention (CDC) to mitigate bacterial meningitis risk. The objective of this study was to survey current CI specialists on: 1) knowledge of current CDC CI recipient immunization recommendations, and 2) impediments to implementation of those guidelines. METHODS: A survey to assess knowledge of the CI recipient vaccination guidelines was administered to the American Academy of Otolaryngology-Head and Neck surgery (AAO-HNS), the American Cochlear Implant Alliance (ACIA), and the American Neurotology Society (ANS). The members of the AAO-HNS and ACIA were invited to participate in the survey via an e-mail. The members of the ANS were polled during a session of their fall meeting. RESULTS: A total of 256 individuals participated: 64 from AAO, 59 from ACIA, and 133 from ANS. Participants reported knowledge of the vaccination guidelines as high among all groups and statistically similar. The survey indicated that the participants noted difficulty in obtaining age-group-specific immunizations. Vaccination status was not consistently reported. CONCLUSION: Cochlear implant providers have high awareness of vaccination guidelines but less detailed knowledge of age specific recommendations. Obtaining age-specific vaccines is a challenge, as is consistent documentation of vaccination. Future efforts should be focused on improving knowledge of age-specific recommendations, easing access of age specific vaccines, and improving documentation. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:2145-2152, 2018. PMID- 29521420 TI - Nodal response after 46 Gy of intensity-modulated radiotherapy is associated with human papillomavirus-related oropharyngeal carcinoma. AB - OBJECTIVES/HYPOTHESIS: This study aimed to analyze the effect of human papillomavirus (HPV)-associated T1-2 node-positive oropharyngeal squamous cell carcinoma (OPSCC) on nodal response, recurrent disease, and survival in patients treated according to the Rotterdam protocol. STUDY DESIGN: Retrospective cohort study. METHODS: In total, 77 patients with T1-2 OPSCC with nodal disease, treated between 2000 and 2012, were included in this study. Patients were treated according to the Rotterdam protocol: 46 Gy of IMRT followed by a local boost using cyberknife or brachytherapy (22 Gy) and neck dissection. The presence of HPV was determined by p16INK4A immunostaining. Outcomes were overall survival, disease-free survival, and the extent of nodal response. Nodal stage was determined following the 7th and 8th American Joint Cancer Committee/Union for International Cancer Control classification. RESULTS: Overall, 68.4% of patients had p16-positive disease, and 35.4% of all patients achieved complete nodal response (pN0) after 46 Gy of intensity-modulated radiotherapy (IMRT). Based on the 7th TNM classification, nodal response (partial or complete) was significantly associated with HPV status (P = .002). Patients with p16-positive OPSCC had an odds ratio (OR) of 4.6 to achieve complete nodal response. However, smoking interacted with this effect. Applying the 8th TNM classification, complete or partial response was associated with HPV status but was not significant (OR: 1.7, P = .138). Complete nodal response led to 100% overall survival in p16-positive OPSCC patients. CONCLUSIONS: HPV-related OPSCCs are associated with complete nodal response after 46 Gy of IMRT. Patients with full regional control (pN0) after IMRT and subsequent neck dissection show a significantly better overall survival, but smoking negatively interacts with this effect. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2333-2340, 2018. PMID- 29521421 TI - The pharmacokinetics and analgesic effects of extended-release buprenorphine administered subcutaneously in healthy dogs. AB - Buprenorphine is a partial MU agonist opioid used for analgesia in dogs. An extended-release formulation (ER-buprenorphine) has been shown to provide effective analgesia for 72 hr in rats and mice. Six healthy mongrel dogs were enrolled in a randomized, blinded crossover design to describe and compare the pharmacokinetics and pharmacodynamics of ER-buprenorphine administered subcutaneous at 0.2 mg/kg (ER-B) and commercially available buprenorphine for injection intravenously at 0.02 mg/kg (IV-B). After drug administration, serial blood samples were collected to measure plasma buprenorphine concentrations using liquid chromatography/mass spectrometry detection. Heart rate, respiratory rate, body temperature, sedation score, and thermal threshold latency were recorded throughout the study. Median (range) terminal half-life, time to maximum concentration, and maximum plasma concentration of ER-buprenorphine were 12.74 hr (10.43-18.84 hr), 8 hr (4-36 hr), and 5.00 ng/ml (4.29-10.98 ng/ml), respectively. Mild bradycardia, hypothermia, and inappetence were noted in both groups. Thermal threshold latency was significantly prolonged compared to baseline up to 12 hr and up to 72 hr in IV-B and ER-B, respectively. These results showed that ER-buprenorphine administered at a dose of 0.2 mg/kg resulted in prolonged and sustained plasma concentrations and antinociceptive effects up to 72 hr after drug administration. PMID- 29521422 TI - Mine Safety and Health Administration's Part 50 program does not fully capture chronic disease and injury in the Illinois mining industry. AB - BACKGROUND: The Mine Safety and Health Administration (MSHA) requires reporting of injuries and illnesses to their Part 50 program. A 2011 study indicated that the Part 50 program did not capture many cases of injury in Kentucky, causing concern about underreporting in other states. METHODS: MSHA Part 50 reports from Illinois for 2001-2013 were linked to Illinois Workers' Compensation Commission (IWCC) data. IWCC cases not found in the Part 50 data were considered unreported. RESULTS: Overall, the Part 50 Program did not capture 66% of IWCC cases from 2001 to 2013. Chronic injuries or illnesses were more likely to be unreported to MSHA. CONCLUSIONS: The majority of occupational injuries and illnesses found in the IWCC from this time period, were not captured by Part 50. Inaccurate reporting of injuries and illnesses to the Part 50 program hinders MSHA's ability to enforce safety and health standards in the mining industry. PMID- 29521423 TI - Is core needle biopsy safe and effective for the assessment of head and neck lesions? PMID- 29521424 TI - Carnosic acid inhibits inflammation response and joint destruction on osteoclasts, fibroblast-like synoviocytes, and collagen-induced arthritis rats. AB - The discovery of new therapeutic drugs with the ability of preventing inflammation and joint destruction with less adverse effects is urgently needed for rheumatoid arthritis (RA). Carnosic acid (CA), a major phenolic compound isolated from the leaves of Rosemary (Rosmarinus officinalis L.), has been reported to have antioxidative and antimicrobial properties. However, its effects on RA have not been elucidated. Here, we investigated the effects of CA on osteoclasts and fibroblast-like synoviocytes in vitro and on collagen-induced arthritis (CIA) in Wistar rats in vivo. Our in vitro and in vivo studies showed that CA suppressed the expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-6, IL-8, IL-17 and MMP-3, and downregulated the production of RANKL. More importantly, we observed that CA inhibited osteoclastogenesis and bone resorption in vitro and exerted therapeutic protection against joint destruction in vivo. Further biochemical analysis demonstrated that CA suppressed RANKL-induced activations of NF-kappaB and MAPKs (JNK and p38) leading to the downregulation of NFATc1. Taken together, our findings provide the convincing evidence that rosemary derived CA is a promising natural compound for the treatment of RA. PMID- 29521425 TI - Keeping it short and (not so) simple: characterizing hERG kinetics with sinusoidal waves. PMID- 29521426 TI - Treating cancer with microRNA replacement therapy: A literature review. AB - microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post transcriptionally by interfering with the translation of one or more target mRNAs. The unique miRNA sequences are involved in many physiological and pathological processes. Dysregulation of miRNAs contributes to the pathogenesis of all types of cancer. Notably, the diminished expression of tumor suppressor miRNAs, such as members of the Let-7 and miR-34 family, promotes tumor progression, invasion and metastasis. The past lustrum in particular, has witnessed substantial improvement of miRNA replacement therapy. This approach aims to restore tumor suppressor miRNA function in tumor cells using synthetic miRNA mimics or miRNA expression plasmids. Here, we provide a comprehensive review of recent advances in miRNA replacement therapy for treatment of cancer and its advantages over conventional gene therapy. We discuss a wide variety of delivery methods and vectors, as well as obstacles that remain to be overcome. Lastly, we review efforts to reverse epigenetic alterations, which affect miRNA expression in cancer cells, and the promising observation that restoring miRNA function re-sensitizes resistant tumor cells to chemotherapeutic drugs. The fact that various miRNA replacement therapies are currently in clinical trial demonstrates the great potential of this approach to treat cancer. PMID- 29521427 TI - Mild Obstructive Sleep Apnea in Children: What is the Best Management Option? PMID- 29521428 TI - Bioturbation facilitates DDT sequestration by activated carbon against recontamination by sediment deposition. AB - We evaluated bioturbation as a facilitator for in situ treatment with a thin layer of activated carbon to treat dichlorodiphenyltrichloroethane (DDT) contaminated sediment and contaminant influx by sediment deposition. Using the freshwater worm Lumbriculus variegatus as a bioturbator, microcosm time-series studies were conducted for 4 mo and monitored for DDT flux and porewater concentration profiles by polyethylene passive samplers. With bioturbators present, the thin-layer activated carbon amendment reduced DDT flux by >90% compared with the same simulated scenario without activated carbon amendment. In contrast, a clean sediment cap without activated carbon was ineffective in reducing flux when bioturbation was present. In simulated scenarios with contaminant influx through deposition of contaminated sediment, bioturbation facilitated in situ activated carbon treatment, reducing 4-mo DDT flux by 77% compared with the same scenario without bioturbation. Porewater concentration profiles and activated carbon dose profiles confirmed effective mixing of activated carbon particles down to 1-cm depth. A mass transfer model was developed to predict flux with consideration of bioturbation and sediment deposition processes. Predicted flux values were consistent with experimental results and confirm that bioturbation activity helps reduce DDT sediment-to-water fluxes in activated carbon-treated sediment with recontamination by contaminated sediment deposition. To our knowledge, this is the first study to combine experimental and modeling results showing how bioturbation enhances activated carbon amendment effectiveness against ongoing contaminant influx by sediment deposition. Environ Toxicol Chem 2018;37:2013-2021. (c) 2018 SETAC. PMID- 29521430 TI - Suicide in men: the time is ripe for active scientific investigations. PMID- 29521429 TI - Systemic antibiotic use for nonbacterial dermatological conditions among referring providers. AB - BACKGROUND: As usage of systemic antibiotic therapies has increased, so too has bacterial resistance. Antibiotic stewardship thus rests in part on judicious use of empiric treatment. The specific factors which underlie erroneous prescription patterns for dermatological conditions have not yet been well elucidated. OBJECTIVE: The objective of this study was to identify whether a predefined group of dermatologic conditions under the heading "pseudobacterial"-including eczematous conditions, arthropod assault, herpes zoster, neurodermatoses, autoimmune blistering disorders, and neutrophilic dermatoses-are associated with increased antibiotic use prior to dermatology referral. METHODS: This observational prospective study included 207 participants referred to an academic dermatology referral center for acute skin conditions which were ultimately deemed to be of a nonbacterial cause. Preceding antibiotic prescription, final diagnosis, and patient, and provider characteristics were reviewed. RESULTS: Antibiotic prescription were provided to 31/207 individuals. Patients with pseudobacterial diagnoses (66/207 individuals) had 4.79 (95% CI, 2.03-11.3) times the odds of empiric antibiotic treatment compared to all others. Rural referring providers (OR, 8.54; 95% CI, 1.81-40.3) and referring providers in areas with a low density of medical specialists (OR, 3.70; 95% CI, 1.43-10.0) also displayed increased odds of empiric antibiotic prescription for nonbacterial skin disease, though the former finding may be limited by the low number of rural vs. urban providers (7 vs. 200) included in the study. CONCLUSION: Patients with noninfectious pseudobacterial dermatological conditions experienced greater odds for unnecessary exposure to antibiotics. Additional independent risk factors included rural settings and diminished access to specialist care. PMID- 29521431 TI - Disentangling schizophrenia spectrum disorders. PMID- 29521432 TI - Psychotic depression and suicide. PMID- 29521433 TI - Author's reply re: Should we implement universal screening with late pregnancy ultrasound to prevent stillbirth? PMID- 29521435 TI - Sexual function and qualify of life in women with spina bifida: Are the women with spina bifida satisfied with their sexual activity? AB - AIMS: As the life expectancy of persons with spina bifida increases, sexual life in adulthood presents a considerable challenge for this population. The purpose of this study was to evaluate the sexual function of young women with spina bifida and its impact on their quality of life (QOL). METHODS: To assess sexual function and QOL by using self-administered questionnaires (Female Sexual Function Index [FSFI] and 36-Item Short Form Health Survey) in young women with spina bifida, we collected data from 44 young women with spina bifida between June 2013 and October 2013 at the spina bifida clinic of our hospital. RESULTS: Sexual dysfunction was noted in 55.5% of women with spina bifida who had sexual activity in the previous month. In sexually active women, the diagnosis, ventriculoperitoneal shunt in situ, mobility, and clean intermittent catheterization did not show a significant difference between each subdomain (desire, arousal, lubrication, orgasm, satisfaction, and pain) and the total FSFI score. However, women who did not have urinary incontinence experienced better sexual function in terms of lubrication and pain scores (P = 0.033 and P = 0.026, respectively). Both the physical and mental composites of QOL were positively weakly correlated with the arousal score of FSFI (r = 0.455, P = 0.044 and r = 0.507, P = 0.023, respectively). CONCLUSIONS: More than half of sexually active women with spina bifida experience sexual dysfunction. Therefore, health-care providers should pay attention to the symptoms and their management. PMID- 29521434 TI - Interaction with macrophages attenuates equine fibroblast-like synoviocyte ADAMTS5 (aggrecanase-2) gene expression following inflammatory stimulation. AB - The joint synovium consists of a heterogeneous cell population, chiefly comprised of macrophages, and fibroblast-like synoviocytes (FLS). An inter-species co culture model was developed to examine interactions between these cells. Equine FLS and the canine macrophage line DH82 were differentially labeled using fluorescent markers and results from direct co-culture compared with those from both indirect co-culture, and conditioned media experiments. The transcript expression of IL-1beta, IL-6, ADAMTS4, and ADAMTS5 in each cell type were determined using species-specific qPCR assays. Lipopolysaccharide stimulation of EFLS rapidly increased IL-1beta, IL-6, ADAMTS4, and ADAMTS5 mRNAs. The induction of ADAMTS5 was significantly reduced when equine FLS were cultured with DH82 cells directly or indirectly. Exposure of equine FLS to denatured conditioned media also significantly reduced ADAMTS5 induction. DH82 cells increased interleukin-1beta expression substantially following LPS stimulation. However, knockdown of interleukin-1beta in DH82 cells, or inhibition of NF-kappaB in equine FLS prior to co-culture did not change the inhibitory effect on equine FLS ADAMTS5 gene expression. This work indicates that macrophages can influence FLS gene expression through a soluble mediator, and modulate the expression of an enzyme critical in osteoarthritis pathology during inflammatory stimulation. (c) 2018 The Authors. Journal of Orthopaedic Research(r) Published by WileyPeriodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 9999:1-8, 2018. PMID- 29521436 TI - MicroRNA-320 involves in the cardioprotective effect of insulin against myocardial ischemia by targeting survivin. AB - : It is generally accepted that insulin exerts an antiapoptotic effect against ischemia/reperfusion through the activation of PI3K/Akt/mTOR pathway. MicroRNAs involve in multiple cardiac pathophysiological processes, including ischemia/reperfusion-induced cardiac injury. However, the regulation of microRNAs in the cardioprotective effect of insulin is rarely discussed. In this study, using a cell model of ischemia through culturing H9C2 cardiac myocytes in serum free medium with hypoxia, we demonstrated that pretreatment with insulin significantly inhibited cell apoptosis and downregulated microRNA-320 (miR-320) expression. Interestingly, miR-320 mimic impaired the cardioprotective effect of insulin against myocardial ischemia injury by targeting survivin, which is a member of the family of inhibitor of apoptosis proteins. Suppression miR-320 expression by miR-320 inhibitor in H9C2 cells with myocardial ischemia mimics the cardioprotective effect of insulin by maintaining survivin expression. Taken together, miR-320-mediated survivin expression involves in cardioprotective effect of insulin against myocardial ischemia injury. SIGNIFICANCE OF THIS STUDY: Myocardial ischemia/reperfusion (I/R) injury remains an important clinical problem with extremely deficient clinical therapies. Insulin exerts an antiapoptotic effect against I/R through the activation of PI3K/Akt/mTOR pathway. Here, we provided evidences to show that microRNA-320 involves in the cardioprotective effect of insulin by targeting survivin, which is an inhibitor of apoptosis protein and functions as a key regulator in cell apoptosis and involves in the tumour genesis and progression. Our findings may provide a new potential therapeutic strategy for I/R injury and ischemic heart disease. PMID- 29521438 TI - Contrast-enhanced ultrasonography for evaluation of blood perfusion in normal canine eyes. AB - OBJECTIVE: This study was performed to evaluate ocular structures using contrast enhanced ultrasonography (CEUS) in dogs to assess the feasibility of CEUS for investigating the blood perfusion of canine eyes. ANIMAL STUDIED: Eight purpose bred beagles were used. PROCEDURES: Blood perfusion and vascularity of the right eye were evaluated using color Doppler, power Doppler, and CEUS with Sonazoid(r) . Vascular changes were quantitatively evaluated by measuring peak intensity, time to initial upslope, and time to peak from the ciliary body, iris, choroid, retina, and the retrobulbar region by CEUS. RESULTS: On CEUS images, all parts of the examined ocular structures were markedly enhanced and clearly identified from the adjacent region. After injection, the contrast agent initially flowed to the choroid and retina at 14.2 seconds, then to the ciliary body and iris at 20 seconds. The blood signal reached its peak intensity in the ciliary body at 27.2 seconds (47.4 +/- 10.63), in the iris at 31.6 seconds (74.00 +/- 41.85), and in the retrobulbar region at 23.4 seconds (149 +/- 24.59). The optic nerve was clearly distinguished from the retrobulbar region over 5 minutes after the initiation of CEUS. Significantly, more vascular signals were detected in the ciliary body and iris by CEUS than by color and power Doppler. CONCLUSION: Blood perfusion of the intraocular structures and the retrobulbar region can be quantitatively and qualitatively analyzed by CEUS. CEUS may be a useful, noninvasive, and sensitive tool for the evaluation of blood perfusion in ocular diseases. PMID- 29521437 TI - First human implant of the Alterra Adaptive PrestentTM : A new self-expanding device designed to remodel the right ventricular outflow tract. AB - Current balloon expandable transcatheter valves have limited applicability to patients with "native" right ventricular outflow tracts (RVOT), meaning those who have had previous surgery and are left with large, compliant, irregular RVOT. The Alterra Adaptive PrestentTM is a self-expanding, partially covered stent that was designed to internally reconfigure these types of RVOT, making them suitable for implantation of a commercially available balloon expandable heart valve, the SAPIEN 3. Herein, we describe the first human implant of this device. PMID- 29521439 TI - Primer selection impacts specific population abundances but not community dynamics in a monthly time-series 16S rRNA gene amplicon analysis of coastal marine bacterioplankton. AB - Primers targeting the 16S small subunit ribosomal RNA marker gene, used to characterize bacterial and archaeal communities, have recently been re-evaluated for marine planktonic habitats. To investigate whether primer selection affects the ecological interpretation of bacterioplankton populations and community dynamics, amplicon sequencing with four primer sets targeting several hypervariable regions of the 16S rRNA gene was conducted on both mock communities constructed from cloned 16S rRNA genes and a time-series of DNA samples from the temperate coastal Santa Barbara Channel. Ecological interpretations of community structure (delineation of depth and seasonality, correlations with environmental factors) were similar across primer sets, while population dynamics varied. We observed substantial differences in relative abundances of taxa known to be poorly resolved by some primer sets, such as Thaumarchaeota and SAR11, and unexpected taxa including Roseobacter clades. Though the magnitude of relative abundances of common OTUs differed between primer sets, the relative abundances of the OTUs were nonetheless strongly correlated. We do not endorse one primer set but rather enumerate strengths and weaknesses to facilitate selection appropriate to a system or experimental goal. While 16S rRNA gene primer bias suggests caution in assessing quantitative population dynamics, community dynamics appear robust across studies using different primers. PMID- 29521440 TI - Patient selection and percutaneous technique of unprotected left main revascularization. AB - Increasing evidence suggests that percutaneous coronary intervention with newer generation drug-eluting stents may be an acceptable alternative, or even preferred in selected cases to the surgical approach, in patients with left main disease. This review will discuss the anatomic factors, the clinical variables, and the procedural strategies to consider, including physiology assessment and imaging guidance, in order to optimize outcomes. PMID- 29521442 TI - Standardization of plasma vitellogenin level for surveying environmental estrogen pollution using the Japanese common goby Acanthogobius flavimanus. AB - Field surveys of the impact of environmental estrogen (EE) pollution in aquatic wildlife have been conducted using vitellogenin (VTG) as a biomarker to evaluate the influence of EE. However, a standard baseline of VTG level that can be used to evaluate EE pollution has not been fully determined. To the best of our knowledge, the present study is the first to determine the standard baseline VTG level for evaluating the biological effects of EE pollution using the Japanese common goby (Acanthogobius flavimanus) as the target model fish. Plasma VTG and estradiol-17beta (E2 ) levels associated with the reproductive cycle of wild goby inhabiting an unpolluted environment were measured. Mean plasma VTG and E2 levels exhibited similar changes, increasing in the yolk vesicle stage and peaking in the tertiary yolk stage in females. However, plasma VTG and E2 levels showed no significant changes in males, remaining at low levels throughout the reproductive cycle. The highest VTG levels in females and males were 1.6 mg ml-1 and 124.87 ng ml-1 , respectively. These results indicate that the baseline level (normal level) in males was approximately 130 ng ml-1 at most. We concluded that the threshold between normal and abnormal levels with a 10% risk rate was 150 ng ml-1 in the wild male goby. Plasma VTG levels in males captured from Nagasaki Harbor were higher than the threshold in each reproductive developmental stage, indicating the possibility of EE pollution at this site. The biological standard baseline for VTG established in this study is useful for assessing EE pollution in natural waters. PMID- 29521441 TI - A horizontally gene transferred copper resistance locus confers hyper-resistance to antibacterial copper toxicity and enables survival of community acquired methicillin resistant Staphylococcus aureus USA300 in macrophages. AB - Excess copper is highly toxic and forms part of the host innate immune system's antibacterial arsenal, accumulating at sites of infection and acting within macrophages to kill engulfed pathogens. We show for the first time that a novel, horizontally gene transferred copper resistance locus (copXL), uniquely associated with the SCCmec elements of the highly virulent, epidemic, community acquired methicillin resistant Staphylococcus aureus (CA-MRSA) USA300, confers copper hyper-resistance. These genes are additional to existing core genome copper resistance mechanisms, and are not found in typical S. aureus lineages, but are increasingly identified in emerging pathogenic isolates. Our data show that CopX, a putative P1B-3 -ATPase efflux transporter, and CopL, a novel lipoprotein, confer copper hyper-resistance compared to typical S. aureus strains. The copXL genes form an operon that is tightly repressed in low copper environments by the copper regulator CsoR. Significantly, CopX and CopL are important for S. aureus USA300 intracellular survival within macrophages. Therefore, the emergence of new S. aureus clones with the copXL locus has significant implications for public health because these genes confer increased resistance to antibacterial copper toxicity, enhancing bacterial fitness by altering S. aureus interaction with innate immunity. PMID- 29521443 TI - Nutrient factories: metabolic function of beneficial microorganisms associated with insects. AB - Many symbiotic microorganisms in animals, including insects, have parallels to microbial nutrient factories of biotechnology: just as the metabolism of individual microorganisms and microbial communities is modified by biotechnologists to produce specific nutrients, so the many insect-associated microorganisms synthesize specific nutrients that support the sustained growth and reproduction of their animal host. Three broad metabolic functions are mediated by insect-associated microorganisms: (i) fermentation of dietary constituents, releasing products that contribute to host carbon and energy metabolism; (ii) overproduction of nutrients, notably essential amino acids, required by the host and (iii) recycling of host waste metabolites. In many systems, the nutrients that are released from living microbial cells have been identified, with evidence for metabolite cross-feeding and shared metabolic pathways both among different microbial taxa and between microorganisms and the host. However, the flux of nutrients from microbial cells to host has rarely been quantified; our understanding of the processes that regulate nutrient transfer is fragmentary; and the scale and mechanism of metabolic adaptations of microorganisms to host nutritional demand are largely unknown. Recent advances in metabolic, microscopical and modelling techniques offer excellent opportunities to resolve these outstanding issues, with insights that can contribute to the effective design of nutrient factories for biotechnological applications. PMID- 29521444 TI - The D313Y genotype-Pathogenic mutation or polymorphism? PMID- 29521445 TI - Functionalized Proline-Rich Peptides Bind the Bacterial Second Messenger c-di GMP. AB - c-di-GMP is an attractive target in the fight against bacterial infections since it is a near ubiquitous second messenger that regulates important cellular processes of pathogens, including biofilm formation and virulence. Screening of a combinatorial peptide library enabled the identification of the proline-rich tetrapeptide Gup-Gup-Nap-Arg, which binds c-di-GMP selectively over other nucleotides in water. Computational and CD spectroscopic studies provided a possible binding mode of the complex and enabled the design of a pentapeptide with even higher binding strength towards c-di-GMP. Biological studies showed that the tetrapeptide inhibits biofilm growth by the opportunistic pathogen P. aeruginosa. PMID- 29521446 TI - Recent Advances in Analytical Pyrolysis to Investigate Organic Materials in Heritage Science. AB - The molecular characterization of organic materials in samples from artworks and historical objects traditionally entailed qualitative and quantitative analyses by HPLC and GC. Today innovative approaches based on analytical pyrolysis enable samples to be analysed without any chemical pre-treatment. Pyrolysis, which is often considered as a screening technique, shows previously unexplored potential thanks to recent instrumental developments. Organic materials that are macromolecular in nature, or undergo polymerization upon curing and ageing can now be better investigated. Most constituents of paint layers and archaeological organic substances contain major insoluble and chemically non-hydrolysable fractions that are inaccessible to GC or HPLC. To date, molecular scientific investigations of the organic constituents of artworks and historical objects have mostly focused on the minor constituents of the sample. This review presents recent advances in the qualitative and semi-quantitative analyses of organic materials in heritage objects based on analytical pyrolysis coupled with mass spectrometry. PMID- 29521448 TI - Is anticoagulation beneficial in acute mastoiditis complicated by sigmoid sinus thrombosis? PMID- 29521449 TI - Dehydroepiandrosterone rehabilitate BRL-3A cells oxidative stress damage induced by hydrogen peroxide. AB - This study aimed to investigate the molecular mechanism of dehydroepiandrosterone (DHEA) rehabilitated BRL-3A cells oxidative stress damage induced by hydrogen peroxide (H2 O2 ). Results showed that DHEA reversed the decrease of cell viability and ameliorated nuclear chromatin damage in H2 O2 -induced BRL-3A cells. DHEA increased the activities of superoxide dismutase, catalase, peroxidase, and glutathione peroxidase, and decreased the reactive oxygen species (ROS) production in H2 O2 -induced BRL-3A cells. DHEA attenuated the protein damage and lipid peroxidation, and reduced the apoptosis in H2 O2 -induced BRL-3A cells. The mRNA levels of Bax, Caspase-9, and Caspase-3 were decreased, while the Bcl-2 mRNA level was increased in H2 O2 -induced BRL-3A cells treated with DHEA. Our results showed that DHEA treatment increased the PI3K and p-Akt protein levels, while decreased the Bax and capase-3 protein levels in H2 O2 -induced BRL 3A cells. However, the rise in PI3K and p-Akt protein levels, and the decrease in Bax and capase-3 protein levels induced by DHEA treatment were reversed when the cells pretreated with LY294002 (PI3K inhibitor). These results indicated that DHEA ameliorated H2 O2 -induced oxidative damage by increasing anti-oxidative enzyme activities and ameliorating the protein damage and lipid peroxidation in BRL-3A cells. In addition, DHEA decreased the apoptosis by inhibiting caspase-3 and Bax protein levels and this action mainly achieved via the activation of PI3K/Akt signaling pathways in H2 O2 -induced BRL-3A cells. These results provided substantial information for DHEA as a nutritional supplement to treat oxidative stress and it related diseases in animals and humans. PMID- 29521447 TI - Influence of symptom typicality for predicting MACE in patients without obstructive coronary artery disease: From the CONFIRM Registry (Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry). AB - Our objective was to assess the prognostic value of symptom typicality in patients without obstructive coronary artery disease (CAD), determined by coronary computed tomographic angiography (CCTA). We identified 4215 patients without prior history of CAD and without obstructive CAD (<50% CCTA stenosis). CAD severity was categorized as nonobstructive (1%-49%) and none (0%). Based upon the Diamond-Forrester criteria for angina pectoris, symptom typicality was classified as asymptomatic, nonanginal, atypical, and typical. Multivariable Cox proportional hazards models were used to assess the risk of major adverse cardiac events (MACE), comprising all-cause mortality, myocardial infarction, unstable angina, and late revascularization, according to symptom typicality. Mean patient age was 57.0 +/-12.0 years (54.9% male). During a median follow-up of 5.3 years (interquartile range, 4.6-5.9 years), MACE were reported in 312 (7.4%) patients. Among patients with nonobstructive CAD, there was an association between symptom typicality and MACE (P for interaction = 0.05), driven by increased risk of MACE among those with typical angina and nonobstructive CAD (hazard ratio: 1.62, 95% confidence interval: 1.06-2.48, P = 0.03). No consistent relationship was found between symptom typicality and MACE among patients without any CAD (hazard ratio: 0.73, 95% confidence interval: 0.34-1.57, P = 0.08). In the CONFIRM registry, patients who presented with concomitant typical angina and nonobstructive CAD had a higher rate of MACE than did asymptomatic patients with nonobstructive CAD. However, the presence of typical angina did not appear to portend worse prognosis in patients with no CAD. PMID- 29521451 TI - Fear and blame in mental health nurses' accounts of restrictive practices: Implications for the elimination of seclusion and restraint. AB - Restrictive practices continue to be used in mental health care despite increasing recognition of their harms and an international effort to reduce and ultimately eliminate their use. The aim of this qualitative study was to explore mental health nurses' views of the potential elimination of these practices. Nine focus groups were conducted with 44 mental health nurses across Australia, and the data analysed using thematic analysis. Overall, the nurses expressed significant fear about the potential elimination of restrictive practices and saw themselves as being blamed for both the use of these practices and the consequences should they be eliminated. Findings detail the conflicts facing staff in balancing the need for ward safety for everyone present while at the same time providing person-centred care. Nurses described the changing role of the mental health nurse in acute settings, being more focussed on risk assessment and medication while at the same time attempting to practise in trauma-informed person-centred ways. The impact on ward safety with increasing acuity of consumers plus the presence of forensic consumers and those affected by methamphetamine was emphasized. Change initiatives need to take into account nurses' deep concerns about the consequences of eliminating all forms of control measures in hospitals and respond to the symptoms and behaviours consumers present with and associated unpredictable and concerning behaviours. Attempts to eliminate restrictive practices should, therefore, be carefully considered and come with a clear articulation of alternatives to ensure the safety of consumers, visitors, and staff. PMID- 29521450 TI - Sustained sex-based treatment differences in acute coronary syndrome care: Insights from the American Heart Association Get With The Guidelines Coronary Artery Disease Registry. AB - BACKGROUND: Sex-based differences in acute coronary syndrome (ACS) mortality may attenuate with age due to better symptom recognition and prompt care. HYPOTHESIS: Age is a modifier of temporal trends in sex-based differences in ACS care. METHODS: Among 104 817 eligible patients with ACS enrolled in the AHA Get With the Guidelines-Coronary Artery Disease registry between 2003 and 2008, care and in-hospital mortality were evaluated stratified by sex and age. Temporal trends within sex and age groups were assessed for 2 care processes: percentage of STEMI patients presenting to PCI-capable hospitals with a DTB time <= 90 minutes (DTB90) and proportion of eligible ACS patients receiving aspirin within 24 hours. RESULTS: After adjustment for clinical risk factors and sociodemographic and hospital characteristics, 2276 (51.7%) women and 6276 (56.9%) men with STEMI were treated with DTB90 (adjusted OR: 0.85, 95% CI: 0.80-0.91, P < 0.0001 for women vs men). Time trend analysis showed an absolute increase ranging from 24% to 35% in DTB90 rates among both men and women (P for trend <0.0001 for each group), with consistent differences over time across the 4 age/sex groups (3-way P-interaction = 0.93). Despite high rate of baseline aspirin use (87%-91%), there was a 9% to 11% absolute increase in aspirin use over time, also with consistent differences across the 4 age/sex groups (all 3-way P-interaction >=0.15). CONCLUSIONS: Substantial gains of generally similar magnitude existed in ACS performance measures over 6 years of study across sex and age groups; areas for improvement remain, particularly among younger women. PMID- 29521453 TI - Sleep on the ward in intensive care unit survivors: a case series of polysomnography. AB - BACKGROUND: Few studies have investigated sleep in patients after intensive care despite the possibility that inadequate sleep might further complicate an acute illness impeding recovery. AIMS: To assess the quality and quantity of a patient's sleep on the ward by polysomnography (PSG) within a week of intensive care unit (ICU) discharge and to explore the prevalence of key in-ICU risk factors for persistent sleep fragmentation. METHODS: We enrolled 20 patients after they have been mechanically ventilated for at least 3 days and survived to ICU discharge. We included all patients over the age of 16 years and excluded patients with advanced cognitive impairment or who were unable to follow simple commands before their acute illness, primary admission diagnosis of neurological injury, uncontrolled psychiatric illness or not fluent in English. RESULTS: Twenty patients underwent an overnight PSG recording on day 7 after ICU discharge (SD, 1 day). ICU survivors provided 292.8 h of PSG recording time with median recording times of 16.8 h (Interquartile range (IQR), 15.0-17.2 h). The median total sleep time per patient was 5.3 h (IQR, 2.6-6.3 h). In a multivariable regression model, postoperative admission diagnosis (P = 0.04) and patient report of poor ICU sleep (P = 0.001) were associated with less slow-wave (restorative) sleep on the wards after ICU discharge. CONCLUSIONS: Patients reported poor sleep while in the ICU, and a postoperative admission diagnosis may identify a high risk subgroup of patients who may derive greater benefit from interventions to improve sleep hygiene. PMID- 29521452 TI - Genomes of ubiquitous marine and hypersaline Hydrogenovibrio, Thiomicrorhabdus and Thiomicrospira spp. encode a diversity of mechanisms to sustain chemolithoautotrophy in heterogeneous environments. AB - Chemolithoautotrophic bacteria from the genera Hydrogenovibrio, Thiomicrorhabdus and Thiomicrospira are common, sometimes dominant, isolates from sulfidic habitats including hydrothermal vents, soda and salt lakes and marine sediments. Their genome sequences confirm their membership in a deeply branching clade of the Gammaproteobacteria. Several adaptations to heterogeneous habitats are apparent. Their genomes include large numbers of genes for sensing and responding to their environment (EAL- and GGDEF-domain proteins and methyl-accepting chemotaxis proteins) despite their small sizes (2.1-3.1 Mbp). An array of sulfur oxidizing complexes are encoded, likely to facilitate these organisms' use of multiple forms of reduced sulfur as electron donors. Hydrogenase genes are present in some taxa, including group 1d and 2b hydrogenases in Hydrogenovibrio marinus and H. thermophilus MA2-6, acquired via horizontal gene transfer. In addition to high-affinity cbb3 cytochrome c oxidase, some also encode cytochrome bd-type quinol oxidase or ba3 -type cytochrome c oxidase, which could facilitate growth under different oxygen tensions, or maintain redox balance. Carboxysome operons are present in most, with genes downstream encoding transporters from four evolutionarily distinct families, which may act with the carboxysomes to form CO2 concentrating mechanisms. These adaptations to habitat variability likely contribute to the cosmopolitan distribution of these organisms. PMID- 29521454 TI - Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation in NEUROD1. AB - The basic helix-loop-helix (bHLH) transcription factor, neuronal differentiation 1 (NEUROD1) (also known as BETA2) is involved in the development of neural elements and endocrine pancreas. Less than 10 reports of adult-onset non-insulin dependent diabetes mellitus (NIDDM) due to heterozygous NEUROD1 mutations and 2 cases with permanent neonatal diabetes mellitus (PNDM) and neurological abnormalities due to homozygous NEUROD1 mutations have been published. A 13 year old female was referred to endocrine department due to hyperglycemia. She was on insulin therapy following a diagnosis of neonatal diabetes mellitus (NDM) at the age of 9-weeks but missed regular follow-up. Parents are second cousin. There was a significant family history of adult onset NIDDM including patient's father. Auxological measurements were within normal ranges. On laboratory examination blood glucose was 33.2 mmol/L with undetectable c-peptide and glycosylated hemoglobin level of 8.9% (73.8 mmol/mol). She had developed difficulty in walking at the age of 4 years which had worsened over time. On further evaluation, a diagnosis of visual impairment, mental retardation, ataxic gait, retinitis pigmentosa and sensory-neural deafness were considered. Cranial magnetic resonance imaging revealed cerebellar hypoplasia. Molecular genetic analysis using targeted next generation sequencing detected a novel homozygous missense mutation, p.Ile150Asn(c.449T>A), in NEUROD1. Both parents and 2 unaffected siblings were heterozygous for the mutation. We report the third case of PNDM with neurological abnormalities caused by homozygous NEUROD1 mutation, the first caused by a missense mutation. Heterozygous carriers of the p.Ile150Asn mutation were either unaffected or diagnosed with diabetes in adulthood. It is currently unclear whether the NEUROD1 heterozygous mutation has contributed to diabetes development in these individuals. PMID- 29521455 TI - Subnaphthalocyanines as Electron Acceptors in Polymer Solar Cells: Improving Device Performance by Modifying Peripheral and Axial Substituents. AB - A new class of subnaphthalocyanines bearing various peripheral and axial substituents have been synthesized for use as electron acceptors in solution processed bulk-heterojunction polymer solar cells. The resulting solar cells exhibit modest photovoltaic performance with contributions from both the polymer donor and subnaphthalocyanine acceptor to the photocurrent. PMID- 29521457 TI - Titanium hypersensitivity causing painful intra-abdominal oedema after staple fixed inguinal hernia repair. PMID- 29521458 TI - Re: Prevention of early-onset group B streptococcal disease. Green-top Guideline No. 36. PMID- 29521460 TI - Genetic association of the ACACB gene with milk yield and composition traits in dairy cattle. AB - Previously, we re-sequenced the whole genomes of eight Holstein bulls with high or low milk protein and fat percentage, and we detected two indels in the ACACB (acetyl-CoA carboxylase beta) gene that were polymorphic between the two groups. Thus, we considered ACACB as a promising candidate gene potentially affecting milk composition traits. Herein, we verified the genetic effects of ACACB on five milk traits in a Chinese Holstein population. We identified six SNPs in the 5' promoter region, five in the 5'- untranslated region (UTR), 11 in exons, four in the 3'-UTR and three in the 3'-flanking region by re-sequencing the entire coding and regulatory regions of ACACB. One of these SNPs (ss1987461005) is reported here for the first time, and three of the SNPs (rs109482081, rs110819816 and rs109281947) were predicted to result in amino acid replacements. Genotype phenotype association analyses showed that all the identified SNPs, except for ss1987461005, rs208919019 and rs134447911, were significantly associated with milk yield, fat yield, fat percentage, protein yield or protein percentage (P < 0.0001 to 0.0484). Linkage disequilibrium analyses were conducted among the identified SNPs to confirm the genetic associations. Two SNPs-rs135874354 (g.66218726T>C) and rs210928430 (g.66218117G>A)-were predicted to alter transcription factor binding sites in the 5'-promoter region of ACACB. A luciferase activity assay showed that the promoter activity of haplotype TG was significantly higher than that of CG (P = 0.0002) and that the promoter activity of haplotype TA was remarkably higher than that of CA (P = 7.4285E-09), showing that the T allele of rs135874354 increased promoter activity. Thus, rs135874354 was considered to be a potentially functional mutation. Our findings have, for the first time, profiled the genetic effect of ACACB on milk production traits in dairy cattle and revealed a potentially causal mutation that requires further the in-depth validation. PMID- 29521459 TI - Heterolytic Si-H Bond Cleavage at a Molybdenum-Oxido-Based Lewis Pair. AB - The reaction of a molybdenum(VI) oxido imido complex with the strong Lewis acid B(C6 F5 )3 gave access to the Lewis adduct [Mo{OB(C6 F5 )3 }(NtBu)L2 ] featuring reversible B-O bonding in solution. The resulting frustrated Lewis pair (FLP) like reactivity is reflected by the compound's ability to heterolytically cleave Si-H bonds, leading to a clean formation of the novel cationic MoVI species 3 a (R=Et) and 3 b (R=Ph) of the general formula [Mo(OSiR3 )(NtBu)L2 ][HB(C6 F5 )3 ]. These compounds possess properties highly unusual for molybdenum d0 species such as an intensive, charge-transfer-based color as well as a reversible redox couple at very low potentials, both dependent on the silane used. Single-crystal X-ray diffraction analyses of 2 and 4 b, a derivative of 3 b featuring the [FB(C6 F5 )3 ]- anion, picture the stepwise elongation of the Mo=O bond, leading to a large increase in the electrophilicity of the metal center. The reaction of 3 a and 3 b with benzaldehyde allowed for the regeneration of compound 2 by hydrosilylation of the benzaldehyde. NMR spectroscopy suggested an unusual mechanism for the transformation, involving a substrate insertion in the B-H bond of the borohydride anion. PMID- 29521461 TI - Wear and Corrosion Interactions at the Titanium/Zirconia Interface: Dental Implant Application. AB - PURPOSE: Dental implants have been shown to have predictable success, but esthetic complications often arise. To reduce tissue shadowing from titanium, zirconia abutments may be used; however, the literature suggests that the use of zirconia leads to greater destruction of the implant interface that may result in biological complications such as titanium tattoos and heavy metal toxicity. Previous studies have examined the mechanical aspects of this implant/abutment relationship, but they have not accounted for the corrosive degradation that also takes place in the dynamic environment of the oral cavity. This study investigated the combined effect of both wear and corrosion on the materials at the implant and abutment interface. MATERIALS AND METHODS: Using a simulated oral tribocorrosive environment, titanium (Ti) and zirconia (Zr) abutment materials were slid against titanium and Roxolid implant alloys. The four couplings (Ti/Ti, Ti/Rox, Zr/Ti, Zr/Rox) were selected for the tribocorrosion tests (N = 3). The testing was conducted for 25K cycles, and the coefficient of friction (CoF) and voltage evolution were recorded simultaneously. Following the tribocorrosion assays, the wear volume loss was calculated, and surface characterization was performed. Statistical analysis was completed using a one-way ANOVA followed by post-hoc Bonferroni comparisons. RESULTS: Zr/Ti groups had the highest CoF (1.1647), and Ti/Ti had the lowest (0.5033). The Zr/Ti coupling generated significantly more mechanical damage than the Ti/Ti group (p = 0.021). From the corrosion aspect, the Ti/Ti groups had the highest voltage drop (0.802 V), indicating greater corrosion susceptibility. In comparison, the Zr/Roxolid group had the lowest voltage drop (0.628 V) and significantly less electrochemical degradation (p = 0.019). Overall, the Ti/Ti group had the largest wear volume loss (15.1 * 107 MUm3 ), while the Zr/Ti group had the least volume loss (2.26 * 107 MUm3 ). Both zirconia couplings had significantly less wear volume than the titanium couplings (p < 0.001). CONCLUSIONS: This study highlights the synergistic interaction between wear and corrosion, which occurs when masticatory forces combine with the salivary environment of the oral cavity. Overall, the zirconia groups outperformed the titanium groups. In fact, the titanium groups generated 5 to 6 times more wear to the implant alloys as compared with the zirconia counterparts. The best performing group was Zr/Ti, and the worst performing group was Ti/Ti. PMID- 29521462 TI - HPV primary cervical screening in England: Women's awareness and attitudes. AB - BACKGROUND: Primary human papillomavirus (HPV) cervical screening is due to be implemented in England within the next 2 years; however, the acceptability of HPV testing as the primary screening test is unclear. This study explores women's awareness and attitudes toward HPV testing/screening. METHODS: Qualitative interviews (semistructured and focus group) were conducted with 46 women (aged 25 65 years) from community and secondary care settings. Data were analyzed by using the inductive-framework method. RESULTS: Women were unaware that cervical screening currently includes HPV testing and lacked HPV-related knowledge. Emotions of shock, fear, and anxiety were reported upon receiving a positive HPV result. For women in long-term relationships, the realization that HPV is a sexually transmitted infection was seen as a barrier to primary HPV testing. Knowledge that HPV testing is a screening test to prevent cervical cancer did not change their attitudes. Women debated the need for continued screening following a negative result. Women feared judgment by the community if they participated with primary HPV screening because they were being tested for a sexually transmitted infection, with the possible attendant perception that they had adopted a high-risk lifestyle in comparison to nonattenders. CONCLUSIONS: The acceptability of HPV testing may be a limiting factor in encouraging participation with screening in the future. PMID- 29521463 TI - Timing of sperm capacitation varies reproducibly among men. AB - Sperm must mature functionally in the process of capacitation to become able to fertilize. Capacitation depends on membrane lipid changes, and can be quantitatively assessed by redistribution of the ganglioside GM1 , the basis of the Cap-ScoreTM sperm function test. Here, differences in Cap-Score were compared among and within men at two time points. Ejaculates were liquefied, washed, and incubated for 3 hr under capacitating (Cap) conditions, then fixed and analyzed immediately (Day0); after being incubated 3 hr under Cap conditions then maintained 22-24 hr in fix (Day1-fix); or after 22-24 hr incubation under Cap conditions prior to fixation (Day1). In all cases, a light fixative previously shown to allow membrane lipid movements was used. Day1-fix and Day1 Cap-Scores were greater than Day0 (p < 0.001; n = 25), whereas Day1-fix and Day1 Cap-Scores were equivalent (p = 0.43; n = 25). In 123 samples from 52 fertile men, Cap-Score increased more than 1SD (7.7; calculated previously from a fertile cohort) from Day0 to Day1-fix in 44% (54/123) of the samples. To test whether timing of capacitation was consistent within an individual, 52 samples from 11 fertile men were classified into either "early" or "late" capacitation groups. The average capacitation group concordance within a donor was 81%. Median absolute deviation (MAD; in Cap-Score units) was used to assess the tightness of clustering of the difference from Day0 to Day1-fix within individuals. The average (2.21) and median (1.98) MAD confirmed consistency within individuals. Together, these data show that the timing of capacitation differed among men and was consistent within men. PMID- 29521464 TI - Performance of the Evolut-R 34 mm versus Sapien-3 29 mm in Transcatheter aortic valve replacement patients with larger annuli: Early outcome results of Evolut-R 34 mm as compared with Sapien-3 29 mm in patients with Annuli >=26 mm. AB - BACKGROUND: Evolut-R 34 mm (received CE mark in January 2017) and Sapien-3 29 mm are the only options for transcatheter aortic valve replacement (TAVR) in patients with annulus >=26 mm. We compared the short-term outcomes of these valves in these patients. METHODS: Data was collected prospectively from consecutive patients with severe aortic stenosis and annulus diameter larger than 26 mm treated by femoral approach TAVR. RESULTS: Between February 1, 2014 to August 19, 2017 Sapien-3 29 mm was implanted in 55 and Evolut-R 34 mm in 37 consecutive patients. Device success rate was 98.2% and 97.3% (P = 1.0) and the composite peri-procedural complication rate was 7.3% and 2.7% (P = .645) in Sapin 3 29 mm and Evolut-R 34 mm, respectively. Composite endpoint of early safety in hospital did not differ significantly [5(9.2%) vs 3(8.1%), P = 1.00], respectively. Prosthetic valve Gradients were significantly lower with Evolut-R 34 mm [maximal (18.0 +/- 5.8 vs 11.2 +/- 4.8 mmHg, P < .001) and mean (10.0 +/- 3.3 vs 6.3 +/- 2.7 mmHg, P < .001)]. Pacemaker implantation rate was high in both groups, and numerically but not statistically significant higher with Evolut-R [10/50 (20.0%) vs 8/28 (28.6%), P = .389]. CONCLUSIONS: As compared to Sapien-3 29 mm the Evolut-R 34 mm is a real alternative for TAVR in patients with a large annulus with a comparable peri-procedural complication rate, better hemodynamic results but a trend for higher pacemaker rate. PMID- 29521465 TI - Long-term outcomes after re-entry device use for recanalization of common iliac artery chronic total occlusions. AB - OBJECTIVE: To examine the impact of re-entry device (RED) use on 1- and 5-year outcomes after endovascular treatment of common iliac artery (CIA) chronic total Occlusions (CTOs). BACKGROUND: There are not enough data regarding the long-term safety and efficacy of RED. METHODS: We performed a two-center retrospective study of 115 patients (140 lesions) undergoing CIA CTO endovascular intervention between 2006 and 2016. Baseline characteristics and long-term outcomes were described. A Cox proportional hazard model was developed to determine if REDs were associated with target lesion revascularization (TLR) or major adverse limb events (MALE) after 1 and 5 years. RESULTS: Among 140 lesions, 43 (31%) required use of a RED. The mean age was 63.9 years and the majority (n = 80) of patients were male. An antegrade crossing approach and treatment of restenotic lesions were less common in the RED group (10% vs. 29%, P < .05 and 0% vs. 21%, P < .05, respectively). There were no significant differences in Rutherford class, pre procedure ABI, or patient presentation. The procedural complication rates were similar between the two groups. The 1- and 5-year TLR rates for lesions treated with re-entry device vs. standard approaches were 11% vs. 9%; P = 0.8 and 29% vs. 29%; P = 0.9 respectively. The 1 and 5-year MALE rates for lesions treated with re-entry device were 5% vs. 6%; P = 0.8 and 11% vs. 11%; P = 0.9 respectively. CONCLUSIONS: This retrospective analysis found that recanalization of CIA occlusions using a RED is safe and is associated with long-term clinical outcomes similar to that of standard crossing techniques. PMID- 29521466 TI - Lipidomics of CHO Cell Bioprocessing: Relation to Cell Growth and Specific Productivity of a Monoclonal Antibody. AB - As the demand for biological therapeutic proteins rises, there is an increasing need for robust and highly efficient bioprocesses, specifically, maximizing protein production by controlling the cellular nutritional and metabolic needs. A comprehensive lipidomics analysis has been performed, for the first time, over the time course of CHO cells producing an IgG1 monoclonal antibody (mAb) with fed batch 5 L bioreactors. The dynamic nature and importance of the CHO lipidome, especially on cellular growth and specific productivity, is demonstrated. A robust LC-MS method using positive and negative mode ESI was developed for lipid identification and quantitation of 377 unique lipids. The analysis revealed large changes in lipid features between the different days in bioprocessing including accumulation of triacylglycerol (TG) and lysophospholipid species with depletion of diacylglycerol (DG) species. Exploring pathway analysis where the lipid data was combined with polar metabolites and transcriptomics (RNA sequencing) revealed differences in lipid metabolism between the various stages of cellular growth and highlighted the role of key features of lipid metabolism on cell growth and specific productivity. The study demonstrates the importance of lipidomics in the expanding role of 'Omics methodologies in gaining insight into cellular behavior during protein production in a fed batch bioprocess. PMID- 29521467 TI - Dual-Selective and Dual-Enhanced SERS Nanoprobes Strategy for Circulating Hepatocellular Carcinoma Cells Detection. AB - The detection of hepatocellular carcinoma (HCC) circulating tumor cells (CTCs) from a blood sample can be a very powerful noninvasive approach for the early detection and therapy of liver cancer. However, the extreme rarity of tumor cells in blood containing billions of other cells makes the capture and identification of CTCs with sufficient sensitivity and specificity a real challenge. Here, a magnetically assisted surface-enhanced Raman scattering (SERS) biosensor for HCC CTC detection is reported for the first time. The biosensor consists of two basic elements: anti-ASGPR antibody-Fe3 O4 @Ag magnetic nanoparticles and anti-GPC3 antibody-Au@Ag@DTNB nanorods. According to the dual-selectivity of the anti-ASGPR and anti-GPC3 antibodies and the dual-enhancement SERS signal of the MNPs silver shell and the Au@Ag NRs SERS tags, a limit of detection of 1 cell mL-1 for HCC CTC in human peripheral blood samples with a linear relationship from 1 to 100 cells mL-1 can be obtained. The system shows good performance in real serum, which suggests it may be a promising tool for HCC clinical diagnosis. PMID- 29521468 TI - Sperm limitation affects sex allocation in a parasitoid wasp Nasonia vitripennis. AB - Insect reproduction is influenced by various external factors including temperature, a well-studied constraint. We investigated to what extent different levels of sperm limitation of males exposed to different heat stresses (34 and 36 degrees C) affect females' offspring production and sex allocation in Nasonia vitripennis. In this haplodiploid parasitoid wasp attacking different species of pest flies, we investigated the effect of the quantity of sperm females received and stored in their spermatheca on their sperm use decisions, hence sex allocation, over successive ovipositions. In particular, we compared the sex allocation of females presenting three levels of sperm limitation (i.e., mated with control, 34 degrees C heat-stressed or 36 degrees C heat-stressed males) on each host they parasitized. To disentangle the potential reduction of sperm quality after a heat stress exposure from that of sperm quantity, we also explored the clutch size and sex ratio produced by females that were partially sperm limited after copulating with multiply mated males. Independently of their sperm numbers, all types of females produced a similar total number of offspring, but the more limited ones had fewer daughters. Sperm limitation further affected the distribution of daughters' production across time. In addition to constraints acting on female physiology, male fertility should therefore be considered in studies measuring reproductive outputs of insects submitted to heat stresses. PMID- 29521469 TI - Oxysterol-binding protein-related protein 2 is not essential for Phytophthora sojae based on CRISPR/Cas9 deletions. AB - Oxysterol-binding protein (OSBP)-related proteins (ORPs) are a large conserved family of lipid transfer proteins in eukaryotes. In oomycetes, some ORPs are the target of the novel oomycide oxathiapiprolin. By searching the Phytophthora sojae genome database, two ORP proteins, PsORP1 (Protein ID: 558498) and PsORP2 (Protein ID: 470921), were found. Here, we investigated the biological function of PsORP2. The expression level of PsORP2 was higher in germinated cysts and late infection than in other developmental stages. However, deletion of PsORP2 using CRISPR/Cas9 had no significant effect on sporangia production, zoospore production, cyst germination, oospore production, virulence or oxathiapiprolin sensitivity. PsORP1 also was not upregulated in DeltaPsORP2 transformants. Collectively, our studies demonstrate that PsORP2 is not an essential protein for development or virulence in P. sojae under the conditions we tested. PMID- 29521470 TI - Behavioral symptoms and psychiatric disorders in child and adolescent long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. AB - BACKGROUND: Prevalence of emotional, behavioral, and psychiatric outcomes in child and adolescent survivors of childhood acute lymphoblastic leukemia treated on a chemotherapy-only protocol were not well defined. METHODS: Self- and parent reported emotional and behavioral symptoms were assessed for 161 survivors of childhood acute lymphoblastic leukemia (51.0% female; mean [SD] age 12.1[2.6] years; 7.5[1.6] years post-diagnosis). Age- and sex-adjusted scores were calculated for standardized measures and compared with 90th percentile of norms. Frequencies of survivor psychiatric disorders from structured diagnostic interviews with parents were compared with the general population. Parent emotional distress and post-traumatic stress symptoms were assessed. Associations between child symptoms/disorders and parent distress were examined with log binomial models, adjusting for highest parent education. RESULTS: Compared with population expectations (10%), more survivors self-reported symptoms of inattention (27.9; 95% CI, 21.0%-35.7%), hyperactivity/impulsivity (26.0%; CI, 19.2%-33.6%), and oppositional-defiant behavior (20.1%; CI, 14.1%-27.3%). Parents reported survivors with more symptoms of inattention (23.6%; CI, 17.2%-31.0%), higher frequencies of obsessive-compulsive disorder (10.3% vs 2%) and oppositional defiant disorder (16.0% vs 9.5%), but not attention deficit/hyperactivity disorder (7.1% vs 7.8%) or generalized anxiety disorder (3.2% vs 4.1%), compared with national norms. Parent-report of child anxiety disorders was associated with parent self-reported emotional distress but not survivor self-report of anxiety. CONCLUSION: A significant minority of survivors have long-term psychiatric morbidity, multi-informant assessment is important to understand these symptom profiles and to inform selection of appropriate interventions. Interventions targeting inattention and oppositional behavior in children and emotional distress in parents are warranted in families with survivors who display behavioral problems. PMID- 29521472 TI - GuideLinerTM as guide catheter extension for the unreachable mammary bypass graft. AB - Percutaneous coronary intervention (PCI) of mammary artery bypass grafts through a trans-radial (TR) approach can present unique challenges, including coaxial vessel engagement of the guiding catheter, adequate visualization of the target lesion, sufficient backup support for equipment delivery, and the ability to reach very distal lesions. The GuideLiner catheter, a rapid exchange monorail mother-in-daughter system, facilitates successful interventions in such challenging anatomy. We present a case of a patient undergoing PCI of a right internal mammary artery (RIMA) graft via TR access in whom the graft could not be engaged with any guiding catheter. Using a balloon tracking technique over a guidewire, a GuideLiner was placed as an extension of the guiding catheter and facilitated TR-PCI by overcoming technical challenges associated with difficult anatomy. PMID- 29521471 TI - Anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS), fractional flow reserve- and intravascular ultrasound-guided management in adult patients. AB - OBJECTIVES: To describe the use of fractional flow reserve (FFR) and intravascular ultrasound (IVUS) in the evaluation of patients with anomalous coronary arteries originating from the opposite sinus of Valsalva (ACAOS). BACKGROUND: ACAOS of the right and left coronary are rare, but may lead to symptoms and impose a risk for sudden cardiac death, depending on several anatomical features. Assessment and risk estimation is challenging in (nonathlete) adults, especially if they present without symptoms or with atypical complaints. METHODS: The team retrospectively studied 30 consecutive patients with ACAOS with interarterial course, who received IVUS- and FFR-guided treatment at our institution between October 2010 and September 2017. RESULTS: FFR was abnormal in only seven patients. IVUS showed the typical slit-like anatomy of the orifice in 23 patients. Based on FFR and/or IVUS results, in conjunction with the clinical presentation, clinical decision was made. A decision for intervention was made if at least two out of three entities were abnormal. Intervention implied unroofing of the coronary artery (n = 10) or coronary artery bypass grafting (n = 1). In all other patients a conservative strategy was followed. No adverse events occurred in the total population after a median of 37 (0-62) months of follow-up. CONCLUSIONS: Conservative treatment may be justifiable in adult patients with ACAOS in the presence of normal FFR and nonsuspicious symptoms, despite the presence of an interarterial course and/or slitlike orifice on IVUS. We recommend the use of FFR and IVUS in the standard work-up for adult patients with ACAOS and propose the use of a flowchart to aid in decision-making. PMID- 29521473 TI - The ecological genetics of Pseudomonas syringae from kiwifruit leaves. AB - Interactions between commensal microbes and invading pathogens are understudied, despite their likely effects on pathogen population structure and infection processes. We describe the population structure and genetic diversity of a broad range of co-occurring Pseudomonas syringae isolated from infected and uninfected kiwifruit during an outbreak of bleeding canker disease caused by P. syringae pv. actinidiae (Psa) in New Zealand. Overall population structure was clonal and affected by ecological factors including infection status and cultivar. Most isolates are members of a new clade in phylogroup 3 (PG3a), also present on kiwifruit leaves in China and Japan. Stability of the polymorphism between pathogenic Psa and commensal P. syringae PG3a isolated from the same leaf was tested using reciprocal invasion from rare assays in vitro and in planta. P. syringae G33C (PG3a) inhibited Psa NZ54, while the presence of Psa NZ54 enhanced the growth of P. syringae G33C. This effect could not be attributed to virulence activity encoded by the Type 3 secretion system of Psa. Together our data contribute toward the development of an ecological perspective on the genetic structure of pathogen populations. PMID- 29521474 TI - Novel method for radial sheath removal using manual pressure over hemostatic pad combined with ulnar compression. AB - OBJECTIVES: Study a novel method using manual pressure on a hemostatic pad and hemoband for ulnar compression as a potential alternative for radial sheath removal. BACKGROUND: The standard for transradial access site (TRA) sheath removal requires an inflatable pressure band over the radial artery and recently a band over the ulnar artery to reduce complications. We present a novel technique using a SoftSeal(r)-STF hemostatic pad over the radial artery combined with a hemoband over the ulnar artery after sheath removal. METHODS: All patients had activated clotting time (ACT); sheath removal was performed immediately upon transfer to the recovery room. A hemoband compressed the ulnar artery, radial artery flow was measured using plethysmography and pulse oximetry while direct pressure applied using SoftSeal-STF hemostatic pad for 15 min after radial sheath removed. Radial artery patency was measured using reverse Barbeau test. If radial artery occlusion (RAO) present, patient was asked to return in one month to repeat test. RESULTS: Fifty-nine patients were enrolled in the study, one-third with diabetes mellitus, one-third with prior coronary artery bypass surgery, and one-third with history of percutaneous coronary intervention. Mean ACT 261 +/- 50 sec, all patients had 4 Fr sheaths and no PCI were performed. Three (6%) patients had minor bleeding requiring use of a pressure band and one (2%) had RAO, which re-canalized at one month. CONCLUSIONS: Manual pressure of SoftSeal-STF hemostatic pad combined with ulnar compression is a potential alternative to current practice with an inflatable pressure band. PMID- 29521475 TI - Few mitochondrial DNA sequences are inserted into the turkey (Meleagris gallopavo) nuclear genome: evolutionary analyses and informativity in the domestic lineage. AB - Mitochondrial DNA (mtDNA) insertions have been detected in the nuclear genome of many eukaryotes. These sequences are pseudogenes originated by horizontal transfer of mtDNA fragments into the nuclear genome, producing nuclear DNA sequences of mitochondrial origin (numt). In this study we determined the frequency and distribution of mtDNA-originated pseudogenes in the turkey (Meleagris gallopavo) nuclear genome. The turkey reference genome (Turkey_2.01) was aligned with the reference linearized mtDNA sequence using last. A total of 32 numt sequences (corresponding to 18 numt regions derived by unique insertional events) were identified in the turkey nuclear genome (size ranging from 66 to 1415 bp; identity against the modern turkey mtDNA corresponding region ranging from 62% to 100%). Numts were distributed in nine chromosomes and in one scaffold. They derived from parts of 10 mtDNA protein-coding genes, ribosomal genes, the control region and 10 tRNA genes. Seven numt regions reported in the turkey genome were identified in orthologues positions in the Gallus gallus genome and therefore were present in the ancestral genome that in the Cretaceous originated the lineages of the modern crown Galliformes. Five recently integrated turkey numts were validated by PCR in 168 turkeys of six different domestic populations. None of the analysed numts were polymorphic (i.e. absence of the inserted sequence, as reported in numts of recent integration in other species), suggesting that the reticulate speciation model is not useful for explaining the origin of the domesticated turkey lineage. PMID- 29521476 TI - Authors' reply re: Prevention of early-onset Group B streptococcal disease. Green top Guideline No. 36. PMID- 29521477 TI - Serial intravascular ultrasound evaluation of the DESolveTM novolimus-eluting bioresorbable coronary scaffold system. AB - INTRODUCTION: Bioresorbable coronary scaffolds (BRS) have been developed to increase the late safety of coronary angioplasty by providing transitory coronary support and then being fully incorporated to the vessel wall. In the present trial, we sought to evaluate the performance and changes over time in the DESolveTM novolimus-eluting BRS using serial intravascular ultrasound (IVUS) in patients submitted to percutaneous coronary interventions. METHODS: Single center, prospective, non-randomized study involving 17 consecutive patients submitted to implantation of the DESolveTM scaffold and serial evaluated with IVUS at different time points (post procedure, 6 and 18 months). Primary endpoint included the variation in lumen, scaffold, and vessel diameter and area along the months. RESULTS: Angiographic success was achieved in all cases. Scaffold area and volume on IVUS were significantly greater at 6 months than at baseline (6.41 +/- 1.35 mm2 vs. 7.35 +/- 1.53 mm2 , P < 0.002; and 101.19 +/- 20.9 mm3 vs. 118.51 +/- 26.6 mm3 , P = 0.001). Late lumen loss was 0.22 +/- 0.30 mm at 6 months and 0.33 +/- 0.44 mm at 18 months. No major adverse cardiac events occurred. At late follow-up (18 months) the scaffold was not visualized by IVUS; therefore the evaluation was restricted to lumen and vessel at that time point. CONCLUSIONS: IVUS serial evaluation of the novel DESolve BRS showed an increase in the device dimensions between baseline and 6 months, with concomitant enlargement of lumen dimensions and effective suppression of neointimal proliferation. At 18 months, no footprint of the scaffold was detected and the initial lumen enlargement was sustained. PMID- 29521478 TI - Regium-pi bonds: An Unexplored Link between Noble Metal Nanoparticles and Aromatic Surfaces. AB - The ability of metal clusters involving elements from group 11 (Ag, Cu, Au) to favorably interact with pi systems of different size and electronic nature was evaluated at the PBE0-D3/def2-TZVPP//PBE0-D3/def2-TZVP level of theory. The M9 clusters (M=Cu, Ag, Au) were used as sigma-hole and sigma-lump donors, and benzene, trifluorobenzene, and hexafluorobenzene as aromatic rings. In addition, the study was expanded to the analysis of extended pi systems by using naphthalene and anthracene as well as their corresponding perfluorinated derivatives. Furthermore, Bader's theory of Atoms in Molecules as well as natural bonding orbital and spin-density calculations were used to further investigate and characterize the regium-pi and sigma-lump complexes described herein. Apparently, regium-pi bonds have not previously been described in the literature and may be of great importance in the understanding of organocatalytic processes involving aromatic substrates as well as in the design of new materials based on this novel subclass of sigma-hole bonding. PMID- 29521479 TI - Robotically performed excimer laser coronary atherectomy: Proof of feasibility. AB - The feasibility, safety, and high technical success of robotically assisted percutaneous coronary intervention (PCI) for the treatment of both simple and complex coronary disease has been demonstrated. As the current generation robotic platform is limited to a rapid exchange system, orbital or rotational atherectomy cannot be performed robotically. However, excimer laser coronary atherectomy is performed with a rapid exchange catheter but its feasibility during robotically assisted PCI is unknown. We report the successful use of laser atherectomy during two complex robotically assisted PCI procedures using the CorPath GRX robotic system. PMID- 29521480 TI - Identification of inner membrane translocase components of TolC-mediated secretion in the cyanobacterium Synechocystis sp. PCC 6803. AB - Cyanobacteria were the first organisms ever to perform oxygenic photosynthesis and still significantly contribute to primary production on a global scale. To assure the proper functioning of their primary metabolism and cell homeostasis, cyanobacteria must rely on efficient transport systems to cross their multilayered cell envelope. However, cyanobacterial secretion mechanisms remain largely unknown. Here, we report on the identification of 11 putative inner membrane translocase components of TolC-mediated secretion in the unicellular cyanobacterium Synechocystis sp. PCC 6803. Gene-inactivation of each of the candidate genes followed by a comprehensive phenotypic characterization allowed to link specific protein components to the processes of protein export (as part of the type I secretion system) and drug efflux (part of the resistance-division nodulation efflux pumps). In addition, mutants in genes sll0141, sll0180 and slr0369 exhibited alterations in pilin glycosylation, but pili structures could still be observed by transmission electron microscopy. By studying the release of outer membrane vesicles (OMVs), an alternative secretion route, on mutants with impaired secretory functions we suggest that the hyper-vesiculating phenotype of the TolC-deficient mutant is related to cell envelope stress management. Altogether, these findings highlight how both classical (TolC-mediated) and nonclassical (OMVs-mediated) secretion systems are crucial for cyanobacterial cell homeostasis. PMID- 29521481 TI - Radioiodine ablation in thyroid cancer patients: renal function and external radiation dose rate at discharge according to patient preparation. AB - BACKGROUND: An elevated thyroid stimulating hormone (TSH) level is essential for the uptake of radioiodine into thyroid remnants and residual thyroid cancer in patients undergoing high-dose radioiodine therapy (HD-RIT). Recently, the use of recombinant human thyroid stimulating hormone (rh- TSH) has increased in preference over the conventional method of thyroid hormone withdrawal (THW). However, the clinical influences of the two methods, aside from the therapeutic effects, have not been widely evaluated. The aim of this work was to investigate the influences of the two methods, particularly on the renal function and external radiation dose rate (EDR) from patients undergoing HD-RIT. METHODS: From February 2012 to November 2016, 667 patients (M:F=138:529, mean age: 47.7 +/- 11.8 years), who underwent first HD-RIT (120, 150, or 180 mCi, 1 mCi = 37 MBq) for ablation of remnant thyroid tissue or residual thyroid cancer, were enrolled. Patients who were proven to have distant metastasis to lung or bone were excluded. Low- to high-risk patients based on 2015 American thyroid association management guidelines who underwent first HD-RIT in our department were included. The period from total thyroidectomy to HD-RIT was limited within 12 months. The following parameters were collected and evaluated: age, gender, histology type and TNM stage of thyroid cancer, glomerular filtration rate on the admission day for total thyroidectomy (baseline GFR), GFR on the day of HD-RIT (follow-up GFR), thyroglobulin (Tg) and thyroid stimulating hormone (TSH) levels on the day of HD RIT, and EDR on the discharge day after HD-RIT. RESULTS: There were 386 patients using the THW method and 281 patients choosing the rh-TSH method. The baseline GFR of the THW group (106+/-16 mL/min/1.73 m2) and that of the rh-TSH group (104+/-17 mL/min/1.73 m2) were within normal limits and there was no significant difference. However, follow- up GFR of the THW group (84+/-17 mL/min/1.73 m2) was much lower than that of the rh-TSH group (104+/-16 mL/min/1.73 m2) (P=0.000). In the THW group, the follow-up GFR decreased significantly (P=0.000), yet the follow-up GFR of the rh-TSH group was not statistically different when compared with its baseline GFR (P=0.142). EDRs were lower in all rh-TSH subgroups compared to those of THW subgroups with statistical significance. Tg and TSH levels were not different between the two groups, excluding a few small-sized subgroups analyses. CONCLUSIONS: In this retrospective analysis of renal function and EDR, the use of rh-TSH appears to help maintain renal function and finally decrease EDR in contrast to the THW method when undergoing HD-RIT. PMID- 29521482 TI - Current application and future perspectives of PSMA PET imaging in prostate cancer. AB - As precision medicine evolves, the contribution of molecular imaging to the management of prostate cancer (PCa) patients, especially for Positron Emission Tomography (PET) imaging, is gaining importance. Highly successful approaches to measure the expression of the prostate specific membrane antigen (PSMA) have been introduced recently. PSMA, the glutamate carboxypeptidase II (GCP-II), is a membrane bound metallo-peptidase that is overexpressed in 90-100% of PCa cells. Due to its selective over-expression, PSMA is a reliable tissue marker for prostate cancer and is considered an ideal target for tumor specific imaging and therapy. A variety of PET and SPECT probes targeting this peptide receptor have been introduced. These are undergoing extensive clinical evaluations. Initial results attest to a high accuracy for disease detection compared conventional radiology (CT or MRI) and other nuclear medicine procedure (choline PET or fluciclovine PET). However, prospective evaluation of the impact on patient management for PSMA-ligand PET and its impact on patient outcome is currently missing. Finally, PSMA inhibitors can be radio-labeled with diagnostic (68Ga-PSMA 11), or therapeutic nuclides (177Lu/225Ac PSMA-617) to be used as theranostic agent. Initial results showed that PSMA-targeted radioligand therapy (RLT) can potentially delay disease progression in metastatic castrate-resistant PCa. This review aims to explore the current application of PSMA based imaging in prostate cancer, reporting about main advantages and limitations of this new theranostic procedure. The future perspectives and potential the applications of this agent will be also discussed. PMID- 29521483 TI - Paying a Premium on Your Premium? Consolidation in the US Health Insurance Industry. PMID- 29521484 TI - Impact of an antimicrobial stewardship program on urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. AB - OBJECTIVE: To analyze the clinical and economic impact of an antimicrobial stewardship program (ASP) targeting urinary tract infections (UTI) caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. METHODS: An observational retrospective study that included adults with a diagnosis of UTI caused by ESBL-producing E. coli admitted to a tertiary care hospital in Barcelona, Spain, between January 2014 and December 2015. The impact of the ASP was analyzed in terms of clinical and economic outcomes. RESULTS: A total of 222 patients met the inclusion criteria and an intervention was made by the ASP team in 104 cases (47%). ASP intervention was an independent variable related to clinical cure (p = 0.008). Other variables influencing clinical outcomes were the McCabe Jackson score (p = 0.005) and outpatient status (p < 0.001). The ASP interventions in this study had no economic impact. CONCLUSIONS: Antimicrobial stewardship has a positive clinical impact on UTIs caused by ESBL-producing E. coli. Further prospective studies are needed to assess the economic impact of ASPs on UTI caused by ESBL-producing E. coli. PMID- 29521485 TI - Evaluation of three different devices to reduce stasis edema in poorly mobile nursing home patients. AB - BACKGROUND: Prolonged immobility in the sitting position in the elderly is known to produce venous stasis with leg edema and possible skin changes. Compression stockings are often applied for this clinical problem. There is few experienced nursing staff available to supervise the difficult task of stocking application. METHODS: The authors have researched other effective and simple devices that may be suitable alternatives. This article reports the results of three different devices to reduce leg edema, as measured by reduction in leg volume: an electro stimulation device, an adjustable compression Velcro(r) wrap and a short stretch bandage, each tested over a two-hour period. RESULTS: In this randomized pilot study including 38 patients, the authors observed no difference in leg volume following electro-stimulation (Veinoplus(r)). They noted a significant reduction in leg volume following use of the other two devices, more with the adjustable Velcro(r) wrap compression (Circaid Juxtafit(r)) than with the short stretch bandage (Rosidal K(r)). Measurement of the interface pressures created by these two devices and also assessing the stiffness created by applying each device for two hours confirm that pressure is more important than stiffness in the reduction of edema in these particular patients. CONCLUSIONS: This pilot study is to be added to the results of previous published studies showing the efficacy in reducing leg edema of Velcro(r) adjustable compression wrap and its ease of use. PMID- 29521486 TI - Relationship between the maximum carotid plaque area and the severity of coronary atherosclerosis. AB - BACKGROUND: Carotid artery plaque is associated with coronary artery disease (CAD). Besides the presence of plaque, plaque characteristics is also related to the severity of CAD. So the characteristic difference of carotid plaque may affect this assessment role. However, it is unclear whether the maximum carotid plaque area can reflect the extents and severity of CAD. METHODS: We enrolled 388 consecutive CAD patients and 45 controls, and 204 patients were studied after excluding 184 patients without carotid plaque or coronary angiogram. Carotid intima media thickness and carotid plaque were measured by carotid ultrasound. Coronary angiography was applied and Gensini score was calculated. Blood lipid and other parameters were also detected. RESULTS: The total and right maximum carotid plaque area were greater in high Gensini Score group than those in low and moderate score groups (both P<0.05) and multivessel disease patients possessed the highest maximum plaque area. The total and right maximum carotid plaque area were also higher in collateral circulation group than those in non collateral group (P=0.036 and 0.002 respectively). Multivariate logistic regression showed that Gensini score (OR=2.458, 95% CI=1.111 to 5.439, P=0.027) was associated with increased total maximum carotid plaque area. The optimal cut off value for predicting the severity of CAD was 46.75 mm2 for total maximum plaque area. CONCLUSIONS: The maximum carotid plaque area can reflect the clinical severity of CAD, and it can be used as a simple noninvasive indicator of severity of coronary atherosclerosis. PMID- 29521487 TI - Growth hormone deficiency and pregnancy: any role for substitution? AB - Growth hormone (GH) is not approved for use during conception and pregnancy. Nevertheless, data from the clinical care practice reveal that most women concieve on GH replacement therapy (GHRT), and more than half continue on GHRT also during pregnancy. GH stimulates the hypothalamic-pituitary-gonadal axis at all levels, and there is evidence that GH deficiency impacts the morphology of reproductive organs, onset of puberty, ovarian function and fertility. Patients with hypopituitarism often conceive using assisted reproductive techniques and several studies support the benefit of GH supplementation for achieving fertility in women with GH deficiency. During gestation the GH system is regulated by the placental growth hormone, which increases continuously with the growth of placenta and stimulates maternal IGF-1 levels, leading to a concomitant decline in pituitary GH secretion. GHRT regimens that aim to mimic the pathophysiology of GH/IGF-1 concentrations during pregnancy continue GHRT during the first trimester, gradually reduce GH dose during the second trimester and stopp GHRT at the beginning of the third trimester. Pregnancy outcomes were not found to be related to GHRT treatment patterns during pregnancy, but female patients with childhood-onset hypopituitarism have lower fertility rates and less positive pregnancy outcomes. Although current guidelines recommend against GHRT during pregnancy, GHRT might be needed for achieving fertility and satisfactory pregnancy outcomes are reported following the decision of patients and physicians for adapting the GHRT dose during pregnancy. PMID- 29521488 TI - The role of adenosyl-methionine in alcoholic liver disease and intrahepatic cholestasis. PMID- 29521489 TI - Child Health and Conflict in Cote d'Ivoire. PMID- 29521490 TI - Heuristics and Heterogeneity in Health Insurance Exchanges: Evidence from the Massachusetts Connector. PMID- 29521491 TI - The Impact of the Massachusetts Health Care Reform on Health Care Use Among Children. PMID- 29521492 TI - Photophysical Tuning of N-Oxide-Based Probes Enables Ratiometric Photoacoustic Imaging of Tumor Hypoxia. AB - Hypoxia results when the oxygen supply to rapidly growing tumors becomes inadequate to support various physiological processes. This plays a role in tumor metastasis and treatment resistance. Therefore, identifying tumor hypoxia can guide treatment planning and predict patient responses. However, hypoxic volumes are heterogeneously dispersed throughout a tumor, making it a challenge to pinpoint them with any degree of accuracy. Herein, we report the development of ratiometric hypoxia probe 1 (rHyP-1), which is a hypoxia-responsive small molecule probe designed for reliable hypoxia detection using photoacoustic imaging. Photoacoustic imaging utilizes near-infrared (NIR) light to induce the production of ultrasound signals, enabling high-resolution image acquisition at centimeter depths. Together with the ratiometric capability of rHyP-1, reliable hypoxia detection with unprecedented spatial resolution is possible while minimizing error associated with concentration dependence and tissue heterogeneity. PMID- 29521493 TI - Dynamic Sparse Sampling for Confocal Raman Microscopy. AB - The total number of data points required for image generation in Raman microscopy was greatly reduced using sparse sampling strategies, in which the preceding set of measurements informed the next most information-rich sampling location. Using this approach, chemical images of pharmaceutical materials were obtained with >99% accuracy from 15.8% sampling, representing an ~6-fold reduction in measurement time relative to full field of view rastering with comparable image quality. This supervised learning approach to dynamic sampling (SLADS) has the distinct advantage of being directly compatible with standard confocal Raman instrumentation. Furthermore, SLADS is not limited to Raman imaging, potentially providing time-savings in image reconstruction whenever the single-pixel measurement time is the limiting factor in image generation. PMID- 29521494 TI - New Insights into the Roles of Mg in Improving the Rate Capability and Cycling Stability of O3-NaMn0.48Ni0.2Fe0.3Mg0.02O2 for Sodium-Ion Batteries. AB - Elements doping has been used to improve the electrochemical performances of O3 type layered transition metal oxide cathodes for sodium-ion batteries. However, their roles and the improvement mechanism have not been clearly understood. Herein, the effects of Mg substitution for Mn on the structure and electrochemical performances of NaMn0.48Ni0.2Fe0.3Mg0.02O2 have been comprehensively investigated and some new insights into the roles of Mg in improving the rate capability and cycling stability have been presented. (1) The substitution of Mg for Mn enlarges the interlayer spacing, which not only enhances Na+ diffusion and the rate capability but also alleviates the lattice strains induced by Na+ intercalation/deintercalation. (2) The substitution of Mg by Mn also shrinks TM-O bond and TMO2 slabs, which enhances the layered structure stability. (3) The Mg substitution also mitigates the structure distortion or volume change of the crystal lattices and suppresses the irreversible phase transitions. (4) The substitution of low-valence Mg2+ for Mn3+ reduces Mn3+ and minimizes Jahn-Teller effect, which also further alleviates the irreversible phase transformations and improves the layered structure stability. This study not only unveils the roles of Mg but also presents some insights into designing the cathode materials with both high rate capability and high cycling stability through the lattice structure regulation. PMID- 29521495 TI - Interface-Targeting Strategy Enables Two-Photon Fluorescent Lipid Droplet Probes for High-Fidelity Imaging of Turbid Tissues and Detecting Fatty Liver. AB - Lipid droplets (LDs) with unique interfacial architecture not only play crucial roles in protecting a cell from lipotoxicity and lipoapoptosis but also closely relate with many diseases such as fatty liver and diabetes. Thus, as one of the important applied biomaterials, fluorescent probes with ultrahigh selectivity for in situ and high-fidelity imaging of LDs in living cells and tissues are critical to elucidate relevant physiological and pathological events as well as detect related diseases. However, available probes only utilizing LDs' waterless neutral cores but ignoring the unique phospholipid monolayer interfaces exhibit low selectivity. They cannot differentiate neutral cores of LDs from intracellular other lipophilic microenvironments, which results in extensively cloud-like background noise and severely limited their bioapplications. Herein, to design LD probes with ultrahigh selectivity, the exceptional interfacial architecture of LDs is considered adequately and thus an interface-targeting strategy is proposed for the first time. According to the novel strategy, we have developed two amphipathic fluorescent probes (N-Cy and N-Py) by introducing different cations into a lipophilic fluorophore (nitrobenzoxadiazole (NBD)). Consequently, their cationic moiety precisely locates the interfaces through electrostatic interaction and simultaneously NBD entirely embeds into the waterless core via hydrophobic interaction. Thus, high-fidelity and background-free fluorescence imaging of LDs are expectably realized in living cells in situ. Moreover, LDs in turbid tissues like skeletal muscle slices have been clearly imaged (up to 82 MUm depth) by a two-photon microscope. Importantly, using N-Cy, we not only intuitively monitored the variations of LDs in number, size, and morphology but also clearly revealed their abnormity in hepatic tissues resulting from fatty liver. Therefore, these unique probes provide excellent imaging tools for elucidating LD-related physiological and pathological processes and the interface targeting strategy possesses universal significance for designing probes with ultrahigh selectivity. PMID- 29521496 TI - Enhanced Out-of-Plane Electrical Transport in n-Type SnSe Thermoelectrics Induced by Resonant States and Charge Delocalization. AB - Doping effects of various elements in the boron, carbon, and pnictogen groups on the electronic structure and electrical transport properties of SnSe were studied from first principles. It is identified that Sb and Bi induce significant resonant states near the conduction band minimum, and increase the delocalization of charge density in the out-of-plane direction. Our Boltzmann transport calculations further demonstrate that these doping effects on the electronic structure are related to the simultaneously improved Seebeck coefficient and electrical conductivity. Using the band unfolding technique, we analyze the resonant states in detail based on the effective band structures. PMID- 29521497 TI - Charge-Transfer-Promoted High Oxygen Evolution Activity of Co@Co9S8 Core-Shell Nanochains. AB - Co@Co9S8 nanochains with core-shell structures are prepared by a direct-current arc-discharge technique and followed sulfurization at 200 degrees C. The nanochains, which consist of uniform nanospheres connecting each other, can range up to several micrometers. The thickness of Co9S8 shell can be changed by regulating the sulfurization time. In this heterostructure of Co@Co9S8, Co nanochains function as a conductive network and can inject electrons into Co9S8, which manipulates the work function of Co9S8 and makes it more apposite for catalysis. The density functional theory calculation also reveals that coupling with Co can significantly reduce the overpotential needed to drive the oxygen evolution process. On the basis of the exclusive structure, Co@Co9S8 nanochains have shown high catalytic activity in the oxygen evolution reaction. Co@Co9S8 reaches an overpotential of 285 mv at 10 mA cm-2, which is much lower than that of Co nanochains (408 mV) and Co9S8 (418 mV). Co@Co9S8 also shows higher catalytic activity and robustness compared to state-of-the-art noble-metal catalyst RuO2. PMID- 29521498 TI - Ancient Chemistry "Pharaoh's Snakes" for Efficient Fe-/N-Doped Carbon Electrocatalysts. AB - The method of fabricating nonprecious metal electrocatalysts with high activity and durability through a facile and eco-friendly procedure is of great significance to the development of low-cost fuel cells and metal-air batteries. Herein, we present that an ancient chemical reaction of "Pharaoh's snakes" can be a fast and convenient technique to prepare Fe-/N-doped carbon (Fe/N-C) nanosheet/nanotube electrocatalysts with sugar, soda, melamine, and iron nitrate as precursors. The resultant Fe/N-C catalyst has a hierarchically porous structure, a large surface area, and uniformly distributed active sites. The catalyst shows high electrocatalytic activities toward both the oxygen reduction reaction with a half-wave potential of 0.90 V (vs reversible hydrogen electrode) better than that of Pt/C and the oxygen evolution reaction with an overpotential of 0.46 V at the current density of 10 mA cm-2 comparable to that of RuO2. The activity and stability of the catalyst are also evaluated in primary and rechargeable Zn-air batteries. In both conditions, three-dimensional Fe/N-C exhibited performances superior to Pt/C. Our work demonstrates a success of utilizing an ancient science to make a state-of-the-art electrocatalyst. PMID- 29521499 TI - Vapor Intrusion Management in China: Lessons Learned from the United States. PMID- 29521500 TI - Addition and Correction to Journey Describing Applications of Oxone in Synthetic Chemistry. PMID- 29521501 TI - Melding Vapor-Phase Organic Chemistry and Textile Manufacturing To Produce Wearable Electronics. AB - Body-mountable electronics and electronically active garments are the future of portable, interactive devices. However, wearable devices and electronic garments are demanding technology platforms because of the large, varied mechanical stresses to which they are routinely subjected, which can easily abrade or damage microelectronic components and electronic interconnects. Furthermore, aesthetics and tactile perception (or feel) can make or break a nascent wearable technology, irrespective of device metrics. The breathability and comfort of commercial fabrics is unmatched. There is strong motivation to use something that is already familiar, such as cotton/silk thread, fabrics, and clothes, and imperceptibly adapt it to a new technological application. (24) Especially for smart garments, the intrinsic breathability, comfort, and feel of familiar fabrics cannot be replicated by devices built on metalized synthetic fabrics or cladded, often heavy designer fibers. We propose that the strongest strategy to create long lasting and impactful electronic garments is to start with a mass-produced article of clothing, fabric, or thread/yarn and coat it with conjugated polymers to yield various textile circuit components. Commonly available, mass-produced fabrics, yarns/threads, and premade garments can in theory be transformed into a plethora of comfortably wearable electronic devices upon being coated with films of electronically active conjugated polymers. The definitive hurdle is that premade garments, threads, and fabrics have densely textured, three-dimensional surfaces that display roughness over a large range of length scales, from microns to millimeters. Tremendous variation in the surface morphology of conjugated polymer-coated fibers and fabrics can be observed with different coating or processing conditions. In turn, the morphology of the conjugated polymer active layer determines the electrical performance and, most importantly, the device ruggedness and lifetime. Reactive vapor coating methods allow a conjugated polymer film to be directly formed on the surface of any premade garment, prewoven fabric, or fiber/yarn substrate without the need for specialized processing conditions, surface pretreatments, detergents, or fixing agents. This feature allows electronic coatings to be applied at the end of existing, high throughput textile and garment manufacturing routines, irrespective of dye content or surface finish of the final textile. Furthermore, reactive vapor coating produces conductive materials without any insulating moieties and yields uniform and conformal films on fiber/fabric surfaces that are notably wash- and wear-stable and can withstand mechanically demanding textile manufacturing routines. These unique features mean that rugged and practical textile electronic devices can be created using sewing, weaving, or knitting procedures without compromising or otherwise affecting the surface electronic coating. In this Account, we highlight selected electronic fabrics and garments created by melding reactive vapor deposition with traditional textile manipulation processes, including electrically heated gloves that are lightweight, breathable, and sweat resistant; surface-coated cotton, silk, and bast fiber threads capable of carrying large current densities and acting as sewable circuit interconnects; and surface-coated nylon threads woven together to form triboelectric textiles that can convert surface charge created during small body movements into usable and storable power. PMID- 29521502 TI - Slow Magnetic Relaxation in a Series of Mononuclear 8-Coordinate Fe(II) and Co(II) Complexes. AB - A series of homoleptic mononuclear 8-coordinate FeII and CoII compounds, [FeII(L2)2](ClO4)2 (2), [FeII(L3)2](ClO4)2 (3), [FeII(L4)2](ClO4)2 (4), [CoII(L1)2](ClO4)2 (5), [CoII(L2)2](ClO4)2 (6), [CoII(L3)2](ClO4)2 (7), and [CoII(L4)2](ClO4)2 (8) (L1 and L2 are 2,9-dialkylcarboxylate-1,10-phenanthroline ligands; L3 and L4 are 6,6'-dialkylcarboxylate-2,2'-bipyridine ligands), have been obtained, and their crystal structures have been determined by X-ray crystallography. The metal center in all of these compounds has an oversaturated coordination number of 8, which is completed by two neutral homoleptic tetradentate ligands and is unconventional in 3d-metal compounds. These compounds are further characterized by electronic spectroscopy, cyclic voltammetry (CV), and magnetic measurements. CV measurements of these complexes in MeCN solution exhibit rich redox properties. Magnetic measurements on these compounds demonstrate that the observed single-ion magnetic (SIM) behavior in the previously reported [FeII(L1)2](ClO4)2 (1) is not a contingent case, since all of the 8-coordinate compounds 2-8 exhibit interesting slow magnetic relaxation under applied direct current fields. PMID- 29521503 TI - Strategy for O-Alkylation of Serine and Threonine from Serinyl and Threoninyl Acetic Acids by Photoinduced Decarboxylative Radical Reactions: Connection between Serine/Threonine and Carbohydrates/Amino Acids at the Side Chain. AB - O-Alkylations of serine and threonine derivatives at the hydroxy group were achieved using photoinduced decarboxylative radical reactions of serinyl and threoninyl acetic acids with an organic photocatalyst without racemization under mild conditions. Photoinduced decarboxylative radical additions of serinyl and threoninyl acetic acids to electron-deficient alkenes provided linked serine and threonine with carbohydrates and amino acids at the side chain. In addition, O methylations containing deuterium and O-benzylation of serine were performed under similar photochemical conditions. PMID- 29521504 TI - Palladium(II)-Catalyzed Mono- and Bis-alkenylation of N-Acetyl-2-aminobiaryls through Regioselective C-H Bond Activation. AB - We developed palladium-catalyzed oxidative coupling of olefins with N-acyl 2 aminobiaryls through a sequence of ortho C-H bond activation/alkene insertion/reductive elimination. Furthermore, we controlled the selectivity of mono- and bis-alkenylation products with the solvent effect. The developed protocol was promising for a broad substrate scope ranging from activated olefins with a wide variety of functional groups to unactivated olefins. PMID- 29521505 TI - Rovibronic Spectroscopy of Sympathetically Cooled 40CaH. AB - We measure the rovibronic transitions X 1Sigma+, v" = 0, J" -> A 1Sigma+, v' = 0 3, J' of CaH+ and obtain rotational constants for the A 1Sigma+ state. The spectrum is obtained using two-photon photodissociation of CaH+ cotrapped with Doppler cooled Ca+. The excitation is driven by a mode-locked, frequency-doubled Ti:Sapph laser, which is then pulse shaped to narrow the spectral bandwidth. The measured values of the rotational constants are in agreement with ab initio theory. PMID- 29521507 TI - Molecular Imaging of Cholesterol and Lipid Distributions in Model Membranes. AB - Over recent decades, lipid membranes have become standard models for examining the biophysics and biochemistry of cell membranes. Interrogation of lipid domains within biomembranes is generally done with fluorescence microscopy via exogenous chemical probes. However, fluorophores have limited partitioning tunability, with the majority segregating into the liquid-disordered phase, and fluorescence only strictly reports on the small percentage of tagged lipids. We present simple, label-free imaging of domain formation in lipid monolayers, with chemical selectivity in unraveling lipid and cholesterol composition in different domain types. Exploiting conventional vibrational contrast in spontaneous Raman imaging, combined with chemometrics analysis, allows for examination of ternary systems containing saturated lipids, unsaturated lipids, and cholesterol. We confirm features commonly observed by fluorescence microscopy and provide a quantitative thermodynamic analysis of cholesterol distribution at the single-monolayer level. PMID- 29521508 TI - Shining Light on New-Generation Two-Dimensional Materials from a Computational Viewpoint. AB - Energy- and sensing-related applications using two-dimensional (2D) materials with tunable optoelectronic properties have been a hot topic of research. The genres of 2D materials grow every day, leading to new possibilities in optoelectronic devices. In this Perspective, we have discussed in a nutshell several impacts of light-matter interactions in new-generation 2D materials. Using reliable computational approaches, in-depth understanding about the fundamental optical absorption and emission character as well as further prediction of the potential applications for these materials in the field of photovoltaics and sensing have been explored. Various modifications of the parent 2D materials by computational designing with enhanced performance have been investigated to guide the experimental efforts. The major computational challenges and their probable solutions for 2D-material-based optoelectronic research have also been briefly outlined. PMID- 29521506 TI - Systematic Analysis of Fatty Acids in Human Cells with a Multiplexed Isobaric Tag (TMT)-Based Method. AB - Fatty acids (FAs) are essential components in cells and are involved in many cellular activities. Abnormal FA metabolism has been reported to be related to human diseases such as cancer and cardiovascular diseases. Identification and quantification of FAs provide insights into their functions in biological systems, but it is very challenging to analyze them due to their structures and properties. In this work, we developed a novel method by integrating FAs tagged with stable isotope labeled aminoxy tandem mass tags (aminoxyTMTs) and mass spectrometric analysis in the positive mode. On the basis of their structures, the aminoxyTMT reagents reacted with the carboxylic acid group of the FAs, resulting in an amine group with high proton affinity covalently attached to the analytes. This enabled the analysis of FAs under the positive electrospray ionization-mass spectrometry (ESI-MS) mode, which is normally more popular and sensitive compared to the negative mode. More importantly, the multiplexed TMT tags allowed us to quantify FAs from several samples simultaneously, which increased the experimental throughput and quantification accuracy. FAs extracted from three types of breast cells, i.e., MCF 10A (normal), MCF7 (minimally invasive) and MDA-MB-231 (highly invasive) cells, were labeled with the six plexed aminoxyTMTs and quantified by LC-MS/MS. The results demonstrated that the abundances of some FAs, such as C22:5 and C20:3, were markedly increased in MCF7 and MDA-MB-231 cancer cells compared to normal MCF 10A cells. For the first time, aminoxyTMT reagents were exploited to label FAs for their identification and quantification in complex biological samples in the positive MS mode. The current method enabled us to confidently identify FAs and to accurately quantify them from several samples simultaneously. Because this method does not have sample restrictions, it can be extensively applied for biological and biomedical research. PMID- 29521509 TI - Intracellularly Activatable Nanovasodilators To Enhance Passive Cancer Targeting Regime. AB - Conventional cancer targeting with nanoparticles has been based on the assumed enhanced permeability and retention (EPR) effect. The data obtained in clinical trials to date, however, have rarely supported the presence of such an effect. To address this challenge, we formulated intracellular nitric oxide-generating nanoparticles (NO-NPs) for the tumor site-specific delivery of NO, a well-known vasodilator, with the intention of boosting EPR. These nanoparticles are self assembled under aqueous conditions from amphiphilic copolymers of poly(ethylene glycol) and nitrated dextran, which possesses inherent NO release properties in the reductive environment of cancer cells. After systemic administration of the NO-NPs, we quantitatively assessed and visualized increased tumor blood flow as well as enhanced vascular permeability than could be achieved without NO. Additionally, we prepared doxorubicin (DOX)-encapsulated NO-NPs and demonstrated consequential improvement in therapeutic efficacy over the control groups with considerably improved DOX intratumoral accumulation. Overall, this proof of concept study implies a high potency of the NO-NPs as an EPR enhancer to achieve better clinical outcomes. PMID- 29521510 TI - Concentration-Dependent Adsorption of CsI at the Muscovite-Electrolyte Interface. AB - The interfacial structure of muscovite in contact with aqueous CsI solutions was measured using surface X-ray diffraction for several CsI concentrations (2-1000 mM). At CsI concentrations up to 200 mM, Cs+ adsorption is likely hindered by H3O+, as both cations compete for the adsorption site above the muscovite hexagonal cavity. Above this concentration, more Cs+ adsorbs than is required to compensate the negatively charged muscovite surface, which means that coadsorption of an anion takes place. The I- anion does not coadsorb in an ordered manner. Moreover, the hydration ring and water layers do not change significantly as a function of the CsI concentration. PMID- 29521511 TI - Lead-Free Perovskite Nanocrystals for Light-Emitting Devices. AB - Lead halide perovskites with nanoscale geometries have received recent attention due to the defect-tolerant high photoluminescence quantum yield at tunable emission wavelengths and the possibility of room-temperature synthesis that does not compromise the physical properties of the materials. These characteristics offer opportunities to advance displays that cover the widest perceivable color. However, lead toxicity obstructs the commercialization of this technology. Therefore, recent efforts have investigated lead-free halide perovskite nanocrystals. Here, we provide our perspectives on the most exciting achievements in the materials design and photophysical properties of lead-free perovskite nanocrystals, particularly for applications in light-emitting devices. This Perspective includes a short summary on the characteristic features of halide perovskite nanocrystals; discussion on the candidate elements to replace lead; methods to prepare colloidal lead-free perovskite nanocrystals; methods to control and enhance the optical properties; a recent demonstration of utilizing lead-free perovskite nanocrystals in light-emitting devices; and an outlook on the field. PMID- 29521513 TI - Considerations for the cost-effective management of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a neuropsychiatric complication commonly associated with liver disease, namely cirrhosis. The inability of the liver to metabolize ammonia results in a buildup of ammonia, which can cross the blood brain barrier and cause significant neurocognitive impairment. Up to 80% of patients with cirrhosis will experience HE and a large proportion of these patients are at high risk of recurrent HE. There are several factors to consider when developing a cost-effective approach to managing HE, such as patient compliance, the adverse event (AE) profile of drug therapy, efficacy of drug therapy, and relative cost-benefits of drug therapy. Pharmacologic agents used for HE treatment and prevention are commonly associated with gastrointestinal AEs, namely diarrhea. While these AEs are mild in nature, they can be bothersome and lead to patient noncompliance, which increases the patient's risk of HE. Furthermore, the complex dosing schedule and self-titration requirement of lactulose, a first-line agent, can be confusing to a patient. A patient's noncompliance with self-titration may result in underuse, increasing the patient's risk of HE, or overuse, increasing the patient's risk of severe AEs. HE imposes a significant economic burden to the patient, patients' caregivers, healthcare systems, and society. HE not only negatively impacts a patient's morbidity and mortality, but also impacts the patient's psychological and social functioning and overall quality of life. HE can impact the patient's ability to work, resulting in reduced productivity and lost wages. A patient with HE may require hospitalization, which accounts for a substantial proportion of costs associated with HE. Given the social and financial burden of HE, cost-effective management of HE is crucial. Early prevention is important to minimize the societal and economic costs associated with HE. PMID- 29521512 TI - Metabolomics Reveals Aryl Hydrocarbon Receptor Activation Induces Liver and Mammary Gland Metabolic Dysfunction in Lactating Mice. AB - The liver and the mammary gland have complementary metabolic roles during lactation. Substrates synthesized by the liver are released into the circulation and are taken up by the mammary gland for milk production. The aryl hydrocarbon receptor (AHR) has been identified as a lactation regulator in mice, and its activation has been associated with myriad morphological, molecular, and functional defects such as stunted gland development, decreased milk production, and changes in gene expression. In this study, we identified adverse metabolic changes in the lactation network (mammary, liver, and serum) associated with AHR activation using 1H nuclear magnetic resonance (NMR)-based metabolomics. Pregnant mice expressing Ahr d (low affinity) or Ahr b (high affinity) were fed diets containing beta naphthoflavone (BNF), a potent AHR agonist. Mammary, serum, and liver metabolomics analysis identified significant changes in lipid and TCA cycle intermediates in the Ahr b mice. We observed decreased amino acid and glucose levels in the mammary gland extracts of Ahr b mice fed BNF. The serum of BNF fed Ahr b mice had significant changes in LDL/VLDL (increased) and HDL, PC, and GPC (decreased). Quantitative PCR analysis revealed ~50% reduction in the expression of key lactogenesis mammary genes including whey acid protein, alpha-lactalbumin, and beta-casein. We also observed morphologic and developmental disruptions in the mammary gland that are consistent with previous reports. Our observations support that AHR activity contributes to metabolism regulation in the lactation network. PMID- 29521514 TI - Influenza in older patients: a call to action and recent updates for vaccinations. AB - Influenza affects millions of people in the United States each year. Older patients are particularly at risk for infection, hospitalization, and death due to influenza-related complications, such as pneumonia. One of the best ways to avoid becoming ill is to have the annual influenza vaccination. Unfortunately, immunization rates are poor in the older adult population, at about 65% each year. Vaccine effectiveness in this population is reduced because of lower seroconversion rates that arise from poorer immunologic response to vaccination. Several new influenza vaccines that have been introduced to the market in recent years attempt to boost immune response, including high-dose formulations and adjuvanted and recombinant vaccines. Managed care pharmacists need to understand the utility of these new agents in populations 65 years or older. This supplement highlights the impact of influenza on older patients, the features of new vaccine preparations, and the economic burden of influenza. PMID- 29521515 TI - Managed care considerations and economic implications of vaccination practices. AB - Influenza is an acute viral respiratory disease caused by the influenza A and B viruses. The epidemiologic characteristics of influenza are in constant flux as the viruses mutate frequently, and the subsequent spread of illness depends on the affected population's susceptibility to the new antigens. These viral mutations necessitate frequent updates to the annual seasonal influenza vaccine. Those most at risk for serious complications of influenza are young children and elderly persons. Although influenza vaccination rates are highest among adults 65 years or older, vaccine effectiveness in this age group is often less than among younger persons. Thus, vigilance in efforts to increase vaccine uptake is warranted through a concerted effort across the entire healthcare and public health spectrum of providers and agencies, including clinicians, health systems, government, and community agencies. Managed care organizations are an excellent case study for implementing systemwide efforts to prevent influenza disease and its consequences. PMID- 29521516 TI - Understanding functionality of sucrose in biscuits for reformulation purposes. AB - We review the functionality of sucrose during the manufacture of biscuits from the perspective of sugar replacement. Besides to providing sweetness, sucrose has important functionalities concerning structure and texture formation. These functionalities also need to be mimicked in reformulated biscuits. First, we review the hypotheses concerning the development of structure and texture of biscuits during manufacturing, which are conveniently summarized in a qualitative way using the Complex Dispersed Systems methodology. Subsequently, we represent the changes of the state of the biscuit during manufacturing in the supplemented state diagram, which indicates the important phase transitions occurring during mixing and baking. We propose that when reformulated biscuits follow similar paths in the state diagram, similar structures and textures can be obtained. Physical theories exist for predicting these phase transitions for existing sucrose-rich biscuits and also reformulated biscuits containing extensive sweeteners as sugar replacers. More accurate predictions of structure and texture can be eventually obtained if they are combined with computational models, including heat and moisture transfer. PMID- 29521517 TI - The Role of Shoe and Sock Sanitization in the Management of Superficial Fungal Infections of the Feet. AB - Because of the ubiquitous nature of dermatophytes and a lack of an adaptive immune response in the nail plate, recurrence and relapse rates associated with superficial fungal infections are high (10%-53%). Cured or improved dermatophytosis patients could become reinfected if exposed to fungal reservoirs, such as an infected shoe, sock, or textile. To prevent this, footwear, sock, and textile sanitization methods can be used. To provide insight into effective sanitization options, the focus of this article is to review footwear, sock, and textile sanitization studies conducted throughout history (1920-2016). Thirty three studies are covered in this review, encompassing techniques ranging from formaldehyde fumigation and foot powder application, to more modern approaches such as UV light and silver-light irradiation technologies. Older sanitization methods (eg, boiling, use of chlorine and salts) are quite limited in their practicality, as they can result in health complications and ruin shoe integrity. Newer approaches to shoe and sock sanitization, such as ozone application and UV irradiation, have shown very promising results. Further research is still needed with these modern techniques, as knowledge gaps and cost prevent the creation of standardized parameters for successful use. By combining sanitization methods with other preventative measures, protection against reinfection may be enhanced. PMID- 29521518 TI - Communicatively Exploring Uncertainty Management of Parents of Children with Type 1 Diabetes. AB - Parents of children with type 1 diabetes (T1D) face uncertainty about the illness. This uncertainty can have negative health consequences for parents and their children. However, little is known about the types of uncertainty associated with T1D diagnosis and subsequent treatment and how this uncertainty is managed. Using uncertainty management theory (UMT) as a framework and 29 in depth interviews with parents of children with T1D, this study found that parents experienced medical, social, and financial forms of uncertainty. Most parents viewed uncertainty negatively and sought to reduce it by seeking information, joining support groups, and turning to technology. However, some parents preferred uncertainty to the certainty of knowing their child had T1D and, at least initially, chose to maintain uncertainty about the disease by avoiding information. This study also provides practical outcomes that health-care providers can use to help parents of children with T1D reduce and manage uncertainty. PMID- 29521519 TI - Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects. AB - Positron emission tomography and multiparametric MRI provide crucial information concerning tumor extent and normal tissue anatomy. Moreover, they are able to visualize biological characteristics of the tumor, which can be considered in the radiation treatment planning and monitoring. In this review we discuss the impact of biological imaging positron emission tomography and multiparametric MRI for radiation oncology, based on the data of the literature and on the experience of our own institution in this field. PMID- 29521520 TI - Biological imaging for individualized therapy in radiation oncology: part I physical and technical aspects. AB - Recently, there has been an increase in the imaging modalities available for radiotherapy planning and radiotherapy prognostic outcome: dual energy computed tomography (CT), dynamic contrast enhanced CT, dynamic contrast enhanced magnetic resonance imaging (MRI), diffusion-weighted MRI, positron emission tomography-CT, dynamic contrast enhanced ultrasound, MR spectroscopy and positron emission tomography-MR. These techniques enable more precise gross tumor volume definition than CT alone and moreover allow subvolumes within the gross tumor volume to be defined which may be given a boost dose or an individual voxelized dose prescription may be derived. With increased plan complexity care must be taken to immobilize the patient in an accurate and reproducible manner. Moreover the physical and technical limitations of the entire treatment planning chain need to be well characterized and understood, interdisciplinary collaboration ameliorated (physicians and physicists within nuclear medicine, radiology and radiotherapy) and image protocols standardized. PMID- 29521521 TI - Positive affect mediates the relationships between resilience, social support and posttraumatic growth of women with infertility. AB - This study aims to explore the relationship between resilience, social support, positive affect and posttraumatic growth among Chinese women with infertility, and to examine the mediating role of positive affect. A convenience sample of 1733 women diagnosed with infertility was recruited from the infertility outpatient clinics at three reproductive hospitals in Shandong Province of China between May 2015 and April 2016. They completed a background questionnaire, the Posttraumatic Growth Inventory, the Perceived Social Support Questionnaire, the Connor-Davidson Resilience Scale, the Positive and Negative Affect Schedule. Individuals reported high levels of PTG (M = 64.81; SD = 16.20). Perceived social support (beta = .11, p < .001), resilience (beta = .18, p < .001) and positive affect (beta = .46, p < .001) were related to PTG. Positive affect may play a mediating role in the relationships between resilience (.125, .201, p < .001), social support (.055, .121, p < .001) and PTG. This study examines the effects of resilience, social support, and positive affect on PTG among Chinese infertile women. Wherein, positive affect may play a mediating role in the relationships between resilience, social support and PTG. PMID- 29521522 TI - Maintaining Sexual Desire in Long-Term Relationships: A Systematic Review and Conceptual Model. AB - The most universally experienced sexual response is sexual desire. Though research on this topic has increased in recent years, low and high desire are still problematized in clinical settings and the broader culture. However, despite knowledge that sexual desire ebbs and flows both within and between individuals, and that problems with sexual desire are strongly linked to problems with relationships, there is a critical gap in understanding the factors that contribute to maintaining sexual desire in the context of relationships. This article offers a systematic review of the literature to provide researchers, educators, clinicians, and the broader public with an overview and a conceptual model of nonclinical sexual desire in long-term relationships. First, we systematically identified peer-reviewed, English-language articles that focused on the maintenance of sexual desire in the context of nonclinical romantic relationships. Second, we reviewed a total of 64 articles that met inclusion criteria and synthesized them into factors using a socioecological framework categorized as individual, interpersonal, and societal in nature. These findings are used to build a conceptual model of maintaining sexual desire in long-term relationships. Finally, we discuss the limitations of the existing research and suggest clear directions for future research. PMID- 29521524 TI - Relationship Between Exposure to Direct-To-Consumer Prescription Drug Advertising (DTCA) and Patients' Belief Accessibility and Medication Adherence. AB - One of the most frequent and strong arguments for supporting direct-to-consumer prescription drug advertising (DTCA) as a positive influence on individuals and society is that DTCA could contribute to improving patients' medication adherence, but systematic empirical research testing this proposed effect is scant. To address this gap and provide an answer to the unresolved question about DTCA effects, this study examined the relationship between overall DTCA exposure and patients' medication adherence through the mechanism of media priming effect increasing medication-related belief accessibility. Results from a survey with a sample of prescription blood thinner takers revealed no significant relationships between DTCA exposure and patients' belief accessibility regarding their medical conditions and drug benefits and risks, and no support for the hypothesized relationship between DTCA exposure and medication adherence. The findings are discussed within the context of DTCA effect research literature, and theoretical and practical implications are presented. PMID- 29521523 TI - MGMT pyrosequencing-based cut-off methylation level and clinical outcome in patients with glioblastoma multiforme. AB - AIM: MGMT promoter methylation has been associated with improved survival in glioblastoma multiforme treated with temozolomide. However, there is no consensus on specific cut-off levels of methylation. The aims of the study were to explore the prognostic impact of MGMT methylation status and to analyze the role of specific cut-off values. MATERIALS & METHODS: We analyzed 108 glioblastoma multiforme patients treated between 2008 and 2013 stratified according to three pyrosequencing-based quantitative methylation in: unmethylated (methylation <9%), intermediate (9-29%) and highly methylated (>29%). RESULTS: The three-class stratification has a prognostic impact (median progression-free survival: 7.97, 11.6 and 15 months respectively; p = 0.004; median OS: 13.2, 15.8 and 19.5 months, respectively; p = 0.0002), especially in patients exposed to temozolomide. CONCLUSION: Our study confirmed that the independent prognostic role of MGMT methylation status. An average level of methylation between all investigated CpGs of 9% may help discriminating between methylated and unmethylated tumors. PMID- 29521525 TI - Neural correlates of children's emotion understanding. AB - This study aimed to develop an EEG paradigm to identify neural correlates of emotion understanding in children. In Experiment 1, children took part in an emotional story task. In Experiment 2, children completed an emotional task and a physical story task Late Positive Potentials (LPP) were demonstrated in response to emotional content in both studies. Together, The study demonstrates the potential value of the LPP as a flexible probe for studying children's emotion understanding and encourages further work into the specificity versus generality of cognitive processes underpinning the LPP in social information processing. PMID- 29521526 TI - CD59: a promising target for tumor immunotherapy. AB - CD59 has been identified as a glycosylphosphatidylinositol-anchored membrane protein that acts as an inhibitor of the formation of the membrane attack complex to regulate complement activation. Recent studies have shown that CD59 is highly expressed in several cancer cell lines and tumor tissues. CD59 also regulates the function, infiltration and phenotypes of a variety of immune cells in the tumor microenvironment. Herein, we summarized recent advances related to the functions and mechanisms of CD59 in the tumor microenvironment. Therapeutic strategies that seek to modulate the functions of CD59 in the tumor microenvironment could be a promising direction for tumor immunotherapy. PMID- 29521527 TI - Sex With Chinese Characteristics: Sexuality Research in/on 21st-Century China. AB - This article examines the changing contours of Chinese sexuality studies by locating recent research in historical context. Our aim is to use the literature we review to construct a picture of the sexual landscape in China and the sociocultural and political conditions that have shaped it, enabling readers unfamiliar with China to understand its sexual culture and practices. In particular, we focus on the consequences of recent changes under the Xi regime for individuals' sexual lives and for research into sexuality. While discussing the social and political regulation of sexuality, we also attend to the emergence of new forms of gendered and sexual subjectivity in postsocialist China. We argue throughout that sexuality in China is interwoven with the political system in a variety of ways, in particular through the tension between neoliberal and authoritarian styles of governance. We explore normative and dissident sexualities as well as forms of sexual conduct that are officially "deviant" but nonetheless tolerated or even tacitly enabled by the party-state. In particular, we highlight the dilemmas and contradictions faced by China's citizens as they negotiate their sexual lives under "socialism with Chinese characteristics." PMID- 29521528 TI - Coverage of Antimicrobial Resistance in the German Press: 1993-2013. AB - The present study explores the coverage of antimicrobial resistance (AMR) and its associated risks in the German press between 1993 and 2013. Using quantitative content analysis, we explored the corpus of newspaper articles to evaluate the quality of risk reporting. Our findings show an overall increase in the quality of risk-related information: articles contain more substantiating statements describing objectively cognizable phenomena with absolute numbers, prevalences, estimations, and tendencies over time. There is also an increase in the level of precision of such statements. On the other hand, the results suggest that there is little contextualization of risk information and mortality data is often communicated in absolute numbers, which makes it harder to understand and interpret the information. While the debate about the risks of AMR is led by the scientific community, the overall tone of the coverage is alarmist, which can result in growing skepticism of scientific expertise. PMID- 29521529 TI - Anti-inflammatory activities of the chemical constituents isolated from Trametes versicolor. AB - Twenty-seven compounds including nine triterpenoids (1-9), eight sterols (10-17), two ribonucleotides (18, 19), four phenols (20-23), three glycosides (24-26), and one furan (27) were isolated from the fruiting bodies of Trametes versicolor (L.) Lloyd. This study is the first confirmation of the presence of the 11 compounds (3, 5, 6, 8, 18, 20, 21, 23-25, and 27) isolated from the Polyporaceae family, with six of these (2 and 12-16) from the genus Trametes. Compounds 3, 4, 10, 11, 16 and 17 were found to significantly inhibit the production of NO, TNF-alpha and IL-6 in a dose-dependent manner. PMID- 29521530 TI - Objectifying or Liberating? Investigation of the Effects of Sexting on Body Image. AB - Scholars are divided as to whether sexting-an unprecedented sexual activity using digital media-is objectifying or sexually liberating. One notion is that sexting involves the representation of an individual's sexuality in the presence of others and thus reinforces objectification. Another perspective contends that the self-portrayal of the body in sexting facilitates the exploration of sexual subjectivity and is, therefore, sexually liberating. By testing a model of sexting, objectified body consciousness (body surveillance, body shame, and body control beliefs), and comfort with nudity (indicator of sexual liberation) on 361 college students in Hong Kong, the current study revealed that, across genders, sexters demonstrated higher levels of body surveillance, body shame, and comfort with nudity than nonsexters. The results suggest that sexting is both sexually objectifying and liberating and that it has opened up a new sexual arena that combines sexual objectification and empowerment. PMID- 29521531 TI - Effects of Substance Cues in Negative Public Service Announcements on Cognitive Processing. AB - This study examined how the presence of substance cues interacted with arousing content level in public service announcements (PSAs) to affect human motivational activation, and as a result, affect cognitive information processing. A 2 (arousing content level: high vs. low arousing content fear appeal PSAs) * 2 (substance cue: absence vs. presence) * 4 (repetition) within-subject factorial design experiment was conducted. Overall, the results indicated that the presence of substance cues in high arousing content fear appeal messages elicited defensive processing, yielding poor audio recognition memory sensitivity and a more conservative criterion bias. However, the addition of substance cues to low arousing content fear appeal messages increased audio recognition sensitivity. The presence of substance cues decreased visual recognition regardless of the arousing content level. Implications and future research are discussed. PMID- 29521533 TI - Classification accuracy of individual and combined executive functioning embedded performance validity measures in mild traumatic brain injury. AB - The development of more sophisticated performance validity measures is important due to concerns with coaching as well as providing clinicians with a greater variety of options when assessing performance validity. Examinees with noncredible performance may find it more difficult to elude detection by PVTs derived from arithmetical summation or logistic regression. The present study evaluated the classification accuracy of several executive functioning (EF) variables as PVTs both individually and when combined into derived variables. The current study evaluated a simple mathematic summation of embedded PVT scores and a logistic regression-based formula based on embedded PVTs from executive function measures. A total of 155 consecutive patients completed neuropsychological evaluation after sustaining a mild traumatic brain injury (MTBI) were studied and were placed into a PVT-PASS (N = 95, mean age = 44.9, SD = 12.55, mean education = 13.45, SD = 2.23, 38% male, 97% Caucasian) or PVT-FAIL group (N = 60, mean age = 44.1, SD = 15.47, mean education = 13.05, SD = 2.58, 55% male, 92% Caucasian). Trail Making Test B, Wisconsin Card Sorting Test, and Stroop Color Word Test were summed and also used in logistic regression to predict whether patients had credible performance. Both the mathematical summation and the logistic regression methods achieved excellent classification accuracy (summation AUC = .79; logistic regression AUC = .82) with higher sensitivity than individual PVTs. PMID- 29521534 TI - The Prognostic Nutrition Index Predicts the Development of Hematological Toxicities in and the Prognosis of Esophageal Cancer Patients Treated with Cisplatin Plus 5-Fluorouracil Chemotherapy. AB - The prognostic nutrition index (PNI), calculated based on serum albumin and lymphocyte counts, predicts the prognosis of several cancers, including operated esophageal cancers. In this study, we determined whether PNI could predict the occurrence of severe adverse events by chemotherapy and chemoradiotherapy, and overall survival in esophageal cancer. We collected data from 191 patients with esophageal cancer treated with at least one course of cisplatin and 5 fluorouracil from 2005 to 2016. We compared the incidences of severe adverse events and overall survival between a high- and a low-PNI group. The optimal cut off value of the Onodera PNI was 43.2. Patients with low PNIs suffered more frequent severe adverse events than did those with high PNIs, and the latter patients survived longer. The PNI was independently prognostic of overall survival and stage. The PNI predicted the development of severe adverse events caused by chemotherapy or chemoradiotherapy, and overall survival, in esophageal cancer patients. PMID- 29521532 TI - Cortical Responses to Chinese Phonemes in Preschoolers Predict Their Literacy Skills at School Age. AB - We investigated whether preschoolers with poor phonological awareness (PA) skills had impaired cortical basis for detecting speech feature, and whether speech perception influences future literacy outcomes in preschoolers. We recorded ERP responses to speech in 52 Chinese preschoolers. The results showed that the poor PA group processed speech changes differentially compared to control group in mismatch negativity (MMN) and late discriminative negativity (LDN). Furthermore, speech perception in kindergarten could predict literacy outcomes after literacy acquisition. These suggest that impairment in detecting speech features occurs before formal reading instruction, and that speech perception plays an important role in reading development. PMID- 29521535 TI - Injury risk functions for frontal oblique collisions. AB - OBJECTIVE: The objective of this article was the construction of injury risk functions (IRFs) for front row occupants in oblique frontal crashes and a comparison to IRF of nonoblique frontal crashes from the same data set. METHOD: Crashes of modern vehicles from GIDAS (German In-Depth Accident Study) were used as the basis for the construction of a logistic injury risk model. Static deformation, measured via displaced voxels on the postcrash vehicles, was used to calculate the energy dissipated in the crash. This measure of accident severity was termed objective equivalent speed (oEES) because it does not depend on the accident reconstruction and thus eliminates reconstruction biases like impact direction and vehicle model year. Imputation from property damage cases was used to describe underrepresented low-severity crashes-a known shortcoming of GIDAS. Binary logistic regression was used to relate the stimuli (oEES) to the binary outcome variable (injured or not injured). RESULTS: IRFs for the oblique frontal impact and nonoblique frontal impact were computed for the Maximum Abbreviated Injury Scale (MAIS) 2+ and 3+ levels for adults (18-64 years). For a given stimulus, the probability of injury for a belted driver was higher in oblique crashes than in nonoblique frontal crashes. For the 25% injury risk at MAIS 2+ level, the corresponding stimulus for oblique crashes was 40 km/h but it was 64 km/h for nonoblique frontal crashes. CONCLUSIONS: The risk of obtaining MAIS 2+ injuries is significantly higher in oblique crashes than in nonoblique crashes. In the real world, most MAIS 2+ injuries occur in an oEES range from 30 to 60 km/h. PMID- 29521536 TI - Autism Narratives in Media Coverage of the MMR Vaccine-Autism Controversy under a Crip Futurism Framework. AB - While previous studies in health communication have examined online news media regarding autism, there is a lack of research that critically examines how such media representations may stigmatize autism and seeks to eliminate the condition, particularly in the context of the resurging measles, mumps, and rubella (MMR) vaccine-autism controversy. To address this gap in the literature, this study analyzes 153 articles that engage the MMR vaccine-autism controversy from the top 10 online news sources in the U.S. from September 2015 through July 2017. It draws from Kafer's (2013) work in Feminist, Crip, Queer, using a lens of crip futurism to interpret three major narrative themes: a death and survival narrative that purports autism as a worst-case scenario, a societal problem narrative, and a preventative narrative that seeks to eliminate the condition. These themes suggest that online news media narratives about autism surrounding the autism-MMR controversy play into stereotypes about autism, including stigmatization and prioritization of preventive behaviors and cures over supporting the lived experiences of autistic individuals. Continued research on the impact of online media portrayals of autism specifically, and disability in health contexts generally, is called for. PMID- 29521537 TI - A Foundation Funding Frontier. PMID- 29521539 TI - Erratum. PMID- 29521540 TI - Summary: FASEB Science Research Conference on Protein Aggregation in Health and Disease. PMID- 29521541 TI - A retrospective analysis of the clinical efficacies and recurrence of Q-switched Nd:YAG laser treatment of nevus of Ota in 224 Chinese patients. AB - BACKGROUND: Nevus of Ota can be treated successfully using the Q-switched (QS) laser; but few studies are long-term retrospective of the efficacy and influencing factor, studies on the recurrence is even less. PURPOSE: Retrospective analysis of the clinical characteristics and recurrence of QS Nd:YAG laser treatment of nevus of Ota in 224 Chinese patients at Laser Cosmetology Center of Department of Dermatology, the Second Hospital, Xi'an Jiaotong University. METHODS: The data of 224 patients with nevus of Ota were analyzed retrospectively, which included the correlation among lesion color, treatment sessions, gender, age, lesion types and effect, and all patients were followed up for 2-10 years. RESULTS: Higher number of treatment sessions that were conducted using the QS Nd:YAG laser system was positively associated with better responses to treatment. 99.11% of patients acquired more than 75% improvement with an average of 3.7 sessions. Only eight patients (3.57%) who had been completely cleared developed recurrence at the same site as before. CONCLUSION: The treatment of nevus of Ota with QS Nd:YAG laser is safe and effective with rare recurrence. PMID- 29521542 TI - Ocular Permeation and Sustained Anti-inflammatory Activity of Dexamethasone from Kaolin Nanodispersion Hydrogel System. AB - PURPOSE: Kaolin can adhere to the mucosa and protect it by absorbing toxins, bacteria, and viruses. Ocular delivery and anti-inflammatory activity of dexamethasone hydrogel system could be advantageous after kaolin incorporation. METHODS: Hydroxypropyl methylcellulose (HPMC) films of dexamethasone have been prepared without and with kaolin by solvent casting method. Differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and scanning electron microscopy (SEM) were utilized for evaluating thermal property, crystallinity, and morphology of the film preparations respectively. In vitro drug release and corneal permeation ex vivo were carried out in phosphate buffer saline of pH 7.4 (PBS) at 34 +/- 0.5 degrees C for 6 h. Anti inflammatory effect of the prepared film was evaluated using carrageenan induced rabbit eye. RESULTS: Disappearance of melting endotherm in the DSC thermogram is the indication of almost complete amorphization of drug in all the films. High-intensity reflections with characteristic peaks of pure drug crystal have resulted extensively reduced ordering of the crystal lattice in the X-ray pattern of all the films. Photomicrographs revealed that the plate-shaped geometry of the drug crystal has almost been lost in absence and presence of the nano-kaolin particles in the films. Kaolin incorporation controlled the drug release up to 6 h. Ocular permeation was diffusion controlled and extended for 6 h or more without exhibiting significant "Burst effect". Adsorption of drug onto the surface of nano-kaolin prolonged the permeation due to cation exchange and hydrogen bonding. Signs of inflammation of the carrageenan induced rabbit eye have been disappeared almost completely after 2 h of film application. CONCLUSIONS: Local controlled delivery sustained anti-inflammatory activity of dexamethasone has been achieved using kaolin incorporated HPMC film. PMID- 29521543 TI - Long-term exercise restores hydrogen sulfide in the kidney and contributes to exercise benefits in 5/6 nephrectomized rats. AB - Physical exercise is shown to have protective effects on chronic kidney disease (CKD). CKD itself is associated with a reduction in renal hydrogen sulfide (H2S) concentration. This study was designed to investigate whether protective effects of exercise in 5/6 nephrectomized (5/6 NX) rats is associated with H2S levels in the kidney? Twenty four male Wistar rats weighing 250-300 g were assigned into 4 groups: 1- Sham 2- Sham exercise 3-5/6 NX 4-5/6 NX+exercise. To induce CKD, 4 days after removing upper and lower one-third parts of the left kidney, total right nephrectomy was performed. In the Sham groups, anesthesia and surgery were performed like the other groups without removal of the kidney mass. Exercise was performed by treadmill at a speed of 18 m/min for 8 weeks. At the end of the twelfth week, blood and kidney samples were collected to measure renal function (levels of plasma urea and creatinine), oxidative stress markers (renal MDA level and SOD activity), and histological indices. Eight weeks exercise significantly improved serum creatinine, BUN, renal MDA level, SOD activity, renal sympathetic nerve activity (RSNA), hypertension, and renal histology in addition to renal H2S level compared to the 5/6 NX group. The results suggest that regular exercise improves renal oxidative status and ameliorates renal damage, hypertension, and RSNA in 5/6 nephrectomized rats. These improvements by exercise might be associated with the increase in renal H2S level. PMID- 29521544 TI - Evaluation of Nurse Practitioner Strategies to Promote Adherence to Childhood Obesity Clinical Guidelines. AB - The significant trend of the obesity epidemic leading to treatment of expensive, lifelong illnesses, especially among Hispanic children, confirms the need for efforts to increase provider adherence to clinical guidelines. This Quality Improvement Project was designed to examine how a practice intervention influenced provider adherence to childhood obesity guidelines among Hispanic children. The practice intervention, based on a unique practice model, consisted of provider awareness, provider involvement, and collaborative support by the researcher. Statistically significant results were obtained regarding guideline adherence. The practice model developed for implementing guidelines in this study will be of benefit to other clinicians. The main project outcome was that the model resulted in significant changes in practice patterns and increased provider adherence to aspects of childhood obesity clinical guidelines. The Practice Improvement Model should be replicated in other settings to evaluate its contribution to improved adherence to any clinical practice guideline. PMID- 29521545 TI - Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Promising Medication for Chronic Obstructive Pulmonary Disease? AB - Chronic obstructive pulmonary disease (COPD) is a complex disorder that primarily affects the lungs and is characterized not only by local pulmonary, but also by systemic inflammation which promotes the development of extrapulmonary and cardiovascular co-morbidities. Angiotensin converting enzyme (ACE) inhibitors and ARBs (angiotensin receptor blockers) are widely used drugs in the treatment of cardiovascular diseases, with growing evidence suggesting potential benefits in COPD patients. The purpose of this review is to describe the correlation of renin angiotensin system (RAS) with COPD pathophysiology and to present the latest data regarding the potential role of RAS blockers in COPD. PMID- 29521547 TI - Reference intervals of aortic pulse wave velocity assessed with an oscillometric device in healthy children and adolescents from Argentina. AB - Age-related reference intervals (RIs) of aortic pulse wave velocity (Ao-PWV) obtained from a large healthy population are lacking in South America. The aims of this study were to determine Ao-PWV RIs in a cohort of healthy children and adolescents from Argentina and to generate year-to-year percentile curves. Ao-PWV was measured in 1000 healthy subjects non-exposed to traditional cardiovascular risk factors (Age: 10-22 y. o., 56% males). First, we evaluated if RIs for males and females were necessaries (correlation and covariate analysis). Second, mean (M) and standard deviation (SD) age-related equations were obtained for cf-PWV, using parametric regression methods based on fractional polynomials. Third, age specific (year to year) percentiles curves (for all, males and females children and adolescents) were generated using the standard normal distribution. They were, age-specific 1st, 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, 97.5th and 99th percentile curves and values. After covariate analysis (i.e., adjusting by age, jugulum-symphysis distance, body weight and height), specific RIs for males and females of children and adolescents were evidenced as necessaries. The equations were For all subjects: Ao-PWV_Mean = 4.98 + 12.86x10-5 Age3. Ao-PWV_SD = 0.47 + 21.00x10-6Age3. For girls: Ao-PWV_Mean = 5.07 + 10.23x10-5Age3. Ao PWV_SD = 0.50 + 10.00x10-6Age3. For boys: Ao-PWV_Mean = 4.87 + 15.81x10-5Age3. Ao PWV_SD = 0.46 + 22.34x10-6Age3. Our study provides the largest database to-date concerning Ao-PWV in healthy children and adolescents in Argentina. Age-related equations (M and SD values) for Ao-PWV are reported by the first time. Specific RIs and percentiles of Ao-PWV are now available according to age and sex for an Argentinian population. PMID- 29521546 TI - Collagen type VI interaction improves human islet survival in immunoisolating microcapsules for treatment of diabetes. AB - Collagens are the most abundant fibrous protein in the human body and constitute the main structural element of the extracellular matrix. It provides mechanical and physiological support for cells. In the pancreas, collagen VI content is more than double that of collagen I or IV. It is a major component of the islet exocrine interface and could be involved in islet-cell survival. To test the impact of collagen VI on human encapsulated pancreatic islets-cells, we tested the effects of exogenous collagen type VI on in vitro functional survival of alginate encapsulated human islet-cells. Concentrations tested ranged from 0.1 to 50 ug/ml. Islets in capsules without collagen type VI served as control. Islet cell interaction with collagen type VI at concentrations of 0.1 and 10 ug/ml, promoted islet-cell viability (p<0.05). Although no improvement in glucose induced insulin secretion (GSIS) was observed, islets in capsules without incorporation of collagen type VI showed more dysfunction and oxygen consumption rates was improved by inclusion of collagen type VI. Our results demonstrate that incorporation of collagen type VI in immunoisolated human islets supports in vitro viability and survival of human pancreatic islets. PMID- 29521548 TI - Longitudinal in vivo intrinsic optical imaging of cortical blood perfusion and tissue damage in focal photothrombosis stroke model. AB - A thorough understanding of the spatiotemporal dynamics of blood supply and tissue viability is of great importance in stroke researches. In the current study, vascular and cellular responses to focal ischemia were monitored with optical coherence tomography on chronic rat photothrombotic stroke model. The 3D mapping of blood perfusion and cellular scattering were achieved by analyzing the temporal dynamics and depth attenuation of intrinsic backscattered light respectively. Optical coherence tomography revealed that vessels of different types presented various spatial and temporal dynamics during the photothrombotic occlusion and the later recovery period. The large distal middle cerebral arteries presented a spontaneous recanalization and the small pial microvessels presented a reperfusion along with newly appeared vessels from the peripheral into the core area. The cortical capillary perfusion presented a weak recovery. Compared to the male group, the female rats showed a faster vascular recovery after photothrombotic. Moreover, the dynamic changes of the cellular scattering signal showed a high spatial and temporal correlation with the cortical capillary perfusion. Combined with well-designed photothrombotic stroke model and chronic optical window, optical coherence tomography imaging offers a unique approach to improve the understanding of stroke procedure and evaluate the treatment outcomes. PMID- 29521549 TI - Cardiac adenovirus-associated viral Presenilin 1 gene delivery protects the left ventricular function of the heart via regulating RyR2 function in post-ischaemic heart failure. AB - Post-ischaemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischaemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post ischaemic heart failure. Adeno-associated viral PSEN1 gene delivery elevated PSEN1 protein expression in a post-infarction rat heart failure model, and this administration normalised the contractile dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca2+ handling and function. Moreover, PSEN1 gene transfer to failing cardiomyocytes reduced sarcoplasmic reticulum (SR) Ca2+ leak, thereby restoring the diminished intracellular Ca2+ transients and SR Ca2+ load. Moreover, PSEN1 gene transfer reversed the phosphorylation of RyR2 in failing cardiomyocytes. However, selective autophagy inhibition did not prevent the PSEN1-induced blockade of RyR2 degradation, making the participation of autophagy in PSEN1-associated RyR2 degradation unlikely. Our results established a role of the cardiac expression of PSEN1 with AAV9 vectors as a promising therapeutic approach for post-ischaemic heart failure. PMID- 29521550 TI - Aldehyde dehydrogenases and the hypothesis of a glycolaldehyde shunt pathway of photorespiration. AB - Aldehyde dehydrogenase enzymes (ALDHs) catalyse the oxidation of a broad range of aliphatic and aromatic aldehydes to their corresponding carboxylic acids using NAD+ or NADP+ as cofactors. In our article published in Scientific Reports, we demonstrated that mutations in Arabidopsis ALDH3I1 and ALDH7B4 genes altered the cellular contents of NAD(P)H, the total as well as the reduction state of glutathione; and decreased the efficiency of photosynthesis, thus placing ALDH activity as an important source of reducing power for cellular redox homeostasis. Our results also revealed that the ALDHs contribute to the reducing power required for the nitrate assimilation. Here, we discussed and elucidated the innovative hypothesis of the glycolaldehyde shunt pathway of photorespiration that would involve ALDHs generating in contrast to the known core photorespiration reactions, a net gain of two moles of NAD(P)H to support nitrate assimilation, glutathione homeostasis and ROS detoxification. PMID- 29521551 TI - Effect of Dial-Out Prefix Change on 9-1-1 Calls at a Large State University. AB - BACKGROUND: Accessing the emergency medical services system via 9-1-1 operators is an effective way for patients to seek urgent health care; however, technological advances and telecommunication practices inundate the 9-1-1 and emergency services infrastructure with unintentional calls that delay response efforts to legitimate medical emergencies. OBJECTIVE: To determine whether the change in university-wide dial-out prefix from "9" to "7" reduced unnecessary calls to a 9-1-1 call center. METHODS: This is a retrospective study conducted utilizing information obtained from the University of North Carolina at Chapel Hill (UNC) Department of Public Safety (DPS) call center. Call center calls received during pre-change, intervening, and post-change periods were included in the study. The cost savings, defined in time and money, resulting from the prefix change were also examined. RESULTS: A total of 33,646 calls were made during the study period (January 11, 2010 through December 31, 2012) and included in the analysis. The prefix change was found to reduce the rate of invalid calls to the call center by 319 calls per month, resulting in a 43% reduction in total calls to the call center while preserving the rate of valid calls. The largest decrease occurred in hang-up calls (a decrease of 232 calls per month), especially those originating from the university. The prefix change was found to save the UNC DPS telecommunications division approximately $798.82 per month and the police officer division approximately $3,874.95 per month. CONCLUSION: A prefix change was not only beneficial to the UNC community but it also has potentially wide reaching effects. A reduction of invalid 9-1-1 calls translates to telecommunicators having more time available to handle true emergencies, phone lines remaining available for true emergencies, and police officers dedicating more time and effort to matters that necessitate officer assistance. Based on the call decrease seen with the prefix change, this study may be used as evidence to advocate for a change of dial-out codes beginning with "9." PMID- 29521552 TI - Factors associated with hospital admission in adult patients with asthma exacerbations: A systematic review. AB - OBJECTIVES: A variable proportion of patients presenting to the emergency department (ED) with acute asthma require admission to hospital. Previous studies have identified select factors associated with admission following ED presentation; however, no review has synthesized the evidence in this regard. This systematic review summarizes the evidence regarding factors associated with hospital admission following ED presentation. METHODS: Searches were conducted in seven electronic databases and common sources of grey literature. Studies reporting disposition for adults after ED presentation were included. Admission proportions and factors associated with hospitalization that remained statistically significant in multivariable analyses (p < 0.05) were reported. RESULTS: Out of an initial 5865 identified articles, 15 articles met full inclusion criteria and 11 were included in the analyses. Female sex (n = 2) and older age (n = 2) were individual factors associated with admission. Patient vital signs and severity followed by patient attributes were the two most frequent domains associated with admission. Admission proportions were analyzed in 10 studies at an median of ~20% with no clear change between 1996 and 2012. CONCLUSIONS: Factors such as patient demographics (e.g., female sex, older age), patient vital signs/severity, and history are associated with admission following ED presentation for acute asthma. These can be employed by ED clinicians to effectively discern patients at high risk for admission and lead to more evidence based decision-making. PMID- 29521553 TI - Exploring accounts of collaborative working between speech and language therapists and stroke association communication support coordinators following stroke. AB - In the United Kingdom, speech and language therapists (SLTs) and Stroke Association communication support coordinators (CSCs) are both employed to provide services for people with communication difficulties following stroke. There is very little literature of this type of collaborative working. This research is unique because it explores collaborative working between SLTs who are employed by the National Health Service and CSCs who are employed by the Stroke Association. Five CSCs and seven SLTs from the East of England participated in a series of in-depth interviews. Data were analysed using thematic analysis informed by an interpretative phenomenological approach. The analysis suggested complex negotiation processes occur at a number of different levels. These levels include negotiation of individual relationships between SLTs and CSCs, negotiating the particular challenges involved in working across organisations and professions, and the need for both roles to negotiate and promote the value of their services at a societal level. The findings of this research are discussed in relation to existing theories and research within the field of collaborative working. Clinical applications are suggested for collaborative working within communication services. We propose that our findings may have relevance to other individuals and organisations delivering services collaboratively. PMID- 29521554 TI - Improving medication appropriateness in nursing home residents by enhancing interprofessional cooperation: A study protocol. AB - Polypharmacy in elderly people is an increasing challenge for health professionals. Drug-Drug interactions, dosing or administration errors can cause preventable incidents and hospitalizations. Due to chronic illness and multi morbidity, older people are considered as a particularly vulnerable group of patients. Furthermore, it is well known that communication between health professionals is often insufficient. The aim of this study is to improve the appropriateness of medication of nursing home residents by establishing a long term structured medication review process and to enhance the interprofessional communication between general practitioners (GPs), nurses and pharmacists. GPs review and adapt medication of residents, nurses perform structured monitoring of residents for drug-related symptoms. Pharmacists check the appropriateness of prescribed therapy by performing a medication analysis. For this purpose, a special electronic platform (SiM-Pl) is developed to extend the original health documentation system with additional tools. SiM-Pl enables participants to gain access to relevant information regardless of time and place and shall facilitate health documentation and exchange of information. All involved health professionals receive a topic-related, specific education. The study is designed as a non-randomized, controlled trial. Health-related benefits and improved quality of life are expected for the participating residents. PMID- 29521555 TI - Improving surgical outcome for gliomas with intraoperative mapping. AB - INTRODUCTION: Radical glioma resection improves overall survival, both in low grade and high-grade glial tumors. However, preservation of the quality of life is also crucial. Areas covered: Due to the diffuse feature of gliomas, which invade the central nervous system, and due to considerable variations of brain organization among patients, an individual cerebral mapping is mandatory to solve the classical dilemma between the oncological and functional issues. Because functional neuroimaging is not reliable enough, intraoperative electrical stimulation, especially in awake patients benefiting from a real-time cognitive monitoring, is the best way to increase the extent of resection while sparing eloquent neural networks. Expert commentary: Here, we propose a paradigmatic shift from image-guided resection to functional mapping-guided resection, based on the study of the dynamic distribution of delocalized cortico-subcortical circuits at the individual level, i.e., the investigation of brain connectomics and neuroplastic potential. This surgical philosophy results in an improvement of both oncological outcomes and quality of life. This highlights the need to reinforce the link between glioma surgery and cognitive neurosciences. PMID- 29521556 TI - Factors influencing physiotherapists' attitudes and beliefs toward chronic low back pain: Impact of a care network belonging. AB - OBJECTIVES: To assess the attitudes and beliefs of physiotherapists (PTs) regarding the management of chronic LBP and to investigate the factors which influence them. METHODS: A cross-sectional study conducted in the French Loire Valley region by a questionnaire sent to the private PTs between June and September 2014. Demographic data and modalities of practices were collected in association with the Pain Attitudes and Beliefs Scale (PABS) which is a specific self-administered questionnaire designed to assess the "biomedical" or "behavioral" (i.e., biopsychosocial) management orientation of PTs toward chronic LBP. RESULTS: One hundred and sixty-eight of the 704 PTs entirely completed the questionnaire (63% of men, 58% >40 years of age) of whom 15 were involved in a LBP care network. A higher biomechanical score was observed with a higher age and lower with full-time employment, less than 20 years of length of practice and a recent LBP-specific training (p < 0.005). Belonging to a LBP care network was associated with a lower biomedical score (p < 0.01) and a higher biopsychosocial score (p < 0.005). CONCLUSIONS: Belonging to a LBP care network, which implies closer collaboration with multidisciplinary rehabilitation teams, was the most significant factor associated with higher biopsychosocial beliefs in PTs toward chronic LBP management. PMID- 29521557 TI - Complete Oral Nutritional Supplements: Dietitian Preferences and Clinical Practice. AB - Oral nutritional supplements (ONS) are frequently prescribed for those at risk of malnutrition. Palatability is an important factor in long-term compliance. ONS selection is typically dietitian led, but the degree to which individual perceptions of palatability influence dietitian clinical decision making is unclear. This study aimed to explore factors that influence dietitians' ONS clinical practice, evaluate dietitian hedonic preferences and overall impression of specific ONS products, and study phenylthiocarbamide (PTC) sensitivity in relation to ONS hedonic ratings. Dietitians were recruited from six urban teaching hospitals. They completed a 10-item Clinical Practices Questionnaire prior to taste testing five samples of three ONS products. A 7-point hedonic Likert scale recorded ONS palatability ratings. A PTC test was conducted. Thirty one dietitians were recruited. Nutritional value, patient palatability, patient acceptability, tolerance and hospital contracts were the factors identified as most likely to influence ONS prescription. All ONS were consistently highly rated for overall impression. The high-protein ONS was most highly rated for all hedonic characteristics. Taste was the highest rated hedonic characteristic across all products. No statistically significant relationship was found between PTC sensitivity and ONS overall impression. The key drivers of ONS dietitian clinical practice were identified. ONS hedonic characteristics and overall impression were highly rated, which suggested this range of products had wide appeal for dietetic professionals. The taste and consistency of the ONS were rated better than other hedonic characteristics (appearance, smell, aftertaste). PMID- 29521558 TI - A better future for the NHS. PMID- 29521560 TI - John Shaw Billings: creator of Index Medicus and medical visionary. PMID- 29521563 TI - A vision for organising the medical literature. PMID- 29521564 TI - Contract and ownership type and patient experience. PMID- 29521565 TI - Fish oil as a potential activator of brown and beige fat thermogenesis. AB - Numerous studies have shown that feeding rodents n-3 polyunsaturated fatty acids attenuates adiposity. Moreover, meta-analyses of human dietary intervention studies indicate that fish oil (eicosapentaenoic and docosahexaenoic acid) supplementation might reduce waist circumference. A recent line of research suggests that browning of white adipose depots and activation of uncoupled respiration in brown fat contributes to these effects. This mini-review summarizes the observations in rodents, highlights several mechanisms that might explain these observations and discusses the translational potential. Given the available in vivo evidence and the ability of human adipocytes to aquire a beige phenotype in response to eicosapentaenoic acid incubation, future studies should test the hypothesis that fish oil activates thermogenic brown and beige adipose tissue in humans. PMID- 29521566 TI - Diabetic serum from older women increases adipogenic differentiation in mesenchymal stem cells. AB - BACKGROUND: Paradoxically, elderly persons with type 2 diabetes mellitus (T2DM) fracture despite having higher bone density than nondiabetics. Systemic factors associated with aging and T2DM may have detrimental, local effects on the skeleton. One such factor could be by altering the microenvironment of the mesenchymal stem cells (MSCs), multipotent progenitors capable of differentiating into adipocytes or osteoblasts. METHODS: Sera were obtained from four participant groups (n = 40 total, 10 per group): (1) young women with normal glucose tolerance (NGTY), (2) postmenopausal women with NGT), (3) postmenopausal women with impaired glucose tolerance (IGT), and (4) postmenopausal women with T2DM. Sera were incubated with human MSCs for 14 days. Cell proliferation and apoptosis were measured using EdU and TUNEL labeling assays, respectively. MSC differentiation for each group was determined using osteogenic and adipogenic gene expression markers quantified by qRT-PCR, as well as Alizarin Red and Oil Red O staining. RESULTS: Expression of adipogenic genes was greater than twofold higher (P < 0.05) in MSCs cultured with T2DM sera compared to those incubated with NGTY, NGT, or IGT sera. The increase in adipogenic gene expression corresponded with increased Oil Red O staining. Despite the increased adipogenic differentiation of MSCs exposed to T2DM sera, cell proliferation and apoptosis rates as well as osteoblastic activity were not significantly different among the four conditions. CONCLUSIONS: Systemic, circulating factors in the serum of older women with T2DM may promote MSC differentiation into adipocytes versus osteoblasts. Increased differentiation of MSCs into adipocytes is one possible mechanism by which T2DM increases fracture risk. PMID- 29521567 TI - Evaluation of the impact of anthropogenic activities on arsenic, cadmium, chromium, mercury, lead, and polycyclic aromatic hydrocarbon levels in seafood from the Gulf of Naples, Italy. AB - The principal aim of this study was to monitor the occurrence of some metals and polycyclic aromatic hydrocarbons (PAHs) in fish and mussels from the Gulf of Naples. A comparison with previous researches of the same area was carried out, and the intakes of these compounds through the diet and their effect on the tolerable intake values (when available) were assessed. Cadmium (Cd), chromium (Cr), and lead (Pb) were detected by flameless atomic absorption spectroscopy (Cd, Cr, and Pb); arsenic (As) and mercury (Hg) were detected by applying the hydride method. PAHs were detected by high-performance liquid chromatography. Widespread contamination was found. Among the metals, Hg showed the highest maximum levels of 284.94 ng/g wet weight (ww) in fish and 480.00 ng/g ww in mussels. Chrysene, phenanthrene, fluoranthene, anthracene, and benzo[k]fluoranthene were the most common PAHs in fish, whereas benzo[a]anthracene, pyrene, phenanthrene, acenaphthylene, and acenaphthene were the most frequently occurring compounds in mussels. The concentrations of As, Cr, Hg, Pb, and PAHs in fish were found to decrease over a period of 30 years, whereas the Cd levels remained constant. The Hg, Pb, and PAH levels in mussels increased over the period 2010 to 2016. Finally, the average consumption of mussels led to the highest effect on the Tolerable Daily Intake of Hg, which was exceeded by 19%. PMID- 29521568 TI - The use of commercially available games for a combined physical and cognitive challenge during exercise for individuals with Parkinson's disease - a case series report. AB - Complexity of an animal's environment has been shown to affect structural and functional changes in the brain. Evidence from animal models of Parkinson's disease (PD) suggests that exercising in an enriched environment may protect against the onset of Parkinsonian symptoms in rats that are exposed to 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine. The variety of activities and visual interfaces that can be created using commercially available gaming devices provide cognitively stimulating as well as physically challenging environments for exercise. This case series will: 1) elaborate on the rationale behind selection of specific games to target common deficits seen in PD; and 2) present preliminary results on clinical outcomes from three pilot participants who each completed six sessions of exercise. All three participants had mild to moderate PD. They were functionally independent individuals leading an active lifestyle. Participants were tested on the outcome measures before and after the six exercise sessions. On average, participants showed a 33.8% (22.8) improvement in functional reach test, 12.7% (35.0) improvement in single limb stance (SLS) time right leg, 55.2% (33.9) improvement in SLS time-left leg, 11.9% (7.3) improvement in 6-min walk test, 2% (6.8) improvement in self-selected gait speed (GS), and 8.0% (5.8) improvement in fastest possible GS. Further investigation is warranted to study if these effects can be replicated over a longer exercise intervention and in a larger group, and if these effects are maintained at follow-up testing after the enriched exercise intervention is discontinued. PMID- 29521569 TI - In It Together: A Qualitative Evaluation of Participant Experiences of a 10-Week, Group-Based, Workplace HIIT Program for Insufficiently Active Adults. AB - Using guidance from the reach, efficacy, adoption, implementation, and maintenance evaluation framework, we aimed to qualitatively evaluate the participant experiences of a workplace high-intensity interval training (HIIT) intervention. Twelve previously insufficiently active individuals (four males and eight females) were interviewed once as part of three focus groups. Perceptions of program satisfaction, barriers to and facilitators of adherence, and persistence to exercise were explored. HIIT initiates interest because of its novelty, provides a sense of accomplishment, and overcomes the barriers of perceived lack of time. The feeling of relatedness between the participants can attenuate negative unpleasant responses during the HIIT sessions. HIIT, in this workplace setting, is an acceptable intervention for physically inactive adults. However, participants were reluctant to maintain the same mode of exercise, believing that HIIT sessions were for the very fit. PMID- 29521570 TI - Platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor in comparison to clopidogrel: a retrospective pharmacodynamic analysis. AB - Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is a mainstay of the prevention of stent thrombosis following percutaneous coronary intervention (PCI). In the 2015 European guidelines for the management of acute coronary syndrome (ACS), prasugrel (PRA) and ticagrelor (TICA) combined with aspirin are recommended as first-line therapy. Clopidogrel (CLO) is recommended as an alternative medication for patients with contradictions to these new drugs. This single-center study analyzed the platelet function of 809 ACS patients undergoing PCI and treatment with DAPT. The platelet response to ADP was determined using Multiplate(r) analyzer at a median of 3 days after PCI in 254 patients treated with PRA (loading dose [LD] 60 mg, 10 mg qd), 162 patients receiving TICA (LD 180 mg, D 90 mg bid), and 393 CLO-treated patients (LD 600 mg, 75 mg qd). An aggregation >468 arbitrary units (AU)*min was defined as "high on treatment platelet reactivity" (HPR), <188 AU*min as "low on-treatment platelet reactivity" (LPR). Platelet response in PRA-treated patients was lower compared to CLO or TICA (median; interquartile range: PRA 220 [163-275] AU*min vs. CLO 268 [186-387] AU*min, p < 0.001 vs. TICA 245 [190-320] AU*min, p = 0.001). Only 1.6% of PRA patients were stratified as HPR and 34.6% as LPR, while in the TICA group 1.9% fulfilled the criteria of HPR and 24.1% criteria of LPR. Sixteen percent of CLO patients were stratified as HPR and 26.2% as LPR. In a real-world cohort of ACS patients following PCI, PRA results in more potent inhibition of platelet function compared to CLO and TICA. TICA achieves a consistent antiplatelet effect with reduced rates of HPR and LPR in relation to CLO. PMID- 29521571 TI - The effects of patient-centered communication, social capital, and internet use on patient empowerment: a cross-sectional study in China. AB - Patient empowerment is a relatively new concept in the context of the Chinese health care system. Based on Street's ecological framework of communication in healthcare settings, this study examined the social, clinical and media factors that could empower patients. Results from a survey of 401 Chinese adults (response rate, 34%) showed that respondents felt more empowered as health care consumers when they reported having more social capital bonding and bridging, and used the Internet for health purposes more often. Importantly, having had more positive patient-centered communicative experiences with health care providers not only predicted patient empowerment, it also moderated the effects of bridging social capital and Internet use on empowerment. Specifically, the more positive the experience of interacting with health care providers, the weaker the effects of bridging social capital and Internet use on patient empowerment. The findings have important implications for patient empowerment in health care, particularly within the context of China. PMID- 29521572 TI - Uncertainty of pesticide residue concentration determined from ordinary and weighted linear regression curve. AB - Determination of pesticide residues is based on calibration curves constructed for each batch of analysis. Calibration standard solutions are prepared from a known amount of reference material at different concentration levels covering the concentration range of the analyte in the analysed samples. In the scope of this study, the applicability of both ordinary linear and weighted linear regression (OLR and WLR) for pesticide residue analysis was investigated. We used 782 multipoint calibration curves obtained for 72 different analytical batches with high-pressure liquid chromatography equipped with an ultraviolet detector, and gas chromatography with electron capture, nitrogen phosphorus or mass spectrophotometer detectors. Quality criteria of the linear curves including regression coefficient, standard deviation of relative residuals and deviation of back calculated concentrations were calculated both for WLR and OLR methods. Moreover, the relative uncertainty of the predicted analyte concentration was estimated for both methods. It was concluded that calibration curve based on WLR complies with all the quality criteria set by international guidelines compared to those calculated with OLR. It means that all the data fit well with WLR for pesticide residue analysis. It was estimated that, regardless of the actual concentration range of the calibration, relative uncertainty at the lowest calibrated level ranged between 0.3% and 113.7% for OLR and between 0.2% and 22.1% for WLR. At or above 1/3 of the calibrated range, uncertainty of calibration curve ranged between 0.1% and 16.3% for OLR and 0% and 12.2% for WLR, and therefore, the two methods gave comparable results. PMID- 29521574 TI - The manual dexterity of nursing students and factors that affect it. AB - AIM: The purpose of this study was to define the manual dexterity of nursing students and factors that affect it. METHODOLOGY: The sample for this descriptive and analytical study was composed of 196 nursing students. The data collection tools were a survey and the Purdue pegboard test. RESULTS: The mean dominant hand dexterity score of the students was determined to be 19.16 +/- 1.36; non-dominant hand dexterity score, 17.04 +/- 1.43; mean both hands dexterity score, 14.58 +/- 1.35; mean right hand + left hand + both hands dexterity score, 50.70 +/- 4.20; and mean assembly skill score, 38.55 +/- 6.02. As a result, manual dexterity of the nursing students is relatively high in the 4th year of their education. Also, the students who have a normal body type, a hobby or have chosen the profession voluntarily have better manual dexterity scores. CONCLUSION: The results of the present study demonstrate that students should be guided to a hobby and adapted to the profession during nursing education. This study may constitute normative data for future study related to this issue, and may be guiding in the achievement of the objectives of nursing training and provision of a higher quality education. PMID- 29521573 TI - Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials. AB - BACKGROUND: Treatment of multiple sclerosis (MS) with interferon beta can lead to the development of antibodies directed against interferon beta that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon beta. OBJECTIVE: To validate the proposed genetic markers and to identify new markers. METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon beta-1b in the Betaferon(r) Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron(r)/BEtaferon(r) in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon beta-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 * 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 * 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 * 10-15). CONCLUSION: The contribution of HLA alleles and HLA-associated single nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon beta was confirmed in the combined analysis of two multi national, multi-center studies. PMID- 29521575 TI - Knowledge, Beliefs, and Communication Behavior of Oncology Health-care Providers (HCPs) regarding Lesbian, Gay, Bisexual, and Transgender (LGBT) Patient Health care. AB - Delivery of culturally competent care toward lesbian, gay, bisexual, and transgender (LGBT) patients depends on how health-care providers (HCPs) communicate with them; however, research about knowledge, attitude, and behavior of HCPs toward LGBT patients is scant. The objectives of our study were to describe oncology HCPs' knowledge and examine if beliefs about LGB and transgender patients mediate the effects of LGBT health-care knowledge on open communication behaviors with LGB and transgender patients, respectively. A total of 1253 HCPs (187 physicians, 153 advance practice professionals (APPs), 828 nurses, and 41 others) at a Comprehensive Cancer Center completed an online survey that included the following measures: LGBT health-care knowledge, beliefs, communication behaviors, willingness to treat LGBT patients, encouraging LGBT disclosure, and perceived importance of LGBT sensitivity training. Only 50 participants (5%) correctly answered all 7 knowledge items, and about half the respondents answered 3 (out of 7) items correctly. Favorable beliefs about LGBT health care mediated the effect of higher LGBT health-care knowledge on open communication behaviors with transgender patients, controlling for effects of type of profession, religious orientation, gender identity, sexual orientation, and having LGBT friends/family. The results of this study demonstrated an overall lack of medical knowledge and the need for more education about LGBT health care among oncology HCPs. PMID- 29521576 TI - New evidence about effects of reproductive variables on child mortality in sub Saharan Africa. AB - There is still considerable uncertainty about how reproductive factors affect child mortality. This study, based on Demographic and Health Survey data from 28 countries in sub-Saharan Africa, shows that mortality is highest for firstborn children with very young mothers. Other children with young mothers, or of high birth order, also experience high mortality. Net of maternal age and birth order, a short preceding birth interval is associated with above average mortality. These patterns change, however, if time-invariant unobserved mother-level characteristics of importance for both mortality and fertility are controlled for in a multilevel-multiprocess model. Most importantly, there are smaller advantages associated with longer birth intervals and being older at first birth. The implications of alternative reproductive 'strategies' are discussed, taking into account that if the mother is older at birth, the child will also be born in a later calendar year, when mortality may be lower. PMID- 29521577 TI - Mediating effects of motor performance, cardiorespiratory fitness, physical activity, and sedentary behaviour on the associations of adiposity and other cardiometabolic risk factors with academic achievement in children. AB - We investigated the associations of cardiometabolic risk factors with academic achievement and whether motor performance, cardiorespiratory fitness, physical activity, or sedentary behaviour mediated these associations. Altogether 175 children 6-8 years-of-age participated in the study. We assessed body fat percentage (BF%), waist circumference, insulin, glucose, triglycerides, HDL cholesterol, and systolic and diastolic blood pressure, leptin, alanine aminotransferase, and gamma-glutamyltransferase (GGT). Reading fluency, reading comprehension, and arithmetic skills were assessed using standardized tests. Speed/agility, balance, and manual dexterity test results were used to calculate motor performance score and physical activity was assessed by combined heart rate and movement sensor and cardiorespiratory fitness by maximal cycle ergometer test. In boys, BF% was inversely associated with reading fluency (beta = -0.262, P = 0.007) and reading comprehension (beta = -0.216, P = 0.025). Motor performance mediated these associations. Leptin was inversely related to reading fluency (beta = -0.272, P = 0.006) and reading comprehension (beta = -0.287, P = 0.003). The inverse association of leptin with reading fluency was mediated by motor performance. In girls, GGT was inversely associated with reading fluency independent of confounders (beta = -0.325, P = 0.007). The inverse association of BF% with academic achievement among boys was largely explained by motor performance. Leptin in boys and GGT in girls were inversely associated with academic achievement independent of confounding factors. PMID- 29521578 TI - Physiologic correlates of culture-bound dissociation: A comparative study of Brazilian spiritist mediums and controls. AB - Mediumship and spirit possession are cultural phenomena found in many societies worldwide. In Brazil, Spiritism (a tradition in which mediumship is emphasized) is the third largest religious denomination. The present study aimed to investigate physiologic correlates of nonpathological dissociative experiences by comparing 20 female spiritist mediums with several years of socially sanctioned practice to 20 female nonmedium control subjects from the same religious context. We measured plasma levels of hormones and neuroactive substances, as well as vital signs and heart rate variability (HRV) parameters, before and immediately after spirit communication. Although no between-group differences were noted in basal physiological parameters, in response to the possession experiences the groups differed in heart rate and in plasma concentrations of noradrenaline, thyroid-stimulating hormone (TSH), prolactin, and creatine phosphokinase (CPK). The changes in parameters indicated an arousal response in mediums and a relaxation response in control participants, and the same pattern of changes was observed in HRV parameters from each group during the possession experiences. However, the changes in physiologic parameters for mediums were mild and of short duration: 1 hour after the possession experiences, no difference in cardiac autonomic regulation was noted. No significant group effect was noted for melatonin. Cognitive control processes may explain the arousal associated with the dissociative state. Findings from this study suggest that pathological and nonpathological dissociation may have different physiological correlates. PMID- 29521579 TI - Spinal ependymoma in adults: a multicenter investigation of surgical outcome and progression-free survival. AB - OBJECTIVE Spinal ependymomas are rare glial neoplasms. Because their incidence is low, only a few larger studies have investigated this condition. There are no clear data concerning prognosis and therapy. The aim of the study was to describe the natural history, perioperative clinical course, and local tumor control of adult patients with spinal ependymomas who were surgically treated under modern treatment standards. METHODS The authors performed a multicenter retrospective study. They identified 158 adult patients with spinal ependymomas who had received surgical treatment between January 2006 and June 2013. The authors analyzed the clinical and histological aspects of these cases to identify the predictive factors for postoperative morbidity, tumor resectability, and recurrence. RESULTS Gross-total resection (GTR) was achieved in 80% of cases. At discharge, 37% of the patients showed a neurological decline. During follow-up the majority recovered, whereas 76% showed at least preoperative status. Permanent functional deterioration remained in 2% of the patients. Transient deficits were more frequent in patients with cervically located ependymomas (p = 0.004) and in older patients (p = 0.002). Permanent deficits were independently predicted only by older age (p = 0.026). Tumor progression was observed in 15 cases. The 5-year progression-free survival (PFS) rate was 80%, and GTR (p = 0.037), WHO grade II (p = 0.009), and low Ki-67 index (p = 0.005) were independent prognostic factors for PFS. Adjuvant radiation therapy was performed in 15 cases. No statistically relevant effects of radiation therapy were observed among patients with incompletely resected ependymomas (p = 0.079). CONCLUSIONS Due to its beneficial value for PFS, GTR is important in the treatment of spinal ependymoma. Gross-total resection is feasible in the majority of cases, with acceptable rates of permanent deficits. Also, Ki-67 appears to be an important prognostic factor and should be included in a grading scheme for spinal ependymomas. PMID- 29521580 TI - Rare case of a recurrent juvenile ossifying fibroma of the lumbosacral spine. AB - Juvenile ossifying fibroma (JOF) is a rare benign bone tumor that occurs most frequently in the craniofacial bones of children and young adults. There are few case reports that describe its involvement outside the craniofacial skeleton, especially within the spinal column. While JOF is classified as a benign lesion, it may be locally aggressive and demonstrate a high propensity for recurrence, even after resection. Definitive surgical management may be challenging in naive cases, but it is particularly challenging in recurrent cases and when extensive spinal reconstruction is warranted. In this report, the authors describe the diagnosis and surgical management of a 29-year-old man who presented with a large recurrent sacral trabecular-subtype JOF. A review of literature regarding JOFs, management of recurrent primary spinal tumors, and sacral reconstruction are discussed. PMID- 29521581 TI - Self-reported occupational blood exposure among paramedics in Poland; a pilot study. AB - INTRODUCTION: Paramedics are at risk of occupational exposure, increased by the immediacy of provided treatment. However, the issue has not been acknowledged by any research in Europe up to date. METHODS: The research aimed at assessing the occupational blood exposure among paramedics in Poland. Respondents represented 21 Polish medical institutions. Their participation was voluntary and anonymous. Paramedics were provided with a self-directed job specific questionnaire adapted to Polish conditions from an original North American version. RESULTS: 118 paramedics participated in the study from institutions constituting the National Emergency Medical System in Poland; including ambulance crews, Helicopter Emergency Medical Services (HEMS) and Emergency Department employees. Occupational exposure was reported by 18.64% of respondents and main route of exposure were needlestick events. CONCLUSIONS: There is a further need to improve education among the paramedics concerning the threat of being infected with blood borne pathogens through all existing routes. Our findings point to the problem as being hidden and considered a shameful issue. PMID- 29521582 TI - The role of rehabilitation after regenerative and orthobiologic procedures for the treatment of tendinopathy: a systematic review. AB - AIM: Significant variability exists in the literature, with no clear consensus to the optimal protocol after a regenerative procedure. Given this uncertainty, the authors systematically reviewed the literature cataloging the different variables that may influence outcomes. METHODS: Search was limited to randomized clinical trials and prospective cohort studies of regenerative procedures for the treatment of tendinopathy. Variables were predetermined, and included: cyrotherapy, pre- and post-procedure nonsteroidal anti-inflammatory drugs use, recommendations for alternative pain medications, immobilization and duration of rest. Variables were categorized based on the influence of the intervention on the three phases of healing. RESULTS: 749 studies were assessed for eligibility, and 60 studies were included. Significant variability existed in the literature. CONCLUSION: Despite the importance of rehabilitation after regenerative procedures, there is a paucity of evidence available to guide clinicians and highlights the need for additional validation. PMID- 29521583 TI - Nanocomposite thin films for triggerable drug delivery. AB - INTRODUCTION: Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion. Areas covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape. Expert opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery. PMID- 29521584 TI - Deep brain stimulation hardware-related infections: 10-year experience at a single institution. AB - OBJECTIVE Deep brain stimulation is an effective surgical treatment for managing some neurological and psychiatric disorders. Infection related to the deep brain stimulator (DBS) hardware causes significant morbidity: hardware explantation may be required; initial disease symptoms such as tremor, rigidity, and bradykinesia may recur; and the medication requirements for adequate disease management may increase. These morbidities are of particular concern given that published DBS related infection rates have been as high as 23%. To date, however, the key risk factors for and the potential preventive measures against these infections remain largely uncharacterized. In this study, the authors endeavored to identify possible risk factors for DBS-related infection and analyze the efficacy of prophylactic intrawound vancomycin powder (VP). METHODS The authors performed a retrospective cohort study of patients who had undergone primary DBS implantation at a single institution in the period from December 2005 through September 2015 to identify possible risk factors for surgical site infection (SSI) and to assess the impact of perioperative (before, during, and after surgery) prophylactic antibiotics on the SSI rate. They also evaluated the effect of a change in the National Healthcare Safety Network's definition of SSI on the number of infections detected. Statistical analyses were performed using the 2-sample t test, the Wilcoxon rank-sum test, the chi-square test, Fisher's exact test, or logistic regression, as appropriate for the variables examined. RESULTS Four hundred sixty-four electrodes were placed in 242 adults during 245 primary procedures over approximately 10.5 years; most patients underwent bilateral electrode implantation. Among the 245 procedures, 9 SSIs (3.7%) occurred within 90 days and 16 (6.5%) occurred within 1 year of DBS placement. Gram-positive bacteria were the most common etiological agents. Most patient- and procedure related characteristics did not differ between those who had acquired an SSI and those who had not. The rate of SSIs among patients who had received intrawound VP was only 3.3% compared with 9.7% among those who had not received topical VP (OR 0.32, 95% CI 0.10-1.02, p = 0.04). After controlling for patient sex, the association between VP and decreased SSI risk did not reach the predetermined level of significance (adjusted OR 0.32, 95% CI 0.10-1.03, p = 0.06). The SSI rates were similar after staged and unstaged implantations. CONCLUSIONS While most patient-related and procedure-related factors assessed in this study were not associated with the risk for an SSI, the data did suggest that intrawound VP may help to reduce the SSI risk after DBS implantation. Furthermore, given the implications of SSI after DBS surgery and the frequency of infections occurring more than 90 days after implantation, continued follow-up for at least 1 year after such a procedure is prudent to establish the true burden of these infections and to properly treat them when they do occur. PMID- 29521585 TI - Accuracy of detecting enlargement of aneurysms using different MRI modalities and measurement protocols. AB - OBJECTIVE Aneurysm growth is considered predictive of future rupture of intracranial aneurysms. However, how accurately neuroradiologists can reliably detect incremental aneurysm growth using clinical MRI is still unknown. The purpose of this study was to assess the agreement rate of detecting aneurysm enlargement employing generally used MRI modalities. METHODS Three silicone flow phantom models, each with 8 aneurysms of various sizes at different sites, were used in this study. The aneurysm models were identical except for an incremental increase in the sizes of the 8 aneurysms, which ranged from 0.4 mm to 2 mm. The phantoms were imaged on 1.5-T and 3-T MRI units with both time-of-flight (TOF) and contrast-enhanced MR angiography. Three independent expert neuroradiologists measured the aneurysms in a blinded manner using different measurement approaches. The individual and agreement detection rates of aneurysm enlargement among the 3 experts were calculated. RESULTS The mean detection rate of any increase in any aneurysmal dimension was 95.7%. The detection rates of the 3 observers (observers A, B, and C) were 98.0%, 96.6%, and 92.7%, respectively (p = 0.22). The detection rates of each MRI modality were 91.3% using 1.5-T TOF, 97.2% using 1.5-T with Gd, 95.8% using 3.0-T TOF, and 97.2% using 3.0-T with Gd (p = 0.31). On the other hand, the mean detection rate for aneurysm enlargement was 54.8%. Specifically, the detection rates of observers A, B, and C were 49.0%, 46.1%, and 66.7%, respectively (p = 0.009). As the incremental enlargement value increased, the detection rate for aneurysm enlargement increased. The use of 1.5 T Gd improved the detection rate for small incremental enlargement (e.g., 0.4-1 mm) of the aneurysm (p = 0.04). The location of the aneurysm also affected the detection rate for aneurysm enlargement (p < 0.0001). CONCLUSIONS The detection rate and interobserver agreement were very high for aneurysm enlargement of 0.4-2 mm. The detection rate for at least 1 increase in any aneurysm dimension did not depend on the choice of MRI modality or measurement protocol. Use of Gd improved the accuracy of measurement. Aneurysm location may influence the accuracy of detecting enlargement. PMID- 29521586 TI - Upregulation of miR-216a exerts neuroprotective effects against ischemic injury through negatively regulating JAK2/STAT3-involved apoptosis and inflammatory pathways. AB - OBJECTIVE Ischemic stroke remains a significant cause of death and disability in industrialized nations. Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) of the JAK2/STAT3 pathway play important roles in the downstream signal pathway regulation of ischemic stroke-related inflammatory neuronal damage. Recently, microRNAs (miRNAs) have emerged as major regulators in cerebral ischemic injury; therefore, the authors aimed to investigate the underlying molecular mechanism between miRNAs and ischemic stroke, which may provide potential therapeutic targets for ischemic stroke. METHODS The JAK2- and JAK3-related miRNA (miR-135, miR-216a, and miR-433) expression levels were detected by real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot analysis in both oxygen glucose deprivation (OGD)-treated primary cultured neuronal cells and mouse brain with middle cerebral artery occlusion (MCAO)-induced ischemic stroke. The miR 135, miR-216a, and miR-433 were determined by bioinformatics analysis that may target JAK2, and miR-216a was further confirmed by 3' untranslated region (3'UTR) dual-luciferase assay. The study further detected cell apoptosis, the level of lactate dehydrogenase, and inflammatory mediators (inducible nitric oxide synthase [iNOS], matrix metalloproteinase-9 [MMP-9], tumor necrosis factor-alpha [TNF-alpha], and interleukin-1beta [IL-1beta]) after cells were transfected with miR-NC (miRNA negative control) or miR-216a mimics and subjected to oxygen glucose deprivation/reoxygenation (OGD/R) damage with 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay, annexin V-FITC/PI, Western blots, and enzyme-linked immunosorbent assay detection. Furthermore, neurological deficit detection and neurological behavior grading were performed to determine the infarction area and neurological deficits. RESULTS JAK2 showed its highest level while miR-216a showed its lowest level at day 1 after ischemic reperfusion. However, miR-135 and miR-433 had no obvious change during the process. The luciferase assay data further confirmed that miR-216a can directly target the 3'UTR of JAK2, and overexpression of miR-216a repressed JAK2 protein levels in OGD/R-treated neuronal cells as well as in the MCAO model ischemic region. In addition, overexpression of miR-216a mitigated cell apoptosis both in vitro and in vivo, which was consistent with the effect of knockdown of JAK2. Furthermore, the study found that miR-216a obviously inhibited the inflammatory mediators after OGD/R, including inflammatory enzymes (iNOS and MMP-9) and cytokines (TNF alpha and IL-1beta). Upregulating miR-216a levels reduced ischemic infarction and improved neurological deficit. CONCLUSIONS These findings suggest that upregulation of miR-216a, which targets JAK2, could induce neuroprotection against ischemic injury in vitro and in vivo, which provides a potential therapeutic target for ischemic stroke. PMID- 29521587 TI - Letter to the Editor. Direct versus indirect bypass for adult ischemic-type moyamoya disease. PMID- 29521588 TI - Letter to the Editor. Fluorescence-aided evaluation of nasoseptal flap perfusion. PMID- 29521589 TI - Letter to the Editor. Treatment of ruptured AVMs. PMID- 29521590 TI - American views of Sir Victor Horsley in the era of Cushing. AB - Sir Victor Horsley was a pioneering British neurosurgeon known for his numerous neurosurgical, scientific, and sociopolitical contributions. Although word of these surgical and scientific achievements quickly spread throughout Europe and North America in the late 19th century, much of modern neurosurgery's view of Horsley has been colored by a single anecdote from John Fulton's biography of Harvey Cushing. In this account, Cushing observes a frenetic Horsley hastily removing a Gasserian ganglion from a patient in the kitchen of a British mansion. Not long after, Cushing left Britain saying that he had little to learn from British neurosurgery. The authors of this paper examined contemporary views of Horsley to assess what his actual reputation was in the US and Canada. The authors conducted a thorough search of references to Horsley using the following sources: American surgical and neurosurgical textbooks; major biographies; diary entries and letters; PubMed; newspaper articles; and surgical and neurosurgical texts. The positive reception of his work is corroborated by invitations for Horsley to speak in America. Research additionally revealed that Horsley had numerous personal and professional relationships with prominent Americans in medicine, including William Osler, John Wheelock Elliot, Ernest Sachs, and (yes) Harvey Cushing. Horsley's contributions to medicine and science were heavily reported in American newspapers; outside of neurosurgery, his strong opposition to the antivivisectionists and his support for alcohol prohibition were widely reported in popular media. Horsley's contributions to neurosurgery in America are undeniable. Writings from and about prominent Americans reveal that he was viewed favorably by those who had met him. Frequent publication of his views in the American media suggests that medical professionals and the public in the US valued his contributions on scientific as well as social issues. Horsley died too young, but not without the international recognition that was rightly his. PMID- 29521591 TI - Solitary fibrous tumor/hemangiopericytoma: treatment results based on the 2016 WHO classification. AB - OBJECTIVE Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a new combined entity for which a soft-tissue-type grading system, ranging from grades I to III, has been introduced in the 2016 WHO classification of tumors of the CNS. The results of the treatment of this new disease entity require evaluation. METHODS The authors retrospectively reevaluated the pathological findings and medical records of patients with SFT/HPC. This study included 60 patients (27 men and 33 women, median age 42.5 years, range 13-69 years) treated at Severance Hospital between February 1981 and February 2016. Four, 40, and 16 patients were categorized as having SFT/HPC grades I, II, and III, respectively. Among these patients, SFTs diagnosed in 7 patients were regraded as grades I (n = 4), II (n = 2), and III (n = 1). RESULTS The median overall survival (OS) was 73.2 months (range 1.4-275.7 months), and the progression-free survival (PFS) after the first operation was 53.8 months (range 1.4-217.7 months). Six patients (10%) showed extracranial metastasis during a median period of 103.7 months (range 31.9-182.3 months). Nineteen patients (31.7%) presented with tumor recurrences. The patients in the grade III group had shorter PFS and OS, as well as a shorter period to extracranial metastasis, compared with patients in the grade II group. In the grade II group, patients who underwent gross-total resection showed longer PFS than those who underwent subtotal resection; however, there was no difference in OS. Patients who underwent adjuvant radiation therapy (RT) after surgery had longer PFS compared with that of patients who did not undergo adjuvant RT. CONCLUSIONS The SFT/HPC grade I group showed a relatively benign course compared with those of the other groups. The grade III group presented a course with a more aggressive nature than that of the grade II group. In the grade II group, the extent of resection and adjuvant RT was significantly associated with longer PFS. The long-term follow-up and periodic systemic evaluation are mandatory to detect systemic metastasis. PMID- 29521592 TI - Factors associated with 30-day ventriculoperitoneal shunt failure in pediatric and adult patients. AB - OBJECTIVE The aim of this study was to provide a comprehensive benchmark of 30 day ventriculoperitoneal (VP) shunt failure rates for a single institution over a 5-year study period for both adult and pediatric patients, to compare this with the results in previously published literature, and to establish factors associated with shunt failure. METHODS A retrospective database search was undertaken to identify all VP shunt operations performed in a single, regional neurosurgical unit during a 5-year period. Data were collected regarding patient age, sex, origin of hydrocephalus, and whether the shunt was a primary or secondary shunt. Operative notes were used to ascertain the type of valve inserted, which components of the shunt were adjusted/replaced (in revision cases), level of seniority of the most senior surgeon who participated in the operation, and number of surgeons involved in the operation. Where appropriate and where available, postoperative imaging was assessed for grade of shunt placement, using a recognized grading system. Univariate and multivariate models were used to establish factors associated with early (30-day) shunt failure. RESULTS Six hundred eighty-three VP shunt operations were performed, of which 321 were pediatric and 362 were adult. The median duration of postoperative follow-up for nonfailed shunts (excluding deaths) was 1263 days (range 525-2226 days). The pediatric 30-day shunt failure rates in the authors' institution were 8.8% for primary shunts and 23.4% for revisions. In adults, the 30-day shunt failure rates are 17.7% for primary shunts and 25.6% for revisions. In pediatric procedures, the number of surgeons involved in the operating theater was significantly associated with shunt failure rate. In adults, the origin of hydrocephalus was a statistically significant variable. Primary shunts lasted longer than revision shunts, irrespective of patient age. CONCLUSIONS A benchmark of 30-day failures is presented and is consistent with current national databases and previously published data by other groups. The number of surgeons involved in shunt operations and the origin of the patient's hydrocephalus should be described in future studies and should be controlled for in any prospective work. The choice of shunt valve was not a significant predictor of shunt failure. Most previous studies on shunts have concentrated on primary shunts, but the high rate of early shunt failure in revision cases (in both adults and children) is perhaps where future research efforts should be concentrated. PMID- 29521593 TI - Inhibition of glioblastoma cell invasion by hsa-miR-145-5p and hsa-miR-31-5p co overexpression in human mesenchymal stem cells. AB - OBJECTIVE Human bone marrow-derived mesenchymal stem cells (hMSCs) show tropism for brain tumors and may be a useful vehicle for drug or gene delivery to malignant gliomas. Recently, some microRNAs (miRNAs) have been shown to suppress the invasiveness of malignant gliomas. METHODS To test their potential to become vehicles for the delivery of miRNA to malignant gliomas, hMSCs were engineered so that hMSC secretion of miRNAs that inhibit glioma cell invasion was enabled without altering the hMSC tropism for glioma cells. RESULTS In coculture, hMSCs cotransfected with hsa-miR-145-5p and -31-5p miRNAs showed markedly reduced invasion by U87 glioma cells in a contact-dependent manner both in vitro and ex vivo, with invasion of hMSCs cotransfected with these 2 miRNAs by the U87 cells reduced to 60.7% compared with control cells. According to a Matrigel invasion assay, the tropism of the hMSCs for U87 cells was not affected. In glioma cell lines U251 and LN229, hMSCs exhibited tropism in vivo, and invasion of hMSCs cotransfected with hsa-miR-145-5p and -31-5p was also significantly less than that of control cells. When U87 cells were coimplanted into the striatum of organotypic rat brain slices with hMSCs cotransfected with hsa-miR-145 and -31 5p, the relative invasive area decreased by 37.1%; interestingly, these U87 cells showed a change to a rounded morphology that was apparent at the invasion front. Whole-genome microarray analysis of the expression levels of 58,341 genes revealed that the co-overexpression of hsa-miR-145-5p and -31-5p downregulated FSCN1 expression in U87 cells. CONCLUSIONS This study demonstrates that miRNA overexpression in hMSCs can alter the function of glioma cells via contact dependent transfer. Co-overexpression of multiple miRNAs may be a useful and novel therapeutic strategy. The study results suggest that hMSCs can be applied as a delivery vehicle for miRNAs. PMID- 29521594 TI - Effect of choice of treatment modality on the incidence of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE Shunt-dependent hydrocephalus (SDHC) may arise after aneurysmal subarachnoid hemorrhage (aSAH) as CSF resorptive mechanisms are disrupted. Using propensity score analysis, the authors aimed to investigate which treatment modality, surgical clipping or endovascular treatment, is superior in reducing rates of SDHC after aSAH. METHODS The authors' multicenter SAH database, comprising 3 stroke centers affiliated with Kyoto University, Japan, was used to identify patients treated between January 2009 and July 2016. Univariate and multivariate analyses were performed to characterize risk factors for SDHC after aSAH. A propensity score model was generated for both treatment groups, incorporating relevant patient covariates to detect any superiority for prevention of SDHC after aSAH. RESULTS A total of 566 patients were enrolled in this study. SDHC developed in 127 patients (22%). On multivariate analysis, age older than 53 years, the presence of intraventricular hematoma, and surgical clipping as opposed to endovascular coiling were independently associated with SDHC after aSAH. After propensity score matching, 136 patients treated with surgical clipping and 136 with endovascular treatment were matched. Propensity score-matched cohorts exhibited a significantly lower incidence of SDHC after endovascular treatment than after surgical clipping (16% vs 30%, p = 0.009; OR 2.2, 95% CI 1.2-4.2). SDHC was independently associated with poor neurological outcomes (modified Rankin Scale score 3-6) at discharge (OR 4.3, 95% CI 2.6-7.3; p < 0.001). CONCLUSIONS SDHC after aSAH occurred significantly more frequently in patients who underwent surgical clipping. Strategies for treatment of ruptured aneurysms should be used to mitigate SDHC and minimize poor outcomes. PMID- 29521595 TI - Association between social factors and performance during Functional Capacity Evaluations: a systematic review. AB - PURPOSE: Determine the association of different social factors with Functional Capacity Evaluation (FCE) performance in adults. MATERIALS AND METHODS: A systematic literature search was performed in MEDLINE, CINAHL, and PsycINFO electronic databases. Studies were eligible if they studied social factor's association with the performance of adults undergoing FCE. Studies were assessed on methodological quality and quality of evidence. The review was performed using best-evidence synthesis methods. RESULTS: Thirteen studies were eligible and 11 social factors were studied. Considerable heterogeneity regarding measurements, populations, and methods existed among the studies. High quality of evidence was found for the association of FCE performance with the country of FCE and examiner's fear behavior; moderate quality of evidence with previous job salary; and low or very low quality of evidence with compensation status, litigation status, type of instruction, time of day (workday), primary or mother language, and ethnicity. Other social factors were not studied. CONCLUSIONS: Evidence for associations of various social factors with FCE performance was found, but robust conclusions about the strength of the associations cannot be made. Quality of evidence ranged from high to very low. Further research on social factors, also within a biopsychosocial context, is necessary to provide a better understanding of FCE performance. Implications for Rehabilitation Research on Functional Capacity Evaluation (FCE) performance and its association with biopsychosocial factors have scarcely addressed the impact of social factors, limiting full understanding of FCE results. The social factors, healthcare (examiner's fear behavior and type of instruction), personal or cultural systems (country of FCE, primary or mother language, and ethnicity), workplace system (previous job salary, time of day (workday)), and legislative and insurance system (compensation and litigation status), have a bearing in FCE performance. Better understanding of factors associating with functional capacity provide insights in FCE, allowing clinicians to improve the evaluations and interpretations of the assessment and better design the rehabilitation program. Better understanding of factors that influence FCE performance, and of unstudied factors, will allow researchers guidance to further investigate the construct of functional capacity. PMID- 29521596 TI - When the grass is greener: Fertility decisions in a cross-national context. AB - In research and policy discourse, conceptualizations of fertility decision-making often assume that people only consider circumstances within national borders. In an integrated Europe, citizens may know about and compare conditions across countries. Such comparisons may influence the way people think about and respond to childrearing costs. To explore this possibility and its implications, we present evidence from 44 in-depth interviews with Polish parents in the United Kingdom and Poland. Explanations of childbearing decisions involved comparisons of policy packages and living standards across countries. Individuals in Poland used richer European countries as an important reference point, rather than recent conditions in Poland. In contrast, migrants often positively assessed their relatively disadvantaged circumstances by using the Polish setting as a reference. The findings could help explain why, despite substantial policy efforts, fertility has remained at very low levels in poorer European countries, while migrants from those countries often have higher fertility abroad. PMID- 29521597 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1-31 October 2017. PMID- 29521598 TI - Rhinovirus infection induces distinct transcriptome profiles in polarized human macrophages. AB - Infections with rhinovirus (RV) cause asthma exacerbations. Recent studies suggest that macrophages play a role in asthmatic airway inflammation and the innate immune response to RV infection. Macrophages exhibit phenotypes based on surface markers and gene expression. We hypothesized that macrophage polarization state alters gene expression in response to RV infection. Cells were derived from human peripheral blood derived monocytes. M1 and M2 polarization was carried out by using IFN-gamma and IL-4, respectively, and RNA was extracted for Affymetrix Human Gene ST2.1 exon arrays. Selected genes were validated by quantitative (q)PCR. Treatment of nonactivated (M0) macrophages with IFN-gamma and IL-4 induced the expression of 252 and 153 distinct genes, respectively, including previously-identified M1 and M2 markers. RV infection of M0 macrophages induced upregulation of 232 genes; pathway analysis showed significant overrepresentation of genes involved in IFN-alpha/beta signaling and cytokine signaling in the immune system. RV infection induced differential expression of 195 distinct genes in M1-like macrophages but only seven distinct genes in M2-like-polarized cells. In a secondary analysis, comparison between M0-, RV-infected, and M1-like polarized, RV-infected macrophages revealed differential expression of 227 genes including those associated with asthma and its exacerbation. qPCR demonstrated increased expression of CCL8, CXCL10, TNFSF10, TNFSF18, IL6, NOD2, and GSDMD and reduced expression of VNN1, AGO1, and AGO2. Together, these data show that, in contrast to M2-like-polarized macrophages, gene expression of M1-like macrophages is highly regulated by RV. PMID- 29521599 TI - Celecoxib restores angiogenic factor expression at the maternal-fetal interface in the BPH/5 mouse model of preeclampsia. AB - Preeclampsia (PE), a hypertensive disease of pregnancy, is a leading cause of fetal and maternal morbidity/mortality. Early angiogenic and inflammatory disturbances within the placenta are thought to underlie the development of the maternal PE syndrome and poor pregnancy outcomes. However, the exact etiology remains largely unknown. Here, we use the BPH/5 mouse model of PE to elucidate the way in which inflammation early in pregnancy contributes to abnormal expression of angiogenic factors at the maternal-fetal interface. We have previously described improvement in maternal hypertension and fetal growth restriction in this model after treatment with the anti-inflammatory cyclooxygenase-2 (Cox2) specific inhibitor celecoxib. To further characterize the mechanisms by which celecoxib improves poor pregnancy outcomes in BPH/5 mice, we determined expression of angiogenic factors and complement pathway components after celecoxib. In BPH/5 implantation sites there was increased hypoxia inducible factor-1alpha ( Hif1alpha), heme oxygenase-1 ( Ho-1), and stem cell factor ( Scf) mRNA concomitant with elevated prostaglandin synthase 2 ( Ptgs2), encoding Cox2, and elevated VEGF protein. Angiopoietin 1 ( Ang1), tunica interna endothelial cell kinase-2 receptor ( Tie2), complement factor 3 ( C3), and complement factor B ( CfB) were increased in midgestation BPH/5 placentae. Whereas BPH/5 expression levels of VEGF, Ang1, and Tie2 normalized after celecoxib, placental C3 and CfB mRNA remained unchanged. However, celecoxib did reduce the pregnancy-specific circulating soluble fms-like tyrosine kinase-1 (sFlt-1) rise in BPH/5 mice at midgestation. These data show that elevated Cox2 during implantation contributes to placental angiogenic factor imbalances in the BPH/5 mouse model of PE. PMID- 29521600 TI - Cecal versus fecal microbiota in Ossabaw swine and implications for obesity. AB - The gut microbiome plays a critical role in the onset and progression of obesity and the metabolic syndrome. However, it is not well documented whether the cecal vs. the fecal microbiome is more relevant when assessing their contributions to these diseases. Here, we amplified the V4 region of the 16S rRNA gene from cecal and fecal samples of female Ossabaw swine fed a low-fat control diet (10.5% fat, n = 4) or Western diet (43.0% fat, 17.8% high fructose corn syrup, 2% cholesterol; n = 3) for 36 wk. Obesity significantly lowered alpha-diversity ( P < 0.05), and there was clear separation in beta-diversity between lean and obese pigs, as well as between cecal and fecal samples ( P < 0.05). Obesity dramatically increased ( P < 0.05) the Firmicutes:Bacteroidetes ratio in fecal samples, and Actinobacteria was higher ( P < 0.05) in fecal vs. cecal samples in obese pigs. Cyanobacteria, Proteobacteria, and Fusobacteria were increased ( P < 0.05), while Spirochaetes, Tenericutes, and Verrucomicrobia were decreased ( P < 0.05) in obese vs. lean pigs. Prevotellaceae was reduced ( P < 0.05) in obese fecal vs. cecal samples. Moreover, cecal samples in obese had greater ( P < 0.05) predicted metabolic capacity for glycan biosynthesis and metabolism and LPS biosynthesis compared with fecal. Obese pigs also had greater ( P < 0.05) capacity for carbohydrate metabolism, which was driven by obese fecal rather than cecal samples and was opposite in lean pigs ( P < 0.05). The observed differences in pro-inflammatory microbiota and their metabolic capacity in cecal vs. fecal samples of obese pigs provide new insight into evaluating the microbiome in the pathogenesis of obesity and metabolic disease. PMID- 29521601 TI - RNA sequencing of kidney distal tubule cells reveals multiple mediators of chronic aldosterone action. AB - The renal aldosterone-sensitive distal tubule (ASDT) is crucial for sodium reabsorption and blood pressure regulation. The ASDT consists of the late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct. Due to difficulties in isolating epithelial cells from the ASDT in large quantities, few transcriptome studies have been performed on this segment. Moreover, no studies exist on isolated DCT2 and CNT cells (excluding intercalated cells), and the role of aldosterone for regulating the transcriptome of these specific cell types is largely unknown. A mouse model expressing eGFP in DCT2/CNT/initial cortical collecting duct (iCCD) principal cells was exploited to facilitate the isolation of these cells in high number and purity. Combined with deep RNA sequencing technology, a comprehensive catalog of chronic aldosterone-regulated transcripts from enriched DCT2/CNT/iCCD principal cells was generated. There were 257 significantly downregulated and 290 upregulated transcripts in response to aldosterone ( P < 0.05). The RNA sequencing confirmed aldosterone regulation of well-described aldosterone targets including Sgk1 and Tsc22d3. Changes in selected transcripts such as S100a1 and Cldn4 were confirmed by RT-qPCR. The RNA sequencing showed downregulation of Nr3c2 encoding the mineralocorticoid receptor (MR), and cell line experiments showed a parallel decrease in MR protein. Furthermore, a large number of transcripts encoding transcription factors were downregulated. An extensive mRNA transcriptome reconstruction of an enriched CNT/iCCD principal cell population was also generated. The results provided a comprehensive database of aldosterone-regulated transcripts in the ASDT, allowing development of novel hypotheses for the action of aldosterone. PMID- 29521602 TI - Role of glial-like type II cells as paracrine modulators of carotid body chemoreception. AB - Mammalian carotid bodies (CB) are chemosensory organs that mediate compensatory cardiorespiratory reflexes in response to low blood PO2 (hypoxemia) and elevated CO2/H+ (acid hypercapnia). The chemoreceptors are glomus or type I cells that occur in clusters enveloped by neighboring glial-like type II cells. During chemoexcitation type I cells depolarize, leading to Ca2+-dependent release of several neurotransmitters, some excitatory and others inhibitory, that help shape the afferent carotid sinus nerve (CSN) discharge. Among the predominantly excitatory neurotransmitters are the purines ATP and adenosine, whereas dopamine (DA) is inhibitory in most species. There is a consensus that ATP and adenosine, acting via postsynaptic ionotropic P2X2/3 receptors and pre- and/or postsynaptic A2 receptors respectively, are major contributors to the increased CSN discharge during chemoexcitation. However, it has been proposed that the CB sensory output is also tuned by paracrine signaling pathways, involving glial-like type II cells. Indeed, type II cells express functional receptors for several excitatory neurochemicals released by type I cells including ATP, 5-HT, ACh, angiotensin II, and endothelin-1. Stimulation of the corresponding G protein-coupled receptors increases intracellular Ca2+, leading to the further release of ATP through pannexin-1 channels. Recent evidence suggests that other CB neurochemicals, e.g., histamine and DA, may actually inhibit Ca2+ signaling in subpopulations of type II cells. Here, we review evidence supporting neurotransmitter-mediated crosstalk between type I and type II cells of the rat CB. We also consider the potential contribution of paracrine signaling and purinergic catabolic pathways to the integrated sensory output of the CB during chemotransduction. PMID- 29521603 TI - Genome-wide map of proximity linkage to renin proximal promoter in rat. AB - A challenge to understanding enhancer-gene relationships is that enhancers are not always sequentially close to the gene they regulate. Physical proximity mapping through sequencing can provide an unbiased view of the chromatin close to the proximal promoter of the renin gene ( Ren). Our objective was to determine genomic regions that physically interact with the renin proximal promoter, using two different genetic backgrounds, the Dahl salt sensitive and normotensive SS 13BN, which have been shown to have different regulation of plasma renin in vivo. The chromatin conformation capture method with sequencing focused at the Ren proximal promoter in rat-derived cardiac endothelial cells was used. Cells were fixed, chromatin close to the Ren promoter was captured, and fragments were sequenced. The clustering of mapped reads produced a genome-wide map of chromatin in contact with the Ren promoter. The largest number of contacts was found on chromosome 13, the chromosome with Ren, and contacts were found on all other chromosomes except chromosome X. These contacts were significantly enriched with genes positively correlated with Ren expression and with mapped quantitative trait loci associated with blood pressure, cardiovascular, and renal phenotypes. The results were reproducible in an independent biological replicate. The findings reported here represent the first map between a critical cardiovascular gene and physical interacting loci throughout the genome and will provide the basis for several new directions of research. PMID- 29521604 TI - Oral presentation to publication: publication rates of abstract presentations across two pediatric neurosurgical meetings. AB - OBJECTIVE Both the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Pediatric Neurological Surgery (AANS/CNS Pediatric Section) and the International Society for Pediatric Neurosurgery (ISPN) annual meetings provide a platform for pediatric neurosurgeons to present, discuss, and disseminate current academic research. An ultimate goal of these meetings is to publish presented results in peer-reviewed journals. The purpose of the present study was to investigate the publication rates of oral presentations from the 2009, 2010, and 2011 AANS/CNS Pediatric Section and ISPN annual meetings in peer-reviewed journals. METHODS All oral presentations from the 2009, 2010, and 2011 AANS/CNS Pediatric Section and ISPN annual meetings were reviewed. Abstracts were obtained from the AANS/CNS Pediatric Section and ISPN conference proceedings, which are available online. Author and title information were used to search PubMed to identify those abstracts that had progressed to publication in peer-reviewed journals. The title of the journal, year of the publication, and authors' country of origin were also recorded. RESULTS Overall, 60.6% of the presented oral abstracts from the AANS/CNS Pediatric Section meetings progressed to publication in peer-reviewed journals, as compared with 40.6% of the ISPN presented abstracts (p = 0.0001). The journals in which the AANS/CNS Pediatric Section abstract-based publications most commonly appeared were Journal of Neurosurgery: Pediatrics (52%), Child's Nervous System (11%), and Journal of Neurosurgery (8%). The ISPN abstracts most often appeared in the journals Child's Nervous System (29%), Journal of Neurosurgery: Pediatrics (14%), and Neurosurgery (9%). Overall, more than 90% of the abstract-based articles were published within 4 years after presentation of the abstracts on which they were based. CONCLUSIONS Oral abstract presentations at two annual pediatric neurosurgery meetings have publication rates in peer-reviewed journal comparable to those for oral abstracts at other national and international neurosurgery meetings. The vast majority of abstract-based papers are published within 4 years of the meeting at which the abstract was presented; however, the AANS/CNS Pediatric Section abstracts are published at a significantly higher rate than ISPN abstracts, which could indicate the different meeting sizes, research goals, and resources of US authors compared with those of authors from other countries. PMID- 29521605 TI - Neurodevelopmental outcomes in children with large temporal arachnoid cysts. AB - OBJECTIVE Management of children with large temporal arachnoid cysts (TACs) remains controversial, with limited data available on their neurodevelopmental outcome. The aim of this study was to examine neurodevelopmental outcomes in children with large TACs. METHODS In this medical center-based cohort study, 25 patients (19 males) who were diagnosed in childhood with large TACs (9 patients [36%] with a Galassi type II and 16 patients [64%] with a Galassi type III TAC) were examined. The mean +/- SD age at assessment was 11.1 +/- 5.6 years (range 2.7-22 years). Twelve patients (48%) had right-sided, 12 (48%) had left-sided, and 1 (4%) had bilateral cysts. Nine patients (36%) underwent surgery for the cyst. The siblings of 21 patients (84%) served as control participants. Neurodevelopmental function was assessed using the Adaptive Behavior Assessment System (ABAS), Vanderbilt Behavioral Rating Scale (VBRS), and Developmental Coordination Disorder Questionnaire (DCDQ), and quality of life was measured using the treatment-oriented screening questionnaire (TOSQ). The results of all instruments except for TOSQ were compared with those of the sibling control participants. RESULTS The mean +/- SD ABAS score of the patients was 93.3 +/- 20.09 compared with 98.3 +/- 18.04 of the sibling control participants (p = 0.251). Regarding the incidence of poor outcome (ABAS score < 80), there was a trend for more patients with TAC to have poor outcome than the sibling controls (p = 0.058). Patients who underwent surgery scored significantly worse with regard to the VBRS total score compared with those who did not (p = 0.020), but not on ABAS, DCD, or TOSQ. The mean score of the cognitive and psychological items on TOSQ was lower than that for the physical items (p < 0.001). CONCLUSIONS Children with a large TAC performed similarly to their sibling control participants in neurodevelopmental function. However, a subgroup of those with cysts did have an increased risk for poor outcomes in general function. Neurodevelopmental assessment should be part of the management of all patients with TAC. PMID- 29521606 TI - Coincident myelomeningocele and gastroschisis: report of 2 cases. AB - Myelomeningocele and gastroschisis, on their own, are both relatively common entities encountered in pediatric surgical care. Coexistence of these pathologies, however, is exceedingly rare. The authors report on 2 patients who presented with myelomeningocele and gastroschisis at birth. They obtained blood for whole-exome analysis for one of the patients and identified 3 mutations that could be related to the underlying anomalies: homozygous mutations in FAM171B and ABCA1 and a hemizygous (X-linked) mutation in COL4A5. Of these, FAM171B and ABCA1 both have function that may be related to the underlying disease. PMID- 29521607 TI - Development of severe hyponatremia due to cerebrospinal fluid leakage following meningomyelocele surgery in a newborn. AB - Cerebrospinal fluid leakage following meningomyelocele surgery is a frequent complication in the wound-healing period and is associated with wound dehiscence. CSF loss can cause severe hyponatremia, especially in the newborn and early infancy periods when dietary sodium content is relatively low. Hyponatremia in the newborn period can result in adverse neurodevelopmental outcomes. In addition, hyponatremia's cerebral effects can increase complications in neurosurgery patients. The authors present the case of a newborn in whom CSF leakage from the operative site and severe hyponatremia developed following meningomyelocele surgery. To the best of their knowledge, severe hyponatremia caused by CSF leakage after meningomyelocele surgery has not been previously reported in the literature. PMID- 29521608 TI - The adversative connectives aber and but in conversational corpora. AB - We analyzed the conversational corpora of two German and two English children to investigate how the different use types of the adversative connectives aber and but influence the probability of monologically versus dialogically constructed utterances in the first year of use. Our findings show that children produce adversative connectives mainly in dialogic structures for illocutionary and theme management purposes, but that the use types of adversative connectives lead to a different distribution of monologic and dialogic clause combinations. The results suggest that monologic and dialogic realizations as a function of text type must be considered when describing the developmental trajectory of the different use types of adversative connectives. PMID- 29521609 TI - Care gap: a comprehensive measure to quantify unmet needs in mental health. AB - AIM: Treatment gap refers to the percentage of individuals who require treatment in a country or a defined community but do not receive it due to various reasons. There is widespread acceptance of 'treatment gap' as a measure of unmet needs in mental health. However, the term 'treatment' carries a medical connotation and implies biomedical treatment (or lack of it) of mental illness and is often interpreted by policymakers, planners and researchers, as well as by non professional stakeholders as exclusively referring to curative clinical psychiatric interventions. This common interpretation results in the exclusion of a range of effective psychosocial interventions available today. Treatment gap also does not include physical health services for persons with mental illness, a major concern due to the relative frequent yet highly unattended physical comorbidity and early mortality of persons with severe mental illness. METHODS & RESULTS: We, therefore, propose a more comprehensive measure of unmet needs. PMID- 29521610 TI - Visual working memory encoding in schizophrenia and first-degree relatives: neurofunctional abnormalities and impaired consolidation. AB - BACKGROUND: Working memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation - i.e. the formation of durable WM representations - is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before. METHOD: We examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation. RESULTS: SCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals. CONCLUSIONS: Findings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker. PMID- 29521611 TI - The association between executive functioning and psychopathology: general or specific? AB - BACKGROUND: We modeled both psychopathology and executive function (EF) as bi factor models to study if EF impairments are transdiagnostic or relate to individual syndromes, and concurrently, if such associations are with general EF or specific EF impairments. METHODS: Data were obtained from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2230). Psychopathology was assessed with parent-report questionnaires at ages 11, 14, 16, and 19, and EF with tasks from the Amsterdam Neuropsychological Tasks program at ages 11 and 19. Bi-factor models were fitted to the data using confirmatory factor analysis. Correlations were estimated to study the associations between general or specific components of both psychopathology and EF. RESULTS: A bi-factor model with a general psychopathology factor, alongside internalizing (INT), externalizing, attention deficit/hyperactivity (ADHD), and autism spectrum (ASD) problem domains, and a bi-factor model with a general EF factor, alongside specific EFs were adequately fitting measurement models. The best-fitting model between EF and psychopathology showed substantial associations of specific EFs with the general psychopathology factor, in addition to distinct patterns of association with ASD, ADHD, and INT problems. CONCLUSIONS: By studying very diverse psychopathology domains simultaneously, we show how EF impairments cross diagnostic boundaries. In addition to this generic relation, ADHD, ASD, and INT symptomatology show separable profiles of EF impairments. Thus, inconsistent findings in the literature may be explained by substantial transdiagnostic EF impairments. Whether general EF or specific EFs are related to psychopathology needs to be further studied, as differences in fit between these models were small. PMID- 29521612 TI - Differences in Growth Reading Patterns for at-Risk Spanish-Monolingual Children as a Function of a Tier 2 Intervention. AB - The present study compares the patterns of growth of beginning reading skills (i.e., phonemic awareness, phonics, fluency, vocabulary and comprehension) of Spanish speaking monolingual students who received a Tier 2 reading intervention with students who did not receive the intervention. All the students in grades K 2 were screened at the beginning of the year to confirm their risk status. A quasi-experimental longitudinal design was used: the treatment group received a supplemental program in small groups of 3 to 5 students, for 30 minutes daily from November to June. The control group did not receive it. All students were assessed three times during the academic year. A hierarchical linear growth modeling was conducted and differences on growth rate were found in vocabulary in kindergarten (p < .001; variance explained = 77.0%), phonemic awareness in kindergarten (p < .001; variance explained = 43.7%) and first grade (p < .01; variance explained = 15.2%), and finally we also find significant growth differences for second grade in oral reading fluency (p < .05; variance explained = 15.1%) and retell task (p < .05; variance explained = 14.5%). Children at risk for reading disabilities in Spanish can improve their skills when they receive explicit instruction in the context of Response to Intervention (RtI). Findings are discussed for each skill in the context of implementing a Tier 2 small group intervention within an RtI approach. Implications for practice in the Spanish educational context are also discussed for children who are struggling with reading. PMID- 29521613 TI - Pseudobizionia ponticola gen. nov., sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated MM-14T, was isolated from seawater sampled from the Yellow Sea in the Republic of Korea and its taxonomic position was investigated using a polyphasic approach. Strain MM-14T grew optimally at 30 degrees C and in the presence of approximately 2.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain MM-14T clustered with the type strain of Hanstruepera neustonica. The novel strain exhibited a 16S rRNA gene sequence similarity value of 96.06 % to the type strain of H. neustonica, but higher 16S rRNA gene sequence similarity values (96.13-96.69 %) to the type strains of Bizionia echini, Bizionia hallyeonensis and Bizionia psychrotolerans. Strain MM 14T contained MK-6 as the predominant menaquinone and iso-C15 : 0, iso-C15 : 1 G and iso-C17 : 0 3-OH as the major fatty acids. The major polar lipids were phosphatidylethanolamine, one unidentified lipid and one unidentified aminolipid. The DNA G+C content of strain MM-14T was 34.6 mol%. The phylogenetic and chemotaxonomic data and other phenotypic properties revealed that strain MM-14T constitutes a new genus and species within the family Flavobacteriaceae of the phylum Bacteroidetes, for which the name Pseudobizionia ponticola gen. nov., sp. nov. is proposed. The type strain of Pseudobizionia ponticola is MM-14T (=KACC 19434T=KCTC 62139T=NBRC 113019T). PMID- 29521614 TI - Moniliella sojae sp. nov., a species of black yeasts isolated from Vietnamese soy paste (tuong), and reassignment of Moniliella suaveolens strains to Moniliella pyrgileucina sp. nov., Moniliella casei sp. nov. and Moniliella macrospora emend. comb. nov. AB - The presence of yeasts at different steps of Vietnamese soy paste production was studied. Yeast growth occurred during primary soybean fermentation, with the cell density reaching 4.106 c.f.u. ml-1, and terminated during brine fermentation. The dominant species were Pichia kudriavzevii and Millerozyma farinosa. Over the span of 14 years, nine strains of Moniliella were isolated. The strains had identical PCR fingerprints generated with primer (GAC)5 and identical D1/D2 and internal transcribed spacer (ITS) sequences. A D1/D2-based phylogeny indicated that the strains were closest to a group of four previously assigned as Moniliella suaveolens strains. Together they form a new lineage that is well separated from all known species, including M. suaveolens (over 12.7 % divergence). ITS sequences indicated the presence of four species differing from each other by 9 57 nt. The name Moniliella sojae sp. nov. is proposed to accommodate the strains isolated from Vietnamese soy paste, Moniliella pyrgileucina sp. nov. is proposed for PYCC 6800 and Moniliella casei sp. nov. is proposed for CBS 157.58. An emended combination Moniliella macrospora is proposed for CBS 221.32 and CBS 223.32. The type strains and MycoBank numbers are: M. sojae sp. nov., SS 4.2T=CBS 126448T=NRRL Y-48680T and MB 822871; M. pyrgileucina sp. nov., PYCC 6800T=CBS 15203T and MB 823030; M. casei sp. nov., CBS 157.58T=IFM 60348T and MB 822872; M. macrospora emend. comb. nov., CBS 221.32T (=MUCL 11527T) and MB 822874. PMID- 29521615 TI - Tenacibaculum todarodis sp. nov., isolated from a squid. AB - A Gram-stain-negative, rod-shaped, aerobic bacterial strain, designated LPB0136T, was isolated from a squid Todarodes pacificus, caught in the East Sea, off Korea. LPB0136T contained a circular chromosome of 3.02 Mb with a DNA G+C content of 30.7 mol%. The genome included 2726 protein-coding genes and three copies of rRNA operons. Phylogenetic analysis of the 16S rRNA gene sequence indicated that this isolate represents a member of the genus Tenacibaculum with an independent genomic species status, showing sequence similarities of 95.9 % to Tenacibaculum aestuarii SMK-4T and Tenacibaculum caenipelagi HJ-26MT. The detected respiratory quinone (MK-6) and major polar lipid (phosphatidylethanolamine) were similar to the chemotaxonomic profile of other species of the genus Tenacibaculum. The major cellular fatty acids profile (iso-C15 : 0, iso-C15 : 0 3-OH and iso-C15 : 0G) was also similar to those of members of genus Tenacibaculum, but the contents and amounts differed from those of closely related neighbours. Many biochemical and physiological characteristics also distinguished the isolate from other species within the genus Tenacibaculum. On the basis of the pholyphasic taxonomic data determined in this study, strain LPB0136T represents a novel species of the genus Tenacibaculum, for which the name Tenacibaculum todarodis sp. nov. is proposed. The type strain is LPB0136T (=KACC 18887T=JCM 31564T). PMID- 29521616 TI - N-acetyl-cysteine increases the replication of Chlamydia pneumoniae and prolongs the clearance of the pathogen from mice. AB - PURPOSE: Within the community, 10 % of acquired pneumonia is caused by Chlamydia pneumoniae. N-acetyl-cysteine (NAC) is one of the most commonly used mucolytics in respiratory diseases, but its effect on C. pneumoniae infection has not yet been investigated. In this study, our aim was to investigate whether NAC influences the replication of C. pneumoniae. After determining that NAC does have an effect on C. pneumoniae replication, the effect of an alternative drug called Ambroxol (Ax) was investigated. METHODOLOGY: The in vitro effect of NAC and Ax was studied on C. pneumoniae-infected A549 and McCoy cells. Furthermore, the influence of NAC and Ax was examined in mice infected intranasally with C. pneumoniae. RESULTS: NAC treatment resulted in approximately sixfold more efficient C. pneumoniae growth in tissue culture compared to the untreated control cells, and this effect was shown to be based on the increased binding of the bacterium to the host cells. The C. pneumoniae-infected mice to which NAC was given had prolonged and more severe infections than the control mice. Ax decreased C. pneumoniae replication in vitro, which was partially associated with the increased expression of indolamine 2,3-dioxygenase. In animals, using the adapted usual human dose, Ax did not alter the number of recoverable C. pneumoniae. CONCLUSION: Based on our results, it might be recommended that a mucolytic agent other than NAC, such as Ax, be used in respiratory diseases suspected to be caused by C. pneumoniae. PMID- 29521617 TI - Retrospective study on clonal relationship of multidrug-resistant Klebsiella spp. indicates closed circulation and initiation of clonal divergence. AB - PURPOSE: Antibiotic resistance patterns often exhibit geographical variations. Periodic analyses of resistance spectra and phylogenetic trends are important guides for facilitating judicious use of therapeutic interventions. The present study retrospectively analysed the infection trends, resistance patterns, and clonal relationships between isolates of Klebsiella spp. from a tertiary care hospital. METHODOLOGY: Bacterial isolates were collected from January 2013 to June 2014 and their resistance profiles were identified using an automated bacterial identification system. A phylogenetic tree was constructed using housekeeping genes with Molecular Evolutionary Genetic Analysis software. The dN/dS ratio was determined by the Synonymous Non-synonymous Analysis Program while polymorphic sites, and the difference per site was calculated using DNA Sequence Polymorphism software. Statistical Package for Social Science software was used to perform all statistical analyses. KEY FINDINGS: The results of this study indicated the prevalence of community-acquired urinary tract and lower respiratory tract infections caused by Klebsiella spp. among geriatric patients. The occurrence of new allelic profiles, a low dN/dS ratio and the lack of strong evolutionary descent between isolates indicated that mutations play a major role in the evolution of the organism. CONCLUSION: The findings of this study highlight the consequences of antimicrobial agents exerting a silent and strong selective force on the evolution of Klebsiella spp. The expansion of such analyses is of great importance for addressing rapidly emerging antibiotic resistant opportunistic pathogens. PMID- 29521619 TI - Application of the Risk-Based Early Warning Method in a Fracture-Karst Water Source, North China. AB - The paper proposes a risk-based early warning considering characteristics of fracture-karst aquifer in North China and applied it in a super-large fracture karst water source. Groundwater vulnerability, types of land use, water abundance, transmissivity and spatial temporal variation of groundwater quality were chosen as indexes of the method. Weights of factors were obtained by using AHP method based on relative importance of factors, maps of factors were zoned by GIS, early warning map was conducted based on extension theory with the help of GIS, ENVI+IDL. The early warning map fused five factors very well, serious and tremendous warning areas are mainly located in northwest and east with high or relatively high transmissivity and groundwater pollutant loading, and obviously deteriorated or deteriorated trend of petroleum. The early warning map warns people where more attention should be paid, and the paper guides decision making to take appropriate protection actions in different warning levels areas. PMID- 29521620 TI - Spatial Variation of Metals in the Batang Arau River, West Sumatera, Indonesia. AB - This paper aims to assess metallic pollution in the Batang Arau River, an important source of freshwater supply for local communities in West Sumatera, Indonesia, by applying multivariate statistical techniques. Sampling was conducted at eight stations along the river from March to May 2014. The results indicate that all the metals studied have similar spatial distribution patterns, with an increasing trend in concentration from upstream to downstream. Total concentration of six metals studied upstream, as background concentration, was 1.050 mg/L, and increased to 2.249 mg/L downstream. Spatial distribution of metals did not show significant variability (p < 0.05) for Cd, Cr, Fe, and Pb, but Co and Mn did. The results of principal component analysis/factor analysis (PCA/FA) and correlation analysis suggest that Cd, Co, and Fe are originated from natural and anthropogenic sources; Cr and Pb are derived from natural sources; and Mn is controlled by anthropogenic sources. PMID- 29521621 TI - Modeling Storm-Influenced Suspended Particulate Matter Flocculation Using a Tide Wave-Combined Biomineral Model. AB - Flocculation of suspended particulate matter (SPM) in marine and estuarine environments is a complex process that is influenced by physical, biological, and chemical mechanisms. The flocculation model of Maggi (2009) was adapted to simulate flocculation under various weather conditions and during different seasons. The adaptation incorporated the effect of tide-wave-combined turbulence on floc dynamics. The model was validated using in situ measurements of floc size and SPM concentration from the southern North Sea during both calm and storm conditions. The results show that tide-wave-combined turbulence needs to be incorporated when simulating flocculation in a tide-wave-dominated environment. The observed seasonal variations in floc size (Fettweis et al., 2014) were reproduced using varying values for various floc strengths in different seasons. The results revealed that the biological effect on floc strength, which enhances aggregation, is stronger during summer, indicating that floc strength in the model should be varied seasonally. PMID- 29521622 TI - Liquid-Gas Mass Transfer of Volatile Substances in an Energy Dissipating Structure. AB - Mass transfer of a range of volatile substances was studied under highly turbulent conditions. The applied setup mimicked drop structures, where the release of volatile organic carbons likely occurs at a high rate. The experiments covered several substances in a range of resistances from residing entirely in the liquid film to being fully in the gas film. The two-film theory yielded a good prediction of the whole measured range. This allowed the experimental validation of a method where two reference substances are applied, to determine the transfer of any other substance - independently of where its resistance to mass transfer resides. One finding was that the range of dimensionless Henry's constants, where both films contributed by more than 5%, was 0.0027 to 1.05, which is over five times higher than the accepted rule of thumb (0.0005-0.18). Another finding was that the ratio between the liquid and the gas film mass transfer coefficients of the reference substances was similar for the two drop configurations studied. If this holds true over a wider range of configurations, such a ratio constitutes a valuable shortcut to the current practice of ignoring gas film resistance in the estimation of mass transfer rates. PMID- 29521623 TI - Thermal Degradation of Long Chain Fatty Acids. AB - The thermal hydrolysis of saturated (C16:0 and C18:0) and unsaturated fatty acids (C16:1, C18:1, and C18:2) was investigated at 90 degrees C to 160 degrees C for 30 min and 8 h durations. Hydrolysis efficiencies were calculated based on mass yield (i.e., mg/g parent compound), which accounted for all C2-C24 by products. Very little degradation (less than 1%) of long chain fatty acids (LCFAs) was observed from 30 min thermal hydrolysis. At 140 and 160 degrees C for 8 h, saturated fatty acids degraded uniformly to C2 to C14. Saturated fatty acids tended to convert to alkanes (1.5-2.0% of total fatty acids) instead of fatty acids (8 h). Thermal hydrolysis did not significantly affect unsaturated LCFA degradation at any duration. The unsaturated by-products seen were the result of cleavage at the allylic or vinylic positions. Thermal hydrolysis of LCFAs with digested sludge was investigated. The amount of VFAs and LCFAs in primary and secondary sludge was increased at 140 and 160 degrees C as a result of lipid degradation in the sludge mixture. Thermal hydrolysis of fatty acids with different catalysts was also investigated. Whereas saturated LCFAs were stable under all catalytic conditions, unsaturated LCFAs were nearly completely degraded when hydrolyzed with hydrogen peroxide and activated carbon or copper sulfate. PMID- 29521625 TI - CRISPR-based herd immunity can limit phage epidemics in bacterial populations. AB - Herd immunity, a process in which resistant individuals limit the spread of a pathogen among susceptible hosts has been extensively studied in eukaryotes. Even though bacteria have evolved multiple immune systems against their phage pathogens, herd immunity in bacteria remains unexplored. Here we experimentally demonstrate that herd immunity arises during phage epidemics in structured and unstructured Escherichia coli populations consisting of differing frequencies of susceptible and resistant cells harboring CRISPR immunity. In addition, we develop a mathematical model that quantifies how herd immunity is affected by spatial population structure, bacterial growth rate, and phage replication rate. Using our model we infer a general epidemiological rule describing the relative speed of an epidemic in partially resistant spatially structured populations. Our experimental and theoretical findings indicate that herd immunity may be important in bacterial communities, allowing for stable coexistence of bacteria and their phages and the maintenance of polymorphism in bacterial immunity. PMID- 29521628 TI - Psoriasis-associated interstitial pneumonia. PMID- 29521626 TI - IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate. AB - Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro, IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly. IgD-only Lyn-/- B cells cannot generate autoantibodies and short-lived plasma cells (SLPCs) in vivo, a fate thought to be driven by intense BCR signaling induced by endogenous antigens. Similarly, IgD-only B cells generate normal germinal center, but impaired IgG1+ SLPC responses to T-dependent immunization. We propose a role for IgD in maintaining the quiescence of autoreactive B cells and restricting their differentiation into autoantibody secreting cells. PMID- 29521624 TI - Functional genomics of lipid metabolism in the oleaginous yeast Rhodosporidium toruloides. AB - The basidiomycete yeast Rhodosporidium toruloides (also known as Rhodotorula toruloides) accumulates high concentrations of lipids and carotenoids from diverse carbon sources. It has great potential as a model for the cellular biology of lipid droplets and for sustainable chemical production. We developed a method for high-throughput genetics (RB-TDNAseq), using sequence-barcoded Agrobacterium tumefaciens T-DNA insertions. We identified 1,337 putative essential genes with low T-DNA insertion rates. We functionally profiled genes required for fatty acid catabolism and lipid accumulation, validating results with 35 targeted deletion strains. We identified a high-confidence set of 150 genes affecting lipid accumulation, including genes with predicted function in signaling cascades, gene expression, protein modification and vesicular trafficking, autophagy, amino acid synthesis and tRNA modification, and genes of unknown function. These results greatly advance our understanding of lipid metabolism in this oleaginous species and demonstrate a general approach for barcoded mutagenesis that should enable functional genomics in diverse fungi. PMID- 29521627 TI - A compartmentalized signaling network mediates crossover control in meiosis. AB - During meiosis, each pair of homologous chromosomes typically undergoes at least one crossover (crossover assurance), but these exchanges are strictly limited in number and widely spaced along chromosomes (crossover interference). The molecular basis for this chromosome-wide regulation remains mysterious. A family of meiotic RING finger proteins has been implicated in crossover regulation across eukaryotes. Caenorhabditis elegans expresses four such proteins, of which one (ZHP-3) is known to be required for crossovers. Here we investigate the functions of ZHP-1, ZHP-2, and ZHP-4. We find that all four ZHP proteins, like their homologs in other species, localize to the synaptonemal complex, an unusual, liquid crystalline compartment that assembles between paired homologs. Together they promote accumulation of pro-crossover factors, including ZHP-3 and ZHP-4, at a single recombination intermediate, thereby patterning exchanges along paired chromosomes. These proteins also act at the top of a hierarchical, symmetry-breaking process that enables crossovers to direct accurate chromosome segregation. PMID- 29521630 TI - Intramuscular haemorrhage in a patient with dermatomyositis and anti-TIF1gamma antibodies. PMID- 29521631 TI - Bullous pemphigoid in a mother (DQB1*03:01:01) and daughter (DRB1*11:01) receiving antidiabetic drugs. PMID- 29521629 TI - A novel base pair deletion in the TRPS1 gene in a Japanese patient with trichorhinophalangeal syndrome. PMID- 29521632 TI - Overexpression of cytotoxic proteins correlates with liver function impairment in patients with drug reaction with eosinophilia and systemic symptoms (DRESS). AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterised by skin rash and multivisceral involvement. The liver is the organ most frequently affected and the degree of liver function impairment often correlates with the mortality rate of DRESS. We aimed to examine the expression of cytotoxic proteins, including soluble Fas ligand (sFasL), TNF-alpha, granulysin, perforin, and granzyme B in the sera and skin lesions of patients with DRESS and evaluate their clinical significance. Our cohort consisted of 21 patients with DRESS and control groups including 39 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 21 patients with maculopapular eruption, and 29 normal controls. Concentrations of cytotoxic proteins in the sera were measured using enzyme-linked immunosorbent assays. Tissue samples were also obtained from typical skin lesions, and immunohistochemical staining was conducted to assess the local expression of cytotoxic proteins. We found that sFasL and granzyme B were significantly overexpressed in the sera of DRESS patients compared to normal controls. Furthermore, the levels of sFasL, perforin, and granzyme B significantly correlated with the serum level of liver enzymes in DRESS patients. Immunohistochemical examination also showed overexpressed cytotoxic proteins in cutaneous DRESS lesions. Cytotoxic proteins may play a vital role in the pathogenesis of DRESS, and serum sFasL, perforin, and granzyme B may also be involved in liver function impairment in DRESS patients. PMID- 29521633 TI - What's new this month? PMID- 29521634 TI - Dermpath & Clinic: Cutaneous Crohn's disease. PMID- 29521635 TI - And next... Adnexa: Onychopapilloma. PMID- 29521636 TI - sQUIZ your knowledge! Long-standing annular lesions in a young man. PMID- 29521637 TI - Risk factors for lethal outcome in patients with pemphigus: a retrospective cohort study. AB - Although pemphigus is associated with increased mortality, little is known regarding factors that influence prognosis. To identify prognostic factors for mortality at five- and 10-year periods after an initial diagnosis of pemphigus. A retrospective cohort study was performed. Data were collected for all patients with a new diagnosis of pemphigus between 1990 and 2011, who were actively followed for at least five years at our centre. The endpoint was overall survival at five and 10 years after pemphigus diagnosis. Based on the test sample, associations between clinical variables and overall survival were assessed using univariate and multivariate analyses. A total of 184 patients were included in the study (mean age: 52.2 +/- 16.1). The major risk factors for lethal outcome at both five and 10 years after diagnosis were age >=65 years at diagnosis (with a multivariate hazard ratio [HR] of 5.9 and 4.2 at five and 10 years, respectively) and neurological disease at diagnosis (with a multivariate HR of 5.4 and 5.1 at 5 and 10 years, respectively). Diabetes mellitus was an independent risk factor for mortality at five years (multivariate HR: 3.8). Two risk factors were independently associated with lethal outcome at 10 years: serum albumin levels <3.5 g/dL (multivariate HR: 3.3) and lung disease at diagnosis (multivariate HR: 3.8). Mucosal involvement in patients with pemphigus vulgaris was not associated with increased mortality. Prognosis of patients with pemphigus is influenced by older age, hypoalbuminaemia, diabetes mellitus, and neurological and respiratory comorbidities at diagnosis. PMID- 29521638 TI - The use of biodegradable microneedle patches to increase penetration of topical steroid for prurigo nodularis. AB - BACKGROUND: The stratum corneum is an almost impermeable barrier. Recently, microneedles have been used to increase drug delivery passing the stratum corneum by incorporating the drug within the microneedle or by coating the surface of the microneedle with the drug. OBJECTIVE: This study was performed to investigate whether applying a biodegradable microneedle patch after topical steroid application increases penetration of the steroid in vitro, as well as treatment efficacy in patients with prurigo nodularis. MATERIALS & METHODS: In vitro penetration of topical steroids after biodegradable microneedle patch application was measured using a 3D skin model. To evaluate the treatment efficacy of the combination of biodegradable microneedle and topical steroids, a split-body clinical study was performed. RESULTS: Penetration of topical steroid in the in vitro skin model was significantly greater in the microneedle-applied skin. In a split-body clinical study with prurigo nodularis patients, the area and height of skin lesions decreased after four weeks of treatment on both sides, however, the microneedle patch side exhibited a significantly greater decrease in both area and height, compared to the control side. The pruritus visual analogue scale was also significantly lower on the microneedle side. CONCLUSION: We suggest that simply applying a microneedle patch after topical steroid application could be a useful strategy for treating refractory skin diseases such as prurigo nodularis. PMID- 29521639 TI - Profile and Antibiotic Susceptibility of Bacteria Isolates in Burn Patients Hospitalized in a Moroccan Hospital: A Cross-sectional Study. AB - OBJECTIVE: The aim of this cross-sectional study is to assess the epidemiological profile and antibiotic susceptibility of bacteria isolates in burn patients hospitalized from 2007 to 2015 in a Moroccan hospital. MATERIALS AND METHODS: Of 627 samples, 451 wounds, 126 blood cultures, and 50 catheter samples were analyzed. A total of 610 microorganisms were isolated from a total of 108 patients. RESULTS: The most prevalent isolates were Pseudomonas aeruginosa (18.5%), Acinetobacter baumannii (14.7%), and Staphylococcus aureus (14.5%); a high prevalence (31.1%) of methicillin-resistant S aureus also was found. Imipenem followed by piperacillin/tazobactam performed best against P aeruginosa. A baumannii isolates showed a very high resistance to imipenem and all beta lactams antibiotics but were sensitive to colistin. CONCLUSIONS: The profile of this bacterial ecology shows there are resistant species requiring frequent use of second-line antibiotics and strengthening of aseptic procedures in burn treatments. PMID- 29521640 TI - A Randomized Controlled Study Evaluating the Clinical Benefits of a Cellulose Acetate Mesh Coated with a Soft Silicone in the Management of Acute Wounds. AB - INTRODUCTION: Dressings are a mainstay for wound management; however, dressing adherence to the wound or periwound area can cause pain and trauma at removal. Dressing-related trauma includes skin reactions, adherence to the wound, and skin stripping. The development of atraumatic wound contact layer dressings has been a major advancement in reducing trauma. OBJECTIVE: This study compares the benefits of a cellulose acetate mesh (CAM) coated with soft silicone versus a flexible polyamide net (FPN) coated with soft silicone. MATERIALS AND METHODS: A multicenter, randomized controlled study was conducted in 70 patients (35 in CAM group [1 patient exclused due to not receiving treatment], 35 in the FPN group) with traumatic, postsurgical, and burn wounds. Wounds were assessed once per week for 4 weeks to measure dressing adherence to the wound bed, percent reepithelialization, and patient tolerance. All wounds were prepared according to standard of care wound management protocol at the time of assessment. RESULTS: In this study, 97.06% (n = 33) of patients in the CAM group and 91.43% (n = 32) in the FPN group did not report dressing adherence during any of the assessments. Average time to complete reepithelialization was 16 days in the CAM group versus 15 days in the FPN group (P = .4958), and both products had excellent tolerance. CONCLUSIONS: This study demonstrated that CAM coated with a soft silicone performed as well as the FPN contact layer in minimizing dressing adherence, time to complete reepithelialization, and patient tolerance. PMID- 29521641 TI - Clinical Assessment of a Biofilm-disrupting Agent for the Management of Chronic Wounds Compared With Standard of Care: A Therapeutic Approach. AB - OBJECTIVE: The authors study the use of a biofilm-disrupting wound gel designed for wound management to determine if disrupting chronic wound biofilm would be therapeutically efficacious. MATERIALS AND METHODS: This prospective, randomized, open-label clinical trial was performed from September 2014 through March 2016. Forty-three patients (22 experimental, 21 control) with chronic, recalcitrant wounds were randomized to a 12-week treatment with a biofilm-disrupting wound gel (experimental) or a broad-spectrum antimicrobial ointment (control). The wound healing rate was assessed by measuring wound size reduction and wound closure rates. RESULTS: Wound size in the experimental group decreased significantly with a 71% reduction in wound area compared with 24% for the control (P < .001). Wound closure was attained in more than half of the patients (14) treated with the experimental product. Fifty-three percent of these patients achieved closure by 12 weeks as opposed to 17% for the control (P < .01). No adverse events related to the experimental product were recorded, but 2 adverse reactions occurred with the control. CONCLUSIONS: The combination of the experimental product and wound debridement significantly improved wound healing rates by disrupting the biofilm, which protects multispecies bacteria within a chronic wound. Given the significant wound size reduction and closure rates observed in these long-term, nonhealing wounds, as well as the lack of related serious adverse events, the investigators believe the biofilm-disrupting wound gel to be a safe and effective treatment for recalcitrant chronic wounds. PMID- 29521642 TI - Assessment of 16-month Sequelae Due to Dog Bites Originally Studied in a French Multicenter Survey from 2009 to 2011. AB - INTRODUCTION: Every year in France dog bites lead to several thousand visits to emergency departments and numerous hospital admissions. OBJECTIVE: This study aims to describe the sequelae 16 months after dog bites. MATERIALS AND METHODS: Following an initial epidemiological study on the severity of 485 dog bites carried out in 8 hospital emergency departments between May 1, 2009, and June 30, 2010, a second study investigating sequelae 16 months after the bite was conducted among 298 patients between September 2010 and December 2011. Data concerning patients' sequelae were collected by telephone or email. RESULTS: Almost half of respondents (47%) reported sequelae; of those patients, most of these reports were aesthetic (9/10). There were more sequelae when the bite was located in the head region or the lower limbs. Sequelae were more frequent among women, when the weight of the biting dog was higher, and when the initial severity of the bite was greater. On the other hand, the link between the patient and the dog, the sex of the dog, the type of aggression, and the age of the patient (< 15 years or >= 15 years) had no impact on the occurrence of sequelae. One patient in 7 still experienced pain 16 months after the bite; women were more likely to experience pain at that timepoint. No articles on dog bite sequelae were found in the literature. CONCLUSIONS: The dissemination of these results among professionals (veterinarians and doctors) and the general population will contribute to making dog owners more aware of the risk of bites and the means of avoiding them. PMID- 29521643 TI - Clinic-based Debridement of Chronic Ulcers Has Minimal Impact on Bacteria. AB - : Outpatient-based sharp debridement is considered an important element for the care of a chronic ulcer. OBJECTIVE: The aim of this study is to evaluate the change in bacterial amounts with sharp debridement in a clinical setting. MATERIALS AND METHODS: Bacterial autofluorescence, quantitative cultures, semiquantitative cultures, and qualitative speciation were performed predebridement and postdebridement during a single clinic visit. RESULTS: Thirty six wounds were included in the analysis. The mean patient age was 62 years (range, 27-83 years), and there were 13 (36.11%) women and 23 (63.89%) men with an average body mass index of 33.8 kg/m2 (range, 16.7-55.9 kg/m2). Of the 36 patients, 24 (66.67%) had type 2 diabetes and 19 (52.78%) had a prior history of lower extremity amputation. Majority of the ulcers were diabetic neuropathic (27, 75%); the most common location was on the plantar aspect of the foot (14, 41.67%) with a mean ulcer duration of 10 months (range, 1-36), mean ulcer area of 6.3 +/- 12.8 cm2 (range, 0.18-62.06 cm2), and mean volume of 2.2 +/- 4.4 cm3 (range, 0.05 9.66 cm3). There was no statistically significant difference in bacterial autofluorescence between the predebridement (4.15 +/- 8.82) and the postdebridement (4.65 +/- 9.48) images (P = .32). There was a statistically significant difference in quantitative culture results between the predebridement (6.7 x 104 +/- 1.4 x 106 CFU/cm2) and the postdebridement (1.7 x 104 +/- 3.1 x 106 CFU/cm2) cultures (P = .04), although this is not a log reduction. CONCLUSIONS: There is no statistically significant difference between the predebridement versus postdebridement semiquantitative culture results or a detectable pattern of change for the most common bacterial species encountered. These results suggest little impact of clinic-based sharp debridement on bacteria. PMID- 29521644 TI - Cost-effectiveness Analysis of Silver Delivery Approaches in the Management of Partial-thickness Burns. AB - INTRODUCTION: Burn injury is a common type of traumatic injury that causes considerable morbidity and mortality, resulting in about 30,000 admissions annually in specialist burn centers and costing around $1 billion per year in the United States. One percent silver sulfadiazine has been utilized widely in the management of burns and newer silver dressings are on the market, including nanocrystalline silver dressings, silver-impregnated hydrofiber dressings, and silver-impregnated foam dressings. OBJECTIVE: This study sought to determine the cost effectiveness of the newer silver dressings using clinical data from an indirect treatment comparison using silver sulfadiazine as the baseline. MATERIALS AND METHODS: A decision analytic model was developed from a US payer's perspective for burn patients with a total body surface area of < 20%. Outcomes were length of stay, infections and incidence of surgical procedures, quality adjusted life years (QALYs), and cost. RESULTS: The meta-analysis reported a statistically significant reduction in length of hospital stay and clinically important reductions in infections and incidence of surgical procedures in favor of the silver barrier dressing compared with other silver dressings. The estimated QALYs were 0.970 versus 0.969 versus 0.969 and mean cost per patient was $15,892, $23,799, and $24,269 for the nanocrystalline silver dressing, silver impregnated hydrofiber dressing, and silver-impregnated foam dressing, respectively. The analysis showed the nanocrystalline silver dressing to be a dominant strategy (less costly with better outcomes). These findings were robust to a range of sensitivity analyses. CONCLUSIONS: According to data from an indirect treatment comparison, this analysis suggests that nanocrystalline silver dressing is the most cost-effective silver delivery system. Prospective head-to head research on the costs and outcomes of these silver delivery systems in this patient population is necessary to validate the results of this economic evaluation. PMID- 29521645 TI - Solution-processed all-oxide bulk heterojunction solar cells based on CuO nanaorod array and TiO2 nanocrystals. AB - We present a method to synthesize CuO nanorod array/TiO2 nanocrystals bulk heterojunction (BHJ) on fluorine-tin-oxide (FTO) glass, in which single crystalline p-type semiconductor of the CuO nanorod array is grown on the FTO glass by hydrothermal reaction and the n-type semiconductor of the TiO2 precursor is filled into the CuO nanorods to form well-organized nano-interpenetrating BHJ after air annealing. The interface charge transfer in CuO nanorod array/TiO2 heterojunction is studied by Kelvin probe force microscopy (KPFM). KPFM results demonstrate that the CuO nanorod array/TiO2 heterojunction can realize the transfer of photo-generated electrons from the CuO nanorod array to TiO2. In this work, a solar cell with the structure FTO/CuO nanoarray/TiO2/Al is successfully fabricated, which exhibits an open-circuit voltage (V oc) of 0.20 V and short circuit current density (J sc) of 0.026 mA cm-2 under AM 1.5 illumination. KPFM studies indicate that the very low performance is caused by an undesirable interface charge transfer. The interfacial surface potential (SP) shows that the electron concentration in the CuO nanorod array changes considerably after illumination due to increased photo-generated electrons, but the change in the electron concentration in TiO2 is much less than in CuO, which indicates that the injection efficiency of the photo-generated electrons from CuO to TiO2 is not satisfactory, resulting in an undesirable J sc in the solar cell. The interface photovoltage from the KPFM measurement shows that the low V oc results from the small interfacial SP difference between CuO and TiO2 because the low injected electron concentration cannot raise the Fermi level significantly in TiO2. This conclusion agrees with the measured work function results under illumination. Hence, improvement of the interfacial electron injection is primary for the CuO nanorod array/TiO2 heterojunction solar cells. PMID- 29521646 TI - Incorporating Advances in Molecular Pathology Into Brain Tumor Diagnostics. AB - Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations. IDH-wild-type (wt) infiltrating astrocytomas are mostly primary GBMs and are characterized by EGFR, PTEN, TP53, NF1, RB1, PDGFRA, and CDKN2A/B alterations, TERT-p mutations, and characteristic copy number alterations including gains of chromosome 7 and losses of 10. Other clinically and genetically distinct infiltrating astrocytomas include the aggressive H3K27M mutant midline gliomas, and smaller subsets that occur in the setting of NF1 or have BRAF V600E mutations. Low-grade pediatric gliomas are both genetically and biologically distinct from their adult counterparts and often harbor a single driver event often involving BRAF, FGFR1, or MYB/MYBL1 genes. Large scale genomic and epigenomic analyses have identified distinct subgroups of ependymomas tightly linked to tumor location and clinical behavior. The diagnosis of embryonal neoplasms also integrates molecular testing: (I) 4 molecularly defined, biologically distinct subtypes of medulloblastomas are now recognized; (II) 3 histologic entities have now been reclassified under a diagnosis of "embryonal tumor with multilayered rosettes (ETMR), C19MC-altered"; and (III) atypical teratoid/rhabdoid tumors (AT/RT) now require SMARCB1 (INI1) or SMARCA4 (BRG1) alterations for their diagnosis. We discuss the practical use of contemporary biomarkers for an integrative diagnosis of central nervous system neoplasia. PMID- 29521647 TI - Murder by Pushing: An Exploratory Analysis of Homicidal Falls From a Height. AB - The difficulty in classifying manner of death in falls from a height provides offenders an opportunity to avoid detection by having a homicide appear otherwise. Twelve fall homicides were qualitatively examined. Results showed that most homicidal falls occurred at remote outdoor locations, were planned by offenders who were in controlling intimate relationships with the victim, and were motivated by gain. Homicide was established using inconsistencies in offender's statements and the physical evidence, inappropriate postoffense behavior, evidence of planning, and improbable alleged victim behavior. Fall homicides pose unique challenges for investigators and may negatively impact on the criminal justice process. PMID- 29521648 TI - Impact of Health Insurance Status on Prostate Cancer Treatment Modality Selection in the United States. AB - OBJECTIVES: A variety of treatment modalities are available for the management of clinically localized prostate cancer in the United States. In addition to clinical factors, treatment modality choice may be influenced by a patient's insurance status. Using a national data set, we investigated the relationship between insurance status and prostate cancer treatment modality selection among nonelderly men in the United States. METHODS: Nonelderly men age 18 to 64 years treated for localized prostate cancer from 2010 to 2014 were identified within the National Cancer Database. Patients with no insurance, Medicaid, or private insurance were included. The chi and multivariable logistic regression analyses were used to evaluate the association of insurance status, other demographic and facility factors, and D'Amico risk classification with treatment modality. RESULTS: We identified 135,937 patients with either no insurance (2.8%), Medicaid (4.2%), or private insurance (92.9%) treated for prostate cancer who underwent cancer-directed treatment or active surveillance between 2010 and 2014. Patients with private insurance were more likely to receive minimally invasive surgery (61.4% vs. 35.4%, respectively; P<0.001) and less likely to receive external beam radiotherapy (10.9% vs. 26.9%, respectively; P<0.001) than patients with no insurance. On multivariable analysis, among patients with no insurance and private insurance, private insurance was the strongest predictor of receipt of minimally invasive surgery (adjusted odds ratio, 2.61; 95% confidence interval, 2.44-2.79; P<0.001). CONCLUSION: Insurance status is a strong predictor of prostate cancer treatment modality among nonelderly men in the United States. PMID- 29521649 TI - Overall Survival Results of the Feasibility Study of Adjuvant Chemotherapy With Docetaxel Plus Cisplatin Followed by Long-term Single-agent Administration of S-1 in Patients With Completely Resected Non-Small Cell Lung Cancer: Thoracic Oncology Research Group (TORG) 0809. AB - OBJECTIVES: The TORG0809 study was a multicenter feasibility study of long-term single-agent therapy with S-1 after docetaxel plus cisplatin therapy in patients with completely resected stage II or stage IIIA non-small cell lung cancer. We report the results of the final overall survival (OS) analysis. PATIENTS AND METHODS: A total of 129 eligible patients received 3 cycles of docetaxel (60 mg/m, day 1) plus cisplatin (80 mg/m, day 1), followed by S-1 at 40 mg/m twice daily for 14 consecutive days, for >6 months (maximum, 1 y). RESULTS: At the cutoff date of April 13, 2016, the median follow-up time was 6.0 years. Of the 129 patients, 43 had died, and 74 patients developed disease recurrence or died. The median OS had not been reached. The 5-year OS rate was 71% [95% confidence interval (CI), 62-78]. The 5-year OS rates in the patients with stage II and stage IIIA were 76% and 68%, respectively. The median recurrence-free survival (RFS) duration was 3.4 years (95% CI, 2.3-5.7). The 5-year RFS rate was 44% (95% CI, 36-53). The 5-year RFS rates in patients with stage II and stage IIIA disease were 57% and 38%, respectively. Disease recurrence occurred in 68 patients, and 62 of these patients received second-line chemotherapy. The most common sites of recurrence were the brain (n=22) and mediastinal lymph nodes (n=22). CONCLUSION: The survival data obtained from this study are promising and comparable to those reported from a previous study conducted in Japan. PMID- 29521650 TI - Emphasis on Systemic Therapy in Women With Pelvic Bone Metastasis at Time of Diagnosis of Cervical Cancer. AB - OBJECTIVE: Cervical cancer presenting with metastases to the bony pelvis is rare. No available literature addresses the treatment and prognosis of these patients. Our objective was to review our experience treating women with this rare presentation. METHODS: We performed a review of all patients treated for cervical cancer at a single institution between January 1, 2007 and November 30, 2014. All patients had pretreatment imaging with computed tomography or positron emission tomography/computed tomography. Included patients had evidence of pelvic bone metastases by imaging before initiation of treatment. RESULTS: A total of 349 women were treated for cervical cancer during the study interval. Of these, 13 (3.7%) were identified as having pelvic bone metastases at initial presentation. Four of 13 patients had pelvic-confined disease and were treated with curative intent radiation. The remainder had disseminated disease and were treated with palliative radiation. Only one complete response was seen. Seven patients received salvage chemotherapy. The median overall survival was 8.5 months. Survival was statistically similar in those who received palliative rather than curative radiotherapy (8.7 vs. 8.1 mo, P=0.76) and in those who received any postradiation chemotherapy (8.9 vs. 6.1 mo, P=0.066). Chemotherapy with bevacizumab resulted in the only 2 long-term survivors (both alive at 32.4 and 37.5 mo). All others have died of disease. CONCLUSIONS: Cervical cancer metastatic to the bony pelvis at initial presentation portends a dismal prognosis. Patients should be informed about this poor prognosis, and allowed to make an informed decision when considering curative-intent versus palliative treatment. Incorporation of bevacizumab appears to improve survival. PMID- 29521651 TI - Preradiotherapy Tumor Volume in Local Control of Squamous Cell Carcinoma of the Supraglottic Larynx. AB - OBJECTIVES: Examine the utility of pretreatment computed tomography in predicting local control (LC) in squamous cell carcinoma of the supraglottic larynx treated with primary radiotherapy (RT). METHODS: In total, 167 patients treated between 1983 and 2013 were reviewed. Patients had received pretreatment diagnostic computed tomographic imaging of the larynx and neck from which primary tumor volume (PrTV) was delineated. LC, larynx function at last follow-up, and RT complications were recorded. PrTV was evaluated with respect to outcome. RESULTS: In this study, median age was 61 years, and mean follow-up was 96 months. In total, 43% had T1-T2, 46% had T3, and 11% had T4 disease; 49% had N0 disease. Median tumor volume, 5.1 cm (0.4 to 188 cm). Mean dose, 74 Gy; 20% received concurrent chemotherapy. Overall, 10-year LC was 78.9%. Ten-year LC stratified by tumor volume was: 0 to 4.9 cm, 90.8%; 5 to 8.9 cm, 67.3%; and >9 cm, 69.4%. Ten year LC with preserved larynx function was: 0 to 4.9 cm, 76.7%; 5 to 8.9 cm, 61.5%; and >9 cm, 53.4%. LC and LC with preserved larynx function was significantly different between PrTV groups (P<0.001). On multivariate analysis, PrTV was a significant predictor of LC and LC with preserved larynx function (P<0.005). Six patients developed soft tissue necrosis; 2 suffered fatal carotid blowouts. Patients with grade 5 complications received concomitant chemotherapy. Four patients required total laryngectomy; 14 required permanent tracheostomy or gastrostomy tube. CONCLUSION: Pretreatment PrTV helps identify patients most likely to experience LC with primary RT alone or combined chemoradiation. LC for supraglottic larynx squamous cell carcinoma is optimal if the PrTV is <5.0 cm. PMID- 29521652 TI - Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats. AB - BACKGROUND: Sleepiness and decrease in attention are dose-limiting side effects of opioids. The orexin/hypocretin system plays an important role in maintaining wakefulness. This study aimed to explore the potential of a nonpeptide orexin receptor agonist to alleviate morphine-induced sedative effects. METHODS: Morphine sedative effects were evaluated as changes in electroencephalogram (EEG), locomotor activity, and acoustic startle response in rats (n = 5 to 9 per group). Effects of intracerebroventricular orexin-A and systemic orexin type-2 receptor agonist, YNT-185, on EEG changes induced by morphine were examined. Furthermore, the authors examined effects of morphine administered with or without YNT-185 on locomotor activity and on acoustic startle response. RESULTS: Morphine-induced, frequent, short epochs of increased power (total epoch duration: 0.5 [0.0 to 8.0] s/10 min during baseline vs. 74.0 [49.0 to 115.0] s/10 min during the post-morphine administration period; P = 0.012). EEG analyses revealed that morphine-induced, high-amplitude, slow activity (increase in spectral power of frequencies less than 15 Hz, baseline vs. postmorphine; P < 0.001). Orexin-A and YNT-185 attenuated these changes. Locomotor activity decreased after morphine (268 [103 to 889] ambulatory movement counts during baseline period [20 min] vs. 138 [7 to 434] counts during 40 to 59 min postadministration; P = 0.012), but did not change after morphine with YNT-185 (363 [121 to 636] vs. 864 [381 to 1092] counts, difference within morphine + YNT 185 group; P = 0.071). Startle response latency was longer after morphine (26 [20 to 28] ms) than after morphine with YNT-185 (17 [16 to 18] ms; P = 0.012). CONCLUSIONS: Orexin-A and/or YNT-185 attenuated morphine-induced sedative effects assessed by EEG changes and behavioral measures in rats. The authors' results suggest that orexin-2 receptor activation alleviates morphine-induced sedative effects. PMID- 29521653 TI - A 1-Point Plan to Eliminate Breast Implant-Associated Anaplastic Large-Cell Lymphoma. PMID- 29521654 TI - Diltiazem-Associated Cardiogenic Shock in Thyrotoxic Crisis. AB - CLINICAL FEATURES: The patient we present is a 39-year-old woman with a history of hyperthyroidism who developed fast atrial fibrillation secondary to thyrotoxic storm. After the initiation of intravenous diltiazem drip, she developed hypotension, bradycardia, then asystole cardiac arrest. THERAPEUTIC CHALLENGE: It is well known that calcium channel blockers and beta blockers should be used with extreme caution if the patient with thyroid storm has decompensated heart failure with reduced ejection fraction. Despite this, it is recognized that guidelines for the management of thyroid storm do not include an algorithm of action in this situation. Thus, dealing with low-output failure during thyroid storm may pose a critical challenge. SOLUTION: A significant portion of patients with thyrotoxic storm have an underlying low-output cardiac failure. Early identification, proper hemodynamic monitoring, and administration of the agents with appropriate pharmacodynamic profile and therapeutic potentials are essential to avoid treatment-induced cardiogenic shock. PMID- 29521655 TI - Selexipag in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension and Eisenmenger Syndrome: First Report. PMID- 29521656 TI - Comparison of treatment of hepatic hydrothorax with catheter drainage versus serial thoracentesis. AB - PURPOSE OF REVIEW: Hepatic hydrothorax is a nonmalignant pleural effusion associated with portal hypertension that may cause increased morbidity or mortality in cirrhotic patients. For patients who are refractory to salt restriction and diuretics, thoracentesis and catheter drainage are necessary for symptomatic relief. This review aimed to identify the best drainage method in patients with hepatic hydrothorax. RECENT FINDINGS: Chest tube placement is discouraged in cases of hepatic hydrothorax due to high complication and mortality rates. Although the complication rate associated with smaller caliber catheter drainage appears lower than with chest tube drainage, patients treated with catheter drainage still had a higher 30-day mortality compared with patients treated by thoracentesis. Catheter drainage was an independent risk factor for 30 day mortality in cirrhotic patients with pleural effusion after adjusting for age, hepatic dysfunction, and other comorbidities. Treating the underlying disorder with liver transplantation can dramatically improve survival in these patients. SUMMARY: The recent evidence supports series thoracentesis as the first line drainage method in cases of hepatic hydrothorax compared with catheter drainage. Further prospective, randomized, controlled trials are necessary to further evaluate the mortality and complication rates of catheter drainage compared with thoracentesis in cirrhotic patients. PMID- 29521657 TI - Stereotactic ablative radiation therapy in lung cancer: an emerging standard. AB - PURPOSE OF REVIEW: Significant advances have been made in the field of stereotactic ablative radiotherapy (SABR) for the treatment of pulmonary neoplasms in recent years. This review aims to summarize recent salient evidence on SABR for early-stage nonsmall cell lung cancer (ES-NSCLC). RECENT FINDINGS: In medically inoperable patients, SABR remains the standard of care. The optimal SABR dosing regimen is being studied. Comparisons with non-SABR radiotherapy regimens with lower doses per fraction revealed benefit of SABR. In operable patients, no prospective clinical trial comparing SABR and surgery has been completed, although multiple trials are currently underway to address this question. SABR is generally cost-effective and safe in most patients, with preserved patient-reported quality of life. However, increased toxicity with SABR is noted in patients with disease close to, or invading the proximal tracheobronchial tree. Significant SABR-related toxicity and mortality is also reported in patients with coexisting interstitial lung disease. Considerations on pathologic confirmation, surveillance and multiple primaries are also addressed. SUMMARY: SABR is an effective and safe treatment for inoperable ES-NSCLC. Ongoing trials and comparative effectiveness research will help to clarify SABR's role in various lung cancer indications going forward. PMID- 29521658 TI - Trophic factors in the treatment and prevention of alimentary tract mucositis. AB - PURPOSE OF REVIEW: Mucositis is a common adverse effect of cytotoxic anticancer treatment with serious implications for the quality of life, morbidity and mortality of cancers patients. Although, evidence supporting the use of certain treatments exists there is no gold standard for preventing or treating mucositis. Current management strategies are scarce with recommendations referring primarily to specific cytotoxic treatment regimens in certain clinical scenarios. RECENT FINDINGS: Trophic factors may contribute to preserve epithelial integrity, function, and accelerate regeneration after chemotherapeutic treatment. Accordingly, various growth factors have been evaluated in the prevention or treatment of alimentary tract mucositis. However, in spite of often showing promising results in preclinical testing currently perlifermin is the only trophic factor recommended for the prevention of mucositis. SUMMARY: More knowledge from representative preclinical models, and testing growth factor interventions across different models, may be the key to advance the field from basic science to clinical application of new growth factors. For promising new therapies, subsequent establishment of adequately powered clinical trials and uniform reporting of mucositis, are important elements to help establish new standard interventions that can be included into the continuously updated clinical recommendations for treatment of mucositis. PMID- 29521659 TI - Contraceptive Management for Women Who Are at High Risk of Thrombosis. AB - Managing contraception for women at high risk for thrombosis poses unique challenges. Combined estrogen and progestin contraceptives increase the risk of both venous and arterial thrombosis. They are contraindicated in women with a history of thrombosis and in other women at high risk for thrombosis. However, progestin-only contraceptives are generally considered safe in this patient population. This paper reviews the evidence linking hormonal contraception and clotting risk, outlines appropriate contraceptive methods for women at high risk for thrombosis, discusses surgical risk for sterilization in the setting of current or past thrombosis, and includes a review of the safety of hormonal methods for women who are fully anticoagulated. In general, long-acting reversible contraception is safe for women with a history of thrombosis and may offer additional noncontraceptive benefits for women who are on anticoagulant therapy, such as improved bleeding profiles. PMID- 29521660 TI - Update in adrenal venous sampling for primary aldosteronism. AB - PURPOSE OF REVIEW: Current guidelines recommend adrenal venous sampling (AVS) to identify the surgically curable causes of hyperaldosteronism. In contrast with this recommendation, AVS remains markedly underutilized in clinical practice, which leads to deny curative adrenalectomy, to many patients with primary aldosteronism. The purpose of this review is to challenge the views that AVS is a technically challenging, invasive and risky procedure, which moreover, is difficult to interpret. RECENT FINDINGS: Several studies, including a large international survey on how AVS is being performed and used at major referral centres worldwide the AVIS-1 Study - and a randomized clinical trial comparing and AVS and a computed tomography based strategy, will be examined. SUMMARY: The results of these studies have sound implications for clinical practice in that they allow to define what to do and what not to do for proper performance and interpretation of AVS and avoidance of the main concern, for example the risk of adrenal vein rupture. PMID- 29521661 TI - Spinal anaesthesia with chloroprocaine 1% versus total intravenous anaesthesia for outpatient knee arthroscopy: A randomised controlled trial. AB - BACKGROUND: Both general and spinal anaesthesia with short-acting local anaesthetics are suitable and reliable for knee arthroscopy as an ambulatory procedure. Chloroprocaine (CP) 1% seems to be the ideal spinal local anaesthetic for this indication. OBJECTIVE: The aim of this study was to compare spinal anaesthesia using CP 1% with general for outpatient knee arthroscopy with regard to procedure times, occurrence of pain, patient satisfaction and recovery, and also costs. DESIGN: A randomised controlled single-centre trial. SETTING: University Medical Centre Mannheim, Department of Anaesthesiology and Surgical Intensive Care Medicine, Mannheim, Germany. April 2014 to August 2015. PATIENTS: A total of 50 patients (women/men, 18 to 80 years old, ASA I to III) undergoing outpatient knee arthroscopy were included. A contra-indication to an allocated anaesthetic technique or an allergy to medication required in the protocol led to exclusion. INTERVENTIONS: Either general anaesthesia with sufentanil, propofol and a laryngeal mask for airway-management or spinal with 40-mg CP 1% were used. We noted procedure times, patient satisfaction/recovery and conducted a 7-day follow-up. MAIN OUTOMES: Primary outcome was duration of stay in the day-surgery centre. Secondary outcomes were first occurrence of pain, patient satisfaction, quality of recovery and adverse effects. In addition, we analysed treatment costs. RESULTS: Spinal had faster recovery than general anaesthesia with patients reaching discharge criteria significantly earlier [117 min (66 to 167) versus 142 min (82 to 228), P = 0.0047]. Pain occurred significantly earlier in the general anaesthesia group (P = 0.0072). Costs were less with spinal anaesthesia (cost ratio spinal: general 0.57). Patients felt significantly more uncomfortable after general anaesthesia (P = 0.0096). CONCLUSION: Spinal anaesthesia with 40-mg CP 1% leads to a significantly earlier discharge and is cheaper compared with general. TRIAL REGISTRATION: German Clinical Trials Register, www.drks.de, identifier: DRKS00005989. PMID- 29521662 TI - Adjusted calculation model of heparin management during cardiopulmonary bypass in obese patients: A randomised controlled trial. AB - BACKGROUND: Anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW). This may be inaccurate in obese patients and lead to heparin overdose with a risk of bleeding. OBJECTIVES: To validate the efficacy and safety of an adjusted calculation model of heparin dosing based on ideal body weight (IBW) rather than TBW in obese CPB patients, with an expected target mean plasma heparin concentration of 4.5 IU ml after onset of CPB in the experimental group. DESIGN: Randomised controlled study. SETTING: University hospital. PATIENTS: Sixty obese patients (BMI >= 30 kg m) scheduled for CPB were included from January to June 2016. INTERVENTIONS: Patients received a bolus dose of unfractionated heparin of either 300 IU kg of TBW or 340 IU kg of IBW before onset of CPB. Additional adjusted boluses were injected to maintain an activated clotting time (ACT) of at least 400 s. MAIN OUTCOME MEASURES: Plasma heparin concentration and ACT were measured at different time points. Total heparin doses and transfusion requirements were recorded. RESULTS: The target heparin concentration of 4.5 IU ml was reached in the IBW group at the onset of CPB and maintained at all time points during CPB. Heparin concentrations were significantly higher in the TBW group after the bolus (6.52 +/- 0.97 vs. 4.54 +/- 1.13 IU ml, P < 0.001) and after cardioplegia (5.10 +/- 1.03 vs. 4.31 +/- 1.00 IU ml, P = 0.02). Total heparin doses were significantly higher in the TBW group. Mean ACT was significantly lower in the IBW group but remained over 400 s during CPB. The correlation between heparin and ACT was poor. Peri-operative bleeding and transfusion requirements were comparable. No thrombotic event occurred in the CPB circuit. CONCLUSION: The current IBW-adjusted regimen of heparin administration may be used efficiently in obese CPB patients, thereby avoiding overdose which cannot be accurately assessed by ACT monitoring alone. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02675647. PMID- 29521663 TI - Predicting mortality in patients with spontaneous bacterial peritonitis using routine inflammatory and biochemical markers. AB - OBJECTIVES: Spontaneous bacterial peritonitis (SBP) is a common and high mortality infectious complication of patients with cirrhosis. New inflammatory markers are associated with morbidity/mortality in various diseases. The aim of our study was to find the 30-day mortality rate of SBP and their predictors. PATIENTS AND METHODS: Seventy patients with cirrhosis complicated with SBP and 55 non-SBP controls were enrolled into the study, and patients were evaluated for mortality rate and its predictors. RESULTS: The 30-day and 3-month mortality rates in the SBP group were 26.1 and 50.7%, respectively. Mortality rates were higher in the SBP group than in the controls. Symptoms at hospital admission and cell counts in ascitic fluid made no difference in predicting 30-day mortality. Patients with SBP with high serum neutrophil counts, high neutrophil-lymphocyte ratio, high C reactive protein (CRP)/albumin ratio, and high model for end-stage liver disease (MELD) score had higher 30-day mortality rates. We determined optimal cutoff values of MELD scores and serum neutrophil counts for predicting 30-day mortality as 20.5 and 6850/mm, respectively. The sensitivity and specificity for the MELD cutoff value were 83.3 and 80.4%, respectively. We also followed up patients for 60 months after SBP; the patients with high inflammatory markers and MELD scores at the time of SBP diagnosis had worse survival compared with the group with lower levels. CONCLUSION: Our results suggest that SBP has high 30-day mortality. MELD scores and inflammatory markers (CRP, CRP albumin ratio, neutrophil-lymphocyte ratio) may be used to predict mortality in patients with SBP. PMID- 29521664 TI - New and emerging therapies in treatment of Clostridium difficile infection. AB - Clostridium difficile infection (CDI) represents one of the most serious nosocomial infections that have grown dramatically over the past decade. Vancomycin and metronidazole are currently used as a standard therapy for CDI. Metronidazole is recommended as a first-line therapy for mild-to-moderate infections and vancomycin is mainly used for severe and/or refractory cases. However, studies have demonstrated that there are quite high CDI relapse rates with both of these medications, which represents a challenge for clinicians. Over the last decade, a number of newer and novel therapeutic options have emerged as promising alternatives to these standard CDI therapies. The following review provides the updated summaries of these newer therapeutic agents and their status in the treatment of CDI. PMID- 29521665 TI - Parental Perception of Flourishing in School-Aged Children: 2011-2012 National Survey of Children's Health. AB - OBJECTIVE: Flourishing reflects positive mental health and thriving and is important for children's development and well-being. Few national studies of flourishing among school-aged children exist. Exposure to socioeconomic disadvantage is negatively associated with social and health outcomes, including flourishing. This analysis describes independent associations of the child, family, school, and neighborhood factors with flourishing, which we hypothesized may contribute to sociodemographic disparities. METHODS: Data from the 2011-2012 National Survey of Children's Health were used to examine parental perception of flourishing among school-aged children (6-17 years of age; n = 59,362). Flourishing was defined as curiosity about learning, resilience, and self regulation. Unadjusted and adjusted associations between sociodemographic, child, family, school and neighborhood factors and flourishing were explored using chi tests and sequential logistic regression models. RESULTS: Overall, 48.4% of school-aged children were perceived by parents to be flourishing. There were significant sociodemographic disparities with non-Hispanic black children (37.4%) and those below the federal poverty level (37.9%) among the least likely to flourish. After adjustment, sex, race/ethnicity, parent education, child's age, physical activity, special health care needs status, adequate sleep, adverse childhood experiences, family meals, hours of television watched, extracurricular activities, school safety, neighborhood safety, neighborhood support, and presence of amenities were significantly associated with flourishing (p < 0.05). Disparities by poverty level and household structure were no longer significant. CONCLUSION: Addressing factors associated with parent-perceived flourishing including child, family, school and neighborhood factors such as physical activity, adequate sleep, and school/neighborhood safety may promote flourishing and reduce disparities. PMID- 29521666 TI - Dual-Task Performance: Influence of Frailty, Level of Physical Activity, and Cognition. AB - BACKGROUND AND PURPOSE: Cognition and level of physical activity have been associated with frailty syndrome. The development of tools that assess deficits related to physical and cognitive frailties simultaneously are of common interest. However, little is known about how much these aspects influence the performance of dual-task tests. Our aims were (a) to verify the influence of frailty syndrome and objectively measured physical activity and cognition on the Timed Up and Go (TUG) test and Timed Up and Go associated with dual-task (TUG-DT) performances; and (b) to compare TUG and TUG-DT performances between older adults who develop frailty syndrome. METHODS: Sixty-four community-dwelling older adults were divided into frail, prefrail, and nonfrail groups, according to frailty phenotype. Assessments included anamnesis, screening of frailty syndrome, cognitive assessment (Addenbrooke's cognitive examination), placement of a triaxial accelerometer to assess level of physical activity, and TUG and TUG-DT (TUG associated with a motor-cognitive task of calling a phone number) performances. After 7 days, the accelerometer was removed. A multiple linear regression was applied to identify which independent variables could explain performances in the TUG and TUG-DT. Subsequently, the analysis of covariance test, adjusted for age, cognition, and level of physical activity covariates, was used to compare test performances. RESULTS: There were no differences in cognition between groups. Significant differences in the level of physical activity were found in the frail group. Compared with the frail group, the nonfrail group required less time and fewer steps to complete the TUG. Regarding the TUG-DT, cognition and age influenced the time spent and number of steps, respectively; however, no differences were found between groups. CONCLUSIONS: Frail older adults presented worse performance in the TUG when compared with nonfrail older adults. The dual-task test does not differentiate older adults with frailty syndrome, regardless of cognitive performance. PMID- 29521667 TI - Estradiol suppresses ingestive response evoked by activation of 5-HT1A receptors in the lateral hypothalamus of ovariectomized rats. AB - The present study investigated the effects of estradiol (E2) on ingestive behavior after activation of 5-HT1A receptors in the lateral hypothalamus (LH) of female rats habituated to eat a wet mash diet. Ovariectomized rats treated with corn oil (OVX) or estradiol cypionate (OVX+E) received local injections into the LH of vehicle or an agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; at a dose of 6 nmol). To determine the involvement of these receptors in food intake, some animals were pretreated with N-[2-[4-(2 methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY-100635, a 5-HT1A receptor full antagonist, at a dose of 0.37 nmol), followed by the injection of the agonist 8-OH-DPAT or its vehicle. The results showed that the injection of 8-OH-DPAT into the LH of OVX rats significantly increased food intake, and the duration and frequency of this behavior. The pretreatment with E2 suppressed the hyperphagic response induced by 8-OH-DPAT in OVX animals. The inhibition of 5-HT1A receptors after pretreatment with WAY 100635 blocked the hyperphagic effects evoked by 8-OH-DPAT in OVX. These results indicate that the activity of LH 5-HT1A receptors could be affected by blood E2 levels. PMID- 29521668 TI - The Omaha System as a Structured Instrument for Bridging Nursing Informatics With Public Health Nursing Education: A Feasibility Study. AB - Advancements in healthcare systems include adoption of health information technology to ensure healthcare quality. Educators are challenged to determine strategies to integrate health information technology into nursing curricula for building a nursing workforce competent with electronic health records, standardized terminology, evidence-based practice, and evaluation. Nursing informatics, a growing specialty field, comprises health information technology relative to the profession of nursing. It is essential to integrate nursing informatics across nursing curricula to effectively position competent graduates in technology-laden healthcare environments. Nurse scholars developed and evaluated a nursing informatics case study assignment used in undergraduate level public health nursing courses. The assignment included an unfolding scenario followed by electronic health record charting using standardized terminology to guide the nursing process. The assignment was delivered either online or in class. Seventy-two undergraduate students completed the assignment and a posttest. Fifty-one students completed a satisfaction survey. Results indicated that students who completed the assignment online demonstrated a higher level of content mastery than those who completed the assignment in class. Content mastery was based on posttest results, which evaluated students' electronic health record charting for the nursing assessment, evidence-based interventions, and evaluations. This innovative approach may be valuable to educators in response to the National Academy of Sciences recommendations for healthcare education reform. PMID- 29521669 TI - The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics. AB - OBJECTIVES: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. METHODS: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. RESULTS: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P = 0.007), and then rose significantly from trimester 3 to postpartum (P = 0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. CONCLUSIONS: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally. PMID- 29521671 TI - Probiotics in digestive, emotional, and pain-related disorders. AB - In recent years, interest in the relationship between gut microbiota and disease states has grown considerably. Indeed, several strategies have been employed to modify the microbiome through the administration of different diets, by the administration of antibiotics or probiotics, or even by transplantation of feces. In the present manuscript, we focus specifically on the potential application of probiotics, which seem to be a safe strategy, in the management of digestive, pain, and emotional disorders. We present evidence from animal models and human studies, notwithstanding that translation to clinic still deserves further investigation. The microbiome influences gut functions as well as neurological activity by a variety of mechanisms, which are also discussed. The design and performance of larger trials is urgently needed to verify whether these new strategies might be useful not only for the treatment of disorders affecting the gastrointestinal tract but also in the management of emotional and pain disorders not directly related to the gut. PMID- 29521670 TI - A Longitudinal Analysis of Daily Pill Burden and Likelihood of Optimal Adherence to Antiretroviral Therapy Among People Living With HIV Who Use Drugs. AB - OBJECTIVES: Among people living with HIV (PLWH), high levels of adherence to prescribed antiretroviral therapy (ART) is required to achieve optimal treatment outcomes. However, little is known about the effects of daily pill burden on adherence amongst PLWH who use drugs. We sought to investigate the association between daily pill burden and adherence to ART among members of this key population in Vancouver, Canada. METHODS: We used data from the AIDS Care Cohort to Evaluate Exposure to Survival Services study, a long-running community recruited cohort of PLWH who use illicit drugs linked to comprehensive HIV clinical records. The longitudinal relationship between daily pill burden and the odds of >=95% adherence to ART among ART-exposed individuals was analyzed using multivariable generalized linear mixed-effects modeling, adjusting for sociodemographic, behavioural, and structural factors linked to adherence. RESULTS: Between December 2005 and May 2014, the study enrolled 770 ART-exposed participants, including 257 (34%) women, with a median age of 43 years. At baseline, 437 (56.7%) participants achieved >=95% adherence in the previous 180 days. Among all interview periods, the median adherence was 100% (interquartile range 71%-100%). In a multivariable model, a greater number of pills per day was negatively associated with >=95% adherence (adjusted odds ratio [AOR] 0.87 per pill, 95% confidence interval [CI] 0.84-0.91). Further analysis showed that once a-day ART regimens were positively associated with optimal adherence (AOR 1.39, 95% CI 1.07-1.80). CONCLUSIONS: In conclusion, simpler dosing demands (ie, fewer pills and once-a-day single tablet regimens) promoted optimal adherence among PLWH who use drugs. Our findings highlight the need for simpler dosing to be encouraged explicitly for PWUD with multiple adherence barriers. PMID- 29521672 TI - Effects of Prone Positioning on Transpulmonary Pressures and End-expiratory Volumes in Patients without Lung Disease. AB - BACKGROUND: The effects of prone positioning on esophageal pressures have not been investigated in mechanically ventilated patients. Our objective was to characterize effects of prone positioning on esophageal pressures, transpulmonary pressure, and lung volume, thereby assessing the potential utility of esophageal pressure measurements in setting positive end-expiratory pressure (PEEP) in prone patients. METHODS: We studied 16 patients undergoing spine surgery during general anesthesia and neuromuscular blockade. We measured airway pressure, esophageal pressures, airflow, and volume, and calculated the expiratory reserve volume and the elastances of the lung and chest wall in supine and prone positions. RESULTS: Esophageal pressures at end expiration with 0 cm H2O PEEP decreased from supine to prone by 5.64 cm H2O (95% CI, 3.37 to 7.90; P < 0.0001). Expiratory reserve volume measured at relaxation volume increased from supine to prone by 0.15 l (interquartile range, 0.25, 0.10; P = 0.003). Chest wall elastance increased from supine to prone by 7.32 (95% CI, 4.77 to 9.87) cm H2O/l at PEEP 0 (P < 0.0001) and 6.66 cm H2O/l (95% CI, 3.91 to 9.41) at PEEP 7 (P = 0.0002). Median driving pressure, the change in airway pressure from end expiration to end-inspiratory plateau, increased in the prone position at PEEP 0 (3.70 cm H2O; 95% CI, 1.74 to 5.66; P = 0.001) and PEEP 7 (3.90 cm H2O; 95% CI, 2.72 to 5.09; P < 0.0001). CONCLUSIONS: End-expiratory esophageal pressure decreases, and end-expiratory transpulmonary pressure and expiratory reserve volume increase, when patients are moved from supine to prone position. Mean respiratory system driving pressure increases in the prone position due to increased chest wall elastance. The increase in end-expiratory transpulmonary pressure and expiratory reserve volume may be one mechanism for the observed clinical benefit with prone positioning. PMID- 29521673 TI - Effects of Resistance Exercise Training on Doxorubicin-Induced Cardiotoxicity. AB - Although highly effective, doxorubicin (DOX) use is limited by a dose-dependent cardiotoxicity. The purpose of this study was to determine whether resistance training (RT) would protect against DOX-induced cardiac dysfunction and determine whether any observed functional preservation is a result of reduced lipid peroxidation or a preservation of the cardiac myosin heavy chain (MHC) isoform distribution. Rats were resistance-trained or remained sedentary for 12 weeks, then treated with 12.5 mg/kg DOX or 0.9% saline. Five days after DOX exposure, cardiac function, lipid peroxidation, and MHC isoform expression were quantified. RT preserved cardiac function and attenuated the alpha-to beta-MHC shift that occurs with DOX treatment. No significant differences in lipid peroxidation were observed between sedentary and RT animals treated with DOX. These data suggest that resistance-type exercise can provide protection against DOX-induced cardiac dysfunction, which may be a result of a preservation of the cardiac MHC isoform distribution. PMID- 29521674 TI - Feasibility of Laparoscopy-assisted Gastrectomy for Gastric Cancer in Elderly Patients: A Case-Control Study. AB - PURPOSE: The present study evaluated the safety and effectiveness of laparoscopic gastrectomy (LG) in elderly gastric cancer patients. PATIENTS AND METHODS: This study included 78 gastric cancer patients aged 80 years or above [39 in the LG group and 39 in the open gastrectomy group (matched)]. Patient characteristics, surgical outcomes, survival time, and immunonutritional status were compared. RESULTS: Mean blood loss was significantly lower in the LG group, although the operation time did not differ. There were no significant differences in the number of dissected lymph nodes, postoperative morbidity, mortality, total hospital stay, and the causes of death. The prognostic nutritional index and skeletal muscle index at 1 year were better maintained in the LG group than in the open gastrectomy group. The overall and relapse-free survivals did not differ. CONCLUSIONS: LG may be feasible in elderly patients with gastric cancer. A prospective randomized controlled trial should be conducted to confirm its efficacy. PMID- 29521675 TI - Splenectomy in Gaucher Disease: A Call for Minimally Invasive Surgery. AB - OBJECTIVE: The objective of this article was to demonstrate that Gaucher disease (GD) patients with refractory hypersplenism and massive splenomegaly may successfully undergo hand-assisted laparoscopic splenectomy (HALS). METHODS: This was a retrospective audit conducted at the Gaucher clinic at a national referral center over a 10-year period. PATIENT POPULATION: This study included 8 GD patients who underwent hand-assisted or conventional laparoscopic splenectomy for massive or complicated splenomegaly between the years 2007 and 2017. RESULTS: Seven patients underwent an elective HALS procedure because of refractory hypersplenism, whereas 1 patient underwent an urgent conventional laparoscopic splenectomy because of torsion of a wandering spleen. Only 1 patient required conversion to open surgery because of multiple adhesions from a previous partial splenectomy. The mean weight of the removed spleens was 2373 g (range, 480 to 4900 g), mean craniocaudal length of the removed spleens was 25 cm (range, 20 to 33.5 cm), and mean operating time was 150 minutes (range, 96 to 280 min). Postoperative complications were limited to 2 patients and included thrombosis of the splenic vein stump in 1 patient, and propagation of a preoperative splenic vein thrombus to the portal system, as well as an accumulation of an intra abdominal hematoma in another patient. There was no mortality. Mean length of hospital stay was 5 days (range, 2 to 11 d). CONCLUSION: HALS for GD patients with refractory hypersplenism and massive splenomegaly is safe and feasible in experienced hands. PMID- 29521676 TI - Another Strategy for the Treatment of Thyroglossal Duct Cyst: Totally Endoscopic Surgery by Breast Approach. AB - OBJECTIVE: Open surgery is the most common treatment of thyroglossal duct cyst (TGDC), but it leaves obvious neck scarring. This study aimed to explore the feasibility and strategy of total endoscopic procedure by breast approach to avoid such scarring on the neck. MATERIALS AND METHODS: This study reviewed 13 patients who underwent endoscopic resection of TGDC and 15 patients who underwent open resection of TGDC. We compared and analyzed factors including operative time, estimated blood loss, postoperative hospitalization, complications, and cosmetic effect. RESULTS: The surgery by the endoscopic approach was successfully completed in 13 cases and no one was converted to an open procedure. Another 15 cases were successfully performed by an open procedure. There were no significant differences between the 2 procedures in the mean cyst size, drainage time, intraoperative blood loss, and postoperative hospital stay. The cosmetic effect was better and the operative time was longer in the endoscopic approach. Two cases had swallowing discomfort after surgery in the endoscopic approach, whereas one case developed this complication in the open approach. On patient treated with each approach developed infection. One patient developed skin bruise and one patient developed subcutaneous hydros in the endoscopic approach, whereas no complications developed in the open approach. There were no incidences of uncontrolled bleeding, tracheal injury, dysphagia, salivary fistula, or asphyxia/dyspnea in both approaches, nor were there any deaths or recurrences of TGDC during the follow-up period. CONCLUSION: With strict indications, the total endoscopic breast procedure is feasible and effective for selected patients. This procedure can be another choice for patients who wish to avoid neck scarring when undergoing treatment for TGDC. PMID- 29521677 TI - Biomechanical Behavior of Tooth-Implant Supported Prostheses With Different Implant Connections: A Nonlinear Finite Element Analysis. AB - PURPOSE: Biomechanical behavior of tooth-implant-supported prostheses (TISPs) with external and internal implants was compared. MATERIALS AND METHODS: Two 3-D models of TISP were designed by varying the implant: external (Model EH) and internal hexagons (Model IH). After loading, von Mises stresses were obtained in implants, abutments, and screws. Principal maximum (sigmamax) and minimum (sigmamin) stresses were analyzed in periodontal ligament (PL), alveolar bone, and periimplant bone. RESULTS: Model IH showed lower stress peaks in axial loading in the implant and in the screw but higher in abutment. In oblique loading, Model IH had lower stresses in the implant, but higher in the abutment and in the screw. In the sigmamax analysis for axial and oblique loads, stress peaks in Model IH were lower in PL, alveolar bone, and periimplant bone. In the sigmamin analysis for axial load, stress peaks in Model IH were lower in PL, but higher in alveolar bone and in periimplant bone. In oblique load, Model IH showed lower stress peaks in PL and alveolar bone, but higher stress peaks in periimplant bone. CONCLUSIONS: TISPs with IH implants do present lower risk of biomechanical failure. PMID- 29521679 TI - Upregulation of long noncoding RNA Gadd45a is associated with sevoflurane-induced neurotoxicity in rat neural stem cells. AB - Emerging evidence has shown that long noncoding RNA (lncRNA) plays a crucial role in controlling neural stem cells' (NSCs) survival. However, the fundamental role of lncRNA underlying sevoflurane-induced neurotoxicity remains poorly elucidated. In the present study, we investigate the effect of sevoflurane-induced neurotoxicity in a concentration-dependent and duration-dependent manner. Furthermore, we assayed the differential profile of lncRNA in rat hippocampal NSCs following sevoflurane exposure, and identified lncRNA Gadd45a and the correlation between lncRNA Gadd45a and Gadd45a. We found that lncRNA Gadd45a and its nearby gene, Gadd45a, were significantly upregulated in NSCs exposed to sevoflurane. Notably, Gadd45a was enriched in the cell cycle-relative pathway including mitogen-activated protein kinases and P53 signaling, whereas lncRNA Gadd45a was positively correlated with Gadd45a. These results suggest lncRNA Gadd45a is associated with sevoflurane-induced toxicity, and thus shed light on a new key target for revealing the molecular mechanism of sevoflurane-induced toxicity. PMID- 29521680 TI - Leptin in the nucleus accumbens blocks the increase of GluA1 phosphorylation induced by acute cocaine administration. AB - Leptin in the rat's nucleus accumbens (NAcc) core has previously shown to disrupt the effects of acute administration of cocaine on both locomotor activity and the phosphorylation levels of glycogen synthase kinase 3beta. In the present study, we further measured the phosphorylation levels of GluA1 after bilateral microinjections of leptin in this site followed by acute administration of cocaine. Interestingly, leptin in the NAcc core significantly blocks the increase of GluA1 phosphorylation levels at serine 845 induced by acute administration of cocaine. These effects were not observed for GluA1 phosphorylation levels at serine 831. We have also found additional evidence that glycogen synthase kinase 3beta may play a major role in mediating these processes. PMID- 29521681 TI - Recovery in the Severely Impaired Arm Post-Stroke After Mirror Therapy: A Randomized Controlled Study. AB - OBJECTIVE: This study aimed to examine the effectiveness of mirror therapy on recovery in the severely impaired arm after stroke. DESIGN: Using single-blind randomized controlled design, patients with severely impaired arm within 1-month post-stroke were assigned to receive mirror therapy (n = 20) or control therapy (n = 21), 30 mins twice daily for 4 wks in addition to conventional rehabilitation. During mirror therapy and control therapy, subjects practiced similar structured exercises in both arms, except that mirror reflection of the unaffected arm was the visual feedback for mirror therapy, but mirror was absent for control therapy so that subjects could watch both arms in exercise. Fugl Meyer Assessment and Wolf Motor Function Test were the outcome measurements. RESULTS: After the intervention, both mirror therapy and control therapy groups had significant arm recovery similarly in Fugl-Meyer Assessment (P = 0.867), Wolf Motor Function Test-Time (P = 0.947) and Wolf Motor Function Test-Functional Ability Scale (P = 0.676). CONCLUSION: Mirror therapy or control therapy, which involved exercises concurrently for the paretic and unaffected arms during subacute stroke, promoted similar motor recovery in the severely impaired arm. PMID- 29521682 TI - Small bowel bleeding: cause and the role of endoscopy and medical therapy. AB - PURPOSE OF REVIEW: The objective is to provide an overview on the cause of small bowel bleeding. We discuss the role of small bowel endoscopy in the management of small bowel bleeding and provide an outline of pharmacotherapy that can be additionally beneficial. RECENT FINDINGS: Small bowel capsule endoscopy (SBCE) is the initial diagnostic investigation of choice in small bowel bleeding. Computed tomography (CT) can be helpful in the context of small bowel tumours. Device assisted enteroscopy (DAE) enables several therapeutic procedures such as argon plasma coagulation (APC) and haemoclip application. It can also guide further management with histology or by marking culprit lesions with India ink. A persistent rate of rebleeding despite APC is increasingly being reported. Pharmacotherapy has an emerging role in the management of small bowel bleeding. Somatostatin analogues are a well tolerated class of drugs that can play an additional role in the management of refractory bleeding secondary to small bowel angioectasias. SUMMARY: SBCE is useful in determining the cause of small bowel bleeding. DAE offers an endoscopic therapeutic approach to small bowel bleeding replacing surgery and intraoperative enteroscopy. Pharmacotherapy, in addition to endotherapy, can play an important role in the management of multifocal, recurring bleeding small bowel lesions. PMID- 29521683 TI - Body mass index and prostate cancer risk in the Carotene and Retinol Efficacy Trial. AB - The aim of this study was to investigate the association between BMI (kg/m) and prostate cancer risk. BMI is a modifiable lifestyle factor and may provide a unique opportunity for primary prevention of prostate cancer if a causal association exists. Data from 11 886 men from the Carotene and Retinol Efficacy Trial (CARET, 1985-1996 with active follow-up through 2005) comprising current and former heavy smokers were analyzed. CARET was a multicenter randomized, double-blind placebo-controlled chemoprevention trial testing daily supplementation of 30 mg beta-carotene+25 000 IU retinyl palmitate for primary prevention of lung cancer. Prostate cancer was a secondary outcome. Nonaggressive disease was defined as Gleason less than 7 and stage I/II. Aggressive disease was primarily defined as at least Gleason 7 or stage III/IV, and secondarily by excluding Gleason 3+4 from the first definition. BMI was calculated from measured weight and height. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer incidence between BMI categories. During follow-up, 883 men were diagnosed with prostate cancer. In the analysis of aggressive disease when Gleason 3+4 was excluded, men with a BMI of at least 35 kg/m had an increased rate of prostate cancer (HR: 1.80, 95% CI: 1.04-3.11, Ptrend=0.04) compared with men with BMI 18 24.9 kg/m. No other differences were seen in risk estimates for overall, nonaggressive or aggressive prostate cancer including all Gleason 7 cases, between BMI categories. Our results show an association between having a BMI of at least 35 kg/m and an increased risk of aggressive prostate cancer (not including Gleason 3+4 tumors), but do not support an association between BMI and risk of overall, aggressive disease including all Gleason 7, or nonaggressive prostate cancer within a population of current and former heavy smokers. PMID- 29521684 TI - Postoperative cesarean pain: real but is it preventable? AB - PURPOSE OF REVIEW: Cesarean section is the most common surgical procedure performed in the world. Postoperative pain management remains a challenge, particularly in a context of enhanced recovery after surgery. Several barriers related to the specific condition of 'postpartum recovery' may prevent application of effective analgesia in this population. The present review focuses on novel approaches of cesarean section postoperative pain assessment, beyond pain-rating intensity, including objective patient-centered recovery parameters. Predictive tools currently available to target patients at high risk of acute and chronic pain are also examined. RECENT FINDINGS: Postoperative pain after cesarean section is more severe than reported in the majority of randomized control trials. Pain seriously interferes with early and also late functional recovery, although Enhanced Recovery after Surgery (ERAS) programmes are being promoted. Pain-rating scores can differ from scores of physical comfort and physical independence, which are priorities for postpartum patients. Further, the value of subjective pain intensity rating to adapt analgesic prescription is misleading and may promote opioid over-prescription. Available tools to predict at-risk patients for severe pain after cesarean section are not easy to use in daily clinical practice and have, at best, moderate predictive value. SUMMARY: Patient and healthcare provider education on reported pain and well tolerated analgesic use is the key to improve postpartum pain management after cesarean section. PMID- 29521685 TI - Cost-Effectiveness Analysis of Syndesmotic Screw Versus Suture Button Fixation in Tibiofibular Syndesmotic Injuries. AB - OBJECTIVES: To evaluate the cost effectiveness of suture buttons compared with syndesmotic screws for repair of tibiofibular syndesmotic injuries. METHODS: A decision tree model was constructed to describe outcomes after syndesmosis repair using suture buttons and syndesmotic screws from the perspective of a capitated health care system. Outcomes were uneventful healing, removal of symptomatic implants, deep infection, and persistent diastasis requiring revision. Weighted literature averages were used to estimate variables for a baseline model. Outcomes were measured in quality adjusted life years. Procedure and implant costs were derived from Medicare reimbursement rates and the University Health System Consortium. An incremental cost-effectiveness ratio threshold of $50,000 per quality-adjusted life years was used to evaluate cost effectiveness. RESULTS: The baseline model did not identify suture buttons to be cost effective. Sensitivity analysis demonstrates the model to be exquisitely sensitive to small changes in reoperation rates and implant price. At median University Health System Consortium implant prices, if the removal rate for symptomatic screws is below 13.7%, then screws are cost effective. If the screw removal rate is greater than 17.5%, then a suture button is cost effective. Within this interval, detailed analysis of the model suggests that screws may be the cost-effective strategy, but that determination should be taken with caution. CONCLUSIONS: Moving away from the practice of routinely removing all syndesmotic screws has changed the financial landscape of syndesmosis repair. At their median cost, suture buttons are likely to be cost effective over screws for symptomatic screw removal rates greater than 17.5%. Cost effectiveness is sensitive to changes in implant removal rates and the number of devices used per patient. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29521686 TI - Do Immediate Postoperative Radiographs Change Patient Management After Fracture Fixation? A Systematic Review. AB - OBJECTIVES: To evaluate whether immediate (0-3 days) postoperative radiography leads to alterations in the management of patients postfracture fixation. DATA SOURCES: Systematic review of English-language articles in the MEDLINE (1946 2016), EMBASE (1974-2016), CDSR (2005-2016), CENTRAL (1948-2016), and Google Scholar databases using Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. STUDY SELECTION: Randomized or non-randomized controlled trials and prospective or retrospective cohort studies that addressed surgical management of the upper extremity, lower extremity or hip fractures were eligible for review. All included studies needed to have performed radiography within 0-3 days of surgery and reported any directly resulting management changes. DATA EXTRACTION: Data were independently extracted by 2 reviewers using a standardized data collection form with predefined data fields for demographics, interventions, study methods, complications, and management outcomes. DATA SYNTHESIS: A random effects model was applied, and pooled effects for absolute benefit increase (ABI) and number needed to treat (NNT) were calculated. CONCLUSIONS: Combining the 11/12 articles that reported by patient numbers, the ABI of immediate postoperative radiography for management change was 0.13% [95% confidence interval (CI), 0.00078%-0.60%; NNT = 753]. The ABI for identification of complications was 0.22% (95% CI, 0.0015%-1.24%; NNT = 453). Current literature suggests that immediate postoperative radiography does not lead to management change in most patients after fracture fixation. More comprehensive reporting, along with further prospective comparative research, is encouraged. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29521687 TI - Reliability of a Condensed Computer-Based Patient Outcomes Scoring Tool in Orthopaedic Trauma Patients. AB - OBJECTIVES: To determine the reliability of a condensed computer-based patient centered outcome score system versus multiple standard uncondensed validated outcome scores used in orthopaedic trauma. DESIGN: Prospective. SETTING: Level I Trauma Center. PATIENTS/PARTICIPANTS: One hundred patients older than 18 years with various orthopaedic injuries were evaluated at a Level I Trauma Clinic. INTERVENTION: Study participants were randomly assigned to complete the paper based and computer-based versions of the EQ-5D and musculoskeletal functional assessment at different times during the same visit. MAIN OUTCOME MEASUREMENTS: Score variability between the computer-based and paper-based versions. RESULTS: The average score difference between the computer-based and paper-based musculoskeletal functional assessment was 0.50, with an SD of 6.03 and a 95% confidence interval of -0.71 to 1.71. For the EQ-5D, the average score difference was 0.12 with an SD of 0.20 and a 95% confidence interval of -0.05 to 0.05. CONCLUSIONS: Because patient-centered outcomes drive the direction of orthopaedic care, it is critical to collect patient data efficiently while minimizing responder burden. This condensed web-based adaptive outcome tool reliably produced similar scores when compared with individual paper scores, and it decreased responder burden and error. PMID- 29521688 TI - Keratoprosthesis Decentration and Tilt Results in Degradation in Image Quality. AB - PURPOSE: To study the effect of decentration and tilt of the type I Boston keratoprosthesis (KPro) on image quality in both aphakic and pseudophakic eyes. METHODS: An optical ray-tracing program was used to simulate the image projected onto the retina in an eye with a perfectly centered KPro, and in eyes with varying degrees of KPro decentration and tilt. Decentration was modeled along a typical white-to-white distance of 12.0 mm, and the corresponding tilt was calculated assuming a radius of curvature of 8.0 mm, the radius of curvature of the backplate of the KPro. Both aphakic and pseudophakic eyes were simulated, and the corresponding modulation transfer function curves, point spread functions, and astigmatism were analyzed. RESULTS: The perfectly centered KPro produced a high-quality image with no induced astigmatism. Increasing decentration beyond approximately 0.5 mm resulted in poorer image quality with a more pronounced effect in the presence of an intraocular lens. Using models of the normal eye as a threshold, image degradation due to decentration becomes clinically significant at approximately 1.4 mm and 0.9 mm for the aphakic and pseudophakic cases, respectively. Astigmatism introduced by decentration is approximately 0.25 D cylinders at those thresholds. CONCLUSIONS: Decentration of up to 0.5 mm had no significant impact on image quality and an attempt at good intraoperative centration of the KPro within this range is important. Conversely, decentration of 0.9 mm or more during surgical implantation can result in significant degradation in retinal image quality including astigmatism. The effect is greater in the pseudophakic eye. PMID- 29521689 TI - Outcomes of Descemet Membrane Endothelial Keratoplasty in Eyes With a Previous Descemet Stripping Automated Endothelial Keratoplasty Graft. AB - PURPOSE: To analyze the outcomes of Descemet membrane endothelial keratoplasty (DMEK) in eyes with previous Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: This retrospective interventional case series included 26 eyes (26 patients) that underwent DMEK to replace a previous DSAEK graft with at least 6 months of follow-up. The outcome measures were indications for surgery, best spectacle-corrected visual acuity (BSCVA), endothelial cell density, rebubbling rate, rejection, and failure. RESULTS: Patient age was 71.9 +/- 12.6 years. The average follow-up time after DMEK was 15.1 +/- 10.6 months. Indications for DMEK were DSAEK graft failure (69%) and a DSAEK suboptimal visual outcome (31%). BSCVA of the entire cohort (n = 26) improved from 1.33 +/- 0.78 logMAR preoperatively to 1.04 +/- 0.78 and 1.06 +/- 0.89 logMAR at 6 months postoperatively and at the last follow-up, respectively (P = 0.019 and P = 0.033). BSCVA among eyes without visual comorbidities (n = 13) improved from 0.84 +/- 0.50 logMAR preoperatively to 0.55 +/- 0.47 and 0.51 +/- 0.49 logMAR at 6 months postoperatively and at final follow-up, respectively (P = 0.023 for both). Of these eyes, 84.6% had improvement in BSCVA at 6 months postoperatively and at last follow-up. In the subgroup of 8 eyes with DMEK for suboptimal visual outcomes after DSAEK, BSCVA improved from 0.81 +/- 0.44 to 0.52 +/- 0.35 logMAR at final follow-up (P = 0.024). When excluding eyes with visual comorbidities, BSCVA of this subgroup (n = 5) improved from 0.54 +/- 0.32 to 0.36 +/- 0.25 logMAR at final follow-up (P = 0.038). BSCVA of this subgroup at 6 months postoperatively was not significantly different from preoperative BSCVA, when including visual comorbidities (n = 8, 0.75 +/- 0.60 logMAR, P = 0.79) and when excluding visual comorbidities (n = 5, 0.40 +/- 0.28 logMAR, P = 0.621). Endothelial cell density decreased from 2753 +/- 307 cells/mm to 1659 +/- 655 cells/mm 6 months after surgery (39.7% loss, P = 0.005). Three eyes (11.5%) required rebubbling, and 5 eyes (19.2%) had secondary graft failure at 2 to 20 months. CONCLUSIONS: DMEK is effective for replacing previous DSAEK not only for graft failure but also for suboptimal visual outcomes. PMID- 29521690 TI - Confocal Microscopy Observation of Cornea Verticillata After Vandetanib Therapy for Medullary Thyroid Carcinoma. AB - PURPOSE: To report 2 cases of cornea verticillata (CV) after vandetanib treatment for medullary thyroid carcinoma (MTC). METHODS: In this retrospective interventional, case-report study, 2 patients who under vandetanib treatment for MTC were referred to our ophthalmology department because of vision complaints. Both subjects underwent a complete ophthalmologic examination, including confocal microscopy (CM) using the Heidelberg Retina Tomograph and Rostock Cornea Module. RESULTS: A 70-year-old man and a 43-year-old woman, both with a history of MTC under treatment with vandetanib for 5 months and 30 months, respectively, presented with blurred vision. In both patients, a mild CV pattern was observed although deposits were more evident in the male patient. CM images showed hyperreflective deposits in the corneal epithelium and subepithelial nerve plexus. Bright microdots were also seen throughout the stroma, along with a few hyperreflective keratocytes in the anterior stroma. CONCLUSIONS: In both patients, vandetanib seemed to be the cause of CV. The CM images supported the idea of drug-lipid complex deposits in vandetanib-induced CV. PMID- 29521691 TI - Feasibility Study of Human Corneal Endothelial Cell Transplantation Using an In Vitro Human Corneal Model. AB - PURPOSE: To test the feasibility of a cell therapy approach to treat corneal endothelial (CE) disorders using an in vitro model of human corneal decompensation. METHODS: A CE decompensation model was established by removal of the Descemet membrane/endothelium complex from cadaveric human corneas in an air interface organ culture system (group 2) and compared with normal corneas (group 1). The posterior stroma of decompensated corneas was seeded with immortalized human corneal endothelial cells (HCEC-12) in group 3 and passage 0 primary human CE cells in group 4 corneas. Functional effects on stromal thickness were determined with histological analysis 3 to 10 days after cell therapy treatment. RESULTS: Removal of the Descemet membrane/endothelium complex in group 2 corneas resulted in a stromal thickness of 903 +/- 86 MUm at 12 hours compared with 557 +/- 72 MUm in group 1 corneas. Stromal thickness reduced from 1218 +/- 153 MUm to 458 +/- 90 MUm (63% +/- 6%, P = 0.001) after cell transplantation in group 3 and from 1100 +/- 86 MUm to 489 +/- 94 MUm (55% +/- 7%, P = 0.00004) in group 4. Posttransplantation histology demonstrated formation of a monolayer of corneal endothelium attached to the posterior stromal surface. CONCLUSIONS: Direct transplantation of cultured human CE cells and immortalized HCEC-12 to bare posterior corneal stroma resulted in formation of an endothelial monolayer and restoration of stromal hydration to physiological thickness, demonstrating the feasibility of cell therapy in treatment of CE decompensation in a human in vitro model. PMID- 29521692 TI - Scleral Shape and Its Correlations With Corneal Astigmatism. AB - PURPOSE: To assess the correlation between the scleral shape and corneal astigmatism. METHODS: Twenty-two participants (11 nonastigmatic and 11 astigmatic) aged from 19 to 36 years and with no previous ocular surgeries were included in this study. Three-dimensional (3D) corneoscleral maps from both eyes (44 eyes) were acquired using a corneoscleral topographer (Eye Surface Profiler). Each 3D map was split into 13 concentric annuli, each 0.5-mm wide, starting at 1.0-mm radius from the corneal apex to the scleral periphery at 7.5 mm from the apex. Each ring was fitted to a quadratic function of the radial distance to the apex, to calculate the elevation difference between the raw data and the fitting surface ring. For each ring, the resulting elevation difference between the original and fit data profile was fit to a sum of sine function. Decentration and astigmatic terms obtained from the sinusoidal fit were analyzed and compared between nonastigmatic and astigmatic groups. RESULTS: In astigmatic eyes, corneal and scleral asymmetry are highly correlated, but both appear independent of each other in nonastigmatic eyes. No significant difference between astigmatic and nonastigmatic eyes was found for the decentration term [P > 0.05/N (Bonferroni)], whereas for the astigmatic component, the differences were statistically significant [P < 0.05/N (Bonferroni)]. CONCLUSIONS: Corneal and scleral shapes are correlated in astigmatic eyes, which suggests that astigmatism is not restricted to the cornea but should rather be considered a property of the entire eye globe. PMID- 29521693 TI - Mechanism of Immunologic Rejection After Deep Anterior Lamellar Keratoplasty. PMID- 29521694 TI - Reply. PMID- 29521696 TI - Contact Dermatitis in Underrepresented Minority. PMID- 29521698 TI - Cervical Laminoplasty: Indications, Surgical Considerations, and Clinical Outcomes. AB - Cervical laminoplasty was initially described for the management of cervical myelopathy resulting from multilevel stenosis secondary to ossification of the posterior longitudinal ligament. The general concepts are preservation of the dorsal elements, preservation of segmental motion, and expansion of the spinal canal via laminar manipulation. No clear evidence suggests that laminoplasty is superior to either posterior laminectomy or anterior cervical diskectomy and fusion. However, laminoplasty has its own advantages, indications, and complications. Surgeons have refined the technique to decrease complication rates and improve efficacy. Recent efforts have highlighted less invasive approaches that are muscle sparing and associated with less postoperative morbidity. Although the long-term outcomes suggest that cervical laminoplasty is safe and effective, continued research on the development of novel modifications that decrease common complications, such as C5 nerve palsy, axial neck pain, and loss of lordosis, is required. PMID- 29521699 TI - A 62-Year-Old Woman With Fever and Exanthema. PMID- 29521700 TI - ACSM's Clinician Profile. PMID- 29521701 TI - Accidental Carbon Monoxide Poisoning in Sports and Other Settings. PMID- 29521702 TI - Cross Body Stretching for Internal Rotation Deficit. PMID- 29521703 TI - Athletic Suicide - Separating Fact From Fiction and Navigating the Challenging Road Ahead. PMID- 29521704 TI - Evaluating the Athlete with Suspected Exercise-Induced Asthma or Bronchospasm. AB - Exercise-induced asthma (EIA) and exercise-induced bronchospasm (EIB)/bronchoconstriction (EIC) describes two clinical entities by which exercise triggers bronchial hyperresponsiveness. Exercise is a common trigger of bronchospasm in the asthmatic (EIA), as well as athletes without the underlying inflammation associated with asthma (EIC/EIB). Approximately 10% to 20% of the general population have EIA or EIB (). The approach to the diagnosis and subsequent management relies on the clinician's ability to recognize clinical signs and symptoms, then selecting the correct diagnostic test. A baseline spirometry/pulmonary function test is recommended for all athletes to evaluate for underlying asthma. Subsequent direct or indirect bronchial provocation testing is recommended to correctly diagnose EIA or EIB (). Athletes should not be treated empirically with bronchodilators based on symptoms alone without confirmatory spirometry and provocative testing. PMID- 29521705 TI - Chest Trauma in Athletic Medicine. AB - While overall sports participation continues at high rates, chest injuries occur relatively infrequently. Many conditions of chest injury are benign, related to simple contusions and strains, but the more rare, severe injuries carry a much higher risk of morbidity and mortality than the typical issues encountered in athletic medicine. Missed or delayed diagnosis can prove to be catastrophic. Sports medicine providers must be prepared to encounter a wide range of traumatic conditions relating to the torso, varying from the benign chest wall contusion to the life-threatening tension pneumothorax. Basic field-side management should be rapid and focused, using the standardized approach of Advanced Traumatic Life Support protocol. Early and appropriate diagnosis and management can help allow safe and enjoyable sports participation. PMID- 29521706 TI - Anabolic Steroid Effect on the Liver. AB - Anabolic steroids are synthetic derivatives of testosterone shown to increase muscle size and strength. Chemical substitutions on the testosterone molecule cause increased potency and duration of action. The 17-alpha-alkylation modification allows steroids to be taken orally, but the slower clearance in the liver makes them more hepatotoxic. The frequency and severity of side effects depends on several factors including the formulation of the drug, route of administration, dosage, duration of use, and individual sensitivity and response. Anabolic steroid users tend to take supraphysiologic doses or multiple steroids and other drugs simultaneously which increases risk of adverse effects. Hepatotoxicity can be seen as elevated liver transaminases, acute cholestatic syndrome, chronic vascular injury, hepatic tumors, and toxicant-associated fatty liver disease, as well as significant changes in lipoproteins. Many of these changes will stabilize or reverse with cessation of steroid use, but some can be life-threatening. Over-the-counter supplements can be contaminated with anabolic steroids, causing hepatotoxicity in unsuspecting consumers. PMID- 29521707 TI - Nutritional Supplements for the Treatment and Prevention of Sports-Related Concussion - Omega 3 Fatty Acids: Evidence Still Lacking? PMID- 29521708 TI - Response to the Letter to the Editor. PMID- 29521709 TI - Intravitreal Triamcinolone Acetonide Injection in a Rodent Model of Anterior Ischemic Optic Neuropathy. AB - INTRODUCTION: The management of nonarteritic anterior ischemic optic neuropathy centers around prevention of second eye involvement, without a uniformly accepted therapy for the involved eye. Several researchers have assessed the benefit of steroids with conflicting results. This experimental study was designed to evaluate the efficacy of a single intravitreal triamcinolone acetonide injection (IVTA) in preserving retinal ganglion cells (RGCs) in a rodent model of anterior ischemic optic neuropathy (rAION). METHODS: The rAION was induced in female Wistar rats. Animals were randomized into 3 groups: 1) untreated, 2) treated with 56 MUg IVTA, and 3) intravitreal saline (placebo). Procedures were performed in the left eye, with the right eye serving as control. After 30 days, animals were sacrificed and eyes were assessed histologically for RGC number. RESULTS: The average number of RGC was significantly lower in rAION subgroups when compared with the control group (P < 0.001). No significant difference was seen between rAION eyes treated with IVTA, placebo, and untreated eyes (P > 0.05%). CONCLUSIONS: In this rodent model for AION, no therapeutic benefit of intravitreal steroid injection was identified. PMID- 29521710 TI - To Tell or Not to Tell: Nursing Students' Attitudes Toward Disclosing Patients' Protected Health Information. PMID- 29521712 TI - Quality of Electronic Nursing Records: The Impact of Educational Interventions During a Hospital Accreditation Process. PMID- 29521711 TI - HIMSS-ANI Recognizes Leadership in Nursing Informatics With Joint Award. PMID- 29521713 TI - Open Lung Biopsy in Nonresolving Acute Respiratory Distress Syndrome Commonly Identifies Corticosteroid-Sensitive Pathologies, Associated With Better Outcome. AB - OBJECTIVES: Approximately half of the patients undergoing lung biopsy for nonresolving acute respiratory distress syndrome exhibit another histologic pattern than diffuse alveolar damage, with some of the pathologies characterized by a potential response to corticosteroids. This study aimed to assess whether open lung biopsy performed in the ICU for nonresolving acute respiratory distress syndrome was able to identify steroid-sensitive diseases and whether patients with a steroid-sensitive pathology experienced different clinical courses and outcomes. DESIGN: Retrospective analysis. SETTING: One 22-bed mixed ICU within a tertiary medical center. PATIENTS: Patients age greater than or equal to 16 years old who met the Berlin definition for acute respiratory distress syndrome and underwent open lung biopsy from January 2007 to January 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 695 patients diagnosed with acute respiratory distress syndrome were identified, 51 (7%) of whom underwent open lung biopsy. An alternative diagnosis to diffuse alveolar damage was found in 29 patients (57%), and a steroid-sensitive pathology was identified in 19 (37%). In-hospital and 180-day mortality rates were 55% and 61%, respectively. There was a significant difference in hospital mortality and 180 day mortality rates between patients with steroid-sensitive pathology and those with steroid-resistant pathology (37% vs 65%; p < 0.045 and 37% vs 75%; p < 0.007, respectively). We did not identify any variable that could reliably predict a steroid-sensitive histologic pattern before open lung biopsy. CONCLUSIONS: Open lung biopsy was able to identify a steroid-sensitive pathology in a significant proportion of nonresolving acute respiratory distress syndrome patients. These patients had a better outcome, with lower hospital mortality and 180-day mortality. PMID- 29521714 TI - Comparison of Antivenom Dosing Strategies for Rattlesnake Envenomation. AB - OBJECTIVES: This study compares maintenance with clinical- and laboratory triggered (as-needed [PRN]) antivenom dosing strategies with regard to patient centered outcomes after rattlesnake envenomation. DESIGN: This is a retrospective cohort study of adult rattlesnake envenomations treated at a regional toxicology center. Data on demographics, envenomation details, antivenom administration, length of stay, and laboratory and clinical outcomes were compared between the PRN and maintenance groups. Primary outcomes were hospital length of stay and total antivenom used, with a hypothesis of no difference between the two dosing strategies. SETTING: A single regional toxicology center PATIENTS:: Three-hundred ten adult patients envenomated by rattlesnakes between 2007 and 2014 were included. Patients were excluded if no antivenom was administered or for receiving an antivenom other than Crofab (BTG International, West Conshohocken, PA). INTERVENTIONS: This is a retrospective study of rattlesnake envenomations treated with and without maintenance antivenom dosing. MAIN RESULTS: One-hundred forty-eight in the maintenance group and 162 in the PRN group were included. There was no difference in demographics or baseline envenomation severity or hemotoxicity (32.7% vs 40.5%; respectively; p = 0.158) between the two groups. Comparing the PRN with the maintenance group, less antivenom was used (8 [interquartile range, 6-12] vs 16 [interquartile range, 12-18] vials, respectively; p < 0.001), and hospital length of stay was shorter (27 hr [interquartile range, 20-44 hr] vs 34 hr [interquartile range, 24-43 hr], respectively; p = 0.014). There were no differences in follow-up outcomes of readmission, retreatment, or bleeding and surgical complications. CONCLUSIONS: Hospital length of stay was shorter, and less antivenom was used in patients receiving a PRN antivenom dosing strategy after rattlesnake envenomation. PMID- 29521715 TI - Simulation-Based Assessment of Critical Care "Front-Line" Providers. AB - OBJECTIVES: Develop a standardized simulation method to assess clinical skills of ICU providers. DESIGN: Simulation assessment. SETTING: Simulation laboratory. SUBJECTS: Residents, Critical Care Medicine fellows, acute care nurse practitioner students. INTERVENTIONS: Performance scoring in scenarios from multiple Critical Care Medicine competency domains. MEASUREMENTS AND MAIN RESULTS: Three-hundred eighty-four performances by 48 participants were scored using checklists (% correct) and holistic "global" ratings (1 [unprepared] to 9 [expert]). One-hundred eighty were scored by two raters. Mean checklist and global scores (+/- SD) ranged from 65.0% (+/- 16.3%) to 84.5% (+/- 17.3%) and 4.7 (+/- 1.4) to 7.2 (+/- 1.2). Checklist and global scores for Critical Care Medicine fellows and senior acute care nurse practitioner students (Experienced group, n = 26) were significantly higher than those for the Novice acute care nurse practitioner students (Novice group, n = 14) (75.6% +/- 15.6% vs 68.8% +/- 21.0% and 6.1 +/- 1.6 vs 5.4 +/- 1.5, respectively; p < 0.05). Residents (Intermediate group, n = 8) scored between the two (75.4% +/- 18.3% and 5.7 +/- 1.7). 38.5% of the Experienced group scored in the top quartile for mean global score, compared with 12.5% of the Intermediate and 7.1% of the Novice groups. Conversely, 50% of the Novice group scored in the lower quartile (< 5.3), compared with 37.5% of the Intermediate and 11.5% of the Experienced groups. Psychometric analyses yielded discrimination values greater than 0.3 for most scenarios and reliability for the eight-scenario assessments of 0.51 and 0.60, with interrater reliability of 0.71 and 0.75, for checklist and global scoring, respectively. CONCLUSIONS: The simulation assessments yielded reasonably reliable measures of Critical Care Medicine decision-making skills. Despite a wide range of performance, those with more ICU training and experience performed better, providing evidence to support the validity of the scores. Simulation-based assessments may ultimately prove useful to determine readiness to assume decision making roles in the ICU. PMID- 29521716 TI - Interprofessional Care and Teamwork in the ICU. AB - OBJECTIVES: We describe the importance of interprofessional care in modern critical care medicine. This review highlights the essential roles played by specific members of the interprofessional care team, including patients and family members, and discusses quality improvement initiatives that require interprofessional collaboration for success. DATA SOURCES: Studies were identified through MEDLINE search using a variety of search phrases related to interprofessional care, critical care provider types, and quality improvement initiatives. Additional articles were identified through a review of the reference lists of identified articles. STUDY SELECTION: Original articles, review articles, and systematic reviews were considered. DATA EXTRACTION: Manuscripts were selected for inclusion based on expert opinion of well-designed or key studies and review articles. DATA SYNTHESIS: "Interprofessional care" refers to care provided by a team of healthcare professionals with overlapping expertise and an appreciation for the unique contribution of other team members as partners in achieving a common goal. A robust body of data supports improvement in patient-level outcomes when care is provided by an interprofessional team. Critical care nurses, advanced practice providers, pharmacists, respiratory care practitioners, rehabilitation specialists, dieticians, social workers, case managers, spiritual care providers, intensivists, and nonintensivist physicians each provide unique expertise and perspectives to patient care, and therefore play an important role in a team that must address the diverse needs of patients and families in the ICU. Engaging patients and families as partners in their healthcare is also critical. Many important ICU quality improvement initiatives require an interprofessional approach, including Awakening and Breathing Coordination, Delirium, Early Exercise/Mobility, and Family Empowerment bundle implementation, interprofessional rounding practices, unit-based quality improvement initiatives, Patient and Family Advisory Councils, end-of-life care, coordinated sedation awakening and spontaneous breathing trials, intrahospital transport, and transitions of care. CONCLUSIONS: A robust body of evidence supports an interprofessional approach as a key component in the provision of high-quality critical care to patients of increasing complexity and with increasingly diverse needs. PMID- 29521717 TI - Long-term Clinical Outcomes of Pars Plana Versus Anterior Chamber Placement of Glaucoma Implant Tubes. AB - PURPOSE: To compare long-term surgical outcomes and complications of pars plana (PP) tube implantation with conventional anterior chamber (AC) tube implantation. MATERIALS AND METHODS: Records of patients undergoing glaucoma tube implant surgery at a single institution between 2007 and 2015 were retrospectively reviewed. Eyes were matched for glaucoma diagnosis and patient age. Demographics, baseline characteristics, and treatment outcomes were recorded. Surgical success was defined as intraocular pressure (IOP) between 6 and 21 mm Hg, no subsequent glaucoma surgeries performed, and at least light perception vision. RESULTS: Fifty-seven eyes that underwent Ahmed or Baerveldt glaucoma drainage device surgery with PP tube placement were compared with 57 eyes with AC tube placement. Mean follow-up was 43.5 months in the PP group and 35.3 months in the AC group (P=0.02). Forty-nine (86.0%) PP eyes and 46 (80.7%) AC eyes achieved surgical success (P=0.45). At last follow-up, mean IOP decreased from 29.0 to 15.1 mm Hg in the PP group (P<0.01) and from 32.7 to 15.6 mm Hg in the AC group (P<0.01). Mean number of medications decreased from 2.9 to 1.1 in the PP group (P<0.01) and from 2.8 to 1.3 in the AC group (P<0.01). Mean IOP and number of medications were similar between PP and AC groups at baseline, last follow-up, and all interim time points (P>0.05 for all). There were 16 complications in the PP group and 14 in the AC group (P=0.67). CONCLUSIONS: Long-term results of glaucoma tube implant surgery with PP versus AC implantation shows effective IOP control with similar rates of surgical success. PMID- 29521718 TI - Clinical Efficacy and Safety Profile of Micropulse Transscleral Cyclophotocoagulation in Refractory Glaucoma. AB - PURPOSE: To investigate the clinical efficacy and safety profile of micropulse transscleral cyclophotocoagulation (MP-CPC) in patients with refractory glaucoma. MATERIALS AND METHODS: Retrospective case series of 79 consecutive patients who underwent MP-CPC at the Wills Eye Hospital from March 23, 2014 to June 23, 2016 and who had at least 3 months of follow-up. Treatment success was defined as an intraocular pressure (IOP) of 6 to 21 mm Hg or a reduction of IOP by 20%. Failure was defined as an inability to meet the criteria for success, need for retreatment >3 times, or need for incisional glaucoma surgery. RESULTS: Patients had a mean follow-up time of 7.8+/-4.5 months. The mean IOP before MP-CPC was 31.9+/-10.2 mm Hg. The IOP was reduced by an average of 51% at the last follow-up and the mean number of IOP lowering medications was reduced from 2.3 at baseline to 1.5 at last follow-up. Treatment success rates were 75% at 3 months, 66% at 6 months, and 67% at last follow-up. Complications of MP-CPC included 7 patients with hypotony (8.8%), 21 patients with prolonged anterior chamber inflammation (1+ cell or flare for >3 mo, 26%), 13 patients with loss of >=2 lines of best corrected visual acuity at 3 months (17%), 4 patients with macular edema (5%), 2 patients with corneal edema and 2 patients with phthisis. CONCLUSIONS: MP-CPC is an effective treatment for patients with refractory glaucoma. Shorter treatment times with more frequent repeat treatments, if necessary, should be considered given the incidence of significant vision loss in this study. PMID- 29521719 TI - Letter in Response to Chiang et al "A Novel Method of Extending Glaucoma Drainage Tube: 'Tube-in-Tube' Technique". PMID- 29521720 TI - A Novel Method of Extending Glaucoma Drainage Tube: "Tube-in-Tube" Technique. PMID- 29521722 TI - Effects of Two Hours of Heavy-Intensity Exercise on the Power-Duration Relationship. AB - INTRODUCTION: Changes in the parameters of the power-time relationship (critical power (CP) and W') during endurance exercise would have important implications for performance. We tested the hypotheses that CP and W', estimated using the end test power (EP) and the work done above EP (WEP), respectively, during a the 3 min all-out test (3MT), can be reliably determined, and would be lower, after completing 2 h of heavy-intensity exercise. METHODS: In study 1, six cyclists completed a 3MT immediately after 2 h of heavy-intensity exercise on two occasions to establish the reliability of EP and WEP. In study 2, nine cyclists completed a control 3MT, and a fatigued 3MT and constant power output tests to 30 min or the limit of tolerance (Tlim) below and above F-EP after 2 h of heavy intensity exercise. RESULTS: In study 1, EP (273 +/- 52 vs 276 +/- 58 W) and WEP (12.4 +/- 4.3 vs 12.8 +/- 4.3 kJ) after 2 h of heavy-intensity exercise were not different (P > 0.05) and were highly correlated (r = 0.99; P < 0.001). In study 2, both EP (F-EP: 282 +/- 52 vs C-EP: 306 +/- 56 W; P < 0.01) and WEP (F-WEP: 14.7 +/- 4.9 vs C-WEP: 18.3 +/- 4.1 kJ; P < 0.05) were lower after 2-h heavy intensity exercise. However, maximum O2 uptake was not achieved during exercise >F-EP and Tlim was shorter than 30 min during exercise =10 showed similar parameters to FNA in both PSM types: sensitivity, 94% in both; specificity, 85% versus 87%; positive predictive value, 93% versus 94%; negative predictive value, 87% in both; and accuracy, 92% for malignant and sensitivity, 85% versus 87%; specificity, 94% in both; positive predictive value, 87% in both; negative predictive value, 93% versus 94%; and accuracy, 92% for benign. The area under the curve was 0.96 (P<0.000; 95% confidence interval, 0.940-0.995). New classifications on the basis of positive likelihood ratio were grouped as follows: A <=8.7 (benign tumor); B >8.7 to <15.5 (indeterminate); and C >=15.5 (malignant). CONCLUSIONS: QE has similar capacity to FNA in PSM evaluation. However, the former can be used potentially as a substitute of the latter in certain cases on the basis of these new SR cutoff-based classifications. PMID- 29521725 TI - Carbon Dioxide Insufflation Increases Colonoscopic Adenoma Detection Rate Compared With Air Insufflation. AB - GOALS: To determine the effect of carbon dioxide insufflation on the most important outcome measure of colonoscopic quality: adenoma detection rate (ADR). BACKGROUND: Bowel cancer is the second most common cause of cancer deaths in males and females in Australia. Carbon dioxide has in recent times become the insufflation methodology of choice for screening colonoscopy for bowel cancer, as this has been shown to have significant advantages when compared with traditional air insufflation. STUDY: Endoscopies performed over a period of 9 months immediately before and after the implementation of carbon dioxide insufflation at endoscopy centers were eligible for inclusion. RESULTS: The difference in ADR between the carbon dioxide and air insufflation methods was statistically significant, with an increased ADR in the carbon dioxide group. The superiority of carbon dioxide insufflation was sustained with a logistic regression model, which showed ADR was significantly impacted by insufflation method. CONCLUSIONS: Carbon dioxide insufflation is known to reduce abdominal pain, postprocedural duration of abdominal pain, abdominal distension, and analgesic requirements. This study represents for the first time the beneficial effect of carbon dioxide insufflation upon the key quality colonoscopy indicator of ADR. PMID- 29521726 TI - Lacrimal Drainage Obstruction and Gastroesophageal Reflux Disease: A Nationwide Longitudinal Cohort Study. AB - GOALS: This study aimed to evaluate the association between gastroesophageal reflux disease (GERD) and development of lacrimal drainage obstruction (LDO). BACKGROUND: It has been hypothesized that GERD may contribute toward the development of LDO. STUDY: This was a retrospective study of Koreans aged 40 to 79 years registered in the Korean National Health Screening Cohort from 2002 to 2013. Incident cases of LDO were identified according to the Korean Classification of Disease. We compared hazard ratios (HRs) for LDO between 22,570 patients with GERD and 112,850 patients without GERD by 1:5 propensity score matched analysis. RESULTS: A total of 135,420 patients, representing 1,237,909 person-years, were evaluated. LDO developed in 1998 (8.9%) patients with GERD and 8565 (7.6%) patients without GERD (P<0.001). The incidence of LDO per 1000 person years in patients with GERD was 9.7 and 8.3 in those without GERD; the age adjusted and sex-adjusted HR was 1.17 (95% confidence interval, 1.11-1.23). This association between GERD and LDO was more pronounced among younger individuals (HR, 1.20 for patients 40 to 59-y old; HR, 1.12 for patients 60 to 79-y old) and among men (HR, 1.20 for men; HR, 1.14 for women). Patients with GERD had a higher risk of LDO than those without GERD, irrespective of history of proton-pump inhibitor use. In the sensitivity analysis, GERD patients with esophagitis had a higher risk of LDO than those without esophagitis. CONCLUSIONS: Our findings suggest that GERD is associated with an increased risk of subsequent LDO and that this effect is more pronounced among adults aged 40 to 59-years old and men. PMID- 29521728 TI - The Chameleon Effect. PMID- 29521727 TI - Jackhammer Esophagus: Symptom Presentation, Associated Distal Contractile Integral, and Assessment of Bolus Transit. AB - GOALS: The aim of our study was to characterize jackhammer esophagus symptoms and their relationship with the distal contractile integral (DCI) and bolus transit. BACKGROUND: Jackhammer esophagus is defined by the Chicago Classification version 3.0. This diagnosis is relatively new, with the most current definition being established in 2014. The forerunners of this diagnosis, nutcracker (or hypercontractile) esophagus, have been associated with noncardiac chest pain (NCCP). STUDY: A retrospective chart review was performed of motility studies from 2011 to 2016. Studies with a diagnosis of jackhammer esophagus, hypercontractile esophagus, nutcracker, esophagogastric junction outflow obstruction, or hypertensive lower esophageal sphincter were reread using Chicago Classification version 3.0, and were included if they met criteria for jackhammer esophagus. Unpaired t-tests were used for analysis (P<=0.05). RESULTS: In total, 142 studies were identified with the above diagnoses. After excluding 84 studies, 58 remained for analysis and 17 were found to have jackhammer esophagus (29%). The mean age was 54 (28 to 75), 5 (29%) were males and 12 (71%) were females. The primary indications were NCCP (5), dysphagia (8), and other causes (4) (cough, heartburn, or regurgitation). The mean DCIs were 17,245 mm Hg*s*cm (NCCP), 14,669 mm Hg*s*cm (dysphagia), and 11,264 mm Hg*s*cm (other causes). The mean DCIs were compared: NCCP versus dysphagia (P=0.41), and NCCP versus other causes (P=0.05). Fifteen (88%) had normal bolus transit for both liquid and viscous swallows. CONCLUSIONS: In our small sample size, dysphagia was frequently the presenting symptom followed by NCCP. Those with NCCP have a trend toward a higher DCI. Bolus transit appeared to be normal in this patient population. More data are needed to further elucidate the genesis of symptoms and how they relate to the degree of contractility. PMID- 29521729 TI - An Emergent Large Vessel Occlusion Screening Protocol for Acute Stroke: A Quality Improvement Initiative. AB - BACKGROUND: Nurses play an integral role in triaging stroke patients. The purpose of this quality improvement initiative was to determine the efficacy of using an emergent large vessel occlusion (ELVO) screening protocol in the emergency department by nursing staff to improve identification of eligible patients as compared with current practice, improving time to endovascular treatment. METHODS: Retrospective chart review was used to identify 76 patients admitted to a large urban stroke center. Of these, 36 presented during a 4-month period before the implementation of the Stroke Vision, Aphasia, Neglect (Stroke VAN) tool for assessing ELVO risk; 40 patients were admitted during the 4 months after implementation of Stroke VAN. RESULTS: The mean door-to-computed tomography angiography scan times were reduced from 119 to 49 minutes (P < .0001) for all patients and reduced from 77 to 27 minutes in a subset of VAN-positive patients. CONCLUSION: Implementation of the VAN screening tool to assess for ELVO was associated with decreased door-to-computed tomography angiography times and more rapid identification of endovascular eligible patients with ischemic stroke. PMID- 29521730 TI - Impact of Alcohol Screening for Traumatic Brain Injury Patients Being Admitted to Neurosurgical Intensive Care Unit. AB - OBJECTIVE: The aims of this study were to determine the prevalence and describe the importance of alcohol screening for all patients with traumatic brain injury (TBI) and examine the relationship between gender, age, Abbreviated Injury Scale (AIS), emergent decompressive craniectomy, Glasgow Coma Scale (GCS) from the emergency department (ED), and the length of stay with alcohol screening. METHOD: This is a retrospective analysis of de-identified data from the 2012 TBI registry of a level 1 trauma center in the Pacific Northwest. MEASUREMENTS AND MAIN RESULTS: Of 1591 patients with TBI, 1273 (80%) were screened for alcohol use and 318 (20%) were not screened. There was a significant association between alcohol screening and AIS (chi(5) = 15.46, P < .001), ED GCS (chi(12) = 22.13, P = .04), sex (chi(1) = 7.86, P <= .001), and age (r = 0.23, P < .001). Women and patients with high AIS (critical), low (mild) AIS, and midrange GCS scores were less likely to be screened, as were younger patients. Urgent decompressive craniectomy (chi(1) = 1.94, P = .16) and length of stay (r = -0.04, P = .14) did not display a significant association with alcohol screening. CONCLUSION: This study uncovered a systemic bias per sex and age for alcohol screening, as well as skewed AIS and GCS scores due to an unknown alcohol intoxication status. An updated ED's triage process and screening tool is recommended to achieve a targeted 100% alcohol screening rate for all head trauma patients in the ED before admission to the neurosurgical intensive care unit. PMID- 29521731 TI - Paroxysmal Sympathetic Hyperactivity and Environmental Factors: A Pilot Study. AB - PROBLEM: Paroxysmal sympathetic hyperactivity (PSH) is a complicated phenomenon that presents as autonomic instability and muscle overactivity in individuals who experience severe brain injury. Identifying potential modifiable environmental nociceptive stimuli is necessary for developing interventions that impact clinical outcomes. OBJECTIVE: The aim of this study was to identify physical environmental nociceptive stimuli that could hinder recovery for children who experience PSH after severe brain injury. METHODOLOGY: This study measured quantitative physical characteristics coupled with data from semistructured interviews, with parents and clinical nurses, to explore the elusive PSH phenomenon after severe brain injury in children. RESULTS: Eight subjects were enrolled in the cohort study. Temperature showed a statistically significant association with PSH (P = .02), with lower temperatures associated with an increased chance of PSH. Blankets were also associated with PSH (P = .009), with the use of blankets associated with a greater chance of PSH. Persons, gown, position, head-of-bed elevation, incontinence of urine and stool, light level, and noise level did not point to a statistically significant association with PSH. Six nursing interviews were conducted with 2 guardian interviews. Themes that are emerging from the qualitative interviews included the priorities of strategies to target auditory, tactile, and visual stimuli. CONCLUSION: Paroxysmal sympathetic hyperactivity environmental strategies need to be explored further in subsequent studies. Environmental interventions could complement pharmacological strategies for the management of this elusive phenomenon with the goal of improving outcomes in children who experience severe brain injury and show PSH. PMID- 29521732 TI - Paroxysmal Sympathetic Hyperactivity and Environmental Factors: A Pilot Study. PMID- 29521733 TI - Neurosciences Continuing Education: An Adult With New-Onset Seizures. AB - The case of a 43-year-old woman with new-onset seizures is presented within the context of a continuing education quiz. Details regarding the underlying etiology and contemporary advances in the literature are referenced. PMID- 29521734 TI - Aneurysmal Subarachnoid Hemorrhage Mortality After Implementation of Nocturnist Advanced Practice Provider Coverage. AB - INTRODUCTION: We hypothesized that a nocturnist advanced practice provider (APP) model compared with overnight neurocritical care coverage with general critical care physicians and neurology residents would provide similar patient outcomes, as measured by patient mortality. METHODS: This study is a retrospective review of healthcare outcomes of aneurysmal subarachnoid hemorrhage (aSAH) patients from 2013 and 2016, after implementation of specialty-trained neurocritical care nocturnist APPs. In 2013, overnight hours were covered by the general intensive care unit team and a junior neurology resident. In 2016, these patients were cared for by APPs overnight. The primary outcome measured was comparison of mortality before and after this change of overnight coverage because the daytime coverage remained similar between years. RESULTS: In 2013, 58 patients were admitted to the neurocritical care unit with aSAH. In 2016, 19 aSAH patients were admitted to the neurocritical care unit. The mean modified Fisher grade was 3.36 in 2013, with 14 of 58 deaths (mortality rate, 24%). In 2016, the mean modified Fisher grade was 3.4. Three patients died (mortality rate, 15.7%). CONCLUSION: The active nocturnist APP model was associated with an approximately 10% reduction in SAH mortality (P = .54). This supports the hypothesis that APPs can provide noninferior care as the previous model. Further studies are needed to demonstrate the effects of both nocturnist and APP-driven models. PMID- 29521735 TI - Are You There? The Growing Need to Get the Right Diagnosis in Disorder of Consciousness. AB - Disorder of consciousness (DOC) can be either an acute and reversible condition or a chronic condition, including vegetative state or minimally conscious state. Herein, we describe a patient who has unexpectedly recovered consciousness after being in a misdiagnosed vegetative state for a long period. A 63-year-old woman was admitted to our rehabilitation center in vegetative state (Coma Recovery Scale-Revised score, 6) and treated with a standard rehabilitation program, including physical therapy and multisensory stimulation, besides psychoactive drugs. After 26 months of such training, she progressively presented with unexpected signs of awareness. Thus, she was submitted to an intensive cognitive rehabilitation with a significant improvement of her performance (Coma Recovery Scale-Revised score, 19). With this report, we want to underline that the early use of paraclinical methods, including neuroimaging and neurophysiological paradigms, is mandatory in DOC to reach a more accurate diagnosis and perform the most appropriate neurorehabilitation. Moreover, diagnosis of functional locked-in syndrome should be considered because some patients with DOC may have covert awareness with the impossibility to display consistent and reproducible behaviors due to a "motor-cognitive dissociation." PMID- 29521736 TI - Empowered to Serve: Implementing Community Stroke Outreach Using Peer Educators to Improve Readiness to Act Among Local Community Members. AB - The purpose of this project was to develop a community-based volunteer group of peer educators to provide stroke education to local residents aimed at increasing stroke awareness and action readiness using the American Heart Association and American Stroke Association's "Empowered to Serve" evidence-based curriculum. The "Don't Miss a Stroke" module addresses the recognition of stroke warning signs, actions to take during a stroke, and stroke prevention. A total of 16 volunteers were recruited and subsequently trained. Six volunteers organized community events during the initial 3 months of the project, reaching more than 300 community members. Most participants (84.9%) identified as female, with a mean age of 63 years. Analysis of variance revealed significant improvements in knowledge regarding stroke immediately after the class, which was present 1 month later (F2,144 = 4.832, P = .009). This approach to raising community awareness about stroke emergencies was effective and did not require significant financial investment. Easy access to the curriculum and availability of free printed materials minimized the overall program costs and enhanced the quality of the educational content. PMID- 29521737 TI - An Unreported Cause of Intrathecal Baclofen Withdrawal Symptoms in a Woman With Spastic Cerebral Palsy Who Received Intrathecal Gablofen. AB - This article details an unreported potential cause of withdrawal symptoms in a patient with cerebral palsy who experienced intrathecal baclofen withdrawal shortly after placement of a baclofen pump with subsequent refill with Gablofen. Initial implantation of the baclofen pump with Lioresal occurred after a successful hospital trial of intrathecal injection via lumbar puncture. However, later, the patient did experience signs and symptoms of baclofen withdrawal after a pump refill was performed with Gablofen. PMID- 29521738 TI - Risk Factors for Falls Among Hospitalized Acute Post-Ischemic Stroke Patients: Erratum. PMID- 29521739 TI - An Emergent Large Vessel Occlusion Screening Protocol for Acute Stroke: A Quality Improvement Initiative. PMID- 29521741 TI - Mortality of the Severely Obese: A Population Study. AB - OBJECTIVE: This study aimed to analyze the Clinical Practice Research Datalink to identify the prognostic factors of all-cause mortality in the severely obese. BACKGROUND: Patients who are severely obese [body mass index (BMI) >=35 kg/m] are at increased risk of all-cause mortality as a result of metabolic sequelae including hyperlipidemia, hypertension, and diabetes. Bariatric surgery has been shown to reduce the severity of the metabolic complications of obesity. METHOD: A case-controlled analysis was carried out of patients with a BMI of 35 kg/m or more from the Clinical Practice Research Datalink, a UK database of primary care clinics. Clinicopathological characteristics at baseline diagnosis were extracted. Cases of all-cause mortality were identified as a clinical endpoint. A Cox proportional hazard model was used to calculate hazard ratios (HRs) for different patient factors. A P value less than 0.050 was defined as significant. RESULTS: A total of 187,061 records were identified for analysis. Median follow up time was 98.0 months (range: 3.0-1095.0). A total of 8655(4.6%) were identified as having died during the study period. The median time from baseline obesity diagnosis until death was 137.0 months (range: 3.0-628.7). Multivariate analysis found bariatric surgery to be associated with reduced risk of all-cause mortality (HR: 0.487; P < 0.001). The following were associated with increased risk of death: male sex (HR: 1.805; P < 0.001), BMI of 60 or greater (HR: 2.541; P < 0.001), hypertension (HR: 2.108; P < 0.001), diabetes (HR: 2.766; P < 0.001), and hyperlipidemia (HR: 1.641; P < 0.001). CONCLUSIONS: Factors such as high BMI, diabetes, hyperlipidemia, and hypertension at first diagnosis of severe obesity were each independently associated with an increased risk of death. Bariatric surgery was shown to be associated with reduced risk of all-cause mortality. Improving access to bariatric surgery and public health campaigns can improve the prognosis of severely obese patients. PMID- 29521740 TI - Antiviral Therapy Reduces Hepatocellular Carcinoma Recurrence in Patients With Low HBV-DNA Levels: A Randomized Controlled Trial. AB - BACKGROUND: Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV) related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. METHODS: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409-0.884; P = 0.010] and 0.509 (95% CI, 0.333-0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio [HR] = 0.316, 95% CI 0.157-0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493-1.240; P = 0.296). CONCLUSIONS: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection. PMID- 29521742 TI - Antibiotic-induced Disruption of Intestinal Microbiota Contributes to Failure of Vertical Sleeve Gastrectomy. AB - OBJECTIVE: The aim of this study was to test whether the perioperative composition of intestinal microbiota can contribute to variable outcomes following vertical sleeve gastrectomy (VSG). SUMMARY OF BACKGROUND DATA: Although bariatric surgery is the most effective treatment for obesity, metabolic outcomes are variable. METHODS: Diet-induced obese mice were randomized to VSG or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days (POD) 1-4. Fecal microbiota was characterized before surgery and on POD 7 and 28. Mice were metabolically characterized on POD 30-32 and euthanized on POD 35. RESULTS: VSG resulted in weight loss and shifts in the intestinal microbiota composition relative to sham-operated mice. Antibiotic exposure resulted in sustained reductions in alpha (within-sample) diversity of microbiota and shifts in its composition. All antibiotic treatments proved to be detrimental to metabolic VSG outcomes, regardless of antimicrobial specificity of antibiotics. These effects involved functionally distinct pathways. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction of key antimicrobial peptides. However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake relative to control VSG mice. CONCLUSION: Dysbiosis induced by brief perioperative antibiotic exposure attenuates weight loss and metabolic improvement following VSG. Potential mechanisms include disruption of bile acid homeostasis and reduction in the production of gut antimicrobial peptides. Results of this study implicate the intestinal microbiota as an important contributor to metabolic homeostasis and a potentially modifiable target influencing clinical outcomes following VSG. PMID- 29521743 TI - Painful Neuroma Treatment of the Supraorbital Nerve and Forehead Neurotization Using Human Cadaveric Nerve Allograft. AB - Neuroma pain can be severe, persistent, and treatment-resistant. Forehead and scalp anesthesia is troublesome for patients. Following an iatrogenic ablative injury to the right supraorbital nerve, with subsequent painful neuroma formation, a human cadaveric nerve allograft (AxoGen, Alachua, FL) was used to restore sensation of the right forehead and treat pain. At 1-year follow-up, the patient was pain-free, and protective sensation to the right forehead was recovered with comparable static and dynamic 2-point discrimination between the injured (20 mm, 12 mm respectively) and the normal side (15 mm, 10 mm respectively). This is the first reported case of using a cadaver nerve allograft for successful direct neurotization of the skin and restoration of sensation in the upper part of the face, and for treating painful neuromas. Moreover, a brief review of the available techniques for treating neuromas of the supraorbital and supratrochlear nerves is provided. PMID- 29521744 TI - Use of Irradiated Homologous Costal Cartilage in Rhinoplasty: Complications in Relation to Graft Location. AB - BACKGROUND: Nasal septal cartilage and conchal cartilages are preferred sources of grafts in augmentation rhinoplasty. Rib cartilage can also be used, but it may evoke a patient's concerns about a scar and an extensive surgery. In such cases, irradiated homologous costal cartilage (IHCC) can be a useful alternative. However, controversy still exists in many literatures regarding complications with use of IHCC. Therefore, the authors reviewed our experiences with IHCC in rhinoplasty and analyzed the complications in relation to graft location. METHODS: A retrospective chart review was made of all patients who underwent rhinoplasty with IHCC between 2007 and 2015. A total of 323 patients were included. The authors considered the cases that required revision surgery for external aesthetic changes as complications. The authors defined major complications, including resorption, infection, fracture, or warping. RESULTS: The total complication rate was 8%. Two fractures (0.6%), 4 fragmentation (1.2%), 4 resorptions (1.2%), 4 infections (1.2%), and 2 warpings (0.6%) were noted. Most of these complications occurred for the septal extension graft. Other complications, including 1 nasal obstruction, 2 visible contours, 3 caudal septal deviations, and 4 cases of unfavorable results (patient unsatisfactions), were noted. CONCLUSIONS: Based on the outcomes of this study, the authors concluded that IHCC is a useful and reliable source of cartilage graft and can serve as an alternative graft material for rhinoplasty. However, care must be taken in use of IHCC graft in areas under tension such as septal extension graft, though its complication rate is low. PMID- 29521745 TI - Longitudinal Follow-up of Individuals With Cleft Lip Using Three-Dimensional Stereophotogrammetry. AB - The usefulness of three-dimensional (3D) stereophotogrammetry for treating cleft lip (CL) has been well documented. However, there are only a few reliable anthropometric analyses in infants with CL because at this age they cannot assume a resting facial position. Since 2014, we have used a handheld 3D imaging system in the operating room to obtain optimal images of infants with CL and palate under general anesthesia. Currently, 168 infants with a unilateral cleft, 50 infants with bilateral clefts, and 47 infants with an isolated cleft palate are being followed up in this way for a maximum of 30 months. Most patients >=3 years of age are cooperative and allow staff to obtain 3D images without sedation. We plan to follow them until adulthood, obtaining 3D images at every intervention. Each year, >150 infants can be added to this ongoing longitudinal study. Using an archive of these digital images, various retrospective studies can be attempted in the future, which include comparisons of the long-term outcomes of various surgical techniques and interventions at different time intervals. This is the first 2-year preliminary report of a 20-year longitudinal study. PMID- 29521746 TI - Conservative Treatment for Delayed Infection After Cranioplasty With Titanium Alloy. AB - Cranioplasty (CP) is considered a low-risk operation in the field of neurosurgery following decompression craniectomy. Nevertheless, CP is still burdened by surgical complications, among which early or late infections are the most common outcome-threatening ones. Most of infection cases occur within a week after CP. Except that, implant-associated scalp infection is the most common complication, and leads to implant removal in many patients with refractory and recurrent infection. The authors reported a patient presenting with epidural infection about 3 months after titanium implant and cured by anti-infective treatment for 2 weeks. PMID- 29521747 TI - Large-Scale Study of Long-Term Vertical Skeletal Stability in a Surgery-First Orthognathic Approach Without Presurgical Orthodontic Treatment: Part II. AB - The surgery-first approach (SFA) is a new paradigm in orthognathic surgery. In our experience over the last 10 years, SFA, particularly for the correction of the class III dentofacial deformity and facial asymmetry, has demonstrated high success rates without any major complications. However, many craniofacial surgeons remain concerned about the skeletal stability of SFA. In the present study, the authors aimed to compare the traditional and SFA with regard to the long-term outcomes of vertical skeletal stability using large-scale data. The authors enrolled patients with skeletal class III dentofacial deformities who had undergone and completed orthognathic surgery between December 2007 and December 2015. The inclusion criteria were based on the presurgical simulation of the dental model, and the authors predicted the potential of the SFA based on this preoperative simulation model. Patients with cleft-related syndromes, and those who had undergone orthognathic surgeries for facial asymmetry or class II deformity were excluded. A total of 104 and 51 class III patients were enrolled in the surgery-first and traditional orthodontics-first groups, respectively. Satisfactory results were achieved in all 155 patients with dentofacial deformity. The initial preoperative measurements of cephalometric analysis, particularly vertical skeletal stability, were similar and well maintained after the procedure in both groups. In conclusion, the SFA without any presurgical orthodontic treatment for correcting dentofacial deformities can achieve similar long-term vertical stability results to the orthodontic treatment-first approach. PMID- 29521748 TI - Delayed Diagnosis of Gorlin-Goltz Syndrome: The Importance of the Multidisciplinary Approach. AB - Gorlin-Goltz syndrome (GGS), also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant inherited disorder with high penetrance and variable expressivity. The classic triad originally described by Gorlin and Goltz in 1960 is composed of multiple nevoid basal cell carcinomas (NBCCs), odontogenic keratocysts (OKCs) in the jaws and bifid ribs. in 1977, this triad was modified by Rayner et al, and to GGS diagnosis, the OKCs had to appear in combination with calcification of the cerebellar falx or palmar and plantar pits. It may occur that although GGS syndrome is a well-known condition, only the specific symptom could be observed by different specialists. Therefore, the patient cannot be placed in an always complex clinical panel. The authors introduce an example in this report. In the present case, the patient had NBCCs, OKCs, and probably other signs of GGS since 1998, and has been treated for this conditions separated, without a diagnosis of a syndromic condition. A 54-year-old white woman was referred to the oral medicine service due to cyst located in the right mandibular body. She had history of skin cancer and undergone surgeries and radiotherapies for the lesions treatment, scars on the skin face due to the lesions removed, and a new ulcerated lesion on the back of was diagnosed. In addition, the patient presented frontal and parietal bossing leading to increased cranial circumference, hypertelorism, strabismus, broad base, and mandibular prognathism. To the image examination, skull radiography revealed calcification of the falx cerebri; on chest X-ray bifid rib was observed and spine radiography showed vertebral osteophytes. Panoramic radiograph showed a well-defined bilocular radiolucent image located in posterior and anterior mandibular region. The whole elements induced us to investigate the patient's past medical history, which revealed that since 1998 had the diagnosis of NBCC and OKC. A multidisciplinary approach becomes necessary for the diagnosis and follow-up of patients with GGS, considering the complexity of the clinical manifestations. Therefore, it is of primary importance for dental surgeons and dermatologists to know the signs and symptoms of GGS to perform early diagnosis and to avoid progression of the oral cysts or metastasis of the skin lesions. PMID- 29521749 TI - Root Fracture as Complication of Surgically Assisted Rapid Maxillary Expansion. AB - A 23 year old male patient was submitted to surgical assisted rapid maxillary expansion (SARME). There were any postoperative complications until the finish of orthodontic expansion process. However, in the 30th postoperative day, patient mentioned pain in upper central incisor. Periapical radiography evidenced a root fracture of central upper right incisor. After endodontic treatment, the fractured apex was removed. After 3 years of follow-up, the patient finished orthodontics, and the damaged tooth was in good aspect. Apical fracture is an unexpected complication of SARME. However, follow-up and correct treatment lead to a good prognosis for tooth maintenance. PMID- 29521750 TI - Localization of the Maxillary Ostium in Relation to the Reduction of Depressed Nasomaxillary Fractures. AB - The aim of this study was to elucidate the precise location of the maxillary ostium using computed tomography for the reduction of depressed nasomaxillary fractures.Computed tomography images (61 males, 42 females; age range, 3-97 years) were analyzed. Coronal sections were cut every 3 mm.The primary maxillary ostium (PMO) was located 24.7% +/- 3.9% of bizygomatic distance (BZD) lateral to septum. The horizontal distance of the PMO significantly increased with age (P = 0.032). The PMO was located 53.3% +/- 8.0% of nasal length (NL) above superior surface of the palatal bone (SP). The vertical-to-horizontal ratio of the PMO decreased with age (P = 0.013). The PMO was located 30.3 +/- 4.3 mm posterior to the tip of nasal bone. The PMO was located 24.6 +/- 4.8 mm posterior to the anterior nasal spine (ANS). The ANS-PMO distance significantly increased with age (P = 0.027). The hiatus semilunaris (HS) was located 11.9% +/- 3.2% of BZD lateral to septum. The HS was located 62.4% +/- 10.3% of NL above SP. The vertical distance of the HS significantly decreased with age (P = 0.019). The accessory maxillary ostium (AMO) was located 14.9% +/- 2.8% of BZD lateral to septum. The horizontal distance of the AMO significantly increased with age (P = 0.027). The AMO was located 44.8% +/- 6.9% of NL above SP. The vertical distance of the AMO significantly decreased with age (P < 0.001). The vertical-to horizontal ratio of the AMO decreased with age (P < 0.001).The distances of the ostium from surgical landmarks measured in this study might be helpful when inserting a small curved elevator into the maxillary ostium in the reduction of medial maxillary fractures. PMID- 29521752 TI - Facial Surgery in Antiquity. PMID- 29521751 TI - Polymethyl Methacrylate Custom-Made Prosthesis: A Novel Three-Dimension Printing Aided Fabrication Technique for Cranial and/or Orbital Reconstruction. AB - BACKGROUND: Over the years, many materials have been used in orbital reconstruction and cranioplasty. Among the materials in current use, polymethyl methacrylate (PMMA) offers a high degree of compatibility with human tissue. OBJECTIVE: This work describes a new, custom-made, 3D printing-aided, prosthetic fabrication process for orbital and/or cranial reconstruction using PMMA. METHODS: On the basis of information obtained from computerized tomography scanning processed in Digital Imaging and Communication in Medicine format and exported to treatment planning software, a 3D prosthesis master model was designed and digitally printed. This was then used to create an injection mold from which the prosthesis was cast in PMMA and implanted in the patient. Five patients with cranial and/or orbital defects of tumoral or traumatic etiology were treated by this method. After 5 to 7 years follow-up, no complications occurred to cause the removal of the prostheses. CONCLUSION: This novel method makes it possible to produce customized PMMA prostheses to treat orbital and/or cranial defects that are cost-effective and individualized to each case. PMID- 29521753 TI - Facial Defect Reconstruction Using the True Scarless Pre-Expanded Forehead Flap. AB - OBJECTIVE: This clinical study describes a reconstructive method for facial soft tissue defects that uses the pre-expanded forehead flap and minimizes donor site morbidities. METHODS: The surgery was subdivided into 3 stages. First stage, an appropriately sized expander was buried underneath the forehead. Second stage, after adequate inflation of the expander, a forehead flap based on the frontal branches of the superficial temporal artery was raised, and the distal portion of the flap was used to reconstruct the facial defect. The cutaneous pedicle of the flap was designed near the frontal hairline. Third stage, 3 weeks later, the flap pedicle was divided, and the forehead incisional scar was melted into the neoreconstructed hairline. RESULTS: Between July 2010 and December 2016, 16 patients underwent facial defect reconstruction. Etiologies included postburn scar (31%), melanocytic nevus (56%), and hemangioma (13%). The mean size of the defects was 8.78 * 5.06 cm (range, 3 * 2.5 to 15 * 7 cm). The average dimension of the forehead flap was 21.63 * 7.38 cm (range, 12 * 4 to 28 * 10 cm). Fifteen flaps survived without any perfusion-related complications. Venous congestion occurred in 1 flap and gradually subsided without any flap loss. Patients were followed after surgery, ranging from 4 to 48 months. Patients and/or their family members were satisfied with the final aesthetic outcomes. CONCLUSION: Facial defect reconstruction using a pre-expanded forehead flap, with the donor-site incisional scar designed along the hairline, can not only provide sufficient tissue for defect reconstruction, but also maximally reduce donor-site morbidities. PMID- 29521754 TI - Antral Wall Approach for Reconstruction of Orbital Floor Fractures Using Anterior Maxillary Sinus Bone Grafts. AB - Isolated orbital wall fractures account for 4% to 16% of all facial fractures. Even a modest change in the position of the bony walls can have a significant impact on orbital volume and globe position. Alloplastic materials or autogenous bone grafts such as the antral maxillary wall can be used to reconstruct small- to medium-size orbital fractures. The main advantage of an antral wall graft is the intraoral approach with minimal morbidity. Nine patients underwent repair of orbital floor fractures using the extraoral and the intraoral antral wall approach. The patients underwent preoperative computed tomography imaging and a minimum of 1 year follow-up. The size of the defects ranged from 0.5 to 1.4 cm. Two patients experienced minor immediate postoperative complications; infraorbital hypoesthesia. On follow-ups, none of our patients suffered from ocular movement restrictions or complications regarding the maxillary antral wall approach. The use of harvested bone grafts from the anterolateral wall of the maxillary sinus is a promising approach for the reconstruction of small- to mid size orbital floor defects with minimal complications and excellent cosmetic and functional results. PMID- 29521755 TI - Anatomical Study of the Zygomaticofacial Foramen and Its Related Canal. AB - The zygomaticofacial branch (ZFb) of the zygomatic nerve passes through the lateral wall of the orbit anterolaterally and traverses the zygomaticofacial foramen (ZFFOUT). However, in terms of intraorbital course, only a few studies have focused on the orbital opening of the ZFb (ZFFIN) and related canal. Therefore, this study aimed to locate the orbital opening and exit of the ZFb of the zygomatic nerve. Twenty sides from 10 fresh frozen cadaveric Caucasian heads were used in this study. The vertical distance between inferior margin of the orbit and ZFFIN (V-ZFFIN), the horizontal distance between the lateral margin of the orbit and ZFFIN (H-ZFFIN), diameter of the ZFFIN (D-ZFFIN), the vertical distance between the inferior margin of the orbit and ZFFOUT (V-ZFFOUT), the horizontal distance between the lateral margin of the orbit and ZFFOUT (H ZFFOUT), and the diameter of the ZFFOUT (D-ZFFOUT) were measured, respectively. The ZFFIN were located 5.1 +/- 2.0 mm superior to the inferior margin of the orbit and 4.3 +/- 1.6 mm medial to the lateral margin of the orbit. The ZFFOUT was located 1.2 +/- 2.9 mm inferior to the inferior margin of the orbit and 1.1 +/- 3.0 mm lateral to the lateral margin of the orbit. The diameter of the ZFFOUT was significantly larger than that of the ZFFIN. Additional knowledge of the zygomatic nerve and its branches might decrease patient morbidity following invasive procedures around the inferolateral orbit. PMID- 29521756 TI - Unilateral Hard Palate Necrosis After Ascending Palatine Artery Embolization. AB - Embolization is a common treatment modality for refractory epistaxis. Here, the authors reported that the first patient with unilateral necrosis of the mucosa overlying the hard palate developed after embolization of ascending palatine artery. A 46-year-old man with a history of maxillofacial trauma complicated by 2 episodes of significant unilateral epistaxis. Although he did not experience any epistaxis after embolization, unilateral necrosis of the mucosa overlying the hard palate developed gradually 2 weeks after embolization. The necrotic tissue of hard palate was treated by surgical debridement and followed by antibiotic and analgesic. PMID- 29521757 TI - Upper First Premolar Positioning Evaluation for the Stability of the Dental Occlusion: Anatomical Considerations. AB - The present study aimed to find the proper distorotation of the upper first premolar to achieve the therapeutic ideal advocated for the stability of the human occlusion. Normal teeth were analyzed and occlusal photocopies of upper arch were made to perform the 2 measurements. The first parameter was the angle formed by the perpendicular to the wire through the buccal cusp and a line connecting the buccal and the lingual cusps of the upper first premolar. The second one was the angle from the buccal line and the sagittal plane of the model. The amount of distorotation was calculated and a method to bond the bracket was suggested. PMID- 29521758 TI - One-Piece Mandibuloplasty Compared to Conventional Mandibuloplasty With Narrowing Genioplasty. AB - BACKGROUND: Recently, the mandibular body and chin shape are known to be important issue as well as the mandibular angle. The authors have performed the one-piece mandibuloplasty from the mandibular angle to the most anterior part of chin to achieve the change of the whole mandibular shape as a one-piece. METHODS: All of 14 patients who complaint prominent mandibular angle and chin were randomly allocated into 2 groups. Group I (n = 7) was treated with conventional mandibuloplasty with narrowing genioplasty and Group II (n = 7) was treated with one-piece mandibuloplasty. Pre- and postoperative clinical photography, cephalometry, computed tomography scan, 3-dimensional photography were taken and occurrence of secondary angle, patient's satisfaction, and operative time were evaluated. RESULTS: The mean volume reduction per side was 41.8 cc on one-piece mandibuloplasty and 36.5 cc on conventional mandibuloplasty with narrowing genioplasty. Furthermore, average lower facial decreased from 64.3 to 61.0 after 6 months postoperatively and was maintained until 3 years on average after the operation. In one-piece mandibuloplasty group shows a little higher satisfaction about mandible body, and it was estimated that the presence of secondary angle makes dissatisfaction. The authors' treatment approach resulted in a shorter total surgery time than conventional technique (70.57 versus 105.14 min, P = 0.002). CONCLUSIONS: One-piece mandibuloplasty based on 3-dimensional printing model turned out to be very successful for the natural shaping of the lower jaw in the patients with the prominent mandible in terms of the technical efficiency and the aesthetic point of view. PMID- 29521759 TI - Three-Dimensional Virtual Treatment Planning: Presurgical Evaluation. AB - OBJECTIVE: This article describes a virtual protocol designed to optimize surgical orthodontic diagnosis and treatment plan. METHODS: A total of 15 patients undergoing orthodontic-surgical treatment have been analyzed with a presurgical virtual three-dimensional (3D) treatment planning, which involves 9 steps. All the patients have been treated with the use of occlusal splint guides projected on the basis of the surgical and orthodontic visualized treatment objective . RESULTS: In all the analyzed patients, a precise and optimal orthodontic presurgical preparation has been obtained. CONCLUSIONS: The 3D analysis seems more precise to interpret than two-dimensional; it provides information and images of craniofacial structures free from perspective distortion and it reduces the steps of the presurgical diagnosis. The simplicity of the protocol described in this paper makes possible to apply it in everyday practice.The study described here allows high-precision planning of orthodontic surgical therapy and optimization of each treatment phase, with consequent advantages in clinical practice: a more accurate orthognathic surgery with predictable results. PMID- 29521760 TI - Vascular Malformation Enlargement During Menopause. AB - Vascular malformations enlarge overtime, particularly during adolescence when follicle-stimulating hormone (FSH) rises. Lesions contain the receptor for follicle-stimulating hormone. FSH also becomes elevated during menopause. We present a patient with a venous malformation of the lip that presented for the first time after she entered menopause which was temporally related to a significant increase in her serum FSH levels that were measured. This observation supports the hypothesis that FSH might influence the pathophysiology of vascular malformations. PMID- 29521761 TI - Office-Based Three-Dimensional Printing Workflow for Craniomaxillofacial Fracture Repair. AB - Three-dimensional printing of patient-specific models is being used in various aspects of craniomaxillofacial reconstruction. Printing is typically outsourced to off-site vendors, with the main disadvantages being increased costs and time for production. Office-based 3-dimensional printing has been proposed as a means to reduce costs and delays, but remains largely underused because of the perception among surgeons that it is futuristic, highly technical, and prohibitively expensive. The goal of this report is to demonstrate the feasibility and ease of incorporating in-office 3-dimensional printing into the standard workflow for facial fracture repair.Patients with complex mandible fractures requiring open repair were identified. Open-source software was used to create virtual 3-dimensional skeletal models of the, initial injury pattern, and then the ideally reduced fractures based on preoperative computed tomography (CT) scan images. The virtual 3-dimensional skeletal models were then printed in our office using a commercially available 3-dimensional printer and bioplastic filament. The 3-dimensional skeletal models were used as templates to bend and shape titanium plates that were subsequently used for intraoperative fixation.Average print time was 6 hours. Excluding the 1-time cost of the 3 dimensional printer of $2500, roughly the cost of a single commercially produced model, the average material cost to print 1 model mandible was $4.30. Postoperative CT imaging demonstrated precise, predicted reduction in all patients.Office-based 3-dimensional printing of skeletal models can be routinely used in repair of facial fractures in an efficient and cost-effective manner. PMID- 29521762 TI - Does a Vascularized Fibula Free Bone Grafted Immediately After Hemimandibulectomy in a Child Grow or Relapse During Adolescence? AB - For young growing children before the end of skeletal maturity, the growth activity of the grafted bone after hemimandibulectomy is not well-known. After an adolescence, such a patient may have facial deformity because the anterior growth point of the mandible is in the condylar neck. A 13-year-old boy was performed hemimandibulectomy with immediate mandibular reconstruction by fibula free flap (FFF) because of a huge ameloblastic fibroma. The authors evaluated the length of FFF on the images of computed tomography (CT) at 5 and 60 months after the operation and compared them by calculating growth rates. Five years after surgery, his facial appearance was symmetry and mandibular function was satisfaction. Although the mandibular bone in the contralateral side grew during 5-year follow-up, the vascularized FFF grafted in the child patient did not significantly grow. Moreover, spontaneous regeneration (SR) and the gradual osteosclerosis were confirmed on the left distal edge of the FFF on the CT imaging. The arrival of SR at the left distal edge of the FFF was considered a part of the reason to compensate the unchanging growth rate of the grafted FFF and contribute for the postoperative good functional and esthetic results. PMID- 29521763 TI - Long-Term Outcomes of Acellular Dermal Allograft as a Tarsal Substitute in the Reconstruction of Extensive Eyelid Defects. AB - PURPOSE: To report the long-term outcomes of using acellular dermal allograft (ADA) as a tarsal substitute for reconstruction of large full-thickness eyelid defects where ipsilateral or contralateral eyelid donor tissue was either not available or tarsoconjunctival transfer was insufficient to cover the full extent of the defect. METHODS: A retrospective review of a consecutive series of 10 patients between May 2003 and April 2012. Main outcome measures were anatomical and functional outcomes and complications. RESULTS: The study cohort included 4 males and 6 females with a mean age of 48.1 years (range 31-64 years). Indications for reconstruction were extensive full-thickness eyelid defects (upper or lower or both) resulting from tumor excision (n = 6), traumatic eyelid defect (n = 2), electrical burn (n = 1), and eyelid necrosis (n = 1). The mean postoperative follow-up was 84.3 months (range 33-164 months). The reconstructive procedure included a variety of techniques using ADA as the posterior lamellar graft. Overall, 7 patients achieved excellent anatomical, cosmetic, and functional results. Reoperation was required in 3 patients (for postoperative upper lid retraction, upper lid entropion, and lower fornix reconstruction) despite acceptable initial results. There were no intraoperative complications, postoperative allergic or immunologic rejection associated with the use of allograft, nor any long-term sequelae. CONCLUSION: The extensive upper and lower eyelid defects with large vertical component can be successfully repaired using ADA as a tarsal substitute. The results of our study with long-term follow-up indicate excellent functional and cosmetic outcomes with minimal morbidity. PMID- 29521764 TI - Suture Fixation of Globe to the Orbital Wall for Complicated Strabismus. AB - PURPOSE: The aim of this study was to observe the surgical outcomes of suture globe fixation to the orbital wall for patients with complicated strabismus. MATERIALS AND METHODS: The medical records of patients with complicated strabismus who were treated at the Zhongshan Ophthalmic Center of Sun Yat-sen University, Guangzhou, China, from January 2010 to June 2015 were retrospectively reviewed. Routine strabismus surgery was not possible in these cases. Eyes were anchored to the orbital wall by simple strong anastomosis of the extraocular muscle and orbital wall tissues using silk suture, which resulted in slight overcorrection of the ultimate ocular position after anchoring. RESULTS: Eight patients with complicated strabismus received suture globe fixation to the orbital wall in our hospital, including 4 cases of strabismus that occurred after severe orbital injury and/or fracture repair, 2 cases of medial rectus rupture after endoscopic sinus surgery, 1 case of complete third nerve palsy, and 1 case of complete sixth nerve palsy. Five patients were male and 3 female, with age ranging from 20.0 to 57.0 years (mean = 38.1 years). The right eyes were involved in 7 cases and the left in 1 case. Five cases underwent globe fixation to the medial orbital wall, 2 cases to the lateral orbital wall, and 1 case to the inferior orbital wall. After at least 6 months follow-up, preoperative horizontal deviation of 60.625 +/- 27.443 prism diopter (PD) (mean +/- standard deviation) was reduced to 16.250 +/- 12.464 PD. The vertical deviation was reduced from 15.000 +/- 12.313 PD to 7.5 +/- 5.244 PD. Two patients achieved orthophoria, and although the remaining 6 patients showed some residual strabismus (undercorrection), their appearance was significantly improved. No other surgical complications occurred in these cases. CONCLUSION: Suture fixation of the globe to the orbital wall by flesh-to-flesh anastomosis of the extraocular muscle and orbital wall tissues achieved a desirable surgical result for complicated strabismus. PMID- 29521765 TI - An Extremely Rare Cause of Orbital Emphysema in a Child. AB - The authors present a rare case of nontraumatic medial orbital wall fracture in an 11-year-old girl. Fractures of the orbital wall secondary to nose blowing have not been previously described in the pediatric population. The patient reported a history of chronic forceful nose blowing, followed by periorbital swelling after an episode of vigorous nose blowing. Erroneous diagnoses of sinusitis and periorbital cellulitis lead to unnecessary antibiotic treatment. The authors hypothesize that repeated and aggressive nose blowing is analogous to stress fractures, leading to weakening and eventual fracture of the medial orbital wall. PMID- 29521766 TI - Changing the Paradigm in Medial Canthal Reconstruction: The Bridge Principle and the Croissant-Like Keystone Island Perforator Flap as An Alternative for Medium Size Soft Tissue Defects in Internal Canthus Reconstruction. AB - INTRODUCTION: Medial canthus is a common area of skin cancer prevalence. Defects in this region represent a challenging reconstructive task. The nasal version of keystone perforator island flap (KPIF) has proven its versatility. The aim of the present study was to expand its utilization in the neighbor medial canthus area. A modified croissant-like KPIF (CKPIF) was used resolving inner convexity-related problems. The presence of procerus in the glabella area, bridging a surface from nasalis up to the frontalis, changed the traditional dissecting flap technique. Thus, the authors introduce the bridge principle, which consists of the indirect transfer of the flap to the defect site through a muscular "bridge" (the procerus). The authors report their experience in medial canthal reconstruction combining a modified KPIF with a new dissecting "principle." METHODS: From November 2016 to July 2017, a series of patients presenting soft tissue defects of various dimensions in the medial canthus, secondary to tumor extirpation, sustained reconstruction with a CKPIF dissected with the bridge principle. RESULTS: A total of 15 patients were treated with this new technique. Their mean age was 75.3 years. The mean size of the defect was 2.08 cm (length) * 1.5 cm (width). All flaps survived without any sign of venous congestion. A transient epiphora presented in 4 patients (4/15 or 26.6%), which was subsided 2 months later. CONCLUSION: A new approach following a novel paradigm was introduced to resolve an old problem. Initial outcomes are encouraging. However, longer series are needed to extract definitive and safer conclusion. PMID- 29521767 TI - Surgical Resection of Vascular Lesions Involving the Buccal Fat Pad. AB - Vascular abnormalities are localized structural irregularities, which are performed during vasculogenesis, angiogenesis, and lymphangiogenesis. The involvement of soft tissue in such vascular malformations is frequent; however, the compromising of the buccal fat pads (Bichat bags) is uncommon, even in specialized centers, such as the plastic clinic of our institution, in which very few patients have been reported in the literature. The purpose of this article is to present a series of 2 patients in which vascular malformations involving the buccal fat pads, which were extracted by intraoral approach. PMID- 29521768 TI - Craniometric Analysis of Frontal Cranial Morphology Following Posterior Vault Distraction. AB - BACKGROUND: Posterior vault distraction osteogenesis (PVDO) is believed to improve frontal contour in infants with syndromic craniosynostosis and turribrachycephaly. This study provides an objective craniometric analysis to determine how PVDO affects anterior cranial morphology. METHODS: A retrospective chart review of patients who underwent PVDO was performed. Inclusion criteria included pre- and postoperative computed tomography (CT) scans within 3 months before surgery and another 1 to 6 months after device removal. Volumetric and craniometric data were derived using Mimics software and compared using paired t test and Wilcoxon rank-sum test. RESULTS: About 65 patients underwent PVDO, and 13 patients met inclusion criteria. Mean age at intervention was 3.4 +/- 4.2 years. Total cranial volume increased 249 +/- 159 cm in all patients (P = 0.0001) and 380 +/- 128 cm in patients younger than 1 year of age (n = 6, P =0 .0008). Supraorbital retrusion decreased from 5.44 +/- 3.89 to 4.54 +/- 3.91 mm postoperatively (P = 0.0004), decreasing significantly in patients without previous frontal surgery and not in those with previous frontal surgery (P = 0.2115; comparison P = 0.0047). Basofrontal angle decreased by 2.92 +/- 2.16 degrees (P = 0.0004) with a greater decrease of 3.33+/-2.68 degrees in those younger than 12 months (P = 0.0289) and 2.58+/-1.74 degrees in those older (P = 0.0079). No change was found in anterior cranial height and anterofrontal angle (P > 0.05). CONCLUSION: PVDO improves frontal contour by decreasing supraorbital retrusion and reducing frontal bossing in syndromic craniosynostosis patients with turribrachycephaly. When combined with its demonstrated efficacy for cranial expansion, these frontal changes likely reinforce PVDO's ability to influence the timing of, and to a degree, the need for frontal surgery in this group. PMID- 29521769 TI - Determining the Patient-Specific Optimum Osteotomy Line for Severe Mandibular Retrognathia Patients. AB - PURPOSE: The purpose of this study is to suggest a patient-specific osteotomy line to optimize the distractor position and thus to minimize the disadvantages of conventional mandibular distraction osteogenesis (MDO) protocols. In addition, this study also aims to compare the conventional MDO protocols with the new MDO protocol proposed in this study in terms of both orthodontic outcomes and mechanical effects of osteotomy level on callus stabilization by means of the finite element method. METHODS: A preoperative patient-specific 3-dimensional bone model was created and segmented by using computed tomography images of an individual patient. Virtual orthodontic set-up was applied to the segmented model prior to the virtual surgery. In order to compare the proposed osteotomy line with the conventional lines used in clinical applications, virtual surgery simulations were performed and callus tissues were modelled for each scenario. The comparison of the success of each osteotomy line was carried out based on the occlusion of the teeth. RESULTS: The osteotomy line determined using the method proposed in this study has resulted in far less malocclusion than the conventional method. Namely, any angular deviation from the optimum osteotomy line determined in this study might result in deep-bite or open-bite. On the other hand, the finite element analysis results have indicated that this deviation also negatively affects the callus stability. CONCLUSION: In order to achieve a better MDO treatment in terms of occlusion of the teeth and the callus stability, the location of the osteotomy line and the distractor position can be computationally determined. The results suggest that MDO protocol developed in this study might be used in clinic to achieve a better outcome from the MDO treatment. PMID- 29521770 TI - It's a Small World After All. PMID- 29521771 TI - Factors Associated With Poor Child Motor Vehicle Restraint on the USA-Mexico Border. AB - Motor vehicle collisions (MVCs) are a significant cause of pediatric morbidity, particularly in low- to middle-income countries. We describe car seat use in children on the USA-Mexico border. A retrospective review was conducted for children 0-9 years old, admitted to the region's only Level I trauma center. Simultaneously, data were obtained from the SAFE KIDS database, a program that encourages car seat use through city checkpoints. There were 250 MVC admissions and nine fatalities in children 0-9 years old from 2010 to 2015. Nine percent of MVCs occurred in Mexico and 49% in El Paso, TX. Comparing trauma admissions to SAFE KIDS, there was some correlation between the location of MVCs and screening checkpoints (r = .50). There was a weaker correlation between injured children's neighborhoods and screening locations (r = .32). Only 37% of parents knew the crash history of the car seat and 3% were using a car seat previously involved in an MVC. While 96% of inspected children were placed appropriately in the backseat, 80% of children were found to be inappropriately restrained. Younger children more likely to be restrained (p < .05). Children from New Mexico and Mexico had the lowest rates of proper restraint and the highest injury severity scores. Proper use of car seats is a public health concern on the USA-Mexico border, and children are not properly restrained. Screening may be improved by focusing where at-risk children live and where most accidents occur. Restraint education is needed, particularly in New Mexico and Mexico. PMID- 29521772 TI - Update in Therapeutics: Prophylactic Antibiotics in Open Fractures. AB - Acute management of open fractures is associated with high morbidity and mortality. Recommended antibiotic regimens for all Gustilo-Anderson fracture grades include first-, second-, and third-generation cephalosporins. Expanded gram-negative coverage is recommended for Grade II and III fractures if a first- or second-generation cephalosporin is selected, and additional anaerobic coverage is required if the open fracture is contaminated with organic or farm-related material. Open fractures endure a high rate of bacterial contamination, and antibiotics have demonstrated effectiveness at reducing infection rates when initiated early. Provided that the expected microbial spectrum is covered, antibiotics should be selected on the basis of patient-specific factors and hospital protocols. PMID- 29521773 TI - Update in Therapeutics: Prophylactic Antibiotics in Open Fractures. PMID- 29521774 TI - Overdoses and Substance Toxicity in Patients Admitted to Intensive Care Units in a Midwestern U.S. City. AB - Toxic exposures with serious outcomes have increased over the last decade. Limited data exists on the pattern and outcomes of overdose-exposure patients requiring intensive care unit (ICU) admission. The primary objective of this study was to characterize the causes, treatments, and outcomes of toxic exposures in a mid-sized Midwestern health system. The secondary objective was to report cumulative economic costs associated with these patients. Data were obtained from medical records of patients 18 years or older with a diagnosis code of overdose admitted to the ICU at 2 teaching hospitals between August 1, 2012, and July 31, 2014. There were 470 (10%) of the 4,495 total ICU admissions that met inclusion criteria during the study period. Average patient age was 39 (SD = 14.2) years, with 64% females. Intentional overdose exposure was the cause of 87% of admissions. The majority (70%) of exposures involved multiple pharmacological agents, including ethanol. Most patients did not require therapeutic maneuvers, nor used decontamination methods. Primary substance classes included analgesics, benzodiazepines, ethanol, selective serotonin reuptake inhibitor antidepressants, and methamphetamine. Two hundred sixty-five (56%) patients were ICU to direct home discharges, whereas 198 (42%) were transferred to a lower level of care. The mortality rate in the sample was 1%. Average hospital charges per admission were $20,375 and average ICU charges were $5,284, which summed to more than $2 million in total charges. Causes, treatments, and outcomes of toxic exposures admitted to the ICU in a mid-sized Midwestern city reveal a potential ICU burden. Financial health care costs associated with these toxic exposures were substantial. Greater public health efforts are needed to attempt to minimize preventable admissions and better understand antecedents. PMID- 29521775 TI - Implementation of a Massive Transfusion Protocol: Evaluation of Its Use and Efficacy. AB - Massive transfusion protocols (MTPs) allow practitioners to follow a prescribed algorithm for the rapid replacement of blood products during a massive hemorrhage. They function as an established protocol to provide consistent treatment. Once implemented, the MTP must be evaluated to ensure best practice. The purpose of this clinical improvement project was to formally evaluate the use and efficacy of an MTP during its first year of implementation. The specific aims were to (1) determine whether MTP activations were missed; (2) compare outcomes between those patients managed by the MTP and those who were not; and (3) provide recommendations to the institution's stakeholders. A retrospective medical record review was conducted with 101 electronic medical records of adult trauma patients treated over 1 year. Patients were identified to have experienced massive bleeding if their medical record contained 1 of 4 indicators: (1) transfusion of uncrossmatched blood; (2) tranexamic acid administration; (3) transfusion of 4 or more units of packed red blood cells (PRBCs) in 1 hr; and/or (4) transfusion of 10 or more units of PRBCs in 24 hr. While 58 patients experienced massive bleeding, only 16 (28%) were managed using the MTP. Although the non-MTP group received fewer transfused blood products due to higher initial and 24-hr hemoglobin levels, more deaths occurred in this group than in the MTP group. The recommendations were to (1) establish well-defined criteria for MTP activation based on the 4 indicators of massive bleeding and (2) regularly evaluate the use and efficacy of the MTP to ensure positive patient outcomes. PMID- 29521776 TI - Community-Based Academic Level I Trauma Center Prepares for the 2016 Republican National Convention. AB - Disaster preparedness has come to the forefront for hospitals since the 9/11 attacks in 2001. Many improvements have been made in emergency management and planning for catastrophic events. Both urban and community hospitals have the same responsibilities and commitments to their patients and communities. When the announcement was made that the 2016 Republican National Convention was going to be held in Cleveland, OH, Cleveland Clinic Akron General (CCAG) had to be confident in its abilities to handle any situation that might arise not just as a community hospital but also as a Level I trauma center. Organizing and preparing for more than a year, CCAG developed a detailed and well-thought-out preparedness program, with senior leadership implementing a clear chain of command. Developing and maintaining a strong and steady defense through detailed preparation, communication, teamwork, and organization are the keys to success. PMID- 29521777 TI - Heads Up: Describing and Implementing a Time-Saving Head Strike Protocol at a Level II Trauma Center. AB - Head strikes can be fatal for patients taking blood thinners (anticoagulants or antiplatelets). Our trauma center instituted the "head strike protocol" to provide uniform and expedited care for adult trauma patients taking preinjury anticoagulants and antiplatelet medications with suspected head injury. The purpose of this article is to describe the development and implementation of the head strike protocol and compare time metrics and outcomes before and after implementing the protocol. Per the head strike protocol, patients with suspected traumatic intracranial hemorrhage (tICH) were screened for anticoagulants or antiplatelet medications by emergency medical service personnel/at first contact, activated as a Level II trauma and received a computed tomographic scan of the head within 30 min of arrival, and started reversal of blood products within 30 min of tICH confirmation. Compared with patients admitted before establishing the head strike protocol, patients treated postimplementation were significantly more likely to have trauma team activation (77% preprotocol vs. 89% postprotocol) and expeditious initiation of reversal agents (68 min preprotocol vs. 21 min postprotocol) and to survive their head injury for patients taking anticoagulants (42% preprotocol vs. 21% postprotocol). There were no differences in mortality for patients taking antiplatelet agents. This comprehensive nurse-driven reversal protocol presents an algorithm for managing patients with suspected tICH taking any preinjury blood thinners, allowing "ownership" by the nursing staff to ensure there are no delays in initiating blood products. This protocol may be particularly salient with the aging of the trauma population and parallel increase in the use of blood thinners. PMID- 29521779 TI - Examining Injury Among Indigenous Young People: A Narrative Scoping Review. PMID- 29521778 TI - Examining Injury Among Indigenous Young People: A Narrative Scoping Review. AB - Indigenous young people of circumpolar developed countries experience a disproportionate incidence of injury compared with non-Indigenous young people. Much has been published about the experience of injury within the general Indigenous population, but literature is limited with regard to Indigenous young people. Trauma nurses, who are important members of the multidisciplinary team that provides injury intervention to Indigenous populations, need to be aware of this literature, as well as subsequent research gaps, to provide effective care to Indigenous young people experiencing injury. The purpose of this study was to provide an updated comprehensive review of the research-based evidence related to all-cause injury for Indigenous young people. An exploratory scoping review was conducted with a narrative synthesis. To locate literature, 7 electronic databases were searched from 2003 to 2017. Criteria were applied to all located articles to determine inclusion and then data were extracted from each study's findings. A total of 15 studies were included in this review that met the inclusion criteria. Themes derived from the knowledge synthesis process are as follows: incidence rates, mechanisms of injury, risk factors, and gaps in research. A strong epidemiological focus has emerged from the research found in this review of injury among Indigenous young people. The results of this review serve as a starting point for trauma nurses to successfully assess, build trusting relationships with, and further research injury among Indigenous young people. PMID- 29521780 TI - Continuing Trauma Care After Discharge, the Experience of Outpatient Trauma Clinics in British Columbia. AB - The recovery process from traumatic injuries, and the potential for complications, extends beyond the time of hospital discharge. In 2014, the Fraser Health Trauma Network established outpatient clinics to provide follow-up care for trauma patients after discharge from hospital. The following research questions were asked: Which services were commonly performed by our trauma clinics and how satisfied were patients with the care they received at our clinics? A survey was distributed to patients after their clinic visit to assess overall satisfaction and areas for improvement. A retrospective medical record review was performed to illustrate and quantify the interventions provided during clinic visits. During the first 22 months of clinic operation, a total of 412 appointments were scheduled and the attendance rate was 88%. The provided services included obtaining additional imaging (41% of visits), providing wound and brace care (16%), and initiating referrals to specialists (12%). Seventy seven patient satisfaction surveys were returned during the study period, 34 in 2014 and 43 in 2015. Seventy-four percent of respondents strongly agreed, and 21% agreed that they were satisfied with the care they received in the clinic. Ninety percent found their visit helpful, and only 10% reported having additional medical issues that were not addressed during the appointment. At trauma clinic follow-up, discharged patients have ongoing care requirements, including a need for further investigation, specialist referral, and wound or brace issues that are likely to benefit from specialist trauma care. Patients were satisfied with the care provided by a postdischarge trauma clinic. PMID- 29521781 TI - A Descriptive Analysis of EtOH Intoxication in our Latino Trauma Patients: An Indication for a Preventive Program. AB - We sought to determine patterns of injury in our Latino trauma community targeting alcohol (EtOH) intoxication as an influential variable. With the information gained in our culturally specific and culturally sensitive trauma community, we can use the information to fine-tune our trauma preventive medicine programs. Trauma injuries are the third largest contributor to racial disparities in the United States. Alcohol is involved in approximately half of all trauma admissions to trauma centers around the country. Some investigators have shown that Latinos have higher rates of high-risk drinking, and this factor is independently associated with mortality after trauma. This study is a retrospective review of 524 Latino blunt and penetrating trauma admissions for years (2012-2014). Electronic medical records with the hospital trauma registry charts were evaluated. The trauma registry database included age, gender, EtOH, mechanism of injury, location, insurance, and disposition. Statistical significance was used with chi-square test. Our results show a predominantly male population with falls being the primary mechanism of injury. Intoxicated injuries occurred mostly at bars/clubs, but a substantial amount occurred at the workplace. Despite having a majority of the injuries occurring with patients that have Medicaid or Charity Care insurance, a certain amount of the alcohol-related injuries had private insurance. Many of our Latino trauma patients are still suffering from trauma-related EtOH intoxication. With the information obtained from our project, we will be able to fine-tune and target our trauma preventive medicine program to provide education for our inner-city Latino community of EtOH intoxication-related trauma injuries. PMID- 29521782 TI - Trauma Providers' Knowledge, Views, and Practice of Trauma-Informed Care. AB - Trauma-informed interventions have been implemented in various settings, but trauma-informed care (TIC) has not been widely incorporated into the treatment of adult patients with traumatic injuries. The purpose of this study was to examine health care provider knowledge, attitudes, practices, competence, and perceived barriers to implementation of TIC. This cross-sectional study used an anonymous web-based survey to assess attitudes, knowledge, perceived competence, and practice of TIC among trauma providers from an urban academic medical center with a regional resource trauma center. Providers (nurses, physicians, therapists [physical, occupational, respiratory]) working in trauma resuscitation, trauma critical care, and trauma care units were recruited. Descriptive statistics summarized knowledge, attitudes, practice, competence, and perceived barriers to TIC and logistic regression analyses examined factors predicting the use of TIC in practice. Of 147 participants, the majority were nurses (65%), followed by therapists (18%) and physicians (17%), with a median 3 years of experience; 75% answered the knowledge items correctly and 89% held favorable opinions about TIC. Nineteen percent rated themselves as less than "somewhat competent." All participants rated the following as significant barriers to providing basic TIC: time constraints, need of training, confusing information about TIC, and worry about retraumatizing patients. Self-rated competence was the most consistent predictor of providers' reported use of specific TIC practices. Despite some variability, providers were generally knowledgeable and held favorable views toward incorporating TIC into their practice. TIC training for trauma providers is needed and should aim to build providers' perceived competence in providing TIC. PMID- 29521784 TI - The "Ideal" Body Weight for Pediatric Gentamicin Dosing in the Era of Obesity: A Population Pharmacokinetic Analysis. AB - BACKGROUND: Obese pediatric patients often require dose reductions when initiating gentamicin therapy. An appropriate method for calculating ideal body weight for dosing gentamicin in pediatric patients has not been validated. METHODS: A retrospective population pharmacokinetic study was designed and included non-intensive care pediatric patients who received gentamicin and had serum gentamicin concentrations sampled. Actual body weight (ABW), adjusted body weight, and fat-free mass (FFM) were used to describe the pharmacokinetic variables. Descriptive statistical methods were used for the population, and pharmacokinetic analysis occurred with NONMEM (ICON Plc, Dublin, Ireland). Simulation was performed to estimate dosing based on adjustments in body weight. RESULTS: A total of 520 patients met inclusion criteria (male 57.3%, mean age 9.6 +/- 4.9 years, ABW 38.0 +/- 24.3 kg). Obesity was present in 21.3% of the patients and overweight in 15.8%. Gentamicin was administered at 2.17 +/- 0.86 mg/kg per dose. A median of 2 (interquartile range, 1-3) gentamicin serum concentrations were sampled at a median 1.8 (interquartile range, 1.1-7.8) hours after a dose. Population pharmacokinetic analysis demonstrated a 2-compartment model with allometrically scaled FFM providing the best fit. Other significant covariates included serum creatinine and age. Simulation demonstrated increased doses per body weight for traditional and once-daily dosing when using FFM for gentamicin dosing. CONCLUSIONS: FFM should be used to adjust ABW for empirically dosing gentamicin in pediatric patients aged 2-18 years. PMID- 29521783 TI - A Multicenter Performance Improvement Program Uses Rural Trauma Filters for Benchmarking: An Evaluation of the Findings. AB - Colorado requires Level III and IV trauma centers to conduct a formal performance improvement program (PI), but provides limited support for program development. Trauma program managers and coordinators in rural facilities rarely have experience in the development or management of a PI program. As a result, rural trauma centers often face challenges in evaluating trauma outcomes adequately. Through a multidisciplinary outreach program, our Trauma System worked with a group of rural trauma centers to identify and define seven specific PI filters based on key program elements of rural trauma centers. This retrospective observational project sought to develop and examine these PI filters so as to enhance the review and evaluation of patient care. The project included 924 trauma patients from eight Level IV and one Level III trauma centers. Seven PI filters were retrospectively collected and analyzed by quarter in 2016: prehospital managed airway for patients with a Glasgow Coma Scale (GCS) score of less than 9; adherence to trauma team activation criteria; evidence of physician team leader presence within 20 min of activation; patient with a GCS score less than 9 in the emergency department (ED): intubated in less than 20 min; ED length of stay (LOS) less than 4 hr from patient arrival to transfer; adherence to admission criteria; documentation of GCS on arrival, discharge, or with change of status. There was a significantly increasing compliance trend toward appropriate documentation of GCS (p trend < .001) and a significantly decreasing compliance trend for ED LOS of less than 4 hr (p trend = .04). Moving forward, these data will be used to develop compliance thresholds, to identify areas for improvement, and create corrective action plans as necessary. PMID- 29521786 TI - Improvised Anesthesia, Surgery, and Resuscitation in Far East Prisoner of War Camps, 1942 to 1945. PMID- 29521785 TI - Introduction. PMID- 29521787 TI - The History of Anesthesia in Antarctica. PMID- 29521788 TI - Broad Horizons: A History of Australian Aeromedical Retrieval. PMID- 29521789 TI - Anesthetists (and Physicians) at Altitude. PMID- 29521790 TI - History of Anesthesia Patient Safety. PMID- 29521791 TI - History of Anesthesia Simulation. PMID- 29521793 TI - Anesthesia at Royal Melbourne Zoological Gardens. PMID- 29521792 TI - Anesthesia in the Humanitarian Context: Coping in Disaster and Emergency Situations. PMID- 29521794 TI - The Lorne Pier to Pub. PMID- 29521796 TI - A selective placement strategy for surgical feeding tubes benefits trauma patients. AB - BACKGROUND: The indications for surgical feeding tube (SFT) placement in trauma patients are poorly defined. Patient selection is critical as complications from SFTs have been reported in up to 70% of patients. A previous analysis by our group determined that 25% of the SFTs we placed were unnecessary and that older patients, patients with head and spinal cord injuries, and patients who needed a tracheostomy were more likely to require long-term SFTs. Following this study, we modified our institutional guidelines for SFT placement. We hypothesized that a more selective placement strategy would result in fewer unnecessary SFTs. METHODS: A retrospective review of all adult patients from 2012 to 2016 with an intensive care unit length of stay longer than 4 days and an SFT placed during admission was conducted. This group was compared to data collected prior to our change in practice (2007-2010). Data from 2011 were excluded as a washout period. "Necessary" SFT use was defined per established guidelines as either daily use of the SFT through discharge or for 28 days or longer and "unnecessary" SFT use as all others. RESULTS: Two hundred fifty-seven SFTs were placed from 2007 to 2010 and 244 from 2012 to 2016. Following implementation of our selective SFT placement strategy, unnecessary SFT placement decreased from 25% in 2007 to 2010 to 8% in 2012 to 2016 (p < 0.0001). Significant predictors of necessary SFT placement by univariate regression were as follows: increasing age (odds ratio [OR] 1.03/year; 95% confidence interval [CI], 1.01-1.04), head injury (OR, 2.80; 95% CI, 1.71-4.60), cervical spinal cord injury (OR, 4.42; 95% CI, 1.34-14.50), and need for tracheostomy (OR, 1.41; 95% CI, 2.21-7.67). The overall complication rate was 11% (9% in the selective group vs. 13% in the preselective group, p = 0.2574) and was highest following open SFT placement (22%). CONCLUSION: A selective placement strategy for SFTs in our trauma population resulted in fewer unnecessary SFTs and a trend toward fewer complications. Surgical feeding tubes should be placed through a percutaneous approach whenever possible. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 29521797 TI - The design of an adaptive clinical trial to evaluate the efficacy of platelets stored at low temperature in surgical patients. AB - BACKGROUND: Storage of platelets at 4 degrees C compared with 22 degrees C may increase both hemostatic activity and storage duration; however, the maximum duration of cold storage is unknown. We report the design of an innovative, prospective, randomized, Bayesian adaptive, "duration finding" clinical trial to evaluate the efficacy and maximum duration of storage of platelets at 4 degrees C. METHODS: Patients undergoing cardiac surgery and requiring platelet transfusions will be enrolled. Patients will be randomized to receive platelets stored at 22 degrees C up to 5 days or platelets stored at 4 degrees C up to 5 days, 10 days, or 15 days. Longer durations of cold storage will only be used if shorter durations at 4 degrees C appear noninferior to standard storage, based on a four-level clinical hemostatic efficacy score with a NIM of a half level. A Bayesian linear model is used to estimate the hemostatic efficacy of platelet transfusions based on the actual duration of storage at 4 degrees C. RESULTS: The type I error rate, if platelets stored at 4 degrees C are inferior, is 0.0247 with an 82% probability of early stopping for futility. With a maximum sample size of 1,500, the adaptive trial design has a power of over 90% to detect noninferiority and a high probability of correctly identifying the maximum duration of storage at 4 degrees C that is noninferior to 22 degrees C. CONCLUSION: An adaptive, duration-finding trial design will generate Level I evidence and allow the determination of the maximum duration platelet storage at 4 degrees C that is noninferior to standard storage at 22 degrees C, with respect to hemostatic efficacy. The adaptive trial design helps to ensure that longer cold storage durations are only explored once substantial supportive data are available for the shorter duration(s) and that the trial stops early if continuation is likely to be futile. PMID- 29521798 TI - A negative computed tomography may be sufficient to safely discharge patients with abdominal seatbelt sign from the emergency department: A case series analysis. AB - BACKGROUND: The presence of an abdominal seatbelt sign (ASBS) following a motor vehicle collision (MVC) is associated with a high risk for occult intra-abdominal injury, prompting imaging studies and a prolonged period of clinical observation. The aim of this study was to determine how a negative computed tomography (CT) of the abdomen/pelvis (A/P) can serve in the safe disposition of these patients. Our hypothesis was that in the setting of a negative CT, the presence of occult intra abdominal injuries requiring a delayed intervention is extremely unlikely. METHODS: The medical charts of patients admitted from January 2014 to December 2016 to a Level I trauma center following an MVC were reviewed for a documentation of an ASBS. Patients who did not have a CT A/P upon admission were excluded. The CT A/P of the remaining patients were then classified as negative if there were no findings of acute vascular, visceral or bony injury or positive if any of these findings was present. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CT A/P for the presence of an intra-abdominal injury were calculated. RESULTS: Over the 3-year study period, 1,108 patients were admitted after an MVC. Of those, 196 (17.7%) had an ASBS upon presentation and 183 (93.4%) of 196 underwent a CT A/P. A total of 114 (62.3%) of 183 had a negative CT A/P. These patients remained hospitalized for a median of 2 (1-35) days with none (0.0%) requiring a delayed laparotomy. The sensitivity of CT A/P in identifying patients requiring an exploratory laparotomy was 100.0%, specificity was 67.9%, NPV was 100.0%, and PPV was 21.7%. The negative likelihood ratio was 0.00. CONCLUSION: For patients with an ASBS following an MVC, a negative CT A/P may be sufficient for safe discharge from the emergency department without any need for additional clinical observation. LEVEL OF EVIDENCE: Therapuetic, level IV. PMID- 29521800 TI - Comfort at the crossroads: Service, therapy and emotional support animals in the intensive care unit and at the end-of-life. PMID- 29521799 TI - Shock volume: Patient-specific cumulative hypoperfusion predicts organ dysfunction in a prospective cohort of multiply injured patients. AB - BACKGROUND: Multiply injured patients are at risk of developing hemorrhagic shock and organ dysfunction. We determined how cumulative hypoperfusion predicted organ dysfunction by integrating serial Shock Index measurements. METHODS: In this study, we calculated shock volume (SHVL) which is a patient-specific index that quantifies cumulative hypoperfusion by integrating abnormally elevated Shock Index (heart rate/systolic blood pressure >= 0.9) values acutely after injury. Shock volume was calculated at three hours (3 hr), six hours (6 hr), and twenty four hours (24 hr) after injury. Organ dysfunction was quantified using Marshall Organ Dysfunction Scores averaged from days 2 through 5 after injury (aMODSD2 D5). Logistic regression was used to determine correspondence of 3hrSHVL, 6hrSHVL, and 24hrSHVL to organ dysfunction. We compared correspondence of SHVL to organ dysfunction with traditional indices of shock including the initial base deficit (BD) and the lowest pH measurement made in the first 24 hr after injury (minimum pH). RESULTS: SHVL at all three time intervals demonstrated higher correspondence to organ dysfunction (R = 0.48 to 0.52) compared to initial BD (R = 0.32) and minimum pH (R = 0.32). Additionally, we compared predictive capabilities of SHVL, initial BD and minimum pH to identify patients at risk of developing high-magnitude organ dysfunction by constructing receiver operator characteristic curves. SHVL at six hours and 24 hours had higher area under the curve compared to initial BD and minimum pH. CONCLUSION: SHVL is a non-invasive metric that can predict anticipated organ dysfunction and identify patients at risk for high-magnitude organ dysfunction after injury. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 29521801 TI - The Combined Utility of EFAST and CXR in Blunt Thoracic Trauma. AB - BACKGROUND: Portable chest x-ray (CXR) and extended FAST (EFAST) screen patients for thoracic injury in the trauma bay. It is unclear if one test alone is sufficient, if both are required, or if the two investigations are complementary. Study objectives were to define the combined diagnostic yield of EFAST and CXR among stable blunt thoracic trauma patients and to determine if a normal EFAST and CXR might obviate the need for CT scan of the chest. METHODS: All blunt trauma patients >=15 years presenting to LAC+USC Medical Center in 2016 were screened. Only patients who underwent CT Thorax were included. Patients were excluded if they presented >24h after injury, were transferred, or if they did not undergo EFAST and CXR. Demographics, physical exam (PEx) of the thorax, injury data, investigations, procedures, and outcomes were collected. EFAST, CXR, and PEx findings were compared to the gold standard CT Thorax to calculate the diagnostic yield of each investigation and combinations thereof in the assessment for clinically significant thoracic injury. RESULTS: 1,311 patients met inclusion/exclusion criteria. Most common mechanisms of injury were motor vehicle collision (n=385, 29%) and auto vs pedestrian (AVP) (n=379, 29%). Mean ISS was 11 (1-75), with mean AIS Chest of 1.6 (1-6). The sensitivities of EFAST, CXR, and PEx, either individually or in combination, were <0.73 in the detection of clinically significant thoracic injury. The most common missed clinically significant injuries were sternal fractures, scapular fractures, clavicular fractures, and pneumothoraces. Motorcycle collisions and AVPs resulted in the highest rates of missed injury. CONCLUSIONS: Even in conjunction with the physical exam, the sensitivity of EFAST+CXR in the detection of clinically significant thoracic injury is low. Therefore, if clinical suspicion for injury exists after blunt thoracic trauma, a normal EFAST+CXR is insufficient to exclude injury and CT scan of the chest should be performed. LEVEL OF EVIDENCE: II STUDY TYPE: Diagnostic Tests/Criteria. PMID- 29521802 TI - Prehospital airway procedures performed in trauma patients by ground forces in Afghanistan. AB - BACKGROUND: Airway management is of critical importance in combat trauma patients. Airway compromise is the second leading cause of potentially survivable death on the battlefield and accounts for approximately 1 in 10 preventable deaths. Reports from the Iraq and Afghanistan wars indicate 4% to 7% incidence of airway interventions on casualties transported to combat hospitals. The goal of this study was to describe airway management in the prehospital combat setting and document airway devices used on the battlefield. METHODS: This study is a retrospective review of casualties that required a prehospital lifesaving airway intervention during combat operations in Afghanistan. We obtained data from the Prehospital Trauma Registry that was linked to the Department of Defense Trauma Registry for outcome data for the time period between January 2013 and September 2014. RESULTS: Seven hundred five total trauma patients were included, 16.9% required a prehospital airway management procedure. There were 132 total airway procedures performed, including 83 (63.4%) endotracheal intubations and 26 (19.8%) nasopharyngeal airway placements. Combat medics were involved in 48 (36.4%) of airway cases and medical officers in 73 (55.3%). Most (94.2%) patients underwent airway procedures due to battle injuries caused by explosion or gunshot wounds. Casualties requiring airway management were more severely injured and less likely to survive as indicated by Injury Severity Score, responsiveness level, Glascow Coma Scale, and outcome. CONCLUSION: Percentages of airway interventions more than tripled from previous reports from the wars in Afghanistan and Iraq. These changes are significant, and further study is needed to determine the causes. Casualties requiring airway interventions sustained more severe injuries and experienced lower survival than patients who did not undergo an airway procedure, findings suggested in previous reports. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level III. PMID- 29521803 TI - Successful acute aorta-caval fistula management in penetrating trauma. PMID- 29521804 TI - Rural accidental injury and death: The neglected disease of modern trauma systems? PMID- 29521805 TI - The Alvarado score should be used to reduce emergency department length of stay and radiation exposure in select patients with abdominal pain. AB - BACKGROUND: Abdominal pain is the common reason patients seek treatment in emergency departments (ED), and computed tomography (CT) is frequently used for diagnosis; however, length of stay (LOS) in the ED and risks of radiation remain a concern. The hypothesis of this study was the Alvarado score (AS) could be used to reduce CT scans and decrease ED LOS for patients with suspected acute appendicitis (AA). METHODS: A retrospective review of patients who underwent CT to rule out AA from January 1, 2015, to December 31, 2015, was performed. Patient demographics, medical history, ED documentation, operative interventions, complications, and LOS were all collected. Alvarado score was calculated from the medical record. Time to CT completion was calculated from times the patient was seen by ED staff, CT order, and CT report. RESULTS: Four hundred ninety-two patients (68.1% female; median age, 33 years) met the inclusion criteria. Most CT scans (70%) did not have findings consistent with AA. Median AS for AA on CT scan was 7, compared with 3 for negative CT (p < 0.001). One hundred percent of female patients with AS of 10 and males with AS of 9 or greater had AA confirmed by surgical pathology. Conversely, 5% or less of female patients with AS of 2 or less and 0% of male patients with AS of 1 or less were diagnosed with AA. One hundred six (21.5%) patients had an AS within these ranges and collectively spent 10,239 minutes in the ED from the time of the CT order until the radiologist's report. CONCLUSION: Males with an AS of 9 or greater and females with AS of 10 should be considered for treatment of AA without imaging. Males with AS of 1 or less and females with AS of 2 or less can be safely discharged with follow-up. Using AS, a significant proportion of patients can avoid the radiation risk, the increased cost, and increased ED LOS associated with CT. LEVEL OF EVIDENCE: Diagnostic IV, therapeutic IV. PMID- 29521806 TI - Prevention of firearm injuries with gun safety devices and safe storage: An Eastern Association for the Surgery of Trauma Systematic Review. AB - BACKGROUND: Over 50,000 homicides and suicides occur each year. An estimated half of all US households are believed to have a firearm present, making them one of the most ubiquitous consumer products. Our goal was to determine if the manner of storage of a firearm in a home could potentially make a difference in the outcomes of intentional and unintentional injuries involving a firearm; specifically addressing the use of gun safes and devices that block/disable firearm function (trigger locks, cable locks, etc.). METHODS: A comprehensive review of the literature was performed. We used Grading of Recommendations Assessment, Development, and Evaluation methodology to assess the breadth and quality of the data specific to our Population, Intervention, Comparator, Outcomes (PICO) questions. RESULTS: A total of 176 studies were initially identified, then, 120 more added after a subsequent literature review, with 97 removed as duplicates. One hundred ninety-one case reports, case series, and reviews were removed because they did not focus on prevention or did not address our comparators of interest. This left a total of two studies which merited inclusion for PICO 1, should gun locks be used to prevent firearm injuries and six studies which merited inclusion for PICO 2, should safe storage for guns be used to prevent firearm injuries. CONCLUSION: PICO 1: We conditionally recommend that gun locks be used to prevent unintentional firearm injury. PICO 2: Because of the large effect size and the reasonable quality of available evidence with safe storage of firearms, we recommend safe storage prevent firearm-related injuries. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 29521807 TI - The contemporary timing of trauma deaths. AB - BACKGROUND: The distribution of trauma deaths was classically described as trimodal. With advances in both technology and trauma systems, this was reevaluated and found to be bimodal in the early 2000s. Over the last decade there have been continued improvements in trauma and intensive care unit (ICU) care, related to damage control techniques and evidence based ICU pathways. A better understanding of the distribution of trauma deaths may be used to improve trauma systems. This study aimed to evaluate the contemporary distribution of trauma deaths after the widespread implementation of modern trauma and critical care principles. METHODS: This study included patients entered in the NTDB from 2008 to 2014. For dead patients, hospital length of stay was equated to time until death. Additional data was collected to include demographics, mechanism of injury, Injury Severity Score, and Abbreviated Injury Scale score. Histograms were plotted to demonstrate peaks in deaths. Survival analysis was performed with Kaplan-Meier curves and Gehan-Breslow generalized Wilcoxon tests. RESULTS: 4,185,009 patients were analyzed. Thirty-four percent of all deaths occurred within the first 24 hours of admission. The factors most associated with death in the first 24 hours were severe abdominal trauma (73%), penetrating trauma (55%), and severe extremity trauma (58%). Among patients with penetrating trauma and an abdominal Abbreviated Injury Scale score of 4 or higher, 83% of deaths occurred within 24 hours. When plotted, the distribution of deaths was seen to fall rapidly after the first 24 hours and continued to be flat for 30 days in all subgroups analyzed. CONCLUSION: In this study, the distribution of trauma deaths no longer appears to be trimodal. This may reflect advances in trauma and ICU care, and the widespread adaption of damage control principles. Early deaths, however, remains a significant challenge, specifically from non-compressible abdominal hemorrhage and extremity trauma. Primary prevention and early hemorrhage control must continue to be a focus of research and trauma systems. LEVEL OF EVIDENCE: Epidemiologic, level IV. PMID- 29521808 TI - Electromyographic Study of Thoracic Paraspinal and Rectus Abdominis Muscles in Amyotrophic Lateral Sclerosis. AB - PURPOSE: The aim of our study was the comparison of active denervation (fibrillation and/or positive sharp wave potentials) in thoracic paraspinal muscles with rectus abdominis in patients with definite amyotrophic lateral sclerosis. METHODS: Ninety-five consecutive patients with clinically definite amyotrophic lateral sclerosis according to the revised El Escorial criteria were studied prospectively over a 5-year period. Concentric needle electromyogram was performed in thoracic paraspinal muscles, in the rectus abdominis at the T9 level, and in limb muscles. RESULTS: Active denervation was present in thoracic paraspinal muscles in 75 patients (79%) and in rectus abdominis in 62 patients (65.3%) (P = 0.02). No significant difference was found between the two muscles regarding the type of onset (bulbar, upper, and lower limbs), amyotrophic lateral sclerosis functional rating scale values, and creatine phosphokinase levels. CONCLUSIONS: Thoracic paraspinal muscles are the first to be tested in patients with amyotrophic lateral sclerosis. Absence of active denervation in T-PSM is rarely associated with active denervation in rectus abdominis. PMID- 29521809 TI - Ostomy Creation for Palliative Care of Patients With Nonresectable Colorectal Cancer and Bowel Obstruction. AB - PURPOSE: The purpose of this study was to review our experience with palliative ostomy surgery in patients with bowel obstruction and advanced stage colorectal cancer. DESIGN: A descriptive, retrospective review of data from a prospectively collected clinical database. SUBJECTS AND SETTING: The sample comprised 86 patients (55 male) who underwent palliative surgery between October 1998 and January 2009. METHODS: All patients undergoing palliative stoma formation without resection for colorectal carcinoma were identified from a prospectively compiled colorectal cancer database. Patients having colorectal stent placement and bypass surgery were excluded from analysis. RESULTS: The median age at surgery was 71 years (interquartile range, 65-79 years). The median survival following ostomy creation was 103 days (interquartile range, 19-263 days). Sixty-nine percent of participants (n = 59) survived 30 days and 18% (n=16) survived 12 months. CONCLUSIONS: Our results confirm that patients undergoing palliative stoma formation have limited life expectancy. Nevertheless, these findings are encouraging when compared to the anticipated outcomes of untreated bowel obstruction. PMID- 29521810 TI - Task interference and distraction efficacy in patients with fibromyalgia: an experimental investigation. AB - Pain has the capacity to interfere with daily tasks. Although task interference by pain is largely unintentional, it can be controlled to a certain extent. Such top-down control over pain has been believed to be reduced in patients with fibromyalgia (FM). In this study, we investigated task interference and distraction efficacy in patients with FM and a matched healthy control group. Forty-nine patients with FM and 49 healthy volunteers performed as quickly as possible (1) a visual localization task in the presence of nonpainful vibrating or painful electric somatic stimuli, and (2) a somatosensory localization task (using nonpainful or painful stimuli). Participants reported on their experience of the somatic stimuli on some of the trials during both localisation tasks. Results indicated that pain interferes with performance of the visual task, in both patients with FM and healthy individuals. Furthermore, participants experienced the pain stimulus as less intense when directing attention away from the pain than when focusing on the pain. Overall, task performance of patients with FM was slower compared with the task performance in the healthy control group. In contrast to our hypotheses, patients with FM and healthy volunteers did not differ in the magnitude of the interference effect and distraction efficacy. In conclusion, current study provides support for contemporary theories claiming that attention modulates the experience of pain and vice versa. However, no evidence was found for an altered attentional processing of pain in patients with FM. Furthermore, results indicate that task interference and distraction efficacy are not just 2 sides of the same coin. PMID- 29521811 TI - Carbenoxolone as a novel therapy for attenuation of cancer-induced bone pain. AB - Pain is a major complication for patients with cancer significantly compromising their quality of life. Current treatment is far from optimal and particularly bone-related cancer pain poses an increasing clinical and socioeconomical problem. Connexins, key proteins in cell-cell communication, have the potential to affect cancer-induced bone pain at multiple levels, including nociceptive signaling and bone degradation. This study tested the analgesic potential of carbenoxolone, a broad-acting connexin blocker, in a mouse model of cancer induced bone pain. In addition, a pharmacological approach was used to elucidate the underlying mechanisms using the 2 specific blockers Gap27 and Gap26. Compared with vehicle treatment, chronic systemic administration of 20 or 40 mg/kg carbenoxolone caused a significantly later onset and attenuation of movement evoked and on-going pain, assessed with limb use and weight bearing, respectively. In addition, the carbenoxolone-treated groups demonstrated a significant delay in time to reach the humane endpoint. Acute intrathecal administration of Gap27 significantly attenuated both limb use and weight bearing, whereas Gap26 had a less pronounced effect. Carbenoxolone treatment had a minor effect on the bone degradation in the early phase of disease progression, whereas no effect was observed in the late phase. Surprisingly, connexin43 was downregulated in the cancer-bearing animals compared with shams. The results suggest that connexins are involved in cancer-induced bone pain, and that carbenoxolone could be a novel analgesic treatment for the pain state. PMID- 29521812 TI - A crucial administration timing separates between beneficial and counterproductive effects of opioids on postoperative pain. PMID- 29521813 TI - Use of prescription opioids before and after an operation for chronic pain (lumbar fusion surgery). AB - Lumbar fusion surgery is usually prompted by chronic back pain, and many patients receive long-term preoperative opioid analgesics. Many expect surgery to eliminate the need for opioids. We sought to determine what fraction of long-term preoperative opioid users discontinue or reduce dosage postoperatively; what fraction of patients with little preoperative use initiate long-term use; and what predicts long-term postoperative use. This retrospective cohort study included 2491 adults undergoing lumbar fusion surgery for degenerative conditions, using Oregon's prescription drug monitoring program to quantify opioid use before and after hospitalization. We defined long-term postoperative use as >=4 prescriptions filled in the 7 months after hospitalization, with at least 3 occurring >30 days after hospitalization. Overall, 1045 patients received long-term opioids preoperatively, and 1094 postoperatively. Among long-term preoperative users, 77.1% continued long-term postoperative use, and 13.8% had episodic use. Only 9.1% discontinued or had short-term postoperative use. Among preoperative users, 34.4% received a lower dose postoperatively, but 44.8% received a higher long-term dose. Among patients with no preoperative opioids, 12.8% became long-term users. In multivariable models, the strongest predictor of long-term postoperative use was cumulative preoperative opioid dose (odds ratio of 15.47 [95% confidence interval 8.53-28.06] in the highest quartile). Cumulative dose and number of opioid prescribers in the 30-day postoperative period were also associated with long-term use. Thus, lumbar fusion surgery infrequently eliminated long-term opioid use. Opioid-naive patients had a substantial risk of initiating long-term use. Patients should have realistic expectations regarding opioid use after lumbar fusion surgery. PMID- 29521815 TI - Electronic Health Record-Related Events in Medical Malpractice Claims: User Error Versus Use Error. PMID- 29521814 TI - Biological Effects From Low Doses and Dose Rates of Ionizing Radiation: Science in the Service of Protecting Humans, a Synopsis. AB - There is considerable controversy regarding risk of health detriment after low level exposure to ionizing radiation. This stems in part from a sort of distance between radiation biologists, epidemiologists, and radiation protection professionals, as well as regulatory institutions. Also, there is a lack of overview of the relevant data and their origins regarding health risks at low doses of ionizing radiation. This feeds seriously into a somewhat hazy fear of ionizing radiation that besets large portions of the public. The current synopsis aims at presenting a holistic view in a concise yet comprehensive manner in order to help people understand the full extent of inputs into attempting to relate low dose radiation exposure to health risk. It emerges again that different approaches must be found for optimal radiation protection replacing the use of the linear no-threshold (LNT) model. PMID- 29521816 TI - Incidence and Causes of Adverse Events in Diagnostic Radiological Studies Requiring Anesthesia in the Wake-Up Safe Registry. AB - OBJECTIVES: General anesthesia or sedation can facilitate the completion of diagnostic radiological studies in children. We evaluated the incidence, predictors, and causes of adverse events (AEs) when general anesthesia is provided for diagnostic radiological imaging. METHODS: Deidentified data from 24 pediatric tertiary care hospitals participating in the Wake-Up Safe registry during 2010-2015 were obtained for analysis. Children 18 years or younger receiving general anesthesia for radiological procedures were identified using Current Procedural Terminology codes, and reported AEs were analyzed if they were associated with anesthetic care at magnetic resonance imaging or computed tomography locations. Logistic regression was used to determine predictors of AE occurrence in cases with complete covariate data. RESULTS: We identified 175,486 anesthetics for diagnostic radiological exams, compared with 83 AEs in magnetic resonance imaging or computed tomography locations (AE incidence of 0.05%). In multivariable analysis, AEs were more likely among patients with American Society of Anesthesiologists physical status IV compared with American Society of Anesthesiologists physical status I patients (adjusted odds ratio, 8.9; 95% confidence interval, 2.8-28.0; P < 0.001). Twenty-three AEs resulted in harm to the patient, whereas 32 AEs required unplanned hospital or intensive care unit admission. Anesthetic complications or issues were the most common cause of AEs (n = 52). CONCLUSIONS: Anesthesia provided for pediatric radiological studies is very safe and with an overall low AE incidence. The contribution of anesthetic complications to reported AEs suggests opportunities for further process improvement in this setting. PMID- 29521817 TI - Modification and Assessment of the Bedside Pediatric Early Warning Score in the Pediatric Allogeneic Hematopoietic Cell Transplant Population. AB - OBJECTIVES: To determine the validity of the Bedside Pediatric Early Warning Score system in the hematopoietic cell transplant population, and to determine if the addition of weight gain further strengthens the association with need for PICU admission. DESIGN: Retrospective cohort study of pediatric allogeneic hematopoietic cell transplant patients from 2009 to 2016. Daily Pediatric Early Warning Score and weights were collected during hospitalization. Logistic regression was used to identify associations between maximum Pediatric Early Warning Score or Pediatric Early Warning Score plus weight gain and the need for PICU intervention. The primary outcome was need for PICU intervention; secondary outcomes included mortality and intubation. SETTING: A large quaternary free standing children's hospital. PATIENTS: One-hundred two pediatric allogeneic hematopoietic cell transplant recipients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 102 hematopoietic cell transplant patients included in the study, 29 were admitted to the PICU. The median peak Pediatric Early Warning Score was 11 (interquartile range, 8-13) in the PICU admission cohort, compared with 4 (interquartile range, 3-5) in the cohort without a PICU admission (p < 0.0001). Pediatric Early Warning Score greater than or equal to 8 had a sensitivity of 76% and a specificity of 90%. The area under the receiver operating characteristics curve was 0.83. There was a high negative predictive value at this Pediatric Early Warning Score of 90%. When Pediatric Early Warning Score greater than or equal to 8 and weight gain greater than or equal to 7% were compared together, the area under the receiver operating characteristic curve increased to 0.88. CONCLUSIONS: In this study, a Pediatric Early Warning Score greater than or equal to 8 was associated with PICU admission, having a moderately high sensitivity and high specificity. This study adds to literature supporting Pediatric Early Warning Score monitoring for hematopoietic cell transplant patients. Combining weight gain with Pediatric Early Warning Score improved the discriminative ability of the model to predict the need for critical care, suggesting that incorporation of weight gain into Pediatric Early Warning Score may be beneficial for monitoring of hematopoietic cell transplant patients. PMID- 29521818 TI - Leveraging Data, the Next Big Advance for Quality Improvement in Colorectal Cancer. PMID- 29521819 TI - Colorectal Cancer Screening and Diagnosis: A Patient-Centered Approach to Understanding Avoidance. PMID- 29521820 TI - What Every Colorectal Surgeon Should Know About: CMS Survey of Global Period Surgical Services. PMID- 29521821 TI - Consensus Statement of Definitions for Anorectal Physiology Testing and Pelvic Floor Terminology (Revised). PMID- 29521822 TI - Perioperative Management of Biologic and Immunosuppressive Medications in Patients With Crohn's Disease. PMID- 29521823 TI - Expert Commentary on Perioperative Management of Biologic and Immunosuppressive Medications in Crohn's Disease. PMID- 29521824 TI - Risk Factors Associated With Circumferential Resection Margin Positivity in Rectal Cancer: A Binational Registry Study. AB - BACKGROUND: Rectal cancer outcomes have improved with the adoption of a multidisciplinary model of care. However, there is a spectrum of quality when viewed from a national perspective, as highlighted by the Consortium for Optimizing the Treatment of Rectal Cancer data on rectal cancer care in the United States. OBJECTIVE: The aim of this study was to assess and identify predictors of circumferential resection margin involvement for rectal cancer across Australasia. DESIGN: A retrospective study from a prospectively maintained binational colorectal cancer database was interrogated. SETTINGS: This study is based on a binational colorectal cancer audit database. PATIENTS: Clinical information on all consecutive resected rectal cancer cases recorded in the registry from 2007 to 2016 was retrieved, collated, and analyzed. MAIN OUTCOME MEASURES: The primary outcome measure was positive circumferential resection margin, measured as a resection margin <=1 mm. RESULTS: A total of 3367 patients were included, with 261 (7.5%) having a positive circumferential resection margin. After adjusting for hospital and surgeon volume, hierarchical logistic regression analysis identified a 6-variable model encompassing the independent predictors, including urgent operation, abdominoperineal resection, open technique, low rectal cancer, T3 to T4, and N1 to N2. The accuracy of the model was 92.3%, with an receiver operating characteristic of 0.783 (p < 0.0001). The quantitative risk associated with circumferential resection margin positivity ranged from <1% (no risk factors) to 43% (6 risk factors). LIMITATIONS: This study was limited by the lack of recorded long-term outcomes associated with circumferential resection margin positivity. CONCLUSIONS: The rate of circumferential resection margin involvement in patients undergoing rectal cancer resection in Australasia is low and is influenced by a number of factors. Risk stratification of outcome is important with the increasing demand for publicly accessible quality data. See Video Abstract at http://links.lww.com/DCR/A512. PMID- 29521825 TI - Lymphatic Drainage of the Splenic Flexure Defined by Intraoperative Scintigraphic Mapping. AB - BACKGROUND: The optimal surgical management of splenic flexure cancer is debated, partly because of an incomplete understanding of the lymphatic drainage of this region. OBJECTIVE: This study aimed to evaluate the normal lymphatic drainage of the human splenic flexure using laparoscopic scintigraphic mapping. DESIGN: This was a clinical trial. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: Thirty consecutive patients undergoing elective colorectal resections without splenic flexure pathology were recruited. INTERVENTION: Technetium-99m was injected subserosally at the splenic flexure. MAIN OUTCOME MEASURES: Lymphatic scintigraphic mapping was undertaken at 15, 30, and 60 minutes using a laparoscopic gamma probe at the left branch of the middle colic, left colic, inferior mesenteric, and ileocolic (control) lymphovascular pedicles. RESULTS: Lymphatic drainage at 60 minutes was strongly dominant in the direction of the left colic pedicle (96% of patients), with a median gamma count of 284 (interquartile range, 113-413), versus the left branch of the middle colic count of 31 (interquartile range, 15-49; p < 0.0001). This equated to a median 9.2 times greater flow to the left colic versus the middle colic. Counts at the left colic were greater than all of the other mapped sites at 15, 30, and 60 minutes (p < 0.001), whereas middle colic and inferior mesenteric artery counts were equivalent. The protocol increased operative duration by 20 to 30 minutes without complications. LIMITATIONS: These results report lymphatic drainage from patients with normal splenic flexures, and caution is necessary when extrapolating to patients with splenic flexure cancers. CONCLUSIONS: The lymphatic drainage of the normal splenic flexure is preferentially directed toward the left colic in the high majority of cases. Retrieving these nodes should be prioritized in splenic flexure cancer resections, with important secondary emphasis on left middle colic nodes, supporting segmental (left hemicolectomy) resection as the procedure of choice. Additional development of colonic sentinel node mapping using these techniques may contribute to individualized surgical therapy morbidity. See Video Abstract at http://links.lww.com/DCR/A495. PMID- 29521826 TI - Prominent Information of jN3 Positive in Stage III Colorectal Cancer Removed by D3 Dissection: Retrospective Analysis of 6866 Patients From a Multi-institutional Database in Japan. AB - BACKGROUND: The presence of main or lateral lymph node metastasis in colorectal cancer is classified as jN3 by the Japanese Society for Cancer of the Colon and Rectum. Whether information on jN3 status adds value to the TNM classification remains unclear. OBJECTIVE: We aimed to assess the prognostic relevance of colorectal cancer nodal staging through the Japanese jN3 categorization compared with that through TNM. DESIGN: This was a retrospective study. SETTING: The study used the multi-institutional database of the Japanese Society for Cancer of the Colon and Rectum. PATIENTS: Clinical and pathological data of 6866 patients with histologically proven stage III colorectal cancer who underwent curative surgery (R0) with D3 dissection between 1995 and 2006 were derived from the database. MAIN OUTCOME MEASURES: We investigated the prognostic significance of jN3 status in each TNM N class (N1/N2a/N2b) and stage (IIIA/IIIB/IIIC) based on cancer specific survival. RESULTS: Comparison of cancer-specific survival rates revealed significant differences between jN3+ and jN3- colorectal cancer patient groups according to the TNM N status (5-year cancer-specific survival; N1, 70.4% (jN3+) vs 85.5% (jN3-), p < 0.001; N2a, 59.2% vs 77.0%, p < 0.001; N2b, 39.2% vs 68.7%, p < 0.001) and the TNM stage (stage IIIA, 72.5% vs 94.9%, p < 0.001; stage IIIB, 67.9% vs 84.0%, p < 0.001; stage IIIC, 42.4% vs 70.6%, p < 0.001). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: Assessment and inclusion of jN3 status are of clinical importance for patients with stage III colorectal cancer with D3 dissection, because it contributes to improved understanding of recurrence risk and subsequent decision-making for follow-up procedures and adjuvant therapy. See Video Abstract at http://links.lww.com/DCR/A506. PMID- 29521827 TI - Management and Outcome After Multivisceral Resections in Patients with Locally Advanced Primary Colon Cancer. AB - BACKGROUND: Locally advanced colon cancer invading surrounding organs or structures is challenging to surgeons and oncologists. Multivisceral resections with tumor removal en bloc with invaded tissues provide the best chance for cure. OBJECTIVE: We aimed to assess the management and outcomes after multivisceral resections in patients with clinically infiltrative, locally advanced primary colon cancer. DESIGN: This is a descriptive retrospective cohort study. SETTINGS: A total of 121 consecutive patients with locally advanced primary colon cancer underwent en bloc multivisceral resections at a tertiary referral unit for colorectal cancer between 2007 and 2014. MAIN OUTCOME MEASURES: Patient demographics, surgical details, histopathological findings, and outcomes were analyzed through registry data and reviews of patient files. RESULTS: An R0 resection was achieved in 112 patients (92.6%), and an R1 resection was achieved in 9 patients (7.4%). Actual tumor cell infiltration in resected tissues was found in 77 patients (63.6%), and inflammation was found in 44 patients (36.4%). The estimated 5-year overall survival was 60.8% and 86.9%. Survival was significantly better after R0 than after R1 resections. After a median follow-up of 28 months, recurrent disease was diagnosed in 25 patients (20.7%). Female sex, low tumor stage, and adjuvant chemotherapy, but not tumor infiltration per se, were independently associated with better overall survival in a multivariate analysis. LIMITATIONS: The main limitations of the study are the retrospective design and the fact that all patients were operated on at 1 institution by a small number of surgeons. CONCLUSIONS: Patients with locally advanced colon cancer can be cured with an R0 resection. All involved surrounding tissues should be removed en bloc with the primary tumor. See Video Abstract at http://links.lww.com/DCR/A548. PMID- 29521828 TI - Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials. AB - BACKGROUND: Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. OBJECTIVE: We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. DESIGN: Independent patient data analysis of a pooled database from 3 phase III trials was performed. SETTINGS: An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. INTERVENTIONS: Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. MAIN OUTCOME MEASURES: To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. RESULTS: Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. LIMITATIONS: The treatment regimens of postoperative chemotherapy are now somewhat outdated. CONCLUSIONS: Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531. PMID- 29521829 TI - Obesity and the Risk of Colonic Diverticulosis: A Meta-analysis. AB - BACKGROUND: The possible relationship between obesity and the risk of colonic diverticulosis has been suggested by recent epidemiologic studies, although the results were inconsistent. OBJECTIVE: This systematic review and meta-analysis was conducted to summarize all of the available data. DATA SOURCES: A comprehensive literature review was conducted using the MEDLINE and EMBASE databases through January 2017. STUDY SELECTION: Studies that compared the risk of colonic diverticulosis among subjects with obesity versus those without obesity were included. MAIN OUTCOME MEASURES: Effect estimates from each study were extracted and combined together using a random-effect, generic inverse variance method. RESULTS: Of 2989 potentially eligible articles, 10 studies (9 cross-sectional studies and 1 prospective cohort study) with 53,520 participants met the eligibility criteria and were included in the meta-analysis. The risk of colonic diverticulosis in obese subjects was significantly higher than in those without obesity, with a pooled OR of 1.41 (95% CI, 1.20-1.65). The statistical heterogeneity was high, with an I of 75%. LIMITATIONS: High statistical heterogeneity and publication bias in favor of positive studies may have been present in this meta-analysis. CONCLUSIONS: A significant association between colonic diverticulosis and obesity was shown in this study. However, additional studies are still required to determine the causality. See Video Abstract at http://links.lww.com/DCR/A500. PMID- 29521830 TI - Human-Derived Amniotic Membrane Is Associated With Decreased Postoperative Intraperitoneal Adhesions in a Rat Model. AB - BACKGROUND: Complications from adhesions after intra-abdominal surgery accounts for ~6% of hospital admissions. Currently, hyaluronate/carboxymethylcellulose represents the main option to prevent postoperative adhesion formation. Human amniotic membrane contains inherent anti-inflammatory properties that mitigate adhesion formation. OBJECTIVE: This study aimed to evaluate adhesion generation after surgical trauma with amniotic membranes compared with standard intraperitoneal adhesion barriers. DESIGN: This study is a double-blinded, prospective evaluation. SETTING: This study was conducted at an animal research facility. ANIMALS: Forty male rats were studied. INTERVENTION: Laparotomy was performed with peritoneal disruption to the cecum. Animals were randomly assigned to 1 of 5 groups: sham, control, saline, hyaluronic acid membrane, or amniotic membrane. Animals were euthanized at 14 days. MAIN OUTCOME MEASURES: Independent gross and histological assessments of adhesions were analyzed between groups by using adhesion scoring and microscopy. Scoring was based on the percentage of the cecum involved (0-4), vascularity of adhesions (0-3), strength (0-3), inflammation (0-3), and fibrosis (0-3). Adhered tissue was harvested for polymerase chain reaction analysis for gene regulation activity. RESULTS: All rats survived 14 days. Adhesions were observed in all animals. There were significantly fewer adhesions in the amniotic membrane group (2) versus hyaluronic acid (3) group (p = 0.01). The percentage of adhesion to the cecum was lower in the amniotic membrane group (29%) than in the hyaluronic acid group (47%, p = 0.04). Histological examination showed no significant difference between or within the 3 groups for inflammation or fibrosis. Genetic analysis of adhered tissues supported high rates of epithelialization and inhibition of fibrosis in the amniotic membrane group. LIMITATIONS: We are limited by the small sample size and the preclinical nature of the study. CONCLUSION: Human-derived amniotic membrane is effective at reducing intraperitoneal adhesion after surgical trauma and is superior to the current antiadhesion barriers. Amniotic membranes are well absorbed and demonstrate short-term safety. See Video Abstract at http://links.lww.com/DCR/A554. PMID- 29521831 TI - Stapled Hemorrhoidopexy: Results at 10-Year Follow-up. AB - BACKGROUND: Despite the advantages of stapled hemorrhoidopexy reported in the literature in terms of postoperative pain, hospital stay, and duration of convalescence, it was described to have a higher recurrence rate compared with conventional hemorrhoidectomy. OBJECTIVE: The aim of this study was to evaluate clinical outcomes and patient satisfaction after stapled hemorrhoidopexy at 10 year follow-up. DESIGN: This was a retrospective cohort analysis conducted on prospectively collected data. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: Eighty-six consecutive patients treated with stapled hemorrhoidopexy for grade 3 hemorrhoidal prolapse between January and December 2006 were included. MAIN OUTCOME MEASURES: Patients satisfaction and recurrence rates were measured. RESULTS: Eighty-six patients (45 men and 41 women; median age, 49 y (range, 31-74 y)) underwent stapled hemorrhoidopexy. Eight patients had urinary retention during the immediate postoperative period, and 2 patients required a reoperation for suture line bleeding. The median hospital stay was 12 hours (range, 12-96 h). No suture line dehiscence, rectovaginal fistula, pelvic sepsis, anal abscess, or anal stenosis was recorded during the follow-up. Seventy-seven patients (90%) completed the expected follow up, with a median duration of 119.0 months (range 115.4-121.8 mo). Among them, 30 patients (39%) experienced a recurrent hemorrhoidal prolapse, 8 of whom needed a reoperation. Thirty-four patients (44%) reported urge to defecate with a median visual analog scale of 1 (range, 1-7). Six patients (8%) reported gas leakage at the last follow-up visit, whereas no liquid or solid stool leakage was recorded. Satisfaction rate at 10-year follow-up was 68%. LIMITATIONS: The study was limited by its small sample size and lack of a control group. CONCLUSIONS: The high recurrence rate and low patient satisfaction rate showed that stapled hemorrhoidopexy reduces its efficacy in the long-term. See Video Abstract at http://links.lww.com/DCR/A510. PMID- 29521832 TI - Draining Setons as Definitive Management of Fistula-in-Ano. AB - BACKGROUND: The ideal management for fistula-in-ano would resolve the disease while preserving anal continence. OBJECTIVE: The purpose of this study was to determine the efficacy of draining seton alone in achieving resolution or significant amelioration of symptoms for patients with fistula-in-ano. DESIGN: This was a retrospective case series involving chart review and telephone interviews. A single colorectal surgeon performed surgeries between June 1, 2005, and June 30, 2014. SETTINGS: The study was conducted by a single surgeon in a large urban city. PATIENTS: Patient >=18 years of age presenting with fistula-in ano of cryptoglandular origin were included. MAIN OUTCOME MEASURES: Resolution of symptoms or significant symptom improvement requiring no additional surgical management and rate of recurrence were measured. RESULTS: A total of 76 patients (53 men) met the inclusion criteria. Mean age was 45 years (range, 19-73 y). The average time to seton removal was 36.6 weeks (range, 6.0-188.0 wk). Mean follow up was 63 months (range, 7-121 mo). Fifty-seven patients (75%) were reached for telephone interview. Fifty-six patients (73.7%) had complete symptom resolution, and 14 (18.4%) had significant amelioration of symptoms with no additional surgical management required. Six (7.9%) had persistent severe symptoms. Five (7.1%) had a recurrence after seton removal. Rates of symptom resolution and recurrence were similar between patients whose setons were removed before or after 26 weeks (median time of seton removal) from the time of placement. Twenty one patients (27.6%) required 1 or more additional operative procedures before planned seton removal to unroof a collection and/or replace the seton, and this represented the most significant risk factor for failure of resolution or improvement or recurrence (relative risk = 7.0). LIMITATIONS: This study was retrospective and represents a single surgeon experience. CONCLUSIONS: Placement of draining seton alone is a viable treatment option for definitive symptomatic management of fistula-in-ano. Because draining setons are sphincter and function preserving, their use should be considered as primary management for fistula-in ano. See Video Abstract at http://links.lww.com/DCR/A552. PMID- 29521833 TI - Understanding Patients' Experiences of Diagnosis and Treatment of Advanced Colorectal Cancer in a Safety-Net Hospital System: A Qualitative Study. AB - BACKGROUND: Greater understanding of barriers to screening of colorectal cancer among lower socioeconomic, particularly Hispanic, patients is needed to improve disparities in care. OBJECTIVE: This study aimed to explore patients' perceptions and experiences of care seeking for colorectal cancer to identify barriers to early diagnosis and treatment. DESIGN: This explorative qualitative study was conducted as a focused ethnography of patients diagnosed with advanced-stage colorectal cancer. SETTINGS: This study was conducted at an urban safety-net hospital. PARTICIPANTS: Thirty lower-income, primarily minority, patients diagnosed with stage III and IV colorectal cancer without prior colorectal cancer screening were selected. MAIN OUTCOME MEASURES: The primary outcomes measured were participants' perceptions and experiences of colorectal cancer and barriers they faced in seeking diagnosis and treatment RESULTS:: Data analysis yielded 4 themes consistently influencing participants' decisions to seek diagnosis and treatment: 1) limited resources for accessing care (structural barriers, including economic, health care and health educational resources); 2) (mis)understanding of symptoms by patients; misdiagnosis of symptoms, by physicians; 3) beliefs about illness and health, such as relying on faith, or self-care when symptoms developed; and 4) reactions to illness, including maintenance of masculinity, confusing interactions with physicians, embarrassment, and fear. These 4 themes describe factors on the structural, health care system, provider and patient level, that interact to make engaging in prevention foreign among this population, thus limiting early detection and treatment of colorectal cancer. LIMITATIONS: This study was limited by selection bias and the lack of generalizability. CONCLUSION: Improving screening rates among lower-income populations requires addressing barriers across the multiple levels, structural, personal, health care system, that patients encounter in seeking care for colorectal cancer. Acknowledging the complex, multilevel influences impacting patient health care choices and behaviors allows for the development of culturally tailored interventions, and educational, financial, and community resources to decrease disparities in cancer screening and care and improve outcomes for these at-risk patients. See Video Abstract at http://links.lww.com/DCR/A473. PMID- 29521834 TI - Rectal Dissection Simulator for da Vinci Surgery: Details of Simulator Manufacturing With Evidence of Construct, Face, and Content Validity. AB - BACKGROUND: Apprenticeship in training new surgical skills is problematic, because it involves human subjects. To date there are limited inanimate trainers for rectal surgery. OBJECTIVE: The purpose of this article is to present manufacturing details accompanied by evidence of construct, face, and content validity for a robotic rectal dissection simulation. DESIGN: Residents versus experts were recruited and tested on performing simulated total mesorectal excision. Time for each dissection was recorded. Effectiveness of retraction to achieve adequate exposure was scored on a dichotomous yes-or-no scale. Number of critical errors was counted. Dissection quality was tested using a visual 7-point Likert scale. The times and scores were then compared to assess construct validity. Two scorer results were used to show interobserver agreement. A 5-point Likert scale questionnaire was administered to each participant inquiring about basic demographics, surgical experience, and opinion of the simulator. Survey data relevant to the determination of face validity (realism and ease of use) and content validity (appropriateness and usefulness) were then analyzed. SETTINGS: The study was conducted at a single teaching institution. SUBJECTS: Residents and trained surgeons were included. INTERVENTION: The study intervention included total mesorectal excision on an inanimate model. MAIN OUTCOME MEASURES: Metrics confirming or refuting that the model can distinguish between novices and experts were measured. RESULTS: A total of 19 residents and 9 experts were recruited. The residents versus experts comparison featured average completion times of 31.3 versus 10.3 minutes, percentage achieving adequate exposure of 5.3% versus 88.9%, number of errors of 31.9 versus 3.9, and dissection quality scores of 1.8 versus 5.2. Interobserver correlations of R = 0.977 or better confirmed interobserver agreement. Overall average scores were 4.2 of 5.0 for face validation and 4.5 of 5.0 for content validation. LIMITATIONS: The use of a da Vinci microblade instead of hook electrocautery was a study limitation. CONCLUSIONS: The pelvic model showed evidence of construct validity, because all of the measured performance indicators accurately differentiated the 2 groups studied. Furthermore, study participants provided evidence for the simulator's face and content validity. These results justify proceeding to the next stage of validation, which consists of evaluating predictive and concurrent validity. See Video Abstract at http://links.lww.com/DCR/A551. PMID- 29521835 TI - Martius Flap for Persistent, Complex Rectovaginal Fistula. PMID- 29521836 TI - A Novel Closure Technique for Complex Abdominal Wounds. AB - INTRODUCTION: Abdominal wound closure is a challenge in patients undergoing colorectal surgery with a complex history of multiple abdominopelvic operations. Loss of domain of the abdominal fascia because of prior laparotomies precludes the use of simple, everyday abdominal wound closure techniques. Furthermore, ongoing intra-abdominal sepsis, with or without a concurrent entero- or colocutaneous fistula, increases the risk of postoperative morbidity and mortality in this patient population. We propose an abdominal wound closure technique for patients with multiple previous complex operations and subsequent ongoing abdominopelvic sepsis. TECHNIQUE: Following completion of the intra abdominal component of the operation, the abdominal wall fascial edges are identified and mobilized to allow for a smooth skin closure. The skin is brought together with a small amount of subcutaneous tissue in the abdominal wound line and sutured with a 1.0 Prolene stitch by using the vertical mattress technique. For both wound edges, a dental roll is inserted between the entry and exit points of the suture, with the suture material placed above and over the dental roll, and thus the dental roll is incorporated within the stitch when it is tied down. These stitches and dental rolls are placed along the length of the wound. No mesh is utilized, and the technique achieves skin closure with development of a subsequent ventral hernia. RESULTS: Good postoperative short-term and long-term overall outcomes were achieved in 14 patients who underwent complex abdominal wound closure. Two patients required further late operative intervention because of the incarceration of the known ventral hernia (at 34 and 120 months postoperatively). CONCLUSIONS: Complex abdominal wound closure in this setting is safe and feasible to achieve a healthy abdominal wall closure and enable healing by primary intention after colorectal surgery. PMID- 29521837 TI - Intersphincteric Component in a Complex Fistula-in-Ano Is Like an Abscess and Should Be Treated Like One. PMID- 29521838 TI - The Authors Reply. PMID- 29521839 TI - Prediction of N0 Irradiated Rectal Cancer Comparing MRI Before and After Preoperative Chemoradiotherapy: Methodological Issues. PMID- 29521840 TI - The Authors Reply. PMID- 29521841 TI - Not Only Mesorectum But Also Infra-mesorectum Excision in Lower Rectal Cancer. PMID- 29521842 TI - The Authors Reply. PMID- 29521843 TI - Transanal TME for Rectal Cancer. PMID- 29521845 TI - How Did Health Care Reform in Massachusetts Impact Insurance Premiums? PMID- 29521846 TI - WITHDRAWN: International Society of Gynecological Pathologists (ISGyP) Endometrial Cancer Project: Guidelines From the Special Techniques and Ancillary Studies Group. AB - Ahead of Print article withdrawn by publisher. PMID- 29521847 TI - Perceptions of Global Warming Among the Poorest Counties in the Southeastern United States. AB - The geographic position and high level of poverty in the southeastern United States are significant risk factors that contribute to the region's high vulnerability to climate change. The goal of this study was to evaluate beliefs and perceptions of global warming among those living in poverty in the poorest counties in the southeastern United States. Results from this project may be used to support public health efforts to increase climate-related messaging to vulnerable and underserved communities. This was an ecological study that analyzed public opinion poll estimates from previously gathered national level survey data (2016). Responses to 5 questions related to beliefs, attitudes, and perceptions of global warming were evaluated. Counties below the national average poverty level (13.5%) were identified among 11 southeastern US states (Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Michigan, North Carolina, South Carolina, Tennessee, Virginia). Student t tests were used to compare public perceptions of global warming among the poorest urban and rural counties with national-level public opinion estimates. Overall, counties below the national poverty level in the southeastern US were significantly less likely to believe that global warming was happening compared with national-level estimates. The poorest rural counties were less likely to believe that global warming was happening than the poorest urban counties. Health care providers and public health leaders at regional and local levels are in ideal positions to raise awareness and advocate the health implications of climate change to decision makers for the benefit of helping underserved communities mitigate and adequately adapt to climate-related threats. PMID- 29521848 TI - Can Statewide Emergency Department, Hospital Discharge, and Violent Death Reporting System Data Be Used to Monitor Burden of Firearm-Related Injury and Death in Rhode Island? AB - CONTEXT: National data on the epidemiology of firearm injuries and circumstances of firearm deaths are difficult to obtain and often are nonreliable. Since firearm injury and death rates and causes can vary substantially between states, it is critical to consider state-specific data sources. OBJECTIVE: In this study, we illustrate how states can systematically examine demographic characteristics, firearm information, type of wound, toxicology tests, precipitating circumstances, and costs to provide a comprehensive picture of firearm injuries and deaths using data sets from a single state with relatively low rates of firearm injury and death. DESIGN: Cross-sectional study. SETTING: Firearm-related injury data for the period 2005-2014 were obtained from the Rhode Island emergency department and hospital discharge data sets; death data for the same period were obtained from the Rhode Island Violent Death Reporting System. MAIN OUTCOME MEASURE: Descriptive statistics were used. Healthcare Cost and Utilization Project cost-to-charge ratios were used to convert total hospital charges to costs. RESULTS: Most firearm-related emergency department visits (55.8%) and hospital discharges (79.2%) in Rhode Island were from assaults; however, most firearm-related deaths were suicides (60.1%). The annual cost of firearm-related hospitalizations was more than $830 000. Most decedents who died because of firearms tested positive for illicit substances. Nearly a quarter (23.5%) of firearm-related homicides were due to a conflict between the decedent and suspect. More than half (59%) of firearm suicide decedents were reported to have had current mental or physical problems prior to death. CONCLUSIONS: Understanding the state-specific magnitude and patterns (who, where, factors, etc) of firearm injury and death may help inform local injury prevention efforts. States with similar data sets may want to adopt our analyses. Surveillance of firearm-related injury and death is essential. Dissemination of surveillance findings to key stakeholders is critical in improving firearm injury prevention. States that are not part of the National Violent Death Reporting System (NVDRS) could work with their other data sources to obtain a better picture of violent injuries and deaths to make the best use of resources. PMID- 29521849 TI - Implementing Statewide Severe Maternal Morbidity Review: The Illinois Experience. AB - CONTEXT: Severe maternal morbidity (SMM) rates in the United States more than doubled between 1998 and 2010. Advanced maternal age and chronic comorbidities do not completely explain the increase in SMM or how to effectively address it. The Centers for Disease Control and Prevention and American College of Obstetricians and Gynecologists have called for facility-level multidisciplinary review of SMM for potential preventability and have issued implementation guidelines. IMPLEMENTATION: Within Illinois, SMM was identified as any intensive or critical care unit admission and/or 4 or more units of packed red blood cells transfused at any time from conception through 42 days postpartum. All cases meeting this definition were counted during statewide surveillance. Cases were selected for review on the basis of their potential to yield insights into factors contributing to preventable SMM or best practices preventing further morbidity or death. If the SMM review committee deemed a case potentially preventable, it identified specific factors associated with missed opportunities and made actionable recommendations for quality improvement. EVALUATION: Approximately 1100 cases of SMM were identified from July 1, 2016, to June 30, 2017, yielding a rate of 76 SMM cases per 10 000 pregnancies. Reviews were conducted on 142 SMM cases. Most SMM cases occurred during delivery hospitalization and more than half were delivered by cesarean section. Hemorrhage was the primary cause of SMM (>50% of the cases). DISCUSSION: Facility-level SMM review was feasible and acceptable in statewide implementation. States that are planning SMM reviews across obstetric facilities should permit ample time for translation of recommendations to practice. Although continued maternal mortality reviews are valuable, they are not sufficient to address the increasing rates of SMM and maternal death. In depth multidisciplinary review offers the potential to identify factors associated with SMM and interventions to prevent women from moving along the continuum of severity. PMID- 29521850 TI - Root-Cause Analysis for Enhancing Public Health Emergency Preparedness: A Brief Report of a Salmonella Outbreak in the Alamosa, Colorado, Water Supply. AB - To demonstrate how public health systems can use root-cause analysis (RCA) to improve learning from critical incidents, the research team utilized a facilitated look-back meeting to examine the public health systems' response to a Salmonella outbreak in the water supply in Alamosa, Colorado. We worked with public health, emergency management agencies, and other stakeholders to identify response challenges related to public health emergency preparedness capabilities, root causes, and lessons learned. The results demonstrate that RCA can help identify systems issues that, if addressed, can improve future responses. Furthermore, RCA can identify more basic issues that go beyond a specific incident or setting, such as the need for effective communication and coordination throughout the public health system, and the social capital needed to support it. PMID- 29521851 TI - A Review of Public Health Training Needs Assessment Approaches: Opportunities to Move Forward. AB - CONTEXT: Assessing training needs of the public health workforce is crucial for creating professional development opportunities to improve knowledge, competence, and effectiveness of this workforce. DISSEMINATION: Regional Public Health Training Centers (RPHTCs) assess workforce training needs and deliver training based on identified needs. To determine training priorities, several needs assessment surveys have been administered by RPHTCs and national public health member organizations. EVALUATION: This study identified the types of training questions being asked to public health practitioners in the various assessment surveys implemented by RPHTCs and national membership organizations. Although the surveys measured similar overarching constructs, multiple approaches with limited consistency were used to measure training needs. DISCUSSION: Although successful in responding to the needs of their targeted constituents, the limited consistency among survey types makes generalization of findings difficult. Disseminating common metrics and aggregate survey findings would increase efficiency in determining workforce training needs and developing targeted training. PMID- 29521852 TI - Just-in-Time Training of the Evidence-Based Public Health Framework, Oklahoma, 2016-2017. AB - Training of practitioners on evidence-based public health has shown to be beneficial, yet overwhelming. Chunking information and proximate practical application are effective techniques to increase retention in adult learning. Evidence-based public health training for practitioners from African American and Hispanic/Latino community agencies and tribes/tribal nations incorporated these 2 techniques. The community-level practitioners alternated attending training and implementing the steps of the evidence-based public health framework as they planned state-funded programs. One year later, survey results showed that participants reported increased confidence in skills that were reinforced by practical and practiced application as compared with posttraining survey results. In addition, at 1 year, reported confidence in skills that were not fortified by proximate application decreased when compared with posttraining confidence levels. All 7 community programs successfully created individualized evidence based action plans that included evidence-based practices and policies across socioecological levels that fit with the unique culture and climate of their own community. PMID- 29521853 TI - Public Health: The Intersection of Food Security and Well-being. PMID- 29521854 TI - Excessive SBP elevation during moderate exercise discriminates patients at high risk of developing left ventricular hypertrophy from hypertensive patients. AB - OBJECTIVE: Hypertensive patients show an excessive elevation of SBP during exercise, although optimal blood pressure (BP) control is required to prevent development of left ventricular hypertrophy (LVH). This study examined whether excessive SBP elevation during moderate exercise is associated with new-onset LVH in these patients. METHODS: A total of 143 hypertensive patients without LVH whose BP had been maintained below 140/90 mmHg with antihypertensives performed cycle ergometer exercise test at moderate intensity to assess SBP elevation during exercise (DeltaSBP). Left ventricular mass index (LVMI) was assessed by echocardiography once a year to identify new-onset LVH. Patients were divided into three groups according to tertiles of DeltaSBP. We examined the associations between DeltaSBP and new-onset LVH using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: The patients (100 men, 65.3 +/- 9.1 years) had resting BP of 126 +/- 16/75 +/- 11 mmHg. New-onset LVH developed in 47 patients (32.9%) within a follow-up period of 2.5 +/- 1.6 years. Higher DeltaSBP was significantly associated with higher incidence of LVH (P < 0.001): 12.8, 27.1, and 58.3% in the lowest, middle, and highest tertiles, respectively. In multivariate analysis, DeltaSBP was a significant independent determinant of new onset LVH (hazard ratio for 10 mmHg increase in DeltaSBP, 1.45; 95% CI 1.22-1.73; P < 0.001). In comparison with the lowest tertile, the hazard ratios of the middle and highest tertiles for incidence of LVH were 3.16 (95% CI 1.07-9.32) and 6.43 (95% CI 2.35-17.62), respectively. CONCLUSION: Excessive SBP elevation during moderate exercise can be used to identify hypertensive patients at high risk of developing LVH. PMID- 29521855 TI - Systematic review methodology in graduate nursing education. PMID- 29521856 TI - Caregivers' experiences of feeding children with cerebral palsy: a systematic review protocol of qualitative evidence. AB - REVIEW QUESTION/OBJECTIVE: The overall objective of this systematic review is to identify, critically appraise and synthesize the literature regarding the feeding experiences of caregivers who care for children with cerebral palsy. The specific review question is: What are the experiences of caregivers feeding children with cerebral palsy? PMID- 29521857 TI - Effectiveness of non-pharmacological strategies for managing delirium in hospitalized postoperative adults: an umbrella review protocol. AB - REVIEW QUESTION/OBJECTIVE: The question of this review: What is the effectiveness of non-pharmacological strategies for the management of delirium in hospitalized adult postoperative patients?The objective of this umbrella review is to determine the effectiveness of non-pharmacological strategies for the management of delirium in adult postoperative patients, 18 years and over, in an acute care hospitalized setting.More specifically, the review aims to identify which non pharmacological strategy/strategies, provided as a single strategy or combined as two or more strategies, is the most effective for management of delirium in hospitalized postoperative adult patients? PMID- 29521858 TI - The association of premorbid neuropsychological conditions with pediatric mild traumatic brain injury/concussion recovery time and symptom severity: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: What is the association of premorbid neuropsychological conditions with mild traumatic brain injury/concussion recovery time and symptom severity in children? PMID- 29521859 TI - Burden of brain tumors in low- and middle-income countries: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to determine the best available evidence on the burden of brain tumors in low- and middle-income countries (LAMICs). More specifically, the objective is to determine the incidence and prevalence rates for brain tumors in LAMICs. PMID- 29521860 TI - Adverse drug reactions in primary care: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of the scoping review is to examine the types of adverse drug reactions experienced by patients in the primary care setting and to map the classes of medications associated with adverse drug reactions. PMID- 29521861 TI - The patient/significant other experience of physical restraint in acute care settings: a qualitative systematic review protocol. AB - REVIEW QUESTION: The overarching question for this qualitative systematic review is: What meanings are attributed to the experience of physical restraint among adult patients or their significant others in acute care hospitals? Specifically the review will seek to answer two questions. PMID- 29521862 TI - Experiences of transgender individuals when accessing health care: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective is to synthesize existing qualitative literature examining the experiences of transgender individuals when accessing health care. PMID- 29521863 TI - Family-oriented interventions for adults with acquired brain injury and their families: a scoping review protocol. AB - REVIEW QUESTION: The aim of this scoping review is to examine the range and nature of family-oriented interventions that have been developed and/or tested for people with acquired brain injuries (ABI) and their families in all settings. Specifically the review questions are. PMID- 29521864 TI - Dedicated education units as a clinical rotation for nursing students: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this scoping review is to explore the existing literature regarding student nurse and nursing faculty perceived experiences and outcomes of dedicated education units, to examine and conceptually map the evidence, and to identify any gaps in the literature. The question of this review is. PMID- 29521865 TI - Perceptions of blood donation among people in Africa: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The aim of this review is to synthesize the best available evidence on the perceptions of blood donation among people living in Africa. PMID- 29521866 TI - The effect of community-based health insurance schemes on utilization of healthcare services in low- and middle-income countries: a systematic review protocol of quantitative evidence. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to identify, appraise and synthesize evidence to establish the effectiveness of community-based health insurance (CBHI) schemes in enhancing the utilization of healthcare services among their members in low- and middle-income countries (LMICs).Specifically, the review objective is to determine if individuals or households enrolled in CBHI schemes in LMICs utilize healthcare services (outpatient visits, hospital admissions, emergency visits, maternal and child healthcare services, or any other services involving the schemes) more frequently than those not included in CBHI schemes. PMID- 29521867 TI - Effectiveness of four-factor prothrombin complex concentrates versus plasma on vitamin K antagonist associated plasma international normalized ratio reversal: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: what is the effectiveness of Kcentra/Beriplex/Confidex compared to plasma for international normalized ratio (INR) reduction in adult patients (18 years and over) on any vitamin K antagonist therapy? PMID- 29521868 TI - Older nurses' experiences of providing direct care in hospital nursing units: a qualitative systematic review. AB - BACKGROUND: Most developed countries throughout the world are experiencing an aging nursing workforce as their population ages. Older nurses often experience different challenges then their younger nurse counterparts. With the increase in older nurses relative to younger nurses potentially available to work in hospitals, it is important to understand the experience of older nurses on high paced hospital nursing units. This understanding will lend knowledge to ways of lessening the loss of these highly skilled experienced workers and improve patient outcomes. OBJECTIVES: To identify, evaluate and synthesize the existing qualitative evidence on older nurses' experiences of providing direct care to patients in hospital nursing units. INCLUSION CRITERIA: The review considered studies which included registered nurses 45 years and over who work as direct caregivers in any type of in-patient hospital nursing unit. The phenomenon of interest was the experience of older nurses in providing direct nursing care in any type of in-patient hospital nursing unit (i.e. including but not limited to medical/surgical units, intensive care units, critical care units, perioperative units, palliative care units, obstetrical units, emergency departments and rehabilitative care units). The review excluded studies focussing entirely on enrolled nurses, licensed practical nurses and licensed vocational nurses. TYPES OF STUDIES: Qualitative data including, but not limited to the following methodologies: phenomenology, grounded theory, ethnography, action research and feminist research. METHODS: The databases CINAHL, PubMed, PsycINFO, Embase, AgeLine, Sociological Abstracts and SocINDEX were searched from inception; the search was conducted on October 13, 2017; no date limiters or language limiters were applied. Each paper was assessed by two independent reviewers for methodological quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Qualitative Research. Any disagreements that arose between the reviewers were resolved through discussion. Data extraction was conducted by two independent reviewers using the standardized qualitative data extraction tool from JBI. The qualitative research findings were pooled using JBI methodology. The JBI process of meta-aggregation was used to identify categories and synthesized findings. RESULTS: Twelve papers were included in the review. Three synthesized findings were extracted from 12 categories and 75 findings. The three synthesized findings extracted from the papers were: (1) Love of nursing: It's who I am and I love it; (2) It's a rewarding but challenging and changing job; it's a different job and it can be challenging; (3) It's a challenging job; can I keep up? CONCLUSIONS: Older nurses love nursing and have created an identity around their profession. They view their profession positively and believe their job to be unlike any other, yet they identify many ongoing challenges and changes. Despite their desire to continue in their role they are often faced with hardships that threaten their ability to stay at the bedside. A key role of hospital administrators to keep older nurses in the workplace is to develop programs to prevent work related illness and to promote health. Given the low ConQual scores in the current systematic review, additional research is recommended to understand the older nurses' experience in providing direct care in hospital nursing units as well as predicting health age of retirement and length of bedside nursing. PMID- 29521869 TI - The impact of the Helping Babies Survive program on neonatal outcomes and health provider skills: a systematic review. AB - OBJECTIVE: The objective of this review was to evaluate the impact of the Helping Babies Survive program on neonatal outcomes and healthcare provider knowledge and skills. INTRODUCTION: The Helping Babies Survive program consists of three modules: Helping Babies Breathe, Essential Care for Every Baby, and Essential Care for Small Babies. It was developed to reduce preventable newborn deaths through skill-based learning using simulation, learning exercises, and peer-to peer training of healthcare providers in low-resource areas. Despite the widespread increase in healthcare provider training through Helping Babies Survive and the growing number of studies that have been conducted, there has been no systematic review of the Helping Babies Survive program to date. INCLUSION CRITERIA: The review included studies on healthcare providers and/or birth attendants providing essential neonatal care during and post birth. Types of interventions were any Helping Babies Survive module (Helping Babies Breathe, Essential Care for Every Baby, Essential Care for Small Babies). Studies including experimental study designs with the following outcomes were considered: neonatal outcomes and/or healthcare provider knowledge and skills obtained, maintained, and used over time. METHODS: PubMed, Embase, Web of Science, ProQuest Databases, Scopus and CINAHL were searched for published studies in English between January 2010 to December 2016. Critical appraisal was undertaken by two independent reviewers using standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). Conflicts were solved through consensus with a third reviewer. Quantitative data were extracted from included studies independently by two reviewers using the standardized data extraction tool from JBI. Conflicts were solved through consensus with a third reviewer. Quantitative data was, where possible, pooled in statistical meta-analysis using RevMan (Copenhagen: The Nordic Cochrane Centre, Cochrane). Where statistical pooling was not possible the findings have been reported narratively. RESULTS: A total of 17 studies were identified - 15 on Helping Babies Breathe (n = 172,685 infants and n = 2,261 healthcare providers) and two on Essential Care for Every Baby (n = 206 healthcare providers). No studies reported on Essential Care for Small Babies. Helping Babies Survive was found to significantly reduce fresh stillbirth rates and first day mortality rates, but was not found to influence stillbirth rates or mortality rates, measured at seven or 28 days post birth. Short-term improvements were significant in knowledge and skills scores but not significant in sustainability over time. Additionally, implementation of resuscitations skills in clinical practice related to the Helping Babies Breathe module including drying/stimulation, suction, and bag and mask ventilation did not show a significant increase after training even though the number of fresh stillbirth and first-day mortality rate decreased. CONCLUSIONS: Helping Babies Survive has a significant positive impact on early neonatal outcomes, including fresh stillbirth and first-day mortality primarily through Helping Babies Breathe, but limited conclusions can be drawn about its impact on other neonatal outcomes. While Helping Babies Survive was found to improve immediate knowledge and skill acquisition, there is some evidence that one-time training may not be sufficient for sustained knowledge or the incorporation of key skills related to resuscitation into clinical practice. Continued research on the sustained knowledge and skills is needed to evaluate the long-term impact of the Helping Babies Survive program. PMID- 29521870 TI - The effect of topical medications on radial artery spasm in patients undergoing transradial coronary procedures: a systematic review. AB - OBJECTIVE: The objective of this review was to identify the effectiveness of topical medications on radial artery spasm (RAS) in patients undergoing transradial percutaneous coronary procedures. INTRODUCTION: Percutaneous coronary procedures were traditionally carried out via the femoral artery; however, over the last 20 years there has been a global increase in the number of proceduralists carrying out percutaneous coronary procedures via the transradial approach. Radial artery spasm remains an issue for the transradial approach, potentially leading to procedural failure. Topical medications have been suggested to reduce the occurrence of RAS during transradial percutaneous coronary procedures. INCLUSION CRITERIA: This review considered papers that included participants aged 18 years and over undergoing non-emergency transradial percutaneous coronary procedures. This review considered papers on the utilization of topical medications prior to commencing the transradial approach for percutaneous coronary procedures to reduce RAS. Topical medications were compared to other medications. The primary outcome was the incidence of RAS as assessed by angiography or ultrasound or resistance felt by the operator while manipulating the catheter. Other outcomes of interest included change in radial artery diameter, measured by angiography or ultrasound, change in radial artery patency and side effects of medications administered. Randomized and quasi randomized controlled trials were considered. METHODS: A three-step search strategy was utilized in this review. A search of various databases was carried out followed by a search for unpublished literature between 1989 to January 2017. Only papers published in English were included in the review. Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instrument from the Joanna Briggs Institute (JBI). There was no need for a third reviewer. Quantitative data was extracted from papers included in the review using the JBI data extraction instrument and entered in to RevMan5 (Copenhagen: The Nordic Cochrane Centre, Cochrane). All results were subject to double data entry. Effect sizes were expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals were calculated for analysis. RESULTS: Only three studies involving 697 participants met the inclusion criteria. There was a statistically significant reduction in the incidence of RAS in patients treated with a eutectic mixture of local anesthetics compared to subcutaneous lidocaine (OR 0.26; 95%CI 0.07,0.96). However there were no significant differences in RAS in studies that compared eutectic mixture of local anesthetics and placebo or a combinations of lidocaine with nitroglycerine compared to placebo. CONCLUSIONS: It is difficult to draw a valid conclusion, given the low number of studies, small sample sizes and heterogeneity between the studies. PMID- 29521871 TI - Effectiveness of exercise interventions on physical function in community dwelling frail older people: an umbrella review of systematic reviews. AB - OBJECTIVES: This umbrella review aimed to determine the effectiveness of exercise interventions, alone or in combination with other interventions, in improving physical function in community-dwelling older people identified as pre-frail or frail. INTRODUCTION: Exercise is said to have a positive impact on muscle mass and strength which improves physical function and hence is beneficial for the treatment of frailty. Several systematic reviews discuss the effects of exercise interventions on physical function parameters, such as strength, mobility, gait, balance and physical performance, and indicate that multi-component exercise, including resistance, aerobic, balance and flexibility training, appears to be the best way in which to improve physical function parameters in frail older people. However, there is still uncertainty as to which exercise characteristics (type, frequency, intensity, duration and combinations) are the most effective and sustainable over the long-term. INCLUSION CRITERIA: Participants were adults, 60 years or over, living in the community and identified as pre-frail or frail. Quantitative systematic reviews, with or without meta-analysis that examined the effectiveness of exercise interventions of any form, duration, frequency and intensity, alone or in combination with other interventions designed to alter physical function parameters in frail older people, were considered. The quantitative outcome measures were physical function, including muscular strength, gait, balance, mobility and physical performance. METHODS: An iterative search strategy for ten bibliometric databases and gray literature was developed. Critical appraisal of seven systematic reviews was conducted independently by two reviewers using a standard Joanna Briggs Institute tool. Data was extracted independently by two reviewers using a standard Joanna Briggs Institute data extraction tool and summarized using a narrative synthesis approach. RESULTS: Seven systematic reviews were included in this umbrella review, with a total of 58 relevant randomized controlled trials and 6927 participants. Five systematic reviews examined the effects of exercise only, while two systematic reviews reported on exercise in combination with a nutritional approach, including protein supplementations, as well as fruit and dairy products. The average exercise frequency was 2-3 times per week (mean 3.0 +/- 1.5 times per week; range 1-7 weekly) for 10-90 minutes per session (mean of 52.0 +/- 16.5 mins) and a total duration of 5-72 weeks with the majority lasting a minimum of 2.5 months (mean 22.7 +/- 17.7 weeks). Multi-component exercise interventions can currently be recommended for pre-frail and frail older adults to improve muscular strength, gait speed, balance and physical performance, including resistance, aerobic, balance and flexibility tasks. Resistance training alone also appeared to be beneficial, in particular for improving muscular strength, gait speed and physical performance. Other types of exercise were not sufficiently studied and their effectiveness is yet to be established. CONCLUSIONS: Interventions for pre frail and frail older adults should include multi-component exercises, including in particular resistance training, as well as aerobic, balance and flexibility tasks. Future research should adopt a consistent definition of frailty and investigate the effects of other types of exercise alone or in combination with nutritional interventions so that more specific recommendations can be made. PMID- 29521872 TI - Artemisinin based combination therapy for uncomplicated malaria management among children under five in Cameroon: a best practice implementation project. AB - OBJECTIVE: The aim of this evidence implementation project is to promote evidence based practice in artemisinin-based combination therapy for managing uncomplicated malaria in children under five, thereby improving patient outcomes and resource utilization in the Bali Health District, Cameroon. INTRODUCTION: The burden of disease attributable to malaria has significantly improved in the last three years, however morbidity and mortality risks are still present, especially for children under five. In children with uncomplicated P. falciparum malaria, there is strong evidence to suggest that artemisinin-based combination therapy (ACT) is effective in treating malaria. The World Health Organization has strong recommendations with high-quality evidence guiding practice in the "test, treat and track" approach using microscopy, rapid diagnostics tests and ACTs. METHODS: This evidence implementation project used the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRiP) audit and feedback tool for promoting evidence-based healthcare involving three phases of activity. RESULTS: We compared compliance with best practice recommendations at baseline against a follow-up compliance at four months, following implementation of strategies identified. Compliance rates improved overall by 31% (R: 20-42) for all criteria and sites, with differences noticed between sites. Nineteen barriers were identified, stratified into clinician, community health worker, patient and policy maker related barriers. CONCLUSIONS: Despite existing barriers to evidence implementation, getting research into practice is possible and does improve quality of care. PMID- 29521873 TI - Non-pharmacological fever management for persons living with HIV: a best practice implementation project. AB - OBJECTIVES: The aim of this evidence implementation project was to integrate the best available evidence on non-pharmacological fever and febrile symptom management into nursing practice at the Shanghai Public Health Clinical Centre, China. INTRODUCTION: Fever is challenging for patients with the human immunodeficiency virus (HIV). Guidelines assert that successful non pharmacological fever management should be the standard of care. To introduce evidence into clinical practice, the Department of Infectious Disease of the Shanghai Public Health Clinical Centre implemented a best practice project. METHODS: This evidence implementation project utilized the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRiP) audit and feedback tool. Seven audit criteria were established on the best available evidence. The project was divided into three phases and conducted over five months. RESULTS: Follow-up audits showed significant improvements. The most significant improvements in compliance occurred in the assessment of suitability of external cooling methods (100%), education for nurses (100%) and patients (100%), and monitoring (93%). A moderate increase was noted in the assessment of fluid intake and output volume (73%). A small increase of 30% in compliance was found in hydration support. No changes in compliance were found in assessment of the cause of fever in the HIV-positive population. CONCLUSIONS: This project led to various changes in the unit including a formal assessment of intake and output volume for PLWHs with chronic fever, a formal assessment of some factors related to the "cause of fever", tailored education programs and materials for both nurses and patients. All these changes are now part of routine nursing practice. Further audits will need to be carried out to sustain practice behavior change and monitor areas for further improvements. PMID- 29521874 TI - Stable Fixation and Immediate Weight-Bearing After Combined Retrograde Intramedullary Nailing and Open Reduction Internal Fixation of Noncomminuted Distal Interprosthetic Femur Fractures. AB - With an aging population, treatment of interprosthetic femur fractures continues to pose a challenge to the orthopaedic surgeon. Retrograde intramedullary nailing combined with open reduction internal fixation using a tissue-preserving plating technique was used in our series of 9 patients with noncomminuted, distal femur fractures. No interfragmentary screws, cables, cerclage wires, or supplemental bone grafts of any type were used. Each patient initiated weight-bearing as tolerated after operative intervention. Every fracture healed at an average of 20 weeks (range 18-24 weeks). Use of a lateral locking plate combined with a retrograde intramedullary nailing enables immediate postoperative weight-bearing and stable fixation for patients with interprosthetic femur fractures. PMID- 29521875 TI - Cytokines in uveitis. AB - PURPOSE OF REVIEW: Increasing evidence supports Th17 cells as key mediators of ocular inflammatory disease. Cytokines that are important for the development and pathologic function of these cells are potential therapeutic targets in patients with immune mediated uveitis. This review provides an overview of these cytokines including recent insights about their roles in ocular inflammation from laboratory and clinical studies. RECENT FINDINGS: Interleukin (IL)-6, IL-10, IL 17, IL-22, IL-23 and tumour necrosis factor-alpha (TNFalpha) are cytokines that have been examined for their functional role in uveitis and their relationship to pathologic Th17 cells. Studies in animal models, particularly in experimental autoimmune uveitis (EAU), have been instrumental in studying the role of these cytokines in disease pathogenesis. More recently, studies on aqueous, vitreous and serum from patients with uveitis using flow cytometry and multiplex ELISA bead-based methodologies have provided insights into the contribution of Th17 cells and the related cytokines in ocular inflammatory diseases. The central role of IL-23 in determining the pathologic Th17 fate has made it an effective therapeutic target in systemic diseases such as psoriasis and thereby an attractive potential target for patients with immune-mediated uveitis. SUMMARY: Th17 cells, and their related cytokines, are important inflammatory mediators in autoimmune uveitis. Animal and human studies continue to provide new information to direct development of new cytokine-targeted therapies for patients with uveitis. PMID- 29521876 TI - Antiretroviral Drug Use in a Cross-Sectional Population Survey in Africa: NIMH Project Accept (HPTN 043): Erratum. PMID- 29521877 TI - A Novel Subcutaneous Site of Islet Transplantation Superior to the Liver. AB - BACKGROUND: Islet transplantation is an attractive treatment for patients with insulin-dependent diabetes mellitus, and currently, the liver is the favored transplantation site. However, an alternative site is desirable because of the low efficiency of hepatic transplantation, requiring 2 to 3 donors for a single recipient, and because the transplanted islets cannot be accessed or retrieved. METHODS: We developed a novel procedure of islet transplantation to the inguinal subcutaneous white adipose tissue (ISWAT) of mice and described functional and morphological characteristics of transplanted syngeneic islets. Also, it was determined whether islet allograft rejection in the ISWAT can be prevented by immunosuppressive agents. Furthermore, it was examined whether human islets function when grafted in this particular site of immune-deficient mice. RESULTS: In this site, transplanted islets are engrafted as clusters and function to reverse streptozotocin-induced diabetes in mice. Importantly, transplanted islets can be visualized by computed tomography and are easily retrievable, and allograft rejection is preventable by blockade of costimulatory signals. Of much importance, the efficiency of islet transplantation in this site is superior to the liver, in which hyperglycemia of diabetic recipient mice is ameliorated after transplantation of 200 syngeneic islets (the islet number yielded from 1 mouse pancreas) to the ISWAT but not to the liver. Furthermore, human islets transplanted in this particular site function to reverse diabetes in immune deficient mice. CONCLUSIONS: Thus, the ISWAT is superior to the liver as the site of islet transplantation, which may lead to improved outcome of clinical islet transplantation. PMID- 29521878 TI - Tailored Y-stent on the Secondary Carina for Recurrent Nonanastomotic Posttransplant Left Bronchial Stenosis. PMID- 29521879 TI - Essential Issues for Pregnancy Counseling in Renal Transplant Women. PMID- 29521880 TI - Acute Antibody-mediated Rejection 1 Week After Lung Transplantation Successfully Treated With Eculizumab, Intravenous Immunoglobulins, and Rituximab. PMID- 29521882 TI - Catatonic Stupor in Schizophrenic Disorders and Subsequent Medical Complications and Mortality. AB - OBJECTIVE: Although catatonia can occur secondary to a general medical condition, catatonia itself has been known to lead to various medical compolications. Although case reports on the association of catatonia with subsequent medical complications have been documented, no comprehensive large-scale study has been performed. To investigate specific medical complications after catatonia, we conducted a retrospective cohort study of specific medical complications of schizophrenia patients with catatonia. METHODS: The 1719 schizophrenia inpatients in our study were categorized into two groups: the catatonia group, i.e., those who exhibited catatonic stupor while they were hospitalized, and the noncatatonia group, i.e., those who never exhibited catatonic stupor. Differences between the two groups in the occurrence of subsequent medical complications were examined using linear and logistic regression analyses, and models were adjusted for potentially confounding factors. RESULTS: The catatonia group had an increased risk for mortality (odds ratio = 4.8, 95% confidence interval = 2.0-10.6, p < .01) and certain specific medical complications, i.e., pneumonia, urinary tract infection, sepsis, disseminated intravascular coagulation, rhabdomyolysis, dehydration, deep venous thrombosis, pulmonary embolism, urinary retention, decubitus, arrhythmia, renal failure, neuroleptic malignant syndrome, hypernatremia, and liver dysfunction (all p values < .01, except for deep venous thrombosis, p = .04 in the multiple linear regression analysis). CONCLUSIONS: Catatonic stupor in schizophrenia substantially raises the risk for specific medical complications and mortality. Hyperactivity of the sympathetic nervous system, dehydration, and immobility, which are frequently involved in catatonia, might contribute to these specific medical complications. In catatonia, meticulous care for both mental and medical conditions should be taken to reduce the risk of adverse medical consequences. PMID- 29521881 TI - Combination immunotherapies implementing adoptive T-cell transfer for advanced stage melanoma. AB - Immunotherapy is a promising method of treatment for a number of cancers. Many of the curative results have been seen specifically in advanced-stage melanoma. Despite this, single-agent therapies are only successful in a small percentage of patients, and relapse is very common. As chemotherapy is becoming a thing of the past for treatment of melanoma, the combination of cellular therapies with immunotherapies appears to be on the rise in in-vivo models and in clinical trials. These forms of therapies include tumor-infiltrating lymphocytes, T-cell receptor, or chimeric antigen receptor-modified T cells, cytokines [interleukin (IL-2), IL-15, IL-12, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-alpha, interferon-alpha, interferon-gamma], antibodies (alphaPD 1, alphaPD-L1, alphaTIM-3, alphaOX40, alphaCTLA-4, alphaLAG-3), dendritic cell based vaccines, and chemokines (CXCR2). There are a substantial number of ongoing clinical trials using two or more of these combination therapies. Preliminary results indicate that these combination therapies are a promising area to focus on for cancer treatments, especially melanoma. The main challenges with the combination of cellular and immunotherapies are adverse events due to toxicities and autoimmunity. Identifying mechanisms for reducing or eliminating these adverse events remains a critical area of research. Many important questions still need to be elucidated in regard to combination cellular therapies and immunotherapies, but with the number of ongoing clinical trials, the future of curative melanoma therapies is promising. PMID- 29521883 TI - Residual Symptoms After Treatment for Depression in Patients With Coronary Heart Disease. AB - OBJECTIVE: Depression is associated with an increased risk of mortality in patients with coronary heart disease (CHD). The risk may be reduced in patients who remit with adequate treatment, but few patients achieve complete remission. The purpose of this study was to identify the symptoms that persist despite aggressive treatment for depression in patients with CHD. METHODS: One hundred twenty-five patients with stable CHD who met the DSM-IV criteria for a moderate to-severe major depressive episode completed treatment with cognitive behavior therapy, either alone or combined with an antidepressant, for up to 16 weeks. Depression symptoms were assessed at baseline and after 16 weeks of treatment. RESULTS: The M (SD) Beck Depression Inventory scores were 30.0 (8.6) at baseline and 8.3 (7.5) at 16 weeks. Seventy seven (61%) of the participants who completed treatment met remission criteria (Hamilton Rating Scale for Depression <=7) at 16 weeks. Loss of energy and fatigue were the most common posttreatment symptoms both in remitters (n = 44, 57%; n = 34, 44.2%) and nonremitters (n = 42, 87.5%; n = 35, 72.9%). These symptoms were not predicted by baseline depression severity, anxiety, demographic, or medical variables including inflammatory markers or cardiac functioning or by medical events during depression treatment. CONCLUSIONS: Fatigue and loss of energy often persist in patients with CHD even after otherwise successful treatment for major depression. These residual symptoms may increase the risks of relapse and mortality. Development of effective interventions for these persistent symptoms is a priority for future research. PMID- 29521884 TI - Childhood Trauma, Perceived Stress, and Hair Cortisol in Adults With and Without Cardiovascular Disease. AB - OBJECTIVE: Childhood trauma has been associated with greater psychological and physical morbidity, including a greater risk of developing cardiovascular disease (CVD). This may partially reflect trauma-induced disturbances in how stress is later perceived and regulated. This study evaluated the associations of childhood trauma with perceived stress and hair cortisol concentrations (HCC) in a large sample of adults with coronary artery disease (CAD) and in non-CVD patients experiencing other nonfatal illnesses. Whether sex, age, or CVD status influenced these associations was also examined. METHODS: A total of 1124 men and women (aged 65.2 [6.9] years) recruited from a hospital cohort completed the Childhood Trauma and Perceived Stress Questionnaires, whereas hair samples were obtained from 598 participants. Health status was confirmed via medical records. RESULTS: Moderate to severe childhood trauma was experienced by 359 participants. Childhood trauma was associated with greater perceived stress levels for the past 2 years (r = .308, p = .01; beta = 0.263, p < .001), but not 3-month cortisol secretion in hair. Perceived stress correlated negatively with age (r = -.241, p < .001). In secondary analyses, age moderated the relation between sexual abuse and perceived stress (beta = -0.067, p = .016). Although sexual abuse was associated with greater levels of perceived stress among all participants, this relation was strongest in younger individuals. CONCLUSIONS: Participants who experienced trauma in their youth reported greater levels of perceived stress, but not HCC, in late adulthood. Whether this suggests intact hypothalamic pituitary-adrenal regulation in those exposed to childhood trauma or whether this reflects the characteristics of our sample requires further investigation. PMID- 29521886 TI - Message from the Editor. PMID- 29521885 TI - The Use of Smartphones as a Digital Security Blanket: The Influence of Phone Use and Availability on Psychological and Physiological Responses to Social Exclusion. AB - OBJECTIVE: Mobile phones are increasingly becoming a part of the social environment, and when individuals feels excluded during a socially stressful situation, they often retreat to the comfort of their phone to ameliorate the negativity. This study tests whether smartphone presence does, in fact, alter psychological and physiological responses to social stress. METHODS: Participants (N = 148, 84% female, mean age = 20.4) were subjected to a peer, social-exclusion stressor. Before exclusion, participants were randomized to one of the following three conditions: (1) phone-present with use encouraged, (2) phone-present with use restricted, or (3) no phone access. Saliva samples and self-report data were collected throughout the study to assess salivary alpha amylase (sAA), cortisol, and feelings of exclusion. RESULTS: Participants in both phone-present conditions reported lower feelings of exclusion compared with individuals who had no access to their phone (F(2,143) = 5.49, p = .005). Multilevel modeling of sAA responses revealed that the individuals in the restricted-phone condition had a significantly different quadratic trajectory after the stressor compared with the phone use (upsilon = -0.12, z = -2.15, p = .032), and no-phone conditions (upsilon = -0.14, z = -2.64, p = .008). Specifically, those in the restricted phone condition showed a decrease in sAA after exclusion, those in the no-phone condition showed a gradual increase, and phone users exhibited little change. Cortisol responses to the stressor did not vary by condition. CONCLUSIONS: Taken together, these results suggest that the mere presence of a phone (and not necessarily phone use) can buffer against the negative experience and effects of social exclusion. PMID- 29521887 TI - Effects of Team-Based Learning on the Core Competencies of Nursing Students: A Quasi-Experimental Study. AB - BACKGROUND: An important goal of nursing education is helping students achieve core competencies efficiently. One proposed way of improving nursing education is team-based learning (TBL). PURPOSE: The aim of this study was to assess the comparative effectiveness of TBL and lecture-style classes in terms of teaching core competencies in nursing education, which include clinical competence skills, problem-solving ability, communication competencies, critical thinking ability, and self-leadership. METHODS: This quasi-experimental study enrolled 183 students as participants, with 95 and 88 in the experimental and control groups, respectively. These two groups attended 6 hours (2 hours weekly for 3 weeks) of TBL and lecture-style classes, respectively. Differences in core competencies between the two groups were compared before and after the intervention. RESULTS: The experimental group achieved significantly higher scores for clinical competence skills, communication competence, critical thinking ability, and self leadership at posttest than at pretest, whereas the control group achieved significantly higher scores for clinical competence skills and critical thinking ability at posttest than at pretest. After the intervention, the experimental group had significantly better clinical competence skills, communication competence, and self-leadership than the control group. CONCLUSION: TBL is an effective approach method to teaching core competencies in nursing education. PMID- 29521888 TI - Assessment of Low-Grade Meniscal and Cartilage Damage of the Knee at 7 T: A Comparison to 3 T Imaging With Arthroscopic Correlation. AB - OBJECTIVES: The aim of this study was to compare the assessment of low-grade meniscal tears and cartilage damage in ultrahigh-field magnetic resonance imaging (MRI) at 7 T to routine clinical MRI at 3 T. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from each patient. Forty-one patients with suspected meniscal damage or mild osteoarthritis (Kellgren-Lawrence score, 0-2) received 7 T as well as routine clinical 3 T consecutively. The imaging protocol at both field strengths consisted of PD-weighted imaging with more than doubled resolution at 7 T. Images were read blinded regarding field strength and patient characteristics by 3 readers with different experience in musculoskeletal MRI (3 years, 6 years, and 10 years) according to a modified whole-organ MRI score of the knee in osteoarthritis and the Score of the International Cartilage Repair Society. Arthroscopic reports as a criterion standard were available for 12 patients. A multifactorial mixed model analysis was performed. RESULTS: The mean cumulated diagnostic score at 7 T was significantly closer to the criterion standard compared with 3 T in patients where criterion standard was available (P < 0.001). In all 41 patients, the damages were rated more severely at 7 T reflected by a mean higher cumulative score in cartilage (P < 0.001) and in the meniscus (P < 0.001). No difference in interreader variability between 3 T and 7 T was observed. Imaging acquisition time was nearly identical. CONCLUSIONS: Morphologic imaging of cartilage and meniscal damage of the knee in ultrahigh-field MRI at 7 T with PD-weighted TSE sequences seemed to have a significantly higher diagnostic accuracy than 3 T and can be performed with equal acquisition times while exploiting higher resolution of 7 T. PMID- 29521889 TI - Editorial. PMID- 29521890 TI - Neuroanesthesiology Update. AB - We provide a synopsis of innovative research, recurring themes, and novel experimental findings pertinent to the care of neurosurgical patients and critically ill patients with neurological diseases. We cover the following broad topics: general neurosurgery, spine surgery, stroke, traumatic brain injury, monitoring, and anesthetic neurotoxicity. PMID- 29521891 TI - 2017 SNACC Annual Meeting Report. PMID- 29521892 TI - Provider Reimbursement Following the Affordable Care Act. AB - Decreasing health care expenditures has been one of the main objectives of the Affordable Care Act. To achieve this goal, the Centers for Medicare and Medicaid Services (CMS) has been tasked with experimenting with provider reimbursement methods in an attempt to increase quality, while decreasing costs. The purpose of this research was to study the effects of the Affordable Care Act on physician reimbursement rates from CMS to determine the most cost-effective method of delivering health care services. The CMS has experimented with payment methods in an attempt to increase cost-effectiveness. Medicare has offered shared cost savings incentives to reward quality care to both primary care providers and preventative services. The CMS has determined fee-for-service payments obsolete, opting instead for a value-based purchasing method of payment. Although a universal payment method has yet to be adopted, it has been evident that a value based purchasing model and preventative care can be used to decrease health care expenditure. PMID- 29521893 TI - Theory X/Y in the Health Care Setting: Employee Perceptions, Attitudes, and Behaviors. AB - Douglas McGregor's conceptualization of Theory X and Theory Y has influenced management practices for almost six decades, despite the relative paucity of empirical support. This empirical study examined the relationships between health care employees' perceptions of (1) manager Theory Y and Theory X orientations; (2) work unit psychological safety, organizational citizenship behavior, and service quality; and (3) the employing entity. The study used survey data from more than 3500 employees of a large US health care system and analyzed them using confirmatory factor and hierarchical regression analyses. Results indicate that McGregor's conceptualization is best considered as two separate constructs-Theory Y and Theory X-rather than as one-dimensional X/Y construct. This study's three dependent variables were positively related to Theory Y and negatively related to Theory X, with larger Theory Y effect sizes. Psychological safety partially mediated the relationship between Theory Y and the dependent variables Y. Practical implications are presented. PMID- 29521894 TI - The Challenges of Leadership. AB - Perhaps in no other period in recent times have the challenges leaders face been so profound. In these times of uncertainty and turbulence, we look to leaders who create a sense of purpose, who generate feelings of trust and optimism, and who tap the passion, talent, and efforts of those so essential to the success of the organization and of the people it serves. Our research suggests that becoming the leader whom people look to and admire requires an active commitment to responding to 5 essential leadership challenges. These are (1) creating a sense of purpose, (2) devising means for aligning the actions of the followers with that sense of purpose, (3) establishing a context that enables others to behave in a way that is consistent with the vision and values of the organization, (4) ensuring that the work that is done provides meaning to those engaging in the work activities, and (5) adding to the sum of everyone's knowledge through learning through reflective actions. In this article, we describe these challenges and offer suggestions that you can take to become a more effective and respected leader. PMID- 29521895 TI - Challenges of Vaccinations in the Era of New Media Communication. AB - Active discussions are underway on whether or not the absence or insufficiency of communication is a decisive factor affecting hesitancy with regard to vaccines. Low-quality services such as insufficient communication can lead to an increase in the population postponing vaccinations in countries without deficiencies in vaccine procurement. This study examines the strategies and tasks of health communication in relation to vaccinations. Social networking services (SNSs) are major channels of health communication in responding to infectious diseases. New videos posted on the Internet attract considerable amounts of attention from SNS users and increase traffic to certain Web sites. However, most of these videos are produced and uploaded by nonexperts. Although medical institutions have striven to convey key messages concerning infectious diseases to the public, in the SNS space, contents differing from scientific evidence acknowledged as the established theory have been disseminated as well. Social networking services can also amplify any unnecessary anxiety about infectious diseases. In addition, as false information about vaccines is circulated or conflicting information surfaces, the confusion of the general public is aggravated and the phenomenon of vaccine hesitancy can be intensified. Therefore, it is necessary to improve vaccination acceptance through strategies that integrate new and old media. At the same time, we need to establish customized public health education for the public, vulnerable groups, and experts. PMID- 29521896 TI - 12-Hour Shifts: A Call for Action. PMID- 29521897 TI - NCF @ Work. PMID- 29521898 TI - Unity in Diversity Through Six Regions. PMID- 29521899 TI - Etc. PMID- 29521900 TI - Responding to Questions About the After-Life. PMID- 29521901 TI - Educating Advanced Practice Nursing Students' Toward Ethical Behaviors. PMID- 29521902 TI - Nursing in the Church. PMID- 29521903 TI - Student TXT. PMID- 29521904 TI - Point-Counterpoint: Narcan Saves Lives, But Does It Make Nurses Enablers? PMID- 29521905 TI - Treatment and Spiritual Care in Mental Health: Recovery As a Journey, Not a Destination. AB - Recovery in mental illness is a person-oriented process that involves self determination/choice, and growth potential. This article discusses eight components of recovery-oriented treatment, and how nurses in any setting can facilitate recovery and encourage the healthy role of spirituality in clients' lives during the recovery process. Biblical references relating to each component of the recovery-oriented process are offered. PMID- 29521906 TI - Integrative Music Therapy: A Healing Intervention. AB - Music plays a significant role in the lives of individuals across the lifespan. Some healthcare providers may not appreciate music therapy and the positive benefits it can have on the environment, patients, caregivers, and healthcare staff. Integrative Music Therapy (IMT) has proven to be effective in multiple settings, offering therapy for behavioral, emotional, physiological, psychological, and psychosocial needs. IMT, performed by a trained, certified professional (MT-BC), does not seek to replace medication or other procedures, but works synergistically with provided healthcare. PMID- 29521907 TI - Stifled Learning: Nursing Students' Experience of Incivility in Clinical Education. AB - Incivility is of great concern in nursing, yet little is known about nursing students' encounters with incivility during clinical education. The lived experience of nursing students who encountered uncivil acts (n = 12) was explored through narrative interviews. Themes describing incivility emerged, including covert criticism and open shaming. Students experienced emotional and physical turmoil, and mixed messages that created a paradox. Further research is needed to understand components of incivility and the negative remnants left by uncivil encounters on nursing students. PMID- 29521908 TI - An Innovative Role for Faith Community Nursing: Palliative Care Ministry. AB - Although the specialty of palliative nursing and palliative care continues to grow in hospital and outpatient settings, a paucity of home-based palliative services remains. This article discusses a new paradigm of faith-based palliative care ministry using faith community nurses (FCNs). Under the leadership of a palliative care doula (a nurse expert in palliative care), nurses in the faith community can offer critical support to those with serious illness. Models such as this provide stimulating content for FCN practice and opportunity to broaden health ministry within faith communities. PMID- 29521909 TI - Power in the Blood: Local Lifesaving Partnerships Between Churches and the American Red Cross. AB - Community blood drives provide a significant quantity of the donated blood needed in the U.S. annually. The American Red Cross collaborates with thousands of blood drive sponsors to make donating easier for individuals. Faith community nurses (FCNs) can promote blood donation by involving churches as sponsors for blood drives. This article shares details on the partnership of the Red Cross and a host church; church member statements about motivation to donate, as well as inability to participate, further inform FCNs. PMID- 29521910 TI - Is Self-Esteem Part of Spiritual Care? PMID- 29521911 TI - Students Learn Curando el Cuerpo-Curando el Alma: Healing the Body-Healing the Soul. PMID- 29521912 TI - Helping Patients Process Bad News. PMID- 29521913 TI - Chat Room. PMID- 29521914 TI - PulseBeats. PMID- 29521915 TI - Student Perceptions of Spirituality and Spiritual Care. AB - Nurse educators must equip students with beginning skills of assessment, communication, and awareness of spiritual care. Barriers to spiritual care-lack of time or of space, inadequate training-reduce nurses' provision of spiritual care. Nursing students observe patient needs for spiritual care, but often are not skilled or comfortable offering spiritual care. This article relays observations of 28 senior nursing students about spirituality and spiritual care with implications for teaching. PMID- 29521916 TI - Journeys to Jamaica: A Healthy Dose of Culture, Competence, and Compassion. AB - Nurse practitioner and doctor of nursing practice students gain cultural awareness and primary care experience on biannual medical mission trips to Jamaica. Faith-based Molloy College's partnership with professional medical volunteers enables students to apply clinical skills, express compassion, and gain interprofessional experience. Volunteers provide care and education for the high prevalence of noncommunicable conditions found in Jamaica. The program enjoys a positive relationship with Jamaica's Ministry of Health; a research study will assess impact on students and patients. PMID- 29521918 TI - Treatment and Spiritual Care in Mental Health: Recovery As a Journey, Not a Destination. PMID- 29521917 TI - Authentic Leadership: Practices to Promote Integrity. AB - Integrity is a highly desired leadership trait. Authentic leaders reflect on their behavior and seek feedback about how their actions affect others. How can a nurse develop as an authentic leader who consistently demonstrates integrity? The following are discussed: Reflection; Connection to Christ and others; Social and Emotional Intelligence providing perceptive competency and social awareness; Aesthetic Qualities whereby leaders apply experiential knowing in leadership situations; and effective expression of Gratitude as a meaningful act of valuing others. PMID- 29521919 TI - An Innovative Role for Faith Community Nursing: Palliative Care Ministry. PMID- 29521920 TI - Context for Practice: Pressure Injury Prevention: The Struggle Continues. PMID- 29521921 TI - Treatment of Dehisced, Thoracic Neonatal Wounds With Single-Use Negative Pressure Wound Therapy Device and Medical-Grade Honey: A Retrospective Case Series. AB - PURPOSE: The purpose of this study was to report on our experience with a portable, single-use negative pressure wound therapy device used in combination with activated active Leptospermum honey (ALH) in the treatment of colonized or infected, dehisced, thoracic wounds in neonates with complex congenital heart disease. DESIGN: Retrospective, descriptive study. SUBJECTS AND SETTING: We reviewed medical records of 18 neonates and reported on findings from 11; the remaining 7 were not included secondary to incomplete records, transfer to a different institution prior to wound healing, or death. The median age of our patients was 12 days (range, 2 days to 5 weeks); their mean gestational age was 34 weeks. All of the neonates had acquired postoperative wound dehiscence that were colonized or infected and were treated in the neonatal intensive care unit (NICU) at Cohen Children's Medical Center (New Hyde Park, New York), a regional perinatal center with a level 4 NICU. METHODS: Wound cultures were obtained on all patients prior to treatment commencement. All cultures were repeated on day 4 of treatment. Systemic antibiotics were administered as necessary. No complications were observed related to the use of negative pressure wound therapy device and ALH. All patients were followed until discharge home or transfer to another facility. The pain scores during placement and removal were acceptable (between 1 and 3; median = 2) using the Neonatal Infant Pain Scale. Staff and parents indicated that the combination of ALH and the negative pressure wound therapy device did not interfere with daily care and parental bonding. CONCLUSIONS: Use of ALH and a single-use negative pressure wound therapy device was successful in this series of 11 neonates with complex congenital heart disease. PMID- 29521922 TI - The Effect of Foot Exercises on Wound Healing in Type 2 Diabetic Patients With a Foot Ulcer: A Randomized Control Study. AB - PURPOSE: The purpose of this study was to investigate the effect of foot exercises on wound healing in type 2 diabetic patients with a diabetic foot ulcer. DESIGN: Prospective, randomized controlled study. SUBJECT AND SETTINGS: Sixty-five patients from an outpatient clinic with grade 1 or 2 ulcers (Wagner classification) who met study criteria agreed to participate; 60 patients completed the study and were included in the final analysis. Subjects were followed up between February 2014 and June 2015. METHODS: Subjects were recruited by the researchers in the clinics where they received treatment. Subjects were randomly allocated to either the control or intervention group. Data were collected using investigator-developed forms: patient information form and the diabetic foot exercises log. Patients in the intervention group received standard wound care and performed daily foot exercises for 12 weeks; the control group received standard wound care but no exercises. The ulcers of the patients in both the intervention and control groups were examined and measured at the 4th, 8th, and 12th weeks. The groups were compared in terms of the ulcer size and depth. To analyze and compare the data, frequency distribution, mean (standard deviation), variance analysis, and the independent samples t test and the chi test were used. RESULTS: The mean ulcer areas were 12.63 (14.43), 6.91 (5.44), 4.30 (3.70), and 3.29 (3.80) cm (P < .05) in the study intervention group, and 24.67 (20.70), 24.75 (20.84), 20.33 (20.79), and 18.52 (21.49) cm in the control group in the 4th, 8th, and 12th weeks, respectively. Significant differences were found between diabetic foot ulcer sizes in the study intervention group in the 4th and 12th weeks compared to beginning baseline (P <= .05). However, only the 12th week was different from the beginning in the control group (P = .000). The mean depths of the ulcers were 0.56 (0.85), 0.42 (0.68), 0.36 (0.50), and 0.28 (0.38) cm in the study intervention group (P < .05) and 0.61 (0.84), 0.82 (1.07), 0.83 (1.21), and 0.80 (1.26) cm in the control group, respectively, at the baseline, and at the 4th, 8th, and 12th weeks, respectively (P = .000). CONCLUSION: The ulcer areas decreased significantly in the study intervention group compared to the control group during the 3 follow-up measurements. An important finding in this study was the DFU area decreased more in those who exercised more. Findings suggests foot exercises should be included in the treatment plan when managing patients with diabetic foot ulcers. PMID- 29521923 TI - Predictors of Pressure Injuries in a Critical Care Unit in Lebanon: Prevalence, Characteristics, and Associated Factors. AB - PURPOSE: The purpose of this study was to identify factors associated with pressure injury in a medical-surgical intensive care unit (MSICU). DESIGN: Retrospective review of medical records. SUBJECTS AND SETTING: We reviewed the medical records of 145 patients who developed a new pressure injury in the MSICU of a 420-bed university medical center in Lebanon. METHODS: Medical records of all patients cared for in the MSICU from December 2014 to June 2017 were reviewed by a research assistant using a standardized form. We extracted potential risk factors for pressure injury including sex, age, weight upon admission, weight at discharge, length of MSICU stay, episodes of hypotension, administration of inotropes/vasopressors, admitting diagnosis, comorbid conditions, and cumulative scores on the Braden Scale for Pressure Sore Risk. The outcome variable was development of any new pressure injury during their stay in our intensive care unit. RESULTS: Forty-nine patents (33.7%) developed a new pressure injury. Bivariate analysis found statistically significant associations between pressure injury occurrences and administration of vasopressors (odds ratio [OR] = 0.42; 95% confidence interval = 0.29-0.87; P = .02), the administration of dopamine (OR = 0.20; 95% confidence interval = 0.04-0.94; P = .04), and hospital-acquired pressure injury. Among the continuous variables, analysis revealed significant relationships between weight at discharge (t = 2.31, P = .02), MSICU length of stay (t = 5.30; P = .000), cumulative Braden Scale score (t = 3.06; P = .002), hypotension (t =-2.74; P = .007), and development a new pressure injury. Multivariate analysis indicated that length of stay (beta= -.110; P = .002), administration of vasopressors (beta=-.266; P = .029), and total hours of hypotension (beta=-.53; P = .041) were significant predictors of pressure injury. CONCLUSIONS: Vasopressor use, hypotension, and length of stay were associated with an increased likelihood of pressure injury in adults managed in an MSICU. None of these factors is specifically evaluated during completion of the Braden Scale for Pressure Sore Risk. Based on these findings we recommend development of a pressure injury scale specific to critically ill adults. PMID- 29521924 TI - Decreasing Incidence of Medical Device-Related Pressure Injuries in a Small Community Hospital: A Quality Improvement Project. AB - One-third of hospital-acquired pressure injuries are related to medical devices. The purpose of this quality improvement project was to create an evidence-based guideline in one acute care hospital setting for the prevention of medical device related pressure injuries (MDRPIs) and to implement the hospital-wide use of a new nasogastric tube securement device to offload pressure to the nares. The first phase of this project comprised development of a guideline along with multiple education opportunities. The second phase of this project consisted of evaluation and subsequent conversion to a new nasogastric tube securement device. This project led to reduced MDRPI incidence rates over the past 12 months. PMID- 29521925 TI - Prevention of Pressure Injuries in the Operating Room: A Quality Improvement Project. AB - Prevention of hospital-acquired pressure injuries (HAPIs) remains a crucial clinical challenge especially for those patients undergoing surgery. The purpose of this project was to examine whether a 5-layer silicone foam dressing applied to the sacrum of patients undergoing vascular surgery decreased the occurrence of sacral pressure injuries and to explore participant characteristics associated with the development of operating room (OR)-related pressure injuries. A pre /postintervention design, quality improvement project in a convenience sample of 81 patients undergoing vascular surgery, in a 700-bed level I trauma acute care setting, in the Northeastern United States. Eighty-one patients undergoing vascular surgery participated in this project. Thirty-seven were in the preintervention group who were identified from the housewide pressure injury prevalence data from May and December 2010 and received standard pressure injury prevention while hospitalized. Forty-four patients in the intervention group were identified from a hospital-based outpatient vascular surgery office and preoperatively received the 5-layer silicone foam dressing in addition to standard care. Data were collected on the third and seventh postoperative days via the electronic medical record and paper medical records. Collected data included age, gender, comorbidities (diabetes, hypertension, peripheral vascular disease and, smoking status), presence of a 5-layer silicone sacral foam dressing, and pressure injury occurrence. Analysis included descriptive statistics, Fisher exact test to compare groups, and logistic regression to identify associated risk factors. More than 50% (n = 19) in the preintervention group developed a hospital-acquired pressure injury while only 1 subject (n = 2%) in the intervention group developed a hospital-acquired pressure injury (P = .000). Findings indicate that, after controlling for age, gender, and other comorbidities, application of a 5-layer silicone sacral foam dressing significantly reduced the likelihood of development of a new pressure injury (OR= 0.04, 95% confidence interval, 0.00-40; P = .006). This pre-/postquality improvement project, using a 5-layer silicone sacral foam dressing in addition to standard operating room pressure injury preventive interventions, for elective vascular surgical cases, resulted in a significant decrease in sacral operating room-related pressure injuries. These findings suggest the effectiveness of a 5 layer silicone foam dressing when added to standard preventive interventions. The findings warrant further investigation of additional preventative interventions in the OR specific to high-risk populations. PMID- 29521926 TI - Clinical Evaluation of a Novel Intrarectal Device for Management of Fecal Incontinence in Bedridden Patients. AB - PURPOSE: The primary objective of the study was to evaluate the safety and efficacy of a stool management kit (SMK) for containment of fecal incontinence in hospitalized bedridden patients. DESIGN: A single-group quasi-experimental study. SUBJECTS AND SETTING: Twenty bedridden adults who had at least 1 episode of fecal incontinence in the prior 24 hours participated in the study. The study setting was the neurological unit of the All India Institute of Medical Sciences in New Delhi, India. METHODS: The study was carried out in 2 phases. The device was placed in situ for up to 24 hours in 10 patients during phase I of the study and up to 120 hours in an additional 10 patients during phase II. Participants were assessed for anorectal injury and peripheral device leakage on a 4- to 6-hourly basis. Sigmoidoscopy was performed to evaluate for any mucosal trauma or alteration of anorectal pathology after retrieval of the device. RESULTS: The device was successfully placed in all patients following the first attempt to place the device; 80% of patients retained the device until planned removal. The SMK diverted fecal matter without anal leakage in 174 (93.5%) out of 186 assessment points in a group of 20 patients. The devices remained in situ for 21 +/- 0.2 and 84.5 +/- 38.9 hours during phase I and phase II, respectively. None experienced anorectal bleeding, sphincter injury, or mucosal ulceration with device usage. Post-device sigmoidoscopy revealed erythema at the site of diverter placement in 2 participants. CONCLUSION: Study findings suggest that the SMK successfully diverted liquid to semiformed fecal exudate without peripheral device leakage in 93.5% of bedridden patients. No serious adverse events occurred. Additional research is needed to compare its effectiveness with that of currently available intrarectal balloon devices. PMID- 29521927 TI - Experience of Nurses Caring for Patients With Neurogenic Bowel Dysfunction: A Qualitative Study. AB - PURPOSE: The purpose of this study was to explore the experience and perceptions of nurses providing bowel care to patients after spinal cord injury. DESIGN: Qualitative study using thematic analysis of semistructured interviews. SUBJECTS AND SETTING: Eleven RNs who provided bowel care to patients following spinal cord injury and were deemed competent to do so by their employer were invited to participate. The study setting was a large, London NHS Trust providing acute hospital care to a population of around 1 million people. METHODS: Semistructured interviews were digitally audio-recorded and transcribed verbatim. Analysis of data was undertaken using Braun and Clark's 6 stages of thematic analysis. RESULTS: Four main themes emerged: (1) unpleasantness of task; (2) perceived patient experience; (3) motivation and avoidance; and (4) barriers to care. There was stoic acceptance of the unpleasant nature of bowel care for the nurse, but unpleasantness for patients was not as readily acknowledged. Perceived patient experience ranged from descriptions of positive aspects of comfort and continence to negative aspects of embarrassment and discomfort. Nurses were motivated by the medical need for bowel care but often saw it as low priority due to the unpleasant nature and displayed avoidance tactics. The barriers concerned inadequate training, the taboo nature of bowel care, and potential sexual interpretations of care. CONCLUSION: Nurses described bowel care as unpleasant but accepted its physiologic need and importance. The standardization of bowel care training and increasing the numbers of nurses trained in bowel care may decrease stigma surrounding provision of care. Study findings suggest that male nurses' experience may differ from female nurses' experience, but this result requires further investigation. PMID- 29521928 TI - Factors Associated With Healthcare-Acquired Catheter-Associated Urinary Tract Infections: Analysis Using Multiple Data Sources and Data Mining Techniques. AB - PURPOSE: The purpose of this study was to identify factors associated with healthcare-acquired catheter-associated urinary tract infections (HA-CAUTIs) using multiple data sources and data mining techniques. SUBJECTS AND SETTING: Three data sets were integrated for analysis: electronic health record data from a university hospital in the Midwestern United States was combined with staffing and environmental data from the hospital's National Database of Nursing Quality Indicators and a list of patients with HA-CAUTIs. METHODS: Three data mining techniques were used for identification of factors associated with HA-CAUTI: decision trees, logistic regression, and support vector machines. RESULTS: Fewer total nursing hours per patient-day, lower percentage of direct care RNs with specialty nursing certification, higher percentage of direct care RNs with associate's degree in nursing, and higher percentage of direct care RNs with BSN, MSN, or doctoral degree are associated with HA-CAUTI occurrence. The results also support the association of the following factors with HA-CAUTI identified by previous studies: female gender; older age (>50 years); longer length of stay; severe underlying disease; glucose lab results (>200 mg/dL); longer use of the catheter; and RN staffing. CONCLUSIONS: Additional findings from this study demonstrated that the presence of more nurses with specialty nursing certifications can reduce HA-CAUTI occurrence. While there may be valid reasons for leaving in a urinary catheter, findings show that having a catheter in for more than 48 hours contributes to HA-CAUTI occurrence. Finally, the findings suggest that more nursing hours per patient-day are related to better patient outcomes. PMID- 29521929 TI - Relationships Among Use of Complementary and Alternative Interventions, Urinary Incontinence, Quality of Life, and Self-esteem in Women With Urinary Incontinence. AB - PURPOSE: The purpose of this study was to examine associations among sociodemographic characteristics, urinary incontinence (UI) characteristics, UI specific quality of life and self-esteem, and use of complementary and alternative medicine (CAM) interventions for UI. DESIGN: Correlational descriptive research. SUBJECTS AND SETTING: This sample comprised 394 female patients 18 years or older cared for in the urology and gynecology outpatient clinics of a university hospital in Samsun, Turkey. METHODS: Participants completed an investigator-developed questionnaire that included 2 validated instruments, King's Health Questionnaire (KHQ) and the Rosenberg Self-esteem Scale. Descriptive statistics were used for demographic data and use of CAM interventions. Variables associated with CAM use were assessed using chi analysis. The differences between using CAM and scales points of the KHQ and the Rosenberg Self-esteem Scale were assessed using the t test, and the relationship between the KHQ and the Rosenberg Self-esteem Scale was assessed using correlation analysis. RESULTS: Thirty-three percent (n = 130) of women indicated using CAM interventions to manage their UI. The most common CAM intervention, reported by 52.6% of respondents, was prayer. Women with lower UI-specific quality of life and self-esteem scores were more likely to report using CAM interventions (P < .05). Women with lower education level used CAM more frequently than others (P < .05). Analysis revealed weak but statistically significant positive correlations for role limitations, physical limitations, social limitations, emotions, sleep/energy level and the symptom severity (P < .001), and personal relationships (P < .01) subdimensions of the KHQ. CONCLUSIONS: One-third of women indicated using CAM methods to manage their UI; the most commonly used intervention was prayer. Women using CAM reported both higher self-esteem and condition-specific health-related quality of life than women who did not use these interventions. PMID- 29521930 TI - When and How to Perform Cultures on Chronic Wounds? AB - PURPOSE: The purpose of this Evidence-Based Report Card was to examine current best evidence related to when and how to perform cultures on chronic wounds to guide clinicians in determining the appropriate treatment. QUESTION: (1) When should cultures be performed on chronic wounds? and (2) What is the best method or technique to perform a culture on a chronic wound? SEARCH STRATEGY: A search of the literature was performed, resulting in 45 publications relevant to the topic. Following a review of titles and abstracts, 7 studies were identified that met inclusion criteria. Key search terms used were "chronic wound," "chronic infected wound," "wound culture," "specimen collection," and "wound swab." Strength of the evidence was rated based on the methodology from Essential Evidence Plus: Levels of Evidence and Oxford Center for Evidence-Based Medicine, adapted by Gray and colleagues. FINDINGS: Seven studies were identified as pertinent to the topic on wound culture and meeting inclusion criteria. The study designs included 1 randomized controlled trial, 1 quasi-experimental comparative study, 1 systematic review, 1 scoping literature review, 1 integrative literature review, and 2 professional organization expert panel reviews (consensus statement and position statement). Of the 7 studies, 3 studies suggest that classic signs of infection may not always be present but culturing may be indicated when additional signs such as pain, necrotic tissue, prolonged or delayed healing, and wound bed deterioration occur. Four studies report that a quantitative culture of wound tissue is the gold standard to obtain a wound culture, but the swab method is an acceptable alternative option. Two articles demonstrate the Levine technique is more reliable than the Z-technique to determine microbial load in the wound bed. The strength of the evidence was identified as 2 level A studies, 1 level B study, and 4 level C studies. Using Johns Hopkins methodology, the quality of the studies was deemed either high quality or good quality. CONCLUSION/RECOMMENDATION: Evidence indicates that identification of potential chronic wound infection should be considered early using clinical signs such as pain, necrotic tissue, delayed healing, and wound deterioration (in addition to classic signs of infection) to determine the need for collecting a culture (Strength of Recommendation Taxonomy [SORT] level 2); and when a culture is deemed necessary, swab culture using the Levine method is a clinically practical alternative if performed correctly (SORT level 1). PMID- 29521933 TI - Getting Ready for WOCNCB Foot Care Certification: Understanding Nail Terminology. PMID- 29521935 TI - Molding Spica Casts to Maintain Alignment of Femur Fractures. AB - BACKGROUND: Femur fractures in young children are frequently treated with spica casting. Texts recommend molding spica casts into valgus and recurvatum to counter deforming muscular forces, but how much overcorrection to aim for has not been evaluated. Our goal was to determine how much valgus and recurvatum is optimal at the time of casting to end up with anatomic alignment. METHODS: Patients 1 to 6 years old with femur fractures treated with spica casts between January 1, 2008 and January 31, 2014 who were followed until radiographic union were included in the study. Patients with underlying medical comorbidities affecting bone quality, refractures, or preexisting femur deformities or that did not have intraoperative imaging were excluded. RESULTS: A total of 52 patients met the inclusion criteria. Average intraoperative angulation was 2.6 degrees of valgus (range: 9 degrees varus to 13 degrees valgus, SD: 4.5) and 1.1 degrees of recurvatum (range: 10 degrees recurvatum to 17 degrees procurvatum, SD: 4.8). At the initial postoperative visit, the average angulation was 2.7 degrees of varus (range: 21 degrees varus to 11degrees valgus, SD: 6.4) and 7.2 degrees of procurvatum (range: 6 degrees recurvatum to 25 degrees procurvatum, SD: 6.6). At the time of radiographic union/wedging average angulation was 2.0 degrees of varus (range: 15 degrees varus to 10 degrees valgus, SD: 5.8) and 8.5 degrees of procurvatum (range: 5 degrees recurvatum to 29 degrees procurvatum, SD: 7.5). Between the intraoperative period to time of union or wedging, fracture alignment gained an average of 4.6 degrees of varus (range: 17 degrees varus to 13 degrees valgus, SD: 6.6) and 9.8 degrees of procurvatum (range: 8 degrees recurvatum to 30 degrees procurvatum, SD: 9.1). Seven patients underwent cast wedging due to loss of reduction before radiographic union, 2 patients underwent reoperation due to excessive angulation in the early postoperative period, and 5 patients developed malunions. CONCLUSION: Femur fractures treated with spica casts gain 5 degrees of varus and 10 degrees of procurvatum between cast application and fracture union. LEVEL OF EVIDENCE: Level IV. PMID- 29521936 TI - Quantifying the Location of the Radial Nerve in Children for Intraoperative Use. AB - BACKGROUND: In adults, a relative "safe zone" for lateral approaches to the elbow has been well described in efforts to reduce iatrogenic injury, typically a minimum of 6 cm proximal to the lateral epicondyle. To avoid iatrogenic injury to the radial nerve intraoperatively, we investigated the distance of the nerve from the distal humeral physis in children. METHODS: All patients who had axial and coronal T1-weighted magnetic resonance imagings of the humerus and elbow between 2005 and 2015 were eligible. Patients were excluded if there was any pathology causing significant alteration to the normal anatomy of the distal humerus or surrounding soft tissue. The axial cut in which the radial nerve was positioned along a line passing through the center of the humerus in the transverse plane was identified, and the location of the nerve was marked. This axial cut was cross-referenced with the corresponding coronal view. The distance along the lateral edge of the humerus in a straight line from the marked location of the radial nerve to the distal humeral physis was measured. RESULTS: In total, 21 magnetic resonance imagings of 20 patients met the inclusion criteria. The mean distance of the radial nerve proximally from the distal humeral physis was as follows by age group: below 1-year old=1.7 cm (range, 1.2 to 2.5 cm); 1 to 2 years old=2.8 cm (range, 1.8 to 3.2 cm); 4 to 5-years old=5.3 cm (range, 5.1 to 5.5 cm); 6-years old and above=7.3 cm (range, 6.0 to 9.2 cm). For below 6-years old, when age was multiplied by 1 cm to define a predicted safe zone all radial nerves were found proximal to this. All patients 6 years and above had measurements that fell into the adult range of >6 cm, whereas no patients below 6 years old had measurements in this range. CONCLUSIONS: The distance of the radial nerve proximally from the distal humeral physis can be safely approximated for children below 6 years of age by multiplying patient age in years by 1 cm. By the age of 6 the distance of the radial nerve falls within the adult range (>6 cm). LEVEL OF EVIDENCE: Level III. PMID- 29521937 TI - Intraoperative Traction May Be a Viable Alternative to Anterior Surgery in Cerebral Palsy Scoliosis >=100 Degrees. AB - BACKGROUND: For large scoliosis, 2 strategies to maximize correction include intraoperative traction and/or anterior release. It is unclear which patients will benefit the most form either approach. The purpose of our study is to compare the radiographic, perioperative clinical outcomes, and health-related quality of life (HRQoL) outcomes of 2 approaches when used in severe neuromuscular scoliosis in the setting of cerebral palsy (CP). METHODS: In total, 23 patients with minimum 2-year follow-up, major curves >=100 degrees, and in whom treatment included posterior spinal fusion were evaluated. Eighteen were treated with posterior spinal fusion with intraoperative traction and 5 with anterior/posterior spinal fusion (APSF). The baseline characteristics, perioperative outcomes, and preoperative and 2-year follow-up data for HRQoL and radiographic measures were compared. RESULTS: The groups had similar age, sex, nutritional and seizure status, GMFCS level, and change in CPCHILD scores. The groups had similar curve magnitude (120 vs. 105 degrees, P=0.330) and flexibility (28% vs. 40%, P=0.090), but the APSF group had less pelvic obliquity (POB) (24 vs. 42 degrees, P=0.009). There were similar postoperative major curves (37 vs. 40 degrees, P=0.350), but greater correction in POB (33.5 vs. 14 degrees of correction, P=0.007) in the traction group. The APSF group had longer anesthesia times (669 vs. 415 min, P=0.005), but similar hospital stays, intensive care unit and days intubated, estimated blood loss, cell saver, and red blood cells used. Although the APSF group had twice the rate of complications (22% vs. 40%) during the first 90 days postoperatively, this did not reach statistical significance. CONCLUSIONS: Both intraoperative traction and anterior surgery were used to aid correction in severe CP scoliosis. Anterior surgery did not offer superior correction or better HRQoL, and was associated with increased operative times, whereas intraoperative traction was associated with greater correction of POB. Intraoperative traction may be a viable alternative to an anterior release in severe CP scoliosis. LEVEL OF EVIDENCE: Level II. PMID- 29521938 TI - The Growth of Trochlear Dysplasia During Adolescence. AB - BACKGROUND: Femoral trochlear dysplasia is a known risk factor for patellar instability. The growth pattern of the normal trochlea is known, but there have been no studies investigating the growth and development of the dysplastic trochlea. The purpose of this study was to assess the growth pattern of trochlear dysplasia in adolescents. METHODS: In a retrospective analysis, magnetic resonance images of adolescents with patellar instability and trochlear dysplasia were evaluated. These images were measured for lateral and medial condylar height, trochlear height, cartilaginous and bony trochlear bump, and cartilaginous and bony sulcus angle. The type of trochlear dysplasia was classified as per Dejour classification. These measurements were plotted against age, and their growth patterns were evaluated using statistical methods. RESULTS: Of 235 knees with patellar instability, trochlear dysplasia was present in 175 knees (74% knees) and these were further analyzed. With increasing age, the mean lateral and medial condylar heights and mean trochlear height showed statistically significant increase (P<0.01). Cartilaginous trochlear bump (slope=0.15, P=0.013) and bony trochlear bump (slope=0.22, P<0.01) increased with age, with some reaching the pathologic value by age of 15.1 years. After age 11 years, there were no significant changes for cartilaginous and bony sulcus angles (cartilage: slope=0.03, P=0.96; bony: slope=-0.90, P=0.11). The mean cartilaginous sulcus angle was significantly greater than the mean bony sulcus angle (P<0.01). All Dejour types of trochlear dysplasia were present across all age groups. CONCLUSIONS: All linear measurements of trochlear dysplasia (condylar height, trochlear height, trochlear bump) increased with age. However, the shape of trochlear dysplasia, as reflected by sulcus angle and Dejour classification, did not change with increasing age. The shape of trochlear dysplasia is most likely a genetic predisposition and does not necessarily change during skeletal growth. LEVEL OF EVIDENCE: Level II-diagnostic, cross-sectional. PMID- 29521939 TI - Quality of Life in Patients With Pancreatic Cancer and Their Caregivers: A Systematic Review. AB - Little is known about quality of life (QOL) of patients with pancreatic cancer and their caregivers compared with adults with other cancers. This systematic review summarizes the available evidence base, identifies its limitations, and recommends directions for research and clinical application. A systematic review was conducted of research on QOL in adults with pancreatic cancer and their caregivers. Quality of life was examined in the following specific domains: psychological, physical, social, sexual, spiritual, and general. Of the 7130 articles reviewed, 36 studies met criteria for inclusion. Compared with healthy adults or population norms, adults with pancreatic cancer had worse QOL across all domains. Compared with patients with other cancer types, patients with pancreatic cancer evidenced worse psychological QOL. Physical and social QOL were either similar or more compromised than in patients with other cancers. Limited data preclude conclusions about sexual, spiritual, and caregiver QOL. Patients with pancreatic cancer evidence decrements in multiple QOL domains, with particular strain on psychological well-being. Methodological limitations of available studies restrict definitive conclusions. Future research with well defined samples, appropriate statistical analyses, and longitudinal designs is needed. Findings from this review support the merits of distress screening, integration of mental health professionals into medical teams, and attention to caregiver burden. PMID- 29521940 TI - Understanding the Pathophysiology of Psychological Distress and Pancreatic Cancer: A Systematic Review. AB - BACKGROUND: Psychological distress is highly prevalent in patients with pancreatic cancer (PC), yet little is known about the pathophysiology underlying the relationship between these 2 diseases. Our aim was to systematically review the evidence examining the pathophysiological mechanisms of the association between PC and psychological distress. METHODS: A systematic review of the literature was conducted using MEDLINE, Embase, PsychINFO, and CINAHL databases and reported according to the preferred reporting items for systematic reviews and meta-analyses guidelines. Studies examining the pathophysiological mechanisms between PC and psychological distress were included for analysis. RESULTS: Eight studies were identified that fulfilled inclusion criteria. Four mechanisms were identified accounting for the possible relationship between psychological distress and PC, including (1) stress-induced beta-adrenergic signaling, (2) interleukin-6-mediated effects, (3) kynurenine pathway upregulation, and (4) altered cerebral glucose metabolism. CONCLUSIONS: The relationship between psychological distress and PC is complex, and our understanding of these mechanisms may have implications for holistic clinical management and oncological outcome. The evidence exploring the pathophysiology of this interaction is sparse, but most well established with regard to the stress-induced beta adrenergic signaling mechanism. Further studies in larger cohorts are required to elucidate the relationship between PC and psychological distress to be able to identify therapeutic targets for both conditions. PMID- 29521941 TI - Stroma - A Double-Edged Sword in Pancreatic Cancer: A Lesson From Targeting Stroma in Pancreatic Cancer With Hedgehog Signaling Inhibitors. AB - Pancreatic cancer is a uniformly lethal malignancy with an abundant dense desmoplastic stroma. Because of its dense stroma, conventional drugs were considered to not penetrate this physical barrier, and this caused a systemic drug resistance. Thus, abolishing this barrier with targeted agents is considered to improve the efficiency of chemotherapeutic treatment. The Hedgehog (Hh) signaling pathway is a critical regulator of pancreas development and plays diversified roles in pancreatic cancer stroma and neoplastic cells. Increasing Hh expression in neoplastic cells added desmoplastic stroma accumulation in orthotopic tumors, and Hh inhibitors that target the stroma have an ability to prolong the overall survival of Pdx-1-Cre/KrasG12D/p53R172H mice models via deleting the stromal components and increasing vascularity in pancreatic tumor. However, the failure of translation from bench to bedside indicate the complexity of the relationship between Hh signaling and desmoplastic stroma, and more insights into the complex relationships between Hh signaling pathway and stroma, even tumor cells, might help redesign Hh-targeted therapy. In this review, we discuss the possible mechanism of translation of Hh inhibitor in the clinic from pathology to molecular mechanism. PMID- 29521942 TI - Predictors of Progression Among Low-Risk Intraductal Papillary Mucinous Neoplasms in a Multicenter Surveillance Cohort. AB - OBJECTIVES: Our aim was to identify baseline characteristics associated with disease progression and malignant transformation in low-risk suspected intraductal papillary mucinous neoplasms (IPMNs). METHODS: This is a retrospective cohort study of prospectively maintained databases of pancreatic cysts at 3 international, academic institutions. Five hundred fifty-nine adult patients with clinically suspected asymptomatic IPMN evaluated by radiologic studies or endoscopic ultrasound between 2003 and 2013 without worrisome features and under surveillance for 12 months or longer were included. We evaluated the relationship of baseline demographics and cyst features to disease progression (size increase, development of worrisome features, or high-grade dysplasia/cancer). RESULTS: After a median of 44 months follow-up, 269 (48%) patients experienced cyst size increase, 68 (12%) developed worrisome features, and 11 (2%) developed high-grade dysplasia/cancer. In multivariable Cox regression analysis, no baseline characteristics were associated with size increase. An initial cyst size of 2 cm or greater, multifocality, history of prostate cancer, and smoking were the strongest predictors of development of new worrisome features. Univariable analysis found male sex, diabetes, and recent weight loss associated with development of high-grade dysplasia/cancer. CONCLUSIONS: Our study demonstrates that low-risk suspected IPMNs carry a small but clinically relevant risk of disease progression and provides data on baseline characteristics that may help in risk stratification. PMID- 29521943 TI - The Dutch Pancreas Biobank Within the Parelsnoer Institute: A Nationwide Biobank of Pancreatic and Periampullary Diseases. AB - OBJECTIVES: Large biobanks with uniform collection of biomaterials and associated clinical data are essential for translational research. The Netherlands has traditionally been well organized in multicenter clinical research on pancreatic diseases, including the nationwide multidisciplinary Dutch Pancreatic Cancer Group and Dutch Pancreatitis Study Group. To enable high-quality translational research on pancreatic and periampullary diseases, these groups established the Dutch Pancreas Biobank. METHODS: The Dutch Pancreas Biobank is part of the Parelsnoer Institute and involves all 8 Dutch university medical centers and 5 nonacademic hospitals. Adult patients undergoing pancreatic surgery (all indications) are eligible for inclusion. Preoperative blood samples, tumor tissue from resected specimens, pancreatic cyst fluid, and follow-up blood samples are collected. Clinical parameters are collected in conjunction with the mandatory Dutch Pancreatic Cancer Audit. RESULTS: Between January 2015 and May 2017, 488 patients were included in the first 5 participating centers: 4 university medical centers and 1 nonacademic hospital. Over 2500 samples were collected: 1308 preoperative blood samples, 864 tissue samples, and 366 follow-up blood samples. CONCLUSIONS: Prospective collection of biomaterials and associated clinical data has started in the Dutch Pancreas Biobank. Subsequent translational research will aim to improve treatment decisions based on disease characteristics. PMID- 29521944 TI - Site-Specific Genomic Alterations in a Well-Differentiated Pancreatic Neuroendocrine Tumor With High-Grade Progression. AB - The major categories of pancreatic neuroendocrine tumor (PanNET) are well differentiated NET and poorly differentiated neuroendocrine carcinoma. Sequencing of these tumors has identified multiple important genes in the pathogenesis of PanNETs, such as DAXX/ATRX, MEN1, TP53, RB, and mTOR pathway genes. We identified a case of well-differentiated PanNET with high-grade progression with simultaneous low- and high-grade histologic regions containing variable genomic profiles. We performed tumor microdissection and analyzed both regions using a 409-gene comprehensive cancer panel using next-generation sequencing in addition to immunohistochemical and morphologic studies. The low-grade region showed a change in the DAXX gene as a copy number variant (CNV) deletion. The high-grade region showed CNV deletion changes in the DAXX gene as well as the MEN1 gene. We observed additional mutational changes in the PTEN gene and SMAD4 gene in the high-grade region. Our data support that high-grade progression in PanNETs may be the result of the progressive accumulation of genetic changes (CNVs and point mutational changes) within the body of the tumor. Next generation sequencing may provide pathologists and clinicians with ancillary information to accurately characterize and treat these tumors. PMID- 29521945 TI - Fecal Elastase Fails to Detect Steatorrhea in Patients With Locally Advanced Pancreatic Cancer. PMID- 29521946 TI - Psychiatric Comorbidities in Patients Undergoing Total Pancreatectomy With Islet Cell Autotransplantation and Associated Mortality. PMID- 29521947 TI - Incidence of Chronic Pancreatitis in Adult Male Population: A 25-Year Follow-up Study. PMID- 29521948 TI - Somatostatinoma Masquerading as Chronic Pancreatitis. PMID- 29521949 TI - Is 18F-Fluorodeoxyglucose the Tracer of Choice for Functional Imaging of Neuroendocrine Tumors Grade 3? A Case Report. PMID- 29521950 TI - Uncomplicated Spontaneous Rupture of a Pancreatic Pseudocyst Into the Stomach Through a Fistula: A Case Report and Review of the Literature. PMID- 29521951 TI - Metastatic Pancreatic Adenocarcinoma in a Patient With Chronic Calcific Pancreatitis and a Heterozygous SPINK1 c.194+2T>C Mutation. PMID- 29521952 TI - Cat-PROM5: a brief psychometrically robust self-report questionnaire instrument for cataract surgery. AB - PurposeTo develop a short, psychometrically robust and responsive cataract patient reported outcome measure suitable for use in high-volume surgical environments.MethodsA prospective study in which participants completed development versions of questionnaires exploring the quality of their eyesight using items harvested from two existing United Kingdom developed parent questionnaires. Participants were 822 patients awaiting cataract surgery recruited from 4 cataract surgical centres based in the UK. Exclusion criteria were other visually significant comorbidities and age <50 years. An iterative multi-stage process of evaluation using Rasch and factor analyses with sequential item reduction was undertaken.ResultsA definitive item set of just five items delivered performance in accordance with the requirements of the Rasch model: no threshold disordering, no misfitting items, Rasch-based reliability 0.90, person separation 2.98, Cronbach's alpha 0.89, good targeting of questions to patients with cataract with pre-operative item mean -0.41 logits and absence of significant floor or ceiling effects, minor deviations of item invariance, and confirmed unidimensionality. The test-re-test repeatability intra-class correlation coefficient was 0.89 with excellent responsiveness to surgery, Cohen's d -1.45 SD. Rasch calibration values are provided for Cat-PROM5 users.ConclusionsA psychometrically robust and highly responsive five-item cataract surgery patient reported outcome measure has been developed, which is suitable for use in high-volume cataract surgical services. PMID- 29521953 TI - Microbubble-based fiber-optic Fabry-Perot pressure sensor for high-temperature application. AB - Using arc discharge technology, we fabricated a fiber-optic Fabry-Perot (FP) pressure sensor with a very low temperature coefficient based on a microbubble that can be applied in a high-temperature environment. The thin-walled microbubble can be fabricated by heating the gas-pressurized hollow silica tube (HST) using a commercial fusion splicer. Then, the well-cut single-mode fiber (SMF) was inserted into the microbubble, and they were fused together. Thus, the FP cavity can be formed between the end of the SMF and the inner surface of the microbubble. The diameter of the microbubble can be up to 360 MUm with the thickness of the wall being approximately 0.5 MUm. Experimental results show that such a sensor has a linear sensitivity of approximately -6.382 nm/MPa, -5.912 nm/MPa at 20 degrees C, and 600 degrees C within the pressure range of 1 MPa. Due to the thermal expansion coefficient of the SMF being slightly larger than that of silica, we can fuse the SMF and the HST with different lengths; thus, the sensor has a very low temperature coefficient of approximately 0.17 pm/ degrees C. PMID- 29521954 TI - Binary wavefront optimization using a simulated annealing algorithm. AB - We propose an idea using a simulated annealing algorithm for amplitude modulation to focus light through disordered media. Using 4096 independently controlled segments of an incident wavefront, the intensity of the target signal is enhanced 73 times over the original intensity of the same output channel. The simulated annealing algorithm and existing amplitude control algorithms for focusing through scattering media are compared experimentally. It is found that the simulated annealing algorithm achieves the highest enhancement when the number of iterations required for optimization is the same. PMID- 29521955 TI - Randomizing phase to remove acousto-optic device wiggle errors for high resolution optical tweezers. AB - Acousto-optic (AO) devices have been used extensively in optical tweezers because of their flexibility and speed; however, these devices have trap positioning inaccuracies that limit their usefulness, especially for high-resolution applications. We show that these inaccuracies are due to interference patterns within the AO device sound fields. We have devised a method that removes these inaccuracies by reducing the coherence of the sound fields by directly controlling and randomizing the phase of the radio frequency voltage input signal. We demonstrate that the trapping inaccuracies are eliminated, for both constant trap position and force-ramp measurements, and that no additional noise is added. We show that this random phase method is applicable to both acousto optic modulator and deflector type devices and can be easily integrated via software upgrade into existing instruments. PMID- 29521956 TI - All-metal frequency-selective absorber/emitter for laser stealth and infrared stealth. AB - In this paper, an all-metal nanostructure is designed with a large frequency ratio (~6) and a large bandwidth ratio (~32), and consists of period slit-box cavities and nanodisk clusters. It is a nearly perfect absorber at 1.064 MUm to achieve laser stealth, a frequency-selective emitter with low emissivity in wavelength ranges 3-5 and 8-14 MUm to achieve infrared stealth, and also an emitter with near unity emissivity at 2.709 MUm and 6.107 MUm to compensate for the decrease of radiation heat transfer owing to the low emissivity. The absorption/emission peaks are all the Lorentzian shape, and the bandwidths, defined as full width at half-maximum, are 35, 408, and 1124 nm at 1.064, 2.709, and 6.107 MUm, respectively. The electric and magnetic field distribution shows that the slit behaves like a capacitor, the box behaves like an inductance, and the nanodisk clusters can excite electric dipole resonance. Considering the solar irradiation, the nanostructure maintains middle-wavelength infrared signal reduction rates greater than 80% from 450 to 1000 K, and long-wavelength infrared signal reduction rates greater than 90% from room temperature to 1000 K. The laser and infrared stealth performances of our nanostructure at 473 K are also studied with different incident angles and polarization angles. PMID- 29521957 TI - Analysis on the characteristic of the optical axis perturbation in a total reflection prismring resonator. AB - The deduction of the augmented 5*5 matrix describing all the possible angular and decentration misalignment perturbation sources on a spherical prism plane during the refraction is presented in detail for the first time. Combining the augmented matrices and the condition of eigenmode self-consistency, the optical axis perturbation properties (described with the optical axis perturbation sensitivity factor SD1, ST1, SD2, and ST2) in a total reflection prism ring resonator are also analyzed. The singular points of the optical axis perturbation sensitivity factor are found at L/R=0.417 for the cases where the misalignments may originate from distinguished type of prisms P1 and P4 in the resonator, respectively. It is shown that the small errors of the prism can cause large optical axis disturbance in the position of the perturbed singular point and its nearby area, and the disturbance for the case where the misalignments originate from prism P1 is more violent than that of prism P4. With some upgrades to find and avoid the singularity of the optical axis in the total reflection prism ring resonator structure successfully, we expect this work will have great potential for designing and optimizing the structure of super-high-precision ring laser gyroscopes. PMID- 29521958 TI - 1200 nm pumped Tm3+:Lu2O3 ceramic lasers. AB - We report on an experimental demonstration of a 1200-nm pumped Tm3+:Lu2O3 ceramic laser. By using a gain-switched, tunable Cr4+:forsterite laser, the excitation spectrum was measured, with optimum pumping bands centered near 1198 nm, 1204 nm, and 1211 nm. The highest slope efficiency of 21.5% was obtained at the pump wavelength of 1204 nm. Comparative energy efficiency measurements performed near 1200-nm and 800-nm pumping further showed that nearly 40% improvement was obtained in slope efficiency measured with respect to the incident pump energy for 1200-nm pumping. A transition was further observed from single-wavelength operation at 2066 nm to dual-wavelength operation near 2066 nm and 1967 nm for absorbed pump energies above 50 MUJ. In this regime, two consecutive output pulses were observed in the time domain. The shortest temporal duration of the first pulse was 1.1 MUs at the incident pulse energy of 105 MUJ. The duration and build-up time of the second pulse remained around 5.9 MUs and 18.5 MUs. We believe that the improved energy efficiency demonstrated for the 1.5% Tm3+:Lu2O3 ceramic with 1200-nm pumping can be used as an alternative scheme for the excitation of Tm3+:Lu2O3 ceramic lasers. PMID- 29521959 TI - Forward modeling of inherent optical properties from flow cytometry estimates of particle size and refractive index. AB - A Mie-based forward modeling procedure was developed to reconstruct bulk inherent optical properties (IOPs) from particle size distributions (PSDs) and real refractive index distributions (PRIDs) obtained using a previously developed flow cytometric (FC) method [Appl. Opt.57, 1705 (2018)APOPAI0003 693510.1364/AO.57.001705]. Given the available PSDs, extrapolations for the particle fraction outside the detection limits of the method and a complex refractive index input (with real part nr directly estimated and imaginary part ni adapted from the literature separately for organic and inorganic components), the model produces volume scattering functions that are integrated to produce scattering and backscattering coefficients, and absorption efficiencies that are used to calculate absorption coefficients. The procedure was applied to PSDs and PRIDs derived from natural samples retrieved in UK coastal waters and analyzed using a CytoSense flow cytometer (CytoBuoy b.v., The Netherlands). Optical closure analysis was carried out between reconstructed IOPs and in situ IOPs measured using an ac-9 spectrophotometer and a BB9 backscattering meter (WET Labs Inc., OR) in the same waters. The procedure is shown to achieve broad agreement with particulate scattering (bp) and backscattering (bbp) [root mean square percentage error (RMS%E): 35.3% and 44.5%, respectively) and to a lesser degree with backscattering ratio (b~bp) (RMS%E: 77%). The procedure, however, generally overestimated particulate absorption (ap) (RMS%E: 202.3%). This degree of closure was dependent on applying recently developed scattering error corrections to both absorption and attenuation in situ measurements. Not only do these results indirectly validate the FC method as a useful tool for PSD and PRID determination in natural particle populations, they also suggest that Mie theory may be a sufficient model for bulk IOP determination, with previously reported difficulties potentially being caused by inadequately corrected IOP measurements. Finally, in a feature unique to the FC method, the concurrent size and refractive index retrieval enabled assessment of the relative contributions that organic versus inorganic, fluorescent versus non-fluorescent fractions of the particle populations had on the IOPs, and identified which size classes had the largest influence on each of these properties. PMID- 29521960 TI - Comprehensive design and calibration of an even aspheric quarter-wave plate for polarization point diffraction interferometry. AB - A polarization point diffraction interferometry (PPDI) system, adopting a specially designed even aspheric quarter-wave plate (EAQWP) in the test path, is proposed for low-reflectivity and high-numerical-aperture spherical surface testing. In terms of the low-reflectivity mirror measurement, the obtained poor fringes contrast, which can significantly affect the measurement accuracy, can be improved by the polarization characteristic of the EAQWP. Simultaneously, the wavefront distortion, especially larger in high-numerical apperture (NA) measurement, can be greatly reduced attributable to the even aspheric surface design instead of the plane. In addition, the pose error introduced by EAQWP is demonstrated in detail, and a difference restoration model is built to calibrate it. Consequently, the location of the EAQWP is fixed in the test path after calibrating the pose error, having no need to be adjusted with the change of the spherical mirror under test, which facilitates the system alignment in practical optical shop testing. Ultimately, the surface error of a spherical mirror with a low-reflectivity of 0.04 and a high NA of 0.5 is measured with PPDI. The experimental results are validated to be in good agreement with that of a ZYGO interferometer. PMID- 29521961 TI - Lensless LED matrix ptychographic microscope: problems and solutions. AB - In this paper, a lensless microscope based on ptychography is presented. It disposes of the mechanic movement necessary for conventional ptychography, instead using an LED matrix to obtain a diverse set of diffraction data. This data is subject to multiple experimental factors that deviate from the standard version of ptychography: namely, imprecise knowledge of the LED positions, partial temporal and spatial coherence, and varying brightness and illumination distribution between individual LEDs. Despite these difficulties, we show here that the diversity in the ptychographic data allows an iterative phase retrieval algorithm to recover excellent, high-resolution images of a resolution test target and a biological sample. PMID- 29521962 TI - Method to measure 3D deformation using defocused images of objects with artificial speckle features. AB - A novel method to measure three-dimensional deformation based on defocused images of an object is presented in this paper. To do this, images of an object with artificial speckle features are taken by a camera. The in-plane coordinates of the points on a specimen surface are obtained according to the camera setup parameters and the defocused distance. The blur band width on the edges of the surface textures is used as a parameter to evaluate the blur degree of an image. Depth dimension is obtained by the relationship of the defocused distance and the blur degree. The relationship is given theoretically and experimentally. The digital image correlation method is used to trace each point on the specimen surface before and after deformation. Three-dimensional deformation can be obtained according to the displacement of each point. Reliability of the method is validated by two experiments. PMID- 29521963 TI - 360-degree large-scale multiprojection light-field 3D display system. AB - This paper proposes a 360-deg large-scale multiprojection light-field 3D display system, which can reconstruct the light field of models in real space. The reconstructed contents can be observed by multiple viewers from different angles and positions simultaneously. In this system, 360 projectors project images onto a cylindrical light-field diffusion screen whose height is 1.8 m and diameter is 3 m. When moving around the system, viewers can see 3D scenes with smooth-motion parallax, and the frame rate can reach 30 fps and above. To achieve a large-scale display, we design a wide-field lens with cylindrical lenses to enlarge the projection image. To promote efficiency of data transmission and render 3D contents in real time, we apply computers equipped with multiple graphic cards, and display data are divided by field programmable gate array. Finally, a 360-deg light-field autocalibration method based on CCD and multiview sampling is proposed, whose calibration effect is strongly confirmed by experiment results. PMID- 29521964 TI - Registration for images in the presence of additive and multiplicative fixed pattern noise. AB - Image registration under conditions of fixed-pattern noise is a difficult problem that has not been solved in the literature. While traditional registration methods are adequate for additive random noise, these are not suited to spatially invariant noise that is additive or multiplicative. We present a method for image registration using a difference operation in the frequency domain. Shift values are then computed by dividing by the object Fourier transform and inverse transforming. The method described is valid for both additive and multiplicative noise and determines shifts with sub-pixel accuracy. Additionally, minimal prior knowledge of the corrupting pattern is required. We compare our method with previous registration methods for varying amounts of noise. Results are presented for both simulated images and images recorded from a thermal camera with significant fixed-pattern noise. PMID- 29521965 TI - Photothermoplastic recording media and its application in the holographic method of determination of the refractive index of liquid objects. AB - The photothermoplastic medium based on the films of photosensitive polymeric composites with semiconductor properties is developed for application in optical information recording and storage, in holographic interferometry, as well as for medical purposes. This medium was used in the modified holographic device for determination of changes of the refractive index of homogeneous and inhomogeneous liquid objects. The technique and holographic equipment were modified by employing the specially developed and produced transparent cuvette of special shape and the phase shifting interferometry method. Experimentally demonstrated precision of the measurements is not less than 10-5. PMID- 29521966 TI - Generalized curved beam back-projection method for near-infrared imaging using banana function. AB - Near-infrared imaging (NIRI) is a sub-surface imaging that makes a trade-off in recovery accuracy with depth of penetration. On the other hand, diffuse optical tomography (DOT) images tissue up to several centimeters. However, DOT reconstruction has a stability issue due to the inverse problem. This paper proposes a generalized continuous-wave technique to image objects of dimensions 4 6 cm comparable to DOT. A nonlinear Rosenbrock's banana function is fitted to the approximate photon path, and the fit parameter thus obtained gives the penetration depth of each channel. The calculated values of absorption change are back-projected along these curved paths for reconstruction without solving the inverse problem. This function serves as an operator for image reconstruction. Here numerical simulations, experimental validation on wax phantom with inclusions, finger joint, and degraded apple have been performed to show potential of the proposed method in imaging. Thus this computationally efficient, reliable, and simple method is suitable for practical and real-time NIRI applications. PMID- 29521967 TI - In-depth photoluminescence spectra of pure CIGS thin films. AB - Photoluminescence spectra of pure CIGS thin films with different Ga in-depth gradients are systematically investigated. Pure Na-free films are prepared with an innovative hybrid deposition technique, whose optical luminescence emission is analyzed as a function of the depth and is correlated to the radiative intrinsic defects of the material. Finally, the highlighted features are correlated with the performances of test solar cells prepared with the same growths. PMID- 29521968 TI - Carbon-based Fresnel optics for hard x-ray astronomy. AB - We investigate the potential of large-scale diffractive-refractive normal incidence transmission lenses for the development of space-based hard x-ray telescopes with an angular resolution in the range of (10-6-10-3) arcsec over a field of view that is restricted by the available detector size. Coherently stepped achromatic lenses with diameters up to 5 m for compact apertures and 13 m in the case of segmentation provide an access to spectrally resolved imaging within keV-wide bands around the design energy between 10 and 30 keV. Within an integration time of 106 s, a photon-limited 5sigma sensitivity down to (10-9-10 7) s-1 cm-2 keV-1 can be achieved depending on the specific design. An appropriate fabrication strategy, feasible nowadays with micro-optical technologies, is considered and relies on the availability of high-purity carbon or polymer membranes. X-ray fluorescence measurements of various commercially available carbon-based materials prove for most of them the existence of a virtually negligible contamination by critical trace elements such as transition metals on the ppm level. PMID- 29521969 TI - Comparison of image reconstruction techniques for optical projection tomography. AB - We present a comparison of image reconstruction techniques for optical projection tomography. We compare conventional filtered back projection, sinogram filtering using the frequency-distance relationship (FDR), image deconvolution, and 2D point-spread-function-based iterative reconstruction. The latter three methods aim to remove the spatial blurring in the reconstructed image originating from the limited depth of field caused by the point spread function of the imaging system. The methods are compared based on simulated data, experimental optical projection tomography data of single fluorescent beads, and high-resolution optical projection tomography imaging of an entire zebrafish larva. We demonstrate that the FDR method performs poorly on data acquired with high numerical aperture optical imaging systems. We show that the deconvolution technique performs best on highly sparse data with low signal-to-noise ratio. The point-spread-function-based reconstruction method is superior for nonsparse objects and data of high signal-to-noise ratio. PMID- 29521970 TI - High-sensitivity birefringent and single-layer coating photonic crystal fiber biosensor based on surface plasmon resonance. AB - A birefringent single-layer coating photonic crystal fiber biosensor based on surface plasmon resonance is proposed to realize high sensitivity, which is easy to implement, in that only gold is deposited externally. The birefringent nature of the structure provides the sensor with high sensitivity. The results show that the biosensor can obtain the wavelength sensitivity of 15180 nm/refractive index unit (RIU) and high linearity with the analyte RI range of 1.40-1.43, corresponding to the resolution of 5.6818*10-6 RIU. Owing to the high sensitivity and simple structure, the proposed sensor can find important applications in biochemical and biological analyte detection. PMID- 29521971 TI - Low-density point eating algorithm for surface reconstruction from dense scans. AB - We present a low-density point eating algorithm for surface reconstruction from dense scans. First, the density map for each scan is estimated and the boundary densities are down-weighted. Subsequently, the poorly scanned low-density overlapping points are eaten up based on a user-specified threshold. Finally, the overlapping areas are thinned by using the moving least-squares operator and the homogeneous points are weighted averaged. The new algorithm can extract smooth but detailed point set surfaces that are as close as possible to the ground truth. The good performance of the new algorithm is demonstrated by comparison with several advanced surface reconstruction algorithms. PMID- 29521972 TI - Extended focus depth for Gaussian beam using binary phase diffractive optical elements. AB - A novel technique to improve the focus depth of a Gaussian beam is presented in this paper. The improvement is based on two-step beam shaping using a cascade of binary phase diffractive optical elements (BPDOEs). The first BPDOE transforms the incident Gaussian beam into a high-order radial Laguerre-Gaussian beam (LGp0). Then the second BPDOE rectifies the obtained LGp0 beam and gives rise to a quasi-Gaussian one in the focal plane of a converging lens. This resulting quasi-Gaussian beam exhibits a lower divergence and larger focus depth compared to the pure Gaussian beam having the same beam waist. These results open new possibilities in laser beam manufacturing and micromachining, and in applications that need an extended focus depth. PMID- 29521973 TI - Single-pulse ablation of multi-depth structures via spatially filtered binary intensity masks. AB - Digital micromirror devices (DMDs) show great promise for use as intensity spatial light modulators. When used in conjunction with pulsed lasers of a timescale below the DMD pixel switching time, DMDs are generally only used as binary intensity masks (i.e., "on" or "off" intensity for each mask pixel). In this work, we show that by exploiting the numerical aperture of an optical system during the design of binary masks, near-continuous intensity control can be accessed, whilst still maintaining high-precision laser-machining resolution. Complex features with ablation depths up to ~60 nm, corresponding to grayscale values in bitmap images, are produced in single pulses via ablation with 150 fs laser pulses on nickel substrates, with lateral resolutions of ~2.5 MUm. PMID- 29521974 TI - Laser-induced-breakdown-spectroscopy-based detection of metal particles released into the air during combustion of solid propellants. AB - Numerous metals and metal compounds are often added to propellants and explosives to tailor their properties such as heat release rate and specific impulse. When these materials combust, these metals can be released into the air, causing adverse health effects such as pulmonary and cardiovascular disease, particulate matter-induced allergies, and cancer. Hence, robust, field-deployable methods are needed to detect and quantify these suspended metallic particles in air, identify their sources, and develop mitigation strategies. Laser-induced breakdown spectroscopy (LIBS) is a technique for elemental detection, commonly used on solids and liquids. In this study, we explored nanosecond-duration LIBS for detecting airborne metals during reactions of solid propellant strands, resulting from additives of aluminum (Al), copper, lead, lead stearate, and mercury chloride. Using the second harmonic of a 10-ns-duration 10-Hz, Nd:YAG laser, plasma was generated in the gas-phase exhaust plume of burning propellant strands containing the target metals. Under the current experimental conditions, the ns LIBS scheme was capable of detecting Al at concentrations of 5%, 10%, and 16% by weight in the propellant strand. As the weight percentage increased, the LIBS signal was detected by more laser shots, up to a point where the system transition from being nonhomogeneous to a more-uniform distribution of particles. Further measurements and increased understanding of the reacting flow field are necessary to quantify the effects of other metal additives besides Al. PMID- 29521975 TI - Evaluating an image-based bidirectional reflectance distribution function measurement setup. AB - We evaluate an image-based multiangle bidirectional reflectance distribution function measurement setup by comparing it to measurements from two commercially available goniospectrophotometers. The image-based setup uses an RGB camera to perform bidirectional measurements of the sample material. We use a conversion matrix to calculate luminance from the captured data. The matrix is calculated using camera spectral sensitivities that are measured with a monochromator. Radiance factor of the sample material is measured using a commercially available tabletop goniospectrophotometer and compared to measurements made using the image based setup in the colorimetric domain. Our measurement setup is validated by comparing the measurements performed using a goniospectrophotometer. Uncertainty and error propagation is calculated and taken into account for validation. The sample material measured is wax-based ink printed on packaging paper substrate commonly used in the print and packaging industry. Results obtained show that the image-based setup can perform bidirectional reflectance measurements with a known uncertainty. The goniospectrophotometer measurements lie within the uncertainty of the measurements performed by the image-based measurement setup. The setup can be used to perform bidirectional reflectance measurements on samples with properties similar to the samples used in this paper. PMID- 29521976 TI - Automated exploitation of sky polarization imagery. AB - We propose an automated method for detecting neutral points in the sunlit sky. Until now, detecting these singularities has been done manually. Results are presented that document the application of this method on a limited number of polarimetric images of the sky captured with a camera and rotating polarizer. The results are significant because a method for automatically detecting the neutral points may aid in the determination of the solar position when the sun is obscured and may have applications in meteorology and pollution detection and characterization. PMID- 29521977 TI - Quantitative birefringence microscopy with collinearly propagating orthogonally polarized beams. AB - Full-field evaluation of spatially varying birefringence is realized by allowing two mutually orthogonally polarized collinearly propagating laser beams to be incident on a birefringent sample. This is achieved by use of a modified Sagnac interferometer. A half-wave plate is placed in the exit path of the interferometer to adjust the polarizations of the incident beams as required. Amplitude components of the light emerging from the birefringent object are then selected and/or combined by a polarizer, and intensities for required orientation of the half-wave plate and the analyzer are digitally recorded. It is shown that a maximum of four frames of intensity data is sufficient for complete evaluation of birefringence. The proposed technique is aimed towards birefringence measurements in microscopic biological specimens where the magnitude of retardation lies in the range of 0-pi radians. Simulated and experimental results are presented. PMID- 29521978 TI - Cross-sectional TEM study of subsurface damage in SPDT machining of germanium optics. AB - In addition to surface roughness and shape precision, the subsurface damage (SSD) generated by single point diamond turning (SPDT) of Ge and Si crystal optics is of increasing importance with decreasing wavelength from infrared through visible, UV, and x-ray. There are various components of SSD, e.g., microcracks, dislocations, strain, and a near-surface amorphous layer, and there are also several techniques to evaluate various components of SSD. Cross-sectional transmission electron microscopy (XTEM) is expensive and not often directly used in the optics laboratory. However, because of its very high sensitivity to SSD and down to atomic resolution, it is often used as an external service for developing SPDT technology and other surface processing techniques. It is shown in the paper that improper sample preparation can generate near-surface amorphization. Measures to avoid this artifact and a test of reliability of XTEM sample preparation are proposed. PMID- 29521979 TI - Demodulation of moire fringes in digital holographic interferometry using an extended Kalman filter. AB - This paper presents a method for extracting multiple phases from a single moire fringe pattern in digital holographic interferometry. The method relies on component separation using singular value decomposition and an extended Kalman filter for demodulating the moire fringes. The Kalman filter is applied by modeling the interference field locally as a multi-component polynomial phase signal and extracting the associated multiple polynomial coefficients using the state space approach. In addition to phase, the corresponding multiple phase derivatives can be simultaneously extracted using the proposed method. The applicability of the proposed method is demonstrated using simulation and experimental results. PMID- 29521980 TI - Multi-objective optimization framework for designing photonic crystal sensors. AB - In this paper, a novel framework for designing optimized photonic crystal (PhC) sensors has been proposed. The complexity of such structures has resulted in the lack of an analytical method to design the structures. Therefore, this framework aims to provide a comprehensive and automatic method to find the best values for the structural parameters without human involvement. The framework is explained with an example of designing a PhC liquid sensor. In the framework, an optimizer called the "multi-objective gray wolf optimizer" is utilized. However, a diverse range of multi-objective optimizer algorithms could be utilized. The results show that the proposed framework can design any kind of PhC sensor. Simplicity, being straightforward, and no human involvement are the advantages of the proposed framework. In addition, a significantly wide range of optimal designs will be found that are suitable for general and specific applications. PMID- 29521981 TI - Passively Q-switched Yb:YAG laser based on a MoSe2 saturable absorber. AB - A MoSe2 nanosheets-based saturable absorber (SA) was fabricated successfully by the liquid-phase exfoliation method. A passively Q-switched crystalline Yb:YAG laser was realized with the MoSe2 SA inserted inside the cavity. The shortest pulses at a wavelength of 1049 nm with a duration of 250 ns, maximum repetition rate of 181 kHz, and an average output power of 158 mW were emitted, corresponding to a maximum pulse energy of 0.87 MUJ. To the best of our knowledge, this is the first experimental demonstration of the nonlinear absorption property of MoSe2 nanoplatelets in a crystalline Yb-doped solid-state laser, which also proves the great potential of the MoSe2 SA as an optical modulator in the 1 MUm spectral region. PMID- 29521982 TI - Continuously tunable optical notch filter and band-pass filter systems that cover the visible to near-infrared spectral ranges. AB - Spatially continuous tunable optical notch and band-pass filter systems that cover the visible (VIS) and near-infrared (NIR) spectral ranges from ~460 nm to ~1,000 nm are realized by combining left- and right-handed circular cholesteric liquid crystal (CLC) wedge cells with continuous pitch gradient. The notch filter system is polarization independent in all of the spectral ranges. The band-pass filter system, when the left- and right-handed CLCs are arranged in a row, is polarization independent, while when they are arranged at right angles, they are polarization dependent; furthermore, the full-width at half-maximum of the band pass filter can be changed reversibly from the original bandwidth of 36 nm to 16 nm. Depending on the CLC materials, this strategy could be applied to the UV, VIS, and IR spectral ranges. Due to the high performance in the broad spectral range, cost-effective facile fabrication process, simple mechanical control, and small size, it is expected that our optical tunable filter strategies could become one of the key parts of laser-based Raman spectroscopy, fluorescence, life science devices, optical communication systems, astronomical telescopes, and so forth. PMID- 29521983 TI - Nanoscale tilt measurement using a cyclic interferometer with polarization phase stepping and multiple reflections. AB - High-accuracy tilt or roll angle measurement is required for a variety of engineering and scientific applications. A cyclic interferometer with multiple reflections has been developed to measure small tilt angles. To accomplish this task, a novel and simple method, phase shift by polarization, was developed. The results of these studies show that the multiple reflection cyclic interferometers can be used to measure object tilts on the order of 0.2 nano-radians. We develop the theory for polarization phase step and show that accurate measurements can be made with the cyclic interferometer. PMID- 29521984 TI - Distribution law of dust concentration by image transmission in a cement workshop. AB - Research on the distribution law of dust concentration is conducive to controlling dust pollution in industry workshops. The traditional experimental method has a common disadvantage in that it only can measure dust concentration of a few sampling points, resulting in limitation of further research about the distribution law of dust concentration in cement workshops. Aimed at revealing more visually and accurately the distribution law of dust concentration, a vision based measurement (VBM) system for dust concentration based on the image transmission is constructed by utilizing an established dust simulation device in cement workshops. The measurement system measured the dust concentration in the X and Z directions with a line-scanning measuring mode and that of end face XOZ in a face-scanning measuring mode. Experimental results show that the distribution law of dust concentration can be regarded as a first exponential function and then oscillating function relationship between the dust concentration and the distance from the dust source in the X direction, a parabolic function between the dust concentration and the distance from the dust source in the Z direction, and a type of laminar or turbulence distribution in the end face XOZ. The proposed VBM and the revealed law can provide a reference for the study of dust concentration distribution and dust control. PMID- 29521985 TI - Multi-aperture stereo reconstruction for artificial compound eye with cross image belief propagation. AB - The artificial compound eye is a new type of camera that has miniature volume and large field of view (FOV), while the captured image is an array of sub-images, and each sub-image captures a part of the full FOV. To obtain a complete image with a full FOV, reconstruction is needed. Due to the parallax between adjacent sub-images, the reconstruction of images is depth related. In this paper, to address the image reconstruction of a specific artificial compound eye-eCley-a cross image belief propagation method is proposed to estimate the depth map. Since the small size and small FOV of the sub-image lead to little contextual information for pairwise matching, the information of neighboring sub-images is integrated into the belief propagation step to propagate the message across images. Therefore, the belief propagation step is able to gather as much information as needed from all the sub-images to obtain an accurate depth result. As a consequence, a stereo image with the full FOV and corresponding depth map can be obtained based on the estimated depth of sub-images. Experimental results on real data show the effectiveness of the proposed method. PMID- 29521986 TI - Heterodyne detection of scattered light: application to mapping and tomography of optically inhomogeneous media. AB - The signal registered by a plane photodetector placed behind an optically inhomogeneous object irradiated by two coherent Gaussian beams intersecting inside the object at a small angle to each other is calculated in the single scattering approximation. In the considered arrangement, only one of the beams hits the detector and serves as the local oscillator for heterodyning the field scattered by the other beam (not hitting the detector). The results of analytical calculation show that the signal detected in this way is contributed only by the region of the inhomogeneous object where the two beams overlap. By moving the scatterer with respect to the overlap region and monitoring the heterodyned signal, with the aid of the derived expression, one can reconstruct the refractive-index relief of the scatterer. We also propose a simple method of spatial mapping of the sample that allows one to estimate the magnitude and characteristic dimensions of the inhomogeneities. PMID- 29521987 TI - Surface proximity effect in sedimentation investigated by digital holographic microscopy. AB - In this paper, we measure the proximity effect of a flat wall on the sedimentation of colloidal particles by the use of digital holographic microscopy (DHM). DHM provides quantitative phase contrast and three-dimensional (3D) imaging in arbitrary time scales that are suitable to investigate various phenomena, including dynamic behavior of colloids. 3D information is obtained by post-processing of the recorded digital holograms through the angular spectrum propagation approach for numerical reconstruction. We have measured the trajectory and velocity of spherical colloids in various distances from a flat wall while they sediment under gravity. The results are in agreement with theoretical studies of Goldman et al. [Chem. Eng. Sci.22, 637 (1967)CESCAC0009 250910.1016/0009-2509(67)80047-2]. We observed an increase in the drag force due to the proximity to the flat wall, which was effective for distances up to several particle sizes. The presented method is capable of being used for different applications in study of colloidal dynamics where 3D information in real time is required. PMID- 29521988 TI - Large depth of focus dynamic micro integral imaging for optical see-through augmented reality display using a focus-tunable lens. AB - We have developed a three-dimensional (3D) dynamic integral-imaging (InIm)-system based optical see-through augmented reality display with enhanced depth range of a 3D augmented image. A focus-tunable lens is adopted in the 3D display unit to relay the elemental images with various positions to the micro lens array. Based on resolution priority integral imaging, multiple lenslet image planes are generated to enhance the depth range of the 3D image. The depth range is further increased by utilizing both the real and virtual 3D imaging fields. The 3D reconstructed image and the real-world scene are overlaid using an optical see through display for augmented reality. The proposed system can significantly enhance the depth range of a 3D reconstructed image with high image quality in the micro InIm unit. This approach provides enhanced functionality for augmented information and adjusts the vergence-accommodation conflict of a traditional augmented reality display. PMID- 29521989 TI - Intensity noise cancellation in solid-state laser at 1.5 MUm using SHG depletion as a buffer reservoir. AB - An absorption mechanism based on second-harmonic generation (SHG) is successfully implemented as a buffer reservoir in a solid-state Er,Yb:Glass laser emitting at the telecom wavelength. We show that a slight absorption mechanism based on SHG rate conversion of 0.016% using a beta barium borate crystal enables the canceling out of the excess intensity noise at the relaxation oscillation frequency, i.e., 35 dB reduction, as well as canceling the amplified spontaneous emission beating at the free spectral range resonances of the laser lying in the gigahertz range. Laser robustness is discussed. PMID- 29521990 TI - Infrared micropolarizer array fabricated using a reversal nanoimprint. AB - Using a reversal nanoimprint and metal evaporation process, we fabricated a micropolarizer array for the 2.5-7 MUm wavelength region. The micropolarizer array has a unique unit, which is composed of 2*3 arrays on an intrinsic silicon substrate. Each array consists of a 200 nm period bilayer Al grating in a 1.3 mm*1.3 mm aperture. The transmittance of transverse magnetic polarization of each array is greater than 65% in the 2.5-7 MUm wavelength range, and the extinction ratio is over 35 dB in the 3-4 MUm and 6-7 MUm wavelength range. This fabricated micropolarizer array has lower costs and better compatibility with microfabrication processes. PMID- 29521991 TI - Error of the slanted edge method for measuring the modulation transfer function of imaging systems. AB - The slanted edge method is a basic approach for measuring the modulation transfer function (MTF) of imaging systems; however, its measurement accuracy is limited in practice. Theoretical analysis of the slanted edge MTF measurement method performed in this paper reveals that inappropriate edge angles and random noise reduce this accuracy. The error caused by edge angles is analyzed using sampling and reconstruction theory. Furthermore, an error model combining noise and edge angles is proposed. We verify the analyses and model with respect to (i) the edge angle, (ii) a statistical analysis of the measurement error, (iii) the full width at half-maximum of a point spread function, and (iv) the error model. The experimental results verify the theoretical findings. This research can be referential for applications of the slanted edge MTF measurement method. PMID- 29521992 TI - Improvement of two-dimensional structured illumination microscopy with an incoherent illumination pattern of tunable frequency. AB - In two-dimensional structured illumination microscopy (2D-SIM), high-resolution images with optimal optical sectioning (OS) cannot be obtained simultaneously. This tradeoff can be overcome by using a tunable-frequency 2D-SIM system and a proper reconstruction method. The goal of this work is twofold. First, we present a computational approach to reconstruct optical-sectioned images with super resolution enhancement (OS-SR) by using a tunable SIM system. Second, we propose an incoherent tunable-frequency 2D-SIM system based on a Fresnel biprism implementation. Integration of the proposed computational method with this tunable structured illumination (SI) system results in a new 2D-SIM system that is advantageous compared to other 2D-SIM systems with comparable complexity, because it provides high-resolution OS images independent of the objective lens used, without the presence of coherent noise and without reducing the contrast of the structured pattern, as in other incoherent implementations. Evaluation of our proposed system is demonstrated with comparative studies of simulated and experimental reconstructed images to validate our theoretical findings. Our experimental results show a simultaneous improvement of the lateral resolution by a factor of 1.8* with the desired OS capability achieved in the resulting OS-SR combination image. Our experimental results also verify that our system can provide better OS capability than the commercial Zeiss ApoTome-SIM system in the investigated study. PMID- 29521993 TI - Polarizer-free two-pixel polarimetric camera by compressive sensing. AB - We propose an original concept of compressive sensing (CS) polarimetric imaging based on a digital micromirror (DMD) array and two single-pixel detectors, without using any polarizer. The polarimetric sensitivity of the proposed setup is due to the tiny difference in Fresnel's coefficients of reflecting mirrors, which is exploited here to form an original reconstruction problem including a CS problem and a source-separation task. We show that a two-step approach, tackling each problem successively, is outperformed by a dedicated combined reconstruction method, which is demonstrated in this paper and preferably implemented through a reweighted fast iterative shrinkage-thresholding algorithm. The combined reconstruction approach is then further improved by including physical constraints specific to the polarimetric imaging context considered, which are implemented in an original constrained generalized forward-backward algorithm. Numerical simulations demonstrate the efficiency of the two-pixel CS polarimetric imaging setup at retrieving polarimetric contrast data with significant compression rate and good reconstruction quality. The influence of experimental imperfections of the DMD is also analyzed through numerical simulations, and 2D polarimetric imaging reconstruction results are finally presented. PMID- 29521994 TI - 2D mono detection spatially super-resolved microwave imaging for radar applications. AB - In this paper, we present an advanced two-dimensional (2D) novel microwave photonic approach to super-resolved radar imaging. Unlike synthetic aperture radar that requires movement to improve resolution by synthetically increasing the antenna's dimensions, our super-resolved imaging solution not only does not require movement to synthetically increase the antenna's dimensions, it also allows this super-resolved sensing with only a single (mono) detector. The operation principle is based upon phased array antennas, which consist of four radiating horn antennas that generate a projected plane at the far field zone. The setting of an appropriate phase to each one of the antenna inputs causes scanning of the projected structured electromagnetic beam over the imaged object. The summing of each azimuth cut of the reflections received from the object at different frequencies can spatially reconstruct the high resolution image of the object despite the fact that the receiving was done with a small size antenna with only a mono detector. Following several CST simulations, experiments, and Matlab code-based simulations, we are able to demonstrate reconstruction results having a satisfying resolution enhancement factor. PMID- 29521995 TI - Telescope-based cavity for negative ion beam neutralization in future fusion reactors. AB - In future fusion reactors, heating system efficiency is of the utmost importance. Photo-neutralization substantially increases the neutral beam injector (NBI) efficiency with respect to the foreseen system in the International Thermonuclear Experimental Reactor (ITER) based on a gaseous target. In this paper, we propose a telescope-based configuration to be used in the NBI photo-neutralizer cavity of the demonstration power plant (DEMO) project. This configuration greatly reduces the total length of the cavity, which likely solves overcrowding issues in a fusion reactor environment. Brought to a tabletop experiment, this cavity configuration is tested: a 4 mm beam width is obtained within a ?1.5 m length cavity. The equivalent cavity g factor is measured to be 0.038(3), thus confirming the cavity stability. PMID- 29521996 TI - Signal-to-noise ratio of single-pixel cameras based on photodiodes. AB - Single-pixel cameras have been successfully used in different imaging applications in the last years. One of the key elements affecting the quality of these cameras is the photodetector. Here, we develop a numerical model of a single-pixel camera, which takes into account not only the characteristics of the incident light but also the physical properties of the detector. In particular, our model considers the photocurrent, the dark current, the photocurrent shot noise, the dark-current shot noise, and the Johnson-Nyquist (thermal) noise of the photodiode used as a light detector. The model establishes a clear relationship between the electric signal and the quality of the final image. This allows us to perform a systematic study of the quality of the image obtained with single-pixel cameras in different contexts. In particular, we study the signal-to noise ratio as a function of the optical power of the incident light, the wavelength, and the photodiode temperature. The results of the model are compared with those obtained experimentally with a single-pixel camera. PMID- 29521997 TI - Ray tracing method for the evaluation of grazing incidence x-ray telescopes described by spatially sampled surfaces. AB - The nested grazing incidence telescope can achieve a large collecting area in x ray astronomy, with a large number of closely packed, thin conical mirrors. Exploiting the surface metrological data, the ray tracing method used to reconstruct the shell surface topography and evaluate the imaging performance is a powerful tool to assist iterative improvement in the fabrication process. However, current two-dimensional (2D) ray tracing codes, especially when utilized with densely sampled surface shape data, may not provide sufficient accuracy of reconstruction and are computationally cumbersome. In particular, 2D ray tracing currently employed considers coplanar rays and thus simulates only these rays along the meridional plane. This captures axial figure errors but leaves other important errors, such as roundness errors, unaccounted for. We introduce a semianalytic, three-dimensional (3D) ray tracing approach for x-ray optics that overcomes these shortcomings. And the present method is both computationally fast and accurate. We first introduce the principles and the computational details of this 3D ray tracing method. Then the computer simulations of this approach compared to 2D ray tracing are demonstrated, using an ideal conic Wolter-I telescope for benchmarking. Finally, the present 3D ray tracing is used to evaluate the performance of a prototype x-ray telescope fabricated for the enhanced x-ray timing and polarization mission. PMID- 29521998 TI - Analysis of the depth of field for integral imaging with consideration of facet braiding. AB - Shallow depth of field is one of the major limitations for integral imaging display. Although there is a series of factors that causes this problem, among them, facet braiding is the major factor. Here, an analysis method of the depth of field based on facet braiding is presented. Simulation and optical experiments are performed to verify the feasibility of the proposed analysis method. PMID- 29521999 TI - Numerical investigation of the thermal effect on Yb-cavity-copumped Er/Yb codoped fiber amplifiers. AB - Thermal effects are critical constraints for developing high-power Er/Yb-codoped fiber amplifiers (EYDFAs), especially those with an auxiliary Yb-band cavity. In this paper, we developed a numerical model to investigate the temperature dependent effects on EYDFAs with an Yb-band cavity with consideration of thermal induced cross-section changes. Our results show that the quantum-defect-induced heat affects the performance of the EYDFA, and its effect varies with the resonant wavelength of the Yb-band cavity. There is a finite applicable resonant wavelength range limited by thermal damage. So, it is important to take into account the thermal effect during the design of such EYDFAs in order to optimize their performance and determine the heat dissipation systems. PMID- 29522000 TI - Dispersion nonlinearity analysis of immersed gratings. AB - An immersed grating is a novel diffraction grating with higher spectral resolution than the classical reflective grating given. Its diffractive surface is immersed in an optical material with high refractive index (n>1). This article provides a comprehensive discussion of the nonlinear dispersion of an immersed grating based on the analysis of its diffraction angle and angular dispersion. PMID- 29522001 TI - Low-cost and highly flexible intraoperative endomicroscopy system for cellular imaging. AB - Optical biopsy, such as probe-based endomicroscopy, represents a promising technique that can provide useful intraoperative assessment of cellular imaging instead of conventional physical biopsy and histology. Despite the merits of endomicroscopy, however, it is limited by the high cost of the optical system, difficulties in a flexible approach by a commercial probe, large-area surveillance, and tissue deformation. In this paper, we have developed a low-cost endomicroscopy system with a highly flexible fiber bundle coupled with a distal microlens, mosaicking algorithm, and robotic scanning device for obtaining large area in vivo cellular imaging to extend the clinical application of endomicroscopy. We have demonstrated that this system can obtain good quality images from ex vivo human stomach tissue. We have also shown the potential of the system to provide a much larger field of view for optical biopsy than conventional endomicroscopy. This could greatly improve the prospects for intraoperative in vivo and in situ evaluation of cellular imaging. PMID- 29522002 TI - Multifunctional all-optical signal processing scheme for wavelength-division multiplexing multicast, wavelength conversion, format conversion, and all-optical encryption using hybrid modulation format exclusive-OR gates based on four-wave mixing in highly nonlinear fiber. AB - A multifunctional optical signal processing scheme for 10-Gbaud quadrature phase shift keying (QPSK) and binary phase shift keying (BPSK) signals based on four wave mixing (FWM) in highly nonlinear fiber (HNLF) is proposed. Wavelength division-multiplexing (WDM) multicast, wavelength conversion, modulation format conversion, and hybrid modulation format exclusive-OR (HMF-XOR) logic gates are realized simultaneously by simulation. One-to-three WDM multicast of 20-Gbps QPSK signals are achieved paying the optical signal-to-noise ratio (OSNR) penalties <0.8 dB at the bit error rate (BER) of 10-3. The converted BPSK signals with high performance are obtained; they are generated from wavelength conversion of 10-Gbps BPSK and format conversion from 20-Gpbs QPSK. In the case of HFM-XOR logic gates, we discuss the extension application in all-optical encryption. Therefore, both theoretical analysis and simulation results are conducted to analyze the feasibility of the dual-channel all-optical encryption for QPSK and BPSK signals. The OSNR penalties of decrypted QPSK and BPSK signals at the BER of 10-3 are 1 dB and 0.7 dB, respectively. The concentrated constellations and clear eye diagrams indicate the high performance of decrypted signals. PMID- 29522003 TI - Performance evaluation of an IMDD optical OFDM-CDMA system. AB - In this paper, we propose a modulation technique for passive optical networks that harnesses two-dimensional prime hop system optical code division multiplexing access (OCDMA) and optical orthogonal frequency-division multiplexing (OFDM) for intensity modulation with direct-detection (IMDD) to enhance users' signal capacity in a cost-effective manner. The theoretical analysis is built from an analytical formula that takes into account both multiple-access interference and photodetector noise. Results show that OFDM OCDMA with multiple users has similar performance to single-user conventional OOFDM for low transmitted powers. PMID- 29522004 TI - Adaptive background interference removal for Fourier ptychographic microscopy. AB - Fourier ptychographic microscopy (FPM) is a recently proposed computational imaging method that achieves both high resolution (HR) and wide field of view. In the conventional FPM model, the sample is assumed to be a 2D thin layer, and a series of low-resolution images at different illumination angles is used for HR image reconstruction. However, in practice, the sample complex amplitude distribution is usually mixed with some unknown background interferences. These background interferences may result from inhomogeneous media distribution or other defocusing layers, etc. The background interference will significantly degrade FPM reconstruction results, but so far it is not considered in the conventional FPM algorithm. Here, we propose a method that adaptively separates background interferences for each illumination angle. Experimental results show that the proposed method has a faster convergence speed and better reconstruction accuracy than the conventional FPM model. PMID- 29522005 TI - Realistic ports in integrating spheres: reflectance, transmittance, and angular redirection. AB - We use Monte Carlo ray-tracing modeling to follow the stochastic trajectories of rays entering a cylindrical port from inside an integrating sphere. This allows us to study and quantify properties of realistic ports of non-negligible length, as opposed to the common thin-port assumption used in most theoretical treatments, where the port is simply considered as a hole in the spherical wall. We show that most practical ports encountered in integrating sphere applications cannot be modeled as thin ports. Indeed, a substantial proportion of rays entering the port can be reflected back into the sphere, with port reflectances as high as 80% demonstrated on realistic examples. This can have significant consequences on estimates of the sphere multiplier and therefore pathlength inside the sphere, a critical parameter in many applications. Moreover, a nonzero port reflectance is inevitably associated with reduced transmittance through the port, with implications in terms of overall throughput. We also discuss angular redistribution effects in a realistic port and the consequences in terms of detected throughput within a fixed numerical aperture. Those results highlight the importance of real port effects for any quantitative predictions of optical systems using integrating spheres. We believe that those effects can be exploited to engineer ports for specific applications and improve the overall sphere performance in terms of pathlength or throughput. This work carries important implications in our theoretical understanding of integrating spheres and on the practical design of optical systems using them. PMID- 29522006 TI - Influence of grating parameters on the performance of a high-power blue external cavity semiconductor laser. AB - The influence of grating parameters, including the diffraction efficiency and ruling density, on the performance of high-power blue external-cavity (EC) semiconductor lasers has been studied. We find that for the Littrow-type EC laser with a zeroth-order diffracted beam as a coupling output, the high zeroth-order diffraction efficiency benefits the high external light extraction efficiency, and the high first-order diffraction efficiency contributes to the low threshold current and the wide wavelength tuning bandwidth. By using a grating with a zeroth-order diffraction efficiency of 76% and a first-order diffraction efficiency of 11.5%, the external light extraction efficiency can reach up to 80% with an output power of more than 1200 mW and a tuning bandwidth of 3.6 nm. When a grating with a first-order diffraction efficiency of 58.5% and a zeroth-order diffraction efficiency of 28.6% is used, the threshold current is reduced by 46% at the central Fabry-Perot resonance wavelength. Moreover, a tuning bandwidth of 8.3 nm ranging from 442.2 nm to 450.5 nm with an output power of more than 500 mW is achieved. Besides, we also find that the high ruling density is helpful in obtaining narrow lasing linewidth, especially for the EC laser system injected with low current. By using a grating with a ruling density of 2400 grooves/mm, the spectral linewidth of the EC laser can be narrowed to be 0.02 nm with an operating current of 300 mA. As the injection current is increased, the lasing linewidth is little affected by the ruling density of the grating due to the broadened feedback spectrum by the flattening of gain spectrum. The results above shed light on the improvement of the performance of EC lasers by selecting appropriate parameters for the grating. PMID- 29522007 TI - Rotation sensing decoupling of a dual-axis K-Rb-21Ne atomic comagnetometer. AB - A dual-axis atomic comagnetometer can sense the angular rotation of two measurement axes simultaneously and independently. However, there is a cross-talk coupling effect between the two axes because of the residual magnetic field and the light shift arising from the pumping laser. Here, we propose a scheme to eliminate the rotation coupling of dual-axis K-Rb-N21e atomic comagnetometers. The residual magnetic field can be effectively removed by controlling the comagnetometer at the magnetic compensation point and the magnetic shielding layer. The light shift could be eliminated by using the K atom light shift to counteract the Rb atom light shift, in which the light shift of K atoms was optimized to the decoupling point by finely adjusting the pumping laser wavelength of the K D1 line. The feasibility and efficiency of this decoupling scheme have been experimentally verified. The output response of the coupling axis is reduced by two orders of magnitude compared to the sensitive axis. This scheme can also be applied to any atomic comagnetometer with hybrid optical pumping that experiences cross-talk coupling. PMID- 29522008 TI - Proposal for realizing an all-optical half adder based on photonic crystals. AB - In this paper, we aim to propose an optical structure for realizing half-adder operation without using the nonlinear Kerr effect. Constructive and destructive interference of optical beams is the main working mechanism of the proposed structure. The phase difference required for the destructive interface will be created by choosing different lengths for the input waveguides of the XOR gate. For the proposed structure, the on-off contrast ratios for SUM and CARRY are 9.77 dB and 6.98 dB, respectively. Also, the delay time and footprint of the proposed structure are about 4 ps and 1056 MUm2, respectively. PMID- 29522009 TI - Automatic multicell identification using a compact lensless single and double random phase encoding system. AB - We investigate the use of compact, lensless, single random phase encoding (SRPE) and double random phase encoding (DRPE) systems for automatic cell identification when multiple cells, either of the same or mixed classes, are in the field of view. A microscope glass slide containing the sample is inputted into the single or double random phase encoding system, which is then illuminated by a coherent or partially coherent light source generating a unique opto-biological signature (OBS) that is captured by an image sensor. Statistical features such as mean, standard deviation, skewness, kurtosis, entropy, and Pearson's correlation coefficient are extracted from the OBSs and used for cell identification with the random forest classifier. With the exception of the correlation coefficient, all features were extracted in both the spatial and frequency domains. Experiments are performed with single random phase encoding and double random phase encoding, and system analysis is presented to show the robustness and classification accuracy of the random phase encoding cell identification systems. The proposed systems are compact, as they are lensless and do not have spatial frequency bandwidth limitations due to the numerical aperture of a microscope objective lens. We demonstrate that cell identification is possible using both the SRPE and DRPE systems. While DRPE systems have been extensively used for image encryption, to the best of our knowledge, this is the first report on using DRPE for automated cell identification. PMID- 29522010 TI - 3D SAPIV particle field reconstruction method based on adaptive threshold. AB - Particle image velocimetry (PIV) is a necessary flow field diagnostic technique that provides instantaneous velocimetry information non-intrusively. Three dimensional (3D) PIV methods can supply the full understanding of a 3D structure, the complete stress tensor, and the vorticity vector in the complex flows. In synthetic aperture particle image velocimetry (SAPIV), the flow field can be measured with large particle intensities from the same direction by different cameras. During SAPIV particle reconstruction, particles are commonly reconstructed by manually setting a threshold to filter out unfocused particles in the refocused images. In this paper, the particle intensity distribution in refocused images is analyzed, and a SAPIV particle field reconstruction method based on an adaptive threshold is presented. By using the adaptive threshold to filter the 3D measurement volume integrally, the three-dimensional location information of the focused particles can be reconstructed. The cross correlations between images captured from cameras and images projected by the reconstructed particle field are calculated for different threshold values. The optimal threshold is determined by cubic curve fitting and is defined as the threshold value that causes the correlation coefficient to reach its maximum. The numerical simulation of a 16-camera array and a particle field at two adjacent time events quantitatively evaluates the performance of the proposed method. An experimental system consisting of a camera array of 16 cameras was used to reconstruct the four adjacent frames in a vortex flow field. The results show that the proposed reconstruction method can effectively reconstruct the 3D particle fields. PMID- 29522011 TI - Picosecond and femtosecond asymmetric switching using a semiconductor optical amplifier-based Mach-Zehnder interferometer. AB - In this paper, we numerically analyze nonlinear asymmetric switching using a semiconductor optical amplifier (SOA) phase-shifter-based Mach-Zehnder interferometer (MZI), for the first time, to the best of our knowledge. The self phase modulation (SPM) effect and nonlinear phase shift in each MZI arm are investigated for different input pulse intensities and linear gains in both picosecond and femtosecond regimes. The input light signal is split unequally over the two arms, where SOAs are placed and act as nonlinear phase shifters in each arm. The finite difference beam propagation method is used to solve the modified nonlinear Schrodinger equation to analyze the wave propagation. In this work, the main nonlinear effects in SOA, such as group velocity dispersion, Kerr effect, two-photon absorption, carrier heating, and spectral hole burning, are considered. Furthermore, the effect of SPM on distortion of the pulse shape and its spectrum, which can be used for pulse shaping in a picosecond-switching scheme, is studied. We depicted red and blue shifts that each pulse experiences in the process of switching in picosecond and femtosecond regimes, respectively. Based on the results for sub-picosecond input pulses, by controlling the bias current level in the MZI arms, the pulse distortion due to nonlinear effects of SOAs can be decreased at the switch output port, and symmetric pulse can be obtained. Switching with higher speed is possible in bulk SOAs in the femtosecond regime using asymmetric MZI-switching structure. PMID- 29522012 TI - Investigation of laser-induced plasma characteristics in bulk water under different focusing arrangements. AB - Laser-induced breakdown spectroscopy (LIBS) has drawn more attention as a new technique for in situ detection of seawater, especially for hydrothermal areas. In order to evaluate the focusing geometry effect on laser-induced plasma in bulk water, four focusing arrangements were tried out with a single lens as well as with a double-lens combination. We demonstrated that, for the same transmission distance in water, the double-lens combination with shorter effective focal length generated more condensed plasma, as shown by the spectroscopic and fast imaging results. Accordingly, the moving breakdown phenomenon significantly decreased with well-improved LIBS intensity, signal-to-noise ratio, and stability. The plasma emissions evidently attenuated along the laser transmission due to the strong absorption effect of the water medium. Based on the acquired results, the performance of a practical detection window was evaluated by combining the regular lens with a customized lens-shaped optical window, and a positive outcome was also reached. The obtained results suggested that improved LIBS detection could be easily achieved via settling another lens window to LIBS system, which is considered helpful for better in situ submarine application. PMID- 29522013 TI - Broadband multilayer anti-reflection coating for mid-infrared range from 7 MUm to 12 MUm. AB - We describe a design concept for broadband anti-reflection coatings for the mid infrared that allows thinner film thickness and characterize its properties in the mid-infrared range from 7 MUm to 12 MUm. Two demonstrator coatings comprising zinc sulfide, yttrium fluoride, and germanium, all of which are deposited by electron beam evaporation on indium phosphide substrates, are optimized for the 7 12 MUm and the 10-12 MUm ranges. They exhibit less than 1.0% reflection over the target wavelength ranges with notably thin coating thickness. PMID- 29522014 TI - Fast correction approach for wavefront sensorless adaptive optics based on a linear phase diversity technique. AB - Wavefront sensorless (WFSless) adaptive optics (AO) systems have been widely studied in recent years. To reach optimum results, such systems require an efficient correction method. This paper presents a fast wavefront correction approach for a WFSless AO system mainly based on the linear phase diversity (PD) technique. The fast closed-loop control algorithm is set up based on the linear relationship between the drive voltage of the deformable mirror (DM) and the far field images of the system, which is obtained through the linear PD algorithm combined with the influence function of the DM. A large number of phase screens under different turbulence strengths are simulated to test the performance of the proposed method. The numerical simulation results show that the method has fast convergence rate and strong correction ability, a few correction times can achieve good correction results, and can effectively improve the imaging quality of the system while needing fewer measurements of CCD data. PMID- 29522015 TI - High-contrast optical vortex detection using the Talbot effect. AB - We apply the near-field Talbot effect to distinguish, characterize, and detect optical vortices. We perform experiments with single-, double-, multiple-slit, and grating diffraction. High-contrast image detection is achieved with the Talbot effect of a grating, even for higher than l=+/-1 orbital angular momentum states. Furthermore, we manipulate the vortex beam with different vortex states and use the Talbot effect for detecting. The experimental results are supported by theoretical simulations and demonstrate that the Talbot effect provides an excellent tool for optical vortex detection. PMID- 29522016 TI - First decadal lunar results from the Moon and Earth Radiation Budget Experiment. AB - A need to gain more confidence in computer model predictions of coming climate change has resulted in greater analysis of the quality of orbital Earth radiation budget (ERB) measurements being used today to constrain, validate, and hence improve such simulations. These studies conclude from time series analysis that for around a quarter of a century, no existing satellite ERB climate data record is of a sufficient standard to partition changes to the Earth from those of un tracked and changing artificial instrumentation effects. This led to the creation of the Moon and Earth Radiation Budget Experiment (MERBE), which instead takes existing decades old climate data to a higher calibration standard using thousands of scans of Earth's Moon. The Terra and Aqua satellite ERB climate records have been completely regenerated using signal-processing improvements, combined with a substantial increase in precision from more comprehensive in flight spectral characterization techniques. This study now builds on previous Optical Society of America work by describing new Moon measurements derived using accurate analytical mapping of telescope spatial response. That then allows a factor of three reduction in measurement noise along with an order of magnitude increase in the number of retrieved independent lunar results. Given decadal length device longevity and the use of solar and thermal lunar radiance models to normalize the improved ERB results to the International System of Units traceable radiance scale of the "MERBE Watt," the same established environmental time series analysis techniques are applied to MERBE data. They evaluate it to perhaps be of sufficient quality to immediately begin narrowing the largest of climate prediction uncertainties. It also shows that if such Terra/Aqua ERB devices can operate into the 2020s, it could become possible to halve these same uncertainties decades sooner than would be possible with existing or even planned new observing systems. PMID- 29522017 TI - Low-order aberration correction of the TMT tertiary mirror prototype based on a warping harness. AB - A warping harness is proposed to simply and efficiently correct low-order aberrations that occur during manufacturing and operation of a telescope. For the Thirty Meter Telescope (TMT) tertiary mirror, the issue to be solved by the warping harness is particularly challenging due to its complicated load conditions and limited mounting space. In this study, first, a new type of whiffletree-based warping harness configuration applied to a 1/4-prototype TMT tertiary mirror is presented and optimized using finite element analysis (FEA) to improve the output precision of the moment actuator. Next, based on the new configuration, a simulation method for a correction process is proposed. The results show that the root mean square value of the mirror-surface error converged from 64.9 to 25.4 nm after correction, which satisfied the requirement document of TMT. Finally, combined with the analysis and calculation results, the moment actuator testing system with high-precision displacement-force-strain is established to assess the system errors. The tests of the moment actuator displacement, stress, strain-output precision, linearity, and repeatability are completed, and all errors were found to be within a controllable range. The results show the validity and feasibility of the designed warping harness, which can prove its applicability in more complicated conditions and, to a certain degree, broaden the application scope of the warping harness. PMID- 29522018 TI - Simultaneous directional curvature and temperature sensor based on a tilted few mode fiber Bragg grating. AB - We demonstrate a directional curvature sensor based on tilted few-mode fiber Bragg gratings (FM-FBGs) inscribed by a UV laser. The eigenmodes of LP01 and LP11 mode groups are simulated along with the fiber bending. The directional curvature sensor is based on the LP11 mode resonance in the tilted FM-FBG. For curvature from 4.883 to 7.625 m-1, the curvature sensitivities at direction of 0 degrees and 90 degrees are measured to be -2.67 and 0.128 dB/m-1, respectively. The temperature variation barely affects the resonance depth of LP11 mode. The proposed curvature sensor clearly demonstrates the potential to simultaneous directional curvature and temperature measurement with the resolutions of 9.15*10 4 m-1 and 0.952 degrees C, respectively. PMID- 29522019 TI - Reducing defocus aberration of a compound and human hybrid eye using liquid lens. AB - We propose a self-adaption focal length adjustment method of a compound and human hybrid eye with a non-uniform microlens array model (NUMLA) to reduce defocus aberration by using the liquid lens. The models are deduced and verified through simulations. The method can self-adaptively adjust the focal length according to object distance and image distance. The results show that (1) the RMS spot radii of the traditional uniform microlens array at different rings are 21 MUm, 187 MUm, 304 MUm, 526 MUm, and 803 MUm. However, those of the NUMLA are 21 MUm, 47 MUm, 98 MUm, 178 MUm, and 287 MUm, which indicates that the NUMLA can reduce the defocus aberration. (2) When the object distance and the image distance vary, the defocus aberration can be significantly reduced through the adjustment of the focal length, which validates the effectiveness of the proposed method. (3) The volumes of the liquid lens in the cavity at the peripheral rings are larger than that at the central rings. The results are beneficial for providing a simple solution to reduce the defocus aberration of the compound and human hybrid eye. PMID- 29522020 TI - Coherent midinfrared supercontinuum generation using a rib waveguide pumped with 200 fs laser pulses at 2.8 MUm. AB - A rib waveguide structure in As2Se3 chalcogenide glass has been designed and numerically analyzed for on-chip coherent supercontinuum generation in the midinfrared region. The waveguide structure possesses an all-normal dispersion profile with dispersion value of -13.22 ps/nm.km at the pump wavelength. Coherent midinfrared supercontinuum spectrum spanning 1.2 to 7.2 MUm has been obtained using a 2.5 mm long rib waveguide when pumped with 200 fs laser pulses of a peak power of 2.5 kW and a repetition rate of 1 kHz at 2.8 MUm. Such highly nonlinear subwavelength size rib waveguide structures are highly applicable for the power efficient on-chip midinfrared coherent supercontinuum sources. Coherent midinfrared supercontinuum sources are very important in frequency metrology, nonlinear microscopy, nondestructive testing, molecular spectroscopy, and optical coherence tomography. PMID- 29522021 TI - Automatic cell identification and visualization using digital holographic microscopy with head mounted augmented reality devices. AB - We propose a compact imaging system that integrates an augmented reality head mounted device with digital holographic microscopy for automated cell identification and visualization. A shearing interferometer is used to produce holograms of biological cells, which are recorded using customized smart glasses containing an external camera. After image acquisition, segmentation is performed to isolate regions of interest containing biological cells in the field-of-view, followed by digital reconstruction of the cells, which is used to generate a three-dimensional (3D) pseudocolor optical path length profile. Morphological features are extracted from the cell's optical path length map, including mean optical path length, coefficient of variation, optical volume, projected area, projected area to optical volume ratio, cell skewness, and cell kurtosis. Classification is performed using the random forest classifier, support vector machines, and K-nearest neighbor, and the results are compared. Finally, the augmented reality device displays the cell's pseudocolor 3D rendering of its optical path length profile, extracted features, and the identified cell's type or class. The proposed system could allow a healthcare worker to quickly visualize cells using augmented reality smart glasses and extract the relevant information for rapid diagnosis. To the best of our knowledge, this is the first report on the integration of digital holographic microscopy with augmented reality devices for automated cell identification and visualization. PMID- 29522022 TI - Robust digital holography design with monitoring setup and reference tilt error elimination. AB - A robust digital holography recording design is presented to complete the work of switching between in-line and off-axis recording methods. We precisely supervise the off-axis angle in off-axis holography, so that the original reconstructed image can be separated by a minimum off-axis angle. In the design, we can also monitor and remove the negative effects of the reference tilt error in phase shifting digital holography. Compared with the conventional digital holographic recording configuration, a supervising unit is introduced to control and to monitor the angle between the reference beam and object beam. By the Fourier analysis on the interferograms recorded by the supervising unit and using the corresponding equations, the off-axis angle, which is crucial to reset the object image in holographic reconstruction, can be calculated accurately and then chosen for the best recording angle. For in-line holography, the error affecting the slight tilt of the reference beam on the retrieved object wavefront can be eliminated completely because the tilt angle is detected by another independent device. Furthermore, by using this advanced design, the experimental arrangement can be transformed flexibly from the in-line recording state to the off-axis state or from the latter one to the former without rebuilding the experimental setup. The availability and effectiveness of this design are verified by a series of experiments. PMID- 29522023 TI - LED light design method for high contrast and uniform illumination imaging in machine vision. AB - In machine vision, illumination is very critical to determine the complexity of the inspection algorithms. Proper lights can obtain clear and sharp images with the highest contrast and low noise between the interested object and the background, which is conducive to the target being located, measured, or inspected. Contrary to the empirically based trial-and-error convention to select the off-the-shelf LED light in machine vision, an optimization algorithm for LED light design is proposed in this paper. It is composed of the contrast optimization modeling and the uniform illumination technology for non-normal incidence (UINI). The contrast optimization model is built based on the surface reflection characteristics, e.g., the roughness, the reflective index, and light direction, etc., to maximize the contrast between the features of interest and the background. The UINI can keep the uniformity of the optimized lighting by the contrast optimization model. The simulation and experimental results demonstrate that the optimization algorithm is effective and suitable to produce images with the highest contrast and uniformity, which is very inspirational to the design of LED illumination systems in machine vision. PMID- 29522024 TI - Evaluation of a flow cytometry method to determine size and real refractive index distributions in natural marine particle populations. AB - A flow cytometric (FC) method was developed to retrieve particle size distributions (PSDs) and real refractive index (nr) information in natural waters. Geometry and signal response of the sensors within the flow cytometer (CytoSense, CytoBuoy b.v., Netherlands) were characterized to form a scattering inversion model based on Mie theory. The procedure produced a mesh of diameter and nr isolines where each particle is assigned the diameter and nr values of the closest node, producing PSDs and particle real refractive index distributions. The method was validated using polystyrene bead standards of known diameter and polydisperse suspensions of oil with known nr, and subsequently applied to natural samples collected across a broad range of UK shelf seas. FC PSDs were compared with independent PSDs produced from data of two LISST-100X instruments (type B and type C). PSD slopes and features were found to be consistent between the FC and the two LISST-100X instruments, but LISST concentrations were found in disagreement with FC concentrations and with each other. FC nr values were found to agree with expected refractive index values of typical marine particle components across all samples considered. The determination of particle size and refractive index distributions enabled by the FC method has potential to facilitate identification of the contribution of individual subpopulations to the bulk inherent optical properties and biogeochemical properties of the particle population. PMID- 29522025 TI - Polymer-optical-fiber-based sensor system for simultaneous measurement of angle and temperature. AB - This paper presents a polymer-optical-fiber (POF)-based sensor system for simultaneous measurement of angle and temperature. The main contribution is obtaining a sensor with higher temperature sensitivity and lower hysteresis on the angle measurements. The annealing was made on the fibers under the conditions of low relative humidity and under water, and a third set of samples without any heat treatment was applied for comparison with the annealed ones. Results of temperature and angle characterization show that the fibers annealed under water presented higher temperature sensitivity and lower errors when compared with the fibers annealed with low humidity or the fibers without annealing. Furthermore, the fibers annealed under water also presented lower hysteresis on the angle characterization. For these reasons, such fibers were employed for the temperature and angle measurements, which results in a sensor system capable of simultaneously measuring the angle and temperature with root-mean-squared error of 0.82 degrees C for temperature and 2.20 degrees for angle, which is further reduced to 1.20 degrees after the application of a dynamic compensation technique for POF curvature sensors. PMID- 29522026 TI - Extreme ultraviolet mask roughness effects in high numerical aperture lithography. AB - Given the reflective nature of extreme ultraviolet lithography and its extremely short operational wavelength, roughness of the optical surfaces is of significant concern. In particular, roughness in the mask multilayer leads to image plane speckle and ultimately patterned line-edge or line-width variability in the imaging process. Here we consider the implications of this effect for future high numerical aperture (NA) systems that are assumed to require anamorphic magnification projection optics. The results show significant anisotropic behavior at high NA as well as a substantial increase in relative patterned line variability in the shadowed direction when comparing 0.55 NA to 0.33 NA, despite the assumption of an anamorphic magnification system. The shadowed-direction patterned line variability is 2* larger than for unshadowed lines, and the majority of the increase in variability occurs in the low frequency regime. PMID- 29522027 TI - Spike encoding and storage properties in mutually coupled vertical-cavity surface emitting lasers subject to optical pulse injection. AB - The generation and storage properties of different spike codes in vertical-cavity surface-emitting lasers with an embedded saturable absorber (VCSELs-SA) are investigated numerically. The results show that different spike codes are generated by injecting an optical pulse into one single VCSEL-SA and can be stored in two mutually coupled VCSELs-SA. In particular, in the case of the generation of spike codes, the effects of the input strength and the temporal duration of the input optical pulse are studied; in the case of the storage of spike codes, the roles of the coupling weight and the coupling delay between the two mutually coupled VCSELs-SA are examined. Simulations reveal that spikes can be triggered if the input strength and the temporal duration exceed the threshold values, and higher values of the input strength and the temporal duration are beneficial for generating more spikes. Moreover, successful storage of a perfectly formed train of spike codes in two mutually coupled VCSELs-SA can also be realized provided that the coupling weight and the coupling delay are larger than the corresponding threshold values. PMID- 29522028 TI - Imaging and applied optics: introduction to the feature issue. AB - This special issue of Applied Optics contains selected papers from OSA's Imaging Congress with particular emphasis on work from mathematics in imaging, computational optical sensing and imaging, imaging systems and applications, and 3D image acquisition and display. PMID- 29522029 TI - Constrained models for optical absorption tomography. AB - We consider the inverse problem of concentration imaging in optical absorption tomography with limited data sets. The measurement setup involves simultaneous acquisition of near-infrared wavelength-modulated spectroscopic measurements from a small number of pencil beams equally distributed among six projection angles surrounding the plume. We develop an approach for image reconstruction that involves constraining the value of the image to the conventional concentration bounds and a projection into low-dimensional subspaces to reduce the degrees of freedom in the inverse problem. Effectively, by reparameterizing the forward model, we impose, simultaneously, spatial smoothness and a choice among three types of inequality constraints, namely, positivity, boundedness, and logarithmic boundedness in a simple way that yields an unconstrained optimization problem in a new set of surrogate parameters. Testing this numerical scheme with simulated and experimental phantom data indicates that the combination of affine inequality constraints and subspace projection leads to images that are qualitatively and quantitatively superior to unconstrained regularized reconstructions. This improvement is more profound in targeting concentration profiles of small spatial variation. We present images and convergence graphs from solving these inverse problems using Gauss-Newton's algorithm to demonstrate the performance and convergence of our method. PMID- 29522030 TI - Design of a large aperture tunable refractive Fresnel liquid crystal lens. AB - A large aperture tunable lens based on liquid crystals, which is considered for near-to-eye applications, is designed, built, and characterized. Large liquid crystal lenses with high quality are limited by very slow switching speeds due to the large optical path difference (OPD) required. To reduce the switching time of the lens, the thickness is controlled through the application of several phase resets, similar to the design of a Fresnel lens. A main point of the paper is the design of the Fresnel structure to have a minimal effect on the image quality. Our modeling and experimental results demonstrate that minimal image degradation due to the phase resets is observable when the segment spacing is chosen by taking into account human eye resolution. Such lenses have applications related to presbyopia and, in virtual reality systems, to solve the well-known issue of accommodation-convergence mismatch. PMID- 29522031 TI - Reduction of the defocusing effect in lensless ghost imaging and ghost diffraction with cosh-Gaussian modulated incoherent sources. AB - The inhibition effect from the cosh-Gaussian modulated incoherent source on the defocusing effect is investigated theoretically in lensless ghost imaging (LGI) and ghost diffraction (LGD) systems. The corresponding numerical simulations are presented to show the influence of the cosh-Gaussian incoherent source on the defocusing effect in LGI and LGD. Compared with the widely used Gaussian incoherent source, it is shown that the defocusing effect in LGI and LGD can be greatly weakened by properly adjusting the modulation parameter omega of the cosh Gaussian source. To explain this phenomenon, the analytical expression for point spread function of the LGI system with the cosh-Gaussian source is derived. PMID- 29522032 TI - Hybrid gray wolf optimizer-artificial neural network classification approach for magnetic resonance brain images. AB - Automated and accurate classification of magnetic resonance images (MRIs) of the brain has great importance for medical analysis and interpretation. This paper presents a hybrid optimized classification method to classify the brain tumor by classifying the given magnetic resonance brain image as normal or abnormal. The proposed system implements a gray wolf optimizer (GWO) combined with a supervised artificial neural network (ANN) classifier to achieve enhanced MRI classification accuracy via selecting the optimal parameters of ANN. The introduced GWO-ANN classification system performance is compared to the traditional neural network (NN) classifier using receiver operating characteristic analysis. Experimental results obviously indicate that the presented system achieves a high classification rate and performs much better than the traditional NN classifier. PMID- 29522033 TI - Target recognition method on retina-like laser detection and ranging images. AB - A target recognition method on retina-like laser detection and ranging images is proposed in this study. The method does not require complicated image preprocessing due to speeded-up robust features (SURF) combined with retina-like sampling as feature match descriptors. Subpixel resampling achieves optimization and avoids affecting the accuracy and precision of target recognition. Several experiments are conducted to analyze the validity of SURF directly. The separate exploration of SURF with Cartesian, log-polar (LP), and inverse LP images are discussed. Furthermore, examples are used to demonstrate the capability of the proposed method. Finally, important conclusions are drawn as follows. (I) SURF extraction becomes difficult when it is directly used in LP images as expected. (II) Applying SURF with an inverse LP process is valid. (III) SURF key match points in inverse LP images are less than those in Cartesian images. (IV) The accuracy of the proposed solution agrees well with that of the Cartesian solution when angle and scale variants are used. The present recognition solution may be used in various applications involving space-variant image processing. PMID- 29522034 TI - Non-line-of-sight 2 * N indoor optical camera communications. AB - We propose, for the first time to the best of our knowledge, a novel non-line-of sight 2*N indoor optical camera communication system, where N is the number of pixels in the camera with a unique packet structure and a detection methodology for extracting the data from the recorded video streams. A comprehensive theoretical model for the proposed system is presented. The proposed system is experimentally investigated, and the measured results show that higher International Standards Organization (ISO) levels and exposure times lead to a reduced transmit power level by 3 dB for every doubling of the exposure time and ISO at a bit error rate of 10-3. It is also shown that when the overlapping area of two interfering transmitters is larger than approximately 30% of the footprints, the data cannot be recovered. PMID- 29522035 TI - Polarimetric infrared imaging simulation of a synthetic sea surface with Mie scattering. AB - A novel method to simulate the polarimetric infrared imaging of a synthetic sea surface with atmospheric Mie scattering effects is presented. The infrared emission, multiple reflections, and infrared polarization of the sea surface and the Mie scattering of aerosols are all included for the first time. At first, a new approach to retrieving the radiative characteristics of a wind-roughened sea surface is introduced. A two-scale method of sea surface realization and the inverse ray tracing of light transfer calculation are combined and executed simultaneously, decreasing the consumption of time and memory dramatically. Then the scattering process that the infrared light emits from the sea surface and propagates in the aerosol particles is simulated with a polarized light Monte Carlo model. Transformations of the polarization state of the light are calculated with the Mie theory. Finally, the polarimetric infrared images of the sea surface of different environmental conditions and detection parameters are generated based on the scattered light detected by the infrared imaging polarimeter. The results of simulation examples show that our polarimetric infrared imaging simulation can be applied to predict the infrared polarization characteristics of the sea surface, model the oceanic scene, and guide the detection in the oceanic environment. PMID- 29522036 TI - Angular distribution of laser-induced fluorescence emission of active dyes in scattering media. AB - Angular dependence of the intensity and the emissive wavelength of the laser induced fluorescence emission in hybrid media (fluorophores+nanoparticles) are investigated using various TiO2 densities as guest nanoscatterers in the ethanolic solutions of the host Rd6G and coumarin 4 (C4) molecules. It is shown that the intensity of the scattered photons varies in terms of the detection angle. When the nanoscatterer density increases at a certain excitation energy, the angular anisotropy enhances. While the emissive wavelength exhibits the spectral shift in terms of the angular variation for Rd6G fluorophores, it remains invariant for C4-based suspension. In the former case, the emissive wavelength undergoes a spectral shift in terms of angular variation. Several factors such as the optical path length in the scattering media, the excitation volume, and the re-absorption events of the fluorescence emissions by the non excited molecules strongly affect the spectral features. In fact, the density of the scatterers, the dye concentration, and the interplay between Stokes shift rate and the overlapping between absorption/emission spectra of the given fluorophores are taken into account as the major parameters to form the angular distribution. PMID- 29522037 TI - Robust method to probe the topological charge of a Bessel beam by dynamic angular double slits. AB - Precisely determining the topological charge (TC) of both integral Bessel beams (IBB) and fractional Bessel beams (FBB) is a key issue for their applications. However, most of the common methods could not probe both the IBB and FBB precisely and robustly. In this paper, we present a robust method to probe the topological charge of a Bessel beam by dynamic angular double slits (ADSs). We find that when a Bessel beam vertically illuminates on a dynamic ADS, the information of the TC can be retrieved from its Fourier transform patterns near the optical axis. Even though there is a small misalignment between the center of the beams and the ADS, the global variation tendency is still good enough to obtain the TC. Based on these properties, the dynamic ADS device combining the method of fitting the experimental data can be used to measure the TC of any Bessel light beam precisely and robustly. The error is less than 2% without the misalignment and is less than 6% with a small misalignment for our experimental data. This method paves a new way to measure the TC of vortex beams. PMID- 29522038 TI - Large-scale clinical validation of noncontact and continuous extraction of blood pressure via multipoint defocused photonic imaging. AB - Blood pressure (BP) is usually measured either invasively, by an intra-arterial catheter, or noninvasively, by a cuff-based sphygmomanometer. While the invasive method is continuous and more accurate, it has the risk of infection and generally is not comfortable for the patient. On the other hand, the cuff-based measurement is safer but less reliable and infrequent. Therefore, a reliable continuous noninvasive BP measurement is highly desirable. In this work, we propose a remote optical system, based on temporal analysis of secondary reflected speckle patterns, for computing a subject's pulse transit time (PTT). Afterward, a model is proposed and clinically validated for converting the PTT value into systolic and diastolic blood pressure. A full statistical analysis is performed over a comparison to a reference device (SOMNOtouch). PMID- 29522039 TI - Achieving a high mode count in the exact electromagnetic simulation of diffractive optical elements. AB - The application of rigorous optical simulation algorithms, both in the modal as well as in the time domain, is known to be limited to the nano-optical scale due to severe computing time and memory constraints. This is true even for today's high-performance computers. To address this problem, we develop the fast rigorous iterative method (FRIM), an algorithm based on an iterative approach, which, under certain conditions, allows solving also large-size problems approximation free. We achieve this in the case of a modal representation by avoiding the computationally complex eigenmode decomposition. Thereby, the numerical cost is reduced from O(N3) to O(N log N), enabling a simulation of structures like certain diffractive optical elements with a significantly higher mode count than presently possible. Apart from speed, another major advantage of the iterative FRIM over standard modal methods is the possibility to trade runtime against accuracy. PMID- 29522040 TI - Kalman filter approach for uncertainty quantification in time-resolved laser induced incandescence. AB - Time-resolved laser-induced incandescence (TiRe-LII) data can be used to infer spatially and temporally resolved volume fractions and primary particle size distributions of soot-laden aerosols, but these estimates are corrupted by measurement noise as well as uncertainties in the spectroscopic and heat transfer submodels used to interpret the data. Estimates of the temperature, concentration, and size distribution of soot primary particles within a sample aerosol are typically made by nonlinear regression of modeled spectral incandescence decay, or effective temperature decay, to experimental data. In this work, we employ nonstationary Bayesian estimation techniques to infer aerosol properties from simulated and experimental LII signals, specifically the extended Kalman filter and Schmidt-Kalman filter. These techniques exploit the time-varying nature of both the measurements and the models, and they reveal how uncertainty in the estimates computed from TiRe-LII data evolves over time. Both techniques perform better when compared with standard deterministic estimates; however, we demonstrate that the Schmidt-Kalman filter produces more realistic uncertainty estimates. PMID- 29522041 TI - Tuning the resonance of polarization-degenerate LP1,l cladding mode in excessively tilted long period fiber grating for highly sensitive refractive index sensing. AB - This work presents a sensitive refractive index sensor based on the dual resonance of an excessively tilted long period fiber grating (Ex-TLPFG). The Ex TLPFG is tuned to couple the guided core mode with only the polarization degenerate cladding mode LP1,l, which consists of TE/TM0,l and HE2,l vector modes. It is found that the p-polarized LP1,lp mode exhibits a higher sensitivity than that of the s-polarized LP1,ls mode. An optimized sensitivity as high as 12182.9 nm/RIU is achieved for the p-polarized LP1,2p mode at the low refractive index region by tuning the initial resonance condition. The sensing performance is also evaluated through the power measurement method for a single resonance band. It is demonstrated that the improved sensitivity in this work for diameter reduced Ex-TLPFG is much higher than that for the conventional LPFG based devices, which makes this sensing platform very attractive for a variety of index sensing applications. PMID- 29522042 TI - Forward scattering of polarized light from birefringent turbid slab media: Monte Carlo simulation. AB - The reduced effective Mueller matrices of forward scattering from birefringent turbid slab media were calculated using a Monte Carlo simulation and were factorized in two dimensions by the Lu-Chipman polar decomposition. For a slab medium with the birefringence axis parallel to the y axis, the polarization parameters have second- or fourth-order rotational symmetry. Especially, the absolute value of linear retardance |delta| shows a characteristic variation; it becomes maximal at the azimuths of 0 degrees and 180 degrees but minimal at 90 degrees and 270 degrees . These features exactly agree with the measurement results. However, when the birefringence axis is inclined to the slab surfaces, the polarization parameters become non-symmetric with respect to the x-z plane, though they are symmetric or anti-symmetric with respect to the y-z plane. Moreover, as the inclination angle becomes larger than 45 degrees , the fast-axis orientation exhibits new centers of the radial pattern whose position becomes closer to the preexisting center. The photon trajectory in the medium may be approximated by a double scattering model in which the photon penetrates forward into a depth, travels along the radial direction, and propagates forward to the front surface for exiting. The non-symmetry of the polarization parameters and the appearance of the second centers of the radial pattern suggest that the radial traveling of the photon may be oblique forward and that the obliqueness angle becomes smaller as the photon exits at distances farther away from the center. PMID- 29522043 TI - Large group delay in a microwave metamaterial analog of electromagnetically induced reflectance. AB - Recently reported metamaterial (MM) analogs of electromagnetically induced reflectance (EIR) enable a unique route to endow classical optical structures with aspects of quantum optical systems. This method opens up many fascinating prospects on novel optical components, such as slow light units, highly sensitive sensors, and nonlinear devices. Here we designed and simulated a microwave MM made from aluminum thin film to mimic the EIR system. High reflectance of about 99 percent and also a large group index at the reflectance window of about 243 are demonstrated, which mainly arise from the enhanced coupling between radiative and nonradiative elements. The interaction between the elements of the unit cell, induced directly or indirectly by the incident electromagnetic wave, leads to a reflectance window, resembling the classical analog of EIR. This reflectance window, caused by the coupling of radiative-nonradiative modes, can be continuously tuned in a broad frequency regime. The strong normal phase dispersion in the vicinity of this reflectance window results in the slow light effect. This scheme provides an alternative way to achieve tunable slow light in a broad frequency band and can find important applications in active and reversibly tunable slow light devices. PMID- 29522044 TI - Numerical simulations of spectral shifts in the far-field spectrum of light due to source correlations. AB - We discuss how to simulate numerically the far-field propagation of the spectrum of light by propagating the cross-spectral density for a planar light source with a given coherence model. To test our approach, we performed simulations for two source models: a Gaussian Schell-model source and a nonuniformly Gaussian correlated source. We show that our algorithm correctly reproduces the theoretical solutions by Emil Wolf for planar Gaussian Schell-model source, namely, the spectral shifts of spectral lines due to source correlations. Our approach can be used for two-dimensional source models in which the spatial coherence components are frequency independent. It can also be used for nonhomogeneous extended sources of partial coherent light. PMID- 29522045 TI - Broadband ultra-flattened dispersion, ultra-low confinement loss and large effective mode area in an octagonal photonic quasi-crystal fiber. AB - In this work, an octagonal Penrose-type photonic quasi-crystal fiber (PQF) with dual-cladding is proposed. By optimizing three geometric degrees of freedom, the PQF exhibits ultra-flattened near-zero dispersion of 0.014+/-0.293 ps/nm/km, ultra-low order confinement loss of 10-4 dB/km, and large effective mode area of over 16.2 MUm2 in a broadband of wavelength from 1.27 to 1.67 MUm, covering almost all optical communication bands. At the common communication wavelength 1.55 MUm, completely opposite trends of the dispersion and the confinement loss varying with the air-filling factor in the inner cladding are demonstrated. In addition, the robustness of optical properties including dispersion, confinement loss, and effective mode area in this PQF is discussed, assuming a deviation +/ 3% of all air holes. PMID- 29522046 TI - Explaining negative refraction without negative refractive indices. AB - Negative refraction through a triangular prism may be explained without assigning a negative refractive index to the prism by using array theory. For the case of a beam incident upon the wedge, the array theory accurately predicts the beam transmission angle through the prism and provides an estimate of the frequency interval at which negative refraction occurs. The hypotenuse of the prism has a staircase shape because it is built of cubic unit cells. The large phase delay imparted by each unit cell, combined with the staircase shape of the hypotenuse, creates the necessary conditions for negative refraction. Full-wave simulations using the finite-difference time-domain method show that array theory accurately predicts the beam transmission angle. PMID- 29522047 TI - Deferred slanted-edge analysis: a unified approach to spatial frequency response measurement on distorted images and color filter array subsets. AB - The slanted-edge method of spatial frequency response (SFR) measurement is usually applied to grayscale images under the assumption that any distortion of the expected straight edge is negligible. By decoupling the edge orientation and position estimation step from the edge spread function construction step, it is shown in this paper that the slanted-edge method can be extended to allow it to be applied to images suffering from significant geometric distortion, such as produced by equiangular fisheye lenses. This same decoupling also allows the slanted-edge method to be applied directly to Bayer-mosaicked images so that the SFR of the color filter array subsets can be measured directly without the unwanted influence of demosaicking artifacts. Numerical simulation results are presented to demonstrate the efficacy of the proposed deferred slanted-edge method in relation to existing methods. PMID- 29522048 TI - Nondiffracting light beams carrying fractional orbital angular momentum. AB - We investigate a new class of nondiffracting optical beams carrying fractional orbital angular momentum (FOAM Bessel beams), which can be constructed by modifying the phase step of the spiral phase plate in a setup originally for the generation of traditional Bessel beams. The FOAM Bessel beams have entirely stable vortex structures, and form an infinite number of orthogonal and complete subsets for monochromatic scalar light in free space. With the advantages of structural stability and orthogonality-completeness, the FOAM Bessel beams are expected to be useful for study and application in various fields of modern optics. PMID- 29522049 TI - Propagation characteristics of controllable dark-hollow beams in a quadratic index medium. AB - In this paper, the propagation of controllable dark-hollow beams (CDHBs) passing through a quadratic-index medium is studied. An analytical expression for the propagation of CDHBs in a quadratic-index medium is presented based on the ABCD matrix method, and the effect of the beam parameters on the evolution of a CDHB is investigated. It is found that the intensity distribution of CDHBs evolves periodically during propagation in the quadratic-index medium. The results indicate that the distance in which the dark-hollow center of a CDHB disappears can be increased by the beam parameters. PMID- 29522050 TI - Wavefront measurement using computational adaptive optics. AB - In many optical imaging applications, it is necessary to correct for aberrations to obtain high quality images. Optical coherence tomography (OCT) provides access to the amplitude and phase of the backscattered optical field for three dimensional (3D) imaging samples. Computational adaptive optics (CAO) modifies the phase of the OCT data in the spatial frequency domain to correct optical aberrations without using a deformable mirror, as is commonly done in hardware based adaptive optics (AO). This provides improvement of image quality throughout the 3D volume, enabling imaging across greater depth ranges and in highly aberrated samples. However, the CAO aberration correction has a complicated relation to the imaging pupil and is not a direct measurement of the pupil aberrations. Here we present new methods for recovering the wavefront aberrations directly from the OCT data without the use of hardware adaptive optics. This enables both computational measurement and correction of optical aberrations. PMID- 29522051 TI - Optical sectioning enhancement using higher-order moment signals in random speckle-structured illumination microscopy. AB - The optical sectioning capability of structured illumination using random speckle patterns is shown by simulations to improve when cumulants beyond the traditional second order are used as the image-forming signals. The improvement scales with the cumulant order, asymptotically approaching confocal performance. As actual experiments operate with finite-size sample estimators instead of true cumulants, purely statistical (nonoptical) effects can result in nonideal behavior. We analyze the finite ensemble effects along with the experimental effects of detector dynamic range through Monte Carlo simulations. Despite these real-world factors, we show when the third-order-derived signal can demonstrate improved sectioning at good signal-to-noise levels set by finite-sample effects. PMID- 29522052 TI - Multi-focus image fusion algorithm based on Laplacian pyramids. AB - In this paper, we propose a method named region mosaicking on Laplacian pyramids (RMLP) to fuse multi-focus images that are captured by microscope. First, we apply the sum-modified Laplacian to measure the focus of multi-focus images. Then the density-based region growing algorithm is utilized to segment the focused region mask of each image. Finally, the mask is decomposed into a mask pyramid to supervise region mosaicking on a Laplacian pyramid. The region level pyramid keeps more original information than the pixel level. The experiment results show that RMLP has the best performance in quantitative comparison with other methods. In addition, RMLP is insensitive to noise and can reduce the color distortion of the fused images on two datasets. PMID- 29522053 TI - Far-field super-oscillation imaging based on the super-oscillation elements and PSF feature extraction algorithm. AB - Suffering from the limited number aperture, a resolution higher than 0.5lambda cannot be obtained in conventional far-field optical imaging systems. Recently, research of the optical super-oscillation lens (SOL) has been demonstrated to realize sub-diffractive focusing in both theory and practice successfully. Nevertheless, these systems usually have characteristics of a localized field of view and low-intensity focal spot surrounded by huge sidelobes, which profoundly restricts their application for super-resolution imaging. In this paper, we artificially segment the SOL into two simple-fabrication portions to generate the super-oscillation optical field and realize off-axis far-field imaging. Meanwhile, the point spread function (PSF) feature extraction algorithm is proposed to break the limitation of low core intensity of the PSF and then effectively extract the sub-diffractive structure annihilated by huge sidelobes. Simulations demonstrate its feasibility and reliability in sub-diffraction information recovery, and targets with a resolution of 250 nm are well recovered in the super-oscillation area. PMID- 29522054 TI - Fresnel diffraction from the edge of a transparent plate in the general case. AB - Fresnel diffraction from the edge of a transparent plate with arbitrary orientation of its surfaces is formulated in transmission mode. It is shown theoretically and evaluated experimentally that the thickness of a plate and the angles between its surfaces, near the edge, can be determined accurately. This allows us to construct a quantitative 3D image of the plate edge. It is also illustrated that the recorded diffraction pattern of a plate edge can be regarded as a hologram produced by the interference of two diffracted waves: one passing above the plate and the other transmitting through the plate near the edge. Thus, the hologram makes it possible to reconstruct the plate's edge as a 3D image, and the approach can be utilized in constructing 3D images of phase objects and in quantitative phase microscopy. PMID- 29522055 TI - Photonic crystals: role of architecture and disorder on spectral properties. AB - Many of the present-day optical devices use photonic crystals. These are multilayers of dielectric media that control the reflection and transmission of light falling on them. In this paper, we study the optical properties of periodic, fractal, and aperiodic photonic crystals and compare them based on their attributes. Our calculations of the band reflectivity and degree of robustness reveal novel features, e.g., fractal photonic crystals are found to reflect the maximum amount of incident light. On the other hand, aperiodic photonic crystals have the largest immunity to disorder. We believe that such properties will be useful in a variety of applications in the field of optical communication. PMID- 29522056 TI - Advances in malaria vaccine development: report from the 2017 malaria vaccine symposium. AB - The Malaria Vaccine Symposium occurred at Johns Hopkins University in Baltimore, MD, USA on April 25th, 2017, coinciding with World Malaria Day and the WHO announcement that the RTS,S malaria vaccine would begin pilot implementation programs in Ghana, Kenya, and Malawi in 2018. Scientists from several disciplines reported progress on an array of malaria vaccine concepts and product candidates, including pre-erythrocytic vaccines that prevent infection, blood-stage vaccines that limit infection and disease, and transmission-blocking vaccines that interrupt the spread of infection. Other speakers highlighted the immunological and genetic considerations that must be addressed by vaccinologists to yield the most efficacious vaccines. Here, we highlight the advances in malaria vaccinology that were reported at the symposium. PMID- 29522058 TI - Structure-composition trends in multicomponent borosilicate-based glasses deduced from molecular dynamics simulations with improved B-O and P-O force fields. AB - We present a comprehensive molecular dynamics (MD) simulation study of composition-structure trends in a set of 25 glasses of widely spanning compositions from the following four systems of increasing complexity: Na2O-B2O3, Na2O-B2O3-SiO2, Na2O-CaO-SiO2-P2O5, and Na2O-CaO-B2O3-SiO2-P2O5. The simulations involved new B-O and P-O potential parameters developed within the polarizable shell-model framework, thereby combining the beneficial features of an overall high accuracy and excellent transferability among different glass systems and compositions: this was confirmed by the good accordance with experimental data on the relative BO3/BO4 populations in borate and boro(phospho)silicate networks, as well as with the orthophosphate fractions in bioactive (boro)phosphosilicate glasses, which is believed to strongly influence their bone-bonding properties. The bearing of the simulated melt-cooling rate on the borate/phosphate speciations is discussed. Each local {BO3, BO4, SiO4, PO4} coordination environment remained independent of the precise set of co-existing network formers, while all trends observed in bond-lengths/angles mainly reflected the glass-network polymerization, i.e., the relative amounts of bridging oxygen (BO) and non-bridging oxygen (NBO) species. The structural roles of the Na+/Ca2+ cations were also probed, targeting their local coordination environments and their relative preferences to associate with the various borate, silicate, and phosphate moieties. We evaluate and discuss the common classification of alkali/alkaline-earth metal ions as charge-compensators of either BO4 tetrahedra or NBO anions in borosilicate glasses, also encompassing the less explored NBO rich regime: the Na+/Ca2+ cations mainly associate with BO/NBO species of SiO4/BO3 groups, with significant relative Na-BO4 contacts only observed in B rich glass networks devoid of NBO species, whereas NBO-rich glass networks also reveal substantial amounts of NBO-bearing BO4 tetrahedra. PMID- 29522057 TI - 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2. AB - Prolyl hydroxylation of hypoxia inducible factor (HIF)-alpha, as catalysed by the Fe(ii)/2-oxoglutarate (2OG)-dependent prolyl hydroxylase domain (PHD) enzymes, has a hypoxia sensing role in animals. We report that binding of prolyl hydroxylated HIF-alpha to PHD2 is ~50 fold hindered by prior 2OG binding; thus, when 2OG is limiting, HIF-alpha degradation might be inhibited by PHD binding. PMID- 29522059 TI - Efficacy of Multicolor Imaging in Patients With Asteroid Hyalosis: Seeing the Unseen. PMID- 29522060 TI - Opsoclonus-Myoclonus Syndrome-Reply. PMID- 29522061 TI - Association of Social Support Network Size With Receipt of Cataract Surgery in Older Adults. AB - Importance: Cataract-related vision impairment is an important public health issue that tends to affect older adults. Little is known about the association between older adults' social support networks and their likelihood of receiving cataract surgery. Objective: To determine if older adults with smaller social support networks are less likely to receive cataract surgery. Design, Setting, and Participants: Retrospective cohort study. The National Health and Aging Trends Study, a nationally representative US survey, administered annually from 2011 to 2015 to a cohort of Medicare beneficiaries 65 years and older with no cataract surgery prior to the start of the study. Main Outcomes and Measures: Multivariable logistic regression was performed to evaluate if the number of persons in an individual's social support network influenced whether that individual received cataract surgery during a given year of the study. Results: Overall, 3448 participants were interviewed from 2011 to 2015 for a total of 9760 observations. Of these observations, 3084 (weighted, 38.81%; 95% CI, 37.28-40.35) were aged 70 to 74 years, 5211 (weighted, 52.32%; 95% CI, 50.19-54.44) were women; 5899 (weighted, 78.53%; 95% CI, 76.29-80.61) were white, 2249 (weighted, 9.55%; 95% CI, 8.45-10.78) were black, 537 (weighted, 7.18%; 95% CI, 5.88-8.73) were Hispanic, and 303 (weighted, 4.74%; 95% CI, 3.56-62.9) reported other races. Medicare beneficiaries with smaller social support networks (0-2 individuals) were less likely to receive cataract surgery in a given year (adjusted odds ratio, 0.60; 95% CI, 0.37-0.96) than those with larger support networks (>=3 individuals). The adjusted predicted proportion of Medicare beneficiaries undergoing cataract surgery was 4.7% (95% CI, 2.7%-6.7%) and 7.5% (95% CI, 6.9% 8.1%) for those with small and large social support networks, respectively. Having fewer non-spouse/partner family members in the support network was associated with decreased odds of receiving cataract surgery (adjusted odds ratio, 0.60; 95% CI, 0.43-0.85), but having spouses/partners (adjusted odds ratio, 0.97; 95% CI, 0.77-1.22) and nonfamily members (adjusted odds ratio, 0.90; 95% CI, 0.72-1.11) did not have a significant association. Conclusions and Relevance: Medicare beneficiaries with fewer non-spouse/partner family members in their social support networks were less likely to receive cataract surgery. These findings suggest that attention should be given to patients with smaller support networks to ensure that they receive cataract surgery when it is indicated. PMID- 29522062 TI - Errors in Questionnaire Scoring Algorithm. PMID- 29522063 TI - Errors in Items and Algorithm in Questionnaire Used in Validation Study. PMID- 29522064 TI - Revisiting Congenital Stationary Night Blindness in the Molecular Era. PMID- 29522065 TI - Opioid Prescription Patterns Among Patients With Head and Neck Cancer. PMID- 29522066 TI - A Test Battery for Inner Speech Functions. AB - Objective: Inner speech, or the ability to talk to yourself in your head, is one of the most ubiquitous phenomena of everyday experience. Recent years have seen growing interest in the role and function of inner speech in various typical and cognitively impaired populations. Although people vary in their ability to produce inner speech, there is currently no test battery which can be used to evaluate people's inner speech ability. Here we developed a test battery which can be used to evaluate individual differences in the ability to access the auditory word form internally. Methods: We developed and standardized five tests: rhyme judgment of pictures and written words, homophone judgment of written words and non-words, and judgment of lexical stress of written words. The tasks were administered to adult healthy native British English speakers (age range 20-72, n = 28-97, varies between tests). Results: In all tests, some items were excluded based on low success rates among participants, or documented regional variability in accent. Level of education, but not age, correlated with task performance for some of the tasks, and there were no gender difference in performance. Conclusion: A process of standardization resulted in a battery of tests which can be used to assess natural variability of inner speech abilities among English speaking adults. PMID- 29522067 TI - Sex differences in attaining cigarette smoking and nicotine dependence milestones in novice smokers. PMID- 29522068 TI - The American Society for Clinical Pathology's 2016-2017 Vacancy Survey of Medical Laboratories in the United States. AB - Objectives: To determine the extent and distribution of workforce shortages within the nation's medical laboratories. Methods: The 2016-2017 Vacancy Survey was conducted through collaboration between the American Society for Clinical Pathology's Institute of Science, Technology, & Policy in Washington, DC, and the Evaluation, Measurement, and Assessment division and Board of Certification in Chicago, Illinois. Data were collected via an internet survey that was distributed to individuals who were able to report on staffing and certifications for their laboratories. Results: Results of the 2016-2017 Vacancy Survey shows decreased vacancy rates for laboratory positions across all departments surveyed compared with 2014. While overall, the data show that vacancy rates are decreasing, overall retirement rates and certification requirements are higher. Conclusions: Focus on the qualifications and certification status of laboratory professionals would be crucial factors in addressing the needs of the laboratory workforce. The field needs to intensify its efforts on recruiting the next generation of laboratory personnel. PMID- 29522069 TI - Methodological and Efficacy Issues in a Randomized Clinical Trial Investigating Vitreous Floater Treatment. PMID- 29522071 TI - Methodological and Efficacy Issues in a Randomized Clinical Trial Investigating Vitreous Floater Treatment. PMID- 29522070 TI - Presentation of TRPM1-Associated Congenital Stationary Night Blindness in Children. AB - Importance: Congenital stationary night blindness (CSNB) implies a stable condition, with the major symptom being nyctalopia present at birth. Pediatric clinical presentation and the course of different genetic subtypes of CSNB have not, to our knowledge, been well described in the era of molecular genetic diagnosis. Objective: To describe the presentation and longitudinal clinical characteristics of pediatric patients with molecularly confirmed TRPM1-associated complete CSNB (cCSNB). Design, Setting, Participants: This study was conducted at the University of Iowa from January 1, 1990, to July 1, 2015, and was a retrospective, longitudinal case series of 7 children (5 [71.4%] female) with TRPM1-associated cCSNB followed up for a mean (SD) of 11.1 (2.8) years. Main Outcomes and Measures: History, ophthalmologic examination findings, full-field electroretinogram (ffERG) results, full-field stimulus threshold testing results, Goldmann visual field results, optical coherence tomography results, and molecular genetic results were evaluated. Presenting symptoms and signs, the correlation of refractive error with electroretinography, and clinical evolution were analyzed. Results: Seven patients (5 [71.4%] female) presented early in childhood with strabismus (n = 6 [86%]), myopia (n = 5 [71%]), and/or nystagmus (n = 3 [43%]). The mean (SD) age at presentation was 8 (4) months and for receiving a diagnosis by ffERG was 7.3 years, with molecular diagnosis at 9.7 years. The mean (SD) length of follow-up was 11 (2.8) years. The best-corrected visual acuity at the most recent visit averaged 20/30 in the better-seeing eye (range, 20/20-20/60). The mean (SD) initial refraction was -2.80 (4.42) diopters (D) and the mean refraction at the most recent visit was -8.75 (3.53) D (range, 4.00 to -13.75 D), with the greatest rate of myopic shift before age 5 years. Full-field electroretinogram results were electronegative, consistent with cCSNB, without a significant change in amplitude over time. No patient or parent noted night blindness at presentation; however, subjective nyctalopia was eventually reported in 5 of 7 patients (71%). The full-field stimulus threshold testing results were moderately subnormal (-29.7 [3.8] dB; normal -59.8 [4.0] dB). Goldmann visual field results were significant for full I-4e, but constricted I 2e isopter. Eight different mutations or rare variants in TRPM1 predicted to be pathogenic were detected, with 3 novel variants. Conclusions and Relevance: Children with TRPM1-associated cCSNB presented before school age with progressive myopia as well as strabismus and nystagmus (but not nyctalopia), with stable, electronegative ffERG results, mildly subnormal full-field stimulus threshold testing results, and a constricted I2e isopter on perimetry. These findings suggest that ffERG and cCSNB genetic testing should be considered for children who present with early-onset myopia, especially in the presence of strabismus and/or nystagmus, and that TRPM1-associated cCSNB is a channelopathy that may present without complaints of night blindness in childhood. PMID- 29522072 TI - Association of Survival With Shorter Time to Radiation Therapy After Surgery for US Patients With Head and Neck Cancer. AB - Importance: Shortening the time from surgery to the start of radiation (TS-RT) is a consideration for physicians and patients. Although the National Comprehensive Cancer Network recommends radiation to start within 6 weeks, a survival benefit with this metric remains controversial. Objective: To determine the association of delayed TS-RT with overall survival (OS) using a large cancer registry. Design, Setting, and Participants: In this observational cohort study, 25 216 patients with nonmetastatic stages III to IV head and neck cancer were identified from the National Cancer Database (NCDB). Exposures: Patients received definitive surgery followed by adjuvant radiation therapy, with an interval duration defined as TS-RT. Main Outcomes and Measures: Overall survival as a function of TS-RT and the effect of clinicopathologic risk factors and accelerated fractionation. Results: We identified 25 216 patients with nonmetastatic squamous cell carcinoma of the head and neck. There were 18 968 (75%) men and 6248 (25%) women and the mean (SD) age of the cohort was 59 (10.9) years. Of the 25 216 patients, 9765 (39%) had a 42-days or less TS-RT and 4735 (19%) had a 43- to 49-day TS-RT. Median OS was 10.5 years (95% CI, 10.0-11.1 years) for patients with a 42-days or less TS-RT, 8.2 years (95% CI, 7.4-8.6 years; absolute difference, -2.4 years, 95% CI, -1.5 to -3.2 years) for patients with a 43- to 49-day TS-RT, and 6.5 years (95% CI, 6.1-6.8 years; absolute difference, -4.1 years, 95% CI, -3.4 to 4.7 years) for those with a 50-days or more TS-RT. Multivariable analysis found that compared with a 42-days or less TS-RT, there was not a significant increase in mortality with a 43- to 49-day TS-RT (HR, 0.98; 95% CI, 0.93-1.04), although there was for a TS-RT of 50 days or more (HR, 1.07; 95% CI, 1.02-1.12). A significant interaction was identified between TS-RT and disease site. Subgroup effect modeling found that a delayed TS-RT of 7 days resulted in significantly worse OS for patients with tonsil tumors (HR, 1.22; 95% CI, 1.05-1.43) though not other tumor subtypes. Accelerated fractionation of 5.2 fractions or more per week was associated with improved survival (HR, 0.93; 95% CI, 0.87-0.99) compared with standard fractionation. Conclusions and Relevance: Delayed TS-RT of 50 days or more was associated with worse overall survival. The multidisciplinary care team should focus on shortening TS-RT to improve survival. Unavoidable delays may be an indication for accelerated fractionation or other dose intensification strategies. PMID- 29522073 TI - Reanalysis of Diesel Engine Exhaust and Lung Cancer Mortality in the Diesel Exhaust in Miners Study Cohort Using Alternative Exposure Estimates and Radon Adjustment. AB - The Diesel Exhaust in Miners Study (DEMS) (United States, 1947-1997) reported positive associations between diesel engine exhaust exposure, estimated as respirable elemental carbon (REC), and lung cancer mortality. This reanalysis of the DEMS cohort used an alternative estimate of REC exposure incorporating historical data on diesel equipment, engine horsepower, ventilation rates, and declines in particulate matter emissions per horsepower. Associations with cumulative REC and average REC intensity using the alternative REC estimate and other exposure estimates were generally attenuated compared with original DEMS REC estimates. Most findings were statistically nonsignificant; control for radon exposure substantially weakened associations with the original and alternative REC estimates. No association with original or alternative REC estimates was detected among miners who worked exclusively underground. Positive associations were detected among limestone workers, whereas no association with REC or radon was found among workers in the other 7 mines. The differences in results based on alternative exposure estimates, control for radon, and stratification by worker location or mine type highlight areas of uncertainty in the DEMS data. PMID- 29522074 TI - Cure With Cryoablation of Arterial Hypertension Due to a Renin-Producing Tumor. AB - BACKGROUND: We herein report on a 20 years old woman with stage I hypertension, who was found to carry a renin-producing tumor (RPT). METHODS: Due to her young age, the patient underwent screening measurement of plasma renin and aldosterone, abdominal computed tomography (CT) angiography, and selective renal vein renin assessment to identify secondary hypertension. RESULTS: The patient was screened for secondary causes of hypertension and was diagnosed with secondary aldosteronism. Therefore, she underwent an abdominal computed tomography (CT) angiography that was reported as unremarkable. Selective renal vein renin studies showed overproduction of renin in the right kidney and a re-evaluation of her CT allowed detection of an 8-mm mass in her right kidney, suggesting the presence of a RPT. Considering the technical difficulty of renal sparing surgery a CT-guided cryoablation was undertaken, which provided long-term cure of arterial hypertension and normalization of plasma active renin concentration. CONCLUSIONS: RPTs usually present with a clinical phenotype featuring stage III and/or malignant hypertension and are held to be exceptionally rare. This case is unique in that it presented with stage I hypertension and a mild clinical phenotype. Moreover, to our knowledge this is the first case of RPTs shown to be safely treated with CT-guided cryoablation and found to be cured at long-term. PMID- 29522075 TI - Characterization of the Relationships Between Sleep Duration, Quality, Architecture, and Chemosensory Function in Nonobese Females. AB - Little is known about the relationship between sleep and chemosensation. The purpose of this study was to characterize the relationship between chemosensory function and sleep duration, quality, and architecture. A total of 56 nonobese (body mass index <30 kg/m2) female participants who denied having diagnosed sleep disorders completed testing. Sleep was measured for two nights using a single channel (A1-A2) electroencephalogram (Zmachine). Sweet taste threshold and preference as well as olfactory threshold, recognition ability, and pleasantness ratings were evaluated. Sweet taste preference was correlated with total sleep time (TST) (P = 0.0074) as well as with the sum of rapid eye movement (REM) and stage N3/slow wave sleep (SWS) duration (P = 0.0008). Participants who slept more than the average TST or more than the average REM + SWS time preferred lower concentrations of sweetness (P = 0.041 and 0.049, respectively), than those whose sleep times fell below the means. Multiple linear regression revealed that REM and SWS predicted ~18% of the variance of sweet taste preference. These findings suggest that scientific and consumer studies related to sweet preference might benefit from screening participants for short sleep duration prior to testing. PMID- 29522077 TI - JAMA Facial Plastic Surgery-The Year in Review, 2017. PMID- 29522076 TI - Drug-Drug Interaction Studies Between Hepatitis C Virus Antivirals Sofosbuvir/Velpatasvir and Boosted and Unboosted Human Immunodeficiency Virus Antiretroviral Regimens in Healthy Volunteers. AB - Background: Combining antiviral regimens in the hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected population can be complex as they share overlapping mechanisms for elimination that may result in drug interactions. The pharmacokinetics, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) with multiple antiretroviral (ARV) regimens were evaluated. Methods: Healthy volunteers were enrolled into 2 phase 1, open-label, randomized, multiple-dose, cross-over studies. SOF/VEL and ARV regimens were administered alone and in combination; ARVs (and pharmacokinetic enhancers) included atazanavir (ATV), cobicistat (COBI), darunavir (DRV), dolutegravir (DTG), efavirenz (EFV), elvitegravir (EVG), emtricitabine (FTC), lopinavir (LPV), raltegravir (RAL), rilpivirine (RPV), ritonavir (RTV), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF). Geometric least squares means ratios (coadministration:alone) and 90% confidence intervals were constructed for area under the plasma concentration-time curve over the dosing interval, maximum concentration, and trough, for all analytes. Safety and tolerability were also evaluated. Results: In total, 237 participants were enrolled. No clinically relevant differences in the pharmacokinetics (PK) of SOF, SOF metabolite GS 331007, or VEL were observed other than an approximate 50% decrease in VEL exposure when administered with EFV/FTC/TDF. No clinically relevant differences in the PK of ARVs were observed when administered with SOF/VEL. Study treatments were well tolerated, including no observed creatinine clearance changes during evaluation of TDF-containing regimens. Conclusions: SOF/VEL and ARV regimens including ATV, COBI, DRV, DTG, EVG, FTC, LPV, RAL, RPV, RTV, TAF, or TDF may be coadministered without dose adjustment. Use of SOF/VEL with EFV-containing regimens is not recommended due to an approximate 50% reduction in VEL exposure. PMID- 29522078 TI - BPRMeth: a flexible Bioconductor package for modelling methylation profiles. AB - Motivation: High-throughput measurements of DNA methylation are increasingly becoming a mainstay of biomedical investigations. While the methylation status of individual cytosines can sometimes be informative, several recent papers have shown that the functional role of DNA methylation is better captured by a quantitative analysis of the spatial variation of methylation across a genomic region. Results: Here, we present BPRMeth, a Bioconductor package that quantifies methylation profiles by generalized linear model regression. The original implementation has been enhanced in two important ways: we introduced a fast, variational inference approach that enables the quantification of Bayesian posterior confidence measures on the model, and we adapted the method to use several observation models, making it suitable for a diverse range of platforms including single-cell analyses and methylation arrays. Availability and implementation: http://bioconductor.org/packages/BPRMeth. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522079 TI - Design Strategy of the Sabes Study: Diagnosis and Treatment of Early HIV Infection Among Men Who Have Sex With Men and Transgender Women in Lima, Peru, 2013-2017. AB - The Sabes study evaluates a treatment-as-prevention intervention in cis-gender men who have sex with men and transgender women in Lima, Peru, populations disproportionately affected by the HIV epidemic. The intervention is designed to prevent onward transmission of HIV by identifying HIV-negative, high-risk individuals, testing them monthly for the presence of HIV, and then rapidly treating those who become HIV positive. The main outcome of interest is the development of a model predicting the population-level impact of early detection of HIV infection and immediate initiation of antiretroviral therapy (ART) in this population From July 2013 to September 2015, 3,336 subjects were screened for HIV; 2,682 (80.4%) were negative and 2,084 began monthly testing. We identified 248 individuals shortly after HIV acquisition, 215 of whom were enrolled in the treatment phase of our study. All participants were followed for 48 weeks and then were referred to the Peruvian Ministry of Health to continue free HIV care and treatment. This intervention demonstrates that it is possible to recruit high risk individuals, screen them for HIV, continue to test those who are initially HIV negative in order to identify incident cases shortly after acquisition, and then rapidly link them to care. PMID- 29522080 TI - Competing Effects Of Indirect Protection And Clustering On The Power Of Cluster Randomized Controlled Vaccine Trials. PMID- 29522081 TI - THE AUTHORS REPLY. PMID- 29522082 TI - Determination of S-Allylmercaptocysteine in Rat Plasma by LC-MS/MS and its Application to a Pharmacokinetics Study. AB - In this work, a rapid, simple, sensitive and specific LC-MS/MS method was developed and validated for the quantification of S-Allylmercaptocysteine (SAMC) in plasma. After a simple sample procedure by one step protein precipitation with acetontrile, the samples were separated on Gemini-NX C18 column (2.1 mm i.d. 150 mm, 3 MUm, Phenomenex). The mobile phase was composed of water-acetonitrile (20:80, v/v) at an isocratic flow rate of 0.3 mL/min. The developed method was validated based on the International Conference on Harmonization (ICH) guidelines. The results show that the method had satisfactory specificity, precision and accuracy in a linear range of 50-3,000 ng/mL for SAMC. The precision conformed to the acceptance criteria, and the lower limit of quantification was 50 ng/mL for the analyte. The plasma samples stored for 10 days or after two freeze-thaw cycles (-80 degrees C) were stable. This method was successfully applied to a pharmacokinetics study of SAMC in rats. It was found that SAMC metabolized very quickly in rats and its plasma half-life was less than 5 min. PMID- 29522083 TI - Can Brain-Derived Neurotrophic Factor Therapy Improve Clinical Outcomes of Cochlear Implantation? PMID- 29522085 TI - Association of CYP2B6 Single-Nucleotide Polymorphisms Altering Efavirenz Metabolism With Hepatitis C Virus (HCV) Treatment Relapse Among Human Immunodeficiency Virus/HCV-Coinfected African Americans Receiving Ledipasvir/Sofosbuvir in the ION-4 Trial. AB - In the ION-4 trial, hepatitis C virus relapse was rare, occurring only in African American patients, 80% receiving efavirenz for human immunodeficiency virus infection. We observed no indication that CYP2B6 polymorphisms associated with increased plasma efavirenz exposure explained the relapses. PMID- 29522086 TI - RE: "CURRENT CHALLENGES AND NEW OPPORTUNITIES FOR GENE-ENVIRONMENT INTERACTION STUDIES OF COMPLEX DISEASES". PMID- 29522087 TI - Eroding Access and Quality of Childbirth Care in Rural US Counties. PMID- 29522088 TI - Lessons From the Testosterone Trials. AB - The Testosterone Trials (TTrials) were a coordinated set of seven placebo controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk. PMID- 29522090 TI - Cranial Computed Tomography, Lumbar Puncture, and Clinical Deterioration in Bacterial Meningitis: A Nationwide Cohort Study. AB - Background: It is unclear how often lumbar puncture (LP) is complicated by cerebral herniation in patients with bacterial meningitis and whether cranial computed tomography (CT) can be used to identify patients at risk for herniation. Methods: We performed a nationwide prospective cohort study of patients with community-acquired bacterial meningitis from 2006 to 2014 and identified patients with clinical deterioration possibly caused by LP. For systematic evaluation of contraindications for LP on cranial CT, these patients were matched to patients in the cohort without deterioration. Four experts, blinded for outcome, scored cranial CT results for contraindications for LP. A Fleiss' generalized kappa for this assessment was determined. Results: Of 1533 episodes, 47 (3.1%) had deterioration possibly caused by LP. Two patients deteriorated within 1 hour after LP (0.1%). In 43 of 47 patients with deterioration, cranial CT was performed prior to LP, so CT results were matched with 43 patients without deterioration. The interrater reliability of assessment of contraindications for LP on cranial CT was moderate (Fleiss' generalized kappa = 0.47). A contraindication for LP was reported by all 4 raters in 6 patients with deterioration (14%) and in 5 without deterioration (11%). Conclusions: LP can be performed safely in the large majority of patients with bacterial meningitis, as it is only very rarely complicated by cerebral herniation. Cranial CT can be considered a screening method for contraindications for LP, but the interrater reliability of this assessment is moderate. PMID- 29522089 TI - Malaria and Nutritional Status Among Children With Severe Acute Malnutrition in Niger: A Prospective Cohort Study. AB - Background: The relationship between malaria infection and nutritional status is complex. Previous studies suggest malaria may increase the incidence and severity of malnutrition, while malnutrition may increase the risk of malaria infection. Here, we report bidirectional associations between malaria and nutritional status among children with uncomplicated severe acute malnutrition (SAM). Methods: This study is a secondary analysis of a randomized, controlled trial for the treatment of uncomplicated SAM in Niger. Children aged 6-59 months were enrolled and followed for 12 weeks. Malaria infection was assessed using an histidine-rich protein 2 (HRP2) rapid diagnostic test at admission and at any follow-up visit with fever. We assessed the association of nutritional status at admission on malaria incidence using Cox proportional hazards regression and malaria infection at admission on nutritional recovery and weight and height gain using linear regression. Results: Of 2399 children included in the analysis, 1327 (55.3%) were infected with malaria at admission. Malaria incidence was 12.1 cases/100 person months among those without malaria infection at admission. Nutritional status at admission was not associated with malaria incidence. Children with malaria infection at admission and subsequently treated with an artemisinin-based combination therapy had increased weight gain (0.38 g/kg/day; 95% confidence interval [CI], 0.07 to 0.69) and reduced height gain (-0.002 mm/day; 95% CI, 0.004 to -0.0008). Conclusions: Malaria infection was common among children treated for uncomplicated SAM. Malaria infection may impair height gain. Proper medical and nutritional management should be ensured to prevent adverse effects of malaria infection. Clinical Trials Registration: NCT01613547. PMID- 29522092 TI - Neuronal Origin of the Temporal Dynamics of Spontaneous BOLD Activity Correlation. AB - Resting-state functional connectivity (FC) has become a major functional magnetic resonance imaging method to study network organization of human brains. There has been recent interest in the temporal fluctuations of FC calculated using short time windows ("dynamic FC") because this method could provide information inaccessible with conventional "static" FC, which is typically calculated using the entire scan lasting several tens of minutes. Although multiple studies have revealed considerable temporal fluctuations in FC, it is still unclear whether the fluctuations of FC measured in hemodynamics reflect the dynamics of underlying neural activity. We addressed this question using simultaneous imaging of neuronal calcium and hemodynamic signals in mice and found coordinated temporal dynamics of calcium FC and hemodynamic FC measured in the same short time windows. Moreover, we found that variation in transient neuronal coactivation patterns was significantly related to temporal fluctuations of sliding window FC in hemodynamics. Finally, we show that the observed dynamics of FC cannot be fully accounted for by simulated data assuming stationary FC. These results provide evidence for the neuronal origin of dynamic FC and further suggest that information relevant to FC is condensed in temporally sparse events that can be extracted using a small number of time points. PMID- 29522091 TI - Beyond heritability: improving discoverability in imaging genetics. AB - Structural neuroimaging measures based on magnetic resonance imaging have been at the forefront of imaging genetics. Global efforts to ensure homogeneity of measurements across study sites have enabled large-scale imaging genetic projects, accumulating nearly 50K samples for genome-wide association studies (GWAS). However, not many novel genetic variants have been identified by these GWAS, despite the high heritability of structural neuroimaging measures. Here, we discuss the limitations of using heritability as a guidance for assessing statistical power of GWAS, and highlight the importance of discoverability-which is the power to detect genetic variants for a given phenotype depending on its unique genomic architecture and GWAS sample size. Further, we present newly developed methods that boost genetic discovery in imaging genetics. By redefining imaging measures independent of traditional anatomical conventions, it is possible to improve discoverability, enabling identification of more genetic effects. Moreover, by leveraging enrichment priors from genomic annotations and independent GWAS of pleiotropic traits, we can better characterize effect size distributions, and identify reliable and replicable loci associated with structural neuroimaging measures. Statistical tools leveraging novel insights into the genetic discoverability of human traits, promises to accelerate the identification of genetic underpinnings underlying brain structural variation. PMID- 29522094 TI - Thermal Requirements and Development Response to Constant Temperatures by Nesidiocoris tenuis (Hemiptera: Miridae), and Implications for Biological Control. AB - Nesidiocoris tenuis (Reuter) (Hemiptera: Miridae), a common zoophytophagus bug, is a biological control agent for several groups of noxious agricultural pests, including whiteflies, aphids, and leafminers. To improve mass-rearing of this species and to optimize its application in integrated pest management, nymphal survival and developmental times of this predator were examined at seven constant temperatures ranging from 14 through 34 degrees C. Eggs developed to adulthood at all temperatures tested. Egg-adult developmental time decreased sharply with increasing temperature, except at 34 degrees C (17.21 d), for which developmental time was significantly longer than that obtained at 31 degrees C (15.59 d). The lowest (11.36%) and highest (28.26%) percentage of mortality was found at 28 and 14 degrees C, respectively. To describe the development rate of immature stages of N. tenuis as a function of temperature, two linear and 26 nonlinear models were fitted. The lower temperature threshold (T0) and thermal constant (K) of total immature stages were estimated by the ordinary (10.94 degrees C and 318.37 DD) and Ikemoto (10.28 degrees C and 339.57 DD) linear models. Based on the Akaike information criterion (AIC), Lactin-1, Analytis-1/Allahyari and Janisch/Kontodimas were the best models to describe the temperature-dependent development rate of egg, nymph and whole immature stages of the predator, respectively. Our findings provide information on N. tenuis biology that will improve application of this predator as a biological control agent. PMID- 29522095 TI - Open science initiatives: challenges for public health promotion. AB - While academic open access, open data and open science initiatives have proliferated in recent years, facilitating new research resources for health promotion, open initiatives are not one-size-fits-all. Health research particularly illustrates how open initiatives may serve various interests and ends. Open initiatives not only foster new pathways of research access; they also discipline research in new ways, especially when associated with new regimes of research use and peer review, while participating in innovation ecosystems that often perpetuate existing systemic biases toward commercial biomedicine. Currently, many open initiatives are more oriented toward biomedical research paradigms than paradigms associated with public health promotion, such as social determinants of health research. Moreover, open initiatives too often dovetail with, rather than challenge, neoliberal policy paradigms. Such initiatives are unlikely to transform existing health research landscapes and redress health inequities. In this context, attunement to social determinants of health research and community-based local knowledge is vital to orient open initiatives toward public health promotion and health equity. Such an approach calls for discourses, norms and innovation ecosystems that contest neoliberal policy frameworks and foster upstream interventions to promote health, beyond biomedical paradigms. This analysis highlights challenges and possibilities for leveraging open initiatives on behalf of a wider range of health research stakeholders, while emphasizing public health promotion, health equity and social justice as benchmarks of transformation. PMID- 29522093 TI - Essential Role for Hypothalamic Calcitonin Receptor-Expressing Neurons in the Control of Food Intake by Leptin. AB - The adipocyte-derived hormone leptin acts via its receptor (LepRb) on central nervous system neurons to communicate the repletion of long-term energy stores, to decrease food intake, and to promote energy expenditure. We generated mice that express Cre recombinase from the calcitonin receptor (Calcr) locus (Calcrcre mice) to study Calcr-expressing LepRb (LepRbCalcr) neurons, which reside predominantly in the arcuate nucleus (ARC). Calcrcre-mediated ablation of LepRb in LepRbCalcrknockout (KO) mice caused hyperphagic obesity. Because LepRb mediated transcriptional control plays a crucial role in leptin action, we used translating ribosome affinity purification followed by RNA sequencing to define the transcriptome of hypothalamic Calcr neurons, along with its alteration in LepRbCalcrKO mice. We found that ARC LepRbCalcr cells include neuropeptide Y (NPY)/agouti-related peptide (AgRP)/gamma-aminobutyric acid (GABA) ("NAG") cells as well as non-NAG cells that are distinct from pro-opiomelanocortin cells. Furthermore, although LepRbCalcrKO mice exhibited dysregulated expression of several genes involved in energy balance, neither the expression of Agrp and Npy nor the activity of NAG cells was altered in vivo. Thus, although direct leptin action via LepRbCalcr cells plays an important role in leptin action, our data also suggest that leptin indirectly, as well as directly, regulates these cells. PMID- 29522096 TI - Intraword Variability in Children With Cochlear Implants: The Long-Term Development up to 5 Years of Age and a Comparison With Children With Normal Hearing. AB - Purpose: This study evaluates intraword or token-to-token variability in the spontaneous speech of Dutch-speaking children with cochlear implants (CIs) longitudinally up to 5 years of age in comparison with intraword variability in age-matched peers with normal hearing (NH). Method: Spontaneous speech samples of 9 children with CI were collected longitudinally up to age 5. The data of the NH control group consisted of cross-sectional recordings. Children's word productions were categorized into 4 response types of the variability score (consistent correct, consistent incorrect, variable with hits, variable with no hits), and the proportion of whole-word variation (PWV) was calculated. Results: PWV was high in both groups of children but decreased with age. All response types of the variability score appeared in both groups. Children with CI were significantly more variable than their peers with NH up to age 4, but this difference has disappeared by age 5. Longer words had a higher PWV and were more often consistent incorrect and variable. Conclusions: Intraword variability was characteristic of children with CI's spontaneous speech productions as it was in children with NH, and a similar factor (word length) affected variability in production. Group comparisons showed higher rates of intraword variability in children with CI, but they seemed to catch up with their peers with NH by age 5. PMID- 29522097 TI - Surgical overview of cardiac echinococcosis: a rare entity. AB - OBJECTIVES: The purpose of this study was to describe our experience with the presentation and management of cardiac echinococcosis and the outcomes. METHODS: We performed a retrospective study from January 2012 to September 2017 in 10 patients operated on for cardiac echinococcosis. There were 6 men and 4 women; the age range was 17-55 years (mean age, 35.9 +/- 12.04 years). Among the 10 patients, 3 had multiple cysts and of the 7 patients with a solitary cyst, 5 cysts were in the left ventricle, 1 was in the right ventricle and 1 was in the interventricular septum. All patients were evaluated with electrocardiography, transthoracic echocardiography, computed tomography/magnetic resonance imaging of the thorax, ultrasound examinations of the abdominal organs, haemagglutination tests and histopathological examination of the cyst. RESULTS: Nine operations were performed using cardiopulmonary bypass. One patient with a pericardial cyst was operated on with a beating heart with cystectomy and partial pericardiectomy. Preoperatively, all patients received albendazole for 2 weeks except for 1 patient who had an emergency operation. Albendazole was continued postoperatively in all patients for 12 weeks. There were no postoperative complications. No recurrences have been observed so far. CONCLUSIONS: Cardiac echinococcosis is an infrequently encountered entity, but with clinical suspicion and early diagnosis it can be successfully managed with good outcomes. PMID- 29522098 TI - Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression. AB - Aims: After birth mammalian cardiomyocytes initiate a last cell cycle which results in binucleation due to cytokinesis failure. Despite its importance for cardiac regenerative therapies, this process is poorly understood. Here, we aimed at a better understanding of the difference between cardiomyocyte proliferation and binucleation and providing a new tool to distinguish these two processes. Methods and results: Monitoring of cell division by time-lapse imaging revealed that rat cardiomyocyte binucleation stems from a failure to properly ingress the cleavage furrow. Astral microtubule required for actomyosin ring anchorage and thus furrow ingression were not symmetrically distributed at the periphery of the equatorial region during anaphase in binucleating cardiomyocytes. Consequently, RhoA, the master regulator of actomyosin ring formation and constriction, non muscle myosin IIB, a central component of the actomyosin ring, as well as IQGAP3 were abnormally localized during cytokinesis. In agreement with improper furrow ingression, binucleation in vitro and in vivo was associated with a failure of RhoA and IQGAP3 to localize to the stembody of the midbody. Conclusion: Taken together, these results indicate that naturally occurring cytokinesis failure in primary cardiomyocytes is due to an aberrant mitotic microtubule apparatus resulting in inefficient anchorage of the actomyosin ring to the plasma cell membrane. Thus, cardiomyocyte binucleation and division can be discriminated by the analysis of RhoA as well as IQGAP3 localization. PMID- 29522099 TI - The Severity of Herpes Zoster in Inflammatory Bowel Disease Patients Treated With Anti-TNF Agents. AB - Aim: There is a paucity of data on the clinical course and the factors affecting the clinical course of herpes zoster (HZ) in inflammatory bowel disease (IBD). Our aim was to determine the impact of anti-TNF therapy and other factors on the clinical course of HZ in IBD patients. Methods: We conducted a retrospective cohort study among a cohort of nation-wide Veterans Affairs patients with IBD who developed incident HZ. The exposed group consisted of eligible study patients who were actively exposed to anti-TNF alone or anti-TNF plus thiopurines at the time of HZ onset. The unexposed group consisted of patients who were only exposed to 5 ASA agents before the onset of HZ without any exposure to anti-TNF medications. The outcome of interest was the development of severe HZ that was defined by including various HZ complications. Results: A total of 295 patients were identified with an incident HZ flare during follow- up duration, and among them 69 met the definition of having a severe flare. In multivariable logistic regression analysis adjusting for sex, age at HZ flare onset, race, Charlson comorbidity score, and receipt of oral anti-HZ treatment, exposure to anti-TNF agent was not associated with an increased risk of severe HZ flare compared to exposure to mesalamine alone (adjusted relative risk (RR) 1.1, 95% confidence intervals (CI): 0.75-1.55). Among the covariates, receipt of oral anti-HZ treatment (adjusted RR 0.42, 95% CI: 0.29-0.61), advancing age at HZ onset (adjusted RR for each year increase in age 1.02, 95% CI: 1.00-1.04), and African American race (adjusted RR with whites as reference 1.58, 95% CI: 1.02-2.44) were significantly associated with the risk of having severe HZ flare. Conclusion: Our study showed that among IBD patients who developed HZ, treatment with anti-TNF agents was not associated with increased risk of developing severe HZ as compared to patients treated with 5-ASA therapy only. 10.1093/ibd/izx115_video1izx115_Video_15786486963001. PMID- 29522100 TI - Validation of the PHQ-9 for Suicidal Ideation in Persons with Inflammatory Bowel Disease. AB - Background: Suicide is a leading cause of death worldwide. Transition from suicidal ideation (SI) to suicide attempt is high within a year of SI onset. The risk of suicide and SI is elevated in persons with inflammatory bowel disease (IBD) versus the general population. We aimed to validate the Patient Heath Questionnaire (PHQ)-9 as a screening tool for SI in IBD and to determine factors associated with SI in IBD. Methods: IBD participants (n = 247) recruited from the community and clinics completed the PHQ-9 and participated in the Structured Clinical Interview for DSM-IV (SCID). We determined the sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of the PHQ-9 in identifying SI as compared to the SCID. Using logistic regression we examined the association of SI with demographic and clinical factors. Results: SI was endorsed by 24 (9.7%) participants on the PHQ-9 and 5 (2.0%) based on the SCID. The PHQ-9 had good sensitivity (100%), specificity (92.2%), and NPV (100%) but low PPV (20.8%) for SI. On univariate analysis, factors strongly associated with SI were depression (OR 13.1; 95%CI: 4.46, 40.5), anxiety (OR 11.3; 95%CI: 4.46, 28.6), and active disease (OR 3.87; 95%CI: 1.54, 9.71). On multivariable analysis, depression (OR 5.54; 95%CI: 1.67, 18.4) and pain (OR 1.14; 95%CI: 1.03, 1.25) were associated with SI. Conclusions: Overall the PHQ-9 is a valid screening tool for SI in IBD patients, and routine implementation of this tool would support screening for depression and SI effectively and efficiently in clinical practice. PMID- 29522101 TI - Methodological and Efficacy Issues in a Randomized Clinical Trial Investigating Vitreous Floater Treatment. PMID- 29522102 TI - Network Analysis of Protein Adaptation: Modeling the Functional Impact of Multiple Mutations. AB - The evolution of new biochemical activities frequently involves complex dependencies between mutations and rapid evolutionary radiation. Mutation co occurrence and covariation have previously been used to identify compensating mutations that are the result of physical contacts and preserve protein function and fold. Here, we model pairwise functional dependencies and higher order interactions that enable evolution of new protein functions. We use a network model to find complex dependencies between mutations resulting from evolutionary trade-offs and pleiotropic effects. We present a method to construct these networks and to identify functionally interacting mutations in both extant and reconstructed ancestral sequences (Network Analysis of Protein Adaptation). The time ordering of mutations can be incorporated into the networks through phylogenetic reconstruction. We apply NAPA to three distantly homologous beta lactamase protein clusters (TEM, CTX-M-3, and OXA-51), each of which has experienced recent evolutionary radiation under substantially different selective pressures. By analyzing the network properties of each protein cluster, we identify key adaptive mutations, positive pairwise interactions, different adaptive solutions to the same selective pressure, and complex evolutionary trajectories likely to increase protein fitness. We also present evidence that incorporating information from phylogenetic reconstruction and ancestral sequence inference can reduce the number of spurious links in the network, whereas preserving overall network community structure. The analysis does not require structural or biochemical data. In contrast to function-preserving mutation dependencies, which are frequently from structural contacts, gain-of-function mutation dependencies are most commonly between residues distal in protein structure. PMID- 29522104 TI - Freedom from pulmonary vein stenosis after multiple applications of epicardial ablation energy. AB - OBJECTIVES: In patients undergoing cardiac surgical procedures, pulmonary vein isolation may be easily accomplished, and it is important to achieve bidirectional conduction block across created lesions. The primary aim of this study was to assess the risk of pulmonary vein stenosis (PVS) after multiple applications of epicardial bipolar radiofrequency energy. METHODS: Thirty-five consecutive patients who were referred for off-pump coronary revascularization with concomitant pulmonary vein isolation and left atrial appendage occlusion were prospectively included in the study. The ablation protocol provided 8 standard epicardial applications of bipolar energy with additional applications until the acute bidirectional conduction block was achieved. Three to 6 months after surgery, patients underwent computed tomography to assess PVS. RESULTS: In all patients, bidirectional conduction block was achieved across the created lesions. In 31 (89%) patients, conduction block was accomplished after the standard 8 energy applications on each side. In 4 (11%) patients, additional applications of energy were needed. All patients had computed tomography (128 total pulmonary veins) scans, which showed no evidence of PVS. CONCLUSIONS: Multiple applications of bipolar radiofrequency energy during off-pump epicardial pulmonary vein isolation did not lead to PVS. Creating bidirectional conduction block using multiple energy applications through created lesions is feasible in all patients using the ablation protocol described. PMID- 29522105 TI - Improved JAK Inhibition in Myelofibrosis-The Long Road Ahead. PMID- 29522103 TI - Designing programs to improve diets for maternal and child health: estimating costs and potential dietary impacts of nutrition-sensitive programs in Ethiopia, Nigeria, and India. AB - Improving maternal and child nutrition in resource-poor settings requires effective use of limited resources, but priority-setting is constrained by limited information about program costs and impacts, especially for interventions designed to improve diet quality. This study utilized a mixed methods approach to identify, describe and estimate the potential costs and impacts on child dietary intake of 12 nutrition-sensitive programs in Ethiopia, Nigeria and India. These potential interventions included conditional livestock and cash transfers, media and education, complementary food processing and sales, household production and food pricing programs. Components and costs of each program were identified through a novel participatory process of expert regional consultation followed by validation and calibration from literature searches and comparison with actual budgets. Impacts on child diets were determined by estimating of the magnitude of economic mechanisms for dietary change, comprehensive reviews of evaluations and effectiveness for similar programs, and demographic data on each country. Across the 12 programs, total cost per child reached (net present value, purchasing power parity adjusted) ranged very widely: from 0.58 to 2650 USD/year among five programs in Ethiopia; 2.62 to 1919 USD/year among four programs in Nigeria; and 27 to 586 USD/year among three programs in India. When impacts were assessed, the largest dietary improvements were for iron and zinc intakes from a complementary food production program in Ethiopia (increases of 17.7 mg iron/child/day and 7.4 mg zinc/child/day), vitamin A intake from a household animal and horticulture production program in Nigeria (335 RAE/child/day), and animal protein intake from a complementary food processing program in Nigeria (20.0 g/child/day). These results add substantial value to the limited literature on the costs and dietary impacts of nutrition-sensitive interventions targeting children in resource limited settings, informing policy discussions and serving as critical inputs to future cost-effectiveness analyses focusing on disease outcomes. PMID- 29522106 TI - Possible Underestimation of the Provision of Palliative Care. PMID- 29522107 TI - Late-onset Rise of 6-MMP Metabolites in IBD Patients on Azathioprine or Mercaptopurine. AB - Background: The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15% 20% of patients preferentially produce the hepatotoxic metabolite 6 methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually begins within 3 months of therapy. We noted patients developing shunting many months or years after starting treatment and aimed to determine how often this late shunting occurs and whether this could be explained by patient factors or concomitant medications. Methods: The New Zealand database of thiopurine metabolite results from 2002 to 2016 (19085 6TGN/6MMP pairs from 7130 patients) was interrogated to identify patients developing a 6MMP/6TGN ratio >20 after at least 4 months treatment. Dosing history, concomitant therapy, and comorbidity data were assessed. Results: Fifteen percent of database patients developed preferential 6-MMP production, and of these, 29 patients had late-onset shunting with sufficient data available for validation. This extrapolates to 90 patients in total, representing 1.7% of IBD patients on thiopurines, or 10% of all those with preferential 6-MMP production. Time from starting therapy to shunting was 5 months to 10.4 years (median, 21 months). Eleven patients had abnormal liver function when shunting was recognized, all with 6MMP >5900 pmol/8 * 108 red blood cells. No common factors were found to explain the late onset. Conclusions: Some IBD patients develop preferential 6MMP production many months or years after commencing therapy. This is important when considering frequency of metabolite monitoring, failure of therapy, or abnormal liver function. 10.1093/ibd/izx081_video1izx081.video15746667546001. PMID- 29522108 TI - A review of gastrointestinal protocols for primary care medical service trips (MSTs) in Latin America and the Caribbean. AB - Background: Gastrointestinal disorders are among the most common conditions encountered on short-term, primary care medical service trips (MSTs) in Latin America and the Caribbean (LAC), but their optimal management remains unclear. There have been no previous attempts to describe the protocols that Western volunteer clinicians use in managing these patients. Methods: A systematic web search was used to identify organizations operating MSTs in LAC. Clinical protocols were downloaded from organizational websites, and organizations were contacted online to obtain those that were not publicly available. Protocols were analysed qualitatively, and content compared with existing international guidelines. Results: Two hundred and twenty-five organizations were identified and contacted to obtain their clinical protocols, and the content of each protocol was qualitatively analysed. Twenty protocols were obtained, of which 75% (15/20) discussed dyspepsia, 65% (13/20) discussed parasites and 60% (12/20) discussed diarrhoea. The protocols infrequently included literature citations. Conclusion: Gastrointestinal disorder protocols used by MSTs in LAC sometimes neglected important aspects of clinical management that are emphasized in international guidelines. This study is a first step in context-specific clinical guideline development for MSTs operating in LAC. PMID- 29522111 TI - Evaluation of transventricular placement of porcine small intestinal submucosa stent valves in the pulmonary position in juvenile sheep model. AB - OBJECTIVES: We assessed the transventricular placement of porcine small intestinal submucosa (SIS) stent valves in a juvenile sheep model at the 3-month follow-up evaluation. METHODS: We constructed a pulmonary stent valve by suturing a porcine SIS bicuspid valve into a bell-shaped 'Z' nitinol stent and implanted 7 SIS stent valves transventricularly in the pulmonary position in 7 sheep. The function of the stent valves was assessed using a pulsatile flow simulation system in vitro. Haemodynamic, angiographic, echocardiographic, histologic and radiographic examinations were carried out before, immediately after implantation and 3 months after implantation. RESULTS: All SIS stent valves were successfully implanted in the pulmonary position in 7 sheep. Angiographic, echocardiographic, haemodyamic and macroscopic studies confirmed firm anchoring and good positioning of the stents immediately after implantation and at 3-month follow-up. All stent valves had good function immediately after implantation and at the end of the protocol, with the exception of 1 stent valve with mild stenosis detected at the end of the protocol. All SIS valves were free of calcifications and thrombus formation, and all stents were intact with no fractures and migration based on postmortem examination and X-radiography. CONCLUSIONS: We demonstrated successful implantation of porcine SIS stent valves in the pulmonary position in sheep with excellent valve function at the 3-month follow-up evaluation. Porcine SIS has potential superiority as a pulmonary stent bioprosthetic valve material, and the bell-shaped nitinol stent has potential superiority as a frame for pulmonary stent valves. PMID- 29522112 TI - Toward Leveraging Human Connectomic Data in Large Consortia: Generalizability of fMRI-Based Brain Graphs Across Sites, Sessions, and Paradigms. AB - While graph theoretical modeling has dramatically advanced our understanding of complex brain systems, the feasibility of aggregating connectomic data in large imaging consortia remains unclear. Here, using a battery of cognitive, emotional and resting fMRI paradigms, we investigated the generalizability of functional connectomic measures across sites and sessions. Our results revealed overall fair to excellent reliability for a majority of measures during both rest and tasks, in particular for those quantifying connectivity strength, network segregation and network integration. Processing schemes such as node definition and global signal regression (GSR) significantly affected resulting reliability, with higher reliability detected for the Power atlas (vs. AAL atlas) and data without GSR. While network diagnostics for default-mode and sensori-motor systems were consistently reliable independently of paradigm, those for higher-order cognitive systems were reliable predominantly when challenged by task. In addition, based on our present sample and after accounting for observed reliability, satisfactory statistical power can be achieved in multisite research with sample size of approximately 250 when the effect size is moderate or larger. Our findings provide empirical evidence for the generalizability of brain functional graphs in large consortia, and encourage the aggregation of connectomic measures using multisite and multisession data. PMID- 29522113 TI - A Controlled Trial of Mass Drug Administration to Interrupt Transmission of Multidrug-Resistant Falciparum Malaria in Cambodian Villages. AB - Background: The increase in multidrug-resistant Plasmodium falciparum in Southeast Asia suggests a need for acceleration of malaria elimination. We evaluated the effectiveness and safety of mass drug administration (MDA) to interrupt malaria transmission. Methods: Four malaria-endemic villages in western Cambodia were randomized to 3 rounds of MDA (a 3-day course of dihydroartemisinin with piperaquine-phosphate), administered either early in or at the end of the study period. Comprehensive malaria treatment records were collected during 2014 2017. Subclinical parasite prevalence was estimated by ultrasensitive quantitative polymerase chain reaction quarterly over 12 months. Results: MDA coverage with at least 1 complete round was 88% (1999/2268), >=2 rounds 73% (1645/2268), and all 3 rounds 58% (1310/2268). Plasmodium falciparum incidence in intervention and control villages was similar over the 12 months prior to the study: 39 per 1000 person-years (PY) vs 45 per 1000 PY (P = .50). The primary outcome, P. falciparum incidence in the 12 months after MDA, was lower in intervention villages (1.5/1000 PY vs 37.1/1000 PY; incidence rate ratio, 24.5 [95% confidence interval], 3.4-177; P = .002). Following MDA in 2016, there were no clinical falciparum malaria cases over 12 months (0/2044 PY) in all 4 villages. Plasmodium vivax prevalence decreased markedly in intervention villages following MDA but returned to approximately half the baseline prevalence by 12 months. No severe adverse events were attributed to treatment. Conclusions: Mass drug administrations achieved high coverage, were safe, and associated with the absence of clinical P. falciparum cases for at least 1 year. Clinical Trials Registration: NCT01872702. PMID- 29522114 TI - Quantifying the stability of oxidatively damaged DNA by single-molecule DNA stretching. AB - One of the most common DNA lesions is created when reactive oxygen alters guanine. 8-oxo-guanine may bind in the anti-conformation with an opposing cytosine or in the syn-conformation with an opposing adenine paired by transversion, and both conformations may alter DNA stability. Here we use optical tweezers to measure the stability of DNA hairpins containing 8-oxoguanine (8oxoG) lesions, comparing the results to predictive models of base-pair energies in the absence of the lesion. Contrasted with either a canonical guanine-cytosine or adenine-thymine pair, an 8oxoG-cytosine base pair shows significant destabilization of several kBT. The magnitude of destabilization is comparable to guanine-thymine 'wobble' and cytosine-thymine mismatches. Furthermore, the measured energy of 8oxoG-adenine corresponds to theoretical predictions for guanine-adenine pairs, indicating that oxidative damage does not further destabilize this mismatch in our experiments, in contrast to some previous observations. These results support the hypothesis that oxidative damage to guanine subtly alters the direction of the guanine dipole, base stacking interactions, the local backbone conformation, and the hydration of the modified base. This localized destabilization under stress provides additional support for proposed mechanisms of enzyme repair. PMID- 29522115 TI - Prediction of Pain and Opioid Utilization in the Perioperative Period in Patients Undergoing Primary Knee Arthroplasty: Psychophysical and Psychosocial Factors. AB - Objective: To identify factors associated with pain severity and opioid consumption in the early perioperative period. Design: Prospective observational cohort study. Setting: Tertiary academic medical center. Subjects: Patients with osteoarthritis older than age 45 years undergoing primary total knee replacement at Brigham and Women's Hospital. A total of 126 patients enrolled. Methods: Preoperatively, pain questionnaires and quantitative sensory testing were performed on patients to develop a psychosocial and psychophysical profile. Postoperatively, pain scores and opioid consumption were measured as primary end points. Univariate and multiple linear regression analyses were performed to determine the predictive value of these characteristics on perioperative pain scores and opioid consumption. Results: Regression analysis revealed several predictors of acute postoperative pain scores including temporal summation of pain (TSP; P = 0.001), body mass index (BMI; P = 0.044), number of previous knee surgeries (P = 0.006), and female gender (P = 0.023). Similarly, predictors of opioid utilization included TSP (P = 0.011), BMI (P = 0.02), age (P = <0.001), and tourniquet time (P = 0.003). Conclusions: The only significant, unique predictors of both pain and opioid consumption were TSP, an index of central pain facilitatory processes, and BMI. Interestingly, psychosocial factors, such as catastrophizing and somatization, although correlated with postoperative pain scores and opioid consumption, generally did not independently explain substantial variance in these measures. This study suggests that BMI and quantitative sensory testing, specifically the temporal summation of pain, may provide value in the preoperative assessment of patients undergoing total knee arthroplasty and other surgeries via predicting their level of risk for adverse pain outcomes. PMID- 29522116 TI - Mechanisms and consequences of oxidant-induced renal preconditioning: an Nrf2 dependent, P21-independent, anti-senescence pathway. AB - Background: P21, a cyclin kinase inhibitor, is upregulated by renal 'ischemic preconditioning' (IPC), and induces a 'cytoresistant' state. However, P21-induced cell cycle inhibition can also contribute to cellular senescence, a potential adverse renal event. Hence, this study assessed whether: (i) IPC-induced P21 upregulation is associated with subsequent renal senescence; and (ii) preconditioning can be established 'independent' of P21 induction and avoid a post-ischemic senescent state? Methods: CD-1 mice were subjected to either IPC (5 15 min) or to a recently proposed 'oxidant-induced preconditioning' (OIP) strategy (tin protoporphyrin-induced heme oxygenase inhibition +/- parental iron administration). P21 induction [messenger RNA (mRNA)/protein], cell proliferation (KI-67, phosphohistone H3 nuclear staining), kidney senescence (P16ink4a; P19Arf mRNAs; senescence-associated beta-galactosidase levels) and resistance to ischemic acute kidney injury were assessed. Results: IPC induced dramatic (10 25*) and persistent P21 activation and 'downstream' tubular senescence. Conversely, OIP did not upregulate P21, it increased, rather than decreased, cell proliferation markers, and it avoided a senescence state. OIP markedly suppressed ischemia-induced P21 up-regulation, it inhibited the development of post-ischemic senescence and it conferred near-complete protection against ischemic acute renal failure (ARF). To assess OIP's impact on a non-P21-dependent cytoprotective pathway, its ability to activate Nrf2, the so-called 'master regulator' of endogenous cell defenses, was assessed. Within 4 h, OIP activated each of three canonical Nrf2-regulated genes (NQO1, SRXN1, GCLC; 3- to 5-fold mRNA increases). Conversely, this gene activation pathway was absent in Nrf2-/- mice, confirming Nrf2 specificity. Nrf2-/- mice also did not develop significant OIP-mediated protection against ischemic ARF. Conclusions: OIP (i) activates the cytoprotective Nrf2, but not the P21, pathway; (ii) suppresses post-ischemic P21 induction and renal senescence; and (iii) confers marked protection against ischemic ARF. In sum, these findings suggest that OIP may be a clinically feasible approach for safely activating the Nrf2 pathway, and thereby confer protection against clinical renal injury. PMID- 29522117 TI - ESR1 and endocrine therapy resistance: more than just mutations. PMID- 29522118 TI - Structural diversity in the strigolactones. AB - Strigolactones (SLs) are a class of signalling molecules secreted by the roots of plants into the rhizosphere. On the one hand, they serve as the signal for recruiting arbuscular mycorrhizal fungi which have a symbiotic relationship with plants. On the other hand, they are also host detection signals for the non symbiotic, pathogenic, root parasitic plants, which use the SLs as germination stimulants. Finally, recently the SLs were discovered to be a new class of plant hormones that regulate processes such as branching/tillering and root architecture. Intriguingly, >25 different SLs have already been discovered that all have the so-called D-ring but otherwise display many differences in structure and functional groups. In this review, we will critically discuss the structural diversity in the SLs. How are they synthesized in plants; how has this structural diversity possibly evolved; what is the biological relevance of this diversity; and what does this imply for the perception of the SLs by receptors in the plant itself and in other organisms? Finally, we conclude that only little is known about the biological significance of this structural diversity, and we will give an outlook on how to elucidate their importance further. PMID- 29522119 TI - Opsoclonus-Myoclonus Syndrome-Additional Clinical Considerations. PMID- 29522120 TI - Policies Affecting Medicaid Beneficiaries' Smoking Cessation Behaviors. AB - Introduction: Smoking rates for Medicaid beneficiaries have remained flat in recent years. Medicaid may support smokers in quitting by covering a broad array of tobacco cessation services without barriers such as copays. This study examines the impact of increasing generosity in Medicaid tobacco cessation coverage policies on smoking and cessation behaviors. Methods: We used 2010 and 2015 National Health Interview Survey data merged with information on state tobacco, Medicaid cessation, and Medicaid eligibility policies to estimate state fixed effects models of cessation medication use, counseling use, quit attempts, and current smoking. Results: Smokers living in states that cover cessation medications but not counseling services were less likely to use counseling. Smokers were more likely to report having tried to quit in states with higher rates of use of cessation medications among Medicaid beneficiaries. We found no impact of Medicaid policies on use of cessation medications. States that impose copays had higher rates of smoking, while those that require counseling as a condition of receiving medication had lower rates of smoking. Additionally, we found that expanding Medicaid eligibility under the Affordable Care Act is associated with decreased smoking prevalence among Medicaid beneficiaries. Conclusion: Covering cessation counseling may encourage smokers that want to quit to use this service. Promoting the use of cessation medications may improve the likelihood that smokers try to quit. Medicaid coverage of cessation services is an important but incomplete strategy in addressing smoking among low-income populations. Implications: States may be able to improve utilization of cessation counseling by providing Medicaid reimbursement for this service. Encouraging utilization of tobacco cessation medications may help more smokers quit. States should consider how to promote effective cessation methods among clinicians and patients. PMID- 29522121 TI - Clinical Criteria of Central Sensitization in Chronic Pelvic and Perineal Pain (Convergences PP Criteria): Elaboration of a Clinical Evaluation Tool Based on Formal Expert Consensus. AB - Background: The evaluation of chronic pelvic and perineal pain (CPP) is often complex. The patient's description of the pain often appears to be disproportionate to the limited findings on physical examination and/or complementary investigations. The concept of central sensitization may allow better understanding and management of patients with CPP. Objective: The aim of this study was to elaborate a clinical evaluation tool designed to simply identify sensitization in pelvic pain. Methods: A list of 63 items was submitted to 22 international CPP experts according to the Delphi method. Results: Ten clinical criteria were adopted for the creation of a clinical evaluation tool: 1) pain influenced by bladder filling and/or urination, 2) pain influenced by rectal distension and/or defecation, 3) pain during sexual activity, 4) perineal and/or vulvar pain in response to normally nonpainful stimulation, 5) pelvic trigger points (e.g., in the piriformis, obturator internus, and/or levator ani muscles), 6) pain after urination, 7) pain after defecation, 8) pain after sexual activity, 9) variable (fluctuating) pain intensity and/or variable pain distribution, 10) migraine or tension headaches and/or fibromyalgia and/or chronic fatigue syndrome and/or post-traumatic stress disorder and/or restless legs syndrome and/or temporomandibular joint dysfunction and/or multiple chemical sensitivity. Conclusions: This process resulted in the elaboration of a clinical evaluation tool designed to identify and appropriately manage patients with CPP comprising a sensitization component. PMID- 29522122 TI - Development and Psychometric Validation of a Question naire Assessing the Impact of Memory Changes in Older Adults. AB - Background and Objectives: Many healthy older adults experience age-related memory changes that can impact their day-to-day functioning. Qualitative interviews have been useful in gaining insight into the experience of older adults who are facing memory difficulties. To enhance this insight, there is a need for a reliable and valid measure that quantifies the impact of normal memory changes on daily living. The primary objective of this study was to develop and validate a new instrument, the Memory Impact Questionnaire (MIQ). Research Design and Methods: We examined the underlying component structure and psychometric properties of the MIQ in a sample of 205 community-dwelling older adults. Results: Principal component analysis revealed three clusters: (a) Lifestyle Restrictions, (b) Positive Coping, and (c) Negative Emotion. Comparisons of the corresponding subscale scores with scores on other instruments revealed good convergent and discriminant validity. In addition, the MIQ subscales and the total score showed good test-retest reliability (rs = 0.65-0.91) and internal consistency (alphas = 0.87-0.93). Discussion and Implications: This novel questionnaire can be used in both clinical and research settings to better understand the impact of memory changes on the day-to-day functioning of older adults and to monitor outcomes of support programs for this population. PMID- 29522123 TI - eMolTox: prediction of molecular toxicity with confidence. AB - Summary: In this work, we present eMolTox, a web server for the prediction of potential toxicity associated with a given molecule. A total of 174 toxicology related in vitro/vivo experimental datasets were used for model construction and Mondrian conformal prediction was used to estimate the confidence of the resulting predictions. Toxic substructure analysis is also implemented in eMolTox. eMolTox predicts and displays a wealth of information of potential molecular toxicities for safety analysis in drug development. Availability and implementation: The eMolTox Server is freely available for use on the web at http://xundrug.cn/moltox. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522124 TI - AnaCoDa: analyzing codon data with Bayesian mixture models. AB - Summary: AnaCoDa is an R package for estimating biologically relevant parameters of mixture models, such as selection against translation inefficiency, non-sense errors and ribosome pausing time, from genomic and high throughput datasets. AnaCoDa provides an adaptive Bayesian MCMC algorithm, fully implemented in C++ for high performance with an ergonomic R interface to improve usability. AnaCoDa employs a generic object-oriented design to allow users to extend the framework and implement their own models. Current models implemented in AnaCoDa can accurately estimate biologically relevant parameters given either protein coding sequences or ribosome foot-printing data. Optionally, AnaCoDa can utilize additional data sources, such as gene expression measurements, to aid model fitting and parameter estimation. By utilizing a hierarchical object structure, some parameters can vary between sets of genes while others can be shared. Genes may be assigned to clusters or membership may be estimated by AnaCoDa. This flexibility allows users to estimate the same model parameter under different biological conditions and categorize genes into different sets based on shared model properties embedded within the data. AnaCoDa also allows users to generate simulated data which can be used to aid model development and model analysis as well as evaluate model adequacy. Finally, AnaCoDa contains a set of visualization routines and the ability to revisit or re-initiate previous model fitting, providing researchers with a well rounded easy to use framework to analyze genome scale data. Availability and implementation: AnaCoDa is freely available under the Mozilla Public License 2.0 on CRAN (https://cran.r project.org/web/packages/AnaCoDa/). PMID- 29522125 TI - Activation of mechanistic target of rapamycin complex 1: the common link between rheumatoid arthritis and diabetes mellitus. PMID- 29522126 TI - Retinal Deposits in a Young Woman. PMID- 29522127 TI - JAMA Oncology-The Year in Review, 2017. PMID- 29522128 TI - Purpose in Life Among Centenarian Offspring. AB - Objectives: Purpose in life (PIL), a feeling of meaning and direction in life, is associated with favorable health outcomes including lower mortality and reduced risk of disease, disability, and cognitive impairment. Since centenarian offspring have been shown to have long health spans we sought to examine whether they have higher PIL than individuals without familial longevity. Method: We compared PIL scores from the Ryff Scales of Psychological Well-Being in centenarian offspring from the New England Centenarian Study (N=361, mean age=82.0 years) with three referent groups: spouses, birth cohort-matched referents, and Health and Retirement Study (HRS) participants. Results: Logistic regression analyses adjusted for age, sex, education, and marital status indicated greater odds of high PIL among centenarian offspring compared with spouse (adjusted odds ratio [aOR] 1.92, 95% CI 1.002-3.68, p=.049) and birth cohort referents (aOR 2.64, 95% CI 1.36-5.14, p=.004). Offspring had an almost three times greater odds of having high PIL than HRS participants (OR 2.93, 95% CI 2.17-3.96, p<0.0001). Discussion: Higher PIL is associated with being an offspring of a long-lived parent and may play a role in the ability to delay age associated illnesses and functional decline. Increasing purposefulness may be a target for interventions to promote healthy aging. PMID- 29522129 TI - Neural Cell Adhesion Molecule 2 (NCAM2)-Induced c-Src-Dependent Propagation of Submembrane Ca2+ Spikes Along Dendrites Inhibits Synapse Maturation. AB - The neural cell adhesion molecule 2 (NCAM2) is encoded by a gene on chromosome 21 in humans. NCAM2 accumulates in synapses, but its role in regulation of synapse formation remains poorly understood. We demonstrate that an increase in NCAM2 levels results in increased instability of dendritic protrusions and reduced conversion of protrusions to dendritic spines in mouse cortical neurons. NCAM2 overexpression induces an increase in the frequency of submembrane Ca2+ spikes localized in individual dendritic protrusions and promotes propagation of submembrane Ca2+ spikes over segments of dendrites or the whole dendritic tree. NCAM2-dependent submembrane Ca2+ spikes are L-type voltage-gated Ca2+ channel dependent, and their propagation but not initiation depends on the c-Src protein tyrosine kinase. Inhibition of initiation or propagation of NCAM2-dependent submembrane Ca2+ spikes reduces the NCAM2-dependent instability of dendritic protrusions. Synaptic boutons formed on dendrites of neurons with elevated NCAM2 expression are enriched in the protein marker of immature synapses GAP43, and the number of boutons with mature activity-dependent synaptic vesicle recycling is reduced. Our results indicate that synapse maturation is inhibited in NCAM2 overexpressing neurons and suggest that changes in NCAM2 levels and altered submembrane Ca2+ dynamics can cause defects in synapse maturation in Down syndrome and other brain disorders associated with abnormal NCAM2 expression. PMID- 29522131 TI - The Complexity of Renal Involvment in IBD-C3 Glomerulopathy in Ulcerative Colitis. PMID- 29522130 TI - Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer. AB - Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored. To address the functional consequences of NTHL1 overexpression, we employed transient overexpression. Both NTHL1 and a catalytically-dead NTHL1 (CATmut) induce DNA damage and genomic instability in non-transformed human bronchial epithelial cells (HBEC) when overexpressed. Strikingly, overexpression of either NTHL1 or CATmut causes replication stress signaling and a decrease in homologous recombination (HR). HBEC cells that overexpress NTHL1 or CATmut acquire the ability to grow in soft agar and exhibit loss of contact inhibition, suggesting that a mechanism independent of NTHL1 catalytic activity contributes to acquisition of cancer-related cellular phenotypes. We provide evidence that NTHL1 interacts with the multifunctional DNA repair protein XPG suggesting that interference with HR is a possible mechanism that contributes to acquisition of early cellular hallmarks of cancer. PMID- 29522132 TI - Co-occurrence Among Intraguild Predators: Avoidance or Aggregation? AB - Intraguild predation (IGP) may interact with prey availability to structure predator communities. However, if predators are able to avoid each other, its effect on predator community structure may be minimized or absent. To determine whether co-occurrence among IG predators is limited, we estimated co-occurrence among predators in experimental plots of maize and soybean. These crops provide high densities of shared resources (aphids) as well as known IG predators (primarily coccinellids). Despite documented intraspecific and interspecific avoidance behaviors, aggregation to patchy resources could bring IG predators into contact. We, therefore, hypothesized that despite documented intraspecific avoidance behaviors, aphidophagous IG coccinellid predators would not significantly avoid co-occurrence, making IGP likely. Co-occurrence was estimated from visual counts of aphid predators and their prey on randomly selected plants over the course of the growing season. For each habitat, we used maximum likelihood analysis to determine whether observed co-occurrence deviated significantly from that expected for each possible pairwise combination of IG predators. We repeated this analysis using published data on co-occurrence among aphid predators on tansy. We found that most co-occurrence among IG predators was random, suggesting that avoidance does not limit co-occurrence. Failure to limit co-occurrence could be the result of ineffective avoidance mechanisms or because predators balance aggregating on shared resources with avoiding IG predators. PMID- 29522133 TI - Varicella Outbreak Surveillance in Schools in Sentinel Jurisdictions, 2012-2015. AB - Background: In 2007, a routine second dose of varicella vaccine was recommended in the United States for children aged 4 to 6 years to better control varicella zoster virus circulation and outbreaks. Sentinel varicella outbreak surveillance was established to assess feasibility of surveillance and describe outbreaks that are occurring. Methods: Through the Centers for Disease Control and Prevention Epidemiology Laboratory Capacity funding, health departments conducted active surveillance for varicella outbreaks in schools from 2012 to 2015. Outbreaks of varicella were defined as >=5 cases in a school within at least 1 incubation period (21 days). School nurses, healthcare providers, or laboratories reported cases and outbreaks of varicella to health departments; demographic, vaccination, and clinical data were collected. Results: Georgia, Houston, Maine, Minnesota, New York City, and Philadelphia participated in all 3 years; Puerto Rico and West Virginia participated in 2012 to 2013; and Kansas and Arkansas participated in 2014 to 2015. Twenty-nine outbreaks including 262 cases were reported. The median size of the outbreaks was 7 cases (range, 5-31 cases), and the median duration was 31 days (range, 4-100 days). Of the case-patients associated with larger outbreaks (>=8 cases), 55.4% were unvaccinated, and 15.7% and 18.1% had received 1 or 2 doses of vaccine, respectively. In small outbreaks (5-7 cases), 33.3% of case-patients were unvaccinated, and 16.7% and 38.5% had received 1 or 2 doses of vaccine, respectively. Conclusions: The majority of cases associated with outbreaks occurred in undervaccinated children (unvaccinated and 1-dose vaccine recipients). Outbreaks with a greater proportion of 2-dose vaccine recipients were smaller. Varicella outbreak surveillance is feasible, and continued monitoring of outbreaks remains important for describing the epidemiology of varicella during the 2-dose varicella vaccination program. PMID- 29522135 TI - Sulfated fucans and a sulfated galactan from sea urchins as potent inhibitors of selectin-dependent hematogenous metastasis. AB - Metastasis is responsible for the majority of cancer-associated deaths, though only a very small number of tumor cells are able to efficiently complete all the steps of that process. Tumor cell survival in the bloodstream is one of the limiting aspects of the metastatic cascade. The formation of tumor cell-platelet complexes that promote tumor cell survival is facilitated by the binding of P selectin on activated platelets to sialyl Lewis-containing oligosaccharides on the surface of tumor cells. Inhibition of this interaction has been shown to attenuate metastasis. Heparin is a potent selectin inhibitor and is capable to block platelet-tumor cell complex formation, thereby attenuating metastasis. Similarly, other sulfated polysaccharides isolated from marine invertebrates attenuate metastasis by a P-selectin-mediated mechanism. In this work, we investigated the selectin-dependent antimetastatic activity of sea urchin sulfated polysaccharides with slight structural differences: a sulfated fucan from Strongylocentrotus franciscanus; a sulfated fucan from Strongylocentrotus droebachiensis; and a sulfated galactan from Echinometra lucunter. The results demonstrate that these fucans and the galactan have different antiselectin activities despite being very similar molecules. Therefore, they may be interesting tools for studies on the structure-function relationship or even for future treatments. PMID- 29522136 TI - Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over extension. AB - Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase. PMID- 29522137 TI - Saksenaea vasiformis Orbital Cellulitis in an Immunocompetent Child Treated With Posaconazole. AB - An 11-year-old immunocompetent girl presented with two and a half months of progressive right orbital cellulitis, which did not respond to multiple courses of antibiotics or prednisone. A panfungal polymerase chain reaction primer was positive for Saksenaea vasiformis, and she completed 5 months of oral posaconazole therapy after debridement. Saksenaea vasiformis is a rare cause of zygomycosis, and it typically causes skin and soft tissue infection in immunocompetent hosts, particularly after a traumatic injury. The diagnosis should be considered in cases with a protracted course that fail to respond to typical antibiotic therapy. Treatment includes surgical debridement, in additional to antifungal therapy with amphotericin B or posaconazole. PMID- 29522140 TI - Measurement of physiological responses to acute stress in multiple occupations: A systematic review and implications for front line healthcare providers. AB - Optimizing performance of individuals in acutely stressful work-related situations requires a deeper understanding of the interaction between the demands of the stimuli and an individual's associated physiological response. Identifying these responses is particularly germane for healthcare professionals, who experience episodes of acute stress on a regular basis. The purpose of this review was to examine and synthesize empirical literature to identify studies assessing physiological responses to acute stress, determine common methods for measuring acute stress in near real-time, and identify common research designs employed across industries. A modified PRISMA approach was followed. Systematic searches were conducted of four databases (PsycINFO, Medline, PubMed, and Turning Research into Practice [TRIP]) to access eligibility. Reference list searches and a hand search were also conducted to identify other articles suitable for inclusion. Studies selected examined an acute physiological response while participants were engaged in a stress-inducing task. Twenty-two articles were included. Fifteen (68.2%) were centered on the human service industry while only three (13.6%) focused on healthcare professionals. Half of the studies incorporated a simulation into the research design while only two (9.1%) articles looked at physiological responses in real-world settings. Heart rate and cortisol emerged as the most common physiological measures collected. This review demonstrates that acute stress is primarily assessed retrospectively, and that there is a pragmatic gap in methodological approach, with many data collection methods inappropriate for the healthcare environment. Future research should capitalize on advancements in sensor technology to passively examine acute stress in healthcare professionals. PMID- 29522138 TI - Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. AB - Importance: Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib. Objective: To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia. Design, Setting, and Participants: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 * 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly. Interventions: Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT. Main Outcomes and Measures: Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data. Results: Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (>=35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; >=50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%). Conclusions and Relevance: In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms. Trial Registration: clinicaltrials.gov Identifier: NCT02055781. PMID- 29522134 TI - Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. PMID- 29522141 TI - Refusing to Become a "Potted Plant". PMID- 29522142 TI - RE: "EXERCISE FOR THE PREVENTION OF LOW BACK PAIN: SYSTEMATIC REVIEW AND META ANALYSIS OF CONTROLLED TRIALS". PMID- 29522143 TI - An Uncommon Cutaneous Lesion. PMID- 29522144 TI - Aqueous Humor Cytokine Levels and Anatomic Response to Intravitreal Ranibizumab in Diabetic Macular Edema. AB - Importance: Variability in response to anti-vascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME) remains a significant clinical challenge. Biomarkers could help anticipate responses to anti-VEGF therapy. Objectives: To investigate aqueous humor cytokine level changes in response to intravitreal ranibizumab therapy for the management of DME, and to determine the association between baseline aqueous levels and anatomic response. Design, Setting, and Participants: In this prospective multicenter cohort study, 49 participants with diabetes mellitus complicated by center-involving DME, with a central subfield thickness of 310 MUm or greater on spectral-domain optical coherence tomography (SD-OCT), were recruited from December 22, 2011, to June 13, 2013 and statistical analysis were performed from March 1, 2017, to June 1, 2017. A total of 48 participants proceeded to follow-up. Interventions: Participants received monthly injections of ranibizumab, 0.5 mg, for 3 months. Aqueous fluid for cytokine analysis was obtained at baseline and repeated at the 2-month visit. Multiplex immunoassay was carried out in duplicate for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemoattractant protein 1. Main Outcomes and Measures: Baseline and 2-month change in aqueous cytokine levels, 3-month change in SD-OCT central subfield thickness and macular volume (MV), and the statistical association between baseline aqueous cytokine levels and these measures of anatomic response to ranibizumab in center-involving DME. Results: Among the 48 participants, the mean (SD) age was 61.9 (7.1) years and 36 participants (75.0%) were men. The following cytokines were lower at month 2 vs baseline: ICAM-1 (median change, -190.88; interquartile range [IQR], -634.20 to -26.54; P < .001), VEGF (median change, -639.45; IQR, -1040.61 to -502.61; P < .001), placental growth factor (median change, -1.31; IQR, -5.99 to -0.01; P < .001), IL-6 (median change, -38.61; IQR, -166.72 to -2.80; P < .001), and monocyte chemoattractant protein 1 (median change, -90.13; IQR, -382.74 to 109.47; P = .01). When controlling for age, foveal avascular zone size, and severity of retinopathy, multiple linear regression determined that increasing baseline aqueous ICAM-1 was associated with a favorable anatomic response, in terms of reduced SD-OCT MV at 3 months (every additional 100 pg/mL of baseline ICAM-1 was associated with a reduction of 0.0379 mm3; P = .01). Conversely, increasing baseline aqueous VEGF was associated with a less favorable SD-OCT MV response at 3 months (every additional 100 pg/mL of baseline VEGF was associated with an increase of 0.0731 mm3; P = .02) and was associated with lower odds of being a central subfield thickness responder (odds ratio, 0.868; 95% CI, 0.755-0.998). Conclusions and Relevance: Elevated aqueous ICAM-1 and reduced VEGF levels at baseline are associated with a favorable anatomic response to ranibizumab in DME, although there is not always direct correlation between anatomic and visual acuity response. PMID- 29522145 TI - GOLabeler: improving sequence-based large-scale protein function prediction by learning to rank. AB - Motivation: Gene Ontology (GO) has been widely used to annotate functions of proteins and understand their biological roles. Currently only <1% of >70 million proteins in UniProtKB have experimental GO annotations, implying the strong necessity of automated function prediction (AFP) of proteins, where AFP is a hard multilabel classification problem due to one protein with a diverse number of GO terms. Most of these proteins have only sequences as input information, indicating the importance of sequence-based AFP (SAFP: sequences are the only input). Furthermore, homology-based SAFP tools are competitive in AFP competitions, while they do not necessarily work well for so-called difficult proteins, which have <60% sequence identity to proteins with annotations already. Thus, the vital and challenging problem now is how to develop a method for SAFP, particularly for difficult proteins. Methods: The key of this method is to extract not only homology information but also diverse, deep-rooted information/evidence from sequence inputs and integrate them into a predictor in a both effective and efficient manner. We propose GOLabeler, which integrates five component classifiers, trained from different features, including GO term frequency, sequence alignment, amino acid trigram, domains and motifs, and biophysical properties, etc., in the framework of learning to rank (LTR), a paradigm of machine learning, especially powerful for multilabel classification. Results: The empirical results obtained by examining GOLabeler extensively and thoroughly by using large-scale datasets revealed numerous favorable aspects of GOLabeler, including significant performance advantage over state-of-the-art AFP methods. Availability and implementation: http://datamining iip.fudan.edu.cn/golabeler. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522146 TI - The US Food and Drug Administration's Approval of Adjuvant Sunitinib for Renal Cell Cancer: A Case of Regulatory Capture? PMID- 29522147 TI - Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. AB - Objective: To update the "Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2008. Participants: The participants include an Endocrine Society-appointed task force of seven medical experts and a methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion: We suggest testing for elevated androgen levels in all women with an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen-progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation. PMID- 29522148 TI - Dexmedetomidine improves the outcomes in paediatric cardiac surgery: a meta analysis of randomized controlled trials. AB - OBJECTIVES: Dexmedetomidine has been shown to decrease cardiac complications in adults undergoing cardiac surgery. Results from clinical trials of dexmedetomidine on outcomes following paediatric cardiac surgery are controversial. METHODS: We searched EMBASE, PubMed and Cochrane CENTRAL databases for randomized controlled trials comparing the effect of dexmedetomidine versus placebo or other anaesthetic drugs in paediatric patients undergoing cardiac surgery. The primary outcome was the duration of mechanical ventilation. The secondary outcomes were intensive care unit stay, hospital length of stay (LOS), incidence of junctional ectopic tachycardia and postoperative deaths. RESULTS: Nine trials with a total of 837 patients were selected. Compared with controls, dexmedetomidine significantly reduced the postoperative duration of mechanical ventilation [in hours; n = 837; weighted mean difference -2.20, 95% confidence interval (CI) -3.51 to -0.90; P = 0.001; I2 = 97%], intensive care unit LOS (in days; n = 737; weighted mean difference -0.47, 95% CI -0.90 to -0.03; P = 0.03; I2 = 97%) and hospital LOS (in days; n = 291; weighted mean difference -1.80, 95% CI -3.36 to -0.25; P = 0.02; I2 = 96%). Dexmedetomidine also significantly reduced the incidence of postoperative junctional ectopic tachycardia (21/292 vs 50/263; risk ratio 0.40, 95% CI 0.25-0.64; P = 0.0001; I2 = 0.0%), but there was no difference between groups in postoperative deaths (4/182 vs 6/153; odds ratio 0.54, 95% CI 0.15-1.93; P = 0.34; I2 = 0.0%). CONCLUSIONS: Perioperative administration of dexmedetomidine to paediatric patients undergoing cardiac surgery may shorten the duration of mechanical ventilation, LOS in the intensive care unit and in the hospital and reduce the incidence of junctional ectopic tachycardia. More high-quality randomized controlled trials are encouraged to verify the beneficial effect of dexmedetomidine before its clinical application in paediatric patients undergoing surgery for congenital heart disease. PMID- 29522149 TI - Patient-Reported Dysphagia After Thyroidectomy: A Qualitative Study. AB - Importance: It is important that clinicians understand consequences of thyoridectomy on swallowing from the patient perspective to better care for this population. Objective: Using rigorous qualitative methodology, this study set out to characterize the effect of swallowing-related symptoms after thyroidectomy on patient quality of life and swallowing-related outcomes. Design, Setting, and Participants: Prospective, grounded theory analysis of interviews with 26 patients at 3 time points after thyroidectomy (2 weeks, 6 weeks, and 6 months). Data were collected from an ongoing clinical trial (NCT02138214), and outpatient interviews were conducted at the University of Wisconsin Hospital and Clinics. All participants were age 21 to 73 years with a diagnosis of papillary thyroid cancer without cervical or distant metastases and had undergone total thyroidectomy. Exclusion criteria were preexisting vocal fold abnormalities (eg, polyps, nodules), neurological conditions affecting the voice or swallowing ability, and/or development of new-onset vocal fold paresis or paralysis (lasting longer than 6 months) after total thyroidectomy. Interventions: Total thyroidectomy. Main Outcomes and Measures: Symptoms of dysphagia and related effects on quality of life elicited through grounded theory analysis of semistructured interviews with patients after thyroidectomy designed to foster an open-ended, patient-driven discussion. Results: Of the 26 patients included, 69% were women (n = 18); mean (SD) age, 46.4 (14.1) years; mean (SD) tumor diameter 2.2 (1.4) cm. Two weeks after thyroidectomy, 80% of participants (n = 20) reported at least 1 swallowing-related symptom when prompted by the interview cards; during the open interview, 53% of participants (n = 14) volunteered discussion of swallowing-related symptoms unprompted. However, only 8% of participants in this study (n = 2) qualified for a follow-up dysphagia evaluation, indicating that the majority of reported symptoms were subjective in nature. Six weeks and 6 months after thyroidectomy, 42% (n = 11) and 17% (n = 4) of participants, respectively, reported continued swallowing symptoms using the prompts; 12% (n = 3) discussed symptoms without prompting cards at both time points. Conclusions and Relevance: Swallowing symptoms after thyroidectomy are underreported in the literature. This study revealed that as many as 80% of patients who have thyroidectomy may experience swallowing-related symptoms after surgery, and many develop compensatory strategies to manage or reduce the burden of these symptoms. Considering the large number of individuals who may experience subjective dysphagia, preoperative counseling should include education and management of such symptoms. PMID- 29522150 TI - Spanish Linguistic Validation for the Velopharyngeal Insufficiency Effects on Life Outcomes. PMID- 29522151 TI - Which are the major players, canonical or non-canonical strigolactones? AB - Strigolactones (SLs) can be classified into two structurally distinct groups: canonical and non-canonical SLs. Canonical SLs contain the ABCD ring system, and non-canonical SLs lack the A, B, or C ring but have the enol ether-D ring moiety, which is essential for biological activities. The simplest non-canonical SL is the SL biosynthetic intermediate carlactone. In plants, carlactone and its oxidized metabolites, such as carlactonoic acid and methyl carlactonoate, are present in root and shoot tissues. In some plant species, including black oat (Avena strigosa), sunflower (Helianthus annuus), and maize (Zea mays), non canonical SLs in the root exudates are major germination stimulants. Various plant species, such as tomato (Solanum lycopersicum), Arabidopsis, and poplar (Populus spp.), release carlactonoic acid into the rhizosphere. These observations suggest that both canonical and non-canonical SLs act as host recognition signals in the rhizosphere. In contrast, the limited distribution of canonical SLs in the plant kingdom, and the structure-specific and stereospecific transportation of canonical SLs from roots to shoots, suggest that plant hormones inhibiting shoot branching are not canonical SLs but, rather, are non-canonical SLs. PMID- 29522152 TI - Methodological and Efficacy Issues in a Randomized Clinical Trial Investigating Vitreous Floater Treatment-Reply. PMID- 29522153 TI - NeSSie: a tool for the identification of approximate DNA sequence symmetries. AB - Motivation: Non-B DNA conformations play an important role in genomic rearrangements, structural three-dimensional organization and gene regulation. Many non-B DNA structures show symmetrical properties as palindromes and mirrors that can form hairpins, cruciform structures or triplexes. A comprehensive tool, capable to perform a fast genome wide search for exact and degenerate symmetrical patterns, is needed for further investigating nucleotide tracts potentially forming non-B DNA structures. Results: We developed NeSSie, an easily customizable C/C++ 64-bit library and tool, based on dynamic programming, to quickly scan for perfect and degenerate DNA palindromes, mirrors and potential triplex forming patterns. In addition, the tool computes linguistic complexity and Shannon entropy measures to verify the repetitive nature of the DNA regions enriched in these motifs. As a case study, the analysis of the Mycobacterium bovis genome is presented. Availability and implementation: http://www.medcomp.medicina.unipd.it/main_site/doku.php? id=nessie and https://github.com/B3rse/nessie. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522154 TI - RSRC1 mutation affects intellect and behaviour through aberrant splicing and transcription, downregulating IGFBP3. AB - RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts. Short hairpin RNA (shRNA)-mediated lentiviral silencing and overexpression of RSRC1 in SH-SY5Y cells demonstrated that RSRC1 has a role in alternative splicing and transcription regulation. Transcriptome profiling of RSRC1-silenced cells unravelled specific differentially expressed genes previously associated with intellectual disability, hypotonia and schizophrenia, relevant to the disease phenotype. Protein-protein interaction network modelling suggested possible intermediate interactions by which RSRC1 affects gene-specific differential expression. Patient-derived induced pluripotent stem cells, differentiated into neural progenitor cells, showed expression dynamics similar to the RSRC1-silenced SH-SY5Y model. Notably, patient neural progenitor cells had 9.6-fold downregulated expression of IGFBP3, whose brain expression is affected by MECP2, aberrant in Rett syndrome. Interestingly, Igfbp3-null mice have behavioural impairment, abnormal synaptic function and monoaminergic neurotransmission, likely correlating with the disease phenotype. PMID- 29522155 TI - Identification of Genes Enriched in GnRH Neurons by Translating Ribosome Affinity Purification and RNAseq in Mice. AB - Gonadotropin-releasing hormone (GnRH) neurons are a nexus of fertility regulation. We used translating ribosome affinity purification coupled with RNA sequencing to examine messenger RNAs of GnRH neurons in adult intact and gonadectomized (GDX) male and female mice. GnRH neuron ribosomes were tagged with green fluorescent protein (GFP) and GFP-labeled polysomes isolated by immunoprecipitation, producing one RNA fraction enhanced for GnRH neuron transcripts and one RNA fraction depleted. Complementary DNA libraries were created from each fraction and 50-base, paired-end sequencing done and differential expression (enhanced fraction/depleted fraction) determined with a threshold of >1.5- or <0.66-fold (false discovery rate P <= 0.05). A core of ~840 genes was differentially expressed in GnRH neurons in all treatments, including enrichment for Gnrh1 (~40-fold), and genes critical for GnRH neuron and/or gonadotrope development. In contrast, non-neuronal transcripts were not enriched or were de-enriched. Several epithelial markers were also enriched, consistent with the olfactory epithelial origins of GnRH neurons. Interestingly, many synaptic transmission pathways were de-enriched, in accordance with relatively low innervation of GnRH neurons. The most striking difference between intact and GDX mice of both sexes was a marked downregulation of genes associated with oxidative phosphorylation and upregulation of glucose transporters in GnRH neurons from GDX mice. This may suggest that GnRH neurons switch to an alternate fuel to increase adenosine triphosphate production in the absence of negative feedback when GnRH release is elevated. Knowledge of the GnRH neuron translatome and its regulation can guide functional studies and can be extended to disease states, such as polycystic ovary syndrome. PMID- 29522157 TI - PriLive: privacy-preserving real-time filtering for next-generation sequencing. AB - Motivation: In next-generation sequencing, re-identification of individuals and other privacy-breaching strategies can be applied even for anonymized data. This also holds true for applications in which human DNA is acquired as a by-product, e.g. for viral or metagenomic samples from a human host. Conventional data protection strategies including cryptography and post-hoc filtering are only appropriate for the final and processed sequencing data. This can result in an insufficient level of data protection and a considerable time delay in the further analysis workflow. Results: We present PriLive, a novel tool for the automated removal of sensitive data while the sequencing machine is running. Thereby, human sequence information can be detected and removed before being completely produced. This facilitates the compliance with strict data protection regulations. The unique characteristic to cause almost no time delay for further analyses is also a clear benefit for applications other than data protection. Especially if the sequencing data are dominated by known background signals, PriLive considerably accelerates consequent analyses by having only fractions of input data. Besides these conceptual advantages, PriLive achieves filtering results at least as accurate as conventional post-hoc filtering tools. Availability and implementation: PriLive is open-source software available at https://gitlab.com/rki_bioinformatics/PriLive. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522156 TI - Electromagnetic signatures of the preclinical and prodromal stages of Alzheimer's disease. AB - Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-beta deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-beta-positive mild cognitive impairment (n = 17, mean age 74.7 +/- 5.4 years, nine males), amyloid-beta negative mild cognitive impairment (n = 11, mean age 73.8 +/- 8.8 years, eight males), amyloid-beta-positive cognitively normal (n = 13, mean age 71.8 +/- 4.4 years, seven males), and amyloid-beta-negative cognitively normal (n = 25, mean age 72.5 +/- 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-beta deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-beta deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease. PMID- 29522158 TI - Resolution of diffuse alveolar haemorrhage after rituximab therapy. PMID- 29522159 TI - Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis. AB - Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%-3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%-6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data. PMID- 29522162 TI - Effect of pembrolizumab on patients harboring uncommon epidermal growth factor receptor mutations. PMID- 29522161 TI - Association Between Loss of Hospital-Based Obstetric Services and Birth Outcomes in Rural Counties in the United States. AB - Importance: Hospital-based obstetric services have decreased in rural US counties, but whether this has been associated with changes in birth location and outcomes is unknown. Objective: To examine the relationship between loss of hospital-based obstetric services and location of childbirth and birth outcomes in rural counties. Design, Setting, and Participants: A retrospective cohort study, using county-level regression models in an annual interrupted time series approach. Births occurring from 2004 to 2014 in rural US counties were identified using birth certificates linked to American Hospital Association Annual Surveys. Participants included 4 941 387 births in all 1086 rural counties with hospital based obstetric services in 2004. Exposures: Loss of hospital-based obstetric services in the county of maternal residence, stratified by adjacency to urban areas. Main Outcomes and Measures: Primary outcomes were county rates of (1) out of-hospital births; (2) births in hospitals without obstetric units; and (3) preterm births (<37 weeks' gestation). Results: Between 2004 and 2014, 179 rural counties lost hospital-based obstetric services. Of the 4 941 387 births studied, the mean (SD) maternal age was 26.2 (5.8) years. A mean (SD) of 75.9% (23.2%) of women who gave birth were non-Hispanic white, and 49.7% (15.6%) were college graduates. Rural counties not adjacent to urban areas that lost hospital-based obstetric services had significant increases in out-of-hospital births (0.70 percentage points [95% CI, 0.30 to 1.10]); births in a hospital without an obstetric unit (3.06 percentage points [95% CI, 2.66 to 3.46]); and preterm births (0.67 percentage points [95% CI, 0.02 to 1.33]), in the year after loss of services, compared with those with continual obstetric services. Rural counties adjacent to urban areas that lost hospital-based obstetric services also had significant increases in births in a hospital without obstetric services (1.80 percentage points [95% CI, 1.55 to 2.05]) in the year after loss of services, compared with those with continual obstetric services, and this was followed by a decreasing trend (-0.19 percentage points per year [95% CI, -0.25 to -0.14]). Conclusions and Relevance: In rural US counties not adjacent to urban areas, loss of hospital-based obstetric services, compared with counties with continual services, was associated with increases in out-of-hospital and preterm births and births in hospitals without obstetric units in the following year; the latter also occurred in urban-adjacent counties. These findings may inform planning and policy regarding rural obstetric services. PMID- 29522163 TI - Corneal Perforation With Iris Plugging. PMID- 29522160 TI - Amygdala-medial prefrontal connectivity relates to stress and mental health in early childhood. AB - Early life stress has been associated with disrupted functional connectivity between the amygdala and medial prefrontal cortex (mPFC), but it is unknown how early in development stress-related differences in amygdala-mPFC connectivity emerge. In a resting-state functional connectivity (rs-FC) analysis with 79 four- to seven-year-old children, we found a significant correlation between more adverse experiences and weaker amygdala-mPFC rs-FC. We also found that weaker amygdala-mPFC rs-FC was associated with higher levels of aggressive behavior and attention problems. These findings suggest that the impact of stress on emotional circuitry is detectable in early childhood and that this impact is associated with mental health difficulties. Connectivity in this circuit may be useful as a marker for mental health risk and for tracking the efficacy of early interventions. PMID- 29522164 TI - Cutaneous Melanoma Metastatic to Anterior Lens Capsule. PMID- 29522167 TI - Pharmacokinetics and pharmacodynamic target attainment of ceftriaxone in adult severely ill sub-Saharan African patients: a population pharmacokinetic modelling study. AB - Background: In sub-Saharan Africa (SSA), the highly albumin-bound beta-lactam ceftriaxone is frequently used for the empirical treatment of severe bacterial infections. Systemic drug exposure of beta-lactams can be altered in critically ill ICU patients, but pharmacokinetic and pharmacodynamic data for non-ICU SSA populations are lacking. Methods: We performed a population pharmacokinetic study in an adult hospital population in Mozambique, treated with ceftriaxone for presumptive severe bacterial infection from October 2014 to November 2015. Four blood samples per patient were collected for total ceftriaxone (CEFt) and unbound ceftriaxone (CEFu) concentration measurement. We developed a population pharmacokinetic model through non-linear mixed effect analysis and performed simulations for different patient variable, dosing and pharmacodynamic target scenarios. Results: Eighty-eight participants yielded 277 CEFt and 276 CEFu concentrations. The median BMI was 18.9 kg/m2 and the median albumin concentration was 29 g/L. In a one-compartment model with non-linear protein binding, creatinine clearance was positively correlated with CEFu clearance. For microorganisms with an MIC of 1 mg/L, simulations demonstrated that with a 1 g twice-daily regimen and a 2 g once-daily regimen, 95.1% and 74.8% would have a CEFu concentration > MIC during half of the dosing interval (fT>MIC = 50%), respectively, whereas this was only 58.2% and 16.5% for the fT>MIC = 100% target. Conclusions: Severely ill adult non-ICU SSA patients may be at substantial risk for underexposure to CEFu during routine intermittent bolus dosing, especially when their renal function is intact. PMID- 29522169 TI - Effects of Mild Perinatal Hypothyroidism on Cognitive Function of Adult Male Offspring. AB - Mild perinatal hypothyroidism may result from inadequate iodine intake, insufficient treatment of congenital hypothyroidism, or exposure to endocrine disrupting chemicals. Because thyroid hormones are critical for brain development, severe hypothyroidism that is untreated in infancy causes irreversible cretinism. Milder hypothyroidism may also affect cognitive development; however, the effects of mild and/or moderate hypothyroidism on brain development are not fully understood. In this study, we examined the behavior of adult male mice rendered mildly hypothyroid during the perinatal period using low dose propylthiouracil (PTU). PTU was administered through drinking water (5 or 50 ppm) from gestational day 14 to postnatal day 21. Cognitive performance, studied by an object in-location test (OLT), was impaired in PTU-treated mice at postnatal week 8. These results suggest that, although the hypothyroidism was mild, it partially impaired cognitive function. We next measured the concentration of neurotransmitters (glutamate, gamma-aminobutyric acid, and glycine) in the hippocampus using in vivo microdialysis during OLT. The concentrations of neurotransmitters, particularly glutamate and glycine, decreased in PTU-treated mice. The expression levels of N-methyl-d-aspartate receptor subunits, which are profound regulators of glutamate neurotransmission and memory function, also were decreased in PTU-treated mice. These data indicate that mild perinatal hypothyroidism causes cognitive disorders in adult offspring. Such disorders may be partially induced secondary to decreased concentrations of neurotransmitters and receptor expression. PMID- 29522170 TI - Malignancy and Mortality in Pediatric-onset Inflammatory Bowel Disease: A Systematic Review. AB - Background: Cancer and death are the most severe outcomes that affect patients with inflammatory bowel disease (IBD). These outcomes are even more severe if they occur at a young age but are rare, even in the general population. We conducted a systematic review to provide an overview of all reported pediatric (PIBD) patients with severe outcome. Methods: A literature search identified publications that reported development of cancer or fatal outcome in PIBD patients. Studies were eligible for inclusion when (1) article written in English, (2) original data, (3) individual patient information, (4) full text available, (5) study population consisting of patients diagnosed with IBD under the age of 19 years, and (6) who developed malignancy or fatality at any point later in life. Results: A total of 98 included studies comprised data of 271 PIBD patients who developed cancer and/or fatal outcome at any point later in life. Meta-analysis demonstrated an increased risk for cancer in PIBD patients (pooled standardized incidence ratio 2.23, 95% CI: 1.98-2.52). The most frequent type of non-fatal cancer was lymphoma, whereas colorectal carcinomas were the most frequently reported type of fatal cancer in PIBD patients and were particularly associated with primary sclerosing cholangitis. The majority of patients with noncancer-related fatal outcomes were diagnosed with ulcerative colitis and most often died due to infectious complications or severe disease-associated complications. Conclusions: The data in this review confirm that PIBD associated malignancy and mortality are rare and detailed clinical characteristics are limited. Prospective and international collaborations are needed to obtain more detailed patient-specific information, which is necessary to investigate the relationship between severe outcomes in PIBD patients and the currently used therapeutic strategies. 10.1093/ibd/izx104_video1izx104_Video5754026434001. PMID- 29522172 TI - Does common prescription medication affect the rate of orthodontic tooth movement? A systematic review. AB - Background: As the taking of any medication may theoretically affect the complex pathways responsible for periodontal tissue homeostasis and the events leading to orthodontic tooth movement, it is considered important for the orthodontist to be able to identify prospective patients' history and patterns of pharmaceutical consumption. Objective: To systematically investigate and appraise the quality of the available evidence regarding the effect of commonly prescribed medications on the rate of orthodontic tooth movement. Search methods: Search without restrictions in eight databases and hand searching until June 2017. Selection criteria: Controlled studies investigating the effect of commonly prescribed medications with emphasis on the rate of orthodontic tooth movement. Data collection and analysis: Following study retrieval and selection, relevant data was extracted and the risk of bias was assessed using the SYRCLE's Risk of Bias Tool. Results: Twenty-seven animal studies, involving various pharmacologic and orthodontic interventions, were finally identified. Most studies were assessed to be at unclear or high risk of bias. The rate of orthodontic tooth movement was shown to increase after the administration of diazepam, Vitamin C and pantoprazole, while simvastatin, atorvastatin, calcium compounds, strontium ranelate, propranolol, losartan, famotidine, cetirizine, and metformin decreased the rate of orthodontic tooth movement. No interference with the rate of orthodontic tooth movement was reported for phenytoin, phenobarbital and zinc compounds, whereas, inconsistent or conflicting effects were noted after the administration of L-thyroxine, lithium compounds, fluoxetine and insulin. The quality of the available evidence was considered at best as low. Conclusions: Commonly prescribed medications may exhibit variable effects on the rate of orthodontic tooth movement. Although the quality of evidence was considered at best as low, raising reservations about the strength of the relevant recommendations, the clinician should be capable of identifying patients taking medications and should take into consideration the possible implications related to the proposed treatment. Registration: PROSPERO (CRD42015029130). PMID- 29522173 TI - Loss of cardiac Wnt/beta-catenin signalling in desmoplakin-deficient AC8 zebrafish models is rescuable by genetic and pharmacological intervention. AB - Aims: Arrhythmogenic cardiomyopathy (AC) is an inherited heart disease characterized by life-threatening ventricular arrhythmias and fibro-fatty replacement of the myocardium. More than 60% of AC patients show pathogenic mutations in genes encoding for desmosomal proteins. By focusing our attention on the AC8 form, linked to the junctional protein desmoplakin (DSP), we present here a zebrafish model of DSP deficiency, exploited to identify early changes of cell signalling in the cardiac region. Methods and results: To obtain an embryonic model of Dsp deficiency, we first confirmed the orthologous correspondence of zebrafish Dsp genes (dspa and dspb) to the human DSP counterpart. Then, we verified their cardiac expression, at embryonic and adult stages, and subsequently we targeted them by antisense morpholino strategy, confirming specific and disruptive effects on desmosomes, like those identified in AC patients. Finally, we exploited our Dsp-deficient models for an in vivo cell signalling screen, using pathway-specific reporter transgenes. Out of nine considered, three pathways (Wnt/beta-catenin, TGFbeta/Smad3, and Hippo/YAP-TAZ) were significantly altered, with Wnt as the most dramatically affected. Interestingly, under persistent Dsp deficiency, Wnt signalling is rescuable both by a genetic and a pharmacological approach. Conclusion: Our data point to Wnt/beta-catenin as the final common pathway underlying different desmosomal AC forms and support the zebrafish as a suitable model for detecting early signalling pathways involved in the pathogenesis of DSP-associated diseases, possibly responsive to pharmacological or genetic rescue. PMID- 29522171 TI - Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing. AB - Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks. PMID- 29522174 TI - Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. AB - Importance: Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective: To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. Design, Setting, and Participants: PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Interventions: Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Main Outcomes and Measures: Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal related events (SA3), clinical progression (SA4), a confirmatory scan for soft tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman rho and Kendall tau via Clayton copula. Results: In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman rho and 0.72 (95% CI, 0.68-0.77) by Kendall tau. Conclusions and Relevance: Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. Trial Registration: clinicaltrials.gov Identifier: NCT01212991. PMID- 29522176 TI - Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis. AB - Background: Several pharmacologic treatments for hirsutism are used in practice; however, their relative efficacy is unclear. Methods: We searched MEDLINE, EMBASE, and CENTRAL through January 2017 for randomized controlled trials (RCTs) with follow-up of at least 6 months that evaluated antiandrogens, insulin sensitizers, and oral contraceptives in women with hirsutism. Independent pairs of reviewers selected and appraised trials. Random-effects network meta-analysis was used to compare individual drugs and classes. Results: We included 43 trials. Estrogen-progestin oral contraceptives pills (OCPs), antiandrogens, and insulin sensitizers were superior to placebo, with standardized mean reductions (95% confidence intervals) of -0.94 (-1.49 to -0.38), -1.29 (-1.80 to -0.79), and 0.62 (-1.00 to -0.23), respectively. Antiandrogen monotherapy, the combination of OCP and antiandrogen, the combination of OCPs and insulin sensitizer, and the combination of antiandrogen and insulin sensitizer were superior to insulin sensitizer monotherapy. The combination of OCPs and antiandrogen was superior to OCPs. Antiandrogen monotherapy with flutamide, finasteride, and spironolactone were each superior to placebo but similar to each other in efficacy. OCPs containing levonorgestrel, cyproterone acetate, or drospirenone were similar in effectiveness to other OCPs or had trivial differences. The certainty in comparisons with placebo was moderate and for head-to-head comparisons was low. Conclusions: Estrogen-progestin OCPs, antiandrogens, and insulin sensitizers are superior to placebo for the treatment of hirsutism. PMID- 29522175 TI - Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole Exome Sequencing. AB - Background: Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods: Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Results: Strong signals were detected for CDKN2A (Pmin = 6.16 * 10-8) in the CM cohort (n = 273) and BAP1 (Pmin = 3.83 * 10-6) in the OM (n = 99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75 * 10 4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37 * 10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions: The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene. PMID- 29522177 TI - miR-214-3p Targets beta-Catenin to Regulate Depressive-like Behaviors Induced by Chronic Social Defeat Stress in Mice. AB - beta-Catenin has been implicated in major depressive disorder (MDD), which is associated with synaptic plasticity and dendritic arborization. MicroRNAs (miRNA) are small noncoding RNAs containing about 22 nucleotides and involved in a variety of physiological and pathophysiological process, but their roles in MDD remain largely unknown. Here, we investigated the expression and function of miRNAs in the mouse model of chronic social defeat stress (CSDS). The regulation of beta-catenin by selected miRNA was validated by silico prediction, target gene luciferase reporter assay, and transfection experiment in neurons. We demonstrated that the levels of miR-214-3p, which targets beta-catenin transcripts were significantly increased in the medial prefrontal cortex (mPFC) of CSDS mice. Antagomir-214-3p, a neutralizing inhibitor of miR-214-3p, increased the levels of beta-catenin and reversed the depressive-like behavior in CSDS mice. Meanwhile, antagomir-214-3p increased the amplitude of miniature excitatory postsynaptic current (mEPSC) and the number of dendritic spines in mPFC of CSDS mice, which may be related to the elevated expression of cldn1. Furthermore, intranasal administered antagomir-214-3p also significantly increased the level of beta-catenin and reversed the depressive-like behaviors in CSDS mice. These results may represent a new therapeutic target for MDD. PMID- 29522178 TI - Non-perceptual Regions in the Left Inferior Parietal Lobe Support Phonological Short-term Memory: Evidence for a Buffer Account? AB - Buffer versus embedded processes accounts of short-term memory (STM) for phonological information were addressed by testing subjects' perception and memory for speech and non-speech auditory stimuli. Univariate and multivariate (MVPA) approaches were used to assess whether brain regions recruited in recognizing speech were involved in maintaining speech representations over a delay. As expected, a left superior temporal region was found to support speech perception. However, contrary to the embedded processes approach, this region failed to show a load effect, or any sustained activation, during a maintenance delay. Moreover, MVPA decoding during the maintenance stage was unsuccessful in this region by a perception classifier or an encoding classifier. In contrast, the left supramarginal gyrus showed both sustained activation and a load effect. Using MVPA, stimulus decoding was successful during the delay period. In addition, a functional connectivity analysis showed that, as memory load increased, the left temporal lobe involved in perception became more strongly connected with the parietal region involved in maintenance. Taken together, the findings provide greater support for a buffer than embedded processes account of phonological STM. PMID- 29522179 TI - Discitis caused by rat bite fever in a rheumatoid arthritis patient on tocilizumab-first ever case. PMID- 29522180 TI - Passive Tick Surveillance Provides an Accurate Early Signal of Emerging Lyme Disease Risk and Human Cases in Southern Canada. AB - Lyme disease is an emerging public health threat in Canada. In this context, rapid detection of new risk areas is essential for timely application of prevention and control measures. In Canada, information on Lyme disease risk is collected through three surveillance activities: active tick surveillance, passive tick surveillance, and reported human cases. However, each method has shortcomings that limit its ability to rapidly and reliably identify new risk areas. We investigated the relationships between risk signals provided by human cases, passive and active tick surveillance to assess the performance of tick surveillance for early detection of emerging risk areas. We used regression models to investigate the relationships between the reported human cases, Ixodes scapularis (Say; Acari: Ixodidae) ticks collected on humans through passive surveillance and the density of nymphs collected by active surveillance from 2009 to 2014 in the province of Quebec. We then developed new risk indicators and validated their ability to discriminate risk levels used by provincial public health authorities. While there was a significant positive relationship between the risk signals provided all three surveillance methods, the strongest association was between passive tick surveillance and reported human cases. Passive tick submissions were a reasonable indicator of the abundance of ticks in the environment (sensitivity and specificity [Se and Sp] < 0.70), but were a much better indicator of municipalities with more than three human cases reported over 5 yr (Se = 0.88; Sp = 0.90). These results suggest that passive tick surveillance provides a timely and reliable signal of emerging risk areas for Lyme disease in Canada. PMID- 29522181 TI - Otolaryngology Resident Education and the Accreditation Council for Graduate Medical Education Core Competencies: A Systematic Review. AB - Importance: To date, there have been no reports in the current literature regarding the use of the Accreditation Council for Graduate Medical Education (ACGME) core competencies in otolaryngology residency training. An evaluation may help educators address these core competencies in the training curriculum. Objectives: To examine the quantity and nature of otolaryngology residency training literature through a systematic review and to evaluate whether this literature aligns with the 6 core competencies. Evidence Review: A medical librarian assisted in a search of all indexed years of the PubMed, Embase, Education Resources Information Center (via EBSCOhost), Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Cochrane Methodology Register), Thomson Reuters Web of Science (Science Citation Index Expanded, Social Sciences Citation Index Expanded, Conference Proceedings Citation Index-Science, and Conference Proceedings Citation Index-Social Science and Humanities), Elsevier Scopus, and ClinicalTrials.gov databases to identify relevant English-language studies. Included studies contained original human data and focused on otolaryngology resident education. Data regarding study design, setting, and ACGME core competencies addressed were extracted from each article. Initial searches were performed on May 20, 2015, and updated on October 4, 2016. Findings: In this systematic review of 104 unique studies, interpersonal communication skills were reported 15 times; medical knowledge, 48 times; patient care, 44 times; practice based learning and improvement, 31 times; professionalism, 15 times; and systems based practices, 10 times. Multiple studies addressed more than 1 core competency at once, and 6 addressed all 6 core competencies. Conclusions and Relevance: Increased emphasis on nonclinical core competencies is needed, including professionalism, interpersonal and communication skills, and systems-based practices in the otolaryngology residency training curriculum. A formal curriculum addressing nonclinical core competencies should be integrated into otolaryngology residency training. PMID- 29522182 TI - Performance of Optimized Wide Pore Superficially Porous Particles for Separation of Proteins and Immunoglobulin G Antibodies. AB - In this study, we studied the chromatographic performance of this newly developed wide pore superficially porous particles (SPPs) with 3.5 MUm particle size and 450 A pore size, for the separation of proteins and Immunoglobulin G antibodies. We studied the selectivity of different phases (C4, SB-C18 and Diphenyl), the effect of temperature, column carryover and column chemical lifetime. We also compared our SPPs with other wide pore SPPs in similar particle sizes and sub 2 u wide pore totally porous particles by van Deemter studies and gradient separations of proteins and immunoglobulin G antibodies. The results showed that the SPPs containing larger pore size gave better chromatographic performance. PMID- 29522185 TI - Maximizing Home Equity or Preventing Home Loss: Reverse Mortgage Decision Making and Racial Inequality. AB - Background and Objectives: Reverse mortgages are loans that allow older homeowners to borrow from their home equity with no repayment due until the borrower dies or moves out of the home. We currently know very little about how homeowners evaluate and experience reverse mortgages as solutions to their financial and housing needs in later life. Furthermore, despite an increasingly diverse population of reverse mortgage borrowers, we know little about how social inequalities may contribute to reverse mortgage decisions and their outcomes. In this paper, we examine reverse mortgage decision-making and experiences in a racially and economically diverse sample of older US homeowners. Research Design and Methods: We conducted 44 in-depth interviews with older homeowners who were considering or who had obtained a reverse mortgage loan. We inductively and iteratively developed a thematic coding scheme that was applied to all interview transcripts. Results: Our analysis produced a dichotomous schema of reverse mortgage decision making that was shaped by social and economic opportunities and constraints. For some participants, reverse mortgages represented strategic tools used to maximize home equity and its benefits. For others, it was an option of last resort to which participants turned when faced with the imminent loss of their home. Discussion and Implications: Focusing on reverse mortgages, our analysis suggests way that social inequalities may be reproduced through financial decisions and the unequal landscapes of opportunity in which they are made. PMID- 29522183 TI - IDH2 mutations are commonly associated with 1p/19q codeletion in diffuse adult gliomas. PMID- 29522184 TI - Brain PET Imaging of alpha7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia. AB - Background: The alpha7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of alpha7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of alpha7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an alpha7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and alpha7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying alpha7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability <=7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of alpha7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, alpha7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for alpha7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects. PMID- 29522186 TI - Assessment of sympathetic neural activity in chronic insomnia: evidence for elevated cardiovascular risk. AB - Study Objectives: Chronic insomnia affects up to 15 per cent of adults. Recent cross-sectional and prospective epidemiological studies report an association between insomnia and hypertension, including incident hypertension, yet mechanisms underlying the association remain unknown. We hypothesized that participants with chronic insomnia would have elevated sympathetic neural outflow, blunted baroreflex sensitivity, and augmented sympathetic neural and cardiovascular reactivity to stress when compared with good-sleeper controls. Methods: Twelve participants with chronic insomnia (11 women, 1 man) and 12 controls (8 women, 4 men) underwent one night of laboratory polysomnography, two weeks of at-home wrist actigraphy, and one night of controlled laboratory sleep prior to a comprehensive morning autonomic function test. The autonomic function test consisted of simultaneous recordings of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram) during a 10 min supine baseline and a 2 min cold pressor test. Results: Baseline blood pressure, heart rate, and MSNA were not different between groups, but sympathetic baroreflex sensitivity was significantly blunted in participants with insomnia (-2.1 +/- 1.0 vs. -4.3 +/- 1.3 bursts/100 heartbeats/mm Hg; p < 0.001). During the cold pressor test, systolic arterial pressure reactivity (Delta21 +/- 11 vs. Delta14 +/- 8 mm Hg; time * group = 0.04) and total MSNA reactivity (Delta127%, 54%-208% vs. Delta52%, 30%-81%; time * group = 0.02) were augmented in chronic insomnia. Conclusions: Participants with chronic insomnia demonstrated impaired sympathetic baroreflex function and augmented neural cardiovascular responsiveness to stress, when compared with controls. These findings support growing evidence of cardiovascular risk and physiological hyperarousal in chronic insomnia. Clinical Trial Registration: NCT02048878. https://clinicaltrials.gov/ct2/show/NCT02048878. PMID- 29522188 TI - Possible Underestimation of the Provision of Palliative Care-Reply. PMID- 29522187 TI - Using the Index of Concentration at the Extremes at multiple geographical levels to monitor health inequities in an era of growing spatial social polarization: Massachusetts, USA (2010-14). AB - Background: Metrics that quantify economic and social spatial polarization at multiple geographical levels are not routinely used by health agencies, despite rising inequalities. Methods: We employed the Index of Concentration at the Extremes (ICE), which quantifies how persons in a specified area are concentrated into the top vs bottom of a specified societal distribution, to examine associations with Massachusetts mortality data (2010-14). Our a priori hypotheses were that these associations would: be greater at the local [census tract (CT)] compared with city/town level; vary by race/ethnicity but not gender; and be greatest for our new ICE for racialized economic segregation. Mortality outcomes comprised: child (< 5 years); premature (< 65 years); and cause-specific (cancer; cardiovascular; diabetes; suicide; HIV/AIDS; accidental poisoning; smoking attributable). Results: As illustrated by child mortality, in multilevel models jointly including CT and city/town metrics, the rate ratio comparing the worst to best-off ICE quintile for the total population ranged from 2.2 [95% confidence interval (CI) 1.6, 3.0] for the CT-level ICE for racialized economic segregation down to 1.1 (95% CI 0.8, 1.7) for the city/town-level ICE for racial segregation; similar patterns occurred by gender and for the non-Hispanic White population. Larger associations for the ICE for racialized economic segregation were at the CT-level for the Black non-Hispanic population (6.9; 95% CI 1.3, 36.9) and at the city/town level for the Hispanic population (6.4; 95% CI 1.2, 35.4). Conclusions: Results indicate that health agencies should employ measures of spatial social polarization at multiple levels to monitor health inequities. PMID- 29522189 TI - Cardiac transplantation in systemic sclerosis: single-centre experience of three cases. PMID- 29522190 TI - Society and personal genome data. AB - Genomic data offer a goldmine of information for understanding the contribution of genetic variation makes to health and disease. The potential of genomic medicine, to predict, diagnose, manage and treat genetic disease, is underpinned by accurate variant interpretation. This in itself hinges on the ability to access large and varied genomic databases. There is now recognition that international collaboration between research and healthcare systems are paramount to delivering the scale of genomic data required. No single research group, institute or country will liberate our understanding, it is only through global cooperation, together with super computing power, will we truly make sense of how genotype and phenotype correlate. Whilst it is logistically possible to create computing systems that talk to each other and aggregate datasets ready to reveal novel correlations, the bottom line is that this will only happen if people (whether they be scientists, clinicians, patients, research participants, policy makers, politicians, law makers) support the principle that we should be donating, accessing and sharing our DNA data in this way. And in order to make the most sense of genomics, given the geographical and ancestral variation between us, such people are likely to be the majority of society. Within this review, a perspective is proffered on the human story that underpins genomic 'big data' access and how we are at a tipping point as a society-we need to decide collectively, are we in? and if so, what needs to be in place to protect us? or are we out? PMID- 29522191 TI - Diesel Exhaust and Lung Cancer-Aftermath of Becoming an IARC Group 1 Carcinogen. AB - The International Agency for Research on Cancer reclassified diesel exhaust from Group 2A (probably carcinogenic to humans) to Group 1 (carcinogenic to humans) in 2012. Since then, reevaluation and reanalysis of 2 major studies (Diesel Exhaust in Miners Study and Trucking Industry Particle Study) that were influential to the International Agency for Research on Cancer evaluation have replicated the original findings and demonstrated the suitability of these epidemiologic data for the quantitative risk assessment needed to set safe exposure limits in occupational and outdoor ambient environments. The challenge now is to protect the workers and general populations in urban areas from the carcinogenicity of diesel exhaust. PMID- 29522192 TI - esATAC: an easy-to-use systematic pipeline for ATAC-seq data analysis. AB - Summary: ATAC-seq is rapidly emerging as one of the major experimental approaches to probe chromatin accessibility genome-wide. Here, we present 'esATAC', a highly integrated easy-to-use R/Bioconductor package, for systematic ATAC-seq data analysis. It covers essential steps for full analyzing procedure, including raw data processing, quality control and downstream statistical analysis such as peak calling, enrichment analysis and transcription factor footprinting. esATAC supports one command line execution for preset pipelines and provides flexible interfaces for building customized pipelines. Availability and implementation: esATAC package is open source under the GPL-3.0 license. It is implemented in R and C++. Source code and binaries for Linux, MAC OS X and Windows are available through Bioconductor (https://www.bioconductor.org/packages/release/bioc/html/esATAC.html). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522193 TI - Insomnia with objective short sleep duration and risk of incident cardiovascular disease and all-cause mortality: Sleep Heart Health Study. AB - Study Objectives: To quantify the association between insomnia or poor sleep with objective short sleep duration and incident cardiovascular disease (CVD) and mortality in the general population. Methods: We conducted a time-to-event analysis of Sleep Heart Health Study data. Questionnaires and at-home polysomnography (PSG) were performed between 1994 and 1998. Participants were followed for a median of 11.4 years (Q1-Q3, 8.8-12.4 years) until death or last contact. The primary exposure was insomnia or poor sleep with short sleep defined as follows: difficulty falling asleep, difficulty returning to sleep, early morning awakenings, or sleeping pill use, 16-30 nights per month; and total sleep of <6 hr on PSG. We used proportional hazard models to estimate the association between insomnia or poor sleep with short sleep and CVD, as well as all-cause mortality. Results: Among 4994 participants (mean age: 64.0 +/- 11.1 years), 14.1 per cent reported insomnia or poor sleep, of which 50.3 per cent slept <6 hr. Among 4437 CVD-free participants at baseline, we observed 818 incident CVD events. After propensity adjustment, there was a 29 per cent higher risk of incident CVD in the insomnia or poor sleep with short sleep group compared with the reference group (HR: 1.29, 95% CI: 1.00, 1.66), but neither the insomnia or poor sleep only nor short sleep only groups were associated with higher incident CVD. Insomnia or poor sleep with objective short sleep was not associated with all-cause mortality (HR: 1.07, 95% CI: 0.86, 1.33). Conclusions: Insomnia or poor sleep with PSG-short sleep was associated with higher risk of incident CVD. Future studies should evaluate the impact of interventions to improve insomnia with PSG-short sleep on CVD. PMID- 29522196 TI - Optimality and identification of dynamic models in systems biology: an inverse optimal control framework. AB - Motivation: Optimality principles have been used to explain many biological processes and systems. However, the functions being optimized are in general unknown a priori. Here we present an inverse optimal control framework for modeling dynamics in systems biology. The objective is to identify the underlying optimality principle from observed time-series data and simultaneously estimate unmeasured time-dependent inputs and time-invariant model parameters. As a special case, we also consider the problem of optimal simultaneous estimation of inputs and parameters from noisy data. After presenting a general statement of the inverse optimal control problem, and discussing special cases of interest, we outline numerical strategies which are scalable and robust. Results: We discuss the existence, relevance and implications of identifiability issues in the above problems. We present a robust computational approach based on regularized cost functions and the use of suitable direct numerical methods based on the control vector parameterization approach. To avoid convergence to local solutions, we make use of hybrid global-local methods. We illustrate the performance and capabilities of this approach with several challenging case studies, including simulated and real data. We pay particular attention to the computational scalability of our approach (with the objective of considering large numbers of inputs and states). We provide a software implementation of both the methods and the case studies. Availability and implementation: The code used to obtain the results reported here is available at https://zenodo.org/record/1009541. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29522194 TI - Neutralization of CD40 ligand costimulation promotes bone formation and accretion of vertebral bone mass in mice. AB - Objective: Immunosuppressive biologics are used in the management of RA and additional immunomodulators are under investigation including modulators of the CD40/CD40 ligand (CD40L) costimulation pathway. Tampering with immune function can have unanticipated skeletal consequences due to disruption of the immuno skeletal interface, a nexus of shared cells and cytokine effectors serving discrete functions in both immune and skeletal systems. In this study, we examined the effect of MR1, a CD40L neutralizing antibody, on physiological bone remodelling in healthy mice. Methods: Female C57BL6 mice were treated with MR1 and BMD was quantified by dual energy X-ray absorptiometry and indices of trabecular bone structure were quantified by micro-CT. Serum biochemical markers were used to evaluate bone turnover and formation indices by histomorphometry. Results: Unexpectedly, MR1 stimulated significant accretion of BMD and trabecular bone mass in the spine, but not in long bones. Surprisingly, bone accretion was accompanied by a significant increase in bone formation, rather than suppression of bone resorption. Mechanistically, MR1-induced bone accrual was associated with increased Treg development and elevated production of cytotoxic T lymphocyte antigen 4, a costimulation inhibitor that promotes T cell anergy and CD8+ T cell expression of the bone anabolic ligand Wnt-10b. Conclusion: Our studies reveal an unexpected bone anabolic activity of pharmacological CD40L suppression. Therapeutic targeting of the CD40L pathway may indeed have unforeseen consequences for the skeleton, but may also constitute a novel strategy to promote bone formation to ameliorate osteoporotic bone loss and reduce fracture risk in the axial skeleton. PMID- 29522195 TI - Neonatal and Pediatric Candidemia: Results From Population-Based Active Laboratory Surveillance in Four US Locations, 2009-2015. AB - Introduction: Candida is a leading cause of healthcare-associated bloodstream infections in the United States. Infants and children have unique risk factors for candidemia, and the Candida species distribution in this group is different that among adults; however, candidemia epidemiology in this population has not been described recently. Methods: We conducted active population-based candidemia surveillance in 4 US metropolitan areas between 2009 and 2015. We calculated incidences among neonates (0-30 days old), infants (0-364 days old), and noninfant children (1-19 years old), documented their clinical features and antifungal drug resistance. Results: We identified 307 pediatric candidemia cases. Incidence trends varied according to site, but overall, the incidence in neonates decreased from 31.5 cases/100000 births in 2009 to 10.7 to 11.8 cases/100000 births between 2012 and 2015, the incidence in infants decreased from 52.1 cases/100000 in 2009 to 15.7 to 17.5 between 2012 and 2015, and the incidence in noninfant children decreased steadily from 1.8 cases/100000 in 2009 to 0.8 in 2014. Common underlying conditions were prematurity in neonates (78%), surgery in nonneonate infants (38%), and malignancy in noninfant children (28%). Most neonate cases were caused by C albicans (67%), whereas non-C. albicans species accounted for 60% of cases in nonneonate infants and noninfant children. Fluconazole and echinocandin resistance rates were low overall. Thirty-day crude mortality was 13%. Conclusions: The incidence of candidemia among neonates and infants declined after 2009 but remained stable from 2012 to 2015. Antifungal drug resistance is uncommon. Reasons for the lack of recent declines in neonatal and infant candidemia deserve further exploration. In this article, we describe the epidemiology of candidemia in children in the United States and on the basis of data collected as part of US Centers for Disease Control and Prevention active population-based surveillance. Trends in incidence, clinical characteristics, species distribution, and resistance rates are presented. PMID- 29522197 TI - Summer-type Hypersensitivity Pneumonitis. PMID- 29522198 TI - Ammonium and arsenic trioxide are potent facilitators of oligonucleotide function when delivered by gymnosis. AB - Oligonucleotide (ON) concentrations employed for therapeutic applications vary widely, but in general are high enough to raise significant concerns for off target effects and cellular toxicity. However, lowering ON concentrations reduces the chances of a therapeutic response, since typically relatively small amounts of ON are taken up by targeted cells in tissue culture. It is therefore imperative to identify new strategies to improve the concentration dependence of ON function. In this work, we have identified ammonium ion (NH4+) as a non-toxic potent enhancer of ON activity in the nucleus and cytoplasm following delivery by gymnosis. NH4+ is a metabolite that has been extensively employed as diuretic, expectorant, for the treatment of renal calculi and in a variety of other diseases. Enhancement of function can be found in attached and suspension cells, including in difficult-to-transfect Jurkat T and CEM T cells. We have also demonstrated that NH4+ can synergistically interact with arsenic trioxide (arsenite) to further promote ON function without producing any apparent increased cellular toxicity. These small, inexpensive, widely distributed molecules could be useful not only in laboratory experiments but potentially in therapeutic ON-based combinatorial strategy for clinical applications. PMID- 29522199 TI - Oesophagopleural fistula following epicardial ventricular tachycardia catheter ablation. PMID- 29522200 TI - Multistate Outbreak of Salmonella Virchow Infections Linked to a Powdered Meal Replacement Product-United States, 2015-2016. AB - Background: Nontyphoidal Salmonella is the leading cause of bacterial gastroenteritis in the United States. Meal replacement products containing raw and "superfood" ingredients have gained increasing popularity among consumers in recent years. In January 2016, we investigated a multistate outbreak of infections with a novel strain of Salmonella Virchow. Methods: Cases were defined using molecular subtyping procedures. Commonly reported exposures were compared with responses from healthy people interviewed in the 2006-2007 FoodNet Population Survey. Firm inspections and product traceback and testing were performed. Results: Thirty-five cases from 24 states were identified; 6 hospitalizations and no deaths were reported. Thirty-one of 33 (94%) ill people interviewed reported consuming a powdered supplement in the week before illness; of these, 30 (97%) reported consuming product A, a raw organic powdered shake product consumed as a meal replacement. Laboratory testing isolated the outbreak strain of Salmonella Virchow from leftover product A collected from ill people's homes, organic moringa leaf powder (an ingredient in product A), and finished product retained by the firm. Firm inspections at 3 facilities linked to product A production did not reveal contamination at the facilities. Traceback investigation identified that the contaminated moringa leaf powder was imported from South Africa. Conclusions: This investigation identified a novel outbreak vehicle and highlighted the potential risk with similar products not intended to be cooked by consumers before consuming. The company issued a voluntary recall of all implicated products. As this product has a long shelf life, the recall likely prevented additional illnesses. PMID- 29522201 TI - The miR206-JunD Circuit Mediates the Neurotoxic Effect of Methylmercury in Cortical Neurons. AB - Methylmercury (MeHg) causes neuronal death through different pathways. Particularly, we found that in cortical neurons it increased the expression of Repressor Element-1 Silencing Transcription Factor (REST), histone deacetylase (HDAC)4, Specificity Protein (Sp)1, Sp4, and reduced the levels of brain-derived neurotrophic factor (BDNF). Herein, in rat cortical neurons we investigated whether microRNA (miR)206 can modulate MeHg-induced cell death by regulating REST/HDAC4/Sp1/Sp4/BDNF axis. MeHg (1 uM) reduced miR206 expression after both 12 and 24 h and miR206 transfection prevented MeHg-induced neuronal death. Furthermore, miR206 reverted MeHg-induced REST and Sp4 increase and BDNF reduction at gene and protein level, and reverted HDAC4 protein increase, but not HDAC4 mRNA upregulation. Moreover, since no miR206 seed sequences were identified in the 3'-untranslated regions (3'-UTRs) of REST and SP4, we investigated the role of JunD, that presents a consensus motif on REST, Sp4, and BDNF promoters. Indeed, MeHg increased JunD mRNA and protein levels, and JunD knockdown counteracted MeHg-induced REST, Sp4 increase, but not BDNF reduction. Furthermore, we identified a miR206 binding site in the 3'-UTR of JunD mRNA (miR206/JunD) and mutagenesis of miR206/JunD site reverted JunD luciferase activity reduction induced by miR206. Finally, miR206 prevented MeHg-increased JunD binding to REST and Sp4 promoters, and MeHg-reduced BDNF expression was determined by the increase of HDAC4 binding on BDNF promoter IV. Collectively, these results suggest that miR206 downregulation induced by MeHg exposure determines an upregulation of HDAC4, that in turn downregulated BDNF, and the activation of JunD that, by binding REST and Sp4 gene promoters, increased their expression. PMID- 29522202 TI - Natural History of Established and De Novo Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis. AB - Background: The course of inflammatory bowel disease (IBD) after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is poorly understood. We describe the natural history of established IBD after LT (including risk of disease progression, colectomy, and neoplasia) and de novo IBD. Methods: In a retrospective cohort, we identified all patients with PSC who underwent LT for advanced PSC at Mayo Clinic, Rochester, Minnesota. Risk factors were identified using multivariate Cox proportional hazard analysis. Results: Three hundred seventy-three patients were identified (mean age, 47.5 +/- 11.7 years; 64.9% male). Over a median (range) of 10 (5.5-17.1) years, 151 patients with PSC-IBD with an intact colon at the time of LT were studied. Post-LT, despite transplant-related immunosuppression, 56/151 (37.1%) required escalation of therapy, whereas 87 had a stable course (57.6%) and 8 patients (5.3%) improved. The 1-, 5-, and 10-year risks of progression of IBD were 4.0%, 18.5%, and 25.5%, respectively. On multivariate analysis, tacrolimus-based immunosuppression post-LT were associated with unfavorable course, and azathioprine use after LT was associated with improved course post-LT. Of 84 patients with no evidence of IBD at the time of LT, 22 (26.2%) developed de novo IBD post-LT. The 1-, 5-, and 10-year cumulative incidences of de novo IBD were 5.5%, 20.0%, and 25.4%, respectively. On univariate analysis, mycophenolate mofetil use after LT was associated with increased risk of de novo IBD, but azathioprine use after LT seemed to be protective. Conclusions: The 10-year cumulative probability of IBD flare requiring escalation of therapy after LT for PSC was 25.5%, despite immunosuppression for LT. The 10-year cumulative risk of de novo IBD after LT for PSC was 25.4%. Transplant-related immunosuppression may modify the risk of de novo IBD, with an increased risk with mycophenolate and a decreased risk with azathioprine. 10.1093/ibd/izx096_video1izx096.video15746673864001. PMID- 29522203 TI - Optimal plasma pretreatment EBV DNA cut-off point for nasopharyngeal cancer patients treated with intensity modulated radiation therapy. AB - Objective: Plasma Epstein-Barr virus (EBV) DNA concentration at the time of diagnosis (pre-EBV) can be used to stratify risk for nasopharyngeal cancer (NPC) patients. However, pre-EBV cut-off values vary among studies. Methods: This was a post hoc analysis of 208 NPC patients from a phase II/III study comparing sequential (SEQ) vs. simultaneous integrated boost (SIB) intensity modulated radiation therapy. The objective was to identify the optimal pre-EBV cut-off value to predict overall survival (OS), progression free survival (PFS) and distant metastatic free survival (DMFS) rates. Results: The pre-EBV and post treatment EBV DNA (post-EBV) were detectable in 59.1% and 3.8% of the patients, respectively. A new pre-EBV cut-off value of 2300 copies/ml was identified by the receiver operating characteristics analysis. This cut-off value showed 82% sensitivity, 59% specificity and 31.7% positive and 93.5% negative predictive values in predicting OS. The 3-year OS, PFS and DMFS were 95.6 vs. 73.8%, 89.8 vs. 55.3% and 93 vs. 70.1% for pre-EBV < vs. >=2300 copies/ml, respectively. Older age group (>=45 years), high pre-EBV and detectable post-EBV concentration were independent predictors for OS, PFS and DMFS in a multivariate analysis. When the stage grouping and pre-EBV value were combined, a subgroup of patients with stage II-III and pre-EBV values <2300 copies/ml. had the best survival outcomes, while the worst survival subgroup was the patients with stage III-IVb with pre EBV values >=2300 copies/ml. Conclusions: Pre-EBV cut-off of 2300 copies/ml is an optimal value predicting OS, PFS and DMFS. PMID- 29522204 TI - Revisiting Pathological Classification Criteria for Adult Idiopathic Inflammatory Myopathies: In-Depth Analysis of Muscle Biopsies and Correlation Between Pathological Diagnosis and Clinical Manifestations. AB - The European Neuromuscular Centre (ENMC) pathological classification criteria of idiopathic inflammatory myopathies (IIMs) are debatable. The aim of this study was to explore their practicability and reproducibility. We conducted a retrospective analysis of 57 cases of IIMs excluding dermatomyositis (DM) and sporadic inclusion body myositis (sIBM) by in-depth analysis of muscle biopsies and comparisons of the clinical characteristics among polymyositis (PM), non specific myositis (NSM) and necrotizing autoimmune myopathy (NAM). In 57 non DM/sIBM-IIM cases, 25 were classified as PM, 15 as NSM, and 17 as NAM. Among them, 51 underwent multilevel sectioning examination of biopsies, with pathological changes at different levels warranting diagnostic rectification in 11 patients (21.57%): 4 PM were reclassified as NSM, and 7 NSM as NAM. Applying atypical CD8+ T cells surrounding non-necrotic muscle fibers resulted in diagnostic rectification from NSM to PM in 2 patients; using 20 T cells (instead of 10) as the threshold for the perivascular infiltration led to diagnostic rectification from NSM to NAM in 9 patients. There were no differences in disease duration or treatment outcomes among the subgroups. The strict pathological criteria to distinguish non-DM/sIBM-IIMs are of limited practicability and reproducibility, and may be of limited clinical significance. PMID- 29522206 TI - In-field assessment of sodium oxybate effect in pediatric type 1 narcolepsy: an actigraphic study. AB - Study Objectives: Sodium oxybate (SXB) is a GABAergic agent widely used as off label treatment in pediatric type 1 narcolepsy (NT1). Here, we aimed at analyzing by wrist actigraphy the sleep/wake profile of NT1 children and adolescents in drug-naive condition and after 1 year of SXB treatment. As secondary aim, we investigated changes on sleepiness, cataplexy, and children's anthropometric profile after 1 year of SXB treatment. Methods: Twenty-four drug-naive NT1 children underwent 7 days of actigraphy during the school week. Information on sleepiness, narcolepsy symptoms, and anthropometric features were collected during the same week with questionnaires and semistructured clinical interview. Children started SXB treatment and underwent a second evaluation encompassing actigraphy, clinical interview, questionnaires, and anthropometric assessment after 1 year of stable treatment. Results: Actigraphy effectively documented an improvement of nocturnal sleep quality and duration coupled with a reduction of diurnal total sleep time, nap frequency, and duration at 1 year follow-up. Reduction of sleepiness, cataplexy frequency and severity, and weight loss, mainly in obese and overweight NT1 children, were also observed at the 1 year follow-up. Conclusions: Actigraphy objectively documented changes in nocturnal sleep quality and diurnal napping behavior after 1 year of SXB treatment, thus representing a valid approach to ecologically assess SXB treatment effect on NT1 children's sleep/wake profile. NT1 symptoms severity and children's anthropometric features also changed as expected. Actigraphy offers the possibility to longitudinally follow up children and has potential to become a key tool to tailor treatment in pediatric patients. PMID- 29522205 TI - Chromatin assembly factor-1 (CAF-1) chaperone regulates Cse4 deposition into chromatin in budding yeast. AB - Correct localization of the centromeric histone variant CenH3/CENP-A/Cse4 is an important part of faithful chromosome segregation. Mislocalization of CenH3 could affect chromosome segregation, DNA replication and transcription. CENP-A is often overexpressed and mislocalized in cancer genomes, but the underlying mechanisms are not understood. One major regulator of Cse4 deposition is Psh1, an E3 ubiquitin ligase that controls levels of Cse4 to prevent deposition into non centromeric regions. We present evidence that Chromatin assembly factor-1 (CAF 1), an evolutionarily conserved histone H3/H4 chaperone with subunits shown previously to interact with CenH3 in flies and human cells, regulates Cse4 deposition in budding yeast. yCAF-1 interacts with Cse4 and can assemble Cse4 nucleosomes in vitro. Loss of yCAF-1 dramatically reduces the amount of Cse4 deposited into chromatin genome-wide when Cse4 is overexpressed. The incorporation of Cse4 genome-wide may have multifactorial effects on growth and gene expression. Loss of yCAF-1 can rescue growth defects and some changes in gene expression associated with Cse4 deposition that occur in the absence of Psh1 mediated proteolysis. Incorporation of Cse4 into promoter nucleosomes at transcriptionally active genes depends on yCAF-1. Overall our findings suggest CAF-1 can act as a CenH3 chaperone, regulating levels and incorporation of CenH3 in chromatin. PMID- 29522207 TI - Genetic diversity of root system architecture in response to drought stress in grain legumes. AB - Climate change has increased the occurrence of extreme weather patterns globally, causing significant reductions in crop production, and hence threatening food security. In order to meet the food demand of the growing world population, a faster rate of genetic gains leading to productivity enhancement for major crops is required. Grain legumes are an essential commodity in optimal human diets and animal feed because of their unique nutritional composition. Currently, limited water is a major constraint in grain legume production. Root system architecture (RSA) is an important developmental and agronomic trait, which plays vital roles in plant adaptation and productivity under water-limited environments. A deep and proliferative root system helps extract sufficient water and nutrients under these stress conditions. The integrated genetics and genomics approach to dissect molecular processes from genome to phenome is key to achieve increased water capture and use efficiency through developing better root systems. Success in crop improvement under drought depends on discovery and utilization of genetic variations existing in the germplasm. In this review, we summarize current progress in the genetic diversity in major legume crops, quantitative trait loci (QTLs) associated with RSA, and the importance and applications of recent discoveries associated with the beneficial root traits towards better RSA for enhanced drought tolerance and yield. PMID- 29522208 TI - Insights About Head Lice Transmission From Field Data and Mathematical Modeling. AB - Head lice infest millions of school-age children every year, both in developed and developing countries. However, little is known about the number of lice transferred among children during school activities, because direct methods to study this are almost impossible to implement. This issue has been addressed following an indirect method, which consist in collecting data of real infestation from several children groups and using a mathematical model of lice colonies to infer how the infestation observed might have evolved. By determining the events that would most likely lead to infestations as those observed, we find that severe infestations are most likely initiated by a relatively large number of lice transferred at the same moment or within relatively short time spans. In turn, analysis of the data obtained from screenings of the same groups of children a few days apart shows evidence of such transmission events. Interestingly, only children with severe infestations could harbor the lice necessary for this type of transmission. Thus, they play the same role as 'superspreaders' in epidemiology. As part of our experimental study it is also shown that a simple procedure of combing can be very effective to remove all mobile lice, and thus could be used as an effective preventive measure against those severe infestations that are responsible for the spread of pediculosis. PMID- 29522209 TI - Evidence of Signaling and Adhesion Roles for beta-Catenin in the Sponge Ephydatia muelleri. AB - beta-Catenin acts as a transcriptional coactivator in the Wnt/beta-catenin signaling pathway and a cytoplasmic effector in cadherin-based cell adhesion. These functions are ancient within animals, but the earliest steps in beta catenin evolution remain unresolved due to limited data from key lineages sponges, ctenophores, and placozoans. Previous studies in sponges have characterized beta-catenin expression dynamics and used GSK3B antagonists to ectopically activate the Wnt/beta-catenin pathway; both approaches rely upon untested assumptions about the conservation of beta-catenin function and regulation in sponges. Here, we test these assumptions using an antibody raised against beta-catenin from the sponge Ephydatia muelleri. We find that cadherin complex genes coprecipitate with endogenous Em beta-catenin from cell lysates, but that Wnt pathway components do not. However, through immunostaining we detect both cell boundary and nuclear populations, and we find evidence that Em beta catenin is a conserved substrate of GSK3B. Collectively, these data support conserved roles for Em beta-catenin in both cell adhesion and Wnt signaling. Additionally, we find evidence for an Em beta-catenin population associated with the distal ends of F-actin stress fibers in apparent cell-substrate adhesion structures that resemble focal adhesions. This finding suggests a fundamental difference in the adhesion properties of sponge tissues relative to other animals, in which the adhesion functions of beta-catenin are typically restricted to cell-cell adhesions. PMID- 29522210 TI - Heterogeneity in the circadian and homeostatic modulation of multiunit activity in the lateral hypothalamus. AB - The lateral hypothalamus (LH) is a relatively large hypothalamic structure containing several neurochemically different, but spatially intermingled, neuronal populations. While the role of these neurons in the homeostatic regulation of diverse physiological and behavioral functions such as sleep/wake cycle has been studied extensively, the impact of sleep history on the electrophysiology of the LH and whether this effect is homogenous across LH is unknown. By combining multiunit activity (MUA) recordings in different regions of LH with electroencephalogram recordings in freely moving rats, we unravelled a heterogeneity of neural-activity patterns within different subregions of LH. This heterogeneity was evident in both the circadian and the vigilance state-dependent modulation of MUA. Interestingly, and consistent with this heterogeneity under baseline conditions, the magnitude of MUA suppression following 6 hr of sleep deprivation (SD) was also different within different locations of LH. Unlike the cortex and in contrast to the predictions of the synaptic homeostatic hypothesis, no correlation was found between the magnitude of activity increase during SD and the percentage of suppression of MUA during recovery sleep. These data provide in vivo evidence of a functional heterogeneity in the circadian and homeostatic modulation of neuronal activity in LH. PMID- 29522211 TI - Innovative methodology for point-of-care circulating cathodic antigen with rapid urine concentration for use in the field for detecting low Schistosoma mansoni infection and for control of cure with high accuracy. AB - Background: Prior to eliminating schistosomiasis, efforts must address accurate and fast individual diagnosis. Diagnosis is still inaccurate by parasitological and point-of-care circulating cathodic antigen (POC-CCA) in areas of low endemicity. Methods: Our group has optimized POC-CCA with a 30 min urine concentration step with no need for specialized technicians or equipment and with high accuracy. We evaluated this new method, called POC-CCA filter (FLT), in two Brazilian endemic areas with distinct profiles. Results: At baseline, POC-CCA had a poor performance with several false results and undefined trace readings, revealing a prevalence rate of 10% against a rate of 23% for POC-CCA FLT, which was similar to the parasitological rates. Accuracy increased from as low as 0.36 to 0.96 after urine concentration in one area. POC-CCA properly diagnosed only half of the cases at three post-treatment time points, while POC-CCA FLT was able to diagnose 96, 83 and 100%, respectively. Conclusions: The improvement of conventional POC methodology by a fast and simple urine concentration step provided not only an increase in its accuracy before and after praziquantel treatment, but also preserved its applicability in low-prevalence endemic areas, allowing the definition of trace readings as negative cases. PMID- 29522213 TI - Cecilia Linde MD PhD, Karolinska Institute, Sweden. PMID- 29522212 TI - The inappropriate occurrence of rapid eye movement sleep in narcolepsy is not due to a defect in homeostatic regulation of rapid eye movement sleep. AB - Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive daytime-sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. The later three symptoms together with a short rapid eye movement (REM) sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48 hr of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10 hr of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our new automated method of deprivation that performs a specific and efficient REM sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase, REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy. PMID- 29522214 TI - Thirty years of heart failure. PMID- 29522215 TI - A Heart Failure Clinic. PMID- 29522216 TI - The Portuguese Society of Cardiology. PMID- 29522217 TI - The Portuguese Journal of Cardiology. PMID- 29522218 TI - Acute and Critical Care Echocardiography. PMID- 29522219 TI - Novel insights in HFpEF, cardiomyopathies, and myocarditis. PMID- 29522220 TI - Titin cardiomyopathy: why we need to go big to understand the giant. PMID- 29522221 TI - Apoptosis Modulation in the Immune System Reveals a Role of Neutrophils in Tissue Damage in a Murine Model of Chlamydial Genital Infection. AB - Background: Chlamydial infection frequently causes damage to the female genital tract. The precise mechanisms of chlamydial clearance and tissue damage are unknown, but studies suggest immunopathology with a particular role of neutrophils. The goal of this study was to understand the contribution of the immune system, in particular neutrophils. Methods: Using Chlamydia muridarum, we infected mice with a prolonged immune response due to expression of B-cell lymphoma 2 (Bcl-2) in hematopoietic cells (Bcl-2 mice), and mice where mature neutrophils are lacking due to the deletion of Myeloid cell leukemia 1 (Mcl-1) in myeloid cells (LysM-cre-mcl-1-flox mice; Mcl-1 mice). We monitored bacterial clearance, cellular infiltrate, and long-term tissue damage. Results: Both mutant strains showed slightly delayed clearance of the acute infection. Bcl-2 mice had a strongly increased inflammatory infiltrate concerning almost all cell lineages. The infection of Bcl-2 mice caused increased tissue damage. The loss of neutrophils in Mcl-1 mice was associated with substantial quantitative and qualitative alterations of the inflammatory infiltrate. Mcl-1 mice had higher chlamydial burden and reduced tissue damage, including lower incidence of hydrosalpinx and less uterine dilation. Conclusions: Inhibition of apoptosis in the hematopoietic system increases inflammation and tissue damage. Neutrophils have broad functions, including a role in chlamydial clearance and in tissue destruction. PMID- 29522222 TI - Altered diurnal states in insomnia reflect peripheral hyperarousal and metabolic desynchrony: a preliminary study. AB - Study Objectives: Insomnia is a common sleep disorder that is associated with a range of adverse outcomes. Patients with insomnia exhibit hyperarousal in multiple domains, including an elevated metabolic rate, but specific metabolic molecular perturbations are unknown. Furthermore, objective clinical markers of insomnia are not available and current assessment of pathological extent relies on self-report. Here, we provide preliminary evidence that chronic insomnia is remarkably reflected in the periphery through detailed metabolic assessments. Methods: Serum from confirmed patients with insomnia and matched good sleepers (n = 15 per group) was sampled at high temporal resolution (every 2 hr over 48 hr). Food intake was controlled by providing hourly isocaloric snacks, and sleep architecture was assessed by overnight polysomnography. Quantitative metabolic assessments were conducted using nuclear magnetic resonance spectroscopy. Results: Global metabolic profiles differentiated patients with insomnia from healthy controls, with elevated amino acid and energy metabolites and reduced branched-chain amino acid catabolic products. Strikingly, branched-chain amino acid catabolism was found to be specifically altered during the night with ~10 per cent increased accumulation of glucose in insomnia patients. Rhythmicity analysis revealed 11 metabolites that cycled diurnally across both groups, with phase advances noted for acetone and delays for lactate and branched-chain amino acids and their products. Conclusions: These preliminary observations suggest that insomnia is associated with quantitative metabolic dysregulation and supports the hyperarousal hypothesis. Furthermore, we posit that these changes lead to a state of metabolic desynchrony in insomnia that is involved in the pathophysiology of the disorder and/or mediates its impact on health outcomes. Clinical Trials Registration: NCT01957111. PMID- 29522223 TI - Evaluation of the Accuracy of Two Marking Methods and the Novel toriCAM Application for Toric Intraocular Lens Alignment. AB - PURPOSE: To compare the accuracy of two common reference marking methods for toric intraocular lens alignment before and after using the novel toriCAM application. METHODS: In this prospective, randomized study, 22 participants were randomly allocated to two groups, either freehand or slit-lamp-assisted marking. Corneal markings at 0 degrees and 180 degrees were made using either method. The toriCAM application on a smartphone was then used to assess the rotational alignment of these markings and compared to the actual alignment as measured by the Zaldivar calipers on the iTrace Topographer (Tracey Technologies, Houston, TX) as a reference. The errors in marking with and without using the application were analyzed for all patients in each cohort and determined for each marking method. RESULTS: Twenty eyes of 11 patients were marked using the freehand method and 20 eyes of the other 11 patients were marked using the slit-lamp method. The mean absolute error of all markings before toriCAM adjustment was 3.18 degrees +/- 2.22 degrees . This was significantly reduced to 1.28 degrees +/- 1.34 degrees after using the application (P < .001). This improvement was also noted separately in the freehand and slit-lamp groups. Comparison of the freehand and slit-lamp methods did not show any statistically significant difference in accuracy at both time points. CONCLUSIONS: The novel toriCAM application is able to significantly improve the accuracy of reference marking for both freehand and slit-lamp methods. [J Refract Surg. 2018;34(3):150-155.]. PMID- 29522224 TI - Clinical Outcomes of SMILE With a Triple Centration Technique and Corneal Wavefront-Guided Transepithelial PRK in High Astigmatism. AB - PURPOSE: To comparatively investigate the clinical outcomes, vector parameters, and corneal aberrations of small incision lenticule extraction (SMILE) with a triple centration technique and corneal wavefront-guided transepithelial photorefractive keratectomy (PRK) for the correction of high astigmatism. METHODS: This retrospective, comparative case series study included 89 eyes (89 patients) that received treatment for myopia with high astigmatism (>= 2.50 diopters) using SMILE with a triple centration technique (SMILE group; 45 eyes) and corneal wavefront-guided transepithelial PRK (transepithelial PRK group; 44 eyes). Visual acuity measurement, manifest refraction, slit-lamp examination, autokeratometry, corneal topography, and evaluation of corneal wavefront aberration were performed preoperatively and at 1, 3, and 6 months after surgery. The safety, efficacy, vector parameters, and corneal aberrations at 6 months after surgery were compared between the two groups. RESULTS: At 6 months after surgery, the transepithelial PRK and SMILE groups exhibited comparable mean uncorrected distance visual acuities (-0.06 +/- 0.07 and -0.05 +/- 0.07 logMAR, respectively), safety, efficacy, and predictability of refractive and visual outcomes. There was a slight but statistically significant difference in the correction index between the transepithelial PRK and SMILE groups (0.96 +/- 0.11 and 0.91 +/- 0.10, respectively). Whereas the transepithelial PRK group exhibited increased corneal spherical aberration and significantly reduced corneal coma and trefoil, no changes in aberrometric values were noted in the SMILE group. CONCLUSIONS: Both SMILE with a triple centration technique and corneal wavefront guided transepithelial PRK are effective and provide predictable outcomes for the correction of high myopic astigmatism, although slight undercorrection was observed in the SMILE group. The triple centration technique was helpful in astigmatism correction by SMILE. [J Refract Surg. 2018;34(3):156-163.]. PMID- 29522225 TI - The Sensitivity of Clinical Outcomes to Centration on the Light-Constricted Pupil for a Shape-Changing Corneal Inlay. AB - PURPOSE: To assess the clinically acceptable range of inlay decentration with respect to the light-constricted pupil center and the coaxially sighted corneal light reflex (CSCLR) for an inlay (Raindrop Near Vision Inlay; ReVision Optics, Inc., Lake Forest, CA) that reshapes the anterior corneal surface. METHODS: In this retrospective, observational cohort study of 115 patients with emmetropic or low hyperopic presbyopia who were implanted with a shape-changing corneal inlay, visual acuity, task performance (in good and dim light), reports of halos and glare, and satisfaction data were collected from the preoperative and 3-month postoperative examinations. Inlay centration with respect to the pupil center and CSCLR was determined from the center of the inlay effect derived from iTrace (Tracey Technologies, Houston, TX) wavefront measurements. Multivariate regression models assessed the influence of inlay position on visual outcomes. RESULTS: On average, monocular uncorrected near visual acuity (UNVA) improved 4.9 +/- 1.7 lines in the treated eye, with no loss in binocular distance vision. Eighty-three percent of implants were centered radially within 0.5 mm of the pupil center. Multivariate analysis of decentration with respect to both the pupil center and CSCLR revealed no significant interaction with the above clinical outcomes, with the exception of UNVA in the treated eye (all P > .05, alpha = 0.05). For decentration of less than 0.75 mm, the change in UNVA was less than 1 line. CONCLUSIONS: Distance and near visual acuity, task performance, severity of halos and glare, and satisfaction were independent of radial decentration of the Raindrop Near Vision Inlay of less than 0.75 mm from the light-constricted pupil. [J Refract Surg. 2018;34(3):164-170.]. PMID- 29522226 TI - Nepafenac Ophthalmic Suspension 0.3% for the Management of Ocular Pain After Photorefractive Keratectomy. AB - PURPOSE: To investigate the effect of nepafenac 0.3% in a once daily dosage regarding pain and healing after photorefractive keratectomy (PRK). METHODS: This was a prospective, comparative, contralateral randomized study of 35 patients undergoing PRK for the correction of low to moderate myopia and myopic astigmatism. After randomization, patients received nepafenac 0.3% ophthalmic suspension once daily in one eye (nepafenac 0.3% group) and nepafenac 0.1% ophthalmic suspension three times a day in the other eye (nepafenac 0.1% group) until the second postoperative day. Pain was evaluated every 2 hours on the day of the operation and then once daily using a scale ranging from 0 to 4. Patients were then examined at 2 weeks and 1, 3, 6, and 12 postoperative months. Visual acuity and subepithelial haze were also assessed. RESULTS: No differences were detected between groups in pain scores, subepithelial haze scores, or visual acuity. Refractive predictability was also similar. CONCLUSIONS: Nepafenac 0.3% ophthalmic suspension in a daily regimen after PRK seems to be an effective treatment for pain and ocular discomfort with effects similar to the 0.1% suspension. [J Refract Surg. 2018;34(3):171-176.]. PMID- 29522227 TI - Progression of Keratoconus in Patients While Awaiting Corneal Cross-linking: A Prospective Clinical Study. AB - PURPOSE: To assess topographical changes in patients with keratoconus while awaiting corneal cross-linking (CXL) treatment. METHODS: In this prospective, double-center, observational clinical study, patients with keratoconus were enrolled. Progression was defined as a change in the curvature within the cone area of at least 1.00 diopter (D) on tangential map and a thinning of 20 MUm at the thinnest point after measurements taken at least 3 months apart. Morphological parameters were assessed at baseline (day of listing for CXL) and on the day of CXL treatment, including slit-lamp biomicroscopy, keratometry (maximum, minimum, and mean), and thinnest corneal thickness using corneal tomography (Pentacam; Oculus Optikgerate GmbH, Wetzlar, Germany). RESULTS: One hundred four eyes of 104 patients were included. The waiting time was 84.8 +/- 62.9 days. Twenty-five percent of patients showed evidence of progression while waiting for treatment. Patients who progressed while waiting for treatment were younger (22.2 +/- 6.79 years) compared to those who did not show evidence of progression (25.4 +/- 5.62 years) (P = .02). Stratification by age groups showed a significant worsening of maximum keratometry of 1.18 +/- 1.37 D in patients younger than 18 years compared to those 18 to 26 years of age and those older than 26 years (P = .002 and .042, respectively). The multivariate model confirmed that the progression steepening of the maximum keratometry while waiting for treatment was associated with age (P = .028). CONCLUSIONS: The results suggest that stratification of waiting time according to the patient's age is required to reduce the risk of further progression of keratoconus. [J Refract Surg. 2018;34(3):177-180.]. PMID- 29522228 TI - The 7-Year Outcomes of Epithelium-Off Corneal Cross-linking in Progressive Keratoconus. AB - PURPOSE: To evaluate the clinical results of epitheliumoff corneal cross-linking (CXL) during a 7-year follow-up. METHODS: This retrospective, non-randomized, single-center interventional study enrolled 34 consecutive eyes of 24 patients with progressive keratoconus undergoing CXL surgery with epithelium removal. Visual, refractive, corneal topographic, pachymetric, and anterior segment changes were evaluated at 1, 3, and 7 years after surgery. RESULTS: Significant reduction of refraction was observed at 1 year postoperatively (P <= .006), with an additional significant reduction between the 1- and 3-year postoperative visits (P <= .002) and no significant changes afterward (P >= .156). Regarding corrected distance visual acuity (CDVA), a significant improvement was detected at 1 year after surgery (P < .001), with an additional improvement between 1 and 3 years postoperatively (P = .001), and no significant changes at the end of the follow-up (P = .518). Significant corneal flattening was observed at 1, 3, and 7 years after surgery (P <= .041). Likewise, a significant central thinning was observed at 1 year postoperatively (P < .001), with no significant changes afterward (P >= .112). Anterior maximum elevation only changed significantly between 1 and 3 years after surgery (P = .002), whereas the posterior maximum elevation changed significantly at all time points of the follow-up (P <= .034). No significant changes with surgery in anterior segment volume (P >= .377) and anterior chamber depth (P >= .142) were detected. CONCLUSIONS: The effect of epithelium-off CXL in progressive keratoconus is maintained 7 years after surgery. Long-term corneal changes after this procedure may be influenced by an age-related corneal stiffening process. [J Refract Surg. 2018;34(3):181-186.]. PMID- 29522229 TI - Predictability of Tunnel Depth for Intrastromal Corneal Ring Segments Implantation Between Manual and Femtosecond Laser Techniques. AB - PURPOSE: To compare the predictability of intrastromal tunnel depth creation for intrastromal corneal ring segments (ICRS) implantation between manual dissection and femtosecond laser using a high-resolution anterior segment optical coherence tomography (AS-OCT). METHODS: This multicenter study included patients with keratoconus who had Ferrara-type ICRS implantation at Hospital de Braga using manual dissection and at the Fernandez-Vega Ophthalmological Institute using the femtosecond laser technique. The intended depth of implantation was compared to the achieved postoperative ICRS depth of each case, measured using a swept-source AS-OCT (CASIA SS-1000; Tomey Corporation, Nagoya, Japan) at three points (proximal, central, and distal end of the implant). RESULTS: The study included 105 eyes in the manual group and 53 eyes in the femtosecond laser group. The differences of the intended versus the achieved depth were statistically higher in the manual group for all positions measured (Wilcoxon ranked-sum, P < .001). In the manual group, there were significant differences between the mean values of intended and achieved depth after surgery for the three locations measured (Wilcoxon signed-rank, P < .05), whereas there were no significant differences in the femtosecond laser group. In the manual group, the proximal part of the stromal tunnel was significantly shallower (-40.87 +/- 69.03 MUm) than the central (-25.54 +/- 71.00 MUm) and distal (-26.52 +/- 73.22 MUm) parts (Friedman test, P < .05). CONCLUSIONS: ICRS implantation assisted by a femtosecond laser provides a more precise procedure considering dissection depth when compared with the manual dissection technique. Such an advantage may provide more predictable clinical results and safer procedures with the femtosecond laser. [J Refract Surg. 2018;34(3):188-194.]. PMID- 29522230 TI - Effect of Conus Eccentricity on Visual Outcomes After Intracorneal Ring Segments Implantation in Keratoconus. AB - PURPOSE: To investigate the potential impact of cone eccentricity on visual outcomes after Keraring (Mediphacos, Belo Horizonte, Brazil) implantation for keratoconus. METHODS: Nineteen eyes from 19 patients with keratoconus who underwent femtosecond laser-assisted Keraring implantation for keratoconus were included in this retrospective study. Uncorrected visual acuity (UDVA), corrected visual acuity (CDVA), keratometric readings, central corneal thickness, maximum keratometric distance from corneal apex (DKmax), corneal thinnest point from corneal apex (DTh), and coma were evaluated preoperatively and 6 months after the Keraring implantation. DKmax and DTh were used as metrics reflecting the eccentricity of the cone. RESULTS: UDVA, CDVA, keratometric readings, and coma improved at 6 months postoperatively. However, there was no correlation between DKmax or DTh and visual outcomes at 6 months postoperatively. CONCLUSIONS: The data did not show any impact of the cone eccentricity on visual outcomes after Keraring implantation for keratoconus at 6 months postoperatively. [J Refract Surg. 2018;34(3):196-200.]. PMID- 29522231 TI - Histological and microRNA Signatures of Corneal Epithelium in Keratoconus. AB - PURPOSE: To illustrate the histopathology of keratoconic corneal epithelia and its micro-ribonucleic acid (miRNA) regulation. METHODS: Corneal epithelia were collected from 27 patients with keratoconus and 26 normal patients after surgery or by impression cytology. The miRNA profile was determined using miRNA microarray. The biological roles of miRNA target genes were delineated by gene ontology and pathway analyses. The expressions of significant miRNAs were validated using TaqMan polymerase chain reaction (PCR), whereas protein localization and expression of the miRNA target genes were examined by immunofluorescence and immunoblotting analyses. RESULTS: Histological assessment showed that corneal epithelia in patients with keratoconus were thinner with loosely packed cells compared to normal patients. Microarray analysis revealed that 12 miRNAs were significantly downregulated in keratoconic corneal epithelia. Gene ontology analysis demonstrated that the predicted miRNA target genes participated in cell junction, cell division, and motor activity, whereas pathway analysis highlighted the involvement of syndecan-mediated signaling pathway. TaqMan PCR validated the altered expression of six miRNAs in corneal epithelia from surgery (hsa-miR-151a-3p, hsa-miR-138-5p, hsa-miR-146b-5p, hsa-miR-194-5p, hsa-miR-28-5p, and hsa-miR-181a-2-3p) and four miRNAs in squamous corneal epithelial samples collected from impression cytology (hsa-miR-151a-3p, hsa-miR 195-5p, hsa-miR-185-5p, and hsa-miR-194-5p). In addition, higher S100A2 expression was found in the epithelial basal cell layer of keratoconic corneal epithelia. CONCLUSIONS: The miRNA and histological analyses in this study demonstrated structural and biological changes in keratoconic corneal epithelia, broadening the understanding of keratoconus pathology. In addition, impression cytology is useful to collect corneal epithelial tissues for gene expression analysis. [J Refract Surg. 2018;34(3):201-211.]. PMID- 29522232 TI - Should the Corvis Biomechanical Index (CBI) Include Corneal Thickness Parameters? PMID- 29522234 TI - Erratum for "Analysis of Accommodative Performance of a New Accommodative Intraocular Lens". PMID- 29522233 TI - Corneal Cross-linking Standardized Terminology. PMID- 29522235 TI - Tip-localized Ca2+ -permeable channels control pollen tube growth via kinase dependent R- and S-type anion channel regulation. AB - Pollen tubes (PTs) are characterized by having tip-focused cytosolic calcium ion (Ca2+ ) concentration ([Ca2+ ]cyt ) gradients, which are believed to control PT growth. However, the mechanisms by which the apical [Ca2+ ]cyt orchestrates PT growth are not well understood. Here, we aimed to identify these mechanisms by combining reverse genetics, cell biology, electrophysiology, and live-cell Ca2+ and anion imaging. We triggered Ca2+ -channel activation by applying hyperpolarizing voltage pulses and observed that the evoked [Ca2+ ]cyt increases were paralleled by high anion channel activity and a decrease in the cytosolic anion concentration at the PT tip. We confirmed a functional correlation between these patterns by showing that inhibition of Ca2+ -permeable channels eliminated the [Ca2+ ]cyt increase, resulting in the abrogation of anion channel activity via Ca2+ -dependent protein kinases (CPKs). Functional characterization of CPK and anion-channel mutants revealed a CPK2/20/6-dependent activation of SLAH3 and ALMT12/13/14 anion channels. The impaired growth phenotypes of anion channel and CPK mutants support the physiological significance of a kinase- and Ca2+ dependent pathway to control PT growth via anion channel activation. Other than unveiling this functional link, our membrane hyperpolarization method allows for unprecedented manipulation of the [Ca2+ ]cyt gradient or oscillations in the PT tips and opens an array of opportunities for channel screenings. PMID- 29522236 TI - Patient Acceptance of Sexual Orientation and Gender Identity Questions on Intake Forms in Outpatient Clinics: A Pragmatic Randomized Multisite Trial. AB - OBJECTIVES: To (1) test whether patient attitudes toward intake forms at three Midwestern outpatient clinics are significantly more negative among those who are asked to complete SOGI questions versus those who are not; and (2) gain an in depth understanding of patient concerns about SOGI questions. STUDY SETTING: Data were collected between 6/29/2015 and 2/29/2016 from new patients (N = 491) who presented at three outpatient clinics in a large academic medical center. This study was originally a quality improvement project, and later, institutional review board approval was obtained for secondary data analysis. STUDY DESIGN: Two stage mixed-methods study. (1) Experimental: New patients at three sites were randomly assigned to complete either routine intake forms (control) or routine intake forms with SOGI questions (experimental); and (2) qualitative: interviews with patients who responded negatively to SOGI questions. PRINCIPAL FINDINGS: There were no significant differences in patient attitudes between experimental and control groups (p > .05). Of those who received SOGI questions, only 3 percent reported being distressed, upset, or offended by the SOGI questions. CONCLUSIONS: Collection of SOGI data as a part of the routine clinical patient intake process is not distressing to 97 percent of patients who are heterosexual, cisgender, and older than 50 years. PMID- 29522237 TI - Eosinophils in fungal diseases: An overview. AB - Eosinophils are the prominent cells in asthma, allergic bronchopulmonary mycosis (ABPMs), and fungal-sensitization-associated asthma, but their roles in the immunopathology of these disorders are not well understood. Moreover, the immunological mechanisms underlying the molecular direct effector interactions between fungi and eosinophils are rare and not fully known. Here, we provide an overview of eosinophil contributions to allergic asthma and ABPMs. We also revise the major general mechanisms of fungal recognition by eosinophils and consider past and recent advances in our understanding of the molecular mechanisms associated with eosinophil innate effector responses to different fungal species relevant to ABPMs (Alternaria alternata, Candida albicans, and Aspergillus fumigatus). We further examine and speculate about the therapeutic relevance of these findings in fungus-associated allergic pulmonary diseases. PMID- 29522243 TI - Frog's DCs have it all in one. AB - Although the amphibian Xenopus laevis produces antibodies as diversified as those from mammals in the primary repertoire, antibody affinity maturation after immunization is relatively poor and has been associated with a poor B cell selection of AID-mediated hypermutations and lack of germinal centers in the spleen, the only secondary lymphoid organ of this amphibian. In this issue of the European Journal of Immunology, Neely et al., [Eur. J. Immunol. 2018. 48: 430 440] have unveiled the role of distinctive dendritic cell (DC) subset, XL cells, which have the capacity to acquire and retain native antigens for B cell maturation. The complementary evidence presented by this study (immunohistology, tracing antigen complexes, flow cytometry analysis and gene expression profiles of sorted XL cells) provides novel fundamental insights into a major evolutionary step in functional and cellular specialization of DC and follicular dendritic cells (FDCs) in regulating B cell responses. PMID- 29522244 TI - The Physico-Chemical Basis of DNA Radiosensitization: Implications for Cancer Radiation Therapy. AB - High-energy radiation is used in combination with radiosensitizing therapeutics to treat cancer. The most common radiosensitizers are halogenated nucleosides and cisplatin derivatives, and recently also metal nanoparticles have been suggested as potential radiosensitizing agents. The radiosensitizing action of these compounds can at least partly be ascribed to an enhanced reactivity towards secondary low-energy electrons generated along the radiation track of the high energy primary radiation, or to an additional emission of secondary reactive electrons close to the tumor tissue. This is referred to as physico-chemical radiosensitization. In this Concept article we present current experimental methods used to study fundamental processes of physico-chemical radiosensitization and discuss the most relevant classes of radiosensitizers. Open questions in the current discussions are identified and future directions outlined, which can lead to optimized treatment protocols or even novel therapeutic concepts. PMID- 29522245 TI - Thromboelastography in wild Florida manatees (Trichechus manatus latirostris). AB - BACKGROUND: Thromboelastography (TEG) provides a comprehensive evaluation of blood clot formation. This test can be used to identify abnormalities in coagulation by assessing multiple aspects of the clotting cascade, including the speed of clot initiation and formation, clot strength, and ultimately fibrinolysis. Thromboembolic disease has been hypothesized to play a role in the pathophysiology of cold stress syndrome (CSS), an important cause of mortality in the threatened Florida manatee (Trichechus manatus latirostris). OBJECTIVES: The objective of this study was to establish thromboelastography RIs using the TEG 5000 with citrated whole blood samples and kaolin activation in wild, healthy manatees. METHODS: In December 2014 and January 2015, 29 wild manatees (17 male and 12 female) were blood sampled as part of the annual wild manatee health assessments organized by United States Geological Survey (USGS). TEG was performed using citrated kaolin-activated samples. RESULTS: The samples were obtained from manatees caught in Crystal River, Citrus County, and used to identify the mean +/- SD of normal TEG parameters: R = reaction time 2.1 minutes (0.8), K = clot formation time 0.8 min (0), alpha angle = 83.1 degrees (2), MA = maximum amplitude 75 mm (7.6), and LY30 = clot lysis 0.41% (0.68). No significant differences were found between manatee size, sex, or time between sampling and running the test. CONCLUSIONS: Manatee TEG parameters demonstrate a relatively hypercoagulable condition when compared to other mammals. This information will facilitate detection of changes in hemostasis during injury and disease and provide a valuable reference range. PMID- 29522246 TI - Biology of IL-2 and its therapeutic modulation: Mechanisms and strategies. AB - Cytokines signal through specific cell surface receptors to broadly regulate immune development, differentiation, proliferation, and survival, thereby influencing cellular fate and function. Accordingly, cytokines are potential therapeutic targets for modulation of immune responses. Indeed, over the last several decades, an increasing number of cytokine-based clinical trials have been performed, collectively using either recombinant forms of cytokines or blocking agents that modulate the actions of cytokines. The pleiotropic actions of cytokines, including their abilities to mediate both inflammatory and protective immune responses, indicate that using or targeting cytokines can have desired but also potentially undesirable effects. Here, we focus on the immunomodulatory cytokine, IL-2. We review the underlying basic science related to IL-2 and its biologic actions, discuss the current state of IL-2-based immunotherapy, and focus on emerging concepts of modulating the activities of this cytokine, including the generation of novel partial cytokine agonists as new potential therapeutics. PMID- 29522248 TI - Continuing Professional Development Quiz. PMID- 29522247 TI - What is your diagnosis? Subcutaneous temporal mass from a cat. PMID- 29522250 TI - The passing of an era. PMID- 29522252 TI - Rapid multiple immunofluorescent staining for the simultaneous detection of cytokeratin and vimentin in the cytology of canine tumors. AB - BACKGROUND: Immunocytochemistry (ICC) is utilized as an advanced technique in veterinary cytology. In tumor diagnosis, cytokeratin and vimentin are markers used to distinguish the origin of tumor cells. Standard enzyme-based ICC has limitations in clinical use; and therefore, more convenient and reliable methods are needed. OBJECTIVES: The purpose of this study was to develop a rapid multiple immunofluorescent (RMIF) detection method for dual cytokeratin and vimentin staining on cytology slides in dogs. METHODS: Air-dried smear samples from solid tumors and sediments of pleural effusions were prepared from dogs (n = 14) that were admitted to the Veterinary Teaching Hospital, Kagoshima University, Japan. Mouse monoclonal anti-human cytokeratin (AE1/AE3) and rabbit monoclonal anti human vimentin (SP20) antibodies were used as primary antibodies, followed by staining with Alexa Fluor-conjugated secondary antibodies. Staining using the RMIF method was compared with enzyme-based ICC staining. RESULTS: Rapid multiple immunofluorescent immunostaining was clear and specific in the evaluated smears, whereas the enzyme-based ICC showed nonspecific signals. By using the RMIF staining method, epithelial cells, mesenchymal cells, and mesothelial cells could be classified on a single smear of a pleural effusion. In smears of lymph nodes with epithelial tumor metastases, the RMIF method successfully detected metastatic epithelial tumor cells. CONCLUSIONS: The RMIF method might be a useful tool for diagnostic cytology in veterinary medicine. PMID- 29522253 TI - In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate. AB - It is known that a small fraction of orally administered norethisterone is metabolically converted to ethinylestradiol. This exploratory, open-label, nonrandomized study was conducted to investigate the systemic exposure to ethinylestradiol after intramuscular administration of norethisterone enantate in comparison with the exposure to ethinylestradiol after administration of a standard combined oral contraceptive. Sixteen healthy premenopausal women received an oral contraceptive (ethinylestradiol 30 MUg/levonorgestrel 150 MUg) once daily for 21 days and-after a 1-week washout period-a single intramuscular dose of 200 mg norethisterone enantate. Blood samples to determine ethinylestradiol in serum were taken over 24 hours after the last dose of ethinylestradiol/levonorgestrel and over 8 weeks after administration of norethisterone enantate. Oral equivalent doses of ethinylestradiol were estimated based on area under the concentration-time curves. The ethinylestradiol serum concentrations observed after administration of norethisterone enantate were relatively low: The mean maximum concentration was only 32% of the maximum observed after ethinylestradiol/levonorgestrel (90% confidence interval, 22.5% 44.7%). The maximum oral equivalent dose of ethinylestradiol was markedly lower than 30 MUg ethinylestradiol per day (20.3 MUg/day; 90% confidence interval, 14.8 28.0 MUg/day). The same applied to the average oral equivalent dose of ethinylestradiol for the 8-week postdose interval (4.41 MUg/day; 90% confidence interval, 3.57-5.46 MUg/day). To conclude, the study results indicate that metabolic conversion of norethisterone to ethinylestradiol also occurs after intramuscular administration of 200 mg norethisterone enantate, but is associated with a lower exposure to ethinylestradiol than the use of a combined oral contraceptive containing 30 MUg ethinylestradiol (plus 150 MUg levonorgestrel). PMID- 29522254 TI - Plasticity of plant defense and its evolutionary implications in wild populations of Boechera stricta. AB - Phenotypic plasticity is thought to impact evolutionary trajectories by shifting trait values in a direction that is either favored by natural selection ("adaptive" plasticity) or disfavored ("nonadaptive" plasticity). However, it is unclear how commonly each of these types of plasticity occurs in natural populations. To answer this question, we measured glucosinolate defensive chemistry and reproductive fitness in over 1500 individuals of the wild perennial mustard Boechera stricta, planted in four common gardens across central Idaho, United States. Glucosinolate profiles-including total glucosinolate concentration as well as the relative abundances and overall diversity of different compounds were strongly plastic both among habitats and within habitats. Patterns of glucosinolate plasticity varied greatly among genotypes. Plasticity among sites was predicted to affect fitness in 27.1% of cases; more often than expected by chance, glucosinolate plasticity increased rather than decreased relative fitness. In contrast, we found no evidence for within-habitat selection on glucosinolate reaction norm slopes (i.e., plasticity along a continuous environmental gradient). Together, our results indicate that glucosinolate plasticity may improve the ability of B. stricta populations to persist after migration to new habitats. PMID- 29522256 TI - Editorial. PMID- 29522255 TI - Does patient reporting lead to earlier detection of drug safety signals? A retrospective comparison of time to reporting between patients and healthcare professionals in a global database. AB - AIMS: To explore if there is a difference between patients and healthcare professionals (HCPs) in time to reporting drug-adverse drug reaction (ADR) associations that led to drug safety signals. METHODS: This was a retrospective comparison of time to reporting selected drug-ADR associations which led to drug safety signals between patients and HCPs. ADR reports were selected from the World Health Organization Global database of individual case safety reports, VigiBase. Reports were selected based on drug-ADR associations of actual drug safety signals. Primary outcome was the difference in time to reporting between patients and HCPs. The date of the first report for each individual signal was used as time zero. The difference in time between the date of the reports and time zero was calculated. Statistical differences in timing were analysed on the corresponding survival curves using a Mann-Whitney U test. RESULTS: In total, 2822 reports were included, of which 52.7% were patient reports, with a median of 25% for all included signals. For all signals, median time to signal detection was 10.4 years. Overall, HCPs reported earlier than patients: median 7.0 vs. 8.3 years (P < 0.001). CONCLUSIONS: Patients contributed a large proportion of reports on drug-ADR pairs that eventually became signals. HCPs reported 1.3 year earlier than patients. These findings strengthen the evidence on the value of patient reporting in signal detection and highlight an opportunity to encourage patients to report suspected ADRs even earlier in the future. PMID- 29522258 TI - Protective effect of dihydromyricetin on LPS-induced acute lung injury. AB - Dihydromyricetin (DHM), a bioactive flavonoid component isolated from Ampelopsis grossedentata, is known to have anti-inflammatory effect, but the effect of DHM on acute lung injury (ALI) is largely unknown. Here, we investigated the effect of DHM on ALI and the underlying mechanism by bioinformatic analyses and animal experiments. We found that pretreatment with DHM ameliorated lung pathological changes and suppressed the inflammation response in lung tissues after LPS challenge. The potential targets of DHM were predicted by DDI-CPI and DRAR-CPI tools and analyzed using the STRING server to predict the functionally related signaling pathways, such as MAPK signaling. Molecular docking calculations indicated that DHM could be embedded tightly into the binding pocket of ERK, JNK, and p38. Furthermore, the activation of MAPK signaling induced by LPS was inhibited by DHM. In conclusion, these findings suggest that DHM may exert its protective effect on ALI by inhibiting MAPK signaling. The present study supports a potential clinical application for DHM in treating ALI and provides a novel design that combines in silico methods with in vivo experiments for drug research. PMID- 29522259 TI - Impact of serotonin reuptake inhibitor use on breast milk supply in mothers of preterm infants: a retrospective cohort study. AB - AIMS: The aims of the present study were to examine the association between late pregnancy exposure to serotonin reuptake inhibitor (SRI) antidepressants and difficulties in achieving an adequate breast milk supply in women who have given birth to preterm infants, while accounting for the potential impacts of underlying maternal psychiatric illness. METHODS: A retrospective cohort study was carried out of 3024 women delivering liveborn preterm infants (<37 weeks' gestation) between January 2004 and December 2008. The primary outcome was postnatal domperidone use, considered to be a valid proxy for the presence and pharmacological management of low milk supply. Relative risks adjusted for maternal sociodemographic characteristics and comorbidities (aRRs) were calculated for low milk supply, comparing women with late pregnancy exposure to SRI antidepressants (n = 86), women with a psychiatric illness but no antidepressant use (n = 126) and women with neither antenatal exposures (n = 2812). RESULTS: Compared with non-exposed women, nonmedicated psychiatric illness [aRR 1.64; 95% confidence interval (CI) 1.16, 2.30] but not late pregnancy SRI use (aRR 1.00; 95% CI 0.59, 1.70) was associated with an increased risk of domperidone use, indicative of low milk supply. CONCLUSIONS: These findings do not support the previously observed negative impacts of antidepressant use on breastfeeding, instead suggesting that women with an underlying psychiatric illness appear at greatest risk of experiencing low milk supply and could benefit from additional breastfeeding education and support. PMID- 29522260 TI - Comparison of incidental versus palpable thyroid nodules presenting for fine needle aspiration biopsy. AB - BACKGROUND: Many attribute the rise in incidence of thyroid cancer to a deluge of radiologically identified incidental thyroid nodules. The clinical implications are unclear. METHODS: A review was performed of all patients who underwent fine needle aspirations of thyroid nodules by our academic medical center's Endocrinology Division between 2006 and 2010. Medical records were reviewed to identify whether the thyroid nodule was discovered incidentally or by palpation. RESULTS: Of 1153 patients, 37.4% underwent a biopsy because of an incidental thyroid nodule. These patients were significantly more likely to be >45 years old, men, white race, and with a body mass index >30 kg/m2 . Of the 17.2% of incidentalomas that led to surgery, 8.5% were found to be thyroid cancer. CONCLUSION: Thyroid nodules discovered incidentally are increasing the diagnosis of subclinical thyroid cancers. Not investigated previously, our study found that the mode of detection was not related to malignancy or surgery. PMID- 29522261 TI - Second primary squamous cell carcinoma in patients with nasopharyngeal carcinoma after radiotherapy-Predictors and prognostic factors. AB - BACKGROUND: We investigated risk and prognostic factors for second primary squamous cell carcinoma (SCC) in patients with nasopharyngeal carcinoma (NPC) after radiotherapy (RT). METHODS: A total of 49 021 patients with NPC were treated at Sun Yat-Sen Cancer Center between January 1970 and December 2009. The incidence and management of second primary SCCs were analyzed. RESULTS: A total of 142 patients (0.29%) developed second primary SCC, with 78.2% in the upper aerodigestive tract. Older age, smoking, and chemotherapy were associated with an increased rate of second primary SCC. The 3, 5, and 10-year overall survival (OS) rates for second primary SCC were 47.18%, 31.69%, and 11.97%, respectively. Advanced age, family history of cancer, and treatment modality were independent prognostic factors for survival. CONCLUSION: Second primary tumors rarely develop in patients with NPC treated with RT, but when this occurs, second primary SCC comprises a majority of these. Intensity-modulated RT may shorten the latency to second primary SCC. Surgery as the first-line treatment may improve survival and prognosis. PMID- 29522262 TI - Cardiac MR Characterization of left ventricular remodeling in a swine model of infarct followed by reperfusion. AB - BACKGROUND: Myocardial infarction (MI) survivors are at risk of complications including heart failure and malignant arrhythmias. PURPOSE: We undertook serial imaging of swine following MI with the aim of characterizing the longitudinal left ventricular (LV) remodeling in a translational model of ischemia-reperfusion mediated MI. ANIMAL MODEL: Eight Yorkshire swine underwent mid left anterior descending coronary artery balloon occlusion to create an ischemia-reperfusion experimental model of MI. FIELD STRENGTH/SEQUENCES: 1.5T Philips Achieva scanner. Serial cardiac MRI was performed at 16, 33, and 62 days post-MI, including cine imaging, native and postcontrast T1 , T2 and dark-blood late gadolinium enhanced (DB-LGE) scar imaging. ASSESSMENT: Regions of interest were selected on the parametric maps to assess native T1 and T2 in the infarct and in remote tissue. Volume of enhanced tissue, nonenhanced tissue, and gray zone were assessed from DB-LGE imaging. Volumes, cardiac function, and strain were calculated from cine imaging. STATISTICAL TESTS: Parameters estimated at more than two timepoints were compared with a one-way repeated measures analysis of variance. Parametric mapping data were analyzed using a generalized linear mixed model corrected for multiple observations. A result was considered statistically significant at P < 0.05. RESULTS: All animals developed anteroseptal akinesia and hyperenhancement on DB-LGE with a central core of nonenhancing tissue. Mean hyperenhancement volume did not change during the observation period, while the central core contracted from 2.2 +/- 1.8 ml at 16 days to 0.08 +/- 0.19 ml at 62 days (P = 0.008). Native T1 of ischemic myocardium increased from 1173 +/- 93 msec at 16 days to 1309 +/- 97 msec at 62 days (P < 0.001). Mean radial and circumferential strain rate magnitude in remote myocardium increased with time from the infarct (P < 0.05). DATE CONCLUSION: In this swine model of MI, serial quantitative cardiac MR exams allow characterization of LV remodeling and scar formation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29522263 TI - In Vitro Evaluation of Cell Compatibility of Dental Cements Used with Titanium Implant Components. AB - PURPOSE: To evaluate the biocompatibility of five dental cement compositions after directly exposing human gingival fibroblast (HGF) and MC3T3-E1 preosteoblast cells to cement alone and cement applied on commercially pure titanium (cpTi) specimens. MATERIALS AND METHODS: Nanostructurally integrated bioceramic (NIB), resin (R), resin-modified glass ionomer (RMGIC), zinc oxide eugenol (ZOE), and zinc phosphate (ZP) compositions were prepared according to the respective manufacturer's instructions. Samples were prepared in cylindrical Teflon molds or applied over the entire surface of polished cpTi discs. All samples were cured for 0.5, 1, 12, or 24 hours post-mixing. Direct contact testing was conducted according to ISO 10993 by seeding 6-well plates at 350,000 cells/well. Plates were incubated at 37 degrees C in a humidified atmosphere with 5% CO2 for 24 hours before individually plating samples and cpTi control discs. Plates were then incubated for an additional 24 hours. Microtetrazolium (MTT) cell viability assays were used to measure sample cytotoxicity. RESULTS: For samples that cured for 24 hours prior to direct contact exposure, only NIB and ZP cements when cemented on cpTi demonstrated cell viability percentages above the minimum biocompatibility requirement (>=70%) for both the investigative cell lines. R, RMGIC, and ZOE cements exhibited moderate to severe cytotoxic effects on both cell lines in direct contact and when cemented on cpTi specimens. For HGF cells, ZOE cemented-cpTi specimens exhibited significantly decreased cytotoxicity, whereas RMGIC cemented-cpTi specimens exhibited significantly increased cytotoxicity. CONCLUSIONS: Despite previous studies that showed enhanced cpTi corrosion activity for fluoride-containing compositions (NIB and ZP), there was no significant difference in cytotoxicity between cement alone and cemented-cpTi. In general, the MC3T3-E1 preosteoblast cells were more sensitive than HGF cells to cement composition. Ultimately, cement composition played a significant role in maintaining host cell compatibility. Results of this work help illustrate the impact of different cement formulations on host cell health and emphasize the need for understanding material properties when selecting certain formulations of dental cements, which can ultimately influence the survival of dental implant systems. PMID- 29522264 TI - A (+)-Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6. AB - Natural products have many health benefits, and their application can improve the quality of life. Recently, the diterpene (+)-larixol and its acetylated congeners demonstrated selective inhibition of the second-messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expanded these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing high throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, termed SH045, as a compound with nanomolar affinity and 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells. Expanding on this finding, TRPC6 inhibition was also observed in rat pulmonary smooth muscle cells. Furthermore, treatment of isolated perfused lung preparations with SH045 led to a decrease in lung ischemia reperfusion edema (LIRE), a life-threatening condition associated with TRPC6 that may occur after organ transplantation. Taken together, and given the inexpensive, straightforward, and scalable preparation of SH045, we report a TRPC6 blocker that holds promise for the translational treatment of LIRE. PMID- 29522265 TI - Polyethylene glycol fusion associated with antioxidants: A new promise in the treatment of traumatic facial paralysis. AB - BACKGROUND: Recent studies in invertebrates have taught us that early cell membrane regeneration is determinant for axonal recovery and survival after trauma. Many authors obtained extraordinary results in neural regeneration using polyethylene glycol fusion protocols, which also involved microsutures and antioxidants. METHODS: Sixty rats were evaluated with functional and histological protocol after facial nerve neurotmesis. Groups A and B had their stumps coapted with microsuture after 24 hours of neurotmesis and groups C and D after 72 hours. In addition to the microstructure, groups B and D used the polyethylene glycol fusion protocol for the modulation of the Ca+2 . RESULTS: At the sixth week, the latency of group D and duration of group B was lower than groups A and C (P = .011). The axonal diameter of the groups that used polyethylene glycol-fusion was higher than those who did not use polyethylene glycol-fusion (P <= .001). CONCLUSION: Although not providing a functional improvement, polyethylene glycol fusion slowed down demyelination. PMID- 29522267 TI - Alterations in plasma cytokine levels in chinese children with autism spectrum disorder. AB - : Genetic alterations, together with environmental risk factors during infancy and childhood, contribute significantly to the etiology of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental condition characterized by impairments in social interaction and restricted, repetitive behaviors. Mounting evidence points to a critical contribution of immunological risk factors to the development of ASD. By affecting multiple neurodevelopmental processes, immune system dysfunction could act as a point of convergence between genetics and environmental factors in ASD. Previous studies have shown altered cytokine levels in individuals with ASD, but research in Asian populations are limited. Here, we measured the plasma levels of 11 candidate cytokines in ASD and typically developing (TD) children. The cohort included 41 TD children and 87 children with ASD, aged 1-6 years. We found that as compared to the TD group, children with ASD had higher plasma levels of Eotaxin, TGF-beta1 and TNF-alpha. The increase in TGF beta1 level was most significant in males, while the increase in Eotaxin was most significant in females. Eotaxin level negatively correlated with the social affect score (SA) in ADOS, while TNF-alpha level positively correlated with total development quotient (DQ), measured using GMDS. These pilot findings suggest potentially important roles of Eotaxin, TGF-beta1 and TNF-alpha in ASD in the Chinese population. Autism Res 2018, 11: 989-999. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Alteration of immune system function is an important risk factor for autism spectrum disorder (ASD). Here we found that the levels of cytokines, including Eotaxin, TGF-beta1 and TNF alpha, are elevated in Chinese children with ASD, as compared to typically developing children. The change in TGF-beta1 level was most prominent in boys, while that of Eotaxin was more significant in girls. These results provide evidence for changes in cytokine profile in Chinese children with ASD. PMID- 29522268 TI - Combined human papillomavirus typing and TP53 mutation analysis in distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), the occurrence of concurrent lung malignancies poses a significant diagnostic challenge because metastatic HNSCC is difficult to discern from second primary lung squamous cell carcinoma (SCC). However, this differentiation is crucial because the recommended treatments for metastatic HNSCC and second primary lung SCC differ profoundly. METHODS: We analyzed the origin of lung tumors in 32 patients with HNSCC using human papillomavirus (HPV) typing and targeted next generation sequencing of all coding exons of tumor protein 53 (TP53). RESULTS: Lung tumors were clearly identified as HNSCC metastases or second primary tumors in 29 patients, thus revealing that 16 patients had received incorrect diagnoses based on clinical and morphological data alone. CONCLUSION: The HPV typing and mutation analysis of all TP53 coding exons is a valuable diagnostic tool in patients with HNSCC and concurrent lung SCC, which can help to ensure that patients receive the most suitable treatment. PMID- 29522266 TI - Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. AB - The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67-4.94), CDH1 (OR: 17.04, 95%CI: 3.54-82), CHEK2 (OR: 2.93, 95%CI: 2.29-3.75), PALB2 (OR: 9.53, 95%CI: 6.25-14.51), and TP53 (OR: 7.30, 95%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73 2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors. PMID- 29522269 TI - A Technique for Digital Impression and Bite Registration for a Single Edentulous Arch. AB - Few studies have reported the application of digital technology for the process of impression and interocclusal recordings in edentulous patients. This article describes a digitizing system for generating digital edentulous models with a jaw relationship by taking direct digital impressions and a virtual bite registration using intraoral digital scanning. A specialized scan retractor was used to make digital impressions of edentulous jaws in patients' mouths using an intraoral scanner. Virtual bite registration was obtained with optical scanning of the buccal surfaces of both jaws at the occlusal vertical dimension. The registration was then used as a reference for aligning both jaws. Digital edentulous models that include the jaw relationship would be clinically beneficial for the fabrication of complete dentures in edentulous patients. PMID- 29522271 TI - Inhibition of PC4 radiosensitizes non-small cell lung cancer by transcriptionally suppressing XLF. AB - Positive cofactor 4 (PC4) participates in DNA damage repair and involved in nonhomologous end joining (NHEJ). Our previous results demonstrated that knockdown of PC4 downregulated the expression of XRCC4-like factor (XLF) in esophageal squamous cell carcinoma. However, the mechanism how PC4 regulates the expression of XLF remains unclear. Here, we found that knockdown of PC4 increased radiosensitivity of non-small cell lung cancer (NSCLC) both in vivo and in vitro. Furthermore, we found that PC4 knockdown downregulated the expression of XLF, whereas recovering XLF expression restored radioresistance in the PC4-knockdown NSCLC cells. In addition, PC4 knockdown inhibited XLF expression by transcriptionally suppressing of XLF. Moreover, PC4 expression correlated with radiosensitivity and was an independent prognostic factor of progression-free survival (PFS) in patients with NSCLC. These findings suggest that PC4 could be used as a promising therapeutic target for NSCLC. PMID- 29522270 TI - Long-Term Spinal Cord Stimulation Alleviates Mechanical Hypersensitivity and Increases Peripheral Cutaneous Blood Perfusion in Experimental Painful Diabetic Polyneuropathy. AB - OBJECTIVES: This study utilizes a model of long-term spinal cord stimulation (SCS) in experimental painful diabetic polyneuropathy (PDPN) to investigate the behavioral response during and after four weeks of SCS (12 hours/day). Second, we investigated the effect of long-term SCS on peripheral cutaneous blood perfusion in experimental PDPN. METHODS: Mechanical sensitivity was assessed in streptozotocin induced diabetic rats (n = 50) with von Frey analysis. Hypersensitive rats (n = 24) were implanted with an internal SCS battery, coupled to an SCS electrode covering spinal levels L2-L5. The effects of four weeks of daily conventional SCS for 12 hours (n = 12) or Sham SCS (n = 12) were evaluated with von Frey assessment, and laser Doppler imaging (LDI). RESULTS: Average paw withdrawal thresholds (PWT) increased during long-term SCS in the SCS group, in contrast to a decrease in the Sham group (Sham vs. SCS; p = 0.029). Twenty-four hours after long-term SCS average PWT remained higher in the SCS group. Furthermore, the SCS group showed a higher cutaneous blood perfusion during long term SCS compared to the Sham group (Sham vs. SCS; p = 0.048). Forty-eight hours after long-term SCS, no differences in skin perfusion were observed. DISCUSSION: We demonstrated that long-term SCS results in decreased baseline mechanical hypersensitivity and results in increased peripheral blood perfusion during stimulation in a rat model of PDPN. Together, these findings indicate that long term SCS results in modulation of the physiological circuitry related to the nociceptive system in addition to symptomatic treatment of painful symptoms. PMID- 29522272 TI - Presence of lytic Epstein-Barr virus infection in nasopharyngeal carcinoma. AB - BACKGROUND: Chromogenic Epstein-Barr virus-encoded RNA (EBER) in situ hybridization (EBER-ISH) is the gold standard to detect Epstein-Barr virus (EBV) but it is difficult to use in conjunction with immunohistochemistry (IHC). In this study, our purpose was to validate the sensitivity and specificity of RNAscope in detection of EBV infection in nasal epithelium and its stroma. METHODS: Fluorescence-based RNAscope EBER-ISH, BRLF1-ISH, and lineage marker-IHC were performed on archived formalin-fixed paraffin-embedded tissues from normal nasal cavity (n = 5), nasopharynx (n = 8), and nasopharyngeal carcinoma (NPC) specimens (n = 10). RESULTS: The EBERs were detected in 10 of 10 NPC samples but was absent in all normal tissues from the nasal cavity and nasopharynx. The EBERs were exclusively located in pan-cytokeratin (pan-CK)-positive tumor epithelial cells but not in CD45-positive leukocytes and vimentin-positive stromal fibroblasts. The level of EBER expression varied in tumor cells within patient and between patients as well. Additionally, 5 of 10 patients had positive BRLF ISH. CONCLUSION: We developed a simple and reproducible method to simultaneously detect mRNA and protein in formalin-fixed paraffin-embedded tissues of NPC. As a single staining, traditional EBER continues to be useful; however, for interpretation of the phenotype of EBV-infected cells, RNAscope is superior. Significantly, we showed that lytic EBV infection took place in NPC tumors. PMID- 29522273 TI - Integrative analysis of competing endogenous RNA network focusing on long noncoding RNA associated with progression of cutaneous melanoma. AB - Cutaneous melanoma (CM) is the most malignant tumor of skin cancers because of its rapid development and high mortality rate. Long noncoding RNAs (lncRNAs), which play essential roles in the tumorigenesis and metastasis of CM and interplay with microRNAs (miRNAs) and mRNAs, are hopefully considered to be efficient biomarkers to detect deterioration during the progression of CM to improve the prognosis. Bioinformatics analysis was fully applied to predict the vital lncRNAs and the associated miRNAs and mRNAs, which eventually constructed the competing endogenous RNA (ceRNA) network to explain the RNA expression patterns in the progression of CM. Further statistical analysis emphasized the importance of these key genes, which were statistically significantly related to one or few clinical features from the ceRNA network. The results showed the lncRNAs MGC12926 and LINC00937 were verified to be strongly connected with the prognosis of CM patients. PMID- 29522274 TI - Neurofibromin (NF1) genetic variant structure-function analyses using a full length mouse cDNA. AB - Neurofibromatosis type 1 (NF1) is caused by pathogenic variants or mutations in the NF1 gene that encodes neurofibromin. We describe here a new approach to determining the functional consequences of NF1 genetic variants. We established a heterologous cell culture expression system using a full-length mouse Nf1 cDNA (mNf1) and human cell lines. We demonstrate that the full-length murine cDNA produces a > 250 kDa neurofibromin protein that is capable of modulating Ras signaling. We created mutant cDNAs representing NF1 patient variants with different clinically relevant phenotypes, and assessed their ability to produce mature neurofibromin and restore Nf1 activity in NF1-/- cells. These cDNAs represent variants in multiple protein domains and various types of clinically relevant predicted variants. This approach will help advance research on neurofibromin structure and function, determine pathogenicity for missense variants, and allow for the development of activity assays and variant-directed therapeutics. PMID- 29522276 TI - Updates From the Literature, March/April 2018. PMID- 29522275 TI - Patterns of recurrence in oral tongue cancer with perineural invasion. AB - BACKGROUND: Although perineural invasion (PNI) is recognized as an adverse prognostic factor in oral tongue squamous cell carcinoma (SCC), the patterns of failure are poorly defined. METHODS: Patients with oral tongue SCC who received primary surgical treatment were identified. Specimens were reviewed by head and neck pathologists. Disease-specific survival (DSS) and locoregional recurrence free survival (LRFS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS) were calculated. The PNI and PNI characteristics were analyzed as predictors of outcome. The utility of grading the extent of PNI was assessed by quantifying the number of PNI foci per slide reviewed, nerve caliber, and percent circumference involved. RESULTS: Patients with PNI had a decreased DSS; however, PNI was not predictive of LRFS or RRFS. Patients with PNI were more likely to develop a distant recurrence and 19.40 (confidence interval [CI] 6.70-56.14; P < .001) times more likely to develop a distant recurrence if PNI foci density was >1. CONCLUSION: The presence of PNI in oral tongue SCC predicts worse DSS, with distant recurrence as the most common pattern of failure. High PNI foci density is associated with worse DRFS. PMID- 29522277 TI - High Body Adiposity Drives Glucose Intolerance and Increases Cardiovascular Risk in Normoglycemic Subjects. AB - OBJECTIVE: The objective of this study was to assess the utility of the 2-hour oral glucose tolerance test (OGTT) value to discriminate between different cardiometabolic profiles and examine the role of body composition in predicting the associated increased risk for glucose impairment, beta-cell dysfunction, and cardiovascular disease (CVD). METHODS: Subjects with normal fasting glucose completed a 2-hour OGTT and were categorized to the carbohydrate metabolism alterations (CMAs) or the control group based on a 2-hour glucose threshold of 7.8 mmol/L. Body composition, visceral adipose tissue, OGTT-based parameters, and cardiovascular risk factors (CVRFs) such as hypertension, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, and smoking status were measured. RESULTS: Subjects with CMAs exhibited a significantly higher 1 hour postload glucose level and a greater decline in beta-cell function and CVRF profiles. After multivariate adjustment, an excess of total body and visceral fat was associated with an increased risk of CMAs, beta-cell dysfunction, CVRFs, and lower whole-body insulin sensitivity. CONCLUSIONS: These data support the etiopathogenic role of body and visceral fat in the development of glucose derangements and CVRFs early on in the metabolic dysregulation process. Thus, body composition analysis and OGTT assessment performed in individuals with normal fasting glucose enable a better identification of patients at risk of developing type 2 diabetes and CVD. PMID- 29522278 TI - Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells. AB - Epstein-Barr virus (EBV) is a ubiquitous oncogenic virus that is associated with B cell lymphomas, including Burkitt lymphoma and Hodgkin lymphoma. Previous studies have shown that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in EBV-associated lymphomas and can be a novel therapeutic target. An oral dual inhibitor of PI3Kgamma and PI3Kdelta, duvelisib, is in clinical trials for the treatment of lymphoid malignancies. In this study, we evaluated how duvelisib affects the activity of the PI3K/Akt signaling pathway and if it has antitumor effects in EBV-associated lymphoma cell lines. We found that the PI3K/Akt signaling pathway was activated in most of the B and T cell lymphoma cell lines tested. Additionally, duvelisib treatment inhibited cellular growth in the tested cell lines. Overall, B cell lines were more susceptible to duvelisib than T and NK cell lines in vitro regardless of EBV infection. However, the additional influence of duvelisib on the tumor microenvironment was not assessed. Duvelisib treatment induced both apoptosis and cell cycle arrest in EBV-positive and -negative B cell lines, but not in T cell lines. Furthermore, duvelisib treatment reduced the expression of EBV lytic genes (BZLF1 and gp350/220) in EBV positive B cell lines, suggesting that duvelisib suppresses the lytic cycle of EBV induced by B cell receptor signaling. However, duvelisib did not induce a remarkable change in the expression of EBV latent genes. These results may indicate that there is therapeutic potential for duvelisib administration in the treatment of EBV-associated B cell lymphomas and other B cell malignancies. PMID- 29522279 TI - An Update on Menopause Management. AB - Menopause-related symptoms frequently lead women to seek health care. Recommendations for prescribing hormone therapy have changed significantly since the publication of initial results from the Women's Health Initiative (WHI) study in 2002. The North American Menopause Society and the American College of Obstetricians and Gynecologists have newer guidelines based on long-term analyses of the WHI participants as well as emerging data from other clinical trials. Women with an intact uterus who are using systemic estrogen must also use a progestogen; however, there are 2 new selective estrogen receptor modulators on the market for use without a progestogen. This review discusses current recommendations and new medications as well as the risks and benefits related to hormone therapy. Evidence-based alternatives to hormone therapy to treat symptoms of menopause are also presented. PMID- 29522280 TI - Diagnostic and prognostic value of serum miR-15a and miR-16-1 expression among egyptian patients with prostate cancer. AB - Prostate cancer (PCa) is considered the most common malignancy in men. The aim of this study is to assess the role of serum miR-15a and miR-16-1 expression in PCa development, diagnosis and prognosis aiming to find a specific noninvasive biomarker. This study comprised 70 patients with PCa, 70 patients complaining of benign prostatic hyperplasia (BPH), 30 patients with chronic prostatitis and 70 controls. Circulating miR-15a and miR-16-1 expression was detected by real-time polymerase chain reaction. Prostate specific antigen levels were measured by enzyme-linked immunosorbent assay. The expression levels of serum miR-15a were decreased in PCa patients compared with controls, chronic prostatitis and BPH patients (0.43 +/- 0.12, 1.7 +/- 0.76, 1.56 +/- 0.34 and 1.53 +/- 0.65, respectively). The expression levels of serum miR-16-1 were decreased in PCa patients compared with controls, chronic prostatitis and BPH patients (0.55 +/- 0.23, 2.15 +/- 0.87, 2.08 +/- 0.54 and 1.96 +/-0.61, respectively). Downregulation of miR-15a and miR-16-1 correlated with higher Gleason score (P = 0.002 and P = 0.006, respectively), higher tumor stage (P = 0.001 and P = 0.01, respectively), PCa metastasis (P = 0.002 and P = 0.025, respectively) and lymph node involvement (P = 0.02 and P = 0.007, respectively). Moreover, Receiver operating characteristic curve analysis revealed that combined miR-15a/miR-16-1 and PSA increased the sensitivity and specificity for the diagnosis of PCa (97.1% and 94.3%, respectively) more than prostate specific antigen alone (82.9% sensitivity and 75.7% specificity). Combined serum miR-15a/miR-16-1 expression and PSA level can be used as promising specific noninvasive biomarkers in the diagnosis and prognosis of PCa better than prostate specific antigen alone. (c) 2018 IUBMB Life, 70(5):437-444, 2018. PMID- 29522281 TI - Treatment with anti-Sclerostin antibody to stimulate mandibular bone formation. AB - BACKGROUND: Anti-Sclerostin antibody (Scl-Ab) is a promising new bone anabolic therapy. Although anti-Scl-Ab stimulates bone formation and repair in the appendicular and axial skeleton, its efficacy in the craniofacial skeleton is still poorly understood. METHODS: Using an established model of Down syndrome dependent bone deficiency, 10 Ts65Dn mice and 10 wild-type mice were treated weekly via i.v. tail vein injection with vehicle or anti-Sclerostin for 3 weeks and euthanized 1 week after. RESULTS: Wild-type mice treated with the anti-Scl-Ab had increased mandibular bone, trabecular thickness, and alveolar height compared with controls. Anti-Scl-Ab increased Ts65Dn mandibular bone parameters such that they were statistically indistinguishable from those in vehicle-treated wild-type mandibles. CONCLUSION: Treatment with anti-Scl-Ab significantly increased mandibular bone mass and alveolar height in wild type mice and normalized mandibular bone mass and alveolar height in Ts65Dn mice. The anti-Scl-Ab therapy represents a novel method for increasing mandibular bone formation. PMID- 29522282 TI - Development and validation of an individualized diagnostic signature in thyroid cancer. AB - New molecular signatures are needed to improve the diagnosis of thyroid cancer (TC) and avoid unnecessary surgeries. In this study, we aimed to develop a robust and individualized diagnostic signature in TC. Gene expression profiles of tumor and nontumor samples were from 13 microarray datasets of Gene Expression Omnibus (GEO) database and one RNA-sequencing dataset of The Cancer Genome Atlas (TCGA). A total of 1246 samples were divided into a training set (N = 435), a test set (N = 247), and one independent validation set (N = 564). In the training set, 115 most frequent differentially expressed genes (DEGs) among the included datasets were used to construct 6555 gene pairs, and 19 significant pairs were detected to further construct the diagnostic signature by a penalized generalized linear model. The signature showed a good diagnostic ability for TC in the training set (area under receiver operating characteristic curve (AUC) = 0.976), test set (AUC = 0.960), and TCGA dataset (AUC = 0.979). Subgroup analyses showed consistent results when considering the type of nontumor samples and microarray platforms. When compared with two existing molecular signatures in the diagnosis of thyroid nodules, the signature (AUC = 0.933) also showed a higher diagnostic ability (AUC = 0.886 for a 7-gene signature and AUC = 0.892 for a 10-gene signature). In conclusion, our study developed and validated an individualized diagnostic signature in TC. Large-scale prospective studies were needed to further validate its diagnostic ability. PMID- 29522283 TI - Differentially expressed and survival-related proteins of lung adenocarcinoma with bone metastasis. AB - Despite recent advances in targeted and immune-based therapies, the poor prognosis of lung adenocarcinoma (LUAD) with bone metastasis (BM) remains a challenge. First, two-dimensional gel electrophoresis (2-DE) was used to identify proteins that were differentially expressed in LUAD with BM, and then matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) was used to identify these proteins. Second, the Cancer Genome Atlas (TCGA) was used to identify mutations in these differentially expressed proteins and Kaplan-Meier plotter (KM Plotter) was used to generate survival curves for the analyzed cases. Immunohistochemistry (IHC) was used to check the expression of proteins in 28 patients with BM and nine patients with LUAD. Lastly, the results were analyzed with respect to clinical features and patient's follow-up. We identified a number of matched proteins from 2-DE. High expression of enolase 1 (ENO1) (HR = 1.67, logrank P = 1.9E-05), ribosomal protein lateral stalk subunit P2 (RPLP2) (HR = 1.77, logrank P = 2.9e-06), and NME/NM23 nucleoside diphosphate kinase 2 (NME1-NME2) (HR = 2.65, logrank P = 3.9E-15) was all significantly associated with poor survival (P < 0.05). Further, ENO1 was upregulated (P = 0.0004) and calcyphosine (CAPS1) was downregulated (P = 5.34E-07) in TCGA LUAD RNA-seq expression data. IHC revealed that prominent ENO1 staining (OR = 7.5, P = 0.034) and low levels of CAPS1 (OR = 0.01, P < 0.0001) staining were associated with BM incidence. Finally, we found that LUAD patients with high expression of ENO1 and RPLP2 had worse overall survival. This is the first instance where the genes ENO1, RPLP2, NME1-NME2 and CAPS1 were associated with disease severity and progression in LUAD patients with BM. Thus, with this study, we have identified potential biomarkers and therapeutic targets for this disease. PMID- 29522286 TI - Response to "Using ideas and methodologies from other authors without proper referencing is a form of plagiarism!" PMID- 29522284 TI - Apoptin-derived peptide reverses cisplatin resistance in gastric cancer through the PI3K-AKT signaling pathway. AB - The prognosis of gastric cancer (GC) remains poor due to clinical drug resistance, and novel drugs are urgently needed. Apoptin-derived peptide (AdP) is an antitumor polypeptide constructed in our laboratory that has been used to combat cisplatin (CDDP) resistance in GC cells. MTT and colony-formation assays and Hoechst 33342 staining were used to measure the cytotoxicity of CDDP and AdP in GC cells. Cell apoptosis was measured using an Annexin-V-FITC/PI dual staining assay. Western blot analysis was conducted to detect the expression of proteins in the PI3K/AKT signaling pathway and resistance-related markers. AdP exerted a specific cytotoxic effect on GC cells and CDDP-resistant GC cells in a concentration- and time-dependent manner. AdP also suppressed cell invasion and migration. Additionally, AdP inhibited the expression of p85, AKT, p-p85, p-AKT, multidrug resistance 1 (MDR1), and aryl hydrocarbon nuclear translocator (ARNT) in the PI3K/AKT/ARNT signaling pathway, which promoted apoptosis and necrosis in GC cells. AdP promoted apoptosis in CDDP-resistant GC cells by suppressing the PI3K/AKT/ARNT signaling pathway and might be considered a candidate agent for the clinical treatment of cisplatin-resistant GC. PMID- 29522287 TI - Using ideas and methodologies from other authors without proper referencing is a form of plagiarism! PMID- 29522288 TI - Anterior Cantilever Resin-Bonded Fixed Dental Prostheses: A Review of the Literature. AB - PURPOSE: This review evaluated the survival rate of single retainer anterior resin-bonded fixed dental prostheses (RBFDPs) to determine whether the choice of material affects their clinical outcome. MATERIALS AND METHODS: An electronic search of the English peer-reviewed dental literature in PubMed was conducted to identify all publications reporting on cantilever RBFDPs until May 2016. Study information extraction and methodological quality assessments were accomplished by two reviewers independently. The searched keywords were as follows: "resin bonded, single retainer, all-ceramic resin-bonded fixed dental prostheses (RBFDPs), all-ceramic RBFDPs, cantilever resin, RBFDPs, cantilever resin-bonded bridge, two units cantilevered, two-unit cantilevered, metal-ceramic cantilever, and metal-ceramic." Furthermore, the ''Related Articles'' feature of PubMed was used to identify further references of interest within the primary search. The bibliographies of the obtained references were used to identify pertinent secondary references. Review articles were also used to identify relevant articles. After the application of exclusion criteria, the definitive list of articles was screened to extract the qualitative data, and the results were analyzed. RESULTS: Overall 2588 articles were dedicated at the first review phase; however, only 311 studies were left after the elimination of duplicates and unrelated studies. Seventeen studies passed the second review phase. Five studies were excluded because they were follow-up studies of the same study cohort. Twelve studies were finally selected. CONCLUSIONS: The use of cantilever RBFDPs showed promising results and high survival rates. PMID- 29522290 TI - Differences in the percutaneous nephrolithotomy practice patterns among Latin American urologists with and without endourology training. AB - PURPOSE: Although the worldwide percutaneous nephrolithotomy (PCNL) practice patterns determined via a survey sent to members of the Endourological Society have been published, differences in PCNL practice patterns among Latin American urologists based on endourological or lithiasis training have not been published. To determine the PCNL practice patterns among Latin American urologists with and without training in endourology. MATERIALS AND METHODS: The SurveyMonkey(r) web platform was used to develop a 27- item survey on PCNL for the treatment of renal stones, and the survey was sent via e-mail and other electronic media to 2000 urologists from 15 Latin American countries. Endourology-trained (group 1) and nontrained urologists (group 2) were analyzed. The group results were compared using the chi-squared and Fisher's exact tests. SPSS version 20 for Windows was used for all analyses. RESULTS: A total of 331 urologists responded to the survey (rate of 16.55%): 221 (66.7%) in group 1 and 110 (33.2%) in group 2). In groups 1 and 2, 91.9% and 63.2% performed PCNL, respectively; 85.1% and 58.5% used preoperative tomography, respectively; 12.7% and 4.7% used preoperative nephrolitometry nomograms, respectively; 45.2% and 32.1% used endoscopic combined intrarenal surgery, respectively; 68.3% and 38.7% used multiple percutaneous tract realization, respectively; and 19.9% and 5.7% used minimally invasive PCNL, respectively (all p=0.0005). CONCLUSIONS: Statistically significant differences were observed in PCNL practice patterns of Latin American urologists with and without training in endourology. Specific training in endourology significantly influence the practice patterns of Latin American urologists. PMID- 29522291 TI - Idiosyncratic reaction after injection of polyacrylate - polyalcohol copolymer. AB - CONTEXT: Polyacrylate-polyalcohol copolymer is a synthetic product, non biodegradable, with low rate of therapeutic failure and lower incidence of reactions at the site of injection, when compared to biodegradable agents. We report an unprecedent, exuberant and persistent inflammatory reaction following injection of that substance. PATIENT: A 17 years-old patient with vesico-ureteral reflux and complete pyelocaliceal right duplication was submitted to treatment with polyacrylate-polyalcohol copolymer (STING technique). In the seventh day of post-operatory, she presented intense dysuria and hypogastric pain, without laboratory exams alterations; a symptomatic treatment was started. After two months, the symptoms persisted and an ultrasound detected thickening of bladder wall close to the uretero-vesical junction. After that exam, a cystostopic biopsy showed epithelial hyperplasia with increased edema of lamina propria, suggesting an adverse reaction to the polymer. After four months, there was complete remission, but the reflux persisted with the same grade. HYPOTHESIS: This is an unprecedent reaction following injection of this copolymer. The presence of characteristics such as absence of infection, temporal relation between treatment and beginning of symptoms, and detection of epithelial hyperplasia at the local of injection reinforce the hypothesis of association of the substance and adverse reaction. In that patient, important complains motivated early investigation of urinary tract, that confirmed those aspects. Maybe if that reaction had occurred in patients with lower capacity of expression (such as in infants) it would be unnoticed. PMID- 29522292 TI - Extensive renal sinus lipomatosis in xanthogranulomatous pyelonephritis simulating liposarcoma. AB - Renal replacement lipomatosis is a condition characterized by varying degrees of renal parenchymal atrophy and perirenal fibrofatty proliferation secondary to chronic inflammation such as xanthogranulomatous pyelonephritis. In severe cases, imaging findings can be misdiagnosed as retroperitoneal liposarcoma. PMID- 29522293 TI - Ureteroscopy and stone treatment in the elderly (>=70 years): prospective outcomes over 5- years with a review of literature. AB - OBJECTIVE: To assess outcomes of ureteroscopy for treatment of stone disease in the elderly. Ureteroscopy (URS) is an increasingly popular treatment modality for urolithiasis and its applications are ever expanding with the development of newer technologies. Its feasibility and outcomes within the elderly population to our knowledge remain under-reported. MATERIALS AND METHODS: We examined the patient demographics and surgical outcomes from our prospective database for patients >=70 years who underwent URS for urolithiasis, in a 5-year period between March 2012 and December 2016. RESULTS: A total of 110 consecutive patients underwent 121 procedures (1.1 procedure/ patient) with a mean age of 77.2 years (range: 70-91 years). Stone location was in the kidney/ pelviureteric junction (PUJ) in 29%, ureter in 37% and in multiple locations in 34%. The initial and final stone free rate (SFR) was 88% and 97% respectively. While 73% were done as true day case procedures, 89% patients were discharged within 24 hours. Eleven patients (9%) underwent complications of which 10 were Clavien I/II including acute urinary retention, urinary tract infection, stent symptoms and pneumonia. One patient underwent Clavien IV complication where they needed intensive care unit admission for urosepsis but fully recovered and were discharged home subsequently. CONCLUSION: Ureteroscopy is a safe and effective method of managing urolithiasis in elderly patients. Although most patients are discharged within 24-hours, consideration needs to be made for patients where social circumstances can impact their discharge planning. PMID- 29522294 TI - Durasphere(r) EXP: a non-biodegradable agent for treatment of primary Vesico Ureteral reflux in children. AB - INTRODUCTION: Durasphere(r) EXP (DEXP) is a compound of biocompatible and non biodegradable particles of zirconium oxide covered with pyrolytic carbon. The aim of this study is to evaluate the durability of off-label use of DEXP in the treatment of primary vesicoureteral reflux in children. MATERIALS AND METHODS: Patients who underwent subureteric injection of DEXP for the correction of primary VUR were retrospectively reviewed . Patients aged >18 years as well as those who had grade-I or -V VUR, anatomic abnormalities (duplicated system, hutch diverticulum), neurogenic bladder or treatment refractory voiding dysfunction were excluded. Radiologic success was defined as the resolution of VUR at the 3rd month control. Success was radiographically evaluated at the end of the first year. RESULTS: Thirty-eight patients (9 boys, 29 girls; mean age, 6.3+/-2.7 years) formed the study cohort. Forty-six renal units received DEXP (grade II: 22; grade III: 18; grade IV: 6). Mean volume per ureteric orifice to obtain the mound was 0.70+/-0.16mL. First control VCUG was done after 3 months in all patients. After the first VCUG, 6 patients had VUR recurrence. Short-term radiologic success of DEXP was 84.2%. Rate of radiologic success at the end of the first year was 69.4% (25/32). Lower age (p:0.006) and lower amount of injected material (p:0.05) were associated with higher success rates at the end of 1 year. CONCLUSION: This is the first study to assess the outcomes of DEXP for treatment of primary VUR in children. After 1 year of follow-up, DEXP had a 69.4% success rate. PMID- 29522295 TI - On thin ice: barriers to adoption of surveillance for patients with stage I testicular seminoma. Survey of US radiation oncologists. AB - PURPOSE: Most men with stage I testicular seminoma are cured with surgery alone, which is a preferred strategy per national guidelines. The current pattern of practice among US radiation oncologists (ROs) is unknown. MATERIALS AND METHODS: We surveyed practicing US ROs via an online questionnaire. Respondent's characteristics, self-rated knowledge, perceived patient compliance rates with observation were analyzed for association with treatment recommendations. RESULTS: We received 353 responses from ROs, of whom 23% considered themselves experts. A vast majority (84%) recommend observation as a default strategy, however this rate drops to 3% if the patient is believed to be noncompliant. 33% of respondents believe that survival is jeopardized in case of disease recurrence, and among these respondents only 5% support observation. 22% of respondents over-estimate the likelihood of noncompliance with observation to be in the 50-80% range. Responders with a higher perceived noncompliance rate are more likely to recommend adjuvant therapy (Fisher's exact p<0.01). Only 7% of respondents recommend observation for stage IS seminoma and 45% administer adjuvant RT in patients with elevated pre-orchiectomy alpha-fetal protein levels. CONCLUSIONS: Many US ROs over-estimate the likelihood that stage I testicular seminoma patients will be noncompliant with surveillance and incorrectly believe that overall survival is jeopardized if disease recurs on surveillance. Observation is quickly dismissed for patients who are not deemed to be compliant with observation, and is generally not accepted for patients with stage IS disease. There is clearly an opportunity for improved physician education on evidence-based management of stage I testicular seminoma. PMID- 29522297 TI - Identification of the Effect of Depression on Risky Sexual Behavior: Exploiting a Natural Experiment. PMID- 29522296 TI - The Diagnostic Value of FNDC5/Irisin in Renal Cell Cancer. AB - PURPOSES: The aim of this study was to determine the diagnostic significance of fibronectin type III domain containing protein 5 (FNDC5)/Irisin levels in the sera of patients with renal cell cancer. MATERIALS AND METHODS: In the study, 48 individuals were evaluated. The patient group included 23 subjects diagnosed with renal tumor, and the control group of 25 healthy individuals. Patients diagnosed with renal tumor received surgical treatment consisting of radical or partial nephrectomy. Blood specimens were collected and serum FNDC5/ Irisin and carcinoembryonic antigen (CEA) levels were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: FNDC5/irisin and CEA levels in renal cancer patients were significantly higher compared with the control group (p=0.0001, p=0.009, respectively). Also, FNDC5 levels was more sensitive and specific than CEA levels. The best cut-off points for FNDC5/ irisin were >105pg/mL and CEA were >2.67ng/mL for renal cancer. CONCLUSIONS: FNDC5/Irisin may be used as a diagnostic biomarker for renal cancer. PMID- 29522298 TI - Sinking, Swimming, or Learning to Swim in Medicare Part D. AB - Under Medicare Part D, senior citizens choose prescription drug insurance offered by numerous private insurers. We examine nonpoor enrollees' actions in 2006 and 2007 using panel data. Our sample reduced overspending by $298 on average, with gains by 81 percent of them. The greatest improvements were by those who overspent most in 2006 and by those who switched plans. Decisions to switch depended on individuals' overspending in 2006 and on individual-specific effects of changes in their current plans. The oldest consumers and those initiating medications for Alzheimer's disease improved by more than average, suggesting that real-world institutions help overcome cognitive limitations. PMID- 29522299 TI - Physician Agency and Adoption of Generic Pharmaceuticals. AB - I examine physician agency in health care services in the context of the choice between brand-name and generic pharmaceuticals. I examine micro-panel data from Japan, where physicians can legally make profits by prescribing and dispensing drugs. The results indicate that physicians often fail to internalize patient costs, explaining why cheaper generics are infrequently adopted. Doctors respond to markup differentials between the two versions, indicating anotheragency problem. However, generics' markup advantages are short-lived, which limits their impact on increasing generic adoption. Additionally, state dependence and heterogeneous doctor preferences affected generics' adoption. Policy makers can target these factors to improve static efficiency. PMID- 29522300 TI - Pricing and Welfare in Health Plan Choice. AB - Premiums in health insurance markets frequently do not reflect individual differences in costs, either because consumers have private information or because prices are not risk rated. This creates inefficiencies when consumers self-select into plans. We develop a simple econometric model to study this problem and estimate it using data on small employers. We find a welfare loss of 2-11 percent of coverage costs compared to what is feasible with risk rating. Only aboutone-quarter of this is due to inefficiently chosen uniform contribution levels. We also investigate the reclassification risk created by risk rating individual incremental premiums, finding only a modest welfare cost. PMID- 29522301 TI - The role of bioactive lipids in the development of soft tissue sarcomas in children - a review article. AB - Soft tissue sarcoma accounts for almost 7% of all malignanttumours in children and adolescents. This heterogeneous groupof mesenchymal and neuroectodermal tissue neoplasms canbe characterized by common biological and clinics traits. Bioactivelipids are described as lipids, the levels of which - whenchanged - lead to changes in cell functioning. The role of bioactivelipids in the biology of neoplasmatic cells is unquestionable.In this paper we present an overview of articles describing theimpact of selected bioactive lipids on the development of sarcomain children. PMID- 29522302 TI - [Significance of biomechanical criteria in proper treatment planning in knee osteoarthritis]. AB - Introduction: Following the established and unequivocal criteriawhen choosing the treatment of knee osteoarthritis, despitepossibility of precise imaging, is still very problematic. This ispartly because doctors of different disciplines: general practitioners,orthopaedic surgeons, rheumatologists, physiotherapists,are involved in the treatment of this disease. For most ofthem the basic criteria to implement the treatment are: pain andassessment of X -ray in the supine position. As a result of that,despite slight and doubtful improvement, treatment is improperlytargeted and extended.The aim of the study was to prove that the correct diagnosis,including biomechanical characteristics of the affected limb,choice of correct treatment, and observance of indications, canshorten treatment, make it more efficient and less expensive. Material and methods: We analyzed of 103 patients qualified for total knee arthroplasty between 2006 and 2011. Theindication was primary and advanced knee osteoarthritis inphases III and IV according to Ahlbacka scale medial displacementof mechanical axis deviation in the lower limb with club--foot (I to IV degrees) and with centre of rotation of angulation(CORA) in the proximal part of the tibia. Only subjects withbody mass index under 25 were included in the study. Surveyswere used to assess the pre operative duration of illness, non-surgical methods of treatment and their effects. Final evaluation was made using the Visual Analogue Scale (10 degrees)of pain (during the effort and rest) and gait efficiency 30 daysafter completed treatment. Results: The 66.5% of patients showed no significant improvementin all assessed parameters, which would justify to continuationof the therapy as described above. PMID- 29522303 TI - [Effect of low -level laser therapy and exercise in reducing the symptoms of disease in patients with osteoarthritis of the knee]. AB - Introduction: Osteoarthritis is the most common disease ofthe joints contributing to the failure of movement. The diseasemostly affects the older part of the population, and is associatedwith suffering and reduced quality of life. Knee osteoarthritiscontributes to joint dysfunction of varying severity. These arecommon causes of chronic ailments limiting physical activity,which may even complicate the performance of activities of dailyliving. Low-level laser therapy is thought to have an analgesiceffect, as well as a biomodulatory effect on the microcirculation.The aim of this study was to evaluate the effectiveness of low- level laser therapy on pain relief and functional improvementin patients with osteoarthritis of the knee. The effects of lasertherapy alone and in combination with exercise were compared. Materials and methods: 40 patients of mean age 65 years withknee osteoarthritis of both sexes were divided into two groups.Laser alone was used in group I (n = 20) and laser combined withkinesistherapy was used in group II (n = 20). All patients receivedthe same dose of laser radiation, which was 3.0 J/cm2, 10 Hz,400 mW. In both groups a series of 10 treatments was performeddaily. VAS, ranges of motion in the knee joint, and the strengthof the quadriceps and biceps femoris muscles were used as thecriteria of pain assessment in both groups. All measurementswere taken before and after treatment. Results: Significant pain reduction: I (p = 0.00009, R = 0.68);II (p = 0.00002, R = 0.86), increased range of flexion in the knee:I (p = 0.000001, R = 0.90); II (p = 0.00002, R = 0.85), increasedrange of extension in the knee: I (p = 0.042, R = 0.87); II (p = 0.0004,R = 0.9) and increased strength of the quadriceps femoris muscle:I (p = 0.03, R = 0.77); II (p = 0.0002, R = 0.9) and the biceps femorismuscle: I (p = 0.04, R = 0.80); II (p = 0.0007, R = 0.91) were foundin both groups after treatment. With the exception of flexion ofthe knee (p = 0.027; r = 0.17), there were no statistically significantdifferences in other analysed parameters between the useof laser alone and laser therapy combined with exercise. Conclusion: The use of laser in knee osteoarthritis reducespain and improves the functional status of the patient. Lasertherapy combined with kinesistherapy produces better therapeuticeffects, and effectively improves the functional status ofknee osteoarthritis. Exercise therapy applied in a series of 10treatments is too short to significantly improve the functionalstatus of the patient. PMID- 29522304 TI - [Untreated deformities of motor system in systemic diseases - a case study]. AB - The synergy of two arthritides coexistence is very rare. In thispaper we describe a 46 -year -old patient with psoriatic and goutyarthritis. The pathologies had been developing for a dozen or soyears in the ulnar area of both upper limbs. The patient electedto undergo surgical treatment in a very advanced stage of thedisease due to increasing psychological discomfort. PMID- 29522305 TI - Protective properties of HDL cholesterol and atherosclerotic plaque calcifications in advanced atherosclerosis in ischaemic stroke patients. AB - Introduction: Atherosclerotic changes in carotid arteries play animportant role in the pathogenesis of ischaemic stroke. To a highextent there is evident asymmetry within the development ofthese changes, affecting just one artery.The aim of the study was to determine the impact of the cardiovascularrisk factors on the presence of haemodynamically significantatherosclerotic changes or occlusion only in one comparedto both of the carotid arteries in patients with ischaemic stroke. Material and methods: Patients diagnosed with ischaemicstroke were retrospectively assessed towards stenosis of >=70%or occlusion in at least one of the internal or common carotidarteries. There were 104 patients enrolled in the study. GroupI consisted of individuals with haemodynamically significant(>=70%) stenosis or occlusion in one carotid artery (n = 48).Group II consisted of patients with bilateral significant (>=70%)stenosis or occlusion in carotid arteries (n = 56). Results: There were no changes found in the presence of non- modifiable stroke risk factors between the groups. In groupI higher HDL level (45.7 vs 38.9 mg/dL, p = 0.038) and significantlymore frequent calcifications in the atherosclerotic plaquesof carotid arteries were found (p = 0.03). There were no differencesin other tested factors between groups. Conclusions: The protective properties of HDL cholesteroland the slow formation of more stable, calcified plaques playan important role only in the development of unilateral advancedatherosclerosis in carotid arteries. The role of HDL cholesterolin stroke pathomechanism needs further studies. PMID- 29522306 TI - [Complications of cardiac surgery: sternal dehiscence after median sternotomy. Analysis of 14,171 cases operated on in years 1990-2009]. AB - Introduction: Dehiscence of the sternum is one of the mostserious complications following cardiac surgery. It occurs after0.2-5% of interventions with sternotomy access.The aim of the study was the evaluation of factors that mayinfluence the frequency of this complication. Material and methods: A retrospective review of 14,171 patientsundergoing median sternotomy for cardiac surgery between 1990and 2009 at the Cardiac Surgery Department of the PomeranianMedical University in Szczecin (Poland) was performed. Thestudied group consisted of 3,999 women (28.2%) and 10,172men (71.8%) aged 11-87 years (59.8 years on average). We analysedcases with sternal dehiscence (SD), which occurred in 298(2.1%) of the patients. Results: The significant risk factors were: male sex (p = 0.0003),age (p < 0.00006), body mass (p < 0.00007), and use of bothinternal thoracic arteries (p < 0.00001). The risk of SD was alsoincreased by coexisting diabetes and chronic obstructive lungdisease (p < 0.012 and p < 0.02 respectively); however, discriminantanalysis revealed that these variables were only linkedto age. Apart from CABG, the type of surgical intervention hadno influence on the frequency of SD. The total length of hospitalstay in patients with SD was more than two times longer thanin the rest of the patients (p < 0.00001). However, there wereno significant differences in postoperative mortality betweenthese two groups - 4.4% in the group with SD and 4.2% in thegroup without it. Conclusions: Not being able to eliminate the influence of riskfactors, since 2010 we decided to introduce changes in themethod of sternum closure by increasing the number of wireloops from 6 to at least 8. For patients heavier than 80 kg, weassumed a ratio of one additional loop per every 10 kg of bodymass, which should result in improved sternum stabilisationand reduce the risk of dehiscence. PMID- 29522307 TI - Exploring the Binding Mechanism of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators in Clinical Trials by Molecular Dynamics Simulations. AB - Metabotropic glutamate receptor 5 (mGlu5) plays a key role in synaptic information storage and memory, which is a well-known target for a variety of psychiatric and neurodegenerative disorders. In recent years, the increasing efforts have been focused on the design of allosteric modulators, and the negative allosteric modulators (NAMs) are the front-runners. Recently, the architecture of the transmembrane (TM) domain of mGlu5 receptor has been determined by crystallographic experiment. However, it has been not well understood how the pharmacophores of NAMs accommodated into the allosteric binding site. In this study, molecular dynamics (MD) simulations were performed on mGlu5 receptor bound with NAMs in preclinical or clinical development to shed light on this issue. In order to identify the key residues, the binding free energies as well as per-residue contributions for NAMs binding to mGlu5 receptor were calculated. Subsequently, the in silico site-directed mutagenesis of the key residues was performed to verify the accuracy of simulation models. As a result, the shared common features of the studied 5 clinically important NAMs (mavoglurant, dipraglurant, basimglurant, STX107, and fenobam) interacting with 11 residues in allosteric site were obtained. This comprehensive study presented a better understanding of mGlu5 receptor NAMs binding mechanism, which would be further used as a useful framework to assess and discover novel lead scaffolds for NAMs. PMID- 29522308 TI - Graphdiyne Sponge for Direct Collection of Oils from Water. AB - Although several sponge-like sorbents have been developed to treat oil spills and chemical leakages, under harsh conditions (e.g., strong acid or alkali; oils on the sea) their efficiencies can be rather limited. Herein, we provide a graphdiyne sponge that is capable of collecting oil pollution effectively. This graphdiyne sponge exhibits excellent adsorption capacity (up to 160 times its own weight), robust stability (even when immersed in strong acid and alkali for 7 days), and remarkable recyclability (up to 100 times). These features suggest that this new adsorbent material might find applicability in the cleanup of oil spills and many organic pollutants under realistic conditions. PMID- 29522309 TI - Selective Gas Permeation in Graphene Oxide-Polymer Self-Assembled Multilayers. AB - The performance of polymer-based membranes for gas separation is currently limited by the Robeson limit, stating that it is impossible to have high gas permeability and high gas selectivity at the same time. We describe the production of membranes based on the ability of graphene oxide (GO) and poly(ethyleneimine) (PEI) multilayers to overcome such a limit. The PEI chains act as molecular spacers in between the GO sheets, yielding a highly reproducible, periodic multilayered structure with a constant spacing of 3.7 nm, giving a record combination of gas permeability and selectivity. The membranes feature a remarkable gas selectivity (up to 500 for He/CO2), allowing to overcome the Robeson limit. The permeability of these membranes to different gases depends exponentially on the diameter of the gas molecule, with a sieving mechanism never obtained in pure GO membranes, in which a size cutoff and a complex dependence on the chemical nature of the permeant is typically observed. The tunable permeability, the high selectivity, and the possibility to produce coatings on a wide range of polymers represent a new approach to produce gas separation membranes for large-scale applications. PMID- 29522310 TI - In Situ Exsolution of Bimetallic Rh-Ni Nanoalloys: a Highly Efficient Catalyst for CO2 Methanation. AB - Unique CO2 methanation catalysts comprising bimetallic Ni-Rh nanoalloy/3DOM LaAlO3 have been successfully prepared via a poly(methyl methacrylate) microsphere colloidal crystal-templating route, followed by the in situ growth of Ni nanoparticles (NPs). Here, we show that unlike traditional Ni particles deposited on a perovskite support, the exsolution of Ni occurs on both the external and internal surface of the porous perovskite substrate, leading to a strong metal-support interaction. Owing to the exsolution of Ni and the formation of Ni-Rh nanoalloys, a 52% enhancement in the methanation turnover frequency was obtained over the Ni-Rh/3DOM LaAlO3 [13.9 mol/(mol h)] compared to Rh/3DOM LaNi0.08Al0.92O3 [9.16 mol/(mol h)] before reduction treatment. The results show that the low-temperature reducibility, rich surface adsorbed oxygen species, and basic sites of the catalyst greatly improve its activity toward CO2 methanation. The hierarchically porous structure of the perovskite support provides a high dispersion of bimetallic Ni-Rh NPs. PMID- 29522312 TI - Rapid Assessment of Sputtered Nanoparticle Ionic Liquid Combinations. AB - A high-throughput method is presented for the efficient assessment of the formation and stability of nanoparticle suspensions in ionic liquids which differ in their cations and anions. As a proof of principle, Ag was sputtered on a cavity array filled with 9 different ionic liquids. Not all nanoparticle ionic liquid combinations form a stable suspension with separated nanoparticles. Directly after synthesis, the formation of nonagglomerated nanoparticle suspensions with sizes from 4 to 9 nm is observed by transmission electron microscopy as well as different time dependencies of the suspension stabilities. Only 3 out of the tested 9 nanoparticle ionic liquid suspensions show long-term stability: Stable suspension of spherical nanoparticles are formed in the ionic liquids 1-butyl-3-methylimidazolium bis(perfluoroethylsulfonyl)imide [Bmim][(Pf)2N], 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [Bmim][(Tf)2N], and 1-butyl-1-methylpyrrolidinum bis(trifluoromethylsulfonyl)imide [BmPyr][(Tf)2N]. PMID- 29522313 TI - Astatotilapia burtoni: A Model System for Analyzing the Neurobiology of Behavior. AB - Most biomedical research is performed using a very limited number of "model" species. In part, this has resulted from a combination of full genomes, manipulation of genes, and short generation times in these species. However, the advent of low-cost sequencing and gene editing in any organism has increased the use of nontraditional organisms. Many scientists have paraphrased the adage by Krogh [ Krogh , A. ( 2018 ) Science 70 , 200 - 204 ] that for many biological problems some species will prove to be most convenient and useful to study. In particular, using organisms most suited to the specific research question can lead to novel insights about fundamental physiological, neurobiological, immunological, and neuroendocrine systems that can advance our understanding of the well-being and health of humans. In addition, such studies have led to new ideas about the evolution and mechanisms that control social behavior. Fishes constitute about 50% of all vertebrate species and are the most diverse vertebrate radiation. Here we review behavioral and neurobiological discoveries of plasticity in social behavior resulting from analysis of an African cichlid fish, showing how its unique behavioral system has facilitated a broad range of discoveries. For many future questions, Astatotilapia burtoni and other cichlid fishes may be ideally suited to study as we advance our understanding of the neural basis of social decisions. PMID- 29522311 TI - CRISPR/Cas9 and Genome Editing for Viral Disease-Is Resistance Futile? AB - Chronic viral infections remain a major public health issue affecting millions of people worldwide. Highly active antiviral treatments have significantly improved prognosis and infection-related morbidity and mortality but have failed to eliminate persistent viral forms. Therefore, new strategies to either eradicate or control these viral reservoirs are paramount to allow patients to stop antiretroviral therapy and realize a cure. Viral genome disruption based on gene editing by programmable endonucleases is one promising curative gene therapy approach. Recent findings on RNA-guided human immunodeficiency virus 1 (HIV-1) genome cleavage by Cas9 and other gene-editing enzymes in latently infected cells have shown high levels of site-specific genome disruption and potent inhibition of virus replication. However, HIV-1 can readily develop resistance to genome editing at a single antiviral target site. Current data suggest that cellular repair associated with DNA double-strand breaks can accelerate the emergence of resistance. On the other hand, a combination antiviral target strategy can exploit the same repair mechanism to functionally cure HIV-1 infection in vitro while avoiding the development of resistance. This perspective summarizes recent findings on the biology of resistance to genome editing and discusses the significance of viral genetic diversity on the application of gene editing strategies toward cure. PMID- 29522314 TI - Fabrication of Uniform Wrinkled Silica Nanoparticles and Their Application to Abrasives in Chemical Mechanical Planarization. AB - A simple one-pot method is reported for the fabrication of uniform wrinkled silica nanoparticles (WSNs). Rapid cooling of reactants at the appropriate moment during synthesis allowed the separation of nucleation and growth stages, resulting in uniform particles. The factors affecting particle size and interwrinkle distance were also investigated. WSNs with particle sizes of 65-400 nm, interwrinkle distances of 10-33 nm, and surface areas up to 617 m2 g-1 were fabricated. Furthermore, our results demonstrate the advantages of WSNs over comparable nonporous silica nanospheres and fumed silica-based products as an abrasive material in chemical mechanical planarization processes. PMID- 29522315 TI - 7 H-Pyrrolo[2,3- d]pyrimidin-4-amine-Based Inhibitors of Calcium-Dependent Protein Kinase 1 Have Distinct Inhibitory and Oral Pharmacokinetic Characteristics Compared with 1 H-Pyrazolo[3,4- d]pyrimidin-4-amine-Based Inhibitors. AB - Selective inhibitors of Cryptosporidium calcium-dependent protein kinase 1 ( CpCDPK1) based on the 1 H-pyrazolo[3,4- d]pyrimidin-4-amine (pyrazolopyrimidine, PP) scaffold are effective in both in vitro and in vivo models of cryptosporidiosis. However, the search for distinct safety and pharmacokinetic (PK) properties has motivated our exploration of alternative scaffolds. Here, we describe a series of 7 H-pyrrolo[2,3- d]pyrimidin-4-amine (pyrrolopyrimidine, PrP)-based analogs of PP CpCDPK1 inhibitors. Most of the PrP-based inhibitors described potently inhibit the CpCDPK1 enzyme, demonstrate no toxicity against mammalian cells, and block proliferation of the C. parvum parasite in the low micromolar range. Interestingly, certain substituents that show reduced CpCDPK1 potency when displayed from a PP scaffold provided notably enhanced efficacy in the context of a PrP scaffold. PK studies on these paired compounds show that some PrP analogs have distinct physiochemical properties compared with their PP counterparts. These results demonstrate that inhibitors based on a PrP scaffold are distinct therapeutic alternatives to previously developed PP inhibitors. PMID- 29522316 TI - Computational Sensing of Staphylococcus aureus on Contact Lenses Using 3D Imaging of Curved Surfaces and Machine Learning. AB - We present a cost-effective and portable platform based on contact lenses for noninvasively detecting Staphylococcus aureus, which is part of the human ocular microbiome and resides on the cornea and conjunctiva. Using S. aureus-specific antibodies and a surface chemistry protocol that is compatible with human tears, contact lenses are designed to specifically capture S. aureus. After the bacteria capture on the lens and right before its imaging, the captured bacteria are tagged with surface-functionalized polystyrene microparticles. These microbeads provide sufficient signal-to-noise ratio for the quantification of the captured bacteria on the contact lens, without any fluorescent labels, by 3D imaging of the curved surface of each lens using only one hologram taken with a lens-free on chip microscope. After the 3D surface of the contact lens is computationally reconstructed using rotational field transformations and holographic digital focusing, a machine learning algorithm is employed to automatically count the number of beads on the lens surface, revealing the count of the captured bacteria. To demonstrate its proof-of-concept, we created a field-portable and cost-effective holographic microscope, which weighs 77 g, controlled by a laptop. Using daily contact lenses that are spiked with bacteria, we demonstrated that this computational sensing platform provides a detection limit of ~16 bacteria/MUL. This contact-lens-based wearable sensor can be broadly applicable to detect various bacteria, viruses, and analytes in tears using a cost-effective and portable computational imager that might be used even at home by consumers. PMID- 29522318 TI - Zwitterionic Polyester-Based Nanoparticles with Tunable Size, Polymer Molecular Weight, and Degradation Time. AB - Biodegradable polymer nanoparticles are an important class of materials used in several applications for their unique characteristics. In particular, the ones stabilized by zwitterionic materials are gaining increased interest in medicine as alternative to the more common ones based on poly(ethylene glycol) thanks to their superior stability and ability to avoid both the accelerated blood clearance and allergic reactions. In this work, a novel class of zwitterionic based NPs has been produced, and a method to independently control the nanoparticle size, degradation time, and polymer molecular weight has been developed and demonstrated. This has been possible by the synthesis and the fine tuning of zwitterionic amphiphilic block copolymers obtained via the combination of ring-opening polymerization and reversible addition-fragmentation chain transfer polymerization. The final results showed that when two block copolymers contain the same number of caprolactone units, the one with longer oligoester lateral chains degrades faster. This phenomenon is in sharp contrast with the one seen so far for the common linear polyester systems where longer chains result in longer degradation times, and it can be used to better tailor the degradation behavior of the nanoparticles. PMID- 29522317 TI - 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization. AB - Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors. PMID- 29522319 TI - Carbon Dioxide Dimer Radical Anion as Surface Intermediate of Photoinduced CO2 Reduction at Aqueous Cu and CdSe Nanoparticle Catalysts by Rapid-Scan FT-IR Spectroscopy. AB - Monitoring of visible light sensitized reduction of CO2 at Cu nanoparticles in aqueous solution by rapid-scan ATR FT-IR spectroscopy on the time scale of seconds allowed structural identification of a one-electron intermediate and demonstrated its kinetic relevancy for the first time. Isotopic labeling (12C: 1632, 1358, 1346 cm-1; 13C: 1588, 1326, 1316 cm-1) revealed a species of carbon dioxide dimer radical anion structure, most likely bound to the catalyst surface through carbon. Intermediacy of Cu-C(?O)OCO2- surface species is in agreement with a recently proposed mechanism for electrocatalytic CO2 reduction at Cu metal nanoparticles based on Tafel slope analysis. Spontaneous decrease of the intermediate after termination of the photosensitization pulse (Sn porphyrin excited at 405 nm) was accompanied by the growth of HCO3-. CO was produced as well, but sensitive detection required photolysis for tens of minutes. A direct kinetic link between a C2O4- surface intermediate and the CO product was also demonstrated for photocatalyzed CO2 reduction at aqueous CdSe nanoparticles, where first order growth of a Cd-C(?O)OCO2- species was accompanied by rise of CO (monitored by a fast Ni complex trap) and HCO3- showing a distinct induction period. The detection of the one-electron surface intermediate and confirmation of its catalytic relevancy was enabled by the delivery of electrons one-by-one by the photosensitization method. The observation of carbon dioxide dimer radical anion points to approaches for rate enhancements of heterogeneous CO2 reduction by creating catalytic environments that favor formation of this intermediate. PMID- 29522320 TI - Solubility of Softwood Hemicelluloses. AB - It is demonstrated that the molecular solubility of softwood hemicelluloses is significantly influenced by pretreatment of the fibers, extraction, and downstream processing. To quantify these effects, four hemicellulose samples were extracted from different thermomechanical pulps of Norway spruce. The molecular solubility of the samples was characterized by size and molar mass distributions, and the morphology of the molecules was studied using high resolution microscopy techniques. All extracted samples were well dispersed in aqueous media creating transparent dispersions, but dynamic light scattering measurements showed that molecular solubility can only be achieved using specific pretreatments and extractions. The procedure yields acetylated galactoglucomannan (AcGGM)-rich hemicelluloses with an average molar mass of 21-35 kDa and a diameter up to 10 nm but also shows that water is a poor solvent for this sample since an association is detected as soon as the concentration is about 20 g/L. These associated hemicellulose dispersions are still absolutely clear on visual inspection, underlining the need for careful measurement when assessing the solubility of wood hemicelluloses. PMID- 29522321 TI - Transport and Retention of Concentrated Oil-in-Water Emulsions in Porous Media. AB - Oil-in-water emulsions are routinely used in subsurface remediation. In these applications, high oil loadings present a challenge to remedial design as mechanistic insights into transport and retention of concentrated emulsions is limited. Column experiments were designed to examine emulsion transport and retention over a range of input concentrations (1.3-23% wt). Droplet breakthrough and retention data from low concentration experiments were successfully described by existing particle transport models. These models, however, failed to capture droplet transport in more concentrated systems. At high oil fraction, breakthrough curves exhibited an early fall at the end of the emulsion pulse and extending tailing. Irrespective of input concentration, all retention profiles displayed hyper-exponential behavior. Here, we extended existing model formulations to include the additional mixing processes occurring when at high oil concentrations-with focus on the influence of deposited mass and viscous instabilities. The resulting model was parametrized with low concentration data and can successfully predict concentrated emulsion transport and retention. The role of retained mass and viscous instabilities on mixing conditions can also be applied more broadly to systems with temporal or spatially variant water saturation or when viscosity contrasts exist between fluids. PMID- 29522322 TI - In Situ Visualization of Assembly and Photonic Signal Processing in a Triplet Light-Harvesting Nanosystem. AB - Real-time visualization of assembly processes and sophisticated signal processing at the nanoscale are two challenging topics in photonic nanomaterials. Here, high quality light-harvesting crystalline nanorods were developed by the coassembly of two polypyridyl Ir(III) and Ru(II) metallophosphors, behaving as the antenna chromophore and energy acceptor, respectively. By using a one-pot or stepwise growth condition, homogeneous and multiblock heterojunction nanorods were prepared, respectively. These nanostructures display multicolor phosphorescence from green to red due to the efficient triplet energy transfer and light harvesting capability at low acceptor doping ratios. Heterojunction nanorods show gradient emission-color switches during different growth stages, in which the real-time stepwise assembly can be vividly visualized using fluorescence microscopy techniques. Triplet excitons were successfully manipulated in both homogeneous and heterojunction nanorods to realize waveguided green, orange, and red emissions and advanced photonic signal logics and encoding/decoding on single multiblock heterojunction nanorod. PMID- 29522323 TI - Seasonally Relevant Cool Temperatures Interact with N Chemistry to Increase Microcystins Produced in Lab Cultures of Microcystis aeruginosa NIES-843. AB - Freshwater cyanobacterial blooms are regularly formed by Microcystis spp., which are well-known producers of the hepatotoxin microcystin. The environmental factors that regulate microcystin synthesis remain unclear. We used reverse transcription-quantitative PCR (RT-qPCR), metabolomics, and toxin profiling (both by LC-MS) to measure the response of Microcystis aeruginosa NIES-843 to nitrogen (N) concentration, N chemistry (nitrate versus urea), and a range of seasonally relevant temperatures. Growth rates at lower temperatures were slower but resulted in increased cellular microcystin content (quota), and at these lower temperatures, N concentration had no effect on toxin production. In contrast, at warmer temperatures, reduction in N concentration increased toxin production, especially when urea was supplied as the nitrogen source. Our culture results demonstrate how temperature may lead to physiological responses ranging from slow growing yet very toxic cells at cool temperatures, to faster growing but less toxic cells at warmer temperatures. This response represents a key interaction in bloom dynamics. Capturing this phenomenon as a temperature-driven toxin phenotype incorporated into models might improve the ability to predict microcystin biosynthesis during cyanobacterial blooms. PMID- 29522324 TI - Exploiting Molecular Weight Distribution Shape to Tune Domain Spacing in Block Copolymer Thin Films. AB - We report a method for tuning the domain spacing ( Dsp) of self-assembled block copolymer thin films of poly(styrene- block-methyl methacrylate) (PS- b-PMMA) over a large range of lamellar periods. By modifying the molecular weight distribution (MWD) shape (including both the breadth and skew) of the PS block via temporal control of polymer chain initiation in anionic polymerization, we observe increases of up to 41% in Dsp for polymers with the same overall molecular weight ( Mn ~ 125 kg mol-1) without significantly changing the overall morphology or chemical composition of the final material. In conjunction with our experimental efforts, we have utilized concepts from population statistics and least-squares analysis to develop a model for predicting Dsp based on the first three moments of the MWDs. This statistical model reproduces experimental Dsp values with high fidelity (with mean absolute errors of 1.2 nm or 1.8%) and provides novel physical insight into the individual and collective roles played by the MWD moments in determining this property of interest. This work demonstrates that both MWD breadth and skew have a profound influence over Dsp, thereby providing an experimental and conceptual platform for exploiting MWD shape as a simple and modular handle for fine-tuning Dsp in block copolymer thin films. PMID- 29522325 TI - A Rational Design of Highly Controlled Suzuki-Miyaura Catalyst-Transfer Polycondensation for Precision Synthesis of Polythiophenes and Their Block Copolymers: Marriage of Palladacycle Precatalysts with MIDA-Boronates. AB - Herein, we report a highly efficient Suzuki-Miyaura catalyst-transfer polycondensation (SCTP) of 3-alkylthiophenes using bench-stable but highly active Buchwald dialkylbiarylphospine Pd G3 precatalysts and N-methylimidodiacetic (MIDA)-boronate monomers. Initially, the feasibility of the catalyst-transfer process was examined by screening various dialkylbiarylphospine-Pd(0) species. After optimizing a small molecule model reaction, we identified both RuPhos and SPhos Pd G3 precatalysts as excellent catalyst systems for this purpose. On the basis of these model studies, SCTP was tested using either RuPhos or SPhos Pd G3 precatalyst, and 5-bromo-4- n-hexylthien-2-yl-pinacol-boronate. Poly(3 hexylthiophene) (P3HT) was produced with controlled molecular weight and narrow dispersity for a low degree of polymerization (DP) only, while attempts to synthesize P3HT having a higher DP with good control were unsuccessful. To improve the control, slowly hydrolyzed 5-bromo-4- n-hexylthien-2-yl-MIDA-boronate was introduced as a new monomer. As a result, P3HT and P3EHT (up to 17.6 kg/mol) were prepared with excellent control, narrow dispersity, and excellent yield (>90%). Detailed mechanistic investigation using 31P NMR and MALDI-TOF spectroscopy revealed that both fast initiation using Buchwald precatalysts and the suppression of protodeboronation due to the protected MIDA-boronate were crucial to achieve successful living polymerization of P3HT. In addition, a block copolymer of P3HT- b-P3EHT was prepared via SCTP by sequential addition of each MIDA-boronate monomer. Furthermore, the same block copolymer was synthesized by one-shot copolymerization for the first time by using fast propagating pinacol boronate and slow propagating MIDA-boronate. PMID- 29522326 TI - Molecular Basis for the Attachment of S-Layer Proteins to the Cell Wall of Bacillus anthracis. AB - Bacterial surface (S) layers are paracrystalline arrays of protein assembled on the bacterial cell wall that serve as protective barriers and scaffolds for housekeeping enzymes and virulence factors. The attachment of S-layer proteins to the cell walls of the Bacillus cereus sensu lato, which includes the pathogen Bacillus anthracis, occurs through noncovalent interactions between their S-layer homology domains and secondary cell wall polysaccharides. To promote these interactions, it is presumed that the terminal N-acetylmannosamine (ManNAc) residues of the secondary cell wall polysaccharides must be ketal-pyruvylated. For a few specific S-layer proteins, the O-acetylation of the penultimate N acetylglucosamine (GlcNAc) is also required. Herein, we present the X-ray crystal structure of the SLH domain of the major surface array protein Sap from B. anthracis in complex with 4,6- O-ketal-pyruvyl-beta-ManNAc-(1,4)-beta-GlcNAc (1,6)-alpha-GlcN. This structure reveals for the first time that the conserved terminal SCWP unit is the direct ligand for the SLH domain. Furthermore, we identify key binding interactions that account for the requirement of 4,6- O ketal-pyruvyl-ManNAc while revealing the insignificance of the O-acetylation on the GlcNAc residue for recognition by Sap. PMID- 29522327 TI - Gas-Phase Reactions of Isoprene and Its Major Oxidation Products. AB - Isoprene carries approximately half of the flux of non-methane volatile organic carbon emitted to the atmosphere by the biosphere. Accurate representation of its oxidation rate and products is essential for quantifying its influence on the abundance of the hydroxyl radical (OH), nitrogen oxide free radicals (NO x), ozone (O3), and, via the formation of highly oxygenated compounds, aerosol. We present a review of recent laboratory and theoretical studies of the oxidation pathways of isoprene initiated by addition of OH, O3, the nitrate radical (NO3), and the chlorine atom. From this review, a recommendation for a nearly complete gas-phase oxidation mechanism of isoprene and its major products is developed. The mechanism is compiled with the aims of providing an accurate representation of the flow of carbon while allowing quantification of the impact of isoprene emissions on HO x and NO x free radical concentrations and of the yields of products known to be involved in condensed-phase processes. Finally, a simplified (reduced) mechanism is developed for use in chemical transport models that retains the essential chemistry required to accurately simulate isoprene oxidation under conditions where it occurs in the atmosphere-above forested regions remote from large NO x emissions. PMID- 29522328 TI - Modification of Lipase with Poly(4-acryloylmorpholine) Enhances Solubility and Transesterification Activity in Anhydrous Ionic Liquids. AB - Tuning the molecular interaction between enzymes and their solvent environment through polymer modification can greatly improve activity and thus utility in biocatalytic reactions. In this work, this approach was exploited to enhance the activity of lipase A (LipA) from Bacillus subtilis in anhydrous ionic liquids (ILs), which are highly attractive solvents for biocatalysis. Specifically, we showed that the transesterification activity of LipA in anhydrous 1-butyl-3 methyl imidazolium hexafluorophosphate ([BMIM][PF6]) was improved up to 19-fold via covalently conjugating the enzyme with the IL-soluble polymer poly(4 acryloylmorpholine) (PAcMO). The increase in transesterification activity correlated with an increase in LipA solubility in [BMIM][PF6] as well as, notably, the number of conjugated PAcMO repeat units. Light scattering results further showed that the attachment of PAcMO disrupted the aggregation of LipA in aqueous buffer, which was used as a proxy to understand the mechanism of activation of LipA in the IL, where aggregation was more pronounced. Additionally, using static light scattering, the Flory-Huggins interaction parameter (chi) for the polymer-IL interactions was determined (0.457). The favorable PAcMO-IL interactions presumably compensated for the unfavorable interactions between the enzyme and IL, which resulted in the improvement in dissolution and, in turn, activity due to reduced diffusional limitations. Through rationally considering chi, a similar approach may be used to tune the molecular interaction between other enzymes and ILs with other polymers, which has widespread implications for the enhancement of biocatalysis in ILs. PMID- 29522329 TI - Proton and Copper Binding to Humic Acids Analyzed by XAFS Spectroscopy and Isothermal Titration Calorimetry. AB - Proton and copper (Cu) binding to soil and lignite-based humic acid (HA) was investigated by combining X-ray absorption fine structure (XAFS) spectroscopy, isothermal titration calorimetry (ITC), and nonideal-competitive-adsorption (NICA) modeling. NICA model calculations and XAFS results showed that bidentate and monodentate complexation occurred for Cu binding to HA. The site-type specific thermodynamic parameters obtained by combining ITC measurements and NICA calculations revealed that copper binding to deprotonated carboxylic-type sites was entropically driven and that to deprotonated phenolic-type sites was driven by entropy and enthalpy. Copper binding to HA largely depended on the site-type and coordination environment, but the thermodynamic binding mechanisms for Cu binding to the specific site-types were similar for the different HAs studied. By comparing the site-type-specific thermodynamic parameters of HA-Cu complexation with those of low molar mass organic acids, the Cu coordination could be further specified. Bidentate carboxylic-Cu complexes made the dominating contributions to Cu binding to HA. The present study not only yields molecular-scale mechanisms of ion binding to carboxylic- and phenolic-type sites of HA but also provides the new insight that the universal nature of site-type-specific thermodynamic data enables quantitative estimation of the binding structures of heavy metal ions to humic substances. PMID- 29522332 TI - Detection of Hydrocarbons by Laser Assisted Paper Spray Ionization Mass Spectrometry (LAPSI MS). AB - Here we introduce a new ambient ionization technique named laser assisted paper spray ionization mass spectrometry (LAPSI MS). In it, a 532 +/- 10 nm, <=10 mW laser pointer was shone on a triangularly cut paper along with high voltage, to effect ionization. The analyte solution was continuously pushed through a fused silica capillary, using a syringe pump, at a preferred infusion rate. LAPSI MS promises enhanced ionization with high signal intensity of polycyclic aromatic hydrocarbons (PAHs), which are normally not ionizable with similar ionization methods involving solvent sprays. LAPSI MS works both in positive and negative modes of ionization. A clear enhancement of signal intensity was visualized in the total ion chronogram for most analytes in the presence of the laser. We speculate that the mechanism of ionization is field assisted photoionization. The field-induced distortion of the potential well can be large in paper spray as the fibers comprising the paper are separated at tens of nanometers apart, and consequently, the analyte molecules are subjected to very large electric fields of the order of 107 Vcm-1. Ionization occurs from their distorted electronic states of reduced ionization energy, using the laser. Negative ion detection is also demonstrated, occurring due to the capture of produced photoelectrons. LAPSI MS can be used for monitoring in situ photoassisted reactions like the decarboxylation of mercaptobenzoic acid in the presence of gold and silver nanoparticles and the dehydrogenation reaction of 2,3-dihydro-1 H-isoindole, which were chosen as examples. As an application, we have shown that paraffin oil, which is usually nonionizable by paper spray or by electrospray ionization can be efficiently detected using this technique. Impurities like mineral oils were detected easily in commercially available coconut oil, pointing the way to applications of social relevance. PMID- 29522331 TI - Accurate, Sensitive, and Precise Multiplexed Proteomics Using the Complement Reporter Ion Cluster. AB - Quantitative analysis of proteomes across multiple time points, organelles, and perturbations is essential for understanding both fundamental biology and disease states. The development of isobaric tags (e.g., TMT) has enabled the simultaneous measurement of peptide abundances across several different conditions. These multiplexed approaches are promising in principle because of advantages in throughput and measurement quality. However, in practice, existing multiplexing approaches suffer from key limitations. In its simple implementation (TMT-MS2), measurements are distorted by chemical noise leading to poor measurement accuracy. The current state-of-the-art (TMT-MS3) addresses this but requires specialized quadrupole-iontrap-Orbitrap instrumentation. The complement reporter ion approach (TMTc) produces high accuracy measurements and is compatible with many more instruments, like quadrupole-Orbitraps. However, the required deconvolution of the TMTc cluster leads to poor measurement precision. Here, we introduce TMTc+, which adds the modeling of the MS2-isolation step into the deconvolution algorithm. The resulting measurements are comparable in precision to TMT-MS3/MS2. The improved duty cycle and lower filtering requirements make TMTc+ more sensitive than TMT-MS3 and comparable with TMT-MS2. At the same time, unlike TMT-MS2, TMTc+ is exquisitely able to distinguish signal from chemical noise even outperforming TMT-MS3. Lastly, we compare TMTc+ to quantitative label free proteomics of total HeLa lysate and find that TMTc+ quantifies 7.8k versus 3.9k proteins in a 5-plex sample. At the same time, the median coefficient of variation improves from 13% to 4%. Thus, TMTc+ advances quantitative proteomics by enabling accurate, sensitive, and precise multiplexed experiments on more commonly used instruments. PMID- 29522330 TI - A General Strategy for Aliphatic C-H Functionalization Enabled by Organic Photoredox Catalysis. AB - Synthetic transformations that functionalize unactivated aliphatic C-H bonds in an intermolecular fashion offer unique strategies for the synthesis and late stage derivatization of complex molecules. Herein we report a general approach to the intermolecular functionalization of aliphatic C-H bonds using an acridinium photoredox catalyst and phosphate salt under blue LED irradiation. This strategy encompasses a range of valuable C-H transformations, including the direct conversions of a C-H bond to C-N, C-F, C-Br, C-Cl, C-S, and C-C bonds, in all cases using the alkane substrate as the limiting reagent. Detailed mechanistic studies are consistent with the intermediacy of a putative oxygen-centered radical as the hydrogen atom-abstracting species in these processes. PMID- 29522333 TI - Exploring the Potential of Data-Independent Acquisition Proteomics Using Untargeted All-Ion Quantitation: Application to Tumor Subtype Diagnosis. AB - Maximizing the recovery of meaningful biological information can facilitate proteomics-guided early detection and precise treatment of diseases. However, the conventional protein and peptide level targeted quantification of untargeted data independent acquisition (DIA) such as sequential window acquisition of all theoretical spectra (SWATH) is not necessarily descriptive of all information. Untargeted all-ion quantification theoretically could retrieve more features in SWATH digital maps by circumventing the initial identification process but is intrinsically susceptible to errors because of the extreme complexity of proteome samples and the poor selectivity of a single ion. In this study, we optimized and applied the untargeted all-ion quantification of SWATH data to differentiate tumor subtypes. Large peptides and low abundant peptides benefited more from untargeted all-ion quantification. Top-ranked significant ions were linked to their corresponding ion envelops, where multiple correlated ions were used for measurement and only ion envelopes containing at least three ions with consistent intensity ratio were kept as refined differentiating features. Multivariate statistical analysis revealed that for the tested data set, the refined markers discovered by untargeted SWATH analysis showed comparable diagnostic power to protein and peptide markers. Limitations and benefits of the approach are further discussed. PMID- 29522334 TI - Radioligand Recognition of Insecticide Targets. AB - Insecticide radioligands allow the direct recognition and analysis of the targets and mechanisms of toxic action critical to effective and safe pest control. These radioligands are either the insecticides themselves or analogs that bind at the same or coupled sites. Preferred radioligands and their targets, often in both insects and mammals, are trioxabicyclooctanes for the gamma-aminobutyric acid (GABA) receptor, avermectin for the glutamate receptor, imidacloprid for the nicotinic receptor, ryanodine and chlorantraniliprole for the ryanodine receptor, and rotenone or pyridaben for NADH+ ubiquinone oxidoreductase. Pyrethroids and other Na+ channel modulator insecticides are generally poor radioligands due to lipophilicity and high nonspecific binding. For target site validation, the structure-activity relationships competing with the radioligand in the binding assays should be the same as that for insecticidal activity or toxicity except for rapidly detoxified or proinsecticide analogs. Once the radioligand assay is validated for relevance, it will often help define target site modifications on selection of resistant pest strains, selectivity between insects and mammals, and interaction with antidotes and other chemicals at modulator sites. Binding assays also serve for receptor isolation and photoaffinity labeling to characterize the interactions involved. PMID- 29522335 TI - Can Urea Be a Seed for Aerosol Particle Formation in Air? AB - Urea is ubiquitous in rainwaters and aqueous aerosols in different environments. However, its atmospheric fate and the exact mechanism on how it influences new particle formation remain completely unexplored. Herein, we have used quantum chemical calculations and Born-Oppenheimer molecular dynamics simulations to explore the potential role of urea in the particle formation events. The results suggest that urea binds more strongly to common acidic precursors than ammonia or monoamines and is capable of binding at most two molecules of an acidic precursor or hydroperoxyl radical via hydrogen bonding interactions. The molecular dynamics simulations suggest that the complex of urea with an acidic precursor or hydroperoxyl radical on the water droplet is stabilized by intermolecular and interfacial hydrogen bonding interactions over the simulation time scale of 10-15 ps. An important implication of these results is that urea may contribute toward the particle formation in marine environments as well as in Asia where the usage of urea for the agricultural activities has increased dramatically over last few decades. Though there is at the moment no evidence of urea being present in the atmospheric gas-phase, we hope our work would inspire field measurements for detecting urea in the gas-phase. PMID- 29522336 TI - Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners. AB - (+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3'-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of beta-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand-target interaction. It was recently demonstrated, however, that the C-3'-phenyl side chain occupied a different space, instead extending toward the M-loop of beta-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+) discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMax increased without concomitant improvements in EC50 such that overall dose-response profiles resembled that of (+)-discodermolide. PMID- 29522337 TI - Overcoming the Failure of Correlation for Out-of-Plane Motions in a Simple Aromatic: Rovibrational Quantum Chemical Analysis of c-C3H2. AB - Truncated, correlated, wave function methods either produce imaginary frequencies (in the extreme case) or nonphysically low frequencies in out-of-plane motions for carbon and adjacent atoms when the carbon atoms engage in pi bonding. Cyclopropenylidene is viewed as the simplest aromatic hydrocarbon, and the present as well as previous theoretical studies have shown that this simple molecule exhibits this behavior in the two out-of-plane bends (OPBs). This nonphysical behavior has been treated by removing nearly linear dependent basis functions according to eigenvalues of the overlap matrix, by employing basis sets where the spd space saturatation is balanced with higher angular momentum functions, by including basis set superposition/incompleteness error (BSSE/BSIE) corrections, or by combining standard correlation methods with explicitly correlated methods to produce hybrid potential surfaces. However, this work supports the recently described hypothesis that the OPB problem is both a method and a basis set effect. The correlated wave function's largest higher-order substitution term comes from a pi -> pi* excitation where constructive interference of both orbitals artificially stabilizes the OPB. By employing schema to overcome this issue, the symmetric OPB nu9 is the predicted to be the second-brightest transition, and it will be observed very close to 775 cm-1. However, more work from the community is required to formulate better how carbon atoms interact with their adjacent atoms in pi-bonded systems. Such bonds are ubiquitous in all of chemistry and beyond. PMID- 29522339 TI - Photochromism of 2-(2-Hydroxyphenyl) Benzothiazole (HBT) and Its Derivatives: A Theoretical Study. AB - Hydroxyphenyl benzothiazole (HBT), is a well-known organic system based on its special characteristic of the excited state hydrogen transfer (ESHT) following photoexcitation. However, the capability of this system regarding photochromism and photoswitching has not been addressed yet. In this study, we have investigated this issue by the aim of the MP2, CC2, ADC(2), and CASSCF theoretical methods. Also, we have considered several electron withdrawing groups and investigated their effects on the photophysical characteristics and spectroscopic properties of the enol and keto tautomers of the titled system. It has been predicted that the main HBT and its considered substitutions fulfill the essential characteristics required for photochromism. Also, substitution is an effective idea for tuning the photophysical nature of HBT and its similar systems. Our theoretical results verify that different substitutions alter the UV absorption of HBT systems from 330 to 351 nm and also the corresponding absorption wavelength of the gamma-forms of 526-545 nm. PMID- 29522338 TI - Comparative Transcriptome Analysis Revealing the Effect of Light on Anthocyanin Biosynthesis in Purple Grains of Wheat. AB - To study the mechanism of anthocyanin-biosynthesis regulation, we examined light regulated gene expression involved in anthocyanin biosynthesis in purple grains of wheat. Ten kinds of anthocyanins were identified from a purple-grained wheat cultivar by HPLC-ESI-MS/MS analysis. Libraries constructed from the total RNA of purple grains under light (L) or dark (D) conditions for 15 or 20 days were sequenced. In total, 1874 differentially expressed genes (DEGs) were identified in L20 vs L15, 1432 DEGs were identified in D20 vs D15, 862 DEGs were identified in D15 vs L15, and 1786 DEGs were identified in D20 vs L20. DEG functional enrichments suggested that light-signal transduction is critical to anthocyanin biosynthesis. The 911 DEGs referred to as light-regulated DEGs (LDEGs) involved a number of genes in anthocyanin biosynthesis, transcription regulation, sugar- and calcium-signaling pathways, and hormone metabolism. These findings laid the foundation for future studies on the regulatory mechanisms of anthocyanin biosynthesis in purple grains of wheat. PMID- 29522340 TI - A Benchmark Study of Electronic Couplings in Donor-Bridge-Acceptor Systems with the FMR-B Method. AB - We present a benchmarking study for the evaluation of electronic couplings in donor-bridge-acceptor systems with the Fock matrix reconstruction-bridge (FMR-B) method. We compile a data set for the benchmark that contains 29 molecules for which reliable experimental coupling values are available: DBA29. This data set is general and includes different types of donor, acceptor, and bridge units as well as different bridge lengths, and it spans a range of couplings from 0.1 to 0.8 eV. We use DBA29 to test FMR-B with 11 density functionals belonging to different classes (pure, global hybrid, and range-separated) and the Hartree-Fock (HF) method. We also test a subset of these methods with nine basis sets from the Pople and Dunning families, which include a varying number of polarization and diffuse functions. We find that the best accuracy and lowest computational cost is obtained with range-separated functionals and compact basis sets. Global hybrids with a large amount of HF exchange also work well because of error cancellation between the approximate exchange-correlation kernel and the HF part. Pure functionals, although less accurate, still provide reasonable results with a consistent underestimation of the experimental values, and they can be used for larger and more computationally demanding systems. PMID- 29522341 TI - White Light Induced E/Z-Photoisomerization of Diphenylamine-Tethered Fluorescent Stilbene Derivatives: Synthesis, Photophysical, and Electrochemical Investigation. AB - A facile synthesis and detailed photophysical investigation of E/Z-isomerization of fluorescent diphenylamine tethered stilbene derivatives (DPASs) under white light exposure have been carried out to understand the effect on fluorescence, electrochemical properties, and photostability under various activation/deactivation pathways. In solution state, in the dark, the E-isomer of DPASs (6a-d) exhibited high fluorescence quantum yields (Phifl ~ 53% to 60% in DMSO). However, on white light exposure, 1H NMR and HPLC studies revealed that pure E-isomer of the DPAS 6a (~9.5 mM) started converting into its Z-form by photoisomerization until it reaches to nearly equilibrium. At low concentrations (~10 MUM), the absorption band of the pure E-isomer in the range of 350-450 nm gradually decreased to adopt Z-conformation 6a' until a photostationary state was reached. The structure of the E-isomer 6a was unequivocally confirmed by X-ray diffraction analysis. The synthesized DPAS compounds 6a-d possessed positive solvatochromic properties, two photon absorption properties, and good thermal stability. The electrochemical investigations using DPASs showed reversible oxidation resulting in formation of a stable radical cation. Owing to useful photophysical, electrochemical and thermal properties, these DPAS derivatives are suitable for their application in biomedical imaging as well as in fabrication of electroluminescent materials. PMID- 29522342 TI - Pd-Catalyzed Divergent C(sp2)-H Activation/Cycloimidoylation of 2-Isocyano-2,3 diarylpropanoates. AB - A Pd-catalyzed site-selective C(sp2)-H activation/cycloimidoylation of 2-isocyano 2,3-diarylpropanoates to construct diverse cyclic imine products has been developed. Six-membered 3,4-dihydroisoquinolines containing a C3 quaternary carbon center were generated dominantly by using bulky Ad2P n-Bu as a ligand, while five-membered 1,1-disubstituted 1 H-isoindoles were formed preferentially in the presence of bidentate phosphine ligand DPPB. The selectivity for 1 H isoindole formation was enhanced by using steric hindered aryl iodides. DFT calculations suggested that the experimentally observed ligand-controlled selectivity was a result of trans effect. PMID- 29522343 TI - Dye-Sensitized Downconversion. AB - Splitting one high-energy photon into two lower energy photons through downconversion has been demonstrated for a variety of combinations of rare earth (RE) ions. However, the low absorption cross section of RE3+ 4f-4f transitions hampers practical application. Therefore, enhancing the absorption by sensitization is crucial. We demonstrate efficient dye-sensitized downconversion using a strong blue/UV absorbing Coumarin dye to sensitize downconversion of the Pr3+-Yb3+ couple in NaYF4 nanocrystals (NCs). Luminescence spectra and lifetime measurements reveal Forster resonant energy transfer (FRET) from Coumarin to Pr3+ in NaYF4:Pr3+Yb3+ NCs, followed by downconversion, resulting in Yb3+ IR emission with ~30 times enhancement. The present study demonstrates the feasibility of dye sensitized downconversion as a promising strategy to engineer strongly absorbing downconversion NCs to enhance the efficiency of photovoltaic cells. PMID- 29522344 TI - Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media. AB - The accuracy of amorphous solubility advantage calculation was evaluated by experimental solubility measurement. Ten structurally diverse compounds were studied to test the generlity of the theoretical calculation. Three reported methods of calculating Gibbs free energy difference between amorphous and crystalline solids were evaluated. Experimental solubility advantage was measured by direct dissolution of amorphous solid in buffer. When necessary, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was predissolved in buffer to inhibit desupersaturation. By direct dissolution, the effect of different preparation methods on amorphous solubility was also studied. Finally, solubility measurement was performed in fasted state simulated intestinal fluid (FaSSIF) to assess the effect of bile salt on the concentration-based amorphous solubility advantage. The results showed that the assumption of constant heat capacity differences between crystal and supercooled liquid or amorphous solid is sufficient for accurate theoretical calculation, which is attributed to the fact that the heat capacity of crystal is nearly parallel to that of supercooled liquid or amorphous solid. Different preparation methods do not have significant impact on amorphous solubility advantage. Experimental measurement agrees with the theoretical calculation within a factor of 0.7 to 1.8. The concentration-based amorphous solubility advantage in FaSSIF agrees well with theoretical calculation. This work demonstrates that theoretical calculation of amorphous solubility advantage is robust and can be applied in early drug development for assessing the utility of the amorphous phase. PMID- 29522345 TI - Base-Mediated Fragmentation of Bicyclic Dihydro-3,6-oxazines: Transformation of Nitroso Diels-Alder Cycloadducts. AB - Nitroso Diels-Alder cycloadditions of benzene oxide with various acyl-nitroso derivatives are described. Treatment of these cycloadducts with methyllithium results in a fast fragmentation reaction, leading to highly functionalized cyclic amino alcohols. The mechanism of the reaction and the role of the epoxide in the fragmentation process are investigated. The reaction proceeds via the formation of an unsaturated imine, which tautomerizes to an enamine if no neighboring epoxide is present. PMID- 29522346 TI - Direct Dehydrogenative Arylation of Benzaldehydes with Arenes Using Transient Directing Groups. AB - The utilization of the transient directing strategy into the direct oxidative dehydrogenative arylation of aldehydes with arenes was reported for the first time. Featured by mild reaction conditions, good functional group compatibility, and great regioselectivity, the method should find broad applications in new medicine and material development and discovery processes. PMID- 29522347 TI - In Vitro, in Silico, and in Vivo Assessments of Intestinal Precipitation and Its Impact on Bioavailability of a BCS Class 2 Basic Compound. AB - In this study, a multipronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound A, a BCS class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets. The in vitro precipitate was found to be noncrystalline with higher solubility than the crystalline API, and was readily soluble when the drug concentration was lowered by dilution. A gastric transit and biphasic dissolution (GTBD) model was developed to better mimic gastric transfer and intestinal absorption. Precipitation was also observed in GTBD, but the precipitate redissolved and partitioned into the organic phase. In vivo data from the phase 1 clinical trial showed linear and dose proportional PK for the formulations with no evidence of in vivo precipitation. While the in vitro precipitation observed in the 2-stage dissolution appeared to overestimate in vivo precipitation, the GTBD model provided absorption profiles consistent with in vivo data. In silico simulation of plasma concentrations by GastroPlus using biorelevant in vitro dissolution data from the tablets and capsules and assuming negligible precipitation was in line with the observed in vivo profiles of the two formulations. The totality of data generated with Compound-A indicated that the bioavailability differences among the three formulations were better explained by the differences in gastric dissolution than intestinal precipitation. The lack of intestinal precipitation was consistent with several other BCS class 2 basic compounds in the literature for which highly supersaturated concentrations and rapid absorption were also observed. PMID- 29522348 TI - Synthesis of Hydrazines via Radical Generation and Addition of Azocarboxylic tert Butyl Esters. AB - A new chemistry of azo compounds that is a radical generation and addition in situ of azocarboxylic tert-butyl esters to synthesize hydrazines has been described. The protocol provides a novel strategy for the synthesis of various hydrazines. The advantages of the transformation include broad substrate scope, benign conditions, and convenient operation. PMID- 29522349 TI - Regioselective Oxidative Ring Cleavage of a Phlorin Analogue: An Approach for Synthesizing Linear Tetrapyrroles. AB - Oxidation of neo-N-confused phlorin 1 with excessive FeCl3 leads to regioselective ring opening, generating three linear tetrapyrroles, i.e., (10 Z,15 Z)-biladienone 2, (10 Z,15 E)-biladienone 3, and 19-methoxy (10 Z,15 E) biladiene 4 with an overall yield of 88%. The coordination of these compounds with Zn(II) is affected by the inverted terminal pyrrolic unit, and the presence of the electron-withdrawing keto moiety. The structural identities were also clearly elucidated by the crystal structures of 3 and 4-Zn and were rationalized by DFT calculations. PMID- 29522350 TI - Hot Hole Collection and Photoelectrochemical CO2 Reduction with Plasmonic Au/p GaN Photocathodes. AB - Harvesting nonequilibrium hot carriers from plasmonic-metal nanostructures offers unique opportunities for driving photochemical reactions at the nanoscale. Despite numerous examples of hot electron-driven processes, the realization of plasmonic systems capable of harvesting hot holes from metal nanostructures has eluded the nascent field of plasmonic photocatalysis. Here, we fabricate gold/p type gallium nitride (Au/p-GaN) Schottky junctions tailored for photoelectrochemical studies of plasmon-induced hot-hole capture and conversion. Despite the presence of an interfacial Schottky barrier to hot-hole injection of more than 1 eV across the Au/p-GaN heterojunction, plasmonic Au/p-GaN photocathodes exhibit photoelectrochemical properties consistent with the injection of hot holes from Au nanoparticles into p-GaN upon plasmon excitation. The photocurrent action spectrum of the plasmonic photocathodes faithfully follows the surface plasmon resonance absorption spectrum of the Au nanoparticles and open-circuit voltage studies demonstrate a sustained photovoltage during plasmon excitation. Comparison with Ohmic Au/p-NiO heterojunctions confirms that the vast majority of hot holes generated via interband transitions in Au are sufficiently hot to inject above the 1.1 eV interfacial Schottky barrier at the Au/p-GaN heterojunction. We further investigated plasmon-driven photoelectrochemical CO2 reduction with the Au/p-GaN photocathodes and observed improved selectivity for CO production over H2 evolution in aqueous electrolytes. Taken together, our results offer experimental validation of photoexcited hot holes more than 1 eV below the Au Fermi level and demonstrate a photoelectrochemical platform for harvesting hot carriers to drive solar-to-fuel energy conversion. PMID- 29522351 TI - Reversible Stereodivergent Cycloaddition of Racemic Helicenes to [60]Fullerene: A Chiral Resolution Strategy. AB - [60]Fullerene and its rarely explored reversible covalent chemistry have been harnessed as an efficient alternative for the chiral resolution of racemates. By using only catalytic amounts of chiral agents, stereodivergent 1,3-dipolar cycloadditions of racemic helicenes onto [60]fullerene were carried out. The formed helicene/fullerene diastereomers were easily separated by conventional chromatography, and afterward, a simple catalyzed 1,3-dipolar retro-cycloaddition afforded helicene starting materials in high optical purity. PMID- 29522353 TI - Estimating Abundance from Occurrence: An Underdetermined Problem. PMID- 29522352 TI - Early Endotyping: A Chance for Intervention in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a syndrome that comprises several lung pathologies, but subphenotyping the various disease subtypes has been difficult. One reason may be that current efforts focused on studying COPD once it has occurred do not allow tracing back to the different origins of disease. This perspective proposes that emphysema originates when susceptible airway, endothelial, and/or hematopoietic cells are exposed to environmental toxins such as cigarette smoke, biomass fuel, or traffic emissions. These susceptible cell types may initiate distinct pathobiological mechanisms ("COPD endotypes") that ultimately manifest the emphysematous destruction of the lung. On the basis of evidence from the "airway" endotype, we suggest that grading these endotypes by severity may allow better diagnosis of disease at early stages when intervention can be designed on the basis of the mechanisms involved. Therefore, genomic, proteomic, and metabolomic studies on at-risk patients will be important in the identification of biomarkers that help designate each endotype. Together with understanding of the involved molecular pathways that lead to disease manifestation, these efforts may lead to development of intervention strategies. PMID- 29522354 TI - Activated Leukocyte Cell Adhesion Molecule: A Novel Regulator of Allergic Inflammation in the Airways. PMID- 29522355 TI - Eight weeks of nitrate supplementation improves blood flow and reduces the exaggerated pressor response during forearm exercise in peripheral artery disease. AB - Peripheral artery disease (PAD) is characterized by a reduced blood flow (BF) and an elevated blood pressure (pressor) response during lower extremity exercise. Although PAD is evident in the upper extremities, no studies have determined BF and pressor responses during upper extremity exercise in PAD. Emerging evidence suggests that inorganic nitrate supplementation may serve as an alternative dietary strategy to boost nitric oxide bioavailability, improving exercising BF and pressor responses during exercise. The present study investigated 1) BF and pressor responses to forearm exercise in patients with PAD ( n = 21) relative to healthy age-matched control subjects ( n = 16) and 2) whether 8 wk of NaNO3 supplementation influenced BF and pressor responses to forearm exercise in patients with PAD. Patients with moderate to severe PAD were randomly assigned to a NaNO3 (1 g/day, n = 13)-treated group or a placebo (microcrystalline cellulose, n = 8)-treated group. Brachial artery forearm BF (FBF; via Doppler) and blood pressure (via finger plethysmography) were measured during mild-intensity (~3.5 kg) and moderate-intensity (~7-kg) handgrip exercise. The absolute change (from baseline) in FBF was reduced (except in the 3.5-kg condition) and BP responses were increased in patients with PAD compared with healthy control subjects in 3.5 and 7-kg conditions (all P < 0.05). Plasma nitrate and nitrite were elevated, exercising (7-kg) DeltaFBF was improved (from 141 +/- 17 to 172 +/- 20 ml/min), and mean arterial pressure response was reduced (from 13 +/- 1 to 9 +/- 1 mmHg, P < 0.05) in patients with PAD that received NaNO3 supplementation for 8 wk relative to those that received placebo. These results suggest that the BF limitation and exaggerated pressor response to moderate-intensity forearm exercise in patients with PAD are improved with 8 wk of NaNO3 supplementation. NEW & NOTEWORTHY Peripheral artery disease (PAD) results in an exaggerated pressor response and reduced blood flow during lower limb exercise; however, the effect of PAD in the upper limbs has remained unknown. These results suggest that 8 wk of inorganic nitrate supplementation improves the blood flow limitation and exaggerated pressor response to moderate-intensity forearm exercise in PAD. PMID- 29522356 TI - Cannabinoids during ischemic strokes: friends or foes? PMID- 29522357 TI - Genipin normalizes depression-like behavior induced by prenatal stress through inhibiting DNMT1. AB - Synthetic antidepressants in current use for the complex etiopathogeneses of depression have slow response and remission as well as various unpleasant side effects. As a result, it is imperative to develop new antidepressants with more effectiveness and less severe side effects. Recent studies demonstrated that genipin, the aglycon of geniposide, extracted from Gardenia jasminoides Ellis has antidepressive effects. However, knowledge regarding the molecular mechanisms of its antidepressant effects remains limited. Employing a depression-like mouse model, we confirmed that genipin is capable of correcting depressions-like behaviors induced by prenatal stress in offspring from prenatally stressed dams (defined as PRS mice). In further experiments, we found that the effect of genipin on PRS mice occurs through DNA demethylation by inhibiting DNA methyltransferase 1 (DNMT1), normalizing the expression of reduced brain-derived neurotrophic factor (BDNF) in the hippocampus. PMID- 29522358 TI - Mobility in pictures: a participatory photovoice narrative study exploring powered mobility provision for children and families. AB - AIM: Rehabilitation professionals are increasingly recognizing mobility as a basic human right and endorsing the efficacy of early powered mobility for children with mobility impairments to foster independence, promote socialization with peers and facilitate participation in family and community life. However, the relationship between mobility and technology provision, when considered in the context of lived experiences of children with mobility impairments and their families, is complex and understudied. Perceptions of these experiences from children's own points of view are especially limited, as is the use of participatory research methods in describing these experiences. The purpose of this study was to empower children and families as co-researchers, investigating their experiences and perspectives of powered mobility provision processes and early use of their mobility technology in their own words and images. Methods: Two families in a major Midwest metropolitan area- one who was receiving a powered wheelchair and one who was receiving a modified powered ride-on toy car- participated as co-researchers from 2015-2016, documenting their experiences with a research camera and narrating their photos to describe meaningful or important aspects of their respective powered mobility provision processes and early use of their devices. RESULTS: Four themes emerged: (1) Dys/Function of Mobility Technology; (2) Daily Life, Play and Participation; (3) Emerging Self/Advocacy and (4) Complex Family/Industry Interplay. Conclusions: These themes and experiences may inform further innovation in powered mobility practices, generate new hypotheses about the role of technology in shaping disability identity and demonstrate the feasibility and impact of using participatory methods more broadly in rehabilitation research. Implications for Rehabilitation Participatory methods may be a useful and underutilized research tool in describing the impact of powered mobility provision processes on child and family experiences of technology and disability. Empowering children and families as co-researchers is important to move the field of powered mobility technology forward in creating innovative, accessible and socially welcoming devices and processes. It is important to capture the similarities and differences in child and family perceptions and experiences within different models of powered mobility provision, such as traditional powered wheelchair prescription and crowdsourced ride-on toy car modification. Powered mobility provision processes and the perceptions and experiences of children and families move beyond business or medical transactions and may help shape disability identity and pride. A disability studies framework may be useful in analyzing the complexities of technology provision and the nuanced interplay between bodies and technology. PMID- 29522359 TI - Inhibitory Effect of Garlic, Purple Onion, and White Onion on Key Enzymes Linked with Type 2 Diabetes and Hypertension. AB - Spices are used in soup preparation in many homes and serve as ingredients in the preparation of several traditional delicacies endowed with natural antioxidants such as polyphenols. The aim of this study is to evaluate the effect of aqueous extract of garlic, white onion, and purple onion on angiotensin-converting enzyme, alpha-amylase, and alpha-glucosidase activity in vitro and determine their antioxidant properties via various antioxidant assays such as OH*, Fe2+ chelation, and 2, 2'-azino-bis 3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical-scavenging assays. The results reveal that aqueous extract of garlic, purple onion, and white onion inhibited angiotensin-converting enzyme, alpha amylase, and alpha-glucosidase in a concentration-dependent manner (0-4 mg/ml). However, purple onion (IC50 = 0.59 mg/ml) had higher inhibitory effect on angiotensin-converting enzyme than white onion (IC50 = 0.66 mg/ml) and purple onion (IC50 = 0.96 mg/ml). Furthermore, white onion had significantly (p < .05) stronger inhibitory effect on alpha-amylase (IC50 = 3.93 mg/mL) than garlic (IC50 = 8.19 mg/ml) and purple onion (IC50 = 8.27 mg/ml). Conversely, garlic (IC50 = 4.50 mg/ml) had no significantly higher inhibitory effect on alpha-glucosidase activity than white onion and purple onion. In addition, the aqueous extracts were able to scavenge 2,2- diphenyl-1-picrylhydrazyl (DPPH*) free radical and reduce Fe3+ to Fe2+ in a dose-dependent manner. Therefore, a possible mechanism by which garlic, white onion, and purple onion exert antidiabetes and antihypertensive properties could be through the inhibitory effect on ACE, alpha amylase, and alpha-glucosidase coupled with their ability to prevent lipid peroxidation in the pancreas and heart, which justify their strong antioxidant properties. PMID- 29522360 TI - Corrigendum. PMID- 29522361 TI - US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. AB - Purpose The outcome and proportion of patients with bone-only (BO) metastatic breast cancer (MBC) has not been well described. We sought to describe the differential outcomes of patients with BO MBC in clinical trials and explore whether there was a discrepancy in radiographic reads between investigator and blinded independent central review. Methods We pooled and analyzed data on 10,521 patients from 13 prospective trials submitted for MBC treatment in initial or supplemental New Drug or Biologics License Applications from 2005. Three subsets were evaluated: BO, bone with other metastases (BWO), and no bone metastases (NBM). Early discordance rate and late discordance rate were calculated from 3,733 and 2,813 patients subject to a blinded independent central review, respectively. Results Bone metastases were identified in 49% (range: 42% to 73%) of patients across trials. BO disease was present in 12.5% (range: 4% to 26%), dependent on subtype. Investigator-assessed progression-free survival (PFS) and overall survival (OS) for the pooled trials demonstrated improved outcomes for the BO subgroup compared with other subgroups (BO v BWO PFS hazard ratio [HR], 0.64; 95% CI, 0.591 to 0.696; BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61; BO v NBM OS HR, 0.68; 95% CI, 0.61 to 0.76). The BO subgroup has a higher early discordance rate and lower late discordance rate than the BWO and NBM subgroups. Conclusion To our knowledge, this review is the largest analysis to date of the BO subgroup of MBC and suggests this subgroup may have a distinct natural history. There also seems to be a difference in how the local investigators assessed progression events in the BO subgroup when compared with the other two groups. PMID- 29522362 TI - Quality of Life During Treatment With Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer. AB - Purpose Chemohormonal therapy with docetaxel and androgen deprivation therapy (ADT+D) for metastatic hormone-sensitive prostate cancer improves overall survival as compared with androgen deprivation therapy (ADT) alone. We compared the quality of life (QOL) between patients with metastatic hormone-sensitive prostate cancer who were treated with ADT+D and those who were treated with ADT alone. Methods Men were randomly assigned to ADT+ D (six cycles) or to ADT alone. QOL was assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P), FACT-Taxane, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Brief Pain Inventory at baseline and at 3, 6, 9, and 12 months. The Wilcoxon signed rank test was used to examine changes over time. Mixed-effect models compared the QOL between arms at each time point. Results Seven hundred ninety men were randomly assigned (ADT+D [n = 397] and ADT[ n = 393]) and completed FACT P (90% at baseline, 86% at 3 months, 83% at 6 months, 78% at 9 months, and 77% at 12 months). ADT+D patients reported a statistically significant decline in FACT-P at 3 months ( P < .001) but FACT-P did not differ significantly between baseline and 12 months ( P = .38). ADT+D FACT-P scores were significantly lower at 3 months ( P = .02) but significantly higher at 12 months ( P = .04) when compared with ADT FACT-P scores. Differences did not exceed the minimal clinically important difference at any time point. ADT+D patients reported significantly lower Functional Assessment of Chronic Illness Therapy-Fatigue scores at 3 months than did ADT patients ( P < .001). Over time, both arms reported significantly poorer FACT-Taxane scores ( P < .001) when compared with baseline. Brief Pain Inventory scores were similar between arms. Conclusion Although ADT+D was associated with statistically worse QOL at 3 months, QOL was better at 12 months for ADT+D patients than for ADT patients. Both arms reported a similar minimally changed QOL over time, suggesting that ADT+D is not associated with a greater long-term negative impact on QOL. PMID- 29522363 TI - MRI to investigate iliac artery wall thickness in triathletes. AB - OBJECTIVES: Endofibrosis was first described in endurance athletes. This rare disease is characterized by intimal hyperplasia of iliac arteries. Due to non specific symptoms diagnosing could be very challenging and delayed. This represents a serious problem not only for affected athletes but also for consulting physicians. The aim of this study was to analyze intimal thickness of iliac arteries using non-contrast magnetic resonance imaging (MRI) in competitive triathletes suffering from exercise induced leg pain consistent with symptoms caused by endofibrosis. METHODS: 18 highly trained triathletes (16 triathletes, 12 male) with a mean age of 45.4 +/- 10.2 years were investigated by non-contrast MRI. We divided subjects into two groups: 10 complaint about exercise- induced leg pain and 7 were free of any symptoms. In all 10 symptomatic athletes consulting physicians excluded musculoskeletal or neurological disorders before and we suspected endofibrosis. One patient was excluded from statistical analysis due to a known recurrent external iliac artery (EIA) occlusion after surgical repair 6 month ago. RESULTS: Mean wall thickness (T) of all 17 subjects was 1.34 +/- 0.11mm for the common iliac artery (CIA) and 1.74 +/- 0.18mm for the EIA. We found no significant differences by comparing T of symptomatic (s) and asymptomatic (a) legs. There were no significant differences in mean ratio of patent artery to whole artery between the symptomatic and asymptomatic legs for the CIA (0.81 vs 0.82, p = 0.87) and for the EIA (0.71 vs 0.72, p = 0.78). MRI shows a thickening of the left EIA (4.41mm) in the patient who suffered from recurrent occlusion of the left EIA and after surgical repair and histological examination confirmed an endofibrotic lesion. CONCLUSION: Non-contrast MRI seems to be an appropriate diagnostic tool to exclude endofibrosis in triathletes, but it cannot be recommended as initial screening modality for athletes suffering from exercise-induced leg pain. PMID- 29522365 TI - Evaluating activities of daily living using an infrared depth sensor: KINECTTM. AB - PURPOSE: With a growing proportion of elderly people in the population, the maintenance of activities of daily living (ADLs) in elderly people is crucial to keep medical costs down. We investigated the ADL measurement accuracy of KINECTTM and Kinect Studio. To eliminate the subjectivity of conventional methods, we numerically assessed motions with computer analysis. METHODS: Eighteen actions that repeated "move" and "stationary" phases, including movement of arms, legs, head and torso were measured using KINECTTM. Errors and standard deviations of joint coordinates at the stationary points outputted from KINECT Studio were evaluated. Simultaneous measurements were performed with KINECTTM using conventional high-performance motion capture, and the output was treated as a true value for comparison. RESULTS: In most motions, errors of the joint coordinates were within 100 mm; however, there were two cases where errors due to the skeleton-model estimation by KINECT Studio increased. Firstly, when a part of the body unexpectedly moved out of the infrared measurable area, and secondly, when parts of the body overlapped each other on the KINECTTM image. CONCLUSIONS: KINECTTM and Kinect Studio are effective for ADL assessment when positions that cause large errors are excluded. Since KINECTTM has sufficient precision, it should also be possible to develop a more appropriate ADL evaluation system with a new algorithm of skeleton-model estimation that does not depend on KINECT Studio. Implications for Rehabilitation The KINECTTM and Kinect Studio are effective for ADL assessment when positions that cause large errors are excluded With an increasing proportion of elderly people in the population, the maintenance of activities of daily living (ADLs) in elderly people is crucial to keep medical costs down Systems such as the KINECTTM can support these goals. PMID- 29522364 TI - Abemaciclib for the treatment of breast cancer. AB - INTRODUCTION: There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms. Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer. Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy. However, currently, besides oestrogen receptor expression, there is a definite lack of predictive biomarkers for response and/or tolerance to abemaciclib, which is important for patient selection. Another problem is that its contribution to overall survival (OS) has not been shown. And while two large the phase 3 study highlighted the anti-tumour effect of abemaciclib, the OS results are awaited. Furthermore, the effect on brain metastases is expected to be unique to abemaciclib as the response of brain metastasis in HR-positive breast cancer patients has been confirmed in a few cases with case collection still ongoing. PMID- 29522366 TI - Effects of bilateral swing-away grab bars on the biomechanics of stand-to-sit and sit-to-stand toilet transfers. AB - PURPOSE: Kinetic characteristics of transfers to and from a toilet performed using bilateral grab bars are not fully quantified to inform grab bar design and configuration. The purpose of this study was to (1) determine effects of bilateral swing-away grab bars on peaks of ankle, knee and hip joint moments during grab bar assisted stand-to-sit and sit-to-stand transfers; and (2) determine effects of three different heights and widths of swing-away grab bars on the same kinetic characteristics. METHODS: Healthy subjects (N = 11, age 25-58 years) performed stand-to-sit and sit-to-stand transfers with and without grab bars. In transfers with grab bars, 9 grab bar configurations were tested by varying their height from the floor (0.787 m, 0.813 m, 0.838 m; 31"-33") and width, the distance of each grab bar from the toilet's centerline (0.330 m, 0.356 m, 0.381 m; 13"-15"). Motion capture, force plate and inverse dynamics analysis were used to determine lower limb joint moments. RESULTS: The use of bilateral grab bars generally reduced the peak magnitude of extension moments at lower limb joints during stand-to-sit and sit-to-stand transfers (p < .05), except the ankle joint moments during stand-to-sit transfers. Relatively few differences in peak joint moments were found between studied grab bar widths or heights. CONCLUSION: The obtained results suggest that the studied ranges of grab bar configurations reduce moment demands on the leg joints and thus decrease difficulty and required lower limb muscle effort to perform the transfers. Implications for Rehabilitation Maximizing the benefits of assistive technology in the built environment requires a careful assessment of their spatial and configurational dimensions, especially in respect to the needs and abilities of the intended users. Examining the kinetic characteristics of transfers to and from a toilet using the swing-away grab bars is useful for informing grab bar design and configuration recommendations for assisted living and skilled nursing facilities. Our findings suggest that the swing-away grab bars located at certain ranges are a reasonable alternative to the grab bars mandated by the current Americans with Disabilities Act (ADA) Accessibility Guidelines. Future research investigating the effects of grab bars on transfer performance should consider additional factors, such as a wider range of abilities and transfer methods of the users. PMID- 29522367 TI - Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy. AB - INTRODUCTION: Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment. Furthermore, TKIs are unable to eradicate leukemic stem cells, allowing the persistence of neoplastic clones. Therefore, there is still clinical need for new agents to overcome common resistance mechanisms to available drugs. This review explores the horizon of drugs actually under investigation for CML patients resistant to conventional treatment. Expert commentary: Radotinib is an ATP-competitive TKI that showed significant activity also in front-line setting and could find employment indications in CML. Asciminib, an allosteric ABL1 inhibitor, could demonstrate a higher capacity in overcoming common TKIs resistant mutations, including T315I, but clinical findings are needed. CML stem cell target will probably require new therapeutic strategies: combinations of several compounds acting with different mechanisms of action are actually under investigation. PMID- 29522368 TI - Migration and perinatal mental health: a global priority. PMID- 29522369 TI - Iron overload: what's TIMP-3 got to do with it. PMID- 29522370 TI - Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis. AB - Myocardial fibrosis and the resultant increases in left ventricular stiffness represent pivotal consequences of chronic pressure overload (PO) that impact both functional capacity and the rates of morbid and mortal events. However, the time course and cellular mechanisms that underlie PO-induced fibrosis have not been completely defined. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that has been shown to be required for insoluble collagen deposition and increased myocardial stiffness in response to PO in mice. As macrophages are associated with increases in fibrillar collagen, the hypothesis that macrophages represent a source of increased SPARC production in the PO myocardium was tested. The time course of changes in the myocardial macrophage population was compared with changes in procollagen type I mRNA, production of SPARC, fibrillar collagen accumulation, and diastolic stiffness. In PO hearts, mRNA encoding collagen type I was increased at 3 days, whereas increases in levels of total collagen protein did not occur until 1 wk and were followed by increases in insoluble collagen at 2 wk. Increases in muscle stiffness were not detected before increases in insoluble collagen content (>1 wk). Significant increases in myocardial macrophages that coincided with increased SPARC were found but did not coincide with increases in mRNA encoding collagen type I. Furthermore, immunohistochemistry and flow cytometry identified macrophages as a cellular source of SPARC. We conclude that myocardial macrophages play an important role in the time-dependent increases in SPARC that enhance postsynthetic collagen processing, insoluble collagen content, and myocardial stiffness and contribute to the development of fibrosis. NEW & NOTEWORTHY Myocardial fibrosis and the resultant increases in left ventricular and myocardial stiffness represent pivotal consequences of chronic pressure overload. In this study a murine model of cardiac fibrosis induced by pressure overload was used to establish a time course of collagen expression, collagen deposition, and cardiac macrophage expansion. PMID- 29522372 TI - Interaction of phase singularities on the spiral wave tail: reconsideration of capturing the excitable gap. AB - The action mechanism of stimulation toward spiral waves (SWs) owing to the complex excitation patterns that occur just after point stimulation has not yet been experimentally clarified. This study sought to test our hypothesis that the effect of capturing excitable gap of SWs by stimulation can also be explained as the interaction of original phase singularity (PS) and PSs induced by the stimulation on the wave tail (WT) of the original SW. Phase variance analysis was used to quantitatively analyze the postshock PS trajectories. In a two dimensional subepicardial layer of Langendorff-perfused rabbit hearts, optical mapping was used to record the excitation pattern during stimulation. After a SW was induced by S1-S2 shock, single biphasic point stimulation S3 was applied. In 70 of the S1-S2-S3 stimulation episodes applied on 6 hearts, the original PS was clearly observed just before the S3 point stimulation in 37 episodes. Pairwise PSs were newly induced by the S3 in 20 episodes. The original PS collided with the newly induced PSs in 16 episodes; otherwise, they did not interact with the original PS. SW shift occurred most efficiently when the S3 shock was applied at the relative refractory period, and PS shifted in the direction of the WT. In conclusion, quantitative tracking of PS clarified that stimulation in desirable conditions induces pairwise PSs on WT and that the collision of PSs causes SW shift along the WT. The results of this study indicate the importance of the interaction of shock-induced excitation with the WT for effective stimulation. NEW & NOTEWORTHY The quantitative analysis of spiral wave dynamics during stimulation clarified the action mechanism of capturing the excitable gap, i.e., the induction of pairwise phase singularities on the wave tail and spiral wave shift along the wave tail as a result of these interactions. The importance of the wave tail for effective stimulation was revealed. PMID- 29522371 TI - UBC-Nepal Expedition: imposed oscillatory shear stress does not further attenuate flow-mediated dilation during acute and sustained hypoxia. AB - Experimentally induced oscillatory shear stress (OSS) and hypoxia reduce endothelial function in humans. Acute and sustained hypoxia may cause increases in resting OSS; however, whether this influences endothelial susceptibility to further increases in OSS is unknown. Healthy lowlanders ( n = 15, 30 +/- 6 yr; means +/- SD) participated in three OSS interventions: two interventions at sea level [normoxia and after 20 min of normobaric hypoxia (acute hypoxia, 11% O2)] and one intervention 5-7 days after a 9-day ascent to 5,050 m (sustained hypoxia). OSS was provoked in the brachial artery using a 30-min distal cuff inflation (75 mmHg). Endothelial function was assessed before and after each intervention by reactive hyperemia flow-mediated dilation (FMD). Shear stress magnitude and patterns were obtained via Duplex ultrasound. Baseline retrograde shear stress and OSS were greater in acute hypoxia versus normoxia ( P < 0.001), and OSS was elevated in sustained hypoxia versus normoxia ( P = 0.011). The intervention further augmented OSS during each condition. Preintervention FMD was decreased by 29 +/- 48% in acute hypoxia and by 25 +/- 31% in sustained hypoxia compared with normoxia ( P = 0.001 and 0.026); these changes correlated with changes in baseline mean and antegrade shear stress. After the intervention, FMD decreased during normoxia (-41 +/- 26%, P < 0.001) and was unaltered during acute or sustained hypoxia. Therefore, a 30-min exposure to OSS reduced FMD during normoxia, a condition with an unchallenged, healthy endothelium; however, imposed OSS did not appear to worsen endothelial function during acute or sustained hypoxia. Exposure to an altered magnitude and pattern of shear stress at baseline in hypoxia may contribute to the insensitivity to further acute augmentation of OSS. NEW & NOTEWORTHY We investigated whether the endothelium remains sensitive to experimental increases in oscillatory shear stress in acute (11% O2) and sustained (2 wk at 5,050 m) hypoxia. Hypoxia altered baseline shear stress and decreased endothelial function (flow-mediated dilation); however, exposure to experimentally induced oscillatory shear stress only impaired flow-mediated dilation in normoxia. PMID- 29522373 TI - Cardiorespiratory interactions in humans and animals: rhythms for life. AB - The cardiorespiratory system exhibits oscillations from a range of sources. One of the most studied oscillations is heart rate variability, which is thought to be beneficial and can serve as an index of a healthy cardiovascular system. Heart rate variability is dampened in many diseases including depression, autoimmune diseases, hypertension, and heart failure. Thus, understanding the interactions that lead to heart rate variability, and its physiological role, could help with prevention, diagnosis, and treatment of cardiovascular diseases. In this review, we consider three types of cardiorespiratory interactions: respiratory sinus arrhythmia (variability in heart rate at the frequency of breathing), cardioventilatory coupling (synchronization between the heart beat and the onset of inspiration), and respiratory stroke volume synchronization (the constant phase difference between the right and the left stroke volumes over one respiratory cycle). While the exact physiological role of these oscillations continues to be debated, the redundancies in the mechanisms responsible for its generation and its strong evolutionary conservation point to the importance of cardiorespiratory interactions. The putative mechanisms driving cardiorespiratory oscillations as well as the physiological significance of these oscillations will be reviewed. We suggest that cardiorespiratory interactions have the capacity to both dampen the variability in systemic blood flow as well as improve the efficiency of work done by the heart while maintaining physiological levels of arterial CO2. Given that reduction in variability is a prognostic indicator of disease, we argue that restoration of this variability via pharmaceutical or device-based approaches may be beneficial in prolonging life. PMID- 29522374 TI - Apelin impairs myogenic response to induce diabetic nephropathy in mice. AB - The cause of the invalid reaction of smooth muscle cells to mechanical stimulation that results in a dysfunctional myogenic response that mediates the disruption of renal blood flow (RBF) in patients with diabetes is debatable. The present study revealed that increased apelin concentration in serum of diabetic mice neutralized the myogenic response mediated by apelin receptor (APJ) and resulted in increased RBF, which promoted the progression of diabetic nephropathy. The results showed that apelin concentration, RBF, and albuminuria:creatinine ratio were all increased in kkAy mice, and increased RBF correlated positively with serum apelin both in C57 and diabetic mice. The increased RBF was accompanied by decreased phosphorylation of myosin light chain (MLC), beta-arrestin, and increased endothelial NOS in glomeruli. Meanwhile, calcium, phosphorylation of MLC, and beta-arrestin were decreased by high glucose and apelin treatment in cultured smooth muscle cells, as well. eNOS was increased by high glucose and increased by apelin in cultured endothelial cells (ECs). Knockdown of beta-arrestin expression in smooth muscle cells cancelled phosphorylation of MLC induced by apelin. Therefore, apelin may induce the progression of diabetic nephropathy by counteracting the myogenic response in smooth muscle cells.-Zhang, J., Yin, J., Wang, Y., Li, B., Zeng, X. Apelin impairs myogenic response to induce diabetic nephropathy in mice. PMID- 29522375 TI - Fropofol decreases force development in cardiac muscle. AB - Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca2+ concentration ([Ca2+]i) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca2+]i in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca2+-activated force ( Fmax) and increased the [Ca2+]i required for 50% of Fmax (Ca50) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.-Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle. PMID- 29522377 TI - Everyday technology use among older deaf adults. AB - PURPOSE: Technology holds great potential to support Deaf individuals as they age into older adulthood. However, it is unclear to what extent Deaf seniors are using technology in everyday life or whether they experience challenges in using technology. The current study explored technology use among older Deaf adults with regard to attitudes, adoption style, and frequency of use for a wide range of technologies, including assistive technologies (ATs) for persons with hearing loss and general, everyday technologies. MATERIALS AND METHODS: We developed a questionnaire that assessed older Deaf adults' use of and experiences with technology. The questionnaire was made available in online and paper versions. Participants (N = 109) were recruited from national conferences and organizations for the Deaf. RESULTS: Overall, we found that the older Deaf adults were technology adopters and regularly use and feel comfortable with a variety of devices. However, we also identified a number of technologies that are not being used by this population, including an AT that appears to have become obsolete and technologies that use sound-based alerts. CONCLUSIONS: Insights on how older Deaf adults are embracing technology and which devices they are actually using can help policy makers, technology developers, and a range of aging services professionals, better meet the needs of this understudied population. Implications for Rehabilitation: Older Deaf adults use a variety of assistive and everyday technologies and must be considered as consumers and included in the design process. Older Deaf adults are generally positive in their attitudes towards technologies but they are infrequent users of potentially beneficial health technologies, highlighting opportunities for future research and development. Assistive technology for the Deaf (TTY/TTD) appears to have become obsolete with advances in modern communication technologies, which has implications for policy decisions. PMID- 29522376 TI - Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F-box protein subunit. AB - Ubiquitin E3 ligases mediate ubiquitination and degradation of intracellular proteins. We have shown that a relatively new Skp, Cullin, F-box (SCF) protein E3 ligase, SCF FBXL19, has an anti-inflammatory effect and controls actin cytoskeleton dynamics via targeting cell membrane receptor and small GTPases for their ubiquitination and degradation, but the molecular regulation of its subunit FBXL19 stability remains unclear. Here we show that FBXL19 degradation is controlled by the balance between its ubiquitination and acetylation. FBXL19 is an unstable protein with a half-life of ~3 h. FBXL19 can be polyubiquitinated, and the proteasome inhibitor MG-132 prolongs FBXL19 half-life, suggesting that FBXL19 degradation is mediated in the ubiquitin-proteasome system. FBXL19 can also be acetylated, and enhancing acetylation of FBXL19 by a deacetylase inhibitor reduces FBXL19 ubiquitination levels. Acetylation-mimic FBXL19 mutant exhibits a longer half-life than wild type. An acetyltransferase CBP catalyzes acetylation of FBXL19. Inhibition or down-regulation of CBP reduces FBXL19 stability, whereas it is increased in CBP-overexpressing cells. Taken together, the data indicate that CBP-mediated acetylation reduces ubiquitination and stabilizes FBXL19. Further, we demonstrate that FBXL19 targets small GTPase Cdc42 for its ubiquitination and degradation, whereas this effect is reversed by inhibition of CBP, suggesting that CBP increases the effect of SCF FBXL19 E3 ligase through acetylation and stabilization of FBXL19. Our study reveals a new molecular model for regulation of SCF E3 ligase function by acetylation and stabilization of its subunit F-box protein.-Wei, J., Dong, S., Yao, K., Martinez, M. F. Y. M., Fleisher, P. R., Zhao, Y., Ma, H., Zhao, J. Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F-box protein subunit. PMID- 29522378 TI - The YebN Leader RNA Acts as a Mn2+ Sensor Required for the Interaction of Xanthomonas oryzae and Rice. AB - Riboswitches are RNA elements that sense metabolites and control gene expression. Recently, the yybP-ykoY riboswitches were found to sense manganese (Mn2+) and regulate the expression of diverse genes. Here, we show that the leader RNA (a yybP-ykoY RNA) of yebN in Xanthomonas oryzae pv. oryzae also functions as a sensor of Mn2+. This leader RNA detects Mn2+ levels in plants and is essential to X. oryzae pv. oryzae virulence. Our data also indicate that Mn2+ is not only required as a microelement for plant growth but also acts as a defense molecule to inhibit pathogen growth. This finding highlights that Mn2+ plays important roles in pathogen-plant interactions and that the yebN leader RNA can be a target candidate for anti-X. oryzae pv. oryzae drug development. PMID- 29522379 TI - Training addiction counselors to deliver a brief psychoeducational intervention for chronic pain among patients in opioid agonist treatment: A pilot investigation. AB - BACKGROUND: Despite high rates of chronic pain among their patients, opioid agonist treatment (OAT) counselors report an absence of training to manage chronic pain. METHODS: A multidisciplinary team developed a tailored training for counselors to screen and address chronic pain via a brief psychosocial intervention, and implemented it with 52 addiction counselors. Data on knowledge (9 true-false items) as well as attitudes, interest, and perceived ability (scored on 5-point Likert-type scales) were collected from counselors before (pre test), after (post-test) training, and after 6 months (follow-up). RESULTS: Pre test knowledge scores varied considerably. Compared to pre-test, mean counselor knowledge scores increased significantly post-training and at follow-up (p's.<05). The training was associated with increases in positive attitudes toward the role of counselors in managing chronic pain, interest in assessing chronic pain, and counselor ability to assess as well as suggest appropriate interventions for pain (all p's <.05). Perceived ability to assess chronic pain and suggest appropriate treatment interventions were higher at follow-up than at pre-test (p's <.05). CONCLUSIONS: Findings related to the initial evaluation of this training were promising, and future research is warranted to further examine the efficacy of training drug counselors on psychosocial interventions to manage chronic pain among OAT patients. PMID- 29522380 TI - Medical specialty choice and well-being at work: Physician's personality as a moderator. AB - We examined whether physicians' personality traits moderate the association between medical specialty and well-being at work. Nationally representative sample of Finnish physicians (n = 2,815; 65% women; aged 25-72 years in 2015) was used. Personality was assessed with the shortened Big Five Inventory. Indicators of well-being at work were measured with scales from Work Ability Index, General Health Questionnaire, Jenkins' Sleep Problems Scale and Suicidal Ideation. Higher extraversion, openness to experience and agreeableness showed as personality traits beneficial for higher well-being at work among person-oriented specialties whereas higher conscientiousness but lower openness and agreeableness showed as personality traits beneficial for higher well-being at work among technique oriented specialties. The role of neuroticism remains minor in general. Physicians' personality traits may moderate the association between medical specialty and well-being at work. PMID- 29522381 TI - Experiences of burnout among drug counselors in a large opioid treatment program: A qualitative investigation. AB - BACKGROUND: Little is known about possible experiences of burnout among drug counselors in opioid treatment programs that are scaling up capacity to address the current opioid treatment gap. METHODS: Participants in this quality improvement study were 31 drug counselors employed by large opioid treatment programs whose treatment capacities were expanding. Experiences of burnout and approaches for managing and/or preventing burnout were examined using individual semi-structured interviews, which were audiotaped, transcribed, and systematically coded by a multidisciplinary team using grounded theory. RESULTS: Rates of reported burnout (in response to an open-ended question) were lower than expected, with approximately 26% of participants reporting burnout. Counselor descriptions of burnout included cognitive, affective, behavioral, and physiological symptoms; and job-related demands were identified as a frequent cause. Participants described both self-initiated (e.g., engaging in pleasurable activities, exercising, taking breaks during workday) and system-supported strategies for managing or preventing burnout (e.g., availing of supervision and paid time off). Counselors provided recommendations for system-level changes to attenuate counselor risk of burnout (e.g., increased staff-wide encounters, improved communication, accessible paid time off, and increased clinical supervision). CONCLUSIONS: Findings suggest that drug counselor burnout is not inevitable, even in opioid treatment program settings whose treatment capacities are expanding. Organizations might benefit from routinely assessing counselor feedback about burnout and implementing feasible recommendations to attenuate burnout and promote work engagement. PMID- 29522382 TI - The Associations of Greek and Religious Organization Participation with College Students' Social Well-Being and Purpose. AB - Two online-survey studies examined the associations of Greek (i.e., sorority and fraternity) and religious (i.e., church or campus ministry) organization participation with college students' social well-being and sense of purpose. In study 1 (N = 281), religious organization membership (versus no membership) was associated with connectedness and purpose, but for Greek organizations the associations held only with respect to level of organization involvement. In study 2 (N = 426), Greek and religious organization membership were both associated with most social well-being and purpose indicators, but only Greek membership was linked to lower loneliness. As in study 1, level of involvement in Greek, but not religious, organizations was linked to social well-being. Hypothesized moderators of the associations between organization membership and the purpose and social well-being variables were not supported. We discuss implications for professionals who work with college students to promote well being, and we present future research ideas. PMID- 29522383 TI - The Influence of Number Magnitude on Vocal Responses. AB - The study investigated whether number magnitude can influence vocal responses. Participants produced either short or long version of the vowel [alpha] (Experiment 1), or high or low-pitched version of that vowel (Experiment 2), according to the parity of a visually presented number. In addition to measuring reaction times (RT) of vocal responses, we measured the intensity, the fundamental frequency (f0) and the first and second formants of the vocalization. The RTs showed that the long and high-pitched vocal responses were associated with large numbers, while short and low-pitched vocal responses were associated with small numbers. It was also found that high-pitched vocalizations were mapped with the odd numbers, while the low-pitched vocalizations were mapped with the even numbers. Finally, large numbers increased the f0 values. The study shows systematic interactions between the processes that represent number magnitude and produce vocal responses. PMID- 29522385 TI - Deprescribing: When trying for less is more. PMID- 29522384 TI - Applying a trauma-informed perspective to loss and change in the lives of older adults. AB - Traumatic events are widely acknowledged to have long-term impacts on individuals, yet only recently have health-care professionals begun to assess for and gain an understanding of trauma in the lives of older adults. For many older adults, trauma is often disenfranchised and overlooked as being either a distant past event (e.g., child abuse) or a normal part of aging (e.g., widowhood). Trauma-informed care, on the other hand, calls for health-care professionals to acknowledge that past and recent events may have been traumatic for older adults and to assess and care plan to reduce or prevent re-traumatization. In this article, we explore the impacts of trauma in later life through a case study of a patient admitted to a long-term care facility. Analysis of this case study suggests several important implications for social work practice in long-term care and the use of person-centered care practices in the care of older adults in general. PMID- 29522386 TI - Hemodynamically, the kidney is at the heart of cardiorenal syndrome. PMID- 29522387 TI - Hypertension in older adults: What is the target blood pressure? PMID- 29522388 TI - Alzheimer dementia: Starting, stopping drug therapy. AB - Alzheimer disease is the most common type of dementia. Two classes of cognition enhancing drugs are approved to treat the symptoms, and both have provided modest benefit in clinical trials. Psychotropic drugs are sometimes used off-label to treat behavioral symptoms of Alzheimer disease. All these medications should be continuously evaluated for clinical efficacy and, when appropriate, discontinued if the primary benefit--preservation of cognitive and functional status and a reduction in behaviors associated with dementia--is no longer being achieved. PMID- 29522389 TI - Primary care management of chronic pelvic pain in women. AB - Chronic pelvic pain in women can arise from many causes and often results in significant declines in function and quality of life. A systematic approach for evaluating patients and initiating a management plan are recommended in the primary care setting. Comprehensive management strategies may include medication, pelvic physical therapy, and behavioral interventions. PMID- 29522390 TI - Which test for CAD should be used in patients with left bundle branch block? AB - Exercise stress electrocardiography is unreliable as a test for obstructive coronary artery disease (CAD) if the patient has left bundle branch block. The authors provide an algorithm for using alternative tests: exercise stress echocardiography, dobutamine echocardiography, computed tomographic (CT) angiography, and nuclear myocardial perfusion imaging. PMID- 29522391 TI - Acute cardiorenal syndrome: Mechanisms and clinical implications. AB - Cardiac and renal dysfunction often coexist, and one begets the other. The association is referred to as cardiorenal syndrome. One subtype, acute cardiorenal syndrome, is often described as a clinical scenario in which acute worsening of cardiac function leads to acute kidney injury. Though this definition covers the basic pathophysiologic framework, a robust clinical definition is still lacking. Acute cardiorenal syndrome is common and often leads to emergency room visits and hospitalization. Our understanding of the hemodynamic mechanisms of acute cardiorenal syndrome is advancing. Correction of hypervolemia is the mainstay of therapy. PMID- 29522392 TI - A 67-year-old woman with bilateral hand numbness. PMID- 29522393 TI - Primary livedo reticularis of the abdomen. PMID- 29522394 TI - Methemoglobinemia in an HIV patient. PMID- 29522395 TI - Ascites from intraperitoneal urine leakage after pelvic radiation. PMID- 29522396 TI - Correction: Update on VTE. AB - In the article, "Update on the management of venous thromboembolism" (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39-46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow: On page 42, left column, the last 5 lines should read: "The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater." And on page 42, right column, the sentence 10 lines from the top should read: "Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors." PMID- 29522398 TI - Surrogate-Based Artifact Removal From Single-Channel EEG. AB - OBJECTIVE: the recent emergence and success of electroencephalography (EEG) in low-cost portable devices, has opened the door to a new generation of applications processing a small number of EEG channels for health monitoring and brain-computer interfacing. These recordings are, however, contaminated by many sources of noise degrading the signals of interest, thus compromising the interpretation of the underlying brain state. In this paper, we propose a new data-driven algorithm to effectively remove ocular and muscular artifacts from single-channel EEG: the surrogate-based artifact removal (SuBAR). METHODS: by means of the time-frequency analysis of surrogate data, our approach is able to identify and filter automatically ocular and muscular artifacts embedded in single-channel EEG. RESULTS: in a comparative study using artificially contaminated EEG signals, the efficacy of the algorithm in terms of noise removal and signal distortion was superior to other traditionally-employed single-channel EEG denoizing techniques: wavelet thresholding and the canonical correlation analysis combined with an advanced version of the empirical mode decomposition. Even in the presence of mild and severe artifacts, our artifact removal method provides a relative error 4 to 5 times lower than traditional techniques. SIGNIFICANCE: in view of these results, the SuBAR method is a promising solution for mobile environments, such as ambulatory healthcare systems, sleep stage scoring, or anesthesia monitoring, where very few EEG channels or even a single channel is available. PMID- 29522399 TI - Robust Support Matrix Machine for Single Trial EEG Classification. AB - Electroencephalogram (EEG) signals are of complex structure and can be naturally represented as matrices. Classification is one of the most important steps for EEG signal processing. Newly developed classifiers can handle these matrix-form data by adding low-rank constraint to leverage the correlation within each data. However, classification of EEG signals is still challenging, because EEG signals are always contaminated by measurement artifacts, outliers, and non-standard noise sources. As a result, existing matrix classifiers may suffer from performance degradation, because they typically assume that the input EEG signals are clean. In this paper, to account for intra-sample outliers, we propose a novel classifier called a robust support matrix machine (RSMM), for single trial EEG data in matrix form. Inspired by the fact that empirical EEG signals contain strong correlation information, we assume that each EEG matrix can be decomposed into a latent low-rank clean matrix plus a sparse noise matrix. We simultaneously perform signal recovery and train the classifier based on the clean EEG matrices. We formulate our RSMM in a unified framework and present an effective solver based on the alternating direction method of multipliers. To evaluate the proposed method, we conduct extensive classification experiments on real binary EEG signals. The experimental results show that our method has outperformed the state-of-the-art matrix classifiers. This paper may lead to the development of robust brain-computer interfaces (BCIs) with intuitive motor imagery and thus promote the broad use of the noninvasive BCIs technology. PMID- 29522400 TI - A Hybrid Network for ERP Detection and Analysis Based on Restricted Boltzmann Machine. AB - Detecting and Please provide the correct one analyzing the event-related potential (ERP) remains an important problem in neuroscience. Due to the low signal-to-noise ratio and complex spatio-temporal patterns of ERP signals, conventional methods usually rely on ensemble averaging technique for reliable detection, which may obliterate subtle but important information in each trial of ERP signals. Inspired by deep learning methods, we propose a novel hybrid network termed ERP-NET. With hybrid deep structure, the proposed network is able to learn complex spatial and temporal patterns from single-trial ERP signals. To verify the effectiveness of ERP-NET, we carried out a few ERP detection experiments that the proposed model achieved cutting-edge performance. The experimental results demonstrate that the patterns learned by the ERP-NET are discriminative ERP components in which the ERP signals are properly characterized. More importantly, as an effective approach to single-trial analysis, ERP-NET is able to discover new ERP patterns which are significant to neuroscience study as well as BCI applications. Therefore, the proposed ERP-NET is a promising tool for the research on ERP signals. PMID- 29522397 TI - Proteolytic processing of palmitoylated Hedgehog peptides specifies the 3-4 intervein region of the Drosophila wing. AB - Cell fate determination during development often requires morphogen transport from producing to distant responding cells. Hedgehog (Hh) morphogens present a challenge to this concept, as all Hhs are synthesized as terminally lipidated molecules that form insoluble clusters at the surface of producing cells. While several proposed Hh transport modes tie directly into these unusual properties, the crucial step of Hh relay from producing cells to receptors on remote responding cells remains unresolved. Using wing development in Drosophila melanogaster as a model, we show that Hh relay and direct patterning of the 3-4 intervein region strictly depend on proteolytic removal of lipidated N-terminal membrane anchors. Site-directed modification of the N-terminal Hh processing site selectively eliminated the entire 3-4 intervein region, and additional targeted removal of N-palmitate restored its formation. Hence, palmitoylated membrane anchors restrict morphogen spread until site-specific processing switches membrane-bound Hh into bioactive forms with specific patterning functions. PMID- 29522401 TI - Wearable Inertial Sensors for Fall Risk Assessment and Prediction in Older Adults: A Systematic Review and Meta-Analysis. AB - Wearable inertial sensors have been widely investigated for fall risk assessment and prediction in older adults. However, heterogeneity in published studies in terms of sensor location, task assessed and features extracted is high, making challenging evidence-based design of new studies and/or real-life applications. We conducted a systematic review and meta-analysis to appraise the best available evidence in the field. Namely, we applied established statistical methods for the analysis of categorical data to identify optimal combinations of sensor locations, tasks, and feature categories. We also conducted a meta-analysis on sensor-based features to identify a set of significant features and their pivot values. The results demonstrated that with a walking test, the most effective feature to assess the risk of falling was the velocity with the sensor placed on the shins. Conversely, during quite standing, linear acceleration measured at the lower back was the most effective combination of feature-placement. Similarly, during the sit-to-stand and/or the stand-to-sit tests, linear acceleration measured at the lower back seems to be the most effective feature-placement combination. The meta-analysis demonstrated that four features resulted significantly higher in fallers: the root-mean-square acceleration in the mediolateral direction during quiet standing with eyes closed [Mean Difference (MD): 0.01 g; 95% Confidence Interval (CI95%): 0.006 to 0.014]; the number of steps (MD: 1.638 steps; CI95%: 0.384 to 2.892) and total time (MD: 2.274 seconds; CI95%: 0.531 to 4.017) to complete the timed up and go test; and the step time (MD: 0.053; CI95%: 0.012 to 0.095; p = 0.01) during walking. PMID- 29522402 TI - Safe Local Navigation for Visually Impaired Users With a Time-of-Flight and Haptic Feedback Device. AB - This paper presents ALVU (Array of Lidars and Vibrotactile Units), a contactless, intuitive, hands-free, and discreet wearable device that allows visually impaired users to detect low- and high-hanging obstacles, as well as physical boundaries in their immediate environment. The solution allows for safe local navigation in both confined and open spaces by enabling the user to distinguish free space from obstacles. The device presented is composed of two parts: a sensor belt and a haptic strap. The sensor belt is an array of time-of-flight distance sensors worn around the front of a user's waist, and the pulses of infrared light provide reliable and accurate measurements of the distances between the user and surrounding obstacles or surfaces. The haptic strap communicates the measured distances through an array of vibratory motors worn around the user's upper abdomen, providing haptic feedback. The linear vibration motors are combined with a point-loaded pretensioned applicator to transmit isolated vibrations to the user. We validated the device's capability in an extensive user study entailing 162 trials with 12 blind users. Users wearing the device successfully walked through hallways, avoided obstacles, and detected staircases. PMID- 29522403 TI - Quantifying the Effects of Increasing Mechanical Stress on Knee Acoustical Emissions Using Unsupervised Graph Mining. AB - In this paper, we investigate the effects of increasing mechanical stress on the knee joints by recording knee acoustical emissions and analyze them using an unsupervised graph mining algorithm. We placed miniature contact microphones on four different locations: on the lateral and medial sides of the patella and superficial to the lateral and medial meniscus. We extracted audio features in both time and frequency domains from the acoustical signals and calculated the graph community factor (GCF): an index of heterogeneity (variation) in the sounds due to different loading conditions enforced on the knee. To determine the GCF, a k-nearest neighbor graph was constructed and an Infomap community detection algorithm was used to extract all potential clusters within the graph-the number of detected communities were then quantified with GCF. Measurements from 12 healthy subjects showed that the GCF increased monotonically and significantly with vertical loading forces (mean GCF for no load = 30 and mean GCF for maximum load [body weight] = 39). This suggests that the increased complexity of the emitted sounds is related to the increased forces on the joint. In addition, microphones placed on the medial side of the patella and superficial to the lateral meniscus produced the most variation in the joint sounds. This information can be used to determine the optimal location for the microphones to obtain acoustical emissions with greatest sensitivity to loading. In future work, joint loading quantification based on acoustical emissions and derived GCF can be used for assessing cumulative knee usage and loading during activities, for example for patients rehabilitating knee injuries. PMID- 29522404 TI - A Speedy Calibration Method Using Riemannian Geometry Measurement and Other Subject Samples on A P300 Speller. AB - P300 spellers are among the most popular brain-computer interface paradigms, and they are used for many clinical applications. However, building the classifier for identifying event-related potential (ERP) responses, i.e., calibrating the P300 speller, is still a time-consuming and user-dependent problem. This paper proposes a novel method to reduce calibration times significantly. In the proposed method, a small number of ERP epochs from the current user were used to build a reference epoch. Based on this reference, the Riemannian distance measurement was used to select similar ERP samples from an existing data pool, which contained other-subject ERP responses. Linear discriminant analysis (LDA), support vector machine, and stepwise LDA were trained as ERP classifiers on the selected database and then were used to identify the user-attended character. With only 12 s of EEG data to calibrate, an average character recognition accuracy for 55 subjects of up to 87.82% was obtained. The LDA that built on other-subject samples that were selected by Riemannian distance outperformed the other classifiers. Compared with other state-of-the-art studies, this method significantly reduces P300 speller calibration times, while maintaining the character recognition accuracy. PMID- 29522405 TI - Wrist-Powered Partial Hand Prosthesis Using a Continuum Whiffle Tree Mechanism: A Case Study. AB - Among the advances in upper extremity prostheses in the past decades, only a small portion of the results were obtained for partial hand prostheses, possibly due to the highly diverse partial hand presentations and limited space for component integration. In an attempt to address these challenges, this paper presents the design, construction, installation, and experimental characterization of a wrist-powered partial hand prosthesis developed in Shanghai Jiao Tong University (hereafter referred to as the JTP hand), customized for a specific amputee. The JTP hand possesses: 1) a continuum whiffle tree mechanism to allow adaptive grasping; 2) a force-magnifying partial gear pair to enhance the power of the grip; and 3) a phalange-embedded disengageable ratchet to enable or disable backdrivability. Various grasps and gestures were formed using the JTP hand. The obtained results suggest that the proposed design might be a viable option for patients with transmetacarpal amputation. PMID- 29522407 TI - Design and Preliminary Evaluation of Electrolarynx With F0 Control Based on Capacitive Touch Technology. AB - An electrolarynx (EL) is one of the most popular voice rehabilitation technologies used after laryngectomy. However, most ELs generate monotonic EL speech, which has been shown to create a particular deficit in speech intelligibility, especially for Chinese Mandarin (Mandarin). Mandarin is a tonal language that makes lexical distinctions using variations in tone. Our purpose is to design an EL that can produce the four Mandarin tones, and to evaluate its performance. We designed a fundamental frequency (F0) control method for Mandarin EL speech and manufactured a touch-controlled electrolarynx (T-EL) prototype. Using monosyllables, disyllabic words, and frequently used phrases, we evaluated speech produced with a T-EL, as well as with monotone (M-EL) and variable frequency modes (P-EL) of a commercially available TruTone EL. A male native Mandarin speaker with laryngectomy volunteered to be the speaker. Results show that the normal speech pitch contours of the four Mandarin tones were most closely matched by the characteristics produced with T-EL. The statistical accuracy of the T-EL's tone and word perception was significantly higher than that of the other EL types. Moreover, the confusion matrix indicates that the listeners could correctly identify the tones of monosyllables and disyllabic words in T-EL speech. Accurate tone judgment can improve the intelligibility of EL speech in Mandarin. The mean opinion score was used to evaluate the listeners' acceptability of EL speech. The scores of the T-EL and M-EL were very close, and the score of the P-EL was significantly lower than that of the other two ELs. However, the results from a single speaker cannot provide sufficient data to conclude which EL has a higher acceptability. The evaluation of multiple EL speakers with different EL types at difference levels of proficiency should be studied in future research. PMID- 29522406 TI - Impact of Targeted Assistance of Multiarticular Finger Musculotendons on the Coordination of Finger Muscles During Isometric Force Production. AB - Neurological injuries often cause degraded motor control. While rehabilitation efforts typically focus on movement kinematics, abnormal muscle activation patterns are often the primary source of impairment. Muscle-based therapies are likely more effective than joint-based therapy. In this paper, we examined the feasibility of biomimetic input mimicking the action of human musculotendons in altering hand muscle coordination. Twelve healthy subjects produced a submaximal isometric dorsal fingertip force, while a custom actuator provided assistance mirroring the actions of either the extrinsic extensor or the intrinsic muscles of the index finger. The biomimetic inputs reduced the activation level of all task-related muscles, but the degree of change was different across the muscles, resulting in significant changes in their coordination (co-contraction ratios) and force-electromyography correlations. Each biomimetic assistance particularly increased the neural coupling between its targeted muscle and the antagonist muscle. Subjects appeared to fully take advantage of the assistance, as they provided minimal level of effort to achieve the task goal. The targeted biomimetic assistance may be used to retrain activation patterns post-stroke by effectively modulating connectivity between the muscles in the functional context and could be beneficial to restore hand function and reduce disability. PMID- 29522408 TI - Improving Acoustic Models in TORGO Dysarthric Speech Database. AB - Assistive speech-based technologies can improve the quality of life for people affected with dysarthria, a motor speech disorder. In this paper, we explore multiple ways to improve Gaussian mixture model and deep neural network (DNN) based hidden Markov model (HMM) automatic speech recognition systems for TORGO dysarthric speech database. This work shows significant improvements over the previous attempts in building such systems in TORGO. We trained speaker-specific acoustic models by tuning various acoustic model parameters, using speaker normalized cepstral features and building complex DNN-HMM models with dropout and sequence-discrimination strategies. The DNN-HMM models for severe and severe moderate dysarthric speakers were further improved by leveraging specific information from dysarthric speech to DNN models trained on audio files from both dysarthric and normal speech, using generalized distillation framework. To the best of our knowledge, this paper presents the best recognition accuracies for TORGO database till date. PMID- 29522409 TI - On the Power Spectrum of Motor Unit Action Potential Trains Synchronized With Mechanical Vibration. AB - This study provides a definitive analysis of the spectrum of a motor unit action potential train (MUAPT) elicited by mechanical vibratory stimulation via a detailed and concise mathematical formulation. Experimental studies demonstrated that MUAPs are not exactly synchronized with the vibratory stimulus but show a variable latency jitter, whose effects have not been investigated yet. Synchronized action potential train was represented as a quasi-periodic sequence of a given MU waveform. The latency jitter of action potentials was modeled as a Gaussian stochastic process, in accordance to the previous experimental studies. A mathematical expression for power spectrum of a synchronized MUAPT has been derived. The spectrum comprises a significant continuous component and discrete components at the vibratory frequency and its harmonics. Their relevance is correlated to the level of synchronization: the weaker the synchronization the more relevant is the continuous spectrum. Electromyography (EMG) rectification enhances the discrete components. The derived equations have general validity and well describe the power spectrum of actual EMG recordings during vibratory stimulation. Results are obtained by appropriately setting the level of synchronization and vibration frequency. This paper definitively clarifies the nature of changes in spectrum of raw EMG recordings from muscles undergoing vibratory stimulation. Results confirm the need of motion artifact filtering for raw EMG recordings during stimulation and strongly suggest to avoid EMG rectification that significantly alters the spectrum characteristics. PMID- 29522410 TI - Android Feedback-Based Training Modulates Sensorimotor Rhythms During Motor Imagery. AB - EEG-based brain computer interface (BCI) systems have demonstrated potential to assist patients with devastating motor paralysis conditions. However, there is great interest in shifting the BCI trend toward applications aimed at healthy users. Although BCI operation depends on technological factors (i.e., EEG pattern classification algorithm) and human factors (i.e., how well the person can generate good quality EEG patterns), it is the latter that is least investigated. In order to control a motor imagery-based BCI, users need to learn to modulate their sensorimotor brain rhythms by practicing motor imagery using a classical training protocol with an abstract visual feedback. In this paper, we investigate a different BCI training protocol using a human-like android robot (Geminoid HI 2) to provide realistic visual feedback. The proposed training protocol addresses deficiencies of the classical approach and takes the advantage of body-abled user capabilities. Experimental results suggest that android feedback-based BCI training improves the modulation of sensorimotor rhythms during motor imagery task. Moreover, we discuss how the influence of body ownership transfer illusion toward the android might have an effect on the modulation of event-related desynchronization/synchronization activity. PMID- 29522411 TI - An ICA-EBM-Based sEMG Classifier for Recognizing Lower Limb Movements in Individuals With and Without Knee Pathology. AB - Surface electromyography (sEMG) data acquired during lower limb movements has the potential for investigating knee pathology. Nevertheless, a major challenge encountered with sEMG signals generated by lower limb movements is the intersubject variability, because the signals recorded from the leg or thigh muscles are contingent on the characteristics of a subject such as gait activity and muscle structure. In order to cope with this difficulty, we have designed a three-step classification scheme. First, the multichannel sEMG is decomposed into activities of the underlying sources by means of independent component analysis via entropy bound minimization. Next, a set of time-domain features, which would best discriminate various movements, are extracted from the source estimates. Finally, the feature selection is performed with the help of the Fisher score and a scree-plot-based statistical technique, prior to feeding the dimension-reduced features to the linear discriminant analysis. The investigation involves 11 healthy subjects and 11 individuals with knee pathology performing three different lower limb movements, namely, walking, sitting, and standing, which yielded an average classification accuracy of 96.1% and 86.2%, respectively. While the outcome of this study per se is very encouraging, with suitable improvement, the clinical application of such an sEMG-based pattern recognition system that distinguishes healthy and knee pathological subjects would be an attractive consequence. PMID- 29522412 TI - Perceptual and Model-Based Evaluation of Ideal Time-Frequency Noise Reduction in Hearing-Impaired Listeners. AB - State-of-the-art hearing aids (HAs) try to overcome the deficit of poor speech intelligibility (SI) in noisy listening environments using digital noise reduction (NR) techniques. The application of time-frequency masks to the noisy sound input is a common NR technique to increase SI. The binary mask with its binary weights and the Wiener filter with continuous weights are representatives of a hard- and a soft-decision approach for time-frequency masking. In normal hearing listeners, the ideal Wiener filter (IWF) outperforms the ideal binary mask (IBM) in terms of SI and speech quality with perfect SI even at very low signal-to-noise ratios. In this paper, both approaches were investigated for hearing-impaired (HI) listeners. Perceptual and auditory model-based measures were used for the evaluation. The IWF outperformed the IBM in terms of SI. Quality-wise, there was no overall difference between the NR algorithms perceived. Additionally, the processed signals were evaluated based on an auditory nerve model using the neurogram similarity metric (NSIM). The mean NSIM values were significantly different for intelligible and unintelligible sentences. The results suggest that a soft-mask seems to be promising for application in HAs. PMID- 29522413 TI - Bilinear Regularized Locality Preserving Learning on Riemannian Graph for Motor Imagery BCI. AB - In off-line training of motor imagery-based brain-computer interfaces (BCIs), to enhance the generalization performance of the learned classifier, the local information contained in test data could be used to improve the performance of motor imagery as well. Further considering that the covariance matrices of electroencephalogram (EEG) signal lie on Riemannian manifold, in this paper, we construct a Riemannian graph to incorporate the information of training and test data into processing. The adjacency and weight in Riemannian graph are determined by the geodesic distance of Riemannian manifold. Then, a new graph embedding algorithm, called bilinear regularized locality preserving (BRLP), is derived upon the Riemannian graph for addressing the problems of high dimensionality frequently arising in BCIs. With a proposed regularization term encoding prior information of EEG channels, the BRLP could obtain more robust performance. Finally, an efficient classification algorithm based on extreme learning machine is proposed to perform on the tangent space of learned embedding. Experimental evaluations on the BCI competition and in-house data sets reveal that the proposed algorithms could obtain significantly higher performance than many competition algorithms after using same filter process. PMID- 29522414 TI - Psychophysical Evaluation of Subdermal Electrical Stimulation in Relation to Prosthesis Sensory Feedback. AB - This paper evaluated the psychophysical properties of subdermal electrical stimulation to investigate its feasibility in providing sensory feedback for limb prostheses. The detection threshold (DT), pain threshold (PT), just noticeable difference (JND), as well as the elicited sensation quality, comfort, intensity, and location were assessed in 16 healthy volunteers during stimulation of the ventral and dorsal forearm with subdermal electrodes. Moreover, the results were compared with those obtained from transcutaneous electrical stimulation. Despite a lower DT and PT, subdermal stimulation attained a greater relative dynamic range (i.e., PT/DT) and significantly smaller JNDs for stimulation amplitude. Muscle twitches and movements were more commonly elicited by surface stimulation, especially at the higher stimulation frequencies, whereas the pinprick sensation was more often reported with subdermal stimulation. Less comfort was perceived in subdermal stimulation of the ventral forearm at the highest tested stimulation frequency of 100 Hz. In summary, subdermal electrical stimulation was demonstrated to be able to produce similar sensation quality as transcutaneous stimulation and outperformed the latter in terms of energy efficiency and sensitivity. These results suggest that stimulation through implantable subdermal electrodes may lead to an efficient and compact sensory feedback system for substituting the lost sense in amputees. PMID- 29522415 TI - A compact hyperspectral camera for measurement of perfusion parameters in medicine. AB - Worldwide, chronic wounds are still a major and increasing problem area in medicine with protracted suffering of patients and enormous costs. Beside conventional wound treatment, for instance kinds of oxygen therapy and cold plasma technology have been tested, providing an improvement in the perfusion of wounds and their healing potential, but these methods are unfortunately not sufficiently validated and accepted for clinical practice to date. Using hyperspectral imaging technology in the visible (VIS) and near infrared (NIR) region with high spectral and spatial resolution, perfusion parameters of tissue and wounds can be determined. We present a new compact hyperspectral camera which can be used in clinical practice. From hyperspectral data the hemoglobin oxygenation (StO2), the relative concentration of hemoglobin [tissue hemoglobin index (THI)] and the so-called NIR-perfusion index can be determined. The first two parameters are calculated from the VIS-part of the spectrum and represent the perfusion of superficial tissue layers, whereas the NIR-perfusion index is calculated from the NIR-part representing the perfusion in deeper layers. First clinical measurements of transplanted flaps and chronic ulcer wounds show, that the perfusion level can be determined quantitatively allowing sensitive evaluation and monitoring for an optimization of the wound treatment planning and for validation of new treatment methods. PMID- 29522416 TI - Lipedema: friend and foe. AB - Background Lipedema is a chronic disorder presenting in women during puberty or other times of hormonal change such as childbirth or menopause, characterized by symmetric enlargement of nodular, painful subcutaneous adipose tissue (fat) in the limbs, sparing the hands, feet and trunk. Healthcare providers underdiagnose or misdiagnose lipedema as obesity or lymphedema. Materials and methods The benefits (friend) and negative aspects (foe) of lipedema were collected from published literature, discussions with women with lipedema, and institutional review board approved evaluation of medical charts of 46 women with lipedema. Results Lipedema is a foe because lifestyle change does not reduce lipedema fat, the fat is painful, can become obese, causes gait and joint abnormalities, fatigue, lymphedema and psychosocial distress. Hypermobility associated with lipedema can exacerbate joint disease and aortic disease. In contrast, lipedema fat can be a friend as it is associated with relative reductions in obesity related metabolic dysfunction. In new data collected, lipedema was associated with a low risk of diabetes (2%), dyslipidemia (11.7%) and hypertension (13%) despite an obese average body mass index (BMI) of 35.3 +/- 1.7 kg/m2. Conclusion Lipedema is a painful psychologically distressing fat disorder, more foe than friend especially due to associated obesity and lymphedema. More controlled studies are needed to study the mechanisms and treatments for lipedema. PMID- 29522417 TI - Differential effect of subcutaneous abdominal and visceral adipose tissue on cardiometabolic risk. AB - Metabolic and cardiovascular diseases are increasing worldwide due to the rise in the obesity epidemic. The metabolic consequences of obesity vary by distribution of adipose tissue. Visceral and ectopic adipose accumulation are associated with adverse cardiometabolic consequences, while gluteal-femoral adipose accumulation are negatively associated with these adverse complications and subcutaneous abdominal adipose accumulation is more neutral in its associations. Gender, race and ethnic differences in adipose tissue distribution have been described and could account for the observed differences in risk for cardiometabolic disease. The mechanisms behind the differential impact of adipose tissue on cardiometabolic risk have started to be unraveled and include differences in adipocyte biology, inflammatory profile, connection to systemic circulation and most importantly the inability of the subcutaneous adipose tissue to expand in response to positive energy balance. PMID- 29522418 TI - The Systems Biology Markup Language (SBML): Language Specification for Level 3 Version 2 Core. AB - Computational models can help researchers to interpret data, understand biological functions, and make quantitative predictions. The Systems Biology Markup Language (SBML) is a file format for representing computational models in a declarative form that different software systems can exchange. SBML is oriented towards describing biological processes of the sort common in research on a number of topics, including metabolic pathways, cell signaling pathways, and many others. By supporting SBML as an input/output format, different tools can all operate on an identical representation of a model, removing opportunities for translation errors and assuring a common starting point for analyses and simulations. This document provides the specification for Version 2 of SBML Level 3 Core. The specification defines the data structures prescribed by SBML, their encoding in XML (the eXtensible Markup Language), validation rules that determine the validity of an SBML document, and examples of models in SBML form. The design of Version 2 differs from Version 1 principally in allowing new MathML constructs, making more child elements optional, and adding identifiers to all SBML elements instead of only selected elements. Other materials and software are available from the SBML project website at http://sbml.org/. PMID- 29522419 TI - SBML Level 3 Package: Flux Balance Constraints version 2. AB - Constraint-based modeling is a well established modeling methodology used to analyze and study biological networks on both a medium and genome scale. Due to their large size and complexity such steady-state flux models are, typically, analyzed using constraint-based optimization techniques, for example, flux balance analysis (FBA). The Flux balance constraints (FBC) Package extends SBML Level 3 and provides a standardized format for the encoding, exchange and annotation of constraint-based models. It includes support for modeling concepts such as objective functions, flux bounds and model component annotation that facilitates reaction balancing. Version two expands on the original release by adding official support for encoding gene-protein associations and their associated elements. In addition to providing the elements necessary to unambiguously encode existing constraint-based models, the FBC Package provides an open platform facilitating the continued, cross-community development of an interoperable, constraint-based model encoding format. PMID- 29522420 TI - A physically based compact I-V model for monolayer TMDC channel MOSFET and DMFET biosensor. AB - In this work, a compact transport model has been developed for monolayer transition metal dichalcogenide (TMDC) channel MOSFET. The analytical model solves the Poisson's equation for the inversion charge density to get the electrostatic potential in the channel. Current is then calculated by solving the drift-diffusion equation. The model makes gradual channel approximation to simplify the solution procedure. The appropriate density of states obtained from the first principle density functional theory simulation has been considered to keep the model physically accurate for monolayer TMDC channel FET. The outcome of the model has been benchmarked against both experimental and numerical quantum simulation results with the help of a few fitting parameters. Using the compact model, detailed output and transfer characteristics of monolayer WSe2 FET have been studied, and various performance parameters have been determined. The study confirms excellent ON and OFF state performances of monolayer WSe2 FET which could be viable for the next generation high-speed, low power applications. Also, the proposed model has been extended to study the operation of a biosensor. A monolayer MoS2 channel based dielectric modulated FET is investigated using the compact model for detection of a biomolecule in a dry environment. PMID- 29522421 TI - Efficient band structure modulations in two-dimensional MnPSe3/CrSiTe3 van der Waals heterostructures. AB - As a research upsurge, van der Waals (vdW) heterostructures give rise to numerous combined merits and novel applications in nanoelectronics fields. Here, we systematically investigate the electronic structure of MnPSe3/CrSiTe3 vdW heterostructures with various stacking patterns. Then, particular attention of this work is paid on the band structure modulations in MnPSe3/CrSiTe3 vdW heterostructures via biaxial strain or electric field. Under a tensile strain, the relative band edge positions of heterostructures transform from type-I (nested) to type-II (staggered). The relocation of conduction band minimum also brings about a transition from indirect to direct band gap. Under a compressive strain, the electronic properties change from semiconducting to metallic. The physical mechanism of strain-dependent band structure may be ascribed to the shifts of the energy bands impelled by different superposition of atomic orbitals. Meanwhile, our calculations manifest that band gap values of MnPSe3/CrSiTe3 heterostructures are insensitive to the electric field. Even so, by applying a suitable intensity of negative electric field, the band alignment transition from type-I to type-II can also be realized. The efficient band structure modulations via external factors endow MnPSe3/CrSiTe3 heterostructures with great potential in novel applications, such as strain sensors, photocatalysis, spintronic and photoelectronic devices. PMID- 29522422 TI - The generation of piezoelectricity and flexoelectricity in graphene by breaking the materials symmetries. AB - Graphene is a non-piezoelectric material. Engineering the piezoelectricity in graphene is possible with the help of impurities, defects and structural modifications. This study reports the mechanism of strain induced polarization and the estimation of piezoelectric and flexoelectric coefficients for graphene system. The combination of charge-dipole potential and the strong many-body potential is employed for describing the inter-atomic interactions. The breaking of symmetry in graphene material is utilized to generate the polarization. Pristine graphene, graphene with circular defect, graphene with triangular defect and trapezium-shaped graphene are considered. Molecular dynamics simulations are performed for straining the graphene atomic systems. The optimization of charge dipole potential functions measure the polarization for these systems. Pristine and circular defect graphene systems show a constant polarization with strain. The polarization is varying with strain for a triangular defected and trapezium shaped graphene system. The local atomic deformation produces a change in polarization with respect to the strain gradient. Estimated piezo and flexo coefficients motivate the usage of graphene in electro-mechanical devices. PMID- 29522423 TI - Examining the Relationship Between Nursing Informatics Competency and the Quality of Information Processing. AB - The purpose of this study was to examine nursing informatics competency and the quality of information processing among nurses in Jordan. The study was conducted in a large hospital with 380 registered nurses. The hospital introduced the electronic health record in 2010. The measures used in this study were personal and job characteristics, self-efficacy, Self-Assessment Nursing Informatics Competencies, and Health Information System Monitoring Questionnaire. The convenience sample consisted of 99 nurses who used the electronic health record for at least 3 months. The analysis showed that nine predictors explained 22% of the variance in the quality of information processing, whereas the statistically significant predictors were nursing informatics competency, clinical specialty, and years of nursing experience. There is a need for policies that advocate for every nurse to be educated in nursing informatics and the quality of information processing. PMID- 29522424 TI - Automated Landslides Detection for Mountain Cities Using Multi-Temporal Remote Sensing Imagery. AB - Landslides that take place in mountain cities tend to cause huge casualties and economic losses, and a precise survey of landslide areas is a critical task for disaster emergency. However, because of the complicated appearance of the nature, it is difficult to find a spatial regularity that only relates to landslides, thus landslides detection based on only spatial information or artificial features usually performs poorly. In this paper, an automated landslides detection approach that is aiming at mountain cities has been proposed based on pre- and post-event remote sensing images, it mainly utilizes the knowledge of landslide-related surface covering changes, and makes full use of the temporal and spatial information. A change detection method using Deep Convolution Neural Network (DCNN) was introduced to extract the areas where drastic alterations have taken place; then, focusing on the changed areas, the Spatial Temporal Context Learning (STCL) was conducted to identify the landslides areas; finally, we use slope degree which is derived from digital elevation model (DEM) to make the result more reliable, and the change of DEM is used for making the detected areas more complete. The approach was applied to detecting the landslides in Shenzhen, Zhouqu County and Beichuan County in China, and a quantitative accuracy assessment has been taken. The assessment indicates that this approach can guarantee less commission error of landslide areal extent which is below 17.6% and achieves a quality percentage above 61.1%, and for landslide areas, the detection percentage is also competitive, the experimental results proves the feasibility and accuracy of the proposed approach for the detection landslides in mountain cities. PMID- 29522425 TI - San Wu Huangqin Decoction, a Chinese Herbal Formula, Inhibits Influenza a/PR/8/34 (H1N1) Virus Infection In Vitro and In Vivo. AB - The San Wu Huangqin Decoction (SWHD), a traditional Chinese medicine formula, is used to treat colds caused by exposure to wind-pathogen, hyperpyrexia, infectious diseases and cancer; moreover, it is used for detoxification. The individual herbs of SWHD, such as Sophora flavescens and Scutellaria baicalensis, exhibit a wide spectrum of antiviral, anti-inflammatory, antibacterial, anticancer and other properties. The Chinese compound formula of SWHD is composed of S. flavescens, S. baicalensis and Rehmannia glutinosa. However, the effect of SWHD on the influenza virus (IFV) and its mechanism remain unknown. The aim of this study was to evaluate, for the first time, whether SWHD could be used to treat influenza. Results showed that SWHD could effectively inhibit influenza A/PR/8/34 (H1N1) virus at different stages of viral replication (confirmed through antiviral effect assay, penetration assay, attachment assay and internalization assay) in vitro. It could reduce the infection of the virus in a dose- and time dependent manner, as confirmed by observing the cell cytopathic effect and calculating the cell viability (p < 0.05). SWHD demonstrated better antiviral activity than oseltamivir in the evaluation of antiviral prophylaxis on influenza (p < 0.05). The antiviral activity of SWHD may be related to its regulation ability on the immune system. Western blot, real-time polymerase chain reaction and indirect immunofluorescence assay showed that the expression of the four target viral proteins of the IFV (namely, haemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP) and matrix-2 (M2)) reduced significantly (p < 0.05). Moreover, SWHD (23.40 and 11.70 g/kg) significantly alleviated the clinical signs, reduced the mortality and increased the survival time of infected mice (p < 0.05). The lung index, virus titres, pathological changes in lung tissues and the expression of key proteins of the IFV in mice also decreased (p < 0.05). In conclusion, SWHD possessed anti-influenza activity. This work provided a new view of complementary therapy and drug discovery for clinical treatment. PMID- 29522427 TI - Cooperative Vehicular Traffic Monitoring in Realistic Low Penetration Scenarios: The COLOMBO Experience. AB - The relevance of effective and efficient solutions for vehicle traffic surveillance is widely recognized in order to enable advanced strategies for traffic management, e.g., based on dynamically adaptive and decentralized traffic light management. However, most related solutions in the literature, based on the powerful enabler of cooperative vehicular communications, assume the complete penetration rate of connectivity/communication technologies (and willingness to participate in the collaborative surveillance service) over the targeted vehicle population, thus making them not applicable nowadays. The paper originally proposes an innovative solution for cooperative traffic surveillance based on vehicular communications capable of: (i) working with low penetration rates of the proposed technology and (ii) of collecting a large set of monitoring data about vehicle mobility in targeted areas of interest. The paper presents insights and lessons learnt from the design and implementation work of the proposed solution. Moreover, it reports extensive performance evaluation results collected on realistic simulation scenarios based on the usage of iTETRIS with real traces of vehicular traffic of the city of Bologna. The reported results show the capability of our proposal to consistently estimate the real vehicular traffic even with low penetration rates of our solution (only 10%). PMID- 29522426 TI - The Mycobiome: A Neglected Component in the Microbiota-Gut-Brain Axis. AB - In recent years, the gut microbiota has been considered as a full-fledged actor of the gut-brain axis, making it possible to take a new step in understanding the pathophysiology of both neurological and psychiatric diseases. However, most of the studies have been devoted to gut bacterial microbiota, forgetting the non negligible fungal flora. In this review, we expose how the role of the fungal component in the microbiota-gut-brain axis is legitimate, through its interactions with both the host, especially with the immune system, and the gut bacteria. We also discuss published data that already attest to a role of the mycobiome in the microbiota-gut-brain axis, and the impact of fungi on clinical and therapeutic research. PMID- 29522428 TI - Antifeedant Activities of Lignans from Stem Bark of Zanthoxylum armatum DC. against Tribolium castaneum. AB - The speciation of a methanolic extract of Zanthoxylum armatum stem bark has enabled the isolation and characterization of 11 known lignans. Among them, five compounds (6, 8-11) are reported in this plant for the first time. All of the chemical structures were elucidated on the basis of NMR spectral analysis. Additionally, their antifeedant activities against Tribolium castaneum were evaluated scientifically. Among them, asarinin (1), with an EC50 of 25.64 ppm, exhibited a much stronger antifeedant activity than the positive control, toosendanin (EC50 = 71.69 ppm). Moreover, fargesin (2), horsfieldin (3), and magnolone (10), with EC50 values of 63.24, 68.39, and 78.37 ppm, showed almost the same antifeedant activity as the positive control. From the perspective of structure-effectiveness relationship, compounds with the chemical group of methylenedioxy exhibited higher antifeedant activities and have potential to be developed into novel antifeedants or potential lead compounds to protect food and crops in storage. PMID- 29522429 TI - Accuracy of Continuous Glucose Monitoring before, during, and after Aerobic and Anaerobic Exercise in Patients with Type 1 Diabetes Mellitus. AB - Continuous glucose monitoring (CGM) plays an important role in treatment decisions for patients with type 1 diabetes under conventional or closed-loop therapy. Physical activity represents a great challenge for diabetes management as well as for CGM systems. In this work, the accuracy of CGM in the context of exercise is addressed. Six adults performed aerobic and anaerobic exercise sessions and used two Medtronic Paradigm Enlite-2 sensors under closed-loop therapy. CGM readings were compared with plasma glucose during different periods: one hour before exercise, during exercise, and four hours after the end of exercise. In aerobic sessions, the median absolute relative difference (MARD) increased from 9.5% before the beginning of exercise to 16.5% during exercise (p < 0.001), and then decreased to 9.3% in the first hour after the end of exercise (p < 0.001). For the anaerobic sessions, the MARD before exercise was 15.5% and increased without statistical significance to 16.8% during exercise realisation (p = 0.993), and then decreased to 12.7% in the first hour after the cessation of anaerobic activities (p = 0.095). Results indicate that CGM might present lower accuracy during aerobic exercise, but return to regular operation a few hours after exercise cessation. No significant impact for anaerobic exercise was found. PMID- 29522430 TI - Energy-Protein Supplementation and Lactation Affect Fatty Acid Profile of Liver and Adipose Tissue of Dairy Cows. AB - This article addresses the hypothesis that lactation stage, parity and energy protein feed additive affect fatty acid composition of blood, liver and adipose tissue of cows. The experiment was conducted on 24 Polish Holstein-Friesian cows divided into two feeding groups. One group of cows was fed solely a total mixed ration, while the other group was fed a ration with the addition of 2 kg of energy-protein supplement per cow/day. During the experiment, the samples of liver, adipose tissue and blood were taken and their fatty acid compositions were determined. Analysis of variance was applied to fatty acid relative weight percentage to determine the effect of the stage of lactation, parity, and energy protein supplement on the fatty acid composition of the tissues. Stage of lactation had a significant impact on the content of many fatty acids in all examined tissues. We found that parity had no effect on fatty acid composition of blood, whereas it significantly affected C16:1 c9 in liver, and C16:1 c9 and C18:0 in adipose tissue. Energy-protein supplement significantly affected the content of most fatty acids in blood (e.g., C18:1 t11 and C18:3 n-3) and liver (C18:3 n-3, both isomers of conjugated linolenic acid and n-3 fatty acids derived from fish oil), but it did not affect the profile of the adipose tissue of cows. According to our best knowledge, this is the first study showing the relationship between parity, stage of lactation and the composition of fatty acids in blood, liver and adipose tissue of cows. PMID- 29522431 TI - Once Daily High Dose Tigecycline Is Optimal: Tigecycline PK/PD Parameters Predict Clinical Effectiveness. AB - OBJECTIVE: The clinical effectiveness of tigecycline depends on appropriate use, and PK/PD (pharmacokinetic/pharmacodynamic) parameters related to dose and dosing interval. METHODS: In our 600-bed university-affiliated teaching hospital, we conducted a tigecycline efficacy review over a three-month period in 34 evaluable patients. Parameters assessed included clinical response, cure or treatment failure, once daily as q12h dosing, maintenance dosing, high dose vs. standard loading regimens, adverse effects, and the effect of infectious disease consultation on outcomes. RESULTS: We found once daily high dose tigecycline (HDT) was highly effective in treating serious systemic infections due to MDR Gram-positive/negative pathogens as well as C. difficile colitis. Adverse effects were infrequent and limited to mild nausea/vomiting. Once daily HDT was highly effective, and the few treatment failures were related to suboptimal/split dosing regimens. CONCLUSION: Once daily HDT was highly effective when used to treat susceptible pathogens and when optimally dosed, i.e., 200-400 mg (IV) loading dose *1, followed by a once daily maintenance dose of 100-200 mg (IV) q24h. PMID- 29522432 TI - Aqueous-Phase Hydrogenolysis of Glycerol over Re Promoted Ru Catalysts Encapuslated in Porous Silica Nanoparticles. AB - Activity improvement of Ru-based catalysts is needed for efficient production of valuable chemicals from glycerol hydrogenolysis. In this work, a series of Re promoted Ru catalysts encapuslated in porous silica nanoparticles (denoted as Re Ru@SiO2) were prepared by coating silica onto the surface of chemically reduced Ru-polyvinylpyrrolidone colloids, and were used to catalyze the conversion of glycerol to diols and alcohols in water. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, X-ray photoelectron spectroscopy (XPS) and temperature-programmed reduction (TPR) were used to characterize these nanoparticles. Effects of Ru/Si atomic ratio, Re addition, glycerol and catalyst concentrations, reaction time, temperature, and hydrogen pressure were investigated. Re addition retarded the reduction of ruthenium oxide, but increased the catalyst reactivity for glycerol hydrogenolysis. Due to its greater Ru content, Re-Ru@ SiO2 showed much better activity (reacted at much lower temperature) and more yields of 1,2-propanediol and overall liquid-phase products than Re-Ru/SiO2 (prepared by conventional impregnation method) reported before. The rate of glycerol disappearance exhibited first-order dependence on glycerol concentration and hydrogen pressure, with an activation energy of 107.8 kJ/mol. The rate constant increased linearly with increasing Ru/Si atomic ratio and catalyst amount. The yield of overall liquid-phase products correlated well with glycerol conversion. PMID- 29522433 TI - Purification and Characterization of a Novel Alginate Lyase from the Marine Bacterium Bacillus sp. Alg07. AB - Alginate oligosaccharides with different bioactivities can be prepared through the specific degradation of alginate by alginate lyases. Therefore, alginate lyases that can be used to degrade alginate under mild conditions have recently attracted public attention. Although various types of alginate lyases have been discovered and characterized, few can be used in industrial production. In this study, AlgA, a novel alginate lyase with high specific activity, was purified from the marine bacterium Bacillus sp. Alg07. AlgA had a molecular weight of approximately 60 kDa, an optimal temperature of 40 degrees C, and an optimal pH of 7.5. The activity of AlgA was dependent on sodium chloride and could be considerably enhanced by Mg2+ or Ca2+. Under optimal conditions, the activity of AlgA reached up to 8306.7 U/mg, which is the highest activity recorded for alginate lyases. Moreover, the enzyme was stable over a broad pH range (5.0 10.0), and its activity negligibly changed after 24 h of incubation at 40 degrees C. AlgA exhibited high activity and affinity toward poly-beta-d mannuronate (polyM). These characteristics suggested that AlgA is an endolytic polyM-specific alginate lyase (EC 4.2.2.3). The products of alginate and polyM degradation by AlgA were purified and identified through fast protein liquid chromatography and electrospray ionization mass spectrometry, which revealed that AlgA mainly produced disaccharides, trisaccharides, and tetrasaccharide from alginate and disaccharides and trisaccharides from polyM. Therefore, the novel lysate AlgA has potential applications in the production of mannuronic oligosaccharides and poly-alpha-l-guluronate blocks from alginate. PMID- 29522434 TI - Effect of Sulfites on Antioxidant Activity, Total Polyphenols, and Flavonoid Measurements in White Wine. AB - Polyphenols content and antioxidant activity are directly related to the quality of wine. Wine also contains sulfites, which are added during the winemaking process. The present study aimed to evaluate the effects of sulfites on the assays commonly used to measure the antioxidant activity and polyphenols and flavonoids content of white wines. The effects of sulfites were explored both in the standard assays and in white wine. The addition of sulfites (at 1-10 MUg) in the standard assays resulted in a significant, positive interference in the Folin Ciocalteu's assay used for polyphenols measurements and in both the Ferric Reducing Antioxidant Power and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical cation decolorization assays, which were used for antioxidant activity evaluation. A negative interference of sulfites (at 1-20 MUg) was observed for the colorimetric aluminium-chloride flavonoids assay. The addition of sulfites to organic white wines (at 25-200 mg/L wine) clearly resulted in a significant overestimation of antioxidant activity and polyphenols content, and in an underestimation of flavonoids concentration. To overcome sulfite interferences, white wines were treated with cross-linked polyvinylpyrrolidone. The total polyphenols content and antioxidant activity measurements obtained after polyvinylpyrrolidone treatment were significantly lower than those obtained in the untreated wines. Flavonoids were expected to be higher after polyvinylpyrrolidone treatment, but were instead found to be lower than for untreated wines, suggesting that in addition to sulfites, other non phenolic reducing compounds were present in white wine and interfered with the flavonoid assay. In view of our results, we advise that a purification procedure should be applied in order to evaluate the quality of white wine. PMID- 29522435 TI - A Novel Synthesis of Highly Functionalized Pyridines by a One-Pot, Three Component Tandem Reaction of Aldehydes, Malononitrile and N-Alkyl-2 cyanoacetamides under Microwave Irradiation. AB - A convenient, fast and environmentally benign procedure for the synthesis of a new series of highly functionalized N-alkylated pyridines as privileged medicinal scaffolds was developed via a unique three-component reaction of easily available aromatic as well as heteroaromatic aldehydes, N-alkyl-2-cyanoacetamides and malononitrile in EtOH in the presence of K2CO3 as a base promoter under microwave irradiation. The presented tandem process is presumed to proceed via Knoevenagel condensation, Michael addition, intramolecular cyclization, autoxidation and subsequent aromatization. Particularly valuable features of this protocol, including high product yields, mild conditions, atom-efficiency, simple execution, short reaction times and easy purification make it a highly efficient and promising synthetic strategy to prepare substituted pyridine nuclei. The proposed mechanism of this novel one-pot reaction and structure elucidation of the products are discussed. PMID- 29522436 TI - Chemical Synthesis of High-Stable Amorphous FeCo Nanoalloys with Good Magnetic Properties. AB - It is difficult to fabricate high-purity amorphous FeCo alloys by traditional physical methods due to their weak glass forming ability. In this work, the fully amorphous FeCo nanoalloys with high purity and good stability have been prepared by a direct chemical reduction of Fe2+ and Co2+ ions with NaBH4 as the reducing agent and polyvinylpyrrolidone (PVP) as the surfactant. The morphologies, surface compositions and particle sizes with their distribution of these amorphous samples can be effectively tuned by the suitable PVP additions. High crystallization temperature up to 468 degrees C, high saturation magnetization of 196.2 A.m2.kg-1 and low coercivity of 83.3 Oe are obtained in amorphous FeCo nanoalloys due to their uniform distribution, weak surface oxidation and low surface B concentration. Good frequency-dependent magnetic properties can be also achieved in the fully compacted amorphous sample with a high density of 7.20 g/cm3. The simple chemical method, high stability and good magnetic properties for these amorphous FeCo nanoalloys promise their significant potential applications in high-power magnetic devices. PMID- 29522437 TI - Interfaces between Model Co-W-C Alloys with Various Carbon Contents and Tungsten Carbide. AB - Interfaces between alloys simulating binders in WC-Co cemented carbides and tungsten carbide were examined on the micro-, nano-, and atomic-scale. The precipitation of fine WC grains and eta-phase occurs at the interface of the alloy with the low carbon content. The precipitation of such grains almost does not occur in the alloy with the medium-low carbon content and does not take place in the alloy with the high carbon content. The formation of Co nanoparticles in the binder alloy with the medium-low carbon content was established. Interfaces in the alloy with the medium-low carbon content characterized by complete wetting with respect to WC and with the high carbon content characterized by incomplete wetting were examined at an atomic scale. The absence of any additional phases or carbon segregations at both of the interfaces was established. Thus, the phenomenon of incomplete wetting of WC by liquid binders with high carbon contents is presumably related to special features of the Co-based binder alloys oversaturated with carbon at sintering temperatures. PMID- 29522438 TI - Effects of Exogenous Application of Protocatechuic Acid and Vanillic Acid to Chlorophylls, Phenolics and Antioxidant Enzymes of Rice (Oryza sativa L.) in Submergence. AB - In this study, effects from application of protocatechuic acid (PA) and vanillic acid (VA) and their mixture on the submergence tolerance of rice were examined. The treatment of 0.01 mM PA and VA did not show significant increase of rice growth as compared to the controls. However, at higher concentrations (0.1-1.0 mM), rice shoot was elevated in submergence by 20.8-22.4%. The survival percentage of rice seedlings at any dose of PA, VA and their mixture was significantly higher than the controls. In general, the mixture of PA and VA was more active to promote shoot elongation and survival in submergence than sole treatment of either PA or VA. The amount of chlorophyll b by PA was significantly increased, while no change in chlorophyll a content was observed. VA remarkably reduced malondialdehyde quantity at three days of submergence, while no significant difference among treatment was observed in PA, the mixture, and respective controls. The two phenolic acids promoted contents of phenolics and flavonoids in rice leaves and roots, however the quantities of endogenous PA and VA in rice were not markedly differed after PA and VA treated on roots of rice seedlings. The ascorbate peroxidase and superoxide dismutase activities were enhanced, while the expression of genes encoding antioxidant enzymes was favored. VA increased the expression level of ascorbate peroxidase genes in higher levels than PA and their mixture, while no significant difference was observed in the other genes including superoxide dismutase, catalase, glutathione reductase, and peroxidase. Findings of this study showed that PA and VA increased the submergence tolerance of rice by promoting the photosynthetic and anti-oxidative processes in rice seedlings. The treatment of PA and VA mixture on seedling roots was potent to promote the submergence tolerance in rice. PMID- 29522440 TI - Do Technical Aids for Patient Handling Prevent Musculoskeletal Complaints in Health Care Workers?-A Systematic Review of Intervention Studies. AB - The physical load ensuing from the repositioning and moving of patients puts health care workers at risk of musculoskeletal complaints. Technical equipment developed to aid with patient handling should reduce physical strain and workload; however, the efficacy of these aids in preventing musculoskeletal disorders and complaints is still unclear. A systematic review of controlled intervention studies was conducted to examine if the risk of musculoskeletal complaints and disorders is reduced by technical patient handling equipment. MEDLINE(r)/PubMed(r), EMBASE(r), Allied and Complementary Medicine Database (AMED), and Cumulative Index of Nursing and Allied Health Literature (CINAHL(r)) were searched using terms for nursing, caregiving, technical aids, musculoskeletal injuries, and complaints. Randomized controlled trials and controlled before-after studies of interventions including technical patient handling equipment were included. The titles and abstracts of 9554 publications and 97 full-texts were screened by two reviewers. The qualitative synthesis included one randomized controlled trial (RCT) and ten controlled before-after studies. A meta-analysis of four studies resulted in a pooled risk ratio for musculoskeletal injury claims (post-intervention) of 0.78 (95% confidence interval 0.68-0.90). Overall, the methodological quality of the studies was poor and the results often based on administrative injury claim data, introducing potential selection bias. Interventions with technical patient handling aids appear to prevent musculoskeletal complaints, but the certainty of the evidence according to GRADE approach ranged from low to very low. PMID- 29522439 TI - Resveratrol in Patients with Minimal Hepatic Encephalopathy. AB - BACKGROUND: Minimal Hepatic Encephalopathy (MHE) is characterized by an impairment of social interaction, emotional behavior, sleep disorders, physical and mental symptoms, and diminished Quality of Life (QoL). The aim of our study is evaluating the potential liver health promoting a perspective of Resveratrol (RV) activities and evaluate whether RV treatment may improve health related quality of life (HRQL) and reduce depression and anxiety in patients with MHE. METHODS: We evaluated depression using the Beck Depression Inventory test, anxiety with State-trait anxiety inventory test, quality of life through SF-36 test, and ammonia serum levels in 70 MHE patients that were randomized into two groups. RESULTS: In the comparison between RV group and placebo group we observed a decrease in Back Depression Inventory (BDI) (p < 0.001), in State-trait anxiety inventory (STAI) (p < 0.001), and improve in physical function (p < 0.001), in role physical (p < 0.05), in body pain (p < 0.05), in general health (p < 0.001), in vitality (p < 0.05), and in social function (p < 0.001). CONCLUSIONS: Resveratrol showed efficacy in the treatment of depression, anxiety, and ammonia serum levels, and improved the quality of life Of MHE patients. PMID- 29522441 TI - miR-146b Inhibits Glucose Consumption by Targeting IRS1 Gene in Porcine Primary Adipocytes. AB - Adipose tissue plays an important role in energy metabolism. Adipose dysfunction is closely related to obesity and type II diabetes. Glucose uptake is the key step for fat synthesis in adipocyte. miRNAs have been proven to play a crucial role in adipocyte differentiation, adipogenesis and glucose homeostasis. In this paper, we firstly reported that miR-146b decreased glucose consumption by up regulating miR-146b in a porcine primary adipocyte model, while the inhibitor of endogenous miR-146b rescued the reduction. Then, miR-146b was predicated to target IRS1 by bioinformatics analysis, and a dual-luciferase reporter assay validated this predication. Western blot analyses indicated both IRS1 and glucose transporter type 4 (GLUT4) were down-regulated by miR-146b overexpression. Our study demonstrated that miR-146b regulated glucose homeostasis in porcine primary pre-adipocyte by targeting IRS1, and provided new understandings on regulations of lipogenesis by miRNAs. PMID- 29522442 TI - Evaluation of Alternative Euthanasia Methods of Neonatal Chickens. AB - Hatched male layer chicks are currently euthanized by maceration in the United States. Public concerns on the use of maceration have led to the search for alternative methods. We hypothesized that gas inhalation and low atmospheric pressure stunning (LAPS) are viable and humane alternatives to instantaneous mechanical destruction. The objective of this study was to evaluate the physiological and behavioral responses of recently hatched male layer chicks when subjected to carbon dioxide, nitrogen inhalation, or LAPS. The study consisted of seven treatments: breathing air (NEG), 25% carbon dioxide (CO2), 50% CO2, 75% CO2, 90% CO2, 100% nitrogen (N2), or LAPS. Ten day-of-hatch, male layer chicks were randomly assigned to each treatment, and each treatment was replicated on ten different days. A custom-made vacuum system was used to reduce air pressure inside the chamber from 100.12 kPa to 15.3 kPa for the LAPS treatment. Serum corticosterone and serotonin levels were measured using commercially available competitive enzyme linked immunosorbent assay (ELISA). Latencies to loss of posture and motionlessness were determined from video recordings. The 25% and 50% CO2 treatments were discontinued after the first replication, as the majority of the chicks recovered. The chicks in the negative (NEG) group had significantly higher levels of corticosterone than the other four euthanasia treatments. On the other hand, the serotonin levels of chicks in the NEG group was significantly lower when compared to the other four euthanasia treatments. The latencies to loss of posture and motionlessness of chicks exposed to 75% and 90% CO2 were significantly shorter than those in the LAPS and N2 inhalation treatments. These data suggest that the stress responses of chicks to the CO2, N2, and LAPS treatments do not differ among each other. However, the CO2 inhalation method was faster in inducing loss of posture and motionlessness in chicks than the LAPS and N2 inhalation treatments. PMID- 29522443 TI - Tool Wear Prediction in Ti-6Al-4V Machining through Multiple Sensor Monitoring and PCA Features Pattern Recognition. AB - Machining of titanium alloys is characterised by extremely rapid tool wear due to the high cutting temperature and the strong adhesion at the tool-chip and tool workpiece interface, caused by the low thermal conductivity and high chemical reactivity of Ti alloys. With the aim to monitor the tool conditions during dry turning of Ti-6Al-4V alloy, a machine learning procedure based on the acquisition and processing of cutting force, acoustic emission and vibration sensor signals during turning is implemented. A number of sensorial features are extracted from the acquired sensor signals in order to feed machine learning paradigms based on artificial neural networks. To reduce the large dimensionality of the sensorial features, an advanced feature extraction methodology based on Principal Component Analysis (PCA) is proposed. PCA allowed to identify a smaller number of features (k = 2 features), the principal component scores, obtained through linear projection of the original d features into a new space with reduced dimensionality k = 2, sufficient to describe the variance of the data. By feeding artificial neural networks with the PCA features, an accurate diagnosis of tool flank wear (VBmax) was achieved, with predicted values very close to the measured tool wear values. PMID- 29522444 TI - Trifunctional Epoxy Resin Composites Modified by Soluble Electrospun Veils: Effect on the Viscoelastic and Morphological Properties. AB - Electrospun veils from copolyethersulfones (coPES) were prepared as soluble interlaminar veils for carbon fiber/epoxy composites. Neat, resin samples were impregnated into coPES veils with unmodified resin, while dry carbon fabrics were covered with electrospun veils and then infused with the unmodified epoxy resin to prepare reinforced laminates. The thermoplastic content varied from 10 wt% to 20 wt%. TGAP epoxy monomer showed improved and fast dissolution for all the temperatures tested. The unreinforced samples were cured first at 180 degrees C for 2 h and then were post-cured at 220 degrees C for 3 h. These sample showed a high dependence on the curing cycle. Carbon reinforced samples showed significant differences compared to the neat resin samples in terms of both viscoelastic and morphological properties. PMID- 29522445 TI - Some Socioeconomic Factors and Lifestyle Habits Influencing the Prevalence of Obesity among Adolescent Male Students in the Hail Region of Saudi Arabia. AB - : A cross-sectional study was conducted to investigate the effect of some socioeconomic factors and lifestyle habits on the prevalence of obesity among adolescent male students in the Hail region, Saudi Arabia. A questionnaire was filled by 1495 male adolescents distributed among 12 schools in the Hail region. Body weight and height were taken, and the Z-score of students was measured using Anthroplus software with a cutoff 1-2 and +2 standard deviations to determine overweight and obesity, respectively. The study revealed that 21.3% of students were overweight and 27% were obese, respectively. There was a negative association between family size of >8 and obesity (OR: 0.68, CI: 0.48-0.92, p = 0.05). Family income of <5000 SR was negatively associated with obesity (OR: 0.59, CI: 0.36-0.97, p = 0.03). Whether a subject's mother worked (odds ratio (OR): 1.43, confidence interval CI: 1.03-1.99, p = 0.03) as well as the subject's mother's education-whether she can read and write, has a middle school degree, or has done postsecondary studies-were positively associated with obesity. Exercise, regardless of the duration, was negatively associated with obesity. In addition, sleeping <6 h/day had a positive association with obesity. CONCLUSION: a >8 family size and a low family income were negatively associated with obesity, while having an educated and working mother was positively associated with obesity. PMID- 29522446 TI - Sucrosomial Iron Supplementation in Anemic Patients with Celiac Disease Not Tolerating Oral Ferrous Sulfate: A Prospective Study. AB - Patients with celiac disease (CD) frequently suffer from iron deficiency anemia (IDA) and may benefit from iron supplementation. However, intolerance to iron sulfate and duodenal atrophy could reduce the efficacy of this supplementation. This study evaluated the efficacy of a new sucrosomial iron formulation in patients with CD. Consecutive patients with CD and IDA were divided into two groups: patients with a known intolerance to iron sulfate were treated with sucrosomial iron (30 mg of iron/day), while those receiving iron supplementation for the first time were assigned to iron sulfate (105 mg of iron/day). Forty three patients were enrolled (38 females, mean age 49 +/- 9 years). After a follow-up of 90 days both groups showed an increase in Hb levels compared to baseline (+10.1% and +16.2% for sucrosomial and sulfate groups, respectively), and a significant improvement in all iron parameters, with no statistical difference between the two groups. Patients treated with sucrosomial iron reported a lower severity of abdominal symptoms, such as abdominal and epigastric pain, abdominal bloating, and constipation, and a higher increase in general well being (+33% vs. +21%) compared to the iron sulfate group. Sucrosomial iron can be effective in providing iron supplementation in difficult-to-treat populations, such as patients with CD, IDA, and known intolerance to iron sulfate. PMID- 29522448 TI - Microglial Immune Response to Low Concentrations of Combustion-Generated Nanoparticles: An In Vitro Model of Brain Health. AB - The brain is the central regulator for integration and control of responses to environmental cues. Previous studies suggest that air pollution may directly impact brain health by triggering the onset of chronic neuroinflammation. We hypothesize that nanoparticle components of combustion-generated air pollution may underlie these effects. To test this association, a microglial in vitro biological sensor model was used for testing neuroinflammatory response caused by low-dose nanoparticle exposure. The model was first validated using 20 nm silver nanoparticles (AgNP). Next, neuroinflammatory response was tested after exposure to size-selected 20 nm combustion-generated nanoparticles (CGNP) collected from a modern diesel engine. We show that low concentrations of CGNPs promote low-grade inflammatory response indicated by increased pro-inflammatory cytokine release (tumor necrosis factor-alpha), similar to that observed after AgNP exposure. We also demonstrate increased production of reactive oxygen species and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) p65 phosphorylation in microglia after CGNP stimulation. Finally, we show conditioned media from CGNP-stimulated microglia significantly reduced hypothalamic neuronal survival in vitro. To our knowledge, this data show for the first time that exposure to AgNP and CGNP elicits microglial neuroinflammatory response through the activation of NF-kappaB. PMID- 29522449 TI - Welcome to the World of Zinc Signaling. AB - Zinc, an essential trace element, plays indispensable roles in multiple cellular processes.[...]. PMID- 29522447 TI - The Inside Story of Adenosine. AB - Several physiological functions of adenosine (Ado) appear to be mediated by four G protein-coupled Ado receptors. Ado is produced extracellularly from the catabolism of the excreted ATP, or intracellularly from AMP, and then released through its transporter. High level of intracellular Ado occurs only at low energy charge, as an intermediate of ATP breakdown, leading to hypoxanthine production. AMP, the direct precursor of Ado, is now considered as an important stress signal inside cell triggering metabolic regulation through activation of a specific AMP-dependent protein kinase. Intracellular Ado produced from AMP by allosterically regulated nucleotidases can be regarded as a stress signal as well. To study the receptor-independent effects of Ado, several experimental approaches have been proposed, such as inhibition or silencing of key enzymes of Ado metabolism, knockdown of Ado receptors in animals, the use of antagonists, or cell treatment with deoxyadenosine, which is substrate of the enzymes acting on Ado, but is unable to interact with Ado receptors. In this way, it was demonstrated that, among other functions, intracellular Ado modulates angiogenesis by regulating promoter methylation, induces hypothermia, promotes apoptosis in sympathetic neurons, and, in the case of oxygen and glucose deprivation, exerts a cytoprotective effect by replenishing the ATP pool. PMID- 29522450 TI - Pilot-Scale Hydrolysis-Aerobic Treatment for Actual Municipal Wastewater: Performance and Microbial Community Analysis. AB - Low-energy cost wastewater treatment is required to change its current energy intensive status. Although promising, the direct anaerobic digestion of municipal wastewater treatment faces challenges such as low organic content and low temperature, which require further development. The hydrolysis-aerobic system investigated in this study utilized the two well-proven processes of hydrolysis and aerobic oxidation. These have the advantages of efficient COD removal and biodegradability improvement with limited energy cost due to their avoidance of aeration. A pilot-scale hydrolysis-aerobic system was built for performance evaluation with actual municipal wastewater as feed. Results indicated that as high as 39-47% COD removal was achieved with a maximum COD load of 1.10 kg/m3.d. The dominant bacteria phyla included Proteobacteria (36.0%), Planctomycetes (15.4%), Chloroflexi (9.7%), Bacteroidetes (7.7%), Firmicutes (4.4%), Acidobacteria (2.5%), Actinobacteria (1.8%) and Synergistetes (1.3%), while the dominant genera included Thauera (3.42%) and Dechloromonas (3.04%). The absence of methanogens indicates that the microbial community was perfectly retained in the hydrolysis stage instead of in the methane-producing stage. PMID- 29522452 TI - Milk Fat Globule Membrane Attenuates High-Fat Diet-Induced Obesity by Inhibiting Adipogenesis and Increasing Uncoupling Protein 1 Expression in White Adipose Tissue of Mice. AB - Milk fat globule membrane (MFGM), a protein-lipid complex surrounding the fat globules in milk, has many health benefits. The aim of the current study was to investigate whether MFGM could prevent obesity through inhibiting adipogenesis and promoting brown remodeling of white adipose tissue (WAT) in mice fed with high-fat diet. C57BL/6 mice were fed a normal diet (ND), high-fat diet (HFD), HFD plus MFGM at 100 mg/kg BW, 200 mg/kg BW or 400 mg/kg BW for 8 weeks. Results showed that MFGM suppressed body weight gain induced by HFD, reduced white adipose tissue (WAT) mass accompanied with the decrease in adipocyte sizes. MFGM was found to have partially improved serum lipid profiles, as well as to have suppressed HFD-induced adipogenesis as shown by reduced expression of peroxisome proliferators-activator receptor-gamma (PPARgamma), CCAAT/enhancer-binding protein-alpha (C/EBPalpha) and sterol regulatory element-binding protein-1c (SREBP-1c). MFGM also markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), showing activation of AMPK pathway. Moreover, MFGM promoted browning of inguinal WAT by upregulation the protein expression of uncoupling protein 1 (UCP1) in HFD mice. Taken together, these findings provide evidence that MFGM may protect against diet induced adiposity by suppressing adipogenesis and promoting brown-like transformation in WAT. PMID- 29522453 TI - Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses. AB - The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis. PMID- 29522451 TI - The Application of Embelin for Cancer Prevention and Therapy. AB - Embelin is a naturally-occurring benzoquinone compound that has been shown to possess many biological properties relevant to human cancer prevention and treatment, and increasing evidence indicates that embelin may modulate various characteristic hallmarks of tumor cells. This review summarizes the information related to the various oncogenic pathways that mediate embelin-induced cell death in multiple cancer cells. The mechanisms of the action of embelin are numerous, and most of them induce apoptotic cell death that may be intrinsic or extrinsic, and modulate the NF-kappaB, p53, PI3K/AKT, and STAT3 signaling pathways. Embelin also induces autophagy in cancer cells; however, these autophagic cell-death mechanisms of embelin have been less reported than the apoptotic ones. Recently, several autophagy-inducing agents have been used in the treatment of different human cancers, although they require further exploration before being transferred from the bench to the clinic. Therefore, embelin could be used as a potential agent for cancer therapy. PMID- 29522454 TI - Effects of Elevated Hydrostatic Pressure against Mesophilic Background Microflora and Habituated Salmonella Serovars in Orange Juice. AB - With recent improvements in the commercial feasibility of high pressure pasteurization units, the technology is gaining rapid acceptability across various sectors of food manufacturing, thus requiring extensive validation studies for effective adoption. Various times (1 min to 10 min) and intensity levels (0 MPa to 380 MPa) of elevated hydrostatic pressure were investigated for decontamination of mesophilic background microflora and inoculated Salmonella in orange juice. Results were analyzed by GLM procedure of SAS using Tukey- and Dunnett-adjusted ANOVA, additionally the Kmax and D-values were calculated using best-fitted (maximum R2) model obtained by GInaFit software. At 380 MPa, for treatments of 1 min to 10 min, D-value of 1.35, and inactivation Kmax of 3.34 were observed for Salmonella serovars. D-values were 5.90 and 14.68 for treatments of 241 MPa and 103 MPa, respectively. Up to 1.01 and >7.22 log CFU/mL reductions (p < 0.05) of habituated Salmonella serovars at planktonic stages were achieved using application of pressure at 380 MPa for 1 min and 10 min, respectively. Mesophilic background microflora counts were reduced (p < 0.05) by 1.68 to 5.29 log CFU/mL after treatment at 380 MPa for 1 min and 10 min, respectively. Treatments below two minutes were less efficacious (p >= 0.05) against the pathogen and background microflora, in vast majority of time and pressure combinations. PMID- 29522455 TI - Fabrication of Fe-Co Magnetostrictive Fiber Reinforced Plastic Composites and Their Sensor Performance Evaluation. AB - The inverse magnetostrictive effect is an effective property for energy harvesting; the material needs to have large magnetostriction and ease of mass production. Fe-Co alloys being magnetostrictive materials have favorable characteristics which are high strength, ductility, and excellent workability, allowing easy fabrication of Fe-Co alloy fibers. In this study, we fabricated magnetostrictive polymer composites, in which Fe-Co fibers were woven into polyester fabric, and discussed their sensor performance. Compression and bending tests were carried out to measure the magnetic flux density change, and the effects of magnetization, bias magnetic field, and the location of the fibers on the performance were discussed. It was shown that magnetic flux density change due to compression and bending is related to the magnetization of the Fe-Co fiber and the bias magnetic field. The magnetic flux density change of Fe-Co fiber reinforced plastics was larger than that of the plastics with Terfenol-D particles. PMID- 29522456 TI - A Data Cleaning Method for Big Trace Data Using Movement Consistency. AB - Given the popularization of GPS technologies, the massive amount of spatiotemporal GPS traces collected by vehicles are becoming a new kind of big data source for urban geographic information extraction. The growing volume of the dataset, however, creates processing and management difficulties, while the low quality generates uncertainties when investigating human activities. Based on the conception of the error distribution law and position accuracy of the GPS data, we propose in this paper a data cleaning method for this kind of spatial big data using movement consistency. First, a trajectory is partitioned into a set of sub-trajectories using the movement characteristic points. In this process, GPS points indicate that the motion status of the vehicle has transformed from one state into another, and are regarded as the movement characteristic points. Then, GPS data are cleaned based on the similarities of GPS points and the movement consistency model of the sub-trajectory. The movement consistency model is built using the random sample consensus algorithm based on the high spatial consistency of high-quality GPS data. The proposed method is evaluated based on extensive experiments, using GPS trajectories generated by a sample of vehicles over a 7-day period in Wuhan city, China. The results show the effectiveness and efficiency of the proposed method. PMID- 29522457 TI - Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets. AB - Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC). Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2) amplification and programmed death-ligand 1 (PD-L1) expression for effectiveness of trastuzumab and pembrolizumab, respectively. Multi-platform molecular analysis of cancer, including GC, may help identify predictive biomarkers to guide selection of therapeutic agents. Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Complementary to molecular characterization of GC is molecular profiling by expression analysis and genomic sequencing of tumor DNA. Initial analysis of patients with gastroesophageal carcinoma demonstrates that the ratio of progression-free survival (PFS) on molecular profile (MP)-based treatment to PFS on treatment prior to molecular profiling exceeds 1.3, suggesting the potential value of MP in guiding selection of individualized therapy. Future strategies aiming to integrate molecular classification and profiling of tumors with therapeutic agents for achieving the goal of personalized treatment of GC are indicated. PMID- 29522458 TI - Moving Object Localization Based on UHF RFID Phase and Laser Clustering. AB - RFID (Radio Frequency Identification) offers a way to identify objects without any contact. However, positioning accuracy is limited since RFID neither provides distance nor bearing information about the tag. This paper proposes a new and innovative approach for the localization of moving object using a particle filter by incorporating RFID phase and laser-based clustering from 2d laser range data. First of all, we calculate phase-based velocity of the moving object based on RFID phase difference. Meanwhile, we separate laser range data into different clusters, and compute the distance-based velocity and moving direction of these clusters. We then compute and analyze the similarity between two velocities, and select K clusters having the best similarity score. We predict the particles according to the velocity and moving direction of laser clusters. Finally, we update the weights of the particles based on K clusters and achieve the localization of moving objects. The feasibility of this approach is validated on a Scitos G5 service robot and the results prove that we have successfully achieved a localization accuracy up to 0.25 m. PMID- 29522459 TI - Which Dendrimer to Attain the Desired Properties? Focus on Phosphorhydrazone Dendrimers. AB - Among the six Critical Nanoscale Design Parameters (CNDPs) proposed by Prof. Donald A. Tomalia, this review illustrates the influence of the sixth one, which concerns the elemental composition, on the properties of dendrimers. After a large introduction that summarizes different types of dendrimers that have been compared with PolyAMidoAMine (PAMAM) dendrimers, this review will focus on the properties of positively and negatively charged phosphorhydrazone (PPH) dendrimers, especially in the field of biology, compared with other types of dendrimers, in particular PAMAM dendrimers, as well as polypropyleneimine (PPI), carbosilane, and p-Lysine dendrimers. PMID- 29522460 TI - Mapping Wildfire Ignition Probability Using Sentinel 2 and LiDAR (Jerte Valley, Caceres, Spain). AB - Wildfire is a major threat to the environment, and this threat is aggravated by different climatic and socioeconomic factors. The availability of detailed, reliable mapping and periodic and immediate updates makes wildfire prevention and extinction work more effective. An analyst protocol has been generated that allows the precise updating of high-resolution thematic maps. For this protocol, images obtained through the Sentinel 2A satellite, with a return time of five days, have been merged with Light Detection and Ranging (LiDAR) data with a density of 0.5 points/m2 in order to obtain vegetation mapping with an accuracy of 88% (kappa = 0.86), which is then extrapolated to fuel model mapping through a decision tree. This process, which is fast and reliable, serves as a cartographic base for the later calculation of ignition-probability mapping. The generated cartography is a fundamental tool to be used in the decision making involved in the planning of preventive silvicultural treatments, extinguishing media distribution, infrastructure construction, etc. PMID- 29522461 TI - Effects of Different Metals on Photosynthesis: Cadmium and Zinc Affect Chlorophyll Fluorescence in Durum Wheat. AB - A comparative study of the effects of exposure to high Cd2+ (50 uM) and excess Zn2+ (600 uM) on photosynthetic performance of hydroponically-grown durum wheat seedlings was performed. At day 8, Cd and Zn were added to the nutrient solution. After 7-days exposure, the chosen concentrations of both metals resulted in similar relative growth rate (RGR) inhibitions of about 50% and comparable retardations of the CO2 assimilation rates (about 30%) in the second developed leaf of wheat seedlings. Analysis of chlorophyll a fluorescence indicated that both metals disturbed photosynthetic electron transport processes which led to a 4- to 5-fold suppression of the efficiency of energy transformation in Photosystem II. Non-specific toxic effects of Cd and Zn, which prevailed, were an inactivation of part of Photosystem II reaction centres and their transformation into excitation quenching forms as well as disturbed electron transport in the oxygen-evolving complex. The specificity of the Cd and Zn modes of action was mainly expressed in the intensity of the toxicity effects: despite the similar inhibitions of the CO2 assimilation rates, the wheat photochemistry showed much more sensitivity to Cd than to Zn exposure. PMID- 29522463 TI - Dating Pupae of the Blow Fly Calliphora vicina Robineau-Desvoidy 1830 (Diptera: Calliphoridae) for Post Mortem Interval-Estimation: Validation of Molecular Age Markers. AB - Determining the age of juvenile blow flies is one of the key tasks of forensic entomology when providing evidence for the minimum post mortem interval. While the age determination of blow fly larvae is well established using morphological parameters, the current study focuses on molecular methods for estimating the age of blow flies during the metamorphosis in the pupal stage, which lasts about half the total juvenile development. It has already been demonstrated in several studies that the intraspecific variance in expression of so far used genes in blow flies is often too high to assign a certain expression level to a distinct age, leading to an inaccurate prediction. To overcome this problem, we previously identified new markers, which show a very sharp age dependent expression course during pupal development of the forensically-important blow fly Calliphora vicina Robineau-Desvoidy 1830 (Diptera: Calliphoridae) by analyzing massive parallel sequencing (MPS) generated transcriptome data. We initially designed and validated two quantitative polymerase chain reaction (qPCR) assays for each of 15 defined pupal ages representing a daily progress during the total pupal development if grown at 17 degrees C. We also investigated whether the performance of these assays is affected by the ambient temperature, when rearing pupae of C. vicina at three different constant temperatures-namely 17 degrees C, 20 degrees C and 25 degrees C. A temperature dependency of the performance could not be observed, except for one marker. Hence, for each of the defined development landmarks, we can present gene expression profiles of one to two markers defining the mentioned progress in development. PMID- 29522462 TI - Venomics-Accelerated Cone Snail Venom Peptide Discovery. AB - Cone snail venoms are considered a treasure trove of bioactive peptides. Despite over 800 species of cone snails being known, each producing over 1000 venom peptides, only about 150 unique venom peptides are structurally and functionally characterized. To overcome the limitations of the traditional low-throughput bio discovery approaches, multi-omics systems approaches have been introduced to accelerate venom peptide discovery and characterisation. This "venomic" approach is starting to unravel the full complexity of cone snail venoms and to provide new insights into their biology and evolution. The main challenge for venomics is the effective integration of transcriptomics, proteomics, and pharmacological data and the efficient analysis of big datasets. Novel database search tools and visualisation techniques are now being introduced that facilitate data exploration, with ongoing advances in related omics fields being expected to further enhance venomics studies. Despite these challenges and future opportunities, cone snail venomics has already exponentially expanded the number of novel venom peptide sequences identified from the species investigated, although most novel conotoxins remain to be pharmacologically characterised. Therefore, efficient high-throughput peptide production systems and/or banks of miniaturized discovery assays are required to overcome this bottleneck and thus enhance cone snail venom bioprospecting and accelerate the identification of novel drug leads. PMID- 29522464 TI - Isolation of Brucella abortus and Brucella melitensis from Seronegative Cows is a Serious Impediment in Brucellosis Control. AB - Brucellosis is a zoonosis occurring worldwide, with economic and public health impacts. Its diagnosis remains a challenge in endemic countries and basically relies on serology. The present study was carried out on two dairy cattle farms allegedly free from brucellosis, but with sporadic cases of abortion. The aim of this study was to investigate the presence of Brucella (B.) spp. in uterine discharge of seronegative cows after abortion. In farm I, B. melitensis biovar (bv) 3 was cultured from two of five cows after abortion, while in farm II, B. abortus bv 1 was cultured from three of eleven cows after abortion. These cows had been intrauterinely infected but remained seronegative until abortion and seroconverted only thereafter. Shedding of brucellae in uterine discharge of culture positive/seronegative aborting cows is a serious problem resulting in maintenance and further spread of infection. Thus, serosurveys in endemic countries have to be accompanied by molecular detection and/or culture of aborted material to close the diagnostic window and to hinder uncontrolled spread. PMID- 29522465 TI - Fine Mapping Identifies SmFAS Encoding an Anthocyanidin Synthase as a Putative Candidate Gene for Flower Purple Color in Solanum melongena L. AB - Anthocyanins are the main pigments in flowers and fruits. These pigments are responsible for the red, red-purple, violet, and purple color in plants, and act as insect and animal attractants. In this study, phenotypic analysis of the purple flower color in eggplant indicated that the flower color is controlled by a single dominant gene, FAS. Using an F2 mapping population derived from a cross between purple-flowered 'Blacknite' and white-flowered 'Small Round', FlowerAnthocyanidin Synthase (FAS) was fine mapped to an approximately 165.6-kb region between InDel marker Indel8-11 and Cleaved Amplified Polymorphic Sequences (CAPS) marker Efc8-32 on Chromosome 8. On the basis of bioinformatic analysis, 29 genes were subsequently located in the FAS target region, among which were two potential Anthocyanidin Synthase (ANS) gene candidates. Allelic sequence comparison results showed that one ANS gene (Sme2.5_01638.1_g00003.1) was conserved in promoter and coding sequences without any nucleotide change between parents, whereas four single-nucleotide polymorphisms were detected in another ANS gene (Sme2.5_01638.1_g00005.1). Crucially, a single base pair deletion at site 438 resulted in premature termination of FAS, leading to the loss of anthocyanin accumulation. In addition, FAS displayed strong expression in purple flowers compared with white flowers and other tissues. Collectively, our results indicate that Sme2.5_01638.1_g00005.1 is a good candidate gene for FAS, which controls anthocyanidin synthase in eggplant flowers. The present study provides information for further potential facilitate genetic engineering for improvement of anthocyanin levels in plants. PMID- 29522467 TI - A Backpack-Mounted Omnidirectional Camera with Off-the-Shelf Navigation Sensors for Mobile Terrestrial Mapping: Development and Forest Application. AB - The use of Personal Mobile Terrestrial System (PMTS) has increased considerably for mobile mapping applications because these systems offer dynamic data acquisition with ground perspective in places where the use of wheeled platforms is unfeasible, such as forests and indoor buildings. PMTS has become more popular with emerging technologies, such as miniaturized navigation sensors and off-the shelf omnidirectional cameras, which enable low-cost mobile mapping approaches. However, most of these sensors have not been developed for high-accuracy metric purposes and therefore require rigorous methods of data acquisition and data processing to obtain satisfactory results for some mapping applications. To contribute to the development of light, low-cost PMTS and potential applications of these off-the-shelf sensors for forest mapping, this paper presents a low-cost PMTS approach comprising an omnidirectional camera with off-the-shelf navigation systems and its evaluation in a forest environment. Experimental assessments showed that the integrated sensor orientation approach using navigation data as the initial information can increase the trajectory accuracy, especially in covered areas. The point cloud generated with the PMTS data had accuracy consistent with the Ground Sample Distance (GSD) range of omnidirectional images (3.5-7 cm). These results are consistent with those obtained for other PMTS approaches. PMID- 29522466 TI - Fluostatins M-Q Featuring a 6-5-6-6 Ring Skeleton and High Oxidized A-Rings from Marine Streptomyces sp. PKU-MA00045. AB - Aromatic polyketides from marine actinomycetes have received increasing attention due to their unusual structures and potent bioactivities. Compared to their terrestrial counterparts, marine aromatic polyketides have been less discovered and their structural and biological diversities are far from being fully investigated. In this study, we employed a PCR-based genome mining method to discover aromatic polyketides in our marine bacteria collection. Five new atypical angucyclinones, fluostatins M-Q (1-5) featuring a unique 6-5-6-6 ring skeleton, were discovered from one "positive" Streptomyces sp. PKU-MA00045. The structures of fluostatins M-Q (1-5) were elucidated based on comprehensive spectroscopic analyses and the crystallographic structure of fluostatin P (4), which contains the most oxidized A-ring, was solved by X-ray diffraction analysis with Cu Kalpha radiation. Compared to the published 16 fluostatin analogues, fluostatins M-Q (1-5) contained a different methoxy group attached at C-7 and hydroxy group attached at C-4, enriching the structural diversity of aromatic polyketides from marine actinomycetes. Genome sequencing of Streptomyces sp. PKU MA00045 revealed the biosynthetic gene cluster of fluostatins M-Q (1-5), which contained different genes and gene organizations compared to known fluostatin gene clusters, facilitating the investigation of the biosynthesis of the unique 6 5-6-6 ring skeleton in all fluostatins. PMID- 29522468 TI - Surface Roughness of Composite Panels as a Quality Control Tool. AB - This paper describes a study of the quantify surface roughness of experimentally manufactured particleboards and sandwiched panels having fibers on the surface layers. Surface quality of specimens before and after being overlaid with thin melamine impregnated papers was determined by employing profilometer equipment. Roughness measurements and Janka hardness were carried out on the specimens conditioned at 60% and 95% relative humidity levels. Based on the findings in this work, surface roughness of the specimens that were exposed two relative humidity exposure showed significant differences from each others. Data determined in this study could be beneficial to understand behavior of such panels exposed different humidity levels. PMID- 29522469 TI - Range Expansion of Tick Disease Vectors in North America: Implications for Spread of Tick-Borne Disease. AB - Ticks are the major vectors of most disease-causing agents to humans, companion animals and wildlife. Moreover, ticks transmit a greater variety of pathogenic agents than any other blood-feeding arthropod. Ticks have been expanding their geographic ranges in recent decades largely due to climate change. Furthermore, tick populations in many areas of their past and even newly established localities have increased in abundance. These dynamic changes present new and increasing severe public health threats to humans, livestock and companion animals in areas where they were previously unknown or were considered to be of minor importance. Here in this review, the geographic status of four representative tick species are discussed in relation to these public health concerns, namely, the American dog tick, Dermacentor variabilis, the lone star tick, Amblyomma americanum, the Gulf Coast Tick, Amblyomma maculatum and the black-legged tick, Ixodes scapularis. Both biotic and abiotic factors that may influence future range expansion and successful colony formation in new habitats are discussed. PMID- 29522470 TI - A Review of Success Factors for Piglet Fostering in Lactation. AB - Piglet movement from one sow to another, or fostering, is required in modern pig farming but there is little available literature on the most effective strategy. In this review, we focus on the behavioural and physiological mechanisms responsible for piglet survival and growth, and have identified six key principles. (1) Colostrum provides piglets with warmth, energy and immunity. It is most accessible during the first 12 h from the birth sow, therefore no piglet should be moved before this; (2) To ensure even intake of birth sow colostrum, techniques such as split suckling prior to piglet movement should be implemented; (3) Udder assessment for functional teats should occur at farrowing, with number of fostered piglets not exceeding teat number; (4) Primiparous sows should receive as many piglets as the udder allows to maximise mammary stimulation, although older parities should be assessed for rearing ability; (5) Piglet fostering should occur between 12 and 24 h and movement kept to a minimum to prevent transfer of disease; Litter outliers should be moved and relocated to a litter of similar size; (6) Piglet movement after 24 h should be minimised. When required, strategies such as nurse usage should be employed. These principles will result in improved farrowing house performance by increasing the litter weight weaned per sow. PMID- 29522471 TI - Outcomes for Women with Gestational Diabetes Treated with Metformin: A Retrospective, Case-Control Study. AB - Metformin is increasingly being used a therapeutic option for the management of gestational diabetes mellitus (GDM). The aim of this study was to compare the maternal characteristics and perinatal outcomes of women with GDM treated with metformin (with or without supplemental insulin) with those receiving other management approaches. A retrospective, case-control study was carried out and 83 women taking metformin were matched 1:1 with women receiving insulin or diet and lifestyle modification alone. Women managed with diet and lifestyle modification had a significantly lower fasting plasma glucose (p < 0.001) and HbA1c (p < 0.01) at diagnosis of GDM. Furthermore, women managed with metformin had a higher early pregnancy body mass index (BMI) compared to those receiving insulin or diet and lifestyle modification (p < 0.001). There was no difference in mode of delivery, birth weight or incidence of large- or small-for-gestational-age neonates between groups. Women receiving glucose lowering therapies had a higher rate of neonatal hypoglycaemia (p < 0.05). The incidence of other adverse perinatal outcomes was similar between groups. Despite their greater BMI, women with metformin-treated GDM did not have an increased risk of adverse perinatal outcomes. Metformin is a useful alternative to insulin in the management of GDM. PMID- 29522472 TI - A Surface Plasmon Resonance-Based Optical Fiber Probe Fabricated with Electropolymerized Molecular Imprinting Film for Melamine Detection. AB - Molecularly imprinted polymer (MIP) films prepared by bulk polymerization suffer from numerous deficiencies, including poor mass transfer ability and difficulty in controlling reaction rate and film thickness, which usually result in poor repeatability. However, polymer film synthesized by electropolymerization methods benefit from high reproducibility, simplicity and rapidity of preparation. In the present study, an Au film served as the refractive index-sensitive metal film to couple with the light leaked out from optical fiber core and the electrode for electropolymerizing MIP film simultaneously. The manufactured probe exhibited satisfactory sensitivity and specificity. Furthermore, the surface morphology and functional groups of the synthesized MIP film were characterized by Atomic Force Microscopy (AFM) and Fourier transform infrared microspectroscopy (FTIR) for further insights into the adsorption and desorption processes. Given the low cost, label-free test, simple preparation process and fast response, this method has a potential application to monitor substances in complicated real samples for out-of-lab test in the future. PMID- 29522473 TI - Dynamic Recrystallization Behavior and Corrosion Resistance of a Dual-Phase Mg-Li Alloy. AB - The hot deformation and dynamic recrystallization behavior of the dual-phase Mg 9Li-3Al-2Sr-2Y alloy had been investigated using a compression test. The typical dual-phase structure was observed, and average of grain size of as-homogenized alloy is about 110 um. It mainly contains beta-Li, alpha-Mg, Al4Sr and Al2Y phases. The dynamic recrystallization (DRX) kinetic was established based on an Avrami type equation. The onset of the DRX process occurred before the peak of the stress-strain flow curves. It shows that the DRX volume fraction increases with increasing deformation temperature or decreasing strain rate. The microstructure evolution during the hot compression at various temperatures and strain rates had been investigated. The DRX grain size became larger with the increasing testing temperature or decreasing strain rate because the higher temperature or lower strain rate can improve the migration of DRX grain boundaries. The fully recrystallized microstructure can be achieved in a small strain due to the dispersed island-shape alpha-Mg phases, continuous the Al4Sr phases and spheroidal Al2Y particles, which can accelerate the nucleation. The continuous Al4Sr phases along the grain boundaries are very helpful for enhancing the corrosion resistance of the duplex structured Mg-Li alloy, which can prevent the pitting corrosion and filiform corrosion. PMID- 29522474 TI - Multiresistant Bacteria Isolated from Activated Sludge in Austria. AB - Wastewater contains different kinds of contaminants, including antibiotics and bacterial isolates with human-generated antibiotic resistances. In industrialized countries most of the wastewater is processed in wastewater treatment plants which do not only include commercial wastewater, but also wastewater from hospitals. Three multiresistant pathogens-extended spectrum beta-lactamase (ESBL) harbouring Enterobacteriaceae (Gram negative bacilli), methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE)-were chosen for screening in a state of the art wastewater treatment plant in Austria. Over an investigation period of six months all three multiresistant pathogens could be isolated from activated sludge. ESBL was the most common resistance mechanism, which was found in different species of Enterobacteriaceae, and in one Aeromonas spp. Sequencing of ESBL genes revealed the dominance of genes encoding members of CTX-M beta-lactamases family and a gene encoding for PER-1 ESBL was detected for the first time in Austria. MRSA and VRE could be isolated sporadically, including one EMRSA-15 isolate. Whereas ESBL is well documented as a surface water contaminant, reports of MRSA and VRE are rare. The results of this study show that these three multiresistant phenotypes were present in activated sludge, as well as species and genes which were not reported before in the region. The ESBL-harbouring Gram negative bacilli were most common. PMID- 29522476 TI - Using Bi-Seasonal WorldView-2 Multi-Spectral Data and Supervised Random Forest Classification to Map Coastal Plant Communities in Everglades National Park. AB - Coastal plant communities are being transformed or lost because of sea level rise (SLR) and land-use change. In conjunction with SLR, the Florida Everglades ecosystem has undergone large-scale drainage and restoration, altering coastal vegetation throughout south Florida. To understand how coastal plant communities are changing over time, accurate mapping techniques are needed that can define plant communities at a fine-enough resolution to detect fine-scale changes. We explored using bi-seasonal versus single-season WorldView-2 satellite data to map three mangrove and four adjacent plant communities, including the buttonwood/glycophyte community that harbors the federally-endangered plant Chromolaena frustrata. Bi-seasonal data were more effective than single-season to differentiate all communities of interest. Bi-seasonal data combined with Light Detection and Ranging (LiDAR) elevation data were used to map coastal plant communities of a coastal stretch within Everglades National Park (ENP). Overall map accuracy was 86%. Black and red mangroves were the dominant communities and covered 50% of the study site. All the remaining communities had <=10% cover, including the buttonwood/glycophyte community. ENP harbors 21 rare coastal species threatened by SLR. The spatially explicit, quantitative data provided by our map provides a fine-scale baseline for monitoring future change in these species' habitats. Our results also offer a method to monitor vegetation change in other threatened habitats. PMID- 29522477 TI - Promising Detoxification Strategies to Mitigate Mycotoxins in Food and Feed. AB - Mycotoxins are secondary fungal metabolites associated with adverse human health and animal productivity consequences.[...]. PMID- 29522479 TI - Strain Behavior of Concrete Panels Subjected to Different Nose Shapes of Projectile Impact. AB - This study evaluates the fracture properties and rear-face strain distribution of nonreinforced and hooked steel fiber-reinforced concrete panels penetrated by projectiles of three different nose shapes: sharp, hemispherical, and flat. The sharp projectile nose resulted in a deeper penetration because of the concentration of the impact force. Conversely, the flat projectile nose resulted in shallower penetrations. The penetration based on different projectile nose shapes is directly related to the impact force transmitted to the rear face. Scabbing can be more accurately predicted by the tensile strain on the rear face of concrete due to the projectile nose shape. The tensile strain on the rear face of the concrete was reduced by the hooked steel fiber reinforcement because the hooked steel fiber absorbed some of the impact stress transmitted to the rear face of the concrete. Consequently, the strain behavior on the rear face of concrete according to the projectile nose shape was confirmed. PMID- 29522478 TI - Marine Spongin: Naturally Prefabricated 3D Scaffold-Based Biomaterial. AB - The biosynthesis, chemistry, structural features and functionality of spongin as a halogenated scleroprotein of keratosan demosponges are still paradigms. This review has the principal goal of providing thorough and comprehensive coverage of spongin as a naturally prefabricated 3D biomaterial with multifaceted applications. The history of spongin's discovery and use in the form of commercial sponges, including their marine farming strategies, have been analyzed and are discussed here. Physicochemical and material properties of spongin-based scaffolds are also presented. The review also focuses on prospects and trends in applications of spongin for technology, materials science and biomedicine. Special attention is paid to applications in tissue engineering, adsorption of dyes and extreme biomimetics. PMID- 29522480 TI - Study of Hyperbranched Poly(ethyleneimine) Polymers of Different Molecular Weight and Their Interaction with Epoxy Resin. AB - Two different commercial hyperbranched poly(ethyleneimine)s (HBPEI), with molecular weights (MW) of 800 and 25,000 g/mol, and denoted as PEI800 and PEI25000, respectively, as well as the mixtures with a Diglycidyl Ether of Bisphenol-A (DGEBA) epoxy resin, have been studied using thermal analysis techniques (DSC, TGA), dielectric relaxation spectroscopy (DRS), and dynamic mechanical analysis (DMA). Only a single glass transition is observed in these mixtures by DSC. DRS of the HBPEIs shows three dipolar relaxations: gamma, beta, and alpha. The average activation energy for the gamma-relaxation is similar for all HBPEIs and is associated with the motion of the terminal groups. The beta relaxation has the same average activation energy for both PEI800 and PEI25000; this relaxation is attributed to the mobility of the branches. The alpha relaxation peak for all the HBPEIs is an asymmetric peak with a shoulder on the high temperature side. This shoulder suggests the existence of ionic charge trapped in the PEI. For the mixtures, the gamma- and beta-relaxations follow the behaviour of the epoxy resin alone, indicating that the epoxy resin dominates the molecular mobility. The alpha-relaxation by DRS is observed only as a shoulder, as a consequence of an overlap with conductivity effects, whereas by DMA, it is a clear peak. PMID- 29522475 TI - Natural Variation in Resistance to Virus Infection in Dipteran Insects. AB - The power and ease of Drosophila genetics and the medical relevance of mosquito transmitted viruses have made dipterans important model organisms in antiviral immunology. Studies of virus-host interactions at the molecular and population levels have illuminated determinants of resistance to virus infection. Here, we review the sources and nature of variation in antiviral immunity and virus susceptibility in model dipteran insects, specifically the fruit fly Drosophila melanogaster and vector mosquitoes of the genera Aedes and Culex. We first discuss antiviral immune mechanisms and describe the virus-specificity of these responses. In the following sections, we review genetic and microbiota-dependent variation in antiviral immunity. In the final sections, we explore less well studied sources of variation, including abiotic factors, sexual dimorphism, infection history, and endogenous viral elements. We borrow from work on other pathogen types and non-dipteran species when it parallels or complements studies in dipterans. Understanding natural variation in virus-host interactions may lead to the identification of novel restriction factors and immune mechanisms and shed light on the molecular determinants of vector competence. PMID- 29522481 TI - Factors Affecting the Power Conversion Efficiency in ZnO DSSCs: Nanowire vs. Nanoparticles. AB - A comparative assessment of nanowire versus nanoparticle-based ZnO dye-sensitized solar cells (DSSCs) is conducted to investigate the main parameters that affect device performance. Towards this aim, the influence of film morphology, dye adsorption, electron recombination and sensitizer pH on the power conversion efficiency (PCE) of the DSSCs is examined. Nanoparticle-based DSSCs with PCEs of up to 6.2% are developed and their main characteristics are examined. The efficiency of corresponding devices based on nanowire arrays (NW) is considerably lower (0.63%) by comparison, mainly due to low light harvesting ability of ZnO nanowire films. The dye loading of nanowire films is found to be approximately an order of magnitude lower than that of nanoparticle-based ones, regardless of their internal surface area. Inefficient anchoring of dye molecules on the semiconductor surface due to repelling electrostatic forces is identified as the main reason for this low dye loading. We propose a method of modifying the sensitizer solution by altering its pH, thereby enhancing dye adsorption. We report an increase in the PCE of nanowire DSSCs from 0.63% to 1.84% as a direct result of using such a modified dye solution. PMID- 29522482 TI - Optimization of Conditions for Extraction of Polyphenols and the Determination of the Impact of Cooking on Total Polyphenolic, Antioxidant, and Anticholinesterase Activities of Potato. AB - In this work we optimized the cooking and extraction conditions for obtaining high yields of total polyphenols from potato and studied the effect of three domestic methods of cooking on total phenols, antioxidant activity, and anticholinesterase activities. The optimization of the experiment was carried out by the experimental designs. The extraction of the polyphenols was carried out by maceration and ultrasonication. Determination of the polyphenols was performed by using the Folin-Ciocalteau reagent method. The antioxidant activity was evaluated by three methods: 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS), and CUPRAC(Cupric reducing antioxidant capacity), the anticholinesterase activity was evaluated by the method of Elmann. The optimum of total phenolic obtained was: 4.668 * 104, 1.406 * 104, 3357.009, 16,208.99 ug Gallic Acid Equivalent (GAE)/g of dry extract for crude potato, steamed potatoes, in boiling water, and by microwave, respectively. The three modes of cooking cause a decrease in the total polyphenol contents, antioxidant and anticholinesterase activities. PMID- 29522483 TI - Virucidal or Not Virucidal? That Is the Question-Predictability of Ionic Liquid's Virucidal Potential in Biological Test Systems. AB - For three decades now, ionic liquids (ILs), organic salts comprising only ions, have emerged as a new class of pharmaceuticals. Although recognition of the antimicrobial effects of ILs is growing rapidly, there is almost nothing known about their possible virucidal activities. This probably reflects the paucity of understanding virus inactivation. In this study, we performed a systematic analysis to determine the effect of specific structural motifs of ILs on three different biological test systems (viruses, bacteria and enzymes). Overall, the effects of 27 different ILs on two non-enveloped and one enveloped virus (P100, MS2 and Phi6), two Gram negative and one Gram positive bacteria (E. coli, P. syringae and L. monocytogenes) and one enzyme (Taq DNA polymerase) were investigated. Results show that while some ILs were virucidal, no clear structure activity relationships (SARs) could be identified for the non-enveloped viruses P100 and MS2. However, for the first time, a correlation has been demonstrated between the effects of ILs on enveloped viruses, bacteria and enzyme inhibition. These identified SARs serve as a sound starting point for further studies. PMID- 29522485 TI - A Descriptive Morphometric Approach of the Skull and Mandible of the Common Opossum (Didelphis Marsupialis Linnaeus, 1758) in the Caribbean and its Clinical Application during Regional Anaesthesia. AB - The aim of this study was to determine the morphometric values of the skull and the mandible of the common opossum from the Caribbean island of Trinidad and Tobago. The skulls and mandibles were obtained from ten opossums captured for research purposes. The skulls and mandibles were prepared and cleaned using standard method. Some anatomical landmarks of the skulls and mandibles were identified and measured. The results were important for identification of the common opossum via comparison and discussion of our results with that of other marsupial species. Furthermore, the results had clinical importance with regard to regional nerve blocks of the infraorbital, inferior alveolar, and mental nerves for dental extraction and head surgery. This study concluded that by using the anatomical landmarks of the infraorbital and mental foramina it will be easier for the veterinarian surgeons during the application of local anesthetic agent for the infraorbital, inferior alveolar, and mental nerve blocks. PMID- 29522486 TI - Internet Use and Psychological Well-Being at Advanced Age: Evidence from the English Longitudinal Study of Aging. AB - This work explores the connection between psychological well-being and Internet use in older adults. The study is based on a sample of 2314 participants in the English Longitudinal Study of Aging. The subjects, aged 50 years and older, were interviewed every two years over the 2006-2007 to 2014-2015 period. The connection between the use of Internet/Email and the main dimensions of psychological well-being (evaluative, hedonic and eudaimonic) was analyzed by means of three generalized estimating equation models that were fitted on 2-year lagged repeated measurements. The outcome variables, the scores on three well being scales, were explained in terms of Internet/Email use, controlling for covariates that included health and socioeconomic indicators. The results support the existence of a direct relationship between Internet/Email use and psychological well-being. The connection between the main predictor and the score of the participants on the scale used to measure the eudaimonic aspect was positive and statistically significant at conventional levels (p-value: 0.015). However, the relevance of digital literacy on the evaluative and the hedonic components could not be confirmed (p-values for evaluative and hedonic dimensions were 0.078 and 0.192, respectively). PMID- 29522484 TI - Antiviral Effects of ABMA against Herpes Simplex Virus Type 2 In Vitro and In Vivo. AB - Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1 adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2 induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 MUM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment. PMID- 29522487 TI - Reanalysis of Epidemiological Investigation of Cancer Risk among People Residing near Nuclear Power Plants in South Korea. AB - Background: A 20-year follow-up study on cancer incidence among people living near nuclear power plants in South Korea ended in 2011 with a finding of significantly, but inconsistently, elevated thyroid cancer risk for females. Reanalysis of the original study was carried out to examine the dose-response relationship further, and to investigate any evidence of detection bias. Methods: In addition to replicating the original Cox proportional hazards models, nested case-control analysis was carried out for all subjects and for four different birth cohorts to examine the effects of excluding participants with pre-existing cancer history at enrollment. The potential for detection bias was investigated using the records of medical utilization and voluntary health checks of comparison groups. Results: The overall risk profile of the total sample was similar to that of the original study. However, in the stratified analysis of four birth cohorts, the cancer risk among people living near nuclear power plants became higher in younger birth cohorts. This was especially true for thyroid cancers of females (hazard ratio (HR) 3.38) and males (HR 1.74), female breast cancers (HR 2.24), and radiation-related cancers (HR 1.59 for males, HR 1.77 for females), but not for radiation-insensitive cancers (HR 0.59 for males, HR 0.98 for females). Based on medical records and health check reports, we found no differences between comparison groups that could have led to detection bias. Conclusions: The overall results suggest elevated risk of radiation-related cancers among residents living near nuclear power plants, controlling for the selective survival effect. This is further supported by the lack of evidence of detection bias and by records of environmental exposure from radiation waste discharge. PMID- 29522488 TI - Detecting Sulfuric and Nitric Acid Rain Stresses on Quercus glauca through Hyperspectral Responses. AB - Acid rain, which has become one of the most severe global environmental issues, is detrimental to plant growth. However, effective methods for monitoring plant responses to acid rain stress are currently lacking. The hyperspectral technique provides a cost-effective and nondestructive way to diagnose acid rain stresses. Taking a widely distributed species (Quercus glauca) in Southern China as an example, this study aims to monitor the hyperspectral responses of Q. glauca to simulated sulfuric acid rain (SAR) and nitric acid rain (NAR). A total of 15 periods of leaf hyperspectral data under four pH levels of SAR and NAR were obtained during the experiment. The results showed that hyperspectral information could be used to distinguish plant responses under acid rain stress. An index (green peak area index, GPAI) was proposed to indicate acid rain stresses, based on the significantly variations in the region of 500-660 nm. Light acid rain (pH 4.5 SAR and NAR) promoted Q. glauca growth relative to the control groups (pH 5.6 SAR and NAR); moderate acid rain (pH 3.0 SAR) firstly promoted and then inhibited plant growth, while pH 3.0 NAR showed mild inhibitory effects during the experiment; and heavy acid rain (pH 2.0) significantly inhibited plant growth. Compared with NAR, SAR induced more serious damages to Q. glauca. These results could help monitor acid rain stress on plants on a regional scale using remote sensing techniques. PMID- 29522489 TI - Bovine Vaccinia: Insights into the Disease in Cattle. AB - Bovine vaccinia (BV), caused by Vaccinia virus (VACV), is a zoonosis characterized by exanthematous lesions in the teats of dairy cows and the hands of milkers and is an important public health issue. Severe VACV-induced lesions in the teats and udder of cows and buffaloes could lead to mastitis and other secondary infections, thereby reducing productivity and resulting in economic losses to the dairy industry. In Brazil, BV re-emerged in the late 1990s and is now endemic in most of the Brazilian territory. In the last 15 years, much effort has been made to know more about this disease and its epidemiology, etiologic agents, and interactions with the host and the environment. In this review, we describe the known dynamics of VACV infection in cattle and the viral shedding routes, as well as the relevance of BV for animal and public health. PMID- 29522490 TI - Suppression of Cell Growth, Migration and Drug Resistance by Ethanolic Extract of Antrodia cinnamomea in Human Lung Cancer A549 Cells and C57BL/6J Allograft Tumor Model. AB - The purpose of this study was to investigate the inhibitory activities of ethanolic extracts from Antrodia cinnamomea (EEAC) on lung cancer. Cell proliferation and cell cycle distribution were analyzed using (3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and flow cytometry, respectively. Wound-healing assay, Western blotting, and a murine tumor model were separately used to examine cell migration, protein expression, and tumor repression. Our results showed that EEAC induced cell cycle arrest at the G0/G1 phase resulting decreased cell viability in A549 cells. Moreover, EEAC up-regulated the growth-suppressing proteins, adenosine 5'-monophosphate activated protein kinase (AMPK), p21 and p27, but down-regulated the growth promoting proteins, protein kinase B (Akt), mammalian tarfet of rapamycin (mTOR), extracellular signal-regulating kinase 1/2 (ERK1/2), retinoblastoma protein (Rb), cyclin E, and cyclin D1. EEAC also inhibited A549 cell migration and reduced expression of gelatinases. In addition, our data showed that tumor growth was suppressed after treatment with EEAC in a murine allograft tumor model. Some bioactive compounds from EEAC, such as cordycepin and zhankuic acid A, were demonstrated to reduce the protein expressions of matrix metalloproteinase (MMP) 9 and cyclin D1 in A549 cells. Furthermore, EEAC enhanced chemosensitivity of A549 to paclitaxel by reducing the protein levels of caveolin-1. Our data suggests that EEAC has the potential to be an adjuvant medicine for the treatment of lung cancer. PMID- 29522492 TI - Challenge for One Health: Co-Circulation of Zoonotic H5N1 and H9N2 Avian Influenza Viruses in Egypt. AB - Highly pathogenic avian influenza (HPAI) H5N1 viruses are currently endemic in poultry in Egypt. Eradication of the viruses has been unsuccessful due to improper application of vaccine-based control strategies among other preventive measures. The viruses have evolved rapidly with increased bird-to-human transmission efficacy, thus affecting both animal and public health. Subsequent spread of potentially zoonotic low pathogenic avian influenza (LPAI) H9N2 in poultry has also hindered efficient control of avian influenza. The H5N1 viruses acquired enhanced bird-to-human transmissibility by (1) altering amino acids in hemagglutinin (HA) that enable binding affinity to human-type receptors, (2) loss of the glycosylation site and 130 loop in the HA protein and (3) mutation of E627K in the PB2 protein to enhance viral replication in mammalian hosts. The receptor binding site of HA of Egyptian H9N2 viruses has been shown to contain the Q234L substitution along with a H191 mutation, which can increase human-like receptor specificity. Therefore, co-circulation of H5N1 and H9N2 viruses in poultry farming and live bird markets has increased the risk of human exposure, resulting in complication of the epidemiological situation and raising a concern for potential emergence of a new influenza A virus pandemic. For efficient control of infection and transmission, the efficacy of vaccine and vaccination needs to be improved with a comprehensive control strategy, including enhanced biosecurity, education, surveillance, rapid diagnosis and culling of infected poultry. PMID- 29522493 TI - Coupling Plant-Derived Cyclotides to Metal Surfaces: An Antibacterial and Antibiofilm Study. AB - Modification of metal surfaces with antimicrobial peptides is a promising approach to reduce bacterial adhesion. Here, cyclic peptides or cycloids, possessing remarkable stability and antimicrobial activities, were extracted and purified from Viola philippica Cav., and identified using mass spectrometry. Cyclotides were subsequently utilized to modify stainless steel surfaces via polydopamine-mediated coupling. The resulting cyclotide-modified surfaces were characterized by Fourier transform infrared (FTIR) spectroscopy and contact angle analysis. The antibacterial capacity of these cyclotides against Staphylococcus aureus was assessed by Alamar blue assay. The antibiofilm capacity of the modified surfaces was assessed by crystal violet assay, and scanning electron microscopy (SEM). A composite of Kalata b1, Varv A, Viba 15 and Viba 17 (P1); Varv E (P2); and Viphi G (P3) were isolated and identified. FTIR analysis of the modified surfaces demonstrated that cyclotides bound to the surfaces and induced reduction of contact angles. Antimicrobial effects showed an order P3 > P1 and P2, with P3-treated surfaces demonstrating the strongest antibiofilm capacity. SEM confirmed reduced biofilm formation for P3-treated surfaces. This study provides novel evidence for cyclotides as a new class for development of antibacterial and antibiofilm agents. PMID- 29522494 TI - Sulfide Stress Cracking Behavior of a Martensitic Steel Controlled by Tempering Temperature. AB - A medium-carbon Cr-Mo-V martensitic steel was thermally processed by quenching (Q) at 890 degrees C and tempering (T) at increasing temperatures from 650 degrees C to 720 degrees C and the effect of tempering temperature, Tt, on sulfide stress cracking (SSC) behaviors was estimated mainly via double cantilever beam (DCB) and electrochemical hydrogen permeation (EHP) tests and microstructure characterization. The results indicate that the threshold stress intensity factor for SSC, KISSC, increased with increasing Tt. The overall and local H concentration around the inclusions decreased with increasing Tt, due to reductions in the amounts of solute atoms, grain boundaries and dislocations, which effectively prevented SSC initiation. Also, increasing Tt caused an increased fraction of high-angle boundaries, which evidently lowered the SSC propagation rate by more frequently diverting the propagating direction and accordingly restricted SSC propagation. The overall SSC resistance of this Q&T treated steel was therefore significantly enhanced. PMID- 29522495 TI - A Computational Fluid Dynamic (CFD) Simulation of PM10 Dispersion Caused by Rail Transit Construction Activity: A Real Urban Street Canyon Model. AB - Particle emissions derived from construction activities have a significant impact on the local air quality, while the canyon effect with reduced natural ventilation contributes to the highest particulate pollution in urban environments. This study attempted to examine the effect of PM10 emissions derived from the construction of a rail transit system in an urban street canyon. Using a 3D computational fluid dynamic (CFD) model based on a real street canyon with different height ratios, this study formulates the impact of height ratio and wind directions on the dispersion and concentration of PM10. The results indicate that parallel flow would cause the concentration of PM10 at the end of the street canyons in all height ratios, and the trends in horizontal, vertical and lateral planes in all street canyons are similar. While in the condition of perpendicular flow, double-eddy circulations occur and lead to the concentration of PM10 in the middle part of the street canyon and leeward of backwind buildings in all height ratios. Furthermore, perpendicular flow will cause the concentration of PM10 to increase if the upwind buildings are higher than the backwind ones. This study also shows that the dispersion of PM10 is strongly associated with wind direction in and the height ratios of the street canyons. Certain measures could, therefore, be taken to prevent the impact on people in terms of the PM10 concentration and the heights of street canyons identified in this research. Potential mitigation strategies are suggested, include measurements below 4 m according to governmental regulations, dust shields, and atomized water. PMID- 29522491 TI - Biological Activities of Stilbenoids. AB - Stilbenoids are a group of naturally occurring phenolic compounds found in various plant species. They share a common backbone structure known as stilbene, but differ in the nature and position of substituents. Stilbenoids are classified as phytoalexins, which are antimicrobial compounds produced de novo in plants to protect against fungal infection and toxins. In this review, the biological effects of stilbenoids such as resveratrol, pterostilbene, gnetol and piceatannol are discussed. Stilbenoids exert various biological activities ranging from cardioprotection, neuroprotection, anti-diabetic properties, depigmentation, anti inflammation, cancer prevention and treatment. The results presented cover a myriad of models, from cell culture to animal studies as well as clinical human trials. Although positive results were obtained in most cell culture and animal studies, further human studies are needed to substantiate beneficial effects of stilbenoids. Resveratrol remains the most widely studied stilbenoid. However, there is limited information regarding the potential of less common stilbenoids. Therefore, further research is warranted to evaluate the salutary effects of various stilbenoids. PMID- 29522496 TI - Efficient Separation of Four Antibacterial Diterpenes from the Roots of Salvia Prattii Using Non-Aqueous Hydrophilic Solid-Phase Extraction Followed by Preparative High-Performance Liquid Chromatography. AB - An efficient preparative procedure for the separation of four antibacterial diterpenes from a Salvia prattii crude diterpenes-rich sample was developed. Firstly, the XION hydrophilic stationary phase was chosen to separate the antibacterial crude diterpenes-rich sample (18.0 g) into three fractions with a recovery of 46.1%. Then, the antibacterial fractions I (200 mg), II (200 mg), and III (150 g) were separated by the Megress C18 preparative column, and compounds tanshinone IIA (80.0 mg), salvinolone (62.0 mg), cryptotanshinone (70.0 mg), and ferruginol (68.0 mg) were produced with purities greater than 98%. The procedure achieved large-scale preparation of the four diterpenes with high purity, and it could act as a reference for the efficient preparation of active diterpenes from other plant extracts. PMID- 29522498 TI - An Experimental Study on Static and Dynamic Strain Sensitivity of Embeddable Smart Concrete Sensors Doped with Carbon Nanotubes for SHM of Large Structures. AB - The availability of new self-sensing cement-based strain sensors allows the development of dense sensor networks for Structural Health Monitoring (SHM) of reinforced concrete structures. These sensors are fabricated by doping cement matrix mterials with conductive fillers, such as Multi Walled Carbon Nanotubes (MWCNTs), and can be embedded into structural elements made of reinforced concrete prior to casting. The strain sensing principle is based on the multifunctional composites outputting a measurable change in their electrical properties when subjected to a deformation. Previous work by the authors was devoted to material fabrication, modeling and applications in SHM. In this paper, we investigate the behavior of several sensors fabricated with and without aggregates and with different MWCNT contents. The strain sensitivity of the sensors, in terms of fractional change in electrical resistivity for unit strain, as well as their linearity are investigated through experimental testing under both quasi-static and sine-sweep dynamic uni-axial compressive loadings. Moreover, the responses of the sensors when subjected to destructive compressive tests are evaluated. Overall, the presented results contribute to improving the scientific knowledge on the behavior of smart concrete sensors and to furthering their understanding for SHM applications. PMID- 29522497 TI - Stem Cells and Engineered Scaffolds for Regenerative Wound Healing. AB - The normal wound healing process involves a well-organized cascade of biological pathways and any failure in this process leads to wounds becoming chronic. Non healing wounds are a burden on healthcare systems and set to increase with aging population and growing incidences of obesity and diabetes. Stem cell-based therapies have the potential to heal chronic wounds but have so far seen little success in the clinic. Current research has been focused on using polymeric biomaterial systems that can act as a niche for these stem cells to improve their survival and paracrine activity that would eventually promote wound healing. Furthermore, different modification strategies have been developed to improve stem cell survival and differentiation, ultimately promoting regenerative wound healing. This review focuses on advanced polymeric scaffolds that have been used to deliver stem cells and have been tested for their efficiency in preclinical animal models of wounds. PMID- 29522499 TI - Robust Angle Estimation for MIMO Radar with the Coexistence of Mutual Coupling and Colored Noise. AB - This paper deals with joint estimation of direction-of-departure (DOD) and direction-of- arrival (DOA) in bistatic multiple-input multiple-output (MIMO) radar with the coexistence of unknown mutual coupling and spatial colored noise by developing a novel robust covariance tensor-based angle estimation method. In the proposed method, a third-order tensor is firstly formulated for capturing the multidimensional nature of the received data. Then taking advantage of the temporal uncorrelated characteristic of colored noise and the banded complex symmetric Toeplitz structure of the mutual coupling matrices, a novel fourth order covariance tensor is constructed for eliminating the influence of both spatial colored noise and mutual coupling. After a robust signal subspace estimation is obtained by using the higher-order singular value decomposition (HOSVD) technique, the rotational invariance technique is applied to achieve the DODs and DOAs. Compared with the existing HOSVD-based subspace methods, the proposed method can provide superior angle estimation performance and automatically jointly perform the DODs and DOAs. Results from numerical experiments are presented to verify the effectiveness of the proposed method. PMID- 29522500 TI - Computerized Hammer Sounding Interpretation for Concrete Assessment with Online Machine Learning. AB - Developing efficient Artificial Intelligence (AI)-enabled systems to substitute the human role in non-destructive testing is an emerging topic of considerable interest. In this study, we propose a novel hammering response analysis system using online machine learning, which aims at achieving near-human performance in assessment of concrete structures. Current computerized hammer sounding systems commonly employ lab-scale data to validate the models. In practice, however, the response signal patterns can be far more complicated due to varying geometric shapes and materials of structures. To deal with a large variety of unseen data, we propose a sequential treatment for response characterization. More specifically, the proposed system can adaptively update itself to approach human performance in hammering sounding data interpretation. To this end, a two-stage framework has been introduced, including feature extraction and the model updating scheme. Various state-of-the-art online learning algorithms have been reviewed and evaluated for the task. To conduct experimental validation, we collected 10,940 response instances from multiple inspection sites; each sample was annotated by human experts with healthy/defective condition labels. The results demonstrated that the proposed scheme achieved favorable assessment accuracy with high efficiency and low computation load. PMID- 29522502 TI - Use of Iodine-131 to Tellurium-132 Ratios for Assessing the Relationships between Human Inhaled Radioactivity and Environmental Monitoring after the Accident in Fukushima. AB - Significant differences in findings were seen between the intake amounts of iodine-131 that were derived from direct measurements and the estimated intake from environmental monitoring data at the Fukushima accident. To clarify these discrepancies, we have investigated the iodine-131 and tellurium-132 body burdens of five human subjects, who after being exposed to a radioactive plume, underwent 21.5 h whole body counter measurements at Fukui Prefectural Hospital, so clear intake scenario and thyroid counter measurement data were available. To determine the iodine-131 and tellurium-132 body burdens, we introduced a new method of whole body counter calibration composed of a self-consistent approach with the time-dependent correction efficiency factors concept. The ratios of iodine-131 to tellurium-132, ranging from 0.96 +/- 0.05 to 2.29 +/- 0.38, were consistent with results of the environmental measurements. The 24 h iodine uptake values ranging from 12.1-16.0% were within euthyroid range in Japanese people. These results suggest, even if the relatively low thyroid iodine uptake in the Japanese population was taken into consideration, that there is no doubt about the consistency between direct measurements and environmental monitoring data. Adequate intake scenario is suggested to be principally important to estimate the inhaled radioactivity in areas in or around nuclear accidents. PMID- 29522501 TI - Isothiocyanates: An Overview of Their Antimicrobial Activity against Human Infections. AB - The use of plant-derived products as antimicrobial agents has been investigated in depth. Isothiocyanates (ITCs) are bioactive products resulting from enzymatic hydrolysis of glucosinolates (GLs), the most abundant secondary metabolites in the botanical order Brassicales. Although the antimicrobial activity of ITCs against foodborne and plant pathogens has been well documented, little is known about their antimicrobial properties against human pathogens. This review collects studies that focus on this topic. Particular focus will be put on ITCs' antimicrobial properties and their mechanism of action against human pathogens for which the current therapeutic solutions are deficient and therefore of prime importance for public health. Our purpose was the evaluation of the potential use of ITCs to replace or support the common antibiotics. Even though ITCs appear to be effective against the most important human pathogens, including bacteria with resistant phenotypes, the majority of the studies did not show comparable results and thus it is very difficult to compare the antimicrobial activity of the different ITCs. For this reason, a standard method should be used and further studies are needed. PMID- 29522503 TI - Relationships among Safety Climate, Safety Behavior, and Safety Outcomes for Ethnic Minority Construction Workers. AB - In many countries, it is common practice to attract and employ ethnic minority (EM) or migrant workers in the construction industry. This primarily occurs in order to alleviate the labor shortage caused by an aging workforce with a lack of new entrants. Statistics show that EM construction workers are more likely to have occupational fatal and nonfatal injuries than their local counterparts; however, the mechanism underlying accidents and injuries in this vulnerable population has been rarely examined. This study aims to investigate relationships among safety climate, safety behavior, and safety outcomes for EM construction workers. To this end, a theoretical research model was developed based on a comprehensive review of the current literature. In total, 289 valid questionnaires were collected face-to-face from 223 Nepalese construction workers and 56 Pakistani construction workers working on 15 construction sites in Hong Kong. Structural equation modelling was employed to validate the constructs and test the hypothesized model. Results show that there were significant positive relationships between safety climate and safety behaviors, and significant negative relationships between safety behaviors and safety outcomes for EM construction workers. This research contributes to the literature regarding EM workers by providing empirical evidence of the mechanisms by which safety climate affects safety behaviors and outcomes. It also provides insights in order to help the key stakeholders formulate safety strategies for EM workers in many areas where numerous EM workers are employed, such as in the U.S., the UK, Australia, Singapore, Malaysia, and the Middle East. PMID- 29522504 TI - Effects of Normovolemic Hemodilution on Survival of Skin Flaps: An Experimental Study. AB - BACKGROUND The aim of this study was to investigate the effects of various ratios of hemodilution on the survival of McFarlane's skin flaps. MATERIAL AND METHODS An experimental study was performed on 42 adult male Wistar rats (weighing 260 to 305 g) allocated to a control group without any volume loss and to 6 study groups with hemodilution ratios of 5%, 10%, 15%, 20%, 25%, and 30%. In all subjects, random-pattern McFarlane's skin flaps were uniformly elevated and re-sutured to the donor sites. The amount of necrosis was evaluated on the 7th day postoperatively and compared among the groups. RESULTS The amounts of flap necrosis in the groups with 5%, 10%, 15%, and 20% hemodilution ratios were significantly lower than that of the control group (p<0.001). In the 25% and 30% hemodilution groups, although there was less necrosis than in the control group, the differences were not statistically significant. Hematocrit levels, which initially decreased in conjunction with the hemodilution ratios, returned to normal levels on the 7th day after the operation. CONCLUSIONS Our results indicated that 20% or less of the total blood volume loss that may be compensated by the normovolemic hemodilution with dextran can improve flap survival. PMID- 29522505 TI - Is ustekinumab effective for psoriatic arthritis with insufficient response to initial treatment? AB - INTRODUCTION: Psoriatic arthritis is an inflammatory arthritis without a clear etiology. Biological therapy is key for its treatment, especially in more complex patients. There are several alternatives for biological treatment, but due to its high cost, it is important to evaluate their real effectiveness. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 12 systematic reviews including three randomized trials overall. We concluded ustekinumab leads to clinical improvement in psoriatic arthritis, and probably is not associated to severe adverse effects. PMID- 29522506 TI - ChromoTrace: Computational reconstruction of 3D chromosome configurations for super-resolution microscopy. AB - The 3D structure of chromatin plays a key role in genome function, including gene expression, DNA replication, chromosome segregation, and DNA repair. Furthermore the location of genomic loci within the nucleus, especially relative to each other and nuclear structures such as the nuclear envelope and nuclear bodies strongly correlates with aspects of function such as gene expression. Therefore, determining the 3D position of the 6 billion DNA base pairs in each of the 23 chromosomes inside the nucleus of a human cell is a central challenge of biology. Recent advances of super-resolution microscopy in principle enable the mapping of specific molecular features with nanometer precision inside cells. Combined with highly specific, sensitive and multiplexed fluorescence labeling of DNA sequences this opens up the possibility of mapping the 3D path of the genome sequence in situ. Here we develop computational methodologies to reconstruct the sequence configuration of all human chromosomes in the nucleus from a super-resolution image of a set of fluorescent in situ probes hybridized to the genome in a cell. To test our approach, we develop a method for the simulation of DNA in an idealized human nucleus. Our reconstruction method, ChromoTrace, uses suffix trees to assign a known linear ordering of in situ probes on the genome to an unknown set of 3D in-situ probe positions in the nucleus from super-resolved images using the known genomic probe spacing as a set of physical distance constraints between probes. We find that ChromoTrace can assign the 3D positions of the majority of loci with high accuracy and reasonable sensitivity to specific genome sequences. By simulating appropriate spatial resolution, label multiplexing and noise scenarios we assess our algorithms performance. Our study shows that it is feasible to achieve genome-wide reconstruction of the 3D DNA path based on super-resolution microscopy images. PMID- 29522507 TI - Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy. AB - During the last decade, our understanding of cancer cell signaling networks has significantly improved, leading to the development of various targeted therapies that have elicited profound but, unfortunately, short-lived responses. This is, in part, due to the fact that these targeted therapies ignore context and average out heterogeneity. Here, we present a mathematical framework that addresses the impact of signaling heterogeneity on targeted therapy outcomes. We employ a simplified oncogenic rat sarcoma (RAS)-driven mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway in lung cancer as an experimental model system and develop a network model of the pathway. We measure how inhibition of the pathway modulates protein phosphorylation as well as cell viability under different microenvironmental conditions. Training the model on this data using Monte Carlo simulation results in a suite of in silico cells whose relative protein activities and cell viability match experimental observation. The calibrated model predicts distributional responses to kinase inhibitors and suggests drug resistance mechanisms that can be exploited in drug combination strategies. The suggested combination strategies are validated using in vitro experimental data. The validated in silico cells are further interrogated through an unsupervised clustering analysis and then integrated into a mathematical model of tumor growth in a homogeneous and resource-limited microenvironment. We assess posttreatment heterogeneity and predict vast differences across treatments with similar efficacy, further emphasizing that heterogeneity should modulate treatment strategies. The signaling model is also integrated into a hybrid cellular automata (HCA) model of tumor growth in a spatially heterogeneous microenvironment. As a proof of concept, we simulate tumor responses to targeted therapies in a spatially segregated tissue structure containing tumor and stroma (derived from patient tissue) and predict complex cell signaling responses that suggest a novel combination treatment strategy. PMID- 29522508 TI - Modules of co-occurrence in the cyanobacterial pan-genome reveal functional associations between groups of ortholog genes. AB - Cyanobacteria are a monophyletic phylogenetic group of global importance and have received considerable attention as potential host organisms for the renewable synthesis of chemical bulk products from atmospheric CO2. The cyanobacterial phylum exhibits enormous metabolic diversity with respect to morphology, lifestyle and habitat. As yet, however, research has mostly focused on few model strains and cyanobacterial diversity is insufficiently understood. In this respect, the increasing availability of fully sequenced bacterial genomes opens new and unprecedented opportunities to investigate the genetic inventory of organisms in the context of their pan-genome. Here, we seek understand cyanobacterial diversity using a comparative genome analysis of 77 fully sequenced and assembled cyanobacterial genomes. We use phylogenetic profiling to analyze the co-occurrence of clusters of likely ortholog genes (CLOGs) and reveal novel functional associations between CLOGs that are not captured by co localization of genes. Going beyond pair-wise co-occurrences, we propose a network approach that allows us to identify modules of co-occurring CLOGs. The extracted modules exhibit a high degree of functional coherence and reveal known as well as previously unknown functional associations. We argue that the high functional coherence observed for the modules is a consequence of the similar-yet diverse nature of cyanobacteria. Our approach highlights the importance of a multi-strain analysis to understand gene functions and environmental adaptations, with implications beyond the cyanobacterial phylum. The analysis is augmented with a simple toolbox that facilitates further analysis to investigate the co occurrence neighborhood of specific CLOGs of interest. PMID- 29522509 TI - Neuronal gain modulability is determined by dendritic morphology: A computational optogenetic study. AB - The mechanisms by which the gain of the neuronal input-output function may be modulated have been the subject of much investigation. However, little is known of the role of dendrites in neuronal gain control. New optogenetic experimental paradigms based on spatial profiles or patterns of light stimulation offer the prospect of elucidating many aspects of single cell function, including the role of dendrites in gain control. We thus developed a model to investigate how competing excitatory and inhibitory input within the dendritic arbor alters neuronal gain, incorporating kinetic models of opsins into our modeling to ensure it is experimentally testable. To investigate how different topologies of the neuronal dendritic tree affect the neuron's input-output characteristics we generate branching geometries which replicate morphological features of most common neurons, but keep the number of branches and overall area of dendrites approximately constant. We found a relationship between a neuron's gain modulability and its dendritic morphology, with neurons with bipolar dendrites with a moderate degree of branching being most receptive to control of the gain of their input-output relationship. The theory was then tested and confirmed on two examples of realistic neurons: 1) layer V pyramidal cells-confirming their role in neural circuits as a regulator of the gain in the circuit in addition to acting as the primary excitatory neurons, and 2) stellate cells. In addition to providing testable predictions and a novel application of dual-opsins, our model suggests that innervation of all dendritic subdomains is required for full gain modulation, revealing the importance of dendritic targeting in the generation of neuronal gain control and the functions that it subserves. Finally, our study also demonstrates that neurophysiological investigations which use direct current injection into the soma and bypass the dendrites may miss some important neuronal functions, such as gain modulation. PMID- 29522510 TI - Coordinated regulation of Arabidopsis microRNA biogenesis and red light signaling through Dicer-like 1 and phytochrome-interacting factor 4. AB - Light and microRNAs (miRNAs) are key external and internal signals for plant development, respectively. However, the relationship between the light signaling and miRNA biogenesis pathways remains unknown. Here we found that miRNA processer proteins DCL1 and HYL1 interact with a basic helix-loop-helix (bHLH) transcription factor, phytochrome-interacting factor 4 (PIF4), which mediates the destabilization of DCL1 during dark-to-red-light transition. PIF4 acts as a transcription factor for some miRNA genes and is necessary for the proper accumulation of miRNAs. DCL1, HYL1, and mature miRNAs play roles in the regulation of plant hypocotyl growth. These results uncovered a previously unknown crosstalk between miRNA biogenesis and red light signaling through the PIF4-dependent regulation of miRNA transcription and processing to affect red light-directed plant photomorphogenesis. PMID- 29522511 TI - Morphogenetic defects underlie Superior Coloboma, a newly identified closure disorder of the dorsal eye. AB - The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye. Our studies revealed the presence of the superior ocular sulcus (SOS), a transient division of the dorsal eye conserved across fish, chick, and mouse. Exome sequencing of superior coloboma patients identified rare variants in a Bone Morphogenetic Protein (Bmp) receptor (BMPR1A) and T-box transcription factor (TBX2). Consistent with this, we find sulcus closure defects in zebrafish lacking Bmp signaling or Tbx2b. In addition, loss of dorsal ocular Bmp is rescued by concomitant suppression of the ventral-specific Hedgehog pathway, arguing that sulcus closure is dependent on dorsal-ventral eye patterning cues. The superior ocular sulcus acts as a conduit for blood vessels, with altered sulcus closure resulting in inappropriate connections between the hyaloid and superficial vascular systems. Together, our findings explain the existence of superior coloboma, a congenital ocular anomaly resulting from aberrant morphogenesis of a developmental structure. PMID- 29522512 TI - 4Cin: A computational pipeline for 3D genome modeling and virtual Hi-C analyses from 4C data. AB - The use of 3C-based methods has revealed the importance of the 3D organization of the chromatin for key aspects of genome biology. However, the different caveats of the variants of 3C techniques have limited their scope and the range of scientific fields that could benefit from these approaches. To address these limitations, we present 4Cin, a method to generate 3D models and derive virtual Hi-C (vHi-C) heat maps of genomic loci based on 4C-seq or any kind of 4C-seq-like data, such as those derived from NG Capture-C. 3D genome organization is determined by integrative consideration of the spatial distances derived from as few as four 4C-seq experiments. The 3D models obtained from 4C-seq data, together with their associated vHi-C maps, allow the inference of all chromosomal contacts within a given genomic region, facilitating the identification of Topological Associating Domains (TAD) boundaries. Thus, 4Cin offers a much cheaper, accessible and versatile alternative to other available techniques while providing a comprehensive 3D topological profiling. By studying TAD modifications in genomic structural variants associated to disease phenotypes and performing cross-species evolutionary comparisons of 3D chromatin structures in a quantitative manner, we demonstrate the broad potential and novel range of applications of our method. PMID- 29522513 TI - Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models. AB - In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 MUg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 MUg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2 deficient tissues. PMID- 29522514 TI - Use of temperature to improve West Nile virus forecasts. AB - Ecological and laboratory studies have demonstrated that temperature modulates West Nile virus (WNV) transmission dynamics and spillover infection to humans. Here we explore whether inclusion of temperature forcing in a model depicting WNV transmission improves WNV forecast accuracy relative to a baseline model depicting WNV transmission without temperature forcing. Both models are optimized using a data assimilation method and two observed data streams: mosquito infection rates and reported human WNV cases. Each coupled model-inference framework is then used to generate retrospective ensemble forecasts of WNV for 110 outbreak years from among 12 geographically diverse United States counties. The temperature-forced model improves forecast accuracy for much of the outbreak season. From the end of July until the beginning of October, a timespan during which 70% of human cases are reported, the temperature-forced model generated forecasts of the total number of human cases over the next 3 weeks, total number of human cases over the season, the week with the highest percentage of infectious mosquitoes, and the peak percentage of infectious mosquitoes that on average increased absolute forecast accuracy 5%, 10%, 12%, and 6%, respectively, over the non-temperature forced baseline model. These results indicate that use of temperature forcing improves WNV forecast accuracy and provide further evidence that temperature influences rates of WNV transmission. The findings provide a foundation for implementation of a statistically rigorous system for real-time forecast of seasonal WNV outbreaks and their use as a quantitative decision support tool for public health officials and mosquito control programs. PMID- 29522515 TI - On geographic barriers and Pleistocene glaciations: Tracing the diversification of the Russet-crowned Warbler (Myiothlypis coronata) along the Andes. AB - We studied the phylogeography and plumage variation of the Russet-crowned Warbler (Myiothlypis coronata), from Venezuela to Bolivia, with focus on populations from Ecuador and northern Peru. We analyzed sequences of mitochondrial and nuclear genes, geographic distributions, as well as photographs of specimens deposited at museum collections. Phylogenetic analyses identified three major lineages formed by populations from: Venezuela and Colombia (M. c. regulus), Ecuador and northern Peru (M. elata, M. castaneiceps, M. orientalis, M. c. chapmani), and central Peru and Bolivia (M. c. coronata). We found further population structure within M. c. regulus and M. c. coronata, and population structure and complexity of plumage variation within the Ecuador-northern Peru lineage. Time-calibrated trees estimated that most intraspecific variation originated during the Pleistocene; however, this pattern may not be attributed to an increase in diversification rate during that period. We discuss these results in the context of the importance of geographic-ecological barriers in promoting lineage diversification along the Andes and put forward a preliminary taxonomic proposal for major lineages identified in this study. PMID- 29522516 TI - Report of a series of 82 cases of Buruli ulcer from Nigeria treated in Benin, from 2006 to 2016. AB - BACKGROUND: Nigeria is one of the countries endemic for Buruli ulcer (BU) in West Africa but did not have a control programme until recently. As a result, BU patients often access treatment services in neighbouring Benin where dedicated health facilities have been established to provide treatment free of charge for BU patients. This study aimed to describe the epidemiological, clinical, biological and therapeutic characteristics of cases from Nigeria treated in three of the four treatment centers in Benin. METHODOLOGY/PRINCIPAL FINDINGS: A series of 82 BU cases from Nigeria were treated in three centres in Benin during 2006 2016 and are retrospectively described. The majority of these patients came from Ogun and Lagos States which border Benin. Most of the cases were diagnosed with ulcerative lesions (80.5%) and WHO category III lesions (82.9%); 97.5% were healed after a median hospital stay of 46 days (interquartile range [IQR]: 32-176 days). CONCLUSIONS/SIGNIFICANCE: This report adds to the epidemiological understanding of BU in Nigeria in the hope that the programme will intensify efforts aimed at early case detection and treatment. PMID- 29522517 TI - A rabies lesson improves rabies knowledge amongst primary school children in Zomba, Malawi. AB - Rabies is an important neglected disease, which kills around 59,000 people a year. Over a third of these deaths are in children less than 15 years of age. Almost all human rabies deaths in Africa and Asia are due to bites from infected dogs. Despite the high efficacy of current rabies vaccines, awareness about rabies preventive healthcare is often low in endemic areas. It is therefore common for educational initiatives to be conducted in conjunction with other rabies control activities such as mass dog vaccination, however there are few examples where the efficacy of education activities has been assessed. Here, primary school children in Zomba, Malawi, were given a lesson on rabies biology and preventive healthcare. Subsequently, a mass dog vaccination programme was delivered in the same region. Knowledge and attitudes towards rabies were assessed by a questionnaire before the lesson, immediately after the lesson and 9 weeks later to assess the impact the lesson had on school children's knowledge and attitudes. This assessment was also undertaken in children who were exposed to the mass dog vaccination programme but did not receive the lesson. Knowledge of rabies and how to be safe around dogs increased following the lesson (both p<0.001), and knowledge remained higher than baseline 9 weeks after the lesson (both p<0.001). Knowledge of rabies and how to be safe around dogs was greater amongst school children who had received the lesson compared to school children who had not received the lesson, but had been exposed to a rabies vaccination campaign in their community (both p<0.001) indicating that the lesson itself was critical in improving knowledge. In summary, we have shown that a short, focused classroom-based lesson on rabies can improve short and medium-term rabies knowledge and attitudes of Malawian schoolchildren. PMID- 29522518 TI - Global child and adolescent mental health: The orphan of development assistance for health. AB - In an analysis of data from the Creditor Reporting System, Chunling Lu and colleagues investigate the level of development assistance from high-income countries towards child and adolescent mental health in low- and middle-income countries. PMID- 29522519 TI - Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study. AB - BACKGROUND: Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood. METHODS AND FINDINGS: We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean [95% CI] 106.4 MUl [88.5-124.3] for fresh RBCs and 192.5 MUl [140.9-244.0] for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean [95% CI] 1.2 * 107 [-1.0 * 107 to 2.5 * 107] for fresh RBCs and 3.6 * 107 [2.5 * 107 to 4.7 * 107] for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa-induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean [95% CI] 15.4 ng/ml [6.7-24.0] for fresh RBCs and 50.3 ng/ml [12.3-88.2] for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar-millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients. CONCLUSIONS: We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition. PMID- 29522520 TI - Comparison of antigen and antibody responses in repeat lymphatic filariasis transmission assessment surveys in American Samoa. AB - BACKGROUND: Current WHO recommendations for lymphatic filariasis (LF) surveillance advise programs to implement activities to monitor for new foci of transmission after stopping mass drug administration (MDA). A current need in the global effort to eliminate LF is to standardize diagnostic tools and surveillance activities beyond the recommended transmission assessment survey (TAS). METHODOLOGY: TAS was first conducted in American Samoa in 2011 (TAS 1) and a repeat TAS was carried out in 2015 (TAS 2). Circulating filarial antigen (CFA) and serologic results from both surveys were analyzed to determine whether interruption of LF transmission has been achieved in American Samoa. PRINCIPAL FINDINGS: A total of 1,134 and 864 children (5-10 years old) were enrolled in TAS 1 and TAS 2, respectively. Two CFA-positive children were identified in TAS 1, and one CFA-positive child was identified in TAS 2. Results of both surveys were below the threshold for which MDA was warranted. Additionally, 1,112 and 836 dried blood spots from TAS 1 and TAS 2, respectively were tested for antibodies to Wb123, Bm14 and Bm33 by luciferase immunoprecipitation system (LIPS) assay and multiplex bead assay. In 2011, overall prevalence of responses to Wb123, Bm14, and Bm33 was 1.0%, 6.8% and 12.0%, respectively. In 2015, overall prevalence of positive Bm14 and Bm33 responses declined significantly to 3.0% (p<0.001) and 7.8% (p = 0.013), respectively. CONCLUSIONS/SIGNIFICANCE: Although passing TAS 1 and TAS 2 and an overall decline in the prevalence of antibodies to Bm14 and Bm33 between these surveys suggests decreased exposure and infection among young children, there were persistent responses in some schools. Clustering and persistence of positive antibody responses in schools may be an indication of ongoing transmission. There is a need to better understand the limitations of current antibody tests, but our results suggest that serologic tools can have a role in guiding programmatic decision making. PMID- 29522521 TI - Characterization of the rhesus macaque (Macaca mulatta) scrub typhus model: Susceptibility to intradermal challenge with the human pathogen Orientia tsutsugamushi Karp. AB - BACKGROUND: Scrub typhus is an important endemic disease in tropical Asia caused by Orientia tsutsugamushi for which no effective broadly protective vaccine is available. The successful evaluation of vaccine candidates requires well characterized animal models and a better understanding of the immune response against O. tsutsugamushi. While many animal species have been used to study host immunity and vaccine responses in scrub typhus, only limited data exists in non human primate (NHP) models. METHODOLOGY/PRINCIPLE FINDINGS: In this study we evaluated a NHP scrub typhus disease model based on intradermal inoculation of O. tsutsugamushi Karp strain in rhesus macaques (n = 7). After an intradermal inoculation with 106 murine LD50 of O. tsutsugamushi at the anterior thigh (n = 4) or mock inoculum (n = 3), a series of time course investigations involving hematological, biochemical, molecular and immunological assays were performed, until day 28, when tissues were collected for pathology and immunohistochemistry. In all NHPs with O. tsutsugamushi inoculation, but not with mock inoculation, the development of a classic eschar with central necrosis, regional lymphadenopathy, and elevation of body temperature was observed on days 7-21 post inoculation (pi); bacteremia was detected by qPCR on days 6-18 pi; and alteration of liver enzyme function and increase of white blood cells on day 14 pi. Immune assays demonstrated raised serum levels of soluble cell adhesion molecules, anti-O. tsutsugamushi-specific antibody responses (IgM and IgG) and pathogen-specific cell-mediated immune responses in inoculated macaques. The qPCR assays detected O. tsutsugamushi in eschar, spleen, draining and non-draining lymph nodes, and immuno-double staining demonstrated intracellular O. tsutsugamushi in antigen presenting cells of eschars and lymph nodes. CONCLUSIONS/SIGNIFICANCE: These data show the potential of using rhesus macaques as a scrub typhus model, for evaluation of correlates of protection in both natural and vaccine induced immunity, and support the evaluation of future vaccine candidates against scrub typhus. PMID- 29522522 TI - Cell walls of the dimorphic fungal pathogens Sporothrix schenckii and Sporothrix brasiliensis exhibit bilaminate structures and sloughing of extensive and intact layers. AB - Sporotrichosis is a subcutaneous mycosis caused by pathogenic species of the Sporothrix genus. A new emerging species, Sporothrix brasiliensis, is related to cat-transmitted sporotrichosis and has severe clinical manifestations. The cell wall of pathogenic fungi is a unique structure and impacts directly on the host immune response. We reveal and compare the cell wall structures of Sporothrix schenckii and S. brasiliensis using high-pressure freezing electron microscopy to study the cell wall organization of both species. To analyze the components of the cell wall, we also used infrared and 13C and 1H NMR spectroscopy and the sugar composition was determined by quantitative high-performance anion-exchange chromatography. Our ultrastructural data revealed a bi-layered cell wall structure for both species, including an external microfibrillar layer and an inner electron-dense layer. The inner and outer layers of the S. brasiliensis cell wall were thicker than those of S. schenckii, correlating with an increase in the chitin and rhamnose contents. Moreover, the outer microfibrillar layer of the S. brasiliensis cell wall had longer microfibrils interconnecting yeast cells. Distinct from those of other dimorphic fungi, the cell wall of Sporothrix spp. lacked alpha-glucan component. Interestingly, glycogen alpha-particles were identified in the cytoplasm close to the cell wall and the plasma membrane. The cell wall structure as well as the presence of glycogen alpha-particles varied over time during cell culture. The structural differences observed in the cell wall of these Sporothrix species seemed to impact its uptake by monocyte-derived human macrophages. The data presented here show a unique cell wall structure of S. brasiliensis and S. schenckii during the yeast parasitic phase. A new cell wall model for Sporothrix spp. is therefore proposed that suggests that these fungi molt sheets of intact cell wall layers. This observation may have significant effects on localized and disseminated immunopathology. PMID- 29522523 TI - Prevalence and risk factors of physical or sexual intimate violence perpetration amongst men in four districts in the central region of Ghana: Baseline findings from a cluster randomised controlled trial. AB - BACKGROUND: Evidence-based interventions are essential in the prevention of violence against women (VAW). An understanding of risk factors for male perpetration of VAW using population-based research is crucial for developing such interventions. This study is a baseline assessment of a two-arm unmatched cluster randomised controlled trial (C-RCT), set up to assess the impact of a Rural Response System (RRS) intervention for preventing violence against women and girls in Ghana. This study aims at assessing past year prevalence and risk factors for sexual or physical intimate partner violence (IPV) perpetration among men. METHODS: The population-based survey involved 2126 men aged 18 and above living in selected communities in 4 districts in the central region of Ghana. Logistic regression techniques were used to determine risk factors for sexual or physical IPV perpetration. All models adjusted for age of respondent and took into account the study design. RESULTS: Half of the men had perpetrated at least one form of violence against their intimate partners in their lifetime while 41% had perpetrated sexual or physical IPV. Majority (93%) of the men had been in relationships in the 12 months preceding the survey, and of these, 23% had perpetrated sexual or physical IPV. Childhood factors associated with sexual or physical IPV included witnessing abuse of mother (aOR:1.40(1.06-1.86)), and neglect (aOR:1.81(1.30-2.50)). Other major risk factors for IPV perpetration were: having multiple partners (aOR:1.76(1.36-2.26)), (involvement in transactional sex (aOR:1.76(1.36-2.26)), substance use (aOR:1.74(1.25-2.43)) and gender inequitable attitudes (aOR:0.94(0.91-0.97)). CONCLUSION: Childhood violence experience and witnessing, risky behaviour (multiple partners, transactional sex, substance use) and gender inequitable attitudes are major risk factors for sexual or physical IPV perpetration. Perpetration of sexual or physical IPV tend to co-occur with non-partner violence and emotional IPV perpetration. Interventions targeting these factors are critical in reducing IPV. PMID- 29522524 TI - Uneven recombination rate and linkage disequilibrium across a reference SNP map for common bean (Phaseolus vulgaris L.). AB - Recombination (R) rate and linkage disequilibrium (LD) analyses are the basis for plant breeding. These vary by breeding system, by generation of inbreeding or outcrossing and by region in the chromosome. Common bean (Phaseolus vulgaris L.) is a favored food legume with a small sequenced genome (514 Mb) and n = 11 chromosomes. The goal of this study was to describe R and LD in the common bean genome using a 768-marker array of single nucleotide polymorphisms (SNP) based on Trans-legume Orthologous Group (TOG) genes along with an advanced-generation Recombinant Inbred Line reference mapping population (BAT93 x Jalo EEP558) and an internationally available diversity panel. A whole genome genetic map was created that covered all eleven linkage groups (LG). The LGs were linked to the physical map by sequence data of the TOGs compared to each chromosome sequence of common bean. The genetic map length in total was smaller than for previous maps reflecting the precision of allele calling and mapping with SNP technology as well as the use of gene-based markers. A total of 91.4% of TOG markers had singleton hits with annotated Pv genes and all mapped outside of regions of resistance gene clusters. LD levels were found to be stronger within the Mesoamerican genepool and decay more rapidly within the Andean genepool. The recombination rate across the genome was 2.13 cM / Mb but R was found to be highly repressed around centromeres and frequent outside peri-centromeric regions. These results have important implications for association and genetic mapping or crop improvement in common bean. PMID- 29522526 TI - Assessing local resilience to typhoon disasters: A case study in Nansha, Guangzhou. AB - Building communities' resilience to natural weather hazards requires the appropriate assessment of such capabilities. The resilience of a community is affected not only by social, economic, and infrastructural factors but also by natural factors (including both site characteristics and the intensity and frequency of events). To date, studies of natural factors have tended to draw on annual censuses and to use aggregated data, thus allowing only a limited understanding of site-specific hot or cold spots of resilience. To improve this situation, we carried out a comprehensive assessment of resilience to typhoon disasters in Nansha district, Guangzhou, China. We measured disaster resilience on 1*1-km grid units with respect to socioeconomic and infrastructural dimensions using a set of variables and also estimated natural factors in a detailed manner with a meteorological modeling tool, the Weather Research and Forecast model. We selected typhoon samples over the past 10 years, simulated the maximum typhoon borne strong winds and precipitation of each sample, and predicted the wind speed and precipitation volume at the 100-year return-level on the basis of extreme value analysis. As a result, a composite resilience index was devised by combining factors in different domains using factor analysis coupled with the analytic hierarchy process. Resilience mapping using this composite resilience index allows local governments and planners to identify potential hot or cold spots of resilience and the dominant factors in particular locations, thereby assisting them in making more rational site-specific measures to improve local resilience to future typhoon disasters. PMID- 29522525 TI - Using genome wide association studies to identify common QTL regions in three different genetic backgrounds based on Iberian pig breed. AB - One of the major limitation for the application of QTL results in pig breeding and QTN identification has been the limited number of QTL effects validated in different animal material. The aim of the current work was to validate QTL regions through joint and specific genome wide association and haplotype analyses for growth, fatness and premier cut weights in three different genetic backgrounds, backcrosses based on Iberian pigs, which has a major role in the analysis due to its high productive relevance. The results revealed nine common QTL regions, three segregating in all three backcrosses on SSC1, 0-3 Mb, for body weight, on SSC2, 3-9 Mb, for loin bone-in weight, and on SSC7, 3 Mb, for shoulder weight, and six segregating in two of the three backcrosses, on SSC2, SSC4, SSC6 and SSC10 for backfat thickness, shoulder and ham weights. Besides, 18 QTL regions were specifically identified in one of the three backcrosses, five identified only in BC_LD, seven in BC_DU and six in BC_PI. Beyond identifying and validating QTL, candidate genes and gene variants within the most interesting regions have been explored using functional annotation, gene expression data and SNP identification from RNA-Seq data. The results allowed us to propose a promising list of candidate mutations, those identified in PDE10A, DHCR7, MFN2 and CCNY genes located within the common QTL regions and those identified near ssc-mir-103-1 considered PANK3 regulators to be further analysed. PMID- 29522527 TI - The importance of geometry in the corneal micropocket angiogenesis assay. AB - The corneal micropocket angiogenesis assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. Measurements from the assay have been used in combination with mathematical modeling to gain insights into the mechanisms of angiogenesis. While previous modeling studies have adopted planar domains to represent the assay, the hemispherical shape of the cornea and asymmetric positioning of the angiogenic source can be seen to affect vascular patterning in experimental images. As such, we aim to better understand: i) how the geometry of the assay influences vessel network formation and ii) how to relate observations from planar domains to those in the hemispherical cornea. To do so, we develop a three-dimensional, off-lattice mathematical model of neovascularization in the cornea, using a spatially resolved representation of the assay for the first time. Relative to the detailed model, we predict that the adoption of planar geometries has a noticeable impact on vascular patterning, leading to increased vessel 'merging', or anastomosis, in particular when circular geometries are adopted. Significant differences in the dynamics of diffusible aniogenesis simulators are also predicted between different domains. In terms of comparing predictions across domains, the 'distance of the vascular front to the limbus' metric is found to have low sensitivity to domain choice, while metrics such as densities of tip cells and vessels and 'vascularized fraction' are sensitive to domain choice. Given the widespread adoption and attractive simplicity of planar tissue domains, both in silico and in vitro, the differences identified in the present study should prove useful in relating the results of previous and future theoretical studies of neovascularization to in vivo observations in the cornea. PMID- 29522528 TI - Development of a reverse genetics system for Sosuga virus allows rapid screening of antiviral compounds. AB - Sosuga virus (SOSV) is a recently discovered zoonotic paramyxovirus isolated from a single human case in 2012; it has been ecologically and epidemiologically associated with transmission by the Egyptian rousette bat (Rousettus aegyptiacus). Bats have long been recognized as sources of novel zoonotic pathogens, including highly lethal paramyxoviruses like Nipah virus (NiV) and Hendra virus (HeV). The ability of SOSV to cause severe human disease supports the need for studies on SOSV pathogenesis to better understand the potential impact of this virus and to identify effective treatments. Here we describe a reverse genetics system for SOSV comprising a minigenome-based assay and a replication-competent infectious recombinant reporter SOSV that expresses the fluorescent protein ZsGreen1 in infected cells. First, we used the minigenome assay to rapidly screen for compounds inhibiting SOSV replication at biosafety level 2 (BSL-2). The antiviral activity of candidate compounds was then tested against authentic viral replication using the reporter SOSV at BSL-3. We identified several compounds with anti-SOSV activity, several of which also inhibit NiV and HeV. Alongside its utility in screening for potential SOSV therapeutics, the reverse genetics system described here is a powerful tool for analyzing mechanisms of SOSV pathogenesis, which will facilitate our understanding of how to combat the potential public health threats posed by emerging bat-borne paramyxoviruses. PMID- 29522529 TI - Physical activity levels in adults and older adults 3-4 years after pedometer based walking interventions: Long-term follow-up of participants from two randomised controlled trials in UK primary care. AB - BACKGROUND: Physical inactivity is an important cause of noncommunicable diseases. Interventions can increase short-term physical activity (PA), but health benefits require maintenance. Few interventions have evaluated PA objectively beyond 12 months. We followed up two pedometer interventions with positive 12-month effects to examine objective PA levels at 3-4 years. METHODS AND FINDINGS: Long-term follow-up of two completed trials: Pedometer And Consultation Evaluation-UP (PACE-UP) 3-arm (postal, nurse support, control) at 3 years and Pedometer Accelerometer Consultation Evaluation-Lift (PACE-Lift) 2-arm (nurse support, control) at 4 years post-baseline. Randomly selected patients from 10 United Kingdom primary care practices were recruited (PACE-UP: 45-75 years, PACE-Lift: 60-75 years). Intervention arms received 12-week walking programmes (pedometer, handbooks, PA diaries) postally (PACE-UP) or with nurse support (PACE-UP, PACE-Lift). Main outcomes were changes in 7-day accelerometer average daily step counts and weekly time in moderate-to-vigorous PA (MVPA) in >=10-minute bouts in intervention versus control groups, between baseline and 3 years (PACE-UP) and 4 years (PACE-Lift). PACE-UP 3-year follow-up was 67% (681/1,023) (mean age: 59, 64% female), and PACE-Lift 4-year follow-up was 76% (225/298) (mean age: 67, 53% female). PACE-UP 3-year intervention versus control comparisons were as follows: additional steps/day postal +627 (95% CI: 198 1,056), p = 0.004, nurse +670 (95% CI: 237-1,102), p = 0.002; total weekly MVPA in bouts (minutes/week) postal +28 (95% CI: 7-49), p = 0.009, nurse +24 (95% CI: 3-45), p = 0.03. PACE-Lift 4-year intervention versus control comparisons were: +407 (95% CI: -177-992), p = 0.17 steps/day, and +32 (95% CI: 5-60), p = 0.02 minutes/week MVPA in bouts. Neither trial showed sedentary or wear-time differences. Main study limitation was incomplete follow-up; however, results were robust to missing data sensitivity analyses. CONCLUSIONS: Intervention participants followed up from both trials demonstrated higher levels of objectively measured PA at 3-4 years than controls, similar to previously reported 12-month trial effects. Pedometer interventions, delivered by post or with nurse support, can help address the public health physical inactivity challenge. TRIAL REGISTRATIONS: PACE-UP isrctn.com ISRCTN98538934; PACE-Lift isrctn.com ISRCTN42122561. PMID- 29522530 TI - Impact of a Family Clinic Day intervention on paediatric and adolescent appointment adherence and retention in antiretroviral therapy: A cluster randomized controlled trial in Uganda. AB - BACKGROUND: In 2013, Uganda adopted a test-and-treat policy for HIV patients 15 years or younger. Low retention rates among paediatric and adolescent antiretroviral therapy (ART) initiates could severely limit the impact of this new policy. This evaluation tested the impact of a differentiated care model called Family Clinic Day (FCD), a family-centered appointment scheduling and health education intervention on patient retention and adherence to monthly appointment scheduling. METHODS: We conducted a cluster randomized controlled trial, from October 2014 to March 2015. Forty-six facilities were stratified by implementing partner and facility type and randomly assigned to the control or intervention arm. Primary outcomes included the proportion of patients retained in care at 6 months and the proportion adherent to their appointment schedule at last study period scheduled visit. Data collection occurred retrospectively in May 2015. Six patient focus group discussions and 17 health workers interviews were conducted to understand perspectives on FCD successes and challenges. RESULTS: A total of 4,715 paediatric and adolescent patient records were collected, of which 2,679 (n = 1,319 from 23 control facilities and 1,360 from 23 intervention facilities) were eligible for inclusion. The FCD did not improve retention (aOR 1.11; 90% CI 0.63-1.97, p = 0.75), but was associated with improved adherence to last appointment schedule (aOR 1.64; 90% CI 1.27-2.11, p<0.001). Qualitative findings suggested that FCD patients benefited from health education and increased psychosocial support. CONCLUSION: FCD scale-up in Uganda may be an effective differentiated care model to ensure patient adherence to ART clinic appointment schedules, a key aspect necessary for viral load suppression. Patient health outcomes may also benefit following an increase in knowledge based on health education, and peer support. Broad challenges facing ART clinics, such as under-staffing and poor filing systems, should be addressed in order to improve patient care. PMID- 29522531 TI - Differential role of MyD88 and TRIF signaling in myeloid cells in the pathogenesis of autoimmune diabetes. AB - Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin producing pancreatic beta cells. While the role of adaptive immunity has been extensively studied, the role of innate immune responses and particularly of Toll like Receptor (TLR) signaling in T1D remains poorly understood. Here we show that myeloid cell-specific MyD88 deficiency considerably protected mice from the development of streptozotocin (STZ)-induced diabetes. The protective effect of MyD88 deficiency correlated with increased expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in pancreatic lymph nodes from STZ treated mice and in bone marrow-derived dendritic cells (BMDC) stimulated with apoptotic cells. Mice with myeloid cell specific TIR-domain-containing adapter inducing interferon-beta (TRIF) knockout showed a trend towards accelerated onset of STZ-induced diabetes, while TRIF deficiency resulted in reduced IDO expression in vivo and in vitro. Moreover, myeloid cell specific MyD88 deficiency delayed the onset of diabetes in Non-Obese Diabetic (NOD) mice, whereas TRIF deficiency had no effect. Taken together, these results identify MyD88 signaling in myeloid cells as a critical pathogenic factor in autoimmune diabetes, which is antagonized by TRIF-dependent responses. This differential function of MyD88 and TRIF depends at least in part on their opposite effects in regulating IDO expression in phagocytes exposed to apoptotic cells. PMID- 29522532 TI - Fluctuations in airway bacterial communities associated with clinical states and disease stages in cystic fibrosis. AB - Bacteria that infect the airways of persons with cystic fibrosis (CF) include a group of well-described opportunistic pathogens as well as numerous, mainly obligate or facultative anaerobic species typically not reported by standard sputum culture. We sequenced the V3-V5 hypervariable region of the bacterial 16S rRNA gene in DNA derived from 631 sputum specimens collected from 111 CF patients over 10 years. We describe fluctuations in the relative abundances of typical CF pathogens, as well as anaerobic species, in relation to changes in patients' clinical state and lung disease stage. Both bacterial community diversity and the relative abundance of anaerobes increased during exacerbation of symptoms (prior to antibiotic treatment), although this trend was not observed uniformly across disease stages. Community diversity and the relative abundance of anaerobic species decreased during antibiotic treatment. These results support current hypotheses regarding the role of anaerobes in CF pulmonary exacerbations and lung disease progression. PMID- 29522533 TI - Quantitative evaluation of maxillary bone deformation by computed tomography in patients with leprosy. AB - BACKGROUND: Facial deformation as a sequela of leprosy is caused not only by a saddle nose but also by regression of the maxilla, as well documented in paleopathological observations of excavated skeletal remains of patients with leprosy. However, maxillary changes in living patients have been evaluated only by the subjective visual grading. Here, we attempted to evaluate maxillary bone deformation in patients with leprosy using three-dimensional computed tomography (3D-CT). METHODS: Three-dimensional images centered on the maxilla were reconstructed using multiplanar reconstruction methods in former patients with leprosy (n = 10) and control subjects (n = 5); the anterior-posterior length of the maxilla (MA-P) was then measured. The difference between the MA-P of the patients and those of controls was evaluated after compensating for individual skull size. These findings were also compared with those from previous paleopathological studies. FINDINGS: Three former patients with lepromatous leprosy showed marked atrophy of the maxilla at the prosthion (-8.6, -11.1 and 17.9 mm) which corresponded with the visual appearance of the maxillary deformity, and these results were consistent with paleopathological findings of excavated skeletal remains. Additionally, the precise bone defects of the maxilla could be individually calculated for accurate reconstructive surgery. INTERPRETATION: We have successfully illustrated maxillary bone deformities in living patients with leprosy. This study also confirmed the maxillary regression described in paleopathological studies. PMID- 29522534 TI - Niemann-Pick type C2 protein supplementation in experimental non-alcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Hepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model. METHODS: Rats were fed a high-fat, high-cholesterol (HFHC) diet for four weeks resulting in moderately severe NASH. Animals were treated with intravenous NPC2 or placebo twice weekly for either the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body weight ratios, histopathological NASH scores, fibrosis, serum liver enzymes, cholesterol, lipoproteins, cytokines, and quantitative polymerase chain reaction derived hepatic gene expression related to cholesterol metabolism, inflammation, and fibrosis. RESULTS: HFHC rats developed hepatomegaly, non fibrotic NASH histopathology, elevated liver enzymes, serum cholesterol, and pro inflammatory cytokines. Their sterol regulatory element binding factor 2 (SREBF2) and low-density lipoprotein receptor (LDL-R) mRNAs were down-regulated compared with rats on standard chow. NPC2 did not improve liver weight, histopathology, levels of serum liver enzymes or pro-inflammatory tumor necrosis factor-alpha (TNFalpha), Interleukin (IL)-6, or IL-1beta in HFHC rats. Two weeks of NPC2 treatment lowered hepatic TNFalpha and COL1A1 mRNA expression. However, this effect was ultimately reversed following additional two weeks of treatment. Four weeks NPC2 treatment of rats raised ATP-binding cassette A1 (ABCA1) and low density lipoprotein receptor (LDLR) mRNAs in the liver, concurrent with a strong tendency towards higher serum high-density lipoprotein (HDL). Furthermore, the peroxisome proliferator activated receptor-gamma (PPARG) gene expression was reduced. CONCLUSIONS: NPC2 proved inefficient at modifying robust hepatic NASH end-points in a HFHC NASH model. Nonetheless, our data suggest that hepatic ABCA1 expression and reverse cholesterol transport were upregulated by NPC2 treatment, thus presenting putative therapeutic effects in diseases associated with deregulated lipid metabolism. PMID- 29522535 TI - Perceived stress and high fat intake: A study in a sample of undergraduate students. AB - OBJECTIVES: Different studies have reported the association between perceived stress and unhealthy diet choices. We aimed to determine whether there is a relationship between perceived stress and fat intake among undergraduate medical students. METHODS/PRINCIPAL FINDINGS: A cross-sectional study was performed including first-year medical students. The outcome of interest was the self report of fat intake assessed using the Block Screening Questionnaire for Fat Intake (high vs. low intake), whereas the exposure was perceived stress (low/normal vs. high levels). The prevalence of high fat intake was estimated and the association of interest was determined using prevalence ratios (PR) and 95% confidence intervals (95%CI). Models were created utilizing Poisson regression with robust standard errors. Data from 523 students were analyzed, 52.0% female, mean age 19.0 (SD 1.7) years. The prevalence of high fat intake was 42.4% (CI: 38.2%-46.7%). In multivariate model and compared with those with lowest levels of stress, those in the middle (PR = 1.59; 95%CI: 1.20-2.12) and highest (PR = 1.92; 95%CI: 1.46-2.53) categories of perceived stress had greater prevalence of fat intake. Gender was an effect modifier of this association (p = 0.008). CONCLUSIONS: Greater levels of perceived stress were associated with higher fat intake, and this association was stronger among males. More than 40% of students reported having high fat consumption. Our results suggest the need to implement strategies that promote decreased fat intake. PMID- 29522536 TI - Reexamining the frequency range of hearing in silver (Hypophthalmichthys molitrix) and bighead (H. nobilis) carp. AB - Silver (Hypophthalmichthys molitrix) and bighead (H. nobilis) carp (collectively bigheaded carp) are invasive fish that threaten aquatic ecosystems in the upper Midwest United States and the Laurentian Great Lakes. Controlling bigheaded carp is a priority of fisheries managers and one area of focus involves developing acoustic deterrents to prevent upstream migration. For an acoustic deterrent to be effective however, the hearing ability of bigheaded carp must be characterized. A previous study showed that bigheaded carp detected sound up to 3 kHz but this range is narrower than what has been reported for other ostariophysans. Therefore, silver and bighead carp frequency detection was evaluated in response to 100 Hz to 9 kHz using auditory evoked potentials (AEPs). AEPs were recorded from 100 Hz to 5 kHz. The lowest thresholds were at 500 Hz for both species (silver carp threshold: 80.6 +/- 3.29 dB re 1 MUPa SPLrms, bighead carp threshold: 90.5 +/- 5.75 dB re 1 MUPa SPLrms; mean +/- SD). These results provide fisheries managers with better insight on effective acoustic stimuli for deterrent systems, however, to fully determine bigheaded carp hearing abilities, these results need to be compared with behavioral assessments. PMID- 29522537 TI - Characterization of photoreceptor degeneration in the rhodopsin P23H transgenic rat line 2 using optical coherence tomography. AB - PURPOSE: To characterize the optical coherence tomography (OCT) appearances of photoreceptor degeneration in the rhodopsin P23H transgenic rat (line 2) in relation to the histological, ultrastructural, and electroretinography (ERG) findings. MATERIALS AND METHODS: Homozygous rhodopsin P23H transgenic albino rats (line 2, very-slow degeneration model) were employed. Using OCT (Micron IV(r); Phoenix Research Labs, Pleasanton, CA, USA), the natural course of photoreceptor degeneration was recorded from postnatal day (P) 15 to P 287. The OCT images were qualitatively observed by comparing them to histological and ultrastructural findings at P 62 and P 169. In addition, each retinal layer was quantitatively analyzed longitudinally during degeneration, compared it to that observed in wild type Sprague-Dawley (SD) rats. The relationships between the ERG (full-field combined rod-cone response, 3.0 cds/m2 stimulation) findings and OCT images were also analyzed. RESULTS: In the qualitative study, the two layers presumably corresponding to the photoreceptor inner segment ellipsoid zone (EZ) and interdigitation zone (IZ) were identified in the P23H rat until PN day 32. However, the photoreceptor inner and outer segment (IS/OS) layer became diffusely hyperreflective on OCT after P 46, and the EZ and IZ zones could no longer be identified on OCT. In contrast, in the SD rats, the EZ and IZ were clearly distinguished until at least P 247. The ultrastructural study showed partial disarrangements of the photoreceptor outer segment discs in the P23H rats at P 62, although a light-microscopic histological study detected almost no abnormality in the outer segment. In the quantitative study, the outer retinal layer including the outer plexiform layer (OPL) and the outer nuclear layer (ONL) became significantly thinner in the P23H rats than in the SD rats after P 71. The thickness of the IS/OS layer was maintained in the P23H rats until P 130, and it became statistically thinner than in the SD rats at P 237. The longitudinal attenuation in the amplitude of the a- and b-waves of ERG was significantly correlated with the thickness of the combined OPL and ONL but not with that of the IS/OS layer. CONCLUSION: OCT showed the degenerated photoreceptor IS/OS layer in rhodopsin P23H transgenic rats (line 2) as a diffuse hyperreflective zone, even in the early stage, with the partially disarranged and destabilized OS discs recognizable by ultrastructural assessment but not by a histological study. The amplitude of the a- and b-waves mainly depends on the thickness of the OPL and ONL layer rather than the thickness of the photoreceptor IS/OS layer in P23H rats. PMID- 29522538 TI - Exome-wide somatic mutation characterization of small bowel adenocarcinoma. AB - Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type. PMID- 29522539 TI - Facilitated sequence assembly using densely labeled optical DNA barcodes: A combinatorial auction approach. AB - The output from whole genome sequencing is a set of contigs, i.e. short non overlapping DNA sequences (sizes 1-100 kilobasepairs). Piecing the contigs together is an especially difficult task for previously unsequenced DNA, and may not be feasible due to factors such as the lack of sufficient coverage or larger repetitive regions which generate gaps in the final sequence. Here we propose a new method for scaffolding such contigs. The proposed method uses densely labeled optical DNA barcodes from competitive binding experiments as scaffolds. On these scaffolds we position theoretical barcodes which are calculated from the contig sequences. This allows us to construct longer DNA sequences from the contig sequences. This proof-of-principle study extends previous studies which use sparsely labeled DNA barcodes for scaffolding purposes. Our method applies a probabilistic approach that allows us to discard "foreign" contigs from mixed samples with contigs from different types of DNA. We satisfy the contig non overlap constraint by formulating the contig placement challenge as a combinatorial auction problem. Our exact algorithm for solving this problem reduces computational costs compared to previous methods in the combinatorial auction field. We demonstrate the usefulness of the proposed scaffolding method both for synthetic contigs and for contigs obtained using Illumina sequencing for a mixed sample with plasmid and chromosomal DNA. PMID- 29522540 TI - An evaluation tool for Myofascial Adhesions in Patients after Breast Cancer (MAP BC evaluation tool): Concurrent, face and content validity. AB - PURPOSE: To investigate the concurrent, face and content validity of an evaluation tool for Myofascial Adhesions in Patients after Breast Cancer (MAP-BC evaluation tool). METHODS: 1) Concurrent validity of the MAP-BC evaluation tool was investigated by exploring correlations (Spearman's rank Correlation Coefficient) between the subjective scores (0 -no adhesions to 3 -very strong adhesions) of the skin level using the MAP-BC evaluation tool and objective elasticity parameters (maximal skin extension and gross elasticity) generated by the Cutometer Dual MPA 580. Nine different examination points on and around the mastectomy scar were evaluated. 2) Face and content validity were explored by questioning therapists experienced with myofascial therapy in breast cancer patients about the comprehensibility and comprehensiveness of the MAP-BC evaluation tool. RESULTS: 1) Only three meaningful correlations were found on the mastectomy scar. For the most lateral examination point on the mastectomy scar a moderate negative correlation (-0.44, p = 0.01) with the maximal skin extension and a moderate positive correlation with the resistance versus ability of returning or 'gross elasticity' (0.42, p = 0.02) were found. For the middle point on the mastectomy scar an almost moderate positive correlation with gross elasticity was found as well (0.38, p = 0.04) 2) Content and face validity have been found to be good. Eighty-nine percent of the respondent found the instructions understandable and 98% found the scoring system obvious. Thirty seven percent of the therapists suggested to add the possibility to evaluate additional anatomical locations in case of reconstructive and/or bilateral surgery. CONCLUSIONS: The MAP-BC evaluation tool for myofascial adhesions in breast cancer patients has good face and content validity. Evidence for good concurrent validity of the skin level was found only on the mastectomy scar itself. PMID- 29522541 TI - Comparison of diurnal variations, gestational age and gender related differences in fetal heart rate (FHR) parameters between appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) fetuses in the home environment. AB - OBJECTIVE: To assess the influence of gender, time of the day and gestational age on fetal heart rate (FHR) parameters between appropriate-for-gestational-age (AGA) and small-for-gestational age (SGA) fetuses using a portable fetal ECG monitor employed in the home setting. METHODS: We analysed and compared the antenatal FHR data collected in the home setting on 61 healthy pregnant women with singleton pregnancies from 24 weeks gestation. Of the 61 women, 31 had SGA fetuses (estimated fetal weight below the tenth gestational centile) and 30 were pregnant with AGA fetuses. FHR recordings were collected for up to 20 h. Two 90 min intervals were deliberately chosen retrospectively with respect to signal recording quality, one during day-time and one at night-time for comparison. RESULTS: Overall, success rate of the fetal abdominal ECG in the AGA fetuses was 75.7% compared to 48.6% in the SGA group. Based on randomly selected episodes of heart rate traces where recording quality exceeded 80% we were able to show a marginal difference between day and night-time recordings in AGA vs. SGA fetuses beyond 32 weeks of gestation. A selection bias in terms of covering different representation periods of fetal behavioural states cannot be excluded. In contrast to previous studies, we neither controlled maternal diet and activity nor measured maternal blood hormone and heart rate as all mothers were monitored in the home environment. CONCLUSION: Based on clinically unremarkable, but statistically significant differences in the FHR parameters between the AGA and SGA group we suggest that further studies with large sample size are required to assess the clinical value of antenatal fetal ECG monitoring. PMID- 29522542 TI - The genetic heterogeneity of Arab populations as inferred from HLA genes. AB - This is the first genetic anthropology study on Arabs in MENA (Middle East and North Africa) region. The present meta-analysis included 100 populations from 36 Arab and non-Arab communities, comprising 16,006 individuals, and evaluates the genetic profile of Arabs using HLA class I (A, B) and class II (DRB1, DQB1) genes. A total of 56 Arab populations comprising 10,283 individuals were selected from several databases, and were compared with 44 Mediterranean, Asian, and sub Saharan populations. The most frequent alleles in Arabs are A*01, A*02, B*35, B*51, DRB1*03:01, DRB1*07:01, DQB1*02:01, and DQB1*03:01, while DRB1*03:01 DQB1*02:01 and DRB1*07:01-DQB1*02:02 are the most frequent class II haplotypes. Dendrograms, correspondence analyses, genetic distances, and haplotype analysis indicate that Arabs could be stratified into four groups. The first consists of North Africans (Algerians, Tunisians, Moroccans, and Libyans), and the first Arabian Peninsula cluster (Saudis, Kuwaitis, and Yemenis), who appear to be related to Western Mediterraneans, including Iberians; this might be explained for a massive migration into these areas when Sahara underwent a relatively rapid desiccation, starting about 10,000 years BC. The second includes Levantine Arabs (Palestinians, Jordanians, Lebanese, and Syrians), along with Iraqi and Egyptians, who are related to Eastern Mediterraneans. The third comprises Sudanese and Comorians, who tend to cluster with Sub-Saharans. The fourth comprises the second Arabian Peninsula cluster, made up of Omanis, Emiratis, and Bahrainis. It is noteworthy that the two large minorities (Berbers and Kurds) are indigenous (autochthonous), and are not genetically different from "host" and neighboring populations. In conclusion, this study confirmed high genetic heterogeneity among present-day Arabs, and especially those of the Arabian Peninsula. PMID- 29522543 TI - NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients. AB - BACKGROUND: Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients. MATERIALS AND METHODS: Functional significant polymorphisms in the promoter of INOS gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to RAS status were preplanned. RESULTS: In the exploratory cohort 1 (TRIBE A), patients with CCTTT any>13repeats (N = 57) showed improved median PFS compared with patients carrying the <=13/<=13 repeats variant (N = 152) (HR, 0.64; 95%CI 0.44-0.92, p = 0.010). Similar results were shown adopting the >26repeats/<=26 repeats (HR, 0.56; 95%CI 0.36-0.87, p = 0.005). In RAS mutant, patient with any>13 repeats (N = 24) had improved PFS results compared with those carrying the <=13/<=13 repeats variant (N = 81) (HR, 0.51; 95%CI 0.30-0.87, p = 30.009). Similar results were found adopting the >26 repeats/<=26 repeats cut off: (HR, 0.52; 95%CI 0.27-0.98, p = 0.035). These data were partially confirmed in the exploratory cohort 2 (TRIBE B): a better median PFS was observed in patients with >26 repeats vs <=26 repeats (N = 205) patients. However, these data were not confirmed in the two validation cohorts. CONCLUSION: We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response. PMID- 29522544 TI - Sex differences in the association between internalizing symptoms and hair cortisol level among 10-12 year-old adolescents in China. AB - Although numerous studies have described the relationship between HPA axis dysregulation and internalizing symptoms among adolescents, research using hair cortisol concentrations in pre- and young adolescent samples has not been reported. We investigated the association of self-reported internalizing symptoms with cortisol concertration in hair among pre- and young adolescents aged 10-12 years. Forty-six boys and 39 girls supplied a hair sample of at least 3 cm in length for an analysis of this period (3 months) cortisol excretion. Saliva cortisol reactivity to the Trier Social Stress Test for Children (TSST-C) also was assessed. The study found a positive association between ratings of depressive symptoms and cumulative levels of hair cortisol only in boys. Furthermore, higher ratings of anxiety symptoms were associated with lower hair cortisol concertration and lower saliva cortisol reactivity among girls. This study provides the first evidence for the notion that depressive symptoms in boys are associated with long-term cortisol concertration in hair, whereas anxiety symptoms in girls are associated with HPA-axis hypoactivity, when hair cortisol concentrations and saliva cortisol reactivity to acute stress are assessed concurrently. PMID- 29522545 TI - Factors associated with patient and health system delays in diagnosis and treatment of tuberculosis in Montenegro, 2015-2016. AB - BACKGROUND: Fundamental measures of control of tuberculosis are early detection and timely treatment of the affected. The aim of this study was to identify factors associated with patient-related and health system-related delays among patients with tuberculosis in the Republic of Montenegro. METHODS: A cross sectional study included 130 tuberculosis patients older than 15 years of age. The inclusion criteria were diagnosis of tuberculosis based on clinical, pathohistological and microbiological findings. Patient delay referred to the number of days between the onset of symptoms and the first consultation with general practitioner (GP). Health system delay represented the number of days between the first consultation with GP and the initiation of tuberculosis treatment.We classified delays longer than median delay length as 'prolonged delays'. Delays greater than 75th percentile of the maximum length of delay were classified as 'extreme delays'. RESULTS: Distribution of patient and health system delay in the overall delay was apprioximately equal (49% vs. 51%). Being married (OR = 2.54, p = 0.026) and having more negative attitudes towards tuberculosis (OR = 4.00, p = 0.045) were associated with extreme patient delay. Greater knowledge on tuberculosis was associated with lower likelihood of prolonged (OR = 0.24, p = 0.031) and extreme (OR = 0.30, p = 0.012) patient delay. Persons with negative sputum smear were more likely to experience prolonged (OR = 7.01, p<0.001) and extreme (OR = 4.40, p = 0.032) health system delay. Persons older than 47 years of age were more likely to experience prolonged health system delay (OR = 2.61, p = 0.042). Specialist consultation delay was associated with prolonged (OR = 1.08, p = 0.001) and extreme (OR = 1.05, p<0.001) health system delay. CONCLUSION: Contribution to overall delay is equally distributed between the patients and the health care system. Improvement of knowledge in the general population and continuing medical education of the health care workers on tuberculosis could lead to reduction in patient and health system delays in treatment of tuberculosis. PMID- 29522546 TI - The problem of home choice in skyline-based homing. AB - Navigation in cluttered environments is an important challenge for animals and robots alike and has been the subject of many studies trying to explain and mimic animal navigational abilities. However, the question of selecting an appropriate home location has, so far, received only little attention. This is surprising, since the choice of a home location might greatly influence an animal's navigation performance. To address the question of home choice in cluttered environments, a systematic analysis of homing trajectories was performed by computer simulations using a skyline-based local homing method. Our analysis reveals that homing performance strongly depends on the location of the home in the environment. Furthermore, it appears that by assessing homing success in the immediate vicinity of the home, an animal might be able to predict its overall success in returning to it from within a much larger area. PMID- 29522547 TI - Sea surface currents and geographic isolation shape the genetic population structure of a coral reef fish in the Indian Ocean. AB - In this contribution, we determine the genetic population structure in the Skunk Clownfish (Amphiprion akallopsisos) across the Indian Ocean, and on a smaller geographic scale in the Western Indian Ocean (WIO). Highly restricted gene flow was discovered between populations on either side of the Indian Ocean using the control region as a mitochondrial marker (mtDNA). We verify this conclusion using 13 microsatellite markers and infer fine scale genetic structuring within the WIO. In total 387 samples from 21 sites were analysed using mtDNA and 13 microsatellite loci. Analysis included estimation of genetic diversity and population differentiation. A haplotype network was inferred using mtDNA. Nuclear markers were used in Bayesian clustering and a principal component analysis. Both markers confirmed strong genetic differentiation between WIO and Eastern Indian Ocean (EIO) populations, and a shallower population structure among Malagasy and East African mainland populations. Limited gene flow across the Mozambique Channel may be explained by its complex oceanography, which could cause local retention of larvae, limiting dispersal between Madagascar and the East African coast. Two other potential current-mediated barriers to larval dispersal suggested in the WIO, the split of the SEC at approximately 10 degrees S and the convergence of the Somali Current with the East African Coast Current at approximately 3 degrees S, were not found to form a barrier to gene flow in this species. PMID- 29522548 TI - Yeast-based assays for characterization of the functional effects of single nucleotide polymorphisms in human DNA repair genes. AB - DNA repair mechanisms maintain genomic integrity upon exposure to various types of DNA damage, which cause either single- or double-strand breaks in the DNA. Here, we propose a strategy for the functional study of single nucleotide polymorphisms (SNPs) in the human DNA repair genes XPD/ERCC2, RAD18, and KU70/XRCC6 and the checkpoint activation gene ATR that are essentially involved in the cell cycle and DNA damage repair. We analyzed the mutational effects of the DNA repair genes under DNA-damaging conditions, including ultraviolet irradiation and treatment with genotoxic reagents, using a Saccharomyces cerevisiae system to overcome the limitations of the human cell-based assay. We identified causal variants from selected SNPs in the present analyses. (i) R594C SNP in RAD3 (human XPD/ERCC2) caused severe reductions in the growth rate of mutant cells upon short-wavelength UV irradiation or chemical reagent treatment. (ii) The growth rates of the selected variants in RAD18, YKU70, and MEC1 were similar to those of wild-type cells on methyl methanesulfonate and hydroxyurea treated media. (iii) We also assessed the structural impact of the SNPs by analyzing differences in the structural conformation and calculating the root mean square deviation, which is a measure of the discordance of the Calpha atoms between protein structures. Based on the above results, we propose that these analytical approaches serve as efficient methods for the identification of causal variants of human disease-causing genes and elucidation of yeast-cell based molecular mechanisms. PMID- 29522549 TI - Attachment anxiety benefits from security priming: Evidence from working memory performance. AB - The present study investigates the relationship between the attachment dimensions (anxious vs. avoidance) and the cognitive performance of individuals, specifically whether the attachment dimensions would predict the working memory (WM) performance. In the n-back task, reflecting the WM capacity, both attachment related and non-attachment related words were used. Participants were randomly assigned into two groups that received either the secure or the neutral subliminal priming. In the secure priming condition, the aim was to induce sense of security by presenting secure attachment words prior to the n-back task performance. In neutral priming condition, neutral words that did not elicit sense of security were presented. Structural equation modeling revealed divergent patterns for attachment anxiety and avoidance dimensions under the different priming conditions. In neutral priming condition, WM performance declined in terms of capacity in the n-back task for individuals who rated higher levels of attachment anxiety. However in the secure priming condition, WM performance was boosted in the n-back task for individuals who rated higher levels of attachment anxiety. In other words, the subliminal priming of the security led to increased WM capacity of individuals who rated higher levels of attachment anxiety. This effect, however, was not observed for higher levels of attachment avoidance. Results are discussed along the lines of hyperactivation and deactivation strategies of the attachment system. PMID- 29522550 TI - Structure-Function relationships of equine menisci. AB - Meniscal pathologies are among the most common injuries of the femorotibial joint in both human and equine patients. Pathological forces and ensuing injuries of the cranial horn of the equine medial meniscus are considered analogous to those observed in the human posterior medial horn. Biomechanical properties of human menisci are site- and depth- specific. However, the influence of equine meniscus topography and composition on its biomechanical properties is yet unknown. A better understanding of equine meniscus composition and biomechanics could advance not only veterinary therapies for meniscus degeneration or injuries, but also further substantiate the horse as suitable translational animal model for (human) meniscus tissue engineering. Therefore, the aim of this study was to investigate the composition and structure of the equine knee meniscus in a site- and age-specific manner and their relationship with potential site-specific biomechanical properties. The meniscus architecture was investigated histologically. Biomechanical testing included evaluation of the shore hardness (SH), stiffness and energy loss of the menisci. The SH was found to be subjected to both age and site-specific changes, with an overall higher SH of the tibial meniscus surface and increase in SH with age. Stiffness and energy loss showed neither site nor age related significant differences. The macroscopic and histologic similarities between equine and human menisci described in this study, support continued research in this field. PMID- 29522551 TI - A high-throughput 3' UTR reporter screening identifies microRNA interactomes of cancer genes. AB - INTRODUCTION: Despite the established contribution of deregulated microRNA (miRNA) function to carcinogenesis, relatively few miRNA-cancer gene interactions have been validated, making it difficult to appreciate the true complexity of miRNA-cancer gene regulatory networks. RESULTS: In this effort, we identify miRNA interactomes of 17 well-established cancer genes, involved in various cancer types, through a miRNome-wide 3' UTR reporter screening. Using a novel and performant strategy for high-throughput screening data analysis, we identify 390 interactions, quadrupling the size of the known miRNA interactome for the cancer genes under investigation. Clear enrichments of established and predicted interactions underscore the validity of the interactome data set. Interactomes appear to be primarily driven by canonical binding site interactions. Nonetheless, non-canonical binding sites, such as offset 6mer and seed-mismatched or G:U wobble sites, also have regulatory activity, albeit clearly less pronounced. Furthermore, we observe enhanced regulation in the presence of 3' supplementary pairing for both canonical and non-canonical binding sites. CONCLUSIONS: Altogether, the cancer gene-miRNA interactome data set represents a unique resource that will aid in the unraveling of regulatory miRNA networks and the dynamic regulation of key protein-coding cancer genes. In addition, it uncovers aspects of the functional miRNA binding site's architecture and the relative contributions of different binding site types. PMID- 29522552 TI - Intestinal parasite infections in a rural community of Rio de Janeiro (Brazil): Prevalence and genetic diversity of Blastocystis subtypes. AB - BACKGROUND: Intestinal parasitic infections are considered a serious public health problem and widely distributed worldwide, mainly in urban and rural environments of tropical and subtropical countries. Globally, soil-transmitted helminths and protozoa are the most common intestinal parasites. Blastocystis sp. is a highly prevalent suspected pathogenic protozoan, and considered an unusual protist due to its significant genetic diversity and host plasticity. METHODOLOGY/MAIN FINDINGS: A total of 294 stool samples were collected from inhabitants of three rural valleys in Rio de Janeiro, Brazil. The stool samples were evaluated by parasitological methods, fecal culture, nested PCR and PCR/Sequencing. Overall prevalence by parasitological analyses was 64.3% (189 out of 294 cases). Blastocystis sp. (55.8%) was the most prevalent, followed by Endolimax nana (18.7%), Entamoeba histolytica complex (7.1%), hookworm infection (7.1%), Entomoeba coli (5.8%), Giardia intestinalis (4.1%), Iodamoeba butchilii (1.0%), Trichuris trichiura (1.0%), Pentatrichomonas hominis (0.7%), Enterobius vermicularis (0.7%), Ascaris lumbricoides (0.7%) and Strongyloides stercoralis (0.7%). Prevalence of IPIs was significantly different by gender. Phylogenetic analysis of Blastocystis sp. and BLAST search revealed five different subtypes: ST3 (34.0%), ST1 (27.0%), ST2 (27.0%), ST4 (3.5%), ST8 (7.0%) and a non identified subtype. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that intestinal parasite infection rates in rural areas of the Sumidouro municipality of Rio de Janeiro, Brazil are still high and remain a challenge to public health. Moreover, our data reveals significant genetic heterogeneity of Blastocystis sp. subtypes and a possible novel subtype, whose confirmation will require additional data. Our study contributes to the understanding of potential routes of transmission, epidemiology, and genetic diversity of Blastocystis sp. in rural areas both at a regional and global scale. PMID- 29522553 TI - Association between chronic pancreatitis and urolithiasis: A population-based cohort study. AB - PURPOSE: Chronic pancreatitis (CP) can cause fat or bile acid malabsorption due to exocrine insufficiency. Fat or bile acid malabsorption has been reported to increase the risk of urolithiasis through increased intestinal oxalate absorption. However, no studies have reported an association between CP and urolithiasis. METHODS: We identified 15,848 patients (age: >=20 years) diagnosed as having CP between 2000 and 2010 from the National Health Insurance Research Database as the study cohort. Beneficiaries without a history of CP were randomly selected and propensity-matched with the study cohort in a 1:4 ratio according to age; sex; comorbidities of hyperlipidemia, diabetes, obesity, hypertension, chronic obstructive pulmonary disease, alcohol-related illness, stroke, and coronary artery disease; and the index date. The prevalence of inflammatory bowel disease (0.44%), hyperparathyroidism (0.10%), or end stage renal disease (1.55%) in CP patients was low, but these comorbidities were also considered in the analysis. All patients were followed until the end of 2011 or withdrawal from the National Health Insurance program to determine the incidence of urolithiasis. RESULTS: The cumulative incidence of urolithiasis was higher in the CP cohort than that in the non-CP cohort (log-rank test, P < 0.001) with a 1.89-fold risk of urolithiasis (95% confidence interval [CI] = 1.74-2.06). The prevalence of CP was higher in men (81.9%) and in patients younger than 49 years (63.5%; mean age: 48.5 +/- 15.3 years). CP was associated with the development of urolithiasis in each age group (<=49 years: aHR = 2.00, 95% CI = 1.81-2.22; 50-64 years: aHR = 1.71, 95% CI = 1.40-2.09; >=65 years: aHR = 1.54, 95% CI = 1.20-1.98) and each sex (women: aHR = 2.10, 95% CI = 1.67-2.66; men; aHR = 1.86, 95% CI = 1.70-2.04). Among the patients without comorbidities, the rate of urolithiasis increased from 2.93/1,000 person-years in non-CP patients to 8.28/1,000 person-years in CP patients. Among the patients with comorbidities, the rate of urolithiasis increased from 6.12/1,000 person-years in non-CP patients to 10.9/1,000 person years in CP patients. The contribution of CP to the relative risk of urolithiasis was greater in patients without comorbidities (without comorbidities: aHR = 2.81, 95% CI = 2.30-3.44) than in those with comorbidities (aHR = 1.76, 95% CI = 1.61 1.94). CONCLUSION: CP is associated with urolithiasis in this population-based cohort study. The contribution of CP to the relative risk of urolithiasis was even greater in patients with a lower risk of urolithiasis, such as those without other comorbidities. Our findings warrant a survey and education on urolithiasis for patients with CP. PMID- 29522554 TI - Scaling participation in payments for ecosystem services programs. AB - Payments for ecosystem services programs have become common tools but most have failed to achieve wide-ranging conservation outcomes. The capacity for scale and impact increases when PES programs are designed through the lens of the potential participants, yet this has received little attention in research or practice. Our work with small-scale marine fisheries integrates the social science of PES programs and provides a framework for designing programs that focus a priori on scaling. In addition to payments, desirable non-monetary program attributes and ecological feedbacks attract a wider range of potential participants into PES programs, including those who have more negative attitudes and lower trust. Designing programs that draw individuals into participating in PES programs is likely the most strategic path to reaching scale. Research should engage in new models of participatory research to understand these dynamics and to design programs that explicitly integrate a broad range of needs, values, and modes of implementation. PMID- 29522555 TI - Heterochronic development of lateral plates in the three-spined stickleback induced by thyroid hormone level alterations. AB - The three-spined stickleback Gasterosteus aculeatus is an important model for studying microevolution and parallel adaptation to freshwater environments. Marine and freshwater forms differ markedly in their phenotype, especially in the number of lateral plates, which are serially repeated elements of the exoskeleton. In fishes, thyroid hormones are involved in adaptation to salinity, as well as the developmental regulation of serially repeated elements. To study how thyroid hormones influence lateral plate development, we manipulated levels of triiodothyronine and thiourea during early ontogeny in a marine and freshwater population with complete and low plate phenotypes, respectively. The development of lateral plates along the body and keel was heterochronic among experimental groups. Fish with a low dosage of exogenous triiodothyronine and those treated with thiourea exhibited retarded development of bony plates compared to both control fish and those treated with higher a triiodothyronine dosage. Several triiodothyronine-treated individuals of the marine form expressed the partial lateral plate phenotype. Some individuals with delayed development of lateral plates manifested 1-2 extra bony plates located above the main row of lateral plates. PMID- 29522556 TI - Activation of DAF-16/FOXO by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans. AB - Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the full longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity. PMID- 29522557 TI - Cardiac electrophysiological adaptations in the equine athlete-Restitution analysis of electrocardiographic features. AB - Exercising horses uniquely accommodate 7-8-fold increases in heart rate (HR). The present experiments for the first time analysed the related adaptations in action potential (AP) restitution properties recorded by in vivo telemetric electrocardiography from Thoroughbred horses. The horses were subjected to a period of acceleration from walk to canter. The QRS durations, and QT and TQ intervals yielded AP conduction velocities, AP durations (APDs) and diastolic intervals respectively. From these, indices of active, lambda = QT/(QRS duration), and resting, lambda0 = TQ/(QRS duration), AP wavelengths were calculated. Critical values of QT and TQ intervals, and of lambda and lambda0 at which plots of these respective pairs of functions showed unity slope, were obtained. These were reduced by 38.9+/-2.7% and 86.2+/-1.8%, and 34.1+/-3.3% and 85.9+/-1.2%, relative to their resting values respectively. The changes in lambda were attributable to falls in QT interval rather than QRS duration. These findings both suggested large differences between the corresponding critical (129.1+/-10.8 or 117.4+/-5.6 bpm respectively) and baseline HRs (32.9+/-2.1 (n = 7) bpm). These restitution analyses thus separately identified concordant parameters whose adaptations ensure the wide range of HRs over which electrophysiological activation takes place in an absence of heart block or arrhythmias in equine hearts. Since the horse is amenable to this in vivo electrophysiological analysis and displays a unique wide range of heart rates, it could be a novel cardiac electrophysiology animal model for the study of sudden cardiac death in human athletes. PMID- 29522558 TI - The relationship between age, axial length and retinal nerve fiber layer thickness in the normal elderly population in Taiwan: The Chiayi eye study in Taiwan. AB - AIMS: To interpret how the thickness of the peripapillary retinal nerve fiber layer (RNFL) changes with increasing age, axial length, or anterior chamber depth as measured by spectral domain optical coherence tomography (OCT) in the normal elderly population in Taiwan. METHODS: A total of 82 volunteers (143 eyes) were enrolled. Generalized estimating equations were used to evaluate the correlation. RESULTS: The RNFL was significantly thinner in the superonasal (p = 0.004), inferotemporal (p = 0.046), and temporolower (p = 0.009) segments with age. The same trend was also observed in the superotemporal (p = 0.330) segment, although it was not statistically significant. The global RNFL thickness decreased by 4.97 MUm per decade (beta = -0.497; p = 0.021), and thinning was significant in the superonasal (-9.90 MUm per decade, p < 0.001) and temporolower (-6.78 MUm per decade, p < 0.001) segments; the same trend showed borderline significance in the superotemporal (-6.96 MUm per decade, p = 0.073) and inferotemporal (-7.23 MUm per decade, p = 0.059) segments. In eyes with longer axial length, the RNFLs significantly decreased in the non-temporal segments. Global RNFL thickness decreased by 3.086 MUm for each additional millimeter of axial length (beta = 3.086; p < 0.001). CONCLUSIONS: Changes in RNFL thickness were correlated with age in the superonasal, superotemporal, inferotemporal, and temporolower segments, and were correlated with axial length in the non-temporal segments. Anterior chamber depth was not correlated with RNFL thickness. PMID- 29522559 TI - Risk factors for colonization and infection by Pseudomonas aeruginosa in patients hospitalized in intensive care units in France. AB - OBJECTIVE: To assess the role of environment, medical care and individual risks factors for P. aeruginosa colonization and infection. STUDY DESIGN AND SETTING: A French multicentric prospective study involved ten ICUs for a five months period. Every adult patient newly hospitalized in ICUs with no P. aeruginosa carriage up to 48 hours after admission was included and weekly screened before discharge or death. Screening swabs were either rectal, sputum or oropharyngeal samples. Hydric environment was also sampled each week. Data on patient clinical features, environmental and device exposures, and antibiotics supports were regularly collected. Multivariate analysis was performed with a multistate model. RESULTS: The overall prevalence of P. aeruginosa carriage was 15.3% (201/1314). Risk factors associated with patient colonization were: use of inactive antibiotics against P. aeruginosa (HR = 1.60 [1.15-2.21] p<0.01), tap water contamination at the entry in the room (HR = 1.66 [1.01-2.27] p<0.05) and mechanical invasive ventilation (HR = 4.70 [2.66-8.31] p<0.0001). Active antibiotics prevented from colonization (HR = 0.67 [0.48-0.93] p = 0.02) and from infection (HR = 0.64 [0.41 1.01] p = 0.05). Interaction between hydric environment antibiotics support was not statistically associated with patient colonization. CONCLUSION: Hydric contamination and antibiotics pressure seem to remain key independent risk factors in P. aeruginosa colonization. These results advocate the need to carry on preventive and targeted interventions toward healthcare associated infections. PMID- 29522560 TI - Development and validation of a weather-based warning system to advise fungicide applications to control dollar spot on turfgrass. AB - Dollar spot is one of the most common diseases of golf course turfgrass and numerous fungicide applications are often required to provide adequate control. Weather-based disease warning systems have been developed to more accurately time fungicide applications; however, they tend to be ineffective and are not currently in widespread use. The primary objective of this research was to develop a new weather-based disease warning system to more accurately advise fungicide applications to control dollar spot activity across a broad geographic and climactic range. The new dollar spot warning system was developed from data collected at field sites in Madison, WI and Stillwater, OK in 2008 and warning system validation sites were established in Madison, WI, Stillwater, OK, Knoxville, TN, State College, PA, Starkville, MS, and Storrs, CT between 2011 and 2016. A meta-analysis of all site-years was conducted and the most effective warning system for dollar spot development consisted of a five-day moving average of relative humidity and average daily temperature. Using this model the highest effective probability that provided dollar spot control similar to that of a calendar-based program across the numerous sites and years was 20%. Additional analysis found that the 20% spray threshold provided comparable control to the calendar-based program while reducing fungicide usage by up to 30%, though further refinement may be needed as practitioners implement this warning system in a range of environments not tested here. The weather-based dollar spot warning system presented here will likely become an important tool for implementing precision disease management strategies for future turfgrass managers, especially as financial and regulatory pressures increase the need to reduce pesticide usage on golf course turfgrass. PMID- 29522561 TI - Socioeconomic inequality in medication persistence in primary and secondary prevention of coronary heart disease - A population-wide electronic cohort study. AB - BACKGROUND: Coronary heart disease (CHD) mortality in England fell by 36% between 2000 and 2007 and it is estimated that approximately 50% of the fall was due to improved treatment uptake. Marked socio-economic inequalities in CHD mortality in the United Kingdom (UK) remain, with higher age-adjusted rates in more deprived groups. Inequalities in the persistence of medication for primary and secondary prevention of CHD may contribute to the observed social gradient and we investigated this possibility in the population of Wales (UK). METHODS AND FINDINGS: An electronic cohort of individuals aged over 20 (n = 1,199,342) in Wales (UK) was formed using linked data from primary and secondary care and followed for six years (2004-2010). We identified indications for medication (statins, aspirin, ACE inhibitors, clopidogrel) recommended in UK National Institute for Clinical Excellence (NICE) guidance for CHD (high risk, stable angina, stable angina plus diabetes, unstable angina, and myocardial infarction) and measured the persistence of indicated medication (time from initiation to discontinuation) across quintiles of the Welsh Index of Multiple Deprivation, an area-based measure of socio-economic inequality, using Cox regression frailty models. In models adjusted for demographic factors, CHD risk and comorbidities across 15 comparisons for persistence of the medications, none favoured the least deprived quintile, two favoured the most deprived quintile and 13 showed no significant differences. CONCLUSIONS: During our study period (2004-2010) we found no significant evidence of socio-economic inequality in the persistence of recommended medication for primary and secondary prevention of CHD. PMID- 29522562 TI - Ancient human mitochondrial DNA and radiocarbon analysis of archived quids from the Mule Spring Rockshelter, Nevada, USA. AB - Chewed and expectorated quids, indigestible stringy fibers from the roasted inner pulp of agave or yucca root, have proven resilient over long periods of time in dry cave environments and correspondingly, although little studied, are common in archaeological archives. In the late 1960s, thousands of quids were recovered from Mule Spring Rockshelter (Nevada, USA) deposits and stored without consideration to DNA preservation in a museum collection, remaining unstudied for over fifty years. To assess the utility of these materials as repositories for genetic information about past inhabitants of the region and their movements, twenty-one quids were selected from arbitrary excavation depths for detailed analysis. Human mitochondrial DNA sequences from the quids were amplified by PCR and screened for diagnostic single nucleotide polymorphisms. Most detected single nucleotide polymorphisms were consistent with recognized Native American haplogroup subclades B2a5, B2i1, C1, C1c, C1c2, and D1; with the majority of the sample set consistent with subclades C1, C1c, and C1c2. In parallel with the DNA analysis, each quid was radiocarbon dated, revealing a time-resolved pattern of occupancy from 347 to 977 calibrated years before present. In particular, this dataset reveals strong evidence for the presence of haplogroup C1/C1c at the Southwestern edge of the US Great Basin from ~670 to 980 cal YBP, which may temporally correspond with the beginnings of the so-called Numic Spread into the region. The research described here demonstrates an approach which combines targeted DNA analysis with radiocarbon age dating; thus enabling the genetic analysis of archaeological materials of uncertain stratigraphic context. Here we present a survey of the maternal genetic profiles from people who used the Mule Spring Rockshelter and the historic timing of their utilization of a key natural resource. PMID- 29522563 TI - Broken replication forks trigger heritable DNA breaks in the terminus of a circular chromosome. AB - It was recently reported that the recBC mutants of Escherichia coli, deficient for DNA double-strand break (DSB) repair, have a decreased copy number of their terminus region. We previously showed that this deficit resulted from DNA loss after post-replicative breakage of one of the two sister-chromosome termini at cell division. A viable cell and a dead cell devoid of terminus region were thus produced and, intriguingly, the reaction was transmitted to the following generations. Using genome marker frequency profiling and observation by microscopy of specific DNA loci within the terminus, we reveal here the origin of this phenomenon. We observed that terminus DNA loss was reduced in a recA mutant by the double-strand DNA degradation activity of RecBCD. The terminus-less cell produced at the first cell division was less prone to divide than the one produced at the next generation. DNA loss was not heritable if the chromosome was linearized in the terminus and occurred at chromosome termini that were unable to segregate after replication. We propose that in a recB mutant replication fork breakage results in the persistence of a linear DNA tail attached to a circular chromosome. Segregation of the linear and circular parts of this "sigma replicating chromosome" causes terminus DNA breakage during cell division. One daughter cell inherits a truncated linear chromosome and is not viable. The other inherits a circular chromosome attached to a linear tail ending in the chromosome terminus. Replication extends this tail, while degradation of its extremity results in terminus DNA loss. Repeated generation and segregation of new sigma replicating chromosomes explains the heritability of post-replicative breakage. Our results allow us to determine that in E. coli at each generation, 18% of cells are subject to replication fork breakage at dispersed, potentially random, chromosomal locations. PMID- 29522564 TI - Randomized controlled trial demonstrates the benefit of RGTA(r) based matrix therapy to treat tendinopathies in racing horses. AB - A randomized controlled trial was performed on racing horses, to evaluate the efficacy of a new class of therapeutic agents in regenerative medicine ReGeneraTing Agents(r) (RGTA(r)), to treat tendinopathies. Preliminary uncontrolled studies on tendon healing in racing horses with RGTA(r) (OTR4131) Equitend(r) showed encouraging results, justifying performing a randomized, controlled, multicenter study with a two-year racing performance follow up. The objective of this study was to evaluate the effect of Equitend(r) versus placebo on acute superficial digital flexor tendonitis in racing French Standardbred Trotters (ST). Twenty-two ST were randomly and blindly assigned to receive with a ratio of 2 to 1, a single Equitend(r) (n = 14) or placebo (n = 8) intralesional injection under ultrasonographic guidance. Horses were evaluated over 4 months, by clinical and ultrasonographic evaluations (day 0, months 1, 2, 4), and their racing performances followed up over the 2 years after treatment. During the first month of treatment, a significant decrease in the cross-sectional area (CSA) was found in the Equitend(r) group (p = 0.04). After 4 months, the number of Equitend(r) treated horses with an improved CSA was significantly higher than the placebo-treated horses (p = 0.03571). The Equitend(r) group returned to their pre-injury performance level, racing in, and winning, significantly more races than the placebo group (p = 0.01399 and 0.0421, respectively). Furthermore, recurrence was significantly higher in the placebo group than in the Equitend(r) group (71.4% vs 16.6%, p = 0.02442). In conclusion, we measured a significant, short-term, reduction effect on CSA and demonstrated a long-term beneficial effect of intralesional injection of Equitend(r) for the treatment of superficial digital flexor tendonitis on racing ST, racing 2. 3 times more often than placebo, with 3.3 times fewer recurrences maintaining pre-injury performance level. This study may open the way for the development of a human treatment of tendonitis. PMID- 29522565 TI - Impacts of age and sex on retinal layer thicknesses measured by spectral domain optical coherence tomography with Spectralis. AB - OBJECTIVE: To examine differences in individual retinal layer thicknesses measured by spectral domain optical coherence tomography (SD-OCT) (Spectralis(r)) produced with age and according to sex. DESIGN: Cross-sectional, observational study. METHODS: The study was conducted in 297 eyes of 297 healthy subjects aged 18 to 87 years. In one randomly selected eye of each participant the volume and mean thicknesses of the different macular layers were measured by SD-OCT using the instrument's macular segmentation software. MAIN OUTCOME MEASURES: Volume and mean thickness of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigmentary epithelium (RPE) and photoreceptor layer (PR). RESULTS: Retinal thickness was reduced by 0.24 MUm for every one year of age. Age adjusted linear regression analysis revealed mean GCL, IPL, ONL and PR thickness reductions and a mean OPL thickness increase with age. Women had significantly lower mean GCL, IPL, INL, ONL and PR thicknesses and volumes and a significantly greater mRNFL volume than men. CONCLUSION: The thickness of most retinal layers varies both with age and according to sex. Longitudinal studies are needed to determine the rate of layer thinning produced with age. PMID- 29522567 TI - The cryoprotectant trehalose could inhibit ERS-induced apoptosis by activating autophagy in cryoprotected rat valves. AB - Valvular diseases are common health problems that are strongly related to high morbidity and mortality; aortic valve allograft transplantation may be a promising way to improve survival and relieve symptoms. However, ideal tissue viability has not been observed with common valve cryopreservation methods, which could lead to apoptosis and necrosis in cryopreserved tissue. It has been observed that trehalose plays a positive role by acting to maintain cell structures and protect cells from stress responses. In this study, we studied the effects of trehalose in protecting rat valve tissue from the cooling process. We found improved higher cell function in rat valves treated with trehalose during cryopreservation than in those treated with dimethyl sulphoxide (DMSO). To further explore the mechanisms, we found that trehalose could down-regulate the expression of cleaved caspase-3, an important molecule involved in cell apoptosis. In addition, treatment with trehalose also decreased Glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP), the key proteins in the endoplasmic reticulum stress (ERS) process. Intriguingly, we observed that trehalose promotes cryoprotected rat valve cell autophagy via an mTOR-independent but p38 MAPK-dependent signaling pathway. Additionally, miR-221 and miR-32 have been implicated in such cell activities. In summary, our study offers a new and meaningful cryopreservation approach for valve allograft storage. PMID- 29522566 TI - Minimal SPI1-T3SS effector requirement for Salmonella enterocyte invasion and intracellular proliferation in vivo. AB - Effector molecules translocated by the Salmonella pathogenicity island (SPI)1 encoded type 3 secretion system (T3SS) critically contribute to the pathogenesis of human Salmonella infection. They facilitate internalization by non-phagocytic enterocytes rendering the intestinal epithelium an entry site for infection. Their function in vivo has remained ill-defined due to the lack of a suitable animal model that allows visualization of intraepithelial Salmonella. Here, we took advantage of our novel neonatal mouse model and analyzed various bacterial mutants and reporter strains as well as gene deficient mice. Our results demonstrate the critical but redundant role of SopE2 and SipA for enterocyte invasion, prerequisite for transcriptional stimulation and mucosal translocation in vivo. In contrast, the generation of a replicative intraepithelial endosomal compartment required the cooperative action of SipA and SopE2 or SipA and SopB but was independent of SopA or host MyD88 signaling. Intraepithelial growth had no critical influence on systemic spread. Our results define the role of SPI1 T3SS effector molecules during enterocyte invasion and intraepithelial proliferation in vivo providing novel insight in the early course of Salmonella infection. PMID- 29522568 TI - Modelling the factor structure of the Child Depression Inventory in a population of apparently healthy adolescents in Nigeria. AB - BACKGROUND: Childhood and adolescent depression is common and often persists into adulthood with negative implications for school performances, peer relationship and behavioural functioning. The Child Depression Inventory (CDI) has been used to assess depression among adolescents in many countries including Nigeria but it is uncertain if the theoretical structure of CDI appropriately fits the experiences of adolescents in Nigeria. This study assessed varying theoretical modelling structure of the CDI in a population of apparently healthy adolescents in Benue state, Nigeria. METHODS: Data was extracted on CDI scale and demographic information from a total of 1, 963 adolescents (aged 10-19 years), who participated in a state wide study assessing adolescent psychosocial functioning. In addition to descriptive statistics and reliability tests, Exploratory Factor Analysis (EFA) and Confirmatory Factor analysis (CFA) were used to model the underlying factor structure and its adequacy. The suggested new model was compared with existing CDI models as well as the CDI's original theoretical model. A model is considered better, if it has minimum Root Mean Square Error of Approximation (RMSEA<0.05), Minimum value of Discrepancy (CMIN/DF<3.0) and Akaike information criteria. All analyses were performed at 95% confidence level, using the version 21 of AMOS and the R software. RESULTS: Participants were 14.7+/-2.1 years and mostly male (54.3%), from Monogamous homes (67.9%) and lived in urban areas (52.2%). The measure of the overall internal consistency of the 2-factor CDI was alpha = 0.84. The 2-factor model had the minimum RMSEA (0.044), CMIN/DF (2.87) and least AIC (1037.996) compared to the other five CDI models. CONCLUSION: The child depression inventory has a 2-factor structure in a non clinical general population of adolescents in Nigeria. Future use of the CDI in related setting may consider the 2-factor model. PMID- 29522569 TI - Treatment outcomes and HPV characteristics for an institutional cohort of patients with anal cancer receiving concurrent chemotherapy and intensity modulated radiation therapy. AB - BACKGROUND: Intensity-modulated radiation therapy (IMRT) has been used to limit treatment-related toxicity for patients with anal squamous cell carcinoma (SCC). The treatment outcomes and HPV characteristics for a cohort of patients receiving definitive concurrent chemotherapy and IMRT are reported. MATERIALS AND METHODS: 52 patients with anal SCC were treated with IMRT and concurrent chemotherapy. Radiation was delivered sequentially to the pelvis and inguinal lymph nodes (45 Gy) and anal tumor (median dose, 54 Gy). Multiplex real-time PCR for 7 high-risk HPV subtypes (n = 22) and p16 immunohistochemistry (n = 21, rated on a 0, 1, and 2+ scale) were performed on available specimens. Survival was estimated using Kaplan-Meier analysis, and toxicities were recorded. RESULTS: Median follow-up was 33 months. Three-year freedom from locoregional failure (FFLRF), freedom from distant metastasis (FFDM), freedom from colostomy (FFC), and overall survival (OS) were 94%, 85%, 91%, and 90%, respectively. Acute grade 2+ skin, GI, and GU toxicities occurred in 83%, 71%, and 19% of evaluable patients, respectively. The rates of late grade 2+ GI and GU toxicities for evaluable patients (n = 32) were 28% and 9%, respectively. Of patients with available pathology, 91% and 71% were positive for HPV and p16 (2+), respectively. HPV genotypes included 16 (n = 17), 33 (n = 2), 18 (n = 1), and 45 (n = 1). HPV and p16 status were associated on Chi square analysis (p = 0.07). Neither HPV nor p16 status was significantly associated with any clinical outcome. For HPV+ patients, 3-year FFLRF, FFDM, FFC, and OS were 100%, 69%, 100%, and 88%, respectively. CONCLUSIONS: In this patient cohort, disease control was excellent for anal SCC treated with definitive concurrent chemotherapy and IMRT, and treatment was well tolerated. HPV and p16 status were not prognostic for treatment outcomes which may be related to our small sample size. PMID- 29522570 TI - Effect of antiretroviral therapy on bone turnover and bone mineral density in men with primary HIV-1 infection. AB - INTRODUCTION: Previous studies indicate that human immunodeficiency virus (HIV) infection and combination antiretroviral therapy (cART) can affect bone turnover. Furthermore, HIV-infected patients have lower bone mineral density (BMD) compared to a healthy reference population. OBJECTIVE: To evaluate the longitudinal effect of HIV-infection and cART on bone turnover markers (BTMs) and BMD in men with primary HIV-infection (PHI). DESIGN, METHODS: Thirty-five PHI-men were divided into two groups, those that received cART for the first time (n = 26) versus no cART (n = 9). Dual-energy X-ray absorptiometry (DXA) was performed on femoral neck (FN), total hip (TH) and lumbar spine (LS) and BTMs (P1NP, alkaline phosphatase, osteocalcin, ICTP and CTX) were measured at baseline and follow-up. RESULTS: At baseline, the median CD4+ T-cell count was 455 cells/mm3 (IQR 320 620) and plasma viral load 5.4 log10 copies/mL (IQR 4.7-6.0) in the cART treated group, compared to 630 (IQR 590-910) and 4.8 (IQR 4.2-5.1) in the untreated group. The median follow-up time was 60.7 weeks (IQR 24.7-96.0). All BTMs, except ICTP, showed a significant increase during cART versus no changes of BTMs in the untreated group. FN and TH BMD showed a significant decrease in both groups. LS BMD did not change in both groups. CONCLUSION: Bone turnover increased in PHI-men treated with cART which was accompanied by a decrease in FN and TH BMD. No increase of bone turnover was seen in untreated PHI-men. Our study suggests that cART results in increased bone turnover and decreased BMD of the hip in PHI-men. PMID- 29522572 TI - Study of stiffness and bearing capacity degradation of reinforced concrete beams under constant-amplitude fatigue. AB - For a reinforced concrete beam subjected to fatigue loads, the structural stiffness and bearing capacity will gradually undergo irreversible degeneration, leading to damage. Moreover, there is an inherent relationship between the stiffness and bearing capacity degradation and fatigue damage. In this study, a series of fatigue tests are performed to examine the degradation law of the stiffness and bearing capacity. The results pertaining to the stiffness show that the stiffness degradation of a reinforced concrete beam exhibits a very clear monotonic decreasing "S" curve, i.e., the stiffness of the beam decreases significantly at the start of the fatigue loading, it undergoes a linear decline phase in the middle for a long loading period, and before the failure, the bearing capacity decreases drastically again. The relationship between the residual stiffness and residual bearing capacity is determined based on the assumption that the residual stiffness and residual bearing capacity depend on the same damage state, and then, the bearing capacity degradation model of the reinforced concrete beam is established based on the fatigue stiffness. Through the established model and under the premise of the known residual stiffness degradation law, the degradation law of the bearing capacity is determined by using at least one residual bearing capacity test data, for which the parameters of the stiffness degradation function are considered as material constants. The results of the bearing capacity show that the bearing capacity degradation of the reinforced concrete beam also exhibits a very clear monotonic decreasing "S" curve, which is consistent with the stiffness degradation process and in good agreement with the experiment. In this study, the stiffness and bearing capacity degradation expressions are used to quantitatively describe their occurrence in reinforced concrete beams. In particular, the expression of the bearing capacity degradation can mitigate numerous destructive tests and save cost. The stiffness and bearing capacity degradation expressions for a reinforced concrete beam can be used to predict the deformation and bearing capacity of a structure during the service process and determine the structural fatigue damage and degree of degradation. PMID- 29522571 TI - Postural sensorimotor training versus sham exercise in physiotherapy of patients with chronic non-specific low back pain: An exploratory randomised controlled trial. AB - : Sensorimotor training (SMT) is popularly applied as exercise in rehabilitation settings, particularly for musculoskeletal pain. With insufficient evidence on its effect on pain and function, this exploratory randomised controlled trial investigated the potential effects of SMT in rehabilitation of chronic non specific low back pain. Two arms received 9x30 minutes physiotherapy with added interventions: The experimental arm received 15 minutes of postural SMT while the comparator arm performed 15 minutes of added sub-effective low-intensity training. A treatment blinded tester assessed outcomes at baseline 2-4 days prior to intervention, pre- and post-intervention, and at 4-week follow-up. Main outcomes were pain and functional status assessed with a 0-100mm visual analogue scale and the Oswestry Disability Questionnaire. Additionally, postural control was analysed using a video-based tracking system and a pressure plate during perturbed stance. Robust, nonparametric multivariate hypothesis testing was performed. 22 patients (11 females, aged 32 to 75 years) with mild to moderate chronic pain and functional limitations were included for analysis (11 per arm). At post-intervention, average values of primary outcomes improved slightly, but not to a clinically relevant or statistically significant extent. At 4-week follow-up, there was a significant improvement by 12 percentage points (pp) on the functional status questionnaire in the SMT-group (95% confidence intervall (CI) = 5.3pp to 17.7pp, p < 0.001) but not in the control group (4 pp improvement, CI = 11.8pp to 19.2pp). However, group-by-time interaction effects for functional status (Q = 3.3, 19 p = 0.07) and pain (Q = 0.84, p = 0.51) were non-significant. Secondary kinematic outcomes did not change over time in either of the groups. Despite significant improvement of functional status after SMT, overall findings of this exploratory study suggest that SMT provides no added benefit for pain reduction or functional improvement in patients with moderate chronic non-specific low back pain. TRIAL REGISTRATION: ClinicalTrials.gov NCT02304120 and related study protocol, DOI: 10.1186/1471-2474-15-382. PMID- 29522573 TI - Octreotide modulates the expression of somatostatin receptor subtypes in inflamed rat jejunum induced by Cryptosporidium parvum. AB - Somatostatins are proteins that are involved in gastrointestinal function. However, little is known with regard to somatostatin receptor subtype (SSTR) expression changes that occur in the jejunum during low-grade inflammation and during subsequent octreotide treatment. The aim of the present study was to investigate the expression of SSTRs in the jejunums of Cryptosporidium parvum (C. parvum)-infected rats by immunohistochemisty, reverse transcription (RT) PCR and quantitative real-time RT-PCR assays. Five-day-old suckling Sprague-Dawley rats (n = 15 for each group) were orally gavaged with 105 Nouzilly isolate (NoI) oocysts. Rats then received 50 MUg/kg/day of octreotide by intraperitoneal injection from day 10 to day 17 post-infection. Animals were sacrificed on days 7 and 14 post-infection for immunohistochemical analysis and on days 14, 35 and 50 for mRNA expression analysis of SSTR subtypes. Histological analysis of jejunum tissues demonstrated infection of C. parvum along the villus brush border on day 7 post-infection and infection clearance by day 14 post-infection. Real-time PCR analysis indicated that in the inflamed jejunum, a significant increase in SSTR1 and SSTR2 expression was observed on day 14 post-infection. Octreotide therapy down-regulated the expression of SSTR2 on day 37 post-infection but significantly increased expression of SSTR1, SSTR2 and SSTR3 on day 50 post-infection. The results indicate that specific SSTRs may regulate the inflammatory pathway in the rat intestinal inflammation model. PMID- 29522574 TI - Using an agent-based model to evaluate the effect of producer specialization on the epidemiological resilience of livestock production networks. AB - An agent-based computer model that builds representative regional U.S. hog production networks was developed and employed to assess the potential impact of the ongoing trend towards increased producer specialization upon network-level resilience to catastrophic disease outbreaks. Empirical analyses suggest that the spatial distribution and connectivity patterns of contact networks often predict epidemic spreading dynamics. Our model heuristically generates realistic systems composed of hog producer, feed mill, and slaughter plant agents. Network edges are added during each run as agents exchange livestock and feed. The heuristics governing agents' contact patterns account for factors including their industry roles, physical proximities, and the age of their livestock. In each run, an infection is introduced, and may spread according to probabilities associated with the various modes of contact. For each of three treatments-defined by one phase, two-phase, and three-phase production systems-a parameter variation experiment examines the impact of the spatial density of producer agents in the system upon the length and size of disease outbreaks. Resulting data show phase transitions whereby, above some density threshold, systemic outbreaks become possible, echoing findings from percolation theory. Data analysis reveals that multi-phase production systems are vulnerable to catastrophic outbreaks at lower spatial densities, have more abrupt percolation transitions, and are characterized by less-predictable outbreak scales and durations. Key differences in network-level metrics shed light on these results, suggesting that the absence of potentially-bridging producer-producer edges may be largely responsible for the superior disease resilience of single-phase "farrow to finish" production systems. PMID- 29522576 TI - Rapid and easy detection of low-level resistance to vancomycin in methicillin resistant Staphylococcus aureus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Vancomycin-intermediately resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with treatment failure. hVISA contains only a subpopulation of cells with increased minimal inhibitory concentrations, and its detection is problematic because it is classified as vancomycin susceptible by standard susceptibility testing and the gold-standard method for its detection is impractical in clinical microbiology laboratories. Recently, a research group developed a machine-learning classifier to distinguish VISA and hVISA from vancomycin-susceptible S. aureus (VSSA) according to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) data. Nonetheless, the sensitivity of hVISA classification was found to be 76%, and the program was not completely automated with a graphical user interface. Here, we developed a more accurate machine-learning classifier for discrimination of hVISA from VSSA and VISA among MRSA isolates in Japanese hospitals by means of MALDI TOF MS data. The classifier showed 99% sensitivity of hVISA classification. Furthermore, we clarified the procedures for preparing samples and obtaining MALDI-TOF MS data and developed all-in-one software, hVISA Classifier, with a graphical user interface that automates the classification and is easy for medical workers to use; it is publicly available at https://github.com/bioprojects/hVISAclassifier. This system is useful and practical for screening MRSA isolates for the hVISA phenotype in clinical microbiology laboratories and thus should improve treatment of MRSA infections. PMID- 29522578 TI - [Chronic kidney disease and renal failure due to lithium treatment]. AB - Lithium has been approved for the treatment of bipolar disorder since the 1970s and even today it is considered a first-line drug for the treatment of this disease. As bipolar disorder often begins between 15-35 years of age and requires long-term treatment, the assessment of the adverse effects of the drugs used is critical. Recently, there has been renewed interest on the risk of chronic kidney disease and kidney failure induced by lithium, with findings suggesting that both complications could be more frequent than previously considered. These data have led to question traditional measures of monitoring renal function such as levels of urea and creatinine, which show signifcant increases only after an important reduction of the glomerular filtration rate. Preliminary data have suggested that certain biomarkers of kidney injury, such as neutrophil gelatinase-associated lipocalin, may be more sensitive indicators of renal damage. The use of new biomarkers that allow early detection of kidney damage could be useful for the monitoring of patients treated with lithium. PMID- 29522575 TI - Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor. AB - Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. Here, we show that the scavenger receptor SR-A6 is an entry receptor for human adenoviruses in murine alveolar macrophage like MPI cells, and important for production of type I interferon. Scavenger receptors contribute to the clearance of endogenous proteins, lipoproteins and pathogens. Knockout of SR-A6 in MPI cells, anti-SR-A6 antibody or the soluble extracellular SR-A6 domain reduced adenovirus type-C5 (HAdV-C5) binding and transduction. Expression of murine SR-A6, and to a lower extent human SR-A6 boosted virion binding to human cells and transduction. Virion clustering by soluble SR-A6 and proximity localization with SR-A6 on MPI cells suggested direct adenovirus interaction with SR-A6. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding and transduction, implying that the viral ligand for SR-A6 is hexon. SR-A6 facilitated macrophage entry of HAdV-B35 and HAdV-D26, two important vectors for transduction of hematopoietic cells and human vaccination. The study highlights the importance of scavenger receptors in innate immunity against human viruses. PMID- 29522577 TI - Women with adenomyosis are at higher risks of endometrial and thyroid cancers: A population-based historical cohort study. AB - OBJECTIVE: Both adenomyosis and endometriosis are characterized by the presence of ectopic endometrial glands and stroma and have been suggested to share some characteristics with malignant tumors. Although accumulating evidence indicates that endometriosis is associated with some cancer types, the cancer risks in patients with adenomyosis have been rarely examined. In this study, we investigated the relationship between adenomyosis and risks of common cancers. METHODS: This study included a cohort of 12,447 women with adenomyosis but not endometriosis, born in 1951-1984, and a cohort of 124,470 adenomyosis-free women matched by birth year. Their medical records (collected between 1996 and 2011) were obtained from the National Health Insurance Research Database of Taiwan. We first compared the distribution of cancer-free survival (CFS) between cohorts with and without adenomyosis. Subsequently, within the adenomyosis cohort, we examined whether time-to-onset of the identified cancer type was correlated with time-to-onset of adenomyosis. The Cox proportional hazards model was used to compare the distribution of CFS between the adenomyosis and adenomyosis-free cohorts and between the early- and late-diagnosed adenomyosis groups. For comparison, we further evaluated the cancer risks for a cohort of 10,962 women with endometriosis but not adenomyosis and a birth-year matched cohort of 109,620 endometriosis-free women. RESULTS: Compared with adenomyosis-free women, patients with adenomyosis had higher risks of endometrial and thyroid cancers, with estimated hazard ratios (HRs) (95% confidence interval) of 2.19 (1.51-3.16) and 1.70 (1.29-2.24), respectively. For both cancers, distributions of CFS were not significantly different between the early- and late-diagnosed adenomyosis groups. Furthermore, compared with endometriosis-free women, patients with endometriosis had higher risks of endometrial and ovarian cancers, with HRs of 1.89 (1.07-3.35) and 2.01 (1.27-3.16), respectively. CONCLUSIONS: Women with adenomyosis are at higher risks of endometrial and thyroid cancers, while women with endometriosis are at higher risks of endometrial and ovarian cancers. PMID- 29522580 TI - [Recovery, a concept of frontier. International perspectives]. PMID- 29522579 TI - [Proposal of informed consent by representation for treatment with clozapine]. AB - Clozapine-induced agranulocytosis, a potentially serious adverse effect, is a limiting factor for its therapeutic use, leading to the suspension of the drug. Its annual incidence in Argentina is 0.05%. In 2000, under provision number 935, the ANMAT approved the Monitoring Program for Ambulatory and Inpatient Patients Treated with Clozapine. In this provision arises the obligation to sign the informed consent where the patient is informed of the risks and benefts of the treatment. In psychiatric care practice patients may not possess, because of their altered psychic state, the level of competence necessary to sign informed consent for their treatment with clozapine. The objective of the present work is to analyze the doctrine of Informed Consent by Representation for the users of clozapine, as well as to propose a decision algorithm for its application in clinical practice. PMID- 29522581 TI - [Historic evolution of psychiatric care paradigms]. AB - The rehabilitation of severely mentally-ill patients and their return to the community are related to historical progress. Their potential of achieving these goals is higher or lower depending on the presence of more or less stigma attached to their condition. Watts and Bennett have divided psychiatric rehabilitation into three phases: Phase 1: Very little was done because there was not much to be done. Patients were rejected and received mistreatment. Phase 2: Their vulnerability was admitted and protection was given to the disabled; services were provided by charity and voluntary religious institutions; there was no clear distinction between illness and poverty. Phase 3: Modern psychiatric rehabilitation began after the two World Wars in the 20th century, with attempts to modify and to oppose disability with the development of other skills. Psychiatric rehabilitation programs help these patients to resume life in the community and prevent their social isolation. By ensuring continuity of their treatment, rehabilitation programs reduce relapses and hospitalizations, thereby contributing to preserve family life and social inclusion. This reduces treatment costs to both families and communities, while promoting patients' reinsertion and recovery in the community according to their individual needs. PMID- 29522582 TI - [Full recovery seems possible and would depend on treatment. The revolutionary promise of open dialogue]. AB - We present an important advance in psychiatry regarding the phenomenon of recovery. Comparative studies between Open Dialogue (OD) and current treatments of schizophrenia and other non-affective psychoses point to an important difference in short and long-term results in favor of this approach developed in Western Lapland. This suggests that OD treatment enhances durable recovery. The prognosis of recovery would depend mainly on the treatment received, and would not be necessarily partial or dependent on a mysterious personal quality. We emphasize the consequent epistemological change regarding the recovery and the offcial view of the problems in mental health. To do this, we briefly recount the concept of recovery, originating in North America in the 1970s, also based on its influence in the countries of Europe, particularly Switzerland, based on the work of a group of user associations and former users of psychiatry, families and social and mental health professionals (Le GREPSY). Traditionally recovery is a controversial issue, which has generated tension and conflict between patients and psychiatry. The Open Dialogue also provides a satisfactory solution, working at a "higher level", where the options concerning the treatment are decided in a real collaboration. PMID- 29522583 TI - [The recovery model: One paradigm, two conceptions]. AB - In recent decades, new models of recovery have been developed in the feld of mental health, based on the transfer of hospital treatment to the community. Community mental health became the standard of care and treatment, and people with mental illness were able to freely congregate and support each other. The new recovery model includes broad aspects of the person and recovery became the "guiding vision" of mental health services. New defnitions of recovery were developed that focus on the difference between recovering from an illness and being in recovering, or in other words, "clinical recovery" versus "personal recovery." This important development represents a huge challenge for policy makers and planners of modern mental health systems. As is clear from this article, efforts to implement a recovery-oriented perspective that will produce a more consumerbased mental health system have just begun. The urgent need to investigate these efforts, taking into account the complexity and many meanings of "recovery", begins to manifest itself in mental health research agendas. Recovery-oriented treatments focus on preparing and training the person with mental disorders to acquire the knowledge necessary to manage their own disease and recovery process, and thus improve overall functioning, health and quality of life. PMID- 29522584 TI - [Community inclusion as a human right and medical necessity for individuals with serious mental illnesses]. AB - Community inclusion refers to equal opportunities for people to participate in the community and willingness to welcome and active community attitude. The opportunity to participate in the community is both a medical necessity and a rights issue. This concept provides a novel theoretical framework for the advancement of mental health policies, programs, and global practices that enable the development of the well-being and health of people with mental disorders. Eleven fundamentals for promoting community inclusion of individuals with serious mental illnesses that are supported by key conceptual, theoretical, and research evidence. These fundamentals reflect beliefs and schemas that need to be present to truly prioritize and facilitate inclusion, intervention strategies and achieve the most impactful objectives that were expected. The greater inclusion, greater community participation, which includes work, education, religion and spiritual participation, and other domains associated with having a life that makes sense, all of which generates physical, cognitive and mental benefts for anyone, disregarding the presence or absence of a mental disorder. The concept of community inclusion offers a transformative next step in the delivery of mental health services that clearly articulates community participation in meaningful areas as the target for promoting full health and wellness. PMID- 29522585 TI - [Therapeutic relationships that promote recovery in the mental health field. An innovate approach]. AB - In recent decades there have been changes in the mental health feld that have also influenced the therapist-client relationship, which is seen as an essential element in the processes of recovery. Our purpose is to present a model of work reflected in therapeutic relationships in the feld of rehabilitation (RTR) that is guided by the principles of recovery. Therapeutic relationships are considered as a means through which it is possible to increase commitment and adherence of people to therapy and also participation in treatment and rehabilitation programs. There is a signifcant correlation between the strength of the therapeutic relationship and improvements in the overall functioning of the person and improvements in community life skills as well as the reduction in the severity level of the symptoms. Different characteristics constitute the RTR and contribute signifcantly to the processes of recovery and inclusion of people with mental illness: the integration between working on the practical aspects of the life of the person (the dimension of "doing") and working on the internal aspects (the dimension of the "being"), the "unconventional limits", the therapist's openness to his life, collaborative work, a "natural" communication, and hope. Professionals as well as service agencies and policy makers need to deepen their understanding of the nature and uniqueness of RTRs and develop the possibility of working through them to promote processes of change, recovery and social inclusion. PMID- 29522586 TI - [Narrative enhancement and cognitive therapy: A group intervention to reduce self stigma in people with severe mental illness]. AB - Research around the world has consistently shown that people with serious mental illness (SMI) are often subject to stronglyheld stigmatizing attitudes held by others in society (e.g., dangerousness, incompetence, inability to work). As a result, people with SMI often experience "internalized stigma" or "self-stigma" which reflects the process by which stigmatizing attitudes are internalized, leading to the loss of previously held or hoped for identities (e.g., self as student, self as worker, self as parent, etc.) and the adoption of identities based on stigmatizing views (e.g., self as dangerous, self as incompetent). In order to reduce the common devastating phenomenon of self-stigma, Narrative Enhancement and Cognitive Therapy (NECT) is a structured, groupbased treatment aimed to reduce self-stigma. It combines psychoeducation to help replace stigmatizing views about mental illness with empirical fndings, cognitive restructuring geared toward teaching skills to challenge negative beliefs about the self, and elements of narratology focused on enhancing one's ability to narrate one's life story. Since its development, nearly a decade ago, it has been implemented in fve different countries and fve languages and studied in three countries with results supporting its positive impact on decreasing self-stigma and improving other positive outcomes. In this paper we briefly review literature on stigma and self-stigma within the context of SMI, the need for treatment focused on decreasing self-stigma, the theoretical rational for the NECT, the format of the intervention and the existing published research. PMID- 29522587 TI - [The "Mental Health" we don't want for our people]. PMID- 29522588 TI - [Anxiety and depression in daily clinical practice]. AB - Anxiety and depression are two important clinical entities associated not only with mental health, but to health and illness in general. However, professionals in most of the non-psychiatric health settings avoid referring to either one. The prime objective of this work is to review publications showing the important correlation between anxiety and depression and various diseases. For the purpose of this study, diseases were divided into specialties, taking into account the bibliographical sources of the articles cited. Based on the information provided by this review, physicians -psychiatry specialists or not- should permanently consider anxiety and depression as important factors when dealing with patients in their daily consultation. Their therapeutic proposal after adopting this approach may lead to a radical change in results, noticeably improving patients' quality of life with the benefcial effects derived from the treatments implemented. This review was conducted with the contributions of scientifc psychosomatics and psychoneuroimmunoendocrinology (PNIE). PMID- 29522589 TI - [Objective and subjective prospective memory in patients with relapsing remitting multiple sclerosis]. AB - INTRODUCTION: prospective memory is the ability to remember actions in the future or remember delayed intentions. OBJECTIVE: to study the relationship between prospective memory complaints with an objective measure of prospective memory and affective-emotional variables such as depression and anxiety. SUBJECTS AND MATERIALS: 51 patients with multiple sclerosis relapsing-remitting and 46 participants in the control group were evaluated with a prospective memory task called El Condor, a questionnaire on subjective complaints of prospective memory, a depression inventory and an anxiety inventory. RESULTS: the control group performed better in El Condor than patients with multiple sclerosis, t = 6263, df = 95, p = 0.000. The prospective memory questionnaire correlated with the depression and the anxiety inventories, but not with El Condor. CONCLUSIONS: subjective prospective memory is associated with depression and anxiety and not with the objective prospective memory in a group of multiple sclerosis patients. The results indicate that the subjective and objective prospective memory must be studied as separate entities or different phenomena. PMID- 29522590 TI - [Factors associated with length of stay and the risk of readmission in an acute psychiatric inpatient facility: A retrospective study]. AB - OBJECTIVE: to investigate factors in?uencing length of stay and predictors for the risk of readmission at an acute psychiatric inpatient unit. METHOD: retrospective cross-sectional clinical fle audit ranging four years back, a random selection of 378 patients was reviewed, including 178 cases and 200 controls. A case control study was employed in the study of length of stay, and for predictors of risk of readmission a retrospective cohort study was used. RESULTS: the 7 variables that were associated with length of stay were: 1- instruction level, 2- place of origin, 3- use of restraints, 4- gender, 5- marital status, 6- drug class, and 7- number of visits. The 9 variables associated with risk of readmission were: 1- history of previous admission, 2- cognitive status, 3- use of seclusion, 4- diagnostic category (personality cluster, bipolar disorder, substance use disorder, adaptive disorder, situational crisis, acute alcoholic intoxication), 5- risk to others at the time of index admission, 6- instruction level, 7- age at frst admission. Proactive and assertive treatment after discharge decreased the risk of readmission. CONCLUSIONS: Length of stay has predictable multifactorial determinants which are diffcult to modify clinically, as inpatient quality of care was not associated with it. Good community network assisting practices appeared to be more likely to reduce risk of readmission. PMID- 29522591 TI - [Hypokalemic rhabdomyolisis and schizophrenia]. AB - The purpose of this report is to emphasize the necessity to periodically explore internal environment variables, as certain metabolic alterations often go unnoticed during antipsychotic treatment. Early detection of such alterations may prevent catastrophic syndromes. We will also stress the clinical relevance of cognitive perseverations in schizophrenic patients, as these often condition habits of consumption which can alter the internal environment. In this clinical case of a schizophrenic patient, a chain of events led to a catastrophic syndrome: a trivial home accident (fall from own height) developed into a condition characterized by oligoanuria, hypokalemia, creatine phosphokinase (CPK) elevation (125,000 IU / L) and acute renal failure with dialysis requirement. This episode was non lethal due to the early implementation of support measures. We performed a revision of the available literature in order to discern the cause of the elevation of CPK. Here we aim to highlight the importance of 1) careful clinical and laboratory monitoring of psychopharmacological treatment, 2) interactions resulting from consumption habits capable of generating unforeseen consequences, 3) the role of the psychiatrist in the context of multidisciplinary work. PMID- 29522592 TI - [Vulnerability]. PMID- 29522593 TI - [From excluded individuals to rights-endowed citizens: The new approaches to disability]. AB - The new models for understanding persons with disabilities and their needs come with an expansion of their rights. This article discusses the new approaches, the changes produced in recent years, and the upcoming challenges posed by the implementation of the Convention on the Rights of Persons with Disabilities (CRPD), which, in Argentina, is on equal par with the Constitution. Additionally, the article mentions the incorporation of the World Health Organization's new multi-dimensional classifcation of disability, which takes into account the impairments suffered by persons along with any limitations on their activities and constraints on participation. The article discusses quality of life models and supports as guidelines for professional action. Finally, the article mentions some consequences of these new approaches for the relevant disciplines in general and for mental health in particular. PMID- 29522594 TI - [Women are human: Brief guide on international human rights law for psychiatrists]. AB - Violence against women has gained public awareness in Argentina over the last few years. As any other social phenomena, gender violence is present in the work of psychiatrists, especially in the way they approach to clinical practice. International human rights' law enshrines the right of every women to live free from violence and to be treated with dignity and respect. This legal framework might nourish the practice of psychiatrists as a proposal for seeking cultural and social common grounds. The paper tries to get readers attention on the potentiality of this legal framework which ultimately, might in?uence not only everyday life but clinical practice as well. PMID- 29522595 TI - [Elder abuse: Twenty years later]. AB - This article analyzes various aspects of elder abuse. Subtypes of abuse, neglect and self-neglect are defned. The phenomenon is analyzed in the context of geriatric institutions, people with dementia, and among the gay, lesbian and trans people. The narrative model is used to exemplify various situations, using authors such as Irving, Ford and Lodge. PMID- 29522596 TI - ["Rosario escapes": Child and adolescent mental health and rights]. AB - This article aims to establish a critical view of the situation of children and teenagers who use mental health emergency services. I describe a situation in the emergency room of a child and adolescent psychiatric hospital, problematized in terms of violation and restitution of rights of children and adolescents. PMID- 29522597 TI - [Social trauma: Clinical practice and analysis of subjectivity]. AB - Clinical and psychosocial assistance demand that we try and understand the complex effect traumatic events have on people and their subjectivity, as well as on our own stance and reference framework. Traumatic situations of social origin affect groups of individuals and the State is to some extent responsible for their genesis and the resolution of their effects. In our professional practice we are faced with problems that concern both the individuals and the relationships they establish. The way highly traumatic events are dealt with is in?uenced by various factors that challenge our therapeutic theories and approaches. The crisis of our time, characterized by uncertainty, violence patterns, intolerance of differences, fracture of social bonds, combined with major technological developments and subjective changes, triggers new and complex ways of connection -even hyperconnectivity- through social media. These vicissitudes of our time confront us with new expressions of discomfort about our own place in the world, deeply affect our identities and reinforce the suffering we experience when faced with the emergency of the devastating power of social trauma. Thus, they become part of our current challenge as professionals. PMID- 29522598 TI - [Vincenzo Chiarugi. La Pazzia, its genres and species: Foundational work of modern psychiatry]. PMID- 29522599 TI - [Madness: its genres and species]. PMID- 29522600 TI - [Autism: Comparing two treatment modalities]. AB - The treatment of autism has been a controversial issue for about four decades. The first formal description of Leo Kanner's autism in the 1940s describes above all the evolution of a homogeneous neuropsychopathological disorder and did not evoke the idea of a possible treatment. Today, researchers trusted to subscribe to a type of therapy that oscillates between cognitive and behavioral treatment. However, other treatments proposals may be pertinent, is what we discussed in the following article. PMID- 29522601 TI - [Levomepromazine as adjuvant sedation in a pediatric intensive care unit]. AB - INTRODUCTION: Sedation of patients in pediatric ICU extubated and in weaning of mechanic ventilation is diffcult under regular sedation, because of the tolerance and/or abstinence generated by its sustained use. The objective of this study is to describe the use of Levomepromazine as sedative coadjuvant in these patients. POPULATION AND METHODS: Observational and longitudinal study in intensive care from Juan P. Garrahan Pediatric Hospital. Patients older than 2 years were included, extubated and in weaning of mechanic ventilation with requirements of additional sedation. The level of basal sedation and post-intervention (levomepromazine 0.5 mg/kg every 8 hours) were evaluated with Ramsay and Khalil scales. Doses of regular sedatives were compared before and after the indication. It was considered positive an increase of 1 in the scales, or a decrease of 20% in the regular sedatives doses. RESULTS: 36 patients, medium age of 8,5 years, average doses of levomepromazine 0.38 mg/kg. 97% showed positive result. The regular sedative doses were reduced more than 20% after the intervention. No adverse effects or deceased were registered. PMID- 29522602 TI - [Use of scales in depression patients in clinical practice in Argentina]. AB - Although depression is a treatable cause of suffering, disability and death, its identifcation and treatment continue to be a challenge in clinical practice and a severe problem for global public health. The main objective of this study was to investigate the frequency with which mental health professionals use scales to assess depressive patients in Argentina and to determine the reasons that constrain such practice. Between July and September 2012 a national survey was conducted by e-mail. Professionals registered in the database of the Argentine Association of Psychiatrists were invited to participate in the survey. Responses were obtained from 243 professionals. Of the total respondents, only 8.7% said they always used scales to assess depressive patients. The reasons recorded by most respondents why scales were not used were: lack of time and the belief that they do not help in clinical practice. Despite the fact that treatment guidelines for depression recommend the use of scales to optimize the assessment and treatment of depressive disorders, this does not seem to be the usual behavior in clinical practice in our country. PMID- 29522604 TI - [Recovery, a concept of frontier. Latinamerican perspectives]. PMID- 29522603 TI - [Epidemiological study on the homicidal behaviour in teenagers]. AB - This study addresses the epidemiology of risk factors and personality traits in adolescents of 16 and 17 years of age, charged with homicide, with a focus on analyzing psychic functioning, socio-demographic variables and family constitution. This is a longitudinal, retrospective and inferential study of the psychiatric assessments of several subjects who were interviewed in the Family Courts of the province of Mendoza. The hypothesis states that adolescents who have violent behavior, impulsivity and diffculty in complying with rules, do so as a result of having been victims of violence in an inadequate family environment. The statistical method employed was ANOVA 2 and sign test for a statically signifcant p<0.05. The study of different variables shows low self criticism and behavioral disorders in childhood among the subjects. PMID- 29522605 TI - [Challenges on the road to personal recovery in Latin America]. AB - The recovery approach proposes a substantial change towards a more holistic perspective that takes into account social needs in mental health. It is a guiding principle in the development of services and research, a lens through which to look at mental health. This article describes four main challenges on the way to the development of a recovery culture in Latin America: Paying attention to local culture; recognizing and encouraging the contribution of users; reducing the emphasis on the diagnostic classification, and paving the way for social justice. Optimal health services can be achieved by combining the knowledge of professionals and high-quality scientifc research, with local popular knowledge and the experience of users. PMID- 29522606 TI - ["Tell me how it is evaluated, and I will tell you what it is": What recovery evaluation is adding to the understanding of recovery]. AB - The concept of "recovery" is still controversial as to what its principal components/dimensions are. From the perspective of a mental health professional, recovery is related to a clinical improvement and to a higher functioning. However, from a users' perspective, its major component is related to hope and having a meaningful life. The present paper analyses recovery by studying English and Spanish scales designed to measure recovery. A total of 44 recovery scales were found, of which only 19 had been made public, evaluated personal recovery from a users' perspective, used a Likert scale for all items and could be adapted to different contexts. The existential dimension (i.e., hope, self-esteem) was addressed by 84% of scales, but only 47% of scales had items tapping on social functioning (i.e., daily life activities). A broad dimension related to general aspects of health, illness management and seeking for treatment, named as "health sickness continuous", was addressed by 63% of the scales. A fnal category of social and family relationships (including connectedness) was addressed by 58% of scales. According to our fndings, scales evaluating personal recovery are organized in terms of privileging a vision of recovery centered on hope over symptomatology or social functioning, posing a severe challenge to articulating results obtained from recovery scales, with other professional instruments used for mental health evaluation. PMID- 29522607 TI - [Embodied narratives of overcoming: A pathway towards recovery?] AB - Narratives play a fundamental role in the recovery of persons with schizophrenia, mainly from the paradigmatic change engendered by the recovery movement. Rather than a methodological tool or a byproduct of recovery, narratives are integral components of this process. This article aims to analyze overcoming narratives, in the light of the corporeality paradigm, based on an emblematic case of a peer support worker. This is a qualitative study carried out in the context of a randomized clinical trial, and it is based on one in-depth interview and focus groups for the construction of the narrative. Thematic analysis was carried out and the following categories were identifed: sense of self and embodiment; experience of time and space; relationship with others; illness experience and overcoming. The embodied narratives of overcoming constitute in the register of a non-linear temporality, and it is based on a dialectical and dialogic process of construction/reconstruction of the sense of self and of the body itself. We propose that embodied narratives are considered as a methodological principle for narrative analysis on recovery, as well as an intrinsic dimension of the recovery journey; that is, as the center of gravity of the process of construction / reconstruction of the sense of self, embodiment and the sense of belonging to the world. PMID- 29522608 TI - [The "recovery model" and the mental health care reform: Evidence, differences and elements for a Latinamerican agenda]. AB - In this article we describe what is known as the recovery approach to mental health, considering the possibilities and potentialities that this model offers to Latin America. We propose that its adoption would enhance the modernization of systems and policies on mental health in the region. Although improvements in these areas are well recognized and documented, the participation of users and the development of services according to their needs and interests constitutes an important gap. We brie?y describe the historical roots of the recovery model and the evidence that supports it, emphasizing how the model has transformed mental health care in different regions of the globe. Some emerging regional experiences following the principles of recovery are described as well. Finally, we propose an agenda to promote an orientation towards recovery in the region. Two underlying principles are highlighted: 1) the leading role that users must play in this process; and 2) the need for a comprehensive contextualization, not only for adapting the model but to start formulating our own paradigm for Latin America, inspired in what has been done in the AngloSaxon world, but open to being locally transformed and shaped. PMID- 29522609 TI - [History from neuropsychology to cognitive neurosciences in Argentina]. AB - The first step from the neuropsychology in Argentina was in 1883 with the thesis of Antonio Pineiro about the brain localization of the language and vision disorders, only few years after Broca. The aim of this work has been to describe the development of the neuropsychology in Argentina and its relation with the psychology, neurology and psychiatry. The first period was into the neurology with its French school in?uence. In 1907, Jose Ingeniero published in French his book about "amusia", Cristofredo Jakob the "folia neurobiologica" where he described the organization of the human brain, Vicente Dimitri in 1933 his book "aphasia" and Bernardo de Quiros in 1959 his works about dyslexia. The psychiatry at the hospices with the German influence from Jakob developed to the modern neuropsychiatry with Juan Carlos Goldar. The argentine school of psychology by the holism and the psychoanalysis influence do not accept the neuropsychology until 1960 where was included at the school of psychology from the university of Buenos Aires (UBA) with the first linguistics works of Juan Azcoaga. At the 80, began the North American influence of the neurology with authors like Carlos Mangone (dementia), Ramon Leiguarda (apraxia), Sergio Starkstein (depression and apathy) and Ricardo Allegri (memory and Alzheimer). In 1982 the Argentine Neuropsychological Society was founded and in 1987 was the working group of dementia from the Argentine Neurological Society. At this moment, Aldo Ferreres organized the chair of neuropsychology at the school of psychology (UBA). Nowadays, the growing as discipline is in context of the psychology, neurology and psychiatry in the way of the recent cognitive neurosciences. PMID- 29522610 TI - [Community residential devices associated with Psychiatric Hospital "Dr. Manuel A. Montes De Oca" in the Province of Buenos Aires, Argentina]. AB - The psychiatric hospital "Dr. Manuel A. Montes de Oca" has developed a Program for the Reform of the Model of Attention and Integral Rehabilitation that includes the implantation of community residential devices in the area of influence of the Institution. This program, which aims at the progressive replacement of asylum beds, has been the subject of an evaluative investigation that has included almost all the devices through a transversal and descriptive design, with instruments of survey created by the equipment and in agreement with the References of the Institution. The present article proposes to initiate a set of evaluative works in different dimensions concerning the institutional reform process, describing the antecedents, the objectives and the methodology and development of the study to achieve the general characterization of the devices. The main results of the study are summarized below on a set of aspects that we consider most signifcant for the characterization of the devices: a) Type of users served; B) Coverage of Care; C) Method of approach; D) Use of social and health services; E) Expenses and returns to the Institution; E) Main barriers encountered in the implementation of such devices. The work concludes with a series of proposals that are based on the survey carried out tending to promote the greatest possible sustainability in the implementation of the selected community devices. PMID- 29522611 TI - [Clinical knowledge as anthropological knowledge: Reflections on the care pact]. AB - A discomfort pervades current Psychiatry: striving to be linked and identifed with Neurology, it cannot however ignore the subjectivity of patients. Moreover, the practice of Psychiatry as a Know-How, should also be subject to a political and ethical dimension. It must rely on justice and politics to the extent that it receives social demands, articulating the attention to vulnerable people with fair institutions (Ricoeur), but also it has to include them in society through their abilities. In this ethical dimension, it should seek to reform assistance institutions so that patients are protected and their rights respected. In this sense, it is necessary to consider the concept of therapeutic alliance (Paul Ricoeur), alliance that is only possible if it takes the form of a mutual promise, from both the therapist and the patient. It is a pact of care, even in situations where the skills and abilities are disproportionate. Clinical knowledge is somehow an anthropological knowledge about man as subject of disease, as homo patiens, but also about he who wants to accompany him in his suffering. PMID- 29522612 TI - [Emergencies in child and adolescent psychiatry]. PMID- 29522613 TI - [Experience of a psychiatric unit in a pediatric hospital in the Province of Cordoba (Argentina): Between epidemiological and legislative changes]. AB - In the past decades, several epidemiological changes have been observed in the demand for child mental health care with an increase in the number of visits as well as hospitalizations due to mental causes. These changes, together with the sanitary guidelines related to mental health, lead to the implementation of a mental health care unit at a pediatric hospital, which required the adjustment of the infrastructure as well as the professional resources available. The diagnosis of the situation and the sanitary context that led to the implementation of the care unit are presented. The performance/management indicators of the psychiatric unit for the period 2009-2015 are: hospitalization cause, psychopathological diagnosis and prolonged hospitalization cause. The hospitalization of children with mental disorders at a pediatric hospital occurs at the crossroads of two paradigms: mental health and pediatrics. PMID- 29522614 TI - [Clinical management of child and adolescent psychiatric emergencies in patients with substance abuse disorders]. AB - This paper addresses the problem of substance abuse disorders in child and adolescent patients within its frequent psychiatric emergency setting. It describes the clinical features that defne the high complexity of these cases, the current state of knowledge regarding clinical management of child and adolescent psychiatric emergencies in patients with substance abuse disorders, and the available treatment strategies in the metropolitan area of Buenos Aires, Argentina. Finally, this article delves into the existence of a metropolitan addiction treatment network, its community outreach and the obstacles it has to conquer in order to attain the international standards for the treatment of substance abuse disorders. PMID- 29522615 TI - [The hospital and the emergencies in our time. Child and adolescents mental health]. AB - In the last decade, the Emergency Department of "Dr. Ricardo Gutierrez" Children's Hospital in the city of Buenos Aires, Argentina, registered a signifcant increase in mental health consultations of children and adolescents. The increase in the demand for assistance was mainly due to self-injurious behavior, suicide attempts and situations of violence and abandonment. We analyze the variables that determine the characteristics of the current consultation and the change in the profile of the institutions called to respond to this demand. Finally, we reflect on the place of childhood and adolescence, considering the influence of cultural and socioeconomic changes of contemporary society. PMID- 29522616 TI - [Times of childhood. Clinic of urgency and helplessness]. AB - In this paper we discuss the "times of childhood", the relevance of what is "urgent" in the construction of psychological subjectivity, the symptoms leading to the identifcation of an early distress in children up to the age of 2, and some other mental health emergencies, such as abuse, violence and Munchausen syndrome. We consider the infant-mother relationship the cornerstone of this clinic of helplessness. We discuss the notion of emergency beyond the classic psychiatric emergency. We conclude there is an urgent need to build work teams (health care professionals, education professionals, professionals in the judicial feld) trained in the early detection of warning signs and early intervention. PMID- 29522617 TI - [Clinical considerations about traumatic effects of sexual abuse in adolescents]. AB - Sexual abuse, even when it occurs during childhood, may manifest symptoms only in adolescence by the effect of the resignifcation of infantile sexuality, characteristic of that vital moment. In cases of child sexual abuse, in the face of the disruption of impulses and identifcations that occurs in adolescence, there can be trauma that limits the possibilities of processing the psychic apparatus, even in the course of a psychotherapeutic treatment. The acting out reveals itself in transference, it calls for the analyst to relocate the suffering of his patient. PMID- 29522618 TI - [Hospitalization for attempted suicide in a children's hospital]. AB - The objective of the study is to describe characteristics of children and adolescents hospitalized with a diagnosis of attempted suicide. A descriptive cross-sectional observational study based on review of medical records to determine characteristics of the institutionalized population in the Hospital Materno Infantil (HIEMI) city of Mar del Plata, Argentine, in the period April 2014 to December 2015 who were admitted under the diagnosis of suicide attempt. Sex, age, methods of self-harm, UCI requirement, previous hospitalizations for retries, psychopathological history of treatment, sexual history and family history of frst-degree abuse of psychiatric disorders is described. 64 children and adolescents were hospitalized for attempted suicide in the period. The 79.68% were female and over 13 years. 23.4% were treated retries. 12.5% used highly lethal methods such as frearms and hanging, 84.37% low lethality methods as sharp intake of psychotropic drugs and self-inflicted injuries and 6% required stay in ICU. 50% of the study population were under some kind of psychopathological treatment, 14% had a history of sexual abuse and 48.4% had a family history of psychiatric illness. Methods of low lethality as ingestion of psychotropic drugs and self-inflicted injuries cutting were more commonly used in women aged 13 to 14 years. PMID- 29522619 TI - [The pain experiences and the vulnerabilities turn on the interpersonal violence among young people in the marginalized populations of Buenos Aires City: A field of intervention in Mental Health]. AB - We present the results of a study in which we interviewed friends of young people, between 15 and 25 years old who died in front of other young people, in marginalized populations from the south part of Buenos Aires. The aim is to characterize the psychosocial experience that is triggered by these deaths among young people from their same networks of sociability. We used a qualitative, exploratory, and descriptive design, composed by the reconstruction of eight biographies and juvenile life tales, through a set of semi-structured interviews. The different contexts of each death are characterized, and also the psychic and social impact that they produce in the personal and social trajectories of young people. We attempt to discuss that such deaths cause pain experiences related to different processes of vulnerability, and that this is in tension with the importance of violence as a way of obtaining recognition and identity respect in youth sociabilities. The visibility of the processes of social vulnerability and the pain of young people close to the death can be very useful for approaches in the feld of mental health with this youth population. PMID- 29522620 TI - ["The most cruel annoyance is not worth a suicide". Interview to Marie Rose Moro]. PMID- 29522621 TI - [Adolescence, addictive disorders and psychopathology. Between the brain systems of reward and the self-regulation]. AB - The author analyzes certain aspects of the psychopathology of addictions in adolescence, from a psychoanalytical and neurobiological point of view. Within the feld of present psychopathology we frequently fnd problems related with use and abuse of substances, particularly in adolescent therapy. Impulsivity, violence, marginalization, and primitive phantasies appear in the setting along with the functioning of the "addictive brain". Several aspects of vulnerability in adolescence, like depressive symptoms or narcissistic unbalance are connected with two basic principles in addiction: 1) drugs as a mean of obtaining pleasure, and 2) drugs as self regulators. The paper also describes the brain reward systems and the effect of drugs as neurotransmitters within the framework of intersubjectivity. A social approach completes the interdisciplinary work and enables us to use different explanatory models. PMID- 29522622 TI - [Increased sensitivity in bipolar disorder detection with the MDQ and BSDS using Ghaemi-Goodwin's criteria for the bipolar spectrum]. AB - INTRODUCTION: Many patients with bipolar disorder (BD) spend around 10 years without a diagnosis and appropriate treatment. The difficulty in distinguishing bipolar from unipolar depression, the prevalence of depressive symptoms along the course of BD and patients' bias in recalling their hypomanic symptoms are some of the factors that contribute to this problem. OBJECTIVE: This study compares the efficiency of several screening instruments for BD detection in a group of patients (n=63) with mood disorders, or cluster B personality disorders. METHOD: The diagnoses were made with structured interviews: Mini International Neuropsychiatric Interview (MINI) and Structured Clinical Diagnostic Interview for axis II (SCID-II). The patients completed the Mood Disorder Questionnaire (MDQ) and Bipolar Spectrum Disorder Scale (BSDS) and were assessed with the Bipolar Index-BI and Ghaemi-Goodwin Bipolar Spectrum Criteria. Sensitivity, specifcity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) were estimated for each instrument, along with Chi2 and T-tests. Statistical analyses were conducted using the SPSS-v16. RESULTS: The BI had the best global performance with 88% specificity and 0.90 of sensitivity. The MDQ-H had the highest specificity and the MDQ-6 the highest sensitivity. However, when combining the MDQ with Ghaemi's criteria, an ostensible augment was obtained in sensitivity while maintaining good predictive values. CONCLUSIONS: The joint assessment of mania symptoms and typical evolving course symptoms in BD increased the probability of BD detection in this clinical sample. PMID- 29522623 TI - [Comparative analysis about hospitalization characteristics in the mental health unit of a general acute care hospital]. AB - INTRODUCTION: In Argentina, like in the rest of the world, deinstitutionalization policies have been implemented. In our country, the shortage of epidemiologic data regarding admissions in mental health is a limitation for the discussion about how this changes should be implemented and its effect. OBJECTIVES: Epidemiologic data of inpatients of the Mental Health Unit of the Teodoro Alvarez General Hospital between June 2012 and May 2013 has been analyzed in order to elaborate a comparative analysis with a previous study that took place in the same unit on the years 2004-2005. MATERIALS AND METHODS: This is naturalistic, descriptive and retrospective study about adult male inpatients admitted in the psychopathology ward of the Alvarez Hospital. Data was taken from the patient's medical history report. RESULTS: There were 51 hospitalizations during the study (versus 82 hospitalizations in the previous one). The average age was 34.4 years. The average patient hospitalization was 46.2 days (versus 45.4), 84% (vs 89.7%) of hospitalizations lasted less than 90 days, although there was an increase in hospitalization that lasted between 90 and 179 days (7.3% vs 13.7%). The most frequent reason for hospitalization was acute psychotic syndrome, 62.7% (versus 48.8%) of the patients had previous psychiatric hospitalizations. The most frequent diagnosis at discharge were: 38.4% schizophrenia and other psychotic disorders (vs 38.1%), 21.5% personality disorders (vs 25%), 17% mood disorders (vs 17.7%), 15.4% substance use related (vs 22.1%). CONCLUSION: There has been a considerable decrease (from 82 to 51) in the total number of hospitalizations and also a decrease in the BTR (bed turnover ratio) from 4.1 to 2.6 and an increase in hospitalizations with a duration superior to 90 days and inferior to 179 days. PMID- 29522625 TI - [Pinel in "the Pampas": First psychiatric diagnosis in the independent era]. PMID- 29522624 TI - [Argentine psychiatric nosologies and nosographies]. AB - Since the late 19th century, Argentinean psychiatrists have been developing classifcations of psychiatric disorders. Their work has had local originality and fruitful exchange with international controversies on the subject. The thinking of some Argentinean psychiatrists transcended the borders of the country and was adopted in the South American region, as was the case with the classifcation proposed by Jose T. Borda. There were also historical anticipations of concepts that were not known in other latitudes: "oligotimia", a category created by Enrique Pichon-Riviere, preceded the characterization of early childhood autism by Leo Kanner. In recent decades, Argentinean psychiatrists have adopted current international classifcations (DSM and CIE), but also actively participated in the elaboration of an original regional proposal: the Latin American Guide to Psychiatric Diagnosis (GLADP-VR 2012), and collaborated with the surveys carried out by the World Health Organization (WHO) for the revision of the future ICD 11. This article provides a detailed description of Argentinian classifcations, extensively quoting each author to provide a clear understanding of their thinking, as well as critical reviews of their proposals. PMID- 29522626 TI - [Usefulness of SCL-90-R and SIMS inventories for the detection of mental health malingering at workplace]. AB - Mental illness is a common cause of work leave. This situation has a negative impact on labor productivity and costs, and may contribute to con?icts affecting workplace environment. The purpose of this investigation is to describe the evaluation results of a total of 89 cases on sick leave for psychological and psychiatric reasons, and to test the convergent validity of scales in the "Positive Symptom Total" (PST) and "Positive Symptom Distress" (PSDI) of the Symptom Checklist Revised (SCL-90-R) by means of the Structured Inventory of Malingered Symptomatology (SIMS). Taking a score higher than 16 in the SIMS as the cut-off point, the analysis focused on whether PST and PSDI scales presented differences in average between malingers and non-malingers. From the total number of cases, 66 were found to be likely cases of malingered mental illness, with different averages in PST (77.02) and PSDI (2.71). Statistical correlation tests allowed to objectify convergent validity and statistical signifcance between the PSDI and PST scales of the inventory SCL-90-R and the SIMS inventory, with a higher average in PSDI scale (0.617) as compared with PST scale (0.413) in Spearman's rho. The results of the investigation confrm the usefulness of both instruments for the assessment of mental illness malingering in employers on sick leave due to mental disorders. PMID- 29522627 TI - [Argentinean psychiatrists and research. Survey on knowledge, attitudes and practices]. AB - Research in the Mental Health field is essential not only in the academic area, but also in the patient care setting. Knowing the attitudes, knowledge and practices in research among psychiatrists allow for the design of interventions to promote their participation. The aim of this study is to explore the current situation of research among psychiatrists in Argentina. A cross sectional 26 question survey was applied between May-August 2014, anonymous and voluntary among psychiatrists and psychiatrists in training in different centers. 378 psychiatrists participated from different centers in Argentina. Among the most relevant results, 97.2% considers it's important to include research in their training as psychiatrists, 46.4% has knowledge about database use and 68.8% has presented work in an academic setting. 88.5% believes research in Argentina is defcient. PMID- 29522629 TI - [Clinical experiencies]. PMID- 29522628 TI - [Scales for internet addiction in spanish population: A proposal]. AB - New technologies and internet use have generated such an intimated bound between users and their devices that an increasing preoccupation about problematic use and addiction has raised. Prevalence studies warn about values higher than 5% in the most restrictive studies. There are many differences in the study of this phenomenon attending to the methodology, conceptualization, object of study, device, or even on-line or off-line use. This lack of consensus has generated a number of scales. An article as the present one proposing a minimum set of scales seems necessary. This article refers to some scales which seem adequate for Spanish population due to their easy application, their validity and their extension of use. We present the validated translations for the YIAT20 and the MPPUSA. We have also done a translation where it was not available a Spanish version for the CIAS and Ko's criteria. PMID- 29522630 TI - [Narrative and psychiatry]. AB - The aim of this work is to analyze the application of the concepts that originate in the narrative, to the learning and teaching of psychiatry. We will also explore how the reading and writing processes in the specialty are developed. PMID- 29522631 TI - [Takotsubo cardiomyopathy: The mind-body continuum]. AB - Takotsubo disease, also called "apical ballooning syndrome", "stress cardiomyopathy" or "broken-heart syndrome" is a potentially lethal entity. It is usually triggered by psychological or physical stress, either individual or collective, as a traumatic experience which is sudden and acute. Clinical presentation is usually accompanied by severe myocardial failure, which generally requires hemodynamic support in Cardiovascular Care Unit. PMID- 29522632 TI - [Is erotomania a defense against melancholy?] AB - In this article we report a clinical case of erotomania whose clinical manifestations are interpreted from the perspective of the Lacan theory. The author postulates, based on clinical data and its psychoanalytic interpretative correlate, a possible link between Clerambault syndrome and melancholia, in which the former operates as a defense against the latter. PMID- 29522633 TI - [Acute and chronic psychoses with cenestopathies and/or hypochondriacal symptoms]. AB - Both cenestopathies (abnormal body sensations) and hypochondriac symptoms can occur in both acute and chronic psychotic disorders. The present article will brie?y describe some psychotic pictures that may accompanied with cenestopathies and/ or hypochondriacal symptoms. All descriptions will be illustrated with clinical examples to facilitate the understanding and delimitation of these diseases. PMID- 29522634 TI - [N-Methyl-D-Aspartate receptor encephalitis: An adolescent case report and literature review. How to manage neuropsychiatric symptoms]. AB - Anti-N-methyl-D-aspartate receptor encephalitis was described as a clinical entity in 2007. The present case report aims to describe the signs and symptoms, differential diagnosis, treatment and course of a sixteen-year-old boy with this disorder who was hospitalized for almost two months. In addition, we will expose the therapeutic management and the diffculties presented in the handling of neuropsychiatric symptoms, considering the complex context of heterogeneous clinical manifestations caused by this disorder. The authors conducted a PubMed, LILACS and Cochrane search and added supplementary methods to compile the major quantity of evidence to support the clinical decisions. To date no systematic reviews or clinical guidelines about the management of psychiatric symptoms in adolescents with this condition were found. Only case reports and series of cases are available. The quality of evidence is poor as long as there are not analytic studies available. The adolescent presented to the emergency department with confusion, speech disturbances and right brachio-crural hemiparesis. During the course of hospitalization he developed a catatonic syndrome, several episodes of psychomotor agitation, sleep disorders and psychotic symptoms. He received successive immunomodulatory therapy for autoimmune encephalitis and psychiatric medication. He was discharged with recovery almost ad integrum. In conclusion, the diagnosis of anti-rNMDA encephalitis should be suspected in previously healthy adolescents with no psychopathological antecedents who suddenly present psychiatric and neurological symptoms. The evolution and prognosis depend on the early initiation of immunomodulating therapy. Psychiatrists should be aware and suspect this entity rapidly and play an important role as consultants for the management of psychiatric and behavioral disturbances. PMID- 29522635 TI - [Use of antidepressants in institutionalized patients with dementia and agitation: Case reports]. AB - Psychological and behavioral symptoms in dementias are frequent: they affect 90% of patients at some point in the evolution of the disease. Their presence determines in general the institutionalization of the person. Also, in that context, it may lead to an abusive prescription of antipsychotics, despite little evidence regarding its effcacy and adverse effects profle. Following this line, the objective of this work will focus on the "use" and "utility" of an under examined pharmacological class in agitated patients with dementia: antidepressants. We will share a clinical experience from the report of ten cases of institutionalized patients. PMID- 29522636 TI - [Treatment-resistant schizophrenia: Neutropenia with olanzapine and clozapine, and stabilization with two depot antipsychotics]. AB - This case report describes a case of a woman with treatment-resistant schizophrenia, who experienced neutropenia induced by olanzapine and clozapine, and reached symptomatic stabilization with a combination of two depot antipsychotics. This report presents a brief review about the incidence of haematologic events by antipsychotics and the evidence of antipsychotic combination in the treatment. PMID- 29522637 TI - [Mixed Munchausen Syndrome with organic comorbidity]. AB - We present a detailed case report that shows a woman patient who has Factitious Disorder manifested by the coexistence both of: A) typical/direct Munchausen and B) Munchausen by proxy or indirect: being the frst one (A) about the own person and the second one (B) about other people (most cases about their own young children). Furthermore, in the reported case we observed that the patient shown the particularity of having positive biological markers for Myasthenia Gravis (serology markers), and having inconsistent clinical manifestations that are typically observed in the exacerbation phase when she still continued in remission phase. In our own bibliographic research we couldn't fnd anything about this case of "Mixed Munchausen Syndrome with organic comorbidity". In the same way as we tried to get information about the diagnostic algorithms and the possible therapeutic treatment strategies we found nothing like this reported before. Finally, this clinical presentation constitutes a blind spot for the scientifc community generating a lack of recognition for this diagnostic category and above all of the confusion that this mental disorder can generate in: a) the inadequate use of therapeutic resources, b) the irrational use of drugs, c) the distortion of institutional instances, and d) the medical behaviors that occurred in this case. PMID- 29522639 TI - [Ludwig Binswanger. Madness as a biographical phenomena in the totality of existence]. PMID- 29522638 TI - [Interview to Eduardo Muller]. PMID- 29522640 TI - [Madness as a biographical phenomena]. PMID- 29522641 TI - Evaluation and Treatment of Hirsutism in Premenopausal Women. PMID- 29522642 TI - Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation. AB - Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules. PMID- 29522643 TI - Anatomic estimation of aortic stenosis severity vs "fusion" of data from computed tomography and Doppler echocardiography. AB - AIM: Two-dimensional, transthoracic echocardiography does not account for the noncircular anatomy of the left ventricular outflow tract (LVOT) and may therefore underestimate LVOT area. Fusion of computed tomography (CT)-derived LVOT area and Doppler-derived flow data has been proposed to improve assessment of aortic valve area (AVA) and classification of aortic stenosis severity. For hemodynamic reasons, effective AVA has to be smaller than anatomic AVA. The aim of the study was to test the "fusion approach" by comparing effective CT-derived AVA with anatomic AVA from CT planimetry. METHODS AND RESULTS: Data of 244 consecutive patients (mean age 81 +/- 5 years, 61% female) with aortic stenosis were retrospectively analyzed comparing effective AVA (calculated from the continuity equation using CT-LVOT and transthoracic Doppler measurements) with anatomic AVA based on CT planimetry. Substituting the LVOT area from transthoracic echocardiography (TTE) by the CT-LVOT resulted in an increase in AVA from 0.74 +/- 0.15 to 0.92 +/- 0.18cm2 (P < .01), which was larger than anatomic AVA (0.82 +/- 0.15cm2). Similar results were obtained based on planimetry from transesophageal echocardiography (TEE; AVA 0.79 +/- 0.14cm2, P < .01 vs CT-LVOT) and in the subgroup presenting with low-gradient severe aortic stenosis and preserved ejection fraction (n = 67, AVA from TTE 0.76 +/- 0.09; from CT-LVOT 0.97 +/- 0.14; CT planimetry 0.86 +/- 0.12; TEE planimetry 0.82 +/- 0.13cm2). CONCLUSION: Fusion of CT-derived LVOT area with Doppler echocardiography results in a calculated effective AVA that is larger than the corresponding anatomic AVA. Therefore, adjustment of partition values may be warranted when using this approach. PMID- 29522644 TI - Couple Differentiation: Mediator or Moderator of Depressive Symptoms and Relationship Satisfaction? AB - The purpose of this investigation was to determine whether differentiation at the couple level would act as a moderator or a mediator in the association between marital satisfaction and depressive symptoms over time. In a sample of 412 couples, a latent profile analysis was performed to determine how couple differentiation scores were clustered. An Actor/Partner Interdependence Model was then estimated via a group comparison procedure in structural equation modeling. There was no evidence of a moderating effect of differentiation. A mediating model was then estimated and there was evidence that differentiation mediated the association between depressive symptoms and relationship satisfaction via actor and partner effects. PMID- 29522645 TI - Non-peptide-based new class of platelet aggregation inhibitors: Design, synthesis, bioevaluation, SAR, and in silico studies. AB - A series of 2-oxo-2-phenylethylidene linked 2-oxo-benzo[1,4]oxazine analogues 17a x and 18a-o, incorporated with a variety of electron-withdrawing as well as electron-donating groups at ring A and ring C, were synthesized under greener conditions in excellent yields (up to 98%). These analogues 17a-x and 18a-o were evaluated for their arachidonic acid (AA)-induced platelet aggregation inhibitory activities in comparison with the standard reference aspirin (IC50 = 21.34 +/- 1.09 ug/mL). Among all the screened compounds, eight analogues, 17i, 17x, 18f, 18g, 18h, 18i, 18l, and 18o, were identified as promising platelet aggregation inhibitors as compared to aspirin. In addition, cytotoxic studies in 3T3 fibroblast cell lines by MTT assay of the promising compounds (17i, 17x, 18f-18i, 18l, and 18o) were also performed and the compounds were found to be non-toxic in nature. Furthermore, the results on the AA-induced platelet aggregation inhibitory activities of these compounds (17i, 17x, 18f-18i, 18l, and 18o) were validated via in silico molecular docking simulation studies. To the best of our knowledge, this is the first report of the identification of non-peptide-based functionalized 2-oxo-benzo[1,4]oxazines as platelet aggregation inhibitors. PMID- 29522646 TI - Full covariate modelling approach in population pharmacokinetics: understanding the underlying hypothesis tests and implications of multiplicity. AB - AIMS: To clarify the hypothesis tests associated with the full covariate modelling (FCM) approach in population pharmacokinetic analysis, investigate the potential impact of multiplicity in population pharmacokinetic analysis, and evaluate simultaneous confidence intervals (SCI) as an approach to control multiplicity. METHODS: Clinical trial simulations were performed using a simple one-compartment pharmacokinetic model. Different numbers of covariates, sample sizes, effect sizes of covariates, and correlations among covariates were explored. The false positive rate (FPR) and power were evaluated. RESULTS: The FPR for the FCM approach dramatically increases with number of covariates. The chance of incorrectly selecting >=1 seemingly clinically relevant covariates can be increased from 5% to a 40-70% range for 10-20 covariates. The SCI approach may provide appropriate control of the family-wise FPR, allowing more appropriate decision making. As a result, the power detecting real effects without incorrectly identifying non-existing effects can be greatly improved by the SCI approach compared to the approach in current practice. The performance of the SCI approach is driven by the ratio of sample size to number of covariates. The FPR can be controlled at 5% and 10% using the SCI approach when the ratio was >=20 and 10, respectively. CONCLUSION: The FCM approach still lies within the framework of statistical testing, and therefore multiplicity is an issue for this approach. It is imperative to consider multiplicity reporting and adjustments in FCM modelling practice to ensure more appropriate decision making. PMID- 29522647 TI - Preventability of serious thromboembolic and bleeding events related to the use of oral anticoagulants: a prospective study. AB - AIMS: To determine the preventability of serious adverse drug reactions (ADRs) related to the use of direct oral anticoagulants (DOACs), and to explore contributing factors to preventable ADRs. Results were compared with vitamin K antagonists (VKAs). METHODS: We conducted a prospective observational study in the emergency departments of two teaching hospitals from July 2015 to January 2016. Patients admitted with a thrombotic or bleeding event while under DOAC or VKA were included. Four independent reviewers assessed causality, seriousness and preventability of ADRs using pilot-tested scales. For cases of serious and potentially preventable ADRs, we performed semi-structured interviews with general practitioners to identify contributing factors to ADRs. The primary outcome was the proportion of serious ADRs that were potentially preventable. RESULTS: The analysis included 46 DOAC and 43 VKA patients (median age 79 years). Gastrointestinal (n = 34) and intracranial (n = 16) bleedings were the most frequent ADRs. Results were that 53% of DOAC- and 61% of VKA-related serious ADRs were deemed potentially preventable. Prescribing issues and inadequate monitoring were frequent for DOAC and VKA respectively. We identified many causes of preventable ADRs that applied to all oral anticoagulants, such as pharmacodynamic drug interactions and lack of communication. CONCLUSIONS: More than half of serious ADRs were potentially preventable for both DOACs and VKAs. Interventions focusing on prescribing, patient education and continuity of care should help improve the use of DOACs in practice. PMID- 29522648 TI - The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function. AB - AIMS: The aim of this study was to compare the effects of the selective M3 muscarinic acetylcholine receptor antagonist darifenacin, oral hyoscine hydrobromide and placebo on motion sickness induced by cross-coupled stimulation. METHODS: The effects of darifenacin 10 mg or 20 mg, hyoscine hydrobromide 0.6 mg and placebo were assessed in a randomized, double-blind, four-way cross over trial of 16 healthy subjects. Motion sickness, skin conductance (a measure of sweating) and psychomotor cognitive function tests were investigated. RESULTS: Hyoscine hydrobromide produced significantly increased tolerance to motion versus placebo (P < 0.05 to P < 0.01). The motion protection effect of darifenacin (10 or 20 mg) was approximately one third that of hyoscine hydrobromide but was not significant versus placebo. Darifenacin and hyoscine hydrobromide both significantly reduced skin conductance versus placebo. Darifenacin produced either no effect or an enhanced effect on cognitive function in contrast to hyoscine hydrobromide, where there was significant impairment of psychomotor performance. CONCLUSION: The results suggest that selective antagonism of the M3 receptor may not be important in the prevention of motion sickness. However, selective M3 antagonism does not impair cognitive function. These observations may be important given that long-term treatment with non-selective anti muscarinic agents such as oxybutynin may lead to an increased incidence of dementia. PMID- 29522649 TI - Integrity of IKK/NF-kappaB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis. AB - A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkalpha knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IkappaB kinase alpha (IKKalpha) is one subunit of the IKK complex required for NF-kappaB activation. IKK/NF-kappaB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-kappaB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-kappaB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-kappaB in these diseases. PMID- 29522651 TI - Combined Non-invasive PIXE/PIGE Analyses of Mammoth Ivory from Aurignacian Archaeological Sites. AB - Among the earliest Homo sapiens societies in Eurasia, the Aurignacian phase of the Early Upper Paleolithic, approximately 40 000-30 000 years ago, mammoth ivory assumed great social and economic significance, and was used to create hundreds of personal ornaments as well as the earliest known works of three-dimensional figurative art in the world. This paper reports on the results of micro-PIXE/PIGE analyses of mammoth-ivory artifacts and debris from five major sites of Aurignacian ivory use. Patterns of variable fluorine content indicate regionally distinctive strategies of ivory procurement that correspond to apparent differences in human-mammoth interactions. Preserved trace elements (Br, Sr, Zn) indicate that differences at the regional level are applicable to sourcing Paleolithic ivory at the regional scale. PMID- 29522650 TI - Consensus recommendations on standardized magnetic resonance imaging protocols for multicenter canine brain tumor clinical trials. AB - The National Cancer Institute Comparative Brain Tumor Consortium, Patient Outcomes Working Group, propose a consensus document in support of standardized magnetic resonance imaging protocols for canine brain tumor clinical trials. The intent of this manuscript is to address the widely acknowledged need to ensure canine brain tumor imaging protocols are relevant and have sufficient equivalency to translate to human studies such that: (1) multi-institutional studies can be performed with minimal inter-institutional variation, and (2) imaging protocols are consistent with human consensus recommendations to permit reliable translation of imaging data to human clinical trials. Consensus recommendations include pre- and postcontrast three-dimensional T1-weighted images, T2-weighted turbo spin echo in all three planes, T2*-weighted gradient recalled echo, T2 weighted fluid attenuated inversion recovery, and diffusion weighted imaging/diffusion tensor imaging in transverse plane; field of view of <=150 mm; slice thickness of <=2 mm, matrix >= 256 for two-dimensional images, and 150 or 256 for three-dimensional images. PMID- 29522652 TI - Anton Chekhov and Robert Koch Cheek to Cheek: A Proteomic Study. AB - Five different letters and post cards as well as the shirt worn by Anton Chekhov on his death bed, stored in the State Literary-Memorial Museum-Reserve A. P. Chekhov Melikhovo (nearby Moscow), have been analyzed by applying EVA (an ethyl vinyl acetate foil studded with crushed strong anion and cation exchangers and with C8 resins) diskettes to these surfaces. Three different eluates (under acidic and basic conditions and with acetonitrile) were analyzed by high resolution mass spectrometry. The environmental microbiota present on samples and the Mycobacterium tuberculosis strain were described by a meta-proteomics approach. Eight identified M. tuberculosis proteins confirmed the presence of the bacterium and the cause of Chekhov's death, in addition to several sequenced peptides belonging to other bacterial species. The human plasma proteins and human keratins, detected on a tiny blood spot on the shirt, demonstrated the power of the combined approach. PMID- 29522653 TI - Fluorinated GluN2B Receptor Antagonists with a 3-Benzazepine Scaffold Designed for PET Studies. AB - To analyze the N-methyl-d-aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B-subunit-containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3-(4 phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1,7-diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7-position), 17 (9-position), 18a-c (1-position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18 F]14 was performed by nucleophilic substitution of the phenol 2 with 2-[18 F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18 F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981, and the non-labeled 3-benzazepine 14 were able to abolish the specific binding of [18 F]14. PMID- 29522654 TI - Deciphering the Surface Composition and the Internal Structure of Alloyed Silver Gold Nanoparticles. AB - Spherical bimetallic AgAu nanoparticles in the molar ratios 30:70, 50:50, and 70:30 with diameters of 30 to 40 nm were analyzed together with pure silver and gold nanoparticles of the same size. Dynamic light scattering (DLS) and differential centrifugal sedimentation (DCS) were used for size determination. Cyclic voltammetry (CV) was used to determine the nanoalloy composition, together with atomic absorption spectroscopy (AAS), energy-dispersive X-ray spectroscopy (EDX) and ultraviolet-visible (UV/Vis) spectroscopy. Underpotential deposition (UPD) of lead (Pb) on the particle surface gave information about its spatial elemental distribution and surface area. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) were applied to study the shape and the size of the nanoparticles. X-ray powder diffraction gave the crystallite size and the microstrain. The particles form a solid solution (alloy) with an enrichment of silver on the nanoparticle surface, including some silver-rich patches. UPD indicated that the surface only consists of silver atoms. PMID- 29522655 TI - Assessment of left atrial size in addition to focused cardiopulmonary ultrasound improves diagnostic accuracy of acute heart failure in the Emergency Department. AB - BACKGROUND: Acute dyspnea is one of the main reasons for admission to Emergency Department (ED). Availability of ultraminiaturized pocket ultrasound devices (PUD) adds diagnostic power to the clinical examination. The aim of this study was to identify an integrated ultrasound approach for diagnosis of acute heart failure (acute HF), using PUD and combining evaluation from lung, heart and inferior vena cava (IVC). METHODS: We included 102 patients presenting to the ED of "Antonio Cardarelli" Hospital in Naples (Italy) for acute dyspnea (AD). All patients underwent integrated ultrasound examination (IUE) of lung-heart-IVC, using PUD. The gold standard was the final diagnosis determined by two expert reviewers: acute heart failure (acute HF) or noncardiac dyspnea. We used 2 * 2 contingency tables to analyze sensitivity, specificity, positive and negative predictive value and accuracy of the three ultrasonic methods, and their combinations for the diagnosis of acute HF, comparing with the final, validated diagnosis. RESULTS: Lung ultrasound (LUS) alone exhibited a good sensitivity (100%) and specificity (82%) and had the highest accuracy (89%) among single modalities (heart and IVC) for the diagnosis of acute HF. The highest accuracy among all methods (96%) was obtained by the combination of positive LUS and either dilated left atrium or EF <= 40% or both (all P < .01 vs single modalities). CONCLUSION: In patients presenting to ED, IUE using PUD is a useful extension of clinical examination and has a reliable diagnostic discriminant ability in the immediate evaluation of acute dyspnea. The combination of positive LUS with focused cardiac ultrasonography (FoCUS), including also dilated left atrium, substantially extends the spectrum of recognizable acute HF. PMID- 29522656 TI - How Polycomb-Mediated Cell Memory Deals With a Changing Environment: Variations in PcG complexes and proteins assortment convey plasticity to epigenetic regulation as a response to environment. AB - Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment. PMID- 29522657 TI - Activated platelet-rich plasma improves cartilage regeneration using adipose stem cells encapsulated in a 3D alginate scaffold. AB - In the current study, the effect of superimposing platelet-rich plasma (PRP) on different culture mediums in a three-dimensional alginate scaffold encapsulated with adipose-derived mesenchymal stem cells for cartilage tissue repair is reported. The three-dimensional alginate scaffolds with co-administration of PRP and/or chondrogenic supplements had a significant effect on the differentiation of adipose mesenchymal stem cells into mature cartilage, as assessed by an evaluation of the expression of cartilage-related markers of Sox9, collagen II, aggrecan and collagen, and glycosaminoglycan assays. For in vivo studies, following induction of osteochondral lesion in a rabbit model, a high degree of tissue regeneration in the alginate plus cell group (treated with PRP plus chondrogenic medium) compared with other groups of cell-free alginate and untreated groups (control) were observed. After 8 weeks, in the alginate plus cell group, functional chondrocytes were observed, which produced immature matrix, and by 16 weeks, the matrix and hyaline-like cartilage became completely homogeneous and integrated with the natural surrounding cartilage in the defect site. Similar effect was also observed in the subchondral bone. The cell-free scaffolds formed fibrocartilage tissue, and the untreated group did not form a continuous cartilage over the defect by 16 weeks. PMID- 29522658 TI - Loss and Rebirth of the Animal Microtubule Organizing Center: How Maternal Expression of Centrosomal Proteins Cooperates with the Sperm Centriole in Zygotic Centrosome Reformation. AB - Centrosomes are the main microtubule organizing centers in animal cells. In particular during embryogenesis, they ensure faithful spindle formation and proper cell divisions. As metazoan centrosomes are eliminated during oogenesis, they have to be reassembled upon fertilization. Most metazoans use the sperm centrioles as templates for new centrosome biogenesis while the egg's cytoplasm re-prepares all components for on-going centrosome duplication in rapidly dividing embryonic cells. We discuss our knowledge and the experimental challenges to analyze zygotic centrosome reformation, which requires genetic experiments to enable scrutinizing respective male and female contributions. Male and female knockout animals and mRNA injection to mimic maternal expression of centrosomal proteins could point a way to the systematic molecular dissection of the process. The most recent data suggest that timely expression of centrosome components in oocytes is the key to zygotic centrosome reformation that uses male sperm as coordinators for de novo centrosome production. PMID- 29522659 TI - [The ophthalmologic signs in cerebellum tumor. Preliminary report]. AB - Introduction: The aim of the study was an analysis of ophthalmicsymptoms coexisting with the tumour of the cerebellum. Material and methods: The study included 14 patients in the agebetween 21-55 years old with the tumor of cerebellum, who wereoperated in the Neurosurgery Clinic of the Pomeranian MedicalUniversity in Szczecin. The comprehensive ophthalmic examinationwere performed before and after 5 days from surgery. Theexaminations included evaluation of: pupillary reactions, visualacuity, fundus ophthalmoscopy, intraocular pressures, eye motility,visual field, optometrical tests and visual manual localization test. Results: The symptoms found before surgery of cerebellumtumors: diplopia (3 persons), early papilloedema (4 persons),nystagmus (2 persons), lack (5 persons) and weakened ofconvergence re??lex (3 persons), latent strabismus (5 persons),manifest strabismus (3 persons). On the 5th day after the surgerywere found: nystagmus (1 person), lack (5 persons) andweakened of the convergence re??lex (3 persons). Visual manuallocalization was disparate depending on location of the tumor inthe cerebellum; prevailed crossed and uncrossed localizations. Conclusions: 1. The natural dynamic of the tumor and surgicaldamage to the posterior cranial cavity structures can be monitoredby assessment of the condition of the organ sight. 2. It isrecommended to make the visual manual localization tests suchas exponent disorders of senso-motorical deviations, which mayoccur in the patients with the cerebellum tumor. PMID- 29522660 TI - [Bi-compartmental gall bladder with the distal part filled with stones and inflamed, and the proximal part not involved - a case report]. AB - Anatomical anomalies of extra-hepatical biliary ducts are fairlycommon, occurring in about 16% of patients. The most commonanomaly is an atypical course of the cystic duct and its outlet to thecommon hepatic duct. Anomalies of the gall bladder are less commonand rarely presented, due to their minor clinical relevance.The paper presents the case of a female patient with a two--compartment gall bladder, the distal part of which was filledwith biliary stones and in??lamed, whereas the proximal partcontained no stones and was not involved. The operation,although difficult because of the atypical anatomy and inflammatoryinfiltration, was uneventful, and the patient eventuallyrecovered. PMID- 29522661 TI - A rare case of unilateral fibrous dysplasia of the condyle of the mandible. Diagnosis and therapy using an axiographic technique and digital X-ray - a case report. AB - Introduction: The aim of the paper is to present the diagnosticprocedure and treatment of a female patient with dysfunction ofthe right temporomandibular joint, caused by fibrous dysplasiaof the head of the right mandibular condyle. Material and methods: In the diagnostic process of bonystructures digital radiography (Digora) was used. To examinethe mobility of the mandible axiographic measurements wereperformed using the Cadiax (Gamma Diagnostic) device. Conclusions: These methods allowed the confirmation of thediagnosis and the determination of a treatment plan whichincluded the use of a therapeutic appliance. The performedprocedures had a positive therapeutic effect. PMID- 29522662 TI - Cerebrospinal meningitis in a 30 -year -old patient as first manifestation of pituitary macroadenoma. AB - Introduction: The most common clinical and neurological signsand symptoms of pituitary macroadenomas include headache,vision impairment and cranial nerve palsy. Case report: The patient presented in this article was admittedto the Intensive Care Unit at regional hospital; at admission, thepatient was unconscious, he had convulsions and spasms, anda 3 -day history of headache and body temperature up to 41.5 degrees C.The patient with suspected neuroinfection was transferred to theDepartment of Infectious Diseases of the Pomeranian MedicalUniversity in Szczecin (PMU), where cerebrospinal meningitisof bacterial etiology was established based on cerebrospinalfluid investigations and the presence of pituitary abscess wassuggested based on magnetic resonance imaging (MRI). Magneticresonance imaging findings included an extensive pathologicallesion with the diameter of 27 * 28 * 38 mm located inthe sellar suprasellar region, with intensive peripheral contrastenhancement. The lesion protrudes into the sphenoid sinusthrough the lowered bottom of sella turcica and the fluid contenthas also been visualized in the sphenoid sinus. After 10 dayantibiotic therapy, the patient was transferred to neurosurgeryward for surgical treatment. The pathological lesion waspartially evacuated during right frontotemporal craniotomy.The patient's general condition after the surgery was moderatelysevere; the patient was conscious, able to follow simplecommands, presenting hemiparesis of the left side of the body,particularly affecting left lower limb and with speech disturbances.The signs of hypopituitarism affecting all hormonalaxes were also observed and the patient was transferred to theDepartment of Endocrinology of the PMU for further treatment.Follow -up MRI scan continued to show the presence of pathologicalmass in the sellar suprasellar region, which penetratedinto the sphenoid sinus through damaged sellar bottom. Aftercorrection of reduced hormone levels and several weeks of antibiotictherapy, the patient was transferred to the Department ofNeurosurgery of the PMU for further surgical treatment. Transsphenoidalresection of the sellar -suprasellar tumor and sphenoidsinus reconstruction were performed. Histopathology reportconfirmed the diagnosis of pituitary adenoma. The patient inrelatively good condition, with partial hemiparesis on the leftside of the body, able to stand with support, not able to walk,with speech disturbances and able to follow commands wastransferred to the rehabilitation center. One year later, follow--up MRI scan showed deepened sella turcica, filled with a masscorresponding to postoperative material. No evidence of diseaseprogression has been found. Conclusion: Neuroinfection may be the first manifestation ofpituitary macroadenoma. PMID- 29522663 TI - [Types of cell death]. AB - Homeostasis in the body is maintained by multiple processes,including the balance between the formation of new cells andtheir dying. This paper describes the mechanism and pathwaysof apoptotic cell death, and the phenomenon of necrosis andautophagy. Furthermore, it describes rarely presented types ofcell death, namely mitotic catastrophe, oncosis and pyroptosis.The course of these processes varies, as emphasized in the paper,and is on the one hand connected with maintaining the stabilityof tissues in physiological processes, but on the other handprocesses of cell death are connected with the induction andprogression of pathological processes. In the paper an attemptwas made to show the basic differences between the describedprocesses and their importance for the body. PMID- 29522664 TI - [Vitamin C- structure, properties, occurrence and functions]. AB - In this paper the structure of vitamin C, its physical and chemicalcharacteristics, and occurrence are presented. The biologicalrole of ascorbic acid, the human body's demand for this vitamin,and its deficiency symptoms are specified. PMID- 29522665 TI - [Study on the quantitative and qualitative of fungi colonizing soybeans (Glycine max L.)]. AB - Introduction: The aim of study was to analyse the qualitativeand quantitative composition of fungi in soybeans on RBCA,YpSs, and DG18 culture media at 25, 37 and 45 degrees C. Material and methods: The analysis included 15 samples of soybeans.The highest number of mould species (23) were isolatedon RBCA at 25 degrees C, followed by xerophilic species (20) on DG18 at25 degrees C, and mesophilic (13) and thermophilic species (4) on YpSsmedium at 37 degrees and 45 degrees C, respectively. Ninety-five strains belongingto 40 species were isolated from soybean samples. The predominantspecies were Penicillium chrysogenum and Eurotiumherbariorum. Conclusion: This study revealed new species of mycobiota notpreviously isolated from soybeans. PMID- 29522666 TI - [The assessment of anxiety in pregnant women in respect of biological, medical and socio-environmental factors]. AB - Introduction: Anxiety in the perinatal period may lead to seriouscomplications resulting in the pathological course of pregnancy,fear and disturbances of delivery, and postnatal emotional problems.The latter, if unsolved in this period, may contribute to theworsening of relations between partners, between a mother anda child, and within a family. They also deteriorate the psychologicalwell -being of a woman. This thesis was aimed at assessingthe occurrence of anxiety in pregnant women throughout eachpregnancy trimester, and attempting to explain its biological,medical and social -environmental determinants. Material and methods: The material for this prospective longitudinalstudy consisted of 181 pregnant residents of Szczecin.Each woman was examined three times during pregnancy, oncein each trimester. The research instruments were: a questionnaireof the author's own design and a standardized instrument -Spielberger's State -Trait Anxiety Inventory (STAI). Conclusions: 1. Anxiety level in the course of pregnancy is lowestin the second trimester. 2. In those women who during pregnancycomplained of discomfort or worsened mood, and in thosewho experienced problems with sleeping, higher intensity ofanxiety is noted throughout the whole period of pregnancy. 3.Such factors as unintended pregnancy, lack of family support,and disapproval of pregnancy by a partner or the communityare associated with suffering from aggravated anxiety in eachtrimester of pregnancy. 4. Women who have a negative judgementof their housing situation and ??inancial standing are atrisk of high levels of anxiety throughout the whole pregnancy.5. Perinatal education is connected with signi??icantly lesseroccurrence of anxiety in each trimester of pregnancy. 6. Failureto have a preventive medical examination prior to pregnancy(woman, man) is related to experiencing signi??icantly higherlevel of anxiety in the ??irst and third trimesters of pregnancy. PMID- 29522667 TI - [Physical activity as a factor reducing aggressive behaviour in adolescents in gymnasium school age]. AB - Introduction: Violence among adolescents is one of the mostserious problems, and has significantly increased in recent years.Studies conducted in 2011 on aggression and violence in schoolsreported that the most widespread form of offence is verbalaggression. As many as 63% of students had experience of beingridiculed, humiliated or offended. According to research, 33%of students suffered from physical aggression (PA).The aim of the study to evaluate the relationship between physicalactivity and the incidence of aggressive behaviour in adolescentsof lower -secondary school age. Material and methods: The study was conducted in autumn2013, in West Pomerania province in Poland, among 807 studentsof a lower -secondary school. A diagnostic survey method witha standardized questionnaire (Aggression Questionnaire) byH. Buss and M. Perry of 1992 (Amity version) was used. Statisticalanalysis was performed in Statistica Pl version 10 using theKruskal-Wallis test and the U Mann-Whitney test with a significance level of p <= 0.05. Results: The Kruskal-Wallis test showed only a statisticallysignificant difference between the groups surveyed in relationto the frequency of attendance at additional sports activitiesand the level of PA (p = 0.02). Conclusions: Subjects who engage in team sports show a highertendency for physical aggression than those engaged in individualsports. Taking into account the higher level of PA in adolescentsperforming sport 3-4 times a week compared to physically inactiveand very active adolescents (more than 5 times a week), itmay be presumed that sport attracts people with high physicalaggression tendencies. Only with strong involvement in sportis the level of aggression reduced. There is a need for researchon the personality of young athletes, which would give credenceto this thesis. PMID- 29522668 TI - [Patients' awareness of the threat of taking antithrombotic and antiplatelet agents due to cardiological recommendations]. AB - Introduction: Nowadays, antithrombotic and antiplatelet agentsare widely used in cardiology. Both agents, apart from theirtherapeutic benefits, have many adverse effects.The main aim of the study was to assess the awareness andknowledge of side effects and possible complications in patientstaking antithrombotic and antiplatelet agents due to cardiologicalrecommendations. Material and methods: A sample of 180 patients (mean age 65years) was studied. A diagnostic survey based on a questionnaireprepared by the researchers was used for measurements. Results: The results indicated that among antithrombotic andantiplatelet agents taken by patients the most often used were:acetylsalicylic acid (140 patients) and clopidogrel (64 patients),while acenocoumarol derivatives were taken by 25 patients.When asked whether the patient obtained information about theside effects of drugs 51% of patients acknowledged obtaininginformation, 22% of patients denied that they were given suchinformation, and 27% of patients admitted that they had forgottenwhether they were informed about side effects. 23% ofpatients described their knowledge of the effects of drugs as wide,57% of patients as basic, and 20% of patients admitted a lackof knowledge in that area. 25% of patients knew the threats ofsudden discontinuation of treatment. 81% of patients could notdescribe management in the case of missing a dose of the drug. Conclusions: The results suggest that in patients on antithrombotictreatment the state of knowledge about complications, sideeffects and interactions of drugs is insufficient. The methodsand scope of education are inadequate. Considering the widespreaduse of antithrombotic treatment, anticoagulation clinicsshould be established. PMID- 29522669 TI - [Is training yoga regulary can have an effective impact on dealing with stress?]. AB - Introduction: The word yoga (Goya) is derived from the Sanskrityii and means: bind, connect, attach and focus attentionon something. It also means connection, and the union. The systemof yoga has collected and systematized Patanjali in his "YogaSittrach" work. Yoga has the task of shaping proper physical cultureand spirit (mind), regardless of religious beliefs, nationalorigin, membership in a social group.The aim of the study was to evaluate the relationship betweenyoga and regular coaching strategy for coping with stress, bloodpressure and abdominal obesity. Material and methods: The study involved 100 people dividedinto 2 groups. The first group comprised students regularly practicingyoga. The second group were randomly selected subjectsnot regularly engaged in sport. The age of the subjects ranged18-60 years and over. Research material was gathered usinga questionnaire designed by the authors, and the mini -COPEtest. In addition, blood pressure and waist circumference weremeasured to assess the prevalence of abdominal obesity. Results: Among people who practice yoga the average waistcircumference was 82.8 +/-8 in women and 90.3 +/-11 in men(p < 0.034). A healthy waistline was found in 43 (86%)subjectsin the yoga group, and 34 (68%) subjects in the control group.Body mass index (BMI) also falls in favour of yoga, and in thisgroup 15 (30%) more subjects had normal BMI. Abdominal obesityand BMI indicating obesity was found in 10 (20%) subjectsfrom the yoga group and 15 (30%) from the control group. Thestudy revealed no significant differences in mean blood pressurebetween the analysed groups. Conclusions: Based on the analysis of the questionnaire mini-COPE people regularly Training Yoga choose more effectivestrategies for coping with stress. Regular practice of yoga isa factor in reducing abdominal obesity. Men who trains yogahave blood pressure lower than those who doesn't practiceany sport. PMID- 29522670 TI - [Clause of conscience implemented in competition law medical in Poland in the context of the implementation of the European Convention on Human Rights]. AB - Freedom of conscience and religion, also called conscience clauselegislation is part of the inherent and inalienable rights of everyhuman being and freedoms protected by the constitution asa fundamental principle of democratic countries working in thelaw. At international level, the most common piece of legislationon this issue is the European Convention on Human Rights of 4November 1950, which Poland is a party. Pursuant to Art. 9 ofthe European Convention Poland is committed to the protectionof freedom of thought, conscience and religion to every personunder its jurisdiction, including the medical professions.In a special way to be protected by the freedom of conscienceof physicians, dentists, nurses and midwives, as the conscienceclause is written in the law governing the exercise of such professionsin Poland. PMID- 29522671 TI - Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors. AB - Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR. PMID- 29522672 TI - Polychlorinated Diphenylsulfides Activate Aryl Hydrocarbon Receptor 2 in Zebrafish Embryos: Potential Mechanism of Developmental Toxicity. AB - It is hypothesized that polychlorinated diphenyl sulfides (PCDPSs) induce lethal toxicity in zebrafish which is mediated by aryl hydrocarbon receptor 2 (Ahr2) activation. In this study an assay was developed based on in vivo exposure of wild-type and Tg(cyp1a:gfp) transgenic zebrafish embryos/larvae to PCDPS congeners (i.e., six dichloro- to heptachloro-diphenyl sulfides) coupled with a zebrafish Ahr2-luciferase reporter gene (LRG) expression. Waterborne PCDPSs were found to be accumulated in zebrafish larvae, and exposure to PCDPSs led to a significant increase in mortality and cyp1s mRNA expression. Furthermore, treatment with PCDPSs caused a significant induction of Ahr2-LRG activity in COS 7 cells, and extremely significant correlations were observed between the in vivo median lethal concentrations and the levels of cyp1s mRNA expression and Ahr2 activation. Molecular dynamics simulations indicated the interaction between dioxins/dioxin-like compounds (DLCs) and six key amino acid residues in the ligand-binding domain of Ahr2 probably determined the susceptibility to dioxins/DLCs in zebrafish. These results strongly support the hypothesis that early life-stage mortality of zebrafish is initiated and mediated by Ahr2 activation. PMID- 29522673 TI - Approaches for Achieving Superlubricity in Two-Dimensional Materials. AB - Controlling friction and reducing wear of moving mechanical systems is important in many applications, from nanoscale electromechanical systems to large-scale car engines and wind turbines. Accordingly, multiple efforts are dedicated to design materials and surfaces for efficient friction and wear manipulation. Recent advances in two-dimensional (2D) materials, such as graphene, hexagonal boron nitride, molybdenum disulfide, and other 2D materials opened an era for conformal, atomically thin solid lubricants. However, the process of effectively incorporating 2D films requires a fundamental understanding of the atomistic origins of friction. In this review, we outline basic mechanisms for frictional energy dissipation during sliding of two surfaces against each other, and the procedures for manipulating friction and wear by introducing 2D materials at the tribological interface. Finally, we highlight recent progress in implementing 2D materials for friction reduction to near-zero values-superlubricity-across scales from nano- up to macroscale contacts. PMID- 29522674 TI - Nongenetic Approach for Imaging Protein Dimerization by Aptamer Recognition and Proximity-Induced DNA Assembly. AB - Herein, we report a nongenetic and real-time approach for imaging protein dimerization on living cell surfaces by aptamer recognition and proximity-induced DNA assembly. We use the aptamer specific for the receptor monomer as a recognition probe. When receptor dimerization occurs, the dimeric receptors bring two aptamer probes into close proximity, thereby triggering dynamic DNA assembly. The proposed approach was successfully applied to visualize dimerization of Met receptor and transforming growth factor-beta type II receptor. This approach allows us to image the two states (monomer/dimer) of a receptor protein on living cell surfaces in real time, opening a universal method for further investigation of protein dimerization and the corresponding activation processes in signal transduction. PMID- 29522675 TI - Chalcone Based Homodimeric PET Agent, 11C-(Chal)2DEA-Me, for Beta Amyloid Imaging: Synthesis and Bioevaluation. AB - Homodimeric chalcone based 11C-PET radiotracer, 11C-(Chal)2DEA-Me, was synthesized, and binding affinity toward beta amyloid (Abeta) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Abeta fibrils. The bivalent ligand 11C-(Chal)2DEA-Me displayed higher binding affinity compared to the corresponding monomer, 11C-Chal-Me, and classical Abeta agents. The radiolabeling yield with carbon-11 was 40-55% (decay corrected) with specific activity of 65-90 GBq/MUmol. A significant ( p < 0.0001) improvement in the binding affinity of 11C-(Chal)2DEA-Me with synthetic Abeta42 aggregates over the monomer, 11C-Chal-Me, demonstrates the utility of the bivalent approach. The PET imaging and biodistribution data displayed suitable brain pharmacokinetics of both ligands with higher brain uptake in the case of the bivalent ligand. Metabolite analysis of healthy ddY mouse brain homogenates exhibited high stability of the radiotracers in the brain with >93% intact tracer at 30 min post injection. Both chalcone derivatives were fluorescent in nature and demonstrated significant changes in the emission properties after binding with Abeta42. The preliminary analysis indicates high potential of 11C-(Chal)2DEA Me as in vivo Abeta42 imaging tracer and highlights the significance of the bivalent approach to achieve a higher biological response for detection of early stages of amyloidosis. PMID- 29522676 TI - Interactions of Soil Species Exposed to CuO NMs are Different From Cu Salt: A Multispecies Test. AB - Although environmental effects are mostly assessed via standard individual species the ecological relevance of multispecies testing is well-recognized and highly recommended. Hence, the effect of copper oxide nanomaterials (CuONM) and CuCl2 were assessed using the validated soil multispecies system (SMS). Besides the individual species (IS) "standard" tests for all, a predation study was done. Toxicity was higher in the SMS than in the IS, and longer exposure showed increased toxicity. The predator ( Hypoaspis aculeifer) preyed most on smaller species, but the net biomass consumed was similar across species. Internal Cu in Folsomia candida reached ca. 140 MUg Cu/g dry weight, fluctuating over time, especialy for CuCl2. Copper was mostly bound to soil components for both Cu forms (<0.2% of the total Cu in soil solution, < 0.007% on the ionic form, but the soil solution content increased with the total added concentration). Hazard Concentrations (HC5) showed higher toxicity and more similarity between Cu forms at longer-term exposure. Risk of NMs is relatively limited at present (IS based instead of SMS) with short exposure times (i.e., longer is required) and too few IS tested. The impact of species interactions is highlighted and is of key importance to include in ecosystem hazard prediction. PMID- 29522677 TI - Soft Picosecond Infrared Laser Extraction of Highly Charged Proteins and Peptides from Bulk Liquid Water for Mass Spectrometry. AB - We report the soft laser extraction and production of highly charged peptide and protein ions for mass spectrometry directly from bulk liquid water at atmospheric pressure and room temperature, using picosecond infrared laser ablation. Stable ion signal from singly charged small molecules, as well as highly charged biomolecular ions, from aqueous solutions at low laser pulse fluence (~0.3 J cm 2) is demonstrated. Sampling via single picosecond laser pulses is shown to extract less than 27 pL of volume from the sample, producing highly charged peptide and protein ions for mass spectrometry detection. The ablation and ion generation is demonstrated to be soft in nature, producing natively folded proteins ions under sample conditions described for native mass spectrometry. The method provides laser-based sampling flexibility, precision and control with highly charged ion production directly from water at low and near neutral pH. This approach does not require an additional ionization device or high voltage applied directly to the sample. PMID- 29522678 TI - pi-Cation Interactions in Molecular Recognition: Perspectives on Pharmaceuticals and Pesticides. AB - The pi-cation interaction that differs from the cation-pi interaction is a valuable concept in molecular design of pharmaceuticals and pesticides. In this Perspective we present an up-to-date review (from 1995 to 2017) on bioactive molecules involving pi-cation interactions with the recognition site, and categorize into systems of inhibitor-enzyme, ligand-receptor, ligand-transporter, and hapten-antibody. The concept of pi-cation interactions offers use of pi systems in a small molecule to enhance the binding affinity, specificity, selectivity, lipophilicity, bioavailability, and metabolic stability, which are physiochemical features desired for drugs and pesticides. PMID- 29522679 TI - Identifying Conformational-Selection and Induced-Fit Aspects in the Binding Induced Folding of PMI from Markov State Modeling of Atomistic Simulations. AB - Unstructured proteins and peptides typically fold during binding to ligand proteins. A challenging problem is to identify the mechanism and kinetics of these binding-induced folding processes in experiments and atomistic simulations. In this Article, we present a detailed picture for the folding of the inhibitor peptide PMI into a helix during binding to the oncoprotein fragment 25-109Mdm2 obtained from atomistic, explicit-water simulations and Markov state modeling. We find that binding-induced folding of PMI is highly parallel and can occur along a multitude of pathways. Some pathways are induced-fit-like with binding occurring prior to PMI helix formation, while other pathways are conformational-selection like with binding after helix formation. On the majority of pathways, however, binding is intricately coupled to folding, without clear temporal ordering. A central feature of these pathways is PMI motion on the Mdm2 surface, along the binding groove of Mdm2 or over the rim of this groove. The native binding groove of Mdm2 thus appears as an asymmetric funnel for PMI binding. Overall, binding induced folding of PMI does not fit into the classical picture of induced fit or conformational selection that implies a clear temporal ordering of binding and folding events. We argue that this holds in general for binding-induced folding processes because binding and folding events in these processes likely occur on similar time scales and do exhibit the time-scale separation required for temporal ordering. PMID- 29522680 TI - Cobalt(II)-Catalyzed Electrooxidative C-H Amination of Arenes with Alkylamines. AB - An environmentally friendly electrochemical protocol about cobalt-catalyzed C-H amination of arenes has been developed, which offers a simple way to access synthetically useful arylamines. In divided cells, a wide variety of arenes and alkylamines are examined to afford C-N formation products without using external oxidants, which avoids the formation of undesired byproducts and exhibits high atom economy. Importantly, the reaction can also be extended to gram level with moderate efficiency. KIE experiments indicate that C-H bond cleavage might not be involved during the rate-limiting step. PMID- 29522681 TI - Space-Confined Strategy toward Large-Area Two-Dimensional Single Crystals of Molecular Materials. AB - Two-dimensional molecular crystals (2DMCs) are a promising candidate for flexible and large-area electronics. Their large-area production requires both low nuclei density and 2D crystal growth mode. As an emerging type of material, their large area production remains a case-by-case practice. Here we present a general, efficient strategy for large-area 2DMCs. The method grows crystals on water surface to minimize the density of nuclei. By controlling the interfacial tension of the water/solution system with a phase transfer surfactant, the spreading area of the solvent increases tens of times, leading to the space-confined 2D growth of molecular crystals. As-grown sub-centimeter-sized 2DMCs floating on the water surface can be easily transferred to arbitrary substrates for device applications. PMID- 29522682 TI - Simulation-Guided Design of Cytochrome P450 for Chemo- and Regioselective Macrocyclic Oxidation. AB - Engineering high chemo-, regio-, and stereoselectivity is a prerequisite for enzyme usage in organic synthesis. Cytochromes P450 can oxidize a broad range of substrates, including macrocycles, which are becoming popular scaffolds for therapeutic agents. However, a large conformational space explored by macrocycles not only reduces the selectivity of oxidation but also impairs computational enzyme design strategies based on docking and molecular dynamics (MD) simulations. We present a novel design workflow that uses enhanced-sampling Hamiltonian replica exchange (HREX) MD and focuses on quantifying the substrate binding for suggesting the mutations to be made. This computational approach is applied to P450 BM3 with the aim to shift regioselectively toward one of the numerous possible positions during beta-cembrenediol oxidation. The predictions are experimentally tested and the resulting product distributions validate our design strategy, as single mutations led up to 5-fold regioselectivity increases. We thus conclude that the HREX-MD-based workflow is a promising tool for the identification of positions for mutagenesis aiming at P450 enzymes with improved regioselectivity. PMID- 29522683 TI - A Carrier-Free Nanostructure Based on Platinum(IV) Prodrug Enhances Cellular Uptake and Cytotoxicity. AB - Flurbiprofen, a hydrophobic COX inhibitor, was coordinated axially with oxoplatin to form a new conjugate, cis, cis, trans-[Pt(IV)(NH3)2Cl2(flurbiprofen)2]. The successful synthesis of this new conjugate was confirmed by 1H, 13C, and 195Pt NMR. The potential of this conjugate being reduced to cisplatin and subsequently exerting its DNA cross-linking ability was verified using cyclic voltammetry (CV), HPLC, and mass spectrometry (MS). This conjugate showed markedly higher cytotoxicity on many cancer cell lines than cisplatin, flurbiprofen, and their physical mixture (mole ratio, cisplatin:flurbiprofen = 1:2). This is consistent with the result of an apoptosis-inducing assay. This conjugate spontaneously assembles carrier-free nanoparticles in aqueous solution, which is confirmed by DLS, TEM, SEM, and AFM, and thus facilitates cellular uptake and markedly improves its cytotoxicity and apoptosis-inducing ability in vitro. PMID- 29522684 TI - Excited-State Dynamics of Dithienylethenes Functionalized for Self-Supramolecular Assembly. AB - The photoswitching and competitive processes of two photochromic dithienylethenes (DTEs) functionalized at both sides with 2-ureido-4[1H]-pyrimidone (UPy) quadruple hydrogen-bonding recognition patterns have been investigated with NMR experiments, ultrafast spectroscopy, and density functional theory (DFT) calculations. The originality of these molecules is their ability to form large supramolecular assemblies induced by light for the closed form (CF) species while the open form (OF) species exist as small oligomers. Photochromic parameters have been determined and photochemical pathways have been rationalized with clear distinction between the antiparallel (OF-AP) and parallel (OF-P) species. A new photocyclization pathway via triplet manifold has been evidenced. The effect of the supramolecular assembly on the photochemical response is discussed. Unlike the photoreversion process, which is unaffected by supramolecular assembly, rate constants of the photocyclization reaction and intersystem crossing process are sensitive to the presence of small OF oligomers. PMID- 29522685 TI - Ligand-Based NMR Study of C-X-C Chemokine Receptor Type 4 (CXCR4)-Ligand Interactions on Living Cancer Cells. AB - Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs. PMID- 29522686 TI - Coupling of Molecular Emitters and Plasmonic Cavities beyond the Point-Dipole Approximation. AB - As the size of a molecular emitter becomes comparable to the dimensions of a nearby optical resonator, the standard approach that considers the emitter to be a point-like dipole breaks down. By adoption of a quantum description of the electronic transitions of organic molecular emitters, coupled to a plasmonic electromagnetic field, we are able to accurately calculate the position-dependent coupling strength between a plasmon and an emitter. The spatial distribution of excitonic and photonic quantum states is found to be a key aspect in determining the dynamics of molecular emission in ultrasmall cavities both in the weak and strong coupling regimes. Moreover, we show that the extreme localization of plasmonic fields leads to the selection rule breaking of molecular excitations. PMID- 29522687 TI - Remote and rural student placement in the Shetland Islands: a reflective essay, with a focus on accident and emergency care. PMID- 29522688 TI - Transformation of medical education through Decentralised Training Platforms: a scoping review. AB - INTRODUCTION: Medical education in South Africa is facing a major paradigm shift. The urgency to increase the number of suitable, qualified and socially accountable health sciences graduates has brought to the fore the need to identify alternative training platforms and learning environments, often in rural areas. Subsequently, the focus has now shifted towards strengthening primary health care and community based health services. This scoping review presents a synopsis of the existing literature on decentralized training platform (DTP) strategies for medical education internationally, outlining existing models within it and its impact. METHODS: This scoping review followed Arksey and O'Malley's framework outlining five stages: (i) identification of a research question, (ii) identification of relevant studies, (iii) study selection criteria, (iv) data charting, and (v) collating, summarizing and reporting results. The literature for the scoping review was found using online databases, reference lists and hand searched journals. Data were charted and sorted inductively according to key themes. RESULTS: A final review included 59 articles ranging over the years 1987-2015 with the largest group of studies falling in the period 2011-2015 (47.5%). Studies mostly employed quantitative (32.2%), qualitative (20.3%), systematic/literature review (18.6%) and mixed methods research approaches (11.9%). The scoping review highlighted a range of DTP strategies for transforming medical education. These include training for rural workforce, addressing context specific competencies to promote social accountability, promoting community engagement, and medical education partnerships. Viable models of DTP include community based education, distributed community engaged learning, discipline based clinical rotations, longitudinal clerkships and dedicated tracks focusing on rural issues. Shorter rural placements and supplemental rural tracks are also described. CONCLUSIONS: This scoping review showed a considerable amount of literature on decentralized training platforms that highlight the necessary adaptations needed for transforming medical education. The rural context is critical for many of these. Further studies are required to address the impact of DTPs on health service outcomes and human resource outcomes. PMID- 29522689 TI - Host-Microbiome Interactions in the Subglottic Space. Bacteria Ante Portas! PMID- 29522690 TI - Physical activity prescription by Canadian Emergency Medicine Physicians. AB - An increase in physical activity has been shown to improve outcomes in many diseases. An estimated 600 000 Canadians receive their primary health care from emergency departments (ED). This study aims to examine physical activity prescription by emergency medicine physicians (EPs) to determine factors that influence decisions to prescribe physical activity. A survey was distributed to EPs via email using the Canadian Association of Emergency Physicians (CAEP) survey distribution protocol. Responses from 20% (n = 332) of emergency physician/residents in Canada were analyzed. Of the EPs, 62.7% often/always counsel patients about preventative medicine (smoking, diet, and alcohol). Only 12.7% (42) often/always prescribe physical activity. The CCFP-trained physicians (College of Family Physicians Canada) were significantly more likely to feel comfortable than CCFP-EM-trained physicians (Family Physicians with Enhanced Skills in Emergency Medicine) prescribing physical activity (p = 0.0001). Both were significantly more likely than the FRCPC-trained EPs (Fellows of the Royal College of Physicians of Canada). Of the EPs, 73.4% (244) believe the ED environment does not allow adequate time for physical activity prescription. Family medicine-trained EPs are more likely to prescribe physical activity; the training they receive may better educate them compared with FRCPC-trained emergency medicine. Further education is required to standardize an approach to ED physical activity prescription. PMID- 29522691 TI - A multifaceted investigation into the effects of acute exercise on indices of brain function. AB - Participation in regular exercise is important for the maintenance and improvement of brain health across the lifespan. These beneficial effects are realized almost immediately, as a single bout of exercise transiently improves cognitive function after cessation from exercise. This postexercise time period represents an opportunity to strategically prescribe cognitively stimulating activities for enhancing brain plasticity and function. Mechanistically, acute exercise is proposed to upregulate brain-derived neurotrophic factor (BDNF) expression and increase regional activation and arousal of brain areas involved in cognitive control; however, the specific mechanisms underlying this facilitation are poorly understood. The purpose of this study was to (i) investigate BDNF responses to small muscle mass exercise to probe a potential mechanism of BDNF release during exercise; (ii) create and validate an equipment free exercise protocol for use in a magnetic resonance imaging (MRI) scanner, with the eventual goal of investigating brain responses during exercise that may underlie improved cognition; and (iii) determine the effect of a very brief bout of high-intensity interval exercise (HIIE) on neuroelectric indices of reinforcement learning in young adults. Serum BDNF, platelet, and the amount of BDNF per platelet responses were measured following short-duration, maximal effort and long-duration, submaximal effort forearm handgrip exercise. We assessed the magnitude and reliability of metabolic responses to a novel whole body isometric contraction (WBI) exercise protocol. We also characterized the amount of head movement created by WBI. The event-related potential component associated with reward-based learning was assessed before and after a bout of HIIE. Forearm handgrip exercise significantly increased serum BDNF, platelets, and BDNF per platelet, suggesting the possibility of splenic and cellular contribution of BDNF in response to handgrip exercise. WBI reliably evokes metabolic responses that are similar in magnitude to previous in-MRI studies, and creates head movement suitable for MRI scanning. HIIE abolishes neuroelectric indices of reward learning, likely owing to incomplete recovery from exercise. These findings advance our understanding of neurochemical and neuroelectric responses to acute exercise and introduce a novel tool that stands to further elucidate the regional brain responses to exercise that may underlie enhanced cognition after exercise. PMID- 29522692 TI - Modulation of motoneurone excitability during rhythmic motor outputs. AB - In quadrupeds, special circuity located within the spinal cord, referred to as central pattern generators (CPGs), is capable of producing complex patterns of activity such as locomotion in the absence of descending input. During these motor outputs, the electrical properties of spinal motoneurones are modulated such that the motoneurone is more easily activated. Indirect evidence suggests that like quadrupeds, humans also have spinally located CPGs capable of producing locomotor outputs, albeit descending input is considered to be of greater importance. Whether motoneurone properties are reconfigured in a similar manner to those of quadrupeds is unclear. The purpose of this review is to summarize our current state of knowledge regarding the modulation of motoneurone excitability during CPG-mediated motor outputs using animal models. This will be followed by more recent work initially aimed at understanding changes in motoneurone excitability during CPG-mediated motor outputs in humans, which quickly expanded to also include supraspinal excitability. PMID- 29522693 TI - Waiting for Godot: Clinical Trials of Extracorporeal Membrane Oxygenation for Pediatric Respiratory Failure. PMID- 29522699 TI - Statistical Behaviors: Personal and Computer-Aided Observations. AB - My early years as a statistician were with the Eastern Co-operative Oncology Group and the Radiation Oncology Therapy Group; three of these years were spent at the Sidney Farber Cancer Institute. Later, I collaborated widely with investigators in many clinical research areas. I reflect on the "statistical interrogations of nature" I saw (and helped some of these) investigators plan and carry out. I look back on their (and my own) statistical behaviors when interpreting the information these interrogations produced and-using a few vignettes and some computer-generated observations-draw some lessons from them. These mainly have to do with making too much of one's data. PMID- 29522694 TI - Chickpea supplementation prior to colitis onset reduces inflammation in dextran sodium sulfate-treated C57Bl/6 male mice. AB - The potential for a chickpea-supplemented diet (rich in fermentable nondigestible carbohydrates and phenolic compounds) to modify the colonic microenvironment and attenuate the severity of acute colonic inflammation was investigated. C57Bl/6 male mice were fed a control basal diet or basal diet supplemented with 20% cooked chickpea flour for 3 weeks prior to acute colitis onset induced by 7-day exposure to dextran sodium sulfate (DSS; 2% w/v in drinking water) and colon and serum levels of inflammatory mediators were assessed. Despite an equal degree of DSS-induced epithelial barrier histological damage and clinical symptoms between dietary groups, biomarkers of the ensuing inflammatory response were attenuated by chickpea pre-feeding, including reduced colon tissue activation of nuclear factor kappa B and inflammatory cytokine production (tumor necrosis factor alpha and interleukin (IL)-18). Additionally, colon protein expression of anti inflammatory (IL-10) and epithelial repair (IL-22 and IL-27) cytokines were increased by chickpea pre-feeding. Furthermore, during acute colitis, chickpea pre-feeding increased markers of enhanced colonic function, including Relmbeta and IgA gene expression. Collectively, chickpea pre-feeding modulated the baseline function of the colonic microenvironment, whereby upon induction of acute colitis, the severity of the inflammatory response was attenuated. PMID- 29522700 TI - Interventions Promoting Colorectal Cancer Screening Among Latino Men: A Systematic Review. AB - INTRODUCTION: Colorectal cancer, the second leading cause of cancer death in the United States, is also among the most preventable cancers. However, Latino men are less likely than non-Latino men to engage in preventive screening. Compared with 60% of non-Latino white men and women, only 42% of Latino men are up to date with colorectal cancer screening guidelines, which may result in diagnosis at advanced disease stages and increased deaths. We evaluated the literature on colorectal cancer screening interventions among Latino men to characterize intervention components effective in increasing colorectal cancer screening. METHODS: Two independent reviewers searched MEDLINE, CINAHL, and PsycINFO to identify articles on intervention studies that promote colorectal cancer screening among Latino men. Inclusion criteria were randomized controlled or comparative effectiveness trials, an outcome of any colorectal cancer screening test, published in English, US-based, results published from January 2004 through December 2016, Latino or Spanish-speaking male participants, and a minimum of one patient-level component. Two other reviewers independently assessed article quality and conducted data abstraction. RESULTS: Forty-four studies met the inclusion criteria; only 7 studies with 20% or more Latinos and 39% or more men were included in the final analyses. The most common intervention strategies included one-on-one interactions with a patient navigator and reducing structural barriers (eg, providing fecal occult blood tests). Interventions using small media produced mixed results. CONCLUSION: Although intervention studies focused on colorectal cancer screening among men of racial/ethnic minorities are scarce, our findings highlight promising strategies that were effective at increasing colorectal cancer screening among Latino men. Additional research in the area of Latino men's health is needed, especially to further develop and test theoretically grounded interventions that promote colorectal cancer screening with larger samples of men and across diverse geographic areas in the United States. PMID- 29522701 TI - Trends in Mortality Among Females in the United States, 1900-2010: Progress and Challenges. AB - INTRODUCTION: We analyzed trends in US female mortality rates by decade from 1900 through 2010, assessed age and racial differences, and proposed explanations and considered implications. METHODS: We conducted a descriptive study of trends in mortality rates from major causes of death for females in the United States from 1900 through 2010. We analyzed all-cause unadjusted death rates (UDRs) for males and females and for white and nonwhite males and females from 1900 through 2010. Data for blacks, distinct from other nonwhites, were available beginning in 1970 and are reported for this and following decades. We also computed age-adjusted all-cause death rates (AADRs) by the direct method using age-specific death rates and the 2000 US standard population. Data for the analysis of decadal trends in mortality rates were obtained from yearly tabulations of causes of death from published compilations and from public use computer data files. RESULTS: In 1900, UDRs and AADRs were higher for nonwhites than whites and decreased more rapidly for nonwhite females than for white females. Reductions were highest among younger females and lowest among older females. Rates for infectious diseases decreased the most. AADRs for heart disease increased 96.5% in the first 5 decades, then declined by 70.6%. AADRs for cancer rose, then decreased. Stroke decreased steadily. Unintentional motor vehicle injury AADRs increased, leveled off, then decreased. Differences between white and nonwhite female all-cause AADRs almost disappeared during the study period (5.4 per 100,000); differences in white and black AADRs remained high (121.7 per 100,000). CONCLUSION: Improvements in social and environmental determinants of health probably account for decreased mortality rates among females in the early 20th century, partially offset by increased smoking. In the second half of the century, other public health and clinical measures contributed to reductions. The persistent prevalence of risk behaviors and underuse of preventive and medical services indicate opportunities for increased female longevity, particularly in racial minority populations. PMID- 29522703 TI - Sigmoid Colon Cancer in a Juvenile Patient Without a Family History of Colorectal Cancer. PMID- 29522702 TI - Disparities in Adverse Perinatal Outcomes Among Pacific Islanders in the Commonwealth of the Northern Mariana Islands. AB - INTRODUCTION: Although other studies have found evidence for perinatal health disparities among Pacific Islanders in other regions, no studies have evaluated racial/ethnic disparities in adverse perinatal health outcomes in the small US island territory of the Commonwealth of the Northern Mariana Islands (CNMI). METHODS: We used retrospective cohort data on 8,427 singleton births from 2007 to 2014 at the Commonwealth Healthcare Corporation (CHCC), the only hospital in the CNMI. We used multivariate logistic regression to estimate risk for preterm birth (<37 weeks) and macrosomia (>4,000 g) among the racial/ethnic groups in the CNMI. RESULTS: Indigenous CNMI mothers (Chamorros and Carolinians, hereinafter Chamorro/Carolinian) and other Pacific Islander mothers were significantly more likely to have a preterm birth than Chinese mothers (adjusted odds ratio [AOR] = 2.7; 95% confidence interval [CI], 2.0-3.6 for Chamorro/Carolinians and AOR = 2.9; 95% CI, 2.1-4.1 for other Pacific Islanders). Additionally, Chamorro/Carolinian mothers and other Pacific Islander mothers were also significantly more likely to deliver babies with macrosomia (AOR = 2.4; 95% CI, 1.7-3.5 and 2.3; 95% CI 1.4-3.6 respectively) than Filipino mothers. CONCLUSION: Although underlying causes for these disparities are still unknown, these findings add to the limited knowledge on maternal and neonatal health among Pacific Islanders and provide support for further research and intervention development to aid in reducing racial/ethnic disparities of perinatal health in the CNMI. PMID- 29522704 TI - Endoscopic Therapy of Jejunal Diphyllobothrium nihonkaiense Infection. PMID- 29522705 TI - Interaction of N-terminal peptide analogues of the Na+,K+-ATPase with membranes. AB - The Na+,K+-ATPase, which is present in the plasma membrane of all animal cells, plays a crucial role in maintaining the Na+ and K+ electrochemical potential gradients across the membrane. Recent studies have suggested that the N-terminus of the protein's catalytic alpha-subunit is involved in an electrostatic interaction with the surrounding membrane, which controls the protein's conformational equilibrium. However, because the N-terminus could not yet be resolved in any X-ray crystal structures, little information about this interaction is so far available. In measurements utilising poly-l-lysine as a model of the protein's lysine-rich N-terminus and using lipid vesicles of defined composition, here we have identified the most likely origin of the interaction as one between positively charged lysine residues of the N-terminus and negatively charged headgroups of phospholipids (notably phosphatidylserine) in the surrounding membrane. Furthermore, to isolate which segments of the N-terminus could be involved in membrane binding, we chemically synthesized N-terminal fragments of various lengths. Based on a combination of results from RH421 UV/visible absorbance measurements and solid-state 31P and 2H NMR using these N terminal fragments as well as MD simulations it appears that the membrane interaction arises from lysine residues prior to the conserved LKKE motif of the N-terminus. The MD simulations indicate that the strength of the interaction varies significantly between different enzyme conformations. PMID- 29522706 TI - A comparison of the efficiency of three sampling methods for use in the molecular and conventional diagnosis of cutaneous leishmaniasis. AB - In human cutaneous leishmaniasis (CL), the success of positive diagnoses and species identifications depends, primarily, on how biopsies are taken and then processed and examined. The efficiency of three methods of taking skin biopsies from suspect cases of CL was compared using the classical methods of microscopy of stained smears, in vitro culture of tissue aspirate, and internal transcribed spacer region 1 (ITS1)-polymerase chain reaction in diagnosing positive cases and identifying the species of Leishmania causing them. From 1994-2014, biopsy samples from the skin lesions of 2232 CL-suspected patients were collected as unstained smears, as smears stained with Giemsa's stain and on filter paper, and compared in the diagnostic tests employed. Matched comparison based on testing biopsy samples from 100 patients, microscopy, in vitro culture and ITS1-PCR were also conducted to assess the most suitable combination of methods for diagnosing leishmaniases. In the 100-case-matched comparison, the three different types of sample proved to be equally good with no significant difference (P > 0.05). However, skin tissue imprints on filter paper revealed most cases of CL. The kappa statistic for measuring the degree of agreement among the three samples was 89%, which is considered good. Agreement was highest between imprints on filter paper and unstained smears, and lowest was for stained smears. In the overall comparison between the ITS1-PCR and conventional methods, the ITS1-PCR using samples from filter papers was the most sensitive method but the difference was insignificant (P = 0.32). The combination of microscopy together with ITS1-PCR on samples from filter papers increased the sensitivity significantly to 46%, compared to using the methods individually (P = 0.003-0.0008). On comparing the results of the tests done on the samples from the 2232 patients after applying ITS1-PCRs to their samples from filter papers, unstained smears, in vitro culture, microscopy, and stained smears showed, respectively, test sensitivities of 81, 69, 64, 57 and 48%. Of the tests and samples adjudicated, ITS1-PCRs run on skin tissue samples from filter papers proved best for the routine laboratory diagnosis of CL. Adding microscopy of stained smears to it, improved its diagnostic value significantly. PMID- 29522707 TI - Characterization of Pax3 and Sox10 transgenic Xenopus laevis embryos as tools to study neural crest development. AB - The neural crest is a multipotent population of cells that originates a variety of cell types. Many animal models are used to study neural crest induction, migration and differentiation, with amphibians and birds being the most widely used systems. A major technological advance to study neural crest development in mouse, chick and zebrafish has been the generation of transgenic animals in which neural crest specific enhancers/promoters drive the expression of either fluorescent proteins for use as lineage tracers, or modified genes for use in functional studies. Unfortunately, no such transgenic animals currently exist for the amphibians Xenopus laevis and tropicalis, key model systems for studying neural crest development. Here we describe the generation and characterization of two transgenic Xenopus laevis lines, Pax3-GFP and Sox10-GFP, in which GFP is expressed in the pre-migratory and migratory neural crest, respectively. We show that Pax3-GFP could be a powerful tool to study neural crest induction, whereas Sox10-GFP could be used in the study of neural crest migration in living embryos. PMID- 29522708 TI - Protective effect of rutin against carbon tetrachloride-induced oxidative stress, inflammation and apoptosis in mouse kidney associated with the ceramide, MAPKs, p53 and calpain activities. AB - Rutin, a natural flavonoid, possess beneficial health effects. However, its renoprotective effect against carbon tetrachloride (CCl4) induced injury and the underlying mechanism is not clarified. The current study aims is to identify the therapeutic effects of rutin on oxidative stress, inflammation and apoptosis in mouse kidney exposed to CCl4. ICR mice received CCl4 with or without rutin co administration for one week. Compared with the control group, mice receiving CCl4 alone showed kidney injury as evidenced by elevation in serum biochemical markers, inflammation, caspase-3 activity and apoptosis in kidney, while rutin administration significantly attenuated these pathophysiological changes. Exploration of the underlying mechanisms of its action demonstrated that rutin reduced the ROS, calpain and ceramide levels in mouse kidneys. Rutin significantly decreased the p53, TNF-alpha, IL-1beta activities and mitogen activated protein kinase (MAPK) phosphorylation in the kidneys. In addition, rutin increased the levels of Bcl-2 protein and reduced levels protein of Bax. Rutin also inhibited the release of cytochrome C from mitochondria in kidneys of the CCl4-treated mice. Taken together, rutin ameliorates CCl4-induced oxidative stress, inflammation and apoptosis through regulating the ceramide, MAPK, p53 and calpain activities and thereby suppressing apoptosis by the mitochondrial pathway. PMID- 29522709 TI - Lactate POCT in mobile intensive care units for septic patients? A comparison of capillary blood method versus venous blood and plasma-based reference methods. AB - AIM OF THE STUDY: We evaluated if the StatStrip Xpress Meter, a Lactate point of care testing (POCT) handled device, could be a valuable tool in the mobile intensive care units (MICU) to assess the severity of septic patients. METHODS: We first investigated POCT analytical performance, then, using samples collected from 50 identified septic patients admitted to the intensive care unit (ICU), we compared lactate values obtained with the device to those obtained with four central laboratory analysers: one whole blood and three plasma-based methods. RESULTS: Results were compared by least squares regression, Bland-Altman plot and by comparing concordance within clinically relevant lactate ranges. We observed a reliable analytical performance of the POCT (CVs < 3.8% for repeatability and <5.0% for reproducibility) an excellent correlation between POCT and central laboratory analysers (R2: 0.96-0.98, slopes:0.83-0.90, intercepts: 0.02-0.03) and an excellent concordance of the POCT results to the central laboratory analyser results (98-100%). CONCLUSION: Whatever the methodology used, lactate values obtained are comparable and transferable between POCT and central laboratory analysers meaning that POCT could be a valuable tool in the MICU to evaluate the severity of septic patients and to better manage their hospital triage. PMID- 29522710 TI - Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens. AB - BACKGROUND: Early high-dose IV vitamin C is being investigated as adjuvant therapy in patients who are critically ill, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose-plasma concentration relationship and safety of four different dosing regimens. METHODS: This was a four-group randomized pharmacokinetic trial. Patients who were critically ill with multiple organ dysfunction were randomized to receive 2 or 10 g/d vitamin C as a twice daily bolus infusion or continuous infusion for 48 h. End points were plasma vitamin C concentrations during 96 h, 12-h urine excretion of vitamin C, and oxalate excretion and base excess. A population pharmacokinetic model was developed using NONMEM. RESULTS: Twenty patients were included. A two compartment pharmacokinetic model with creatinine clearance and weight as independent covariates described all four regimens best. With 2 g/d bolus, plasma vitamin C concentrations at 1 h were 29 to 50 mg/L and trough concentrations were 5.6 to 16 mg/L. With 2 g/d continuous, steady-state concentrations were 7 to 37 mg/L at 48 h. With 10 g/d bolus, 1-h concentrations were 186 to 244 mg/L and trough concentrations were 14 to 55 mg/L. With 10 g/d continuous, steady-state concentrations were 40 to 295 mg/L at 48 h. Oxalate excretion and base excess were increased in the 10 g/d dose. Forty-eight hours after discontinuation, plasma concentrations declined to hypovitaminosis levels in 15% of patients. CONCLUSIONS: The 2 g/d dose was associated with normal plasma concentrations, and the 10 g/d dose was associated with supranormal plasma concentrations, increased oxalate excretion, and metabolic alkalosis. Sustained therapy is needed to prevent hypovitaminosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02455180; URL: www.clinicaltrials.gov. PMID- 29522711 TI - Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats. AB - Liver fibrosis is one of the most serious conditions affecting patients worldwide. In the present study, the role of nitric oxide and KATP channel was investigated for the first time in the possible protection mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats. Nicorandil (3 mg/kg/day) was given orally 24 h after bile duct ligation for 14 days till the end of the experiment. Nicorandil group showed marked improvement in liver function tests, hepatic oxidative stress and inflammatory markers as well as inducible and endothelial nitric oxide synthase protein expressions. Furthermore, nicorandil administration led to significant decrement of phosphorylated protein kinase C, fibrosis and hepatic stellate cells activation as indicated by decreased alpha smooth muscle actin expression. Oral co-administration of glibenclamide (5 mg/kg/day) (a KATP channel blocker) with nicorandil mostly showed similar improvement though not reaching to that of nicorandil group. However, co adminstration of L-NAME (15 mg/kg/day) (an inhibitor of nitric oxide synthase) completely abolished the protective effects of nicorandil and produced more or less similar results to that of untreated bile duct ligated group. In conclusion, nicorandil is an effective therapy against the development of bile duct ligation induced liver fibrosis in rats where nitric oxide plays a more prominent role in the protective effect of nicorandil than KATP channel opening. PMID- 29522712 TI - Identification of enzymes responsible for dantrolene metabolism in the human liver: A clue to uncover the cause of liver injury. AB - Dantrolene is used for malignant hyperthermia during anesthesia, and it sometimes causes severe liver injury as a side effect. Dantrolene is metabolized to acetylaminodantrolene, which is formed via the reduction of dantrolene to aminodantrolene and subsequent acetylation. Formation of hydroxylamine during the metabolic process may be associated with liver injury. We identified the enzymes responsible for dantrolene metabolism in humans to elucidate the mechanism of liver injury. Dantrolene reductase activity was not detected in human liver microsomes, but it was detected in cytosol. Formation was increased in the presence of N1-methylnicotineamide, which is an electron donor to aldehyde oxidase 1 (AOX1). Potent inhibitors of AOX1 and a correlation study with a marker of AOX1 activity, namely phthalazine oxidase activity, in a panel of 28 human liver cytosol samples supported the role of AOX1 in dantrolene reduction. Acetylaminodantrolene formation from aminodantrolene was highly detected in recombinant N-acetyltransferase (NAT) 2 rather than NAT1. A glutathione trapping assay revealed the formation of hydroxylamine via an AOX1-dependent reduction of dantrolene but not via hydroxylation of aminodantrolene. In conclusion, we found that AOX1 and NAT2 were responsible for dantrolene metabolism in humans and that AOX1-dependent metabolism determines dantrolene-induced liver injury. PMID- 29522713 TI - Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility. AB - Exendin-4, a 39 amino acid peptide isolated from the saliva of the Gila monster, plays an important role in regulating glucose homeostasis, and is used clinically for the treatment of type 2 diabetes. Exendin-4 shares 53% sequence identity with the incretin hormone glucagon-like peptide 1 (GLP-1) but, unlike GLP-1, is highly resistant to proteolytic enzymes such as dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase 24.11 (NEP 24.11). Herein, we focused on the structure and function of the C-terminal Trp-cage of exendin-4, and suggest that it may be structurally required for resistance to proteolysis by NEP 24.11. Using a series of substitutions and truncations of the C-terminal Trp-cage, we found that residues 1-33, including the N-terminal and helical regions of wild-type (WT) exendin-4, is the minimum motif required for both high peptidase resistance and potent activity toward the GLP-1 receptor comparable to WT exendin-4. To improve the therapeutic utility of C-terminally truncated exendin-4, we incorporated various fatty acids into exendin-4(1-33) in which Ser33 was substituted with Lys for acylation. Exendin-4(1-32)K-capric acid exhibited the most well balanced activity, with much improved therapeutic utility for regulating blood glucose and body weight relative to WT exendin-4. PMID- 29522714 TI - SETD2 indicates favourable prognosis in gastric cancer and suppresses cancer cell proliferation, migration, and invasion. AB - SET domain containing protein 2 (SETD2, also known as HYPB) is a 230-kD protein which is located at cytogenetic band p21.31 of chromosome 3. SETD2 is usually transformed or eradicated in multiple forms of tumours in humans. However, its primary function in gastric cancer (GC) remains unclear. In the current study, we investigated the mRNA and protein expression levels of SETD2 using immunohistochemistry, qPCR, RT-PCR, and immunoblotting. The function of SETD2 in GC cells was investigated by MTT and transwell assays. Our results revealed remarkably lower levels of SETD2 mRNA and protein in the tumour samples than in tumour-adjacent tissues. Decreased expression of SETD2 mRNA was observed in 122 (79.7%) of 153 primary tumour tissue samples. On the basis of the overall survival analysis, we could interpret that a low expression of SETD2 was correlated with a poor prognosis (P < 0.001, log-rank test). Multivariate survival analysis indicated that SETD2 was an obvious prognostic factor in patients with GC. SETD2 overexpression in GC cell lines significantly inhibited cell proliferation, migration, and invasion. Altogether, the investigation demonstrated the clinical significance of SETD2 expression, supporting the fundamental principle that a decrease in its level is an unfavourable event in the progression and prognosis of GC. Therefore, down-regulated SETD2 can presumably be a potential negative prognostic and progression marker for GC. PMID- 29522715 TI - LncRNA FABP5P3/miR-589-5p/ZMYND19 axis contributes to hepatocellular carcinoma cell proliferation, migration and invasion. AB - Hepatocellular carcinoma (HCC) contributes to cancer-related deaths greatly every year in the world. However, there is still no radical method for HCC treatment. Here we screened out a lncRNA FABP5P3 that was up-regulated in HCC tissues. Patients with higher FABP5P3 expression displayed poorer survival rate. FABP5P3 depletion in HCC cell lines and sample cells remarkably inhibited the abilities of proliferation, migration and invasion. In mechanism, we showed that FABP5P3 bond to miR-589-5p which served as a tumor suppressor. MiR-589-5p targeted directly the mRNA of ZMYND19 whose function has not been defined in HCC. FABP5P3 promoted HCC development and progression by sponging miR-589-5p and up-regulating ZMYND19 expression. In sum, we showed that FABP5P3/miR-589-5p/ZMYND19 axis regulates cell proliferation and migration in HCC, which may serve as a new target for HCC treatment. PMID- 29522716 TI - Combined inhibition of EGFR and c-ABL suppresses the growth of fulvestrant resistant breast cancer cells through miR-375-autophagy axis. AB - Fulvestrant is the FDA-approved "pure anti-estrogen" agent for malignant breast cancer therapy. But endocrine resistance causes drug failure. A new approach is desired for fulvestrant-resistant breast cancer (FRBC) therapy. This study aims to find an effective approach to inhibit FRBC for patients with advanced breast cancer. MTT assay was first performed to detect the effect of inhibitors of c-ABL (imatinib) and EGFR (lapatinib) on FRBC cells. Microarray analysis was carried out to identify microRNA which is significantly changed between parental and FRBC cells. The related mechanisms were analyzed by qRT-PCR, MTT, AO staining and western blotting. Dual treatment significantly inhibited cell growth of FRBC and upregulated microRNA-375 (miR-375). Overexpression of miR-375 inhibited growth of FRBC cells, reduced autophagy, and decreased expression of ATG7 and LC3-II. Dual treatment elevated expression of miR-375 more than any single one of these two inhibitors. Overexpression of miR-375 increased cell growth inhibition induced by dual treatment, and the effect was attenuated when miR-375 was inhibited. In conclusion, we identified that combined inhibition of EGFR and c-ABL can suppress the growth of FRBC cells and elucidated a mechanism within FRBC cells involving regulation of miR-375 and autophagy. Dual treatment may be useful for inhibiting fulvestrant-resistant breast cancer. PMID- 29522717 TI - Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants. AB - Synthetic cannabinoids (SCBs), synonymous with 'K2', 'Spice' or 'synthetic marijuana', are psychoactive drugs of abuse that frequently result in clinical effects and toxicity more severe than those classically associated with Delta9 tetrahydrocannabinol such as extreme agitation, hallucinations, supraventricular tachycardia, syncope, and seizures. JWH-018 is one of the earliest compounds identified in various SCB products, and our laboratory previously demonstrated that JWH-018 undergoes extensive metabolism by cytochromes P450 (P450), binds to, and activates cannabinoid receptors (CBRs). The major enzyme involved in the metabolism of JWH-018 is CYP2C9, a highly polymorphic enzyme found largely in the intestines and liver, with *1 being designated as the wild type, and *2 and *3 as the two most common variants. Three different major products have been identified in human urine and plasma: JWH-018 (omega)-OH, JWH-018 (omega-1)-OH(R), and JWH 018 (omega-1)-OH(S). The (omega-1)-OH metabolite of JWH-018 is a chiral molecule, and is thus designated as either (omega-1)-OH(R) or (omega-1)-OH(S). Here, in vitro enzyme kinetic assays performed with human recombinant CYP2C9 variants (*1, *2, and *3) revealed that oxidative metabolism by CYP2C9*3 resulted in significantly less formation of (omega)-OH and (omega-1)-OH metabolites. Surprisingly, CYP2C9*2 was roughly 3.6-fold more efficient as the CYP2C9*1 enzyme based on Vmax/Km, increasing the rate of JWH-018 metabolism and allowed for a much more rapid elimination. These results suggest that genetic polymorphisms of P450 enzymes result in the production of varying levels of biologically active JWH-018 metabolites in some individuals, offering a mechanistic explanation for the diverse clinical toxicity often observed following JWH-018 abuse. PMID- 29522718 TI - Knockdown of survivin results in inhibition of epithelial to mesenchymal transition in retinal pigment epithelial cells by attenuating the TGFbeta pathway. AB - Proliferative vitreoretinopathy (PVR) is a common complication of open globe injury and the most common cause of failed retinal detachment surgery. The response by retinal pigment epithelial (RPE) cells liberated into the vitreous includes proliferation and migration; most importantly, epithelial to mesenchymal transition (EMT) of RPE plays a central role in the development and progress of PVR. For the first time, we show that knockdown of BIRC5, a member of the inhibitor of apoptosis protein family, using either lentiviral vector based CRISPR/Cas9 nickase gene editing or inhibition of survivin using the small molecule inhibitor YM155, results in the suppression of EMT in RPE cells. Knockdown of survivin or inhibition of survivin significantly reduced TGFbeta induced cell proliferation and migration. We further demonstrated that knockdown or inhibition of survivin attenuated the TGFbeta signaling by showing reduced phospho-SMAD2 in BIRC5 knockdown or YM155-treated cells compared to controls. Inhibition of the TGFbeta pathway using TGFbeta receptor inhibitor also suppressed survivin expression in RPE cells. Our studies demonstrate that survivin contributes to EMT by cross-talking with the TGFbeta pathway in RPE cells. Targeting survivin using small-molecule inhibitors may provide a novel approach to treat PVR disease. PMID- 29522719 TI - Tsc1 controls the development and function of alveolar macrophages. AB - Alveolar macrophages (AMs) are pivotal for maintaining the lung homeostasis, but how the development and function of AMs regulated remains largely unknown. In the present study, we demonstrated that the number of AMs was controlled by the Tsc1 protein. Cd11c-specific deletion of Tsc1 caused inefficient transition from pre AMs to AMs in lung, which led to a great reduction of AM population. Ablation of Tsc1 downregulated the expression of surface marker CD64 and SiglecF on AMs. We further showed that conditional knockout of Tsc1 led to enhanced proliferation and increased reactive oxygen species (ROS) production and phagocytosis in AMs. These results indicated that Tsc1 was a critical regulator of development, proliferation and function in AMs. PMID- 29522720 TI - Lhx2, an evolutionarily conserved, multifunctional regulator of forebrain development. AB - A hundred years after Lhx2 ortholog apterous was identified as a critical regulator of wing development in Drosophila, LIM-HD gene family members have proved to be versatile and powerful components of the molecular machinery that executes the blueprint of embryogenesis across vertebrate and invertebrate species. Here, we focus on the spatio-temporally varied functions of LIM homeodomain transcription factor LHX2 in the developing mouse forebrain. Right from its earliest known role in telencephalic and eye field patterning, to the control of the neuron-glia cell fate switch, and the regulation of axon pathfinding and dendritic arborization in late embryonic stages, LHX2 has been identified as a fundamental, temporally dynamic, always necessary, and often sufficient factor in a range of critical developmental phenomena. While Lhx2 mutant phenotypes have been characterized in detail in multiple brain structures, only recently have we advanced in our understanding of the molecular mechanisms by which this factor acts. Common themes emerge from how this multifunctional molecule controls a range of developmental steps in distinct forebrain structures. Examining these shared features, and noting unique aspects of LHX2 function is likely to inform our understanding of how a single factor can bring about a diversity of effects and play central and critical roles across systems and stages. The parallels in LHX2 and APTEROUS functions, and the protein complexes they participate in, offer insights into evolutionary strategies that conserve tool kits and deploy them to play new, yet familiar roles in species separated by hundreds of millions of years. PMID- 29522721 TI - Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons. AB - The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naive offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine. PMID- 29522722 TI - TRIM28 and the control of transposable elements in the brain. AB - TRIM28 is an epigenetic co-repressor protein that mediates transcriptional silencing. TRIM28 participates, together with the large family of Kruppel associated box domain zinc finger proteins (KRAB-ZFP) transcription factors, in the repression of transposable elements (TE). Recent advances indicate that TRIM28-based repression of TEs occurs in the mammalian brain and may provide beneficial effects through the regulation of transcriptional networks. Here, we provide an overview of TRIM28-related functions, highlighting the role of controlling TEs in neural progenitor cells and discuss how this mechanism may have contributed to the evolution of the complex human brain. Finally, we outline future considerations for the field. PMID- 29522724 TI - Long-term treatment with anti-VEGF does not induce cell aging in primary retinal pigment epithelium. AB - Anti-Vascular Endothelial Growth Factor (VEGF) therapy is given repeatedly for an extended period of time to patients when treated for age-related macular degeneration. While short-term effects of anti-VEGF agents on retinal pigment epithelial (RPE) cells have been investigated, the effects of long-term and repeated treatment on these cells are scarce. In this study, we have investigated the effects of anti-VEGF treatment after long-term, repeated treatment on cell aging and morphology. The experiments were conducted in primary porcine RPE cells passage one and two. Cells were treated with 125 MUg/ml bevacizumab, ranibizumab, aflibercept or rituximab once a week for 1 day, 4 days, 7 days, 4 weeks and 12 weeks. Cell survival was evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide tetrazolium (MTT) and trypan blue exclusion assay. Activity of beta-galactosidase was assessed in a commercially available assay. Influence of these compounds was investigated on the expression of cathepsin D and amyloid beta, and the expression and phosphorylation of mechanistic target of rapamycin (mTOR), all proteins involved in senescence and aging, in Western blot. The secretion of Pigment Epithelium Derived Factor (PEDF) and Transforming Growth Factor (TGF)-beta was investigated in Enzyme-linked Immunosorbent Assay (ELISA). The cellular morphology was investigated with electron microscopy, investigating the number and area of mitochondria and autophagosomes. Statistical analysis was conducted using a mixed linear model. Weekly treatment up to 12 weeks displayed no toxic effects on RPE cells in any of the substances tested. Ranibizumab showed a significant increase in beta-galactosidase signal on day 4 (p < 0.05) and 7 (p < 0.05) after treatment. In long-term, however, ranibizumab displayed no significant difference to untreated cells. Bevacizumab displayed a significant reduction of the beta-galactosidase signal after 12 weeks (p < 0.05). Aflibercept significantly decreased beta-galactosidase after 1 day (p < 0.01) and 12 weeks (p < 0.05). Rituximab and bevacizumab also decreased beta-galactosidase signal after 12 weeks (p < 0.05). The expression of mTOR, phospho-mTOR, amyloid beta and cathepsin D was not significantly altered by any of the compounds tested. RPE cells secreted considerate amounts of TGF-beta. Bevacizumab treated cells showed significantly lower TGF-beta secretion than ranibizumab and rituximab (p < 0.05). In contrast, only small amounts of PEDF were secreted which were not altered by any substance tested. Ultrastructural analysis showed no alterations in mitochondria after long-term treatment with either substance. Autophagosomes were not reduced by long-term anti-VEGF treatment compared to control. However, the area of autophagosomes in bevacizumab and aflibercept treated cells was significantly less compared to both ranibizumab and rituximab treated cells (all p < 0.05). Taken together, weekly treatment with VEGF-antagonists up to 3 months does not induce premature aging in primary RPE cells in any tested compound. A significant difference can be found between bevacizumab and aflibercept on the one hand, and ranibizumab (and rituximab) on the other hand, with more autophagosomal area in ranibizumab and (rituximab). Taken together, our data provide indications for long-term safety of anti-VEGF compounds. Further research is warranted. PMID- 29522723 TI - Canine corneal epithelial cells possess a sustained proliferative capacity and generate a spontaneously derived cell line. AB - We have previously reported characteristics of canine corneal epithelial cells in vitro and found that canine corneal epithelial cells could maintain their proliferative capacity even after continuous culture without the use of feeder cells and growth promoting additives. The objective of this study was to elucidate proliferative characteristics of canine corneal epithelial cells independent of feeder cells and growth promoting additives, with the aim of developing a spontaneously derived corneal epithelial cell line. Canine and rabbit corneal epithelial cells were harvested from the limbus and cultured with, or without, feeder cells and growth promoting additives, and both were passaged continuously until growth arrest. Canine corneal epithelial cells could proliferate independently, and could be passaged more times than rabbit cells. A canine corneal epithelial cell line, cCEpi, which could be passaged more than 100 times without using feeder cells and growth promoting additives, was established. cCEpi cells maintained a cell morphology close to the primary culture and expressed p63, cytokeratin 15 (K15), and K3. Although changes in colony morphology, shortening of the population doubling time and a heteroploid karyotype were observed, cCEpi was not tumorigenic. Stratified cell sheets cultured from cCEpi were morphologically and immunohistologically similar to sheets cultivated from early passage cells. In conclusion, canine corneal epithelial cells can proliferate independent of feeder cells and growth promoting additives. cCEpi maintains properties similar to normal corneal epithelial cells and could be a useful source for studies in cellular biology and for developing novel therapies. PMID- 29522725 TI - Small molecules targeting heterotrimeric G proteins. AB - G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors regulating many human and animal physiological functions. Their implication in human pathophysiology is obvious with almost 30-40% medical drugs commercialized today directly targeting GPCRs as molecular entities. However, upon ligand binding GPCRs signal inside the cell through many key signaling, adaptor and regulatory proteins, including various classes of heterotrimeric G proteins. Therefore, G proteins are considered interesting targets for the development of pharmacological tools that are able to modulate their interaction with the receptors, as well as their activation/deactivation processes. In this review, old attempts and recent advances in the development of small molecules that directly target G proteins will be described with an emphasis on their utilization as pharmacological tools to dissect the mechanisms of activation of GPCR-G protein complexes. These molecules constitute a further asset for research in the "hot" areas of GPCR biology, areas such as multiple G protein coupling/signaling, GPCR-G protein preassembly, and GPCR functional selectivity or bias. Moreover, this review gives a particular focus on studies in vitro and in vivo supporting the potential applications of such small molecules in various GPCR/G protein-related diseases. PMID- 29522727 TI - What is adaptation and how should it be measured? AB - Adaptation is a defining property of living systems. It occurs when organisms become better suited to their environment. The phenomena that people find most fascinating about biological systems are, in general, the result of adaptive processes. Examples include the mammalian central nervous system, the flight of birds and insects, photosynthesis, and the human hand. However, despite the centrality of adaptation for biology, there is no generally agreed quantitative way to describe the degree to which an organism is adapted. Here, we address this situation by proposing a quantitative measure of adaptation. We also present results of computer simulations which demonstrate that some changes in parameter values cause mean adaptedness and mean relative fitness to change in opposite directions. This indicates that adaptedness and relative fitness are distinct concepts. We suggest that the measure of adaptedness proposed in this work may help to resolve questions about 'units of selection' and 'major transitions in evolution'. PMID- 29522726 TI - Valnoctamide: The effect on relieving of neuropathic pain and possible mechanisms. AB - The purpose of this study is to assess the possible anti-allodynic and antihyperalgesic effect of valnoctamide, an amide derivative of valproic acid, at the doses of 40, 70 and 100 mg/kg (i.p.) in neuropathic pain model induced by chronic constriction injury in rats, by using dynamic plantar test and plantar test (Hargreaves method), and to evaluate that the possible role of certain serotonin, noradrenergic, opioid and GABAergic receptors by pre-treatment with 1 mg/kg (i.p.) ketanserin, yohimbine, naloxone and 0.5 mg/kg (i.p.) bicuculline, respectively. 70 and 100 mg/kg valnoctamide significantly increased the mechanical and thermal thresholds decreasing with the development of neuropathy and demonstrated anti-allodynic and antihyperalgesic activity. Limited contribution of serotonin 5-HT2A/2C receptors and alpha2-adrenoceptors, and significant contribution of GABAA and opioid receptors to the anti-allodynic activity have been identified whereas remarkable contribution of opioid receptors and significant contribution of serotonin 5-HT2A/2C receptors, alpha2 adrenoceptors, GABAA receptors to the antihyperalgesic activity have been identified. Based upon these findings and considering that valnoctamide has safer side-effect profile, it is possible to say that valnoctamide is a potential agent that might be used alone or in combination with the other effective therapies in the alleviating of neuropathic pain. PMID- 29522728 TI - Unraveling within-host signatures of dengue infection at the population level. AB - Dengue virus causes worldwide concern with nearly 100 million infected cases reported annually. The within-host dynamics differ between primary and secondary infections, where secondary infections with a different virus serotype typically last longer, produce higher viral loads, and induce more severe disease. We build upon the variable within-host virus dynamics during infections resulting in mild dengue fever and severe dengue hemorrhagic fever. We couple these within-host virus dynamics to a population-level model through a system of partial differential equations creating an immuno-epidemiological model. The resulting multiscale model examines the dynamics of between-host infections in the presence of two circulating virus strains that involves feedback from the within-host and between-hosts interactions, encompassing multiple scales. We analytically determine the relationship between the model parameters and the characteristics of the model's solutions, and find an analytical threshold under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our immuno-epidemiological model, allowing the simulation of population dynamics under variable parameter conditions. PMID- 29522729 TI - Living in Their World. PMID- 29522730 TI - The Moving Target of Flu. PMID- 29522731 TI - Microbiome Research in a Social World. AB - Should we get our microbiomes sequenced? Do we shape our microbes, or do our microbes shape us? These are just a few of the questions at the border between microbiome science and humanities. PMID- 29522732 TI - For Want of a Template. PMID- 29522734 TI - Tiny Microbes Inspire Modern Microbe Hunters to Think Big. PMID- 29522733 TI - Extreme Excitement about Archaea. PMID- 29522735 TI - From "A"IV to "Z"IKV: Attacks from Emerging and Re-emerging Pathogens. AB - 100 years after the infamous "Spanish flu" pandemic, the 2017-2018 flu season has been severe, with numerous infections worldwide. In between, there have been continuous, relentless attacks from (re-)emerging viruses. To fully understand viral pathogenesis and develop effective medical countermeasures, we must strengthen current surveillance and basic research efforts. PMID- 29522736 TI - Genomic Insights into Zika Virus Emergence and Spread. AB - The emergence and spread of Zika virus in the Americas continues to challenge our disease surveillance systems. Virus genome sequencing during the epidemic uncovered the timescale of Zika virus transmission and spread. Yet, we are only beginning to explore how genomics can enhance our responses to emerging viruses. PMID- 29522737 TI - No Vacillation on HPV Vaccination. AB - Evidence of the safety and protective benefits of human papillomavirus virus (HPV) vaccines as an anti-cancer measure is overwhelming. However, vaccine uptake varies widely across countries and falls short of levels needed to achieve population immunity. We highlight policy measures that would help ensure greater worldwide coverage and save lives. PMID- 29522738 TI - Using Metagenomics to Characterize an Expanding Virosphere. AB - We know less about viruses than any other lifeform. Fortunately, metagenomics has led to a massive expansion in the known diversity of the virosphere. Here, we discuss how metagenomics has changed our understanding of RNA viruses and present some of the remaining challenges, including characterization of the "dark matter" of divergent viral genomes. PMID- 29522739 TI - The Past and Future Biology of the Human Microbiome in an Age of Extinctions. AB - The evolutionary fate of humans is intimately linked with that of our microbiome. Medical and technological advances have caused large-scale changes in the composition and maturation of human-associated microbial communities, increasing our susceptibility to infectious and developmental diseases. Restoration of the human microbiome must become a priority for biomedicine. PMID- 29522740 TI - The Soil-Borne Legacy. AB - Plants greatly rely on their root microbiome for uptake of nutrients and protection against stresses. Recent studies have uncovered the involvement of plant stress responses in the assembly of plant-beneficial microbiomes. To facilitate durable crop production, deciphering the driving forces that shape the microbiome is crucial. PMID- 29522741 TI - Major New Microbial Groups Expand Diversity and Alter our Understanding of the Tree of Life. AB - The recent recovery of genomes for organisms from phyla with no isolated representative (candidate phyla) via cultivation-independent genomics enabled delineation of major new microbial lineages, namely the bacterial candidate phyla radiation (CPR), DPANN archaea, and Asgard archaea. CPR and DPANN organisms are inferred to be mostly symbionts, and some are episymbionts of other microbial community members. Asgard genomes encode typically eukaryotic systems, and their inclusion in phylogenetic analyses results in placement of eukaryotes as a branch within Archaea. Here, we illustrate how new genomes have changed the structure of the tree of life and altered our understanding of biology, evolution, and metabolic roles in biogeochemical processes. PMID- 29522742 TI - The Human Gut Microbiome: From Association to Modulation. AB - Our understanding of the human gut microbiome continues to evolve at a rapid pace, but practical application of thisknowledge is still in its infancy. This review discusses the type of studies that will be essential for translating microbiome research into targeted modulations with dedicated benefits for the human host. PMID- 29522744 TI - Targeting Antibiotic Tolerance, Pathogen by Pathogen. AB - Antibiotic tolerance, the capacity of genetically susceptible bacteria to survive the lethal effects of antibiotic treatment, plays a critical and underappreciated role in the disease burden of bacterial infections. Here, we take a pathogen-by pathogen approach to illustrate the clinical significance of antibiotic tolerance and discuss how the physiology of specific pathogens in their infection environments impacts the mechanistic underpinnings of tolerance. We describe how these insights are leading to the development of species-specific therapeutic strategies for targeting antibiotic tolerance and highlight experimental platforms that are enabling us to better understand the complexities of drug tolerant pathogens in in vivo settings. PMID- 29522745 TI - The Biology of CRISPR-Cas: Backward and Forward. AB - In bacteria and archaea, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins constitute an adaptive immune system against phages and other foreign genetic elements. Here, we review the biology of the diverse CRISPR-Cas systems and the major progress achieved in recent years in understanding the underlying mechanisms of the three stages of CRISPR-Cas immunity: adaptation, crRNA biogenesis, and interference. The ecology and regulation of CRISPR-Cas in the context of phage infection, the roles of these systems beyond immunity, and the open questions that propel the field forward are also discussed. PMID- 29522743 TI - Multiscale Evolutionary Dynamics of Host-Associated Microbiomes. AB - The composite members of the microbiota face a range of selective pressures and must adapt to persist in the host. We highlight recent work characterizing the evolution and transfer of genetic information across nested scales of host associated microbiota, which enable resilience to biotic and abiotic perturbations. At the strain level, we consider the preservation and diversification of adaptive information in progeny lineages. At the community level, we consider genetic exchange between distinct microbes in the ecosystem. Finally, we frame microbiomes as open systems subject to acquisition of novel information from foreign ecosystems through invasion by outsider microbes. PMID- 29522746 TI - Contemporary Phage Biology: From Classic Models to New Insights. AB - Bacteriophages, discovered about a century ago, have been pivotal as models for understanding the fundamental principles of molecular biology. While interest in phage biology declined after the phage "golden era," key recent developments, including advances in phage genomics, microscopy, and the discovery of the CRISPR Cas anti-phage defense system, have sparked a renaissance in phage research in the past decade. This review highlights recently discovered unexpected complexities in phage biology, describes a new arsenal of phage genes that help them overcome bacterial defenses, and discusses advances toward documentation of the phage biodiversity on a global scale. PMID- 29522750 TI - Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines. AB - Enveloped viruses enter cells by inducing fusion of viral and cellular membranes, a process catalyzed by a specialized membrane-fusion protein expressed on their surface. This review focuses on recent structural studies of viral fusion proteins with an emphasis on their metastable prefusion form and on interactions with neutralizing antibodies. The fusion glycoproteins have been difficult to study because they are present in a labile, metastable form at the surface of infectious virions. Such metastability is a functional requirement, allowing these proteins to refold into a lower energy conformation while transferring the difference in energy to catalyze the membrane fusion reaction. Structural studies have shown that stable immunogens presenting the same antigenic sites as the labile wild-type proteins efficiently elicit potently neutralizing antibodies, providing a framework with which to engineer the antigens for stability, as well as identifying key vulnerability sites that can be used in next-generation subunit vaccine design. PMID- 29522748 TI - How to Build a Bacterial Cell: MreB as the Foreman of E. coli Construction. AB - Cell shape matters across the kingdoms of life, and cells have the remarkable capacity to define and maintain specific shapes and sizes. But how are the shapes of micron-sized cells determined from the coordinated activities of nanometer sized proteins? Here, we review general principles that have surfaced through the study of rod-shaped bacterial growth. Imaging approaches have revealed that polymers of the actin homolog MreB play a central role. MreB both senses and changes cell shape, thereby generating a self-organizing feedback system for shape maintenance. At the molecular level, structural and computational studies indicate that MreB filaments exhibit tunable mechanical properties that explain their preference for certain geometries and orientations along the cylindrical cell body. We illustrate the regulatory landscape of rod-shape formation and the connectivity between cell shape, cell growth, and other aspects of cell physiology. These discoveries provide a framework for future investigations into the architecture and construction of microbes. PMID- 29522751 TI - SnapShot: Microbial Hydrocarbon Bioremediation. AB - Hydrocarbon-degrading bacteria are phylogenetically and physiologically diverse and employ layered strategies to sense hydrocarbons, respond transcriptionally, and then move toward an oil source. They then produce biopolymers that increase hydrocarbon bioavailability. This SnapShot highlights how these bacteria respond to and then remove hydrocarbon contaminants from the environment. To view this SnapShot, open or download the PDF. PMID- 29522749 TI - Protein-Injection Machines in Bacteria. AB - Many bacteria have evolved specialized nanomachines with the remarkable ability to inject multiple bacterially encoded effector proteins into eukaryotic or prokaryotic cells. Known as type III, type IV, and type VI secretion systems, these machines play a central role in the pathogenic or symbiotic interactions between multiple bacteria and their eukaryotic hosts, or in the establishment of bacterial communities in a diversity of environments. Here we focus on recent progress elucidating the structure and assembly pathways of these machines. As many of the interactions shaped by these machines are of medical importance, they provide an opportunity to develop novel therapeutic approaches to combat important human diseases. PMID- 29522752 TI - RNA helicase DDX5 participates in oxLDL-induced macrophage scavenger receptor 1 expression by suppressing mRNA degradation. AB - The DEAD box protein DDX5, an ATP-dependent RNA helicase, plays an important role in transcriptional regulation and is associated with solid tumors and leukemia. However, its role in oxLDL-induced lipid uptake in macrophages remains unclear. In this study, we detected the expression of DDX5 mRNA and protein in oxidized low-density lipoprotein (oxLDL)-treated human primary macrophages that were induced from monocytes isolated from human peripheral blood with or without several chemical inhibitors using quantitative real-time PCR (qRT-PCR) or Western blotting. We found that oxLDL induced DDX5 expression to be independent of both the MAPK and NF-kappaB pathways. We also found that DDX5 promoted macrophage lipid uptake by evaluating the fluorescence intensity of engulfed dil-oxLDL. Various scavenger receptors that participate in lipid uptake were detected in siR DDX5 transfected macrophages using qRT-PCR and Western blotting. Macrophage scavenger receptor A (MSR1) was found to be involved the upregulation of DDX5 mediated lipid uptake. Through the use of a dual luciferase reporter assay system and incubation with cycloheximide (CHX) MG132 and actidione (ActD), we found that DDX5 promoted MSR1 protein expression by stabilizing MSR1 mRNA. Moreover, the mechanism involved in DDX5 regulation of MSR1 mRNA was also explored using mass spectrum analysis; Immunoprecipitations (IPs) and RNA- Immunoprecipitations (R IPs) revealed that mettl3 was involved in DDX5-mediated MSR1 mRNA stabilization. In addition, we also demonstrated that DDX5 inhibited mettl3 to catalyze m6a methylation in MSR1 mRNA, which contributed to the maintenance of MSR1 mRNA stability. In conclusion, ox-LDL promotes DDX5 expression in macrophages, which interacts with mettl3 to stabilize MSR1 mRNA by decreasing the m6a modification of MSR1 mRNA, ultimately promoting lipid uptake in macrophages. PMID- 29522747 TI - Subcellular Organization: A Critical Feature of Bacterial Cell Replication. AB - Spatial organization is a hallmark of all living systems. Even bacteria, the smallest forms of cellular life, display defined shapes and complex internal organization, showcasing a highly structured genome, cytoskeletal filaments, localized scaffolding structures, dynamic spatial patterns, active transport, and occasionally, intracellular organelles. Spatial order is required for faithful and efficient cellular replication and offers a powerful means for the development of unique biological properties. Here, we discuss organizational features of bacterial cells and highlight how bacteria have evolved diverse spatial mechanisms to overcome challenges cells face as self-replicating entities. PMID- 29522753 TI - ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN deficient breast cancer cells to cisplatin. AB - PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by gamma-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. PMID- 29522754 TI - The formation of giant plasma membrane vesicles enable new insights into the regulation of cholesterol efflux. AB - Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4. Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation. Conversely, pharmacological inhibition of cholesterol efflux blocks GPMV formation. We show that microtubule stabilization via paclitaxel treatment and increased tubulin acetylation via HDAC6 inhibition promotes the formation of GPMVs with concomitant reduction in cellular cholesterol in a cell model of NPC disease. The pan-deacetylase inhibitor panobinostat, which has been shown to reduce the severity of cholesterol storage in NPC, elicited a similar response. Further, the disruption of actin polymerization inhibits the formation of GPMVs, whereas the small GTP-binding protein Arl4c promotes actin remodeling at sites overlapping with GPMV formation. Thus, monitoring the formation of GPMVs provides a new avenue to better understand diseases whose pathology may be sensitive to alterations in cellular cholesterol. PMID- 29522755 TI - Influence of microvascular sutures on shear strain rate in realistic pulsatile flow. AB - Arterial thrombus formation is directly related to the mechanical shear experienced by platelets within flow. High shear strain rates (SSRs) and large shear gradients cause platelet activation, aggregation and production of thrombus. This study, for the first time, investigates the influence of pulsatile flow on local haemodynamics within sutured microarterial anastomoses. We measured physiological arterial waveform velocities experimentally using Doppler ultrasound velocimetry, and a representative example was applied to a realistic sutured microarterial geometry. Computational geometries were created using measurements taken from sutured chicken femoral arteries. Arterial SSRs were predicted using computational fluid dynamics (CFD) software, to indicate the potential for platelet activation, deposition and thrombus formation. Predictions of steady and sinusoidal inputs were compared to analyse whether the addition of physiological pulse characteristics affects local intravascular flow characteristics. Simulations were designed to evaluate flow in pristine and hand sutured microarterial anastomoses, each with a steady-state and sinusoidal pulse component. The presence of sutures increased SSRmax in the anastomotic region by factors of 2.1 and 2.3 in steady-state and pulsatile flows respectively, when compared to a pristine vessel. SSR values seen in these simulations are analogous to the presence of moderate arterial stenosis. Steady-state simulations, driven by a constant inflow velocity equal to the peak systolic velocity (PSV) of the measured pulsatile flow, underestimated SSRs by ~ 9% in pristine, and ~ 19% in sutured vessels compared with a realistic pulse. Sinusoidal flows, with equivalent frequency and amplitude to a measured arterial waveform, represent a slight improvement on steady-state simulations, but still SSRs are underestimated by 1-2%. We recommend using a measured arterial waveform, of the form presented here, for simulating pulsatile flows in vessels of this nature. Under realistic pulsatile flow, shear gradients across microvascular sutures are high, of the order ~ 7.9 * 106 m-1 s-1, which may also be associated with activation of platelets and formation of aggregates. PMID- 29522756 TI - Promoter methylation and Hoxd4 regulate UII mRNA tissue-specific expression in olive flounder (paralichthys olivaceus). AB - The peptide urotensin II (UII) mediates multiple physiology effects in mammals and fishes, and UII expression shows a tissue-specific pattern. However the mechanism is still unknown. In the present study high level of UII mRNA was detected in the caudal neurosecretory system (CNSS) of the olive flounder when compared to other tissues. We examined whether epigenetic mechanisms of DNA methylation are involved in UII gene expression. Methylation DNA immune precipitation (MeDIP) assay showed low methylation of UII promoter in CNSS tissue compared with muscle and spinal cord. Methylation of UII promoter was further assessed through bisulphate sequencing analysis. Low level methylation (31%) in CpG island of UII promoter was detected in CNSS tissue, while methylation status in muscle and spinal cord was 89% and 91%, respectively. In addition, high conserved sites of Hoxd4 in UII promoter were found. Activation of Hoxd4 mRNA using transretinoic acid (RA) resulted in 18-fold increase of UII mRNA expression in CNSS and high locomotor activity in medaka, confirming that Hoxd4 is also involved in UII gene transcriptional regulation. Taken together, our data provide the first evidence of the epigenetic mechanism of promoter methylation in transcriptional regulation of UII expression in a tissue-specific manner, and Hoxd4 may also participate in UII gene transcription in flounder. PMID- 29522757 TI - Synaptic loss and firing alterations in Axotomized Motoneurons are restored by vascular endothelial growth factor (VEGF) and VEGF-B. AB - Vascular endothelial growth factor (VEGF), also known as VEGF-A, was discovered due to its vasculogenic and angiogenic activity, but a neuroprotective role for VEGF was later proven for lesions and disorders. In different models of motoneuronal degeneration, VEGF administration leads to a significant reduction of motoneuronal death. However, there is no information about the physiological state of spared motoneurons. We examined the trophic role of VEGF on axotomized motoneurons with recordings in alert animals using the oculomotor system as the experimental model, complemented with a synaptic study at the confocal microscopy level. Axotomy leads to drastic alterations in the discharge characteristics of abducens motoneurons, as well as to a substantial loss of their synaptic inputs. Retrograde delivery of VEGF completely restored the discharge activity and synaptically-driven signals in injured motoneurons, as demonstrated by correlating motoneuronal firing rate with motor performance. Moreover, VEGF treated motoneurons recovered a normal density of synaptic boutons around motoneuronal somata and in the neuropil, in contrast to the low levels of synaptic terminals found after axotomy. VEGF also reduced the astrogliosis induced by axotomy in the abducens nucleus to control values. The administration of VEGF-B produced results similar to those of VEGF. This is the first work demonstrating that VEGF and VEGF-B restore the normal operating mode and synaptic inputs on injured motoneurons. Altogether these data indicate that these molecules are relevant synaptotrophic factors for motoneurons and support their clinical potential for the treatment of motoneuronal disorders. PMID- 29522758 TI - C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1. AB - Hexanucleotide repeat expansions in the C9orf72 gene are a common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the function of C9orf72 in neural development and the pathogenic mechanism underlying neurodegeneration are unknown. We found that disrupting C9orf72 expression by using C9orf72 constructs that lack the complete DENN domain result in reduced GTPase activity in zebrafish embryos, demonstrating the indispensability of the complete DENN domain. This effect was phenocopied by knocking down endogenous C9orf72 expression by using morpholinos. C9orf72 deficient zebrafish embryos exhibited impaired axonogenesis and motility defects. The C9orf72 deficiency upregulated the expression of tp53 and caused neuronal apoptosis. Knockdown Tp53 in the C9orf72-deficient embryos rescued only the apoptotic phenotype but not the phenotype with axonal and motility defects. The C9orf72 deficiency also induced ccng1 (encodes Cyclin G1) mRNA expression, and injection of a dominant-negative Cyclin G1 construct rescued the axonal impairment, apoptosis, and motility defects in the C9orf72-deficient embryos. Our results revealed the GTPase activity of C9orf72 and demonstrated that Cyclin G1 is an essential downstream mediator for C9orf72 in neural development and motility. Furthermore, downregulating Cyclin G1 was sufficient to rescue all the defects caused by C9orf72 deficiency. In summary, we revealed a novel regulatory mechanism underlying the role of C9orf72 in neurological and motility defects. This result facilitates understanding the function of the C9orf72 gene in the developing nervous system and provides a potential mechanism underlying the pathogenesis of ALS-FTD. PMID- 29522759 TI - Dorsal and ventral stream contribution to the paired-object affordance effect. AB - Visual extinction, a parietal syndrome in which patients exhibit perceptual impairments when two objects are simultaneously presented in the visual field, is reduced when objects are correctly positioned for action, indicating that action helps patients' visual attention. Similarly, healthy individuals make faster action decisions on object pairs that appear in left/right standard co-location for actions in comparison to object pairs that appear in a mirror location, a phenomenon called the paired-object affordance effect. However, the neural locus of such effect remains debated and may be related to the activity of ventral or dorsal brain regions. The present fMRI study aims at determining the neural substrates of the paired-object affordance effect. Fourteen right-handed participants made decisions about semantically related (i.e. thematically related and co-manipulated) and unrelated object pairs. Pairs were either positioned in a standard location for a right-handed action (with the active object - lid - in the right visual hemifield, and the passive object - pan - in the left visual hemifield), or in the reverse location. Behavioral results showed a suppression of the observed cost of correctly positioning related pairs for action when performing action decisions (deciding if the two objects are usually used together), but not when performing contextual decisions (deciding if the two objects are typically found in the kitchen). Anterior regions of the dorsal stream (e.g. supplementary motor area) responded to inadequate object co positioning for action, but only when the perceptual task required action decisions. In the ventral cortex, the left lateral occipital complex showed increased activation for objects correctly positioned for action in all conditions except when neither task demands nor object relatedness was relevant for action. Thus, fMRI results demonstrated a joint contribution of ventral and dorsal cortical streams to the paired-affordance effect. They further suggest that this contribution may depend on contextual situations and task demands, in line with flexible views of affordance evocation. PMID- 29522760 TI - Stress-evoking emotional stimuli exaggerate deficits in motor function in Parkinson's disease. AB - Recent animal studies have shown that stress can profoundly affect motor behaviour and worsen motor deficits associated with Parkinson's disease (PD) by acting on the dopaminergic system, possibly due to stress-associated emotional changes. However, systematic investigation of the influence of acute emotional stressors on motor function in PD is scarce. Here we examined the effect of repeated exposure to negative emotional stimuli on grip-force control in PD. Eighteen patients with idiopathic PD (tested off-medication) and 18 healthy controls produced an isometric precision grip contraction at 15% of maximum force while viewing a series of unpleasant, pleasant, or neutral emotional images (blocked presentation; without visual feedback of force output). Force output was continuously recorded together with change in forearm muscle activity using electromyography. While viewing unpleasant images, PD participants exhibited increased variability and 4-8 Hz oscillations of force output, and greater flexor muscle activity. With feedback occluded, the decay in force amplitude was pronounced, but not modulated by emotion. In contrast, in controls, the decay in force amplitude was attenuated while viewing unpleasant images compared with pleasant and neutral images. The findings in PD may reflect an increased number of motor units discharging and reduced ability to use sensory feedback to alter the descending drive. Modulation of synaptic input to the motoneuron pool could result from acute stress-induced enhancement of sympathetic activity and/or amplification of dopamine depletion. Corroborating previous findings in animal models of PD, exposure to stress-evoking emotional stimuli can exacerbate impairments in fine motor control in individuals with PD. PMID- 29522761 TI - Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction. AB - BACKGROUND: Prostaglandin E2 (PGE2) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We recently reported that PGE2 via its EP3 receptor could reduce cardiac contractility of isolated myocytes and the working heart preparation. We thus hypothesized that there is an imbalance in the EP3/EP4 ratio towards EP3 in the failing heart and that overexpression of EP4 in a mouse model of heart failure would improve cardiac function. METHODS AND RESULTS: Our hypothesis was tested in a mouse model of myocardial infarction (MI) with the use of AAV9-EP4 driven by the myosin heavy chain promoter to overexpress EP4 in the cardiac myocytes. Echocardiography was performed to assess cardiac function. We found that overexpression of EP4 improved shortening fraction (p = 0.0025), ejection fraction (p = 0.0003), and reduced left ventricular dimension at systole (p = 0.0013). Overexpression of EP4 also significantly reduced indices of cardiac hypertrophy and interstitial collagen fraction. Animals treated with AAV9-EP4 also had a significant decrease in TNFalpha mRNA expression and in the number of macrophages and T cells migrated post MI coupled with a reduction in the expression of iNOS. CONCLUSION: Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production. PMID- 29522762 TI - Bidirectional regulation of HDAC5 by mAKAPbeta signalosomes in cardiac myocytes. AB - Class IIa histone deacetylases (HDACs) are transcriptional repressors whose nuclear export in the cardiac myocyte is associated with the induction of pathological gene expression and cardiac remodeling. Class IIa HDACs are regulated by multiple, functionally opposing post-translational modifications, including phosphorylation by protein kinase D (PKD) that promotes nuclear export and phosphorylation by protein kinase A (PKA) that promotes nuclear import. We have previously shown that the scaffold protein muscle A-kinase anchoring protein beta (mAKAPbeta) orchestrates signaling in the cardiac myocyte required for pathological cardiac remodeling, including serving as a scaffold for both PKD and PKA. We now show that mAKAPbeta is a scaffold for HDAC5 in cardiac myocytes, forming signalosomes containing HDAC5, PKD, and PKA. Inhibition of mAKAPbeta expression attenuated the phosphorylation of HDAC5 by PKD and PKA in response to alpha- and beta-adrenergic receptor stimulation, respectively. Importantly, disruption of mAKAPbeta-HDAC5 anchoring prevented the induction of HDAC5 nuclear export by alpha-adrenergic receptor signaling and PKD phosphorylation. In addition, disruption of mAKAPbeta-PKA anchoring prevented the inhibition by beta adrenergic receptor stimulation of alpha-adrenergic-induced HDAC5 nuclear export. Together, these data establish that mAKAPbeta signalosomes serve to bidirectionally regulate the nuclear-cytoplasmic localization of class IIa HDACs. Thus, the mAKAPbeta scaffold serves as a node in the myocyte regulatory network controlling both the repression and activation of pathological gene expression in health and disease, respectively. PMID- 29522763 TI - Enhanced MiR-711 transcription by PPARgamma induces endoplasmic reticulum stress mediated apoptosis targeting calnexin in rat cardiomyocytes after myocardial infarction. AB - MicroRNA 711 (miR-711) levels in the heart change dynamically after myocardial infarction (MI). As peroxisome proliferator-activated receptor gamma (PPARgamma) can upregulate miR-711 in adipocytes and cardiac fibroblasts, this study examined the precise mechanism of PPARgamma-mediated miR-711 upregulation and its role in the heart in the early stages after MI. In a rat model of MI induced by left anterior descending coronary artery ligation, immunohistochemical and western blot analyses revealed increased PPARgamma expression in cardiomyocyte nuclei after MI. PPARgamma modulated miR-711 levels in neonatal rat cardiomyocytes, and chromatin immunoprecipitation and luciferase assays revealed that it bound the premiR-711 promoter to upregulate miR-711. Bioinformatics analysis identified calnexin as a putative miR-711 target; this was confirmed by luciferase, western blot, and real-time polymerase chain reaction analyses. Additionally, the transfection of a miR-711 mimic into cardiomyocytes induced the endoplasmic reticulum (ER) stress-induced apoptosis response by upregulating glucose regulated protein 78 (GRP78), activating transcription factor (ATF6), spliced X box binding protein 1 (XBP1), apoptotic signal-regulating kinase 1 (ASK1), CCAAT enhancer binding protein homologous protein (CHOP), caspase-12, and endoplasmic reticulum oxidoreductase 1 alpha (ERO1a). Similarly, on day 2 after MI, increased miR-711 levels in the heart were accompanied by increased cardiomyocyte apoptosis, decreased calnexin levels, and increased levels of GRP78, ATF6, spliced XBP1, ASK1, CHOP, and caspase-12, as well as cardiomyocytes apoptosis. The mechanism underlying these effects may involve the direct binding of PPARgamma to the pre-miR-711 promoter for the upregulation of miR-711, which may induce ER stress-mediated cardiomyocyte apoptosis via calnexin. These findings augment the general knowledge of the post-MI pathological process and suggest a therapeutic strategy for cardiac remodelling in the early stages after MI. PMID- 29522764 TI - Does the use of hormonal contraceptives affect the mental rotation performance? AB - Oral contraceptive pill (OC) is one of the most popular form of contraception. Despite both behavioral and neuroimaging evidence of its significant impact on female brain and cognitive functions, much remains to be discovered regarding OCs targets in the brain and mechanisms of action. In the present study mental rotation performance was compared between women using anti-androgenic oral contraceptives (n = 35), naturally cycling (NC) women (n = 33) and men (n = 29). On average, OC users were less accurate than NC women and men. Men performed the task more accurately than NC women, but the difference reached significance only in the highest angular disparity condition (150 deg). The response time was positively related with progesterone level while accuracy was negatively related with 17beta-estradiol level, in NC, but not OC women. The comparison of slope and intercept values (parameters relating response time to angular disparity) revealed the main result of present study: OC users exhibited significantly lower slope compared to men and NC women, but there were no differences in intercept between groups. These results suggest that OC users instead of using rotation in mind strategy implemented some alternative method(s). We conclude that lower performance accuracy of OC users could be related to a less efficient performance strategy. PMID- 29522765 TI - The roles of microsporidia spore wall proteins in the spore wall formation and polar tube anchorage to spore wall during development and infection processes. AB - Microsporidia are highly specialized obligate intracellular, spore forming divergent fungi with a wide variety host range that includes most vertebrates and invertebrates. The resistant spores are surrounded by a rigid cell wall which consists of three layers: the electron-lucent chitin and protein inner endospore, the outer-electron-dense and mainly proteinaceous exospore and plasma membrane. Interestingly, microsporidia owns a special invasion organelle, called polar tube, coiled within the interior of the spore wall and attached to anchoring disk at the anterior end of spore. Spore wall and polar tube are the major apparatuses for mature spores adhering and infecting to the host cells. In this review, we summarize the research advances in spore wall proteins (SWPs) related to spore adherence and infection, and SWPs and deproteinated chitin spore coats (DCSCs) interaction associated with SWPs deposit processes and spore wall assembly. Furthermore, we highlight the SWPs-polar tube proteins (PTPs) interaction correlated to polar tube orderly orientation, arrangement and anchorage to anchoring disk. Based on results obtained, it is helpful to improve understanding of the spore wall assembly and polar tube orderly arrangement mechanisms and molecular pathogenesis of microsporidia infection. Also, such information will provide a basis for developing effective control strategies against microporidia. PMID- 29522766 TI - Multilocus characterization of Sarcocystis falcatula-related organisms isolated in Brazil supports genetic admixture of high diverse SAG alleles among the isolates. AB - In a previous study in Brazil, six isolates of Sarcocystis spp. recovered from budgerigars fed sporocysts excreted by opossums of the genus Didelphis were characterized by means of sequencing fragments of gene coding cytochrome B (CYTB), internal transcribed spacer 1 (ITS1), and surface antigen genes (SAG2, SAG3 and SAG4). The isolates shared identical ITS1 and CYTB sequences, but differed at SAG2, SAG3 and SAG4: three allele variants of SAG2, 3 allele variants of SAG3 and 2 allele variants of SAG4 were encountered in three multilocus genotypes (MLGs) (MLG1, MLG2, and MLG3). At ITS1 and CYTB, all the isolates from budgerigars were identical to the Sarcocystis falcatula-like isolate 59-2016-RS BR that was detected in a barefaced ibis (Phimosus infuscatus) causing necrotizing meningoencephalitis in Brazil. At ITS1 locus, all the above isolates were clearly distinct from Sarcocystis neurona, Sarcocystis falcatula, Sarcocystis lindsayi, and Sarcocystis speeri, the four known species of Sarcocystis that use opossums of the genus Didelphis as definitive hosts. Here, we replicated the experiment above to identify additional MLGs or other species of Sarcocystis. Fifteen budgerigars were experimentally infected with sporocysts of Sarcocystis spp. from 12 opossums of the genus Didelphis. All the birds died 9 19 days after infection and tissue samples containing merozoites and schizonts of Sarcocystis spp. were recovered. Fractions of sequences coding for 18S ribosomal RNA gene (18S), CYTB, ITS1, SAG2, SAG3 and SAG4 were PCR amplified and sequenced from the infected lungs. In addition, fractions of 18S, SAG2, SAG3 and SAG4 were sequenced from the isolate 59-2016-RS-BR and fractions of 18S were sequenced from the six isolates from budgerigars described above. From the results, all the isolates shared identical 18S, ITS1 and CYTB sequences. Among the 15 new isolates from budgerigars, three allele variants of SAG2, 3 allele variants of SAG3 and 2 allele variants of SAG4 were encountered in five MLGs, of which four were novel (MLG1, MLG4, MLG5, MLG6 and MLG7). Isolate 59-2016-RS-BR was assigned to an eighth MLG (MLG8). Molecular data pointed that Sarcocystis assigned to MLGs 1 to 8 are variants of the same species, but the SAG-based trees of the isolates conflicted, which supports genetic admixture among them. The sarcocystinae studied have high diversity of SAG alleles per locus and the correlation of such an abundant variety of SAG alleles to host specificity and pathogenicity needs to be assessed. Remains to be elucidated if the parasites studied here and S. falcatula are variants of the same species that have diverged to the point of possessing differences at ITS1 level, but that are still capable of exchanging genes. PMID- 29522767 TI - Akt modulation by miR-145 during exercise-induced VSMC phenotypic switching in hypertension. AB - AIMS: This study investigated whether long-term exercise can influence vascular smooth muscle cells (VSMCs) phenotypic switching in mesenteric arteries of hypertensive rats, with a focus on the modulation of protein kinase B (PKB/Akt) signaling by microRNA-145 (miR-145). MAIN METHODS: In the exercise intervention experiment, mesenteric arteries from 3-month-old spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were isolated for histological observation, phenotypic marker analysis, Akt phosphorylation quantification, and miR-145 evaluation after being subjected to moderate-intensity treadmill training (E) or being sedentary (C) for 8 weeks. In the transfection experiment, VSMCs were harvested to determine Akt phosphorylation and mRNA expressions of the upstream and downstream signaling molecules. KEY FINDINGS: Calponin, a VSMC contractile marker, was significantly up-regulated in SHR-E relative to SHR-C (P < 0.05); while osteopontin (OPN), a dedifferentiation marker, was down-regulated in SHR-E relative to SHR-C (P < 0.05). Exercise significantly normalized the expression of miR-145 and significantly enhanced Akt phosphorylation (P < 0.05). In VSMCs over expressing miR-145, Akt phosphorylation was significantly decreased (P < 0.05) with inhibited mRNA of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor substrate 1 (IRS-1). In VSMCs transfected with miR-145 inhibitor, Akt phosphorylation and mRNA of IGF-1R and IRS-1 were all down regulated. miR-145 did not exhibit a clear effect on p70 ribosomal kinase (p70S6K), the downstream of Akt, following the transfections. SIGNIFICANCE: Overall, exercise remodels arterioles in hypertension and induces VSMCs maintaining contractile phenotype, in which miR-145 appears to be involved by inversely regulating Akt signaling via its upstream signals. PMID- 29522768 TI - High intensity exercise preconditioning provides differential protection against brain injury following experimental stroke. AB - AIMS: Different modes of physical activity provide cerebrovascular protection against thromboembolic events. Based on recent reports high intensity exercise protocols appear to raise cerebral VEGF levels leading to efficient cerebral angiogenesis. The present study aims to address if moderate continuous training (MCT) and high intensity interval training (HIT) differ in preconditioning against ischemic stroke. METHODS: Wistar rats were subjected to HIT or MCT for 8 weeks before transient middle cerebral artery occlusion (tMCAO) surgery. As indexes for improved angiogenic signals, VEGF-A and its pivotal receptor VEGF-R2 were immunoblotted just before occlusive stroke. KEY FINDINGS: Both training protocols induced a remarkable protection against neurological deficit and tissue injury following stroke. Cerebral infarctions were better improved in HIT animals which explained the slightly but not significantly higher neurological function. HIT brains developed higher levels of cortical VEGF-A and striatal VEGF-R2. SIGNIFICANCE: These data conclude preconditioning with high intensity protocols might excel continued moderate exercise to induce VEGF signaling and alleviate stroke outcomes. Further investigations may provide complementary mechanistic views. PMID- 29522769 TI - N-Acetyl-l-Cysteine treatment efficiently prevented pre-diabetes and inflamed dysmetabolic liver development in hypothalamic obese rats. AB - AIM: Hypothalamic obese rats are characterized by pre-diabetes, dyslipidemia, hyperadiposity, inflammation and, liver dysmetabolism with oxidative stress (OS), among others. We studied endocrine-metabolic dysfunctions and, liver OS and inflammation in both monosodium l-glutamate (MSG)-neonatally damaged and control litter-mate (C) adult male rats, either chronically treated with N-Acetyl-l Cysteine since weaned (C-NAC and MSG-NAC) or not. METHODOLOGY: We evaluated circulating TBARS, glucose, insulin, triglycerides, uric acid (UA) and, aspartate and alanine amino-transferase; insulin sensitivity markers (HOMA indexes, Liver Index of Insulin Sensitivity -LISI-) were calculated and liver steps of the insulin-signaling pathway were investigated. Additionally, we monitored liver OS (protein carbonyl groups, GSH and iNOS level) and inflammation-related markers (COX-2 and TNFalpha protein content; gene expression level of Il1b, Tnfalpha and Pai-1); and carbohydrate and lipid metabolic functions (glucokinase/fructokinase activities and, mRNA levels of Srebp1c, Fas and Gpat). KEY FINDINGS: Chronic NAC treatment in MSG rats efficiently decreased the high circulating levels of triglycerides, UA, transaminases and TBARS, as well as peripheral (high insulinemia and HOMA indexes) and liver (LISI and the P-AKT:AKT and P-eNOS:eNOS protein ratio values) insulin-resistance. Moreover, NAC therapy in MSG rats prevented liver dysmetabolism by decreasing local levels of OS and inflammation markers. Finally, NAC-treated MSG rats retained normal liver glucokinase and fructokinase activities, and Srebp1c, Fas and Gpat (lipogenic genes) expression levels. SIGNIFICANCE: Our study strongly supports that chronic oral antioxidant therapy (NAC administration) prevented the development of pre-diabetes, dyslipidemia, and inflamed-dysmetabolic liver in hypothalamic obese rats by efficiently decreasing high endogenous OS. PMID- 29522770 TI - Therapeutic evaluation of solid lipid nanoparticle of quercetin in pentylenetetrazole induced cognitive impairment of zebrafish. AB - BACKGROUND: Quercetin is a major flavonoid in various plants. It possesses the multiple pharmacological actions like vascular integrity and regulatory action of the blood-brain barrier. AIMS: The present study is focused on evaluating the role of solid lipid nanoparticle of quercetin in pentylenetetrazole (PTZ) induced cognitive impairment of Danio rerio species. MAIN METHODS: The memory impairment of zebrafish was induced by exposing of PTZ in 7.5 mM solution. The pretreatment of solid lipid nanoparticle of quercetin (SLN-Q; 5 and 10 mg/kg) was administered by single intraperitoneal (i.p.) injection. The reference control i.e., donepezil (10 mg/kg) was administered by single intraperitoneal (i.p.) injection. The learning and memory levels were evaluated with different tests like light and dark chamber test; partition preference test; and three (horizontal) compartment tests. In addition, the PTZ induced biochemical changes such as acetylcholinesterase activity, lipid peroxidation, and reduced glutathione levels were assessed in the brain of zebrafish. KEY FINDINGS: The solid lipid nanoparticle of quercetin found to possess the attenuating effect in PTZ induced neurocognitive impairments along with amelioration of biochemical changes. This effect is similar to that of donepezil pretreated group. SIGNIFICANCE: Therefore, this solid lipid nanoparticle of quercetin can be used as future nanomedicine for various neurodegenerative disorders like Alzheimer and Parkinson disorders due to its potential anti-oxidative, anti-lipid peroxidative and acetylcholinesterase inhibitory actions. PMID- 29522771 TI - The contribution of chronic intermittent hypoxia to OSAHS: From the perspective of serum extracellular microvesicle proteins. AB - OBJECTIVE: Obstructive sleep apnea hypopnea syndrome (OSAHS) is an independent risk factor for many clinical complications. However, how OSAHS cause multiple organ injury and initiate inter-organ communication remains unclear. Moreover, despite it is well-recognized that chronic intermittent hypoxia (CIH) is a main feature of OSAHS, specific contribution of CIH to overall OSAHS-initiated pathological complications remains unclear. This study aimed to use an unbiased proteomic approach to determine whether OSAHS alters protein profiles of serum extracellular microvesicles (SEMVs) and how CIH contributes to such alterations. METHODS: Tandem mass tag (TMT)-labeled quantitative proteomics assay was used to compare the differentially expressed proteins (DEPs) in SEMVs of OSAHS patients and non-OSAHS subjects. To evaluate the contribution of CIH to OSAHS, CIH rodent model was constructed and the same comparative proteomics study was performed in SEMVs from CIH and normoxia rats. The similarity and disparity of DEPs and DEPs related functions predicted by bioinformatics tools were compared in above mentioned two models, and several DEPs were selected and further verified by ELISA or Western blotting. RESULTS: TMT-labeled quantitative proteomics assay unravels 32 DEPs in OSAHS patient SEMVs from a total of 560 human SEMV proteins identified. Four DEPs, namely C-reactive protein (CRP), Haptoglobin (HP),Fibronectin (FN1) and Platelet factor 4 (PF4), were further verified by ELISA and three of them (CRP, FN1 and Hp) showed significant difference in expression level between OSAHS and non-OSAHS groups. In SEMVs of rat CIH model, 121 DEPs out of 723 proteins were identified. By comparing the DEPs identified from the two models, 3 proteins (CRP and FN1 and F13a1) were found identical with the same alteration pattern (CRP was upregulated, FN1 and F13a1 were downregulated) in SEMVs from OSAHS patients and CIH rats, which were further verified by Western blotting. Computational functional analysis further revealed the common and distinct DEP-involved pathways under OSAHS or CIH status. CONCLUSIONS: This study provides the first evidence that OSAHS causes significant alteration in SEMV protein composition, which may contribute to OSAHS-triggered multiple organ injury and organ-to-organ communication. Moreover, we have demonstrated that CIH is the primary contributor for increased inflammatory protein expression in SEMV. As CRP is being increasingly recognized not only as a marker but also a mediator of inflammatory response to tissue injury, increased SEMV CRP in CIH/OSAHS may play an important role in OSAHS-induced tissue injury, suggesting SEMV CRP might be a therapeutic target against OSAHS-related complications. PMID- 29522772 TI - Impaired brain energy gain upon a glucose load in obesity. AB - BACKGROUND: There is evidence that the brain's energy status is lowered in obesity despite of chronic hypercaloric nutrition. The underlying mechanisms are unknown. We hypothesized that the brain of obese people does not appropriately generate energy in response to a hypercaloric supply. METHODS: Glucose was intravenously infused in 17 normal weights and 13 obese participants until blood glucose concentrations reached the postprandial levels of 7 mmol/L and 10 mmol/L. Changes in cerebral adenosine triphosphate (ATP) and phosphocreatine (PCr) content were measured by 31phosphorus magnetic resonance spectroscopy and stress hormonal measures regulating glucose homeostasis were monitored. Because vitamin C is crucial for a proper neuronal energy synthesis we determined circulating concentrations during the experimental testing. RESULTS: Cerebral high-energy phosphates were increased at blood glucose levels of 7 mmol/L in normal weights, which was completely missing in the obese. Brain energy content moderately raised only at blood glucose levels of 10 mmol/L in obese participants. Vitamin C concentrations generally correlated with the brain energy content at blood glucose concentrations of 7 mmol/L. CONCLUSIONS: Our data demonstrate an inefficient cerebral energy gain upon a glucose load in obese men, which may result from a dysfunctional glucose transport across the blood-brain barrier or a downregulated energy synthesis in mitochondrial oxidation processes. Our finding offers an explanation for the chronic neuroenergetic deficiency and respectively missing satiety perception in obesity. PMID- 29522773 TI - Effects of ovariectomy and exercise training intensity on energy substrate and hepatic lipid metabolism, and spontaneous physical activity in mice. AB - BACKGROUND: Menopause is associated with fatty liver, glucose dysregulation, increased body fat, and impaired bone quality. Previously, it was demonstrated that single sessions of high-intensity interval exercise (HIIE) are more effective than distance- and duration-matched continuous exercise (CE) on altering hepatic triglyceride (TG) metabolism and very-low density lipoprotein-TG (VLDL-TG) secretion. METHODS: Six weeks training using these modalities was examined for effects on hepatic TG metabolism/secretion, glucose tolerance, body composition, and bone mineral density (BMD) in ovariectomized (OVX) and sham operated (SHAM) mice. OVX and SHAM were assigned to distance- and duration matched CE and HIIE, or sedentary control. RESULTS: Energy expenditure during exercise was confirmed to be identical between CE and HIIE and both similarly reduced post-exercise absolute carbohydrate oxidation and spontaneous physical activity (SPA). OVX vs. SHAM displayed impaired glucose tolerance and greater body fat despite lower hepatic TG, and these outcomes were not affected by training. Only HIIE increased hepatic AMPK in OVX and SHAM, but neither training type impacted VLDL-TG secretion. As expected, BMD was lower in OVX, and training did not affect long bones. CONCLUSIONS: The results reveal intensity-dependent effects on hepatic AMPK expression and general exercise effects on subsequent SPA and substrate oxidation that is independent of estrogen status. These findings support the notion that HIIE can impact aspects of liver physiology in females while the effects of exercise on whole body substrate selection appear to be independent of training intensity. However, neither exercise approach mitigated the impairment in glucose tolerance and elevated body fat occurring in OVX mice. PMID- 29522774 TI - Fiber-based fluorescent microsphere immunoassay (FMIA) as a novel multiplex serodiagnostic tool for simultaneous detection and differentiation of all clinically relevant fowl adenovirus (FAdV) serotypes. AB - The recent emergence of fowl aviadenovirus (FAdV) induced disease outbreaks in chicken flocks worldwide, with distinct aetiologies confined to particular FAdV species and serotypes, is increasingly urging the need for specific and mass applicable antibody screening systems. Despite this exigency, there are to date no available serological procedures which satisfactorily combine the criteria for sensitive detection of antibodies against FAdVs, diagnostic reliability in face of cross-reactions and requirements for a rapid and large-scale application. In order to address this gap, a multiplexed fluorescent microsphere immunoassay (FMIA) based on recombinant FAdV fiber proteins from six different serotypes FAdV 1, -2, -4, -8a, -8b and -11 was developed, which enabled simultaneous detection of antibodies against all clinically relevant serotypes in a single reaction within a high throughput setting. Based on a panel of >300 monospecific antisera raised against each of the 12 FAdV serotypes, 100% serotype-specificity was demonstrated for FAdV-1 (FAdV-A) and FAdV-4 (FAdV-C) fiber-based analytes. Analytes based on serotypes affiliated to FAdV-D and FAdV-E exhibited moderately lower specificities of 91.2-95.7%. This was attributed almost exclusively to mutual recognition between FAdV-2 and -11 field strains and to a much lesser extent to reference strains, supporting earlier proposals to merge them into a single serotype. Similarly, extensive cross-reactions between FAdV-8a and -8b were noted. Altogether intraspecies cross-reactions can be attributed to viruses with a close etiological intersection. Antisera against other important avian viruses remained negative by the FMIA, further validating its specificity. Compared to the virus-neutralization (VN) test, FMIA and individual fiber-based enzyme-linked immunosorbent assays (ELISAs) were equally sensitive in the detection of sera against FAdV-2 and -11, as well as FAdV-8a and -8b field strains, while they were even superior to VN test in detection of FAdV-1 and FAdV 4 responses, likely attributed to a relative abundance of fiber antibodies early upon infection. Moreover, application of the FMIA on field samples comprising a diversified response against all 12 FAdV serotypes further consolidated its specificity and agreement with VN test. PMID- 29522775 TI - The influence of interferon-beta supplemented human dendritic cells on BCG immunogenicity. AB - INTRODUCTION: Tuberculosis (TB) remains a huge worldwide burden, despite extensive vaccination coverage with the Bacillus Calmette-Guerin (BCG), the only vaccine available against this disease, indicating that BCG-driven immunity is inadequate to protect the human population against TB. This underscore the critical necessitate to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection. AIM OF THE WORK: To examine whether the exogenous addition of IFN-beta could improve dendritic cell (DC) response to Mycobacterium bovis (M. bovis) and to evaluate the effect induced by the infection of human DCs with M. bovis (with and without IFN-beta) and Mycobacterium tuberculosis (Mtb) on DC viability as well as to compare the ability of BCG and Mtb to provide DCs with a Th1-polarizing capacity through the assessment of the immunoregulatory cytokines interleukin (IL)-12, IL-10 and interferon-gamma (IFN-gamma). METHODS: Immature DCs (iDCs) were generated in vitro using peripheral blood monocytes separated by anti-CD14-conjugated microbeads in the presence of granulocyte macrophage-colony-stimulating factor (GM-CSF) and IL-4, cultured cells were analyzed using flow cytometry, then we tested DC viability after inoculation with M. bovis (with and without IFN-beta pretreatment) and Mtb using light microscopic examination and trypan blue exclusion method. Additionally, supernatants from infected-DCs cultures were analyzed for IFN-gamma, IL-12 and IL-10 by ELISA. RESULTS: The viability of BCG-infected DCs was significantly higher than that of Mtb-infected DCs (61.55% vs 52.10%). BCG-infected DC produced significantly more IL-12 (p = 0.02) and less IL-10 (p = 0.01) compared with Mtb-infected cells. IFN beta-pretreated BCG-infected DCs produced significantly larger amounts of IL-12 than did BCG-infected DCs (p = 0.03) and Mtb-infected cells (p < 0.001). CONCLUSION: IFN-beta improves DC functions following BCG infection, thus assuming that IFN-beta could be used as a vaccine adjuvant. PMID- 29522776 TI - A new background subtraction method for Western blot densitometry band quantification through image analysis software. AB - Since its first description, Western blot has been widely used in molecular labs. It constitutes a multistep method that allows the detection and/or quantification of proteins from simple to complex protein mixtures. Western blot quantification method constitutes a critical step in order to obtain accurate and reproducible results. Due to the technical knowledge required for densitometry analysis together with the resources availability, standard office scanners are often used for the imaging acquisition of developed Western blot films. Furthermore, the use of semi-quantitative software as ImageJ (Java-based image-processing and analysis software) is clearly increasing in different scientific fields. In this work, we describe the use of office scanner coupled with the ImageJ software together with a new image background subtraction method for accurate Western blot quantification. The proposed method represents an affordable, accurate and reproducible approximation that could be used in the presence of limited resources availability. PMID- 29522777 TI - Validation of an immunoturbidimetric assay for assessment of C reactive protein in synovial fluid. PMID- 29522778 TI - Amelioration by nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer's disease in rats. AB - The present study evaluated the effects of s-nitrosoglutathione (GSNO), a nitrosothiol and sustained NO releaser, on experimental model of sporadic Alzheimer's disease (sAD) in rats. Levels of Abeta40, Abeta42 and BDNF were assessed in brain hippocampal homogenates for correlative purposes. Intracerebroventricular-Streptozotocin (icv-STZ) induced increased escape latencies (acquisition) and reduced time in target quadrant (probe trial) in Morris Water Maze (MWM) test at 3 months post icv-STZ administration. These behavioural changes were associated with increased Abeta depositions and lowered BDNF levels in brain hippocampal homogenates. Pre-treatment with GSNO (50 MUg/kg/day), reduced the icv-STZ induced cognitive deficits in acquisition and probe trials in the MWM. The icv-STZ induced elevations in Abeta40 and Abeta42 and reduced levels of BDNF in hippocampal homogenates were also attenuated after GSNO treatment in these rats. The NO-precursor, l-arginine (100 mg/kg) induced similar effects on behavioural and biochemical parameters tested but was marginally less consistent as compared to those seen with GSNO. The results suggest that GSNO ameliorates the cognitive deficits and associated brain biochemical changes in this experimental model of sporadic AD, and NO-BDNF interactions could play crucial role in these effects. PMID- 29522779 TI - No meditation-related changes in the auditory N1 during first-time meditation. AB - Recent studies link meditation expertise with enhanced low-level attention, measured through auditory event-related potentials (ERPs). In this study, we tested the reliability and validity of a recent finding that the N1 ERP in first time meditators is smaller during meditation than non-meditation - an effect not present in long-term meditators. In the first experiment, we replicated the finding in first-time meditators. In two subsequent experiments, we discovered that this finding was not due to stimulus-related instructions, but was explained by an effect of the order of conditions. Extended exposure to the same tones has been linked with N1 decrement in other studies, and may explain N1 decrement across our two conditions. We give examples of existing meditation and ERP studies that may include similar condition order effects. The role of condition order among first-time meditators in this study indicates the importance of counterbalancing meditation and non-mediation conditions in meditation studies that use event-related potentials. PMID- 29522780 TI - Response of zebrafish larvae to mild electrical stimuli: A 96-well setup for behavioural screening. AB - BACKGROUND: Zebrafish larvae have a high potential as model system to replace rodents, especially in screening and drug discovery applications. However, an experimental setup to deliver mild electrical stimuli with simultaneous high throughput behavioural tracking has not yet been described. NEW METHOD: A new tool was designed, making the delivery of electrical stimuli in a 96-well plate format possible. Using custom made electrode clips that can be slid over the walls of a square 96-well plate, 80 larvae could be tested simultaneously and behavioural responses recorded. RESULTS: As proof of principle, two applications were tested: 1) The behavioural response after a single stimulus and the effect of buprenorphine on this response. 2) Habituation of locomotor activity to multiple stimuli and the involvement of the NMDA receptor. Reduced locomotor activity was observed after a single 5 V stimulus, however not with lower intensity stimuli. Pre-treatment with the analgesic buprenorphine prevented this response. Specificity of buprenorphine was confirmed using the antagonist naloxone. Habituation of locomotor activity was seen in response to multiple stimuli, depending on the inter stimulus interval. Treatment with the NMDA receptor antagonist memantine disrupted behavioural habituation. COMPARISON WITH EXISTING METHODS: The equipment and setup described here are the first of its kind using a 96-well plate format, thereby increasing the potential throughput in screening applications using zebrafish larvae. CONCLUSION: The combination of the described electrode clips for stimulus delivery and behavioural tracking allows for the use of zebrafish larvae in a new array of medium to high throughput applications. PMID- 29522781 TI - Extraction of corticospinal tract microstructural properties in chronic stroke. AB - BACKGROUND: Information about the structural integrity of the corticospinal tract (CST) from diffusion-weighted imaging can improve our ability to understand motor outcomes in people with upper limb impairment after stroke, especially those with severe impairment. Yet, there is no consensus on which method of CST generation most accurately represents function and impairment in individuals with chronic stroke. NEW METHOD: The aim of the study was to compare different methods of CST reconstruction and resulting microstructural properties, as well as the relationship between these properties and motor function and impairment. Fifteen individuals with mild-moderate impairment and 15 with severe impairment who were in the chronic phase post-stroke underwent a diffusion-weighted imaging scan and motor function and impairment assessments. RESULTS: Different relationships existed between reconstruction methods, microstructural properties, and impairment and function. In severe stroke, fractional anisotropy (FA) emerged over and above apparent diffusion coefficient (ADC) and tract number to index CST integrity; FA correlated with impairment and function, whereas ADC and tract number did not correlate. No significant differences between methods or microstructural properties were found in mild-moderate stroke. COMPARISON WITH EXISTING METHODS: Our study demonstrates that CST reconstruction method influences the extraction of microstructural integrity in individuals with chronic severe stroke, with FA appearing to be the most representative method. A similar line of investigation is warranted earlier post-stroke. CONCLUSION: Differences in this data set highlight the need to establish a common methodology for CST reconstruction and analysis which may eliminate discrepancies in interpreting DWI and enhance biomarker use post-stroke for motor function. PMID- 29522782 TI - Cortical stimulation in conscious rats controls joint inflammation. AB - The neuronal control of the immune system is fundamental to the development of new therapeutic strategies for inflammatory disorders. Recent studies reported that afferent vagal stimulation attenuates peripheral inflammation by activating specific sympathetic central and peripheral networks, but only few subcortical brain areas were investigated. In the present study, we report that afferent vagal stimulation also activates specific cortical areas, as the parietal and cingulate cortex. Since these cortical structures innervate sympathetic-related areas, we investigate whether electrical stimulation of parietal cortex can attenuate knee joint inflammation in non-anesthetized rats. Our results show that cortical stimulation in rats increased sympathetic activity and improved joint inflammatory parameters, such as local neutrophil infiltration and pro inflammatory cytokine levels, without causing behavioral disturbance, brain epileptiform activity or neural damage. In addition, we superposed the areas activated by afferent vagal or cortical stimulation to map common central structures to depict a brain immunological homunculus that can allow novel therapeutic approaches against inflammatory joint diseases, such as rheumatoid arthritis. PMID- 29522783 TI - Optical measurement of glutamate in slice preparations of the mouse retina. AB - Signaling by glutamatergic synapses plays an important role in visual processing in the retina. In this study, we used an enzyme-linked fluorescence assay system to monitor the dynamics of extracellular glutamate in a slice preparation from the mouse retina. High K stimulation induced an elevation of fluorescence in the inner plexiform layer (IPL) of the retina when glutamate transporters were inhibited by dl-threo-beta-benzyloxyaspartic acid (TBOA). The high K-induced fluorescence signals in the IPL were inhibited by the calcium channel blocker Cd2+. Blockade of GABAergic and glycinergic circuits by picrotoxin and strychnine also elevated the fluorescence signals in the IPL. Thus, the enzyme-linked fluorescence assay system might be useful for monitoring the bulk concentration of extracellular glutamate released by synapses in the inner retina. PMID- 29522784 TI - Multi-hospital point prevalence study of healthcare-associated infections in 28 adult intensive care units in Brazil. AB - BACKGROUND: Healthcare-associated infection (HAI) represents a major problem for patient safety worldwide. AIM: To provide an up-to-date picture of the extent, aetiology, risk factors and patterns of infections in intensive care units (ICUs) in 28 Brazilian hospitals of different sizes. METHODS: A one-day point prevalence survey in 2016 enrolled the ICUs of hospitals from the 12 meso-regions in Minas Gerais state, south-east Brazil. Hospitals were classified as university or non university hospitals. All patients with >48 h of admission to the study ICUs at the time of the survey were included. FINDINGS: In total, 303 patients were studied; of these, 155 (51.2%) were infected and 123 (79.4%) had at least one ICU acquired infection. The most common ICU-acquired infections were pneumonia (53.0%) and bloodstream infection (27.6%). One hundred and nineteen bacterial isolates were cultured; the most common were Acinetobacter baumannii (27.1%), Pseudomonas aeruginosa (27.1%) and Staphylococcus aureus (39.0%). According to type of infection, the most common pathogens were P. aeruginosa (30.4%) in pneumonia, coagulase-negative staphylococci (23.4%) and Enterobacteriaceae (23.4%) in bloodstream infections, and Enterobacteriaceae (47.6%) in urinary tract infections. CONCLUSION: This study found that the overall prevalence of ICU acquired infections in surveyed Brazilian hospitals was higher than that reported in most European countries and the USA. A greater proportion of infections were caused by non-fermenting Gram-negative bacteria. These observations, along with a high rate of antimicrobial use, illustrate the urgent need for HAIs to be a priority in the public health agenda of Brazil. PMID- 29522785 TI - Vitamin D3 inhibits the proliferation of T helper cells, downregulate CD4+ T cell cytokines and upregulate inhibitory markers. AB - 1 alpha, 25-dihydroxyvitamin D3 (VitD3) has been suggested to have strong modulatory properties in the immune system. Researchers in the present study primarily aimed to understand the effect of VitD3 on human CD4+ T cell proliferation in antigen presenting cells (APCs) free condition in vitro. The effect of VitD3 on intracellular cytokine responses trend to Th1, Th2, Th17 and Th22 was evaluated using the flow cytometry. Moreover the effect of VitD3 on the expression of inhibitory markers such as PD1, PD-L1, and CTLA4 which are induced upon polyclonal T cell receptor (TCR) activation on CD4+ T cells, was assessed. We observed that the stimulation of CD4+ T cells with VitD3, suppressed proliferation capacity, enhanced the expression of PD1, PD-L1 and CTLA4 inhibitory markers on CD4+ T cells, and diminished the percentage of pro inflammatory cytokines including, IFN-gamma, IL-17, and IL-22 except IL-4 in CD4+ T cells. The data suggested a potential insight into the consideration of VitD3 in the prevention/control of pro-inflammatory immune response/autoimmune disorders. PMID- 29522786 TI - Pavlovian-to-instrumental transfer: A new paradigm to assess pathological mechanisms with regard to the use of Internet applications. AB - At present, there is a considerable lack of human studies that investigated the impact of conditioned cues on instrumental responding although these processes are considered as core mechanisms contributing to the development and maintenance of addictive behaviours. No studies are available that assessed these processes with regard to Internet gaming or Internet shopping applications. We thus developed a Pavlovian-to-instrumental transfer (PIT)-Paradigm implementing appetitive stimuli related to Internet gaming and Internet shopping applications and investigated whether an outcome-specific PIT-Effect is observed. In addition, we assessed whether the problematic use of gaming or shopping applications, personality traits and stress would affect the acquisition of knowledge of the experimental contingencies during Pavlovian training and the impact of conditioned stimuli on instrumental responding. A PIT-Paradigm, screenings for Internet gaming disorder and Internet shopping disorder (s-IAT), and questionnaires on personality traits (NEO-FFI, BIS-15) and perceived stress (PSQ20) were administered to sixty-six participants. The PIT-Paradigm demonstrated the effects of stimuli conditioned to rewards related to Internet gaming and Internet shopping applications on instrumental responding to obtain such rewards. Findings also indicated that severity of problematic Internet gaming, but not Internet shopping, contributed to the acquisition of knowledge of the experimental contingencies. Stress, extraversion, neuroticism and gender emerged as further predictors. The strength of expectancy of the different reinforcers affected the 'gaming PIT'-Effect; however, none of the variables assessed in the present study showed any effect on the 'shopping PIT'-Effect. Future studies including participants with pathological use patterns that can be classified as internet use disorder are warranted to extend these findings. PMID- 29522787 TI - An update on the reasons for placement and replacement of direct restorations. AB - AIM: The aim of this study was to review patterns of restoration placement and replacement. A previous study had been carried out in the late 1990s and this study sought to update the literature in this important aspect of dental practice. METHOD: Studies based on the protocol of Mjor (1981) were selected. Such studies involved participating dentists completing a proforma each time a patient presented for a new or replacement restoration. RESULTS: Twenty-five papers were included in this study, of which 12 were included in the original review. The pre-1998 review reported on the placement of 32,697 restorations, of which 14,391 (44%) were initial placements and 18,306 (56%) were replacements. The new studies included in the post-1998 review reported on an additional 54,023 restorations, of which 22,625 (41.9%) were initial placements and 31,398 (58.1%) were replacements. Therefore, across all studies considered, information is available on 86,720 restorations, of which 37,016 (42.7%) were new placements and 49,704 (57.3%) were replacements. Comparing review periods, there was a reduction in the placement of amalgam restorations from 56.7% (pre-1998 review) to 31.2% (post-1998 review), with a corresponding increase in the placement of resin composites from 36.7% to 48.5%. The most common use of amalgam was seen in Nigeria (71% of restorations), Jordan (59% of restorations) and the UK (47% of restorations). The most frequent use of resin composite was seen in Australia (55% of restorations), Iceland (53% of restorations) and Scandinavia (52% of restorations). Secondary caries was the most common reason for replacing restorations (up to 59% of replacement restorations). CONCLUSION: In the years subsequent to the initial review, replacement of restorations still accounts for more than half of restorations placed by dentists, and the proportion of replacement restorations continues to increase. Trends towards the increased use of resin composites is noted in recent years. CLINICAL SIGNIFICANCE: Further research is required in this area to investigate changes in the approaches to the restoration of teeth, especially with increased understanding of the concept of restoration repair as an alternate to replacement. PMID- 29522788 TI - Urinary afamin levels are associated with the progression of diabetic nephropathy. AB - AIMS: In this study, we applied quantitative proteomic analysis to identify urinary proteins associated with diabetic nephropathy (DN). METHODS: Two dimensional image-converted analysis of liquid chromatography and mass spectrometry detected the proteins differentially excreted between normoalbuminuric and macroalbuminuric patients with type 2 diabetes mellitus (T2DM) (n = 6 each). Urinary levels of excreted proteins were measured by multiple reaction monitoring (MRM) analysis using an independent sample set (n = 77). Urinary afamin levels were measured by ELISA in T2DM and DN patients enrolled in this cohort study (n = 203). RESULTS: One-hundred-four proteins displayed significant alterations in excretion. Nine of these candidates were validated by MRM analysis. Among them, the levels of afamin, CD44 antigen, and lysosome-associated membrane glycoprotein 2, which have not previously been implicated in DN, were significantly associated with both the urinary albumin to creatinine ratio (ACR) and eGFR. We further measured afamin levels in urine collected from T2DM patients who did not yet have significant kidney disease (ACR < 300 mg/g or eGFR change rate <= 3.3%/year). The urinary afamin to creatinine ratio (Afa/Cre) was significantly higher in patients who progressed to a more severe DN stage or had early renal decline than in patients who did not. CONCLUSIONS: Afa/Cre was significantly increased in T2DM patients who subsequently developed DN. Afa/Cre may be useful to predict patients with T2DM at high risk of nephropathy before the development of macroalbuminuria or reduced kidney function, although further validation studies in a larger population are needed. PMID- 29522789 TI - Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: A systematic review and meta-analysis. AB - Nutrition therapy is considered a key component of diabetes management, yet evidence around the ideal macronutrient composition of the diet remains inconclusive. A systematic review and meta-analysis was performed to assess the effects of carbohydrate-restricted diets (<=45% of total energy) compared to high carbohydrate diets (>45% of total energy) on glycemic control in adults with diabetes mellitus. Six databases were searched for articles published between January 1980 and August 2016. Primary outcome was between-group difference in HbA1c change. Individual effect sizes were standardized, and a meta-analysis performed to calculate pooled effect size using random effects. 25 RCTs involving 2412 participants were included. Carbohydrate-restricted diets, in particular those that restrict carbohydrate to <26% of total energy, produced greater reductions in HbA1c at 3 months (WMD -0.47%, 95% CI: -0.71, -0.23) and 6 months (WMD -0.36%, 95% CI: -0.62, -0.09), with no significant difference at 12 or 24 months. There was no difference between moderately restricted (26-45% of total energy) and high carbohydrate diets at any time point. Although there are issues with the quality of the evidence, this review suggests that carbohydrate restricted diets could be offered to people living with diabetes as part of an individualised management plan. PMID- 29522791 TI - A literature scoping review of eating practices and food environments in 1 and 2 person households in the UK, Australia and USA. AB - The purpose of this article is to map the data currently available on the subject of eating practices and food environments in small (i.e. one- and two-person) households. Specifically, the enquiry is focused on commensality; the act of eating together. Research dates from the late 1980s, however, there are few recent publications on this subject. Searching Ovid MEDLINE, PsycINFO, CINAHL, Web of Science, Scopus, ProQuest and Google Scholar, 2949 papers were found, but only 457 discussed any element of the research questions. These were further distilled to a count of 117, by abstract reading to 53 at which point, quality, location and study focus eliminated a further 34 articles leaving 19 articles. After full reading, it was clear that only seven of these focused on the research question in detail and these are marked as four-star articles by bold text. The 19 articles are analysed for quality and their aspects of relevance to the central research question is discussed. PMID- 29522790 TI - Thrombopoietin (TPO) induces thrombocytic colony formation of kidney cells synergistically with kit ligand A and a non-secretory TPO variant exists in common carp. AB - The development of mammalian megakaryocytes and platelets is regulated by numerous cytokine signals, primarily through the thrombopoietin (TPO)/c-MPL axis. Although non-mammalian vertebrates are known to possess nucleated thrombocytes functionally equivalent to mammalian platelets, the dynamics of the thrombocyte development remains unclear. Here we identified TPO and a splice variant (TPO-v) caused by the intron retention in common carp (Cyprinus carpio). Both the tpo and its variant transcripts were highly expressed in heart and liver. Recombinant carp TPO (rcTPO) was produced and purified in HEK293T cells stably expressing tpo, but TPO-v was shown not to be secreted from the transfectants. rcTPO induced the formation of colony-forming unit-thrombocyte (CFU-T) colonies which were recognized by a monoclonal antibody against carp thrombocytes expressing c-mpl and cd41, in a dose-dependent manner. The combination of rcTPO and recombinant carp Kit ligand A (rcKITLA) exerted a significant synergistic effect on three types of colony formation: thrombocytic colonies, thrombocytic burst colonies and thrombocytic/erythroid colonies. Utilizing this colony assay to examine the distribution of thrombocytic progenitor cells in carp, we demonstrated that carp head and trunk kidney play a primary role in thrombopoiesis, while the spleen does not. Our results indicate that carp possess mechanisms of TPO- and KITLA dependent thrombopoiesis similar to those in other vertebrates and the sites of thrombopoiesis are restricted to the kidney, the primary hematopoietic organ in the teleost fish. PMID- 29522792 TI - Differences in statin associated neuroprotection corresponds with either decreased production of IL-1beta or TNF-alpha in an in vitro model of neuroinflammation-induced neurodegeneration. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins' CNS effects have been reported clinically, few studies to date have compared multiple statins' neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0-100 MUM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration. To achieve this, HAPI microglia were treated with LPS (0.1 MUg/mL; 24 h), resulting in increased reactive oxygen species (ROS), nitric oxide, and IL-1beta, TNF-alpha and PGE2 release. Conditioned media ("HAPI-CM") was then transferred to SH-SY5Y neuroblastoma cells, and effects on cellular viability, mitochondrial membrane permeability, apoptosis, autophagy and ROS production assessed. Of the statins investigated, only atorvastatin, pravastatin and rosuvastatin protected SH-SY5Y cells from LPS-induced decreases in cellular viability; this appeared mediated through reduced caspase 3/7 activation and was associated with decreased IL-1beta (atorvastatin, pravastatin) and/or TNF-alpha (atorvastatin, pravastatin, rosuvastatin). Only pravastatin conferred protection at all tested concentrations. ROS production and autophagic vacuole formation was decreased by all statins, suggesting these two mechanisms are unlikely to be sole mediators of neuroprotection seen with selected statins. Ultimately, our model suggests that despite all statins reducing microglial inflammation, subsequent effects on neuronal viability and cell death signalling pathways varies between statins. Our findings highlight the need to consider individual statins as inducing discrete pharmacological effects within the CNS in future in vitro/in vivo studies and in clinical practice. PMID- 29522793 TI - Botulinum toxin type A affects the transcriptome of cell cultures derived from muscle biopsies of controls and spastic patients. AB - Botulin toxin (BTX) is widely used for treating skeletal muscle spasticity. Experimental reports on BTX treatment were mainly focused on the neuromuscular junction, while relatively little is known about toxin effects on the muscle cell itself. We investigated possible impact of BTX type A on skeletal muscle cell transcriptome by microarray analysis in muscle-derived cell cultures (fibroblasts, myoblasts and myotubes) from controls and spastic patients, and results were then validated at transcript and protein level. BTX-A treatment of control cells induced major changes in the myogenic component of the transcriptome, whereas the same treatment had a negligible effect in the fibrogenic component. BTX-A treatment of cell cultures from spastic patients induced an increased number of genes differentially expressed both in the fibrogenic and myogenic components. Specifically, BTX-A had a major effect on cell cycle-related genes in myoblasts, on muscle contraction-related genes in myotubes, and on extracellular matrix-related genes in fibroblasts from spastic patients. Our findings show that in vitro BTX-A treatment differentially affects transcript expression in muscle cells from spastic patients compared to those from controls suggesting a direct effect of BTX-A on muscle-specific functional pathways. PMID- 29522794 TI - Selenium and GPX4, a vital symbiosis. AB - Selenium has transitioned from an environmental poison and carcinogen to an essential micronutrient associated with a broad array of health promoting effects. These beneficial effects are now accepted to be linked to its incorporation into selenoproteins, a family of rare proteins utilizing a specialized translation machinery to integrate selenium in the form of selenocysteine. Despite this recognized role, much less is known regarding the actual role of selenium in these proteins. Here, we will provide the reader with an overview of the essential role of specific selenoproteins and their link to pathology based on mouse studies and relevant mutations discovered in humans. Additionally, we will cover recent insights linking a non-interchangeable role for selenium in glutathione peroxidase 4 and its function in suppressing ferroptosis. This critical dependency ultimately generates a strong reliance on metabolic pathways that regulate selenium metabolism and its incorporation into proteins, such as the mevalonate pathway. PMID- 29522796 TI - Measuring advertising effectiveness in Travel 2.0 websites through eye-tracking technology. AB - The advent of Web 2.0 is changing tourists' behaviors, prompting them to take on a more active role in preparing their travel plans. It is also leading tourism companies to have to adapt their marketing strategies to different online social media. The present study analyzes advertising effectiveness in social media in terms of customers' visual attention and self-reported memory (recall). Data were collected through a within-subjects and between-groups design based on eye tracking technology, followed by a self-administered questionnaire. Participants were instructed to visit three Travel 2.0 websites (T2W), including a hotel's blog, social network profile (Facebook), and virtual community profile (Tripadvisor). Overall, the results revealed greater advertising effectiveness in the case of the hotel social network; and visual attention measures based on eye tracking data differed from measures of self-reported recall. Visual attention to the ad banner was paid at a low level of awareness, which explains why the associations with the ad did not activate its subsequent recall. The paper offers a pioneering attempt in the application of eye-tracking technology, and examines the possible impact of visual marketing stimuli on user T2W-related behavior. The practical implications identified in this research, along with its limitations and future research opportunities, are of interest both for further theoretical development and practical application. PMID- 29522795 TI - Associations of nocturnal sleep with experimental pain and pain catastrophizing in healthy volunteers. AB - Strong alterations of night sleep (e.g., sleep deprivation, insomnia) have appeared to affect pain in inducing hyperalgesic changes. However, it has remained unclear whether everyday variations of night sleep in healthy individuals have any influence on pain processing. Forty healthy subjects were studied by portable polysomnography (PSG) and sleep questionnaire during two non consecutive nights at home. Experimental pain parameters (pressure pain threshold, temporal summation = TS, conditioned pain modulation = CPM) and situational pain catastrophizing (Situational Catastrophizing Questionnaire = SCQ) were always assessed the evening before and the morning after sleep recording in a pain laboratory. Linear regression analyses were computed to test the prediction of overnight changes in pain by different sleep parameters. Significant prediction of changes in pain parameters by sleep parameters was limited (2 out of 12 analyses), indicating that everyday variations in sleep under non-pathological and low stress conditions are only weakly associated with pain. PMID- 29522797 TI - Effect of bolus volume and flow time on temporospatial coordination in oropharyngeal pressure production in healthy subjects. AB - The effects of bolus volume and flow time on the sequential coordination of tongue pressure (TP) and pharyngeal pressure (PP), which are important in the biomechanics of swallowing, are unclear. In this study, we measured TP and PP simultaneously in 10 healthy adults at multiple points during dry swallowing and the swallowing of 5 ml and 15 ml of liquids with different viscosities, and investigated changes in the timing of the onset, peak, and offset of these pressures. TP was measured using a sensor sheet system with five measuring points on the hard palate, and PP was measured using a manometry catheter with four measuring points. The order and correlations of sequential events, such as onset, peak, and offset times of pressure production, at each pressure measuring point were analyzed on the synchronized waveforms. We found that the differences between the TP and PP onset times decreased when the bolus volume was larger. The change in bolus volume had very little effect on peak time or offset time. The flow time of the bolus affected the appearance of onset and peak time for both TP and PP. A time difference between TP and PP emerged as the flow time increased, with TP starting to appear before PP. This may be the first detailed analysis of pressure-flow dynamics that treats the mouth and pharynx as a single functional unit. We believe that our analysis is an important step toward extending future research to include a wider range of age groups and dysphagia patients. PMID- 29522798 TI - Maternal and developmental toxicity of the hallucinogenic plant-based beverage ayahuasca in rats. AB - Rats were treated orally with ayahuasca (AYA) on gestation days (GD) 6-20 at doses corresponding to one-(1X) to eight-fold (8X) the average dose taken by a human adult in a religious ritual, and the pregnancy outcome evaluated on GD21. Rats treated with 4X and 8X doses died during the treatment period (44 and 52%), and those that survived showed kidney injury. Rats surviving the 8X dose showed neuronal loss in hippocampal regions and in the raphe nuclei, and those from the 2X dose neuronal loss in CA1. Delayed intrauterine growth, induced embryo deaths and increased occurrence of foetal anomalies were observed at the 8X dose. At non lethal doses, AYA enhanced embryolethality and the incidence of foetal soft tissue and skeleton anomalies. This study suggested that AYA is developmentally toxic and that its daily use by pregnant women may pose risks for the conceptus. PMID- 29522799 TI - Bioinformatical analysis and prediction of Nicotiana benthamiana bHLH transcription factors in Phytophthora parasitica resistance. AB - The basic helix-loop-helix (bHLH) family, one of the largest transcription factor groups in plants, regulates many critical developmental processes. However, their functions in plant defense have not been extensively studied in Nicotiana benthamiana, an important model plant species for phytopathology. Here, we identified N. benthamiana bHLH genes (NbbHLHs) using a whole-genome searching approach, and found that the NbbHLHs are highly enriched and some subfamilies are selectively expanded in N. benthamiana. The results showed that gene duplication may be responsible for bHLH family expansion in this plant. Furthermore, we analyzed their expression profiles upon infection with Phytophthora parasitica. Finally, 28 candidate NbbHLHs may play important roles in Phytophthora pathogen resistance using cis-element analysis and protein-interaction network prediction. Taken together, our results established a platform for future studies of the gene family and provide molecular insights into plant immune responses against P. parasitica. PMID- 29522800 TI - Genome-wide identification and comprehensive analysis of Excretory/Secretory proteins in nematodes provide potential drug targets for parasite control. AB - Nematodes are responsible for causing severe diseases in plants, humans and other animals. Infection is associated with the release of Excretory/Secretory (ES) proteins into host cytoplasm and interference with the host immune system which make them attractive targets for therapeutic use. The identification of ES proteins through bioinformatics approaches is cost- and time-effective and could be used for screening of potential targets for parasitic diseases for further experimental studies. Here, we identified and functionally annotated 93,949 ES proteins, in the genome of 73 nematodes using integration of various bioinformatics tools. 30.6% of ES proteins were found to be supported at RNA level. The predicted ES proteins, annotated by Gene Ontology terms, domains, metabolic pathways, proteases and enzyme class analysis were enriched in molecular functions of proteases, protease inhibitors, c-type lectin and hydrolases which are strongly associated with typical functions of ES proteins. We identified a total of 452 ES proteins from human and plant parasitic nematodes, homologues to DrugBank-approved targets and C. elegans RNA interference phenotype genes which could represent potential targets for parasite control and provide valuable resource for further experimental studies to understand host-pathogen interactions. PMID- 29522801 TI - Spectrum structures and biological functions of 8-mers in the human genome. AB - The spectra of k-mer frequencies can reveal the structures and evolution of genome sequences. We confirmed that the trimodal spectrum of 8-mers in human genome sequences is distinguished only by CG2, CG1 and CG0 8-mer sets, containing 2,1 or 0 CpG, respectively. This phenomenon is called independent selection law. The three types of CG 8-mers were considered as different functional elements. We conjectured that (1) nucleosome binding motifs are mainly characterized by CG1 8 mers and (2) the core structural units of CpG island sequences are predominantly characterized by CG2 8-mers. To validate our conjectures, nucleosome occupied sequences and CGI sequences were extracted, then the sequence parameters were constructed through the information of the three CG 8-mer sets respectively. ROC analysis showed that CG1 8-mers are more preference in nucleosome occupied segments (AUC > 0.7) and CG2 8-mers are more preference in CGI sequences (AUC > 0.99). This validates our conjecture in principle. PMID- 29522802 TI - Identification of a conserved linear B-cell epitope in the Staphylococcus aureus GapC protein. AB - The GapC protein of Staphylococcus aureus (S. aureus) is a surface protein that is highly conserved among Staphylococcus strains, and it can induce protective humoral immune responses. However, B-cell epitopes in S. aureus GapC have not been reported. In this study, we generated a monoclonal antibody (mAb2A9) targeting S. aureus GapC. Through a passive immunity test, mAb2A9 was shown to partially protect mice against S. aureus infection. We screened the motif 236PVATGSLTE243 that is recognized by mAb2A9 using a phage-display system. The motif sequence exactly matched amino acids 236-243 of the S. aureus GapC protein. Then, we identified the key amino acids in the motif using site-directed mutagenesis. Site-directed mutagenesis revealed that residues P236, G240, L242, and T243 formed the core of the 236PVATGSLT243 motif. In addition, this epitope was proven to be located on the surface of S. aureus, and it induced a protective humoral immune response against S. aureus infection in immunized mice. Overall, our results characterized a conserved B-cell epitope, which will be an attractive target for designing effective epitope-based vaccines against S. aureus infection. PMID- 29522803 TI - Assessment of the antibiofilm and antiquorum sensing activities of Eucalyptus globulus essential oil and its main component 1,8-cineole against methicillin resistant Staphylococcus aureus strains. AB - Antibacterial resistance is an increasingly serious threat to global public health. The search for new anti-infection agents from natural resources, with different mode of actions and competitive effects became a necessity. In this study, twenty height methicillin-resistant Staphylococcus aureus (MRSA) strains were investigated for their biofilm formation ability. Subsequently, the antibiofilm effects of Eucalyptus globulus essential oil and its main component 1,8-cineole, against MRSA, as well as their antiquorum sensing potential, were evaluated. Our results displayed the potent efficacy of both E. globulus essential oil and 1,8-cineole against the development of biofilms formed by the methicillin-resistant strains. Additionally, E. globulus essential oil showed more potent of anti-QS activity, even at a low concentration, when compared to 1,8-cineole. All these property of tested agents may pave the way to prevent the development of biofilm formation by MRSA and subsequently the spreading of nosocomial infection. PMID- 29522804 TI - Molecular Dynamics simulations of the Strings and Binders Switch model of chromatin. AB - In recent years interest has grown on the applications of polymer physics to model chromatin folding in order to try to make sense of the complexity of experimental data emerging from new technologies such as Hi-C or GAM, in a principled way. Here we review the methods employed to efficiently implement Molecular Dynamics computer simulations of polymer models, focusing in particular on the String&Binders Switch (SBS) model. The constant improvement of such methods and computer power is returning increasingly more accurate insights on the structure and molecular mechanisms underlying the spatial organization of chromosomes in the cell nucleus. We aim to provide an account of the state of the art of computational techniques employed in this type of investigations and to review recent applications of such methods to the description of real genomic loci, such as the Sox9 locus in mESC. PMID- 29522806 TI - Pattern recognition receptors in fungal immunity. AB - Over the last decade, invasive fungal infections have emerged as a growing threat to human health worldwide and novel treatment strategies are urgently needed. In this context, investigations into host-pathogen interactions represent an important and promising field of research. Antigen presenting cells such as macrophages and dendritic cells are strategically located at the frontline of defence against potential invaders. Importantly, these cells express germline encoded pattern recognition receptors (PRRs), which sense conserved entities from pathogens and orchestrate innate immune responses. Herein, we review the latest findings regarding the biology and functions of the different classes of PRRs involved in pathogenic fungal recognition. We also discuss recent literature on PRR collaboration/crosstalk and the mechanisms involved in inhibiting/regulating PRR signalling. Finally, we discuss how the accumulated knowledge on PRR biology, especially Dectin-1, has been used for the design of new immunotherapies against fungal infections. PMID- 29522805 TI - Nonuniform sampling in multidimensional NMR for improving spectral sensitivity. AB - The development of multidimensional NMR spectroscopy enabled an explosion of structural and dynamical investigations on proteins and other biomacromolecules. Practical limitations on data sampling, based on the Jeener paradigm of parametric sampling of indirect time domains, have long placed limits on resolution in the corresponding frequency dimensions. The emergence of nonuniform sampling (NUS) in indirect time dimensions circumvents those limitations, affording high resolution spectra from short data records collected in practically realized measurement times. In addition to substantially improved resolution, NUS can also be exploited to improve sensitivity, with gains comparable to those obtained using cryogenically cooled probes. We describe a general approach for acquiring and processing multidimensional NUS NMR data for improving sensitivity. PMID- 29522807 TI - Oxidative responses and fungal infection biology. AB - The balance between reactive oxygen species and reactive nitrogen species production by the host and stress response by fungi is a key axis of the host pathogen interaction. This review will describe emerging themes in fungal pathogenesis underpinning this axis. PMID- 29522808 TI - Behavioral reconsolidation interference with episodic memory within-subjects is elusive. AB - In studies of behavioral reconsolidation interference, reactivation of a consolidated memory using some form of reminder is followed by the presentation of new information that can cause interference with that memory. Under these conditions, the interference not only impairs retrieval by indirect processes such as cue interference, but supposedly disrupts the original memory trace directly. Almost all studies of behavioral reconsolidation interference in episodic memory in humans have employed between-subjects paradigms, and deduced reminder effects from intrusion errors. Such studies might introduce confounds arising, for example, from differences in retrieval strategies engendered by the pre-test treatments. We therefore set out to examine whether behavioral reconsolidation interference in episodic memory might be demonstrated within subjects and by direct memory strength rather than intrusion errors. In three separate experiments, we attempted to disrupt reconsolidation of episodic object picture memory using a reminder + retroactive interference manipulation. We applied the manipulation over three consecutive days, using a forced-choice recognition test without intrusions from interfering learning, keeping all other study and test parameters constant. No effects of reminder-potentiated interference were observed for measures of accuracy, response times, subjective expressions of recollection, or levels of confidence, as substantiated by Bayesian analyses. These results highlight the difficulty of observing clear behavioral reconsolidation interference effects within-subjects in human episodic memory, and provide some indications of what might be boundary conditions for its demonstration. PMID- 29522809 TI - Onset and Evolution of Clinically Apparent Myasthenia Gravis After Resection of Non-myasthenic Thymomas. AB - Patients with thymoma and without clinical or electromyographical myasthenic signs may occasionally develop myasthenia several years after thymectomy. Hereby, we investigated the predictors and the evolution of this peculiar disease. We performed a retrospective analysis in 104 consecutive patients who underwent thymectomy between 1987 and 2013 for thymoma without clinical or electromyographic signs of myasthenia gravis. Predictors of post-thymectomy onset of myasthenia gravis were investigated with univariate time-to-disease analysis. Evolution of myasthenia was analyzed with time-to-regression analysis. Eight patients developed late myasthenia gravis after a median period of 33 months from thymectomy. No significant correlation was found for age, gender, Masaoka's stage, and World Health Organization histology. Only high preoperative serum acetylcholine-receptor antibodies titer (>0.3 nmol/L) was significantly associated with post-thymectomy myasthenia gravis at univariate time-to-disease (P = 0.003) analysis. Positron emission tomography was always performed in high titer patients, and increased metabolic activity was detected in 4 of these patients. Surgical treatment through redo-sternotomy or video-assisted thoracoscopy was performed in these last cases with a remission in all patients after 12, 24, 32 and 48 months, respectively. No patient under medical treatment has yet developed a complete remission. In our study the presence of preoperative high-level serum acetylcholine receptor antibodies was the only factor significantly associated with the development of post-thymectomy myasthenia gravis. The persistence of residual islet of ectopic thymic tissue was one of the causes of the onset of myasthenia and its surgical removal was successful. PMID- 29522810 TI - Vascular Complications in the Sapien 3 Era: Continued Role of Transapical Approach to Transcatheter Aortic Valve Replacement. AB - With the introduction of the latest generation Sapien 3 (S3) transcatheter aortic valve, there has been a reduction in the usage of transapical (TA) approach for transcatheter aortic valve replacements in many centers. However, despite the smaller sheath size and the more streamlined delivery system, vascular complications continue to occur, especially in patients with peripheral vascular disease. Thus, our institution has maintained a stringent TA protocol aiming to prevent these complications. We hypothesize that this protocol has helped to reduce vascular complications and improve outcomes at our institution even in the S3 era. All transcatheter aortic valve replacement procedures done at our institution were considered for analysis. Patients were grouped according to whether their procedure was done before (Pre-S3 era) or after (S3 era) the introduction of the S3 valve, as well as whether they underwent a TA or a transfemoral (TF) approach. A femoral artery intraluminal diameter of <7.5 mm in the Pre-S3 era and <5.5 mm in the S3 era with circumferential calcifications triggered TA approach consideration. Vascular complications included vascular perforation, dissection, flow-limiting stenosis, unplanned vascular surgery, significant postprocedural bleeding, hematoma at the access site, and retroperitoneal bleed. The Welch t test of unequal variance and chi-squared test were used as appropriate. An alpha of <0.05 was considered significant. A total of 275 patients were included in the analysis (121 Pre-S3 era and 154 S3 era). The TA approach was utilized in 45% in the Pre-S3 era vs 15% in the S3 era (P < 0.001). Within the S3 era, 131 underwent the TF approach compared with 23 who underwent the TA approach. TA and TF patients were similar in all preoperative characteristics except hypertension. Mortality was significantly lower in the S3 era (0% vs 4% in the pre-S3 era, P = 0.02). Overall rates of vascular complications were similar between the Pre-S3 and the S3 eras (16% vs 14%, P = 0.63). Overall adverse outcomes were similar between the TA and the TF groups. TA patients saw significantly longer intensive care unit stay and total hospital stay. Our results show that despite a smaller sheath size, vascular complications continue at a similar rate into the S3 era. This occurred in the setting of an ongoing aggressive TA utilization in select patients, specifically those with peripheral vascular disease. Maintaining this approach is likely a large contributor to both our current success and reduced mortality. PMID- 29522811 TI - Contact dermatitis and patch testing for the allergist. AB - OBJECTIVE: To review of contact dermatitis (CD) and its key allergens and provide updates and recommendations for the practicing allergist. DATA SOURCES: Through the use of various scientific search engines (eg, PubMed and MEDLINE), we reviewed literature on CD, patch tests (PTs), key allergens, occupational dermatitis, and treatment. STUDY SELECTIONS: Studies on CD, important allergens, and PTs were considered. RESULTS: Contact-induced dermatitis may be due to allergic CD, irritant CD, systemic CD, contact urticaria, and protein CD. Key allergens include metals (nickel, gold), topical medicaments (topical corticosteroids), and cosmetics and personal care products (fragrances and preservatives such as methyl- and methylchloro-isothiazolinone). Present relevance of a positive PT result is the combination of definite, probable, and possible relevance and should be correlated with the patient's history and physical examination. Treatment of allergic CD includes identification of relevant allergens, patient education, avoidance, and provision of alternative products the patient can use. CONCLUSION: CD is a common inflammatory skin disease and should be suspected in patients presenting with acute, subacute, or chronic dermatitis. The gold standard for diagnosing allergic CD is a PT. This article provides practical recommendations for the diagnosis and management of CD commonly seen by the allergist in their practice. PMID- 29522812 TI - Abnormal lung function at preschool age asthma in adolescence? AB - BACKGROUND: Asthma often begins early in childhood. However, the risk for persistence is challenging to evaluate. OBJECTIVE: This longitudinal study relates lung function assessed with impulse oscillometry (IOS) in preschool children to asthma in adolescence. METHODS: Lung function was measured with IOS in 255 children with asthma-like symptoms aged 4-7 years. Baseline measurements were followed by exercise challenge and bronchodilation tests. At age 12-16 years, 121 children participated in the follow-up visit, when lung function was assessed with spirometry, followed by a bronchodilation test. Asthma symptoms and medication were recorded by a questionnaire and atopy defined by skin prick tests. RESULTS: Abnormal baseline values in preschool IOS were significantly associated with low lung function, the need for asthma medication, and asthma symptoms in adolescence. Preschool abnormal R5 at baseline (z-score >=1.645 SD) showed 9.2 odds ratio (95%CI 2.7;31.7) for abnormal FEV1/FVC, use of asthma medication in adolescence, and 9.9 odds ratio (95%CI 2.9;34.4) for asthma symptoms. Positive exercise challenge and modified asthma-predictive index at preschool age predicted asthma symptoms and the need for asthma medication, but not abnormal lung function at teenage. CONCLUSION: Abnormal preschool IOS is associated with asthma and poor lung function in adolescence and might be utilised for identification of asthma persistence. PMID- 29522813 TI - Paradoxical roles of ATF6alpha and ATF6beta in modulating disease severity caused by mutations in collagen X. AB - Whilst the role of ATF6alpha in modulating the unfolded protein response (UPR) has been well documented, the function of its paralogue ATF6beta is less well understood. Using knockdown in cell culture and gene ablation in mice we have directly compared the roles of ATF6alpha & beta in responding to the increased ER stress induced by mutant forms of type X collagen that cause the ER stress associated metaphyseal chondrodysplasia type Schmid (MCDS). ATF6alpha more efficiently deals with the disease-associated ER stress in the absence of ATF6beta and conversely, ATF6beta is less effective in the absence of ATF6alpha. Furthermore, disease severity in vivo is increased by ATF6alpha ablation and decreased by ATF6beta ablation. In addition, novel functions for each paralogue are described including an ATF6beta-specific role in controlling growth plate chondrocyte proliferation. The clear demonstration of the intimate relationship of the two ATF6 isoforms and how ATF6beta can moderate the activity of ATF6alpha and vice versa is of great significance for understanding the UPR mechanism. The activities of both ATF6 isoforms and their separate roles need consideration when deciding how to target increased ER stress as a means of treating MCDS and other ER stress-associated diseases. PMID- 29522814 TI - Contrasting patterns of diversification in two sister species of martins (Aves: Hirundinidae): The Sand Martin Riparia riparia and the Pale Martin R. diluta. AB - Species not only responded idiosyncratically to past climate changes, there were also regionally contrasting effects on spatio-temporal diversification patterns. Studies of closely related species appear to be a particularly promising comparative approach to disentangle such regionally differential impacts. In this study, we undertook a comprehensive geographic sampling to investigate the evolutionary history of the Holarctic Sand Martin Riparia riparia and the chiefly Central and East Asian Pale Martin R. diluta. Previous phylogenetic studies using only a limited geographic sampling, particularly for the latter, revealed the two to be genetically distinct, with the former showing only a shallow genetic structure in mitochondrial DNA. Based on one mitochondrial, one autosomal and one Z-linked nuclear marker, we confirmed the shallow genetic structure in R. riparia even when including the morphologically relatively distinct subspecies R. r. shelleyi from the Nile Valley in Egypt and probably the Middle East. On the other hand the different subspecies of R. diluta, i.e. R. d. diluta from Central Asia, R. d. indica from the northwestern Indian Subcontinent, R. d. tibetana from the Tibetan Plateau and R. d. fohkienensis from southeastern China, were found to be genetically distinct. Their diversification started before the Early to Middle Pleistocene Transition, which was followed by a pronounced succession of glacial and interglacial periods. These rather old divergence events contrast with the lack of any strong phylogeographic structure in R. riparia. Strongly structured populations and regional diversification have been reported in different forest passerine families of South-East Asia. Here we demonstrate, however, that species characteristic of open-country habitats such as R. diluta might display a similar pattern. Morphometric analyses of 120 individuals revealed no clear differences between the different subspecies of R. diluta. Given their similarity also in plumage features, we refrain from proposing any splits despite their marked genetic differentiation, pending further studies and particularly the discovery of potential secondary contact zones. PMID- 29522815 TI - Roles of VPH2 and VMA6 in localization of V-ATPase subunits, cell wall functions and filamentous development in Candida albicans. AB - The vacuolar-type H+-ATPase (V-ATPase) is known to be associated with various cellular processes. Several V-ATPase subunits have been identified in C. albicans. However, there are still a few V-ATPase subunits and assembly factors that remain uncharacterized. In this study, we identified one of putative V ATPase assembly factors, Vph2, and V0 subunit, Vma6, and explored their potential functions in C. albicans. Our results revealed that Vph2 and Vma6 were required for the correct distribution of V0 subunit Vph1 and V1 subunit Tfp1. Furthermore, Vph2 and Vma6 played an important role in endocytosis and vacuolar acidification. Disruption of VPH2 or VMA6 affected cell wall stress resistance and composition, accompanying induction of cell wall integrity (CWI) pathway. Besides, deletion of VPH2 or VMA6 led to weakened hyphal development in Spider medium that was not dependent on Hog1 activation. Moreover, the vph2Delta/Delta and vma6Delta/Delta mutants displayed attenuated virulence in a mouse model of systemic candidiasis. Taken together, our data indicated that Vph2 and Vma6 were essential for the proper localization of V-ATPase subunits, cell wall functions, filamentous growth and C. albicans pathogenesis, and provided the potential to better exploit V ATPase-related proteins as antifungal targets. PMID- 29522816 TI - Therapeutic Strategy for Incarcerated Obturator Hernia Using Preoperative Manual Reduction and Laparoscopic Repair. AB - BACKGROUND: Obturator hernia (OH) is a rare but serious disease associated with high morbidity and mortality due to advanced patient age and comorbidities. This study evaluated the feasibility of a laparoscopic approach to OH. STUDY DESIGN: We retrospectively reviewed the records of 32 patients (median age 84 years; 31 women) with OH treated between 2003 and 2016. RESULTS: Five patients with incidental OH underwent total extraperitoneal (TEP) repair. Of 27 patients with incarcerated OH, 18 patients underwent laparotomy, 13 of which required bowel resection, and the remaining 9 patients underwent preoperative ultrasound-guided manual OH reduction. Of 6 patients with successful OH release, 3 and 2 patients underwent TEP and transabdominal preperitoneal repair, respectively, and 1 patient declined the operation. Three patients with failure underwent laparoscopic exploration and conversion to open operation for bowel resection. Comparing the open and laparoscopic groups, the median operation times were 67.5 minutes vs 124 minutes, respectively (p = 0.004); median postoperative stay was 19 vs 11 days, respectively (p = 0.028); and Clavien-Dindo grade II or higher complications tended to be lower (28% vs 8%, respectively; p = 0.359). Even in patients without bowel resection, the median postoperative stay was significantly shorter in the laparoscopic group compared with the open group (7.5 vs 15 days, respectively; p = 0.032). During a mean follow-up of 24.5 months, the 3-year recurrence rate for OH was 25% for non-mesh repair and 0% for mesh repair (p = 0.335). Three- and 5-year cumulative survival rates were 83% and 71%, respectively. CONCLUSIONS: Laparoscopic operations after ultrasound-guided manual reduction can be an alternative to emergent laparotomy in select OH patients. PMID- 29522817 TI - Gaussian-input Gaussian mixture model for representing density maps and atomic models. AB - A new Gaussian mixture model (GMM) has been developed for better representations of both atomic models and electron microscopy 3D density maps. The standard GMM algorithm employs an EM algorithm to determine the parameters. It accepted a set of 3D points with weights, corresponding to voxel or atomic centers. Although the standard algorithm worked reasonably well; however, it had three problems. First, it ignored the size (voxel width or atomic radius) of the input, and thus it could lead to a GMM with a smaller spread than the input. Second, the algorithm had a singularity problem, as it sometimes stopped the iterative procedure due to a Gaussian function with almost zero variance. Third, a map with a large number of voxels required a long computation time for conversion to a GMM. To solve these problems, we have introduced a Gaussian-input GMM algorithm, which considers the input atoms or voxels as a set of Gaussian functions. The standard EM algorithm of GMM was extended to optimize the new GMM. The new GMM has identical radius of gyration to the input, and does not suddenly stop due to the singularity problem. For fast computation, we have introduced a down-sampled Gaussian functions (DSG) by merging neighboring voxels into an anisotropic Gaussian function. It provides a GMM with thousands of Gaussian functions in a short computation time. We also have introduced a DSG-input GMM: the Gaussian input GMM with the DSG as the input. This new algorithm is much faster than the standard algorithm. PMID- 29522818 TI - Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder. AB - BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type alpha synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy type alpha-synuclein pathology and possibly an increased risk for later cognitive dysfunction. PMID- 29522820 TI - Interventional programmes to improve cognition during healthy and pathological ageing: Cortical modulations and evidence for brain plasticity. AB - A growing body of evidence suggests that healthy elderly individuals and patients with Alzheimer's disease retain an important potential for neuroplasticity. This review summarizes studies investigating the modulation of neural activity and structural brain integrity in response to interventions involving cognitive training, physical exercise and non-invasive brain stimulation in healthy elderly and cognitively impaired subjects (including patients with mild cognitive impairment (MCI) and Alzheimer's disease). Moreover, given the clinical relevance of neuroplasticity, we discuss how evidence for neuroplasticity can be inferred from the functional and structural brain changes observed after implementing these interventions. We emphasize that multimodal programmes, which combine several types of interventions, improve cognitive function to a greater extent than programmes that use a single interventional approach. We suggest specific methods for weighting the relative importance of cognitive training, physical exercise and non-invasive brain stimulation according to the functional and structural state of the brain of the targeted subject to maximize the cognitive improvements induced by multimodal programmes. PMID- 29522819 TI - Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic beta cells. AB - Diphosphoinositol pentakisphosphate (IP7) is critical for the exocytotic capacity of the pancreatic beta-cell, but its regulation by the primary instigator of beta cell exocytosis, glucose, is unknown. The high Km for ATP of the IP7-generating enzymes, the inositol hexakisphosphate kinases (IP6K1 and 2) suggests that these enzymes might serve as metabolic sensors in insulin secreting beta-cells and act as translators of disrupted metabolism in diabetes. We investigated this hypothesis and now show that glucose stimulation, which increases the ATP/ADP ratio, leads to an early rise in IP7 concentration in beta-cells. RNAi mediated knock down of the IP6K1 isoform inhibits both glucose-mediated increase in IP7 and first phase insulin secretion, demonstrating that IP6K1 integrates glucose metabolism and insulin exocytosis. In diabetic mouse islets the deranged ATP/ADP levels under both basal and glucose-stimulated conditions are mirrored in both disrupted IP7 generation and insulin release. Thus the unique metabolic sensing properties of IP6K1 guarantees appropriate concentrations of IP7 and thereby both correct basal insulin secretion and intact first phase insulin release. In addition, our data suggest that a specific cell signaling defect, namely, inappropriate IP7 generation may be an essential convergence point integrating multiple metabolic defects into the commonly observed phenotype in diabetes. PMID- 29522821 TI - Cell toxicity by ricin and elucidation of mechanism of Ricin inactivation. AB - Castor cake is a by-product of the extraction of oil from from seeds of castor plants (Ricinus communis). This by-product contains high levels of proteins, but a toxic protein, ricin, limits its use as an animal feed. Ricin can be efficiently inactivated by treatment with calcium oxide (CaO), which can be evaluated by a cytotoxicity assay using LLC-MK2 cells. The mechanism by which the CaO treatment inactivates ricin, however, is unclear. We report the structural changes responsible for ricin inactivation. Purified ricin was treated with 0.6% CaO and then analyzed by mass spectrometry. This treatment degraded the ricin at preferential sites. The aqueous CaO solution had a pH >12, which preferentially cleaved asparagine residues, followed by glutamine, serine and glycine residues. The alkaline pH affected the tertiary structure of the ricin, cleaving its polypeptide chains and thereby eliminating its cytotoxic activity. PMID- 29522822 TI - Vanillic acid and syringic acid: Exceptionally robust aromatic moieties for inhibiting in vitro self-assembly of type I collagen. AB - Excess collagen fibril accumulation is one of the leading causes for stroke and myocardial infarction, thus inducing interest in identifying and studying the compounds, which inhibits collagen fibril formation. Herein, inhibition of self assembly of collagen has been studied using syringic acid and vanillic acid. These plant phytochemicals are well known antioxidants and they reduce oxidative stress as well. Inhibitory effect on collagen fibrils using syringic and vanillic acid has been studied using varying biophysical techniques. Circular Dichroism and FT-IR studies clearly showed the changes in secondary structure of collagen with the increasing concentration of vanillic acid and syringic acid. DLS measurements showed an acute aggregation upon treatment with these compounds and an inhibitory effect was also visualized using morphological studies. In addition, the decreased rate in the formation of collagen fibrils proves that these compounds are efficient to inhibit collagen fibril formation. This opens a new arena for the development of novel targeted delivery systems for diseases related to collagen accumulation. PMID- 29522823 TI - Morphological, structural, thermal, compositional, vibrational, and pasting characterization of white, yellow, and purple Arracacha Lego-like starches and flours (Arracacia xanthorrhiza). AB - This work is focused on the chemical, structural, morphological, thermal, IR vibrational, and pasting characterization of isolated white, yellow, and purple Arracacha starches from Colombia. Inductive couple plasma showed that these starches are rich in potassium. Scanning Electron Microscopy (SEM) images show that the starch granules are formed by ovoid fully filled Lego-like starch microparticles, the circular cross-section has a diameter between 9 and 15MUm and mayor axis between 20 and 30MUm. Each one of these ovoids is formed by irregular wedge-shaped 6 to 10 isolated starch granules with an average size between 4 and 12MUm. The amylose content ranged between 31 and 36%. Arracacha starches exhibited high viscosity values (between 20.000 and 28.000cP), which could be influenced by the high content of potassium ions, due to the C-H~K Van Der Waals interaction that was identified by using IR spectroscopy. According to the X-ray diffraction analysis, the starch patterns exhibited broad diffracted peaks which could be associated with the existence of nano-crystals and lamellae; the Differential Scanning calorimetry (DSC) result showed starches with a low gelatinization temperature of about 60 degrees C. PMID- 29522824 TI - Antiacanthain A: New proteases isolated from Bromelia antiacantha Bertol. (Bromeliaceae). AB - Crude extract (CE) from pulp of Bromelia antiacantha Bertol. mature fruit, contains at least 3 cysteine proteases with proteolytic activity. By single step cation exchange chromatography (Hi-trap SP-HP) of partially purified CE, the protease with the lowest pI, Antiacanthain A (AntA), was isolated. It showed maximum activity at pH9, and 75% of remaining activity was maintained over a wide pH range (pH6-10). The AntA activity exhibits a constant increase up to 70 degrees C. Maintains almost 100% of its activity at 45 at pH6 and 9. A 60% of AntA was active by titration with specific inhibitor, E64. Amidasic activity was studied with pyroglutamyl-phenyl-leucyl-paranitroaniline (PFLNA) substrate having higher AntA catalytic efficiency of (kcat/Km=470s-1M-1) relative to stem bromelain (kcat/Km=305s-1M-1). Esterase activity using p-nitrophenyl esters of N alpha-CBZ-l-Lysine (z-L-LysONp) showed a 10-fold higher catalytic efficiency for AntA (kcat/Km=6376s-1M-1) relative to stem bromelain (kcat/Km=688s-1M-1). Incubation with 8M Urea did not affect AntA activity and remained unchanged for 18h, with 6M GndHCl resulted in a 41% decrease in activity after 30min incubation, maintained this activity 18h. AntA exhibits high sequence identity with proteases of the Bromeliaceae family. PMID- 29522825 TI - Glyco-Mapper: A Chinese hamster ovary (CHO) genome-specific glycosylation prediction tool. AB - Glyco-Mapper is a novel systems biology product quality prediction tool created using a new framework termed: Discretized Reaction Network Modeling using Fuzzy Parameters (DReaM-zyP). Within Glyco-Mapper, users fix the nutrient feed composition and the glycosylation reaction fluxes to fit the model glycoform to the reference experimental glycoform, enabling cell-line specific glycoform predictions as a result of cell engineering strategies. Glyco-Mapper accurately predicts glycoforms associated with genetic alterations that result in the appearance or disappearance of one or more glycans with an accuracy, sensitivity, and specificity of 96%, 85%, and 97%, respectively, for publications between 1999 and 2014. The modeled glycoforms span a large range of glycoform engineering strategies, including the altered expression of glycosylation, nucleotide sugar transport, and metabolism genes, as well as an altered nutrient feeding strategy. A glycoprotein-producing CHO cell line reference glycoform was modeled and a novel Glyco-Mapper prediction was experimentally confirmed with an accuracy and specificity of 95% and 98%, respectively. Glyco-Mapper is a product quality prediction tool that provides a streamlined way to design host cell line genomes to achieve specific product quality attributes. PMID- 29522826 TI - Metabolic engineering to guide evolution - Creating a novel mode for L-valine production with Corynebacterium glutamicum. AB - Evolutionary approaches are often undirected and mutagen-based yielding numerous mutations, which need elaborate screenings to identify relevant targets. We here apply Metabolic engineering to Guide Evolution (MGE), an evolutionary approach evolving and identifying new targets to improve microbial producer strains. MGE is based on the idea to impair the cell's metabolism by metabolic engineering, thereby generating guided evolutionary pressure. It consists of three distinct phases: (i) metabolic engineering to create the evolutionary pressure on the applied strain followed by (ii) a cultivation phase with growth as straightforward screening indicator for the evolutionary event, and (iii) comparative whole genome sequencing (WGS), to identify mutations in the evolved strains, which are eventually re-engineered for verification. Applying MGE, we evolved the PEP and pyruvate carboxylase-deficient strain C. glutamicum Deltappc Deltapyc to grow on glucose as substrate with rates up to 0.31 +/- 0.02 h-1 which corresponds to 80% of the growth rate of the wildtype strain. The intersection of the mutations identified by WGS revealed isocitrate dehydrogenase (ICD) as consistent target in three independently evolved mutants. Upon re-engineering in C. glutamicum Deltappc Deltapyc, the identified mutations led to diminished ICD activities and activated the glyoxylate shunt replenishing oxaloacetate required for growth. Intracellular relative quantitative metabolome analysis showed that the pools of citrate, isocitrate, cis-aconitate, and L-valine were significantly higher compared to the WT control. As an alternative to existing L-valine producer strains based on inactivated or attenuated pyruvate dehydrogenase complex, we finally engineered the PEP and pyruvate carboxylase-deficient C. glutamicum strains with identified ICD mutations for L-valine production by overexpression of the L-valine biosynthesis genes. Among them, C. glutamicum Deltappc Deltapyc ICDG407S (pJC4ilvBNCE) produced up to 8.9 +/- 0.4 g L-valine L 1, with a product yield of 0.22 +/- 0.01 g L-valine per g glucose. PMID- 29522827 TI - Measurement error is often neglected in medical literature: a systematic review. AB - OBJECTIVES: In medical research, covariates (e.g., exposure and confounder variables) are often measured with error. While it is well accepted that this introduces bias and imprecision in exposure-outcome relations, it is unclear to what extent such issues are currently considered in research practice. The objective was to study common practices regarding covariate measurement error via a systematic review of general medicine and epidemiology literature. STUDY DESIGN AND SETTING: Original research published in 2016 in 12 high impact journals was full-text searched for phrases relating to measurement error. Reporting of measurement error and methods to investigate or correct for it were quantified and characterized. RESULTS: Two hundred and forty-seven (44%) of the 565 original research publications reported on the presence of measurement error. 83% of these 247 did so with respect to the exposure and/or confounder variables. Only 18 publications (7% of 247) used methods to investigate or correct for measurement error. CONCLUSIONS: Consequently, it is difficult for readers to judge the robustness of presented results to the existence of measurement error in the majority of publications in high impact journals. Our systematic review highlights the need for increased awareness about the possible impact of covariate measurement error. Additionally, guidance on the use of measurement error correction methods is necessary. PMID- 29522828 TI - Phylogenetic analysis of the Belgian HIV-1 epidemic reveals that local transmission is almost exclusively driven by men having sex with men despite presence of large African migrant communities. AB - To improve insight in the drivers of local HIV-1 transmission in Belgium, phylogenetic, demographic, epidemiological and laboratory data from patients newly diagnosed between 2013 and 2015 were combined and analyzed. Characteristics of clustered patients, paired patients and patients on isolated branches in the phylogenetic tree were compared. The results revealed an overall high level of clustering despite the short time frame of sampling, with 47.6% of all patients having at least one close genetic counterpart and 36.6% belonging to a cluster of 3 or more individuals. Compared to patients on isolated branches, patients in clusters more frequently reported being infected in Belgium (95.1% vs. 47.6%; p < 0.001), were more frequently men having sex with men (MSM) (77.9% vs. 42.8%; p < 0.001), of Belgian origin (68.2% vs. 32.9%; p < 0.001), male gender (92.6% vs. 65.8%; p < 0.001), infected with subtype B or F (87.8% vs. 43.4%; p < 0.001) and diagnosed early after infection (55.4% vs. 29.0%; p < 0.001). Strikingly, Sub Saharan Africans (SSA), overall representing 27.1% of the population were significantly less frequently found in clusters than on individual branches (6.0% vs. 41.8%; p < 0.001). Of the SSA that participated in clustered transmission, 66.7% were MSM and this contrasts sharply with the overall 12.0% of SSA reporting MSM. Transmission clusters with SSA were more frequently non-B clusters than transmission clusters without SSA (44.4% versus 18.2%). MSM-driven clusters with patients of mixed origin may account, at least in part, for the increasing spread of non-B subtypes to the native MSM population, a cross-over that has been particularly successful for subtype F and CRF02_AG. The main conclusions from this study are that clustered transmission in Belgium remains almost exclusively MSM-driven with very limited contribution of SSA. There were no indications for local ongoing clustered transmission of HIV-1 among SSA. PMID- 29522829 TI - Impella support compared to medical treatment for post-cardiac arrest shock after out of hospital cardiac arrest. AB - AIMS: To compare survival outcomes of Impella support and medical treatment in patients with post-cardiac arrest cardiogenic shock related to acute myocardial infarction (AMI). METHODS: Retrospective single center study of patients resuscitated from out of hospital cardiac arrest (OHCA) due to AMI with post cardiac arrest cardiogenic shock between September 2014 and September 2016. Patients were either assisted with Impella or received medical treatment only. Survival outcomes were compared using propensity score-matched analysis to account for differences in baseline characteristics between both groups. RESULTS: A total of 90 consecutive patients with post-cardiac arrest shock due to AMI were included; 27 patients in the Impella group and 63 patients in the medical treatment group. Patients with Impella support had a longer duration of low-flow time (29.54 +/- 10.21 versus 17.57 +/- 8.3 min, p < 0.001), higher lactate levels on admission (4.75 [IQR 3.8-11] versus 3.6 [IQR 2.6-3.9] mmol/L, p = 0.03) and lower baseline systolic LVEF (25% [IQR 25-35] versus 45% [IQR 35-51.25], p < 0.001) as compared to patients without circulatory support. After propensity score matching, patients with Impella support had a significantly higher survival to hospital discharge (65% versus 20%, p = 0.01) and 6-months survival (60% versus 20%, p = 0.02). CONCLUSION: The results from our study suggest that Impella support is associated with significantly better survival to hospital discharge and at 6 months compared to medical treatment in OHCA patients admitted with post-cardiac arrest cardiogenic shock and AMI. PMID- 29522830 TI - Self-learning basic life support: A randomised controlled trial on learning conditions. AB - AIM OF THE STUDY: To investigate whether pure self-learning without instructor support, resulted in the same BLS-competencies as facilitator-led learning, when using the same commercially available video BLS teaching kit. METHODS: First-year medical students were randomised to either BLS self-learning without supervision or facilitator-led BLS-teaching. Both groups used the MiniAnne kit (Laerdal Medical, Stavanger, Norway) in the students' local language. Directly after the teaching and three months later, all participants were tested on their BLS competencies in a simulated scenario, using the Resusci Anne SkillReporterTM (Laerdal Medical, Stavanger, Norway). The primary outcome was percentage of correct cardiac compressions three months after the teaching. Secondary outcomes were all other BLS parameters recorded by the SkillReporter and parameters from a BLS-competence rating form. RESULTS: 240 students were assessed at baseline and 152 students participated in the 3-month follow-up. For our primary outcome, the percentage of correct compressions, we found a median of 48% (interquartile range (IQR) 10-83) for facilitator-led learning vs. 42% (IQR 14-81) for self-learning (p = 0.770) directly after the teaching. In the 3-month follow-up, the rate of correct compressions dropped to 28% (IQR 6-59) for facilitator-led learning (p = 0.043) and did not change significantly in the self-learning group (47% (IQR 12 78), p = 0.729). CONCLUSIONS: Self-learning is not inferior to facilitator-led learning in the short term. Self-learning resulted in a better retention of BLS skills three months after training compared to facilitator-led training. PMID- 29522831 TI - In-hospital cardiac arrest after a rapid response team review: A matched case control study. AB - AIM: Study the incidence and reasons behind in-hospital cardiac arrests (IHCAs) after rapid response team (RRT) reviews. METHODS: We conducted a matched case control study at Tampere University Hospital, Finland. Data on adult patients who were triaged to remain on general ward after first (index) RRT review without treatment limitations but who suffered an IHCA within the following 48 h were prospectively collected for 5.3 years. These cases were matched (age +/-3 years, sex, surgical/medical ward, admission year) at a 1:4 ratio to controls (no ICHA after RRT review). RESULTS: Of 2653 index RRT reviews, 17 patients suffered an IHCA on general ward within the 48 h after review. Their 30-day mortality rate was 88%. The incidence was 6.3/1000 index RRT reviews or 4.6/100,000 hospital admissions. Patients who suffered an IHCA within 48 h after RRT review were more likely to have a preceding ICU admission, and their median national early warning scores (NEWSs) at the end of the index RRT reviews (=last NEWSs) were higher than those of the controls. Higher last NEWS was the only factor associated with ICHA after RRT review (OR 1.22, 95% CI 1.00-1.49, p = 0.048) in a conditional multivariable regression model. CONCLUSIONS: IHCA within 48 h after an index RRT review on general ward is a rare event with poor prognosis. It is independently associated with higher NEWS at the end of the index RRT review. Careful consideration is stressed, when patients with high NEWS are left on ward after RRT reviews. PMID- 29522832 TI - Formation of protein corona in vivo affects drug release from temperature sensitive liposomes. AB - Thermally triggered drug release from temperature-sensitive liposomes (TSL) holds great promise for cancer therapy. Different types of TSL have been designed recently for heat triggered drug release inside tumor blood vessels or after accumulation into the tumor interstitium. However, justification of drug release profiles is for far mainly based on in vitro release data. While these methods could be good enough to give early indication about the thermal sensitivity of TSL, they are still far from being optimum. This is because these methods do not take into consideration the actual adsorption of proteins onto the surface of TSL after their in vivo administration, also known as "protein corona" and the influence this could have on drug release. Therefore, in this study we compared thermal triggered drug release profile of two different types of doxorubicin encapsulated TSL; namely the lysolipid-containing TSL (LTSL) and traditional TSL (TTSL) after their in vivo recovery from the blood circulation of CD-1 mice. Ex vivo release profile at 42 degrees C was then tested either in the presence of full plasma or after removal of unbound plasma proteins (i.e. protein corona coated TSL). Our data showed that the influence of the environment on drug release profile was very much dependent on the type of TSL. LTSL release profile was consistently characterized by ultrafast drug release independent on the conditions tested. On the contrary, TTSL release profile changed significantly. Doxorubicin release from in vivo recovered TTSL was slow and incomplete in the presence of unbound plasma proteins, whereas very rapid drug release was detected from in vivo recovered and purified protein corona-coated TTSL in the absence of unbound proteins. Using mass spectrometry and quantification of protein adsorption, we confirmed that this discrepancy is due to the changes in protein adsorption onto TTSL when heated in the presence of unbound proteins leading to reduction in drug release. In summary this study showed that the formation of the in vivo corona on TSL will have a dramatic impact on their release profile and is dependent on both their lipid composition and the protein content of the environment in which drug release is triggered. PMID- 29522834 TI - Transferrin-targeted, resveratrol-loaded liposomes for the treatment of glioblastoma. AB - Glioblastomas (GBMs) are highly aggressive brain tumors with a very grim prognosis even after multi-modal therapeutic regimens. Conventional chemotherapeutic agents frequently lead to drug resistance and result in severe toxicities to non-cancerous tissues. Resveratrol (RES), a natural polyphenol with pleiotropic health benefits, has proven chemopreventive effects in all the stages of cancer including initiation, promotion and progression. However, the poor physico-chemical properties of RES severely limit its use as a free drug. In this study, RES was loaded into PEGylated liposomes (RES-L) to counter its drawbacks as a free drug. Since transferrin receptors (TfRs) are up-regulated in GBM, the liposome surface was modified with transferrin moieties (Tf-RES-L) to make them cancer cell-specific. The liposomal nanomedicines developed in this project were aimed at enhancing the physico-chemical properties of RES and exploiting the passive and active targeting capabilities of liposomes to effectively treat GBM. The RES-L were stable, had a good drug-loading capacity, prolonged drug-release in vitro and were easily scalable. Flow cytometry and confocal microscopy were used to study the association with, and internalization of, Tf-L into U-87 MG cells. The Tf-RES-Ls were significantly more cytotoxic and induced higher levels of apoptosis accompanied by activation of caspases 3/7 in GBM cells when compared to free RES or RES-L. The ability of RES to arrest cells in the S-phase of the cell cycle, and selectively induce production of reactive oxygen species in cancer cells were probably responsible for its cytotoxic effects. The therapeutic efficacy of RES formulations was evaluated in a subcutaneous xenograft mouse model of GBM. A tumor growth inhibition study and a modified survival study showed that Tf-RES-Ls were more effective than other treatments in their ability to inhibit tumor growth and improve survival in mice. Overall, the liposomal nanomedicines of RES developed in this project exhibited favorable in vitro and in vivo efficacies, which warrant their further investigation for the treatment of GBMs. PMID- 29522833 TI - Ferritin-based drug delivery systems: Hybrid nanocarriers for vascular immunotargeting. AB - Ferritin subunits of heavy and light polypeptide chains self-assemble into a spherical nanocage that serves as a natural transport vehicle for metals but can include diverse cargoes. Ferritin nanoparticles are characterized by remarkable stability, small and uniform size. Chemical modifications and molecular re engineering of ferritin yield a versatile platform of nanocarriers capable of delivering a broad range of therapeutic and imaging agents. Targeting moieties conjugated to the ferritin external surface provide multivalent anchoring of biological targets. Here, we highlight some of the current work on ferritin as well as examine potential strategies that could be used to functionalize ferritin via chemical and genetic means to enable its utility in vascular drug delivery. PMID- 29522836 TI - Distinct phenotypes of spontaneous activity and induction of amphetamine sensitization in inbred Roman high- and low-avoidance rats: Vulnerability and protection. AB - The psychogenetically selected Roman high- (RHA) and low-avoidance (RLA) rats are being proposed as a valuable animal model of individual vulnerability to the two distinct neurobiological mechanisms of behavioral sensitization to psychostimulants, namely induction and expression. Most hallmarks of their divergent phenotypes are also found in the inbred RHA (RHA-I) and RLA (RLA-I) strains. For instance, they differ in the expression of sensitization to amphetamine. However, the pattern of spontaneous activity of the inbred rats seems to differ from that of outbred Roman strains. The present work shows the relevance of analyzing spontaneous activity as a covariant in order to determine the significance of day effect in the induction of behavioral sensitization to amphetamine (regime: 11 days, 1 mg/kg, i.p.) in the inbred strains and, for comparison, the standard low activity Sprague-Dawley (SD) strain. Our results also confirm that, in parallel to the outbred strains, only inbred RHA rats showed sensitization during the induction phase, here detectable from day 9 of treatment, while RLA-I and SD strains did not. Inbred RLA rats provide an interesting model to study individual resistance to sensitization, with nuances due to their underlying high spontaneous activity phenotype. PMID- 29522835 TI - Annexin V conjugated nanobubbles: A novel ultrasound contrast agent for in vivo assessment of the apoptotic response in cancer therapy. AB - In vivo assessment of apoptotic response to cancer therapy is believed to be very important for optimizing management of treatment. However, few noninvasive strategies are currently available to monitor the therapeutic response in vivo. Ultrasonography has been used to detect apoptotic cell death in vivo, but a high frequency transducer is needed. Fortunately, the capability of ultrasound contrast agents (UCAs) to exit the leaky vasculature of tumors enables ultrasound targeted imaging of molecular events in response to cancer therapy. In this study, we prepared a novel nano-sized UCA, namely, Annexin V-conjugated nanobubbles (AV-NBs, 635.5 +/- 25.4 nm). In vitro studies revealed that AV-NBs were relatively stable and highly echogenic. Moreover, these AV-NBs could easily extravasate into the tumor vasculature and recognize the apoptotic cells with high specificity and affinity in tumors sensitive to chemotherapy. Ultrasound imaging results demonstrated that AV-NBs had higher echogenicity and significantly greater enhancement compared with the untargeted control NBs (P < 0.01) inside the tumors after chemotherapy. Taken together, this study provides a promising method to accurately evaluate therapeutic effects at the molecular level to support cancer management. PMID- 29522837 TI - Chewing ameliorates the effects of restraint stress on pERK-immunoreactive neurons in the rat insular cortex. AB - We investigated the effects of chewing on the anterior and posterior insular cortices during restraint stress using phosphorylated extracellular signal regulated kinase (pERK) levels as a marker of neuronal responses. The stress only group demonstrated increased numbers of pERK-immunoreactive cells in both the anterior and posterior insular cortices compared to the control group (p < 0.01). In the stress with chewing group, the stress-induced increase of pERK immunoreactive cell numbers was suppressed in both insular cortices and these differences were statistically significant compared to the stress-only group (p < 0.01). The suppressive effects of chewing were more prominent in the anterior insular cortex than in the posterior insular cortex. In general, the anterior insular cortex contributes to emotional processing, whereas the posterior insular cortex is associated with sensorimotor processes. Therefore, these results suggest that chewing ameliorates the emotional and sensorimotor responses to stress in the anterior and posterior insular cortices, respectively, with a greater effect on emotion-forming processes than on sensorimotor processes. PMID- 29522838 TI - Region-specific differences in bioenergetic proteins and protein response to acute high fat diet in brains of low and high capacity runner rats. AB - Aerobic capacity is a strong predictor of mortality. Low capacity runner (LCR) rats exhibit reduced mitochondrial function in peripheral organs. A high fat diet (HFD) can worsen metabolic phenotype in LCR rats. Little is known about metabolic changes in the brains of these rats, however. This study examined protein markers of mitochondrial function and metabolism as a function of aerobic running capacity and an acute HFD in four brain regions: the striatum, hippocampus, hypothalamus, and substantia nigra. After 3 days HFD or chow diets, we measured peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC1-alpha), nuclear respiratory factors 1 (Nrf-1), mitochondrial transcription factor A (TFAM), and phosphorylated (activated) AMP-activated protein kinase (p-AMPK) protein levels in the four brain regions. LCR rats exhibited lower levels of mitochondrial proteins (PGC1-alpha, Nrf-1, TFAM), and greater p-AMPK, in striatum, but not in the other brain regions. Mitochondrial protein levels were greater in HFD LCR striatum, while p-AMPK was lower in this group. Markers of lower mitochondrial biogenesis and increased metabolic demand were limited to the LCR striatum, which nevertheless maintained the capacity to respond to an acute HFD challenge. PMID- 29522840 TI - Complementary landmarks facilitate ant navigation. AB - Visual landmarks are important navigational aids to many animals, and when more than one is available their juxtaposition can convey valuable new information to a navigator about progress toward a goal, depending on the landmarks' comparative distinctiveness. We investigated the effect of presenting rock ant colonies (Temnothorax albipennis) with identical horizontal landmarks either side of their route, versus one horizontal landmark paired with a sloping landmark, as they navigated to a new nest site. Our findings suggest that ants can obtain more navigational information from a combination of dissimilar landmarks: the average tortuosity of the route taken between old and new nests was significantly lower when a horizontal landmark was paired with a monotonically downward sloping landmark (the paths were more direct). The impact on available navigational information from the similarity or dissimilarity of nearby landmarks is likely made through more distinctive visual panoramas, and could be an influential factor in individual and collective animal decision-making about which routes are followed. Furthermore, the effect of landmark complementarity may be relevant to a wide range of species, including other insects or birds, and highlights the possibility that there is an intrinsic difference in the informational content of natural vs. artificial environments. PMID- 29522839 TI - The ontogeny of food-caching behaviour in New Zealand robins (Petroica longipes). AB - Hoarding or caching behaviour is a widely-used paradigm for examining a range of cognitive processes in birds, such as social cognition and spatial memory. However, much is still unknown about how caching develops in young birds, especially in the wild. Studying the ontogeny of caching in the wild will help researchers to identify the mechanisms that shape this advantageous foraging strategy. We examined the ontogeny of food caching behaviour in a wild New Zealand passerine, the North Island robin (Petroica longipes). For 12-weeks following fledging, we observed 34 juveniles to examine the development of caching and cache retrieval. Additionally, we compared the caching behaviour of juveniles at 12 weeks post-fledging to 35 adult robins to determine whether juveniles had developed adult-like caching behaviour by this age. Juveniles began caching mealworms shortly after achieving foraging independency. Multivariate analyses revealed that caching rate increased and handling time decreased with increasing age. Juveniles spontaneously began retrieving caches as soon as they had begun to cache and their retrieval rates then remained constant throughout their ensuing development. Likewise, the number of sites used by juveniles did not change with age. Juvenile sex, caregiver sex and the duration of post fledging parental care did not influence the development of caching, cache retrieval, the number of cache sites used and the time juveniles spent handling mealworms. At 12 weeks post-fledging, juveniles demonstrated levels of caching, cache retrieval and cache site usage that were comparable to adults. However, juvenile prey handling time was still longer than adults. The spontaneous emergence of cache retrieval and the consistency in the number of cache sites used throughout development suggests that these aspects of caching in North Island robins are likely to be innate, but that age and experience have an important role in the development of adult caching behaviours. PMID- 29522841 TI - Quantifying the social structure of a large captive flock of greater flamingos (Phoenicopterus roseus): Potential implications for management in captivity. AB - An appropriate social environment for species held in captivity is key for ensuring both good welfare and reproductive performance. Species with a complex social structure may suffer if their social requirements are not taken into consideration as part of management and husbandry strategies. Here we aim to understand the drivers of social structure, and the link between social structure and reproduction in a flock of 281 greater flamingos (Phoenicopterus roseus) at WWT Slimbridge Wetland Centre. Proximity-based associations between birds were measured three and four times per day (depending upon season and husbandry) from 2012 to 2016. To determine the effect of reproductive activity on social structure, display and nesting behaviour were also recorded for the 2015 breeding season (April-July). Results showed that birds displayed a wider range of social relationships, and that affiliations within the flock were not random. This flamingo flock was differentiated into discrete subgroups, and social structure was stable across some years, but not over all seasons. Social bonds were more consistent across seasons into the nesting period rather than outside of it. During breeding, not all birds that displayed built a nest, and not all displaying birds nested. Future research should further investigate differences in display and nesting patterns within a flock, and determine how the social structure of large flocks compares to smaller flocks of this species. Comparing captive data to information on wild bird sociality would be relevant to highlight any differences in patterns of assortment and connectivity. PMID- 29522842 TI - A type III complement factor D deficiency: Structural insights for inhibition of the alternative pathway. PMID- 29522844 TI - Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by butyrate. AB - BACKGROUND: Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the TH2 cytokines IL-5 and IL-13, which promote acute asthma exacerbation. Short-chain fatty acids (SCFAs) have been shown to attenuate T cell-mediated allergic airway inflammation. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown. OBJECTIVE: We investigated the immunomodulatory role of SCFAs in regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved. METHODS: We assessed the role of SCFAs in regulating survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in the ILC2 driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s. RESULTS: We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s. CONCLUSION: Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity and can serve as a potential therapeutic target for asthma. PMID- 29522843 TI - IL-25 enhances TH17 cell-mediated contact dermatitis by promoting IL-1beta production by dermal dendritic cells. AB - BACKGROUND: In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce TH2 cytokine production by various cell types, including TH2 cells, TH9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in TH2-type immune responses. Because both TH2-type and TH17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing TH2-type immune responses. However, the precise role of IL-25 in the pathogenesis of fluorescein isothiocyanate-induced CHS is poorly understood. OBJECTIVE: We investigated the contribution of IL-25 to CHS using Il25-/- mice. METHODS: CHS was evaluated by means of measurement of ear skin thickness in mice after fluorescein isothiocyanate painting. Skin dendritic cell (DC) migration, hapten-specific TH cell differentiation, and detection of IL 1beta-producing cells were determined by using flow cytometry, ELISA, and immunohistochemistry, respectively. RESULTS: In contrast to thymic stromal lymphopoietin, we found that IL-25 was not essential for skin DC migration or hapten-specific TH cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell- and non-immune cell-derived IL-25 was important for hapten-specific TH17 cell-mediated rather than TH2 cell-mediated inflammation in the elicitation phase of CHS by enhancing TH17-related, but not TH2-related, cytokines in the skin. In particular, IL-1beta produced by dermal DCs in response to IL-25 was crucial for hapten-specific TH17 cell activation, contributing to induction of local inflammation in the elicitation phase of CHS. CONCLUSION: Our results identify a novel IL-25 inflammatory pathway involved in induction of TH17 cell-mediated, but not TH2 cell-mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS. PMID- 29522845 TI - Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy? AB - The Learning Early About Peanut Allergy (LEAP) study proved that early introduction of peanut significantly prevented the development of peanut allergy. However, in regard to similar attempts to prevent egg allergy through early egg introduction, the Prevention of Egg Allergy in High-risk Infants with Eczema (PETIT) study is the only randomized intervention trial to show a statistically significant effect. Meta-analysis of those studies indicated that neither the total amount nor pretreatment of egg showed any effect on egg allergy at the age of 12 months. However, raw egg powder resulted in a significantly higher prevalence of allergic reactions at initial introduction, whereas use of boiled egg was much safer. The prevalence of atopic dermatitis/eczema at introduction of egg correlated significantly with the subsequent prevalence of allergic reactions at initial introduction. In addition, the prevalence of egg allergy in the late introduction group correlated significantly with the prevalence of atopic dermatitis at introduction, even when the atopic dermatitis was proactively treated with a topical corticosteroid ointment. It is definitely true that the number of trials and number of participants in each trial are insufficient for drawing firm conclusions, especially regarding the optimal dose, raw versus boiled, when to start, and for whom to intervene. Therefore we propose various studies that should be performed to generate stronger data and conclusions. However, on the basis of the most recent results, we postulate that simultaneous intervention by both early boiled egg introduction and eczema treatment is probably indispensable for primary prevention of egg allergy. PMID- 29522846 TI - A RAB27A 5' untranslated region structural variant associated with late-onset hemophagocytic lymphohistiocytosis and normal pigmentation. PMID- 29522847 TI - Immune modulation by neuronal electric shock waves. PMID- 29522850 TI - Dietary therapy for eosinophilic esophagitis. AB - Eosinophilic esophagitis is a chronic, immune-mediated esophageal disease triggered predominantly, but not exclusively, by food antigens. Presently, available food allergy tests are suboptimal to predict food triggers for eosinophilic esophagitis, especially in adults. Elemental diets (exclusive feeding with amino acid-based formulas) and empiric 6-food elimination diets (withdrawing milk, wheat, egg, soy, nuts, and fish/seafood for 6 weeks) have consistently shown the best efficacy rates. However, their high level of restriction and need for multiple endoscopies have hampered their implementation in clinical practice. Currently, milk, wheat/gluten, and egg are the most common food triggers in children and adults from the United States, Spain, and Australia. Hence less restrictive empiric schemes, such as a 4-food elimination diet (dairy, gluten-containing cereals, egg, and legumes) or a 2-food elimination diet (dairy and gluten-containing cereals) have been lately developed with good efficacy rates (2-food elimination diet, 43%; 4-food elimination diet in adults, 54%; and 4-food elimination diet in children, 64%). A step-up approach (2-4-6) might result in prompt recognition of a majority of responders with few food triggers, reducing the number of endoscopies and costs and shortening the diagnostic process. Standardization of food reintroduction, novel food allergy testing, and studies evaluating a milk elimination diet in children and the long term outcomes of dietary interventions are warranted. PMID- 29522848 TI - Electronic cigarettes: One size does not fit all. AB - Electronic cigarettes (ECs) have been growing rapidly in popularity among youth and adults in the United States over the last decade. This increasing prevalence is driven partially by the ability to customize devices, flavors, and nicotine content and the general notion that ECs are harmless, particularly in comparison with conventional cigarettes. In vitro and in vivo murine models have demonstrated a number of harmful biological effects of e-liquids and their aerosols. However, limited clinical data exist on whether these effects translate into detrimental long-term outcomes in human subjects. The short-term harmful respiratory effects of EC use demonstrated in nonsmokers argue against their use. However, slightly more favorable data exist for the respiratory benefits of substituting conventional cigarettes with ECs and the short-term efficacy of ECs as smoking cessation tools. Nonetheless, available research is severely limited in regard to long-term outcomes and by study designs fraught with bias, pointing to the need for additional research efforts with well-designed longitudinal studies to guide US Food and Drug Administration regulatory efforts. The hurdle presented by diverse device designs and e-liquid permutations, which contribute to the inconsistency of available data, also highlights the need for legislative standardization of ECs. PMID- 29522849 TI - Knob protein enhances epithelial barrier integrity and attenuates airway inflammation. AB - BACKGROUND: Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. OBJECTIVE: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. METHODS: Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. RESULTS: Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. CONCLUSION: Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma. PMID- 29522851 TI - The parasitic 68-mer peptide FhHDM-1 inhibits mixed granulocytic inflammation and airway hyperreactivity in experimental asthma. PMID- 29522852 TI - Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines. PMID- 29522853 TI - Nasal epithelium as a proxy for bronchial epithelium for smoking-induced gene expression and expression Quantitative Trait Loci. PMID- 29522854 TI - Chronic Amyloid beta Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3. AB - Microglia are instrumental for recognition and elimination of amyloid beta1-42 oligomers (AbetaOs), but the long-term consequences of AbetaO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AbetaO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AbetaO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. AbetaO infusion evoked a sustained inflammatory response including activation of NF kappaB, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors. Abeta1-42 plaques were not detectable likely due to microglial elimination of infused oligomers. In addition, we found upregulation of neuronal inhibitory ligands and their cognate microglial receptors, while downregulation of Esr1 and Scn1a, encoding estrogen receptor alpha and voltage-gated sodium-channel Na(v)1.1, respectively, was observed. These changes were associated with impaired hippocampus-dependent spatial memory and resembled early neurological changes seen in Alzheimer's disease. To investigate the role of inflammatory actions in memory deterioration, we performed MCC950 infusion, which specifically blocks the NLRP3 inflammasome. MCC950 attenuated AbetaO-evoked microglia reactivity, restored expression of neuronal inhibitory ligands, reversed downregulation of ERalpha, and abolished memory impairments. Furthermore, MCC950 abrogated AbetaO-invoked reduction of serum IL-10. These findings provide evidence that in response to AbetaO infusion microglia change their phenotype, but the resulting inflammatory changes are sustained for at least one month after the end of AbetaO challenge. Lasting NLRP3 driven inflammatory alterations and altered hippocampal gene expression contribute to spatial memory decline. PMID- 29522855 TI - Na+, K+-ATPase Activating Antibody Displays in vitro and in vivo Beneficial Effects in the Pilocarpine Model of Epilepsy. AB - Na+, K+-ATPase is an important regulator of brain excitability. Accordingly, compelling evidence indicates that impairment of Na+, K+-ATPase activity contributes to seizure activity in epileptic mice and human with epilepsy. In addition, this enzyme is crucial for plasma membrane transport of water, glucose and several chemical mediators, including glutamate, the major excitatory transmitter in the mammalian brain. Since glucose hypometabolism and increased glutamate levels occur in clinical and experimental epilepsy, we aimed the present study to investigate whether activation of Na+, K+-ATPase activity with specific antibody (DRRSAb) would improve glucose uptake and glutamate release in pilocarpine-treated mice. We found decreased uptake of the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-il)amino]-2-desoxi-d-glucose (2-NBDG) in cerebral slices from pilocarpine-treated animals. Interestingly, decreased 2 NBDG uptake was not detected in DRRSAb-treated slices, suggesting a protective effect of the Na+, K+-ATPase activator. Moreover, DRRSAb prevented the increase in glutamate levels in the incubation media of slices from pilocarpine-treated mice. In addition, in vivo intrahippocampal injection of DRRSAb restored crossing activity of pilocarpine-treated mice in the open-field test. Overall, the present data further support the hypothesis that activation of the Na+, K+-ATPase is a promising therapeutic strategy for epilepsy. PMID- 29522857 TI - Isoform-dependent Regulation of Drebrin Dynamics in Dendritic Spines. AB - Dendritic spines have stable filamentous actin (F-actin) and dynamic F-actin. The formation of stable F-actin plays a pivotal role in spine formation. Drebrin binds to and stabilizes F-actin in dendritic spines. Interestingly, the conversion of the drebrin E isoform to drebrin A occurs in parallel with synapse formation, suggesting that this conversion promotes synapse formation via F-actin accumulation. In this study, we measured the dynamics of GFP-tagged drebrin E (GFP-DE) and drebrin A (GFP-DA) in cultured hippocampal neurons by fluorescence recovery after photobleaching analysis. We found that GFP-DA has a larger stable fraction than GFP-DE. The stable drebrin fraction reflects its accumulation in dendritic spines, therefore the isoform conversion may increase the amount of stable F-actin in dendritic spines. The stable fraction was dependent on the drebrin A-specific sequence "Ins2", located in the middle of the drebrin protein. In addition, F-actin depolymerization with latrunculin A significantly reduced the stable GFP-DA fraction. These findings indicate that preferential binding of drebrin A to F-actin than drebrin E causes higher stable fraction of drebrin A in dendritic spines, although the F-actin-binding ability of purified drebrin E and drebrin A are comparable. Therefore, we suggest that a drebrin isoform conversion from drebrin E to drebrin A in dendritic spines results in the accumulation of drebrin-bound stable F-actin, which plays a pivotal role in synapse formation. PMID- 29522858 TI - Glucocorticoid receptor gene expression in a CLP-induced ARDS-like rat model treated with dexamethasone and metyrapone. AB - Glucocorticoids (GCs) are used for acute respiratory distress syndrome (ARDS) to improve or prevent lung injury. The mechanisms underlying the effects of GCs involve inadequate GC-receptor (GR)-mediated downregulation of pro-inflammatory factors despite elevated levels of cortisol. Within this context, knowledge of the transcriptional pattern of the GR gene in response to variations in physiological parameters may shed light on this issue. We addressed this problem by measuring plasmatic corticosterone (CCT) levels and assessing GR expression at transcript and protein levels in rats with caecal ligation and puncture (CLP) induced ARDS-like syndrome treated with dexamethasone and metyrapone. Seventy male rats were randomized into three main groups: Naive (any treatment), Sham (caecum-exposed) and CLP. CLP animals were divided into three groups according to pretreatments performed before surgery: CLP sal (0.9% NaCl ip), CLP metyrapone (50 mg.kg-1 ip) and CLP dexamethasone (0.5 mg.kg-1 ip). Our results showed that CLP sal promotes elevation in CCT levels, which are significantly reduced with metyrapone to levels comparable to untreated animals when dexamethasone is used. In this hormonal milieu, the GR gene transcript levels of both variants, GRalpha and GRbeta, are produced in comparable levels and in response to caecum-exposing surgery. Nonetheless, the expression of the GRalpha variant demonstrated positive sensitivity to variations in CCT levels and was downregulated in animals treated with dexamethasone. Moreover, nuclear translocation of GR protein decreased with high levels of plasma CCT and higher GR translocation was found in animals with moderate CCT levels; in either case, the process seemed to be positively associated with the CLP procedure. PMID- 29522856 TI - Effects of Platelet-Activating Factor on Brain Microvascular Endothelial Cells. AB - Platelet-activating factor (PAF) is a potent phospholipid mediator that exerts various pathophysiological effects by interacting with a G protein-coupled receptor. PAF has been reported to increase the permeability of the blood-brain barrier (BBB) via incompletely characterized mechanisms. We investigated the effect of PAF on rat brain microvascular endothelial cells (RBMVEC), a critical component of the BBB. PAF produced a dose-dependent increase in cytosolic Ca2+ concentration; the effect was prevented by the PAF receptor antagonist, WEB2086. The effect of PAF on cytosolic Ca2+ was abolished in Ca2+-free saline or in the presence of L-type voltage-gated Ca2+ channel inhibitor, nifedipine, indicating that Ca2+ influx is critical for PAF-induced increase in cytosolic Ca2+. PAF produced RBMVEC depolarization; the effect was inhibited by WEB2086. In cells loaded with [(4-amino-5-methylamino-2',7'-difluoro-fluorescein)diacetate] (DAF FM), a nitric oxide (NO)-sensitive fluorescent dye, PAF increased the NO level; the effect was prevented by WEB2086, nifedipine or by l-NAME, an inhibitor of NO synthase. Immunocytochemistry studies indicate that PAF reduced the immunostaining of ZO-1, a tight junction-associated protein, increased F-actin fibers, and produced intercellular gaps. PAF produced a decrease in RBMVEC monolayer electrical resistance assessed with Electric Cell-Substrate Impedance Sensing (ECIS), indicative of a disruption of endothelial barrier function. In vivo studies indicate that PAF increased the BBB permeability, assessed with sodium fluorescein and Evans Blue methods, via PAF receptor-dependent mechanisms, consequent to Ca2+ influx and increased NO levels. Our studies reveal that PAF alters the BBB permeability by multiple mechanisms, which may be relevant for central nervous system (CNS) inflammatory disorders. PMID- 29522859 TI - Creation of knock out and knock in mice by CRISPR/Cas9 to validate candidate genes for human male infertility, interest, difficulties and feasibility. AB - High throughput sequencing (HTS) and CRISPR/Cas9 are two recent technologies that are currently revolutionizing biological and clinical research. Both techniques are complementary as HTS permits to identify new genetic variants and genes involved in various pathologies and CRISPR/Cas9 permits to create animals or cell models to validate the effect of the identified variants, to characterize the pathogeny of the identified variants and the function of the genes of interest and ultimately to provide ways of correcting the molecular defects. We analyzed a cohort of 78 infertile men presenting with multiple morphological anomalies of the sperm flagella (MMAF), a severe form of male infertility. Using whole exome sequencing (WES), homozygous mutations in autosomal candidate genes were identified in 63% of the tested subjects. We decided to produce by CRISPR/cas9 four knock-out (KO) and one knock-in (KI) mouse lines to confirm these results and to increase our understanding of the physiopathology associated with these genetic variations. Overall 31% of the live pups obtained presented a mutational event in one of the targeted regions. All identified events were insertions or deletions localized near the PAM sequence. Surprisingly we observed a high rate of germline mosaicism as 30% of the F1 displayed a different mutation than the parental event characterized on somatic tissue (tail), indicating that CRISPR/Cas9 mutational events kept happening several cell divisions after the injection. Overall, we created mouse models for 5 distinct loci and in each case homozygous animals could be obtained in approximately 6 months. These results demonstrate that the combined use of WES and CRISPR/Cas9 is an efficient and timely strategy to identify and validate mutations responsible for infertility phenotypes in human. PMID- 29522860 TI - Multi-function microfluidic platform for sensor integration. AB - The limited availability of metabolite-specific sensors for continuous sampling and monitoring is one of the main bottlenecks contributing to failures in bioprocess development. Furthermore, only a limited number of approaches exist to connect currently available measurement systems with high throughput reactor units. This is especially relevant in the biocatalyst screening and characterization stage of process development. In this work, a strategy for sensor integration in microfluidic platforms is demonstrated, to address the need for rapid, cost-effective and high-throughput screening in bioprocesses. This platform is compatible with different sensor formats by enabling their replacement and was built in order to be highly flexible and thus suitable for a wide range of applications. Moreover, this re-usable platform can easily be connected to analytical equipment, such as HPLC, laboratory scale reactors or other microfluidic chips through the use of standardized fittings. In addition, the developed platform includes a two-sensor system interspersed with a mixing channel, which allows the detection of samples that might be outside the first sensor's range of detection, through dilution of the sample solution up to 10 times. In order to highlight the features of the proposed platform, inline monitoring of glucose levels is presented and discussed. Glucose was chosen due to its importance in biotechnology as a relevant substrate. The platform demonstrated continuous measurement of substrate solutions for up to 12 h. Furthermore, the influence of the fluid velocity on substrate diffusion was observed, indicating the need for in-flow calibration to achieve a good quantitative output. PMID- 29522861 TI - Association of regular walking and body mass index on metabolic syndrome among an elderly Korean population. AB - Aging is associated with increased body fat and lower lean body mass, which leads to increased prevalence of obesity and metabolic syndrome. This study aimed to investigate the association of regular participation in walking and body mass index (BMI) with metabolic syndrome and its 5 criteria in elderly Koreans. A total of 3554 (male = 1581, female = 1973) elderly subjects (age >= 65 years), who participated in the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V) were analyzed in this cross-sectional study. Participation in walking activity, BMI, metabolic syndrome and its 5 criteria; waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose (FG) levels, triglyceride (TG) levels, and high-density lipoprotein cholesterol (HDLC) levels, were measured. Subjects were categorized into four groups based on the duration and regularity of their walks and BMI. In the regular walking (>=30 min of continuous walking a day, on >=5 days a week) and normal weight (BMI < 23 kg/m2) group, WC, SBP, DBP, FG, and TG levels were significantly lower, and HDL-C levels were significantly higher, compared to the non-regular walking and overweight (BMI >= 23 kg/m2) group. Furthermore, the odds of metabolic syndrome was 4.36 times higher (Odds ratio [OR]: 4.36, 95% confidence interval [CI]: 3.37-5.63) in the non-regular walking and overweight group than that of the regular walking and normal weight group after controlling for the influence of age, sex, and smoking status. Moreover, The BMI (beta = 0.328, R2 = 0.152) were more contributing factors than Regular walking (beta = 0.011) for metabolic syndrome. In conclusions, regular participation in walking activity and implementing weight control may reduce the incidence rate of metabolic syndrome in elderly Koreans, with weight management serving as the greater influences of the two. PMID- 29522862 TI - Age-dependent changes at the blood-brain barrier. A Comparative structural and functional study in young adult and middle aged rats. AB - Decreased beta-amyloid clearance in Alzheimer's disease and increased blood-brain barrier permeability in aged subjects have been reported in several articles. However, morphological and functional characterization of blood-brain barrier and its membrane transporter activity have not been described in physiological aging yet. The aim of our study was to explore the structural changes in the brain microvessels and possible functional alterations of P-glycoprotein at the blood brain barrier with aging. Our approach included MR imaging for anatomical orientation in middle aged rats, electronmicroscopy and immunohistochemistry to analyse the alterations at cellular level, dual or triple-probe microdialysis and SPECT to test P-glycoprotein functionality in young and middle aged rats. Our results indicate that the thickness of basal lamina increases, the number of tight junctions decreases and the size of astrocyte endfeet extends with advanced age. On the basis of microdialysis and SPECT results the P-gp function is reduced in old rats. With our multiparametric approach a complex regulation can be suggested which includes elements leading to increased permeability of blood brain barrier by enhanced paracellular and transcellular transport, and factors working against it. To verify the role of P-gp pumps in brain aging further studies are warranted. PMID- 29522863 TI - Neuropsychological benefits of computerized cognitive rehabilitation training in Ugandan children surviving severe malaria: A randomized controlled trial. AB - BACKGROUND: Computerized cognitive rehabilitation training (CCRT) may be beneficial for alleviating persisting neurocognitive deficits in Ugandan severe malaria survivors. We completed a randomized controlled trial of CCRT for both severe malaria and non-malaria cohorts of children. METHODS: 150 school-age severe malaria and 150 non-malaria children were randomized to three treatment arms: 24 sessions of Captain's Log CCRT for attention, working memory and nonverbal reasoning, in which training on each of 9 tasks difficulty increased with proficiency; a limited CCRT arm that did not titrate to proficiency but randomly cycled across the simplest to moderate level of training; and a passive control arm. Before and after 2 months of CCRT intervention and one year following, children were tested with the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), computerized CogState cognitive tests, the Behavior Rating Inventory for Executive Function (BRIEF), and the Achenbach Child Behavior Checklist (CBCL). RESULTS: Malaria children assigned to the limited-CCRT intervention arm were significantly better than passive controls on KABC-II Mental Processing Index (P = 0.04), Sequential Processing (working memory) (P = 0.02) and the Conceptual Thinking subtest (planning/reasoning) (P = 0.02). At one year post-training, the limited CCRT malaria children had more rapid CogState card detection (attention) (P = 0.02), and improved BRIEF Global Executive Index (P = 0.01) as compared to passive controls. Non-malaria children receiving CCRT significantly benefited only on KABC-II Conceptual Thinking (both full- and limited-CCRT; P < 0.01), CogState Groton maze chase and learning (P < 0.01), and CogState card identification (P = 0.05, full CCRT only). Improvements in KABC-II Conceptual Thinking planning subtest for the non-malaria children persisted to one-year follow-up only for the full-CCRT intervention arm. CONCLUSION: For severe malaria survivors, limited CCRT improved attention and memory outcomes more than full CCRT, perhaps because of the greater repetition and practice on relevant training tasks in the absence of the performance titration for full CCRT. There were fewer significant cognitive and behavior benefits for the non malaria children, with the exception of the planning/reasoning subtest of Conceptual Thinking, with stronger full- compared to limited-CCRT improvements persisting to one-year follow-up. PMID- 29522864 TI - The correlation between nonylphenol concentration in brain regions and resulting behavioral impairments. AB - Nonylphenol (NP) has been introduced as the most common endocrine disturbing chemical (EDC) in the environment. NP exerts several adverse effects on the reproductive system, immune system, and central nervous system (CNS) via its potent hormonal activity. In this study, the correlation between NP concentration and the resulting memory impairment and induction of anxiety was examined in adult rats. NP (at doses of 0.2 or 2 mg/kg) and corn oil (as NP vehicle) were orally administrated for 35 days. On day 36, animals were evaluated for anxiety and cognitive performance using elevated plus maze and Morris water maze test, respectively. Rats were sacrificed afterwards for serum, cerebrospinal fluid (CSF), amygdala, and hippocampus NP level measurement using high performance liquid chromatography (HPLC). The behavioral results indicated that NP exposure at the dose of 2 mg/kg significantly reduces spatial learning and memory. Additionally, anxiety-like behavior was increased in animals received NP exposure compared to the vehicle group. Analysis of HPLC results showed that high quantity of NP is accumulated in hippocampus and amygdala tissues. Regression analysis showed a significant linear correlation between NP concentration and behavioral impairment. Overall, these data demonstrate the significant relationship between NP concentration in particular brain regions and the behavioral deficit. PMID- 29522865 TI - Intradetrusor Injections of Botulinum Toxin Type A in Children With Spina Bifida: A Multicenter Study. AB - OBJECTIVE: To assess the effectiveness of intradetrusor injections of botulinum toxin type A (IDBTX-A) in children with spina bifida. METHODS: All patients aged less than 16 years old who underwent IDBTX-A between 2002 and 2016 at 6 institutions were included in a retrospective study. Our primary endpoint was the success rate of IDBTX-A defined as both clinical improvement (no incontinence episodes between clean intermittent catheterizations [CICs], absence of urgency, and less than 8 CICs per day) and urodynamic improvement (resolution of detrusor overactivity and normal bladder compliance for age) lasting >=12 weeks. Predictive factors of success were assessed through univariate analysis. RESULTS: Fifty-three patients with a mean age of 8.5 years were included. All patients were under CIC and 88.7% had received anticholinergics with either poor efficacy or bothersome adverse events. The global success rate of the first injection (clinical and urodynamic) was 30%. Patients with closed spinal dysraphism had a significantly better success rate than patients with myelomeningocele (P = .002). The clinical success rate was 66% and was significantly associated with maximum urethral closure pressure (34 cm H2O vs 54.4 cm H2O, P = .02). The urodynamic success rate was 34%. Maximum cystometric capacity (P <.0001) and compliance (P = .01) significantly improved after the first IDBTX-A and maximum detrusor pressure tended to decrease (P = .09) except in the subgroup of patients with poor compliance. After a mean follow-up of 3.7 years, 23 patients (43.4%) required augmentation cystoplasty. Excluding 6 patients who were lost to follow-up, 38.3% of patients were still undergoing botulinum toxin injections at last follow-up. CONCLUSION: In this series, despite the fact that IDBTX-A enabled clinical improvement in 66% patients, urodynamic outcomes were poor resulting in a low global success rate (30%). PMID- 29522866 TI - Sexual Quality of Life After Treatment of Stress Urinary Incontinence With Adjustable Tension-free Mesh System in Women Who Were Sexually Active Before Surgery. AB - OBJECTIVE: To assess the sexuality and quality of life of sexually active women with stress or mixed urinary incontinence (SUI or MUI) after surgery with adjustable tension-free suburethral mesh system (transobturator adjustable tape or transvaginal adjustable tape). MATERIALS AND METHODS: This intervention study with 2 years of follow-up (visits at 3 months, 1 year, and 2 years) involved 60 women with SUI or MUI who underwent surgery using transobturator adjustable tape or transvaginal adjustable tape during 2008-2014 in a Spanish region. The variables of interest measured pre- and postintervention were the global scores on the following questionnaires: (1) the Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire-12; (2) the International Consultation on Incontinence Questionnaire; and (3) the Incontinence Quality of Life Questionnaire. Mixed linear models were constructed to determine the effect of the intervention on the outcome variables. RESULTS: A significant improvement (P <.001) was seen over time in all the questionnaires, although between the 1- and 2-year visits there was a slight deterioration in all of them. CONCLUSION: The technique provided an improved quality of life and sexuality, which was maintained at all the postoperative visits compared with baseline. PMID- 29522867 TI - A Homeopathic Alternative to Potassium Citrate in Patients With Recurrent Nephrolithiasis. PMID- 29522868 TI - Tumor Contact Surface Area As a Predictor of Functional Outcomes After Standard Partial Nephrectomy: Utility and Limitations. AB - OBJECTIVE: To evaluate contact surface area (CSA) between the tumor and parenchyma as a predictor of ipsilateral parenchyma and function preserved after partial nephrectomy (PN). Previous studies suggested that CSA is a strong predictor of functional outcomes but the limitations of CSA have not been adequately explored. PATIENTS AND METHODS: Four hundred nineteen patients managed with standard PN for solitary tumor with necessary studies to evaluate and analyze ipsilateral preoperative or postoperative parenchymal mass and function. Parenchymal mass and CSA were measured using contrast-enhanced computed tomography <2 months prior and 3-12months after PN. CSA was calculated: 2pird, where r = radius and d = intraparenchymal depth. Pearson-correlation evaluated relationships between CSA and ipsilateral parenchymal mass or function preserved. Multivariable regression assessed predictors of function preserved. Conceptually, the CSA paradigm should function better for exophytic tumors than endophytic ones. RESULTS: Median tumor size was 3.5 cm and R.E.N.A.L. was 8. Median global and ipsilateral glomerular filtration rate preserved were 89% and 79%, respectively. Median ipsilateral parenchymal mass preserved was 85% and significantly higher for exophytic masses (P = .001). Median CSA was 22.8 cm2 and significantly less for exophytic masses (P = .02). CSA associated with both ipsilateral function and mass preserved (both P < .05), but the correlations were only modest (r = 0.25 and 0.36, respectively). On multivariable analysis, CSA associated with function preserved for exophytic masses (P = .01), but not for endophytic ones (P = .27). CONCLUSION: CSA associates with functional outcomes after standard PN, although the strength of the correlations was modest, unlike previous studies, and CSA was not an independent predictor for endophytic tumors. Further study will be required to evaluate the utility of CSA in various clinical settings. PMID- 29522869 TI - The 2D-3D Registration Method in Image Fusion Is Accurate and Helps to Reduce the Used Contrast Medium, Radiation, and Procedural Time in Standard EVAR Procedures. AB - OBJECTIVE: This study aimed to evaluate the accuracy and the effectiveness of 2D 3D registration method of image fusion (IF) technology in endovascular aneurysm repair (EVAR). METHODS: We performed a review of our institutional endovascular aortic database of patients who had undergone EVAR between 2011 and 2015 before and after the installation of a 3D IF computed tomography system in our hybrid operating room. RESULTS: The accuracy was assessed in 14 endovascular procedures and showed a median registration error of 1.8 mm at the origin of the right renal artery and 1.0 mm at the origin of the left renal artery and a complete visual accuracy in 42% of the cases. EVAR was performed using the intraoperative IF technique with a 2D-3D registration method in 105 patients (group IF), whereas 47 patients done without served as controls. The IF group had a significantly reduced amount of used contrast compared with controls with a median of 58 mL and P < 0.0001. The intraoperative exposition to radiation was similar between the 2 groups with a median dose area product of 2,343.7 cGy cm2 in the IF group and 3,219 cGy cm2 among the controls (P = 0.457). The radiation dose in the sub group IF (including patients operated by the 2 most experienced surgeons) was lower than that in sub controls (median, 1,087 cG cm2 vs. 2,705.3 cG cm2, P = 0.012). The procedure time and the time of intraoperative radiation did not differ between the study groups (P = 0.117 and 0.106, respectively), as did not fluoroscopy time in the sub group IF (median, 6.3 min, vs. 9.5 min, P = 0.067), but for the 2 most experienced surgeons, the procedural time was shortened when using IF (P = 0.002). CONCLUSIONS: The 2D-3D registration method of IF guidance is accurate to delineate the vessels of interest and could help the execution of the EVAR procedures with a significantly reduced amount of contrast medium and also with reduced radiation and shorter procedural duration when surgeons are more familiar with EVAR and IF. PMID- 29522870 TI - Comparison of Measurement and Grading of Carotid Stenosis with Computed Tomography Angiography and Doppler Ultrasound. AB - BACKGROUND: Doppler ultrasound (DUS) and computed tomography angiography (CTA) are the most commonly used imaging modalities for carotid disease. The aim of this study was to test the accuracy and reproducibility of CTA-derived measurements of carotid stenosis and compare them with those obtained by DUS. METHODS: Images of 100 carotid arteries of patients who underwent carotid DUS at our unit and CTA of the carotids within a 28-day period were identified retrospectively from multidisciplinary team meeting records. CTAs were assessed by 2 investigators, each using a manual and a semi-automated method. With both methods, the degree of stenosis was calculated using the North American Symptomatic Carotid Endarterectomy Trial equation and graded as mild (0-49%), moderate (50-69%), or severe (70-99%). Cohen's kappa and specificity and sensitivity for >=50% stenosis were calculated. RESULTS: The interobserver agreement was moderate (kappa 0.407, weighted-kappa 0.517) for the manual method and good (kappa 0.786, weighted-kappa 0.842) for the semi-automated method. Using DUS as the gold standard, the semi-automated method had greater sensitivity (75%) and specificity (91%) in detecting clinically significant carotid artery stenosis (>=50%) than the manual one (63% and 86%, respectively). Agreement between DUS and the semi-automated method of CTA reporting was moderate (kappa 0.453, 95% confidence interval [CI]: 0.320-0.586, weighted-kappa 0.598, 95% CI: 0.486 0.710), whereas DUS and the manual method of CTA reporting had only fair agreement (kappa 0.344, 95% CI: 0.209-0.478, weighted-kappa 0.446, 95% CI: 0.315 0.577). CONCLUSIONS: CTA tends to underestimate the degree of stenosis when compared with DUS. The semi-automated method of CTA reporting has greater reproducibility and greater agreement with DUS. These findings have practical implications when CTA is used to measure the degree of carotid stenosis in clinical practice. PMID- 29522871 TI - Standardization of a Carbon Dioxide Automated System for Endovascular Aortic Aneurysm Repair. AB - BACKGROUND: Endovascular aortic repair (EVAR) is presently the preferred treatment for abdominal aortic aneurysm; however, it requires the injection of a contrast medium, which can hamper the renal function. Other nontoxic agents such as carbon dioxide (CO2) have been sporadically tested in this setting with uncertain results. The aim of the study is to investigate the efficacy of a new standardized CO2 injection method in standard EVAR procedures. METHODS: Between August and October 2016, 31 consecutive patients (median age 76.1 [interquartile range {IQR}: 7.4] years) were submitted to standard EVAR. Proximal and distal endograft landing zones were identified by the injection of 100 mL of CO2 at 300 mm Hg, through an 11 cm 10F femoral sheath by a specifically manufactured automated injection device (Angiodroid Srl, San Lazzaro, Bologna, Italy). Before EVAR deployment, a confirmative injection with a conventional contrast medium was accomplished. The possibility of precisely visualizing the proximal and distal landing zones by CO2 digital subtraction angiography (DSA) was evaluated considering the contrast medium injection obtained in the same procedure as a gold standard. Similarly, the possible presence of endoleak was assessed at the end of the procedure by the 2 techniques. RESULTS: CO2 DSA allowed to identify the juxtarenal landing zone of the endograft in 19/31 cases (61%) and the distal one in 31/31 (100%). In 12 (39%) cases, CO2 injection failed to visualize at least the lowest renal artery. This occurred in large aneurysms with scarce thrombotic apposition and a luminal volume greater than 95.9 (IQR: 25.2) mm3. Completion CO2 DSA detected type II endoleaks (ELIIs) in 10 cases compared with 2 of conventional contrast media. CONCLUSIONS: The injection of nontoxic CO2 through an automated device allowed to perform EVAR procedures effectively, in the majority of cases. In some cases, a single injection of a minimum amount of conventional contrast medium can be used to overcome the lack of renal artery visualization by CO2. ELIIs are more frequently visualized with CO2 compared with standard contrast medium. Although the CO2 injection technique needs further amelioration particularly in the renal arteries detection, this technique appears promising and possibly substitutive of the standard contrast medium, with significant benefit for the renal function. PMID- 29522872 TI - External Validation and Evaluation of Reliability of the FARP2 Score to Predict Early Graft Failure after Infrainguinal Bypass. AB - BACKGROUND: To evaluate the accuracy of the FARP2 (female gender [F], bypass after a previous angioplasty [A], Redo bypass [R], and Pedal bypass [P2]) scoring system in predicting early graft failure (EGF) after infrainguinal bypass surgery (IBS). METHODS: Charts of patients who underwent IBS between January 2014 and January 2017 in 2 tertiary academic centers were evaluated retrospectively. In follow-ups, 1 week after operation, detailed physical examination was done, Doppler ultrasonography was performed 1 month after operation, and integrity of the graft was evaluated. Calculation of FARP2 score was performed by a single surgeon (M.S.) who was well informed regarding FARP2 scoring system. The FARP2 scoring system was evaluated as following: female gender 1 point, bypass after a previous angioplasty 1 point, redo bypass 1 point, and pedal bypass 2 points. RESULTS: Totally, 231 patients (180 men and 51 women) were enrolled in the study. The mean FARP2 score was 0.52 +/- 0.73. The graft occlusion occurred in 23 patients (10%). Presence of critical leg ischemia was lower in patients who faced early graft occlusion (P = 0.002). On the other hand, Rutherford classification score was significantly higher in patients who did not face graft occlusion (4.1 vs. 3.4, P = 0.007). Moreover, unsuccessful angioplasty history and history of previous surgery were more common in that group (P < 0.001 and P < 0.001, respectively). None of the patients faced acute pulse loss, numbness loss, or ulcerative lesion after unsuccessful angioplasty. The mean interval between unsuccessful angioplasty and bypass was 1 +/- 1.2 days in our study, which may have a role to prevent undesirable clinical consequences. The FARP2 score was 1.5 +/- 1.2 and 0.4 +/- 0.6 in patients who faced graft occlusion and in patients without occlusion (P < 0.001). Multivariate regression analysis identified that critical leg scheme, presence of unsuccessful angioplasty history, and history of previous bypass operation were found as a predictive factor for EGF (P = 0.044, P < 0.001, and P = 0.003, respectively). Finally, our study demonstrated that patients with FARP2 score 3-4 have 2.88-fold increased graft occlusion risk when compared with patients with FARP2 score 1-2. CONCLUSIONS: Our study externally validates that the FARP2 scoring system is related with EGF after IBS. The FARP2 score may be an effective practice in prediction of EGF in patients with peripheral arterial bypass surgery. PMID- 29522873 TI - Catheter-Directed Thrombolysis Versus Pharmacomechanical Thrombectomy for Upper Extremity Deep Venous Thrombosis: A Cost-Effectiveness Analysis. AB - BACKGROUND: Upper extremity deep vein thrombosis represents (UEDVT) 2-3% of all deep vein thrombosis. Catheter directed thrombolysis (CDT) was replaced largely by pharmacomechanical thrombolysis (PMT) in our institution. In this study we compared the immediate and 1-year results as well as the total hospital costs between CDT and PMT in the treatment of UEDVT. METHODS: From 2006 to 2013, 55 patients with UEDVT were treated with either CDT or PMT at Helsinki University Hospital. Of them, 43 underwent thoracoscopic rib resection later to relieve phlebography-confirmed vein compression. This patient cohort was prospectively followed up with repeated phlebographies. CDT was performed to 24 patients, and 19 had PMT with a TrellisTM device. Clinical evaluation and vein patency assessment were performed with either phlebography or ultrasound 1 year after the thrombolysis. Primary outcomes were immediate technical success, 1-year vein patency, and costs of the initial treatment. RESULTS: The immediate overall technical success rate, defined as recanalization of the occluded vein and removal of the fresh thrombus, was 91.7% in the CDT group and 100% in the PMT group (n.s.). The median thrombolytic time was significantly longer in CDT patients than that in PMT patients (21.1 vs. 0.33 hr, P < 0.00001). There were no procedure-related complications. The 1-year primary assisted patency rate was similar in both the groups (91.7% and 94.7%). There were no recurrences of clinical DVT. The hospital costs for the acute period were significantly lower in the PMT group than those in the CDT group (medians: 11,476 ? and 5,975 ? in the CDT and PMT groups, respectively [P < 0.00001]). CONCLUSIONS: The clinical results of the treatment of UEDVT with CDT or PMT were similar. However, PMT required shorter hospital stay and less intensive surveillance, leading to lower total costs. PMID- 29522874 TI - A Trainee Perspective to Issues Needing Redressal in Current Vascular Surgery Training Programs: Survey Results from 2004 to 2015. AB - BACKGROUND: Vascular surgery training and practice have been constantly evolving in the last 2 decades. The goal of this study is to report the changing trends in perspectives of vascular surgery trainees on current training program and issues that need redressal in vascular training and practice. METHODS: Vascular surgery trainees in the United States, who attended the Society of Clinical Vascular Surgery meeting from 2004 to 2015, were surveyed annually with an anonymous questionnaire during the meet. Questions pertaining to their endovascular and open surgical learning experience, independent performance of procedures, challenges of job search, starting an independent practice, and their perception of issues in vascular surgery training were analyzed. Responses from the first half of the decade (2004-2009) were compared with the second half (2010-2015) to identify evolving trends in trainee perception. RESULTS: Among the 908 vascular surgery trainees who attended the annual meeting from 2004 to 2015, 670 (74%) trainees responded to the questionnaire. The mean age of vascular trainees was 32.5 years. In the latter half of the decade, there was a 2-fold increase in female trainees, from 12.3% to 23.6% (P = 0.002), and the integrated program trainees also increased from 0% to 12% of respondents (P = 0.0023). Trainee satisfaction with endovascular training improved from 78% to 90% (P = 0.0001), and satisfaction with open surgical experience was unchanged at 83% over the 10 year period (P = 0.16). The perception of vascular laboratory experience improved with only 35% vs. 27% (P = 0.016) of respondents dissatisfied, despite only a third of respondents actually performing the noninvasive tests in both the former and the latter half of the decade, respectively. CONCLUSIONS: Although the quality of vascular cases during training has improved, vascular trainees desire shorter training paradigms, and vascular laboratory education is still viewed as deficient. These findings can be used by training programs to re-examine their curricula and implement changes to improve the quality of training the next generation of vascular surgeons. PMID- 29522875 TI - Predicting Technical Success after Fistuloplasty: An Analysis of 176 Procedures. AB - BACKGROUND: Significant stenoses in arteriovenous fistulae (AVFs) or arteriovenous grafts (AVGs) with limitation of flow and dialysis inadequacy should prompt consideration for fistuloplasty. We sought to identify fistulae, lesions, and patient-specific variables, which predict for outcomes after fistuloplasty. METHODS: Data were extracted retrospectively from a renal access database from 2011 to 2016 of patients undergoing fistuloplasty. Demographics, comorbidities, outcomes of intervention, and flow rates documented on preintervention and postintervention duplex were collected. Secondary analysis of factors associated with postfistuloplasty flow rates of >600 mL/min, previously shown to be predictive of not requiring future intervention, was performed. RESULTS: Of 204 attempted fistuloplasties, 176 were completed. One hundred forty (79.5%) were native AVFs and 34 (19.3%), AVGs (no data for 2). Median stenosis treated was 75%, with a majority (43.8%) in the proximal outflow vein. Flow rate on duplex after fistuloplasty was significantly better in AVFs (mean improvement 189.2 mL/min) than that in AVGs (mean improvement 51.8 mL/min; P = 0.034). Greatest flow improvement occurred for needling site stenotic lesions compared with other locations (from anastomosis to central vein) but was not significant. Brachio-brachial or brachio-axillary AVGs did significantly (P < 0.05) worse than all other fistulae types. The presence of hypertension was predicted for postfistuloplasty flow rate of >600 mL/min. CONCLUSIONS: Flow rates after fistuloplasty vary depending on the type of fistula treated and the presence of hypertension. Knowledge of this can lead to better patient selection and counseling for fistuloplasty. PMID- 29522876 TI - The effect of pH on citric acid cough challenge: A randomised control trial in chronic cough and healthy volunteers. AB - INTRODUCTION: Citric acid has been used for over six decades to induce cough; however the mechanism of its pro-tussive effect is still not fully understood. We assessed the response to inhalation of citric acid at varying levels of acidity to determine if the pH of the solution plays a role in the induction of cough. Data was collected from both healthy volunteers and patients with chronic cough. METHODS: 20 chronic cough patients and 20 healthy volunteers were recruited and underwent three cough challenges on separate days. Each visit involved 5 repeated one second inhalations of 300 mM citric acid solution. The concentration of the citrate cation remained constant, but the pH of the solution altered by the addition of sodium bicarbonate to 3, 5 and 6, representing the pKa values of the individual acid moieties. The total number of coughs elicited was recorded for each inhalation. RESULTS: Two subjects withdrew and were not included in the analysis. Participants were gender matched, each group consisting of 12 females. 74% of chronic coughers coughed at pH 3 (mean coughs 16), 89% coughed at pH 5 (18) and 63% coughed at pH 6 (7). In healthy volunteers, 60% of subjects coughed at pH 3 (9), 30% of subjects coughed at pH 5 (3), and 10% of subjects coughed at pH 6 (0). Thus chronic cough patients coughed more than healthy volunteers and did not exhibit a clear pH concentration response. There was also a greater variability in their response to individual challenges. PMID- 29522877 TI - Metabonomic profiling of chronic intermittent hypoxia in a mouse model. AB - Chronic intermittent hypoxia (ChIH) is a dominant feature of obstructive sleep apnoea (OSA) and is associated to metabolic alterations and oxidative stress (OS). Although management of OSA is well established, the research of new biomarkers that are independent of confounding factors remains necessary to improve the early detection of comorbidity and therapeutic follow-up. In this study, the urinary metabonomic profile associated to intermittent hypoxia was evaluated in a mouse model. When exposed to intermittent hypoxia, animals showed a significant alteration in energy metabolism towards anaerobic pathways and signs of OS imbalance. A compensatory response was observed over time. Our data also indicates an excess production of vitamin B3, liver function modulations and a stimulation of creatine synthesis which could be used to evaluate the ChIH repercussions. As well, TMAO and allantoin could constitute interesting biomarker candidates, respectively in the context of cardiovascular risk and OS associated to OSA. PMID- 29522878 TI - Quantification of molecular heterogeneity in kidney tissue by targeted proteomics. AB - : Renal diseases are driven by alterations in the entity of proteins within the kidney, at the level of single cells, nephron subunits (such as glomerulus and tubule), tissues and body fluids. Histologically, kidney diseases are extremely heterogeneous. Mass-spectrometry based proteomics provides a unique opportunity to interrogate heterogeneity and dynamics of various proteome layers within the kidney to better understand physiology and pathophysiology, and to translate signaling networks into therapies. Yet, the success of this endeavor will largely depend on improving proteomic data acquisition methods toward increased reproducibility. Here, we provide an overview of targeted proteomics studies in renal tissue and their insights into major renal diseases such as diabetic nephropathy, acute kidney injury and chronic kidney disease. The technical approaches currently include antibody-based and mass spectrometry based approaches, range from single-cells to single-nephrons to bulk tissue proteomic acquisitions, and are applied to physiological studies and translational approaches in biomarker discovery. Within this context, we identify key challenges in proteomics of kidney biopsies. We also suggest that novel models of translational nephrology have increased need for targeted acquisition of proteomics data with focus on primary urinary cells, organoids and induced renal epithelial cells (IRECs). In conclusion, targeted proteomics will be very beneficial to identify heterogenic disease mechanisms that drive renal disease and further emerge as an important tool in translational kidney research. SIGNIFICANCE: Improved targeted proteomics technologies will be an important cornerstone of renal systems medicine in order to identify and tackle the heterogenic disease mechanisms driving renal disease. PMID- 29522879 TI - Complementary transcriptome and proteome profiling in cabbage buds of a recessive male sterile mutant provides new insights into male reproductive development. AB - : Plant male reproductive development is a very complex biological process that involves multiple metabolic pathways. To reveal novel insights into male reproductive development, we conducted an integrated profiling of gene activity in the developing buds of a cabbage recessive genetic male sterile mutant. Using RNA-Seq and label-free quantitative proteomics, 2881 transcripts and 1245 protein species were identified with significant differential abundance between the male sterile line 83121A and its isogenic maintainer line 83121B. Analyses of function annotations and correlations between transcriptome and proteome and protein interaction networks were also conducted, which suggested that the male sterility involves a complex regulatory pattern. Moreover, several key biological processes, such as fatty acid metabolism, tapetosome biosynthesis, amino acid metabolism and protein synthesis and degradation were identified as being of relevance to male reproductive development. A large number of protein species involved in sporopollenin synthesis, amino acid synthesis, ribosome assembly, protein processing in endoplasmic reticulum and lipid transfer were observed to be significantly down-accumulated in 83121A buds, indicating their potential roles in the regulation of cabbage microspore abortion. In summary, the conjoint analysis of the transcriptome and proteome provided a global picture regarding the molecular dynamics in male sterile buds of 83121A. BIOLOGICAL SIGNIFICANCE: Male sterile mutants are excellent materials for the study of plant male reproductive development. This study revealed the molecular dynamics of recessive male sterility in cabbage at the transcriptome and proteome levels, which deepens our understanding of the metabolic pathways involved in male development. Moreover, the male sterility-related genes identified in this study could provide a reference for the artificial regulation of cabbage fertility by using genetic engineering technology, which may result in potential applications in agriculture such as production of hybrid seeds using male sterility. PMID- 29522880 TI - Systematically integrated metabonomic-proteomic studies of Escherichia coli under ciprofloxacin stress. AB - : Many antibiotics are used to kill pathogenic Escherichia coli each year, resulting in an increase in the number of antibiotic-resistant strains. In this study, an integrated metabonomic-proteomic method was performed to systematically compare the profiles of metabolites and proteins with or without ciprofloxacin (CFLX) treatment. Proteomics identified 290 altered proteins including 143 with decreased and 147 increased expression, respectively. Metabonomics identified 65 altered metabolites including 58 and 7 with decreased and increased expression, respectively. The integrated analysis showed that the CFLX inhibited the DNA replication and increased the expression of DNA gyrase and DNA topoisomerase 1, while causing a sharp decrease in metabolic activity such as the alanine, aspartate and glutamate metabolism. Moreover, CFLX affected the biosynthesis of aminoacyl- transfer RNAs (tRNAs), leading to an increase in aminoacyl-tRNAs ligases, but limited the aminoacyl-tRNAs-mediated-biosynthesis of related amino acids. In this study, we identified the metabolite and protein profiles under CFLX stress, indicating the mode of action of antibiotics in E. coli. Furthermore, the decreasing metabolic activity in E. coli may be an effective strategy to escape killing by antimicrobials or toxic compounds. The results of this study will advance our understanding of the mechanisms underlying the resistance of bacteria to antibiotics. BIOLOGICAL SIGNIFICANCE: To investigate the biological impact of antibiotics stress on Escherichia coli, we applied an integrated metabonomic-proteomic method to systematically compare the profiles of metabolites and proteins between with and without antibiotics ciprofloxacin (CFLX) treatment. Following bioinformatics analysis showed that CFLX inhibited the DNA replication and increased the expression of DNA gyrase and DNA topoisomerase, while causing a sharp increase in the alanine, aspartate and glutamate metabolism. Moreover, CFLX affected the biosynthesis of tRNAs and limited the generation of related amino acids metabolites. In a summary, our results will provide the metabolite and protein profiles under CFLX stress, indicating the mode of action of antibiotics in E. coli. The results of this study will advance our understanding of the mechanisms underlying the resistance of bacteria to antibiotics. PMID- 29522881 TI - Evaluation of the antioxidant system and neurotoxic effects observed in Rhamdia branneri (Teleostei: Heptapteridae) sampled from streams of the lower Iguazu River basin. AB - The use of multiple biomarkers has been shown to be an efficient method for evaluating environmental contamination. In this work, we evaluate neurotoxic effects and the antioxidant system responses of the R. branneri collected in two streams of lower Iguazu River basin, relating them with different percentage of vegetation coverture, presence of pesticides and fall and winter seasons. The biological samples were collected in March and August of 2015, from two streams that belong to the lower Iguazu River basin (Brazil): the Manoel Gomes River and the Arquimedes Stream. Soil analyses were performed, and the results showed the presence of the following organophosphates in the Manoel Gomes River and the Arquimedes Stream: disulfoton, methyl parathion, and ronnel. The present study detected inhibition of cholinesterase activity in the brain and muscle of fish samples during the fall from the Manoel Gomes River and the Arquimedes Stream. In the Manoel Gomes River, elevated lipoperoxidation was also observed during the fall. It was observed that the increase or decrease of biomarkers was related to temporal variation and, possibly, to the exposure of animals to agrochemicals. Although the Manoel Gomes River and the Arquimedes Stream are located in regions with large areas of vegetation, the soil analyses show that agrochemical residues are able to reach these locations, which suggests that the fauna are in contact with oxidant and anti-cholinesterase agents during the fall, in addition to respond differently during each season. PMID- 29522882 TI - Erratum to: A randomized, open label trial of methadone continuation versus forced withdrawal in a combined US prison and jail: Findings at 12 months post release [Drug and Alcohol Dependence 184 (2018) 57-63]. PMID- 29522883 TI - Congenital disorders of bone and blood. AB - Bone and marrow are the two facets of the same organ, in which bone and hematopoietic cells coexist and interact. Marrow and skeletal tissue influence each-other and a variety of genetic disorders directly targets both of them, which may result in combined hematopoietic failure and skeletal malformations. Other conditions primarily affect one organ with secondary influences on the other. For instance, various forms of congenital anemias reduce bone mass and induce osteoporosis, while osteoclast failure in osteopetrosis prevents marrow development reducing medullary cavities and causing anemia and pancytopenia. Understanding the pathophysiology of these conditions may facilitate diagnosis and management, although many disorders are presently incurable. This article describes several congenital bone diseases and their relationship to hematopoietic tissue. PMID- 29522884 TI - Microarray analysis in pregnancies with isolated echogenic bowel. AB - INTRODUCTION: Fetal echogenic bowel is a frequent sonographic finding, demonstrated in about 1% of pregnancies. The advised evaluation of fetal echogenic bowel includes maternal serology, genetic testing for cystic fibrosis, detailed sonographic anatomic survey, and invasive prenatal testing for fetal chromosomal aberrations. The objective of our study was to evaluate the risk for clinically significant chromosomal microarray analysis (CMA) findings in pregnancies with isolated echogenic bowel. METHODS: Data from all CMA analyses performed due to isolated echogenic bowel reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained. Risk estimation was performed comparing the rate of abnormal microarray findings to the control population, based on a systematic review of 9272 pregnancies and a large local cohort of 5541 fetuses with normal ultrasound, undergoing CMA testing due to maternal request. RESULTS: Of 103 CMA analyses performed due to isolated echogenic bowel, two (1.94%) pathogenic findings were detected (47,XYY and 16p11.2 duplication). This risk was not significantly elevated compared to the control groups. In addition, three variants of unknown significance were demonstrated. CONCLUSIONS: To our best knowledge, our study is the first report describing the rate of clinically significant copy number variants in pregnancies with isolated echogenic bowel. According to our results, it seems that pregnancies with isolated echogenic bowel do not have an increased risk for abnormal CMA compared to fetuses with no evidence of sonographic anomalies. Our findings suggest that the consideration to perform CMA analysis in such pregnancies should not differ from any pregnancy with normal ultrasound. PMID- 29522885 TI - Effects of in-office bleaching on human enamel and dentin. Morphological and mineral changes. AB - BACKGROUND: The effects of HP-based products upon dental enamel and dentin are inconclusive. AIM: To evaluate changes in micromorphology and composition of calcium (Ca) and phosphate (P) in enamel and dentin after the application of 37.5% hydrogen peroxide (HP) and 35% carbamide peroxide (CP) METHODS: Crowns of 20 human teeth were divided in two halves. One half was used as control specimen and the other as experimental specimen. The control specimens were kept in artificial saliva, and the experimental specimens were divided into four groups (n=5 each): group 1 (enamel HP for 45min); group 2 (dentin HP for 45min); group 3 (enamel CP for 90min); and group 4 (dentin CP for 90min). The morphological changes were evaluated using confocal laser scanning microscopy (CLSM), while the changes in the composition of Ca and P were assessed using environmental scanning electron microscopy combined with a microanalysis system (ESEM+EDX). The results within each group and between groups were compared using the Wilcoxon test and Mann-Whitney U-test, respectively (p<0.05). RESULTS: Similar morphological changes in the enamel and no changes in dentin were assessed with both products. Ca and P decreased in enamel and dentin, without significant differences between them or with respect to their control specimens (p>0.05). CONCLUSIONS: When bleaching products with a neutral pH are used in clinical practice, both, the concentration and the application time should be taken into account in order to avoid possible structural and mineral changes in enamel and dentin. PMID- 29522886 TI - Medication Errors With Pediatric Liquid Acetaminophen After Standardization of Concentration and Packaging Improvements. AB - OBJECTIVE: To assess the impact of the 2011 changes in pediatric single ingredient liquid acetaminophen product packaging and standardization of the acetaminophen concentration (160 mg/5 mL) on poison control center exposures due to medication errors. METHODS: National Poison Data System (NPDS) data from January 1, 2007, through December 31, 2016, were used to identify medication error exposures involving single-ingredient liquid acetaminophen in children younger than 12 years of age. Surveys were conducted through 6 regional poison control centers to obtain additional information on a subset of exposures. RESULTS: The annual frequency of NPDS exposures due to medication errors with single-ingredient liquid acetaminophen products was 8260 +/- 670 exposures/year during 2007-2011. Children <2 years of age accounted for 66% of exposures. The overall rate of exposures fell to 6669 +/- 662 during 2012-2016 (19% decrease; P = .005). Four percent of exposures led to health care facility referrals. Caregivers involved with exposures in children <2 years of age cited health professionals as the source of dosing information in only 69% of cases despite the absence of specific dosing directions for these children on product labels. CONCLUSIONS: Implementation of a single concentration for pediatric liquid acetaminophen products and packaging changes were associated with a decrease in medication errors reported to poison control centers. Medication errors are particularly problematic for children <2 years of age, for whom there are no specific labeled dosing instructions. Improved efforts to provide caregivers with dosing instructions for these children are encouraged. PMID- 29522887 TI - Quantitative metrics for drug-target ligandability. AB - Ligandability is a prerequisite for druggability and is a much easier concept to understand, model and predict because it does not depend on the complex pharmacodynamic and pharmacokinetic mechanisms in the human body. In this review, we consider a metric for quantifying ligandability from experimental data. We discuss ligandability in terms of the balance between effort and reward. The metric is evaluated for a standard set of well-studied drug targets - some traditionally considered to be ligandable and some regarded as difficult. We suggest that this metric should be used to systematically improve computational predictions of ligandability, which can then be applied to novel drug targets to predict their tractability. PMID- 29522888 TI - The dynamics of cortical folding waves and prematurity-related deviations revealed by spatial and spectral analysis of gyrification. AB - In the human brain, the appearance of cortical sulci is a complex process that takes place mostly during the second half of pregnancy, with a relatively stable temporal sequence across individuals. Since deviant gyrification patterns have been observed in many neurodevelopmental disorders, mapping cortical development in vivo from the early stages on is an essential step to uncover new markers for diagnosis or prognosis. Recently this has been made possible by MRI combined with post-processing tools, but the reported results are still fragmented. Here we aimed to characterize the typical folding progression ex utero from the pre- to the post-term period, by considering 58 healthy preterm and full-term newborns and infants imaged between 27 and 62 weeks of post-menstrual age. Using a method of spectral analysis of gyrification (SPANGY), we detailed the spatial-frequency structure of cortical patterns in a quantitative way. The modeling of developmental trajectories revealed three successive waves that might correspond to primary, secondary and tertiary folding. Some deviations were further detected in 10 premature infants without apparent neurological impairment and imaged at term equivalent age, suggesting that our approach is sensitive enough to highlight the subtle impact of preterm birth and extra-uterine life on folding. PMID- 29522889 TI - Role of regression analysis and variation of rheological data in calculation of pressure drop for sludge pipelines. AB - Sludge pumps in wastewater treatment plants are often oversized due to uncertainty in calculation of pressure drop. This issue costs millions of dollars for industry to purchase and operate the oversized pumps. Besides costs, higher electricity consumption is associated with extra CO2 emission which creates huge environmental impacts. Calculation of pressure drop via current pipe flow theory requires model estimation of flow curve data which depends on regression analysis and also varies with natural variation of rheological data. This study investigates impact of variation of rheological data and regression analysis on variation of pressure drop calculated via current pipe flow theories. Results compare the variation of calculated pressure drop between different models and regression methods and suggest on the suitability of each method. PMID- 29522890 TI - The role of autochthonous organic matter in radioactive cesium accumulation to riverine fine sediments. AB - Anthropogenically released radioactive cesium (RCs) poses serious ecological and environmental concerns given its persistency in the environment. Although accumulation of RCs in aqueous and sedimentary environments is often reported to associate with organic matter (OM), the mechanisms responsible remain unclear. Here, we investigated RCs in fine sediments along the Abukuma River, the largest river near the Fukushima Daiichi Nuclear Power Plant, 1.5-4 years after the accident. Measuring the density-separated sediment fractions with a broad range of OM content (%) indicated that the RCs concentration (Bq.kg-1) is positively correlated with OM content for intermediate-density fractions in which OM is primarily characterized by autochthonous origin. This relationship, however, did not hold for light-density fractions containing a high proportion of large-size allochthonous OM. Furthermore, H2O2-assisted OM digestion and amorphous material dissolution treatments resulted in only a minor reduction in sedimentary RCs. These results along with the fact that sediments with high autochthonous OM content showed high specific surface area indicated that RCs is tightly associated with finer-grained and chemically non-labile inorganic fractions concurrently resident with autochthonous OM. Overall, our findings highlight that autochthonous OM exerts a significant control on the accumulation, transport, and fate of RCs in aqueous and sedimentary environments. PMID- 29522891 TI - Influence of composition and concentration of saline water on cation exchange behavior in forward osmosis desalination. AB - Thin film composite (TFC) membranes are the gold standard for the application of forward osmosis (FO) in seawater desalination and wastewater treatment. However, bidirectional mass transport phenomena in this process still hinder its wider application. A deeper understanding of ion transport behavior in various solution conditions is critical for the fabrication of FO membrane and future development of FO process. In this work, we systematically investigated the influences of solution chemistry on ion mass transport in TFC FO membranes. Our results suggested that the mass transports of cations were much larger than those of anions in FO processes, and monovalent cations with smaller hydrated radius could induce greater cation exchange than divalent cations. Though anions did not participate in the cation exchange processes directly, cations paired with nitrate could transport through the TFC membrane more readily than those paired with chloride or sulfate. Additionally, a set of experiments with series solution concentrations confirmed the existence of cation transport bottleneck for one TFC FO membrane. We found that the cation transport capacity of TFC membranes was mainly determined by the concentration of feed solution and the generation of cation exchange behavior was independent of water transport. Engineering implications of our findings for FO application were also discussed. PMID- 29522892 TI - Reply to the comment of Rothschild B. "Maltese cross interpretation". PMID- 29522893 TI - Mapping of atrial fibrillation: A test of faith. PMID- 29522894 TI - How to map and ablate parahisian ventricular arrhythmias. PMID- 29522895 TI - Should we consider the next implantable cardioverter-defibrillator trial in patients with acute coronary syndrome and monomorphic ventricular tachycardia? PMID- 29522896 TI - Erythropoietin alleviates hepatic steatosis by activating SIRT1-mediated autophagy. AB - Erythropoietin (EPO), besides its stimulatory effect on erythropoiesis, is beneficial to insulin resistance and obesity. However, its role in hepatic steatosis remains unexplored. Activating autophagy seems a promising mechanism for improving fatty liver disease. The present study investigated the role of EPO in alleviating hepatic steatosis and sought to determine whether its function is mediated by the activation of autophagy. Here, we show that EPO decreased hepatic lipid content significantly in vivo and in vitro. Furthermore, EPO/EPO receptor (EPOR) signalling induced autophagy activation in hepatocytes as indicated by western blot assay, transmission electron microscopy, and confocal microscopy. In addition, EPO increased the co-localization of autophagosomes and cellular lipids as shown by double labelling of the autophagy marker light chain microtubule associated protein 3 (LC3) and lipids. Importantly, suppression of autophagy by an inhibitor or small interfering RNA (siRNA) abolished the EPO-mediated alleviation hepatic steatosis in vitro. Furthermore, EPO up-regulated sirtuin 1 (SIRT1) expression, and siRNA-mediated SIRT1 silencing abrogated the EPO-induced increases in LC3 protein and deacetylation levels, thereby preventing the alleviation of hepatic steatosis. Taken together, this study revealed a new mechanism wherein EPO alleviates hepatic steatosis by activating autophagy via SIRT1-dependent deacetylation of LC3. This finding might have therapeutic value in the treatment of hepatic steatosis. PMID- 29522898 TI - Interindividual and intraindividual variability of fasted state gastric fluid volume and gastric emptying of water. AB - The amount and composition of gastrointestinal media are crucial parameters in oral drug delivery. In fasted state, variable residual gastric volumes and gastric emptying behavior often cause variable drug release and absorption from oral drug products. Unfortunately, interindividual and intraindividual variability of the gastric conditions in fasted state are currently insufficiently mapped. In this work, datasets from 5 MRI studies with 16 treatments in total were pooled. The interindividual and intraindividual variability of residual gastric volumes after 10 h overnight fasting and the subsequent emptying of 240 mL of water were compared in healthy human subjects under conditions mimicking clinical studies. This work shows that even under standardized clinical conditions, residual gastric volumes and water emptying are highly variable. Interestingly, interindividual and intraindividual variabilities of both parameters were comparable, suggesting that the variability within the studies was mainly resulting from intraindividual day-to-day variations. The mean resting volumes in all conducted investigations amounted to 25 +/- 18 mL (n = 120). Furthermore, 85 +/- 13% (n = 22) of initially available gastric volume (resting volume plus 240 mL) was emptied after 30 min. The findings of this work will hopefully contribute to a better comprehension of the variability of oral drug release and absorption. PMID- 29522897 TI - Interdisciplinary team-based care for patients with chronic pain on long-term opioid treatment in primary care (PPACT) - Protocol for a pragmatic cluster randomized trial. AB - BACKGROUND: Chronic pain is one of the most common, disabling, and expensive public health problems in the United States. Interdisciplinary pain management treatments that employ behavioral approaches have been successful in helping patients with chronic pain reduce symptoms and regain functioning. However, most patients lack access to such treatments. We are conducting a pragmatic clinical trial to test the hypothesis that patients who receive an interdisciplinary biopsychosocial intervention, the Pain Program for Active Coping and Training (PPACT), at their primary care clinic will have a greater reduction in pain impact in the year following than patients receiving usual care. METHODS/DESIGN: This is an effectiveness-implementation hybrid pragmatic clinical trial in which we randomize clusters of primary care providers and their patients with chronic pain who are on long-term opioid therapy to 1) receive an interdisciplinary behavioral intervention in conjunction with their current health care or 2) continue with current health care services. Our primary outcome is pain impact (a composite of pain intensity and pain-related interference) measured using the PEG, a validated three-item assessment. Secondary outcomes include pain-related disability, patient satisfaction, opioids dispensed and health care utilization. An economic evaluation assesses the resources and costs necessary to deliver the intervention and its cost-effectiveness compared with usual care. A formative evaluation employs mixed methods to understand the context for implementation in the participating health care systems. DISCUSSION: This trial will inform the feasibility of implementing interdisciplinary behavioral approaches to pain management in the primary care setting, potentially providing a more effective, safer, and more satisfactory alternative to opioid-based chronic pain treatment. Clinical Trials Registration Number: NCT02113592. PMID- 29522899 TI - Impact of fast and conservative freeze-drying on product quality of protein mannitol-sucrose-glycerol lyophilizates. AB - PURPOSE: Mannitol/sucrose formulations are employed to generate lyophilizates for biopharmaceuticals with an elegant cake appearance. The aim of this study was to dry protein/mannitol/sucrose formulations as fast as possible without loss of cake appearance and protein stability. Glycerol was included as potential additional protein stabilizer. Three proteins (lysozyme and two monoclonal antibodies) at low and high concentration were analyzed comparing fast with conservative freeze-drying. METHODS: Freeze-drying cycle development was carried out with mannitol/sucrose formulations. A product temperature (Tp) close to the Te of mannitol and clearly above the Tg' of sucrose was targeted. Protein formulations were exposed to the final fast lyophilisation process and to a conservative freeze-drying cycle. Lyophilizates were characterized by differential scanning calorimetry, Karl-Fischer titration and X-ray diffractometry. Additionally, macroscopic cake appearance and reconstitution times were evaluated. Protein stability was characterized by UV/Vis spectroscopy, light obscuration and size exclusion chromatography. RESULTS: The fast freeze drying cycle resulted in a primary drying time of 7 h (Tp: -10 degrees C) and a secondary drying time of 2 h in contrast to 47 h (Tp: -39 degrees C) and 12 h for the conservative cycle. Lyophilizates showed Tg values above 60 degrees C, a residual moisture level of 1%, reconstitution times of less than 35 s, delta mannitol and elegant cake appearance. Mannitol/sucrose ratios below 4/1 did not lead to complete mannitol crystallization and were therefore not suitable for the selected process conditions. Characterisation of protein stability rendered low aggregation and particle levels for both, fast and conservative freeze-drying conditions. CONCLUSIONS: It was shown that fast freeze-drying of mannitol/sucrose formulations above Tg' at a Tp of -10 degrees C resulted in good protein process stability and appropriate cake characteristics at maximum time reduction. PMID- 29522901 TI - The influence of CYP1A2 genotype in the blood pressure response to caffeine ingestion is affected by physical activity status and caffeine consumption level. AB - This study aimed to investigate whether the influence of CYP1A2 genotype in the blood pressure (BP) response to caffeine ingestion was affected by physical activity status and habitual caffeine consumption. Thirty-seven participants (19 50 years old) took place in the study and were categorized according to i) genotype: CYP1A2 (AA) "fast metabolizer", and CYP1A2 (AC) "slow metabolizer"; ii) physical activity level: sedentary (S) and physically active (A); and iii) caffeine consumption level: non-habitual caffeine consumer (NC) and habitual heavy caffeine consumer (C). All groups had BP assessed before (basal) and 1 hourh after (post) caffeine ingestion (6 mg.kg-1). It was observed that AC genotype individuals had increased basal-DBP and post-caffeine SBP when compared to AA individuals. Additionally, acute caffeine ingestion increased SBP only in the AC group. It was also found that physical activity only modulated the BP responses to acute caffeine ingestion in AC individuals. Furthermore, the results indicated that the habitual heavy caffeine consumers AC individuals had increased basal-DBP when compared to the AA ones. Our results suggest that the influence of CYP1A2 genotype in the basal and post-caffeine BP response to caffeine ingestion is modified by physical activity status and caffeine consumption level. PMID- 29522900 TI - Deep Learning and Its Applications in Biomedicine. AB - Advances in biological and medical technologies have been providing us explosive volumes of biological and physiological data, such as medical images, electroencephalography, genomic and protein sequences. Learning from these data facilitates the understanding of human health and disease. Developed from artificial neural networks, deep learning-based algorithms show great promise in extracting features and learning patterns from complex data. The aim of this paper is to provide an overview of deep learning techniques and some of the state of-the-art applications in the biomedical field. We first introduce the development of artificial neural network and deep learning. We then describe two main components of deep learning, i.e., deep learning architectures and model optimization. Subsequently, some examples are demonstrated for deep learning applications, including medical image classification, genomic sequence analysis, as well as protein structure classification and prediction. Finally, we offer our perspectives for the future directions in the field of deep learning. PMID- 29522902 TI - Financial circumstances, mastery, and mental health: Taking unobserved time stable influences into account. AB - This paper examines whether low income and subjective financial strain are associated with mental health, as well as whether mastery weakens this association. We analyze three waves of a large sample of Canadians and utilize random and fixed effects regression strategies to assess bias introduced by unobserved time-stable confounders. In random effects models, both low income and subjective financial strain are associated with distress and anger. In fixed effects models that control for all time-stable confounders, the effect of low income is reduced to non-significance for both outcomes. The effect of subjective strain is also reduced in fixed effects models, but remained statistically significant. Sobel tests indicated that the effect of subjective strain on mental health is transmitted through mastery, but this indirect path is modest in magnitude. When interactions are tested, mastery weakens the association between subjective strain and distress, and this effect is robust to the influence of time-stable controls, but mastery does not buffer the subjective strain-anger relationship in either random or fixed-effects models. Finally, moving below the low income threshold increases anger for low mastery individuals, but seems to reduce anger when moving below the low income threshold is coupled with increases in mastery. Collectively, our findings demonstrate the importance of assessing the influence of unobserved time-stable confounders in stress research. Further, discrepancies in the moderating role of mastery reinforce calls for the assessment of multiple outcomes in mental health research. PMID- 29522903 TI - Activation of steroid hormone receptors: Shed light on the in silico evaluation of endocrine disrupting chemicals. AB - Endocrine disrupting chemicals (EDCs) are of great concern given their potential influence on the endocrine system. In silico methods for the evaluation of EDCs have been widely recognized. However, subcellular molecular mechanisms of action, such as ligand-receptor interactions, receptor conformational switch and protein protein interactions, are needed for the development of mechanism-based in silico models. Here, molecular mechanisms of action for steroid hormone receptors (SHRs), the important targets of EDCs, are systematically reviewed. Ligand binding and ligand-receptor interactions are required for SHR activation, and facilitate the nuclear translocation and the dimerization of SHRs. Coregulator recruitment results from conformational switch of SHR, which regulates the transcription and results in either an agonistic or an antagonistic effect. EDCs potentially interfere with SHRs by influencing ligand-receptor interactions, nuclear translocation, dimerization and coregulator recruitment. These new findings shed light on the development of mechanism-based computational models for the evaluation of EDCs. PMID- 29522904 TI - Dual-signal amplified photoelectrochemical biosensor for detection of N6 methyladenosine based on BiVO4-110-TiO2 heterojunction, Ag+-mediated cytosine pairs. AB - Herein, a novel dual-signal amplified photoelectrochemical (PEC) biosensor was successfully developed for the highly selective detection of N6-methyladenosine (m6A) methylated RNA. The PEC biosensor comprised BiVO4-110-TiO2 heterojunction and gold nanoparticle decorated MoS2 (MoS2-AuNPs) as the photoactive materials, horseradish peroxidase conjugated biotin (HRP-Biotin) as the enzymatic unit, Ag+ mediated cytosine pairs (C-Ag+-C) as the signal amplification unit, and the anti m6A antibody as the m6A methylated RNA recognition unit. Following immunoreaction between m6A and the anti-m6A antibody, the C-Ag+-C structure of the hairpin DNA unfolded, yielding the duplex strand DNA (dsDNA) and releasing Ag+ ions. Superoxide ions (O2-) generated by the action of HRP on H2O2 then served as an electron donor, resulting in the deposition of Ag on AuNPs surface and resulting in an increased photocurrent. Based on this change f the photocurrent, m6A could be accurately assayed using this dual-signal amplified PEC biosensor. The biosensor showed high selectivity and a very low detection limit of 1.665 pM for m6A, and was successfully applied to evaluate the content change of m6A in leaves of maize seedling and chicken fetal hepatocytes samples after treatment with chemical mutagen of ethylmethane sulfonate and hormone of insulin, respectively. PMID- 29522905 TI - Stochastic DNA walker for electrochemical biosensing sensitized with gold nanocages@graphene nanoribbons. AB - A target-driven stochastic DNA walking electrochemical biosensor sensitized with gold nanocages@graphene nanoribbons (Au NCs@GNRs) was explored for sensitive detection of target DNA. Benefited from the large surface area and excellent conductivity of Au NCs and GNRs, the proposed sensing platform not only improved the electron transfer kinetics involved in electrochemical reactions, but also enhanced the loading capability for stem-loop structural DNA segment (H). Upon the addition of target DNA, the hairpin structure of H was opened and H:target DNA duplex was formed based on toehold-mediated DNA strand displacement. In the presence of exonuclease III (Exo III), the H:target DNA duplex was digested. As a result, target DNA spontaneously dissociated from H:target DNA duplex and then hybridized with another H strand. Therefore, the continuous locomotion of target DNA unceasingly triggered new digestion process from near to far along the electrode surface, resulting in great signal amplification. The proposed strategy exhibited excellent detection performances for DNA analysis in complex matrix such as human serum, which illuminated the practical application field of the sensing platform. PMID- 29522906 TI - Daily therapy with a slow-releasing H2S donor GYY4137 enables early functional recovery and ameliorates renal injury associated with urinary obstruction. AB - OBJECTIVES: To assess the effects of slow-releasing H2S donor GYY4137 on post obstructive renal function and injury following unilateral ureteral obstruction (UUO) by using the UUO and reimplantation (UUO-R) model in rats and to elucidate potential mechanisms by using an in vitro model of epithelial-mesenchymal transition (EMT). METHODS: Male Lewis rats underwent UUO at the left ureterovesical junction. From post-operative day (POD) 1-13, rats received daily intraperitoneal (IP) injection of phosphate buffered saline (PBS, 1 mL) or GYY4137 (200 MUmol/kg/day in 1 mL PBS, IP). On POD 14, the ureter was reimplanted back into the bladder, followed by a right nephrectomy. Urine and serum samples were collected to monitor renal function. On POD 30, the left kidney was removed and tissue sections were stained with H&E, TUNEL, CD68, CD206, myeloperoxidase, and Masson's trichrome to determine cortical thickness, apoptosis, inflammation, and fibrosis. In our in vitro model of EMT, NRK52E cells were treated with 10 ng/mL TGF-beta1, 10 MUM GYY4137 and/or 50 MUM GYY4137. Western blot analysis was performed to determine the expression of E-cadherin, vimentin, Smad7 and TGF beta1 receptor II (TbetaRII). RESULTS: GYY4137 led to a moderate decrease in post obstructive serum creatinine, cystatin C and FENa. We also observed a trend towards a decrease in post-obstructive proteinuria following GYY4137 treatment. Histologically, we observed a significant decrease in apoptosis, inflammation, and fibrosis. Furthermore, our in vitro studies demonstrate that in the presence of TGF-beta1, GYY4137 significantly decreases vimentin and TbetaRII and significantly increases E-cadherin and Smad7. CONCLUSIONS: H2S may help to accelerate the recovery of renal function post-obstruction and attenuates renal injury associated with UUO. It is possible that H2S mitigates fibrosis by regulating the TGF-beta1-mediated EMT pathway. Taken together, our data suggest that H2S may be a potential novel therapy for improving renal function and limiting renal injury associated with obstructive uropathy. PMID- 29522907 TI - Nitric oxide reduces oxidative stress in cancer cells by forming dinitrosyliron complexes. AB - The chelatable iron pool (CIP) is a small but chemically significant fraction of total cellular iron. While this dynamic population of iron is limited, it is redox active and capable of generating reactive oxygen species (ROS) that can lead to oxidative stress which is associated with various pathologies. Nitric oxide (*NO), is a free radical signalling molecule that regulates numerous physiological and pathological conditions. We have previously shown that macrophages exposed to endogenously generated or exogenously administered nitric oxide (*NO) results in its interaction with CIP to form dinitrosyliron complexes with thiol containing ligands (DNICs). In this study we assessed the consequences of DNIC formation in cancer cells as *NO is known to be associated with numerous malignancies. Incubation of cancer cells with *NO led to a time and dose dependent increase in formation of DNICs. The formation of DNICs results in the sequestration of the CIP which is a major source of iron for redox reactions and reactive oxygen species (ROS) generation. Therefore, we set out to test the antioxidant effect of *NO by measuring the ability of DNICs to protect cells against oxidative stress. We observed that cancer cells treated with *NO were partially protected against H2O2 mediated cytotoxicity. This correlated to a concomitant decrease in the formation of oxidants when *NO was present during H2O2 treatment. Similar protective effects were achieved by treating cells with iron chelators in the presence of H2O2. Interestingly, *NO decreased the rate of cellular metabolism of H2O2 suggesting that a proportion of H2O2 is consumed via reactions with cellular iron. When the CIP was artificially increased by supplementation of cells with iron, a significant decrease in the cytoprotective effect of *NO was observed. Notably, *NO concentrations, at which cytoprotective and antioxidant effects were observed, correlated with concentration-dependent increases in DNIC formation. Collectively, these results demonstrate that *NO has antioxidant properties by its ability to sequester cellular iron. This could play a significant role in variety of diseases involving ROS mediated toxicity like cancer and neurodegenerative disorders where *NO has been shown to be an important etiologic factor. PMID- 29522908 TI - Pharmacokinetics of a novel human intravenous immunoglobulin 10% in patients with primary immunodeficiency diseases: Analysis of a phase III, multicentre, prospective, open-label study. AB - Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga(r); Octapharma) in 51 patients aged 2-75 years with common variable immunodeficiency (n = 43) or X-linked agammaglobulinaemia (n = 8). Patients were treated with IVIG 10% every 3 (n = 21) or 4 weeks (n = 30) at a dose of 200-800 mg/kg for 12 months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15 min post-infusion. The maximum concentration of total IgG (mean +/- SD) was 21.82 +/- 5.83 g/L in patients treated 3-weekly and 17.42 +/- 3.34 g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2 g/L for patients on the 3-week schedule and between 8.10 and 8.65 g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5-65.9) days, with generally similar values for the IgG subclasses (26.7-38.0 days). Median half-lives for specific antibodies ranged between 21.3 and 51.2 days for anti-cytomegalovirus, anti-Haemophilus influenzae, anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti-Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections. PMID- 29522909 TI - Rose Bengal attached and dextran coated gadolinium oxide nanoparticles for potential diagnostic imaging applications. AB - We report here, reverse micelle mediated synthesis of multifunctional dextran (dex) coated Gd2O3 nanoparticles (NPs) carrying rose bengal (RB) dye for magnetic resonance and optical imaging. The diameter of these RB attached dex coated Gd2O3 NPs (Gd-dex-RB NPs) was found to be ~17 nm as measured by TEM. NMR line broadening effect on the surrounding water protons affirmed the paramagnetic nature of these NPs. Optical properties of Gd-dex-RB NPs were validated by UV-Vis and fluorescence spectroscopy. Time dependent release profile of RB from NPs at two different pH of 7.4 and 5.0 revealed that these NPs behave as slow releasing system. In-vitro study revealed that NPs are efficiently taken up by cells and show optical activity in cellular environment. In vitro cell viability (SRB) assay was performed on cancerous (A-549, U-87) and normal (HEK-293) cell lines, showed the absence of cytotoxic effect of Gd-dex-RB NPs. Therefore, such multifunctional NPs can be efficiently used for bio-imaging and optical tracking. PMID- 29522910 TI - Real-world incidence of cancer following a first unprovoked venous thrombosis: Results from the EPIGETBO study. AB - BACKGROUND: Venous thromboembolism (VTE) can be the first manifestation of cancer; however, the current incidence of malignancy in unselected patients with first unprovoked VTE needs to be confirmed. MATERIAL AND METHODS: Between March 1st, 2013 and February 28th, 2015 we included and followed-up all patients living in the Brest district, France, who were seen in hospitals or the community for a first symptomatic unprovoked VTE event. The primary study outcome was the one year incidence of cancer. RESULTS: 526 patients, mean age 66.6 +/- 18.1 years, 246 (46.8%) men, were included in the study. In the year following VTE, 26 patients were diagnosed with cancer, corresponding to a one-year cumulative incidence of cancer of 5.06% (95% CI 3.47-7.35). Age >=60, smoking and pulmonary embolism were significantly associated with cancer diagnosis in multivariate analysis. Fifty percent of cancers were patent at the time of VTE diagnosis, mostly detected on CTPA (Computed Tomographic Pulmonary Angiography) performed for pulmonary embolism assessment. After excluding patients with patent cancer at VTE diagnosis, the one-year incidence of cancer was 2.65% (95% CI: 1.55-4.52); in multivariate analysis, only current smoking was independently associated with a significant 5.4-fold increased risk for cancer diagnosis (HR 5.40; 95% CI 1.31 22.27). No cancer was diagnosed in patients aged 50 years or younger. CONCLUSION: The one-year incidence of cancer after a first unprovoked VTE was 5.06%. Half of the cancers were diagnosed during the diagnosis procedure for pulmonary embolism using CTPA. PMID- 29522911 TI - Clinical relevance of syncope in patients with pulmonary embolism. AB - BACKGROUND: Syncope is an unusual clinical manifestation of pulmonary embolism (PE), and the clinical significance of syncope in PE patients remains controversial. We investigated the incidence of syncope, examined the clinical factors associated with syncope, and assessed the association between syncope and the short-term outcomes of PE. METHODS: We retrospectively classified patients presenting with PE into 2 groups: patients with syncope and those without syncope. We compared the clinical and computed tomography parameters between the groups. RESULTS: Among 1084 patients diagnosed with PE, 45 (4.2%) presented with syncope. Four patients which presented with cardiac arrest were excluded from the study. The syncope group showed significantly higher blood biomarker levels and higher rates of central PE and right ventricular dilation than the control group. Unprovoked PE (odds ratio [OR] 8.046, 95% confidence interval [CI] 3.073-21.069, p < 0.001), female sex (OR 3.419, 95% CI 1.348-8.675, p = 0.010), central PE (OR 2.854, 95% CI 1.298-6.278, p = 0.009), and troponin I level (OR 2.812, 95% CI 1.765-4.480, p < 0.001) were observed to be independent factors associated with syncope in PE patients. However, multivariate analysis showed that the presence of syncope was not a significant predictor of adverse outcomes and recurrent venous thromboembolism in PE patients. CONCLUSIONS: Although syncope is associated with a more severe form of PE, it does not influence the short-term prognosis of PE. Central PE, blood troponin I level, unprovoked PE, and female sex were observed to be clinical factors related with syncope in patients with PE. PMID- 29522912 TI - Incidence, clinical characteristics, and associated diseases in patients with immune thrombocytopenia: A nationwide population-based study in Taiwan. AB - INTRODUCTION: Immune thrombocytopenia (ITP) is an immune-mediated disease; it has been reported to be associated with several diseases. The data on ITP in patients with hepatitis B, tuberculosis, or thyroid diseases are relatively scarce. In addition, these diseases are not rare in Taiwan, together with hepatitis C and Helicobacter pylori which are also related to ITP. METHODS AND MATERIALS: We identified 1223 ITP patients and characterized these patients between 2000 and 2013 from the National Health Insurance Research Database. The adult ITP patients were matched with non-ITP patients. RESULTS: The overall incidence of ITP was 2.59/100,000 person-years. The frequencies of hepatitis B and C in adult ITP patients were much higher than those indicated in previous studies. The frequencies of non-traumatic intracerebral hemorrhage and gastrointestinal bleeding during hospitalization among ITP patients were low. The diseases associated with increased risks of ITP included hepatitis B (OR = 18.70, 95% CI = 9.71-36.03), hepatitis C (OR = 54.43, 95% CI = 15.94-185.88), hepatitis B and hepatitis C (OR = 7.02, 95% CI = 1.47-33.56), tuberculosis (OR = 5.37, 95% CI = 2.72-10.61), Helicobacter pylori infection (OR = 5.93, 95% CI = 3.16-11.10), hyperthyroidism (OR = 3.43, 95% CI = 2.09-5.64), hypothyroidism (OR = 6.70, 95% CI = 2.35-19.13), and simple and unspecified goiter (OR = 2.68, 95% CI = 1.43 5.03). CONCLUSIONS: Surveying for the diseases which are frequent and related to increased risks of ITP among patients with newly diagnosed ITP should be considered. PMID- 29522914 TI - Nonsuicidal self-injury in community adolescents: A systematic review of prospective predictors, mediators and moderators. AB - Nonsuicidal self-injury (NSSI) usually starts during adolescence and is associated with an array of psychological and psychiatric symptoms and future suicide attempts. The aim of this study is to determine prospective predictors, mediators and moderators of NSSI in adolescent community samples in order to target prevention and treatment strategies. Two team members searched online databases independently. Thirty-nine studies were included in the review. Several variables were seen to prospectively predict NSSI: female gender, family-related variables, peer victimisation, depression, previous NSSI and self-concept. Few studies analysed mediators and moderators. Low self-concept was highlighted as a relevant moderator in the relationship between intra/interpersonal variables and NSSI. Implications of these findings are discussed. The considerable heterogeneity between studies posed a limitation to determine robust predictors of NSSI. Further prospective studies using standardised measures of predictors and outcomes are needed to ascertain the most at risk individuals and develop prevention strategies. PMID- 29522913 TI - Socioeconomic disadvantage and psychological deficits: Pathways from early cumulative risk to late-adolescent criminal conviction. AB - Early exposure to multiple risk factors has been shown to predict criminal offending, but the mechanisms responsible for this association are poorly understood. Integrating social-environmental and dispositional theories of crime this research investigated the capacity of family socioeconomic disadvantage and individual psychological deficits to mediate the association between childhood cumulative risk and late adolescent criminal convictions. Male participants in the 1986 Northern Finland Birth Cohort Study (n = 3414) were followed from the prenatal period through age 19-20. The data were analyzed by estimating a structural equation model of the hypothesized pathways. The results found support for both processes of influence, and the model sustained a statistically significant direct effect of cumulative risk on crime. Socioeconomic disadvantage and psychological deficits contribute to criminal offending independently and with roughly equal magnitude. The results point to the utility of both environmental and psychological interventions to prevent criminality among children at risk. PMID- 29522915 TI - Isotopically nonstationary metabolic flux analysis (INST-MFA): putting theory into practice. AB - Typically, 13C flux analysis relies on assumptions of both metabolic and isotopic steady state. If metabolism is steady but isotope labeling is not allowed to fully equilibrate, isotopically nonstationary metabolic flux analysis (INST-MFA) can be used to estimate fluxes. This requires solution of differential equations that describe the time-dependent labeling of network metabolites, while iteratively adjusting the flux and pool size parameters to match the transient labeling measurements. INST-MFA holds a number of unique advantages over approaches that rely solely upon steady-state isotope enrichments. First, INST MFA can be applied to estimate fluxes in autotrophic systems, which consume only single-carbon substrates. Second, INST-MFA is ideally suited to systems that label slowly due to the presence of large intermediate pools or pathway bottlenecks. Finally, INST-MFA provides increased measurement sensitivity to estimate reversible exchange fluxes and metabolite pool sizes, which represents a potential framework for integrating metabolomic analysis with 13C flux analysis. This review highlights the unique capabilities of INST-MFA, describes newly available software tools that automate INST-MFA calculations, presents several practical examples of recent INST-MFA applications, and discusses the technical challenges that lie ahead. PMID- 29522916 TI - Concise total synthesis of acylated phenolic glycosides vitexnegheteroin A and ovatoside D. AB - Starting from readily available vanillin and alpha-D-acetobromo glucose, two natural acylated phenolic glycosides vitexnegheteroin A and ovatoside D were synthesized for the first time in 4 steps with overall yields of 54% and 65%, respectively. The key steps involve the directly regioselective O-6 acylation of vanillin beta-D-glucopyranoside with acyl chlorides, and simultaneous removal of the allyl protecting groups on the phenolic acid moiety and reduction of the aldehyde in the aglycon moiety by using Pd(PPh)3-NaBH4 system in one pot. PMID- 29522917 TI - DNA damage response following X-irradiation in oral cancer cell lines HSC3 and HSC4. AB - OBJECTIVE: The objective of this study was to characterize the DNA damage response in two human oral cancer cell lines following X-irradiation. DESIGN: To visualize radiation-induced cell cycle alterations, two human oral cancer cell lines, HSC3 and HSC4, expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were established in this study. G2 arrest kinetics following irradiation were obtained from two-color flow cytometric analysis and pedigrees of Fucci fluorescence. DNA double strand break repair kinetics were obtained from immunofluorescence staining for phosphorylated histone H2AX, p53-binding protein 1, phosphorylated DNA-dependent protein kinase catalytic subunit, and breast cancer susceptibility gene 1. RESULTS: Both cell lines showed apparent G2 arrest after 10 Gy of irradiation, but it was more enhanced in the HSC3-Fucci cells. Radiosensitivity was higher in the HSC3-Fucci cells than in HSC4-Fucci cells. Pedigree analysis of Fucci fluorescence revealed that the HSC3-Fucci cells exhibited a significantly longer green phase (normally indicating S/G2/M phases, but here reflective of G2 arrest) when irradiated in the red phase (G1 phase) than HSC4-Fucci cells irradiated in either red or green phases. Non-homologous end joining was marginally suppressed during the G1 phase and markedly more likely to be impaired during the S/G2 phases in HSC3-Fucci cells. When G2 arrest was abrogated by checkpoint kinase 1 or Wee1 inhibitors, only HSC4-Fucci cells exhibited radiosensitization. CONCLUSIONS: We characterized DNA damage response in HSC3-Fucci and HSC4-Fucci cells following irradiation and the former demonstrated inefficient non-homologous end joining, especially during the S/G2 phases, resulting in enhanced G2 arrest. These findings may have clinical implications for oral cancer. PMID- 29522918 TI - Discovery of novel drug candidates for inhibition of soluble epoxide hydrolase of arachidonic acid cascade pathway implicated in atherosclerosis. AB - Soluble epoxide hydrolase (sEH), a key enzyme belonging to cytochrome P450 pathway of arachidonic acid cascade is a novel therapeutic drug target against atherosclerosis. The enzyme breaks down epoxyeicosatrienoic acid (EETs) to dihydroxy-eicosatrienoic acids (DHETs) and reduces beneficial cardiovascular properties of EETs. Thus, the present work is aimed at identification of potential leads as sEH inhibitors which will sustain the beneficial properties of EETs in vivo. PubChem and ZINC databases were screened for drug-like compounds based on Lipinski's rule of five and in silico toxicity filters. The binding potential of the drug-like compounds with sEH was explored using molecular docking. The top ranked lead (ZINC23099069) showed higher GOLD score compared with that of the control, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) and displayed two hydrogen bonds with Tyr383 and His420 and eleven residues involved in hydrophobic interactions with sEH. The apo_sEH and sEH_ZINC23099069 complex showed stable trajectories during 20 ns time scale of molecular dynamics (MD) simulation. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) binding free energy analysis showed that electrostatic energy is the driving energy component for interaction of the lead with sEH. These results demonstrate ZINC23099069 to be a promising drug candidate as sEH inhibitor against atherosclerosis instead of the present urea-based inhibitors. PMID- 29522919 TI - Brief report: Preliminary study on evaluation of spasticity in patients with brain lesions using mechanomyography. AB - BACKGROUND: Electromyography and the modified Ashworth scale (MAS) are among the most effective methods for evaluating spasticity; however, these are often inappropriate for clinical use, owing to the complicated procedure and subjective evaluation outcomes. METHODS: A passive stretch reflex test was performed on 10 subjects with brain lesions. Furthermore, mechanomyography and electromyography were conducted on the vastus lateralis muscle (agonist) and semitendinosus muscle (antagonist) of the subjects with brain lesions. A new equation to define the normalized hull area; that is, the mechanomyography (MMG) ratio, was applied to quantify the triaxial motion of the agonist muscle versus antagonist muscles, reflecting the electromyographic firing point of the spastic muscle. FINDINGS: The MMG ratio was proposed, which statistically distinguishes the spastic and normal muscles (p = 0.01) and exhibits a concordance with the conventional mean MAS (r = 0.69, p = 0.01). INTERPRETATION: Patients suspected to have spasticity of 0 to 1+ grade can be quantitatively evaluated using the normalized hull area ratio, which can be used as an additional clinical indicator for spasticity evaluation. REGISTRATION OF CLINICAL TRIALS: The study was conducted in conformity with the Helsinki declaration principles and performed in the Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); 2010; KCT0002385; A new approach of spasticity measurement using mechanomyography in patients with brain lesions: A randomized pilot study for a parallel randomized controlled trial; October 8, 2015 [Cited on July 21, 2017]; [1 screen]. Available from: https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=7805<ype=&rtyp =. PMID- 29522920 TI - DNA polymerase I proofreading exonuclease activity is required for endonuclease V repair pathway both in vitro and in vivo. AB - Deamination of adenine can occur spontaneously under physiological conditions to generate the highly mutagenic lesion, deoxyinosine (hypoxanthine deoxyribonucleotide, dI). In DNA, dI preferably pairs with cytosine rather than thymine and results in A:T to G:C transition mutations after DNA replication. The deamination of adenine is enhanced by ROS from exposure of DNA to ionizing radiation, UV light, nitrous acid, or heat. In Escherichia coli, dI repair is initiated by endonuclease V (endo V; nfi gene product) nicking but a complete repair mechanism has yet to be elucidated. Using in vitro minimum component reconstitution assays, we previously showed that endo V, DNA polymerase I (pol I), and E. coli DNA ligase were sufficient to repair this dI lesions efficiently and that the 3'-5' exonuclease of pol I is essential. Here we employed a phagemid based T-I substrate mimicking adenine deamination product to demonstrate pol I proofreading exonuclease is required by the endo V repair pathway both in vitro and in vivo. In vivo we found that the repair level of an nfi mutant (11%) was almost 8-fold lower than the wild type (87%). while the polA-D424A strain, a pol I mutant defective in 3'-5' exonuclease, showed a high repair level similar to wild type (both more than 80%). Using additional C-C mismatch as strand discrimination marker we found that the high level of dI removal in polA-D424A was due to strand loss (more than 60%) associated with incomplete repair. Thus, pol I proofreading exonuclease is the major function responsible for dI lesion removal after endoV nicking both in vitro and in vivo. Finally, using MALDI-TOF to analyze single-nucleotide extension product we show that the pol I proofreading exonuclease excises only 2-nt 5' upstream of endo V incision site further honing the role of pol I in the endoV dI dependent repair pathway. PMID- 29522921 TI - Simultaneous determination of 210Po and 210Pb in solid samples: A new method for 210Pb determination. AB - A new method has been developed for determination of 210Pb and a simultaneous determination of 210Po and 210Pb was performed in solid samples. 210Po and 210Pb were sequentially leached at 250 degrees C with HNO3+HF, HClO4 and HCl. Twenty percent of the leaching solution was used for 210Po determination by alpha spectrometry after 210Po spontaneous deposition on a silver disc from a weak HCl solution that containing hydroxylamine hydrochloride, sodium citrate and 209Po tracer. The remains of the leaching solution were used for determination of 210Pb, conducted by precipitation as PbCrO4 at about pH < 4, purification with an anion-exchange resin column, source preparation as PbSO4, and measurement with a beta-counter. The procedure has been checked with the IAEA-327, a certified reference material, showing good agreement with the recommended values. The lower limits of detection for 3 g soil sample were found to be 0.17 Bq kg-1 for 210Po and 0.92 Bq kg-1 for 210Pb. A variety species of soil and sediment samples have been analysed using the procedure, showing average yields of 95.2 +/- 2.6% for 210Po and 91.0 +/- 8.3% for 210Pb. PMID- 29522922 TI - Tritium internal dose estimation from measurements with liquid scintillators. AB - Tritium may exist in several chemical and physical forms in workplaces, common occurrences are in vapor or liquid form (as tritiated water) and in organic form (e.g. thymidine) which can get into the body by inhalation or by ingestion. For internal dose assessment it is usually assumed that urine samples for tritium analysis are obtained after the tritium concentration inside the body has reached equilibrium following intake. Comparison was carried out for two types of vials, two efficiency calculation methods and two available liquid scintillation devices to highlight the errors of the measurements. The results were used for dose estimation with MONDAL-3 software. It has been shown that concerning the accuracy of the final internal dose assessment, the uncertainties of the assumptions used in the dose assessment (for example the date and route of intake, the physical and chemical form) can be more influential than the errors of the measured data. Therefore, the improvement of the experimental accuracy alone is not the proper way to improve the accuracy of the internal dose estimation. PMID- 29522923 TI - Parameters affecting acetate concentrations during in-situ biological hydrogen methanation. AB - Surplus electricity may be supplied to anaerobic digesters as H2 gas to upgrade the CH4 content of biogas. Acetate accumulation has been observed following H2 injections, but the parameters determining the degree of acetate accumulation are not well understood. The pathways involved during H2 consumption and acetate kinetics were evaluated in continuous lab reactors and parallel batch 13C experiments. Acetate accumulation increased during initial H2 injections as organic loading rate increased and CO2 levels decreased below 7%. The share of CH4 in H2 and 13C mass balances increased after repeated H2 injections, which corresponded with the increase of Methanomicrobiales observed via qPCR. The organic loading rate, the inorganic carbon level and level of methanogen adaption hence determine acetate kinetics during biomethanation of H2. The three identified parameters may form the base of a decision tool to assess acetate accumulation during H2 injections to an anaerobic digester. PMID- 29522924 TI - Anaerobic digestion of chicken manure by a leach-bed process coupled with side stream membrane ammonia separation. AB - This study pioneered the use of a single-stage methanogenic leach bed reactor (LBR) for high-solids (total solid content: 14%-16%) anaerobic mono-digestion of chicken manure. Chicken manure was loaded into the LBR in cloth sachets without adding any bulking agents. Ammonia was separated and recovered by placing a hydrophobic gas diffusion membrane in a leachate collection chamber. Methane production in the membrane-integrated LBR was 0.272 m3/kgVS and 2.3 times higher than that in the control LBR. The results revealed that using membrane-integrated LBR for anaerobic digestion is a simple and cost-efficient technology for the mono-digestion of chicken manure and ammonia removal. PMID- 29522925 TI - Preparation, characterization and Cr(VI) adsorption evaluation of NaOH-activated carbon produced from Date Press Cake; an agro-industrial waste. AB - Date Press Cake (DPC) is an inevitable by-product of date processing industries and may pose environmental problems if not managed properly. In this study, DPC was converted into activated carbon using solid NaOH under various activation conditions. The prepared activated carbon showed high specific surface area (2025.9 m2 g-1) and microporous texture (86.01%). It was successfully applied for the adsorption of Cr(VI) from aqueous solutions with maximum monolayer adsorption capacities as high as 282.8 mg g-1 (pH = 2) and 198.0 mg g-1 (pH = 5). The kinetic and isotherm experimental data of Cr(VI) adsorption onto the activated carbon were best described by Elovich and Redlich-Peterson models, respectively. It was found that the Cr(VI) adsorption onto the DPC-derived activated carbon was predominantly a chemisorption process with limited desorption rates (below 50%). Overall, Date Press Cake could be considered as an abundant and renewable agro industrial precursor for the production of high quality activated carbon. PMID- 29522926 TI - Effects of anode spacing and flow rate on energy recovery of flat-panel air cathode microbial fuel cells using domestic wastewater. AB - A flat-panel air-cathode microbial fuel cell (FA-MFC) is known to overcome the low conductivity and biodegradability of domestic wastewater. This study evaluated the normalized energy recovery (NER) based on the volume of wastewater treated (NERV) and chemical oxygen demand (COD) removal (NERCOD) using FA-MFCs with three anode spacing conditions and different flow rates (within a hydraulic retention time of 30 min). Generation of current was similar (11.7 +/- 0.5 mA) at different spacings; however, COD removal was affected by the flow rates. The NERV for both acetate and domestic wastewater showed good agreements with the flow rates in all anode spacing conditions. The NERCOD results were negatively correlated with the COD removal rates, independent of the anode spacing. The FA MFCs yielded an NERCOD of 0.22 kWh/kg-COD from extremely low-strength domestic wastewater (150 mg-COD/L). The FA-MFC has a significant potential as an energy sustainable wastewater treatment technology. PMID- 29522927 TI - A randomised-controlled trial investigating potential underlying mechanisms of a functionality-based approach to improving women's body image. AB - Focusing on body functionality is a promising technique for improving women's body image. This study replicates prior research in a large novel sample, tests longer-term follow-up effects, and investigates underlying mechanisms of these effects (body complexity and body-self integration). British women (N = 261) aged 18-30 who wanted to improve their body image were randomised to Expand Your Horizon (three online body functionality writing exercises) or an active control. Trait body image was assessed at Pretest, Posttest, 1-week, and 1-month Follow Up. To explore whether changes in body complexity and body-self integration 'buffer' the impact of negative body-related experiences, participants also completed beauty-ideal media exposure. Relative to the control, intervention participants experienced improved appearance satisfaction, functionality satisfaction, body appreciation, and body complexity at Posttest, and at both Follow-Ups. Neither body complexity nor body-self integration mediated intervention effects. Media exposure decreased state body satisfaction among intervention and control participants, but neither body complexity nor body-self integration moderated these effects. The findings underscore the value of focusing on body functionality for improving body image and show that effects persist one month post-intervention. PMID- 29522928 TI - Impact damage visualization in a honeycomb composite panel through laser inspection using zero-lag cross-correlation imaging condition. AB - A fully non-contact laser-based nondestructive inspection (NDI) system is developed to detect and visualize damage in structures. The study focuses on the size quantification and characterization of a barely visible impact damage (BVID) in a honeycomb composite panel. The hardware consists of a Q-switched Nd:YAG pulse laser that probes the panel by generating broadband guided waves via thermo elastic expansion. The laser, in combination with a set of galvano-mirrors is used to raster scan over a two-dimensional surface covering the damaged region of an impacted quasi-isotropic [60/0/-60]s honeycomb composite panel. The out-of plane velocities are measured at a fixed location normal to the surface by a laser Doppler vibrometer (LDV). An ultrasonic full wavefield assembled from the three-dimensional space-time data matrix in the interrogated area is first acquired and then processed for imaging the impacted damage area. A wavenumber filtering technique in terms of wave vectors is applied to distinguish the forward and backward wavefields in the wavenumber-frequency domain. A zero-lag cross correlation (ZLCC) imaging condition is then employed in the space frequency domain for damage imaging. The ZLCC imaging condition consists of cross correlating the incident and reflected wavefields in the entire scanned region. The condition not only images the damage boundary between incident and reflected waves outside the damage region but also, for longer time windows, enables to capture the momentary standing waves formed within the damaged region. The ZLCC imaging condition imaged two delaminated region: a main delamination, which was a skewed elliptic with major and minor axis lengths roughly 17 mm and 10 mm respectively, and a secondary delamination region approximately 6 mm by 4 mm, however, which can only be shown at higher frequency range around 80-95 kHz. To conclude, the ZLCC results were in very good agreement with ultrasonic C-scan and X-ray computed tomographic (X-ray CT) scan results. Since the imaging condition is performed in the space-frequency domain, the imaging from ZLCC can also reveal resonance modes which are shown in the main delaminated area by windowing a narrow frequency band sequentially. PMID- 29522929 TI - Tertiary treatment of landfill leachate by an integrated Electro Oxidation/Electro-Coagulation/Electro-Reduction process: Performance and mechanism. AB - This study presents an integrated Electro-Oxidation/Electro-Coagulation/Electro Reduction (EO/EC/ER) process for tertiary landfill leachate treatment. The influence of variables including leachate characteristics and operation conditions on the performance of EO/EC/ER process was evaluated. The removal mechanisms were explored by comparing results of anode, cathode, and bipolar electrode substitution experiments. The performance of the process in a scaled-up reactor was investigated to assure the feasibility of the process. Results showed that simultaneous removal of carbonaceous and nitrogenous pollutants was achieved under optimal conditions. Ammonia removal was due to the free chlorine generation of EO while organic matter degradation was achieved by both EO and EC processes. Nitrate removal was attributed to both ER and EC processes, with the higher removal achieved by ER process. In a scaled-up reactor, the EO/EC/ER process was able to remove 50-60% organic matter and 100% ammonia at charge of 1.5 Ah/L with energy consumption of 15 kW h/m3. Considering energy cost, the process is more efficient to meet the requirement of organic removal efficiency less than 70%. These results show the feasibility and potential of the EO/EC/ER process as an alternative tertiary treatment to achieve the simultaneous removal of organic matter, ammonia, nitrate, and color of leachate. PMID- 29522930 TI - Formation of chlorinated haloacetic acids by chlorination of low molecular weight compounds listed on pollutant release and transfer registers (PRTRs). AB - Anthropogenic compounds accidentally released to the environment could be important precursors of disinfection byproducts (DBPs) in drinking water treatment processes. In this study, the haloacetic acid formation potentials (HAAFPs) of 155 anthropogenic compounds listed on the Japanese pollutant release and transfer register (PRTR) system were evaluated. The results showed that phenolic and aromatic amine compounds were important HAA precursors, and chlorinated phenols showed high HAAFPs (>400 MUg/mgC). Moreover, trichlorfon and ethyl chloroacetate (HAAFP of 104.9 and 602.3 MUg/mgC, respectively) were also important HAA precursors because of their ability to undergo hydrolysis. Although most anthropogenic compounds with high HAAFPs showed high chlorine consumptions, no clear correlation between HAAFPs and chlorine consumptions was found in this study. In addition, the quantitative structure-activity relationship (QSAR) approach was a useful tool for predicting the chlorine consumption of organic compounds but was not effective for predicting HAAFPs based on the information currently available. A scenario study assuming a hypothetical accidental release predicted that the release of 3,4-dichloroaniline (HAAFP of 407.6 MUg/mgC) would lead to a violation of the current drinking water quality standards for HAAs in Japan. PMID- 29522932 TI - Passion or addiction? Correlates of healthy versus problematic use of videogames in a sample of French-speaking regular players. AB - A criticism of current diagnostic approaches to gaming disorder is that they fail to take into account that high and repeated engagement is not problematic per se, nor is it necessarily associated with adverse consequences. To tackle this controversy, we used Confirmatory Factor Analysis (CFA) to test, in regular gamers (N = 268), whether high (but healthy) engagement can be distinguished from problematic engagement by using the Addiction-Engagement Questionnaire (Charlton & Danforth, 2007). We then tested whether differential relationships exist between the engagement and addiction constructs, DSM-5 criteria for Internet gaming disorder (IGD), and psychological factors linked to gaming use and misuse (self-reported impulsivity, motives to play, and depression). Results indicated that a model holding engagement and addiction as two distinct, but related, constructs fits the data well. Second, we showed that although both constructs are linked to the number of IGD criteria endorsed, the relationship is more pronounced for the addiction construct. Third, a differential pattern of correlations was observed with the other study variables, further supporting the need to distinguish the two constructs. Our study emphasizes that research is needed to refine the diagnostic approach to gaming disorder to avoid conflating healthy passion with pathological behavior. PMID- 29522931 TI - Salivary cortisol and cortisone responses to short-term psychological stress challenge in late adolescent and young women with different hyperandrogenic states. AB - Hyperandrogenic disorders have been associated with psychological distress, reduced quality of life, anxiety and depression. The hypothalamic-pituitary adrenal (HPA) axis plays a pivotal role in the adaptive response to stressor events. Salivary cortisol (SalF) and cortisone (SalE) testing have been proven to be useful in the evaluation of HPA-axis activity. This study investigated whether SalF and SalE responses to two putative stressor levels differed between the hyperandrogenic states in late adolescent and young women, thus measuring the HPA axis adaptive response to acute stress events. We selected 161 drug-free females aged 16-19 years from a large population previously enrolled in a cross-sectional epidemiological study. Saliva was collected in the morning before and after two putative stressor events consisting in a self-filled questionnaire (weaker stressor) and in a structured interview plus physical examination by an endocrinologist (stronger stressor). SalF and SalE, as well as blood steroids, were assessed by liquid chromatography-tandem mass spectrometry. Subjects were subdivided into different groups according to the presence of: isolated menstrual irregularities (MI, oligo-amenorrhea; n = 22), isolated hirsutism (HIR, modified Ferriman-Gallwey score >= 8; n = 26), isolated hyperandrogenaemia (HT, testosterone >0.438 ng/mL; n = 14), and polycystic ovary syndrome (PCOS, MI with HIR and/or HT, n = 16). The remaining 83 apparently healthy subjects were used as controls. SalF and SalE significantly decreased after the weaker stressor, following the physiologic diurnal loss, in all the groups except for isolated HIR, where they remained unchanged (P = 0.091 and P = 0.118, respectively). In contrast, SalF and SalE remained unchanged after the stronger stressor in isolated MI, isolated HT and controls, whereas SalF increased significantly in isolated HIR (P = 0.011), and SalE increased significantly both in isolated HIR (P = 0.005) and in PCOS (P = 0.011) groups. SalF percentage variation in response to the stronger stressor was positively associated with systolic blood pressure in PCOS (P = 0.018), and both SalF and SalE percentage variations were positively associated with diastolic blood pressure in the isolated HIR group (P = 0.010 and P = 0.006, respectively). In addition, in the isolated HIR group, the SalF percentage variation was negatively associated with HDL cholesterol levels (P = 0.005). Finally, SalF and SalE percentage variations were positively associated with circulating androstenedione (P = 0.031 and P = 0.011, respectively) and DHEA (P = 0.020 and P = 0.003, respectively) in the isolated HIR group. In conclusion, this study demonstrates that hirsute and PCOS adolescent and young women are characterized by HPA-axis overactivity in response to stressful stimuli, as detectable by salivary glucocorticoid measurements. These data also indicate that the higher the HPA-axis activity, the higher the adrenal androgen output and the worse the metabolic profile. PMID- 29522933 TI - Low rates of alcohol and tobacco use, strong cultural ties for Native American college students in the Southwest. AB - INTRODUCTION: College attendance is associated with an increased risk for substance use yet we know little about substance use among Native American college students and its regional variation. This study examined alcohol, tobacco, and drug use and their relation to gender, institution, age, and cultural involvement among Native American college students in the Southwest. METHODS: Native American community college and university students in a large Southwest city (N = 347) completed an online survey about past-month and lifetime substance use and involvement in cultural activities. RESULTS: Cultural involvement was related to less past-month substance use. In the past month, 43% drank alcohol, 27% binge drank, 20% used drugs, and 13% were current smokers. Males, community college students, and older individuals were more likely to have a positive CAGE-AID and have used drugs more than 100 times. Younger individuals were more likely to use marijuana in the past month. CONCLUSIONS: These findings highlight cultural strengths and comparatively low rates of tobacco and alcohol use among Native American college students in the Southwest. PMID- 29522934 TI - Electronic cigarette use and smoking cessation behavior among adolescents in China. AB - OBJECTIVE: China produces the majority of the world's electronic cigarettes (e cigarettes) and e-cigarettes have become popular in the country, especially among young people. However, little is known about the characteristics of e-cigarette use in China and how it is associated with smoking cessation behavior. This study focuses on the adolescent group in China and examines their perception and use of e-cigarettes and the association with smoking abstinence. METHODS: We use a mobile app-based survey on smoking behavior conducted in November 2015 in China, and focus on a sample of 2042 adolescents aged between 12 and 18. Awareness, perception, use of e-cigarettes are examined as well as the behaviors of promoting e-cigarettes and of smoking cessation. A logistic regression is performed to test the association between e-cigarette use and smoking abstinence behavior. RESULTS: In 2015, nearly 90% of the surveyed adolescents in China were aware of e-cigarettes, while over a quarter of the respondents were ever users. The odds ratio for ever users of e-cigarettes to have tried to quit smoking conventional cigarettes was 1.60 that of never users. For those who tried to quit smoking, 36.02% indicated that they used e-cigarettes to help quit. However, only 13.52% of those who had used e-cigarettes to help quit smoking were successful in quitting. CONCLUSIONS: This study is one of the first empirical research on e cigarette use among Chinese adolescents. E-cigarettes are widely known and quite popular among Chinese adolescents. As the association between e-cigarette use and smoking cessation behavior is less than clear, more empirical research is called for to help form evidence-based regulatory policy on e-cigarettes in China. PMID- 29522935 TI - Extended endoscopic endonasal approach for recurrent or residual symptomatic craniopharyngiomas. AB - OBJECTIVES: Removal of recurrent or residual symptomatic craniopharyngiomas is more challenging than the primary surgery. The extended endoscopic endonasal (EEE) approach has been proposed an alternative surgical route for removal of various suprasellar tumors including craniopharyngiomas currently. In this study, we summarized the operative experience and described the feasibility and advantages of this technique in recurrent or residual symptomatic craniopharyngiomas. PATIENTS AND METHODS: A retrospective review of 15 patients (9 males and 6 females) whom underwent EEE approach between April 2012 and February 2017, were included in this study. The lesions included 8 purely suprasellar craniopharyngiomas (2 extraventricular, 6 intraextraventricular), 3 both intra- and suprasellar craniopharyngiomas, and 4 intrasellar craniopharyngiomas. The mean preoperative (that is, EEE approach) tumor volume was 10.54 cm3. The mean follow-up period was 23.1 months (range, 8-54). All patients were analyzed in terms of the treatment effect, complictions and follow up results. RESULTS: Total removal of tumors was achieved in 12 patients (80.0%) and subtotal removal in 3 cases (20.0%). The pituitary stalks were identified in 11 patients during operations and secured in 8 patients. Postoperative visual acuity was improved in 10 cases, and normalization of the impairment was achieved in 3 patients. There were no significant differences between pre and postoperative endocrine function, except in one patient with normal preoperative pituitary hormone function who suffered postoperative hypopituitarism. Postoperative diabetes insipidus (DI) occurred in 14 patients including 6 patients who had long-term DI and others reporting transient postoperative DI. No cerebrospinal fluid (CSF) leak was identified. There were no deaths or major complications. Obesity developed in 2 patients, with no deaths and recurrent cases during follow-up period. CONCLUSION: The pure EEE approach is a safe, effective alternative for treatment of recurrent or residual symptomatic craniopharyngiomas owing to its advantages including wide-angle view, close observation and elimination of brain retraction. Larger studies with further follow-up is needed to assess the long-term efficacy of this minimal access approach. PMID- 29522936 TI - Evaluation of DNA ploidy with intraoperative flow cytometry may predict long-term survival of patients with supratentorial low-grade gliomas: Analysis of 102 cases. AB - OBJECTIVE: The objective of the present study was evaluation of the prognostic significance of DNA ploidy assessed with intraoperative flow cytometry (iFC) during resection of low-grade gliomas (LGG). PATIENTS AND METHODS: Retrospective analysis of 102 consecutive cases of newly diagnosed WHO grade II supratentorial gliomas, surgical removal of which was accompanied by iFC, was done. There were 46 diffuse astrocytomas (DA) and 56 oligodendrogliomas (OD). According to iFC, 68 tumors (67%) were considered non-aneuploid and 34 (33%) aneuploid. Median extent of resection (EOR) was 95% (mean, 89.0 +/- 14.5%). Postoperative FRT with or without adjuvant chemotherapy was administered in 24 cases (24%). RESULTS: With median follow-up of 29.9 months (range, 9.4-66.9 months), neither median overall survival (OS) nor median progression-free survival (PFS) were reached. The 3-year actuarial OS and PFS rates were 95.8% and 86.3%, respectively. Non-aneuploid DNA histogram type of the tumor was associated with significantly longer OS both in univariate (P = 0.0094) and multivariate (P = 0.0232) analyses, and with longer PFS in univariate analysis (P = 0.0184). Aneuploidy was encountered more frequently in DA, than in OD (43% vs. 25% of cases; P = 0.0488). Tumor progression was noted in 15 DA and 4 patients succumbed to the disease; in this subgroup the main unfavorable prognostic factors for OS and PFS were presence of aneuploidy (P = 0.0510) and MIB-1 index ?3.9% (P = 0.0141), respectively. Aneuploid DA more frequently progressed to glioblastoma than to anaplastic astrocytoma, but this difference did not reach statistical significance (P = 0.1362). In contrast, only one OD progressed (non-aneuploid neoplasm), and no one patient with such tumor died of the disease. CONCLUSIONS: DNA ploidy assessed with iFC may be effectively used as prognostic indicator in cases of LGG, especially of DA. Aneuploid tumors demonstrate more aggressive clinical course translated into shorter OS of patients. Thus, their detection during surgery may be helpful for decision on the optimal EOR, and for choice of the most appropriate postoperative adjuvant therapy. PMID- 29522937 TI - Utility of P300 ERP in monitoring post-trauma mental health: A longitudinal study in military personnel returning from combat deployment. AB - Military service members (SMs) returning from combat are at high risk of developing neuropsychiatric conditions such as posttraumatic stress disorder (PTSD) and major depression. Symptom dynamics following reintegration into civilian life may be magnified over time such that some SMs present with delayed onset and may not reach a diagnostic threshold for months to years. Monitoring the trajectory of mental health in the aftermath of combat trauma can therefore be particularly important in enhancing diagnosis. In this study, we investigated the possible utility of the P300 event-related potential (ERP) as an objective marker for monitoring post-trauma mental health. SMs recently returned from a combat deployment were recruited to undergo a baseline assessment, with subsequent follow-up assessment at 6 or 12 months later. At each assessment, ERPs were recorded using a conventional visual oddball task and a set of psychological scores assessing PTSD, depression, and psychosocial functioning were obtained. We observed that the individuals with overall improved psychological scores at follow-up had increased P300 amplitude and shortened P300 latency, and the individuals with overall worsened psychological scores at follow-up had prolonged P300 latency. The degree of change in aggregate psychological score was significantly correlated with the magnitude of change in P300 amplitude (r = 0.72, p < 0.0001) and latency (r = 0.42, p = 0.0201). These findings suggest that the P300 may be utilized as a quantitative biomarker for tracking the changes of mental health longitudinally. It may offer clinicians an objective tool for the assessment of the dynamics of mental health following trauma, and perhaps also for monitoring recovery during treatment. PMID- 29522938 TI - Factor analysis of regional brain activation in bipolar and healthy individuals reveals a consistent modular structure. AB - BACKGROUND: The neurophysiological substrates of cognition and emotion, as seen with fMRI, are generally explained using modular structures. The present study was designed to probe the modular structure of cognitive-emotional processing in bipolar and healthy individuals using factor analysis and compare the results with current conceptions of the neurophysiology of bipolar disorder. METHODS: Exploratory factor analysis was used to assess patterns of covariation among brain regions-of-interest activated during the Continuous Performance Task with Emotional and Neutral Distractors in healthy and bipolar individuals without a priori constraints on the number or composition of latent factors. RESULTS: Results indicated a common cognitive-emotional network consisting of prefrontal, medial temporal, limbic, parietal, anterior cingulate and posterior cingulate modules. However, reduced brain activation to emotional stimuli in the frontal, medial temporal and limbic modules was apparent in the bipolar relative to the healthy group, potentially accounting for emotional dysregulation in bipolar disorder. LIMITATIONS: This study is limited by a relatively small sample size recruited at a single site. The results have yet to be validated on a larger independent sample. CONCLUSIONS: Although the modular structure of cognitive emotional processing is similar in bipolar and healthy individuals, activation in response to emotional/neutral cues varies. These findings are not only consistent with recent conceptions of mood regulation in bipolar disorder, but also suggest that regional activation can be considered within tighter modular structures without compromising data interpretation. This demonstration may serve as a template for data reduction in future region-of-interest analyses to increase statistical power. PMID- 29522939 TI - Temporal dynamics and longitudinal co-occurrence of depression and different anxiety syndromes in youth: Evidence for reciprocal patterns in a 3-year prospective study. AB - BACKGROUND: Depression is highly comorbid with anxiety in youth. It is frequently reported that anxiety precedes depression; however, evidence surrounding the temporal precedence of anxiety over depression is mixed. Many studies of anxiety depression co-occurrence lump distinct forms of anxiety, obscuring information regarding trajectories of specific anxiety syndromes. This study sought to more accurately describe the development of anxiety and depression over time by moving beyond the question of temporal precedence to investigate a developmentally dynamic model of anxiety-depression co-occurrence. METHODS: A community sample of 665 youth (M= 11.8, SD= 2.4; 55% female) completed repeated self-report measures of depression and anxiety (social, physical, and separation anxiety) over a 3 year longitudinal study. Prospective associations between distinct syndromes of anxiety with depression were analyzed using an autoregressive cross-lagged path model over four time points. RESULTS: Physical symptoms and depression symptoms reciprocally predicted each other, above and beyond the stability of either domain. Social anxiety and depression symptoms similarly predicted each other in a systematic pattern. LIMITATIONS: Our study is limited in its generalizability to other forms of anxiety, like worry. Additional research is needed to determine whether similar patterns exist in clinical populations, and whether these processes maintain symptoms once they reach diagnostic levels. CONCLUSIONS: The development of syndromes of depression, physical, and social anxiety during childhood and adolescence occurs in a predictable, systematic reciprocal pattern, rather than sequentially and unidirectionally (i.e., anxiety syndromes precede depression). Results are clinically useful for predicting risk for disorder, and demonstrate the necessity of tracking symptom levels across domains. PMID- 29522940 TI - Secular trends in excess mortality of late-life depression. AB - BACKGROUND: Late-life depression is associated with premature mortality, however, little is known whether excess mortality rates of depression have changed over time. This study aims to identify and explain secular trends in excess mortality of major depressive disorder (MDD) and subthreshold depression (SUBD). METHODS: Cohort-sequential-longitudinal study of 4084 community-dwelling older adults in the Netherlands based on data from the Longitudinal Aging Study Amsterdam (LASA). Six measurement cycles were included from 1992/93 until 2008/09, each linked to the overall 5-year mortality, covering a 16-year time span. MDD and SUBD were identified using a two-stage screening procedure with the Center for Epidemiological Studies Depression Scale and the Diagnostic Interview Schedule. Age and sex were covariates. Education, health and lifestyle factors, and use of antidepressants were included as putative explanatory factors. Generalized Estimating Equations was used to investigate the association between the interaction 'Depression * Time' and 5-year mortality, and to find explanatory factors for the trend. RESULTS: A downward trend in excess mortality of MDD was found (OR = .92, 95%-CI:.85-.99, P = .04), adjusted for age and sex, which could not be explained by education, health and lifestyle factors, nor antidepressants use. Sex differences in the trend were not found (P = .77). No trend in excess mortality of SUBD was found (OR = 1.01, 95%-CI: .97-1.04, P = .65). LIMITATIONS: The findings do not imply a similar trend for other countries. CONCLUSIONS: The results indicate a favorable development in excess mortality of community dwelling older adults with MDD, while those with SUBD do not show a clear trend in excess mortality. PMID- 29522941 TI - Validating pre-treatment body mass index as moderator of antidepressant treatment outcomes: Findings from CO-MED trial. AB - BACKGROUND: Currently, there are no valid clinical or biological markers to personalize the treatment of depression. Recent evidence suggests that body mass index (BMI) may guide the selection of antidepressant medications with different mechanisms of action. METHODS: Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants with BMI measurement (n = 662) were categorized as normal- or underweight (<25), overweight (25-<30), obese I (30 <35), and obese II+ (>=35). Logistic regression analysis with remission as the dependent variable and treatment arm-by-BMI category interaction as the primary independent variable was used to evaluate if BMI differentially predicted response to escitalopram (SSRI) monotherapy, bupropion-escitalopram combination, or venlafaxine-mirtazapine combination, after controlling for gender and baseline depression severity. RESULTS: Remission rates among the three treatment arms differed on the basis of pre-treatment BMI (chi-square=12.80, degrees of freedom=6, p = .046). Normal- or under-weight participants were less likely to remit with the bupropion-SSRI combination (26.8%) than SSRI monotherapy (37.3%, number needed to treat or NNT = 9.5) or venlafaxine-mirtazapine combination (44.4%, NNT = 5.7). Conversely, obese II+ participants were more likely to remit with bupropion-SSRI (47.4%) than SSRI monotherapy (28.6%, NNT = 5.3) or venlafaxine-mirtazapine combination (37.7%, NNT = 10.3). Remission rates did not differ among overweight and obese I participants. LIMITATIONS: Secondary analysis, higher rates of obesity than the general population. CONCLUSIONS: Antidepressant selection in clinical practice can be personalized with BMI measurements. Bupropion-SSRI combination should be avoided in normal- or under weight depressed outpatients as compared to SSRI monotherapy and venlafaxine mirtazapine combination and preferred in those with BMI>=35. PMID- 29522942 TI - Anxiety disorders and figural fluency: A measure of executive function. AB - BACKGROUND: Anxiety possibly interferes with executive functioning, although most studies rely on anxiety symptoms or lack control for comorbid depression. The objective of the present study is to examine the association between executive functioning and (individual) anxiety disorders with ak,ld without controlling for depression. METHOD: Generalized anxiety disorder (GAD), panic disorder with and without agoraphobia, agoraphobia, social phobia, as well as depressive disorder according to DSM-IV criteria were assessed with the Mini International Neuropsychiatric Interview in 82,360 community-dwelling people participating in the Lifelines cohort. Figural fluency as a measure of executive functioning was assessed with the Ruff Figural Fluency Test (RFTT). Linear regression analyses with the RFFT score as the dependent variable and psychiatric diagnosis as independent variables (dummies) were performed, adjusted for potential confounders. Multivariate results are presented with and without adjustment for depression. RESULTS: Presence of any anxiety disorder was associated with worse performance on the RFFT (B = - 0.78, SE = 0.32, p = .015), independent of depression. No dose-response relationship with the number of anxiety disorders was found. Only agoraphobia and generalized anxiety disorder were significantly associated with the RFFT score in the multivariate models. Agoraphobia remained significant when further adjusted for depressive disorder (B = - 1.14, SE = 0.41, p < .01), while GAD did not (B = 0.013, SE = 0.431, p = .975). LIMITATIONS: Executive function was tested by only one measure, namely figural fluency. CONCLUSION: Agoraphobia is associated with worse executive functioning. Treatment of agoraphobia could be influenced by the executive dysfunction which clinicians should be aware of when regular treatment fails. PMID- 29522943 TI - Distinct patterns of blood oxygenation in the prefrontal cortex in clinical phenotypes of schizophrenia and bipolar disorder. AB - BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) are characterized by different clinical symptoms, and have previously been considered as categorically separate. However, several lines of evidence controversially suggest that these two disorders may run on a continuum. While it is therefore important to evaluate the subtle differences between SZ and BD, few studies have investigated the difference of brain functioning between the two by focusing on the common symptoms of cognitive functioning and impulsivity, rather than positive/negative and mood symptoms. Recent developments in near-infrared spectroscopy (NIRS) technology have enabled noninvasive assessment of brain function in people with psychiatric disorders. METHODS: Near-infrared spectroscopy (NIRS) using 24 channels was conducted during the verbal fluency task (VFT) and Stroop color-word task (SCWT) in 38 patients diagnosed with SZ, 34 patients with BD, and 26 age- and sex-matched healthy controls. RESULTS: Oxyhemoglobin changes in the prefrontal cortex (PFC) were significantly lower particularly in the SZ compared to control group during the VFT. On the other hand, these were significantly lower particularly in the BD and SZ group to control group during the SCWT. Regression analysis showed that hemodynamic changes were significantly correlated with verbal memory and impulsivity in both disorders. CONCLUSION: These findings suggest that different hemodynamic responses in the prefrontal cortex might reflect cognitive functioning and impulsivity, providing a greater insight into SZ and BD pathophysiology. PMID- 29522944 TI - Inflammatory markers and cortisol parameters across depressive subtypes in an older cohort. AB - BACKGROUND: There is growing evidence that inflammatory and cortisol dysregulation are underlying pathophysiological mechanisms in the aetiology of major depressive disorder, particularly in younger adults. However, findings of biological disturbances in late-life depression have been divergent, probably due to the even greater heterogeneity of depression in older adults with aging processes influencing biological factors. Using empirically derived subtypes may enable the identification of biological disturbances underlying depression in older adults. METHODS: Data were used from the Netherlands Study of Depression in Older Persons (NESDO) of 359 persons aged 60 years or older, with a current diagnosis of major depressive disorder (MDD). Depressive subtypes (severe atypical, severe melancholic, and moderate severe subtype) that were previously identified through latent class analysis (LCA), were examined on differences in inflammatory markers including C-reactive protein (CRP), interleukin-6 (IL-6), and neutrophil gelatinase-associated lipocalin (NGAL), as well as cortisol parameters. RESULTS: No differences in measures for inflammation and cortisol across subtypes were observed in uncorrected or for putative confounders corrected models. LIMITATIONS: Several subjects had missing cortisol and inflammatory data, decreasing the power. However, results did not change after imputation analysis. DISCUSSION: In this cohort of depressed older adults, no differences in inflammation and cortisol measures between depression subtypes were observed. This is probably due to the many (patho)physiological processes that are involved in aging, thereby clouding the results. PMID- 29522945 TI - Association between major depressive episode and risk of type 2 diabetes: A large prospective cohort study in Chinese adults. AB - OBJECTIVE: We aimed to prospectively evaluate the association between major depressive episode (MDE) and risk of type 2 diabetes in a Chinese population. METHODS: We used data from the China Kadoorie Biobank study, in which 461,213 participants free of diabetes, coronary heart disease, stroke, and cancer were followed from baseline (2004-2008) to December 31, 2013. A modified Chinese version of Composite International Diagnostic Interview Short-Form (CIDI-SF) was used to assess past year MDE. Participants who responded positive to depression screening questions but did not meet the diagnosis criteria were considered as having depressive symptoms only. Incident diabetes cases were identified through linkage with established regional disease registries and national health insurance databases. Cox proportional hazards regression model was used to calculate hazard ratio (HR) and 95% confidence interval (CI) for the association after adjusting for diabetes risk factors. RESULTS: We documented 8784 incident type 2 diabetes cases during a follow-up of 3291,908 person-years. We observed a higher incidence rate of type 2 diabetes in participants with MDE than those without, and the multivariable-adjusted HR was 1.31 (95% CI 1.04-1.66). Compared with participants without depressive symptoms, the HR (95% CI) was 1.19 (1.05 1.35) for participants with depressive symptoms only and 1.32 (1.05-1.68) for those with MDE. LIMITATIONS: The prevelance of past year MDE based on CIDI-SF was low, which might result in a selection bias. CONCLUSIONS: In our large prospective cohort study of Chinese adults, MDE was significantly and independently associated with an increased risk of type 2 diabetes. PMID- 29522947 TI - Are studies of psychotherapies for depression more or less generalizable than studies of antidepressants? AB - BACKGROUND: The generalizability of findings from studies exploring the efficacy of psychotherapy and antidepressants has been called into question in part because studies exclude many patients. Despite this, the frequency with which psychotherapy and antidepressant studies use specific inclusion and exclusion criteria has never been compared. We explored the exclusion criteria used in psychotherapy and pharmacotherapy studies from 1995 to 2014. METHOD: Systematic literature searches were conducted in PubMed, Medline, PsycINFO, and Embase of published randomized controlled trials (RCTs) of the treatment of major depressive disorder (MDD) in adults with either antidepressants (vs. placebos) or psychotherapy (vs. placebos, treatments as usual, or other controls). RESULTS: Most psychotherapy (81%) and antidepressant (100%) trials excluded patients with milder symptoms as well as patients with elevated suicidal risk (56-75%), psychotic symptoms (84-88%), or substance misuse (75-81%). Psychotherapy studies were less likely to exclude patients on the basis of brief episode duration (0% vs. 48%) and co-morbid Axis I disorders (6% vs. 27%). However, psychotherapy studies excluded patients with more severe symptoms more frequently (38%) than antidepressant studies (8%). CONCLUSIONS: Overall, psychotherapy studies appear somewhat more inclusive than antidepressant studies. On average, antidepressant studies appear to target patients with more chronic and severe, as well as more purely depressive presentations. PMID- 29522946 TI - 12-month trajectories of depressive symptoms among nurses-Contribution of personality, job characteristics, coping, and burnout. AB - BACKGROUND: Job related factors have been associated with higher risk for developing depression, but past studies lacked full consideration of individual factors such as personality and coping. We sought to evaluate associations of personality, coping, job characteristics, and burnout with 12-month trajectories of depressive symptoms among nursing workers. METHODS: Cohort of nursing workers (N = 281) in a private hospital system, with baseline assessments of personality, job characteristics, and coping. Burnout and depression were measured at baseline and during monthly follow-ups. Linear mixed modeling was used to examine contributions to between- and within-individual variation in monthly depressive symptoms. RESULTS: Personality trait of negative affectivity accounted for 36% of between-individual variation in depressive symptoms over 12 months, while job characteristics and coping explained an additional 5% and 8% of this variation, respectively. Exhaustion dimension of burnout was associated with between individual variation in depressive symptoms (fixed effect beta coefficient 2.44, p < 0.001), but not with within-individual variation in symptoms. Disengagement dimension of burnout was not associated with between-individual variation in depressive symptoms, but contributed to within-individual variation in depressive symptoms over time (fixed effect beta coefficient 0.52, p = 0.01). LIMITATIONS: Participants were nursing workers within a single hospital system. Participants who were excluded due to missing baseline data were more likely of non-white race, which may also limit the generalizability of our results. We used latent variables to represent certain job and coping characteristics, which may make our results less comparable with other studies examining the role of these factors in work-associated depression. CONCLUSIONS: Future interventions to prevent depression in healthcare workers should consider multiple job and individual factors. Potential components include strategies to manage negative affectivity and reduce avoidant coping, such as cognitive reframing and mindfulness-based techniques, and organizational approaches to address burnout through augmentation of job resources. PMID- 29522948 TI - Nationwide Healthcare utilization among children with epilepsy in the United States: 2003-2014. AB - BACKGROUND: Epilepsy is particularly frequent among children, yet updated and nationwide healthcare utilization estimates are scanty in the United States. OBJECTIVE: To analyze healthcare utilization among children with epilepsy. METHODS: Data on children (<=17-year-old) were extracted from the Medical Expenditure Panel Survey (MEPS) 2003-2014. Epilepsy was identified using the clinical classification code 83. Healthcare utilization (Inpatient admission, outpatient visits, prescription medication including refill, emergency room visits, and home health provider visits) was compared between children with epilepsy and those without epilepsy. A negative binomial model was used to assess the relationship between epilepsy and healthcare utilizations accounting for the influence of extraneous factors. RESULTS: In all, a weighted 457,873 children (0.84%) had epilepsy in United States. The unadjusted proportion and the mean annual number of health care service utilization were higher in children with epilepsy compared to those without epilepsy. Children with epilepsy had almost 3.3 more outpatient visits (95% CI: 2.281-4.274), 7.9 more medication prescriptions including refills (95% CI: 6.058-9.662), nearly 0.4 more emergency department visits (95% CI: 0.278-0.438) and nearly 12 more home health provider visits (95% CI: 1.988-21.756) than those without epilepsy. The adjusted marginal effect of epilepsy on inpatient admission was not statistically significant. CONCLUSION: unadjusted and adjusted healthcare utilization is considerably higher in children with epilepsy compared to those without epilepsy in the United States with heterogeneity across individual services. PMID- 29522949 TI - Overexpression of long non-coding RNA H19 promotes invasion and autophagy via the PI3K/AKT/mTOR pathways in trophoblast cells. AB - BACKGROUND: Preeclampsia (PE), characterized by hypertension and proteinuria, is a leading cause of perinatal and maternal mortality. Considering that mutation of H19 gene is closely associated with PE, we aimed to explore the functional role of long non-coding RNA H19 (lncRNA-H19) in trophoblast cells. METHODS: Expression of lncRNA-H19 in placenta tissues from patients with PE and healthy pregnant women after delivery was determined by quantitative reverse transcription PCR. Then, lncRNA-H19 was abnormally expressed in JEG-3 and HTR-8 cells by stable cell transfection. Cell viability and invasion were assessed by using CCK-8 and Matrigel-coated Millicell system, respectively. Expression of key proteins associated with invasion and autophagy as well as key kinases in the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathways were measured by Western blot analysis. Number of GFP-labeled autophagosomes was counted under a confocal microscope. RESULTS: Level of lncRNA H19 in the placenta tissues from PE patients was higher than that from healthy controls. LncRNA-H19 overexpression reduced cell viability but increased invasion of JEG-3 and HTR-8 cells. LncRNA-H19 silence showed the opposite effects. In addition, lncRNA-H19 overexpression promoted autophagy in trophoblast cells. Furthermore, phosphorylated levels of key kinases in the PI3K/AKT/mTOR pathways were enhanced by lncRNA-H19 overexpression while were reduced by lncRNA-H19 silence. CONCLUSION: LncRNA-H19, which was up-regulated in PE, reduced cell viability but promoted invasion and autophagy in trophoblast cells, along with activation of the PI3K/AKT/mTOR pathways. Our study provides a theoretical basis for pathogenesis of PE, aiding to identification of novel therapeutic strategies for PE. PMID- 29522950 TI - Structures of isothiocyanates attributed to reactive oxygen species generation and microtubule depolymerization in HepG2 cells. AB - The structure of the isothiocyanates (ITCs)-erucin, sulforaphane, erysolin, sulforaphene, and phenethyl isothiocyanate-were assessed as well as their respective in vitro anticancer activity on the hepatocellular carcinoma cell line HepG2. All of these ITCs induced both apoptotic and necrotic cell death. FTIR analysis indicated that the ITCs caused changes in cellular components comparable to vinblastine. Despite no observable effect on DNA, the ITCs all induced generation of intracellular reactive oxygen species (ROS) and suppressed microtubule polymerization. The variation in sulfur oxidation states and the presence of an aromatic ring on the ITC side chain affected microtubule depolymerization and intracellular ROS generation, leading to apoptotic and necrotic cancer cell death. Knowing the influences of structural variations of the ITC side chain would be useful for selecting the more potent ITCs (i.e., erysolin) for the design and development of effective chemopreventive agents. PMID- 29522951 TI - Melanomacrophage response and hepatic histopathologic biomarkers in the guppy Poecilia reticulata exposed to iron oxide (maghemite) nanoparticles. AB - Although iron oxide nanoparticles (IONPs) have been widely used in nanomedicine and nanoremediation, their ecotoxicological effects on aquatic organisms remain unclear. In this study, the melanomacrophage center (MMC) response and hepatic histopathologic biomarkers were investigated in female guppies, Poecilia reticulata, exposed to citrate-functionalized IONPs (gamma-Fe2O3) at an environmentally relevant iron concentration (0.3 mg L-1) over 21 days. The animals were collected at the beginning of the experiment and after 3, 7, 14, and 21 days of exposure. Guppies exposed to IONPs showed increases in the number, area, and perimeter of MMC when compared with the unexposed ones, especially after 7 days of exposure. The results showed an increase in the frequency of histopathologic changes in fish after 7 days of exposure to IONPs, such micro- and macro-vesicular steatosis, melanomacrophage aggregates, exudate, and hemorrhagic foci. The acute (3 and 7 days) and long-term (14 and 21 days) exposure of P. reticulata to IONPs induced high histopathologic indexes associated with circulatory disorders and inflammatory responses. Results showed that the MMC response and histopathologic index are important biomarkers to indicate the environmental impact of IONPs, confirming that the guppy P. reticulata is a target of ecotoxicity of IONPs. PMID- 29522952 TI - Azoles additively inhibit cytochrome P450 1 (EROD) and 19 (aromatase) in rainbow trout (Oncorhynchus mykiss). AB - Antifungal azoles are widely used in medicine, agriculture, and material protection and several antifungal azoles have been found in environmental samples. Although these compounds were designed to inhibit fungal enzymes such as lanosterol-14-demethylase (cytochrome P450 (CYP) 51), it is well established that the inhibitory actions of azoles are not specific for fungal CYP isozymes. We refined a gill filament assay to determine the inhibition of CYP1, measured as reduced 7-ethoxyresorufin-O-deethylase (EROD) activity, in rainbow trout (Oncorhynchus mykiss) gill tissue ex vivo. The advantage of this method is that both induction and inhibition of EROD are performed ex vivo. Among thirteen azoles studied, the five that caused the strongest inhibition of gill EROD activity at a concentration of 5 MUM were selected for concentration-response assessment. These compounds (bifonazole, clotrimazole, imazalil, miconazole, and prochloraz) showed IC50 values ranging from 0.1 to 1.5 MUM. CYP19 (aromatase) inhibition was measured using microsomes from rainbow trout brains. Concentration response curves for CYP19 inhibition were determined for letrozole, bifonazole, clotrimazole, imazalil, miconazole and prochloraz, which gave IC50 values ranging from 0.02 to 3.3 MUM. It was further found that mixtures of the five most potent azoles reduced both CYP1 and 19 catalytic activity in an additive fashion (IC50 = 0.7 MUM and 0.6 MUM, in the respective assay). Bifonazole (IC50 = 0.1 MUM) is not previously known to inhibit CYP1 activity. The additive inhibition of CYP1 and CYP19 catalytic activity is an important finding of the present study. We conclude that this additive action of azoles could mediate adverse impacts on CYP regulated physiological functions in environmentally exposed fish. PMID- 29522953 TI - Decomposition of lignocellulose and readily degradable carbohydrates during sewage sludge biodrying, insights of the potential role of microorganisms from a metagenomic analysis. AB - Sewage sludge biodrying is a waste treatment method that uses bio-heat generated from organic degradation to remove moisture from sewage sludge. Lignocellulose and carbohydrate decomposition is important when assessing biodrying performance. This study investigated lignocellulose and carbohydrate decomposition, and the potential microbial functions during biodrying. We determined the lignocellulose and carbohydrate contents, assayed related enzyme activity, performed a complete metagenomic study on sewage sludge biodrying material during the thermophilic phase, annotated potential genetic function involved in the decomposition, and summarized the key metabolic pathways. The results indicated that lignocellulose, readily degradable carbohydrates, and starch, significantly decomposed after biodrying. During the thermophilic phase, the majority of lignocellulose and carbohydrate-related enzymes showed significantly higher activity, and glycoside hydrolases and glycosyl transferases showed higher gene counts and reads. Moreover, the top five microorganisms enriched with carbohydrate-active enzyme genes, i.e., Bacillus, Intrasporangium, Tetrasphaera, Rhodobacter, and Streptomyces, were also among the top ten ecologically dominant genera. These findings highlight the crucial phases for biodrying process, reveal the ecologically functional diversity of biodrying-originated microbial consortia, and suggest potential candidates for optimizing biodrying decomposition. PMID- 29522954 TI - Hearing sounds as words: Neural responses to environmental sounds in the context of fluent speech. AB - Environmental sounds (ES) can be understood easily when substituted for words in sentences, suggesting that linguistic context benefits may be mediated by processes more general than some language-specific theories assert. However, the underlying neural processing is not understood. EEG was recorded for spoken sentences ending in either a spoken word or a corresponding ES. Endings were either congruent or incongruent with the sentence frame, and thus were expected to produce N400 activity. However, if ES and word meanings are combined with language context by different mechanisms, different N400 responses would be expected. Incongruent endings (both words and ES) elicited frontocentral negativities corresponding to the N400 typically observed to incongruent spoken words. Moreover, sentential constraint had similar effects on N400 topographies to ES and words. Comparison of speech and ES responses suggests that understanding meaning in speech context may be mediated by similar neural mechanisms for these two types of stimuli. PMID- 29522955 TI - Validation of a routine gas chromatography mass spectrometry method for 2 hydroxyglutarate quantification in human serum as a screening tool for detection of idh mutations. AB - High circulating levels of 2-hydroxyglutarate (2HG) have been reported in patients with determinate isocitrate dehydrogenase (IDH) mutated tumors. Recent studies indicate that in malignancies such as acute myeloid leukemia (AML), measurements of 2HG in serum provide useful diagnostic and prognostic information and improve patient selection and monitoring of IDH-targeted treatments. In the current study, we validated a sensitive and specific gas chromatography mass spectrometry (GC-MS) method specifically intended to quantify serum levels of 2HG in routine clinical laboratories. Extraction was liquid-liquid with ethyl acetate, and derivatization was reduced to 3 min of microwave irradiation. The analytical method was linear over a wide dynamic range, presenting acceptable intraday and day-to-day precision and accuracy. The limit of quantification was 10 ng/mL, process efficiency ranged between 38% and 49%, and recovery of added 2HG was 99-105%. 2HG was found to be stable in serum for up to 48 h at both 4 degrees C and at ambient temperature, and after three freeze-thaw cycles. Microwave derivatizated extracts in the autosampler were found to be stable for up to 120 h. In summary, the present method is useful for quantification of 2HG serum levels in patients with IDH mutated malignancies in clinical laboratories. PMID- 29522956 TI - Metformin impacts cecal bile acid profiles in mice. AB - Bile acids (BAs) are major components of bile synthesized from cholesterol and take part in the digestion of dietary lipids, as well as having signaling functions. They undergo extensive microbial metabolism inside the gastrointestinal tract. Here, we present a method of ultra-high pressure liquid chromatography coupled to ion trap mass spectrometry for quantification of 45 BAs in mouse cecum. The system was validated in regard to sensitivity with limits of detection and quantification (0.6-24.9 nM), interday accuracy (102.4%), interday precision (15.2%), recovery rate (74.7%), matrix effect (98.2%) and carry-over effect (<1.1%). Afterwards, we applied our method to investigate the effect of metformin on BA profiles. Diabetic mice were treated with metformin for 1 day or 14 days. One day of treatment resulted in a significant increase of total BA concentration (2.7-fold increase; db/db metformin 5.32 MUmol/g, db/db control mice 1.95 MUmol/g), most notable in levels of 7-oxodeoxycholic, 3-dehydrocholic and cholic acid. We observed only minor impact on BA metabolism after 14 days of metformin treatment, compared to the single treatment. Furthermore, healthy wild type mice had elevated concentrations of allocholic and omega-muricholic acid compared to diabetic mice. Our method proved the applicability of profiling BAs in cecum to investigate intestinal BA metabolism in diabetes and pharmacological applications. PMID- 29522957 TI - Protein A affinity chromatography of Chinese hamster ovary (CHO) cell culture broths containing biopharmaceutical monoclonal antibody (mAb): Experiments and mechanistic transport, binding and equilibrium modeling. AB - Protein A-based affinity chromatography is a highly-efficient separation method to capture, purify and isolate biosimilar monoclonal antibodies (mAb) - an important medical product of biopharmaceutical industrial manufacturing. It is considered the most expensive step in purification downstream operations; therefore, its performance optimization offers a great cost saving in the overall production expenditure. The biochemical mixture-separating specific interaction experiments with Chinese hamster ovary (CHO) cell culture harvest, containing glycosylated extracellular immunoglobulins (Ig), were made using five different state-of-the-art commercial resins. Packing breakthrough curves were recorded at an array of prolonged residence times. A mathematical simulation model was developed, applied and validated in combination with non-linear regression algorithms on bed effluent concentrations to determine the previously-unknown binding properties of stationary phase materials. Apart from the columns' differential partitioning, the whole external system was also integrated. It was confirmed that internal pore diffusion is the global rate-limiting resistance of the compound retention process. Immobilizing substrate characteristics, obtained in this engineering study, are indispensable for the scale-up of the periodic counter-current control with mechanistic load, elution and wash reduction. Furthermore, unit's volumetric flow screening measurements revealed dynamic effect correlation to eluate quality parameters, like the presence of aggregates, the host cell-related impurities at supernatant's extended feeding, and titre. Numerical sensitivity outputs demonstrated the impacts of fluidics (e.g. axial dispersion coefficient), thermodynamics (Langmuir adsorption) and mass transfer fluxes. PMID- 29522958 TI - Post-traumatic stress symptoms are associated with physical multimorbidity: Findings from the Adult Psychiatric Morbidity Survey 2007. AB - BACKGROUND: Studies on the association between symptoms of post-traumatic stress disorder (PTSD) and physical multimorbidity (i.e., >=2 chronic conditions) are lacking. Thus, we assessed the association between PTSD symptoms and physical multimorbidity using nationally representative, community-based data of the UK adult population. METHODS: Data from the 2007 Adult Psychiatric Morbidity Survey were analyzed. PTSD symptoms were assessed using the 10-item Trauma Screening Questionnaire (TSQ). A total score of >=6 points indicated a probable PTSD. Information was collected on 20 doctor/other health professional diagnosed physical health conditions that were present in the past 12 months. Multimorbidity was defined as >=2 physical diseases. Multivariable logistic regression and mediation analyses were conducted to analyze the association between PTSD and physical multimorbidity, and the influence of behavioral and psychological factors in this association. RESULTS: Among 7403 individuals aged >=16 years [mean age (SD) = 46.3 (18.6) years; 51.5% females], the prevalence of PTSD increased from 2.1% in individuals with no physical conditions to 5.4% in those with >=4 physical conditions. After adjustment for sociodemographic factors and lifetime occurrence of a traumatic event, PTSD was associated with higher odds for physical multimorbidity (Odds Ratio [OR] = 2.47; 95% Confidence Interval [CI]: 1.71-3.56). Anxiety, depression, and disordered eating explained 35%, 21%, and 8% of the PTSD-multimorbidity association, respectively. LIMITATIONS: Causality or temporal associations cannot be established due to the cross sectional nature of the study. In addition, PTSD and physical conditions were assessed using self-reports. CONCLUSIONS: PTSD symptoms may be risk factors for physical multimorbidity. Anxiety and depressive symptoms might play an important role in this association. Screening for chronic physical conditions among individuals with PTSD and treating them simultaneously may lead to better clinical outcomes. PMID- 29522959 TI - Young adult's attachment style as a partial mediator between maternal functioning and young adult offsprings' functioning. AB - BACKGROUND: The quality of our early attachment relationships with primary caregivers is carried forward to new developmental domains, including interpersonal contexts in adulthood. One of the factors that can disrupt early attachment is maternal depression, which may be associated with less responsive care and may impede the development of a secure attachment. Moreover, this disruption in secure attachment may act as a mechanism by which offspring of depressed mothers are more likely to experience their own psychopathology. In this study we predicted that attachment anxiety and avoidance would mediate the relationship between maternal depression diagnosis and functional impairment predicting young adult offspring's functional impairment. METHODS: This study utilized longitudinal data from 98 families with clinically diagnosed depressed and well mothers, and two of their young adult children, an older and younger sibling (N = 123, Female = 75, Mage = 22.09, SD = 2.57). Mother's and young adult children's functioning was based on clinical ratings on the Global Assessment Scale. Attachment was based on the young adult's self-report on the Experiences in Close Relationships. RESULTS: Results indicate that maternal diagnosis and functional impairment predicted offspring's functional impairment. This relationship was partially mediated through offspring's attachment anxiety, but not attachment avoidance. LIMITATIONS: The mediator and outcome variable were measured concurrently, thus causal implications are limited. CONCLUSIONS: Our study provides critical evidence that early experiences with depressed mothers may have influence into young adulthood in typical and atypical domains of development. This work extends our understanding of the impact of early experiences in long-term development, and may have treatment implications for intervening on both maternal and romantic relationships to improve attachment. PMID- 29522960 TI - Towards an evidence-based unified psychodynamic protocol for emotional disorders. AB - BACKGROUND: In psychotherapy research unified, transdiagnostic and modular treatments have emerged. This is true for both cognitive-behavioral therapy and psychodynamic therapy. Recently, two unified psychodynamic protocols were presented, one for anxiety disorders, another for depressive disorders. Integrating the treatment principles for these two highly prevalent disorder groups into one protocol for "emotional disorders" may be useful for both clinical practice and training in psychotherapy. METHODS: After updating the evidence for psychodynamic therapy in anxiety and depressive disorders in terms of randomized controlled trials (RCTs) by a systematic search, the treatment elements applied in those RCTs providing evidence for the efficacy of psychodynamic therapy in depressive or anxiety disorders were reviewed and compared. RESULTS: Twenty-seven RCTs for anxiety or depressive disorders were identified. A review revealed a high overlap between the principles used for the psychodynamic treatment of anxiety and depressive disorders, reflecting the transdiagnostic nature of psychodynamic therapy. The overlap suggested to integrate the identified treatment principles into one unified psychodynamic protocol for "emotional disorders" (UPP-EMO). As a result, seven treatment principles or modules were distilled which can be flexibly applied depending on the patient's symptoms and needs. In addition, a separate module addresses diagnostic assessment. Across modules, a focus on resources has been included. LIMITATIONS: Despite being based on RCTs, UPP-EMO has not yet been examined in an RCT - which is planned as a next step. CONCLUSIONS: As psychodynamic therapy is transdiagnostic in origin focusing on core underlying processes of mental disorders, acceptability of UPP-EMO among psychodynamic psychotherapists is likely to be high. PMID- 29522961 TI - The validation of the Supervision of Thesis Questionnaire (STQ). AB - BACKGROUND: The supervision process is characterized by differences between the supervisors' and the students' expectations before the start of writing a bachelor thesis as well as after its completion. A review of the literature did not reveal any scientifically tested questionnaire for evaluating nursing students' expectations of the supervision process when writing a bachelor thesis. OBJECTIVES: The aim of the study was to determine the construct validity and internal consistency reliability of a questionnaire for measuring nursing students' expectations of the bachelor thesis supervision process. DESIGN & METHODS: The study had a developmental and methodological design carried out in four steps including construct validity and internal consistency reliability statistical procedures: construction of the items, assessment of face validity, data collection and data analysis. SETTINGS & PARTICIPANTS: This study was conducted at a university in southern Sweden, where students on the "Nursing student thesis, 15 ECTS" course were consecutively selected for participation. Of the 512 questionnaires distributed, 327 were returned, a response rate of 64%. RESULTS: Five factors with a total variance of 74% and good communalities, >=0.64, were extracted from the 10-item STQ. The internal consistency of the 10 items was 0.68. The five factors were labelled: The nature of the supervision process, The supervisor's role as a coach, The students' progression to self support, The interaction between students and supervisor and supervisor competence. CONCLUSIONS: A didactic, useful and secure questionnaire measuring nursing students' expectations of the bachelor thesis supervision process based on three main forms of supervision was created. PMID- 29522963 TI - Nursing students' perceived stress, coping strategies, health and supervisory approaches in clinical practice: A Slovak and Czech perspective. PMID- 29522962 TI - Scale for the study of nursing students' perception of intimate partner violence: Adaptation and validation. AB - BACKGROUND: Intimate partner violence (IPV) is one of the most important challenges facing today's society. Health professionals, and nurses in particular, play a leading role in addressing this problem. Having an instrument to study Nursing students' perception of this type of violence may enable appropriate and necessary educational strategies for their pre-service training and help them identify and address IPV in their future careers. OBJECTIVES: To adapt and validate the IPV scale of Beccaria et al. (2011) in order to study nursing students' perception of IPV. METHOD: The original instrument (63 items) underwent back-translation. Statistical and metrical analysis in a sample of 1064 students of the four-year Nursing degree program at four public universities in Catalonia (Spain) were based on their responses to the Spanish version. RESULTS: The results of the exploratory factorial analysis and subsequent confirmatory analysis showed that the data had an adequate fit for a four-factor model. The reliability analysis showed adequate internal consistency for each subscale in the instrument: Education (0.83); Identification of the Victim (0.72); Nursing Role and Values (0.78), and Identification of the Perpetrator (0.66). CONCLUSION: The translation, cultural adaptation and validation process of the original IPV scale resulted in a Spanish-language instrument (IPV scale Spanish version) with 32 items in four subscales. We concluded that the Spanish version of the instrument is reliable and valid, and that its implementation would enable the assessment of nursing students' perception of IPV situations. PMID- 29522965 TI - An analysis of crack growth in dentin at the microstructural scale. AB - Dentin is a biocomposite possessing complex hierarchical structure, which endows this hard tissue with excellent damage tolerance. In this study, crack growth in dentin at the microstructural scale is investigated and the synergistic effects of plastic deformation of intertubular dentin (ITD), elasticity and fracture properties of peritubular dentin (PTD), and fracture properties of PTD/ITD interface on the fracture of dentin are explored. A micromechanical model is developed, which captures the experimentally observed fracture process of dentin, i.e. occurrence of microcracking of PTD ahead of the main crack. It is found through numerical simulations that high relative stiffness and low cohesive strength of PTD increase the propensity of microcracking of PTD, whereas reduce the plastic dissipation and toughness of the microstructure of dentin. The microcracking of PTD can be also promoted by low toughness of PTD. The large friction angle and weak strain hardening of ITD could promote the microcracking of PTD, and simultaneously enhance the toughness of the microstructure of dentin. In addition, it is identified that the cohesive strength of the PTD/ITD interface plays a crucial role in dominating fracture mechanisms; low cohesive strength leads to fracture of interface and suppresses microcracking of PTD, which provides an explanation for the crack deflection along interface observed in experiments. Nevertheless, the toughness of interface has a negligible influence on the fracture of dentin. PMID- 29522964 TI - Preparation and biocompatibility evaluation of polypropylene mesh coated with electrospinning membrane for pelvic defects repair. AB - Composite mesh with different materials composition could compensate for the drawbacks brought by single component mesh. Coating a membrane layer on the surface of macroporous mesh is a common method for preparing composite medical mesh. Electrospinning and dipping methods were introduced to form the two kinds of membrane-coated PP meshes (electro-mesh and dip-mesh); several properties were measured based on subcutaneous implantation model in rat. The results revealed that continuous tissue ingrowth could be observed for electro-mesh only with evidences of strength increase (electro-mesh: 0 week - 13.1 +/- 0.88 N, 2 week - 16.87 +/- 1.39 N, 4 week - 22.04 +/- 2.05 N) and thickness increase (electro mesh: 0 week - 0.437 +/- 0.023 mm, 2 week - 0.488 +/- 0.025 mm, 4 week - 0.576 +/ 0.028 mm). However, no tissues were observed for dip-mesh in the first 2 weeks, both on macroscopic level and microscopic level, proved by strength data (dip mesh: 0 week - 13.36 +/- 1.06 N, 2 week - 13.4 +/- 1.33 N, 4 week - 18.61 +/- 1.89 N) and thickness data (dip-mesh: 0 week - 0.439 +/- 0.018 mm, 2 week - 0.439 +/- 0.019 mm, 4 week - 0.502 +/- 0.032 mm). Electro-mesh had larger surface area decrease (10.74 +/- 1.22%) than that of dip-mesh (2.78 +/- 0.52%). The adhesion level of electro-mesh (medium adhesion) was also higher than that of dip-mesh (mild adhesion). Even if showing differences in several properties, both meshes were similar under histological observation, with the ability to support fresh tissues ingrowth. Considering operation environment, electro-mesh seems more suitable than dip-mesh with a rapid tissue growing, medium adhesion rate for repairing pelvic floor defects. PMID- 29522966 TI - Clinical experiences of ultrasound-guided lumbar erector spinae plane block for hip joint and proximal femur surgeries. PMID- 29522967 TI - Is ultrasound guided erector spinae plane block sufficient for surgical anesthesia in minor surgery at thoracal region? PMID- 29522968 TI - Development of a SPR aptasensor containing oriented aptamer for direct capture and detection of tetracycline in multiple honey samples. AB - Although surface plasmon resonance (SPR) technique and aptamer technology shows great potential in analytical and biological chemistry, direct capture and analysis of small molecules using SPR remains tough. Detection sensitivity of aptasensor and recognition ability of aptamer is limited, because direct immobilization of aptamer causes large steric hindrance and strand entanglement. Herein, we chose a typical small molecule-tetracycline (Mw. 444.4 g/mol) as a model, and combined aptamer technology, DNA nanostructure, and commercial Biacore T200 SPR instrument to develop a straightforward format SPR aptasensor. Anti tetracycline aptamer (Apt76) was fabricated on the top of a tetrahedron nanostructure to provide a better accessibility to tetracycline than the single stranded Apt76 (ss-Apt76), and thus to improve sensitivity of the SPR aptasensor. The aptasensor was then validated in real world application for tetracycline screening in multiple honey samples, achieving good recovery rates of 80.20 114.3%, intuitive sensorgrams indicating the binding kinetic properties, and high specificity towards tetracycline. LOD of the tetrahedron-based SPR aptasensor was obtained using the real honey sample and calculated to be 0.0069 MUg/kg, which was 10-fold range lower than that of the ss-Apt76-based aptasensor. The proof-of concept demonstrated that aptamers of small molecules can be oriented immobilized on the SPR surface in a uniform nanoscale distance in both lateral and vertical direction, so as to achieve better conformational folding and better accessibility to small molecules. The concept is promising to be a universal and powerful tool for other ligand immobilization and SPR studies for both real world detection and molecular interaction. PMID- 29522969 TI - Ultrasensitive Faraday cage-type electrochemiluminescence assay for femtomolar miRNA-141 via graphene oxide and hybridization chain reaction-assisted cascade amplification. AB - In this study, a novel electrochemiluminescence (ECL) biosensor for sensitive detection of femtomolar miRNA-141 was constructed on the basis of Faraday cage type strategy via graphene oxide (GO) and hybridization chain reaction (HCR) assisted cascade amplification. A capture probe (CP) was immobilized on Fe3O4@SiO2@Au nanoparticles as capture unit, which could catch the miRNA-141, and the immobilization of the signal unit (Ru(phen)32+-HCR/GO) was allowed via nucleic acid hybridization. The prepared biosensor exhibited two advantages for signal amplification: firstly, GO could lap on the electrode surface directly, extending Outer Helmholtz Plane (OHP) of the sensor due to the large surface area and good electronic transport property; secondly, HCR-assisted cascade amplification was designed by anchoring all HCR products on the GO surface, then embedding Ru(phen)32+ as a signal readout pathway. All these signal molecules could take part in electrochemical reactions, thus further enhancing the ECL signal drastically. Therefore, the proposed sensor constructed by integrating HCR with Faraday cage-type strategy displayed an ultrasensitive detection platform for the miRNA-141 with a low detection limit of 0.03 fM. In addition, this proposed biosensor provides a universal platform for analysis of other microRNAs. PMID- 29522970 TI - Glucose biosensor based on disposable electrochemical paper-based transducers fully fabricated by screen-printing. AB - This paper describes a new approach for the massive production of electrochemical paper-based analytical devices (ePADs). These devices are fully fabricated by screen-printing technology and consist of a lineal microfluidic channel delimited by hydrophobic walls (patterned with diluted ultraviolet screen-printing ink in chromatographic paper grade 4) and a three-electrode system (printed with carbon and/or Ag/AgCl conductive inks). The printing process was characterised and optimized for pattern each layer with only one squeeze sweep. These ePADs were used as transducers to develop a glucose biosensor. Ionic strength/pH buffering salts, electrochemical mediator (ferricyanide) and enzyme (glucose dehydrogenase FAD-dependent) were separately stored along the microfluidic channel in order to be successively dissolved and mixed after the sample dropping at the entrance. The analyses required only 10 ul and the biosensors showed good reproducibility (RSD = 6.2%, n = 10) and sensitivity (0.426 C/M cm2), wide linear range (0.5-50 mM; r2 = 0.999) and low limit of detection (0.33 mM). Furthermore, the new biosensor was applied for glucose determination in five commercial soft-drinks without any sample treatment before the analysis. These samples were also analysed with a commercial enzymatic-kit assay. The results indicated that both methods provide accurate results. PMID- 29522971 TI - P2X receptor-ion channels in the inflammatory response in adipose tissue and pancreas-potential triggers in onset of type 2 diabetes? AB - Type 2 diabetes is reaching an alarming prevalence worldwide. Its complex pathogenesis certainly includes a pivotal role of low-grade inflammation, which could be triggered by excessive purinergic signaling. In this complex scenario, extracellular ATP impairs the function of two key players: beta-cell and adipose tissue. In the former, P2Y and possibly some P2X receptors-ion channels regulate insulin secretion, but it is still debated whether excessive ATP can via P2X receptors impair beta-cell function directly or whether cell damage is due to an excessive systemic release of cytokines. In human adipocytes, the P2X7 receptor promotes the release of inflammatory cytokines, at least in part via inflammasome activation, likely contributing to systemic insulin resistance. This receptor inflammasome system is also strongly activated in macrophages infiltrating both pancreas and adipose tissue, mediating a deleterious cross-talk that perpetuates the damage. PMID- 29522972 TI - Whole Tumor Histogram-profiling of Diffusion-Weighted Magnetic Resonance Images Reflects Tumorbiological Features of Primary Central Nervous System Lymphoma. AB - PURPOSE: Diffusion weighted imaging (DWI) quantifies motion of hydrogen nuclei in biological tissues and hereby has been used to assess the underlying tissue microarchitecture. Histogram-profiling of DWI provides more detailed information on diffusion characteristics of a lesion than the standardly calculated values of the apparent diffusion coefficient (ADC)-minimum, mean and maximum. Hence, the aim of our study was to investigate, which parameters of histogram-profiling of DWI in primary central nervous system lymphoma can be used to specifically predict features like cellular density, chromatin content and proliferative activity. PROCEDURES: Pre-treatment ADC maps of 21 PCNSL patients (8 female, 13 male, 28-89 years) from a 1.5T system were used for Matlab-based histogram profiling. Results of histopathology (H&E staining) and immunohistochemistry (Ki 67 expression) were quantified. Correlations between histogram-profiling parameters and neuropathologic examination were calculated using SPSS 23.0. RESULTS: The lower percentiles (p10 and p25) showed significant correlations with structural parameters of the neuropathologic examination (cellular density, chromatin content). The highest percentile, p90, correlated significantly with Ki 67 expression, resembling proliferative activity. Kurtosis of the ADC histogram correlated significantly with cellular density. CONCLUSIONS: Histogram-profiling of DWI in PCNSL provides a comprehensible set of parameters, which reflect distinct tumor-architectural and tumor-biological features, and hence, are promising biomarkers for treatment response and prognosis. PMID- 29522973 TI - Metabolomic characterization of pitaya fruit from three red-skinned cultivars with different pulp colors. AB - Pitaya is a new fruit crop, whose exotically colored fruits have excellent nutritional and antioxidant properties. In this study, the primary metabolite profiles of three pitaya cultivars i.e. 'Guanhuahong' (red peel with red pulp), 'Guanhuabai' (red peel with white pulp) and 'Guanhuahongfen' (red peel with pink pulp) were investigated using GC-MS and Ultraviolet-visible spectroscopy. In the fruit pulp, levels of starch, organic acids, and inositol decreased as the fruit matured. Glucose, fructose, sucrose and sorbitol contents increased gradually during fruit maturation and reached their highest levels in the pulp at the mature stage. Citramalic acid was identified for the first time in the pulp of Hylocereus species. Higher levels of total phenols, flavonoids and antioxidant activities were detected in the peel than in the pulp during fruit maturation of all three cultivars. The finding of higher levels of total phenols and flavonoids in the pitaya peel than in the pulp at the mature stage suggests that pitaya peels are a good source of natural phenols and flavonoids. PMID- 29522974 TI - Genetics of HbA1c: a case study in clinical translation. AB - Glycated hemoglobin (HbA1c) measures the amount of glucose in the blood in the previous 2-3 months and is used to test whether an individual has diabetes (HbA1c>=6.5%), or how well they are managing their diabetes. Genome-wide association studies have successfully identified multiple genomic loci influencing HbA1c, through both glycemic (factors that affect the amount blood glucose levels) and erythrocytic (factors that affect the red blood cell) pathways. Inaccuracies in HbA1c, due to non-glycemic variants, could lead to suboptimal care or adverse health consequences. A recently published example is the erythrocytic variant (rs1050828) in G6PD, which leads to the artificial lowering of HbA1c and missed diagnosis of diabetes using current thresholds. In this review we will discuss recent insights into the genetic etiology of HbA1c, and how these can translate to the clinic. PMID- 29522975 TI - Rapid detection of Klebsiella pneumoniae, Klebsiella oxytoca, Raoultella ornithinolytica and other related bacteria in food by lateral-flow test strip immunoassays. AB - Bacteria of the genera Klebsiella and Raoultella, which are present in foods and the natural environment, are associated with health hazards in humans. In the present study, two types of strips-based methods were developed to detect these bacteria simply and quickly. One method used lateral-flow test strips (LFTS) in combination with anti-Klebsiella antibodies labeled with palladium nanoparticles that bind to target bacteria, allowing their visualization. In the other, the antibodies were immobilized on nitrocellulose membranes, and urease activity was measured using an ion sensitive field effect transistor pH sensor. Testing of a combination of these two methods on 72 cultured strains successfully identified all 25 strains of Klebsiella pneumoniae, Klebsiella oxytoca and Raoultella ornithinolytica. This approach also accurately identified 76 of 77 (99%) strains isolated from meats and pastries. When combined with preculture, this method was accurate in identifying 19 of 26 (73%) target bacteria in food. These results suggest that the novel combination of strip-based assays may be effective for the on-site monitoring of food production plants, and thereby enhance food safety. PMID- 29522976 TI - New perspectives on central amygdala function. AB - The central nucleus of the amygdala (CEA) is a striatum-like structure orchestrating a diverse set of adaptive behaviors, including defensive and appetitive responses [1-3]. Studies using anatomical, electrophysiological, imaging and optogenetic approaches revealed that the CEA network consists of recurrent inhibitory circuits comprised of precisely connected functionally and genetically defined cell types that can select and control specific behavioral outputs [3,4,5*,6*,7-9,11,12]. While bivalent functionality of the CEA in adaptive behavior has been clearly demonstrated, we are just beginning to understand to which degree individual CEA circuit elements are functionally segregated or overlapping. Importantly, recent studies seem to suggest that optogenetic manipulations of the same, or overlapping cell populations can give rise to distinct, or sometimes even opposite, behavioral phenotypes [5*,6*,9-12]. In this review, we discuss recent progress in our understanding of how defined CEA circuits can control defensive and appetitive behaviors, and how seemingly contradictory results could point to an integrated concept of CEA function. PMID- 29522977 TI - Heterogeneity in hippocampal place coding. AB - The discovery of place cells provided fundamental insight into the neural basis by which the hippocampus encodes spatial memories and supports navigation and prompted the development of computational models to explain the emergence of their spatial selectively. Many such works posit that input from entorhinal grid cells is critical to the formation of place fields, a prediction that has received mixed experimental support. Potentially reconciling seemingly conflicting findings is recent work indicating that subpopulations of pyramidal neurons are functionally distinct and may be driven to varying degrees by different inputs. Additionally, new studies have demonstrated that hippocampal principal neurons encode a myriad of features extending beyond current position. Here, we highlight recent evidence for how extensive heterogeneity in connectivity and genetic expression could interact with membrane biophysics to enable place cells to encode a diverse range of stimuli. These recent findings highlight the need for more computational models that integrate these heterogeneous features of hippocampal principal neurons. PMID- 29522978 TI - BMI and disordered eating in urban, African American, adolescent girls: The mediating role of body dissatisfaction. AB - OBJECTIVE: This study examined the mediating role of body dissatisfaction between Body Mass Index (BMI) and subsequent disordered eating (e.g. dieting and restricting/purging) among early adolescent African American girls. STUDY DESIGN: Participants included 701 African American girls in 6th and 7th grades in urban schools serving low-income communities, mean age 12.15 (SD = 0.72) years. Participants were assessed at baseline and approximately 6 months later. Objectively measured height and weight were used to calculate BMI z-score. Participants completed questionnaires on body size dissatisfaction and recent dieting and restricting/purging behaviors. RESULTS: At baseline, 51.5% of participants were overweight/obese, and 60.4% expressed body dissatisfaction and a desire to be smaller. Path analytic analyses revealed change in body dissatisfaction significantly mediates the relation between initial BMI z-score and increases in dieting behaviors (B = 0.924, SE = 0.280, p = 0.001) but not restricting/purging behaviors (p = 0.05). CONCLUSIONS: Body dissatisfaction explains some associations between excess body weight and subsequent disordered eating symptoms among early adolescent, African American girls. Body dissatisfaction, identified by screening, may be an indicator of further negative consequences, including disordered eating behaviors. PMID- 29522979 TI - High-dose vitamin D in Addison's disease regulates T-cells and monocytes: A pilot trial. AB - OBJECTIVES: On the basis of the immunomodulatory actions of vitamin D (VD), we investigated the effects of high-dose VD therapy over a 3 mo period on the immune response in patients with Addison's disease (AD). METHODS: This randomized, controlled, crossover trial included 13 patients with AD who received either cholecalciferol (4000 IU/d) for 3 mo followed by 3 mo placebo oil or the sequential alternative placebo followed by verum. Glucocorticoid replacement doses remained stable. The primary outcome measures were changes in 25 hydroxyvitamin D3 (25(OH)D3) levels and immune cells including T helper cells (Th; CD3+CD4+), late-activated Th cells (CD3+CD4+HLA-DR+), regulatory T cells (CD3+CD4+CD25brightCD127dim/neg), cytotoxic T cells (Tc; CD3+CD8+), late activated Tc cells (CD3+CD8+HLA-DR+), and monocytes. The explorative analysis included the correlation of changes with VD-related gene polymorphisms and 21 hydroxylase antibody titers. RESULTS: Ten of 13 patients (77%) were VD deficient. Median 25(OH)D3 concentrations increased significantly to 41.5 ng/ml (median changes: 19.95 ng/ml; P = 0.0005) after 3 mo of cholecalciferol treatment. Within the T-cells, only the late-activated Th (median changes: 1.6%; P = 0.02) and late activated Tc cells (median changes: 4.05%; P = 0.03) decreased, whereas monocytes (median changes: 1.05%; P = 0.008) increased after VD therapy. T-cell changes were associated with two polymorphisms (CYP27B1-rs108770012 and VDR-rs10735810), but no changes in the 21-hydroxylase antibody titers were observed. CONCLUSIONS: Three months of treatment with cholecalciferol achieved sufficient 25(OH)D3 levels and can regulate late-activated T-cells and monocytes in patients with AD. Explorative analysis revealed potential genetic contributions. This pilot trial provides novel insights about immunomodulation in AD. PMID- 29522980 TI - Beyond Markov: Accounting for independence violations in causal reasoning. AB - Although many theories of causal cognition are based on causal graphical models, a key property of such models-the independence relations stipulated by the Markov condition-is routinely violated by human reasoners. This article presents three new accounts of those independence violations, accounts that share the assumption that people's understanding of the correlational structure of data generated from a causal graph differs from that stipulated by causal graphical model framework. To distinguish these models, experiments assessed how people reason with causal graphs that are larger than those tested in previous studies. A traditional common cause network (Y1<-X->Y2) was extended so that the effects themselves had effects (Z1<-Y1<-X->Y2->Z2). A traditional common effect network (Y1->X<-Y2) was extended so that the causes themselves had causes (Z1->Y1->X<-Y2<-Z2). Subjects' inferences were most consistent with the beta-Q model in which consistent states of the world-those in which variables are either mostly all present or mostly all absent-are viewed as more probable than stipulated by the causal graphical model framework. Substantial variability in subjects' inferences was also observed, with the result that substantial minorities of subjects were best fit by one of the other models (the dual prototype or a leaky gate models). The discrepancy between normative and human causal cognition stipulated by these models is foundational in the sense that they locate the error not in people's causal reasoning but rather in their causal representations. As a result, they are applicable to any cognitive theory grounded in causal graphical models, including theories of analogy, learning, explanation, categorization, decision-making, and counterfactual reasoning. Preliminary evidence that independence violations indeed generalize to other judgment types is presented. PMID- 29522981 TI - What factors influences dietary and non-dietary vitamin D intake among pregnant women in an African population? AB - OBJECTIVE: Data on dietary vitamin D (vitD) intake, sunlight exposure, and the associated determinants are lacking in Africa. The aim of this study was to establish the factors influencing vitD intake and sunlight exposure among pregnant women in an African population with the goal of improving maternal vitD nutrition. METHODS: A population-based cross-sectional study was conducted among 703 mother-infant pairs accessing postnatal care at the five main health facilities in Cape Coast, Ghana in 2016. Information on sociodemographic characteristics and sunlight exposure practices during pregnancy were collected using a structured questionnaire. A semiquantitative food frequency questionnaire was used to estimate vitD intake during pregnancy. RESULTS: VitD nutrition awareness during pregnancy was low in the study area. Education, occupation, ethnicity, and marital status influenced vitD intake in this population. In a multivariable linear regression adjusting for potential confounders, lack of information on essential nutrients needed in pregnancy, and infrequent consumption of recommended foods resulted in 10.51 ug (95% confidence interval [CI], -19.59 to -1.42) and 26.18 ug (95% CI, -47.18 to -5.17) reduction in vitD intake, respectively. Lack of information on the importance of vitD in pregnancy, and on their dietary and non-dietary sources resulted in 11.76 ug (95% CI, -21.53 to -2.00) and 26.34 ug (95% CI, -52.47 to -0.21) reduction in vitD intake, respectively. Employment status of mothers was associated with statistically significant higher sunlight exposure. CONCLUSIONS: The study findings call for rolling out literacy and nutrition education programs targeted at women in sub Saharan African countries to help improve maternal nutrition. PMID- 29522982 TI - Financial decision making power is associated with moderate to severe anemia: A prospective cohort study among pregnant women in rural South India. AB - OBJECTIVE: According to the World Health Organization, about half of all pregnant women in India suffer from some form of anemia. While poor nutrition is the most common cause, social factors, such as gender and religion, also impact anemia status. This study investigates the relationship between anemia and socioeconomic and health-related factors among pregnant women in Mysore, India. DESIGN: Prospective cohort study conducted between January 2009 and 2012 SETTING: 144 rural villages ten or more kilometers outside of Mysore City received integrated antenatal care and HIV testing services provided by mobile medical clinic in their communities. PARTICIPANTS: 1675 pregnant women from the villages were screened. All women and their infants were then followed up for up to a year after childbirth. METHODS: women who provided informed consent underwent an interviewer-administered questionnaire, physical examination by a doctor, and antenatal laboratory investigations including blood test for anemia. Women were followed through pregnancy and 12 months after childbirth to assess mother-infant health outcomes. Anemia was categorised as normal, mild, moderate, and severe, with moderate/severe anemia defined as a hemoglobin concentration of less than 100 g/l. MEASUREMENTS AND FINDINGS: two out of three pregnant women were anemic at baseline (1107/1654; 66.9%). Of those women, 32.7% (362) had mild anemia, 64.0% (708) had moderate anemia, and 3.3% (37) had severe anemia. Anemia was associated with lower education among spouses (p = 0.021) and lower household income (p = 0.022). Women living in a household where others had control over household decision-making had lower odds of moderate/severe anemia (Adjusted Odds Ratio: 0.602; 95% Confidence Interval: 0.37-0.97) as compared to women who shared decision-making power with others in the household. CONCLUSION: Interventions to reduce anemia should focus on education among men and other household decision makers on the importance of nutrition during pregnancy in India. IMPLICATIONS FOR PRACTICE: To our knowledge, this research is one of the first to examine how control of household resources is related to risk for anemia among pregnant women in India. Our data suggests that interventions aimed at reducing anemia may need to address economic factors beyond nutrition and iron status to reduce the burden of anemia among women in developing countries. PMID- 29522983 TI - Endocytosis of particulate matter induces cytokine production by neutrophil via Toll-like receptor 4. AB - Particulate matter (PM) with a median diameter <2.5 MUm, is associated with respiratory and cardiovascular diseases. We previously reported the biological effects of PM in vivo, and although neutrophils play an important role in initiating inflammation, few reports have focused on the relationship between PM inhalation and immune responses. Here, we investigated the effect of PM particle size on neutrophils, including their endocytosis activity and reactive oxygen species (ROS) production. Flow cytometry analysis indicated that 1 MUm particles are readily endocytosed by neutrophils and that endocytosis is reduced at 4 degrees C. Inhibitors of the pleckstrin homology domain of dynamin repressed this process; however, GTPase and clathrin inhibitors did not affect endocytosis. Endocytosis by neutrophils in Toll-like receptor 4 (TLR4)- and MyD88-knockout mice was reduced compared with that in wild-type mice, indicating that TLR4 and MyD88 are important for the process. Neutrophil-mediated endocytosis caused oxidative stress, and N-acetylcysteine enhanced endocytosis. Expression levels of the oxidative stress markers, heme oxygenase-1 and p62 protein, were increased in an endocytosis-dependent manner. Phagocytosed neutrophils produced IL-6 and TNFalpha, whose production was decreased by dynamin inhibitors. We observed that infiltrated CD11b-positive cells in bronchoalveolar lavage fluid endocytose PMs. Overall, these results indicate that endocytosis and ROS production via TLR4 are important for the initiation of immune responses by neutrophils. PMID- 29522984 TI - Porcine reproductive and respiratory syndrome virus induces HMGB1 secretion via activating PKC-delta to trigger inflammatory response. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes inflammatory injuries in infected pigs. PRRSV induces secretion of high mobility group box 1 (HMGB1) that enhances inflammatory response. However, the mechanism of PRRSV induced HMGB1 secretion is unknown. Here, we discovered PRRSV induced HMGB1 secretion via activating protein kinase C-delta (PKCdelta). HMGB1 secretion was positively correlated with PKCdelta activation in PRRSV-infected cells in a dose and time-dependent manner. Suppression of PKCdelta with inhibitor and siRNA significantly blocked PRRSV-induced HMGB1 translocation and secretion, which indicates PKCdelta activation is essential for the PRRSV-mediated HMGB1 secretion. In addition, PKCdelta knockdown in PRRSV-infected cells led to downregulation of inflammatory cytokines, including IL-1beta and IL-6. Moreover, PRRSV E and pORF5a proteins were found to activate PKCdelta and consequent HMGB1 secretion. These results demonstrate PRRSV activates PKCdelta to induce HMGB1 secretion via E and pORF5a. This finding provides insights on the inflammatory response and pathogenesis of PRRSV infection. PMID- 29522985 TI - Persistent organic pollutants and penile bone mineral density in East Greenland and Canadian polar bears (Ursus maritimus) during 1996-2015. AB - Persistent organic pollutants (POPs) are long-range transported to the Arctic via atmospheric and oceanic currents, where they biomagnify to high concentrations in the tissues of apex predators such as polar bears (Ursus maritimus). A major concern of POP exposure is their physiological effects on vital organ-tissues posing a threat to the health and survival of polar bears. Here we examined the relationship between selected POPs and baculum bone mineral density (BMD) in the East Greenland and seven Canadian subpopulations of polar bears. BMD was examined in 471 bacula collected between years 1996-2015 while POP concentrations in adipose tissue were determined in 67-192 of these individuals collected from 1999 to -2015. A geographical comparison showed that baculum BMD was significantly lowest in polar bears from East Greenland (EG) when compared to Gulf of Boothia (GB), Southern Hudson (SH) and Western Hudson (WH) Bay subpopulations (all p < 0.05). The calculation of a T-score osteoporosis index for the EG subpopulation using WH bears as a reference group gave a T-score of -1.44 which indicate risk of osteopenia. Concentrations of SigmaPCB74 (polychlorinated biphenyls), SigmaDDT3 (dichlorodiphenyltrichloroethanes), p,p'-DDE (dichlorodiphenyldichloroethylene), SigmaHCH3 (hexachlorohexane) and alpha-HCH was significantly highest in EG bears while SigmaPBDE (polybrominated diphenyl ethers), BDE-47 and BDE-153 was significantly highest in SH bears (all p < 0.04). Statistical analyses of individual baculum BMD vs. POP concentrations showed that BMD was positively correlated with SigmaPCB74, CB-153, HCB (hexachlorobenzene), SigmaHCH, beta-HCH, ClBz (chlorobenzene), SigmaPBDE and BDE-153 (all p < 0.03). In conclusion, baculum density was significantly lowest in East Greenland polar bears despite the positive statistical correlations of BMD vs. POPs. Other important factors such as nutritional status, body mass and body condition was not available for the statistical modelling. Since on-going environmental changes are known to affect these, future studies need to incorporate nutritional, endocrine and genetic parameters to further understand how POP exposure may disrupt bone homeostasis and affect baculum BMD across polar bear subpopulations. PMID- 29522986 TI - Occurrence and spatial distribution of chemical contaminants in edible fish species collected from UK and proximate marine waters. AB - The occurrence of a range of regulated and emerging organic environmental contaminants was investigated in 182 samples of edible marine fish sampled mainly from UK marine regions, but extending northerly to the coast of Norway and south to the Algarve. These species (sprats, mackerel, turbot, halibut, herring, grey mullet, sea bass, grey mullet, sardines, etc.) are among those considered to be at the highest risk of contamination with regulated contaminants such as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, dioxins), and polychlorinated biphenyls (PCBs), but the occurrence of polybrominated diphenylethers (PBDEs) and polybrominated biphenyls (PBBs) was also investigated. Sub-sets of samples (50-75) were also analysed for emerging contaminants: polychlorinated naphthalenes (PCNs), polybrominated and mixed halogenated dibenzo p-dioxins, dibenzofurans and biphenyls (PBDD/Fs, PXDD/Fs and PXBs) and perfluoroalkyl substances (PFAS). Contaminant occurrence varied with species and location, but all measured contaminants were detected, with sprats, sea bass, sardines, mackerel, and herring showing higher tissue concentrations. The concentrations of the different contaminants in the various samples were mapped utilising the GPS coordinate data of the capture locations to visualise spatial distribution levels. In terms of catch location, fish sampled from the coasts of southern Britain, north-western France and the Irish Sea appeared to contain proportionately higher levels of some contaminants - e.g. samples from the Irish Sea tended to show higher PCN concentrations, whereas higher levels of PCBs were observed in some fish sampled off the coasts of northern France. Similarly, samples of mullet from the southeast coast of UK showed much higher concentrations of BDE-99 than the other regions. In terms of occurrence trends, PCDD/F and PCB concentrations show a modest decline over the last decade but where limited background data is available for emerging contaminants, there is no evidence of downward trends. PMID- 29522987 TI - Harnessing biochemical and structural cues for tenogenic differentiation of adipose derived stem cells (ADSCs) and development of an in vitro tissue interface mimicking tendon-bone insertion graft. AB - Tendon-bone interface tissue is extremely challenging to engineer because it exhibits complex gradients of structure, composition, biologics, and cellular phenotypes. As a step toward engineering these transitional zones, we initially analyzed how different (topographical or biological) cues affect tenogenic differentiation of adipose-derived stem cells (ADSCs). We immobilized platelet derived growth factor - BB (PDGF-BB) using polydopamine (PD) chemistry on random and aligned nanofibers and investigated ADSC proliferation and tenogenic differentiation. Immobilized PDGF greatly enhanced the proliferation and tenogenic differentiation of ADSCs; however, nanofiber alignment had no effect. Interestingly, the PDGF immobilized aligned nanofiber group showed a synergistic effect with maximum expression of tenogenic markers for 14 days. We also generated a nanofiber surface with spatially controlled presentation of immobilized PDGF on an aligned architecture, mimicking native tendon tissue. A gradient of immobilized PDGF was able to control the phenotypic differentiation of ADSCs into tenocytes in a spatially controlled manner, as confirmed by analysis of the expression of tenogenic markers and immunofluorescence staining. We further explored the gradient formation strategy by generation of a symmetrical gradient on the nanofiber surface for the generation of a structure mimicking bone-patellar-tendon-bone with provision for gradient immobilization of PDGF and controlled mineralization. Our study reveals that, together with biochemical cues, favorable topographical cues are important for tenogenic differentiation of ADSCs, and gradient presentation of PDGF can be used as a tool for engineering stem cell-based bone-tendon interface tissues. PMID- 29522989 TI - Detours on the phloem sugar highway: stem carbon storage and remobilization. AB - For trees to survive, they must allocate resources between sources and sinks to maintain proper function. The vertical transport pathway in tree stems is essential for carbohydrates and other solutes to move between the canopy and the root system. To date, research and models emphasize the role of tree stems as 'express' sugar highways. However, recent investigations using isotopic markers suggest that there is considerable storage and exchange of phloem-transported sugars with older carbon (C) reserves within the stem. Thus, we suggest that stems play an important role not only in long-distance transport, but also in the regulation of the tree's overall C balance. A quantitative partitioning of stem C inputs among storage and sinks, including tissue growth, respiration, and export to roots, is still lacking. Combining methods to better quantify the dynamics and controls of C storage and remobilization in the stem will help to resolve central questions of allocation and C balance in trees. PMID- 29522988 TI - Early preemptive ICU admission for newly diagnosed high-risk acute myeloid leukemia patients. PMID- 29522990 TI - Identification of a unique insertion in plant organellar DNA polymerases responsible for 5'-dRP lyase and strand-displacement activities: Implications for Base Excision Repair. AB - Plant mitochondrial and chloroplast genomes encode essential proteins for oxidative phosphorylation and photosynthesis. For proper cellular function, plant organelles must ensure genome integrity. Although plant organelles repair damaged DNA using the multi-enzyme Base Excision Repair (BER) pathway, the details of this pathway in plant organelles are largely unknown. The initial enzymatic steps in BER produce a 5'-deoxyribose phosphate (5'-dRP) moiety that must be removed to allow DNA ligation and in plant organelles, the enzymes responsible for the removal of a 5'-dRP group are unknown. In metazoans, DNA polymerases (DNAPs) remove the 5'-dRP moiety using their intrinsic lyase and/or strand-displacement activities during short or long-patch BER sub-pathways, respectively. The plant model Arabidopsis thaliana encodes two family-A DNAPs paralogs, AtPolIA and AtPolIB, which are the sole DNAPs in plant organelles identified to date. Herein we demonstrate that both AtPolIs present 5'-dRP lyase activities. AtPolIB performs efficient strand-displacement on a BER-associated 1-nt gap DNA substrate, whereas AtPolIA exhibits only moderate strand-displacement activity. Both lyase and strand-displacement activities are dependent on an amino acid insertion that is exclusively present in plant organellar DNAPs. Within this insertion, we identified that residue AtPollB-Lys593 acts as nucleophile for lyase activity. Our results demonstrate that AtPolIs are functionally equipped to play a role in short-patch BER and suggest a major role of AtPolIB in a predicted long-patch BER sub-pathway. We propose that the acquisition of insertion 1 in the polymerization domain of AtPolIs was a key component in their evolution as BER associated and replicative DNAPs. PMID- 29522992 TI - Multi-block analysis coupled with GC-FID and ATR-MIR for the evaluation of thermal degradation in vegetable oils. AB - The effect of heating in twenty-four different oil samples was evaluated via iodine value (IV), gas chromatography (GC) and mid-infrared (MIR) analyses. Common components and specific weights analysis (CCSWA) was applied to distribute the samples according to their most relevant characteristics, thereby revealing the influence of heating on composition. Instrumental analysis indicated a high amount of beneficial fatty acids, such as alpha-linolenic acid, in less exploited oils such as chia oil. This oil can present nutritional damage when subjected to high temperatures and is thus less recommended for frying. Conversely, oils containing high amounts of linoleic acid, such as almond and nut oils, as well as those containing equivalent amounts of alpha-linolenic and linoleic acids, such as golden flaxseed and flaxseed oils, displayed greater resistance to temperature. The 3008/cm band exhibited greater intensity in oils with a higher degree of unsaturation, such as chia and linseed oils, a phenomenon mainly influenced by the presence of linoleic and alpha-linolenic fatty acids. After heating, there was a decrease in the intensity of this band. The main parameter discriminating the tested oil samples based on CCSWA was the degree of unsaturation. Overall, the employed statistical method was effective in analyzing the data obtained via the applied techniques, revealing the influence of each assessed parameter. PMID- 29522991 TI - The C-terminal tail of the NEIL1 DNA glycosylase interacts with the human mitochondrial single-stranded DNA binding protein. AB - The 16.5 kb mitochondrial genome is subjected to damage from reactive oxygen species (ROS) generated in the cell during normal cellular metabolism and external sources such as ionizing radiation and ultraviolet light. ROS cause harmful damage to DNA bases that could result in mutagenesis and various diseases, if not properly repaired. The base excision repair (BER) pathway is the primary pathway involved in maintaining the integrity of mtDNA. Several enzymes that partake in BER within the nucleus have also been identified in the mitochondria. The nei-like (NEIL) DNA glycosylases initiate BER by excising oxidized pyrimidine bases and others such as the ring-opened formamidopyrimidine and the hydantoin lesions. During BER, the NEIL enzymes interact with proteins that are involved with DNA replication and transcription. In the current manuscript, we detected NEIL1 in purified mitochondrial extracts from human cells and showed that NEIL1 interacts with the human mitochondrial single-stranded DNA binding protein (mtSSB) via its C-terminal tail using protein painting, far western analysis, and gel-filtration chromatography. Finally, we scrutinized the NEIL1-mtSSB interaction in the presence and absence of a partial-duplex DNA substrate using a combination of multi-angle light scattering (MALS) and small angle X-ray scattering (SAXS). The data indicate that NEIL1 and homotetrameric mtSSB form a larger ternary complex in presence of DNA, however, the tetrameric form of mtSSB gets disrupted by NEIL1 in the absence of DNA as revealed by the formation of a smaller NEIL1-mtSSBmonomer complex. PMID- 29522993 TI - SLC6A19 is a novel putative gene, induced by dioxins via AhR in human hepatoma HepG2 cells. AB - The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8 pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver. PMID- 29522994 TI - Incidence of real-world automotive parent and halogenated PAH in urban atmosphere. AB - This study reports results from a tunnel experiment impact of real-world traffic related particle and gas parent and halogenated polycyclic aromatic hydrocarbons (PAHs and HPAHs) on urban air. The traffic related emission characteristics and subsequent environmental behavior of these compounds were investigated. To understand the significance of real-world transport emissions to the urban air, traffic-related mass emissions of PAHs and HPAHs were estimated based on measured emission factors. According to our results, PAHs and HPAHs emissions via particulate phase were greater than those via gaseous phase; particles in 2.1-3.3 MUm size fraction, have the major contribution to particulate PAHs and HPAHs emissions. Over all, contribution of traffic-related emission of PAHs (only ~3% of the total PAHs emission in China) is an overstated source of PAHs pollution in China. Actually, exhaust pipe emission contributed much less than the total traffic-related emission of pollutants. PMID- 29522995 TI - Critical analysis of the relationship between imposex and butyltin body burden in Nassarius reticulatus and Nucella lapillus. AB - Imposex is a disorder caused by organotins, mainly tributyltin, which results in the appearance of male sexual characteristics in females of gastropod mollusks. The main objective of this work was to make a critical analysis of the relationship between imposex and butyltin body burdens in Nucella lapillus and Nassarius reticulatus. Specifically, this study evaluates possible additive effects among butyltins, proposes scales of effects based on robust statistical criteria as alternatives to existing ones and defines the body burdens of TBT in N. lapillus and N. reticulatus corresponding to the assessment classes (ACs) of the Vas Deferens Sequence Index (VDSI) established by OSPAR. Data of organotin body burdens and biological effects was retrieved from the ICES Dataset and from scientific literature. All responses, except the percentage of females displaying Imposex (IMPF) in Nucella lapillus, showed a sigmoidal profile regarding to the body burden of mono- (MBT), di- (DBT) and tributyltin and sum of butyltins (SumBTs). TBT and the SumBTs were better indicators of the VDSI or Relative Penis Size Index/Relative Penis Length Index (RPSI/RPLI) responses than MBT or DBT in most cases. From a statistical point of view, RPSI/RPLI and VDSI were better indicators of contamination by TBT than IMPF, although both RPSI and RPLI showed lower sensitivity than VDSI. The model used for describing the joint effect of butyltins provided a statistically significant fitting to the data assuming a null effect for both MBT and DBT for N. lapillus, and a lower toxic contribution of MBT and DBT with respect to TBT for N. reticulatus. RPSI or RPLI values, equivalent to the ACs for VDSI, were proposed as alternative criteria when measuring moderate to high levels of imposex. TBT concentrations in N. reticulatus and N. lapillus tissues, corresponding to the ACs were calculated and provided valuable information for cross-species comparisons. PMID- 29522996 TI - Effects of childhood multiple maltreatment experiences on depression of socioeconomic disadvantaged elderly in Brazil. AB - Childhood maltreatment is a risk factor for depression in nonelderly individuals. We investigated the effect of childhood abuse and neglect on the development of geriatric depression and its severity in socioeconomically disadvantaged individuals. A cross-sectional study investigated 449 individuals aged 60-103 years sorted by data using the enrollment list health coverage from the city of Porto Alegre, Brazil. The fifteen-item Geriatric Depression Scale was used to assess depression. The Childhood Trauma Questionnaire was used to identify emotional and physical neglect, in addition to emotional, physical, and sexual abuse. Geriatric depression was associated with emotional and physical abuse and neglect. Emotional abuse and neglect, as well as physical abuse, increased the odds of an individual developing severe depression. Correlations were observed for combined forms of maltreatment, with two to five maltreatment types producing mild to moderate symptoms. Similar trends were observed for severe symptoms in a limited number of cases. The cross-sectional design limit causal inference. Retrospective measurement of childhood maltreatment may increase recall and response bias. Late-life depression and its severity significantly correlated with the extent of childhood emotional and physical abuse and neglect. Thus, research should focus on supporting trauma survivors late in life, particularly when they come from low or middle income countries because these patients have higher rates of depression in elderly populations. PMID- 29522997 TI - Effects of perceptual load and socially meaningful stimuli on crossmodal selective attention in Autism Spectrum Disorder and neurotypical samples. AB - The present study examined whether increasing visual perceptual load differentially affected both Socially Meaningful and Non-socially Meaningful auditory stimulus awareness in neurotypical (NT, n = 59) adults and Autism Spectrum Disorder (ASD, n = 57) adults. On a target trial, an unexpected critical auditory stimulus (CAS), either a Non-socially Meaningful ('beep' sound) or Socially Meaningful ('hi') stimulus, was played concurrently with the presentation of the visual task. Under conditions of low visual perceptual load both NT and ASD samples reliably noticed the CAS at similar rates (77-81%), whether the CAS was Socially Meaningful or Non-socially Meaningful. However, during high visual perceptual load NT and ASD participants reliably noticed the meaningful CAS (NT = 71%, ASD = 67%), but NT participants were unlikely to notice the Non-meaningful CAS (20%), whereas ASD participants reliably noticed it (80%), suggesting an inability to engage selective attention to ignore non-salient irrelevant distractor stimuli in ASD. PMID- 29522998 TI - Critical age windows in the impact of lifetime smoking exposure on respiratory symptoms and disease among ever smokers. AB - BACKGROUND: Despite extensive knowledge of smoking effects on respiratory disease, there is no study including all age windows of exposure among ever smokers. The objective of this study was to assess the effects from smoking exposure in utero, early childhood, adolescence and adulthood on respiratory health outcomes in adult male and female ever smokers. METHODS: Respiratory health outcomes were assessed in 10,610 participants of the European Community Respiratory Health Survey (ECRHS) I who reported a history of ever smoking by questionnaire. The associations of maternal smoking in utero, maternal smoking during childhood, age of smoking debut and pack-years of smoking with respiratory symptoms, obstructive diseases and bronchial hyperreactivity were analysed using generalized linear regression, non-linearity between age of smoking debut and outcomes were assessed by Generalized additive mixed models. RESULTS: Respiratory symptoms and asthma were more frequent in adults if their mother smoked during pregnancy, and, in men, also if mother smoked in childhood. Wheeze and >=3 respiratory symptoms declined with later smoking debut among women [<=10 years: OR = 3.51, 95% CI 1.26, 9.73; 11-12 years: 1.57[1.01-2.44]; 13-15 years: 1.11[0.94-1.32] and <=10 years: 3.74[1.56-8.83]; 11-12 years: 1.76[1.19-2.56]; 13 15 years: 1.12[0.94-1.35], respectively]. Effects of increasing number of packyears were pronounced in women (Chronic Obstructive Pulmonary Disease (COPD): OR/10 packyears women: 1.33 [1.18, 1.50], men: 1.14 [1.04, 1.26] pinteraction = 0.01). CONCLUSIONS: Among ever smokers, smoking exposure in each stage of the lifespan show persistent harmful effects for adult respiratory health, while women appeared to be more vulnerable to an early age of smoking debut and amount of smoking in adulthood. PMID- 29522999 TI - Bacillus licheniformis in geogenic dust induces inflammation in respiratory epithelium. AB - Exposure to environmental geogenic (or earth-derived) dust can lead to more frequent and severe infections in the human airway. Particulate matter < 10 um (PM10) is the component of air pollution that is commonly associated with the exacerbation of respiratory diseases. We have previously demonstrated that mice exposed to geogenic dust PM10 experienced an exacerbation of inflammatory responses to influenza A virus. Whether geogenic dust PM10 also exacerbates respiratory bacterial infection is not yet known, nor are the components of the dust that drive these responses. We treated airway bronchial epithelial cells (NuLi-1) with UV-irradiated geogenic dust PM10 from six remote Western Australian towns. High levels of IL-6 and IL-8 production were observed, as well as persistent microbial growth. 16 S rRNA sequencing of the growth identified the microbe as Bacillus licheniformis, a spore-forming, environmentally abundant bacterium. We next investigated the interaction of B. licheniformis with respiratory epithelium in vitro to determine whether this exacerbated infection with a bacterial respiratory pathogen (non-typeable Haemophilus influenzae, NTHi). Heat treatment (100 degrees C) of all PM10 samples eliminated B. licheniformis contamination and reduced epithelial inflammatory responses, suggesting that heat-labile and/or microbial factors were involved in the host response to geogenic dust PM10. We then exposed NuLi-1 epithelium to increasing doses of the isolated Bacillus licheniformis (multiplicity of infection of 10:1, 1:1 or 0.1:1 bacteria: cells) for 1, 3, and 24 h. B. licheniformis and NTHi infection (association and invasion) was assessed using a standard gentamicin survival assay, and epithelial release of IL-6 and IL-8 was measured using a bead based immunoassay. B. licheniformis was cytotoxic to NuLi-1 cells at 24 h. At 3 h post-challenge, B. licheniformis elicited high IL-6 and IL-8 inflammatory responses from NuLi-1 cells compared with cells treated with heat-treated geogenic dust PM10 (p < 0.0001). Whilst treatment of cells with B. licheniformis increased inflammation, this did not make the cells more susceptible to NTHi infection. This study highlights that geogenic dust PM10 can harbour viable bacterial spores that induce inflammation in respiratory epithelium. The impact on respiratory health from inhalation of bacterial spores in PM10 in arid environments may be underestimated. Further investigation into the contribution of B. licheniformis and the wider dust microbiome to respiratory infection is warranted. PMID- 29523000 TI - Neighborhood resolved fiber orientation distributions (NRFOD) in automatic labeling of white matter fiber pathways. AB - Accurate digital representation of major white matter bundles in the brain is an important goal in neuroscience image computing since the representations can be used for surgical planning, intra-patient longitudinal analysis and inter-subject population connectivity studies. Reconstructing desired fiber bundles generally involves manual selection of regions of interest by an expert, which is subject to user bias and fatigue, hence an automation is desirable. To that end, we first present a novel anatomical representation based on Neighborhood Resolved Fiber Orientation Distributions (NRFOD) along the fibers. The resolved fiber orientations are obtained by generalized q-sampling imaging (GQI) and a subsequent diffusion decomposition method. A fiber-to-fiber distance measure between the proposed fiber representations is then used in a density-based clustering framework to select the clusters corresponding to the major pathways of interest. In addition, neuroanatomical priors are utilized to constrain the set of candidate fibers before density-based clustering. The proposed fiber clustering approach is exemplified on automation of the reconstruction of the major fiber pathways in the brainstem: corticospinal tract (CST); medial lemniscus (ML); middle cerebellar peduncle (MCP); inferior cerebellar peduncle (ICP); superior cerebellar peduncle (SCP). Experimental results on Human Connectome Project (HCP)'s publicly available "WU-Minn 500 Subjects + MEG2 dataset" and expert evaluations demonstrate the potential of the proposed fiber clustering method in brainstem white matter structure analysis. PMID- 29523002 TI - Segmentation of white matter hyperintensities using convolutional neural networks with global spatial information in routine clinical brain MRI with none or mild vascular pathology. AB - We propose an adaptation of a convolutional neural network (CNN) scheme proposed for segmenting brain lesions with considerable mass-effect, to segment white matter hyperintensities (WMH) characteristic of brains with none or mild vascular pathology in routine clinical brain magnetic resonance images (MRI). This is a rather difficult segmentation problem because of the small area (i.e., volume) of the WMH and their similarity to non-pathological brain tissue. We investigate the effectiveness of the 2D CNN scheme by comparing its performance against those obtained from another deep learning approach: Deep Boltzmann Machine (DBM), two conventional machine learning approaches: Support Vector Machine (SVM) and Random Forest (RF), and a public toolbox: Lesion Segmentation Tool (LST), all reported to be useful for segmenting WMH in MRI. We also introduce a way to incorporate spatial information in convolution level of CNN for WMH segmentation named global spatial information (GSI). Analysis of covariance corroborated known associations between WMH progression, as assessed by all methods evaluated, and demographic and clinical data. Deep learning algorithms outperform conventional machine learning algorithms by excluding MRI artefacts and pathologies that appear similar to WMH. Our proposed approach of incorporating GSI also successfully helped CNN to achieve better automatic WMH segmentation regardless of network's settings tested. The mean Dice Similarity Coefficient (DSC) values for LST-LGA, SVM, RF, DBM, CNN and CNN-GSI were 0.2963, 0.1194, 0.1633, 0.3264, 0.5359 and 5389 respectively. PMID- 29523001 TI - Suicidal shot in the mouth with rubber bullets. AB - Rubber bullets weapons can have tragic consequences when used at short range and on vulnerable body areas. A man in his forties was found deceased at his house, covered in blood. A "non-lethal" firearm was found near the bed: the "SAPL GC27". This is a single shot handgun with mini Gomm Cogne ammunition: 12 rubber spherical pellets, 7.4 mm in diameter. The findings were consistent with an intra buccal shot, and an ingestion-inhalation of blood and projectiles. Cause of the death was linked to both the hemorrhage due to mouth and aero digestive crossroad trauma, responsible of a mechanical asphyxia, and blood absorption in lungs. This case insists on the deadly potential of this weapon if misused. Fortunately, the term "non-lethal" has been progressively replaced, but sometimes still can be seen, especially in gunsmith and webstores. It should be deleted to avoid confusion among inexperienced people, and at best, this weapon should be restricted to certain professions. PMID- 29523003 TI - Similar Aquaporin9 and MAPK Expression Profiles in the Liver of Types 1 and 2 Diabetes Mellitus. AB - Aquaporin-9 (AQP9) is an aquaglyceroporin that biophysically conducts water, glycerol, and other small solutes. AQP9 is expressed in hepatocytes on the sinusoidal surfaces of hepatocyte plates in the liver, where it is considered responsible for the glycerol uptake in gluconeogenesis. However, limited information is available on the expression and regulating mechanism of AQP9 in different hyperglycemia models. Thus, this study examined the expression patterns of AQP9 and mitogen-activated protein kinase (MAPK) in Types 1 and 2 diabetes mellitus (DM) to clarify the roles and regulating mechanism of AQP9 in gluconeogenesis. Compared with the control group, the AQP9 expression significantly increased in both Types 1 and 2 DM, and the increased expression was associated with the activation of phosphorylated JNK (p-JNK) and the inhibition of phosphorylated p38 (p-p38). By contrast, phosphorylated ERK remained stable in the liver with Type 1 or 2 DM. These effects could be reversed by insulin treatment. That is, insulin downregulated AQP9 by inhibiting p-JNK and activating p-p38. The upregulation of AQP9 could be involved in gluconeogenesis and co-regulated by the JNK and p38 MAPK pathway in both Types 1 and 2 DM. PMID- 29523004 TI - Cystic Encephalomalacia following Vasculopathy and Vasospasm of Proximal Intracranial Arteries Due to Pneumococcal Meningitis in a Infant. AB - Despite the availability of modern antibiotics, pneumococcal meningitis in both children and adults remains a severe disease-one known to frequently cause grave complications and residual disability. Although the appearance of arterial vasospasms in bacterial meningitis systematically has been investigated and reported on for adult patients, such research is lacking when it comes to infants. We report on a 4-week-old infant who, 6 days after onset of pneumococcal meningitis, suffered severe neurological deterioration with treatment-resistant seizures and coma. Generalized cortical and subcortical edema developed in conjunction with diminished cerebral blood flow, as depicted in magnetic resonance angiography and serial Doppler-sonographic examinations. The ischemia resulted in extensive cystic encephalomalacia. We propose that the degree of variation in cerebral blood flow in the acute phase was the result of an extensive arterial vasculopathy involving vasospasms. Awareness of this complication and prospective serial Doppler-sonographic examinations may improve our understanding of the connection between brain edema and vasculopathy. At present, however, no effective treatment appears available. PMID- 29523005 TI - MicroRNAs and Target Genes in Pituitary Adenomas. PMID- 29523006 TI - The Effects of Supplementation with Chromium on Insulin Resistance Indices in Women with Polycystic Ovarian Syndrome: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. AB - Recently, the effects of nutritional supplementation on improvement or prevention of polycystic ovary syndrome (PCOS) have been considered. Several studies have been carried out on the effect of chromium supplementation in improving PCOS patients. This study aimed to summarize the available findings regarding the effect of chromium on improving the polycystic ovary syndrome. The review includes randomized controlled trials (RCTs) comparing chromium treatment with placebo or other treatments in women with PCOS. Women with PCOS diagnosed according to the ESHRE/ASRM or NIH criteria in reproductive age were eligible. Electronic searches using the MeSH terms were conducted in the following databases: Medline, Embase, Scopus, Web of Science, and The Cochrane Library. Effects were measured as weighted mean difference (WMD) and 95% confidence intervals (CI) for studies of PCOS and control subjects were calculated by using random-effects model. The initial search yielded potentially 100 relevant articles of randomized clinical trials on dietary chromium supplements: 16 from Pubmed, 36 from Embase, 29 from Scopus, and 19 from Web of Science. After studying these publications, 5 were potentially eligible and retrieved in full text. The five studies included in the meta-analysis reported data on 137 women with PCOS and 131 controls. A meta-analysis of 5 studies showed a non-significant difference in fasting insulin between chromium, and placebo or other treatment (mean difference (MD): -1.14; (95% CI: -4.11 to 1.83, p=0.45). We retrieved two randomized controlled trials, in which Quantitative Insulin Sensitivity Check Index (QUICKI) was compared between chromium, and placebo or other treatment in 156 women with PCOS. Meta-analysis of two RCTs showed no significant difference in QUICKI score between chromium and placebo (MD: 0.01; 95% CI: -0.01 to 0.04, p=0.34). Two randomized controlled trials compared Homeostatic Model Assessment Insulin Resistance (HOMA-IR) between chromium, and placebo or other treatment in 81 women with PCOS. After combining the data, there was a significantly lower HOMA-IR in the chromium group (MD: -1.68; 95% CI: -2.42 to -0.94, p<0.001). One RCT reported a significant difference in Homeostatic Model Assessment-beta-cell function (HOMA-B) between chromium and placebo groups (-15.5+/-32.3 vs. +13.6+/ 23.1, p<0.001). No significant effect of chromium on fasting insulin and QUICKI score was found in women with PCOS. Chromium supplementation significantly improved HOMA-IR and HOMA-B among patients with diabetes. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials in well characterized studies that address the limitations in the current evidence are needed before definitive claims can be made about the effect of chromium supplementation. PMID- 29523007 TI - Incidence of Diabetic Ketoacidosis of New-Onset Type 1 Diabetes in Children and Adolescents in Different Countries Correlates with Human Development Index (HDI): An Updated Systematic Review, Meta-Analysis, and Meta-Regression. AB - Type 1 diabetes mellitus (T1DM) is usually diagnosed by insulin deficiency at a young age. Diabetic ketoacidosis (DKA) represents a severe complication occurring before the first diagnosis of T1DM. Actually, the data situation is still unsettled in assessing the current state of diagnosis. This study summarizes the latest rates of DKA of new-onset T1DM in children and adolescents in different countries available over the last five years. Different T1DM-related, geographical and socioeconomic moderators are suitable to explain the heterogeneity of observed DKA rates. A systematic literature search using PubMed, EMBASE*, and MedLine* (*via OVID) was conducted to extract worldwide DKA rates covering publications from April 2011 to May 2016. We define DKA consistently by pH<7.3 or bicarbonate<15 mmol/l. We identified 34 suitable studies covering DKA rates in 25 countries. Overall DKA rates were compared to earlier studies to identify a temporal trend. We further applied a random effects meta-analysis and used meta-regression to reveal moderators of DKA rate heterogeneity. This review evaluating 34 studies includes 47 000 children and adolescents in total. DKA rates varied from 14.7% (Denmark) to 79.8% (Saudi Arabia). DKA rates are still high but a decline can also be recognized. The meta-regression shows that latitude (p<0.000) and human development index (HDI) (p<0.000) are moderators of DKA rates. The frequency of DKA rates occurrence varies widely for different countries. Both latitude and HDI partially explain the observed heterogeneity, while other moderators such as density of physicians showed no obvious correlation. PMID- 29523008 TI - Correction: Incidence of Diabetic Ketoacidosis of New-Onset Type 1 Diabetes in Children and Adolescents in Different Countries Correlates with Human Development Index (HDI): An Updated Systematic Review, Meta-Analysis, and Meta-Regression. PMID- 29523009 TI - Effect of Vitamin K Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Clinical Trials. AB - Type 2 diabetes mellitus (T2DM) is one of the most important public health issues. Vitamin K supplementation might have favorable effect on risk factors of T2DM. The aim of this study was to perform a systematic review and meta-analysis of interventional studies to examine the effect of vitamin K supplementation on glycemic indices. A systematic search was performed in electronic databases including PubMed, Science Direct, ProQuest, Institute of Scientific Information Web of Science, and Google scholar up to July 2017. We used a random effects model to estimate pooled effect size of fasting blood sugar (FBS), 2-h oral glucose tolerance test (2-h OGTT), fasting insulin (FINS), and homeostasis model assessment-estimated insulin resistance (HOMA-IR). Five clinical trials (533 participants) fulfilled the eligibility criteria of the present meta-analysis. Overall, meta-analysis could not show any beneficial effect of vitamin K supplementation on FBS (-0.91 mg/dl, 95% CI: -2.57, 0.76, p=0.28), FINS (-0.35 MUIU/ml, 95% CI: -1.70, 1.00, p=0.61), HOMA-IR (-0.06, 95% CI: -0.32, -0.19, p=0.63), and 2-h OGTT (-4.00 mg/dl, 95% CI: -20.00, 11.99, p=0.62). Sensitivity analysis showed that overall estimates were not affected by elimination of any study. We did not observe any evidence regarding publication bias. In conclusion, vitamin K supplementation had no significant effect on glycemic control in healthy subjects. However, further studies should be performed on diabetic and pre-diabetic patients to determine the effect of vitamin K supplementation on impaired glycemic control. PMID- 29523010 TI - Associations Between Thyroid and Blood Pressure in Euthyroid Adults: A 9-Year Longitudinal Study. AB - Longitudinal studies considering associations between thyroid function in the reference range (RR) with blood pressure (BP) are scarce and contradictory. We aimed to investigate the associations of serum thyrotropin (TSH) and free T4 (FT4) with different components of BP also incident prehyperetension (preHTN) and HTN during a 9-year follow-up. A sum of 2282 euthyroid individuals from an ongoing population-based cohort study were selected. A sex-stratified multivariate generalized estimating equation (GEE) method was employed. Moreover, a multivariate transitional model was used considering preceding BP status as a predictor of dichotomous outcomes of preHTN and HTN. Multivariate-adjusted GEE analysis revealed a decreasing trend for systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP) throughout the study period in both men and women, either adjusted for serum TSH or FT4 levels. Serum FT4 within the RR was positively associated with all BP parameters in total population and in men, but serum TSH had a statistically significant mild increasing effect only on SBP, DBP and MAP of men. Multivariate transitional model found no association between serum TSH levels within the reference range (RR) and BP status; regarding serum FT4, a 1 ng/dl higher FT4 was associated with 40% increased risk of preHTN [OR (95% CI), 1.40 (1.02-1.90)], but not with HTN [OR (95% CI), 0.93 (0.80-1.09)]. It is concluded that serum FT4 within the RR is more strongly associated with BP parameters compared to TSH. This association is not consistent between men and women. Moreover, higher FT4 is associated with increased risk of preHTN. PMID- 29523011 TI - Perioperative Use of Anticoagulant and Platelet-inhibiting Medications for Elective Spine Surgery: Results of a Nationwide Survey. AB - BACKGROUND AND STUDY AIMS: Perioperative use of anticoagulant and platelet inhibiting agents by patients undergoing spine surgery poses the dilemma of increased risk of hemorrhage. We examined the standards of use for these medications and expert opinions through a nationwide survey. MATERIALS AND METHODS: An online-based survey was conducted by invitation. A personal token to access the survey was sent to one representative of each neurosurgical and orthopaedic unit performing spine surgery and to all other active members of the Swiss Society of Neurosurgery and the Swiss Society of Spinal Surgery. A total of 97 e-mail invitations were sent to 19 representatives of neurosurgical or orthopaedic units and 78 registered neurosurgeons and orthopaedic surgeons who potentially perform spine surgery. RESULTS: From February to April 2016, 40 surgeons (26 neurosurgeons, 14 orthopaedic surgeons) completed the survey (41%). Among the respondents, 55% prescribed prophylactic heparin preoperatively; depending on the procedure, 83 to 95% prescribed heparin postoperatively. Depending on the type of surgery, 23 to 48% discontinued acetylic acid preoperatively, and 80 to 87% always discontinued clopidogrel preoperatively. On average, platelet inhibition was resumed 4 +/- 2.5 days postoperatively. Orthopaedic surgeons recommenced platelet inhibition earlier than neurosurgeons (p = 0.013). Anticoagulation with rivaroxaban was discontinued 3 +/- 2 days before surgery. Depending on the indication, 72 to 98% of respondents temporarily replaced traditional anticoagulation therapy (vitamin K antagonists) with heparin perioperatively. CONCLUSION: Administration and discontinuation of anticoagulant and platelet-inhibiting medications in the perioperative setting of spinal surgery differ vastly between different units and surgeons. Recommendations from the spine surgeon societies may be helpful to develop nationwide guidelines. PMID- 29523012 TI - Risk of Postoperative Performance Status Worsening after Resection of Lesions Involving the Motor Pathway: A Multinomial Logistic Regression Model. AB - BACKGROUND AND STUDY OBJECTIVE: In surgery for gliomas and brain metastases, preservation of neurologic functions is essential to ensure a good quality of life and the eligibility for adjuvant therapies. This article assesses which factors could influence the functional outcome in patients with lesions located in the motor pathways. MATERIALS AND METHODS: A total of 92 patients with gliomas and metastases involving the motor pathways were studied for concerns regarding quality of life (Karnofsky performance status [KPS] and modified Rankin scale [mRS]) before and after surgical treatment supported by intraoperative neuromonitoring. Patient-related, surgery-related, and lesion-related data were recorded to identify the relationships with postoperative performance status. The relationship between lesions and the corticospinal tract were investigated with preoperative magnetic resonance imaging sequences and tractographic reconstructions. RESULTS: Means of preoperative mRS and KPS were 1.91 +/- 1.34 and 80.8 +/- 20, and at 30 days postoperatively they were 1.93 +/- 1.63 and 79.8 +/- 24.4, respectively. The better preoperative performance status was a predictor of better outcome in terms of quality of life. Gender showed a statistical association with ?KPS (p = 0.033) and ?mRS (p = 0.031). A recurrent lesion was a predictor of poor functional outcome (p= 0.045 for KPS at 30 days).A left-sided lesion showed a statistical association with a lesser improvement with respect to right sided. Complications were associated with a lesser functional improvement (?mRS, ?KPS, and clinical improvement: p = 0.001, p = 0.006, and p = 0.003, respectively). Hemorrhagic complications were associated with the worst functional prognosis. CONCLUSIONS: In our experience, factors associated with worse functional prognosis and quality of life were a poor preoperative performance status, female gender, operating on a recurrent lesion, involvement of the left corticospinal tract, and surgical or medical postoperative complications. PMID- 29523013 TI - A Clinical Study on Axial Symptoms and Imaging Changes in Paraspinal Muscles after Cervical Posterior Open-door Laminoplasty. AB - OBJECTIVE: This research aimed to gain a better understanding of the relationship between cervical posterior open-door laminoplasty on axial symptoms, the net cross-sectional area of paraspinal muscles, and the degree of pimelosis. METHOD: A retrospective study was conducted on a consecutive series of 37 patients who had underwent cervical posterior open-door laminoplasty + lateral mass fixation and bone graft fusion between January 2015 and July 2015. All patients received postoperative examinations at 6 months and 18 months after the operation. For each follow-up visit, the VAS Rating Scale and ODI Function Index Questionnaire were filled out. Meanwhile, a C-Spine X-ray and MRI of the patients were taken. In the measurements taken with ImageJ 1.51 K Software, the cervical vertebra MRI T2-weighted image cross-section for each segment was measured separately, mainly including the mean T2 signal value of the contour area and the net area of the paraspinal muscles. RESULTS: Differences between VAS and ODI (%) at three different time points were of statistical significance (p < 0.01). Pairwise comparisons of the results showed that VAS and ODI (%) at different times were clearly different (p < 0.01). Differences in the mean T2 signal value and net area at different times were of statistical significance (p < 0.01). Pairwise comparisons of the results indicated that the mean T2 signal value and net area at different times were clearly different (p < 0.01). The corresponding analytical results for VAS, ODI (%), and the mean of the T2 signal value and net area demonstrated that VAS6 months after surgery was positively correlated to the net area of C3/4 and C4/5 (r = 0.352, p < 0.05; r = 0.338, p < 0.05). The analogous analytical results for the mean T2 signal value and net area were of no statistical significance (p > 0.05). CONCLUSIONS: We believe that axial symptoms after cervical spine surgery does not affect the recovery of neurological function. There is a process of acute or subacute enlargement of paraspinal muscles on segments C3/4 and C4/5 after the operation, while the results of the follow-up visits show that there is a gradual process of atrophy in local posterior muscles, which may be related to axial symptoms. The degree of pimelosis of the neck paraspinal muscles may have no relationship with axial symptoms. PMID- 29523014 TI - [Medicolegal Assessment for Chronic Musculoskeletal Pain - 4th Update of the German Guideline for Medicolegal Assessment of Persons in Chronic Pain]. AB - Medicolegal assessments of claimants with chronic muskuloskeletal pain conditions are frequent. The first German guideline published in 2005 for the medicolegal assessment of claimants in chronic pain is now available in its 4th version (AWMF register number 094 - 003). It gives recommendations for the procedure and serves to ensure the quality of expert opinions when complaints about chronic pain are the leading symptom. In the current version, the indications for ordering medical assessments in pain syndromes have been reformulated, the assessment criteria have been adapted to ICF specifications, and an unequivocal distinction has been introduced between questions of state and causal assessment. A separate chapter on symptom validity assessment has been engrafted. PMID- 29523015 TI - [Weighting of Orthopaedics & Trauma Surgery in the Medical State Examination - Comparison of the Written Examination with the National Catalogue of Learning Objectives in Surgery]. AB - BACKGROUND: The national competence-based catalogue of learning-goals in surgery (NKLC) defines competence levels for each of its 230 goals, including "competence level in 1: factual knowledge" up to "competence level 3: independent action". Aside from the cumulative examinations influencing the learning behaviour of students, those teaching targets do not affect the second state examination. This study analyses the extent to which the questions of the German second medical licensing examination compiled by the IMPP (central German institute for medical and pharmaceutical examinations) are congruent with the trauma-surgical and orthopaedic learning goals in the NKLC, in which this thematic focus is emphasised. MATERIAL AND METHODS: Exam questions from autumn 2009 to autumn 2014 (n = 11) were retrospectively analysed. Orthopaedic and trauma-surgical teaching targets defined in NKLC were identified by five senior orthopaedic physicians and trauma surgery experts. All questions addressing one of these learning goals were identified and analysed (re: the number of learning goals, the number of questions addressing a trauma-surgical, or orthopaedic goal, as well as different competency levels). RESULTS: We found 113 learning goals of NKLC (49.1% of the overall NKLC learning goals) identified as orthopaedic or trauma surgery subjects. During the study period, 543 questions included teaching targets referring to orthopaedic or trauma surgery subjects (15.6% of the total of 3480 questions). Per exam, a mean of 49.36 +/- 14.1 questions (minimum 30; maximum 80) was identified that addressed a learning goal referring to these issues. For each exam, 13.45 +/- 6.39 (minimum 6; maximum 24) questions referred to learning goals of competence level 3a and b, 21.45 +/- 9.94 (minimum 9; maximum 39) questions referred to learning goals of competence level 2, and 14.45 +/- 6.36 (minimum 6; maximum 25) questions referred to learning goals of competence level 1. Most questions addressed the topic: "disorders of the rheumatic spectrum" (n = 16 questions in autumn 2009). CONCLUSION: Questions focusing on orthopaedic and trauma surgery appeared sufficiently often during the second state examination. There is a thematic imbalance, and important clinical learning goals tagged with high competence levels were not addressed in a satisfactory manner. This indicates that a clear adjustment between the state examination and NKLC is necessary. PMID- 29523016 TI - [Debridement in Focal Cartilage Damage of the knee. Systematical review of the literature and recommendations of the working group "clinical tissue regeneration" of the German Society of Orthopaedics and Trauma (DGOU)]. AB - BACKGROUND: In clinical practice, there is still no definite treatment algorithm for focal, partial thickness cartilage lesions (grade II - III). It is well established that debridement (shaving/lavage) of large degenerative cartilage lesions is not recommended, but there is no such recommendation in the case of focal, partial thickness cartilage defects. MATERIALS AND METHODS: The scientific rationale of cartilage shaving and joint lavage was investigated and a systematic analysis was performed of the literature on the clinical effect of cartilage debridement. Furthermore, a consensus statement on this issue was developed by the working group on Clinical Tissue Regeneration of the German Society of Orthopaedics and Trauma (DGOU). RESULTS: The therapeutic approach is different for asymptomatic lesions with biomechanical stable residual cartilage tissue and clinically symptomatic defects with unstable fragments. The benefit of a joint lavage or surface smoothening of focal partial thickness has not been proved. Even more importantly, the mechanical or thermal resection of cartilage tissue even induces a zone of necrosis in adjacent cartilage, and thus leads to additional injury. Therefore, large scale smoothening (shaving) of clinically asymptomatic, fibrillated or irregular cartilage defects should not be performed. However, if there are clinical symptoms, resection of unstable and delaminated cartilage fragments may be reasonable, as it can reduce harmful shear tension in residual tissue. This can help to brake the progression of the damage and avoid formation of free bodies. CONCLUSION: The decision criteria for debridement of partial thickness focal cartilage lesions are multifactorial and include the clinical symptoms, the size and the degree of the defect, the stability of remaining cartilage, localisation of the defect, and individual patient-specific parameters. Debridement is not recommended for asymptomatic lesions, but may be reasonable for symptomatic cases with unstable tissue. PMID- 29523017 TI - [Guideline for the Diagnosis and Treatment of COPD Patients - Issued by the German Respiratory Society and the German Atemwegsliga in Cooperation with the Austrian Society of Pneumology]. AB - This document is a revision of the guideline for diagnosis and treatment of COPD that replaces the version from 2007. A multitude of recent reports regarding risk factors, diagnosis, assessment, prevention and pharmacological as well as non pharmacological treatment options made a major revision mandatory. The new guideline is based on the GOLD document taking into account specifics in Germany and Austria. PMID- 29523018 TI - Aromatherapy for treatment of postoperative nausea and vomiting. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is a common, unpleasant phenomenon and current therapies are not always effective for all patients. Aromatherapy has been suggested as an addition to the available treatment strategies. This review was originally published in 2012 and updated in 2017. OBJECTIVES: The main objective was to establish the efficacy and safety of aromatherapy comparable to standard pharmacological treatments for PONV in adults and children. SEARCH METHODS: We searched CENTRAL; MEDLINE; Embase; CINAHL; CAM on PubMed; Informit; LILACS; and ISI Web of Science as well as grey literature sources and the reference lists of retrieved articles up to March 2017. The original search was performed in August 2011. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) where aromatherapy was used to treat PONV. Interventions were all types of aromatherapy compared to placebo or with standard antiemetics. Primary outcomes were severity and duration of PONV. Secondary outcomes were adverse reactions, use of rescue antiemetics and patient satisfaction. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias in the included studies and extracted data. For dichotomous outcome variables, we used a random-effects model and calculated risk ratio (RR) with associated 95% confidence interval (95% CI). For continuous outcome variables, we used a random-effects model and calculated standardized mean difference (SMD) with associated 95% CI. We used the GRADE software to compile 'Summary of findings' tables. MAIN RESULTS: We included seven new studies with 663 participants in the 2017 update; five RCTs and two CCTs. These were added to the nine previously included studies (six RCTs and three CCTs with a total of 373 participants) for a total of 16 included studies and 1036 participants in this updated review. The mean age and range data for all participants were not reported for all studies. We identified two registered trials that met the inclusion criteria for this review; however there are no results for these studies yet.Overall, the GRADE assessment of evidence quality ranged from moderate to very low. The method of randomization in 11 of the 12 included RCTs was explicitly stated and adequate. Incomplete or methodologically diverse reporting of data affected the completeness of the analysis. Data on additional aromatherapies were added in the 2017 update (blended aromatherapy products, and peppermint products). Heterogeneity of outcome measures and time points between studies affected the completeness of the analysis.In the summary of the findings of six studies, we did not find aromatherapy to be effective in reducing nausea severity in comparison to placebo (SMD -0.22, 95% CI -0.63 to 0.18, P value = 0.28, 241 participants, level of evidence: low). Those participants receiving aromatherapy were no more likely to be free of nausea at the end of the treatment period than those receiving placebo (RR 3.25, 95% CI 0.31 to 34.33, P value = 0.33, 4 trials, 193 participants, evidence level: very low), however they were less likely to require rescue antiemetics (RR 0.60, 95% CI 0.37 to 0.97, P value = 0.04, 7 trials, 609 participants, evidence level: low). There were no data reported on adverse events or patient satisfaction for this comparison.A specific comparison of peppermint aromatherapy to placebo did not show evidence of an effect on nausea severity at five minutes post-treatment in the pooled results (SMD -0.18, 95% CI -0.86 to 0.49, P value = 0.59, 4 trials, 115 participants, evidence level: low). There were no data reported on nausea duration, use of rescue antiemetics, adverse events or patient satisfaction for this comparison.When we pooled studies comparing isopropyl alcohol to standard antiemetic treatment in a GRADE summary of findings, in terms of nausea duration, there was a significant effect on the time in minutes to a 50% reduction in nausea scores (SMD -1.10, 95% CI -1.43 to -0.78, P value < 0.00001, 3 trials, 176 participants, evidence level: moderate). Fewer participants who received isopropyl alcohol required rescue antiemetics (RR 0.67, 95% CI 0.46 to 0.98, P value = 0.04, 215 participants, 4 trials, evidence level: moderate). Two studies with 172 participants measured patient satisfaction; there were high levels of satisfaction across both aromatherapy and standard treatment groups and no differences found (evidence level: low). There were no data reported on nausea severity or adverse events for this comparison.There was no difference in effectiveness between isopropyl alcohol vapour inhalation and placebo for reducing the proportion of participants requiring rescue antiemetics (RR 0.39, 95% CI 0.12 to 1.24, P value = 0.11, 291 participants, 4 trials, evidence level: very low). There were no data reported on nausea severity, nausea duration, adverse events or patient satisfaction for this comparison. AUTHORS' CONCLUSIONS: Overall, for nausea severity at the end of treatment, aromatherapy may have similar effectiveness to placebo and similar numbers of participants were nausea free. However, this finding is based on low-quality evidence and therefore very uncertain. Low-quality evidence also suggests that participants who received aromatherapy may need fewer antiemetic medications, but again, this is uncertain. Participants receiving either aromatherapy or antiemetic medications may report similar levels of satisfaction with their treatment, according to low-quality evidence. PMID- 29523019 TI - Application of Sparse Linear Discriminant Analysis and Elastic Net for Diagnosis of IgA Nephropathy: Statistical and Biological Viewpoints AB - Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis diagnosed based on renal biopsy. Mesangial IgA deposits along with the proliferation of mesangial cells are the histologic hallmark of IgAN. Non invasive diagnostic tools may help to prompt diagnosis and therapy. The discovery of potential and reliable urinary biomarkers for diagnosis of IgAN depends on applying robust and suitable models. Applying two multivariate modeling methods on a urine proteomic dataset were obtained from IgAN patients, and comparison of the results of these methods were the purpose of this study. Methods: Two models were constructed for urinary protein profiles of 13 patients and 8 healthy individuals, based on sparse linear discriminant analysis (SLDA) and elastic net (EN) regression methods. A panel of selected biomarkers with the best coefficients were proposed and further analyzed for biological relevance using functional annotation and pathway analysis. Results: Transferrin, alpha1 antitrypsin, and albumin fragments were the most important up-regulated biomarkers, while fibulin-5, YIP1 family member 3, prasoposin, and osteopontin were the most important down-regulated biomarkers. Pathway analysis revealed that complement and coagulation cascades and extracellular matrix-receptor interaction pathways impaired in the pathogenesis of IgAN. Conclusion: SLDA and EN had an equal importance for diagnosis of IgAN and were useful methods for exploring and processing proteomic data. In addition, the suggested biomarkers are reliable candidates for further validation to non-invasive diagnose of IgAN based on urine examination. PMID- 29523020 TI - Psychometric Properties of the Physical Educators' Self-Efficacy Toward Including Students With Disabilities-Autism Among Chinese Preservice Physical Education Teachers. AB - Teachers' self-efficacy is a critical predictor for successful inclusive physical education. However, little is known about preservice physical educators' self efficacy toward teaching students with autism spectrum disorders in China. A sound instrument is necessary to measure their self-efficacy level. This validation study examined the psychometric properties of the Chinese version of the Physical Educators' Self-Efficacy Toward Including Students with Disabilities Autism. A multisection survey form was administered to preservice physical educators in Mainland China (n = 205) and Hong Kong (n = 227). The results of confirmatory factor analysis confirmed the one-factor model of the scale in the total sample and each of the two samples. Invariance tests across the two samples supported configural and metric invariance but not scalar invariance. The scale scores showed good internal reliability and were correlated with theoretically relevant constructs (i.e., burnout and life satisfaction) in the total sample and subsamples. These findings generally support the utility of the scale for use among Chinese preservice physical educators. PMID- 29523022 TI - Effectiveness of external cues to facilitate task performance in people with neurological disorders: a systematic review and meta-analysis. AB - PURPOSE: To examine in people with neurological disorders, which method/s of providing external cues to improve task performance are most effective. METHODS: Medline, EMBASE, and PsycINFO were systematically searched. Two reviewers independently screened, extracted data, and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Twenty six studies were included. Studies examined a wide-range of cues including visual, tactile, auditory, verbal, and multi-component cues. Cueing (any type) improved walking speed when comparing cues to no cues (mean difference (95% confidence interval): 0.08 m/s (0.06-0.10), I2 = 68%, low quality of evidence). Remaining evidence was analysed narratively; evidence that cueing improves activity-related outcomes was inconsistent and rated as very low quality. It was not possible to determine which form of cueing may be more effective than others. CONCLUSION: Providing cues to encourage successful task performance is a core component of rehabilitation, however there is limited evidence on the type of cueing or which tasks benefit most from external cueing. Low-quality evidence suggests there may be a beneficial effect of cueing (any type) on walking speed. Sufficiently powered randomised controlled trials are needed to inform therapists of the most effective cueing strategies to improve activity performance in populations with a neurological disorder. Implications for rehabilitation Providing cues is a core component of rehabilitation and may improve successful task performance and activities in people with neurological conditions including stroke, Parkinson's disease, Alzheimer's disease, traumatic brain injury, and multiple sclerosis, but evidence is limited for most neurological conditions with much research focusing on stroke and Parkinson's disease. Therapists should consider using a range of different types of cues depending on the aims of treatment and the neurological condition. There is currently insufficient evidence to suggest one form of cueing is superior to other forms. Therapists should appreciate that responding optimally to cues may take many sessions to have an effect on activities such as walking. Further studies should be conducted over a longer timeframe to examine the effects of different types of cues towards task performance and activities in people with neurological conditions. PMID- 29523021 TI - Psychometric Properties of the Test of Gross Motor Development-3 for Children With Visual Impairments. AB - Results of the Test of Gross Motor Development-2 (TGMD-2) consistently show acceptable validity and reliability for children/adolescents who are sighted and those who have visual impairments. Results of the Test of Gross Motor Development 3 (TGMD-3) are often valid and reliable for children who are sighted, but its psychometric properties are unknown for children with visual impairments. Participants (N = 66; Mage = 12.93, SD = 2.40) with visual impairments completed the TGMD-2 and TGMD-3. The TGMD-3 results from this sample revealed high internal consistency (omega = .89-.95), strong interrater reliability (ICC = .91-.92), convergence with the TGMD-2 (r = .96), and good model fit, chi2(63) = 80.10, p = .072, chi2/df ratio = 1.27, RMSEA = .06, CFI = .97. Researchers and practitioners can use the TGMD-3 to assess the motor skill performance for children/adolescents with visual impairments and most likely produce results that are valid and reliable. PMID- 29523023 TI - Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with a multifactorial pathophysiology. Full comprehension of IBD pathology is still out of reach and, therefore, treatment is far from ideal. Nevertheless, components involved in IBD pathogenesis including environmental, genetic, microbial, and immunological factors are continuously being investigated and the improved knowledge contributes to the development of new therapies. In this article we review the aspects of the immunopathogenesis of IBD, with focus on mucosal immunity, and discuss mechanisms of action for current and emerging biological therapies. PMID- 29523024 TI - A developed antibody-drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line. AB - Rituximab is a chimeric monoclonal antibody directed against B-lymphocyte specific antigen CD20, which is used for the treatment of B-cell malignancies. However, the effectiveness of rituximab is limited partly due to treatment resistance. The aim of this study was to develop rituximab-based antibody drug conjugate (ADC) to enhance rituximab activity. In this study, monomethyl auristatin E (MMAE) was covalently conjugated to dithiothreitol -reduced rituximab via a valine-citrulline peptide linker (rituximab-vcMMAE). The conjugates were then characterized by using nonreducing sodium dodecyl sulfate polyacrylamide electrophoresis (SDS-PAGE) and cell-based enzyme-linked immunosorbent assay (ELISA). The cytotoxic activity of the ADC was evaluated against Raji (human B-cell lymphoma; CD20-positive) and MOLT-4 (T lymphoblast; acute lymphoblastic leukemia; CD20-negative) cell lines. In addition, the colony formation assay was used to identify the propagation ability of ADC-treated cells in vitro. Results from nonreducing SDS-PAGE revealed various species of rituximab MC-Val-Cit-PABC-MMAE (rituximab-vcMMAE), as compared with unconjugated rituximab. The binding capacity of rituximab-vcMMAE to the CD20-positive cell was similar to that of the parental rituximab. Most importantly, our results revealed that rituximab-vcMMAE was highly potent against the CD20-positive cell line, but not against the CD20-negative cell. At the same time, rituximab-vcMMAE was able to inhibit colony formation in CD20-positive cells. These data indicate that rituximab-vcMMAE may be a highly effective and selective therapy for the treatment of B-cell lymphoma. PMID- 29523025 TI - Twin pregnancy with chromosomal abnormalities mimicking a gestational trophoblastic disorder and coexistent foetus on ultrasound. PMID- 29523026 TI - Outcome after stenting and debridement for spontaneous esophageal rupture. AB - OBJECTIVES: Surgical repair has been the most common treatment of esophageal effort rupture (Boerhaave syndrome). Stent-induced sealing of the perforation has increasingly been used with promising results. We present our eight years' experience with stent-based and organ-preserving treatment. MATERIALS AND METHODS: Medical records of 15 consecutive patients with Boerhaave syndrome from February 2007 to May 2015 were retrospectively registered in a database. Treatment was sealing of the perforation by stenting, chest tube drainage and debridement of the contaminated thorax. After median 25 months nine out of 10 patients responded to questions on fatigue and Ogilvie's dysphagia score. RESULTS: Fifteen patients, aged median 67.5 years (range 39-88), had a primary hospital stay of 20 days (range 1-80 days). Overall in-hospital mortality was 13%. Observation time was 44 months (range 0-87) and 10 patients were alive of August 2017. Ten patients (67%) needed surgical chest debridement. Five patients (33%) were restented for leakage, migration and for stent removal. Eleven patients (73%) had complications, which included pleural empyema (n = 4), fatal aortic bleeding, lung arterial bleeding, lung embolism, drain-induced lung laceration and respiratory failure. Dysphagia score was low (median 0.5) meaning that they were able to feed themselves. Total fatigue score (mean 14.6) was slightly increased (p = .05) compared with a reference population. CONCLUSIONS: The mortality rate after initial stenting of effort rupture seems to be comparable to standard surgical repair. Most patients required further intervention, either by restenting and/or surgical debridement. The functional result in these patients was satisfactory. PMID- 29523027 TI - Vesicovaginal fistula in Uganda. AB - Kitovu Hospital in Masaka, Uganda, is a leading obstetric fistula repair centre in the country with the highest rates of fistula in the world. In this retrospective case review, the regional incidence and causative factors were studied in patients with vesicovaginal fistula (VVF) who were admitted at Kitovu Hospital. Fistula history included severity (ICIQ score), causes and outcomes of VVF were measured. Women suffered with symptoms of VVF for an average of 4.97 years with an average ICIQ severity score of 7.21. Patients travelled an average distance of 153 km and the majority travelled by public transport. Rates of prolonged labour were high. 69% of fistula-causing delivery resulted in stillbirth and 12% resulted in early neonatal death. Following surgery, 94% of patients were dry on discharge. Impact statement What is already known on this subject? Vesicovaginal fistula (VVF) is a severe, life-changing injury. Although largely eradicated from the Western world thanks to modern obstetric practice, VVF is still highly prevalent in developing countries where factors such as young childbearing age and poor access to emergency obstetric care increase the incidence (Wall et al. 2005 ). At the current rate of fistula repair, it is estimated that it would take 400 years to treat those already suffering with fistula, providing that no new cases emerged (Browning and Patel 2004 ). What do the results of this study add? The Ugandan women in this study reiterate tales of foetal loss, social isolation and epic journeys in search of fistula repair, as previously described in the literature. The study offers some hope for prompt help-seeking during labour and after fistulas are developed. It demonstrates the success of fistula repairs at Kitovu Hospital but highlights the paucity of service provision across Uganda. What are the implications of these findings for clinical practice and/or further research? Further epidemiological research is required to quantify the true burden of the disease. Only by raising the profile of VVF in both developing and developed countries, can there be a collaborative effort to make universal change. To embark upon the prevention and cure of the disease it is necessary to continue tackling issues of poverty and gender inequality. PMID- 29523028 TI - A novel therapeutics agent: antioxidant effects of hydroxylfasudil on rat kidney and liver tissues in a protamine sulphate-induced cystitis rat model; preliminary results. AB - Cystitis is defined as an inflammation of the bladder caused by a bacterial infection, and it can be dangerous and painful when it spreads through the internal organs. In this study, antioxidant effects of hydroxylfasudil (HF) at the enzymatic and molecular level on kidney and liver tissues in cystitis rat model, which is caused by inflammation of the rat bladder with a protamine sulphate (PS), was examined. Quantitative changes of reduced glutathione (GSH) and lipid peroxidation (LPO) levels, which are a marker for oxidative stress, were determined in rat kidney and liver tissues for each groups. And then molecular and biochemical impact of HF treatment on antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT) in cystitis model were studied. The results suggest that HF could be beneficial to the renal and hepatic antioxidant system. Thus, HF might be used as a novel therapeutics agent to eliminate interstitial cystitis. PMID- 29523029 TI - Head injury and the internet: are resources reliable and readable? PMID- 29523030 TI - Condom use and self-efficacy among female sex workers with steady partners in China. PMID- 29523033 TI - Germline mosaicism in a DMD family: incidental identification in prenatal diagnosis. PMID- 29523034 TI - Ten-year follow-up on adoption of endodontic technology and clinical guidelines amongst Danish general dental practitioners. AB - OBJECTIVE: The aim of this study was to re-assess the adoption of certain endodontic technology and central treatment principles of root canal treatments as advocated by guidelines presented by the European Society of Endodontology. MATERIAL AND METHODS: The questionnaire included the same questions in 2003 and 2013. The general dental practitioners (GDPs) anonymously reported how frequent ('often', 'occasionally', and 'never') they used certain endodontic technology and adhered to central treatment principles. The statistical analyses were performed using Chi-squared test and Goodman-Kruskal's gamma-coefficient as an association measure. RESULTS: The overall response rate of the 2013 group was 46.5% (n = 531). The frequencies of GDPs reporting often use of rubber dam, apex locator and rotary NiTi instruments were significantly higher (p < .0001) than in 2003, as well as reporting the use of composite resin for coronal sealing (p < .019). Adoption was significantly influenced by the factors gender (p = .601) and time since graduation (p = .361), and the cluster analyses revealed the neglected use of rubber dam to be associated with no established postoperative recall system. CONCLUSIONS: After 10 years, there was a higher frequency of GDPs who had adopted certain endodontic technologies. However, progress towards high-quality root canal treatment might be obstructed as the majority of GDPs avoids consistent use of rubber dam, and routinely neglects recalls for postoperative controls of their endodontic treatments. PMID- 29523036 TI - Immature ovarian teratoma with gliomatosis peritonei with adenocarcinomatous differentiation in one of the lymph node's metastasis. PMID- 29523035 TI - Intrapartum synthetic oxytocin and breastfeeding: a retrospective cohort study. AB - Non-pulsatile oxytocin given during labour can negatively affect breastfeeding. The aim of this study was to assess whether intrapartum oxytocin administration has any effect on breastfeeding. Secondly, to assess whether some maternal or neonatal variables influence breastfeeding. A retrospective cohort study was done, comparing two groups: women exposed (n = 101) and not exposed to oxytocin (n = 100) during labour. Women with caesarean section, vacuum extraction/forceps, twin pregnancy, breech presentation, premature neonates and with an Apgar score <7 at 5 minutes were excluded. Duration of breastfeeding was evaluated by a phone call interview. A regression analysis was done, evaluating possible confounding factors. The use of oxytocin during labour was demonstrated to be a predictor of impaired first hour breastfeeding (OR =2.493, CI: 1.05-5.92; p = .038). At three months' postpartum, 26.7% women in the exposed group versus 14% in the non exposed group were not breastfeeding (p = .035). This result was not statistically significant when adjusting for possible confounders. High pregestational body mass index was the best predictor of an impaired third month's postpartum breastfeeding (OR =0.901, CI: 0.835-0.972; p = .007). Intrapartum oxytocin administration could inhibit first hour breastfeeding. A novel association was detected, pregestational body mass index was a predictor of impaired breastfeeding at three months, possibly confounding the oxytocin effect. Additional prospective studies are needed to investigate potential associations between intrapartum oxytocin and breastfeeding. Impact statement What is already known on this subject? Oxytocin is a common medical intervention during labour. Some studies suggest a negative association between intrapartum oxytocin dose, newborn sucking and an increased risk of early breastfeeding discontinuation. However, some maternal variables were not considered in these studies and the impact synthetic oxytocin may have on breastfeeding has not been thoroughly researched. What do the results of this study add? In this study, intrapartum oxytocin administration seems to inhibit the first hour breastfeeding. However, a novel association was detected, high pregestational body mass index was a predictor of impaired breastfeeding at three months, possibly confounding oxytocin effects. What are the implications of these findings for clinical practice and/or further research? Additional prospective studies are needed to investigate potential associations between intrapartum oxytocin and breastfeeding. Therefore, health care professionals should help obese women, starting from conception, to maximise breastfeeding outcomes as much as possible. PMID- 29523037 TI - Is Hba1c level of diabetic patients associated with penile prosthesis implantation infections? AB - BACKGROUND AND OBJECTIVES: Diabetes mellitus is an important risk factor for erectile dysfunction (ED). Penile prosthesis implantation surgery is the final solution for diabetic patients with ED, but infections thereof are still a serious risk factor. While some studies suggest that most infections associated with penile prosthesis implantation are associated to high glycated hemoglobin (HbA1c) levels, other research did support such relationship. MATERIALS AND METHODS: The current study assessed retrospectively, the association between HbA1c level and penile prosthesis surgery infection. We retrieved and reviewed the records of 300 diabetic patients who had penile prosthesis surgery at our Institution (January 2012-November 2016). Patients' mean age was 55.26 +/- 10.9 years (31% patients were <50 years of age), and mean HbA1c was 7.60 +/- 1.90%. RESULTS: Infection rate among diabetics was 0.67%. Prevalence of prosthesis infection among patients with HbA1c <= 9% was 0.9%, compared with 0% among patients with HbA1c > 9%. Prosthesis infection risk did not significantly increase with higher HbA1c levels, with no meaningful difference in the median or mean level of HbA1c in the infected and non-infected diabetic patients. CONCLUSION: Findings do not support the use of HbA1c values among diabetic patients who are candidates for penile prosthesis implantation surgery in order to identify and exclude those who might be prone to increased risk of prosthesis infections. Future studies would benefit from larger sample sizes in order to support or refute our findings. PMID- 29523038 TI - Bowel on the bowl: a case report of spontaneous post-partum vaginal evisceration of small bowel. PMID- 29523040 TI - Atrial impairment in transthyretin cardiac amyloidosis: an early marker of cardiac involvement and a prognostic factor. PMID- 29523041 TI - Cardiometabolic risk factors, physical activity and psychiatric status in patients in long-term psychiatric inpatient departments. AB - PURPOSE: Cardiovascular diseases are a major cause for the markedly reduced life expectancy in people with severe mental illness (SMI). Hospital departments should provide adequate prevention of cardiometabolic risk by optimizing prevention and treatment. Characteristics of cardiometabolic risk factors in inpatients are still not well known. We aimed to describe the status of cardiometabolic risk factors in inpatients with SMI and identify associations with psychiatric status and treatment. METHODS: A cross sectional descriptive study of inpatients with SMI from long term psychosis treatment wards in South Eastern Norway was performed. Comprehensive assessments of cardiometabolic risk factors, physical activity, lifestyle habits, symptoms, life satisfaction and treatment were made. Associations and potential prognostic factors were analyzed using linear and logistic regressions. RESULTS: A total of 83 patients were included in the study, but many individual datasets were incomplete. Over half of the subjects had unhealthy eating habits. Obesity (class 1-3) was found in 44%, 23% had elevated fasting triglycerides, 26% had elevated blood pressure and 78% smoked daily. Low levels of physical activity were significantly associated with higher levels of depression (p = .007). A nominal increase in cardiometabolic risk factors was found for olanzapine and clozapine users. CONCLUSION: Inpatients in long term psychosis treatment wards have alarmingly high cardiometabolic risk. Level of physical activity was associated with both psychiatric and somatic health. Focus on lifestyle and somatic health should be an integral part of the treatment for hospitalized SMI patients. PMID- 29523042 TI - The retroneural approach: an alternative technique for lumbar transforaminal epidural steroid injections. AB - BACKGROUND: Compared with other available injection techniques for lumbar transforaminal epidural steroid injections (LTFESIs), the traditionally performed subpedicular approach is associated with a higher risk of spinal cord infarction, a rare but catastrophic complication. PURPOSE: To assess the short-term efficacy of the retroneural approach for computed tomography (CT)-guided LTFESIs with respect to different needle-tip positions. MATERIAL AND METHODS: This retrospective analysis included 238 patients receiving 286 CT-guided LTFESIs from January 2013 to January 2016. Short-term outcomes in terms of pain relief were assessed using the visual analogue scale (VAS) at baseline and 30 min after. The needle-tip location was categorized as extraforaminal, junctional, or foraminal relative to the neural foramen. Additionally, the distance from the needle tip to the nerve root was measured. RESULTS: A mean pain reduction of 3.22 points (+/ 2.17 points) on the VAS was achieved. The needle-tip location was extraforaminal in 48% (136/286), junctional in 42% (120/286), and foraminal in 10% (28/286) of the cases. The mean distance from the needle tip to the nerve root was 3.83 mm (+/-3.37 mm). There was no significant correlation between pain relief and needle tip position in relation to the neural foramen. Therapy success was not dependent on the distance between the needle tip and the nerve root. No major complications were observed. CONCLUSION: In our population treated with LTFESIs, the retroneural approach was shown to be an effective technique, with no significant differences in pain relief following different needle-tip positions. PMID- 29523043 TI - Light axis adjustment with a sterilised photostimulation device for visually evoked potential monitoring. AB - Intraoperative monitoring of visually evoked potentials (VEPs) is sometimes unachievable because of light axis misalignments caused by frontal scalp-flap reflection and intraoperative manipulation. Here, we present a new method of intraoperative VEP monitoring that involves a sterilised photostimulation device that can be adjusted in position following disturbances from frontal scalp-flap reflection or intraoperative manipulation. PMID- 29523044 TI - A murine model of radiation-induced capsule-tissue reactions around smooth silicone implants. AB - As the availability of breast reconstruction using implants is becoming widespread and many implant recipients undergo radiation therapy, there is an increasing interest in understanding the potential complications associated with capsule-tissue interactions in response to irradiation. Accordingly, our medical institution designed an animal experiment to investigate the effects of irradiation on capsular contracture. A total of 40 mice (C57BL6) were divided into four groups according to whether or not they received irradiation and the time from implantation to irradiation. After each mouse received a specially fabricated, 1.5 cm semi-spherical silicone implant inserted into the area below the panniculus carnosus, half of the mice were irradiated using singe administration of a 10 Gy dose of radiation (6 MeV). Subsequently, data from gross inspection, histological analysis and immunohistochemical analysis were obtained at one and three months postoperatively and analyzed. Changes that occurred near the capsule led to the phenomenon of contracture subsequent to encapsulation. Our findings suggest that the inflammation reaction occurring near the implant becomes aggravated by 'radiation toxicity' and creates an environment conducive to capsular contracture. The present study demonstrated the process by which the complication of capsular contracture may occur during the treatment of human breast cancer via radiotherapy. These findings may serve as the basis for research and development of future treatments of capsular contracture. PMID- 29523045 TI - Correction to: Firquet et al., Forty to fifty-five year-old women and iron deficiency: clinical considerations and quality of life. PMID- 29523046 TI - Serum procalcitonin levels together with clinical features and inflammatory markers in women with tubo-ovarian abscess for discriminating requirements for surgery for full recovery. AB - Tubo-ovarian abscess (TOA) coexists in 15% of cases with pelvic inflammatory disease. Medical treatment is the first line of approach in women with TOA, however, 25% of cases fail to respond to antibiotics, therefore, these cases need to undergo surgical intervention. We aimed to determine factors leading to failure of medical treatment in women diagnosed with TOA. According to our results among 144 women, 27 cases required surgical intervention for full recovery. None of the demographic, sonographic or laboratory findings, including procalcitonin level, had significant predictive value for the failure of medical treatment in women with TOA. Impact statement What is already known on this subject? Tubo-ovarian abscess (TOA) coexists in 15% of cases with pelvic inflammatory disease. Medical treatment is the first line approach in women with TOA, however, 25% of cases fail to respond to antibiotics, therefore, these cases need to undergo surgical intervention. Several risk factors have been evaluated in order to predict the failure of medical treatment. What do the results of this study add? None of the variables, including age, parity, mass diameter, serum CRP, procalcitonin levels and sedimentation rate had significant value for predicting TOA cases that required surgical intervention for full recovery. What are the implications of these findings for clinical practice and/or further research? In clinical practice, identification of risk factors leading to the failure of medical treatment helps clinicians to inform patients and help surgeons predict those who need surgical intervention. PMID- 29523047 TI - Introducing consumer directed care in residential care settings for older people in Australia: views of a citizens' jury. AB - Objectives Health services worldwide are increasingly adopting consumer directed care approaches. Traditionally, consumer directed care models have been implemented in home care services and there is little guidance as to how to implement them in residential care. This study used a citizens' jury to elicit views of members of the public regarding consumer directed care in residential care. Methods A citizens' jury involving 12 members of the public was held over two days in July 2016, exploring the question: For people with dementia living in residential care facilities, how do we enable increased personal decision making to ensure that care is based on their needs and preferences? Jury members were recruited through a market research company and selected to be broadly representative of the general public. Results The jury believed that person centred care should be the foundation of care for all older people. They recommended that each person's funding be split between core services (to ensure basic health, nutrition and hygiene needs are met) and discretionary services. Systems needed to be put into place to enable the transition to consumer directed care including care coordinators to assist in eliciting resident preferences, supports for proxy decision makers, and accreditation processes and risk management strategies to ensure that residents with significant cognitive impairment are not taken advantage of by goods and service providers. Transparency should be increased (perhaps using technologies) so that both the resident and nominated family members can be sure that the person is receiving what they have paid for. Conclusions The views of the jury (as representatives of the public) were that people in residential care should have more say regarding the way in which their care is provided and that a model of consumer directed care should be introduced. Policy makers should consider implementation of consumer directed care models that are economically viable and are associated with high levels of satisfaction among users. PMID- 29523048 TI - Changes in extracellular matrix in subcutaneous small resistance arteries of patients with essential hypertension. AB - BACKGROUND: In the development of hypertensive microvascular remodeling, a relevant role may be played by changes in extracellular matrix proteins. Aim of this study was the to evaluate some extracellular matrix components within the tunica media of subcutaneous small arteries in 9 normotensive subjects and 12 essential hypertensive patients, submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region. PATIENTS AND METHODS: Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media to internal lumen ratio was measured. In addition, fibronectin, laminin, transforming growth factor-beta-1 (TGF-beta1) and emilin-1 contents within the tunica media were evaluated by immunofluorescence and relative immunomorphometrical analysis (immunopositivity % of area). The total collagen content and collagen subtypes within the tunica media were evaluated using both Sirius red staining (under polarized light) and immunofluorescence assay. RESULTS: Normotensive controls had less total and type III collagen in respect with hypertensive patients. Fibronectin and TGF-beta1 tunica media content was significantly greater in essential hypertensive patients, compared with normotensive controls, while laminin and emilin-1 tunica media content was lesser in essential hypertensive patients, compared with normotensive controls. A significant correlation was observed between fibronectin tunica media content and media to lumen ratio. CONCLUSIONS: Our results indicate that, in small resistance arteries of patients with essential hypertension, a relevant fibrosis may be detected; fibronectin and TGF-beta1 tunica media content is increased, while laminin and emilin-1 content is decreased; these changes might be involved in the development of small resistance artery remodeling in humans. PMID- 29523049 TI - Adaptation and Retention of a Perceptual-Motor Task in Children: Effects of a Single Bout of Intense Endurance Exercise. AB - We assessed the effect of an acute intense exercise bout on the adaptation and consolidation of a visuomotor adaptation task in children. We also sought to assess if exercise and learning task presentation order could affect task consolidation. Thirty-three children were randomly assigned to one of three groups: (a) exercise before the learning task, (b) exercise after the learning task, and (c) only learning task. Baseline performance was assessed by practicing the learning task in a 0 degrees rotation condition. Afterward, a 60 degrees rotation-adaptation set was applied followed by three rotated retention sets after 1 hr, 24 hr, and 7 days. For the exercise groups, exercise was presented before or after the motor adaptation. Results showed no group differences during the motor adaptation while exercise seemed to enhance motor consolidation. Greater consolidation enhancement was found in participants who exercised before the learning task. Our data support the importance of exercise to improve motor memory consolidation in children. PMID- 29523050 TI - Negative Effects of Makeup Use on Perceptions of Leadership Ability Across Two Ethnicities. AB - Cosmetics alter social perceptions, and prior work suggests that cosmetic use may aid female intrasexual competition, making women appear more dominant to other women but more prestigious to other men. It is unclear whether these findings reflect general improvements in perceptions of traits related to women's dominance or if they are specific to mating contexts only. Here, across two ethnicities, we examined effects of cosmetics used for a social night out on perceptions of women's leadership ability, a trait that denotes competence/high status outside of mating contexts. Participants of African and Caucasian ethnicity judged faces for leadership ability where half of the trials differed in ethnicity (own- vs. other-ethnicity face pairs) and the subtlety of the color manipulation (50% vs. 100%). Regardless of the participant's sex or ethnicity, makeup used for a social night out had a negative effect on perceptions of women's leadership ability. Our findings suggest that, in prior work, women are afforded traits related to dominance, as makeup enhances perceptions of traits that are important for successful female mating competition but not other components of social dominance such as leadership. PMID- 29523051 TI - Verapamil as a culprit of palbociclib toxicity. AB - A promising drug, palbociclib, received accelerated approval as a first line treatment when used with the aromatase inhibitor, letrozole, for postmenopausal women with hormone receptor positive advanced or metastatic breast cancer. We report a case of a patient who presented with febrile neutropenia, grade 3 stomatitis with lip swelling, periorbital edema, and transaminitis while on palbociclib and verapamil. Labs normalized upon discontinuation of verapamil and our patient was able to continue treatment with palbociclib and letrozole. Verapamil's inhibition of both permeability-glycoprotein (P-gp) and CYP3A4 is suspected to have led to the adverse side effects seen in our patient. PMID- 29523052 TI - Influence of Music Style and Rate on Repetitive Finger Tapping. AB - Auditory cues, including music, are commonly used in the treatment of persons with Parkinson's disease. Yet, how music style and movement rate modulate movement performance in persons with Parkinson's disease have been neglected and remain limited in healthy young populations. The purpose of this study was to determine how music style and movement rate influence movement performance in healthy young adults. Healthy participants were asked to perform repetitive finger movements at two pacing rates (70 and 140 beats per minute) for the following conditions: (a) a tone only, (b) activating music, and (c) relaxing music. Electromyography, movement kinematics, and variability were collected. Results revealed that the provision of music, regardless of style, reduced amplitude variability at both pacing rates. Intermovement interval was longer, and acceleration variability was reduced during both music conditions at the lower pacing rate only. These results may prove beneficial for designing therapeutic interventions for persons with Parkinson's disease. PMID- 29523053 TI - The Evaluation of Changes of Angles in Selected Joints During Topspin Forehand in Table Tennis. AB - The aims of this study were to evaluate movement patterns of topspin forehand, to define the main principles of performing this shot, and to determine the essential differences in individual types of topspin forehand. In total, 10 female high-level athletes participated in this study. The BTS analysis system was used with a novel model for the range-of-motion measurement. An acoustic sensor was attached to the racket for identification of a ball-racket contact. Players, performing topspin forehand, attempt to achieve maximal racket velocity based on the principles of proximal-to-distal sequences and summation of speed with a stretch-shortening character of cycle. The essential differences between type of topspin forehand occurred in the range of motion. Increased power of topspin shot was accompanied by a significant increase in range of motion in most of the studied joints and body segments, in particular in the rotation movement of the upper body, pelvis and shoulders, flexion and rotation in the shoulder and elbow joints, and flexion and rotation in knee joints. PMID- 29523054 TI - White matter lesions and brain atrophy in systemic lupus erythematosus patients: correlation to cognitive dysfunction in a cohort of systemic lupus erythematosus patients using different definition models for neuropsychiatric systemic lupus erythematosus. AB - Aim The aim of this study was to evaluate the extent of white matter lesions, atrophy of the hippocampus and corpus callosum, and their correlation with cognitive dysfunction (CD), in patients diagnosed with systemic lupus erythematosus (SLE). Methods Seventy SLE patients and 25 healthy individuals (HIs) were included in the study. To evaluate the different SLE and neuropsychiatric SLE (NPSLE) definition schemes, patients were grouped both according to the American College of Rheumatology (ACR) definition, as well as the more stringent ACR-Systemic Lupus International Collaborating Clinics definition. Patients and HIs underwent a 3 Tesla brain MRI and a standardized neuropsychological test. MRI data were evaluated for number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum. Differences between groups and subgroups were evaluated for significance. Number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum were correlated to cognitive dysfunction. Results The total volume of white matter lesions was significantly larger in SLE patients compared to HIs ( p = 0.004). However, no significant differences were seen between the different SLE subgroups. Atrophy of the bilateral hippocampus was significantly more pronounced in patients with NPSLE compared to those with non-NPSLE (right: p = 0.010; left p = 0.023). Significant negative correlations between cognitive test scores on verbal memory and number and volume of white matter lesions were present. Conclusion SLE patients have a significantly larger volume of white matter lesions on MRI compared to HIs and the degree of white matter lesion volume correlates to cognitive dysfunction, specifically to verbal memory. No significant differences in the number or volume of white matter lesions were identified between subgroups of SLE patients regardless of the definition model used. PMID- 29523055 TI - A case of refractory lupus nephritis complicated by psoriasis vulgaris that was controlled with secukinumab. AB - It has been reported that T helper 17 cells are involved in the pathogenesis of systemic lupus erythematosus, but there is no report on interleukin-17-targeted therapy. We report a case of a 62-year-old female who presented with psoriasis vulgaris and refractory lupus nephritis. Because her conditions were resistant to conventional treatment, and flow cytometry confirmed the proliferation of activated T helper 17 cells in peripheral blood, and examination of a renal biopsy tissue sample confirmed infiltration of numerous interleukin-17-positive lymphocytes to the renal interstitium, administration of the anti-interleukin-17A antibody secukinumab was initiated. After starting secukinumab the clinical and biological features were improved. PMID- 29523056 TI - An Investigation Into Force Sense at the Shoulder. AB - Proprioception is assessed more often through joint position sense and kinesthesia than force sense. The purpose of this study is to investigate force sense at the shoulder. A total of 12 subjects were recruited. An ipsilateral force reproduction protocol at the shoulder at 50 degrees , 70 degrees , and 90 degrees and 120%, 140%, and 160% baseline torque. Dependent variables were constant error (CE) and root mean square error. An effect was found for load on absolute (p = .001) and normalized CE (p < .001). CE decreased with increased load. An effect for angle was found for absolute root mean square error (p = .002), more accurate at 50 degrees (p = .01), but no effect when normalized (p = .19). With increased loads, subjects undershot the target and CE approached zero. Because of the differing behavior in CE and root mean square error, and absolute and normalized data, force sense studies should examine error from these perspectives. PMID- 29523057 TI - Implementation of Fee-Free Maternal Health-Care Policy in Ghana: Perspectives of Users of Antenatal and Delivery Care Services From Public Health-Care Facilities in Accra. AB - In 2008, the government of Ghana implemented a national user fee maternal care exemption policy through the National Health Insurance Scheme to improve financial access to maternal health services and reduce maternal as well as perinatal deaths. Although evidence shows that there has been some success with this initiative, there are still issues relating to cost of care to beneficiaries of the initiative. A qualitative study, comprising 12 focus group discussions and 6 interviews, was conducted with 90 women in six selected urban neighborhoods in Accra, Ghana, to examine users' perspectives regarding the implementation of this policy initiative. Findings showed that direct cost of delivery care services was entirely free, but costs related to antenatal care services and indirect costs related to delivery care still limit the use of hospital-based midwifery and obstetric care. There was also misunderstanding about the initiative due to misinformation created by the government through the media.We recommend that issues related to both direct and indirect costs of antenatal and delivery care provided in public health-care facilities must be addressed to eliminate some of the lingering barriers relating to cost hindering the smooth operation and sustainability of the maternal care fee exemption policy. PMID- 29523059 TI - The Ribosome as an Allosterically Regulated Molecular Machine. AB - The ribosome as a complex molecular machine undergoes significant conformational rearrangements during the synthesis of polypeptide chains of proteins. In this review, information obtained using various experimental methods on the internal consistency of such rearrangements is discussed. It is demonstrated that allosteric regulation involves all the main stages of the operation of the ribosome and connects functional elements remote by tens and even hundreds of angstroms. Data obtained using Forster resonance energy transfer (FRET) show that translocation is controlled in general by internal mechanisms of the ribosome, and not by the position of the ligands. Chemical probing data revealed the relationship of such remote sites as the decoding, peptidyl transferase, and GTPase centers of the ribosome. Nevertheless, despite the large amount of experimental data accumulated to date, many details and mechanisms of these phenomena are still not understood. Analysis of these data demonstrates that the development of new approaches is necessary for deciphering the mechanisms of allosteric regulation of the operation of the ribosome. PMID- 29523060 TI - Properties of Bacterial and Archaeal Branched-Chain Amino Acid Aminotransferases. AB - Branched-chain amino acid aminotransferases (BCATs) catalyze reversible stereoselective transamination of branched-chain amino acids (BCAAs) L-leucine, L isoleucine, and L-valine. BCATs are the key enzymes of BCAA metabolism in all organisms. The catalysis proceeds through the ping-pong mechanism with the assistance of the cofactor pyridoxal 5'-phosphate (PLP). BCATs differ from other (S)-selective transaminases (TAs) in 3D-structure and organization of the PLP binding domain. Unlike other (S)-selective TAs, BCATs belong to the PLP fold type IV and are characterized by the proton transfer on the re-face of PLP, in contrast to the si-specificity of proton transfer in fold type I (S)-selective TAs. Moreover, BCATs are the only (S)-selective enzymes within fold type IV TAs. Dual substrate recognition in BCATs is implemented via the "lock and key" mechanism without side-chain rearrangements of the active site residues. Another feature of the active site organization in BCATs is the binding of the substrate alpha-COOH group on the P-side of the active site near the PLP phosphate group. Close localization of two charged groups seems to increase the effectiveness of external aldimine formation in BCAT catalysis. In this review, the structure function features and the substrate specificity of bacterial and archaeal BCATs are analyzed. These BCATs differ from eukaryotic ones in the wide substrate specificity, optimal temperature, and reactivity toward pyruvate as the second substrate. The prospects of biotechnological application of BCATs in stereoselective synthesis are discussed. PMID- 29523061 TI - Features of Protein-Protein Interactions in the Cyanobacterial Photoprotection Mechanism. AB - Photoprotective mechanisms of cyanobacteria are characterized by several features associated with the structure of their water-soluble antenna complexes - the phycobilisomes (PBs). During energy transfer from PBs to chlorophyll of photosystem reaction centers, the "energy funnel" principle is realized, which regulates energy flux due to the specialized interaction of the PBs core with a quenching molecule capable of effectively dissipating electron excitation energy into heat. The role of the quencher is performed by ketocarotenoid within the photoactive orange carotenoid protein (OCP), which is also a sensor for light flux. At a high level of insolation, OCP is reversibly photoactivated, and this is accompanied by a significant change in its structure and spectral characteristics. Such conformational changes open the possibility for protein protein interactions between OCP and the PBs core (i.e., activation of photoprotection mechanisms) or the fluorescence recovery protein. Even though OCP was discovered in 1981, little was known about the conformation of its active form until recently, as well as about the properties of homologs of its N and C domains. Studies carried out during recent years have made a breakthrough in understanding of the structural-functional organization of OCP and have enabled discovery of new aspects of the regulation of photoprotection processes in cyanobacteria. This review focuses on aspects of protein-protein interactions between the main participants of photoprotection reactions and on certain properties of representatives of newly discovered families of OCP homologs. PMID- 29523062 TI - Enteroviruses: Classification, Diseases They Cause, and Approaches to Development of Antiviral Drugs. AB - The genus Enterovirus combines a portion of small (+)ssRNA-containing viruses and is divided into 10 species of true enteroviruses and three species of rhinoviruses. These viruses are causative agents of the widest spectrum of severe and deadly epidemic diseases of higher vertebrates, including humans. Their ubiquitous distribution and high pathogenicity motivate active search to counteract enterovirus infections. There are no sufficiently effective drugs targeted against enteroviral diseases, thus treatment is reduced to supportive and symptomatic measures. This makes it extremely urgent to develop drugs that directly affect enteroviruses and hinder their development and spread in infected organisms. In this review, we cover the classification of enteroviruses, mention the most common enterovirus infections and their clinical manifestations, and consider the current state of development of anti-enteroviral drugs. One of the most promising targets for such antiviral drugs is the viral Internal Ribosome Entry Site (IRES). The classification of these elements of the viral mRNA translation system is also examined. PMID- 29523063 TI - Adsorption of Bacteriophages on Bacterial Cells. AB - The biological functions of bacteriophage virions come down to the solution of three basic problems: to provide protection of viral nucleic acid from the factors of extracellular environment, to recognize a host suitable for phage replication, and to provide the delivery of nucleic acid through bacterial cell envelopes. This review considers the main regularities of phage-cell interaction at the initial stages of infection of tailed bacteriophages, from the reversible binding with receptors on the surface to the beginning of phage DNA entry. Data on the structure and functions of the phage adsorption apparatus, the main quantitative characteristics of the adsorption process, and the mechanisms of adaptation of phages and their hosts to each other effective at the stage of adsorption are presented. PMID- 29523064 TI - Hevein-Like Antimicrobial Peptides of Plants. AB - Plant antimicrobial peptides represent one of the evolutionarily oldest innate immunity components providing the first line of host defense to pathogen attacks. This review is dedicated to a small, currently actively studied family of hevein like peptides that can be found in various monocot and dicot plants. The review thoroughly describes all known peptides belonging to this family including data on their structures, functions, and antimicrobial activity. The main features allowing to assign these peptides to a separate family are given, and the specific characteristics of each peptide are described. Further, the mode of action for hevein-like peptides, their role in plant immune system, and the applications of these molecules in biotechnology and medicine are considered. PMID- 29523065 TI - Amyloid Properties of Titin. AB - This review considers data on structural and functional features of titin, on the role of this protein in determination of mechanical properties of sarcomeres, and on specific features of regulation of the stiffness and elasticity of its molecules, amyloid aggregation of this protein in vitro, and possibilities of formation of intramolecular amyloid structure in vivo. Molecular mechanisms are described of protection of titin against aggregation in muscle cells. Based on the data analysis, it is supposed that titin and the formed by it elastic filaments have features of amyloid. PMID- 29523066 TI - Exogenous 8-Oxo-7,8-dihydro-2'-deoxyguanosine: Biomedical Properties, Mechanisms of Action, and Therapeutic Potential. AB - 8-Oxo-7,8-dihydroguanine (8-oxo-G) is a key biomarker of oxidative damage to DNA in cells, and its genotoxicity is well-studied. In recent years, it has been confirmed experimentally that free 8-oxo-G and molecules containing it are not merely inert products of DNA repair or degradation, but they are actively involved in intracellular signaling. In this review, data are systematized indicating that free 8-oxo-G and oxidized (containing 8-oxo-G) extracellular DNA function in the body as mediators of stress signaling and initiate inflammatory and immune responses to maintain homeostasis under the action of external pathogens, whereas exogenous 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) exhibits pronounced antiinflammatory and antioxidant properties. This review describes known action mechanisms of oxidized guanine and 8-oxo-G-containing molecules. Prospects for their use as a therapeutic target are considered, as well as a pharmaceutical agent for treatment of a wide range of diseases whose pathogenesis is significantly contributed to by inflammation and oxidative stress. PMID- 29523067 TI - Three-Finger Proteins from the Ly6/uPAR Family: Functional Diversity within One Structural Motif. AB - The discovery in higher animals of proteins from the Ly6/uPAR family, which have structural homology with snake "three-finger" neurotoxins, has generated great interest in these molecules and their role in the functioning of the organism. These proteins have been found in the nervous, immune, endocrine, and reproductive systems of mammals. There are two types of the Ly6/uPAR proteins: those associated with the cell membrane by GPI-anchor and secreted ones. For some of them (Lynx1, SLURP-1, SLURP-2, Lypd6), as well as for snake alpha-neurotoxins, the target of action is nicotinic acetylcholine receptors, which are widely represented in the central and peripheral nervous systems, and in many other tissues, including epithelial cells and the immune system. However, the targets of most proteins from the Ly6/uPAR family and the mechanism of their action remain unknown. This review presents data on the structural and functional properties of the Ly6/uPAR proteins, which reveal a variety of functions within a single structural motif. PMID- 29523068 TI - Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors: A Combinatorial Approach. AB - Highly active antiretroviral therapy (HAART) is one of the most effective means for fighting against HIV-infection. HAART primarily targets HIV-1 reverse transcriptase (RT), and 14 of 28 compounds approved by the FDA as anti-HIV drugs act on this enzyme. HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) hold a special place among HIV RT inhibitors owing to their high specificity and unique mode of action. Nonetheless, these drugs show a tendency to decrease their efficacy due to high HIV-1 variability and formation of resistant virus strains tolerant to clinically applied HIV NNRTIs. A combinatorial approach based on varying substituents within various fragments of the parent molecule that results in development of highly potent compounds is one of the approaches aimed at designing novel HIV NNRTIs. Generation of HIV NNRTIs based on pyrimidine derivatives explicitly exemplifies this approach, which is discussed in this review. PMID- 29523069 TI - Mathematical Modeling of Bioassays. AB - The high affinity and specificity of biological receptors determine the demand for and the intensive development of analytical systems based on use of these receptors. Therefore, theoretical concepts of the mechanisms of these systems, quantitative parameters of their reactions, and relationships between their characteristics and ligand-receptor interactions have become extremely important. Many mathematical models describing different bioassay formats have been proposed. However, there is almost no information on the comparative characteristics of these models, their assumptions, and predictive insights. In this review we suggested a set of criteria to classify various bioassays and reviewed classical and contemporary publications on these bioassays with special emphasis on immunochemical analysis systems as the most common and in-demand techniques. The possibilities of analytical and numerical modeling are discussed, as well as estimations of the minimum concentrations that may be detected in bioassays and recommendations for the choice of assay conditions. PMID- 29523070 TI - Textpresso Central: a customizable platform for searching, text mining, viewing, and curating biomedical literature. AB - BACKGROUND: The biomedical literature continues to grow at a rapid pace, making the challenge of knowledge retrieval and extraction ever greater. Tools that provide a means to search and mine the full text of literature thus represent an important way by which the efficiency of these processes can be improved. RESULTS: We describe the next generation of the Textpresso information retrieval system, Textpresso Central (TPC). TPC builds on the strengths of the original system by expanding the full text corpus to include the PubMed Central Open Access Subset (PMC OA), as well as the WormBase C. elegans bibliography. In addition, TPC allows users to create a customized corpus by uploading and processing documents of their choosing. TPC is UIMA compliant, to facilitate compatibility with external processing modules, and takes advantage of Lucene indexing and search technology for efficient handling of millions of full text documents. Like Textpresso, TPC searches can be performed using keywords and/or categories (semantically related groups of terms), but to provide better context for interpreting and validating queries, search results may now be viewed as highlighted passages in the context of full text. To facilitate biocuration efforts, TPC also allows users to select text spans from the full text and annotate them, create customized curation forms for any data type, and send resulting annotations to external curation databases. As an example of such a curation form, we describe integration of TPC with the Noctua curation tool developed by the Gene Ontology (GO) Consortium. CONCLUSION: Textpresso Central is an online literature search and curation platform that enables biocurators and biomedical researchers to search and mine the full text of literature by integrating keyword and category searches with viewing search results in the context of the full text. It also allows users to create customized curation interfaces, use those interfaces to make annotations linked to supporting evidence statements, and then send those annotations to any database in the world. Textpresso Central URL: http://www.textpresso.org/tpc. PMID- 29523071 TI - Identification, characterization and gene expression analyses of important flowering genes related to photoperiodic pathway in bamboo. AB - BACKGROUND: Bamboo is an important member of the family Poaceae and has many inflorescence and flowering features rarely observed in other plant groups. It retains an unusual form of perennialism by having a long vegetative phase that can extend up to 120 years, followed by flowering and death of the plants. In contrast to a large number of studies conducted on the annual, reference plants Arabidopsis thaliana and rice, molecular studies to characterize flowering pathways in perennial bamboo are lacking. Since photoperiod plays a crucial role in flower induction in most plants, important genes involved in this pathway have been studied in the field grown Bambusa tulda, which flowers after 40-50 years. RESULTS: We identified several genes from B. tulda, including four related to the circadian clock [LATE ELONGATED HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION1 (TOC1), ZEITLUPE (ZTL) and GIGANTEA (GI)], two circadian clock response integrators [CONSTANS A (COA), CONSTANS B (COB)] and four floral pathway integrators [FLOWERING LOCUS T1, 2, 3, 4 (FT1, 2, 3, 4)]. These genes were amplified from either gDNA and/or cDNA using degenerate as well as gene specific primers based on homologous sequences obtained from related monocot species. The sequence identity and phylogenetic comparisons revealed their close relationships to homologs identified in the temperate bamboo Phyllostachys edulis. While the four BtFT homologs were highly similar to each other, BtCOA possessed a full length B-box domain that was truncated in BtCOB. Analysis of the spatial expression of these genes in selected flowering and non-flowering tissue stages indicated their possible involvement in flowering. The diurnal expression patterns of the clock genes were comparable to their homologs in rice, except for BtZTL. Among multiple BtCO and BtFT homologs, the diurnal pattern of only BtCOA and BtFT3, 4 were synchronized in the flower inductive tissue, but not in the non flowering tissues. CONCLUSION: This study elucidates the photoperiodic regulation of bamboo homologs of important flowering genes. The finding also identifies copy number expansion and gene expression divergence of CO and FT in bamboo. Further studies are required to understand their functional role in bamboo flowering. PMID- 29523072 TI - Neuroprotective dobutamine treatment upregulates superoxide dismutase 3, anti oxidant and survival genes and attenuates genes mediating inflammation. AB - BACKGROUND: Labor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult. The beta1-adrenergic agonist dobutamine protects against hypoxia/aglycemia induced neuronal damage. We aimed to identify the associated protective biological processes involved. RESULTS: Hippocampal slices from 6 days old mice showed significant changes of gene expression comparing slices with or without dobutamine (50 mM) in the following two experimental paradigms: (1) control conditions versus lipopolysacharide (LPS) stimulation and (2) oxygen glucose deprivation (OGD), versus combined LPS/OGD. Dobutamine depressed the inflammatory response by modifying the toll-like receptor-4 signalling pathways, including interferon regulatory factors and nuclear factor kappa B activation in experimental paradigm 1. The anti-oxidant defense genes superoxide dismutase 3 showed an upregulation in the OGD paradigm while thioredoxin reductase was upregulated in LPS paradigm. The survival genes Bag-3, Tinf2, and TMBIM-1, were up-regulated in paradigm 1. Moreover, increased levels of SOD3 were verified on the protein level 24 h after OGD and control stimulation in cultures with or without preconditioning with LPS and dobutamine, respectively. CONCLUSIONS: Neuroprotective treatment with dobutamine depresses expression of inflammatory mediators and promotes the defense against oxidative stress and depresses apoptotic genes in a model of neonatal brain hypoxia/ischemia interpreted as pharmacological preconditioning. We conclude that beta1-adrenoceptor activation might be an efficient strategy for identifying novel pharmacological targets for protection of the neonatal brain. PMID- 29523073 TI - Association between admission anemia and long-term mortality in patients with acute myocardial infarction: results from the MONICA/KORA myocardial infarction registry. AB - BACKGROUND: Previous studies have shown that the presence of anemia is associated with increased short- and long-term outcomes in patients with acute myocardial infarction (AMI). This study aims at examining the impact of admission anemia on long-term, all-cause mortality following AMI in patients recruited from a population-based registry. Contrary to most prior studies, we distinguished between patients with mild and moderate to severe anemia. METHODS: This prospective study was conducted in 2011 patients consecutively hospitalized for AMI that occurred between January 2005 and December 2008. Patients who survived more than 28 days after AMI were followed up until December 2011. Hemoglobin (Hb) concentration was measured at hospital admission and classified according to the World Health Organization (WHO). Mild anemia was defined as Hb concentration of 11 to < 12 g/dL in women and 11 to < 13 g/dL in men; moderate to severe anemia as Hb concentration of < 11 g/dL. Adjusted Cox regression models were calculated to compare survival in patients with and without anemia. RESULTS: Mild anemia and moderate to severe anemia was found in 183 (9.1%) and 100 (5%) patients, respectively. All-cause mortality after a median follow-up time of 4.2 years was 11.9%. The Cox regression analysis showed significantly increased mortality risks in both patients with mild (HR 1.74, 95% CI 1.23-2.45) and moderate to severe anemia (HR 2.05, 95% CI 1.37-3.05) compared to patients without anemia. CONCLUSION: This study shows that anemia adversely affects long-term survival following AMI. However, further studies are needed to confirm that anemia can solely explain worse long-term outcomes after AMI. PMID- 29523074 TI - In silico comparative analysis of GGDEF and EAL domain signaling proteins from the Azospirillum genomes. AB - BACKGROUND: The cyclic-di-GMP (c-di-GMP) second messenger exemplifies a signaling system that regulates many bacterial behaviors of key importance; among them, c di-GMP controls the transition between motile and sessile life-styles in bacteria. Cellular c-di-GMP levels in bacteria are regulated by the opposite enzymatic activities of diguanylate cyclases and phosphodiesterases, which are proteins that have GGDEF and EAL domains, respectively. Azospirillum is a genus of plant-growth-promoting bacteria, and members of this genus have beneficial effects in many agronomically and ecologically essential plants. These bacteria also inhabit aquatic ecosystems, and have been isolated from humus-reducing habitats. Bioinformatic and structural approaches were used to identify genes predicted to encode GG[D/E]EF, EAL and GG[D/E]EF-EAL domain proteins from nine genome sequences. RESULTS: The analyzed sequences revealed that the genomes of A. humicireducens SgZ-5T, A. lipoferum 4B, Azospirillum sp. B510, A. thiophilum BV ST, A. halopraeferens DSM3675, A. oryzae A2P, and A. brasilense Sp7, Sp245 and Az39 encode for 29 to 41 of these predicted proteins. Notably, only 15 proteins were conserved in all nine genomes: eight GGDEF, three EAL and four GGDEF-EAL hybrid domain proteins, all of which corresponded to core genes in the genomes. The predicted proteins exhibited variable lengths, architectures and sensor domains. In addition, the predicted cellular localizations showed that some of the proteins to contain transmembrane domains, suggesting that these proteins are anchored to the membrane. Therefore, as reported in other soil bacteria, the Azospirillum genomes encode a large number of proteins that are likely involved in c-di-GMP metabolism. In addition, the data obtained here strongly suggest host specificity and environment specific adaptation. CONCLUSIONS: Bacteria of the Azospirillum genus cope with diverse environmental conditions to survive in soil and aquatic habitats and, in certain cases, to colonize and benefit their host plant. Gaining information on the structures of proteins involved in c-di-GMP metabolism in Azospirillum appears to be an important step in determining the c di-GMP signaling pathways, involved in the transition of a motile cell towards a biofilm life-style, as an example of microbial genome plasticity under diverse in situ environments. PMID- 29523075 TI - Relationship between self-efficacy, self-care behaviour and glycaemic control among patients with type 2 diabetes mellitus in the Malaysian primary care setting. AB - BACKGROUND: Self-efficacy has been shown to be positively correlated with self care behaviour and glycaemic control among patients with type 2 diabetes mellitus. However, such evidence is lacking in the Malaysian primary care setting. The objectives of this study were to i) determine the levels of self efficacy, self-care behaviour and glycaemic control among patients with type 2 diabetes mellitus in the Malaysian primary care setting ii) determine the relationship between self-efficacy, self-care behaviour and glycaemic control iii) determine the factors associated with glycaemic control. METHODS: This was a cross-sectional study involving patients with type 2 diabetes mellitus from two public primary care clinics in Malaysia. Self-efficacy and self-care behaviour levels were measured using previously translated and validated DMSES and SDSCA questionnaires in Malay versions, respectively. Glycaemic control was measured using HbA1c. RESULTS: A total of 340 patients with type 2 diabetes mellitus were recruited. The total mean (+/-SD) of self-efficacy and self-care behaviour scores were 7.33 (+/-2.25) and 3.76 (+/-1.87), respectively. A positive relationship was found between self-efficacy and self-care behaviour (r 0.538, P < 0.001). Higher self-efficacy score was shown to be correlated with lower HbA1c (r - 0.41, P < 0.001). Multiple linear regression analysis demonstrated that higher self efficacy scores (b - 0.398; 95% CI: -0.024, - 0.014; P < 0.001), shorter duration of diabetes (b 0.177; 95% CI: 0.002, 0.007; P < 0.001) and smaller waist circumference (b 0.135; 95% CI: 0.006, 0.035; P = 0.006), were significantly associated with good glycaemic control. CONCLUSION: This study demonstrated that higher self-efficacy was correlated with improved self-care behaviour and better glycaemic control. Findings of this study suggest the importance of including routine use of self-efficacy measures in the management of type 2 diabetes mellitus in primary care. PMID- 29523076 TI - Normal sleep bouts are not essential for C. elegans survival and FoxO is important for compensatory changes in sleep. AB - BACKGROUND: Sleep deprivation impairs learning, causes stress, and can lead to death. Notch and JNK-1 pathways impact C. elegans sleep in complex ways; these have been hypothesized to involve compensatory sleep. C. elegans DAF-16, a FoxO transcription factor, is required for homeostatic response to decreased sleep and DAF-16 loss decreases survival after sleep bout deprivation. Here, we investigate connections between these pathways and the requirement for sleep after mechanical stress. RESULTS: Reduced function of Notch ligand LAG-2 or JNK-1 kinase resulted in increased time in sleep bouts during development. These animals were inappropriately easy to arouse using sensory stimulation, but only during sleep bouts. This constellation of defects suggested that poor quality sleep bouts in these animals might activate homeostatic mechanisms, driving compensatory increased sleep bouts. Testing this hypothesis, we found that DAF-16 FoxO function was required for increased sleep bouts in animals with defective lag-2 and jnk-1, as loss of daf-16 reduced sleep bouts back to normal levels. However, loss of daf-16 did not suppress arousal thresholds defects. Where DAF-16 function was required differed; in lag-2 and jnk-1 animals, daf-16 function was required in neurons or muscles, respectively, suggesting that disparate tissues can drive a coordinated response to sleep need. Sleep deprivation due to mechanical stimulation can cause death in many species, including C. elegans, suggesting that sleep is essential. We found that loss of sleep bouts in C. elegans due to genetic manipulation did not impact their survival, even in animals lacking DAF 16 function. However, we found that sleep bout deprivation was often fatal when combined with the concurrent stress of mechanical stimulation. CONCLUSIONS: Together, these results in C. elegans confirm that Notch and JNK-1 signaling are required to achieve normal sleep depth, suggest that DAF-16 is required for increased sleep bouts when signaling decreases, and that failure to enter sleep bouts is not sufficient to cause death in C. elegans, unless paired with concurrent mechanical stress. These results suggest that mechanical stress may directly contribute to death observed in previous studies of sleep deprivation and/or that sleep bouts have a uniquely restorative role in C. elegans sleep. PMID- 29523078 TI - AxonTracer: a novel ImageJ plugin for automated quantification of axon regeneration in spinal cord tissue. AB - BACKGROUND: Quantification of axon regeneration in spinal cord tissue sections is a fundamental step to adequately determine if an applied treatment leads to an anatomical benefit following spinal cord injury. Recent advances have led to the development of therapies that can promote regeneration of thousands of injured axons in vivo. Axon labeling methods and in the application of regeneration enabling stem cell grafts have increased the number of detectable regenerating axons by orders of magnitudes. Manual axon tracing in such cases is challenging and laborious, and as such there is a great need for automated algorithms that can perform accurate tracing and quantification in axon-dense tissue sections. RESULTS: We developed "AxonTracer", a fully automated software algorithm that traces and quantifies regenerating axons in spinal cord tissue sections. AxonTracer is an open source plugin for the freely available image-processing program ImageJ. The plugin identifies transplanted cells grafts or other regions of interest (ROIs) based on immunohistological staining and quantifies regenerating axons within the ROIs. Individual images or groups of images (batch mode) can be analyzed sequentially. In batch mode, a unique algorithm identifies a reference image for normalization, as well as a suitable image for defining detection parameters. An interactive user interface allows for adjustment of parameters defining ROI size, axon detection sensitivity and debris cleanup. Automated quantification of regenerating axons by AxonTracer correlates strongly with semi-manual quantification by the widely-used ImageJ plugin NeuronJ. However, quantification with AxonTracer is automated and reduces the need for user input compared to alternative methods. CONCLUSIONS: AxonTracer is a freely available open-source tool for automated analysis of regenerating axons in the injured nervous system. An interactive user interface provides detection parameter adjustment, and usage does not require prior image analysis experience. Raw data as well as normalized results are stored in spreadsheet format and axon tracings are superimposed on raw images allowing for subjective visual verification. This software allows for automated, unbiased analysis of hundreds of axon-dense images, thus providing a useful tool in enabling in vivo screens of axon regeneration following spinal cord injury. PMID- 29523077 TI - An interpretable framework for clustering single-cell RNA-Seq datasets. AB - BACKGROUND: With the recent proliferation of single-cell RNA-Seq experiments, several methods have been developed for unsupervised analysis of the resulting datasets. These methods often rely on unintuitive hyperparameters and do not explicitly address the subjectivity associated with clustering. RESULTS: In this work, we present DendroSplit, an interpretable framework for analyzing single cell RNA-Seq datasets that addresses both the clustering interpretability and clustering subjectivity issues. DendroSplit offers a novel perspective on the single-cell RNA-Seq clustering problem motivated by the definition of "cell type", allowing us to cluster using feature selection to uncover multiple levels of biologically meaningful populations in the data. We analyze several landmark single-cell datasets, demonstrating both the method's efficacy and computational efficiency. CONCLUSION: DendroSplit offers a clustering framework that is comparable to existing methods in terms of accuracy and speed but is novel in its emphasis on interpretabilty. We provide the full DendroSplit software package at https://github.com/jessemzhang/dendrosplit . PMID- 29523079 TI - HT-eQTL: integrative expression quantitative trait loci analysis in a large number of human tissues. AB - BACKGROUND: Expression quantitative trait loci (eQTL) analysis identifies genetic markers associated with the expression of a gene. Most existing eQTL analyses and methods investigate association in a single, readily available tissue, such as blood. Joint analysis of eQTL in multiple tissues has the potential to improve, and expand the scope of, single-tissue analyses. Large-scale collaborative efforts such as the Genotype-Tissue Expression (GTEx) program are currently generating high quality data in a large number of tissues. However, computational constraints limit genome-wide multi-tissue eQTL analysis. RESULTS: We develop an integrative method under a hierarchical Bayesian framework for eQTL analysis in a large number of tissues. The model fitting procedure is highly scalable, and the computing time is a polynomial function of the number of tissues. Multi-tissue eQTLs are identified through a local false discovery rate approach, which rigorously controls the false discovery rate. Using simulation and GTEx real data studies, we show that the proposed method has superior performance to existing methods in terms of computing time and the power of eQTL discovery. CONCLUSIONS: We provide a scalable method for eQTL analysis in a large number of tissues. The method enables the identification of eQTL with different configurations and facilitates the characterization of tissue specificity. PMID- 29523080 TI - Genome sequence of an aflatoxigenic pathogen of Argentinian peanut, Aspergillus arachidicola. AB - BACKGROUND: Aspergillus arachidicola is an aflatoxigenic fungal species, first isolated from the leaves of a wild peanut species native to Argentina. It has since been reported in maize, Brazil nut and human sputum samples. This aflatoxigenic species is capable of secreting both B and G aflatoxins, similar to A. parasiticus and A. nomius. It has other characteristics that may result in its misidentification as one of several other section Flavi species. This study offers a preliminary analysis of the A. arachidicola genome. RESULTS: In this study we sequenced the genome of the A. arachidicola type strain (CBS 117610) and found its genome size to be 38.9 Mb, and its number of predicted genes to be 12,091, which are values comparable to those in other sequenced Aspergilli. A comparison of 57 known Aspergillus secondary metabolite gene clusters, among closely-related aflatoxigenic species, revealed nearly half were predicted to exist in the type strain of A. arachidicola. Of its predicted genes, 691 were identified as unique to the species and 60% were assigned Gene Ontology terms using BLAST2GO. Phylogenomic inference shows CBS 117610 sharing a most recent common ancestor with A. parasiticus. Finally, BLAST query of A. flavus mating type idiomorph sequences to this strain revealed the presence of a single mating type (MAT1-1) idiomorph. CONCLUSIONS: Based on A. arachidicola morphological, genetic and chemotype similarities with A. flavus and A. parasiticus, sequencing the genome of A. arachidicola will contribute to our understanding of the evolutionary relatedness among aflatoxigenic fungi. PMID- 29523081 TI - An application of restricted mean survival time in a competing risks setting: comparing time to ART initiation by injection drug use. AB - BACKGROUND: Restricted mean survival time (RMST) is an underutilized estimand in time-to-event analyses. Herein, we highlight its strengths by comparing time to (1) all-cause mortality and (2) initiation of antiretroviral therapy (ART) for HIV-infected persons who inject drugs (PWID) and persons who do not inject drugs. METHODS: RMST to death was determined by integrating the Kaplan-Meier survival curve to 5 years of follow-up. To account for the competing risks of death and loss-to-clinic when estimating time to ART, we calculated RMST to ART initiation by estimating the area between the survival curve for ART initiation and the cumulative incidence curve for death or loss-to-clinic. We standardized all curves using inverse probability of exposure weights. RESULTS: We followed 3044 HIV-positive, ART-naive persons from enrollment into the Johns Hopkins HIV Clinical Cohort from 1996 to 2014. PWID had a - 0.19 year (95% confidence interval (CI): - 0.29, - 0.10) difference in survival over 5 years of follow-up compared to persons who did not inject drugs. There was no difference between the two groups in time not on ART while alive and in clinic (RMST difference = 0.08, 95% CI: -0.10, 0.36). CONCLUSIONS: PWID have similar expected time to ART initiation after properly accounting for their greater risk of death and loss-to clinic. PMID- 29523082 TI - Visual quality assessment of the liver graft by the transplanting surgeon predicts postreperfusion syndrome after liver transplantation: a retrospective cohort study. AB - BACKGROUND: The discrepancy between demand and supply for liver transplants (LT) has led to an increased transplantation of organs from extended criteria donors (ECD). METHODS: In this single center retrospective analysis of 122 cadaveric LT recipients, we investigated predictors of postreperfusion syndrome (PRS) including transplant liver quality categorized by both histological assessment of steatosis and subjective visual assessment by the transplanting surgeon using multivariable regression analysis. Furthermore, we describe the relevance of PRS during the intraoperative and postoperative course of LT recipients. RESULTS: 53.3% (n = 65) of the patients suffered from PRS. Risk factors for PRS were visually assessed organ quality of the liver grafts (acceptable: OR 12.2 [95% CI 2.43-61.59], P = 0.002; poor: OR 13.4 [95% CI 1.48-121.1], P = 0.02) as well as intraoperative norepinephrine dosage before reperfusion (OR 2.2 [95% CI 1.26 3.86] per 0.1 MUg kg- 1 min- 1, P = 0.01). In contrast, histological assessment of the graft was not associated with PRS. LT recipients suffering from PRS were hemodynamically more instable after reperfusion compared to recipients not suffering from PRS. They had lower mean arterial pressures until the end of surgery (P < 0.001), received more epinephrine and norepinephrine before reperfusion (P = 0.02 and P < 0.001, respectively) as well as higher rates of continuous infusion of norepinephrine (P < 0.001) and vasopressin (P = 0.02) after reperfusion. Postoperative peak AST was significantly higher (P = 0.001) in LT recipients with PRS. LT recipients with intraoperative PRS had more postoperative adverse cardiac events (P = 0.05) and suffered more often from postoperative delirium (P = 0.04). CONCLUSIONS: Patients receiving ECD liver grafts are especially prone to PRS. Anesthesiologists should keep these newly described risk factors in mind when preparing for reperfusion in patients receiving high-risk organs. PMID- 29523083 TI - Fast and efficient short read mapping based on a succinct hash index. AB - BACKGROUND: Various indexing techniques have been applied by next generation sequencing read mapping tools. The choice of a particular data structure is a trade-off between memory consumption, mapping throughput, and construction time. RESULTS: We present the succinct hash index - a novel data structure for read mapping which is a variant of the classical q-gram index with a particularly small memory footprint occupying between 3.5 and 5.3 GB for a human reference genome for typical parameter settings. The succinct hash index features two novel seed selection algorithms (group seeding and variable-length seeding) and an efficient parallel construction algorithm, which we have implemented to design the FEM (Fast(F) and Efficient(E) read Mapper(M)) mapper. FEM can return all read mappings within a given edit distance. Our experimental results show that FEM is scalable and outperforms other state-of-the-art all-mappers in terms of both speed and memory footprint. Compared to Masai, FEM is an order-of-magnitude faster using a single thread and two orders-of-magnitude faster when using multiple threads. Furthermore, we observe an up to 2.8-fold speedup compared to BitMapper and an order-of-magnitude speedup compared to BitMapper2 and Hobbes3. CONCLUSIONS: The presented succinct index is the first feasible implementation of the q-gram index functionality that occupies around 3.5 GB of memory for a whole human reference genome. FEM is freely available at https://github.com/haowenz/FEM . PMID- 29523084 TI - A circulating microRNA signature as noninvasive diagnostic and prognostic biomarkers for nonalcoholic steatohepatitis. AB - BACKGROUND: Noninvasive biomarkers are urgently needed for patients with nonalcoholic steatohepatitis (NASH) to assist in diagnosis, monitoring disease progression and assessing treatment response. Recently several exploratory studies showed that circulating level of microRNA is associated with NASH and correlated with disease severity. Although these data were encouraging, the application of circulating microRNA as biomarkers for patient screening and stratification need to be further assessed under well-controlled conditions. RESULTS: The expression of circulating microRNAs were profiled in diet-induced NASH progression and regression models to assess the diagnostic and prognostic values and the translatability between preclinical mouse model and men. Since these mice had same genetic background and were housed in the same conditions, there were minimal confounding factors. Histopathological lesions were analyzed at distinct disease progression stages along with microRNA measurement which allows longitudinal assessment of microRNA as NASH biomarkers. Next, differentially expressed microRNAs were identified and validated in an independent cohorts of animals. Thirdly, these microRNAs were examined in a NASH regression model to assess whether they would respond to NASH treatment. MicroRNA profiling in two independent cohorts of animals validated the up-regulation of 6 microRNAs (miR-122, miR-192, miR-21, miR-29a, miR-34a and miR-505) in NASH mice, which was designated as the circulating microRNA signature for NASH. The microRNA signature could accurately distinguish NASH mice from lean mice, and it responded to chow diet treatment in a NASH regression model. To further improve the performance of microRNA-based biomarker, a new composite biomarker was proposed, which consists of miR-192, miR-21, miR-505 and ALT. The new composite biomarker outperformed the microRNA signature in predicting NASH mice which had NAS > 3, and deserves further validations in large scale studies. CONCLUSION: The present study supported the translation of circulating microRNAs between preclinical models and humans in NASH pathogenesis and progression. The microRNA-based composite biomarker may be used for non-invasive diagnosis, clinical monitoring and assessing treatment response for NASH. PMID- 29523086 TI - Transplant renal artery stenosis caused by the stretch of an artey branch: a case report and literature review. AB - BACKGROUND: Renal transplant is the preferred treatment option for these patients with end-stage renal disease. Transplant renal artery stenosis (TRAS) is one of the most common and serious vascular complications after renal transplantation, and most of the TRAS occurred in the anastomosis. The complication must be diagnosed and treated timely, otherwise the function of transplanted kidney may be losed. CASE PRESENTATION: A 46-year-old male with end-stage renal disease of unknown cause received a cadaveric renal transplant one year ago. Although three antihypertensive medications were administrated, his blood pressure gradually increased to 190/120 mmHg 3 weeks posttransplantation. Also the level of creatinine increased to 194 MUmol/L.Color Doppler ultrasonography indicated a decreased resistance index (RI) in intrarenal arteries and increased blood flow of the transplant renal artery, therefore, a vascular complication of TRAS was suspected. Arteriography was performed and demonstrated TRAS caused by stretch of an artery branch, and the TRAS occurred in the distal site of the anastomosis instead of the anastomosis. Percutaneous transluminal bare stent implantation treatment was successfully performed. Satisfactory clinical efficacy with improvement in transplant renal function and renovascular hypertension was achieved after the interventional treatment. CONCLUSION: To our knowledge this is the first reported case of TRAS caused by stretch of an artery branch. When refractory hypertension and allograft dysfunction are presented posttransplantation, TRAS should be suspected. Color Doppler ultrasonography as a non-invasive examination may provide some valuable information, three-dimention CT can be useful for further diagnosis, but is seldom necessary. Arteriography provides the definitive diagnosis of TRAS. Percutaneous transluminal stent implantation treatment of TRAS has high success rate with minimal invasion and complications. When an artery branch situated on the stenosis, a bare stent rather than covered stent is the preferred choice. PMID- 29523085 TI - Comparative assessment of strategies to identify similar ligand-binding pockets in proteins. AB - BACKGROUND: Detecting similar ligand-binding sites in globally unrelated proteins has a wide range of applications in modern drug discovery, including drug repurposing, the prediction of side effects, and drug-target interactions. Although a number of techniques to compare binding pockets have been developed, this problem still poses significant challenges. RESULTS: We evaluate the performance of three algorithms to calculate similarities between ligand-binding sites, APoc, SiteEngine, and G-LoSA. Our assessment considers not only the capabilities to identify similar pockets and to construct accurate local alignments, but also the dependence of these alignments on the sequence order. We point out certain drawbacks of previously compiled datasets, such as the inclusion of structurally similar proteins, leading to an overestimated performance. To address these issues, a rigorous procedure to prepare unbiased, high-quality benchmarking sets is proposed. Further, we conduct a comparative assessment of techniques directly aligning binding pockets to indirect strategies employing structure-based virtual screening with AutoDock Vina and rDock. CONCLUSIONS: Thorough benchmarks reveal that G-LoSA offers a fairly robust overall performance, whereas the accuracy of APoc and SiteEngine is satisfactory only against easy datasets. Moreover, combining various algorithms into a meta predictor improves the performance of existing methods to detect similar binding sites in unrelated proteins by 5-10%. All data reported in this paper are freely available at https://osf.io/6ngbs/ . PMID- 29523087 TI - Changes in MLST profiles and biotypes of Corynebacterium diphtheriae isolates from the diphtheria outbreak period to the period of invasive infections caused by nontoxigenic strains in Poland (1950-2016). AB - BACKGROUND: Corynebacterium diphtheriae is a re-emerging pathogen in Europe causing invasive infections in vaccinated persons and classical diphtheria in unvaccinated persons. In the presented study we analysed genetic changes in C. diphtheriae isolates collected in Poland from the period before the introduction of the mass anti-diphtheria vaccination to the present time when over 98% of the population is vaccinated. METHODS: A total of 62 C. diphtheriae isolates collected in the 1950s-1960s, 1990s and 2000-2016 in Poland were investigated. Examined properties of the isolates included toxigenic status, presence of tox gene, biotype, MLST type (ST) and type of infection. RESULTS: A total of 12 sequence types (STs) were identified among the analysed C. diphtheriae isolates. The highest variability of STs was observed among isolates from diphtheria and asymptomatic carriers collected in the XX century. Over 95% of isolates collected from invasive and wound infections in 2004-2016 belonged to ST8. Isolates from the XX century represented all four biotypes: mitis, gravis, intermedius and belfanti, but the belfanti biotype appeared only after the epidemic in the 1990s. All except three isolates from the XXI century represented the biotype gravis. CONCLUSIONS: During a diphtheria epidemic period, non-epidemic clones of C. diphtheriae might also disseminate and persist in a particular area after the epidemic. An increase of the anti-diphtheria antibody level in the population causes not only the elimination of toxigenic strains from the population but may also influence the reduction of diversity of C. diphtheriae isolates. MLST types do not reflect the virulence of isolates. Each ST can be represented by various virulent variants representing various pathogenic capacities, for example toxigenic non-invasive, nontoxigenic invasive and nontoxigenic non-invasive. PMID- 29523088 TI - An increasing number of hand injuries in an elderly population - a retrospective study over a 30-year period. AB - BACKGROUND: Both the number and the proportion of elderly people in the society increase. The number of elderly subjects with a disability due to a disease has decreased resulting in more active elderly. Therefore, an increase in numbers of injury in the elderly population can be expected; a hypothesis that was investigated in the present study. METHODS: Two-hundred sixteen patients with an age of > 65 years, and admitted to a hand surgery ward with a hand injury, were retrospectively collected at four different 2-years periods over a 30 years time (1980-81 to 2010-11). Information about patient gender, age at injury, injury place and mechanism (s), injured structures, duration of hospital stay, number of out patient visits and rehabilitation visits as well as social status was collected. The injuries were classified with the Modified Hand Injury Severity Score (MHISS). RESULTS: Most injured patients were men (72%) and the number of patients who reported to be healthy significantly decreased (67% to 18%) during the study period. The number of injuries increased over the study period (n = 24 to n = 83/2-year period). Outside home was the most common injury place and a saw or a fall was the most frequent injury mechanism. Several fingers were most often injured. The majority of the injuries were classified to be Minor or Moderate (MHISS) and a fracture was the most common injured structure. CONCLUSIONS: We found an increased number of hand injuries over a 30-year period in combination with a decrease in patients reported health treated at a hand surgery ward. Further studies regarding hand trauma in the elderly population will be valuable for future prevention and rehabilitation of this patient group. PMID- 29523089 TI - Effect of whole-body electromyostimulation and / or protein supplementation on obesity and cardiometabolic risk in older men with sarcopenic obesity: the randomized controlled FranSO trial. AB - BACKGROUND: Sarcopenic Obesity (SO) is characterized by low lean and high fat mass; i.e. from a functional aspect a disproportion between engine (muscle) and mass to be moved (fat). At present, most research focuses on the engine, but the close "cross talk" between age-associated adipose and skeletal muscle tissue inflammation calls for comprehensive interventions that affect both components alike. Protein and exercise are likely candidates, however with respect to the latter, the enthusiasm for intense and frequent exercise is rather low, especially in functionally limited older people. The aim of this study was therefore to evaluate the effect of whole-body electromyostimulation (WB-EMS), a time-efficient, joint-friendly and highly customizable exercise technology, on obesity parameters and cardiometabolic risk in men with SO. METHODS: One-hundred community-dwelling (cdw) Bavarian men >=70 years with SO were randomly assigned to either (a) whey protein supplementation (WPS), (b) WB-EMS and protein supplementation (WB-EMS&P) or (c) non-intervention control (CG). Protein supplementation contributed to an intake of 1.7-1.8 g/kg/body mass/d, WB-EMS consisted of 1.5 * 20 min/week (85 Hz, 350 MUs, 4 s of strain-4 s of rest) with moderate-high intensity. Using an intention to treat approach with multiple imputation, the primary study endpoint was total body fat mass (TBF), secondary endpoints were trunk fat mass (TF), waist circumference (WC) and total cholesterol/HDL-cholesterol ratio (TC/HDL-C). RESULTS: After 16 weeks of intervention, TBF was reduced significantly in the WPS (- 3.6 +/- 7.2%; p = 0.005) and WB-EMS&P (- 6.7 +/- 6.2%; p < 0.001), but not in the CG (+ 1.6 +/- 7.1%; p = 0.191). Changes in the WB-EMS&P (p < 0.001) and the WPS group (p = 0.011) differ significantly from the CG. TF decreased in the WB-EMS&P (p < 0.001) and WPS (p = .117) and increased in the CG (p = .159); WC decreased significantly in the treatment groups and was maintained in the CG. Lastly, the TC/HDL-C ratio improved significantly in the WB-EMS&P and WPS group and was maintained in the CG. Significant differences between WB-EMS&P and WPS were determined for waist circumference only (p = 0.015; TBF: p = 0.073; TF: p = 0.087; TC/HDL-C: p = .773). CONCLUSION: Moderate-high dosed whey protein supplementation, especially when combined with WB-EMS, may be a feasible choice to address obesity and cardiometabolic risk in older cdw men with SO unable or unmotivated to exercise conventionally. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02857660 ; registration date: 05/01/2017. PMID- 29523091 TI - Membranous nephropathy succeeding autologous hematopoietic stem cell transplant: a case report. AB - BACKGROUND: Membranous nephropathy (MN), the leading cause of nephrotic syndrome in adults, is characterized by the deposition of subepithelial immune deposits. Most of the cases are primary, while only approximately 25% of the cases are secondary to some known diseases. Recently, MN has been considered to be a possible presentation of chronic graft-versus-host disease (GVHD) of the kidney in allogeneic hematopoietic stem cell transplantation (HSCT) patients. In autologous HSCT populations, there have been scarce reports of associated MN, as a result of immune dysregulation leading to systemic autoimmunity and miming chronic GVHD. CASE PRESENTATION: We report an exceptional case of MN associated to an acute renal failure occurring within days following an autologous HSCT indicated by multiple myeloma. There was no evidence of GVHD or myeloma relapse. A complete remission of nephrotic syndrome with normalization of renal function were rapidly obtained by corticosteroid therapy. CONCLUSION: This is the first published case of acute renal failure due to MN occurring in the acute phase of an autologous HSCT. These findings support the antibodymediated autoimmune glomerular disease. PMID- 29523090 TI - Health economic evaluations of non-pharmacological interventions for persons with dementia and their informal caregivers: a systematic review. AB - BACKGROUND: This systematic review aims to review the literature on trial-based economic evaluations of non-pharmacological interventions directly targeted at persons with dementia as well as persons with mild cognitive impairment and their respective caregivers. METHODS: A systematic literature research was conducted for the timeframe from 2010 to 2016 in the following databases: Centre for Reviews and Dissemination, EconLit, Embase, Cochrane Library, PsycINFO and PubMed. Study quality was assessed according to the Drummond criteria. RESULTS: In total sixteen publications were identified. Health economic evaluations indicated the cost-effectiveness of physical exercise interventions and occupational therapy. There was also evidence to suggest that psychological and behavioral therapies are cost-effective. Health economic studies investigating psychosocial interventions mainly targeted towards informal caregivers showed inconsistent results. CONCLUSIONS: Due to the increasing prevalence of dementia non-pharmacological interventions and their health economic impact are of increasing importance for health care decision-makers and HTA agencies. PMID- 29523093 TI - Continuous hypoxia reduces the concentration of streptomycin in the blood. AB - BACKGROUND: A high incidence and mortality of plague in the past two decades occurred in the Qinghai-Tibet Plateau, China. High dose streptomycin (6-8 g/d) remained the first practical strategy for controlling the progressive, vicious clinical circumstances for patients with pneumonic plague in the Plateau, as opposed to the routine dosage recommended by the World Health Organization. To investigate whether patients with pneumonic plague truly required a large dosage of streptomycin in the hypoxic environment of the Tibetan Plateau, we investigated the hypothesis that hypoxic environment would change the pharmacokinetics of streptomycin in vivo. METHODS: (1) We retrospectively analyzed the data of pneumonic plague patients administered streptomycin from January 1, 2000 to December 31, 2012 in these areas, which came from the database of the Qinghai Center for Disease Control; and (2) We used a persistent hypoxia chamber to simulate the plateau hypoxic environment and fed Sprague Dawley rats in the chambers for one month. Then, we continuously administered hypoxic rats a single loading dose (200 mg/kg) of streptomycin and analyzed its concentrations by high performance liquid chromatography. The pharmacokinetic profiles were analyzed using a non-compartmental method in the Phoenix WinNonlin program. RESULTS: (1) There were 32 cases of patients with pneumonic plague in the past two decades totally and 9 of them died (all-cause mortality 28.125%, 9/32), including 7 cases died of delayed diagnosis without treatment of streptomycin, and the only 2 patients received normal dose of streptomycin. (2) The pharmacokinetic behaviors of streptomycin were different between the hypoxic and normal rats. Administration in a hypoxic state resulted in 74.81% and 29.28% decreases in maximum plasma concentration and area under the concentration-time curve from time zero to infinity compared with those values under normal condition for streptomycin. CONCLUSIONS: These results indicated that hypoxic condition could significantly decrease the absorption rate and extent of streptomycin. Therefore, patients with pneumonic plague require higher doses of streptomycin to maintain effective drug concentrations in Qing Hai and the Tibetan Plateau. PMID- 29523092 TI - The role of the general practitioner in multidisciplinary teams: a qualitative study in elderly care. AB - BACKGROUND: In the western world, a growing number of the older people live at home. In the Netherlands, GPs are expected to play a pivotal role in the organization of integrated care for this patient group. However, little is known about how GPs can play this role best. Our aim for this study was to unravel how GPs can play a successful role in elderly care, in particular in multidisciplinary teams, and to define key concepts for success. METHODS: A mixed qualitative research model in four multidisciplinary teams for elderly care in the Netherlands was used. With these four teams, consisting of 46 health care and social service professionals, we carried out two rounds of focus-group interviews. Moreover, we performed semi-structured interviews with four GPs. We analysed data using a hybrid inductive/deductive thematic analysis. RESULTS: According to the health care and social service professionals in our study, the role of GPs in multidisciplinary teams for elderly care was characterized by the ability to 'see the bigger picture'. We identified five key activities that constitute a successful GP role: networking, facilitating, team building, integrating care elements, and showing leadership. Practice setting and phase of multidisciplinary team development influenced the way in which GPs fulfilled their roles. According to team members, GPs were the central professionals in care services for older people. The opinions of GPs about their own roles were diverse. CONCLUSIONS: GPs took an important role in successful care settings for older people. Five key concepts seemed to be important for best practices in care for frail older people: networking (community), facilitating (organization), team building (professional), integrating care elements (patient), and leadership (personal). Team members from primary care and social services indicated that GPs had an indispensable role in such teams. It would be advantageous for GPs to be aware of this attributed role. Attention to leadership competencies and to the diversity of roles in multidisciplinary teams in GP training programmes seems useful. The challenge is to convince GPs to take a lead, also when they are not inclined to take this role in organizing multidisciplinary teams for older people. PMID- 29523094 TI - Pediatric multiple sclerosis: a review. AB - BACKGROUND: Pediatric-onset multiple sclerosis (POMS) prevalence and incidence rates are increasing globally. No disease-modifying therapy are approved for MS pediatric population. Hence, we aim to review the literature on POMS to guide treating physicians on the current understanding of diagnosis and management of pediatric MS. METHODS: The authors performed a literature search and reviewed the current understanding on risk factors and disease parameters in order to discuss the challenges in assessing and implementing diagnosis and therapy in clinical practice. RESULTS: The revised International Pediatric MS group diagnostic criteria improved the accuracy of diagnosis. Identification of red flags and mimickers (e.g. acute disseminated encephalomyelitis and neuromyelitis optica) are vital before establishing a definitive diagnosis. Possible etiology and mechanisms including both environmental and genetic risk factors are highlighted. Pediatric MS patients tend to have active inflammatory disease course with a tendency to have brainstem / cerebellar presentations at onset. Due to efficient repair mechanisms at early life, pediatric MS patients tend to have longer time to reach EDSS 6 but reach it at earlier age. Although no therapeutic randomized clinical trials were conducted in pediatric cohorts, open-label multi-center studies reported efficacy and safety results with beta interferons, glatiramer acetate and natalizumab in similar adult cohorts. Several randomized clinical trials assessing the efficacy and safety of oral disease-modifying therapies are ongoing in pediatric MS patients. CONCLUSION: Pediatric MS has been increasingly recognized to have a more inflammatory course with frequent infratentorial presentations at onset, which would have important implications in the future management of pediatric cohorts while awaiting the results of ongoing clinical trials. PMID- 29523095 TI - The relationship between health literacy and patient activation among frequent users of healthcare services: a cross-sectional study. AB - BACKGROUND: Frequent users of healthcare services are a vulnerable population that deserves attention due to high costs and negative outcomes such as lower quality of life and higher mortality. Healthcare systems should offer interventions tailored to their needs and to their level of health literacy, including strategies to promote activation. The relationship between health literacy and patient activation remains to be explored. The aim of this study was to examine the association between health literacy and patient activation in a population of frequent users of healthcare services with chronic diseases. METHODS: Cross-sectional data were collected (before randomization) through a clinical trial evaluating a case management intervention in primary care. Participants (n = 247) were recruited from the list of frequent users of 4 Family Medicine Groups (FMG) in the Saguenay-Lac-St-Jean region of Quebec (Canada). They completed questionnaires by self-report during an encounter with a research assistant: (1) the Newest Vital Sign (NVS) to evaluate health literacy (independent variable); and (2) the Patient Activation Measure-13 (PAM-13) to evaluate patient activation (dependent variable). The relationship between health literacy and activation was examined using biserial correlations. RESULTS: No association was found between health literacy (independent variable) and patient activation (rb = 0.075, rho = 0.07) for this population of frequent users of healthcare services. CONCLUSIONS: This study suggests that there is no relationship between health literacy and patient activation among frequent users of healthcare services. TRIAL REGISTRATION: NCT01719991 . Registered October 25, 2012. PMID- 29523096 TI - Separation of functionally divergent muscle precursor cell populations from porcine juvenile muscles by discontinuous Percoll density gradient centrifugation. AB - BACKGROUND: Satellite cells (SC) and their descendants, muscle precursor cells (MPC), play a key role in postnatal muscle development, regeneration, and plasticity. Several studies have provided evidence that SC and MPC represent a heterogeneous population differing in their biochemical and functional properties. The identification and characterization of functionally divergent SC subpopulations should help to reveal the precise involvement of SC/MPC in these myogenic processes. The aim of the present work was therefore to separate SC subpopulations by using Percoll gradients and to characterize their myogenic marker profiles and their functional properties (adhesion, proliferation, and differentiation). RESULTS: SC/MPC from muscles of 4-day-old piglets were isolated by trypsin digestion and enriched by Percoll density gradient centrifugation. A mixed myogenic cell population was obtained from the 40/70% interface (termed: mixed P40/70) of a 25/40/70% Percoll gradient. Thereafter, by using a more stepped 25/40/50/70% Percoll gradient, mixed P40/70 was divided into subpopulation 40/50 (SP40/50) collected from the 40/50% interface and subpopulation 50/70 (SP50/70) collected from the 50/70% interface. All three isolated populations proliferated and showed a myogenic phenotype characterized by the ability to express myogenic markers (Pax7, MyoD1, Desmin, and MyoG) and to differentiate into myotubes. However, compared with mixed P40/70, SP40/50 and SP50/70 exhibited distinct functional behavior. Growth kinetic curves over 90 h obtained by the xCELLigence system and proliferation assays revealed that SP40/50 and mixed P40/70 constituted a fast adhering and fast proliferating phenotype. In contrast, SP50/70 showed considerably slower adhesion and proliferation. The fast proliferating SP40/50 showed the highest myogenic differentiation potential with higher fusion rates and the formation of more middle-sized and large myotubes. CONCLUSIONS: The described Percoll density gradient centrifugation represents a useful tool for subdividing pig SC/MPC populations with divergent myogenic functions. The physiological role of SC subpopulations during myogenesis and the interaction of these populations can now be analyzed to a greater extent, shedding light on postnatal growth variations in pigs and probably in other animals. PMID- 29523097 TI - A digital assessment system for evaluating kinetic tremor in essential tremor and Parkinson's disease. AB - BACKGROUND: Spiral drawing on papers is a common tremor evaluation tool for diagnosing patients with essential tremor (ET) or Parkinson's disease (PD). No standard drawing methods and parameters that use graphic tablets are yet available for objective evaluation. METHODS: This study established a tremor assessment system for tremor severity by using graphic tablets. Twelve patients with ET and twelve patients with PD were tested to establish system algorithms, and six additional patients were tested with the developed system to evaluate its performance. The patients also performed spiral drawing with three guiding paradigms on a graphic tablet: traced along a given spiral (S1), performed freehand drawing (S2), and traced along a guiding point (S3). Three parameters were calculated to quantify tremor severity: the means of radial difference per radian (|dr/dtheta|), the means of radial difference per second (|dr/dt|), and the area under curve (AUC) of the frequency spectrum of the velocity. Each patient's drawing was also evaluated using a visual rating scale (VRS) by experienced physicians. The interrater reliability was examined to identify the most consistent test paradigm. RESULTS: The parameter |dr/dtheta| and AUC correlated well with the VRS (R > 0.8) in S1, S2 and S3 tests. The S1 test presented the best interrater reliability (Weighted Kappa coefficient, k = 0.80) among three tests. The Weighted Kappa coefficients are 0.67 and 0.71 in S2 and S3 tests, respectively. CONCLUSIONS: We developed three different guiding paradigms for spiral drawing on a digital graphic tablet for clinical tests. Three parameters were calculated to represent the tremor severity in spiral drawing and used to quantify temporal and spatial characteristics of tremor, and provided good correlation with current clinical assessments. The test "traced along a given spiral" is recommended due to its good interrater reliability. PMID- 29523099 TI - Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report. AB - BACKGROUND: Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC or Hay-Wells syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis. CASE PRESENTATION: We describe a patient presenting clinical features reminiscent of AEC syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63, IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK; a maternally inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele. CONCLUSIONS: To our knowledge, this is the fourth family reported with CHUK-deficiency and the second patient with immune abnormalities. This is the first case of CHUK-deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo. In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described. PMID- 29523098 TI - Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study. AB - BACKGROUND: The aim of this study was to evaluate whether the glutathione S transferase M1 (GSTM1) and T1 (GSTT1) null alleles may contribute to carbamazepine-induced hepatotoxicity. METHODS: A cross-sectional prospective study was conducted to identify the frequency distribution of GSTM1 and GSTT1 alleles in 129 Tunisian epileptic patients treated with carbamazepine. Null alleles were determined using a Polymerase Chain Reaction. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by standard methods. RESULTS: Our results showed that the frequencies of GSTM1 (-) null allele and GSTT1 null (-) allele were 74.4 and 17.8% respectively. The ALT and AST levels were elevated in 46 (35.7%) and 33 (25.6%) cases. The mean values of ALT and AST were approximately 1.32 and 3.61 times higher than the upper limit of normal levels, respectively. The values of ALT and AST were significantly higher in GSTM1 (-) allele than in GSTM1 (+) (p = 10-3.and 0.004, respectively). The level of ALT was significantly higher in combination of GSTM1 (-)/T1(-) than in combined GSTM1(-)/T1(+) and combined GSTM1(+)/T1(+) (p = 0.2 and 0.03, respectively), and that of AST was significantly higher in combination of GSTM1( )/T1(-) and in combination of GSTM1(+)/T1(-) than in combination of GSTM1(+)/T1(+) (p = 10-3 and 10-3, respectively). CONCLUSIONS: Our findings suggest that the GSTM1 (-) allele may be considered as a key factor for the development of carbamazepine-induced hepatotoxicity. Results related to GSTT (-) allele and elevation in AST levels should be considered with caution as AST may be elevated in other pathophysiological conditions. PMID- 29523100 TI - Loss-to-follow-up and delay to treatment initiation in Pakistan's national tuberculosis control programme. AB - BACKGROUND: Researchers and policy-makers have identified loss to follow-up as a major programmatic problem. Therefore, the objective of this study is to quantify TB related pre-treatment loss to follow up and treatment delay in private sector health care facilities in Pakistan. METHODS: This was a retrospective, descriptive cohort study using routinely collected programmatic data from TB referral, diagnosis and treatment registers. Data from 48 private healthcare facilities were collected using an online questionnaire prepared in ODK Collect, for the period October 2015 to March 2016. Data were analysed using SPSS. We calculated the: (1) number and proportion of patients who were lost to follow-up during the diagnostic period, (2) number and proportion of patients with pre treatment loss to follow-up, and (3) the number of days between diagnosis and initiation of treatment. RESULTS: One thousand five hundred ninety-six persons with presumptive TB were referred to the laboratory. Of these, 96% (n = 1538) submitted an on-the-spot sputum sample. Of the 1538 people, 1462 (95%) people subsequently visited the laboratory to submit the early morning (i.e. the second) sample. Hence, loss to follow-up during the diagnostic process was 8% overall (n = 134). Of the 1462 people who submitted both sputum samples, 243 (17%) were diagnosed with sputum smear-positive pulmonary TB and 231 were registered for anti-TB treatment, hence, loss in the pre-treatment phase was 4.9% (n = 12). 152 persons with TB (66%) initiated TB treatment either on the day of TB diagnosis or the next day. A further 79 persons with TB (34%) commenced TB treatment within a mean time of 7 days (range 2 to 64 days). CONCLUSION: Concentrated efforts should be made by the National TB Control Programme to retain TB patients and innovative methods such as text reminders and behavior change communication may need to be used and tested. PMID- 29523101 TI - Comparison of accelerometer measured levels of physical activity and sedentary time between obese and non-obese children and adolescents: a systematic review. AB - BACKGROUND: Obesity has been hypothesized to be associated with reduced moderate to-vigorous physical activity (MVPA) and increased sedentary time (ST). It is important to assess whether, and the extent to which, levels of MVPA and ST are suboptimal among children and adolescents with obesity. The primary objective of this study was to examine accelerometer-measured time spent in MVPA and ST of children and adolescents with obesity, compared with MVPA recommendations, and with non-obese peers. METHODS: An extensive search was carried out in Medline, Cochrane library, EMBASE, SPORTDiscus, and CINAHL, from 2000 to 2015. Study selection and appraisal: studies with accelerometer-measured MVPA and/or ST (at least 3 days and 6 h/day) in free-living obese children and adolescents (0 to 19 years) were included. Study quality was assessed formally. Meta-analyses were planned for all outcomes but were precluded due to the high levels of heterogeneity across studies. Therefore, narrative syntheses were employed for all the outcomes. RESULTS: Out of 1503 records, 26 studies were eligible (n = 14,739 participants; n = 3523 with obesity); 6/26 studies involved children aged 0 to 9 years and 18/26 involved adolescents aged 10.1 to19 years. In the participants with obesity, the time spent in MVPA was consistently below the recommended 60 min/day and ST was generally high regardless of the participant's age and gender. Comparison with controls suggested that the time spent in MVPA was significantly lower in children and adolescents with obesity, though differences were relatively small. Levels of MVPA in the obese and non-obese were consistently below recommendations. There were no marked differences in ST between obese and non-obese peers. CONCLUSIONS: MVPA in children and adolescents with obesity tends to be well below international recommendations. Substantial effort is likely to be required to achieve the recommended levels of MVPA among obese individuals in obesity treatment interventions. This systematic review has been registered on PROSPERO (International Database of Prospective Register Systematic Reviews; registration number CRD42015026882). PMID- 29523102 TI - The role of community health workers and local leaders in reducing attrition among participant in the AIDS indicator survey and HIV incidence in a national cohort study in Rwanda. AB - BACKGROUND: Retention of participants in longitudinal prospective surveys can challenging for population health researchers. Community health workers (CHWs) may help reduce attrition. METHODS: We used data came from a longitudinal prospective household-based survey targeting women and men in Rwanda, collected between June 2013 and December 2014. The sample was drawn from a population that included all residents of all 30 districts, 416 sectors, and 14,837 villages in Rwanda. The outcome measure was time to loss-to-follow-up. Follow up visits occurred at three, six and nine, and 12 months. A Cox proportional hazards model was constructed to identify factors independently associated with time to loss-to follow-up. RESULTS: Overall, 14,222 respondents consented to be interviewed at baseline. At the end of 12 months of follow up, 13,728 were revisited and consented to participate at 12 months of follow up. The overall attrition rate was 8.0%. A majority of those lost (54.3%) were less than 25 years of age, male (55.1%), not living in union (67.3%), had no education level or had primary education level (71.4%), or were in the highest wealth index (54.2%). Compared to illiterate, secondary education was negatively associated with attrition. CONCLUSION: The Rwanda AIDS indicator and HIV incidence survey recorded a very high retention of participants after 12 months. CHWs and local leaders played a major role to reduce attrition rate and identifying factors associated with loss to-follow-up can help CHWs strengthen the quality of longitudinal survey data. PMID- 29523103 TI - Androgen deprivation therapy during and after post-prostatectomy radiotherapy in patients with prostate cancer: a case control study. AB - BACKGROUND: Here we assessed the influence of androgen deprivation therapy (ADT) during and/or after post-prostatectomy radiotherapy (RT) on biochemical recurrence (BCR) and radiographic progression in patients with prostate cancer. METHODS: Patients with prostate cancer who underwent post-prostatectomy RT were analyzed. BCR and radiographic progression after RT were compared according to the concurrent or salvage ADT. Cox regression analyses were used to identify risk factors for BCR and radiographic progression. RESULTS: Of the 227 patients who underwent post-prostatectomy RT, 95 (41.9%) received concurrent ADT for a median of 17.0 months. Despite more aggressive disease characteristics in the concurrent ADT group than in the RT-only group, the former had a better 5-year BCR-free survival rate than the latter (66.1 vs. 53.9%; p = 0.016), whereas the radiographic progression rate was not significantly different between two groups. On the other hand, salvage ADT after post-RT BCR significantly delayed radiographic progression (5-year radiographic progression-free survival; 75.2 vs. 44.5%; p = 0.002). CONCLUSIONS: Concurrent ADT improved BCR-free survival, and salvage ADT after post-RT BCR improved radiographic progression-free survival. To maximize the oncological benefit, ADT of sufficient duration should be implemented. PMID- 29523104 TI - Prognostic models for complete recovery in ischemic stroke: a systematic review and meta-analysis. AB - BACKGROUND: Prognostic models have been increasingly developed to predict complete recovery in ischemic stroke. However, questions arise about the performance characteristics of these models. The aim of this study was to systematically review and synthesize performance of existing prognostic models for complete recovery in ischemic stroke. METHODS: We searched journal publications indexed in PUBMED, SCOPUS, CENTRAL, ISI Web of Science and OVID MEDLINE from inception until 4 December, 2017, for studies designed to develop and/or validate prognostic models for predicting complete recovery in ischemic stroke patients. Two reviewers independently examined titles and abstracts, and assessed whether each study met the pre-defined inclusion criteria and also independently extracted information about model development and performance. We evaluated validation of the models by medians of the area under the receiver operating characteristic curve (AUC) or c-statistic and calibration performance. We used a random-effects meta-analysis to pool AUC values. RESULTS: We included 10 studies with 23 models developed from elderly patients with a moderately severe ischemic stroke, mainly in three high income countries. Sample sizes for each study ranged from 75 to 4441. Logistic regression was the only analytical strategy used to develop the models. The number of various predictors varied from one to 11. Internal validation was performed in 12 models with a median AUC of 0.80 (95% CI 0.73 to 0.84). One model reported good calibration. Nine models reported external validation with a median AUC of 0.80 (95% CI 0.76 to 0.82). Four models showed good discrimination and calibration on external validation. The pooled AUC of the two validation models of the same developed model was 0.78 (95% CI 0.71 to 0.85). CONCLUSIONS: The performance of the 23 models found in the systematic review varied from fair to good in terms of internal and external validation. Further models should be developed with internal and external validation in low and middle income countries. PMID- 29523105 TI - Monoclonal immunoglobulin heavy chain gene rearrangement in Fuchs' uveitis. AB - BACKGROUND: Fuchs' uveitis (FU) is occasionarlly complicated with heavy vitreous opacity. We have performed vitrectomy procedures to remove vitreous opacity in affected patients as part of differential diagnosis for primary vitreoretinal lymphoma (PVRL). CASE PRESENTATION: We retrospectively reviewed the clinical records of five patients who first visited the Uveitis Clinic of the University of Tokyo Hospital between 2009 and 2013, were diagnosed with FU and underwent a vitrectomy for removal of dense vitreous opacity. All were diagnosed as FU by ocular findings and elevation of Goldmann-Witmer coefficient (GWC) value for the rubella virus (RV) antibody. In examinations of the vitreous body, cytological diagnosis, elevation of IL-10/IL-6 ratio, and the kappa/lambda ratio in flow cytometry findings were negative in all cases, whereas monoclonal immunoglobulin heavy chain (IgH) gene rearrangement was positive in 4 cases and negative in 1 case. CONCLUSIONS: Although monoclonal IgH gene rearrangement is thought to be a reliable biomarker for PVRL, a high percentage of vitreous specimens from our FU patients showed pseudo-positive results. Ophthalmologists must take care regarding possible pseudo-positive findings when performing differential diagnosis between FU and PVRL. Combinations of results of cytological diagnosis, IL-10/IL-6 ratio, kappa/lambda ratio, and IgH gene rearrangement may be necessary for a definitive diagnosis of PVRL and differentiation from FU. PMID- 29523106 TI - One-year follow-up of accelerated transepithelial corneal collagen cross-linking for progressive pediatric keratoconus. AB - BACKGROUND: Keratoconus typically presents in the teenage years and is more advanced in younger patients when compared with adults. In the present study, we aimed to assess the safety and efficacy of accelerated transepithelial corneal collagen cross-linking (ATE-CXL) in children with progressive keratoconus. METHODS: In this retrospective consecutive study, 18 eyes were enrolled from 17 pediatric patients (15 boys and 2 girls) with a mean age of 14.44 +/- 1.98 years. Manifest refraction, best-corrected visual acuity (BCVA), steepest meridian keratometry (K1), flattest meridian keratometry (K2), maximum keratometry (Kmax), thinnest corneal thickness (TCT), posterior central elevation (PCE), and posterior mean elevation (PME) were measured before and after ATE-CXL. The patients were followed-up at 1, 6, and 12 months. Repeated measures analysis of variance was used for statistical analysis. P < 0.05 was considered statistically significant. RESULTS: There were no complications in any case during or after ATE CXL. BCVA improved from 0.64 +/- 0.32 preoperatively to 0.69 +/- 0.32 at 1-year postoperatively. The Kmax value was 56.67 +/- 9.60 D before the treatment and 56.19 +/- 8.55 D, 56.08 +/- 8.85 D, and 55.94 +/- 8.46 D at 1, 6, and 12 months postoperatively, respectively. No statistically significant differences were present in K1, K2, Kmax, PCE, and TCT before and after ATE-CXL during the 12 month follow-up (P > 0.05). CONCLUSIONS: ATE-CXL is a safe and effective treatment in pediatric progressive keratoconus patients. The long-term effects need further observation. TRIAL REGISTRATION: Retrospectively registered. Registration number: ChiCTR-OIC-16008181 . Registered 29 March 2016. PMID- 29523107 TI - Phenolic compounds as antioxidants and chemopreventive drugs from Streptomyces cellulosae strain TES17 isolated from rhizosphere of Camellia sinensis. AB - BACKGROUND: Oxidative stress in an intracellular environment created by the accumulation of reactive oxygen species results in oxidative damage to biomolecules which ultimately become a hallmark for severe diseases like cancer, aging, diabetes, and cardiovascular and neurodegenerative diseases. METHODS: Various in vitro assays were employed to assess the antioxidant potential of strain, DNA protective activity was demonstrated using DNA nicking assay and cytotoxicity of the extract was evaluated using MTT assay. Further identification of the compounds was done using UPLC analysis. RESULTS: The extract of Streptomyces cellulosae strain TES17 demonstrated significant antioxidant activity with percentage inhibition of 78.47 +/- 0.23, 91.08 +/- 0.98 and 82.08 +/- 0.93 for DPPH, ABTS and superoxide radical assays at 5 mg/mL, respectively. Total antioxidant and reducing power were found to be 76.93 +/- 0.76 and 231.96 +/- 0.51 mg AAE/100 mg of dry extract, respectively. Moreover, the extract was shown to inhibit lipid peroxidation upto 67.18 +/- 1.9% at 5 mg/mL. TPC and TFC measured in the extract was 55 mg GAE/100 mg and 11.17 +/- 4.05 mg rutin/100 mg, respectively. The protective nature of the TES17 extract to oxidative stress induced damaged DNA was shown by percentage of supercoiled DNA i.e. Form I was increased from 26.38 to 38.20% at concentrations ranging from 2 MUg to 10 MUg. TES17 extract also showed the cytotoxic activity against lung cancer cell line with 74.7 +/- 1.33% inhibition whereas, limited toxicity was observed against normal cell line with percentage viability of 87.71 +/- 6.66 at same concentration (30 MUg/mL) tested. The antioxidant capacity of extract was well correlated with its TPC and TFC and this in turn was in keeping with the UPLC analysis which also revealed the presence of phenolic compounds that were responsible for the antioxidant and cytotoxic potential of S. cellulosae strain TES17. CONCLUSIONS: The present study describes that S. cellulosae strain TES17 isolated from the rhizosphere of Camellia sinensis (tea) plant; produces potent compounds with antioxidant activity, further might be developed into therapeutic drugs to combat oxidative stress. PMID- 29523108 TI - Preventing cervical cancer using HPV self-sampling: direct mailing of test-kits increases screening participation more than timely opt-in procedures - a randomized controlled trial. AB - BACKGROUND: Cervical cancer screening participation remains insufficient in most countries. Our aim was to evaluate whether offering a HPV self-sampling kit, either mailed directly to the woman's home or using timely opt-in procedures for ordering the kit, increased screening participation compared with a standard second reminder. METHODS: In this randomized, controlled effectiveness trial, 9791 Danish women aged 30-64 who were due to receive the second reminder were equally randomized to either: 1) direct mailing of a second reminder and a self sampling kit (directly mailed group); 2) mailing of a second reminder that offered a self-sampling kit to be ordered by e-mail, text message, phone, or webpage (opt-in group); or 3) mailing of a second reminder to attend regular cytology screening (control group). In an intention-to-treat analysis, we estimated the participation rate at 180 days post intervention, by returning a self-sample or attending regular cytology screening. We calculated the proportion of women with a positive HPV self-sample who attended for cervical cytology triage at the general practitioner within 90 days. RESULTS: Participation was significantly higher in the directly mailed group (38.0%) and in the opt-in group (30.9%) than in the control group (25.2%) (participation difference (PD): 12.8%, 95% CI: 10.6-15.0% and PD: 5.7%, 95% CI: 3.5-7.9%, respectively). Within 90 days, 107 women (90.7%, 95% CI: 83.9-95.3%) with a HPV-positive self-sample attended follow-up. CONCLUSIONS: Offering the opportunity of HPV self-sampling as an alternative to regular cytology screening increased participation; the direct mailing strategy was the most effective invitation strategy. A high compliance with follow-up was seen. TRIAL REGISTRATION: Current Controlled Trials NCT02680262 . Registered 10 February 2016. PMID- 29523109 TI - Extract from Astragalus membranaceus inhibit breast cancer cells proliferation via PI3K/AKT/mTOR signaling pathway. AB - BACKGROUND: Astragalus membranaceus (AM) is a commonly used herb in traditional Chinese medicine (TCM), which has been used as an essential tonic to treat various diseases for more than 2000 years. In this study, we aimed to investigate the biological effects of extract from AM on breast cancer cell and its mechanism. METHODS: To prepare the extract, dried AM were ground and extracted with water extraction-ethanol supernatant method. Then the main isoflavones in the extract was detect by HPLC analysis. Furthermore, the anti-proliferative activity of AM extract was examined by MTT assay and morphological observation. Cell apoptosis was evaluated with flow cytometric analysis. The expressions of total and phosphorylated PI3K, GS3Kbeta, Akt and mTOR were determined by western blot analysis. RESULTS: HPLC analysis demonstrated that AM extract contained with four kinds of isoflavones, campanulin, ononin, calycosin and formononetin. The MTT test and morphological observation indicated that cells proliferation of MCF 7, SK-BR-3 and MDA-MB-231were inhibited by AM extract in a dose dependent manner. Furthermore, flow cytometric analysis displayed that after treated with 25 MUg/ml and 50 MUg/ml AM extract, apoptosis of breast cancer cells was significantly increased as compared with DMSO and blank control group (all p < 0.05). Western blot analysis found that the level of p-PI3K, p-GS3Kbeta, p-Akt, and p-mTOR were significantly decreased, but the level of total-mTOR was observably increased as compared with DMSO control group. CONCLUSIONS: Taken together, the inhibited cell proliferation and induced cell apoptosis effect of AM extract via PI3K/AKT/mTOR pathway confirmed the anti-tumor potential of AM. Therefore, our findings provide a new insight into anti-cancer effect of AM extract as a promising agent in breast cancer treatment. PMID- 29523110 TI - CD31 and VEGF are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma. AB - BACKGROUND: Patients suffering from squamous cell carcinoma of the larynx (LSCC) with lymphatic metastasis have a relatively poor prognosis and often require radical therapeutic management. The mechanisms which drive metastasis to the lymph nodes are largely unknown but may be promoted by a pro-angiogenic tumor microenvironment. In this study, we examined whether the number of microvessels and the expression level of vascular endothelial growth factor (VEGF) in the primary tumor are correlated with the degree of lymph node metastasis (N-stage), tumor staging (T) and survival time in LSCC patients. METHODS: Tissue-Microarrays of 97 LSCC patients were analyzed using immunohistochemistry. The expression of VEGF was scored as intensity of staining (low vs high) and the number of CD31 positive vessels (median =7 vessels per visual field) was counted manually. Scores were correlated with N-stage, T-stage and 5-year overall survival rate. RESULTS: A high expression of angiogenic biomarkers was not associated with poor overall survival in the overall cohort of patients. Instead high CD31 count was associated with early stage cancer (p = 0.004) and in this subgroup high VEGF expression correlated with poor survival (p = 0.032). Additionally, in early stage cancer a high vessel count was associated with an increased recurrence rate (p = 0.004). CONCLUSION: Only in the early stage subgroup a high expression of angiogenic biomarkers was associated with reduced survival and an increased rate of recurrence. Thus, biomarkers of angiogenesis may be useful to identify high risk patients specifically in early stage LSCC. PMID- 29523111 TI - Crude extract and fractions from Eugenia uniflora Linn leaves showed anti inflammatory, antioxidant, and antibacterial activities. AB - BACKGROUND: This study showed phytochemical composition and evaluates the anti inflammatory, and analgesic activities of crude extract (CE) and fractions from E. uniflora Linn leaves. METHODS: Polyphenols present in crude extract (CE), in aqueous fraction (AqF), and ethyl acetate (EAF) treated fractions from E. uniflora Linn leaves were shown by chromatographic analysis in order to conduct a phytochemical characterization. Antibacterial activity was evaluated based on minimum inhibitory concentrations (MICs) determined using the agar dilution method. Doses of 50, 100, and 200 mg/kg of the CE and fractions were applied for conducting in vivo models (male Swiss mice, 8-10 weeks old). The peritonitis experimental model was induced by carrageenan following of Myeloperoxidase activity (MPO), Total glutathione and malondialdehyde (MDA), IL-1beta and TNF alpha levels by spectroscopic UV/VIS analysis. Antinociceptive activity was evaluated based on an abdominal writhing model and hot plate test. The results were statistically evaluated using one-way analysis of variance (ANOVA), followed by Bonferroni's post-hoc test. The level of statistical significance was p < 0.05. RESULTS: High-performance liquid chromatography with photodiode array detection (HPLC-DAD) detected varying concentrations of gallic acid, ellagic acid, and myricitrin in the CE and fractions obtained from E. uniflora Linn leaves (0.05-0.87%w/w, 0.20-0.32%w/w, and 1.71-6.56%w/w, respectively). In general, the CE had lower MIC values than the fractions, including the lowest MIC against the MRSA strain. The CE and AqF also significantly reduced leukocyte migration and MPO activity (p < 0.05). In addition, AqF significantly reduced IL 1beta and TNF-alpha levels (p < 0.05). Furthermore, the CE and fractions exhibited an antioxidant effect (p < 0.05) and peripheral analgesic activity (p < 0.05). CONCLUSIONS: The CE and fractions from the studied E. uniflora Linn leaves exhibited antibacterial, anti-inflammatory, antioxidant, and analgesic activity in the performed assays. PMID- 29523112 TI - Do hypoxia and L-mimosine modulate sclerostin and dickkopf-1 production in human dental pulp-derived cells? Insights from monolayer, spheroid and tooth slice cultures. AB - BACKGROUND: To understand the responses of the dental pulp to hypoxia is of high relevance for regenerative endodontics and dental traumatology. Here, we aimed to reveal the effects of hypoxia and the hypoxia mimetic agent L-mimosine (L-MIM) on the production of sclerostin (SOST) and dickkopf-1 (DKK-1) in human dental pulp derived cells (DPC). METHODS: DPC in monolayer, spheroid and tooth slice cultures were treated with L-MIM or hypoxia. Resazurin-based toxicity and MTT assays were performed to determine cell viability. mRNA and protein levels of SOST and DKK-1 were measured with quantitative reverse transcription PCR and ELISA, respectively. To validate the hypoxia-like response, SDF-1, VEGF and IL-8 were assessed. In addition Western blots for HIF-1alpha, HIF-2alpha and HIF-3alpha were done. RESULTS: Cells were vital upon treatment procedures and showed increased levels of HIF-1alpha, and HIF-2alpha. In monolayer cultures, mRNA levels of SOST and DKK-1 were downregulated by L-MIM and hypoxia, respectively. A significant downregulation of SOST by hypoxia was found at the protein level compared to untreated cells while the effect on DKK-1 and the impact of L-MIM on SOST and DKK-1 did not reach the level of significance at the protein level. In spheroid cultures, mRNA levels of SOST and DKK-1 were downregulated by L-MIM. A significant downregulation of DKK-1 upon hypoxia treatment was found at the protein level while the impact of hypoxia on SOST and the effect of L-MIM on SOST and DKK-1 did not reach the level of significance. SOST and DKK-1 were also produced in tooth slices, but no pronounced modulation by L-MIM or hypoxia was found. Evaluation of SDF-1, VEGF and IL-8 showed a hypoxia-like response in the culture models. CONCLUSIONS: There is no pronounced influence of hypoxia and L MIM on DPC viability, SOST and DKK-1 protein production. However, the specific response depends on the culture model and the level of evaluation (mRNA or protein). These results deepen our understanding about the role of hypoxia and the potential impacts of hypoxia-based strategies on dental pulp. PMID- 29523113 TI - School sociodemographic characteristics and obesity in schoolchildren: does the obesity definition matter? AB - BACKGROUND: Existing evidence on the role of sociodemographic variables as risk factors for overweight and obesity in school-aged children is inconsistent. Furthermore, findings seem to be influenced by the obesity definition applied. Therefore, this study aimed to investigate if school sociodemographic indicators were associated with weight status in Irish primary schoolchildren and whether this association was sensitive to different obesity classification systems. METHODS: A nationally representative cross-sectional sample of 7542 Irish children (53.9% girls), mean age 10.4 (+/-1.2SD) years, participating in the Childhood Obesity Surveillance Initiative in the 2010, 2012/2013 or 2015/2016 waves were included. Height, weight and waist circumference were objectively measured. Five definitions of obesity were employed using different approaches for either body mass index (BMI) or abdominal obesity. Associations between overweight and obesity and sociodemographic variables were investigated using adjusted multilevel logistic regression analyses. RESULTS: Children attending disadvantaged schools were more likely to be overweight and obese than their peers attending non-disadvantaged schools, regardless of the obesity classification system used. Associations remained significant for the BMI-based obesity definitions when the sample was stratified by sex and age group, except for boys aged 8-10.5 years. Only boys aged >=10.5 years in disadvantaged schools had higher odds of abdominal obesity (UK 1990 waist circumference growth charts: OR = 1.56, 95%CI = 1.09-2.24; waist-to-height ratio: OR = 1.78, 95%CI = 1.14 2.79) than those in non-disadvantaged schools. No associations were observed for school urbanisation level. CONCLUSIONS: School socioeconomic status was a strong determinant of overweight and obesity in Irish schoolchildren, and these associations were age- and sex-dependent. School location was not associated with overweight or obesity. There remains a need to intervene with school-aged children in disadvantaged schools, specifically among those approaching adolescence, to prevent a trajectory of obesity into adult life. PMID- 29523114 TI - Preferences for befriending schemes: a survey of patients with severe mental illness. AB - BACKGROUND: Befriending has become a widely used method for tackling social isolation in individuals with severe mental illness (SMI), and evidence exists to support its effectiveness. However, patient preferences for befriending remain unclear. We aimed to determine whether patients with SMI want a volunteer befriender and, if so, the volunteer characteristics and character of the relationship they would prefer. METHODS: A survey of outpatients was conducted across London-based community mental health teams, for individuals diagnosed with affective or psychotic disorders. Questions consisted of measures of demographic characteristics, befriending preferences and social context, including measures of time spent in activities, number of social contacts, loneliness and subjective quality of life (SQOL). Binary logistic regressions were used to investigate potential predictors of willingness to participate in befriending. RESULTS: The sample comprised of 201 participants with a mean age of 43 years. The majority (58%) of the sample indicated willingness to participate in befriending. In univariable analyses this was associated with less time spent in activities in the previous week, higher level of loneliness and lower SQOL. When all three variables were tested as predictors in a multivariable analysis, only lower SQOL remained significantly associated with willingness to take part in befriending. Relative to other options presented, large proportions of participants indicated preference for weekly (44%), 1-hour (39%) meetings with a befriender, with no limits on the relationship duration (53%). Otherwise, patient preferences exhibited great variability in relation to other characteristics of befriending schemes. CONCLUSIONS: A substantial number of patients with SMI appear willing to take part in a befriending scheme. Patients with lower SQOL are more likely to accept befriending, so that befriending schemes may be a realistic option to help patients with particularly low SQOL. The large variability in preferences for different types of befriending suggests that there is no one-size-fits-all formula and that schemes may have to be flexible and accommodate different individual preferences. PMID- 29523115 TI - Testosterone and androstanediol glucuronide among men in NHANES III. AB - BACKGROUND: Most of the androgen replacement therapies were based on serum testosterone and without measurements of total androgen activities. Whether those with low testosterone also have low levels of androgen activity is largely unknown. We hence examined the association between testosterone and androstanediol glucuronide (AG), a reliable measure of androgen activity, in a nationally representative sample of US men. METHODS: Cross-sectional analysis was based on 1493 men from the Third National Health and Nutrition examination Survey (NHANES III) conducted from 1988 to 1991. Serum testosterone and AG were measured by immunoassay. Kernel density was used to estimate the average density of serum AG concentrations by quartiles of testosterone. RESULTS: Testosterone was weakly and positively correlated with AG (correlation coefficient = 0.18). The kernel density estimates show that the distributions are quite similar between the quartiles of testosterone. After adjustment for age, the distributions of AG in quartiles of testosterone did not change. The correlation between testosterone and AG was stronger in men with younger age, lower body mass index, non-smoking and good self-rated health and health status. CONCLUSIONS: Serum testosterone is weakly correlated with total androgen activities, and the correlation is even weaker for those with poor self-rated health. Our results suggest that measurement of total androgen activity in addition to testosterone is necessary in clinical practice, especially before administration of androgen replacement therapy. PMID- 29523116 TI - NSCLC molecular testing in Central and Eastern European countries. AB - BACKGROUND: The introduction of targeted treatments for subsets of non-small cell lung cancer (NSCLC) has highlighted the importance of accurate molecular diagnosis to determine if an actionable genetic alteration is present. Few data are available for Central and Eastern Europe (CEE) on mutation rates, testing rates, and compliance with testing guidelines. METHODS: A questionnaire about molecular testing and NSCLC management was distributed to relevant specialists in nine CEE countries, and pathologists were asked to provide the results of EGFR and ALK testing over a 1-year period. RESULTS: A very high proportion of lung cancer cases are confirmed histologically/cytologically (75-100%), and molecular testing of NSCLC samples has been established in all evaluated CEE countries in 2014. Most countries follow national or international guidelines on which patients to test for EGFR mutations and ALK rearrangements. In most centers at that time, testing was undertaken on request of the clinician rather than on the preferred reflex basis. Immunohistochemistry, followed by fluorescent in situ hybridization confirmation of positive cases, has been widely adopted for ALK testing in the region. Limited reimbursement is a significant barrier to molecular testing in the region and a disincentive to reflex testing. Multidisciplinary tumor boards are established in most of the countries and centers, with 75-100% of cases being discussed at a multidisciplinary tumor board at specialized centers. CONCLUSIONS: Molecular testing is established throughout the CEE region, but improved and unbiased reimbursement remains a major challenge for the future. Increasing the number of patients reviewed by multidisciplinary boards outside of major centers and access to targeted therapy based on the result of molecular testing are other major challenges. PMID- 29523117 TI - Prevalence of and characteristics associated with insomnia and obstructive sleep apnea among veterans with knee and hip osteoarthritis. AB - BACKGROUND: Few studies have examined patterns of specific sleep problems among individuals with osteoarthritis (OA). The primary objective of this study was to examine prevalence of symptoms of insomnia and obstructive sleep apnea (OSA) among Veterans with OA. Secondary objectives were to assess proportions of individuals with insomnia and OSA symptoms who may have been undiagnosed and to examine Veterans' characteristics associated with insomnia and OSA symptoms. METHODS: Veterans (n = 300) enrolled in a clinical trial completed the Insomnia Severity Index (ISI) and the Berlin Questionnaire (BQ) at baseline; proportions of participants with symptoms consistent with insomnia and OSA were calculated, using standard cut-offs for ISI and BQ. For Veterans with insomnia and OSA symptoms, electronic medical records were searched to identify whether there was a diagnosis code for these conditions. Multivariable linear (ISI) and logistic (BQ) regression models examined associations of the following characteristics with symptoms of insomnia and OSA: age, gender, race, self-reported general health, body mass index (BMI), diagnosis of post-traumatic stress disorder (PTSD), pain severity, depressive symptoms, number of joints with arthritis symptoms and opioid use. RESULTS: Symptoms consistent with insomnia and OSA were found in 53 and 66% of this sample, respectively. Among participants screening positive for insomnia and OSA, diagnosis codes for these disorders were present in the electronic medical record for 22 and 51%, respectively. Characteristics associated with insomnia were lower age (beta (SE) = - 0.09 (0.04), 95% confidence interval [CI] = - 0.16, - 0.02), having a PTSD diagnosis (beta (SE) = 1.68 (0.73), CI = 0.25, 3.11), greater pain severity (beta (SE) = 0.36 (0.09), CI = 0.17, 0.55), and greater depressive symptoms (beta (SE) = 0.84 (0.07), CI = 0.70, 0.98). Characteristics associated with OSA were higher BMI (odds ratio [OR] = 1.13, CI = 1.06, 1.21), greater depressive symptoms (OR = 1.12, CI = 1.05, 1.20), and opioid use (OR = 0.51, CI = 0.26, 0.99). CONCLUSIONS: Insomnia and OSA symptoms were very common in Veterans with OA, and a substantial proportion of individuals with symptoms may have been undiagnosed. Characteristics associated with insomnia and OSA symptoms were consistent with prior studies. TRIAL REGISTRATION: NCT01130740 . PMID- 29523118 TI - Clinical utility of a non-invasive urine test for risk assessing patients with no obvious benign cause of hematuria: a physician-patient real world data analysis. AB - BACKGROUND: The non-invasive Cxbladder urine test system has demonstrated clinical utility in ruling out urothelial carcinoma (UC) in patients with asymptomatic microscopic hematuria (AMH), suggesting that the number of invasive diagnostic tests, including cystoscopy, used in this patient population may be reduced by Cxbladder testing prior to conducting a full urological work-up. The aim of this study was to demonstrate the enhanced clinical utility of communicating objective information on diagnostic decisions made by individual physicians on individual patients with AMH. METHODS: Three hundred ninety-six physician-patient decisions were generated from twelve participant physicians evaluating real world case notes from the same 33 patients presenting with AMH. Each physician reviewed and recommended diagnostic tests and procedures based on each patient's referral data and then re-evaluated their clinical recommendation following disclosure of the non-invasive Cxbladder urine test result. Changes assessed were the total number of requested diagnostic procedures and the number of invasive procedures, including cystoscopy, following addition of information from Cxbladder in the Triage and Triage and Detect modalities. RESULTS: Physicians made significant changes to their diagnostic behavior for patients with AMH when presented with Cxbladder test results, including a reduction in the number of total and invasive procedures including cystoscopy for individuals identified as having a low probability of UC. The intensity of investigation was targeted and increased, including use of total procedures and cystoscopy, for patients identified by Cxbladder tests as having a high probability of UC: urologists increased the level of investigation for both total procedures and invasive procedures. The outcome resulted in patients with a high risk of UC receiving appropriate guideline-recommended invasive diagnostic tests. Patients who tested negative were offered fewer and significantly less invasive procedures. This change in physician behavior results in an increased clinical and patient utility, lower risk of missed UC and invasive test-related harm incidents. CONCLUSIONS: This study demonstrated the potential for increased clinical resolution and significantly enhanced patient management, when physicians consider Cxbladder test results in their clinical evaluation. The change in physician behavior led to more appropriate diagnostic procedure selection and resource allocation to the benefit of both patients and healthcare systems. PMID- 29523119 TI - Comparison of mesenchymal stem cells obtained by suspended culture of synovium from patients with rheumatoid arthritis and osteoarthritis. AB - BACKGROUND: Mobilization of mesenchymal stem cells (MSCs) from the synovium was revealed using a "suspended synovium culture model" of osteoarthritis (OA). The pathology of rheumatoid arthritis (RA) differs from that of OA. We investigated whether mobilization of MSCs from the synovium also occurred in RA, and we compared the properties of synovial MSCs collected from suspended synovium culture models of RA and OA. METHODS: Human synovium was harvested during total knee arthroplasty from the knee joints of patients with RA (n = 8) and OA (n = 6). The synovium was suspended in a bottle containing culture medium and a culture dish at the bottom. Cells were harvested from the dish and analyzed. RESULTS: No significant difference was observed between RA and OA in the harvested cell numbers per g of synovium. However, the variation in the number of cells harvested from each donor was greater for RA than for OA. The harvested cells were multipotent and no difference was observed in the cartilage pellet weight between RA and OA. The surface epitopes of the cells in RA and OA were similar to those of MSCs. CONCLUSION: Mobilization of MSCs from the synovium was demonstrated using a suspended synovium culture model for RA. The harvested cell numbers, chondrogenic potentials, and surface epitope profiles were comparable between the RA and OA models. PMID- 29523120 TI - Prevalence and correlates of herbal medicine use among type 2 diabetic patients in Teaching Hospital in Ethiopia: a cross-sectional study. AB - BACKGROUND: Type 2 Diabetes Mellitus (T2DM) patients are increasingly using herbal remedies due to the fact that sticking to the therapeutic regimens is becoming awkward. However, studies towards herbal medicine use by diabetic patients is scarce in Ethiopia. Therefore, the aim of the current study was to explore the prevalence and correlates of herbal medicine use with different sociodemographic variables among type 2 diabetes patients visiting the diabetic follow-up clinic of University of Gondar comprehensive specialized hospital (UOGCSH), Ethiopia. METHODS: A hospital-based cross sectional study was employed on 387 T2DM patients visiting the diabetes illness follow-up care clinic of UOGCSH from October 1 to November 30, 2016. An interviewer-administered questionnaire regarding the demographic and disease characteristics as well as herbal medicine use was completed by the study subjects. Descriptive, univariate and multivariate logistic regression statistics were performed to determine prevalence and come up with correlates of herbal medicine use. RESULTS: From 387 participants, 62% were reported to be herbal medicine users. The most prevalent herbal preparations used were Garlic (Allium sativum L.) (41.7%), Giesilla (Caylusea abyssinica (fresen.) (39.6%), Tinjute (Otostegia integrifolia Benth) (27.2%), and Kosso (Hagenia abyssinicaa) (26.9%). Most of herbal medicine users (87.1%) didn't consult their physicians about their herbal medicine use. Families and friends (51.9%) were the frontline sources of information about herbal medicine followed by other DM patients who used herbal medicines (28.9%). CONCLUSIONS: The present study revealed a high rate of herbal medicine use along with a very low rate use disclosure to the health care professionals. Higher educational status, a family history of DM, duration of T2DM and presence of DM complications were identified to be strong predictors of herbal medicine use. From the stand point of high prevalence and low disclosure rate, it is imperative for health care providers to strongly consult patients regarding herbal medicine use. PMID- 29523121 TI - Caesarean section rate and cost control effectiveness of case payment reform in the new cooperative medical scheme for delivery: evidence from Xi County, China. AB - BACKGROUND: In China, increases in both the caesarean section (CS) rates and delivery costs have raised questions regarding the reform of the medical insurance payment system. Case payment is useful for regulating the behaviour of health providers and for controlling the CS rates and excessive increases in medical expenses. New Cooperative Medical Scheme (NCMS) agencies in Xi County in Henan Province piloted a case payment reform (CPR) in delivery for inpatients. We aimed to observe the changes in the CS rates, compare the changes in delivery related variables, and identify variables related to delivery costs before and after the CPR in Xi County. METHODS: Overall, 28,314 cases were selected from the Xi County NCMS agency from 2009 to 2010 and from 2014 to 2015. One-way ANOVA and chi-square tests were used to compare the distributions of CS and vaginal delivery (VD) before and after the CPR under different indicators. We applied multivariate linear regressions for the total medical cost of the VD and CS groups and total samples to identify the relationships between medical expenses and variables. RESULTS: The CS rates in Xi County increased from 26.1% to 32.5% after the CPR. The length of stay (LOS), total medical cost, and proportion of county hospitals increased in the CS and VD groups after the CPR, which had significant differences. The total medical cost in the CS and VD groups as well as the total samples was significantly influenced by inpatient age, LOS, and hospital type, and had a significant correlation with the CPR in the VD group and the total samples. CONCLUSION: The CPR might fail to control the growth of unreasonable medical expenses and regulate the behaviour of providers, which possibly resulted from the unreasonable compensation standard of case payments, prolonged LOS, and the increasing proportion of county hospitals. The NCMS should modify the case payment standard of delivery to inhibit providers' motivation to render CS services. The LOS should be controlled by implementing clinical guidelines, and a reference system should be established to guide patients in choosing reasonable hospitals. PMID- 29523122 TI - Modified Essex-Lopresti procedure with percutaneous calcaneoplasty for comminuted intra-articular calcaneal fractures: a retrospective case analysis. AB - BACKGROUND: The ideal treatment for comminuted intraarticular calcaneal fractures is still debated. Open reduction and internal fixation (ORIF) is the most popular surgical procedure; however, wound complications, implant choice, and infection remain major concerns. This study aimed to demonstrate the results of an innovative, minimally invasive surgical procedure, namely, a closed reduction technique using large-diameter Steinmann pins and percutaneous calcaneoplasty using injectable calcium sulfate cement (MIIG X3, Wright Medical Technology, Inc., Arlington, TN), in patients with comminuted calcaneal fractures. METHODS: From January 2012 to January 2014, 20 patients (three women, 17 men) with comminuted calcaneus fractures (Sanders classification type III and Essex Lopresti classification joint-depression type fracture) were included. Plain films and CT scans were obtained preoperatively in all patients. The operation was performed within three days post-injury, and patients were not allowed to bear weight until three months postoperatively. During this period, the patients were educated on how to perform bed exercises for joints above the surgical site, including muscle strengthening and body conditioning. Early active range of motion exercises for the ankle and forefoot began 3 to 6 weeks postoperatively. All patients were followed up regularly. The results were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle score and Bohler's angle of the calcaneus. RESULTS: After an average follow-up of two years, none of the patients required further surgery or experienced soft tissue complications. The clinical results were rated good to excellent on the AOFAS scale in 80% of the cases (16 of 20 patients), and most patients had pain relief and returned to their former daily activities at the same level as before the injury. CONCLUSIONS: A modified Essex-Lopresti procedure with percutaneous calcaneoplasty appears to be a safe and effective procedure to treat comminuted calcaneal fractures with acceptable functional results. Long-term outcomes and additional cases using this technique are required to support our conclusion. PMID- 29523124 TI - COMPLETE - a school-based intervention project to increase completion of upper secondary school in Norway: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Drop out from upper secondary school represents a risk for the future health and wellbeing of young people. Strengthening of psychosocial aspects of the learning environment may be an effective strategy to promote completion of upper secondary school. This paper is a study protocol of a school based cluster randomized controlled trial (RCT) evaluating two school-based interventions, namely the Dream School Program (DSP) and the Mental Health Support Team (MHST). The interventions aim to improve psychosocial learning environments and subsequently school achievements and decrease drop-out and absence. METHODS/DESIGN: The COMPLETE RCT is aimed at youth in upper secondary school, grade 1 (age 15-16 years), and examines the effect of the combination of the DSP and the MHST; and the DSP only, compared with a comparison group on the following primary outcomes: student completion, presence, average grade, and self-reported mental health. Seventeen upper secondary schools from four counties in Norway were randomized to one of the three arms: 1) DSP and MHST; 2) DSP; and 3) comparison (offered DSP intervention in 2018/2019). The study will evaluate the interventions based on information from two cohorts of students (cohort 1 (C1) and cohort 2 (C2)). For C1, data was collected at baseline (August 2016), and at first follow-up seven months later. Second follow-up will be collected 19 months after baseline. For C2, data was collected at baseline (August 2017), and first and second follow-up will be collected similarly to that of C2 seven and 19 months respectively after baseline. Process evaluations based on focus groups, interviews and observation will be conducted twice (first completed spring 2017). DISCUSSION: The COMPLETE trial is a large study that can provide useful knowledge about what interventions might effectively improve completion of upper secondary school. Its thorough process evaluation will provide critical information about barriers and points of improvement for optimizing intervention implementation. Findings can guide school development in the perspective of improving psychosocial learning environments and subsequent completion of upper secondary schooling. TRIAL REGISTRATION: The trial was retrospectively registered in the ClinicalTrials.gov register on December 22.2017: NCT03382080 . PMID- 29523123 TI - Co-expression of TIMP-1 and its cell surface binding partner CD63 in glioblastomas. AB - BACKGROUND: We have previously identified tissue inhibitor of metalloproteinases 1 (TIMP-1) as a prognostic marker in glioblastomas. TIMP-1 has been associated with chemotherapy resistance, and CD63, a known TIMP-1-binding protein, has been suggested to be responsible for this effect. The aim of this study was to assess CD63 expression in astrocytomas focusing on the prognostic potential of CD63 alone and in combination with TIMP-1. METHODS: CD63 expression was investigated immunohistochemically in a cohort of 111 astrocytomas and correlated to tumor grade and overall survival by semi-quantitative scoring. CD63 expression in tumor associated microglia/macrophages was examined by double-immunofluorescence with ionized calcium-binding adapter molecule 1 (Iba1). The association between CD63 and TIMP-1 was investigated using previously obtained TIMP-1 data from our astrocytoma cohort. Cellular co-expression of TIMP-1 and CD63 as well as TIMP-1 and the tumor stem cell-related markers CD133 and Sox2 was investigated with immunofluorescence. TIMP-1 and CD63 protein interaction was detected by an oligonucleotide-based proximity ligation assay and verified using co immunoprecipitation. RESULTS: The expression of CD63 was widely distributed in astrocytomas with a significantly increased level in glioblastomas. CD63 levels did not significantly correlate with patient survival at a protein level, and CD63 did not augment the prognostic significance of TIMP-1. Up to 38% of the CD63+ cells expressed Iba1; however, Iba1 did not appear to impact the prognostic value of CD63. A significant correlation was found between TIMP-1 and CD63, and the TIMP-1 and CD63 proteins were co-expressed at the cellular level and located in close molecular proximity, suggesting that TIMP-1 and CD63 could be co-players in glioblastomas. Some TIMP-1+ cells expressed CD133 and Sox2. CONCLUSION: The present study suggests that CD63 is highly expressed in glioblastomas and that TIMP-1 and CD63 interact. CD63 does not add to the prognostic value of TIMP-1. Co expression of TIMP-1 and stem cell markers as well as the wide expression of CD63 might suggest a role for TIMP-1 and CD63 in glioblastoma stemness. PMID- 29523125 TI - Infection prevention behaviour and infectious disease modelling: a review of the literature and recommendations for the future. AB - BACKGROUND: Given the importance of person to person transmission in the spread of infectious diseases, it is critically important to ensure that human behaviour with respect to infection prevention is appropriately represented within infectious disease models. This paper presents a large scale scoping review regarding the incorporation of infection prevention behaviour in infectious disease models. The outcomes of this review are contextualised within the psychological literature concerning health behaviour and behaviour change, resulting in a series of key recommendations for the incorporation of human behaviour in future infectious disease models. METHODS: The search strategy focused on terms relating to behaviour, infectious disease and mathematical modelling. The selection criteria were developed iteratively to focus on original research articles that present an infectious disease model with human-human spread, in which individuals' self-protective health behaviour varied endogenously within the model. Data extracted included: the behaviour that is modelled; how this behaviour is modelled; any theoretical background for the modelling of behaviour, and; any behavioural data used to parameterise the models. RESULTS: Forty-two papers from an initial total of 2987 were retained for inclusion in the final review. All of these papers were published between 2002 and 2015. Many of the included papers employed a multiple, linked models to incorporate infection prevention behaviour. Both cognitive constructs (e.g., perceived risk) and, to a lesser extent, social constructs (e.g., social norms) were identified in the included papers. However, only five papers made explicit reference to psychological health behaviour change theories. Finally, just under half of the included papers incorporated behavioural data in their modelling. CONCLUSIONS: By contextualising the review outcomes within the psychological literature on health behaviour and behaviour change, three key recommendations for future behavioural modelling are made. First, modellers should consult with the psychological literature on health behaviour/ behaviour change when developing new models. Second, modellers interested in exploring the relationship between behaviour and disease spread should draw on social psychological literature to increase the complexity of the social world represented within infectious disease models. Finally, greater use of context-specific behavioural data (e.g., survey data, observational data) is recommended to parameterise models. PMID- 29523126 TI - MYC amplification in subtypes of breast cancers in African American women. AB - BACKGROUND: MYC overexpression is associated with poor prognosis in breast tumors (BCa). The objective of this study was to determine the prevalence of MYC amplification and associated markers in BCa tumors from African American (AA) women and determine the associations between MYC amplification and clinico pathological characteristics. METHODS: We analyzed 70 cases of well characterized archival breast ductal carcinoma specimens from AA women for MYC oncogene amplification. Utilizing immune histochemical analysis estrogen receptor (ER), progesterone receptor (PR), and (HER2/neu), were assessed. Cases were Luminal A (ER or PR+, Ki-67 < 14%), Luminal B (ER or PR+, Ki-67 = > 14% or ER or PR+ HER2+), HER2 (ER-, PR-, HER2+), and Triple Negative (ER-, PR-, HER2-) with basal like phenotype. The relationship between MYC amplification and prognostic clinico pathological characteristics was determined using chi square and logistic regression modeling. RESULTS: Sixty-five (97%) of the tumors showed MYC gene amplification (MYC: CEP8 > 1). Statistically significant associations were found between MYC amplification and HER2-amplified BCa, and Luminal B subtypes of BCa (p < 0.0001), stage (p < 0.001), metastasis (p < 0.001), and positive lymph node status (p = 0.039). MYC amplification was associated with HER2 status (p = 0.01) and tumor size (p = 0.01). High MYC amplification was seen in grade III carcinomas (MYC: CEP8 = 2.42), pre-menopausal women (MYC: CEP8 = 2.49), PR negative status (MYC: CEP8 = 2.42), and ER-positive status (MYC: CEP8 = 2.4). CONCLUSIONS: HER2 positive BCas in AA women are likely to exhibit MYC amplification. High amplification ratios suggest that MYC drives HER2 amplification, especially in HER2 positive, Luminal B, and subtypes of BCa. PMID- 29523127 TI - Positive predictive value of medical student specialty choices. AB - BACKGROUND: Although medical school programs oriented toward postgraduate specialty training have the potential to reduce the duration and cost of medical school for US medical students, success depends on the ability of students to predict their postgraduate specialties. It is clear that first-year choices are poorly predictive, but it is not known when predictions become sufficiently reliable to support specialty-oriented learning programs. We therefore examined the predictive value of specialty preferences expressed at the ends of the first, second and third years of medical school and asked whether concurrent expressions of confidence in choices improved predictive ability. We also investigated the possibility that discrepancies between predicted and actual postgraduate specialty training were related to scores on an examination of knowledge in basic biomedical sciences required for US medical school graduation (the United States Medical Licensing Examination (USLME) Step 1 examination). METHOD: We calculated positive and negative predictive values (PPV and NPV, respectively) for specialty choices and the sensitivity and specificity of asking for choices for 634 University of Colorado School of Medicine students who trained in 23 accredited residencies from 2011 through 2015. We examined the effect of confidence in first choices in 609 students, and in 334 students, sought an association between USMLE Step 1 scores and switching from postgraduate training specialties predicted at the end of year 2. RESULTS: The PPV of first choices improved from years 1 through 3. NPV was high throughout. PPVs of year 3 first choices ranged from 79% in Anesthesiology to 95% in Psychiatry. Expressions of confidence in first choices did not improve PPV. Sensitivity of asking for first choices increased with time; specificity was consistently high. USLME Step 1 scores were higher for students who ultimately trained in specialties more competitive than first-choice specialties at the end of year 2. CONCLUSIONS: Specialty-oriented learning programs during medical school must accommodate students who change career plans. The PPV of specialty first choices improves each year, but even year 3 predictions can be inaccurate with potential loss of students from specialty specific programs. USMLE Step 1 scores appeared to affect career plans expressed at the end of year 2. PMID- 29523128 TI - Association between objectively measured physical activity and body mass index with low back pain: a large-scale cross-sectional study of Japanese men. AB - BACKGROUND: The relationship between the combination of physical activity (PA) and body mass index (BMI) with low back pain (LBP) is unclear. The present study offers a cross-sectional assessment of how combinations of PA and BMI are related to LBP in Japanese men. METHODS: Participants were 4022 Japanese men (mean age = 47) who underwent regular clinical examinations. PA was measured using a uniaxial accelerometer and divided into tertiles (PAhigh, PAmiddle, PAlow). A self administered questionnaire was used to report on persistent LBP experience, drinking and smoking habits, and any existing lifestyle diseases. After covariance adjustment, a logistic regression model was used to assess how combinations of PA and BMI are related to persistent LBP. RESULTS: 428 of the participants had persistent LBP. A clear negative dose-response relationship was found between PA levels and persistent LBP (P for linearity = 0.012). Regarding BMI, odd ratios were shown to be higher in the overweight/obese category (BMI >= 25 kg/m2) than for the normal weight category (BMI < 25 kg/m2). When the PAhigh was taken as the reference in the normal weight category, odds ratios for PAlow and PAmiddle in the normal weight category were shown to be high. Moreover, in the overweight/obese category, odd ratios for every fitness level were also high as for the normal weight category. CONCLUSION: The present study showed that both PA and BMI are related to persistent LBP. Also, the prevalence of persistent LBP became higher when PAlow and high BMI are combined rather than the group of PAhigh and low BMI combination. PMID- 29523130 TI - Correction to: SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease. AB - Following publication of the original article [1] the authors reported that the first affiliation ("Medical Center of the Graduate School, Nanchang University, China") had been added in error, and that the correct author information is as given in this erratum. PMID- 29523129 TI - Educational video-assisted versus conventional informed consent for trauma related debridement surgery: a parallel group randomized controlled trial. AB - BACKGROUND: We investigated whether, in the emergency department (ED), educational video-assisted informed consent is superior to the conventional consent process, to inform trauma patients undergoing surgery about the procedure, benefits, risks, alternatives, and postoperative care. METHODS: We conducted a prospective randomized controlled trial, with superiority study design. All trauma patients scheduled to receive trauma-related debridement surgery in the ED of Kaohsiung Medical University Hospital were included. Patients were assigned to one of two education protocols. Participants in the intervention group watched an educational video illustrating informed consent information, whereas those in the control group read an informed consent document. The primary outcome was knowledge scores and the secondary outcome was assessment of patient satisfaction. A multivariable regression model, with predefined covariates, was used to analyze differences in knowledge scores and patient satisfaction levels between the groups. RESULTS: A total of 142 patients were enrolled, with 70 and 72 assigned to the intervention and control groups, respectively. Mean knowledge scores were higher in the intervention (72.57 +/- 16.21 (SD)) than in the control (61.67 +/- 18.39) group. By multivariate analysis, the intervention group had significantly greater differences in knowledge scores (coefficient: 7.646, 95% CI: 3.381-11.911). Age, injury severity score, and baseline knowledge score significantly affected the differences in knowledge scores. Significant improvements were observed in patients' perception of statements addressing comprehension of the information provided, helpfulness of the supplied information for decision making, and satisfaction with the informed consent process. Multivariate analysis showed significant correlations between video education and patient satisfaction. CONCLUSIONS: Both the educational approach and severity of injury may have an impact on patient understanding during the informed consent process in an emergency environment. Video-assisted informed consent may improve the understanding of surgery and satisfaction with the informed consent process for trauma patients in the ED. Institutions should develop structured methods and other strategies to better inform trauma patients, facilitate treatment decisions, and improve patient satisfaction. TRIAL REGISTRATION: The ClinicalTrials.gov Identifier is NCT01338480 . The date of registration was April 18, 2011 (retrospectively registered). PMID- 29523131 TI - Traditional Chinese medicine pharmacovigilance in signal detection: decision tree based data classification. AB - BACKGROUND: Traditional Chinese Medicine (TCM) is a style of traditional medicine informed by modern medicine but built on a foundation of more than 2500 years of Chinese medical practice. According to statistics, TCM accounts for approximately 14% of total adverse drug reaction (ADR) spontaneous reporting data in China. Because of the complexity of the components in TCM formula, which makes it essentially different from Western medicine, it is critical to determine whether ADR reports of TCM should be analyzed independently. METHODS: Reports in the Chinese spontaneous reporting database between 2010 and 2011 were selected. The dataset was processed and divided into the total sample (all data) and the subsample (including TCM data only). Four different ADR signal detection methods PRR, ROR, MHRA and IC- currently widely used in China, were applied for signal detection on the two samples. By comparison of experimental results, three of them-PRR, MHRA and IC-were chosen to do the experiment. We designed several indicators for performance evaluation such as R (recall ratio), P (precision ratio), and D (discrepancy ratio) based on the reference database and then constructed a decision tree for data classification based on such indicators. RESULTS: For PRR: R1-R2 = 0.72%, P1-P2 = 0.16% and D = 0.92%; For MHRA: R1-R2 = 0.97%, P1-P2 = 0.20% and D = 1.18%; For IC: R1-R2 = 1.44%, P2-P1 = 4.06% and D = 4.72%. The threshold of R,Pand Dis set as 2%, 2% and 3% respectively. Based on the decision tree, the results are "separation" for PRR, MHRA and IC. CONCLUSIONS: In order to improve the efficiency and accuracy of signal detection, we suggest that TCM data should be separated from the total sample when conducting analyses. PMID- 29523132 TI - Invasion and replication of Yersinia ruckeri in fish cell cultures. AB - BACKGROUND: Like many members of the Enterobacteriaceae family, Yersinia ruckeri has the ability to invade non professional phagocytic cells. Intracellular location is advantageous for the bacterium because it shields it from the immune system and can help it cross epithelial membranes and gain entry into the host. In the present manuscript, we report on our investigation regarding the mechanisms of Y. ruckeri's invasion of host cells. RESULTS: A gentamycin assay was applied to two isolates, belonging to both the biotype 1 (ATCC 29473) and biotype 2 (A7959-11) and using several cell culture types: Atlantic Salmon Kidney, Salmon Head Kidney and, Chinook salmon embryos cells at both low and high passage numbers. Varying degrees of sensitivity to Y. ruckeri infection were found between the cell types and the biotype 1 strain was found to be more invasive than the non-motile biotype 2 isolate. Furthermore, the effect of six chemical compounds (Cytochalasin D, TAE 226, vinblastine, genistein, colchicine and, N-acetylcysteine), known to interfere with bacterial invasion strategies, were investigated. All of these compounds had a significant impact on the ability of the bacterium to invade host cells. Changes in the concentration of bacterial cells over time were investigated and the results suggested that neither isolate could survive intracellularly for sustained periods. CONCLUSIONS: These results suggest that Y. ruckeri can gain entrance into host cells through several mechanisms, and might take advantage of both the actin and microtubule cytoskeletal systems. PMID- 29523133 TI - Obesity as disruptor of the female fertility. AB - Both obesity and overweight are increasing worldwide and have detrimental influences on several human body functions including the reproductive health. In particular, obese women undergo perturbations of the 'hypothalamic pituitary ovarian axis', and frequently suffer of menstrual dysfunction leading to anovulation and infertility. Besides the hormone disorders and subfertility that are common in the polycystic ovary syndrome (PCOS), in obesity the adipocytes act as endocrine organ. The adipose tissue indeed, releases a number of bioactive molecules, namely adipokines, that variably interact with multiple molecular pathways of insulin resistance, inflammation, hypertension, cardiovascular risk, coagulation, and oocyte differentiation and maturation. Moreover, endometrial implantation and other reproductive functions are affected in obese women with complications including delayed conceptions, increased miscarriage rate, reduced outcomes in assisted conception treatments.On the contrary, weight loss programs through lifestyle modification in obese women, have been proven to restore menstrual cyclicity and ovulation and improve the likelihood of conception. PMID- 29523134 TI - Effects of herbal nutraceuticals and/or zinc against Haemonchus contortus in lambs experimentally infected. AB - BACKGROUND: The gastrointestinal parasitic nematode Haemonchus contortus is a pathogenic organism resistant to several anthelmintics. This study assessed the efficacy of a medicinal herbal mixture (Herbmix) and organic zinc, as an essential trace element for the proper functioning of both unspecific and specific immune defensive mechanisms, against experimental infections with H. contortus in lambs. All lambs were infected orally with approximately 5000 third stage larvae of a strain of H. contortus susceptible to anthelmintics (MHco1). Twenty-four female lambs 3-4 months of age were divided into four groups: unsupplemented animals (control), animals supplemented with Herbmix (Hmix), animals supplemented with organic zinc (Zn) and animals supplemented with Herbmix and organic zinc (Hmix+Zn). Eggs per gram (EPG) of faeces were quantified 20, 28, 35, 42, 49, 56, 62 and 70 d post-infection and mean abomasal worm counts were assessed 70 d post-infection. Samples of blood were collected from each animal 7, 35, 49 and 70 d post-infection. RESULTS: Quantitative analyses of the bioactive compounds in Herbmix identified three main groups: flavonoids (9964.7 MUg/g), diterpenes (4886.1 MUg/g) and phenolic acids (3549.2 MUg/g). Egg counts in the lambs treated with Hmix, Zn and Hmix+Zn decreased after 49 d. The EPGs in the Zn and Hmix+Zn groups were significantly lower on day 56 (P < 0.05 and P < 0.01, respectively), and the EPGs and mean worm counts were significantly lower on day 70 in all supplemented groups (P < 0.05 and P < 0.01). Hemograms of complete red blood cells of each animal identified clinical signs of haemonchosis after day 35. Serum calprotectin concentrations and IgA levels were significantly affected by treatment. The treatment influenced serum malondialdehyde concentrations (P < 0.05) and sulfhydryl groups (P < 0.01) of antioxidant status. The mineral status was unaltered in all lambs. CONCLUSION: A direct anthelmintic impact on the viability of nematodes was not fully demonstrated, but the treatments with herbal nutraceuticals and zinc likely indirectly contributed to the increase in the resistance of the lambs to nematode infection. PMID- 29523135 TI - Post-operative left atrial volume index is a predictor of the occurrence of permanent atrial fibrillation after mitral valve surgery in patients who undergo mitral valve surgery. AB - BACKGROUND: Atrial fibrillation (AF) can occur even after the correction of mitral valve (MV) pathology in patients who have pre-operative sinus rhythm and undergo MV surgery. However, the factors associated with the occurrence of AF after MV surgery are still unclear. The aim of this retrospective study was to investigate the factors determining the occurrence of permanent AF after MV surgery in patients with preoperative sinus rhythm who underwent MV surgery. METHODS: Four hundred and forty-two patients (mean age 46 +/- 12, 190 men) who underwent MV surgery and sinus rhythm were investigated retrospectively. Transthoracic echocardiography was performed before and after MV surgery at the time of dismissal. RESULTS: Permanent post-operative AF occurred in 81 (18%) patients even after successful MV surgery and preoperative sinus rhythm. It was more common in rheumatic etiology, a presence of mitral stenosis, lower pre- and post-operative left ventricular ejection fraction, higher post-operative mean diastolic pressure gradient across mitral prosthesis, larger post-operative left atrial volume index (LAVI) and lesser degrees of reduction in LAVI after surgery. In multiple regression analysis, post-operative LAVI was found to be an independent predictor for occurrence of AF. Post-operative LAVI > 39 ml/m2 was the cut-off value for best prediction of new onset permanent AF (sensitivity: 79%, AUC: 0.762, SE: 0.051, p < 0.001). CONCLUSION: New-onset permanent post operative AF is not uncommon, even after successful MV surgery despite pre operative sinus rhythm. Larger post-operative LAVI was an independent predictor for the occurrence of AF. PMID- 29523136 TI - Characterisation of feline renal cortical fibroblast cultures and their transcriptional response to transforming growth factor beta1. AB - BACKGROUND: Chronic kidney disease (CKD) is common in geriatric cats, and the most prevalent pathology is chronic tubulointerstitial inflammation and fibrosis. The cell type predominantly responsible for the production of extra-cellular matrix in renal fibrosis is the myofibroblast, and fibroblast to myofibroblast differentiation is probably a crucial event. The cytokine TGF-beta1 is reportedly the most important regulator of myofibroblastic differentiation in other species. The aim of this study was to isolate and characterise renal fibroblasts from cadaverous kidney tissue of cats with and without CKD, and to investigate the transcriptional response to TGF-beta1. RESULTS: Cortical fibroblast cultures were successfully established from the kidney tissue of cats with normal kidney function (FCF) and cats with chronic kidney disease (CKD-FCF). Both cell types expressed the mesenchymal markers vimentin, CD44 and CD29, and were negative for the epithelial marker cytokeratin, mesangial cell marker desmin and endothelial cell marker vWF. Only CKD-FCF expressed VCAM-1, a cell marker associated with inflammation. Incubation with TGF-beta1 (0-10 ng/ml) induced a concentration dependent change in cell morphology, and upregulation of myofibroblast marker gene alpha-SMA expression alongside collagen 1alpha1, fibronectin, TGF-beta1 and CTGF mRNA. These changes were blocked by the TGF-beta1 receptor 1 antagonist SB431542 (5 MUM). CONCLUSIONS: FCF and CKD-FCF can be cultured via a simple method and represent a model for the investigation of the progression of fibrosis in feline CKD. The findings of this study suggest TGF-beta1 may be involved in fibroblast-myofibroblast transition in feline CKD, as in other species. PMID- 29523137 TI - Antibody levels to recombinant VAR2CSA domains vary with Plasmodium falciparum parasitaemia, gestational age, and gravidity, but do not predict pregnancy outcomes. AB - BACKGROUND: Maternal malaria is a tropical scourge associated with poor pregnancy outcomes. Women become resistant to Plasmodium falciparum pregnancy malaria as they acquire antibodies to the variant surface antigen VAR2CSA, a leading vaccine candidate. Because malaria infection may increase VAR2CSA antibody levels and thereby confound analyses of immune protection, gravidity-dependent changes in antibody levels during and after infection, and the effect of VAR2CSA antibodies on pregnancy outcomes were evaluated. METHODS: Pregnant women enrolled in a longitudinal cohort study of mother-infant pairs in Ouelessebougou, Mali provided plasma samples at enrollment, gestational week 30-32, and delivery. Antibody levels to VAR2CSA domains were measured using a multiplex bead-based assay. RESULTS: Antibody levels to VAR2CSA were higher in multigravidae than primigravidae. Malaria infection was associated with increased antibody levels to VAR2CSA domains. In primigravidae but not in secundigravidae or multigravidae, antibodies levels sharply declined after an infection. A relationship between any VAR2CSA antibody specificity and protection from adverse pregnancy outcomes was not detected. CONCLUSIONS: During malaria infection, primigravidae acquire short lived antibodies. The lack of an association between VAR2CSA domain antibody reactivity and improved pregnancy outcomes suggests that the recombinant proteins may not present native epitopes targeted by protective antibodies. PMID- 29523138 TI - Translation, cross-cultural adaptation and reliability of the German version of the migraine disability assessment (MIDAS) questionnaire. AB - BACKGROUND: The Migraine Disability Assessment (MIDAS) is a brief questionnaire and measures headache-related disability. This study aimed to translate and cross culturally adapt the original English version of the MIDAS to German and to test its reliability. METHODS: The standardized translation process followed international guidelines. The pre-final version was tested for clarity and comprehensibility by 34 headache sufferers. Test-retest reliability of the final version was quantified by 36 headache patients completing the MIDAS twice with an interval of 48 h. Reliability was determined by intraclass correlation coefficients and internal consistency by Cronbach's alpha. RESULTS: All steps of the translation process were followed, documented and approved by the developer of the MIDAS. The expert committee discussed in detail the complex phrasing of the questions that refer to one to another, especially exclusion of headache-days from one item to the next. The German version contains more active verb sentences and prefers the perfect to the imperfect tense. The MIDAS scales intraclass correlation coefficients ranged from 0.884 to 0.994 and was 0.991 (95% CI: 0.982 0.995) for the MIDAS total score. Cronbach's alpha for the MIDAS as a whole was 0.69 at test and 0.67 at retest. CONCLUSIONS: The translation process was challenged by the comprehensibility of the questionnaire. The German version of the MIDAS is a highly reliable instrument for assessing headache related disability with moderate internal consistency. Provided validity testing of the German MIDAS is successful, it can be recommended for use in clinical practice as well as in research. PMID- 29523139 TI - An assessment of the malaria-related knowledge and practices of Tanzania's drug retailers: exploring the impact of drug store accreditation. AB - BACKGROUND: Since 2003 Tanzania has upgraded its approximately 7000 drug stores to Accredited Drug Dispensing Outlets (ADDOs), involving dispenser training, introduction of record keeping and enhanced regulation. Prior to accreditation, drug stores could officially stock over-the-counter medicines only, though many stocked prescription-only antimalarials. ADDOs are permitted to stock 49 prescription-only medicines, including artemisinin combination therapies and one form of quinine injectable. Oral artemisinin monotherapies and other injectables were not permitted at any time. By late 2011 conversion was complete in 14 of 21 regions. We explored variation in malaria-related knowledge and practices of drug retailers in ADDO and non-ADDO regions. METHODS: Data were collected as part of the Independent Evaluation of the Affordable Medicines Facility - malaria (AMFm), involving a nationally representative survey of antimalarial retailers in October December 2011. We randomly selected 49 wards and interviewed all drug stores stocking antimalarials. We compare ADDO and non-ADDO regions, excluding the largest city, Dar es Salaam, due to the unique characteristics of its market. RESULTS: Interviews were conducted in 133 drug stores in ADDO regions and 119 in non-ADDO regions. Staff qualifications were very similar in both areas. There was no significant difference in the availability of the first line antimalarial (68.9% in ADDO regions and 65.2% in non-ADDO regions); both areas had over 98% availability of non-artemisinin therapies and below 3.0% of artemisinin monotherapies. Staff in ADDO regions had better knowledge of the first line antimalarial than non-ADDO regions (99.5% and 91.5%, p = 0.001). There was weak evidence of a lower price and higher market share of the first line antimalarial in ADDO regions. Drug stores in ADDO regions were more likely to stock ADDO certified injectables than those in non-ADDO regions (23.0% and 3.9%, p = 0.005). CONCLUSIONS: ADDO conversion is frequently cited as a model for improving retail sector drug provision. Drug stores in ADDO regions performed better on some indicators, possibly indicating some small benefits from ADDO conversion, but also weaknesses in ADDO regulation and high staff turnover. More evidence is needed on the value-added and value for money of the ADDO roll out to inform retail policy in Tanzania and elsewhere. PMID- 29523140 TI - Immunization with recombinant Salmonella expressing SspH2-EscI protects mice against wild type Salmonella infection. AB - BACKGROUND: Enhancing caspase-1 activation in macrophages is helpful for the clearance of intracellular bacteria in mice. Our previous studies have shown that EscI, an inner rod protein of type III system in E. coli can enhance caspase-1 activation. The purpose of this study was to further analyze the prospect of EscI in the vaccine design. RESULTS: A recombinant Salmonella expressing SspH2-EscI fusion protein using the promotor of Salmonella effector SspH2, X4550(pYA3334-P SspH2-EscI), was constructed. A control recombinant Salmonella expressing SspH2 only X4550(pYA3334-P-SspH2) was also constructed. In the early stage of in vitro infection of mouse peritoneal macrophages, X4550(pYA3334-P-SspH2-EscI) could significantly (P < 0.05) enhance intracellular caspase-1 activation and pyroptotic cell death of macrophages, when compared with X4550(pYA3334-P-SspH2). Except for the intracellular pH value, the levels of reactive oxygen species, intracellular concentration of calcium ions, nitric oxide and mitochondrial membrane potential in macrophages were not significantly different between the cells infected with X4550(pYA3334-P-SspH2-EscI) and those infected with X4550(pYA3334-P-SspH2). Besides, only lower inflammatory cytokines secretion was induced by X4550(pYA3334-P-SspH2-EscI) than X4550(pYA3334-P-SspH2). After intravenous immunization of mice (1 * 106 cfu/mouse), the colonization of X4550(pYA3334-P-SspH2-EscI) in mice was significantly limited at one week post immunization (wpi), when compared with X4550(pYA3334-P-SspH2) (P < 0.05). The population of activated CD8+T lymphocytes in mouse spleens induced by X4550(pYA3334-P-SspH2-EscI) was lower than that induced by X4550(pYA3334-P-SspH2) at 2-3 wpi, and the ratio of CD4+T cells to CD8+T cells decreased. The blood coagulation assay indicated that no significant difference was found between X4550(pYA3334-P-SspH2-EscI) and uninfected control, while X4550(pYA3334-P-SspH2) could induce the quick coagulation. Notably, immunization of X4550(pYA3334-P SspH2-EscI) could limit the colonization of challenged Salmonella strains in the early stage of infection and provide more effective protection. CONCLUSION: The activation of caspase-1 in macrophages by EscI can be used in the design of live attenuated Salmonella vaccine candidate. PMID- 29523141 TI - The efficacy of sentinel lymph node mapping with indocyanine green in cervical cancer. AB - BACKGROUND: Lymph node metastasis is a significant predictive factor for disease recurrence and survival in cervical cancer patients. Given the importance of lymph node metastasis, it is imperative that patients harboring metastasis are identified and can undergo appropriate treatment. Sentinel lymph node (SLN) mapping has drawn attention as a lymph node mapping technique. We evaluated the feasibility and efficacy of (SLN) mapping using indocyanine green (ICG) in cervical cancer. METHODS: We performed a single-center, retrospective study of 103 surgically treated cervical cancer patients who underwent SLN mapping. After using ICG to detect SLN during surgery, we removed the SLNs followed by laparoscopic or robotic-assisted radical surgery and bilateral pelvic lymphadenectomy. RESULTS: Stage IB1 was the most common (61.17%). At least one SLN was detected in all cases. Eighty-eight patients (85.44%) had bilateral pelvic SLNs. The mean number of SLN per patient was 2.34. The side-specific sensitivity was 71.43%, the specificity was 100%, the negative predictive value (NPV) was 93.98%, and the false negative rate (FNR) was 28.57%. In cases of tumors smaller than 2 cm with negative lymph node metastasis on imaging, the study revealed a side-specific sensitivity of 100%, a specificity of 100%, a NPV of 100%, and a FNR of 0%. Large tumor size (>= 4 cm), a previous history of a loop electrosurgical excision procedure (LEEP), depth of invasion (>= 50%), the microscopic parametrial (PM) invasion, and vaginal extension were significantly associated with the false-negative detection of SLN. Moreover, the microscopic PM invasion was the only risk factor of the false-negative detection of SLN in multivariate analysis. CONCLUSION: SLN mapping with ICG in cervical cancer is feasible and has high detection rate. The sensitivity of 100% was high enough to perform SLN biopsy alone in an early stage in which the tumor is less than 2 cm, with no lymphadenopathy on image examination. However, for large or invasive tumors, we would have to be cautious about performing SLN biopsy alone. TRIAL REGISTRATION: Retrospectively registered 2017-0600. PMID- 29523143 TI - Retraction Note: Association between serum vitamin D levels and the risk of kidney stone: evidence from a meta-analysis. AB - The Editors are retracting this article [1] because post-publication peer review has identified multiple errors in the methodology of this meta-analysis, which invalidate the conclusions drawn. PMID- 29523142 TI - Lipid accelerating the fibril of islet amyloid polypeptide aggravated the pancreatic islet injury in vitro and in vivo. AB - BACKGROUND: The fibrillation of islet amyloid polypeptide (IAPP) triggered the amyloid deposition, then enhanced the loss of the pancreatic islet mass. However, it is not clear what factor is the determinant in development of the fibril formation. The aim of this study is to investigate the effects of lipid on IAPP fibril and its injury on pancreatic islet. METHODS: The fibril form of human IAPP (hIAPP) was tested using thioflavin-T fluorescence assay and transmission electron microscope technology after incubated with palmitate for 5 h at 25 degrees C. The cytotoxicity of fibril hIAPP was evaluated in INS-1 cells through analyzing the leakage of cell membrane and cell apoptosis. Type 2 diabetes mellitus (T2DM) animal model was induced with low dose streptozotocin combined the high-fat diet feeding for two months in rats. Plasma biochemistry parameters were measured before sacrificed. Pancreatic islet was isolated to evaluate their function. RESULTS: The results showed that co-incubation of hIAPP and palmitate induced more fibril form. Fibril hIAPP induced cell lesions including cell membrane leakage and cell apoptosis accompanied insulin mRNA decrease in INS-1 cell lines. In vivo, Plasma glucose, triglyceride, rIAPP and insulin increased in T2DM rats compared with the control group. In addition, IAPP and insulin mRNA increased in pancreatic islet of T2DM rats. Furthermore, T2DM induced the reduction of insulin receptor expression and cleaved caspase-3 overexpression in pancreatic islet. CONCLUSIONS: Results in vivo and in vitro suggested that lipid and IAPP plays a synergistic effect on pancreatic islet cell damage, which implicated in enhancing the IAPP expression and accelerating the fibril formation of IAPP. PMID- 29523144 TI - The use and preference of artemether as a first-choice treatment for malaria: results from a cross-sectional survey in the Bata district, Equatorial Guinea. AB - BACKGROUND: Malaria is endemic in Equatorial Guinea with stable transmission, and it remains a major cause of morbidity and mortality in children under 5 years of age. Adherence to artemisinin-based combination therapy (ACT) as a first-line treatment for uncomplicated malaria is critical to malaria control. Six years after the introduction of artesunate-amodiaquine (AS/AQ) therapy in Equatorial Guinea, adherence to the first-line treatment seems to be low in the Bata district. The factors associated with the choice of malaria treatment have not been studied previously in this area; therefore, this study aimed to analyse the preference and use of artemether as malaria treatment and its related factors in the Bata district of Equatorial Guinea. METHODS: In 2013, a cross-sectional study was conducted in the Bata district, which involved 428 households. Bivariate and multivariate statistical analyses were conducted to determine the relevance of socio-economic, geographical, and behavioural factors that played a role in the preference and use of artemether as malaria treatment. RESULTS: Artemether was considered the best treatment for malaria by 110 caregivers (26%), and was the antimalarial most administrated in the Bata district. It was prescribed to 117 children (27.34%); while, only 6.78% were administered AS/AQ. Caregivers living <= 3 km from the nearest health facility were almost two times more likely to consider artemether as the best treatment than those living farther away (95% CI 0.31-0.86). Caregivers with at least a secondary school education were 2.7 times more likely to consider artemether as the best treatment than those less educated. Children whose caregivers considered artemether the best treatment against malaria were five times more likely to be treated with artemether than children with caregivers who did not consider it the best (OR 5.07, 95% CI 2.93 8.78). In contrast, children that reported weakness as a symptom were less likely to be treated with artemether than those with other symptoms (OR 0.47, 95% CI 0.28-0.78). CONCLUSION: Caregivers, public and private health staff, and drug sellers need to understand the importance of using ACT to treat uncomplicated malaria and the dangers of using artemisinin monotherapy. PMID- 29523145 TI - Linc00659, a long noncoding RNA, acts as novel oncogene in regulating cancer cell growth in colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers and causes of cancer-related death worldwide. In patients with CRC, metastasis is a crucial problem that leads to treatment failure and is the primary cause of the lethality of colon cancer. Long noncoding RNAs (lncRNAs) have recently emerged as critical molecules in the development, cell growth, apoptosis, and metastasis of CRC. METHOD: We investigated the transcriptome profiles of human lncRNAs in the primary tumor tissues and in the corresponding normal mucosa of two patients with CRC by using a microarray approach. The expression levels of lncRNAs were verified in colon cancer by real-time PCR. Using bioinformatics approach to illustrate putative biological function of Linc00659 in colon cancer. The effects of Linc00659 on cell growth, proliferation, cell cycle and apoptosis were studies by in vitro assays. RESULTS: Our data revealed that compared with adjacent normal tissues, 201 lncRNAs were deregulated (fold change >= 4 or <= 0.25) in CRC tissues. Among them, the expression levels of Linc00659 were significantly increased in colon cancer, and high expression levels were correlated with poor survival in patients with CRC. Bioinformatics analysis results indicated that Linc00659 was significantly coexpressed with cycle-related genes in CRC. Linc00659 expression knockdown could significantly suppress colon cancer cell growth by impairing cell cycle progression. In addition, our results showed that Linc00659 expression knockdown could accelerate cell apoptosis in colon cancer cells treated with chemotherapy drugs. Meanwhile, our results also demonstrated that silencing of Linc00659 expression leads to cell growth inhibition and induced apoptosis, possibly by suppressing PI3K-AKT signaling in colon cancer. CONCLUSION: Linc00659 is a novel oncogenic lncRNA involved in colon cancer cell growth by modulating the cell cycle. Our findings give an insight into lncRNA regulation and provide an application for colon cancer therapy. PMID- 29523146 TI - Chronic disease management perspectives of colorectal cancer survivors using the Veterans Affairs healthcare system: a qualitative analysis. AB - BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the US. CRC survivors may have complex healthcare needs requiring care from both specialists and primary care. Our objective was to understand how CRC survivors perceive their survivorship care, especially management of their cardiovascular-related chronic diseases. METHODS: We identified patients diagnosed with non-metastatic CRC between 10/1/2007 and 12/31/2015 at Veterans Affairs Medical Centers in North Carolina or Virginia. In 2016, we conducted telephone-based, semi-structured interviews to assess survivors' experiences with cancer survivorship and changes in health priorities. Interviews were conducted until thematic saturation was reached. Interviews were audio-recorded, transcribed, and coded. RESULTS: The 25 participants were, on average, 64 years old and approximately 4 years post-CRC diagnosis at the time of interview; most were white (60%), male (92%), and diagnosed with colon cancer (64%) as opposed to rectal cancer. CRC survivors reported: (1) a shift in focus from surviving cancer to reducing cardiovascular disease risk (e.g., by managing weight); (2) challenges with taking medications for CVD-related conditions; (3) new recognition of the importance of engaging with primary care providers. CONCLUSIONS: Experiences with cancer shapes how survivors view their health. Management of cardiovascular-related chronic disease is important to veteran CRC survivors. There is a need to deliver cardiovascular disease risk reduction programs tailored for CRC survivors. PMID- 29523147 TI - Omega-6/omega-3 fatty acid intake of children and older adults in the U.S.: dietary intake in comparison to current dietary recommendations and the Healthy Eating Index. AB - BACKGROUND: Omega-6 and omega-3 fatty acids (FAs) and their ratio have been shown to affect cognitive function in children and older adults. With these analyses, we aimed to describe omega-6 and omega-3 FA intake among children and older adults in light of FA intake recommendations and with consideration of overall diet. METHODS: Data were merged from two cross-sectional studies with 219 children 7 to 12 years old and one longitudinal study with 133 adults 65 to 79 years old. Demographic data, anthropometric data, and Healthy Eating Index scores were used to study relations among the omega-6 to omega-3 FA ratio and age, education, body mass index, and diet quality. FA intake, demographic, and anthropometric data were examined using partial correlations, t-tests, and analysis of variance. RESULTS: Most children and adults consumed at least the recommended amount of alpha-linolenic acid (LNA; omega-3) for their age and gender without consuming high amounts of linoleic acid (LA; omega-6), but did not consume sufficient eicosapentaenoic acid (EPA; omega-) and docosahexaenoic acid (DHA; omega-3). The average omega-6 to omega-3 ratios in both groups were lower than previously reported. Eating lower ratios was associated with healthier diets and consuming adequate amounts of several other nutrients. No demographic or anthropometric variables were related to FA intake in children. Adults with a college degree had significantly lower ratios than those without a college degree. CONCLUSIONS: American children and older adults are able to consume more balanced omega-6 to omega-3 ratios than has been indicated by commodity data. However, very few American children met even the lowest recommendations for EPA and DHA intake. Research is needed to clarify recommendations for the optimal ratio across development, which may aid in increasing EPA and DHA intake and improving health outcomes in the United States. TRIAL REGISTRATION: ClinicalTrials.gov NCT02199808 13 July 2014, NCT01823419 (retrospectively registered) 20 March 2013, and NCT01515098 18 January 2012. PMID- 29523148 TI - Using normalisation process theory to evaluate the implementation of a complex intervention to embed the surgical safety checklist. AB - BACKGROUND: The surgical Safety Checklist (SSC) was introduced in 2008 to improve teamwork and reduce the mortality and morbidity associated with surgery. Although mandated in many health care institutions around the world, challenges in implementation of the SSC continue. To use Normalisation Process Theory (NPT) to help understand how/why implementation of a complex intervention coined Pass The Baton (PTB) could help explain what facets of the Surgical Safety Checklist use led to its' integration in practice, while others were not. METHODS: A longitudinal multi-method study using survey and interviews was undertaken. Implementation of PTB involved; change champions, audit and feedback, education and prompts. Following implementation, surgical teams were surveyed using the NOrmalization MeAsure Development (NoMAD) and subsequently interviewed to explore the impact of PTB on their use of the checklist at 6 and 12 months respectively. Respondents' self-reported perceptions of implementation of PTB was explained using the four NPT constructs; coherence, cognitive participation, collective action, and reflexive monitoring. Survey data were analysed using descriptive statistics. Interview data were coded inductively and content analysed using a framework derived from NPT. RESULTS: The NoMAD survey response rate was 59/150 (39.3%). Many (45/59, 77.6%) survey respondents saw the value in PTB, while 50/59 (86.2%) would continue to use it; 45/59 (77.6%) believed that PTB could easily be integrated into existing workflows, and 48/59 (82.8%) thought that feedback could improve PTB in the future. A total of 8 interviews were completed with 26 surgical team members. Nurses and physicians held mixed views towards coherence while buy-in and participation relied on individuals' investment in the implementation process and the ability to modify PTB. Participants generally recognised the benefit and value of using PTB in the ongoing implementation the checklist. CONCLUSIONS: Workarounds and flexible co-construction in implementation designed to improve team communications in surgery may facilitate their normalisation in practice. PMID- 29523149 TI - Metabolic engineering of the 2-ketobutyrate biosynthetic pathway for 1-propanol production in Saccharomyces cerevisiae. AB - BACKGROUND: To produce 1-propanol as a potential biofuel, metabolic engineering of microorganisms, such as E. coli, has been studied. However, 1-propanol production using metabolically engineered Saccharomyces cerevisiae, which has an amazing ability to produce ethanol and is thus alcohol-tolerant, has infrequently been reported. Therefore, in this study, we aimed to engineer S. cerevisiae strains capable of producing 1-propanol at high levels. RESULTS: We found that the activity of endogenous 2-keto acid decarboxylase and alcohol/aldehyde dehydrogenase is sufficient to convert 2-ketobutyrate (2 KB) to 500 mg/L 1 propanol in yeast. Production of 1-propanol could be increased by: (i) the construction of an artificial 2 KB biosynthetic pathway from pyruvate via citramalate (cimA); (ii) overexpression of threonine dehydratase (tdcB); (iii) enhancement of threonine biosynthesis from aspartate (thrA, thrB and thrC); and (iv) deletion of the GLY1 gene that regulates a competing pathway converting threonine to glycine. With high-density anaerobic fermentation of the engineered S. cerevisiae strain YG5C4231, we succeeded in producing 180 mg/L 1-propanol from glucose. CONCLUSION: These results indicate that the engineering of a citramalate mediated pathway as a production method for 1-propanol in S. cerevisiae is effective. Although optimization of the carbon flux in S. cerevisiae is necessary to harness this pathway, it is a promising candidate for the large-scale production of 1-propanol. PMID- 29523150 TI - Characterization of immortalized human dermal microvascular endothelial cells (HMEC-1) for the study of HDL functionality. AB - BACKGROUND: Primary cultures endothelial cells have been used as models of endothelial related diseases such atherosclerosis. Biological behavior of primary cultures is donor-dependent and data could not be easily reproducible; endothelial cell lines are emerging options, particularly, human dermal microvascular endothelial cells (HMEC-1), that should be validated to substitute primary cultures for the study of HDL functions. METHODS: Morphology, size and granularity of cells were assessed by phase contrast microscopy and flow cytometry of HMEC-1. The adhesion molecules, ICAM-1and VCAM-1 after TNF-alpha stimulation, and endothelial markers CD105 endoglin, as well as HDL receptor SR BI were determined by flow cytometry. Internalization of HDL protein was demonstrated by confocal microscopy using HDL labeled with Alexa Fluor 488. HUVECs were used as reference to compared the characteristics with HMEC-1. RESULTS: HMEC-1 and HUVEC had similar morphologies, size and granularity. HMEC-1 expressed endothelial markers as HUVECs, as well as functional SR-B1 receptor since the cell line was able to internalize HDL particles. HMEC-1 effectively increased ICAM-1 and VCAM-1 expression after TNF-alpha stimulation. HUVECs showed more sensibility to TNF-alpha stimulus but the range of ICAM-1 and VCAM-1 expression was less homogeneous than in HMEC-1, probably due to biological variation of the former. Finally, the expression of adhesion molecules in HMEC-1 was attenuated by co-incubation with HDL. CONCLUSION: HMEC-1 possess characteristics of endothelial cells, similar to HUVECs, being a cell line suitable to evaluate the functionality of HDL vis-a-vis the endothelium. PMID- 29523151 TI - Oxygen effects on rhamnolipids production by Pseudomonas aeruginosa. AB - BACKGROUND: Rhamnolipids are the most extensively studied biosurfactants and has been successfully used in various areas from bioremediation to industrial fields. Rhamnolipids structural composition decide their physicochemical properties. Different physicochemical properties influence their application potential. Rhamnolipids can be produced at both aerobic conditions and anaerobic conditions by Pseudomonas aeruginosa. This study aims to evaluate the oxygen effects on the rhamnolipids yield, structural composition, physicochemical properties and the rhl-genes expression in P. aeruginosa SG. Results will guide researchers to regulate microbial cells to synthesize rhamnolipids with different activity according to diverse application requirements. RESULTS: Quantitative real-time PCR analysis revealed that rhlAB genes were down-regulated under anaerobic conditions. Therefore, strain P. aeruginosa SG anaerobically produced less rhamnolipids (0.68 g/L) than that (11.65 g/L) under aerobic conditions when grown in media containing glycerol and nitrate. HPLC-MS analysis showed that aerobically produced rhamnolipids mainly contained Rha-C8-C10, Rha-Rha-C10-C12:1 and Rha-Rha-C8-C10; anaerobically produced rhamnolipids mainly contained Rha-C10 C12 and Rha-C10-C10. Anaerobically produced rhamnolipids contained more mono rhamnolipids (94.7%) than that (54.8%) in aerobically produced rhamnolipids. rhlC gene was also down-regulated under anaerobic conditions, catalyzing less mono rhamnolipids to form di-rhamnolipids. Aerobically produced rhamnolipids decreased air-water surface tension (ST) from 72.2 to 27.9 mN/m with critical micelle concentration (CMC) of 60 mg/L; anaerobically produced rhamnolipids reduced ST to 33.1 mN/m with CMC of 80 mg/L. Anaerobically produced rhamnolipids emulsified crude oil with EI24 = 80.3%, and aerobically produced rhamnolipids emulsified crude oil with EI24 = 62.3%. Both two rhamnolipids products retained surface activity (ST < 35.0 mN/m) and emulsifying activity (EI24 > 60.0%) under temperatures (4-121 degrees C), pH values (4-10) and NaCl concentrations less than 90 g/L. CONCLUSIONS: Oxygen affected the rhl-genes expression in P. aeruginosa, thus altering the rhamnolipids yield, structural composition and physicochemical properties. Rhamnolipids produced at aerobic or anaerobic conditions was structurally distinct. Two rhamnolipids products had different application potential in diverse biotechnologies. Although both rhamnolipids products were thermo-stable and halo-tolerant, aerobically produced rhamnolipids possessed better surface activity, implying its well wetting activity and desorption property; anaerobically produced rhamnolipids exhibited better emulsifying activity, indicating its applicability for enhanced oil recovery and bioremediation of petroleum pollution. PMID- 29523152 TI - Short-term culture of adult bovine ovarian tissues: chorioallantoic membrane (CAM) vs. traditional in vitro culture systems. AB - BACKGROUND: A suitable culture system is important for follicle growth in adult bovine ovarian tissue. This study aimed to assess the avian chorioallantoic membrane (CAM) for short-term culture of adult bovine ovarian tissues compared with a traditional in vitro culture system. METHODS: Ovarian cortical tissues (1 2 mm3), collected from slaughtered adult cows, were randomly assigned to control, CAM or in vitro culture groups. In the control group, ovarian tissues were fixed with paraformaldehyde without culture. In CAM and in vitro culture groups, the ovarian tissues were cultured for up to 5 days and then fixed. Ovarian tissues were examined on culture days 0, 1, 3 and 5 for angiogenesis, follicle morphology and growth. In all groups, primordial and growing (healthy and atretic) follicle densities were determined. RESULTS: In the CAM culture, the avian blood vessel density increased (p < 0.01) over time with a decline (p < 0.001) in the bovine blood vessel density. Healthy primordial, atretic primordial and healthy growing follicle densities were higher (p < 0.05) in CAM-cultured ovarian tissues than in vitro-cultured tissues. Regardless of the culture system, the density of healthy primordial follicles decreased (p < 0.001) over time with an increase in healthy growing follicles on day 3 (p < 0.01) and an increase in atretic (primordial and growing) follicles during the 5-day culture period (p < 0.001). The proportions of healthy primordial and atretic growing follicles were also affected by culture day (p < 0.001). CONCLUSIONS: The CAM culture in chick embryos supported the bovine ovarian tissue grafts for 3 days demonstrating that CAM can be used as a satisfactory short-term culture system to assess ovarian tissue health, and to study follicle activation and development. PMID- 29523153 TI - Cost-effectiveness in extracorporeal life support in critically ill adults in the Netherlands. AB - BACKGROUND: Extracorporeal life support (ECLS) is used to support the cardiorespiratory function in case of severe cardiac and/or respiratory failure in critically ill patients. According to the ELSO guidelines ECLS should be considered when estimated mortality risk approximates 80%. ECLS seems an efficient therapy in terms of survival benefit, but no undisputed evidence is delivered yet. The aim of the study is to assess the health-related quality of life after ECLS treatment and its cost effectiveness. METHODS: We will perform a prospective observational cohort study. All adult patients who receive ECLS in the participating centers will be included. Exclusion criteria are patients in whom the ECLS is only used to bridge a procedure (like a high risk percutaneous coronary intervention or surgery) or the absence of informed consent. Data collection includes patient characteristics and data specific for ECLS treatment. Severity of illness and mortality risk is measured as precisely as possible using measurements for the appropriate age group and organ failure. For analyses on survival patients will act as their own control as we compare the actual survival with the estimated mortality on initiation of ECLS if conservative treatment would have been continued. Survivors are asked to complete validated questionnaires on health related quality of life (EQ5D-5 L) and on medical consumption and productivity losses (iMTA/iPCQ) at 6 and 12 months. Also the health related quality of life 1 month prior to ECLS initiation will be obtained by a questionnaire, if needed provided by relatives. With an estimated overall survival of 62% 210 patients need to be recruited to make a statement on cost effectiveness for all ECLS indications. DISCUSSION: If our hypothesis that ECLS treatment is cost-effective is confirmed by this prospective study this could lead to an even broader use of ECLS treatment. TRIAL REGISTRATION: The trial is registered at ( NCT02837419 ) registration date July 19, 2016 and with the Dutch trial register, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6599. PMID- 29523154 TI - Loss of miR-204 expression is a key event in melanoma. AB - Cutaneous melanoma (CM) is a malignancy with increasing occurrence. Its microRNA repertoire has been defined in a number studies, leading to candidates for biological and clinical relevance: miR-200a/b/c, miR-203, miR-205, miR-204, miR 211, miR-23b and miR-26a/b. Our work was aimed to validate the role of these candidate miRNAs in melanoma, using additional patients cohorts and in vitro cultures. miR-26a, miR-204 and miR-211 were more expressed in normal melanocytes, while miR-23b, miR-200b/c, miR-203 and miR-205 in epidermis and keratinocytes. None of the keratinocyte-related miRNAs was associated with any known mutation or with clinical covariates in melanoma. On the other hand, the loss of miR-204 was enriched in melanomas with NRAS sole mutation (Fisher exact test, P = 0.001, Log Odds = 1.67), and less frequent than expected in those harbouring CDKN2A mutations (Fisher exact test, P = 0.001, Log Odds - 1.09). Additionally, miR-204 was associated with better prognosis in two independent melanoma cohorts and its exogenous expression led to growth impairment in melanoma cell lines. Thus, miR 204 represents a relevant mechanism in melanoma, with potential prognostic value and its loss seems to act in the CDKN2A pathway, in cooperation with NRAS. PMID- 29523155 TI - The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis. AB - BACKGROUND: MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). METHODS: Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 umol/kg and (4) ACLT + MIV 711, 100 umol/kg. Subchondral bone and articular cartilage structures were assessed by uCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 umol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured. RESULTS: In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus. CONCLUSIONS: MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA. PMID- 29523156 TI - Low dose Naltrexone for induction of remission in inflammatory bowel disease patients. AB - BACKGROUND: Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function. METHODS: Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples. RESULTS: Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected. CONCLUSIONS: Naltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients. PMID- 29523157 TI - Neuromuscular blockade is associated with the attenuation of biomarkers of epithelial and endothelial injury in patients with moderate-to-severe acute respiratory distress syndrome. AB - BACKGROUND: Neuromuscular blockade (NMB) is a therapy for acute respiratory distress syndrome (ARDS). However, the mechanism by which NMB may improve outcome for ARDS patients remains unclear. We sought to determine whether NMB attenuates biomarkers of epithelial and endothelial lung injury and systemic inflammation in ARDS patients, and whether the association is dependent on tidal volume size and the initial degree of hypoxemia. METHODS: We performed a secondary analysis of patients enrolled in the ARDS network low tidal volume ventilation (ARMA) study. Our primary predictor variable was the number of days receiving NMB between study enrollment and day 3. Our primary outcome variables were the change in concentration of biomarkers of epithelial injury (serum surfactant protein-D (SP D)), endothelial injury (von Willebrand factor (VWF)), and systemic inflammation (interleukin (IL)-8). Multivariable regression analysis was used to compare the change in biomarker concentration controlling for multiple covariates. Patients were stratified by treatment arm (12 versus 6 cm3/kg) and by an initial arterial oxygen tension (PaO2) to fractional inspired oxygen (FiO2) (P/F) ratio of 120. RESULTS: A total of 446 (49%) patients had complete SP-D, VWF, and IL-8 measurements on study enrollment and day 3. After adjusting for baseline differences, each day of NMB was associated with a decrease in SP-D (-23.7 ng/ml/day, p = 0.029), VWF (-33.5% of control/day, p = 0.015), and IL-8 (-362.6 pg/ml/day, p = 0.030) in patients with an initial P/F less than or equal to 120 and receiving low tidal volume ventilation. However, patients with a P/F ratio of greater than 120 or receiving high tidal volume ventilation had either no change or an increase in SP-D, WVF, or IL-8 concentrations. CONCLUSION: NBM is associated with decreased biomarkers of epithelial and endothelial lung injury and systemic inflammation in ARDS patients receiving low tidal volume ventilation and those with a P/F ratio less than or equal to 120. PMID- 29523158 TI - Study on the progression types of cancer in patients with breast cancer undergoing eribulin chemotherapy and tumor microenvironment. AB - BACKGROUND: Recently, the concepts of progression due to pre-existing lesions (PPL) and progression due to new metastasis (PNM) have been proposed to differentiate the progression types of treatment-resistant cancers. Previously, the differences between these two progression types did not affect the determination of treatment strategies since both PPL and PNM are classified as progressive disease based on the response evaluation criteria in solid tumors (RECIST) diagnostic criteria. On the other hand, tumor infiltrating lymphocytes (TILs) are effective when used as indicators for monitoring the immune tumor microenvironment (iTME) in the cancer host, and TILs play an important role as biomarkers in predicting prognosis and therapeutic effects. This study focused on the progression types of cancer in patients undergoing eribulin chemotherapy. In addition, the iTME in individuals with PPL and PNM was evaluated using TILs as a marker. METHODS: Of the 52 patients with locally advanced or metastatic breast cancer who underwent chemotherapy with eribulin, 40 remained in the study, and 12 patients were dropout cases. The antitumor effect was evaluated based on the RECIST criteria using version 1.1. TILs were defined as the infiltrating lymphocytes within tumor stroma and were expressed in proportion to the field investigated. In PPL cases, the high-TIL group was considered as type I and the low-TIL group was classified as type II. In PNM cases, the high-TIL group was considered as type III and the low-TIL group was classified as type IV. RESULTS: In 19 cases, individuals with type I progression had significantly longer progression free survival and overall survival (OS) compared to those with type III progression (p = 0.040, p < 0.001, log-rank). Individuals with type I progression had significantly prolonged survival post progression compared to those with type II progression (p = 0.048, log-rank). A multivariate analysis that validate the effect of OS showed that these were independent factors of good prognosis (p = 0.003; hazard ratio [HR] = 0.065) (p = 0.006; HR = 0.105). CONCLUSIONS: The effects of eribulin chemotherapy suggested that patients with progressive-type breast cancer that proliferates in a good iTME may have a good prognosis. PMID- 29523159 TI - C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. AB - BACKGROUND: Triptolide is a structurally unique diterpene triepoxide with potent antitumor activity. However,the effect and mechanism of triptolide on hepatocellular carcinoma (HCC) is not well studied. METHODS: Cells were treated with triptolide, and the anti-HCC activity of triptolide was evaluated using flow cytometry, western blot, and xenograft studies. MicroRNA microarray and quantitative reverse-transcription polymerase chain reaction was used to identify differential microRNAs induced by triptolide. Chromatin immunoprecipitation assay was employed to study the interaction between c-Myc and genomic regions of miR106b-25. MicroRNAs overexpression and knockdown experiments were performed to determine the role of these microRNAs in triptolide-induced apoptosis. RESULTS: Triptolide inhibited cell proliferation and induced marked apoptosis in multiple HCC cell lines with different p53 status. Several signaling molecules involved in different pathways were altered after the treatment of triptolide. Xenograft tumor volume was significantly reduced in triptolide-treated group compared with vehicle control group. Two miRNA clusters, miR-17-92 and miR-106b-25, were significantly suppressed by triptolide, which resulted in the upregulation of their common target genes, including BIM, PTEN, and p21. In HCC samples, high levels of these miRNA clusters correlated with shorter recurrence free survival. Triptolide inhibited the expression of theses miRNAs in a c-Myc-dependent manner, which enhanced triptolide-induced cell death. We further showed that triptolide down-regulated the expression of c-Myc through targeting ERCC3, a newly identified triptolide-binding protein. CONCLUSIONS: The triptolide-induced modulation of c-Myc/miRNA clusters/target genes axis enhances its potent antitumor activity, which indicates that triptolide serves as an attractive chemotherapeutic agent against HCC. PMID- 29523161 TI - Health system innovations: adapting to rapid change. AB - This paper introduces the Thematic Issue on Innovation in Health Systems in Low- and Middle-Income Countries. PMID- 29523160 TI - A novel progesterone receptor membrane component (PGRMC) in the human and swine parasite Taenia solium: implications to the host-parasite relationship. AB - BACKGROUND: We have previously reported that progesterone (P4) has a direct in vitro effect on the scolex evagination and growth of Taenia solium cysticerci. Here, we explored the hypothesis that the P4 direct effect on T. solium might be mediated by a novel steroid-binding parasite protein. METHODS: By way of using immunofluorescent confocal microscopy, flow cytometry analysis, double-dimension electrophoresis analysis, and sequencing the corresponding protein spot, we detected a novel PGRMC in T. solium. Molecular modeling studies accompanied by computer docking using the sequenced protein, together with phylogenetic analysis and sequence alignment clearly demonstrated that T. solium PGRMC is from parasite origin. RESULTS: Our results show that P4 in vitro increases parasite evagination and scolex size. Using immunofluorescent confocal microscopy, we detected that parasite cells showed expression of a P4-binding like protein exclusively located at the cysticercus subtegumental tissue. Presence of the P4-binding protein in cyst cells was also confirmed by flow cytometry. Double-dimension electrophoresis analysis, followed by sequencing the corresponding protein spot, revealed a protein that was previously reported in the T. solium genome belonging to a membrane-associated progesterone receptor component (PGRMC). Molecular modeling studies accompanied by computer docking using the sequenced protein showed that PGRMC is potentially able to bind steroid hormones such as progesterone, estradiol, testosterone and dihydrodrotestosterone with different affinities. Phylogenetic analysis and sequence alignment clearly demonstrated that T. solium PGRMC is related to a steroid-binding protein of Echinoccocus granulosus, both of them being nested within a cluster including similar proteins present in platyhelminths such as Schistocephalus solidus and Schistosoma haematobium. CONCLUSION: Progesterone may directly act upon T. solium cysticerci probably by binding to PGRMC. This research has implications in the field of host-parasite co evolution as well as the sex-associated susceptibility to this infection. In a more practical matter, present results may contribute to the molecular design of new drugs with anti-parasite actions. PMID- 29523162 TI - Effect of gamma-secretase inhibitor on Th17 cell differentiation and function of mouse psoriasis-like skin inflammation. AB - BACKGROUND: Th17 cells and its effective cytokine IL-17A play an important role in the pathogenesis of abnormal immune responses in psoriasis. Notch1 signaling has been implicated in Th17 cell differentiation and function. In this study, our aim was to evaluate the possible inhibitory effect of Notch1 signaling inhibitor, gamma-secretase inhibitor DAPT, on psoriatic Th17 cell differentiation and function in a mouse model of psoriasis-like skin inflammation. METHODS: Mouse psoriasis-like skin inflammation model was established by topical 5% imiquimod (IMQ) application, and experimental mice were divided into control group, IMQ treated group and IM + DAPT-treated group. DAPT and the equivalent amount of Dimethyl sulfoxide was intraperitoneally injected in IMQ + DAPT-treated group and the other two experimental groups respectively. Skin tissues of the three experimental groups were acquired and stained with haematoxylin and eosin (HE). Splenic single-cells and serum were collected to detect the percentage of Th17 cells, the mRNA expression levels of Notch1 and its target gene Hes-1, Th17 specific transcription factor RORgammat and its effective cytokines IL-17A, as well as IL-17A serum concentration. In addition, splenic CD4+ T cells from IMQ treated mice were isolated and treated by DAPT to further measure the inhibitory effect of DAPT on the Th17 cell differentiation and IL-17A secretion in vitro. RESULTS: DAPT treatment alleviated the severity of IMQ-induced mouse psoriasis like skin inflammation and decreased the scores of erythema, scaling and thickening. HE stain reveals obviously reduced epidermal hyperplasia and dermal inflammatory cells infiltration in IMQ + DAPT-treated mice. The increased expression of splenic Th17 cell percentage, along with Notch1, Hes-1, RORgammat and IL-17A mRNA and IL-17A serum concentration in IMQ-treated mice were significantly decreased when experimental mice were treated by IMQ and DAPT combinedly. Data obtained from in vitro study in IMQ-treated mice also demonstrated that blocking Notch1 signaling by DAPT can result in a dose dependent decrease of Th17 cell proportion, mRNA expression of Notch1, Hes-1, RORgammat and IL-17A as well as IL-17A secretion in splenic CD4+ T cells. CONCLUSION: These data suggest that Notch1 inhibition by DAPT can effectively alleviate the severity of mouse psoriasis-like skin inflammation by regulating the differentiation and function of Th17 cells, indicating that DAPT might be a potential therapeutic candidate for the treatment of psoriatic inflammation. PMID- 29523163 TI - Quartz-Seq2: a high-throughput single-cell RNA-sequencing method that effectively uses limited sequence reads. AB - High-throughput single-cell RNA-seq methods assign limited unique molecular identifier (UMI) counts as gene expression values to single cells from shallow sequence reads and detect limited gene counts. We thus developed a high throughput single-cell RNA-seq method, Quartz-Seq2, to overcome these issues. Our improvements in the reaction steps make it possible to effectively convert initial reads to UMI counts, at a rate of 30-50%, and detect more genes. To demonstrate the power of Quartz-Seq2, we analyzed approximately 10,000 transcriptomes from in vitro embryonic stem cells and an in vivo stromal vascular fraction with a limited number of reads. PMID- 29523164 TI - Mitochondrial genome data confirm that yaks can serve as the intermediate host of Echinococcus canadensis (G10) on the Tibetan Plateau. AB - BACKGROUND: Cervids used to be considered the only animal intermediate hosts of the G10 genotype of Echinococcus canadensis. Yaks are often herded in the Qinghai Tibet Plateau, China, where echinococcosis remains prevalent. However, no E. canadensis G10 cases have been recorded in yaks until now. The aim of our study was to identify causative agents of echinococcosis in yaks in this region. METHODS: Total genomic DNA was extracted from the germinal layer of one hydatid using a Blood and Tissue Kit. Full-length mitochondrial (mt) cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes were amplified by PCR. All purified PCR products were directly sequenced in both directions. Then seven pairs of overlap primers were designed to amplify the entire mt genome sequence of a suspected E. canadensis G10 isolate. Phylogenetic analyses were performed based on concatenated nucleotides from the 12 protein-coding genes of mt genomes of Echinococcus species in a Bayesian framework using MrBayes v3.1 and implementing the GTR + I + G model. RESULTS: Hydatids were found in yaks (n = 129) when organs were inspected at the slaughterhouse in Maqu county, Gannan Tibetan Autonomous Prefecture, Gansu Province, China in October 2016. Of these, 33 (25.6%) harbored up to a dozen hydatid cysts. One cyst from each yak was characterized by sequencing its mitochondrial (mt) cox1 and nad1 genes. On the basis of these sequence data, 32 cysts were identified as Echinococcus granulosus (sensu stricto) (G1-G3) and the remaining one was identified as the G10 genotype of E. canadensis. Its mt genome was then fully sequenced and compared with that of the G10 genotype in GenBank (AB745463). Phylogenetic analysis using complete mt genomes confirmed the Chinese cyst as belonging to the G10 genotype. CONCLUSIONS: To our knowledge, this is the first report globally of E. canadensis (G10) from yaks in China, which suggests that the G10 genotype has a wider geographical distribution and broader host range than previously believed. This genotype has therefore potential risks to human health and animal husbandry. PMID- 29523165 TI - Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome. AB - BACKGROUND: There is a preponderance of evidence implicating diabetes with increased coronary artery disease (CAD) and calcification (CAC) in human patients with metabolic syndrome (MetS), but the effect of diabetes on CAD severity in animal models remains controversial. We investigated whether diabetes exacerbates CAD/CAC and intracellular free calcium ([Ca2+]i) dysregulation in the clinically relevant Ossabaw miniature swine model of MetS. METHODS: Sixteen swine, eight with alloxan-induced diabetes, were fed a hypercaloric, atherogenic diet for 6 months. Alloxan-induced pancreatic beta cell damage was examined by immunohistochemical staining of insulin. The metabolic profile was confirmed by body weight, complete blood panel, intravenous glucose tolerance test (IVGTT), and meal tolerance test. CAD severity was assessed with intravascular ultrasound and histology. [Ca2+]i handling in coronary smooth muscle (CSM) cells was assessed with fura-2 ratiometric imaging. RESULTS: Fasting and post-prandial blood glucose, total cholesterol, and serum triglycerides were elevated in MetS diabetic swine. This group also exhibited hypoinsulinemia during IVGTT and less pancreatic beta cell mass when compared to lean and MetS-nondiabetic swine. IVUS analysis revealed that MetS-diabetic swine had greater percent wall coverage, percent plaque burden, and calcium index when compared to lean and MetS nondiabetic swine. Fura-2 imaging of CSM [Ca2+]i revealed that MetS-nondiabetic swine exhibited increased sarcoplasmic reticulum Ca2+ store release and Ca2+ influx through voltage-gated Ca2+ channels compared to lean swine. MetS-diabetic swine exhibited impaired Ca2+ efflux. CONCLUSIONS: Diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with MetS, accompanied by progression of [Ca2+]i dysregulation in advanced CAD/CAC. These results recapitulate increased CAD in humans with diabetes and establish Ossabaw miniature swine as an animal model for future MetS/diabetes comorbidity studies. PMID- 29523166 TI - Predominant envelope variable loop 2-specific and gp120-specific antibody dependent cellular cytotoxicity antibody responses in acutely SIV-infected African green monkeys. AB - BACKGROUND: The initial envelope (Env)-specific antibody response in acutely HIV 1-infected individuals and simian immunodeficiency virus (SIV)-infected rhesus monkeys (RMs) is dominated by non-neutralizing antibodies targeting Env gp41. In contrast, natural primate SIV hosts, such as African green monkeys (AGMs), develop a predominant Env gp120-specific antibody response to SIV infection. However, the fine-epitope specificity and function of SIV Env-specific plasma IgG, and their potential role on autologous virus co-evolution in SIV-infected AGMs and RMs remain unclear. RESULTS: Unlike the dominant linear gp41-specific IgG responses in RMs, SIV-infected AGMs demonstrated a unique linear variable loop 2 (V2)-specific plasma IgG response that arose concurrently with high gp120 directed antibody-dependent cellular cytotoxicity (ADCC) activity, and SIVsab infected cell binding responses during acute infection. Moreover, SIV variants isolated from SIV-infected AGMs exhibited high amino acid mutation frequencies within the Env V1V2 loop compared to those of RMs. Notably, the linear V2 specific IgG epitope in AGMs overlaps with an analogous region of the HIV V2 loop containing the K169 mutation epitope identified in breakthrough viruses from RV144 vaccinees. CONCLUSION: Vaccine-elicited Env V2-specific IgG responses have been proposed as an immune correlate of reduced risk in HIV-1/SIV acquisition in humans and RMs. Yet the pathways to elicit these potentially-protective V2 specific IgG responses remain unclear. In this study, we demonstrate that SIV infected AGMs, which are the natural hosts of SIV, exhibited high plasma linear V2-specific IgG binding responses that arose concurrently with SIV Env gp120 directed ADCC-mediating, and SIV-infected cell plasma IgG binding responses during acute SIV infection, which were not present in acutely SIV-infected RMs. The linear V2-specific antibody response in AGMs targets an overlapping epitope of the proposed site of vaccine-induced immune pressure defined in the moderately protective RV144 HIV-1 vaccine trial. Identifying host factors that control the early elicitation of Env V2-specific IgG and ADCC antibody responses in these natural SIV hosts could inform vaccination strategies aimed at rapidly inducing potentially-protective HIV-1 Env-specific responses in humans. PMID- 29523167 TI - Organizational- and system-level characteristics that influence implementation of shared decision-making and strategies to address them - a scoping review. AB - BACKGROUND: Shared decision-making (SDM) is poorly implemented in routine care, despite being promoted by health policies. No reviews have solely focused on an in-depth synthesis of the literature around organizational- and system-level characteristics (i.e., characteristics of healthcare organizations and of healthcare systems) that may affect SDM implementation. A synthesis would allow exploration of interventions to address these characteristics. The study aim was to compile a comprehensive overview of organizational- and system-level characteristics that are likely to influence the implementation of SDM, and to describe strategies to address those characteristics described in the literature. METHODS: We conducted a scoping review using the Arksey and O'Malley framework. The search strategy included an electronic search and a secondary search including gray literature. We included publications reporting on projects that promoted implementation of SDM or other decision support interventions in routine healthcare. We screened titles and abstracts, and assessed full texts for eligibility. We used qualitative thematic analysis to identify organizational- and system-level characteristics. RESULTS: After screening 7745 records and assessing 354 full texts for eligibility, 48 publications on 32 distinct implementation projects were included. Most projects (N = 22) were conducted in the USA. Several organizational-level characteristics were described as influencing the implementation of SDM, including organizational leadership, culture, resources, and priorities, as well as teams and workflows. Described system-level characteristics included policies, clinical guidelines, incentives, culture, education, and licensing. We identified potential strategies to influence the described characteristics, e.g., examples how to facilitate distribution of decision aids in a healthcare institution. CONCLUSIONS: Although infrequently studied, organizational- and system-level characteristics appear to play a role in the failure to implement SDM in routine care. A wide range of characteristics described as supporting and inhibiting implementation were identified. Future studies should assess the impact of these characteristics on SDM implementation more thoroughly, quantify likely interactions, and assess how characteristics might operate across types of systems and areas of healthcare. Organizations that wish to support the adoption of SDM should carefully consider the role of organizational- and system-level characteristics. Implementation and organizational theory could provide useful guidance for how to address facilitators and barriers to change. PMID- 29523168 TI - A comparison of efficacy of six prediction models for intravenous immunoglobulin resistance in Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is the most common pediatric vasculitis. Several models have been established to predict intravenous immunoglobulin (IVIG) resistance. The present study was aimed to evaluate the efficacy of prediction models using the medical data of KD patients. METHODS: We collected the medical records of patients hospitalized in the Department of Cardiology in Children's Hospital of Soochow University with a diagnosis of KD from Jan 2015 to Dec 2016. IVIG resistance was defined as recrudescent or persistent fever >=36 h after the end of their IVIG infusion. RESULTS: Patients with IVIG resistance tended to be younger, have higher occurrence of rash and changes of extremities. They had higher levels of c-reactive protein, aspartate aminotransferase, neutrophils proportion (N%), total bilirubin and lower level of albumin. Our prediction model had a sensitivity of 0.72 and a specificity of 0.75. Sensitivity of Kobayashi, Egami, Kawamura, Sano and Formosa were 0.72, 0.44, 0.48, 0.20, and 0.68, respectively. Specificity of these models were 0.62, 0.82, 0.66, 0.91, and 0.48, respectively. CONCLUSIONS: Our prediction model had a powerful predictive value in this area, followed by Kobayashi model while all the other prediction models had less excellent performances than ours. PMID- 29523169 TI - Dedicated mobile application for drug adverse reaction reporting by patients with relapsing remitting multiple sclerosis (Vigip-SEP study): study protocol for a randomized controlled trial. AB - BACKGROUND: The reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD. The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD. METHODS/DESIGN: We designed a multi-centric, open cluster randomized controlled trial, called the Vigip-SEP study (NCT03029897), using the App My eReport France(r) to report ADR to the appropriate authorities in E2B language, in accordance with European regulations. RR-MS patients who were initiated on, or switched, first-line DMD will be included. In the experimental arm, a neurologist will introduce the patient to the App to report ADR to the appropriate French authorities. In the control arm, the patient will be informed of the existence of the App but will not be introduced to its use and will then report ADR according to the usual reporting procedures. Primary assessment criteria are defined as the average number of ADR per patient and per center. We assume that the App will increase patient reporting by 10-fold. Therefore, we will require 24 centers (12 per arm: 6 MS academic expert centers, 3 general hospitals, 3 private practice neurologists), allowing for an expected enrollment of 180 patients (alpha risk 5%, power 90% and standard deviation 4%). DISCUSSION: Increasing patient reporting of ADR in a real-life setting is extremely important for therapeutic management of RR-MS, particularly for monitoring newly approved DMD to gain better knowledge of their safety profiles. To increase patient involvement, teaching patients to use tools, such as mobile applications, should be encouraged, and these tools should be tested rigorously. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT03029897 . Registered on 20 January 2017. PMID- 29523170 TI - Does feedback on daily activity level from a Smart watch during inpatient stroke rehabilitation increase physical activity levels? Study protocol for a randomized controlled trial. AB - BACKGROUND: Practicing activities improves recovery after stroke, but many people in hospital do little activity. Feedback on activity using an accelerometer is a potential method to increase activity in hospital inpatients. This study's goal is to investigate the effect of feedback, enabled by a Smart watch, on daily physical activity levels during inpatient stroke rehabilitation and the short term effects on simple functional activities, primarily mobility. METHODS/DESIGN: A randomized controlled trial will be undertaken within the stroke rehabilitation wards of the Second Affiliated hospital of Anhui University of Traditional Chinese Medicine, Hefei, China. The study participants will be stroke survivors who meet inclusion criteria for the study, primarily: able to participate, no more than 4 months after stroke and walking independently before stroke. Participants will all receive standard local rehabilitation and will be randomly assigned either to receive regular feedback about activity levels, relative to a daily goal tailored by the smart watch over five time periods throughout a working day, or to no feedback, but still wearing the Smart watch. The intervention will last up to 3 weeks, ending sooner if discharged. The data to be collected in all participants include measures of daily activity (Smart watch measure); mobility (Rivermead Mobility Index and 10-metre walking time); independence in personal care (Barthel Activities of Daily Living (ADL) Index); overall activities (the World Health Organization (WHO) Disability Assessment Scale, 12-item version); and quality of life (the Euro-Qol 5L5D). Data will be collected by assessors blinded to allocation of the intervention at baseline, 3 weeks or at discharge (whichever is the sooner); and a reduced data set will be collected at 12 weeks by telephone interview. The primary outcome will be change in daily accelerometer activity scores. Secondary outcomes are compliance and adherence to wearing the watch, and changes in mobility, independence in personal care activities, and health-related quality of life. DISCUSSION: This project is being implemented in a large city hospital with limited resources and limited research experience. There has been a pilot feasibility study using the Smart watch, which highlighted some areas needing change and these are incorporated in this protocol. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02587585 . Registered on 30 September 2015. Chinese Clinical Trial Registry, ChiCTR-IOR-15007179 . Registered on 8 August 2015. PMID- 29523171 TI - Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a progressively debilitating neurological condition in which the immune system abnormally erodes the myelin sheath insulating the nerves. Mesenchymal stem cells (MSC) have been used in the last decade to safely treat certain immune and inflammatory conditions. METHODS: A safety and feasibility study was completed on the use of umbilical cord MSC (UCMSC) as a treatment for MS. In this 1-year study, consenting subjects received seven intravenous infusions of 20 * 106 UCMSC over 7 days. Efficacy was assessed at baseline, 1 month and 1 year after treatment, including magnetic resonance imaging (MRI) scans, Kurtzke Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale, Nine-Hole Peg Test, 25-Foot Walk Test, and RAND Short Form-36 quality of life questionnaire. RESULTS: Twenty subjects were enrolled in this study. No serious adverse events were reported. Of the mild AEs denoted as possibly related to treatment, most were headache or fatigue. Symptom improvements were most notable 1 month after treatment. Improvements were seen in EDSS scores (p < 0.03), as well as in bladder, bowel, and sexual dysfunction (p < 0.01), in non-dominant hand average scores (p < 0.01), in walk times (p < 0.02) and general perspective of a positive health change and improved quality of life. MRI scans of the brain and the cervical spinal cord showed inactive lesions in 15/18 (83.3%) subjects after 1 year. CONCLUSIONS: Treatment with UCMSC intravenous infusions for subjects with MS is safe, and potential therapeutic benefits should be further investigated. Trial registration ClinicalTrials.gov NCT02034188. Registered Jan 13, 2014. https://clinicaltrials.gov/ct2/show/NCT02034188. PMID- 29523172 TI - Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies. AB - BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. METHOD: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed. RESULTS: Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature. CONCLUSION: Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation. PMID- 29523173 TI - Upscaling Participatory Action and Videos for Agriculture and Nutrition (UPAVAN) trial comparing three variants of a nutrition-sensitive agricultural extension intervention to improve maternal and child nutritional outcomes in rural Odisha, India: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Maternal and child undernutrition have adverse consequences for pregnancy outcomes and child morbidity and mortality, and they are associated with low educational attainment, economic productivity as an adult, and human wellbeing. 'Nutrition-sensitive' agriculture programs could tackle the underlying causes of undernutrition. METHODS/DESIGN: This study is a four-arm cluster randomised controlled trial in Odisha, India. Interventions are as follows: (1) an agricultural extension platform of women's groups viewing and discussing videos on nutrition-sensitive agriculture (NSA) practices, and follow-up visits to women at home to encourage the adoption of new practices shown in the videos; (2) women's groups viewing and discussing videos on NSA and nutrition-specific practices, with follow-up visits; and (3) women's groups viewing and discussing videos on NSA and nutrition-specific practices combined with a cycle of Participatory Learning and Action meetings, with follow-up visits. All arms, including the control, receive basic nutrition training from government community frontline workers. Primary outcomes, assessed at baseline and 32 months after the start of the interventions, are (1) percentage of children aged 6-23 months consuming >= 4 out of 7 food groups per day and (2) mean body mass index (BMI) (kg/m2) of non-pregnant, non-postpartum (gave birth > 42 days ago) mothers or female primary caregivers of children aged 0-23 months. Secondary outcomes are percentage of mothers consuming >= 5 out of 10 food groups per day and percentage of children's weight-for-height z-score < -2 standard deviations (SD). The unit of randomisation is a cluster, defined as one or more villages with a combined minimum population of 800 residents. There are 37 clusters per arm, and outcomes will be assessed in an average of 32 eligible households per cluster. For randomisation, clusters are stratified by distance to nearest town (< 10 km or >= 10 km), and low (< 30%), medium (30-70%), or high (> 70%) proportion of Scheduled Tribe or Scheduled Caste (disadvantaged) households. A process evaluation will assess the quality of implementation and mechanisms behind the intervention effects. A cost-consequence analysis will compare incremental costs and outcomes of the interventions. DISCUSSION: This trial will contribute evidence on the impacts of NSA extension through participatory, low-cost, video-based approaches on maternal and child nutrition and on whether integration with nutrition specific goals and enhanced participatory approaches can increase these impacts. TRIAL REGISTRATION: ISRCTN , ISRCTN65922679 . Registered on 21 December 2016. PMID- 29523174 TI - The role of atorvastatin in suppressing tumor growth of uterine fibroids. AB - BACKGROUND: Medical therapeutic options remain quite limited for uterine fibroids treatment. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have anti-tumoral effects on multiple cancer types, however, little is known about their effects on uterine fibroids. METHODS: Initially, we conducted a retrospective study of 120 patients with uterine fibroids and hyperlipidemia from the Second Affiliated Hospital of Wenzhou Medical University. Then, we evaluated the effect of atorvastatin on proliferation and apoptosis both in immortalized uterine fibroids cells and primary uterine fibroids cells. Furthermore, the molecular mechanism by which atorvastatin suppressed uterine fibroids cell growth was explored. RESULTS: Our results showed that atorvastatin use for 1 or 2 years significantly suppressed growth of uterine fibroids. Atorvastatin inhibited the proliferation of immortalized and primary uterine fibroids cells in a dose and time-dependent manner and stimulated apoptosis of uterine fibroids cells by inducing caspase-3 activation, up-regulating Bim and down-regulating Bcl-2. Additionally, atorvastatin treatment suppressed phosphorylation of ERK1/2 and JNK. Furthermore, GGPP, a downstream lipid isoprenoid intermediate, significantly rescued the effect of atorvastatin. CONCLUSIONS: These results suggest that atorvastatin exerts anti-tumoral effects on uterine fibroids through inhibition of cell proliferation and induction of apoptosis in HMG-CoA-dependent pathway. Our results provide the first clinical and preclinical data on the use of atorvastatin as a promising nonsurgical treatment option for uterine fibroids. PMID- 29523175 TI - Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): statistical analysis plan. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator dependent preterm infants. METHODS/DESIGN: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22 day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data. TRIAL REGISTRATION: Netherlands Trial Register, NTR2768 . Registered on 17 February 2011. EudraCT, 2010-023777-19. Registered on 2 November 2010. PMID- 29523176 TI - Environmental risk factors and changing spatial patterns of human seropositivity for Echinococcus spp. in Xiji County, Ningxia Hui Autonomous Region, China. AB - BACKGROUND: Human echinococcoses are parasitic helminth infections that constitute a serious public health concern in several regions across the world. Cystic (CE) and alveolar echinococcosis (AE) in China represent a high proportion of the total global burden of these infections. This study was conducted to predict the spatial distribution of human seropositivity for Echinococcus species in Xiji County, Ningxia Hui Autonomous Region (NHAR), with the aim of identifying communities where targeted prevention and control efforts are required. METHODS: Bayesian geostatistical models with environmental and demographic covariates were developed to predict spatial variation in the risk of human seropositivity for Echinococcus granulosus (the cause of CE) and E. multilocularis (the cause of AE). Data were collected from three cross-sectional surveys of school children conducted in Xiji County in 2002-2003, 2006-2007 and 2012-2013. Environmental data were derived from high-resolution satellite images and meteorological data. RESULTS: The overall seroprevalence of E. granulosus and E. multilocularis was 33.4 and 12.2%, respectively, across the three surveys. Seropositivity for E. granulosus was significantly associated with summer and winter precipitation, landscape fragmentation variables and the extent of areas covered by forest, shrubland, water and bareland/artificial surfaces. Seropositivity for E. multilocularis was significantly associated with summer and winter precipitations, landscape fragmentation variables and the extent of shrubland and water bodies. Spatial correlation occurred over greater distances for E. granulosus than for E. multilocularis. The predictive maps showed that the risk of seropositivity for E. granulosus expanded across Xiji during the three surveys, while the risk of seropositivity for E. multilocularis became more confined in communities located in the south. CONCLUSIONS: The identification of high-risk areas for seropositivity for these parasites, and a better understanding of the role of the environment in determining the transmission dynamics of Echinococcus spp. may help to guide and monitor improvements in human echinococcosis control strategies by allowing targeted allocation of resources. PMID- 29523177 TI - Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington's disease. AB - The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a multifunctional neuronal calcium sensor (NCS) that controls Ca2+ and protein homeostasis through gene regulation and protein-protein interactions. Downregulation of DREAM is part of an endogenous neuroprotective mechanism that improves ATF6 (activating transcription factor 6) processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington's disease (HD). Whether modulation of DREAM activity can also ameliorate cognition deficits in HD mice has not been studied. Moreover, it is not known whether DREAM downregulation in HD is unique, or also occurs for other NCS family members. Using the novel object recognition test, we show that chronic administration of the DREAM-binding molecule repaglinide, or induced DREAM haplodeficiency delays onset of cognitive impairment in R6/1 mice, another HD model. The mechanism involves a notable rise in the levels of transcriptionally active ATF6 protein in the hippocampus after repaglinide administration. In addition, we show that reduction in DREAM protein in the hippocampus of HD patients was not accompanied by downregulation of other NCS family members. Our results indicate that DREAM inhibition markedly improves ATF6 processing in the hippocampus and that it might contribute to a delay in memory decline in HD mice. The mechanism of neuroprotection through DREAM silencing in HD does not apply to other NCS family members. PMID- 29523179 TI - A young female presenting with heart failure secondary to eosinophilic myocarditis: a case report and review of the literature. AB - BACKGROUND: Eosinophilic myocarditis is one of the fatal complications of idiopathic hypereosinophilic syndromes. Given the rarity of this form of myocarditis, it is often under-recognized. We describe a young girl who presented with features of heart failure. To our knowledge, this is the first reported case of eosinophilic myocarditis in a young Sri Lankan female. CASE PRESENTATION: A previously healthy 21 year old Sri Lankan female admitted with shortness of breath for 1 week duration with associated low grade fever and profuse sweating. She was mildly febrile and dyspnoeic with absent ankle oedema. She was tachycardic and had elevated Jugular venous pressure with negative Kussmaul sign. Blood pressure was 100/70 mmHg. Clinically there was no cardiomegaly and heart sounds were slightly muffled with gallop rhythm. Bilateral basal fine end inspiratory crackles and mild hepatosplenomegaly were noted. The laboratory examinations showed leucocytosis with severe eosinophilia with no abnormal cells. Her ESR, Troponin I and Brain natriuretic peptide were elevated with normal CRP and electrocardiogram showed sinus tachycardia with wide spread ST depression. Heart failure was evident on chest X-ray and 2D-echocardiogram showed global left ventricular hypokinesia with 40% ejection fraction and a thin layer of pericardial effusion. Mild hepatosplenomegaly without lymphadenopathy was detected in the ultrasound scan. Bone marrow biopsy showed hypereosinophilia with no evidence of bone marrow infiltration. FIP1L1-PDGFRA fusion transcript and BCR ABL transcript were not detected. Secondary causes for hypereosinophilia were excluded and the diagnosis of idiopathic hypereosinophilic syndrome and eosinophilic myocarditis was made. She had good response to steroids clinically and biochemically with complete recovery of left ventricular function. She is now on steroid to be continued at least 6 months to 1 year. CONCLUSION: Eosinophilic myocarditis is a rare but fatal disease if left untreated. Hence clinicians should have high index of suspicion to diagnose eosinophilic myocarditis in clinical context of heart failure due to myocarditis. The diagnoses of eosinophilic myocarditis may often be challenged especially in a poor recourse setting. However available investigation should be used to diagnose this condition without delay. Early treatment with systemic steroids may prevent fatal outcome and therapies for this disease have yet to be validated in large prospective studies. PMID- 29523178 TI - The bromodomain-containing protein Ibd1 links multiple chromatin-related protein complexes to highly expressed genes in Tetrahymena thermophila. AB - BACKGROUND: The chromatin remodelers of the SWI/SNF family are critical transcriptional regulators. Recognition of lysine acetylation through a bromodomain (BRD) component is key to SWI/SNF function; in most eukaryotes, this function is attributed to SNF2/Brg1. RESULTS: Using affinity purification coupled to mass spectrometry (AP-MS) we identified members of a SWI/SNF complex (SWI/SNFTt) in Tetrahymena thermophila. SWI/SNFTt is composed of 11 proteins, Snf5Tt, Swi1Tt, Swi3Tt, Snf12Tt, Brg1Tt, two proteins with potential chromatin interacting domains and four proteins without orthologs to SWI/SNF proteins in yeast or mammals. SWI/SNFTt subunits localize exclusively to the transcriptionally active macronucleus during growth and development, consistent with a role in transcription. While Tetrahymena Brg1 does not contain a BRD, our AP-MS results identified a BRD-containing SWI/SNFTt component, Ibd1 that associates with SWI/SNFTt during growth but not development. AP-MS analysis of epitope-tagged Ibd1 revealed it to be a subunit of several additional protein complexes, including putative SWRTt, and SAGATt complexes as well as a putative H3K4-specific histone methyl transferase complex. Recombinant Ibd1 recognizes acetyl-lysine marks on histones correlated with active transcription. Consistent with our AP-MS and histone array data suggesting a role in regulation of gene expression, ChIP-Seq analysis of Ibd1 indicated that it primarily binds near promoters and within gene bodies of highly expressed genes during growth. CONCLUSIONS: Our results suggest that through recognizing specific histones marks, Ibd1 targets active chromatin regions of highly expressed genes in Tetrahymena where it subsequently might coordinate the recruitment of several chromatin-remodeling complexes to regulate the transcriptional landscape of vegetatively growing Tetrahymena cells. PMID- 29523180 TI - Evaluating the effect of delayed activation of rapid response teams on patient outcomes: a systematic review protocol. AB - BACKGROUND: Rapid response teams have been widely adopted across the world. Although evidence for their efficacy is not clear, they remain a popular means to detect and react to patient deterioration. This may in part be due to there being no standardized approach to their usage or implementation. A key component of their ability to be effective is the speed of response. OBJECTIVE: The objective of this review is to evaluate the effect of delayed response by rapid response teams on hospital mortality (primary), cardiac arrest, and intensive care transfer rates (secondary). METHODS: This review will include randomized and non randomized studies which examined the effect of delayed response times by rapid response teams on patient mortality, cardiac arrest, and intensive care unit admission rates. This review will include studies of adult patients who have experienced a rapid response team consultation. The search strategy will utilize a combination of keywords and MeSH terms. MEDLINE and Embase will be searched, as well as examining gray literature. Two reviewers will independently screen retrieved citations to determine if they meet inclusion criteria. Studies will be selected that provide information about the impact of response time on patient outcomes. Comparisons will be made between consults that arrive in a timely manner and consults that are delayed. Quality assessment of randomized studies will be conducted in accordance with guidelines from the Cochrane Handbook for Systematic Reviews of Interventions. Quality assessment of non-randomized studies will be based on the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) assessment tool. Results of the review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DISCUSSION: This systematic review will identify and synthesize evidence around the impact of delayed response by rapid response teams on patient mortality, cardiac arrest, and intensive care transfer rates. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration: CRD42017071842 . PMID- 29523181 TI - Autologous chyle fat grafting for the treatment of hypertrophic scars and scar related conditions. AB - BACKGROUND: Scarring is the product of natural restoration, yet its treatment remains challenging. Both collagen and fibroblasts are abnormally abundant in scars, leading to scar hyperplasia or contracture. Several clinical studies have reported that wrinkles at the recipient site are reduced, pores are narrowed, pigmentation is decreased, and skin is softened after autologous fat transplantation. In this study, we investigated the ability of autologous chyle fat injection to normalize the fibroblasts and collagen of scar tissue in 80 adult patients with hypertrophic scars resulting from severe burns received more than 1 year previously. METHODS: The patients underwent autologous chyle fat injection, and scar samples were collected at different time points. Differences in the number of adipocytes before and after chylosis were assessed by cell culture, and changes in the structural organization of the scars were detected via histologic and immunohistochemical analyses. RESULTS: After preparation, the chyle fat contained few autologous adipocytes and large amounts of extracellular matrix. Following the injection of chyle fat, the thickness, color, and elasticity of hypertrophic scar tissue tended toward normalization, and patient satisfaction increased. The three adipose tissue donor sites used for the preparation of chyle fat were the abdomen, buttocks, and inner thigh, of which the inner thigh yielded the best therapeutic outcomes. The density and quantity of fibroblasts in the scars decreased following the injection of chyle fat, and the arrangement, quantity, and shape of type III collagen fibers tended toward normalization. After three treatments, the results of immunohistochemical staining showed that type III collagen was significantly less abundant than before treatment. CONCLUSIONS: Autologous chyle fat transplantation has a good therapeutic effect on hypertrophic scar tissue. The injection of chyle fat into hypertrophic scar tissue reduced the density and quantity of fibroblasts and prompted the arrangement, quantity, and shape of type III collagen to normalize. PMID- 29523182 TI - Cerebrospinal fluid-stem cell interactions may pave the path for cell-based therapy in neurological diseases. AB - Recent studies have suggested that the regulation of endogenous neural stem cells (NSCs) or transplanting of exogenous nerve cells are the newest and most promising methods for the treatment of dementia and other neurological diseases. The special location and limited number of endogenous NSCs, however, restrict their clinical application. The success in directional differentiation of exogenous stem cells from other tissue sources into neural cells has provided a novel source for NSCs. Study on the relative mechanisms is still at the preliminary stage. Currently the induction methods include: 1) cell growth factor induction; 2) chemical induction; 3) combined growth factor-chemical induction; or 4) other induction methods such as traumatic brain tissue homogenate, gene transfection, traditional Chinese medicine, and coculture induction. Cerebrospinal fluid (CSF), as a natural medium under physiological conditions, contains a variety of progrowth peptide factors that can promote the proliferation and differentiation of mesenchymal stromal cells (MSCs) into neural cells through the corresponding receptors on the cell surface. This suggests that CSF can not only nourish the nerve cells, but also become an effective and suitable inducer to increase the yield of NSCs. However, some other studies believed that CSF contained certain inhibitory components against the differentiation of primary stem cells into mature neural cells. Based on the above background, here we review the relative literature on the influence of the CSF on stem cells in order to provide a more comprehensive reference for the wide clinical application of NSCs in the future. PMID- 29523183 TI - Association of serum ADAMTS-7 levels with left ventricular reverse remodeling after ST-elevation myocardial infarction. AB - BACKGROUND: Left ventricular reverse remodeling (LVRR) in patients with ST elevation myocardial infarction (STEMI) is associated with a good prognosis. Serum levels of ADAMTS-7 might be used for the prognosis of STEMI. This study aimed to investigate the relationship between serum ADAMTS-7 levels and LVRR. METHODS: This was a prospective study of 104 patients with STEMI who underwent revascularization and 63 controls. ADAMTS-7 serum levels were measured on days 1, 3, and 7 and in months 1 and 6 after STEMI. A decrease >= 15% of the left ventricular end-systolic volume at 6 months was defined as LVRR. RESULTS: The serum levels of ADAMTS-7 in patients with LVRR were lower than those without LVRR (3.84 +/- 2.26 vs. 5.02 +/- 2.54, P = 0.032) 7 days after STEMI and the difference between day 7 and day 1 (DeltaADAMTS-7) was even significantly lower ( 1.31 +/- 0.94 vs. - 0.30 +/- 0.22, P = 0.021). Multivariate analysis showed that DeltaADAMTS-7(day 7 minus day 1) was independently associated with LVRR (OR = - 0.322, 95% CI = - 0.996 to - 0.074, P = 0.028). Receiver operating characteristic (ROC) curve analysis showed that LVRR could be predicted (sensitivity 89%, specificity 82%, and area under the curve 0.896) when DeltaADAMTS-7(day 7 minus day 1) was < - 0.39. CONCLUSIONS: DeltaADAMTS-7(day 7 minus day 1) might be a potential predictive factor for LVRR. PMID- 29523184 TI - The long sepsis journey in low- and middle-income countries begins with a first step...but on which road? PMID- 29523185 TI - Imatinib-induced fulminant liver failure in chronic myeloid leukemia: role of liver transplant and second-generation tyrosine kinase inhibitors: a case report. AB - BACKGROUND: There is a worldwide problem of acute liver failure and mortality associated with remaining on the waiting for a liver transplant. In this study, we highlight results published in recent years by leading transplant centers in evaluating imatinib-induced acute liver failure in chronic myeloid leukemia and follow-up in liver transplantation. CASE PRESENTATION: A 36-year-old brown skinned woman (mixed Brazilian race) diagnosed 1 year earlier with chronic myeloid leukemia was started after delivery of a baby and continued for 6 months with imatinib mesylate (selective inhibitor of Bcr-Abl tyrosine kinase), which induced liver failure. We conducted a literature review using the PubMed database for articles published through September 2017, and we demonstrate a role of liver transplant in this situation for imatinib-induced liver failure. We report previously published results and a successful liver transplant after acute liver failure due to imatinib-induced in chronic myeloid leukemia treatment. CONCLUSIONS: We report a case of a successful liver transplant after acute liver failure resulting from imatinib-induced chronic myeloid leukemia treatment. The literature reveals the importance of prompt acute liver failure diagnosis and treatment with liver transplant in selected cases. PMID- 29523186 TI - Mesenchymal stem cells: potential application for the treatment of hepatic cirrhosis. AB - Nowadays, orthotopic liver transplantation is considered the most efficient approach to the end stage of chronic hepatic cirrhosis. Because of the limitations of orthotopic liver transplantation, stem cells are an attractive therapeutic option. Mesenchymal stem cells (MSCs) especially show promise as an alternative treatment for hepatic cirrhosis in animal models and during clinical trials. Nevertheless, the homing of transplanted MSCs to the liver occurs in limited numbers. Therefore, we review the strategies for enhancing the homing of MSCs, mainly via the delivery routes, optimizing cell culture conditions, stimulating the target sites, and genetic modification. PMID- 29523187 TI - Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails. AB - BACKGROUND: The advent of human-induced pluripotent stem cells holds great promise for producing ample individualized hepatocytes. Although previous efforts have succeeded in generating hepatocytes from human pluripotent stem cells in vitro by viral-based expression of transcription factors and/or addition of growth factors during the differentiation process, the safety issue of viral transduction and high cost of cytokines would hinder the downstream applications. Recently, the use of small molecules has emerged as a powerful tool to induce cell fate transition for their superior stability, safety, cell permeability, and cost-effectiveness. METHODS: In the present study, we established a novel efficient hepatocyte differentiation strategy of human pluripotent stem cells with pure small-molecule cocktails. This method induced hepatocyte differentiation in a stepwise manner, including definitive endoderm differentiation, hepatic specification, and hepatocyte maturation within only 13 days. RESULTS: The differentiated hepatic-like cells were morphologically similar to hepatocytes derived from growth factor-based methods and primary hepatocytes. These cells not only expressed specific hepatic markers at the transcriptional and protein levels, but also possessed main liver functions such as albumin production, glycogen storage, cytochrome P450 activity, and indocyanine green uptake and release. CONCLUSIONS: Highly efficient and expedited hepatic differentiation from human pluripotent stem cells could be achieved by our present novel, pure, small-molecule cocktails strategy, which provides a cost effective platform for in vitro studies of the molecular mechanisms of human liver development and holds significant potential for future clinical applications. PMID- 29523189 TI - A case of acute necrotizing pancreatitis complicated with non ST elevation myocardial infarction. AB - BACKGROUND: Acute pancreatitis is an inflammatory condition with varying severity and a range of local and systemic complications. Here we report a patient with acute necrotizing pancreatitis complicated with a true non ST elevation myocardial infarction. CASE PRESENTATION: A 58 year old lady was admitted to our unit with acute onset epigastric pain and vomiting for 4 h duration. Following admission she complained of retrosternal tightening type of a chest pain. She had elevated serum amylase and cardiac troponin. Electrocardiogram (ECG) revealed lateral ischaemia. Contrast computerized tomography abdomen revealed acute severe necrotizing pancreatitis. CONCLUSIONS: Nonspecific ECG changes can occur in patients with acute pancreatitis. But the diagnosis of true myocardial infarction in a context of acute pancreatitis using ECGs, 2D echocardiography, cardiac biomarkers and coronary angiograms can be challenging with the choice of revascularization therapy and safety of antiplatelet agents and anticoagulant therapy. Decision making regarding the management of such a patient is also critical. PMID- 29523188 TI - Azoramide, a novel regulator, favors adipogenesis against osteogenesis through inhibiting the GLP-1 receptor-PKA-beta-catenin pathway. AB - BACKGROUND: The reciprocal fate decision of mesenchymal stem cells (MSCs) to either bone or adipocytes is determined by Wnt-related signaling and the glucagon like peptide-1 receptor (GLP-1R). Azoramide, an ER stress alleviator, was reported to have an antidiabetic effect. In this study, we investigated the function of azoramide in regulating the lineage determination of MSCs for either adipogenic or osteogenic differentiation. METHODS: In this study, microcomputed tomography and histological analysis on bone morphogenetic protein (BMP)2-induced parietal periosteum bone formation assays, C3H10T1/2 and mouse bone marrow MSC derived bone formation and adipogenesis assays, and specific staining for bone tissue and lipid droplets were used to evaluate the role of azoramide on the lineage determination of MSC differentiation. Cells were harvested for Western blot and quantitative real-time polymerase chain reaction (PCR), and immunofluorescence staining was used to explore the potential mechanism of azoramide for regulating MSC differentiation. RESULTS: Based on MSC-derived bone formation assays both in vivo and in vitro, azoramide treatment displayed a cell fate determining ability in favor of adipogenesis over osteogenesis. Further mechanistic characterizations disclosed that both the GLP-1R agonist peptide exendin-4 (Ex-4) and GLP-1R small interfering (si)RNA abrogated azoramide dual effects. Moreover, cAMP-protein kinase A (PKA)-mediated nuclear beta-catenin activity was responsible for the negative function of azoramide on bone formation in favor of adipogenesis. CONCLUSIONS: These data provide the first evidence to show that azoramide may serve as an antagonist against GLP-1R in MSC lineage determination. PMID- 29523190 TI - Differentiation of human induced pluripotent stem cells into nucleus pulposus like cells. AB - BACKGROUND: Intervertebral disc (IVD) degeneration is characterized by an early decrease in cellularity of the nucleus pulposus (NP) region, and associated extracellular matrix changes, reduced hydration, and progressive degeneration. Cell-based IVD therapy has emerged as an area of great interest, with studies reporting regenerative potential for many cell sources, including autologous or allogeneic chondrocytes, primary IVD cells, and stem cells. Few approaches, however, have clear strategies to promote the NP phenotype, in part due to a limited knowledge of the defined markers and differentiation protocols for this lineage. Here, we developed a new protocol for the efficient differentiation of human induced pluripotent stem cells (hiPSCs) into NP-like cells in vitro. This differentiation strategy derives from our knowledge of the embryonic notochordal lineage of NP cells as well as strategies used to support healthy NP cell phenotypes for primary cells in vitro. METHODS: An NP-genic phenotype of hiPSCs was promoted in undifferentiated hiPSCs using a stepwise, directed differentiation toward mesodermal, and subsequently notochordal, lineages via chemically defined medium and growth factor supplementation. Fluorescent cell imaging was used to test for pluripotency markers in undifferentiated cells. RT PCR was used to test for potential cell lineages at the early stage of differentiation. Cells were checked for NP differentiation using immunohistochemistry and histological staining at the end of differentiation. To enrich notochordal progenitor cells, hiPSCs were transduced using lentivirus containing reporter constructs for transcription factor brachyury (T) promoter and green fluorescent protein (GFP) fluorescence, and then sorted on T expression based on GFP intensity by flow cytometry. RESULTS: Periods of pellet culture following initial induction were shown to promote the vacuolated NP cell morphology and NP surface marker expression, including CD24, LMalpha5, and Basp1. Enrichment of brachyury (T) positive cells using fluorescence-activated cell sorting was shown to further enhance the differentiation efficiency of NP-like cells. CONCLUSIONS: The ability to efficiently differentiate human iPSCs toward NP-like cells may provide insights into the processes of NP cell differentiation and provide a cell source for the development of new therapies for IVD diseases. PMID- 29523191 TI - LRRC15 promotes osteogenic differentiation of mesenchymal stem cells by modulating p65 cytoplasmic/nuclear translocation. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are a reliable resource for bone regeneration and tissue engineering, but the molecular mechanisms of differentiation remain unclear. The tumor antigen 15-leucine-rich repeat containing membrane protein (LRRC15) is a transmembrane protein demonstrated to play important roles in cancer. However, little is known about its role in osteogenesis. This study was to evaluate the functions of LRRC15 in osteogenic differentiation of MSCs. METHODS: Osteogenic-induction treatment and the ovariectomized (OVX) model were performed to investigate the potential relationship between LRRC15 and MSC osteogenesis. A loss-of-function study was used to explore the functions of LRRC15 in osteogenic differentiation of MSCs in vitro and in vivo. NF-kappaB pathway inhibitor BAY117082, siRNA, nucleocytoplasmic separation, and ChIP assays were performed to clarify the molecular mechanism of LRRC15 in bone regulation. RESULTS: Our results first demonstrated that LRRC15 expression was upregulated upon osteogenic induction, and the level of LRRC15 was significantly decreased in OVX mice. Both in-vitro and in-vivo experiments detected that LRRC15 was required for osteogenesis of MSCs. Mechanistically, LRRC15 inhibited transcription factor NF-kappaB signaling by affecting the subcellular localization of p65. Further studies indicated that LRRC15 regulated osteogenic differentiation in a p65-dependent manner. CONCLUSIONS: Taken together, our findings reveal that LRRC15 is an essential regulator for osteogenesis of MSCs through modulating p65 cytoplasmic/nuclear translocation, and give a novel hint for MSC-mediated bone regeneration. PMID- 29523193 TI - Human amniotic mesenchymal stem cells improve ovarian function in natural aging through secreting hepatocyte growth factor and epidermal growth factor. AB - BACKGROUND: Although many reports show that various kinds of stem cells have the ability to recover function in premature ovarian aging, few studies have looked at stem cell treatment of natural ovarian aging (NOA). We designed this experimental study to investigate whether human amniotic mesenchymal stem cells (hAMSCs) retain the ability to restore ovarian function, and how hAMSCs work in this process. METHODS: To build the NOA mouse model, the mice were fed for 12-14 months normally with young fertile female mice as the normal control group (3-5 months old). Hematoxylin and eosin staining permitted follicle counting and showed the ovarian tissue structure. An enzyme-linked immunosorbent assay was used to detect the serum levels of the sex hormones estradiol (E2), anti mullerian hormone (AMH), and follicle-stimulating hormone (FSH). The proliferation rate and marker expression level of human ovarian granule cells (hGCs) (ki67, AMH, FSH receptor, FOXL2, and CYP19A1) were measured by flow cytometry (FACS). Cytokines (growth factors) were measured by a protein antibody array methodology. After hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were co-cultured with hGCs, proliferation (ki67) and apoptosis (Annexin V) levels were analyzed by FACS. After HGF and EGF were injected into the ovaries of natural aging mice, the total follicle numbers and hormone levels were tested. RESULTS: After the hAMSCs were transplanted into the NOA mouse model, the hAMSCs exerted a therapeutic activity on mouse ovarian function by improving the follicle numbers over four stages. In addition, our results showed that hAMSCs significantly promoted the proliferation rate and marker expression level of ovarian granular cells that were from NOA patients. Meanwhile, we found that the secretion level of EGF and HGF from hAMSCs was higher than other growth factors. A growth factor combination (HGF with EGF) improved the proliferation rate and inhibited the apoptosis rate more powerfully after a co-culture with hGCs, and total follicle numbers and hormone levels were elevated to a normal level after the growth factor combination was injected into the ovaries of the NOA mouse model. CONCLUSIONS: These findings provide insight into the notion that hAMSCs play an integral role in resistance to NOA. Furthermore, our present study demonstrates that a growth factor combination derived from hAMSCs plays a central role in inhibiting ovarian aging. Therefore, we suggest that hAMSCs improve ovarian function in natural aging by secreting HGF and EGF. PMID- 29523192 TI - The sponge holobiont in a changing ocean: from microbes to ecosystems. AB - The recognition that all macroorganisms live in symbiotic association with microbial communities has opened up a new field in biology. Animals, plants, and algae are now considered holobionts, complex ecosystems consisting of the host, the microbiota, and the interactions among them. Accordingly, ecological concepts can be applied to understand the host-derived and microbial processes that govern the dynamics of the interactive networks within the holobiont. In marine systems, holobionts are further integrated into larger and more complex communities and ecosystems, a concept referred to as "nested ecosystems." In this review, we discuss the concept of holobionts as dynamic ecosystems that interact at multiple scales and respond to environmental change. We focus on the symbiosis of sponges with their microbial communities-a symbiosis that has resulted in one of the most diverse and complex holobionts in the marine environment. In recent years, the field of sponge microbiology has remarkably advanced in terms of curated databases, standardized protocols, and information on the functions of the microbiota. Like a Russian doll, these microbial processes are translated into sponge holobiont functions that impact the surrounding ecosystem. For example, the sponge-associated microbial metabolisms, fueled by the high filtering capacity of the sponge host, substantially affect the biogeochemical cycling of key nutrients like carbon, nitrogen, and phosphorous. Since sponge holobionts are increasingly threatened by anthropogenic stressors that jeopardize the stability of the holobiont ecosystem, we discuss the link between environmental perturbations, dysbiosis, and sponge diseases. Experimental studies suggest that the microbial community composition is tightly linked to holobiont health, but whether dysbiosis is a cause or a consequence of holobiont collapse remains unresolved. Moreover, the potential role of the microbiome in mediating the capacity for holobionts to acclimate and adapt to environmental change is unknown. Future studies should aim to identify the mechanisms underlying holobiont dynamics at multiple scales, from the microbiome to the ecosystem, and develop management strategies to preserve the key functions provided by the sponge holobiont in our present and future oceans. PMID- 29523195 TI - A novel monoclonal antibody efficiently blocks the infection of serotype 4 fowl adenovirus by targeting fiber-2. AB - A recent outbreak of hepatitis-hydropericardium syndrome caused by serotype 4 fowl adenovirus (FAdV-4) has resulted in significant economic losses to the poultry industry worldwide. However, little is known about the molecular pathogenesis of FAdV-4. In this study, a novel monoclonal antibody (mAb) targeting the fiber-2 protein of FAdV-4 was generated, mAb 3C2. Indirect immunofluorescence assay showed that mAb 3C2 neither reacted with serotype 8 fowl adenovirus (FAdV-8) nor reacted with the fiber-1 protein of FAdV-4; it specifically reacted with the fiber-2 protein of FAdV-4. Notably, mAb 3C2 could efficiently immunoprecipitate the fiber-2 protein in chicken liver cells either infected with FAdV-4 or transfected with pcDNA3.1-Fiber2. Moreover, mAb 3C2 demonstrated marked neutralizing activity against FAdV-4 and could efficiently inhibit the infection of FAdV-4 in vitro. Using truncated fiber-2 constructs, the epitope recognized by mAb 3C2 was determined to be located between amino acids 416-448 at the C-terminus of fiber-2. Our data not only provide a foundation for the establishment of a rapid fiber-2 peptide-based diagnostic assay for FAdV-4 but also highlight the critical role of the fiber-2 protein in mediating infection by FAdV-4. Furthermore, the epitope recognized by 3C2 might serve as a novel target for the development of a vaccine targeting FAdV-4. PMID- 29523194 TI - Incidence and risk factors of neonatal infections in a rural Bangladeshi population: a community-based prospective study. AB - BACKGROUND: Infections cause about one fifth of the estimated 2.7 million annual neonatal deaths worldwide. Population-based data on burden and risk factors of neonatal infections are lacking in developing countries, which are required for the appropriate design of effective preventive and therapeutic interventions in resource-poor settings. METHODS: We used data from a community-based cluster randomized trial conducted to evaluate the impact of two umbilical cord cleansing regimens with chlorhexidine solution on neonatal mortality and morbidity in a rural area of Sylhet District in Bangladesh. Newborns were assessed four times in the first 9 days of life by trained community health workers (CHWs) using a WHO IMCI-like clinical algorithm. Cumulative incidence of the first episode of infections in the first 9 days of life was estimated using survival analysis technique accounting for survival bias and competing risk of death before the occurrence of infection. A multivariable generalized estimating equation log binomial regression model was used to identify factors independently associated with infections. RESULTS: Between 2007 and 2009, 30,267 newborns who received at least one postnatal assessment visit by a CHW within the first 9 days of life were included in this study. Cumulative incidence of infections in the first 9 days of life was 14.5% (95% CI 14.1-14.9%). Significant risk factors included previous child death in the family [RR 1.10 (95% CI 1.02-1.19)]; overcrowding [RR 1.14 (95% CI 1.04-1.25)]; home delivery [RR 1.86 (95% CI 1.58-2.19)]; unclean cord care [RR 1.15 (95% CI 1.03-1.28)]; multiple births [RR 1.34 (95% CI 1.15 1.56)]; low birth weight [reference: >= 2500 g, RR (95% CI) for < 1500, 1500 1999, and 2000-2499 g were 4.69 (4.01-5.48), 2.15 (1.92-2.42), and 1.15 (1.07 1.25) respectively]; and birth asphyxia [RR 1.65 (1.51-1.81)]. Higher pregnancy order lowered the risk of infections in the study population [compared to first pregnancy, RR (95% CI) for second, third, and >= fourth pregnancy babies were 0.93 (0.85-1.02), 0.88 (0.79-0.97), and 0.79 (0.71-0.87), respectively]. CONCLUSION: Neonatal infections and associated deaths can be reduced by identifying and following up high-risk mothers and newborns and promoting facility delivery and clean cord care in resource-poor countries like Bangladesh where the burden of clinically ascertained neonatal infections is high. Further research is needed to measure the burden of infections in the entire neonatal period, particularly in the second fortnight and its association with essential newborn care. TRIAL REGISTRATION: NCT00434408 . Registered February 9, 2007. PMID- 29523196 TI - 2-deoxy-2-[18]fluoro-D-glucose PET/CT (18FDG PET/CT) may not be a viable biomarker in Pompe disease. AB - BACKGROUND: Pompe disease (PD) is an autosomal recessive, lysosomal storage disease due to a mutation of the acid alpha-glucosidase (GAA) gene. In adult patients, PD is characterized by slowly progressive limb-girdle and trunk myopathy and restrictive respiratory insufficiency. Enzyme replacement therapy (ERT) is available, improving or stabilizing muscle-function in some and slowing deterioration in other patients. Unfortunately, there is no biomarker available to indicate therapeutic efficacy and/or disease activity. Whole body MRI depicts all skeletal muscles demonstrating foci of atrophic muscles, i.e., late and irreversible pathological changes. Any method indicating the localizations of increased muscle glycogen storage, muscle inflammation and/or degradation could possibly help identifying newly afflicted tissue and may be of prognostic value. We therefore investigated 2-deoxy-2-[18]fluoro-D-glucose (FDG) PET, a biomarker for glucose-metabolism, as a tool to evaluate disease activity and prognosis in PD. METHODS: In a pilot study, we investigated four patients by FDG dynamic PET/CT while on ERT. One patient had FDG-PET/CT twice, before and after 12 months on ERT. Dynamic FDG-PET/CT quantifies the metabolic rate of glucose utilisation in mg/ml/min. MRI was performed in parallel with pelvic and thigh muscles semi quantitatively scored for atrophy and disease-activity. RESULTS: None of the muscles analysed showed a focally increased FDG-uptake. Thus, quantification of muscle glucose metabolism could not be calculated. However, increased FDG-uptake, i.e., increased glucose utilisation, was observed in the respiratory muscles of one patient with severe, restrictive respiratory failure. In contrast, specific MRI sequences showed oedematous as well as atrophic muscle areas in PD. CONCLUSIONS: Our pilot study demonstrates that FDG-uptake does not correlate with glycogen storage in vivo. In contrast, MRI is an excellent tool to demonstrate the extent of muscle involvement. Specific MRI sequences may even demonstrate early changes possibly allowing prognostic predictions or localization of early stages of PD. PMID- 29523197 TI - Radial shockwave treatment promotes human mesenchymal stem cell self-renewal and enhances cartilage healing. AB - BACKGROUND: Shockwaves and mesenchymal stem cells (MSCs) have been widely accepted as useful tools for many orthopedic applications. However, the modulatory effects of shockwaves on MSCs remain controversial. In this study, we explored the influence of radial shockwaves on human bone marrow MSCs using a floating model in vitro and evaluated the healing effects of these cells on cartilage defects in vivo using a rabbit model. METHODS: MSCs were cultured in vitro, harvested, resuspended, and treated with various doses of radial shockwaves in a floating system. Cell proliferation was evaluated by growth kinetics and Cell Counting Kit-8 (CCK-8) assay. In addition, the cell cycle and apoptotic activity were analyzed by fluorescence activated cell sorting. To explore the "stemness" of MSCs, cell colony-forming tests and multidifferentiation assays were performed. We also examined the MSC subcellular structure using transmission electron microscopy and examined the healing effects of these cells on cartilage defects by pathological analyses. RESULTS: The results of growth kinetics and CCK-8 assays showed that radial shockwave treatment significantly promoted MSC proliferation. Enhanced cell growth was also reflected by an increase in the numbers of cells in the S phase and a decrease in the numbers of cells arrested in the G0/G1 phase in shockwave-treated MSCs. Unexpectedly, shockwaves caused a slight increase in MSC apoptosis rates. Furthermore, radial shockwaves promoted self-replicating activity of MSCs. Transmission electron microscopy revealed that MSCs were metabolically activated by shockwave treatment. In addition, radial shockwaves favored MSC osteogenic differentiation but inhibited adipogenic activity. Most importantly, MSCs pretreated by radial shockwaves exhibited an enhanced healing effect on cartilage defects in vivo. Compared with control groups, shockwave-treated MSCs combined with bio-scaffolds significantly improved histological scores of injured rabbit knees. CONCLUSIONS: In the present study, we found that radial shockwaves significantly promoted the proliferation and self-renewal of MSCs in vitro and safely accelerated the cartilage repair process in vivo, indicating favorable clinical outcomes. PMID- 29523198 TI - Compassionate use programs in Italy: ethical guidelines. AB - BACKGROUND: This article proposes a retrospective analysis of a compassionate use (CU), using a case study of request for Avelumab for a patient suffering from Merkel Cell Carcinoma. The study is the result of a discussion within a Provincial Ethics Committee (EC) following the finding of a high number of requests for CU program. The primary objective of the study is to illustrate the specific ethical and clinical profiles that emerge from the compassionate use program (CUP) issue. The secondary goals are: a) to promote a moral reflection among physicians who require approval for the CUP and b) provide the basis for recommendations on how to request CUP. MAIN BODY: The instruments for carrying out the analysis of the case study and the discussion are as follows: Analysis of the audio-recording of the EC meeting regarding the selected Case study. In-depth discussion of topics that emerged during the meeting by means of administration of 5 semi-structured interviews with 2 doctors involved in the case (proposing physician and palliative physician) and with 3 components of the EC who played a major role in the EC internal discussion. CONCLUSIONS: In an exploration of emerging clinical and ethical issues, four primary themes arise: 1. efficacy, safety of the treatment and patient's quality of life; 2. clear, realistic, adequate communication; 3. right to hope; 4. simultaneous Palliative Care approach. The results of ethical analysis carried out concern two areas: 1) ethical profiles relating to the use of CUP; 2) the role of the EC concerning the compassionate use of drugs and the need to provide recommendations on how to request CUP. With the aim of implementing these conclusions, the provincial EC of Reggio Emilia chose to steer the request for drugs for compassionate use through recommendations for good clinical and ethical practice based on the following assumptions: 1) the "simultaneous care" approach must be preferred. Secondly, 2) the EC's assessment must be part of the decision-making process that the care team conducts before proposing compassionate use to the patient. PMID- 29523199 TI - The relationship between childhood adversity, recent stressors, and depression in college students attending a South African university. AB - BACKGROUND: College students are at risk of depression. This risk may be increased by the experience of childhood adversity and/or recent stressors. This study examined the association between reported experiences of childhood adversity, recent stressors and depression during the last 12 months in a cohort of South African university students. METHODS: Six hundred and eighty-six first year students at Stellenbosch University in South Africa completed a health focused e-survey that included items on childhood adversity, recent stressors and mood. Individual and population attributable risk proportions (PARP) between experiences of childhood adversity and 12-month stressful experiences and 12 month depression were estimated using multivariate binomial logistic regression analysis. RESULTS: About one in six students reported depression during the last 12 months. Being a victim of bullying and emotional abuse or emotional neglect during childhood were the strongest predictors of depression in the past year at both individual and population level. With regard to recent stressors, a romantic partner being unfaithful, serious ongoing arguments or break-ups with some other close friend or family member and a sexual or gender identity crisis were the strongest predictors of depression. The predictor effect of recent stressors was significantly reduced in the final model that adjusted for the type and number of childhood traumatic experiences. At a population level, academic stress, serious ongoing arguments or break-ups with a close friend or family member, and serious betrayal by someone close were the variables that yielded the highest PARP. CONCLUSIONS: Our findings suggest a significant relationship between early adversity, recent stressors, and depression here and throughout, consistent with the broader literature on predictors of depression. This study contributes to the limited data on college students' mental health in low and middle income countries including on the African continent. The findings provide information on the population level effect sizes of trauma as a risk factor for depression, as well as on the relationship between specific recent stressors and depression in college students. PMID- 29523200 TI - Evaluating characteristics of PROSPERO records as predictors of eventual publication of non-Cochrane systematic reviews: a meta-epidemiological study protocol. AB - BACKGROUND: Epidemiology and the reporting characteristics of systematic reviews (SRs) and meta-analyses (MAs) are well known. However, no study has analyzed the influence of protocol features on the probability that a study's results will be finally reported, thereby indirectly assessing the reporting bias of International Prospective Register of Systematic Reviews (PROSPERO) registration records. OBJECTIVE: The objective of this study is to explore which factors are associated with a higher probability that results derived from a non-Cochrane PROSPERO registration record for a systematic review will be finally reported as an original article in a scientific journal. METHODS/DESIGN: The PROSPERO repository will be web scraped to automatically and iteratively obtain all completed non-Cochrane registration records stored from February 2011 to December 2017. Downloaded records will be screened, and those with less than 90% fulfilled or are duplicated (i.e., those sharing titles and reviewers) will be excluded. Manual and human-supervised automatic methods will be used for data extraction, depending on the data source (fields of PROSPERO registration records, bibliometric databases, etc.). Records will be classified into published, discontinued, and abandoned review subgroups. All articles derived from published reviews will be obtained through multiple parallel searches using the full protocol "title" and/or "list reviewers" in MEDLINE/PubMed databases and Google Scholar. Reviewer, author, article, and journal metadata will be obtained using different sources. R and Python programming and analysis languages will be used to describe the datasets; perform text mining, machine learning, and deep learning analyses; and visualize the data. We will report the study according to the recommendations for meta-epidemiological studies adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for SRs and MAs. DISCUSSION: This meta-epidemiological study will explore, for the first time, characteristics of PROSPERO records that may be associated with the publication of a completed systematic review. The evidence may help to improve review workflow performance in terms of research topic selection, decision-making regarding team selection, planning relationships with funding sources, implementing literature search strategies, and efficient data extraction and analysis. We expect to make our results, datasets, and R and Python code scripts publicly available during the third quarter of 2018. PMID- 29523201 TI - Preliminary studies on isolates of Clostridium difficile from dogs and exotic pets. AB - BACKGROUND: Clostridium difficile infection (CDI) is recognised as an emerging disease in both humans and some animal species. During the past few years, insights into human CDI epidemiology changed and C. difficile is also considered as an emerging community-acquired pathogen. Certain ribotypes (RT) are possibly associated with zoonotic transmission. The objective of this study was to assess the presence of C. difficile in a population of pets and to characterise the isolates. RESULTS: Faecal samples from a total of 90 diarrhoeic dogs and 24 from exotic animal species (both diarrhoeic and non-diarrhoeic) were analysed. Clostridium difficile was isolated from 6 (6.7%) dogs and one reptile sample (4.2%). Four (66.7%) of the six dog strains were capable of producing toxins. Four known different RTs were detected in dogs (010, 014, 123 and 358) and a new one was found in a faecal sample of an exotic animal. This new RT isolate was negative for all toxin genes tested and belonged to sequence type 347 which has been proposed as a Clade-III member. Importantly, two dog strains showed a stable resistance to metronidazole (initial MIC values: 128 and 48 MUg/ml). CONCLUSIONS: The results obtained in this study suggest the implementation of antimicrobial susceptibility surveillance programs to assess the prevalence of metronidazole resistance in dogs; molecular studies to elucidate C. difficile metronidazole resistance mechanisms are warranted. Based on the similarity between the ribotypes observed in dogs and those described in humans, the zoonotic transmission should be further explored. Furthermore, exotic animals have shown to harbor uncommon C. difficile strains which require further genomic studies. PMID- 29523202 TI - Co-circulation of different A. phagocytophilum variants within cattle herds and possible reservoir role for cattle. AB - BACKGROUND: Anaplasma phagocytophilum is a zoonotic tick-borne intracellular alpha-proteobacterium causing tick-borne fever, which leads to significant economic losses in domestic ruminants in Europe. Its epidemiological cycles are complex and reservoir host species of bovine strains have not yet been identified. Given that little genetic information is available on strains circulating within a defined bovine environment, our objective was to assess the genetic diversity of A. phagocytophilum obtained from the same farms over time. METHODS: Blood samplings were performed several times in two European herds. In the French herd, 169 EDTA-blood samples were obtained from 115 cows (32 were sampled two to four times). In the German herd, 20 cows were sampled six times (120 EDTA-blood samples). The presence of A. phagocytophilum DNA was assessed using a qPCR targeting msp2. The positive DNA samples underwent MLST at nine genetic markers (typA, ctrA, msp4, pleD, recG, polA, groEL, gyrA, and ankA). For each locus, sequences were aligned with available bacterial sequences derived from cattle, horse, dog, and roe deer hosts, and concatenated neighbor joining trees were constructed using three to six loci. RESULTS: Around 20% (57/289) of samples were positive. Forty positive samples from 23 French and six German cows (11 of them being positive at two time points) were sequenced. Six loci (typA, ctrA, msp4, pleD, recG, and polA) allowed to build concatenated phylogenetic trees, which led to two distinct groups of bovine variants in the French herd (hereafter called A and B), whereas only group A was detected in the German herd. In 42% of French samples, double chromatogram peaks were encountered in up to four loci. Eleven cows were found infected three weeks to 17 months after first sampling and harboured a new variant belonging to one or the other group. CONCLUSIONS: Our results demonstrate the occurrence of two major bovine strain groups and the simultaneous infection of single cows by more than one A. phagocytophilum strain. This challenges the role of cattle as reservoirs for A. phagocytophilum. This role may be facilitated via long-term bacterial persistence in individual cows and active circulation at the herd scale. PMID- 29523203 TI - Computer simulation of syringomyelia in dogs. AB - BACKGROUND: Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked. RESULTS: For normal conditions the pressure in the SAS was approximately 400 Pa and the same applied to all stress components in the spinal cord. The stress was uniformly distributed along the length of the spinal cord. When the blockage between the cranial and spinal CSF spaces forced the cord to move with the cardiac cycle, shear and axial normal stresses in the cord increased significantly. The sites where the elevated stress was most pronounced coincided with the axial locations where the syringes typically form, but they were at the perimeter rather than in the central portion of the cord. This elevated stress originated from the bending of the cord at the locations where its curvature was high. CONCLUSIONS: The results suggest that it is possible that repetitive stressing of the spinal cord caused by its exaggerated movement could be a cause for the formation of initial syringes. Further consideration of factors such as cord tethering and the difference in mechanical properties of white and grey matter is needed to fully explore this possibility. PMID- 29523204 TI - Individualized controlled ovarian stimulation in expected poor-responders: an update. AB - Controlled ovarian stimulation with subsequent multi-follicular development continues to be a keystone in ART. Evidence supports an individualized approach to ovarian stimulation, usually involving combinations of ovarian reserve tests, body mass index and age to tailor the exogenous gonadotropin dose, and potentially adjuvant treatment aiming for high safety and a shortening of time to live birth. While stimulation and trigger concepts have been developed successfully in normo- and hyperresponder patients, the poor responder patient remains difficult to manage. However, recent advances in definition and classification of the expected poor ovarian responder patient might enable a more accurate and clinically useful interpretation of new treatment concepts in a more homogenous study population. In the present review, we discuss the classification of the expected poor ovarian responder patient as well as clinically useful measurements of efficacy for controlled ovarian stimulation, and finally, we discuss the evidence for clinical management of patients with expected poor ovarian response, including adjuvant treatments such as growth hormone, androgens, and LH activity.In conclusion, the best available evidence supports that the treatment of the expected poor ovarian response patient should be individualized in all steps of ART, including the choice of GnRH analogue, the gonadotropin type and dose, ovulation trigger, and the possible use of adjuvant therapies. PMID- 29523205 TI - Pathologic and biochemical characterization of PrPSc from elk with PRNP polymorphisms at codon 132 after experimental infection with the chronic wasting disease agent. AB - BACKGROUND: The Rocky Mountain elk (Cervus elaphus nelsoni) prion protein gene (PRNP) is polymorphic at codon 132, with leucine (L132) and methionine (M132) allelic variants present in the population. In elk experimentally inoculated with the chronic wasting disease (CWD) agent, different incubation periods are associated with PRNP genotype: LL132 elk survive the longest, LM132 elk are intermediate, and MM132 elk the shortest. The purpose of this study was to investigate potential mechanisms underlying variations in incubation period in elk of different prion protein genotypes. Elk calves of three PRNP genotypes (n = 2 MM132, n = 2 LM132, n = 4 LL132) were orally inoculated with brain homogenate from elk clinically affected with CWD. RESULTS: Elk with longer incubation periods accumulated relatively less PrPSc in the brain than elk with shorter incubation periods. PrPSc accumulation in LM132 and MM132 elk was primarily neuropil-associated while glial-associated immunoreactivity was prominent in LL132 elk. The fibril stability of PrPSc from MM132 and LM132 elk were similar to each other and less stable than that from LL132 elk. Real-time quaking induced conversion assays (RT-QuIC) revealed differences in the ability of PrPSc seed from elk of different genotypes to convert recombinant 132 M or 132 L substrate. CONCLUSIONS: This study provides further evidence of the importance of PRNP genotype in the pathogenesis of CWD of elk. The longer incubation periods observed in LL132 elk are associated with PrPSc that is more stable and relatively less abundant at the time of clinical disease. The biochemical properties of PrPSc from MM132 and LM132 elk are similar to each other and different to PrPSc from LL132 elk. The shorter incubation periods in MM132 compared to LM132 elk may be the result of genotype-dependent differences in the efficiency of propagation of PrPSc moieties present in the inoculum. A better understanding of the mechanisms by which the polymorphisms at codon 132 in elk PRNP influence disease pathogenesis will help to improve control of CWD in captive and free-ranging elk populations. PMID- 29523206 TI - Effectiveness and cost-effectiveness of humanistic counselling in schools for young people with emotional distress (ETHOS): study protocol for a randomised controlled trial. AB - BACKGROUND: One in ten children in Britain have been identified as experiencing a diagnosable mental health disorder. School-based humanistic counselling (SBHC) may help young people identify, address, and overcome psychological distress. Data from four pilot trials suggest that SBHC may be clinically effective. However, a fully powered randomised controlled trial (RCT) is needed to provide a robust test of its effectiveness, to assess its cost-effectiveness, and to determine the process of change. METHODS/DESIGN: The Effectiveness and Cost effectiveness Trial of Humanistic Counselling in Schools (ETHOS) is a two-arm, parallel-group RCT comparing the clinical and cost-effectiveness of SBHC with Pastoral Care as Usual (PCAU) in school settings. Eligibility criteria for young people include being between 13 and 16 years of age and experiencing moderate to severe levels of emotional distress. Participants are randomised to receive either SBHC or PCAU. SBHC is delivered in up to 10 weekly, individual sessions in their school with a qualified, experienced counsellor who has also received training using a clinical practice manual. Adherence to the SBHC model is assessed by a sub-team of auditors and in clinical supervision. PCAU consists of the schools' pre-existing systems for supporting the emotional health and well being of students. The primary outcomes are psychological distress measured using the Young Person's Clinical Outcomes in Routine Evaluation (YP-CORE) and costs evaluated using the Client Service Receipt Inventory (CSRI). Secondary outcomes include psychological difficulties, levels of depression, anxiety and self esteem, well-being, school engagement, educational outcomes and achievement of personal goals. Qualitative interviews with participants, parents and school staff will look to identify the mechanisms of change in SBHC. Researchers administering the measures are blind to allocation. The trial requires n = 306 participants (n = 153 in each group), with 90% power to detect a standardised mean difference (SMD) of 0.5. An intention-to-treat analysis will be undertaken. DISCUSSION: This RCT is powered to detect clinically meaningful differences, and will make a major contribution to the evidence base for mental health provision for adolescents. It will have implications for all stakeholders, including policy makers, statutory advisory bodies for child welfare, head teachers, children and young people practitioners, child welfare and parenting organisations, and young people. TRIAL REGISTRATION: Controlled Trials International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ID: ISRCTN10460622 . Registered on 11 May 2016. PMID- 29523207 TI - Oxysterol levels and metabolism in the course of neuroinflammation: insights from in vitro and in vivo models. AB - BACKGROUND: Oxysterols are cholesterol derivatives that have been suggested to play a role in inflammatory diseases such as obesity, atherosclerosis, or neuroinflammatory diseases. However, the effect of neuroinflammation on oxysterol levels has only been partially studied so far. METHODS: We used an HPLC-MS method to quantify over ten oxysterols both in in vitro and in vivo models of neuroinflammation. In the same models, we used RT-qPCR to analyze the expression of the enzymes responsible for oxysterol metabolism. Using the BV2 microglial cell line, we explored the effect of lipopolysaccharide (LPS)-induced (M1-type) and IL-4-induced (M2-type) cell activation on oxysterol levels. We also used LPS activated co-cultures of mouse primary microglia and astrocytes. In vivo, we induced a neuroinflammation by administering LPS to mice. Finally, we used a mouse model of multiple sclerosis, namely the experimental autoimmune encephalomyelitis (EAE) model, that is characterized by demyelination and neuroinflammation. RESULTS: In vitro, we found that LPS activation induces profound alterations in oxysterol levels. Interestingly, we could discriminate between control and LPS-activated cells based on the changes in oxysterol levels both in BV2 cells and in the primary co-culture of glial cells. In vivo, the changes in oxysterol levels were less marked than in vitro. However, we found in both models increased levels of the GPR183 agonist 7alpha,25 dihydroxycholesterol. Furthermore, we studied in vitro the effect of 14 oxysterols on the mRNA expression of inflammatory markers in LPS-activated co culture of microglia and astrocytes. We found that several oxysterols decreased the LPS-induced expression of pro-inflammatory markers. CONCLUSIONS: These data demonstrate that inflammation profoundly affects oxysterol levels and that oxysterols can modulate glial cell activation. This further supports the interest of a large screening of oxysterol levels when studying the interplay between neuroinflammation and bioactive lipids. PMID- 29523208 TI - Single-bundle versus double-bundle autologous anterior cruciate ligament reconstruction: a meta-analysis of randomized controlled trials at 5-year minimum follow-up. AB - BACKGROUND: Both single-bundle (SB) and double-bundle (DB) techniques were widely used in anterior cruciate ligament (ACL) reconstruction recently. Nevertheless, up to now, no consensus has been reached on whether the DB technique was superior to the SB technique. Moreover, follow-up of the included studies in the published meta-analyses is mostly short term. Our study aims to compare the mid- to long term outcome of SB and DB ACL reconstruction concerning knee stability, clinical function, graft failure rate, and osteoarthritis (OA) changes. METHODS: This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, Embase, and the Cochrane Library were searched from inception to October 2017. The study included only a randomized controlled trial (RCT) that compared SB and DB ACL reconstruction and that had a minimum of 5-year follow-up. The Cochrane Collaboration's risk of bias tool was used to assess the risk of bias for all included studies. Stata/SE 12.0 was used to perform a meta-analysis of the clinical outcome. RESULTS: Five RCTs were included, with a total of 294 patients: 150 patients and 144 patients in the DB group and the SB group, respectively. Assessing knee stability, there was no statistical difference in side-to-side difference and negative rate of the pivot shift test. Considering functional outcome, no significant difference was found in proportion with International Knee Documentation Committee (IKDC) grade A, IKDC score, Lysholm scores, and Tegner scores. As for graft failure rate and OA changes, no significant difference was found between the DB group and the SB group. CONCLUSION: The DB technique was not superior to the SB technique in autologous ACL reconstruction regarding knee stability, clinical function, graft failure rate, and OA changes with a mid- to long-term follow-up. PMID- 29523209 TI - Signature of circular RNAs in human induced pluripotent stem cells and derived cardiomyocytes. AB - BACKGROUND: Circular RNAs (circRNAs) are regarded as a novel class of noncoding RNA regulators. Although a number of circRNAs have been identified by bioinformatics analysis of RNA-seq data, tissue and disease-specific circRNAs are still to be uncovered to promote their application in basic research and clinical practice. The purpose of this study was to explore the circRNA profiles in human induced pluripotent stem cells (hiPSCs) and hiPSC-derived cardiomyocytes (hiPSC CMs), and to identify cardiac or disease-specific circRNAs. METHODS: hiPSCs were generated from fibroblasts, and then further differentiated to hiPSC-CMs by modulating WNT signaling in RPMI+B27 medium. Following high-throughput RNA sequencing, circRNAs were extracted and quantified by a combined strategy known as CIRCexplorer. Integrative analysis was performed to illuminate the correlation between circRNAs and their parental linear isoforms. Cardiac and disease-specific expression of circRNAs was confirmed by quantitative reverse-transcription PCR. RESULTS: In this study, a total of 5602 circRNAs were identified in hiPSCs and hiPSC-CMs. Our data indicated, for the first time, more enriched expression of circRNAs in differentiated cardiomyocytes than in undifferentiated hiPSCs. In addition to the host gene-dependent expression, our integrative analysis also identified a number of circRNAs showing host gene-independent expression in hiPSCs and hiPSC-CMs. CircRNAs including circSLC8A1, circCACNA1D, circSPHKAP and circALPK2 showed cardiac-selective expression during cardiac differentiation and human heart-specific enrichment in fetal tissues. Furthermore, circSLC8A1 abnormally increased in heart tissues from patients suffering from dilated cardiomyopathy. CONCLUSIONS: CircRNAs are highly enriched in hiPSC-differentiated CMs, and cardiac-specific circRNAs such as circSLC8A1, circCACNA1D, circSPHKAP and circALPK2 may serve as biomarkers of CMs. Detection of the excessive expression of circSLC8A1 provides a potential approach for pathological status indication of heart disease. PMID- 29523210 TI - Survey of Anaplasma phagocytophilum and Anaplasma sp. 'Omatjenne' infection in cattle in Africa with special reference to Ethiopia. AB - BACKGROUND: As evidence of the infection of domestic animals by Anaplasma phagocytophilum and Anaplasma sp. 'Omatjenne' is presently becoming available, understanding the epidemiological and ecological significance of infection is important to quantify the clinical and socio-economic impact of the diseases they cause. METHODS: The first aim of this study was to analyse the occurrence of A. phagocytophilum and Anaplasma sp. 'Omatjenne' in cattle samples collected from selected African countries using a polymerase chain reaction and restriction enzyme fragment length polymorphism. Secondly, this study was aimed at the molecular identification of Ehrlichia spp. and Anaplasma spp. infection in ruminants raised under different production systems in selected sites in central Ethiopia. RESULTS: In total, 695 samples from cattle in six African countries were analysed. Overall, 45 positive results were obtained for Anaplasma sp. 'Omatjenne' (6.47%) and 19 for A. phagocytophilum (2.73%). Anaplasma sp. 'Omatjenne' was detected in all countries except Tanzania while A. phagocytophilum was detected only in samples from Ethiopia. The proportion of samples tested positive for Anaplasma sp. 'Omatjenne' ranged from 1.2% in Morocco to 16% in Rwanda. The occurrence of both agents is now confirmed in African cattle. For the survey in Ethiopia a semi-nested 16S rDNA polymerase chain reaction followed by restriction fragment length polymorphism was used for the identification of Ehrlichia spp. and Anaplasma spp. in blood samples. Randomly selected samples were also analysed by pCS20 polymerase chain reaction for the detection of E. ruminantium. Positive results were obtained for E. ruminantium and five species of Anaplasma including a zoonotic species. To our knowledge, this is the first report of infection of domestic ruminants with A. phagocytophilum, A. ovis and Anaplasma sp. 'Omatjenne' in Ethiopia. CONCLUSION: The present study showed widespread occurrence of Anaplasma sp. 'Omatijenne' in African cattle and five Anaplasma species in Ethiopia. PMID- 29523211 TI - Pediatric rheumatology infusion center: report on therapeutic protocols and infusions given over 4 Years with focus on adverse events over 1 Year. AB - BACKGROUND: Children with chronic rheumatic disease often require intravenous (IV) therapy. Our center has instituted standardized protocols for use of IV medications in rheumatology patients. Herein, we introduce the therapeutic protocols and report on their short-term safety. METHODS: This was an institutional review board (IRB) approved retrospective chart review of all patients who had received IV infusions between the years 2012 and 2015 at a single center, prescribed by a pediatric rheumatologist. Infusion medications included abatacept, belimumab, cyclophosphamide, immune globulin, infliximab, methylprednisolone, N-acetylcysteine, pamidronate disodium, rituximab, and tocilizumab. For calendar year 2015, all adverse infusions reactions were recorded along with treatment strategies used to manage them, and outcomes. Rates of adverse events were calculated per infusion medication. RESULTS: During calendar years 2012-2015, 7585 IV infusions were administered to 398 unique patients. In the year 2015, 2187 infusions were administered to 224 patients, with 34 patients experiencing 41 infusion reactions (1.9% of all infusions). Rituximab had the highest rate of adverse drug reactions with 10 patients experiencing reactions during 106 infusions (9.4%). None of the reactions were life-threatening, and only 6 resulted in discontinuation of therapy. CONCLUSIONS: In a recent 4-year span, the UAB Pediatric Rheumatology Infusion Center has given thousands of IV infusions with minimal adverse reactions over a one-year reporting period. The combination of standard infusion protocols, experience of and communication between physicians and nurses who staff the center, and safety of the medications themselves, allows for safe IV administration of a variety of therapies for pediatric rheumatology patients. TRIAL REGISTRATION: Not applicable; this was a retrospective study. PMID- 29523212 TI - Development of polymorphic EST microsatellite markers for the sand fly, Phlebotomus papatasi (Diptera: Psychodidae). AB - BACKGROUND: Phlebotomus papatasi is a widely distributed sand fly species in different tropical and sub-tropical regions including the Middle East and North Africa. It is considered an important vector that transmits Leishmania major parasites, the causative agents of cutaneous leishmaniasis. The development of microsatellite markers for this sand fly vector is of high interest to understand its population structure and to monitor its geographic dispersal. RESULTS: Fourteen polymorphic microsatellite markers were developed with simple di-, tri- and tetra-nucleotide repeats. The F statistics calculated for the 14 markers revealed high genetic diversity; expected heterozygosity (He) ranged from 0.407 to 0.767, while observed heterozygosity (Ho) was lower and ranged from 0.083 to 0.514. The number of alleles sampled fall in the range of 9-29. Three out of 14 markers deviated from Hardy-Weinberg expectations, no significant linkage disequilibrium was detected and high values for inbreeding coefficient (FIS) were likely due to inbreeding. CONCLUSIONS: The development of these functional microsatellites enable a high resolution of P. papatasi populations. It opens a path for researchers to perform multi locus-based population genetic structure analyses, and comparative mapping, a part of the efforts to uncover the population dynamics of this vector, which is an important global strategy for understanding the epidemiology and control of leishmaniasis. PMID- 29523213 TI - Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. AB - Mesenchymal stem cells (MSCs) are multipotent stem cells that have gained significant attention in the field of regenerative medicine. The differentiation potential along with paracrine properties of MSCs have made them a key option for tissue repair. The paracrine functions of MSCs are applied through secreting soluble factors and releasing extracellular vesicles like exosomes and microvesicles. Extracellular vesicles are predominantly endosomal in origin and contain a cargo of miRNA, mRNA, and proteins that are transferred from their original cells to target cells. Recently it has emerged that extracellular vesicles alone are responsible for the therapeutic effect of MSCs in plenty of animal diseases models. Hence, MSC-derived extracellular vesicles may be used as an alternative MSC-based therapy in regenerative medicine. In this review we discuss MSC-derived extracellular vesicles and their therapeutic potential in various diseases. PMID- 29523216 TI - MiR-148b functions as a tumor suppressor by targeting endoplasmic reticulum metallo protease 1 in human endometrial cancer cells. AB - This study was aimed to investigate the tumor suppressive role of miR-148b in regulating endoplasmic reticulum metalloprotease 1 (ERMP1) expression and oxidative stress response in endometrial cancer cells. Human endometrial cancer RL95-2 cells were used and transfected with miR-148b mimic, miR-148b inhibitor, and their scrambled negative control. Thereafter, the transfection efficiency was determined by qRT-PCR and cell viability was assessed by MTT assay. The luciferase reporter assay, Western blot, and qRT-PCR were conducted to determine the target gene of miR-148b. ERMP1 might be the target of miR148b and thereby the over-expression and down-regulation of ERMP1 on proliferation of RL95-2 cells were assessed. Next, the expression of hypoxia-inducible factor 1 (HIF-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) were analyzed by Western blot. Intracellular reactive oxygen species (ROS) was determined using dichlorofluorescin diacetate (DCFDA). Results showed that differential expression of miR-148b or ERMP1 was observed in normal endometrial tissues and endometrial cancerous tissues. Enhanced expression of miR-148b effectively inhibited viability of RL95-2 cells. ERMP1 was the target of miR-148b. ERMP1 silence obviously suppressed proliferation of RL95-2 cells. Thus, miR-148b repressed cell proliferation likely through down-regulating ERMP1. Furthermore, it was observed that miR-148b significantly decreased expression of HIF1 and Nrf-2 by down regulating ERMP1. The intracellular ROS level was enhanced by miR-148b via down regulating ERMP1. To concluded, our results suggested that miR-148b suppressed cell proliferation and regulated oxidative stress response in human endometrial cancer RL95-2 cells by inhibiting ERMP1. PMID- 29523214 TI - Polymer-mineral scaffold augments in vivo equine multipotent stromal cell osteogenesis. AB - BACKGROUND: Use of bioscaffolds to direct osteogenic differentiation of adult multipotent stromal cells (MSCs) without exogenous proteins is a contemporary approach to bone regeneration. Identification of in vivo osteogenic contributions of exogenous MSCs on bioscaffolds after long-term implantation is vital to understanding cell persistence and effect duration. METHODS: This study was designed to quantify in vivo equine MSC osteogenesis on synthetic polymer scaffolds with distinct mineral combinations 9 weeks after implantation in a murine model. Cryopreserved, passage (P)1, equine bone marrow-derived MSCs (BMSC) and adipose tissue-derived MSCs (ASC) were culture expanded to P3 and immunophenotyped with flow cytometry. They were then loaded by spinner flask on to scaffolds composed of tricalcium phosphate (TCP)/hydroxyapatite (HA) (40:60; HT), polyethylene glycol (PEG)/poly-L-lactic acid (PLLA) (60:40; GA), or PEG/PLLA/TCP/HA (36:24:24:16; GT). Scaffolds with and without cells were maintained in static culture for up to 21 days or implanted subcutaneously in athymic mice that were radiographed every 3 weeks up to 9 weeks. In vitro cell viability and proliferation were determined. Explant composition (double-stranded (ds)DNA, collagen, sulfated glycosaminoglycan (sGAG), protein), equine and murine osteogenic target gene expression, microcomputed tomography (MUCT) mineralization, and light microscopic structure were assessed. RESULTS: The ASC and BMSC number increased significantly in HT constructs between 7 and 21 days of culture, and BMSCs increased similarly in GT constructs. Radiographic opacity increased with time in GT-BMSC constructs. Extracellular matrix (ECM) components and dsDNA increased significantly in GT compared to HT constructs. Equine and murine osteogenic gene expression was highest in BMSC constructs with mineral containing scaffolds. The HT constructs with either cell type had the highest mineral deposition based on MUCT. Regardless of composition, scaffolds with cells had more ECM than those without, and osteoid was apparent in all BMSC constructs. CONCLUSIONS: In this study, both exogenous and host MSCs appear to contribute to in vivo osteogenesis. Addition of mineral to polymer scaffolds enhances equine MSC osteogenesis over polymer alone, but pure mineral scaffold provides superior osteogenic support. These results emphasize the need for bioscaffolds that provide customized osteogenic direction of both exo- and endogenous MSCs for the best regenerative potential. PMID- 29523215 TI - Hydrogen sulfide promotes immunomodulation of gingiva-derived mesenchymal stem cells via the Fas/FasL coupling pathway. AB - BACKGROUND: Mesenchymal stem cells derived from gingiva (GMSCs) display profound immunomodulation properties in addition to self-renewal and multilineage differentiation capacities. Hydrogen sulfide (H2S) is not only an environmental pollutant, but also is an important biological gas transmitter in health and disease. METHODS: We used an in-vitro coculture system and a mouse colitis model to compare the immunomodulatory effects between control and H2S-deficient GMSCs. The flow cytometry analysis was used for T-cell apoptosis and T-helper 17 (Th17) and regulatory T (Treg) cell differentiation. RESULTS: We revealed that GMSCs exerted their immunomodulatory effect by inducing T-cell apoptosis, promoting Treg cell polarization, and inhibiting Th17 cell polarization in vitro. The levels of H2S regulated the immunomodulatory effect of GMSCs. Mechanically, H2S deficiency downregulated the expression of Fas in GMSCs, resulting in reduced secretion of monocyte chemotactic protein 1 (MCP-1), which in turn led to decreased T-cell migration to GMSCs mediated by MCP-1. Moreover, H2S deficiency downregulated the expression of Fas ligand (FasL) in GMSCs. The Fas/FasL coupling induced T-cell apoptosis by GMSCs was attenuated in H2S-deficient GMSCs. Consistent with this, H2S-deficient GMSCs showed attenuated therapeutic effects on colitis in vivo, which could be restored by treatment with the H2S donor, NaHS. CONCLUSIONS: These findings showed that H2S was required to maintain immunomodulation of GMSCs, which was mediated by Fas/FasL coupling-induced T-cell apoptosis. PMID- 29523217 TI - Adjuvant chemotherapy following surgical resection improves survival in patients with early-stage small cell lung cancer. AB - The purpose of this study was to determine the effects of resection coupled with standard chemotherapy on survival prognosis of patients with early-stage small cell lung carcinoma (SCLC). Patients (n=110) with mediastinal lymph node-negative SCLC were enrolled in this study. The baseline clinical data of patients with surgery was retrospectively reviewed. Overall and progression-free survival were measured by Kaplan-Meier and log-rank test analyses. Ninety-eight patients received mediastinoscopy biopsy and pulmonary lobectomy or sublobar resection, and 67 patients underwent adjuvant chemotherapy after pulmonary lobectomy. Adjuvant chemotherapy after surgical intervention was associated with longer OS (median OS 42.14 months (m) vs. 33.53 m, p =0.01) and PFS (median PFS 25.20 m vs. 13.48 m, p =0.000) compared to resection alone for all patients. Adjuvant chemotherapy was associated with improvement of survival for N1 patients with stage II (median OS 36.42 m vs. 26.68 m, p =0.021). The median PFS was 19.02 months (16.08, 21.96) and 13.25 months (10.19, 16.30) (p=0.031), respectively, for patients of N1 stage who received chemotherapy and those who did not. Cox regression analysis demonstrated that age, TNM stage (N stage, not T stage), and chemotherapy were independent risk factors that might affect overall survival in patients with mediastinal lymph node-negative SCLC. These findings suggest that the application of adjuvant chemotherapy following pulmonary lobectomy is associated with improvements of survival prognoses for patients with SCLC. The combination of surgical intervention with conventional therapy should be taken into consideration as a prospective multidisciplinary regimen for early stage SCLC. PMID- 29523218 TI - Knockdown of urothelial carcinoma associated 1 suppressed cell growth and migration through regulating miR-301a and CXCR4 in osteosarcoma MHCC97 cells. AB - Liver cancer is one of the most common malignancies in the world with a leading cause of cancer-related mortality. Accumulating evidences have highlighted the critical role of long noncoding RNAs (lncRNAs) in various cancers. The present study aimed to explore the role of lncRNA urothelial carcinoma associated 1 (UCA1) in cell growth and migration in MHCC97 cells and its underlying mechanism. Firstly, we assessed the expression of UCA1 in MHCC97 and other three cell lines by qRT-PCR. Then, the expression of UCA1, miR-301a and CXCR4 in MHCC97 cells were altered by transient transfection. The effects of UCA1 and miR-301 on cell viability, migration, invasion, and apoptosis were assessed. The results revealed that UCA1 expression was relatively higher in MHCC97 cells than that in MG63, hFOB1.19 and OS-732 cells. Knockdown of UCA1 reduced cell viability, inhibited migration and invasion, and promoted cell apoptosis. However, the effect of UCA1 knockdown on cell growth and migration was blocked by miR-301a overexpression, whose expression was regulated by UCA1. We also found that miR-301a positively regulated the CXCR4 expression. CXCR4 inhibition reversed the effect of miR-301a overexpression on cell growth and migration. Moreover, miR-301a activated the Wnt/beta-catenin and NF-?B pathways via regulating CXCR4. The present study demonstrated that UCA1 inhibition exerted an anti-growth and anti-migration role in MHCC97 cells through regulating miR-301a and CXCR4 expressions. PMID- 29523219 TI - TIMP-3 increases the chemosensitivity of laryngeal carcinoma to cisplatin via facilitating mitochondria-dependent apoptosis. AB - Laryngeal carcinoma is a kind of head and neck carcinoma with high incidence and mortality. Chemotherapy treatments ofhuman laryngeal carcinoma may fail due to the development of chemo-resistance. Tissue inhibitor of metalloproteinases 3 (TIMP3) has been shown to be implicated in a number of pathological processes typical for cancer. The present study aims to investigate the involvement of TIMP 3 in chemo-resistance of laryngeal carcinoma. We showed that TIMP3 expression was significantly decreased in chemo-resistant laryngeal carcinoma tissues compared with chemo-sensitivity tissues. Patients with low TIMP-3 expression exhibited poorer overall survival than those with high TIMP-3 expression. Moreover, cisplatin-resistant Hep-2 cells (Hep-2/R) were associated with inhibition of mitochondrial membrane potential (MMP) depolarization after cisplatin challenge. In addition, cisplatin resulted in a more pronounced cytochrome c release from mitochondria to cytoplasm in Hep-2 cells than in their resistant variants. Overexpression of TIMP-3 by adenovirus encoding TIMP-3 cDNA remarkably enhanced cisplatin-induced apoptosis, cytochrome c release and caspase activation in Hep 2/R cells, thereby sensitizing cancer cells to cisplatin. On the other hand, downregulation of TIMP-3 markedly inhibited cisplatin-induced apoptosis in Hep-2 cells through attenuating mitochondria-dependent pathway activation. Taken together, these results demonstrate that decreased TIMP-3 expression may contribute cisplatin resistance via inhibition of mitochondria-dependent apoptosis, indicating that forced TIMP-3 expression may be a useful strategy to improve the efficacy of cisplatin to treat laryngeal carcinoma. PMID- 29523220 TI - Overexpression of uric acid transporter SLC2A9 inhibits proliferation of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. While, the mechanisms of HCC progression are not well understood. Recent studies demonstrated the potential contribution of uric acid transporter SLC2A9 to tumor suppression. However, the roles and underlying mechanisms are still unknown. We aim to study the roles and mechanisms of SLC2A9 in HCC. The present study showed that SLC2A9 expression was decreased in human HCC tissues and cell lines. In addition, Overexpression of SLC2A9 inhibited HCC cell proliferation. SCL2A9 induced HCC cell apoptosis by inhibiting the expression of caspase-3. Meanwhile, our study also revealed that upregulation of SLC2A9 reduced intracellular reactive oxygen species (ROS) accumulation. Furthermore, SLC2A9 increased the mRNA and protein expression of tumor suppressor p53 in HCC cells. Probenecid inhibits SLC2A9 mediated uric acid transport, which promotes cell proliferation, inhibits cell apoptosis, induced intracellular ROS and decreases the expression of p53 in HCC cells. Therefore, the present study demonstrated that SLC2A9 may be a novel tumor suppressor gene and a potential therapeutic target in HCC. PMID- 29523221 TI - miR-132 targets FOXA1 and exerts tumor-suppressing functions in thyroid cancer. AB - MicroRNA-132 (miR-132) has been proven to be a tumor suppressor in several types of tumors. However, the expression andthe role of miR-132 in human thyroid cancer are still poorly understood. The aim of the present study was to examine the potential roles and molecular mechanism of miR-132 in thyroid cancer. We found that miR-132 expression levels were significantly downregulated in thyroid cancer tissues and cell lines. Function assays showed that overexpression of miR-132 in TPC1 inhibited cell proliferation, migration and invasion. Forkhead box protein A1 (FOXA1) was identified as a direct target of miR-132 in thyroid cancer cells. Knockdown of FOXA1 in TPC1 cells significantly inhibited cell proliferation, migration, invasion, which mimicked the suppression effect induced by miR-132 overexpression. Restoration of FOXA1 expression partially reversed the suppression effect induced by miR-132 overexpression. Taken together, these results suggested that miR-132 acts as a tumor suppressor in thyroid cancer through targeting FOXA1. PMID- 29523222 TI - Up-regulation of lncRNA CASC2 suppresses cell proliferation and metastasis of breast cancer via inactivating of the TGF-beta signaling pathway. AB - Long noncoding RNA cancer susceptibility candidate 2 (CASC2) has been identified to regulate the initiation and progression of multiple tumorous diseases. However, it was rarely reported in breast cancer. In present study, lncRNA CASC2 was found to be significantly down-regulated in breast cancer tissues and cell lines. We got this point with the quantitative real time-PCR. Furthermore, gain of-function assays demonstrated that overexpression of lncRNA CASC2 significantly repressed proliferation and metastasis while caused cell cycle arrest and much more early apoptosis of breast cancer. Additionally, based on the above research, we illustrated that the inactivation of TGF-beta signal pathway was involved in the function of lncRNA CASC2. Collectively, lncRNA CASC2 was a key factor in the tumorigenesis and malignancy of breast cancer, thereby possibly was a potential therapy target for the treatment of breast cancer. PMID- 29523223 TI - Knockdown of long non-coding RNA CAT104 inhibits the proliferation, migration and invasion of human osteosarcoma cells by regulating microRNA-381. AB - Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. This study aimed to explore the effects of long non-coding RNA CAT104 and microRNA-381 (miR-381) on osteosarcoma cell proliferation, migration, invasion and apoptosis, as well as the underlying potential mechanism. We found that CAT104 was highly expressed in osteosarcoma MG-63 and OS-732 cells. Knockdown of CAT104 significantly inhibited OS-732 cell proliferation, migration and invasion, but promoted cell apoptosis. CAT104 regulated the expression of miR 381 and miR-381 participated in the effects of CAT104 on OS-732 cells. Zinc finger E box binding homeobox 1 (ZEB1) was a direct target gene of miR-381, which was involved in the regulatory roles of miR381 in OS-732 cell proliferation, migration, invasion and apoptosis, as well as c-Jun Nterminal kinase (JNK) and Wnt/beta-catenin pathways. In conclusion, our research verified that suppression of CAT104 exerted significant inhibitory effects on osteosarcoma cell proliferation, migration and invasion by regulating the expression of miR-381 and downstream ZEB1, as well as JNK and Wnt/beta-catenin pathways. PMID- 29523224 TI - MicroRNA-377 targets zinc finger E-box-binding homeobox 2 to inhibit cell proliferation and invasion of cervical cancer. AB - A large number of microRNAs (miRNAs) are aberrantly expressed in cervical cancer and play crucial roles in the onset and progression of cervical cancer by acting as either oncogene or tumor suppressor. Therefore, investigation on the expression, biological roles and underlying mechanisms of miRNAs in cervical cancer might provide valuable therapeutic targets in the treatment for patients with this disease. In this study, miRNA377 (miR-377) was downregulated in cervical cancer tissues and cell lines. Decreased miR-377 expression was strongly correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis and distant metastasis in patients with cervical cancer. Enhanced expression of miR-377 prohibited cell proliferation and invasion in cervical cancer. Bioinformatics analysis predicted that zinc finger E-box binding homeobox 2 (ZEB2) was a potential target of miR-377. Subsequent experiments confirmed that ZEB2 is a direct target gene of miR-377 in cervical cancer. In addition, ZEB2 was overexpressed in cervical cancer tissues and was inversely related with miR-377 level. Furthermore, the suppressive effects of miR 377 on cervical cancer proliferation and invasion were rescued by restored ZEB2 expression. Overall, our findings indicated that miR-377 decreases proliferation and invasion of cervical cancer cells by directly targeting ZEB2 and provides novel evidence of miR-377 as a novel therapeutic strategy for the therapy of patients with this malignancy. PMID- 29523225 TI - H19 facilitates tongue squamous cell carcinoma migration and invasion via sponging miR-let-7. AB - The long noncoding RNA (lncRNA) H19 has been described to participate in various tumors metastasis. Nevertheless, whether H19 promotes or impedestongue squamous cell carcinoma (TSCC) cells migration and invasion remains controversial. Here, we found that the expression of H19 was elevated in TSCC tissues compared with adjacent normal tissues. Moreover, we demonstrated that the expression of H19 was higher in metastasized tumors compared with un-metastasized tumors. Consistently, TSCC cells express higher levels of H19 than human squanous cells. Subsequently, depletion of H19 impaired the migration and invasion ability of TSCC cells. Mechanisticlly, we demonstrated that H19 functions as a competing endogenous RNA (ceRNA) to sponge miRNA let-7a, leading to an increase in a let-7a target, the key regulator of tumor metastasis HMGA2, which is enriched in TSCC tissues and cell lines. Intriguingly, inhibition of let-7a significantly rescued short hairpin H19 (shH19) induced decrease of TSCC migration and invasion. These findings revealed that H19/let-7a/HMGA2/EMT axis plays a critical role in the regulation of TSCC migration and invasion, which may provide a new therapeutic target for TSCC cancers. PMID- 29523226 TI - Downregulation of lncRNA UCA1 inhibits proliferation and invasion of cervical cancer cells through miR-206 expression. AB - Cervical cancer has the second highest incidence rate among cancers in females, accounting for a majority of cancer-related deaths globally. However, the mechanism of cervical cancer pathogenesis is still unclear. UCA1 is considered an oncogene that can transcribe into a long noncoding RNA (lncRNA). This study aimed to determine the function of UCA1 in cervical cancer. A series of experiments involving BrdU, MTS, scratch-adhesion test, and cell invasion assays were conducted to determine the cellular capabilities of proliferation, viability, migration, and invasion, respectively. Binding sites between UCA1 and miR-143 were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT-PCR and immunoblot, respectively. The results shown that the upregulation of lncRNA UCA1 was found in human cervical cancer. Interference of lncRNA UCA1 inhibited cell proliferation, migration, invasion, and viability. Results of the luciferase reporter assay revealed a binding site between lncRNA UCA1 and miR-206. Knockdown of lncRNA UCA1 could directly upregulate miR-206 expression. VEGF downregulation was also observed after knockdown of lncRNA UCA1. Moreover, co-transfection of anti-miR 206 oligodeoxyribonucleotide (AMO-206) in cervical cancer cells reversed the effect of lncRNA UCA1 on VEGF. Therefore, we concluded that LncRNA UCA1 is upregulated in cervical cancer, and its knockdown can upregulate miR-206, thus, suppressing the growth of cervical cancer cells. LncRNA UCA1 is a potential target in cervical cancer treatment. PMID- 29523228 TI - Resource Utilization for Initial Hospitalization in Pediatric Heart Transplantation in the United States. AB - Pediatric heart transplantation (HT) is resource intensive. Event-driven pediatric databases do not capture data on resource use. The objective of this study was to evaluate resource utilization and identify associated factors during initial hospitalization for pediatric HT. This multicenter retrospective cohort study utilized the Pediatric Health Information Systems database (43 children's hospitals in the United States) of children <=19 years of age who underwent transplant between January 2007 and July 2013. Demographic variables including site, payer, distance and time to center, clinical pre- and post-transplant variables, mortality, cost, and charge were the data collected. Total length of stay (LOS) and charge for the initial hospitalization were used as surrogates for resource use. Charges were inflation adjusted to 2013 dollars. Of 1,629 subjects, 54% were male, and the median age at HT was 5 years (IQR [interquartile range] 0 to 13). The median total and intensive care unit LOS were 51 (IQR 23 to 98) and 23 (IQR 9 to 58) days, respectively. Total charge and cost for hospitalization were $852,713 ($464,900 to $1,609,300) and $383,600 ($214,900 to $681,000) respectively. Younger age, lower volume center, southern region, and co morbidities before transplant were associated with higher resource use. In later years, charges increased despite shorter LOS. In conclusion, this large multicenter study provides novel insight into factors associated with resource use in pediatric patients having HT. Peritransplant morbidities are associated with increased cost and LOS. Reducing costs in line with LOS will improve health care value. Regional and center volume differences need further investigation for optimizing value-based care and efficient use of scarce resources. PMID- 29523227 TI - Usefulness of Urinary N-Terminal Fragment of Titin to Predict Mortality in Dilated Cardiomyopathy. AB - Titin is associated with myocardial stiffness and hypertrophy, and mutations in its gene have been identified in cardiac myopathies such as dilated cardiomyopathy (DC). It has recently been reported that in damaged muscle, the N terminal fragment of titin (Titin-N) is cleaved by calpain-3, and urinary Titin-N (U-TN) could be a marker of sarcomere damage. We aimed to investigate the impact of U-TN on prognosis of DC. We measured urinary levels of Titin-N/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 102 patients with DC, and followed up all the patients (mean 1,167 days). The patients were divided into 3 groups based on the U-TN/Cr: first (U-TN/Cr <3.35, n = 34), second (3.35 <= U-TN/Cr <7.26, n = 34), and third (7.26 <= U-TN/Cr, n = 34) tertiles. In the Kaplan-Meier analysis, cardiac and all-cause mortality progressively increased from the first to the second and third groups (p <0.05, respectively). In the Cox proportional hazard analyses, U-TN/Cr was a predictor of cardiac and all-cause mortality in patients with DC (p <0.05, respectively). U-TN, a possible marker of sarcomere damage, can identify high-risk patients with DC. PMID- 29523229 TI - Using the Flp Recombinase to Induce Site-Specific Protein-DNA Nicks. AB - A natural and frequent occurring replication insult is generated by the action of DNA Topoisomerase I (Top1). When Top1 gets trapped in a cleavage complex on the DNA, a protein-linked DNA nick (PDN) is generated. Today it is known that PDNs are generated at a high incidence in the cell. If not rapidly removed, PDNs can have a profound impact on cell destiny, as a nick in proliferating cells is passively transformed into a single-ended DSB, when encountered by the replication machinery. A DSB can in turn lead to chromosomal rearrangements and thus jeopardize genome stability if not appropriately repaired. In order to study repair pathways associated with PDNs, we have developed a cellular system (Flp nick), where we can generate a single PDN at a specific genomic site in the model organism Saccharomyces cerevisiae. The system takes advantages of the Flp recombinase, which catalytically operates like Top1 by generating a nick in the DNA backbone and during this process becomes covalently linked to the DNA. Flp cleaves at well-defined target sites. Thus, a target site has been inserted in the genome and a mutant Flp, which cleaves but do not religate, is expressed. In this way, a single PDN mimicking the one generated by Top1 is induced at a known genomic site. The Flp-nick system allows detailed molecular analysis of repair pathways associated with this type of damage and can be designed to study repair at any genomic context. PMID- 29523231 TI - Assaying Mutations Associated With Gene Conversion Repair of a Double-Strand Break. AB - DNA double-strand break (DSB) is a cytotoxic lesion and needs to be repaired immediately. There are several metabolic pathways evolved to repair a DSB. Gene conversion is one of the least error-prone pathway for repair of a DNA DSB. Despite this there is nearly 1000-fold increase in mutation rate associated with gene conversion. Not only higher mutation rate is associated with gene conversion but also there is a very distinct mutation profile compared to spontaneous mutation events. Gene conversion is characterized by the presence of very high frameshift mutation events and other complex mutations that are not present during regular DNA replication. Another DNA DSB repair pathway widely studied is "break-induced replication" (BIR). BIR has been shown to be highly mutagenic in nature. BIR may lead to chromosomal rearrangement and has potential to cause cluster mutations with serious disease implications. In this chapter, the design of assay systems to study various mutation types and experimental procedures to measure specific mutation frequency associated with gene conversion are discussed. PMID- 29523230 TI - High-Throughput Analysis of DNA Break-Induced Chromosome Rearrangements by Amplicon Sequencing. AB - The mechanistic understanding of how DNA double-strand breaks (DSB) are repaired is rapidly advancing in part due to the advent of inducible site-specific break model systems as well as the employment of next-generation sequencing (NGS) technologies to sequence repair junctions at high depth. Unfortunately, the sheer volume of data produced by these methods makes it difficult to analyze the structure of repair junctions manually or with other general-purpose software. Here, we describe methods to produce amplicon libraries of DSB repair junctions for sequencing, to map the sequencing reads, and then to use a robust, custom python script, Hi-FiBR, to analyze the sequence structure of mapped reads. The Hi FiBR analysis processes large data sets quickly and provides information such as number and type of repair events, size of deletion, size of insertion and inserted sequence, microhomology usage, and whether mismatches are due to sequencing error or biological effect. The analysis also corrects for common alignment errors generated by sequencing read mapping tools, allowing high throughput analysis of DSB break repair fidelity to be accurately conducted regardless of which suite of NGS analysis software is available. PMID- 29523232 TI - Investigation of Break-Induced Replication in Yeast. AB - Break-induced replication (BIR) is an important mechanism aimed to repair one ended double-strand DNA breaks. BIR is initiated by invasion of a broken DNA end into a homologous template followed by DNA synthesis that can proceed for hundreds of kilobases to the end of the chromosome. Unlike S-phase replication, BIR is carried out by a migrating DNA bubble and is associated with conservative inheritance of newly synthesized DNA. The unusual mode of DNA synthesis during BIR leads to an increased level of genetic instabilities including increased mutagenesis and chromosomal rearrangements. Here, we describe our experimental system in yeast Saccharomyces cerevisiae where BIR is initiated by a site specific DNA break and where the repair involves two copies of chromosome III. This system allows investigation of BIR using genetic and molecular biology approaches, and can be used for characterization of the BIR mechanism, roles of individual proteins in BIR, and for the analysis of genetic instabilities associated with BIR. PMID- 29523234 TI - Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions. AB - Discovery of novel tool compounds and drug leads against a range of unorthodox protein targets has pushed both experimental screening methodologies as well as the field of structure-based design to the limit in recent years. Increasingly, it has been recognized that some of the most desirable targets for the development of small-molecule effectors are actually protein-protein and protein nucleic acid interactions. There are numerous nontrivial challenges to pursuing small-molecule lead compounds directed toward PPIs and PNIs: relatively shallow cavities, large surface areas that are natively complexed to macromolecules, complex patterns of interstitial waters, a paucity of "hot spots," large conformational changes upon ligand binding, etc. Although there have been some notable successes targeting PPIs in the last decade, there has been distinctly less success in the realm of targeting PNIs. This chapter focuses on an approach, successfully applied by our group to address the challenge of gaining traction on the PPI target RAD52, which is a protein that binds both single-stranded and double-stranded DNA, and is an anticancer target for certain types of cancer. There are many approaches to tackling the difficult problems of finding effective small molecules that disrupt PPIs and PNIs, but the methods presented here offer a series of elegant solutions, which integrate experimental HTS, biophysical methods, docking, and molecular dynamics in a powerful way. Additionally, the structural knowledge gained from these studies provides a means for rationally understanding what features lead to ligand affinity in these fascinating and highly unorthodox pockets. PMID- 29523233 TI - Targeting Allostery with Avatars to Design Inhibitors Assessed by Cell Activity: Dissecting MRE11 Endo- and Exonuclease Activities. AB - For inhibitor design, as in most research, the best system is question dependent. We suggest structurally defined allostery to design specific inhibitors that target regions beyond active sites. We choose systems allowing efficient quality structures with conformational changes as optimal for structure-based design to optimize inhibitors. We maintain that evolutionarily related targets logically provide molecular avatars, where this Sanskrit term for descent includes ideas of functional relationships and of being a physical embodiment of the target's essential features without requiring high sequence identity. Appropriate biochemical and cell assays provide quantitative measurements, and for biomedical impacts, any inhibitor's activity should be validated in human cells. Specificity is effectively shown empirically by testing if mutations blocking target activity remove cellular inhibitor impact. We propose this approach to be superior to experiments testing for lack of cross-reactivity among possible related enzymes, which is a challenging negative experiment. As an exemplary avatar system for protein and DNA allosteric conformational controls, we focus here on developing separation-of-function inhibitors for meiotic recombination 11 nuclease activities. This was achieved not by targeting the active site but rather by geometrically impacting loop motifs analogously to ribosome antibiotics. These loops are neighboring the dimer interface and active site act in sculpting dsDNA and ssDNA into catalytically competent complexes. One of our design constraints is to preserve DNA substrate binding to geometrically block competing enzymes and pathways from the damaged site. We validate our allosteric approach to controlling outcomes in human cells by reversing the radiation sensitivity and genomic instability in BRCA mutant cells. PMID- 29523235 TI - A Proximity Ligation-Based Method for Quantitative Measurement of D-Loop Extension in S. cerevisiae. AB - Homologous recombination faithfully restores the sequence information interrupted by a DNA double-strand break by referencing an intact DNA molecule as a template for repair DNA synthesis. DNA synthesis is primed from 3'-OH end of the invading DNA strand in the displacement loop (D-loop). Here, we describe a simple and quantitative proximity ligation-based assay to study the initiation of homologous recombination-associated DNA synthesis initiated at the D-loop and final product formation. The D-loop extension assay overcomes the semiquantitative nature and some limitations of the current PCR-based technique and facilitates the study of the recombination-associated DNA synthesis. PMID- 29523237 TI - S1-seq Assay for Mapping Processed DNA Ends. AB - During meiosis, the specialized cell division giving rise to gametes, numerous DNA double-strand breaks (DSBs) are introduced at multiple places throughout the genome by the topoisomerase-like protein Spo11. Homologous recombination, a highly conserved DSB repair pathway, is employed for their repair and ensures the formation of chiasmata and the proper segregation of homologous chromosomes. In the initial steps of recombination, end resection takes place, wherein Spo11 is endonucleolytically released and the 5'-terminal strands of each DSB are exonucleolytically processed, exposing the ssDNA necessary to identify a homologous repair template. DNA removed by DSB processing is reconstituted by DNA synthesis, which copies genetic information from the intact homologous template. We developed a next-generation sequencing assay, termed S1-seq, to study DNA end resection genome-wide at high-spatial resolution during yeast meiotic recombination. The assay relies on the fact that removal of the ssDNA tails of resected DSBs marks the position where resection stopped. Molecular features of resection are revealed by sequencing of these ssDNA-to-dsDNA junctions and comparison to high-resolution Spo11 DSB maps. We describe the experimental and computational methods for S1-seq as applied to meiosis in the SK1 strain of budding yeast Saccharomyces cerevisiae and discuss how it can also be applied to map DSBs and recombination intermediates. PMID- 29523236 TI - Monitoring Recombination During Meiosis in Budding Yeast. AB - Homologous recombination is fundamental to sexual reproduction, facilitating accurate segregation of homologous chromosomes at the first division of meiosis, and creating novel allele combinations that fuel evolution. Following initiation of meiotic recombination by programmed DNA double-strand breaks (DSBs), homologous pairing and DNA strand exchange form joint molecule (JM) intermediates that are ultimately resolved into crossover and noncrossover repair products. Physical monitoring of the DNA steps of meiotic recombination in Saccharomyces cerevisiae (budding yeast) cultures undergoing synchronous meiosis has provided seminal insights into the molecular basis of meiotic recombination and affords a powerful tool for dissecting the molecular roles of recombination factors. This chapter describes a suit of electrophoretic and Southern hybridization techniques used to detect and quantify the DNA intermediates of meiotic recombination at recombination hotspots in budding yeast. DSBs and recombination products (crossovers and noncrossovers) are resolved using one-dimensional electrophoresis and distinguished by restriction site polymorphisms between the parental chromosomes. Psoralen cross-linking is used to stabilize branched JMs, which are resolved from linear species by native/native two-dimensional electrophoresis. Native/denaturing two-dimensional electrophoresis is employed to determine the component DNA strands of JMs and to measure the processing of DSBs. These techniques are generally applicable to any locus where the frequency of recombination is high enough to detect intermediates by Southern hybridization. PMID- 29523238 TI - Methods for Controlled Protein Depletion to Study Protein Function during Meiosis. AB - Proteins with potential roles in meiotic recombination often have essential or important functions during the mitotic cell cycle. In addition, proteins may have different functions at different times during meiosis. In such cases, it can be challenging to precisely determine protein function during meiosis using null or hypomorphic mutants. One example is the Sgs1-Top3-Rmi1 helicase-decatenase complex, which is required for normal vegetative growth and genome stability. In such cases, conditional loss-of-function mutants can be useful. In this chapter, we describe the construction of two types of conditional mutants, meiotic depletion alleles and auxin-induced degradation alleles, that allow protein depletion specifically during budding yeast meiosis, and illustrate their use with Sgs1. We also describe a modified method for the isolation of meiotic recombination intermediates that combines previous psoralen cross-linking and cetyltrimethylammonium bromide isolation methods. PMID- 29523240 TI - Analysis of Meiotic Double-Strand Break Initiation in Mammals. AB - The repair of programmed DNA double-strand breaks (DSBs) physically tethers homologous chromosomes in meiosis to allow for accurate segregation through meiotic cell divisions. This process, known as recombination, also results in the exchange of alleles between parental chromosomes and contributes to genetic diversity. In mammals, meiotic DSBs occur predominantly in a small fraction of the genome, at sites known as hotspots. Studies of the formation and repair of meiotic DSBs in mammals are challenging, because few cells undergo meiotic DSB formation at a given time. To better understand the initiation and control of meiotic recombination in mammals, we have devised a highly sensitive method to map the sites of meiotic DSBs genome wide. Our method first isolates DNA bound to DSB repair proteins and then specifically sequences the associated single stranded DNA. This protocol has generated the first meiotic DSB maps in several mammals and the only map of meiotic DSBs in humans. PMID- 29523239 TI - Quantitative Methods to Investigate the 4D Dynamics of Heterochromatic Repair Sites in Drosophila Cells. AB - Heterochromatin is mostly composed of long stretches of repeated DNA sequences prone to ectopic recombination during double-strand break (DSB) repair. In Drosophila, "safe" homologous recombination (HR) repair of heterochromatic DSBs relies on a striking relocalization of repair sites to the nuclear periphery. Central to understanding heterochromatin repair is the ability to investigate the 4D dynamics (movement in space and time) of repair sites. A specific challenge of these studies is preventing phototoxicity and photobleaching effects while imaging the sample over long periods of time, and with sufficient time points and Z-stacks to track repair foci over time. Here we describe an optimized approach for high-resolution live imaging of heterochromatic DSBs in Drosophila cells, with a specific emphasis on the fluorescent markers and imaging setup used to capture the motion of repair foci over long-time periods. We detail approaches that minimize photobleaching and phototoxicity with a DeltaVision widefield deconvolution microscope, and image processing techniques for signal recovery postimaging using SoftWorX and Imaris software. We present a method to derive mean square displacement curves revealing some of the biophysical properties of the motion. Finally, we describe a method in R to identify tracts of directed motions (DMs) in mixed trajectories. These approaches enable a deeper understanding of the mechanisms of heterochromatin dynamics and genome stability in the three-dimensional context of the nucleus and have broad applicability in the field of nuclear dynamics. PMID- 29523241 TI - Inducing and Detecting Mitotic DNA Synthesis at Difficult-to-Replicate Loci. AB - Our conventional understanding of the process of DNA replication is that it occurs in the S-phase of the cell division cycle. However, during investigations into the mechanism by which common fragile sites (CFSs) drive genome instability, we observed that some DNA synthesis was still occurring in early mitosis at these loci. This curious phenomenon of mitotic DNA synthesis (which we now term "MiDAS") appears to be a form of break-induced DNA replication (BIR), a DNA repair process based on homologous recombination that has been characterized in detail only in lower eukaryotes. During MiDAS, it is proposed that parts of the human genome that are not fully replicated when cells enter mitotic prophase complete their replicative cycle at that point. To date, the loci that most depend upon this process are those whose replication can be affected by oncogene induced DNA replication stress (RS), most notably, CFSs. From our studies, it is clear that the successful completion of MiDAS at CFSs can minimize chromosome missegregation and nondisjunction. Nevertheless, it is still not clear which loci that can undergo MiDAS, whether MiDAS is associated with mutations or genome rearrangements, or whether MiDAS really is a form of BIR. In this review, we describe methods for detecting MiDAS both in prometaphase cells and directly on isolated metaphase chromosomes. In addition, we have included methods for combining MiDAS detection either with immunofluorescence (IF) detection of proteins that are recruited to the MiDAS loci, or with fluorescence in situ hybridization using probes that target specific genomic loci. PMID- 29523242 TI - An Approach to Detect and Study DNA Double-Strand Break Repair by Transcript RNA Using a Spliced-Antisense RNA Template. AB - A double-strand break (DSB) is one of the most dangerous DNA lesion, and its repair is crucial for genome stability. Homologous recombination is considered the safest way to repair a DNA DSB and requires an identical or nearly identical DNA template, such as a sister chromatid or a homologous chromosome for accurate repair. Can transcript RNA serve as donor template for DSB repair? Here, we describe an approach that we developed to detect and study DNA repair by transcript RNA. Key features of the method are: (i) use of antisense (noncoding) RNA as template for DSB repair by RNA, (ii) use of intron splicing to distinguish the sequence of the RNA template from that of the DNA that generates the RNA template, and (iii) use of a trans and cis system to study how RNA repairs a DSB in homologous but distant DNA or in its own DNA, respectively. This chapter provides details on how to use a spliced-antisense RNA template to detect and study DSB repair by RNA in trans or cis in yeast cells. Our approach for detection of DSB repair by RNA in cells can be applied to cell types other than yeast, such as bacteria, mammalian cells, or other eukaryotic cells. PMID- 29523243 TI - Assaying Repair at DNA Nicks. AB - Nicks are the most common form of DNA damage, but they have only recently been shown to initiate damage that requires repair. Analysis of the pathways of nick repair in human cells has benefited from the development of enzymes that target nicks to specific sites in the genome and of reporters that enable rapid analysis of homology-directed repair and mutagenic end joining. Nicks undergo efficient repair by single-stranded oligonucleotide donors complementary to either the nicked or intact DNA strand, via pathways that are normally suppressed by RAD51. Here we discuss the details of reporter assays that take advantage of the convenience and sensitivity of flow cytometry to analyze pathways of repair at targeted DNA nicks. These assays are readily carried out in 96-well format cell culture plates, enabling mechanistic questions to be addressed by determining the contributions of specific factors by depletion and/or ectopic expression. PMID- 29523244 TI - Recovery of Alternative End-Joining Repair Products From Drosophila Embryos. AB - In this chapter, we describe a method for the recovery and analysis of alternative end-joining (alt-EJ) DNA double-strand break repair junctions following I-SceI cutting in Drosophila melanogaster embryos. Alt-EJ can be defined as a set of Ku70/80 and DNA ligase 4-independent end-joining processes that are typically mutagenic, producing deletions, insertions, and chromosomal rearrangements more frequently than higher-fidelity repair pathways such as classical nonhomologous end joining or homologous recombination. Alt-EJ has been observed to be upregulated in HR-deficient tumors and is essential for the survival and proliferation of these cells. Alt-EJ shares many initial processing steps with homologous recombination, specifically end resection; therefore, studying alt-EJ repair junctions can provide useful insight into aborted HR repair. Here, we describe the injection of plasmid constructs with specific cut sites into Drosophila embryos and the subsequent recovery of alt-EJ repair products. We also describe different analytical approaches using this system and how amplicon sequencing can be used to provide mechanistic information about alt EJ. PMID- 29523245 TI - Preface. PMID- 29523246 TI - Electrospun polystyrene fibers knitted around imprinted acrylate microspheres as sorbent for paraben derivatives. AB - Parabens are used as antimicrobial preservatives in food, cosmetic products and pharmaceuticals regardless of their endocrine disrupting effect. In this study, highly selective molecular imprinted polymers (MIPs) were synthesized in submicron-sizes and converted to an SPME fiber coating through electrospinning process in order to determine parabens in water samples. Conversion of MIP to a fiber is achieved via creation of spacial knitting around MIP by polystyrene. The selectivity and extraction ability of the fibers were compared with the commercial fibers and the corresponding non-imprinted polymer (NIP) coated fiber. The coated fiber showed better extraction ability among them. Also, the results revealed that the fiber has better selectivity for benzyl paraben and the other structurally-related compounds, such as methyl and propyl paraben. Extraction efficiency of prepared fibers for three parabens has been tested by spiking bottled, tap and sea water samples. The recoveries changed between 92.2 +/- 0.8 and 99.8 +/- 0.1 for three different water types. This method could be used for selective and sensitive determination of parabens in aqueous samples. PMID- 29523247 TI - Graphene blended with SnO2 and Pd-Pt nanocages for sensitive non-enzymatic electrochemical detection of H2O2 released from living cells. AB - This paper described a novel, facile and nonenzymatic electrochemical biosensor to detect hydrogen peroxide (H2O2). The sensor was fabricated based on Pd-Pt nanocages and SnO2/graphene nanosheets modified electrode (PdPt NCs@SGN/GCE). The electrochemical behavior of PdPt NCs@SGN/GCE exhibited excellent catalytic activity toward H2O2 with fast response, high selectivity, superior sensitivity, low detection limit of 0.3 MUM and large linear range from 1 MUM to 300 MUM. Under these obvious advantages, the constructed biosensor provided to be reliable for determination of H2O2 secreted from human cervical cancer cells (Hela cells). Hence, the proposed biosensor is a promising candidate for detection of H2O2 in situ released from living cells in clinical diagnostics. PMID- 29523248 TI - Switched photoelectrochemistry of carbon dots for split-type immunoassay. AB - A novel and general strategy of split-type immunoassay is developed based on redox chemical reaction modulated photoelectrochemistry of carbon dots (CDs). Specifically, the photocurrent of the CDs sensitized titanium dioxide nanoparticles (TiO2 NPs) modified fluorine doped indium tin oxide (FTO) (that is the FTO/TiO2/CDs) electrode was inhibited obviously by KMnO4 due to the oxidation of surface hydroxyl groups of CDs to electron accepting carbonyls. While the inhibited photocurrent of the KMnO4 treated FTO/TiO2/CDs electrode can be restored by ascorbic acid (AA) because of the regeneration of electron donating hydroxyls to promote electron-hole separation. Take carcinoembryonic antigen (CEA) as a model analyte and alkaline phosphate (ALP) as a catalytic label tracer to hydrolyze ascorbic acid 2-phosphate (AAP) for producing AA, which greatly stimulated the photocurrent of the transducer of KMnO4 treated FTO/TiO2/CDs photoelectrode for signal output. This redox chemical reaction modulated PEC strategy enabled the separation of the immunoreaction from the photoelectrode (that is, a split-type PEC detection), eliminating potential damage of biomolecules during the PEC detection processes and leading to enhanced throughput detection as compared to conventional PEC configurations. A low detection limit of 7.0 fg/mL was achieved for CEA. This convenient, split-type PEC immunoassay with high throughput may be easily extended to other bioaffinity assays for versatile targets. PMID- 29523249 TI - Capillary microextraction of volatiles device for enhanced BTEX vapors sampling based on a phenyl modified PDMS sol-gel adsorption phase. AB - A novel phenyl modified PDMS (PhPDMS) sol-gel adsorption phase was developed for use with the capillary microextraction of volatiles (CMV) device, and determined to provide significant enhancement in BTEX recoveries when sampling trace (ng) amounts of these volatiles at ambient conditions. The previously reported reusable PDMS-CMV device has been demonstrated to rapidly and efficiently extract target compound's vapors in forensic and environmental applications. An improved recovery for VOCs was achieved with a cryofocusing system while extracting at -10 degrees C, but it was found to be impractical for field sampling. This report details a modification to the CMV's chemistry, by the successful introduction of phenyl groups to the PDMS sol-gel adsorption phase, allowing enhanced performance at ambient extraction conditions. Higher average recoveries, determined through a broad concentration range, were demonstrated for PhPDMS-CMV over its original PDMS-CMV, from cans simulating a closed space set-up. Within 7.8 (+/-10%) and 3.5 (+/-6%) folds higher for benzene and toluene, respectively and 2 (+/-2%) folds for ethylbenzene and xylenes. Significant higher retaining capabilities were demonstrated also at the more challenging set-up, simulating an open space environment. Whereas, benzene had completely breakthrough the PDMS-CMV, its reliable detection was still confirmed with PhPDMS-CMV pumping at 2 L or 6 L air, concentration dependent. At least 50 folds (+/-26%) more toluene was retained with PhPDMS-CMV at 6 L air than with PDMS-CMV. The enhanced overall performance lead to determination of trace LODs with the new CMV of 0.002, 0.00035 and 0.00015 ppm for benzene, toluene, ethyl benzene and xylenes, respectively. As proof of concept, for the first time solvent extraction is presented for the new CMV as an alternative to thermal desorption extraction. Extraction efficiencies of 60% for TEX, and lower concentration dependent for benzene, were demonstrated with the ease and rapid application of 100 MUL acetone through the device. The improvements described in this study continues to build on the potential for the use of the reusable new CMV device by expanding its possible potential applications for fast and sensitive air sampling of VOCs. The solvent extraction step may offer compatibility with LC-based systems. PMID- 29523250 TI - Influence of collecting substrate on the Raman imaging of micron-sized particles. AB - The influence of six common substrates on the Raman imaging of micron-sized inorganic aerosol particles was examined. Laboratory-generated single-component particles of calcite (CaCO3) and mixed particles of calcite (CaCO3), nitratine (NaNO3), hematite (Fe2O3) and anglesite (PbSO4) were deposited by cascade impaction on Ag, In, Si, SiO2, microscope slide and TEM-grid substrates. The spectral contribution of substrates to Raman images of the deposited particles was evaluated by Multivariate Curve Resolution. The shape and intensity of the substrate spectra affect the effectiveness capability of the spectral deconvolution. The substrates were characterized and compared with respect to their effect on the reconstruction of Raman images of aerosol particles. The TEM grid substrate yielded spatially stable sample measurements with a homogeneous spectral contribution, satisfactory Raman map reconstruction and the potential for application in other techniques (e.g., SEM-EDX). PMID- 29523251 TI - Ion mobility-derived collision cross section database: Application to mycotoxin analysis. AB - The recent hyphenation of ion mobility spectrometry (IMS) with high resolution mass spectrometry (HRMS) has risen as a powerful technique for both targeted and non-targeted screening, reducing background noise and allowing separation of isomeric and isobaric compounds. Nevertheless, such an approach remains largely unexplored in food safety applications, such as mycotoxin analysis. To implement ion mobility in routinely MS-based mycotoxin workflows, searchable databases with collusion cross section (CCS) values and accurate mass-values are required. This paper provides for the first time a traveling-wave IMS (TWIMS)-derived CCS database for mycotoxins, including more than 100 CCS values. The measurements showed high reproducibility (RSD < 2%) across different instrumental conditions as well as several complex cereal matrices, showing a mean inter-matrix precision of RSD <0.9%. As a proof of concept, the database was applied to the analysis of several spiked as well as naturally incurred cereal-based samples. In addition, the effect of adducts on the drift time was studied in a series of mycotoxins in order to understand potential deviations from expected drift time behaviors. Overall, our study confirmed that CCS values represent a physicochemical property that can be used alongside the traditional molecular identifiers of precursor ion accurate mass, fragment ions, isotopic pattern, and retention time. PMID- 29523252 TI - Covalent organic framework as efficient desorption/ionization matrix for direct detection of small molecules by laser desorption/ionization mass spectrometry. AB - Covalent organic framework (COF) was explored as a novel matrix with a high desorption/ionization efficiency for direct detection of small molecules by laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS). By using COF as an LDI MS matrix, we could detect not only biological micro molecules such as amino acids and fatty acids, but also emerging environmental pollutants like bisphenol S (BPS) and pyrene. With COF as the matrix, higher desorption/ionization efficiency, and less background interference were achieved than the conventional organic matrices. Good salt tolerance (as high as 500 mM NaCl) and repeatability allowed the detection limit of amino acids was 90 fmol. In addition, COF matrix performed well for amino acids analysis in the honey sample. The ionization mechanism was also discussed. These results demonstrate that COF is a powerful matrix for small molecules analysis in real samples by MS. PMID- 29523253 TI - Antipsychotic drug poisoning monitoring of clozapine in urine by using coffee ring effect based surface-enhanced Raman spectroscopy. AB - Antipsychotics are the drugs most often involved in drug poisoning cases, and therefore, therapeutic drug monitoring (TDM) is necessary for safe and effective medication administration of these drugs. In this study, a coffee ring effect based surface-enhanced Raman spectroscopy (CRE-SERS) method was developed and successfully used to monitor antipsychotic poisoning by using urine samples for the first time. The established method exhibited excellent SERS performance since more hot spots were obtained in the "coffee ring". Using the optimized CRE-SERS method, the sensitivity was improved one order more than that of the conventional method with reasonable reproducibility. The antipsychotic drug clozapine (CLO) spiked into urine samples at 0.5-50 MUg mL-1 was quantitatively detected, at concentrations above the thresholds for toxicity. The CRE-SERS method allowed CLO and its metabolites to be ultimately distinguished from real poisoning urine samples. The coffee-ring effect would provide more opportunities for practical applications of the SERS-based method. The frequent occurrence of drug poisoning may have created a new area for the application of the CRE-SERS method. It is anticipated that the developed method will also have great potential for other drug poisoning monitoring. PMID- 29523254 TI - A fluorescent sensor for fast detection of peroxynitrite by removing of C=N in a benzothiazole derivative. AB - A simple structured reaction-based probe for peroxynitrite (ONOO-) was developed by using benzothiazole hydrazone base of the excited-state intramolecular proton transfer (ESIPT) dye. It was constructed from 2-hydrazinylpyridine and 3 (benzo[d]thiazol-2-yl)-2-hydroxy-5-methylbenzaldehyde which possesses itself weak fluorescence and displayed prominent fluorescence response towards ONOO- by oxidizes the C=N bond to an aldehyde in aqueous solution. The probe exhibited excellent selectivity and high sensivity towards ONOO- with a low dectection limit of 5.8 * 10-8 M in physiological condition. Moreover, the probe could realize fast recognition to ONOO- in as short as 60 s. In addition, the probe was also successfully used for living cell imaging. PMID- 29523255 TI - Construction of surface charge-controlled reduced graphene oxide-loaded Fe3O4 and Pt nanohybrid for peroxidase mimic with enhanced catalytic activity. AB - Hybrid nanomaterials with synergistic effect are highly potential for developing advanced nanozymes. Herein, we designed a nanozyme assembled by polyethylenimine (PEI)-protected reduced graphene oxide anchoring iron oxide (PRGI) and Pt nanoparticle using electrostatic interaction, PRGI/Pt nanohybrid. The different ratio of PRGI nanocomposite and Pt nanoparticle could control PRGI/Pt nanohybrid's surface charge and stability, which determined PRGI/Pt nanohybrid's catalytic activity. At the mass ratio of 0.8, the as-obtained PRGI/Pt nanohybrid showed the highest catalytic ability, and was better than Pt nanoparticle at different pH and temperature, although the PRGI/Pt nanohybrid showed lower affinity for TMB than Pt nanoparticle, which maybe attributed to the fact that PRGI/Pt nanohybrid possessed better product desorption ability or larger contact area. Furthermore, PRGI/Pt nanohybrid showed much higher catalytic activity than the sum of PRGI nanocomposite and Pt nanoparticle, indicating the strong cooperation between PRGI nanocomposite and Pt nanoparticle. Our study also provided a new way to conveniently construct nanozyme based on hybrid nanomaterials. PMID- 29523256 TI - Ratiometric fluorescence sensing of mercuric ion based on dye-doped lanthanide coordination polymer particles. AB - This work focused on the development of a novel ratiometric fluorescence sensor for detection of Hg2+ by using dye-doped lanthanide infinite coordination polymer (Ln-ICP) particles. The dye-doped Ln-ICP used herein was prepared by self assemble of adenosine monophosphate (AMP) with Ce3+ and Tb3+ (Ce/Tb-AMP) through self-adaptive chemistry, in which the fluorescent dye coumarin was encapsulated during the assembly process as a guest molecule. Under 310 nm irradiation, the obtained coumarin@Ce/Tb-AMP itself emitted characteristic green luminescence of Tb3+, accompanied with a weak fluorescence at 445 nm originated from coumarin encapsulated in the Ce/Tb-AMP networks. The fluorescence emission of coumarin became strong when it was released to the solution. In the presence of Hg2+, the coumarin@Ce/Tb-AMP was destroyed due to the specific coordination interaction between AMP and Hg2+, which leaded to the release of coumarin to the solution meanwhile. Consequently, the fluorescence of Ce/Tb-AMP was quenched, while that of coumarin enhanced. On the basis of this strategy, we developed a novel ratiometric fluorescent sensor for the detection of Hg2+ by measuring the ratio of fluorescent intensity of the coumarin@Ce/Tb-AMP suspension, which showed a wide linear range from 0.08 to 1000 nM and detection limit of 0.03 nM with high selectivity and sensitivity. Furthermore, the constructed ratiometric fluorescent sensor was successfully applied in detecting Hg2+ in drinking water and human blood serum (HBS) with satisfactory results. PMID- 29523257 TI - A resumable two-photon fluorescent probe for Cu2+ and S2- based on magnetic silica core-shell Fe3O4@SiO2 nanoparticles and its application in bioimaging. AB - A two-photon fluorescent probe for Cu2+ and S2- has been strategically prepared with naphthalimide derivative platform (NPE) covalently grafted onto the surface of magnetic core-shell Fe3O4@SiO2 nanoparticles. The probe (NPE-Fe3O4@SiO2) exhibits selective response to Cu2+ with enhanced fluorescence and efficient separation of Cu2+ with external magnetic field. The consequent product NPE Fe3O4@SiO2-Cu of NPE-Fe3O4@SiO2 and Cu2+ can work as an excellent sensor for S2- by removing Cu2+ from the complex with fluorescence decreased, recovering the fluorescence of the probe. Therefore, the constituted Off-On-Off type fluorescence monitoring system means the probe is resumable. Moreover, the probe has been used to quantitatively detect Cu2+ and S2- with low detection limits, which are 0.28 MUM and 0.12 MUM, respectively. Furthermore, the probe shows low cytotoxicity and excellent membrane permeability, which has been successfully applied for monitoring Cu2+ and S2- in living cells and imaging Cu2+ in deep tissue with two-photon excited fluorescence. PMID- 29523258 TI - Increasing concentration and application frequency of silver diamine fluoride results in more arrested carious lesions being stained black but no other important adverse effects. PMID- 29523259 TI - Very low certainty in the evidence suggesting lack of association between high anxiety and patient satisfaction with dental implant treatment outcomes. PMID- 29523260 TI - 3-millimeter height abutments result in less early interproximal bone loss than 1 mm height abutments. PMID- 29523261 TI - Implant survival may be high in patients with Sjogren syndrome. PMID- 29523262 TI - Predictors of sleep-disordered breathing in pregnancy. AB - BACKGROUND: Sleep-disordered breathing (SDB) is common in pregnancy, but there are limited data on predictors. OBJECTIVES: The objective of this study was to develop predictive models of sleep-disordered breathing during pregnancy. STUDY DESIGN: Nulliparous women completed validated questionnaires to assess for symptoms related to snoring, fatigue, excessive daytime sleepiness, insomnia, and restless leg syndrome. The questionnaires included questions regarding the timing of sleep and sleep duration, work schedules (eg, shift work, night work), sleep positions, and previously diagnosed sleep disorders. Frequent snoring was defined as self-reported snoring >=3 days per week. Participants underwent in-home portable sleep studies for sleep-disordered breathing assessment in early (6-15 weeks gestation) and mid pregnancy (22-31 weeks gestation). Sleep-disordered breathing was characterized by an apnea hypopnea index that included all apneas, plus hypopneas with >=3% oxygen desaturation. For primary analyses, an apnea hypopnea index >=5 events per hour was used to define sleep-disordered breathing. Odds ratios and 95% confidence intervals were calculated for predictor variables. Predictive ability of the logistic models was estimated with area under the receiver-operating-characteristic curves, along with sensitivities, specificities, and positive and negative predictive values and likelihood ratios. RESULTS: Among 3705 women who were enrolled, data were available for 3264 and 2512 women in early and mid pregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%, respectively. At each time point in gestation, frequent snoring, chronic hypertension, greater maternal age, body mass index, neck circumference, and systolic blood pressure were associated most strongly with an increased risk of sleep-disordered breathing. Logistic regression models that included current age, body mass index, and frequent snoring predicted sleep-disordered breathing in early pregnancy, sleep-disordered breathing in mid pregnancy, and new onset sleep-disordered breathing in mid pregnancy with 10-fold cross-validated area under the receiver-operating characteristic curves of 0.870, 0.838, and 0.809. We provide a supplement with expanded tables, integrated predictiveness, classification curves, and an predicted probability calculator. CONCLUSION: Among nulliparous pregnant women, logistic regression models with just 3 variables (ie, age, body mass index, and frequent snoring) achieved good prediction of prevalent and incident sleep disordered breathing. These results can help with screening for sleep-disordered breathing in the clinical setting and for future clinical treatment trials. PMID- 29523264 TI - Interleukin-10 rs1800871 (-819C/T) and ATA haplotype are associated with preeclampsia in a Tunisian population. AB - OBJECTIVES: Interleukin-10 (IL-10) is implicated in several aspects of pregnancy. As genetic predisposition can be involved in the development of preeclampsia, the association between IL-10's promoter region polymorphisms and this pathology has been investigated, although with conflicting results. To date, only a small cohort study (total n = 40) has evaluated this association in the African continent, and none have been conducted in Tunisia. Hence, we evaluated the association between these polymorphisms and the risk of preeclampsia in a large Tunisian cohort. STUDY DESIGN: 345 preeclampsia patients and 300 controls were genotyped for the IL-10 promoter region variants -1082A/G, -819C/T and -592A/C using real-time PCR. MAIN OUTCOME MEASURES: Differences in means were determined by Student's t-test, while intergroup significance was assessed by Pearson chi2 or 2-way ANOVA. Genotypes were tested for Hardy-Weinberg equilibrium (HWE) in the control and cases. Logistic regression analysis was performed in order to determine the odds ratios and 95% confidence intervals associated with the linkage disequilibrium risk. RESULTS: An increased frequency of the -819 T (minor) allele and the -819 T/T genotype was seen in preeclampsia cases. Also, three-locus haplotype (-1082AG/-819CT/-592AC) analysis identified the ATA haplotype as having a higher incidence in women with preeclampsia (OR = 1.48, 95% CI: 1.03-2.11) and this was confirmed by multivariate regression analysis (OR = 1.65, 95% CI: 1.13-2.43) after controlling for covariates. CONCLUSIONS: We suggest that the IL-10 -819 T/T variant and the ATA haplotype, which are associated with low production of IL 10, represent genetic risk factors for preeclampsia in Tunisian women. PMID- 29523263 TI - Aberrant pro-atrial natriuretic peptide/corin/natriuretic peptide receptor signaling is present in maternal vascular endothelium in preeclampsia. AB - OBJECTIVE: Corin is a serine protease that converts pro-atrial natriuretic peptide (pro-ANP) to atrial natriuretic peptide (ANP), a cardiac hormone that regulates salt-water balance and blood pressure. ANP is degraded by natriuretic peptide receptor (NPR). This study was to determine if aberrant pro-ANP/corin/NPR signaling is present in maternal vascular system in preeclampsia. STUDY DESIGN: Maternal venous blood was obtained from 197 pregnant women (84 normotensive, 16 complicated with chronic hypertension (CHT), 11 mild and 86 severe preeclampsia). Plasma corin and pro-ANP concentrations were measured by enzyme-linked immunosorbent assay. Maternal subcutaneous fat tissue was obtained from 12 pregnant women with cesarean section delivery (6 normotensive and 6 preeclampsia). Vascular ANP and its receptors NPR-A, NPR-B, and NPR-C expression were examined by immunostaining of paraffin embedded subcutaneous fat tissue sections. RESULTS: Corin concentrations were significantly higher in mild (2.78 +/- 0.67 ng/ml, p < .05) and severe (2.53 +/- 0.18 ng/ml, p < .01) preeclampsia than in normotensive (1.58 +/- 0.08 ng/ml) and CHT (1.55 +/- 0.20 ng/ml) groups. Pro-ANP concentrations were significantly higher in CHT (1.59 +/- 0.53 ng/ml, p < .05) and severe preeclampsia (1.42 +/- 0.24 ng/ml, p < .01) than in normotensive (0.48 +/- 0.06 ng/ml) and mild preeclampsia (0.52 +/- 0.09 ng/ml) groups. ANP and NPR-B expression was undetectable in maternal vessels from normotensive and preeclamptic pregnancies, but reduced NPR-A expression and increased NPR-C expression was found in maternal vessel endothelium in preeclampsia. CONCLUSIONS: ANP is a vasodilator and NPR-C is a clearance receptor for ANP. The finding of upregulation of NPR-C expression suggests that circulating ANP clearance or degradation is increased in preeclampsia. These results also suggest that pro ANP/corin/NPR signaling is dominant in the vascular system in preeclampsia. PMID- 29523265 TI - Criteria based audit in the management of eclampsia at a public sector tertiary care hospital in Karachi, Pakistan. AB - OBJECTIVE: To evaluate the practice of Eclampsia management at a tertiary care public sector hospital. PATIENTS & METHODS: We conducted criteria based audit of 93 Eclampsia patients admitted in Gynae unit III, Civil hospital and Dow University of Health Sciences Karachi, between 1st January 2016 and 31st December 2016. Management practices were assessed using evidence-based criteria for care. A clinical criteria for standards of care were developed from Royal College of Obstetrician & Gynecologist (RCOG/NICE) guidelines, World Health Organization (WHO) manual, twelve criteria were identified for the audit purpose. RESULT: Total deliveries during study periods were 5323,with 93 cases were of Eclampsia, giving prevalence of 1.7%. Majority were antepartum (67%), followed by postpartum (21%) cases. Mean age of patients was 25 years while mean parity was 1.4. Majority 48% were un-booked and 36% were referred. Cesarean section was the main mode of delivery (53%) while 24% delivered vaginally. Live birth rate was 65%. History and examination was performed in 98% of patients. MgSO4 loading dose was given in 81%, antihypertensive labetalol/hydralazine were given in 29% of cases with acute severe hypertension. Initial investigation were sent in 84% of patients and repeat investigations within 12 h were done in 74% of cases. Reflexes were monitored in 12% of cases, consultant was informed in 37% of cases, management plan was made in 74% of cases, 98% patients were delivered within 12 h of admission. CONCLUSION: Suboptimal care was observed in monitoring of patients after magnesium sulphate, and in the management plan of patients. PMID- 29523266 TI - Indications for delivery in pre-eclampsia. AB - OBJECTIVE: Examine the frequency with which the most accepted indicators for delivery in pre-eclampsia are used in a population with predominantly late-onset (birth > 32 weeks) pre-eclampsia (PE). METHODS: Retrospective cohort study using the St George Public Hospital (SGH) Hypertension in Pregnancy database. Demographic, pregnancy, and outcome details were extracted and verified by comparison with data collection sheets. RESULTS: From 2001 to 2013, 908 women (970 babies) with PE were included, of which a subgroup of 303 women (33%) had clearly delineated delivery triggers available. This subgroup of women had similar demographic and outcome characteristics to the total PE population. In this group, the most common maternal trigger for delivery apart from gestational age 37+ weeks was difficult to control/severe hypertension (114 cases, 38%) and the most common fetal trigger intrauterine growth restriction (IUGR: 14 cases, 4%). 78 (35%) of term women had no specific delivery trigger other than gestation. A primary maternal trigger and/or associated complication was slightly more common in those delivering <37 weeks vs 37+ weeks (52 vs 38%, p = .03), while a fetal or combined maternal/fetal complication was over four times more common in preterm women (25 vs 6%, p < .001). CONCLUSION: In our population of predominantly late-onset PE, maternal triggers for delivery (predominantly severe hypertension) far outweigh fetal triggers (predominantly IUGR). Fetal and mixed indicators for delivery were relatively more common in women delivering preterm, possibly reflecting the severity of placental dysfunction in this subgroup. PMID- 29523267 TI - A randomized trial of ambulatory blood pressure monitoring versus clinical blood pressure measurement in the management of hypertension in pregnancy. A feasibility study. AB - To assess the feasibility of a prospective randomised trial of ambulatory blood pressure monitoring (ABPM) versus clinic blood pressure (CBP) readings for managing pregnancy hypertension. The primary outcome measure was admission to hospital. The secondary measures were number of antenatal attendances, use of anti-hypertensive drugs and duration of hospital stay. In general, there were no statistical differences between the two groups including the primary outcome, the rate of hospital admission p=0.76. 89% of participants would undergo ABPM in future pregnancies. A randomised trial of ABPM in pregnancy using this methodology is feasible and acceptable to pregnant women. PMID- 29523268 TI - The reduction in circulating levels of estrogen and progesterone in women with preeclampsia. AB - Abnormalities in the development of placental vasculature in early pregnancy and the failure of transformation of the spiral arteries are associated with the pathogenesis of preeclampsia. Sex hormones influence neovascularisation during pregnancy. However the profiling of estrogen and progesterone in preeclampsia is controversial. In this study we investigated the serum levels of estrogen and progesterone in women with preeclampsia. Blood samples were collected from 86 preeclamptic and 97 gestation-matched normotensive pregnancies. The levels of 17beta-estradiol (E2), progesterone and 2-methoxyestradiol (2-ME) in serum were measured. In addition, the levels of E2 and progesterone in conditioned media from preeclamptic or normotensive term placental explant cultures or placental explants that had been treated with hydrogen peroxide (H2O2) were measured. The expression of estrogen receptors (ER) and progesterone receptors (PR) in preeclamptic and control placentae were measured by immunohistochemistry. The serum levels of E2, progesterone and 2-ME were significantly reduced in women with preeclampsia compared to controls. There was no difference in the serum levels of E2 and progesterone between severe and mild or between early-onset and late-onset preeclampsia as well as between preeclampsia with and without fetal growth restriction (FGR). The levels of E2 and progesterone in preeclamptic placental explants cultures were significantly lower than in normotensive term placental explant cultures. Treatment with H2O2 was found to be associated with a reduction in E2 production by the placenta. We demonstrated lower levels of estrogen in preeclampsia and speculate that this reduction may be due to the impairment of placental function in preeclampsia. PMID- 29523269 TI - Early diagnosis of preeclampsia using placental growth factor: An operational pilot study in Maputo, Mozambique. AB - In well-resourced settings, reduced circulating maternal free placental growth factor (PlGF) aids in either predicting or confirming the diagnosis of preeclampsia, fetal growth restriction, stillbirth, preterm birth, and delivery within 14 days of testing when pre-eclampsia is suspected. This operational pilot implementation of maternal plasma PlGF in women with suspected preeclampsia was conducted in six antenatal clinics in Maputo, Mozambique (six control clinics for comparison). The primary outcome was transfer to higher levels of care, following the informative PlGF assay. Of antenatal visits, 133/31,993 (0.42%) and 20/33,841 (0.06%) resulted in pre-eclampsia-related transfers of care for women attending intervention and control clinics, respectively (p < .0001). The clinic-to delivery for women with low PlGF (<100 pg/ml) interval was shorter, (vs normal PlGF (median 10 days [IQR 1-25] vs 36 [11-83], p < .0001)). Low PlGF was associated with younger maternal age, higher blood pressure, earlier delivery, more therapeutic interventions, preterm birth, lower birth weight, and perinatal loss. In addition, one-third of hypertensive women with PlGF < 50 pg/ml suffered a stillbirth. In urban Mozambican women with symptoms and/or signs suggestive of preeclampsia, low maternal plasma PlGF concentrations are associated with increased risks of adverse pregnancy outcomes, especially early delivery and stillbirth. Therefore, introducing PlGF into the clinical care of women with suspected preeclampsia was associated with increased transfers to higher levels of care; low PlGF (<100 pg/ml) was associated with increased maternal and perinatal risks. PlGF < 50 pg/ml is particularly associated with stillbirth in women with suspected preeclampsia. PMID- 29523270 TI - Polycystic ovary syndrome, body mass index and hypertensive disorders in pregnancy. AB - OBJECTIVE: Some studies of women with polycystic ovary syndrome (PCOS) report increased prevalence of hypertensive disorders in pregnancy, while others do not. Several of these studies do not control for obesity. We aimed to study whether PCOS is associated with hypertensive disorders in pregnancy and whether it is dependent on body mass index (BMI). STUDY DESIGN: We present a cross-sectional analysis of 3732 women from Denmark, Estonia, Iceland, Norway and Sweden, born in 1945-72, who participated in the Respiratory Health In Northern Europe (RHINE) study and answered an extensive women's health questionnaire on menstruation, PCOS, infertility, pregnancy history and childbirth. The main outcome measurement was hypertensive disorders of pregnancy. We adjusted for smoking, age, infertility treatment and study center. Effect modification by BMI was assessed. RESULTS: PCOS was related to hypertensive disorders in pregnancy with a relative risk (RR) of 1.62 (95% CI 1.09-2.42). This relationship was found among underweight women with a BMI of <18.5 kg/m2 [RR = 5.2 (95% CI 1.66-16.5)] and obese women with a BMI of >=30 kg/m2 [RR = 2.36 (95% CI 1.29-4.31)], but not among normal-weight women, BMI 18.5-25 kg/m2 [1.08 (0.53-2.20)], or overweight women, BMI 25-30 kg/m2 [1.24 (0.50-3.08)] (p-interaction = 0.041). CONCLUSION: Polycystic ovary syndrome is associated with hypertensive disorders in pregnancy. This association only occurs among underweight and obese women and not among normal-weight and slightly overweight women. PMID- 29523271 TI - Association of gene polymorphisms of aldosterone synthase and angiotensin converting enzyme in pre-eclamptic South African Black women. AB - INTRODUCTION: The exact cause of preeclampsia (PE) remains elusive. Recently, many researchers have focused on the role of genetic variations in pathogenesis of PE. The renin-angiotensin-aldosterone system is affected in the pathogenesis of PE. OBJECTIVES: To determine association of gene polymorphisms of aldosterone synthase (CYP11B2) and angiotensin converting enzyme (ACE) in PE and normotensive South African Black women. METHODS: A group of 603 South African Black pregnant women, 246 normotensive and 357 with PE, was recruited. Purified DNA was extracted from venous blood. The distribution and frequencies of gene polymorphisms of CYP11B2 (C-344T) and ACE deletion/insertion (D/I) were determined by real time polymerase chain reaction. RESULTS: As the main outcome measure, the risk of C allele for PE was 1.28 (95%CI: 0.94-1.74; p = .1) for all allele comparisons. Thus no significant association with development of PE was observed for the CYP11B2 variants. However, post analysis of the distribution of TT genotypes of CYP11B2 were higher in the HIV uninfected normotensive than in the HIV uninfected PE group (OR: 0.47, 95%CI: 0.27-0.79, p = .0027). The C alleles of late-onset PE and HIV uninfected PE were higher than all normotensive and HIV uninfected normotensive (OR: 1.47, 95%CI: 1.02-2.10, p = .03 and OR: 1.77, 95%CI: 1.13-2.81, p = .0094 respectively). The CT genotype of CYP11B2 was statistically significant between normotensive and PE in HIV uninfected groups (OR: 2.24, 95%CI: 1.28-3.98, p = .0026). There was no significant difference in frequencies of D/I for ACE gene in PE. PMID- 29523272 TI - Nitrate-rich dietary supplementation during pregnancy: The pros and cons. AB - Inorganic nitrate (NO3) due to its potential endogenous conversion to nitric oxide (NO), is suggested as a compensatory fuel for disrupted NO pathways in the case of pathological stats during pregnancy. Dietary NO3-rich supplement in the NO-deficient pregnant women is now suggested as a more appealing choice with fewer off-target effects which can attenuate hypertension and preeclampsia, improve placental blood flow and subsequently enhance maternal and neonatal health. There is also an increasing public interest and common health claims regarding beneficial effects of NO3-rich dietary supplements like beetroot byproducts in pregnant women. Conversely, NO3-rich dietary supplementation during pregnancy may be accompanied with a wide range of unexpected maternal and fatal adverse outcomes such as methemoglobinemia, alteration in embryonic cells and malignant transformation, as well as thyroid disorders. In conclusion, use of dietary inorganic NO3 as a common supplement during pregnancy is currently on a long way from bench to bedside. PMID- 29523273 TI - Maternal serum levels and placental expression of hepcidin in preeclampsia. AB - Preeclampsia (PE) is a multifactorial pregnancy-induced syndrome and infection could have a role in its etiopathogenesis. Hepcidin, central regulator of iron homeostasis, is an antimicrobial peptide induced by inflammatory/infective stimuli. Therefore, hepcidin could be a good nonspecific marker of infection in PE. In a cross-sectional study, we assessed maternal serum levels (ELISA) and placental expression (Real-Time PCR and ELISA) of hepcidin in PE and normal pregnancies. In a prospective study, hepcidin maternal serum levels were assessed in early pregnancy before PE onset and in age matched controls. Hepcidin protein and gene expressions were significantly decreased in PE placentae with normal fetal growth compared to controls and PE with Fetal Growth Restriction (FGR), respectively. In contrast, we did not find significant differences in maternal serum hepcidin levels in PE vs gestational age-matched controls. Hepcidin serum levels in the first half of pregnancy were found significantly higher in women who subsequently developed PE compared to mothers having a physiological pregnancy until term. Altered hepcidin expression in PE placentae could be explained by direct infective/inflammatory stimuli. Furthermore, high hepcidin levels in maternal serum could be an early marker of PE, further emphasizing the role of inflammatory status before symptoms onset in PE. PMID- 29523274 TI - An sFlt-1:PlGF ratio of 655 is not a reliable cut-off value for predicting perinatal outcomes in women with preeclampsia. AB - OBJECTIVES: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is increased in preeclampsia. This study evaluated perinatal outcomes in cases with an sFlt-1:PlGF ratio above 655. STUDY DESIGN: We retrospectively analyzed data from all consecutive women with singleton pregnancies who presented with clinically manifest preeclampsia and underwent immediate sFlt-1:PlGF assessment. Cases with an sFlt-1:PlGF ratio >= 655 were matched 1:1 for gestational age to controls with a ratio < 655. MAIN OUTCOME MEASURES: The 5-min Apgar score and the arterial cord pH. RESULTS: There was a significant association of sFlt-1:PlGF ratios >= 655 with fetal distress (40% in cases vs. 3.3% in controls; p < .01) and neonatal sepsis (23.3% vs. 0%; p = .02), but not with impaired Apgar score (9 vs. 9 at 5 min; p = .45) or lower arterial cord pH (7.24 +/- 0.09 vs. 7.26 +/- 0.08; p = .73). Perinatal mortality (20% vs. 16.7%; p = .9), intrauterine growth restriction (IUGR; 30% vs. 13.3%; p = .2), and small-for-gestational-age fetuses (SGA; 30% vs. 16.7%; p = .35) were proportionally distributed among cases and controls. IUGR and SGA diagnoses were most common in cases with sFlt1:PlGF ratios >= 1000, as was respiratory distress. CONCLUSIONS: An sFlt-1:PlGF ratio above 655 is not predictive of impaired perinatal outcomes, and insufficiently reliable for predicting outcomes in cases with clinical signs of preeclampsia. Our data suggest that an extremely high sFlt 1:PlGF ratio above 1000 might be more useful. PMID- 29523275 TI - Soluble fms-like tyrosine kinase-1, placental growth factor and their ratio as a predictor for pre-eclampsia in East Asians. AB - OBJECTIVE: To assess the clinical utility of the sFlt-1:PlGF ratio rule-in/rule out pre-eclampsia either directly or after correcting each marker for gestation and maternal weight. METHODS: This was a prospective cohort study. sFlt-1, PlGF were measured in 965 women randomized to undergo a single blood withdraw between 20 and 39 weeks of gestation. sFlt-1, PlGF and the sFlt-1:PlGF ratio temporal relationship was determined. sFlt-1 and PlGF were converted to multiples of the expected gestational median (MoM) and adjusted for maternal weight. The 90th centile of the adjusted sFlt-1MoM:PlGFMoM ratio was determined. Clinical utility of the sFlt-1:PlGF ratio (>=38) to rule in/rule-out pre-eclampsia (PE) after 20 weeks of gestation versus that of the sFlt-1MoM:PlGFMoM 90th percentile was assessed in 81 women admitted for management of antenatal hypertension. RESULTS: The sFlt-1:PlGF ratio had quadratic relationship with gestation whereas the sFlt 1MoM:PlGFMoM ratio log distribution that was Gaussian with a mean of zero and a standard deviation of 0.85 with a 90th percentile equal to 1.08. Thirty-four (42%) of the 81 women admitted for management of their antenatal hypertension had PE, 26 (76.4%) had a sFlt-1:PlGF ratio >= 38. Four of the remaining 8 PE affected pregnancies with sFlt-1:PlGF ratio <38 delivered within 7 days, 3 were preterm. Two of the 3 preterm PE pregnancies had sFlt-1MoM:PlGFMoM exceeding 90th percentile. CONCLUSION: The relative level of the sFlt-1 to PlGF carries prognostic value. A sFlt-1MoM:PlGFMoM ratio exceeding the 90th centile resulted in additional detection of pregnancies which developed PE compared to the conventional sFlt-1:PlGF ratio. PMID- 29523276 TI - Analytical validation of soluble fms-like tyrosine and placental growth factor assays on B.R.A.H.M.S KRYPTOR Compact Plus automated immunoassay platform. AB - BACKGROUND: Preeclampsia is one of the leading hypertensive disorders of pregnancy. Angiogenic biomarkers such as anti-angiogenic factor soluble fms-like tyrosine kinase 1 (sFlt1) and pro-angiogenic factor placental growth factor (PlGF) are involved in the pathophysiology of preeclampsia. OBJECTIVE: The aim of this study is to validate the analytical performance of sFlt1 and PlGF on the B.R.A.H.M.S KRYPTOR Compact Plus (ThermoFisher Scientific). STUDY DESIGN: We examined K2-EDTA plasma samples from 50 patients on B.R.A.H.M.S KRYPTOR Compact Plus, an automated immunoassay platform. QC materials were used to assess intra- and inter-precision of the assay. Lower limit of quantitation and interference studies were determined using pooled patient plasma. RESULTS: The sFlt1 and PlGF assays demonstrated an analytical measuring range of 90-69,000 pg/mL and 11-7000 pg/mL, respectively (r2 > 0.99). Lower limit of quantitation (20% CV) was interpolated to be 35 pg/mL for sFlt1 and 10 pg/mL for PlGF. Total precision for both assay displayed CVs of <10%. Interference studies showed that both assays were not significantly affected by hemolysis up to an H-index of 1100 for sFlt1 and 300 for PlGF; L- and I-index of 800 and 80 respectively for both assays. The Passing-Bablok regression analysis for sFlt1/PlGF yielded an equation of y = 1.05x + 0.02, and the Bland Altman analysis showed an average bias of 0.84. CONCLUSION: Plasma levels of sFlt1 and PlGF measured on the B.R.A.H.M.S KRYPTOR Compact Plus platform demonstrate excellent analytical performance and are acceptable as clinical grade assays. PMID- 29523277 TI - Apparent systemic 11beta-dehydroxysteroid dehydrogenase 2 activity is increased in preeclampsia but not in intrauterine growth restriction. AB - OBJECTIVE: The enzyme 11beta-dehydroxysteroid dehydrogenase 2 (11beta-HSD2) converts active cortisol (F) to inactive cortisone (E). A reduced 11beta-HSD2 activity in the placenta has been demonstrated for prematurity, low birth weight, and preeclampsia. We hypothesized that disturbed placental function rather than a maternal response contributes to decreased 11betaHSD2 activity as reflected by a diminished conversion of F to E. Hence, the aim of the present study was to estimate the systemic activity of 11beta-HSD2 throughout gestation and in pregnancies complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) by calculating maternal serum F/E ratios. METHODS: A total of 188 maternal serum samples were analyzed for nine glucocorticoid metabolites by gas chromatography-mass spectrometry (GC-MS) and F/E ratios were calculated. Study Group A: In a longitudinal set 33 healthy pregnant women were analyzed at three different time points throughout gestation and one postpartum. Study Group B: Cross-sectionally additional 56 patients were enrolled. We compared patients with PE (N = 14) and IUGR (N = 14) with gestational age matched healthy controls (CTRL = 28). RESULTS: Group A: The apparent 11beta-HSD2 activity dropped in the second trimester being restored to first trimester levels (P value = 0.016). Group B: The 11beta-HSD2 activity was high in PE (P value < 0.05) but not in the IUGR group as compared to CTRL. CONCLUSION: The increased apparent serum 11beta-HSD2 activity observed with advancing gestation in normal pregnancy may reflect an elevated general increase in enzyme activity due to a higher placental mass. The high systemic 11beta-HSD2 activity in PE but not in IUGR however suggests an increased F deactivation in maternal tissue in PE rather than in the placenta since placental insufficiency in the absence of PE does not significantly alter F/E ratio. PMID- 29523278 TI - Predictors of oedema type in reversible posterior leukoencephalopathy syndrome with preeclampsia or eclampsia. AB - OBJECTIVE: To explore the predictive factors of oedema types in reversible posterior leukoencephalopathy syndrome (RPLS) with preeclampsia (PE) and eclampsia, which is closely related to reversible lesions and clinical recovery. METHOD: We collected data from 44 consecutive patients diagnosed with RPLS in PE or eclampsia between 2013 and 2017. All patients were classified into vasogenic oedema (n = 31) or cytotoxic oedema (n = 13) groups according to magnetic resonance imaging (MRI) results. General information, clinical data, biochemical indicators and imaging features were collected retrospectively to explore the differences between the groups. Furthermore, we analysed potential predictive factors by logistic regression. RESULTS: The occurrence rates of immune disease and stillbirth, hospitalization time and the levels of serum albumin (ALB), lactate dehydrogenase (LDH), aspartate transaminase (AST) and alanine aminotransferase (ALT) were higher, while the values of systolic blood pressure (SBP), mean arterial pressure (MAP) and 24-h urine protein were lower in the cytotoxic oedema patients than those in the vasogenic oedema patients (p < .05). The ALB concentration was closely correlated with vasogenic oedema, while AST and ALT were closely correlated with cytotoxic oedema by logistic regression (p < .05). CONCLUSION: The levels of ALB, AST and ALT are potential predictors for the development of oedema in RPLS. ALB is related to vasogenic oedema by a possible mechanism of decreased colloid osmotic pressure, while AST and ALT are related to cytotoxic oedema by a possible mechanism of endothelial dysfunction. PMID- 29523279 TI - Pharmacokinetics of amlodipine besylate at delivery and during lactation. AB - BACKGROUND: Amlodipine is rarely used in the treatment of pregnant hypertensive women due to limited pharmacokinetic data during pregnancy and the postpartum period. OBJECTIVE: To evaluate the pharmacokinetics of amlodipine besylate in the peri-partum period including quantities of placental passage, breast milk excretion and infant exposure. STUDY DESIGN: This was a prospective study of pregnant women who were prescribed 5 mg of amlodipine daily for treatment of chronic hypertension and delivered at term. Cord and maternal blood samples were collected at delivery. On postpartum day 2, six paired maternal plasma and breast milk samples were obtained at 4, 6, 8, 12, 15 and 24 h following amlodipine dosing. Infant plasma samples were collected 24-48 h after delivery. All samples were analyzed for amlodipine concentration. A one compartment, first-order model was used to calculate pharmacokinetic estimates for maternal plasma. RESULTS: Of the 16 patients enrolled in the study, 11 had cord blood and maternal serum collected at delivery, of which only 6 produced sufficient breast milk for sampling. Amlodipine was detected in infant cord blood plasma with a mean concentration of 0.49 +/- 0.29 ng/mL compared to mean maternal serum level of 1.27 +/- 0.84 ng/mL. Amlodipine concentrations in both in breast milk and infant plasma were undetectable at the lower limit of assay detection (<0.1 ng/mL). In the immediate postpartum period, the amlodipine elimination half-life was 13.7 +/ 4.9 h, the area under the curve was 53.4 +/- 19.8 ng*h/mL and the peak concentration was 2.0 +/- 1.0 ng/mL. CONCLUSIONS: Amlodipine does cross the placenta in measurable quantities, but is not detected in breast milk or infant plasma at 24-48 h of life indicating that it is likely safe to use during the peripartum period. PMID- 29523280 TI - Can thrombophilia worsen maternal and perinatal outcomes in cases of severe preeclampsia? AB - OBJECTIVE: To evaluate whether thrombophilia worsens maternal and foetal outcomes among patients with severe preeclampsia (PE). METHOD: From October 2009 to October 2014, an observational retrospective cohort study was performed on pregnant women with severe PE diagnosed before 34 weeks of gestation and their newborns hospitalized at the Clinics Hospital, FMUSP. Patients who had no heart disease, nephropathies, pre-gestational diabetes, gestational trophoblastic disease, foetal malformation, or twin pregnancy and who underwent thrombophilia screening during the postnatal period were included. New pregnancies of the same patient; cases of foetal morphological, genetic, or chromosomal abnormalities after birth; and women who used heparin or acetylsalicylic acid during pregnancy were excluded. Factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C, protein S, homocysteine, lupus anticoagulant, and anticardiolipin IgG and IgM antibodies were analysed. The groups with and without thrombophilia were compared regarding their maternal clinical and laboratory parameters and perinatal outcomes. RESULTS: Of the 127 patients selected, 30 (23.6%) had thrombophilia (hereditary or acquired). We found more white patients in thrombophilia group (p = .036). Analysis of maternal parameters showed a tendency of thrombophilic women to have more thrombocytopenia (p = .056) and showed worsening of composite laboratory abnormalities (aspartate aminotransferase >= 70 mg/dL, alanine aminotransferase >= 70 mg/dL, platelets < 100,000/mm3, serum creatinine >= 1.1 mg/dL; p = .017). There were no differences in foetal perinatal outcomes. CONCLUSION: The presence of thrombophilia leads to worsening of maternal laboratory parameters among patients with severe forms of PE but without worsening perinatal outcomes. PMID- 29523281 TI - Severe pre-eclampsia among pregnant women with sickle cell disease and HIV. AB - OBJECTIVE: The relationship between sickle cell disease (SCD) and severe pre eclampsia is poorly established. It is also unknown whether the occurrence of HIV infection among women with SCD modifies their risk level for severe pre eclampsia. We hypothesized that pregnant women with SCD are at an elevated risk for severe pre-eclampsia as a result of heightened endothelial damage; and the combination of SCD-HIV augments the inflammatory processes of endothelial damage leading to amplified risk for severe pre-eclampsia. STUDY DESIGN: We analyzed more than 57 million pregnancy-related hospitalizations and births in the US from January 1, 2002 through December 31, 2014. MAIN OUTCOME MEASURES: We applied multivariable survey logistic regression to generate odds ratios for the association between SCD, HIV and SCD-HIV status and severe pre-eclampsia with adjustment for potential confounders. RESULTS: Of the total 57,326,459 pregnant women, 57,198,505 (99.78%) did not have SCD or HIV, 73,064 (12.7 per 10,000) had HIV only, 54,890 (9.58 per 10,000) had SCD only and 222 (0.39 per 100,000) had both SCD and HIV. Mothers with SCD and HIV-SCD experienced a significant elevation in risk for severe pre-eclampsia of about 60% (OR = 1.61; 95% CI = 1.44, 1.79) and of more than 300% (OR = 4.28; 95% CI = 1.35, 13.62) respectively. CONCLUSION: In the largest study on SCD and pre-eclampsia in the world, we established SCD to be strongly associated with severe pre-eclampsia. Another unique finding is the synergistic effect of amplified risk for severe pre eclampsia among mothers with the combined SCD-HIV status. PMID- 29523282 TI - The effect of labetalol and nifedipine MR on blood pressure in women with chronic hypertension in pregnancy. AB - AIM: To compare the blood pressure (BP) lowering effects of labetalol and nifedipine modified release (MR) in hypertensive pregnant women. We also investigated the effect on the heart rate (HR) and determined the proportion of time spent in target. METHODS: This was an exploratory study. Women with chronic hypertension taking either labetalol or nifedipine were offered 24-h ambulatory blood pressure monitoring (ABPM). Sleep, wake and drug ingestion times were self reported. An indirect response model was used to analyse the systolic BP (SBP), diastolic BP (DBP) and HR time-series; the effect of gestation and type of drug was evaluated. RESULTS: Forty-eight women were recruited: 24 in each group. There was no difference in clinical characteristics. In women taking nifedipine there was a positive association between the dose of nifedipine and pre-dose BP p = .002, this was not present in the labetalol group. There was a difference between the drug effects on both the SBP and DBP time-series (p = .014). In comparison to labetalol, there was less variation in day time BP in those women prescribed nifedipine. Women on labetalol spent a larger proportion of time with their DBP below target (<80 mmHg). The HR dynamics were qualitatively different, a stimulatory effect was found with nifedipine compared to an inhibitory effect with labetalol. CONCLUSION: There are significant and important differences between the BP lowering effects of nifedipine and labetalol. A large randomised control trial is required to investigate the relationship between BP variability and time in target on pregnancy outcomes. PMID- 29523284 TI - Resistance exercise and sports performance: The minority report. AB - Resistance exercise is typically performed to increase both muscle size and strength and is regularly incorporated into training programs for sports performance. Presumably, the exercise would be expected to increase the force producing capabilities of skeletal muscle, which may have subsequent influence on various sports related abilities. Interestingly, few studies are designed to examine sports related benefits of resistance exercise while including a proper control group to account for adaptations to simply performing the sports related task. Much of our knowledge on resistance exercise for sport is based off cross sectional work showing that stronger athletes tend to perform at the highest level, along with cross-sectional work demonstrating that higher levels of strength are associated with various performance related parameters. Although there is a large body of cross-sectional literature providing a rationale for resistance exercise for sport, its implementation is largely based on the following: 1) An increase in muscle size will produce an increase in strength and 2) a stronger muscle will increase sports performance. However, there is a lack of evidence to support these assumptions. The weight of evidence suggests that resistance exercise may indirectly impact sports performance through injury prevention, as opposed to directly improving sport related abilities. PMID- 29523283 TI - The role of angiogenic biomarkers and uterine artery Doppler in pregnant women with systemic lupus erythematosus or antiphospholipid syndrome. AB - OBJECTIVE: To evaluate the usefulness of the uterine artery mean pulsatility index (mPI-UtA) and the sFlt-1/PlGF ratio in women with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) for the prediction of placental dysfunction-related adverse outcomes (AO), namely pre-eclampsia (PE) and intrauterine growth restriction (IUGR), and for differential diagnosis between PE and SLE flares. STUDY DESIGN: Observational prospective cohort study of 57 pregnant women with SLE or APS. MAIN OUTCOME MEASURES: mPI-UtA and sFlt 1/PlGF ratio in maternal serum were obtained at four gestational age periods (11 14, 19-22, 24-29 and 32-34 weeks). Comparisons among pregnancies with normal outcome, SLE flare and AO were performed. RESULTS: Overall, we had 44 ongoing pregnancies (36 with SLE and 8 with APS) of which most (n = 35, 80%) were uncomplicated. The overall rate of AO was 9% (n = 4), that was diagnosed at a mean (SD) gestational age of 34.1 (7.5) weeks. Five SLE patients (14%) suffered a SLE flare. No differences for these markers were found between normal pregnancies and those affected by SLE flare. mUtA-PI values were significantly higher in the AO group when compared with normal and SLE flare groups, at 19-22 weeks (1.52, 0.95 and 0.76) and 32-34 weeks (1.13, 0.68 and 0.65), respectively. The sFlt 1/PlGF ratio was significantly higher in the AO group at 24-29 weeks (191.1, 3.1 and 9.2), respectively. CONCLUSION: Our preliminary results indicate that mPI-UtA and sFlt1/PlGF ratio may be useful to predict AO in women with SLE, and to make the differential diagnosis with a lupus flare. PMID- 29523285 TI - Michelangelo Buonarroti (1475-1564) had the deconditioning syndrome while painting the Sistine Chapel ceiling. PMID- 29523286 TI - A thermodynamic approach to the problem of consciousness. AB - What is the nature of qualia? Why qualia are subjective? This article is an attempt to provide speculative answers to these questions based on what we know about thermodynamics. The proposed answer to the first question is that qualia are self-organized structures built by exported entropy. The proposed answer to the second question is that qualia are subjective because entropy-decreasing phenomena cannot be observed physically. PMID- 29523287 TI - Objective assessment of the degree of improvement or deterioration with patients by means of Ipsative Trend Analysis of resting electroencephalograms. AB - : We report on a new quantitative EEG-approach, called Ipsative Trend Assessment which is based on the spatio-temporally defined patterns which are generated by the global interaction of cortical neurons. METHODS: The data were acquired from EEGs being recorded under resting conditions. Target variables are not the usually employed absolute values of the spectral parameters but rather their change being calculated from successive recordings with a single subjects design. RATIONALE: Since the resting-EEG does not provide specific information, we had to decide what else might be addressed by that method. CONCLUSIONS: Our hypothesis according to which the SR-EEG indicates Selye's behaviorally non-specific General Adaptation Syndrome is based on good evidence. MAIN FINDINGS: Dynamic pattern comparison between subsequent EEGs on the single case level is a hitherto neglected method, which may be utilize, for instance, with regard to objective therapeutic outcome assessment. SIGNIFICANCE: In order to substantiate the clinical meaningfulness of our new approach we report two case vignettes of psychiatric impairments. Apart from that, our procedure should provide the desperately needed objective assessment of the therapeutic effect with any disease displaying a certain proportion of unspecific symptoms. PMID- 29523288 TI - It has not been proven why or that most research findings are false. AB - The claim has been made that it can be proven that most published findings in medical, biological, and allied sciences are false and that the reason for this can be proven and explained with a mathematical model. It has not, however, been mathematically proven that most research findings are false, and this can be proven. The model used in the proof is incoherent and has been falsified. Furthermore, advice to researchers derived from the model is misleading and distracts from more important issues in experimental standards. PMID- 29523289 TI - A new model for chronic diseases. AB - Chronic diseases are defined diseases whose symptoms last for at least six months and tend to worsen over time. In Europe, they cause at least 86% of deaths. In this speculative unifying model I set a new hypothesis for the etiology of the majority of chronic diseases. The main aim is to put order and observe our organism in a systemic way, connecting pathologies we now see as disconnected phenomena, with the conceptual frameworks of complex systems and network medicine. Chronic diseases could be caused by a first unsolved acute infection. In case the pathogen cannot be completely eliminated, it becomes a persistent infectious. After the acute episode, some mild symptoms will occur and probably disappear; the chronic disease will remain latent over time. It will manifest even after years or decades, in the presence of another acute infection, a particular stress, trauma, or another event. The presence of the persistent infectious elicits changes in the immune and systemic regulation, and these processes degenerate over time. They will assume their rules and patterns, being independent from the initial stimulus. The key to understand the dynamics and individuality of chronic diseases is the immune system and its networks. The immune mechanisms that can lead to the persistent response are mainly the switch from the Th1 to the Th2 immunity and the molecular mimicry. The first persistent infectious will also modify the susceptibility to other pathogens, facilitating new infections and new consequent persistent infectious. From the immune point of view, our organism is divided into three compartments: the outer one, which comprehend all the surfaces in contact with the environment, the intermediate one, which comprehend the internal organs and tissues, and the innermost one, comprehending the Central Nervous System and the adluminal compartment of the seminiferous tubule. The immune key-role is played respectively by the mucosa associated lymphoid tissue, the endothelium, the blood-brain barrier and blood testis barrier. The chronic diseases follow a progressive scheme, involving the three compartments from the outer to the innermost one. The primer microorganism at the origin of the majority of diseases could be streptococcus, or staphylococcus. Both cause acute in children, with a great variability of responses and symptoms, and both cause molecular mimicry. This model can be tested and proved in more ways, I propose here some of them. It could pave the way to a radical change in our comprehension and therapeutic approaches to chronic diseases. PMID- 29523290 TI - Menstrual chest pain, spontaneous coronary dissection, and takotsubo syndrome: Any connections? PMID- 29523291 TI - ERCP induced and non-ERCP-induced acute pancreatitis: Two distinct clinical entities? AB - Acute pancreatitis (AP) is a common gastrointestinal disease of varied etiology; however, the most common causes of AP are gallstones and alcohol abuse. AP has emerged as the most frequent complication after endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis is generally a clinically irrelevant condition; however, it can be severe or even fatal in up to 0.8% of cases. Different clinical courses and outcomes have been observed between mild and severe AP of different etiologies (i.e., non-ERCP AP and post-ERCP AP), which opens the discussion as to whether they are the same or distinct clinical entities. PMID- 29523292 TI - Could ryanodine receptor dysfunction be linked to PKR brain accumulations in Alzheimer's disease? PMID- 29523294 TI - Plasma creatine as a marker of mitochondrial dysfunction. AB - Mitochondrial dysfunction (MD) is a complex pathophysiological phenomenon, linked with many inherited and acquired diseases. A clinical evaluation of MD requires rather extensive approach, while no gold-standard circulating biomarker has been established so far. Partly produced in mitochondria, creatine thus might be considered as a sensible compound of mitochondrial bioenergetics. Increased plasma creatine perhaps is linked with MD, illustrating disturbances in its utilization in the stressed organelle. PMID- 29523295 TI - Molecular hypotheses to explain the shared pathways and underlying pathobiological causes in catatonia and in catatonic presentations in neuropsychiatric disorders. AB - The pathobiological causes, the shared cellular and molecular pathways in catatonia and in catatonic presentation in neuropsychiatric disorders are yet to be determined. The hypotheses in this paper have been deduced from the latest scientific research findings and clinical observations of patients with genetic disorders, behavioral phenotypes and other family members suffering mental disorders. The first hypothesis postulates that catatonia and the heterogeneity of catatonic signs and symptoms involve nucleolar dysfunction arising from abnormalities of the brain-specific, non-coding micro-RNA, SNORD115 genes (either duplications or deletions) which result in pathobiological dysfunction of various combinations in the downstream pathways (possibly along with other genes in these shared pathways). SNORD115 controls five genes CRHR1, PBRM1, TAF1, DPM2, and RALGPS1 as well as the alternative splicing of serotonin 2C receptor. SNORD115 abnormalities with varying downstream multigene involvement would account for catatonia across the life span within some subtypes of autism spectrum disorders, schizophrenia, bipolar and major depressive disorder, psychosis, genetic disorders, and in immune disorders such as anti-N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis as well as the susceptibility to the neuroleptic malignant syndrome (NMS) if environmentally triggered. Furthermore, SNORD115 genes may underlie a genetic vulnerability when environmental triggers result in excess serotonin producing the serotonin syndrome, a condition similar to NMS in which catatonia may occur. Dysfunction of SNORD115-PBRM1 connecting with SMARCA2 as well as other proven schizophrenia-associated genes might explain why traditionally catatonia has been classified with schizophrenia. SNORD115-TAF1 and SNORD-DPM2 dysfunction introduce possible clues to the parkinsonism and increased creatinine phosphokinase in NMS, while abnormalities of SNORD115-RALGPS1 suggest links to both anti-NMDAR encephalitis and the proven predisposing catatonic SHANK3 gene. The second hypothesis postulates that periodic catatonia (PC) on 15q15 involves abnormalities of vacuolar protein sorting 39 (VPS39), a proven de novo schizophrenic gene in this chromosomal locus and part of the HOPS complex. These will impact the autophagic and endocytic pathways, thereby lowering lysosomal degradation. VPS39 mutations may be considered also to disrupt lysosome mitochondria tethering and transport of lipids and calcium through membrane contact sites (MCSs). To account for the periodicity in PC it is speculated that the mammalian equivalent of the vacuole and mitochondria patch (vCLAMP) would be altered by VPS39 mutations and subsequently followed by the mammalian equivalent of endoplasmic reticulum mitochondria encounter structure (ERMES) restoring mitochondrial homeostasis. Future precision psychiatry will require accurate pathophysiologically-defined psychiatric diagnoses to accelerate the discovery of specific molecular-targeted medications to improve therapeutic outcomes. PMID- 29523293 TI - Perceived fatigue and energy are independent unipolar states: Supporting evidence. AB - Persistent fatigue is a common problem (~20-45% of U.S. population), with higher prevalence and severity in people with medical conditions such as cancer, depression, fibromyalgia, heart failure, sleep apnea and multiple sclerosis. There are few FDA-approved treatments for fatigue and great disagreement on how to measure fatigue, with over 250 instruments used in research. Many instruments define fatigue as "a lack of energy", thus viewing energy and fatigue states as opposites on a single bipolar continuum. In this paper, we hypothesize that energy and fatigue are distinct perceptual states, should be measured using separate unipolar scales, have different mechanisms, and deficits should be treated using tailored therapies. Energy and fatigue independence has been found in both exploratory and confirmatory factor analysis studies. Experiments in various fields, including behavioral pharmacology and exercise science, often find changes in energy and not fatigue, or vice versa. If the hypothesis that energy and fatigue are independent is correct, there are likely different mechanisms that drive energy and fatigue changes. Energy could be increased by elevated dopamine and norepinephrine transmission and binding. Fatigue could be increased by elevated brain serotonin and inflammatory cytokines and reduced histamine binding. The hypothesis could be tested by an experiment that attempts to produce simultaneously high ratings of energy and fatigue (such as with two drugs using a randomized, double-blind, placebo-controlled design), which would offer strong evidence against the common viewpoint of a bipolar continuum. If the hypothesis is correct, prior literature using bipolar instruments will be limited, and research on the prevalence, mechanisms, and treatment of low energy and elevated fatigue as separate conditions will be needed. In the immediate future, measuring both energy and fatigue using unipolar measurement tools may improve our understanding of these states and improve therapeutic outcomes. PMID- 29523296 TI - The aberrant urethral meatus as a possible aetiological factor of recurrent post coital urinary infections in young women. AB - Recurrent urinary tract infections (rUTI) in women is a common cause of morbidity worldwide. In young women recurrent cystitis associated with sexual intercourse is quite common; however not all sexually active women will suffer a post-coital UTI episode. A variety of possible predisposing factors has been described, including behavioral risk patterns, genetic factors and increased virulence of certain subtypes of uropathogens. It has long been regarded that anatomical anomalies are rare in this setting of rUTIs. The shorter distance of the urethra to the anus has been the only anatomical risk factor described that is marginally significant in predisposing women for rUTIs. We hereby present a hypothesis that focuses on the shorter distance of the urethral meatus to the vaginal opening as the mainstay of sexually-induced rUTIs. In this theory of "functional hypospadias", the low misplacement of the urethral opening allows for easier advancement of pathogen-laden mucous by penile thrust and increased friction during intercourse. Our hypothesis suggests that a shorter distance of the urethral meatus to the vaginal opening (and not the anus itself) is an anatomical risk factor for recurrent post-coital cystitis. Verification of this hypothesis might lead to a more patient-oriented approach by alerting clinicians in looking for an aberrant meatus and save the patient from unnecessary imaging and endoscopic examinations often used in these cases. Moreover it may also aid the patient in understanding her anatomy and modify behavioral risk practices. PMID- 29523297 TI - Immediate and complete restoration of peripheral nerve function after injury is attainable by a combination of surgical and chemical interventions. AB - Despite significant advances in almost every other aspect of medicine, physicians are still unable to restore function after nerve injury with any consistency or reliability. The current standard of care (which involves coaptation of the two ends via epineurial sutures) is largely unchanged from its first description over 400 years ago, and unfortunately leads to a recovery that is at best slow (taking months or years) and partial. Encouragingly, two new conceptual approaches are being developed that separately have been shown to improve outcomes. The first approach involves optimization of the mechanical aspects of nerve coaptation (with an emphasis on exceedingly "clean cuts" of the axon ends and moving any suture material far away from the coaptation site). The second approach involves manipulation of the chemical composition of the local environment at the cut ends of the nerve in order to promote re-establishment of membranous continuity. Though neither approach currently leads to results that reach those of uninjured controls, there is reason to believe that these two approaches can be used concurrently. Thus, we hypothesize that immediate and complete restoration of peripheral nerve function after injury is attainable by a combination of surgical and chemical interventions. The combination could be tested in rodents and non human primates by assessing histology, electrical activity, intracellular diffusion, and functional status and could likely rapidly move to a clinical trial in humans. If the hypothesis is proven to be true, its impact would be profound, as it would positively affect not only recovery after traumatic nerve injury, but also functional status after allotransplantation, as well as introduce the prospects of advanced interfaces between human nerves and computer circuits. PMID- 29523298 TI - The role of trophoblastic epigenetic reprogrammation in benign tumor cells on malignant progression: A molecular hypothesis. AB - Cancer tissues and placental ones share many properties such as invasiveness, metastasis and local immunosuppressive effects. The goal of the present article is to hypothesize a theory about cancer origin that links placental and cancerous tissues at molecular level. This hypothesis explain that cancer origin could be due to low hypoxic conditions in the peripheral zones of benign tumors which might up-regulate the expression of IGF2, and, consequently, trophoblastic genes. In fact, many phenotypic characteristics and molecular markers are shared between these two cell types (cancerous and trophoblastics ones), providing evidences to support this hypothesis. As a consequence, it could be interesting to demonstrate whether cancer start with a cellular reprogrammation towards a trophoblastic fate in order to design new antitumoral strategies focused on this fact. PMID- 29523299 TI - Clinical manifestations of pachychoroid may be secondary to pachysclera and increased scleral rigidity. AB - Current imaging advancements have led to emergence of pachychoroid as an association of important vision threatening diseases like chronic serous chorioretinopathy and polypoidal choroidal vasculopathy. While the precise relation between thick choroid and such disorder is being investigated, the etiology behind pachychoroid remains elusive. We hypothesize pachychoroid to be a resultant of impeded vascular outflow due to thick sclera and increased scleral rigidity. We discuss our hypothesis in the perspective of other choroidal manifestations of anomalously thick scleral structure. PMID- 29523300 TI - Application of 3D printing technology in RGPCL simulation fitting. AB - The rigid gas permeable contact lens (RGPCL) is an ideal choice to improve the corrective vision of patients with a high degree of refractive error, keratoconus and corneal transplantation. However, RGPCL fitting is not an easy work for those patients with extremely irregular corneal surface. Technicians or doctors often need to try many times to determine the relatively satisfied lens customization parameters. This repeated try-on process not only increases discomfort of patients, but also will increase the risks of corneal epithelial shedding or corneal infection. In order to conduct RGP fitting in a faster and safer manner, a new method of simulating RGPCL fitting in 3D printing technology was assumed. The preliminary experimental results indicated that this method could effectively reduce the number of try-on and increase patient satisfaction, while decrease the risk of epithelial shedding or infection. PMID- 29523301 TI - Categorising bone defect hematomas - Enhance early bone healing. AB - Fracture hematoma formation describes a transitional phase that involves a dynamic and tightly choreographed interaction between the fibrin matrix, cells, and cytokines that guides the ensuing bone repair. Here we propose a novel hypothesis to explain why hematomas in conjunction with critical sized bone defects are prone to differentiate into fibrous tissues, which eventually results in non-unions of the bone. We postulate that certain hematoma qualities are triggers that influence cell biological behaviours and that the release of certain growth factors determines what pattern of remodelling will prevail: intramembranous or endochondral ossification. A detailed characterization of the structural parameters of hematomas will allow researchers to create a microenvironment that aids the migration of mesenchymal stromal cells into the hematoma where, once established, they accelerate the bone healing process. Such a strategy would be particularly useful when faced with the complications arising from large recalcitrant bone defects that often fail to heal naturally. PMID- 29523302 TI - Sleep and gravity. AB - What is known about sleep results from years of observation at the surface of the Earth. Since a few decade man has been able to reach space, escape from the earth attraction and spend days and nights in a weightless condition. Some major physiological changes have been observed during long stays and in particular the sleep duration in space is shorter than on ground. This paper reviews a novel hypothesis proposing that sleep is partly due to gravity. Gravity is a fundamental part of our environment, but is elusive and difficult to apprehend. At the same time, all creatures on Earth undergo cycles of activity and periods of rest (although not always sleep). Careful analysis of previous research on sleep, on Earth, in space and in water, shows that gravity differs in these three situations, and sleep also varies, at least in its duration. On Earth, Rapid Eye Movement (REM) sleep is conditioned by gravity; in space, astronauts have a shorter sleep duration and this is even more striking when a test subject is immersed in water for a week. In conclusion, sleep is partly due to gravity, which acts on our body and brain during the wake period. PMID- 29523303 TI - Dissecting spontaneous cerebrospinal fluid collection. AB - Hydrocephalus is a common condition in the pediatric population known to have many causes and presentation patterns. We report from the analysis of 2 cases the existence of a new complication of pediatric hydrocephalus. Naming this entity "dissecting intraparenchymal cerebrospinal fluid collection", we advance a hypothesis regarding its pathophysiology and discuss its clinical implications and management. PMID- 29523304 TI - The Viral Quinta Columna Strategy: A new biological hypothesis to study infections in humans. AB - Small viral proteins with cationic domains can be involved in multiple biological processes including cell penetration or interaction with intracellular targets. Within the last two decades several reports indicated that the C-terminus of HIV 1 Vpr is a cell penetrating sequence, a PP2A-dependent death domain and also displays toxicity against Gram-negative E. coli. Interestingly, HIV-1 Vpr, as well as some cationic proteins encoded by different viruses, share similar physical properties with the unique anti-microbial human cathelicidin LL37 peptide. Consistent with these observations, the Viral Quinta Columna Hypothesis predicts that virally-encoded cationic peptides encoded by multiple viruses may at the same time i) behave as new cathelicidin-like viral positive effectors of innate immunity, mainly through electrostatic interactions with microbial walls, and also display specific toxic cellular effects through interactions with specific intracellular targets such as PP2A proteins. In this context, virally encoded cationic peptides, potentially detectable in biological fluids, may define a new paradigm for a viral control of homeostasis. Finally, we can also predict that characterization of virally encoded sequences with anti-infective effects may serve as template for the design of new efficient therapeutics polypeptides. PMID- 29523305 TI - Ammonia: A novel target for the treatment of non-alcoholic steatohepatitis. AB - Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from steatosis, through non-alcoholic steatohepatitis (NASH) to cirrhosis. The development of fibrosis is the most important factor contributing to NASH associated morbidity and mortality. Hepatic stellate cells (HSCs) are responsible for extracellular matrix deposition in conditions of frank hepatocellular injury and are key cells involved in the development of fibrosis. In experimental models and patients with NASH, urea cycle enzyme gene and protein expression is reduced resulting in functional reduction in the in vivo capacity for ureagenesis and subsequent hyperammonemia at a pre-cirrhotic stage. Ammonia has been shown to activate HSCs in vivo and in vitro. Hyperammonemia in the context of NASH may therefore favour the progression of fibrosis and the disease. We therefore hypothesise that ammonia is a potential target for prevention of fibrosis progression of patients with NASH. PMID- 29523306 TI - Validation of RUNX1 as a potential target for treating circadian clock-induced obesity through preventing migration of group 3 innate lymphoid cells into intestine. AB - The impact of unrhythmic circadian clock on obesity has started to be increasingly appreciated nowadays. Recently it was discovered that interaction between intestinal microbiota and unrhythmic circadian clock plays a key role in such a process. It involves relaying signals from microbiota through dendritic cells to group 3 innate lymphoid cells in the intestine and in the end impacting some of the key transcription factors of circadian clock. Breaking such a signal relay may prove to be an effective way reducing unrhythmic circadian clock induced obesity. Here, we propose a hypothesis and design experiments to prove that suppressing one of the transcription factors, RUNX1, plays a key role in the homing of ILC3 cells to intestine. Such suppression is in response to a retinoic acid-RARalpha binding initiated pathway and results in the upregulation of gut homing chemokine receptor CCR9 and downregulation of lymphoid tissue-homing receptor CCR7, which can then guide ILC3 cells to intestine. Therapies that can specifically sustain Runx1 expression in ILC3 cells may assist preventing the ever-escalating obesity problem in modern society. PMID- 29523307 TI - Acquaintance to Artificial Neural Networks and use of artificial intelligence as a diagnostic tool for tuberculosis: A review. AB - Tuberculosis [TB] has afflicted numerous nations in the world. As per a report by the World Health Organization [WHO], an estimated 1.4 million TB deaths in 2015 and an additional 0.4 million deaths resulting from TB disease among people living with HIV, were observed. Most of the TB deaths can be prevented if it is detected at an early stage. The existing processes of diagnosis like blood tests or sputum tests are not only tedious but also take a long time for analysis and cannot differentiate between different drug resistant stages of TB. The need to find newer prompt methods for disease detection has been aided by the latest Artificial Intelligence [AI] tools. Artificial Neural Network [ANN] is one of the important tools that is being used widely in diagnosis and evaluation of medical conditions. This review aims at providing brief introduction to various AI tools that are used in TB detection and gives a detailed description about the utilization of ANN as an efficient diagnostic technique. The paper also provides a critical assessment of ANN and the existing techniques for their diagnosis of TB. Researchers and Practitioners in the field are looking forward to use ANN and other upcoming AI tools such as Fuzzy-logic, genetic algorithms and artificial intelligence simulation as a promising current and future technology tools towards tackling the global menace of Tuberculosis. Latest advancements in the diagnostic field include the combined use of ANN with various other AI tools like the Fuzzy-logic, which has led to an increase in the efficacy and specificity of the diagnostic techniques. PMID- 29523308 TI - Assessment of tuberculosis contact investigation in Shanghai, China: An 8-year cohort study. AB - BACKGROUND: Tuberculosis (TB) contact investigation has been observed as a useful programmatic tool in active case finding. We collected data of contact cases to evaluate the effectiveness of TB contact investigation programme in Shanghai, China. METHODS: Since 2009, we screened and followed up the close contacts of bacteria-positive TB cases in Songjiang, Shanghai and calculated the incidence of TB in close contacts and confirmed the transmission by genotyping and sequencing. RESULTS: A total of 4584 close contacts of 1765 contagious TB index cases were followed up for an average of 4 years. About 62 contacts (333/100 000, 95% CI: 256-428) developed TB excluding 6 co-prevalent cases. The contact cases consisted 1.50% (39/2592) of all the bacteria-positive cases in population. Transmission links were confirmed in 60% (9/15) familial contacts and 22% (2/9) in non familial contacts. Source cases come from more than close contacts and both index and contact cases created other secondary cases in community. CONCLUSIONS: Familial contacts are more likely to acquire TB from the index, indicating the priority of family members in TB contact investigation in China. However, most non-familial contacts were infected from sources in the community and contact cases attributed little to case finding in the TB-prevalent setting. Thus, active case finding should be strengthened in general population. PMID- 29523309 TI - Quercetin 3-O-glucoside recovered from the wild Egyptian Sahara plant, Euphorbia paralias L., inhibits glutamine synthetase and has antimycobacterial activity. AB - Tuberculosis remains a major health problem accentuated by the rise of resistance to all available drugs. Therefore, this study was launched to discover a novel antituberculosis agent from wild Egyptian Sahara plants. Twelve such plants were screened, in vitro, for their activity against various Mycobacterium species. The most active plant, Euphorbia paralias, was further fractionated with different organic solvents, and the activity of the obtained fractions was determined by the agar diffusion and broth microdilution methods. The methanol fraction was the most active against Mycobacterium spp., and was non-toxic in doses up to 10 g/kg of animal weight. Its main component was separated by column chromatography, and then identified by ultraviolet spectroscopy and nuclear magnetic resonance analysis as quercetin-3-O-beta-D-glucoside. Docking analysis suggested that quercetin-3-O-beta-D-glucoside inhibits the glutamine synthetase enzyme, a promising target for the development of antituberculosis drugs. This prediction was confirmed by an in vitro glutamine synthetase biosynthetic assay. To the best of our knowledge, and based on bioinformatics mining of the BioPhytMol database, this is the first report on the antimycobacterial activity of Euphorbia paralias plant. It is also the first report on the inhibition of mycobacterial glutamine synthetase by the flavonoid quercetin. PMID- 29523310 TI - Killer (FASL regulatory) B cells are present during latent TB and are induced by BCG stimulation in participants with and without latent tuberculosis. AB - Regulatory B cells (Bregs) have been shown to be present during several disease states. The phenotype of the cells is not completely defined and the function of these cells differ between disease. The presence of FASL expressing (killer) B cells during latent and successfully treated TB disease have been shown but whether these cells are similar to regulatory B cells remain unclear. We assessed the receptor expression of FASL/IL5 (killer B cells), CD24/CD38 (regulatory B cells) on whole peripheral blood of participants with untreated active TB and healthy controls. We then isolated B cells from a second cohort of M.tb exposed (Quantiferon (QFN) positive) and unexposed (Quantiferon negative) HIV negative participants, and evaluated the frequency of killer B cells induced following stimulation with BCG and/or CD40 and IL5. Our data reveal no difference in the expression on CD24 and CD38 between participants with active TB and the controls. There was also no difference in the frequency of regulatory B cells measured in the peripheral blood mononuclear cells (PBMC) fraction between latent TB and uninfected controls. We did however notice that regulatory B cells (CD24hiCD38hi) population express the FASL receptor. The expression of killer B cell phenotype (CD178+IL5RA+) was significantly higher in controls compared to those with active TB disease (1,06% vs 0,455%). Furthermore, we found that BCG restimulation significantly induced the FASL/IL5RA B cells but this was only evident in the QFN positive group. Our data suggest that both regulatory and killer B cells are present during latent and active TB disease but that the frequency of these populations are increased during latent disease. We also show that the FASL+IL5RA+ B killer B cells are induced in latent TB infection following BCG restimulation but whether these cells are indicative of protection remains unclear. PMID- 29523311 TI - Mycobacterium tuberculosis infection induces IL-10 gene expression by disturbing histone deacetylase 6 and histonedeacetylase 11 equilibrium in macrophages. AB - Mycobacterium tuberculosis (MTB) infection is a significant contributor to dysregulated T cell-mediated immune response. Here we aimed to evaluate the mechanism of MTB infection in promoting interleukin-10 (IL-10) upregulation. The IL-10 levels in MTB infected THP-1 cells were evaluated with enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). In challenged THP-1 cells, the HDAC6 and HDAC11 mRNA and protein levels were monitored at varied duration after MTB infection. Further, chromatin immunoprecipitation (ChIP) analysis was used to investigate the interaction between IL-10 expression and HDAC6 or HDAC11. HDAC6 and HDAC11 were overexpressed or silenced to study their effects on IL-10 regulation. IL-10 was upregulated after MTB challenge in a time- and dose-dependent manner. Similarly, HDAC6 and HDAC11 were also upregulated by MTB challenge. Overexpression or silencing of HDAC6 and HDAC11 changed IL-10 expression correspondingly. MTB infection disturbs the HDAC6/HDAC11 levels to induce IL-10 expression. Strategies to counteract the dysregulation of HDAC6/HDAC11 would potentially alleviate the immunological disordered following MTB infection. PMID- 29523312 TI - Diagnostic performance of an optimized transcriptomic signature of risk of tuberculosis in cryopreserved peripheral blood mononuclear cells. PMID- 29523313 TI - Modulation of iron status biomarkers in tuberculosis-diabetes co-morbidity. AB - Tuberculosis (TB) and diabetes mellitus (DM) remain vital disease burdens in developing countries and the dual burden of DM and TB clearly signifies a growing global public health concern. While modulation of iron status biomarkers in TB is well described, very little is known about the association of these markers with TB-DM. To examine the association of circulating iron status biomarkers in TB disease, we examined the systemic levels of ferritin, hepcidin, soluble transferrin receptor (sTfR), transferrin, apotransferrin and hemopexin in pulmonary TB (PTB) individuals with DM (PTB-DM), without DM (PTB) and those with diabetes only (DM). Circulating levels of ferritin and hepcidin were significantly enhanced in PTB-DM and PTB compared to the DM group. On the other hand, the circulating levels of transferrin and apotransferrin were significantly diminished in PTB-DM and PTB compared to the DM group. The levels of ferritin and hepcidin exhibited a significant positive relationship with HbA1c, whereas apotransferrin exhibited negative relationship with HbA1c in PTB-DM and PTB. ROC analysis revealed that ferritin, hepcidin and transferrin are markers that can distinguish PTB-DM from DM individuals. Our results suggest that some of these circulating iron status markers could prove useful as biomarkers to monitor disease severity. PMID- 29523314 TI - A multicentre verification study of the QuantiFERON(r)-TB Gold Plus assay. AB - OBJECTIVES: The aim of this verification study was to compare the QuantiFERON(r) TB Gold Plus (QFT-Plus) to the QuantiFERON(r)-TB Gold In Tube (QFT-GIT). The new QFT-Plus test contains an extra antigen tube which, according to the manufacturer additionally elicits a CD8+ T-cell response above the CD4+ T-cell response. We assessed the value of this tube in detecting recent latent tuberculosis infections. METHODS: Between May 2015 and December 2016, 1031 subjects underwent QFT-Plus and QFT-GIT test. Overall agreement between both tests and performance for different test indications and/or immune states was assessed. A difference of >0.6 IU/mL interferon-gamma release between the two antigen tubes of the QFT-Plus assay was considered a true difference and used as estimation for CD8+ T-cell response. RESULTS: Analysis of the QuantiFERON tests resulted in an overall agreement between assays of 95%. Subjects considered to be recently exposed to tuberculosis had significantly more often a true difference in interferon-gamma release compared to all other subjects (p = 0.029). CONCLUSION: Results of QFT Plus are highly comparable to QFT-GIT. Although there is an indication that a true difference in interferon-gamma release between the antigen tubes is associated with recent latent tuberculosis infection, the QFT-Plus could not be used to exclude recent exposure. PMID- 29523315 TI - Activity loss by H46A mutation in Mycobacterium tuberculosis isocitrate lyase is due to decrease in structural plasticity and collective motions of the active site. AB - Mycobacterium tuberculosis isocitrate lyase (MtbICL) is a crucial enzyme of the glyoxylate cycle and is a validated anti-tuberculosis drug target. Structurally distant, non-active site mutation (H46A) in MtbICL has been found to cause loss of enzyme activity. The aim of the present work was to explore the structural alterations induced by H46A mutation that caused the loss of enzyme activity. The structural and dynamic consequences of H46A mutation were studied using multiple computational methods such as docking, molecular dynamics simulation and residue interaction network analysis (RIN). Principal component analysis and cross correlation analysis revealed the difference in conformational flexibility and collective modes of motions between the wild-type and mutant enzyme, particularly in the active site region. RIN analysis revealed that the active site geometry was disturbed in the mutant enzyme. Thus, the dynamic perturbation of the active site led to enzyme transition from its active form to inactive form upon mutation. The computational analyses elucidated the mutant-specific conformational alterations, differential dominant motions, and anomalous residue level interactions that contributed to the abrogated function of mutant MtbICL. An understanding of interactions of mutant enzymes may help in modifying the existing drugs and designing improved drugs for successful control of tuberculosis. PMID- 29523316 TI - M. bovis infection in pigs: Improvement of the gamma-IFN assay efficiency in this species using a maintenance medium. AB - The interferon-gamma (IFN-gamma) test measures cell mediated immune response (CMI) during the early stages of tuberculosis infection. Although Bovine Tuberculosis (BT) spread in feral pigs is widely documented in literature, the effectiveness of IFN-gamma in this species has been only recently reported. One of the major obstacle of this assay is that whole blood samples should be stimulated with purified protein derivative (PPD) cocktail within 8 h from the blood sampling. This study set up a defined broth culture in which lymphocytes, the cell population predominantly responsible for IFN-gamma production, are maintained in a steady-state and their vitality is preserved. The IFN-gamma production measured from the samples added with the maintenance medium and stored at 4 degrees C was similar to the enzyme-linked immunosorbent assay (ELISA) optical density values obtained from the same assay performed within 8 h from sampling. PMID- 29523317 TI - Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG. AB - WHO reported 10.4 million new tuberculosis (TB) cases and 1.8 million deaths in 2015, making M. tuberculosis the most successful human pathogen with highest mortality among infectious diseases [1,2]. Drug-resistant TB is a major threat to global TB control [2,3]. Recently Torres et al. [4] identified 14 novel substitutions in M. tuberculosis-KatG (the enzyme associated with resistance to isoniazid-an important first-line anti-TB drug) and demonstrated that 12 of the 14 can cause INH-resistance in M. smegmatis. This study presents an in silico structure-based analysis of these 14 amino acid substitutions using homology models and x-ray crystal structures (when available) in M. tuberculosis. Our models demonstrate that several of these mutations cluster around three openings in the KatG tertiary structure which appear to initiate channels to the heme group at the catalytic center of the enzyme. We studied the effects of these mutations on the tertiary structure of KatG, focusing on conformational changes in the three channels in the protein structure. Our results suggest that the 14 novel mutations sufficiently restrict one or more of these access channels, thus potentially preventing INH from reaching the catalytic heme. These observations provide valuable insights into the structure-based origins of INH resistance and provide testable hypotheses for future experimental studies. PMID- 29523318 TI - Distinct properties of a hypoxia specific paralog of single stranded DNA binding (SSB) protein in mycobacteria. AB - In addition to the canonical Single Stranded DNA Binding (SSBa) protein, many bacterial species, including mycobacteria, have a paralogous SSBb. The SSBb proteins have not been well characterized. While in B. subtilis, SSBb has been shown to be involved in genetic recombination; in S. coelicolor it mediates chromosomal segregation during sporulation. Sequence analysis of SSBs from mycobacterial species suggests low conservation of SSBb proteins, as compared to the conservation of SSBa proteins. Like most bacterial SSB proteins, M. smegmatis SSBb (MsSSBb) forms a stable tetramer. However, solution studies indicate that MsSSBb is less stable to thermal and chemical denaturation than MsSSBa. Also, in contrast to the 5-20 fold differences in DNA binding affinity between paralogous SSBs in other organisms, MsSSBb is only about two-fold poorer in its DNA binding affinity than MsSSBa. The expression levels of ssbB gene increased during UV and hypoxic stresses, while the levels of ssbA expression declined. A direct physical interaction of MsSSBb and RecA, mediated by the C-terminal tail of MsSSBb, was also established. The results obtained in this study indicate a role of MsSSBb in recombination repair during stress. PMID- 29523319 TI - Major genotype families and epidemic clones of Mycobacterium tuberculosis in Omsk region, Western Siberia, Russia, marked by a high burden of tuberculosis-HIV coinfection. AB - This population-based study characterized Mycobacterium tuberculosis isolates from HIV-positive and HIV-negative tuberculosis (TB) patients in the Omsk region in Western Siberia, Russia. We sought to gain insight into the major genotype families and epidemic and endemic clones of M. tuberculosis in the area with a high burden and adverse trend of TB/HIV coinfection. The study collection included M. tuberculosis isolates from 207 newly-diagnosed patients with pulmonary TB; 55 (26.5%) of patients were HIV-infected. The M. tuberculosis isolates were subjected to drug susceptibility testing and molecular typing based on spoligotyping and analysis of the robust genotype and cluster-specific markers. Patients with disseminated TB disease were more prevalent in the HIV positive (34.5%) than in the HIV-negative group (4.6%) (P < .001). The Beijing genotype was predominant (62.3% of isolates), and its major subtypes were 94-32 cluster (Central Asian/Russian strain, n = 80) and B0/W148-cluster (successful Russian strain, n = 28). The main non-Beijing families were represented by Latin American Mediterranean (14.5%), T family (11.1%), Ural (5.8%), and Haarlem (3.9%). Under multivariate logistic regression analysis, MDR was associated with Beijing genotype and not associated with HIV coinfection status (P < .001). Beijing genotype isolates were found more frequently in TB/HIV patients than in TB HIV-negative patients (74.5% versus 57.9%, respectively; P = .031). The non Beijing genotypes were mainly drug susceptible except for the drug-resistant Ural SIT262 isolates. To summarize, the alarming situation in the Omsk region in Siberia regarding TB/HIV coinfection is seriously influenced by the active circulation of M. tuberculosis isolates of MDR-associated Beijing genotype. Among the non-Beijing families, emergence of the drug-resistant Ural family strains of spoligotype SIT262 warrants attention. PMID- 29523320 TI - Mycobacterial nucleoid associated proteins: An added dimension in gene regulation. AB - Nucleoid associated proteins (NAPs) are known organisers of chromosomal structure and regulators of transcriptional expression. The number of proposed NAPs in mycobacteria are significantly lower than the number identified in other organisms. An interesting feature of mycobacterial NAPs is their low sequence similarity with those in other species, a property that has hindered their identification. In this review, we discuss the current evidence for the proposed classification of six mycobacterial proteins, Lsr2, EspR, mIHF, HupB, MDP2 and NapM, as NAPs in mycobacterial species with an emphasis on their roles in modulating chromosome structure and transcriptional regulation. In addition, we highlight the technical difficulties associated with investigating and providing evidence for the classification of proteins as NAPs in mycobacteria. We also address the role of mycobacterial NAPs as mediators of stress responses and highlight the recent developments aimed at targeting NAP-DNA interactions for the development of novel anti-TB drugs. PMID- 29523321 TI - Utility of the T-SPOT(r).TB test's borderline category to increase test resolution for results around the cut-off point. AB - BACKGROUND: Accurate identification of individuals with TB infection, is required to achieve the WHO's End TB Strategy goals. While there is general acceptance that the T-SPOT.TB test borderline category provides an opportunity to increase test resolution of results around the test cut-off point, this has not been investigated. METHODS: 645,947 tests were analyzed to determine frequency of borderline results, effect of age and time between tests and associations between subjects' clinical risk factors and retest results. RESULTS: 645,947 tests produced 93.5% negatives, 4% positives, 0.6% invalids, and 1.8% borderlines. Within the borderline results, 5044 were repeated, with 59.2%, 20.0% and 20.2% resolving to negative, positive and borderline, respectively. Age of subject did not affect retest results; however, time between tests indicated that retest resolution occurred with greatest frequency after 90 days. TB risk factors were provided for 2640 subjects and 17% of low risk subjects with a high initial borderline resolved to negative while 27.6% of subjects with high risk and an initial low borderline resolved to positive, suggesting that these subjects could have been inappropriately classified if using a single cut-off point test with no borderline category. CONCLUSION: This study demonstrates the utility of the T SPOT.TB test's borderline category to increase test resolution around the test cut-off point. PMID- 29523322 TI - Mechanisms of resistance to delamanid, a drug for Mycobacterium tuberculosis. AB - Delamanid, a bicyclic nitroimidazooxazole, is effective against M. tuberculosis. Previous studies have shown that resistance to a bicyclic nitroimidazooxazine, PA 824, is caused by mutations in an F420-dependent bio-activation pathway. We investigated whether the same mechanisms are responsible for resistance to delamanid. Spontaneous resistance frequencies were determined using M. bovis BCG Tokyo (BCG) and M. tuberculosis H37Rv. F420 high-performance liquid chromatography (HPLC) elution patterns of homogenates of delamanid-resistant BCG colonies and two previously identified delamanid-resistant M. tuberculosis clinical isolates were examined, followed by sequencing of genes in the F420 dependent bio-activation pathway. Spontaneous resistance frequencies to delamanid were similar to those of isoniazid and PA-824. Four distinct F420 HPLC elution patterns were observed, corresponding to colonies with mutations on fgd1, fbiA, fbiB, and fbiC with no change in the ddn mutants from the wildtype. Complementation with the wildtype sequence of the mutated gene restored susceptibility. The two delamanid-resistant clinical isolates had ddn mutations and the wildtype F420 HPLC elution pattern. In conclusion, delamanid-resistant bacilli have mutations in one of the 5 genes in the F420-dependent bio-activation pathway with distinct F420 HPLC elution patterns. Both genetic and phenotypic changes may be considered in the development of a rapid susceptibility test for delamanid. PMID- 29523323 TI - Tuberculosis determination using SERS and chemometric methods. AB - Nanostructures have been multiplying the advantages of Raman spectroscopy and further amplify the advantages of Raman spectroscopy is a continuous effort focused on the appropriate design of nanostructures. Herein, we designed different shapes of plasmonic nanostructures such as Vertical, Zig Zag, Slant nanorods and Spherical nanoparticles employing the DC magnetron sputtering system as SERS-active substrates for ultrasensitive detection of target molecules. The fabricated plasmonic nanostructures sensitivity and uniformity were exploited by reference dye analyte. These nanostructures were utilized in the label free detection of infectious disease, Tuberculosis (TB). For the first time, TB detection from serum samples using SERS has been demonstrated. Various multivariate statistical methods such as principal component analysis, support vector machine, decision tree and random forest were developed and tested their ability to discriminate the healthy and active TB samples. The results demonstrate the performance of the SERS spectra, chemometric methods and potential of the method in clinical diagnosis. PMID- 29523324 TI - Screening and identification of four serum miRNAs as novel potential biomarkers for cured pulmonary tuberculosis. AB - Rapid and efficient methods for the determination of cured pulmonary tuberculosis (TB) are lacking. We screened serum miRNAs using the Solexa sequencing method among untreated TB patients, two-month treated TB patients, cured TB patients, and healthy controls. A total of 100 differentially expressed miRNAs were identified in cured TB patients, including 37 up-regulated (fold change >1.50, P < 0.05) and 63 down-regulated (fold change <0.60, P < 0.05) miRNAs. Gene ontology (GO) enrichment analysis revealed that most of the predicted genes were present in the nucleus with a strong protein binding function. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis strongly suggested alterations in the metabolic pathways. Following quantitative real time chain reaction (qRT-PCR), significantly reduced expression levels of miR-21-5p (0.30, P < 0.001), miR-92a 3p (0.63, P < 0.001), and miR-148b-3p (0.17, P < 0.001) were found in the cured TB patients compared with the untreated TB patients, while significantly increased expression levels of miR-21-5p (2.09, P = 0.001), miR-92a-3p (1.40, P = 0.005), and miR-148b-3p (4.80, P = 0.003) were found in the untreated TB patients compared with the healthy controls. And significantly increased level of miR-125a 5p was found between two-month treated TB patients and untreated TB patients (1.81, P = 0.004). We established a cured TB model with 83.96% accuracy by four miRNAs (miR-21-5p, miR-92a-3p, miR-148b-3p, and miR-125a-5p), and also established a diagnostic model with 70.09% accuracy. Our study provides experimental data for establishing objective indicators of cured TB, and also provides a new experimental basis to understand the pathogenesis and prognosis of TB. PMID- 29523325 TI - Impaired TNF, IL-1beta, and IL-17 production and increased susceptibility to Mycobacterium tuberculosis infection in HTLV-1 infected individuals. AB - IFN-gamma and TNF play critical roles in the control of Mycobacterium tuberculosis infection. Despite leading to an exaggerated production of inflammatory cytokines, HTLV-1 infection increases the risk of developing tuberculosis (TB). However, the immune mechanisms accounting for this phenomenon are still unclear. The aim of this study was to evaluate immunological aspects of the HTLV-1/M. tuberculosis co-infection. In this cross-sectional study, the levels of TNF, IL-1beta, and IL-17 were determined by ELISA in the supernatants of either unstimulated or tuberculin purified protein derivative (PPD) stimulated peripheral blood mononuclear cells. Cells from HTLV-1 infected individuals produced lower levels of TNF following PPD stimulation compared to unstimulated cells. IL-1beta and IL-17 production by cells from HTLV-1/M. tuberculosis co infected individuals was lower than in cells from patients with TB. Impairment in TNF, IL-1beta, and IL-17 production upon stimulation with mycobacterial antigens may contribute to the increased susceptibility to M. tuberculosis infection observed in HTLV-1 infected individuals. PMID- 29523326 TI - Polymorphisms in Rv3806c (ubiA) and the upstream region of embA in relation to ethambutol resistance in clinical isolates of Mycobacterium tuberculosis from North India. AB - Mutations at embB306 are the most prevalent polymorphisms associated with ethambutol (EMB) resistance, responsible for 40-60% of EMB resistant clinical cases of tuberculosis (TB). The present study analyzed additional mutations associated with EMB resistance in the embB, embC, embA and Rv3806c (ubiA) genes in 29 EMB resistant and 29 EMB susceptible clinical isolates of M. tuberculosis selected from 360 patients with TB. The entire ubiA gene, mutational hotspot regions of embB, embC, and upstream region of embA were screened for polymorphisms by DNA sequencing and the results correlated with minimum inhibitory concentrations (MIC) of EMB. The most common polymorphism identified in ubiA was at codon 149 (GAA to GAC), occurring in 5/29 (17.2%) resistant isolates and 7/29 (24%) susceptible isolates. Mutations in embB were most common at codon 306 (ATG to ATC/GTG), occurring only in EMB resistant isolates (20/29; 69%). Mutations in the upstream region of embA at -8, -11, -12 and -60 codons also occurred in EMB resistant strains (8/29; 27.5%) of which 6/8 (75%) were observed in isolates with EMB MIC >=16 MUg/ml. Though no polymorphisms associated with EMB resistance were identified in ubiA, polymorphisms upstream to embA may contribute to high level EMB resistance. PMID- 29523327 TI - Investigating the inhibitory potential of 2-Aminopurine metal complexes against serine/threonine protein kinases from Mycobacterium tuberculosis. AB - Tuberculosis - a disease caused by Mycobacterium tuberculosis (Mtb), is one of the most devastating disease. The discovery of Ser/Thr protein kinases (STPKs) in Mtb opened a new avenue for developing anti-tubercular inhibitors. The in-vivo inhibitory effects of many metal ions have been demonstrated in literature. But, one of the limitations of metal ions as inhibitors is their inability to traverse the hydrophobic membrane due to polar nature and their propensity for non specific interactions. To overcome this, we attached a metal ion to 2-A9P - an analog derived from a cell permeable scaffold, 2-Aminopurine (2-AP) which is a known kinase inhibitor. We investigated the inhibitory potential of 2-AP and its analog 2-A9P against protein kinase B (PknB) and showed that both of these can inhibit Mtb STPKs. Next, we evaluated the latent inhibitory activity of metal ions and for the first time showed that they can inhibit the phosphotransfer reaction in PknB, PknG and PknL. Subsequently, 6 different metal complexes (MC) of 2-A9P were used for inhibitory studies and their estimated IC50 values show that most MCs inhibited PknB with low micromolar potency. Further, MIC values determined for the six MCs against Mtb showed that MC-4 and MC-6 exhibit whole cell inhibitory activity. Cytotoxicity studies show that MC-4 and MC-6 do not affect cell viability of A549 cell lines, suggesting that these inhibitors can be further developed as anti-tubercular agents. PMID- 29523328 TI - Screening of antitubercular compound library identifies novel ATP synthase inhibitors of Mycobacterium tuberculosis. AB - A limited number of anti-tuberculosis drug candidates with novel mode of action have entered clinical trials in recent years. ATP synthase is one such validated drug target which has yielded a drug recently. The aim of this study was to identify the novel chemical scaffolds targeting the Mycobacterium tuberculosis (M. tuberculosis) ATP synthase. In this study, inverted membrane vesicles of Mycobacterium smegmatis were prepared to establish luciferin based ATP estimation assay. This assay was used to screen 700 compounds which were earlier found to be active on the whole cell of M. tuberculosis. Antibacterial activity of hits against various susceptible and drug-resistant strains of M. tuberculosis was evaluated using the microplate alamar blue assay and their cytotoxicity was also determined to select the safe compounds for further study. Screening of 700 compounds resulted in the identification of two compounds (5228485 and 5220632) exhibiting an IC50 of 0.32 and 4.0 MUg/ml respectively. Both compounds showed excellent anti-TB activity (MIC of 0.5-2.0 MUg/ml against Mtb H37Rv) and low cytotoxicity in human cell line and sub-mitochondrial particles. The three dimensional structure of M. tuberculosis ATPase was predicted using in-silico approach and docking studies were performed with the active compounds. The interaction between compounds and bacterial ATP synthase was confirmed by molecular docking analysis. In conclusion screening of compound library has resulted in the identification of two novel chemical scaffolds targeting mycobacterial ATP synthase. PMID- 29523329 TI - A comparison of Rv0559c and Rv0560c expression in drug-resistant Mycobacterium tuberculosis in response to first-line antituberculosis drugs. AB - Drug resistance to Mycobacterium tuberculosis is a major health problem worldwide. Mycobacterium tuberculosis can progress to be mono-drug resistant or multi-drug resistant by improper treatment. The chemical stress of M. tuberculosis was performed in this study. Rv0559c is an unknown secreted protein. Rv0560c is a putative benzoquinone methyltransferase of M. tuberculosis cell. Rv0559c gene is located downstream of Rv0560c gene. Both genes respond to salicylate stress. Drug susceptible, isoniazid resistant, rifampicin resistant and multi-drug resistant phenotypes of M. tuberculosis clinical isolates were used to determine the expression of Rv0559c and Rv0560c by qRT-PCR. In all of mycobacteria strains there was up-regulation in both genes when stressed with isoniazid. This study determined the expression of both genes, which may play important roles in the drug resistance mechanism of mycobacteria. PMID- 29523330 TI - IgG subclasses' response to a set of mycobacterial antigens in different stages of Mycobacterium tuberculosis infection. AB - Despite the reported high heterogeneity of the human immune response to tuberculosis (TB), new studies may contribute to the understanding of Mycobacterium tuberculosis immunopathogenesis. To investigate the patterns of humoral response during latent (LTBI) and active TB, we evaluated specific IgG subclasses' response, by ELISA, to a set of mycobacterial antigens (Rv2029c, Rv2031c, Rv2034, Rv2628, Rv3353c ESAT6:CFP10, and the new chimeric PstS1(285 374):CFP10) in plasma samples from exposed uninfected controls (ExC, n = 24), LTBI (n = 61), and TB (n = 15) donors. In general, the TB group showed statistically higher levels of IgG1, and lower levels of IgG3. Keeping specificities >=90%, the highest sensitivity for TB detection was observed for IgG1-ESAT6:CFP10 (93.3%), followed by IgG2-Rv3353 (86.7%), IgG1-Rv3353 (69.2%) and IgG1-PstS1(285-374):CFP10 (53.3%). The combinatory of high IgG1-ESAT6:CFP10, followed by low IgG2-Rv3353c titers increased the specificity for TB detection to 100%. Only IgG3-ESAT6:CFP10 showed statistical differences between ExC and LTBI, detecting 50% of the LTBI donors. For the first time, higher levels of IgG2 PstS1(285-374):CFP10 and IgG2-Rv3353 were observed in LTBI and ExC, as compared with a lower or absent immunoreactivity among TB. This study demonstrates differential modulation of subclasses' profiles for the stages of infection, which may contribute to the further development of new diagnostic tools. PMID- 29523331 TI - The utility of pharmacokinetic studies for the evaluation of exposure-response relationships for standard dose anti-tuberculosis drugs. AB - Tuberculosis (TB) is a major public health problem. Many countries still fall below the minimum World Health Organization (WHO) TB treatment target success rate. There is conflicting evidence about whether concentrations of anti tuberculosis drugs given at standard doses have an effect on treatment outcomes. The current data correlating anti-TB drug concentrations and treatment outcome is limited. This article summarized the existing literature and their utility in evaluating the association between each anti-TB drug's concentrations using current target concentrations and treatment outcomes in patients with pulmonary tuberculosis receiving standard WHO-recommended dosing. PMID- 29523332 TI - An IclR like protein from mycobacteria regulates leuCD operon and induces dormancy-like growth arrest in Mycobacterium smegmatis. AB - leuCD operon encodes isopropylmalate isomerase (IPMI), an essential enzyme in leucine biosynthesis. Leucine biosynthesis is one of the essential metabolic pathways for Mycobacterium tuberculosis survival inside the macrophage. In this study, we identified an IclR like transcription regulator, Rv2989 involved in regulation of leuCD expression. Further, we have shown that the Rv2989 binding site overlaps with the promoter region of leuCD, indicating its direct involvement in the regulation of this operon. Ectopic expression of Rv2989 in M. smegmatis induced growth arrest with significantly decreased levels of leuCD transcript. However, supplementation with leucine could not reverse the growth arrest, suggesting the involvement of Rv2989 in the regulation of other essential pathways. Growth-arrested cells were elongated, had lost acid fastness and accumulated lipid droplets similar to a dormancy-like state. In conclusion, the Rv2989 expression has pleiotropic effects on M. smegmatis. It negatively regulates leuCD operon and induces dormancy-like growth arrest. PMID- 29523333 TI - I3-Ag85 effect on phthiodiolone dimycocerosate synthesis. AB - The multiplicity of drug resistant Mycobacterium tuberculosis (Mtb) strains is a growing health issue. New therapies are needed, acting on new targets. The I3 Ag85 was already reported to reduce the amount of trehalose dimycolate lipid of the mycobacterial cell wall. This inhibitor of Ag85C increased the mycobacterial wall permeability. We previously showed that M. tuberculosis strains, even multi drug resistant and extensively-drug resistant strains, can be susceptible to vancomycin when concomitantly treated with a drug altering the cell envelope integrity. We investigated the effect of the I3-Ag85 on vancomycin susceptibility of M. tuberculosis. Although no synergy was observed, a new target of this drug was discovered: the production of phthiodiolone dimycocerosate (PDIM B). PMID- 29523334 TI - The 7-phenyl benzoxaborole series is active against Mycobacterium tuberculosis. AB - We identified a series of novel 7-phenyl benzoxaborole compounds with activity against Mycobacterium tuberculosis. Compounds had a range of activity with inhibitory concentrations (IC90) as low as 5.1 MUM and no cytotoxicity against eukaryotic cells (IC50 > 50 MUM). Compounds were active against intracellular mycobacteria cultured in THP-1 macrophages. We isolated and characterized resistant mutants with mutations in NADH dehydrogenase (Ndh) or the regulatory protein Mce3R. Mutations suggest that Ndh may be the target of this series. PMID- 29523336 TI - Replication stress in mitochondria. AB - Mitochondrial DNA (mtDNA), which is essential for mitochondrial and cell function, is replicated and transcribed in the organelle by proteins that are entirely coded in the nucleus. Replication of mtDNA is challenged not only by threats related to the replication machinery and orchestration of DNA synthesis, but also by factors linked to the peculiarity of this genome. Indeed the architecture, organization, copy number, and location of mtDNA, which are markedly distinct from the nuclear genome, require ad hoc and complex regulation to ensure coordinated replication. As a consequence sub-optimal mtDNA replication, which results from compromised regulation of these factors, is generally associated with mitochondrial dysfunction and disease. Mitochondrial DNA replication should be considered in the context of the organelle and the whole cell, and not just a single genome or a single replication event. Major threats to mtDNA replication are linked to its dependence on both mitochondrial and nuclear factors, which require exquisite coordination of these crucial subcellular compartments. Moreover, regulation of replication events deals with a dynamic population of multiple mtDNA molecules rather than with a fixed number of genome copies, as it is the case for nuclear DNA. Importantly, the mechanistic aspects of mtDNA replication are still debated. We describe here major challenges for human mtDNA replication, the mechanistic aspects of the process that are to a large extent original, and their consequences on disease. PMID- 29523335 TI - Development of a non-human primate BCG infection model for the evaluation of candidate tuberculosis vaccines. AB - The lack of validated immunological correlates of protection makes tuberculosis vaccine development difficult and expensive. Using intradermal bacille Calmette Gurein (BCG) as a surrogate for aerosol Mycobacterium tuberculosis (M.tb) in a controlled human infection model could facilitate vaccine development, but such a model requires preclinical validation. Non-human primates (NHPs) may provide the best model in which to do this. Cynomolgus and rhesus macaques were infected with BCG by intradermal injection. BCG was quantified from a skin biopsy of the infection site and from draining axillary lymph nodes, by culture on solid agar and quantitative polymerase chain reaction. BCG was detected up to 28 days post infection, with higher amounts of BCG detected in lymph nodes after high dose compared to standard dose infection. Quantifying BCG from lymph nodes of cynomolgus macaques 14 days post-high dose infection showed a significant reduction in the amount of BCG detected in the BCG-vaccinated compared to BCG naive animals. Demonstrating a detectable vaccine effect in the lymph nodes of cynomolgus macaques, which is similar in magnitude to that seen in an aerosol M.tb infection model, provides support for proof-of-concept of an intradermal BCG infection model and evidence to support the further evaluation of a human BCG infection model. PMID- 29523337 TI - Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. AB - BACKGROUND AND OBJECTIVES: Thrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. PATIENTS AND METHODS: We performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies. RESULTS: No differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24 40.93], p = .03). CONCLUSIONS: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE. PMID- 29523338 TI - Current aspects of Fabry's disease. PMID- 29523339 TI - Not always is an infection. PMID- 29523340 TI - Giant cell myositis associated with myasthenia gravis and thymoma. PMID- 29523341 TI - Exercise oximetry in patients with arterial claudication. PMID- 29523342 TI - Migraine. AB - Migraine is a chronic paroxysmal neurological disorder characterised by multiphase attacks of head pain and a myriad of neurological symptoms. The underlying genetic and biological underpinnings and neural networks involved are coming sharply into focus. This progress in the fundamental understanding of migraine has led to novel, mechanism-based and disease-specific therapeutics. In this Seminar, the clinical features and neurobiology of migraine are reviewed, evidence to support available treatment options is provided, and emerging drug, device, and biological therapies are discussed. PMID- 29523343 TI - Effect of dental monomers and initiators on Streptococcus mutans oral biofilms. AB - OBJECTIVE: Resin-based composites are known to elute leachables that include unincorporated starting materials. The objective of this work was to determine the effect of common dental monomers and initiators on Streptococcus mutans biofilm metabolic activity and biomass. METHODS: S. mutans biofilms were inoculated in the presence of bisphenol A glycerolate dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA), camphorquinone (CQ), and ethyl 4 (dimethylamino)benzoate (4E) at 0.01MUg/mL up to 500MUg/mL, depending on the aqueous solubility of each chemical. Biofilms were evaluated at 4h and 24h for pH (n=3-8), biomass via crystal violet (n=12), metabolic activity via tetrazolium salt (n=12), and membrane permeability for selected concentrations via confocal microscopy (n=6). Parametric and non-parametric statistics were applied. RESULTS: 500MUg/mL TEGDMA reduced 24h metabolic activity but not biomass, similar to prior results with leachables from undercured BisGMA-TEGDMA polymers. 50MUg/mL BisGMA reduced biofilm biomass and activity, slightly delayed the pH drop, and decreased the number of cells with intact membranes. 100MUg/mL CQ delayed the pH drop and metabolic activity at 4h but then significantly increased the 24h metabolic activity. 4E had no effect up to 10MUg/mL. SIGNIFICANCE: Monomers and initiators that leach from resin composites affect oral bacterial biofilm growth in opposite ways. Leachables, which can be released for extended periods of time, have the potential to alter oral biofilm biomass and activity and should be considered in developing and evaluating new dental materials. PMID- 29523344 TI - Pediatric triage education: An integrative literature review. AB - INTRODUCTION: The objective of this study was to review the currently published literature on the topic of pediatric triage education. METHOD: An integrative review of the literature was conducted using database searching and historical record review. RESULTS: A wide variety of pediatric triage educational methods exist, but studies with the highest-quality ratings most often used simulation programs or a standardized curriculum. Although there was a good deal of heterogeneity in terms of the outcomes measured, the accuracy of triage improved following educational interventions. DISCUSSION: Additional research is needed to compare different methods of pediatric triage education directly. Emergency nurses should be aware that pediatric triage is a high-risk event, and some educational methods may have advantages over others. In addition, although retention of pediatric triage skills is affected by the method and timing of pediatric triage education, emergency nurses should remain aware that improved pediatric triage skills could lead to improved pediatric outcomes, and target this as an area for further research. PMID- 29523345 TI - Above, Beyond, and Over the Side rails: Evaluating the New Memorial Emergency Department Fall-Risk-Assessment Tool. AB - INTRODUCTION: Patient falls are a significant issue in hospitalized patients and financially costly to hospitals. The Joint Commission requires that patients be assessed for fall risk and interventions in place to mitigate the risk of falls. It is imperative to have a patient population/setting specific fall risk assessment tool to identify patients at risk for falling. The purpose of this study was to evaluate the reliability and validity of the 2013 Memorial ED Fall Risk Assessment tool (MEDFRAT) specifically designed for the ED population. METHOD: A two-phase prospective design was used for this study. Phase one determined the interrater reliability of the MEDFRAT. Phase two assessed the validity of the MEDFRAT in an emergency department (ED) within a 600-bed academic/teaching institution; Level II Trauma Center with >100,000 annual patient visits. RESULTS: The Memorial ED Fall Risk Assessment Tool was validated in this ED setting. The tool demonstrated positive interrater reliability (k=0.701) and when implemented with a falls prevention strategy and staff education demonstrated a 48% decrease in ED fall rate (0.57 falls/1000 patient visits) post implementation during the study period. DISCUSSION: The MEDFRAT, an evidenced based ED-specific fall risk tool was implemented on the basis of the risk factors consistently identified in the literature: prior fall history, impaired mobility, altered mental status, altered elimination, and the use of sedative medication. The Memorial ED Fall Risk Assessment Tool demonstrated to be a valid tool for this hospital system. PMID- 29523346 TI - Acetabular-epiphyseal angle and hip dislocation in cerebral palsy: a preliminary study. AB - OBJECTIVE: To relate, in non-ambulatory subjects with palsy, Reimers' migration percentage with standardized radiological measurements, including the acetabular epiphyseal angle. METHOD: Descriptive, observational and transversal study of 15 individuals with cerebral palsy at levels IV and V of the Gross Motor Function Classification System, aged between 3 and 9 years. Radiological measurements of the acetabular index, Hilgenreiner's epiphyseal angle, acetabular-epiphyseal angle, neck-shaft angle and Reimers' migration percentage of each of the hips were performed. RESULTS: Correlations between acetabular index, epiphyseal angle and acetabular-epiphyseal angle were obtained with respect to the Reimers migration percentage. For hips with a migration rate of 15% or less, a positive correlation was observed between acetabular and epiphyseal angles. CONCLUSIONS: In our population, the measurement between acetabular and epiphyseal inclination represents the highest association with the hip migration percentage. PMID- 29523347 TI - Preparation and evaluation of a hydrophilic interaction and cation-exchange chromatography stationary phase modified with 2-methacryloyloxyethyl phosphorylcholine. AB - In this work, 2-methacryloyloxyethyl phosphorylcholine (MPC) was used as a ligand to prepare a novel mixed-mode chromatography (MMC) stationary phase by the thiol ene click reaction onto silica (MPC-silica). It was found that this MPC-silica showed the retention characteristics of hydrophilic interaction chromatography (HILIC) and weak cation exchange chromatography (WCX) under suitable mobile phase conditions. In detail, acidic and basic hydrophilic compounds and puerarin from pueraria were separated quickly with HILIC mode. Meanwhile, six standard proteins were allowed to reach baseline separation in WCX mode, and protein separation from egg white was also achieved with this mode. In addition, reduced/denatured lysozyme could be refolded with the MPC-silica column. In the meantime, the MPC silica has been applied for refolding with simultaneous purification of recombinant human Delta-like1-RGD (rhDll1-RGD) expressed in Escherichia coli. The results show that the mass recovery and purity of rhDll1-RGD could reach 63.4% and 97% by one step, respectively. Furthermore, the reporter assay results demonstrated that refolded with simultaneously purified rhDll1-RGD could efficiently activate the signalling pathway in a dose-dependent manner. In general, this MPC-silica has good resolution and selectivity in the separation of polar compounds and protein samples in different high-performance liquid chromatography (HPLC) modes, and it successfully achieved refolding with simultaneous purification of denatured protein. PMID- 29523348 TI - New 3D-printed sorbent for extraction of steroids from human plasma preceding LC MS analysis. AB - In recent years, there has been an increasing worldwide interest in the use of alternative sample preparation methods that are proceeded by separation techniques. Fused deposition modeling (FDM) is a 3D printing technique that is based the consecutive layering of softened/melted thermoplastic materials. In this study, a group of natural steroids and sexual hormones - namely, aldosterone, cortisol, beta-estradiol, testosterone, dihydrotestosterone, and synthetic methyltestosterone and betamethasone - were separated and determined using an optimized high-performance liquid chromatography coupled to mass spectrometry (LC-MS) method in positive ionization mode. 3D-printed sorbents were selected as the pre-concentration technique because they are generally low cost, fast, and simple to make and automate. Furthermore, the use of 3D-printed sorbents helps to minimize potential errors due to their repeatability and reproducibility, and their ability to eliminate carry over by using one printed sorbent for a single extraction of steroids from biological matrices. The extraction procedure was optimized and the parameters influencing 3D-printed Layfomm 60(r) based sorbent and LC-MS were studied, including the type of extraction solvent used, sorption and desorption times, temperature, and the salting-out effect. To demonstrate this method's applicability for biological sample analysis, the SPME-LC-MS method was validated for its ability to simultaneously quantify endogenous steroids. This evaluation confirmed good linearity and an R2 that was between 0.9970 and 0.9990. The recovery rates for human plasma samples were 86.34-93.6% for the studied steroids with intra- and inter-day RSDs of 1.44-7.42% and 1.44-9.46%, respectively. To our knowledge, this study is the first time that 3D-printed sorbents have been used to extract trace amounts of endogenous low-molecular-weight compounds, such as steroids, from biological samples, such as plasma. PMID- 29523349 TI - Application of a symbolic motion structure representation algorithm to identify upper extremity kinematic changes during a repetitive task. AB - Efficient and holistic identification of fatigue-induced movement strategies can be limited by large between-subject variability in descriptors of joint angle data. One promising alternative to traditional, or computationally intensive methods is the symbolic motion structure representation algorithm (SMSR), which identifies the basic spatial-temporal structure of joint angle data using string descriptors of temporal joint angle trajectories. This study attempted to use the SMSR to identify changes in upper extremity time series joint angle data during a repetitive goal directed task causing muscle fatigue. Twenty-eight participants (15 M, 13 F) performed a seated repetitive task until fatigued. Upper extremity joint angles were extracted from motion capture for representative task cycles. SMSRs, averages and ranges of several joint angles were compared at the start and end of the repetitive task to identify kinematic changes with fatigue. At the group level, significant increases in the range of all joint angle data existed with large between-subject variability that posed a challenge to the interpretation of these fatigue-related changes. However, changes in the SMSRs across participants effectively summarized the adoption of adaptive movement strategies. This establishes SMSR as a viable, logical, and sensitive method of fatigue identification via kinematic changes, with novel application and pragmatism for visual assessment of fatigue development. PMID- 29523350 TI - Surgical fixation of midshaft clavicle fractures: A systematic review of biomechanical studies. AB - PURPOSE: Surgical treatment of displaced midshaft clavicle fractures requires a decision between plate fixation and intramedullary (IM) fixation. Numerous studies report on the biomechanical properties of various repair constructs. The goal of this systematic review was to provide an overview of studies describing the biomechanical properties of the most commonly used surgical fixations of midshaft clavicle fractures. Additionally, we aimed to translate these biomechanical results into clinically relevant conclusions. METHODS: A computer aided search of the EMBASE and PudMed/MEDLINE databases was conducted. Studies included for review compared biomechanical properties of plate fixation with IM fixation and superiorly positioned plates with anteroinferiorly positioned plates for midshaft clavicle fractures. RESULTS: Fifteen studies were eligible for inclusion. Plate fixation seemed to form a more robust construct than IM fixation in terms of stiffness and failure loading. The remaining clavicle was stronger after removal of the IM device than after removal of the plate. Superior plating of transverse fractures generally seemed to provide greater stiffness and strength during bending loads than anteroinferior plating did. The absence of cortical alignment in wedge and comminuted fractures directly influenced the fixation stability for both IM fixation and plate fixation, regardless of location. CONCLUSION: Each type of fracture fixation has biomechanical advantages and disadvantages. However, exact thresholds of stiffness for inducing healing and failure strength to withstand refractures are unknown. The clinical relevance of the biomechanical studies may be arguable. Since none of the studies investigate the effect of tissue adaptation over time they should be interpreted with caution. PMID- 29523351 TI - Long-term variability of macrobenthic community in a shallow coastal lagoon (Valli di Comacchio, northern Adriatic): Is community resistant to climate changes? AB - A time series data of macrobenthic invertebrates of Valli di Comacchio lagoon (northern Adriatic) from 1996 to 2015, was analysed using Biological Traits Analysis, structural indices, AMBI and M-AMBI indices, with a twofold aim to: firstly, test the resilience of the system, and, secondly, test the influence of climate changes, in terms of temperature and precipitation pattern, on macrobenthic dynamics. Along the studied period macrobenthic community showed marked fluctuations, in terms of richness, diversity, biological traits and ecological groups, which could be related with environmental instability of the lagoon. At the same time, a general tendency towards a deterioration of ecological condition of the lagoon was observed, with a general decrease in species richness, diversity, percentage of sensitive species, and a general increase in the proportion of the more opportunistic trait modalities, such as deposit feeders, burrowing, infaunal and short living animals. Increasing yearly temperature explained only a small part of the variability of macrobenthic community, in terms of biological traits and diversity indices, and this was likely due to the effect of natural fluctuations of environmental parameters and anthropogenic disturbance. Nevertheless, all metrics used are consistent in identifying the response of benthic community to a severe disturbance, likely related with the summer heatwave in 2003. Less marked signs of disturbance were observed also in relations to the thermal anomaly of 2012. Biological Traits Analysis combined with more classical structural and ecological indices, proved to be efficient in identifying temporal changes of the community. Our results suggest that the expected increase in frequency, magnitude and duration of heatwaves could pose serious threat to the resilience capacity of lagoonal macrobenthic community. PMID- 29523352 TI - Questions regarding relative merit of ultrasonography compared with chest radiograph to detect pneumonia. PMID- 29523354 TI - Limitation of therapeutic effort in departments of internal medicine. PMID- 29523353 TI - Can anticoagulation therapy in cerebral venous thrombosis associated with Behcet's disease be stopped without relapse? AB - There is as yet no consensus on the treatment of cerebral venous thrombosis (CVT) in Behcet's disease, and the place of anticoagulation is also still being debated. This report is of a series of seven patients with Behcet's disease (BD) associated CVT, for which anticoagulation was stopped, and discusses the possibility of stopping anticoagulation during follow-up while receiving optimal treatment for BD. The diagnosis of BD was established during follow-up, which lasted a median of 120 [range: 60-1490] days after CVT diagnosis. The median duration of anticoagulation therapy was 29.5 months. On stopping anticoagulation, concomitant treatment then included colchicine, steroids and azathioprine, all introduced after BD was diagnosed. With a median follow-up of 25 months after anticoagulation interruption, only one relapse of CVT was observed. No relapse of CVT or other venous thrombosis was observed in the six patients treated by steroids associated with an immunosuppressant or colchicine. Our results emphasize that corticosteroids are essential for the treatment of BD-associated CVT, and that anticoagulant therapy may be safely stopped during follow-up in the presence of optimal BD treatment (steroids alone or with immunosuppressive drugs). PMID- 29523355 TI - Complicated pulmonary hydatid cyst with pleural and airway communication. PMID- 29523357 TI - Cellular effects of AP102, a somatostatin analog with balanced affinities for the hSSTR2 and hSSTR5 receptors. AB - BACKGROUND: Somatostatin analogs (SSAs) are first-line medical therapy for the treatment of acromegaly and neuroendocrine tumors that express somatostatin receptors (SSTR). Somatostatin suppresses secretion of a large number of hormones through the stimulation of the five SSTR. However, unbalanced inhibition of secretion as observed with the highly potent SSAs pasireotide causes hyperglycaemia mainly by inhibiting insulin secretion. In contrast, AP102 a new SSAs has neutral effect on blood glucose while suppressing GH secretion. Our objective was to establish the cellular effects of AP102 on SSTR2 and SSTR5 that may explain the differences observed between AP102 and other SSAs. METHODS: We compared the binding and agonist activity of AP102 with somatostatin-14, octreotide and pasireotide in HEK293 cells transfected with human SSTR2 and SSTR5 receptors. SSAs signal transduction effects (cAMP concentrations) were measured in forskolin-treated cells in the presence of SSAs. Proliferation and apoptotic effects were determined and binding assays were performed using 125I- somatostatin-14. RESULTS: AP102 has comparable affinity and agonist effect to octreotide at SSTR2 (IC50's of 112 pM and 244 pM, respectively; EC50's of 230 pM and 210 pM, respectively) in contrast to pasireotide that exhibits a 12-27 fold higher IC50 (3110 pM) and about 5-fold higher EC50 (1097 pM). At SSTR5, AP102 has much higher affinity and stimulating effect than octreotide (IC50's of 773 pM and 16,737 pM, respectively; EC50's of 8526 pM and 26,800 pM), and an intermediate affinity and agonist effect between octreotide and pasireotide. AP102, octreotide and pasireotide have variable anti-proliferative effects on HEK cells transfected with SSTR2 and SSTR5. CONCLUSION: AP102 is a new SSA that better reduces signaling at SSTR2 than SSTR5 and prevents cell proliferation at both receptors. The euglycaemic effect of AP102 observed in preclinical studies may be related to this intermediate agonistic potency between pasireotide and octreotide at SSTR2 and SSTR5. PMID- 29523356 TI - Factors associated with prescription opioid misuse in adults aged 50 or older. AB - BACKGROUND: Although prescription opioid misuse in older adults results in serious health complications, this issue has been overlooked. PURPOSE: This study aimed to describe the prevalence of prescription opioid misuse and identify factors associated with misuse in adults aged 50 years or older. METHODS: This study used a cross-sectional design with a convenience sample. One hundred and thirty patients with chronic pain aged 50 years or older, taking prescription opioids, participated in the study. FINDINGS: Approximately 35% of the participants misused their prescription opioids. Factors associated with opioid misuse included age (younger), level of education (higher), level of depression (moderate level), alcohol use problem, illicit drug use, and a higher level of pain interference on walking ability and normal walk. Significant predictors of opioid misuse included education, illicit drug use, depression, and pain interference with normal work. DISCUSSION: Our study provided important information to health-care providers about identifying high-risk older adults. PMID- 29523358 TI - Injury patterns of child abuse: Experience of two Level 1 pediatric trauma centers. AB - PURPOSE: This study examines non-accidental trauma (NAT) fatalities as a percentage of all injury fatalities and identifies injury patterns in NAT admissions to two level 1 pediatric trauma centers. METHODS: We reviewed all children (<5years old) treated for NAT from 2011 to 2015. Patient demographics, injury sites, and survival were obtained from both institutional trauma registries. RESULTS: Of 4623 trauma admissions, 557 (12%) were due to NAT. However, 43 (46%) of 93 overall trauma fatalities were due to NAT. Head injuries were the most common injuries sustained (60%) and led to the greatest increased risk of death (RR 5.1, 95% CI 2.0-12.7). Less common injuries that increased the risk of death were facial injuries (14%, RR 2.9, 95% CI 1.6-5.3), abdominal injuries (8%, RR 2.8, 95% CI 1.4-5.6), and spinal injuries (3%, RR 3.9, 95% CI 1.8-8.8). Although 76% of head injuries occurred in infants <1year, children ages 1-4years old with head injuries had a significantly higher case fatality rate (27% vs. 6%, p<0.001). CONCLUSION: Child abuse accounts for a large proportion of trauma fatalities in children under 5years of age. Intracranial injuries are common in child abuse and increase the risk of death substantially. Preventing NAT in infants and young children should be a public health priority. TYPE OF STUDY: Retrospective Review. LEVEL OF EVIDENCE: II. PMID- 29523359 TI - The glucagon like peptide-2 'axis': Capacity for production and response following intestinal resection or repair of gastroschisis in infants. AB - PURPOSE: This study investigates the relationship between the enteric hormone glucagon-like peptide 2 (GLP-2) production, sensitivity, and intestinal adaptation in infants following resection or repair of gastroschisis. METHODS: With IRB approval (UCalgary #10656), consent was obtained from families of infants undergoing surgery for prospective monitoring of nutritional status, GLP 2 levels, and where possible, tissue sampling. RESULTS: Infants who adapted and weaned from parenteral nutrition (PN) had increased GLP-2 (86+/-32) n=24 vs. controls: 45+/-20 n=10 and vs. patients on prolonged PN: 42+/-6 pM, n=10). This was maintained to one year: weaned patients: 72+/-49 vs. non-weaned: 35+/-15 pM (p<0.05). Infants with gastroschisis (n=33) had decreased GLP-2 levels until enteral function was achieved and then became elevated: (21+/-15 with first feeding vs. 102+/-60 at full feeds and 60+/-19 pM at one year). There were no changes in the density or distribution of GLP-2 producing L-cells related to gestational age, nor in the expression of the GLP-2 receptor. CONCLUSION: GLP-2 levels correlate with intestinal adaptation in infants, and with recovery of intestinal function in gastroschisis. GLP-2 productive capacity (L-cell expression) and GLP-2 receptor expression do not vary with maturity. The findings support a role for GLP-2 in regulating intestinal function. Further study is suggested. PMID- 29523360 TI - Public Health England's Migrant Health Guide: an online resource for primary care practitioners. AB - Approximately 13% of the UK population in 2015 was born overseas. Most migrants have come to the UK to work or study although there has been a small increase in the number of asylum applications in the UK in recent years, reflective of the ongoing humanitarian situation across Europe. Migrants in the UK tend to be young and healthy, but some may face unique health needs as a result of their experiences before, during and after migration. For these needs to be appropriately recognised and addressed, evidence-based advice is needed for UK professionals. The Migrant Health Guide is a free online tool for healthcare professionals. It was launched in 2011 and is widely used in the UK and internationally. It has four sections: 1) Migrants and the NHS-information on access and entitlements to the National Health Service (NHS); 2) Assessing patients-includes a checklist for initial healthcare assessments and advice for patients travelling abroad to visit friends and relatives; 3) Countries-country specific advice on infectious diseases, women's health and nutritional and metabolic concerns; and 4) Health topics-information about communicable and non communicable diseases and other health issues. The guide has undergone an extensive update in 2017. In particular, the pages on mental health and human trafficking have been expanded. A formal evaluation will obtain feedback on the guide and measure changes in awareness, knowledge, opinions, attitudes and behaviour of end users. Findings will inform future revisions and updates to the guide. Public Health England's Migrant Health Guide is a valuable resource for healthcare professionals. The relaunched guide builds on the previous version in raising awareness of key issues and providing evidence-based advice to improve the health of migrants and refugees internationally and in the UK. PMID- 29523361 TI - Melatonin mitigates bisphenol A-induced estradiol production and proliferation by porcine ovarian granulosa cells in vitro. AB - Melatonin plays a crucial role in the amelioration of reproductive toxicity induced by endocrine-disrupting chemicals. However, very few studies have investigated the mitigating effects of melatonin on BPA-induced dysfunction in porcine granulosa cells. In the present study, primary granulosa cells were cultured in serum-low conditions with bisphenol A (BPA) (10 MUM) with or without melatonin (100 MUM), followed by evaluation of estradiol synthesis and cell proliferation. Our results showed that BPA significantly increased estradiol concentration and granulosa cell proliferation. Interestingly, melatonin co incubation reduced the high levels of estradiol in porcine ovarian granulosa cells induced by BPA stimulation. Furthermore, melatonin co-incubation also attenuated BPA-induced proliferation as shown by a decline in the Ki67-positive cell ratio and PCNA expression level. However, treatment with melatonin-alone did not dramatically reduce estradiol levels or expression of proliferative regulatory protein markers (Ki67, PCNA). We hypothesize that the regulation by melatonin of estradiol biosynthesis and cellular proliferation is highly correlated with BPA stimulation. In conclusion, this study first showed that melatonin mitigated BPA-induced estradiol increase and proliferation in porcine ovarian granulosa cells in vitro. Our results suggest that melatonin may be a promising pharmacologic agent for preventing the potential reproductive toxicity caused by endocrine-disrupting chemicals. PMID- 29523362 TI - Recruitment of patients into head and neck clinical trials: acceptability of studies to patients from perspective of the research team. AB - We reviewed longitudinal recruitment data to assess recruitment into head and neck cancer trials, and to identify factors that could influence this and affect their acceptability to patients. We retrieved data from the prospective computerised database (2009-2016) to measure acceptability to patients using the recruitment:screening ratio, and compared observational with interventional studies, single specialty (or site) with multispecialty (or site) studies, and "step-up" randomisation with "non-inferiority" randomisation designs. A total of 1283 patients were screened and 583 recruited. The recruitment:screening ratio for all National Institute for Health Research (NIHR) portfolio studies combined was 0.47 (486/1133). Studies that involved treatment by several specialties or at several sites had a significantly adverse impact on acceptability (p=0.01). Recruitment into non-inferiority randomised controlled studies was lower than that into step-up randomised studies (p=0.06). The complexity of a study's design did not compromise recruitment. Treatment across several specialties or several sites and perceived non-inferiority designs, reduced the acceptability of some trials. PMID- 29523363 TI - Patient internet health resource utilization prior to emergency department visits. PMID- 29523364 TI - Implementing the MOLST (medical orders for life-sustaining treatments): Challenges faced by nursing home staff. AB - This study examined how the Medical Orders for Life-sustaining Treatment (MOLST) is implemented in two nursing homes in Massachusetts; one had primarily long-term care residents and high hospice utilization, the other had low hospice utilization and a high proportion of post-acute care residents. Qualitative in person interviews with 21 staff members who had a role implementing the MOLST explored their experiences using the form in their daily work routines. Staff at both nursing homes described benefits of the MOLST such as providing guidance for staff and family. Yet, they also gave detailed accounts of challenges they face in implementing the form. They reported problems with the form itself such as confusing language and conflicting categories as well as a set of procedural challenges that undermined the timely completion of the form. The nursing home with more post-acute care residents faced more challenges with transferability of the MOLST to and from hospitals. PMID- 29523365 TI - Koch Postulate: Why Should we Grow Bacteria? PMID- 29523366 TI - Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. AB - CONTEXT: Initial treatment for most bladder cancers (BCs) involves transurethral resection (TUR) or tumours. Often more cancer is found after the initial treatment in around half of patients, requiring a second resection. Repeat transurethral resection (reTUR) is recommended for high-risk, non-muscle-invasive bladder cancer (NMIBC) to remove any residual disease and improve cancer outcomes. OBJECTIVE: To systematically review the practice and therapeutic benefit of an early reTUR for high-risk NMIBC. EVIDENCE ACQUISITION: A systematic review of original articles was performed using PubMed/Medline and Web of Science databases in December 2016 (initial) and October 2017 (final). We searched the references of included papers. EVIDENCE SYNTHESIS: We screened 15 209 manuscripts and selected 31 detailing 8409 persons with high-grade Ta and T1BC for inclusion. Detrusor muscle was found at initial TUR histology in 30-100% of cases. Residual tumour at reTUR was found in 17-67% of patients following Ta and in 20-71% following T1 cancer. Most residual tumours (36-86%) were found at the original resection site. Upstaging occurred in 0-8% (Ta to >=T1) and 0-32% (T1 to >=T2) of cases. Conflicting data report the impact of reTUR on subsequent recurrence and cancer-specific mortality. Recurrence for Ta was 16% in the reTUR group versus 58% in the non-reTUR group. For T1, recurrence ranged from 18% to 56%, but no clear trend was identified between reTUR and control. No clear relationship between reTUR and progression was found for Ta, although for T1 rates were higher in the non-reTUR group in series with control populations (5/6 studies). Overall mortality was slightly reduced in the reTUR group in two studies with controls (22-30% vs 26-36% [no reTUR]). CONCLUSIONS: Residual tumour is common after TUR for high-risk NMIBC. The reTUR helps in the diagnosis of this residual cancer and may improve outcomes for cancers initially staged as T1. PATIENT SUMMARY: Some bladder cancers (BCs) are aggressive but confined to the bladder surface. Initial treatment includes endoscopic resection. More cancer is found after the initial treatment in approximately half of patients. In the aggressive but confined group of BC, a second resection, a few weeks after the first, may help find this residual cancer and improve outcomes, although the evidence quality for this is weak. PMID- 29523367 TI - [Delayed pseudoaneurysm of deep femoral artery after surgical intervention of hip fracture. Presentation of a case]. AB - The diagnosis of pseudoaneurysm of the deep femoral artery as a late complication after orthopaedic surgery is uncommon. The causes of the injury of the artery may be due to the intervention technique itself (mainly the orthopaedic materials or the use of clips), and less frequently by fragments displaced by the trochanter. A case of pseudoaneurysm of the deep femoral artery by a less displaced trochanter fragment is presented in this article, showing how the different professionals interacted, and with the intervention of specialists in angioradiology to resolve it. PMID- 29523368 TI - Targeted Therapies and Immunotherapy for Gynecologic Malignancies: Living Longer, Living Better With Noncytotoxic Options in Recurrent Disease. PMID- 29523369 TI - Corrigendum to 'Effects of Delayed-release Dimethyl Fumarate (DMF) on Health related Quality of Life in Patients With Relapsing-remitting Multiple Sclerosis: An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies: [Clinical Therapeutics 36 (2014) 1958-1971]. PMID- 29523371 TI - Opportunities for Prevention and Intervention of Opioid Overdose in the Emergency Department. PMID- 29523370 TI - Physiologic facet capsule stretch can induce pain & upregulate matrix metalloproteinase-3 in the dorsal root ganglia when preceded by a physiological mechanical or nonpainful chemical exposure. AB - BACKGROUND: Neck pain from cervical facet loading is common and induces inflammation and upregulation of nerve growth factor (NGF) that can sensitize the joint afferents. Yet, the mechanisms by which these occur and whether afferents can be pre-conditioned by certain nonpainful stimuli are unknown. This study tested the hypothesis that a nonpainful mechanical or chemical insult predisposes a facet joint to generate pain after a later exposure to typically nonpainful distraction. METHODS: Rats were exposed to either a nonpainful distraction or an intra-articular subthreshold dose of NGF followed by a nonpainful distraction two days later. Mechanical hyperalgesia was measured daily and C6 dorsal root ganglia (DRG) tissue was assayed for NGF and matrix metalloproteinase-3 (MMP-3) expression on day 7. FINDINGS: The second distraction increased joint displacement and strains compared to its first application (p = 0.0011). None of the initial exposures altered behavioral sensitivity in either of the groups being pre-conditioned or in controls; but, sensitivity was established in both groups receiving a second distraction within one day that lasted until day 7 (p < 0.024). NGF expression in the DRG was increased in both groups undergoing a pre conditioning exposure (p < 0.0232). Similar findings were observed for MMP-3 expression, with a pre-conditioning exposure increasing levels after an otherwise nonpainful facet distraction. INTERPRETATION: These findings suggest that nonpainful insults to the facet joint, when combined, can generate painful outcomes, possibly mediated by upregulation of MMP-3 and mature NGF. PMID- 29523372 TI - Effectiveness of an Arthroscopic Technique to Correct Supination Losses of 90 degrees or More. AB - PURPOSE: To present a new arthroscopic method for treating supination losses. METHODS: Six patients (15-71 y) were eligible for this study. All had a history of trauma to the wrist more than 6 months previously. Five of them had sustained a distal radius fracture: 3 had been treated with a volar plate (1 of them for an extra-articular malunion), 1 with an external fixator and K-wires, and 1 had been treated in a cast. One of these patients underwent a further operation for correcting an intra-articular malunion. The last patient underwent an open reduction of a transscaphoid perilunate dislocation. During a standard radiocarpal arthroscopy, a curved periosteal elevator was inserted through the 6R portal into the volar-radial corner of the triangular fibrocartilage complex and advanced proximally gliding on the anterior ulnar head surface. The volar capsule was then distended with the periosteal elevator and by means of gentle sweeping motion adherences between them, the volar capsule and the ulnar head were freed. Finally, the arthroscopic release was combined with a gentle passive supination force applied by the surgeon. Full supination was maintained in an orthosis for 2 to 3 days. Afterward, regular physical therapy was instituted. Concomitant surgery, arthroscopic or open, was performed in all to treat associated conditions. RESULTS: Full supination (90 degrees ) was achieved in all intraoperatively. At a mean follow-up of 3.3 years, mean supination was 76 degrees in the latest follow-up (range, 50 degrees to 90 degrees ). Mean improvement in supination was 80 degrees (range, 50 degrees to 100 degrees ). No distal radioulnar instability or other complications were noted. CONCLUSIONS: The method presented proved effective in severe forms of supination deficits. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 29523373 TI - The Effect of Triangular Fibrocartilage Complex Tear on Wrist Proprioception. AB - PURPOSE: This study examined the influence of triangular fibrocartilage complex (TFCC) deep fiber tears on wrist proprioception. METHODS: The study involved 48 subjects: 24 with deep fiber TFCC tears and 24 with healthy wrists. A specially created sensor measured wrist proprioception in 3 axes of movement. Absolute differences between target and subject-reproduced angles were compared in injured and healthy wrists and in injured and contralateral patient wrists. A greater difference in reproduced angles was deemed to reflect a lesser ability to approximate a target angle. RESULTS: In wrists with TFCC injuries, 40 degrees pronation and 60 degrees pronation showed significantly greater differences between target and subject-reproduced angles compared with those in the control wrists. In wrists with TFCC injuries, 40 degrees pronation demonstrated significantly greater differences between target and subject-reproduced angles than did those in patients' contralateral wrists. Proportions of outliers with absolute differences greater than 6 degrees were significantly higher in 60 degrees supination and 40 degrees pronation in wrists with TFCC injuries. CONCLUSIONS: Deep TFCC fiber detachment may lead to decreased wrist proprioception in 60 degrees and 40 degrees forearm rotation. CLINICAL RELEVANCE: Deep TFCC fiber tear may contribute to decreased wrist rotational positioning sense and may have biomechanical importance in distal radioulnar joint stability. PMID- 29523374 TI - The Long-Term Outcome After Early and Late Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To compare long-term clinical and radiographic outcomes in patients undergoing either early (group A) or late (group B) surgery after anterior cruciate ligament (ACL) injury. METHODS: ACL reconstruction using hamstring tendon autografts was performed in 30 patients in group A (median age, 23 years; range, 17-49 years) and 31 patients in group B (median age, 27 years; range, 17 38 years). The patients in group A were operated on within 5 months (median, 3 months; range, 2-5 months) of injury, whereas those in group B were operated on more than 24 months (median, 30 months; range, 24-48 months) after injury. The follow-up period was 10 years (median, 117 months [range, 77-222 months] in group A and 129 months [range, 77-206 months] in group B; P = .44). Multiple objective clinical evaluation tests and patient-reported outcome measures were obtained preoperatively and at follow-up. At follow-up, radiographic assessments of knee osteoarthritis (OA) bilaterally were performed. RESULTS: The frequency of meniscectomy at the index operation was significantly lower in group A (20%) than in group B (52%) (P = .01). There were no significant differences between the groups in terms of Tegner and Lysholm scores and laxity tests both preoperatively and at follow-up. Both groups improved over time in terms of Tegner and Lysholm scores (P < .05). At follow-up, significantly more medial-compartment OA in the index knee was found in group B than in group A (P = .037) according to the Ahlback classification system. The index knee showed significantly more OA than the contralateral knee in both groups (P < .01). CONCLUSIONS: Patients who underwent early ACL reconstruction required significantly fewer meniscectomies at the index operation than patients who underwent late reconstruction and showed significantly less OA on the medial side of the knee 10 years after reconstruction. However, no significant differences were found between the groups in terms of clinical assessments. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29523375 TI - Heyde syndrome: Correction of anemia after aortic valve replacement in a hemodialysis patient. PMID- 29523376 TI - Acute renal failure and severe neurotoxicity after unintentional overdose of valacyclovir in a geriatric population: A case report. PMID- 29523377 TI - Extrapulmonary Tumors and Sarcoidosis. An Incidental or Real association? PMID- 29523378 TI - Recent developments and key barriers to advanced biofuels: A short review. AB - Biofuels are regarded as one of the most viable options for reduction of CO2 emissions in the transport sector. However, conventional plant-based biofuels (e.g., biodiesel, bioethanol)'s share of total transportation-fuel consumption in 2016 was very low, about 4%, due to several major limitations including shortage of raw materials, low CO2 mitigation effect, blending wall, and poor cost competitiveness. Advanced biofuels such as drop-in, microalgal, and electro biofuels, especially from inedible biomass, are considered to be a promising solution to the problem of how to cope with the growing biofuel demand. In this paper, recent developments in oxy-free hydrocarbon conversion via catalytic deoxygenation reactions, the selection of and lipid-content enhancement of oleaginous microalgae, electrochemical biofuel conversion, and the diversification of valuable products from biomass and intermediates are reviewed. The challenges and prospects for future development of eco-friendly and economically advanced biofuel production processes also are outlined herein. PMID- 29523379 TI - [Anemia, a new severity factor in young infants with acute viral bronchiolitis?] AB - INTRODUCTION: The role of anemia is raised as a risk of low respiratory infection of the child, but there are no data on anemia as a severity factor in acute viral bronchiolitis (AVB) in infants. METHODS: All infants less than 16 weeks old admitted to Montpellier University Hospital from 2015/10/01 to 2016/04/01 for AVB were included in a retrospective observational study. The primary objective was to determine whether the hemoglobin (Hb) concentration on admission was an independent factor of clinical severity, judged by the modified Wood's clinical asthma score (m-WCAS). The secondary objective was to assess the impact of Hb level on the characteristics of hospitalization, including the type and duration of respiratory support. RESULTS: The m-WCAS was used at least once during hospitalization in 180 out of 220 patients (82%), making it possible to distinguish patients with mild AVB (maximum m-WCAS<2, n=81) from patients with severe AVB (maximum m-WCAS>2, n=99). A logistic regression model indicated that the Hb concentration, for every 1g/dL decrement, was an independent factor of AVB severity (OR 1.16 [1.03-1.29], P=0.026). A level under 10g/dL on admission was associated with a higher use of continuous positive airway pressure (P<0.001), as well as a longer duration of respiratory support (P=0.01). CONCLUSION: This study suggested that anemia may influence the clinical expression of AVB in young infants. PMID- 29523380 TI - Outcome of children born after pregnancy denial. AB - INTRODUCTION: Denial of pregnancy remains a phenomenon little known to healthcare professionals. Yet its repercussions are far from negligible. The aim of this study was to assess whether denial of pregnancy has an impact on the infant's development. PATIENTS AND METHOD: This prospective study included 51 full-term infants born in Nancy Regional Maternity Hospital between 1 January 2009 and 30 June 2015. In this study, the development of the children was followed longitudinally. We collected data during the neonatal period, at 9months, and at 2years of age from the infants' file and standardized medical certificates, and current data through a telephone questionnaire. Three fundamental aspects of the infants' development were analyzed: height and weight growth, psychomotor development, and the existence of pathologies. Given that this was a preliminary study aiming at exploring facts, no statistical tests were carried out. RESULTS: The rate of denial of pregnancy was one birth in 300 during the study period. These infants showed proportional intrauterine growth restriction, which leveled out later, with their height and weight growth normal by month 9. The full-term perinatal mortality rate was 5%. The infants showed no sign of increased morbidity; 20% of them presented with delayed psychomotor development at 9months of age, with an increased impact as they grew older. The rate reached 30% after 24months, half of which were language disorders. CONCLUSION: The results of this preliminary study point out the need for thorough monitoring of these infants throughout infancy. PMID- 29523381 TI - Iatrogenic trigeminal post-traumatic neuropathy: a retrospective two-year cohort study. AB - With the growing demand for dental work, trigeminal nerve injuries are increasingly common. This retrospective cohort study examined 53 cases of iatrogenic trigeminal nerve injury seen at the Department of Oral and Maxillofacial Surgery, University Hospitals of Leuven between 2013 and 2014 (0.6% among 8845 new patient visits). Patient records were screened for post-traumatic trigeminal nerve neuropathy caused by nerve injury incurred during implant surgery, endodontic treatment, local anaesthesia, tooth extraction, or specifically third molar removal. The patients ranged in age from 15 to 80years (mean age 42.1years) and 68% were female. The referral delay ranged from 1day to 6.5years (average 10months). The inferior alveolar nerve (IAN) was most frequently injured (28 cases), followed by the lingual nerve (LN) (21 cases). Most nerve injuries were caused during third molar removal (24 cases), followed by implant placement (nine cases) and local anaesthesia injuries (nine cases). Pain symptoms were experienced by 54% of patients suffering IAN injury, compared to 10% of patients with LN injury. Persistent neurosensory disturbances were identified in 60% of patients. While prevention remains the key issue, timely referral seems to be a critical factor for the successful treatment of post traumatic neuropathy. PMID- 29523382 TI - The comparative pharmacokinetic study of Yuanhu Zhitong prescription based on five quality-markers. AB - BACKGROUND: According to the compatibility theory, therapeutic effects of Chinese medicine prescription are generally attributed to the synergism of multi-herbs. Quality-markers, as the crucial effective components, play a key role in the interaction of compatibility. Pharmacokinetic studies could illustrate the interaction between multiple components in dynamics perspective. PURPOSE: This study aims to establish a rapid, reliable and sensitive ultra performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous determination of corydaline, tetrahydropalmatine, protopine, imperatorin and isoimperatorin (quality-markers of Yuanhu Zhitong prescription) in rat plasma, and then applied to the comparative pharmacokinetic study for clearing the interaction of compatibility in Yuanhu Zhitong prescription. METHODS: Five quality-markers were separated on a Waters Acquity UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 um) by gradient elution with 0.1% formic acid-water and 0.1% formic acid-acetonitrile. Detection was performed in the positive ionization and multiple reaction monitoring mode. The analytical method was validated and successfully applied to the comparative pharmacokinetic study after oral administration of Yuanhu Zhitong prescription and single-herb extracts. RESULTS: Calibration curves showed good linearity over the concentration ranges of 0.25 500 ng/ml for corydaline, tetrahydropalmatine and isoimperatorin, 0.1-200 ng/ml for protopine, and 0.5-500 ng/ml for imperatorin, respectively. Compared with Rhizoma corydalis group, AUC0-t and AUC0-infinity significantly increased (p < 0.01 for corydaline and tetrahydropalmatine, and p < 0.05 for protopine) after oral administration of Yuanhu Zhitong prescription extract. Meanwhile, Cmax of corydaline and tetrahydropalmatine increased remarkably, from 93.00 ug/l to 196.35 ug/l for corydaline (p < 0.05) and 181.62 ug/l to 311.22 ug/l for tetrahydropalmatine (p < 0.01). In addition, MRT0-t and MRT0-infinity of corydaline, as well as Tmax of protopine in Yuanhu Zhitong prescription group were obviously delayed compared to Rhizoma corydalis group (p < 0.01). CONCLUSION: These achieved results indicated that the compatibility of Rhizoma corydalis and Radix Angelicae dahuricae lead to greater absorption of corydaline, tetrahydropalmatine and protopine, which would be help to better understand the compatibility mechanism of Yuanhu Zhitong prescription. PMID- 29523383 TI - The Impact of Vocal and Laryngeal Pathologies Among Professional Singers: A Meta analysis. AB - OBJECTIVE: Professional singers are more likely to develop laryngeal pathologies and symptoms associated with misuse and overuse of the voice. However, different studies have shown conflicting evidence. We aim to perform a systematic review and quantitative meta-analysis to determine the prevalence and risk of laryngeal pathologies and symptoms among professional singers. METHODS: Four electronic databases (MEDLINE, PubMed, EMBASE, and CINAHL) were searched, with no language restrictions. From 3368 potential studies, a total of 21 studies met our inclusion criteria. A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. All cohort, case-control, or cross-sectional studies that reported the risk of laryngeal pathologies in singers were included. Data were pooled by a random effects model and the pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: There was a positive relationship between singing and laryngeal pathologies. There was an increased risk of hoarseness (OR: 2.00, 95% CI: 1.61-2.49), gastroesophageal reflux disease (GERD) (OR: 1.45, 95% CI: 1.19-1.77), Reinke edema (OR: 2.15, 95% CI: 1.08-4.30), and polyps (OR: 2.10, 95% CI: 1.06-4.14) in professional singers. CONCLUSION: Professional singers are at an increased risk of laryngeal pathologies and symptoms associated with vocal misuse and overuse, particularly hoarseness, GERD, edema, and polyps. PMID- 29523384 TI - Application and development of genome editing technologies to the Solanaceae plants. AB - Genome editing technology using artificial nucleases, including zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regulatory interspaced short palindromic repeats (CRISPR)-Cas9, can mutagenize the target sites of genes of interest. This technology has been successfully applied in several crops, including the Solanaceae plants, such as tomato, potato, tobacco, and petunia. Among the three nucleases, CRISPR-Cas9 is the best for breeding, crop improvement, and the functional analysis of genes of interest, because of its simplicity and high efficiency. Although the technology is useful for reverse genetics, its use in plants is limited due to a lack of regeneration protocols and sequence information. In this review, the present status of genome editing technology in Solanaceae plants is described, and techniques that may improve genome editing technologies are discussed. PMID- 29523385 TI - Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors. AB - Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome. PMID- 29523386 TI - The effects of zinc supplementation on primary human retinal pigment epithelium. AB - Population-based and interventional studies have shown that elevated zinc levels can reduce the progression to advanced age-related macular degeneration. The objective of this study was to assess whether elevated extracellular zinc has a direct effect on retinal pigment epithelial cells (RPE), by examining the phenotype and molecular characteristics of increased extracellular zinc on human primary RPE cells. Monolayers of human foetal primary RPE cells were grown on culture inserts and maintained in medium supplemented with increasing total concentrations of zinc (0, 75, 100, 125 and 150 MUM) for up to 4 weeks. Changes in cell viability and differentiation as well as expression and secretion of proteins were investigated. RPE cells developed a confluent monolayer with cobblestone morphology and transepithelial resistance (TER) >200 Omega*cm2 within 4 weeks. There was a zinc concentration-dependent increase in TER and pigmentation, with the largest effects being achieved by the addition of 125 MUM zinc to the culture medium, corresponding to 3.4 nM available (free) zinc levels. The cells responded to addition of zinc by significantly increasing the expression of Retinoid Isomerohydrolase (RPE65) gene; cell pigmentation; Premelanosome Protein (PMEL17) immunoreactivity; and secretion of proteins including Apolipoprotein E (APOE), Complement Factor H (CFH), and High Temperature Requirement A Serine Peptidase 1 (HTRA1) without an effect on cell viability. This study shows that elevated extracellular zinc levels have a significant and direct effect on differentiation and function of the RPE cells in culture, which may explain, at least in part, the positive effects seen in clinical settings. The results also highlight that determining and controlling of available, as opposed to total added, zinc will be essential to be able to compare results obtained in different laboratories. PMID- 29523387 TI - Research on the advancement of standards and specifications of biologics in Korea. PMID- 29523388 TI - Phyllodes tumors of the breast: The British Columbia Cancer Agency experience. AB - PURPOSE: Phyllodes tumors of the breast are uncommon fibroepithelial lesions for which optimal management remains unclear. This retrospective population-based study reports treatment and outcomes for patients with phyllodes tumors and evaluates characteristics that influence outcome. MATERIALS AND METHODS: Data were analysed on 183 patients with newly diagnosed phyllodes tumors from 1999 to 2014. Five-year Kaplan-Meier local recurrence and survival were compared between cohorts with benign (n=83), borderline (n=50) and malignant phyllodes tumor (n=49) histology. RESULTS: Median (range) follow-up was 65 (0.5-197) months. Local excision was performed in 163 and mastectomy in 19 patients. Eleven patients with malignant phyllodes tumors received radiation therapy. Overall, local recurrence occurred in 8.7%, distant metastases in 4.4%, and cause specific deaths in 3.8%. Five-year Kaplan-Meier outcomes among women with benign, borderline, and malignant phyllodes tumors were: local recurrence 6% vs 9% vs 21%, P=0.131; overall survival 96% vs 100% vs 82%, P=0.002; and disease-free survival 94% vs 91% vs 67%, P<0.001. Five-year Kaplan-Meier local recurrence among women with negative vs close vs positive margins were 8% vs 6% vs 37%, P<0.001. Corresponding rates for intermediate vs pushing vs infiltrative borders were 6% vs 6% vs 33%, P=0.006. Positive margins and infiltrative tumor borders were associated with increased local recurrence (all P<=0.006), and the latter remained significant in exploratory analyses after adjusting for margin status and phyllodes tumor classification. CONCLUSIONS: Five-year outcomes among women with phyllodes tumors were comparable to those reported in the literature. Exploratory analysis has suggested that infiltrative tumor borders may be used in conjunction with margin status to assess local recurrence risk. PMID- 29523389 TI - Postural tachycardia syndrome - Diagnosis, physiology, and prognosis. AB - Postural tachycardia syndrome (POTS) is a heterogeneous clinical syndrome that has gained increasing interest over the past few decades due to its increasing prevalence and clinical impact on health-related quality of life. POTS is clinically characterized by sustained excessive tachycardia upon standing that occurs in the absence of significant orthostatic hypotension and other medical conditions and or medications, and with chronic symptoms of orthostatic intolerance. POTS represents one of the most common presentations of syncope and presyncope secondary to autonomic dysfunction in emergency rooms and in cardiology, neurology, and primary care clinics. The most sensitive method to detect POTS is a detailed medical history, physical examination with orthostatic vital signs or brief tilt table test, and a resting 12-lead electrocardiogram. Additional diagnostic testing may be warranted in selected patients based on clinical signs. While the precise etiology remains unknown, the orthostatic tachycardia in POTS is thought to reflect convergence of multiple pathophysiological processes, as a final common pathway. Based on this, POTS is often described as a clinical syndrome consisting of multiple heterogeneous disorders, with several underlying pathophysiological processes proposed in the literature including partial sympathetic neuropathy, hyperadrenergic state, hypovolemia, mast cell activation, deconditioning, and immune-mediated. These clinical features often overlap, however, making it difficult to categorize individual patients. Importantly, POTS is not associated with mortality, with many patients improving to some degree over time after diagnosis and proper treatment. This review will outline the current understanding of diagnosis, pathophysiology, and prognosis in POTS. PMID- 29523390 TI - Pseudodiverticular exophytic growth of a GIST of the jejunum with focus on imaging. PMID- 29523391 TI - Value of ictal and interictal epileptiform discharges and high frequency oscillations for delineating the epileptogenic zone in patients with focal cortical dysplasia. AB - OBJECTIVES: There are different neurophysiological markers of the Epileptogenic Zone (EZ), but their sensitivity and specificity for the EZ is not known in Focal Cortical Dysplasia (FCD) patients. METHODS: We studied patients with FCD who underwent stereoelectroencephalography (SEEG) and surgery. We marked in the SEEG: (a) typical and atypical interictal epileptiform patterns, (b) ictal onset patterns, and (c) rates of ripples (80-250 Hz) and fast ripples (FRs) (>250 Hz). High frequency oscillations were marked automatically during one hour of deep sleep. Surgical outcome was defined as good (Engel I) or poor (Engel II-IV). We computed the sensitivity and, as a measure of specificity, the false positive rate to identify the EZ, and compared them across the different neurophysiological markers. RESULTS: We studied 21 patients, 19 with FCD II. Ictal and typical interictal pattern were the markers with highest sensitivity, while the atypical interictal pattern had the lowest. We found no significant difference in specificity among markers. However, there is a tendency that FRs had the lowest false positive rate. CONCLUSION: The typical interictal pattern has the highest sensitivity. The clinical use of FRs is limited by their low sensitivity. SIGNIFICANCE: We suggest to analyze the typical interictal pattern first. FRs should be analyzed in a second step. If, for instance, a focus with FRs and no typical interictal pattern is found, this area could be considered for resection. PMID- 29523392 TI - Endometriosis, endometrioma, and ART results: Current understanding and recommended practices. AB - Endometriosis and infertility are linked in a complex relationship, and a number of different pathogenetic mechanisms may associate the two. Endometriosis is diagnosed in 6-8% of women undergoing ART. Women with endometriosis appear to have similar ART outcomes compared to controls in terms of live birth rates, despite a lower oocyte quality. Laparoscopy should not be routinely performed before ART with the only aim to diagnose mild or moderate endometriosis, but if the latter is found, surgical removal can be considered, as it might improve pregnancy rates. In case of more severe forms of the disease (endometrioma and deep infiltrating endometriosis), the benefits of surgery before ART are uncertain and must be balanced against risks. Management decisions should be individualized based on patient choice, age, associated symptoms, and the risk of repeat surgery. PMID- 29523393 TI - Towards a Natural History of Soil Bacterial Communities. AB - Despite the enormous diversity of bacteria, a recent study reveals that soils are globally dominated by a small list of taxa. Characterizing the traits of these bacteria offers the potential for predicting functional differences among soil communities. PMID- 29523394 TI - Presynaptic striatal dopaminergic depletion predicts the later development of freezing of gait in de novo Parkinson's disease: An analysis of the PPMI cohort. AB - INTRODUCTION: The current study was designed to determine whether the degree of presynaptic striatal dopamine depletion can predict the later development of freezing of gait (FOG) in Parkinson's disease (PD). METHODS: This retrospective cohort study included 390 de novo patients with PD without FOG at baseline. The participants were divided into tertiles according to the baseline dopamine transporter (DAT) uptake of each striatal subregion, and the cumulative risk of FOG was compared using the Kaplan-Meier method. Cox proportional hazard models were used to assess the predictive power of DAT uptake of striatal subregions for the development of FOG. RESULTS: During a median follow-up period of 4.0 years, 143 patients with PD (36.7%) developed FOG. The severe reduction group of DAT uptake in the caudate nucleus and putamen had a significantly higher incidence of FOG than that of the mild and moderate reduction groups. Multivariate Cox regression analyses showed that DAT uptakes in the caudate nucleus (hazard ratio [HR] 0.551; 95% confidence interval [CI] 0.392-0.773; p = 0.001) and putamen (HR 0.441; 95% CI 0.214-0.911; p = 0.027) predicted the development of FOG. In addition, male sex, higher postural instability and gait difficulty score, and a lower Montreal Cognitive Assessment score were also significant predictors of FOG. CONCLUSION: Our finding suggests that presynaptic striatal dopaminergic denervation predicts the later development of FOG in de novo patients with PD, which may provide reliable insight into the mechanism of FOG in terms of nigrostriatal involvement. PMID- 29523395 TI - Exhibiting caution with use of big data: The case of amphetamine in Iceland's prescription registry. AB - BACKGROUND: Data from large electronic databases are increasingly used in epidemiological research, but golden standards for database validation remain elusive. The Prescription Registry (IPR) and the National Health Service (NHS) databases in Iceland have not undergone formal validation, and gross errors have repeatedly been found in Icelandic statistics on pharmaceuticals. In 2015, new amphetamine tablets entered the Icelandic market, but were withdrawn half a year later due to being substandard. Return of unused stocks provided knowledge of the exact number of tablets used and hence a case where quality of the data could be assessed. OBJECTIVE: A case study of the quality of statistics in a national database on pharmaceuticals. METHODS: Data on the sales of the substandard amphetamine were obtained from the Prescription Registry and the pharmaceuticals statistics database. Upon the revelation of discrepancies, explanations were sought from the respective institutions, the producer, and dose dispensing companies. RESULTS: The substandard amphetamine was available from 1.9.2015 until 15.3.2016. According to NHS, 73990 tablets were sold to consumers in that period, whereas IPR initially stated 82860 tablets to have been sold, correcting to 74796 upon being notified about errors. The producer stated 72811 tablets to have been sold, and agreed with the dose dispensing companies on sales to those. The producer's numbers were confirmed by the Medicines Agency. CONCLUSION: Over registration in the IPR was 13.8% before correction, 2.7% after correction, and 1.6% in the NHS. This case provided a unique opportunity for external validation of sales data for pharmaceuticals in Iceland, revealing enormous quality problems. The case has implications regarding database integrity beyond Iceland. PMID- 29523396 TI - To Each his Own. PMID- 29523399 TI - Physical and chemical trigger factors in environmental intolerance. AB - BACKGROUND: Individuals with environmental intolerance (EI) react to exposure from different environmental sources at levels tolerated by most people and that are below established toxicological and hazardous thresholds. The main aim of this study was to determine the prevalence of attributing symptoms to chemical and physical sources in the environment among individuals with different forms of self-reported EI and in referents. METHODS: Cross-sectional data from a population-based study, the Vasterbotten Environmental Health Study (n = 3406), were used and individuals with self-reported EI to chemicals, buildings, electromagnetic fields and sounds as well as a group with multiple EIs were identified. The Environmental-Symptom Attribution Scale was used to quantify degree to which health symptoms are attributed to 40 specific environmental exposures and sources, with subscales referring to the four types of EI. RESULTS: All EI groups, except the group with building related intolerance (BRI), reported more symptoms from the expected sources compared to the referents. In addition, individuals with chemical and sound intolerance reported symptoms from building related trigger factors, and individuals with electromagnetic hypersensitivity reported symptoms from chemical trigger factors. CONCLUSIONS: The study suggests that individuals with BRI react to fewer and more specific trigger factors than do individuals with other EIs, and that it is important to ask about different sources since three of the EI groups attribute their symptoms to a wide variety of sources in addition to the sources to which their EI implicates. PMID- 29523397 TI - 0.9% NaCl (Normal Saline) - Perhaps not so normal after all? AB - Crystalloid infusion is widely employed in patient care for volume replacement and resuscitation. In the United States the crystalloid of choice is often normal saline. Surgeons and anesthesiologists have long preferred buffered solutions such as Ringer's Lactate and Plasma-Lyte A. Normal saline is the solution most widely employed in medical and pediatric care, as well as in hematology and transfusion medicine. However, there is growing concern that normal saline is more toxic than balanced, buffered crystalloids such as Plasma-Lyte and Lactated Ringer's. Normal saline is the only solution recommended for red cell washing, administration and salvage in the USA, but Plasma-Lyte A is also FDA approved for these purposes. Lactated Ringer's has been traditionally avoided in these applications due to concerns over clotting, but existing research suggests this is not likely a problem. In animal models and clinical studies in various settings, normal saline can cause metabolic acidosis, vascular and renal function changes, as well as abdominal pain in comparison with balanced crystalloids. The one extant randomized trial suggests that in very small volumes (2 l or less) normal saline is not more toxic than other crystalloids. Recent evidence suggests that normal saline causes substantially more in vitro hemolysis than Plasma-Lyte A and similar solutions during short term storage (24 hours) after washing or intraoperative salvage. There are now abundant data to raise concerns as to whether normal saline is the safest replacement solution in infusion therapy, red cell washing and salvage, apheresis and similar uses. In the USA, Plasma-Lyte A is also FDA approved for use with blood components and is likely a safer solution for these purposes. Its only disadvantage is a higher cost. Additional studies of the safety of normal saline for virtually all current clinical uses are needed. It seems likely that normal saline will eventually be abandoned in favor of safer, more physiologic crystalloid solutions in the coming years. PMID- 29523398 TI - Different patterns of ovarian recovery after cancer treatment suggest various individual ovarian susceptibilities to chemotherapy. AB - The relationship between early recovery of menstrual activity and blood anti Mullerian hormone (AMH) concentrations were investigated within the first year post-chemotherapy in 32 young patients with breast cancer. All were treated by surgery and the same chemotherapy protocol (three cycles of FEC100 plus three cycles of taxanes). Menstrual activity, blood AMH (using picoAMH ELISA) and FSH concentrations were measured longitudinally before, during and up to 12 months after the end of chemotherapy (six samples per patient). Among the cohort, 17 patients recovered spontaneous cycles at +6 months (fast recovery) whereas the remaining 15 patients were still amenorrheic at that time (slow recovery). Blood AMH differed between these two subgroups at each time of the recovery phase starting at 3 months post-chemotherapy. The AMH patterns were also different: rapid and large increase in the fast recovery versus slow and partial increase in the slow recovery subgroup. No difference in ovarian recovery was observed between patients with a hormone positive or negative tumour. In conclusion, studying the post-chemotherapy patterns of menstrual activity and AMH, two paces of early ovarian recovery are distinguishable in young breast cancer patients who received the same chemotherapy protocol. This suggests different individual ovarian susceptibilities to chemotherapy. PMID- 29523400 TI - Discussion. PMID- 29523401 TI - Predicting pulmonary function after lung resection: Did you account for induction chemoradiation? PMID- 29523402 TI - Expanding the results of the Ross operation. PMID- 29523403 TI - Discussion. PMID- 29523404 TI - Burden of preoperative atrial fibrillation in patients undergoing coronary artery bypass grafting. AB - BACKGROUND: This study compares early and late outcomes in patients undergoing coronary artery bypass grafting with and without preoperative atrial fibrillation in a contemporary, nationally representative Medicare cohort. METHODS: In the Medicare-Linked Society of Thoracic Surgeons database, 361,138 patients underwent isolated coronary artery bypass from 2006 to 2013, of whom 37,220 (10.3%) had preoperative atrial fibrillation; 13,161 (35.4%) were treated with surgical ablation and were excluded. Generalized estimating equations were used to compare 30-day mortality and morbidity. Long-term survival was summarized using Kaplan Meier curves and Cox regression models. Stroke and systemic embolism incidence was modeled using the Fine-Gray model and the CHA2DS2-VASc score was used to analyze stroke risk. Median follow-up was 4 years. RESULTS: Preoperative atrial fibrillation was associated with a higher adjusted in-hospital mortality (odds ratio [OR], 1.5; P < .0001) and combined major morbidity including stroke, renal failure, prolonged ventilation, reoperation, and deep sternal wound infection (OR, 1.32; P < .0001). Patients with preoperative atrial fibrillation experienced a higher adjusted long-term risk of all-cause mortality and cumulative risk of stroke and systemic embolism compared to those without atrial fibrillation. At 5 years, the survival probability in the preoperative atrial fibrillation versus no atrial fibrillation groups stratified by CHA2DS2-VASc scores was 74.8% versus 86.3% (score 1-3), 56.5% versus 73.2% (score 4-6), and 41.2% versus 57.2% (score 7-9; all P < .001). CONCLUSIONS: Preoperative atrial fibrillation is independently associated with worse early and late postoperative outcomes. CHA2DS2-VASc stratifies risk, even in those without preoperative atrial fibrillation. PMID- 29523405 TI - Optimized induction of beta common receptor enhances the neuroprotective function of erythropoietin in spinal cord ischemic injury. AB - BACKGROUND: Paraplegia remains the most feared complication of complex thoracoabdominal aortic intervention. Although erythropoietin (EPO) has demonstrated neuroprotective effects in spinal cord ischemia, it does not work until expression of the beta common receptor subunit of the EPO receptor (betacR) is induced by ischemia. We hypothesized that the betacR can be induced by diazoxide (DZ), amplifying the neuroprotective effects of EPO in spinal cord ischemia-reperfusion injury. METHODS: For the DZ time trial, adult male C57/BL6 mice received DZ (20 mg/kg) by oral gavage. Spinal cords were harvested after 0, 12, 24, 36, and 48 hours of administration. To evaluate optimal dosing, DZ was administered at 0, 5, 10, 20, and 40 mg/kg. The expression of betacR was assessed by Western blot analysis. Five groups were studied: PBS (pretreatment)+PBS (immediately before), PBS+EPO, DZ+PBS, DZ+EPO, and sham (without cross-clamping). Spinal cord ischemia was induced by 4 minutes of thoracic aortic cross-clamping. Functional scoring (Basso Mouse Score) was done at 12-hour intervals for 48 hours, and spinal cords were harvested for histological analysis. RESULTS: Western blot analysis demonstrated that optimal betacR up-regulation occurred at 36 hours after DZ administration, and the optimal DZ dosage for betacR induction was 20 mg/kg. Motor function at 48 hours after treatment was significantly better preserved in the DZ+EPO group compared with all other groups, and was significantly better preserved in the DZ only and EPO only groups compared with control (PBS+PBS). CONCLUSIONS: Pharmacologic up-regulation of betacR with DZ can increase the efficacy of EPO in preventing spinal cord ischemia and reperfusion injury. Improved understanding of this synergetic mechanism may serve to further prevent ischemic complications for high-risk aortic intervention. PMID- 29523406 TI - Discussion. PMID- 29523407 TI - Glycogen synthase kinase 3beta inhibition reduces mitochondrial oxidative stress in chronic myocardial ischemia. AB - OBJECTIVES: Glycogen synthase kinase 3beta (GSK-3beta) inhibition has been reported to increase microvascular density and improve myocardial blood flow in a porcine model of chronic myocardial ischemia and metabolic syndrome. Inhibition of GSK-3beta can also be cardioprotective by modulating fibrosis signaling and mitochondrial-induced apoptosis. We hypothesized GSK-3beta inhibition would have a beneficial effect on myocardial fibrosis and oxidative stress in a porcine model of chronic myocardial ischemia and metabolic syndrome. METHODS: Pigs were fed a high fat diet for 4 weeks followed by placement of an ameroid constrictor to the left circumflex coronary artery. Three weeks later animals received either no drug or a GSK-3beta inhibitor. The diets and placebo/GSK-3beta inhibition were continued for an additional 5 weeks, the pigs were then euthanized, and the myocardial tissue was harvested. Collagen expression was analyzed via Picrosirius staining. Oxidative stress was analyzed via Oxyblot analysis. Protein expression was analyzed via Western blot. RESULTS: GSK-3beta inhibition was associated with decreased collagen expression and oxidative stress in the ischemic and nonischemic myocardial tissue compared with control. There was a decrease in profibrotic proteins transforming growth factor-beta, p-SMAD2/3, and matrix metalloproteinase-9, and in proapoptotic and oxidative stress proteins, apoptosis inducing factor, the cleaved caspase 3/caspase 3 protein ratio and phosphorylated myeloid cell leukemia sequence-1 in the GSK-3beta inhibited group compared with the control. CONCLUSIONS: In the setting of metabolic syndrome and chronic myocardial ischemia, inhibition of GSK-3beta decreases collagen formation and oxidative stress in myocardial tissue. GSK-3beta inhibition might be having this beneficial effect by downregulating transforming growth factor-beta/SMAD2/3 signaling and decreasing mitochondrial induced cellular stress. PMID- 29523408 TI - TG/HDL-C ratio and visceral adiposity index may be useful in assessment of insulin resistance in adults with type 1 diabetes in clinical practice. AB - BACKGROUND: Insulin resistance (IR) is an important clinical issue in patients with type 1 diabetes due to worse metabolic control and risk of development of chronic complications. OBJECTIVE: The aim of the study was to evaluate simple and easily available parameters as indirect markers of IR in adults with type 1 diabetes and correlate it with the results of hyperinsulinemic-euglycemic clamp. METHODS: The study included 88 patients (62 men), aged 34.1 +/- 6.5 years, with type 1 diabetes with a median disease duration of 8 (7-13) years and mean HbA1c of 7.6 +/- 1.5%. Tissue sensitivity to insulin was assessed on the basis of glucose distribution rate (GDR) obtained in the course of hyperinsulinemic euglycemic clamp. In addition, indirect markers of IR, such as estimated GDR, presence of features of metabolic syndrome, visceral adiposity index (VAI), and the triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio, were evaluated. RESULTS: In the study group, IR defined as GDR <4 mg/kg/min was observed in 33 (37.5%) patients. Group with IR had significantly higher postprandial glycemia (9.1 +/- 2.0 vs 8.4 +/- 1.1 mmol/L, P = .04), serum TG level (1.11 [0.75-1.92] vs 0.85 [0.60-1.08] mmol/L, P = .001), lower HDL-C level (1.59 +/- 0.38 vs 1.8 +/- 0.5 mmol/L, P = .02), higher TG/HDL-C ratio (1.60 [1.00 3.13] vs 1.05 [0.62-1.53], P = .001), and higher VAI (2.61 [1.31-4.25] vs 1.56 [0.96-2.25], P = .002). Significant relationship between GDR and TG/HDL-C ratio and VAI, adjusted for age, sex, HbA1c, and duration of diabetes was revealed (respectively, odds ratio 1.90 [95% confidence interval 1.15-3.15], P = .01 and odds ratio 1.47 [95% confidence interval 1.06-2.04], P = .01). CONCLUSIONS: TG/HDL-C ratio and VAI appear to be clinically useful tools to assess IR in adults with type 1 diabetes. PMID- 29523409 TI - DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group. AB - PURPOSE: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. RESULTS: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08 1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. CONCLUSION: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival. PMID- 29523410 TI - An atlas to aid delineation of para-aortic lymph node region in cervical cancer: Design and validation of contouring guidelines. AB - INTRODUCTION: Previous studies have investigated the anatomical distribution of para-aortic lymph nodes (PAN) in patients with cervical cancer. However, an atlas for accurate clinical target volume (CTV) delineation has yet to be defined. The purpose of this study was to design and verify a computerized tomography (CT) atlas to provide guidance for contouring the PAN CTV in patients with cervical cancer. MATERIALS AND METHODS: This prospective study included 21 cervical cancer patients (design cohort) with 39 pathological PAN identified on (18)F-FDG PET-CT. PAN [left lateral para-aortic (LLPA), aorto-caval (AC), right para-caval (RPC) nodes] were delineated on CT simulation scans. Measurements were taken from the volumetric centre of the nodes to the edge of aorta and inferior vena-cava (IVC). Initially the aorta and IVC were expanded by the mean distance to the lymph node centre to create a CTV. Expansion margins were then increased asymmetrically until the CTV resulted in a clinically acceptable number of PAN included. The CTV was validated on a further 10 patients (validation cohort) with 29 PAN. A detailed contouring guide and accompanying visual atlas for elective PAN CTV delineation was created based on the validated margins. RESULTS: For the design cohort (n = 21 patients, 39 PAN), the mean distance from the centre of the node to the aorta was 8 mm (range 4-17) for both LLPA (range 4-17) and AC (range 4-15) regions. Mean distance from the IVC to the centre of the nodes was 5 mm (range 4 6) in the RPC region and 6 mm (range 3-15) in the AC region. No PAN was superior to the T12-L1 interspace or the left renal vein or inferior to the L5-S1 interspace. For validation cohort (n = 10 patients, 29 PAN), mean distance from centre of the node to the aorta was 9 mm (range 5-15) in the LLPA region, 7 mm (range 6.5-14) in the AC region. Mean distance from the ICV to the centre of the nodes was 3 mm (range 2.5-4) in the RPC region and 5 mm (range 3-10) in the AC region. A CTV expansion from the aorta of 10 mm circumferentially and 15 mm laterally, and from the IVC of 8 mm anteromedially and 6 mm posterolaterally resulted in coverage of 97% (38/39) of PAN in the design cohort. On prospective validation, the described CTV included 97% (28/29) of PAN in the validation cohort. CONCLUSION: We propose the following PAN CTV; expansion from aorta of 10 mm circumferentially except 15 mm laterally, expansion from the IVC of 8 mm anteromedial and 6 mm posterolaterally. The suggested CTV includes 97% (28/29) PAN in a validated patient cohort. A detailed guide and accompanying visual atlas is provided to aid delineation of the PAN CTV in patients with cervical cancer. PMID- 29523411 TI - Applying Lean-Six-Sigma Methodology in radiotherapy: Lessons learned by the breast daily repositioning case. AB - BACKGROUND & PURPOSE: Lean Six Sigma Methodology (LSSM) was introduced in industry to provide near-perfect services to large processes, by reducing improbable occurrence. LSSM has been applied to redesign the 2D-2D breast repositioning process (Lean) by the retrospective analysis of the database (Six Sigma). MATERIALS & METHODS: Breast patients with daily 2D-2D matching before RT were considered. The five DMAIC (define, measure, analyze, improve, and control) LSSM steps were applied. The process was retrospectively measured over 30 months (7/2014-12/2016) by querying the RT Record&Verify database. Two Lean instruments (Poka-Yoke and Visual Management) were considered for advancing the process. The new procedure was checked over 6 months (1-6/2017). RESULTS: 14,931 consecutive shifts from 1342 patients were analyzed. Only 0.8% of patients presented median shifts >1 cm. The major observed discrepancy was the monthly percentage of fractions with almost zero shifts (AZS = 13.2% +/- 6.1%). Ishikawa fishbone diagram helped in defining the main discrepancy con-causes. Procedure harmonization involving a multidisciplinary team to increase confidence in matching procedure was defined. AZS was reduced to 4.8% +/- 0.6%. Furthermore, distribution symmetry improvement (Skewness moved from 1.4 to 1.1) and outlier reduction, verified by Kurtosis diminution, demonstrated a better "normalization" of the procedure after the LSSM application. CONCLUSIONS: LSSM was implemented in a RT department, allowing to redesign the breast repositioning matching procedure. PMID- 29523412 TI - Treatment of intraarticular calcaneal fractures by reconstruction plate. Results and complications of 86 fractures. AB - OBJECTIVE: To evaluate the results of surgical treatment of intraarticular calcaneal fractures, and also to analyze the variables that influence the final clinical and radiological outcomes as well as the complications. MATERIAL AND METHODS: We retrospectively analyzed 86 intraarticular calcaneal fractures in 78 patients, who underwent surgery with an extended lateral approach and reconstruction plate. The mean age was 48 years (16-74 years) and the mean follow up was 4.6 years (9-99 months); 54 patients (69.2%) suffered falls from less than 3m in height or banal injuries and 24 patients (30.8%) falls from more than 3m in height or high energy-accidents. According to the Sanders classification we operated 12 (15%) typeII, 54 (62.8%) typeIII and 20 (23.2%) typeIV fractures. RESULTS: The postoperative mean AOFAS score was 73.9 points, with good or excellent results in 57% of the patients. Twelve cases (14%) suffered surgical wound complications and 11 (12.8%) required subtalar arthrodesis. Significantly better results were obtained in the patients younger than 30 years old, patients that fell from less than 3m in height and patients with Sanders fractures types II and III compared to typeIV, which were associated with higher rate of subtalar arthrodesis. CONCLUSIONS: We consider that open reduction and internal fixation of intraarticular fractures of the calcaneus with reconstruction plate is a valid treatment alternative. Given the complications described and the secondary subtalar arthrodesis rate, we recommend a meticulous technique carried out by experienced surgeons. PMID- 29523413 TI - Insula-Retrosplenial Cortex Overconnectivity Increases Internalizing via Reduced Insight in Autism. AB - BACKGROUND: Internalizing symptoms like anxiety and depression are common and impairing in autism spectrum disorder (ASD). Here, we test the hypothesis that aberrant functional connectivity among three brain networks (salience network [SN], default mode network [DMN], and frontoparietal network [FPN]) plays a role in the pathophysiology of internalizing in ASD. METHODS: We examined the association between resting-state functional connectivity and internalizing in 102 adolescents and young adults with ASD (n = 49) or typical development (n = 53). Seed-to-target functional connectivity was contrasted between adolescents and young adults with ASD and typically developing subjects using a recent parcellation of the human cerebral cortex, and connections that were aberrant in ASD were analyzed dimensionally as a function of parent-reported internalizing symptoms. RESULTS: Three connections demonstrated robust overconnectivity in ASD: 1) the anterior insula to the retrosplenial cortex (i.e., SN-DMN), 2) the anterior insula to the frontal pole (i.e., SN-FPN), and 3) the dorsolateral prefrontal cortex to the retrosplenial cortex (i.e., FPN-DMN). These differences remained significant after controlling for age, and no age-related effects survived correction. The SN-DMN connection was associated with greater internalizing in ASD, mediated by a bigger difference between self- and parent reported internalizing. Control analyses found that the other two connections were not associated with internalizing, and SN-DMN connectivity was not associated with a well-matched control measure (externalizing symptoms). CONCLUSIONS: The present findings provide novel evidence for a specific link between SN-DMN overconnectivity and internalizing in ASD. Further, the mediation results suggest that intact anterior insula-retrosplenial connectivity may play a role in an individual's generating insight into his or her own psychopathology. PMID- 29523414 TI - Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex. AB - BACKGROUND: Testing hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive and thus are unlikely to participate in NMDAR antagonist mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses. Thus, if presynaptic NMDARs enhance gamma-aminobutyric acid release at PVBC-to-PC synapses, they could participate in NMDAR-dependent PC disinhibition. Here, we examined whether presynaptic NMDAR effects could modulate gamma-aminobutyric acid release at PVBC-to-PC synapses in mouse PFC. METHODS: Using whole-cell recordings from synaptically connected pairs in mouse PFC, we determined whether NMDA or NMDAR antagonist application affects PVBC-to-PC inhibition in a manner consistent with a presynaptic mechanism. RESULTS: NMDAR activation enhanced by ~40% the synaptic current at PVBC-to-PC pairs. This effect was consistent with a presynaptic mechanism given that it was 1) observed with postsynaptic NMDARs blocked by intracellular MK801, 2) associated with a lower rate of transmission failures and a higher transmitter release probability, and 3) blocked by intracellular MK801 in the PVBC. NMDAR antagonist application did not affect the synaptic currents in PVBC-to-PC pairs, but it reduced the inhibitory currents elicited in PCs with simultaneous glutamate release by extracellular stimulation. CONCLUSIONS: We demonstrate that NMDAR activation enhances PVBC-to-PC inhibition in a manner consistent with presynaptic mechanisms, and we suggest that the functional impact of this presynaptic effect depends on the activity state of the PFC network. PMID- 29523415 TI - Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response. AB - BACKGROUND: Patients with psychotic depression exhibit elevated cortisol levels. Competitively antagonizing cortisol at the glucocorticoid receptor with mifepristone demonstrated therapeutic benefit in early studies of patients with psychotic depression. We present a combined analysis of all controlled phase 2 and 3 studies to report antipsychotic differences between treatment with mifepristone or placebo and to evaluate the relative contributions to response of attaining an a priori-defined, high mifepristone plasma level and markers of glucocorticoid receptor antagonism (increases in adrenocorticotropin hormone and cortisol) with treatment. METHODS: Data from five similarly designed double-blind phase 2 or 3 studies evaluating the efficacy and safety of 7-day treatment with mifepristone for the psychotic symptoms of psychotic depression were pooled for analysis (mifepristone n = 833; placebo n = 627). Clinical assessments were performed at baseline and on days 7, 14, 28, 42, and 56. Mifepristone, adrenocorticotropin hormone, and cortisol samples were collected at baseline and day 7. RESULTS: Combined results demonstrated meaningful efficacy (p < .004) for mifepristone in reducing psychotic symptoms with wide safety margins. Patients in the a priori-defined, high mifepristone plasma level group (>=1637 ng/mL) demonstrated a more significant treatment effect over placebo (p = .0004). A number needed to treat of 7 and 48 was observed in the high and low mifepristone plasma level groups, respectively. Adverse events were similar in mifepristone- and placebo-treated patients. CONCLUSIONS: A high mifepristone plasma level carried the strongest association with response, followed by changes in adrenocorticotropin hormone and cortisol. Therapeutic plasma levels of mifepristone were most likely to be achieved with the 1200 mg/day dose. PMID- 29523417 TI - Molecular and cellular interplay in virus-induced tumors in solid organ recipients. AB - Patients following solid organ transplantation show a higher risk of developing cancer compared to the general population. Elevated risk is likely due to the interplay of a combination of factors, such as chronic inflammation, coexisting medical conditions, immunosuppressive regimen and persistent infection with oncogenic viruses. In addition, the tumor microenvironment plays a pivotal role in cancer progression, by driving recruitment and in situ differentiation of anti inflammatory cells of the adaptive and innate immune system such as regulatory T cells, Th17, Dendritic Cells, Myeloid Derived Suppressor Cells, Type 2 Macrophages. Here we discuss the molecular role and the contribution to oncogenesis of Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) and Hepatitis C virus (HCV) in immunocompromised patients and describe how these viruses may contribute to oncogenesis both directly and indirectly. PMID- 29523416 TI - Effectiveness of Cetuximab as First-Line Therapy for Patients With Wild-Type KRAS and Unresectable Metastatic Colorectal Cancer in Real-Life Practice: Results of the EREBUS Cohort. AB - INTRODUCTION: Few real-life data are available on cetuximab benefit. The EREBUS cohort was performed to assess metastases resection rate, use, safety, and survival outcomes in wild-type KRAS (Kirsten rat sarcoma viral oncogene) patients with initially unresectable metastatic colorectal cancer (mCRC) treated by cetuximab in real practice. PATIENTS AND METHODS: The study cohort comprised patients initiating cetuximab between January 2009 and December 2010 in 65 French centers, with initially unresectable mCRC and wild-type KRAS. Kaplan-Meier analysis estimated 24-month probability of metastases resection and progression free survival, and 36-month overall survival (OS). Cox proportional hazards models investigated factors associated with survival outcomes. RESULTS: Among the 389 patients included, median age was 64 years, 67.4% were male, 77.9% had Eastern Cooperative Oncology Group performance status <= 1, and hepatic metastases were most frequent at baseline (n = 146 exclusively, n = 149 not exclusively, n = 94 nonliver only). Median duration of cetuximab use was 4.8 months. Metastases resection was performed in 106 patients (27.2%) (n = 60 liver exclusively, n = 33 not exclusively, n = 13 nonliver only). The 24-month probability (95% confidence interval) of metastases resection occurrence was 33.6% (28.5-39.3). Median progression-free survival was 9.2 (8.5-9.8) months for the total cohort and 13.0 (11.6-15.1) for those resected; median OS was 23.0 (20.6-26.3) months for the total cohort and was not reached after 36 months for those who were resected. The strongest factor associated with higher OS was metastases resection with complete remission (hazard ratio, 0.41; 95% confidence interval, 0.19-0.88). CONCLUSION: This cohort study highlights in French real life practice the benefit of cetuximab in first-line mCRC therapy, notably in case of metastases resection with complete remission. PMID- 29523418 TI - Childhood asthma exacerbations and ADRB2 polymorphism: Caution is needed. PMID- 29523419 TI - Reply. PMID- 29523420 TI - The Treatment of Acute Pain in the Emergency Department: A White Paper Position Statement Prepared for the American Academy of Emergency Medicine. AB - BACKGROUND: Pain is one of the most common reasons patients present to the emergency department (ED). Emergency physicians should be aware of the numerous opioid and nonopioid alternatives available for the treatment of pain. OBJECTIVES: To provide expert consensus guidelines for the safe and effective treatment of acute pain in the ED. METHODS: Multiple independent literature searches using PubMed were performed regarding treatment of acute pain. A multidisciplinary panel of experts in Pharmacology and Emergency Medicine reviewed and discussed the literature to develop consensus guidelines. RECOMMENDATIONS: The guidelines provide resources for the safe use of opioids in the ED as well as pharmacological and nonpharmacological alternatives to opioid analgesia. Care should be tailored to the patient based on their specific acute painful condition and underlying risk factors and comorbidities. CONCLUSIONS: Analgesia in the ED should be provided in the most safe and judicious manner, with the goals of relieving acute pain while decreasing the risk of complications and opioid dependence. PMID- 29523421 TI - Cervical Tuberculous Lymphadenitis. PMID- 29523422 TI - Diffuse Pneumatosis Coli. PMID- 29523423 TI - Capnocytophaga canimorsus: An Emerging Pathogen in Immunocompetent Patients Experience from an Emergency Department. AB - BACKGROUND: Capnocytophaga canimorsus is a bacterium of the normal oral flora of dogs and cats. Human infection is caused by animal bite but is rarely observed, mainly in immunocompromised patients. We present 2 cases of C. canimorsus infection that occurred in immunocompetent patients and caused multiorgan failure and in both cases severe neurologic involvement. CASE REPORT: In the first case, we present a 69-year-old immunocompetent woman with septic shock derived from skin and soft tissue infection after a dog's bite. She developed ischemic necrosis evolving to gangrene of both forefeet and hands, infective aortic endocarditis, and neurologic involvement caused by large hemispheric hypodense lesions compatible with ischemic septical lesions. In the second case, we present a 65-year-old immunocompetent man with meningitis after a dog's bite. Despite antibiotic therapy, he developed neurologic clinical deterioration, with right sensitive hemisyndrome associated with lack of strength and motor skills of the right hand. Radiologic findings were consistent with the diagnosis of cerebritis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Clinicians should always be aware of this pathogen, both in immunocompromised and immunocompetent patients, and consider prophylactic antibiotics after exposure. PMID- 29523424 TI - Clinical Mimics: An Emergency Medicine-Focused Review of Streptococcal Pharyngitis Mimics. AB - BACKGROUND: Pharyngitis is a common disease in the emergency department (ED). Despite a relatively low incidence of complications, there are many dangerous conditions that can mimic this disease and are essential for the emergency physician to consider. OBJECTIVE: This article provides a review of the evaluation and management of group A beta-hemolytic Streptococcal (GABHS) pharyngitis, as well as important medical conditions that can mimic this disease. DISCUSSION: GABHS pharyngitis often presents with fever, sore throat, tonsillar exudates, and anterior cervical lymphadenopathy. History and physical examination are insufficient for the diagnosis. The Centor criteria or McIsaac score can help risk stratify patients for subsequent testing or treatment. Antibiotics may reduce symptom duration and suppurative complications, but the effect is small. Rheumatic fever is uncommon in developed countries, and shared decision making is recommended if antibiotics are used for this indication. Oral analgesics and topical anesthetics are important for symptom management. Physicians should consider alternate diagnoses that may mimic GABHS pharyngitis, which can include epiglottitis, infectious mononucleosis, Kawasaki disease, acute retroviral syndrome, Lemierre's syndrome, Ludwig's angina, peritonsillar abscess, retropharyngeal abscess, and viral pharyngitis. A focused history and physical examination can help differentiate these conditions. CONCLUSIONS: GABHS may present similarly to other benign and potentially deadly diseases. Diagnosis and treatment of pharyngitis should be based on clinical evaluation. Consideration of pharyngitis mimics is important in the evaluation and management of ED patients. PMID- 29523425 TI - Inadvertent Left Ventricle Endocardial or Uncomplicated Right Ventricular Pacing: How to Differentiate in the Emergency Department. AB - BACKGROUND: Temporary transvenous pacemaker implantation is an important and critical procedure for emergency physicians. Traditionally, temporary pacemakers are inserted by electrocardiography (ECG) guidance in the emergency department because fluoroscopy at the bedside in an unstable patient can be limited by time and equipment availability. However, in the presence of atrial septal defect, ventricular septal defect, and patent foramen ovale, the pacemaker lead can be implanted inadvertently into the left ventricle or directly into the coronary sinus instead of right ventricle. Regular pacemaker rhythm can be achieved despite inadvertent implantation of the pacemaker lead into the left ventricle, leading to ignorance of the possibility of lead malposition. CASE REPORT: A 65 year-old female patient with hemodynamic instability and complete atrioventricular block underwent temporary pacemaker implantation via right jugular vein with ECG guidance at the emergency department. Approximately 12 h after implantation, it was noticed that the ECG revealed right bundle branch block (RBBB)-type paced QRS complexes. Diagnostic workup revealed that the lead was inadvertently located in the left ventricular apex. This case illustrates the importance of careful scrutiny of the 12-lead ECG and imaging clues in identifying lead malposition in the emergency department. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Because inadvertent left ventricle endocardial pacing carries a high risk for systemic embolization, it is important to determine whether an RBBB pattern induced by ventricular pacing is the result of a malpositioned lead or uncomplicated transvenous right ventricular pacing. PMID- 29523426 TI - In-Hospital Sepsis Mortality Rates Comparing Tertiary and Non-Tertiary Hospitals in Washington State. AB - BACKGROUND: More than a million people a year in the United States experience sepsis or sepsis-related complications, and sepsis remains the leading cause of in-hospital deaths. Unlike many other leading causes of in-hospital mortality, sepsis detection and treatment are not dependent on the presence of any technology or services that differ between tertiary and non-tertiary hospitals. OBJECTIVE: To compare sepsis mortality rates between tertiary and non-tertiary hospitals in Washington State. METHODS: A retrospective longitudinal, observational cohort study of 73 Washington State hospitals for 2010-2015 using data from a standardized state database of hospital abstracts. Abstract records on adult patients (n = 86,378) admitted through the emergency department (ED) from 2010 through 2015 in all tertiary (n = 7) and non-tertiary (n = 66) hospitals in Washington State. RESULTS: The overall mortality rate for all hospitals was 6.5%. In the fully adjusted model, the odds ratio for in-hospital death was higher in non-tertiary hospitals compared with tertiary hospitals (odds ratio 1.25; 95% confidence interval 1.17-1.35; p < 0.001). CONCLUSIONS: We observed higher sepsis mortality rates in non-tertiary hospitals, compared with tertiary hospitals. Because most patients who are treated for sepsis are treated outside of tertiary hospitals, and the number of patients treated for sepsis in non-tertiary hospitals seems to be rising, a better understanding of the cause or causes for this differential is crucial. PMID- 29523427 TI - Physiologic distribution of PSMA-ligand in salivary glands and seromucous glands of the head and neck on PET/CT. AB - OBJECTIVES: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is used for detection and (re)staging of prostate cancer. However, healthy salivary, seromucous, and lacrimal glands also have high PSMA-ligand uptake. This study aimed to describe physiologic PSMA ligand uptake distribution characteristics in the head and neck to aid in PSMA PET/CT interpretation and to identify possible new clinical applications for PSMA ligand imaging. STUDY DESIGN: Thirty consecutive patients who underwent PSMA PET/CT for prostate cancer were evaluated. Tracer maximum standardized uptake values (SUVmax) in the salivary, seromucous, and lacrimal glands were determined visually and quantitatively. Overall and intraindividual variations were reported. RESULTS: All gland locations had increased tracer uptake. The mean SUVmax +/- standard deviation varied: parotid 12.3 +/- 3.9; submandibular 11.7 +/ 3.5; sublingual 4.5 +/- 1.9; soft palate 2.4 +/- 0.5; pharyngeal wall 4.3 +/- 1.3; nasal mucosa 3.4 +/- 0.9; supraglottic larynx 2.7 +/- 0.7; and lacrimal 6.2 +/- 2.2. The parotid had the largest overall variation in SUVmax (5.2-22.9), and the sublingual glands had the largest mean intraindividual difference (18.1%). CONCLUSIONS: Major and minor salivary and seromucous glands consistently have high PSMA-ligand uptake. Minor gland locations can be selectively visualized by this technique for the first time. This provides potential new applications such as quantification of present salivary gland tissues and individualization of radiotherapy for head and neck cancer or lutetium-177-PSMA radionuclide treatment. PMID- 29523428 TI - Differential expression of organic cation transporter 3 in oral submucous fibrosis-associated buccal squamous cell carcinoma. AB - OBJECTIVE: The aim of this study was to examine the expression of organic cation transporter 3 (OCT3) in patients with oral submucous fibrosis (OSF)-associated buccal squamous cell carcinoma (BSCC) and to explore its clinical significance. STUDY DESIGN: A total of 56 tissue specimens were collected from patients, among which there were 13 specimens with normal buccal mucosa (NBM), 13 with oral submucous fibrosis (OSF), 10 with OSF-associated BSCC (BSCC-OSF), 10 with well differentiated BSCC (BSCC-I), and 10 with poorly to moderately differentiated BSCC (BSCC-II+III), based on pathologic examination. The expression of OCT3 was detected by using immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction. RESULTS: There was a significant difference in both the protein and mRNA expression levels of OCT3 among the NBM, OSF, BSCC-OSF, BSCC-I, and BSCC-II+III groups (protein: F = 82.45 [P < .0001]; mRNA: F = 50.69 [P < .0001]). The expression of OCT3 from NBM to OSF to BSCC-OSF was gradually upregulated. In addition, as BSCC became better differentiated, the expression of OCT3 increased. CONCLUSIONS: The expression of OCT3 was associated with OSF progression and the differentiation of BSCC. OCT3 expression may serve as a molecular marker for the prevention and early diagnosis of OSF and BSCC. PMID- 29523429 TI - Correction to Lancet Diabetes Endocrinol 2018; 6: 186-96. PMID- 29523430 TI - Does electroconvulsive therapy damage the brain? PMID- 29523431 TI - Electroconvulsive therapy and risk of dementia in patients with affective disorders: a cohort study. AB - BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe episodes of mood disorders. Temporary memory loss is a common side-effect, but ongoing discussions exist regarding potential long-term adverse cognitive outcomes. Only a few studies have examined the frequency of dementia in patients after ECT. The aim of this study was to examine the association between ECT and risk of subsequent dementia in patients with a first-time hospital diagnosis of affective disorder. METHODS: We did a cohort study of patients aged 10 years and older in Denmark with a first-time hospital contact for an affective disorder from Jan 1, 2005, through Dec 31, 2015, identified in the Danish National Patient Registry with ICD-10 codes F30.0 to F39.9. From the registry we retrieved information on all ECTs registered for patients and followed up patients for incidental dementia (defined by hospital discharge diagnoses or acetylcholinesterase inhibitor use) until Oct 31, 2016. We examined the association between ECT and dementia using Cox regression analyses with multiple adjustments and propensity-score matching on sociodemographic and clinical variables. FINDINGS: Of 168 015 patients included in the study, 5901 (3.5%) patients had at least one ECT. During the median follow-up of 4.9 years (IQR 2.4 7.8) and 872 874 person years, the number of patients who developed dementia was 111 (0.1%) of 99 045 patients aged 10-49 years, 965 (2.7%) of 35 945 aged 50-69 years, and 4128 (12.5%) of 33 025 aged 70-108 years. 217 (3.6%) of the 5901 patients treated with ECT developed dementia, whereas of 162 114 patients not treated with ECT 4987 (3.1%) developed dementia. The corresponding incidences were 70.4 cases per 10 000 person-years (95% CI 61.6-80.5) and 59.2 per 10 000 person-years (57.6-60.8). In patients younger than 50 years and 50-69 years, ECT was not associated with a risk of dementia compared with age-matched patients who were not given ECT (age-adjusted hazard ratio [HR] 1.51, 95% CI 0.67-3.46, p=0.32; and 1.15, 0.91-1.47, p=0.22, respectively). In patients aged 70 years and older, ECT was associated with a decreased rate of dementia (0.68, 95% CI 0.58 0.80; p<0.0001), but in the propensity-score matched sample the HR was attenuated (0.77, 0.59-1.00; p=0.062). 31 754 patients (17.6%) died during follow-up (mortality rate per 1000 person-years 35.7, 95% CI 35.3-36.2) and supplementary analyses suggested that the risk of dementia, taking the competing mortality risk into account, was not significantly associated with ECT (subdistribution HR 0.98, 95% CI 0.76-1.26; p=0.24). INTERPRETATION: ECT was not associated with risk of incidental dementia in patients with affective disorders after correcting for the potential effect of patient selection or competing mortality. The findings from this study support the continued use of ECT in patients with severe episodes of mood disorders, including those who are elderly. FUNDING: Danish Council for Independent Research, Danish Medical Research Council, the Velux Foundation, the Jascha Foundation, and the Doctor Sofus Carl Emil Friis and Olga Doris Friis grant. PMID- 29523432 TI - Getting better. PMID- 29523433 TI - Practice Guideline: Approach to the Child with Rhinorrhea. PMID- 29523434 TI - Breathlessness: the rift between objective measurement and subjective experience. PMID- 29523435 TI - Tibial artery duplex ultrasound-derived peak systolic velocities may be an objective performance measure after above-knee endovascular therapy for arterial stenosis. AB - OBJECTIVE: The ankle-brachial index (ABI) is a well-established measure of distal perfusion in lower extremity ischemia; however, the ABI is of limited value in patients with noncompressible lower extremity arteries. We sought to demonstrate whether duplex ultrasound-determined tibial artery velocities can be used as an alternative to ABI as an objective performance measure after endovascular treatment of above-knee arterial stenosis. METHODS: Thirty-six patients undergoing above-knee endovascular intervention had preprocedure and postprocedure duplex ultrasound examination within 6 months of intervention. Preprocedure vs postprocedure changes in tibial artery mean peak systolic velocity (PSV; mean of proximal, mid, and distal velocities) were compared with changes in ABI and a reference (control) cohort of 68 patients without peripheral vascular disease. RESULTS: Thirty-six patients (41 limbs) had an above-knee endovascular intervention and had preprocedure and postprocedure duplex ultrasound examinations of the ipsilateral extremity including the tibial arteries. Before the procedure, mean tibial artery PSVs in the 36 patients undergoing intervention were outside (below) the 95% confidence intervals for the control patients. In comparing preprocedure and postprocedure PSVs, the mean anterior tibial (P < .01), mean peroneal (P < .01), and mean posterior tibial (P < .01) PSVs all increased and correlated with an increase in ABI (P < .01). After endovascular intervention, duplex ultrasound-derived mean PSVs fell within or near established reference ranges for patients without peripheral arterial disease. Mean tibial artery PSV increases were similar in patients with and without noncompressible vessels. CONCLUSIONS: Tibial artery PSVs increase, correlate with an increase in ABI, and fall within or near confidence intervals for normal controls after above-knee endovascular interventions. After endovascular intervention, tibial artery PSVs can supplement ABI as an objective performance measure in patients with and in particular without compressible tibial arteries. PMID- 29523436 TI - Persistent symptom relief after revascularization in patients with single-artery chronic mesenteric ischemia. AB - OBJECTIVE: An isolated stenosis of the celiac artery (CA) or the superior mesenteric artery (SMA) is frequently detected in patients with abdominal complaints. The dilemma is whether these patients suffer from chronic mesenteric ischemia (CMI) and whether they will benefit from revascularization. We evaluated the long-term clinical success rates for single CA or SMA revascularization in patients with gastrointestinal symptoms and confirmed mucosal ischemia. METHODS: This was a retrospective cohort analysis of 59 consecutive patients with gastrointestinal symptoms and a single atherosclerotic mesenteric artery stenosis who were referred to our tertiary care institution between 2006 and 2010 for standardized diagnostic workup of CMI, including measurement of mucosal ischemia with visible light spectroscopy or gastric-jejunal tonometry. Patients with multidisciplinary consensus diagnosis of CMI underwent surgical or endovascular revascularization. The primary outcome was clinical response to revascularization, defined as relief of presenting symptoms as experienced by the patient. RESULTS: Consensus diagnosis of CMI was obtained in 37 of 59 patients. Isolated CA stenosis was present in 30 of 37 patients (81%) and isolated SMA stenosis in seven patients. After a mean follow-up of 5.0 +/- 3.0 years, 27 of 37 patients (73%) experienced sustained symptom relief after revascularization. Response was not related to lesion localization (CA, 73%; SMA, 71%; P = .919). CONCLUSIONS: Revascularization of the CA or SMA provides persistent symptom relief in 73% of patients diagnosed with CMI due to single atherosclerotic mesenteric artery stenosis. PMID- 29523437 TI - Active smoking in claudicants undergoing lower extremity bypass predicts decreased graft patency and worse overall survival. AB - OBJECTIVE: Performing lower extremity bypass (LEB) in actively smoking claudicants remains controversial. Whereas some surgeons advocate a strict nonoperative approach to active smokers, citing perceived inferior outcomes, others will proceed with surgical bypass if the patient is anatomically suited and medical management has failed. The purpose of this study was to determine the impact of active smoking on LEB outcomes among claudicants. METHODS: All patients undergoing infrainguinal LEB for claudication in the Vascular Study Group of New England from 2003 to 2016 were analyzed. Smoking was defined as active tobacco use within 1 month of surgery. End points included in-hospital outcomes; long term primary, assisted primary, and secondary patency; and mortality. Univariate, Cox multivariable, and Kaplan-Meier methods were used to determine the impact of smoking. Propensity score matching was performed to control for intergroup differences. RESULTS: Of 1789 LEBs, 971 (54%) were performed in nonsmokers and 818 (46%) in smokers. The follow-up rate was 87% at a mean of 382 days (standard error, +/-6.8 days). Smokers were younger (60 vs 68 years; P < .001) and were less likely to have multiple comorbidities, including hypertension, coronary artery disease, congestive heart failure, diabetes, and chronic renal insufficiency (P <= .05); they were more likely to have an above-knee popliteal bypass target (52% vs 43%; P = .001). Smokers also had lower rates of postoperative major cardiac events (2.4% vs 5.3%; P = .002) and perioperative blood transfusion (5.6% vs 11%; P < .001) compared with nonsmokers, but there was no difference in respiratory complications, wound complications, or mortality. At 2-year follow-up, smokers demonstrated inferior primary patency (48% vs 61%; P = .03) and assisted primary patency (59% vs 74%; P = .01), with comparable rates of secondary patency and overall mortality. Propensity matching yielded two similar groups (n = 450 for each). Propensity-matched smokers had significantly decreased 2-year primary patency (43% vs 58%; P = .02), assisted primary patency (54% vs 71%; P = .03), and 10-year survival (69% vs 76%; P < .01). Cox multivariable analysis confirmed that smoking was an independent predictor of diminished primary patency (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.0-1.6; P = .03), assisted primary patency (HR, 1.4; 95% CI, 1.1-1.8; P = .004), and overall survival (HR, 1.3; 95% CI, 1.1-1.5; P < .001). CONCLUSIONS: Despite the fact that smokers are younger and have fewer comorbidities than nonsmokers, active smoking at the time of LEB for claudication is associated with decreased long-term patency and decreased overall survival. Surgeons should consider smoking an important risk factor for worse LEB outcomes in smokers compared with nonsmokers. PMID- 29523438 TI - Reinterventions after fenestrated or branched endovascular aortic aneurysm repair. AB - OBJECTIVE: Reinterventions after fenestrated or branched endovascular aneurysm repair (F/B-EVAR) are sometimes necessary to maintain aneurysm exclusion or endograft and target artery patency. These reinterventions are nontrivial, potentially associated with morbidity, mortality, and resource utilization. Whereas rates, types, and outcomes of reintervention after infrarenal EVAR have been well described, they have not been well described for F/B-EVAR. We sought to characterize the morbidity, mortality, and resource utilization due to reinterventions after F/B-EVAR. METHODS: All F/B-EVAR variables collected prospectively through a single-institution, Institutional Review Board-approved registry, which included patients enrolled in a physician-sponsored investigational device exemption trial (G130210), were reviewed (November 2010 December 2016). Reinterventions were defined as any procedure that was aneurysm related, device related, or target artery related. For patients with more than one reintervention, each intervention occurrence was treated as a discrete event. Reintervention type, indication, timing (perioperative, days 0-30; short term, days 31-180; midterm, >180 days), inpatient/outpatient, length of stay, and morbidity/mortality were recorded. Reintervention success was defined as resolution of the indication. RESULTS: Among 123 consecutive F/B-EVARs (mean follow-up, 25 months), 32 patients (25%) underwent 54 reinterventions (one reintervention, 20 (63%) patients; two reinterventions, 6 (19%) patients; three reinterventions, 4 (13%) patients; four reinterventions, 1 (3.1%) patient; and six reinterventions, 1 (3.1%) patient). The most frequent indications were type III endoleaks (n = 15 [28%]), target artery occlusions (n = 7 [13%]), and stenoses (n = 6 [11%]). These were performed in the perioperative, short-term, and midterm time frames 17%, 41%, and 43% of the time, respectively. Reinterventions were percutaneous (67%), inpatient procedures (61%), with median length of stay of 5 days. Of the 32 reintervention patients, 4 experienced access site complications and 4 died <30 days after reintervention (3 were adjudicated as not aneurysm related/not reintervention related). In 31 of 32 (97%) patients, reintervention success was achieved. CONCLUSIONS: Reinterventions after F/B-EVAR were necessary in 26% of patients, most commonly for type III endoleaks and target artery complications. Whereas all but one reintervention was successful, many of these required complex procedures with significant morbidity and mortality. Development of strategies to eliminate type III endoleaks by improving component junction integrity and to ensure target artery primary patency are key next steps in the evolution of F/B-EVAR. PMID- 29523439 TI - The impact of prior aortic surgery on outcomes after multibranched endovascular aortic aneurysm repair. AB - OBJECTIVE: The purpose of this study was to evaluate the impact of prior aortic surgery on outcomes after multibranched endovascular aneurysm repair (MBEVAR) of thoracoabdominal aortic aneurysms (TAAAs) and pararenal aortic aneurysms (PRAAs). METHODS: From July 2005 to October 2016, there were 153 patients who underwent elective endovascular repair of TAAA and PRAA using multibranched stent grafts. Data on demographics, procedural details, and outcomes were collected prospectively. RESULTS: The mean age was 73 +/- 8 years, and 113 of 153 (74%) were men. Mean aneurysm diameter was 67 +/- 9 mm. Before MBEVAR, 68 of 153 (44%) patients had undergone a prior aortic surgery; 49 of 68 (72%) had prior open aortic surgery, 15 of 68 (22%) had prior endovascular aortic surgery, and 4 of 68 (6%) had both. There were no significant differences in age, sex, preoperative aneurysm diameter, or medical comorbidities (coronary artery disease, lung disease, diabetes mellitus, or hypertension) in patients with previous aortic surgery compared with those without. Patients with previous aortic surgery had higher fluoroscopy times (131 +/- 59 vs 118 +/- 54 minutes; P = .18) and procedural times (370 +/- 101 vs 345 +/- 118 minutes; P = .27) during MBEVAR, but these differences did not reach statistical significance. Patients without previous aortic intervention had higher rates of postoperative paraplegia (9/85 [11%]) vs (0/68 [0%]; P = .005) compared with those with previous aortic surgery. Of 153 patients, 3 (2%) had a postoperative stroke, and this was not different between the two groups. Median follow-up time was 2.5 years (interquartile range, 1.0-4.5 years) and did not differ between those with and those without previous aortic surgery. Kaplan-Meier estimated 5-year freedom from aneurysm-related mortality and overall mortality was 90% and 48%, respectively, and did not differ between the two groups. There was also no difference in branch vessel occlusion between the two groups. CONCLUSIONS: A high proportion of patients undergoing MBEVAR for TAAA or PRAA have already undergone prior open or endovascular aortic procedures, but this does not appear to increase the complication rate or affect midterm clinical outcomes. Patients with prior aortic surgery who undergo MBEVAR have lower rates of paraplegia compared with those without prior surgery, which may be due to effective recruitment of collateral circulation. PMID- 29523441 TI - Visual and Refractive Outcomes in Manual versus Femtosecond Laser-Assisted Cataract Surgery: A Single-Center Retrospective Cohort Analysis of 1838 Eyes. AB - PURPOSE: Femtosecond laser-assisted cataract surgery (FLACS) has emerged as an alternative to manual cataract surgery (MCS) for corneal incision and capsulorhexis creation, as well as nuclear fragmentation. This study compares postoperative refractive and visual outcomes in eyes receiving MCS or FLACS. DESIGN: Single-center, comparative, retrospective cohort analysis. PARTICIPANTS: Consecutive eyes receiving FLACS and MCS from July 1, 2012, to July 31, 2015, at a single tertiary care center. METHODS: Demographic data, ocular history, preoperative measurements and biometry, and postoperative surgical results were retrospectively obtained and statistically analyzed using a generalized linear mixed model adjusting for differences in baseline characteristics and within patient correlation. A 2-tailed P value <0.05 was considered statistically significant throughout the study. MAIN OUTCOME MEASURES: Percentage of eyes achieving absolute error (AE) <=0.5 diopters (D). Secondary outcomes included percentage of eyes with AE <=0.25 D and <=1.0 D, and percentage of distance targeted eyes achieving uncorrected distance visual acuity (UDVA) of 20/20 or better, 20/25 or better, and 20/30 or better. RESULTS: A total of 883 eyes received MCS and 955 received FLACS among 1089 patients. Some 82.6% of FLACS eyes and 78.8% of MCS eyes had <=0.5 D of AE at 3 weeks, representing an adjusted odds ratio (OR) of 1.28 (95% confidence interval [CI], 0.98-1.66) of FLACS relative to MCS being within target. Some 97.1% of FLACS and 97.2% of MCS eyes had <=1.0 D of AE (OR, 0.96; 95% CI, 0.57-1.60) and 49.3% of FLACS and 46.3% of MCS eyes, <=0.25 D of AE (OR, 1.13; 95% CI, 0.91-1.39). Factors predictive of a favorable refractive outcome included axial length between 22 and 24.8 mm, receiving a toric intraocular lens, less preoperative cylinder, and greater preoperative average keratometry. There was no significant difference in the percentage of patients targeted for distance who achieved UDVA of 20/20 or better (P = 0.30), 20/25 or better (P = 0.06), or 20/30 or better (P = 0.66) vision. CONCLUSIONS: Postoperatively, there was no statistically significant difference found between eyes undergoing FLACS and eyes undergoing MCS with respect to refractive and visual outcomes. PMID- 29523442 TI - Investigation of the Unstable Total Hip Arthroplasty. AB - The investigation of recurrent instability after total hip arthroplasty requires a thorough history and physical examination focused on characterizing the dislocation events and the patient factors that contribute to instability. Radiographic studies include plain radiographs, in particular a cross-table lateral, and computed tomography to accurately assess the implant orientation relative to the patient's native anatomy. More advanced imaging such as magnetic resonance imaging may be useful to assess abductor tendon integrity. A classification system, based on etiology of recurrent instability, is available and helpful to guide treatment strategy. Finally, emerging research has debunked the previous characterization of an acetabular "safe zone" and further identified lumbar spine disease and surgical fusion as a significant risk factor for recurrent instability. Current and future research efforts target radiographic assessment of lumbopelvic alignment in diagnosis, treatment, and prevention of recurrent total hip arthroplasty instability. PMID- 29523440 TI - Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs that Orchestrate the Rapid Recall Response of Memory CD8+ T Cells. AB - Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3beta (GSK3beta) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-gamma (IFN-gamma) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3beta at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8+ T cells to rapidly acquire effector function. PMID- 29523443 TI - Editorial-The Prevention and Management of Instability in THA. PMID- 29523444 TI - Adult Reconstruction Hip and Knee Fellowship Program Content and Accessibility. AB - BACKGROUND: The objective of the study was to assess the accessibility and content of accredited adult reconstruction hip and knee fellowship program websites. METHODS: Using the online database of the American Association of Hip and Knee Surgeons (AAHKS), we compiled a list of accredited adult hip and knee/tumor reconstruction fellowship programs. A full list of adult reconstruction hip and knee fellowship programs was gathered from the AAHKS website. The program website links they provided were evaluated. A Google search was conducted to identify program websites and analyzed for accessibility and content in 3 domains: program overview, applying/recruitment, and education. RESULTS: At the time the study was conducted, there were 78 accredited adult reconstruction hip and knee fellowship programs identified through the AAHKS program directory. Three of the 78 programs identified had a functional link on the AAHKS fellowship program directory; however, Google search identified 60 websites. Eighteen programs did not have a website and were not evaluated for content. Data analysis of content in the domains of program details, application process/recruitment, and education revealed that most websites included a program description and director name with contact information. However, they were not as comprehensive in the application process/recruitment and education domains. CONCLUSIONS: AAHKS provides a reasonable method of identifying programs. Yet, most programs can readily be identified using a Google search (76.9%). Although most fellowship program websites contained program details, there is still paucity of information for fellowship candidates. PMID- 29523445 TI - Certificate-of-Need State Laws and Total Knee Arthroplasty. AB - BACKGROUND: Many states in the United States have certificate-of-need (CON) programs designed to restrain health care costs and prevent overutilization of health care resources. The goal of this study was to characterize the associations between CON regulations and total knee arthroplasty (TKA) by comparing states with and without CON programs. METHODS: Publicly available data were used to classify states in to CON or non-CON categories. The 100% Medicare Standard Analytical Files from 2005 through 2014 were then used to compare primary TKA procedure volumes, charges, reimbursements, and distribution of procedures based on facility volumes between the groups. Adverse events such as infection and emergency room visits after TKA were also evaluated. RESULTS: Although CON status was associated with lower per capita utilization of TKA, the annual incidence of TKA appears to have increased over time more rapidly in states with CON laws compared with non-CON states (overall increase of 5.6% vs 2.3%, P < .01). When normalized to the Medicare population, the incidence of TKA increased 2.0% in CON states, whereas it actually decreased 7.2% in states without CON regulations (P = .011). Average reimbursement (and thus Medicare spend) was 5% to 10% lower in non-CON states at all time points (P < .0001). In non-CON states, relatively more TKAs appear to be performed in lower volume hospitals. Examination of adverse events rates did not reveal any strong associations between any adverse outcome and CON status. CONCLUSION: CON programs appear to have influenced the delivery of care for TKA. Although our data suggest that these laws are associated with lower per capita utilization of TKA and the use of higher-volume facilities, we were unable to detect any strong evidence that CON regulations have been associated with improved quality of care or have limited growth in the utilization of this procedure over time. Confounding population and geographic factors may influence these findings and further study is needed to determine whether or not these programs have served their purpose and should be retained. PMID- 29523446 TI - Reasons for Ninety-Day Emergency Visits and Readmissions After Elective Total Joint Arthroplasty: Results From a US Integrated Healthcare System. AB - BACKGROUND: Previous studies evaluating reasons for 30-day readmissions following total joint arthroplasty (TJA) may underestimate hospital-based utilization of healthcare resources during a patient's episode-of-care. We sought to identify common reasons for 90-day emergency department (ED) visits and hospital readmissions following primary elective unilateral TJA. METHODS: Patients from July 1, 2012 through June 30, 2015 having primary elective TJA and at least one 90-day postoperative ED-only visit and/or readmission for any reason were identified using the Kaiser Permanente Total Joint Replacement Registry. Chart reviews for ED visits/readmissions included 13 surgical and 11 medical reasons. The 2344 total hips and 5520 total knees were analyzed separately. RESULTS: Incidence of at least one ED visit following total hip arthroplasty (THA) was 13.4% and 4.5% for readmissions. The most frequent reasons for ED visits were swelling (15.6%) and pain (12.8%); the most frequent reasons for readmissions were infection (12.5%) and unrelated elective procedures (9.0%). The incidence of at least one ED visit following total knee arthroplasty (TKA) was 13.8%, and the incidence of readmission was 5.5%. The most frequent reasons for ED visits were pain (15.8%) and swelling (15.6%); the most common readmission reasons were gastrointestinal (19.1%) and manipulation under anesthesia (9.4%). CONCLUSION: Swelling and pain related to the procedure were the most frequent reasons for 90 day ED visits after both THA and TKA. Readmissions were most commonly due to infection or unrelated procedures for THA and gastrointestinal or manipulation under anesthesia for TKA. Modifications to discharge protocols may help prevent or alleviate these issues, avoiding unnecessary hospital returns. PMID- 29523447 TI - Adverse outcomes of pregnancy-associated Zika virus infection. AB - The spread of Zika virus to the Americas was accompanied by surge in the number of infants with CNS abnormalities leading to a declaration of a health emergency by the WHO. This was accompanied by significant responses from governmental health agencies in the United States and Europe that resulted in significant new information described in the natural history of this perinatal infection in a very short period of time. Although much has been learned about Zika virus infection during pregnancy, limitations of current diagnostics and the challenges for accurate serologic diagnosis of acute Zika virus infection has restricted our understanding of the natural history of this perinatal infection to infants born to women with clinical disease during pregnancy and to Zika exposed infants with obvious clinical stigmata of disease. Thus, the spectrum of disease in infants exposed to Zika virus during pregnancy remains to be defined. In contrast, observations in informative animal models of Zika virus infections have provided rational pathways for vaccine development and existing antiviral drug development programs for other flaviviruses have resulted in accelerated development for potential antiviral therapies. This brief review will highlight some of the current concepts of the natural history of Zika virus during pregnancy. PMID- 29523448 TI - Substantially reduced incidence of genital warts in women and men six years after HPV vaccine availability in Sweden. AB - BACKGROUND: Between 2007 and 2011, opportunistic HPV-vaccination was available in Sweden and partially subsidized to girls aged 13-17, reaching a ~30% overall coverage. METHODS: All Swedish women/men aged 15-44 were followed between 2006 and 2012 for condyloma. Average annual percent changes (AAPCs) in incidence were estimated. RESULTS: Substantial decreases were seen in women aged 15-24 from 2008 onwards (AACP-range: -8.5% to -18.5%); similar effects were seen for men aged 15 29 (AACP-range: -7.0% to -16.6%) from 2010-onwards. DISCUSSION: Despite low population vaccination coverage in women and no coverage in men, similar condyloma incidence reductions were observed among men and women, with delays of >1 years in men. PMID- 29523449 TI - In vitro and in vivo evaluation of a single chain antibody fragment generated in planta with potent rabies neutralisation activity. AB - Rabies causes more than 60,000 human deaths annually in areas where the virus is endemic. Importantly, rabies is one of the few pathogens for which there is no treatment following the onset of clinical disease with the outcome of infection being death in almost 100% of cases. Whilst vaccination, and the combination of vaccine and rabies immunoglobulin treatment for post-exposure administration are available, no tools have been identified that can reduce or prevent rabies virus replication once clinical disease has initiated. The search for effective antiviral molecules to treat those that have already developed clinical disease associated with rabies virus infection is considered one of the most important goals in rabies research. The current study assesses a single chain antibody molecule (ScFv) based on a monoclonal antibody that potently neutralises rabies in vitro as a potential therapeutic candidate. The recombinant ScFv was generated in Nicotiana benthamiana by transient expression, and was chemically conjugated (ScFv/RVG) to a 29 amino acid peptide, specific for nicotinic acetylcholine receptor (nAchR) binding in the CNS. This conjugated molecule was able to bind nAchR in vitro and enter neuronal cells more efficiently than ScFv. The ability of the ScFv/RVG to neutralise virus in vivo was assessed using a staggered administration where the molecule was inoculated either four hours before, two days after or four days after infection. The ScFv/RVG conjugate was evaluated in direct comparison with HRIG and a potential antiviral molecule, Favipiravir (also known as T-705) to indicate whether there was greater bioavailability of the ScFv in the brains of treated mice. The study indicated that the approach taken with the ScFv/RVG conjugate may have utility in the design and implementation of novel tools targetting rabies virus infection in the brain. PMID- 29523450 TI - No effect of an additional early dose of measles vaccine on hospitalization or mortality in children: A randomized controlled trial. AB - BACKGROUND: Non-specific effects (NSEs) of vaccines have increasingly gained attention in recent years. Recent studies suggest that live vaccines, such as measles vaccine (MV), have beneficial effects on health, while inactivated vaccines, such as the diphtheria-tetanus-pertussis (DTP) vaccine, may have harmful effects. If this is the case, it should improve child health to move MV closer to the last vaccination with DTP. The objective of this study was to investigate the NSEs of an additional early dose of MV on hospitalization or mortality. METHODS: Children were randomized to receive either the standard MV at 9 months (control) or an additional early dose of MV 4 weeks after the third dose of DTP-containing Pentavalent vaccine and the standard MV at 9 months (intervention). In this analysis of a secondary outcome in the trial, we investigated the effect of the intervention on a composite endpoint of over-night hospitalization with or without recovery, or death without previous hospitalization, in children between 4.5 and 36 months of age in the Nouna HDSS in Burkina Faso. We used Cox proportional hazards regression with repeated events and time since study enrolment as underlying time-scale. RESULTS: Among 2258 children in the intervention and 2238 children in the control group we observed a total of 464 episodes of hospitalization or mortality. There was no difference between intervention and control group (HR = 1.00, 95% Confidence Interval (CI) 0.83-1.20). Results from the per-protocol and intention-to-treat analysis were similar. Although no significant, results suggest a possible beneficial effect of early MV in children that had not been exposed to an OPV campaign after enrolment (HR = 0.83, 95% CI 0.55-1.29). CONCLUSIONS: We did not detect any effect of early MV on subsequent hospitalization or mortality. However, possible effects of early MV could have been obscured by NSEs of the frequent OPV campaigns. Registration: The trial was registered at ClinicalTrials.gov, NCT01644721. PMID- 29523451 TI - Prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B strains, China. AB - OBJECTIVE: To systematically investigate the prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B (NmB) in China. METHODS: A total of 485 NmB strains isolated in 29 provinces of China between 1968 and 2016 were selected from the culture collection of the national reference laboratory according to the isolation year, location, and source. Multi-locus sequence typing (MLST) and porA gene sequencing were performed on all 485 study strains; PCR was used to detect the fHbp, nadA, and nhba gene of 432 strains; positive amplification products from the fHbp and nadA genes from all strains, as well as those of the nhba gene from 172 representative strains, were sequenced. RESULTS: MLST results showed that the predominant (putative) clonal complexes (CCs) of NmB isolates have changed over time in China. While strains that could not be assigned to existing (p)CCs were the biggest proportion, CC4821 was the most prevalent lineage (36.0%) since 2005. PCR and sequence analysis revealed that the 4CMenB and rLP2086 vaccine candidates were highly diverse. Respectively, 152 PorA genotypes and 83 VR2 sequences were identified with significant diversity within a single CC; the complete nadA gene was found in ten of 432 study strains; fHbp was present in most strains (422/432) with variant 2 predominating (82.9%) in both patient- and carrier- derived isolates; almost all strains harbored the nhba gene while sequences were diverse. CONCLUSIONS: With regards to clonal lineages and vaccine candidate proteins, NmB isolates from China were generally diverse. Further studies should be performed to evaluate the cross-protection of present vaccines against Chinese NmB strains. PMID- 29523452 TI - Ultrasonographic appearance of ulnar nerve at different points of elbow. PMID- 29523453 TI - Social determinants are crucial factors in the long-term prognosis of severely decompensated acute heart failure in patients over 75 years of age. AB - BACKGROUND: The association between social factors and the long-term prognosis of acute heart failure (AHF) remains unclear. METHODS AND RESULTS: One thousand fifty-one AHF patients were screened, and 915 were enrolled. Four hundred forty two AHF patients >=75 years of age (the elderly cohort) were also included in a sub-analysis. Participants who fulfilled one of the three marital status-, offspring-, and living status-related criteria were considered socially vulnerable. On this basis they were classified into the socially vulnerable (n=396) and non-socially vulnerable (n=519) groups in the overall cohort, and the socially vulnerable (n=219) and non-socially vulnerable (n=223) groups in the elderly cohort. Kaplan-Meier curves showed that the survival rate of the socially vulnerable group was significantly poorer than that of the non-socially vulnerable group in the overall (p=0.049) and elderly (p=0.004) cohorts. A multivariate Cox regression model revealed that social vulnerability was an independent predictor of 1000-day mortality in the overall [hazard ratio (HR): 1.340, 95% confidence interval (CI): 1.003-1.043, p=0.048] and elderly cohort (HR: 1.531, 95% CI: 1.027-2.280, p=0.036). Regarding the components of social vulnerability, the marital status was an independent factor in the elderly cohort (HR: 1.500, 95% CI 1.043-2.157, p=0.029). CONCLUSION: Social vulnerability was independently associated with long-term outcomes in AHF patients, especially in the elderly cohort. Organization of the social structure of AHF patients might be able to improve their prognosis. PMID- 29523455 TI - 3D geophysical imaging for site-specific characterization plan of an old landfill. AB - As it is well-known, the characterization plan of an old landfill site is the first stage of the project for the treatment and reclamation of contaminated lands. It is a preliminary in-situ study, with collection of data related to pollution phenomena, and is aimed at defining the physical properties and the geometry of fill materials as well as the possible migration paths of pollutants to the surrounding environmental targets (subsoil and groundwater). To properly evaluate the extent and potential for subsoil contamination, waste volume and possible leachate emissions from the landfill have to be assessed. In such perspective, the integrated use of geophysical methods is an important tool as it allows a detailed 3D representation of the whole system, i.e. waste body and hosting environment (surrounding rocks). This paper presents a very accurate physical and structural characterization of an old landfill and encasing rocks obtained by an integrated analysis of data coming from a multi-methodological geophysical exploration. Moreover, drillings were carried out for waste sampling and characterization of the landfill body, as well as for calibration of the geophysical modeling. PMID- 29523454 TI - Involvement of taste receptors in the effectiveness of sublingual immunotherapy. PMID- 29523456 TI - Low temperature degradation of polychlorinated dibenzo-p-dioxins and dibenzofurans over a VOx-CeOx/TiO2 catalyst with addition of ozone. AB - In order to find a catalyst to destroy polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) with high efficiency, a homemade VOx-CeOx/TiO2 catalyst was prepared, and then tested in the flue gas of a waste incinerator at temperatures of 180-240 degrees C. The results shows the best removal efficiency (93.4%) was attained already at 200 degrees C, yet degradation efficiency further raised with temperature, until 240 degrees C. Ozone (500 ppm) was also introduced into the system to increase the activity of catalyst, and removal efficiency of PCDD/Fs increased further to 97.4% and 98.8% at 200 and 240 degrees C, respectively. In addition, a lab-scale reaction system was installed to study the degradation mechanism of PCDD/Fs. Octa-chlorinated dibenzo-p-dioxin (OCDD) was selected as the study object due to the most stable structure and maximum chlorine atom number. The intermediate products resulting from the conversion of OCDD were monitored using gas chromatography/mass spectrometry and Fourier transform infrared spectroscopy and a possible reaction pathway was proposed. Dechlorination persists until the complete conversion of OCDD. Oxidation decomposes OCDD-molecules mainly into organic substances having one, two or more benzene rings, yet also alkanes, cycloalkanes and heterocompounds of sulphur, nitrogen, and halogens appear. However, more work is still needed to fit those trace products into mechanistic schemes. PMID- 29523457 TI - Short-term efficacy of minimally invasive treatments for adult obstructive sleep apnea: A systematic review and network meta-analysis of randomized controlled trials. AB - Many treatments have been proposed for adult obstructive sleep apnea (OSA), but no comprehensive comparison of all interventions has been performed. We aimed to compare and rank the effectiveness of all minimally invasive treatments for adult OSA in a systematic review and network meta-analysis. Literature was searched within Ovid MedLine, EMBASE Classic+Embase, Cochrane library, and Cochrane Database of Systematic Reviews from inception to Aug 9th, 2016 for randomized controlled trials comparing minimally invasive treatments for adult OSA. The outcomes were the changes in apnea-hypopnea index (AHI) and Epworth sleepiness scale (ESS). Frequentist approach to network meta-analysis was used and treatment hierarchy was summarized according to the surfaces under the cumulative ranking curves. Eighty-nine randomized controlled trials comprising 6346 adult OSA participants and comparing 18 different interventions were included. In comparison with no treatment, positive airway pressure (PAP) was most effective in reducing AHI (23.28 [weighted mean difference]; 95% confidence interval: 19.20 27.35). PAP was ranked first followed by mandibular advancement device (MAD) in reducing AHI. Exercise was ranked first followed by cervico-mandibular support collar in reducing ESS. Considering the effectiveness in reducing both AHI and ESS, PAP was ranked the best, followed by MAD and positional therapy, while lifestyle modification alone was the least effective intervention. Interventions that are highly effective in reducing objective laboratory-derived AHI do not demonstrate equivalent effectiveness in improving patients' subjective sleepiness. Future improvement of the interventions is necessary to simultaneously improve both objective and subjective outcomes. PMID- 29523458 TI - Bilateral pathologic mandibular fracture in maxillary osteonecrosis induced by bisphosphonates. PMID- 29523459 TI - Change in Nephrometry Scoring in Small Renal Masses (<4 cm) on Active Surveillance: Preliminary Observations From Tayside Active Surveillance Cohort (TASC) Study. AB - RATIONALE AND OBJECTIVES: Prediction of growth, in particular knowing the possibility of aggressive cancer in small renal masses on active surveillance, remains poorly understood. The study was designed to determine whether serial nephrometry score measurements could predict possibility of aggressive malignancy (grade of cancer) in patients with small renal masses opting for active surveillance initially. MATERIALS AND METHODS: One hundred sixteen patients between January 2000 and December 2016 undergoing partial nephrectomy were recruited. Out of these, 97 were analyzed using different nephrometry scoring systems. Measurement of nephrometry scores (Radius of tumors, Exo/Endophytic; Nearness of tumors to the collecting system or sinus; Anterior/posterior; Location in relation to polar lines, Preoperative Aspects and Dimensions Used for Anatomical, Centrality Index) was performed by two researchers. Among the patients opting for partial nephrectomy, 40 were on active surveillance for at least 12 months (mean 32; 12-60 months) before partial nephrectomy. Computed tomography scan images of these patients were retrieved and analyzed including comparison to histopathology. RESULTS: Nephrometry scores measured on serial computed tomography scan images showed a significant correlation between change in score and grade of cancer on multivariate analysis (P value .001). Addition of multivariate analysis to nomogram based on change in size alone did not improve predictive value of area under the curve significantly. CONCLUSIONS: Change in nephrometry scoring measurements correlates with grade of cancer in small renal masses but falls short of significantly predicting presence of malignancy or grade of cancer on nomogram in patients opting for active surveillance for small renal masses. At present, this approach may be inadequate for decision-making. PMID- 29523460 TI - [Identifying indicators of good practice in clinical and healthcare management]. AB - OBJECTIVE: To identify good practices in order to develop and implement indicators of health outcomes for clinical and healthcare management, as well as the characteristics for an indicator to be considered adequate. METHODOLOGY: A scoping review was performed, with the following phases: 1) Search and identification of bibliography. 2) Selection of relevant documents. Including those studies that discussed issues related to good practices for the use of health indicators in the management field. Those published in a language other than English or Spanish or before 2006 were excluded. 3) Analysis and extraction of information. 4) Consultation with stakeholders, using a qualitative methodology through Concept Mapping, with the participation of 40 experts (decision-makers, scientific societies, and health professionals). The data collection process included an inductive and structured procedure, with prioritisation of ideas grouped into clusters, according to feasibility and importance criteria (0-10 scale). RESULTS: Good practices identified 2 levels: 1) macro-management: Define a framework for the evaluation of indicators and establish a benchmark of indicators. 2) meso-management: Establish indicators according to evidence and expert consensus, taking into account priority areas and topics, testing before final use, and communicate results adequately. The characteristics of a suitable indicator are: 1) Approach of an important issue, 2) Scientific validity, 3) Possibility of measurement with reliable data, 4) Meaning of useful and applicable measurement, and 5) Wide scope. CONCLUSIONS: The best practices for the use of indicators in clinical and healthcare management can make it easier to monitor performance and accountability, as well as to support the decision-making addressed at the development of initiatives for quality improvement. PMID- 29523461 TI - [It is possible to improve the semen samples collection? A survey of opinion about different proposed non-surgical procedures]. PMID- 29523462 TI - Cognitively Impaired Physicians: How Do We Detect Them? How Do We Assist Them? AB - Our older physicians, an increasing number of those in practice, constitute a valuable human resource in the medical profession. Professional satisfaction, increasing life expectancy, concerns regarding financial security, and reluctance to retire are among the many reasons a physician might choose to extend practice into later adulthood. Despite the benefits of experience and expertise acquired by older physicians, cognitive changes associated with normal or pathological aging have been shown to have a significant negative effect on physician performance. Age-based cognitive assessment of physicians has been adopted in some countries and by some U.S. healthcare institutions for patient protection and improvement of physician quality of life, but there is no general guideline for the assessment and assistance of cognitively impaired late career physicians in the United States. Self-reports and reports from peers are an inadequate safeguard, leaving impaired physicians and their patients at risk. In this discussion, we will describe cognitive aging, the effects of cognitive aging on physician performance, some current monitoring systems, and recommendations for identifying and assisting physicians found to be impaired. PMID- 29523463 TI - Cataplexy plus presence of HLA-DQB1*0602 allele can predict Hypocretin-1 deficiency. PMID- 29523464 TI - [Tuberculous pneumothorax: Diagnosis and treatment]. AB - BACKGROUND: Pneumothorax is a serious complication of cavitary pulmonary tuberculosis. The aim of this study was to describe clinical futures, to highlight challenges of its management. METHODS: A retrospective multicentric and descriptive study including 65 patients treated for PT (1999-2015) was conducted to figure out clinical futures and its work-up. RESULTS: The mean age was 37.8 years. The sex ratio was 3.6. Smoking history and incarceration were noted respectively in 67.6 and 15.3% of cases. Acute respiratory failure and cachexia were reported in 26.1 and 10.7% of cases. The PT was inaugural in 41.5% of cases. Pyo-pneumothorax was noted in 69.2% of cases. The duration of antituberculous treatment ranged from 6 to 15 months for susceptible TB and was at least 12 months for resistant TB (4 cases). Thoracic drainage was performed in 90.7% patients. Its average length was 47 days. The drain drop was noted in 20% of cases. Bronchopleural fistula was diagnosed in 6 cases and pleural infection in 5 of cases. Surgery treatment was necessary in 6 cases. Mean time to surgery was 171 days. Six patients had pleural decortication associated with pulmonary resection in 4 cases. Persistent chronic PT was noted in 12.6% and chronic respiratory failure in 3% of cases and death in 15.3% of cases. CONCLUSION: The diagnosis of the PT is often easy. Its treatment encounters multiples difficulties. Duration of thoracic drainage and anti-TB treatment are usually long. Surgery is proposed lately. PMID- 29523465 TI - Low Rates of Major Complications for Radiofrequency Ablation of Atrial Fibrillation Maintained Over 14 Years: A Single Centre Experience of 2750 Consecutive Cases. AB - BACKGROUND: Despite technological advances, studies continue to report high complication rates for atrial fibrillation (AF) ablation. We sought to review complication rates for AF ablation at a high-volume centre over a 14-year period and identify predictors of complications. METHODS: We reviewed prospectively collected data from 2750 consecutive AF ablation procedures at our institution using radiofrequency energy (RF) between January 2004 and May 2017. All cases were performed under general anaesthetic with transoesophageal echocardiography (TEE), 3D-mapping and an irrigated ablation catheter. Double transseptal puncture was performed under TEE guidance. All patients underwent wide antral circumferential isolation of the pulmonary veins (30W anteriorly, 25W posteriorly) with substrate modification at operator discretion. RESULTS: Of 2255 initial and 495 redo procedures, ablation strategies were: pulmonary vein isolation (PVI) only 2097 (76.3%), PVI+ LA lines 368 (13.4%), PVI+posterior wall 191 (6.9%), PVI+cavotricuspid isthmus 277 (10.1%). There were 23 major (0.84%) and 20 minor (0.73%) complications. Cardiac tamponade (five cases - 0.18%) and phrenic nerve palsy (one case - 0.04%) rates were very low. Major vascular complications necessitating surgery or blood transfusion occurred in five patients (0.18%). There were no cases of death, permanent disability, atrio oesophageal fistulae or symptomatic pulmonary vein (PV) stenosis, although there were five TEE probe-related complications (0.18%). Female gender (OR 2.14; 95% CI 1.07-4.26) but not age >70 (OR 1.01) was the only multivariate predictor of complications. CONCLUSIONS: Atrial fibrillation ablation performed at a high volume centre using RF can be achieved with a low major complication rate in a representative AF population over a sustained period of time. PMID- 29523466 TI - Improving the Prescribing Gap For Guideline Recommended Medications Post Myocardial Infarction. AB - BACKGROUND: We assessed the effect of a pre-discharge medication checklist on discharge prescription rates of guideline recommended medications following myocardial infarction. In addition, we assessed what proportion of the residual prescribing gap following implementation of the checklist was due to the presence of contraindications. METHODS: We examined baseline prescription rates of guideline recommended medications in 100 patients discharged from our institution following acute myocardial infarction. We then introduced a pre-discharge checklist and reassessed discharge medications and reasons for non-prescription of guideline recommended medications in 447 patients with acute myocardial infarction. RESULTS: We demonstrated a significant gap in the prescription of guideline recommended secondary prevention medications at the time of discharge in our pre-intervention cohort. Introduction of a pre-discharge checklist resulted in a significant improvement in the prescription rates of all guideline recommended secondary prevention medications, with aspirin increasing from 90% to 97% (p=0.004), Adenosine diphosphate (ADP) receptor antagonist from 84% to 96% (p=0.0001), B-blocker from 79% to 87% (p=0.03), statin from 88% to 96% (p=0.002) and angiotensin converting enzyme (ACE) inhibitor from 58% to 70% (p=0.03). The residual gap in prescribing was largely explained by the presence of contraindications or absence of an indication in the case of ACE-inhibitors. Once these were taken into account there was a residual gap of 0-4% which represents genuine non-adherence to the guidelines. CONCLUSIONS: Introduction of a pre discharge checklist led to significant improvement in prescription rates of all five guideline recommended secondary prevention medications. The residual gap in medication prescription following introduction of the checklist was largely due to the presence of contraindications rather than non-adherence. PMID- 29523467 TI - Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors. AB - A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development. PMID- 29523468 TI - Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents. AB - 4-(Nitrophenyl)hydrazone derivatives of N-acylhydrazone were synthesized and screened for suppress lymphocyte proliferation and nitrite inhibition in macrophages. Compared to an unsubstituted N-acylhydrazone, active compounds were identified within initial series when hydroxyl, chloride and nitro substituents were employed. Structure-activity relationship was further developed by varying the position of these substituents as well as attaching structurally-related substituents. Changing substituent position revealed a more promising compound series of anti-inflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Anti-inflammatory activity of compounds is achieved by modulating IL-1beta secretion and prostaglandin E2 synthesis in macrophages and by inhibiting calcineurin phosphatase activity in lymphocytes. Compound SintMed65 was advanced into an acute model of peritonitis in mice, where it inhibited the neutrophil infiltration after being orally administered. In summary, we demonstrated in great details the structural requirements and the underlying mechanism for anti-inflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the anti-inflammatory drug development in general. PMID- 29523469 TI - A novel series of 4-methyl substituted pyrazole derivatives as potent glucagon receptor antagonists: Design, synthesis and evaluation of biological activities. AB - A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC50 = 0.09 MUM, 0.06 MUM, 0.07 MUM and 0.08 MUM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC50 = 0.22 MUM, 0.26 MUM, 0.44 MUM and 0.46 MUM, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist. PMID- 29523471 TI - Helicobacter pylori infection in Egypt; a very common disease with low evidence based clinical practice. PMID- 29523470 TI - Copper concentrations in Egyptian infants with cholestasis: A single center study. AB - BACKGROUND AND STUDY AIMS: Hepatobiliary cholestatic disorders produce excess copper (Cu) retention in the liver, which is toxic and may cause hepatitis, fulminant hepatic failure, cirrhosis and death. In this study, we measured hepatic Cu and tested its correlation with serum Cu (S. Cu) and serum ceruloplasmin (S. ceruloplasmin) in cholestatic infants. PATIENTS AND METHODS: 41 cholestatic infants were enrolled as cases and 11 healthy infants as control subjects. S. Cu and S. ceruloplasmin were done for all infants and hepatic Cu was measured in the liver specimen in cases. RESULTS: Cases were 63.5% males with their age ranging between 1 and 7 months, while control subjects were 45.5% males with an age range between 3 and 18 months. Among cases, 41.5% had biliary atresia and 58.5% had intrahepatic cholestasis. Cholestatic infants had significantly higher levels of S. Cu and S. ceruloplasmin than control subjects and their hepatic Cu concentration was significantly higher than literature control. Infants with biliary atresia showed higher levels of Cu indices, with no statistical significance. Serum and hepatic Cu levels positively correlated with each other and with S. ceruloplasmin. Results of ROC curve showed that S. Cu was highly sensitive and specific for predicting hepatic Cu concentration at cut-off 181 MUg/dl. CONCLUSION: Serum and hepatic Cu concentrations were markedly elevated in patients with cholestasis and positively correlated with each other and with S. ceruloplasmin. S. Cu level can predict hepatic Cu concentration. PMID- 29523472 TI - EUS of pancreatic ascariasis. AB - Ascaris is a common cause of acute pancreatitis in developing countries. The mechanism of ascariasis induced acute pancreatitis include obstruction of papilla of Vater, invasion of common bile duct, or pancreatic duct (PD). PD ascariasis is a rare diagnosis. Endoscopic ultrasound is a highly accurate method to diagnose the aetiology of idiopathic acute pancreatitis with reference to biliary and pancreatic ascariasis. Treatment usually consist of endoscopic removal of worms with dormia basket or forceps on side viewing endoscopy. Ascaris induced pancreatitis is generally mild and worm extraction is associated with rapid relief of symptoms. We present a case of PD ascariasis diagnosed on endoscopic ultrasound. PMID- 29523473 TI - Re: MRI anatomical preoperative evaluation of distally based peroneus brevis muscle flap in reconstructive surgery of the lower limb. PMID- 29523474 TI - Mini-guts in a dish: Perspectives of adult Cystic Fibrosis (CF) patients and parents of young CF patients on organoid technology. AB - BACKGROUND: Organoid technology enables the cultivation of human tissues in a dish. Its precision medicine potential could revolutionize the Cystic Fibrosis (CF) field. We provide a first thematic exploration of the patient perspective on organoid technology to set the further research agenda, which is necessary for responsible development of this ethically challenging technology. METHODS: 23 semi-structured qualitative interviews with 14 Dutch adult CF patients and 12 parents of young CF patients to examine their experiences, opinions, and attitudes regarding organoid technology. RESULTS: Four themes emerged: (1) Respondents express a close as well as a distant relationship to organoids; (2) the open-endedness of organoid technology sparks hopes and concerns, (3) commercial use evokes cautiousness. (4) Respondents mention the importance of sound consent procedures, long-term patient engagement, responsible stewardship, and stringent conditions for commercial use. CONCLUSIONS: The precision medicine potential of organoid technology can only be realized if the patient perspective is taken adequately into account. PMID- 29523475 TI - Survey on the Contemporary Management of Intraoperative Urethral Injuries During Penile Prosthesis Implantation. AB - BACKGROUND: Intraoperative urethral injury is an uncommon event during the placement of a penile prosthesis, and alternative management strategies have been proposed with continuation of implantation after urethral injury. AIM: To evaluate surgeon practices in the management of intraoperative urethral injury. METHODS: An online survey was sent to the society listservs of the Genitourinary Reconstructive Surgeons (GURS) and the Sexual Medicine Society of North America (SMSNA). Physicians were queried on their fellowship training, experience with penile prosthesis implantation, and management of urethral injuries during prosthesis placement. The response data were analyzed using SAS 9.4 (SAS Institute, Cary, NC, USA). The chi2 test and Fisher exact test were used to determine associations between variables. OUTCOMES: Survey responses. RESULTS: 131 survey responses were analyzed. Of the responders, 41.2% were GURS fellowship trained, 19.1% were SMSNA trained, 30.5% were non-fellowship trained, and 9.2% were trained in other fellowships. 25.4% of participants performed more than 50 implantations per year, 37.7% performed 20 to 50 per year, and 36.9% performed fewer than 20 per year. Urethral injury during prosthesis implantation was uncommon, with 26.2% reporting 0 injury, 58.5% reporting 1 to 3 injuries, and 15.4% reporting more than 3 career injuries. Injuries were most commonly encountered during corporal dilation (71.1%) compared with corporal exposure (12.5%) or penile straightening maneuvers (7.0%). There was no statistically significant difference with aborting or continuing implantation among GURS trained, SMSNA-trained, other fellowship-trained, and non-fellowship-trained surgeons. Of all responders, 55% would abort the procedure after distal urethral injury, whereas 45% would continue the procedure with unilateral or bilateral insertion of cylinders. Patient factors that increased likelihood of terminating the procedure in the case of urethral injury included immunosuppression, spinal cord injury, and clean intermittent catheterization dependence. CLINICAL IMPLICATIONS: A urethral injury during penile prosthesis implantation might not mandate termination of the procedure despite classic teaching. STRENGTHS AND LIMITATIONS: The strength of this study is that it provides difficult to obtain epidemiologic data on the frequency and management of this clinically significant injury. Limitations include the inherent biases from a survey-based study including response bias and recall bias. The survey response rate could not be obtained. CONCLUSION: Urethral injury during penile prosthesis implantation is a rare but clinically significant risk of the procedure, with many variations in management of the injury. Termination and delayed implantation might not be necessary after injury, although long-term outcome data are difficult to obtain. Sexton SJ, Granieri MA, Lentz AC. Survey on the Contemporary Management of Intraoperative Urethral Injuries During Penile Prosthesis Implantation. J Sex Med 2018;15:576-581. PMID- 29523476 TI - Health-Related Lifestyle Factors and Sexual Dysfunction: A Meta-Analysis of Population-Based Research. AB - BACKGROUND: Sexual dysfunction is a common problem among men and women and is associated with negative individual functioning, relationship difficulties, and lower quality of life. AIM: To determine the magnitude of associations between 6 health-related lifestyle factors (cigarette smoking, alcohol intake, physical activity, diet, caffeine, and cannabis use) and 3 common sexual dysfunctions (erectile dysfunction, premature ejaculation, and female sexual dysfunction). METHODS: A comprehensive literature search of 10 electronic databases identified 89 studies that met the inclusion criteria (452 effect sizes; N = 348,865). Pooled mean effects (for univariate, age-adjusted, and multivariable-adjusted estimates) were computed using inverse-variance weighted random-effects meta analysis and moderation by study and population characteristics were tested using random-effects meta-regression. RESULTS: Mean effect sizes from 92 separate meta analyses provided evidence that health-related lifestyle factors are important for sexual dysfunction. Cigarette smoking (past and current), alcohol intake, and physical activity had dose-dependent associations with erectile dysfunction. Risk of erectile dysfunction increased with greater cigarette smoking and decreased with greater physical activity. Alcohol had a curvilinear association such that moderate intake was associated with a lower risk of erectile dysfunction. Participation in physical activity was associated with a lower risk of female sexual dysfunction. There was some evidence that a healthy diet was related to a lower risk of erectile dysfunction and female sexual dysfunction, and caffeine intake was unrelated to erectile dysfunction. Publication bias appeared minimal and findings were similar for clinical and non-clinical samples. CLINICAL TRANSLATION: Modification of lifestyle factors would appear to be a useful low risk approach to decreasing the risk of erectile dysfunction and female sexual dysfunction. STRENGTHS AND LIMITATIONS: Strengths include the testing of age adjusted and multivariable-adjusted models and tests of potential moderators using meta-regression. Limitations include low statistical power in models testing diet, caffeine, and cannabis use as risk factors. CONCLUSION: Results provide compelling evidence that cigarette smoking, alcohol, and physical activity are important for sexual dysfunction. Insufficient research was available to draw conclusions regarding risk factors for premature ejaculation or for cannabis use as a risk factor. These findings should be of interest to clinicians treating men and women with complaints relating to symptoms of sexual dysfunction. Allen MS, Walter EE. Health-Related Lifestyle Factors and Sexual Dysfunction: A Meta-Analysis of Population-Based Research. J Sex Med 2018;15:458 475. PMID- 29523478 TI - Stability of Genetic and Environmental Influences on Female Sexual Functioning. AB - BACKGROUND: Genetic factors have been implicated in the etiology of female sexual dysfunction. Yet, how much the dynamic nature of sexual functioning is influenced by changes in genetic and/or environmental factors remains unknown. AIM: To explore temporal stability of genetic and environmental influences on female sexual functioning over a 4-year period. METHODS: Data on desire, arousal, lubrication, orgasm, satisfaction, and pain were collected in 2009 and 2013 using the Female Sexual Function Index and were available for 1,209 British twin women. OUTCOMES: To track the stability of genetic influences the Female Sexual Function Index sub-domain and total scores were subject to multivariate twin analyses for repeated measures. RESULTS: Desire showed a lower heritability at follow-up (37% vs 14%) whereas for arousal and sexual pain the heritability at follow-up was higher compared to baseline (28% vs 34% and 30% vs 45%, respectively). The heritability of lubrication remained stable at 27%. According to the best-fitting additive environmental (AE) Cholesky model for all domains except for sexual pain there were no new genetic factors expressing themselves over the 4-year period, but an addition of new, unique environmental determinants could be observed. For sexual pain an additional genetic factor could be observed at follow-up, explaining 39% of the phenotypic variance. CLINICAL TRANSLATION: The biological pre-disposition to sexual problems seems to remain relatively stable over time. CONCLUSIONS: This is the first study to investigate the genetic stability of female sexual functioning in a large population sample of women. White ethnicity and the relatively high mean age of women asks for caution in extrapolating the findings to other ethnic and age groups. The findings highlight the value of more in-depth exploration of the non-shared environmental influences that could provide clues to the mechanisms behind remittance and/or persistence of sexual problems. Integration of these findings may provide a useful conceptual framework for the treatment and prevention of certain types of sexual problems. Burri A, Ogata S. Stability of Genetic and Environmental Influences on Female Sexual Functioning. J Sex Med 2018;15:550-557. PMID- 29523477 TI - Predictors of Sexual Intercourse Frequency Among Couples Trying to Conceive. AB - BACKGROUND: Little is known about the predictors of sexual intercourse frequency (SIF) among couples trying to conceive despite the well-established link between SIF and fecundity. AIM: To evaluate men's and women's demographic, occupational, and lifestyle predictors of SIF among couples. METHODS: 469 Couples without a history of infertility participating in the Longitudinal Investigation of Fertility and the Environment Study (2005-2009) were followed up for <=1 year while trying to conceive. At enrollment, both partners were interviewed about demographic, occupational, lifestyle, and psychological characteristics using standardized questionnaires. Multivariable generalized linear mixed models with Poisson distribution were used to estimate the adjusted percent difference in SIF across exposure categories. OUTCOMES: SIF was recorded in daily journals and summarized as average SIF/mo. RESULTS: The median (interquartile range) SIF during follow-up was 6 (4-9) acts/mo. For every year increase in age for women and men, SIF decreased by -0.8% (95% CI -2.5 to 1.0%) and -1.7% (95% CI -3.1 to 0.3%). Women with high school education or less and those of non-white race had 34.4% and 16.0% higher SIF, respectively. A similar trend was seen for men's education and race. Only couples where both partners (but not just 1 partner) worked rotating shifts had -39.1% (95% CI -61.0 to -5.0%) lower SIF compared to couples where neither partner worked rotating shifts. Men's (but not women's) exercise was associated with 13.2% (95% CI 1.7-26.0%) higher SIF. Diagnosis of a mood or anxiety disorder in men (but not women) was associated with a 26.0% (95% CI -42.7 to -4.4%) lower SIF. Household income, smoking status, body mass index, night work, alcohol intake, and psychosocial stress were not associated with SIF. CLINICAL TRANSLATION: Even among couples trying to conceive, there was substantial variation in SIF. Both partners' age, education, race, and rotating shift work as well as men's exercise and mental health play an important role in determining SIF. CONCLUSIONS: As this was a secondary analysis of an existing study, we lacked information on many pertinent psychological and relationship quality variables and the hormonal status of participants, which could have affected SIF. The unique population-based couple design, however, captured both partners' demographics, occupational characteristics, and lifestyle behaviors in advance of their daily, prospective reporting of SIF, which was a major strength. Important predictors of SIF among couples attempting to conceive include men's exercise and mental health and both partners' age, education, race, and rotating shift work. Gaskins AJ, Sundaram R, Buck Louis GM, et al. Predictors of Sexual Intercourse Frequency Among Couples Trying to Conceive. J Sex Med 2018;15:519 528. PMID- 29523479 TI - Andrianne Mini-Jupette Graft at the Time of Inflatable Penile Prosthesis Placement for the Management of Post-Prostatectomy Climacturia and Minimal Urinary Incontinence. AB - BACKGROUND: After radical prostatectomy (RP), erectile dysfunction, often necessitating the need for inflatable penile prosthesis (IPP) insertion, and urinary incontinence and climacturia can ensue. AIM: To assess the efficacy and safety of the mini-jupette, a mesh used to approximate the medial aspects of the 2 corporotomies at the time of IPP insertion, for the management of climacturia and urine leakage in patients with minimal incontinence. METHODS: We conducted a pilot multicenter study of patients with post-RP erectile dysfunction and climacturia and/or mild urinary incontinence (<=2 pads/day [ppd]) undergoing IPP insertion with concomitant placement of a mini-jupette graft. OUTCOMES: Pre- and postoperative erectile function, continence and climacturia, and overall surgical outcomes were assessed. RESULTS: 38 patients underwent the mini-jupette procedure. The mean age of the population was 65.3 years (SD = 7.7). 30 had post RP climacturia and 32 patients had post-RP incontinence (mean = 1.3 ppd, SD = 0.8). 31 patients received Coloplast Titan, 4 received AMS 700 LGX, and 3 received AMS 700 CX IPPs. Mean corporotomy size was 2.9 cm (SD = 1.0). Mean graft measurements were 3.2 cm (SD = 0.9) for width, 3.3 cm (SD = 1.3) for length, and 11.0 cm2 (SD = 5.1) for surface area. At a mean follow-up of 5.1 months (SD = 6.9), there were 5 postoperative complications (13.2%) of which 4 required explantation. Climacturia and incontinence were subjectively improved in 92.8% and 85.7%, respectively. Mean ppd decreased by 1.3 postoperatively. CLINICAL IMPLICATIONS: The Andrianne mini-jupette is a feasible adjunct to IPP placement that can be used for subsets of patients with post-RP climacturia and/or minimal incontinence. STRENGTHS AND LIMITATIONS: Strengths of this study include the novel nature of this intervention, the multi-institutional nature of the study, and the promising results demonstrated. Limitations include the retrospective nature of the study and the heterogeneity of the techniques and grafts used by different surgeons involved. CONCLUSION: Longer follow-up and larger patient cohorts are needed to confirm the long-term safety and benefits of this intervention. Yafi FA, Andrianne R, Alzweri L, et al. Andrianne Mini-Jupette Graft at the Time of Inflatable Penile Prosthesis Placement for the Management of Post-Prostatectomy Climacturia and Minimal Urinary Incontinence. J Sex Med 2018;15:789-796. PMID- 29523480 TI - [Management by assisted reproductive technology in women with endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - Should the presence of endometriosis change the management of assisted reproductive technology? There is no difference in pregnancy rate after IVF between an agonist or antagonist protocol in patients with endometriosis, so the choice between one or the other of these protocols is free. But the review of the literature has shown an improvement in the chances of pregnancy in case of prolonged ovulation suppression before stimulation for IVF with a GnRH agonist analogue or with oral contraception, especially in cases of severe endometriosis. Endometriosis, regardless of the stage and type of lesions, would have no effect on the IVF results in terms of pregnancy rate and live birth rate, but with a lower number of oocytes collected, especially in cases of severe endometriosis. In a context of superficial endometriosis without pain and of infertility, surgical treatment of superficial endometriosis is not recommended just to increase the chances of pregnancy in IVF. Surgery may have a place in case of failure of IVF to improve the results of the ART. In case of recurrence of endometriosis, surgery is not better than IVF, a medico-surgical concertation is recommended. In addition, studies on ovulation stimulation for IVF do not show any aggravation of the symptoms associated with endometriosis lesions, or an acceleration of its progression, or an increase in the rate of recurrence of the disease. PMID- 29523481 TI - [Typologies of Madrid's citizens (Spain) at the end-of-life: cluster analysis]. AB - OBJECTIVE: To establish typologies within Madrid's citizens (Spain) with regard to end-of-life by cluster analysis. METHOD: The SPAD 8 programme was implemented in a sample from a health care centre in the autonomous region of Madrid (Spain). A multiple correspondence analysis technique was used, followed by a cluster analysis to create a dendrogram. A cross-sectional study was made beforehand with the results of the questionnaire. RESULTS: Five clusters stand out. Cluster 1: a group who preferred not to answer numerous questions (5%). Cluster 2: in favour of receiving palliative care and euthanasia (40%). Cluster 3: would oppose assisted suicide and would not ask for spiritual assistance (15%). Cluster 4: would like to receive palliative care and assisted suicide (16%). Cluster 5: would oppose assisted suicide and would ask for spiritual assistance (24%). CONCLUSIONS: The following four clusters stood out. Clusters 2 and 4 would like to receive palliative care, euthanasia (2) and assisted suicide (4). Clusters 4 and 5 regularly practiced their faith and their family members did not receive palliative care. Clusters 3 and 5 would be opposed to euthanasia and assisted suicide in particular. Clusters 2, 4 and 5 had not completed an advance directive document (2, 4 and 5). Clusters 2 and 3 seldom practiced their faith. This study could be taken into consideration to improve the quality of end-of-life care choices. PMID- 29523482 TI - Solidarity outpatient clinics in Greece: a survey of a massive social movement. AB - OBJECTIVE: Until 2016, around 3 million persons had limited access to health care in Greece due to the economic crisis. We describe a massive solidarity movement of community clinics and pharmacies in Greece. METHOD: We conducted a survey in 2014-15 and describe the characteristics of community clinics and pharmacies spontaneously established all over Greece after 2008. RESULTS: A characteristic of the 92 active solidarity clinics is autonomous collective functioning, free services, and funding from non-governmental sources. The largest clinics examined more than 500 uninsured or partly insured patients per month. Clinics covered a wide range of clinical and preventive services. Funding, availability of drugs, vaccines, medical material and their legal status were the main problems identified. The solidarity movement involved thousands of health professionals covering essential population needs. CONCLUSIONS: The community outpatient clinics were an outstanding example of solidarity and temporarily alleviated the health needs of a large part of the population. PMID- 29523483 TI - Prenatal screening for fetal and obstetric complications: New opportunities and challenges. PMID- 29523484 TI - Patterns of injecting and non-injecting drug use by sexual behaviour in people who inject drugs attending services in England, Wales and Northern Ireland, 2013 2016. AB - BACKGROUND: Higher levels of drug use have been reported in lesbian, gay, bisexual and transgender (LGBT) communities, some of which can be explained by sexualised drug use, including 'chemsex'; the use of drugs before or during planned sexual activity to sustain, enhance, disinhibit or facilitate sex. We explored injecting and non-injecting drug use by sexual behaviour among people who inject drugs (PWID) in England, Wales and Northern Ireland. METHODS: Data were used from an unlinked-anonymous survey of PWID (2013-2016), where participants recruited through services self-completed a questionnaire. We included sexually active participants who had injected in the previous year, and compared injecting and non-injecting drug use between men reporting sex with men (MSM) and heterosexual men, and between women reporting sex with women (WSW) and heterosexual women. The questionnaire did not include GHB/GBL and methamphetamine use. RESULTS: There were 299 MSM, 3215 heterosexual male, 122 WSW and 1336 heterosexual female participants. MSM were more likely than heterosexual men to use drugs associated with chemsex: injected or non-injected mephedrone (adjusted OR (AOR) 2.22, 95%CI 1.54-3.22; AOR 2.15, 95%CI 1.48-3.11) and injected or non injected ketamine (AOR 1.98, 95%CI 1.29-3.05; AOR 2.57, 95%CI 1.59-4.15). MSM were also more likely to inject methadone, inhale solvents, take ecstasy, cocaine or speed. WSW were more likely than heterosexual women to use non-injected mephedrone (AOR 2.19, 95%CI 1.20-3.99) and use injected or non-injected ketamine (AOR 5.58, 95%CI 2.74-11.4; AOR 3.05, 95%CI 1.30-7.19). WSW were also more likely to inject methadone, inject cocaine, use non-injected cocaine, crack, benzodiazepines or ecstasy, inhale solvents, or smoke cannabis. CONCLUSION: Injecting and non-injecting drug use differed between MSM/WSW and heterosexual men and women. The use of drugs that have been associated with chemsex and sexualised drug use is more common among both MSM and WSW than heterosexual men and women. PMID- 29523485 TI - Risk-stratification, resource availability, and choice of surgical location for the management of parturients with abnormal placentation: a survey of United States-based obstetric anesthesiologists. AB - BACKGROUND: Parturients with abnormally adherent placentas present anesthetic challenges that include risk-stratification, management planning and resource utilization. The labor and delivery unit may be remote from the main operating room services. METHODS: Division chiefs of North American obstetric anesthesiology services were surveyed about their practices and management of parturients with an abnormally adherent placenta. RESULTS: Eighty-four of 122 chiefs, representing 103 hospital sites, responded to the survey (response rate 69%). Sixty-one percent of respondents agreed that women with preoperative placental imaging that was "suspicious" of placenta accreta represented a lower risk category; all other suggested descriptions fell into a higher risk category. Seventy-nine percent of respondents indicated that lower risk cases were managed on the labor and delivery unit, while 71% indicated that higher risk cases would be managed in the main operating room. Institutions where all cases were managed on the labor and delivery unit had better access to human and technical resources, were less remote from their main operating areas, and promoted neuraxial rather than general anesthesia, even for parturients perceived to be at higher risk. CONCLUSIONS: Obstetric anesthesia leaders identified patients at lower clinical risk and those less likely to require greater resources. Additional resources were available in institutions where all abnormal placentation cases were managed on the labor and delivery unit. Practitioners should consider risk-stratification and resource availability when planning high risk cases. PMID- 29523486 TI - A Convergent Mixed-Methods Exploration of the Effects of Community-Engaged Coursework on Graduate Student Learning. AB - OBJECTIVE: To examine the impact of a community-engaged assignment on graduate student learning in the nutritional sciences. DESIGN: Convergent mixed-methods design with parallel data collection and terminal merging of data. Data were composed of grant proposals, reflection papers, and informal course evaluations from 2 semesters of the same course. Fall students wrote proposals on behalf of a community partner whereas spring students wrote fictitious grants to improve nutrition on their campus. SETTING: A large public university in northeastern US. PARTICIPANTS: Students enrolled in the fall (n = 19) or spring (n = 14) semester of the same graduate nutrition course. PHENOMENON OF INTEREST: Grant quality, student engagement, and collaboration with peers. ANALYSIS: Quantitative rubric based rating of grant proposals, emergent and thematic qualitative coding of open ended responses, and independent-samples t test of Likert-scale questions. Data were compared between semesters and reported in a contiguous narrative approach. RESULTS: Students across semesters experienced academic and personal gains from the assignment. Comparatively, fall students expressed enhanced engagement, improved group dynamics, more frequent application of the assignment to their lives, and a better aggregate grant score. CONCLUSIONS AND IMPLICATIONS: Both experiential and community-engaged coursework can enhance learning outcomes at the graduate level and prepare students for careers in nutrition. PMID- 29523487 TI - Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. METHODS: A meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. RESULTS: Four eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81-0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=-1.13, P=0.26). CONCLUSION: CETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration. PMID- 29523488 TI - Evaluation and Management of Hypoactive Sexual Desire Disorder. AB - INTRODUCTION: Hypoactive sexual desire disorder (HSDD) often has a negative impact on the health and quality of life of women; however, many women do not mention-let alone discuss-this issue with their physicians. Providers of gynecologic services have the opportunity to address this subject with their patients. AIM: To review the diagnosis and evidence-based treatment of low sexual desire in women with a focus on strategies that can be used efficiently and effectively in the clinic. METHODS: The Medline database was searched for clinically relevant publications on the diagnosis and management of HSDD. RESULTS: HSDD screening can be accomplished during an office visit with a few brief questions to determine whether further evaluation is warranted. Because women's sexual desire encompasses biological, psychological, social, and contextual components, a biopsychosocial approach to evaluating and treating patients with HSDD is recommended. Although individualized treatment plan development for patients requires independent medical judgment, a simple algorithm can assist in the screening, diagnosis, and management of HSDD. Once a diagnosis of HSDD has been made, interventions can begin with office-based counseling and progress to psychotherapy and/or pharmacotherapy. Flibanserin, a postsynaptic 5-hydroxytryptamine 1A agonist and 2A antagonist that decreases serotonin levels and increases dopamine and norepinephrine levels, is indicated for acquired, generalized HSDD in premenopausal women and is the only agent approved in the United States for the treatment of HSDD in women. Other strategies to treat HSDD include using medications indicated for other conditions (eg, transdermal testosterone, bupropion). Bremelanotide, a melanocortin receptor agonist, is in late-stage clinical development. CONCLUSIONS: Providers of gynecologic care are uniquely positioned to screen, counsel, and refer patients with HSDD. Options for pharmacotherapy of HSDD are currently limited to flibanserin, approved by the US Food and Drug Administration, and off-label use of other agents. Clayton AH, Kingsberg SA, Goldstein I. Evaluation and Management of Hypoactive Sexual Desire Disorder. Sex Med 2018;6:59-74. PMID- 29523489 TI - Male Sexual Quality Of Life Is Maintained Satisfactorily Throughout Life In The Amazon Rainforest. AB - INTRODUCTION: The Amazon Rainforest is a cradle of biodiversity, where different ethnic groups have specific sexual habits. AIMS: To define the average sexual quality of life of Amazonian men 18 to 69 years old, evaluate the influence of aging on their sexual function, and calculate the prevalence of premature ejaculation, delayed ejaculation, and hypoactive sexual desire disorder. METHODS: A cross-sectional quantitative probability sample study was performed with a demographically representative population (N = 385), with data collected privately at participants' houses, including men who had been sexually active for a minimum of 6 months. The Male Sexual Quotient (MSQ) was used to measure sexual satisfaction and function. Statistical analysis was performed with SPSS 21.0 using the Kruskal-Wallis test (P < .05), and a multiple linear regression analysis was performed to investigate which factors could predict participants' quality of sexual life. MAIN OUTCOME MEASURES: MSQ scores. RESULTS: The response rate was 81.69%. The mean age was 36.00 +/- 12.95 years, and most men had mixed ethnicity (63.11%), were self-employed (42.07%), had a monthly earned income of US$0 to US$460 (46.75%), and were single (36.10%). The mean MSQ score was 80.39 +/- 12.14 (highly satisfied). None of the demographic characteristics showed a statistically significant influence on sexual satisfaction. The difference in quality of sexual life was statistically significant compared with age (P < .01). The domains of desire (P < .01), partner satisfaction (P = .04), and erection quality (P < .01, P = .03, P = .02) were statistically significant. Prevalences of sexual dysfunctions were 36.54% for premature ejaculation, 6.5% for delayed ejaculation, and 11.69% for hypoactive sexual desire disorder. CONCLUSIONS: Independent of age, these men have an excellent quality of sexual life. Sexual domains such as desire, partner satisfaction, and erection quality are related to the correlation between sexual quality of life and aging. However, the prevalence of premature ejaculation seems to be slightly higher than in other parts of the world. Teixeira T, Nazima M, Hallak J. Male Sexual Quality Of Life Is Maintained Satisfactorily Throughout Life In The Amazon Rainforest. Sex Med 2018;6:90-96. PMID- 29523490 TI - Thrombotic microangiopathy in a very young infant with mitral valvuloplasty. AB - BACKGROUND: Thrombotic microangiopathies (TMA) are microvascular occlusive disorders characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and red cell fragmentation. Post-operative TMA mostly occurs in adult patients with cardiovascular surgery, with the distinct pathophysiology from classical thrombotic thrombocytopenic purpura (TTP) although the exact pathophysiology remains unclear. CASE PRESENTATION: A one-month-old infant developed TMA after the initial surgery of double outlet right ventricle. ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) activity was sustained (64%) with the undetectable inhibitor. Von Willebrand factor (VWF) multimer analyses showed absent high-molecular weight multimers. Echocardiography disclosed severe mitral regurgitation. The mitral valve repair 32 days after the initial valvuloplasty led to prompt resolution of TMA. These suggested that TMA occurred in association with valvulopathy-triggered turbulent shear flow, mechanical hemolysis and endothelial damage. The consumption of large VWF multimers might account for the vascular high shear stress shown in Heyde syndrome. CONCLUSION: The youngest case of post-operative TMA underscores the critical coagulopathy after the first surgical intervention for congenital heart disease. PMID- 29523491 TI - Cascade screening program for familial hypercholesterolemia. AB - INTRODUCTION AND OBJECTIVE: Early detection of heterozygous familial hypercholesterolemia (HFH) is needed to prevent premature cardiovascular events. Our aim isto describe the course of an HFH screening detection day in the Northern Cadiz Health Area in Spain and to analyze the data recorded. SUBJECTS AND METHODS: Descriptive study of an FH cascade screening program. Index cases (ICs) and their 1st and 2nd grade relatives were appointed during a weekend by the FH Foundation. Venous blood samples were taken from the subjects for genetic, blood, and chemistry tests; specialized medical consultation and physical examination were performed. RESULTS: The study sample consisted of 132 subjects: 21 ICs and 111 relatives (16 under 18years old), with a mean age of 11.4years (SD4.57). Mean age of subjects over 18years was 45.2years. A gene mutation was found in 90 relatives. Mean age at diagnosis was 25years (SD17.7) for relatives and for 36.4years (SD17.2; P=.01) for ICs. Smoking rate was higher in relatives than in ICs (26.3% vs 4.8%; P=.02) and corneal arcus was more common in ICs as compared to relatives (47.6% vs 12.6%; P<.001). Prior myocardial infarction was recorded in 14.3% of ICs and 4.2% of relatives respectively (P=.07). Maximum lipid lowering treatment was being administered to 43.1%. CONCLUSIONS: The screening detection approach identified the estimated 4% population with HFH in the area, and allows for diagnosing HFH 11.4years earlier. PMID- 29523492 TI - Optic Nerve Head Elevation in an Asymptomatic Child: Worry or Watch? PMID- 29523495 TI - Predicting outcome and improving treatment for Lassa fever. PMID- 29523494 TI - Age at First Concussion Influences the Number of Subsequent Concussions. AB - BACKGROUND: Individuals who sustain their first concussion during childhood may be at greater risk of sustaining multiple concussions throughout their lifetime because of a longer window of vulnerability. This article aims to estimate the association between age at first concussion and number of subsequent concussions. PATIENTS AND METHODS: A total of 23,582 collegiate athletes from 26 universities and military cadets from three military academies completed a concussion history questionnaire (65% males, age 19.9 +/- 1.4 years). Participants self-reported concussions and age at time of each injury. Participants with a history of concussion (n = 3,647, 15.5%) were categorized as having sustained their first concussion during childhood (less than ten years old) or adolescence (>=10 and <=18 years old). Poisson regression was used to model age group (childhood, adolescence) predicting the number of subsequent concussions (0, 1, 2+). A second Poisson regression was developed to determine whether age at first concussion predicted the number of subsequent concussions. RESULTS: Participants self reporting their first concussion during childhood had an increased risk of subsequent concussions (rate ratio = 2.19, 95% confidence interval: 1.82, 2.64) compared with participants self-reporting their first concussion during adolescence. For every one-year increase in age at first concussion, we observed a 16% reduction in the risk of subsequent concussion (rate ratio = 0.84, 95% confidence interval: 0.82, 0.86). CONCLUSIONS: Individuals self-reporting a concussion at a young age sustained a higher number of concussions before age 18. Concussion prevention, recognition, and reporting strategies are of particular need at the youth level. PMID- 29523493 TI - Antecedents of Screening Positive for Attention Deficit Hyperactivity Disorder in Ten-Year-Old Children Born Extremely Preterm. AB - BACKGROUND: The incidence of attention deficit hyperactivity disorder is higher among children born very preterm than among children who are mature at birth. METHODS: We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4, which allowed classification of the child as having or not having symptoms of attention deficit hyperactivity disorder. For 422 children, we also had a teacher report, and for 583 children, we also had a parent report of whether or not a physician made an attention deficit hyperactivity disorder diagnosis. RESULTS: The risk profile of screening positive for attention deficit hyperactivity disorder based on a parent's report differed from the risk profile based on the teacher's report, whereas the risk profile according to a physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age (parent, physician, and two observers), maternal obesity (parent, physician, and two observers), maternal smoking (parent, physician, and two observers), magnesium given at delivery for seizure prophylaxis (parent and two observers), recovery of Mycoplasma sp. from the placenta (teacher and two observers), low gestational age (parent and two observers), low birth weight (teacher and physician), singleton (parent, physician, and two observers), male (parent, teacher, physician, and two observers), mechanical ventilation on postnatal day seven (physician), receipt of a sedative (parent and two observers), retinopathy of prematurity (parent), necrotizing enterocolitis (physician), antibiotic receipt (physician and two observers), and ventriculomegaly on brain scan (parent and two observers). CONCLUSIONS: The multiplicity of risk factors identified can be subsumed as components of four broad themes: low socioeconomic state, immaturity or vulnerability, inflammation, and epigenetic phenomena. PMID- 29523496 TI - Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study. AB - BACKGROUND: Between Nov 3, 2014, and Feb 24, 2017, 70 cases of high-level azithromycin-resistant (HL-AziR; minimum inhibitory concentration [MIC] >=256 mg/L) Neisseria gonorrhoeae were reported from across England. Whole-genome sequencing was done to investigate this outbreak to determine whether the ongoing outbreak represented clonal spread of an HL-AziR N gonorrhoeae strain identified in Leeds. We also wanted to elucidate the molecular mechanisms of azithromycin resistance in N gonorrhoeae in the UK. METHODS: In this observational study, whole-genome sequencing was done on the HL-AziR N gonorrhoeae isolates from England. As comparators, 110 isolates from the UK and Ireland with a range of azithromycin MICs were also sequenced, including eight isolates from Scotland with azithromycin MICs ranging from 0.12 mg/L to 1.00 mg/L that were N gonorrhoeae multi-antigen sequence type 9768 (ST9768), which was the sequence type initially responsible for the outbreak. The presence of mutations or genes associated with azithromycin resistance was also investigated. FINDINGS: 37 of the 60 HL-AziR isolates from England belonged to ST9768, and were genetically similar (mean 4.3 single-nucleotide polymorphisms). A 2059A->G mutation was detected in three or all four alleles of the 23S rRNA gene. Five susceptible ST9768 isolates had one mutated 23S rRNA allele and one low-level resistant ST9768 isolate had two mutated alleles. INTERPRETATION: Sustained transmission of a successful HL-AziR clone was seen across England. Mutation 2059A->G was found in isolates with lower azithromycin MICs. Azithromycin exposure might have provided the selection pressure for one or two mutated copies of the 23S rRNA gene to recombine with wild-type copies, leading to three or four mutated copies and the HL-AziR phenotype. HL-AziR could emerge in isolates with low azithromycin MICs and eliminate the effectiveness of azithromycin as part of dual therapy for the treatment of gonorrhoea. FUNDING: Public Health England. PMID- 29523498 TI - Dual antimicrobial therapy for gonorrhoea: what is the role of azithromycin? PMID- 29523497 TI - Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study. AB - BACKGROUND: Lassa fever is a viral haemorrhagic disease endemic to west Africa. No large-scale studies exist from Nigeria, where the Lassa virus (LASV) is most diverse. LASV diversity, coupled with host genetic and environmental factors, might cause differences in disease pathophysiology. Small-scale studies in Nigeria suggest that acute kidney injury is an important clinical feature and might be a determinant of survival. We aimed to establish the demographic, clinical, and laboratory factors associated with mortality in Nigerian patients with Lassa fever, and hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever. METHODS: We did a retrospective, observational cohort study of consecutive patients in Nigeria with Lassa fever, who tested positive for LASV with RT-PCR, and were treated in Irrua Specialist Teaching Hospital. We did univariate and multivariate statistical analyses, including logistic regression, of all demographic, clinical, and laboratory variables available at presentation to identify the factors associated with patient mortality. FINDINGS: Of 291 patients treated in Irrua Specialist Teaching Hospital between Jan 3, 2011, and Dec 11, 2015, 284 (98%) had known outcomes (died or survived) and seven (2%) were discharged against medical advice. Overall case-fatality rate was 24% (68 of 284 patients), with a 1.4 times increase in mortality risk for each 10 years of age (p=0.00017), reaching 39% (22 of 57) for patients older than 50 years. Of 284 patients, 81 (28%) had acute kidney injury and 104 (37%) had CNS manifestations and thus both were considered important complications of acute Lassa fever in Nigeria. Acute kidney injury was strongly associated with poor outcome (case-fatality rate of 60% [49 of 81 patients]; odds ratio [OR] 15, p<0.00001). Compared with patients without acute kidney injury, those with acute kidney injury had higher incidence of proteinuria (32 [82%] of 39 patients) and haematuria (29 [76%] of 38) and higher mean serum potassium (4.63 [SD 1.04] mmol/L) and lower blood urea nitrogen to creatinine ratio (8.6 for patients without clinical history of fluid loss), suggesting intrinsic renal damage. Normalisation of creatinine concentration was associated with recovery. Elevated serum creatinine (OR 1.3; p=0.046), aspartate aminotransferase (OR 1.5; p=0.075), and potassium (OR 3.6; p=0.0024) were independent predictors of death. INTERPRETATION: Our study presents detailed clinical and laboratory data for Nigerian patients with Lassa fever and provides strong evidence for intrinsic renal dysfunction in acute Lassa fever. Early recognition and treatment of acute kidney injury might significantly reduce mortality. FUNDING: German Research Foundation, German Center for Infection Research, Howard Hughes Medical Institute, US National Institutes of Health, and World Bank. PMID- 29523499 TI - [Hair tourniquet syndrome in melanocytic nevus]. PMID- 29523500 TI - Ethical Concerns of and Risk Mitigation Strategies for Crowdsourcing Contests and Innovation Challenges: Scoping Review. AB - BACKGROUND: Crowdsourcing contests (also called innovation challenges, innovation contests, and inducement prize contests) can be used to solicit multisectoral feedback on health programs and design public health campaigns. They consist of organizing a steering committee, soliciting contributions, engaging the community, judging contributions, recognizing a subset of contributors, and sharing with the community. OBJECTIVE: This scoping review describes crowdsourcing contests by stage, examines ethical problems at each stage, and proposes potential ways of mitigating risk. METHODS: Our analysis was anchored in the specific example of a crowdsourcing contest that our team organized to solicit videos promoting condom use in China. The purpose of this contest was to create compelling 1-min videos to promote condom use. We used a scoping review to examine the existing ethical literature on crowdsourcing to help identify and frame ethical concerns at each stage. RESULTS: Crowdsourcing has a group of individuals solve a problem and then share the solution with the public. Crowdsourcing contests provide an opportunity for community engagement at each stage: organizing, soliciting, promoting, judging, recognizing, and sharing. Crowdsourcing poses several ethical concerns: organizing-potential for excluding community voices; soliciting-potential for overly narrow participation; promoting potential for divulging confidential information; judging-potential for biased evaluation; recognizing-potential for insufficient recognition of the finalist; and sharing-potential for the solution to not be implemented or widely disseminated. CONCLUSIONS: Crowdsourcing contests can be effective and engaging public health tools but also introduce potential ethical problems. We present methods for the responsible conduct of crowdsourcing contests. PMID- 29523501 TI - Impact of Medication Adherence on Mortality and Cardiovascular Morbidity: Protocol for a Population-Based Cohort Study. AB - BACKGROUND: Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, such as coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. CVD is the leading threat to global health, whether measured by mortality, morbidity, or economic cost. Long-term administration of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers improves survival in patients with stablished coronary heart disease. Nevertheless, adherence to prescribed medication is poor for long-term drug treatment. OBJECTIVE: We aim to assess the relationship between adherences to the four pharmacological groups recommended for secondary prevention and the clinical outcomes of cardiovascular morbidity and mortality in patients with established CHD according to the level of adherence to these drugs in a population of incident cases of acute coronary syndrome (ACS). METHODS: Population-based cohort study of patients with a first episode of ACS during 2006 2015 in the Information System for Research in Primary Care (SIDIAP) database. We will estimate adherence to these drugs. The primary endpoint is a composite of all-cause mortality, ACS, and ischaemic stroke. Bivariate analyses will be performed estimating odds ratios for categorical variables and mean differences for continuous variables. Hazard ratios for adherences will be calculated for outcome events using Cox proportional hazard regression models, and proportionality of hazards assumption will be tested. RESULTS: We expect to estimate adherence to all four study treatments, the incidence of MACE, and to analyze if this incidence is associated with the level of drug adherence. CONCLUSIONS: We expect to find that adherent patients have a lower risk of the primary endpoints compared with nonadherent patients. TRIAL REGISTRATION: This study protocol was classified as EPA-OD by the AEMPS (IJG-EST-2017-01-2017-01, 07/04/2017) and registered in the EU PAS register (EUPAS19017, 09/05/2017). PMID- 29523502 TI - A Skin Cancer Prevention Facial-Aging Mobile App for Secondary Schools in Brazil: Appearance-Focused Interventional Study. AB - BACKGROUND: The incidence of melanoma is increasing faster than any other major cancer both in Brazil and worldwide. Southeast Brazil has especially high incidences of melanoma, and early detection is low. Exposure to ultraviolet (UV) radiation is a primary risk factor for developing melanoma. Increasing attractiveness is a major motivation among adolescents for tanning. A medical student-delivered intervention that takes advantage of the broad availability of mobile phones and adolescents' interest in their appearance indicated effectiveness in a recent study from Germany. However, the effect in a high-UV index country with a high melanoma prevalence and the capability of medical students to implement such an intervention remain unknown. OBJECTIVE: In this pilot study, our objective was to investigate the preliminary success and implementability of a photoaging intervention to prevent skin cancer in Brazilian adolescents. METHODS: We implemented a free photoaging mobile phone app (Sunface) in 15 secondary school classes in southeast Brazil. Medical students "mirrored" the pupils' altered 3-dimensional (3D) selfies reacting to touch on tablets via a projector in front of their whole grade accompanied by a brief discussion of means of UV protection. An anonymous questionnaire capturing sociodemographic data and risk factors for melanoma measured the perceptions of the intervention on 5-point Likert scales among 356 pupils of both sexes (13-19 years old; median age 16 years) in grades 8 to 12 of 2 secondary schools in Brazil. RESULTS: We measured more than 90% agreement in both items that measured motivation to reduce UV exposure and only 5.6% disagreement: 322 (90.5%) agreed or strongly agreed that their 3D selfie motivated them to avoid using a tanning bed, and 321 (90.2%) that it motivated them to improve their sun protection; 20 pupils (5.6%) disagreed with both items. The perceived effect on motivation was higher in female pupils in both tanning bed avoidance (n=198, 92.6% agreement in females vs n=123, 87.2% agreement in males) and increased use of sun protection (n=197, 92.1% agreement in females vs n=123, 87.2% agreement in males) and independent of age or skin type. All medical students involved filled in a process evaluation revealing that they all perceived the intervention as effective and unproblematic, and that all pupils tried the app in their presence. CONCLUSIONS: The photoaging intervention was effective in changing behavioral predictors for UV protection in Brazilian adolescents. The predictors measured indicated an even higher prospective effectiveness in southeast Brazil than in Germany (>90% agreement in Brazil vs >60% agreement in Germany to both items that measured motivation to reduce UV exposure) in accordance with the theory of planned behavior. Medical students are capable of complete implementation. A randomized controlled trial measuring prospective effects in Brazil is planned as a result of this study. PMID- 29523503 TI - The Physiological Bases of Hidden Noise-Induced Hearing Loss: Protocol for a Functional Neuroimaging Study. AB - BACKGROUND: Rodent studies indicate that noise exposure can cause permanent damage to synapses between inner hair cells and high-threshold auditory nerve fibers, without permanently altering threshold sensitivity. These demonstrations of what is commonly known as hidden hearing loss have been confirmed in several rodent species, but the implications for human hearing are unclear. OBJECTIVE: Our Medical Research Council-funded program aims to address this unanswered question, by investigating functional consequences of the damage to the human peripheral and central auditory nervous system that results from cumulative lifetime noise exposure. Behavioral and neuroimaging techniques are being used in a series of parallel studies aimed at detecting hidden hearing loss in humans. The planned neuroimaging study aims to (1) identify central auditory biomarkers associated with hidden hearing loss; (2) investigate whether there are any additive contributions from tinnitus or diminished sound tolerance, which are often comorbid with hearing problems; and (3) explore the relation between subcortical functional magnetic resonance imaging (fMRI) measures and the auditory brainstem response (ABR). METHODS: Individuals aged 25 to 40 years with pure tone hearing thresholds <=20 dB hearing level over the range 500 Hz to 8 kHz and no contraindications for MRI or signs of ear disease will be recruited into the study. Lifetime noise exposure will be estimated using an in-depth structured interview. Auditory responses throughout the central auditory system will be recorded using ABR and fMRI. Analyses will focus predominantly on correlations between lifetime noise exposure and auditory response characteristics. RESULTS: This paper reports the study protocol. The funding was awarded in July 2013. Enrollment for the study described in this protocol commenced in February 2017 and was completed in December 2017. Results are expected in 2018. CONCLUSIONS: This challenging and comprehensive study will have the potential to impact diagnostic procedures for hidden hearing loss, enabling early identification of noise-induced auditory damage via the detection of changes in central auditory processing. Consequently, this will generate the opportunity to give personalized advice regarding provision of ear defense and monitoring of further damage, thus reducing the incidence of noise-induced hearing loss. PMID- 29523505 TI - HRT may have positive effects on heart structure, study finds. PMID- 29523506 TI - How can the NHS become a millennial friendly employer? PMID- 29523504 TI - Hepcidin agonists as therapeutic tools. AB - Hepcidin agonists are a new class of compounds that regulate blood iron levels, limit iron absorption, and could improve the treatment of hemochromatosis, beta thalassemia, polycythemia vera, and other disorders in which disrupted iron homeostasis causes or contributes to disease. Hepcidin agonists also have the potential to prevent severe complications of siderophilic infections in patients with iron overload or chronic liver disease. This review highlights the preclinical studies that support the development of hepcidin agonists for the treatment of these disorders. PMID- 29523507 TI - DNA Damage Response Alterations Predict Responses to Anti-PD-1/PD-L1. AB - DNA damage response alterations are linked to improved responses to anti-PD-1/PD L1 in urothelial carcinoma. PMID- 29523508 TI - SS18-SSX Induces the Expression of Neurogenic Genes to Drive Synovial Sarcoma. AB - SS18-SSX usurps the PRC1.1 repressive complex to drive expression of a synovial sarcoma gene signature. PMID- 29523509 TI - SHP2 Inhibition May Resensitize NSCLC Tumors to ALK Inhibitors. AB - Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation. PMID- 29523510 TI - Engineered IL2/IL2Rbeta Pairs May Enhance the Efficacy of T-cell Therapy. AB - Orthogonal IL2/IL2Rbeta pairs allow selective targeting of engineered autologously transferred T cells. PMID- 29523511 TI - Patients with cerebral palsy are being failed on multiple levels. PMID- 29523512 TI - Jury finds trainee GP not guilty of sexually assaulting five patients. PMID- 29523513 TI - Pregnancy in women with congenital heart disease. PMID- 29523514 TI - Baby with brain damage dies after parents run out of legal options. PMID- 29523515 TI - Acute glomerulonephritis secondary to Streptococcus anginosus. AB - Streptococcus anginosus is a clinically important pathogen that is emerging globally but remains poorly investigated. Here, we report the first case of acute glomerulonephritis resulting from infection with S. anginosus Glomerulonephritis is typically caused by S. pyogenes and reports secondary to other strains including S. zooepidemicus and S. constellatus exist. Infection with S. anginosus in this patient was associated with acute nephritis (haematuria, oedema and hypertension), nephrotic syndrome and progressive azotemia. There was activation of the complement system. The presence of low C1q and elevated anti-C1q binding complexes points to a potential pathogenic role. Testing for streptococcal antigens was strongly positive. Emerging nephritogenic strains of S. anginosus present a significant health concern for both developed and developing countries. PMID- 29523516 TI - Hodgkin's Lymphoma presenting as an obstructing endobronchial mass-A rare presentation. AB - We report a case of Hodgkin's lymphoma presenting as an endobronchial mass in a 40-year-old man with history of 8 months of non-specific symptoms like cough, fatigue and weight loss. Initially he was treated with broad-spectrum antibiotics for suspicion of pneumonia without recovery. Radiographic work-up showed cavitary consolidation of the upper lobe of the left lung, followed by bronchoscopy which showed obstructing mass of the upper lobe of the left lung mimicking primary lung carcinoma. Immunohistochemical staining of the specimen was suggestive of Hodgkin's lymphoma. The patient responded well to the chemotherapy regimen. PMID- 29523520 TI - Cardiovascular events in ankylosing spondylitis: a 2018 meta-analysis. PMID- 29523517 TI - Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study). AB - BACKGROUND: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction. METHODS AND RESULTS: Participants were 4864 men and women aged >=65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)-a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95% confidence interval, 8.6-11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95% confidence interval, 5.3-6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (P=0.084), and did not vary significantly by reduced versus preserved ejection fraction (P=0.734). CONCLUSIONS: Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention. PMID- 29523519 TI - Ultrasonography in psoriatic arthritis: which sites should we scan? PMID- 29523521 TI - Can ultrasound of the major salivary glands assess histopathological changes induced by treatment with rituximab in primary Sjogren's syndrome? PMID- 29523522 TI - Cell function in disease: there are more than two parties at play. PMID- 29523523 TI - Advances in the Understanding of the Genetic Determinants of Congenital Heart Disease and Their Impact on Clinical Outcomes. PMID- 29523525 TI - Acute Myocardial Infarction Mortality During Dates of National Interventional Cardiology Meetings. AB - BACKGROUND: Previous research has found that patients with acute cardiovascular conditions treated in teaching hospitals have lower 30-day mortality during dates of national cardiology meetings. METHODS AND RESULTS: We analyzed 30-day mortality among Medicare beneficiaries hospitalized with acute myocardial infarction (overall, ST-segment-elevation myocardial infarction, and non-ST segment-elevation myocardial infarction) from January 1, 2007, to November 31, 2012, in major teaching hospitals during dates of a major annual interventional cardiology meeting (Transcatheter Cardiovascular Therapeutics) compared with identical nonmeeting days in the +/-5 weeks. Treatment differences were assessed. We used a database of US physicians to compare interventional cardiologists who practiced and did not practice during meeting dates ("stayers" and "attendees," respectively) in terms of demographic characteristics and clinical and research productivity. Unadjusted and adjusted 30-day mortality rates were lower among patients admitted during meeting versus nonmeeting dates (unadjusted, 15.3% [482/3153] versus 16.7% [5208/31 556] [P=0.04]; adjusted, 15.4% versus 16.7%; difference -1.3% [95% confidence interval, -2.7% to -0.1%] [P=0.05]). Rates of interventional cardiologist involvement were similar between dates (59.5% versus 59.8% of hospitalizations; P=0.88), as were percutaneous coronary intervention rates (30.2% versus 29.1%; P=0.20). Mortality reductions were largest among patients with non-ST-segment-elevation myocardial infarction not receiving percutaneous coronary intervention (16.9% versus 19.5% adjusted 30-day mortality; P=0.008). Compared with stayers, attendees were of similar age and sex, but had greater publications (18.9 versus 6.3; P<0.001), probability of National Institutes of Health funding (5.3% versus 0.4%; P<0.001), and clinical trial leadership (10.3% versus 3.9%; P<0.001), and they performed more percutaneous coronary interventions annually (85.6 versus 63.3; P<0.001). CONCLUSIONS: Hospitalization with acute myocardial infarction during Transcatheter Cardiovascular Therapeutics meeting dates was associated with lower 30-day mortality, predominantly among patients with non-ST-segment-elevation myocardial infarction who were medically managed. PMID- 29523524 TI - Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients. AB - BACKGROUND: Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change. METHODS AND RESULTS: Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with P<5*10-8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (beta=12.5; P=4.17*10-8). G-allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (beta=5.54; P=0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis P value of 3.71*10-8. HMGCS2, a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. CONCLUSIONS: These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852. PMID- 29523526 TI - NHS should reject online GP schemes that "cherry pick" patients, say LMCs. PMID- 29523527 TI - Parts of new Scottish GP contract could benefit English colleagues, say GPs. PMID- 29523529 TI - In rural Iowa, 340B program funds critical services. PMID- 29523528 TI - Stringent or nonstringent complete remission and prognosis in acute myeloid leukemia: a Danish population-based study. AB - Stringent complete remission (sCR) of acute myeloid leukemia is defined as normal hematopoiesis after therapy. Less sCR, including non-sCR, was introduced as insufficient blood platelet, neutrophil, or erythrocyte recovery. These latter characteristics were defined retrospectively as postremission transfusion dependency and were suggested to be of prognostic value. In the present report, we evaluated the prognostic impact of achieving sCR and non-sCR in the Danish National Acute Leukaemia Registry, including 769 patients registered with classical CR (ie, <5% blasts in the postinduction bone marrow analysis). Individual patients were classified as having sCR (n = 360; 46.8%) or non-sCR (n = 409; 53.2%) based on data from our national laboratory and transfusion databases. Survival analysis revealed that patients achieving sCR had superior overall survival (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.10 1.64) as well as relapse-free survival (HR, 1.25; 95% CI, 1.03-1.51) compared with those with non-sCR after adjusting for covariates. Cox regression analysis regarding the impact of the stringent criteria for blood cell recovery identified these as significant and independent variables. In conclusion, this real-life register study supports the international criteria for response evaluation on prognosis and, most importantly, documents each of the 3 lineage recovery criteria as contributing independently. PMID- 29523530 TI - Roundtable report takes high-level approach to drug shortages. PMID- 29523531 TI - Real-world observational data factor into FDA's decisions. PMID- 29523532 TI - Treatment patterns for patients hospitalized with chronic obstructive pulmonary disease. AB - PURPOSE: Medication treatment patterns for chronic obstructive pulmonary disease (COPD) in inpatient settings were examined, as were the characteristics of patients treated with long-acting bronchodilators (LABDs) during hospitalization. METHODS: This retrospective study was conducted using inpatient administrative data from hospitals and medical centers nationwide. All patients discharged from the hospital from January 1, 2010, through December 31, 2012, who were at least 40 years of age, had a primary discharge diagnosis of COPD or a secondary diagnosis of COPD with a primary diagnosis of a respiratory condition, and treatment with a bronchodilator were included. Treatment patterns were described for inpatient use of medications, including short-acting beta-agonists (SABAs), long-acting beta-agonists (LABAs), short-acting muscarinic antagonists (SAMAs), and long-acting muscarinic antagonists. Logistic regression predicted characteristics of patients receiving LABDs. RESULTS: Only 5.5% of patients did not receive an SABA during the hospitalization: 71.7% received a single-product SABA, and 46.4% received an SABA-SAMA combination product, with some patients switching between or using SABA and SABA-SAMA combinations concurrently. Most patients (80.9%) received systemic corticosteroids, and nearly all (91.6%) were treated with antibiotics. Only 52.2% of patients received LABDs (39.3% LABAs). Patients treated with LABDs were more likely to have a primary COPD diagnosis, prior hospitalizations, spirometry use, and fewer comorbidities. CONCLUSION: A review of COPD-related inpatient admissions found that the majority of patients received the primary recommended treatments for acute exacerbations of COPD (SABAs, systemic corticosteroids, and antibiotics). However, maintenance therapy had been initiated for only about half of patients before discharge. PMID- 29523533 TI - Randomized trial of oral versus intravenous acetaminophen for postoperative pain control. AB - PURPOSE: Results of a study comparing pain control outcomes with preoperative oral versus intraoperative i.v. acetaminophen use in adults undergoing total hip or knee arthroplasty are reported. METHODS: A single-center, randomized, placebo controlled, equivalence trial was conducted. Patients were assigned (1:1) to receive 2 500-mg capsules of acetaminophen before surgery, with an i.v. placebo infusion during surgery (the oral group), or 2 oral placebo capsules followed by an i.v. infusion of acetaminophen 1,000 mg/100 mL (the i.v. group). Patients were followed after postanesthesia care unit (PACU) admission up to 24 hours postoperatively. RESULTS: Among 486 patients included in a modified intention-to treat analysis (mean +/- S.D. age, 66.3 +/- 9.4 years), there were no significant differences in preoperative and intraoperative use of pain medication between the oral and i.v. groups. Postoperative opioid use in morphine milligram equivalents (MMEs) was equivalent in the oral and i.v. groups (i.e., the mean difference in median MME values was within the prespecified equivalence margin), with no significant between-group differences in mean pain scores over 24 hours. CONCLUSION: In patients undergoing hip or knee arthroplasty, oral acetaminophen given preoperatively was equivalent to i.v. acetaminophen administered in the operating suite in controlling pain in the immediate postoperative period. I.V. acetaminophen was not superior to oral acetaminophen in reducing postoperative nausea and vomiting, time to ambulation, time to first dose of as-needed pain medication, length of PACU stay, or total length of hospital stay. PMID- 29523534 TI - Establishment of a pharmacist-led service for patients at high risk for opioid overdose. AB - PURPOSE: A program at a family medicine clinic to provide naloxone prescriptions in conjunction with education on naloxone use and opioid hazards to patients at risk for opioid overdose is described. SUMMARY: Consistent with a 2016 Centers for Disease Control and Prevention (CDC) guideline on opioid prescribing for chronic pain, a family medicine clinic implemented updated controlled substance agreements and medical record templates for documentation of pain management visits and established a pharmacist-led naloxone clinic. Chart reviews were performed to identify patients eligible for naloxone, as defined by the CDC guideline. A standard visit template was constructed to guide patient education regarding overdose risks and naloxone use. The teach-back method was used to ensure patient understanding, and patients were encouraged to bring a friend or family member to clinic visits. To address medication access barriers, community resources for patient referral for assistance were identified. Barriers to attendance at pharmacist-conducted visits necessitated changes in clinic workflow to incorporate education into prescheduled physician visits and education of some patients via telephone. During the first 6 months of clinic operations, 49 patients were identified as being at risk for opioid overdose; pharmacists educated 84% of those patients and subsequently confirmed that 69% had filled a naloxone prescription. CONCLUSION: Naloxone prescribing and provision of education on naloxone use to at-risk patients in a family medicine clinic can help ensure access to life-saving medication and reinforce CDC recommendations on safe prescribing of opioids. PMID- 29523535 TI - Association between postgraduate year 2 residency program characteristics and primary project publication. AB - PURPOSE: The association among residency program and research mentor characteristics, program director perceptions, and the publication of the primary research project for postgraduate year 2 (PGY2) graduates was assessed. METHODS: Using a validated electronic survey, residency program directors (RPDs) of critical care PGY2 graduates were asked about primary research project publication success, program and research project mentor characteristics, and RPDs' perceptions surrounding project completion. RESULTS: All 55 RPDs surveyed responded; 44 (79%) reported being a research project mentor. PGY2 research project publications in 2011 and 2012 totaled 26 (37%) and 27 (35%), respectively. A significant relationship existed between research project publication and the number of residents in the program (p < 0.01); the perception among the RPDs that research project publication is important to their employer (p < 0.01); and the research mentor's funding source (p = 0.04), employer (p < 0.01), number of prior publications (p = 0.01), and research training (p < 0.01). Variables independently associated with the publication of 2 or more research projects versus no publications included the number of graduates in the PGY2 program (odds ratio [OR], 5.6; p < 0.01), the RPD's perception that the employer valued research project publication (OR, 10.2; p < 0.01), and the number of prior publications by the least-experienced research mentor (OR, 23.5; p = 0.01). The publication of 1 research project versus no research projects was also independently associated with the RPD's perception that the employer valued research project publication (OR, 5.1; p = 0.04). CONCLUSION: A survey of RPDs of critical care PGY2 residents found that the number of PGY2 residents, the number of publications by the least experienced research mentor, and the perception that publishing the residents' research projects is important to the employer were independently associated with publication rates of residency research projects. PMID- 29523536 TI - Nonadministration of medication doses for venous thromboembolism prophylaxis in a cohort of hospitalized patients. AB - PURPOSE: Results of a study to characterize patterns of nonadministration of medication doses for venous thromboembolism (VTE) prevention among hospitalized patients are presented. METHODS: The electronic records of all patients admitted to 4 floors of a medical center during a 1-month period were examined to identify patients whose records indicated at least 1 nonadministered dose of medication for VTE prophylaxis. Proportions of nonadministered doses by medication type, intended route of administration, and VTE risk categorization were compared; reasons for nonadministration were evaluated. RESULTS: Overall, 12.7% of all medication doses prescribed to patients in the study cohort (n = 75) during the study period (857 of 6,758 doses in total) were not administered. Nonadministration of 1 or more doses of VTE prophylaxis medication was nearly twice as likely for subcutaneous anticoagulants than for all other medication types (231 of 1,112 doses [20.8%] versus 626 of 5,646 doses [11.2%], p < 0.001). For all medications prescribed, the most common reason for nonadministration was patient refusal (559 of 857 doses [65.2%]); the refusal rate was higher for subcutaneous anticoagulants than for all other medication categories (82.7% versus 58.8%, p < 0.001). Doses of antiretrovirals, immunosuppressives, antihypertensives, psychiatric medications, analgesics, and antiepileptics were less commonly missed than doses of electrolytes, vitamins, and gastrointestinal medications. CONCLUSION: Scheduled doses of subcutaneous anticoagulants for hospitalized patients were more likely to be missed than doses of all other medication types. PMID- 29523537 TI - Implementation of an integrated computerized prescriber order-entry system for chemotherapy in a multisite safety-net health system. AB - PURPOSE: The development of a computerized prescriber order-entry (CPOE) system for chemotherapy in a multisite safety-net health system and the challenges to its successful implementation are described. SUMMARY: Before CPOE for chemotherapy was first implemented and embedded in the electronic medical record system of Harris Health System (HHS), pharmacy personnel relied on regimen specific preprinted order sets. However, due to differences in practice styles and workflow logistics, the paper orders across the 3 facilities were mostly site specific, with varying clinical content. Many of these order sets had not been approved by the oncology subcommittee. In addition, disparities in clinical knowledge and lack of communication contributed to inconsistencies in order set development. Led by medical directors from medical oncology departments at the 3 facilities, pharmacy administrators, and information technology representatives, HHS committed resources to supporting the adoption and use of a CPOE system for chemotherapy. Five practical lessons of broad applicability have been learned: engagement of interprofessional stakeholders, optimization of workflow before CPOE implementation, requirement of verification tool for CPOE, consolidation of protocols, and commitment to ongoing training and support. Evaluation of the CPOE system demonstrated a systemwide reduction in medication errors by 75% (p < 0.05). Satisfaction with the CPOE system varied among sites and was unchanged institutionwide 6 months after the CPOE implementation. CONCLUSION: The development and implementation of CPOE for chemotherapy at a multisite safety-net health system created opportunities to optimize patient care and reduce variations through interprofessional collaborations. Initial evaluation suggested that CPOE reduced the medication-order error rate and improved user satisfaction in 1 of 3 facilities. PMID- 29523538 TI - Why all the fuss about paediatric ACL rupture: isn't the meniscus much more important? PMID- 29523539 TI - Just a painful swelling of the ankles? PMID- 29523540 TI - Tumor-Derived TGFbeta Alters the Ability of Plasmacytoid Dendritic Cells to Respond to Innate Immune Signaling. AB - A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDCs generally correlates with a poor prognosis, suggesting that pDCs may play an important role in the host-tumor relationship. Here, we analyze the influence of pDCs in solid tumor development using two different tumor models: TC-1 and B16 OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDCs showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDCs to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGFbeta is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that natural killer (NK) cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the cross-talk among pDCs, NK, and regulatory T cells in the promotion of tumor growth and their role in the development of antitumor immune responses.Significance: These findings highlight the importance of pDCs in the cross-talk between tumor cells and the immune system. Cancer Res; 78(11); 3014-26. (c)2018 AACR. PMID- 29523541 TI - Peli1 Modulates the Subcellular Localization and Activity of Mdmx. AB - Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation independent, promoting cytoplasmic localization of Mdmx, which in turn resulted in p53 activation. Consistent with this, knockdown or knockout Peli1 in human cancer cells induced nuclear localization of Mdmx and suppressed p53 activity. Myc-induced tumorigenesis was accelerated in Peli1-null mice and associated with downregulation of p53 function. Clinical samples of human cutaneous melanoma had decreased Peli1 expression, which was associated with poor overall survival. Together, these results demonstrate that Peli1 acts as a critical factor for the Mdmx-p53 axis by modulating the subcellular localization and activity of Mdmx, thus revealing a novel mechanism of Mdmx deregulation in human cancers.Significance: Peli1-mediated regulation of Mdmx, a major inhibitor of p53, provides critical insight into activation of p53 function in human cancers. Cancer Res; 78(11); 2897-910. (c)2018 AACR. PMID- 29523542 TI - Virulence Traits of Environmental and Clinical Legionella pneumophila Multilocus Variable-Number Tandem-Repeat Analysis (MLVA) Genotypes. AB - Legionella pneumophila causes water-based infections resulting in severe pneumonia. Recently, we showed that different MLVA-8 (multilocus variable-number tandem-repeat analysis using 8 loci) genotypes dominated different sites of a drinking-water distribution system. Each genotype displayed a unique temperature dependent growth behavior. Here we compared the pathogenicity potentials of different MLVA-8 genotypes of environmental and clinical strains. The virulence traits studied were hemolytic activity and cytotoxicity toward amoebae and macrophages. Clinical strains were significantly more hemolytic than environmental strains, while their cytotoxicity toward amoebae was significantly lower at 30 degrees C. No significant differences were detected between clinical and environmental strains in cytotoxicity toward macrophages. Significant differences in virulence were observed between the environmental genotypes (Gt). Gt15 strains showed a significantly higher hemolytic activity. In contrast, Gt4 and Gt6 strains were more infective toward Acanthamoeba castellanii Moreover, Gt4 strains exhibited increased cytotoxicity toward macrophages and demonstrated a broader temperature range of amoebal lysis than Gt6 and Gt15 strains. Understanding the virulence traits of Legionella genotypes may improve the assessment of public health risks of Legionella in drinking water.IMPORTANCELegionella pneumophila is the causative agent of a severe form of pneumonia. Here we demonstrated that clinical strains were significantly more cytotoxic toward red blood cells than environmental strains, while their cytotoxicity toward macrophages was similar. Genotype 4 (Gt4) strains were highly cytotoxic toward amoebae and macrophages and lysed amoebae in a broader temperature range than to the other studied genotypes. The results can explain the relatively high success of Gt4 in the environment and in clinical samples; thus, Gt4 strains should be considered a main factor for the assessment of public health risks of Legionella in drinking water. Our findings shed light on the ecology, virulence, and pathogenicity potential of different L. pneumophila genotypes, which can be a valuable parameter for future modeling and quantitative microbial risk assessment of Legionella in drinking-water systems. PMID- 29523543 TI - Isoprenoid quinones resolve the stratification of microbial redox processes in a biogeochemical continuum from the photic zone to deep anoxic sediments of the Black Sea. AB - The stratified water column of the Black Sea serves as a model ecosystem for studying the interactions of microorganisms with major biogeochemical cycles. Here we provide detailed analysis of isoprenoid quinones to study microbial redox processes in the ocean. In a continuum from the photic zone through the chemocline into deep anoxic sediments of the southern Black Sea, diagnostic quinones and inorganic geochemical parameters indicate niche segregation between redox processes and corresponding shifts in microbial community composition. Quinones specific for oxygenic photosynthesis and aerobic respiration dominate oxic waters, while quinones associated with thaumarchaeal ammonia-oxidation and bacterial methanotrophy, respectively, dominate a narrow interval in suboxic waters. Quinone distributions indicate highest metabolic diversity within the anoxic zone, with anoxygenic photosynthesis being a major process in its photic layer. In the dark anoxic layer, quinone profiles indicate occurrence of bacterial sulfur and nitrogen cycling, archaeal methanogenesis, and archaeal methanotrophy. Multiple novel ubiquinone isomers, possibly originating from unidentified intra-aerobic anaerobes, occur in this zone. The respiration modes found in the anoxic zone continue into shallow subsurface sediments, but quinone abundances rapidly decrease within the upper 50 cm below sea floor, reflecting the transition to lower energy availability. In the deep subseafloor sediments, quinone distributions and geochemical profiles indicate archaeal methanogenesis/methanotrophy and potentially bacterial fermentative metabolisms. We observed that sedimentary quinone distributions track lithology, which supports prior hypotheses that deep biosphere community composition and metabolisms are determined by environmental conditions during sediment deposition.Importance Microorganisms play crucial roles in global biogeochemical cycles. Yet, we have only a fragmentary understanding of the diversity of microorganisms and their metabolisms, as the majority remains uncultured. Thus, culture-independent approaches are critical for determining microbial diversity and active metabolic processes. In order to resolve the stratification of microbial communities in the Black Sea, we comprehensively analyzed redox process specific isoprenoid quinone biomarkers in a unique continuous record from the photic zone through the chemocline into anoxic subsurface sediments. We describe an unprecedented quinone diversity that allowed us to detect distinct biogeochemical processes including oxygenic photosynthesis, archaeal ammonia oxidation, aerobic methanotrophy and anoxygenic photosynthesis in defined geochemical zones. PMID- 29523544 TI - Monitoring Viable Cells of the Biological Control Agent Lactobacillus plantarum PM411 in Aerial Plant Surfaces by Means of a Strain-Specific Viability Quantitative PCR Method. AB - A viability quantitative PCR (v-qPCR) assay was developed for the unambiguous detection and quantification of Lactobacillus plantarum PM411 viable cells in aerial plant surfaces. A 972-bp region of a PM411 predicted prophage with mosaic architecture enabled the identification of a PM411 strain-specific molecular marker. Three primer sets with different amplicon lengths (92, 188, and 317 bp) and one TaqMan probe were designed. All the qPCR assays showed good linearity over a 4-log range and good efficiencies but differed in sensitivity. The nucleic acid-binding dye PEMAX was used to selectively detect and enumerate viable bacteria by v-qPCR. The primer set amplifying a 188-bp DNA fragment was selected as the most suitable for v-qPCR. The performance of the method was assessed on apple blossoms, pear, strawberry, and kiwifruit leaves in potted plants under controlled environmental conditions, as well as pear and apple blossoms under field conditions, by comparing v-qPCR population estimations to those obtained by qPCR and specific plate counting on de Man-Rogosa-Sharpe (MRS)-rifampin. The population estimation did not differ significantly between methods when conditions were conducive to bacterial survival. However, under stressful conditions, differences between methods were observed due to cell death or viable but-nonculturable state induction. While qPCR overestimated the population level, plate counting underestimated this value in comparison to v-qPCR. PM411 attained stable population levels of viable cells on the flower environment under high relative humidity. However, the unfavorable conditions on the leaf surface and the relatively dryness in the field caused an important decrease in the viable population.IMPORTANCE The v-qPCR method in combination with plate counting and qPCR is a powerful tool for studies of colonization and survival under field conditions, to improve formulations and delivery strategies of PM411, and to optimize the dose and timing of spray schedules. It is expected that PEMAX v-qPCR could also be developed for monitoring other strains on plant surfaces not only as biological control agents but also beneficial bacteria useful in the sustainable management of crop production. PMID- 29523545 TI - Microbiome Dynamics in a Large Artificial Seawater Aquarium. AB - Artificial habitats for animals have high commercial and societal value. Microbial communities (microbiomes) in such habitats may play ecological roles similar to those in nature. However, this hypothesis remains largely untested. Georgia Aquarium's Ocean Voyager (OV) exhibit is a closed-system aquatic habitat that mimics the oligotrophic open ocean and houses thousands of large marine animals, including fish, sea turtles, and whale sharks. We present a 14-month time series characterizing the OV water column microbiome. The composition and stability of the microbiome differed from those of natural marine environments with similar chemical features. The composition shifted dramatically over the span of 2 weeks and was characterized by bloom events featuring members of two heterotrophic bacterial lineages with cosmopolitan distributions in the oceans. The relative abundances of these lineages were inversely correlated, suggesting an overlap in ecological niches. Transcript mapping to metagenome-assembled genomes (MAGs) of these taxa identified unique characteristics, including the presence and activity of genes for the synthesis and degradation of cyanophycin, an amino acid polymer linked to environmental stress and found frequently in cyanobacteria but rarely in heterotrophic bacteria. The dominant MAGs also contained and transcribed plasmid-associated sequences, suggesting a role for conjugation in adaptation to the OV environment. These findings indicate a highly dynamic microbiome despite the stability of the physical and chemical parameters of the water column. Characterizing how such fluctuations affect microbial function may inform our understanding of animal health in closed aquaculture systems.IMPORTANCE Public aquariums play important societal roles, for example, by promoting science education and helping conserve biodiversity. The health of aquarium animals depends on interactions with the surrounding microbiome. However, the extent to which aquariums recreate a stable and natural microbial ecosystem is uncertain. This study describes the taxonomic composition of the water column microbiome over 14 months in a large indoor aquatic habitat, the Ocean Voyager exhibit at the Georgia Aquarium. Despite stable water column conditions, the exhibit experienced blooms in which the abundance of a single bacterial strain increased to over 65% of the community. Genome analysis indicated that the OV's dominant strains share unique adaptations, notably genes for storage polymers associated with environmental stress. These results, interpreted alongside data from natural ocean systems and another artificial seawater aquarium, suggest a highly dynamic aquarium microbiome and raise questions of how microbiome stability may affect the ecological health of the habitat. PMID- 29523546 TI - Landscape-Scale Factors Affecting the Prevalence of Escherichia coli in Surface Soil Include Land Cover Type, Edge Interactions, and Soil pH. AB - Escherichia coli is deposited into soil with feces and exhibits subsequent population decline with concomitant environmental selection. Environmentally persistent strains exhibit longer survival times during this selection process, and some strains have adapted to soil and sediments. A georeferenced collection of E. coli isolates was developed comprising 3,329 isolates from 1,428 soil samples that were collected from a landscape spanning the transition from the grasslands to the eastern deciduous forest biomes. The isolate collection and sample database were analyzed together to discover how land cover, site characteristics, and soil chemistry influence the prevalence of cultivable E. coli in surface soil. Soils from forests and pasture lands had equally high prevalences of E. coli Edge interactions were also observed among land cover types, with proximity to forests and pastures affecting the likelihood of E. coli isolation from surrounding soils. E. coli is thought to be more prevalent in sediments with high moisture, but this was observed only in grass- or crop dominated lands in this study. Because differing E. coli phylogroups are thought to have differing ecology profiles, isolates were also typed using a novel single nucleotide polymorphism (SNP) genotyping assay. Phylogroup B1 was the dominant group isolated from soil, as has been reported in all other surveys of environmental E. coli Although differences were small, isolates belonging to phylogroups B2 and D were associated with wooded areas, slightly more acidic soils, and soil sampling after rainfall events. In contrast, isolates from phylogroups B1 and E were associated with pasture lands.IMPORTANCE The consensus is that complex niches or life cycles should select for complex genomes in organisms. There is much unexplained biodiversity in E. coli, and its cycling through complex extrahost environments may be a cause. In order to understand the evolutionary processes that lead to adaptation for survival and growth in soil, an isolate collection that associates soil conditions and isolate genome sequences is required. An equally important question is whether traits selected in soil or other extrahost habitats can be transmitted to E. coli residing in hosts via gene flow. The new findings about the distribution of E. coli in soil at the landscape scale (i) enhance our capability to study how extrahost environments influence the evolution of E. coli and other bacteria, (ii) advance our knowledge of the environmental biology of this microbe, and (iii) further affirm the emerging scientific consensus that E. coli in waterways originates from nonpoint sources not associated with human activity or livestock farming. PMID- 29523547 TI - A Mutation in PGM2 Causing Inefficient Galactose Metabolism in the Probiotic Yeast Saccharomyces boulardii. AB - The probiotic yeast Saccharomyces boulardii has been extensively studied for the prevention and treatment of diarrheal diseases, and it is now commercially available in some countries. S. boulardii displays notable phenotypic characteristics, such as a high optimal growth temperature, high tolerance against acidic conditions, and the inability to form ascospores, which differentiate S. boulardii from Saccharomyces cerevisiae The majority of prior studies stated that S. boulardii exhibits sluggish or halted galactose utilization. Nonetheless, the molecular mechanisms underlying inefficient galactose uptake have yet to be elucidated. When the galactose utilization of a widely used S. boulardii strain, ATCC MYA-796, was examined under various culture conditions, the S. boulardii strain could consume galactose, but at a much lower rate than that of S. cerevisiae While all GAL genes were present in the S. boulardii genome, according to analysis of genomic sequencing data in a previous study, a point mutation (G1278A) in PGM2, which codes for phosphoglucomutase, was identified in the genome of the S. boulardii strain. As the point mutation resulted in the truncation of the Pgm2 protein, which is known to play a pivotal role in galactose utilization, we hypothesized that the truncated Pgm2 might be associated with inefficient galactose metabolism. Indeed, complementation of S. cerevisiaePGM2 in S. boulardii restored galactose utilization. After reverting the point mutation to a full-length PGM2 in S. boulardii by Cas9-based genome editing, the growth rates of wild-type (with a truncated PGM2 gene) and mutant (with a full-length PGM2) strains with glucose or galactose as the carbon source were examined. As expected, the mutant (with a full-length PGM2) was able to ferment galactose faster than the wild-type strain. Interestingly, the mutant showed a lower growth rate than that of the wild-type strain on glucose at 37 degrees C. Also, the wild-type strain was enriched in the mixed culture of wild type and mutant strains on glucose at 37 degrees C, suggesting that the truncated PGM2 might offer better growth on glucose at a higher temperature in return for inefficient galactose utilization. Our results suggest that the point mutation in PGM2 might be involved in multiple phenotypes with different effects.IMPORTANCESaccharomyces boulardii is a probiotic yeast strain capable of preventing and treating diarrheal diseases. However, the genetics and metabolism of this yeast are largely unexplored. In particular, molecular mechanisms underlying the inefficient galactose metabolism of S. boulardii remain unknown. Our study reports that a point mutation in PGM2, which codes for phosphoglucomutase, is responsible for inferior galactose utilization by S. boulardii After correction of the mutated PGM2 via genome editing, the resulting strain was able to use galactose faster than a parental strain. While the PGM2 mutation made the yeast use galactose slowly, investigation of the genomic sequencing data of other S. boulardii strains revealed that the PGM2 mutation is evolutionarily conserved. Interestingly, the PGM2 mutation was beneficial for growth at a higher temperature on glucose. We speculate that the PGM2 mutation was enriched due to selection of S. boulardii in the natural habitat (sugar-rich fruits in tropical areas). PMID- 29523548 TI - Resveratrol as a growth substrate for bacteria from the rhizosphere. AB - Resveratrol is among the best-known secondary plant metabolites because of its antioxidant, anti-inflammatory and anticancer properties. It also is an important allelopathic chemical widely credited with protection of plants from pathogens. The ecological role of resveratrol in natural habitats is difficult to establish rigorously because it does not seem to accumulate outside of plant tissue. It is likely that bacterial degradation plays a key role in determining the persistence, and thus the ecological role, of resveratrol in soil. Here we report the isolation of an Acinetobacter species that can use resveratrol as a sole carbon source from the rhizosphere of peanut plants. Both molecular and biochemical techniques indicate that the pathway starts with the conversion of resveratrol to 3,5-dihydroxybenzaldehyde and 4-hydroxybenzaldehyde. The aldehydes are oxidized to substituted benzoates that subsequently enter central metabolism. The gene that encodes the enzyme responsible for the oxidative cleavage of resveratrol was cloned, and expressed in E. coli to establish its function. Its physiological role in the resveratrol catabolic pathway was established by knockouts and by RT-qPCR demonstration of expression during growth on resveratrol. The results establish the presence and capabilities of resveratrol degrading bacteria in the rhizosphere of the peanut plants and set the stage for studies to evaluate the role of the bacteria in plant allelopathy.IMPORTANCE In addition to its antioxidant properties, resveratrol is an example of a broad array of allelopathic chemicals produced by plants to inhibit competitors, herbivores and pathogens. Bacterial degradation of such chemicals in the rhizosphere would reduce the effects of the chemicals. Therefore, it is important to understand the activity and ecological role of bacteria that biodegrade resveratrol near the plants that produce it. This study describes the isolation from the peanut rhizosphere of bacteria that can grow on resveratrol. Characterization of the initial steps in the biodegradation sets the stage for investigation of the evolution of the catabolic pathways responsible for biodegradation of resveratrol and its homologs. PMID- 29523549 TI - A decade of Streptococcus thermophilus phage evolution in an Irish dairy plant. AB - Phages of Streptococcus thermophilus present a major threat to the production of many fermented dairy products. To date, only a handful of studies have assessed the biodiversity of S. thermophilus phages in dairy fermentations. In order to develop strategies to limit phage predation in this important industrial environment, it is imperative that such studies are undertaken and that phage host interactions of this species are better defined. The present study investigated the biodiversity and evolution of phages within an Irish dairy fermentation facility over an eleven year period. This resulted in the isolation of 17 genetically distinct phages, all of which belong to the so-called cos group. Evolution of phages within the factory appears to be influenced by phages from other dairy plants introduced into the factory for whey protein powder production. Modular exchange, primarily within the regions encoding lysogeny and replication functions, was the major observation among the phages isolated between 2006 and 2016. Furthermore, the genotype of the first isolate in 2006 was observed continuously across the following decade highlighting the ability of these phages to prevail in the factory setting for extended periods of time. The proteins responsible for host recognition were analysed and carbohydrate binding domains (CBDs) were identified in the distal tail (Dit), the baseplate proteins and the Tail-associated lysin (Tal) variable regions (VR1 and VR2) of many isolates. This consolidates the notion that S. thermophilus phages recognise a carbohydrate receptor on the cell surface of their host.Importance Dairy fermentations are consistently threatened by the presence of bacterial viruses (bacteriophages or phages), which may lead to a reduction in acidification rates or even complete loss of the fermentate. These phages may persist in factories for long periods of time. The objective of the current study was to monitor the progression of phages infecting the dairy bacterium Streptococcus thermophilus over a period of eleven years in an Irish dairy plant so as to understand how these phages evolve. A focused analysis of the genomic region that encodes host recognition functions highlighted that these proteins harbour a variety of carbohydrate binding domains, which corroborates the notion that phages of S. thermophilus recognise carbohydrate receptors at the initial stages of the phage cycle. PMID- 29523550 TI - Tissue Localization and Variation of Major Symbionts in Haemaphysalis longicornis, Rhipicephalus haemaphysaloides, and Dermacentor silvarum in China. AB - Ticks are important disease vectors, as they transmit a variety of human and animal pathogens worldwide. Symbionts that coevolved with ticks confer crucial benefits to their host in nutrition metabolism, fecundity, and vector competence. Although over 100 tick species have been identified in China, general information on tick symbiosis is limited. Here, we visualized the tissue distribution of Coxiella sp. and Rickettsia sp. in lab-reared Haemaphysalis longicornis and Rhipicephalus haemaphysaloides by fluorescent in situ hybridization. We found that Coxiella sp. colonized exclusively the Malpighian tubules and ovaries of H. longicornis, while Rickettsia sp. additionally colonized the midgut of R. haemaphysaloides We also investigated the population structure of microbiota in Dermacentor silvarum ticks collected from Inner Mongolia, China, and found that Coxiella, Rickettsia, and Pseudomonas are the three dominant genera. No significant difference in microbiota composition was found between male and female D. silvarum ticks. We again analyzed the tissue localization of Coxiella sp. and Rickettsia sp. and found that they displayed tissue tropisms similar to those in R. haemaphysaloides, except that Rickettsia sp. colonized the nuclei of spermatids instead of ovaries in D. silvarum Altogether, our results suggest that Coxiella sp. and Rickettsia sp. are the main symbionts in the three ticks and reside primarily in midgut, Malpighian tubules, and reproductive tissues, but their tissue distribution varies in association with species and sexes.IMPORTANCE Tick-borne diseases constitute a major public health burden, as they are increasing in frequency and severity worldwide. The presence of symbionts helps ticks to metabolize nutrients, promotes fecundity, and influences pathogen infections. Increasing numbers of tick-borne pathogens have been identified in China; however, knowledge of native ticks, especially tick symbiosis, is limited. In this study, we analyze the distribution of Coxiella sp. and Rickettsia sp. in tissues of laboratory-reared Haemaphysalis longicornis and Rhipicephalus haemaphysaloides and field-collected Dermacentor silvarum We found that the localization patterns of Coxiella sp. in three Chinese tick species were similar to those of other tick species. We also found a previously undefined intracellular localization of Rickettsia sp. in tick midgut and spermatids. In addition, we demonstrate that tissue tropisms of symbionts vary between species and sexes. Our findings provide new insights into the tissue localization of symbionts in native Chinese ticks and pave the way for further understanding of their functional capabilities and symbiotic interactions with ticks. PMID- 29523551 TI - Reconstituting the Evolutionary History of Cronobacter Driven by Differentiated CRISPR Activity. AB - Cronobacter strains harboring the CRISPR-Cas system are important foodborne pathogens causing serious neonatal infections. However, the specific role of the CRISPR-Cas system in bacterial evolution remains relatively unexplored. In this study, we investigated the impact of CRISPR-Cas in Cronobacter evolution and obtained 137 new whole-genome sequences of Cronobacter by next-generation sequencing technology. Among the strains examined (n=240), 90.6% (193/213) of prevalent species Cronobacter sakazakii, Cronobacter malonaticus, and Cronobacter dublinensis strains had intact CRISPR-Cas systems. Two rare species, Cronobacter condimenti (n=2) and Cronobacter universalis (n=6), lacked and preserved the CRISPR-Cas system at a low frequency (1/6), respectively. These results suggest that the presence of one CRISPR-Cas system in Cronobacter is important for the species to maintain genome homeostasis for survival. The Cronobacter ancestral strain was likely to harbored both subtype I-E and I-F CRISPR-Cas systems, during the long evolutionary process, subtype I-E was retained, while subtype I-F selectively degenerated in Cronobacter species and was even lost in the major Cronobacter pathovars. Moreover, significantly higher CRISPR activity was observed in plant-associated species C. dublinensis than in the virulence-related species C. sakazakii and C. malonaticus Similar spacers of CRISPR arrays were rarely found among species, suggesting intensive change through adaptive acquisition and loss. Differentiated CRISPR activity appears to be the product of environmental selective pressure and might contribute to the bidirectional divergence and speciation of CronobacterIMPORTANCE This study reports the evolutionary history of Cronobacter under the selective pressure of the CRISPR Cas system. One CRISPR-Cas system in Cronobacter is important for maintaining genome homeostasis, whereas two types of systems may be redundant and not conducive for acquiring beneficial DNA for environmental adaption and pathogenicity. Differentiated CRISPR activity has contributed to the bidirectional divergence and genetic diversity of Cronobacter This perspective makes a significant contribution to the literature by providing new insights into CRISPR-Cas systems in general, while further expanding the roles of CRISPR beyond conferring adaptive immunity and demonstrating a link to adaptation and species divergence in a genus. Moreover, our study provides new insights into the balance between genome homeostasis and the uptake of beneficial DNA related to CRISPR based activity in the evolution of Cronobacter. PMID- 29523552 TI - The Lysine 299 Residue Endows the Multisubunit Mrp1 Antiporter with Dominant Roles in Na+ Resistance and pH Homeostasis in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is generally regarded as a moderately salt- and alkali tolerant industrial organism. However, relatively little is known about the molecular mechanisms underlying these specific adaptations. Here, we found that the Mrp1 antiporter played crucial roles in conferring both environmental Na+ resistance and alkali tolerance whereas the Mrp2 antiporter was necessary in coping with high-KCl stress at alkaline pH. Furthermore, the Deltamrp1 Deltamrp2 double mutant showed the most-severe growth retardation and failed to grow under high-salt or alkaline conditions. Consistent with growth properties, the Na+/H+ antiporters of C. glutamicum were differentially expressed in response to specific salt or alkaline stress, and an alkaline stimulus particularly induced transcript levels of the Mrp-type antiporters. When the major Mrp1 antiporter was overwhelmed, C. glutamicum might employ alternative coordinate strategies to regulate antiport activities. Site-directed mutagenesis demonstrated that several conserved residues were required for optimal Na+ resistance, such as Mrp1A K299, Mrp1C I76, Mrp1A H230, and Mrp1D E136 Moreover, the chromosomal replacement of lysine 299 in the Mrp1A subunit resulted in a higher intracellular Na+ level and a more alkaline intracellular pH value, thereby causing a remarkable growth attenuation. Homology modeling of the Mrp1 subcomplex suggested two possible ion translocation pathways, and lysine 299 might exert its effect by affecting the stability and flexibility of the cytoplasm-facing channel in the Mrp1A subunit. Overall, these findings will provide new clues to the understanding of salt alkali adaptation during C. glutamicum stress acclimatization.IMPORTANCE The capacity to adapt to harsh environments is crucial for bacterial survival and product yields, including industrially useful Corynebacterium glutamicum Although C. glutamicum exhibits a marked resistance to salt-alkaline stress, the possible mechanism for these adaptations is still unclear. Here, we present the physiological functions and expression patterns of C. glutamicum putative Na+/H+ antiporters and conserved residues of Mrp1 subunits, which respond to different salt and alkaline stresses. We found that the Mrp-type antiporters, particularly the Mrp1 antiporter, played a predominant role in maintaining intracellular nontoxic Na+ levels and alkaline pH homeostasis. Loss of the major Mrp1 antiporter had a profound effect on gene expression of other antiporters under salt or alkaline conditions. The lysine 299 residue may play its essential roles in conferring salt and alkaline tolerance by affecting the ion translocation channel of the Mrp1A subunit. These findings will contribute to a better understanding of Na+/H+ antiporters in sodium antiport and pH regulation. PMID- 29523553 TI - Estrogen Degraders and Estrogen Degradation Pathway Identified in an Activated Sludge. AB - The environmental release and fate of estrogens are becoming an increasing public concern. Bacterial degradation has been considered the main process for eliminating estrogens from wastewater treatment plants. Various bacterial isolates are reportedly capable of aerobic estrogen degradation, and several estrogen degradation pathways have been proposed in proteobacteria and actinobacteria. However, the ecophysiological relevance of estrogen-degrading bacteria in the environment is unclear. In this study, we investigated the estrogen degradation pathway and corresponding degraders in activated sludge collected from the Dihua Sewage Treatment Plant, Taipei, Taiwan. Cultivation dependent and cultivation-independent methods were used to assess estrogen biodegradation in the collected activated sludge. Estrogen metabolite profile analysis revealed the production of pyridinestrone acid and two A/B-ring cleavage products in activated sludge incubated with estrone (1 mM), which are characteristic of the 4,5-seco pathway. PCR-based functional assays detected sequences closely related to alphaproteobacterial oecC, a key gene of the 4,5 seco pathway. Metagenomic analysis suggested that Novosphingobium spp. are major estrogen degraders in estrone-amended activated sludge. Novosphingobium sp. strain SLCC, an estrone-degrading alphaproteobacterium, was isolated from the examined activated sludge. The general physiology and metabolism of this strain were characterized. Pyridinestrone acid and the A/B-ring cleavage products were detected in estrone-grown strain SLCC cultures. The production of pyridinestrone acid was also observed during the aerobic incubation of strain SLCC with 3.7 nM (1 MUg/liter) estrone. This concentration is close to that detected in many natural and engineered aquatic ecosystems. The presented data suggest the ecophysiological relevance of Novosphingobium spp. in activated sludge.IMPORTANCE Estrogens, which persistently contaminate surface water worldwide, have been classified as endocrine disruptors and human carcinogens. We contribute new knowledge on the major estrogen biodegradation pathway and estrogen degraders in wastewater treatment plants. This study considerably advances the understanding of environmental estrogen biodegradation, which is instrumental for the efficient elimination of these hazardous pollutants. Moreover, this study substantially improves the understanding of microbial estrogen degradation in the environment. PMID- 29523554 TI - Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production. AB - RATIONALE: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. OBJECTIVE: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. METHODS AND RESULTS: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25 hydroxycholesterol after LIPA inhibition contributed to defective mitochondria associated membrane leading to mitochondrial oxidative stress-induced NLRP3 (NOD like receptor family, pyrin domain containing) inflammasome activation and caspase-1-dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. CONCLUSIONS: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance. PMID- 29523556 TI - Prevalent Cardiovascular Disease Events and T1 Mapping Defined Hepatic Fibrosis. PMID- 29523555 TI - Association of Liver Fibrosis With Cardiovascular Diseases in the General Population: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: The association of cardiovascular diseases (CVD) with liver fibrosis is poorly understood. We aim to assess the association of liver fibrosis by T1 mapping magnetic resonance imaging and CVD in MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AND RESULTS: MESA enrolled 6814 participants free of clinical CVD at baseline (2000-2002). A subsample of participants underwent T1 mapping magnetic resonance imaging 10 years after the baseline (Y10 MESA exam, 2010-2012). Liver T1 maps were generated avoiding vessels and biliary ducts from which native T1 (n=2087) and extracellular volume fraction (ECV, n=1234) were determined. Higher ECV and native T1 were indicators of liver fibrosis. Linear regression analysis evaluated the cross-sectional relationship between liver native T1 and ECV at Y10 MESA exam with a history of CVD events (atrial fibrillation, heart failure, and coronary heart disease [CHD]). Of the 2087 participants (68.7+/-9.1 years; 46% females), 153 had prior CVD events (78 atrial fibrillation, 25 heart failure, and 78 CHD). History of CVD events was associated with 18.5 ms higher liver native T1 (P<0.001) and 1.4% greater ECV (P=0.06). Prior atrial fibrillation was related to higher liver native T1 (beta=21.1; P=0.001) and greater ECV (beta=2.2; P=0.02), whereas previous heart failure was associated with greater liver ECV (beta=4.1; P=0.02). There was also a relationship of prior CHD with liver native T1 (beta=13; P=0.05) and ECV (beta=1.9; P=0.05), which was attenuated by adjustment for coronary artery calcium score (beta=7.1 and 1.6; P=0.37 and 0.13, respectively). CONCLUSIONS: Liver fibrosis by T1-mapping magnetic resonance imaging is associated with history of heart failure, atrial fibrillation, and CHD in a multiethnic cohort. The association of liver fibrosis and CHD is at least in part mediated by atherosclerosis. PMID- 29523557 TI - Endovascular treatment for acute ischaemic stroke in routine clinical practice: prospective, observational cohort study (MR CLEAN Registry). AB - OBJECTIVE: To determine outcomes and safety of endovascular treatment for acute ischaemic stroke, due to proximal intracranial vessel occlusion in the anterior circulation, in routine clinical practice. DESIGN: Ongoing, prospective, observational cohort study. SETTING: 16 centres that perform endovascular treatment in the Netherlands. PARTICIPANTS: 1488 patients included in the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry who had received endovascular treatment, including stent retriever thrombectomy, aspiration, and all alternative methods for acute ischaemic stroke within 6.5 hours from onset of symptoms between March 2014 and June 2016. MAIN OUTCOME MEASURES: The primary outcome was the modified Rankin Scale (mRS) score, ranging from 0 (no symptoms) to 6 (death) at 90 days after the onset of symptoms. Secondary outcomes were excellent functional outcome (mRS score 0-1), good functional outcome (mRS score 0-2), and favourable functional outcome (mRS score 0-3) at 90 days; score on the extended thrombolysis in cerebral infarction scale at the end of the intervention procedure; National Institutes of Health Stroke Scale score 24-48 hours after intervention; and complications that occurred during intervention, hospital admission, or three months' follow up period. Outcomes and safety variables in the MR CLEAN Registry were compared with the MR CLEAN trial intervention and control arms. RESULTS: A statistically significant shift was observed towards better functional outcome in patients in the MR CLEAN Registry compared with the MR CLEAN trial intervention arm (adjusted common odds ratio 1.30, 95% confidence interval 1.02 to 1.67) and the MR CLEAN trial control arm (1.85, 1.46 to 2.34). The reperfusion rate, with successful reperfusion defined as a score of 2B-3 on the extended thrombolysis in cerebral infarction score, was 58.7%, the same as for patients in the MR CLEAN trial. Duration from onset of stroke to start of endovascular treatment and from onset of stroke to successful reperfusion or last contrast bolus was one hour shorter for patients in the MR CLEAN Registry. Symptomatic intracranial haemorrhage occurred in 5.8% of patients in the MR CLEAN Registry compared with 7.7% in the MR CLEAN trial intervention arm and 6.4% in the MR CLEAN trial control arm. CONCLUSION: In routine clinical practice, endovascular treatment for patients with acute ischaemic stroke is at least as effective and safe as in the setting of a randomised controlled trial. PMID- 29523558 TI - Drug-Associated Risk Tool: development and validation of a self-assessment questionnaire to screen for hospitalised patients at risk for drug-related problems. AB - INTRODUCTION: Identifying patients with a high risk for drug-related problems (DRPs) might optimise the allocation of targeted pharmaceutical care during the hospital stay and on discharge. OBJECTIVE: To develop a self-assessment screening tool to identify patients at risk for DRPs and validate the tool regarding feasibility, acceptability and the reliability of the patients' answers. DESIGN: Prospective validation study. SETTING: Two mid-sized hospitals (300-400 beds). PARTICIPANTS: 195 patients, exclusion criteria: under 18 years old, patients with a health status not allowing a meaningful communication (eg, delirium, acute psychosis, advanced dementia, aphasia, clouded consciousness state), palliative or terminally ill patients. METHODS: Twenty-seven risk factors for the development of DRPs, identified in a previous study, provided the basis of the self-assessment questionnaire, the Drug-Associated Risk Tool (DART). Consenting patients filled in DART, and we compared their answers with objective patient data from medical records and laboratory data. RESULTS: One hundred and sixty four patients filled in DART V.1.0 in an average time of 7 min. After a first validation, we identified statements with a low sensitivity and revised the wording of the questions related to heart insufficiency, renal impairment or liver impairment. The revised DART (V.2.0) was validated in 31 patients presenting heart insufficiency, renal impairment or liver impairment as comorbidity and reached an average specificity of 88% (range 27-100) and an average sensitivity of 67% (range 21-100). CONCLUSIONS: DART showed a satisfying feasibility and reliability. The specificity of the statements was mostly high. The sensitivity varied and was higher in statements concerning diseases that require regular disease control and attention to self-care and drug management. Asking patients about their conditions, medications and related problems can facilitate getting a first, broad picture of the risk for DRPs and possible pharmaceutical needs. PMID- 29523559 TI - Incidence of delirium in the Canadian emergency department and its consequences on hospital length of stay: a prospective observational multicentre cohort study. AB - OBJECTIVE: We aim to determine the incidence of delirium and describe its impacts on hospital length of stay (LOS) among non-delirious community-dwelling older adults with an 8-hour exposure to the emergency department (ED) environment. DESIGN: This is a prospective observational multicentre cohort study (March-July 2015). Patients were assessed two times per day during their entire ED stay and up to 24 hours on hospital ward. SETTING: The study took place in four Canadian EDs. PARTICIPANTS: 338 included patients: (1) aged >=65 years; (2) who had an ED stay >=8 hours; (3) were admitted to hospital ward and (4) were independent/semi independent. MAIN OUTCOMES AND MEASURES: The primary outcomes of this study were incident delirium in the ED or within 24 hours of ward admission and ED and hospital LOS. Functional and cognitive status were assessed using validated Older Americans Resources and Services and the modified Telephone Interview for Cognitive Status tools. The Confusion Assessment Method was used to detect incident delirium. Univariate and multivariate analyses were conducted to evaluate outcomes. RESULTS: Mean age was 76.8 (+/-8.1), 17.7% were aged >85 years old and 48.8% were men. The mean incidence of delirium was 12.1% (n=41). Median IQR ED LOS was 32.4 (24.5-47.9) hours and hospital LOS was 146.6 (75.2-267.8) hours. Adjusted mean hospital LOS was increased by 105.4 hours (4.4 days) (95% CI 25.1 to 162.0, P<0.001) for patients who developed an episode of delirium compared with non-delirious patient. CONCLUSIONS: An incident delirium was observed in one of eight independent/semi-independent older adults after an 8 hour ED exposure. An episode of delirium increases hospital LOS by 4 days and therefore has important implications for patients and could contribute to ED overcrowding through a deleterious feedback loop. PMID- 29523561 TI - Patterns and trends of potentially inappropriate high-density lipoprotein cholesterol testing in Australian adults at high risk of cardiovascular disease from 2008 to 2014: analysis of linked individual patient data from the Australian Medicare Benefits Schedule and Pharmaceutical Benefits Scheme. AB - OBJECTIVES: We examine the extent to which the adult Australian population on lipid-lowering medications receives the level of high-density lipoprotein cholesterol (HDL-C) testing recommended by national guidelines. DATA: We analysed records from 7 years (2008-2014) of the 10% publicly available sample of deidentified, individual level, linked Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) electronic databases of Australia. METHODS: The PBS data were used to identify individuals on stable prescriptions of lipid lowering treatment. The MBS data were used to estimate the annual frequency of HDL-C testing. We developed a methodology to address the issue of 'episode coning' in the MBS data, which causes an undercounting of pathology tests. We used a published figure on the proportion of unreported HDL-C tests to correct for the undercounting and estimate the probability that an HDL-C test was performed. We judged appropriateness of testing frequency by comparing the HDL-C testing rate to guidelines' recommendations of annual testing for people at high risk for cardiovascular disease. RESULTS: We estimated that approximately 49% of the population on stable lipid-lowering treatment did not receive any HDL-C test in a given year. We also found that approximately 19% of the same population received two or more HDL-C tests within the year. These levels of underutilisation and overutilisation have been changing at an average rate of 2% and -4% a year, respectively, since 2009. The yearly expenditure associated with test overutilisation was approximately $A4.3 million during the study period, while the cost averted because of test underutilisation was approximately $A11.3 million a year. CONCLUSIONS: We found that approximately half of Australians on stable lipid-lowering treatment may be having fewer HDL-C testing than recommended by national guidelines, while nearly one-fifth are having more tests than recommended. PMID- 29523560 TI - Effects of family group conferences among high-risk patients of chronic disability and their significant others: study protocol for a multicentre controlled trial. AB - INTRODUCTION: Many patients and family members experience a large gap between the protected environment during inpatient medical rehabilitation and life in the community after discharge. They feel insufficiently prepared to cope with the consequences of their disability in daily life. This study protocol describes the design measuring the effectiveness and implementation of family group conferences on the empowerment of patients with a high risk of chronic disability and their significant others. METHODS AND ANALYSIS: A multicentre controlled trial will be carried out in 12 rehabilitation centres in the Netherlands. A total of 328 clinically admitted patients will participate (>=18 years, diagnosed with acquired brain injury, spinal cord injury or leg amputation), and their significant others will be included. During three family group conferences, supported by the social worker, the patient, significant other and their social network will be stimulated in collaboration, to set up participation goals, determine the needed help and make a concrete action plan. Self-reported questionnaires will be collected at baseline, clinical discharge, and 3 months and 6 months following clinical discharge. Empowerment as the primary outcome is operationalised as self-efficacy and participation. Secondary outcome measures are psychological (eg, coping, neuroticism) and environmental (eg, family functioning, social support) factors. This is the first controlled trial evaluating the effectiveness of family group conferences in rehabilitation medicine among adult patients and their significant others, providing us with knowledge in improving rehabilitation care. ETHICS AND DISSEMINATION: This study has been approved by the Medical Ethics Committee of the University Medical Center Utrecht (number 15-617/C). The results will be published in peer-reviewed journals and presented in local, national and international conferences. TRIAL REGISTRATION NUMBER: NTR5742; Pre-results. PMID- 29523562 TI - Agreement between electronic and paper Epworth Sleepiness Scale responses in obstructive sleep apnoea: secondary analysis of a randomised controlled trial undertaken in a specialised tertiary care clinic. AB - OBJECTIVES: Originally developed as a paper questionnaire, the electronic Epworth Sleepiness Scale (ESS) is widely used in sleep clinics and sleep population research. Despite potential differences between computer-based and conventional questionnaire delivery, studies have not evaluated the agreement between electronic and paper versions of the ESS. Given the widespread use of the ESS, a bias between results would present considerable data concerns. Thus, the aim of this study was to examine agreement between electronic and paper ESS responses in obstructive sleep apnoea (OSA). DESIGN: We undertook a secondary analysis of baseline data from a randomised controlled trial (ANZCTR: ACTRN12611000847910). SETTING: Data were collected in a tertiary sleep research laboratory located in Sydney, Australia. PARTICIPANTS: Data were analysed from 112 adult patients with OSA. MEASUREMENTS: Patients were given the English version of the ESS as part of a battery of sleep laboratory questionnaires. They completed electronic and subsequently paper ESS questionnaires on the same day. RESULTS: We found no significant difference between electronic and paper ESS questionnaires (mean=0.1, SD=2.1, 95% CI -0.3 to 0.5, P=0.57) or heteroscedasticity. There was no evidence of bias along the range of the measure. 95% limits of agreement at 4.3 and -4.1 were comparable with previous data. CONCLUSIONS: We found no evidence of bias between electronic and paper ESS questionnaires in this sample of patients with OSA, as the two formats displayed sufficient agreement to be clinically comparable. Regardless of severity, patients reported the same level of daytime sleepiness with the same level of accuracy across both measures. TRIAL REGISTRATION NUMBER: ACTRN12611000847910; Pre-results. PMID- 29523563 TI - What integrated care means from an older person's perspective? A scoping review protocol. AB - INTRODUCTION: According to the 2013 WHO Global Forum on Innovation for Ageing Populations, disabilities and morbidities associated with ageing could be minimised by accessing preventive care. One way of improving the management of multimorbidity in the older population is through the provision of 'integrated care'. Although integrated care means different things to different people, it typically symbolises continuity in care, thus preventing older patients' from falling through gaps in the health care system. Many initiatives have attempted to improve the integration of care; however, these are typically designed from a particular policy or system perspective. Relatively little is known about patient expectations and experiences of integrated care, which is vital for developing and implementing better models of care. The proposed scoping review aims to map literature on older patients'' views, expectations, experiences and perspectives of integrated care. METHODS AND ANALYSIS: Multiple electronic databases including PubMed, Web of Science, Embase, PsychInfo, Google Scholar, Cochrane Library, CINAHL and ProQuest Dissertations will be searched for appropriate articles between August and December 2017. Reference lists of selected articles will also be searched for similar articles. Two experienced researchers will conduct an initial search of the literature to identify relevant articles. Abstracts of the identified articles will be reviewed collectively by two researchers to identify potential further studies. Full texts of the potential studies will be sourced and screened for the inclusion criteria. Appropriate qualitative and quantitative methods will be used to extract data from each included study. ETHICS AND DISSEMINATION: The scoping review will synthesise findings from studies reporting on patients' views and expectations of integrated care. This review expects to find information relating to facilitators and barriers of integrated care from an older person's perspective. The findings from the review will be applied when working with stakeholders representing older people, healthcare, aged care and community providers, researchers and policy makers to develop and evaluate a more locally tailored and person-centred approach to integrated care. PMID- 29523564 TI - Using HTA and guideline development as a tool for research priority setting the NICE way: reducing research waste by identifying the right research to fund. AB - BACKGROUND: The National Institute for Health and Care Excellence (NICE) was established in 1999 and provides national guidance and advice to improve health and social care. Several steps in the research cycle have been identified that can support the reduction of waste that occurs in biomedical research. The first step in the process is ensuring appropriate research priority setting occurs so only the questions that are needed to fill existing gaps in the evidence are funded. This paper summarises the research priority setting processes at NICE. METHODS: NICE uses its guidance production processes to identify and prioritise research questions through systematic reviews, economic analyses and stakeholder consultations and then highlights those priorities by engagement with the research community. NICE also highlights its methodological areas for research to ensure the appropriate development and growth of the evidence landscape. RESULTS: NICE has prioritised research questions through its guidance production and methodological work and has successfully had several research products funded through the National Institute for Health Research and Medical Research Council. This paper summarises those activities and results. CONCLUSIONS: This activity of NICE therefore reduces research waste by ensuring that the research it recommends has been systematically prioritised through evidence reviews and stakeholder input. PMID- 29523565 TI - Feasibility of real-time capture of routine clinical data in the electronic health record: a hospital-based, observational service-evaluation study. AB - OBJECTIVES: The electronic health record (EHR) is underused in the hospital setting. The aim of this service evaluation study was to respond to National Health Service (NHS) Digital's ambition for a paperless NHS by capturing routinely collected cardiac outpatient data in the EHR to populate summary patient reports and provide a resource for audit and research. DESIGN: A PowerForm template was developed within the Cerner EHR, for real-time entry of routine clinical data by clinicians attending a cardiac outpatient clinic. Data captured within the PowerForm automatically populated a SmartTemplate to generate a view-only report that was immediately available for the patient and for electronic transmission to the referring general practitioner (GP). RESULTS: During the first 8 months, the PowerForm template was used in 61% (360/594) of consecutive outpatient referrals increasing from 42% to 77% during the course of the study. Structured patient reports were available for immediate sharing with the referring GP using Cerner Health Information Exchange technology while electronic transmission was successfully developed in a substudy of 64 cases, with direct delivery by the NHS Data Transfer Service in 29 cases and NHS mail in the remainder. In feedback, the report's immediate availability was considered very or extremely important by >80% of the patients and GPs who were surveyed. Both groups reported preference of the patient report to the conventional typed letter. Deidentified template data for all 360 patients were successfully captured within the Trust system, confirming availability of these routinely collected outpatient data for audit and research. CONCLUSION: Electronic template development tailored to the requirements of a specialist outpatient clinic facilitates capture of routinely collected data within the Cerner EHR. These data can be made available for audit and research. They can also be used to enhance communication by populating structured reports for immediate delivery to patients and GPs. PMID- 29523566 TI - Long-term clinical parameters after switching to nocturnal haemodialysis: a Dutch propensity-score-matched cohort study comparing patients on nocturnal haemodialysis with patients on three-times-a-week haemodialysis/haemodiafiltration. AB - OBJECTIVES: Nocturnal haemodialysis (NHD), characterised by 8-hour sessions >=3 times a week, is known to improve clinical parameters in the short term compared with conventional-schedule haemodialysis (HD), generally 3*3.5-4 hours a week. We studied long-term effects of NHD and used patients on conventional HD/haemodiafiltration (HDF) as controls. DESIGN: Four-year prospective follow-up of patients who switched to NHD; we compared patients with patients on HD/HDF using propensity score matching. SETTING: 28 Dutch dialysis centres. PARTICIPANTS: We included 159 patients starting with NHD any time since 2004, aged 56.7+/-12.9 years, with median dialysis vintage 2.3 (0.9-5.1) years. We propensity-score matched 100 patients on NHD to 100 on HD/HDF. PRIMARY AND SECONDARY OUTCOME MEASURES: Control of hypertension (predialysis blood pressure, number of antihypertensives), phosphate (phosphate, number of phosphate binders), nutritional status and inflammation (albumin, C reactive protein and postdialysis weight) and anaemia (erythropoiesis-stimulating agent (ESA) resistance). RESULTS: Switching to NHD was associated with a non-significant reduction of antihypertensives compared with HD/HDF (OR <2 types 2.17, 95% CI 0.86 to 5.50, P=0.11); and a prolonged lower need for phosphate binders (OR <2 types 1.83, 95% CI 1.10 to 3.03, P=0.02). NHD was not associated with significant changes in blood pressure or phosphate. NHD was associated with significantly higher albumin over time compared with HD/HDF (0.70 g/L/year, 95% CI 0.10 to 1.30, P=0.02). ESA resistance decreased significantly in NHD compared with HD/HDF, resulting in a 33% lower ESA dose in the long term. CONCLUSIONS: After switching to NHD, the lower need for antihypertensives, phosphate binders and ESA persists for at least 4 years. These sustained improvements in NHD contrast significantly with the course of these parameters during continued treatment with conventional-schedule HD and HDF. NHD provides an optimal form of dialysis, also suitable for patients expected to have a long waiting time for transplantation or those convicted to indefinite dialysis. PMID- 29523567 TI - Perspectives of healthcare providers on the nutritional management of patients on haemodialysis in Australia: an interview study. AB - OBJECTIVE: To describe the perspectives of healthcare providers on the nutritional management of patients on haemodialysis, which may inform strategies for improving patient-centred nutritional care. DESIGN: Face-to-face semistructured interviews were conducted until data saturation, and thematic analysis based on principles of grounded theory. SETTING: 21 haemodialysis centres across Australia. PARTICIPANTS: 42 haemodialysis clinicians (nephrologists and nephrology trainees (15), nurses (12) and dietitians (15)) were purposively sampled to obtain a range of demographic characteristics and clinical experiences. RESULTS: Six themes were identified: responding to changing clinical status (individualising strategies to patient needs, prioritising acute events, adapting guidelines), integrating patient circumstances (assimilating life priorities, access and affordability), delineating specialty roles in collaborative structures (shared and cohesive care, pivotal role of dietary expertise, facilitating access to nutritional care, perpetuating conflicting advice and patient confusion, devaluing nutritional specialty), empowerment for behaviour change (enabling comprehension of complexities, building autonomy and ownership, developing self-efficacy through engagement, tailoring self-management strategies), initiating and sustaining motivation (encountering motivational hurdles, empathy for confronting life changes, fostering non-judgemental relationships, emphasising symptomatic and tangible benefits, harnessing support networks), and organisational and staffing barriers (staffing shortfalls, readdressing system inefficiencies). CONCLUSIONS: Organisational support with collaborative multidisciplinary teams and individualised patient care were seen as necessary for developing positive patient-clinician relationships, delivering consistent nutrition advice, and building and sustaining patient motivation to enable change in dietary behaviour. Improving service delivery and developing and delivering targeted, multifaceted self-management interventions may enhance current nutritional management of patients on haemodialysis. PMID- 29523568 TI - Identifying priority policy issues and health system research questions associated with recovery outcomes for burns survivors in India: a qualitative inquiry. AB - OBJECTIVES: This study aimed to identify priority policy issues and health system research questions associated with recovery outcomes for burns survivors in India. DESIGN: Qualitative inquiry; data were collected through semistructured in depth interviews and focus group discussions. SETTING: Nine sites in urban and rural settings across India, through primary, secondary and tertiary health facilities. PARTICIPANTS: Healthcare providers, key informants, burns survivors and/or their carers. RESULTS: Participants acknowledged the challenges of burns care and recovery, and identified the need for prolonged rehabilitation. Challenges identified included poor communication between healthcare providers and survivors, limited rehabilitation services, difficulties with transportation to health facility and high cost associated with burns care. Burns survivors and healthcare providers identified the stigma attached with burns as the biggest challenge within the healthcare system, as well as in the community. Systems barriers (eg, limited infrastructure and human resources), lack of economic and social support, and poor understanding of recovery and rehabilitation were identified as major barriers to recovery. CONCLUSIONS: Though further research is needed for addressing gaps in data, strengthening of health systems can enable providers to address issues such as developing/providing, protocols, capacity building, effective coordination between key organisations and referral networks. PMID- 29523569 TI - A tailored strategy for designing the Walk-Copenhagen (WALK-Cph) intervention to increase mobility in hospitalised older medical patients: a protocol for the qualitative part of the WALK-Cph project. AB - INTRODUCTION: Older medical patients (>65 years) represent 54% of the admissions to Danish medical and emergency departments. Acute admissions and bed-rest during hospitalisation are independent risk factors for death and dependency in older patients. Even short hospitalisations are associated with increased dependency in activities of daily living after discharge. Interventions that increase mobility during hospitalisation are therefore important. The purpose of this protocol is to describe the intervention design of the WALK-Copenhagen project, aimed at increasing 24 hours mobility in older medical patients during acute hospitalisations and following discharge. METHODS AND ANALYSIS: This study is based on ethnographic fieldwork and interviews. Workshops are used to develop and co-design the intervention in collaboration with key stakeholders (patients, relatives, health professionals and researchers). The theory of cultural learning processes, and the cultural historical activity theory will be used to help us understand the interaction between health professionals, structures and objects in relation to mobility in the medical departments. ETHICS AND DISSEMINATION: The project will adhere to the directives of the Helsinki Declaration. Ethical approval was not required for the study since formal ethical approval is not mandatory for studies that do not involve biomedical issues (I-Suite no: 05078) according to Danish law. Informed consent was obtained for all participants. The results will be disseminated to health professionals, managers, patients and relatives, who will be invited to afternoon meetings where the project will be discussed. The results will be published in peer-reviewed scientific journals and presented at scientific conferences. PMID- 29523570 TI - The role of clothing in participation of persons with a physical disability: a scoping review protocol. AB - INTRODUCTION: Clothing is an important aspect of nearly all human societies from performing social and cultural functions to indicating social status, a form of protection and a way for self-expression. It can help or hinder the ability to fulfil everyday activities and social roles and with the rising industry of wearable technologies, smart textiles are adding health-monitoring functions to clothing. The influence that clothing can have on the life of someone with a physical disability is significant, and further research is needed to understand it better. To achieve this, a scoping review will be performed with the aim of understanding the role of clothing in participation (ie, at home, in the community, etc) of individuals with a physical disability. This article presents the protocol and procedure to be adopted. METHODS AND ANALYSIS: An in-depth iterative analysis of the scientific literature from six databases (MEDLINE, Embase, CINAHL, Scopus, PsycINFO and ERIC) as well as a hand search of grey literature and reference lists will be performed. After an abstract and full-text review of references by three reviewers independently, data from the selected articles will be tabulated and synthesised with a qualitative and quantitative approach using the International Classification of Functioning, Disability and Health as a unifying conceptual framework. A multidisciplinary consultation group of experts from various stakeholder groups will be involved in multiple steps to ensure validation and relevance of the data. ETHICS AND DISSEMINATION: As this is a review involving analysis of data available in the public domain and does not involve human participants, ethical approval was not required. Results will be presented in a co-constructed format with the expert consultation group to ensure validity and maximise its practicality moving forward. Our dissemination plan includes peer-reviewed publications, presentations and stakeholder meetings. PMID- 29523571 TI - Cognitive-behavioural therapy (CBT) for renal fatigue (BReF): a feasibility randomised-controlled trial of CBT for the management of fatigue in haemodialysis (HD) patients. AB - INTRODUCTION: Fatigue is one of the most common and disabling symptoms in end stage kidney disease, particularly among in-centre haemodialysis patients. This two-arm parallel group feasibility randomised controlled trial will determine whether a fully powered efficacy trial is achievable by examining the feasibility of recruitment, acceptability and potential benefits of a cognitive-behavioural therapy (CBT)-based intervention for fatigue among in-centre haemodialysis patients. METHODS: We aim to recruit 40 adult patients undergoing in-centre haemodialysis at secondary care outpatient dialysis units, who meet clinical levels of fatigue. Patients will be randomised individually (using a 1:1 ratio) to either a 4-6 weeks' CBT-based intervention (intervention arm) or to a waiting list control (control arm). The primary feasibility outcomes include descriptive data on numbers within each recruiting centre meeting eligibility criteria, rates of recruitment, numbers retained postrandomisation and treatment adherence. To assess the potential benefits of the cognitive-behavioural therapy for renal fatigue intervention, secondary self-report outcomes include measures of fatigue severity (Chalder Fatigue Questionnaire), fatigue-related functional impairment (Work and Social Adjustment Scale), sleep quality (Pittsburgh Sleep Quality Index), depression (Patient Health Questionnaire-9) and anxiety (Generalised Anxiety Disorder-7). Changes in fatigue perceptions (Brief Illness Perception Questionnaire), cognitive and behavioural responses to fatigue (Cognitive and Behavioural Responses to Symptoms Questionnaire), sleep hygiene behaviours (Sleep Hygiene Index) and physical activity (International Physical Activity Questionnaire-short form) will also be explored. These self-report measures will be collected at baseline and 3 months postrandomisation. Nested qualitative interviews will be conducted postintervention to explore the acceptability of the intervention and identify any areas in need of improvement. The statistician and assessor will be blinded to treatment allocation. ETHICS AND DISSEMINATION: A National Health Service (NHS) Research Ethics Committee approved the study. Any amendments to the protocol will be submitted to the NHS Committee and study sponsor. TRIAL REGISTRATION NUMBER: ISRCTN91238019;Pre-results. PMID- 29523572 TI - Prognostic significance of autoantibodies for idiopathic pulmonary fibrosis: protocol for a systematic review. AB - INTRODUCTION: Idiopathic pulmonary fibrosis(IPF) is chronic fibrosing interstitial pneumonia of unknown aetiology. IPF is diagnosed based on the exclusion of known causes such as connective tissue diseases(CTDs). However, some patients fail to meet defined CTD criteria regardless of an implication of immunological involvement and these cases were described in a variety of terms. The classification criteria of this clinical entity consist of a combination of clinical, serological and morphological findings and it is reported to be distinct from IPF. However, the significance of the sole presence of autoantibodies complicated with IPF is still unknown. Therefore, this systematic review aims to clarify the significance of autoantibodies complicated with IPF. METHODS AND ANALYSIS: IPF with any autoantibody associated with CTDs is eligible for the review. Primary outcomes are all-cause mortality and pulmonary-cause mortality, while secondary outcomes include a progression of the disease, a deterioration of health-related quality of life and the development of a defined CTD. Primary studies of any type except a case report are included. Two reviewers search four electronic databases such as Medline, EMBASE, Science Citation Index Expanded and Google Scholar from each inception through 1 February 2018 and extract data independently. A risk of bias in individual studies is assessed by the Quality in Prognostic Studies tool. Meta-analysis is sought to be conducted if three or more studies report an outcome for a specific autoantibody with the same statistics. If it is inappropriate to combine data due to substantial heterogeneity, the result is reported qualitatively. Subgroup and sensitivity analyses are considered to identify the source of heterogeneity. The Grades of Recommendation, Assessment, Development and Evaluation method is applied to evaluate the evidence level of the result. ETHICS AND DISSEMINATION: There is no concerning ethical issue. The result will be sought for publication. PROSPERO REGISTRATION NUMBER: CRD42017077336. PMID- 29523573 TI - Correction: Qualitative meta-synthesis of barriers and facilitators that influence the implementation of community pharmacy services: perspectives of patients, nurses and general medical practitioners. PMID- 29523574 TI - Correction: Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia. PMID- 29523575 TI - Correction: Fabry disease due to D313Y and novel GLA mutations. PMID- 29523576 TI - Correction: Variations in childbirth interventions in high-income countries: protocol for a multinational cross-sectional study. PMID- 29523578 TI - Dermatologists criticise Facebook and Instagram for removing psoriasis images. PMID- 29523577 TI - Correction: Understanding frailty: a qualitative study of European healthcare policy-makers' approaches to frailty screening and management. PMID- 29523579 TI - Pop a million happy pills? Antidepressants, nuance, and the media. PMID- 29523580 TI - "Exploited" doctors are keeping overstretched NHS going, says GP leader. PMID- 29523581 TI - Government must introduce incentives to retain older GPs, says BMA. PMID- 29523583 TI - Erratum for Research Article: "Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves TH1/TFH fate bifurcation in malaria" by T. Lonnberg, V. Svensson, K. R. James, D. Fernandez-Ruiz, I. Sebina, R. Montandon, M. S. F. Soon, L. G. Fogg, A. S. Nair, U. N. Liligeto, M. J. T. Stubbington, L.-H. Ly, F. Otzen Bagger, M. Zwiessele, N. D. Lawrence, F. Souza Fonseca-Guimaraes, P. T. Bunn, C. R. Engwerda, W. R. Heath, O. Billker, O. Stegle, A. Haque, S. A. Teichmann. PMID- 29523584 TI - One domain fits all: Using disordered regions to sequester misfolded proteins. AB - Small heat shock proteins (sHsps) are adenosine triphosphate-independent chaperones that protect cells from misfolded proteins. In this issue, Grousl et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201708116) show that the yeast sHsp Hsp42 uses a prion-like intrinsically disordered domain to bind and sequester misfolded proteins in protein deposition sites. PMID- 29523582 TI - Structures of respiratory syncytial virus G antigen bound to broadly neutralizing antibodies. AB - Respiratory syncytial virus (RSV) is a top cause of severe lower respiratory tract disease and mortality in young children and the elderly. The viral envelope G glycoprotein contributes to pathogenesis through its roles in host cell attachment and modulation of host immunity. Although the G glycoprotein is a target of protective RSV-neutralizing antibodies, its development as a vaccine antigen has been hindered by its heterogeneous glycosylation and sequence variability outside a conserved central domain (CCD). We describe the cocrystal structures of two high-affinity broadly neutralizing human monoclonal antibodies bound to the RSV G CCD. The antibodies bind to neighboring conformational epitopes, which we named antigenic sites gamma1 and gamma2, that span a highly conserved surface, illuminating an important region of vulnerability. We further show that isolated RSV G CCD activates the chemokine receptor CX3CR1 and that antibodies block this activity. These studies provide a template for rational vaccine design targeting this key contributor to RSV disease. PMID- 29523585 TI - Metastasis inside-out: dissemination of cancer cell clusters with inverted polarity. PMID- 29523586 TI - Little and large: the effects of twin growth discordance. PMID- 29523588 TI - Tackling acute coronary syndrome in low-income and middle-income countries. PMID- 29523587 TI - Characterisation of mesenchymal stem cells from patients with amyotrophic lateral sclerosis. AB - AIMS: Mesenchymal stem cells (MSCs) have recently been tested in clinical trials to treat severe diseases, including amyotrophic lateral sclerosis (ALS). Since autologous MSCs are frequently used for therapy, we aimed to evaluate the possible influence of the disease on characteristics and function of these cells. METHODS: MSCs were isolated from the bone marrow of patients with ALS and compared with MSCs from healthy controls (HC). The cells were tested for phenotype, growth properties, differentiation ability, metabolic activity, secretory potential, expression of genes for immunomodulatory molecules and for the ability to regulate proliferation of mitogen-stimulated peripheral blood leucocytes. MSCs from patients with ALS and HC were either unstimulated or treated with proinflammatory cytokines for 24 hours before testing. RESULTS: MSCs isolated from patients with ALS have a higher differentiation potential into adipocytes, express elevated levels of mRNA for interleukin-6, but produce less hepatocyte growth factor than MSCs from HC. On the other hand, there were no significant differences between MSCs from patients with ALS and HC in the expression of phenotypic markers, growth properties, metabolic activity, osteogenic differentiation potential and immunoregulatory properties. CONCLUSIONS: The results suggest that, in spite of some differences in cytokine production, MSCs from patients with ALS can be useful as autologous cells in therapy of ALS. PMID- 29523589 TI - Temporal trends in the contribution of Chagas cardiomyopathy to mortality among patients with heart failure. AB - BACKGROUND: Chagas cardiomyopathy (ChC) prevalence is decreasing in Brazil and medical therapies for heart failure (HF) have improved in the last decade. Whether these changes modified the prognosis of ChC relative to non-Chagas cardiomyopathies (NChC) remains unknown. This study evaluated the temporal trends in population attributable risk (PAR) of ChC for 2-year mortality among patients with HF enrolled at years 2002-2004 (era 1) and 2012-2014 (era 2) in a Brazilian university hospital. METHODS: We prospectively studied 362 (15% with ChC) and 582 (18% with ChC) HF patients with ejection fraction <=50% in eras 1 and 2, respectively and estimated the PAR of ChC for 2-year mortality. RESULTS: There were 145 deaths (29 in ChC) in era 1 and 85 deaths (26 in ChC) in era 2. In multivariable Cox-regression analysis adjusted for age, sex, ejection fraction, heart rate, body mass index, hypertension, diabetes mellitus, systolic blood pressure and ischaemic/valvar aetiology, ChC was associated with higher risk of death in era 1 (HR (95% CI)=1.92 (1.00 to 3.71), p=0.05) and era 2 (HR (95% CI)=3.51 (1.94 to 6.36), p<0.001). In fully adjusted analysis, the PAR of ChC for mortality increased twofold from era 1 (PAR (95% CI)=11.0 (2.8 to 18.5)%) to era 2 (PAR (95% CI)=21.9 (16.5 to 26.9)%; p=0.023 versus era 1). CONCLUSION: Although the absolute death rates decreased over time in the ChC and NChC groups, the PAR of ChC for mortality increased among patients with HF, driven by increases in the HR associated with ChC. Our results highlight the need for additional efforts aiming to prevent and treat ChC. PMID- 29523591 TI - Studying the Effect of Vitamin D Supplementation on Vascular Function in CKD: A Work in Progress. PMID- 29523590 TI - Signaling function of PRC2 is essential for TCR-driven T cell responses. AB - Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell-driven autoimmune diseases. PMID- 29523592 TI - The Authors Reply. PMID- 29523593 TI - Evaluation of Potential Living Kidney Donors in the APOL1 Era. PMID- 29523594 TI - Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP mutated prostate cancer. AB - AKT-mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine-63-chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN-deficient and SPOP-mutated prostate cancer cells in culture, patient-derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single-agent targeting of HDAC3 in prostate cancer. PMID- 29523595 TI - Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection. AB - Thoracic aortic aneurysm and dissection (TAAD) is due to degeneration of the aorta and causes a high mortality rate, while molecular mechanisms for the development of TAAD are still not completely understood. In the present study, 3 aminopropionitrile (BAPN) treatment was used to induce TAAD mouse model. Through transcriptome analysis, we found the expression levels of genes associated with interleukin-3 (IL-3) signaling pathway were up-regulated during TAAD development in mouse, which were validated by real-time PCR. IL-3 positive cells were increased in TAAD mouse aortas, especially for smooth muscle cells (SMCs). IL-3 deficiency reduced BAPN-induced TAAD formation. We then examined the matrix metalloproteinases (MMPs) expression during TAAD formation in both wild-type and IL-3 deficient mice, showing that MMP12 were significantly down-regulated in IL-3 deficient aortas. Mechanistically, we found recombinant IL-3 could increase MMP12 production and activity from macrophages in vitro Silencing of IL-3 receptor beta, which was mainly expressed in macrophages but not SMCs, diminished the activation of c-Jun N terminal kinase (JNK)/extracellular-regulated protein kinases 1/2 (ERK1/2)/AP-1 signals, and decreased MMP12 expression in IL-3 stimulated macrophages. Moreover, both circulating and aortic inflammation were decreased in IL-3 deficient aortas. Taken together, our results demonstrated that IL-3 stimulated the production of MMP12 from macrophages by a JNK- and ERK1/2 dependent AP-1 pathway, contributing to TAAD formation. Thus, the IL-3/IL 3Rbeta/MMP12 signals activation may be an important pathological mechanism for progression of TAAD. PMID- 29523596 TI - The pseudogene-derived long non-coding RNA SFTA1P suppresses cell proliferation, migration, and invasion in gastric cancer. AB - Pseudogenes were once regarded as transcriptionally inactive and without specific molecular function. However, current evidence shows that pseudogene-derived long non-coding RNAs (lncRNAs) may be crucial regulators of human cancer development, including gastric cancer (GC). In the present study, we report that a pseudogene derived lncRNA named surfactant associated 1, pseudogene (SFTA1P), which is 693 nt long, was significantly down-regulated in GC tissues compared with that in the adjacent normal tissues. In addition, decreased SFTA1P expression was strongly correlated with advanced tumor lymph node metastasis (TNM) stage, larger tumor size, lymphatic metastasis, and poor prognosis of patients with GC. Moreover, gain-of-function experiments revealed that the overexpression of SFTA1P inhibits cell proliferation, migration, and invasion, thus verifying the tumor inhibitory role of SFTA1P in GC. Furthermore, we investigated the potential action mechanism of SFTA1P. Our results showed that down-regulation of SFTA1P may be associated with decreased TP53 expression. In summary, our work suggests that the pseudogene derived lncRNA SFTA1P functions as a tumor suppressor in GC and thus may act as a potential diagnostic and therapeutic target of GC. PMID- 29523598 TI - Effectiveness of antidepressants. PMID- 29523597 TI - Cross-Talk between Myeloid-Derived Suppressor Cells and Mast Cells Mediates Tumor Specific Immunosuppression in Prostate Cancer. AB - Immunotherapy, including the use of checkpoint inhibitors, is a potent therapeutic approach for some cancers, but has limited success with prostate tumors, in which immune suppression is instigated by the tumor. The immunosuppressive capacity of mast cells, which promote adenocarcinoma development in the prostate, prompted our investigation on whether mast cells promote tolerance to SV40 Large-T antigen, the transforming oncogene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. The incidence of adenocarcinoma was reduced in the offspring of a cross between TRAMP mice and mast cell-deficient KitWsh mice. TRAMP mice are tolerant to the SV40 Large T antigen, which is otherwise immunogenic in normal syngeneic B6 mice. Genetic ablation of mast cells in TRAMP mice restored their ability to mount a tumor specific cytotoxic T-cell response. In KitWsh-TRAMP mice, the restored T-cell immunity correlated with the reduced activity of polymorphonuclear myeloid derived suppressor cells (PMN-MDSC), along with their reduced expression of Arg1, Nos2, and Stat3 Having found that CD40L-expressing mast cells can interact in vivo with CD40-expressing PMN-MDSC, we then determined that only KitWsh-TRAMP mice reconstituted with mast cells expressing CD40L could restore PMN-MDSCs suppressive functions, T-cell unresponsiveness and adenocarcinoma development. Thus, mast cells have an immunoregulatory effect on PMN-MDSCs activity through CD40L-CD40 interaction, favoring immunosuppression and tumor onset. In prostate cancer patients, in silico analyses correlated poor clinical outcomes with high expression of genes related to mast cells and PMN-MDSCs. Cancer Immunol Res; 6(5); 552-65. (c)2018 AACR. PMID- 29523599 TI - MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study. AB - Hepatic drug transporters play a pivotal role in the excretion of drugs from the body, in drug-drug interactions, as well as in drug-induced liver toxicity. Hepatocytes cultured in sandwich configuration are an advantageous model to investigate the interactions of drug candidates with apical efflux transporters in a biorelevant manner. However, the commonly used "offline" assays (i.e., that rely on measuring intracellular accumulated amounts after cell lysis) are time- and resource-consuming, and the data output is often highly variable. In the present study, we used confocal microscopy to investigate the inhibitory effect of all marketed HIV protease inhibitors (10 MUM) on the apical efflux transporter multidrug resistance-associated protein 2 (MRP2; ABCC2) by visualizing the biliary accumulation of the fluorescent substrate 5(6)-carboxy-2',7' dichlorofluorescein (CDF). This method was applied with sandwich-cultured human and rat hepatocytes. Alterations in the biliary excretion index of CDF were calculated on the basis of quantitative analysis of fluorescence intensities in the confocal images. In human hepatocytes, lopinavir followed by tipranavir, saquinavir, atazanavir, and darunavir were the most potent inhibitors of MRP2 mediated efflux of CDF. In rat hepatocytes, tipranavir inhibited Mrp2-mediated CDF efflux most potently, followed by lopinavir and nelfinavir. In conclusion, a comparison of these findings with previously published data generated in offline transporter inhibition assays indicates that this microscopy-based approach enables investigation of the inhibitory effect of drugs on efflux transporters in a very sensitive but nondestructive manner. PMID- 29523600 TI - A Promising Microtubule Inhibitor Deoxypodophyllotoxin Exhibits Better Efficacy to Multidrug-Resistant Breast Cancer than Paclitaxel via Avoiding Efflux Transport. AB - Multidrug resistance (MDR) is a common limitation for the clinical use of microtubule-targeting chemotherapeutic agents, and it is the main factor for poor prognoses in cancer therapy. Here, we report on deoxypodophyllotoxin (DPT), a promising microtubule inhibitor in phase 1, as a promising candidate to circumvent this obstacle. DPT remarkably suppressed tumor growth in xenograft mice bearing either paclitaxel (PTX)-sensitive MCF-7/S or acquired resistance MCF 7/Adr (MCF-7/A) cells. Also, DPT exhibited similar accumulation in both tumors, whereas PTX displayed much a lower accumulation in the resistant tumors. In vitro, DPT exhibited a much lower resistance index (0.552) than those of PTX (754.5) or etoposide (38.94) in both MCF-7/S and MCF-7/A cells. Flow cytometry analysis revealed that DPT (5 and 10 nM) caused arrest of the G2/M phase in the two cell lines, whereas PTX (up to 10 nM) had no effect on cell-cycle progression of the MCF-7/A cells. Microtubule dynamics assays revealed that DPT destabilized microtubule assembly in a different mode. Cellular pharmacokinetic assays indicated comparable intracellular and subcellular accumulations of DPT in the two cell lines but a much lower retention of PTX in the MCF-7/A cells. Additionally, transport assays revealed that DPT was not the substrate of P glycoprotein, breast cancer resistance protein, or MDR-associated protein 2, indicating a lower occurrence rate of MDR. DPT might be a promising microtubule inhibitor for breast cancer therapy, especially for treatment of drug-resistant tumors. PMID- 29523602 TI - Providing safe, efficient and affordable sedation in endoscopy. PMID- 29523601 TI - Pharmacokinetics-Based Identification of Potential Therapeutic Phthalides from XueBiJing, a Chinese Herbal Injection Used in Sepsis Management. AB - XueBiJing, an injectable five-herb preparation, has been incorporated into routine sepsis care in China. Phthalides, originating from XueBiJing's component herbs Ligusticum chuanxiong rhizomes and Angelica sinensis roots, are believed to contribute to its therapeutic effects due to their presence in the preparation and antisepsis-related properties. This investigation aimed to identify potential therapeutic phthalides that are bioavailable to act on XueBiJing's therapeutic targets and that could serve as pharmacokinetic markers to supplement classic biomarkers for sepsis care. Among 10 phthalides detected in XueBiJing, senkyunolides I and G were the major circulating phthalides in human subjects, but their different pharmacokinetics might influence their contribution to XueBiJing's therapeutic action. Senkyunolide I exhibited a large distribution volume (1.32 l/kg) and was moderately bound in plasma (54% unbound), whereas senkyunolide G exhibited a small distribution volume (0.10 l/kg) and was extensively bound in plasma (3% unbound). Clearance of senkyunolide I from the systemic circulation was governed by UGT2B15-mediated hepatic glucuronidation; the resulting electrophilic glucuronides were conjugated with glutathione in the liver. Senkyunolide G was selectively bound to albumin (99%) in human plasma. To our knowledge, the human pharmacokinetic data of XueBiJing's phthalides are reported here for the first time. Based on this investigation and such investigations of the other component herbs, follow-up pharmacodynamic assessments of bioavailable herbal compounds are planned to elucidate XueBiJing's chemical basis responsible for its therapeutic action. Senkyunolides I and G, having the preceding disposition characteristics that could be detectably altered by septic pathophysiology, could serve as pharmacokinetic markers for sepsis care. PMID- 29523603 TI - Resolution of severe fetal distress following treatment of maternal diabetic ketoacidosis. AB - Diabetic ketoacidosis (DKA) during pregnancy is a serious metabolic complication of diabetes with high mortality and morbidity if not detected and treated immediately. We report a case of a woman with type 1 diabetes mellitus who had poorly controlled diabetes in the first half of pregnancy and developed DKA at 29 weeks gestation. At presentation, she had a pathological fetal heart tracing but delivery was delayed for maternal stabilisation and reversal of acidosis. Once hyperglycaemia, acidosis and maternal stabilisation were achieved, fetal compromise resolved and delivery was no longer indicated. The patient was subsequently discharged home. She delivered vaginally a 2400 g baby at 34 weeks gestation after presenting with spontaneous rupture of membranes. PMID- 29523604 TI - Autoimmune haemolytic anaemia in a patient with advanced lung adenocarcinoma and chronic lymphocytic leukaemia receiving nivolumab and intravenous immunoglobulin. AB - We describe a rare case of severe autoimmune haemolytic anaemia (AIHA) in the setting of underlying chronic lymphocytic leukaemia receiving intravenous immunoglobulin, history of warm IgG autoantibody and treatment with nivolumab for advanced non-small cell lung cancer. In this report, we describe AIHA as a potential serious immune-related adverse event from immune checkpoint inhibitors, discuss other potential contributing factors and review previously described cases of AIHA in patients receiving programmed death 1 (PD-1) inhibitors. In the era of immunotherapy, we hope to add literature to raise awareness of potential immune-related sequelae such as AIHA. We aim to highlight the importance of close monitoring for prompt identification and management of potentially fatal AIHA and immune-related adverse events of PD-1 inhibitors by holding immunotherapy and treating with high-dose steroids, particularly in subgroups which may be at increased risk. PMID- 29523605 TI - Lead in a case of encephalopathy. AB - A 2-year-old boy with a history of pica was admitted with vomiting and treated overnight for viral tonsillitis. A week later, he presented with a prolonged afebrile seizure and required intubation and ventilation. Antibiotics and acyclovir were started. Despite extensive investigations including MRI head, no cause was identified. Four days later, he deteriorated with signs of raised intracranial pressure. On day 5, blood lead concentration in the sample collected at admission was reported as grossly elevated, consistent with a diagnosis of severe lead poisoning from ingesting lead-containing paint at the family home. Chelation therapy was started but, unfortunately, he did not make a neurological recovery, and care was withdrawn. A serious case review identified a lack of awareness of lead poisoning and its relation to pica as a root cause. We report this case to share our experience and the importance of considering lead poisoning in children with pica. PMID- 29523606 TI - Atypical presentation of aural tuberculosis with complication. AB - Tuberculosis involving mastoid and ear is an uncommon entity presenting with myriads of non-specific features and difficult to diagnose, being a paucibacillary condition. The involvement of otomastoid compartment is hypothesised to be of haematogenous origin. Rarely it can spread directly via tympanic membrane perforation or via reflux through eustachian tube. The usual picture of presentation tends to be one of indolent ear infection not responsive to usual antibiotic treatment and symptomatology being out of proportion to examination findings. We present a case of aural tuberculosis presenting with zygomatic and Bezold abscess without other symptoms, and the usefulness of GeneXpert test in mycobacterial detection in such paucibacillary conditions. PMID- 29523607 TI - Differing effects of an immersive virtual reality programme on unilateral spatial neglect on activities of daily living. AB - In clinical practice, therapists often encounter cases of unilateral spatial neglect (USN) observed in far and near space. In this case report, immersive virtual reality (VR) technology was adopted as a therapy tool in a patient with stroke with severe near and far space neglect. Neuropsychological tests in near and far space as well as the Catherine Bergego Scale (CBS), as an index of neglect in daily living, were measured preintervention and postintervention. Improvement of neuropsychological tests, particularly in far space, was clearly demonstrated postintervention. However, CBS score did not change postintervention. This may be because the patient unsuccessfully translated these visual search task skills used in far space to activities of daily living. Our findings suggest the potential use of immersive VR technology in patients with USN and highlight the VR programme's limited ability to fully recover a patient's disability in natural settings. PMID- 29523608 TI - Considering exercise-associated hyponatraemia as a continuum. AB - Exercise-associated hyponatraemia (EAH) always involves a component of overhydration relative to available exchangeable sodium stores. In the majority of cases, this is purely due to excessive consumption of fluids during exercise. In a lesser number of cases, it is apparent that excessive sodium loss through sweat may play a role by decreasing the amount of acutely available exchangeable sodium. Two cases demonstrating the latter, one in an individual with cystic fibrosis (CF) and another in an endurance athlete without CF, demonstrate how elevated dermal sweat losses may contribute to a relative dilutional EAH along a pathophysiological continuum. PMID- 29523609 TI - Iatrogenic water intoxication in a female adolescent with hypopituitarism. AB - The authors report a case of a 15-year-old girl with hypopituitarism due to pituitary stalk interruption syndrome diagnosed in the neonatal period. The patient was admitted to the emergency room with impaired consciousness and hypoglycaemia. The day before, she increased her water intake to about 1.5 L to perform a pelvic ultrasound. In the following hours, she developed vomiting and food refusal. Blood analysis revealed hypoglycaemia, hyponatraemia, decreased serum osmolality and normal urinary density. Hyponatraemia and adrenal crisis were managed with a gradual but slow resolution of consciousness and electrolytic balance. This case describes an episode of iatrogenic water intoxication in a patient under desmopressin treatment. Although uncommon, dilutional hyponatraemia is the main complication of desmopressin treatment. We reinforce the importance of patients and caregivers' long-life education for the potential complications of an increase in fluid intake in patients treated with desmopressin. PMID- 29523610 TI - Nasal oncocytoma causing unilateral epiphora in an elderly patient: the vital role of nasendoscopy. AB - Oncocytomas are rare glandular tumours, typically found in salivary glands and kidneys. A 76-year-old man presented to an ophthalmology department after 3 months of persistent right-sided epiphora. Lacrimal syringing and a fluorescein dye test demonstrated an obstruction at the level of the nasolacrimal duct (NLD). Owing to the patient's history of dacryocystitis, endoscopic dacryocystorhinostomy was organised. When in theatre however, nasendoscopy identified a polypoid mass at the lateral aspect of the inferior turbinate, obstructing the right NLD opening. Histopathology confirmed an oncocytoma. There was no local destruction or distant metastases. The mass was resected, a Monoka stent inserted and symptomatic relief achieved. In this case, the cause of epiphora was initially missed because no direct nasal examination was performed. It is vital that patients with unilateral epiphora undergo an endoscopic nasal examination before arranging treatment. This could prevent delayed diagnoses, ensure prompt and appropriate management, and reduce morbidity and mortality. PMID- 29523611 TI - Multifactorial non-cirrhotic hyperammonaemic encephalopathy. AB - A 51-year-old female presented with acute confusion associated with a non specific headache and lethargy. The patient's history included bipolar disorder on valproate and recent travel to northern Vietnam. The patient was subsequently found to have hyperammonaemia as well as a urinary tract infection and bacteraemia with Klebsiellapneumoniae The patient was presumed to have a multifactorial non-cirrhotic hyperammonaemic encephalopathy due to a combination of a urinary tract infection and bacteraemia with K. pneumoniae, a urease producing bacteria, and also valproate use, a medication known to interfere with ammonia elimination. The patient's treatment included supportive care, ceasing valproate, empiric then rationalised antibiotics, N-acetylcysteine and L carnitine. We present a case of non-cirrhotic hyperammonaemic encephalopathy and explain why it is multifactorial in origin. PMID- 29523612 TI - Primary malignant melanoma of the ascending colon. AB - Malignant gastrointestinal melanoma is usually a metastatic lesion. We report the case of a 67-year-old female patient who presented with intermittent abdominal pain, fever, rigor and diarrhoea. CT scan of the abdomen revealed a large mass at the right iliac fossa with features concerning for intra-abdominal abscess. Exploratory laparotomy confirmed the preoperative diagnosis of abscess, and a right hemicolectomy was performed. Histopathological examination of the surgical specimen was indicative of malignant melanoma, and immunohistochemical examination showed positivity to S100 protein, Melan-A, HMB-45 and vimentin. A series of postoperative clinical, laboratory and imaging examinations revealed no suspicious lesions in the skin, eye, leptomeninges or other sites. Therefore, the diagnosis of primary colonic melanoma was confirmed. Only 36 additional cases of primary colonic melanoma have been reported to date. These rare neoplasms are challenging to diagnose and usually require a multidisciplinary treatment approach, including surgery, chemotherapy and possibly immunotherapy or radiotherapy. PMID- 29523613 TI - Flupirtine drug-induced liver injury in a patient developing acute liver failure. AB - A patient is admitted with complaints of recent onset nausea, discomfort, jaundice and blood tests that reveal severe hepatitis. At the time, she had been taking medication with Hypericum perforatum (St John's wort) for 6 months, and 6 weeks before this event, she took flupirtine maleate. A few days after being admitted, she developed encephalopathy progressing to acute liver failure (ALF) requiring unsuccessful liver transplantation. The patient was ultimately diagnosed with drug-induced liver injury (DILI). In this context, while H. perforatum could interfere with other medication or trigger DILI itself, flupirtine appears to have triggered the DILI, given its liver toxicity capacity. DILI is one of the major ALF causes and can jeopardise patient's life. Accordingly, all efforts to reduce medication potentially hazardous to the liver are recommended. PMID- 29523614 TI - Selective internal radiation therapy (SIRT) with yttrium-90 microspheres for unresectable intrahepatic cholangiocarcinoma. AB - Unresectableintrahepaticcholangiocarcinoma has a very poor prognosis despite various treatment options. The case presented describes the diagnostic challenges of a young pregnant woman with unresectable cholangiocarcinoma. The current treatment options for cholangiocarcinoma have limited evidence and high recurrence rate. Given the young age of this patient, selective internal radiotherapy was trialled with traditional chemotherapy with a clinically significant result. This case highlights the delays when diagnosing cholangiocarcinoma in younger patients and the possibility of selective internal radiation therapy in combination with chemotherapy as a potential first-line treatment for a complete response in unresectable disease. PMID- 29523615 TI - Treatment of relapsed multiple myeloma complicated by cardiac extramedullary plasmacytoma with D-PACE chemotherapy. AB - Cardiac extramedullary plasmacytomas (EMPs) are rare and may be a seen as a complication of multiple myeloma (MM) or in isolation. Here, we describe a case of cardiac EMP that presented clinically as a congestive heart failure exacerbation in a patient with relapsed and refractory IgG lambda MM. We highlight radiographic imaging in conjunction with laboratory biomarkers at presentation and in response to D-PACE (dexamethasone, cisplatin (Platinol), doxorubicin (Adriamycin), cyclophosphamide and etoposide) systemic chemotherapy. PMID- 29523616 TI - Mesenteric vasculitis and ischaemia: every second counts. PMID- 29523617 TI - Syphilitic gastritis: a rare presentation of secondary syphilis. PMID- 29523618 TI - Spontaneous suprachoroidal haemorrhage with exudative retinal detachment in pregnancy-induced hypertension. PMID- 29523619 TI - Multiple cutaneous metastases as the first sign of metastatic carcinoma of unknown primary. PMID- 29523620 TI - Images in ophthalmia nodosa: an unusual presentation of red eye. PMID- 29523621 TI - A rare cause of periorbital swelling. PMID- 29523622 TI - Retinopathy and bone marrow failure revealing Coats plus syndrome. PMID- 29523623 TI - Coordinated Ramping of Dorsal Striatal Pathways preceding Food Approach and Consumption. AB - The striatum controls food-related actions and consumption and is linked to feeding disorders, including obesity and anorexia nervosa. Two populations of neurons project from the striatum: direct pathway medium spiny neurons and indirect pathway medium spiny neurons. The selective contribution of direct pathway medium spiny neurons and indirect pathway medium spiny neurons to food related actions and consumption remains unknown. Here, we used in vivo electrophysiology and fiber photometry in mice (of both sexes) to record both spiking activity and pathway-specific calcium activity of dorsal striatal neurons during approach to and consumption of food pellets. While electrophysiology revealed complex task-related dynamics across neurons, population calcium was enhanced during approach and inhibited during consumption in both pathways. We also observed ramping changes in activity that preceded both pellet-directed actions and spontaneous movements. These signals were heterogeneous in the spiking units, with neurons exhibiting either increasing or decreasing ramps. In contrast, the population calcium signals were homogeneous, with both pathways having increasing ramps of activity for several seconds before actions were initiated. An analysis comparing population firing rates to population calcium signals also revealed stronger ramping dynamics in the calcium signals than in the spiking data. In a second experiment, we trained the mice to perform an action sequence to evaluate when the ramping signals terminated. We found that the ramping signals terminated at the beginning of the action sequence, suggesting they may reflect upcoming actions and not preconsumption activity. Plasticity of such mechanisms may underlie disorders that alter action selection, such as drug addiction or obesity.SIGNIFICANCE STATEMENT Alterations in striatal function have been linked to pathological consumption in disorders, such as obesity and drug addiction. We recorded spiking and population calcium activity from the dorsal striatum during ad libitum feeding and an operant task that resulted in mice obtaining food pellets. Dorsal striatal neurons exhibited long ramps in activity that preceded actions by several seconds, and may reflect upcoming actions. Understanding how the striatum controls the preparation and generation of actions may lead to improved therapies for disorders, such as drug addiction or obesity. PMID- 29523624 TI - U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. AB - On July 17, 2017, the FDA approved neratinib (NERLYNX; Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. The primary endpoint was invasive disease-free survival (iDFS), defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified HR of 0.66 [95% confidence interval (CI), 0.49-0.90, P = 0.008]. The estimated iDFS rate at 2 years was 94.2% (95% CI, 92.6%-95.4%) in patients treated with neratinib versus 91.9% (95% CI, 90.2%-93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE), with a 40% incidence of grade 3 or 4 diarrhea, and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Clin Cancer Res; 24(15); 3486-91. (c)2018 AACRSee related commentary by Unni et al., p. 3483. PMID- 29523625 TI - Goldilocks Dosing of TKIs: A Dose that Is Just Right Leads to Optimal Outcomes. AB - Higher concentrations of TKIs, such as pazopanib, are associated with improved outcomes in advanced RCC. A phase III trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome. Clin Cancer Res; 24(13); 2979-80. (c)2018 AACRSee related article by Sternberg et al., p. 3005. PMID- 29523626 TI - Small-Animal 18F-FDG PET for Research on Octopus vulgaris: Applications and Future Directions in Invertebrate Neuroscience and Tissue Regeneration. AB - This study aimed to develop a method of administering 18F-FDG to the common octopus in order to perform a PET biodistribution assay characterizing glucose metabolism in organs and regenerating tissues. Methods: Seven animals (two of which had a regenerating arm) were anesthetized with 3.7% MgCl2 in artificial seawater and then injected with 18-30 MBq of isosmotic 18F-FDG through either the left branchial heart or the anterior vena cava. After an uptake time of about 50 min, the animals were sacrificed and placed on the bed of a small-animal PET scanner, and 10-min static acquisitions were obtained at 3-4 bed positions to visualize the entire body. To confirm image interpretation, internal organs of interest were collected and counted with a gamma-counter. Results: Administration through the anterior vena cava resulted in a good full-body distribution of 18F FDG as seen on the PET images. Uptake was high in the mantle mass and relatively lower in the arms. In particular, the brain, optic lobes, and arms were clearly identified and were measured for their uptake (SUVmax: 6.57 +/- 1.86, 7.59 +/- 1.66, and 1.12 +/- 0.06, respectively). Interestingly, 18F-FDG uptake was up to 3 fold higher in the highly proliferating areas of regenerating arms. Conclusion: This study represents a stepping-stone to the use of noninvasive functional techniques for addressing questions about invertebrate neuroscience and regenerative medicine. PMID- 29523627 TI - Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Site in Human Brain. AB - The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacologic evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/alpha2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure V T (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. V T estimates were high in the striatum (105 +/- 21 mL?cm 3), medium in the cingulate cortex (62 +/- 10 mL?cm-3), and low in the cerebellum (41 +/- 7 mL?cm-3). Test-retest reliability was reasonable. The uptake was dose dependently reduced throughout the brain by pretreatment with idazoxan, with an average block across all regions of about 60% (V T, ~30 mL?cm-3) at the highest dose (80 mg). The median effective dose for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion: 11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability. PMID- 29523628 TI - A Noninvasive Method for Quantifying Cerebral Blood Flow by Hybrid PET/MRI. AB - Although PET with 15O-water is the gold standard for imaging cerebral blood flow (CBF), quantification requires measuring the arterial input function (AIF), which is an invasive and noisy procedure. To circumvent this problem, we propose a noninvasive PET/MRI approach that eliminates the need to measure AIF by using global CBF determined by phase-contrast (PC) MRI as a reference region. This approach not only is noninvasive but also involves no additional imaging time, because PC MRI and 15O-water PET are acquired simultaneously. The purpose of this study was to test the accuracy of this hybrid method in an animal model in which AIF was measured directly and CBF was varied by changing the arterial CO2 tension. Methods: PET and MRI data were simultaneously acquired in juvenile pigs at hypocapnia (n = 5), normocapnia (n = 5), and hypercapnia (n = 4). CBF was measured by the MRI reference method and by PET alone using an MRI-compatible blood sampling system to measure AIF. Results: Global CBF estimates from PC MRI and 15O-water PET agreed well, with a correlation coefficient of 0.9 and a slope of 0.88. Strong positive correlations (R2 > 0.96) were also found between regional CBF generated by the PET-only and the MRI-reference methods. Conclusion: These findings demonstrate the accuracy of this hybrid PET/MRI approach, which might prove useful in patients for whom obtaining accurate CBF measurements is challenging. PMID- 29523629 TI - 90Y-DOTATOC Dosimetry-Based Personalized Peptide Receptor Radionuclide Therapy. AB - Pretherapy PET with 86Y-DOTATOC is considered the ideal dosimetry protocol for 90Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90Y-DOTATOC using 90Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m2; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90Y-DOTATOC PET/CT at 5 h after therapy and 90Y DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90Y-DOTATOC is feasible using 90Y DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles. PMID- 29523631 TI - Update on 18F-Fluciclovine PET for Prostate Cancer Imaging. AB - PET is a functional imaging method that can exploit various aspects of tumor biology to enable greater detection of prostate cancer than can be provided by morphologic imaging alone. Anti-1-amino-3-18F-flurocyclobutane-1-carboxylic acid (18F-fluciclovine) is a nonnaturally occurring amino acid PET radiotracer that was recently approved by the U.S. Food and Drug Administration for detection of suspected recurrent prostate cancer. The tumor-imaging features of this radiotracer mirror the upregulation of transmembrane amino acid transport that occurs in prostate cancer because of increased amino acid metabolism for energy and protein synthesis. This continuing medical education article provides an overview on 18F-fluciclovine PET diagnostic capabilities for primary and metastatic disease, including reviews of published comparisons to conventional imaging and other molecular imaging agents. Additionally, the imaging procedure and image interpretation are detailed, including physiologic and pathologic uptake patterns and pitfalls. PMID- 29523630 TI - Clinical Impact of Respiratory Motion Correction in Simultaneous PET/MR, Using a Joint PET/MR Predictive Motion Model. AB - In PET imaging, patient motion due to respiration can lead to artifacts and blurring, in addition to quantification errors. The integration of PET imaging with MRI in PET/MRI scanners provides spatially aligned complementary clinical information and allows the use of high-contrast, high-spatial-resolution MR images to monitor and correct motion-corrupted PET data. On a patient cohort, we tested the ability of our joint PET/MRI-based predictive motion model to correct respiratory motion in PET and show it can improve lesion detectability and quantitation and reduce image artifacts. Methods: Using multiple tracers and multiple organ locations, we applied our motion correction method to 42 clinical PET/MRI patient datasets containing 162 PET-avid lesions. Quantitative changes were calculated using SUV changes in avid lesions. Lesion detectability changes were explored with a study in which 2 radiologists identified lesions in uncorrected and motion-corrected images and provided confidence scores. Results: Mean increases of 12.4% for SUVpeak and 17.6% for SUVmax after motion correction were found. In the detectability study, confidence scores for detecting avid lesions increased, with a rise in mean score from 2.67 to 3.01 (of 4) after motion correction and a rise in detection rate from 74% to 84%. Of 162 confirmed lesions, 49 showed an increase in all 3 metrics-SUVpeak, SUVmax, and combined reader confidence score-whereas only 2 lesions showed a decrease. We also present clinical case studies demonstrating the effect that respiratory motion correction of PET data can have on patient management, with increased numbers of detected lesions, improved lesion sharpness and localization, and reduced attenuation based artifacts. Conclusion: We demonstrated significant improvements in quantification and detection of PET-avid lesions, with specific case study examples showing where motion correction has the potential to affect diagnosis or patient care. PMID- 29523633 TI - MANAGEMENT OF ENDOCRINE DISEASE: Management of Cushing's syndrome during pregnancy: solved and unsolved questions. AB - With fewer than 200 reported cases, Cushing's syndrome (CS) in pregnancy remains a diagnostic and therapeutic challenge. In normal pregnancies, misleading signs may be observed such as striae or hypokalemia, while plasma cortisol and urinary free cortisol may rise up to 2- to 3-fold. While the dexamethasone suppression test is difficult to use, reference values for salivary cortisol appear valid. Apart from gestational hypertension, differential diagnosis includes pheochromocytoma and primary aldosteronism. The predominant cause is adrenal adenoma (sometimes without decreased ACTH), rather than Cushing's disease. There are considerable imaging pitfalls in Cushing's disease. Aberrant receptors may, in rare cases, lead to increased cortisol production during pregnancy in response to HCG, LHRH, glucagon, vasopressin or after a meal. Adrenocortical carcinoma (ACC) is rare and has poor prognosis. Active CS during pregnancy is associated with a high rate of maternal complications: hypertension or preeclampsia, diabetes, fractures; more rarely, cardiac failure, psychiatric disorders, infection and maternal death. Increased fetal morbidity includes prematurity, intrauterine growth retardation and less prevalently stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism. Therapy is also challenging. Milder cases can be managed conservatively by controlling comorbidities. Pituitary or adrenal surgery should ideally be performed during the second trimester and patients should then be treated for adrenal insufficiency. Experience with anticortisolic drugs is limited. Metyrapone was found to allow control of hypercortisolism, with a risk of worsening hypertension. Cabergoline may be an alternative option. The use of other drugs is not advised because of potential teratogenicity and/or lack of information. Non-hormonal (mechanical) contraception is recommended until sustained biological remission is obtained. PMID- 29523634 TI - Longitudinally evaluated the relationship between body fat percentage and the risk for type 2 diabetes mellitus: Korean Genome and Epidemiology Study (KoGES). AB - BACKGROUND: Body fat plays the significant role in maintaining glucose homeostasis. However, it is not fully identified how body fat percentage (BF%) has an impact on the development of type 2 diabetes mellitus (T2DM). Thus, this study was to evaluate the incidental risk for T2DM according to BF% level. METHODS: In a community-based Korean cohort, 5972 Korean adults were divided into quintile groups by BF% and followed up for 10 years to monitor the development of T2DM. Cox proportional hazard model was used to evaluate the hazard ratios (HRs) for T2DM according to BF% quintile. Additionally, subgroup analysis was conducted by low and high level of BF% (cut-off: 25 in men and 35 in women) and body mass index (BMI). RESULTS: In adjusted model, compared to the BF% quintile 1 group, the risk for T2DM significantly increased over BF% of 22.8% in men and 32.9% in women (>=quintile 4). The level of BF% related to the increased risk for T2DM was lower in non-obese men (22.8%) than obese men (28.4%). In subgroup analysis, men with low BMI (<25) and high BF% (>=25) had the highest risk for T2DM than other subgroups (HRs: 1.83 (1.33-2.52)). However, this association did not show the statistical significance in women (HRs: 1.63 (0.98-2.72)). CONCLUSION: The incidental risk for T2DM significantly increased over the specific level of BF%, which was lower in non-obese population than obese population. Gender difference was suggested in the incidental relationship between BF% and T2DM. PMID- 29523632 TI - Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis. AB - Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 ug/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population. PMID- 29523635 TI - Germline Variants in the POT1-Gene in High-Risk Melanoma Patients in Austria. AB - Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n = 163) or with a positive family history (n = 133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used.In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counseling. PMID- 29523637 TI - Robust PhiC31-Mediated Genome Engineering in Drosophila melanogaster Using Minimal attP/attB Phage Sites. AB - Effective genome engineering should lead to a desired locus change with minimal adverse impact to the genome itself. However, flanking loci with site-directed recombinase recognition sites, such as those of the phage PhiC31 integrase, allows for creation of platforms for cassette exchange and manipulation of genomic regions in an iterative manner, once specific loci have been targeted. Here we show that a genomic locus engineered with inverted minimal phage PhiC31 attP/attB sites can undergo efficient recombinase-mediated cassette exchange (RMCE) in the fruit fly Drosophila melanogaster. PMID- 29523636 TI - Repeat-Specific Functions for the C-Terminal Domain of RNA Polymerase II in Budding Yeast. AB - The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeast Saccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD. PMID- 29523638 TI - Complement C3 and Risk of Diabetic Microvascular Disease: A Cohort Study of 95202 Individuals from the General Population. AB - BACKGROUND: Whether the complement system is involved in the development of diabetic microvascular disease is unknown. We tested the hypothesis that high concentrations of complement C3 are associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. METHODS: We studied 95202 individuals from the general population with baseline measurements of complement C3, genotyped for rs1065489, rs429608, and rs448260 determining concentrations of complement C3, and enrolled in the Copenhagen General Population Study from 2003 through 2013, following them until April 10, 2013. Rs1065489, rs429608, and rs448260 were identified with genome wide association scans in 3752 individuals from the Copenhagen City Heart Study. RESULTS: The cumulative incidence was increased from the lowest tertile to the highest tertile of complement C3 for diabetic retinopathy (log-rank trend, P = 1 * 10-20), nephropathy (P = 7 * 10-15), and neuropathy (P = 5 * 10-10). Multifactorially adjusted hazard ratios for a 1 SD higher concentration of complement C3 were 1.87 (95% CI, 1.61-2.18) for diabetic retinopathy, 1.90 (1.62 2.23) for diabetic nephropathy, and 1.56 (1.29-1.89) for diabetic neuropathy. The multifactorially adjusted hazard ratio for individuals with the highest vs lowest tertile of complement C3 was 3.29 (1.78-6.07) for retinopathy, 2.71 (1.42-5.16) for nephropathy, and 2.40 (1.26-4.54) for neuropathy. CONCLUSIONS: High baseline concentrations of complement C3 were associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. These epidemiological findings were substantiated by a Mendelian randomization approach, potentially indicating causality. PMID- 29523639 TI - Neurogranin as Cerebrospinal Fluid Biomarker for Alzheimer Disease: An Assay Comparison Study. AB - BACKGROUND: Neurogranin in cerebrospinal fluid (CSF) correlates with cognitive decline and is a potential novel biomarker for Alzheimer disease (AD) dementia. We investigated the analytical and diagnostic performance of 3 commonly used neurogranin assays in the same cohort of patients to improve the interpretability of CSF neurogranin test results. METHODS: The neurogranin Erenna(r) assay from Washington University, St. Louis, MO (WashU); ELISA from ADx Neurosciences; and ELISA from Gothenburg University, Molndal, Sweden (UGot), were compared using silver staining and Western blot after gel electrophoresis. Clinical performance of the 3 assays was compared in samples from individuals diagnosed with subjective cognitive decline (n = 22), and in patients with AD (n = 22), frontotemporal dementia (n = 22), dementia with Lewy bodies (n = 22), or vascular dementia (n = 20), adjusted for sex and age. RESULTS: The assays detected different epitopes of neurogranin: the WashU assay detected the N-terminal part of neurogranin (S10-D23) and a C-terminal part (G49-G60), the ADx assay detected C-terminal neurogranin truncated at P75, and the UGot assay detected the C terminal neurogranin with intact ending (D78). Spearman rho was 0.95 between ADx and WashU, 0.87 between UGot and WashU, and 0.81 between UGot and ADx. ANCOVA (analysis of covariance) showed group differences for ranked neurogranin concentrations in each assay (all P < 0.05), with specific increases in AD. CONCLUSIONS: Although the 3 assays target different epitopes on neurogranin and have different calibrators, the high correlations and the similar group differences suggest that the different forms of neurogranin in CSF carry similar diagnostic information, at least in the context of neurodegenerative diseases. PMID- 29523640 TI - Prospective associations between white matter hyperintensities and lower extremity function. AB - OBJECTIVE: To evaluate the relationship of white matter hyperintensities (WMH) with decline in lower extremity function (LEF) over approximately 3 years in dementia-free older adults with memory complaints. METHODS: We obtained brain MRI data from 458 community-dwelling adults, aged 70 years or over, at baseline, and from 358 adults over an average follow-up of 963 days. We evaluated LEF using the Short Physical Performance Battery (SPPB). We related baseline WMH volumes and progression to SPPB scores over time, using mixed-effect linear regressions. For the secondary analyses, we categorized baseline WMH volume into quartiles, and dichotomized the WMH progression to compare fast and slow progression. RESULTS: Baseline WMH volume (beta = -0.017, 95% confidence interval [CI] -0.025 to 0.009), as well as WMH progression (beta = -0.002, 95% CI -0.003 to -0.001), significantly associated with a decline in SPPB performance in adjusted analyses. Compared with the lowest quartile of baseline WMH volume, the highest quartile associated with a decline in SPPB performance (beta = -0.301, 95% CI -0.558 to 0.044). Fast progression also associated with a decline in SPPB performance. We found clinically meaningful differences in the SPPB, with higher scores in participants with slow progression of WMH, at both 24 and 36 months. CONCLUSIONS: Baseline level and WMH progression associated with longitudinal decline in SPPB performance among older adults. We detected clinically meaningful differences in SPPB performance on comparing fast with slow progression of WMH, suggesting that speed of WMH progression is an important determinant of LEF during aging. PMID- 29523641 TI - CPAP as treatment of sleep apnea after stroke: A meta-analysis of randomized trials. AB - OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the effectiveness of continuous positive airway pressure (CPAP) in stroke patients with sleep disordered breathing (SDB). METHODS: In a systematic literature search of electronic databases (MEDLINE, Embase, and the Cochrane Library) from 1980 to November 2016, we identified RCTs that assessed CPAP compared to standard care or sham CPAP in adult patients with stroke or TIA with SDB. Mean CPAP use, odds ratios (ORs), and standardized mean differences (SMDs) were calculated. The prespecified outcomes were adherence to CPAP, neurologic improvement, adverse events, new vascular events, and death. RESULTS: Ten RCTs (564 participants) with CPAP as intervention were included. Two studies compared CPAP with sham CPAP; 8 compared CPAP with usual care. Mean CPAP use across the trials was 4.53 hours per night (95% confidence interval [CI] 3.97 5.08). The OR of dropping out with CPAP was 1.83 (95% CI 1.05-3.21, p = 0.033). The combined analysis of the neurofunctional scales (NIH Stroke Scale and Canadian Neurological Scale) showed an overall neurofunctional improvement with CPAP (SMD 0.5406, 95% CI 0.0263-1.0548) but with a considerable heterogeneity (I2 = 78.9%, p = 0.0394) across the studies. Long-term survival was improved with CPAP in 1 trial. CONCLUSION: CPAP use after stroke is acceptable once the treatment is tolerated. The data indicate that CPAP might be beneficial for neurologic recovery, which justifies larger RCTs. PMID- 29523642 TI - Psychiatric comorbidity is associated with disability progression in multiple sclerosis. AB - OBJECTIVE: Emerging evidence suggests that comorbidity may influence disability outcomes in multiple sclerosis (MS); we investigated the association between psychiatric comorbidity and MS disability progression in a large multiclinic population. METHODS: This retrospective cohort study accessed prospectively collected information from linked clinical and population-based health administrative databases in the Canadian provinces of British Columbia and Nova Scotia. Persons with MS who had depression, anxiety, or bipolar disorder were identified using validated algorithms using physician and hospital visits. Multivariable linear regression models fitted using an identity link with generalized estimating equations were used to determine the association between psychiatric comorbidity and disability using all available Expanded Disability Status Scale (EDSS) scores. RESULTS: A total of 2,312 incident cases of adult onset MS were followed for a mean of 10.5 years, during which time 35.8% met criteria for a mood or anxiety disorder. The presence of a mood or anxiety disorder was associated with a higher EDSS score (beta coefficient = 0.28, p = 0.0002, adjusted for disease duration and course, age, sex, socioeconomic status, physical comorbidity count, and disease-modifying therapy exposure). Findings were statistically significant among women (beta coefficient = 0.31, p = 0.0004), but not men (beta coefficient 0.22, p = 0.17). CONCLUSION: Presence of psychiatric comorbidities, which were common in our incident MS cohort, increased the severity of subsequent neurologic disability. Optimizing management of psychiatric comorbidities should be explored as a means of potentially mitigating disability progression in MS. PMID- 29523644 TI - Age-accelerated cognitive decline in asymptomatic adults with CSF beta-amyloid. AB - OBJECTIVE: Compare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of beta-amyloid (Abeta) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile. METHODS: Three hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations. Cutoffs for Abeta42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5 years), and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group * age at each visit on cognitive and hippocampal volume outcomes. RESULTS: Two hundred fifteen participants (69%) were biomarker negative (preclinical AD stage 0), 46 (15%) were Abeta+ only (preclinical AD stage 1), 25 (8%) were Abeta+ and tau+ (preclinical AD stage 2), and 28 (9%) were tau+ only. Both stage 1 and stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and nonlinear decline on list-learning and set-shifting measures compared to stage 0. The tau+ only group did not significantly differ from stage 0 in rates of cognitive decline. CONCLUSION: In an asymptomatic at-risk cohort, elevated CSF Abeta (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures. PMID- 29523645 TI - Implementing Keytruda/Pembrolizumab Testing in Clinical Practice. PMID- 29523643 TI - Cognitive impairment and intracranial atherosclerotic stenosis in general population. AB - OBJECTIVE: To investigate the association between asymptomatic intracranial atherosclerosis and cognitive impairment in the Atherosclerosis Risk in Communities (ARIC) cohort. METHODS: ARIC participants underwent high-resolution 3T magnetic resonance angiography and a neuropsychology battery and neurologic examination adjudicated by an expert panel to detect mild cognitive impairment (MCI) and dementia. We adjusted for demographic and vascular risk factors in weighted logistic regression analysis, accounting for stratified sampling design and attrition, to determine the association of intracranial atherosclerotic stenosis (ICAS) with cognitive impairment. RESULTS: In 1,701 participants (mean age 76 +/- 5.3, 41% men, 71% whites, 29% blacks) with adequate imaging quality and no history of stroke, MCI was identified in 578 (34%) and dementia in 79 (4.6%). In white participants, after adjustment for demographic and vascular risk factors, ICAS >=50% (vs no ICAS) was strongly associated with dementia (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.7-10.0) and with any cognitive impairment (OR 1.7, 95% CI 1.1-2.8). In contrast, no association was found between ICAS >=50% and MCI or dementia in blacks, although the sample size was limited and estimates were imprecise. CONCLUSION: Our results suggest that asymptomatic ICAS is independently associated with cognitive impairment and dementia in whites. PMID- 29523646 TI - Phase II Study of Preoperative Treatment with External Radiotherapy Plus Panitumumab in Low-Risk, Locally Advanced Rectal Cancer (RaP Study/STAR-03). AB - BACKGROUND: Treatment with fluoropyrimidines and concomitant long-course external radiotherapy (RTE) is the standard of care in locally advanced rectal cancer (LARC) preoperative chemoradiation. A randomized phase II study (RaP/STAR-03) was conducted that aimed to evaluate the activity and safety of the monoclonal antibody anti-epidermal growth factor receptor panitumumab as a single agent in combination with radiotherapy in low-risk LARC preoperative treatment. MATERIALS AND METHODS: Patients had adenocarcinoma of the mid-low rectum, cT3N- or cT2 T3N+, KRAS wild-type status, and negative circumferential radial margin. Panitumumab was administered concomitant to RTE. Rectal surgery was performed 6-8 weeks after the end of preoperative treatment. The adjuvant chemotherapy regimen was FOLFOX. The primary endpoint was the pathologic complete response (pCR) rate. The sample size was calculated using Simon's two-stage design. A pCR of 16% was considered to qualify the experimental treatment for further testing. RESULTS: Ninety-eight patients were enrolled in 13 Italian centers from October 2012 to October 2015. Three panitumumab infusions were administered in 92 (93.4%) patients. The RTE compliance was median dose 50.4 Gy; >=28 fractions in 82 (83.7%) patients. Surgical treatment was performed in 92 (93.9%) patients, and no severe intraoperative complications were observed. A pCR was observed in 10 (10.9%) patients (95% confidence interval, 4.72%-17.07%). Pathological downstaging occurred in 45 (45.9%) patients. Grade 3 toxicities were observed in 22 (22.3%) patients, and the common adverse events were skin rash in 16 (16.3%) patients. No grade 4 toxicities were reported. CONCLUSION: The pCR rate (our primary endpoint), at only 10.9%, did not reach the specified level considered suitable for further testing. However, the analysis showed a good toxicity profile and compliance to concomitant administration of panitumumab and RTE in preoperative treatment of LARC. The pCR evaluation in all wild-type RAS is ongoing. IMPLICATIONS FOR PRACTICE: The aim of the RaP/STAR-03 study was to evaluate the activity and safety of monoclonal antibody anti-epidermal growth factor receptor (EGFR) panitumumab as a single agent without chemotherapy in low risk, locally advanced rectal cancer (LARC) preoperative treatment. Nevertheless, the use of panitumumab in combination with radiotherapy in preoperative treatment in patients with KRAS wild type and low-risk LARC did not reach the pathologic complete response primary endpoint. This study showed a good toxicity profile and compliance to combination treatment. Further analysis of NRAS and BRAF on tissue and circulating levels of the EGFR ligands and vascular factors (soluble vascular endothelial growth factor, E-selectin) may provide insight on the potential molecular pathways involved in the anti-EGFR response. PMID- 29523647 TI - Looking Back, Looking Forward: The Ethical Framing of Complementary and Alternative Medicine in Oncology Over the Last 20 Years. PMID- 29523649 TI - Projected Temperature-Related Years of Life Lost From Stroke Due To Global Warming in a Temperate Climate City, Asia: Disease Burden Caused by Future Climate Change. AB - BACKGROUND AND PURPOSE: Global warming has attracted worldwide attention. Numerous studies have indicated that stroke is associated with temperature; however, few studies are available on the projections of the burden of stroke attributable to future climate change. We aimed to investigate the future trends of stroke years of life lost (YLL) associated with global warming. METHODS: We collected death records to examine YLL in Tianjin, China, from 2006 to 2011. We fitted a standard time-series Poisson regression model after controlling for trends, day of the week, relative humidity, and air pollution. We estimated temperature-YLL associations with a distributed lag nonlinear model. These models were then applied to the local climate projections to estimate temperature related YLL in the 2050s and 2070s. We projected temperature-related YLL from stroke in Tianjin under 19 global-scale climate models and 3 different greenhouse gas emission scenarios. RESULTS: The results showed a slight decrease in YLL with percent decreases of 0.85%, 0.97%, and 1.02% in the 2050s and 0.94%, 1.02%, and 0.91% in the 2070s for the 3 scenarios, respectively. The increases in heat related annual YLL and the decreases in cold-related YLL under the high emission scenario were the strongest. The monthly analysis showed that the most significant increase occurred in the summer months, particularly in August, with percent changes >150% in the 2050s and up to 300% in the 2070s. CONCLUSIONS: Future changes in climate are likely to lead to an increase in heat-related YLL, and this increase will not be offset by adaptation under both medium emission and high emission scenarios. Health protections from hot weather will become increasingly necessary, and measures to reduce cold effects will also remain important. PMID- 29523648 TI - Quorum-sensing regulator RhlR but not its autoinducer RhlI enables Pseudomonas to evade opsonization. AB - When Drosophila melanogaster feeds on Pseudomonas aeruginosa, some bacteria cross the intestinal barrier and eventually proliferate in the hemocoel. This process is limited by hemocytes through phagocytosis. P. aeruginosa requires the quorum sensing regulator RhlR to elude the cellular immune response of the fly. RhlI synthesizes the autoinducer signal that activates RhlR. Here, we show that rhlI mutants are unexpectedly more virulent than rhlR mutants, both in fly and in nematode intestinal infection models, suggesting that RhlR has RhlI-independent functions. We also report that RhlR protects P. aeruginosa from opsonization mediated by the Drosophila thioester-containing protein 4 (Tep4). RhlR mutant bacteria show higher levels of Tep4-mediated opsonization, as compared to rhlI mutants, which prevents lethal bacteremia in the Drosophila hemocoel. In contrast, in a septic model of infection, in which bacteria are introduced directly into the hemocoel, Tep4 mutant flies are more resistant to wild-type P. aeruginosa, but not to the rhlR mutant. Thus, depending on the infection route, the Tep4 opsonin can either be protective or detrimental to host defense. PMID- 29523650 TI - Thalamic Diaschisis in Acute Ischemic Stroke: Occurrence, Perfusion Characteristics, and Impact on Outcome. AB - BACKGROUND AND PURPOSE: Ipsilateral thalamic diaschisis (ITD) describes the reduction of thalamic function, metabolism, and perfusion resulting from a distant lesion of the ipsilateral hemisphere. Our aim was to evaluate the perfusion characteristics and clinical impact of ITD in acute middle cerebral artery stroke, which does not directly affect the thalamus. METHODS: One hundred twenty-four patients with middle cerebral artery infarction were selected from a prospectively acquired cohort of 1644 patients who underwent multiparametric computed tomography (CT), including CT perfusion for suspected stroke. Two blinded readers evaluated the occurrence of ITD, defined as ipsilateral thalamic hypoperfusion present on >=2 CT perfusion maps. Perfusion alterations were defined according to the Alberta Stroke Program Early CT Score regions. Final infarction volume and subacute complications were assessed on follow-up imaging. Clinical outcome was quantified using the modified Rankin Scale. Multivariable linear and ordinal logistic regression analysis were applied to identify independent associations. RESULTS: ITD was present in 25/124 subjects (20.2%, ITD+). In ITD+ subjects, perfusion of the caudate nucleus, internal capsule, and lentiform nucleus was more frequently affected than in ITD- patients (each with P<0.001). In the ITD+ group, larger cerebral blood flow (P=0.002) and cerebral blood volume (P<0.001) deficit volumes, as well as smaller cerebral blood flow cerebral blood volume mismatch (P=0.021) were observed. There was no independent association of ITD with final infarction volume or clinical outcome at discharge in treatment subgroups (each with P>0.05). ITD had no influence on the development of subacute stroke complications. CONCLUSIONS: ITD in the form of thalamic hypoperfusion is a frequent CT perfusion finding in the acute phase in middle cerebral artery stroke patients with marked involvement of subcortical areas. ITD does not result in thalamic infarction and had no independent impact on patient outcome. Notably, ITD was misclassified as part of the ischemic core by automated software, which might affect patient selection in CT perfusion-based trials. PMID- 29523651 TI - Transcranial Direct Current Stimulation Does Not Improve Language Outcome in Subacute Poststroke Aphasia. AB - BACKGROUND AND PURPOSE: The aim of the present study is to investigate the effect of transcranial direct current stimulation on word-finding treatment outcome in subacute poststroke aphasia. METHODS: In this multi-center, double-blind, randomized controlled trial with 6-month follow-up, we included 58 patients with subacute aphasia (<3 months poststroke), who were enrolled in a stroke rehabilitation program. Patients participated in 2 separate intervention weeks. Each intervention week included 5 daily sessions of 45-minute word-finding therapy combined with either anodal transcranial direct current stimulation (1 mA, 20 minutes; experimental group) or sham transcranial direct current stimulation (control group) over the left inferior frontal gyrus. The primary outcome measure was the Boston Naming Test. Secondary outcome measures included naming performance for trained/untrained picture items and verbal communication. RESULTS: Both the experimental (n=26) and the control group (n=32) improved on the Boston Naming Test over the intervention period and 6-month follow-up; however, there were no significant differences between groups. Also for the secondary outcome measures, no significant differences were found. CONCLUSIONS: The results of the present study do not support an effect of transcranial direct current stimulation as an adjuvant treatment in subacute poststroke aphasia. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl/trialreg/admin/rctview.asp. Unique identifier: NTR4364. PMID- 29523652 TI - Age-Specific Associations of Renal Impairment With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Transient Ischemic Attack and Stroke. AB - BACKGROUND AND PURPOSE: It has been hypothesized that cerebral small vessel disease (SVD) and chronic renal impairment may be part of a multisystem small vessel disorder, but their association may simply be as a result of shared risk factors (eg, hypertension) rather than to a systemic susceptibility to premature SVD. However, most previous studies were hospital based, most had inadequate adjustment for hypertension, many were confined to patients with lacunar stroke, and none stratified by age. METHODS: In a population-based study of transient ischemic attack and ischemic stroke (OXVASC [Oxford Vascular Study]), we evaluated the magnetic resonance imaging markers of cerebral SVD, including lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular space. We studied the age-specific associations of renal impairment (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and total SVD burden (total SVD score) adjusting for age, sex, vascular risk factors, and premorbid blood pressure (mean blood pressure during 15 years preevent). RESULTS: Of 1080 consecutive patients, 1028 (95.2%) had complete magnetic resonance imaging protocol and creatinine measured at baseline. Renal impairment was associated with total SVD score (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.69-2.75; P<0.001), but only at age <60 years (<60 years: OR, 3.97; 95% CI, 1.69-9.32; P=0.002; 60-79 years: OR, 1.01; 95% CI, 0.72-1.41; P=0.963; >=80 years: OR, 0.95; 95% CI, 0.59-1.54; P=0.832). The overall association of renal impairment and total SVD score was also attenuated after adjustment for age, sex, history of hypertension, diabetes mellitus, and premorbid average systolic blood pressure (adjusted OR, 0.76; 95% CI, 0.56-1.02; P=0.067), but the independent association of renal impairment and total SVD score at age <60 years was maintained (adjusted OR, 3.11; 95% CI, 1.21-7.98; P=0.018). Associations of renal impairment and SVD were consistent for each SVD marker at age <60 years but were strongest for cerebral microbleeds (OR, 5.84; 95% CI, 1.45-23.53; P=0.013) and moderate-severe periventricular white matter hyperintensities (OR, 6.28; 95% CI, 1.54-25.63; P=0.010). CONCLUSIONS: The association of renal impairment and cerebral SVD was attenuated with adjustment for shared risk factors at older ages, but remained at younger ages, consistent with a shared susceptibility to premature disease. PMID- 29523653 TI - Mbf1 ensures Polycomb silencing by protecting E(z) mRNA from degradation by Pacman. AB - Under stress conditions, the coactivator Multiprotein bridging factor 1 (Mbf1) translocates from the cytoplasm into the nucleus to induce stress-response genes. However, its role in the cytoplasm, where it is mainly located, has remained elusive. Here, we show that Drosophila Mbf1 associates with E(z) mRNA and protects it from degradation by the exoribonuclease Pacman (Pcm), thereby ensuring Polycomb silencing. In genetic studies, loss of mbf1 function enhanced a Polycomb phenotype in Polycomb group mutants, and was accompanied by a significant reduction in E(z) mRNA expression. Furthermore, a pcm mutation suppressed the Polycomb phenotype and restored the expression level of E(z) mRNA, while pcm overexpression exhibited the Polycomb phenotype in the mbf1 mutant but not in the wild-type background. In vitro, Mbf1 protected E(z) RNA from Pcm activity. Our results suggest that Mbf1 buffers fluctuations in Pcm activity to maintain an E(z) mRNA expression level sufficient for Polycomb silencing. PMID- 29523655 TI - An E(z) escape from Pacman ensures Polycomb silencing. PMID- 29523658 TI - Molecular Diagnostics: Another Battle Brewing. PMID- 29523654 TI - On the nature and function of organizers. AB - Organizers, which comprise groups of cells with the ability to instruct adjacent cells into specific states, represent a key principle in developmental biology. The concept was first introduced by Spemann and Mangold, who showed that there is a cellular population in the newt embryo that elicits the development of a secondary axis from adjacent cells. Similar experiments in chicken and rabbit embryos subsequently revealed groups of cells with similar instructive potential. In birds and mammals, organizer activity is often associated with a structure known as the node, which has thus been considered a functional homologue of Spemann's organizer. Here, we take an in-depth look at the structure and function of organizers across species and note that, whereas the amphibian organizer is a contingent collection of elements, each performing a specific function, the elements of organizers in other species are dispersed in time and space. This observation urges us to reconsider the universality and meaning of the organizer concept. PMID- 29523659 TI - Letter to the Editor: Who's Watching the Kids? PMID- 29523656 TI - A Restricted Role for FcgammaR in the Regulation of Adaptive Immunity. AB - By their interaction with IgG immune complexes, FcgammaR and complement link innate and adaptive immunity, showing functional redundancy. In complement deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcgammaR-knockout mice, it has been concluded that FcgammaRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcgammaRs (FcgammaRI/II/III/IV-/- mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcgammaRIIb-deficient mice, FcgammaRI/II/III/IV-/- mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcgammaRs in the modulation of the adaptive immune response in vivo. We conclude that FcgammaRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity. PMID- 29523657 TI - 15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-kappaB Regulators in Bacterial Pneumonia. AB - Specialized proresolving mediators (SPMs) decrease NF-kappaB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-kappaB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-kappaB regulators A20 and single Ig IL-1R-related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) receptor-dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-kappaB-induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-kappaB activity and to establish mechanisms for NF kappaB regulation by SPMs for pneumonia resolution. PMID- 29523660 TI - Letter to the Editor: No Evidence to Promote Interim FDG-PET Adapted Therapy in the NCCN Guidelines for Hodgkin Lymphoma. PMID- 29523661 TI - Idelalisib and Rituximab in 17p Deletion-Positive Splenic Marginal Zone Lymphoma. AB - Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell malignancy involving the spleen and bone marrow. Various cytogenetic abnormalities with prognostic value have been identified in SMZL. Complexity of karyotype, 14q aberrations, and TP53 deletions have been found to be poor prognostic indicators. We report an unusual case of SMZL with a complex karyotype including 17p deletion, primarily refractory to 2 chemoimmunotherapy regimens, that responded well to treatment with phosphatidylinositol-3-kinase delta (PI3Kdelta) inhibitors idelalisib and rituximab. PMID- 29523662 TI - A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy. AB - Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDGFRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus. PMID- 29523663 TI - NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018. AB - The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL. PMID- 29523664 TI - Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors. AB - Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM 1) evaluated. A single nucleotide polymorphism in rs523349 (5-alpha-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as >=3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index >=25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level <=3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment associated MetS requires further characterization. PMID- 29523665 TI - Patient-Reported Distress in Myelodysplastic Syndromes and Its Association With Clinical Outcomes: A Retrospective Cohort Study. AB - Background: NCCN defines distress as a multifactorial, unpleasant emotional experience of a psychological nature that may interfere with patients' ability to cope with cancer symptoms and treatment. Patients with myelodysplastic syndromes (MDS) are at risk for distress due to the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress data from adult ambulatory patients with MDS visiting a single, tertiary care medical center from July 2013 to September 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with NCCN Distress Thermometer (DT) and Problem List (PL) scores. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Results: We abstracted 376 DT scores (median, 1; range, 0-10) from 606 visits and 110 patients (median, 2 DT scores/patient; range, 1-16). NCCN Guidelines suggest that patients with DT scores >=4 should be evaluated for referral to specialty services to address unmet needs. A total of 54 patients (49%) had at least 1 DT score >=4 and 20 (18%) had 2 or more DT scores >=4; 98 patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median, 4 problems/patient/visit; range, 1-23). The 5 most frequently reported problems were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification at diagnosis, a single point increase on the DT was associated with an increased risk of death (hazard ratio, 1.18; 95% CI, 1.01-1.36). Conclusions: Patients with MDS experience a high burden of distress, and patient-reported distress is associated with clinical outcomes. Distress should be further studied as a prognostic variable and a marker of unmet needs in MDS. PMID- 29523666 TI - Adherence to the World Cancer Research Fund/American Institute for Cancer Research Guideline Is Associated With Better Health-Related Quality of Life Among Chinese Patients With Breast Cancer. AB - Background: The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guideline provides recommendations for cancer prevention among cancer survivors. Limited data have examined whether guideline adherence is related to health-related quality of life (HRQoL) among Chinese patients with breast cancer. Methods: An ongoing prospective cohort study involving 1,462 Chinese women with early-stage breast cancer assessed exercise, diet, and body mass index (BMI) at baseline and at 18-months follow-up after diagnosis. Each assessment recorded patient habits within the previous 12 months. HRQoL was evaluated by the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). We first compared the level of adherence to WCRF/AICR recommendations before and after cancer diagnosis. We then examined whether adherence to these recommendations after diagnosis was associated with HRQoL at 18 months. Results: The mean adherence score significantly increased from baseline (3.2; SD, 1.1) to 18-month follow-up (3.9; SD, 1.1; P<.001). Overall, increasing adherence to the WCRF/AICR guideline was associated with higher scores of global health status/quality of life (QoL; Ptrend=.011), physical (Ptrend<.001) and role functioning (Ptrend=.024), and lower scores for fatigue (Ptrend=.016), nausea and vomiting (Ptrend<.001), pain (Ptrend=.004), dyspnea (Ptrend=.030), loss of appetite (Ptrend=.007), and diarrhea (Ptrend=.020). Patients with cancer who met the BMI recommendation had higher scores for physical functioning (P=.001) and lower scores for fatigue (P=.024), pain (P<.001), and dyspnea (P=.045). Adherence to physical activity recommendation was associated with better scores of global health status/QoL (P<.001), physical functioning (P=.003), fatigue (P=.002), pain (P=.018), and dyspnea (P=.021). Higher adherence to diet recommendation was associated with lower scores of nausea and vomiting (Ptrend=.005), loss of appetite (Ptrend=.026), constipation (Ptrend=.040), and diarrhea (Ptrend=.031). Conclusions: Chinese patients with breast cancer made positive lifestyle changes early after cancer diagnosis. Increased adherence to WCRF/AICR recommendations after cancer diagnosis may improve HRQoL. Our data suggest that Chinese patients with breast cancer should follow the WCRF/AICR guideline to improve overall well being. PMID- 29523667 TI - Trends in Outcomes of Patients With Metastatic Cancer Undergoing Intubation and Mechanical Ventilation: Results of the National Hospital Discharge Survey. AB - Background: There has been an overall decline in intensive care unit mortality over the past 2 decades, including in patients undergoing intubation and mechanical ventilation (MV). Whether this decline extends to patients with metastatic cancer remains unknown. We analyzed the outcomes of patients with metastatic cancer undergoing intubation/MV using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis and procedure codes were used to identify patients with metastatic cancer who underwent intubation/MV. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study trends in outcomes. Results: During the 10-year study period, 200,350 patients with metastatic cancer and who underwent intubation/MV were identified; the mean age was 65.3 years and 46.2% were men. There was an increase in the total number of patients with metastatic cancer who underwent intubation/MV during the study period, from 36,881 in 2001 2002 to 51,003 in 2009-2010 (P<.001). The overall inpatient mortality rate was 57.3%, discharge to a care facility (DTCF) rate was 40.9% among patients alive at discharge, and mean LOS was 11.1 days. No significant trends were seen in rates of mortality, DTCF, or LOS from 2001 to 2010. Conclusions: In this national database, there was an increase in the number of patients with metastatic cancer who underwent intubation/MV. These patients had high rates of inpatient mortality and DTCF, which did not improve during the study period. Therefore, novel solutions are required to improve outcomes for these patients. PMID- 29523668 TI - Ten-Year Trends in Antiemetic Prescribing in Patients Receiving Highly Emetogenic Chemotherapy. AB - Purpose: Prevention of chemotherapy-induced nausea and vomiting is essential to preserve quality of life in patients with cancer receiving highly emetogenic chemotherapy (HEC). Recently, new drugs (eg, fosaprepitant, and the newer neurokinin-1 receptor antagonists [NK1RAs] rolapitant and netupitant) and updated antiemetic guidelines have emerged. However, trends in real-world antiemetic use are understudied. Methods: We identified patients treated with an initial dose of HEC (either cisplatin or doxorubicin/cyclophosphamide) from January 2006 to June 2016 using administrative claims data from a US commercial insurance database (OptumLabs). Antiemetic use was determined by identifying intravenous/oral/transdermal administration within +/-1 day of the chemotherapy dose and/or prescription fill from 14 days before to 7 days after chemotherapy. We used descriptive statistics to present patient demographics, chemotherapy drugs administered, presence/absence of a central intravenous access device, and antiemetics used. Results: A total of 23,030 patients (67.3%) received doxorubicin/cyclophosphamide and 11,206 (32.7%) received cisplatin. Dexamethasone and 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) were consistently used by 85% to 95% of patients, consistent with guideline recommendations. NK1RAs were underused early on, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use increased precipitously starting in 2009, preceding a sharp decrease in aprepitant use beginning in 2011. Receipt of olanzapine, rolapitant, and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used by most patients receiving HEC, in accordance with guideline recommendations. NK1RA use was less adherent with guidelines. PMID- 29523672 TI - Geriatric Oncology Education for the Oncologist is Overdue. PMID- 29523671 TI - Genomic Testing in Lung Cancer: Past, Present, and Future. AB - Precision medicine commonly refers to the selection of the most effective cancer treatments based on the presence of specific biomarkers (eg, genomic abnormalities) in a patient's tumor. Therefore, genomic testing is used to identify patients whose tumors harbor the vulnerability that is sensitive to corresponding targeted therapies. This approach allows for the selection of patients who have the greatest chance of deriving benefit from the treatments, reduces toxicity, and significantly improves outcome; precision medicine is recommended for advanced non-small cell lung cancer. This article reviews the evolution of genomic testing in lung cancer, from its development, including first success and failures, to its current use in the care of patients with lung cancer, and addresses future considerations, such as the expected increase of targetable abnormalities, the need to follow the genomic profile over time, and tumor heterogeneity. PMID- 29523670 TI - Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology. AB - Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS. PMID- 29523669 TI - Community Oncologists' Decision-Making for Treatment of Older Patients With Cancer. AB - Background: This study's objectives were to describe community oncologists' beliefs about and confidence with geriatric care and to determine whether geriatric-relevant information influences cancer treatment decisions. Methods: Community oncologists were recruited to participate in 2 multisite geriatric oncology trials. Participants shared their beliefs about and confidence in caring for older adults. They were also asked to make a first-line chemotherapy recommendation (combination vs single-agent vs no chemotherapy) for a hypothetical vignette of an older patient with advanced pancreatic cancer. Each oncologist received one randomly chosen vignette that varied on 3 variables: age (72/84 years), impaired function (yes/no), and cognitive impairment (yes/no). Other patient characteristics were held constant. Logistic regression models were used to identify associations between oncologist/vignette-patient characteristics and treatment decisions. Results: Oncologist response rate was 61% (n=305/498). Most oncologists agreed that "the care of older adults with cancer needs to be improved" (89%) and that "geriatrics training is essential" (72%). However, <25% were "very confident" in recognizing dementia or conducting a fall risk or functional assessment, and only 23% reported using the geriatric assessment in clinic. Each randomly varied patient characteristic was independently associated with the decision to treat: younger age (adjusted odds ratio [aOR], 5.01; 95% CI, 2.73-9.20), normal cognition (aOR, 5.42; 95% CI, 3.01-9.76), and being functionally intact (aOR, 3.85; 95% CI, 2.12-7.00). Accounting for all vignettes across all scenarios, 161 oncologists (52%) said they would offer chemotherapy. All variables were independently associated with prescribing single-agent over combination chemotherapy (older age: aOR, 3.22; 95% CI 1.43-7.25, impaired cognition: aOR, 3.13; 95% CI, 1.36-7.20, impaired function: aOR, 2.48; 95% CI, 1.12-5.72). Oncologists' characteristics were not associated with decisions about providing chemotherapy. Conclusion: Geriatric-relevant information, when available, strongly influences community oncologists' treatment decisions. PMID- 29523674 TI - Does Chemotherapy Induce Metastases? PMID- 29523675 TI - Chimeric Antigen Receptor T Cell Therapy and the Kidney: What the Nephrologist Needs to Know. PMID- 29523676 TI - Immunoglobulin G-Degrading Enzyme of Streptococcus pyogenes (IdeS), Desensitization, and the Kidney Allocation System: Complementary Approaches to Increase Transplantation in Highly HLA Sensitized Patients. PMID- 29523677 TI - Treatment Choices for Hepatitis C in Patients with Kidney Disease. PMID- 29523678 TI - Protecting Donors and Safeguarding Altruism in the United States: The Living Donor Protection Act. PMID- 29523679 TI - Parathyroidectomy in the Management of Secondary Hyperparathyroidism. AB - Secondary hyperparathyroidism develops in CKD due to a combination of vitamin D deficiency, hypocalcemia, and hyperphosphatemia, and it exists in nearly all patients at the time of dialysis initiation. There is insufficient data on whether to prefer vitamin D analogs compared with calcimimetics, but the available evidence suggests advantages with combination therapy. Calcium derangements, patient adherence, side effects, and cost limit the use of these agents. When parathyroid hormone level persists >800 pg/ml for >6 months, despite exhaustive medical interventions, monoclonal proliferation with nodular hyperplasia is likely present along with decreased expression of vitamin D and calcium-sensing receptors. Hence, surgical parathyroidectomy should be considered, especially if concomitant disorders exist, such as persistent hypercalcemia or hyperphosphatemia, tissue or vascular calcification including calciphylaxis, and/or worsening osteodystrophy. Parathyroidectomy is associated with 15%-57% greater survival in patients on dialysis, and it also improves hypercalcemia, hyperphosphatemia, tissue calcification, bone mineral density, and health-related quality of life. The parathyroidectomy rate in the United States declined to approximately seven per 1000 dialysis patient-years between 2002 and 2011 despite an increase in average parathyroid hormone levels, reflecting calcimimetics introduction and uncertainty regarding optimal parathyroid hormone targets. Hospitalization rates are 39% higher in the first postoperative year. Hungry bone syndrome occurs in approximately 25% of patients on dialysis, and profound hypocalcemia requires high doses of oral and intravenous calcium along with calcitriol supplementation. Total parathyroidectomy with autotransplantation carries a higher risk of permanent hypocalcemia, whereas risk of hyperparathyroidism recurrence is higher with subtotal parathyroidectomy. Given favorable long-term outcomes from observational parathyroidectomy cohorts, despite surgical risk and postoperative challenges, it is reasonable to consider parathyroidectomy in more patients with medically refractory secondary hyperparathyroidism. PMID- 29523680 TI - Overcoming Translational Barriers in Acute Kidney Injury: A Report from an NIDDK Workshop. AB - AKI is a complex clinical condition associated with high mortality, morbidity, and health care costs. Despite improvements in methodology and design of clinical trials, and advances in understanding the underlying pathophysiology of rodent AKI, no pharmacologic agent exists for the prevention or treatment of AKI in humans. To address the barriers that affect successful clinical translation of drug targets identified and validated in preclinical animal models of AKI in this patient population, the National Institute of Diabetes and Digestive and Kidney Diseases convened the "AKI Outcomes: Overcoming Barriers in AKI" workshop on February 10-12, 2015. The workshop used a reverse translational medicine approach to identify steps necessary to achieve clinical success. During the workshop, breakout groups were charged first to design feasible, phase 2, proof-of-concept clinical trials for delayed transplant graft function, prevention of AKI (primary prevention), and treatment of AKI (secondary prevention and recovery). Breakout groups then were responsible for identification of preclinical animal models that would replicate the pathophysiology of the phase 2 proof-of-concept patient population, including primary and secondary end points. Breakout groups identified considerable gaps in knowledge regarding human AKI, our understanding of the pathophysiology of AKI in preclinical animal models, and the fidelity of cellular and molecular targets that have been evaluated preclinically to provide information regarding human AKI of various etiologies. The workshop concluded with attendees defining a new path forward to a better understanding of the etiology, pathology, and pathophysiology of human AKI. PMID- 29523681 TI - Half-life-extended recombinant coagulation factor IX-albumin fusion protein is recycled via the FcRn-mediated pathway. AB - The neonatal Fc receptor (FcRn) has a pivotal role in albumin and IgG homeostasis. Internalized IgG captured by FcRn under acidic endosomal conditions is recycled to the cell surface where exocytosis and a shift to neutral pH promote extracellular IgG release. Although a similar mechanism is proposed for FcRn-mediated albumin intracellular trafficking and recycling, this pathway is less well defined but is relevant to the development of therapeutics exploiting FcRn to extend the half-life of short-lived plasma proteins. Recently, a long acting recombinant coagulation factor IX-albumin fusion protein (rIX-FP) has been approved for the management of hemophilia B. Fusion to albumin potentially enables internalized proteins to engage FcRn and escape lysosomal degradation. In this study, we present for the first time a detailed investigation of the FcRn mediated recycling of albumin and the albumin fusion protein rIX-FP. We demonstrate that following internalization via FcRn at low pH, rIX-FP, like albumin, is detectable within the early endosome and rapidly (within 10-15 min) traffics into the Rab11+ recycling endosomes, from where it is exported from the cell. Similarly, rIX-FP and albumin taken up by fluid-phase endocytosis at physiological pH traffics into the Rab11+ recycling compartment in FcRn-positive cells but into the lysosomal compartment in FcRn-negative cells. As expected, recombinant factor IX (without albumin fusion) and an FcRn interaction-defective albumin variant localized to the lysosomal compartments of both FcRn-expressing and nonexpressing cells. These results indicate that FcRn-mediated recycling via the albumin moiety is a mechanism for the half-life extension of rIX-FP observed in clinical studies. PMID- 29523682 TI - The length of the interleukin-11 receptor stalk determines its capacity for classic signaling. AB - Interleukin (IL)-11 is a multifunctional cytokine that was traditionally recognized for its hematopoietic and anti-inflammatory functions, but has recently been shown also to be involved in tumorigenesis. IL-11 signaling is initiated by binding of the cytokine to the IL-11 receptor (IL-11R), which is not directly involved in signaling but required for IL-11 binding to the signal transducing receptor glycoprotein (gp) 130. In classic signaling, IL-11 binds to the membrane-bound IL-11R to initiate signal transduction. Additionally, IL-11 signaling can be initiated via soluble IL-11R, known as trans-signaling, and this pathway only requires the three extracellular domains of the IL-11R, but not stalk, transmembrane, or intracellular region. Here, we analyzed the role of the IL-11R stalk region, a 55 amino acid stretch connecting the extracellular domains with the transmembrane helix, in classic IL-11 signaling with the help of cytokine-dependent cell lines. We showed that the stalk region is crucial for IL 11 signaling via the membrane-bound IL-11R. Using different deletion variants, we found that a minimal length of 23 amino acid residues is required for efficient signal transduction. We further found that classic IL-11 signaling depended solely on the length, but not the sequence, of the IL-11R stalk region, suggesting that the stalk functions as a spacer in the signaling complex. We previously described the IL-11R stalk region as determinant of proteolysis and regulator of IL-11 trans-signaling. The results presented here reveal an additional function in classic IL-11 signaling, highlighting the importance of the IL-11R stalk in IL-11 signaling. PMID- 29523683 TI - Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone. AB - The transcription factor Hes family basic helix-loop-helix transcription factor 1 (Hes1) is a downstream effector of Notch signaling and plays a crucial role in orchestrating developmental processes during the embryonic stage. However, its aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the present study, we report the discovery of small organic molecules (JI051 and JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1) via an interaction domain comprising two tryptophan residues, prompting us to search a chemical library of 1,800 small molecules enriched for indole-like pi electron-rich pharmacophores for a compound that blocks Hes1-mediated transcriptional repression. This screening identified a lead compound whose extensive chemical modification to improve potency yielded JI051, which inhibited HEK293 cell proliferation with an EC50 of 0.3 MUm Unexpectedly, using immunomagnetic isolation and nanoscale LC-MS/MS, we found that JI051 does not bind TLE1 but instead interacts with prohibitin 2 (PHB2), a cancer-associated protein chaperone. We also found that JI051 stabilizes PHB2's interaction with Hes1 outside the nucleus, inducing G2/M cell-cycle arrest. Of note, JI051 dose dependently reduced cell growth of the human pancreatic cancer cell line MIA PaCa 2, and JI130 treatment significantly reduced tumor volume in a murine pancreatic tumor xenograft model. These results suggest a previously unrecognized role for PHB2 in the regulation of Hes1 and may inform potential strategies for managing pancreatic cancer. PMID- 29523684 TI - Acute loss of iron-sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells. AB - Iron-sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant-negative variants of the primary Fe-S biogenesis scaffold protein iron sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming associated with loss of Fe S-containing proteins in several major cellular compartments. Using multiple metabolomics platforms, we observed a ~12-fold increase in intracellular citrate content in Fe-S-deficient cells, a surge that was due to loss of aconitase activity. The excess citrate was generated from glucose-derived acetyl-CoA, and global analysis of cellular lipids revealed that fatty acid biosynthesis increased markedly relative to cellular proliferation rates in Fe-S-deficient cells. We also observed intracellular lipid droplet accumulation in both acutely Fe-S-deficient cells and iron-starved cells. We conclude that deficient Fe-S biogenesis and acute iron deficiency rapidly increase cellular citrate concentrations, leading to fatty acid synthesis and cytosolic lipid droplet formation. Our findings uncover a potential cause of cellular steatosis in nonadipose tissues. PMID- 29523685 TI - The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling after cholestatic liver injury. AB - Under various conditions of liver injury, the intrahepatic biliary epithelium undergoes dynamic tissue expansion and remodeling, a process known as ductular reaction. Mouse models defective in inducing such a tissue-remodeling process are more susceptible to liver injury, suggesting a crucial role of this process in liver regeneration. However, the molecular mechanisms regulating the biliary epithelial cell (BEC) dynamics in the ductular reaction remain largely unclear. Here, we demonstrate that the transcription factor Kruppel-like factor 5 (Klf5) is highly enriched in mouse liver BECs and plays a key role in regulating the ductular reaction, specifically under cholestatic injury conditions. Although mice lacking Klf5 in the entire liver epithelium, including both hepatocytes and BECs (Klf5-LKO (liver epithelial-specific knockout) mice), did not exhibit any apparent phenotype in the hepatobiliary system under normal conditions, they exhibited significant defects in biliary epithelial tissue remodeling upon 3,5 diethoxycarbonyl-1,4-dihydrocollidine-induced cholangitis, concomitantly with exacerbated cholestasis and reduced survival rate. In contrast, mice lacking Klf5 solely in hepatocytes did not exhibit any such phenotypes, confirming Klf5's specific role in BECs. RNA-sequencing analyses of BECs isolated from the Klf5-LKO mouse livers revealed that the Klf5 deficiency primarily affected expression of cell cycle-related genes. Moreover, immunostaining analysis with the proliferation marker Ki67 disclosed that the Klf5-LKO mice had significantly reduced BEC proliferation levels upon injury. These results indicate that Klf5 plays a critical role in the ductular reaction and biliary epithelial tissue expansion and remodeling by inducing BEC proliferation and thereby contributing to liver regeneration. PMID- 29523686 TI - Inhibition of strigolactone receptors by N-phenylanthranilic acid derivatives: Structural and functional insights. AB - The strigolactone (SL) family of plant hormones regulates a broad range of physiological processes affecting plant growth and development and also plays essential roles in controlling interactions with parasitic weeds and symbiotic fungi. Recent progress elucidating details of SL biosynthesis, signaling, and transport offers many opportunities for discovering new plant-growth regulators via chemical interference. Here, using high-throughput screening and downstream biochemical assays, we identified N-phenylanthranilic acid derivatives as potent inhibitors of the SL receptors from petunia (DAD2), rice (OsD14), and Arabidopsis (AtD14). Crystal structures of DAD2 and OsD14 in complex with inhibitors further provided detailed insights into the inhibition mechanism, and in silico modeling of 19 other plant strigolactone receptors suggested that these compounds are active across a large range of plant species. Altogether, these results provide chemical tools for investigating SL signaling and further define a framework for structure-based approaches to design and validate optimized inhibitors of SL receptors for specific plant targets. PMID- 29523687 TI - Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. AB - G protein-coupled receptors (GPCRs) are key signaling proteins that regulate nearly every aspect of cell function. Studies of GPCRs have benefited greatly from the development of molecular tools to monitor receptor activation and downstream signaling. Here, we show that mini G proteins are robust probes that can be used in a variety of assay formats to report GPCR activity in living cells. Mini G (mG) proteins are engineered GTPase domains of Galpha subunits that were developed for structural studies of active-state GPCRs. Confocal imaging revealed that mG proteins fused to fluorescent proteins were located diffusely in the cytoplasm and translocated to sites of receptor activation at the cell surface and at intracellular organelles. Bioluminescence resonance energy transfer (BRET) assays with mG proteins fused to either a fluorescent protein or luciferase reported agonist, superagonist, and inverse agonist activities. Variants of mG proteins (mGs, mGsi, mGsq, and mG12) corresponding to the four families of Galpha subunits displayed appropriate coupling to their cognate GPCRs, allowing quantitative profiling of subtype-specific coupling to individual receptors. BRET between luciferase-mG fusion proteins and fluorescent markers indicated the presence of active GPCRs at the plasma membrane, Golgi apparatus, and endosomes. Complementation assays with fragments of NanoLuc luciferase fused to GPCRs and mG proteins reported constitutive receptor activity and agonist induced activation with up to 20-fold increases in luminescence. We conclude that mG proteins are versatile tools for studying GPCR activation and coupling specificity in cells and should be useful for discovering and characterizing G protein subtype-biased ligands. PMID- 29523688 TI - Proteomics reveals novel protein associations with early endosomes in an epidermal growth factor-dependent manner. AB - The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is an integral component of proliferative signaling. EGFRs on the cell surface become activated upon EGF binding and have an increased rate of endocytosis. Once in the cytoplasm, the EGF.EGFR complex is trafficked to the lysosome for degradation, and signaling is terminated. During trafficking, the EGFR kinase domain remains active, and the internalized EGFR can continue signaling to downstream effectors. Although effector activity varies based on the EGFR's endocytic location, it is not clear how this occurs. In an effort to identify proteins that uniquely associate with the internalized, liganded EGFR in the early endosome, we developed an early endosome isolation strategy to analyze their protein composition. Post-nuclear supernatant from HeLa cells stimulated with and without EGF were separated on an isotonic 17% Percoll gradient. The gradient was fractionated, and early endosomal fractions were pooled and immunoisolated with an EEA1 mAb. The isolated endosomes were validated by immunoblot using antibodies against organelle-specific marker proteins and transmission EM. These early endosomes were also subjected to LC-MS/MS for proteomic analysis. Five proteins were detected in endosomes in a ligand dependent manner: EGFR, RUFY1, STOML2, PTPN23, and CCDC51. Knockdown of RUFY1 or PTPN23 by RNAi indicated that both proteins play a role in EGFR trafficking. These experiments indicate that endocytic trafficking of activated EGFR changes the protein composition, membrane trafficking, and signaling potential of the early endosome. PMID- 29523689 TI - An unexpected vestigial protein complex reveals the evolutionary origins of an s triazine catabolic enzyme. AB - Cyanuric acid is a metabolic intermediate of s-triazines, such as atrazine (a common herbicide) and melamine (used in resins and plastics). Cyanuric acid is mineralized to ammonia and carbon dioxide by the soil bacterium Pseudomonas sp. strain ADP via three hydrolytic enzymes (AtzD, AtzE, and AtzF). Here, we report the purification and biochemical and structural characterization of AtzE. Contrary to previous reports, we found that AtzE is not a biuret amidohydrolase, but instead it catalyzes the hydrolytic deamination of 1-carboxybiuret. X-ray crystal structures of apo AtzE and AtzE bound with the suicide inhibitor phenyl phosphorodiamidate revealed that the AtzE enzyme complex consists of two independent molecules in the asymmetric unit. We also show that AtzE forms an alpha2beta2 heterotetramer with a previously unidentified 68-amino acid-long protein (AtzG) encoded in the cyanuric acid mineralization operon from Pseudomonas sp. strain ADP. Moreover, we observed that AtzG is essential for the production of soluble, active AtzE and that this obligate interaction is a vestige of their shared evolutionary origin. We propose that AtzEG was likely recruited into the cyanuric acid-mineralizing pathway from an ancestral glutamine transamidosome that required protein-protein interactions to enforce the exclusion of solvent from the transamidation reaction. PMID- 29523690 TI - Cross-talk between chromatin acetylation and SUMOylation of tripartite motif containing protein 24 (TRIM24) impacts cell adhesion. AB - Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional cross-talk between histone acetylation and TRIM24 SUMOylation. Binding of TRIM24 to chromatin via its tandem PHD-bromodomain, which recognizes unmethylated lysine 4 and acetylated lysine 23 of histone H3 (H3K4me0/K23ac), led to TRIM24 SUMOylation at lysine residues 723 and 741. Inactivation of the bromodomain, either by mutation or with a small-molecule inhibitor, IACS-9571, abolished TRIM24 SUMOylation. Conversely, inhibition of histone deacetylation markedly increased TRIM24's interaction with chromatin and its SUMOylation. Of note, gene expression profiling of MCF7 cells expressing WT versus SUMO-deficient TRIM24 identified cell adhesion as the major pathway regulated by the cross-talk between chromatin acetylation and TRIM24 SUMOylation. In conclusion, our findings establish a new link between histone H3 acetylation and SUMOylation of the reader protein TRIM24, a functional connection that may bear on TRIM24's oncogenic function and may inform future studies of PTM cross-talk between histones and epigenetic regulators. PMID- 29523693 TI - Antibody receptors steal the sweet spotlight. AB - Immunoglobulin G (IgG) antibodies function, in part, through ligation of cell surface Fc receptors such as FcgammaRIIIA (also known as CD16A). IgG glycosylation is known to impact antibody function, but the role of FcgammaRIIIA glycans, if any, is unclear. Patel et al. now reveal that these glycans do impact protein conformation and IgG affinity and display cell-specific glycosylation patterns, leading to a potential model in which the affinity and possibly function of Fc receptors is dictated by the cell type and its surface glycome. PMID- 29523691 TI - Structure-function analyses of a stereotypic rheumatoid factor unravel the structural basis for germline-encoded antibody autoreactivity. AB - Rheumatoid factors (RFs) are autoantibodies against the fragment-crystallizable (Fc) region of IgG. In individuals with hematological diseases such as cryoglobulinemia and certain B cell lymphoma forms, the RFs derived from specific heavy- and light-chain germline pairs, so-called "stereotypic RFs," are frequently produced in copious amounts and form immune complexes with IgG in serum. Of note, many structural details of the antigen recognition mechanisms in RFs are unclear. Here we report the crystal structure of the RF YES8c derived from the IGHV1-69/IGKV3-20 germline pair, the most common of the stereotypic RFs, in complex with human IgG1-Fc at 2.8 A resolution. We observed that YES8c binds to the CH2-CH3 elbow in the canonical antigen-binding manner involving a large antigen-antibody interface. On the basis of this observation, combined with mutational analyses, we propose a recognition mechanism common to IGHV1-69/IGKV3 20 RFs: (1) the interaction of the Leu432-His435 region of Fc enables the highly variable complementarity-determining region (CDR)-H3 to participate in the binding, (2) the hydrophobic tip in the CDR-H2 typical of IGHV1-69 antibodies recognizes the hydrophobic patch on Fc, and (3) the interaction of the highly conserved RF light chain with Fc is important for RF activity. These features may determine the putative epitope common to the IGHV1-69/IGKV3-20 RFs. We also showed that some mutations in the binding site of RF increase the affinity to Fc, which may aggravate hematological diseases. Our findings unravel the structural basis for germline-encoded antibody autoreactivity. PMID- 29523692 TI - Membrane protein serendipity. AB - My scientific career has taken me from chemistry, via theoretical physics and bioinformatics, to molecular biology and even structural biology. Along the way, serendipity led me to work on problems such as the identification of signal peptides that direct protein trafficking, membrane protein biogenesis, and cotranslational protein folding. I've had some great collaborations that came about because of a stray conversation or from following up on an interesting paper. And I've had the good fortune to be asked to sit on the Nobel Committee for Chemistry, where I am constantly reminded of the amazing pace and often intricate history of scientific discovery. Could I have planned this? No way! I just went with the flow .... PMID- 29523694 TI - Anti-microRNA-222 (anti-miR-222) and -181B suppresses growth of tamoxifen resistant xenografts in mouse by targeting TIMP3 protein and modulating mitogenic signal. PMID- 29523695 TI - PTPROt inactivates the oncogenic fusion protein BCR/ABL and suppresses transformation of K562 cells. PMID- 29523696 TI - Treatment of PC12 cells with nerve growth factor induces proteasomal degradation of T-cadherin that requires tyrosine phosphorylation of its cadherin domain. PMID- 29523698 TI - Identification of T-cadherin as a novel target of DNA methyltransferase 3B and its role in the suppression of nerve growth factor-mediated neurite outgrowth in PC12 cells. PMID- 29523697 TI - Role of DNA methyltransferases in regulation of human ribosomal RNA gene transcription. PMID- 29523699 TI - Predictive Value of Parkinsonian Primates in Pharmacologic Studies: A Comparison between the Macaque, Marmoset, and Squirrel Monkey. AB - The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold-standard animal model of Parkinson disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism, and psychosis. Three species have been used in most studies-the macaque, marmoset, and squirrel monkey-the last much less so than the first two species; however, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing pharmacologic studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism, and psychosis in each of these species and have calculated their predictive value of success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false-positive rate of 38.1%, whereas the marmoset has a positive predictive value of 76.9% and a false-positive rate of 15.6%. For parkinsonism, the macaque has a positive predictive value of 68.2% and a false-positive rate of 44.4%, whereas the marmoset has a positive predictive value of 86.9% and a false-positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, whereas the marmoset has 100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope our results will help in the design of pharmacologic experiments and will facilitate the drug discovery and development process in PD. PMID- 29523701 TI - Using molecular simulation to explore the nanoscale dynamics of the plant kinome. AB - Eukaryotic protein kinases (PKs) are a large family of proteins critical for cellular response to external signals, acting as molecular switches. PKs propagate biochemical signals by catalyzing phosphorylation of other proteins, including other PKs, which can undergo conformational changes upon phosphorylation and catalyze further phosphorylations. Although PKs have been studied thoroughly across the domains of life, the structures of these proteins are sparsely understood in numerous groups of organisms, including plants. In addition to efforts towards determining crystal structures of PKs, research on human PKs has incorporated molecular dynamics (MD) simulations to study the conformational dynamics underlying the switching of PK function. This approach of experimental structural biology coupled with computational biophysics has led to improved understanding of how PKs become catalytically active and why mutations cause pathological PK behavior, at spatial and temporal resolutions inaccessible to current experimental methods alone. In this review, we argue for the value of applying MD simulation to plant PKs. We review the basics of MD simulation methodology, the successes achieved through MD simulation in animal PKs, and current work on plant PKs using MD simulation. We conclude with a discussion of the future of MD simulations and plant PKs, arguing for the importance of molecular simulation in the future of plant PK research. PMID- 29523700 TI - Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target. AB - Mutations in the MeCP2 gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with histone deacetylase 3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classic drug discovery approaches. Here, we performed RNA sequencing (RNA-seq) on nine motor cortex and six cerebellar autopsy samples from RTT patients and controls. This approach identified 1887 significantly affected genes in the motor cortex and 2110 genes in the cerebellum, with a global trend toward increased expression. Pathway-level analysis identified enrichment in genes associated with mitogen-activated protein kinase signaling, long-term potentiation, and axon guidance. A survey of our RNA-seq results also identified a significant decrease in expression of the CHRM4 gene, which encodes a receptor [muscarinic acetylcholine receptor 4 (M4)] that is the subject of multiple large drug discovery efforts for schizophrenia and Alzheimer's disease. We confirmed that CHRM4 expression was decreased in RTT patients, and, excitingly, we demonstrated that M4 potentiation normalizes social and cognitive phenotypes in Mecp2+/- mice. This work provides an experimental paradigm in which translationally relevant targets can be identified using transcriptomics in RTT autopsy samples, back modeled in Mecp2+/- mice, and assessed for preclinical efficacy using existing pharmacological tool compounds. PMID- 29523702 TI - Multiple target sites for designing candidate drugs. AB - Rational drug discovery strategy requires a design of small molecules as candidate drugs which can specifically inhibit a target protein or any other macromolecule and effectively interfere in a defined physiological process. One of the important bacterial protein targets aimed toward developing new antibiotics is peptidyl-tRNA hydrolase (Pth). The discovery that cytarabine, a known anticancer drug, binds to Pth from Acinetobacter baumannii in a cleft located away from the catalytic site of this enzyme, published in Biochemical Journal, opens up interesting new avenues for drug design. An approach involving crystallographic identification of multiple ligand-binding sites on a target protein surface could enable iterative optimization of multiple high-affinity ligands, which may synergistically interfere in the target function with enhanced effect. PMID- 29523703 TI - Modern statistics, multiple testing and wishful thinking. PMID- 29523704 TI - Is occupational biomass smoke exposure an overlooked driver of respiratory health? PMID- 29523705 TI - To Readmission and Beyond! PMID- 29523706 TI - Length of Stay and Cost of Pediatric Readmissions. AB - BACKGROUND AND OBJECTIVES: Readmissions burden the health care system. Despite increasing attention to readmission rates, little is known about the duration and cost of readmissions. The objective of this study was to assess, nationally, the length of stay (LOS) and costs for 30-day readmissions in children. METHODS: We performed a retrospective analysis of 30-day readmissions by using the 2013 Nationwide Readmissions Database. We used generalized linear mixed effects models adjusted for important clinical and demographic factors to assess LOS and cost for index admissions, readmissions, and the episode of care (index admission plus readmission). RESULTS: A total of 125 183 (4.5%) children had a 30-day readmission; 87.1% of readmissions were to the same hospital. Readmitted children had an adjusted episode LOS that was 2 times longer (5.8 vs 2.9 days) and total costs that were 2.3 times higher ($12 250 vs $5340) than those who were not readmitted. Associations of readmissions with episode LOS and costs varied significantly by condition (P < .001). Children readmitted to a different versus the same hospital had an episode LOS that was the same (5.8 days; P = .279) but higher episode of care costs ($15 876 vs $11 661; P < .001). CONCLUSIONS: Readmitted children spend twice as many days in the hospital compared with children who are not readmitted and have higher hospital costs, especially when readmitted to a different hospital. In addition to readmission rate, readmission metrics may benefit from measurement of total LOS and costs for both the index admission and its associated readmission. PMID- 29523707 TI - Structure of the catalytic F1 head of the F1-Fo ATP synthase from Trypanosoma brucei. PMID- 29523708 TI - Stochastically pumped adaptation and directional motion of molecular machines. AB - Recent developments in synthetic molecular motors and pumps have sprung from a remarkable confluence of experiment and theory. Synthetic accomplishments have facilitated the ability to design and create molecules, many of them featuring mechanically bonded components, to carry out specific functions in their environment-walking along a polymeric track, unidirectional circling of one ring about another, synthesizing stereoisomers according to an external protocol, or pumping rings onto a long rod-like molecule to form and maintain high-energy, complex, nonequilibrium structures from simpler antecedents. Progress in the theory of nanoscale stochastic thermodynamics, specifically the generalization and extension of the principle of microscopic reversibility to the single molecule regime, has enhanced the understanding of the design requirements for achieving strong unidirectional motion and high efficiency of these synthetic molecular machines for harnessing energy from external fluctuations to carry out mechanical and/or chemical functions in their environment. A key insight is that the interaction between the fluctuations and the transition state energies plays a central role in determining the steady-state concentrations. Kinetic asymmetry, a requirement for stochastic adaptation, occurs when there is an imbalance in the effect of the fluctuations on the forward and reverse rate constants. Because of strong viscosity, the motions of the machine can be viewed as mechanical equilibrium processes where mechanical resonances are simply impossible but where the probability distributions for the state occupancies and trajectories are very different from those that would be expected at thermodynamic equilibrium. PMID- 29523709 TI - Reply to Hearty and Tormey: Use the scientific method to test geologic hypotheses, because rocks do not whisper. PMID- 29523710 TI - Listen to the whisper of the rocks, telling their ancient story. PMID- 29523712 TI - The ADAPTOR PROTEIN-3 Complex Mediates Pollen Tube Growth by Coordinating Vacuolar Targeting and Organization. AB - Pollen tube growth is an essential step for successful plant reproduction. Vacuolar trafficking and dynamic organization are important for pollen tube growth; however, the key proteins involved in these processes are not well understood. Here, we report that the ADAPTOR PROTEIN-3 (AP-3) complex and its tonoplast cargo PROTEIN S-ACYL TRANSFERASE10 (PAT10) are critical for pollen tube growth in Arabidopsis (Arabidopsis thaliana). AP-3 is a heterotetrameric protein complex consisting of four subunits, delta, beta, u, and sigma. AP-3 regulates tonoplast targeting of several cargoes, such as PAT10. We show that functional loss of any of the four AP-3 subunits reduces plant fertility. In ap-3 mutants, pollen development was normal but pollen tube growth was compromised, leading to reduced male transmission. Functional loss of PAT10 caused a similar reduction in pollen tube growth, suggesting that the tonoplast association of PAT10 mediated by AP-3 is crucial for this process. Indeed, the Ca2+ gradient during pollen tube growth was reduced significantly due to AP-3 loss of function, consistent with the abnormal targeting of CALCINUERIN B-LIKE2 (CBL2) and CBL3, whose tonoplast association depends on PAT10. Furthermore, we show that the pollen tubes of ap-3 mutants have vacuoles with simplified tubules and bulbous structures, indicating that AP-3 affects vacuolar organization. Our results demonstrate a role for AP-3 in plant reproduction and provide insights into the role of vacuoles in polarized cell growth. PMID- 29523711 TI - FERTILIZATION-INDEPENDENT SEED-Polycomb Repressive Complex 2 Plays a Dual Role in Regulating Type I MADS-Box Genes in Early Endosperm Development. AB - Early endosperm development presents a unique system in which to uncover epigenetic regulatory mechanisms because the contributing maternal and paternal genomes possess differential epigenetic modifications. In Arabidopsis (Arabidopsis thaliana), the initiation of endosperm coenocytic growth upon fertilization and the transition to endosperm cellularization are regulated by the FERTILIZATION-INDEPENDENT SEED (FIS)-Polycomb Repressive Complex 2 (PRC2), a putative H3K27 methyltransferase. Here, we address the possible role of the FIS PRC2 complex in regulating the type I MADS-box gene family, which has been shown previously to regulate early endosperm development. We show that a subclass of type I MADS-box genes (C2 genes) was expressed in distinct domains of the coenocytic endosperm in wild-type seeds. Furthermore, the C2 genes were mostly up regulated biallelically during the extended coenocytic phase of endosperm development in the FIS-PRC2 mutant background. Using allele-specific expression analysis, we also identified a small subset of C2 genes subjected to FIS-PRC2 dependent maternal or FIS-PRC2-independent paternal imprinting. Our data support a dual role for the FIS-PRC2 complex in the regulation of C2 type I MADS-box genes, as evidenced by a generalized role in the repression of gene expression at both alleles associated with endosperm cellularization and a specialized role in silencing the maternal allele of imprinted genes. PMID- 29523713 TI - Darkened Leaves Use Different Metabolic Strategies for Senescence and Survival. AB - In plants, an individually darkened leaf initiates senescence much more rapidly than a leaf from a whole darkened plant. Combining transcriptomic and metabolomic approaches in Arabidopsis (Arabidopsis thaliana), we present an overview of the metabolic strategies that are employed in response to different darkening treatments. Under darkened plant conditions, the perception of carbon starvation drove a profound metabolic readjustment in which branched-chain amino acids and potentially monosaccharides released from cell wall loosening became important substrates for maintaining minimal ATP production. Concomitantly, the increased accumulation of amino acids with a high nitrogen-carbon ratio may provide a safety mechanism for the storage of metabolically derived cytotoxic ammonium and a pool of nitrogen for use upon returning to typical growth conditions. Conversely, in individually darkened leaf, the metabolic profiling that followed our 13C-enrichment assays revealed a temporal and differential exchange of metabolites, including sugars and amino acids, between the darkened leaf and the rest of the plant. This active transport could be the basis for a progressive metabolic shift in the substrates fueling mitochondrial activities, which are central to the catabolic reactions facilitating the retrieval of nutrients from the senescing leaf. We propose a model illustrating the specific metabolic strategies employed by leaves in response to these two darkening treatments, which support either rapid senescence or a strong capacity for survival. PMID- 29523714 TI - Reduced Arogenate Dehydratase Expression: Ramifications for Photosynthesis and Metabolism. AB - Arogenate dehydratase (ADT) catalyzes the final step of phenylalanine (Phe) biosynthesis. Previous work showed that ADT-deficient Arabidopsis (Arabidopsis thaliana) mutants had significantly reduced lignin contents, with stronger reductions in lines that had deficiencies in more ADT isoforms. Here, by analyzing Arabidopsis ADT mutants using our phenomics facility and ultra performance liquid chromatography-mass spectrometry-based metabolomics, we describe the effects of the modulation of ADT on photosynthetic parameters and secondary metabolism. Our data indicate that a reduced carbon flux into Phe biosynthesis in ADT mutants impairs the consumption of photosynthetically produced ATP, leading to an increased ATP/ADP ratio, the overaccumulation of transitory starch, and lower electron transport rates. The effect on electron transport rates is caused by an increase in proton motive force across the thylakoid membrane that down-regulates photosystem II activity by the high-energy quenching mechanism. Furthermore, quantitation of secondary metabolites in ADT mutants revealed reduced flavonoid, phenylpropanoid, lignan, and glucosinolate contents, including glucosinolates that are not derived from aromatic amino acids, and significantly increased contents of putative galactolipids and apocarotenoids. Additionally, we used real-time atmospheric monitoring mass spectrometry to compare respiration and carbon fixation rates between the wild type and adt3/4/5/6, our most extreme ADT knockout mutant, which revealed no significant difference in both night- and day-adapted plants. Overall, these data reveal the profound effects of altered ADT activity and Phe metabolism on secondary metabolites and photosynthesis with implications for plant improvement. PMID- 29523716 TI - RETRACTION: Vol. 170: 2432-2443, 2016. PMID- 29523715 TI - Exploiting CELLULOSE SYNTHASE (CESA) Class Specificity to Probe Cellulose Microfibril Biosynthesis. AB - Cellulose microfibrils are the basic units of cellulose in plants. The structure of these microfibrils is at least partly determined by the structure of the cellulose synthase complex. In higher plants, this complex is composed of 18 to 24 catalytic subunits known as CELLULOSE SYNTHASE A (CESA) proteins. Three different classes of CESA proteins are required for cellulose synthesis and for secondary cell wall cellulose biosynthesis these classes are represented by CESA4, CESA7, and CESA8. To probe the relationship between CESA proteins and microfibril structure, we created mutant cesa proteins that lack catalytic activity but retain sufficient structural integrity to allow assembly of the cellulose synthase complex. Using a series of Arabidopsis (Arabidopsis thaliana) mutants and genetic backgrounds, we found consistent differences in the ability of these mutant cesa proteins to complement the cellulose-deficient phenotype of the cesa null mutants. The best complementation was observed with catalytically inactive cesa4, while the equivalent mutation in cesa8 exhibited significantly lower levels of complementation. Using a variety of biophysical techniques, including solid-state nuclear magnetic resonance and Fourier transform infrared microscopy, to study these mutant plants, we found evidence for changes in cellulose microfibril structure, but these changes largely correlated with cellulose content and reflected differences in the relative proportions of primary and secondary cell walls. Our results suggest that individual CESA classes have similar roles in determining cellulose microfibril structure, and it is likely that the different effects of mutating members of different CESA classes are the consequence of their different catalytic activity and their influence on the overall rate of cellulose synthesis. PMID- 29523717 TI - Polyamines Regulate Strawberry Fruit Ripening by Abscisic Acid, Auxin, and Ethylene. AB - Polyamines (PAs) participate in many plant growth and developmental processes, including fruit ripening. However, it is not clear whether PAs play a role in the ripening of strawberry (Fragaria ananassa), a model nonclimacteric plant. Here, we found that the content of the PA spermine (Spm) increased more sharply after the onset of fruit coloration than did that of the PAs putrescine (Put) or spermidine (Spd). Spm dominance in ripe fruit resulted from abundant transcripts of a strawberry S-adenosyl-l-Met decarboxylase gene (FaSAMDC), which encodes an enzyme that generates a residue needed for PA biosynthesis. Exogenous Spm and Spd promoted fruit coloration, while exogenous Put and a SAMDC inhibitor inhibited coloration. Based on transcriptome data, up- and down-regulation of FaSAMDC expression promoted and inhibited ripening, respectively, which coincided with changes in several physiological parameters and their corresponding gene transcripts, including firmness, anthocyanin content, sugar content, polyamine content, auxin (indole-3-acetic acid [IAA]) content, abscisic acid (ABA) content, and ethylene emission. Using isothermal titration calorimetry, we found that FaSAMDC also had a high enzymatic activity with a Kd of 1.7 * 10-3 m In conclusion, PAs, especially Spm, regulate strawberry fruit ripening in an ABA dominated, IAA-participating, and ethylene-coordinated manner, and FaSAMDC plays an important role in ripening. PMID- 29523718 TI - Potential negative effects of anti-histamines on male reproductive function. AB - Histamine (HA) is a pleiotropic biogenic amine synthesized exclusively by histidine decarboxylase (HDC) in most mammalian tissues. The literature on the role of HA within the male gonad has expanded over the last years, attracting attention to potential unexpected side-effects of anti-histamines on testicular function. In this regard, HA receptors (HRH1, HRH2 and HRH4) have been described in Leydig cells of different species, including human. Via these receptors, HA has been reported to trigger positive or negative interactions with the LH/hCG signaling pathway depending upon its concentration, thereby contributing to the local control of testicular androgen levels. It should then be considered that anti-histamines may affect testicular homeostasis by increasing or decreasing steroid production. Additionally, HRH1 and HRH2 receptors are present in peritubular and germ cells, and HRH2 antagonists have been found to negatively affect peritubular cells and reduce sperm viability. The potential negative impact of anti-histamines on male reproduction becomes even more dramatic if we consider that HA has also been associated with human sexual behavior and penile erection. What is more, although testicular mast cells are the major source of locally produced HA, recent studies have described HDC expression in macrophages, Leydig cells and germ cells, revealing the existence of multiple sources of HA within the testis. Undoubtedly, the more we learn about the testicular histaminergic system, the more opportunities there will be for rational design of drugs aimed at treating HA-related pathologies, with minimum or nule negative impact on fertility. PMID- 29523719 TI - Self-perceived risk of STIs in a population-based study of Scandinavian women. AB - OBJECTIVE: This study examined the associations between current behaviours/characteristics and self-perceived risk for STIs, among randomly selected women aged 18-45 years from Denmark, Norway and Sweden. METHOD: A population-based, cross-sectional, questionnaire study (paper based, web based and telephone based) was conducted during 2011-2012. We compared medium-high STI risk perception with no/low risk perception. The associations were explored for women who had ever had sexual intercourse and for women with a new partner in the last 6 months using multivariable logistic regression. RESULT: The overall prevalence of medium-high STI risk perception was 7.4%. It was highest among women aged 18-24 years (16.2%) and among the Danish women (8.8%). Number of new sexual partners in the last 6 months (>=3vs 0 partners, OR 14.94, 95% CI 13.20 to 16.94) was strongly associated with medium-high STI risk perception. Among women with a new partner in the last 6 months, lack of condom use increased medium-high STI risk perception (OR 1.73, 95% CI 1.52 to 1.96). Genital warts in the last year, binge drinking and being single were associated with increased risk perception and remained statistically significant after additional adjustments were made for number of new partners and condom use with new partners in the last 6 months. CONCLUSION: Subjective perception of risk for STI was associated with women's current risk-taking behaviours, indicating women generally are able to assess their risks for STIs. However, a considerable proportion of women with multiple new partners in the last 6 months and no condom use still considered themselves at no/low risk for STI. PMID- 29523720 TI - Impact of emergency department surge and end of shift on patient workup and treatment prior to referral to internal medicine: a health records review. AB - BACKGROUND: The goal of this study was to determine if ED surge and end-of-shift assessment of patients affect the extent of diagnostic tests, therapeutic interventions and accuracy of diagnosis prior to referral to internal medicine. METHODS: This study was a health records review of consecutive patients referred to the internal medicine service with an ED diagnosis of heart failure, chronic obstructive pulmonary disease (COPD) or sepsis starting 1 December 2013 until 100 cases for each condition had been obtained. We developed a scoring system in consultation with emergency and internal medicine physicians to uniformly assess the completeness of treatments and investigations performed. These scores, expressed as percentage of possible points, were compared at high and low surge levels and at middle and end of shift at time of patient referral. End of shift was defined as 7:30-8:30, 15:30-16:30 and 23:30-00:30 as our shift changes occur at 8:00, 16:00 and 24:00. Rate of admission, diversion to other services and diagnosis disagreements were also assessed. RESULTS: We included 308 patients (101 heart failure, 101 COPD, 106 sepsis) with a mean age of 74.7. Comparing middle of shift to end of shift, the mean scores were 91.9% versus 91.8% (difference 0.1% (95% CI -2.4 to 3.0)) for investigations and 73.0% versus 70.4% (difference 2.6% (95% CI -1.8 to 7.4)) for treatments. Comparing low to high surge times, the mean scores were 92.1% versus 91.7% (difference 0.4% (95% CI 1.2 to 2.4)) for investigations and 71.4% versus 73.6% (difference -2.2% (95% CI 5.6 to 1.3)) for treatments. We found low rates of diversion to alternate services (8.9% heart failure, 0% COPD, 6.6% sepsis) and low rates of diagnosis disagreement (4.0% heart failure, 10.9% COPD, 8.5% sepsis). CONCLUSIONS: We found no evidence that surge levels and end of shift impact the extent of investigations and treatments provided to patients diagnosed in the ED with heart failure, COPD or sepsis and referred to internal medicine. PMID- 29523721 TI - MRSA nares swab is a more accurate predictor of MRSA wound infection compared with clinical risk factors in emergency department patients with skin and soft tissue infections. AB - OBJECTIVES: Skin and soft tissue infections (SSTI) caused by methicillin resistant Staphylococcus aureus (MRSA) are prevalent in the emergency department (ED). We determined whether MRSA nasal carriage better identifies patients with MRSA wound infection than clinical risk factors or emergency medicine (EM) provider's choice of discharge prescriptions. METHODS: Adult patients presenting to a large academic medical centre ED in the USA with SSTI between May 2010 and November 2011 were screened. Research assistants administered a questionnaire regarding MRSA risk factors, and MRSA nares swab PCR testing, wound culture results and information on antibiotics prescribed at discharge were collected. Measures of classification accuracy for nares swab, individual risk factors and physician's prescription for MRSA coverage were compared with gold standard wound culture. RESULTS: During the study period, 116 patients with SSTI had both wound cultures and nares swabs for MRSA. S. aureus was isolated in 59.5%, most often MRSA (75.4%). Thirty patients (25.9%) had a positive MRSA nares swab and culture for a sensitivity of 57.7% and specificity of 92.2%. Positive predictive value (PPV) for MRSA nares swab was 85.7% and positive likelihood ratio was 7.4, while negative predictive value was 72.8% and negative likelihood ratio 0.5. None of the individual risk factors nor EM provider's prescription for MRSA coverage had a PPV or positive likelihood ratio higher than nares swabs. CONCLUSIONS: MRSA nares swab is a more accurate predictor of MRSA wound infection compared with clinical risk factors or EM provider's choice of antibiotics. MRSA nares swab may be a useful tool in the ED. PMID- 29523722 TI - Ultrasound evaluation of the respiratory changes of the inferior vena cava and axillary vein diameter at rest and during positive pressure ventilation in spontaneously breathing healthy volunteers. AB - INTRODUCTION: Ultrasound assessment of the inferior vena cava (IVC) has gained favour in aiding fluid management decisions for controlled, mechanically ventilated patients as well as in non-mechanically ventilated, spontaneously breathing patients. Its utility in spontaneously breathing patients during positive pressure non-invasive ventilation has not yet been determined. The use of the axillary vein, as an alternative option to the IVC due to its ease of accessibility and independence from intra-abdominal pressure, has also not been evaluated. The aim of this study was to assess respiratory variation in IVC and axillary vein diameters in spontaneously breathing participants (Collapsibility Index) and with the application of increasing positive end-expiratory pressure (PEEP) via positive pressure non-invasive ventilation (Distensibility Index). METHODS: The IVC and axillary vein diameters of 28 healthy adult volunteers were measured, using ultrasound, at baseline and with increasing PEEP via non-invasive ventilation. The Collapsibility Index and Distensibility Index of these vessels were calculated and compared for each vessel. The association between increasing PEEP levels and the indices was evaluated. RESULTS: Positive pressure delivered via non-invasive ventilation produced a similar degree of diameter change in the IVC and the axillary vein, that is, the Distensibility Index was similar whether measured in the IVC or the axillary vein (P=0.21, 0.47 and 0.17 at baseline, 5 and 10 cmH2O PEEP, respectively). Individual study participants' IVC and axillary veins, however, had variable responses to PEEP; that is, there appeared to be no consistent relationship between PEEP and the diameter changes. CONCLUSION: While the axillary vein could potentially be used as an alternative vessel to the IVC to assess for volume responsiveness in controlled, mechanically ventilated patients as well as in non-mechanically ventilated, spontaneously breathing patients, neither vein should be used to guide fluid management decisions in spontaneously breathing patients during positive pressure non-invasive ventilation. PMID- 29523723 TI - Rescuing rabbits. PMID- 29523726 TI - Protecting the UK's alpaca population. PMID- 29523724 TI - Northern Ireland set to get its first vet school. PMID- 29523727 TI - US farmers 'massively overusing' antibiotics. PMID- 29523730 TI - Equine disease surveillance: quarterly summary. PMID- 29523731 TI - Pilot protocol for the control of contagious equine metritis in Great Britain. PMID- 29523732 TI - Cat neutering: the earlier the better to tackle overpopulation. PMID- 29523734 TI - Managing mental health problems in practice. PMID- 29523735 TI - Male-to-female ratio at Vet Record. PMID- 29523736 TI - Male-to-female ratio at Vet Record. PMID- 29523737 TI - Graphic representation of Northern Ireland. PMID- 29523738 TI - Appropriate/inappropriate language. PMID- 29523739 TI - Appropriate/inappropriate language. PMID- 29523740 TI - Graphic representation of Northern Ireland. PMID- 29523741 TI - One tier is better that two. PMID- 29523743 TI - At last, some movement on food labelling. PMID- 29523744 TI - Imagining life without Dreamer. AB - Dr Naomi Harvey, a zoologist, describes how she has learnt to deal with her anticipatory grief. PMID- 29523747 TI - Substrate preferences of long-chain acyl-CoA synthetase and diacylglycerol acyltransferase contribute to enrichment of flax seed oil with alpha-linolenic acid. AB - Seed oil from flax (Linum usitatissimum) is enriched in alpha-linolenic acid (ALA; 18:3Delta9cis,12cis,15cis ), but the biochemical processes underlying the enrichment of flax seed oil with this polyunsaturated fatty acid are not fully elucidated. Here, a potential process involving the catalytic actions of long chain acyl-CoA synthetase (LACS) and diacylglycerol acyltransferase (DGAT) is proposed for ALA enrichment in triacylglycerol (TAG). LACS catalyzes the ATP dependent activation of free fatty acid to form acyl-CoA, which in turn may serve as an acyl-donor in the DGAT-catalyzed reaction leading to TAG. To test this hypothesis, flax LACS and DGAT cDNAs were functionally expressed in Saccharomyces cerevisiae strains to probe their possible involvement in the enrichment of TAG with ALA. Among the identified flax LACSs, LuLACS8A exhibited significantly enhanced specificity for ALA over oleic acid (18:1Delta9cis ) or linoleic acid (18:2Delta9cis,12cis ). Enhanced alpha-linolenoyl-CoA specificity was also observed in the enzymatic assay of flax DGAT2 (LuDGAT2-3), which displayed ~20 times increased preference toward alpha-linolenoyl-CoA over oleoyl-CoA. Moreover, when LuLACS8A and LuDGAT2-3 were co-expressed in yeast, both in vitro and in vivo experiments indicated that the ALA-containing TAG enrichment process was operative between LuLACS8A- and LuDGAT2-3-catalyzed reactions. Overall, the results support the hypothesis that the cooperation between the reactions catalyzed by LACS8 and DGAT2 may represent a route to enrich ALA production in the flax seed oil. PMID- 29523748 TI - High-density lipoprotein protects cardiomyocytes against necrosis induced by oxygen and glucose deprivation through SR-B1, PI3K, and AKT1 and 2. AB - The cardioprotective lipoprotein HDL (high-density lipoprotein) prevents myocardial infarction and cardiomyocyte death due to ischemia/reperfusion injury. The scavenger receptor class B, type 1 (SR-B1) is a high-affinity HDL receptor and has been shown to mediate HDL-dependent lipid transport as well as signaling in a variety of different cell types. The contribution of SR-B1 in cardiomyocytes to the protective effects of HDL on cardiomyocyte survival following ischemia has not yet been studied. Here, we use a model of simulated ischemia (oxygen and glucose deprivation, OGD) to assess the mechanistic involvement of SR-B1, PI3K (phosphatidylinositol-3-kinase), and AKT in HDL-mediated protection of cardiomyocytes from cell death. Neonatal mouse cardiomyocytes and immortalized human ventricular cardiomyocytes, subjected to OGD for 4 h, underwent substantial cell death due to necrosis but not necroptosis or apoptosis. Pretreatment of cells with HDL, but not low-density lipoprotein, protected them against OGD induced necrosis. HDL-mediated protection was lost in cardiomyocytes from SR-B1-/ mice or when SR-B1 was knocked down in human immortalized ventricular cardiomyocytes. HDL treatment induced the phosphorylation of AKT in cardiomyocytes in an SR-B1-dependent manner. Finally, chemical inhibition of PI3K or AKT or silencing of either AKT1 or AKT2 gene expression abolished HDL-mediated protection against OGD-induced necrosis of cardiomyocytes. These results are the first to identify a role of SR-B1 in mediating the protective effects of HDL against necrosis in cardiomyocytes, and to identify AKT activation downstream of SR-B1 in cardiomyocytes. PMID- 29523749 TI - Management of tandem occlusions in acute ischemic stroke - intracranial versus extracranial first and extracranial stenting versus angioplasty alone: a systematic review and meta-analysis. AB - BACKGROUND: Optimal technical approaches of large-vessel anterior circulation acute ischemic strokes with concomitant extracranial internal carotid artery tandem occlusions is controversial. PURPOSE: This systematic review and meta analysis evaluates: the overall outcomes of patients with tandem occlusions treated with second-generation mechanical thrombectomy devices; differences in outcomes of extracranial versus intracranial first approaches; and differences in outcomes of extracranial stenting at time of procedure versus angioplasty alone. METHODS: MEDLINE, EMBASE, and the Web of Science was searched through September 2017 for studies evaluating patients presenting with acute tandem occlusions of the extracranial ICA and intracranial ICA, and/or proximal MCA treated with second-generation mechanical thrombectomy devices. Outcomes were pooled across studies using the random-effects model and expressed as cumulative incidence (event rate) and 95% CI. RESULTS: Thirty-three studies were included in analysis. Overall mRS<=0-2 at 90 days was 47% (95% CI 42% to 51%). No statistical difference was seen in 90-day mRS<=0-2 for patients treated with extracranial versus intracranial first approaches, 53% (95% CI 44% to 61%) vs 49% (95% CI 44% to 57%) (P=0.58). No statistical difference was seen in 90-day mRS<=0-2 for patients treated with extracranial stenting versus angioplasty alone, 49% (95% CI 42% to 56%) vs 49% (95% CI 33% to 65%) (P=0.39). No other statistical differences in outcome or safety were identified. CONCLUSIONS: Nearly half of all tandem occlusion patients treated with mechanical thrombectomy have good neurological outcomes. No statistical differences in outcome are identified between extracranial first versus intracranial first approaches, nor extracranial stenting versus angioplasty alone. PMID- 29523750 TI - Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins. AB - In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD. PMID- 29523752 TI - Drug discovery targeting the mTOR pathway. AB - Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential. Therefore, mTOR lends itself very well as a therapeutic target for innovative cancer treatment. mTOR was initially identified as the target of the antibiotic rapamycin that displayed remarkable antitumor activity in vitro Promising preclinical studies using rapamycin and its derivatives (rapalogs) demonstrated efficacy in many human cancer types, hence supporting the launch of numerous clinical trials aimed to evaluate the real effectiveness of mTOR-targeted therapies. However, rapamycin and rapalogs have shown very limited activity in most clinical contexts, also when combined with other drugs. Thus, novel classes of mTOR inhibitors with a stronger antineoplastic potency have been developed. Nevertheless, emerging clinical data suggest that also these novel mTOR-targeting drugs may have a weak antitumor activity. Here, we summarize the current status of available mTOR inhibitors and highlight the most relevant results from both preclinical and clinical studies that have provided valuable insights into both their efficacy and failure. PMID- 29523753 TI - Prospective use of unmanned aerial vehicles for military medical evacuation in future conflicts. AB - In order to continue to deliver outstanding medical care on the battlefield, the UK Defence Medical Services must continue to adapt, overcome and actively embrace change. One potential area is the rapid proliferation and sophistication of automated and remote systems such as unmanned aerial vehicles (UAVs). UAVs are already used to deliver blood to remote military locations in Afghanistan and defibrillators to those that need them in the USA and Sweden. An area of future opportunity would be to facilitate rapid evacuation of wounded personnel from high intensity, high threat, remote and austere areas directly to specialist care. Such a capability would reduce threat to human life while allowing rapid extraction of casualties from high risk or inaccessible environments straight back to Role 3 care, all of which in these situations is either not possible or carries too much risk using conventional aerial assets. The article aims to highlight a potential future capability, stimulate debate and reflection, all of which is essential for innovation and future organisational development. The potential uses and benefits of UAVs are highlighted including both the challenges and rewards of utilising UAVs for casualty evacuation. Key benefits are reduced risk to human life, cost, ability to insert into areas conventional aircraft cannot and the rapidity of transfer. Challenges are likely to be airspace management, decisions on appropriate level of care to deliver during transit and ultimately user acceptability. The article also highlights that in order to maximise our ability to exploit new technologies, all arms and trades within the military must be involved in collective research and development. Furthermore, sensible corroboration with private companies will further enhance our ability to acquire products that best serve our needs. PMID- 29523754 TI - UK military doctors; stigma, mental health and help-seeking: a comparative cohort study. AB - INTRODUCTION: Studies suggest that medical doctors can suffer from substantial levels of mental ill-health. Little is known about military doctors' mental health and well-being; we therefore assessed attitudes to mental health, self stigma, psychological distress and help-seeking among UK Armed Forces doctors. METHODS: Six hundred and seventy-eight military doctors (response rate 59%) completed an anonymous online survey. Comparisons were made with serving and ex military personnel (n=1448, response rate 84.5%) participating in a mental health related help-seeking survey. Basic sociodemographic data were gathered, and participants completed measures of mental health-related stigmatisation, perceived barriers to care and the 12-Item General Health Questionnaire. All participants were asked if in the last three years they had experienced stress, emotional, mental health, alcohol, family or relationship problems, and whether they had sought help from formal sources. RESULTS: Military doctors reported fewer mental disorder symptoms than the comparison groups. They endorsed higher levels of stigmatising beliefs, negative attitudes to mental healthcare, desire to self-manage and self-stigmatisation than each of the comparison groups. They were most concerned about potential negative effects of and peer perceptions about receiving a mental disorder diagnosis. Military doctors reporting historical and current relationship, and alcohol or mental health problems were significantly and substantially less likely to seek help than the comparison groups. CONCLUSIONS: Although there are a number of study limitations, outcomes suggest that UK military doctors report lower levels of mental disorder symptoms, higher levels of stigmatising beliefs and a lower propensity to seek formal support than other military reference groups. PMID- 29523751 TI - Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome? AB - Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed. PMID- 29523755 TI - Forgetting ourselves: epistemic costs and ethical concerns in mindfulness exercises. AB - Mindfulness exercises are presented as being compatible with almost any spiritual, religious or philosophical beliefs. In this paper, we argue that they in fact involve imagining and conceptualising rather striking and controversial claims about the self, and the self's relationship to thoughts and feelings. For this reason, practising mindfulness exercises is likely to be in tension with many people's core beliefs and values, a tension that should be treated as a downside of therapeutic interventions involving mindfulness exercises, not unlike a side effect. Clients ought to be informed of these metaphysical aspects of the exercises, and mental health providers ought to take them into account in assessing which course of treatment to recommend. Given these concerns, the casual way in which mindfulness exercises are presently distributed by mental health providers to the general public is inappropriate. PMID- 29523756 TI - Resuscitation decisions at the end of life: medical views and the juridification of practice. AB - BACKGROUND: Concerns about decision making related to resuscitation have led to two important challenges in the courts resulting in new legal precedents for decision-making practice. Systematic research investigating the experiences of doctors involved in decisions about resuscitation in light of the recent changes in law remains lacking. AIM: To analyse the practice of resuscitation decision making on hospital wards from the perspectives of doctors. DESIGN: The data presented in this paper were collected as part of a wider research study of end of-life care in an acute hospital setting. Data collection comprised ethnographic non-participant observation on two acute hospital wards and individual interviews with patients, relatives and healthcare professionals caring for patients thought to be approaching the end of life. Data were analysed using a constructivist grounded theory approach. RESULTS: Discussions and decision making about resuscitation present many challenges for those involved on acute medical wards. The data highlight the potential for multiple interpretations of legal precedents, creating misunderstandings that may impact patient care in less positive ways. CONCLUSIONS: This paper provides unique insights into how doctors respond to the changing medico-legal culture and the subsequent effects on patient care. It demonstrates how the juridification of medical practice can occur. It highlights the potential benefit of a structure to support clinicians, patients and relatives in discussing and navigating decisions around care at the end of life in line with the patient's wishes and preferences. Recommendations for future research are made and legal ramifications are discussed. PMID- 29523757 TI - Making medical decisions for an incompetent older adult when both a proxy and an advance directive are available: which is more likely to reflect the older adult's preferences? AB - OBJECTIVES: To investigate which of two sources of information about an older adult's wishes-choices made in an advance directive or proxy's opinion-provides better insight into the older adult's preferences measured in hypothetical clinical situations involving decisional incapacity. METHODS: Secondary analyses of data collected from 157 community-dwelling, decisionally competent adults aged 70 years and over who attended a group information session on advance directives with their proxy. Older adults were invited to complete a directive introduced during the session, designed to express healthcare preferences. An average of 3 months later, older adults were asked during an interview whether they would want to receive each of four medical interventions and what their goals of care would be should they develop one of three sudden health events, assuming that they had severe dementia. Proxies were asked to guess the older adult's answers in each of the seven scenarios. RESULTS: Eighty per cent of the older adults completed the directive. Choices they made in the directive were more in line with the preferences they stated during the interview than were their proxies' guesses at their answers. However, concordance was relatively low, with percentages of agreement ranging from 43% to 83% across scenarios. CONCLUSIONS: Findings suggest that a directive might provide better insight into a person's wishes than the person's proxy, although neither source is perfect. A multifaceted decision making model that includes both sources of information might better serve the interests of older adults who have lost the capacity to make decisions on their own. TRIAL REGISTRATION NUMBER: ISRCTN89993391; Post-results. PMID- 29523758 TI - Correction: Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival. PMID- 29523759 TI - Landscape of Tumor Mutation Load, Mismatch Repair Deficiency, and PD-L1 Expression in a Large Patient Cohort of Gastrointestinal Cancers. AB - The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (P < 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P < 0.0001).Implications: TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy. Mol Cancer Res; 16(5); 805-12. (c)2018 AACR. PMID- 29523760 TI - FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth. AB - Breast cancer is a complex and heterogeneous disease, with distinct histologic features dictating the therapy. Although the clinical outcome of breast cancer patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in breast cancer therapy are needed. As a "faster" alternative to reach this aim, we evaluated whether lamotrigine, a broadly used anticonvulsant, could be "repurposed" as an antitumoral drug in breast cancer. Our data show that lamotrigine inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells (BCC), including hormone-resistant cell models. These effects were associated with cell-cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27Kip1, and p21Waf1/Cip1), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. Lamotrigine also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, lamotrigine induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, lamotrigine significantly reduced tumor growth in vivo, increasing FoxO3a expression.Implications: The anticonvulsant drug lamotrigine shows strong antiproliferative activity on breast cancer, both in vitro and in vivo Thus, drug repurposing could represent a valuable option for a molecularly targeted therapy in breast cancer patients. Mol Cancer Res; 16(6); 923-34. (c)2018 AACR. PMID- 29523761 TI - Identification of Cdk1-LATS-Pin1 as a Novel Signaling Axis in Anti-tubulin Drug Response of Cancer Cells. AB - The Hippo pathway is a signaling cascade that plays important roles in organ size control, tumorigenesis, metastasis, stress response, stem cell differentiation, and renewal during development and tissue homeostasis and mechanotransduction. Recently, it has been observed that loss of the Hippo pathway core component LATS (large tumor suppressor) or overexpression of its downstream targets YAP and its paralog TAZ causes resistance of cancer cells to anti-tubulin drugs. However, YAP and TAZ mediates anti-tubulin drug-induced apoptosis independent of its upstream regulator LATS and the Hippo pathway. Thus, the underlying molecular mechanism of how LATS is involved in the anti-tubulin drug response remains unknown. Proteomic approaches, SILAC and BioID, were used to identify the isomerase Pin1 as a novel LATS-interacting protein after anti-tubulin drug treatment. Treatment with anti tubulin drugs activated cyclin-dependent kinase 1 (CDK1), which phosphorylates LATS2 at five S/T-P motifs that functionally interact with the WW domain of Pin1 and inhibit its antiapoptotic function. Thus, these data identify Cdk1 and Pin1 as a novel upstream regulator and downstream mediator, respectively, of LATS in antitubulin drug response. Further studies on this novel Cdk1-LATS-Pin1 signaling axis will be important for understanding the molecular mechanisms of drug resistance and will provide useful information for targeting of this pathway in the future.Implications: This study provides new insight on the molecular mechanism of anti-tubulin drug resistance and suggests novel therapeutic targets for drug-resistant cancers. Mol Cancer Res; 16(6); 1035-45. (c)2018 AACR. PMID- 29523762 TI - Functional Toll-like Receptor 4 Overexpression in Papillary Thyroid Cancer by MAPK/ERK-Induced ETS1 Transcriptional Activity. AB - Emerging evidence suggests that unregulated Toll-like receptor (TLR) signaling promotes tumor survival signals, thus favoring tumor progression. Here, the mechanism underlying TLR4 overexpression in papillary thyroid carcinomas (PTC) mainly harboring the BRAFV600E mutation was studied. TLR4 was overexpressed in PTC compared with nonneoplastic thyroid tissue. Moreover, paired clinical specimens of primary PTC and its lymph node metastasis showed a significant upregulation of TLR4 levels in the metastatic tissues. In agreement, conditional BRAFV600E expression in normal rat thyroid cells and mouse thyroid tissue upregulated TLR4 expression levels. Furthermore, functional TLR4 expression was demonstrated in PTC cells by increased NF-kappaB transcriptional activity in response to the exogenous TLR4-agonist lipopolysaccharide. Of note, The Cancer Genome Atlas data analysis revealed that BRAFV600E-positive tumors with high TLR4 expression were associated with shorter disease-free survival. Transcriptomic data analysis indicated a positive correlation between TLR4 expression levels and MAPK/ERK signaling activation. Consistently, chemical blockade of MAPK/ERK signaling abrogated BRAFV600E-induced TLR4 expression. A detailed study of the TLR4 promoter revealed a critical MAPK/ERK-sensitive Ets-binding site involved in BRAFV600E responsiveness. Subsequent investigation revealed that the Ets-binding factor ETS1 is critical for BRAFV600E-induced MAPK/ERK signaling-dependent TLR4 gene expression. Together, these data indicate that functional TLR4 overexpression in PTCs is a consequence of thyroid tumor-oncogenic driver dysregulation of MAPK/ERK/ETS1 signaling.Implications: Considering the participation of aberrant NF-kappaB signaling activation in the promotion of thyroid tumor growth and the association of high TLR4 expression with more aggressive tumors, this study suggests a prooncogenic potential of TLR4 downstream signaling in thyroid tumorigenesis. Mol Cancer Res; 16(5); 833-45. (c)2018 AACR. PMID- 29523763 TI - Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma. AB - While high-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants [by DNA next-generation sequencing (NGS) using a 50 gene Ion Torrent panel] and gene expression (using the NanoString PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT). NGS was performed on plasma cell free DNA (cfDNA) on a select group of patients (n = 14) to assess the utility of using cfDNA to monitor these changes. A total of 86 genes had significant changes in RNA expression after NACT. Thirty eight genetic variants (including SNPs) from 6 genes were identified in tumors pre-NACT, while 59 variants from 19 genes were detected in the cfDNA. The number of DNA variants were similar after NACT. Of the 59 variants in the plasma pre NACT, only 6 persisted, whereas 33 of 38 specific variants in the tumor DNA remained unchanged. Pathway analysis showed the most significant alterations in the cell cycle and DNA damage pathways.Implications: Gene expression profiles at the time of interval debulking provide additional genetic information that could help impact treatment decisions after NACT; although, continued collection and analysis of matched tumor and cfDNA from multiple time points are needed to determine the role of cfDNA in the management of HGSOC. Mol Cancer Res; 16(5); 813-24. (c)2018 AACR. PMID- 29523765 TI - Targeting CREB Pathway Suppresses Small Cell Lung Cancer. AB - Small cell lung cancer (SCLC) is the most deadly subtype of lung cancer due to its dismal prognosis. We have developed a lentiviral vector-mediated SCLC mouse model and have explored the role of both the NF-kappaB and CREB families of transcription factors in this model. Surprisingly, induction of NF-kappaB activity, which promotes tumor progression in many cancer types including non small cell lung carcinoma (NSCLC), is dispensable in SCLC. Instead, suppression of NF-kappaB activity in SCLC tumors moderately accelerated tumor development. Examination of gene expression signatures of both mouse and human SCLC tumors revealed overall low NF-kappaB but high CREB activity. Blocking CREB activation by a dominant-negative form of PKA (dnPKA) completely abolished the development of SCLC. Similarly, expression of dnPKA or treatment with PKA inhibitor H89 greatly reduced the growth of SCLC tumors in syngeneic transplantation models. Altogether, our results strongly suggest that targeting CREB is a promising therapeutic strategy against SCLC.Implications: Activity of the transcription factor CREB is elevated in SCLC tumors, which helps to maintain its neuroendocrine signature and cell proliferation. Our results highlight the importance of targeting the CREB pathway to develop new therapeutics to combat SCLC. Mol Cancer Res; 16(5); 825-32. (c)2018 AACR. PMID- 29523766 TI - Nucleoside Diphosphate Kinase-3 (NME3) Enhances TLR5-Induced NFkappaB Activation. AB - Bacterial flagellin is a potent activator of NFkappaB signaling, inflammation, and host innate immunity, and recent data indicate that flagellin represents a novel antitumor ligand acting through toll-like receptor 5 (TLR5) and the NFkappaB pathway to induce host immunity and aid in the clearance of tumor xenografts. To identify innate signaling components of TLR5 responsible for these antitumor effects, a loss-of-function high-throughput screen was employed utilizing carcinoma cells expressing a dynamic NFkappaB bioluminescent reporter stimulated by Salmonella typhimurium expressing flagellin. A live cell screen of a siRNA library targeting 691 known and predicted human kinases to identify novel tumor cell modulators of TLR5-induced NFkappaB activation uncovered several interesting positive and negative candidate regulators not previously recognized, including nucleoside diphosphate kinase 3 (NME3), characterized as an enhancer of signaling responses to flagellin. Targeted knockdown and overexpression assays confirmed the regulatory contribution of NME3 to TLR5-mediated NFkappaB signaling, mechanistically downstream of MyD88. Furthermore, Kaplan-Meier survival analysis showed that NME3 expression correlated highly with TLR5 expression in breast, lung, ovarian, and gastric cancers, and furthermore, high level expression of NME3 increased overall survival for patients with breast, lung, and ovarian cancer, but the opposite in gastric cancer. Together, these data identify a previously unrecognized proinflammatory role for NME3 in signaling downstream of TLR5 that may potentiate cancer immunotherapies.Implications: Proinflammatory signaling mediated by innate immunity engagement of flagellin-activated TLR5 in tumor cells results in antitumor effects through NME3 kinase, a positive downstream regulator of flagellin-mediated NFkappaB signaling, enhancing survival for several human cancers. Mol Cancer Res; 16(6); 986-99. (c)2018 AACR. PMID- 29523764 TI - ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer. AB - Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously, we observed that S1P is exported out of human breast cancer cells by ATP-binding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathologic consequences of these events to breast cancer progression and metastasis have not been elucidated. Here, it is demonstrated that high expression of ABCC1, but not ABCB1, is associated with poor prognosis in breast cancer patients. Overexpression of ABCC1, but not ABCB1, in human MCF7 and murine 4T1 breast cancer cells enhanced S1P secretion, proliferation, and migration of breast cancer cells. Implantation of breast cancer cells overexpressing ABCC1, but not ABCB1, into the mammary fat pad markedly enhanced tumor growth, angiogenesis, and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival of mice. Interestingly, S1P exported via ABCC1 from breast cancer cells upregulated transcription of sphingosine kinase 1 (SPHK1), thus promoting more S1P formation. Finally, patients with breast cancers that express both activated SPHK1 and ABCC1 have significantly shorter disease-free survival. These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.Implication: Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancer worsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression. Mol Cancer Res; 16(6); 1059-70. (c)2018 AACR. PMID- 29523767 TI - Protease Activities Triggered by Ralstonia solanacearum Infection in Susceptible and Tolerant Tomato Lines. AB - Activity-based protein profiling (ABPP) is a powerful proteomic technique to display protein activities in a proteome. It is based on the use of small molecular probes that react with the active site of proteins in an activity dependent manner. We used ABPP to dissect the protein activity changes that occur in the intercellular spaces of tolerant (Hawaii 7996) and susceptible (Marmande) tomato plants in response to R. solanacearum, the causing agent of bacterial wilt, one of the most destructive bacterial diseases in plants. The intercellular space -or apoplast- is the first battlefield where the plant faces R. solanacearum Here, we explore the possibility that the limited R. solanacearum colonization reported in the apoplast of tolerant tomato is partly determined by its active proteome. Our work reveals specific activation of papain-like cysteine proteases (PLCPs) and serine hydrolases (SHs) in the leaf apoplast of the tolerant tomato Hawaii 7996 on R. solanacearum infection. The P69 family members P69C and P69F, and an unannotated lipase (Solyc02g077110.2.1), were found to be post-translationally activated. In addition, protein network analysis showed that deeper changes in network topology take place in the susceptible tomato variety, suggesting that the tolerant cultivar might be more prepared to face R. solanacearum in its basal state. Altogether this work identifies significant changes in the activity of 4 PLCPs and 27 SHs in the tomato leaf apoplast in response to R. solanacearum, most of which are yet to be characterized. Our findings denote the importance of novel proteomic approaches such as ABPP to provide new insights on old and elusive questions regarding the molecular basis of resistance to R. solanacearum. PMID- 29523768 TI - Protein Acetylation and Butyrylation Regulate the Phenotype and Metabolic Shifts of the Endospore-forming Clostridium acetobutylicum. AB - Clostridium acetobutylicum is a strict anaerobic, endospore-forming bacterium, which is used for the production of the high energy biofuel butanol in metabolic engineering. The life cycle of C. acetobutylicum can be divided into two phases, with acetic and butyric acids being produced in the exponential phase (acidogenesis) and butanol formed in the stationary phase (solventogenesis). During the transitional phase from acidogenesis to solventogenesis and latter stationary phase, concentration peaks of the metabolic intermediates butyryl phosphate and acetyl phosphate are observed. As an acyl group donor, acyl phosphate chemically acylates protein substrates. However, the regulatory mechanism of lysine acetylation and butyrylation involved in the phenotype and solventogenesis of C. acetobutylicum remains unknown. In our study, we conducted quantitative analysis of protein acetylome and butyrylome to explore the dynamic change of lysine acetylation and butyrylation in the exponential phase, transitional phase, and stationary phase of C. acetobutylicum Total 458 lysine acetylation sites and 1078 lysine butyrylation sites were identified in 254 and 373 substrates, respectively. Bioinformatics analysis uncovered the similarities and differences between the two acylation modifications in C. acetobutylicum Mutation analysis of butyrate kinase and the central transcriptional factor Spo0A was performed to characterize the unique role of lysine butyrylation in the metabolic pathway and sporulation process of C. acetobutylicum Moreover, quantitative proteomic assays were performed to reveal the relationship between protein features (e.g. gene expression level and lysine acylation level) and metabolites in the three growth stages. This study expanded our knowledge of lysine acetylation and butyrylation in Clostridia and constituted a resource for functional studies on lysine acylation in bacteria. PMID- 29523770 TI - Metabolic regulation of photosynthesis. AB - Photosynthesis is fundamental to biomass production, but is a dynamic process sensitive to environmental constraints. In recent years, approaches to increase biomass and grain yield by altering photosynthetically related processes in the plant have received considerable attention. However, improving biomass yield requires a predictive understanding of the molecular mechanisms that allow photosynthesis to be adjusted. The important roles of metabolic reactions external to those directly involved in photosynthesis are highlighted in this review; however, our major focus is on the routes taken to improve photosynthetic carbon assimilation and to increase photosynthetic efficiency and consequently biomass yield. PMID- 29523771 TI - Glycobiology of syndecan-1 in bacterial infections. AB - Syndecan-1 (Sdc1) is a major cell surface heparan sulfate (HS) proteoglycan of epithelial cells, a cell type targeted by many bacterial pathogens early in their pathogenesis. Loss of Sdc1 in mice is a gain-of-function mutation that significantly decreases the susceptibility to several bacterial infections, suggesting that subversion of Sdc1 is an important virulence strategy. HS glycosaminoglycan (GAG) chains of cell surface Sdc1 promote bacterial pathogenesis by facilitating the attachment of bacteria to host cells. Engagement of cell surface Sdc1 HS chains by bacterial adhesins transmits signal through the highly conserved Sdc1 cytoplasmic domain, which can lead to uptake of intracellular bacterial pathogens. On the other hand, several bacteria that do not require Sdc1 for their attachment and invasion stimulate Sdc1 shedding and exploit the capacity of Sdc1 ectodomain HS GAGs to disarm innate defense mechanisms to evade immune clearance. Recent data suggest that select HS sulfate motifs, and not the overall charge of HS, are important in the inhibition of innate immune mechanisms. Here, we discuss several examples of Sdc1 subversion in bacterial infections. PMID- 29523769 TI - The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders. AB - As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated. mTOR forms the complexes mTOR Complex 1 and mTOR Complex 2 and can impact multiple neurodegenerative disorders that include Alzheimer's disease, Huntington's disease, and Parkinson's disease. SIRT1 can control stem cell proliferation, block neuronal injury through limiting programmed cell death, drive vascular cell survival, and control clinical disorders that include dementia and retinopathy. It is important to recognize that oversight of programmed cell death by mTOR and SIRT1 requires a fine degree of precision to prevent the progression of neurodegenerative disorders. Additional investigations and insights into these pathways should offer effective and safe treatments for neurodegenerative disorders. PMID- 29523773 TI - Phosphoinositide 3-kinase delta (PI3Kdelta) in respiratory disease. AB - Defining features of chronic airway diseases include abnormal and persistent inflammatory processes, impaired airway epithelial integrity and function, and increased susceptibility to recurrent respiratory infections. Phosphoinositide 3 kinases (PI3K) are lipid kinases, which contribute to multiple physiological and pathological processes within the airway, with abnormal PI3K signalling contributing to the pathogenesis of several respiratory diseases. Consequently, the potential benefit of targeting PI3K isoforms has received considerable attention, being viewed as a viable therapeutic option in inflammatory and infectious lung disorders. The class I PI3K isoform, PI3Kdelta (Phosphoinositide 3-kinases delta) is of particular interest given its multiple roles in modulating innate and adaptive immune cell functions, airway inflammation and corticosteroid sensitivity. In this mini-review, we explore the role of PI3Kdelta in airway inflammation and infection, focusing on oxidative stress, ER stress, histone deacetylase 2 and neutrophil function. We also describe the importance of PI3Kdelta in adaptive immune cell function, as highlighted by the recently described Activated PI3K Delta Syndrome, and draw attention to some of the potential clinical applications and benefits of targeting this molecule. PMID- 29523772 TI - Glycosylation pathways at the ocular surface. AB - Glycosylation is a major form of enzymatic modification of organic molecules responsible for multiple biological processes in an organism. The biosynthesis of glycans is controlled by a series of glycosyltransferases, glycosidases and glycan-modifying enzymes that collectively assemble and process monosaccharide moieties into a diverse array of structures. Many studies have provided insight into various pathways of glycosylation at the ocular surface, such as those related to the biosynthesis of mucin-type O-glycans and N-glycans on proteins, but many others still remain largely unknown. This review provides an overview of the different classes of glycans described at the ocular surface focusing on their biosynthetic pathways and biological relevance. A precise understanding of these pathways under physiological and pathological conditions could help identify biomarkers and novel targets for therapeutic intervention. PMID- 29523774 TI - The multiple lives of DEAD-box RNA helicase DP103/DDX20/Gemin3. AB - Gemin3, also known as DDX20 or DP103, is a DEAD-box RNA helicase which is involved in more than one cellular process. Though RNA unwinding has been determined in vitro, it is surprisingly not required for all of its activities in cellular metabolism. Gemin3 is an essential gene, present in Amoeba and Metazoa. The highly conserved N-terminus hosts the helicase core, formed of the helicase- and DEAD-domains, which, based on crystal structure determination, have key roles in RNA binding. The C-terminus of Gemin3 is highly divergent between species and serves as the interaction site for several accessory factors that could recruit Gemin3 to its target substrates and/or modulate its function. This review article focuses on the known roles of Gemin3, first as a core member of the survival motor neuron (SMN) complex, in small nuclear ribonucleoprotein biogenesis. Although mechanistic details are lacking, a critical function for Gemin3 in this pathway is supported by numerous in vitro and in vivo studies. Gene expression activities of Gemin3 are next underscored, mainly messenger ribonucleoprotein trafficking, gene silencing via microRNA processing, and transcriptional regulation. The involvement of Gemin3 in abnormal cell signal transduction pathways involving p53 and NF-kappaB is also highlighted. Finally, the clinical implications of Gemin3 deregulation are discussed including links to spinal muscular atrophy, poliomyelitis, amyotrophic lateral sclerosis, and cancer. Impressive progress made over the past two decades since the discovery of Gemin3 bodes well for further work that refines the mechanism(s) underpinning its multiple activities. PMID- 29523775 TI - A Case of Levofloxacin-Induced Hepatotoxicity. AB - BACKGROUND Levofloxacin covers a broad spectrum of pathogens and is readily prescribed by clinicians. Hepatotoxicity is a known but unusual complication of levofloxacin use. Here, we present a case of severe transaminitis caused by levofloxacin. CASE REPORT A young man in his thirties with a history of asthma, chronic alcoholism, methamphetamine intravenous drug abuse (IVDA), and non compliant insulin-dependent diabetes mellitus (IDDM) presented to an emergency department with suicidal ideation. Vital signs were stable and the patient was noted to have cellulitis of the right forearm, for which cultures were drawn, and he received IV clindamycin. He was admitted to behavioral medicine for further care. Blood cultures were positive for gram-negative rods and he was transferred to the medicine ward. Cultures eventually grew Brevundimonas diminuta. Clindamycin was discontinued and he was started on levofloxacin. Transaminase levels measured soon after levofloxacin administration showed aminotransferase levels raised to approximately 50 times baseline within a few days. Levofloxacin was discontinued due to concern about drug-induced hepatotoxicity. After discontinuation, transaminase levels decreased immediately. Work-up for other causes of transaminitis revealed no other etiology. CONCLUSIONS Clinicians should remain mindful that levofloxacin can induce hepatotoxicity in rare cases. In patients presenting with acute liver injury who have recently taken levofloxacin, it would be wise to remain cognizant of the possibility of levofloxacin-induced hepatotoxicity. PMID- 29523776 TI - Combination of Luteolin and Solifenacin Improves Urinary Dysfunction Induced by Diabetic Cystopathy in Rats. AB - BACKGROUND The purpose of the present study was to assess the effect of luteolin and solifenacin on diabetic cystopathy (DCP) and to investigate the mechanism of action. A novel link between the overexpression of c-Kit in the bladder and voiding dysfunction was identified in rats with DCP. MATERIAL AND METHODS A rat model of DCP was successfully established by intraperitoneal injection of streptozotocin and a diet high in glucose and lipids, and animals were treated with luteolin and solifenacin. The effect of luteolin and solifenacin on urinary dysfunction in DCP rats was investigated by assessing bladder pressure and performing a volume test. The protein levels of c-Kit, stem cell factor (SCF), p110, and phosphorylated p110 in the bladder were detected by Western blot analysis and immunohistochemical staining. RESULTS In DCP rats, the protein levels of c-Kit, SCF and phosphorylated p110 in the bladder were significantly increased. However, oral treatment of DCP rats with luteolin combined with solifenacin resulted in effective improvement of overactive bladder and reduced the protein expression of c-Kit, SCF, and phosphorylated p110. Moreover, the effect of luteolin combined with solifenacin on maximum voiding pressure and residual urine volume was improved compared to that of luteolin alone. CONCLUSIONS Luteolin improved overactive bladder in DCP rats, which may be due to SCF/c-kit inhibition, as well as the downregulation of the phosphoinositide-3 kinase signaling pathway. Moreover, solifenacin enhanced the potential pharmacological effect of luteolin in the treatment of DCP. PMID- 29523777 TI - Intracellular Desmoglein-2 cleavage sensitizes epithelial cells to apoptosis in response to pro-inflammatory cytokines. AB - Desmosomal cadherins mediate intercellular adhesion and have also been shown to regulate homeostatic signaling in epithelial cells. We have previously reported that select pro-inflammatory cytokines induce Dsg2 ectodomain cleavage and shedding from intestinal epithelial cells (IECs). Dsg2 extracellular cleaved fragments (Dsg2 ECF) function to induce paracrine pro-proliferative signaling in epithelial cells. In this study, we show that exposure of IECs to pro inflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) resulted in Dsg2 intracellular cleavage and generation of a ~55 kDa fragment (Dsg2 ICF). Dsg2 intracellular cleavage is mediated by caspase-8 and occurs prior to Dsg2 extracellular cleavage and the execution of apoptosis. Expression of exogenous Dsg2 ICF in model IECs resulted in increased sensitivity to apoptotic stimuli and apoptosis execution. Additionally, expression of the Dsg2 ICF repressed the anti-apoptotic Bcl-2 family member proteins Bcl-XL and Mcl1. Taken together, our findings identify a novel mechanism by which pro inflammatory mediators induce modification of Dsg2 to activate apoptosis and eliminate damaged cells, while also promoting release of Dsg2 ECF that promotes proliferation of neighboring cells and epithelial barrier recovery. PMID- 29523778 TI - Publisher Correction: Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. AB - In the original version of this Article the colour key for the amino acid enrichment score was inadvertently omitted from the lower panel of Figure 5b during the production process. This has now been corrected in the PDF and HTML versions of the Article. PMID- 29523779 TI - Agreement between hospital and primary care on diagnostic labeling for COPD and heart failure in Toronto, Canada: a cross-sectional observational study. AB - Patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF) are frequently cared for in hospital and in primary care settings. We studied labeling agreement for COPD and HF for patients seen in both settings in Toronto, Canada. This was a retrospective observational study using linked hospital primary care electronic data from 70 family physicians. Patients were 20 years of age or more and had at least one visit in both settings between 1 January 2012 and 31 December 2014. We recorded labeling concordance and associations with clinical factors. We used capture-recapture models to estimate the size of the populations. COPD concordance was 34%; the odds ratios (ORs) of concordance increased with aging (OR 1.84 for age 75+ vs. <65, 95% CI 0.92-3.69) and more inpatient admissions (OR 2.89 for 3+ visits vs. 0 visits, 95% CI 1.59-5.26). HF concordance was 33%; the ORs of concordance decreased with aging (OR 0.39 for 75+ vs. <65, 95% CI 0.18-0.86) and increased with more admissions (OR = 2.39; 95% CI 1.33-4.30 for 3+ visits vs. 0 visits). Based on capture-recapture models, 21-24% additional patients with COPD and 18-20% additional patients with HF did not have a label in either setting. The primary care prevalence was estimated as 748 COPD patients and 834 HF patients per 100,000 enrolled adult patients. Agreement levels for COPD and HF were low and labeling was incomplete. Further research is needed to improve labeling for these conditions. PMID- 29523780 TI - Author Correction: Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations. AB - In the original version of this Article, the Acknowledgement section omitted financial support from the Deutsche Forschungsgemeinschaft grant SFB 958/A4. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 29523781 TI - ELF3 promotes epithelial-mesenchymal transition by protecting ZEB1 from miR-141 3p-mediated silencing in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and currently the third leading cause of cancer-related deaths, worldwide. Epithelial mesenchymal transition (EMT) plays a major role in HCC progression. In this study, we first found that the expression of E74-like ETS transcription factor 3 (ELF3), a member of the E-twenty-six family of transcription factors, was increased in HCC tissues, and that ELF3 overexpression was associated with poor prognoses for HCC patients. Gain-of-function and loss-of-function studies revealed that increased ELF3 expression promoted HCC cell proliferation, migration, and invasion, while these processes were inhibited when ELF3 was silenced. Additionally, ELF3 was found to promote EMT, which we demonstrated through decreased E-cadherin expression and increased N-cadherin and fibronectin expression. ELF3 knockdown reversed EMT via repressing ZEB1 expression through miR-141-3p upregulation. Chromatin immunoprecipitation assays revealed that ELF3 bound to the miR-141-3p promoter, suppressing miR-141-3p expression. Taken together, our data show that ELF3 repressed E-cadherin and promoted EMT in HCC cells by suppressing miR-141-3p, thereby activating ZEB1. Thus, ELF3 may be a potential prognostic biomarker and/or therapeutic target for HCC. PMID- 29523782 TI - The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update. AB - The contact sites that the endoplasmic reticulum (ER) forms with mitochondria, called mitochondria-associated membranes (MAMs), are a hot topic in biological research, and both their molecular determinants and their numerous roles in several signaling pathways are is continuously evolving. MAMs allow the exchange between both organelles of lipids, calcium (Ca2+), and likely reactive oxygen species, allowing adaptations of both cellular bioenergetics and cell fate depending of cellular needs or stresses. Therefore, it is not surprising that MAMs affect cellular metabolism. Nevertheless, recent arguments suggest that MAMs could also act as key hub of hormonal and/or nutrient signaling in several insulin-sensitive tissues, pointing a specific role of MAMs in the control of glucose homeostasis. Here, I provide a brief review and update on current key signaling roles of the MAMs in the control of glucose homeostasis in both health and metabolic diseases. Particularly, the relevance of ER-mitochondria miscommunication in the disruption of glucose homeostasis is analyzed in details in the liver, skeletal muscle, adipose tissue, and beta cells of the pancreas. PMID- 29523783 TI - Real-world data on prognosis and outcome of primary plasma cell leukemia in the era of novel agents: a multicenter national study by the Greek Myeloma Study Group. AB - We have studied the efficacy and the prognostic impact of novel agents in 50 primary plasma cell leukemia (pPCL) patients registered in our database. Eighty percent of patients were treated upfront with novel agent-based combinations; 40% underwent autologous stem cell transplantation (ASCT). Objective response rate was 76; 38% achieved at least very good partial response (>=vgPR) and this correlated significantly with bortezomib-based therapy plus ASCT. At the time of evaluation, 40 patients had died. Early mortality rate (<=1 month) was 6%. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 18 months respectively, both significantly longer in patients treated with bortezomib-based therapy + ASCT vs. others (PFS: 18 vs. 9 months; p = 0.004, OS: 48 vs. 14 months; p = 0.007). Bortezomib-based therapy + ASCT predicted for OS in univariate analysis. In multivariate analysis, achievement of >=vgPR and LDH >= 300 U/L were significant predictors for OS. These real-world data, based on one of the largest reported national multicenter series of pPCL patients treated mostly with novel agents support that, among the currently approved induction therapies, bortezomib-based regimens are highly effective and reduce the rate of early mortality whereas in combination with ASCT consolidation they prolong OS. PMID- 29523785 TI - Brain and eyes of Kerygmachela reveal protocerebral ancestry of the panarthropod head. AB - Recent discoveries of fossil nervous tissue in Cambrian fossils have allowed researchers to trace the origin and evolution of the complex arthropod head and brain based on stem groups close to the origin of the clade, rather than on extant, highly derived members. Here we show that Kerygmachela from Sirius Passet, North Greenland, a primitive stem-group euarthropod, exhibits a diminutive (protocerebral) brain that innervates both the eyes and frontal appendages. It has been surmised, based on developmental evidence, that the ancestor of vertebrates and arthropods had a tripartite brain, which is refuted by the fossil evidence presented here. Furthermore, based on the discovery of eyes in Kerygmachela, we suggest that the complex compound eyes in arthropods evolved from simple ocelli, present in onychophorans and tardigrades, rather than through the incorporation of a set of modified limbs. PMID- 29523784 TI - MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state. AB - Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers. PMID- 29523786 TI - CDK6 inhibits white to beige fat transition by suppressing RUNX1. AB - Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6 -/- mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1alpha by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases. PMID- 29523787 TI - Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. AB - Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFbeta production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFbeta-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFbeta as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies. PMID- 29523788 TI - SLIT2/ROBO1 axis contributes to the Warburg effect in osteosarcoma through activation of SRC/ERK/c-MYC/PFKFB2 pathway. AB - Cellular metabolic reprogramming is the main characteristic of cancer cells and identification of targets using this metabolic pattern is extremely important to treat cancers, such as osteosarcoma (OS). In this study, SLIT2 and ROBO1 were upregulated in OS, and higher expression of ROBO1 was associated with worse overall survival rate. Furthermore, in vitro and in vivo experiments demonstrated that the SLIT2/ROBO1 axis promotes proliferation, inhibits apoptosis, and contributes to the Warburg effect in OS cells. Mechanistically, the SLIT2/ROBO1 axis exerted cancer-promoting effects on OS via activation of the SRC/ERK/c MYC/PFKFB2 pathway. Taken together, the findings reveal a previously unappreciated function of SLIT2/ROBO1 signaling in OS, which is intertwined with metabolic alterations that promote cancer progression. Targeting the SLIT2/ROBO1 axis may be a potential therapeutic approach for patients with OS. PMID- 29523790 TI - MRN complex-dependent recruitment of ubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways. AB - Mutations in BLM in Bloom Syndrome patients predispose them to multiple types of cancers. Here we report that BLM is recruited in a biphasic manner to annotated DSBs. BLM recruitment is dependent on the presence of NBS1, MRE11 and ATM. While ATM activity is essential for BLM recruitment in early phase, it is dispensable in late phase when MRE11 exonuclease activity and RNF8-mediated ubiquitylation of BLM are the key determinants. Interaction between polyubiquitylated BLM and NBS1 is essential for the helicase to be retained at the DSBs. The helicase activity of BLM is required for the recruitment of HR and c-NHEJ factors onto the chromatin in S- and G1-phase, respectively. During the repair phase, BLM inhibits HR in S-phase and c-NHEJ in G1-phase. Consequently, inhibition of helicase activity of BLM enhances the rate of DNA alterations. Thus BLM utilizes its pro- and anti-repair functions to maintain genome stability. PMID- 29523789 TI - Insc:LGN tetramers promote asymmetric divisions of mammary stem cells. AB - Asymmetric cell divisions balance stem cell proliferation and differentiation to sustain tissue morphogenesis and homeostasis. During asymmetric divisions, fate determinants and niche contacts segregate unequally between daughters, but little is known on how this is achieved mechanistically. In Drosophila neuroblasts and murine mammary stem cells, the association of the spindle orientation protein LGN with the stem cell adaptor Inscuteable has been connected to asymmetry. Here we report the crystal structure of Drosophila LGN in complex with the asymmetric domain of Inscuteable, which reveals a tetrameric arrangement of intertwined molecules. We show that Insc:LGN tetramers constitute stable cores of Par3-Insc LGN-GalphaiGDP complexes, which cannot be dissociated by NuMA. In mammary stem cells, the asymmetric domain of Insc bound to LGN:GalphaiGDP suffices to drive asymmetric fate, and reverts aberrant symmetric divisions induced by p53 loss. We suggest a novel role for the Insc-bound pool of LGN acting independently of microtubule motors to promote asymmetric fate specification. PMID- 29523791 TI - Ultrafast nonlinear optical response of Dirac fermions in graphene. AB - The speed of solid-state electronic devices, determined by the temporal dynamics of charge carriers, could potentially reach unprecedented petahertz frequencies through direct manipulation by optical fields, consisting in a million-fold increase from state-of-the-art technology. In graphene, charge carrier manipulation is facilitated by exceptionally strong coupling to optical fields, from which stems an important back-action of photoexcited carriers. Here we investigate the instantaneous response of graphene to ultrafast optical fields, elucidating the role of hot carriers on sub-100 fs timescales. The measured nonlinear response and its dependence on interaction time and field polarization reveal the back-action of hot carriers over timescales commensurate with the optical field. An intuitive picture is given for the carrier trajectories in response to the optical-field polarization state. We note that the peculiar interplay between optical fields and charge carriers in graphene may also apply to surface states in topological insulators with similar Dirac cone dispersion relations. PMID- 29523792 TI - Months-long real-time generation of a time scale based on an optical clock. AB - Time scales consistently provide precise time stamps and time intervals by combining atomic frequency standards with a reliable local oscillator. Optical frequency standards, however, have not been applied to the generation of time scales, although they provide superb accuracy and stability these days. Here, by steering an oscillator frequency based on the intermittent operation of a 87Sr optical lattice clock, we realized an "optically steered" time scale TA(Sr) that was continuously generated for half a year. The resultant time scale was as stable as International Atomic Time (TAI) with its accuracy at the 10-16 level. We also compared the time scale with TT(BIPM16). TT(BIPM) is computed in deferred time each January based on a weighted average of the evaluations of the frequency of TAI using primary and secondary frequency standards. The variation of the time difference TA(Sr) - TT(BIPM16) was 0.79 ns after 5 months, suggesting the compatibility of using optical clocks for time scale generation. The steady signal also demonstrated the capability to evaluate one-month mean scale intervals of TAI over all six months with comparable uncertainties to those of primary frequency standards (PFSs). PMID- 29523793 TI - Improved Graph Embedding for Robust Recognition with outliers. AB - Artifacts in biomedical signal recordings, such as gene expression, sonar image and electroencephalogram, have a great influence on the related research because the artifacts with large value usually break the neighbor structure in the datasets. However, the conventional graph embedding (GE) used for dimension reduction such as linear discriminant analysis, principle component analysis and locality preserving projections is essentially defined in the L2 norm space and is prone to the presence of artifacts, resulting in biased sub-structural features. In this work, we defined graph embedding in the L1 norm space and used the maximization strategy to solve this model with the aim of restricting the influence of outliers on the dimension reduction of signals. The quantitative evaluation with different outlier conditions demonstrates that an L1 norm-based GE structure can estimate hyperplanes, which are more stable than those of conventional GE-based methods. The applications to a variety of datasets also show that the proposed L1 GE is more robust to outlier influence with higher classification accuracy estimated. The proposed L1 GE may be helpful for capturing reliable mapping information from the datasets that have been contaminated with outliers. PMID- 29523794 TI - Complementarity of assembly-first and mapping-first approaches for alternative splicing annotation and differential analysis from RNAseq data. AB - Genome-wide analyses estimate that more than 90% of multi exonic human genes produce at least two transcripts through alternative splicing (AS). Various bioinformatics methods are available to analyze AS from RNAseq data. Most methods start by mapping the reads to an annotated reference genome, but some start by a de novo assembly of the reads. In this paper, we present a systematic comparison of a mapping-first approach (FARLINE) and an assembly-first approach (KISSPLICE). We applied these methods to two independent RNAseq datasets and found that the predictions of the two pipelines overlapped (70% of exon skipping events were common), but with noticeable differences. The assembly-first approach allowed to find more novel variants, including novel unannotated exons and splice sites. It also predicted AS in recently duplicated genes. The mapping-first approach allowed to find more lowly expressed splicing variants, and splice variants overlapping repeats. This work demonstrates that annotating AS with a single approach leads to missing out a large number of candidates, many of which are differentially regulated across conditions and can be validated experimentally. We therefore advocate for the combined use of both mapping-first and assembly first approaches for the annotation and differential analysis of AS from RNAseq datasets. PMID- 29523795 TI - Factors associated with negative T-SPOT.TB results among smear-negative tuberculosis patients in China. AB - We compared the positive rates of T-SPOT.TB and bacterial culture in the smear negative PTB, and analyzed the factors affecting the results of negative T SPOT.TB and bacterial culture. Retrospective evaluation of data from smear negative PTB patients who underwent T-SPOT.TB and bacterial culture were done. The agreement and concordance were analyzed between T-SPOT.TB and bacterial culture. Multivariable logistic regression analysis was used to explore the factors associated with positive results of T-SPOT.TB and bacterial culture in smear-negative PTB. 858 eligible smear-negative PTB patients were included in the study. The agreement rate was 25.6% (22.7~28.5%) between T-SPOT.TB and bacterial culture in smear- negative PTB patients. The positive rate of T-SPOT.TB was higher than that of bacterial culture in smear-negative PTB patients (p < 0.001). There were nearly no concordance between T-SPOT.TB and bacterial culture (p > 0.05). Using multivariable logistic regression analysis we found that older age >= 60 years (OR = 0.469, 95% CI: 0.287-0.768) and decreased albumin (OR = 0.614, 95% CI: 0.380-0.992) were associated with negative diagnostic results of T SPOT.TB in smear-negative PTB patients. Female (OR = 0.654, 95% CI: 0.431-0.992) were associated with negative diagnostic results of bacteria culture in smear negative PTB patients. Our results indicated that the older age and decreased albumin were independently associated with negative T-SPOT.TB responses. PMID- 29523796 TI - Glyco-engineered Long Acting FGF21 Variant with Optimal Pharmaceutical and Pharmacokinetic Properties to Enable Weekly to Twice Monthly Subcutaneous Dosing. AB - Pharmacological administration of FGF21 analogues has shown robust body weight reduction and lipid profile improvement in both dysmetabolic animal models and metabolic disease patients. Here we report the design, optimization, and characterization of a long acting glyco-variant of FGF21. Using a combination of N-glycan engineering for enhanced protease resistance and improved solubility, Fc fusion for further half-life extension, and a single point mutation for improving manufacturability in Chinese Hamster Ovary cells, we created a novel FGF21 analogue, Fc-FGF21[R19V][N171] or PF-06645849, with substantially improved solubility and stability profile that is compatible with subcutaneous (SC) administration. In particular, it showed a low systemic clearance (0.243 mL/hr/kg) and long terminal half-life (~200 hours for intact protein) in cynomolgus monkeys that approaches those of monoclonal antibodies. Furthermore, the superior PK properties translated into robust improvement in glucose tolerance and the effects lasted 14 days post single SC dose in ob/ob mice. PF 06645849 also caused greater body weight loss in DIO mice at lower and less frequent SC doses, compared to previous FGF21 analogue PF-05231023. In summary, the overall PK/PD and pharmaceutical profile of PF-06645849 offers great potential for development as weekly to twice-monthly SC administered therapeutic for chronic treatment of metabolic diseases. PMID- 29523797 TI - Intensified summer monsoon and the urbanization of Indus Civilization in northwest India. AB - Today the desert margins of northwest India are dry and unable to support large populations, but were densely occupied by the populations of the Indus Civilization during the middle to late Holocene. The hydroclimatic conditions under which Indus urbanization took place, which was marked by a period of expanded settlement into the Thar Desert margins, remains poorly understood. We measured the isotopic values (delta18O and deltaD) of gypsum hydration water in paleolake Karsandi sediments in northern Rajasthan to infer past changes in lake hydrology, which is sensitive to changing amounts of precipitation and evaporation. Our record reveals that relatively wet conditions prevailed at the northern edge of Rajasthan from ~5.1 +/- 0.2 ka BP, during the beginning of the agricultural-based Early Harappan phase of the Indus Civilization. Monsoon rainfall intensified further between 5.0 and 4.4 ka BP, during the period when Indus urban centres developed in the western Thar Desert margin and on the plains of Haryana to its north. Drier conditions set in sometime after 4.4 ka BP, and by ~3.9 ka BP an eastward shift of populations had occurred. Our findings provide evidence that climate change was associated with both the expansion and contraction of Indus urbanism along the desert margin in northwest India. PMID- 29523798 TI - Oat evolution revealed in the maternal lineages of 25 Avena species. AB - Cultivated hexaploid oat has three different sets of nuclear genomes (A, C, D), but its evolutionary history remains elusive. A multiplexed shotgun sequencing procedure was explored to acquire maternal phylogenetic signals from chloroplast and mitochondria genomes of 25 Avena species. Phylogenetic analyses of the acquired organelle SNP data revealed a new maternal pathway towards hexaploids of oat genome evolution involving three diploid species (A. ventricosa, A. canariensis and A. longiglumis) and two tetraploid species (A. insularis and A. agadiriana). Cultivated hexaploid A. sativa acquired its maternal genome from an AC genome tetraploid close to A. insularis. Both AC genome A. insularis and AB genome A. agadiriana obtained a maternal genome from an ancient A, not C, genome diploid close to A. longiglumis. Divergence dating showed the major divergences of C genome species 19.9-21.2 million years ago (Mya), of the oldest A genome A. canariensis 13-15 Mya, and of the clade with hexaploids 8.5-9.5 Mya. These findings not only advance our knowledge on oat genome evolution, but also have implications for oat germplasm conservation and utilization in breeding. PMID- 29523799 TI - High-affinity ligands of the colchicine domain in tubulin based on a structure guided design. AB - Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub MUM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K b value of 2.87 * 108 M-1 which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand. PMID- 29523800 TI - Cerebrospinal fluid neurogranin and TREM2 in Huntington's disease. AB - Biomarkers of Huntington's disease (HD) in cerebrospinal fluid (CSF) could be of value in elucidating the biology of this genetic neurodegenerative disease, as well as in the development of novel therapeutics. Deranged synaptic and immune function have been reported in HD, and concentrations of the synaptic protein neurogranin and the microglial protein TREM2 are increased in other neurodegenerative diseases. We therefore used ELISAs to quantify neurogranin and TREM2 in CSF samples from HD mutation carriers and controls. CSF neurogranin concentration was not significantly altered in HD compared to controls, nor was it significantly associated with disease burden score, total functional capacity or motor score. An apparent increase in CSF TREM2 in manifest HD was determined to be due to increasing TREM2 with age. After age adjustment, there was no significant alteration of TREM2 in either HD group, nor any association with motor, functional or cognitive score, or brain volume quantified by MRI. Both analyses were well-powered, and sample size calculations indicated that several thousand samples per group would be needed to prove that disease-associated alterations do in fact exist. We conclude that neither neurogranin nor TREM2 is a useful biofluid biomarker for disease processes in Huntington's disease. PMID- 29523801 TI - Small-RNA sequencing identifies dynamic microRNA deregulation during skeletal muscle lineage progression. AB - Skeletal muscle satellite cells are quiescent adult resident stem cells that activate, proliferate and differentiate to generate myofibres following injury. They harbour a robust proliferation potential and self-renewing capacity enabling lifelong muscle regeneration. Although several classes of microRNAs were shown to regulate adult myogenesis, systematic examination of stage-specific microRNAs during lineage progression from the quiescent state is lacking. Here we provide a genome-wide assessment of the expression of small RNAs during the quiescence/activation transition and differentiation by RNA-sequencing. We show that the majority of small RNAs present in quiescent, activated and differentiated muscle cells belong to the microRNA class. Furthermore, by comparing expression in distinct cell states, we report a massive and dynamic regulation of microRNAs, both in numbers and amplitude, highlighting their pivotal role in regulation of quiescence, activation and differentiation. We also identify a number of microRNAs with reliable and specific expression in quiescence including several maternally-expressed miRNAs generated at the imprinted Dlk1-Dio3 locus. Unexpectedly, the majority of class-switching miRNAs are associated with the quiescence/activation transition suggesting a poised program that is actively repressed. These data constitute a key resource for functional analyses of miRNAs in skeletal myogenesis, and more broadly, in the regulation of stem cell self-renewal and tissue homeostasis. PMID- 29523802 TI - Polygonumins A, a newly isolated compound from the stem of Polygonum minus Huds with potential medicinal activities. AB - Polygonumins A, a new compound, was isolated from the stem of Polygonum minus. Based on NMR results, the compound's structure is identical to that of vanicoside A, comprising four phenylpropanoid ester units and a sucrose unit. The structure differences were located at C-3""'. The cytotoxic activity of polygonumins A was evaluated on several cancer cell lines by a cell viability assay using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The compound showed the highest antiproliferative (p < 0.05) activities against K562 (Human Leukaemia Cell Line), MCF7 (Human breast adenocarcinoma cell line), and HCT116 (Colorectal cancer cells) cells. Cytotoxic studies against V79 4 cells were carried out and showed that polygonumins A was toxic at 50 ug/ml, suggesting that this compound may be used as an anticancer drug without affecting normal cells. Polygonumins A also showed promising activity as an HIV-1 protease inhibitor with 56% relative inhibition. Molecular docking results indicated that the compound possesses high binding affinity towards the HIV protease over the low binding free energy range of -10.5 to -11.3 kcal/mol. P. minus is used in Malaysian traditional medicine for the treatment of tumour cells. This is the first report on the use of P. minus as an HIV-1 protease inhibitor. PMID- 29523803 TI - Automated high throughput animal CO1 metabarcode classification. AB - We introduce a method for assigning names to CO1 metabarcode sequences with confidence scores in a rapid, high-throughput manner. We compiled nearly 1 million CO1 barcode sequences appropriate for classifying arthropods and chordates. Compared to our previous Insecta classifier, the current classifier has more than three times the taxonomic coverage, including outgroups, and is based on almost five times as many reference sequences. Unlike other popular rDNA metabarcoding markers, we show that classification performance is similar across the length of the CO1 barcoding region. We show that the RDP classifier can make taxonomic assignments about 19 times faster than the popular top BLAST hit method and reduce the false positive rate from nearly 100% to 34%. This is especially important in large-scale biodiversity and biomonitoring studies where datasets can become very large and the taxonomic assignment problem is not trivial. We also show that reference databases are becoming more representative of current species diversity but that gaps still exist. We suggest that it would benefit the field as a whole if all investigators involved in metabarocoding studies, through collaborations with taxonomic experts, also planned to barcode representatives of their local biota as a part of their projects. PMID- 29523804 TI - Mechanisms by which Bisphenol A affect the photosynthetic apparatus in cucumber (Cucumis sativus L.) leaves. AB - Bisphenol A (BPA), a widely distributed pollutant, suppresses photosynthesis in leaves. In previous studies on higher plants, the plants were treated by BPA through irrigation to root. This method cannot distinguish whether the BPA directly suppresses photosynthesis in leaves, or indirectly influences photosynthesis through affecting the function of root. Here, only the leaves but not the roots of cucumber were infiltrated with BPA solution. The photosystem II and I (PSII, PSI) were insensitive to BPA under darkness. BPA aggravated the PSII but not the PSI photoinhibition under light. BPA also inhibited CO2 assimilation, and the effect of BPA on PSII photoinhibition disappeared when the CO2 assimilation was blocked. The H2O2 accumulated in BPA-treated leaves under light. And the BPA-caused PSII photoinhibition was prevented under low (2%) O2. We also proved that the BPA-caused PSII photoinhibition depend on the turnover of D1 protein. In conclusion, this study proved that BPA could directly suppress photosynthesis in leaves, however, BPA does not damage PSII directly, but inhibits CO2 assimilation and over-reduces the electron transport chain under light, which increases the production of reactive oxygen species (H2O2), the over accumulated ROS inhibits the turnover of D1 protein and consequently aggravates PSII photoinhibition. PMID- 29523805 TI - Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome. AB - Down syndrome, caused by trisomy 21, is characterized by a variety of medical conditions including intellectual impairments, cardiovascular defects, blood cell disorders and pre-mature aging phenotypes. Several somatic stem cell populations are dysfunctional in Down syndrome and their deficiencies may contribute to multiple Down syndrome phenotypes. Down syndrome is associated with muscle weakness but skeletal muscle stem cells or satellite cells in Down syndrome have not been investigated. We find that a failure in satellite cell expansion impairs muscle regeneration in the Ts65Dn mouse model of Down syndrome. Ts65Dn satellite cells accumulate DNA damage and over express Usp16, a histone de-ubiquitinating enzyme that regulates the DNA damage response. Impairment of satellite cell function, which further declines as Ts65Dn mice age, underscores stem cell deficiencies as an important contributor to Down syndrome pathologies. PMID- 29523806 TI - Increased intracellular activity of MP1102 and NZ2114 against Staphylococcus aureus in vitro and in vivo. AB - Treatment of Staphylococcus aureus infections remains very difficult due to its capacity to survive intracellularly and its multidrug resistance. In this study, the extracellular/intracellular activities of plectasin derivatives-MP1102/NZ2114 were investigated against three methicillin-susceptible/-resistant S. aureus (MSSA/MRSA) strains in RAW 264.7 macrophages and mice to overcome poor intracellular activity. Antibacterial activities decreased 4-16-fold under a mimic phagolysosomal environment. MP1102/NZ2114 were internalized into the cells via clathrin-mediated endocytosis and macropinocytosis and distributed in the cytoplasm; they regulated tumor necrosis factor-alpha, interleukin-1beta and interleukin-10 levels. The extracellular maximal relative efficacy (Emax) values of MP1102/NZ2114 towards the three S. aureus strains were >5-log decrease in colony forming units (CFU). In the methicillin-resistant and virulent strains, MP1102/NZ2114 exhibited intracellular bacteriostatic efficacy with an Emax of 0.42-1.07-log CFU reduction. In the MSSA ATCC25923 mouse peritonitis model, 5 mg/kg MP1102/NZ2114 significantly reduced the bacterial load at 24 h, which was superior to vancomycin. In MRSA ATCC43300, their activity was similar to that of vancomycin. The high virulent CVCC546 strain displayed a relatively lower efficiency, with log CFU decreases of 2.88-2.91 (total), 3.41-3.50 (extracellular) and 2.11-2.51 (intracellular) compared with vancomycin (3.70). This suggests that MP1102/NZ2114 can be used as candidates for treating intracellular S. aureus. PMID- 29523807 TI - Ultraviolet-irradiated endothelial cells secrete stem cell factor and induce epidermal pigmentation. AB - Ultraviolet (UV)-associated hyperpigmented skins are characterized with increased vasculature underlying pigmentation, suggestive of the possible biological role of endothelial cells in the regulation of skin pigmentation during UV irradiation. In this study, we showed that UV-irradiated endothelial cells significantly increased the pigmentation of melanocytes through epithelial mesenchymal crosstalk. The stimulatory effect of endothelial cells was further demonstrated using ex vivo human skin. RNA sequence analysis and enzyme-linked immunosorbent assay showed that endothelial cells secrete more stem cell factor (SCF) upon UV irradiation than non-irradiated cells. The increased pigmentation elicited by endothelial cells was abrogated following inhibition of SCF/c-KIT signaling. Together these results suggest that endothelial cells are activated upon UV exposure to release melanogenic factors such as SCF, which contributes to the development of skin hyperpigmentation during chronic sun exposure. PMID- 29523808 TI - Grb2 and GRAP connect the B cell antigen receptor to Erk MAP kinase activation in human B cells. AB - The B cell antigen receptor (BCR) employs enzymatically inactive adaptor proteins to facilitate activation of intracellular signaling pathways. In animal model systems, adaptor proteins of the growth factor receptor-bound 2 (Grb2) family have been shown to serve critical functions in lymphocytes. However, the roles of Grb2 and the Grb2-related adaptor protein (GRAP) in human B lymphocytes remain unclear. Using TALEN-mediated gene targeting, we show that in human B cells Grb2 and GRAP amplify signaling by the immunoglobulin tail tyrosine (ITT) motif of mIgE-containing BCRs and furthermore connect immunoreceptor tyrosine-based activation motif (ITAM) signaling to activation of the Ras-controlled Erk MAP kinase pathway. In contrast to mouse B cells, BCR-induced activation of Erk in human B cells is largely independent of phospholipase C-gamma activity and diacylglycerol-responsive members of Ras guanine nucleotide releasing proteins. Together, our results demonstrate that Grb2 family adaptors are critical regulators of ITAM and ITT signaling in naive and IgE-switched human B cells. PMID- 29523809 TI - Factors associated with prostate specific antigen testing in Australians: Analysis of the New South Wales 45 and Up Study. AB - Australia has one of the highest incidence rates of prostate cancer (PC) worldwide, due in part to widespread prostate specific antigen (PSA) testing. We aimed to identify factors associated with PSA testing in Australian men without a diagnosis of prostate cancer or prior prostate disease. Participants were men joining the 45 and Up Study in 2006-2009, aged >=45 years at recruitment. Self completed questionnaires were linked to cancer registrations, hospitalisations, health services data and deaths. Men with a history of PC, radical prostatectomy or a "monitoring" PSA test for prostate disease were excluded. We identified Medicare reimbursed PSA tests during 2012-2014. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) for the association between having PSA tests and factors of interest. Of the 62,765 eligible men, 51.8% had at least one screening PSA test during 2012-2014. Factors strongly associated with having a PSA test included having 27+ general practitioner consultations (versus 3-9 consultations; OR = 2.00; 95%CI = 1.90-2.11), benign prostatic hyperplasia treatment (versus none; OR = 1.59(95%CI = 1.49-1.70), aged 60-69 years (versus 50 59 years; OR = 1.54; 95%CI = 1.48-1.60). These results emphasise the important role of primary care in decision making about PSA testing. PMID- 29523810 TI - Latent class modeling to compare testing platforms for detection of antibodies against the Chlamydia trachomatis antigen Pgp3. AB - Latent class modeling can be used to combine the results of multiple tests to compare the sensitivity and specificity of those tests in the absence of a gold standard. Seroepidemiology for chlamydia infection may be useful for determining the cumulative risk of infection within a population. Initial studies using the Chlamydia trachomatis immunodominant antigen Pgp3 have shown utility for seroepidemiology of sexually transmitted chlamydia and the eye disease trachoma. We present our latent class modeling results for comparison of antibody data obtained from three different Pgp3-based platforms - multiplex bead array, ELISA, and lateral flow assay. Sensitivity and specificity estimates from the best fitting latent class models were similar to estimates derived from those previously obtained using a nucleic acid amplification test as a gold standard for sensitivity and non-endemic pediatric specimens for specificity, although the estimates from latent class models had wider confidence intervals. The modeling process and evaluation highlighted the importance of including as many antibody tests as possible when fitting a latent class model to ensure that as many patterns as possible are available for evaluation. Future studies designed to evaluate antibody test performance in the absence of a gold standard should utilize as many tests as possible. PMID- 29523811 TI - Systematic Evaluation of Non-Uniform Sampling Parameters in the Targeted Analysis of Urine Metabolites by 1H,1H 2D NMR Spectroscopy. AB - Non-uniform sampling (NUS) allows the accelerated acquisition of multidimensional NMR spectra. The aim of this contribution was the systematic evaluation of the impact of various quantitative NUS parameters on the accuracy and precision of 2D NMR measurements of urinary metabolites. Urine aliquots spiked with varying concentrations (15.6-500.0 uM) of tryptophan, tyrosine, glutamine, glutamic acid, lactic acid, and threonine, which can only be resolved fully by 2D NMR, were used to assess the influence of the sampling scheme, reconstruction algorithm, amount of omitted data points, and seed value on the quantitative performance of NUS in 1H,1H-TOCSY and 1H,1H-COSY45 NMR spectroscopy. Sinusoidal Poisson-gap sampling and a compressed sensing approach employing the iterative re-weighted least squares method for spectral reconstruction allowed a 50% reduction in measurement time while maintaining sufficient quantitative accuracy and precision for both types of homonuclear 2D NMR spectroscopy. Together with other advances in instrument design, such as state-of-the-art cryogenic probes, use of 2D NMR spectroscopy in large biomedical cohort studies seems feasible. PMID- 29523812 TI - A comprehensive sediment dynamics study of a major mud belt system on the inner shelf along an energetic coast. AB - Globally mud areas on continental shelves are conduits for the dispersal of fluvial-sourced sediment. We address fundamental issues in sediment dynamics focusing on how mud is retained on the seabed on shallow inner shelves and what are the sources of mud. Through a process-based comprehensive study that integrates dynamics, provenance, and sedimentology, here we show that the key mechanism to keep mud on the seabed is the water-column stratification that forms a dynamic barrier in the vertical that restricts the upward mixing of suspended sediment. We studied the 1000 km-long mud belt that extends from the mouth of the Changjiang (Yangtze) River along the coast of Zhejiang and Fujian Provinces of China and ends on the west coast of Taiwan. This mud belt system is dynamically attached to the fluvial sources, of which the Changjiang River is the primary source. Winter is the constructive phase when active deposition takes place of fine-grained sediment carried mainly by the Changjiang plume driven by Zhe-Min Coastal Currents southwestward along the coast. PMID- 29523813 TI - PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. AB - Prostate cancer (PCa) patients are risk-stratified on the basis of clinical stage and PSA level at diagnosis and the Gleason Score (GS) in prostate biopsy. However, these parameters are not completely accurate in discriminating between high- and low-risk disease, creating a need for a reliable marker to determine aggressiveness. Prostate-specific membrane antigen (PSMA) appears to fulfill this need. We analyzed 79 prostate biopsies and 28 prostatectomies to assess whether PSMA expression detected by immunohistochemistry is related to GS. PSMA expression was correlated with GS in both sample types (biopsies, P < 0.0001 and prostatectomy samples, P = 0.007). We observed lower PSMA expression in Gleason pattern 3 than Gleason pattern 4, suggesting that this biomarker could be useful to distinguish between these entities (p < 0.0001). The best cut-off value of 45% immunopositivity was determined by receiver operating characteristic (ROC) curve analysis. In Gleason pattern 3 vs. Gleason pattern 4 and 5, PSMA sensitivity was 84.1% (95% CI 76.5%-91.7%) and specificity was 95.2% (95% CI 90.6%-99.8%), with an area under the curve of 93.1 (95% CI 88.8-97.4). Our results suggest that PSMA represents a potential ally for the pathologist in the diagnostic work-up of PCa to overcome long-standing morphological classification limits. PMID- 29523814 TI - Identification of new abscisic acid receptor agonists using a wheat cell-free based drug screening system. AB - Abscisic acid (ABA) is the main phytohormone involved in abiotic stress response and its adaptation, and is a candidate agrichemical. Consequently, several agonists of ABA have been developed using the yeast two-hybrid system. Here, we describe a novel cell-free-based drug screening approach for the development and validation of ABA receptor agonists. Biochemical validation of this approach between 14 ABA receptors (PYR/PYL/RCARs) and 7 type 2C-A protein phosphatases (PP2CAs) revealed the same interactions as those of previous proteome data, except for nine new interactions. By chemical screening using this approach, we identified two novel ABA receptor agonists, JFA1 (julolidine and fluorine containing ABA receptor activator 1) and JFA2 as its analog. The results of biochemical validation for this approach and biological analysis suggested that JFA1 and JFA2 inhibit seed germination and cotyledon greening of seedlings by activating PYR1 and PYL1, and that JFA2 enhanced drought tolerance without inhibiting root growth by activating not only PYR1 and PYL1 but also PYL5. Thus, our approach was useful for the development of ABA receptor agonists and their validation. PMID- 29523815 TI - Intensify3D: Normalizing signal intensity in large heterogenic image stacks. AB - Three-dimensional structures in biological systems are routinely evaluated using large image stacks acquired from fluorescence microscopy; however, analysis of such data is muddled by variability in the signal across and between samples. Here, we present Intensify3D: a user-guided normalization algorithm tailored for overcoming common heterogeneities in large image stacks. We demonstrate the use of Intensify3D for analyzing cholinergic interneurons of adult murine brains in 2 Photon and Light-Sheet fluorescence microscopy, as well as of mammary gland and heart tissues. Beyond enhancement in 3D visualization in all samples tested, in 2 Photon in vivo images, this tool corrected errors in feature extraction of cortical interneurons; and in Light-Sheet microscopy, it enabled identification of individual cortical barrel fields and quantification of somata in cleared adult brains. Furthermore, Intensify3D enhanced the ability to separate signal from noise. Overall, the universal applicability of our method can facilitate detection and quantification of 3D structures and may add value to a wide range of imaging experiments. PMID- 29523816 TI - Purkinje cell BKchannel ablation induces abnormal rhythm in deep cerebellar nuclei and prevents LTD. AB - Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC-/- mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease. PMID- 29523817 TI - Genetic diversity of the enterohaemolysin gene (ehxA) in non-O157 Shiga toxin producing Escherichia coli strains in China. AB - Non-O157 Shiga toxin-producing Escherichia coli (STEC) is increasingly recognized as an important enteric foodborne pathogen. The hallmark of the disease is the production of Shiga toxins; however, there are other virulence factors that contribute to the pathogenesis of STEC. This study aimed to investigate the prevalence and genetic diversity of the enterohaemolysin gene, ehxA, among non O157 STEC strains from human, animal, and food sources. The ehxA gene was amplified from 138 (31.8%) of 434 non-O157 STEC strains, among which 36 unique ehxA sequences were identified. Based on ehxA sequence analysis, three phylogenetic ehxA groups (I II, and III) were determined. Correlations between ehxA groups and sources, serotypes, and virulent gene profiles were observed. The ehxA group II strains were mostly diarrhoeal patient-derived and may demonstrate higher pathogenic potential compared with the ehxA group I and group III strains. Five types of replicons (I1-Ig, FIB, K, F, and B/O) were identified in the 138 ehxA-positive strains, and 3.6%, 5.8%, and 52.2% of the strains harboured toxB, katP and espP genes, respectively, implying marked genetic diversity of ehxA containing plasmids in non-O157 STEC strains. Sequence-based ehxA genotyping might be important in modern strain typing and in epidemiological surveillance of non-O157 STEC infections. PMID- 29523818 TI - Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria. AB - Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a nuclear and mitochondrial protein that in nuclei and in vitro repairs blocked 3' DNA termini such as 3' phosphotyrosine conjugates resulting from stalling of topoisomerase I-DNA intermediates. Its mutation also causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Because Tdp1 colocalizes with mitochondria following oxidative stress, we hypothesized that Tdp1 repairs mitochondrial DNA (mtDNA) and that mtDNA damage mediates entry of Tdp1 into the mitochondria. To test this, we used S. cerevisiae mutants, cultured mouse and human cells, and a Tdp1 knockout mouse. H2O2- and rotenone-induced cellular and intramitochondrial reactive oxygen species (ROS) activated oxidant-responsive kinases P38 and ERK1, and the translocation of Tdp1 from the nucleus to the mitochondria via the TIM/TOM complex. This translocation occurred independently of mtDNA. Within the mitochondria, Tdp1 interacted with Ligase III and reduced mtDNA mutations. Tdp1 deficient tissues had impaired mitochondrial respiration and decreased viability. These observations suggest that Tdp1 maintains mtDNA integrity and support the hypothesis that mitochondrial dysfunction contributes to the pathology of SCAN1. PMID- 29523819 TI - Suspension Palatoplasty for Obstructive Sleep Apnea- A Preliminary Study. AB - Suspension palatoplasty, a new surgical technique to treat obstructive sleep apnea (OSA), has been developed to correct the retropalatal obstruction in patients with small tonsils (grade I/II) and anterior-posterior palatal (A-P) obstruction. The objecteive of this preliminary study was to investigate the effectiveness and change in retropalatal airway dimensions after suspension palatoplasty. This retrospective case series study included 25 consecutive male adults with OSA. Unique technical features of suspension palatoplasty are exposure of pterygomandibular raphe and suspension of palatopharyngeus muscle to the raphe. Six months after suspension palatoplasty, apnea-hyponea index significantly reduced from 39.8 to 15.1 (effect size = 1.6). None experienced postoperative bleeding and velopharyngeal insufficiency 1 month following surgery. Subjective snoring severity (visual analogue scale) and daytime sleepiness (the Epworth Sleepiness Scale) significantly improved (8.7 vs 2.0 and 10.2 vs 4.9, respectively). A-P dimension of the retropalatal airspace widened significantly on perioperative endoscopy (23.0 units vs 184.6 unites) as well as posterior air space in cephalometry (7.6 mm vs 10.2 mm). Our preliminary findings show that suspension palatoplasty seems to be an effective OSA surgery in the specific patient population with minimal complications, however, further studies including a large number of patients are required to confirm the findings. PMID- 29523820 TI - ZFP226 is a novel artificial transcription factor for selective activation of tumor suppressor KIBRA. AB - KIBRA has been suggested as a key regulator of the hippo pathway, regulating organ size, cell contact inhibition as well as tissue regeneration and tumorigenesis. Recently, alterations of KIBRA expression caused by promotor methylation have been reported for several types of cancer. Our current study aimed to design an artificial transcription factor capable of re-activating expression of the tumor suppressor KIBRA and the hippo pathway. We engineered a new gene named 'ZFP226' encoding for a ~23 kDa fusion protein. ZFP226 belongs to the Cys2-His2 zinc finger type and recognizes a nine base-pair DNA sequence 5' GGC-GGC-GGC-3' in the KIBRA core promoter P1a. ZFP226 showed nuclear localization in human immortalized kidney epithelial cells and activated the KIBRA core promoter (p < 0.001) resulting in significantly increased KIBRA mRNA and protein levels (p < 0.001). Furthermore, ZFP226 led to activation of hippo signaling marked by elevated YAP and LATS phosphorylation. In Annexin V flow cytometry assays ZFP226 overexpression showed strong pro-apoptotic capacity on MCF-7 breast cancer cells (p < 0.01 early-, p < 0.001 late-apoptotic cells). We conclude that the artificial transcription factor ZFP226 can be used for target KIBRA and hippo pathway activation. This novel molecule may represent a molecular tool for the development of future applications in cancer treatment. PMID- 29523821 TI - p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage. AB - Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation. PMID- 29523822 TI - Using dual eye tracking to uncover personal gaze patterns during social interaction. AB - We report the personal eye gaze patterns of people engaged in face-to-face getting acquainted conversation. Considerable differences between individuals are underscored by a stability of eye gaze patterns within individuals. Results suggest the existence of an eye-mouth gaze continuum. This continuum includes some people showing a strong preference for eye gaze, some with a strong preference for mouth gaze, and others distributing their gaze between the eyes and mouth to varying extents. Additionally, we found evidence of within participant consistency not just for location preference but also for the duration of fixations upon the eye and mouth regions. We also estimate that during a 4-minute getting acquainted conversation mutual face gaze constitutes about 60% of conversation that occurs via typically brief instances of 2.2 seconds. Mutual eye contact ranged from 0-45% of conversation, via very brief instances. This was despite participants subjectively perceiving eye contact occurring for about 70% of conversation. We argue that the subjective perception of eye contact is a product of mutual face gaze instead of actual mutual eye contact. We also outline the fast activity of gaze movements upon various locations both on and off face during a typical face-to-face conversation. PMID- 29523823 TI - Evaluation of the therapeutic effects of QuickOpt optimization in Chinese patients with chronic heart failure treated by cardiac resynchronization. AB - In this trial, long-term therapeutic effects and clinical improvements in Chinese chronic heart failure patients optimized by QuickOpt or echocardiography were compared for atrioventricular (AV) and interventricular (VV) delay optimizations after cardiac resynchronization therapy (CRT) with pacing (CRT-P) or with pacing and defibrillator (CRT-D) therapy. One hundred and ninety-six subjects (50%) had dilated cardiomyopathy, 108 (27.6%) had ischemic heart disease and 112 (28.6%) were hypertensive and were randomized into QuickOpt (198) or echocardiographic optimization (control) (194) groups at <=2-weeks post-implantation. Programmed AV/VV delay was optimized at baseline and at 3 and 6 months. Left ventricular end systolic volume (LVESV), New York Heart Association (NYHA) class, specific activity scale (SAS), and the six-minute walk tests (6MWT) were evaluated by blinded researchers at 12 months. Of the QuickOpt group, LVESV decreased significantly by 24.7% +/- 33.9% compared with baseline, while LVESV of Controls decreased by 25.1% +/- 36.1% (P = 0.924). NYHA class, SAS and 6MWT also improved similarly in both groups at 12 months. Mortality in both groups was not significantly different (11.0% vs 7.6%, P = 0.289). However, there was a significant difference in the time required for optimization by QuickOpt compared with echocardiography (3.33 +/- 3.11 vs 58.79 +/- 27.03 minutes, P < 0.000). PMID- 29523824 TI - Effects of In vivo Emergent Tigecycline Resistance on the Pathogenic Potential of Acinetobacter baumannii. AB - Multidrug-resistant lineages of Acinetobacter baumannii (MDRAB) are important nosocomial pathogens. As tigecycline remains active against most MDRAB we sought to investigate whether tigecycline resistance impacts biological fitness. The effects of treatment-emergent tigecycline resistance were investigated in vitro and in vivo using two pre- (AB210; W6976) and post-therapy (AB211; W7282) clinical pairs, recovered from individual patients, where tigecycline resistance was associated with up-regulated efflux activity. All isolates belonged to the same epidemic UK lineage. Significant differences were observed in end-point survival proportions between AB210 and AB211, but not between W6976 and W7282, using the Galleria mellonella infection model. Isolate AB211 outcompeted AB210 in vivo, in contrast to isolate W7282, which was outcompeted by its pre-therapy counterpart, W6972. Whole-genome sequencing of isolates W6976 and W7282 revealed a mutation in the adeABC regulatory gene, adeS in W7282; resulting in a Ser-8 -> Arg substitution. Previous whole-genome comparison of AB210 and AB211 also identified a non-synonymous mutation in adeS, among several other lesions in genes involved in biofilm formation and DNA mismatch repair; consistent with the phenotypic differences described here. In conclusion, the differing effects on the wider phenotype were not predictable from the antibiograms or clonal lineage, despite a common mechanism of tigecycline resistance. PMID- 29523825 TI - Investigation of 12 X-STR loci in Mongolian and Eastern Han populations of China with comparison to other populations. AB - Due to the unique inheritance pattern, X-chromosomal short tandem repeats (X STRs) have several advantages in complex kinship cases, such as deficiency cases or grandparent-grandchild and half-sisters testing. In our study, 541 unrelated individuals gathered from Mongolian and Eastern Chinese Han populations were successfully genotyped using the Investigator Argus X-12 kit. We calculated allele/haplotype frequencies and other forensic parameters of the two populations and further explored their genetic distance with already published Chinese populations and six global populations. Our results showed that the 12 X-STR markers were highly informative in the two populations when compared with nine other Chinese populations: significant differences were found at several loci. Geographically neighboring populations or different ethnic groups within the same area appeared to have closer evolutionary relationships. We also analyzed population genetic structure by performing clustering with the STRUCTURE program and Principal Coordinate Analysis (PCoA), and we found that the Chinese and other populations enrolled in this study could be distinguished. Furthermore, Mongolian males were distinguishable from the other studied males by a moderate genetic distance. Our study also expanded the X-STR database, which could facilitate the appropriate application of the 12 X-STR markers in the forensic field in China. PMID- 29523826 TI - PEG/Dextran Double Layer Influences Fe Ion Release and Colloidal Stability of Iron Oxide Nanoparticles. AB - Despite preliminary confidence on biosafety of polymer coated iron oxide nanoparticles (SPIONs), toxicity concerns have hampered their clinical translation. SPIONs toxicity is known to be due to catalytic activity of their surface and release of toxic Fe ions originating from the core biodegradation, leading to the generation of reactive oxygen species (ROS). Here, we hypothesized that a double-layer polymeric corona comprising of dextran as an interior, and polyethylene glycol (PEG) as an exterior layer better shields the core SPIONs. We found that ROS generation was cell specific and depended on SPIONs concentration, although it was reduced by sufficient PEG immobilization or 100 uM deferoxamine. 24 h following injection, PEGylated samples showed reduction of biodistribution in liver, heterogenous biodistribution profile in spleen, and no influence on NPs blood retention. Sufficient surface masking or administration of deferoxamine could be beneficial strategies in designing and clinical translation of future biomedical SPIONs. PMID- 29523827 TI - Hsp90 interacts with multiple dengue virus 2 proteins. AB - Infections with the mosquito-borne dengue virus (DENV) remain a significant public health challenge. In the absence of a commercial therapeutic to treat DENV infection, a greater understanding of the processes of cellular replication is required. The abundant cellular chaperone protein heat shock protein 90 (Hsp90) has been shown to play a proviral role in the replication cycle of several viruses, predominantly through the stabilization of specific viral proteins. To investigate any potential role of Hsp90 in DENV infection the interaction between Hsp90 and DENV proteins was determined through co-immunoprecipitation experiments. Six DENV proteins namely envelope (E) and nonstructural (NS) proteins NS1, NS2B, NS3, NS4B and NS5 were shown to interact with Hsp90, and four of these proteins (E, NS1, NS3 and NS5) were shown to colocalize to a variable extent with Hsp90. Despite the extensive interactions between Hsp90 and DENV proteins, inhibition of the activity of Hsp90 had a relatively minor effect on DENV replication, with inhibition of Hsp90 resulting in a decrease of cellular E protein (but not nonstructural proteins) coupled with an increase of E protein in the medium and an increased virus titer. Collectively these results indicate that Hsp90 has a slight anti-viral effect in DENV infection. PMID- 29523828 TI - Quantum man-in-the-middle attack on the calibration process of quantum key distribution. AB - Quantum key distribution (QKD) protocol has been proved to provide unconditionally secure key between two remote legitimate users in theory. Key distribution signals are transmitted in a quantum channel which is established by the calibration process to meet the requirement of high count rate and low error rate. All QKD security proofs implicitly assume that the quantum channel has been established securely. However, the eavesdropper may attack the calibration process to break the security assumption of QKD and provide precondition to steal information about the final key successfully. In this paper, we reveal the security risk of the calibration process of a passive-basis-choice BB84 QKD system by launching a quantum man-in-the-middle attack which intercepts all calibration signals and resends faked ones. Large temporal bit-dependent or basis dependent detector efficiency mismatch can be induced. Then we propose a basis dependent detector efficiency mismatch (BEM) based faked states attack on a single photon BB84 QKD to stress the threat of BEM. Moreover, the security of single photon QKD systems with BEM is studied simply and intuitively. Two effective countermeasures are suggested to remove the general security risk of the calibration process. PMID- 29523829 TI - An optical system via liquid crystal photonic devices for photobiomodulation. AB - Photobiomodulation or low-level light therapy (LLLT) has extensive applications based on light-induced effects in biological systems. Photobiomodulation remains controversial because of a poorly understood biochemical mechanism limited by the well-known biphasic dose response or Arndt-Schulz curve. The Arndt-Schulz curve states that an optimal dose of light is a key factor for realizing a therapeutic effect. In this report, we demonstrate a tunable optical system for photobiomodulation to aid physicians in overcoming the constraints of light due to biphasic dose response. The tunable optical system is based on a white light emitting diode and four liquid crystal (LC) photonic devices: three LC phase retarders, and one LC lens. The output light of the tunable optical system exhibits electrical tunability for the wavelength, energy density and beam size. The operating principle is introduced, and the experimental results are presented. The proposed concept can be further extended to other electrically tunable photonic devices for different clinical purposes for photobiomodulation. PMID- 29523830 TI - Re-assessment of multiple testing strategies for more efficient genome-wide association studies. AB - Although enormous costs have been dedicated to discovering relevant disease related genetic variants, especially in genome-wide association studies (GWASs), only a small fraction of estimated heritability can be explained by these results. This is the so-called missing heritability problem. The conventional use of overly conservative multiple testing strategies based on controlling the familywise error rate (FWER), in particular with a genome-wide significance threshold of P <5 * 10-8, is one of the most important issues from a statistical perspective. To help resolve this problem, we performed comprehensive re assessments of currently available strategies using recently published, extremely large-scale GWAS data sets of rheumatoid arthritis and schizophrenia (>50,000 subjects). The estimates of statistical power averaged for all disease-related genetic variants of the standard FWER-based strategy were only 0.09% for the rheumatoid arthritis data and 0.04% for the schizophrenia data. To design more efficient strategies, we also conducted an extensive comparison of multiple testing strategies by applying false discovery rate (FDR)-controlling procedures to these data sets and simulations, and found that the FDR-based procedures achieved higher power than the FWER-based strategy, even at a strict FDR level (e.g., FDR = 1%). We also discuss a useful alternative measure, namely "partial power," which is an averaged power for detecting the clinically and biologically meaningful genetic factors with the largest effects. Simulation results suggest that the FDR-based procedures can achieve sufficient partial power (>80%) for detecting these factors (odds ratios of >1.05) with 80,000 subjects, and thus this may be a useful measure for defining realistic objectives of future GWASs. PMID- 29523831 TI - Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy. AB - BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC) randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid. PMID- 29523832 TI - Intolerable side effects during propranolol therapy for infantile hemangioma: frequency, risk factors and management. AB - Currently, propranolol is the most preferred systemic therapy for problematic infantile hemangiomas (IHs). However, the side effects such as bronchial hyperreactivity may be intolerable. The aim of this study was to evaluate the frequency, risk factors and management of intolerable side effects (ISEs) during propranolol therapy. In total, 1260 children were studied. The incidence of ISEs was 2.1% (26 patients). Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 and 3 patients received atenolol and prednisolone as second-line therapy, respectively. Treatment response was observed in 92.3% (24/26) of cases (showing excellent or good response to therapy). No toxicity-related permanent treatment discontinuation occurred during atenolol or prednisolone therapy. In the univariate analysis, younger age, premature birth, and lower body weight were associated with ISEs (P < 0.05). In the multivariate analysis, only age (95% confidence interval [CI]: 1.201-2.793, P = 0.009) and body weight (95% CI: 1.036 1.972, P = 0.014) were associated with ISEs. Our study suggests that ISEs are rare in patients with IHs who are treated with propranolol. Predictive factors for ISEs include younger age and lower body weight. Atenolol and prednisolone are effective and safe alternatives to propranolol in the treatment of refractory IHs. PMID- 29523833 TI - Stabilizing spin spirals and isolated skyrmions at low magnetic field exploiting vanishing magnetic anisotropy. AB - Skyrmions are topologically protected non-collinear magnetic structures. Their stability is ideally suited to carry information in, e.g., racetrack memories. The success of such a memory critically depends on the ability to stabilize and manipulate skyrmions at low magnetic fields. The non-collinear Dzyaloshinskii Moriya interaction originating from spin-orbit coupling drives skyrmion formation. It competes with Heisenberg exchange and magnetic anisotropy favoring collinear states. Isolated skyrmions in ultra-thin films so far required magnetic fields as high as several Tesla. Here, we show that isolated skyrmions in a monolayer of Co/Ru(0001) can be stabilized down to vanishing fields. Even with the weak spin-orbit coupling of the 4d element Ru, homochiral spin spirals and isolated skyrmions were detected with spin-sensitive scanning tunneling microscopy. Density functional theory calculations explain the stability of the chiral magnetic features by the absence of magnetic anisotropy energy. PMID- 29523834 TI - Human tactile detection of within- and inter-finger spatiotemporal phase shifts of low-frequency vibrations. AB - When we touch an object, the skin copies its surface shape/texture, and this deformation pattern shifts according to the objects movement. This shift pattern directly encodes spatio-temporal "motion" information of the event, and has been detected in other modalities (e.g., inter-aural time differences for audition and first-order motion for vision). Since previous studies suggested that mechanoreceptor-afferent channels with small receptive field and slow temporal characteristics contribute to tactile motion perception, we tried to tap the spatio-temporal processor using low-frequency sine-waves as primitive probes in our previous study. However, we found that asynchrony of sine-wave pair presented on adjacent fingers was difficult to detect. Here, to take advantage of the small receptive field, we investigated within-finger motion and found above threshold performance when observers touched localized sine-wave stimuli with one finger. Though observers could not perceptually discriminate rightward from leftward motion, the adaptation occurred in a direction-sensitive way: the motion/asynchronous detection was impaired by adapting to asynchronous stimuli moving in the same direction. These findings are consistent with a possibility that human can directly encode short-range spatio-temporal patterns of skin deformation by using phase-shifted low-frequency components, in addition to detecting short- and long-range motion using energy shifts of high-frequency components. PMID- 29523835 TI - Author Correction: Prevalence and risk factors associated with stroke in middle aged and older Chinese: A community-based cross-sectional study. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29523836 TI - Type III interferon-induced CBFbeta inhibits HBV replication by hijacking HBx. AB - Hepatitis B virus (HBV) and its associated chronic infection remain serious health threats worldwide. However, there is still no impactful approach for clinical treatment of hepatitis B patients. Therefore, developing a better understanding of the interactions between HBV and its host is particularly important. HBV infection has been reported to induce type-III but not type-I or type-II interferon (IFN). In this study, we identified CBFbeta, an HIV enhancer, as an HBV restriction factor that is specifically induced by type-III IFN in the early stages of HBV infection. Type-III IFN-induced IL-10 played an important role in the production of CBFbeta. Interestingly, the interaction between CBFbeta and HBV-encoded regulatory protein X (HBx) enhanced the stability of CBFbeta, but notably blocked HBx-mediated promotion of HBV replication. CBFbeta expression was lower in HBV patients than in healthy persons, and the addition of serum from HBV patients inhibited CBFbeta expression in HepG2 cells. On the contrary, HBV via HBsAg inhibited type-III IFN-induced CBFbeta expression and decreased the anti-HBV activity of type-III IFN, suggesting that HBV inhibits antiviral interferon-stimulated gene (ISG) expression and induces IFN resistance. Collectively, our results demonstrate that type-III IFN-triggered and IL-10 induced CBFbeta are crucial factors for inhibiting HBV replication, and the HBx CBFbeta-HBsAg axis reveals a new molecular mechanism of interaction between HBV and its hosts. PMID- 29523837 TI - Association of nocturnal blood pressure patterns with inflammation and central and peripheral estimates of vascular health in rheumatoid arthritis. AB - Predictors of adverse cardiovascular outcomes include elevated nighttime systolic blood pressure (SBP) and a non-dipping pattern. We investigated whether these factors correlate with systemic inflammation, cardiovascular risk, and markers of central and peripheral vascular damage in rheumatoid arthritis (RA), a disease characterized by excess cardiovascular risk. Twenty-four-hour ambulatory blood pressure monitoring was applied in patients and controls. Vascular assessments included measurement of arterial stiffness (pulse wave velocity) and carotid atherosclerosis (carotid intima-media thickness). Peripheral vascular resistance was estimated from impedance cardiography. Cardiovascular risk was calculated from the Framingham Heart Study. RA patients exhibited a higher prevalence of non dipping pattern, elevated nighttime SBP and blunted dipping, compared to controls without cardiovascular comorbidities. Among RA patients, dipping levels correlated with arterial stiffness, and nighttime SBP with all vascular markers and cardiovascular risk. After adjustment for inflammation, the above associations with vascular measures were no longer significant. Plain categorization to dippers and non-dippers did not reveal any differences regarding inflammation, vascular measurements, and cardiovascular risk. However, the combination of a non-dipping profile with high nighttime SBP was accompanied by significantly higher levels of arterial stiffness and cardiovascular risk, compared to non-dippers with normal nighttime SBP; these parameters were similar between the latter group and dippers. Inflammation appears to mediate the observed associations of nighttime SBP and dipping levels with markers of subclinical vascular damage in RA patients. In these patients, the combination of a non-dipping profile with elevated nighttime SBP is accompanied by prominent subclinical vascular impairment and confers the highest cardiovascular risk. PMID- 29523838 TI - Publisher Correction: Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. AB - The original version of the Supplementary Information associated with this Article inadvertently omitted Supplementary Table 1. The HTML has now been updated to include a corrected version of the Supplementary Information. PMID- 29523839 TI - Annotation of the Corymbia terpene synthase gene family shows broad conservation but dynamic evolution of physical clusters relative to Eucalyptus. AB - Terpenes are economically and ecologically important phytochemicals. Their synthesis is controlled by the terpene synthase (TPS) gene family, which is highly diversified throughout the plant kingdom. The plant family Myrtaceae are characterised by especially high terpene concentrations, and considerable variation in terpene profiles. Many Myrtaceae are grown commercially for terpene products including the eucalypts Corymbia and Eucalyptus. Eucalyptus grandis has the largest TPS gene family of plants currently sequenced, which is largely conserved in the closely related E. globulus. However, the TPS gene family has been well studied only in these two eucalypt species. The recent assembly of two Corymbia citriodora subsp. variegata genomes presents an opportunity to examine the conservation of this important gene family across more divergent eucalypt lineages. Manual annotation of the TPS gene family in C. citriodora subsp. variegata revealed a similar overall number, and relative subfamily representation, to that previously reported in E. grandis and E. globulus. Many of the TPS genes were in physical clusters that varied considerably between Eucalyptus and Corymbia, with several instances of translocation, expansion/contraction and loss. Notably, there was greater conservation in the subfamilies involved in primary metabolism than those involved in secondary metabolism, likely reflecting different selective constraints. The variation in cluster size within subfamilies and the broad conservation between the eucalypts in the face of this variation are discussed, highlighting the potential contribution of selection, concerted evolution and stochastic processes. These findings provide the foundation to better understand terpene evolution within the ecologically and economically important Myrtaceae. PMID- 29523840 TI - Collective effects of common SNPs and risk prediction in lung cancer. AB - Lung cancer is the leading cause of cancer deaths in both men and women in the US. While most sporadic lung cancer cases are related to environmental factors such as smoking, genetic susceptibility may also play an important role and a number of lung cancer associated single-nucleotide polymorphisms (SNPs) have been identified although many remain to be found. The collective effects of genome wide minor alleles of common SNPs, or the minor allele content (MAC) in an individual, have been linked with quantitative variations of complex traits and diseases. Here we studied MAC in lung cancer using previously published SNPs data sets (US and Finland samples) and found higher MAC in cases relative to matched controls. A set of 5400 SNPs with MA (MAF < 0.5) more common in cases (P < 0.08) and linkage disequilibrium (LD) r2 = 0.3 was found to have the best predictive accuracy. These results identify higher MAC in lung cancer susceptibility and provide a meaningful genetic method to identify those at risk of lung cancer. PMID- 29523841 TI - Optimising the transport properties and reactivity of microbially-synthesised magnetite for in situ remediation. AB - Engineered nanoparticles offer the potential for remediation of land and water that has been contaminated by organics and metals. Microbially synthesized nano scale magnetite, prepared from Fe(III) oxides by subsurface Fe(III)-reducing bacteria, offers a scalable biosynthesis route to such a nano-scale remediation reagent. To underpin delivery of "bionanomagnetite" (BNM) nanomaterial during in situ treatment options, we conducted a range of batch and column experiments to assess and optimise the transport and reactivity of the particles in porous media. Collectively these experiments, which include state of the art gamma imaging of the transport of 99m Tc-labelled BNM in columns, showed that non toxic, low cost coatings such as guar gum and salts of humic acid can be used to enhance the mobility of the nanomaterial, while maintaining reactivity against target contaminants. Furthermore, BNM reactivity can be enhanced by the addition of surface coatings of nano-Pd, extending the operational lifetime of the BNM, in the presence of a simple electron donor such as hydrogen or formate. PMID- 29523842 TI - Large enhancement of response times of a protein conformational switch by computational design. AB - The design of protein conformational switches-or proteins that change conformations in response to a signal such as ligand binding-has great potential for developing novel biosensors, diagnostic tools, and therapeutic agents. Among the defining properties of such switches, the response time has been the most challenging to optimize. Here we apply a computational design strategy in synergistic combination with biophysical experiments to rationally improve the response time of an engineered protein-based Ca2+-sensor in which the switching process occurs via mutually exclusive folding of two alternate frames. Notably, our strategy identifies mutations that increase switching rates by as much as 32 fold, achieving response times on the order of fast physiological Ca2+ fluctuations. Our computational design strategy is general and may aid in optimizing the kinetics of other protein conformational switches. PMID- 29523843 TI - B49, a BST-2-based peptide, inhibits adhesion and growth of breast cancer cells. AB - Bone marrow stromal antigen 2 (BST-2) also known as Tetherin has been implicated in the growth and progression of many cancers. BST-2 employs its pro-tumor effects through the formation of BST-2:BST-2 dimers which ultimately promotes cell to cell and cell to matrix adhesion, cell motility, survival, and growth. The aim of this study was to evaluate the effect of a novel BST-2-based peptide B49 on adhesion and growth of breast cancer cells. Homotypic/heterotypic adhesion, three-dimensional spheroid formation, and anchorage-independent growth were used to assess the effect of B49 on cell adhesion and growth. Additionally, we provide evidence of the anti-tumor effect of B49 in a preclinical mouse model of breast cancer. Results show that breast cancer cell adhesion to other cancer cells or components of the tumor microenvironment were inhibited by B49. Most well-known evaluation indexes of cancer cell growth, including spheroid formation, anchorage-independent, and primary tumor growth were significantly inhibited by B49. These data affirm that i) BST-2 plays a key role in mediating breast cancer cell adhesion and growth, and ii) B49 and its analog B49Mod1 significantly inhibits BST-2-mediated cancer cell adhesion and growth. Therefore, B49 and its analogs offer a promising anti-adhesion and therapeutic lead for BST 2-dependent cancers. PMID- 29523844 TI - Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling. AB - Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate that autophagy aims to clear out exhausted mitochondria, as determined by enhanced localization of p62 and Lysotracker-red to mitochondria. In addition, we newly demonstrate that NGF differentiation is accompanied by increased mitochondrial remodeling involving higher levels of fission (P-Drp1) and fusion proteins (Opa1 and Mfn2), as well as induction of Sirt3 and the transcription factors mtTFA and PPARgamma, which regulate mitochondria biogenesis and metabolism to sustain increased mitochondrial mass, potential, and bioenergetics. Overall, our data indicate a new NGF-dependent mechanism involving mitophagy and extensive mitochondrial remodeling, which plays a key role in both neurogenesis and nerve regeneration. PMID- 29523845 TI - Whole transcriptome profiling of Late-Onset Alzheimer's Disease patients provides insights into the molecular changes involved in the disease. AB - Alzheimer's Disease (AD) is the most common cause of dementia affecting the elderly population worldwide. We have performed a comprehensive transcriptome profiling of Late-Onset AD (LOAD) patients using second generation sequencing technologies, identifying 2,064 genes, 47 lncRNAs and 4 miRNAs whose expression is specifically deregulated in the hippocampal region of LOAD patients. Moreover, analyzing the hippocampal, temporal and frontal regions from the same LOAD patients, we identify specific sets of deregulated miRNAs for each region, and we confirm that the miR-132/212 cluster is deregulated in each of these regions in LOAD patients, consistent with these miRNAs playing a role in AD pathogenesis. Notably, a luciferase assay indicates that miR-184 is able to target the 3'UTR NR4A2 - which is known to be involved in cognitive functions and long-term memory and whose expression levels are inversely correlated with those of miR-184 in the hippocampus. Finally, RNA editing analysis reveals a general RNA editing decrease in LOAD hippocampus, with 14 recoding sites significantly and differentially edited in 11 genes. Our data underline specific transcriptional changes in LOAD brain and provide an important source of information for understanding the molecular changes characterizing LOAD progression. PMID- 29523846 TI - NF-kappaB is weakly activated in the NOD mouse model of type 1 diabetes. AB - Type 1 diabetes is an autoimmune disease characterised by selective destruction of pancreatic beta cells by the immune system. The transcription factor nuclear factor-kappa B (NF-kappaB) regulates innate and adaptive immune responses. Using gene targeting and in vitro analysis of pancreatic islets and immune cells, NF kappaB activation has been implicated in type 1 diabetes development. Here we use a non-obese diabetic (NOD) mouse model that expresses a luciferase reporter of transcriptionally active NF-kappaB to determine its activation in vivo during development of diabetes. Increased luciferase activity was readily detected upon treatment with Toll-like receptor ligands in vitro and in vivo, indicating activation of NF-kappaB. However, activated NF-kappaB was detectable at low levels above background in unmanipulated NOD mice, but did not vary with age, despite the progression of inflammatory infiltration in islets over time. NF kappaB was highly activated in an accelerated model of type 1 diabetes that requires CD4+ T cells and inflammatory macrophages. These data shed light on the nature of the inflammatory response in the development of type 1 diabetes. PMID- 29523847 TI - A Facile Approach to Prepare Multiple Heteroatom-Doped Carbon Materials from Imine-Linked Porous Organic Polymers. AB - In this paper, we proposed a new strategy to prepare multiple heteroatom doped (N, P-doped) porous carbon materials with high surface area of ~1,535 m2 g-1 simply by pyrolysis of imine-linked porous organic polymers (POPs) synthesized via Schiff base condensation. The strategy is simple without any post-processing and various heteroatoms could be involved. Scanning electron microscopy, Raman spectra, Nitrogen gas adsorption-desorption, X-ray photoelectron spectroscopy have been used to characterize the morphology, the structure and the composition of the materials. The multiple heteroatom doped porous carbon materials also display high electrocatalytic performance as exampled by the application in oxygen reduction, which showed the catalyst favors 4-electron transfer during the process, along with superior stability and higher tolerance to methanol as compared to the Pt/C. These results indicate the present method is promising for the preparation of multi-heteroatom doped carbon materials in the application of electrocatalysis. PMID- 29523848 TI - Statistical ensembles without typicality. AB - Maximum-entropy ensembles are key primitives in statistical mechanics. Several approaches have been developed in order to justify the use of these ensembles in statistical descriptions. However, there is still no full consensus on the precise reasoning justifying the use of such ensembles. In this work, we provide an approach to derive maximum-entropy ensembles, taking a strictly operational perspective. We investigate the set of possible transitions that a system can undergo together with an environment, when one only has partial information about the system and its environment. The set of these transitions encodes thermodynamic laws and limitations on thermodynamic tasks as particular cases. Our main result is that the possible transitions are exactly those that are possible if both system and environment are assigned the maximum-entropy state compatible with the partial information. This justifies the overwhelming success of such ensembles and provides a derivation independent of typicality or information-theoretic measures. PMID- 29523849 TI - p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response. AB - Hyperproliferative keratinocytes induced by trauma, hyperkeratosis and/or inflammation display molecular signatures similar to those of palmoplantar epidermis. Inherited gain-of-function mutations in RHBDF2 (encoding iRHOM2) are associated with a hyperproliferative palmoplantar keratoderma and squamous oesophageal cancer syndrome (termed TOC). In contrast, genetic ablation of rhbdf2 in mice leads to a thinning of the mammalian footpad, and reduces keratinocyte hyperproliferation and migration. Here, we report that iRHOM2 is a novel target gene of p63 and that both p63 and iRHOM2 differentially regulate cellular stress associated signalling pathways in normal and hyperproliferative keratinocytes. We demonstrate that p63-iRHOM2 regulates cell survival and response to oxidative stress via modulation of SURVIVIN and Cytoglobin, respectively. Furthermore, the antioxidant compound Sulforaphane downregulates p63-iRHOM2 expression, leading to reduced proliferation, inflammation, survival and ROS production. These findings elucidate a novel p63-associated pathway that identifies iRHOM2 modulation as a potential therapeutic target to treat hyperproliferative skin disease and neoplasia. PMID- 29523851 TI - A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling. AB - The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E2 and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H2 receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling. PMID- 29523850 TI - Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4. AB - Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-gamma (IFNgamma) production in stimulated natural killer cells, and decreased circulating IFNgamma concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNgamma-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease. PMID- 29523852 TI - Nutritional status and gait speed in a nationwide population-based sample of older adults. AB - The association between nutritional status and gait speed remains unclear. This study described gait speed in older adults and quantified the association between overweight, obesity, undernutrition risk and gait speed. Gait speed as potential indicator of nutritional outcomes was also explored. A cross-sectional analysis was conducted in a population-based sample of 1,500 older adults >=65 years old. Compared to "normal body mass index" women, odds ratio for a slow gait speed was approximately 2-fold higher in"overweight", 4-fold higher in "obese" and 6-fold higher in women at "undernutrition risk". "Undernutrition risk" category resulted from joining "undernutrition risk/undernutrition". For men, these associations were in the same direction, but the odds ratio estimates halved. In women, identified gait speed cut-offs were 0.87 m/s for "obesity" and 0.79 m/s for "undernutrition risk". In men, 0.94 m/s is the cut-off in which most older adults were correctly classified relative to "undernutrition risk". About half of Portuguese older adults presented a gait speed <=0.8 m/s. Overweight, obesity and undernutrition risk were directly and increasingly associated with slow gait speed, but approximately twice as high in women compared to men. Gait speed revealed potential utility in marking nutritional problems, but further investigation is recommended. PMID- 29523853 TI - Greenhouse gas released from the deep permafrost in the northern Qinghai-Tibetan Plateau. AB - Deep carbon pool in permafrost regions is an important component of the global terrestrial carbon cycle. However, the greenhouse gas production from deep permafrost soils is not well understood. Here, using soils collected from 5-m deep permafrost cores from meadow and wet meadow on the northern Qinghai-Tibetan Plateau (QTP), we investigated the effects of temperature on CO2 and N2O production under aerobic incubations and CH4 production under anaerobic incubations. After a 35-day incubation, the CO2, N2O and CH4 production at -2 degrees C to 10 degrees C were 0.44~2.12 mg C-CO2/g soil C, 0.0027~0.097 mg N N2O/g soil N, and 0.14~5.88 MUg C-CH4/g soil C, respectively. Greenhouse gas production in deep permafrost is related to the C:N ratio and stable isotopes of soil organic carbon (SOC), whereas depth plays a less important role. The temperature sensitivity (Q10) values of the CO2, N2O and CH4 production were 1.67 4.15, 3.26-5.60 and 5.22-10.85, without significant differences among different depths. These results indicated that climate warming likely has similar effects on gas production in deep permafrost and surface soils. Our results suggest that greenhouse gas emissions from both the deep permafrost and surface soils to the air will increase under future climate change. PMID- 29523854 TI - Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism. AB - Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response. Neutralization of oxidative stress reverses cisplatin toxicity independent of the mechanism of cell death and TP53 mutational status. Cisplatin-induced oxidative stress triggers rapid shifts in carbon flux in 3 commonly utilized catabolic pathways: glycolysis, pentose phosphate pathway and citric acid cycle. Among these metabolic shifts, decreased flux from pyruvate into lactate is the only metabolic effect consistently observed across multiple HNSCC cell lines of varying genomic backgrounds and may reflect differential cisplatin sensitivity. Oxidative stress is a critical component of cisplatin cytotoxicity in HNSCC and is reflected in acute changes in carbon flux from pyruvate into lactate. This suggests that lactate may contribute to a metabolic signature of acute cisplatin toxicity, and could prove useful in optimizing cisplatin-based treatment regimens in HNSCC. PMID- 29523855 TI - A simple and robust real-time qPCR method for the detection of PIK3CA mutations. AB - PIK3CA mutations are seemingly the most common driver mutations in breast cancer with H1047R and E545K being the most common of these, accounting together for around 60% of all PIK3CA mutations and have promising therapeutic implications. Given the low sensitivity and the high cost of current genotyping methods we sought to develop fast, simple and inexpensive assays for PIK3CA H1047R and E545K mutation screening in clinical material. The methods we describe are based on a real-time PCR including a mutation specific primer combined with a non-productive oligonucleotide which inhibits wild-type amplification and a parallel internal control reaction. We demonstrate consistent detection of PIK3CA H1047R mutant DNA in genomic DNA extracted from frozen breast cancer biopsies, FFPE material or cancer cell lines with a detection sensitivity of approximately 5% mutant allele fraction and validate these results using both Sanger sequencing and deep next generation sequencing methods. The detection sensitivity for PIK3CA E545K mutation was approximately 10%. We propose these methods as simple, fast and inexpensive diagnostic tools to determine PIK3CA mutation status. PMID- 29523856 TI - Expanding the toolbox for cryopreservation of marine and freshwater diatoms. AB - Diatoms constitute the most diverse group of microalgae and have long been recognised for their large biotechnological potential. In the wake of growing research interest in new model species and development of commercial applications, there is a pressing need for long-term preservation of diatom strains. While cryopreservation using dimethylsulfoxide (DMSO) as a cryoprotective agent is the preferred method for long-term strain preservation, many diatom species cannot be successfully cryopreserved using DMSO. Therefore, in this study, we studied cryopreservation success in six different diatom species, representing the major morphological and ecological diatom groups, using a range of DMSO concentrations and Plant Vitrification Solution 2 (PVS2) as an alternative cryoprotectant to DMSO. In addition, we tested whether suppressing bacterial growth by antibiotics accelerates the post-thaw recovery process. Our results show that the effects of cryoprotectant choice, its concentration and the addition of antibiotics are highly species specific. In addition, we showed that PVS2 and antibiotics are useful agents to optimize cryopreservation of algae that cannot survive the traditional cryopreservation protocol using DMSO. We conclude that a species-specific approach will remain necessary to develop protocols for diatom cryopreservation and to increase their representation in public culture collections. PMID- 29523857 TI - Physical Exercise and Spatial Training: A Longitudinal Study of Effects on Cognition, Growth Factors, and Hippocampal Plasticity. AB - Physical exercise has been suggested to improve cognitive performance through various neurobiological mechanisms, mediated by growth factors such as BDNF, IGF I, and VEGF. Moreover, animal research has demonstrated that combined physical and cognitive stimulation leads to increased adult neurogenesis as compared to either experimental condition alone. In the present study, we therefore investigated whether a sequential combination of physical and spatial training in young, healthy adults elicits an additive effect on training and transfer gains. To this end, we compared the effects of (i) eight 20-minute sessions of cycling, (ii) sixteen 30-minute sessions of spatial training, (iii) a combination of both, and included (iv) a passive control cohort. We assessed longitudinal changes in cognitive performance, growth factor levels, and T1 relaxation of hippocampal subfields (acquired with 7 T MRI). While substantial physical and spatial training gains were elicited in all trained groups, longitudinal transfer changes did not differ between these groups. Notably, we found no evidence for an additive effect of sequential physical and spatial training. These results challenge the extrapolation from the findings reported in animals to young, healthy adults. PMID- 29523858 TI - Phagocytosis depends on TRPV2-mediated calcium influx and requires TRPV2 in lipids rafts: alteration in macrophages from patients with cystic fibrosis. AB - Whereas many phagocytosis steps involve ionic fluxes, the underlying ion channels remain poorly defined. As reported in mice, the calcium conducting TRPV2 channel impacts the phagocytic process. Macrophage phagocytosis is critical for defense against pathogens. In cystic fibrosis (CF), macrophages have lost their capacity to act as suppressor cells and thus play a significant role in the initiating stages leading to chronic inflammation/infection. In a previous study, we demonstrated that impaired function of CF macrophages is due to a deficient phagocytosis. The aim of the present study was to investigate TRPV2 role in the phagocytosis capacity of healthy primary human macrophage by studying its activity, its membrane localization and its recruitment in lipid rafts. In primary human macrophages, we showed that P. aeruginosa recruits TRPV2 channels at the cell surface and induced a calcium influx required for bacterial phagocytosis. We presently demonstrate that to be functional and play a role in phagocytosis, TRPV2 might require a preferential localization in lipid rafts. Furthermore, CF macrophage displays a perturbed calcium homeostasis due to a defect in TRPV2. In this context, deregulated TRPV2-signaling in CF macrophages could explain their defective phagocytosis capacity that contribute to the maintenance of chronic infection. PMID- 29523859 TI - The dose-response analysis between BMI and common chronic diseases in northeast China. AB - High body mass index (BMI) predisposes to several chronic diseases, but a large scale systematic and detailed study of dose-response relationship between BMI and chronic diseases has not been reported previously. In this study, we aimed to investigate the relationship between BMI and 3 chronic diseases (hypertension, dyslipidemia and MetS) in northeast China. A sample of 16412 participants aged 18~79 years old were included in Jilin province in 2012. The lambda-mu-sigma (LMS) method was applied to examine the trend of BMI by age, and the restricted cubic splines were used to investigate the non-linear associations (dose-response curve) between BMI and chronic diseases. It was pointed out that BMI increased rapidly when young, then kept steady in middle age, and finally declined slowly in old age, and accordingly age was divided into 3 segments, which were different by gender. The odds ratios (ORs) of BMI for the chronic diseases increased relatively slowly when young, then increased dramatically in middle-age and old population, especially for men. Further, the ORs of BMI among non-smokers were lower than those among smokers, and the same trend was shown to be more apparent among drinkers and non-drinkers. The risk of BMI for common chronic diseases increased dramatically in middle-aged, especially for men with drinking and smoking habits. PMID- 29523861 TI - Oxic Fe(III) reduction could have generated Fe(II) in the photic zone of Precambrian seawater. AB - Many marine Precambrian iron formations (IF) record deep anoxic seawater enriched in Fe(II) (i.e. ferruginous) overlain by mildly oxygenated surface water. This is reflected by iron-rich sediments forming in deep basins, and relatively iron-poor sediments forming in shallow, sunlit waters. Such an iron gradient is often interpreted as a redox interface where dissolved Fe(II) was oxidized and precipitated as Fe(III)-bearing minerals. As such, sedimentary iron enrichments are proxy to the progressive oxidation of the oceans through geological time. However, this interpretation is founded on the assumption that Fe(II) could not persist within an oxygenated water column. Here, we cultivated cyanobacteria in an illuminated column supplied with Fe(II)-rich seawater medium in a laboratory scale analog of a continental margin supporting IF deposition. We first observed Fe(II) oxidation with oxygen, then biologically-mediated reduction of Fe(III) (oxyhydr)oxides, which maintained a pool of Fe(II) in the presence of oxygen. Such steady-state iron redox cycling may have maintained dissolved, and hence mobile Fe(II) in oxygenated seawater above ferruginous deep basins such as those inferred for many Precambrian IF. PMID- 29523860 TI - Allele-specific expression in a family quartet with autism reveals mono-to biallelic switch and novel transcriptional processes of autism susceptibility genes. AB - Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring's postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from the PFC of both offspring. However, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified a novel site of RNA-editing in KMT2C in addition to new monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD. PMID- 29523862 TI - Antimicrobial Photodynamic therapy enhanced by the peptide aurein 1.2. AB - In the past few years, the World Health Organization has been warning that the post-antibiotic era is an increasingly real threat. The rising and disseminated resistance to antibiotics made mandatory the search for new drugs and/or alternative therapies that are able to eliminate resistant microorganisms and impair the development of new forms of resistance. In this context, antimicrobial photodynamic therapy (aPDT) and helical cationic antimicrobial peptides (AMP) are highlighted for the treatment of localized infections. This study aimed to combine the AMP aurein 1.2 to aPDT using Enterococcus faecalis as a model strain. Our results demonstrate that the combination of aPDT with aurein 1.2 proved to be a feasible alternative capable of completely eliminating E. faecalis employing low concentrations of both PS and AMP, in comparison with the individual therapies. Aurein 1.2 is capable of enhancing the aPDT activity whenever mediated by methylene blue or chlorin-e6, but not by curcumin, revealing a PS-dependent mechanism. The combined treatment was also effective against different strains; noteworthy, it completely eliminated a vancomycin-resistant strain of Enterococcus faecium. Our results suggest that this combined protocol must be exploited for clinical applications in localized infections as an alternative to antibiotics. PMID- 29523863 TI - Interferon-beta deficiency at asthma exacerbation promotes MLKL mediated necroptosis. AB - Defective production of antiviral interferon (IFN)-beta is thought to contribute to rhinovirus-induced asthma exacerbations. These exacerbations are associated with elevated lung levels of lactate dehydrogenase (LDH), indicating occurrence of cell necrosis. We thus hypothesized that reduced lung IFN-beta could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-beta-/- mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflammation. Double-stranded RNA (dsRNA) was then given for additional 3 days to induce exacerbation. HDM induced an eosinophilic inflammation, which was not associated with increased expression of cleaved caspase-3, cleaved PARP or elevated bronchoalveolar lavage fluid (BALF) LDH levels in wild-type. However, exacerbation evoked by HDM + dsRNA challenges increased BALF levels of LDH, apoptotic markers and the necroptotic markers receptor-interacting protein (RIP)-3 and phosphorylation of mixed linage kinase domain-like protein (pMLKL), compared to HDM + saline. Absence of IFN-beta at exacerbation further increased BALF LDH and protein expression of pMLKL compared to wild-type. We demonstrate that cell death markers are increased at viral stimulus-induced exacerbation in mouse lungs, and that absence of IFN-beta augments markers of necroptotic cell death at exacerbation. Our data thus suggest a novel role of deficient IFN-beta production at viral-induced exacerbation. PMID- 29523864 TI - Race/ethnicity and insurance status disparities in access to direct acting antivirals for hepatitis C virus treatment. AB - OBJECTIVE: Despite availability of highly effective direct acting antivirals (DAA), barriers in access to these therapies limit our ability to achieve HCV eradication. We aim to evaluate overall rates and predictors of HCV treatment across four community-based health-care systems focusing on race/ethnicity and insurance-specific disparities. METHODS: We retrospectively evaluated all adults with chronic HCV at four health care systems from 1 January 2011 to 28 February 2017, which included a large proportion of ethnic minorities, two safety-net systems, and a broad payer mix across four states. Overall and stratified HCV treatment rates were calculated using Kaplan-Meier methods. Multivariate logistic regression models evaluated for predictors of receiving treatment. RESULTS: Among 29,544 chronic HCV patients (60.5% male, 38.4% black, 8.8% Hispanic, 18.7% Medicaid, 25.9% Medicare, 22.5% private/commercial), overall annual treatment rates were stable from 2011 (0.5%) to 2013 (2.0%), but increased from 2014 (4.8%) to 2017 (16.9%) after availability of DAAs. While similar treatment rates were observed by sex, significantly lower odds of treatment were observed in Hispanics (OR 0.48, 95% CI 0.39-0.60, p < 0.001) compared to non-Hispanic whites and among those with Medicaid (OR 0.21, 95% CI 0.20-0.24, p < 0.001) compared to commercially insured patients. CONCLUSIONS: Among our cohort of 29,544 chronic HCV patients, we observed significant improvements in HCV treatment rates after the availability of DAAs in 2014, but overall treatment rates remained <20% in 2017. The lowest rates of treatment were seen among Hispanics and those with Medicaid or indigent care insurance, which is concerning given these are particularly vulnerable populations. PMID- 29523865 TI - Response to Marlicz et al. PMID- 29523866 TI - Bleeding granuloma pyogenicum in rectum. PMID- 29523867 TI - Dos and Don'ts in the Management of Cirrhosis: A View from the 21st Century. PMID- 29523868 TI - Identifying temporal patterns in patient disease trajectories using dynamic time warping: A population-based study. AB - Time is a crucial parameter in the assessment of comorbidities in population based studies, as it permits to identify more complex disease patterns apart from the pairwise disease associations. So far, it has been, either, completely ignored or only, taken into account by assessing the temporal directionality of identified comorbidity pairs. In this work, a novel time-analysis framework is presented for large-scale comorbidity studies. The disease-history vectors of patients of a regional Spanish health dataset are represented as time sequences of ordered disease diagnoses. Statistically significant pairwise disease associations are identified and their temporal directionality is assessed. Subsequently, an unsupervised clustering algorithm, based on Dynamic Time Warping, is applied on the common disease trajectories in order to group them according to the temporal patterns that they share. The proposed methodology for the temporal assessment of such trajectories could serve as the preliminary basis of a disease prediction system. PMID- 29523869 TI - Correlation between the 24-h urinary angiotensinogen or aldosterone level and muscle mass: Japan shimanami health promoting program study. AB - Our previous report indicated that sarcopenia is associated with arterial stiffness and cardiovascular death. The renin-angiotensin system (RAS) plays an important role in cardiovascular disease and its activation may be correlated with sarcopenia according to basic research. However, few clinical studies have assessed the correlation between skeletal muscle loss and RAS component concentrations in healthy subjects. The purpose of this study was to investigate the relationships between the excretion of angiotensinogen (AGT) and aldosterone (Ald) in 24-h urine samples and clinical and sarcopenic indices. A total of 344 people participated in a voluntary medical check-up program, "Anti-Aging Doc", and underwent measurement of their sarcopenia-related indices. Urine samples were collected for 24-h within 8 weeks after a medical check-up using a partition cup and a proportional sampling method. Urine AGT and Ald levels were evaluated by enzyme-linked immunosorbent assay (ELISA). After compensating for possible confounding parameters, including baPWV, the 24-h urinary excretion of AGT was independently and negatively associated with the thigh muscle cross-sectional area. On the other hand, urinary Ald excretion was not associated with sarcopenia related indices after compensation, even though it showed a modest but significantly positive association with sarcopenic indices in single regression analysis. Urinary AGT was related to sarcopenic indices and may be involved in the pathogenesis of sarcopenia. On the other hand, urinary Ald was not related to sarcopenic indices when considering other risk factors. PMID- 29523870 TI - Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis. AB - Patients with psychotic disorders are at high risk for type 2 diabetes mellitus, and there is increasing evidence that patients display glucose metabolism abnormalities before significant antipsychotic medication exposure. In the present study, we examined insulin action by quantifying insulin sensitivity in first-episode psychosis (FEP) patients and unaffected siblings, compared to healthy individuals, using a physiological-based model and comprehensive assessment battery. Twenty-two unaffected siblings, 18 FEP patients, and 15 healthy unrelated controls were evaluated using a 2-h oral glucose tolerance test (OGTT), with 7 samples of plasma glucose and serum insulin concentration measurements. Insulin sensitivity was quantified using the oral minimal model method. Lipid, leptin, free fatty acids, and inflammatory marker levels were also measured. Anthropometric, nutrient, and activity assessments were conducted; total body composition and fat distribution were determined using whole-body dual energy X-ray absorptiometry. Insulin sensitivity significantly differed among groups (F = 6.01 and 0.004), with patients and siblings showing lower insulin sensitivity, compared to controls (P = 0.006 and 0.002, respectively). Body mass index, visceral adipose tissue area (cm2), lipids, leptin, free fatty acids, inflammatory markers, and activity ratings were not significantly different among groups. There was a significant difference in nutrient intake with lower total kilocalories/kilogram body weight in patients, compared to siblings and controls. Overall, the findings suggest that familial abnormal glucose metabolism or a primary insulin signaling pathway abnormality is related to risk for psychosis, independent of disease expression and treatment effects. Future studies should examine underlying biological mechanisms of insulin signaling abnormalities in psychotic disorders. PMID- 29523871 TI - GATA4 as a novel regulator involved in the development of the neural crest and craniofacial skeleton via Barx1. AB - The role of GATA-binding protein 4 (GATA4) in neural crest cells (NCCs) is poorly defined. Here we showed that mouse NCCs lacking GATA4 exhibited developmental defects in craniofacial bone, teeth, and heart. The defects likely occurred due to decreased cell proliferation at the developmental stage. The in vitro results were consistent with the mouse model. The isobaric tags for relative and absolute quantitation assay revealed that BARX1 is one of the differentially expressed proteins after GATA4 knockdown in NCCs. On the basis of the results of dual luciferase, electro-mobility shift, and chromatin immunoprecipitation assays, Barx1 expression is directly regulated by GATA4 in NCCs. In zebrafish, gata4 knockdown affects the development of NCCs derivatives. However, the phenotype in zebrafish could be partly rescued by co-injection of gata4 morpholino oligomers and barx1 mRNA. This study identified new downstream targets of GATA4 in NCCs and uncovered additional evidence of the complex regulatory functions of GATA4 in NCC development. PMID- 29523873 TI - RIP3 is an upregulator of aerobic metabolism and the enhanced respiration by necrosomal RIP3 feeds back on necrosome to promote necroptosis. PMID- 29523872 TI - The mTOR-S6 kinase pathway promotes stress granule assembly. AB - Stress granules are cytoplasmic mRNA-protein complexes that form upon the inhibition of translation initiation and promote cell survival in response to environmental insults. However, they are often associated with pathologies, including neurodegeneration and cancer, and changes in their dynamics are implicated in ageing. Here we show that the mTOR effector kinases S6 kinase 1 (S6K1) and S6 kinase 2 (S6K2) localise to stress granules in human cells and are required for their assembly and maintenance after mild oxidative stress. The roles of S6K1 and S6K2 are distinct, with S6K1 having a more significant role in the formation of stress granules via the regulation of eIF2alpha phosphorylation, while S6K2 is important for their persistence. In C. elegans, the S6 kinase orthologue RSKS-1 promotes the assembly of stress granules and its loss of function sensitises the nematodes to stress-induced death. This study identifies S6 kinases as regulators of stress granule dynamics and provides a novel link between mTOR signalling, translation inhibition and survival. PMID- 29523874 TI - Extracellular anti-angiogenic proteins augment an endosomal protein trafficking pathway to reach mitochondria and execute apoptosis in HUVECs. AB - Classic endocytosis destinations include the recycling endosome returning to the plasma membrane or the late endosome (LE) merging with lysosomes for cargo degradation. However, the anti-angiogenic proteins angiostatin and isthmin, are endocytosed and trafficked to mitochondria (Mito) to execute apoptosis of endothelial cells. How these extracellular proteins reach mitochondria remains a mystery. Through confocal and super-resolution fluorescent microscopy, we demonstrate that angiostatin and isthmin are trafficked to mitochondria through the interaction between LE and Mito. Using purified organelles, the LE-Mito interaction is confirmed through in vitro lipid-fusion assay, as well as single vesicle total internal reflection fluorescent microscopy. LE-Mito interaction enables the transfer of not only lipids but also proteins from LE to Mito. Angiostatin and isthmin augment this endosomal protein trafficking pathway and make use of it to reach mitochondria to execute apoptosis. Cell fractionation and biochemical analysis identified that the cytosolic scaffold protein Na+/H+ exchanger regulatory factor 1 (NHERF1) associated with LE and the t-SNARE protein synaptosome-associated protein 25 kDa (SNAP25) associated with Mito form an interaction complex to facilitate LE-Mito interaction. Proximity ligation assay coupled with fluorescent microscopy showed that both NHERF1 and SNAP25 are located at the contacting face between LE and Mito. RNAi knockdown of either NHERF1 or SNAP25 suppressed not only the mitochondrial trafficking of angiostatin and isthmin but also their anti-angiogenic and pro-apoptotic functions. Hence, this study reveals a previously unrealized endosomal protein trafficking pathway from LE to Mito that allows extracellular proteins to reach mitochondria and execute apoptosis. PMID- 29523875 TI - Insulin sensitivity is reduced in children with high body-fat regardless of BMI. AB - PURPOSE: To examine the association between insulin sensitivity and adiposity in children stratified according to their body mass index (BMI: normal weight, NW; overweight or obese, OW/OB) and body-fat percentage (BF%: adipose or NonAdipose), and determine whether cardiorespiratory fitness (CRF) ameliorates any deleterious associations. METHODS: This prospective cohort study comprises a cross-sectional and longitudinal analyses of data collected at baseline and 2 years later on children (7.7-13.4 years) attending public school in Denmark. Levels of CRF were measured using the Andersen test, whereas BF% was measured by dual-energy X-ray absorptiometry (DXA). Fasting plasma glucose and insulin concentrations were measured and the homoeostatic model assessment of insulin resistance (HOMA-IR) used to assess insulin sensitivity. RESULTS: Approximately 8% of children classified as normal weight by BMI had high BF% (NW + Adipose). Children with high BF% had significantly higher insulin (NW + adipose: 32.3%; OW/OB + Adipose: 52.2%) and HOMA-IR scores (NW + Adipose: 32.3%; OW/OB + Adipose: 55.3%) than children classified as NW without high BF% (reference group; NW + NonAdipose). Adjusting for CRF reduced this difference, but did not completely ameliorate these associations. Longitudinally, children with high BF% (OW/OB + Adipose or NW + Adipose) had significantly worse insulin sensitivity 2 years later than NW + NonAdipose children (All p < 0.001). The few children (n = 14) who improved their BMI or BF% during the 2 years follow-up, no longer had significantly worse insulin sensitivity than children with NW + NonAdipose. CONCLUSION: High BF% in children is associated with significantly lower insulin sensitivity even when BMI is considered NW. Longitudinally, insulin sensitivity is lower in children with high BF% with or without high BMI. The CRF was a significant covariate in these models, but CRF did not completely ameliorate the effects of high BF% on insulin sensitivity. PMID- 29523877 TI - Diet-induced obesity suppresses cortical bone accrual by a neuropeptide Y dependent mechanism. AB - OBJECTIVE: To determine whether age and neuropeptide Y (NPY) were involved in the skeletal response to extended periods of diet-induced obesity. METHODS: Male wild type (WT) and NPY null (NPYKO) mice were fed a mild (23% fat) high-fat diet for 10 weeks from 6 or 16 weeks of age. Metabolism and bone density were assessed during feeding. Skeletal changes were assessed by microCT and histomorphometry. RESULTS: High-fat feeding in 6-week-old WT mice led to significantly increased body weight, adiposity and serum leptin levels, accompanied with markedly suppressed cortical bone accrual. NPYKO mice were less susceptible to fat accrual but, importantly, displayed a complete lack of suppression of bone accrual or cortical bone loss. In contrast, when skeletally mature (16 week old) mice underwent 10 weeks of fat feeding, the metabolic response to HFD was similar to younger mice, however bone mass was not affected in either WT or NPYKO. Thus, growing mice are particularly susceptible to the detrimental effects of HFD on bone mass, through suppression of bone accrual involving NPY signalling. CONCLUSION: This study provides new insights into the relationship between the opposing processes of a positive weight/bone relationship and the negative 'metabolic' effect of obesity on bone mass. This negative effect is particularly active in growing skeletons, which have heightened sensitivity to changes in obesity. In addition, NPY is identified as a fundamental driver of this negative 'metabolic' pathway to bone. PMID- 29523876 TI - Association between maternal mid-gestation vitamin D status and neonatal abdominal adiposity. AB - OBJECTIVES: Lower vitamin D status has been associated with adiposity in children through adults. However, the evidence of the impact of maternal vitamin-D status during pregnancy on offspring's adiposity is mixed. The objective of this study was to examine the associations between maternal vitamin-D [25(OH)D] status at mid-gestation and neonatal abdominal adipose tissue (AAT) compartments, particularly the deep subcutaneous adipose tissue linked with metabolic risk. METHODS: Participants (N = 292) were Asian mother-neonate pairs from the mother offspring cohort, Growing Up in Singapore Towards healthy Outcomes. Neonates born at >=34 weeks gestation with birth weight >=2000 g had magnetic resonance imaging (MRI) within 2-weeks post-delivery. Maternal plasma glucose using an oral glucose tolerance test and 25(OH)D concentrations were measured. 25(OH)D status was categorized into inadequate (<=75.0 nmol/L) and sufficient (>75.0 nmol/L) groups. Neonatal AAT was classified into superficial (sSAT), deep subcutaneous (dSAT), and internal (IAT) adipose tissue compartments. RESULTS: Inverse linear correlations were observed between maternal 25(OH)D and both sSAT (r = -0.190, P = 0.001) and dSAT (r = -0.206, P < 0.001). Each 1 nmol/L increase in 25(OH)D was significantly associated with reductions in sSAT (beta = -0.14 (95% CI: -0.24, 0.04) ml, P = 0.006) and dSAT (beta = -0.04 (-0.06, -0.01) ml, P = 0.006). Compared to neonates of mothers with 25(OH)D sufficiency, neonates with maternal 25(OH)D inadequacy had higher sSAT (7.3 (2.1, 12.4) ml, P = 0.006), and dSAT (2.0 (0.6, 3.4) ml, P = 0.005) volumes, despite similar birth weight. In the subset of mothers without gestational diabetes, neonatal dSAT was also greater (1.7 (0.3, 3.1) ml, P = 0.019) in neonates with maternal 25(OH)-inadequacy. The associations with sSAT and dSAT persisted even after accounting for maternal glycemia (fasting and 2-h plasma glucose). CONCLUSIONS: Neonates of Asian mothers with mid gestation 25(OH)D inadequacy have a higher abdominal subcutaneous adipose tissue volume, especially dSAT (which is metabolically similar to visceral adipose tissue in adults), even after accounting for maternal glucose levels in pregnancy. PMID- 29523878 TI - Improving therapeutic efficacy of IL-12 intratumoral gene electrotransfer through novel plasmid design and modified parameters. AB - The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines results in serious, potentially life-threatening, adverse effects. By contrast, nucleic acid transfer via electroporation (EP) is a safe and effective method of delivering plasmid-encoded cytokines to tumors. Intratumoral delivery of IL-12 plasmid DNA by electroporation (IT-pIL12-EP) produced objective response rates in Phase 2 clinical trials in metastatic melanoma. However, only 17.9% of patients receiving IT-pIL12-EP show a complete therapeutic response. Here, we sought to improve the antitumor efficacy of our clinical IT-pIL12-EP plasmid electroporation platform. We evaluated multiple plasmid designs for IL-12 expression. IL-12 expression from a plasmid incorporating a picornavirus-derived co-translational P2A site was the most effective in expressing IL-12p70. In addition, modifying the electroporation parameters improved transfection efficiency and expression of plasmid-derived IL-12p70, as well as its downstream effector IFN-gamma in vivo. Finally, using a murine melanoma model that is representative of the intended target patient population, we show that combining modified electroporation conditions with the pIL12-P2A plasmid expression enhances the systemic antitumor response. These improvements to the IT-pIL12-EP platform may improve patient clinical response rates and survival when translated to clinical trials. PMID- 29523879 TI - AAV1.NT-3 gene therapy increases muscle fiber diameter through activation of mTOR pathway and metabolic remodeling in a CMT mouse model. AB - Neurotrophin 3 (NT-3) has well-recognized effects on peripheral nerve and Schwann cells, promoting axonal regeneration and associated myelination. In this study, we assessed the effects of AAV.NT-3 gene therapy on the oxidative state of the neurogenic muscle from the TremblerJ (Tr J ) mice at 16 weeks post-gene injection and found that the muscle fiber size increase was associated with a change in the oxidative state of muscle fibers towards normalization of the fiber type ratio seen in the wild type. NT-3-induced fiber size increase was most prominent for the fast twitch glycolytic fiber population. These changes in the Tr J muscle were accompanied by increased phosphorylation levels of 4E-BP1 and S6 proteins as evidence of mTORC1 activation. In parallel, the expression levels of the mitochondrial biogenesis regulator PGC1alpha, and the markers of glycolysis (HK1 and PK1) increased in the TrJ muscle. In vitro studies showed that recombinant NT 3 can directly induce Akt/mTOR pathway activation in the TrkC expressing myotubes but not in myoblasts. In addition, myogenin expression levels were increased in myotubes while p75 NTR expression was downregulated compared to myoblasts, indicating that NT-3 induced myoblast differentiation is associated with mTORC1 activation. These studies for the first time have shown that NT-3 increases muscle fiber diameter in the neurogenic muscle through direct activation of mTOR pathway and that the fiber size increase is more prominent for fast twitch glycolytic fibers. PMID- 29523880 TI - Widespread transduction of astrocytes and neurons in the mouse central nervous system after systemic delivery of a self-complementary AAV-PHP.B vector. AB - Until recently, adeno-associated virus 9 (AAV9) was considered the AAV serotype most effective in crossing the blood-brain barrier (BBB) and transducing cells of the central nervous system (CNS), following systemic injection. However, a newly engineered capsid, AAV-PHP.B, is reported to cross the BBB at even higher efficiency. We investigated how much we could boost CNS transgene expression by using AAV-PHP.B carrying a self-complementary (sc) genome. To allow comparison, 6 weeks old C57BL/6 mice received intravenous injections of scAAV2/9-GFP or scAAV2/PHP.B-GFP at equivalent doses. Three weeks postinjection, transgene expression was assessed in brain and spinal cord. We consistently observed more widespread CNS transduction and higher levels of transgene expression when using the scAAV2/PHP.B-GFP vector. In particular, we observed an unprecedented level of astrocyte transduction in the cortex, when using a ubiquitous CBA promoter. In comparison, neuronal transduction was much lower than previously reported. However, strong neuronal expression (including spinal motor neurons) was observed when the human synapsin promoter was used. These findings constitute the first reported use of an AAV-PHP.B capsid, encapsulating a scAAV genome, for gene transfer in adult mice. Our results underscore the potential of this AAV construct as a platform for safer and more efficacious gene therapy vectors for the CNS. PMID- 29523881 TI - In vivo selection with lentiviral expression of Bcl2T69A/S70A/S87A mutant in hematopoietic stem cell-transplanted mice. AB - Current in vivo selections for hematopoietic stem cell (HSC)-based gene therapy are drug dependent and not without risk of cytotoxicity or tumorigenesis. We developed a new in vivo selection system with the non-phosphorylatable Bcl2 mutant Bcl2T69A/S70A/S87A (Bcl2AAA), which makes in vivo selection drug independent and without risk of cytotoxicity or tumorigenesis. We demonstrated in HSC-transplanted mice that Bcl2AAA facilitated efficient in vivo selection in the absence of any exogenously applied drugs under both myeloablative and non myeloablative conditioning. In mice transplanted with retrovirally transduced sca 1-positive bone marrow cells, the marked cell level increased from 26.38% of input transduced cells to 92.61 +/- 0.95% of peripheral blood cells for myeloablative transplantation or to 37.82 +/- 6.35% for non-myeloablative transplantation 6 months after transplantation. Bcl2AAA did not induce tumorigenesis and does not influence hematopoiesis and the function of the reconstituted blood system. However, the high-level constitutive expression of Bcl2AAA mediated by retroviral vector induced exhaustion of the marked cells after tertiary transplantation. Fortunately, low-level constitutive expression of Bcl2AAA driven by an internal promoter in lentiviral vector could both maintain the marked cell level (24.13 +/- 5.27%, 27.17 +/- 5.51%, 24.33 +/- 5.08%, and 22.07 +/- 4.44% for primary, secondary, tertiary, and quaternary recipients) and avoid the exhaustion of the marked cells even in quaternary recipients. Importantly, the low-level constitutive expression of Bcl2AAA did not induce tumorigenesis. Thus, the in vivo selection employing the low-level constitutive expression of Bcl2AAA provides a general platform which is relevant for widespread applications of gene therapy. PMID- 29523882 TI - HIV-based lentivirus-mediated vasoactive intestinal peptide gene delivery protects against DIO animal model of Type 2 diabetes. AB - Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM. VIP gene expression was shown by immunocytochemistry (ICC) and VIP peptide secretion was confirmed by ELISA both in HepG2 liver and MIN6 pancreatic beta cell lines. Functional properties of VIP were demonstrated by cAMP production assay and glucose-stimulated insulin secretion test (GSIS). Intraperitoneal (IP) delivery of LentiVIP vectors into mice significantly increased serum VIP concentrations compared to control mice. Most importantly, LentiVIP delivery in DIO animal model of T2DM resulted in improved insulin sensitivity, glucose tolerance and protection against STZ induced diabetes in addition to reduction in serum triglyceride/cholesterol levels. Collectively, these data suggest LentiVIP delivery should be evaluated as an experimental therapeutic approach for the treatment of T2DM. PMID- 29523883 TI - Prognostic importance of pretransplant disease status for posttransplant outcomes in patients with adult T cell leukemia/lymphoma. AB - Adult T cell leukemia/lymphoma (ATL) is an aggressive T cell lymphoma with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo HSCT) can be a curative treatment for ATL, a significant proportion of allo-HSCT recipients suffer from relapse/progression of ATL. Here we aimed to clarify the risk factors for and outcomes after posttransplant relapse/progression. We retrospectively reviewed 76 patients with ATL who received allo-HSCT at our institute. At the time of allo-HSCT, disease status was complete response in 17 patients, partial response in 29, stable disease (SD) in 18, and progressive disease (PD) in 12. In multivariate analysis, SD/PD at allo-HSCT, lymphoma subtype, reduced-intensity conditioning regimen, and time from diagnosis to allo HSCT were associated with risk of relapse/progression. After allo-HSCT, 26 patients had relapse/progression at a median of 66 days (range, 13-2064 days). The 2-year overall survival rate after relapse/progression was only 19%. Compared with acute-type, lymphoma-type experienced local recurrence more frequently (1/15 acute vs. 7/11 lymphoma, P < 0.01) and had a significantly longer OS after relapse/progression (median; 112 days in acute vs. 554 days in lymphoma, P < 0.01). Since the prognosis of patients with ATL who experienced relapse/progression after allo-HSCT was poor, strategies to reduce the risk of these outcomes are warranted. PMID- 29523884 TI - Extending autologous transplantation as first line therapy in multiple myeloma patients with severe renal impairment: a retrospective study by the SFGM-TC. AB - Renal impairment is a common complication of multiple myeloma (MM), accounting for 20-30% of MM patients at diagnosis and 40-50% of patients during the course of their disease. This feature is associated with poor prognosis and shorter survival as compared to patients with normal renal function (NRF). Therefore, therapeutic management is challenging as autologous stem cell transplantation (ASCT) is often not considered as a valuable strategy, mainly due to concerns of toxicity. In this retrospective and multicenter study, we included 55 MM patients with dialysis-dependent or independent renal failure who underwent high-dose melphalan-based ASCT in order to assess the efficacy outcomes and toxicities of this strategy. Response to ASCT was at least VGPR (very good PR) in 58% of patients and 96% of patients who also received bortezomib-based induction were at least in PR after ASCT. Median OS was 76 months and median PFS was 55 months, similarly to MM patients with NRF. In multivariate analysis, dose of melphalan (140 mg/m2) was correlated with better PFS (18 months, P = 0.005). Toxicities included febrile neutropenia (75%) and severe mucositis (34%). Overall, this work confirmed that ASCT conditioned by 140 mg/m2 melphalan is a beneficial procedure for MM patients with renal failure. PMID- 29523885 TI - Cost-effectiveness analysis of haploidentical vs matched unrelated allogeneic hematopoietic stem cells transplantation in patients older than 55 years. AB - Due to limited donor availability, high comorbidities, and cost issues, allogeneic hematopoietic stem cell transplant is not universally accessible. The aim of this study was to conduct a cost-effectiveness analysis of haploidentical vs matched unrelated transplant. This retrospective study included patients with hematological malignancies older than 55 years who underwent haploidentical or matched unrelated transplant between 2011 and 2013 in Marseille. The incremental cost-effectiveness ratio has been calculated using the mean overall survival and the mean transplant costs. Costs were calculated using a micro-costing strategy from the hospital perspective and a time horizon at 2 years. Haploidentical transplant was considered an innovative procedure and matched unrelated transplant as the reference. Probabilistic and sensitivity analyses were performed on the incremental cost-effectiveness ratio. During inclusion, 29 patients underwent haploidentical transplant and 63 matched unrelated transplant. In haploidentical and matched unrelated transplant, the mean overall survival was 19.4 (1.6) months and 15.1 (1.2) months (p = 0.06), respectively, and the mean cost was 98,304 (40,872) ? and 151,373 (65,742) ? (p < 0.01), respectively. The incremental cost-effectiveness ratio was assessed to -148,485 (-1,265,550; 64,368) ? per life year gained. Among older patients suffering from hematological malignancies, haploidentical transplant seemed in our analysis to be cost effective compared with matched unrelated transplant. PMID- 29523886 TI - Bortezomib is safe in and stabilizes pulmonary function in patients with allo HSCT-associated pulmonary CGVHD. AB - Pulmonary chronic graft-versus-host disease (p-CGVHD) following allogeneic HSCT is devastating with limited proven treatments. Although sporadically associated with pulmonary toxicity, the proteasome inhibitor bortezomib may be efficacious in p-CGVHD. We sought to establish safety and tolerability of bortezomib in pilot, open-label trial of patients with p-CGVHD. The primary endpoint was adverse events. Efficacy was assessed by comparing FEV1 decline prior to p-CGVHD diagnosis to during the bortezomib treatment period. The impact on pulmonary function testing of prior long-term bortezomib treatment in multiple myeloma (MM) patients was also assessed as a safety analysis. Seventeen patients enrolled in the pilot study with a mean time to p-CGVHD diagnosis of 3.36 years (+/-1.88 years). Bortezomib was well tolerated without early dropouts. The median FEV1 decline prior to the diagnosis of p-CGVHD was -1.06%/month (-5.36, -0.33) and during treatment was -0.25%/month (-9.42, 3.52). In the safety study, there was no significant difference in any PFT parameter between 73 patients who received bortezomib and 68 patients who did not for MM. Thus, we conclude that bortezomib has acceptable safety and tolerability in patients with compromised pulmonary function. The efficacy of proteosomal inhibition should be assessed in a large trial of chronic p-CGVHD patients. PMID- 29523887 TI - Epithelial barrier dysfunction as permissive pathomechanism in human intestinal graft-versus-host disease. PMID- 29523888 TI - Comparison of outcomes following transplantation with T-replete HLA haploidentical donors using post-transplant cyclophosphamide to matched related and unrelated donors for patients with AML and MDS aged 60 years or older. AB - Allografting from HLA-haploidentical donors (HID) is being increasingly utilized worldwide for patients lacking a conventional matched donor. However, its efficacy in older patients with AML and MDS is unclear. We analyzed 127 consecutive allografts for AML/MDS patients aged >= 60 years at our center to compare outcomes using HID to those of contemporaneous transplants using matched sibling (MRD) or matched unrelated (MUD) donors. Patient characteristics were similar except HID transplants were more likely in non-white patients and were more commonly performed with reduced intensity conditioning and a marrow graft. For MRD, MUD and HID transplants respectively, 2-year estimates of non-relapse mortality (17, 23, and 9%), relapse (32, 34, and 33%), overall survival (OS) (62, 55, and 67%) and disease-free survival (DFS) (51, 43, and 58%) were not significantly different. Maximum cumulative incidences of grade 2-4 acute GVHD were not different (27, 37, 39%), but incidences of NIH grade moderate to severe (39, 35, 15%, p = 0.028 MUD vs. HID, p = 0.026 MRD vs. HID) and severe chronic GVHD (9, 12, 0%, p = 0.030 MUD vs. HID, p = 0.009 MRD vs. HID) were significantly higher in MRD and MUD than in HID transplants. On multivariable analysis, donor type was not a significant determinant of OS, DFS, TRM, or relapse. However, male gender and high/very high Disease Risk Index (DRI) were associated with significantly higher rates of relapse (HR 1.94, p = 0.047 for male gender, HR 2.48, p = 0.004 for high/very high DRI) and lower OS (HR 1.94, p = 0.018 for male gender, HR 1.80, p = 0.025 for high/very high DRI). HIDs are an acceptable alternative to matched donors in older patients with AML and MDS. PMID- 29523889 TI - Peripheral blood stem cell mobilisation with G-CSF alone versus G-CSF and cyclophosphamide after bortezomib, cyclophosphamide and dexamethasone induction in multiple myeloma. AB - Bortezomib-based induction is often used in transplant-eligible patients with myeloma. The optimal peripheral blood stem cell (PBSC) mobilisation strategy in this context is unclear. We reviewed the efficacy of G-CSF alone (G-alone) vs. G CSF and cyclophosphamide (G-cyclo: standard dose: 1.5-2 g/m2; high dose: 3-4 g/m2) PBSC mobilisation strategies in 288 patients who only received bortezomib, cyclophosphamide and dexamethasone (VCD) induction prior to autograft across six apheresis centres from November 2012 to June 2017. 'Uncomplicated successful mobilisation' was defined as achieving a PBSC yield of >=4 * 106/kg within two aphereses, without plerixafor or mobilisation-associated toxicity (predominantly febrile neutropenia, FN). Success rates were 84% in G-cyclo standard dose (6% FN), 64% in G-cyclo high dose (18% FN) and 69% in G-alone (plerixafor successfully salvaged 8/9 patients). Median total stem cell yield was significantly higher with G-cyclo, but not different between the two cyclophosphamide doses. Age greater than the median of 61 years was associated with higher failure rates (22 vs. 11%, p = 0.01) and lower PBSC yield, especially in the G-alone group. Prior radiotherapy exposure did not impact on collection success. Our observations suggest that both G-cyclo standard dose and G-alone are reasonable mobilisation strategies. The former may be preferred if salvage plerixafor is unavailable. PMID- 29523890 TI - Pretransplant comprehensive geriatric assessment in hematopoietic cell transplantation: a single center experience. PMID- 29523891 TI - Potential for primary productivity in a globally-distributed bacterial phototroph. AB - Aerobic anoxygenic phototrophs (AAnPs) are common in marine environments and are associated with photoheterotrophic activity. To date, AAnPs that possess the potential for carbon fixation have not been identified in the surface ocean. Using the Tara Oceans metagenomic dataset, we have identified draft genomes of nine bacteria that possess the genomic potential for anoxygenic phototrophy, carbon fixation via the Calvin-Benson-Bassham cycle, and the oxidation of sulfite and thiosulfate. Forming a monophyletic clade within the Alphaproteobacteria and lacking cultured representatives, the organisms compose minor constituents of local microbial communities (0.1-1.0%), but are globally distributed, present in multiple samples from the North Pacific, Mediterranean Sea, the East Africa Coastal Province, and the Atlantic. This discovery may require re-examination of the microbial communities in the oceans to understand and constrain the role this group of organisms may play in the global carbon cycle. PMID- 29523892 TI - Predicting the structure of soil communities from plant community taxonomy, phylogeny, and traits. AB - There are numerous ways in which plants can influence the composition of soil communities. However, it remains unclear whether information on plant community attributes, including taxonomic, phylogenetic, or trait-based composition, can be used to predict the structure of soil communities. We tested, in both monocultures and field-grown mixed temperate grassland communities, whether plant attributes predict soil communities including taxonomic groups from across the tree of life (fungi, bacteria, protists, and metazoa). The composition of all soil community groups was affected by plant species identity, both in monocultures and in mixed communities. Moreover, plant community composition predicted additional variation in soil community composition beyond what could be predicted from soil abiotic characteristics. In addition, analysis of the field aboveground plant community composition and the composition of plant roots suggests that plant community attributes are better predictors of soil communities than root distributions. However, neither plant phylogeny nor plant traits were strong predictors of soil communities in either experiment. Our results demonstrate that grassland plant species form specific associations with soil community members and that information on plant species distributions can improve predictions of soil community composition. These results indicate that specific associations between plant species and complex soil communities are key determinants of biodiversity patterns in grassland soils. PMID- 29523894 TI - Cultivation of EPC and co-cultivation with MSC on beta-TCP granules in vitro is feasible without fibronectin coating but influenced by scaffolds' design. AB - INTRODUCTION: Meanwhile, the osteoconductive properties of frequently used synthetic bone grafts can be improved by the use of osteoinductive cells and growth factors. Nevertheless, the cultivation of endothelial progenitor cells (EPC) seems to be difficult and requires a pre-conditioning of the scaffolds with fibronectin. Additionally, the influence of the scaffolds' design on cell cultivation is not fully elucidated. METHODS: As scaffold, a commercially available beta-tricalcium phosphate was used. 5 * 105 EPC, or 5 * 105 MSC or a combination of each 2.5 * 105 cells was seeded onto the granules. We investigated seeding efficiency, cell morphology, cell metabolism, adherence, apoptosis and gene expression of EPC and MSC in this in vitro study on days 2, 6 and 10. RESULTS: Total number of adherent cells was higher on the beta-TCP without fibronectin coating. The number of cells in all approaches significantly declined when a solid beta-TCP was used. Metabolic activity of MSC was comparable throughout the scaffolds and increased until day 10. Additionally, the amount of supernatants VEGF was higher for MSC than for EPC. DISCUSSION: Our results demonstrate that a coating of the scaffold for successful cultivation of EPC in vitro is not necessary. Furthermore, our study showed that structural differences of the scaffolds significantly influenced cell adherence and metabolic activity. Thereby, the influence on EPC seems to be higher than on MSC. PMID- 29523893 TI - Redundant regulation of localization and protein stability of DmPar3. AB - Apical-basal polarity is an important characteristic of epithelia and Drosophila neural stem cells. The conserved Par complex, which consists of the atypical protein kinase C and the scaffold proteins Baz and Par6, is a key player in the establishment of apical-basal cell polarity. Membrane recruitment of Baz has been reported to be accomplished by several mechanisms, which might function in redundancy, to ensure the correct localization of the complex. However, none of the described interactions was sufficient to displace the protein from the apical junctions. Here, we dissected the role of the oligomerization domain and the lipid-binding motif of Baz in vivo in the Drosophila embryo. We found that these domains function in redundancy to ensure the apical junctional localization of Baz: inactivation of only one domain is not sufficient to disrupt the function of Baz during apical-basal polarization of epithelial cells and neural stem cells. In contrast, mutation of both domains results in a strongly impaired protein stability and a phenotype characterized by embryonic lethality and an impaired apical-basal polarity in the embryonic epithelium and neural stem cells, resembling a baz-loss of function allele. Strikingly, the binding of Baz to the transmembrane proteins E-Cadherin, Echinoid, and Starry Night was not affected in this mutant protein. Our findings reveal a redundant function of the oligomerization and the lipid-binding domain, which is required for protein stability, correct subcellular localization, and apical-basal cell polarization. PMID- 29523895 TI - [Correction to: Telephone enquiries on the topic of malignant hyperthermia]. PMID- 29523897 TI - Coordinating bracket torque and incisor inclination : Part 2: Reproducibility and statistical measures of the torque coordination angle (TCA). AB - PURPOSE: To determine the reproducibility and statistical measures of the torque coordination angle (TCA). METHODS: A total of 107 final cephalograms and corresponding casts were included, all reflecting treatment outcomes that met high qualitative standards, one of them being a Peer Assessment Rating (PAR) score of <=3. Based on these records, the TCA was measured as a parameter to identify differences related to tooth morphology and bracket position between the torque-relevant reference plane at the bracket base and the long axis of a tooth. All measurements were performed on upper and lower central incisors (U1 and L1). RESULTS: Several reproducibility assessments for the TCA measurements yielded good results, including objectivity at 1.26 +/- 0.81 degrees (U1) or 1.41 +/- 1.18 degrees (L1), examiner reliability at 1.30 +/- 0.97 degrees (U1) or 1.25 +/- 0.82 degrees (L1), and method reliability at 1.80 +/- 1.13 degrees (U1) or 1.53 +/- 1.07 degrees (L1). The statistical measures revealed a high degree of interindividual variability. With bracket placement 4.5 mm (U1) or 4.0 mm (L1) above the incisal edge, the differences between the maximum and minimum TCA values were similarly large in both jaws (21.0 degrees for U1 or 20.0 degrees for L1), given mean TCA values of 24.6 +/- 3.6 degrees (U1) or 22.9 +/- 4.3 degrees (L1). Moving the bracket placement from 3.5 to 5.5 mm (U1) or from 3.0 to 5.0 mm (L1) changed the mean TCA values by 4.5 degrees (U1) or 3.2 degrees (L1). CONCLUSIONS: The TCA is a suitable cephalometric parameter to identify differences related to tooth morphology and bracket placement. Given its high interindividual variability, the fixed torque value of a specific bracket system should not be expected to produce the same incisor inclinations across patients. PMID- 29523896 TI - A Review of the Current Evidence on Gadolinium Deposition in the Brain. AB - Over the past 3 years, gadolinium-based contrast agents have been linked to MRI signal changes in the brain, which have been found to be secondary to gadolinium deposition in the brain, particularly in the dentate nuclei and globus pallidus even in patients having an intact blood-brain barrier and a normal renal function. This tends to occur more in linear agents than with macrocyclic agents. Nonetheless, there has been no significant evidence that this has any clinical consequence. We reviewed the current evidence related to this new phenomenon and the precautionary approach taken by regulatory agencies. PMID- 29523898 TI - Understanding cardiovascular physiology of ageing. PMID- 29523899 TI - Association between survival and non-selective prehospital aspirin and heparin administration in patients with out-of-hospital cardiac arrest: a propensity score-matched analysis. PMID- 29523900 TI - Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability. AB - PURPOSE: Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood-brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge. METHODS: We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants' global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates. RESULTS: Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P = 0.008; P = 0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P = 0.02). Higher E-selectin was associated with worse global cognition (P = 0.006 at 3 months; P = 0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P = 0.05) and E-selectin (P = 0.02) were associated with increased disability in ADLs at 3 months. CONCLUSIONS: S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury. PMID- 29523901 TI - Association between spousal emotional abuse and reproductive outcomes of women in India: findings from cross-sectional analysis of the 2005-2006 National Family Health Survey. AB - PURPOSE: Spousal violence against women is a global public health problem. In India, approximately 40% of women report spousal violence. Like physical and sexual violence, emotional violence may be a determinant of women's health. This study explores the association between exposure to spousal emotional abuse and poor reproductive outcomes in Indian women. METHODS: Data on 60,350 women, collected in the Third Indian National Family Health Survey were analysed to assess the impact of spousal emotional abuse on seven reproductive outcomes: age at first birth, number of children, terminated pregnancies, unwanted pregnancies, access to prenatal and skilled delivery care, and breastfeeding. Spousal emotional abuse was assessed using two overlapping constructs: emotional violence and controlling behaviour. Multivariable logistic regression was used for analysis. RESULTS: Spousal emotional violence and controlling behaviour was reported by 16 and 38% of the women, respectively. In unadjusted analyses, spousal emotional violence was associated with all adverse reproductive outcomes, except breastfeeding. Controlling for socio-demographic risk factors attenuated the association, and further adjustment for other forms of violence removed all significant associations. Spousal controlling behaviour was significantly associated with all outcomes, except breastfeeding. The effects remained statistically significant in multivariable regression. CONCLUSIONS: Women's experience of violence may be under-reported. When other forms of violence were adjusted for, emotional violence was not associated with adverse reproductive outcomes, whereas controlling behaviour remained associated with all but one adverse reproductive outcome. Therefore, spousal controlling behaviour requires further investigation as a determinant of reproductive health. PMID- 29523902 TI - [Diagnosis and treatment of degenerative disc lesions of the wrist]. AB - BACKGROUND: The triangular fibrocartilage complex (TFCC) widens the radiocarpal joint and takes part in load transmission from the carpus to the forearm. It is thereby prone to degenerative changes. The painful situation that can accompany degeneration is called ulnar impaction. DIAGNOSIS: Clinical examination helps differentiate between various causes of ulnar-sided wrist pain. Standard X-rays are needed to determine ulnar variance and stress radiographs can depict narrowing of the ulnocarpal joint space under load. MRI may prove degeneration of the TFCC itself or may indirectly confirm ulnar impaction in the presence of bone marrow edema in the ulnar head or at the proximal ulnar aspect of the lunate. TREATMENT: If conservative treatment fails to alleviate symptoms, arthroscopy may be indicated. On the one hand, this completes the diagnostic cascade, and, on the other hand, allows decompression of the ulnocarpal joint space by resection of the TFCC with partial resection of the ulnar head (wafer resection). In the case of ongoing pain, ulnar shortening sufficiently alleviates ulnar-sided wrist pain. Thereby, modern standardized operation techniques are safe enough to ensure bone healing at the osteotomy site. The aim of alleviating ulnar-sided wrist pain is mostly achieved if the correct treatment option is chosen. PMID- 29523903 TI - Commentary on: Medial Osteoectomy as a Routine Procedure in Rhinoplasty: Six-Year Experience with an Innovative Technique. PMID- 29523904 TI - Risk Factor Analysis for Survival of Becker-Type Expander in Immediate Breast Reconstruction. AB - BACKGROUND: Breast reconstruction with a Becker-type expander is a common technique following mastectomy. However, inconsistency remains in the literature regarding risk factors for the survival of a Becker-type expander following immediate breast reconstruction. This study's purpose is to investigate possible risk factors for the Becker-type expander survival and to evaluate the complications related to expander removal following immediate breast reconstruction. METHODS: We performed a retrospective chart review of consecutive women who underwent a mastectomy followed by immediate breast reconstruction with a Becker-type expander from November 2010 to November 2016. Electronic medical records were analyzed retrospectively for demographic, clinical, operative characteristics, and outcomes. Univariate Cox regression analysis was performed to determine the risk factors for the survival of the Becker-type expander following immediate breast reconstruction. RESULTS: A total of 74 Becker-type expanders were used in 72 patients who underwent immediate breast reconstruction. The patients' ages ranged from 27 to 71 years, with a mean +/- standard deviation age of 44.6 +/- 9.1 years. The most frequent complication was capsular contracture which occurred in 25 breasts (33.8%) followed by mastectomy skin flap necrosis in 6 breasts (8.1%), seroma in 4 breasts (5.4%), nipple-areolar complex necrosis in 4 breasts (5.4%), hematoma in 3 breasts (4.1%), and infection in 2 breasts (2.7%). The mean intraoperative expander fill volume (109.6 +/- 66.9 cc [p = 0.039]) and mean total volume (386.5 +/- 94.7 cc [p = 0.034]) were both significantly lower for patients with capsular contracture compared with those without capsular contracture. In patients with partial NAC necrosis, the mean mastectomy specimen volume (737.5 +/- 242.8 cc) was significantly higher compared with patients without partial NAC necrosis (489.8 +/- 219.0 cc; p = 0.027). A univariate Cox regression analysis showed that smoking and neoadjuvant therapy were significantly associated with expander removal (p = 0.023 and p = 0.006, respectively). CONCLUSION: The total volume of the expander and intraoperative fill volume of the expander appear to be predictive factors in the development of capsular contracture. However, there is no statistically significant association between radiotherapy and capsular contracture or expander survival in contrast with other published reports. Our findings reveal that the main risk factors for the survival of Becker-type expanders following immediate breast reconstruction are smoking and neoadjuvant therapy. To our knowledge, this is the first study to evaluate the most likely risk factors associated with Becker-type expander survival in immediate breast reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29523905 TI - Intra-articular solitary fibrous tumor of the knee. AB - A rare case of intra-articular solitary fibrous tumor of the knee in an 84-year old man is presented. This case report illustrates that solitary fibrous tumor should be included in the extended differential diagnosis of an intra-articular soft tissue mass. PMID- 29523906 TI - Normal imaging laterality on magnetic resonance imaging of the medial epicondyle of the elbow on the dominant side of adolescent male baseball players. AB - OBJECTIVE: Multimodality elbow screening of adolescent baseball players shows apparent laterality in morphology and signal intensity of the medial epicondyle on dedicated magnetic resonance imaging. We aimed to elucidate actual imaging laterality in the medial epicondyle by comparing magnetic resonance images of the dominant and contradominant elbows and to clarify the clinical meaning and mechanism of this phenomenon. MATERIALS AND METHODS: We used a 0.2-T dedicated magnetic resonance imaging scanner. Eighty adolescent baseball players were enrolled and divided into four age groups: 9-10 years (13 patients); 11 years (28 patients); 12 years (24 patients) and 13-14 years (15 patients). The long and short axes of the ossification center and distance of the epiphyseal plate and the cartilage of the lower pole of the medial epicondyle were measured. Signal intensity of the ossification center was visually evaluated. RESULTS: Owing to their age, ossification and cartilage size on the dominant side were significantly larger in all boys (P < 0.01). All age groups had larger ossification and cartilage in the dominant elbow (P < 0.01). Ossification showed an apparent lower signal intensity on the dominant side (P < 0.01). CONCLUSIONS: Larger ossification and cartilage size of the medial epicondyle in the dominant elbow suggested that the medial collateral ligament to the medial epicondyle induces excessive repetitive tensile stress, but without clinical symptoms. Functional or microanatomical damage of the medial epicondyle may induce a lower ossification signal in the dominant elbow, thereby decreasing fatty bone marrow and inducing sclerotic changes. PMID- 29523907 TI - Shorter treatment times reduce the impact of intra-fractional motion : A real time 4DUS study comparing VMAT vs. step-and-shoot IMRT for prostate cancer. AB - PURPOSE: To evaluate the impact of shorter treatment times on intra-fractional motion of the prostate during external beam radiotherapy. METHODS: 53 h of intra fractional motion of the prostate were recorded in real-time by 4D ultrasound (4DUS) during 720 fractions in 28 patients, 14 of which whom treated with step and-shoot intensity-modulated radiotherapy (IMRT) and 14 of whom were treated with volumetric arc therapy (VMAT). RESULTS: The average VMAT fraction was recorded for 2 min 43 s and was substantially shorter than the average step-and shoot IMRT fraction at 6 min 13 s. Average radial displacement of the prostate per fraction was substantially and significantly reduced from 1.31 +/- 1.28 mm (n = 357 step-and-shoot IMRT fractions) to 0.96 +/- 1.04 mm (n = 363 VMAT fractions), p = 0.00004. Radial, vertical, and longitudinal root-mean-square (r. m. s.) error per fraction was reduced from 1.55 to 1.12 mm (-28%, p < 0.0001), from 1.16 to 0.77 mm (-34%, p < 0.0001), and from 0.79 to 0.56 mm (-29%, p = 0.0002), respectively. Lateral intra-fractional motion was generally small and did not differ significantly. The prostate remained during 95% of fraction time within 4.55 mm of the isocenter in case of step-and-shoot IMRT and within 2.45 mm in case of VMAT. The variance of displacements increased linearly with time, and the rate was the same for both step-and-shoot IMRT and VMAT patients. CONCLUSIONS: The position of the prostate changed less during shorter fractions, limiting fraction-average and end-of-fraction variance. This substantially and significantly reduced the impact of intra-fractional motion during shorter VMAT fractions as compared to longer step-and-shoot IMRT fractions. PMID- 29523908 TI - A Novel Wound Retractor Combining Continuous Irrigation and Barrier Protection Reduces Incisional Contamination in Colorectal Surgery. AB - BACKGROUND: Surgical site infection (SSI) remains a persistent and morbid problem in colorectal surgery. Key to its pathogenesis is the degree of intraoperative bacterial contamination at the surgical site. The purpose of this study was to evaluate a novel wound retractor at reducing bacterial contamination. METHODS: A prospective multicenter pilot study utilizing a novel wound retractor combining continuous irrigation and barrier protection was conducted in patients undergoing elective colorectal resections. Culture swabs were collected from the incision edge prior to device placement and from the exposed and protected incision edge prior to device removal. The primary and secondary endpoints were the rate of enteric and overall bacterial contamination on the exposed incision edge as compared to the protected incision edge, respectively. The safety endpoint was the absence of serious device-related adverse events. RESULTS: A total of 86 patients were eligible for analysis. The novel wound retractor was associated with a 66% reduction in overall bacterial contamination at the protected incision edge compared to the exposed incision edge (11.9 vs. 34.5%, P < 0.001), and 71% reduction in enteric bacterial contamination (9.5% vs. 33.3%, P < 0.001). The incisional SSI rate was 2.3% in the primary analysis and 1.2% in those that completed the protocol. There were no adverse events attributed to device use. CONCLUSIONS: A novel wound retractor combining continuous irrigation and barrier protection was associated with a significant reduction in bacterial contamination. Improved methods to counteract wound contamination represent a promising strategy for SSI prevention (NCT 02413879). PMID- 29523909 TI - Laparoscopic Versus Open Transverse Colectomy: A Systematic Review and Meta Analysis. AB - OBJECTIVES: The survival benefits, oncological adequacy, effectiveness, and safety of laparoscopic transverse colectomy (LTC) were compared with that of open transverse colectomy (OTC) using a meta-analysis. METHODS: EMBASE, Medline, Cochrane library, and Google scholar databases were searched for the last 20 years. Meta-analyses were performed using both fixed-effects and random-effects models. Five-year disease-free survival and overall survival were estimated using the inverse variance hazard ratio method. RESULTS: No survival benefits were detected between the two LTC and OTC cohorts. OTC showed shorter operative time by 38 min compared to LTC [mean difference (MD) = 38(15.23-60.77), p = 0.001]. However, LTC was associated with earlier postoperative recovery. The time to flatus and time to oral intake for LTC were MD = -1.12(-1.68 to -0.55, p = 0.001) and MD = -1.57(-2.38 to -0.76, p = 0.001), respectively. In addition, LTC was associated with a shorter hospital stay by 4.5 days [MD = -4.64(-7.52 to -1.75), p = 0.002]. CONCLUSIONS: Compared to OTC, LTC provides similar survival benefits, earlier postoperative recovery, and shorter hospital stay by 4.5 days. PMID- 29523910 TI - Tracking Multidrug-Resistant Klebsiella pneumoniae from an Italian Hospital: Molecular Epidemiology and Surveillance by PFGE, RAPD and PCR-Based Resistance Genes Prevalence. AB - Antimicrobial-resistant Klebsiella pneumoniae represent a global public health concern. K. pneumoniae strains isolated during 2010 and 2014-2016 within a single hospital of Molise Region, Central Italy, were analyzed testing antimicrobial susceptibility, clonality by pulsed-field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD)-PCR, and prevalence of carbapenem resistance genes by PCR. Forty isolates (23 wild-type in 2010 and 17 non-wild-type in 2014 2016) were collected from hospitalized patients (65.2 +/- 18.1 years old, 75% male, 80% from intensive care unit-ICU). K. pneumoniae showed multidrug-resistant profiles and 15 resistotypes were identified (discriminatory power D = 0.88). The 69.6 and 17.4% of isolates in 2010 resulted intermediate and resistant to imipenem, respectively, and 91.3% was sensitive to meropenem, while 88.2% of isolates of 2014-2016 were resistant to both antibiotics. PFGE identified 16 clusters versus 23 by RAPD, 26 pulsotypes versus 33 RAPD patterns (D >= 0.97). PFGE separated strains according to isolation period and identified an outbreak occurred in the ICU during December 2014 and January 2015. No strains harbored blaGES, blaIMP, blaNDM-1, and blaOXA-48 genes, as well as AmpC plasmid-mediated beta-lactamases genes. Only K. pneumoniae isolated during 2014-2016 were blaKPC positive. Prevalence of blaVIM was 87 and 76.5% during 2010 and 2014-2016, respectively. No strains colistin-resistant harbored mcr-1 plasmid-mediated resistance gene. The study findings underline an increased circulation of multidrug-resistant K. pneumoniae within the hospital, and the acquisition of carbapenem resistance mechanism. The implementation of surveillance and molecular characterization of isolates are needed to identify outbreaks, reduce the spread of resistance, and guide empirical therapy. PMID- 29523911 TI - A new anatomical insight into the aetiology of lateral trunk of suprascapular nerve neuropathy: isolated infraspinatus atrophy. AB - INTRODUCTION: Although the pathomechanism of isolated infraspinatus atrophy (ISA) in throwing sports is known to be traction, it is unclear why only some players are affected. One likely explanation is that the infraspinatus pulling force exerted by its contracture generate the compressive resultant component force (Fn) compressing the lateral trunk of the suprascapular nerve (LTSN) against the edge of scapular spine. This paper makes two key assumptions (1) the course of LTSN in relation to the scapular spine, defined as the suprascapular-scapular spine angle (SSSA) is the key individual anatomical feature influencing the Fn magnitude, and thus potentially ISA development (2) SSSA is correlated with scapular notch type. MATERIALS AND METHODS: The bone landmarks of the LTSN course were identified in 18 formalin-fixed cadaveric shoulders, and the SSSA was measured in 101 dry scapulae. The correlation between the SSSA and suprascapular notch type was evaluated. The Fn value was simulated mathematically based on the values of the SSSA of 101 dry scapulae and the prevalence of ISA in chosen throwing sports, as given in the literature: i.e., beach volleyball - 34% (group A1 - 34%; group A2-remaining 66% of scapulae) and tennis - 52% (group B1 - 52%; group B2-remaining 48% of scapulae). RESULTS: The mean SSSA value was 44.57 degrees (+/- 7.9) and Fn 79 N (+/- 13.1). No statistically significant correlation was revealed between suprascapular notch type and SSSA. Groups A1 and B1 possessed significantly lower SSSA values (p < 0.000) and significantly higher Fn magnitude (p < 0.000) than groups A2 and B2 respectively. The average difference of Fn was 28.1% between group A1 and A2 and 31% between group B1 and B2. CONCLUSIONS: The SSSA has a wide range of values depending on the individual: the angle influencing the magnitude of the compressive resultant force Fn on the LTSN at the lateral edge of the scapular spine via contraction of the infraspinatus muscle. The prevalence of ISA in throwing sports may be correlated with the SSSA of the LTSN. However, further combined clinical, MRI or/and CT studies are needed to confirm this. PMID- 29523912 TI - [Cladribine tablets : Oral immunotherapy of relapsing-remitting multiple sclerosis with short yearly treatment periods]. AB - BACKGROUND: The selective modulation of lymphocyte numbers and function is an attractive concept in the treatment of relapsing-remitting multiple sclerosis (RMS). OBJECTIVE: Cladribine tablets (Mavenclad(r)), an oral RMS medication with an innovative treatment concept, have been available since August 2017. This review article summarizes the currently available clinical study data on cladribine tablets and aspects of their use in clinical practice. RESULTS: Cladribine tablets are administered during two treatment phases of 8-10 (two times 4-5) days with a 1-year interval. The drug selectively reduces the number of T and B lymphocytes, which are subsequently gradually reconstituted with divergent kinetics. A pronounced and sustained effect on the clinical and paraclinical MS disease activity is achieved with good tolerability and a favorable overall safety profile. After completing the two short treatment phases, a relevant proportion of the treated patients experience a prolonged treatment-free period with absence of relevant disease activity. Regular monitoring of lymphocyte counts and reliable contraception during the required time frames are the most important safety measures. There is no evidence of an increased risk of malignancies. CONCLUSION: Cladribine tablets are an important addition to the therapeutic landscape in RMS. With patient-friendly short dosing periods and a favorable adverse event profile, cladribine tablets provide a sustained and strong reduction of MS disease activity. The primary target population for cladribine tablets is patients with relevant MS disease activity (highly active RMS) while on first-line treatment, e. g. with injectable disease modifying drugs. PMID- 29523913 TI - [Autoimmune encephalitis with psychotic symptoms : Diagnostics, warning signs and practical approach]. AB - Despite intensive research, a precise cause of schizophrenic and schizoaffective disorders has not yet been identified. Therefore, psychiatric diagnoses are still made based on clinical ICD-10/DSM-5 criteria and not on any objective markers; however, various causes or pathophysiological processes may ultimately lead to similar symptoms. An important task for the future of psychiatry is to identify disease subtypes with a distinct pathophysiology to develop more specific and causally acting therapies. A new diagnostic entity has become established in clinical neurology and psychiatry in recent years: autoimmune encephalitis with psychotic symptoms caused by specific antineuronal antibodies has been identified as a rare but potentially treatable cause of psychotic disorders; however, these inflammatory brain diseases are not reliably detected by routine psychiatric diagnostics. Therefore, this qualitative review is intended to provide structured support for clinical practice, which, guided by clinical warning signals, enables a rapid and reliable diagnosis as well as the initiation of immunotherapy. In the case of psychiatric symptoms, the additional onset of focal neurological signs, disturbances of consciousness and orientation, autonomic instability or epileptic seizures and electroencephalograph (EEG) abnormalities should always be followed by a more specific cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Although the scientific evidence indicates that only a small subgroup of patients is affected, the swift and correct diagnosis is of high therapeutic and prognostic relevance for the affected individuals. PMID- 29523914 TI - Identification of novel microRNA inhibiting actin cytoskeletal rearrangement thereby suppressing osteoblast differentiation. AB - We report the role of miR-1187 in regulation of osteoblast functions. Over expression of miR-1187 inhibited osteoblast differentiation. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay identified BMPR-II and ArhGEF-9 as direct targets of miR-1187. ArhGEF-9 activates Cdc42 which has a major role in actin reorganization. BMP-2 also induces actin polymerization. Role of miR-1187 in actin reorganization was determined by western blotting, immunofluorescence, and in vivo gene silencing studies. Reduced protein levels of BMPR-II, activated Cdc42, and downstream signaling molecules were observed in miR-1187-transfected osteoblasts. miR-1187 over-expression resulted in decreased actin polymerization. Additionally, P-cofilin, which does not bind F-actin, was decreased in miR-1187-transfected cells. These results were corroborated by administration of BMPR-II exogenously in miR-1187-transfected osteoblasts. Silencing of miR-1187 in neonatal mice mitigated all the inhibitory effects of miR-1187 on actin cytoskeletal rearrangement. Importantly, in vivo treatment of miR-1187 inhibitor to ovariectomized BALB/c mice led to significant improvement in trabecular bone microarchitecture. Overall, miR-1187 functions as a negative regulator of osteogenesis by repressing BMPR-II and ArhGEF-9 expression thus suppressing non-Smad BMP2/Cdc42 signaling pathway and inhibiting actin reorganization. miR-1187 functions as a negative regulator of osteogenesis by repressing BMPR-II expression, which in turn, suppresses non-Smad BMP2/Cdc42 signaling pathway, thus inhibiting actin cytoskeletal rearrangement. Silencing of miR-1187 significantly improves trabecular bone microarchitecture. As miR-1187 exerts a negative regulatory role in osteoblasts function, hence, we propose that therapeutic approaches targeting miR-1187 could be useful in enhancing the bone formation and treatment of pathological conditions of bone loss. PMID- 29523915 TI - [Penile cancer: diagnosis and staging]. AB - Penile cancer is often an obvious visual diagnosis but histologic verification should be obtained prior to treatment. The clinical examination should determine the tumor stage and whether it has infiltrated the cavernous bodies and/or the urethra and it should adequately assess the inguinal lymph nodes. Preoperative imaging of the lesion is only indicated in equivocal cases. Curative treatment requires the complete removal of the primary tumor and all metastatic lymph nodes. Lymph node management is the key prognostic factor in the treatment of penile cancer. No imagining technique such as the ultrasound, CT, MRI or PET/CT is able to adequately detect micrometastatic lymph nodes. Therefore, invasive (inguinal) lymph node diagnosis is indicated for all tumour stages from pT1G2. Over 90% of penile cancer cases can be cured with early diagnosis and adequate treatment if routine self-examination and physical examinations are regularly performed. PMID- 29523916 TI - The peptide lycosin-I attenuates TNF-alpha-induced inflammation in human umbilical vein endothelial cells via IkappaB/NF-kappaB signaling pathway. AB - OBJECTIVE: The peptide lycosin-I has anti-bacterial and anti-cancer capacities. However, the anti-inflammatory activity of lycosin-I remains unknown. We investigated whether lycosin-I could attenuate inflammation. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with lycosin-I before exposure to tumor necrosis factor-alpha (TNF-alpha). The expression of intercellular cell adhesion molecule-1 (ICAM-1), nuclear transcription factor-kappa B (NF-kappaB) p65 and inhibitory subunit of NF-kappaB alpha (IkappaBalpha) was evaluated by western blot. The expression of interleukin 6 (IL-6) and interleukin-8 (IL-8) was detected by quantitative RT-PCR or ELISA. Immunofluorescence analysis was used to determine the impact of lycosin-I on NF kappaB pathway. C57BL/6 mice were pretreated with lycosin-I before exposure with lipopolysaccharide (LPS). RESULTS: Lycosin-I significantly reduced the TNF-alpha enhanced expression of IL-6, IL-8 and ICAM-1. Lycosin-I also inhibited the human monocyte cells adhesion to HUVECs. We further demonstrated that lycosin-I could effectively suppress the reaction of endothelial cells to TNF-alpha by inhibiting IkappaBalpha degradation. Subsequently, the phosphorylation and translocation of NF-kappaB p65 could also be attenuated. Furthermore, lycosin-I exhibited a significant protection of C57BL/6 mice against LPS-induced death. CONCLUSIONS: Our results suggested that the anti-inflammatory activity of lycosin-I was associated with NF-kappaB activation and lycosin-I had potential to be a novel therapeutic candidate for inflammatory diseases. PMID- 29523917 TI - How do different extracorporeal circulation systems affect metoprolol bioavailability in coronary artery bypass surgery patients. AB - PURPOSE: Cardiac surgery and conventional extracorporeal circulation (CECC) impair the bioavailability of drugs administered by mouth. It is not known whether miniaturized ECC (MECC) or off-pump surgery (OPCAB) affect the bioavailability in similar manner. We evaluated the metoprolol bioavailability in patients undergoing CABG surgery with CECC, MECC, or having OPCAB. METHODS: Thirty patients, ten in each group, aged 44-79 years, scheduled for CABG surgery were administered 50 mg metoprolol by mouth on the preoperative day at 8-10 a.m. and 8 p.m., 2 h before surgery, and thereafter daily at 8 a.m. and 8 p.m. Blood samples were collected up to 12 h after the morning dose on the preoperative day and on first and third postoperative days. Metoprolol concentration in plasma was analyzed using liquid chromatography-mass spectrometry. RESULTS: The absorption of metoprolol was markedly reduced on the first postoperative day in all three groups, but recovered to the preoperative level on the third postoperative day. The geometric means (90% confidence interval) of AUC0-12 on the first and third postoperative days versus the preoperative day were 44 (26-74)% and 109 (86-139)% in the CECC-group, 28 (16-50)% and 79 (59-105)% in the MECC-group, and 26 (12 56)% and 96 (77-119)% in the OPCAB-group, respectively. Two patients in the CECC group and two in the MECC-group developed atrial fibrillation (AF). The bioavailability and the drug concentrations of metoprolol in patients developing AF did not differ from those who remained in sinus rhythm. CONCLUSION: The bioavailability of metoprolol by mouth was markedly reduced in the early phase after CABG with no difference between the CECC-, MECC-, and OPCAB-groups. PMID- 29523918 TI - Impact of Climate Variability and Landscape Patterns on Water Budget and Nutrient Loads in a Peri-urban Watershed: A Coupled Analysis Using Process-based Hydrological Model and Landscape Indices. AB - Nutrient discharge into peri-urban streams and reservoirs constitutes a significant pressure on environmental management, but quantitative assessment of non-point source pollution under climate variability in fast changing peri-urban watersheds is challenging. Soil and Water Assessment Tool (SWAT) was used to simulate water budget and nutrient loads for landscape patterns representing a 30 year progression of urbanization in a peri-urban watershed near Tianjin metropolis, China. A suite of landscape pattern indices was related to nitrogen (N) and phosphorous (P) loads under dry and wet climate using CANOCO redundancy analysis. The calibrated SWAT model was adequate to simulate runoff and nutrient loads for this peri-urban watershed, with Nash-Sutcliffe coefficient (NSE) and coefficient of determination (R2) > 0.70 and percentage bias (PBIAS) between -7 and +18 for calibration and validation periods. With the progression of urbanization, forest remained the main "sink" landscape while cultivated and urban lands remained the main "source" landscapes with the role of orchard and grassland being uncertain and changing with time. Compared to 1984, the landscape use pattern in 2013 increased nutrient discharge by 10%. Nutrient loads modelled under wet climate were 3-4 times higher than that under dry climate for the same landscape pattern. Results indicate that climate change could impose a far greater impact on runoff and nutrient discharge in a peri-urban watershed than landscape pattern change. PMID- 29523919 TI - Efficacy and Safety of Low-Dose Amiodarone Therapy for Tachyarrhythmia in Congenital Heart Disease. AB - Amiodarone (AMD) is a class III anti-arrhythmic drug that is highly effective for tachyarrhythmia treatment. AMD is widely used in adults with congenital heart disease (CHD); however, higher doses of AMD (> 200 mg/day) can cause various non cardiac side effects. The purpose of this study was to assess the efficacy, safety, and adverse events of low-dose AMD (<= 200 mg/day) for tachyarrhythmia in patients with CHD. We retrospectively studied 80 patients with CHD and tachyarrhythmia who received oral low-dose AMD (<= 200 mg/day) from January 2004 to March 2016. Low-dose AMD therapy was used to treat supraventricular tachycardia (SVT) in 51 patients and ventricular tachycardia (VT) in 29 patients. After a mean follow-up of 2.9 years for SVT and 3.2 years for VT, 36% and 65% of the patients with SVT and VT, respectively, were free from a first tachyarrhythmia recurrence for 3 years. The incidence of AMD-induced side effects was 23%, and all these cases consisted of thyroid dysfunction. Low-dose AMD was effective for the treatment of tachyarrhythmia in patients with CHD and had a relatively low incidence of side effects. These findings suggest that low-dose AMD is useful and effective for decreasing the frequency of tachyarrhythmia in patients with CHD and has a low incidence of side effects. PMID- 29523920 TI - Diminished Cardiac Performance and Left Ventricular Dimensions in Neonates with Congenital Diaphragmatic Hernia. AB - INTRODUCTION: Newborns with congenital diaphragmatic hernia (CDH) have varying degrees of pulmonary hypoplasia and pulmonary hypertension (PH), and there is limited evidence that cardiac dysfunction is present. We sought to study early neonatal biventricular function and performance in these patients by reviewing early post-natal echocardiography (ECHO) measurements and comparing them to normal term newborns. METHODS: Retrospective case-control study reviewing clinical and ECHO data on term newborns with CDH and normal controls born between 2009 and 2016. Patients were excluded if major anomalies, genetic syndromes, or no ECHO available. PH was assessed by ductal shunting and tricuspid regurgitant jet velocity. Speckle-tracking echocardiography was used to assess myocardial deformation using velocity vector imaging. RESULTS: Forty-four patients with CDH and 18 age-matched controls were analyzed. Pulmonary pressures were significantly higher in the CDH cohort (systolic pulmonary arterial pressure to systolic blood pressure of 103 +/- 13 vs. 78 +/- 29%, p = 0.0001). CDH patients had decreased RV fractional area change (FAC - 28.6 +/- 11.1 vs. 36.2 +/- 9.6%, p = 0.02), tricuspid annular plane of systolic excursion (TAPSE-5.6 +/- 1.6 vs. 8.6 +/- 1.6 mm, p = 0.0001), and RV outflow tract stroke distance (8.6 +/- 2.7 vs. 14.0 +/- 4.5 cm, p = 0.0001) compared with controls. The left ventricular (LV) ejection fraction was similar in both groups, but CDH patients had a decreased LV end diastolic volume by Simpson's rule (2.7 +/- 1.0 vs. 5.0 +/- 1.8 mL, p = 0.0001) and LVOT stroke distance (9.7 +/- 3.4 vs. 12.6 +/- 3.6 cm, p = 0.004). Biventricular global longitudinal strain (GLS) was markedly decreased in the CDH population compared to controls (RV-GLS: - 9.0 +/- 5.3 vs. - 19.5 +/- 1.4%, p = 0.0001; LV GLS: - 13.2 +/- 5.8 vs. - 20.8 +/- 3.5%, p = 0.0001). CONCLUSION: CDH newborns have evidence of biventricular dysfunction and decreased cardiac output. Abnormal function may be a factor in the non-response to pulmonary arterial vasodilators in CDH patients. A two-pronged management strategy aimed at improving cardiac function, as well as reducing pulmonary artery pressure in CDH newborns, may be warranted. PMID- 29523921 TI - Impact of Hybrid Stage 1 Palliation for Hypoplastic Left Heart Syndrome: Histopathological Findings. AB - The purpose of the study is to analyze the impact of hybrid stage 1 palliation on right ventricular myocardial pathology in hypoplastic left heart syndrome. Sufficient amount of right ventricular biopsies could be obtained from 16 of 32 patients who underwent Norwood operation between 2007 and 2013. Histopathological findings of right ventricle in patients who underwent primary Norwood operation (primary group, n = 5), patients with aortic atresia (HS1P AA group, n = 6) or aortic stenosis (HS1P AS group, n = 5) who underwent staged Norwood palliation following hybrid stage 1 palliation were compared. To eliminate the influence of right ventricular pressure afterload, right ventricular biopsies were obtained from patients with truncus arteriosus communis (TAC group, n = 6) at total correction. The percentage of myocardial fibrosis was significantly higher in both HS1P groups than in TAC group; moreover, it was significantly higher in HS1P AA group than in primary group. Capillary vascular density was significantly lower in all hypoplastic left heart syndrome groups than in TAC group. At the sub endocardial layer, collagen type I/III ratios were higher in HS1P AA group than in other hypoplastic left heart syndrome groups. The proportions of N-cadherin immunolocalized to myocyte termini were lower in all hypoplastic left heart syndrome groups than in TAC group. Right ventricle in hypoplastic left heart syndrome showed more significant ischemic change and myocardial immaturity than that in truncus arteriosus communis. Hybrid stage 1 palliation for aortic atresia would be a risk factor for further right ventricular myocardial ischemia. PMID- 29523922 TI - A Novel Mechanism for Improved Exercise Performance in Pediatric Fontan Patients After Cardiac Rehabilitation. AB - Patients with a Fontan circulation have impaired exercise capacity. Cardiac rehabilitation (CR) has shown promise in enhancing peak exercise parameters in this population, but an improvement in submaximal exercise has not been consistently demonstrated. We assessed the hypothesis that participation in CR will be associated with more efficient oxygen extraction and ventilation during submaximal exercise. In this prospective study, pediatric Fontans completed two 60 min CR sessions per week for 12 weeks. Cardiopulmonary exercise testing and stress echocardiography were performed at baseline and last CR session, and then compared with a paired sample t test. Ten pediatric Fontans completed the study. Five had tricuspid atresia and five had hypoplastic left heart syndrome. No serious adverse events occurred during CR sessions. Peak indexed oxygen consumption increased by a mean of 3.7 mL/kg/min (95% CI 1.5-5.9; p = 0.004), and peak oxygen pulse increased by a mean of 0.9 mL/beat (95% CI 0.4-1.4; p = 0.004). The peak respiratory exchange ratio did not change significantly. The significant difference in oxygen pulse became evident during submaximal exercise without a corresponding difference in echocardiographic stroke volume. Indexed oxygen consumption at ventilatory anaerobic threshold increased by a mean of 3.0 mL/kg/min (95% CI - 0.07 to 6.0; p = 0.055). The slope for the volume of expired ventilation to volume of carbon dioxide production improved by a mean of 4.5 (95% CI - 8.4 to - 0.6; p = 0.03). We observed significant improvements in both submaximal and peak exercise performance in pediatric Fontans undergoing CR with no serious adverse events. These changes appeared to be mediated, at least in part, by more efficient oxygen extraction and ventilation. PMID- 29523923 TI - Validation of Right Atrial Area as a Measure of Right Atrial Size and Normal Values of in Healthy Pediatric Population by Two-Dimensional Echocardiography. AB - Right atrial (RA) size is a prognostic indicator for heart failure and cardiovascular death in adults. Data regarding use of RA area (RAA) by two dimensional echocardiography as a surrogate for RA size and allometric modeling to define appropriate indexing of the RAA are lacking. Our objective was to validate RAA as a reliable measure of RA size and to define normal reference values by transthoracic echocardiography (TTE) in a large population of healthy children and develop Z-scores using a validated allometric model for indexing RAA independent of age, sex, and body size. Agreement between RAA and volume by 2D, 3D TTE, and MRI was assessed. RAA not volume by 2D TTE is an excellent surrogate for RA size. RAA/BSA1 has an inverse correlation with BSA with a residual relationship to BSA (r = - 0.54, p < 0.0001). The allometric exponent (AE) derived for the entire cohort (0.85) also fails to eliminate the residual relationship. The entire cohort divided into two groups with a BSA cut-off of 1 m2 to provide the best-fit allometric model (r = 0). The AE by least square regression analysis for each group is 0.95 and 0.88 for BSA < 1 m2 and > 1 m2, respectively, and was validated against an independent sample. The mean indexed RAA +/- SD for BSA <= 1 m2 and > 1 m2 is 9.7 +/- 1.3 cm2 and 8.7 +/- 1.3 cm2, respectively, and was used to derive Z-scores. RAA by 2D TTE is superior to 2D or 3D echocardiography-derived RA volume as a measure of RA size using CMR as the reference standard. RAA when indexed to BSA1, decreases as body size increases. The best-fit allometric modeling is used to create Z scores. RAA/BSA0.95 for BSA < 1 m2 and RAA/BSA0.88 for those with BSA > 1 m2 can be used to derive Z scores. PMID- 29523924 TI - The central zone has increased 68Ga-PSMA-11 uptake: "Mickey Mouse ears" can be hot on 68Ga-PSMA-11 PET. AB - PURPOSE: Given the good correlation between PSMA expression and intraglandular tumour aggressiveness based on immunohistochemistry, there is increasing interest in 68Ga-PSMA-11 PET/MRI for staging prostate cancer (PCA). Therefore, accurate knowledge of prostate anatomy as well as normal distribution of PSMA within the prostate gland is becoming essential. The aim of this study was to investigate the physiological intraprostatic distribution of 68Ga-PSMA-11. METHODS: We retrospectively analysed all patients who underwent a staging 68Ga-PSMA-11 PET/MRI scan between June 2016 and January 2018 for high-risk PCA, underwent radical prostatectomy in our institution, and gave written consent for further data analysis. In each patient, standardized volumes of interest (VOIs) were placed bilaterally in the central, transition and peripheral zones within the zonal anatomy according to T2 weighted sequences in the axial and coronal planes. VOIs were only placed if they were safely within healthy tissue without spillover from the PCA. SUVmax and SUVmean were determined and their differences among the regions were assessed using the Wilcoxon signed-ranks test. RESULTS: Of 283 consecutive patients scanned with 68Ga-PSMA-11 PET/MR, 31 were analysed. A total of 133 VOIs were placed, 46 in the central zone, 41 in the transition zone and 46 in the peripheral zone. Differences in SUVmax between the central zone (mean 3.9 +/- 0.58) and transition zone (mean 3.2 +/- 0.59) and between the central zone and peripheral zone (mean 2.7 +/- 0.54) were statistically significant (both p < 0.001). CONCLUSION: Our results suggest that higher 68Ga-PSMA-11 accumulation in the central zone than in the transition and peripheral zones is normal, and leads to a pattern resembling "Mickey Mouse ears" on 68Ga-PSMA-11 PET. This pattern could be helpful in avoiding false-positive interpretations of PET scans. PMID- 29523925 TI - TSPO PET with [18F]GE-180 sensitively detects focal neuroinflammation in patients with relapsing-remitting multiple sclerosis. AB - PURPOSE: Expression of the translocator protein (TSPO) is upregulated in activated macrophages/microglia and is considered to be a marker of neuroinflammation. We investigated the novel TSPO ligand [18F]GE-180 in patients with relapsing-remitting multiple sclerosis (RRMS) to determine the feasibility of [18F]GE-180 PET imaging in RRMS patients and to assess its ability to detect active inflammatory lesions in comparison with the current gold standard, contrast-enhanced magnetic resonance imaging (MRI). METHODS: Nineteen RRMS patients were prospectively included in this study. All patients underwent TSPO genotyping and were classified as high-affinity, medium-affinity or low-affinity binders (HAB/MAB/LAB). PET scans were performed after administration of 189 +/- 12 MBq [18F]GE-180, and 60-90 min summation images were used for visual analysis and assessment of standardized uptake values (SUV). The frontal nonaffected cortex served as a pseudoreference region (PRR) for evaluation of SUV ratios (SUVR). PET data were correlated with MRI signal abnormalities, i.e. T2 hyperintensity or contrast enhancement (CE). When available, previous MRI data were used to follow the temporal evolution of individual lesions. RESULTS: Focal lesions were identified as hot spots by visual inspection. Such lesions were detected in 17 of the 19 patients and overall 89 [18F]GE-180-positive lesions were found. TSPO genotyping revealed 11 patients with HAB status, 5 with MAB status and 3 with LAB status. There were no associations between underlying binding status (HAB, MAB and LAB) and the signal intensity in either lesions (SUVR 1.87 +/- 0.43, 1.95 +/- 0.48 and 1.86 +/- 0.80, respectively; p = 0.280) or the PRR (SUV 0.36 +/- 0.03, 0.40 +/- 0.06 and 0.37 +/- 0.03, respectively; p = 0.990). Of the 89 [18F]GE-180-positive lesions, 70 showed CE on MRI, while the remainder presented as T2 lesions without CE. SUVR were significantly higher in lesions with CE than in those without (2.00 +/- 0.53 vs. 1.60 +/- 0.15; p = 0.001). Notably, of 19 [18F]GE-180-positive lesions without CE, 8 previously showed CE, indicating that [18F]GE-180 imaging may be able to detect lesional activity that is sustained beyond the blood-brain barrier breakdown. CONCLUSION: [18F]GE-180 PET can detect areas of focal macrophage/microglia activation in patients with RRMS in lesions with and without CE on MRI. Therefore, [18F]GE-180 PET imaging is a sensitive and quantitative approach to the detection of active MS lesions. It may provide information beyond contrast-enhanced MRI and is readily applicable to all patients. [18F]GE-180 PET imaging is therefore a promising new tool for the assessment of focal inflammatory activity in MS. PMID- 29523926 TI - Parametric mapping using spectral analysis for 11C-PBR28 PET reveals neuroinflammation in mild cognitive impairment subjects. AB - PURPOSE: Neuroinflammation and microglial activation play an important role in amnestic mild cognitive impairment (MCI) and Alzheimer's disease. In this study, we investigated the spatial distribution of neuroinflammation in MCI subjects, using spectral analysis (SA) to generate parametric maps and quantify 11C-PBR28 PET, and compared these with compartmental and other kinetic models of quantification. METHODS: Thirteen MCI and nine healthy controls were enrolled in this study. Subjects underwent 11C-PBR28 PET scans with arterial cannulation. Spectral analysis with an arterial plasma input function was used to generate 11C PBR28 parametric maps. These maps were then compared with regional 11C-PBR28 VT (volume of distribution) using a two-tissue compartment model and Logan graphic analysis. Amyloid load was also assessed with 18F-Flutemetamol PET. RESULTS: With SA, three component peaks were identified in addition to blood volume. The 11C PBR28 impulse response function (IRF) at 90 min produced the lowest coefficient of variation. Single-subject analysis using this IRF demonstrated microglial activation in five out of seven amyloid-positive MCI subjects. IRF parametric maps of 11C-PBR28 uptake revealed a group-wise significant increase in neuroinflammation in amyloid-positive MCI subjects versus HC in multiple cortical association areas, and particularly in the temporal lobe. Interestingly, compartmental analysis detected group-wise increase in 11C-PBR28 binding in the thalamus of amyloid-positive MCI subjects, while Logan parametric maps did not perform well. CONCLUSIONS: This study demonstrates for the first time that spectral analysis can be used to generate parametric maps of 11C-PBR28 uptake, and is able to detect microglial activation in amyloid-positive MCI subjects. IRF parametric maps of 11C-PBR28 uptake allow voxel-wise single-subject analysis and could be used to evaluate microglial activation in individual subjects. PMID- 29523927 TI - [Aerogenic tumor seeding : A new invasive criterion for lung carcinomas]. AB - The new concept of spread through air spaces (STAS) was introduced for pulmonary adenocarcinomas in the 2015 WHO classification for lung cancer. Yet, available data demonstrate that STAS is of high prognostic impact and associated with specific clinic-pathological characteristics. This article provides a comprehensive overview of recent developments in this field. PMID- 29523928 TI - MicroRNA-218 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells and Accelerates Bone Fracture Healing. AB - As a regulator of osteogenesis, microRNA-218 (miR-218) is reported to promote osteogenesis of mesenchymal stem cells (MSCs). However, the in vivo osteogenic effect of miR-218 remains elusive. In this study, miR-218 was confirmed to promote osteogenic differentiation of MSCs by stimulating the alkaline phosphatase activity, calcium nodule formation, and osteogenic marker gene expression. For in vivo study, the miR-218-overexpressing BMSCs were locally administrated into the fracture sites in a femur fracture mouse model. Based on the X-rays, micro-computed tomography, mechanical testing, histology, and immunohistochemistry examinations, miR-218 overexpression improved new bone formation and accelerated fracture healing. These findings suggest that miR-218 may be a promising therapeutic target for bone repair in future clinical applications. PMID- 29523929 TI - Pulsed electromagnetic fields preserve bone architecture and mechanical properties and stimulate porous implant osseointegration by promoting bone anabolism in type 1 diabetic rabbits. AB - : The effects of exogenous pulsed electromagnetic field (PEMF) stimulation on T1DM-associated osteopathy were investigated in alloxan-treated rabbits. We found that PEMF improved bone architecture, mechanical properties, and porous titanium (pTi) osseointegration by promoting bone anabolism through a canonical Wnt/beta catenin signaling-associated mechanism, and revealed the clinical potential of PEMF stimulation for the treatment of T1DM-associated bone complications. INTRODUCTION: Type 1 diabetes mellitus (T1DM) is associated with deteriorated bone architecture and impaired osseous healing potential; nonetheless, effective methods for resisting T1DM-associated osteopenia/osteoporosis and promoting bone defect/fracture healing are still lacking. PEMF, as a safe and noninvasive method, have proven to be effective for promoting osteogenesis, whereas the potential effects of PEMF on T1DM osteopathy remain poorly understood. METHODS: We herein investigated the effects of PEMF stimulation on bone architecture, mechanical properties, bone turnover, and its potential molecular mechanisms in alloxan-treated diabetic rabbits. We also developed novel nontoxic Ti2448 pTi implants with closer elastic modulus with natural bone and investigated the impacts of PEMF on pTi osseointegration for T1DM bone-defect repair. RESULTS: The deteriorations of cancellous and cortical bone architecture and tissue-level mechanical strength were attenuated by 8-week PEMF stimulation. PEMF also promoted osseointegration and stimulated more adequate bone ingrowths into the pore spaces of pTi in T1DM long-bone defects. Moreover, T1DM-associated reduction of bone formation was significantly attenuated by PEMF, whereas PEMF exerted no impacts on bone resorption. We also found PEMF-induced activation of osteoblastogenesis-related Wnt/beta-catenin signaling in T1DM skeletons, but PEMF did not alter osteoclastogenesis-associated RANKL/RANK signaling gene expression. CONCLUSION: We reveal that PEMF improved bone architecture, mechanical properties, and pTi osseointegration by promoting bone anabolism through a canonical Wnt/beta-catenin signaling-associated mechanism. This study enriches our basic knowledge for understanding skeletal sensitivity in response to external electromagnetic signals, and also opens new treatment alternatives for T1DM-associated osteopenia/osteoporosis and osseous defects in an easy and highly efficient manner. PMID- 29523930 TI - DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response. AB - Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 / 5.0 ug/cm2, 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (>= 10%) between the asbestos dose at 5 ug/cm2 and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = - 1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target. PMID- 29523931 TI - In utero and lactational exposure to BDE-47 promotes obesity development in mouse offspring fed a high-fat diet: impaired lipid metabolism and intestinal dysbiosis. AB - In this study, we investigated the effects of in utero and lactational exposure to BDE-47 on the progression of obesity and metabolic dysfunction in a diet induced obesity model. Pregnant ICR mice were treated via oral gavage with low doses of BDE-47 (0, 0.002, and 0.2 mg/kg body weight) from gestational day 6 to postnatal day 21. After weaning, male offspring were fed an AIN93-based normal diet (ND) or high-fat diet (HFD: 60% calories from fat) for 14 weeks. We examined body weight, liver weight, histopathology, blood biochemistry, gene expression, and serum metabolic changes. A combination of 16S rRNA gene sequencing and 1H NMR based metabolomics was conducted to examine the effects of BDE-47 on the gut microbiome. Results showed that in utero and lactational exposure to BDE-47 caused a worsening of HFD-induced obesity, hepatic steatosis, and injury; impaired glucose homeostasis and metabolic dysfunction, and mRNA levels of genes involved in lipid metabolism were significantly altered in the BDE-47-treated HFD group. The gut microbiome were perturbed by BDE-47, causing diversity reduction, compositional alteration, and metabolic changes. These changes were more pronounced for BDE-47-treated HFD mice. All these results indicate that early life exposure to low doses of BDE-47 can promote obesity and the development of metabolic dysfunction. PMID- 29523932 TI - Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone. AB - Adult neurogenesis is the process by which neural stem cells give rise to new functional neurons in specific regions of the adult brain, a process that occurs throughout life. Significantly, neurodegenerative and psychiatric disorders present suppressed neurogenesis, activated microglia, and neuroinflammation. Traffic-related air pollution has been shown to adversely affect the central nervous system. As the cardinal effects of air pollution exposure are microglial activation, and ensuing oxidative stress and neuroinflammation, we investigated whether acute exposures to diesel exhaust (DE) would inhibit adult neurogenesis in mice. Mice were exposed for 6 h to DE at a PM2.5 concentration of 250-300 MUg/m3, followed by assessment of adult neurogenesis in the hippocampal subgranular zone (SGZ), the subventricular zone (SVZ), and olfactory bulb (OB). DE impaired cellular proliferation in the SGZ and SVZ in males, but not females. DE reduced adult neurogenesis, with male mice showing fewer new neurons in the SGZ, SVZ, and OB, and females showing fewer new neurons only in the OB. To assess whether blocking microglial activation protected against DE-induced suppression of adult hippocampal neurogenesis, male mice were pre-treated with pioglitazone (PGZ) prior to DE exposure. The effects of DE exposure on microglia, as well as neuroinflammation and oxidative stress, were reduced by PGZ. PGZ also antagonized DE-induced suppression of neurogenesis in the SGZ. These results suggest that DE exposure impairs adult neurogenesis in a sex-dependent manner, by a mechanism likely to involve microglia activation and neuroinflammation. PMID- 29523933 TI - Predator-prey interactions of nematode-trapping fungi and nematodes: both sides of the coin. AB - Nematode-trapping fungi develop complex trapping devices to capture and consume nematodes. The dynamics of these organisms is especially important given the pathogenicity of nematodes and, consequently, the potential application of nematode-trapping fungi as biocontrol agents. Furthermore, both the nematodes and nematode-trapping fungi can be easily grown in laboratories, making them a unique manipulatable predator-prey system to study their coevolution. Several different aspects of these fungi have been studied, such as their genetics and the different factors triggering trap formation. In this review, we use the nematode trapping fungus Arthrobotrys oligospora (which forms adhesive nets) as a model to describe the trapping process. We divide this process into several stages; namely attraction, recognition, trap formation, adhesion, penetration, and digestion. We summarize the latest findings in the field and current knowledge on the interactions between nematodes and nematode-trapping fungi, representing both sides of the predator-prey interaction. PMID- 29523934 TI - Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells. AB - Cell-penetrating peptides (CPPs) can translocate across the plasma membrane of living eukaryotic cells and enter the cytosol without significantly affecting cell viability. Consequently, CPPs have been used for the intracellular delivery of biological cargo such as proteins and oligonucleotides. However, the mechanisms underlying the translocation of CPPs across the plasma membrane remain unclear. In this mini-review, we summarize the experimental results regarding the entry of CPPs into lipid bilayer vesicles obtained using three methods: the large unilamellar vesicle (LUV) suspension method, the giant unilamellar vesicle (GUV) suspension method, and the single GUV method. The advantages and disadvantages of these methods are also discussed. Experimental results to date clearly indicate that CPPs can translocate across lipid bilayers and enter the vesicle lumen. Three models for the mechanisms and pathways by which CPPs translocate across lipid bilayers are described: (A) through pores induced by CPPs, (B) through transient prepores, and (C) via formation of inverted micelles. Both the pathway of translocation and the efficiency of entry of CPPs depend on the lipid composition of the bilayer and the type of CPP. We also describe the interaction of CPPs with bacterial cells. Some CPPs have strong antimicrobial activities. There are two modes of action of CPPs on bacterial cells: CPPs can induce damage to the plasma membrane and thus increase permeability, or CPPs enter the cytosol of bacterial cells without damaging the plasma membrane. The information currently available on the elementary processes by which CPPs enter lipid bilayer vesicles and bacterial cells is valuable for elucidating the mechanisms of entry of CPPs into the cytosol of various eukaryotic cells. PMID- 29523935 TI - Impacts of environmental conditions on product formation and morphology of Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica is an industrially important microorganism with distinctive physiological and metabolic characteristics. A variety of external factors (e.g., pH, temperature, and nutrient availability) influences the behavior of the yeast and may act as stress conditions which the cells must withstand and adapt. In this mini review, the impacts of environmental factors on the morphology and metabolite production by Y. lipolytica are summarized. In this regard, detailed insights into the effectors involved in the dimorphic transition of Y. lipolytica, the cultivation conditions employed, as well as the methods applied for the morphological characterization are highlighted. Concerning the metabolism products, a special focus is addressed on lipid and citric acid metabolites which have attracted significant attention in recent years. The dependence of lipid and citric acid productivity on key process parameters, such as media composition and physico-chemical variables, is thoroughly discussed. This review attempts to provide a recent update on the topic and will serve as a meaningful resource for researchers working in the field. PMID- 29523936 TI - Streptomyces clavuligerus shows a strong association between TCA cycle intermediate accumulation and clavulanic acid biosynthesis. AB - Clavulanic acid (CA) is produced by Streptomyces clavuligerus (S. clavuligerus) as a secondary metabolite. Knowledge about the carbon flux distribution along the various routes that supply CA precursors would certainly provide insights about metabolic performance. In order to evaluate metabolic patterns and the possible accumulation of tricarboxylic acid (TCA) cycle intermediates during CA biosynthesis, batch and subsequent continuous cultures with steadily declining feed rates were performed with glycerol as the main substrate. The data were used to in silico explore the metabolic capabilities and the accumulation of metabolic intermediates in S. clavuligerus. While clavulanic acid accumulated at glycerol excess, it steadily decreased at declining dilution rates; CA synthesis stopped when glycerol became the limiting substrate. A strong association of succinate, oxaloacetate, malate, and acetate accumulation with CA production in S. clavuligerus was observed, and flux balance analysis (FBA) was used to describe the carbon flux distribution in the network. This combined experimental and numerical approach also identified bottlenecks during the synthesis of CA in a batch and subsequent continuous cultivation and demonstrated the importance of this type of methodologies for a more advanced understanding of metabolism; this potentially derives valuable insights for future successful metabolic engineering studies in S. clavuligerus. PMID- 29523937 TI - Dynamic Water Hydrogen-Bond Networks at the Interface of a Lipid Membrane Containing Palmitoyl-Oleoyl Phosphatidylglycerol. AB - Lipid membrane interfaces are complex environments that host essential cellular processes such as binding of proteins or drug molecules. A key open question is how water molecules at the interface of membranes with anionic lipids participate in protein binding. To address this question, we studied the dynamics of water hydrogen bonding at the interface of membranes composed of phosphatidylcholine and phosphatidylglycerol, and implemented an algorithm to identify hydrogen bonded networks at the interface of a lipid membrane, and to characterize their dynamics and linear connections. We find that the membrane interface is characterized by a rich network of hydrogen-bonded water chains that bridge lipid headgroups, some of which form transient lipid clusters. Water-mediated bridges between with lipid phosphate groups are dynamic, with residence lifetimes on the order of picoseconds. These clusters of water/lipid headgroup hydrogen bonds could provide a platform for the binding of proteins or of drug molecules with cationic groups. PMID- 29523939 TI - Determination of phthalic acid esters in different baby food samples by gas chromatography tandem mass spectrometry. AB - In this work, a new method has been developed for the determination of 14 phthalic acid esters (i.e., benzylbutyl phthalate (BBP), bis-2-n-butoxyethyl phthalate (DBEP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), bis-2 ethoxyethyl phthalate (DEEP), diethyl phthalate (DEP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), bis-isopentyl phthalate (DIPP), bis (2 methoxyethyl) phthalate (DMEP), dimethyl phthalate (DMP), di-n-octyl phthalate (DNOP), bis-n-pentyl phthalate (DNPP), dipropyl phthalate (DPP)) and one adipate (bis (2-ethylhexyl) adipate (DEHA)) in different baby foods. Separation was carried out by gas chromatography triple quadrupole tandem mass spectrometry while the previous extraction of the samples was carried out using the QuEChERS method. The methodology was validated for four baby food samples (two fruit compotes of different compositions and two meat and fish purees with vegetables) using dibutyl phthalate-3,4,5,6-d4 (DBP-d4) as internal standard. Determination coefficients (R2) of matrix-matched calibration curves were above 0.9922 in all cases while relative recovery values ranged between 70 and 120%, with relative standard deviation values below 19%. The limits of quantification of the method ranged between 0.03 and 1.11 MUg/kg. Finally, the analysis of commercially available samples was carried out finding the presence of BBP, DEHA, DEP, DIDP, and DPP in some of the studied samples. PMID- 29523940 TI - Highly cysteine-selective fluorescent nanoprobes based on ultrabright and directly synthesized carbon quantum dots. AB - Strongly green fluorescent carbon dots (CQDs) have been directly synthesized from 2,4-diaminophenylhydrazine and 2-hydroxy-5-methylisophthalaldehyde through a facile solvothermal method. The novel CQDs exhibit high fluorescence quantum yield and excellent water solubility due to the abundant amino and hydroxy groups on their surface. The use of the as-prepared CQDs combined with Cu2+ constructed a "turn-on" switch cysteine-responsive nanoprobe. In the CQDs-Cu2+ assemblies, the binding of Cu2+ to CQDs results in the fluorescence quenching of CQDs by electron transfer mechanism, while the addition of cysteine leads to the fluorescence recovery because of the competitive binding between cysteine and CQDs to Cu2+. The nanoprobes showed high sensitivity to cysteine with the detection limit of 2.6 nmol L-1. The selectivity investigation results demonstrated that the Cu2+-integrated nanoparticles were highly selective toward cysteine over the other amino acids and biologically related metal ions. The proposed nanoprobe was then employed for detecting the recovery of cysteine in rabbit serum and plasma samples and imaging the cysteine in cancer cells, and the recovery was found to be 98.2-104.0%. This "synthesis-modification integration" strategy for the fabrication of CQDs may offer a new sight for the preparation of multifunctional nanostructures and broadening the application of CQDs in bioimaging. Graphical abstract Fluorescent carbon dots (CQDs) were directly synthesized from 2,4-diaminophenylhydrazine and 2-hydroxy-5 methylisophthalaldehyde. CQDs exhibit high fluorescence quantum yield and excellent water solubility due to the abundant amino and hydroxy groups on their surface. The use of CQDs combined with Cu2+ constructed a cysteine-responsive nanoprobe, which showed high sensitivity to cysteine with the detection limit of 2.6 nM. PMID- 29523941 TI - Development and in-house validation of a rapid and simple to use ELISA for the detection and measurement of the mycotoxin sterigmatocystin. AB - Sterigmatocystin (STG) is a highly toxic secondary fungal metabolite structurally closely related to the well-known carcinogenic aflatoxins. Its presence has been reported in grains and grain-based products as well as in other foodstuffs like nuts, green coffee beans, spices, beer and cheese. Due to the lack of suitable data on the occurrence of STG, in 2013, the European Food Safety Authority (EFSA) could not characterise its risk for human health and recommended that more data on STG in food and feed needed to be collected. In order to provide a new tool for the specific detection of STG, a competitive enzyme-linked immunosorbent assay (ELISA) was developed, optimised and validated in this study based on a sensitive monoclonal antibody specific to STG with no cross-reactivity with aflatoxins. The sample preparation method for rice, wheat and maize was based on a modified QuEChERS (quick, easy, cheap, effective, rugged and safe) approach. The assay was validated for the detection of STG in rice, wheat and maize in accordance with the guidelines for validation of semi-quantitative screening methods included in Commission Regulation (EU) 519/2014. The screening target concentration (STC) was set at 1.5 MUg/kg. The cutoffs for rice, wheat and maize were 1.2, 1.2 and 1.3 MUg/kg and the false suspected rates were 0.34, 1.15 and 0.78%, respectively. Good correlation was found between the results obtained by the STG ELISA and LC-MS/MS method for naturally contaminated rice samples. This validated method can be applied as a sensitive and high-throughput screening for the presence of STG in a range of agricultural commodities. Graphical abstract A new enzyme-linked immunosorbent assay based on an antibody specific to sterigmatocystin for the detection of this mycotoxin in corn, wheat and rice. PMID- 29523942 TI - Hollow fiber microextraction: a new hybrid microextraction technique for trace analysis. AB - A new hybrid microextraction technique (hollow fiber microextraction) is presented that uses the main concepts and advantages of the modern miniaturized devices used for trace analysis. This novel analytical approach uses devices made of polypropylene membranes (10.0 mm long and 0.6 mm internal diameter) in which convenient organic solvents are embedded that promote fast kinetics during the enrichment process, using the floating sampling technology concept. An innovative analytical cycle is also proposed by use of low-cost disposable devices during the microextraction stage together with a user-friendly ("single liquid desorption step") back-extraction stage in compliance with green analytical chemistry principles. To evaluate the performance of the proposed technique, 18 polycyclic aromatic hydrocarbons (PAHs) were used as model compounds and were monitored by gas chromatography coupled with mass spectrometry. Under optimized experimental conditions, assays performed on 25 mL aqueous samples spiked with the PAHs at trace level yielded average recoveries between (14.5 +/- 8.2)% (dibenzo[a,h]anthracene) and (90.4 +/- 8.4)% (benzo[a]anthracene) with use of a device in which n-nonane had been embedded. Low detection limits were also achieved (2.50-6.00 ng L-1), as well as good linear dynamic ranges (20.00-2000.00 ng L-1), with suitable coefficients of determination (r2 > 0.9905) and appropriate precision (relative standard deviation below 15%). By use of the standard addition method, the proposed hybrid microextraction technique had remarkable performance to monitor PAHs at the ultratrace level in several types of matrices, including surface water, wastewater, soil, tea, and fish liver samples. From the data obtained, the new hybrid hollow fiber microextraction technique proved to be user-friendly, eco-friendly, cost-effective, and very competitive for routine work. In short, the novel microextraction technique proposed herein is a remarkable alternative to other well-established microextraction techniques for ultratrace analysis of emerging compounds in real matrices. Graphical abstract Innovative analytical procedure for hollow fiber microextraction (HFMUE). GC gas chromatography, LD liquid desorption. PMID- 29523943 TI - Characterization of potential plasma biomarkers related to cognitive impairment by untargeted profiling of phospholipids using the HILIC-ESI-IT-TOF-MS system. AB - Early diagnosis of neural changes causing cognitive impairment is critical for development of preventive therapies for dementia. Biomarkers currently characterized cannot be extensively applied due to the invasive sampling of cerebrospinal fluid. The other imaging approaches are either expensive or require a high technique. Phospholipids (PLs), which are basic constituents of neurons, might be a key variable in the pathogenesis of cognitive impairment. Changes in plasma PL provide the possibility for development of novel biomarkers with minimal invasion and high patient acceptance. In this work, a HILIC-ESI-IT-TOF-MS system was introduced for untargeted profiling of plasma PLs to investigate the relationship between changes of plasma PL profiles and cognitive impairment. A total of 272 types of PL molecular structures were characterized in human plasma and quantified through the internal standard method. Univariate analysis shows 29 PLs were significantly different between the control (n = 41) and the cognitive impairment (CI) group (n = 41). Multivariate analysis (PCA and OPLS-DA) was conducted based on these 29 potential PL biomarkers. Both univariate and multivariate analyses show abnormality of PL metabolism in the CI group, and the downregulation of ethanolamine plasmalogen (pPE) supply, especially those with PUFAs, in the circulation system should be strongly associated with neurodegeneration. A discriminative model was established with satisfied fit (R2) and prediction (Q2) abilities, and the classification test showed better recognition of the CI group than the control group indicating that this model of PL biomarkers could be used as indicators for screening of CI. Graphical abstract Characterization of potential plasma biomarkers related to cognitive impairment by untargeted profiling of phospholipids. PMID- 29523944 TI - Bioaccessible peptides released by in vitro gastrointestinal digestion of fermented goat milks. AB - In this study, ultrafiltered goat milks fermented with the classical starter bacteria Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus salivarus subsp. thermophilus or with the classical starter plus the Lactobacillus plantarum C4 probiotic strain were analyzed using ultra-high performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF MS/MS) and/or high performance liquid chromatography-ion trap (HPLC-IT-MS/MS). Partial overlapping of the identified sequences with regard to fermentation culture was observed. Evaluation of the cleavage specificity suggested a lower proteolytic activity of the probiotic strain. Some of the potentially identified peptides had been previously reported as angiotensin-converting enzyme (ACE) inhibitory, antioxidant, and antibacterial and might account for the in vitro activity previously reported for these fermented milks. Simulated digestion of the products was conducted in the presence of a dialysis membrane to retrieve the bioaccessible peptide fraction. Some sequences with reported physiological activity resisted digestion but were found in the non-dialyzable fraction. However, new forms released by digestion, such as the antioxidant alphas1-casein 144YFYPQL149, the antihypertensive alphas2-casein 90YQKFPQY96, and the antibacterial alphas2-casein 165LKKISQ170, were found in the dialyzable fraction of both fermented milks. Moreover, in the fermented milk including the probiotic strain, the k-casein dipeptidyl peptidase IV inhibitor (DPP-IV) 51INNQFLPYPY60 as well as additional ACE inhibitory or antioxidant sequences could be identified. With the aim of anticipating further biological outcomes, quantitative structure activity relationship (QSAR) analysis was applied to the bioaccessible fragments and led to potential ACE inhibitory sequences being proposed. Graphical abstract Ultrafiltered goat milks were fermented with the classical starter bacteria (St) and with St plus the L. plantarum C4 probiotic strain. Samples were analyzed using HPLC-IT-MS/MS and UPLC-Q-TOF-MS/MS. After simulated digestion and dialysis, some of the active sequences remained and new peptides with reported beneficial activities were released. PMID- 29523945 TI - Comparison of cerebral perfusion in perimesencephalic subarachnoid hemorrhage and aneurysmal subarachnoid hemorrhage. AB - PURPOSE: Perimesencephalic hemorrhage (PMH) is a benign subtype of nonaneurysmal subarachnoid hemorrhage (SAH). We aimed to investigate if cerebral perfusion in PMH is less affected than in aneurysmal SAH (aSAH). METHODS: From a prospective cohort of 80 patients with spontaneous SAH, we included PMH patients (n = 15) and selected aSAH patients (n = 39) with similar clinical grade at admission (World Federation of Neurosurgeons Scale-WFNS I/II). Computed tomography (CT) perfusion was performed at < 72 h and/or at 8-10 days. Cerebral perfusion parameter values were compared between groups with nonparametric tests. Subgroup analyses compared PMH and aSAH patients stratified according to aneurysmal location (anterior or posterior circulation) and blood burden (Fisher grade). RESULTS: At < 72 h, no significant differences in perfusion parameters were found between PMH and aSAH patients. At 8-10 days, PMH patients had lower MTT than aSAH patients, and a trend for higher CBF. PMH patients had higher CBF and CBV at < 72 h when compared to posterior circulation aSAH patients. When compared to aSAH patients with similar blood burden, PMH patients had higher CBF and lower MTT at < 72 h, and lower MTT at 8-10 days. CONCLUSION: PMH patients had better cerebral perfusion compared to patients with aSAH, particularly during the vasospasm time window. After stratifying for the amount of blood, PMH patients also had better cerebral perfusion in the first 72 h after SAH. These results are in line with the better clinical presentation and prognosis of PMH, and possibly with a different etiology. PMID- 29523947 TI - Does she have adnexal torsion? Prediction of adnexal torsion in reproductive age women: methodological issues. PMID- 29523946 TI - Imaging in pediatric appendicitis is key to a low normal appendix percentage: a national audit on the outcome of appendectomy for appendicitis in children. AB - PURPOSE: A laparoscopic approach for emergency appendectomy is increasingly used, in pediatric patients as well. The objective of this study is to audit the current state of diagnostic work-up, surgical techniques and its outcome in children with acute appendicitis. METHODS: A prospective consecutive observational cohort study was carried out in a 2-month study period. All patients under 18 years that were operated for suspected acute appendicitis were included. Primary outcome was the infectious complication rate after open and laparoscopic approach; secondary outcomes were preoperative use of imaging and post-operative predictive value of imaging, normal appendix rate and children with a postoperative ileus. RESULTS: A total of 541 children were operated for suspected acute appendicitis in 62 Dutch hospitals. Preoperative imaging was used in 98.9% of children. The normal appendix rate was 3.1%. In 523 children an appendectomy was performed. Laparoscopy was used in 61% of the patients and conversion rate was 1.7%. Complicated appendicitis was diagnosed in 29.4% of children. Overall 30-day complication rate was 11.9% and similar after open and laparoscopic. No difference was found in superficial surgical site infections, nor in intra-abdominal abscesses between the open and laparoscopic approach. Complicated appendicitis is an independent risk factor for infectious complications. CONCLUSION: The laparoscopic approach is most frequently used, except for young children. Superficial surgical site infections are more frequent after open surgery only in patients with complicated appendicitis. The normal appendix rate is low, most likely because of routine preoperative imaging. PMID- 29523948 TI - Substantial utilization of Facebook, Twitter, YouTube, and Instagram in the prostate cancer community. AB - PURPOSE: To measure the usage rate of social media (SoMe) resources in the prostate cancer community, we performed a comprehensive quantitative and qualitative assessment of SoMe activity on the topic of PCa on the four most frequented platforms. METHODS: We scanned the SoMe platforms Facebook, Twitter, YouTube, and Instagram for "prostate cancer" as a cross-sectional analysis or during a defined time period. Sources were included if their communication centered on PCa by title and content. We assessed activity measurements for each SoMe source and classified the sources into six functional categories. RESULTS: We identified 99 PCa-related Facebook groups that amassed 31,262 members and 90 Facebook pages with 283,996 "likes". On YouTube, we found 536 PCa videos accounting for 43,966,634 views, 52,655 likes, 8597 dislikes, and 12,393 comments. During a 1-year time period, 32,537 users generated 110,971 tweets on #ProstateCancer on Twitter, providing over 544 million impressions. During a 1 month time period, 638 contributors posted 1081 posts on Instagram, generating over 22,000 likes and 4,748,159 impressions. Among six functional categories, general information/support dominated the SoMe landscape on all SoMe platforms. CONCLUSION: SoMe activity on the topic of PCa on the four most frequented platforms is high. Facebook groups, YouTube videos, and Twitter tweets are mainly used for giving general information on PCa and education. High SoMe utilization in the PCa community underlines its future role for communication of PCa. PMID- 29523949 TI - The effect of auxin (indole-3-acetic acid) on the growth rate and tropism of the sporangiophore of Phycomyces blakesleeanus and identification of auxin-related genes. AB - The roles of fungal auxins in the regulation of elongation growth, photo-, and gravitropism are completely unknown. We analyzed the effects of exogenous IAA (indole-3-acetic acid), various synthetic auxins including 1-NAA (1 naphthaleneacetic acid) and 2,4-D (2,4-dichlorophenoxyacetic acid), and the auxin transport inhibitor NPA (N-1-naphtylphtalamic acid) on the growth rate and bending of the unicellular sporangiophore of the zygomycete fungus, Phycomyces blakesleeanus. Sporangiophores that were submerged in an aqueous buffer responded to IAA with a sustained enhancement of the growth rate, while 1-NAA, 2,4-D, and NPA elicited an inhibition. In contrast, sporangiophores kept in air responded to IAA with a 20 to 40% decrease of the growth rate, while 1-NAA and NPA elicited an enhancement. The unilateral and local application of IAA in the growing zone of the sporangiophore elicited in 30 min a moderate negative tropic bending in wild type C2 and mutant C148madC, which was, however, partially masked by a concomitant avoidance response caused by the aqueous buffer. Auxin transport related genes ubiquitous in plants were found in a BLAST search of the Phycomyces genome. They included members of the AUX1 (auxin influx carrier protein 1), PILS (PIN-LIKES, auxin transport facilitator protein), and ABCB (plant ATP-binding cassette transporter B) families while members of the PIN family were absent. Our observations imply that IAA represents an intrinsic element of the sensory transduction of Phycomyces and that its mode of action must very likely differ in several respects from that operating in plants. PMID- 29523950 TI - Congenic mapping and candidate gene analysis for streptozotocin-induced diabetes susceptibility locus on mouse chromosome 11. AB - Streptozotocin (STZ) has been widely used to induce diabetes in rodents. Strain dependent variation in susceptibility to STZ has been reported; however, the gene(s) responsible for STZ susceptibility has not been identified. Here, we utilized the A/J-11SM consomic strain and a set of chromosome 11 (Chr. 11) congenic strains developed from A/J-11SM to identify a candidate STZ-induced diabetes susceptibility gene. The A/J strain exhibited significantly higher susceptibility to STZ-induced diabetes than the A/J-11SM strain, confirming the existence of a susceptibility locus on Chr. 11. We named this locus Stzds1 (STZ induced diabetes susceptibility 1). Congenic mapping using the Chr. 11 congenic strains indicated that the Stzds1 locus was located between D11Mit163 (27.72 Mb) and D11Mit51 (36.39 Mb). The Mpg gene, which encodes N-methylpurine DNA glycosylase (MPG), a ubiquitous DNA repair enzyme responsible for the removal of alkylated base lesions in DNA, is located within the Stzds1 region. There is a close relationship between DNA alkylation at an early stage of STZ action and the function of MPG. A Sanger sequence analysis of the Mpg gene revealed five polymorphic sites in the A/J genome. One variant, p.Ala132Ser, was located in a highly conserved region among rodent species and in the minimal region for retained enzyme activity of MPG. It is likely that structural alteration of MPG caused by the p.Ala132Ser mutation elicits increased recognition and excision of alkylated base lesions in DNA by STZ. PMID- 29523951 TI - Small-scale topography modulates elevational alpha-, beta- and gamma-diversity of Andean leaf beetles. AB - Elevational diversity gradients are typically studied without considering the complex small-scale topography of large mountains, which generates habitats of strongly different environmental conditions within the same elevational zones. Here we analyzed the importance of small-scale topography for elevational diversity patterns of hyperdiverse tropical leaf beetles (Coleoptera: Chrysomelidae). We compared patterns of elevational diversity and species composition of beetles in two types of forests (on mountain ridges and in valleys) and analyzed whether differences in the rate of species turnover among forest habitats lead to shifts in patterns of elevational diversity when scaling up from the local study site to the elevational belt level. We sampled beetle assemblages at 36 sites in the Podocarpus National Park, Ecuador, which were equally distributed over two forest habitats and three elevational levels. DNA barcoding and Poisson tree processes modelling were used to delimitate putative species. On average, local leaf beetle diversity showed a clear hump-shaped pattern. However, only diversity in forests on mountain ridges peaked at mid elevation, while beetle diversity in valleys was similarly high at low- and mid elevation and only declined at highest elevations. A higher turnover of species assemblages at lower than at mid-elevations caused a shift from a hump-shaped diversity pattern found at the local level to a low-elevation plateau pattern (with similar species numbers at low and mid-elevation) at the elevational belt level. Our study reveals an important role of small-scale topography and spatial scale for the inference on gradients of elevational species diversity. PMID- 29523953 TI - Comparison of three classifications for lymph node evaluation in patients undergoing total mesorectal excision for rectal cancer. AB - PURPOSE: The present study compared the prognostic value of the lymph node ratio (LNR) and the 6th and the 7th TNM edition as three different lymph node classifications for rectal cancer patients. METHODS: A total of 630 patients who underwent total mesorectal excision for primary rectal cancer between October 2001 and December 2007 were included. Prognostic factors of overall survival were analyzed using Cox proportional hazards models. RESULTS: The median follow-up was 36.1 months and the 5-year overall survival rate was 70.3 +/- 4.7%. The median number of lymph nodes was 15.0 (12.0-19.0). All three lymph node evaluations correlated with survival (p < 0.0001). The assessment of nodal status in the 7th TNM edition enabled further prognostic stratification. The prognostic value of the three classifications were independent of neoadjuvant therapy and lymph node count. On multivariate analyses, the N2 stage of the 6th TNM edition (Hazard ratio 2.08; 95% confidence interval 1.21-3.58) and the N2b stage of the 7th TNM edition (2.18; 1.17-4.07) correlated with poor survival. A LNR of 0.42-0.69 was also associated with unfavorable prognosis (2.97; 1.46-6.03), as was an LNR > 0.69 (2.51; 1.04-6.05). The LNR did not provide prognostic information in addition to the N stage of the TNM classifications. CONCLUSIONS: The evaluated lymph node classifications were of comparable prognostic utility in patients with rectal cancer. The LNR did not provide prognostic information in addition to the N stage of the TNM classifications. PMID- 29523952 TI - Control of grain size in rice. AB - KEY MESSAGE: Summary of rice grain size. Rice is one of the most important crops in the world. Increasing rice yield has been an urgent need to support the rapid growth of global population. The size of grains is one of major components determining rice yield; thus, grain size has been an essential target during rice breeding. Understanding the genetic and molecular mechanisms of grain size control can provide new strategies for yield improvement in rice. In general, the final size of rice grains is coordinately controlled by cell proliferation and cell expansion in the spikelet hull, which sets the storage capacity of the grain and limits grain filling. Recent studies have identified several quantitative trait loci and a number of genes as key grain size regulators. These regulators are involved in G protein signaling, the mitogen-activated protein kinase signaling pathway, the ubiquitin-proteasome pathway, phytohormone signalings, or transcriptional regulation. In this review, we summarize current knowledge on grain size control in rice and discuss the genetic and molecular mechanisms of these grain size regulators. PMID- 29523954 TI - Do femoral head collapse and the contralateral condition affect patient-reported quality of life and referral pain in patients with osteonecrosis of the femoral head? AB - PURPOSES: The objectives of this study were to investigate patient-reported outcomes and referral pain at the first visit in patients with osteonecrosis of the femoral head (ONFH) and to clarify the influence of collapse of the femoral head and the contralateral condition. METHODS: The study included 105 patients (130 hips) with ONFH at the first visit, who were divided into two groups based on the presence of bilateral walking hip pain (bilateral group 25 patients, 50 hips) and unilateral hip pain (unilateral group 80 patients, 80 hips). We compared the Short Form-36 (SF-36), Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ), and visual analog scale (VAS) responses for hip, knee, and low back pain between the groups to investigate the influence of the contralateral condition. Regarding the influence of femoral head collapse, we investigated these subjects based on the stage classification in the unilateral group. RESULTS: The physical component summary (PCS) of the SF-36 and all domains of the JHEQ were poorer in the bilateral group than in the unilateral group. In addition, the VAS score for low back pain was significantly poorer in the bilateral group than in the unilateral group. Regarding the collapse of the femoral head, the SF-36 for the PCS and JHEQ for pain had a significant relationship in the ONFH stage. The VAS scores for hip and knee pain had a significant relationship in the ONFH stage. CONCLUSION: Collapse of the femoral head and the contralateral condition of ONFH strongly affect patients' activities of daily life. PMID- 29523955 TI - The role of synovial fluid analysis in the detection of periprosthetic hip and knee infections: a systematic review and meta-analysis. AB - INTRODUCTION: This study tried to ascertain (1) the accuracy of synovial fluid white blood cell count and polymorphonucleate percentage in the diagnosis of periprosthetic hip and knee infections, (2) which test yielded superior test performance, and (3) the influence on diagnostic accuracy of study characteristics such as patient number, study design, study level, anatomic site, and threshold value. METHODS: A systematic search was conducted including papers assessing more effective cutoffs for synovial fluid tests, having comparative design, evaluating an exclusive cohort of hip or knee prostheses, including a clear definition of infected cases, and reporting sufficient data for the calculation of true-positive, false-positive, false-negative, and true-negative. RESULTS: A total of 375 articles were collected and, given the inclusion criteria, ten manuscripts were included. These studies assessed 1155 hip prostheses (276 infected cases) and 1235 knee prostheses (401 infected cases). The specificity of synovial fluid white blood cell count was significantly increased by using the threshold value >= 3000 cell/MUL (p = 0.006); the sensitivity of polymorphonucleate percentage was significantly higher in detecting knee infections (p = 0.034). DISCUSSION: Both tests had a high specificity and sensitivity in detecting periprosthetic joint infections, and no clear superiority of one over the other existed. Furthermore, cutoff and anatomic site significantly influenced synovial fluid white blood cell count and polymorphonucleate percentage, respectively. CONCLUSION: Synovial fluid analysis is adequate in differentiating patients with periprosthetic hip and knee infections. Our data confirms international guidelines suggesting the use of 3000 cell/MUL as cutoff threshold for synovial fluid white blood cell count. Since an anatomic site effect has been demonstrated, the goal of future studies will be to identify different cutoffs for hip and knee prostheses. PMID- 29523957 TI - The light at the end of the tunnel: an unusual case of acute kidney injury in a pediatric patient: Questions. PMID- 29523956 TI - A novel method of using elastic bionic fixation device for distal tibiofibular syndesmosis injury. AB - PURPOSE: To describe and evaluate the novel method of using elastic bionic fixation device in treating the distal tibiofibular syndesmosis (DTS) injury. METHODS: From June 2013 to January 2014, 17 subjects with ankle fractures combined with DTS separation were treated by the elastic bionic fixation device. The syndesmotic parameters, healing, functional scores, and possible complications were recorded. RESULTS: All patients had a mean follow-up of 23.35 +/- 4.39 months (range, 15-28 months). Syndesmotic parameters returned to normal after surgery and remained normal throughout the follow-up period. X-ray examinations at 12 months follow-up showed no cable breakage of the elastic bionic fixation device or instrument invalidation compared to that of immediate post-operative X-ray films. Besides, no signs of articular degeneration and arthritis were observed. Furthermore, change in bone density near the fibular fixing button or tibial screw nut was also not detected. Primary wound healing was observed in 16 patients, while the remaining one showed redness and swelling of lateral ankle incision and got wound healing after seven to ten days of antibiotic therapy and local radio frequency physiotherapy. All obtained excellent and good outcomes according to the AOFAS score at 12 months after surgery. CONCLUSIONS: The use of elastic bionic fixation device appears to be a promising option in treating DTS injury because it can provide stable and reliable elastic fixation, good functional recovery, and relatively fewer complications. PMID- 29523958 TI - Assessment and management of fluid overload in children on dialysis. AB - Dysregulation of intravascular fluid leads to chronic volume overload in children with end-stage kidney disease (ESKD). Sequelae include left ventricular hypertrophy and remodeling and impaired cardiac function. As a result, cardiovascular complications are the commonest cause of mortality in the pediatric dialysis population. The clinical need to optimize intravascular volume in children with ESKD is clear; however, its assessment and management is the most challenging aspect of the pediatric dialysis prescription. Minimizing chronic fluid overload is a key priority; however, excessive ultrafiltration is toxic to the myocardium and can precipitate intradialytic symptoms. This review outlines emerging objective techniques to enhance the assessment of fluid overload in children on dialysis and outlines evidence for current management strategies to address this clinical problem. PMID- 29523959 TI - The light at the end of the tunnel: an unusual case of acute kidney injury in a pediatric patient: Answers. AB - Monoclonal gammopathies are a rare diagnosis in pediatric patients. A 19-year-old female patient with past medical history of hypogammaglobulinemia and natural killer cell deficiency and stage III follicular lymphoma, in remission, presented with a right-sided pneumonia, noted to have acute kidney injury and proteinuria. Complement C3 and C4 levels were normal. Anti-double-stranded DNA antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibodies were negative. A renal biopsy showed numerous fractured tubular casts that were periodic acid-Schiff and silver-stain negative and fuchsinophilic on trichrome stain, with associated giant cells, tubulitis, acute tubular injury, and tubular rupture. The tubular casts had 3+ staining for lambda light chains and 0-1+ staining for kappa light chains. These findings were consistent with light chain cast nephropathy (LCCN). Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. A bone marrow biopsy showed normal trilineage hematopoiesis and also revealed an atypical B cell population detected by flow cytometry. Pathology specimens from lesions in the distal small bowel were characteristic of diffuse large B cell lymphoma (DLBCL). Chemoreduction therapy followed by chemotherapy was initiated for the DLBCL. Three months after initiation of chemotherapy, the patient's creatinine has improved by > 50%. The likely cause of her LCCN was the new diagnosis of a DLBCL. Other risk factors include her history of hypogammaglobulinemia, natural killer (NK) cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. Our patient may be the youngest reported case of LCCN. Treatment of LCCN is based on treating the underlying clonal plasma cell or B cell proliferation, typically with chemotherapy. PMID- 29523960 TI - Taurine is an amino acid with the ability to activate autophagy in adipocytes. AB - Alterations in adipocyte characteristics are highly implicated in the pathology of obesity. In a recent article, we demonstrated that high-fat diet-induced obesity impairs lysosomal function, thereby suppressing autophagy in mice white adipose tissue. Taurine, an amino acid naturally contained in the normal diet and existing ubiquitously in tissues, has been reported to improve insulin resistance and chronic inflammation in animal models, but underlying mechanisms remain unclear. From these findings, we hypothesized that improvement of obese pathology by taurine may be mediated through recovery of autophagy. In matured 3T3-L1 mouse adipocytes, treatment with taurine-promoted autophagy. Moreover, taurine-induced nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy- and lysosome-related factors. As this translocation is regulated by several kinase pathways, including extracellular signal-related kinase 1 and 2 (ERK1/2) and mechanistic target of rapamycin protein kinase complex 1 (MTORC1), we examined related signaling elements. Consequently, taurine-reduced phosphorylation levels of ERK1/2 but did not alter the phosphorylation of MTORC1 pathway-associated adenosine monophosphate-activated protein kinase or ribosomal protein S6 kinase. Taken together, these results suggest that taurine may enhance TFEB nuclear translocation through ERK1/2 to accelerate autophagy. The effect discovered in this study may represent a novel mechanism for the improvement of obesity-related pathology by taurine. PMID- 29523961 TI - Expression of TpNRAMP5, a metal transporter from Polish wheat (Triticum polonicum L.), enhances the accumulation of Cd, Co and Mn in transgenic Arabidopsis plants. AB - MAIN CONCLUSION: TpRNAMP5 is mainly expressed in the plasma membrane of roots and basal stems. It functions as a metal transporter for Cd, Mn and Co accumulation. Numerous natural resistance-associated macrophage proteins (NRAMPs) have been functionally identified in various plant species, including Arabidopsis, rice, soybean and tobacco, but no information is available on NRAMP genes in wheat. In this study, we isolated a TpNRAMP5 from dwarf Polish wheat (DPW, Triticum polonicum L.), a species with high tolerance to Cd and Zn. Expression pattern analysis revealed that TpNRAMP5 is mainly expressed in roots and basal stems of DPW. TpNRAMP5 was localized at the plasma membrane of Arabidopsis leaf protoplast. Expression of TpNRAMP5 in yeast significantly increased yeast sensitivity to Cd and Co, but not Zn, and enhanced Cd and Co concentrations. Expression of TpNRAMP5 in Arabidopsis significantly increased Cd, Co and Mn concentrations in roots, shoots and whole plants, but had no effect on Fe and Zn concentrations. These results indicate that TpNRAMP5 is a metal transporter enhancing the accumulation of Cd, Co and Mn, but not Zn and Fe. Genetic manipulation of TpNRAMP5 can be applied in the future to limit the transfer of Cd from soil to wheat grains, thereby protecting human health. PMID- 29523962 TI - Analysis of genetic composition and transmitted parental heterozygosity of natural 2n gametes in Populus tomentosa based on SSR markers. AB - MAIN CONCLUSION: Natural 2n female gametes and transmission of parental heterozygosity by natural 2n gametes in Populus tomentosa are reported for the first time, which provides a new approach to polyploid breeding. Naturally occurring 2n pollen is widespread in Populus tomentosa and plays an important role in polyploid breeding. However, the competitiveness of 2n pollen is lower than that of haploid pollen during pollination and fertilization, so 2n pollen is less efficient at fertilizing haploid female gametes to produce polyploids. In theory, polyploids can also be obtained when 2n female gametes are fertilized by haploid pollen. Thus, the question becomes whether natural 2n female gametes exist in P. tomentosa, which can be answered by examining the genetic composition of natural 2n gametes. In this study, the origin of 87 triploids from the hybrid combination "X-2 * Z-5" was identified by SSR markers and 21% of natural 2n gametes were found to originate from female parents. Four SSR loci with low recombination rates were used to identify the genetic composition of natural 2n gametes. The results showed that the genetic composition of 2n female gametes was mainly characterized by SDR, while 2n male gametes were mainly produced by FDR. Moreover, the transmission of parental heterozygosity by natural 2n gametes, which is significantly different between female and male parents in FDR and SDR types, was analysed using 42 SSR primers. Here, we report naturally occurring 2n female gametes for the first time in P. tomentosa and reveal the genetic constitution and transmitted parental heterozygosity of these gametes. Our results provide a foundation for theoretical research into 2n gametes and their application in new polyploid breeding strategies. PMID- 29523963 TI - Changes in quality of life in patients with postmenopausal osteoporosis receiving weekly bisphosphonate treatment: a 2-year multicenter study in Japan. AB - We investigated changes in quality of life (QOL), including pain, in Japanese women aged >= 55 years who were diagnosed as having osteoporosis at 265 centers across Japan and treated continuously with once-weekly bisphosphonates for 24 months. In 2650 evaluable patients, a significant improvement in QOL was observed from 3 months after enrollment onward and maintained throughout the 2-year observation period. A significant improvement in scores was observed for all domains of the Euro QOL 5 Dimension (EQ-5D), and the "pain", "health perception", and "posture, figure" domains of the Japanese Osteoporosis QOL Questionnaire (JOQOL). Factors identified as significantly contributing to QOL change were "fractures within the year before enrollment", "presence of spondylosis deformans", "presence of osteoarthritis", "use of activated vitamin D3", and "age" based on the JOQOL, and "presence of spondylosis deformans", "use of activated vitamin D3", and "age" based on the EQ-5D. The results suggested that the patients' perception of treatment effects, such as improvement in pain, contributes to treatment continuation. Osteoporosis patients should be informed that continuous treatment with once-weekly bisphosphonates can lead to a significant improvement in QOL regardless of concomitant locomotor diseases, to encourage them to remain on treatment. In conclusion, continuous bisphosphonate treatment improved the QOL even in patients with locomotor diseases, and the concomitant use of activated vitamin D3 may also facilitate further improvement in QOL. PMID- 29523964 TI - Functional analysis of MeCIPK23 and MeCBL1/9 in cassava defense response against Xanthomonas axonopodis pv. manihotis. AB - KEY MESSAGE: MeCIPK23 interacts with MeCBL1/9, and they confer improved defense response, providing potential genes for further genetic breeding in cassava. Cassava (Manihot esculenta) is an important food crop in tropical area, but its production is largely affected by cassava bacterial blight. However, the information of defense-related genes in cassava is very limited. Calcium ions play essential roles in plant development and stress signaling pathways. Calcineurin B-like proteins (CBLs) and CBL-interacting protein kinases (CIPKs) are crucial components of calcium signals. In this study, systematic expression profile of 25MeCIPKs in response to Xanthomonas axonopodis pv. manihotis (Xam) infection was examined, by which seven candidate MeCIPKs were chosen for functional investigation. Through transient expression in Nicotiana benthamiana leaves, we found that six MeCIPKs (MeCIPK5, MeCIPK8, MeCIPK12, MeCIPK22, MeCIPK23 and MeCIPK24) conferred improved defense response, via regulating the transcripts of several defense-related genes. Notably, we found that MeCIPK23 interacted with MeCBL1 and MeCBL9, and overexpression of these genes conferred improved defense response. On the contrary, virus-induced gene silencing of either MeCIPK23 or MeCBL1/9 or both genes resulted in disease sensitive in cassava. To our knowledge, this is the first study identifying MeCIPK23 as well as MeCBL1 and MeCBL9 that confer enhanced defense response against Xam. PMID- 29523965 TI - Qualitative and quantitative spectrometric evaluation of soluble microbial products formation in aerobic granular sludge system treating nitrate wastewater. AB - In present study, the characteristics of soluble microbial products (SMP) were evaluated in aerobic granular sludge system during denitrification process under different chemical oxygen demand/nitrogen (C/N) ratios. Batch experiment showed that the effluent nitrate (NO3--N) concentration were 15.24 +/- 1.83 and 1.72 +/- 1.53 mg/L at C/N ratio of 1 and 6, respectively. For the release of SMP, the protein (PN) and polysaccharide contents increased from 1.23 +/- 0.38 and 7.46 +/ 1.13 mg/L to 1.80 +/- 0.76 and 10.53 +/- 1.24 mg/L with increasing C/N ratios, respectively. Excitation-emission matrix identified four peaks in SMP, including aromatic PN-like, tryptophan PN-like, fulvic acid-like and humic acid-like substances. Fluorescence regional integration suggested that biodegradable PN like substances occupied the percentage between 53.0 and 61.7% in SMP. Synchronous fluorescence spectra coupled with two-dimensional correlation spectroscopy indicated that the release of SMP fractions in the early stage (0 150 min) changed in the following sequences: PN-like fraction > fulvic acid-like fraction. PMID- 29523966 TI - Soluble CD163 and soluble CD14 plasma levels but not cellular HIV-DNA decrease during successful interferon-free anti-HCV therapy in HIV-1-HCV co-infected patients on effective combined anti-HIV treatment. AB - Soluble CD163, soluble CD14 and cellular HIV-1-DNA levels reflect two different aspects of HIV infection: immune activation and the reservoir of infected cells. The aim of this study was to describe their relationships in a cohort of HIV-HCV co-infected patients successfully treated for both HCV and HIV infections. Fifty five patients were recruited and studied prior to the start of direct-acting antivirals (DAAs) (T0), at week 12 of DAA treatment (T1) and 24 weeks after T0 (T2). The subjects were classified as having undetectable plasma HIV viraemia (UV) or low-level viraemia (LLV) in the 18 months before T2. Plasma levels of sCD163 and of sCD14 were comparable in patients with UV and in subjects with LVL at T0, T1 and T2. The HIV DNA level was positively correlated with LLV but not with sCD163 and sCD14 levels; these two markers of inflammation were positively correlated (p = 0.017). Soluble CD163 and sCD14 decreased over time from T0 to T2 (p = 0.000 and p = 0.034, respectively). In conclusion, the significant decrease in sCD163 and sCD14 levels in patients cured of HCV infection, regardless of the presence of LLV, suggests a main role for HCV in immune activation in HIV-HCV co infected patients. PMID- 29523967 TI - Diagnostic-driven antifungal approach in neutropenic patients at high risk for chronic disseminated candidiasis: preliminary observations on the role of 1,3 beta-D-glucan antigenemia and multiphasic contrast-enhanced computed tomography. PMID- 29523968 TI - Genomic characterization of the novel Ralstonia phage RPSC1. AB - In this paper, I describe the genomic characteristics of a Ralstonia phage infecting Ralstonia solanacearum. The Ralstonia phage RPSC1 was isolated from a soil sample collected in Sichuan Province, in southwestern China. The complete genome of RPSC1 is composed of a linear double-stranded DNA 39,628 bp in length, with G+C content of 61.55%, and 43 putative protein-coding genes. All the putative protein-coding genes were on the same strand. No tRNA-encoding genes were identified. Phylogenetic and comparative genomics analyses indicate that Ralstonia phage RPSC1 should be considered a new member of the family Podoviridae. The wide host range contributes to the potential of Ralstonia phage RPSC1 as a biocontrol agent. PMID- 29523970 TI - Stem cells in the treatment of central nervous system disease. PMID- 29523969 TI - Developmental validation of GlobalFilerTM PCR amplification kit: a 6-dye multiplex assay designed for amplification of casework samples. AB - The GlobalFilerTM PCR Amplification Kit is a single multiplex assay that amplifies a set of 24 markers, which encompass the European Standard Set and CODIS (Combined DNA Index System) recommended composite set of loci. In addition to more loci and a 6-dye chemistry format, the Master Mix has been formulated to allow higher sample loading volume for trace DNA samples. The GlobalFilerTM Kit has been optimized to deliver high performance on casework samples, while also delivering fast thermal cycling, with an amplification time of approximately 80 min. Here, we report the results of the developmental validation study which followed the SWGDAM (Scientific Working Group on DNA Analysis Methods) guidelines and includes data for PCR-based studies, sensitivity, species specificity, stability, precision, reproducibility and repeatability, concordance, stutter, DNA mixtures, and performance on mock casework samples. The results validate the multiplex design as well as demonstrate the kit's robustness, reliability, and suitability as an assay for human identification with casework DNA samples. PMID- 29523971 TI - Emission of volatile halogenated compounds, speciation and localization of bromine and iodine in the brown algal genome model Ectocarpus siliculosus. AB - This study explores key features of bromine and iodine metabolism in the filamentous brown alga and genomics model Ectocarpus siliculosus. Both elements are accumulated in Ectocarpus, albeit at much lower concentration factors (2-3 orders of magnitude for iodine, and < 1 order of magnitude for bromine) than e.g. in the kelp Laminaria digitata. Iodide competitively reduces the accumulation of bromide. Both iodide and bromide are accumulated in the cell wall (apoplast) of Ectocarpus, with minor amounts of bromine also detectable in the cytosol. Ectocarpus emits a range of volatile halogenated compounds, the most prominent of which by far is methyl iodide. Interestingly, biosynthesis of this compound cannot be accounted for by vanadium haloperoxidase since the latter have not been found to catalyze direct halogenation of an unactivated methyl group or hydrocarbon so a methyl halide transferase-type production mechanism is proposed. PMID- 29523972 TI - YcfDRM is a thermophilic oxygen-dependent ribosomal protein uL16 oxygenase. AB - YcfD from Escherichia coli is a homologue of the human ribosomal oxygenases NO66 and MINA53, which catalyse histidyl-hydroxylation of the 60S subunit and affect cellular proliferation (Ge et al., Nat Chem Biol 12:960-962, 2012). Bioinformatic analysis identified a potential homologue of ycfD in the thermophilic bacterium Rhodothermus marinus (ycfDRM). We describe studies on the characterization of ycfDRM, which is a functional 2OG oxygenase catalysing (2S,3R)-hydroxylation of the ribosomal protein uL16 at R82, and which is active at significantly higher temperatures than previously reported for any other 2OG oxygenase. Recombinant ycfDRM manifests high thermostability (Tm 84 degrees C) and activity at higher temperatures (Topt 55 degrees C) than ycfDEC (Tm 50.6 degrees C, Topt 40 degrees C). Mass spectrometric studies on purified R. marinus ribosomal proteins demonstrate a temperature-dependent variation in uL16 hydroxylation. Kinetic studies of oxygen dependence suggest that dioxygen availability can be a limiting factor for ycfDRM catalysis at high temperatures, consistent with incomplete uL16 hydroxylation observed in R. marinus cells. Overall, the results that extend the known range of ribosomal hydroxylation, reveal the potential for ycfD-catalysed hydroxylation to be regulated by temperature/dioxygen availability, and that thermophilic 2OG oxygenases are of interest from a biocatalytic perspective. PMID- 29523973 TI - Influence of synovectomy on blood loss and need for transfusion in standard total knee replacement. AB - BACKGROUND: Synovial proliferation is a rather frequent intraoperative finding during the surgery of a total knee replacement. The aim of this study is to asses whether the standard procedure of a synovectomy results in changes in blood loss and in the need for transfusion in the immediate postoperative time after the total knee replacement. METHODS: A prospective cohort study was performed with 120 patients undergoing total knee replacement (60 with synovectomy and 60 without it). Data on gender, age, and hemoglobin concentration prior to and after surgery were obtained. A bivariate and multivariate logistic regression analysis was performed. RESULTS: The male gender as a protective factor [RR 0.25 (0.06 1.01)] and the low preoperative hemoglobin as a risk factor [RR 6.22 (2.48 15.58)] were significant in bivariate analysis. However, only the presence of low preoperative hemoglobin was shown to have an independent risk factor for the need for transfusion [RR 8.55 (2.77-26.45)]. CONCLUSION: The practice of synovectomy showed no difference either in blood loss or in the number of transfusions. The findings of this study indicate that the practice of a synovectomy in a standard total knee replacement does not generate any benefit or prejudice as to the blood factor of the total knee arthroplasty. PMID- 29523974 TI - Preservation of the articular capsule and short lateral rotator in direct anterior approach to total hip arthroplasty. AB - INTRODUCTION: In total hip arthroplasty via a direct anterior approach, the femur must be elevated at the time of femoral implant placement. For adequate elevation, division of the posterior soft tissues is necessary. However, if we damage and separate the posterior muscle tissue, we lose the benefits of the intermuscular approach. Furthermore, damage to the posterior soft tissue can result in posterior dislocation. We investigate that protecting the posterior soft tissue increases the joint stability in the early postoperative period and results in a lower dislocation rate. METHODS: We evaluated muscle strength recovery by measuring the maximum width of the internal obturator muscle on CT images (GE-Healthcare Discovery CT 750HD). We compared the maximum width of the muscle belly preoperatively versus 10 days and 6 months postoperatively. As clinical evaluations, we also investigated the range of motion of the hip joint, hip joint function based on the Japanese Orthopaedic Association hip score (JOA score), and the dislocation rate 6 months after surgery. RESULTS: The width of the internal obturator muscle increased significantly from 15.1 +/- 3.1 mm before surgery to 16.4 +/- 2.8 mm 6 months after surgery. The JOA score improved significantly from 50.8 +/- 15.1 points to 95.6 +/- 7.6 points. No dislocations occurred in this study. CONCLUSIONS: We cut only the posterosuperior articular capsule and protected the internal obturator muscle to preserve muscle strength. We repaired the entire posterosuperior and anterior articular capsule. These treatments increase joint stability in the early postoperative period, thus reducing the dislocation rate. LEVEL OF EVIDENCE: Therapeutic, Level IV. PMID- 29523975 TI - Noble gas supported boron-pentagonal clusters B5Ngn3+: exploring the structures and bonding. AB - A novel type of trivalent BNg five-membered cational species B5Ngn3+(Ng = He~Rn, n = 1~5) has been found and investigated theoretically using the B3LYP and MP2 methods with the def2-QZVPPD and def2-TZVPPD basis sets. The geometry, harmonic vibrational frequencies, bond energies, charge distribution, bond nature, aromaticity, and energy decomposition analysis of these structures were reported. The calculated B-Ng bond energy is quite large (the averaged bond energy is in the range of 209.2~585.76 kJ mol-1) for heavy rare gases and increases with the Ng atomic number. The analyses of the molecular wavefunction show that in the BNg compounds of heavy Ng atoms Ar~Rn, the B-Ng bonds are of typical covalent character. Nuclear independent chemical shifts display that both B53+ and B5Ngn3+(n=1~5) have obvious aromaticity. Energy decomposition analysis shows that these BNg compounds are mainly stabilized by the sigma-donation from the Ng valence p orbital to the B53+ LUMO. These findings offer valuable clues toward the design and synthesis of new stable Ng-containing compounds. PMID- 29523976 TI - Correction to: Process-induced degradation of bioresorbable PDLGA in bone tissue scaffold production. AB - The original version of this article unfortunately contained a mistake. E. Themistou was missing from the author group and so is now included with this erratum. PMID- 29523977 TI - Determination of noise pollution on university campuses: a case study at Cukurova University campus in Turkey. AB - The aims of this study are to identify via harnessing noise mapping the effects of noise pollution at Cukurova University campus on the academic setting and to reveal the obtained change values in noise pollution on the campus during the period 2010-2017. In line with these aims, the first step has been to map the highway-induced environmental noise on Cukurova University campus during daytime (07:00-19:00) and evening (19:00-23:00) hours by employing SoundPLAN 7.3 software. Traffic-induced noise distribution maps for years 2010 and 2017 on the campus were analyzed by threshold values stipulated by the Regulation on Environmental Noise Assessment and Management that is compliance with the European Union Directive on Environmental Noise (2002/49/EC) and after the conducted analyses, traffic-induced environmental noise measured on Cukurova University campus since the past to that date was identified in terms of spatial change. The Regulation defines threshold values, namely, (1) 65 dB(A) for daytime from 07:01 to 19:00, (2) 60 dB(A) for evening-from 19:01 to 23:00, (3) 55 dB(A) for night time-from 23:01 to 07:00. It was then identified in the research area that faculty buildings of Science and Letters, Engineering, Architecture, Faculty of Economics and Administrative Sciences, Dentistry, Faculty of Law, and Communication devoid of any vegetation space to set a barrier between emission source highway and front walls of buildings facing the roadside were the structures most severely exposed to the noise. In the research area, the comparison of year 2017 noise distribution with respect to year 2010 manifested that the regions exposed to noise value 35 dB(A) and below, 35-45 dB(A), and 45 55 dB(A) levels decreased while a proportional increase was detected in regions exposed to 60 dB(A) noise value that is close to the legal threshold value and noise level above 65 dB(A). PMID- 29523979 TI - Correction to: Microbial diversity of saline environments: searching for cytotoxic activities. AB - The original version of this article (Diaz-Cardenas et al. 2017) unfortunately contained a mistake in Fig. 1. The pie chart of Fig. 1 should explain the distribution of the relative abundance of the Bacteria and Archaea strains isolated at Zipaquira salt mine: Proteobacteria 39%; Actinobacteria 9%, Bacteroidetes 1%, Archaea 3% and Firmicutes 48% instead of NOMBRE DE CATEGORIA [PORCENTAJE]. The corrected Fig. 1 and caption are given below. PMID- 29523980 TI - Noninvasive quantitation of rat cerebral blood flow using 99mTc-HMPAO-assessment of input function with dynamic chest planar imaging. AB - BACKGROUND: Cerebral blood flow (CBF) quantitation using technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) generally requires assessment of input function by arterial blood sampling, which would be invasive for small animals. We therefore performed chest dynamic planar imaging, instead of arterial blood sampling, to estimate the input function and establish noninvasive quantitation method of rat CBF using the image-derived input function. RESULTS: Integrated radioactivity concentration in the heart-blood pool on planar images (AUCBlood-planar) was identical to that in arterial blood samples (AUCBlood sampling). Radioactivity concentration in the brain determined by SPECT imaging (CBrain-SPECT) was identical to that using brain sampling (CBrain-sampling). Noninvasively calculated CBF obtained by dividing CBrain-SPECT by AUCBlood-planar was well correlated with conventionally estimated CBF obtained by dividing CBrain sampling by AUCBlood-sampling. CONCLUSION: Rat CBF could be noninvasively quantitated using 99mTc-HMPAO chest dynamic planar imaging and head SPECT imaging without arterial blood sampling. PMID- 29523978 TI - PACAP and its role in primary headaches. AB - Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC1, VPAC1, and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that PACAP is involved in nociception. In support, abolishment of PACAP synthesis or reception leads to diminished pain responses, whereas systemic PACAP-38 infusion triggers pain behavior in animals and delayed migraine-like attacks in migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute migraine attacks and in cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of PACAP, a change that can be reduced when headache is treated. The data presented in this review indicate that PACAP and its receptors may be promising targets for migraine therapeutics. PMID- 29523981 TI - Healthcare efficiency assessment using DEA analysis in the Slovak Republic. AB - A regional disparity is becoming increasingly important growth constraint. Policy makers need quantitative knowledge to design effective and targeted policies. In this paper, the regional efficiency of healthcare facilities in Slovakia is measured (2008-2015) using data envelopment analysis (DEA). The DEA is the dominant approach to assessing the efficiency of the healthcare system but also other economic areas. In this study, the window approach is introduced as an extension to the basic DEA models to evaluate healthcare technical efficiency in individual regions and quantify the basic regional disparities and discrepancies. The window DEA method was chosen since it leads to increased discrimination on results especially when applied to small samples and it enables year-by-year comparisons of the results. Two stable inputs (number of beds, number of medical staff), three variable inputs (number of all medical equipment, number of magnetic resonance (MR) devices, number of computed tomography (CT) devices) and two stable outputs (use of beds, average nursing time) were chosen as production variable in an output-oriented 4-year window DEA model for the assessment of technical efficiency in 8 regions. The database was made available from the National Health Information Center and the Slovak Statistical Office, as well as from the online databases Slovstat and DataCube. The aim of the paper is to quantify the impact of the non-standard Data Envelopment Analysis (DEA) variables as the use of medical technologies (MR, CT) on the results of the assessment of the efficiency of the healthcare facilities and their adequacy in the evaluation of the monitored processes. The results of the analysis have shown that there is an indirect dependence between the values of the variables over time and the results of the estimated efficiency in all regions. The regions that had low values of the variables over time achieved a high degree of efficiency and vice versa. Interesting knowledge was that the gradual addition of variables number of MR, number of CT and number of medical devices together, to the input side did not have a significant impact on the overall estimated efficiency of healthcare facilities. PMID- 29523983 TI - Scientific Session of the 16th World Congress of Endoscopic Surgery, jointly hosted by Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) & Canadian Association of General Surgeons (CAGS), Seattle, Washington, USA, 11-14 April 2018: Video Abstracts. PMID- 29523982 TI - Single-incision laparoscopic cholecystectomy is responsible for increased adverse events: results of a meta-analysis of randomized controlled trials. AB - BACKGROUND: Over the last decade, single-incision laparoscopic cholecystectomy (SLC) has gained popularity, although it is not evident if benefits of this procedure overcome the potential increased risk. Aim of the study is to compare the outcome of SLC with conventional multi-incision laparoscopic cholecystectomy (MLC) in a meta-analysis of randomized controlled trials only. METHODS: A systematic Medline, Embase, and Cochrane Central Register of Controlled Trials literature search of articles on SLC and MLC for any indication was performed in June 2017. The main outcomes measured were overall adverse events, pain score (VAS), cosmetic results, quality of life, and incisional hernias. Linear regression was used to model the effect of each procedure on the different outcomes. RESULTS: Forty-six trials were included and data from 5141 participants were analysed; 2444 underwent SLC and 2697 MLC, respectively. Mortality reported was nil in both treatment groups. Overall adverse events were higher in the SLC group (RR 1.41; p < 0.001) compared to MLC group, as well severe adverse events (RR 2.06; p < 0.001) and even mild adverse events (RR 1.23; p = 0.041). This was confirmed also when only trials including 4-port techniques (RR 1.37, p = 0.004) or 3-port techniques were considered (RR 1.89, p = 0.020). The pain score showed a standardized mean difference (SMD) of - 0.36 (p < 0.001) in favour of SLC. Cosmetic outcome by time point scored a SMD of 1.49 (p < 0.001) in favour of SLC. Incisional hernias occurred more frequently (RR 2.97, p = 0.005) in the SLC group. CONCLUSIONS: Despite SLC offers a better cosmetic outcome and reduction of pain, the consistent higher rate of adverse events, both severe and mild, together with the higher rate of incisional hernias, should suggest to reconsider the application of single incision techniques when performing cholecystectomy with the existing technology. PMID- 29523984 TI - Acute cholecystitis: comparing clinical outcomes with TG13 severity and intended laparoscopic versus open cholecystectomy in difficult operative cases. AB - INTRODUCTION: The revised Tokyo Guidelines include criteria for determining the severity of acute cholecystitis with treatment algorithms based on severity. The aim of this study was to investigate the relationship of the revised Tokyo Guidelines severity grade to clinical outcomes of cholecystectomy for acute cholecystitis. METHODS: We identified 66 patients with acute cholecystitis from a prior study of difficult cholecystectomy cases. We examined the relationship between severity grade and multiple variables related to perioperative and postoperative outcomes. RESULTS: A more severe revised Tokyo Guidelines grade was associated with a higher number of complications (p = 0.03) and a higher severity of complications (p = 0.01). Severity grade did not predict operative time, estimated blood loss, intensive care unit admission or length of stay. Compared to planned open cholecystectomy, intended laparoscopic cholecystectomy was associated with significantly fewer total and Clavien-Dindo grade 3 complications, fewer intensive care unit admissions, and shorter length of stay (p values range from 0.03 to < 0.0001). CONCLUSION: In technically difficult operations for acute cholecystitis, the revised Tokyo guidelines severity grade correlates with the number and severity of complications. However, intended performance of laparoscopic cholecystectomy rather than open cholecystectomy in difficult operations predicts broader beneficial outcomes than severity grade. PMID- 29523985 TI - Response rate does not affect patient-reported outcome after lumbar discectomy. AB - PURPOSE: Quality registers give unique possibilities to achieve information from large groups of patients, but outcome must be interpreted carefully due to less stringent data collection and lower follow-up rates than in research projects. We tried to quantify any outcome differences between a national spine quality register and a prospective observational study. METHODS: Adult patients treated with lumbar discectomy between 2004 and 2010 were retrieved from the Swedish Spine register (Swespine) (n = 7791) and from the single center lumbar disc herniation study (LDHS) in Stockholm (n = 177). The mean follow-up rates at 1 and 2 years were 73 and 62%, compared to 98 and 99%, respectively. Patient-reported outcome measurements included VAS for back and leg pain, ODI, EQ-5D, patient satisfaction, and global assessment. RESULTS: When comparing the two cohorts at baseline, there were minor differences in the patient-reported outcome measurements, all within reported minimal clinical important differences (MCID). Mean outcome improved significantly in both groups after surgery. All outcomes at 1 and 2 years were similar and within the reported MCID in both groups. Complications and reoperations were similar, except for more surgical site infections in the LDHS group. CONCLUSIONS: Higher response rates than seen in Swespine are not needed to achieve reasonably representative data on patient reported outcome for large cohorts. Two-year data do not seem to add additional information. These slides can be retrieved under Electronic Supplementary Material. PMID- 29523986 TI - Intra- and inter-rater reliability of spinal flexibility measurements using ultrasonic (US) images for non-surgical candidates with adolescent idiopathic scoliosis: a pilot study. AB - PURPOSE: This study aimed to determine the intra- and inter-rater reliabilities of spinal flexibility measurements using ultrasound imaging on non-surgical candidates with adolescent idiopathic scoliosis (AIS). METHODS: Twenty-eight consecutive consented AIS subjects (25 F; 3 M) were recruited; 24 subjects' data were used for analysis. This study explored curve magnitude differences between standing, prone and voluntary maximum side-bending postures to assess the reliability of spinal flexibility (SF). Two raters were included in this study. Four flexibility indices, PRSI, BRPI, B-PRSI, BRSI, based on the postural changes from standing to prone and from prone to bending position were defined. The reliability analysis was evaluated using the intra-class correlation coefficient (ICC) [1, 2] and the standard error of measurements (SEM). RESULTS: The ICC [1, 2] values of the intra-rater (R2 only) and inter-rater (R1 vs R2) reliabilities of the measurements (PRSI, BRPI, B-PRSI, BRSI) were (0.82, 0.64, 0.78, 0.91) and (0.78, 0.76, 0.84, 0.94), respectively. Among the four indices, the BRPI had the highest SEM values 1.42, and 0.73 for intra- and inter-raters results, respectively, while BRSI had the lowest SEM 0.04 and 0.02 for intra- and inter rater, respectively. CONCLUSIONS: The BRPI, BRSI and B-PRSI could be measured reliably on US images when the Cobb angle at prone position was not close to zero. Using these three indices, information may provide more comprehensive information about the SF. Validity of spinal flexibility measurements still needed to be confirmed with a clinical study with more subjects. These slides can be retrieved under Electronic Supplementary Material. PMID- 29523987 TI - Decreasing trend of hip fractures incidence in Italy between 2007 and 2014: epidemiological changes due to population aging. AB - : We analyzed hospitalization for hip fractures in elderly Italian people from 2007 to 2014. The number of fractures increased by 5.50% (women + 3.36; men + 12.9%) only due to people aged >= 85 years old. Incidence rates per 10,000 inhabitants decreased in all the age groups (65-74, 75-84, and also >= 85). PURPOSE: To assess the burden of hip fractures in elderly Italian population moving from our previous researches documented a reduced incidence of hip fractures in Italian women aged 65-74 years old. METHODS: We analyzed national hospitalization records from 2007 to 2014 to compute age- and sex-specific rates at national and regional level. RESULTS: Seven hundred forty-one thousand six hundred thirty-three a total of 741,633 hospitalizations were observed in people >= 65 (women 568,203; men 173,430), with an overall increase of 5.50% over the 8 year period (females + 3.36; males + 12.9%). About 43.75% of total hip fractures were suffered by patients aged >= 85 years old. Women aged >= 85 accounted for 34.49% (n = 255,763) of total fractures. The incidence rate per 10,000 inhabitants in people aged 65-74 decreased from 28.65 to 25.31 in women (- 13.02%) and from 13.41 to 11.65 in men (- 13.12%). Incidence per 10,000 in people 75-84 decreased from 121.6 to 105.2 in women (- 13.49%) and from 55.8 to 47.5 in men (- 14.87%). Also, in people aged >= 85, the incidence per 10,000 declined from 300.99 to 268.72 in women (- 10.72%) and from 174.59 to 171.17 in men (- 1.96%). Standardized rates (SR) per 10,000 in the overall population aged 65 years old and over decreased between 2007 and 2014 from 22.9 to 20.1 and from 7.0 to 6.3 in women and men, respectively. Decreasing trends were documented in all Italian regions between 65 and 79 years old, with further reduction up to 84 years old in 16 regions out of 20. Region Lazio showed a decreasing trend also in people aged > 85 years old. CONCLUSION: While the number of hospitalizations for hip fractures in Italy is still increasing due to the fractures occurring in people >= 85 years old, incidence rates are decreasing in all the age groups, including the oldest one, possibly because the number of subjects aged >= 85 is growing faster than the number of fractures. PMID- 29523988 TI - Post-ruminal effects of rumen-protected methionine supplementation with low protein diet using long-term simulation and in vitro digestibility technique. AB - Microbial degradation in the rumen and dietary availability of methionine amino acid have been reported as limiting in dairy ruminants. The aim of the present study was to examine the post-ruminal effects of feeding ruminants different concentrations of rumen-protected methionine (RPM) in low crude protein diets using the long-term rumen simulation method (Rusitec) followed by in vitro abomasum and ileum digestibility technique. The experiment contained four treatment groups: (1) high protein, without RPM supplementation (HP); (2) low protein, without RPM supplementation (LP); (3) low protein supplementation with low RPM (LPLM); and (4) low protein supplementation with high RPM (LPHM) mixed per 20 +/- 0.04 g basal diet in every fermenter. The results showed that the LPLM and LPHM groups had significantly higher disappearance of crude protein and neutral detergent fiber in the abomasum and ileum than the HP treatment (P < 0.05) and were the same as the LP group (P > 0.05). The proportions of short chain fatty acids and total volatile fatty acids in the abomasum and ileum were the same between the LPHM and HP groups (P > 0.05); however, the LPLM group was found to be significantly (P < 0.05) lower than the HP group and similar to the LP group (P > 0.05). Rusitec pH before or after changing feed bags and daily ammonia nitrogen production in the abomasum and ileum were non significantly (P > 0.05) different among all groups. In conclusion, RPM supplementation with low crude protein diets promoted post-ruminal digestibility and production of volatile fatty acids. PMID- 29523989 TI - Purse-string closure technique reduces the incidence of incisional hernias following the reversal of temporary ileostomy. AB - PURPOSE: The incidence of incisional hernia (IH) at ileostomy closure site has not been sufficiently evaluated. Temporary loop ileostomy is routinely used in patients after low anterior resection for rectal cancer. The goal of this study was to compare the IH rates of standard suture skin closure and purse-string skin closure techniques. PATIENTS AND METHODS: Patients undergoing ileostomy reversal and follow-up CT scan at the University Hospital Frankfurt between January 2009 and December 2015 were retrospectively analyzed regarding IH and associated risk factors. Patients received either direct stitch skin closure (group DC) or purse string skin closure (group PS). RESULTS: In total, 111 patients underwent ileostomy reversal in the aforementioned period. In 88 patients, a CT scan was performed 12-24 months after ileostomy reversal for cancer follow-up. Median follow-up was 12 months. Median time interval between ileostoma formation and closure was 12 (+/- 4 SD) weeks. In 19 of 88 patients (21.5%), an IH was detected. The incidence of IH detected by CT scan was significantly lower in the PS group (n = 7, 12.9%) compared to the DC group (n = 12, 35.2%, p = 0.017). CONCLUSIONS: This retrospective study shows an advantage of the purse-string skin closure technique in ileostomy reversals. The use of this technique for skin closure following ileostomy reversals is recommended to reduce the IH rates. Randomized controlled trials are needed to confirm these findings. PMID- 29523990 TI - Colorectal cancer surveillance in Portuguese families with lynch syndrome: a cohort study. AB - PURPOSE: Lynch syndrome (LS) is associated with a high risk of colorectal cancer (CRC). The aim of this study was to assess the cumulative risk for the development of colorectal adenomas or carcinomas in a LS CRC surveillance program and to audit the quality of the endoscopic procedures. METHODS: We evaluated 147 asymptomatic LS mutation carriers, without previous CRC, in a surveillance program with colonoscopy every 12-18 months, between 2005 and 2016. Data was obtained by retrospective review of colonoscopy reports and hospital clinical files. The main outcome was assessed using Kaplan-Meier curves. Logistic regression was used to study the risk of developing adenomas. RESULTS: Patients were under surveillance for 1092 observation years (mean, 7.7 years/patient). Most exams presented adequate bowel preparation (83.5%) and 99.2% achieved cecal intubation. The estimated risk for adenomas at age 60 was 75.6% in men (95%CI, 60.5-88.3) and 65.5% in women (95%CI, 50.8-79.7). Male gender (OR 2.4; 95%CI, 1.2 4.9; p = 0.018) and age at start of surveillance > 40 years (OR 3.7; 95%CI, 1.8 7.7; p < 0.001) were independent risk factors for adenoma detection. CRC was diagnosed in 11 patients with an estimated cumulative risk at age 60 of 18.4% (95%CI, 9.2-34.8%); 72.7% of CRC were classified as stage I; no patient died from CRC. CONCLUSION: A colonoscopic surveillance program in LS patients allowed the detection of adenomas in a large group of mutation carriers and diagnosis of early-stage carcinomas. Our findings may help other teams to adopt similar strategies or to refer patients early to specialized centers. PMID- 29523991 TI - Aflibercept in diabetic macular edema refractory to previous bevacizumab: outcomes and predictors of success. PMID- 29523992 TI - Treated retinal breaks: clinical course and outcomes. AB - PURPOSE: To report rates and timing of retreatments, new break formation, and vitreoretinal surgical intervention after initial treatment of retinal breaks, and to identify factors associated with increased rates of additional vitreoretinal interventions. METHODS: Retrospective, consecutive case series of all patients who were diagnosed with a retinal break and underwent laser retinopexy for prophylaxis of retinal detachment at the Bascom Palmer Eye Institute, Miami, FL, from 2013 through 2016 were reviewed. The main outcome measure was if additional laser treatment or vitreoretinal surgical procedure was performed after the initial laser retinopexy. RESULTS: Additional laser retinopexy was performed in 75 (18.7%) of 401 study eyes over 113 sessions: 58 (51.3%) sessions to retreat the original tear and 55 (48.7%) to treat a new tear. Vitreoretinal surgery for retinal detachment after the initial laser retinopexy was performed in 23 (5.7%) eyes. Risk factors associated with vitreoretinal surgery after initial laser treatment included superotemporal location (OR = 3.62; p = 0.008), vitreous hemorrhage (OR = 2.62; p = 0.017), and multiple breaks (OR = 2.60; p = 0.014). CONCLUSIONS: Additional treatment is often performed after the initial treatment of a retinal break. Although progression to retinal detachment is not common, regular follow-up examinations are recommended. PMID- 29523993 TI - Structural changes of macular inner retinal layers in early normal-tension and high-tension glaucoma by spectral-domain optical coherence tomography. AB - PURPOSE: Assessment of the diagnostic ability of segmented macular inner retinal layer thickness and peripapillary retinal nerve fiber layer (pRNFL) measured by spectral-domain optical coherence tomography (SD-OCT) in patients with normal tension (NT) and high-tension (HT) perimetric and preperimetric glaucoma. METHODS: The 212 participants included 45 healthy subjects, 55 patients with ocular hypertension, 56 patients with preperimetric glaucoma, and 56 patients with perimetric glaucoma. The preperimetric and perimetric groups were further subdivided into NT and HT groups. Sectoral and global thickness of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (mGCL), inner plexiform layer (mIPL), ganglion cell complex (mGCC), and pRNFL were measured using SD-OCT (Spectralis, Heidelberg Engineering, Germany). Diagnostic performance was ascertained by sectoral and global comparison of the sensitivities at specificity >= 95%. RESULTS: For all layers, the largest thickness decrease was reported in the HT perimetric group. In all groups, the sensitivities of mGCL showed a comparable diagnostic value to pRNFL in order to distinguish between healthy subjects and glaucoma patients. In the perimetric group, mGCL (85.7%) exhibited higher sensitivities than mRNFL (78.6%) and mGCC (78.6%). Both mRNFL and pRNFL demonstrated equal diagnostic performance in the HT perimetric group (88.5 and 96.2%), in the NT groups, mRNFL was inferior to all other layers. CONCLUSION: The sensitivities of mGCL and mRNFL were comparable to the sensitivities of pRNFL. In clinical application, mGCL and mRNFL, with a focus on the temporal and inferior sectors, may provide a convincing supplementation to pRNFL. CLINICAL TRIAL REGISTRATION: Erlangen Glaucoma Registry www.clinicaltrials.gov ID: NCT00494923. PMID- 29523994 TI - Prevalence of chronic postsurgical pain after thoracotomy and total knee arthroplasty: a retrospective multicenter study in Japan (Japanese Study Group of Subacute Postoperative Pain). AB - We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods. PMID- 29523995 TI - The role of simulation training in anesthesiology resident education. AB - An increasing number of reports indicate the efficacy of simulation training in anesthesiology resident education. Simulation education helps learners to acquire clinical skills in a safe learning environment without putting real patients at risk. This useful tool allows anesthesiology residents to obtain medical knowledge and both technical and non-technical skills. For faculty members, simulation-based settings provide the valuable opportunity to evaluate residents' performance in scenarios including airway management and regional, cardiac, and obstetric anesthesiology. However, it is still unclear what types of simulators should be used or how to incorporate simulation education effectively into education curriculums. Whether simulation training improves patient outcomes has not been fully determined. The goal of this review is to provide an overview of the status of simulation in anesthesiology resident education, encourage more anesthesiologists to get involved in simulation education to propagate its influence, and stimulate future research directed toward improving resident education and patient outcomes. PMID- 29523997 TI - Production of pikromycin using branched chain amino acid catabolism in Streptomyces venezuelae ATCC 15439. AB - Branched chain amino acids (BCAA) are catabolized into various acyl-CoA compounds, which are key precursors used in polyketide productions. Because of that, BCAA catabolism needs fine tuning of flux balances for enhancing the production of polyketide antibiotics. To enhance BCAA catabolism for pikromycin production in Streptomyces venezuelae ATCC 15439, three key enzymes of BCAA catabolism, 3-ketoacyl acyl carrier protein synthase III, acyl-CoA dehydrogenase, and branched chain alpha-keto acid dehydrogenase (BCDH) were manipulated. BCDH overexpression in the wild type strain resulted in 1.3 fold increase in pikromycin production compared to that of WT, resulting in total 25 mg/L of pikromycin. To further increase pikromycin production, methylmalonyl-CoA mutase linked to succinyl-CoA production was overexpressed along with BCDH. Overexpression of the two enzymes resulted in the highest titer of total macrolide production of 43 mg/L, which was about 2.2 fold increase compared to that of the WT. However, it accumulated and produced dehydroxylated forms of pikromycin and methymycin, including their derivatives as well. It indicated that activities of pikC, P450 monooxygenase, newly became a bottleneck in pikromycin synthesis. PMID- 29523996 TI - New-onset atrial fibrillation: an update. AB - New-onset atrial fibrillation (NOAF) is the most common perioperative complication of heart surgery, typically occurring in the perioperative period. NOAF commonly occurs in patients who are elderly, or have left atrial enlargement, or left ventricular hypertrophy. Various factors have been identified as being involved in the development of NOAF, and numerous approaches have been proposed for its prevention and treatment. Risk factors include diabetes, obesity, and metabolic syndrome. For prevention of NOAF, beta-blockers and amiodarone are particularly effective and are recommended by guidelines. NOAF can be treated by rhythm/rate control, and antithrombotic therapy. Treatment is required in patients with decreased cardiac function, a heart rate exceeding 130 beats/min, or persistent NOAF lasting for >= 48 h. It is anticipated that anticoagulant therapies, as well as hemodynamic management, will also play a major role in the management of NOAF. When using warfarin as an anticoagulant, its dose should be adjusted based on PT-INR. PT-INR should be controlled between 2.0 and 3.0 in patients aged < 70 years and between 1.6 and 2.6 in those aged >= 70 years. Rate control combined with antithrombotic therapies for NOAF is expected to contribute to further advances in treatment and improvement of survival. PMID- 29523998 TI - Rapid nonapeptide synthesis during a critical period of development in the prairie vole: plasticity of the paraventricular nucleus of the hypothalamus. AB - Vasopressin (VP) and oxytocin (OT) are involved in modulating basic physiology and numerous social behaviors. Although the anatomical distributions of nonapeptide neurons throughout development have been described, the functional roles of VP and OT neurons during development are surprisingly understudied, and it is unknown whether they exhibit functional changes throughout early development. We utilized an acute social isolation paradigm to determine if VP and OT neural responses in eight nonapeptide cell groups differ at three different stages of early development in prairie voles. We tested pups at ages that are representative of the three rapid growth stages of the developing brain: postnatal day (PND)2 (closed eyes; poor locomotion), PND9 (eye opening; locomotion; peak brain growth spurt), and PND21 (weaning). Neural responses were examined in pups that (1) were under normal family conditions with their parents and siblings, (2) were isolated from their parents and siblings and then reunited, and (3) were isolated from their parents and siblings. We found that VP and OT neural activity (as assessed via Fos co-localization) did not differ in response to social condition across development. However, remarkably rapid VP and OT synthesis in response to social isolation was observed only in the paraventricular nucleus of the hypothalamus (PVN) and only in PND9 pups. These results suggest that PVN nonapeptide neurons exhibit distinct cellular properties during a critical period of development, allowing nonapeptide neurons to rapidly upregulate peptide production in response to stressors on a much shorter timescale than has been observed in adult animals. PMID- 29523999 TI - Correction to: Investigation of brain structure in the 1-month infant. AB - The authors regret that, in this article, there was an error in the analyses comparing infant male and female regional brain volume differences. PMID- 29524000 TI - Nutritional implications of olives and sugar: attenuation of post-prandial glucose spikes in healthy volunteers by inhibition of sucrose hydrolysis and glucose transport by oleuropein. AB - PURPOSE: The secoiridoid oleuropein, as found in olives and olive leaves, modulates some biomarkers of diabetes risk in vivo. A possible mechanism may be to attenuate sugar digestion and absorption. METHODS: We explored the potential of oleuropein, prepared from olive leaves in a water soluble form (OLE), to inhibit digestive enzymes (alpha-amylase, maltase, sucrase), and lower [14C(U)] glucose uptake in Xenopus oocytes expressing human GLUT2 and [14C(U)]-glucose transport across differentiated Caco-2 cell monolayers. We conducted 7 separate crossover, controlled, randomised intervention studies on healthy volunteers (double-blinded and placebo-controlled for the OLE supplement) to assess the effect of OLE on post-prandial blood glucose after consumption of bread, glucose or sucrose. RESULTS: OLE inhibited intestinal maltase, human sucrase, glucose transport across Caco-2 monolayers, and uptake of glucose by GLUT2 in Xenopus oocytes, but was a weak inhibitor of human alpha-amylase. OLE, in capsules, in solution or as naturally present in olives, did not affect post-prandial glucose derived from bread, while OLE in solution attenuated post-prandial blood glucose after consumption of 25 g sucrose, but had no effect when consumed with 50 g of sucrose or glucose. CONCLUSION: The combined inhibition of sucrase activity and of glucose transport observed in vitro was sufficient to modify digestion of low doses of sucrose in healthy volunteers. In comparison, the weak inhibition of alpha-amylase by OLE was not enough to modify blood sugar when consumed with a starch-rich food, suggesting that a threshold potency is required for inhibition of digestive enzymes in order to translate into in vivo effects. PMID- 29524001 TI - Intake of dietary saturated fatty acids and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort: associations by types, sources of fatty acids and substitution by macronutrients. AB - PURPOSE: The association between dietary saturated fatty acids (SFA) intake and type 2 diabetes (T2D) remains unclear. This study aimed at investigating the association between SFA intake and T2D risk based on (1) individual SFA (differing in carbon chain length), (2) food sources of SFA and (3) the substituting macronutrients. METHODS: 37,421 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort were included in this study. Baseline dietary intake was assessed by a validated food frequency questionnaire. T2D risks were estimated by Cox regression models adjusted for non-dietary and dietary covariates. RESULTS: 893 incident T2D cases were documented during 10.1-year follow-up. We observed no association between total SFA and T2D risk. Marginally inverse associations were found for lauric acid (HR per 1 SD of energy%, 95% CI 0.92, 0.85-0.99), myristic acid (0.89, 0.79 0.99), margaric acid (0.84, 0.73-0.97), odd-chain SFA (pentadecylic plus margaric acids; 0.88, 0.79-0.99), and cheese derived SFA (0.90, 0.83-0.98). Soft and liquid fats derived SFA was found related to higher T2D risk (1.08, 1.01-1.17). When substituting SFA by proteins, carbohydrates and polyunsaturated fatty acids, significantly higher risks of T2D were observed (HRs per 1 energy% ranging from 1.05 to 1.15). CONCLUSION: In this Dutch population, total SFA does not relate to T2D risk. Rather, the association may depend on the types and food sources of SFA. Cheese-derived SFA and individual SFA that are commonly found in cheese, were significantly related to lower T2D risks. We cannot exclude the higher T2D risks found for soft and liquid fats derived SFA and for substituting SFA with other macronutrients are influenced by residual confounding by trans fatty acids or limited intake variation in polyunsaturated fatty acids and vegetable protein. PMID- 29524002 TI - Modeling habitat suitability for chimpanzees (Pan troglodytes verus) in the Greater Nimba Landscape, Guinea, West Africa. AB - Tropical forests and the biodiversity within them are rapidly declining in the face of increasing human populations. Resource management and conservation of endangered species requires an understanding of how species perceive and respond to their environments. Species distribution modeling (SDM) is an appropriate tool for identifying conservation areas of concern and importance. In this study, SDM was used to identify areas of suitable chimpanzee (Pan troglodytes verus) habitat within the Greater Nimba Landscape, Guinea, West Africa. This location was ideal for investigating the effects of landscape structure on habitat suitability due to the topographic variation of the landscape and the Critically Endangered status of the Western chimpanzee. Additionally, this is the only mountainous, long-term chimpanzee study site and little is known about the effects of topography on chimpanzee behavior. Suitable habitat was predicted based on the location of direct and indirect signs of chimpanzee presence and the spatial distribution of 12 biophysical variables within the study area. Model performance was assessed by examining the area under the curve. The overall predictive performance of the model was 0.721. The variables most influencing habitat suitability were the normalized difference vegetation index (37.8%), elevation (27.3%), hierarchical slope position (11.5%), surface brightness (6.6%), and distance to rivers (5.4%). The final model highlighted the isolation and fragmentation of chimpanzee habitat within the Greater Nimba Landscape. Understanding the factors influencing chimpanzee habitat suitability, specifically the biophysical variables considered in this study, will greatly contribute to conservation efforts by providing quantitative habitat information and improving survey efficiency. PMID- 29524003 TI - The tissue distribution and excretion study of paeoniflorin-6'-O-benzene sulfonate (CP-25) in rats. AB - Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) is a novel ester derivative of paeoniflorin (Pae). Compared to Pae, CP-25 has higher lipid solubility, bioavailability and better bioactivity. However, the tissue distribution and excretion of CP-25 still remain unknown. The LC-MS method was applied to investigate the tissue distribution and excretion of CP-25 in rats. As such, 50 mg/kg of CP-25 and Pae were administered to rats in multiple doses via an oral route. CP-25 and Pae were distributed widely and rapidly in all the tested tissues. Compared with Pae, the concentrations of CP-25 were almost increased evidently in most tissues. The highest CP-25 level was found in the liver (1476.33 +/- 535.20 ng/g, male; 1970.38 +/- 177.21 ng/g, female) at 3 h, and a high concentration of CP-25 was detected in male and female intestine, synovium, muscle, lung, and brain. Following a single oral dose of 50 mg/kg of CP-25 in rats, the total excretion of CP-25 was merely 21.8% (18.40, 3.19 and 0.22% for feces, bile and urine, respectively) in males; and was approximately 21.3% (14.04, 7.16 and 0.14% for feces, bile and urine, respectively) in females. The results indicated that the CP-25 concentration was higher in major tissues than Pae; CP-25 was primarily excreted through the feces; and there were gender related differences in the tissue distribution and excretion. PMID- 29524004 TI - Antixenosis and antibiosis response of common bean (Phaseolus vulgaris) to two spotted spider mite (Tetranychus urticae). AB - The two-spotted spider mite, Tetranychus uticae Koch (Acari: Tetranychidae), is globally one of the most devastating pests that feed on numerous crops, including common bean (Phaseolus vulgaris L.). This study was aimed to evaluate the effects of genotype and morphological attributes of common bean on T. uticae. Forty common bean accessions were used to investigate antixenosis and antibiosis through assessing mite feeding preference and reproduction under laboratory conditions. Three resistant (i.e., 56, 63, 238) and two susceptible (i.e., 182, 236) accessions, along with cultivars Naz (resistant) and Akhtar (susceptible), were used in a life-table study. Both antixenosis and antibiosis mechanism were observed in all of the accessions, albeit a negative correlation occurred. Significant differences were observed for all traits of T. urticae: developmental time of immature stages, reproduction, adult longevity and life-table parameters. Based on the intrinsic rate of increase, the accessions 56, 63, 182, 238, and cv. Naz impose high antibiotic effects on T. urticae. Although significant variation existed among accessions for morphological factors, only glandular trichomes correlated with mite fecundity and feeding preference. PMID- 29524005 TI - The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. AB - BACKGROUND: Nivolumab was the first programmed death receptor 1 (PD-1) immune checkpoint inhibitor to demonstrate long-term survival benefit in a clinical trial setting for advanced melanoma patients. OBJECTIVE: To evaluate the cost effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. METHODS: A Markov state-transition model was developed to estimate the lifetime costs and benefits of nivolumab versus ipilimumab and dacarbazine for BRAF mutation-negative patients and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutation-positive patients. Covariate adjusted parametric curves for time to progression, pre-progression survival, and post-progression survival were fitted based on patient-level data from two trials and long-term ipilimumab survival data. Indirect treatment comparisons between nivolumab, ipilimumab, and dacarbazine were informed by these covariate-adjusted parametric curves, controlling for differences in patient characteristics. Kaplan Meier data from the literature were digitised and used to fit progression-free and overall survival curves for dabrafenib and vemurafenib. Patient utilities and resource use data were based on trial data or the literature. Patients are assumed to receive nivolumab until there is no further clinical benefit, assumed to be the first of progressive disease, unacceptable toxicity, or 2 years of treatment. RESULTS: Nivolumab is the most cost-effective treatment option in BRAF mutation-negative and mutation-positive patients, with incremental cost effectiveness ratios of L24,483 and L17,362 per quality-adjusted life year, respectively. The model results are most sensitive to assumptions regarding treatment duration for nivolumab and the parameters of the fitted parametric survival curves. CONCLUSIONS: Nivolumab is a cost-effective treatment for advanced melanoma patients in England. PMID- 29524006 TI - Remote ischemic preconditioning fails to reduce infarct size in the Zucker fatty rat model of type-2 diabetes: role of defective humoral communication. AB - Remote ischemic preconditioning (RIPC), the phenomenon whereby brief ischemic episodes in distant tissues or organs render the heart resistant to infarction, has been exhaustively demonstrated in preclinical models. Moreover, emerging evidence suggests that exosomes play a requisite role in conveying the cardioprotective signal from remote tissue to the myocardium. However, in cohorts displaying clinically common comorbidities-in particular, type-2 diabetes-the infarct-sparing effect of RIPC may be confounded for as-yet unknown reasons. To investigate this issue, we used an integrated in vivo and in vitro approach to establish whether: (1) the efficacy of RIPC is maintained in the Zucker fatty rat model of type-2 diabetes, (2) the humoral transfer of cardioprotective triggers initiated by RIPC are transported via exosomes, and (3) diabetes is associated with alterations in exosome-mediated communication. We report that a standard RIPC stimulus (four 5-min episodes of hindlimb ischemia) reduced infarct size in normoglycemic Zucker lean rats, but failed to confer protection in diabetic Zucker fatty animals. Moreover, we provide novel evidence, via transfer of serum and serum fractions obtained following RIPC and applied to HL-1 cardiomyocytes subjected to hypoxia-reoxygenation, that diabetes was accompanied by impaired humoral communication of cardioprotective signals. Specifically, our data revealed that serum and exosome-rich serum fractions collected from normoglycemic rats attenuated hypoxia-reoxygenation-induced HL-1 cell death, while, in contrast, exosome-rich samples from Zucker fatty rats did not evoke protection in the HL-1 cell model. Finally, and unexpectedly, we found that exosome-depleted serum from Zucker fatty rats was cytotoxic and exacerbated hypoxia-reoxygenation induced cardiomyocyte death. PMID- 29524007 TI - Insights into the karyotype evolution and speciation of the beetle Euchroma gigantea (Coleoptera: Buprestidae). AB - Euchroma Dejean, 1833 (Buprestidae: Coleoptera) is a monotypic genus comprising the species Euchroma gigantea, with populations presenting a degree of karyotypic variation/polymorphism rarely found within a single taxonomic (specific) unit, as well as drastically incompatible meiotic configurations in populations from extremes of the species range. To better understand the complex karyotypic evolution of E. gigantea, the karyotypes of specimens from five populations in Brazil were investigated using molecular cytogenetics and phylogenetic approaches. Herein, we used FISH with histone genes as well as sequencing of the COI to determine differential distribution of markers and relationships among populations. The analyses revealed new karyotypes, with variability for chromosome number and morphology of multiple sex chromosome mechanisms, occurrence of B chromosome variants (punctiform and large ones), and high dispersion of histone genes in different karyotypes. These data indicate that chromosomal polymorphism in E. gigantea is greater than previously reported, and that the species can be a valuable model for cytogenetic studies. The COI phylogenetic and haplotype analyses highlighted the formation of three groups with chromosomally polymorphic individuals. Finally, we compared the different karyotypes and proposed a model for the chromosomal evolution of this species. The species E. gigantea includes at least three cytogenetically polymorphic lineages. Moreover, in each of these lineages, different chromosomal rearrangements have been fixed. Dispersion of repetitive sequences may have favored the high frequency of these rearrangements, which could be related to both adaptation of the species to different habitats and the speciation process. PMID- 29524008 TI - Insulin adsorption on functionalized silica surfaces: an accelerated molecular dynamics study. AB - We study the influence of surface functionalization of a silica surface on insulin adsorption using accelerated molecular dynamics simulation. Three different functional groups are studied, CH3, OH, and COOH. Due to the partial charges of these groups, the surface polarity of silica is strongly altered. We find that the adsorption energies of insulin change in agreement with the decreasing surface polarity. Conformational changes in the adsorbed protein and the magnitude of the molecular dipole moment in the adsorbed state are consistent with this result. We conclude that protein adsorption on functionalized polar surfaces is governed by the induced changes in surface polarity. PMID- 29524009 TI - Reproducibility of acquiring ultrasonographic infant hip images by the Graf method after an infant hip ultrasound training course. AB - PURPOSE: The objective screening of infant hips using ultrasonography (Graf method) is gaining favor in the diagnosis of developmental dysplasia of the hip in Japan. However, the accuracy of the Graf method is dependent on the examiner's experience and technique. The purpose of this study was to investigate the reproducibility of acquiring ultrasonic hip images and their evaluation after examiners attended an infant hip ultrasound training course. MATERIALS AND METHODS: Ultrasonic images of 70 hips of 35 newborns who were screened by ultrasonography using the Graf method, were evaluated. The images were acquired by two inexperienced examiners who attended the training course. The inter- and intra-examiner measurement errors as well as reproducibility were calculated based on the images obtained. RESULTS: The intra-examiner measurement error in the acquired images of the same hip was minor. The inter-examiner measurement error was also small. The intra- and inter-examiner agreements of the Graf classification were high. The intra-examiner reproducibility of the acquired ultrasonic images was substantial, and the inter-examiner reproducibility was almost perfect. CONCLUSIONS: Our results demonstrated that inexperienced examiners could obtain ultrasonic infant hip joint images with minor differences and high reproducibility after the training course. Our findings raise the possibility of extending the infant hip ultrasound course in Japan. PMID- 29524010 TI - A cancer registry-based analysis on the non-white populations reveals a critical role of the female sex in early-onset melanoma. AB - PURPOSE: Most melanoma studies have been performed in the white population who exhibits the highest incidence rate due to their skin sensitivity to UV radiation. Previous publications have shown that young women (approximately under the menopausal age) exhibit higher incidence rates than men of the same age, and the causes are mostly attributed to their sun behavior or indoor tanning. In our recent publications, we suggested that higher risk in younger women was due to pathophysiological factors, such as hormonal impact, and thus this higher risk in young women should be shared across ethnicities regardless of their skin color or UV behavior. METHODS: A total of 13,208 non-white melanoma patients from SEER and 15,226 from WHO CI5-Plus were extracted for analysis. Age-specific incidence rates, female-to-male incidence rate ratios, and p values were calculated. RESULTS: As observed in the white population, younger women and older men showed higher melanoma incidence rates than their peers of the other gender in all ethnic groups. The highest female-to-male incidence rate ratios were observed in the pubescent and reproductive ages. Previously this gender discrepancy in the white population was attributed to the preference of skin tanning in young females. There is no evidence to show that darker-skinned young females adopt a similar tanning preference. Thus the age-dependent gender difference in the risk of melanoma is shared across ethnic groups and is perhaps independent of UV behavior. CONCLUSIONS: Our results highlight the importance of gender as one of the melanoma risk factors beyond traditional UV radiation, which warrants further investigation and may provide a base for an improved prevention strategy. PMID- 29524011 TI - HIVprotI: an integrated web based platform for prediction and design of HIV proteins inhibitors. AB - A number of anti-retroviral drugs are being used for treating Human Immunodeficiency Virus (HIV) infection. Due to emergence of drug resistant strains, there is a constant quest to discover more effective anti-HIV compounds. In this endeavor, computational tools have proven useful in accelerating drug discovery. Although methods were published to design a class of compounds against a specific HIV protein, but an integrated web server for the same is lacking. Therefore, we have developed support vector machine based regression models using experimentally validated data from ChEMBL repository. Quantitative structure activity relationship based features were selected for predicting inhibition activity of a compound against HIV proteins namely protease (PR), reverse transcriptase (RT) and integrase (IN). The models presented a maximum Pearson correlation coefficient of 0.78, 0.76, 0.74 and 0.76, 0.68, 0.72 during tenfold cross-validation on IC50 and percent inhibition datasets of PR, RT, IN respectively. These models performed equally well on the independent datasets. Chemical space mapping, applicability domain analyses and other statistical tests further support robustness of the predictive models. Currently, we have identified a number of chemical descriptors that are imperative in predicting the compound inhibition potential. HIVprotI platform ( http://bioinfo.imtech.res.in/manojk/hivproti ) would be useful in virtual screening of inhibitors as well as designing of new molecules against the important HIV proteins for therapeutics development. PMID- 29524012 TI - The SbcC and SbcD homologs of the cyanobacterium Anabaena sp. strain PCC7120 (Alr3988 and All4463) contribute independently to DNA repair. AB - The ubiquitous SbcCD exonuclease complex has been shown to perform an important role in DNA repair across prokaryotes and eukaryotes. However, they have remained uncharacterized in the ancient and stress-tolerant cyanobacteria. In the cyanobacterium Anabaena sp. strain PCC7120, SbcC and SbcD homologs, defined on the basis of the presence of corresponding functional domains, are annotated as hypothetical proteins, namely Alr3988 and All4463 respectively. Unlike the presence of sbcC and sbcD genes in a bicistronic operon in most organisms, these genes were distantly placed on the chromosome in Anabaena, and found to be negatively regulated by LexA. Both the genes were found to be essential in Anabaena as the individual deletion mutants were non-viable. On the other hand, the proteins could be individually overexpressed in Anabaena with no effect on normal cell physiology. However, they contributed positively to enhance the tolerance to different DNA damage-inducing stresses, such as mitomycin C and UV- and gamma-radiation. This indicated that the two proteins, at least when overexpressed, could function independently and mitigate the damage caused due to the formation of DNA adducts and single- and double-strand breaks in Anabaena. This is the first report on possible independent in vivo functioning of SbcC and SbcD homologs in any bacteria, and the first effort to functionally characterize the proteins in any cyanobacteria. PMID- 29524013 TI - Monitoring land cover change and its dynamic mechanism on the Qehan Lake Basin, Inner Mongolia, North China, during 1977-2013. AB - The Qehan Lake Basin is located in the north of the Otindag Sandy Land, where the fragile eco-environment is sensitive to climate change and human activity. We analyzed land cover change and the concomitant processes of ecological change based on multi-spectral scanning (MSS), thematic mapper (TM), and enhanced TM (ETM+) images. The results showed that from 1977 to 2000, the area of dune sand increased significantly by 840.2 km2, while the area of high cover grassland (HCGL), medium cover grassland (MCGL), and low cover grassland (LCGL) reduced by 140.6, 207.3, and 463.3 km2, respectively. Additionally, the area of wetland decreased by 112.9 km2. During the period of 1977 to 2000, the land cover condition index (LCCI) reached a low of 27.7, which indicated serious eco environmental challenges in the Qehan Lake watershed. However, the process of desertification was reversed, and vegetation cover was gradually restored after 2000. From 2000 to 2013, the area of LCGL increased by 369.2 km2 (13.4%), while the area of dune sand decreased by 560.1 km2 (29.4%). The LCCI improved to reach 29.18 in 2013, demonstrating a significant eco-environmental improvement. Although climate change, human activity, and ecological policies have together determined the scope and extent of desertification in the watershed, the most fundamental factor in the restoration of vegetation was precipitation. PMID- 29524015 TI - Hemophagocytic Lymphohistiocytosis in Loeys-Dietz Syndrome. PMID- 29524014 TI - Development of the Cancer Survivor Profile-Breast Cancer (CSPro-BC) app: patient and nurse perspectives on a new navigation tool. AB - PURPOSE: Despite advancements in care, cancer survivors continue to report unmet needs following active cancer treatment. The Cancer Survivor Profile-Breast Cancer (CSPro-BC) application (app) was developed to help address these needs, using breast cancer survivors (BCS) as a pilot group. This paper describes the app development, BCS and nurse perceptions of the app, and changes made based on this feedback. METHODS: The CSPro-BC app was developed for use on an iPad and includes (1) administration of a 15-20-min survey assessing 18 needs, (2) generation of a profile of needs, relative to a reference group of BCS (median 2 years post-treatment), and (3) provision of problem-specific online resources. Perceptions of the app were evaluated using both quantitative and qualitative approaches. Feedback was elicited from nurse navigators and BCS. BCS were recruited until the point of saturation. RESULTS: BCS (N = 11) were middle-aged and a median of 2.4 months post active treatment. Structured questionnaires indicated the following: survey covered meaningful problem areas, profile display was clear, and nurse's involvement was helpful. Follow-up interviews (2 weeks later) revealed that BCS shared their profile with others, but most BCS did not use the resources and those who did thought there were too many. Nurses (N = 3) said the app increased appointment time, but prompted them to discuss areas often not covered in typical BCS follow-up. CONCLUSIONS: Feedback by end users directly informed revision of the app. IMPLICATIONS FOR CANCER SURVIVORS: The CSPro-BC app has been optimized based on BCS feedback. PMID- 29524016 TI - Prevalence of Co-occurring Medical and Behavioral Conditions/Symptoms Among 4- and 8-Year-Old Children with Autism Spectrum Disorder in Selected Areas of the United States in 2010. AB - We compared the prevalence of various medical and behavioral co-occurring conditions/symptoms between 4- and 8-year-olds with autism spectrum disorder (ASD) from five sites in the Autism and Developmental Disabilities Monitoring Network during the 2010 survey year, accounting for sociodemographic differences. Over 95% of children had at least one co-occurring condition/symptom. Overall, the prevalence was higher in 8- than 4-year-olds for 67% of co-occurring conditions/symptoms examined. Further, our data suggested that co-occurring conditions/symptoms increased or decreased the age at which children were first evaluated for ASD. Similarly, among the 8-year-olds, the prevalence of most co occurring conditions/symptoms was higher in children with a previous ASD diagnosis documented in their records. These findings are informative for understanding and screening co-occurring conditions/symptoms in ASD. PMID- 29524017 TI - The Association Between Sequence Learning on the Serial Reaction Time Task and Social Impairments in Autism. AB - It is assumed that learning on the Serial Reaction Time (SRT) task is related to learning involved in social skill development affected in autism, but this assumption has hardly been investigated. We have therefore examined associations between SRT task learning and social impairment measured by the Social Responsiveness Scale in 72 autistic and non-autistic adults. Results revealed a positive correlation between deterministic sequence learning, putatively involving explicit learning, and social impairment in autistic adults but not in non-autistic adults. No correlations with probabilistic learning were found. These results suggest that the type of learning that helps autistic adults during a deterministic SRT task hinders them during social development, and call for further investigating the ecological validity of the SRT task. PMID- 29524018 TI - Advancing the study of sluggish cognitive tempo via DSM, RDoC, and hierarchical models of psychopathology. AB - Sluggish cognitive tempo (SCT) is separable from attention-deficit/hyperactivity disorder (ADHD) and other psychopathologies, and growing evidence demonstrates SCT to be associated with impairment in both children and adults. However, it remains unclear how SCT should optimally be conceptualized. In this article, we argue that multiple models of psychopathology should be leveraged to make substantive advances to our understanding of SCT. Both categorical and dimensional approaches should be used, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology, the Research Domain Criteria (RDoC) initiative, and hierarchical models of psychopathology. Studies are needed to determine whether individuals categorized with SCT can be reliably identified and differentiated from individuals without SCT in pathophysiological, neuropsychological, behavioral, and daily life functioning. Studies are also needed to evaluate the validity and utility of SCT as a transdiagnostic and dimensional construct. In considering SCT as a dimensional and potentially transdiagnostic construct, we describe ways in which SCT might be examined within the RDoC framework, including negative valence systems, cognitive systems, and arousal/regulatory systems, as well as within hierarchical models of psychopathology. Conceptualizing SCT within both categorical and dimensional models of psychopathology will help to better understand the causes, developmental pathways, and clinical implications of SCT, both as a construct in its own right and also in relation to other psychopathologies. PMID- 29524019 TI - Aberrant GSH reductase and NOX activities concur with defective CFTR to pro oxidative imbalance in cystic fibrosis airways. AB - Cystic fibrosis (CF) is associated to impaired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel also causing decreased glutathione (GSH) secretion, defective airway bacterial clearance and inflammation. Here we checked the main ROS-producing and ROS-scavenging enzymes as potential additional factors involved in CF pathogenesis. We found that CFBE41o-cells, expressing F508del CFTR, have increased NADPH oxidase (NOX) activity and expression level, mainly responsible of the increased ROS production, and decreased glutathione reductase (GR) activity, not dependent on GR protein level decrease. Furthermore, defective CFTR proved to cause both extracellular and intracellular GSH level decrease, probably by reducing the amount of extracellular GSH-derived cysteine required for cytosolic GSH synthesis. Importantly, we provide evidence that defective CFTR and NOX/GR activity imbalance both contribute to NADPH and GSH level decrease and ROS overproduction in CF cells. PMID- 29524020 TI - Cross regulation between mTOR signaling and O-GlcNAcylation. AB - The hexosamine biosynthetic pathway (HBP) integrates glucose, amino acids, fatty acids and nucleotides metabolisms for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is the nucleotide sugar donor for O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) processes. O-GlcNAc transferase (OGT) is the enzyme which transfers the N-acetylglucosamine (O-GlcNAc) residue onto target proteins. Several studies previously showed that glucose metabolism dysregulations associated with obesity, diabetes or cancer correlated with an increase of OGT expression and global O-GlcNAcylation levels. Moreover, these diseases present an increased activation of the nutrient sensing mammalian target of rapamycin (mTOR) pathway. Other works demonstrate that mTOR regulates protein O-GlcNAcylation in cancer cells through stabilization of OGT. In this context, we studied the cross-talk between these two metabolic sensors in vivo in obese mice predisposed to diabetes and in vitro in normal and colon cancer cells. We report that levels of OGT and O-GlcNAcylation are increased in obese mice colon tissues and colon cancer cells and are associated with a higher activation of mTOR signaling. In parallel, treatments with mTOR regulators modulate OGT and O GlcNAcylation levels in both normal and colon cancer cells. However, deregulation of O-GlcNAcylation affects mTOR signaling activation only in cancer cells. Thus, a crosstalk exists between O-GlcNAcylation and mTOR signaling in contexts of metabolism dysregulation associated to obesity or cancer. PMID- 29524021 TI - Focus on fatty acids in the neurometabolic pathophysiology of psychiatric disorders. AB - Continuous research into the pathophysiology of psychiatric disorders, such as major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and schizophrenia, suggests an important role for metabolism. This narrative review will provide an up-to-date summary of how metabolism is thought to be involved in the pathophysiology of these psychiatric disorders. We will focus on (I) the important role of fatty acids in these metabolic alterations, (II) whether fatty acid alterations represent epiphenomena or risk factors, and (III) similarities and dissociations in fatty acid alterations between different psychiatric disorders. (Historical) epidemiological evidence links fatty acid intake to psychiatric disorder prevalence, corroborated by altered fatty acid concentrations measured in psychiatric patients. These fatty acid alterations are connected with other concomitant pathophysiological mechanisms, including biological stress (hypothalamic-pituitary-adrenal (HPA)-axis and oxidative stress), inflammation, and brain network structure and function. Metabolomics and lipidomics studies are underway to more deeply investigate this complex network of associated neurometabolic alterations. Supplementation of fatty acids as disease-modifying nutraceuticals has clinical potential, particularly add-on eicosapentaenoic acid (EPA) in depressed patients with markers of increased inflammation. However, by interpreting the observed fatty acid alterations as partly (mal)adaptive phenomena, we attempt to nuance translational expectations and provide new clinical applications for these novel neurometabolic insights, e.g., to predict treatment response or depression recurrence. In conclusion, placing fatty acids in context can contribute to further understanding and optimized treatment of psychiatric disorders, in order to diminish their overwhelming burden of disease. PMID- 29524022 TI - Experimental and theoretical study of donor-pi-acceptor compounds based on malononitrile. AB - A set of different donor-pi-acceptor compounds having dicyanovinyl as the acceptor and aryl moieties as donors were synthesized by Knoevenagel condensation. The UV-visible absorption and fluorescence spectra were investigated in different solvents. The optical band gab energy (Eg) was linearly correlated with the Hammett resonance effect of the donor to reveal that the higher the value of Hammett resonance effect of a donor, the lower the Eg of the molecule. The photophysical data revealed that compounds M4-M6 are typical molecular rotors with fluorescence due to twisted intramolecular charge transfer. Compound M5 revealed the largest Stokes shift (11,089 cm-1) making it a useful fluorescent sensor for the changes of the microenvironment. The effect of substituents on the optical properties of donor-pi-acceptor compounds having dicyanovinyl as the acceptor are studied using density functional theory and time dependent density functional theory (DFT/TD-DFT). The optical transitions are thoroughly examined to reveal the impact of subtituents on both absorption and fluorescence, mainly through the modification of the structure in the excited state. The theoretical results have shown that TD-DFT calculations, with a hybrid exchange-correlation and the long-range corrected density functional PBEPBE with a 6-311++G** basis set, was reasonably capable of predicting the excitation energies, the absorption and the emission spectra of these molecules. PMID- 29524023 TI - Dental caries prevention in children and adolescents: a systematic quality assessment of clinical practice guidelines. AB - OBJECTIVES: To evaluate the quality of clinical practice guidelines (CPGs) for dental caries prevention in children and adolescents MATERIALS AND METHODS: We performed a systematic search of CPGs on caries preventive measures between 2005 and 2016. We searched MEDLINE, EMBASE, LILACS, TripDatabase, websites of CPG developers, compilers of CPGs, scientific societies and ministries of health. We included CPGs with recommendations on sealants, fluorides and oral hygiene. Three reviewers independently assessed the included CPGs using the AGREE II instrument. We calculated the standardised scores for the six domains and made a final recommendation about each CPG. Also, we calculated the overall agreement among calibrated reviewers with the intraclass correlation coefficient (ICC). RESULTS: Twenty-two CPGs published were selected from a total of 637 references. Thirteen were in English and nine in Spanish. The overall agreement between reviewers was very good (ICC = 0.90; 95%CI 0.89-0.92). The mean score for each domain was the following: Scope and purpose 89.6 +/- 12%; Stakeholder involvement 55.0 +/- 15.6%; Rigour of development 64.9 +/- 21.2%; Clarity of presentation 84.8 +/- 14.1%; Applicability 30.6 +/- 31.5% and Editorial independence 59.3 +/- 25.5%. Thirteen CPGs (59.1%) were assessed as "recommended", eight (36.4%) "recommended with modifications" and one (4.5%) "not recommended". CONCLUSIONS: The overall quality of CPGs in caries prevention was moderate. The domains with greater deficiencies were Applicability, Stakeholder involvement and Editorial independence. CLINICAL RELEVANCE: Clinicians should use the best available CPGs in dental caries prevention to provide optimal oral health care to patients. PMID- 29524024 TI - Assessing abrasion of orthodontic surface sealants using a modified ophthalmic optical coherence tomography device. AB - OBJECTIVE: Optical coherence tomography (OCT) is a clinical standard in ophthalmology. Currently, its application in dentistry is gaining increasing interest. In this study, we tested the possibility to use a modified commercially available spectral domain OCT (SD-OCT) to assess the layer thickness of orthodontic surface sealants. MATERIALS AND METHODS: Reference samples of surface sealants for calibration and repeatability testing were measured using a micrometer screw. SD-OCT measurements were compared with micro-CT and light microscopic analyses. After validating the calibration of the SD-OCT, surface sealant layer thickness after aging (thermo cycling) and simulation of professional tooth cleaning (PTC) was assessed using the SD-OCT on 45 extracted teeth assigned to three test groups (n = 15 each): Light BondTM Sealant, Pro Seal(r), and Opal(r) Seal. RESULTS: SD-OCT showed excellent repeatability and accuracy for measurements of surface sealant layer thickness. Compared with micro CT, SD-OCT showed better accordance with the reference measurements. The analysis of surface sealants after thermo cycling and PTC revealed poor resistance of Light Bond after only aging and demonstrated substantial wear of all sealants after aging and PTC. CONCLUSION: Imaging using commercially available ophthalmic SD-OCT might represent a suitable non-invasive methodology for longitudinal assessments of surface sealant layer thickness in vitro and in vivo. CLINICAL RELEVANCE: SD-OCT might be a suitable non-invasive method for longitudinal assessments of surface sealant durability in clinical trials. PMID- 29524025 TI - Root-end surgery with leucocyte- and platelet-rich fibrin and an occlusive membrane: a randomized controlled clinical trial on patients' quality of life. AB - OBJECTIVES: The aim of this study was to investigate the impact of the adjunct of leukocyte- and platelet-rich fibrin (LPRF) to root-end surgery (RES) on the patients' quality of life during the first week post RES. MATERIALS AND METHODS: Patients in need of RES were recruited for an open randomized controlled clinical trial (RCT) with a 2 * 2 factorial design. They were randomly allocated to the test (+LPRF) and control (-LPRF) group. Each group was subsequently divided into two strata: with or without an occlusive membrane (Bio-Gide(r), Geistlich Biomaterials, Switzerland; BG). After RES, the patients completed daily for 1 week a visual analog pain scale (VAS) and a 5-point Likert-type scale questionnaire concerning activity impairment, occurrence of symptoms, and medication use. RESULTS: Fifty patients were included, equally divided between the test and control group. Only one patient in the "-LPRF+BG-group" had to take additional antibiotics due to a persistent jaw swelling. There was no evidence (p <= 0.05) for a difference between the test and control group in VAS, occurrence of pain symptoms, impairment of daily activities, and medication use, over the 7 days and daily during the 7 days post RES. CONCLUSIONS: There was no statistical significant evidence for improvement of patients' quality of life during the first week post RES with LPRF in comparison with RES without LPRF. CLINICAL RELEVANCE: Although LPRF seems to be an inexpensive and autologous agent to reduce pain and swelling post RES, this RCT does not provide a statistical significant evidence for that. PMID- 29524026 TI - Allogeneic bone block for challenging augmentation-a clinical, histological, and histomorphometrical investigation of tissue reaction and new bone formation. AB - OBJECTIVES: The aim of the present study was the histological investigation of an allogeneic spongious bone block for horizontal and vertical ridge augmentation in humans. The amount of new bone, soft tissue, and residual bone substitute were histomorphometrically assessed after a mean healing period of 6 months. MATERIALS AND METHODS: Fourteen patients received augmentation with an allogeneic spongious bone block (Tutobone(r), Tutogen Medical, Neunkirchen, Germany). After 6 months of healing, 28 implants were placed with simultaneous harvesting of bone biopsies for histological and histomorphometrical analysis. Moreover, samples from the bone blocks were collected as blanks and analyzed histologically. The formation of new bone, connective tissue, and remaining bone substitute material as well as vascularization and formation of multinucleated giant cells (MNCGs) within the augmentation bed were analyzed. RESULTS: New bone formation could be observed primarily in close proximity to the bone block. Histomorphometrical analyses showed 18.65 +/- 12.20% newly formed bone, 25.93 +/- 12.36% allogeneic spongious bone block, and 53.45 +/- 10.34% connective tissue. MNCGs were observed on the biomaterial surface. Furthermore, organic residues were evident, as donor-related cellular remnants within the osteocyte lacunae were found in the blank bone blocks and in the analyzed biopsies. CONCLUSION: Despite the presence of donor related organic remnants, the bone block shows the ability to serve as a scaffold for new bone formation. Within the limits of the present study, the detect organic remnants seemed not to affect the bone formation or influence the host in the long term. CLINICAL RELEVANCE: Clinicians have to make a conscious choice of the applied biomaterials with regard to their components and structure to support tissue regeneration and maintain patient safety. PMID- 29524027 TI - Retention rates and caries-preventive effects of two different sealant materials: a randomised clinical trial. AB - OBJECTIVES: The aim of this study was to compare the caries-preventive effect and the retention rates of sealants prepared with a new modified and a high-viscosity glass-ionomer cement (GIC) in recently erupted first permanent molars. MATERIALS AND METHODS: Fifty-six children (224 teeth) were included in a split-mouth randomised clinical trial. All children had their four first permanent molars sealed with either Clinpro XT Varnish (CXT) or Fuji IX GP FAST (FJ). FJ sealants were placed according to the ART protocol. Retention rates and caries-preventive effect of both materials were assessed clinically after 24 months, and survival curves were created according to the Kaplan-Meier method. For sealant retention rates, analyses were performed according to both the traditional method and modified sealant retention categorisation. RESULTS: FJ sealants were retained longer in comparison to CXT sealants (p < 0.05), regardless of the categorisation used. In relation to the caries-preventive effect, no statistically significant differences were observed between materials (p = 0.99). Sealants prepared with the high-viscosity GIC according to the ART protocol survived longer than those prepared with the modified GIC, but both materials were equally effective in preventing cavitated dentine lesions over 24 months. CONCLUSION: We concluded that GIC-based sealants are effective in preventing dentine caries lesions. PMID- 29524028 TI - Randomised controlled trial on differential learning of toothbrushing in 6- to 9 year-old children. AB - OBJECTIVES: This study aimed to evaluate the effect of differential learning of toothbrushing compared to habitual toothbrushing and instruction/demonstration of toothbrushing on plaque reduction and gingival inflammation of primary school children. METHODS: Children (6-9 years) were subjected to a toothbrushing training consisting of 15 days (3 * 5 days, interval 2 days, 3 min/day) and randomly assigned to one of three groups (each n = 18): habitual toothbrushing/control, instruction/demonstration of toothbrushing, differential learning of toothbrushing. The differential learning approach comprised 15 different movement exercises (1/day), while instruction/demonstration of toothbrushing was based on repetitive practice of toothbrushing. Plaque (Turesky modified Quigley-Hein plaque index (T-QHI)) and papilla bleeding (papilla bleeding index (PBI)) scores were assessed prior to the first toothbrushing (t0, baseline) and 21 (t1), 42 (t2) and 63 (t3) days after beginning of the study. Primary statistical analyses were performed with cumulative logit regression models with repeated measures. The global significance level was set to 5% two sided. RESULTS: At all time points, PBI and T-QHI were significantly reduced by differential learning compared to instruction/demonstration of toothbrushing and habitual toothbrushing. Compared to baseline, differential learning improved PBI and T-QHI significantly at all time points. In the other groups, no significant reduction of PBI compared to baseline was observed. T-QHI was significantly reduced by habitual toothbrushing only at t1 and by instruction/demonstration of toothbrushing at t1 and t2. Differential learning had an improved effect on posterior compared to anterior teeth. CONCLUSION: Differential learning of toothbrushing improved plaque reduction and reduced gingival inflammation compared to habitual toothbrushing and instruction/demonstration of toothbrushing in 6- to 9-year-old children in mixed dentition. CLINICAL RELEVANCE: Toothbrushing skills of children might be improved by differential learning. TRIAL REGISTRATION: ISRCTN14951343, https://www.isrctn.com/ISRCTN14951343? PMID- 29524029 TI - Effect of platelet-rich fibrin palatal bandage on pain scores and wound healing after free gingival graft: a randomized controlled clinical trial. AB - OBJECTIVE: This prospective randomized clinical trial was conducted to determine whether the application of a platelet-rich fibrin (PRF) palatal bandage after harvesting free gingival grafts (FGG) would improve healing of donor sites and decrease pain scores and patient discomfort. MATERIALS AND METHODS: Twenty-four patients received FGG to augment keratinized tissue dimensions. The application of a PRF bandage was decided randomly (n = 12 in each group). Patients reported their pain levels for the first 7 days of healing using the visual analog scale (VAS), 101-point numerical rating scale (NRS-101), and 4-point verbal rating scale (VRS-4). The patients' pre-operative anxiety levels were measured using three anxiety scales. The healing of the donor sites was evaluated and compared to preoperative records. Data were assessed and recorded before surgery and at 1, 2, 3, 4, and 8 weeks postoperatively. RESULTS: Dental anxiety and state-trait anxiety were evaluated at baseline and correlated to the postoperative pain scores. There were no significant differences in anxiety levels between the two groups; yet, they could potentially influence the outcome of any surgery and were included as covariates. The patients in the PRF group reported significantly lower pain scores and their pain levels returned to baseline levels earlier, compared to the control group. CONCLUSIONS: PRF palatal bandages significantly reduced postoperative pain and discomfort and facilitated wound healing after harvesting FGG. CLINICAL RELEVANCE: The study provided evaluation of patient centered outcomes, which is timely, significant, and could benefit both periodontists and patients. PMID- 29524030 TI - Vitreous IL-8 and VEGF levels in diabetic macular edema with or without subretinal fluid. AB - PURPOSE: To determine the cytokine levels in vitreous samples of diabetic macular edema (DME) patients in comparison with nondiabetic patients, and to evaluate the effect of subretinal fluid on the cytokine levels of vitreous samples. METHODS: In this prospective case-control study, 11 eyes of 11 patients with DME and subretinal fluid, 11 eyes of 11 patients with DME without subretinal fluid, and 14 eyes of 14 patients who had undergone vitreoretinal surgery for the epiretinal membrane or a macular hole (control group) were evaluated. The blood glycated hemoglobin (HbA1c) level, vitreous vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) levels were determined. RESULTS: The vitreous VEGF level of patients in DME groups was significantly higher than the control group (p < 0.001) without significant difference between DME patients with and without subretinal fluid (p = 0.796). The vitreous IL-8 level of DME patients with subretinal fluid was significantly higher than both control (p = 0.002) and DME without subretinal fluid groups (p = 0.019). The blood HbA1c level was significantly higher in DME group with subretinal fluid than those without subretinal fluid (8.7 +/- 1.32 and 7.1 +/- 1.13%, respectively, p = 0.010). The only significant correlation was between vitreous VEGF level and blood HbA1c level in DME patients without subretinal fluid (r = 0.813, p = 0.002). CONCLUSIONS: IL-8 level in vitreous samples was higher in DME patients with subretinal fluid than those without subretinal fluid, suggesting that inflammation is an important factor in the progression of DME leading to the subretinal fluid formation in diabetic patients. PMID- 29524032 TI - Evaluation of a Placement Coaching Program for Recipients of Disability Insurance Benefits in Switzerland. AB - Purpose During 2009-2013 a pilot project was carried out in Zurich which aimed to increase the income of disability insurance (DI) benefit recipients in order to reduce their entitlement to DI benefits. The project consisted of placement coaching carried out by a private company that specialized in this field. It was exceptional with respect to three aspects: firstly, it did not include any formal training and/or medical aid; secondly, the coaches did not have the possibility of providing additional financial incentives or sanctioning lack of effort; and thirdly due to performance bonuses, the company not only had incentives to bring the participants into (higher paid) work, but also to keep them there for 52 weeks. This paper estimates the medium-run effects of the pilot project and assesses the net benefit from the Swiss social security system. Methods Different propensity score matching estimators are applied to administrative longitudinal data in order to construct suitable control groups. Results The estimates indicate a reduction in DI benefits and an increase in income even in the medium run. A simple cost-benefit analysis suggests that the pilot project was a profitable investment for the social security system. Conclusion Given a healthy labor market, it seems possible to enhance the employment prospects of disabled persons with a relatively inexpensive intervention, which does not include any explicit investments in human capital. PMID- 29524031 TI - Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma. AB - Axitinib is a potent second-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The plasma axitinib level was measured at 0, 2, 4, 8, and 12 h after administration (C0, C2, C4, C8, and C12; ng/mL) on day 7 of the treatment. Genetic polymorphisms related to axitinib pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed. Axitinib C0 and AUC0-12 in patients with UGT1A1 poor metabolisers (*6/*6, *6/*28, and *28/*28; n = 10) were significantly higher than those in patients with UGT1A1 extensive metabolisers (*1/*1, *1/*6,*1/*28, and *27/*28; n = 36) (23.6 vs. 7.8 ng/mL, p = 0.030, and 441.3 vs. 217.1 ng h/mL, p = 0.007). The cutoff levels of C0 to predict >= G2 hypothyroidism and >= G2 anorexia were 6.6 and 7.1 ng/mL, respectively (p = 0.005 and p = 0.035). The overall survival (OS) in patients with C0 > 5 ng/mL was significantly better than that in patients with C0 < 5 ng/mL (p = 0.022). Genetic polymorphisms in UGT1A1 were significantly associated with the plasma axitinib level. The plasma axitinib level was significantly associated with the frequency of AEs and OS in patients with mRCC. No direct relationship was observed between UGT1A1 genotypes and the frequency of AEs or OS. PMID- 29524033 TI - HIV Care After Jail: Low Rates of Engagement in a Vulnerable Population. AB - The criminal justice system is a critical area of focus to improve HIV outcomes and reduce health disparities. We analyzed demographic, incarceration, socioeconomic, and clinical data for HIV-positive persons released to the community from the Dallas County Jail (1450 incarcerations, 1111 unique individuals) between January 2011 and November 2013. The study population was 68% black and 14% Hispanic; overall linkage to care within 90 days of release was 34%. In adjusted analyses, Hispanics were more likely to link than whites (aOR 2.33 [95% CI: 1.55-3.50]), and blacks were as likely to link as whites (aOR 1.14 [95% CI: 0.84-1.56]). The majority of HIV-positive jail releases did not re engage in HIV care after release, though Hispanics were twice as likely as other groups to link to care. Further efforts are needed to improve the transition from jail to community HIV care with particular attention to issues of housing, mental illness, and substance use. PMID- 29524034 TI - Mineral oil residues in soil and apple under temperate conditions of Kashmir, India. AB - The study was undertaken to ascertain the persistence of Orchol-13, a mineral oil used against insect pests of horticultural fruit crops in soil and apple following the dormant and summer applications of 2 and 0.75% respectively. Soil samples were collected during dormant, while as both soil and apple samples were collected during summer season. Samples were collected at 0, 1, 3, and 5 days post treatment in both the seasons. Average recoveries of paraffinic constituents (which constitute about 60% of mineral oils by composition) from soil and apple at 1 MUg ml-1 spiking level were found to be 74.18 and 76.81% respectively. The final quantification of paraffinic constituents was performed on gas chromatograph equipped with flame ionization detector (GC-FID). No paraffinic constituents of mineral oil could be detected in soil and apple at 0 day post treatment in both the seasons. PMID- 29524035 TI - In vivo assembly of a truncated H subunit mutant of the Rhodobacter sphaeroides photosynthetic reaction centre and direct electron transfer from the QA quinone to an electrode. AB - We address a challenge in the engineering of proteins to redirect electron transfer pathways, using the bacterial photosynthetic reaction centre (RC) pigment-protein complex. Direct electron transfer is shown to occur from the QA quinone of the Rhodobacter sphaeroides RC containing a truncated H protein and bound on the quinone side to a gold electrode. In previous reports of binding to the quinone side of the RC, electron transfer has relied on the use of a soluble mediator between the RC and an electrode, in part because the probability of QB quinone reduction is much greater than that of direct electron transfer through the large cytoplasmic domain of the H subunit, presenting a ~ 25 A barrier. A series of C-terminal truncations of the H subunit were created to expose the quinone region of the RC L and M proteins, and all truncated RC H mutants assembled in vivo. The 45M mutant was designed to contain only the N-terminal 45 amino acid residues of the H subunit including the membrane-spanning alpha-helix; the mutant RC was stable when purified using the detergent N-dodecyl-beta-D maltoside, contained a near-native ratio of bacteriochlorophylls to bacteriopheophytins, and showed a charge-separated state of [Formula: see text]. The 45M-M229 mutant RC had a Cys residue introduced in the vicinity of the QA quinone on the newly exposed protein surface for electrode attachment, decreasing the distance between the quinone and electrode to ~ 12 A. Steady-state photocurrents of up to around 200 nA/cm2 were generated in the presence of 20 mM hydroquinone as the electron donor to the RC. This novel configuration yielded photocurrents orders of magnitude greater than previous reports of electron transfer from the quinone region of RCs bound in this orientation to an electrode. PMID- 29524036 TI - Ankylosing spondylitis monocyte-derived macrophages express increased level of A2A adenosine receptor and decreased level of ectonucleoside triphosphate diphosphohydrolase-1 (CD39), A1 and A2B adenosine receptors. AB - Macrophages play an important role in the ankylosing spondylitis (AS) auto inflammatory responses and fibrocartilage destruction. Adenosine is a key modulator of inflammatory conditions. The various effects of adenosine are mediated by its interaction with adenosine receptors (AR). In this study, we investigated the mRNA expression of A1, A2A, A2B, and A3 adenosine receptors, ectonucleoside triphosphate diphosphohydrolase-1 (CD39), and ecto-5'-nucleotidase (CD73) in the monocyte-derived macrophages from AS patients in comparison to healthy controls. We also explored the correlation between analyzed gene expression and patients' clinical manifestations. Whole blood-separated monocytes from 23 healthy controls and 23 active AS patients were stimulated by macrophage colony-stimulating factor (M-CSF) for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. Analysis of adenosine receptors (ADORA1? ADORA2A? ADORA2B? ADORA3), CD39 and CD73 gene expression was performed by SYBR green real-time PCR. Our results demonstrated monocyte-derived macrophages from AS patients expressed increased level of A2AAR and reduced level of A1, A2BAR, and CD39 mRNA compared to healthy controls. We found an inverse correlation between A2AAR mRNA expression and Bath Ankylosing Spondylitis Functional Index (BASFI) score in AS patients. According to our results, altered expression level of adenosine-relying system would be involved in AS macrophage dysfunction and inflammation and correlated with functional status in AS patients. PMID- 29524037 TI - C60 Fullerene Effects on Diphenyl-N-(trichloroacetyl)-amidophosphate Interaction with DNA In Silico and Its Cytotoxic Activity Against Human Leukemic Cell Line In Vitro. AB - New representative of carbacylamidophosphates - diphenyl-N-(trichloroacetyl) amidophosphate (HL), which contains two phenoxy substituents near the phosphoryl group, was synthesized, identified by elemental analysis and IR and NMR spectroscopy, and tested as a cytotoxic agent itself and in combination with C60 fullerene.According to molecular simulation results, C60 fullerene and HL could interact with DNA and form a rigid complex stabilized by stacking interactions of HL phenyl groups with C60 fullerene and DNA G nucleotide, as well as by interactions of HL CCl3 group by ion-pi bonds with C60 molecule and by electrostatic bonds with DNA G nucleotide.With the use of MTT test, the cytotoxic activity of HL against human leukemic CCRF-CM cells with IC50 value detected at 10 MUM concentration at 72 h of cells treatment was shown. Under combined action of 16 MUM C60 fullerene and HL, the value of IC50 was detected at lower 5 MUM HL concentration and at earlier 48 h period of incubation, besides the cytotoxic effect of HL was observed at a low 2.5 MUM concentration at which HL by itself had no influence on cell viability. Binding of C60 fullerene and HL with minor DNA groove with formation of a stable complex is assumed to be one of the possible reasons of their synergistic inhibition of CCRF-CEM cells proliferation.Application of C60 fullerene in combination with 2.5 MUM HL was shown to have no harmful effect on structural stability of blood erythrocytes membrane. Thus, combined action of C60 fullerene and HL in a low concentration potentiated HL cytotoxic effect against human leukemic cells and was not followed by hemolytic effect. PMID- 29524038 TI - Progress test utopia. AB - This paper discusses the advantages of progress testing. A utopia is described where medical schools would work together to develop and administer progress testing. This would lead to a significant reduction of cost, an increase in the quality of measurement and phenomenal feedback to learner and school. Progress testing would also provide more freedom and resources for more creative in-school assessment. It would be an educationally attractive alternative for the creation of cognitive licensing exams. A utopia is always far away in the future, but by formulating a vision for that future we may engage in discussions on how to get there. PMID- 29524039 TI - Enhanced Inulin Saccharification by Self-Produced Inulinase from a Newly Isolated Penicillium sp. and its Application in D-Lactic Acid Production. AB - In order to find an alternative for commercial inulinase, a strain XL01 identified as Penicillium sp. was screened for inulinase production. The broth after cultivated was centrifuged, filtered, and used as crude enzyme for the following saccharification. At pH 5.0 and 50 degrees C, the crude enzyme released 84.9 g/L fructose and 20.7 g/L glucose from 120 g/L inulin in 72 h. In addition, simultaneous saccharification and fermentation of chicory flour for D lactic acid production was carried out using the self-produced crude inulinase and Lactobacillus bulgaricus CGMCC 1.6970. A high D-lactic acid titer and productivity of 122.0 g/L and 1.69 g/(L h) was achieved from 120 g/L chicory flour in 72 h. The simplicity for inulinase production and the high efficiency for D-lactic acid fermentation provide a perspective and profitable industrial biotechnology for utilization of the inulin-rich biomass. PMID- 29524040 TI - Site-Directed Mutagenesis of Cytochrome P450 2D6 and 2C19 Enzymes: Expression and Spectral Characterization of Naturally Occurring Allelic Variants. AB - Genetic polymorphism of the cytochrome P450 (CYP) genes particularly affects CYP2D6 and CYP2C19 to a functionally relevant extent, and it is therefore crucial to elucidate the enzyme kinetic and molecular basis for altered catalytic activity of these allelic variants. This study explored the expression and function of the reported alleles CYP2D6*2, CYP2D6*10, CYP2D6*17, CYP2C19*23, CYP2C19*24, and CYP2C19*25 with respect to gene polymorphisms. Site-directed mutagenesis (SDM) was carried out to generate these six alleles. After DNA sequencing, the CYP2D6 and CYP2C19 wild types alongside with their alleles were each independently co-expressed with NADPH-CYP oxidoreductase (OxR) in Escherichia coli. The expressed proteins were analyzed using Western blotting, reduced carbon monoxide (CO) difference spectral scanning, and cytochrome c reductase assay. Results from Western blot revealed the presence of all CYP wild type and allelic proteins in E. coli membrane fractions. The reduced CO difference spectra scanning presented the distinct peak of absorbance at 450 nm, and the cytochrome c reductase assay has confirmed that spectrally active OxR was expressed in each protein preparation. As a conclusion, the results obtained from this study have proven the CYP variants to be immunoreactive and spectrally active and are suitable for use to examine biotransformation and interaction mechanism of the enzymes. PMID- 29524041 TI - Robot-Assisted Fracture Surgery: Surgical Requirements and System Design. AB - The design of medical devices is a complex and crucial process to ensure patient safety. It has been shown that improperly designed devices lead to errors and associated accidents and costs. A key element for a successful design is incorporating the views of the primary and secondary stakeholders early in the development process. They provide insights into current practice and point out specific issues with the current processes and equipment in use. This work presents how information from a user-study conducted in the early stages of the RAFS (Robot Assisted Fracture Surgery) project informed the subsequent development and testing of the system. The user needs were captured using qualitative methods and converted to operational, functional, and non-functional requirements based on the methods derived from product design and development. This work presents how the requirements inform a new workflow for intra-articular joint fracture reduction using a robotic system. It is also shown how the various elements of the system are developed to explicitly address one or more of the requirements identified, and how intermediate verification tests are conducted to ensure conformity. Finally, a validation test in the form of a cadaveric trial confirms the ability of the designed system to satisfy the aims set by the original research question and the needs of the users. PMID- 29524042 TI - Automated reaction database and reaction network analysis: extraction of reaction templates using cheminformatics. AB - Both the automated generation of reaction networks and the automated prediction of synthetic trees require, in one way or another, the definition of possible transformations a molecule can undergo. One way of doing this is by using reaction templates. In view of the expanding amount of known reactions, it has become more and more difficult to envision all possible transformations that could occur in a studied system. Nonetheless, most reaction network generation tools rely on user-defined reaction templates. Not only does this limit the amount of chemistry that can be accounted for in the reaction networks, it also confines the wide-spread use of the tools by a broad public. In retrosynthetic analysis, the quality of the analysis depends on what percentage of the known chemistry is accounted for. Using databases to identify templates is therefore crucial in this respect. For this purpose, an algorithm has been developed to extract reaction templates from various types of chemical databases. Some databases such as the Kyoto Encyclopedia for Genes and Genomes and RMG do not report an atom-atom mapping (AAM) for the reactions. This makes the extraction of a template non-straightforward. If no mapping is available, it is calculated by the Reaction Decoder Tool (RDT). With a correct AAM-either calculated by RDT or specified-the algorithm consistently extracts a correct template for a wide variety of reactions, both elementary and non-elementary. The developed algorithm is a first step towards data-driven generation of synthetic trees or reaction networks, and a greater accessibility for non-expert users. PMID- 29524044 TI - Recurrent complex regional pain syndrome type I in a patient with amyotrophic lateral sclerosis: a case report. PMID- 29524043 TI - Chemokine CXCL3 mediates prostate cancer cells proliferation, migration and gene expression changes in an autocrine/paracrine fashion. AB - INTRODUCTION: We have previously indicated that CXCL3 was upregulated in the tissues of prostate cancer, and exogenous administration of CXCL3 played a predominant role in the tumorigenicity of prostate cancer cells. In the present study, we further explored the role and the underlying mechanism of CXCL3 overexpression in the oncogenic potential of prostate cancer in an autocrine/paracrine fashion. METHODS: CXCL3-overexpressing prostate cancer cell line PC-3 and immortalized prostate stromal cell line WPMY-1 were established by gene transfection. CCK-8, transwell assays and growth of tumor xenografts were conducted to characterize the effects of CXCL3 on PC-3 cells' proliferation and migration. Western blotting was conducted to test whether CXCL3 could affect the expression of tumorigenesis-associated genes. RESULTS: The results showed that CXCL3 overexpression in PC-3 cells and the PC-3 cells treated with the supernatants of CXCL3-transfected WPMY-1 cells stimulated the proliferation and migration of PC-3 cells in vitro and in a nude mouse xenograft model. Western blotting revealed higher levels of p-ERK, Akt and Bcl-2 and lower levels of Bax in the tumor xenografts transplanted with CXCL3-transfected PC-3 cells. Moreover, the tumor xenografts derived from the PC-3 cells treated with supernatants of CXCL3-transfected WPMY-1 cells showed higher expression of ERK, Akt and Bcl-2 and lower expression of Bax. CONCLUSIONS: These findings suggest that CXCL3 autocrine/paracrine pathways are involved in the development of prostate cancer by regulating the expression of the target genes that are related to the progression of malignancies. PMID- 29524045 TI - Closed loop control of microscopic particles incorporating steady streaming and visual feedback. AB - Automatic manipulation of microscopic particles is very important in biology, especially in new lab-on-chip systems for automatic testing and DNA manipulation. We suggest a particle manipulation system (PMS) based on vibrating piezoelectric beams creating steady streaming flow in a viscous liquid. The flow is nearly unidirectional and it is used to control the position and velocity of the particles in the workspace of the PMS. The particles position in the PMS are controlled by visual feedback. This study presents the manipulation method, the system's model describing its behavior and characterizes experimentally its performance. The PMS is capable moving a 2-200 MUm particle in a workspace of 8x8 mm2 with an absolute accuracy of 0.2 MUm. The characteristic velocity in 500 cP Si oil, is 20 MUm/s using an actuation voltage amplitude of 5 V and can reach 250 MUm/s using 15 V respectively. We can also move a constellation of several particles in various sizes without changing the distance between them. The accuracy of the manipulation can be increased by enhancing the amplification of the microscope on the expanse of a smaller workspace field of view. PMID- 29524046 TI - A Population-based Study on Lymph Node Retrieval in Patients with Esophageal Cancer: Results from the Dutch Upper Gastrointestinal Cancer Audit. AB - BACKGROUND: For esophageal cancer, the number of retrieved lymph nodes (LNs) is often used as a quality indicator. The aim of this study is to analyze the number of retrieved LNs in The Netherlands, assess factors associated with LN yield, and explore the association with short-term outcomes. This is a population-based study on lymph node retrieval in patients with esophageal cancer, presenting results from the Dutch Upper Gastrointestinal Cancer Audit. STUDY DESIGN: For this retrospective national cohort study, patients with esophageal carcinoma who underwent esophagectomy between 2011 and 2016 were included. The primary outcome was the number of retrieved LNs. Univariable and multivariable regression analyses were used to test for association with >= 15 LNs. PATIENTS AND RESULTS: 3970 patients were included. Between 2011 and 2016, the median number of LNs increased from 15 to 20. Factors independently associated with >= 15 LNs were: 0 10 kg preoperative weight loss (versus: unknown weight loss, odds ratio [95% confidence interval]: 0.71 [0.57-0.88]), Charlson score 0 (versus: Charlson score 2: 0.76 [0.63-0.92]), cN2 category (reference: cN0, 1.32 [1.05-1.65]), no neoadjuvant therapy and neoadjuvant chemotherapy (reference: neoadjuvant chemoradiotherapy, 1.73 [1.29-2.32] and 2.15 [1.54-3.01]), minimally invasive transthoracic (reference: open transthoracic, 1.46 [1.15-1.85]), open transthoracic (versus open and minimally invasive transhiatal, 0.29 [0.23-0.36] and 0.43 [0.32-0.59]), hospital volume of 26-50 or > 50 resections/year (reference: 0-25, 1.94 [1.55-2.42] and 3.01 [2.36-3.83]), and year of surgery [reference: 2011, odds ratios (ORs) 1.48, 1.53, 2.28, 2.44, 2.54]. There was no association of >= 15 LNs with short-term outcomes. CONCLUSIONS: The number of LNs retrieved increased between 2011 and 2016. Weight loss, Charlson score, cN category, neoadjuvant therapy, surgical approach, year of resection, and hospital volume were all associated with increased LN yield. Retrieval of >= 15 LNs was not associated with increased postoperative morbidity/mortality. PMID- 29524047 TI - Structure and Inhibitor Specificity of L,D-Transpeptidase (LdtMt2) from Mycobacterium tuberculosis and Antibiotic Resistance: Calcium Binding Promotes Dimer Formation. AB - The final step of peptidoglycan (PG) synthesis in all bacteria is the formation of cross-linkage between PG-stems. The cross-linking between amino acids in different PG chains gives the peptidoglycan cell wall a 3-dimensional structure and adds strength and rigidity to it. There are two distinct types of cross linkages in bacterial cell walls. D,D-transpeptidase (D,D-TPs) generate the classical 4?3 cross-linkages and the L,D-transpeptidase (L,D-TPs) generate the 3?3 non-classical peptide cross-linkages. The present study is aimed at understanding the nature of drug resistance associated with L,D-TP and gaining insights for designing novel antibiotics against multi-drug resistant bacteria. Penicillin and cephalosporin classes of beta-lactams cannot inhibit L,D-TP function; however, carbapenems inactivate its function. We analyzed the structure of L,D-TP of Mycobacterium tuberculosis in the apo form and in complex with meropenem and imipenem. The periplasmic region of L,D-TP folds into three domains. The catalytic residues are situated in the C-terminal domain. The acylation reaction occurs between carbapenem antibiotics and the catalytic Cys 354 forming a covalent complex. This adduct formation mimics the acylation of L,D TP with the donor PG-stem. A novel aspect of this study is that in the crystal structures of the apo and the carbapenem complexes, the N-terminal domain has a muropeptide unit non-covalently bound to it. Another interesting observation is that the calcium complex crystallized as a dimer through head and tail interactions between the monomers. PMID- 29524048 TI - Uses and Meanings of "Context" in Studies on Children's Knowledge: A Viewpoint from Anthropology and Constructivist Psychology. AB - Though context has yet to receive an unequivocal definition, it is a concept that frequently appears in research in children's knowledge and its construction. This article examines the scope and meaning of context in genetic psychology and social anthropology in order to better understand the relationship between children's construction of knowledge and the context in which it occurs. Meta theoretical, theoretical and methodological complexities arise when the concept is analyzed in the two disciplines, and these will also be addressed herein. The fields of anthropology and constructive psychology are both affected by the relationship between the building of knowledge and the social practices surrounding this process. Finally, based on these empirical examinations, the article explores how research methodologies could incorporate the notion of context in research focused on the construction of knowledge. PMID- 29524049 TI - Differences between horse selection based on two forms of osteochondrosis in fetlock. AB - Horses lose potential opportunities because of health problems. Available breeding strategies are not effective enough, probably also because of the different definition used and its genetic usefulness. The aim of the study was to compare the genetic background estimated by the genome-wide association study (GWAS) for osteochondrosis using two different scaling osteochondrosis (OC)/healthy and osteochondrosis dissecans (OCD)/healthy systems for evaluating the disease status of investigated fetlock joints. Two hundred one Warmblood horses trained for performance tests (87 stallions and 114 mares) were phenotyped and genotyped. Four fetlock x-ray images per horse were collected using the RTG Girth HF 80 and Vet Scan ray 3600. The DNA of each horse was genotyped using the BeadChip 70K. To identify SNPs that significantly affect the probability of osteochondrosis, two different methods were applied: the Cochran-Armitage test based on an additive mode of inheritance and logistic regression. The genetic background for osteochondrosis, expressed in the number of SNPs found with significant associations with osteochondrosis, was higher by evaluation in the scale of OCD/healthy horses (16 SNPs on several chromosomes mainly on the ECA1 and ECA10) than OC/healthy (2 SNPs on the ECA15 and one SNP on the ECA10). Detailed definition of osteochondrosis is needed in breeding and in veterinary practice. The genetic background for osteochondrosis and osteochondrosis dissecans seems not the same. Suggestive SNPs could be the candidate markers for osteochondrosis but should be checked on a larger population before usage. PMID- 29524050 TI - Role of Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM) is the most common primary malignant cancer of brain, which is extremely aggressive and carries a dreadful prognosis. Current treatment protocol runs around radiotherapy, surgical resection, and temozolomide with median overall survival of around 12-15 months. Due to its heterogeneity and mutational load, immunotherapy with chimeric antigen receptor (CAR) T cell therapy can be a promising treatment option for recurrent glioblastoma. Initial phase 1 studies have shown that this therapy is safe without dose-limiting side effects and it also has a better clinical outcome. Therefore, CAR T cell therapy can be a great future tool in our armamentarium to treat advanced GBM. In this article, we have explained the structure, mechanism of action, and rationale of CAR T cell therapy in GBM; we also discussed various antigenic targets and clinical outcome of initial studies of this novel therapy. PMID- 29524051 TI - Neuroinflammation, Gut Microbiome, and Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease that develops insidiously and causes dementia finally. There are also clinical complications in advanced dementia, such as eating problems, infections, which will lead to the decline of patients' life quality, and the rising cost of care for AD to our society. AD will be important public health challenge. Early detection of AD may be a key issue to prevent, delay, and stop the disease. Gut microbiome and neuroinflammation are closely related with nervous system diseases, although the specific mechanism is not clear. This review introduces the relationship between neuroinflammation, gut microbiome, and AD. PMID- 29524052 TI - A Novel Five-Node Feed-Forward Loop Unravels miRNA-Gene-TF Regulatory Relationships in Ischemic Stroke. AB - The complex and interlinked cascade of events regulated by microRNAs (miRNAs), transcription factors (TF), and target genes highlight the multifactorial nature of ischemic stroke pathology. The complexity of ischemic stroke requires a wider assessment than the existing experimental research that deals with only a few regulatory components. Here, we assessed a massive set of genes, miRNAs, and transcription factors to build a miRNA-gene-transcription factor regulatory network to elucidate the underlying post-transcriptional mechanisms in ischemic stroke. Feed-forward loops (three-node, four-node, and novel five-node) were converged to establish regulatory relationships between miRNAs, TFs, and genes. The synergistic function of miRNAs in ischemic stroke was predicted and incorporated into a novel five-node feed-forward loop. Significant miRNA-TF pairs were identified using cumulative hypergeometric distribution. Two subnetworks were derived from the extensive miRNA-TF regulatory network and analyzed to predict the molecular mechanism relating the regulatory components. NFKB and STAT were identified to be the chief regulators of innate inflammatory and neuronal survival mechanisms, respectively. Exclusive novel interactions between miR-9 and miR-124 with TLX, BCL2, and HDAC4 were identified to explain the post-stroke induced neurogenesis mechanism. Therefore, this network-based approach to delineate miRNA, TF, and gene interactions might promote the development of effective therapeutics against ischemic stroke. PMID- 29524053 TI - Reproductive success and contaminant associations in tree swallows (Tachycineta bicolor) used to assess a Beneficial Use Impairment in U.S. and Binational Great Lakes' Areas of Concern. AB - During 2010-2014, tree swallow (Tachycineta bicolor) reproductive success was monitored at 68 sites across all 5 Great Lakes, including 58 sites located within Great Lakes Areas of Concern (AOCs) and 10 non-AOCs. Sample eggs were collected from tree swallow clutches and analyzed for contaminants including polychlorinated biphenyls (PCBs), dioxins and furans, polybrominated diphenyl ethers, and 34 other organic compounds. Contaminant data were available for 360 of the clutches monitored. Markov chain multistate modeling was used to assess the importance of 5 ecological variables and 11 of the dominant contaminants in explaining the pattern of egg and nestling failure rates. Four of 5 ecological variables (Female Age, Date within season, Year, and Site) were important explanatory variables. Of the 11 contaminants, only total dioxin and furan toxic equivalents (TEQs) explained a significant amount of the egg failure probabilities. Neither total PCBs nor PCB TEQs explained the variation in egg failure rates. In a separate analysis, polycyclic aromatic hydrocarbon exposure in nestling diet, used as a proxy for female diet during egg laying, was significantly correlated with the daily probability of egg failure. The 8 sites within AOCs which had poorer reproduction when compared to 10 non-AOC sites, the measure of impaired reproduction as defined by the Great Lakes Restoration Initiative, were associated with exposure to dioxins and furan TEQs, PAHs, or depredation. Only 2 sites had poorer reproduction than the poorest performing non AOC. Using a classic (non-modeling) approach to estimating reproductive success, 82% of nests hatched at least 1 egg, and 75% of eggs laid, excluding those collected for contaminant analyses, hatched. PMID- 29524054 TI - The effects of fluoxetine on attachment and righting behaviours in marine (Gibbula unbilicalis) and freshwater (Lymnea stagnalis) gastropods. AB - Recent studies have highlighted that antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) entering aquatic systems through wastewater discharges might impact organisms at environmentally relevant concentrations. In this study, two snail species (Gibbula unbilicalis and Lymnea stagnalis) representing the marine and freshwater environments were exposed to a large range of fluoxetine concentrations (1 ng L-1-1 mg L-1) and two distinct behaviours (foot detachment and righting time) were recorded. Fluoxetine significantly caused foot detachment only at the higher of the concentrations (1 mg L-1) in both species during the course of this short term 1.5 h and 4 h exposures. In this study, lowest observed effect concentrations (LOECs) for foot detachment fell repeatedly within the range for other gastropod snails exposed to fluoxetine. Fluoxetine effected righting times in a concentration dependant manner but only significantly within G. unbilicalis in the highest concentration. Reviewing existing data on the effects of antidepressants on a range of endpoints in gastropod molluscs reveals wide variability of results. The importance of publishing 'negative' and/or non-dramatic results to aid risk assessment are discussed along with the variability between antidepressants, model species, experimental designs and endpoints. PMID- 29524055 TI - Morphometric and Vascular Modifications of the Clitoris During Pregnancy: A Longitudinal, Pilot Study. AB - During pregnancy, women go through a series of physical and emotional changes that may have an impact on their sexuality. The aim of the study was to examine modifications in sexual function during pregnancy by means of translabial ultrasonography and administration of questionnaires on sexual activity. Eighteen healthy and adult (25-35 years) pregnant women without sexual dysfunction and with a stable heterosexual relationship were examined at 10-12, 18-20, and 30-32 weeks of gestation. Patients underwent ultrasonographic translabial clitoral volume and labia minora thickness measurements and color Doppler assessment of the dorsal clitoral and posterior labial arteries. On the same day, each patient completed the two-factor Italian McCoy Female Questionnaire (MFSQ) and the Female Sexual Function Index (FSFI). The mean clitoral body volume progressively increased during pregnancy, and color Doppler analysis of the dorsal clitoral artery showed a significant decrease in the pulsatility index from the first to the third trimester. Similarly, the labia minora thickness increased and the posterior labial artery pulsatility index progressively decreased throughout gestation. The MFSQ score for sexuality and partnership and the number of intercourses/week did not significantly change during the study period. However, the MFSQ score for partnership reached the lowest value in the third trimester of pregnancy. Analysis of the FSFI data showed no significant differences throughout pregnancy for the majority of the domains (sexual desire, arousal, orgasm, lubrication, and pain), with the exception of the satisfaction item, which decreased during the third trimester. A significant proportion of women are concerned that changes in their body during pregnancy may have a detrimental effect on sexuality. Despite significant changes in genital morphology and vascularity throughout gestation, these modifications do not seem to have an impact on sexual function in pregnancy. PMID- 29524056 TI - Prioritizing a One Health Approach in the Immediate Fight Against Antimicrobial Resistance. AB - Antimicrobial resistance is a major threat to global health security. While the global community has made recent advances to mitigate the threat of antimicrobial resistance, we continue to face challenges in creating solutions and concrete actions that will yield the greatest immediate impact. To examine the critical areas in human, animal and environmental health that contribute to the emergence and spread of antimicrobial resistance, the Forum on Microbial Threats of the U.S. National Academies of Sciences, Engineering and Medicine hosted a public workshop on June 20-21, 2017 in Washington, DC. This article summarizes the final synthesis discussion that took place at the workshop on suggestions for immediate actions and implementation that are feasible and cost-effective for combating antimicrobial resistance across the One Health domains. The priorities that emerged from the participants' discussions addressed the following topics: (1) Surveillance; (2) Stewardship, Infection Prevention and Behavior Modification; (3) Basic and Applied Research and Development; and (4) Global Policy and Coordination. PMID- 29524057 TI - Antibiotic-Resistant Genes and Pathogens Shed by Wild Deer Correlate with Land Application of Residuals. AB - The purpose of this study was to investigate genetic biomarkers of zoonotic enteric pathogens and antibiotic-resistant genes (ARGs) in the feces of white tailed deer (Odocoileus virginianus) as related to proximity of deer to land that receives livestock manure or human waste biosolid fertilizers. Deer feces were collected in the St. Lawrence River Valley and Adirondack State Park of New York. Campylobacter spp. 16S rDNA was detected in 12 of 232 fecal samples (8 of 33 sites). Salmonellae were cultivated from 2 of 182 fecal samples (2 of 29 sites). Genetic virulence markers for Shiga-like toxin I (stx1) and enterohemolysin (hylA) were each detected in one isolate of Escherichia coli; E. coli O157 was not detected in any of 295 fecal samples. ARGs detected in deer feces included ermB (erythromycin-resistant gene; 9 of 295 fecal samples, 5 of 38 sites), vanA (vancomycin-resistant gene; 93 of 284 samples, 33 of 38 sites), tetQ (tetracycline-resistant gene; 93 of 295 samples, 25 of 38 sites), and sul(I) (sulfonamide-resistant gene; 113 of 292 samples, 28 of 38 sites). Genetic markers of pathogens and ARGs in deer feces were spatially associated with collection near concentrated animal feeding operations (CAFOs; Campylobacter spp., tetQ, and ermB) and land-applied biosolids (tetQ). These results indicate that contact with human waste biosolids or animal manure may be an important method of pathogen and ARG transmission and that deer in proximity to land-applied manure and human waste biosolids pose increased risk to nearby produce and water quality. PMID- 29524059 TI - Vaccination Against Porcine Circovirus-2 Reduces Severity of Tuberculosis in Wild Boar. AB - Tuberculosis (TB) in wild boar (Sus scrofa) may be affected by coinfections with other pathogens, such as porcine circovirus type 2 (PCV2). Therefore, sanitary measures focused on controlling PCV2 could be useful in reducing the impact of TB in this wild suid. The aim of this study was to explore whether vaccination against PCV2 targeting young animals affects TB prevalence and TB severity in wild boar. The study was conducted on a game estate in mid-western Spain. Seventy animals of ages ranging from 4 to 8 months were captured, individually identified, vaccinated against PCV2 and released, forming a vaccinated group. Not captured animals cohabiting with the vaccinated wild boar constituted the control group. Animals from both groups were hunted between 2013 and 2016 and a TB diagnosis based on pathological assessment and microbiological culture was made in all of them. The effect of PCV2 vaccination on TB prevalence and severity was explored using generalized lineal models. Whereas TB prevalence was similar in vaccinated and control groups (54.55 vs. 57.78%), vaccinated animals showed less probabilities to develop generalized TB lesions. Furthermore, mean TB severity score was significantly lower in vaccinated animals (1.55 vs. 2.42) suggesting a positive effect of PCV2 vaccination. PMID- 29524061 TI - The effect of orthokeratology on axial length elongation in children with myopia: Contralateral comparison study. AB - PURPOSE: To evaluate the effectiveness of the orthokeratology (OK) lens slowing myopic progression compared with no intervention in pediatric eyes METHODS: A retrospective review of medical records was performed on 45 monocular myopic subjects 7 to 13 years of age who were treated with monocular ortho-k lens and followed-up for more than 12 months. The monocular myopia in the subjects' eyes was -0.75 to -4.25 D (diopter), and near emmetropia in the contralateral and with the-rule astigmatism no greater than -1.50 D. Axial elongation OU, reflecting the progression of myopia was measured at baseline using the same AL-Scan Optical Biometer and compared between the two eyes of each individual every six months for one year in all subjects and for two years in 9 subjects. RESULTS: After 12 months of lens wear, axial length had increased by 0.36 +/- 0.23mm in the control eyes (P < 0.001) but showed far less change (+0.07 +/- 0.21 mm) in the OK eyes (P = 0.038). The nine subjects followed-up for 2 years showed no axial length change (+0.16 +/- 0.25 mm) in the OK eyes (P = 0.095) after 24 months and significant axial length growth (+0.38 +/- 0.26 mm; P = 0.002) in the control eyes. Control eyes showed progressive axial length growth throughout the study compared with the one OK lens eye. CONCLUSIONS: Using a contralateral eye study design, which prevented the influence of potential confounding factors, Effectiveness of the OK lens was proved. Myopic progression within a subject was excellent compared with no intervention. PMID- 29524060 TI - Chromosomally encoded and plasmid-mediated polymyxins resistance in Acinetobacter baumannii: a huge public health threat. AB - Acinetobacter baumannii is an opportunistic pathogen associated with nosocomial and community infections of great clinical relevance. Its ability to rapidly develop resistance to antimicrobials, especially carbapenems, has re-boosted the prescription and use of polymyxins. However, the emergence of strains resistant to these antimicrobials is becoming a critical issue in several regions of the world because very few of currently available antibiotics are effective in these cases. This review summarizes the most up-to-date knowledge about chromosomally encoded and plasmid-mediated polymyxins resistance in A. baumannii. Different mechanisms are employed by A. baumannii to overcome the antibacterial effects of polymyxins. Modification of the outer membrane through phosphoethanolamine addition, loss of lipopolysaccharide, symmetric rupture, metabolic changes affecting osmoprotective amino acids, and overexpression of efflux pumps are involved in this process. Several genetic elements modulate these mechanisms, but only three of them have been described so far in A. baumannii clinical isolates such as mutations in pmrCAB, lpxACD, and lpsB. Elucidation of genotypic profiles and resistance mechanisms are necessary for control and fight against resistance to polymyxins in A. baumannii, thereby protecting this class for future treatment. PMID- 29524062 TI - The role of programmed death ligand-1 and tumor-infiltrating lymphocytes in breast cancer overexpressing HER2 gene. AB - PURPOSE: The purpose of the study is to investigate the prognostic significance of programmed death ligand-1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in HER2+ breast cancer (BC). METHODS: HER2+ BC cases (n = 191) were collected between 1996 and 2013. Tissue microarray (TMA) slides were stained with two clones of PD-L1 antibodies (28-8 and 22C3) and the percentage of positive membranous staining was scored. TILs of the full sections were also scored using percentage scale. RESULTS: Clone 28-8 had expression in >= 1% of the tumor cells in 25.7% of the cases, while clone 22C3 in >= 1% of the tumor cells was expressed in 11.5% of the cases. In the multivariate analysis, higher expression of PD-L1 (clone 28-8) in tumor correlated with lower risk of tumor recurrence, with HR of 0.4 (p = 0.033). Higher level of TILs (> 15%) predicts better overall survival (OS) in all patients with HR of 0.35 (p = 0.0046). In the group of patients who were treated with trastuzumab-based adjuvant chemotherapy, lower PD-L1 (clone 28-8) expression in TILs correlated with tumor recurrence (p = 0.034). In the group of patients who were treated with non trastuzumab-based adjuvant chemotherapy, lower TILs and lower PD-L1 (clone 28-8) expression in tumor had borderline statistical significance in association with tumor recurrence (p = 0.064 and 0.083, respectively). In the group of patients who were treated with trastuzumab-based adjuvant chemotherapy, PD-L1 or TILs was not statistically significant to predict 5-year survival. In the group of patients who were treated with non-trastuzumab-based adjuvant chemotherapy, low TILs (p = 0.009) correlated with 5-year death due to disease. CONCLUSION: We conclude that PD-L1 may have prognostic significance in HER2+ BCs. PMID- 29524063 TI - Major pathologic response to alectinib in ALK-rearranged adenocarcinoma of the lung. AB - BACKGROUND: Alectinib is a highly selective tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) and provided a significantly prolonged progression-free survival compared with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) harboring rearrangements of the ALK gene. Here, we present the first surgical case of ALK-rearranged lung adenocarcinoma with major pathological response in resected specimens after treatment with alectinib. CASE PRESENTATION: A 65-year-old female with clinical stage IIIA-N2 ALK-rearranged adenocarcinoma originating from the left lower lobe presented. Involvement of lower para-tracheal node was pathologically confirmed by endobronchial ultrasound-guided biopsy. Alectinib was prescribed, as the patient may not tolerate radiotherapy due to a mental illness. After 3 months' treatment with alectinib, a remarkable radiological and metabolic response was achieved. The patient did not tolerate further continuation of alectinib treatment, and surgery was performed without any morbidity. Only < 10% tumor cells were viable in all resected specimens, indicating major pathological response to alectinib. CONCLUSIONS: Salvage surgery after alectinib treatment may be safe and effective for initially unresectable NSCLC harboring ALK-rearrangements. PMID- 29524064 TI - Occurrence of deoxynivalenol and zearalenone in brewing barley grains from Brazil. AB - Barley (Hordeum vulgare L.) is an important cereal crop for food and represents one of the main ingredients in beer production. Considering the importance of barley and its derived products, the knowledge about the mycotoxin contamination in the barley production is essential in order to assess its safety. In this study, the levels of deoxynivalenol (DON) and zearalenone (ZEN) in brewing barley were determined using a LC-MS/MS method. A survey was conducted in 2015 to estimate the mycotoxin levels in these products (n = 76) from four crop regions in Brazil. The results showed high levels of DON and ZEN in the analyzed samples, with contamination levels of 94 and 73.6%, respectively. The mean levels of DON and ZEN ranged from 1700 to 7500 MUg/kg and from 300 to 630 MUg/kg, respectively. Barley samples from regions 1 and 2 presented higher levels of ZEN and DON, respectively, and those from region 4 presented lower levels of both. Co occurrence of DON and ZEN was seen in the majority of the barley grain samples, and the mycotoxin content was above the maximum levels established by the Brazilian and European regulations. PMID- 29524065 TI - Sclerosing pneumocytoma diagnosed by preoperative endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). AB - BACKGROUND: Sclerosing pneumocytoma is a rare lung tumor that is usually recognized as a solitary nodule in the lung. Surgical removal is recommended; however, its clinical diagnosis is still an issue because it is difficult to differentiate from lung adenocarcinomas using a tiny sample obtained from biopsy. CASE PRESENTATION: We report a case of pulmonary sclerosing pneumocytoma located in the upper lobe of the right lung of a 34-year-old woman, which was diagnosed before surgery by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). A 3-cm irregular mass was detected by chest X-ray without any symptoms. She was referred to our hospital after being followed for 10 years in her previous clinic. During this follow-up period, the tumor had grown to 5 cm. We performed the EBUS-TBNA for the diagnosis. The histological findings obtained by EBUS-TBNA consisted of alveolar type 2-like cells that were positive for napsin A and round cells that were positive for vimentin. Based on these immunostaining results, we successfully diagnosed sclerosing pneumocytoma before surgery. Right upper lobectomy was performed, and the pathological diagnosis of the surgical specimen was also confirmed as sclerosing pneumocytoma. CONCLUSIONS: We herein report a case of sclerosing pneumocytoma, which was clinically diagnosed by EBUS-TBNA and resected surgically. PMID- 29524066 TI - Implantable devices for heart failure monitoring and therapy. AB - Heart failure (HF), the cardiovascular epidemic of the twenty-first century, is associated with significant comorbidities and high mortality. The prevalence of HF is estimated around 6.5 million people and is expected to increase to 8 million by the year 2030. The associated costs to care for these patients continue to increase. Despite the advancement of pharmacologic therapy with significant improvement in morbidity and mortality, the 5-year survival for heart failure still stands at 61%. The challenges faced by HF patients include difficulty with lifestyle modifications, nonadherence to complex medical regimens, financial limitations, lack of access to medical care, and unfavorable side effects. The sickest HF patients, who are ACC/AHA stage D, have advanced therapeutic options such as left ventricular assist devices and orthotopic heart transplant; however, the majority of patients are ACC/AHA stage C and/or not candidates for such advanced care. With constraints placed on hospitals by Medicare on HF readmissions as well as the multiple comorbidities imposed by this disease, intense interest is focused on the development of implantable devices as add-on therapy. This review discusses the innovative devices under varying stages of investigation or approved for monitoring and treatment of HF. PMID- 29524067 TI - The impact of oral anti-diabetic medications on heart failure: lessons learned from preclinical studies. AB - The prevalence of heart failure (HF) in the diabetic population has rapidly increased over the past 2 decades, triggering research about the impact of oral anti-diabetic medications on it. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. On the other hand, recent promising clinical data from oral SGLT2 inhibitors mainly lack mechanistic explanation from experimental studies. Hence, it is critical to understand the lessons learned from prior translational studies to gain a better knowledge of the mechanisms of oral anti-diabetic drugs in HF. This review aims to summarize the results from preclinical studies regarding the interaction between oral anti-diabetic medications and heart failure development and/or exacerbation. Although there is a wide spectrum of controversial results, the underlying hope is that the clinical success rate will improve and the adverse events during ineffective targeted therapy will be limited. PMID- 29524069 TI - A Commentary on Commercial Genetic Testing and the Future of the Genetic Counseling Profession. AB - Commercial genetic testing laboratories are increasingly employing genetic counselors. As a result, the role of these or many genetic counselors is shifting from primarily direct patient counseling in clinics and hospitals to more laboratory-centered activities that involve case coordination, customer liaison, variant classification, marketing, and sales. Given the importance of these commercial entities to the genetic counseling profession, this commentary examines the current financial situation of four publicly traded, genetic testing companies. It also explores how the various roles of genetic counselors are likely to be affected by the financial pressures these companies face. PMID- 29524068 TI - Gut microbiota and its implications in small bowel transplantation. AB - The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBTand the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host-microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice. PMID- 29524070 TI - Psychometric Evaluation of the Turkish Form of the Spiritual Care Competence Scale. AB - The methodological study was aimed to assess the psychometric properties of the Turkish version of the Spiritual Care Competence Scale (SCCS-T). The research was conducted on final-year Turkish nursing students (n = 297) in the faculties of nursing and health science in two cities in the western part of Turkey. Exploratory factor analysis revealed that three factors accounted for 75.18% of the explained variance. The Cronbach's alpha coefficient for the SCCS-T was .97. The three-factor model of the SCCS-T was found to be a reliable and valid scale for evaluating spiritual care competencies of Turkish nursing students and nurses. PMID- 29524071 TI - Helping Carers Care: An Exploratory Study of Factors Impacting Informal Family Carers and Their Use of Aged Care Services. AB - This exploratory study considered the role of informal carers and their decision making regarding various aged care services that supposedly support their ageing relatives. Consideration was given to the stressors and overall well-being of informal carers and the support services they did or did not receive during their time of caregiving. A questionnaire was utilised to gain exploratory quantitative and qualitative data plus basic demographic information from informal carers who connected with a single caregiver association based in Victoria, Australia. Several themes emerged from the analysis of data regarding carer well-being, carer decision-making and carer relationships-particularly with respect to the various authorities and organisations ostensibly responsible for supporting carers. While the majority of participants indicated a religious association, nevertheless spiritual considerations were not stress factors paramount in their decision-making or their criticism of carer support services. Other concerns dominated such as the need of having appropriate practical support, better case management, organisational transparency and greater recognition of the role of informal carers. Although this research was isolated to a particular locality, carers in similar situations globally have indicated comparable stresses and challenges further indicating that greater accountability and improved organisation are required for the support of carers internationally. Recommendations are suggested for how service providers can support carers-most importantly, the need for ongoing government assessment and government service improvement in order to help carers care into the future. PMID- 29524072 TI - Synthesis, Bioassays and Field Evaluation of Hydroxycoumarins and their Alkyl Derivatives as Repellents or Kairomones for Aedes albopictus Skuse (Diptera: Culicidae). AB - In recent years, a significant increase in mosquito-borne diseases has been recorded worldwide. Faced with the limitations of existing methods for controlling the vector mosquito population, the development of attractants to bait traps and repellents to limit host-vector contacts could be promising and environmentally-friendly control strategies. The purpose of this study was to evaluate the effect of hydroxycoumarins and their alkyls derivatives against Aedes albopictus, the main vector of several arboviruses. Synthesis, bioassays and field trials were carried out in Madagascar. The results showed that 3, 4 and 6-hydroxycoumarins are attractive to this mosquito, 4-hydroxycoumarin being the most effective both in the laboratory and under field conditions. In addition, a good synergistic effect was found with octenol to attract mosquitoes and especially Ae. albopictus in comparison to other mosquito species living in sympatry. On the contrary, the 4-s-butoxycoumarin and 4-s-pentoxycoumarin derivatives had a repellent effect with the former showing the most significant effect. Further optimization of the dose and structure of these products will be carried out in order to maximize their utility for the control of Ae. albopictus and other mosquitoes. PMID- 29524073 TI - Correction to: Eculizumab: A Review in Generalized Myasthenia Gravis. AB - The article Eculizumab: A Review in Generalized Myasthenia Gravis, written by Sohita Dhillon, was originally published Online First without open access. PMID- 29524074 TI - Correction to: Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors. AB - The dose (mg/day) for Clonazepam which reads. PMID- 29524075 TI - Correction to: Myocardial T1 mapping and extracellular volume quantification: an overview of technical and biological confounders. AB - The article "Myocardial T1 mapping and extracellular volume quantification: an overview of technical and biological confounders", written by "Stefan K. Piechnik and Michael Jerosch-Herold", was originally published Online First without open access. PMID- 29524076 TI - Non-compact myocardium assessment by cardiac magnetic resonance: dependence on image analysis method. AB - To compare image analysis methods for the assessment of left ventricle non compaction from cardiac magnetic resonance (CMR) imaging. CMR images were analyzed in 20 patients and 10 normal subjects. A reference model of the MR signal was introduced and validated based on image data. Non-compact (NC) myocardium size and distribution were assessed by tracing a single, continuous contour delimiting trabeculated region (Jacquier) or by one-by-one selection of trabeculae (Grothoff). The global non-compact/compact (NC/C) ratio, the NC mass, and the segmental NC/C ratio were assessed. Results were compared with the reference model. A significant difference between Grothoff and Jacquier approaches in the estimation of NC/C ratio (32.08 +/- 6.63 vs. 19.81 +/- 5.72, p < 0.0001) and NC mass (26.59 +/- 8.36 vs. 14.15 +/- 5.73 g/m2, p < 0.0001) was found. The Grothoff approach better matches the expected signal distribution. Inter-observer reproducibility of both Grothoff and Jacquier methods was adequate (9.71 and 8.22%, respectively) with no significant difference between observers. Jacquier and Grothoff approaches are not interchangeable so that specific diagnostic thresholds should be used for different image analysis methods. Grothoff method seems to better capture the true extension of trabeculated tissue. PMID- 29524077 TI - Evaluation of mitral regurgitation by an integrated 2D echocardiographic approach in patients undergoing transcatheter aortic valve replacement. AB - The purpose of this study was to evaluate mitral regurgitation (MR) severity in patients undergoing transcatheter aortic valve replacement (TAVR) by standardized assessment of two-dimensional (2D) transthoracic echocardiography (TTE) and 1 year echocardiographic and clinical outcomes. Pre- and post-procedural TTE's of patients undergoing TAVR between 2008 and 2014 were analyzed. MR was graded according to current guidelines with a systematic and integrated approach. Longitudinal echocardiographic and clinical results were analyzed. Regression analysis was performed for change in MR grade at follow-up, using pre-determined variables and confounders. Pre- and post-procedural TTE were available in 213 subjects. Significant MR was seen in 22% at baseline and 15% at follow-up; MR grade >= 3 in < 10%. Severity did not change in 61%, and decreased in 20% of the patients. Overall, the prevalence of MR grades pre- and post TAVR was not significantly different, nor influenced by MR etiology or TAVR prosthesis type. However, higher MR grades and pacemaker absence at baseline, were independently correlated to more improvement of MR after TAVR. Regarding clinical outcomes, NYHA class improved in two-thirds of the patients, irrespective of the baseline MR grade. Overall survival was not significantly different amongst MR grades post TAVR. MR grading using an systematic 2D echocardiographic approach in patients undergoing TAVR is feasible in clinical practice. Our data revealed a relatively frequent prevalence of significant MR (although grade >= 3 was scarce), overall no change in the MR grade at 1 year follow-up, improvement of functional NYHA class, and no significant differences in long-term survival amongst the post-TAVR MR grades. PMID- 29524078 TI - A Preliminary Exploration of the Barriers to Delivering (and Receiving) Exposure Based Cognitive Behavioral Therapy for Anxiety Disorders in Adult Community Mental Health Settings. AB - Despite the effectiveness of exposure-based cognitive behavioral therapy (CBT) for anxiety disorders, few individuals in need receive this treatment, particularly in community mental health settings serving low-income adults. The present study took a preliminary step to understand these barriers by conducting a series of key informant interviews and focus groups among patients, providers, clinical administrators, and policy makers. Several themes emerged as barriers to the delivery of exposure-based CBT in these settings, including therapist training and compentency issues, logistical issues, and funding stream issues. Clinical implications and future research that can build from these data are discussed. PMID- 29524079 TI - Infertility and recurrent miscarriage in a patient with autoimmune atrophic gastritis. PMID- 29524080 TI - A can't miss diagnosis for rash in a peritoneal dialysis patient. PMID- 29524081 TI - Performance status and in-hospital mortality of elderly patients with community acquired pneumonia. AB - To evaluate the role of performance status evaluated by the Eastern Cooperative Oncology Group (ECOG) score in predicting 30-day mortality in subjects hospitalized for community acquired pneumonia (CAP), this was a prospective study of patients consecutively hospitalized for CAP at a large University Hospital in Italy. Performance status was evaluated using the ECOG score that in a 0-5 point scale indicates progressive functional deterioration. The end-point of the study is the 30-day mortality. Two-hundred-sixteen patients were enrolled, 75.9% were aged > 70 years, 31.5% had severe pneumonia at CURB-65 score (3-4), and 27.5% of patients had severe disability (ECOG 3-4). Thirty-day mortality is 15.3%. Progression in ECOG score independently increases the probability of 30-day mortality at multivariable logistic regression analysis (HR 2.19, 95% CI 1.60 3.01, p < 0.0001). ECOG 3 or 4 determines a four-fold increase in 30-day mortality (HR 4.07, 95% CI 1.84-9.02, p < 0.001). ECOG score 3 or 4 is highly predictive of death in patients classified at low risk of mortality by CURB-65 (0 2 points) score. Functional status is directly related to outcome in elderly patients hospitalized for CAP. The use of a very simple and fast tool, such as the ECOG score, might help to better stratify the risk of short-term mortality, especially in patients otherwise classified at low risk of death by CURB-65 score. PMID- 29524083 TI - Progress in neuroscience in Africa: editorial. PMID- 29524082 TI - Diagnostic Approach to Fine Needle Aspirations of Cystic Lesions of the Salivary Gland. AB - Fine needle aspiration (FNA) has diagnostic and therapeutic value in the management of salivary gland cysts. Rendering an accurate diagnosis from an aspirated salivary gland cyst is challenging because of the broad differential diagnosis, possibility of sampling error, frequent hypocellularity of specimens, morphologic heterogeneity, and overlapping cytomorphology of many cystic entities. To date, there have been no comprehensive review articles providing a practical diagnostic approach to FNA of cystic lesions of salivary glands. This article reviews the cytopathology of salivary gland cysts employing 2017 World Health Organization terminology, addresses the accuracy of FNA, and presents The Milan System approach for reporting in cystic salivary gland cases. The utility of separating FNA specimens from salivary gland cysts, based upon the presence of mucin and admixed lymphocytes in cyst fluid is demonstrated. A reliable approach to interpreting FNA specimens from patients with cystic salivary gland lesions is essential to accurately determine which of these patients may require subsequent surgery. PMID- 29524084 TI - Correction to: Preparation of Controlled-Release Particles Based on Spherical Porous Silica Used as the Drug Carrier by the Dry Coating Method. AB - In the present notation, the formula names and the formulas (page 7, left column, lines 20-21) do not correspond to each other. It is a completely incorrect description, due to a typesetting mistake by the publisher. See below for details. The original article has been corrected. PMID- 29524085 TI - A Literature Review of Blood-Disseminated P. marneffei Infection and a Case Study of this Infection in an HIV-Negative Child with Comorbid Eosinophilia. AB - BACKGROUND: The typical manifestations of Penicillium marneffei (nowadays Talaromyces marneffei) infection in children without human immunodeficiency virus (HIV) remain unclear. The current work presents the case of a child without an underlying disease who was infected with P. marneffei comorbid with eosinophilia. CASE PRESENTATION: A 2-year-old male was infected with P. marneffei. A physical examination revealed a high-grade fever, ulcerated lesions in the oral mucosa, anemia, pruritic erythematous papules on the sac and thigh and watery diarrhea. A chest enhanced computed tomography scan showed multiple small, nodular, high density shadows in the lungs, multiple lymphadenectasis in the hilum of the lungs and mediastinum, and liquid in the right pleural cavity. The patient's plasma was negative for HIV. Routine blood tests initially indicated that the patient had leucopenia; however, later tests indicated that he had leukocytosis. This peak was caused by a significant increase in eosinophils. The total IgE and specific allergen levels were normal. The stool was negative for parasite eggs. Aspergillus antigen (galactomannan, GM) levels were significantly increased and were present in the serum for a relatively long period. CONCLUSIONS: Eosinophilia can occur during P. marneffei infection, and this finding might provide additional information on the activity of this intracellular parasite. In addition, GM detection might be useful for monitoring the effect of antifungal treatments; however, this theory requires more data for verification. PMID- 29524087 TI - Vanishing time in the pursuit of happiness. AB - Happiness can be conceptualized as a positive affective state or as a goal whose pursuit ironically pulls the pursuer away from achieving it (Mauss, Tamir, Anderson, & Savino in Emotion, 11(4), 807-815, 2011). But how do people think about time during this latter, never-ending pursuit of happiness? The present investigation asks how seeking happiness influences perceptions of time availability. Four studies demonstrated that trait-level happiness seeking (Study 1) as well as direct manipulation of happiness seeking (Studies 2, 3, and 4) consistently reveal the same pattern: reduced feelings of time availability while pursuing happiness. This negative effect on time availability is mitigated when happiness seems like it has been achieved (Study 2) or seems quick to achieve (Study 3). In addition, pursuing happiness can ultimately decrease happiness, in part, by reducing perceptions of time availability (Study 4), extending theories on happiness, goal pursuit, and perceptions of time. PMID- 29524086 TI - Aberrant methylation-mediated silencing of lncRNA CTC-276P9.1 is associated with malignant progression of esophageal squamous cell carcinoma. AB - Downregulation and aberrant hypermethylation of long non-coding RNA CTC-276P9.1 have been detected in limited tumors. However, the distribution of methylated CpG sites and biological role of CTC-276P9.1 in esophageal squamous cell carcinoma (ESCC) progression and prognosis have not been fully clarified. The present study was to investigate the expression status and the distribution of methylated CpG sites within the three CpG islands of CTC-276P9.1, further to clarify its functional role and prognostic value in ESCC development and prognosis. Significant downregulation of CTC-276P9.1 was detected in esophageal cancer cells and ESCC tissues, and the expression of CTC-276P9.1 in ESCC tissues was associated with TNM stage, pathological differentiation, lymph node metastasis, and distant metastasis or recurrence. The expression level of CTC-276P9.1 in esophageal cancer cells was significantly reversed by treatment with 5-Aza-dC and TSA. The aberrant hypermethylation of the regions around the transcription start site was more tumor specific and associated with the expression levels of CTC 276P9.1. Moreover, histone modification may also participate in the regulation of CTC-276P9.1. Furthermore, over-expression of CTC-276P9.1 inhibited esophageal cancer cells proliferation and invasion in vitro, decreased the expression of proliferative markers and inhibited esophageal cancer cells invasion probably by regulating EMT. In addition, the dysregulation and hypermethylation of the regions around the transcription start site of CTC-276P9.1 were associated with poorer ESCC patients' survival. These findings suggest that CTC-276P9.1 may act as a tumor suppressor and may be employed as a new prognostic factor and therapeutic target for ESCC. PMID- 29524088 TI - Reliability and correlation analysis of computed methods to convert conventional 2D radiological hindfoot measurements to a 3D setting using weightbearing CT. AB - PURPOSE: The exact radiographic assessment of the hindfoot alignment remains challenging. This is reflected in the different measurement methods available. Weightbearing CT (WBCT) has been demonstrated to be more accurate in hindfoot measurements. However, current measurements are still performed in 2D. This study wants to assess the use of computed methods to convert the former uniplanar hindfoot measurements obtained after WBCT towards a 3D setting. METHODS: Forty eight patients, mean age of 39.6 +/- 13.2 years, with absence of hindfoot pathology were included. A WBCT was obtained, and images were subsequently segmented and analyzed using computer-aided design operations. In addition to the hindfoot angle (HA), other ankle and hindfoot parameters such as the anatomical tibia axis, talocalcaneal axis (TCA), talocrural angle, tibial inclination (TI), talar tilt, and subtalar vertical angle were determined in 2D and 3D. RESULTS: The mean [Formula: see text] was [Formula: see text] of valgus +/- 3.2 and the [Formula: see text] was [Formula: see text] of valgus +/- 6.5. These angles differed significantly from each other with a [Formula: see text]. The correlation between both showed to be good by [Formula: see text] Pearson correlation coefficient (r) of 0.72 ([Formula: see text]). The [Formula: see text] showed to be excellent when compared to the [Formula: see text], which was good. Similar findings were obtained in other angles. The highest correlation was seen between the [Formula: see text] and [Formula: see text] (r = 0.83, [Formula: see text]) and an almost perfect agreement in the [Formula: see text] ([Formula: see text]). CONCLUSION: This study shows a good and reliable correlation between the [Formula: see text] and [Formula: see text]. However, the [Formula: see text] overcomes the shortcomings of inaccuracy and provides valuable spatial data that could be incorporated during computer-assisted surgery to assess the multiplanar correction of a hindfoot deformity. PMID- 29524089 TI - Asthma Management in the Era of Smart-Medicine: Devices, Gadgets, Apps and Telemedicine. AB - Asthma is the most common chronic pediatric condition. Effective asthma management requires a proactive and inclusive approach that controls the patient's symptoms and prevents recurrence of exacerbations. Clinicians should encourage patients to become involved in their management since self-management approaches have proven to be an effective means for chronic illness treatment. Novel forms of self-monitoring and management are technological interventions. In the last decade, novel technology has been developed and used to improve asthma control since it is a powerful agent that addresses a variety of challenges in chronic disease management such as education, communication and adherence. A myriad of technology-based strategies are available although many of these are not evidence based and further studies are needed to evaluate their efficacy in specific asthma-control endpoints. Herein, authors present a review of current and future technology-based options for asthma management and a comparison between them. PMID- 29524090 TI - Nocturnal blood pressure fluctuation and associated influential factors in severe obstructive sleep apnea patients with hypertension. AB - PURPOSE: Obstructive sleep apnea syndrome (OSAS) can induce dramatic blood pressure (BP) fluctuations during sleep and it can be associated with hypertension. We investigated the properties and associated influential factors of BP fluctuation in severe OSAS with and without hypertension. METHODS: Two hundred one severe OSAS subjects were divided into hypertensive and normotensive groups. BP was continuously monitored via measurement of pulse transmit time (PTT). The value of apnea-related systolic BP elevation (DeltaSBP) was used to reflect the amplitude of BP fluctuation, and the SBP index (the number of DeltaSBP > 10 mmHg per hour of sleep time) was used to stand for the frequency of significant BP fluctuations. RESULTS: Compared with the normotensive group, ?SBP and SBP index were higher in the hypertensive group (13.8 +/- 4.4 mmHg vs 10.9 +/ 3.1 mmHg; 44.8 +/- 21.3 events/h vs 26.8 +/- 15.8 events/h, all p < 0.001). Multiple regression analysis showed that percentage of sleep time with oxygen saturation < 90% (TST90) and SBP index correlated more with mean level of awakeness and sleep SBP than with apnea-hypopnea index (AHI). Analysis of all apnea events demonstrated that ?SBP and the frequency of BP fluctuations were more remarkable following hypoxia than following arousal; ?SBP correlated more with oxygen desaturation degree (r = 0.388, p < 0.01) and minimal SpO2 (r = 0.392, p < 0.01) than with apnea length and desaturation duration. CONCLUSIONS: In severe OSAS, nocturnal and awake BP levels are associated more with the nocturnal hypoxic duration and BP fluctuation than with AHI. Nocturnal BP fluctuation can be induced by both hypoxia and arousal, and especially by hypoxia. TRIAL REGISTRATION: NCT02876471. PMID- 29524091 TI - Towards a prediction model for drug-induced sleep endoscopy as selection tool for oral appliance treatment and positional therapy in obstructive sleep apnea. AB - PURPOSE: To evaluate the effect of different passive maneuvers on upper airway patency during drug-induced sleep endoscopy (DISE) compared to recent literature on treatment outcomes of positional therapy (PT), oral appliance therapy (OAT), and combined treatment in obstructive sleep apnea (OSA) patients. METHODS: A retrospective, single-center cohort study including a consecutive series of 200 OSA patients. All patients underwent DISE with and without manually performed jaw thrust and lateral head rotation by using the VOTE classification. The effect of these maneuvers were analyzed by using the sum VOTE score comparing non positional (NPP) and positional OSA patients (PP). RESULTS: Two hundred patients were included (80.5% male) with a mean age of 50.1 +/- 11.7 years, a BMI of 27.0 +/- 3.1 kg/m2, and a median AHI of 19.2 events per hour. Forty-four percent of the patients were NPP; of the remaining 56%, 34% was diagnosed with supine isolated and 66% with supine predominant POSA. Manually performed jaw thrust showed a reduction of sum VOTE score of 66.7% in all subgroups. The effect of lateral head rotation was a reduction of 33.3% in NPP and supine predominant PP and 50% in supine isolated PP. Combining these maneuvers a reduction of more than 75% was seen in all patients. CONCLUSIONS: The present model leaves room for improvement. The effect of manually performed jaw thrust is greater and the effect of lateral head rotation alone is less than what was expected compared to recent literature on treatment outcome of OAT, PT, and combined treatment. PMID- 29524092 TI - The relationship of the uvula with snoring and obstructive sleep apnea: a systematic review. AB - Currently, the relationship between uvula size and sleep-disordered breathing (snoring and obstructive sleep apnea) lacks data for objective interpretation. This study conducted a systematic review of the international literature for research describing the measurable characteristics of the uvula (i.e., size, length, width) and any association with snoring and obstructive sleep apnea (OSA). PubMED, Scopus, Google Scholar, Embase, and the Cochrane Library were each systematically searched from inception through November 15, 2016. We screened 1037 titles and abstracts. We conducted a full review of 54 downloaded articles. Sixteen articles met inclusion and exclusion criteria. The 16 studies included a total of 2604 patients. The selected articles included data and information for (1) normative data for uvular size in the control groups, (2) snoring and uvula size, (3) OSA and uvula size, and (4) overall uvula function. Our review noted variability in findings; however, in general, a uvular length > 15 mm was considered elongated and a uvular width > 10 mm was considered to be wide. The studies included in this systematic review reveal a relationship between uvula size, snoring, and OSA. Further, larger uvulas appear associated with more severe snoring and OSA. The direct correlation between uvula size and its relationship specifically to snoring and OSA remain as topics for future prospective research. PMID- 29524093 TI - Single-centre experience on transthyretin familial amyloid polyneuropathy: case series and literature review. AB - Familial amyloid polyneuropathy (FAP) is a most often length-dependent axonal neuropathy, often part of a multisystem disorder also affecting other organs, such as cardiac, gastrointestinal, genitourinary, renal, meningeal and eye tissue. It is most frequently the result of a mutation in the TTR gene, most commonly a p.Val50Met mutation. TTR-FAP is a rare autosomal dominant heritable disabling, heterogeneous disease in which early diagnosis is of pivotal importance when attempting treatment. This paper discusses the course of four Belgian FAP patients with different TTR mutations (p.Val48Met; p.Val52Ala; p.Ala59Val; p.Val50Met). We also review the diagnosis and differential diagnosis of TTR-FAP, diagnostic studies, follow-up, its current treatment and those in development, prognosis and the importance of genetic counseling. At first, TTR FAP is often misdiagnosed as a chronic inflammatory demyelinating polyneuropathy or chronic idiopathic axonal polyneuropathy. Genetic testing is obligatory to confirm the diagnosis of TTR-FAP, except in familial cases. Biopsy samples are an asset in diagnosing TTR-FAP but can be falsely negative. At the moment, tafamidis meglumine is considered as first-line treatment in stage I neurological disease. Patients eligible for liver transplantation should be carefully selected when first-line therapy fails. PMID- 29524094 TI - Unusual side effects due to clobazam: a case report with edema of the extremities. PMID- 29524095 TI - Correction to: Complementary and Alternative Medicine Among Persons living with HIV in the Era of Combined Antiretroviral Treatment. AB - In the original publication of the article, the given and family name of the fourth author was not correct. The name has been corrected with this erratum. PMID- 29524096 TI - Strength of Implementation Intentions to Use Condoms Among Men Who Have Sex with Men. AB - Although pre-exposure prophylaxis (PrEP) use is increasing among men who have sex with men (MSM), condoms remain key to HIV prevention. Implementation intentions which link a behavioral action plan with a situation or cue-may predict condom use. The Strength of Implementation Intentions Scale (SIIS), which assesses condom use implementation intentions, has not been evaluated among MSM. A structural model tested whether the SIIS mediated the relationship between condom use intentions and condomless sex acts among 266 sexually-active MSM (56% White, 26% Black, 15% Latino, Mage = 32.54). After controlling for PrEP use, HIV-status, and demographics (chi2(107) = 140.06, CFI = 0.98, TLI = 0.97, RMSEA = 0.03), the SIIS fully mediated the relationship between condom use intentions and condomless sex acts. The SIIS can serve as a fidelity check for interventions, a mediator in theoretical models, and future studies should incorporate implementation intentions into HIV prevention interventions for MSM. PMID- 29524097 TI - Reconstructing Unrooted Phylogenetic Trees from Symbolic Ternary Metrics. AB - Bocker and Dress (Adv Math 138:105-125, 1998) presented a 1-to-1 correspondence between symbolically dated rooted trees and symbolic ultrametrics. We consider the corresponding problem for unrooted trees. More precisely, given a tree T with leaf set X and a proper vertex coloring of its interior vertices, we can map every triple of three different leaves to the color of its median vertex. We characterize all ternary maps that can be obtained in this way in terms of 4- and 5-point conditions, and we show that the corresponding tree and its coloring can be reconstructed from a ternary map that satisfies those conditions. Further, we give an additional condition that characterizes whether the tree is binary, and we describe an algorithm that reconstructs general trees in a bottom-up fashion. PMID- 29524098 TI - Analysis of a Prey-Predator Model with Non-local Interaction in the Prey Population. AB - Non-local reaction-diffusion equation is an important area to study the dynamics of the individuals which compete for resources. In this paper, we describe a prey dependent predator-prey model with Holling type II functional response with a generalist predator. In particular, we want to see the behavior of the system in the presence of non-local interaction. Introduction of non-local intraspecific competition in prey population leads to some new characteristics in comparison with the local model. Comparisons have been made between the local and non-local interactions of the system. The range of non-local interaction enlarges the parametric domain on which stationary patterns exist. The periodic oscillation for the local model in the Hopf domain can be stabilized by suitable limit of strong non-local interaction. An increase in the range of non-local interaction increases the Turing domain up to a certain level, and then, it decreases. Also, increasing the range of non-local interaction results in the overlap of nearby foraging areas and hence alters the size of the localized patches and formation of multiple stationary patches. Numerical simulations have been carried out to validate the analytical findings and to establish the existence of multiple stationary patterns, oscillatory solution, two-periodic solution and other spatiotemporal dynamics. PMID- 29524100 TI - 'All by myself': interns' reports of their experiences taking consent in Irish hospitals. AB - BACKGROUND: Obtaining patient consent is a fundamental process in surgical practice and is integral in respecting and safeguarding patient autonomy. It has been reported that the task of consenting patients frequently lies with junior doctors, who have the least experience of the procedure. AIM: To examine the role of interns in the consent process in the Irish context as well as to identify their concerns. METHODS: A 12-point questionnaire, assessing interns' experience with surgical consent, was circulated to interns in three Irish university teaching hospitals based in different geographical locations. Interns who had never worked in a surgical team were excluded from the analysis. RESULTS: Out of 104 interns, 60 interns returned questionnaires. Of these, 58 (96.7%) had consented a patient for a surgical procedure. Forty-four interns (73.3%) had never been supervised by a senior doctor. Of the 58 interns who had obtained surgical consent, six interns (10.3%) reported knowledge of 'all' the steps of the procedure. Only five interns (8.6%) reported that they were aware of all the risks of the procedures and 34 interns (58.6%) reported they knew 'most' of the risks. Twenty-five interns (43%) reported that they had, at some point, been explained the risks of the procedures by a senior colleague. CONCLUSION: The majority of interns reported that they had taken consent for a procedure without full knowledge of the procedure and its complications. Supervision or instruction from a senior colleague was reported by a minority. PMID- 29524099 TI - Emotion dysregulation and functional connectivity in children with and without a history of major depressive disorder. AB - Recent interest has emerged in understanding the neural mechanisms by which deficits in emotion regulation (ER) early in development may relate to later depression. Corticolimbic alterations reported in emotion dysregulation and depression may be one possible link. We examined the relationships between emotion dysregulation in school age, corticolimbic resting-state functional connectivity (rs-FC) in preadolescence, and depressive symptoms in adolescence. Participants were 143 children from a longitudinal preschool onset depression study who completed the Children Sadness Management Scale (CSMS; measuring ER), Child Depression Inventory (CDI-C; measuring depressive symptoms), and two resting-state MRI scans. Rs-FC between four primary regions of interest (ROIs; bilateral dorsolateral prefrontal cortex [dlPFC] and amygdala) and six target ROIs thought to contribute to ER were examined. Findings showed that ER in school age did not predict depressive symptoms in adolescence, but did predict preadolescent increases in dlPFC-insula and dlPFC-ventromedial PFC rs-FC across diagnosis, as well as increased dlPFC-dorsal anterior cingulate cortex (dACC) rs FC in children with a history of depression. Of these profiles, only dlPFC-dACC rs-FC in preadolescence predicted depressive symptoms in adolescence. However, dlPFC-dACC connectivity did not mediate the relationship between ER in school age and depressive symptoms in adolescence. Despite the absence of a direct relationship between ER and depressive symptoms and no significant rs-FC mediation, the rs-FC profiles predicted by ER are consistent with the hypothesis that emotion dysregulation is associated with abnormalities in top-down control functions. The extent to which these relationships might confer greater risk for later depression, however, remains unclear. PMID- 29524101 TI - Frequency of Behcet's disease among a group of visually impaired adults. AB - BACKGROUND: Behcet's disease (BD) is one of the reasons of acquired visual impairment among young adults. Ocular involvement is a significant cause of disability in BD. The objective of this study is to assess the prevalence of BD among a group of adults who has visual impairment. METHODS: Ankara Metropolitan Municipality Education and Technology Center is one of the official institutions which records and follows the demographic data of visually impaired people in Turkey. In November 2014, there were 675 visually impaired people recorded at this center. Medical history was taken from 294 adults by phone in November and December of 2014. Participants were asked if the visual impairment had been either acquired or congenital. If the patients had BD or suspicious BD, they were recalled for detailed investigation which would be carried out by an internist, a rheumatologist and an ophthalmologist. RESULTS: Two hundred thirteen of 294 (72.4%) visually impaired adults were male. One hundred nine of 294 (37.1%) had acquired visual impairment. Six (5.5%) of those 109 patients had BD. Overall prevalence of BD among study group was 2.04%.The median age of people with BD was 35 years. The median age at BD diagnosis was 16.5 years and the median duration from diagnosis to visual loss was 2.5 years. CONCLUSION: BD is still one of the causes of acquired visual impairment in Turkey. In this study, BD prevalence among a visually impaired adult group was 2.04%. BD accounted for 5.5% among adults who had acquired visual impairment. In a study of 1965, BD prevalence among people with acquired blindness was 12%. However, this study was conducted at pre-immunosuppressive period. Our prevalence is obviously lower than those studies. Extended population-based studies are needed for population estimations. PMID- 29524103 TI - The benefits of a Neurogenetics clinic in an adult Academic Teaching Hospital. AB - Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and are complex, requiring a dedicated Neurogenetics clinic. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe. In November 2014, we established the monthly adult Neurogenetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions that may potentially have an underlying genetic basis, in the presence or absence of a family history. We performed a retrospective cohort analysis, reviewing symptoms and work-up data. Twenty-seven patients attended a pilot clinic over 12 months. Conditions encountered included Parkin-related PD, leucodystrophy, ataxia, fronto-temporal lobar degeneration, spinocerebellar ataxia type 6 (SCA6) and ataxia-telangiectasia. Identification of pathogenic mutations directed screening, treatment and facilitated onward genetic counselling (n = 10, 33%). A number of novel mutations were identified in MAPT gene ("missing tau mutation" McCarthy et al., Brain, 2015), SLCA1 gene and GRN (progranulin). Phenotypic features not previously reported were seen; e.g. writer's cramp in SCA6; paroxysmal myoclonus in the glucose transporter protein type 1 (GLUT1) deficiency. Breast cancer screening for ATM mutations carriers and referral to international experts in two undiagnosed patients were arranged. The establishment of a Neurogenetics clinic has addressed a gap in service and allowed identification of rare and atypical diagnoses. PMID- 29524102 TI - Neurological autoantibodies in drug-resistant epilepsy of unknown cause. AB - BACKGROUND: Autoimmune epilepsy is a rarely diagnosed condition. Recognition of the underlying autoimmune condition is important, as these patients can be resistant to antiepileptic drugs. AIMS: To determine the autoimmune and oncological antibodies in adult drug-resistant epilepsy of unknown cause and identify the clinical, radiological, and EEG findings associated with these antibodies according to data in the literature. METHODS: Eighty-two patients with drug-resistant epilepsy of unknown cause were prospectively identified. Clinical features were recorded. The levels of anti-voltage-gated potassium channel complex (anti-VGKCc), anti-thyroid peroxidase (anti-TPO), anti-nuclear antibody (ANA), anti-glutamic acid decarboxylase (anti-GAD), anti-phospholipid IgG and IgM, anti-cardiolipin IgG and IgM, and onconeural antibodies were determined. RESULTS: Serum antibody positivity suggesting the potential role of autoimmunity in the aetiology was present in 17 patients with resistant epilepsy (22.0%). Multiple antibodies were found in two patients (2.6%). One of these patients (1.3%) had anti-VGKCc and ANA, whereas another (1.3%) had anti-VGKCc and anti TPO. A single antibody was present in 15 patients (19.5%). Of the 77 patients finally included in the study, 4 had anti-TPO (5.2%), 1 had anti-GAD (1.3%), 4 had anti-VGKCc (5.2%) 8 had ANA (10.3%), and 2 had onconeural antibodies (2.6%) (1 patient had anti-Yo and 1 had anti-MA2/TA). The other antibodies investigated were not detected. EEG abnormality (focal), focal seizure incidence, and frequent seizures were more common in antibody-positive patients. CONCLUSION: Autoimmune factors may be aetiologically relevant in patients with drug-resistant epilepsy of unknown cause, especially if focal seizures are present together with focal EEG abnormality and frequent seizures. PMID- 29524104 TI - Festschrift for Ronan O'Connell: pouchitis, ulcerative colitis and the microbiome. AB - The hypothesis of altered bacterial communities contributing to the development of pouchitis began a scientific quest to link host mucosal factors, microbial metabolism and spatial structure of the colonic microbiome in ulcerative colitis, reaching its apotheosis with the integration of advanced spatial sampling with laser capture microdissection, mucin array profiling, molecular microbiology and next-generation sequencing technologies. This article, part of a festschrift, summarises the contributions of the O'Connell lab to the field of host-microbial interactions in inflammatory bowel disease. PMID- 29524105 TI - Author Correction to: Denosumab: A Review in Postmenopausal Osteoporosis. AB - In the original publication the name of the fourth reviewer was incorrectly published. PMID- 29524106 TI - Association Study Between Metallothionein-3 Protein Polymorphisms and Autism. AB - Genetic susceptibility to high mercury body burden has been suggested as an autism risk factor in children. Metallothionein III (MT3) is the brain-specific form of the metallothionein family, which plays a key role in metal metabolism. We therefore looked for genetic variations in the MT3 gene that might increase the predisposition to autism. DNA was extracted from 132 autistic children and 132 age and gender-matched unrelated controls. All the samples were analyzed for nine single nucleotide polymorphisms (SNPs) with minor allele frequency > 10% in the MT3 gene. The mRNA levels of MT3 in white blood cells were evaluated by real time PCR. We did not detect any association between these MT3 polymorphisms and the mRNA levels of MT3. We did not detect any association between MT3 polymorphisms and autism risk. However, we detected four novel MT3 SNPs that are not in the human SNP database. The clinical importance of these SNPs needs further investigation. Our data suggest that MT3 gene polymorphisms are not associated with autism. PMID- 29524107 TI - A review on breeding and genetic strategies in Iranian buffaloes (Bubalus bubalis). AB - The aim of current study was to review breeding progress and update information on genetic strategies in Iranian buffaloes. Iranian buffalo is one of the vital domestic animals throughout north, north-west, south and south-west of Iran with measurable characteristics both in milk and meat production. The species plays an important role in rural economy of the country due to its unique characteristics such as resistance to diseases and parasites, having long productive lifespan and showing higher capability of consuming low-quality forage. In Iran, total production of milk and meat devoted to buffaloes are 293,000 and 24,700 tons, respectively. Selection activities and milk yield recording are carrying out by the central government through the Animal Breeding Centre of Iran. The main breeding activities of Iranian buffaloes included the estimation of genetic parameters and genetic trends for performance traits using different models and methods, estimation of economic values and selection criteria and analysis of population structure. Incorporating different aspects of dairy buffalo management together with improved housing, nutrition, breeding and milking, is known to produce significant improvements in buffalo production. Therefore, identifying genetic potential of Iranian buffaloes, selection of superior breeds, improving nutritional management and reproduction and developing the education and increasing the skills of practical breeders can be useful in order to enhance the performance and profitability of Iranian buffaloes. PMID- 29524108 TI - Precursor and Neutral Loss Scans in an RF Scanning Linear Quadrupole Ion Trap. AB - Methodology for performing precursor and neutral loss scans in an RF scanning linear quadrupole ion trap is described and compared to the unconventional ac frequency scan technique. In the RF scanning variant, precursor ions are mass selectively excited by a fixed frequency resonance excitation signal at low Mathieu q while the RF amplitude is ramped linearly to pass ions through the point of excitation such that the excited ion's m/z varies linearly with time. Ironically, a nonlinear ac frequency scan is still required for ejection of the product ions since their frequencies vary nonlinearly with the linearly varying RF amplitude. In the case of the precursor scan, the ejection frequency must be scanned so that it is fixed on a product ion m/z throughout the RF scan, whereas in the neutral loss scan, it must be scanned to maintain a constant mass offset from the excited precursor ions. Both simultaneous and sequential permutation scans are possible; only the former are demonstrated here. The scans described are performed on a variety of samples using different ionization sources: protonated amphetamine ions generated by nanoelectrospray ionization (nESI), explosives ionized by low-temperature plasma (LTP), and chemical warfare agent simulants sampled from a surface and analyzed with swab touch spray (TS). We lastly conclude that the ac frequency scan variant of these MS/MS scans is preferred due to electronic simplicity. In an accompanying manuscript, we thus describe the implementation of orthogonal double resonance precursor and neutral loss scans on the Mini 12 using constant RF voltage. Graphical Abstract ?. PMID- 29524109 TI - Correction to: Risk of Adverse Outcomes for Older People with Dementia Prescribed Antipsychotic Medication: A Population Based e-Cohort Study. AB - This article was originally published under a Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0), but has now been made available under a Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The PDF and HTML versions of the paper have been modified accordingly. PMID- 29524110 TI - Lifestyle factors, cardiovascular disease and all-cause mortality in middle-aged and elderly women: a systematic review and meta-analysis. AB - Cardiovascular disease (CVD) risk factors, incidence and death increases from around the time of menopause comparing to women in reproductive age. A healthy lifestyle can prevent CVD, but it is unclear which lifestyle factors may help maintain and improve cardiovascular health for women after menopausal transition. We conducted a systematic review and meta-analysis of prospective cohort studies to evaluate the association between modifiable lifestyle factors (specifically smoking, physical activity, alcohol intake, and obesity), with CVD and mortality in middle-aged and elderly women. Pubmed, Embase, among other databases and reference lists were searched until February 29th, 2016. Study specific relative risks (RR) were meta-analyzed using random effect models. We included 59 studies involving 5,358,902 women. Comparing current versus never smokers, pooled RR were 3.12 (95% CI 2.15-4.52) for CHD incidence, 2.09 (95% CI 1.51-2.89) for stroke incidence, 2.76 (95% CI 1.62-4.71) for CVD mortality and 2.22 (95% CI 1.92-2.57) for all-cause mortality. Physical activity was associated with a decreased risk of 0.74 (95% CI 0.67-0.80) for overall CVD, 0.71 (95% CI 0.67-0.75) for CHD, 0.77 (95% CI 0.70-0.85) for stroke, 0.70 (95% CI 0.58-0.84) for CVD mortality and 0.71 (95% CI 0.65-0.78) for all-cause mortality. Comparing moderate drinkers versus non-drinkers, the RR was 0.72 (95% CI 0.56-0.91) for CHD, 0.63 (95% CI 0.57-0.71) for CVD mortality and 0.80 (95% CI 0.76-0.84) for all-cause mortality. For women with BMI 30-35 kg/m2 the risk was 1.67 (95% CI 1.24-2.25) for CHD and 2.3 (95% CI 1.56-3.40) for CVD mortality, compared to normal weight. Each 5 kg/m2 increase in BMI was associated with 24% (95% CI 16-33%) higher risk for all-cause mortality. This meta-analysis suggests that physical activity and moderate alcohol intake were associated with a reduced risk for CVD and mortality. Smoking and higher BMI were associated with an increased risk of these endpoints. Adherence to a healthy lifestyle may substantially lower the burden of CVD and reduce the risk of mortality among middle-aged and elderly women. However, this review highlights important gaps, as lack of standardized methods in assessing lifestyle factors and lack of accurate information on menopause status, which should be addressed by future studies in order to understand the role of menopause on the association between lifestyle factors and cardiovascular events. PMID- 29524111 TI - Highlights from the Tenth International Symposium of Thrombosis and Anticoagulation (ISTA X), September 22 and 23, 2017, Salvador, Bahia, Brazil. AB - To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Tenth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on September 22 and 23, 2017. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings. PMID- 29524112 TI - The predictive value of the CHA2DS2-VASc score in patients with mechanical mitral valve thrombosis. AB - Prosthetic valve thrombosis (PVT) is a potentially life-threatening complication associated with high morbidity and mortality. The CHA2DS2-VASc is a clinical score used to determine thromboembolism risk in non-valvular atrial fibrillation patients. Therefore; in this study, we aimed to determine predictive value of the CHA2DS2-VASc score for development of PVT in patients with mechanical prosthetic valve. This was a retrospective study included 417 consecutive patients with mechanic prosthetic valve in whom transesophageal echocardiography (TEE) was performed due to different clinical indications from January 2004 to June 2016. After evaluation according to exclusion criteria, 267 patients with mechanic prosthetic valve were enrolled in the study. The definitive diagnosis of the PVT was made as proposed by TEE finding. The study population was divided into two groups; PVT patients (154 patients) and control group (113 patients) with functional prosthetic valve. The CHA2DS2-VASc score was calculated for each patient from the hospital electronic database. The mechanical mitral valve thrombosis predictive value of variables including CHA2DS2-VASc score was tested in our study. The mean CHA2DS2-VASc score was significantly higher in PVT patients compared to control patients (2.51 +/- 1.54 vs. 1.13 +/- 1.21, p < 0.01). Both on univariate and multivariate analysis demonstrated that the CHA2DS2 VASc score is independently associated with PVT (p < 0.001 and p < 0.001, respectively). The patients whose CHA2DS2-VASc score >= 1-3 had 6.20 times higher risk for thrombus formation, and patients whose CHA2DS2-VASc score >= 4 had 16.6 times higher risk for thrombus formation compared to patients with CHA2DS2-VASc score = 0 (p < 0.001 and p < 0.001, respectively). The CHA2DS2-VASc score may be a significant independent predictor of PVT in patients with prosthetic valve and the CHA2DS2-VASc score >= 2.5 or more was associated with increased PVT in patients with prosthetic valve. Thus; it may be an applicable risk scoring system to assess the risk of development of PVT in patients with prosthetic valve. PMID- 29524113 TI - Correction to: Strategies to Support the Education Goals of Youth and Young Adults with Serious Mental Health Conditions: A Case Study. AB - The original version of this article unfortunately contained a mistake. The spelling of the fifth author's name was incorrectly published as Masha Ellison. PMID- 29524114 TI - Cryotherapy and Radiofrequency Ablation for Eradication of Barrett's Esophagus with Dysplasia or Intramucosal Cancer. AB - BACKGROUND AND AIMS: Endoscopic ablation therapy has become the mainstay of treatment of Barrett's associated dysplasia and intramucosal cancer (IMC). The widely available techniques for ablation are radiofrequency ablation (RFA) and cryotherapy. Our aim was to compare eradication rates of metaplasia and dysplasia with both these modalities. PATIENTS AND METHODS: Retrospective review of prospectively collected database of patients who underwent endoscopic therapy for Barrett's dysplasia or IMC from 2006 to 2011 was performed. Demographic features, comorbidities, and endoscopic data including length of Barrett's segment, hiatal hernia size, interventions during the endoscopy and histological results were reviewed. RESULTS: Among 154 patients included, 73 patients were in the RFA and 81 patients were in the cryotherapy group. There was complete eradication of intestinal metaplasia (CE-IM) in 81 (52.6%), complete eradication of dysplasia (CE-D) in 133 (86.4%), and persistent dysplasia or cancer in 19 patients (12.3%). Compared to RFA, cryotherapy patients were found to be older and less likely to have undergone endoscopic mucosal resection. On multivariate analysis, patients who underwent RFA had a threefold higher odds of having CE-IM than those who underwent cryotherapy (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.4-6.0, p = 0.004), but CE-D were similar between the two groups (OR 1.7, 95% CI 0.66 4.3, p = 0.28). CONCLUSIONS: Endoscopic therapy is highly effective in eradication of Barrett's associated neoplasia. Patients who underwent cryotherapy were equally likely to achieve CE-D but not CE-IM than patients who underwent RFA. Patient characteristics and preferences may effect choice of treatment selection and outcomes. PMID- 29524115 TI - Self-Formation Assessed by Cumulative Summation Test Does Not Reach Recommended Thresholds for Optical Diagnosis of Colorectal Polyps <= 7 mm. AB - BACKGROUND AND AIMS: Accurate optical diagnosis of diminutive polyps would allow implementing a resect and discard strategy. We evaluated the learning curve of a single training session followed by self-education in subjects with no endoscopic experience. METHODS: Learning curves were evaluated in 38 subjects employing learning curve-cumulative summation (LC-CUSUM) tests, with each participant attending one training session regarding narrow band imaging and optical diagnosis and then individually assessing 100 lesions, receiving feedback after each diagnosis. Diagnostic accuracy was subsequently evaluated in 180 patients with lesions <= 7 mm. Evaluators predicted each polyp's histology and recommended a surveillance interval. Determinants of accuracy were explored using regression analysis. RESULTS: According to the LC-CUSUM curve, 20 evaluators (52.6%) reached diagnostic competence after 57 lesions (IQR 55-76.5). During the diagnostic performance assessment, 11,666 diagnoses and 6840 follow-up recommendations were generated. Considering high confidence diagnoses, accuracy was 81.3% (80.5 82.1%), negative predictive value (NPV) for rectosigmoid adenomas 78.6% (76.4 80.6%), and sensitivity for adenomas 86.6% (85.8-87.4%). Two (5.3%) evaluators reached a >= 90% accuracy, 3 (7.9%) presented a NPV for rectosigmoid adenomas >= 90%, and 18 (47.4%) a sensitivity for adenomas >= 90%. Multivariable logistic regression showed high confidence and size >= 5 mm as the strongest predictors of accuracy. Fifteen (39.5%) evaluators recommended a correct or reduced follow-up interval in over 90% of subjects. CONCLUSIONS: Self-formation after a single training session did not allow most evaluators to reach the required accuracy. LC CUSUM tests did not identify competent evaluators. Despite these results, 86.7% of follow-up intervals would have been corrected or reduced. PMID- 29524116 TI - Patient-specific and global convolutional neural networks for robust automatic liver tumor delineation in follow-up CT studies. AB - Radiological longitudinal follow-up of tumors in CT scans is essential for disease assessment and liver tumor therapy. Currently, most tumor size measurements follow the RECIST guidelines, which can be off by as much as 50%. True volumetric measurements are more accurate but require manual delineation, which is time-consuming and user-dependent. We present a convolutional neural networks (CNN) based method for robust automatic liver tumor delineation in longitudinal CT studies that uses both global and patient specific CNNs trained on a small database of delineated images. The inputs are the baseline scan and the tumor delineation, a follow-up scan, and a liver tumor global CNN voxel classifier built from radiologist-validated liver tumor delineations. The outputs are the tumor delineations in the follow-up CT scan. The baseline scan tumor delineation serves as a high-quality prior for the tumor characterization in the follow-up scans. It is used to evaluate the global CNN performance on the new case and to reliably predict failures of the global CNN on the follow-up scan. High-scoring cases are segmented with a global CNN; low-scoring cases, which are predicted to be failures of the global CNN, are segmented with a patient-specific CNN built from the baseline scan. Our experimental results on 222 tumors from 31 patients yield an average overlap error of 17% (std = 11.2) and surface distance of 2.1 mm (std = 1.8), far better than stand-alone segmentation. Importantly, the robustness of our method improved from 67% for stand-alone global CNN segmentation to 100%. Unlike other medical imaging deep learning approaches, which require large annotated training datasets, our method exploits the follow up framework to yield accurate tumor tracking and failure detection and correction with a small training dataset. Graphical abstract Flow diagram of the proposed method. In the offline mode (orange), a global CNN is trained as a voxel classifier to segment liver tumor as in [31]. The online mode (blue) is used for each new case. The input is baseline scan with delineation and the follow-up CT scan to be segmented. The main novelty is the ability to predict failures by trying the system on the baseline scan and the ability to correct them using the patient-specific CNN. PMID- 29524117 TI - Finite element modelling and validation for breast cancer detection using digital image elasto-tomography. AB - Finite element (FE) models are increasingly used to validate experimental data in breast cancer. This research constructed a biomechanical FE model for breast shaped phantoms used to develop and validate a mechanical vibration based screening system. Such models do not currently exist but would enhance development of this screening technology. Three phantoms were modelled: healthy, with 10 and 20 mm inclusions. The overall goal was to create models with enough accuracy to replace experimental phantoms in providing data to optimize diagnostic algorithms for digital image-based elasto-tomography (DIET) screening technologies. FE model results were validating against experimental DIET phantom data for over 4000 collected points on each model and phantom using cross correlation coefficients between experimental simulated data and direct comparison. Results showed good to strong correlation ranging from 0.7 to 1.0 in all cases with over 90% having a value over 0.9. Magnitudes for each frame of the dynamic response also matched well, indicating that the material properties and geometry were accurate enough to provide this level of correlation. These results justify the use of FE model generated data for in silico diagnostic algorithm development testing. The overall modelling and validation approach is not overly complex, and thus generalizable to similar problems using mechanical properties of silicone phantoms, and might be extensible to human cases with further work. Graphical abstract Validate that dynamic displacements show that the model can be used in place of phantoms for rapid development of diagnostic algorithms that use surface motion to detect underlying mechanical properties. PMID- 29524118 TI - Bipedal gait model for precise gait recognition and optimal triggering in foot drop stimulator: a proof of concept. AB - Electrical stimulators are often prescribed to correct foot drop walking. However, commercial foot drop stimulators trigger inappropriately under certain non-gait scenarios. Past researches addressed this limitation by defining stimulation control based on automaton of a gait cycle executed by foot drop of affected limb/foot only. Since gait is a collaborative activity of both feet, this research highlights the role of normal foot for robust gait detection and stimulation triggering. A novel bipedal gait model is proposed where gait cycle is realized as an automaton based on concurrent gait sub-phases (states) from each foot. The input for state transition is fused information from feet-worn pressure and inertial sensors. Thereafter, a bipedal gait model-based stimulation control algorithm is developed. As a feasibility study, bipedal gait model and stimulation control are evaluated in real-time simulation manner on normal and simulated foot drop gait measurements from 16 able-bodied participants with three speed variations, under inappropriate triggering scenarios and with foot drop rehabilitation exercises. Also, the stimulation control employed in commercial foot drop stimulators and single foot gait-based foot drop stimulators are compared alongside. Gait detection accuracy (98.9%) and precise triggering under all investigations prove bipedal gait model reliability. This infers that gait detection leveraging bipedal periodicity is a promising strategy to rectify prevalent stimulation triggering deficiencies in commercial foot drop stimulators. Graphical abstract Bipedal information-based gait recognition and stimulation triggering. PMID- 29524120 TI - A Beacon in the Dark: Canakinumab. A New Therapeutic Perspective in Chronic Tophaceous Gout. AB - : Gout is the most common form of arthritis in adults. It is often associated with other comorbidities, which contraindicate the use of conventional therapies. The discovery of the role of interleukin-1beta (IL-1beta) in orchestrating the monosodium urate crystal-induced inflammatory response offered new therapeutic prospects to refractory patients, or to those in whom standard therapies are contraindicated. This paper describes a clinical case of a 65-year-old man with chronic tophaceous gouty arthropathy and subintrant flares, who had comorbidities contraindicating the use of conventional gout therapies-to which he did not respond-who was treated with canakinumab, a monoclonal selective inhibitor of IL 1beta. The patient reported a gradual, rapid, and significant reduction in pain, with a response observed within 12 h of the administration of the drug. Consistent with previous clinical studies, canakinumab appeared to be a viable, safe, and effective alternative to conventional therapies in this patient with gout who had limited therapeutic options. FUNDING: Novartis Farma, Italy. PMID- 29524119 TI - Differing Relationship of Psycho-Social Variables with Active Ulcerative Colitis or Crohn's Disease. AB - PURPOSE: How psycho-social variables affect the degree of disease activity in patients with ulcerative colitis (UC) or Crohn's disease (CD) is incompletely understood. Therefore, we measured and compared the impact of psycho-social variables on the active disease state in UC and CD. METHOD: One hundred and twenty-two UC and 305 CD patients with active disease completed questionnaires detailing their psychological symptoms, threatening experiences, disease-coping strategies, satisfaction with life, quality of life, and demographics. RESULTS: UC and CD patients were aged (mean, SD) 38.6 +/- 14.0 and 45.2 +/- 15.1 years, respectively. The psychological symptom index (median, IQR) was greater in UC 1.24 (0.8) than CD 0.9 (0.8), p < 0.001. UC used more emotion-focused strategies, 24.5 (5.7) than CD, 23.0 (5.7), p < 0.03; problem-focused strategies, 16.4 (4.5) vs. 15.4 (4.2), p < 0.04; and dysfunctional strategies, 23.7 (5.7) vs. 22.0 (5.0), p < 0.01. UC activity correlated with gender, age, economic status, psychological symptoms, threatening experiences, all coping strategies, satisfaction with life, and quality of life (p < 0.02-0.001). CD activity correlated with economic status, psychological symptoms, threatening experiences, dysfunctional strategies, satisfaction with life, and quality of life (p < 0.05 0.001). UC activity was predicted by psychological symptoms (9.1% variance), economic status (6.9%), problem-focused strategies (4.2%), and threatening experiences (1.3%); CD activity by threatening experiences (5% variance) and psychological symptoms (4%). In path analysis, psychological symptoms and problem focused strategies mediated the effects of economic status, age, and threatening experiences on UC activity. In CD, the dominant pathway was threatening experiences impacting on psychological symptoms. CONCLUSION: The impact of psycho social variables on the active disease state differs between UC and CD, thus indicating a need for specifically tailored psychotherapies. PMID- 29524122 TI - Factors to consider in the verification of urinary biomarkers. PMID- 29524121 TI - Combined prednisone and levothyroxine improve treatment of severe thrombocytopenia in hepatitis B with compensatory cirrhosis accompanied by subclinical and overt hypothyroidism. AB - The aim of the present study was to investigate the relationship between hypothyroidism and thrombocytopenia in hepatitis B-related compensatory liver cirrhosis and to determine whether treatment with levothyroxine and prednisone is superior in a multicenter, open-label, observational study in China. In total, 125 consecutive hepatitis B-related compensated liver cirrhosis patients with severe thrombocytopenia accompanied by hypothyroidism were included. The patients were divided into four groups according to treatment strategy: a control group (n=29), a prednisone group (n=25), a levothyroxine group (n=32) and a prednisone plus levothyroxine group (n=39). Severe thrombocytopenia was more prevalent in hepatitis B-associated compensatory liver cirrhosis patients with hypothyroidism than in euthyroid patients (29.6% vs. 14.7%, P<0.05). Combination treatment with prednisone and levothyroxine decreased the risk of bleeding and improved platelet recovery compared to control treatment and treatment with either prednisone or levothyroxine alone. The platelet count before therapy, serum thyroid stimulating hormone and combination treatment with prednisone and levothyroxine were associated with bleeding events. Therefore, the present study suggests that hypothyroidism is associated with severe thrombocytopenia in hepatitis B associated compensatory liver cirrhosis. Treatment with prednisone plus levothyroxine may present a novel approach in these patients. PMID- 29524123 TI - BCI induces apoptosis via generation of reactive oxygen species and activation of intrinsic mitochondrial pathway in H1299 lung cancer cells. AB - The compound (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) is known as an inhibitor of dual specific phosphatase 1/6 and mitogen activated protein kinase. However, its precise anti-lung cancer mechanism remains unknown. In this study, the effects of BCI on the viability of non-small cell lung cancer cell lines NCI-H1299, A549, and NCI-H460 were evaluated. We confirmed that BCI significantly inhibited the viability of p53(-) NCI-H1299 cells as compared to NCI-H460 and A549 cells, which express wild-type p53. Furthermore, BCI treatment increased the level of cellular reactive oxygen species and pre treatment of cells with N-acetylcysteine markedly attenuated BCI-mediated apoptosis of NCI-H1299 cells. BCI induced cellular morphological changes, inhibited viability, and produced reactive oxygen species in NCI-H1299 cells in a dose-dependent manner. BCI induced processing of caspase-9, caspase-3, and poly ADP-ribose polymerase as well as the release of cytochrome c from the mitochondria into the cytosol. In addition, BCI downregulated Bcl-2 expression and enhanced Bax expression in a dose-dependent manner in NCI-H1299 cells. However, BCI failed to modulate the expression of the death receptor and extrinsic factor caspase-8 and Bid, a linker between the intrinsic and extrinsic apoptotic pathways in NCI-H1299 cells. Thus, BCI induces apoptosis via generation of reactive oxygen species and activation of the intrinsic pathway in NCI-H1299 cells. PMID- 29524124 TI - Interactive effects of water stress and powdery mildew (Blumeria graminis) on the alkaloid production of Achnatherum inebrians infected by Epichloe endophyte. PMID- 29524125 TI - Differential impact of flow and mouth leak on oropharyngeal humidification during high-flow nasal cannula: a neonatal bench study. AB - BACKGROUND: Heated humidification is paramount during neonatal high-flow nasal cannula (HFNC) therapy. However, there is little knowledge about the influence of flow rate and mouth leak on oropharyngeal humidification and temperature. METHODS: The effect of the Optiflow HFNC on oropharyngeal gas conditioning was investigated at flow rates of 4, 6 and 8 L min-1 with and without mouth leak in a bench model simulating physiological oropharyngeal air conditions during spontaneous breathing. Temperature and absolute humidity (AH) were measured using a digital thermo-hygrosensor. RESULTS: Without mouth leak, oropharyngeal temperature and AH increased significantly with increasing flow (P < 0.001). Mouth leak did not affect this increase up to 6 L min-1, but at 8 L min-1, temperature and AH plateaued, and the effect of mouth leak became statistically significant (P < 0.001). CONCLUSIONS: Mouth leak during HFNC had a negative impact on oropharyngeal gas conditioning when high flows were applied. However, temperature and AH always remained clinically acceptable. PMID- 29524127 TI - Editing the Epigenome: Overview, Open Questions, and Directions of Future Development. AB - The introduction of CRISPR/Cas has resulted in a strong impulse for the field of gene-targeted epigenome reprogramming. In this approach EpiEditors are applied in cells, which consist of a DNA-binding part for targeting and a functional part to induce chromatin modifications at targeted genome loci. The accumulating evidence of epigenetic reprogramming of a given genomic locus resulting in gene expression changes indicated causal relationships of epigenetic marks instructing gene expression and opened the field for mainstream applications. In this perspective, an overview of the current status of the field is provided, including its applications and future perspectives. The dependence of critical parameters like specificity, effectivity, and sustainability of epigenome editing on experimental settings and conditions including the expression levels and the duration of the expression of the EpiEditors, their DNA-binding affinity and specificity, and the cross talk between EpiEditors and cellular chromatin modifiers is discussed. Once established in fully functional "plug-and-play" mode, epigenome editing will allow to better understand epigenetic expression control and to translate such knowledge into therapeutic tools. PMID- 29524126 TI - Potential use of prostate specific membrane antigen (PSMA) for detecting the tumor neovasculature of brain tumors by PET imaging with 89Zr-Df-IAB2M anti-PSMA minibody. AB - Tumor angiogenesis has attracted increasing attention because of its potential as a valuable marker in the differential diagnosis of brain tumors as well as a novel therapeutic target. Prostate-specific membrane antigen (PSMA) is expressed by the neovasculature endothelium of some tumors, with little to no expression by the tumor cells or normal vasculature endothelium. The aim of this study was to investigate the potential of PSMA for the evaluation of the tumor neovasculature of various brain tumors and the possibility of detecting PSMA expression in brain tumors using PET imaging with 89Zr-Df-IAB2M (anti-PSMA minibody). Eighty-three tissue specimens including gliomas, metastatic brain tumors, primary central nervous system lymphomas (PCNSL), or radiation necroses were analyzed by immunohistochemical staining with PSMA antibody. 89Zr-Df-IAB2M PET scans were performed in three patients with recurrent high-grade gliomas or metastatic brain tumor. PSMA was highly expressed in the vascular endothelium of high-grade glioma and metastatic brain tumor, whereas PSMA was poorly expressed in the vascular endothelium of PCNSL and radiation necrosis. PSMA expression in high-grade gliomas and a metastatic brain tumor was clearly visualized by PET imaging with 89Zr-Df-IAB2M. Furthermore, a trend toward a positive correlation between the degree of 89Zr-Df-IAB2M uptake and PSMA expression levels in tumor specimens was observed. PET imaging of PSMA using 89Zr-Df-IAB2M may have potential value in the differential diagnosis of high-grade glioma from PCNSL or radiation necrosis as well as in the prediction of treatment efficacy and assessment of treatment response to bevacizumab therapy for high-grade glioma. PMID- 29524128 TI - Zinc Fingers, TALEs, and CRISPR Systems: A Comparison of Tools for Epigenome Editing. AB - The completion of genome, epigenome, and transcriptome mapping in multiple cell types has created a demand for precision biomolecular tools that allow researchers to functionally manipulate DNA, reconfigure chromatin structure, and ultimately reshape gene expression patterns. Epigenetic editing tools provide the ability to interrogate the relationship between epigenetic modifications and gene expression. Importantly, this information can be exploited to reprogram cell fate for both basic research and therapeutic applications. Three different molecular platforms for epigenetic editing have been developed: zinc finger proteins (ZFs), transcription activator-like effectors (TALEs), and the system of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins. These platforms serve as custom DNA-binding domains (DBDs), which are fused to epigenetic modifying domains to manipulate epigenetic marks at specific sites in the genome. The addition and/or removal of epigenetic modifications reconfigures local chromatin structure, with the potential to provoke long-lasting changes in gene transcription. Here we summarize the molecular structure and mechanism of action of ZF, TALE, and CRISPR platforms and describe their applications for the locus-specific manipulation of the epigenome. The advantages and disadvantages of each platform will be discussed with regard to genomic specificity, potency in regulating gene expression, and reprogramming cell phenotypes, as well as ease of design, construction, and delivery. Finally, we outline potential applications for these tools in molecular biology and biomedicine and identify possible barriers to their future clinical implementation. PMID- 29524130 TI - Generation of TALE-Based Designer Epigenome Modifiers. AB - Manipulation of gene expression can be facilitated by editing the genome or the epigenome. Precise genome editing is traditionally achieved by using designer nucleases which are generally exploited to eliminate a specific gene product. Upon the introduction of a site-specific DNA double-strand break (DSB) by the nuclease, endogenous DSB repair mechanisms are in turn harnessed to induce DNA sequence changes that can result in target gene inactivation. Minimal off-target effects can be obtained by endowing designer nucleases with the highly specific DNA-binding domain (DBD) derived from transcription activator-like effectors (TALEs). In contrast, epigenome editing allows gene expression control without inducing changes in the DNA sequence by specifically altering epigenetic marks, as histone tails modifications or DNA methylation patterns within promoter or enhancer regions. Importantly, this approach allows both up- and downregulation of the target gene expression, and the effect is generally reversible. TALE-based designer epigenome modifiers combine the high specificity of TALE-derived DBDs with the power of epigenetic modifier domains to induce fast and long-lasting changes in the epigenetic landscape of a target gene and control its expression. Here we provide a detailed description for the generation of TALE-based designer epigenome modifiers and of a suitable reporter cell line to easily monitor their activity. PMID- 29524129 TI - Designing Epigenome Editors: Considerations of Biochemical and Locus Specificities. AB - The advent of locus-specific protein recruitment technologies has enabled a new class of studies in chromatin biology. Epigenome editors enable biochemical modifications of chromatin at almost any specific endogenous locus. Their locus specificity unlocks unique information including the functional roles of distinct modifications at specific genomic loci. Given the growing interest in using these tools for biological and translational studies, there are many specific design considerations depending on the scientific question or clinical need. Here we present and discuss important design considerations and challenges regarding the biochemical and locus specificities of epigenome editors. These include how to account for the complex biochemical diversity of chromatin; control for potential interdependency of epigenome editors and their resultant modifications; avoid sequestration effects; quantify the locus specificity of epigenome editors; and improve locus specificity by considering concentration, affinity, avidity, and sequestration effects. PMID- 29524132 TI - Allele-Specific Epigenome Editing. AB - The discovery and adaptation of the CRISPR/Cas system for epigenome editing has allowed for a straightforward design of targeting modules which can direct epigenetic editors to virtually any genomic site. This advancement in DNA targeting technology brings allele-specific epigenome editing into reach, a "super-specific" variation of epigenome editing whose goal is an alteration of chromatin marks at only one selected allele of the target genomic locus. This technology would be useful for the treatment of diseases caused by a mutant allele with a dominant effect, because allele-specific epigenome editing allows the specific silencing of the mutated allele leaving the healthy counterpart expressed. Moreover, it may allow the direct correction of aberrant imprints in imprinting disorders where editing of DNA methylation is needed in one allele only. Here, we describe some principal setups of allele-specific epigenome editing systems and present exemplary data illustrating the feasibility of the concept. PMID- 29524133 TI - Key to Delivery: The (Epi-)genome Editing Vector Toolbox. AB - Curing a genetic disease by repairing the underlying genetic defect is a fascinating concept that has been addressed so far by gene compensation therapy. For this, a functional copy of the gene in question together with elements controlling its expression is produced as a vector and introduced ex vivo into the patient's own cells that subsequently are reinfused. Alternatively, vectors are administered directly in vivo. Although this strategy resulted in impressive therapeutic benefits for patients, the ultimate goal of gene therapy, i.e., a cure by repairing the actual genetic or epigenetic defect, remained an unresolved task. With the advent of designer DNA-binding domains, this goal is coming into reach. These domains are either combined with nucleases and used as molecular precision scissors for introducing DNA breaks at defined sites in the cell's genome preparing for position-selective DNA repair, or they are used as programmable DNA-binding units for positioning epigenome-modifying domains to predefined target sequences. However, for reaching its full potential, these components need to be delivered into cells in an efficient and safe manner. Here, we summarize current viral and non-viral delivery approaches applicable for genome and epigenome editing and discuss their respective advantages and limitations. PMID- 29524131 TI - Neuroepigenetic Editing. AB - Studies of the mammalian nervous system have revealed widespread epigenetic regulation underlying gene expression intrinsic to basic neurobiological function as well as neurological disease. Over the past decade, a critical role has emerged for the neural regulation of chromatin-modifying enzymes during both development and adulthood, and in response to external stimuli. These biochemical data are complemented by numerous next generation sequencing (NGS) studies that quantify the extent of chromatin and DNA modifications in neurons. Neuroepigenetic editing tools can be applied to distinguish between the mere presence and functional relevance of such modifications to neural transcription and animal behavior. This review discusses current advances in neuroepigenetic editing, highlighting methodological considerations pertinent to neuroscience, such as delivery methods and the spatiotemporal specificity of editing. Although neuroepigenetic editing is a nascent field, the studies presented in this review demonstrate the enormous potential of this approach for basic neurobiological research and therapeutic application. PMID- 29524134 TI - CRISPR/dCas9 Switch Systems for Temporal Transcriptional Control. AB - In a swift revolution, CRISPR/Cas9 has reshaped the means and ease of interrogating biological questions. Particularly, mutants that result in a nuclease-deactivated Cas9 (dCas9) provide scientists with tools to modulate transcription of genomic loci at will by targeting transcriptional effector domains. To interrogate the temporal order of events during transcriptional regulation, rapidly inducible CRISPR/dCas9 systems provide previously unmet molecular tools. In only a few years of time, numerous light and chemical inducible switches have been applied to CRISPR/dCas9 to generate dCas9 switches. As these inducible switch systems are able to modulate dCas9 directly at the protein level, they rapidly affect dCas9 stability, activity, or target binding and subsequently rapidly influence downstream transcriptional events. Here we review the current state of such biotechnological CRISPR/dCas9 enhancements. Specifically we provide details on their flaws and strengths and on the differences in molecular design between the switch systems. With this we aim to provide a selection guide for researchers with keen interest in rapid temporal control over transcriptional modulation through the CRISPR/dCas9 system. PMID- 29524135 TI - Delivery of Designer Epigenome Modifiers into Primary Human T Cells. AB - The development of tools which allow for the precise alterations of the epigenetic landscape in desired genomic locations presents exciting possibilities toward further understanding how gene expression is regulated and opportunities to harness these properties for therapeutic purposes. In contrast to gene knockout strategies, targeted epigenome modifications, such as editing of DNA methylation, can mediate gene expression modulation without changing the genomic sequence. Thereby, in a therapeutic context, this strategy may offer a safer route as compared to gene disruption using designer nucleases that, to reach high efficiencies, relies on the occurrence of random mutations to inactivate the target gene. In addition, therapeutic benefit is influenced not only by the intrinsic safety and efficacy of the tools used but also by methods that allow efficient and non-toxic transfer of the selected reagents in the target cells. Here, we describe a detailed protocol, for safe delivery of TALE-based designer epigenome modifiers in the form of in vitro transcribed mRNA into primary human CD4+ T cells to efficiently silence the expression of an exemplary human gene (i.e., CCR5). PMID- 29524136 TI - Viral Expression of Epigenome Editing Tools in Rodent Brain Using Stereotaxic Surgery Techniques. AB - Delivery of molecular tools for targeted epigenome editing in rodent brain can be facilitated by the use of viral vector-mediated gene transfer coupled with stereotaxic surgery techniques. Here, we describe the surgical protocol utilized by our group, which is optimized for herpes simplex virus (HSV)-mediated delivery into mouse brain. The protocol outlined herein could also be applied for delivery of adeno-associated viruses (AAV) or lentiviruses in both mice and rats. This method allows for efficient viral transgene expression and subsequent epigenome editing in rodent brain with excellent spatiotemporal control. Nearly any brain region of interest can be targeted in rodents at every stage of postnatal life. Owing to the versatility, reproducibility, and utility of this technique, it is an important method for any laboratory interested in studying the cellular, circuit, and behavioral consequences of in vivo neuroepigenome editing. PMID- 29524137 TI - Stable Expression of Epigenome Editors via Viral Delivery and Genomic Integration. AB - The advent of precise genomic targeting systems has revolutionized epigenome editing through fusion of epigenetic effector proteins with engineered DNA binding proteins. However, the delivery of plasmid DNA to express these fusion proteins via conventional transient transfection has certain consequences which need to be considered during the experimental design. Transient transfection achieves peak gene expression between 24 and 96 h post-transfection after which the foreign gene is lost through cell division and degradation. The use of cell lines stably expressing the effector fusion protein of interest provides several advantages compared to standard transfection methods, and the most suitable means for creating these cell lines was found to be viral delivery followed by stable integration of the transgenes into the host genome. Here we describe a practical protocol to generate murine cell lines stably expressing fusion proteins of chromatin regulators and DNA-binding proteins using a retroviral murine stem cell virus (MSCV)-based vector system. PMID- 29524138 TI - Purified Protein Delivery to Activate an Epigenetically Silenced Allele in Mouse Brain. AB - The ability to activate or repress specific genes in the brain could have a tremendous impact for understanding and treating neurological disorders. Artificial transcription factors based on zinc finger, TALE, and CRISPR/Cas9 programmable DNA-binding platforms have been widely used to regulate the expression of specific genes in cultured cells, but their delivery into the brain represents a critical challenge to apply such tools in live animals. In previous work, we developed a purified, zinc finger-based artificial transcription factor that could be injected systemically, cross the blood-brain barrier, and alter expression of a specific gene in the brain of an adult mouse model of Angelman syndrome. Importantly, our mode of delivery produced widespread distribution throughout the brain. Here we describe our most current methods for the production and purification of the factor, dosage optimization, and use of live animal fluorescence imaging to visualize the kinetics of distribution. PMID- 29524139 TI - Non-viral Methodology for Efficient Co-transfection. AB - The potential impact of CRISPR/Cas9, TALE, and zinc finger technology is immense, both with respect to their use as tools for understanding the roles and functions of the genomic elements and epigenome modifications in an endogenous context and as new methods for treatment of diseases. Application of such technologies has drawn attention, however, to the prevailing lack of effective delivery methods. Promising viral and non-viral methods both currently fall short when the efficient delivery of large plasmids or multiple plasmids is required. Therefore, the use of TALE and CRISPR platforms has been severely limited in applications where selection methods to increase the relative proportion of treated cells are not applicable, and it represents a significant bottleneck in the further application of these tools as therapeutics.The protocol presented here describes the synthesis of a dendronized polymer as a highly efficient and nontoxic transfection agent. Furthermore, the optimization of the polymer as a co transfection reagent for large and multiple plasmids in cell lines is described, in addition to general considerations for co-transfection experiments. Usage of this method has allowed for significantly improved large plasmid co-transfection efficiency over Lipofectamine 2000 in multiple cell lines, allowing an improved delivery of CRISPR/dCas9 and TALE systems. PMID- 29524140 TI - Chromatin Immunoprecipitation in Human and Yeast Cells. AB - Chromatin immunoprecipitation (ChIP) is an invaluable method to characterize interactions between proteins and genomic DNA, such as the genomic localization of transcription factors and posttranslational modification of histones. DNA and proteins are reversibly and covalently crosslinked using formaldehyde. Then the cells are lysed to release the chromatin. The chromatin is fragmented into smaller sizes either by micrococcal nuclease (MNase) or sonication and then purified from other cellular components. The protein-DNA complexes are enriched by immunoprecipitation (IP) with antibodies that target the epitope of interest. The DNA is released from the proteins by heat and protease treatment, followed by degradation of contaminating RNAs with RNase. The resulting DNA is analyzed using various methods, including PCR, qPCR, or sequencing. This protocol outlines each of these steps for both yeast and human cells. PMID- 29524141 TI - Chromatin Immunoprecipitation and High-Throughput Sequencing (ChIP-Seq): Tips and Tricks Regarding the Laboratory Protocol and Initial Downstream Data Analysis. AB - Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) has become an essential tool for epigenetic scientists. ChIP-seq is used to map protein-DNA interactions and epigenetic marks such as histone modifications at the genome-wide level. Here we describe a complete ChIP-seq laboratory protocol (tailored toward processing tissue samples as well as cell lines) and the bioinformatic pipelines utilized for handling raw sequencing files through to peak calling. PMID- 29524142 TI - Generation of Whole Genome Bisulfite Sequencing Libraries for Comprehensive DNA Methylome Analysis. AB - Whole genome bisulfite sequencing (WGBS) enables the detection of DNA methylation at single base-pair resolution. The treatment of DNA with sodium bisulfite allows the discrimination of methylated and unmethylated cytosines, but the power of this technology can be limited by the input amounts of DNA and the length of DNA fragments due to DNA damage caused by the desulfonation process. Here, we describe a WGBS library preparation protocol that minimizes the loss and damage of DNA, generating high quality libraries amplified with fewer PCR cycles, and hence data with fewer PCR duplicates, from lower amounts of input material. Briefly, genomic DNA is sheared, end-repaired, 3'-adenylated, and ligated to adaptors with fewer cleanup steps in between, minimizing DNA loss. The adapter ligated DNA is then treated with sodium bisulfite and amplified with few PCR cycles to reach the yield needed for sequencing. PMID- 29524143 TI - Approaches for the Analysis and Interpretation of Whole Genome Bisulfite Sequencing Data. AB - DNA methylation is a covalent modification of DNA that plays important roles in processes such as the regulation of gene expression, transcription factor binding, and suppression of transposable elements. The use of whole genome bisulfite sequencing (WGBS) enables the genome-wide identification and quantification of DNA methylation patterns at single-base resolution and is the gold standard for analysis of DNA methylation. Computational analysis of WGBS data can be particularly challenging, as many computationally intensive steps are required. Here, we outline a step-by-step approach for the analysis and interpretation of WGBS data. First, sequencing reads must be trimmed, quality checked, and aligned to the genome. Second, DNA methylation levels are estimated at each cytosine position using the aligned sequence reads of the bisulfite treated DNA. Third, regions of differential cytosine methylation between samples can be identified. Finally, these data need to be visualized and interpreted in the context of the biological question at hand. PMID- 29524144 TI - Whole-Genome Bisulfite Sequencing for the Analysis of Genome-Wide DNA Methylation and Hydroxymethylation Patterns at Single-Nucleotide Resolution. AB - The analysis of genome-wide epigenomic alterations including DNA methylation and hydroxymethylation has become a subject of intensive research for many biological and disease-associated investigations. Whole-genome bisulfite sequencing (WGBS) using next-generation sequencing technologies is currently considered as the gold standard for a comprehensive and quantitative analysis of DNA methylation throughout the genome. However, bisulfite conversion does not allow distinguishing between cytosine methylation and hydroxymethylation requiring an additional chemical or enzymatic step to identify hydroxymethylated cytosines. Here we provide two detailed protocols based on commercial kits for the preparation of sequencing libraries for the comprehensive whole-genome analysis of DNA methylation and/or hydroxymethylation. If only DNA methylation is of interest, sequencing libraries can be constructed from limited amounts of input DNA by ligation of methylated adaptors to the fragmented DNA prior to bisulfite conversion. For samples with significant levels of hydroxymethylation such as stem cells or brain tissue, we describe the protocol of oxidative bisulfite sequencing (OxBs-seq), which in its current version uses a post-bisulfite adaptor tagging (PBAT) approach. Two methylomes need to be generated: a classic methylome following bisulfite conversion and analyzing both methylated and hydroxymethylated cytosines and a methylome analyzing only methylated cytosines, respectively. We also provide a step-by-step description of the data analysis using publicly available bioinformatic tools. The described protocols have been successfully applied to different human samples and yield robust and reproducible results. PMID- 29524145 TI - Locus-Specific DNA Methylation Analysis by Targeted Deep Bisulfite Sequencing. AB - DNA methylation, i.e., the methylation of cytosine at carbon atom C5, has an important role in the regulation of gene expression. The methylation status of each cytosine in a specific genomic region can be determined by targeted deep bisulfite sequencing at single-molecule resolution. Here we describe the design of PCR primers that are used to amplify specific sequences from bisulfite converted DNA, the preparation of sequencing libraries, the sequencing of these libraries on the MiSeq system, as well as the analysis of the sequence reads. Using appropriate software tools such as amplikyzer2, it is easy to analyze complex multiplexed samples with several regions of interest, to determine the mean methylation values of all CpG dinucleotides in a region or of each CpG dinucleotide across all or selected reads, and to compare these values between different samples and between different alleles within a sample. PMID- 29524146 TI - DNA Methylation Analysis by Bisulfite Conversion Coupled to Double Multiplexed Amplicon-Based Next-Generation Sequencing (NGS). AB - Methylation of cytosine bases in DNA is one of the main epigenetic signals regulating gene expression and chromatin structure. The distribution of DNA methylation in the genome has a cell-type-specific pattern and can be modulated by internal or external stimuli. One of the most powerful approaches to investigate DNA methylation patterns is bisulfite conversion of the DNA followed by DNA sequencing, which allows to determine methylation patterns at a single cytosine resolution. Here, we present a protocol for bisulfite DNA methylation analysis of targeted genomic regions using amplicon-based next-generation sequencing (NGS) on an Illumina sequencing system. We use a PCR-free library generation approach and implement a nested strategy for double molecular barcoding of samples (combining indexing of adapters and in-line barcoding of individual amplicons) which allows highly multiplexed sequencing. Also, we discuss the main limitations of this technology in particular in relation to clonal DNA amplification and other PCR artifacts. PMID- 29524147 TI - Cell-to-Cell Transcription Variability as Measured by Single-Molecule RNA FISH to Detect Epigenetic State Switching. AB - Single-molecule RNA fluorescent in situ hybridization (smRNA FISH) allows for the visualization, localization, and quantification of RNA transcripts within individual cells and tissues using custom-designed fluorescently labeled oligonucleotide probes. Here we describe a protocol for the preparation, imaging, and analysis of a smRNA FISH experiment that can be applied to any RNA of choice. We also provide insights as to how this powerful tool can be used to study epigenetic regulation, for example, following the epigenetic editing of genes. PMID- 29524148 TI - Establishment of Cell Lines Stably Expressing dCas9-Fusions to Address Kinetics of Epigenetic Editing. AB - Epigenetic editing is a promising approach to modulate the local chromatin environment of target genes with the ultimate goal of stable gene expression reprogramming. Epigenetic editing tools minimally consist of a DNA-binding domain and an effector domain. The CRISPR/dCas9 platform, where mutations in the nuclease domains render the Cas9 protein inactive, is widely used to guide epigenetic effectors to their intended genomic loci. Its flexible nature, simple use, and relatively low cost have revolutionized the research field of epigenetic editing. Although effective expression modulation is readily achieved, only a few studies have addressed the maintenance of the induced effects on endogenous loci. Here, we describe a detailed protocol to engineer cells that stably express the CRISPR/dCas9-effectors. The protocol involves modification of published dCas9 based plasmid vectors for easy transfer of the effector domain between the vector designed for transient transfection and the vector used for establishing cell lines stably expressing the dCas9-effector fusion protein. Transient transfection of the dCas9-effector-producing cells with sgRNA-expressing plasmids allows studying of the maintenance of epigenetic editing. Targeting various genes in different chromatin contexts and/or co-targeting multiple CRISPR/dCas9-effectors can be used to unravel rules underlying maintained gene expression reprogramming. PMID- 29524149 TI - Editing of DNA Methylation Using dCas9-Peptide Repeat and scFv-TET1 Catalytic Domain Fusions. AB - DNA methylation, one of the most studied epigenetic modifications, regulates many biological processes. Dysregulation of DNA methylation is implicated in the etiology of several diseases, such as cancer and imprinting diseases. Accordingly, technologies designed to manipulate DNA methylation at specific loci are very important, and many epigenome editing technologies have been developed, based on zinc finger proteins, TALEs, and CRISPR/dCas9 targeting. We describe a protocol to induce and assess DNA demethylation on a target gene. It is based on a modification of the dCas9-SunTag system for efficient, targeted demethylation at specific DNA loci. The original SunTag system consists of ten copies of the GCN4 peptide separated by 5-amino-acid linkers. To achieve efficient recruitment of an anti-GCN4 scFv fused to the ten-eleven (TET) 1 hydroxylase, an enzyme that demethylates DNA, we changed the linker length to 22 amino acids. PMID- 29524150 TI - Chemical Inducible dCas9-Guided Editing of H3K27 Acetylation in Mammalian Cells. AB - The ability to edit specific epigenetic modifications at defined gene loci is pivotal to understand the biological function of these epigenetic marks. Here we describe a new inducible method to integrate the dCas9-based genome targeting with abscisic acid (ABA)-based chemically induced proximity (CIP) technologies to modify histone tail modifications at specific genome loci in living cells. ABA leads to rapid hetero-dimerization of the PYL and ABI proteins, which can be individually fused to dCas9 and a histone-modifying enzyme core domain. In the presence of ABA and locus-specific sgRNAs, this histone-modifying activity can be recruited to a specific genome locus to achieve histone editing with perfect temporal control. Herein, we describe the use of this technique in HEK293T cells to control the recruitment of the p300 acetyltransferase core domain to the human IL1RN locus to ectopically increase the acetylation of H3K27 and induce the expression of IL1RN gene. PMID- 29524151 TI - Screening Regulatory Element Function with CRISPR/Cas9-based Epigenome Editing. AB - Genomic regulatory elements that control gene expression play an important role in many traits and diseases. Identifying the regulatory elements associated with each gene or phenotype and understanding the function of that element remain a significant challenge. To address this technological need, we developed CRISPR/Cas9-based epigenomic regulatory element screening (CERES) for improved high-throughput screening of regulatory element activity in the native genomic context. This protocol includes detailed instructions for design and cloning of gRNA libraries, construction of endogenous reporter cell lines via CRISPR/Cas9 mediated knock-in of fluorescent proteins, overall screen design, and recovery of the gRNA library for enrichment analysis. This protocol will be generally useful for implementing genome engineering technologies for high-throughput functional annotation of putative regulatory elements in their native chromosomal context. PMID- 29524152 TI - Difficulties in identifying the bacterial species from the genus Clostridium in a case of injury-related osteitis. AB - Most Clostridium species are part of saprophytic microflora in humans and animals; however, some are well-known human pathogens. We presented the challenges in identifying the Clostridium species isolated from a patient with an infected open dislocation of the proximal interphalangeal joint of the fourth digit of the right hand. The clinical materials were intraoperative samples collected from a patient diagnosed with an injury-related infection, with soft tissue loss and tendon sheath involvement. The available biochemical, molecular, and genetic techniques were used in identifying the isolated bacteria. The isolated bacterium was shown to have low biochemical activity; hence, it was not definitively identified via biochemical tests Api 20A or Rapid 32A. Vitek 2 and mass spectrometry methods were equally inconclusive. Clostridium tetani infection was strongly suspected based on the bacterium's morphology and the appearance of its colonies on solid media. It was only via the 16S rRNA sequencing method, which is non-routine and unavailable in most clinical laboratories, that this pathogen was excluded. Despite appropriate pre-laboratory procedures, which are critical for obtaining reliable test results, the routine methods of anaerobic bacterium identification are not always useful in diagnostics. Diagnostic difficulties occur in the case of environment-derived bacteria of low or not fully understood biological activity, which are absent from databases of automatic bacterial identification systems. PMID- 29524153 TI - Small mammals as sentinels of antimicrobial-resistant staphylococci. AB - A total of 39 coagulase-negative staphylococci and seven Staphylococcus aureus strains were isolated from small mammal feces, i.e., the striped field mouse (Apodemus agrarius) and the yellow-necked mouse (A. flavicollis) in two sampling areas, deciduous forest and karst plains. MALDI-TOF analysis revealed five species of coagulase-negative staphylococci: S. sciuri, S. hominis, S. warneri, S. haemolyticus, and S. xylosus. All strains were susceptible to tetracycline, linezolid, vancomycin, and teicoplanin. Three MRSA strains with the mecA gene were detected. The beta-lactamase gene blaZ was detected in ampicillin-resistant staphylococci and in the high-level resistant strains (oxacillin over 2 mg/L) mecA gene. The mecC gene was not detected by PCR. Erythromycin-resistant staphylococci harbored the ermC gene and/or the efflux gene msrA. There were no detectable dfr genes in trimethoprim-resistant staphylococci and the rifampicin resistant strains were without mutation in the rpoB gene. In summary, wild small mammals may serve as sentinels of mecA-positive S. aureus with erythromycin resistance genes ermC and efflux msrA. Small mammals appear to be useful indicators of antibiotic resistance. PMID- 29524154 TI - Evaluation of a Semi-automatic Right Ventricle Segmentation Method on Short-Axis MR Images. AB - The purpose of this study was to evaluate a semi-automatic right ventricle segmentation method on short-axis cardiac cine MR images which segment all right ventricle contours in a cardiac phase using one seed contour. Twenty-eight consecutive short-axis, four-chamber, and tricuspid valve view cardiac cine MRI examinations of healthy volunteers were used. Two independent observers performed the manual and automatic segmentations of the right ventricles. Analyses were based on the ventricular volume and ejection fraction of the right heart chamber. Reproducibility of the manual and semi-automatic segmentations was assessed using intra- and inter-observer variability. Validity of the semi-automatic segmentations was analyzed with reference to the manual segmentations. The inter- and intra-observer variability of manual segmentations were between 0.8 and 3.2%. The semi-automatic segmentations were highly correlated with the manual segmentations (R2 0.79-0.98), with median difference of 0.9-4.8% and of 3.3% for volume and ejection fraction parameters, respectively. In comparison to the manual segmentation, the semi-automatic segmentation produced contours with median dice metrics of 0.95 and 0.87 and median Hausdorff distance of 5.05 and 7.35 mm for contours at end-diastolic and end-systolic phases, respectively. The inter- and intra-observer variability of the semi-automatic segmentations were lower than observed in the manual segmentations. Both manual and semi-automatic segmentations performed better at the end-diastolic phase than at the end systolic phase. The investigated semi-automatic segmentation method managed to produce a valid and reproducible alternative to manual right ventricle segmentation. PMID- 29524156 TI - Spectroscopic methods to analyze drug metabolites. AB - Drug metabolites have been monitored with various types of newly developed techniques and/or combination of common analytical methods, which could provide a great deal of information on metabolite profiling. Because it is not easy to analyze whole drug metabolites qualitatively and quantitatively, a single solution of analytical techniques is combined in a multilateral manner to cover the widest range of drug metabolites. Mass-based spectroscopic analysis of drug metabolites has been expanded with the help of other parameter-based methods. The current development of metabolism studies through contemporary pharmaceutical research are reviewed with an overview on conventionally used spectroscopic methods. Several technical approaches for conducting drug metabolic profiling through spectroscopic methods are discussed in depth. PMID- 29524155 TI - Reproductive genetics and the aging male. AB - PURPOSE: To examine current evidence of the known effects of advanced paternal age on sperm genetic and epigenetic changes and associated birth defects and diseases in offspring. METHODS: Review of published PubMed literature. RESULTS: Advanced paternal age (> 40 years) is associated with accumulated damage to sperm DNA and mitotic and meiotic quality control mechanisms (mismatch repair) during spermatogenesis. This in turn causes well-delineated abnormalities in sperm chromosomes, both numerical and structural, and increased sperm DNA fragmentation (3%/year of age) and single gene mutations (relative risk, RR 10). An increase in related abnormalities in offspring has also been described, including miscarriage (RR 2) and fetal loss (RR 2). There is also a significant increase in rare, single gene disorders (RR 1.3 to 12) and congenital anomalies (RR 1.2) in offspring. Current research also suggests that autism, schizophrenia, and other forms of "psychiatric morbidity" are more likely in offspring (RR 1.5 to 5.7) with advanced paternal age. Genetic defects related to faulty sperm quality control leading to single gene mutations and epigenetic alterations in several genetic pathways have been implicated as root causes. CONCLUSIONS: Advanced paternal age is associated with increased genetic and epigenetic risk to offspring. However, the precise age at which risk develops and the magnitude of the risk are poorly understood or may have gradual effects. Currently, there are no clinical screenings or diagnostic panels that target disorders associated with advanced paternal age. Concerned couples and care providers should pursue or recommend genetic counseling and prenatal testing regarding specific disorders. PMID- 29524157 TI - Development of a column-switching LC-MS/MS method of tramadol and its metabolites in hair and application to a pharmacogenetic study. AB - Hair is a valuable specimen for monitoring long-term drug use. Tramadol is an effective opioid analgesic but is associated with risks such as drug dependence and unexpected toxicity arising from genetic differences in metabolism. However, few studies have been performed on the distribution of tramadol and its metabolites in hair. In the present study, a column-switching LC-MS/MS method was developed and fully validated for the simultaneous determination of tramadol and its phase I and II metabolites in hair. Furthermore, the distribution of tramadol and its metabolites in hair was investigated in a pharmacogenetic study. Tramadol and its metabolites were extracted from hair using methanol and injected onto LC MS/MS. The validation results of selectivity, matrix effect, linearity, precision and accuracy were satisfactory. The (mean) concentrations of O-desmethyltramadol (ODMT) and N,O-didesmethyltramadol (NODMT) in the CYP2D6*10/*10 and CYP2D6*5/*5 groups were lower than those in the CYP2D6*wt/*wt group, while the (mean) concentrations of N-desmethyltramadol (NDMT) were higher. Moreover, the ratios of ODMT/tramadol, NDMT/tramadol and NODMT/NDMT were well correlated with the CYP2D6 genotypes. The developed method was successfully applied to the clinical study, which demonstrated that the concentrations of a drug and its metabolites in hair were dependent on the polymorphism of its metabolizing enzyme. PMID- 29524158 TI - Simultaneous determination of 14 oral antihyperglycaemic drugs in human urine by liquid chromatography-tandem mass spectrometry. AB - A simple, sensitive, and rapid assay based on hydrophilic interaction liquid chromatography (HILIC) with tandem mass spectrometry was developed and validated for the simultaneous determination of metformin and 13 other oral antihyperglycaemic drugs in human urine using metoprolol as an internal standard. A simple sample clean-up procedure using the "dilute and shoot" approach enabled fast and reliable analysis. Chromatographic separation was performed on a HILIC column using an elution gradient of mobile phase A, composed of 1 mM ammonium formate (pH 5), and mobile phase B, composed of acetonitrile, at a flow rate of 0.35 mL/min. Quantitation was performed on a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode by using electrospray ionization in positive ion mode. The total chromatographic run time was 20 min. Calibration curves for each analyte were linear over concentration ranges of 2-300, 5-400, or 20-500 ng/mL, with a coefficient of determination above 0.99. The method was validated for selectivity, sensitivity, recovery, linearity, accuracy and precision, system suitability, robustness, and stability. Inter-batch and intra batch coefficients of variation across four validation runs were <= 13.62%. The present method was successfully applied for the analysis of metformin and nateglinide in urine samples after their oral administration to healthy human subjects under fasted conditions. PMID- 29524159 TI - Exercise Professionals with Advanced Clinical Training Should be Afforded Greater Responsibility in Pre-Participation Exercise Screening: A New Collaborative Model between Exercise Professionals and Physicians. AB - Regular exercise improves health but can also induce adverse responses. Although such episodes are rare, many guidelines for pre-participation exercise screening have historically had a low threshold for recommending medical clearance prior to the commencement of exercise, placing the responsibility for decision making about exercise participation on physicians. The 'clearance to exercise' model still occurs widely in practice, but creates cost burdens and barriers to the uptake of exercise. Moreover, many physicians are not provided the training, nor time in a standard consultation, to be able to effectively perform this role. We present a model for pre-participation exercise screening and the initial assessment of clients wishing to commence an exercise programme. It is designed to guide professional practice for the referral, assessment and prescription of exercise for people across the health spectrum, from individuals who are apparently healthy, through to clients with pre-existing or occult chronic conditions. The model removes the request that physicians provide a 'clearance' for patients to engage in exercise programmes. Instead the role of physicians is identified as providing relevant clinical guidance to suitably qualified exercise professionals to allow them to use their knowledge, skills and expertise in exercise prescription to assess and manage any risks related to the prescription and delivery of appropriate exercise programmes. It is anticipated that removing unjustified barriers to exercise participation, such as mandated medical review, will improve the uptake of exercise by the unacceptably high proportion of the population who do not undertake sufficient physical activity for health benefit. PMID- 29524160 TI - Development of Foundational Movement Skills: A Conceptual Model for Physical Activity Across the Lifespan. AB - Evidence supports a positive association between competence in fundamental movement skills (e.g., kicking, jumping) and physical activity in young people. Whilst important, fundamental movement skills do not reflect the broad diversity of skills utilized in physical activity pursuits across the lifespan. Debate surrounds the question of what are the most salient skills to be learned which facilitate physical activity participation across the lifespan. In this paper, it is proposed that the term 'fundamental movement skills' be replaced with 'foundational movement skills'. The term 'foundational movement skills' better reflects the broad range of movement forms that increase in complexity and specificity and can be applied in a variety of settings. Thus, 'foundational movement skills' includes both traditionally conceptualized 'fundamental' movement skills and other skills (e.g., bodyweight squat, cycling, swimming strokes) that support physical activity engagement across the lifespan. A proposed conceptual model outlines how foundational movement skill competency can provide a direct or indirect pathway, via specialized movement skills, to a lifetime of physical activity. Foundational movement skill development is hypothesized to vary according to culture and/or geographical location. Further, skill development may be hindered or enhanced by physical (i.e., fitness, weight status) and psychological (i.e., perceived competence, self-efficacy) attributes. This conceptual model may advance the application of motor development principles within the public health domain. Additionally, it promotes the continued development of human movement in the context of how it leads to skillful performance and how movement skill development supports and maintains a lifetime of physical activity engagement. PMID- 29524161 TI - Comment on: "Effect of High-Intensity Interval Training on Total, Abdominal and Visceral Fat Mass: A Meta-Analysis". PMID- 29524162 TI - Author's Reply to Li et al: Comment on: "Effect of High-Intensity Interval Training on Total, Abdominal and Visceral Fat Mass: A Meta-Analysis". PMID- 29524163 TI - Nuclear myocardial perfusion imaging in stable angina pectoris : Sometimes being wrong is all right. PMID- 29524164 TI - Enhancement of brain-targeting delivery of danshensu in rat through conjugation with pyrazine moiety to form danshensu-pyrazine ester. AB - Tetramethylpyrazine was introduced to the structure of danshensu (DSS) as P glycoprotein (P-gp)-inhibiting carrier, designing some novel brain-targeting DSS pyrazine derivatives via prodrug delivery strategy. Following the virtual screening, three DSS-pyrazine esters (DT1, DT2, DT3) were selected because of their better prediction parameters related to brain-targeting. Among them, DT3 was thought to be a promising candidate due to its appropriate bioreversible property in vitro release assay. Further investigation with regard to DT3's brain targeting effects in vivo was also reported in this study. High-performance liquid chromatography-diode array detection (HPLC-DAD) method was established for the quantitative determination of DT3 and DSS in rat plasma, brain homogenate after intravenous injection. In vivo metabolism of DT3 indicated that it was first converted into DT1, DT2, then the generation of DSS, which could be the result of carboxylesterase activity in rat blood and brain tissue. Moreover, the brain pharmacokinetics of DT3 was significantly altered with 2.16 times increase in half-life compared with that of DSS, and its drug targeting index (DTI) was up to 16.95. Above these data demonstrated that DT3 had better tendency of brain targeting delivery, which would be positive for the treatment of brain-related disorders. PMID- 29524166 TI - Antithymocyte Globuline Therapy and Bradycardia in Children. AB - In antithymocyte globulin (ATG) treated patients occasionally bradycardia has been noticed. Therefore, we retrospectively analyzed the occurrence of bradycardia in ATG-treated children. Using medical records between 2007 and 2012 we identified children undergoing a combined therapy with ATG and glucocorticoids (ATG group, n = 22). The incidence of bradycardia was compared to that registered in children treated with glucocorticoids alone (glucocorticoid alone group, n = 21). Heart rates (HR) were registered before and on days 0-3, 4-7 and 8-14 after the ATG or steroid administration. The rate of bradycardic episodes was higher during ATG therapy than in the steroid alone group, while severe bradycardia occurred only in the ATG group (97 versus 32, p = 0.0037, and 13 versus 0, p = 0.0029, respectively). There was an interaction between the time and treatment group on HR (p = 0.046). Heart rates in ATG and steroid alone groups differed significantly on day 0-3 and day 4-7 (p = 0.046, p = 0.006, respectively). Within the ATG group HR was lower on days 4-7 compared to the days before and the days 8 14 values (p < 0.001, 95%CI: 0.020-0.074). These findings indicate that transient asymptomatic bradycardia is probably more common with ATG therapy than previously reported. HR should be closely monitored during and after ATG therapy. PMID- 29524165 TI - Phospholipid Magnesome-a nasal vesicular carrier for delivery of drugs to brain. AB - The goal of this work was to investigate a new nasal carrier for enhanced drug delivery to brain, we call Phospholipid Magnesome. The system contains soft phospholipid vesicles, composed of phospholipid, water, propylene glycol, magnesium salt, and the mucoadhesive polymer, alginate. The carrier was characterized by various methods: electron microscopy, calorimetry, and dynamic light scattering. The ability of the carrier's vesicles to entrap various molecules was studied by CLSM and ultracentrifugation combined with HPLC quantification. Mucoadhesivity of the carrier was tested in vitro using porcine nasal mucosa. The delivery of rohdamine 6G, insulin, and epidermal growth factor was estimated by two methods, multiphoton microscopy and near infrared (NIR) imaging. Pharmacodynamic effects of nasal treatment with oxytocin and insulin incorporated in Phospholipid Magnesome were evaluated in animal models. Results show that the system is composed of soft multilamellar nanosized vesicles with the ability to entrap both lipophilic and hydrophilic molecules. The mucoadhesivity test results indicate a prolonged contact time of the drug with the nasal membrane as compared to control. Multiphoton microscopy and NIR imaging of brain show effective delivery of the tested molecules to brain following nasal administration in Phospholipid Magnesome relative to controls. Moreover, the results of the pharmacodynamic study measuring the antinociceptive effect of oxytocin administrated nasally to an animal model indicate the efficiency of the Phospholipid Magnesome as compared to three control systems. Further, nasal administration of insulin resulted in a strong and prolonged hypoglycemic effect for the drug incorporated in the new carrier but not for control systems. Based on the results of the histopathological test, the carrier is safe for local administration on the nasal membrane. In conclusion, the results of this study suggest that Phospholipid Magnesome nasal carrier is able to improve drug effects, probably by a combined mechanism, absorption enhancement, and prolongation of mucosal contact. PMID- 29524167 TI - TIMP3 Promoter Methylation Represents an Epigenetic Marker of BRCA1ness Breast Cancer Tumours. AB - Tumours presenting BRCAness profile behave more aggressively and are more invasive as a consequence of their complex genetic and epigenetic alterations, caused by impaired fidelity of the DNA repair processes. Methylation of promoter CpG islands represents an alternative mechanism to inactivate DNA repair and tumour suppressor genes. In our study, we analyzed the frequency of methylation changes of 24 tumour suppressor genes and explored their association with BRCAness profile. BRCA1ness profile and aberrant methylation were studied in 233 fresh frozen breast tumour tissues by Multiplex Ligation-dependent Probe Amplification (MLPA) and Methylation Specific (MS)-MLPA methods, respectively. Our analyses revealed that 12.4% of the breast cancer (BC) patients had tumours with a BRCA1ness profile. TIMP3 showed significantly higher (p = 5.8x10-5) methylation frequency in tumours with BRCA1ness, while methylation of APC, GSTP1 and RASSF1 promoters was negatively associated with BRCA1ness (r = 0.0017, r = 0.007 and r = 0.046, respectively). TIMP3 methylation was also associated with triple negative (TN) BC. Furthermore, TN tumours showing BRCA1ness showed stronger association with TIMP3 methylation (p = 0.0008) in comparison to TN tumours without BRCA1ness (p = 0.009). In conclusion, we confirmed that TIMP3 methylation is a marker for TN tumours and furthermore we showed for the first time that TIMP3 promoter methylation is an epigenetic marker of BRCA1ness tumours. PMID- 29524168 TI - Cell Cycle Markers in the Evaluation of Bladder Cancer. AB - Bladder cancer (BC) is a heterogeneous neoplasia characterized by a high number of recurrences. Standardized clinical and morphological parameters are not always sufficient to predict individual tumor behavior. The aim of this study was to evaluate the expression of cell cycle regulators proteins as potential adjuvant in prognosis and monitoring of this disease. Block paraffin samples from patients with urothelial bladder carcinoma treated by transurethral resection (TUR) were collected to immunohistochemistry analysis for proteins p16, p21, p27, p53, pRb and Ki-67. Chisquare, logistic regression and Kaplan-Meier curve were used to analyze the prognostic value of these markers. Of the 93 patients included in the study, the main categories of staging observed were T1 (53%) and Ta (29%), and the distribution between tumor grades was 58% of patients with low grade to 42% of patients with high grade. The expressions of p16, p21, p27, p53, pRb and Ki-67 were altered in 31%, 42%, 60%, 91%, 27% and 56% of patients, respectively. The immunohistochemical expression of Ki-67 was associated with tumor histological grade (p = 0.016), and expression of pRb with recurrence-free survival (p = 0.035), but no isolated marker was significant associated with recurrence and progression in multivariate analysis. More than two markers abnormally expressed were associated with presence of recurrence (p = 0.005) and lower recurrence-free surviva (p = 0.004). Our panel marker has important prognostic value for BC, especially when more than two have altered expression predicting good clinical recurrence implication. PMID- 29524170 TI - Physicochemical parameters and microbiological status of honey produced in an urban environment in Serbia. AB - Honey is a natural substance produced by honey bees (the genus Apis) enjoyed by people due to its unique nutritional and medicinal properties. The aim of this study was to determine the physicochemical parameters (moisture, ash, water insoluble content, reducing sugars, sucrose, free acidity, diastase activity, hydroxymethylfurfural, and electrical conductivity) and microbiological status (total number of aerobic mesophilic bacteria, total number of sulfite-reducing clostridia, the presence of Salmonella spp., total numbers of fungi and yeasts and the presence of Clostridium botulinum) in honey (honeydew, blossom, sunflower, acacia, and linden) produced in an urban environment in Serbia. We analyzed 19 apiary samples of honey, collected during the 2011 harvesting season, by using recommendation methods. Physicochemical parameters of the examined honey produced in the urban environment indicated the honeys were of acceptable quality. Bacillus spp. were detected in four honeys, yeasts were detected in three honeys, and Clostridium botulinum type E was detected in one honey using PCR. The current study also showed the presence of diverse honey varieties in Serbia. PMID- 29524171 TI - Flexible versus common technology to estimate economies of scale and scope in the water and sewerage industry: an application to England and Wales. AB - The water industry presents several structures in different countries and also within countries. Hence, several studies have been conducted to evaluate the presence of economies of scope and scale in the water industry leading to inconclusive results. The lack of a common methodology has been identified as an important factor contributing to divergent conclusions. This paper evaluates, for the first time, the presence of economies of scale and scope in the water industry using a flexible technology approach integrating operational and exogenous variables of the water companies in the cost functions. The empirical application carried out for the English and Welsh water industry evidenced that the inclusion of exogenous variables accounts for significant differences in economies of scale and scope. Moreover, completely different results were obtained when the economies of scale and scope were estimated using common and flexible technology methodological approaches. The findings of this study reveal the importance of using an appropriate methodology to support policy decision making processes to promote sustainable urban water activities. PMID- 29524169 TI - Clinical use of cardiac PET/MRI: current state-of-the-art and potential future applications. AB - Combined PET/MRI is a novel imaging method integrating the advances of functional and morphological MR imaging with PET applications that include assessment of myocardial viability, perfusion, metabolism of inflammatory tissue and tumors, as well as amyloid deposition imaging. As such, PET/MRI is a promising tool to detect and characterize ischemic and non-ischemic cardiomyopathies. To date, the greatest benefit may be expected for diagnostic evaluation of systemic diseases and cardiac masses that remain unclear in cardiac MRI, as well as for clinical and scientific studies in the setting of ischemic cardiomyopathies. Diagnosis and therapeutic monitoring of cardiac sarcoidosis has the potential of a possible 'killer-application' for combined cardiac PET/MRI. In this article, we review the current evidence and discuss current and potential future applications of cardiac PET/MRI. PMID- 29524172 TI - Biodegradation of kraft lignin by newly isolated Klebsiella pneumoniae, Pseudomonas putida, and Ochrobactrum tritici strains. AB - Bacterial systems have drawn an increasing amount of attention on lignin valorization due to their rapid growth and powerful environmental adaptability. In this study, Klebsiella pneumoniae NX-1, Pseudomonas putida NX-1, and Ochrobactrum tritici NX-1 with ligninolytic potential were isolated from leaf mold samples. Their ligninolytic capabilities were determined by measuring (1) the cell growth on kraft lignin as the sole carbon source, (2) the decolorization of kraft lignin and lignin-mimicking dyes, (3) the micro-morphology changes and transformations of chemical groups in kraft lignin, and (4) the ligninolytic enzyme activities of these three isolates. To the best of our knowledge, this is the first report that Ochrobactrum tritici species can depolymerize and metabolize lignin. Moreover, laccase, lignin peroxidase, and Mn-peroxidase showed high activities in P. putida NX-1. Due to their excellent ligninolytic capabilities, these three bacteria are important supplements to ligninolytic bacteria library and could be valuable in lignin valorization. PMID- 29524173 TI - Association between urinary cadmium and chronic musculoskeletal pain in residents of cadmium-contaminated area in Northwest Thailand. AB - Cadmium exposure is known to cause adverse health effects in different organs of the human body but whether the effects result in chronic musculoskeletal pain (CMP) remain inclusive. The present study, therefore, aims to examine the relationship between urinary cadmium levels and CMP. An observational retrospective cohort study was conducted in two areas having different levels of cadmium contamination for comparison. The subjects enrolled into the study were individuals ages 18 and above who have lived in the studied areas for 1 year or more. The evaluation of chronic pain was carried out using a questionnaire and urine samples were collected for analysis of urinary cadmium levels. The data were analyzed using multiple logistic regression. The likelihood of CMP increased in a correlation with elevations in urinary cadmium from < 0.359, 0.359-0.753, 0.754-1.742, and >= 1.743 MUg/g creatinine, adjusted odds ratio 1.07 (95% CI 0.62 1.86), 1.33 (95% CI 0.76-2.32), and 2.26 (95% CI 1.28-3.99) respectively. A positive association was found in our study between urinary cadmium level and CMP suggesting that cadmium exposure might cause neurological damage and/or tissue/muscle injury which in turn causing CMP. PMID- 29524174 TI - Antimicrobial, cytotoxic and antioxidative evaluation of natural deep eutectic solvents. AB - Natural deep eutectic solvents (NADES) are a new generation of green solvents. They are mixtures of two or three compounds such as choline chloride as a cationic salt and alcohols, acids, amides, amines or sugars as hydrogen-bond donors. Although the majority of NADES' components are of natural origin and therefore NADES are often presumed to be non-toxic, the evaluation of their toxicity and biodegradability must accompany the research on their synthesis and application. Therefore, the aim of this work was to investigate the effect of ten synthesised NADES towards bacteria (i.e., Escherichia coli, Proteus mirabilis, Salmonella typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus), yeast (i.e., Candida albicans) and human cell lines (i.e., HeLa, MCF-7 and HEK293T). In addition, oxygen radical absorbance capacity (ORAC) method was used to determine the antioxidative activity of the tested NADES. Differences in toxicity response between microorganisms and cell lines were observed, and only NADES that contained organic acid showed toxicity towards the test systems. Furthermore, the NADES containing compounds that possess antioxidative activity also showed antioxidative activity. However, research whose primary purpose is the synthesis and application of NADES must be followed by an evaluation of their biological properties (e.g., antimicrobial activity, toxicity towards animal cells and antioxidative or other biological activity) to find the solvent with the best profile for wider industrial applications. PMID- 29524175 TI - Application of UV-visible absorption spectroscopy combined with two-dimensional correlation for insight into DOM fractions from native halophyte soils in a larger estuarine delta. AB - UV-visible absorption spectroscopy combined with principal component analysis (PCA) and two-dimensional correlation (2D correlation) is used to trace components of dissolved organic matter (DOM) extracted from soils in a larger estuarine delta and to investigate spatial variations of DOM fractions. Soil samples of different depths were collected from native halophyte soils along a saline gradient, i.e., Suaeda salsa Comm. (SSC), Chenopodium album Comm. (CAC), Phragmites australis Comm. (PAC), and Artemisia selengensis Comm. (ASC). Molecular weights of DOM within the SSC soil profile were the lowest, followed by the CAC, PAC, and ASC soil profiles. Humification degree of DOM within the ASC soil profile was the highest, followed by the PAC, SSC, and CAC soil profiles. DOM within the soil profiles mainly contained phenolic, carboxylic, microbial products, and aromatic and alkyl groups through the PCA, which presented the significant differentiation among the four native halophyte soil profiles. The 2D UV correlation spectra of DOM within the SSC soil profile indicated that the variations of the phenolic groups were the largest, followed by the carboxylic groups, microbial products, and humified organic materials according to the band changing order of 285 -> 365 -> 425 -> 520 nm. The 2D UV correlation spectra of DOM within the CAC soil profiles determined that the decreasing order of the variations was phenolic groups > carboxylic groups > microbial products according the band changing order of 285 -> 365 -> 425 nm. The 2D UV correlation spectra of DOM within the PAC soil profile proved that the variations of the phenolic groups were larger than those of the carboxylic groups according to the band changing order of 285 -> 365 nm. The 2D UV correlation spectra of DOM within the ASC soil profile demonstrated that the variations of the phenolic groups were larger than those of the other DOM fractions according to the broad cross-peak at 285/365-700 nm. PMID- 29524176 TI - Correction to: Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis. AB - In the print publication the name of the seventh author was incorrectly published. PMID- 29524177 TI - Components of metabolic syndrome in relation to plasma levels of retinol binding protein 4 (RBP4) in a cohort of people aged 65 years and older. AB - PURPOSE: Elevated plasma concentration of retinol binding protein 4 (RBP4) has recently emerged as a potential risk factor as a component of developing metabolic syndrome (MS). Therefore, this study aimed to analyse the relationship between components of MS and concentrations of plasma RBP4 in a population of subjects 65 years and older. METHODS: The study sample consisted of 3038 (1591 male) participants of the PolSenior study, aged 65 years and older. Serum lipid profile, concentrations of RBP4, glucose, insulin, C-reactive protein, IL-6, and activity of aminotransferases were measured. Nutritional status (BMI/waist circumference) and treatment with statins and fibrates were evaluated. Glomerular filtration rate (eGFR), de Ritis ratio, and fatty liver index (FLI), as well as HOMA-IR were calculated. RESULTS: Our study revealed a strong relationship between components of MS and RBP4 in both sexes: plasma RBP4 levels were increased in men by at least 3*, and in women by at least 4*. Hypertriglyceridemia was most strongly associated with elevated plasma RBP4 levels. Multivariate, sex-adjusted regression analysis demonstrated that chronic kidney disease [OR 1.86 (95% CI 1.78-1.94)], hypertriglyceridemia [OR 1.52 (1.24 1.87)], hypertension [OR 1.15 (1.12-1.19)], low serum HDL cholesterol [OR 0.94 (0.92-0.97)], and age > 80 years [OR 0.86 (0.81-0.90)] were each independently associated with RBP4 concentration (all p < 0.001). CONCLUSIONS: In Caucasians 65 years and older, RBP4 serum levels are associated with a number of components of MS, independent of sex and kidney function. Hypertriglyceridemia as a component of MS is most significantly related to RBP4 concentration. PMID- 29524178 TI - Trading off switch costs and stimulus availability benefits: An investigation of voluntary task-switching behavior in a predictable dynamic multitasking environment. AB - In the present study, we introduce a novel, self-organized task-switching paradigm that can be used to study more directly the determinants of switching. Instead of instructing participants to randomly switch between tasks, as in the classic voluntary task-switching paradigm (Arrington & Logan, 2004), we instructed participants to optimize their task performance in a voluntary task switching environment in which the stimulus associated with the previously selected task appeared in each trial after a delay. Importantly, the stimulus onset asynchrony (SOA) increased further with each additional repetition of this task, whereas the stimulus needed for a task switch was always immediately available. We conducted two experiments with different SOA increments (i.e., Exp. 1a = 50 ms, Exp. 1b = 33 ms) to see whether this procedure would induce switching behavior, and we explored how people trade off switch costs against the increasing availability of the stimulus needed for a task repetition. We observed that participants adapted their behavior to the different task environments (i.e., SOA increments) and that participants switched tasks when the SOA in task switches approximately matched the switch costs. Moreover, correlational analyses indicated relations between individual switch costs and individual switch rates across participants. Together, these results demonstrate that participants were sensitive to the increased availability of switch stimuli in deciding whether to switch or to repeat, which in turn demonstrates flexible adaptive task selection behavior. We suggest that performance limitations in task switching interact with the task environment to influence switching behavior. PMID- 29524179 TI - Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome. AB - Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting. Tumours (47/53) showed positive staining for IGF-1R by IHC. IGF-1R nuclear labelling was observed in 10/47 cases. IGF-1R staining was mostly non-nuclear in low-grade tumours, while IGF-1R nuclear labelling was predominant in high-grade gliomas (p = 0.0001). Survival was significantly longer in patients with gliomas having non-nuclear IGF-1R localization than in patients with nuclear IGF-1R tumours (p = 0.016). In gliomas, IGF-1R nuclear localization was significantly associated with both high grade tumours and increased risk of death. Based on a prospective design, we provide evidence of a potential usefulness of intracellular localization of IGF 1R as prognostic factor in paediatric patients with gliomas. PMID- 29524180 TI - Cigarette Smoking among US- and Foreign-Born European and Arab American Non Hispanic White Men and Women. AB - Using 15 years (2000-2014) of restricted cross-sectional National Health Interview Survey data (n = 276,914), we estimated and compared the age-adjusted and sex-specific prevalence of cigarette smoking between US- and foreign-born Europeans and Arab Americans and examined associations between ethnicity and current smoking. Arab Americans were categorized as non-Hispanic Whites born in 15 countries located in the Middle East. Current smoking, average cigarettes per day, and quit attempts were compared. Collectively, we found that current smoking was highest among males compared to females. Prevalence was highest among Arab American males (26%) compared to other US-born (24%) and foreign-born European males (21%). US-born males smoked more cigarettes per day (20.2) yet more Arab American males (61%) tried to quit in the last year compared to European (41%) and US-born (42%) counterparts. Arab American females were least likely to smoke compared to other groups. In crude analyses, Arab American males had greater odds (OR = 1.33; 95% CI = 1.02, 1.74) of smoking compared to US-born White males. After adjusting for demographics, socioeconomic status, health insurance, comorbidity, and acculturation effects, Arab American males had lower odds (OR = 0.64; 95% CI = 0.46, 0.88) of current smoking compared to US-born males. Arab American females had lower odds (OR = 0.28; 95% CI = 0.15, 0.53) of current smoking compared to US-born White females. This is the first national study to examine smoking among Arab Americans. Our study was limited to cigarette smoking behaviors as opposed to other forms of tobacco consumption. More studies are needed to explore smoking among US- and foreign-born Europeans and Arab Americans. PMID- 29524181 TI - Obesity, Overweightness, and Depressive Symptomology Among American Indian Youth. AB - OBJECTIVES: Despite evidence that American Indian adolescents are at a heightened risk of obesity/overweightness and experiencing depression, relative to other groups, there exists a dearth of studies that have examined the association between objective and perceptual measures of obesity and overweightness and depression with this understudied group. Our study represents one of the first studies to examine this association among American Indian youth. METHODS: Using a subsample of American Indian youth from waves I and II of the National Longitudinal Study of Adolescent Health (a survey of schools and students in the USA, with wave I collected in 1994 and wave II collected in 1995), we explore this association. We examine three measures of weight: obesity, body mass index, and weight perception. We also consider gender-specific models and a subsample of non-Hispanic whites, in order to assess race differences in the obesity and overweightness-depression relationship. RESULTS: Our findings reveal that neither of our objective measures of weight, obesity, nor body mass index are significant predictors of depressive symptoms for either American Indian or white youth. However, we find evidence that the subjective measure of weight perception is a significant predictor of depressive symptoms for white females, but not for American Indian females. CONCLUSIONS: Our results contribute to past findings that measures of obesity/overweightness weight may be more important to white female's mental health than females from other racial groups, although additional research is warranted. PMID- 29524182 TI - Prevalence and Phylogenetic Analysis of Crimean-Congo Hemorrhagic Fever Virus in Ticks from Different Ecosystems in Xinjiang, China. AB - The Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the genus Orthonairovirus and family Nairoviridae, is transmitted by ticks and causes severe hemorrhagic disease in humans. To study the epidemiology of CCHFV in different ecosystems in Xinjiang, China, a total of 58,932 ticks were collected from Tarim Basin, Junggar Basin, Tianshan Mountain, and Altai Mountain from 2014 to 2017. Hyalomma asiaticum asiaticum was the dominant tick species in Tarim and Junggar basins, whereas Dermacentor nuttalli and Hyalomma detritum were found in Tianshan Mountain and Altai Mountain, respectively. Reverse transcription polymerase chain reaction of the CCHFV small (S) genome segment was used for the molecular detection. The CCHFV-positive percentage was 5.26%, 6.85%, 1.94%, and 5.56% in Tarim Basin, Junggar Basin, Tianshan Mountain, and Altai Mountain, respectively. Sequences of the S segment were used for phylogenetic analysis and the results showed that the newly identified CCHFV strains belonged to two clades. Our study confirms that H. asiaticum asiaticum is the major vector of CCHFV in desert habitats which is consistent with previous studies, and also suggests that H. detritum and D. nuttalli are emerging vectors for CCHFV in Xinjiang. Moreover, this study reports the presence of CCHFV in the mountain habitat of Xinjiang for the first time, suggesting that future surveillance of CCHFV should also include mountainous areas. PMID- 29524183 TI - A Retrospective Comparative Study of Primary Versus Revisional Roux-en-Y Gastric Bypass: Long-Term Results. AB - AIMS: To compare the perioperative parameters and excess weight loss between patients operated by laporoscopic Roux-en-Y gastric bypass (LRYGB), as a primary operation or a revisional, for insufficient weight loss after vertical banded gastroplasty (VBG) or adjustable gastric banding (AGB). METHODS: A retrospective analysis of all patients who underwent a LRYGB was performed for the period 2004 2011. Demographics, preoperative body mass index (BMI), co-morbidities, operation time, conversion rate, perioperative complications, hospitalization period, and % of excess BMI loss (%EBMIL) were investigated and compared between groups. RESULTS: Three hundred forty-two laparoscopic gastric bypass operations were performed, 245 were primary, and 97 revisional. Median follow-up was 30 months (range 0-108 months). Mean BMI (kg/m2) before bypass was 45.2 for primary laparoscopic Roux-en-Y gastric bypass (pLRYGB) and 41.1 for revisional laparoscopic Roux-en-Y gastric bypass (rLRYGB). Median operative time and length of stay were longer for rLRYGB 157.5 versus 235 min (p < 0.001) and 6 versus 6.5 days (p = 0.05). Conversion to laparotomy was performed in eight patients, 0.4% of primary and 7.2% of revisional. Morbidity rate was 6.5% in pLRYGB versus 10% in rLRYGB (NS). There was one death in the primary group. Percentage of EBMIL was significantly lower in the revisional group at 12, 18, and 24 months of follow up. CONCLUSIONS: Revisional and primary gastric bypass have no statistical differences in terms of morbidity. The % of excess BMI loss is lower after revisional gastric bypass during the first 2 years of follow-up. The trend of weight loss or weight regain was similar in both groups. PMID- 29524184 TI - Development of De Novo Diabetes in Long-Term Follow-up After Bariatric Surgery. AB - INTRODUCTION: While bariatric surgery leads to significant prevention and improvement of type 2 diabetes, patients may rarely develop diabetes after bariatric surgery. The aim of this study was to determine the incidence and the characteristic of new-onset diabetes after bariatric surgery over a 17-year period at our institution. METHODS: Non-diabetic patients who underwent bariatric surgery at a single academic center (1997-2013) and had a postoperative glycated hemoglobin (HbA1c) >= 6.5%, fasting blood glucose (FBG) >= 126 mg/dl, or positive glucose tolerance test were identified and studied. RESULTS: Out of 2263 non diabetic patients at the time of bariatric surgery, 11 patients had new-onset diabetes in the median follow-up time of 9 years (interquartile range [IQR], 4 12). Bariatric procedures performed were Roux-en-Y gastric bypass (n = 7), adjustable gastric banding (n = 3), and sleeve gastrectomy (n = 1). The median interval between surgery and diagnosis of diabetes was 6 years (IQR, 2-9). At the last follow-up, the median HbA1c and FBG values were 6.3% (IQR, 6.1-6.5) and 95 mg/dl (IQR, 85-122), respectively. Possible etiologic factors leading to diabetes were weight regain to baseline (n = 6, 55%), steroid-induced after renal transplantation (n = 1), pancreatic insufficiency after pancreatitis (n = 1), and unknown (n = 3). CONCLUSION: De novo diabetes after bariatric surgery is rare with an incidence of 0.4% based on our cohort. Weight regain was common (> 50%) in patients who developed new-onset diabetes suggesting recurrent severe obesity as a potential etiologic factor. All patients had good glycemic control (HbA1c <= 7%) in the long-term postoperative follow-up. PMID- 29524185 TI - Endoscopic Fistula-jejunostomy for Chronic Gastro-jejunal Fistula After Sleeve Gastrectomy. AB - INTRODUCTION: Proximal gastric leak is one of the most common complications after laparoscopic sleeve gastrectomy (LSG). Endoscopy is the gold standard treatment for acute staple-line leaks. Surgery is the most effective treatment modality in case of chronic fistula. MATERIAL AND METHODS: A 55-year- old man presented an acute leak after LSG. The leak was treated with metal stent deployment with temporary closure. After 6 months, he presented leak recurrence with general sepsis, perigastric-infected collection, and gastro-jejunal fistula. RESULTS: Endoscopic internal drainage (EID) was performed; however, due to fistula persistence, a surgical procedure was proposed. The patient refused revisional surgery; therefore, endoscopic salvage procedure was decided. A fully covered metal stent was deployed in order to bypass the perigastric collection creating an endoscopic gastro-jejunal anastomosis. CONCLUSION: Revisional surgery is the gold standard treatment for chronic fistula after SG. Endoscopic treatment with SEMS deployment may be a sound option in selected cases especially after failure of other endoscopic techniques or refusal of revisional surgery. PMID- 29524186 TI - Want Change Not Coins. PMID- 29524187 TI - Factors That Influence Pancreatic Beta Cell Function and Insulin Resistance in Newly Diagnosed Type 2 Diabetes Patients: A Sub-Analysis of the MARCH Trial. AB - INTRODUCTION: The Metformin and Acarbose in Chinese as the initial Hypoglycemic treatment (MARCH) trial has demonstrated a similar efficacy in HbA1c reduction between acarbose and metformin treatments in newly diagnosed type 2 diabetes mellitus (T2DM) patients. The current sub-analysis of the MARCH trail aims to evaluate the baseline characteristics that may influence the improvement of pancreatic beta-cell function and insulin resistance after acarbose therapy in Chinese patients with newly diagnosed T2DM. METHODS: Of the 784 patients who entered the MARCH trail, 391 were assigned to the acarbose therapy group; 304 of these completed 48 weeks of follow-up of acarbose therapy. At 48 weeks, on the basis of the tertiles of change in homeostasis model assessment-beta cell function (?HOMA-beta) and homeostasis model assessment-insulin resistance (?HOMA IR), the subjects were divided into lowly, mediumly, and highly improved groups. RESULTS: In the highly improved HOMA-beta group, patients had higher systolic blood pressure (SBP), 2-h postprandial blood glucose (PBG), hemoglobin A1c (HbA1c), and lower high-density lipoprotein cholesterol (HDL-c), fasting serum insulin (FINS) concentration, and HOMA-IR in comparison to the lowly improved group (p < 0.05). A positive correlation was observed between HbA1c, SBP, and highly improved ?HOMA-beta (p < 0.05), while an inverse correlation was evident between HDL-c and highly improved ?HOMA-beta (p < 0.05). The highly improved HOMA IR group had a significantly higher body mass index (BMI), fasting blood glucose (FBG), FINS concentration, and HOMA-beta in comparison to the lowly improved group (p < 0.05). A positive correlation was observed between FBG, waist circumference, and highly improved HOMA-IR (p < 0.05). CONCLUSION: Newly diagnosed T2DM Chinese patients with lower baseline HDL-c and higher HbA1c and SBP values are more likely to achieve improvement in beta cell function whereas baseline fasting blood glucose and waist circumference were the significant factors associated with improvement in insulin resistance with acarbose therapy. TRIAL REGISTRATION: The clinical trial registry number was ChiCTR-TRC-08000231. PMID- 29524188 TI - Adverse Drug Events Associated with Low-Dose (10 mg) Versus High-Dose (25 mg) Empagliflozin in Patients Treated for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Empagliflozin is a new, emerging oral hypoglycemic agent (OHA) which has shown significant benefits in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease. In this analysis, our aim was to systematically compare the adverse drug events (ADEs) associated with a low (10 mg) versus a high (25 mg) dose of empagliflozin as (1) monotherapy, (2) as an add-on to other OHAs, and (3) as an add-on specifically to metformin, in patients who were treated for T2DM. METHODS: This was a systematic review and meta-analysis of randomized controlled trials that compared empagliflozin 10 mg versus 25 mg in patients who were treated for T2DM and which reported adverse drug reactions as their clinical endpoints. Statistical analysis was carried out using the latest version of the RevMan software (ver. 5.3) whereby odds ratios (OR) and 95% confidence intervals (CI) were generated. RESULTS: Eight trials with a total number of 8514 patients treated for T2DM were included in this meta-analysis and systematic review, of whom 4261 patients received 10 mg empagliflozin and 4253 patients received 25 mg empagliflozin. Our results showed that there were no significant differences between the patients with T2DM receiving 10 empagliflozin and those receiving 25 mg empagliflozin in terms of drug-related adverse effects (OR 1.06, 95% CI 0.93-1.21; P = 0.40, I2 = 0%), adverse events leading to drug discontinuation (OR 0.99, 95% CI 0.86-1.14; P = 0.87, I2 = 0%), and serious adverse events (OR 1.06, 95% CI 0.95-1.18; P = 0.31, I2 = 0%) when empagliflozin was provided as monotherapy or as an add-on to other anti-diabetic medications. The same results were obtained when empagliflozin was used as an add-on to metformin or as monotherapy. The duration of the follow-up periods did not affect the results. However, the incidence of genital and urinary tract infections (UTIs) was significantly higher in female patients than in male patients with 10 or 25 mg empagliflozin. CONCLUSIONS: The incidence of ADEs was not significantly different in T2DM patients receiving 10 versus 25 mg empagliflozin as monotherapy or as add-on to metformin or other anti-diabetic drugs during a shorter or longer follow-up period. However, genital and UTIs were more common in female patients with T2DM irrespective of empagliflozin dosage. PMID- 29524189 TI - Perspectives of Patients with Insulin-Treated Type 1 and Type 2 Diabetes on Hypoglycemia: Results of the HAT Observational Study in Central and Eastern European Countries. AB - INTRODUCTION: The aim of this study was to determine the level of awareness of hypoglycemia, the level of fear for hypoglycemia, and the response to hypoglycemic events among insulin-treated diabetes patients from Central and Eastern Europe (CEE). The impact of hypoglycemia on the use of healthcare resources and patient productivity was also assessed. METHODS: This was a multicenter, non-interventional, two-part, patient self-reported questionnaire study that comprised both a retrospective cross-sectional evaluation and a prospective observational evaluation. Study participants were insulin-treated adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) from CEE. RESULTS: Most patients (85.4% T1DM and 83.6% T2DM) reported normal hypoglycemia awareness. The median hypoglycemia fear score was 5 out of 10 for T1DM and 4 out of 10 for T2DM patients. Patients increased glucose monitoring, consulted a doctor/nurse, and/or reduced the insulin dose in response to hypoglycemia. As a consequence of hypoglycemia, patients took leave from work/studies or arrived late and/or left early. Hospitalization was required for 31 (1.2%) patients with T1DM and 66 (2.1%) patients with T2DM. CONCLUSION: Hypoglycemia impacts patients' personal and social functioning, reduces productivity, and results in additional costs, both direct (related to increased use of healthcare resources) and indirect (related to absenteeism. FUNDING: Novo Nordisk. PMID- 29524190 TI - Insulin Glargine Combined with Oral Antidiabetic Drugs for Asians with Type 2 Diabetes Mellitus: A Pooled Analysis to Identify Predictors of Dose and Treatment Response. AB - INTRODUCTION: In Asia, patients with type 2 diabetes mellitus (T2DM) often have suboptimal glycemic control for many years prior to initiating basal insulin. Active titration of basal insulin is also required to improve glycemic outcomes. This pooled analysis was conducted to determine the impact of patient baseline covariates on the required dose of basal insulin and treatment response, for the improved management of Asian patients with T2DM. METHODS: Data on insulin-naive Asian patients with T2DM who initiated and fully titrated insulin glargine 100 U/mL (Gla-100) for >= 20 weeks were pooled from seven randomized, controlled, treat-to-target trials. Covariance and multivariate linear/logistic regression analyses were applied to determine the impact of the baseline covariates on Gla 100 dose (primary outcome) and treatment response (secondary outcomes) at week 24 for patients from Asia (N = 724) and from China alone (n = 249). Based on the multivariate analysis for the primary outcome in the Asian population, a nomogram was developed. RESULTS: The dose of Gla-100 at week 24 was negatively correlated with age and positively correlated with body mass index (BMI) and fasting plasma glucose (FPG) at baseline in both Asian and Chinese populations. In both populations, higher baseline glycated hemoglobin (HbA1c) was associated with a lower reduction in HbA1c from baseline, higher HbA1c at week 24, and a lower chance of achieving HbA1c < 7% at week 24. The constructed nomogram enables calculation of the likely dose of Gla-100 required by Asian patients with T2DM to achieve HbA1c < 7% at week 24. CONCLUSIONS: Higher doses of Gla-100 are likely to be required in younger patients or patients with higher baseline BMI or FPG. The nomogram developed in this study can aid clinicians to titrate the dose of Gla 100 appropriately. Evidence in this pooled analysis also indicates that initiating basal insulin at a lower HbA1c can lead to greater glycemic control. FUNDING: Sanofi China Investment Company. PMID- 29524191 TI - Pregnancy After Tubal Sterilization in a Woman Treated with Biologics for Severe Psoriasis. AB - Little is known about whether immunosuppressed patients mount the immunological response necessary to ensure tubal occlusion. Theoretical concern for non occlusion has limited the use of hysteroscopic sterilization in patients on immunosuppressive therapies. The effects of tumor necrosis factor-alpha (TNF alpha) blockers and interleukin (IL)-17 inhibitors on contraception and pregnancy for patients with psoriasis are poorly documented. We report a case of pregnancy that ended in miscarriage in a patient treated first with TNF-alpha and then with IL-17 inhibitors for severe psoriasis after tubal sterilization with micro inserts. Our observation suggests that the efficacy of tubal sterilization by micro-inserts may be impaired by these two biologics and that the risk of miscarriage may be increased in women with psoriasis treated with secukinumab. PMID- 29524192 TI - An Advanced Formulation of a Magnesium Dietary Supplement Adapted for a Long-Term Use Supplementation Improves Magnesium Bioavailability: In Vitro and Clinical Comparative Studies. AB - While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag(r), was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element). Magnesium release profile was determined by dissolving the tablets in solutions simulating the gastrointestinal tract environment. A randomized double-blind crossover controlled trial of ChronoMag(r) versus reference tablet (3 * 100 mg magnesium element tablets) in 12 normo-magnesemic healthy volunteers was conducted to evaluate the bioavailability of the patented magnesium chloride tablets (two 50 mg magnesium tablets, once-a-day intake). While the reference tablet released 100% of its magnesium within 1 h of dissolution, release from the magnesium chloride formulation was continuous for 6 h. Cumulative urinary magnesium levels compared to those with the reference tablet were 76% (0-5 h), 89% (0-10 h), and 87% (0-24 h). Elimination after 24 h was fairly similar with both supplements. Our results suggest that the new magnesium chloride formulation, providing continuous low-dose magnesium release throughout the gastrointestinal tract, improves absorption and bioavailability. This formulation conforms to the physiological mechanism of magnesium absorption throughout the digestive tract, allowing high absorption, and may improve gastrointestinal tolerance in long-term use. PMID- 29524193 TI - Effect of Dietary Zinc-Nanoparticles on Growth Performance, Anti-Oxidative and Immunological Status of Fish Reared Under Multiple Stressors. AB - Zinc is one of the essential micronutrients that can be obtained via water and diet in aquatic animals to meet their physiological needs. The present study was designed to understand the effect of the supplementation of zinc nanoparticles (Zn-NPs) in mitigating abiotic and biotic stress in Pangasius hypophthalmus. Two zinc nanoparticle-incorporated diets with 10 and 20 mg/kg nanoparticles and a control without zinc nanoparticles were formulated. To study the effect of formulated feeds on stress tolerance, fish were exposed to sublethal dose (4 ppm) of Pb (lead) and temperature at 34 degrees C. Two hundred and seventy-three fish were randomly distributed into seven treatment groups in triplicates, namely a control group (no Zn-NPs and no Pb and temperature exposure, Ctr/Ctr), control diet fed and exposed to Pb (Ctr/Pb), control diet fed and concurrently exposed to Pb and temperature (Pb-T/Ctr), and Zn-NPs 10 and 20 mg/kg diet with or without stressors (Zn-NPs 10 mg/kg, Zn-NPs 20 mg/kg, Pb-T/Zn-NPs 10 mg/kg, Pb-T/Zn-NPs 20 mg/kg). The effect of Zn-NPs on growth performance, stress biomarkers, biochemical and immunological responses, and survival of P. hypophthalmus following challenge with pathogenic bacteria were evaluated. The growth performance was noticeably (p < 0.01) enhanced, and anti-oxidative stress (catalase, superoxide dismutase, and glutathione-s-transferase) significantly reduced in the Zn-NPs supplemented groups. Similarly, immunological parameters such as total protein, albumin, globulin, and A/G ratio significantly improved, and stress biomarkers such as blood glucose, cortisol, and HSP 70 were reduced in Zn-NPs supplemented groups. Overall, the results suggest that supplementation of dietary Zn-NPs with less concentration in the diet has a definitive role in the mitigation of abiotic and biotic stress in P. hypophthalmus. PMID- 29524194 TI - Endogenous Hydrogen Sulfide Promotes Apoptosis via Mitochondrial Pathways in the Livers of Broilers with Selenium Deficiency Exudative Diathesis Disease. AB - Hydrogen sulfide (H2S), an endogenous gasotransmitter, plays an important role in apoptosis. Exudative diathesis (ED) disease is associated with dietary selenium (Se) deficiency in broilers. The liver is one of the target organs of Se deficiency; however, little is known about the effect of H2S on apoptosis via mitochondrial pathways in the livers of broilers with ED disease. In the present study, we aimed to investigate the correlation between endogenous H2S and mitochondrial-mediated apoptosis in the livers of broilers with ED disease, as induced by Se deficiency. One hundred twenty healthy, 1-day-old broilers were randomly assigned to one of two groups (60 each) based on diet: Basal diet (control group, 0.2 mg/kg Se) or a low-Se diet (-Se group, 0.033 mg/kg Se). At day 20, 15 broilers of a similar weight were sacrificed from the control group, while the same number of broilers were euthanatized from the -Se group when displaying typical symptoms of ED between days 18 and 25. The livers were collected, and apoptosis was measured using a TUNEL assay. Additionally, H2S concentration, the expression of H2S synthases of cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST), as well as mitochondrial apoptosis-related genes of Bcl-2, Bax, Bak, Cyt-C, Caspase-9, Caspase-3, and p53, were examined in livers. The results indicated that Se deficiency could induce apoptosis in the livers of broilers. Swelling, fractures, and vacuolization were visible in the mitochondrial cristae in the livers of the -Se group. The expression of H2S synthase-related genes and H2S concentration was significantly enhanced (P < 0.05) in the livers of the -Se group compared to controls. Moreover, a low-Se diet downregulated (P < 0.05) the level of Bcl-2 and upregulated (P < 0.05) the levels of Bax, Bak, Cyt-C, Caspase-9, Caspase-3, and p53. These results suggest that an H2S increase in the livers of ED broilers, which was induced by Se deficiency, is related to apoptosis mediated by mitochondrial pathways. PMID- 29524195 TI - Maternal Selenium Supplementation Enhanced Skeletal Muscle Development Through Increasing Protein Synthesis and SelW mRNA Levels of their Offspring. AB - The present study aimed to investigate the influence of maternal selenium supplementation on the skeletal muscle development of the offspring. A total of 720 Ross 308 broiler breeders at 24-week-old were allocated into 3 treatments with 6 replicates of 40 hens each and fed with 0 mg/kg-(group Se/C), 0.5 mg/kg organic-(group Se/O), and 0.5 mg/kg inorganic-(group Se/I) selenium, respectively for 8 weeks. The male offspring from each nutritional treatment were divided and housed into 8 cages of 12 birds each and fed with a commercial diet supplemented with selenium from Na2SeO3 at 0.15 mg/kg. Results showed that Se/O group had the highest selenium deposition (P < 0.05) in the egg yolk and albumen. Furthermore, maternal selenium supplementation promoted breast muscle yield; increased serum insulin and IGF-I concentration; upregulated AKT, mammalian target of rapamycin (mTOR), P70S6K, Myf5, MyoD, MyoG, and SelW mRNA levels; and improved the phosphorylation of AKT at Serine 473 residue, mTOR at Serine 2448 residue, and FOXO at Serine 256 residue in skeletal muscles of the offspring. In contrast, the hens' diet supplemented with selenium could result in reduction of uric acid level in serum and downregulation of Atrogin-1 and MuRF1 mRNA levels in the skeletal muscle of the offspring. Additionally, no significant effect on the skeletal muscle development post-hatch was observed between organic and inorganic selenium supplementation. In conclusion, maternal organic selenium supplementation improved selenium deposition in egg; however, no significant effect has been detected on the breast muscle development of the offspring of broiler breeder compared with inorganic selenium supplementation. PMID- 29524196 TI - Vanadium in Biosphere and Its Role in Biological Processes. AB - Ultra-trace elements or occasionally beneficial elements (OBE) are the new categories of minerals including vanadium (V). The importance of V is attributed due to its multifaceted biological roles, i.e., glucose and lipid metabolism as an insulin-mimetic, antilipemic and a potent stress alleviating agent in diabetes when vanadium is administered at lower doses. It competes with iron for transferrin (binding site for transportation) and with lactoferrin as it is secreted in milk also. The intracellular enzyme protein tyrosine phosphatase, causing the dephosphorylation at beta subunit of the insulin receptor, is inhibited by vanadium, thus facilitating the uptake of glucose inside the cell but only in the presence of insulin. Vanadium could be useful as a potential immune-stimulating agent and also as an antiinflammatory therapeutic metallodrug targeting various diseases. Physiological state and dose of vanadium compounds hold importance in causing toxicity also. Research has been carried out mostly on laboratory animals but evidence for vanadium importance as a therapeutic agent are available in humans and large animals also. This review examines the potential biochemical and molecular role, possible kinetics and distribution, essentiality, immunity, and toxicity-related study of vanadium in a biological system. PMID- 29524197 TI - Erratum to: Oxygen Transport to Tissue XXXV. PMID- 29524198 TI - Molecular Characterization of Pneumococcal Surface Protein A (PspA), Serotype Distribution and Antibiotic Susceptibility of Streptococcus pneumoniae Strains Isolated from Pakistan. AB - INTRODUCTION: Pakistan has one of the highest burdens of pneumococcal diseases in the world, but unfortunately studies in this demanding research area are limited in the region. Pneumococcal surface protein A (PspA) is the next generation pneumococcal vaccine candidate as the protein locates on the Streptococcus pneumoniae surface. Its gene, pspA, might be encoded by all pneumococci, and the protein has proven immunogenicity. The molecular characterization of PspA, pneumococcal serotype distribution and antibiotic susceptibility are important for regional diversity studies. METHODS: In this study, we examined 38 pneumococcal isolates from pneumococcal diseased (pneumonia/meningitis) patients blood or cerebrospinal fluid. There were no specific inclusion or exclusion criteria, but all the individuals [ages 1 month to 12 years (male/female)] had undergone no antibiotic treatment in at least the past 3 months and had no vaccination history. We investigated the serotype distribution, antibiotic susceptibility, prevalence of the PspA family and its active domain's fusion, expression and antigenicity. RESULTS: Our finding shows that serotype 19F is the most prevalent (23.6%) followed by 18B (15.78%) (non-vaccine type) in all isolated pneumococcal strains. All strains were susceptible to chloramphenicol and linezolid, while 80% were resistant to gentamycin. Genotyping revealed that ~ 80% (N = 31/38) of pneumococcal strains produce PspA belonging to family 2 and clade 3. We further selected three active domains of PspA (family 2 and clade 3) by in silico analysis, merged together into a fusion gene for expression study, and its antigenicity was analyzed by Western blotting. CONCLUSION: Serotypes 19F and 18B (non-vaccine type) are the most prevalent in the Pakistani pneumococcal isolates. The PspA family 2 proteins produced by Pakistani pneumococcal isolates have high sequence homologies with each other and differ from those produced by strains isolated in the rest of the world. The PspA fusion peptide had a proven antigenic response in western blotting, with no considerable correlation among pneumococcal serotypes, antibiotic susceptibility and PspA family/clade distribution. PMID- 29524199 TI - Self-pressurized air-Q(r) intubating laryngeal airway versus the LMA(r) ClassicTM: a randomized clinical trial. AB - PURPOSE: The self-pressurized air-Q(r) (air-Q SP) intubating laryngeal airway is a relatively new supraglottic airway (SGA) device. The intracuff pressure of air Q dynamically equilibrates with the airway pressure and adjusts to the patient's pharyngeal and periglottic anatomy, potentially providing improved airway fit and seal. The aim of this prospective randomized study was to compare the clinical performance of air-Q to the LMA(r) ClassicTM SGA. METHODS: Adult patients requiring general anesthesia for elective surgery were prospectively enrolled and randomly assigned to either air-Q SP or the LMA Classic SGA. Oropharyngeal leak pressure (primary endpoint), success rate, insertion features (insertion time, ease of insertion, requirement for device manipulation), sealing function, gastric insufflation, bronchoscopic view, and oropharyngeal complications at device insertion and following its removal (sore throat, dysphagia, dysphonia) were compared. RESULTS: The mean (standard deviation [SD]) oropharyngeal leak pressure just after insertion was similar in the air-Q SP and LMA [16.8 (4.9) vs 18.6 (5.5) cm H2O, respectively; mean difference, 1.8 cm H2O; 95% CI, -0.5 to 4.2; P = 0.13] and did not differ at ten minutes following device insertion. Median [interquartile range (IQR)] peak inspiratory pressure just after insertion was lower in the air-Q SP (11.0 [10.0-13.0] vs 13.0 [11.0-14.0] cmH2O, median difference, 1.0 cm H2O; 95% CI, 0.0 to 2.0; P = 0.03) but no difference was observed at ten minutes. The median [IQR] insertion time was faster with the air Q SP (15.9 [13.6-20.3] sec vs 24 [21.2-27.1] sec; median difference, 8.1 sec; 95% CI, 5.6 to 9.9; P < 0.001) and improved bronchoscopic viewing grade were seen with the air-Q SP immediately after insertion (P < 0.001). No differences between the groups were observed with respect to the rate of successful insertion at first attempt, overall insertion success rate, ease of insertion, and complications. CONCLUSIONS: The air-Q SP had similar leak pressures but a faster insertion time and superior bronchoscopic viewing grade when compared with the LMA Classic. The air-Q SP is a suitable alternative to the LMA Classic in adult patients and may be a superior conduit for tracheal intubation. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02206438). Registered 1 August 2014. PMID- 29524200 TI - Prevalence of discordant elevations of state entropy and bispectral index in patients at amnestic sevoflurane concentrations: a historical cohort study. AB - BACKGROUND: Processed electroencephalogram (EEG) monitors help assess the hypnotic state during general anesthesia or sedation. Maintaining the bispectral index (BIS) or state entropy (SE) between 40 and 60 has been recommended to mitigate anesthesia awareness. Nonetheless, SEs > 70 were frequently observed at end-tidal sevoflurane concentrations unlikely to allow awareness. We sought to determine the prevalence of elevated discordant measurements during BIS and SE monitoring. METHODS: Electronic data collected over 11 months at two academic hospitals were retrospectively reviewed. At the hospital using SE, all cases were included with patients >= 18 yr and sevoflurane administered for at least 30 min during surgery. A cohort of cases propensity matched by age and American Society of Anesthesiologist Physical Status were selected from the hospital using BIS. Elevated discordant EEG indices were defined as values > 70 occurring during stable end-tidal sevoflurane concentrations > 1.5%. The odds ratio (OR) based on the probability of a case having at least one elevated discordant SE or BIS lasting >= two minutes (primary endpoint) was calculated. RESULTS: At each hospital, 3,690 cases were studied. The mean (95% confidence interval [CI]) incidence of cases with at least one interval of an elevated discordant EEG index lasting at least two minutes was 3.6% (2.8% to 4.4%) for SE compared with 0.24% (0.17% to 0.27%) for BIS (pooled OR, 17.0; 95% CI, 8.3 to 34.7; P < 0.001). CONCLUSIONS: The prevalence of an elevated discordant EEG index is much greater with SE than with BIS. Elevated index values occurring at anesthetic concentrations well above the awareness threshold need to be assessed to determine if they indicate an inadequate depth of anesthesia requiring treatment or if they simply reflect the underlying monitoring algorithm. PMID- 29524202 TI - A Case Report of Conservative Management for a Roller-Coaster-Related Vitreous Haemorrhage. AB - The purpose of this report is to describe the case and management of an unexplained vitreous haemorrhage that occurred after repeated roller-coaster riding. The authors inadvertently demonstrate the value of observation over immediate surgery in certain situations and review the literature on vitreoretinal and other ocular complications after roller-coaster riding. A 26 year-old male presented 12 h after riding high-velocity roller-coasters with a left vitreous haemorrhage. A hazy view of the retina and B-scan revealed a bullous area of superior-temporal retinal lifting. A diagnosis of a presumed macula-on retinal detachment was made and the patient was listed for a pars plana vitrectomy retinal detachment repair. An abnormal clotting result, which was subsequently found out to be erroneous, ultimately delayed the procedure. During this delay the vision and retinal view improved to an extent whereby the diagnosis of a retinoschisis with an intraretinal cyst was made and surgery was avoided. The patient regained 6/6 vision, without the need to undergo surgery. Historically the management of an unexplained vitreous haemorrhage was observation with serial B-scans. The current evidence and practice for treating unexplained vitreous haemorrhage have since moved towards early surgical intervention. The authors highlight that despite the current trend, a place remains for conservative management for selected cases. PMID- 29524203 TI - Cognitive and Behavioural Outcomes of Paediatric Liver Transplantation for Ornithine Transcarbamylase Deficiency. AB - Ornithine Trans-Carbamylase (OTC) deficiency is the most common disorder of the urea cycle. Cognitive impairments in skills such as attention and executive function have been reported in individuals with OTC deficiency who are managed with medication. In some cases, children undergo liver transplantation (LTx) to correct the metabolic defect. The metabolic and medical outcomes of LTx are generally good. However, little is known about the impacts on cognition. In this study, four children (three female) completed detailed neuropsychological batteries prior to (n = 6) and following LTx (n = 8 assessments). Children's age at assessment ranged from 3 to 11 years. The battery included standardised, age referenced measures of intellectual ability (IQ), attention, memory and educational ability. Additionally, parent measures of behaviour and executive function were administered. Generally, there was little change in overall IQ following LTx. Memory and academic skills were at expected levels for the three female patients and gains were made after LTx. Children showed ongoing impairments in attention and parent rated executive function. In conclusion, the immediate effect of LTx on cognition may not appear beneficial in the short-term and impairments in IQ, attention and behaviour persisted after the procedure. However, LTx seems to enable stabilisation to premorbid function in the longer term. PMID- 29524201 TI - A Dominant Negative Antisense Approach Targeting beta-Catenin. AB - There have been many attempts to unveil the therapeutic potential of antisense molecules during the last decade. Due to its specific role in canonical Wnt signalling, beta-catenin is a potential target for an antisense-based antitumour therapy. In order to establish such a strategy with peptide nucleic acids, we developed a reporter assay for quantification of antisense effects. The luciferase-based assay detects splice blocking with high sensitivity. Using this assay, we show that the splice donor of exon 13 of beta-catenin is particularly suitable for an antisense strategy, as it results in a truncated protein which lacks transactivating functions. Since the truncated proteins retain the interactions with Tcf/Lef proteins, they act in a dominant negative fashion competing with wild-type proteins and thus blocking the transcriptional activity of beta-catenin. Furthermore, we show that the truncation does not interfere with binding of cadherin and alpha-catenin, both essential for its function in cell adhesion. Therefore, the antisense strategy blocks Wnt signalling with high efficiency but retains other important functions of beta-catenin. PMID- 29524204 TI - Author's reply to: Cancer screening policy in Hungary. PMID- 29524206 TI - Clinical evaluation of human papillomavirus 16/18 oncoprotein test for cervical cancer screening and HPV positive women triage. AB - HPV-16 and -18 account for about 80% of cervical cancers. We evaluated the performance of HPV-16/18 oncoprotein to predict precancer and cancer in corresponding tissue biopsy specimens. 1,008 women attending cervical cancer screening program and 638 women referred to colposcopy with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from 4 hospitals were recruited (1,646 in total). All women were tested OncoE6 (AVC), Liquid-Based Cytology (Hologic) and cobas HPV test (Roche). Colposcopy was performed on women with any abnormal results. The final diagnoses were based on a consensus panel review of the histology. There were 919 normal, 69 CIN1, 53 CIN2, 91 CIN3,474 squamous cell carcinoma(SCC) and 40 adenocarcinoma (ADC) cases, the prevalence of OncoE6 was 1.7%, 10.1%, 13.2%, 44.0%, 80.4% and 65.0%, respectively. The percent positive for cobas was higher than that of OncoE6 in detection of HPV16/18 in entire population (p < 0.001). However, the disparity of positive rate between these two tests became tiny among cervical cancer patients (CIN2: 26.4% vs. 13.2%, CIN3: 73.6% vs. 44.0%, SCC: 84.0% vs. 80.4%, ADC: 67.5% vs. 65.0%). OncoE6 was less sensitive than cobas (73.9% vs. 93.6%, p < 0.001), but more specific (97.1% vs. 75.4%, p < 0.001) for CIN3+ in entire population; OncoE6 yielded a sensitivity of 77.7% and a specificity of 91.0% for CIN3+ among cobas positive women, which can reduce nearly half of the colposcopy referral numbers. OncoE6 can be considered as a useful tool for cervical cancer screening and a potential powerful biomarker for HPV positive triage. PMID- 29524205 TI - Organization of afferents to the orbitofrontal cortex in the rat. AB - The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas. PMID- 29524207 TI - MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women. AB - Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI density and serum hormone concentrations in postmenopausal women. This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N = 118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density. Compared to women with "minimal" BPE, those who had "marked" BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, ptrend across all categories = 0.001; 150% increase, ptrend = 0.001; and 158% increase, ptrend = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast. PMID- 29524208 TI - Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. AB - Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the ApcMin/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the ApcMin/+ /DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP-PKA-CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis. PMID- 29524210 TI - (Meth)acrylate allergy: frequently missed? PMID- 29524211 TI - Cancer screening policy in Hungary. PMID- 29524209 TI - Morphology of the utricular otolith organ in the toadfish, Opsanus tau. AB - The utricle provides the vestibular reflex pathways with the sensory codes of inertial acceleration of self-motion and head orientation with respect to gravity to control balance and equilibrium. Here we present an anatomical description of this structure in the adult oyster toadfish and establish a morphological basis for interpretation of subsequent functional studies. Light, scanning, and transmission electron microscopy techniques were applied to visualize the sensory epithelium at varying levels of detail, its neural innervation and its synaptic organization. Scanning electron microscopy was used to visualize otolith mass and morphological polarization patterns of hair cells. Afferent nerve fibers were visualized following labeling with biocytin, and light microscope images were used to make three-dimensional (3-D) reconstructions of individual labeled afferents to identify dendritic morphology with respect to epithelial location. Transmission electron micrographs were compiled to create a serial 3-D reconstruction of a labeled afferent over a segment of its dendritic field and to examine the cell-afferent synaptic contacts. Major observations are: a well defined striola, medial and lateral extra-striolar regions with a zonal organization of hair bundles; prominent lacinia projecting laterally; dependence of hair cell density on macular location; narrow afferent dendritic fields that follow the hair bundle polarization; synaptic specializations issued by afferents are typically directed towards a limited number of 7-13 hair cells, but larger dendritic fields in the medial extra-striola can be associated with > 20 hair cells also; and hair cell synaptic bodies can be confined to only an individual afferent or can synapse upon several afferents. PMID- 29524212 TI - One-Step and Nondestructive Reduction of Cr(VI) in Pork by High-Energy Electron Beam Irradiation. AB - : Because of the wide use of chromium-containing feed, much hexavalent chromium (Cr(VI)) tends to accumulate in pork. In order to decrease the toxicity of Cr(VI) containing pork for human beings, high-energy electron beam (HEEB) irradiation was used to reduce highly toxic Cr(VI) to low toxic trivalent chromium (Cr(III)) in lean, fat, and marbled pork. HEEB irradiation could efficiently and nondestructively reduce both free and adsorbed Cr(VI) in pork, achieving the highest reductive efficiency (RE) of 98.03%. Therein, hydrated electrons (eaq- ) and hydrogen radical (*H) generated during the irradiation process probably played key roles in the reduction. The effects of irradiation dose, initial concentration of Cr(VI), pH, temperature, salinity, and oil on the RE were investigated to obtain the optimal reduction conditions, proving the high universality of this approach. This work provides a clean and low-cost method for removing Cr(VI) from pork, which is important to ensure food safety. PRACTICAL APPLICATION: This work describes a facile, nondestructive, and clean method for removing Cr(VI) from meat product, which may have a potential application prospect in ensuring food quality and safety. PMID- 29524213 TI - Origin and Processing Methods Slightly Affect Allergenic Characteristics of Cashew Nuts (Anacardium occidentale). AB - The protein content and allergen composition was studied of cashews from 8 different origins (Benin, Brazil, Ghana, India, Ivory Coast, Mozambique, Tanzania, Vietnam), subjected to different in-shell heat treatments (steamed, fried, drum-roasted). On 2D electrophoresis, 9 isoforms of Ana o 1, 29 isoforms of Ana o 2 (11 of the acidic subunit, 18 of the basic subunit), and 8 isoforms of the large subunit of Ana o 3 were tentatively identified. Based on 1D and 2D electrophoresis, no difference in allergen content (Ana o 1, 2, 3) was detected between the cashews of different origins (P > 0.5), some small but significant differences were detected in allergen solubility between differently heated cashews. No major differences in N- and C-terminal microheterogeneity of Ana o 3 were detected between cashews of different origins. Between the different heat treatments, no difference was detected in glycation, pepsin digestibility, or IgE binding of the cashew proteins. PMID- 29524214 TI - Localization of nectin-2alpha at the boundary between the adjacent somata of the clustered cholinergic neurons and its regulatory role in the subcellular localization of the voltage-gated A-type K+ channel Kv4.2 in the medial habenula. AB - The medial habenula (MHb), implicated in stress, depression, memory, and nicotine withdrawal syndromes, receives septal inputs and sends efferents to the interpeduncular nucleus. We previously showed that the immunoglobulin-like cell adhesion molecules (CAMs) nectin-2alpha and nectin-2delta are expressed in astrocytes in the brain, but their expression in neurons remains unknown. We showed here by immunofluorescence microscopy that nectin-2alpha, but not nectin 2delta, was prominently expressed in the cholinergic neurons in the developing and adult MHbs and localized at the boundary between the adjacent somata of the clustered cholinergic neurons where the voltage-gated A-type K+ channel Kv4.2 was localized. Analysis by immunoelectron microscopy on this boundary revealed that Kv4.2 was localized at the membrane specializations (MSs) with plasma membrane darkening in an asymmetrical manner, whereas nectin-2alpha was localized on the apposed plasma membranes mostly at the outside of these MSs, but occasionally localized at their edges and insides. Nectin-2alpha at this boundary was not colocalized with the nectin-2alpha-binding protein afadin, other CAMs, or their interacting peripheral membrane proteins, suggesting that nectin-2alpha forms a cell adhesion apparatus different from the Kv4.2-associated MSs. Genetic ablation of nectin-2 delayed the localization of Kv4.2 at the boundary between the adjacent somata of the clustered cholinergic neurons in the developing MHb. These results revealed the unique localization of nectin-2alpha and its regulatory role in the localization of Kv4.2 at the MSs in the MHb. PMID- 29524215 TI - Associations between statin use and risk of non-Hodgkin lymphomas by subtype. AB - Non-Hodgkin lymphomas (NHL) are a group of cancers with highly heterogeneous biology and clinical features. Statins are increasingly prescribed to prevent cardiovascular diseases. Early evidence shows a preventive effect of statins for some cancers, but their effect on NHL risk is unclear. We conducted a population based nested case-control study involving 5,541 NHL cases and 27,315 controls matched for gender, age, place of residence and length of period of available prescription drug data. We assessed the use of statins prior to diagnosis (excluding the 12 months prior to the index date). We used conditional logistic regression models to estimate odds ratio (OR) and 95% confidence interval (CI) for use of any statin, adjusting for medical conditions, number of family physician visits for 5 years prior to index date, healthcare utilization, income and use of other medications. Over one-quarter of cases and controls were prescribed statins. Ever-use of any statin was associated with lower risk of Total NHL (OR = 0.82, 95% CI 0.76-0.89) and of certain subtypes including diffuse large B-cell lymphomas (DLBCL, OR = 0.77, 95% CI 0.65-0.92), plasma cell neoplasms (PCN, OR = 0.76, 95% CI 0.63-0.91) and other B-cell NHL (0.75, 0.59 0.95). Analysis by statin type suggested that the association was limited to high potency statin and lipophilic statin users. No clear duration or dose-response relationships were observed. Our findings provide evidence that statin use can reduce the risk of DLBCL and plasma cell lymphomas, but not other NHL types. Further studies are warranted to verify these associations and to examine the biological mechanisms. PMID- 29524216 TI - Recombinase Polymerase Amplification Combined with Lateral Flow Strip for Listeria monocytogenes Detection in Food. AB - : Listeria monocytogenes is an important food-borne pathogenic bacterium that causes human disease, resulting in economic losses worldwide. The current detection methods for L. monocytogenes are not well suited for direct field testing because they involve complicated, time-consuming operations. A simple, efficient method is vital for L. monocytogenes detection. In this study, we combined isothermal recombinase polymerase amplification (RPA) with a lateral flow (LF) strip to rapidly and reliably detect L. monocytogenes. In the presence of biotin- and digoxin-modified primers, RPA produced numerous digoxin- and biotin-attached duplex DNA products. These products were detected on an LF strip via dual immunoreactions (digoxin on the duplex DNA reacted with the anti-digoxin antibody on the gold nanoparticle (Au-NP) and the biotin on the duplex DNA captured by the streptavidin on the LF test zone). The accumulation of Au-NPs produced characteristic bands, enabling the visual detection of L. monocytogenes without instrumentation. This assay could be used to detect L. monocytogenes within 15 min, including DNA amplification with RPA for 10 min at 39 degrees C and visualization of the amplicons by LF strips for 5 min. Experiments confirmed a detection limit as low as 300 fg of DNA and 1.5 * 101 CFU in pure cultures. Furthermore, RPA-LF exhibited no cross-reactions with pathogens. Evaluation of the method with food samples indicated that the detection limit was substantially improved to 1.5 * 10 degrees CFU for the original bacterial content in 25 g/mL samples after enrichment for 6 hr. RPA-LF can be used as a sensitive and rapid detection technique for L. monocytogenes. PRACTICAL APPLICATION: Recombinase polymerase amplification (RPA) can amplify target DNA at 37 to 42 degrees C without a thermal cycler. Lateral flow (LF) strips are portable, cheap and easy to operate. RPA combined with LF strips to detect Listeria monocytogenes can be widely used in remote areas. PMID- 29524217 TI - Comment on Amezquita et al. (2017) "Conspicuousness, color resemblance, and toxicity in geographically diverging mimicry: The pan-Amazonian frog Allobates femoralis". AB - Amezquita et al. (2017) recently concluded that species of the Allobates femoralis group are toxic to mice at levels equivalent to syntopic alkaloid containing poison frogs, which they attributed to the presence of alkaloids in skin secretions. However, the chemical composition of skin secretions was not analyzed, and here we present additional data supporting the absence of alkaloids in skin secretions of the Allobates femoralis group. Instead, we suggest the observed toxicity was caused by the anesthetic benzocaine, which was applied to the buccal cavity to euthanize frogs prior to skin removal. We show that orally administered benzocaine is rapidly incorporated into the skin of species that sequester and do not sequester alkaloids, which casts doubt on the conclusion that Allobates femoralis group skin secretions are toxic and makes the results of experiments with alkaloid-containing species of Adelphobates and Ameerega uninterpretable. To prevent experimental errors and misinterpretations in studies of amphibian chemical defense, we encourage researchers to test the chemical composition of samples prior to experimentation, include all necessary controls to detect false positives, conduct small pilot studies for new methods, and consider the limitations of particular methods and their ability to address the intended research questions. PMID- 29524218 TI - Effects of Hydrogen-Donating or Metal-Chelating Antioxidants on the Oxidative Stability of Organogels Made of Beeswax and Grapeseed Oil Exposed to Light Irradiation. AB - : To enhance the oxidative stability of organogels made from grapeseed oil, the antioxidant effects of sesamol, alpha-tocopherol, beta-carotene, ethylenediaminetetraacetic acid (EDTA), and citric acid were determined in beeswax-based organogels stored under light or in the dark conditions at 25 degrees C. Without the addition of antioxidants, the organogels rapidly oxidized under light irradiation but not during storage in the dark. Sesamol showed the highest antioxidant activity at concentrations of 10 to 40 ppm, whereas the other compounds exhibited no antioxidant activity at 10 ppm. alpha-Tocopherol and beta carotene improved the oxidative stability of organogels at concentrations above 40 and 100 ppm, respectively. The addition of sesamol yielded better oxidative stability than the addition of EDTA or a mixture of sesamol and citric acid. Sesamol can improve the oxidative stability of organogels, which could lead to economic benefits for the food industry. PRACTICAL APPLICATION: Recently, interest in organogels has increased due to their properties of maintaining a solid state at room temperature and composition of trans-free and highly unsaturated fatty acids. However, the addition of antioxidants is necessary due to the high degree of unsaturation in organogels. The results of this study showed that the addition of sesamol significantly enhanced the oxidative stability of organogels under light irradiation. Therefore, the use of sesamol supplemented organogels could prolong the shelf-life of bakery or meat food products. PMID- 29524219 TI - Whole Tibetan Hull-Less Barley Exhibit Stronger Effect on Promoting Growth of Genus Bifidobacterium than Refined Barley In Vitro. AB - : The gut microbiota has recently become a new route for research at the intersection of diet and human health. The aim of this study was to investigate whether whole Tibetan hull-less barley (WHB) and refined Tibetan hull-less barley (RHB) caused differentiation of the fecal microbiota in vitro. The microbiota accessible ingredients in the 2 barley samples were studied using an in vitro enzymatic digestion procedure. After in vitro digestion, insoluble dietary fiber, phenolic compounds, proteins, and beta-glucans were 93.2%, 103.4%. 18.8%, and 10.2% higher provided by WHB flour as compared with RHB flour based on the same mass amount. However, due to the significantly higher content of insoluble dietary fiber, WHB digesta had lower percentage contents of fast fermentable substrates including dietary fiber and starch as compared with RHB digesta. The results of Next-generation sequencing of the bacterial 16SrRNA gene showed that both WHB and RHB fermentation had significantly promoted the growth of Bifidobacterium and inhibited the growth of pathogenic bacteria such as Dorea, Escherichia, Oscillopira, and Ruminococcus. Moreover, in response to WHB fermentation, the relative abundance of Bifidobacterium increased by 78.5% and 92.8% as compared with RHB and fructo-oligosaccharides (FOs). Both WHB and RHB are good sources of fermentable dietary fiber with the ability to yield high concentration of short chain fatty acids (SCFAs) as compared to FOs. However, the higher fraction of soluble fiber in RHB digesta increase higher amounts of SCFA compared with WHB digesta. Our findings shed light on the complex interactions of whole cereals with gut microbiota and the possible impact on host health. PRACTICAL APPLICATION: Until now, only few reports have regarded the impact of in vitro digestion in components of whole grain with complex food matrix. Moreover, our findings shed light on the complex interactions of whole cereals with gut microbiota and the possible impact on host health. PMID- 29524220 TI - Erythromelalgia: improvement in pain with transcranial magnetic stimulation. PMID- 29524221 TI - Postharvest Ultrasound-Assisted Freeze-Thaw Pretreatment Improves the Drying Efficiency, Physicochemical Properties, and Macamide Biosynthesis of Maca (Lepidium meyenii). AB - A novel technique of ultrasound-assisted freeze-thaw pretreatment (UFP) was developed to improve the drying efficiency of maca and bioactive amide synthesis in maca. The optimal UFP conditions are ultrasonic processing 90 min at 30 degrees C with 6 freeze-thaw cycles. Samples with freeze-thaw pretreatment (FP), ultrasound pretreatment (UP), and UFP were prepared for further comparative study. A no pretreatment (NP) sample was included as a control. The results showed that UFP improved the drying efficiency of maca slices, showing the highest effective moisture diffusivity (1.75 * 10-9 m2 /s). This result was further supported by low-field nuclear magnetic resonance (LF-NMR) analysis and scanning electron microscopy (SEM). The rehydration capacity and protein content of maca slices were improved by UFP. More importantly, contents of bioactive macamides and their biosynthetic precursors were increased in 2.5- and 10-fold, respectively. In conclusion, UFP is an efficient technique to improve drying efficiency, physicochemical properties, and bioactive macamides of maca, which can be applied in the industrial manufacture of maca products. PMID- 29524222 TI - Composition and Physicochemical Characterization of Fiber-Rich Food Processing Byproducts. AB - : A wide range of fiber-rich food processing byproducts from various sources have been proposed as value-added ingredients for producing healthier food products. Characterizing their composition and physicochemical properties is crucial to understand their potential uses. Eight fiber-rich byproducts from different sources were fractionated into 2 different particle-size ranges. Different (P <= 0.05) proximate composition and physicochemical properties (pasting properties, water-binding capacity, and oil-binding capacity) were exhibited by them. These properties enabled hierarchical cluster analysis and principal component analysis to group the byproducts into 3 different clusters by functionality and from this, assigned ingredients in each cluster to a potential end-uses. Some end use examples include, as a source of fat, protein, sugar, and insoluble fiber; and for uses as a thickening agent, water-binder, emulsion-enhancer, and fat-binder. PRACTICAL APPLICATION: The data presented in this study can be used by food manufacturers and product developers as the basis for choosing fiber-rich byproducts for specific applications and assist them in developing specific formulation and processing strategies. This characterization will reduce the time for development of fiber-rich foods, increasing industrial uses of byproducts, and decreasing food waste. PMID- 29524223 TI - NCR+ ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice. AB - Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features. We observed that NCR+ ILC3 exhibited high basal expression of the signal dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-gamma, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL 23 signaling in ILC3. PMID- 29524224 TI - Caveolin-1, cancer and therapy resistance. AB - Resistance of solid tumors to chemo- and radiotherapy remains a major obstacle in anti-cancer treatment. Herein, the membrane protein caveolin-1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma-mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance-promoting effects of CAV1 in tumors, and emphasize its role in the tumor-stroma communication as well as the resulting malignant phenotype of epithelial tumors. PMID- 29524225 TI - Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study. AB - Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In our study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake. PMID- 29524226 TI - Caspase-3 regulates the migration, invasion and metastasis of colon cancer cells. AB - Caspase-3 (CASP3) is a major mediator of apoptosis activated during cellular exposure to cytotoxic drugs, radiotherapy or immunotherapy. It is often used as a marker for efficacy of cancer therapy. However, recent reports indicate that caspase-3 has also non-apoptotic roles such as promotion of tumor relapse and tumor angiogenesis. Therefore, the roles of caspase-3 in tumor progression remain to be defined clearly. In our study, we established caspase-3 knockout (KO) colon cancer cell lines by use of the CRISPR technology. In vitro, caspase-3 knockout HCT116 cells were significantly less clonogenic in soft agar assays. They were also significantly less invasive and more sensitive to radiation and mitomycin C than control cells. In vivo, CASP3KO cells formed tumors at rates similar to control cells but were significantly more sensitive to radiotherapy. They were also less prone to pulmonary metastasis when inoculated either subcutaneously or intravenously. At the mechanistic level, caspase-3 gene knockout appeared to cause reduced EMT phenotypes when compared to parental HCT116 cells. Indeed, they showed significantly increased E-cadherin expression, reduced N-cadherin, Snail, Slug and ZEB1 expression than control cells. Therefore, therapeutic targeting of caspase-3 may not only increase the sensitivity of cancer cell to chemotherapy and radiotherapy, but also inhibit cancer cell invasion and metastasis. PMID- 29524227 TI - Effect of Dipping and Vacuum Impregnation Coating Techniques with Alginate Based Coating on Physical Quality Parameters of Cantaloupe Melon. AB - : Edible coating based on sodium alginate solution was applied to fresh-cut cantaloupe melon by dipping and vacuum impregnation coating methods. One aim of this work is to produce more technical information concerning these conventional and novel coating processes. For this purpose, the effect of various coating parameters (dipping time, draining time, time length of the vacuum period, vacuum pressure, atmospheric restoration time) with several levels on physical quality parameters (percentage of weight gain, color, and texture) of noncoated and coated samples were determined in order to define adequate coating process parameters to achieve a successful coating application. Additionally, the effects of dipping and vacuum impregnation processes were compared. Both processes improved the firmness of the melon pieces. However, vacuum impregnation application had higher firmness and weight gain results, and had significant effect (P < 0.05) on color (lower luminosity, higher redness, yellowness, and chroma values). Experimental results affirm that vacuum impregnation method can be used successively to improve mechanical and structural properties of food products. PRACTICAL APPLICATION: Type of edible coating technique and the parameters used significantly affect the physical quality characteristics of coated food products. The work presented produced more technical information concerning dipping and vacuum impregnation coating techniques, along with evaluating the effects of various coating parameters with several levels. The results revealed that vacuum impregnation technique is a successful coating method; however the effects should be carefully assessed for each product. PMID- 29524228 TI - Antibiotics-induced modulation of large intestinal microbiota altered aromatic amino acid profile and expression of neurotransmitters in the hypothalamus of piglets. AB - The evidence of gut microbiota-mediated modulation of brain function has been widely recognized from studies using germ-free rodents or animals with oral antibiotic-induced microbiota depletion. Since the large intestine harbors greater numbers and more diverse of microbes than in the small intestine, large intestinal microbiota may play a crucial role in the modulation of brain function. In this study, a large intestinal microbiota-targeted strategy was used to investigate the impact of large intestinal microbiota on brain function. Twelve piglets (12.08 +/- 0.28 kg) fitted with a T-cannula at the distal ileum were fed a standard diet and randomly assigned to two groups (n = 6) for ileal infusion of either saline or antibiotics. After 25 days of infusion, ileal and fecal microbiota, serum amino acids and neurotransmitters, and hypothalamic transcriptomics were analyzed. While the antibiotic infusion did not change the proximal ileal microbial composition, it markedly altered the fecal microbial composition and increased aromatic amino acid (AAAs) metabolism (p < 0.05), suggesting the infusion specifically targeted large intestinal microbes. Concentrations of AAAs were likewise decreased in the blood and hypothalamus (p < 0.05) by antibiotic infusion. Antibiotic infusion further decreased concentrations of hypothalamic 5-hydroxytryptamine (5-HT) and dopamine, in line with AAAs being their precursors. An up-regulation in gene expressions of neurotransmitter transporters and synthetases was observed (q < 0.001). In conclusion, the distalileal-antibiotic infusion altered neurotransmitter expression in the porcine hypothalamus and this effect occurred simultaneously with changes in both the large intestinal microbiota, and AAAs in the large intestine, blood and hypothalamus. These findings indirectly indicate that large intestinal microbiota affects hypothalamic neurotransmitter expressions. Read the Editorial Highlight for this article on page 208. PMID- 29524229 TI - Corticofugal circuits: Communication lines from the cortex to the rest of the brain. AB - Pyramidal cells in cortical Layers 5 and 6 are the only cells in the cerebral cortex with axons that leave the cortex to influence the thalamus. Layer 6 cells provide modulatory feedback input to all thalamic nuclei. Layer 5 cells provide driving input to higher-order thalamic nuclei and do not innervate first-order nuclei, which get their driving inputs from subcortical sources. Higher-order nuclei innervated by Layer 5 cells thus seem to be involved with cortico-thalamo cortical communication. The Layer 5 axons branch to also target additional subcortical structures that mediate interactions with the external environment. These corticofugal pathways represent the only means by which the cortex influences the rest of the neuraxis and thus are essential for proper cortical function and species survival. Here we review current understanding of the corticofugal pathways from Layers 5 and 6 and speculate on their functional contributions to neural processing and behavior. PMID- 29524230 TI - Transfusion-transmitted malaria masquerading as sickle cell crisis with multisystem organ failure. AB - BACKGROUND: Fever accompanying vaso-occlusive crisis is a common presentation in patients with sickle cell disease (SCD) and carries a broad differential diagnosis. Here, we report a case of transfusion-transmitted malaria in a patient with SCD presenting with acute vaso-occlusive crisis and rapidly decompensating to multisystem organ failure (MSOF). CASE REPORT: An 18-year-old African American male with SCD was admitted after multiple days of fever and severe generalized body pain. He received monthly blood transfusions as stroke prophylaxis. A source of infection was not readily identified, but treatment was initiated with continuous intravenous fluids and empiric antibiotics. The patient developed acute renal failure, acute hypoxic respiratory failure, and shock. He underwent red blood cell (RBC) exchange transfusion followed by therapeutic plasma exchange and continuous veno-venous hemodialysis. A manual peripheral blood smear revealed intraerythrocytic inclusions suggestive of Plasmodium, and molecular studies confirmed Plasmodium falciparum infection. Intravenous artesunate was given daily for 1 week. A look-back investigation involving two hospitals, multiple blood suppliers, and state and federal public health departments identified the source of malaria as a unit of RBCs transfused 2 weeks prior to admission. CONCLUSIONS: Clinical suspicion for transfusion-related adverse events, including hemolytic transfusion reactions and transfusion-transmitted infections, should be high in typically and atypically immunocompromised patient populations (like SCD), especially those on chronic transfusion protocols. Manual blood smear review aids in the evaluation of patients with SCD presenting with severe vaso-occlusive crisis and MSOF and can alert clinicians to the need for initiating aggressive therapy like RBC exchange and artesunate therapy. PMID- 29524231 TI - Dynamics of neuroeffector coupling at cardiac sympathetic synapses. AB - KEY POINTS: The present study demonstrates, by in vitro and in vivo analyses, the novel concept that signal transmission between sympathetic neurons and the heart, underlying the physiological regulation of cardiac function, operates in a quasi synaptic fashion. This is a result of the direct coupling between neurotransmitter releasing sites and effector cardiomyocyte membranes. ABSTRACT: Cardiac sympathetic neurons (SNs) finely tune the rate and strength of heart contractions to match blood demand, both at rest and during acute stress, through the release of noradrenaline (NE). Junctional sites at the interface between the two cell types have been observed, although whether direct neurocardiac coupling has a role in heart physiology has not been clearly demonstrated to date. We investigated the dynamics of SN/cardiomyocyte intercellular signalling, both by fluorescence resonance energy transfer-based imaging of cAMP in co-cultures, as a readout of cardiac beta-adrenergic receptor activation, and in vivo, using optogenetics in transgenic mice with SN-specific expression of Channelrhodopsin 2. We demonstrate that SNs and cardiomyocytes interact at specific sites in the human and rodent heart, as well as in co-cultures. Accordingly, neuronal activation elicited intracellular cAMP increases only in directly contacted myocytes and cell-cell coupling utilized a junctional extracellular signalling domain with an elevated NE concentration. In the living mouse, optogenetic activation of cardiac SNs innervating the sino-atrial node resulted in an instantaneous chronotropic effect, which shortened the heartbeat interval with single beat precision. Remarkably, inhibition of the optogenetically elicited chronotropic responses required a high dose of propranolol (20-50 mg kg-1 ), suggesting that sympathetic neurotransmission in the heart occurs at a locally elevated NE concentration. Our in vitro and in vivo data suggest that the control of cardiac function by SNs occurs via direct intercellular coupling as a result of the establishment of a specific junctional site. PMID- 29524232 TI - Association Between Excessive Alcohol Consumption and Echocardiographic Parameters According to the Presence of Flushing Reaction in Korean Men: A Community-Based Study. AB - BACKGROUND: The objective of this study was to investigate the effect of excessive alcohol consumption on heart reflected by various echocardiographic parameters according to the presence or absence of flushing reaction that might reflect acetaldehyde metabolism. METHODS: A total of 854 Korean men without significant cardiovascular diseases who underwent echocardiography and participated in the Korean Healthy Twin Study were used as subjects of this study. These subjects were classified into 3 categories: nondrinker, moderate drinker (<=196 g/wk), and heavy drinker (>196 g/wk) within 2 strata of flushing reaction to alcohol drinking. Association between echocardiographic measurements and categories of the amount of alcohol consumption considering flushing reaction were evaluated using mixed linear regression model. RESULTS: The proportion of flushers among drinkers was 39.5% (278 of 703). In stratified analysis by flushing reaction, nonflushers showed significantly higher left ventricular mass index (beta: 4.605; 95% CI: 0.966, 8.243) and significantly lower ratio of peak early diastolic velocities (E peak) over peak late diastolic velocities of mitral inflow (beta: -0.103; 95% CI: -0.198, -0.008) in heavy drinkers compared to nondrinkers. Flushers showed significantly higher left atrial (LA) volume index (beta: 2.712; 95% CI: 0.456, 4.968) in heavy drinkers and significantly lower ratio of E peak over the peak early diastolic mitral annular velocities (beta: 0.493; 95% CI: -0.902, -0.085) in moderate drinkers compared to nondrinkers. However, the interaction according to flushing reaction was only statistically significant for the association between alcohol consumption and LA volume index (p for interaction = 0.004). CONCLUSIONS: Alcohol consumption is associated with changes in cardiac structure and function. Such association might be influenced by acetaldehyde metabolism. PMID- 29524233 TI - Radioimmunotherapy of solid tumors: Approaches on the verge of clinical application. AB - While radioimmunotherapy (RIT) for the treatment of hematological malignancies such as indolent B-cell lymphoma has proven quite successful, clinical results of RIT in solid tumors have only been moderate in the past. The reasons were manifold and can be mostly attributed to the different biological properties of solid tumors vs hematological cancers. Furthermore, the slow clearance of the radiolabelled antibody prevents the use of radiation doses necessary to achieve clinical responses. The long biological half-life of radioimmunoconjugates results in high background levels and is the main reason for radiation related toxicities. In recent years, researchers and clinicians have developed solutions for the successful application of RIT for the treatment of solid tumors. These include compartmental route of administration, neoadjuvant therapies, and pretargeting approaches. In this review, recent developments in RIT for the treatment of solid tumors that address these restrictions as well as future perspectives will be highlighted from a clinical perspective. PMID- 29524234 TI - Measuring Pavlovian appetitive conditioning in humans with the postauricular reflex. AB - Despite its evolutionary and clinical significance, appetitive conditioning has been rarely investigated in humans. It has been proposed that this discrepancy might stem from the difficulty in finding suitable appetitive stimuli that elicit strong physiological responses. However, this might also be due to a possible lack of sensitivity of the psychophysiological measures commonly used to index human appetitive conditioning. Here, we investigated whether the postauricular reflex-a vestigial muscle microreflex that is potentiated by pleasant stimuli relative to neutral and unpleasant stimuli-may provide a valid psychophysiological indicator of appetitive conditioning in humans. To this end, we used a delay differential appetitive conditioning procedure, in which a neutral stimulus was contingently paired with a pleasant odor (CS+), while another neutral stimulus was not associated with any odor (CS-). We measured the postauricular reflex, the startle eyeblink reflex, and skin conductance response (SCR) as learning indices. Taken together, our results indicate that the postauricular reflex was potentiated in response to the CS+ compared with the CS , whereas this potentiation extinguished when the pleasant odor was no longer delivered. In contrast, we found no evidence for startle eyeblink reflex attenuation in response to the CS+ relative to the CS-, and no effect of appetitive conditioning was observed on SCR. These findings suggest that the postauricular reflex is a sensitive measure of human appetitive conditioning and constitutes a valuable tool for further shedding light on the basic mechanisms underlying emotional learning in humans. PMID- 29524235 TI - Comparison of MEMS switches and PIN diodes for switched dual tuned RF coils. AB - PURPOSE: To evaluate the performance of micro-electromechanical systems (MEMS) switches against PIN diodes for switching a dual-tuned RF coil between 19 F and 1 H resonant frequencies for multi-nuclear lung imaging. METHODS: A four-element fixed-phase and amplitude transmit-receive RF coil was constructed to provide homogeneous excitation across the lungs, and to serve as a test system for various switching methods. The MR imaging and RF performance of the coil when switched between the 19 F and 1 H frequencies using MEMS switches, PIN diodes and hardwired configurations were compared. RESULTS: The performance of the coil with MEMS or PIN diode switching was comparable in terms of RF measurements, transmit efficiency and image SNR on both 19 F and 1 H nuclei. When the coil was not switched to the resonance frequency of the respective nucleus being imaged, reductions in the transmit efficiency were observed of 32% at the 19 F frequency and 12% at the 1 H frequency. The coil provides transmit field homogeneity of +/ 12.9% at the 1 H frequency and +/-14.4% at the 19 F frequency in phantoms representing the thorax with the air space of the lungs filled with perfluoropropane gas. CONCLUSION: MEMS and PIN diodes were found to provide comparable performance in on-state configuration, while MEMS were more robust in off-state high-powered operation (>1 kW), providing higher isolation and requiring a lower DC switching voltage than is needed for reverse biasing of PIN diodes. In addition, clear benefits of switching between the 19 F and 1 H resonances were demonstrated, despite the proximity of their Larmor frequencies. PMID- 29524236 TI - Acute hypertensive stress imaged by cardiac hyperpolarized [1-13 C]pyruvate magnetic resonance. AB - PURPOSE: Deranged metabolism is now recognized as a key causal factor in a variety of heart diseases, and is being studied extensively. However, invasive methods may alter metabolism, and conventional imaging techniques measure tracer uptake but not downstream metabolism. These challenges may be overcome by hyperpolarized MR, a noninvasive technique currently crossing the threshold into human trials. The aim of this study was to image metabolic changes in the heart in response to endogastric glucose bolus and to acute hypertension. METHODS: Five postprandial pigs were scanned with hyperpolarized [1-13 C]pyruvate cardiac MR at baseline, after oral glucose bolus, and after infusion of angiotensin-II. RESULTS: No effect of glucose bolus was seen using hyperpolarized [1-13 C]pyruvate MR despite changes in circulating substrates. During angiotensin-II infusion, blood pressure increased 179% (P = 0.008) and ejection fraction decreased from 54 +/- 2% to 47 +/- 6% (P = 0.03) The hemodynamic changes were accompanied by increases in the hyperpolarized [1-13 C]pyruvate MR derived ratios of lactate/alanine (from 0.58 +/- 0.13 to 0.78 +/- 0.06, P = 0.03) and bicarbonate/alanine (from 0.55 +/- 0.12 to 0.91 +/- 0.14, P = 0.007). CONCLUSION: Glucose loading did not alter cardiac metabolism, but during acute hypertensive stress, cardiac aerobic, carbohydrate metabolism, and pyruvate-lactate exchange was altered. Hyperpolarized MR allows noninvasive evaluation of acute changes in cardiac metabolism. However, hemodynamics must be taken into account when interpreting the results. PMID- 29524237 TI - Compression in Working Memory and Its Relationship With Fluid Intelligence. AB - Working memory has been shown to be strongly related to fluid intelligence; however, our goal is to shed further light on the process of information compression in working memory as a determining factor of fluid intelligence. Our main hypothesis was that compression in working memory is an excellent indicator for studying the relationship between working-memory capacity and fluid intelligence because both depend on the optimization of storage capacity. Compressibility of memoranda was estimated using an algorithmic complexity metric. The results showed that compressibility can be used to predict working memory performance and that fluid intelligence is well predicted by the ability to compress information. We conclude that the ability to compress information in working memory is the reason why both manipulation and retention of information are linked to intelligence. This result offers a new concept of intelligence based on the idea that compression and intelligence are equivalent problems. PMID- 29524238 TI - Rapid, theoretically artifact-free calculation of static magnetic field induced by voxelated susceptibility distribution in an arbitrary volume of interest. AB - PURPOSE: To demonstrate a computationally efficient and theoretically artifact free method to calculate static field (B0 ) inhomogeneity in a volume of interest induced by an arbitrary voxelated susceptibility distribution. METHODS: Our method computes B0 by circular convolution between a zero-filled susceptibility matrix and a shifted, voxel-integrated dipolar field kernel on a grid of size NS +NT - 1 in each dimension, where NS and NT are the sizes of the susceptibility source and B0 target grids, respectively. The computational resource requirement is independent of source-target separation. The method, called generalized susceptibility voxel convolution, is demonstrated on three susceptibility models: an ellipsoid, MR-compatible screws, and a dynamic human heartbeat model. RESULTS: B0 in an ellipsoid calculated by generalized susceptibility voxel convolution matched an analytical solution nearly exactly. The method also calculated screw induced B0 in agreement with experimental data. Dynamic simulation demonstrated its computational efficiency for repeated B0 calculations on time-varying susceptibility. On the contrary, conventional and alias-subtracted k-space discretized Fourier convolution methods showed nonnegligible aliasing and Gibbs ringing artifacts in the tested models. CONCLUSION: Generalized susceptibility voxel convolution can be a fast and reliable way to compute susceptibility induced B0 when the susceptibility source is not colocated with the B0 target volume of interest, as in modeling B0 variations from motion and foreign objects. PMID- 29524239 TI - Analysis of antigen-antibody cross-reactivity among lineages and sublineages of Babesia microti parasites using human babesiosis specimens. AB - BACKGROUND: Human babesiosis is caused mainly by Babesia microti and has recently become a public health concern due to an increase in transfusion-transmitted infection. Thus, the development of an antibody detection method with high specificity and sensitivity is a priority. Seroreactivity against B. microti has been reported to be highly specific not only to B. microti lineages but also to sublineages. This study aimed to elucidate the human antibody reactivity against various lineages, including US, Kobe, and Hobetsu, and sublineages (North America and East Asia) in the US lineage. STUDY DESIGN AND METHODS: Twenty samples obtained from individuals infected with B. microti in the United States were tested for the presence of anti-B. microti antibodies using indirect immunofluorescence assay (IFA) and Western blotting (WB) to indicate antigens of each (sub-)lineage. RESULTS: By IFA, 20 samples showed reactivity to the North America sublineage (titer range, 64-4096), 16 to the East Asia sublineage (64 512), 10 to the Kobe (64-128), and five to the Hobetsu (64). Antibody titers to the East Asia sublineage, Kobe, and Hobetsu were significantly lower than those to the North America sublineage (p < 0.01). By WB, in parallel with the IFA results, 18 samples showed strong reactions to the North America sublineage, weak reactions to the East Asia sublineage, and near-zero reactions to the Kobe and Hobetsu. CONCLUSION: Human antibodies induced by B. microti infection are highly specific against B. microti lineages and sublineages with low cross-reactivity. Developing a precise antibody detection method may require specific antigens based on B. microti lineages and sublineages. PMID- 29524241 TI - The relationship between GABA and stress: 'it's complicated'. PMID- 29524240 TI - Indications for and outcomes of therapeutic plasma exchange after cardiac transplantation: A single center retrospective study. AB - INTRODUCTION: Limited data are available describing indications for and outcomes of therapeutic plasma exchange (TPE) in cardiac transplantation. METHODS: In a retrospective study of patients who underwent cardiac transplantation at Duke University Medical Center from 2010 to 2014, we reviewed 3 TPE treatment patterns: a Single TPE procedure within 24 h of transplant; Multiple TPE procedures initiated within 24 h of transplant; and 1 or more TPE procedures beginning >24 h post-transplant. Primary and secondary outcomes were overall survival (OS) and TPE survival (TS), respectively. RESULTS: Of 313 patients meeting study criteria, 109 (35%) underwent TPE. TPE was initiated in 82 patients within 24 h, 40 (37%) receiving a single procedure (Single TPE), and 42 (38%) multiple procedures (Multiple TPE). Twenty-seven (25%) began TPE >24 h after transplant (Delayed TPE). The most common TPE indication was elevated/positive panel reactive or human leukocyte antigen antibodies (32%). With a median follow up of 49 months, the non-TPE treated and Single TPE cohorts had similar OS (HR 1.08 [CI, 0.54, 2.14], P = .84), while the Multiple and Delayed TPE cohorts had worse OS (HR 2.62 [CI, 1.53, 4.49] and HR 1.98 [CI, 1.02, 3.83], respectively). The Multiple and Delayed TPE cohorts also had worse TS (HR 2.59 [CI, 1.31, 5.14] and HR 3.18 [CI, 1.56, 6.50], respectively). Infection rates did not differ between groups but was independently associated with OS (HR 2.31 [CI, 1.50, 3.54]). CONCLUSIONS: TPE is an important therapeutic modality in cardiac transplant patients. Prospective studies are needed to better define TPE's different roles in this patient population. PMID- 29524242 TI - Moving functional classification of dorsal horn neurons from art to science. PMID- 29524243 TI - Toward a noninvasive estimate of interstitial fluid pressure by dynamic contrast enhanced MRI in a rat model of cerebral tumor. AB - PURPOSE: This study demonstrates a DCE-MRI estimate of tumor interstitial fluid pressure (TIFP) and hydraulic conductivity in a rat model of glioblastoma, with validation against an invasive wick-in-needle (WIN) technique. An elevated TIFP is considered a mark of aggressiveness, and a decreased TIFP a predictor of response to therapy. METHODS: The DCE-MRI studies were conducted in 36 athymic rats (controls and posttreatment animals) with implanted U251 cerebral tumors, and with TIFP measured using a WIN method. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE-MRI data, the MRI parameters required for estimating TIFP noninvasively were estimated. Two models, a fluid mechanical model and a multivariate empirical model, were used for estimating TIFP, as verified against WIN-TIFP. RESULTS: Using DCE-MRI, the mean estimated hydraulic conductivity (MRI-K) in U251 tumors was (2.3 +/- 3.1) * 10-5 (mm2 /mmHg s) in control studies. Significant positive correlations were found between WIN TIFP and MRI-TIFP in both mechanical and empirical models. For instance, in the control group of the fluid-mechanical model, MRI-TIFP was a strong predictor of WIN-TIFP (R2 = 0.76, p < .0001). A similar result was found in the bevacizumab treated group of the empirical model (R2 = 0.93, p = .014). CONCLUSION: This research suggests that MRI dynamic studies contain enough information to noninvasively estimate TIFP in this, and possibly other, tumor models, and thus might be used to assess tumor aggressiveness and response to therapy. PMID- 29524244 TI - Simultaneous auto-calibration and gradient delays estimation (SAGE) in non Cartesian parallel MRI using low-rank constraints. AB - PURPOSE: To correct gradient timing delays in non-Cartesian MRI while simultaneously recovering corruption-free auto-calibration data for parallel imaging, without additional calibration scans. METHODS: The calibration matrix constructed from multi-channel k-space data should be inherently low-rank. This property is used to construct reconstruction kernels or sensitivity maps. Delays between the gradient hardware across different axes and RF receive chain, which are relatively benign in Cartesian MRI (excluding EPI), lead to trajectory deviations and hence data inconsistencies for non-Cartesian trajectories. These in turn lead to higher rank and corrupted calibration information which hampers the reconstruction. Here, a method named Simultaneous Auto-calibration and Gradient delays Estimation (SAGE) is proposed that estimates the actual k-space trajectory while simultaneously recovering the uncorrupted auto-calibration data. This is done by estimating the gradient delays that result in the lowest rank of the calibration matrix. The Gauss-Newton method is used to solve the non-linear problem. The method is validated in simulations using center-out radial, projection reconstruction and spiral trajectories. Feasibility is demonstrated on phantom and in vivo scans with center-out radial and projection reconstruction trajectories. RESULTS: SAGE is able to estimate gradient timing delays with high accuracy at a signal to noise ratio level as low as 5. The method is able to effectively remove artifacts resulting from gradient timing delays and restore image quality in center-out radial, projection reconstruction, and spiral trajectories. CONCLUSION: The low-rank based method introduced simultaneously estimates gradient timing delays and provides accurate auto-calibration data for improved image quality, without any additional calibration scans. PMID- 29524245 TI - Compatibility of intravenous pentoxifylline with other medications infused concurrently in preterm infants with late-onset sepsis. PMID- 29524246 TI - An experimental model for calcium carbonate urolithiasis in goats. AB - BACKGROUND: Calcium carbonate is a common urolith type in small ruminants with no high-yield experimental model to evaluate animal susceptibility or preventative measure response. HYPOTHESIS: That novel plastic winged implants would allow accumulation and quantification of calcium carbonate calculus formation in goats on a high-calcium diet and identify individual variation between goats in the mass of calculi produced. ANIMALS: Eight nonpregnant 3- and 4-year-old Boer-cross does, weighing 22.3-39.5 kg, determined to be healthy based on physical examination, were used in these experiments. METHODS: Prospective cohort study for in vivo experimental model development. Implants were placed into the urinary bladder lumen in 8 goats over 2 evaluation periods. The alfalfa-based ration had a total ration Ca : P of 3.29 and 3.84 : 1, respectively. Urine was collected at 0, 28, 56, and 84 days in the 1st experiment; blood and urine at those timepoints in the 2nd experiment. For each evaluation period, the implants were removed 84 days after implantation and weighed. Accumulated calculi mass was calculated and compared between goats and was analyzed for composition. RESULTS: Implant retention was 100% and 86% in the 2 studies. All goats with retained implants accumulated calcium carbonate at a mean implant gain per day across studies ranging from 0.44 to 57.45 mg. Two goats accumulated (0.44-7.65 mg/day and 33.64 & 57.45 mg/day) significantly more urolith material than the cohort across both studies (P = .047). No routine analytes on blood or urine were found to be explanatory for the difference observed. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings form a basis for implant and diet selection for use in future studies of urolithiasis development and for studies regarding individual susceptibility to urolithiasis. PMID- 29524247 TI - The role of fish intake on asthma in children: A meta-analysis of observational studies. AB - BACKGROUND: The evidence is mixed on the use of long chain Omega-3 fatty acids in the prevention and management of childhood asthma. METHODS: We conducted a systematic search and meta-analysis investigating the role of fish intake, the main dietary source of long chain omega-3 fatty acids, on asthma in children. RESULTS: A total of 1119 publications were identified. Twenty-three studies on fish intake in association with childhood asthma were included in the final review. In 15 of 23 studies, early introduction of fish (6-9 months) and regular consumption (at least once a week) improved asthma symptoms and reduced risk in children 0-14 years as compared to no fish consumption; 6 of 23 showed no effect and 2 of 23 studies suggest adverse effects. Meta-analysis revealed an overall "beneficial effect" for "all fish" intake on "current asthma" [OR: 0.75; 95%CI: 0.60-0.95] and "current wheeze" [OR: 0.62; 95%CI: 0.48-0.80] in children up to 4.5 years old. An overall protective effect of "fatty fish" intake as compared to "no fish" intake in children 8-14 years old was also observed [OR: 0.35; 95%CI: 0.18-0.67]. CONCLUSION: This meta-analysis suggests that introduction of fish early in life (6-9 months) and regular consumption of all fish (at least once a week) reduces asthma and wheeze in children up to 4.5 years old, while fatty fish intake may be beneficial in older children. Future well-designed clinical trials are recommended to confirm the promising findings documented in this literature analysis. PMID- 29524248 TI - A 2D spiral turbo-spin-echo technique. AB - PURPOSE: 2D turbo-spin-echo (TSE) is widely used in the clinic for neuroimaging. However, the long refocusing radiofrequency pulse train leads to high specific absorption rate (SAR) and alters the contrast compared to conventional spin-echo. The purpose of this work is to develop a robust 2D spiral TSE technique for fast T2 -weighted imaging with low SAR and improved contrast. METHODS: A spiral-in/out readout is incorporated into 2D TSE to fully take advantage of the acquisition efficiency of spiral sampling while avoiding potential off-resonance-related artifacts compared to a typical spiral-out readout. A double encoding strategy and a signal demodulation method are proposed to mitigate the artifacts because of the T2 -decay-induced signal variation. An adapted prescan phase correction as well as a concomitant phase compensation technique are implemented to minimize the phase errors. RESULTS: Phantom data demonstrate the efficacy of the proposed double encoding/signal demodulation, as well as the prescan phase correction and concomitant phase compensation. Volunteer data show that the proposed 2D spiral TSE achieves fast scan speed with high SNR, low SAR, and improved contrast compared to conventional Cartesian TSE. CONCLUSION: A robust 2D spiral TSE technique is feasible and provides a potential alternative to conventional 2D Cartesian TSE for T2 -weighted neuroimaging. PMID- 29524249 TI - A probabilistic network model for structural transitions in biomolecules. AB - Biological macromolecules often undergo large conformational rearrangements during a functional cycle. To simulate these structural transitions with full atomic detail typically demands extensive computational resources. Moreover, it is unclear how to incorporate, in a principled way, additional experimental information that could guide the structural transition. This article develops a probabilistic model for conformational transitions in biomolecules. The model can be viewed as a network of anharmonic springs that break, if the experimental data support the rupture of bonds. Hamiltonian Monte Carlo in internal coordinates is used to infer structural transitions from experimental data, thereby sampling large conformational transitions without distorting the structure. The model is benchmarked on a large set of conformational transitions. Moreover, we demonstrate the use of the probabilistic network model for integrative modeling of macromolecular complexes based on data from crosslinking followed by mass spectrometry. PMID- 29524250 TI - Improved protein model quality assessments by changing the target function. AB - Protein modeling quality is an important part of protein structure prediction. We have for more than a decade developed a set of methods for this problem. We have used various types of description of the protein and different machine learning methodologies. However, common to all these methods has been the target function used for training. The target function in ProQ describes the local quality of a residue in a protein model. In all versions of ProQ the target function has been the S-score. However, other quality estimation functions also exist, which can be divided into superposition- and contact-based methods. The superposition-based methods, such as S-score, are based on a rigid body superposition of a protein model and the native structure, while the contact-based methods compare the local environment of each residue. Here, we examine the effects of retraining our latest predictor, ProQ3D, using identical inputs but different target functions. We find that the contact-based methods are easier to predict and that predictors trained on these measures provide some advantages when it comes to identifying the best model. One possible reason for this is that contact based methods are better at estimating the quality of multi-domain targets. However, training on the S-score gives the best correlation with the GDT_TS score, which is commonly used in CASP to score the global model quality. To take the advantage of both of these features we provide an updated version of ProQ3D that predicts local and global model quality estimates based on different quality estimates. PMID- 29524251 TI - A case of subepidermal autoimmune bullous disease with autoantibodies against 200 and 290-kDa antigens. PMID- 29524253 TI - 5-alpha-reductase inhibitor treatment for frontal fibrosing alopecia: an evidence based treatment update. AB - BACKGROUND: Treatment for frontal fibrosing alopecia (FFA) is challenging, and its treatment regimen often mirrors other lymphocytic-predominant cicatricial alopecia. 5-alpha-reductase inhibitor (5ARI) has been reported with some treatment success in severe cases of FFA. OBJECTIVE: To carry out evidence-based analysis of articles published on treatment efficacy and safety of 5-alpha reductase inhibitor for the treatment of FFA. METHODS: Articles published on the use of 5ARI to treat FFA between 2005 and 2017 were reviewed, analysed and graded according to the American College of Physicians outcome study grading system. RESULTS: There were two studies with moderate level of evidence that described the efficacy of 5ARI for the treatment of FFA. 5ARI was commonly used as adjunctive therapy with positive results in recalcitrant disease. Mild to moderate hair regrowth was reported in one grade 2 and three lower grade (one grade 3 and two grade 4) studies. There is limited evidence on the safety aspects of this medication in most studies that were analysed. LIMITATIONS: Database studies might not fully account for confounders and are subjected to variations in methodology and data collection. CONCLUSION: This review demonstrated that FFA patients treated with 5ARI could achieve either disease stability or reduction in the rate of progression in selected cases. A well-designed randomized, double blind, controlled study would strengthen the role of 5ARI as part of treatment armamentarium for FFA. PMID- 29524252 TI - Early food allergy and respiratory allergy symptoms and attention deficit/hyperactivity disorder in Chinese children: A cross-sectional study. AB - BACKGROUND: The relationship between food allergy and respiratory allergy and attention-deficit/hyperactivity disorder (ADHD) in children is rarely investigated. The objective of this study was to determine whether early food allergy and respiratory allergy symptoms are associated with the prevalence of ADHD in Chinese school-age children. METHODS: This cross-sectional study was conducted in school-age children using cluster-stratified methods from 9 cities across China between November and December 2005. A family and social environmental questionnaire including the diagnosis history of ADHD and allergic diseases (food allergy, allergic rhinitis, and bronchial asthma), as well as general information, was completed by parents. RESULTS: The prevalence of both allergic rhinitis (20.4%) and asthma (11.6%) in the food allergy group was significantly higher than in the non-food allergy group (9.0% and 2.8%, respectively; both P < .001). The multivariable analysis showed that single food allergy (OR = 1.53, 95% CI: 1.13-2.05, P = .005), food allergy complicated with allergic rhinitis or asthma (OR = 3.36, 95% CI: 2.19-5.14, P < .001), and food allergy complicated with allergic rhinitis and asthma simultaneously (OR = 4.08, 95% CI: 2.05-8.11, P < .001) were independently associated with the increased risk of ADHD. CONCLUSIONS: Early food allergy is associated with ADHD in school age children. Early food allergy and respiratory allergy symptoms independently and synergistically contributed to higher risk of ADHD. Monitoring food allergy in early life could help in the early prediction and intervention for the consequent allergy march and ADHD in children. PMID- 29524254 TI - Mutilating male genital Crohn's without gastrointestinal involvement. PMID- 29524255 TI - Long-term optimization of outcomes with flexible adalimumab dosing in patients with moderate to severe plaque psoriasis. AB - BACKGROUND: The recently updated dosing recommendation for adalimumab for moderate to severe plaque psoriasis states that patients with inadequate response to adalimumab every other week (EOW) after 16 weeks may benefit from an increase in dosing frequency to 40 mg every week (EW). OBJECTIVE: To determine the long term efficacy of adalimumab in patients with psoriasis with flexibility to escalate and de-escalate between EOW and EW dosing. METHODS: Data from an open label study in patients with psoriasis who had received adalimumab in phase 2/3 studies and their extensions were included. Patients initially received 40 mg adalimumab EOW for 24 weeks. From weeks 24-252, patients whose Psoriasis Area and Severity Index response was <50% (PASI 50) could have their dose-escalated to 40 mg EW and were re-evaluated at 6 and 12 weeks and then every 12 weeks thereafter. Patients who had their dose-escalated and achieved a PASI 75 response were de escalated to EOW and could re-escalate to EW if response fell below PASI 50 again; no further de-escalation was allowed. Changes in PASI scores were reported at the last visit before dose escalation or de-escalation. RESULTS: By week 24, 64.1% of patients in the overall population (n = 1256) achieved >=PASI 75 response, 40.3% >=PASI 90 response and 21.7% PASI 100 response. Patients who had a 0.8). The analysis was conducted for the overall population and for each participating country. RESULTS: Overall, 524 dermatologists and 3821 patients with psoriasis were included in the survey. Concordance of patient and dermatologist perceptions of psoriasis severity was fair both at diagnosis, and at the time of the survey (61% agreement, kappa = 0.326 and 55% agreement, kappa = 0.370, respectively). Higher levels of concordance were reported when patients assessed their psoriasis as moderate-to severe (using Investigator's Global Assessment/Physician's Global Assessment [IGA/PGA] 5-point scale of 3 or 4). Concordance regarding symptoms ranged from fair to moderate (kappa = 0.241-0.575). Satisfaction with psoriasis control was fair (39% agreement, kappa = 0.213). Results showed different patterns of concordance across the participating countries although a low concordance was observed on the satisfaction with psoriasis control in all of them. CONCLUSION: Results from this multinational real-world survey indicate different perceptions between patients with psoriasis and their dermatologist with respect to psoriasis severity, symptoms and disease control. PMID- 29524268 TI - Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. AB - Reproduction and fertility are regulated via hormones of the hypothalamic pituitary-gonadal (HPG) axis. Control of this reproductive axis occurs at all levels, including the brain and pituitary, and allows for the promotion or inhibition of gonadal sex steroid secretion and function. In addition to guiding proper gonadal development and function, gonadal sex steroids also act in negative- and positive-feedback loops to regulate reproductive circuitry in the brain, including kisspeptin neurones, thereby modulating overall HPG axis status. Additional regulation is also provided by sex steroids made within the brain, including neuroprogestins. Furthermore, because reproduction and survival need to be coordinated and balanced, the HPG axis is able to modulate (and be modulated by) stress hormone signalling, including cortiscosterone, from the hypothalamic pituitary-adrenal (HPA) axis. This review covers recent data related to the neural, hormonal and stress regulation of the HPG axis and emerging interactions between the HPG and HPA axes, focusing on actions at the level of the brain and pituitary. PMID- 29524272 TI - Segregation analysis revealed hemizygotic causative mutations in a pseudoxanthoma elasticum patient. PMID- 29524273 TI - Major prognostic factors for recurrence and survival independent of the American Joint Committee on Cancer eighth edition staging system in patients with cutaneous squamous cell carcinoma treated with multimodality therapy. AB - BACKGROUND: The purpose of this study was to assess changes resulting from the American Joint Committee on Cancer (AJCC) eighth edition for cutaneous squamous cell carcinoma (SCC) and evaluate pertinent excluded factors. METHODS: In 101 patients receiving surgery and postoperative radiation, recurrence and survival were estimated by cumulative incidence and Kaplan-Meier method. Time-to-event analysis was performed using Cox proportional hazards and Fine-Gray competing risks regression models. RESULTS: The 2-year locoregional recurrence, overall survival (OS), and cause-specific mortality rates were 25%, 72%, and 13%, respectively. The AJCC eighth edition upstaged T classification in 50% of patients and overall stage in 39%. In multivariate analysis, immunosuppression and in-transit metastasis were associated with locoregional recurrence. Older age and in-transit metastasis were associated with worse OS. In univariate analysis (limited by number of events), cause-specific mortality was associated with positive margin, in-transit metastasis, and the seventh edition dichotomized T classification and overall stage. CONCLUSION: In-transit metastasis was significantly associated with locoregional recurrence, OS, and cause-specific mortality. Efforts should be made to define in-transit metastasis in the staging system. PMID- 29524274 TI - Information properties of morphologically complex words modulate brain activity during word reading. AB - Neuroimaging studies of the reading process point to functionally distinct stages in word recognition. Yet, current understanding of the operations linked to those various stages is mainly descriptive in nature. Approaches developed in the field of computational linguistics may offer a more quantitative approach for understanding brain dynamics. Our aim was to evaluate whether a statistical model of morphology, with well-defined computational principles, can capture the neural dynamics of reading, using the concept of surprisal from information theory as the common measure. The Morfessor model, created for unsupervised discovery of morphemes, is based on the minimum description length principle and attempts to find optimal units of representation for complex words. In a word recognition task, we correlated brain responses to word surprisal values derived from Morfessor and from other psycholinguistic variables that have been linked with various levels of linguistic abstraction. The magnetoencephalography data analysis focused on spatially, temporally and functionally distinct components of cortical activation observed in reading tasks. The early occipital and occipito temporal responses were correlated with parameters relating to visual complexity and orthographic properties, whereas the later bilateral superior temporal activation was correlated with whole-word based and morphological models. The results show that the word processing costs estimated by the statistical Morfessor model are relevant for brain dynamics of reading during late processing stages. PMID- 29524276 TI - The search for loci under selection: trends, biases and progress. AB - Detecting genetic variants under selection using FST outlier analysis (OA) and environmental association analyses (EAAs) are popular approaches that provide insight into the genetic basis of local adaptation. Despite the frequent use of OA and EAA approaches and their increasing attractiveness for detecting signatures of selection, their application to field-based empirical data have not been synthesized. Here, we review 66 empirical studies that use Single Nucleotide Polymorphisms (SNPs) in OA and EAA. We report trends and biases across biological systems, sequencing methods, approaches, parameters, environmental variables and their influence on detecting signatures of selection. We found striking variability in both the use and reporting of environmental data and statistical parameters. For example, linkage disequilibrium among SNPs and numbers of unique SNP associations identified with EAA were rarely reported. The proportion of putatively adaptive SNPs detected varied widely among studies, and decreased with the number of SNPs analysed. We found that genomic sampling effort had a greater impact than biological sampling effort on the proportion of identified SNPs under selection. OA identified a higher proportion of outliers when more individuals were sampled, but this was not the case for EAA. To facilitate repeatability, interpretation and synthesis of studies detecting selection, we recommend that future studies consistently report geographical coordinates, environmental data, model parameters, linkage disequilibrium, and measures of genetic structure. Identifying standards for how OA and EAA studies are designed and reported will aid future transparency and comparability of SNP-based selection studies and help to progress landscape and evolutionary genomics. PMID- 29524275 TI - Mutations in the fourth beta-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers. AB - Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5-mediated activation of canonical Wnt signaling and mediates sclerostin-dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth beta-propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth beta-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants. PMID- 29524277 TI - Sinecatechins ointment 10% (Veregen(r)) for genital warts: percutaneous penetration of epigallocatechin gallate concentrations in the stratum corneum collected by adhesive tape stripping method. PMID- 29524278 TI - p53 promotes its own polyubiquitination by enhancing the HDM2 and HDMX interaction. AB - HDM2 and HDMX are two homologs essential for controlling p53 tumor suppressor activity under normal conditions. Both proteins bind different sites on the p53 N terminus, and while HDM2 has E3 ubiquitin ligase activity towards p53, HDMX does not. Nevertheless, HDMX is required for p53 polyubiquitination and degradation, but the underlying molecular mechanism remains unclear. Alone, HDMX and HDM2 interact via their respective C-terminal RING domains but here we show that the presence of p53 induces an N-terminal interface under normal cellular conditions. This results in an increase in HDM2-mediated p53 polyubiquitination and degradation. The HDM2 inhibitor Nutlin-3 binds the N-terminal p53 binding pocket and is sufficient to induce the HDM2-HDMX interaction, suggesting that the mechanism depends on allosteric changes that control the multiprotein complex formation. These results demonstrate an allosteric interchange between three different proteins (HDMX-HDM2-p53) and help to explain the molecular mechanisms of HDM2-inhibitory drugs. PMID- 29524279 TI - Epidermal necrolysis and autoimmune diseases: two more observations supporting the concept that 'toxic' epidermal necrolysis can be 'non-toxic'. PMID- 29524281 TI - Incubation with macroalgae induces large shifts in water column microbiota, but minor changes to the epibiota of co-occurring macroalgae. AB - Macroalgae variably promote and deter microbial growth through release of organic carbon and antimicrobial compounds into the water column. Consequently, macroalgae influence the microbial composition of the surrounding water column and biofilms on nearby surfaces. Here, we use manipulative experiments to test the hypotheses that (i) Nereocystis luetkeana and Mastocarpus sp. macroalgae alter the water column microbiota in species-specific manner, that (ii) neighbouring macroalgae alter the bacterial communities on the surface (epibiota) of actively growing Nereocystis luetkeana meristem fragments (NMFs), and that (iii) neighbours alter NMF growth rate. We also assess the impact of laboratory incubation on macroalgal epibiota by comparing each species to wild counterparts. We find strong differences between the Nereocystis and Mastocarpus epibiota that are maintained in the laboratory. Nereocystis and Mastocarpus alter water column bacterial community composition and richness in a species specific manner, but cause only small compositional shifts on NMF surfaces that do not differ by species, and do not change richness. Co-incubation with macroalgae results in significant change in abundance of fivefold more genera in the water column compared to NMF surfaces, although the direction (i.e., enrichment or reduction) of shift is generally consistent between the water and NMF surfaces. Finally, NMFs grew during the experiment, but growth did not depend on the presence or identity of neighbouring macroalgae. Thus, macroalgae exhibit a strong and species-specific influence on the water column microbiota, but a much weaker influence on the epibiota of neighbouring macroalgae. Overall, these results support the idea that macroalgae surfaces are highly selective and demonstrate that modulations of macroalgal microbiota operate within an overarching paradigm of host species specificity. PMID- 29524280 TI - Redesign of LAOBP to bind novel l-amino acid ligands. AB - Computational protein design is still a challenge for advancing structure function relationships. While recent advances in this field are promising, more information for genuine predictions is needed. Here, we discuss different approaches applied to install novel glutamine (Gln) binding into the Lysine/Arginine/Ornithine binding protein (LAOBP) from Salmonella typhimurium. We studied the ligand binding behavior of two mutants: a binding pocket grafting design based on a structural superposition of LAOBP to the Gln binding protein QBP from Escherichia coli and a design based on statistical coupled positions. The latter showed the ability to bind Gln even though the protein was not very stable. Comparison of both approaches highlighted a nonconservative shared point mutation between LAOBP_graft and LAOBP_sca. This context dependent L117K mutation in LAOBP turned out to be sufficient for introducing Gln binding, as confirmed by different experimental techniques. Moreover, the crystal structure of LAOBP_L117K in complex with its ligand is reported. PMID- 29524282 TI - Cutaneous pseudolymphoma caused by Poly Implant Prothese breast implants. PMID- 29524283 TI - Diverse Reactivity of Platinum SF3 and SF2 Complexes towards EtOH and Me3 SiOEt. AB - The complex trans-[Pt(F)(SF3 )(PCy3 )2 ] (1) shows a diverse reactivity pattern at the SF3 ligand towards ethanol and Me3 SiOEt. This led by deoxyfluorination or alcoholysis to the generation of platinum complexes bearing a metal-bound S(O)F or S(OEt)2 group. For the latter reaction trans-[Pt(F){S(F)(OEt)2 }(PCy3 )2 ] is suggested as an intermediate. In reactivity studies of trans-[Pt(F)(SF2 )(PCy3 )2 ][BF4 ] the complex [Pt(F){S(F)(OEt)}(PCy3 )2 ][BF4 ] was prepared, which does not react with ethanol. PMID- 29524284 TI - Blunt cannula subcision is more effective than Nokor needle subcision for acne scars treatment. AB - BACKGROUND AND AIM: A comprehensive study comparing two different modalities, Nokor needle subcision (NNS) and blunt cannula subcision (BCS), for treatment of acne scars, has not been reported previously. The aim was to compare the effectiveness of these two methods based on patient's and doctor's satisfaction measures, in addition to the late complications 3 months postsubcision. METHOD OF INTERVENTION: Patients had 18-65 years old, with acne scars on both malar sides. They were treated at one malar side with NNS and with BCS at another side. They were monitored during the first week, at one and 3 months postintervention. Patient's and two dermatologist's satisfactions were compared during 3 months, for each modality and between modalities. RESULTS: From 34 patients, 29.4%, 55.9%, and 14.7% had mild, moderate, and severe acne scars, respectively. Ecchymosis, nodule formation post-NNS, and edema after BCS were the complications. Patients were satisfied with BCS during 3-month monitoring (P = .021), but not with NNS (P = .353). Physician-1 was satisfied from the outcome of both BCS and NNS procedures (P = .044 and .006, respectively). However, physician 2 was only satisfied with NNS at the month 3 than the month 1 (P = .002). All patients and physicians were significantly more satisfied with BCS than NNS (P = .000). Anyway, at the month 3, physician-2 had no significant different points of view about applied methods (P = .25). DISCUSSION: Considering the complications and satisfaction rates, BCS was more efficient than NNS for acne scar treatment. Then, we suggest BCS as a good replacement for NNS. PMID- 29524285 TI - Vulvar neoplasms in 275 women with genital lichen sclerosus and impact of treatment: a retrospective chart review. PMID- 29524286 TI - MALDI-MS argininyl bufadienolide esters fingerprint from parotoid gland secretions of Rhinella arenarum: Age, gender, and seasonal variation. AB - In many amphibians, the granular glands can be grouped in special regions forming macroglands. This is the case of toads, characterized by the presence of a pair of parotoid macroglands, strategically located to give protection by poison release in case of attacks. The product secreted consists of a wide variety of chemical compounds including proteins, peptides, biogenic amines, toxic steroidal bufadienolides, and various alkaloids, depending on the species. In this work, using Rhinella arenarum, we have performed, for the first time, the matrix assisted-ultraviolet laser desorption/ionization mass spectrometry and tandem mass spectrometry characterization of the components of the secretion used as crude material, just suspended in MeOH (or MeCN). The crude sample as a whole (whole suspension) was spotted on the matrix assisted-ultraviolet laser desorption plate for analysis. Electrospray ionization-Orbitrap was used for cross-checking experiments. The pattern of signals obtained at m/z ranges 600 to 800 and 1200 to 1600 could be assigned as the argininyl bufadienolide esters fingerprint characteristic of female and male. Variation patterns for gender (female, male), age (non-reproductive, reproductive), and season (non reproductive, reproductive) are described. PMID- 29524287 TI - Antiaging and antioxidant effects of topical autophagy activator: A randomized, placebo-controlled, double-blinded study. AB - BACKGROUND: Recently, potential roles of autophagy in skin homeostasis received many interests. But, little has been reported for the potential antiaging effects of autophagy activator. OBJECTIVE: With the newly synthesized autophagy activator, heptasodium hexacarboxymethyl dipeptide-12 (AquatideTM) in vitro and clinical efficacy of the topical autophagy activator as an antiaging cosmeceutical ingredient was evaluated. METHODS: Antioxidant effect of AquatideTM was evaluated by radical scavenging assay. In vitro effect was assessed by measuring the cytotoxicity of hydrogen peroxide in cultured normal human epidermal keratinocytes. Clinical evaluation was performed by a randomized, placebo-controlled, double-blinded study. Antioxidant efficacy was observed by measuring the carbonylated proteins in stratum corneum (SC) by fluorescein-5 thiosemicarbazide (FTZ) staining. RESULTS: Radical scavenging effects of Aquatide were observed with the ABTS assay, and significant reduction in hydrogen peroxide induced cytotoxicity was observed in AquatideTM-treated cells. Autophagy inhibitor treatment abrogated cytoprotective effects of AquatideTM. In a clinical study, statistically significant increase in skin elasticity was observed after 4 and 8 weeks. Quantitative analysis of carbonylated proteins in SC also showed significant reduction in AquatideTM-treated group, which is consistent with the in vitro data. CONCLUSION: These results suggest that autophagy plays important roles in antioxidant system and aging process in skin, and topical autophagy activators can be potential cosmeceutical ingredients for skin antiaging. PMID- 29524288 TI - Effect of narrow-band ultraviolet B on the serum of 25-hydroxyvitamin D in vitiligo patients. AB - BACKGROUND: Narrow-band ultraviolet B (NB-UVB) is the gold standard in the treatment of vitiligo. 25-hydroxyvitamin D (25-OH- vitamin D) might play a physiological role in photo-induced melanogenesis in human skin so the association between vitamin D levels and vitiligo still needs to be investigated more thoroughly. OBJECTIVE: we aim to investigate the influence of cumulative doses of NB-UVB phototherapy on vitamin D in patients with vitiligo and their correlation with NB-UVB-induced pigmentation. METHODS: Eighty patients of vitiligo and twenty number of age and sex matched controls were recruited in a case-control study. Patients with vitiligo were treated with NB-UVB twice weekly for 24 weeks. 25-hydroxy vitamin D levels were measured at 0, 12, and 24 weeks in the cases and at 0 only in control by enzyme-linked immunosorbent assay (ELISA) and Vitiligo Area Severity Index (VASI) were calculated at 0 (baseline) and 24 weeks. RESULTS: The mean baseline level of 25-hydroxyvitamin D (at 0 week) was significantly lower in patients than the control group. Levels of 25(OH) vitamin D at 12 and 24 weeks showed significant improvement and Patients show significant reduction in VASI score after 24 weeks of therapy. CONCLUSIONS: Cumulative doses of NB-UVB therapy improve low vitamin D levels in patients with vitiligo, which might have a significant role in NB-UVB-induced repigmentation and may contribute to its therapeutic efficacy but further studies with larger sample size are needed to prove the complete mechanisms of NB-UVB-induced pigmentations and vitamin D in vitiligo. PMID- 29524289 TI - Age-related changes in the ease of dynamical transitions in human brain activity. AB - Executive functions, a set of cognitive processes that enable flexible behavioral control, are known to decay with aging. Because such complex mental functions are considered to rely on the dynamic coordination of functionally different neural systems, the age-related decline in executive functions should be underpinned by alteration of large-scale neural dynamics. However, the effects of age on brain dynamics have not been firmly formulated. Here, we investigate such age-related changes in brain dynamics by applying "energy landscape analysis" to publicly available functional magnetic resonance imaging data from healthy younger and older human adults. We quantified the ease of dynamical transitions between different major patterns of brain activity, and estimated it for the default mode network (DMN) and the cingulo-opercular network (CON) separately. We found that the two age groups shared qualitatively the same trajectories of brain dynamics in both the DMN and CON. However, in both of networks, the ease of transitions was significantly smaller in the older than the younger group. Moreover, the ease of transitions was associated with the performance in executive function tasks in a doubly dissociated manner: for the younger adults, the ability of executive functions was mainly correlated with the ease of transitions in the CON, whereas that for the older adults was specifically associated with the ease of transitions in the DMN. These results provide direct biological evidence for age related changes in macroscopic brain dynamics and suggest that such neural dynamics play key roles when individuals carry out cognitively demanding tasks. PMID- 29524290 TI - Dosimetric comparison of three intensity-modulated radiation therapies for left breast cancer after breast-conserving surgery. AB - PURPOSE: This study aimed to evaluate dosimetric differences of intensity modulated radiation therapy (IMRT) in target and normal tissues after breast conserving surgery. METHODS: IMRT five-field plan I, IMRT six-field plan II, and field-in-field-direct machine parameter optimization-IMRT plan III were designed for each of the 50 patients. One-way analysis of variance was performed to compare differences, and P < 0.05 was considered statistically significant. RESULTS: Homogeneity index of plan III is lower than those of plans I and II. No difference was identified in conformity index of targets. Plan I exhibited difference in mean dose (Dmean ) for the heart (P < 0.05). Plan I featured smaller irradiation dose volumes in V5 , V20 (P < 0.05) of the left lung than II. Plan I exhibited significantly higher V5 in the right lung than plans II and III (P < 0.05). Under plan I, irradiation dose at V5 in the right breast is higher than that in plans II and III. Patients in plan III presented less total monitor unit and total treatment time than those in plans I and II (P < 0.05). CONCLUSION: IMRT six-field plans II, and field-in-field-direct machine parameter optimization-IMRT plans III can reduce doses and volumes to the lungs and heart better while maintaining satisfying conformity index and homogeneity index of target. Nevertheless, plan II neglects target movements caused by respiration. In the same manner, plan III can substantially reduce MU and shorten patient treatment time. Therefore, plan III, which considers target movement caused by respiration, is a more practical radiation mode. PMID- 29524291 TI - Eligibility criteria and outcome measures adopted in clinical trials of treatments of cutaneous leishmaniasis: systematic literature review covering the period 1991-2015. AB - OBJECTIVE: To document the sources of heterogeneity in outcomes and shortcomings in trial designs reported by previous systematic reviews. METHODS: Systematic review of clinical trials of CL treatments published since 1991, to assess and compare eligibility criteria and outcome measures in trials (any type of treatment) of CL (any form) reported before and after the publication of the CONSORT statement. RESULTS: We identified 106 eligible trials published between 1991 and 2015, 74% after the 2001 CONSORT statement; 58% (n = 63) were on Old World CL and 37% (n = 40) in New-World CL; overall, 11 531 patients enrolled in 243 treatment groups on 30 different treatments. Both requirements and definitions for eligibility and outcome criteria varied. Compliance with CONSORT requirements increased for studies published after the 2010 update. As for entry criteria, 94% of studies had a requirement for sex (74% of those enrolling also women excluded those who were pregnant or lactating), 69% for age (variable age ranges), 99% parasitological confirmation, 43% prior duration of illness (14% excluded cases with previous episodes), 46% defined the number, 28% the size and 13% the type of lesions (27% with restrictions as to their anatomical location). Follow-up ranged 1-24 months, with 14% and 91% of studies, respectively, having defined initial and final cure. CONCLUSIONS: This review documents changes in reporting before and after the publication of the CONSORT statement. Lack of standardisation, compounded with the small number of trials relative to the magnitude of the disease in its multiple forms, and with the range of treatments tested explains why evidence to inform treatment guidelines is generally weak for CL. Adopting standardised methodologies will improve the quality and consistency of clinical trials, and ultimately yield better treatments for CL. PMID- 29524292 TI - Review and clinical experience exploring evidence, clinical efficacy, and safety regarding nonsurgical treatment of feminine rejuvenation. AB - INTRODUCTION: The use of energy-based devices for the treatment of vaginal laxity, orgasmic dysfunction, and stress incontinence, such as minimally ablative fractional laser and radiofrequency, is gaining momentum. This review aims to answer clinical questions on the application of energy-based devices for feminine genital rejuvenation. METHODS: The target group includes physicians involved in esthetic medicine and feminine genital rejuvenation. A literature review was conducted on technologies in use for feminine rejuvenation to explore their safety, efficacy, tolerability, patient satisfaction, and clinical usability. A panel of physicians with clinical experience conducting these types of treatment reviewed and discussed the results of the literature search and gave clinical evidence-based recommendations. RESULTS: Energy-based devices may induce wound healing, stimulating new collagen, and elastin fiber formation. Radiofrequency treatment may also increase small nerve fiber density in the papillary dermis, improving nerve sensitivity, sexual function, including arousal and orgasmic dysfunction. Both minimally ablative fractional laser and radiofrequency has been shown to be effective when treating mild to moderate primary or secondary vulvovaginal laxity and associated secondary conditions. These treatments are reported to be safe, effective, and well tolerated with a rapid return to activities of daily living. CONCLUSIONS: As this is an evolving medical field, clinical evidence often lacks robustness. Studies and clinical experience suggest that feminine genital rejuvenation using energy-based devices seems an attractive option for patients with mild-to-moderate medical conditions. The treatment can be safely and effectively delivered by trained staff as part of the comprehensive care, that is, currently available to women. PMID- 29524293 TI - BASIS: The blood pressure awareness and insight scale. AB - Impaired illness awareness or not accepting that one has hypertension (HTN) may be an important predictor of treatment adherence and optimal blood pressure control. The purpose of this study was to perform a systematic review of available instruments to evaluate HTN awareness, and subsequently present a novel scale that measures the core domains of subjective illness awareness in HTN. Based on the absence of any validated HTN specific measure identified through our review, the Blood Pressure Awareness and Insight Scale (BASIS) was developed (www.illnessawarenessscales.com). An online survey platform was used to collect data on 100 participants. BASIS showed good concurrent (r(98) = .65, P < 0.001) and discriminant validity, internal consistency (Cronbach's alpha = .75), and 1 month test-retest reliability (ICC = 0.77). BASIS is a comprehensive, easy-to-use instrument specifically designed to measure subjective HTN awareness. BASIS may be used in research studies and clinical practice to assess the impact of HTN awareness on treatment adherence and clinical outcomes. PMID- 29524294 TI - Development of clinically relevant QA procedures for the BrainLab ExacTrac imaging system. AB - PURPOSE: The aim of this study was to develop Quality Assurance procedures for the BrainLab ExacTrac (ET) imaging system following the TG 142 recommendations for planar kV imaging systems. MATERIALS AND METHODS: A custom-designed 3D printed holder was used to position the Standard Imaging QCkV-1 phantom at isocenter, facing the ET X ray tubes. The linac's light field (collimator at 450) was used to position the phantom holder. The ET images were exported to ARIA where geometric distortion was checked. The DICOM images were analyzed in the PIPSpro software. The following parameters were recorded (technique 80 kV/2mAs): spatial resolution (Modulated Transfer Function (MTF) F50/F40/F30), contrast-to noise ratio (CNR), and noise. A baseline was generated for future image analysis. Beam quality and exposure were measured using the Unfors R/F detector. Using a rod holder, the detector was placed at isocenter, facing each ET X-ray tube. The measurements were performed for all preset protocols ranging from cranial low (80 kV/6.3 mAs) to abdomen high (145 kV/25 mAs). The total exposure was converted to dose. RESULTS AND DISCUSSION: The image quality parameters were close for the two tubes. A common baseline was therefore generated. The average baseline values (both tubes, both images/tube) were 1.06/1.18/1.30, 1.32, and 67.3 for the MTF F50/F40/F30, noise, and CNR respectively. The procedure described here was used for another 24 sets. Using a positioning template and 3D printed phantom holder, experimental reproducibility has been acceptably high. The measured phantom dimensions were within 1 mm from the nominal values. The measured kV values were within 2% of the nominal values. The exposure values for the two tubes were comparable. The range of total measured dose was 0.099 mGy (cranial low) to 1.353 mGy (abdomen high). CONCLUSIONS: A reliable process has been implemented for QA of the ET imaging system by characterizing the system's performance at isocenter, consistent with clinical conventions. PMID- 29524295 TI - MICAL1 facilitates breast cancer cell proliferation via ROS-sensitive ERK/cyclin D pathway. AB - Molecule interacting with CasL 1 (MICAL1) is a multidomain flavoprotein mono oxygenase that strongly involves in cytoskeleton dynamics and cell oxidoreduction metabolism. Recently, results from our laboratory have shown that MICAL1 modulates reactive oxygen species (ROS) production, and the latter then activates phosphatidyl inositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performed this study to assess the involvement of MICAL1 in breast cancer cell proliferation and to explore the potential molecular mechanism. We noticed that depletion of MICAL1 markedly reduced cell proliferation in breast cancer cell line MCF-7 and T47D. This effect of MICAL1 on proliferation was independent of wnt/beta-catenin and NF kappaB pathways. Interestingly, depletion of MICAL1 significantly inhibited ROS production, decreased p-ERK expression and unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increased p-ERK level as well as p-ERK nucleus translocation. Moreover, we investigated the effect of MICAL1 on cell cycle-related proteins. MICAL1 positively regulated CDK4 and cyclin D expression, but not CDK2, CDK6, cyclin A and cyclin E. In addition, more expression of CDK4 and cyclin D by MICAL1 overexpression was blocked by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuated the increase in the p-ERK level in MICAL1-overexpressed breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells. PMID- 29524297 TI - Dual-inflammatory cytokines on TiO2 nanotube-coated surfaces used for regulating macrophage polarization in bone implants. AB - Excessive immune responses following the use of implantable, biomaterial-based medical devices represent a substantial challenge for treatment efficacy and patient well-being. Specifically, after implantation, pro-inflammatory M1 macrophages are activated by cytokines such as interferon-gamma (IFN-gamma) followed by anti-inflammatory M2 macrophages polarized by cytokines including interleukin-4 (IL-4), leading to healing and long-term stability of implants. Here, we report the loading of an immunomodulatory cytokine,IL-4, into TiO2 nanotubes (TNTs) followed by hydrogel coating on the TNTs for subsequent release of IL-4. Finally, IFN-gamma was added onto the gel layer to effect rapid release. The release rates of both cytokines from the samples were monitored using an immersion test in phosphate-buffered solution. The cytocompatibility of the sample was evaluated using cultures of osteoblasts and macrophages. Macrophage phenotype switching in vitro was examined via cytokine secretion and gene expression analyses. In vitro testing showed that the sample could stimulate macrophage polarization from the M1 to M2 phenotype at the desired period owing to temporal release of IFN-gamma and IL-4. Another biomaterial containing only IL 4 in TNTs was also able to modulate the transformation of M1 to M2 although with weaker effect than that containing IFN-gamma and IL-4. The biomaterial may be useful as an osteoimplant in vivo owing to the inflammation caused by a wound or implantation. This study provided biomaterials capable of facilitating smooth M1 to M2 macrophages switching, which might be helpful to research immune responses of tissues to implants and will likely contribute to the development of bone substitute materials. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1878-1886, 2018. PMID- 29524296 TI - Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic beta-cell apoptosis. AB - Liraglutide, a human long-lasting GLP-1 analogue, is currently regarded as a powerful treatment option for type 2 diabetes. Apart from glucoregulatory and insulinotropic actions, liraglutide increases beta-cell mass through stimulation of beta-cell proliferation and islet neogenesis, as well as inhibition of beta cell apoptosis. However, the underline molecular mechanisms have not been fully characterized. In this study, we investigated the mechanism by which liraglutide preserves islet beta-cells in an animal model of overt diabetes, the obese db/db mice, and protects a mouse pancreatic beta-cell line (betaTC-6 cells) against apoptosis. Treatment of 12-week-old diabetic mice with liraglutide for 2 weeks had no appreciable effects on blood non-fasting glucose concentration, islet insulin content and body weight. However, morphological and biochemical examination of diabetic mouse pancreatic islets demonstrated that liraglutide restores islet size, reduces islet beta-cell apoptosis and improves nephrin expression, a protein involved in beta-cell survival signalling. Our results indicated that liraglutide protects betaTC-6 cells from serum withdrawal-induced apoptosis through inhibition of caspase-3 activation. The molecular mechanism of the anti-apoptotic action of liraglutide in betaTC-6-cells comprises stimulation of PI3-kinase-dependent AKT phosphorylation leading to the phosphorylation, hence inactivation of the pro-apoptotic protein BAD and inhibition of FoxO1 transcription factor. In conclusion, we provided evidence that the GLP-1 analogue liraglutide exerts important beneficial effects on pancreatic islet architecture and beta-cell survival by protecting cells against apoptosis. These findings extend our understanding of the actions of liraglutide and further support the use of GLP-1R agonists in the treatment of patients with type 2 diabetes. PMID- 29524298 TI - Oxidation-assisted structural elucidation of compounds containing a tertiary amine side chain using liquid chromatography mass spectrometry. AB - A novel analytical technique for the structural elucidation of compounds bearing a tertiary amine side chain via "in vial" instantaneous oxidation and liquid chromatography mass spectrometry (LC-MS) was developed. A series of lidocaine homologs and benzimidazole derivatives with a major/single amine representative base peak in both their EI-MS and ESI-MS/MS spectra were subjected to oxidation by a 0.1% solution of hydrogen peroxide (including several 16 O/18 O exchange experiments), followed by LC-ESI-MS/MS analysis. The N-oxide counterparts promoted extensive fragmentation with complete coverage of all parts of the molecule, enabling detailed structural elucidation and unambiguous identification of the unoxidized analytes at low nanogram per milliliter levels. PMID- 29524299 TI - Comprehensive analysis by liquid chromatography Q-Orbitrap mass spectrometry: Fast screening of peptides and organic molecules. AB - The number of substances nominally listed in the prohibited list of the World Anti-Doping Agency increases each year. Moreover, many of these substances do not have a single analytical target and must be monitored through different metabolites, artifacts, degradation products, or biomarkers. A new analytical method was developed and validated for the simultaneous analysis of peptides and organic molecules using a single sample preparation and LC-Q-HRMS detection. The simultaneous analysis of 450 target molecules was performed after cleanup on a mixed-mode solid-phase extraction cartridge, combined with untreated urine. The cleanup solvent and reconstitution solvent were the most important parameters for achieving a comprehensive sample preparation approach. A fast chromatographic run based on a multistep gradient was optimized under different flows; the detection of all substances without isomeric coelution was achieved in 11 minutes, and the chromatographic resolution was considered a critical parameter, even in high resolution mass spectrometry detection. The mass spectrometer was set to operate by switching between positive and negative ionization mode for FULL-MS, all-ion fragmentation, and FULL-MS/MS2 . The suitable parameters for the curved linear trap (c-trap) conditions were determined and found to be the most important factors for the development of the method. Only FULL-MS/MS2 enables the detection of steroids and peptides at concentrations lower than the minimum required performance levels set by World Anti-Doping Agency (1 ng mL-1 ). The combination of the maximum injection time of the ions into the c-trap, multiplexing experiments, and loop count under optimized conditions enabled the method to be applied to over 10 000 samples in only 2 months during the 2016 Rio Summer Olympic and Paralympic Games. The procedure details all aspects, from sample preparation to mass spectrometry detection. FULL-MS data acquisition is performed in positive and negative ion mode simultaneously and can be applied to untargeted approaches. PMID- 29524300 TI - Estrogen receptor-beta of microglia underlies sexual differentiation of neuronal protection via ginsenosides in mice brain. AB - AIMS: Streptococcus pneumoniae infection in acute bacterial meningitis can lead to widespread brain damage and mortality. Inflammatory responses by immune cells in the brain are thought to determine the degree of brain injury. Yet, the mechanisms underlying host responses to pneumococcal meningitis are largely unknown. To explore host responses as a potential therapeutic target for preventing brain injury after pneumococcal meningitis. METHODS: We evaluated signaling mechanisms that minimize neuronal damage caused by pneumococcal infection; specifically, we assessed pathways related to neuronal survival after enhancing estrogen receptor-beta (ER-beta) expression using a natural therapeutic substance known as ginsenoside Rb1 and Rg3 enhanced ginseng. RESULTS: Tissue damage caused by bacterial infection was reduced in Rb1/Rg3-treated mice as a result of microglial activation and the inhibition of apoptosis. Furthermore, Rb1 upregulated the expression of brain-derived neurotrophic factor (BDNF) as well as anti-apoptotic factors including Bcl-2 and Bcl-xL. Using BV2 microglial cells in vitro, Rb1 treatment inhibited microglial apoptosis in a manner associated with JAK2/STAT5 phosphorylation. CONCLUSION: After S. pneumoniae infection in mice, particularly in female mice, Rb1-containing ginseng increased bacterial clearance and survival. These findings inform our understanding of the host immune response to pneumococcal meningitis. PMID- 29524301 TI - Robust optimization in lung treatment plans accounting for geometric uncertainty. AB - Robust optimization generates scenario-based plans by a minimax optimization method to find optimal scenario for the trade-off between target coverage robustness and organ-at-risk (OAR) sparing. In this study, 20 lung cancer patients with tumors located at various anatomical regions within the lungs were selected and robust optimization photon treatment plans including intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were generated. The plan robustness was analyzed using perturbed doses with setup error boundary of +/-3 mm in anterior/posterior (AP), +/-3 mm in left/right (LR), and +/-5 mm in inferior/superior (IS) directions from isocenter. Perturbed doses for D99 , D98 , and D95 were computed from six shifted isocenter plans to evaluate plan robustness. Dosimetric study was performed to compare the internal target volume-based robust optimization plans (ITV-IMRT and ITV-VMAT) and conventional PTV margin-based plans (PTV-IMRT and PTV-VMAT). The dosimetric comparison parameters were: ITV target mean dose (Dmean ), R95 (D95 /Dprescription ), Paddick's conformity index (CI), homogeneity index (HI), monitor unit (MU), and OAR doses including lung (Dmean , V20 Gy and V15 Gy ), chest wall, heart, esophagus, and maximum cord doses. A comparison of optimization results showed the robust optimization plan had better ITV dose coverage, better CI, worse HI, and lower OAR doses than conventional PTV margin based plans. Plan robustness evaluation showed that the perturbed doses of D99 , D98 , and D95 were all satisfied at least 99% of the ITV to received 95% of prescription doses. It was also observed that PTV margin-based plans had higher MU than robust optimization plans. The results also showed robust optimization can generate plans that offer increased OAR sparing, especially for normal lungs and OARs near or abutting the target. Weak correlation was found between normal lung dose and target size, and no other correlation was observed in this study. PMID- 29524302 TI - Treatment outcomes of TB-infected individuals attending public sector primary care clinics in rural Liberia from 2015 to 2017: a retrospective cohort study. AB - OBJECTIVES: In June 2015, Partners in Health (PIH) and the Liberian Ministry of Health began a community health worker (CHW) programme containing food support, reimbursement of transport and social assistance to address gaps in tuberculosis (TB) treatment exacerbated by the 2014-2015 Ebola virus disease (EVD) epidemic. The purpose of this article was to analyse the performance of routine clinical TB care and the effects of this CHW programme. METHODS: Retrospective cohort study utilising data from TB patient registers at a census of all health facilities treating TB in the south-east region of Liberia from January 2015 - April 2017. Competing risks Cox regression analyses were used to generate subhazard ratios (sHR) analysing factors associated with rates of TB cure (smear negative), treatment completion (no smear), lost to follow-up (LTFU) and death. RESULTS: LTFU rates decreased 76% pre- vs. post-CHW intervention, from 14.6% in pre intervention to 3.4% post-intervention (P < 0.001). Although the post intervention had better cure rates (sHR 1.07, CI 0.58-1.9), treatment completion (sHR 1.53, CI 1.00 2.39) and lower death rates (sHR 0.64, CI 0.34-1.2), statistical significance was not reached. Younger patients had significantly lower death and cure rates, while older patients had higher LTFU and cure rates. Overall, 31% of patients were cured, 44% completed treatment without a confirmatory smear, 5% were LTFU, 9% died, 0.5% failed treatment, and 10% transferred out. CONCLUSIONS: In challenging environments, LTFU can be reduced by CHW accompaniment and socio-economic assistance to patients with TB. Approaches are needed to improve cure verification in young patients and reduce mortality. PMID- 29524304 TI - Relevance and Application of Read-Across - Mini Review of European Consensus Platform for Alternatives and Scandinavian Society for Cell Toxicology 2017 Workshop Session. AB - Structure activity relationship (SAR)-based read-across is an effective approach for addressing data gaps in human health risk assessment for 'data-poor' chemicals. In read-across, available data on chemical structural analogues are used to predict the toxicity potential of the data-poor chemical. This approach has long been recognized by regulatory agencies and used by industry to evaluate the hazards of chemicals for which there are limited direct data. Construction of a scientifically robust SAR-based read-across hazard assessment is a complex and iterative process involving multiple considerations in each step. Traditional in vivo data generated using regulatory guideline compliant study designs typically forms the basis for read-across assessments. Recently, however, new data streams have been explored and incorporated to enhance read-across predictivity. These in vitro and omics data streams may be used in different ways involving identification of hazards or to provide insight into modes of action for observed toxicological responses. These 'new approach methods' can also enable comparison of biological responses across analogues or a category of structurally related chemicals in order to establish a pattern of biological similarity in addition chemical similarity and/or to help address potency differences across a category. The purpose of this workshop session was to inform on practical considerations in conducting SAR-based read-across assessments and to review recent activities related to application of new approach methods to the practice of read-across. PMID- 29524303 TI - Tanshinone IIA prevents left ventricular remodelling via the TLR4/MyD88/NF-kappaB signalling pathway in rats with myocardial infarction. AB - In this study, we aim to investigate the role of tanshinone IIA in myocardial infarction (MI), especially in left ventricular remodelling (VR) and the underlying mechanism involving the TLR4/MyD88/NF-kappaB signalling pathway. Sprague-Dawley (SD) rats (n = 96) were selected, and 12 of them underwent sham surgery. The remaining 84 rats were subjected to MI modelling. HE and MT staining were carried out to estimate infract size, histopathological changes and fibrosis degree. Macrophage infiltration and cardiomyocyte apoptosis were evaluated by immunohistochemistry and TUNEL staining. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to determine the expression levels of TLR4, MyD88 and NF-kappaB. Serum levels of IL-2, IL-6, IL-8, TNF-a, procollagen I Cpropeptide (PICP), and procollagen III N-propeptide (PIIINP) were measured using enzyme-linked immunosorbent assay (ELISA). The heart weight/body weight, mean arterial pressure (MAP), left ventricular end-systolic pressure (LVESP), +dP/dt and -dP/dt increased while the ventricular function and the left ventricular end-diastole pressure (LVEDP) decreased in MI rats. Compared with the rats undergoing sham surgery, MI rats showed larger infarct size, severer fibrosis, higher expression levels of TLR4, NF-kappaB-P65, MyD88, IL-2, IL-6, IL-8, TNF-a, PICP and PIIINP as well as enhanced macrophage infiltration, cardiomyocyte apoptosis. After treatment with tanshinone IIA combined with LPS for 4 weeks, the rats showed better condition than those treated with only LPS. These results indicate that tanshinone IIA attenuates MI and prevents left VR. Importantly, inhibition of TLR4/MyD88/NF-kappaB signalling pathway is a key step in this process. PMID- 29524306 TI - 2017 Reviewer Acknowledgment. PMID- 29524305 TI - Clinical evaluation of simultaneously applied monopolar radiofrequency and targeted pressure energy as a new method for noninvasive treatment of cellulite in postpubertal women. AB - INTRODUCTION: This study investigates noninvasive cellulite treatments based on simultaneous application of monopolar radiofrequency (RF) and targeted pressure energy to evaluate efficacy and safety and to see whether simultaneous application has any benefits in noninvasive cellulite treatments. METHODS: Thirty women with cellulite (fibrous/adipose/aqueous types) received 4 gluteofemoral treatments (~24 minutes; ~1000 cm2 ) using a simultaneous application of RF and targeted pressure energy. Clinical improvement was assessed using a pentile grading scale and satisfaction questionnaires. Hip/thigh circumference was measured. Ultrasonography and thermography observed changes in dermal/subcutaneous tissue composition and in gluteofemoral thermal profile. Evaluation at 3 months posttreatment was compared against the baseline. RESULTS: The clinical improvement averaged 2.17 +/- 0.95 (54% improvement). Cellulite was reduced in 93% of cases, while 73% of patients showed good/very good/excellent improvement, with most significant improvement seen in patients with moderately severe cellulite. Hips and thigh circumference decreased on average by 2.31 cm and 2.13 cm, respectively (P < .001). Patient satisfaction was very high, averaging 4.47 +/- 0.57 points (1-5 scale). Ultrasonography revealed smoothing and thickening (+0.28 +/- 0.15 mm) of the dermis and an average reduction of 1.96 +/- 1.60 mm in fat thickness (P < .05). Subjects with significant cellulite reduction had a more homogenous thermal profile at follow-up as a result of therapy-induced diminution of topographic skin defects. No adverse events were recorded. CONCLUSION: The application is effective and safe for treating cellulite. The level of clinical improvement after 4 sessions is comparable to results reported after 6-20 sessions in studies on stand-alone RF/laser/targeted pressure energy devices. The technology is promising and deserves further attention and research. PMID- 29524307 TI - Plasma cell diseases and organ transplant: A comprehensive review. AB - Plasma cell diseases are a class of hematologic diseases that are sometimes present as preexisting diagnoses prior to organ transplantation, causative factors leading to a need for organ transplantation, or may occur posttransplant as part of the spectrum of posttransplant lymphoproliferative disorders. Herein, we review the most common plasma cell diseases, both as coexisting with other causes of organ failure, but also as a primary underlying cause for organ failure. In many cases, treatment of the underlying clonal disease may be indicated before proceeding with organ transplant. This review aims to provide current and relevant data regarding the management of these conditions in the organ transplant patient, for transplant providers, and those who take care of these patients. PMID- 29524308 TI - Differences in midterm outcomes in infants with hypoplastic left heart syndrome diagnosed with necrotizing enterocolitis: NPCQIC database analysis. AB - INTRODUCTION: Neonates with hypoplastic left heart syndrome (HLHS) are at increased risk for necrotizing enterocolitis (NEC). Initial hospital outcomes are well described, but minimal midterm data exist. Goal of this study was to compare outcomes of HLHS infants with NEC (HLHS-NEC) to HLHS without NEC (HLHS-nNEC) during the interstage period. METHODS: Data were reviewed from 55 centers using the NPC-QIC database. Case-control study with one HLHS-NEC matched to HLHS-nNEC neonates in a 1:3 ratio based on institutional site, type of surgical repair, and gestational age +/-1 week was performed. Baseline demographics as well as outcome data were recorded. The t tests or chi-square tests were performed as appropriate. RESULTS: There were 57 neonates in the HLHS-NEC (14 Norwood-BT, 37 Norwood-RVPA, and 6 hybrid) and 171 neonates in the HLHS-nNEC group. There were significant differences between the HLHS-NEC versus HLHS-nNEC for presence of atrioventricular valve regurgitation (7% vs 2%), use of extracorporeal membrane oxygenation (11% vs 2%), hospital stay (60.4 +/- 30.0 vs 36.3 +/- 33.6 days), Z score weight at discharge (-2.1 vs -1.6), incidence of no oral intake (33% vs 14%), and use of formula only nutrition at discharge (61% vs 29%), respectively. There were no significant differences between groups in readmission rates due to adverse gastrointestinal events, use of gastrointestinal medications, interstage deaths, or Z-score weight at time of second surgery. HLHS-NEC continued to be more likely to be entirely tube dependent for enteral intake at time prior to the second procedure (39% vs 15%). CONCLUSIONS: Despite similar baseline characteristics, HLHS-NEC infants had significant differences in hospital course compared with HLHS-nNEC neonates. In addition, HLHS-NEC infants were less likely to be fed orally during the entire interstage period. Future studies are needed minimize NEC in this high risk population to possibly improve oral feeds. PMID- 29524309 TI - MiR-577 suppresses epithelial-mesenchymal transition and metastasis of breast cancer by targeting Rab25. AB - BACKGROUND: MicroRNAs can act as both tumor suppressor genes and oncogenes and participate in cell proliferation, metastasis, and apoptosis. Low levels of miR 577 are found in several cancers, for example, thyroid carcinoma, glioblastoma, and hepatocellular carcinoma. The aim of this study was to investigate the effect of miR-577 on breast cancer (BC). METHODS: The relative level of miR-577 in 120 BC tissues and cells was detected by real-time PCR. MDA-MB-231 cells with upregulated miR-577 and MCF-7 cells with downregulated miR-577 were established. Transwell invasion assays were used to examine the invasiveness of cells. Epithelial-mesenchymal transition (EMT) markers were evaluated by immunofluorescence and Western blot. Targeted combinations of miR-577 and Rab25 were analyzed by luciferase assays. Xenograft models were used to examine the effect of miR-577 on BC metastasis. RESULTS: MiR-577 expression was significantly suppressed in BC tissues. Tumor size, tumor stage, and lymphatic metastasis were attributed to miR-577 expression. Moreover, miR-577 overexpression strongly inhibited the invasiveness and EMT of BC cells in vitro. MiR-577 directly regulated Rab25 in BC. Rab25 upregulation by miR-577 decreased the levels of E cadherin and increased the levels of Vimentin. Notably, Rab25 knockdown inhibited BC invasion; however, an increase in Rab25 counteracted the invasive effect of miR-577 in BC. CONCLUSION: Results indicated that miR-577 suppressed EMT by inhibiting Rab25 expression in BC. MiR-577 and Rab25 are considered potential targets of BC treatment. PMID- 29524310 TI - Onset patterns in autism: Variation across informants, methods, and timing. AB - : While previous studies suggested that regressive forms of onset were not common in autism spectrum disorder (ASD), more recent investigations suggest that the rates are quite high and may be under-reported using certain methods. The current study undertook a systematic investigation of how rates of regression differed by measurement method. Infants with (n = 147) and without a family history of ASD (n = 83) were seen prospectively for up to 7 visits in the first three years of life. Reports of symptom onset were collected using four measures that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective). Latent class growth models were used to classify individual trajectories to see whether regressive onset patterns were infrequent or widespread within the ASD group. A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings. Rates of regression were much lower using retrospective or categorical measures (from 29 to 47%). Agreement among different measurement methods was low. Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The accuracy of widely used methods of measuring onset is questionable and the present findings argue against their widespread use. Autism Res 2018, 11: 788 797. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study examines different ways of measuring the onset of symptoms in autism spectrum disorder (ASD). The present findings suggest that declining developmental skills, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The results question the accuracy of widely used methods of measuring symptom onset and argue against their widespread use. PMID- 29524311 TI - Correlation of morphological parameters and visual acuity with neurological development in former preterm children aged 4-10 years. AB - PURPOSE: The objective of this study was to investigate the relationship between visual acuity, peripapillary retinal nerve fibre layer (pRNFL), retinal thickness at the fovea and other factors with the neurologic status of former preterm children. METHODS: In this cross-sectional hospital based study in a maximum care tertiary centre, detailed anthropometric and ophthalmological data of former preterm children ranging from 4 to 10 years of age with a gestational age (GA) <=32 weeks were assessed. Analyses of the correlation between pRNFL and foveal thickness, as well as visual acuity (VA) parameters at 4-10 years of age, with neurological development were evaluated at 2 years of age by Bayley Scales II of Infant Development, including Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI). RESULTS: Data were available for 106 former preterm children. Univariate analysis revealed a correlation between PDI with pRNFL thickness (B = 0.43; p = 0.013), VA (B = -29.2; p < 0.001), GA (B = 2.7; p = 0.002), retinopathy of prematurity (ROP; B = -16.3; p < 0.001) and intraventricular haemorrhages (IVH; B = -22.9; p < 0.001) but not with strabismus or foveal thickness. In the multivariable analysis, the association remained for visual acuity and IVH, but not for pRNFL thickness or ROP. Mental Developmental Index (MDI) was associated with visual acuity (B = -34.3; p = 0.001), GA (B = 2.53; p = 0.02) and IVH (B = -15.4; p = 0.02), the latter also in the multivariable analysis. CONCLUSION: This study revealed an association between PDI at 2 years of age and lower visual acuity later in childhood. However, there was no correlation between retinal morphology and neurologic outcome in former preterm children after adjusting for several potential confounders. PMID- 29524312 TI - Tay bridge and extracellular-regulated kinase activity are required for motoneuron function in the Drosophila neural system. AB - Extracellular regulated kinase (Erk) activity is required during neural development for the specification of cell fates in neuroblasts and neuronal lineages, and also regulates several aspects of the activity and survival of mature neurons. The activation of Erk is regulated at multiple levels by kinases and phosphatases that alter its phosphorylation state and by other proteins that regulate its subcellular localization. Here, we find that tay bridge (tay), a negative regulator of Erk in Drosophila imaginal discs, is required in the motoneurons to regulate the number and size of neuromuscular synapses in these cells. The expression of Tay is maximal in motoneurons with low levels of activated ERK, suggesting that Tay modulates the activity of Erk in these cells. We also found that loss of tay expression and increased Erk activity specifically in the motoneurons cause a reversible decrease in walking speed. Impaired motoneurons activity may be caused by alterations in the functionality and number of synaptic boutons developing at the neuromuscular junction in tay mutants. PMID- 29524313 TI - Pulmonary artery hypertension following coronary artery bypass grafting: a case report. AB - Post-operative pulmonary complications in coronary artery bypass grafting (CABG) surgery are mostly reversible. We report a patient who developed pulmonary arterial hypertension (PAH) post-CABG and did not have pulmonary hypertension prior to surgery. PAH Group 1 was diagnosed after right and left heart catheterization. To the best of our knowledge, this is the only reported case of a patient developing PAH post-CABG surgery. This could be explained by immunological and/or haemostatic changes triggered by cardiopulmonary bypass. We hope that as more knowledge is gained regarding the pathophysiology of PAH, cases like these could be better understood. PMID- 29524314 TI - Semaphorin 4D levels in heart failure patients: a potential novel biomarker of acute heart failure? AB - AIMS: Semaphorin 4D (Sema4D) is expressed on platelets and T-cells and known to be involved in inflammation. The aims of this study include comparing Sema4D and N terminal pro brain natriuretic peptide (NT-proBNP) serum levels in heart failure (HF) patients to a control group, evaluating the correlation between Sema4D and NT-proBNP levels, and assessing Sema4D serum levels in HF patients during acute exacerbation and remission. METHODS AND RESULTS: Forty-five patients diagnosed with HF (based on echocardiographic findings, positive NT-proBNP levels, and normal C-reactive protein) and 11 healthy controls (declaring no chronic diseases or medications) comprised the study population. Demographic, clinical, laboratory, and echocardiographic data were used to create the study database. NT-proBNP and Sema4D serum samples were taken on admission and discharge. NT-proBNP levels were significantly higher in the HF group than in controls (P < 0.001). Sema4D levels were significantly higher in HF patients than in healthy controls (2143.04 +/- 1253 vs. 762.18 +/- 581.6 ng/mL, P < 0.001, respectively). Using linear regression, a higher creatinine level was found to predict both higher levels of NT-proBNP and Sema4D (P = 0.05 and P < 0.014, respectively), while a reduced ejection fraction was found to predict higher NT proBNP levels only (P < 0.001 and P = 0.87, respectively). Average Sema4D levels reduced significantly at remission (3534.94 +/- 1650.55 vs. 2455.67 +/- 1424, P = 0.03), while mean NT-proBNP levels did not change significantly. CONCLUSIONS: Sema4D levels in HF patients' serum are significantly higher than in healthy controls. Clinical improvement caused rapid reduction in Sema4D levels, possibly reflecting the inflammatory aspect of HF. These findings might suggest that Sema4D can be used as a diagnostic biomarker of acute HF. Further studies of Sema4D and HF are warranted. PMID- 29524315 TI - Serum calcitonin negative mixed medullary-follicular carcinoma initially diagnosed as medullary thyroid carcinoma by fine-needle aspiration cytology: A case report and review of the literatures. AB - Medullary thyroid carcinoma (MTC) is potentially lethal. A prompt and accurate diagnosis is the prerequisite for the treatment of MTC. Fine-needle aspiration (FNA) is a reliable diagnostic tool in the assessment of thyroid nodules. However, cytologic assessment of MTC based on FNA has several drawbacks due to morphological variants. We present a case of MTC diagnosed through FNA cytology, which was eventually histologically confirmed as a mixed medullary-follicular carcinoma with negative serum calcitonin expression. Hence, diagnosis of MTC based on FNA should be applied with caution. Ultrasound characteristics of suspicious thyroid nodules are recommended to be evaluated by FNA. However, calcitonin levels should be measured in both the FNA washout fluid and serum when features of MTC are presented or cytology result is inconclusive. If adequate FNA sample is available, a supplementary immunocytochemical staining of markers such as calcitonin, chromogranin, carcinoembryonic antigen, and thyroglobulin is helpful for a correct diagnosis of MTC. PMID- 29524316 TI - Risk factors associated with malignancy and with triage to surgery in thyroid nodules classified as Bethesda category IV (FN/SFN). AB - BACKGROUND: Thyroid nodules diagnosed as Bethesda category IV [follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)] are recommended for surgery. However, only 10%-40% of these nodules turn out to be malignant on histopathological examination. Therefore, selection for surgery of nodules diagnosed as Bethesda category IV is important. We aimed to define predictive factors for malignancy and factors associated with triage to surgery. METHODS: The records of all patients with nodules who underwent fine needle aspiration biopsy (FNAB) and classified by Bethesda reporting system as FN/SFN between January 2011 and July 2017 at our institution were reviewed. Univariate and multivariate analysis were performed to select independent factors associated with thyroid cancer, and with triage to surgery. Using independent risk factors for malignancy predictive index categories were created. RESULTS: Among 6910 nodules that underwent FNAB, 180 (2.6%) were diagnosed as FN/SFN. Of the 180 patients, 139 (77%) underwent surgery with the associated malignancy rate of 37% (51/139) (upper boundary). Risk of malignancy among all FN/SFN nodules was 28% (lower boundary). Solid structure, size >= 4 cm, microcalcification, hypoechogenicity, and increased vascularization were found to be significant and independent risk factors associated for malignancy. None of the clinical and ultrasound factors were associated with triage to surgery. CONCLUSIONS: Our findings showed that using predictive factors for malignancy in the Bethesda IV category as risk indices, 17% of patients who had nodules without any risk factors could be spared surgery. Predictive indices could be considered for the malignancy risk and for selection of patients for surgery. PMID- 29524317 TI - Determinants of health seeking behaviour following rabies exposure in Ethiopia. AB - The objective of this study was to identify factors that determine medical treatment seeking behaviour following potential rabies exposure after being bitten by a suspected dog and the likelihood of compliance to receive sufficient doses of post-exposure prophylaxis after the visit to a health centre visit. A detailed survey based on case investigation was conducted on suspected rabid dog bite cases in three areas of Ethiopia. Two multivariable logistic regression models were created with a set of putative variables to explain treatment seeking and compliance outcomes. Based on the registered bite cases at each health centre and the set of unregistered bite cases derived by contact tracing, 655 bite victim cases were identified to have occurred between September 2013 and August 2014. Of these evaluated bite incidences, 465 cases were considered to have been caused by a potentially rabid dog. About 77% of these suspected rabid dog bite victims visited a health centre, while 57% received sufficient doses of PEP. The overall likelihood of seeking medical services following rabies exposure was higher for people bitten by dogs of unknown ownership, where the bite was severe, being bitten on the leg, spend of more than 100 USD per month and where the victim lived close to the nearest health centre, while the likelihood of receiving sufficient doses of PEP was sensitive to monthly spending and distance to health centre. However, the evaluated factors did only explain a part of the variation among the three districts. The district in which victims lived appeared to have a relevant influence on the likelihood of seeking medical treatment but did not improve the prediction on the likelihood of treatment compliance. Given the insights obtained from this study, improvements in the rural districts with regard to accessibility of post-exposure prophylaxis delivering health centres in shorter distance could improve health seeking behaviour. In addition, in rural districts, majority of exposed persons who seek medical treatment tend to comply with treatment regimen, indicating that the promotion of medical treatment through awareness creation campaigns could be beneficial. PMID- 29524319 TI - Efficacy of hypofractionated radiotherapy in patients with non-melanoma skin cancer: Results of a systematic review. AB - Radiation oncologists are increasingly tasked with the management of elderly patients with non-melanoma skin cancer, unsuitable for surgical intervention due to inoperable lesions and/or poor performance status. In this cohort, hypofractionated radiotherapy, delivered either daily, alternative daily or once weekly is highly effective. A systematic literature search was conducted of PUBMED, MEDLINE and EMBASE databases using the algorithm ('radiotherapy' OR 'radiation therapy' OR 'brachytherapy') AND ('hypofraction' OR 'hypofractionated' OR 'hypofractionation') AND ('skin neoplasms' OR 'carcinoma' OR 'malignancy') AND ('skin' OR 'epidermis' OR 'epidermal' OR 'cutaneous'). Forty relevant publications (1983-2017) encompassing 12,337 irradiated lesions were retrieved. Studies documented a mean age of 71.73 years and male predilection (54.5%). Both external beam radiotherapy and brachytherapy were utilized. Tumour subtype was squamous cell carcinoma (23.5%), basal cell carcinoma (75.2%) or others (1.3%). Irradiated lesions were primary (or denovo) (92.6%), located on the head and neck (95.7%) and received definitive therapy (96.5%). Analysis demonstrated a mean weighted total radiotherapy dose (38.15 Gy), dose per fraction (7.95 Gy) and treatments per week (2.98). Despite significant heterogeneity in the study population, the radiotherapy delivered and follow-up, local recurrence rate (crude or Kaplan-Meier analysis) did not exceed 7.9% in all but three of the 36 publications providing these data. Twenty-nine publications documented local control exceeding 90%. There is a body of evidence documenting the efficacy of hypofractionated radiotherapy as an option that confers no obvious disadvantage in local control when compared to traditional more protracted radiotherapy schedules. PMID- 29524318 TI - Whole genome sequence and phenotypic characterization of a Cbm+ serotype e strain of Streptococcus mutans. AB - We report the whole genome sequence of the serotype e Cbm+ strain LAR01 of Streptococcus mutans, a dental pathogen frequently associated with extra-oral infections. The LAR01 genome is a single circular chromosome of 2.1 Mb with a GC content of 36.96%. The genome contains 15 phosphotransferase system gene clusters, seven cell wall-anchored (LPxTG) proteins, all genes required for the development of natural competence and genes coding for mutacins VI and K8. Interestingly, the cbm gene is genetically linked to a putative type VII secretion system that has been found in Mycobacteria and few other Gram-positive bacteria. When compared with the UA159 type strain, phenotypic characterization of LAR01 revealed increased biofilm formation in the presence of either glucose or sucrose but similar abilities to withstand acid and oxidative stresses. LAR01 was unable to inhibit the growth of Strpetococcus gordonii, which is consistent with the genomic data that indicate absence of mutacins that can kill mitis streptococci. On the other hand, LAR01 effectively inhibited growth of other S. mutans strains, suggesting that it may be specialized to outcompete strains from its own species. In vitro and in vivo studies using mutational and heterologous expression approaches revealed that Cbm is a virulence factor of S. mutans by mediating binding to extracellular matrix proteins and intracellular invasion. Collectively, the whole genome sequence analysis and phenotypic characterization of LAR01 provides new insights on the virulence properties of S. mutans and grants further opportunities to understand the genomic fluidity of this important human pathogen. PMID- 29524320 TI - Voxel-based measurement sensitivity of spatially resolved near-infrared spectroscopy in layered tissues. AB - We quantitatively investigated the measurement sensitivity of spatially resolved spectroscopy (SRS) across six tissue models: cerebral tissue, a small animal brain, the forehead of a fetus, an adult brain, forearm muscle, and thigh muscle. The optical path length in the voxel of the model was analyzed using Monte Carlo simulations. It was found that the measurement sensitivity can be represented as the product of the change in the absorption coefficient and the difference in optical path length in two states with different source-detector distances. The results clarified the sensitivity ratio between the surface layer and the deep layer at each source-detector distance for each model and identified changes in the deep measurement area when one of the detectors was close to the light source. A comparison was made with the results from continuous-wave spectroscopy. The study also identified measurement challenges that arise when the surface layer is inhomogeneous. Findings on the measurement sensitivity of SRS at each voxel and in each layer can support the correct interpretation of measured values when near-infrared oximetry or functional near-infrared spectroscopy is used to investigate different tissue structures. PMID- 29524321 TI - In vivo photoacoustic imaging of chorioretinal oxygen gradients. AB - Chorioretinal imaging has a crucial role for the patients with chorioretinal vascular diseases, such as neovascular age-related macular degeneration. Imaging oxygen gradients in the eye could better diagnose and treat ocular diseases. Here, we describe the use of photoacoustic ocular imaging (PAOI) in measuring chorioretinal oxygen saturation (CR - sO2) gradients in New Zealand white rabbits (n = 5) with ocular ischemia. We observed good correlation (R2 = 0.98) between pulse oximetry and PAOI as a function of different oxygen percentages in inhaled air. We then used an established ocular ischemia model in which intraocular pressure is elevated to constrict ocular blood flow, and notice a positive correlation (R2 = 0.92) between the injected volume of phosphate buffered saline (PBS) and intraocular pressure (IOP) as well as a negative correlation (R2 = 0.98) between CR - sO2 and injected volume of PBS. The CR sO2 was measured before (baseline), during (ischemia), and after the infusion (600-MUL PBS). The ischemia-reperfusion model did not affect the measurement of the sO2 using a pulse oximeter on the animal's paw, but the chorioretinal PAOI signal showed a nearly sixfold decrease in CR - sO2 (n = 5, p = 0.00001). We also observe a sixfold decrease in CR - sO2 after significant elevation of IOP during ischemia, with an increase close to baseline during reperfusion. These data suggest that PAOI can detect changes in chorioretinal oxygenation and may be useful for application to imaging oxygen gradients in ocular disease. PMID- 29524322 TI - Detection of Somatic Mutation in Exon 12 of DNA Polymerase beta in Ovarian Cancer Tissue Samples AB - Background: DNA polymerase beta (pol beta) is a key enzyme of base excision repair pathway. It is a 1-kb gene consisting of 14 exons. Its catalytic part lies between exon 8 and exon 14. Exon 12 has a role in deoxyribonucleotide triphosphate selection for nucleotide transferase activity. Methods: Genomic DNA was isolated from ovarian carcinoma samples. Single strand conformation polymorphism method was used to detect mutation in genomic DNA. Results: Twenty four patients of the 152 pair of tumor samples (15.8%) exhibited a point mutation (C->G) in position 725 in exon 12, which shifts proline to arginine (P242R). Statistical analysis showed a significant (p < 0.001) relationship between pol beta mutation and the age of detection. Conclusion: This is a newly reported somatic mutation of pol beta in ovarian carcinoma patients from India. PMID- 29524323 TI - Cytotoxic Oligomers and Fibrils Trapped in a Gel-like State of alpha-Synuclein Assemblies. AB - alpha-Synuclein (alpha-Syn) aggregation is associated with Parkinson's disease (PD) pathogenesis. In PD, the role of oligomers versus fibrils in neuronal cell death is debatable, but recent studies suggest oligomers are a proximate neurotoxin. Herein, we show that soluble alpha-Syn monomers undergo a transformation from a solution to a gel state on incubation at high concentration. Detailed characterization of the gel showed the coexistence of monomers, oligomers, and short fibrils. In vitro, the gel was highly cytotoxic to human neuroblastoma cells. The individual constituents of the gel are short-lived species but toxic to the cells. They comprise a structurally heterogeneous population of alpha-helical and beta-sheet-rich oligomers and short fibrils with the cross-beta motif. Given the recent evidence of the gel-like state of the protein associated with neurodegenerative diseases, the gel state of alpha-Syn in this study represents a mechanistic and structural model for the in vivo toxicity of alpha-Syn in PD. PMID- 29524324 TI - Evaluation of ionic liquids supported on silica as a sorbent for fully automated online solid-phase extraction with LC-MS determination of sulfonamides in bovine milk samples. AB - Sulfonamides are antibiotics widely used in the treatment of diseases in dairy cattle. However, their indiscriminate use for disease control may lead to their presence in tissues and milk and their determination requires a sample preparation step as part of an analytical approach. Among the several sample preparation techniques available, those based upon the use of sorptive materials have been widely employed. Recently, the application of ionic liquids immobilized on silica surfaces or polymeric materials has been evaluated for such an application. This manuscript addresses the evaluation of silica-based ionic liquid obtained by a sol-gel synthesis process by basic catalysis as sorbent for online solid-phase extraction with liquid chromatography and electrospray ionization time-of-flight mass spectrometry for sulfonamides determination. Infrared vibrational spectroscopy confirmed the presence of the ionic liquid on the silica surface, suggesting that the ionic liquid was anchored on to the silica surface. Other sorbents varying the ionic liquid alkyl chain were also synthesized and evaluated by off-line solid-phase extraction in the sulfonamide extraction. As the length of the alkyl chain increased, the amount of extracted sulfonamides decreased, possibly due to a decrease in the electrostatic interaction caused by the reduction in the polarity, as well as the presence of a hexafluorophosphate anion that increases the hydrophobic character of the material. The use of 1-butyl-3-methylimidazolium hexafluorophosphate as a selective ionic liquid sorbent enabled the isolation and sulfonamide preconcentration in bovine milk by online solid-phase extraction with liquid chromatography and electrospray ionization time-of-flight mass spectrometry. The limit of quantification for the method developed was 5-7, 5 MUg/mL, with extraction recoveries ranging between 74 and 93% and intra- and interassay between 1.5-12.5 and 2.3-13.1, respectively. PMID- 29524325 TI - A New Anode for Lithium-Ion Batteries Based on Single-Walled Carbon Nanotubes and Graphene: Improved Performance through a Binary Network Design. AB - Carbon nanomaterials, especially graphene and carbon nanotubes, are considered to be favorable alternatives to graphite-based anodes in lithium-ion batteries, owing to their high specific surface area, electrical conductivity, and excellent mechanical flexibility. However, the limited number of storage sites for lithium ions within the sp2 -carbon hexahedrons leads to the low storage capacity. Thus, rational structure design is essential for the preparation of high-performance carbon-based anode materials. Herein, we employed flexible single-walled carbon nanotubes (SWCNTs) with ultrahigh electrical conductivity as a wrapper for 3D graphene foam (GF) by using a facile dip-coating process to form a binary network structure. This structure, which offered high electrical conductivity, enlarged the electrode/electrolyte contact area, shortened the electron-/ion-transport pathways, and allowed for efficient utilization of the active material, which led to improved electrochemical performance. When used as an anode in lithium-ion batteries, the SWCNT-GF electrode delivered a specific capacity of 953 mA h g-1 at a current density of 0.1 A g-1 and a high reversible capacity of 606 mA h g-1 after 1000 cycles, with a capacity retention of 90 % over 1000 cycles at 1 A g-1 and 189 mA h g-1 after 2200 cycles at 5 A g-1 . PMID- 29524326 TI - Anaphylactic hypotension causes renal and adrenal sympathoexcitaion and induces c fos in the hypothalamus and medulla oblongata. AB - NEW FINDINGS: What is the central question of this study? Whether anaphylaxis affects sympathetic outflows to the brown adipose tissue (BAT) and adrenal gland and whether anaphylaxis affects some brain areas in association with sympathetic regulation. What is the main finding and its importance? Sympathoexcitatory responses to anaphylaxis occurred regionally in the kidney and adrenal gland, but not in the thermogenesis-related BAT. Further, anaphylactic hypotension also caused increase in c-fos immunoreactivity in the hypothalamic and medullary areas. Moreover, catecholaminergic neurons of the brainstem cause adrenal sympathoexcitation in a baroreceptor-independent manner. ABSTRACT: We previously reported that sympathetic nerve activity (SNA) to the kidney and the hindlimb increases during anaphylactic hypotension in anaesthetized rats. Based on this evidence, we examined effects of anaphylactic hypotension on SNA to the brown adipose tissue (BAT), and the adrenal gland and kidney in anaesthetized rats. We demonstrated that adrenal and renal SNA, but not BAT-SNA, were stimulated. In addition, the effects of anaphylaxis on neural activities of the hypothalamic and medullary nuclei, which are candidates for relaying efferent SNA to the peripheral organs, were investigated via immunohistochemical staining of c-fos. Anaphylaxis increased c-fos expression in the neurons of the paraventricular nucleus (PVN) of the hypothalamus and in those of the nucleus tractus solitarii (NTS) and rostral ventrolateral medulla (RVLM) of the medulla oblongata; c-fos was expressed in gamma-aminobutyric acid (GABA)-ergic neurons of the NTS and in the catecholaminergic neurons of the RVLM. In addition, c-fos expression in the rostral NTS and mid NTS during anaphylaxis was reduced by sinoaortic baroreceptor denervation; however, increased c-fos expression in the caudal NTS and RVLM or adrenal sympathoexcitation were not affected by sinoaortic baroreceptor denervation. These results indicated that anaphylactic hypotension activates the hypothalamic PVN and the medullary NTS and RVLM independently of the baroreflex pathway. Further, it stimulated efferent SNA to the adrenal gland and kidney to restore blood pressure. PMID- 29524327 TI - Integrin alphaV beta3 can substitute for collagen-binding beta1 -integrins in vivo to maintain a homeostatic interstitial fluid pressure. AB - NEW FINDINGS: What is the central question of this study? Collagen-binding beta1 integrins function physiologically in cellular control of dermal interstitial fluid pressure (PIF ) in vivo and thereby participate in control of extravascular fluid volume. During anaphylaxis, simulated by injection of compound 48/80, integrin alphaV beta3 takes over this physiological function. Here we addressed the question whether integrin alphaV beta3 can replace collagen-binding beta1 integrin to maintain a long-term homeostatic PIF . What is the main finding and its importance? Mice lacking the collagen-binding integrin alpha11 beta1 show a complex dermal phenotype with regard to the interstitial physiology apparent in the control of PIF . Notably dermal PIF is not lowered with compound 48/80 in these animals. Our present data imply that integrin alphaV beta3 is the likely candidate that has taken over the role of collagen-binding beta1 -integrins for maintaining a steady-state homeostatic PIF . A better understanding of molecular processes involved in control of PIF is instrumental for establishing novel treatment regimens for control of oedema formation in anaphylaxis and septic shock. ABSTRACT: Accumulated data indicate that cell-mediated contraction of reconstituted collagenous gels in vitro can serve as a model for cell-mediated control of interstitial fluid pressure (PIF ) in vivo. A central role for collagen-binding beta1 -integrins in both processes has been established. Furthermore, integrin alphaV beta3 takes over the role of collagen-binding beta1 integrins in mediating contraction after perturbations of collagen-binding beta1 integrins in vitro. Integrin alphaV beta3 is also instrumental for normalization of dermal PIF that has been lowered due to mast cell degranulation with compound 48/80 (C48/80) in vivo. Here we demonstrate a role of integrin alphaV beta3 in maintaining a long term homeostatic dermal PIF in mice lacking the collagen binding integrin alpha11 beta1 (alpha11-/- mice). Measurements of PIF were performed after circulatory arrest. Furthermore, cell-mediated integrin alphaV beta3 -directed contraction of collagenous gels in vitro depends on free access to a collagen site known to bind several extracellular matrix (ECM) proteins that form substrates for alphaV beta3 -directed cell attachment, such as fibronectin and fibrin. A streptococcal collagen-binding protein, CNE, specifically binds to and blocks this site on the collagen triple helix. Here we show that whereas CNE perturbed alphaV beta3 -directed and platelet-derived growth factor BB-induced normalization of dermal PIF after C48/80, it did not affect alphaV beta3 dependent maintenance of a homeostatic dermal PIF . These data imply that dynamic modification of the ECM structure is needed during acute patho-physiological modulations of PIF but not for long-term maintenance of a homeostatic PIF . Our data thus show that collagen-binding beta1 -integrins, integrin alphaV beta3 and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis. PMID- 29524328 TI - Similar but Not the Same: First Kinetic and Structural Analyses of a Methanol Dehydrogenase Containing a Europium Ion in the Active Site. AB - Since the discovery of the biological relevance of rare earth elements (REEs) for numerous different bacteria, questions concerning the advantages of REEs in the active sites of methanol dehydrogenases (MDHs) over calcium(II) and of why bacteria prefer light REEs have been a subject of debate. Here we report the cultivation and purification of the strictly REE-dependent methanotrophic bacterium Methylacidiphilum fumariolicum SolV with europium(III), as well as structural and kinetic analyses of the first methanol dehydrogenase incorporating Eu in the active site. Crystal structure determination of the Eu-MDH demonstrated that overall no major structural changes were induced by conversion to this REE. Circular dichroism (CD) measurements were used to determine optimal conditions for kinetic assays, whereas inductively coupled plasma mass spectrometry (ICP-MS) showed 70 % incorporation of Eu in the enzyme. Our studies explain why bacterial growth of SolV in the presence of Eu3+ is significantly slower than in the presence of La3+ /Ce3+ /Pr3+ : Eu-MDH possesses a decreased catalytic efficiency. Although REEs have similar properties, the differences in ionic radii and coordination numbers across the series significantly impact MDH efficiency. PMID- 29524329 TI - Antifungal properties and biocompatibility of silver nanoparticle coatings on silicone maxillofacial prostheses in vitro. AB - Patients with facial prostheses suffer from yeast, Candida albicans, infections. This study aimed to determine the biocompatibility and antifungal properties of silicone facial prostheses coated with silver nanoparticles (Ag NPs) in vitro. Medical grade silicone discs were coated with 5 and 50 mg L-1 dispersions of either Ag NPs or AgNO3 . Coatings were fully characterized using scanning electron microscopy and energy dispersive X-ray spectroscopy. The biocompatibility was examined using human dermal fibroblasts (Hs68), whereas antifungal efficacy was tested against C. albicans (NCPF-3179). The fibroblast viability was assessed by measuring lactate dehydrogenase (LDH) activity, protein content and tissue electrolytes. There were no effects on the LDH activity of fibroblast cell homogenates, and leak of LDH activity into external media remained low (0.1-0.2 IU mL-1 ). Sublethal effects of Ag NP coatings on membrane permeability/ion balance was not observed, as measured by stable homogenate Na+ and K+ concentrations. Some Ag (13 mg L-1 ) was detected from the AgNO3 coatings in the media, but total Ag remained below detection limit (<1.2 ug L-1 ) for the Ag NP coatings; indicating the latter were stable. When fibroblasts grown on silver coatings were challenged with C. albicans, the Ag NP coating was effective at preventing fungal growth as measured by ethanol production by the yeast, and without damaging the fibroblasts. Ethanol production decreased from 43.2 +/- 25.02 in controls to 3.6 umol mL-1 in all the silver treatments. Data shows that silicone prosthetic materials coated with Ag NPs are biocompatible with fibroblast cells in vitro and show antifungal properties. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1038-1051, 2018. PMID- 29524330 TI - Are spikes noninferior to high-frequency oscillations? PMID- 29524331 TI - Meaning making, self-determination theory, and the question of wisdom in personality. AB - Self-determination theory (SDT) has advanced the most comprehensive model of motives for human flourishing in the field of personality psychology and beyond. In this article, we evaluate SDT relative to the process of meaning making, particularly from a narrative perspective, showing what SDT can and cannot explain about the construction of self-identity and its relation to human flourishing. On the one hand, SDT explains how subjective assessments of need fulfillment drive the process of self-determined living. The internal motives that follow such fulfillment serve as important themes in people's life stories that predict several markers of hedonic and eudaimonic well-being. On the other hand, SDT's focus on subjective fulfillment limits what SDT can explain about how wisdom, which is a canonical good of both eudaimonia and meaning making, helps people make sense of life's more difficult or unfulfilling events. SDT may facilitate a facet of wisdom that is more subjective and experiential but not the critical facet of wisdom defined by objectively more complex structures of interpretation. PMID- 29524332 TI - Electrophysiologic lessons from the European multicenter study of Guillain-Barre syndrome subtype diagnosis. PMID- 29524333 TI - CAAT/enhancer binding protein-homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice. AB - Ischemia/reperfusion injury (IRI) is one of the main causes of liver dysfunction after liver surgery. Involvement of endoplasmic reticulum (ER) stress in various diseases has been demonstrated, and CAAT/enhancer binding protein-homologous protein (CHOP) is a transcriptional regulator that is induced by ER stress. It is also a key regulator of ER stress-mediated apoptosis. The aim of this study was to investigate the role of CHOP in liver IRI. Wild type (WT) and CAAT/enhancer binding protein-homologous protein knockout (CHOP-/-) mice were subjected to 70% liver warm ischemia/reperfusion for 60 minutes. At different times after reperfusion, liver tissues and blood samples were collected for evaluation. Induction of ER stress including CHOP expression was ascertained. Liver damage was evaluated based on serum liver enzymes, liver histology, and neutrophil infiltration. Hepatocyte death including apoptosis was assessed. Liver warm IRI induced ER stress in both WT and CHOP-/- mice. In addition, CHOP expression was up-regulated in WT mice. At 6 hours after reperfusion, liver damage was attenuated in CHOP-/- mice. On the basis of terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling staining, apoptotic and necrotic cells were significantly reduced in CHOP-/- mice. CHOP deficiency also reduced the cleavage of caspase 3 and expression of the proapoptotic protein B cell lymphoma 2-associated X protein. Liver IRI induces CHOP expression, and CHOP deficiency attenuates liver IRI by inhibiting apoptosis. Elucidation of the function of CHOP in liver IRI may contribute to further investigation for a therapy against liver IRI associated with the ER stress pathway. Liver Transplantation 24 645-654 2018 AASLD. PMID- 29524335 TI - Eculizumab in refractory myasthenic crisis. PMID- 29524336 TI - Robotic complete mesocolic excision with high vascular tie and intracorporeal side-to-side anastomosis with omental pedicle flap - a video vignette. PMID- 29524334 TI - In vitro and in vivo characterization of the bifunctional MU and delta opioid receptor ligand UFP-505. AB - BACKGROUND AND PURPOSE: Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reducing side-effects. We have evaluated the mixed MU opioid receptor agonist/ delta opioid receptor antagonist UFP-505 in vitro and in vivo. EXPERIMENTAL APPROACH: We measured receptor density and function in single MU, delta and MU /delta receptor double expression systems. GTPgamma35 S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment. In some experiments, we collected tissues to measure receptor densities. KEY RESULTS: UFP-505 bound to MU receptors with full agonist activity and to delta receptors as a low efficacy partial agonist At MU, but not delta receptors, UFP-505 binding recruited arrestin. Unlike morphine, UFP-505 treatment internalized MU receptors and there was some evidence for internalization of delta receptors. Similar data were obtained in a MU /delta receptor double expression system. In rats, acute UFP-505 or morphine, injected intrathecally, was antinociceptive. In tissues harvested from these experiments, MU and delta receptor density was decreased after UFP-505 but not morphine treatment, in agreement with in vitro data. Both morphine and UFP-505 induced significant tolerance. CONCLUSIONS AND IMPLICATIONS: In this study, UFP-505 behaved as a full agonist at MU receptors with variable activity at delta receptors. This bifunctional compound was antinociceptive in rats after intrathecal administration. In this model, dual targeting provided no advantages in terms of tolerance liability. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc. PMID- 29524337 TI - Testing the dualistic model of passion using a novel quadripartite approach: A look at physical and psychological well-being. AB - OBJECTIVE: Passion research has focused extensively on the unique effects of both harmonious passion and obsessive passion (Vallerand, 2015). We adopted a quadripartite approach (Gaudreau & Thompson, 2010) to test whether physical and psychological well-being are distinctly related to subtypes of passion with varying within-person passion combinations: pure harmonious passion, pure obsessive passion, mixed passion, and non-passion. METHOD: In four studies (total N = 3,122), we tested whether passion subtypes were differentially associated with self-reported general health (Study 1; N = 1,218 undergraduates), health symptoms in video gamers (Study 2; N = 269 video game players), global psychological well-being (Study 3; N = 1,192 undergraduates), and academic burnout (Study 4; N = 443 undergraduates) using latent moderated structural equation modeling. RESULTS: Pure harmonious passion was generally associated with more positive levels of physical health and psychological well-being compared to pure obsessive passion, mixed passion, and non-passion. In contrast, outcomes were more negative for pure obsessive passion compared to both mixed passion and non-passion subtypes. CONCLUSIONS: This research underscores the theoretical and empirical usefulness of a quadripartite approach for the study of passion. Overall, the results demonstrate the benefits of having harmonious passion, even when obsessive passion is also high (i.e., mixed passion), and highlight the costs associated with a pure obsessive passion. PMID- 29524338 TI - Autonomous orientation predicts longevity: New findings from the Nun Study. AB - OBJECTIVE: Work on longevity has found protective social, cognitive, and emotional factors, but to date we have little understanding of the impact of motivational dynamics. Autonomy orientation, or stable patterns of self regulation, is theorized to be a protective factor for long-term mental and physical health (Ryan & Deci, 2017), and it is therefore a prime candidate for examining how stable psychosocial factors are linked to longevity, or life expectancy. METHOD: Essays written in the 1930s by participants in the Nun Study were coded for indicators of an autonomy orientation. These were selected in line with an extensive theoretical literature based in self-determination theory (Deci & Ryan, 1985). Essays were coded for the propensity for choice in action, susceptibility to pressure, self-reflection, integration of experiences, and parental support for autonomy. These coded variables were used to predict age of death. RESULTS: Using 176 codable essays provided by now-deceased participants, linear regression analyses revealed that choiceful behavior, self-reflection, and parent autonomy support predicted age of death. Participants who demonstrated these stable and beneficial motivational characteristics lived longer. CONCLUSIONS: Personality constructs reflecting a healthy form of self-regulation are associated with long-term health. Implications for health interventions are discussed. PMID- 29524339 TI - Becoming who you are: An integrative review of self-determination theory and personality systems interactions theory. AB - One of the enduring missions of personality science is to unravel what it takes to become a fully functioning person. In the present article, the authors address this matter from the perspectives of self-determination theory (SDT) and personality systems interactions (PSI) theory. SDT (a) is rooted in humanistic psychology; (b) has emphasized a first-person perspective on motivation and personality; (c) posits that the person, supported by the social environment, naturally moves toward growth through the satisfaction of basic psychological needs for autonomy, competence, and relatedness. PSI theory (a) is rooted in German volition psychology; (b) has emphasized a third-person perspective on motivation and personality; and (c) posits that a fully functioning person can form and enact difficult intentions and integrate new experiences, and that such competencies are facilitated by affect regulation. The authors review empirical support for SDT and PSI theory, their convergences and divergences, and how the theories bear on recent empirical research on internalization, vitality, and achievement flow. The authors conclude that SDT and PSI theory offer complementary insights into developing a person's full potential. PMID- 29524340 TI - Creation and Implementation of an Outpatient Pathway for Atrial Fibrillation in the Emergency Department Setting: Results of an Expert Panel. AB - Atrial fibrillation and flutter (AF) is a common condition among emergency department (ED) patients in the United States. Traditionally, ED care for primary complaints related to AF focus on rate control, and patients are often admitted to an inpatient setting for further care. Inpatient care may include further telemetry monitoring and diagnostic testing, rhythm control, a search for identification of AF etiology, and stroke prophylaxis. However, many patients are eligible for safe and effective outpatient management pathways. They are widely used in Canada and other countries but less widely adopted in the United States. In this project, we convened an expert panel to create a practical framework for the process of creating, implementing, and maintaining an outpatient AF pathway for emergency physicians to assess and treat AF patients, safely reduce hospitalization rates, ensure appropriate stroke prophylaxis, and effectively transition patients to longitudinal outpatient treatment settings from the ED and/or observation unit. To support local pathway creation, the panel also reached agreement on a protocol development plan, a sample pathway, consensus recommendations for pathway components, sample pathway metrics, and a structured literature review framework using a modified Delphi technique by a technical expert panel of emergency medicine, cardiology, and other stakeholder groups. PMID- 29524341 TI - Geographical discrimination of Glechomae Herba based on fifteen phenolic constituents determined by LC-MS/MS method combined with chemometric methods. AB - Glechomae Herba (GH) is rich in bioactive phenolic constituents and is widely used for treatment of cholelithiasis, urolithiasis and dropsy. The simultaneous determination of phenolic constituents in GH from different geographical origins is significant for authentication and quality control purposes. In this study, we developed a strategy integrating targeted analysis and chemometric methods for quality evaluation and discrimination of GH from different geographical origins. Firstly, an accurate and reliable liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of 15 phenolic constituents in GH from different geographical origins. The established method was well validated in terms of desirable specificity, linearity, precision and accuracy. Secondly, the quantitative data were subjected to principal component analysis and orthogonal partial least squares discriminant analysis. Thirdly, a heatmap visualization was employed for clarifying the distribution of 15 phenolic compounds in GH from different geographical origins. These results indicated that GH samples from Shandong province obviously differ from those from other provinces in the content of bioactive phenolic constituents. Collectively, the proposed platform might be a suitable tool for quality evaluation and discrimination of GH from different geographical origins, providing promising perspectives in tracking the formulation processes of traditional Chinese medicine products. PMID- 29524342 TI - Driving under the influence of cocaine: Quantitative determination of basic drugs in oral fluid obtained during roadside controls and a controlled study with cocaine users. AB - Using the Belgian Drugs and Driving procedure, 36% of the cocaine-positive oral fluid (OF) screening results were not confirmed in plasma. This study investigates the impact of the choice of screening devices and confirmation matrix on the detection of cocaine use. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method quantifying cocaine, benzoylecgonine (BZE), and other basic drugs in OF was developed and validated. This method monitored OF samples obtained either from a roadside (n = 12) or a double-blind controlled study with cocaine users (n = 10) who were given either a capsule containing 300 mg of cocaine-HCl or a placebo. The OF data were compared to plasma concentrations to obtain concentration-time profiles. In addition, the sensitivity and accuracy of the Drugwipe5S(r) was assessed. A significant difference between the OF volume collected at baseline/placebo (median 0.93 mL [range 0.43-1.92 mL]) or after cocaine-HCL intake (0.79 mL [0.30-1.21 mL]) was observed. The median OF/Plasma at the 3 collection time points were 10.7, 13.8, 6.7 for cocaine and 0.8, 1.7, 0.8 for BZE, respectively. The Drugwipe5S(r) detected cocaine use until at least 4 hours after intake. When applying the Belgian legal confirmation decision limit of 10 ng/mL in OF, an accuracy of 75% 98% was observed, depending on the study setting. Cocaine concentrations in OF were much higher and were detected longer as compared to plasma, when applying the same decision limit. From a toxicological viewpoint, the longer detection window with the higher sensitivity of Cocaine and BZE is beneficial to detect drivers in the crash/fatigue phase. PMID- 29524343 TI - Translation and validation of the Chinese powerlessness assessment tool. AB - The objectives of this study were to translate the powerlessness assessment tool (PAT) into Chinese, and to evaluate its psychometric performance. The PAT was translated into Chinese and was evaluated in patients with chronic wounds. Mean PAT scores were compared between various wound types to evaluate the scale's power to differentiate wound severity (PUSH score). There were 154 consecutive patients included in this study. All items were included, and the results of item domain correlation (r ranged from 0.838 to 0.967) and small-group analysis (critical ratio, p < 0.05) were satisfactory. Furthermore, the Chinese PAT also showed good criterion validity when correlated with the Cardiff wound impact schedule (r = 0.726, p < 0.01). Exploratory factor analysis of these items extracted only two domains instead of the hypothesized three domains: self perception of behavioral control and decision making (9 items) and emotional responses to perceived control (3 items), explained 82.045% of the variance. Sensitivity was demonstrated between patients with different activity of daily living, wound severity (PUSH score) and wound types. The internal consistency of all scales of the Chinese PAT was consistently high (Cronbach's alpha ranged from 0.939 to 0. 965) and split-half reliability was 0.901. In conclusion, the validated Chinese PAT has good psychometric properties, and may be used to objectively evaluate the powerlessness experience of Chinese patients with chronic wounds. PMID- 29524344 TI - Knights Without Armor. PMID- 29524345 TI - Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of nicotine and its metabolites in placenta and umbilical cord. AB - Tobacco exposure during pregnancy is associated with obstetric and fetal complications. We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine nicotine, cotinine, and hydroxycotinine (OH-cotinine) in placenta (PL) and umbilical cord (UC). Specimens were homogenized in water, followed by solid-phase extraction. Chromatographic separation was performed using an Atlantis(r) HILIC Silica column. Detection was accomplished in electrospray in positive mode. Method validation included: linearity (5 to 1000 ng/g), accuracy (86.9 to 105.2% of target concentration in PL, and 89.1 to 105.0% in UC), imprecision (6.8 to 11.8% in PL, and 7.6 to 12.2% in UC), limits of detection (2 ng/g for cotinine and OH-cotinine, and 5 ng/g for nicotine) and quantification (5 ng/g), selectivity (no endogenous or exogenous interferences), matrix effect (-34.1 to -84.5% in PL, %CV = 9.1-24.0%; -18.9 to 84.7% in UC, %CV = 10.2-23.9%), extraction efficiency (60.7 to 131.5% in PL, and 64.1 to 134.2% in UC), and stability 72 h in the autosampler (<11.5% loss in PL, and < 13% loss in UC). The method was applied to 14 PL and UC specimens from tobacco users during pregnancy. Cotinine (6.8-312.2 ng/g in PL; 6.7-342.3 ng/g in UC) was the predominant analyte, followed by OH-cotinine (10 mg of pure protein per liter of cell culture under deuterated conditions) and that protein solubility is unaffected at the crystallization concentrations tested. Using unlabeled carbon source and recycled heavy water, we were able to get 65-77% deuterium incorporation, sufficient for most neutron based techniques, and in a very cost-effective way. For most deuterated proteins characterized in the literature, the solubility and thermal stability is reduced. The data reported here is consistent with these observations and it was clear that there are measurable differences between hydrogenous and deuterated versions of the same protein in Tm and how they crystallize. PMID- 29524428 TI - Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini. AB - Staphylococcus aureus and related species are highly adapted to their hosts and have evolved numerous strategies to evade the immune system. S. aureus shows resistance to killing following uptake into the phagosome, which suggests that the bacterium evades intracellular killing mechanisms used by neutrophils. We recently discovered an S. aureus protein (SPIN for Staphylococcal Peroxidase INhibitor) that binds to and inhibits myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. To allow for comparative studies between multiple SPIN sequences, we identified a panel of homologs from species closely related to S. aureus. Characterization of these proteins revealed that SPIN molecules from S. agnetis, S. delphini, S. schleiferi, and S. intermedius all bind human MPO with nanomolar affinities, and that those from S. delphini, S. schleiferi, and S. intermedius inhibit human MPO in a dose-dependent manner. A 2.4 A resolution co-crystal structure of SPIN-delphini bound to recombinant human MPO allowed us to identify conserved structural features of SPIN proteins, and to propose sequence-dependent physical explanations for why SPIN-aureus binds human MPO with higher affinity than SPIN-delphini. Together, these studies expand our understanding of MPO binding and inhibition by a recently identified component of the staphylococcal innate immune evasion arsenal. PMID- 29524430 TI - Biophysical and biochemical studies on glycoxidatively modified human low density lipoprotein. AB - Methylglyoxal (MGO), a reactive dicarbonyl metabolite is a potent arginine directed glycating agent which has implications for diabetes-related complications. Dicarbonyl metabolites are produced endogenously and in a state of misbalance, they contribute to cell and tissue dysfunction through protein and DNA modifications causing dicarbonyl stress. MGO is detoxified by glyoxalase 1 (GLO1) system in the cytoplasm. Reactive oxygen species (ROS) are known to aggravate the glycation process. Both the processes are closely linked, and their combined activity is often referred to as "glycoxidation" process. Glycoxidation of proteins has several consequences such as type 2 diabetes mellitus (T2DM), aging etc. In this study, we have investigated the glycation of low-density lipoprotein (LDL) using different concentrations of MGO for varied incubation time periods. The structural perturbations induced in LDL were analyzed by UV Vis, fluorescence, circular dichroism spectroscopy, molecular docking studies, polyacrylamide gel electrophoresis, FTIR, thermal denaturation studies, Thioflavin T assay and isothermal titration calorimetry. The ketoamine moieties, carbonyl content and HMF content were quantitated in native and glycated LDL. Simulation studies were also done to see the effect of MGO on the secondary structure of the protein. We report structural perturbations, increased carbonyl content, ketoamine moieties and HMF content in glycated LDL as compared to native analog (native LDL). We report the structural perturbations in LDL upon modification with MGO which could obstruct its normal physiological functions and hence contribute to disease pathogenesis and associated complications. PMID- 29524433 TI - Reply by Authors. PMID- 29524432 TI - Editorial Comment. PMID- 29524431 TI - A critical evaluation of the Beckman Coulter Access hsTnI: Analytical performance, reference interval and concordance. AB - INTRODUCTION: We investigated the analytical performance, outlier rate, carryover and reference interval of the Beckman Coulter Access hsTnI in detail and compared it with historical and other commercial assays. MATERIALS AND METHODS: We compared the imprecision, detection capability, analytical sensitivity, outlier rate and carryover against two previous Access AccuTnI assay versions. We established the reference interval with stored samples from a previous study and compared the concordances and variances with the Access AccuTnI+3 as well as with two commercial assays. RESULTS: The Access hsTnI had excellent analytical sensitivity with the calibration slope 5.6 times steeper than the Access AccuTnI+3. The detection capability was markedly improved with the SD of the blank 0.18-0.20 ng/L, LoB 0.29-0.33 ng/L and LoD 0.58-0.69 ng/L. All the reference interval samples had a result above the LoB value. At a mean concentration of 2.83 ng/L the SD was 0.28 ng/L (CV 9.8%). Carryover (0.005%) and outlier (0.046%) rates were similar to the Access AccuTnI+3. The combined male and female 99th percentile reference interval was 18.2 ng/L (90% CI 13.2-21.1 ng/L). Concordance amongst the assays was poor with only 16.7%, 19.6% and 15.2% of samples identified by all 4 assays as above the 99th, 97.5th and 95th percentiles. Analytical imprecision was a minor contributor to the observed variances between assays. CONCLUSION: The Beckman Coulter Access hsTnI assay has excellent analytical sensitivity and precision characteristics close to zero. This allows cTnI measurement in all healthy individuals and the capability to identify numerically small differences between serial samples as statistically significant. Concordance in healthy individuals remains poor amongst assays. PMID- 29524434 TI - Epidermal regulation of bone morphogenesis through the development and regeneration of osteoblasts in the zebrafish scale. AB - Bone is a connective tissue composed of many cell types, including osteoblasts. How bones acquire their unique size and shape during development remains poorly understood. Herein we investigated the molecular and cellular mechanisms of bone morphogenesis in the zebrafish scale by using transgenic lines to enable visualization of specific types of osteoblasts. We demonstrate that the zebrafish scale contains three distinct types of osteoblasts: (i) a monolayer of central osteoblasts along the inner surface of scales; (ii) marginal osteoblasts elongated along the scale edge; and (iii) submarginal osteoblasts located between the central and marginal osteoblast populations. The size of the central osteoblasts increases progressively during development, suggesting that scale growth is mediated primarily by cell growth rather than the recruitment of new osteoblasts. In addition, the total number of central osteoblasts increases in regenerated scales and is correlated with scale size, possibly allowing for the rapid growth of regenerating scales. Moreover, osteoblast proliferation is not detected during regeneration, suggesting that the osteoblasts originate from post mitotic precursor cells. Sonic hedgehog a (shha) is expressed in the epidermal cells that make contact with the marginal osteoblasts. Pharmacological inhibition of Hedgehog (Hh) signaling during regeneration reduces the number of marginal osteoblasts and interferes with scale growth, indicating that epidermis-derived Shh regulates scale regeneration. Finally, genetic inhibition of Wnt/planar cell polarity (PCP) signaling in the epidermis results in misorientation of scales with regard to the body axis. These results reveal a novel role for the epidermis in the regulation of bone patterning, namely the regeneration of osteoblasts and directional bone growth. PMID- 29524435 TI - Cellular and network processes of noradrenergic modulation in the olfactory system. AB - Norepinephrine (NE), a central neuromodulator, influences sensory processing at the behavioral and physiological levels, potentially by regulating signal-to noise ratio in sensory neural networks. To understand neuromodulatory function at the perceptual level, one must understand the neural mechanisms underlying these effects. In this review, we illustrate this process using the olfactory system as a model system. We discuss basic computations in the olfactory system and their modulation by NE. We review known cellular effects of NE in the olfactory bulb and cortex and how these effects modulate olfactory computation. We then illustrate how computational modeling can relate cellular and perceptual data using the example of NE modulation of odor detection thresholds. PMID- 29524437 TI - Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices. AB - The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 uM, 1 uM and 10 uM) and mGluR5 positive allosteric modulator CDPPB (1 uM and 10 uM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release. PMID- 29524436 TI - Early onset cigarette smokers exhibit greater P300 reactivity to smoking-related stimuli and report greater craving. AB - Adolescence is a period during which a number of critical neuromaturation processes occur and the vulnerability for developing nicotine dependence is extremely high. Thus, early-onset (EO; age < 16 years old), relative to late onset (LO; age >= 16 years old), tobacco smoking may be uniquely deleterious for developmentally immature systems that regulate neural signaling reactivity. This study investigated how age of tobacco smoking onset affects neurophysiological measures of smoking cue reactivity and reported craving in adult smokers. EO smokers (EOS; n = 8; 4 females), LO smokers (LOS; n = 10; 5 females), and healthy non-smokers (HNS; n = 10; 5 females) participated in an event-related potential (ERP) cue reactivity study with tactile and image stimuli. Participants handled neutral objects during one interval and smoking-related objects during a second interval. After each interval, they viewed smoking-related, neutral, or arousing images using an oddball paradigm. P300 ERPs and craving for tobacco were recorded during each session. P300 amplitudes were significantly higher in central midline (Cz) channel to smoking, but not neutral or arousing, images after handling smoking objects. Specifically, Cz P300 smoking amplitudes were significantly greater in EOS, relative to LOS and HNS, and associated with greater craving at baseline. There were no other group differences in mood or craving. EOS exhibited greater P300 reactivity to smoking-related stimuli, relative to LOS, suggesting a more sensitized neural response. EO smoking during early neuromaturation may alter neurophysiological signaling involved in responding to smoking-related stimuli, which could impact the outcome of smoking cessation interventions. PMID- 29524438 TI - Effects of combined treatment with ochratoxin A and citrinin on oxidative damage in kidneys and liver of rats. AB - A multimycotoxin analysis approach in grains results in frequent simultaneous findings of nephrotoxic mycotoxins ochratoxin A (OTA) and citrinin (CTN). The mechanism of CTN and OTA toxicities in biological systems is not fully understood but it is known that oxidative stress is involved. In this study, oxidative damage of DNA, lipids, and the concentration of glutathione (GSH), as well as possible antioxidative effects of resveratrol (RSV) were studied in vivo. Male adult Wistar rats were treated orally with OTA (0.125 and 0.250 mg kg-1 b.w.), RSV (20 mg kg-1 b.w.) for 21 days, CTN (20 mg kg-1 b.w.) for two days or with their combinations. The hOGG1 modified comet assay revealed kidneys and liver oxidative DNA damage in OTA + CTN treated animals, which was not reversed by RSV. CTN did not reduce glutathione (GSH) or increase malondialdehyde (MDA) concentration in any tissue, while OTA reduced kidneys GSH and increased kidneys and liver MDA. RSV increased GSH concentrations in all tissues and decreased MDA concentration in the liver only. Oxidative stress is involved in the toxicity of OTA and CTN but it seems that it differs significantly in organs. Most of the effects on GSH and MDA in combined toxicity may be attributed to the toxic effects of OTA. RSV was effective in restoring the depleted GSH in all tissues but had no effect on the MDA concentration and DNA damage. PMID- 29524439 TI - Physicochemical characterization of E. coli-derived human serum albumin and its comparison with the human plasma counterpart reveals it as a promising biosimilar. AB - Human serum albumin one of the most demanded proteins possess an array of clinical and biotechnological applications. Currently, the prime source for HSA production is the human blood which possesses the risk of pathogen contamination and is limited. Thus, there exists an indispensable need to promote non-animal derived HSA production. In the present work, we have exploited the opportunity and promoted the preparation of pathogen-free rHSA from the E. coli host which is blessed with numerous advantages like scalability, cost-effectiveness etc. Upon overcoming the difficulties to produce functional rHSA in E. coli, through engineering the biological system of protein folding in the cell, the E. coli derived rHSA has been purified to homogeneity. Its detailed physicochemical characterization has been performed, by monitoring its conformational properties, secondary and tertiary structure elements, surface properties, ligand binding properties, stability issues etc. These parameters of the recombinant protein have been compared with the naturally occurring protein from the human source. The outcome of the comparison reveals that the recombinant protein resembles exactly the same as the natural one. Hence, we propose and promote that the E. coli-derived rHSA is an ideal biosimilar for human blood plasma-derived serum albumin. PMID- 29524440 TI - A novel model for protein sequence similarity analysis based on spectral radius. AB - Advances in sequencing technologies led to rapid increase in the number and diversity of biological sequences, which facilitated development in the sequence research. In this paper, we present a new method for analyzing protein sequence similarity. We calculated the spectral radii of 20 amino acids (AAs) and put forward a novel 2-D graphical representation of protein sequences. To characterize protein sequences numerically, three groups of features were extracted and related to statistical, dynamics measurements and fluctuation complexity of the sequences. With the obtained feature vector, two models utilizing Gaussian Kernel similarity and Cosine similarity were built to measure the similarity between sequences. We applied our method to analyze the similarities/dissimilarities of four data sets. Both proposed models received consistent results with improvements when compared to that obtained by the ClustalW analysis. The novel approach we present in this study may therefore benefit protein research in medical and scientific fields. PMID- 29524442 TI - Nanocrystals of a potent p38 MAPK inhibitor embedded in microparticles: Therapeutic effects in inflammatory and mechanistic murine models of osteoarthritis. AB - This study aimed to formulate nanocrystal-polymer particles (NPPs) containing the potent p38alpha/beta MAPK inhibitor PH-797804 (PH-NPPs) and to test their extended-release properties over months in comparison to those of conventional PH microparticles for the intra-articular treatment of inflammatory and mechanistic murine models mirroring aspects of human osteoarthritis (OA). The steps of the study were (i) to formulate PH nanocrystals (wet milling), (ii) to encapsulate a high payload of PH nanocrystals in fluorescent particles (spray drying), (iii) to assess in vitro drug release, (iv) to evaluate PH-NPP toxicity to human OA synoviocytes (MTT test), (v) to investigate the in vivo bioactivity of the particles in mice in an inflammatory antigen-induced arthritis (AIA) model (using histology and RT-qPCR) and (vi) to investigate the in vivo bioactivity of the particles in the OA model obtained by mechanistic surgical destabilization of the medial meniscus (DMM) (using histology, micro-CT, and multiplex ELISA). The PH nanocrystals stabilized with vitamin E TPGS had a monomodal size distribution. The PH-NPPs had a mean diameter of 14.2 MUm and drug loading of ~31.5% (w/w), and ~20% of the PH was released over 3 months. The NPPs did not exhibit toxicity to cultured human OA synoviocytes at 100 * IC50. Finally, in vivo studies showed good retention of PH-NPPs in the joint and adjacent tissues for up to 2 months, and the PH-NPPs exhibited good functional relevance by significantly reducing inflammation and joint destruction and by inhibiting several biomarkers (e.g., IL 1beta). In conclusion, local treatment with PH-NPPs, used as an extended-release drug delivery system, improved inflammation and joint degradation in two distinct mouse models, indicating treatment potential for human OA. PMID- 29524441 TI - Modelling the effects of bacterial cell state and spatial location on tuberculosis treatment: Insights from a hybrid multiscale cellular automaton model. AB - If improvements are to be made in tuberculosis (TB) treatment, an increased understanding of disease in the lung is needed. Studies have shown that bacteria in a less metabolically active state, associated with the presence of lipid bodies, are less susceptible to antibiotics, and recent results have highlighted the disparity in concentration of different compounds into lesions. Treatment success therefore depends critically on the responses of the individual bacteria that constitute the infection. We propose a hybrid, individual-based approach that analyses spatio-temporal dynamics at the cellular level, linking the behaviour of individual bacteria and host cells with the macroscopic behaviour of the microenvironment. The individual elements (bacteria, macrophages and T cells) are modelled using cellular automaton (CA) rules, and the evolution of oxygen, drugs and chemokine dynamics are incorporated in order to study the effects of the microenvironment in the pathological lesion. We allow bacteria to switch states depending on oxygen concentration, which affects how they respond to treatment. This is the first multiscale model of its type to consider both oxygen driven phenotypic switching of the Mycobacterium tuberculosis and antibiotic treatment. Using this model, we investigate the role of bacterial cell state and of initial bacterial location on treatment outcome. We demonstrate that when bacteria are located further away from blood vessels, less favourable outcomes are more likely, i.e. longer time before infection is contained/cleared, treatment failure or later relapse. We also show that in cases where bacteria remain at the end of simulations, the organisms tend to be slower-growing and are often located within granulomas, surrounded by caseous material. PMID- 29524443 TI - Readily prepared biodegradable nanoparticles to formulate poorly water soluble drugs improving their pharmacological properties: The example of trabectedin. AB - The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis(r). The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis(r), but does not have the drawback of severe local vascular toxicity in the injection site. PMID- 29524444 TI - Early and late selection processes have separable influences on the neural substrates of attention. AB - To improve our understanding of the mechanisms of target selection, we examined how the spatial separation of salient items and their similarity to a pre-defined target interact using lateralised electrophysiological correlates of visual spatial attention (N2pc component) and visual short-term memory (VSTM; SPCN component). Using these features of target selection, we sought to expand on previous work proposing a model of early and late selection, where the N2pc is suggested to reflect the selection probability of visual stimuli (Aubin and Jolicoeur, 2016). The authors suggested that early-selection processes could be enhanced when items are adjacent. In the present work, the stimuli were short oriented lines, all of which were grey except for two that were blue and hence salient. A decrease in N2pc amplitude with decreasing spatial separation between salient items was observed. The N2pc increased in amplitude with increasing similarity of salient distractors to the target template, but only in target absent trials. There was no interaction between these two factors, suggesting that separable attentional mechanisms influenced the N2pc. The findings suggest that selection is initially based on easily-distinguished attributes (i.e., both blue items) followed by a later identification-based process (if necessary), which depends on feature similarity to a target template. For the SPCN component, the results were in line with previous work: for target-present trials, an increase in similarity of salient distractors was associated with an increase in SPCN amplitude, suggesting more information was maintained in VSTM. In sum, results suggest there is a need for further inspection of salient distractors when they are similar to the target, increasing the need for focal attention, demonstrated by an increase in N2pc amplitude, followed by a higher probability of transfer to VSTM, demonstrated by an increase in SPCN amplitude. PMID- 29524445 TI - Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. AB - Favipiravir, also known as T-705, is an antiviral drug that has been approved in 2014 in Japan to treat pandemic influenza virus infections. The drug is converted intracellularly into its active, phosphoribosylated form, which is recognized as a substrate by the viral RNA-dependent RNA polymerase. Interestingly, besides its anti-influenza virus activity, this molecule is also able to inhibit the replication of flavi-, alpha-, filo-, bunya-, arena-, noro-, and of other RNA viruses, which include neglected and (re)emerging viruses for which no antiviral therapy is currently available. We will discuss the potential of favipiravir as a broad-spectrum countermeasure against infections caused by such neglected RNA viruses. Favipiravir has already been used off-label to treat patients infected with the Ebola virus and the Lassa virus. Because of the particular set-up of the clinical trials during these outbreaks, clear conclusions on the efficacy of favipiravir could not be made. For several viruses, it was demonstrated that the barrier of resistance development against favipiravir is high. Favipiravir has been shown to be well tolerated in healthy volunteers and in influenza virus infected patients; however, caution is needed because of the teratogenic risks of this molecule. Because of its antiviral activity against different RNA viruses and its high barrier for resistance, the potential of favipiravir as a broad spectrum antiviral seems promising, but safety and potency issues should be overcome before this drug or similar molecules could be used to treat large patient groups. PMID- 29524446 TI - Beta-glucan enhances the response to SVCV infection in zebrafish. AB - The antiviral effects of beta-glucan, an immunostimulatory agent were studied in zebrafish both in vitro and in vivo. Here we show that zebrafish ZF4 cells as well as whole fish primed with yeast beta-glucan zymosan exhibited increased cytokine expression and elevated response to spring viremia of carp virus (SVCV) infection. In vitro, previous treatment of beta-glucan enhanced ZF4 cell viability against SVCV infection which is associated to the activation of interferon signaling pathway and inflammatory cytokines gene expression. In vivo, the SVCV-infected fish primed with beta-glucan had a higher survival rate (~73%) than the control SVCV-infected group (~33%). Additionally, up-regulation of the expression of a set of genes involved in innate immune response was detected in zebrafish intraperitoneally injected of beta-glucan: il1b, il6, il8, il10 and tnfa transcripts showed increased expression that appear to be rapid (2 days) but not long-lived (less than 2 weeks). The present study is, to our knowledge, the first to combine cell culture and in vivo approaches to describe host response to beta-glucan stimulation and viral infection in zebrafish. PMID- 29524447 TI - Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding. AB - The objective was to compare, with the same data set, the predictive performance of 3 in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (also referring to HepatoPac(r)) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e., direct scaling method without binding correction, conventional method based either on the unbound fraction in plasma (fup) according to the free-drug hypothesis, or based on an fup value adjusted for the albumin [ALB]-facilitated hepatic uptake phenomenon). Accordingly, the role of ALB binding was specifically challenged, and consequently, the ALB production was monitored in parallel to the metabolic stability. The ALB concentration data were used to compare the in vitro assays and to adjust the value of fup of each drug to mimic the ALB-facilitated hepatic uptake phenomenon. The results confirmed that the direct and conventional IVIVE methods generally overpredicted and underpredicted the CL in vivo in humans, respectively. However, the underprediction of the conventional IVIVE method based on fup was significantly reduced from data generated with the HepatoPac(r) system compared with the 2 other in vitro assays, which is possibly because that system is producing ALB at a rate much closer to the in vivo condition in liver. Hence, these observations suggest that the presence of more ALB molecules per hepatocyte in that HepatoPac(r) system may have facilitated the hepatic uptake of several bound drugs because their intrinsic CL was increased instead of being decreased by the ALB binding effect. Accordingly, the IVIVE method based on the fup value adjusted for the ALB-facilitated uptake phenomenon gave the lowest prediction bias from the statistical analyses. This study indicated that the HepatoPac(r) system combined with the adjusted value of fup was the most reliable IVIVE method and revealed the importance of quantifying the in vitro-to-in vivo variation of ALB concentration to improve the CL predictions, which would help any future physiologically based pharmacokinetics modeling exercise. PMID- 29524448 TI - Aegeline inspired synthesis of novel beta3-AR agonist improves insulin sensitivity in vitro and in vivo models of insulin resistance. AB - BACKGROUND AND PURPOSE: In our drug discovery program of natural product, earlier we have reported Aegeline that is N-acylated-1-amino-2- alcohol, which was isolated from the leaves of Aeglemarmelos showed anti-hyperlipidemic activity for which the QSAR studies predicted the compound to be the beta3-AR agonist, but the mechanism of its action was not elucidated. In our present study, we have evaluated the beta3-AR activity of novel N-acyl-1-amino-3-arylopropanol synthetic mimics of aegeline and its beneficial effect in insulin resistance. In this study, we have proposed the novel pharmacophore model using reported molecules for antihyperlipidemic activity. The reported pharmacophore features were also compared with the newly developed pharmacophore model for the observed biological activity. EXPERIMENTAL APPROACH: Based on 3D pharmacophore modeling of known beta3AR agonist, we screened 20 synthetic derivatives of Aegeline from the literature. From these, the top scoring compound 10C was used for further studies. The in-slico result was further validated in HEK293T cells co trransfected with human beta3-AR and CRE-Luciferase reporter plasmid for beta3-AR activity.The most active compound was selected and beta3-AR activity was further validated in white and brown adipocytes differentiated from human mesenchymal stem cells (hMSCs). Insulin resistance model developed in hMSC derived adipocytes was used to study the insulin sensitizing property. 8 week HFD fed C57BL6 mice was given 50 mg/Kg of the selected compound and metabolic phenotyping was done to evaluate its anti-diabetic effect. RESULTS: As predicted by in-silico 3D pharmacophore modeling, the compound 10C was found to be the most active and specific beta3-AR agonist with EC50 value of 447 nM. The compound 10C activated beta3AR pathway, induced lipolysis, fatty acid oxidation and increased oxygen consumption rate (OCR) in human adipocytes. Compound 10C induced expression of brown adipocytes specific markers and reverted chronic insulin induced insulin resistance in white adipocytes. The compound 10C also improved insulin sensitivity and glucose tolerance in 8 week HFD fed C57BL6 mice. CONCLUSION: This study enlightens the use of in vitro insulin resistance model close to human physiology to elucidates the insulin sensitizing activity of the compound 10C and edifies the use of beta3AR agonist as therapeutic interventions for insulin resistance and type 2 diabetes. PMID- 29524449 TI - Facilitation of fear learning by prior and subsequent fear conditioning. AB - Classical fear conditioning is perhaps the premier model system used to study the neurobiological basis of memory formation. Prior work has resulted in a good understanding of both the molecular mechanisms and neural circuits supporting this form of learning. However, much of what is known about these mechanisms comes from studies in which fear memory is acquired using a single, isolated training session. Given that we cannot divorce the acquisition of new information from the backdrop on which it occurs, studies are needed to determine how the acquisition of fear memory is affected by other learning events. Here, we used rats to describe the time course by which auditory fear conditioning can facilitate learning to a different fear learning event, which alone is insufficient to support long-term fear memory. First, we replicated previous findings showing that although a single trial of light and shock produces little evidence of memory, two identical trials spaced 60 min or 24 h apart support long term memory. Next, we report that a typical auditory fear conditioning session facilitated memory formation when rats were subsequently exposed to a single trial of light and shock 60 min or 24 h, but not 4 min, later. Finally, we show that learning can be enhanced retroactively if auditory fear conditioning occurs 60 min, but not 24 h, after a single light-shock pairing. These data demonstrate that a weak fear conditioning trial can be enhanced by prior and subsequent fear conditioning depending on the timing between training events. PMID- 29524450 TI - Visual mismatch response and fMRI signal adaptation correlate in the occipital temporal cortex. AB - Several electrophysiological studies found response differences to a given stimulus when it is repeated frequently as compared to when it occurs rarely in oddball sequences. Initially defined in acoustic perception, such difference also exists in the visual modality and is referred to as visual mismatch negativity (vMMN). However, the repetition of a stimulus also leads to the reduction of the blood oxygen-level dependent (BOLD) signal (fMRI adaptation, fMRIa) when compared to alternating stimuli in fMRI experiments. So far no study compared the vMMN to fMRIa within the same paradigm and participants. Here we tested the possible connection between fMRIa and vMMN in a visual oddball paradigm in two separate sessions, acquiring electrophysiological and neuroimaging data for real and false characters from the same participants. We found significant visual mismatch response (vMM) as well as fMRIa for both character types. Importantly, the magnitude of the vMM over the CP1 electrode cluster showed a significant correlation with the fMRIa within the letter form area, for real characters. This finding suggests that similar neural mechanisms are responsible for the two phenomena. PMID- 29524451 TI - Effects of intranasal oxytocin on satiety signaling in people with schizophrenia. AB - Overweight and obesity in schizophrenia are prevalent, affecting half to three quarters of people with schizophrenia. Hyperphagia and increased meal size have also been implicated as significant contributors to the weight gain problem. Oxytocin has shown to play a role in appetite control in humans and is considered an anorexigenic peptide. This two-day, within-subjects, challenge study involved the examination of satiety after administration of 24 IU oxytocin (intranasal) vs. placebo in participants with a DSM-IV diagnosis of schizophrenia (N = 16). Self reported satiety along with a preload-test meal paradigm were utilized as well as related laboratory measures (insulin, glucose, and leptin), and measures of taste and smell. There were no statistically significant differences between the groups on self-reported satiety or test meal consumption, insulin or glucose levels, or sensory measures. A significant treatment difference was found (F = 5.22, df = 1,97.6, p = 0.025), with a decrease in leptin in the oxytocin group post-administration, but no time effect (F = 1.67, df = 6,95.1, p = 0.180) or treatment by time interaction (F = 1.36. df = 3,4.16, p = 0.261). Despite the small sample and mostly negative findings, we encourage more work to use higher and repeated doses of oxytocin, and to further examine the effect of oxytocin on leptin in schizophrenia as this may be important for understanding both weight control and psychopathology. PMID- 29524452 TI - Protective effects of saffron and its active components against oxidative stress and apoptosis in endothelial cells. AB - In this study, we investigated the role of mitogen-activated protein kinase (MAPK) signaling pathways in mediation of the protective effects of saffron extract, saffron essential oil, safranal and crocin on bovine aortic endothelial cells against oxidative injury. The viability of cells in response to H2O2 induced toxicity (0.4, 2 and 10 mM) was measured using resazurin assay in the presence or absence of saffron extract (2-40 MUg/ml), saffron oil (2-40 MUg/ml), safranal (2-40 MUM) and crocin (2-40 MUM). Dichlorodihydrofluorescin diacetate was used as an indicator for the amount of reactive oxygen species (ROS) in cells at the same concentrations of samples as the former test. In addition, propidium iodide staining of the fragmented DNA was performed to measure the level of apoptotic cells by the application of 2-10 MUM of crocin and safranal. Finally, the proteins involved in apoptosis were detected using western blotting at the concentration of 0, 2, 10 MUM for crocin and safranal. The results indicated that all tested moieties improved viability and reduced ROS production in H2O2-treated cells (p < 0.001 compared to H2O2). In addition, a significant decrease in apoptosis (3-35%) was observed in the cells that were treated with crocin and safranal. The observed protective effects of crocin and safranal were associated with the activation of SAPK/JNK and inhibition of ERK 1/2 that are related to MAPK pathways. The antioxidant and anti-apoptotic activities of saffron and its ingredients in endothelial cells are mediated via MAPK signaling pathways and might be of therapeutic potential for endothelial dysfunctionalities. PMID- 29524453 TI - Cervical cancer screening in Montreal: Building evidence to support primary care and policy interventions. AB - In Canada, over 40% of invasive cervical cancers occur among women who have never been screened. Although 12% of Canadian women have never been screened, this number can be as high as 43% among certain social groups. Little is published on factors associated with screening uptake and inequalities among women residing in Quebec. Four waves of the Canadian Community Health Survey (2003, 2005, 2008, 2012, N = 6393) were utilized to assess lifetime screening and screening in the previous 3 years among women residing in Montreal. Chi-squared statistics were calculated, Poisson regression was utilized to model prevalence ratios, and prevalence differences were calculated. In total, 13.6% of women had never been screened and 12.1% had not been screened in the previous 3 years. Immigrant status was the strongest predictor of never being screened [recent vs non immigrant: Prevalence Ratio (PR), 3.9 (95% Confidence Interval (CI): 2.9-5.4)] and not having a primary care physician (PCP) was the strongest predictors of not being screened recently [PR = 3.0 (95% CI: 2.3-3.9)]. The two most common reasons for not being screened were not "know[ing] it was necessary" and not "get[ting] around to it." These results provide a description of sub-populations which might benefit from cervical screening interventions: immigrants and women without a PCP. Interventions targeting access to PCPs, expanding training of non-physicians to conduct screening, organized screening, or autoadministered screening test may mitigate inequalities. Future work should assess their acceptability and feasibility, and evaluate the impact of these types of primary care and policy interventions. PMID- 29524455 TI - A new selective broth enrichment automated method for detection of carbapenem resistant Enterobacteriaceae from rectal swabs. AB - We evaluated the performance of an automated, rapid (TAT 4-8 h), liquid-culture method for carbapenem-resistant Enterobacteriaceae (CRE) detection from rectal swabs, in a setting of KPC-producing Klebsiella pneumoniae endemicity. With 600 samples (22 positive for CRE, 3.7%), the system sensitivity and specificity, at 8 h, were 100% and 99.2%, respectively. PMID- 29524454 TI - Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes. AB - BACKGROUND: Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. PURPOSE: Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. EXPERIMENTAL APPROACH: We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1-20.0 mg/kg), and multiple ascending doses (1.0-20 mg/kg/day; 14 days treatment). KEY RESULTS: Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. CONCLUSIONS AND INTERPRETATIONS: Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day. PMID- 29524456 TI - From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression. AB - BACKGROUND: Biological pathways underlying major depressive disorder (MDD) can be viewed as systems biology networks. The psycho-immune-neuroendocrine (PINE) network comprises central nervous, immune, endocrine and autonomic systems, integrating biological mechanisms of MDD. Such networks exhibit recurrent motifs with specific functions, including positive and negative feedback loops, and are subject to critical transitions, influenced by feedback loop transitions (FLTs). AIMS: We aim to identify critical feedback loops and their FLTs, as well sentinel network nodes (SNNs), key network nodes that drive FLTs, within the PINE network. Examples of biomarkers are provided which may reflect early warning signs of impending critical transition to MDD. RESULTS: Disruption of homeostatic feedback loops reflects the physiological transition to MDD. Putative FLTs are identified within hypothalamic-pituitary-adrenal (HPA) and sympathetic-parasympathetic axes, the kynurenine pathway, gut function and dysbiosis. CONCLUSIONS: Progression from health to disease is driven by FLTs in the PINE network, which is likely to undergo changes characteristic of system instability. Biomarkers of system instability may effectively predict the critical transition to MDD. PMID- 29524457 TI - Factors Related to Nevus-Associated Cutaneous Melanoma: A Case-Case Study. AB - A proportion of cutaneous melanomas display neval remnants on histologic examination. Converging lines of epidemiologic and molecular evidence suggest that melanomas arising from nevus precursors differ from melanomas arising de novo. In a large, population-based study comprising 636 cutaneous melanomas subjected to dermatopathology review, we explored the molecular, host, and environmental factors associated with the presence of neval remnants. We found that nevus-associated melanomas were significantly associated with younger age at presentation, non-brown eye color, trunk site, thickness of less than 0.5 mm, and BRAFV600E mutation. Compared with patients with de novo melanomas, those with nevus-associated tumors were more likely to self-report many moles on their skin as a teenager (odds ratio = 1.94, 95% confidence interval = 1.01-3.72) but less likely to report many facial freckles (odds ratio = 0.49, 95% confidence interval = 0.25-0.96). They also had high total nevus counts (odds ratio = 2.18, 95% confidence interval = 1.26-3.78). On histologic examination, nevus-associated melanomas exhibited less dermal elastosis in adjacent skin compared with de novo melanomas (odds ratio = 0.55, 95% confidence interval = 0.30-1.01). These epidemiologic data accord with the emerging molecular paradigm that nevus associated melanomas arise through a distinct sequence of causal events that differ from those leading to other cutaneous melanomas. PMID- 29524458 TI - Neuroinflammatory priming to stress is differentially regulated in male and female rats. AB - Exposure to stressors can enhance neuroinflammatory responses, and both stress and neuroinflammation are predisposing factors in the development of psychiatric disorders. Females suffer disproportionately more from several psychiatric disorders, yet stress-induced changes in neuroinflammation have primarily been studied in males. Here we tested whether exposure to inescapable tail shock sensitizes or 'primes' neuroinflammatory responses in male and female rats. At 24 h post-stress, male and female rats exposed to a peripheral immune challenge enhanced neuroinflammatory responses and exacerbated anxiety- and depressive-like behaviors. These changes are likely glucocorticoid dependent, as administering exogenous CORT, caused a similar primed inflammatory response in the hippocampus of male and female rats. Further, stress disinhibited anti-inflammatory signaling mechanisms (such as CD200R) in the hippocampus of male and female rats. In males, microglia are considered the likely cellular source mediating neuroinflammatory priming; stress increased cytokine expression in ex vivo male microglia. Conversely, microglia isolated from stressed or CORT treated females did not exhibit elevated cytokine responses. Microglia isolated from both stressed male and female rats reduced phagocytic activity; however, suggesting that microglia from both sexes experience stress-induced functional impairments. Finally, an immune challenge following either stress or CORT in females, but not males, increased peripheral inflammation (serum IL-1beta). These novel data suggest that although males and females both enhance stress-induced neuroinflammatory and behavioral responses to an immune challenge, this priming may occur through distinct, sex-specific mechanisms. PMID- 29524459 TI - Current trends to comprehend lipid metabolism in diatoms. AB - Diatoms are the most dominant phytoplankton species in oceans and they continue to receive a great deal of attention because of their significant contributions in ecosystems and the environment. Due to triacylglycerol (TAG) profiles that are abundant in medium-chain fatty acids, diatoms have emerged to be better feed stocks for biofuel production, in comparison to the commonly studied green microalgal species (chlorophytes). Importantly, diatoms are also known for their high levels of the essential omega3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and are considered to be a promising alternative source of these components. The two most commonly exploited diatoms include Thalassiosira pseudonana and Phaeodactylum tricornutum. Although obvious similarities between diatoms and chlorophytes exist, there are some substantial differences in their lipid metabolism. This review provides an overview on lipid metabolism in diatoms, with P. tricornutum as the most explored model. Special emphasis is placed on the synthesis and incorporation of very long chain omega3 fatty acids into lipids. Furthermore, current approaches including genetic engineering and biotechnological methods aimed at improving and maximizing lipid production in P. tricornutum are also discussed. PMID- 29524461 TI - Endolymphatic Interventions for the Treatment of Chylothorax and Chylous Ascites in Neonates: Technical and Clinical Success and Complications. AB - BACKGROUND: The aim of this study was to report the technical and clinical success of performing minimally invasive endolymphatic embolization in neonates presenting with a chylothorax or chylous ascites. METHODS: Three neonates, 2 males and 1 female, with a mean age of 28 days (range: 19-39 days) presented with a chylothorax or chylous ascites that was refractory to conservative management. All 3 patients (1 previously reported) underwent intranodal lymphangiography, followed by thoracic duct embolization, with 1 patient undergoing additional sclerosis of the retroperitoneal abdominal lymphatics. RESULTS: Lymphangiography, thoracic duct embolization, and sclerosis of the retroperitoneal abdominal lymphatics were technically successful. The chylothorax resolved in both the patients. Persistent chylous ascites was noted after treatment which resolved after surgical placement of a vicryl mesh and fibrin sealant. One major complication occurred with nontarget embolization of glue into the lungs requiring embolectomy. CONCLUSIONS: Thoracic duct and retroperitoneal abdominal lymphatic embolization can be performed in neonates. Resolution of chylothorax was seen in 2 patients (one previously reported) after embolization, whereas 1 patient with chylous ascites required surgical management after endolymphatic intervention. PMID- 29524460 TI - Necroptosis in cardiovascular disease - a new therapeutic target. AB - Contrary to the apoptosis-necrosis binary view of cell death, recent experimental evidence demonstrates that several forms of necrosis, represented by necroptosis, are regulated or programmed in nature. Multiple death stimuli known to be associated with cardiovascular disease are capable of causing either apoptosis or necroptosis. Whether a cell dies from apoptosis or necroptosis has distinct consequences on inflammation. It is known that apoptosis, a non-lytic form of death mediated by the caspase family of proteases, does not generally evoke an immune response. Necroptosis, on the other hand, is a lytic form of cell death. Due to the rapid loss of plasma membrane integrity, cells dying from necroptosis release proinflammatory intracellular contents and subsequently cause inflammation. Our review delineates various genetic and biochemical evidence that demonstrates a compelling role of necroptosis in the pathogenesis and/or progression of cardiovascular disease including myocardial infarction, atherosclerosis, and aortic aneurysm. Through recent studies of necroptosis in cardiovascular diseases, we attempt to discuss the role of necroptosis in vascular inflammation as well as the potential of necroptosis inhibitors in future clinical management of cardiovascular events. Inhibiting necroptosis in the vasculature has an overall protective role and necroptosis may represent a new therapeutic target to prevent the development and progression of cardiovascular diseases. PMID- 29524463 TI - Nanoparticle titanium dioxide affects the growth and microRNA expression of switchgrass (Panicum virgatum). AB - Nanoparticle TiO2 is a common chemical used in daily life. As increasing usage of TiO2, it is becoming a potentially dangerous contaminant to the environment. However, the impact of TiO2 is not well understood. In this paper, switchgrass was employed to investigate the impacts of nanoparticle TiO2 on plant growth and development as well as the potential impact on the expression of microRNAs (miRNAs). TiO2 significantly affected switchgrass seed generation as well as plant growth and development in a dose-dependent manner. Particularly, TiO2 significantly inhibited root development. miRNA expressions were also significantly altered. Nanoparticle TiO2 may regulate plant development through controlling the expression of certain miRNAs. Among the 16 tested miRNAs, the expression of some miRNAs, such as miR390 and miR399 was increased with increasing TiO2 concentrations; the expression of some miRNAs, such as miR169 was decreased with increasing TiO2 concentrations; the other miRNAs show different expression patterns. PMID- 29524462 TI - Endovascular Repair of Blunt Thoracic Aortic Trauma: Is Postimplant Hypertension an Incidental Finding? AB - BACKGROUND: Blunt thoracic aortic injury (BTAI) is the second most common cause of death in trauma patients. Nowadays, thoracic endovascular aortic repair (TEVAR) has become the treatment of choice because of lower rates of mortality, paraplegia, and stroke. However, concerns have been raised whether graft implantation is related to the development of hypertension in the postoperative period. The aim of this study was to report short- and long-term outcomes of patients undergoing TEVAR for BTAIs at a tertiary hospital and to investigate postimplant hypertension. METHODS: Between January 2005 and January 2016, 23 patients with blunt thoracic aortic trauma underwent TEVAR. Median age was 44 years (range, 18-73). Among them, 14 (60.9%) patients were diagnosed with aortic rupture, whereas 9 (39.1%) with pseudoaneurysm. Alpha single thoracic stent graft was deployed in 21 patients, and the rest 2 patients received 2 stent grafts. RESULTS: Complete exclusion of the injury was feasible in all subjects (100% primary success). The left subclavian artery (SCA) was intentionally covered in 6 patients (26%). Intraoperative complications included one nonfatal stroke managed conservatively and one external iliac artery rupture treated with iliofemoral bypass. One patient (4.3%) died on the first postoperative day in the intensive care unit (ICU) because of hemorrhagic shock. The overall 30-day mortality and morbidity were 4.3% and 8.7%, respectively. New-onset postimplantation arterial hypertension was observed in 8 (34.8%) previously nonhypertensive patients. Younger age (P = 0.027) and SCA coverage (P = 0.01) were identified as potential risk factors for the development of postimplant hypertension, whereas the presence of concomitant injuries (P = 0.3) and intraoperative complications (P = 0.1) were not. After a median follow-up of 100 months (range, 18-120), 6 of them still remain on antihypertensive therapy, whereas the other 2 did not require permanent treatment. CONCLUSIONS: TEVAR is a safe approach in the treatment of BTAI associated with low short- and long-term morbidity and mortality rates. Lower age and SCA coverage may contribute to the development of postimplant hypertension. Further larger cohort studies are warranted to elucidate the underlying mechanisms of postimplant hypertension. PMID- 29524464 TI - Effects of shear stress on microalgae - A review. AB - Cultivation of microalgae requires consideration of shear stress, which is generated by operations such as mixing, circulation, aeration and pumping that are designed to facilitate mass and heat transfer as well as light distribution in cultures. Excessive shear stress can cause increased cell mortality, decreased growth rate and cell viability, or even cell lysis. This review examines the sources of shear stress in different cultivation systems, shear stress tolerance of different microalgal species and the physiological factors and environmental conditions that may affect shear sensitivity, and potential approaches to mitigate the detrimental effects of shear stress. In general, green algae have the greatest tolerance to shear stress, followed by cyanobacteria, haptophytes, red algae, and diatoms, with dinoflagellates comprising the most shear-sensitive species. The shear-sensitivity of microalgae is determined primarily by cell wall strength, cell morphology and the presence of flagella. Turbulence, eddy size, and viscosity are the most prominent parameters affecting shear stress to microalgal cells during cultivation. PMID- 29524465 TI - The antithrombotic, anticoagulant activity and toxicity research of ambinine, an alkaloid from the tuber of Corydalis ambigua var. amurensis. AB - Ambinine, the major alkaloid of the tuber of Corydalis ambigua var. amurensis, has protective effects on H9C2 myocardial cells. In the present paper, we observed that ambinine demonstrates activities of both anticoagulation and thrombolysis in vitro by significantly degrading the blood clot and delaying the plasma recalcification time (PRT) in a dose-dependent manner (0.5-2 mg/mL). We further studied its safety profile of acute and subacute toxicity by repeated dose intravenous injection. The median lethal dosage (LD50) of mice given by oral and intravenous administration of ambinine were approximate 800, 41.60 mg/kg, respectively. The acute toxicity research results suggested that compared with an intravenous administration, the oral route is safer to administer ambinine as the promising lead compound for thrombosis. In subacute toxicity research, when mice were given ambinine at doses of 1.40 and 2.10 mg/kg for 7 days by injection, significant alteration of the relative kidney weight, the relative liver weight and serum biochemistry parameters and marked histopathological changes of them were found. PMID- 29524466 TI - Will they like me? Neural and behavioral responses to social-evaluative peer feedback in socially and non-socially anxious females. AB - The current study examined neural and behavioral responses to social-evaluative feedback processing in social anxiety. Twenty-two non-socially and 17 socially anxious females (mean age = 19.57 years) participated in a Social Judgment Paradigm in which they received peer acceptance/rejection feedback that was either congruent or incongruent with their prior predictions. Results indicated that socially anxious participants believed they would receive less social acceptance feedback than non-socially anxious participants. EEG results demonstrated that unexpected social rejection feedback elicited a significant increase in theta (4-8 Hz) power relative to other feedback conditions. This theta response was only observed in non-socially anxious individuals. Together, results corroborate cognitive-behavioral studies demonstrating a negative expectancy bias in socially anxiety with respect to social evaluation. Furthermore, the present findings highlight a functional role for theta oscillatory dynamics in processing cues that convey social-evaluative threat, and this social threat-monitoring mechanism seems less sensitive in socially anxious females. PMID- 29524467 TI - Is it about me? Time-course of self-relevance and valence effects on the perception of neutral faces with direct and averted gaze. AB - Most face processing research has investigated how we perceive faces presented by themselves, but we view faces everyday within a rich social context. Recent ERP research has demonstrated that context cues, including self-relevance and valence, impact electrocortical and emotional responses to neutral faces. However, the time-course of these effects is still unclear, and it is unknown whether these effects interact with the face gaze direction, a cue that inherently contains self-referential information and triggers emotional responses. We primed direct and averted gaze neutral faces (gaze manipulation) with contextual sentences that contained positive or negative opinions (valence manipulation) about the participants or someone else (self-relevance manipulation). In each trial, participants rated how positive or negative, and how affectively aroused, the face made them feel. Eye-tracking ensured sentence reading and face fixation while ERPs were recorded to face presentations. Faces put into self-relevant contexts were more arousing than those in other-relevant contexts, and elicited ERP differences from 150 to 750 ms post-face, encompassing EPN and LPP components. Self-relevance interacted with valence at both the behavioural and ERP level starting 150 ms post-face. Finally, faces put into positive, self-referential contexts elicited different N170 ERP amplitudes depending on gaze direction. Behaviourally, direct gaze elicited more positive valence ratings than averted gaze during positive, self-referential contexts. Thus, self-relevance and valence contextual cues impact visual perception of neutral faces and interact with gaze direction during the earliest stages of face processing. The results highlight the importance of studying face processing within contexts mimicking the complexities of real world interactions. PMID- 29524468 TI - Characterizing age-related decline of recognition memory and brain activation profile in mice. AB - Episodic memory decline is one of the earlier deficits occurring during normal aging in humans. The question of spatial versus non-spatial sensitivity to age related memory decline is of importance for a full understanding of these changes. Here, we characterized the effect of normal aging on both non-spatial (object) and spatial (object location) memory performances as well as on associated neuronal activation in mice. Novel-object (NOR) and object-location (OLR) recognition tests, respectively assessing the identity and spatial features of object memory, were examined at different ages. We show that memory performances in both tests were altered by aging as early as 15 months of age: NOR memory was partially impaired whereas OLR memory was found to be fully disrupted at 15 months of age. Brain activation profiles were assessed for both tests using immunohistochemical detection of c-Fos (neuronal activation marker) in 3and 15 month-old mice. Normal performances in NOR task by 3 month-old mice were associated to an activation of the hippocampus and a trend towards an activation in the perirhinal cortex, in a way that did significantly differ with 15 month-old mice. During OLR task, brain activation took place in the hippocampus in 3 month-old but not significantly in 15 month-old mice, which were fully impaired at this task. These differential alterations of the object- and object-location recognition memory may be linked to differential alteration of the neuronal networks supporting these tasks. PMID- 29524469 TI - An evaluation of common markers of muscle denervation in denervated young-adult and old rat gastrocnemius muscle. AB - A large part of age-related muscle wasting is due to incomplete reinnervation of fibres that have become denervated following motoneuron loss. Neural cell adhesion molecule (NCAM) and sodium channel NaV1.5 are considered markers for denervation, but the time course of changes in their expression following denervation has never been systematically evaluated in young-adult and old muscle. To assess the time course of denervation-induced changes in their expression, the left gastrocnemius muscle in 15 young-adult (5-month) and 10 old (25-month) male Wistar rats was denervated for 1, 2 or 4 weeks, while the right muscle served as an internal control. Sections were stained for alpha bungarotoxin, to visualise the neuromuscular junctions, combined with NCAM, polysialylated NCAM (PSA-NCAM) or NaV1.5. In young-adult animals, denervation induced a transient decrease in junctional and cytoplasmic NCAM expression, while in the old NCAM expression was increased after 2 weeks. Cytoplasmic PSA-NCAM was increased in both young-adult and old fibres after 2 weeks denervation with a further increase after 4 weeks in the young only. The junctional PSA-NCAM was transiently increased or decreased in the young and old muscles, respectively. NaV1.5 expression decreased after 1 and 2 weeks of denervation in NaV1.5 in young muscle fibres before returning to control levels, whereas old muscle fibres displayed a transient increase after 1 week followed by a decrease and a return to control levels after 2 and 4 weeks respectively. In conclusion, NCAM and NaV1.5 are not unequivocally elevated with denervation and consequently are not adequate markers of fibre denervation. PMID- 29524470 TI - Reactivation of denervated Schwann cells by neurons induced from bone marrow derived mesenchymal stem cells. AB - The use of neurons induced from stem cells has been introduced as an effective strategy for promoting peripheral nerve regeneration (PNR). The evolution and role of native denervated Schwann cells (SCs) were often ignored when exploring the mechanisms underlying neural transplantation therapy for PNR. The aim of this study was to understand if following injury, native denervated SCs could be reactivated by transplanting of neurons induced from bone marrow-derived mesenchymal stem cells (NI-BMSCs) to promote PNR. We co-cultured denervated SCs with NI-BMSCs in vitro, tested the proliferation of denervated SCs, and measured the expression and secretion of neurotrophic factors and neural adhesion molecules of the denervated SCs. Concurrently, 48 adult male Sprague-Dawley rats were randomly divided into 4 even groups of 12 rats each: normal group, phosphate buffered saline (PBS) injection group, BMSCs transplantation group and NI-BMSCs transplantation group. PBS injection and cells transplantation were performed 4 weeks post-injury. After 4 weeks of NI-BMSCs transplantation, the survival of seeded NI-BMSCs was examined, proliferation and ultrastructure of native denervated SCs were detected, and myelination, axonal regeneration and the sciatic functional index measurements were also determinated. Our results demonstrated that NI-BMSCs reactivated denervated SCs both in vitro and in vivo and promoted sciatic nerve regeneration. PMID- 29524471 TI - Electroacupuncture restores hippocampal synaptic plasticity via modulation of 5 HT receptors in a rat model of depression. AB - OBJECTIVE: The study aimed to determine the effect of electroacupuncture (EA) on Wistar Kyoto (WKY) depressive model rats and explore the possible mechanism of EA on hippocampal CA1 region neuronal synaptic plasticity. METHODS: The male WKY rats were randomized to three experimental groups (EA, Sham EA, and Model group, n = 8/group), and Wistar rats as the normal control group (n = 8). EA treatment was administered once daily for 3 weeks at acupuncture points Baihui (GV20) and Yintang (EX-HN3). In the Sham EA group, acupuncture needles were inserted superficially into the acupoints without electrical stimulation. On day 21, the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT) were conducted. After the behavioral tests, long-term potentiation (LTP) was evoked at Schaffer collateral-CA1 synapses in hippocampal slices in vitro by electrophysiological recording, 5-HTT, 5-HT1A and 5-HT1 B protein levels in the hippocampus CA1 region were examined by using Western blot. RESULT: EA significantly decreased immobility in FST and improved sucrose intake compared with the Sham EA and Model groups. The center time and total move time in OFT were significantly increased in the EA group compared to the Model group. Compared with those of the Sham EA and Model groups, the fEPSP slope of the EA group increased significantly, and the LTP induction was successful. EA significantly decreased 5-HTT protein expression in the hippocampus CA1 region in comparison to the Sham EA and Model groups. Additionally, EA down regulated the 5 HT1A protein expression in the hippocampus CA1 region in comparison to the Sham EA group. CONCLUSION: EA could ameliorate depressive-like behaviors by restoring hippocampus CA1 synaptic plasticity, which might be mainly mediated by regulating 5-HT receptor levels. PMID- 29524473 TI - Parental strategies for influencing the diet of their children - A qualitative study from disadvantaged areas. AB - BACKGROUND: A social gradient is evident in the prevalence of childhood overweight and obesity, to the disadvantage of children with low socioeconomic status (SES). Parents have a substantial influence on their children's dietary behaviours and weight development through the way they interact with the children around food. This study aims to explore the variation of how parents with low SES influence their child's dietary behaviours. METHODS: A phenomenographic design and analysis was used on 29 sessions of motivational interviewing with mothers and fathers participating in the Healthy School Start intervention study in 2012. The parents had a maximum of 12 years of education and resided in areas targeted for socioeconomic development. In the sessions, parents explored changes that they wanted to make in the home environment regarding their child's dietary behaviours. RESULTS: Five categories of guidance of children's dietary habits were found ranging from silently guiding to enforcement. The categories of guidance were structurally related to each other through positive to negative impact of parental recognition of responsibility for the child's behaviours, level of trust in the child's satiety response, and level of parental emotional distress. CONCLUSION: The results suggest that parents use situation-specific guidance with both negative and positive impacts on child behaviours. Depending on the type of guidance used, parents are in need of different supporting strategies to enhance positive parent-child interplay. Suggestions for intervention strategies are provided where specific focus on parental responsibility recognition, emotional self-regulation, increased responsiveness, and cooperation between parents are highlighted. PMID- 29524472 TI - The biological effects of long-term exposure of human bronchial epithelial cells to total particulate matter from a candidate modified-risk tobacco product. AB - Cigarette smoking is the leading cause of preventable lung cancer (LC). Reduction of harmful constituents by heating rather than combusting tobacco may have the potential to reduce the risk of LC. We evaluated functional and molecular changes in human bronchial epithelial BEAS-2B cells following a 12-week exposure to total particulate matter (TPM) from the aerosol of a candidate modified-risk tobacco product (cMRTP) in comparison with those following exposure to TPM from the 3R4F reference cigarette. Endpoints linked to lung carcinogenesis were assessed. Four week 3R4F TPM exposure resulted in crisis and epithelial to mesenchymal transition (EMT) accompanied by decreased barrier function and disrupted cell-to cell contacts. By week eight, cells regained E-cadherin expression, suggesting that EMT was reversible. Increased levels of inflammatory mediators were noted in cells treated to 3R4F TPM but not in cells treated to the same or a five-fold higher concentration of cMRTP TPM. A 20-fold higher concentration of cMRTP TPM increased oxidative stress and DNA damage and caused reversible EMT. Anchorage independent growth was observed in cells treated to 3R4F or a high concentration of cMRTP TPM. 3R4F TPM-derived clones were invasive, while cMRTP TPM-derived clones were not. Long-term exposure to TPM from the cMRTP had a lower biological impact on BEAS-2B cells compared with that of exposure to TPM from 3R4F. PMID- 29524474 TI - Eating less or more - Mindset induced changes in neural correlates of pre-meal planning. AB - Obesity develops due to an imbalance between energy intake and expenditure. Besides the decision about what to eat, daily energy intake might be even more dependent on the decision about the portion size to be consumed. For decisions between different foods, attentional focus is considered to play a key role in the choice selection. In the current study, we investigated the attentional modulation of portion size selection during pre-meal planning. We designed a functional magnetic resonance task in which healthy participants were directed to adopt different mindsets while selecting their portion size for lunch. Compared with a free choice condition, participants reduced their portion sizes when considering eating for health or pleasure, which was accompanied by increased activity in left prefrontal cortex and left orbitofrontal cortex, respectively. When planning to be full until dinner, participants selected larger portion sizes and showed a trend for increased activity in left insula. These results provide first evidence that also the cognitive process of pre-meal planning is influenced by the attentional focus at the time of choice, which could provide an opportunity for influencing the control of meal size selection by mindset manipulation. PMID- 29524475 TI - Approach to permanent His bundle pacing in challenging implants. PMID- 29524476 TI - Effect of dual-chamber minimal ventricular pacing on paroxysmal atrial fibrillation incidence in myotonic dystrophy type 1 patients: A prospective, randomized, single-blind, crossover study. AB - BACKGROUND: Atrial fibrillation (AF) is a common finding in the myotonic dystrophy type 1 (DM1) population. Pacemakers (PMs) may facilitate the diagnosis and management of frequent subclinical asymptomatic AF episodes. OBJECTIVE: The purpose of this study was to evaluate the effect of minimal ventricular pacing on paroxysmal AF incidence in DM1 patients during a 24-month follow-up period. METHODS: We enrolled 70 DM1 patients (age 43.4 +/- 13.8 years; 39 women) who underwent dual-chamber PM implantation. Patients were randomized to minimizing ventricular pacing features (ON) or not (OFF). Patients crossed over to the opposite pacing programming 12 months later. We counted the number of DM1 patients with at least 1 episode of AF, the AF total duration, and the burden recorded by PM diagnostics during the MVP ON and OFF phases. RESULTS: Twenty-five DM1 patients (41.7%) showed at least 1 AF episode. Seven patients (11.7%) demonstrated AF episodes during MVP ON phase and 25 patients (41.7%) during MVP OFF phase (P <.001). Thirty-five patients had no AF during MVP ON or OFF phase, 3 patients had AF episodes only during MVP ON phase, 21 patients had AF episodes only during MVP OFF phase, and 4 patients had AF episodes during MVP ON and OFF phases. Activation of the MVP algorithm was associated with a 44% reduction in relative risk of developing AF. Furthermore, during the MVP ON phases, the study population showed a shorter total AF duration and a lower AF burden. CONCLUSION: MVP is an efficacy strategy for reducing the risk of AF in DM1 patients who have undergone PM implantation. PMID- 29524477 TI - Left atrial appendage ligation and atrial fibrillation: A tool to "snare" greater success? PMID- 29524478 TI - Decreasing neurologic injury in children after hypoxic injury: Is transcutaneous doppler the way to go? PMID- 29524479 TI - Goldilocks and the three post-cardiac arrest subjects. PMID- 29524480 TI - Bisphenol A stimulates differentiation of rat stem Leydig cells in vivo and in vitro. AB - Bisphenol A (BPA) is widely used in consumer products and a potential endocrine disruptor linked with sexual precocity. However, its action and underlying mechanisms on male sexual maturation is unclear. In the present study, we used a unique in vivo ethane dimethane sulfonate (EDS)-induced Leydig cell regeneration model that mimics the pubertal development of Leydig cells and an in vitro stem Leydig cell differentiation model to examine the roles of BPA in Leydig cell development in rats. Intratesticular exposure to doses (100 and 1000 pmol/testis) of BPA from post-EDS day 14-28 stimulated Leydig cell developmental regeneration process by increasing serum testosterone level and Leydig cell-specific gene (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, and Hsd11b1) and their protein expression levels. BPA did not alter serum luteinizing hormone and follicle stimulating hormone levels as well as the proliferative capacity of Leydig cells in vivo. In vitro study demonstrated that BPA (100 nmol/L) stimulated the differentiation of stem Leydig cells by increasing medium testosterone levels and up-regulating Leydig cell-specific gene (Lhcgr, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and their proteins but did not affect their proliferation measured by EdU incorporation. In conclusion, BPA stimulates the differentiation of stem Leydig cells in rat testes, thus possibly causing sexual precocity in the male. PMID- 29524481 TI - Changes in metformin use and other antihyperglycemic therapies after insulin initiation in patients with type 2 diabetes. AB - AIMS: When patients with type 2 diabetes initiate insulin, metformin should be continued while continuation of other antihyperglycemics has unclear benefit. We aimed to identify practice patterns in antihyperglycemic therapy during the insulin transition, and determine factors associated with metformin continuation. METHODS: We performed a retrospective analysis of the Look AHEAD (Action for Health in Diabetes) trial which randomized overweight/obese adults under ambulatory care for type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. Among the 931 participants who initiated insulin over ten years, we described longitudinal changes in antihyperglycemic medications during the insulin transition, and performed multivariable logistic regression to estimate the association between patient characteristics and metformin continuation. RESULTS: Before insulin initiation, 81.0% of patients used multiple antihyperglycemics, the most common being metformin, sulfonylureas, and thiazolidinediones. After insulin initiation, metformin was continued in 80.3% of patients; other antihyperglycemics were continued less often, yet 58.0% of patients were treated with multiple non-insulin antihyperglycemics. Metformin continuation was inversely associated with age (fully adjusted (a) OR 0.60 per 10 years [0.42-0.86]), serum creatinine above safety thresholds (aOR 0.09 [0.02 0.36]), lower income (P = 0.025 for trend), taking more medications (aOR 0.92 per medication [0.86-0.98]), and initiating rapid, short, or premixed insulin (aOR 0.59 [0.39-0.89]). CONCLUSIONS: The vast majority of patients with type 2 diabetes continue metformin after insulin initiation, consistent with guidelines. Other antihyperglycemics are frequently continued along with insulin, and further research is needed to determine which, if any, patients may benefit from this. PMID- 29524482 TI - The effects of metformin on maternal haemodynamics in gestational diabetes mellitus: A pilot study. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a major clinical challenge and is likely to remain so as the incidence of GDM continues to increase. AIM: To assess longitudinal changes in maternal haemodynamics amongst women diagnosed with GDM requiring either metformin or dietary intervention in comparison to low risk healthy controls. METHODOLOGY: Fifty-six pregnant women attending their first appointment at the GDM clinic and 60 low-risk healthy pregnant controls attending their routine antenatal clinics were recruited and assigned to three groups: GDM Metformin (GDM-M), GDM Diet (GDM-D) and Control. Non-invasive assessment of maternal haemodynamics, using recognised measures of arterial stiffness and central blood pressure (Arteriograph(r)), were undertaken under controlled conditions within four gestational windows: antenatal; AN1 (26-28 weeks), AN2 (32-34 weeks) and AN3 (37-40 weeks), and postnatal (PN) (6-8 weeks after delivery). Data were analysed using a linear mixed model incorporating gestational age and other relevant predictors, including age, blood pressure (BP), baseline bodyweight and pulse as fixed effects, and patient as a random effect. RESULTS: Fitted linear mixed models showed evidence of a two-way interaction effect between groups (GDM-D, GDM-M and Control) and stages of gestation (AN1, AN2, AN3 and PN) for maternal haemodynamic parameters: brachial artery augmentation index (AIx) (p = 0.004), aortic AIx (p = 0.008), and central systolic BP (p = 0.001). However, differences in respect of aortic pulse wave velocity (p = 0.001) and heart rate (p < 0.001) were only significant for gestational stage. At AN2, we did not observe any evidence that the mean brachial Aix in the GDM-M was different from the control group (p = 0.158). CONCLUSION: AIx and central systolic BP measures of arterial stiffness are adversely affected by GDM in comparison to controls during pregnancy. The possible beneficial effects of metformin therapy seen at 32 to 34 weeks of gestation require further exploration. PMID- 29524483 TI - Elevated serum ferritin concentration is associated with incident type 2 diabetes mellitus in a Chinese population: A prospective cohort study. AB - AIMS: We aimed to evaluate the association between serum ferritin levels and incident type 2 diabetes mellitus risk in a Chinese population. METHODS: This cohort study assessed 2225 Chinese individuals aged 25-75 years. Diabetes mellitus was diagnosed using the 1999 World Health Organization definition with a median follow-up period of 20 months. Cox proportional hazard models were used to estimate adjusted hazard ratios and 95% confidence intervals (CI) for incident diabetes when serum ferritin concentrations increased by one standard deviation. RESULTS: During the follow-up period, 112 cases (62 men and 50 women) of type 2 diabetes mellitus were identified. Baseline serum ferritin levels were higher in the diabetes than the non-diabetes group. After adjusting for age, body mass index, waist circumference, mean arterial pressure, fasting plasma glucose, fasting insulin, hemoglobin A1c, total cholesterol, high-density lipoprotein cholesterol, alanine transaminase and triglyceride levels, family history of diabetes mellitus, pork meat consumption, neutrophil/lymphocyte ratio, education, and annual household income, the hazard ratios for incident diabetes corresponding to one standard deviation increase in serum ferritin levels were 1.17 (95% CI 1.03, 1.34), 1.20 (95% CI 1.003, 1.43), and 1.03 (95% CI 0.82, 1.31) for the total population, men, and women, respectively. CONCLUSIONS: High serum ferritin levels were associated with a higher risk of incident type 2 diabetes mellitus independent of traditional risk factors in the total population and men. PMID- 29524484 TI - Clinical correlates of sudomotor dysfunction in patients with type 2 diabetes and peripheral neuropathy. AB - AIMS: To investigate the factors associated with abnormal electrochemical skin conductance (ESC) in patients with type 2 diabetes mellitus (T2D) and early diabetic peripheral neuropathy (DPN). METHODS: We recruited 523 consecutive patients with T2D (median age: 50 [interquartile range: 16] years; median T2D duration: 4 [5] years). Sudomotor dysfunction was defined as an ESC <60 uS, and DPN as a neuropathy disability score (NDS) >=6. Logistic regression was performed to determine the predictors of sudomotor dysfunction in patients with DPN. RESULTS: The prevalence of sudomotor dysfunction was 29% for all patients and 84.5% for patients with DPN. A significant negative correlation was observed between the NDS and ESC measurements (r = -0.52, p < 0.0001). In the univariate analysis, abnormal ESC measures were associated with age, diabetes duration, glycated hemoglobin, diabetic retinopathy, insulin therapy, and foot abnormalities. In the multivariate analysis, ESC abnormalities were associated with age, diabetes duration, glycated hemoglobin levels, insulin therapy, and foot deformities. There was a robust association between foot deformities and abnormal ESC (p = 0.049; odds ratio = 16.02) in patients with DPN. CONCLUSION: Sudomotor dysfunction is highly prevalent in patients with T2D, especially in those with DPN. Various diabetes-related factors were linked to lower ESC values, indicating an association between chronic hyperglycemia and sudomotor function. We also observed a strong relationship between foot deformities and ESC abnormalities. We conclude that the factors associated with DPN are also relevant to sudomotor dysfunction. PMID- 29524485 TI - Effective removal of copper from aqueous solutions by modified magnetic chitosan/graphene oxide nanocomposites. AB - In the present work, a novel magnetic chitosan/graphene oxide nanocomposite (MCGON) was synthesized for the removal of Cu2+ from aqueous solutions. The adsorbent was composed of graphene oxide (GO) modified by ethylenediamine (ED), Fe3O4 nanoparticles and chitosan-g-poly(acrylic acid-co-2-acrylamido-2 methylpropane sulfonic acid) copolymer. The composition and structure of adsorbents were characterized by FTIR, SEM, EDX, XRD, TGA, VSM and BET analysis. The magnetic MCGON with a high specific surface area of (132.9m2g-1), large pore volume (4.03cm3g-1), small particle size (15nm) and strong saturation magnetization (3.82emug-1) was used as an efficient adsorbent for the removal of Cu2+ ions from wastewater. The results showed that the adsorption of Cu2+ onto MCGON exhibited a maximum adsorption capacity of 217.4mgg-1. Kinetics, thermodynamics and equilibrium isotherm of the removal of copper (II) ions were carefully investigated. Adsorption of Cu2+ onto nanocomposite followed pseudo second-order and Langmuir isotherm models. Thermodynamic parameters exhibited that the sorption process was feasible, spontaneous and endothermic in nature. These results provide evidences for the efficient removal of heavy metals from industrial wastewater. PMID- 29524486 TI - In silico prediction of active site and in vitro DNase and RNase activities of Helicoverpa-inducible pathogenesis related-4 protein from Cicer arietinum. AB - Plants are endowed with an innate immune system, which enables them to protect themselves from pest and pathogen. The participation of pathogenesis-related (PR) proteins is one of the most crucial events of inducible plant defense response. Herein, we report the characterization of CaHaPR-4, a Helicoverpa-inducible class II PR-4 protein from chickpea. Bioinformatic analysis of CaHaPR-4 protein indicated the presence of a signal peptide, barwin domain but it lacks the chitin binding site/hevein domain. The recombinant CaHaPR-4 is bestowed with RNase and bivalent ion-dependent DNase activity. Further, the RNA and DNA binding sites were identified and confirmed by analyzing interactions between mutated CaHaPR-4 with the altered active site and ribonuclease inhibitor, 5'ADP and DNase inhibitor, 2-nitro-5-thiocyanobenzoic acid (NTCB) using 3D modeling and docking studies. Moreover, CaHaPR-4 shows antifungal activity as well as growth inhibiting properties against neonatal podborer larvae. To the best of our knowledge, this is the first report of a PR-4 showing RNase, DNase, antifungal and most importantly insect growth inhibiting properties against Helicoverpa armigera simultaneously. PMID- 29524487 TI - Metabolic responses and arginine kinase expression of juvenile cuttlefish (Sepia pharaonis) under salinity stress. AB - The pharaoh cuttlefish Sepia pharaonis is particularly sensitive to environmental changes in its breeding environment. The breeding of S. pharaonis larvae was carried out in different salinities for 48h, and the changes in survival rate, histological structure, energy metabolism, and anti-oxidative stress parameters were investigated and correlated with arginine kinase (AK) expression changes in muscle and liver tissues. The suitable salinity for larvae cultivation ranged from 24 to 300/00, and the survival rate showed a significant decline at 210/00 salinity. Histological observations of muscle and liver showed that changes in salinity and osmotic pressure had an adverse effect on tissue structure. Measurements of glycogen and lactic acid levels suggested that S. pharaonis could dynamically adjust energy metabolism to provide additional energy under unsuitable salinity. The protein levels and enzyme activities of AK in muscle significantly increased at 210/00 salinity. The results were consistent with prompt replenishment of phosphoarginine stores during salinity stress to maintain a dynamic ATP balance, suggesting that AK plays an important role in the regulation of energy metabolism. This study provides insight into metabolic changes during salinity stress and sheds light on the functional role of AK in S. pharaonis. PMID- 29524488 TI - Regulated basal and bolus insulin release from glucose-responsive core-shell microspheres based on concanavalin A-sugar affinity. AB - Individual insulin therapy considering the heterogeneity of insulin resistance between patients may bring more benefits than conventional therapy. Therefore, in glucose-responsive insulin delivery systems, more attention should be paid on further regulation of insulin release to meet individual requirements. Our study shows the feasibility of using a photo-crosslinkable shell layer to regulate basal and bolus insulin release from glucose-responsive Con A-polysaccharides network. Core-shell microspheres were fabricated through a two-step high-speed shear-emulsification method. The morphology was observed by SEM and TEM, and the core-shell structure was confirmed by the differences in chemical composition between core-shell and single-layer microspheres obtained from XPS and IR analysis. In vitro insulin release test revealed that the core-shell microspheres with or without light-irradiation could maintain corresponding bolus and basal insulin release in response to different glucose concentration but enable much lower burst release compared with single-layer microspheres without shell. Meanwhile, insulin release rate and amount could be further decreased upon light irradiation owing to the photo-induced cycloaddition of cinnamate pendant groups of the shell material. The released insulin was proved to remain active according to fluorescence and circular dichroism analysis. The HDF cell viability assessment suggested that the core-shell microspheres possessed no in vitro cytotoxicity. PMID- 29524489 TI - A novel monitoring approach of antibody-peptide binding using "bending" capillary electrophoresis. AB - Recently, the in-capillary electrophoresis assay has been applied to variety kinds of analyses owing to its multiple functional integrating features, including mixing of samples, reaction process of the mixtures, and the separation and detection in one capillary system. However, the micro-reactor still has its limitations to the currently available applications, especially the mixing step of the samples inside the capillary could not be well controlled automatically or manually. Herein, we have developed a novel capillary electrophoresis assay for the detection of antibody-peptide binding inside a bending capillary. Its efficacy was monitored using an anti-FLAG M2 antibody and its ligand conjugated with FAM dye (FAM-DYKD). The antibody and the peptide were mixed inside the bending capillary with sequential injections. It was found that the numbers of semi-circle on the capillary interfered by the antibody and peptide binding dynamic. Additionally, an online competition assay was performed, which further validated the efficacy of the bending capillary device on monitoring the dynamic binding between the antigen and antibody. In summary, our data suggests that the novel assay is a practical approach in monitoring the antibody-antigen complex formation at a nano-scale. It could be applied to detect any biomolecule biomolecule interaction as a general strategy. PMID- 29524491 TI - Knockdown of LMW-PTP enhances stress resistance in Caenorhabditis elegans. AB - Low molecular weight protein tyrosine phosphatase (LMW-PTP) is highly conserved across almost all living organisms and is involved in the modulation of a number of cellular proteins related to important signaling pathways. In this study, we isolated lmwptp (Y94H6A.7) of Caenorhabditis elegans, the homolog of human ACP1, and set up an effective feeding-based RNA interference (RNAi) knockdown against this gene. We found that knockdown of lmwptp decreased damage associated with heat shock, oxidative stress and UV irradiation in wild-type worms, however, its deficiency didn't further reduce the stress resistance of daf-16 or hsf-1 mutants and didn't further increase the stress sensitivity associated with age-1, akt-1 or akt-2 mutants, but it enhanced the stress resistance of daf-2 mutants. Further studies demonstrated that this stress tolerance could be attributed to increased daf-16 nuclear accumulation and enhanced expression of both superoxide dismutase 3 protein (SOD-3) and heat shock protein-16.2 (HSP-16.2) in response to stress. Additionally, quantitative real-time PCR results showed that the expression of hsf-1 and its target genes were up-regulated in lmwptp-knockdown worms under stress conditions. Together these results indicated that lmwptp is related to stress resistance of worms, and it is likely associated with the insulin/IGF-1 like signaling (IIS) pathway. PMID- 29524490 TI - Neuroprotective effects of Coptis chinensis Franch polysaccharide on amyloid-beta (Abeta)-induced toxicity in a transgenic Caenorhabditis elegans model of Alzheimer's disease (AD). AB - This study aims to investigate the neuroprotective effects of Coptis chinensis Franch polysaccharide (CCP) on Abeta1-42 transgenic CL4176 Caenorhabditis elegans, as well as its mechanism of action. The results in life span experiment showed that CCP could significantly increase the lifespan of C. elegans and the effect is in the descending order of 100mg/L>500mg/L>200mg/L. The behavioral experiments also demonstrated that CCP at the concentration of 100mg/L could delay the paralysis rate of C. elegans, which was significantly different from the control group. In terms of Abeta toxicity in C. elegans, morphological observation using Thioflavin S staining method indicated that the deposition of Abeta protein in the head area of the untreated C. elegans was much more than those in the CCP (100mg/L)-treated CL4176. In line with this finding, fluorogenic quantitative real-time PCR confirmed that the transcriptional levels of HSP16.2 (Y46H3A.D) and HSP16.41 (Y46H3A.E) in C. elegans was 21 times and 79 times higher than those in untreated control. Thus, these data demonstrate that CCP could reduce Abeta-induced toxicity by delaying the aging, decreasing the rate of paralysis, inhibiting the deposition of Abeta, and increasing the expression levels of HSP genes in transgenic C. elegans. PMID- 29524492 TI - Functional roles of C-terminal extension (CTE) of salt-dependent peptidase activity of the Natrialba magadii extracellular protease (NEP). AB - Nep (Natrialba magadii extracellular protease) is a halolysin-like peptidase secreted by the haloalkaliphilic archaeon Natrialba magadii. Many extracellular proteases have been characterized from archaea to bacteria as adapted to hypersaline environments retaining function and stability until 4.0M NaCl. As observed in other secreted halolysins, this stability can be related to the presence of a C-terminal extension (CTE) sequence. In the present work, we compared the biochemical properties of recombinant Nep protease with the truncated form at the 134 amino acids CTE (Nep?CTE), that was more active in 4M NaCl than the non-truncated wild type enzyme. Comparable to the wild type, Nep?CTE protease is irreversibly inactivated at low salt solutions. The substrate specificity of the truncated Nep?CTE was similar to that of wild type form as demonstrated by a combinatorial library of FRET substrates. The enzyme stability, the effect of different salts and the thermodynamics assays using different lengths of substrates demonstrated similarities between the two forms. Altogether, these data provide further information on the stability and structural determinants of halolysins under different salinities, especially concerning the enzymatic behavior. PMID- 29524493 TI - Generation and screening of efficient neutralizing single domain antibodies (VHHs) against the critical functional domain of anthrax protective antigen (PA). AB - Since anthrax is an acute infectious disease, detection and neutralization of the toxins of pathogenic Bacillus anthracis are of great importance. The critical role of protective antigen (PA) component of tripartite anthrax toxin in toxin entry into the host cell cytosol provided a great deal of effort to generate monoclonal antibodies against this constitute. Regarding the importance of anthrax detection/neutralization and unique physicochemical and pharmacological features of VHHs as single domain antibodies, the present study aimed to generate VHHs against the receptor binding domain of PA, termed PAD4. After camel immunization, a gene repertoire of VHH fragments with a diversity of 4.7*108 clones was produced, followed by constructing a VHH phage display library. A stringent successive biopanning was then carried out to isolate the phages displaying high affinity VHHs against PAD4.Polyclonal and monoclonal Enzyme linked immunosorbent assay (ELISA) verified binding specificity of phages to the target protein. Modeling of VHHs together with the docking simulation studies, illustrated the binding site of antibodies on antigen. Docking analysis revealed that all selected VHHs potently cover the key functional residues of PAD4. Since the selected VHHs could cover and block the receptor binding loops of PA, they could be proposed as hopeful anti-Anthrax candidates. PMID- 29524494 TI - Identification, characterization and immune response of prophenoloxidase from the blue swimmer crab Portunus pelagicus and its antibiofilm activity. AB - Prophenoloxidase is a conserved Cu-containing enzyme acting as a major defense molecule in the immune response of crustaceans. In the present research, we purified prophenoloxidase from the haemolymph of Portunus pelagicus (Pp-proPO) by Blue Sepharose CL-6B chromatography. Pp-proPO exhibited only one band with molecular weight of 75kDa on SDS-PAGE. The purified Pp-proPO was characterized through X-ray diffraction (XRD) and high-performance liquid chromatography (HPLC). Pp-proPO showed phagocytic activity on the yeast Saccharomyces cerevisiae as well as encapsulation on sepharose CL-6B beads associated with CM sepharose and beads of sodium alginate. Pp-proPO also led to strong agglutination on human erythrocytes. Furthermore, Pp-proPO showed magnified PO activity when altered with activated particles acting as pathogen combined molecular patterns (PAMPs), metal ions or other chemicals. Pp-proPO showed relevant antibiofilm activity on Gram negative bacteria Pseudomonas aeruginosa and Escherichia coli. Overall, the above results allowed us to claim that Pp-proPO play a key role in immune defense mechanisms of P. pelagicus crabs, in particular towards microbial pathogens; notably we added basic information to the functional characterization of Pp proPO, as well as to understand its immunological role in crustaceans defense systems. PMID- 29524495 TI - Characterization of the glutathione S-transferases that belong to the GSTFuA class in Ceriporiopsis subvermispora: Implications in intracellular detoxification and metabolism of wood-derived compounds. AB - Glutathione S-transferases (GSTs) of wood-degrading fungi play essential roles in cellular detoxification processes and endogenous metabolism. Fungal GSTs of GSTFuA class are suggested to be involved in lignin degradation. Ceriporiopsis subvermispora is one of the important model fungi of the selective lignin degraders, we found it interesting to study its GSTs. Here, we characterized the activities of two GSTs of the GSTFuA class of C. subvermispora (CsGST63524 and CsGST83044). A high-yield expression systems involving Escherichia coli was developed for each of these enzymes. Both enzymes were found to exhibit GSH conjugation activity toward 1-chloro-2,4-dinitrobenzene, and GSH-peroxidase activity toward cumene hydroperoxide. Both enzymes showed high GSH-conjugation activity under basic conditions (pH8.0 to 9.0), and the optimum temperature for their activity was 40 degrees C. In addition, three fluorescent compounds were used i.e., methylumbelliferyl acetovanillone was used to monitor etherase activity, and 5-chloromethylfluorescein diacetate and 4-methylumbelliferyl acetate to monitor esterase activity. CsGST83044 exhibited both etherase and esterase activities, while CsGST63524 displayed only esterase activity, which was much higher than that of CsGST83044. These findings imply the functional diversity of the GSTFuA class GSTs of C. subvermispora, suggesting that each protein plays distinctive roles in both the fungal detoxification system and wood compound metabolism. PMID- 29524496 TI - In vivo efficacy and pharmacokinetics of bi-aryl oxazolidinone RBx 11760 loaded polylactic acid-polyethylene glycol nanoparticles in mouse hematogenous bronchopneumonia and rat groin abscess caused by Staphylococcus aureus. AB - RBx 11760 is a bi-aryl oxazolidinone antibacterial agent active against Staphylococcus aureus but has poor solubility. Here we have encapsulated RBx 11760 in PLA-PEG NPs with an aim to improve physicochemical, pharmacokinetics and in vivo efficacy. The average size and zeta potential of RBx 11760 loaded NPs were found to be 106.4 nm and -22.2 mV, respectively. The absolute size of nanoparticles by HRTEM was found to be approximately 80 nm. In vitro antibacterial agar well diffusion assay showed clear zone of inhibition of bacterial growth. In pharmacokinetic study, nanoparticle showed 4.6-fold and 7 fold increase in AUCinf and half-life, respectively, as compared to free drug. RBx 11760 nanoparticle significantly reduced bacterial counts in lungs and improved the survival rate of immunocompromised mice as compared to free drugs. Thus, RBx 11760 loaded nanoparticles have strong potential to be used as nanomedicine against sensitive and drug resistant Staphylococcus aureus infections. PMID- 29524497 TI - Postoperative in-stent protrusion is an important predictor of perioperative ischemic complications after carotid artery stenting. AB - BACKGROUND AND PURPOSE: Although in-stent protrusion is a potential risk factor for thromboembolism following carotid artery stenting, the correlation between in stent protrusion and postoperative ipsilateral stroke has not been well examined. MATERIALS AND METHODS: We retrospectively reviewed 342 consecutive carotid artery lesions in 319 patients who underwent carotid artery stenting between April 2008 and April 2015. After excluding cases with carotid artery dissection and acute occlusion, 301 lesions in total of 277 patients were included in the analysis. We examined the association between in-stent protrusion, which was detected by intravascular ultrasound, and postoperative ipsilateral stroke within 30 days. RESULTS: In-stent protrusion was observed in 47 (15.6%) lesions, of which postoperative ipsilateral stroke within 30 days occurred with 4 (8.5%) lesions. All these events occurred within 10 days after treatment. On the other hand, only 1 (0.39%) of the 256 lesions without in-stent protrusion showed this symptom, and the event occurred at 30days after treatment. Thus, lesions with in-stent protrusion had a higher cumulative risk of ipsilateral stroke than those without in-stent protrusion (8.5% vs 0.4% at 30 days, log-rank P < 0.001). In-stent protrusion, which was more often seen in symptomatic lesions, was associated with a vulnerable plaque assessed by MRI. After adjustment for postoperative stroke risks such as symptomatic lesions, plaque vulnerability, age or sex, in-stent protrusion was still significantly associated with postoperative ipsilateral stroke within 30 days (OR = 27.03, P = 0.001). CONCLUSIONS: Postoperative ipsilateral stroke was observed more frequently in patients with demonstrated in stent protrusion (ISP) following CAS. PMID- 29524498 TI - Objective evaluation of cerebrovascular reactivity for acetazolamide predicts cerebral hyperperfusion after carotid artery stenting: Comparison with region of interest methods. AB - BACKGROUND AND PURPOSE: Hemodynamic impairments are considered risk factors of cerebral hyperperfusion after carotid artery stenting (CAS); measurement by Single-photon emission computed tomography (SPECT) using a subjective region of interest (ROI) method lacks consistency and reproducibility. MATERIALS AND METHODS: The present study compared objective perfusion analysis (stereotactic extraction estimation [SEE] method) with the ROI method for preoperative SPECT to predict the hyperperfusion phenomenon (HPP) after CAS. Preoperative resting asymmetry index (cerebral blood flow [CBF] ratio from the affected to unaffected hemisphere) and cerebrovascular reactivity (CVR) to acetazolamide were measured by N-isopropyl-p-[123I]-iodoamphetamine SPECT using the SEE and ROI method in 84 patients. CBF was also measured the day after CAS. Perfusion data with the highest area under the curve (AUC) by receiver-operating characteristic (ROC) analysis was considered a perfusion risk factor of HPP. Multivariate analyses for clinical characteristics and perfusion risk factors were performed to determine predictors of HPP. RESULTS: The HPP was observed in 10 patients (11.9%). Female sex, contralateral stenosis, and degree of stenosis were significantly associated with HPP development on univariate analysis, and symptomatic stenosis was not found to be a significant factor. On SPECT analysis, CVR in the MCA area by SEE method had the highest AUC (0.981). Multivariate analysis showed that CVR in the MCA area was a significant predictor of HPP (P=0.041). To predict hyperperfusion, the ROC curve of the CVR showed a cutoff value of -0.60%, sensitivity of 94.6%, and specificity of 100% (P<0.001). CONCLUSIONS: Objective SEE method had better a predictive capability than ROI method to identify risk of hyperperfusion after CAS. PMID- 29524499 TI - CT angiography for one-year follow-up of intracranial aneurysms treated with the WEB device: Utility in evaluating aneurysm occlusion and WEB compression at one year. AB - BACKGROUND AND PURPOSE: The WEB is an innovative flow disruption device for cerebral aneurysm embolization with rapidly expanding indications. Our purpose was to evaluate the diagnostic performance of computed tomography angiography (CTA) at 1-year follow-up of aneurysms treated with the WEB. MATERIALS AND METHODS: Between April 2014 and May 2016, the study prospectively included patients treated with the WEB at our institution, and followed up within 24hours by CTA and at 1year by CTA, time-of-flight magnetic resonance angiography (TOF MRA) and digital subtraction angiography (DSA). The diagnostic quality of imaging data was assessed based on the confidence index, artifacts, and WEB shape depiction. The imaging diagnostic performance was assessed using 3 criteria at 1year: aneurysm occlusion status and worsening, and WEB shape compression. Interobserver and intermodality agreement was determined by calculating kappa values. RESULTS: The study ultimately included 16 patients (9 women, mean age 53+/-7.6years). CTA quality confidence was scored as 2/2, artifacts 0.4/2 and WEB shape depiction 1.9/2, superior to TOF MRA for the latter two criteria. Aneurysm occlusion was adequate in 93.7% of patients, with CTA showing excellent interobserver reproducibility and agreement with DSA on a 4-grade scale (kappa=1.00), while TOF MRA yielded good reproducibility (kappa=0.76) and agreement with DSA (kappa=0.69). CTA also identified aneurysm occlusion worsening (43.7%) and WEB compression (81.2%) in excellent agreement with DSA (kappa=0.85 and 1.00). CONCLUSIONS: CTA is a reproducible and reliable technique for the follow-up of aneurysms treated with the WEB device. PMID- 29524500 TI - Messages from the second International Conference on Clinical Metagenomics (ICCMg2). AB - Clinical metagenomics (CMg) refers to as the application of metagenomic sequencing of clinical samples in order to recover clinically-relevant information. Due to the increasing access to next-generation sequencing (NGS) facilities, CMg is a gast-growing field. In this context, we held the second International Conference on Clinical Metagenomics (ICCMg2) in Geneva in October 2017. During the two days of the conference, several aspects of CMg were addressed, which we propose to summarize in the present manuscript. Besides, we also discuss the evolution of CMg from the last conference held in 2016. In brief, many technical issues related to CMg are expected to be successfully addressed in the coming years. Conversely, assessing the clinical value of CMg, implementing a quality process, storage of data and the ethics of CMg are emerging challenges. PMID- 29524502 TI - Combined treatment with benzo[a]pyrene and 1alpha,25-dihydroxyvitamin D3 induces expression of plasminogen activator inhibitor 1 in monocyte/macrophage-derived cells. AB - Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)2D3 enhances BaP toxicity, including BaP-DNA adduct formation. We further investigated the cross-talk between BaP and 1,25(OH)2D3 signaling pathways, and found that combined treatment with these compounds induces mRNA and protein expression of plasminogen activator inhibitor 1 (PAI-1) in monocyte/macrophage-derived THP-1 and U937 cells. Protein synthesis inhibitor treatment did not inhibit induction of the PAI-1 gene (SERPINE1) in these cells. BaP plus 1,25(OH)2D3 induced differentiation markers, inhibited cellular proliferation, and induced apoptosis and oxidative stress in these cells. Reactive oxygen species scavenger treatment suppressed apoptosis but not SERPINE1 induction in cells treated with BaP plus 1,25(OH)2D3. Thus, combined treatment with BaP and 1,25(OH)2D3 induced SERPINE1 mRNA expression in these cells through a mechanism that does not require de novo protein synthesis or reactive oxygen species production. These findings suggest that induction of the proinflammatory factor PAI-1 plays a role in BaP toxicity. Interestingly, PAI-1 knockdown decreased expression of the cell surface antigen CD14, a monocytic differentiation marker, in THP-1 cells treated with BaP plus 1,25(OH)2D3. PAI-1 induction may also be related to a function of monocytes/macrophages in response to xenobiotic and vitamin D signaling. PMID- 29524503 TI - Autophagy as a compensation mechanism participates in ethanol-induced fetal adrenal dysfunction in female rats. AB - Autophagy plays a vital role in embryonic development and cell differentiation. Our previous study demonstrated that prenatal ethanol exposure (PEE) resulted in intrauterine growth retardation (IUGR) and adrenal developmental toxicities in rat offspring. The present study focused on PEE-induced autophagy as an underlying mechanism and its biological significance in female fetal rats. Female fetuses in the PEE group exhibited lower body weights and suffered adrenal structural abnormalities compared to the controls. Cell proliferation was inhibited, the insulin-like growth factor 1 (IGF1) pathway was reduced, and autophagy was activated in the glands of female fetal rats. Ethanol increased the ratio of microtubule-associated protein light chain 3 beta-II (LC3beta-II) to LC3beta-I in vitro, and it reduced cortisol levels in time- and concentration dependent manners in human adrenocortical carcinoma cells (NCI-H295A). Bafilomycin A1 inhibited autophagy, steroidogenic factor 1 (SF1) protein and steroidogenesis in the present study. Rapamycin with ethanol up-regulated autophagy and SF1 expression and activated steroidogenesis when compared with ethanol alone. In addition, ethanol inhibited IGF1 receptor (IGF1R) and phospho mTOR (Ser2448) expression in a concentration-dependent manner. These results demonstrate that PEE activated autophagy in fetal adrenal glands, and the underlying mechanism may be associated with inhibition of the IGF1R/phospho-mTOR (Ser2448) pathway. Autophagy may be a compensatory mechanism for the PEE-induced inhibition of fetal adrenal steroidogenesis to maintain fetal adrenal development. PMID- 29524501 TI - Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. AB - The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes. PMID- 29524504 TI - Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates cardiac fibrosis induced by myocardial infarction in mice. AB - BACKGROUND AND PURPOSE: Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). EXPERIMENTAL APPROACH: GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function. Expression of SUMO-1, PML, TGF beta1 and Pin1 was measured with Western blot or Real-time PCR. Collagen content, cell viability and myofibroblast transformation were measured in neonatal mouse cardiac fibroblasts (NMCFs). Promyelocytic leukemia (PML) protein was over expressed by plasmid transfection. KEY RESULTS: GA improved cardiac fibrosis and dysfunction, and decreased SUMO-1 expression in MI mice. GA (>20 MUM) inhibited NMCF viability in a dose-dependent manner. Nontoxic GA (10 MUM) restrained angiotensin II (Ang II)-induced myofibroblast transformation and collagen production. GA also inhibited expression of TGF-beta1 mRNA and protein in vitro and in vivo. GA suppressed PML SUMOylation and PML nuclear body (PML-NB) organization, and disrupted expression and recruitment of Pin1 (a positive regulator of TGF-beta1 mRNA), whereas over-expression of PML reversed that. CONCLUSIONS AND IMPLICATIONS: Inhibition of SUMO-1 by GA alleviated MI-induced heart dysfunction and fibrosis, and the SUMOylated PML/Pin1/TGF-beta1 pathway is crucial for GA-inhibited cardiac fibrosis. PMID- 29524505 TI - The Effect of Vasectomy Reversal on Prostate Cancer Risk: International Meta Analysis of 684,660 Vasectomized Men. AB - PURPOSE: Evidence of the effect of vasectomy on prostate cancer is conflicting with the issue of detection bias a key criticism. We examined the effect of vasectomy reversal on prostate cancer risk in a cohort of vasectomized men. Evidence of a protective effect would be consistent with a harmful effect of vasectomy on prostate cancer risk while nullifying the issue of detection bias. MATERIALS AND METHODS: Data were sourced from a total of 5 population level linked health databases in Australia, Canada and the United Kingdom. Cox proportional hazards regression analysis was used to compare the risk of prostate cancer in 9,754 men with vasectomy reversal to the risk in 684,660 with vasectomy but no reversal. Data from each jurisdiction were combined in a meta-analysis. RESULTS: The combined analysis showed no protective effect of vasectomy reversal on the incidence of prostate cancer compared to that in men with vasectomy alone (HR 0.92, 95% CI 0.70-1.21). CONCLUSIONS: These results align with those of previous studies showing no evidence of a link between vasectomy and prostate cancer. PMID- 29524506 TI - A 17-Gene Genomic Prostate Score Assay Provides Independent Information on Adverse Pathology in the Setting of Combined Multiparametric Magnetic Resonance Imaging Fusion Targeted and Systematic Prostate Biopsy. AB - PURPOSE: Multiparametric magnetic resonance imaging and biopsy based molecular tests such as the 17-gene Oncotype DX(r) Genomic Prostate ScoreTM assay are increasingly performed to improve risk stratification in men with clinically localized prostate cancer. The prostate score assay was previously shown to be a significant independent predictor of adverse pathology findings at radical prostatectomy in men diagnosed by systematic biopsies only. Therefore, we investigated the ability of the prostate score assay to predict adverse pathology findings in the setting of magnetic resonance imaging guided prostate biopsy. MATERIALS AND METHODS: We identified men diagnosed with NCCN(r) (National Comprehensive Cancer Network(r)) very low, low or intermediate risk prostate cancer who underwent simultaneous multiparametric magnetic resonance imaging fusion targeted and systematic prostate biopsy with subsequent radical prostatectomy within 6 months. Prostate score assay testing was performed on biopsy tissue with the highest Gleason score. The primary outcome of the study was adverse pathology findings, defined as Gleason score 4 + 3 or greater disease and/or pT3+ at radical prostatectomy. Independent predictors of adverse pathology findings were determined in a multivariable model to adjust for clinical parameters. RESULTS: A total of 134 men were eligible for primary analysis. On univariable analysis the UCLA score, magnetic resonance imaging, prostate score assay results and biopsy Gleason score were significant predictors of adverse pathology findings. After multivariable adjustment prostate score assay values remained a significant predictor of adverse pathology results (prostate score assay per 20 U OR 3.28, 95% CI 1.74-6.62, p <0.001). A wide and overlapping distribution of prostate score assay results was seen across PI-RADS(r) (Prostate Imaging Reporting and Data System) version 2 scores. CONCLUSIONS: The prostate score assay result is an independent predictor of adverse pathology findings in patients who were diagnosed with very low, low or intermediate risk prostate cancer in the setting of multiparametric magnetic resonance imaging fusion prostate biopsy. This assay can be useful as an independent technology or an adjunct technology to multiparametric magnetic resonance imaging to individualize risk stratification of low and intermediate risk prostate cancer. PMID- 29524508 TI - What determines the speed of speech recognition? Evidence from congenitally blind adults. AB - It is a matter of debate, whether and how improved auditory discrimination abilities enable speeded speech comprehension in congenitally blind adults. Previous research has concentrated on semantic and syntactic aspects of processing. Here we investigated phonologically mediated spoken word access processes by means of word onset priming. Blind adults and age- and gender matched sighted adults listened to spoken word onsets (primes) followed by complete words (targets). Phonological overlap between primes and targets varied. Blind participants made faster lexical decision responses than sighted participants, yet their speeded responses were not restricted to phonologically overlapping trials. Furthermore, timing of Event Related Potential (ERP) results did not differ between blind and sighted participants. Together these results suggest that blind and sighted listeners are equally fast in implicit phonological encoding and lexical matching mechanisms. It appears that blind adults' speeded speech processing emerges when phonological analysis makes promising word candidates available for further processing. As one possible interpretation, we speculate that lexical selection processes in blind adults do not need to wait for information from the visual domain, while auditory-visual integration mechanisms are mandatorily implemented in speech recognition routines of sighted adults. PMID- 29524507 TI - Verbal short-term memory capacities and executive function in semantic and syntactic interference resolution during sentence comprehension: Evidence from aphasia. AB - This study examined the role of verbal short-term memory (STM) and executive function (EF) underlying semantic and syntactic interference resolution during sentence comprehension for persons with aphasia (PWA) with varying degrees of STM and EF deficits. Semantic interference was manipulated by varying the semantic plausibility of the intervening NP as subject of the verb and syntactic interference was manipulated by varying whether the NP was another subject or an object. Nine PWA were assessed on sentence reading times and on comprehension question performance. PWA showed exaggerated semantic and syntactic interference effects relative to healthy age-matched control subjects. Importantly, correlational analyses showed that while answering comprehension questions, PWA' semantic STM capacity related to their ability to resolve semantic but not syntactic interference. In contrast, PWA' EF abilities related to their ability to resolve syntactic but not semantic interference. Phonological STM deficits were not related to the ability to resolve either type of interference. The results for semantic interference are consistent with prior findings indicating a role for semantic but not phonological STM in sentence comprehension, specifically with regard to maintaining semantic information prior to integration. The results for syntactic interference are consistent with the recent findings suggesting that EF is critical for syntactic processing. PMID- 29524509 TI - Cerebellar contribution to spatial realignment: A tDCS study during multiple-step prism adaptation. AB - Several processes are devoted to error reduction in response to a visual displacement, such as the one induced by wedge prisms. Strategic calibration and spatial realignment contribute to the iteratively process that allows a progressive adjustment of motor commands to reduce the magnitude of errors. Isolating the specific contributions to motor behaviour coming from these distinct processes is not possible using traditional single-step Prism Adaptation (PA), where participants are directly exposed to full prismatic shift. Here, we selectively investigated the effect of realignment on motor behaviour by means of a PA paradigm (the multiple-step PA) that allows to elude the development of strategic calibration. We tested for a specific cerebellar contribution to realignment by means of transcranial Direct Current Stimulation (tDCS) in healthy subjects. Confirming and expanding previous imaging and stimulation results, our study causally demonstrates cerebellar involvement in spatial realignment. Additionally, our results point to a possible contribution of the cerebellum in automatic online control. The role of a cortico-cerebellar network accounting for this results and possible clinical applications are proposed and discussed. PMID- 29524510 TI - WebPropagate: A Web Server for Network Propagation. AB - Network propagation is a powerful tool for genetic analysis which is widely used to identify genes and genetic modules that underlie a process of interest. Here we provide a graphical, web-based platform (http://anat.cs.tau.ac.il/WebPropagate/) in which researchers can easily apply variants of this method to data sets of interest using up-to-date networks of protein-protein interactions in several organisms. PMID- 29524511 TI - Structural and Biochemical Insights into the Multiple Functions of Yeast Grx3. AB - The yeast Saccharomyces cerevisiae monothiol glutaredoxin Grx3 plays a key role in cellular defense against oxidative stress and more importantly, cooperates with BolA-like iron repressor of activation protein Fra2 to regulate the localization of the iron-sensing transcription factor Aft2. The interplay among Grx3, Fra2 and Aft2 responsible for the regulation of iron homeostasis has not been clearly described. Here we solved the crystal structures of the Trx domain (Grx3Trx) and Grx domain (Grx3Grx) of Grx3 in addition to the solution structure of Fra2. Structural analyses and activity assays indicated that the Trx domain also contributes to the glutathione S-transferase activity of Grx3, via an inter domain disulfide bond between Cys37 and Cys176. NMR titration and pull-down assays combined with surface plasmon resonance experiments revealed that Fra2 could form a noncovalent heterodimer with Grx3 via an interface between the helix turn-helix motif of Fra2 and the C-terminal segment of Grx3Grx, different from the previously identified covalent heterodimer mediated by Fe-S cluster. Comparative affinity assays indicated that the interaction between Fra2 and Aft2 is much stronger than that between Grx3 and Aft2, or Aft2 toward its target DNA. These structural and biochemical analyses enabled us to propose a model how Grx3 executes multiple functions to coordinate the regulation of Aft2-controlled iron metabolism. PMID- 29524512 TI - Corneal Dystrophy Mutations Drive Pathogenesis by Targeting TGFBIp Stability and Solubility in a Latent Amyloid-forming Domain. AB - Numerous mutations in the corneal protein TGFBIp lead to opaque extracellular deposits and corneal dystrophies (CDs). Here we elucidate the molecular origins underlying TGFBIp's mutation-induced increase in aggregation propensity through comprehensive biophysical and bioinformatic analyses of mutations associated with every major subtype of TGFBIp-linked CDs including lattice corneal dystrophy (LCD) and three subtypes of granular corneal dystrophy (GCD 1-3). LCD mutations at buried positions in the C-terminal Fas1-4 domain lead to decreased stability. GCD variants show biophysical profiles distinct from those of LCD mutations. GCD 1 and 3 mutations reduce solubility rather than stability. Half of the 50 positions within Fas1-4 most sensitive to mutation are associated with at least one known disease-causing mutation, including 10 of the top 11 positions. Thus, TGFBIp aggregation is driven by mutations that despite their physico-chemical diversity target either the stability or solubility of Fas1-4 in predictable ways, suggesting straightforward general therapeutic strategies. PMID- 29524513 TI - Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice. AB - Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1 ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6 h after its administration. Irisin administration (6 h) increased PGC-1alpha mRNA in the hippocampus and prefrontal cortex and reduced (1 h) PGC-1alpha mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1 h) in both structures and remained reduced up to 6 h in the prefrontal cortex. Moreover, BDNF administered at 0.25 MUg/mouse, i.c.v. (1 and 6 h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1alpha mRNA in the hippocampus (6 h) and prefrontal cortex (1 and 6 h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6 h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6 h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1alpha, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation. PMID- 29524514 TI - Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model. AB - The persistent activation of N-methyl-d-aspartate acid receptors (NMDARs) seems to be responsible for a series of changes in neurons associated with neuropathic pain, including the failure of opioids that act through mu-opioid receptors (MORs) to provide efficacious pain relief. As the noradrenergic locus coeruleus (LC) forms part of the endogenous analgesic system, we explored how intra-LC administration of morphine, a MORs agonist, alone or in combination with MK-801, a NMDARs antagonist, affects the sensorial and affective dimension of pain in a rat model of neuropathic pain; chronic constriction injury (CCI). Intra-LC microinjection of morphine induced analgesia in CCI rats, as evident in the von Frey and cold plate test 7 and 30 days after surgery, although it was not able to reverse pain-related aversion when evaluated using the place escape/avoidance test. However, the thermal anti-nociception produced by morphine was enhanced when it was administered to the LC of CCI animals in combination with MK-801, without altering its effects on the mechanical thresholds. Furthermore, pain related aversion was reduced by co-administration of these agents, yet only in the short-term CCI (7 day) rats. Overall the data indicate that administration of morphine to the LC produces analgesia in nerve injured animals and that this effect is potentiated in specific pain modalities by the co-administration of MK 801. While a combination of morphine and MK-801 could reduce pain-related aversion in short-term neuropathic animals, it was ineffective in the long-term, suggesting that its sensorial effects and its influence on the affective component of pain are regulated by different mechanisms. PMID- 29524515 TI - MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? AB - MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD. PMID- 29524516 TI - Exploring the impact of parthenolide as anti-quorum sensing and anti-biofilm agent against Pseudomonas aeruginosa. AB - AIMS: Pseudomonas aeruginosa is a well-known pathogen responsible for various infections due to its capability to develop biofilm and various virulent phenotypes that are regulated by quorum sensing. Pathogenesis of the bacteria may be halted by interfering with the signaling molecules and the quorum sensing receptors. Therefore, the present study explores the potential of parthenolide, a sesquiterpene lactone of feverfew plant, as a promising candidate against P. aeruginosa PAO1 associated virulence factors and biofilm. MAIN METHODS: Effect of parthenolide on virulence and biofilm formation of P. aeruginosa was studied using standard protocols. Mechanism of action was studied using Real-time PCR as well as molecular docking studies. KEY FINDINGS: Significant decrease in virulence factors and biofilm formation was observed when treated with the sub MIC concentration (1 mM) of parthenolide. Gene expression studies showed the down regulation of autoinducer synthase (lasI, rhlI) as well as their receptors (lasR and rhlR) with remarked repression of lasR by 57% compared to the control. Biofilm-associated fluorescent microscopic studies after staining with FITC-ConA and propidium iodide showed reduced extracellular polymeric substance (EPS) production and killing of bacterial cells after treatment with parthenolide. SIGNIFICANCE: The study is important as it reports for the first time the potential of parthenolide as an anti-quorum and anti-biofilm agent. This study will be helpful in designing of new quorum sensing inhibitors that help in the eradication of infections and can be given in combination with the antibiotics. PMID- 29524517 TI - Heme oxygenase-1 protects liver against ischemia/reperfusion injury via phosphoglycerate mutase family member 5-mediated mitochondrial quality control. AB - AIMS: Heme oxygenase-1 (HO-1), an endogenous cytoprotective enzyme, is reported that can be localized in mitochondria under stress, contributing to preserve mitochondrial function. Mitochondrial quality control (QC) is essential to cellular health and recovery linked with redox homeostasis. Recent studies reported that phosphoglycerate mutase family member (PGAM) 5, a mitochondria resident phosphatase, plays critical role in mitochondrial homeostasis. Therefore, we aim to investigate cytoprotective mechanisms of HO-1 in I/R-induced hepatic injury focusing on mitochondrial QC associated with PGAM5 signaling. MAIN METHODS: Mice were subjected to 60 min of hepatic ischemia followed by 6 h reperfusion and were pretreated twice with hemin (HO-1 inducer, 30 mg/kg) or zinc protoporphyrin (ZnPP; HO-1 inhibitor, 10 mg/kg) 16 and 3 h before ischemia. KEY FINDINGS: I/R increased hepatic and mitochondrial HO activity, which was augmented by hemin. I/R-induced hepatocellular and mitochondrial damages were attenuated by hemin and augmented by ZnPP. Meanwhile, I/R increased mitochondrial biogenesis, as evidenced by increased mitochondrial DNA contents and mitochondrial transcription factor A protein expression. Hemin augmented these results. I/R impaired mitophagy, as indicated by decreases in Parkin protein expression and the number of mitophagic vacuoles. These changes were attenuated by hemin. Hemin attenuated the I/R-induced increase in mitochondrial fission related protein, dynamin-related protein 1, and the decrease in PGAM5 protein expression. Furthermore, PGAM5 siRNA abolished the effect of HO-1 on mitochondrial QC in HepG2 cells subjected to hypoxia/reoxygenation. SIGNIFICANCE: Our findings suggest that HO-1 protects against I/R-induced hepatic injury via regulation of mitochondrial QC by PGAM5 signaling. PMID- 29524518 TI - Changes in expression of P2X7 receptors in rat myometrium at different gestational stages and the mechanism of ATP-induced uterine contraction. AB - AIMS: Given the importance of ATP in the control of uterine activity for successful labor and involution, this study was performed to measure the level of P2X7 receptors (P2X7Rs) in rat myometrium at different gestational stages and to investigate the mechanisms of ATP-induced uterine contraction. MATERIALS AND METHODS: Myometrial tissues were obtained from rats at different gestational stages and the level of P2X7Rs was measured by ELISA. In other experiments, the effect of 1 mM ATP was tested on spontaneous contraction and the underlying mechanisms were investigated. KEY FINDINGS: P2X7Rs were expressed in nonpregnant uterine tissues, progressively increased throughout pregnancy, and markedly peaked during postpartum involution. ATP significantly increased the force of spontaneous contraction in all uterine strips from different gestational stages with marked increase during labor and postpartum. ATP could not maintain the force when external Ca2+ was removed. In addition, ATP was able to cause tonic transient contraction in the absence of external Ca2+. SIGNIFICANCE: P2X7Rs are functionally regulated and contributed to ATP-induced uterine contraction. The sensitivity of the myometrium to ATP increases as pregnancy progresses and it involves Ca2+ influx and Ca2+ release pathways. The clear effects of ATP on contractility suggest its physiological requirement for successful labor and postpartum involution. PMID- 29524519 TI - SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma. AB - AIMS: In hepatocellular carcinoma (HCC), the regulatory protease Dipeptidyl peptidase IV (DPPIV/CD26), that possesses pro-apoptotic properties, has been found abnormally regulated. The protease inhibitor SerpinB3, exerting anti apoptotic activity, has also been described to be upregulated, especially in HCCs with poor prognosis. The aim of this study was to investigate the possible relationship between these two molecules in HCC patients and in experimental models. MATERIALS AND METHODS: DPPIV/CD26 and SerpinB3 expression was measured in liver specimens of 67 patients with HCC. HepG2 and Huh7 cells, stably transfected to overexpress SerpinB3, and respective control cells were used to assess biological and metabolic modifications of DPPIV/CD26 activity induced by this serpin. KEY FINDINGS: DPPIV/CD26 and SerpinB3 were localized in the same tumoral areas and both molecules were correlated with the grade of tumor differentiation, with the highest values detected in GI tumors. Cell lines over-expressing SerpinB3 displayed upregulation of DPPIV/CD26, likely as a feedback mechanism, due to the DPPIV/CD26 protease activity inhibition by SerpinB3, as confirmed by the similar behavior induced by the inhibitor Sitagliptin. Moreover, they exhibited lower glycogen storage and higher lipid accumulation, typical effects of DPPIV/CD26. SIGNIFICANCE: A close connection between SerpinB3 and DPPPIV has been identified, but further studies are required to better understand the mechanism by which these proteins communicate and exert metabolic effects in HCC. PMID- 29524520 TI - The tumor antagonistic steroidal alkaloid Solanidine prompts the intrinsic suicidal signal mediated DFF-40 nuclear import and nucleosomal disruption. AB - : Aim Deformity in the cellular homeostatic event associated with cell survival and apoptosis are committing factors for carcinogenesis. Interventions of these events by pharmacologically active agent gain predominance in cancer treatment. In current investigation Solanidine, a steroidal alkaloid was evaluated on tumorigenesis by targeting death signal using multiple tumor cells and model systems. MAIN METHODS: Anti-proliferative effect was evaluated using cytotoxic studies. Prolonged cytotoxic effect of Solanidine was examined by colony formation assay. Exhibition of apoptotic hallmark induced by Solanidine was examined using FACS analysis, Annexin-V staining, Acridine orange staining, TUNEL assay. Altered gene expression was evaluated using Immunoblot, Immunofluorescence and Immunohistochemistry technique. In-vitro results were revalidated in EAC solid tumor and CAM xenograft model. KEY FINDINGS: Solanidine exerts its potential effect in a target specific manner. The cytotoxic/anticlonogenic activity was due to induction of typical cellular apoptotic hallmarks and cell cycle blockage at S-G2/M phase. The molecular events underlying this effect is through activation of intrinsic pathway via Bax, Bad and Cytochrome c activation by neutralizing Bcl-2 expression, along with downregulated PI3K/Akt survival signal. As a consequence, downstream pro apoptogenic gene, active Caspase-3 was over expressed by Solanidine to cleave its substrate PARP and promotes nuclear import of DFF-40. Anti-carcinogenic aptitude was further confirmed by murine solid tumors and in-vivo CAM xenograft studies. SIGNIFICANCE: Solanidine emerged as active molecule against tomorigenesis by activating nuclear import of DFF-40 mediated nucleosomal disruption and cell demise. It can be developed as a potential apoptogenic small molecule for cancer therapy. PMID- 29524521 TI - Decrease in paracellular permeability and chemosensitivity to doxorubicin by claudin-1 in spheroid culture models of human lung adenocarcinoma A549 cells. AB - Chemotherapy resistance is a major problem in the treatment of cancer, but the underlying mechanisms are not fully understood. We found that the expression levels of claudin-1 (CLDN1) and 3, tight junctional proteins, are upregulated in cisplatin (CDDP)-resistant human lung adenocarcinoma A549 (A549R) cells. A549R cells showed cross-resistance to doxorubicin (DXR). Here, the expression mechanism and function of CLDN1 and 3 were examined. CLDN1 and 3 were mainly localized at tight junctions concomitant with zonula occludens (ZO)-1, a scaffolding protein, in A549 and A549R cells. The phosphorylation levels of Src, MEK, ERK, c-Fos, and Akt in A549R cells were higher than those in A549 cells. The expression levels of CLDN1 and 3 were decreased by LY-294002, a phosphoinositide 3-kinase (PI3K) inhibitor, and BAY 11-7082, an NF-kappaB inhibitor. The overexpression of CLDN1 and 3 decreased the paracellular permeability of DXR in A549 cells. Hypoxia levels in A549R and CLDN1-overexpressing cells (CLDN1/A549) were greater than those in A549, mock/A549, and CLDN3/A549 cells in a spheroid culture model. In contrast, accumulation in the region inside the spheroids and the toxicity of DXR in A549R and CLDN1/A549 cells were lower than those in other cells. Furthermore, the accumulation and toxicity of DXR were rescued by CLDN1 siRNA in A549R cells. We suggest that CLDN1 is upregulated by CDDP resistance through activation of a PI3K/Akt/NF-kappaB pathway, resulting in the inhibition of penetration of anticancer drugs into the inner area of spheroids. PMID- 29524522 TI - Genetic aberrations in macroautophagy genes leading to diseases. AB - The catabolic process of macroautophagy, through the rapid degradation of unwanted cellular components, is involved in a multitude of cellular and organismal functions that are essential to maintain homeostasis. Those functions include adaptation to starvation, cell development and differentiation, innate and adaptive immunity, tumor suppression, autophagic cell death, and maintenance of stem cell stemness. Not surprisingly, an impairment or block of macroautophagy can lead to severe pathologies. A still increasing number of reports, in particular, have revealed that mutations in the autophagy-related (ATG) genes, encoding the key players of macroautophagy, are either the cause or represent a risk factor for the development of several illnesses. The aim of this review is to provide a comprehensive overview of the diseases and disorders currently known that are or could be caused by mutations in core ATG proteins but also in the so called autophagy receptors, which provide specificity to the process of macroautophagy. Our compendium underlines the medical relevance of this pathway and underscores the importance of the eventual development of therapeutic approaches aimed at modulating macroautophagy. PMID- 29524523 TI - Identification of a novel trafficking pathway exporting a replication protein, Orc2 to nucleus via classical secretory pathway in Plasmodium falciparum. AB - Malaria parasites use an extensive secretory pathway to traffic a number of proteins within itself and beyond. In higher eukaryotes, Endoplasmic Reticulum (ER) membrane bound transcription factors such as SREBP are reported to get processed en route and migrate to nucleus under the influence of specific cues. However, a protein constitutively trafficked to the nucleus via classical secretory pathway has not been reported. Herein, we report the presence of a novel trafficking pathway in an apicomplexan, Plasmodium falciparum where a homologue of an Origin Recognition Complex 2 (Orc2) goes to the nucleus following its association with the ER. Our work highlights the unconventional role of ER in protein trafficking and reports for the first time an ORC homologue getting trafficked through such a pathway to the nucleus where it may be involved in DNA replication and other ancillary functions. Such trafficking pathways may have a profound impact on the cell biology of a malaria parasite and have significant implications in strategizing new antimalarials. PMID- 29524524 TI - Seasonal changes in plasma levels of thyroid hormones and the effects of the hormones on cellular ATP content in common bottlenose dolphin. AB - In general, thyroid hormones (THs) stimulate cellular metabolism by inducing ATP utilization that collaterally leads to thermogenesis. However, in cetaceans, TH functions and the contribution of THs to cold adaptation are not fully understood. To investigate the role of THs in metabolism of cetaceans, seasonal changes in circulating levels in THs were investigated in the common bottlenose dolphin Tursiops truncatus that were monitored under two different conditions for two years, with routine measurements of body temperature (BT), water temperature (WT) and air temperature (AT). The effects of THs on ATP synthesis were determined using cultured cells. Blood samples were collected from the species kept in different conditions at the Taiji Whale Museum located in the temperate zone and at Okinawa Expo Park in the subtropical zone. Circulating levels in total thyroxine (T4) for the dolphins at both aquaria and total 3,5,3'-tri iodothyronine (T3) levels in dolphins at Taiji were measured by enzyme-linked immunoassay methods, respectively, and average concentrations were compared among seasons. To confirm the effects of THs on ATP synthesis, T3 or T4 was administrated to cultured kidney cells from the same species and cellular ATP contents were quantified at 0, 24, 48, 96 and 192 h after administration. BT of common bottlenose dolphins in each aquarium was measured for health check by chance in Taiji and every morning in Okinawa. WT in pools and AT were also measured every morning. Circulating T4 levels in autumn and winter were lower than those in spring and summer in dolphins in Taiji where WT and AT varied greatly from season to season. T4 levels showed a small difference between spring and autumn in dolphins in Okinawa with warmer WT and AT in smaller amplitude ranges than in Taiji. Total T3 level in Taiji was highest in spring and lowest in autumn as T4 levels, but not significant. The BT of dolphins in Taiji was also lower in autumn and winter compared with those in spring and summer, whereas the BT of dolphins in Okinawa fell in autumn but rose in summer, albeit to a lesser extent than in Taiji. Cellular ATP was increased by administration of both T3 and T4 compared to control. Collectively, these results suggest that the cellular metabolic activities regulated by THs may be enhanced in dolphins exposed to increasing surrounding temperature for lipolysis and reduced in dolphins exposed to colder conditions for fat accumulation. PMID- 29524525 TI - Evaluating the interactions between red stingray (Dasyatis akajei) melanocortin receptors and elephant shark (Callorhinchus milii) MRAP1 and MRAP2 following stimulation with either stingray ACTH(1-24) or stingray Des-Acetyl-alphaMSH: A pharmacological study in Chinese Hamster Ovary cells. AB - Previous studies on bony vertebrate MC2R orthologs (i.e., ray finned fishes, amphibians, reptiles, birds, and mammals) have shown that these MC2R orthologs have an obligatory requirement for interaction with bony vertebrate MRAP1 orthologs to a) allow for the trafficking of the MC2R ortholog to the plasma membrane; and b) to allow activation by ACTH, but not by any MSH-sized ligand. In addition, previous studies have found that co-expression of teleost and mammalian MC4R orthologs with corresponding MRAP2 has positive effects on sensitivity to stimulation by alphaMSH or ACTH. MRAP1 and MRAP2 paralogs have been detected in the genome of a cartilaginous fish (elephant shark), yet two cartilaginous fish MC2R orthologs (elephant shark and red stingray) do not apparently require MRAP1 for trafficking to the plasma membrane when expressed in Chinese Hamster Ovary (CHO) cells, and both orthologs can be activated by either ACTH or MSH-sized ligands. This study was done to determine whether sensitivity to stimulation by ACTH(1-24) or Des-Acetyl-alphaMSH is affected when stingray (sr) MC1R, MC2R, MC3R, MC4R or MC5R were co-expressed in CHO cells with either elephant shark (es) MRAP1 or esMRAP2. The results indicated that co-expression with heterologous MRAP1 increased the sensitivity of all five stingray melanocortin receptors for srACTH(1-24), but had not statistically significant effect on stimulation by srDes-Acetyl-alphaMSH for any of the stingray melanocortin receptors. Conversely, co-expression with esMRAP2 only enhanced sensitivity for srDes-Acetyl-alphaMSH for srMC4R, but had no effect on the other stingray orthologs, and there was no increase in sensitivity for srACTH(1-24) for any of the stingray melanocortin receptors. It appears then that some stingray melanocortin receptors have retained the ability to interact with a cartilaginous MRAP1 paralog. These results are discussed with reference to radiation of MRAP-related accessory proteins in cartilaginous fishes. PMID- 29524526 TI - Development of cross-protective Eimeria-vectored vaccines based on apical membrane antigens. AB - Recently, the availability of protocols supporting genetic complementation of Eimeria has raised the prospect of generating transgenic parasite lines which can function as vaccine vectors, expressing and delivering heterologous proteins. Complementation with sequences encoding immunoprotective antigens from other Eimeria spp. offers an opportunity to reduce the complexity of species/strains in anticoccidial vaccines. Herein, we characterise and evaluate EtAMA1 and EtAMA2, two members of the apical membrane antigen (AMA) family of parasite surface proteins from Eimeria tenella. Both proteins are stage-regulated, and the sporozoite-specific EtAMA1 is effective at inducing partial protection against homologous challenge with E. tenella when used as a recombinant protein vaccine, whereas the merozoite-specific EtAMA2 is not. In order to test the ability of transgenic parasites to confer heterologous protection, E. tenella parasites were complemented with EmAMA1, the sporozoite-specific orthologue of EtAMA1 from E. maxima, coupled with different delivery signals to modify its trafficking and improve antigen exposure to the host immune system. Vaccination of chickens using these transgenic parasites conferred partial protection against E. maxima challenge, with levels of efficacy comparable to those obtained using recombinant protein or DNA vaccines. In the present work we provide evidence for the first known time of the ability of transgenic Eimeria to induce cross protection against different Eimeria spp. Genetically complemented Eimeria provide a powerful tool to streamline the complex multi-valent anticoccidial vaccine formulations that are currently available in the market by generating parasite lines expressing vaccine targets from multiple eimerian species. PMID- 29524527 TI - Imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1 decrease the parasite burden in mice with acute toxoplasmosis. AB - The current therapeutic arsenal for toxoplasmosis is restricted to drugs non specific to the parasite which cause important side effects. Development of more efficient and specific anti-Toxoplasma compounds is urgently needed. Imidazo[1,2 b]pyridazines designed to inhibit the calcium-dependent protein kinase 1 of Toxoplasma gondii (TgCDPK1) and effective against tachyzoite growth in vitro at submicromolar ranges were modified into hydrochloride salts to be administered in vivo in a mouse model of acute toxoplasmosis. All protonated imidazo[1,2 b]pyridazine salts (SP230, SP231 and SP232) maintained their activity on TgCDPK1 and T. gondii tachyzoites. Rat and mouse liver microsomes were used to predict half-life and intrinsic clearance, and the pharmacokinetic profile of the most rapidly degraded imidazo[1,2b]pyridazine salt (SP230) was determined in serum, brain and lungs of mice after a single administration of 50 mg/kg. Compounds were then tested in vivo in a murine model of acute toxoplasmosis. Mice infected with tachyzoites of the ME49 strain of T. gondii were treated for 4, 7 or 8 days with 25 or 50 mg/kg/day of SP230, SP231 or SP232. The parasite burdens were strongly diminished (>90% reduction under some conditions) in the spleen and the lungs of mice treated with imidazo[1,2-b]pyridazine salts compared with untreated mice, without the need for pre-treatment. Moreover, no increases in the levels of hepatic and renal toxicity markers were observed, demonstrating no significant signs of short-term toxicity. To conclude, imidazo[1,2-b]pyridazine salts have strong efficacy in vivo on acute toxoplasmosis and should be further tested in a model of mouse congenital toxoplasmosis. PMID- 29524528 TI - The prognostic value of acute-on-chronic liver failure during the course of severe alcoholic hepatitis. AB - BACKGROUND & AIMS: A better identification of factors predicting death is needed in alcoholic hepatitis (AH). Acute-on-chronic liver failure (ACLF) occurs during the course of liver disease and can be identified when AH is diagnosed (prevalent ACLF [pACLF]) or during follow-up (incidental ACLF [iACLF]). This study analyzed the impact of ACLF on outcomes in AH and the role of infection on the onset of ACLF and death. METHODS: Patients admitted from July 2006 to July 2015 suffering from biopsy-proven severe (s)AH with a Maddrey discriminant function (mDF) >=32 were included. Infectious episodes, ACLF, and mortality were assessed during a 168-day follow-up period. Results were validated on an independent cohort. RESULTS: One hundred sixty-five patients were included. Mean mDF was 66.3 +/- 20.7 and mean model for end-stage liver disease score was 26.8 +/- 7.4. The 28 day cumulative incidence of death (CID) was 31% (95% CI 24-39%). Seventy-nine patients (47.9%) had pACLF. The 28-day CID without pACLF and with pACLF-1, pACLF 2, and pACLF-3 were 10.4% (95% CI 5.1-18.0), 30.8% (95% CI 14.3-49.0), 58.3% (95% CI 35.6-75.5), and 72.4% (95% CI 51.3-85.5), respectively, p <0.0001. Twenty-nine patients (17.5%) developed iACLF. The 28-day relative risk of death in patients developing iACLF was 41.87 (95% CI 5.2-335.1; p <0.001). A previous infection was the only independent risk factor for developing iACLF during the follow-up. Prevalence, incidence, and impact on prognosis of ACLF were confirmed in a validation cohort of 97 patients with probable sAH. CONCLUSIONS: ACLF is frequent during the course of sAH and is associated with high mortality. Infection strongly predicts the development of ACLF in this setting. LAY SUMMARY: In patients with chronic liver disease, an acute deterioration of liver function combined with single or multiple organ failures is known as acute-on-chronic liver failure. This study shows that acute-on-chronic liver failure is frequent during the course of severe alcoholic hepatitis. In severe alcoholic hepatitis, acute-on-chronic liver failure is associated with high mortality and frequently occurs after an infection. PMID- 29524529 TI - The long-term prognosis of alcoholic hepatitis is poor and independent of disease severity for patients surviving an acute episode. PMID- 29524530 TI - Hepatitis D virus replication is sensed by MDA5 and induces IFN-beta/lambda responses in hepatocytes. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. METHODS: HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. RESULTS: Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2NTCP cells. HDV strongly activated IFN-beta and IFN-lambda in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2NTCP and HepaRGNTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. CONCLUSION: Active replication of HDV induces an IFN-beta/lambda response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state. LAY SUMMARY: In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong IFN beta/lambda response in innate immune competent cell lines. MDA5 is the key sensor for the recognition of hepatitis D virus replicative intermediates. An IFN activated state did not prevent hepatitis D virus replication in vitro, indicating that hepatitis D virus is resistant to self-induced innate immune responses and therapeutic IFN treatment. PMID- 29524531 TI - Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. AB - BACKGROUND & AIMS: Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Herein, we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP. METHODS: Male Balb/C mice were treated with or without antibiotics and a single dose of orally administered APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period) and ZT12 (when the light is off-start of active period). RESULTS: In agreement with previous findings, hepatic injury was markedly enhanced at ZT12 compared with ZT0. Interestingly, upon antibiotic treatment, ZT12 displayed a protective effect against APAP hepatotoxicity similar to ZT0. Moreover, mice that received the cecal content from ZT12 showed more severe liver damage than mice that received the cecal content from ZT0. 16S sequencing data revealed significant differences in the cecal content between ZT0 and ZT12 in the compositional level. Furthermore, metabolomic analysis showed that the gut microbial metabolites were also different between ZT0 and ZT12. Specifically, the level of 1-phenyl-1,2 propanedione (PPD) was significantly higher at ZT12 than ZT0. Treatment with PPD alone did not cause obvious liver damage. However, PPD synergistically enhanced APAP-induced hepatic injury in vivo and in vitro. Finally, we found Saccharomyces cerevisiae, which could reduce intestinal PPD levels, was able to markedly alleviate APAP-induced liver damage at ZT12. CONCLUSIONS: The gut microbial metabolite PPD was responsible, at least in part, for the diurnal variation of hepatotoxicity induced by APAP by decreasing glutathione levels. LAY SUMMARY: Acetaminophen (APAP) induced acute liver failure because of over dose is a leading public health problem. APAP-induced liver injury exhibits diurnal variation, specifically APAP causes more severe liver damage when taken at night compared with in the morning. Herein, we showed that gut microbial metabolite, 1 phenyl-1,2-propanedione is involved in the rhythmic hepatotoxicity induced by APAP, by depleting hepatic glutathione (an important antioxidant) levels. Our data suggest gut microbiota may be a potential target for reducing APAP-induced acute liver injury. PMID- 29524532 TI - Radiofrequency ablation vs. surgery for perivascular hepatocellular carcinoma: Propensity score analyses of long-term outcomes. AB - BACKGROUND & AIMS: The therapeutic outcomes of surgical resection (SR) or radiofrequency ablation (RFA) for perivascular hepatocellular carcinoma (HCC) have not been compared. The aim of this study was to compare SR with RFA as first line treatment in patients with perivascular HCC and to evaluate the long-term outcomes of both therapies. METHODS: This retrospective study was approved by the institutional review board. The requirement for informed consent was waived. Between January 2006 and December 2010, a total of 283 consecutive patients with small perivascular HCCs (<=3 cm, Barcelona Clinic Liver Cancer stage 0 or A) underwent SR (n = 182) or RFA (n = 101) as a first-line treatment. The progression-free survival (PFS) and overall survival (OS) rates were compared by propensity score matching. Subgroup analysis of these outcomes was conducted according to the type of hepatic vessels. RESULTS: The median follow-up was 7.8 years. Matching yielded 62 pairs of patients. In the two matched groups, the PFS rates at 5 and 10 years were 58.0% and 17.8%, respectively, in the SR group, and 25.4% and 14.1%, respectively, in the RFA group (p <0.001). The corresponding OS rates at 5 and 10 years were 93.5% and 91.9% in the SR group and 82.3% and 74.1% in the RFA group, respectively (p <0.001). In contrast to those in patients with perivenous HCCs, subgroup analysis indicated that extrahepatic recurrence and OS were significantly different according to the treatment modality in patients with periportal HCCs (p = 0.004 and p <0.001, respectively). CONCLUSIONS: In patients with small perivascular HCCs, SR provided better long-term tumor control and OS than RFA, particularly for periportal tumors. LAY SUMMARY: Surgical resection and radiofrequency ablation are both treatment options for perivascular hepatocellular carcinoma. We compared outcomes in patients treated with either method. Surgical resection provided better long-term tumor control and overall survival than radiofrequency ablation for patients with a small perivascular hepatocellular carcinoma (<=3 cm) as a first-line treatment, particularly for periportal tumors. The location of the tumor and the type of peritumoral hepatic vessels need to be considered when choosing between surgical resection and radiofrequency ablation for small HCCs. PMID- 29524533 TI - Reply to: "The long-term prognosis of alcoholic hepatitis is poor and independent of disease severity for patients surviving an acute episode". PMID- 29524534 TI - Non-posttransplant lymphoproliferative disorder malignancy after hematopoietic stem cell transplantation in patients with primary immunodeficiency: UK experience. PMID- 29524535 TI - Advances in the approach to the patient with food allergy. AB - Advances in food allergy diagnosis, management, prevention, and therapeutic interventions have been significant over the past 2 decades. Evidence-based national and international guidelines have streamlined food allergy diagnosis and management, whereas paradigm-shifting work in primary prevention of peanut allergy has resulted in significant modifications in the approach to early food introduction in infants and toddlers. Innovative investigation of food allergy epidemiology, systems biology, effect, and management has provided important insights. Although active therapeutic approaches to food allergy remain experimental, progress toward licensed therapies has been substantial. Mechanistic understanding of the immunologic processes underlying food allergy and immunotherapy will inform the future design of therapeutic approaches targeting the food-induced allergic response. Global strategies to mitigate the substantial medical, economic, and psychosocial burden of food allergy in affected subjects and families will require engagement of stakeholders across multiple sectors in research, health care, public health, government, educational institutions, and industry. However, the relationship between the well-informed allergy care provider and the patient and family remains fundamental for optimizing the care of the patient with food allergy. PMID- 29524536 TI - Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma. AB - BACKGROUND: The single-center double-blind, randomized controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FENO) in combination with asthma symptoms (FENO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (Australian New Zealand Clinical Trials Registry, no. 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FENO group. However, the effect of FENO-guided management on the development of asthma in the offspring is unknown. OBJECTIVE: We sought to investigate the effect of FENO-guided asthma management during pregnancy on asthma incidence in childhood. METHODS: A total of 179 mothers consented to participate in the Growing into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FENO-guided asthma management on childhood asthma incidence. RESULTS: A total of 140 children (78%) were followed up at 4 to 6 years of age. FENO-guided as compared to symptoms-only approach significantly reduced doctor-diagnosed asthma (25.9% vs 43.2%; odds ratio [OR], 0.46, 95% CI, 0.22-0.96; P = .04). Furthermore, frequent wheeze (OR, 0.27; 95% CI, 0.09-0.87; P = .03), use of short-acting beta-agonists (OR, 0.49; 95% CI, 0.25-0.97; P = .04), and emergency department visits for asthma (OR, 0.17; 95% CI, 0.04-0.76; P = .02) in the past 12 months were less common in children born to mothers from the FENO group. Doctor-diagnosed asthma was associated with common risk alleles for early onset asthma at gene locus 17q21 (P = .01 for rs8069176; P = .03 for rs8076131), and higher airways resistance (P = .02) and FENO levels (P = .03). A causal mediation analysis suggested natural indirect effects of FENO-guided asthma management on childhood asthma through "any use" and "time to first change in dose" of inhaled corticosteroids during the MAP trial (OR: 0.83; 95% CI: 0.59-0.99, and OR: 0.90; 95% CI: 0.70-1.03, respectively). CONCLUSIONS: FENO-guided asthma management during pregnancy prevented doctor-diagnosed asthma in the offspring at preschool age, in part mediated through changes in use and dosing of inhaled corticosteroids during the MAP trial. PMID- 29524537 TI - Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. AB - BACKGROUND: Airway type 2 inflammation is usually corticosteroid sensitive, but the role of type 2 inflammation as a mechanism of asthma in patients receiving high-dose inhaled corticosteroids (ICSs) is uncertain. OBJECTIVE: We sought to determine whether airway type 2 inflammation persists in patients treated with ICSs and to evaluate the clinical features of patients with steroid-resistant airway type 2 inflammation. METHODS: We used quantitative PCR to generate a composite metric of type 2 cytokine gene expression (type 2 gene mean [T2GM]) in induced sputum cells from healthy control subjects, patients with severe asthma receiving ICSs (n = 174), and patients with nonsevere asthma receiving ICSs (n = 85). We explored relationships between asthma outcomes and T2GM values and the utility of noninvasive biomarkers of airway T2GM. RESULTS: Sputum cell T2GM values in asthmatic patients were significantly increased and remained high after treatment with intramuscular triamcinolone. We used the median T2GM value as a cutoff to classify steroid-treated type 2-low and steroid-resistant type 2-high (srT2-high) subgroups. Compared with patients with steroid-treated type 2-low asthma, those with srT2-high asthma were older and had more severe asthma. Blood eosinophil cell counts predicted srT2-high asthma when body mass index was less than 40 kg/m2 but not when it was 40 kg/m2 or greater, whereas blood IgE levels strongly predicted srT2-high asthma when age was less than 34 years but not when it was 34 years or greater. CONCLUSION: Despite ICS therapy, many asthmatic patients have persistent airway type 2 inflammation (srT2-high asthma), and these patients are older and have more severe disease. Body weight and age modify the performance of blood-based biomarkers of airway type 2 inflammation. PMID- 29524538 TI - Chaperone-like effect of ceftriaxone on HEWL aggregation: A spectroscopic and computational study. AB - BACKGROUND: Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a beta-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein (GFAP) and alpha-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. METHODS: Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. RESULTS: We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. CONCLUSIONS: Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance These results, in addition to our previous studies on alpha-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis. PMID- 29524539 TI - Turning off NADPH oxidase-2 by impeding p67phox activation in infected mouse macrophages reduced viral entry and inflammation. AB - BACKGROUND: Targeting cells of the host immune system is a promising approach to fight against Influenza A virus (IAV) infection. Macrophage cells use the NADPH oxidase-2 (NOX2) enzymatic complex as a first line of defense against pathogens by generating superoxide ions O2- and releasing H2O2. Herein, we investigated whether targeting membrane -embedded NOX2 decreased IAV entry via raft domains and reduced inflammation in infected macrophages. METHODS: Confocal microscopy and western blots monitored levels of the viral nucleoprotein NP and p67phox, NOX2 activator subunit, Elisa assays quantified TNF-alpha levels in LPS or IAV activated mouse or porcine alveolar macrophages pretreated with a fluorescent NOX inhibitor, called nanoshutter NS1. RESULTS: IAV infection in macrophages promoted p67phox translocation to the membrane, rafts clustering and activation of the NOX2 complex at early times. Disrupting rafts reduced intracellular viral NP. NS1 markedly reduced raft clustering and viral entry by binding to the C-terminal of NOX2 also characterized in vitro. NS1 decrease of TNF-alpha release depended on the cell type. CONCLUSION: NOX2 participated in IAV entry and raft-mediated endocytosis. NOX2 inhibition by NS1 reduced viral entry. NS1 competition with p67phox for NOX2 binding shown by in silico models and cell-free assays was in agreement with NS1 inhibiting p67phox translocation to membrane-embedded NOX2 in mouse and porcine macrophages. GENERAL SIGNIFICANCE: We introduce NS1 as a compound targeting NOX2, a critical enzyme controlling viral levels and inflammation in macrophages and discuss the therapeutic relevance of targeting the C-terminal of NADPH oxidases by probes like NS1 in viral infections. PMID- 29524540 TI - Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits myeloperoxidase activity in inflammatory cells. AB - BACKGROUND: Myeloperoxidase (MPO) generates hypochlorous acid (HOCl) during inflammation and infection. We showed that secoisolariciresinol diglucoside (SDG) scavenges radiation-induced HOCl in physiological solutions. However, the action of SDG and its synthetic version, LGM2605, on MPO-catalyzed generation of HOCl is unknown. The present study evaluated the effect of LGM2605 on human MPO, and murine MPO from macrophages and neutrophils. METHODS: MPO activity was determined fluorometrically using hypochlorite-specific 3'-(p-aminophenyl) fluorescein (APF). The effect of LGM2605 on (a) the peroxidase cycle of MPO was determined using Amplex Red while the effect on (b) the chlorination cycle was determined using a taurine chloramine assay. Using electron paramagnetic resonance (EPR) spectroscopy we determined the effect of LGM2605 on the EPR signals of MPO. Finally, computational docking of SDG was used to identify energetically favorable docking poses to enzyme's active site. RESULTS: LGM2605 inhibited human and murine MPO activity. MPO inhibition was observed in the absence and presence of Cl-. EPR confirmed that LGM2605 suppressed the formation of Compound I, an oxoiron (IV) intermediate [Fe(IV)O] containing a porphyrin pi-radical of MPO's catalytic cycle. Computational docking revealed that SDG can act as an inhibitor by binding to the enzyme's active site. CONCLUSIONS: We conclude that LGM2605 inhibits MPO activity by suppressing both the peroxidase and chlorination cycles. EPR analysis demonstrated that LGM2605 inhibits MPO by decreasing the formation of the highly oxidative Compound I. This study identifies a novel mechanism of LGM2605 action as an inhibitor of MPO and indicates that LGM2605 may be a promising attenuator of oxidant-dependent inflammatory tissue damage. PMID- 29524542 TI - Visual acuity recovery following traumatic hyphema in a pediatric population. AB - PURPOSE: To determine the rate of visual recovery following hyphema caused by traumatic blunt force injury in children. METHODS: The medical records of patients evaluated between July 2008 and July 2014 were reviewed retrospectively. Primary outcome measures included presenting and follow-up visual acuities. RESULTS: At total of 56 eyes of 55 children (<18 years of age) were diagnosed with hyphema following blunt force nonpenetrating injury. The average patient age was 10.3 +/- 3.2 years. The majority of subjects were male (78%). Presenting visual acuities ranged from logMAR 0.0 (Snellen equivalent, 20/20) to light perception. Rebleeding occurred in 4 subjects (7.1%). Visual acuity demonstrated improvement over the first 28 days following injury, with 59% achieving visual acuity of logMAR 0.0 (Snellen equivalent, 20/20) and 82% recovering vision to logMAR 0.2 (Snellen equivalent 20/30) by day 28. All but 1 patient (43 of 44 eyes, 98%) had a best-corrected visual acuity of better than or equal to logMAR 0.2 at their last recorded follow-up. CONCLUSIONS: There is good potential for visual recovery following uncomplicated traumatic hyphema in children. In our patient cohort, the majority of patients had significant improvement in visual acuity within the first 28 days; in some children visual acuity continued to improve beyond the first month. PMID- 29524541 TI - Surface Plasmon Resonance kinetic analysis of the interaction between G quadruplex nucleic acids and an anti-G-quadruplex monoclonal antibody. AB - BACKGROUND: G-quadruplexes (G4s) are nucleic acids secondary structures formed in guanine-rich sequences. Anti-G4 antibodies represent a tool for the direct investigation of G4s in cells. Surface Plasmon Resonance (SPR) is a highly sensitive technology, suitable for assessing the affinity between biomolecules. We here aimed at improving the orientation of an anti-G4 antibody on the SPR sensor chip to optimize detection of binding antigens. METHODS: SPR was employed to characterize the anti-G4 antibody interaction with G4 and non-G4 oligonucleotides. Dextran-functionalized sensor chips were used both in covalent coupling and capturing procedures. RESULTS: The use of two leading molecule for orienting the antibody of interest allowed to improve its activity from completely non-functional to 65% active. The specificity of the anti-G4 antobody for G4 structures could thus be assessed with high sensitivity and reliability. CONCLUSIONS: Optimization of the immobilization protocol for SPR biosensing, allowed us to determine the anti-G4 antibody affinity and specificity for G4 antigens with higher sensitivity with respect to other in vitro assays such as ELISA. Anti-G4 antibody specificity is a fundamental assumption for the future utilization of this kind of antibodies for monitoring G4s directly in cells. GENERAL SIGNIFICANCE: The heterogeneous orientation of amine-coupling immobilized ligands is a general problem that often leads to partial or complete inactivation of the molecules. Here we describe a new strategy for improving ligand orientation: driving it from two sides. This principle can be virtually applied to every molecule that loses its activity or is poorly immobilized after standard coupling to the SPR chip surface. PMID- 29524543 TI - A phosphoglycolate phosphatase/AUM-dependent link between triacylglycerol turnover and epidermal growth factor signaling. AB - Mammalian phosphoglycolate phosphatase (PGP, also known as AUM or glycerol-3 phosphate phosphatase) is a small molecule-directed phosphatase important for metabolite repair and lipid metabolism. Although PGP was first characterized as an enzyme involved in epidermal growth factor (EGF) signaling, PGP protein substrates have remained elusive. Here we show that PGP depletion facilitates fatty acid flux through the intracellular triacylglycerol/fatty acid cycle, and that phosphatidylinositol-4,5-bisphosphate (PIP2), produced in a side branch of this cycle, is critical for the impact of PGP activity on EGF-induced signaling. Loss of endogenous PGP expression amplified both EGF-induced EGF receptor autophosphorylation and Src-dependent tyrosine phosphorylation of phospholipase C gamma1 (PLCgamma1). Furthermore, EGF enhanced the formation of circular dorsal ruffles in PGP-depleted cells via Src/PLCgamma1/protein kinase C (PKC)-dependent signaling to the cytoskeleton. Inhibition of adipose triglyceride lipase normalized the increased PIP2 content, reduced EGF-dependent PLCgamma1 hyperphosphorylation, and decreased the elevated dorsal ruffle formation of PGP depleted cells. Our data explain how PGP exerts control over EGF-induced cellular protein tyrosine phosphorylation, and reveal an unexpected influence of triacylglycerol turnover on growth factor signaling. PMID- 29524544 TI - Postembryonic development of pycnogonids: A deeper look inside. AB - Sea spiders form a small, enigmatic group of recent chelicerates, with an unusual bodyplan, oligosegmented larvae and a postembryonic development that is punctuated by many moults. To date, only a few papers examined the anatomical and ultrastructural modifications of the larvae and various instars. Here we traced both internal and external events of the whole postembryonic development in Nymphon brevirostre HODGE 1863 using histology, SEM, TEM and confocal microscopy. During postembryonic development, larvae of this species undergo massive reorganization: spinning apparatus and chelar glands disappear; larval legs redifferentiate; three new segments and the abdomen are formed with their corresponding internal organs and appendages; circulatory and reproductive systems develop anew and the digestive and the nervous systems change dramatically. The body cavity remains schizocoelic throughout development, and no traces of even transitory coeloms were found in any instar. In Nymphon brevirostre, just like in Artemia salina LINNAEUS 1758 the heart arises through differentiation of the already existing schizocoel, and thus the circulatory systems of arthropods and annelids are not homologous. We found that classical chelicerate tagmata, prosoma and opisthosoma, are inapplicable to adult pycnogonids, with the most striking difference being the fate and structure of the seventh appendage-bearing segment. PMID- 29524545 TI - Expression of the alpha toxin of Clostridium perfringens in Lactobacillus casei genome and evaluation of its immune effects in mice. AB - We previously developed a stable and marker-free Lactobacillus casei strain (PPalphaT Deltaupp) that contained a chromosomally integrated expression cassette (PPalphaT) that enabled the surface expression of the Clostridium perfringens alpha toxin. To measure immune responses against the alpha toxin, specific pathogen-free BALB/c mice were inoculated with L. casei PPalphaT Deltaupp by oral gavage. Then, specific immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies and cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM). The results showed that alpha toxin-specific IgA and IgG antibodies and cytokines were markedly increased following immunization. Natural alpha toxin challenge and neutralization tests were performed. The results showed that immunized mice can fully resist 1.5 minimum lethal doses of toxin. These results indicated that the immunized mice can produce not only humoral immunity, but also cellular immunity. These results provide a new pathway for the development of a safe, effective, and food-grade vaccine. PMID- 29524546 TI - An in silico structural and physicochemical characterization of TonB-dependent copper receptor in A. baumannii. AB - Acinetobacter baumannii is an opportunistic multidrug resistant pathogen. TonB dependent copper receptor is an outer membrane protein and has a role in binding of A. baumannii to host cell via attachment to fibronectin. Moreover, it is highly expressed in biofilm community. In this study the properties of copper receptor were analyzed in silico and its vaccine potential was investigated. TonB dependent copper and iron receptor domains plus one plug domain at N-terminal were determined by domain analysis. Topology modeling showed 22 beta-strands, 11 loops and 10 periplasmic turns. Interaction of this protein with TonB2 energy transducer was also indicated. Beside the antigenicity, this protein could take part in bacterial virulence. The more preferable 3D structure was selected amongst all 26 predicted structures, refined and used in prediction of ligand binding site and conformational epitope. The results of B and T-cell epitope mapping indicated 8 potential areas in the protein sequence and structure that seems to be able to stimulate both humoral and cellular immune responses. Based on the alignment result, this protein and all selected epitopes are extremely conserved among A. baumannii strains which can be tested as sub unit vaccine by in vivo studies. PMID- 29524547 TI - Safety characterisation and inhibition of fungi and bacteria by a novel multiple enterocin-producing Enterococcus lactis 4CP3 strain. AB - This study aims to characterise a potential bacteriocinogenic lactic acid bacterial strain isolated from a raw pink shrimp (Palaemon serratus) and evaluate its safety aspect. The strain designated as 4CP3 was noted to display antibacterial activities (P < 0.05) against Gram-positive and Gram-negative foodborne pathogens (Listeria monocytogenes and Pseudomonas aeruginosa) and some filamentous fungi (e.g. Aspergillus niger A79). Phenotypic and molecular techniques as well as phylogenetic analysis identified the isolate 4CP3 as Enterococcus lactis. Its produced antimicrobial substance was determined as a bacteriocin that was stable over a wide range of pH (2-10) and after heating at 100 degrees C for 15 min. The maximum bacteriocin production was 1400 AU/ml recorded after 12 h of incubation in de Man, Rogosa and Sharpe (MRS) broth medium at 30 degrees C. The mode of action of the bacteriocin produced by 4CP3 strain was identified as bactericidal against L. monocytogenes EGDe 107776 and P. aeruginosa ATCC 27853. By specific PCR amplifications, E. lactis 4CP3 was shown to produce the enterocins A, B and P. To our knowledge, this feature is newly described for E. lactis strain isolated from raw shrimps. Regarding safety aspect of E. lactis 4CP3, it has been demonstrated that this strain was not haemolytic, gelatinase negative, sensitive to vancomycin, and free of common antibiotic resistance genes and virulence factors. Therefore, it may be useful as a safe natural agent in preservation of foods or as a new probiotic strain in food and feed. PMID- 29524548 TI - Plant microRNAs: Front line players against invading pathogens. AB - Plants are attacked by a large number of pathogens. To defend against these pathogens, plants activate or repress a vast array of genes. For genetic expression and reprogramming, host endogenous small RNAs (sRNAs) are the key factors. Among these sRNAs, microRNAs (miRNAs) mediate gene regulation through RNA silencing at the post-transcriptional level and play an essential role in the defense responses to biotic and abiotic stress. In the recent years, high throughput sequencing has enabled the researchers to uncover the role of plant miRNAs during pathogen invasion. So here we have reviewed the recent research findings illustrating the plant miRNAs active involvement in various defense processes during fungal, bacterial, viral and nematode infections. However, rapid validation of direct targets of miRNAs is the dire need of time, which can be very helpful in improving the plant resistance against various pathogenic diseases. PMID- 29524549 TI - Antibiofilm effect of Nocardiopsis sp. GRG 1 (KT235640) compound against biofilm forming Gram negative bacteria on UTIs. AB - Urinary tract infections (UTIs) are diverse public health complication and caused by range of pathogens, however mostly Gram negative bacteria cause significant life threatening risks to different populations. The prevalence rate and antimicrobial resistance among the Gram negative uropathogens alarmed significantly heighten the economic burden of these infections. In this study, we investigated the antibiofilm efficiency of Pyrrolo [1,2-a] pyrazine-1,4 dione,hexahydro-3-(2-methylpropyl) extracted from endophytic actinomycetes Nocardiopsis sp. GRG 1 (KT235640) against P. mirabilis and E. coli. The extracted compound was characterized through TLC, HPLC, GC-MS, LC-MS and confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM). The compound, Pyrrolo [1,2-a] pyrazine-1, 4-dione, hexahydro-3-(2-methylpropyl) inhibits both bacterial biofilm formation as well as reduces the viability of preformed biofilms. Furthermore, CLSM image shows cell shrinkage, disorganized cell membrane and loss of viability. The SEM result also confirms the cell wall degradation in treated cells of the bacteria. Hence, the Pyrrolo [1,2-a]pyrazine 1,4-dione, hexahydro-3-(2-methylpropyl) is active against P. mirabilis and E. coli. PMID- 29524550 TI - ecco: An error correcting comparator theory. AB - Building on the work of Ralph Miller and coworkers (Miller and Matzel, 1988; Denniston et al., 2001; Stout and Miller, 2007), I propose a new formalization of the comparator hypothesis that seeks to overcome some shortcomings of existing formalizations. The new model, dubbed ecco for "Error-Correcting COmparisons," retains the comparator process and the learning of CS-CS associations based on contingency. ecco assumes, however, that learning of CS-US associations is driven by total error correction, as first introduced by Rescorla and Wagner (1972). I explore ecco's behavior in acquisition, compound conditioning, blocking, backward blocking, and unovershadowing. In these paradigms, ecco appears capable of avoiding the problems of current comparator models, such as the inability to solve some discriminations and some paradoxical effects of stimulus salience. At the same time, ecco exhibits the retrospective revaluation phenomena that are characteristic of comparator theory. PMID- 29524551 TI - The influence of familiarity and temperature on the huddling behavior of two mouse species with contrasting social systems. AB - Huddling with other individuals is an effective way to reduce heat loss. This cooperative behavior requires that the individuals tolerate each other's presence at least for a certain time or under certain circumstances. In our study, we investigated the effects of ambient temperature and familiarity on the huddling behavior of two closely related mouse species, the mound-building mouse (Mus spicilegus) and the house mouse (Mus musculus musculus). While their geographic distribution overlaps, their social systems differ in many aspects. Whereas house mice are territorial, mound-building mice tolerate each other and live in groups during winter. In laboratory experiments we found that familiarity and ambient temperature influenced the huddling behavior of both species. Familiar individuals were more likely to huddle, but while mound-building mice did so at all temperatures, huddling in house mice increased with lower temperatures. Our results are consistent with the previous knowledge about these species' social systems and might provide us with more details about their sociality. Investigating huddling behavior might be a good way to measure social tolerance between individuals within a species and compare social systems of different species. PMID- 29524552 TI - The influence of lameness and individuality on movement patterns in sheep. AB - We investigated how individuality and lameness altered social organisation by assessing food-directed movement patterns in sheep. One hundred and ninety-six mature Merino ewes were walked in 16 different runs around a 1.1 km track following a food source. Flock position and lameness were measured and temperament was assessed using an Isolation Box Test. The mean value for the correlations of position between a run and the run preceding it was r = 0.55 +/- SEM 0.03. All correlations between runs were positive (r = 0.08-0.76) and all but two were statistically significant (P < 0.05). The weakest and least statistically significant correlations were for run 14: where all 16 runs were conducted approximately 3 times a week, except with an interval of 20 weeks between runs 13 and 14. Additionally, there were differences in overall positions for a lame versus a non-lame individual (all P < 0.05) with lame sheep being further back in position when compared to their non-lame mean positions. These results indicate the movement patterns, as measured by flock position during a food-directed forced movement order are relatively stable provided tests occur frequently, possibly on a bi-weekly basis. However, further work will be required to better account for individual animal variation. PMID- 29524553 TI - Spatial midsession reversal learning in rats: Effects of egocentric Cue use and memory. AB - The midsession reversal task has been used to investigate behavioral flexibility and cue use in non-human animals, with results indicating differences in the degree of control by environmental cues across species. For example, time-based control has been found in rats only when tested in a T-maze apparatus and under specific conditions in which position and orientation (i.e., egocentric) cues during the intertrial interval could not be used to aid performance. Other research in an operant setting has shown that rats often produce minimal errors around the reversal location, demonstrating response patterns similar to patterns exhibited by humans and primates in this task. The current study aimed to reduce, but not eliminate, the ability for rats to utilize egocentric cues by placing the response levers on the opposite wall of the chamber in relation to the pellet dispenser. Results showed that rats made minimal errors prior to the reversal, suggesting time-based cues were not controlling responses, and that they switched to the second correct stimulus within a few trials after the reversal event. Video recordings also revealed highly structured patterns of behavior by the majority of rats, which often differed depending on which response was reinforced. We interpret these findings as evidence that rats are adept at utilizing their own egocentric cues and that these cues, along with memory for the recent response-reinforcement contingencies, aid in maximizing reinforcement over the session. PMID- 29524554 TI - Bafilomycin A1 increases the sensitivity of tongue squamous cell carcinoma cells to cisplatin by inhibiting the lysosomal uptake of platinum ions but not autophagy. AB - The role of autophagy in tongue squamous cell carcinoma (TSCC) cisplatin resistance is unclear. We aimed to identify a possible synergistic effect of autophagy inhibitors and cisplatin in TSCC cells and explore the underlying mechanism. Our results indicate that autophagic flux was high in TSCC cells; Autophagy inhibitor bafilomycin A1 increased cisplatin cytotoxicity in TSCC cells by inhibiting lysosomal uptake of platinum and enhancing intracellular platinum ion binding to DNA; Autophagy gene (Atg5) knockout in TSCC cells did not duplicate the above-mentioned sensitization of bafilomycin A1. Furthermore, we found that cisplatin resistance of TSCC cells was related to cisplatin inducing lysosome biogenesis in a TFEB-dependent manner, which was regulated by c-Abl. In summary, this is the first study to show that Bafilomycin A1 increases the sensitivity of TSCC cells to cisplatin by inhibiting lysosomal function but not autophagy. Lysosomes may be a potential target to increase cisplatin cytotoxicity toward TSCC cells. PMID- 29524556 TI - Primary and acquired EGFR T790M-mutant NSCLC patients identified by routine mutation testing show different characteristics but may both respond to osimertinib treatment. AB - Primary EGFR T790M mutation is occasionally identified by routine mutation testing in tyrosine kinase inhibitor (TKI)-naive patients with non-small cell lung cancer (NSCLC). We herein aimed to compare the characteristics of primary and acquired T790M mutations in NSCLC patients, and their response to osimertinib. Using amplification refractory mutation system (ARMS) detection, primary T790M was identified in 0.5% (46/8723) of TKI-naive patients, whereas acquired T790M was detected in 49.7% (71/143) of TKI-relapsed patients. T790M always coexisted with a sensitizing EGFR mutation. Primary T790M more commonly coexisted with L858R, whereas acquired T790M was more likely to coexist with exon 19 deletions. Moreover, next-generation sequencing (NGS) showed that concomitant sensitizing EGFR and primary T790M mutant allele frequencies (MAFs) were highly concordant, but acquired T790M MAFs were significantly lower than the sensitizing EGFR MAFs. Sixteen acquired T790M-mutant patients received osimertinib. The median progression-free survival (PFS) was 8.1 months. Four primary T790M-mutant patients received osimertinib and the median PFS was 8.0 months. Together, our study demonstrates that primary and acquired T790M-mutant patients show distinct differences in some clinical and molecular characteristics, but may both respond to osimertinib treatment. PMID- 29524555 TI - Elevated phospholipase D activity in androgen-insensitive prostate cancer cells promotes both survival and metastatic phenotypes. AB - Prostate cells are hormonally driven to grow and divide. Typical treatments for prostate cancer involve blocking activation of the androgen receptor by androgens. Androgen deprivation therapy can lead to the selection of cancer cells that grow and divide independently of androgen receptor activation. Prostate cancer cells that are insensitive to androgens commonly display metastatic phenotypes and reduced long-term survival of patients. In this study we provide evidence that androgen-insensitive prostate cancer cells have elevated PLD activity relative to the androgen-sensitive prostate cancer cells. PLD activity has been linked with promoting survival in many human cancer cell lines; and consistent with the previous studies, suppression of PLD activity in the prostate cancer cells resulted in apoptotic cell death. Of significance, suppressing the elevated PLD activity in androgen resistant prostate cancer lines also blocked the ability of these cells to migrate and invade MatrigelTM. Since survival signals are generally an early event in tumorigenesis, the apparent coupling of survival and metastatic phenotypes implies that metastasis is an earlier event in malignant prostate cancer than generally thought. This finding has implications for screening strategies designed to identify prostate cancers before dissemination. PMID- 29524557 TI - Enhanced anti-tumor efficacy of temozolomide-loaded carboxylated poly(amido amine) combined with photothermal/photodynamic therapy for melanoma treatment. AB - Chemotherapy is an important treatment for malignant tumors; however, its efficacy and clinical application are limited by its side effects and drug resistance properties. Chemotherapy and phototherapy exhibit synergistic anti tumor effects. In the present study, a carboxylated poly(amido-amine) (PAMAM) with low cytotoxicity was synthesized as a delivery nanocarrier for loading chemotherapeutic drugs, temozolomide (TMZ), and fluorescent dye indocyanine green (ICG). Hyaluronic acid (HA), which targets the CD44-overexpressing cancer cells, was modified on the nanocarrier surface to enhance the selective killing of melanoma cells. Temperature effect and singlet oxygen production experiments showed that the ICG-loaded nanoparticles exhibited good capability to generate heat and singlet oxygen under near-infrared (NIR) light (808 nm) irradiation. In vivo imaging measurement confirmed that the ICG-encapsulated nanoparticle was delivered successfully and effectively accumulated in the tumor site. In vitro and in vivo experiments revealed that the joint application of TMZ- and ICG loaded nanoparticle can kill melanoma cells and suppress growth after NIR light irradiation. Thus, HA-modified carboxylated PAMAM loaded with TMZ and ICG serves as a promising nanoplatform for melanoma treatment. PMID- 29524558 TI - EGFR-TKI-induced HSP70 degradation and BER suppression facilitate the occurrence of the EGFR T790 M resistant mutation in lung cancer cells. AB - Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790 M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790 M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation. We show that EGFR-TKI treatment causes increased DNA damage and enhanced gene mutation rates, which are secondary to the EGFR-TKI-induced reduction of HSP70 protein. Importantly, HSP70 overexpression delays the occurrence of Erlotinib-induced EGFR T790 M mutation. We further demonstrate that HSP70 interacts with multiple enzymes in the base excision repair (BER) pathway and promotes not only the efficiency but also the fidelity of BER. Collectively, our findings show that EGFR-TKI treatment facilitates gene mutation and the emergence of EGFR T790 M secondary mutation by the attenuation of BER via induction of HSP70 protein degradation. PMID- 29524559 TI - Caregiver and expecting caregiver support for early peanut introduction guidelines. AB - BACKGROUND: Recent guidelines recommend early peanut introduction (EPI) beginning around 4 to 6 months of age in infants with severe eczema and/or egg allergy and around 6 months for all other infants. Caregiver preferences for such practices are unknown. OBJECTIVE: To determine levels of support for early allergenic solid food recommendations among new and expecting caregivers of infants at risk for peanut allergy. METHODS: We explored preferences for EPI and in-office allergy risk assessment (IRA) through a nationally representative survey of expecting (n = 1,000) and new caregivers of infants younger than 1 year (n = 1,000). RESULTS: Among a primarily female (99.7%), married (80.3%), and white (74.4%) sample, 29% had no or vague awareness of the new guidelines, 61% had no or minimal concern for their child developing food allergy, but 54% felt timing of food introduction has moderate to strong importance for developing food allergy. Only 31% expressed willingness for EPI before or around 6 months of age, with 40% reporting willingness to introduce peanut after 11 months of age, similar to tree nuts and seafood. However, 60% reported willingness to introduce egg before 8 months of age. A total of 51% and 56.8% were unwilling to allow IRA methods, such as skin testing and oral challenge, before 11 months of age, respectively. Odds of willingness to delay peanut introduction (odds ratio, 0.79; 95% confidence interval, 0.65-0.96) and undergo challenge (odds ratio, 0.67; 95% confidence interval, 0.54-0.82) after 6 months of age were lower among expecting caregivers. CONCLUSION: Among new and expecting caregivers, there is poor current willingness and questionable support for early allergenic solid food recommendations, including IRA before introduction. Willingness was better among expecting vs current caregivers. These trends underscore a need for broader formal implementation planning to facilitate early allergen introduction and maximize its preventive benefits. PMID- 29524560 TI - RAS-mediated oncogenic signaling pathways in human malignancies. AB - Abnormally activated RAS proteins are the main oncogenic driver that governs the functioning of major signaling pathways involved in the initiation and development of human malignancies. Mutations in RAS genes and or its regulators, most frequent in human cancers, are the main force for incessant RAS activation and associated pathological conditions including cancer. In general, RAS is the main upstream regulator of the highly conserved signaling mechanisms associated with a plethora of important cellular activities vital for normal homeostasis. Mutated or the oncogenic RAS aberrantly activates a web of interconnected signaling pathways including RAF-MEK (mitogen-activated protein kinase kinase) ERK (extracellular signal-regulated kinase), phosphoinositide-3 kinase (PI3K)/AKT (protein kinase B), protein kinase C (PKC) and ral guanine nucleotide dissociation stimulator (RALGDS), etc., leading to uncontrolled transcriptional expression and reprogramming in the functioning of a range of nuclear and cytosolic effectors critically associated with the hallmarks of carcinogenesis. This review highlights the recent literature on how oncogenic RAS negatively use its signaling web in deregulating the expression and functioning of various effector molecules in the pathogenesis of human malignancies. PMID- 29524561 TI - Need for more holistic therapeutic and management strategies to understand the causal or correlative link of the Abeta amyloid pathway with Alzheimer's disease for a more efficient treatment. PMID- 29524562 TI - Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats. AB - Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration. PMID- 29524563 TI - Serum proatrial natriuretic peptide concentrations during oral glucose-induced acute hyperinsulinemia in lean and obese men. AB - Atrial natriuretic peptide (ANP) is primarily seen as a hormone involved in salt and water homeostasis and blood pressure regulation. Evidence supports a link between metabolism and ANP. Circulating ANP concentrations are low in obese individuals with insulin resistance and hyperinsulinemia. The dynamic relationship between insulin and ANP has been sparsely studied. We therefore measured circulating concentrations of midregional proatrial natriuretic peptide (MR-proANP), a stable marker of ANP secretion, and insulin in lean and obese men during an oral glucose challenge. One hundred and three obese men (body mass index (BMI) >=30.0 kg/m2) were compared with 27 lean men (BMI = 20.0-24.9 kg/m2). During a 75 g oral glucose challenge, circulating concentrations of MR-proANP and insulin were measured at baseline and every half hour for 2 h. Fasting MR-proANP concentrations were lower in the obese men as compared with the lean men (median (interquartile range): 51.2 (38.7-64.7) pmol/L vs. 69.3 (54.3-82.9) pmol/L, P = 0.002). During the oral glucose challenge, serum MR-proANP concentrations fell steadily in the obese men (P < 0.0001), whereas there was no significant fall in the lean men (P = 0.14). However, the time-course curves of MR-proANP did not display a clear reciprocal relation to the time-course curves of insulin. Adjusted for age, the area under curve (AUC) for MR-proANP was inversely correlated with AUC for insulin (r = -0.38, P < 0.0001). In conclusion, during an oral glucose challenge, serum MR-proANP concentrations drop significantly in obese individuals, but the time-course curves of MR-proANP do not display a reciprocal relationship to the time-course curves of insulin. PMID- 29524564 TI - New cycloartane-type ester triterpenes from Euphorbia pterococca and biological evaluation. AB - From acetonic extract of the whole plant Euphorbia pterococca Brot. (Euphorbiaceae), four new cycloartane-type ester triterpenes named cycloartenyl 2'E,4'E-decadienoate (1), cycloartenyl-2'E,4'Z-decadienoate (2), 24 methylenecycloartanyl-2'E,4'Z-tetradecadienoate (3), and 24-oxo-29 norcycloartanyl-2'E,4'Z-hexadecadienoate (4) were obtained along with nine known tetracyclic triterpenes (5-13). Their structures were established mainly by extensive use of spectroscopic techniques, including 1D (1H and 13C) and 2D homo- and heteronuclear NMR experiments (COSY, HSQC, HMBC and NOESY), and mass spectrometry (HRESIMS), and by comparison with data reported in the literature. In addition, the new compounds 1-3 have been tested for cytotoxicity, trypanocidal effects and on enzymes involved in endocannabinoid degradation. While inactive in all assays up to 100 MUM, 1 showed selective inhibition of alpha/beta-hydrolase 12 with an IC50 of 11.6 +/- 1.9 MUM. PMID- 29524565 TI - Impact of prenatal hypoxia on fetal bone growth and osteoporosis in ovariectomized offspring rats. AB - Prenatal hypoxia causes intrauterine growth retardation. It is unclear whether/how hypoxia affects the bone in fetal and offspring life. This study showed that prenatal hypoxia retarded fetal skeletal growth in rats, inhibited extracellular matrix (ECM) synthesis and down-regulated of insulin-like growth factor 1 (IGF1) signaling in fetal growth plate chondrocytes in vivo and in vitro. In addition, ovariectomized (OVX) was used for study of postmenopausal osteoporosis. Compared with the control, OVX offspring in prenatal hypoxic group showed an enhanced osteoporosis in the femurs, associated with reduced proteoglycan and IGF1 signaling. The results indicated prenatal hypoxia not only delayed fetal skeletal growth, but also increased OVX-induced osteoporosis in the elder offspring probably through down-regulated IGF1 signaling and inhibition of ECM synthesis, providing important information of prenatal hypoxia on functional and molecular bone growth and metabolism in fetal and offspring. PMID- 29524566 TI - High-level embryonic globin production with efficient erythroid differentiation from a K562 erythroleukemia cell line. AB - A reliable cell line capable of robust in vitro erythroid differentiation would be useful to investigate red blood cell (RBC) biology and genetic strategies for RBC diseases. K562 cells are widely utilized for erythroid differentiation; however, current differentiation methods are insufficient to analyze globin proteins. In this study, we sought to improve erythroid differentiation from K562 cells to enable protein-level globin analysis. K562 cells were exposed to a variety of reagents, including hemin, rapamycin, imatinib, and/or decitabine (known erythroid inducers), and cultured in a basic culture medium or erythropoietin-based differentiation medium. All single reagents induced observable erythroid differentiation with higher glycophorin A (GPA) expression but were insufficient to produce detectable globin proteins. We then evaluated various combinations of these reagents and developed a method incorporating imatinib preexposure and an erythropoietin-based differentiation culture containing both rapamycin and decitabine capable of efficient erythroid differentiation, high-level GPA expression (>90%), and high-level globin production at protein levels detectable by hemoglobin electrophoresis and high performance liquid chromatography. In addition, beta-globin gene transfer resulted in detectable adult hemoglobin. In summary, we developed an in vitro K562 erythroid differentiation model with high-level globin production. This model provides a practical evaluation tool for hemoglobin production in human erythroid cells. PMID- 29524567 TI - PD-1 deficiency augments bone marrow failure in a minor-histocompatibility antigen mismatch lymphocyte infusion model. AB - Although PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life-threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1 deficient (PD-1 knockout [KO]) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe bone marrow (BM) hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN infused mice relative to mice that received B6 LN cell infusion. Mice that received PD-1 KO LN cells had more CD8+ T-cell infiltration of the BM and greater expansion of H60-specific CD8+ T cells than did their B6 LN-infused counterparts. In the spleen, CD8+ T cells were skewed to an effector memory phenotype, suggesting accelerated differentiation of PD-1 KO T cells. Our data suggest that PD-1 dysregulation has a role in murine BM failure and vigilance in irAE monitoring may be desirable to treat early AA and related cytopenias. PMID- 29524568 TI - Impact of persistent and cleared preformed HLA DSA on kidney transplant outcomes. AB - Preformed HLA donor-specific antibodies (DSA) only detected with Luminex have been associated with increased risk of antibody-mediated rejection (ABMR) and graft failure after kidney transplantation (KT). Their evolution after KT may modify this risk. We analyzed postransplant evolution of preformed DSA identified retrospectively and their impact on outcomes of 370 KT performed 2006-2014. Antibodies were monitored prospectively at 1-3-5 years after KT and if any dysfunction. Early acute ABMR was more frequent among patients with preformed DSA class-I or I + II than isolated class-II (29.4% vs 4.5%, p = 0.02). One year post KT, 20 of 34 patients with functioning KT had persistent DSA. Preformed DSA class II persisted more frequently than class-I/I + II (66.7% vs 33.3%; p = 0.031). The only risk factor independently associated with persistence was pretransplant MFI. Patients with de novo DSA had the highest risk of ABMR (HR 22.2 [CI 6.1-81.2]). Although recipients with persisting preformed DSA had significantly increased ABMR risk (HR 14.7 [CI 6.5-33.0]), those with cleared preformed DSA also had a higher risk than those without DSA (HR 7.01 [CI 2.2-21.8]). Preformed DSA are a very important risk factor for ABMR and graft loss. Patients who clear preformed DSA still show an increased risk of ABMR and graft loss after KT. PMID- 29524569 TI - Developmental neurotoxicity resulting from pharmacotherapy of preterm labor, modeled in vitro: Terbutaline and dexamethasone, separately and together. AB - Terbutaline and dexamethasone are used in the management of preterm labor, often for durations of treatment exceeding those recommended, and both have been implicated in increased risk of neurodevelopmental disorders. We used a variety of cell models to establish the critical stages at which neurodifferentiation is vulnerable to these agents and to determine whether combined exposures produce a worsened outcome. Terbutaline selectively promoted the initial emergence of glia from embryonic neural stem cells (NSCs). The target for terbutaline shifted with developmental stage: at later developmental stages modeled with C6 and PC12 cells, terbutaline had little effect on glial differentiation (C6 cells) but impaired the differentiation of neuronotypic PC12 cells into neurotransmitter phenotypes. In contrast to the specificity shown by terbutaline, dexamethasone affected both neuronal and glial differentiation at all stages, impairing the emergence of both cell types in NSCs but with a much greater impairment for glia. At later stages, dexamethasone promoted glial cell differentiation (C6 cells), while shifting neuronal cell differentiation so as to distort the balance of neurotransmitter phenotypes (PC12 cells). Finally, terbutaline and dexamethasone interacted synergistically at the level of late stage glial cell differentiation, with dexamethasone boosting the ability of terbutaline to enhance indices of glial cell growth and neurite formation while producing further decrements in glial cell numbers. Our results support the conclusion that terbutaline and dexamethasone are directly-acting neuroteratogens, and further indicate the potential for their combined use in preterm labor to worsen neurodevelopmental outcomes. PMID- 29524570 TI - Calpeptin is neuroprotective against acrylamide-induced neuropathy in rats. AB - The aim of this study is to explore the potent neuroprotective effect of calpeptin (CP) on neuron damage induced by acrylamide (ACR) and its mechanism. Behavioural indicators such as hind limb splay, rota-rod performance, and gait analysis were assessed weekly to evaluate neurobehavioural changes after ACR and/or CP administration. The histopathological alterations and the changes of MU calpain, m-calpain, microtubule-associated protein 2 (MAP2), and alpha-tubulin and beta-tubulin protein levels in spinal cord were determined. Results showed that after administration of 30 mg/kg ACR, decreased body weight, attenuated neurobehavioural function, injury of motor neuron, increased protein levels of m calpain and beta-tubulin, suppressed MAP2 protein level, and no significant changes of MU-calpain and alpha-tubulin protein levels were observed compared with the control group rats. After administration of 200 MUg/kg CP, partially restored body weight and neurobehavioural function, improvement of motor neuron injury, decreased protein levels of m- calpain and beta-tubulin, and reversed effects of MAP2 protein level were observed compared with the ACR group rats. Our results suggested that CP alleviates neuropathy induced by ACR in rats. The calpain's overactivation causes the degrading of MAP2 and eventually leads to the destruction of microtubules (MTs), which may be one of the mechanisms of cytoskeletal damage induced by ACR. PMID- 29524571 TI - Risk assessment of pyrrolizidine alkaloids in food of plant and animal origin. AB - Acute liver toxicity, specifically in the form of hepatic veno-occlusive disease (HVOD), is known from reports on human poisonings following ingestions of 1,2 unsaturated pyrrolizidine alkaloids (PAs) containing herbs. Recently PA exposure via common foods contaminated via PA-producing plants raised concern, especially regarding the potential of genotoxicity and carcinogenicity. The health risks related to the estimated exposures to PAs from food were assessed. With respect to common foods, herbal teas and teas are the main sources through which consumers can be exposed to PAs. For high long-term consumption of these foods a possible health concern has been revealed in the assessment of chronic risks referring to a BMDL10 of 237 MUg/kg bw per day recently established by EFSA based on model averaging for data on riddelliine. However, acute health damage from acute or short-term intake of PAs via common food is considered to be unlikely. Food supplements on the basis of PA-producing plants may significantly contribute to PA exposures and their intake is associated with risks of acute and chronic toxicity. However, no health risks have to be expected from the consumption of food supplements based on oil-based preparations of PA-producing plants, which were described to be free of PAs. PMID- 29524572 TI - Susceptibility of multiple polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 genes to myocardial infarction in Han Chinese. AB - We aimed to investigate the association of 12 extensively studied polymorphisms in adiponectin (ADIPOQ), adiponectin receptor-1 (ADIPOR1) and adiponectin receptor-2 (ADIPOR2) genes with myocardial infarction in Han Chinese. This is a hospital-based, cross-sectional, case-control study, including 717 myocardial infarction patients and 612 controls. Myocardial infarction was confirmed through electrocardiogram/anatomopathological examinations. All polymorphisms met the Hardy-Weinberg equilibrium (p > 0.05). The genotype/allele counts of ADIPOQ gene rs2241766 (p = 0.001/0.003) and ADIPOR2 gene rs10773989 (p < 0.001/=0.008) differed significantly between patients and controls. Under the recessive model, rs2241766 (odds ratio [OR] = 4.16, 95% confidence interval [CI]: 1.83-9.49, p = 0.001) and rs10773989 (OR = 8.40, 95% CI: 2.54-27.8, p < 0.001) were associated with the significantly increased risk of myocardial infarction. Haplotype analysis revealed none or marginal significance, and there was no likelihood of genetic interaction as indicated by multifactor dimensionality reduction (MDR). Logistic regression analysis indicated that age, total cholesterol, hypertension, rs2241766, rs1342387, rs10773989 and rs1044471 were significant contributors, and a nomogram based on these contributors exhibited a good predictive utility (C index: 0.795, p < 0.001). Our findings demonstrate that two polymorphisms, rs2241766 in ADIPOQ gene and rs10773989 in ADIPOR2 gene, especially under the recessive model of inheritance, played independent leading roles in susceptibility to myocardial infarction in Han Chinese. PMID- 29524573 TI - Lipopolysaccharide causes NFKB-mediated induction of inducible nitric oxide synthase gene and more production of nitric oxide in air-breathing catfish, Clarias magur (Hamilton). AB - The magur catfish (Clarias magur) is a facultative air-breather and regularly encounters with various environmental changes along with exposure to various bacterial pathogens in its natural habitats. Occurrence of various biochemical adaptational strategies related to nitrogen metabolism in magur catfish is already known. The present investigation aimed at determining the possible induction of inducible nitric oxide synthase (inos) gene and stimulation of nitric oxide (NO) production in this catfish while challenging with lipopolysaccharide (LPS, a bacterial endotoxin) treatment, and also to determine the involvement of nuclear factor kappa B (NFkB) in induction of inos gene. Intra peritoneal injection of LPS led to more production and accumulation of NO in different body tissues of magur catfish as a consequence of induction of iNOS activity. The induction of iNOS activity was associated with the induction of inos gene as evidenced by more expression of inos mRNA and more abundance of iNOS enzyme protein in different tissues of magur catfish with certain variations in zonal specific expression patterns. Similar observations related to more production of NO and induction of inos gene were also made when the isolated hepatocytes were treated with LPS in vitro condition. LPS treatment also led to activation of NFKB in hepatic cells. However, in presence of a specific inhibitor of NFkB, the LPS-mediated induction of inos gene and extra production of NO were almost blocked, thereby suggesting that the induction of inos gene due to LPS treatment was mediated via the NFkB in magur catfish. It is hypothesized that the induction of iNOS activity, and more synthesis and accumulation of NO could serve as indicators to determine the pathophysiological conditions of the fish living in bacterial contaminated water bodies. Further, it can be contemplated that more synthesis of NO through iNOS enzyme probably serves as an important pharmacological tool against fish pathogen and also plays an important role in host defense mechanisms in this unique group of magur catfish. PMID- 29524574 TI - Identification and differential expression of microRNAs in testis and ovary of Amur sturgeon (Acipenser schrenckii). AB - BACKGROUND: MicroRNAs (miRNAs) cooperate with sex-related genes in post transcriptional regulation and play extremely important roles in the establishment of sexually dimorphic traits in animals. However, the gonad miRNAs and expression patterns of miRNAs in sturgeon have not been investigated. METHODS: In the present study, we used high-throughput small RNA sequencing (RNA Seq) to discover gonad miRNAs from the ovaries and testes of Amur sturgeons (Acipenser schrenckii). Further, microarray and real-time PCR assays were performed to identify the expression patterns of gonad miRNAs. RESULTS: As a result, a total of 679 conserved and 51 novel miRNAs were successfully discovered in the gonads of A. schrenckii. Moreover, we found wide sequence variations (isomiRs) in gonad miRNAs, including 5' and 3' isomiRs. Our microarray analysis further characterized the 730 miRNAs expression profiles, which indicated that 117 differentially expressed miRNAs were detected with sex-biased patterns: 71 testis-biased and 46 ovary-biased miRNAs. Based on bioinformatics prediction, we found that there were functional differences between the testis-biased and ovary biased miRNA targets involved in reproductive-related GO and KEGG pathways. Further, the association of the differentially expressed miRNAs and sex-related target mRNAs was uncovered. Finally, the expression patterns of 11 sex-biased miRNAs and 7 sex-related targets were validated in testes and ovaries using real time PCR. Putative, negatively expressed miRNA-mRNA relationships were confirmed, such as Dmrt1 and asc-miR-2779, AR and asc-miR-203b-3p, foxl2 and asc-miR-30d. CONCLUSION: This study provides information regarding the gonad miRNAs in sturgeon. The differential expression miRNAs in the gonads will help us to further understand the role of miRNA-mediated post-transcriptional regulation in the ovary and testis of sturgeon. PMID- 29524575 TI - Piwil1 gene is regulated by hypothalamic-pituitary-gonadal axis in turbot (Scophthalmus maximus): A different effect in ovaries and testes. AB - As constituent factors of Piwi-interacting RNA (piRNA) pathways, Piwi proteins are essential for germline maintenance and gonadal development. Previous studies show that Piwi-piRNA pathways could be regulated by hypothalamic-pituitary gonadal (HPG) axis, however, related studies have not been reported in marine species. Here we reported the identification of turbot (Scophthalmus maximus) piwil1 gene, which was abundantly expressed in testis and ovary in a tissue specific manner. Phylogenetic and genomic structure analyses revealed that piwil1 was conserved in its sequence and function during vertebrate evolution. We also investigated the effects of HPG axis hormones, including human chorionic gonadotropin (hCG), estradiol-17beta (E2) and 17alpha-methyltestosterone (MT), on gonadal piwil1 expression via in vivo and in vitro approaches. In ovary, hCG and E2 suppressed piwil1 expression both in vivo and in vitro, and MT increased piwil1 expression in vivo. In testis, hCG had upregulating effects on piwil1 expression in vivo and in vitro, and MT also increased piwil1 expression in vitro. In addition, E2 suppressed expression of piwil1 in vivo. These results indicated that the decreased or increased expression of piwil1 regulated by hormones might play a crucial role during gonadal differentiation and development in S. maximus. PMID- 29524576 TI - A novel non-coding RNA within an intron of CDH2 and association of its SNP with non-syndromic cleft lip and palate. AB - BACKGROUND: Genome-wide linkage analysis and whole genome sequencing in a Van der Woude syndrome (VWS) family revealed that the SNP, rs539075, within intron 2 of the cadherin 2 gene (CDH2) co-segregated with the disease phenotype. RESULTS: A study with nonsyndromic cleft lip with or without cleft palate (NSCL +/- P) cases (N = 292) and controls (N = 287) established association of this SNP with NSCL +/ P as a risk factor. RT-PCR based expression analysis of the SNP-harbouring region of intron 2 of CDH2 in the clefted lip and/or palate tissues of 16 patients revealed that the mutant allele expressed in all those individuals having it (hetero-/homozygous), whereas the wild type allele expressed in <50% of the samples in which it was present. The intronic transcript was also present in the prospective lip and palate region of 13.5 dpc mouse embryo, detected by RNA in situ hybridization and RT-PCR. CONCLUSIONS: These results including the in silico, characterization of the ~200 nt-intronic transcript showed that conformationally it fits best with noncoding small RNA, possibly a precursor of miRNA. Its function in the orofacial organogenesis remains to be elucidated which will enable us to define the role of this mutant ncRNA in the clefting of lip and palate. PMID- 29524577 TI - Kernel machine SNP set analysis provides new insight into the association between obesity and polymorphisms located on the chromosomal 16q.12.2 region: Tehran Lipid and Glucose Study. AB - INTRODUCTION: Obesity is a serious health problem that leads to low quality of life and early mortality. To the purpose of prevention and gene therapy for such a worldwide disease, genome wide association study is a powerful tool for finding SNPs associated with increased risk of obesity. To conduct an association analysis, kernel machine regression is a generalized regression method, has an advantage of considering the epistasis effects as well as the correlation between individuals due to unknown factors. MATERIALS AND METHODS: In this study, information of the people who participated in Tehran cardio-metabolic genetic study was used. They were genotyped for the chromosomal region, evaluation 986 variations located at 16q12.2; build 38hg. Kernel machine regression and single SNP analysis were used to assess the association between obesity and SNPs genotyped data. RESULTS: We found that associated SNP sets with obesity, were almost in the FTO (P = 0.01), AIKTIP (P = 0.02) and MMP2 (P = 0.02) genes. Moreover, two SNPs, i.e., rs10521296 and rs11647470, showed significant association with obesity using kernel regression (P = 0.02). CONCLUSION: In conclusion, significant sets were randomly distributed throughout the region with more density around the FTO, AIKTIP and MMP2 genes. Furthermore, two intergenic SNPs showed significant association after using kernel machine regression. Therefore, more studies have to be conducted to assess their functionality or precise mechanism. PMID- 29524578 TI - Impact of eNOS 27-bp VNTR (4b/a) gene polymorphism with the risk of Systemic Lupus Erythematosus in south Indian subjects. AB - OBJECTIVE: Endothelial nitric oxide synthase (eNOS) is constitutively expressed by vascular endothelium including glomerular endothelium. Functional polymorphisms, -786T>C (rs2070744) promoter variant, 27 bp VNTR (4b/a) in intron 4 and 894G>T (rs1799983) exon variant of eNOS are known to alter the eNOS expression and activity leading to altered NO levels and contribute to the development of vascular and renal disease risk. Thus it might have a role in SLE risk and development of glomerulonephritis. Hence, the present study is aimed to investigate the role of eNOS polymorphisms in South Indian SLE patients. METHODS: Five hundred and four subjects (219 SLE cases and 285 controls) were included in the present case-control study. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for -786T>C and 894G>T SNPs. Another, 4a4b variable number of tandem repeat polymorphism was genotyped using direct PCR method using primer pairs flanking the 27 bp direct repeat region in intron 4 of eNOS gene. RESULTS: Our analysis revealed that intron 4 27 bp VNTR genotype frequency differ significantly between the SLE patients and controls (OR: 1.73, 95% CI %:1.18-2.54, P = 0.004). Further, "a allele" frequency was significantly higher in SLE patients as compared to the controls (20 vs. 13.8%) (OR: 1.56, 95%CI: 1.11-2.18, P = 0.01). However, promoter polymorphism -786T>C and missense variant 894G>T were not significantly different between the SLE cases and controls (OR: 0.92, 95%CI: 0.64-1.33, P = 0.7 and OR: 1.4, 95%CI: 0.95-2.06, P = 0.095 respectively). Furthermore, no association was found between any of the three polymorphisms with lupus nephritis phenotype. Increased plasma nitrate levels were observed in SLE patients (36.79 +/- 2.83 MUM/L) as compared to healthy controls (28.53 +/- 1.94 MUM/L) (P = 0.01). In addition, the genotype-based simulations have indicated that combined effect of eNOS polymorphisms contribute to 30.5% variability in NO production. CONCLUSION: Results of the present study indicate that 27-bp VNTR polymorphism in intron 4 of eNOS gene polymorphism may be the significant risk factor for SLE in south Indian subjects. PMID- 29524579 TI - Transcriptomic analysis of Portunus trituberculatus reveals a critical role for WNT4 and WNT signalling in limb regeneration. AB - The swimming crab (Portunus trituberculatus) is among the most economically important seawater crustacean species in Asia. Despite its commercial importance and being well-studied status, genomic and transcriptomic data are scarce for this crab species. In the present study, limb bud tissue was collected at different developmental stages post amputation for transcriptomic analysis. Illumina RNA-sequencing was applied to characterise the limb regeneration transcriptome and identify the most characteristic genes. A total of 289,018 transcripts were obtained by clustering and assembly of clean reads, producing 150,869 unigenes with an average length of 956 bp. Subsequent analysis revealed WNT signalling as the key pathway involved in limb regeneration, with WNT4 a key mediator. Overall, limb regeneration appears to be regulated by multiple signalling pathways, with numerous cell differentiation, muscle growth, moult, metabolism, and immune-related genes upregulated, including WNT4, LAMA, FIP2, FSTL5, TNC, HUS1, SWI5, NCGL, SLC22, PLA2, Tdc2, SMOX, GDH, and SMPD4. This is the first experimental study done on regenerating claws of P. trituberculatus. These findings expand existing sequence resources for crab species, and will likely accelerate research into regeneration and development in crustaceans, particularly functional studies on genes involved in limb regeneration. PMID- 29524580 TI - MicroRNA-128 inhibits proliferation and invasion of glioma cells by targeting COX 2. AB - MicroRNAs (miRNA), a class of small noncoding RNAs, regulates message RNA (mRNA) by targeting the 3'-untranslated region (3'-UTR) resulting in suppression of gene expression. In this study, we identified the expression and function of miR-128, which was found to be downregulated in glioma tissues and glioma cells by real time PCR. Overexpression of miR-128 mimics into LN229 and U251 cells could inhibit proliferation and invasion of glioma cells. However, the inhibitory effects of miR-128 mimics on the invasion and proliferation of glioma cells were reversed by overexpression of cyclooxygenase-2 (COX-2). Our data showed that COX 2 was a candidate target of miR-128. Luciferase activity of 3'-UTR of COX-2 was reduced in the presence of miR-128. Additionally, miR-128 obviously decreased COX 2 mRNA stability determined by real time PCR. Contrarily, we found that miR-128 inhibitor significantly increased the COX-2 mRNA expression, and elevated the protein expression of MMP9 and ki67, and promoted the proliferation of glioma cells. Furthermore, luciferase activity of the 3'-UTR was upregulated by miR-128 inhibitor. All of these results supported that miR-128 was a direct regulator of COX-2. Further studies proved that COX-2 was elevated in glioma tissues and its expression was negatively correlated with the levels of miR-128. These findings may establish miR-128 as a new potential target for the treatment of patients with gliomas. PMID- 29524581 TI - De novo assembly, gene annotation, and marker development using Illumina paired end transcriptome sequencing in the Crassadoma gigantea. AB - Crassadoma gigantea is an important commercial marine bivalve species in Baja California and Mexico. In this study, we have applied RNA-Seq technology to profile the transcriptome of the C. gigantea for the first time. A total of 80,832,518 raw reads were produced from a Illumina HiSeq4000 platform, and 77,306,198 (95.64%) clean reads were generated after trimming the adaptor sequences. The transcriptome assembled into 158,855 transcripts with an N50 size of 1995 bp and an average size of 1008 bp. A number of DNA repair related genes, such as MSH3, EGF, TGF, IGF, FGF, encoding different groups of growth factors were found in the transcriptome data of C. gigantean. In addition, immune related genes Toll-like receptor (TLR) including TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, and TLR9 was also observed in C. gigantean. A set of 12 polymorphic microsatellite loci were firstly developed and characterized in C. gigantea. The results show that the number of alleles and expected heterozygosity ranged from 3 to 9 and from 0.254 to 0.820, respectively. The average polymorphic information content was 0.790. These microsatellite loci will facilitate future studies of population structure and conservation genetics in this species. PMID- 29524583 TI - Surgical site identification with personal digital device: A prospective pilot study. AB - BACKGROUND: Various means to facilit ate accurate biopsy site identification have been proposed. OBJECTIVE: To determine the accuracy of biopsy site identification by using photographs taken with a patient's digital device by a dermatologist versus professional medical photography. METHODS: Photographs of circled biopsy sites were taken with personal digital devices by the principal investigator (PI). Another set of photographs was taken by a professional photographer. Secondary photographs were taken of the biopsy site location pointed to by the staff and PI on the basis of the personal digital device image and professional medical photography, respectively. On the basis of secondary photographs, 2 independent dermatologists determined whether the skin biopsy locations pointed out by the staff were consistent with the ones pointed out by PI. RESULTS: Per dermatologist A, the staff correctly identified all 53 biopsy sites. Per dermatologist B, the staff were correct on 51 of 53 observations. Dermatologist C, the final arbiter, concurred with dermatologist A on the 2 cases in which dermatologist B was not certain of the location of the biopsy site. LIMITATIONS: The mean interval from initial biopsy to reidentification of the site was 36.2 days. CONCLUSION: Utilizing patients' personal digital devices is a cost effective, Health Insurance Portability and Accountability Act-compliant, and readily available means to identify skin biopsy sites. PMID- 29524582 TI - Associations Between Perceived Stress and Chemotherapy-Induced Peripheral Neuropathy and Otoxicity in Adult Cancer Survivors. AB - CONTEXT: The most common adverse effects from neurotoxic chemotherapy are chemotherapy-induced neuropathy (CIPN), hearing loss, and tinnitus. Although associations between perceived stress and persistent pain, hearing loss, and tinnitus are documented, no studies have examined these associations in cancer survivors who received neurotoxic chemotherapy. OBJECTIVES: In this cross sectional study, we evaluated for associations between perceived stress and the occurrence of CIPN, hearing loss, and tinnitus, in 623 adult cancer survivors who received platinum and/or taxane compounds. METHODS: Survivors completed self report measures of hearing loss, tinnitus, and perceived stress (i.e., Impact of Events Scale-Revised [IES-R]). Separate logistic regression analyses were done for each neurotoxicity to evaluate whether each of the IES-R subscale (i.e., intrusion, avoidance, hyperarousal) and total scores made a significant independent contribution to neurotoxicity group membership. RESULTS: Of the 623 survivors in this study, 68.4% had CIPN, 34.5% reported hearing loss, and 31.0% reported tinnitus. Older age, higher body mass index, poorer functional status, being born prematurely, cancer diagnosis, and higher intrusion (P = 0.013), hyperarousal (P = 0.014), and total (P = 0.047) IES-R scores were associated with CIPN. Older age, being male, poorer functional status, a worse comorbidity profile, and a higher IES-R hyperarousal (P = 0.007) score were associated with hearing loss. Being male, having less education, a worse comorbidity profile, and a higher IES-R hyperarousal (P = 0.029) score were associated with tinnitus. CONCLUSION: These findings suggest that increased levels of perceived stress are associated with the most common chemotherapy-induced neurotoxicities. PMID- 29524584 TI - Pathologist characteristics associated with accuracy and reproducibility of melanocytic skin lesion interpretation. AB - BACKGROUND: Diagnostic interpretations of melanocytic skin lesions vary widely among pathologists, yet the underlying reasons remain unclear. OBJECTIVE: Identify pathologist characteristics associated with rates of accuracy and reproducibility. METHODS: Pathologists independently interpreted the same set of biopsy specimens from melanocytic lesions on 2 occasions. Diagnoses were categorized into 1 of 5 classes according to the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system. Reproducibility was determined by pathologists' concordance of diagnoses across 2 occasions. Accuracy was defined by concordance with a consensus reference standard. Associations of pathologist characteristics with reproducibility and accuracy were assessed individually and in multivariable logistic regression models. RESULTS: Rates of diagnostic reproducibility and accuracy were highest among pathologists with board certification and/or fellowship training in dermatopathology and in those with 5 or more years of experience. In addition, accuracy was high among pathologists with a higher proportion of melanocytic lesions in their caseload composition and higher volume of melanocytic lesions. LIMITATIONS: Data gathered in a test set situation by using a classification tool not currently in clinical use. CONCLUSION: Diagnoses are more accurate among pathologists with specialty training and those with more experience interpreting melanocytic lesions. These findings support the practice of referring difficult cases to more experienced pathologists to improve diagnostic accuracy, although the impact of these referrals on patient outcomes requires additional research. PMID- 29524585 TI - Mining the tree of life: Host defense peptides as antiviral therapeutics. AB - Discovering new therapeutics for human viral diseases is important for combatting emerging infectious viruses and omnipresent circulating viruses as well as those that can become resistant to the drugs we currently have available. The innate host defense peptide (HDP) repertoire present in animals is a wealth of potential antimicrobial agents that could be mined to meet these needs. While much of the body of research regarding HDPs is in the context of bacteria, there is increasing evidence that they can be an effective source for antivirals. Peptides can be identified in a number of ways, including eco-conservation-minded approaches. Those shown to have antiviral properties can be modified to exhibit desired properties as the relationship between structure and function is elucidated and then developed into therapeutics for human use. This review looks at the discovery and therapeutic potential of HDPs for human viral infections. PMID- 29524587 TI - Spasticity or periodic limb movements? Lessons from a not-uncommon case report. PMID- 29524586 TI - Drug delivery and epimorphic salamander-type mouse regeneration: A full parts and labor plan. AB - The capacity to regenerate entire body parts, tissues, and organs had generally been thought to be lost in evolution with very few exceptions (e.g. the liver) surviving in mammals. The discovery of the MRL mouse and the elucidation of the underlying molecular pathway centering around hypoxia inducible factor, HIF 1alpha, has allowed a drug and materials approach to regeneration in mice and hopefully humans. The HIF-1alpha pathway is ancient and permitted the transition from unicellular to multicellular organisms. Furthermore, HIF-1alpha and its regulation by PHDs, important oxygen sensors in the cell, provides a perfect drug target. We review the historical background of regeneration biology, the discovery of the MRL mouse, and its underlying biology, and novel approaches to drugs, targets, and delivery systems (see Fig. 1). PMID- 29524588 TI - Leisure time physical activity, perception of impact of pain and life satisfaction after spinal cord injury. PMID- 29524589 TI - Air pollution as a determinant of rheumatoid arthritis. AB - Pollution has long been incriminated in many cardiovascular and respiratory diseases. More recently, studies evaluated the potential role for particulate pollutants in autoimmune diseases, including rheumatoid arthritis (RA). The incidence of RA was found to be higher in urban areas. Living near air pollution emitters was associated with higher risks of developing RA and of producing RA specific autoantibodies. Nevertheless, no strong epidemiological evidence exists to link one or more specific air pollution particles to RA. The presence in the bronchi of lymphoid satellite islands (inducible bronchus-associated lymphoid tissue, iBALT) is strongly associated with both inflammatory lung disease and RA associated lung disease. Diesel exhaust particles can stimulate iBALT formation. The induction by air pollution of an inflammatory environment with high citrullination levels in the lung may induce iBALT formation, thereby causing a transition toward a more specific immune response via the production of anti citrullinated peptide antibodies. Air pollution not only triggers innate immune responses at the molecular level, increasing the levels of proinflammatory cytokines and reactive oxygen species, but is also involved in adaptive immune responses. Thus, via the aryl hydrocarbon receptor (AHR), diesel exhaust particles can trigger a T-cell switch to the Th17 profile. Finally, in the murine collagen-induced arthritis model, animals whose lymphocytes lack the AHR develop milder arthritis. PMID- 29524590 TI - Evaluation, validation and refinement of noninvasive diagnostic biomarkers for endometriosis (ENDOmarker): A protocol to phenotype bio-specimens for discovery and validation. AB - OBJECTIVE: Endometriosis is a chronic, estrogen dependent condition that affects 5-10% of reproductive aged women and is associated with pelvic pain and infertility. As the approach to therapy shifts from surgical ablation to pharmacological control, a non-surgical mode of diagnosis would be desirable. The ENDOmarker study was designed by the NICHD Reproductive Medicine Network (RMN) to obtain well characterized and phenotyped bio specimens in a standardized fashion from women with and without endometriosis. DESIGN: Development of a diagnostic test. SETTING: Academic medical centers. PATIENTS: This study will enroll up to 500 participants, and follow them for up to 5 months. Included subjects are aged 18-44, scheduled to undergo gynecologic surgery (laparoscopy/laparotomy) for clinical reasons. INTERVENTIONS: Presence and stage of endometriosis (or its absence) is characterized by visual examination at the time of surgery. Subjects will undergo extensive clinical evaluation pre-operatively and at visits one and four months postoperatively. Endometrial biopsy, blood, urine and disease specific questionnaires will be collected at each visit. MAIN OUTCOME: Samples will be placed in a bio-repository to be used to validate and optimize the clinical use of genomic classifiers of the endometrium alone or in combination with serum cytokines as a non-surgical composite marker of endometriosis. CONCLUSION: This protocol can serve as a reference for objective collection of high quality bio specimens for discovery or validation of potential nonsurgical diagnosis of presence or severity of disease. PMID- 29524591 TI - Efficient production of a recombinant Venerupis philippinarum defensin (VpDef) in Pichia pastoris and characterization of its antibacterial activity and stability. AB - VpDef is a novel defensin isolated from the clam Venerupis philippinarum. Previously it was expressed in Escherichia coli; however, the E. coli-derived recombinant VpDef did not show effective antimicrobial activity against Staphyloccocus aureus or the Gram-negative bacteria tested. As such, the goal of this study was to design, express, and purify a recombinant VpDef (rVpDef) in Pichia pastoris and to determine its antibacterial potency and stability. A 6.9 KDa rVpDef was successfully expressed as a secreted peptide in P. pastoris, and the amount of rVpDef accumulation was shown to reach as high as approximate 60 MUg per 1 ml of culture medium only after an initial optimization was performed. The purified rVpDef demonstrated a broad antibacterial spectrum and was active against six typical common bacteria, both Gram-positive and Gram-negative. A minimal inhibition concentration of as low as 50 MUg/ml was observed for rVpDef against the growth of E. coli O157 (ATCC 35150). Moreover, rVpDef was tolerant to temperature shock and proteinase digestion and maintained a high stability over a relatively broad pH range. In addition, rVpDef had a low hemolytic activity against rabbit erythrocytes. Taken together, this study demonstrated that rVpDef could be produced in a large-scale manner in P. pastoris and has a good antibacterial activity and suitable stability. This is the first report on heterologous expression of a biologically active VpDef in P. pastoris, supporting its use for both research and application purposes. PMID- 29524592 TI - Evaluation of drug permeation under fed state conditions using mucus-covered Caco 2 cell epithelium. AB - The absence of a surface-lining mucus layer is a major pitfall for the Caco-2 epithelial model. However, this limitation can be alleviated by applying biosimilar mucus (BM) to the apical surface of the cell monolayer, thereby constructing a mucosa mimicking in vivo conditions. This study aims to elucidate the influence of BM as a barrier towards exogenic compounds such as permeation enhancers, and components of fed state simulated intestinal fluid (FeSSIF). Caco 2 cell monolayers surface-lined with BM were exposed to several compounds with distinct physicochemical properties, and the cell viability and permeability of the cell monolayer was compared to that of cell monolayers without BM and well established mucus-secreting epithelial models (HT29-MTX-E12 cell monolayers and HT29-MTX-E12/Caco-2 cell co-culture monolayers). Exposure of BM-covered cells to constituents from FeSSIF revealed that it comprised a strong, hydrophilic barrier effect as 90% of BM-covered cells remained viable for >4 h, and the permeation rate of hydrophobic drugs was reduced. In contrast, the permeation rate of hydrophilic drugs was largely unaffected. Control monolayers displayed a loss of barrier function and <10% viable cells. The efficacy of fatty acid permeation enhancers were altered when investigated in BM-covered cells as compared to all the other studied epithelial models. Thus, Caco-2 cell monolayers surface-lined with BM constitute a valuable in vitro model that makes it possible to mimic intestinal fed state conditions when studying drug permeation. PMID- 29524593 TI - Mechanism of the formation of hollow spherical granules using a high shear granulator. AB - Recently, we have developed a novel granulation technology to manufacture hollow spherical granules (HSGs) for controlled-release formulations; however, the mechanism of the granulation is still unclear. The aim of this study is to determine the mechanism of the formation of the HSGs using a high shear granulator. Samples of granulated material were collected at various times during granulation and were investigated using scanning electron microscope and X-ray computed tomography. It was observed that the granulation proceeded by drug layering to the polymer, followed by formation of a hollow in the granule. In addition, it was also found that generation of a crack in the adhered drug layer and air flow into the granules might be involved in forming the hollow in the structure. Observation of the granulation of formulations with different types of drugs and polymers indicated that negative pressure in the granules occurred and the granules caved in when the hollow was formed. The hollow-forming speed and the shell density of the hollow granules depended on the particular drug and polymer. Taken together, the granulation mechanism of HSGs was determined and this information will be valuable for HSGs technology development. PMID- 29524594 TI - Pediatric and Gynecologic Rates of Documentation of Last Menstrual Period in Female Adolescents. AB - STUDY OBJECTIVE: The American Academy of Pediatrics and American College of Obstetricians and Gynecologists have identified the menstrual cycle as essential in assessing overall health of adolescent girls. Menses should be considered a "vital sign" and documentation of last menstrual period (LMP) is recommended at every patient encounter. The aim of this study was to estimate and compare LMP documentation among adolescent and pediatric health care providers. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study identified a random sample of 50 female patients seen in the general pediatrics (PEDS), adolescent medicine (AM), and pediatric and adolescent gynecology (PAG) ambulatory clinics at Phoenix Children's Hospital between January 1, 2016 and March 31, 2016. INTERVENTIONS AND MAIN OUTCOME MEASURES: Rates of LMP documentation were compared between clinics using the Pearson chi2 test. Multivariable logistic regression analyses quantified the association of clinic and LMP documentation, with adjustments for visit reason, provider gender, and age at presentation. RESULTS: Rates of LMP documentation were 100% for adolescent gynecologists, but significantly lower for general pediatricians (14%) and AM (60%) providers (P < .0001). These findings were confirmed in multivariable analyses (PAG vs PEDS: odds ratio [OR], 280; 95% confidence interval [CI], 32-2331; PAG vs AM: OR, 34; 95% CI, 4.4-270; AM vs PEDS: OR, 3.8; 95% CI, 1.3-11.0). CONCLUSION: Adolescent gynecologists document LMP routinely. In contrast, LMP documentation rates in AM, and especially in PEDS, were significantly lower. Quality improvement methods such as incorporation of an LMP section into the vitals portion of an electronic medical record could help improve rates of compliance. PMID- 29524595 TI - Treatment Modalities in Adolescents Who Present with Heavy Menstrual Bleeding. AB - STUDY OBJECTIVE: On this study we sought to determine the relationship of bleeding disorders to iron deficiency anemia. Additionally, this study was undertaken to examine all current treatment modalities used in a menorrhagia clinic with respect to heavy menstrual bleeding management to identify the most effective options for menstrual management in the setting of an underlying bleeding disorder. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We performed a retrospective chart review of adolescents younger than 21 years with heavy menstrual bleeding attending a multidisciplinary hematology adolescent gynecology clinic. Information including demographic characteristics, bleeding diathesis, hematologic parameters, treatment, and the diagnosis was extracted from each chart. Subjects were grouped into 2 categories on the basis of the diagnosis of a bleeding disorder. Hemoglobin level, iron deficiency anemia, and need for transfusion were compared between a bleeding disorder and no bleeding disorder group. Subjects were grouped into categories depending on hormonal modality and treatment success of the groups were compared. RESULTS: Seventy-three subjects were tested for a bleeding disorder. Of the subjects who completed testing, 34 (46%) were diagnosed with a bleeding disorder. Thirty-nine subjects (54%) had heavy menstrual bleeding because of other causes. There was no significant difference in hemoglobin between those with and without a bleeding disorder. Iron deficiency anemia was significantly higher in subjects without a bleeding disorder. In a comparison of hormone therapy success, the levonorgestrel intrauterine device (89%, 8 out of 9 subjects) had the highest rate of menstrual suppression followed by norethindrone acetate 5-10 mg/d (83%, 5 out of 6 subjects), and the transdermal patch (80%, 4 out of 5 subjects). All subjects using tranexamic acid as well as hormonal therapy had 100% achievement of menstrual suppression. CONCLUSION: A high frequency of bleeding disorders was found in those tested. Subjects with a bleeding disorder were less likely to present with severe anemia requiring blood transfusion and less likely to have iron deficiency anemia. Although combined oral contraceptives were commonly used clinically for menstrual suppression, they were not found to be the most effective option. PMID- 29524596 TI - The neurochemistry of agitation in Alzheimer's disease: a systematic review. AB - OBJECTIVE: To provide an up-to-date systematic review of the characteristics, methodology and findings of studies that have investigated the neurochemistry of agitation in Alzheimer's disease (AD). METHODS: Electronic databases were searched for published peer-reviewed articles which provided data on any neurotransmitter system in relation to agitation in AD. Screening of titles and abstracts and data extraction from full texts were conducted in duplicate. RESULTS: Forty-five studies were included. Monoamines (serotonin, dopamine and noradrenaline) were most commonly investigated. A variety of methods were used to investigate the neurochemistry underlying agitation in AD and, although there were several conflicting findings, there was evidence of serotonergic deficit, relatively preserved dopaminergic function and compensatory overactivity of postsynaptic noradrenergic neurons in agitation in AD. CONCLUSIONS: Disruption of the dynamic balance between multiple neurotransmitter systems could impair functional neural networks involved in affective regulation and executive function. Differences in study design and methodology may have contributed to conflicting findings. Future studies that overcome these limitations (e.g. using standardized criteria to define agitation) and employ neuroimaging methods such as MRI/PET to investigate specific neural networks are needed to clarify the role of neurotransmitter alterations in these patients. PMID- 29524597 TI - Lipid nanoparticles to counteract gastric infection without affecting gut microbiota. AB - Helicobacter pylori infection is one of the major risk factors for gastric cancer development. Available antibiotic-based treatments not only fail in around 20% of patients but also have a severe negative impact on the gut microbiota. Recently, we demonstrated that nanostructured lipid carriers (NLC), even without any drug loaded, are bactericidal against H. pylori at low concentrations. This work aims to clarify NLC mode of action and to evaluate if their bactericidal effect is specific to H. pylori without affecting bacteria from microbiota. NLC were produced by hot homogenization followed by ultrasonication method, using Precirol(r)ATO5 and Miglyol(r)812 as lipids and Tween(r)60 as a surfactant. NLC were able to eradicate H. pylori without affecting the other tested bacteria (Lactobacillus, E. coli, S. epidermidis and S. aureus). Bioimaging assays demonstrated that NLC rapidly bind to and cross the H. pylori bacterial membrane, destabilizing and disrupting it, which leads to leakage of the cytoplasmic contents and consequent bacterial death. In an era where efficient alternatives to antibiotics are urgent, NLC are an interesting route to be explored in the quest for new antibiotic-free therapies to fight H. pylori infection. PMID- 29524599 TI - A stress-enhanced model for discovery of disease-modifying gene: Ece1-suppresses the toxicity of alpha-synuclein A30P. AB - Parkinson's disease (PD) is a progressive motor neurodegenerative disorder, characterized by a selective loss of dopaminergic neurons in the substantia nigra. The complexity of disease etiology includes both genetic and environmental factors. No effective drug that can modify disease progression and protect dopamine neurons from degeneration is presently available. Human alpha-Synuclein A30P (A30P) is a mutant gene identified in early onset PD and showed to result selective dopamine neuron loss in transgenic A30P flies and mice. Paraquat (PQ) is an herbicide and an oxidative stress generator, linked to sporadic PD. We hypothesized that vital PD modifier genes are conserved across species and would show unique transcriptional changes to oxidative stress in animals expressing a PD-associated gene, such as A30P. We also hypothesized that manipulation of PD modifier genes would provide neuroprotection across species. To identify disease modifier genes, we performed two independently-duplicated experiments of microarray, capturing genome-wide transcriptional changes in A30P flies, chronically fed with PQ-contaminated food. We hypothesized that the best time point of identifying a disease modifier gene is at time when flies showed maximal combined toxicity of A30P transgene and PQ treatment during an early stage of disease and that effective disease modifiers gene are those showing transcriptional changes to oxidative stress in A30P expressing and not in wild type animals. Fly Neprilysin3 (Nep3) is one identified gene that is highly conserved. Its mouse and human homolog is endothelin-converting enzyme-1 (Ece1). To investigate the neuroprotective effect of Ece1, we used NS1 cells and mouse midbrain neurons expressing A30P, treated with or without PQ. We found that ECE1 expression protected against A30P toxicity on cell viability, on neurite outgrowth and ameliorated A30P accumulation in vitro. Expression of ECE1 in vivo suppressed dopamine neuron loss and alleviated the corresponding motor deficits in mice with A30P-expression. Our study leverages a new approach to identify disease modifier genes using a stress-enhanced PD animal model. PMID- 29524598 TI - Controlling drug release from mesoporous silica through an amorphous, nanoconfined 1-tetradecanol layer. AB - Mesoporous silica materials are promising nano-carriers for drug delivery systems. Even though there are many strategies for controlling the drug release kinetics, these must be adapted through trial and error on a case-by-case basis. Here we explore the possibility of tailoring the release kinetics of hydrophilic, water soluble therapeutic agents from mesoporous silica through addition of a hydrophobic excipient, 1-tetradecanol. In vitro drug release experiments performed at 37 degrees C, in phosphate buffer solution (pH 7.4) show that the addition of tetradecanol yields slower drug release kinetics, which was correlated with the presence of a liquid fatty alcohol interfacial layer. The layer mass is 11-23 wt.% of the metoprolol-loaded silica sample, and it causes up to 1.6 times decrease of initial release rate with respect to materials without the fatty alcohol. This effect does not depend of carrier pore arrangement, being noticed for both hexagonal MCM-41 and cubic KIT-5 mesoporous silica. The toxicity of tetradecanol-containing materials was evaluated by formazan-based viability assay on Opossum kidney epithelial cell line, and no significant toxicity was observed. PMID- 29524600 TI - Neurophysiology of the pedunculopontine tegmental nucleus. AB - The interest in the pedunculopontine tegmental nucleus (PPTg), a structure located in the brainstem at the level of the pontomesencephalic junction, has greatly increased in recent years because it is involved in the regulation of physiological functions that fail in Parkinson's disease and because it is a promising target for deep brain stimulation in movement disorders. The PPTg is highly interconnected with the main basal ganglia nuclei and relays basal ganglia activity to thalamic and brainstem nuclei and to spinal effectors. In this review, we address the functional role of the main PPTg outputs directed to the basal ganglia, thalamus, cerebellum and spinal cord. Together, the data that we discuss show that the PPTg may influence thalamocortical activity and spinal motoneuron excitability through its ascending and descending output fibers, respectively. Cerebellar nuclei may also relay signals from the PPTg to thalamic and brainstem nuclei. In addition to participating in motor functions, the PPTg participates in arousal, attention, action selection and reward mechanisms. Finally, we discuss the possibility that the PPTg may be involved in excitotoxic degeneration of the dopaminergic neurons of the substantia nigra through the glutamatergic monosynaptic input that it provides to these neurons. PMID- 29524601 TI - Smoking Cessation in Clinical Practice: How to Get Patients to Stop. AB - Tobacco use is an etiologic agent for many diseases treated by cardiac, vascular, and thoracic surgeons and contributes to increased perioperative complications and long-term risk. Smoking cessation may be challenging for patients and can be frustrating for clinicians. Lack of familiarity and pessimistic views toward cessation methods lead to underuse by physicians. Evidence-supported measures that increase chances of cessation include direct physician advice, approved pharmacotherapy, structured counseling, and a follow-up plan. Approved pharmacotherapy consists of varenicline, bupropion, or nicotine replacement therapy in the form of long-acting patches and short-acting forms of nicotine such as gum, lozenges, prescription nasal spray, or prescription inhaler. Direct physician advice is critical and strengthened when combined with more in-depth counseling from a specialist who may have more expertise and time. Integrating assessment and referral to counseling services into a clinical workflow can deliver resources in an efficient manner with the goal of providing the best available resources to all patients. PMID- 29524602 TI - Surgical Approaches to Hypertrophic Obstructive Cardiomyopathy. AB - Left ventricular outflow tract obstruction secondary to hypertrophic obstructive cardiomyopathy remains a challenging entity facing clinicians. Despite the success of invasive therapies, some clinicians remain hesitant because of early results with unacceptable morbidity and mortality rates. However, current literature strongly suggests improved short- and long-term outcomes with extended septal myectomy and alcohol septal ablation compared with patients not undergoing such interventions. This review evaluates hypertrophic obstructive cardiomyopathy treatment with a focus on short- and long-term outcomes, perioperative complications, and major tenets of surgical intervention. The data reveal mortality rates approaching zero, and perioperative complications occur infrequently. Alcohol septal ablation and extended septal myectomy both consistently decrease left ventricular outlet tract pressure gradients and result in improved functional capacity with lower New York Heart Association class and should be recommended as treatment for patients with symptoms refractory to standard medical treatment. PMID- 29524603 TI - Descending Aortopexy and Posterior Tracheopexy for Severe Tracheomalacia and Left Mainstem Bronchomalacia. AB - Posterior descending aortopexy can relieve posterior intrusion of the left mainstem bronchus that may limit the effectiveness of posterior tracheobronchopexy. We review outcomes of patients undergoing both descending aortopexy and posterior tracheopexy for severe tracheobronchomalacia with posterior intrusion and left mainstem compression to determine if there were resolution of clinical symptoms and bronchoscopic evidence of improvement in airway collapse. All patients who underwent both descending aortopexy and posterior tracheopexy from October 2012 to October 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores based on standardized dynamic airway evaluation by anatomical region, and persistent airway intrusion requiring reoperation were collected. Data were analyzed by Wald and Wilcoxon signed-rank tests. Thirty-two patients underwent descending aortopexy and posterior tracheopexy at median age of 18 months (interquartile range 6-40 months). Median follow-up was 3 months (interquartile range 1-7 months). There were statistically significant improvements in clinical symptoms postoperatively, including cough, noisy breathing, prolonged and recurrent respiratory infections, ventilator dependence, blue spells, and brief resolved unexplained events (all P < 0.001), as well as exercise intolerance (P = 0.033), transient respiratory distress requiring positive pressure (P = 0.003), and oxygen dependence (P = 0.007). Total tracheomalacia scores improved significantly (P < 0.001), with significant segmental improvements in the middle (P = 0.003) and lower (P < 0.001) trachea, and right (P = 0.011) and left (P < 0.001) mainstem bronchi. Two patients (6%) had persistent airway intrusion requiring reoperation with anterior aortopexy or tracheopexy. Descending aortopexy and posterior tracheopexy are effective in treating severe tracheobronchomalacia and left mainstem intrusion with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy. PMID- 29524604 TI - Altered global microRNA expression in hepatic stellate cells LX-2 by angiotensin (1-7) and miRNA-1914-5p identification as regulator of pro-fibrogenic elements and lipid metabolism. AB - The development of new therapeutic strategies to control or reverse hepatic fibrosis requires thorough knowledge about its molecular and cellular basis. It is known that the heptapeptide angiotensin-(1-7) [ang-(1-7)] can reduce hepatic fibrosis and steatosis in vivo; therefore, it is important to uncover the mechanisms regulating its activity and cellular model of investigation. Ang-(1-7) is a peptide of the renin-angiotensin system (RAS), and here we investigated its modulatory effect on the expression pattern of microRNAs (miRNAs) in hepatic stellate cells (HSCs) LX-2, which transdifferentiate into fibrogenic and proliferative cells. We compared the miRNA profiles between quiesced, activated and ang-(1-7)-treated activated HSCs to identify miRNAs that may regulate their transdifferentiation. Thirteen miRNAs were pointed, and cellular and molecular analyses identified miRNA-1914-5p as a molecule that contributes to the effects of ang-(1-7) on lipid metabolism and on the pro-fibrotic environment control. In our cellular model, we also analyzed the regulators of fatty acid metabolism. Specifically, miRNA-1914-5p regulates the expression of malonyl-CoA decarboxylase (MLYCD) and phosphatidic acid phosphohydrolase (PAP or Lipin-1). Additionally, Lipin-1 was closely correlated with mRNA expression of peroxisome proliferator activated receptors (PPAR)-alpha and -gamma, which also contribute to lipid homeostasis and to the reduction of TGF-beta1 expression. These findings provide a novel link between RAS and lipid metabolism in controlling HSCs activation. PMID- 29524606 TI - Downregulation of glycine decarboxylase enhanced cofilin-mediated migration in hepatocellular carcinoma cells. AB - Metabolic reprogramming is a hallmark of cancer. Glycine decarboxylase (GLDC), an oxidoreductase, plays an important role in amino acid metabolism. While GLDC promotes tumor initiation and proliferation in non-small cell lung cancer and glioma and it was reported as a putative tumor suppressor gene in gastric cancer, the role of GLDC in hepatocellular carcinoma (HCC) is unknown. In the current study, microarray-based analysis suggested that GLDC expression was low in highly malignant HCC cell lines, and clinicopathological analysis revealed a decrease in GLDC in HCC tumor samples. While the knockdown of GLDC enhanced cancer cell migration and invasion, GLDC overexpression inhibited them. Mechanistic studies revealed that GLDC knockdown increased the levels of reactive oxygen species (ROS) and decreased the ratio of glutathione/oxidized glutathione (GSH/GSSG), which in turn dampened the ubiquitination of cofilin, a key regulator of actin polymerization. Consequently, the protein level of cofilin was elevated, which accounted for the increase in cell migration. The overexpression of GLDC reversed the phenotype. Treatment with N-acetyl-L-cysteine decreased the protein level of cofilin while treatment with H2O2 increased it, further confirming the role of ROS in regulating cofilin degradation. In a tumor xenographic transplant nude mouse model, the knockdown of GLDC promoted intrahepatic metastasis of HCC while GLDC overexpression inhibited it. Our data indicate that GLDC downregulation decreases ROS-mediated ubiquitination of cofilin to enhance HCC progression and intrahepatic metastasis. PMID- 29524605 TI - Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. AB - Reactive oxygen species (ROS) are byproducts of oxygen metabolism best known for their damaging potential, but recent evidence has exposed their role as secondary messengers, which regulate cell function through redox-activatable signaling systems. In immune cells, specifically in T cells, redox-sensitive signaling pathways have been implicated in controlling several functional domains; including cell cycle progression, T effector cell differentiation, tissue invasion and inflammatory behavior. T cells from patients with the autoimmune disease rheumatoid arthritis (RA) have emerged as a valuable model system to examine the functional impact of ROS on T cell function. Notably, RA T cells are distinguished from healthy T cells based on reduced ROS production and undergo "reductive stress". Upstream defects leading to the ROSlow status of RA T cells are connected to metabolic reorganization. RA T cells shunt glucose away from pyruvate and ATP production towards the pentose phosphate pathway, where they generate NADPH and consume cellular ROS. Downstream consequences of the ROSlow conditions in RA T cells include insufficient activation of the DNA repair kinase ATM, bypassing of the G2/M cell cycle checkpoint and biased differentiation of T cells into IFN-gamma and IL-17-producing inflammatory cells. Also, ROSlow T cells rapidly invade into peripheral tissue due to dysregulated lipogenesis, excessive membrane ruffling, and overexpression of a motility module dominated by the scaffolding protein Tks5. These data place ROS into a pinnacle position in connecting cellular metabolism and protective versus auto-aggressive T cell immunity. Therapeutic interventions for targeted ROS enhancement instead of ROS depletion should be developed as a novel strategy to treat autoimmune tissue inflammation. PMID- 29524607 TI - Genistein attenuates seizure-induced hippocampal brain-derived neurotrophic factor overexpression in ovariectomized rats. PMID- 29524608 TI - Huge Bursitis Associated With Scapular Osteochondroma Presenting as a Giant Mass of the Chest Wall: A Case Presentation. PMID- 29524609 TI - The incidence of unexpected uterine malignancy in women undergoing hysteroscopic myomectomy or polypectomy: A national population-based study. AB - OBJECTIVE: The objective of this study was to investigate the incidence of unexpected uterine malignancy (UUM) diagnosed after hysteroscopic surgery for presumed submucosal leiomyomas or endometrial polyps. STUDY DESIGN: From the Korean national health insurance database between January 1, 2009 and December 31, 2015, we analyzed inpatient sample data that were extracted by a stratified random sampling (gender and age) method. We extracted women with or without UUM that was diagnosed after hysteroscopic surgery using diagnosis codes and procedure codes. RESULTS: A total of 11,866 women who underwent hysteroscopic surgery were extracted from 4,476,495 women. The mean age of the patients who underwent hysteroscopic surgery was 37.8 +/- 0.1 years. A hysteroscopic myomectomy or polypectomy was performed in 3498 and 8368 women, respectively. The incidence of UUM diagnosed after hysteroscopic myomectomy or polypectomy was 0.86% and 1.11%, respectively. The logistic regression analysis showed that the risk of UUM increased with age (Odds Ratio (OR), 1.61; 95% Confidence Interval (CI), 1.47-1.77; P < 0.001) and did not indicate hysteroscopic myomectomy or polypectomy (OR, 1.21; 95% CI, 0.93-1.55; P = 0.151). CONCLUSIONS: The incidence of UUM diagnosed after hysteroscopic myomectomy (0.86%) or polypectomy (1.11%) was higher than that of UUM diagnosed after hysterectomy (0.19%) or myomectomy (0.12%) for presumed benign leiomyoma. The incidence of UUM increased over the age of 50. PMID- 29524610 TI - Racial disparities in vaccination for seasonal influenza in early childhood. AB - OBJECTIVES: Influenza vaccination is the best protection against infection and severe complications of disease, such as hospitalization and death. Therefore, it is important to accurately estimate vaccination coverage and to evaluate the role of race/ethnicity. This study examines racial disparities in influenza vaccination among children using a nationally representative sample. STUDY DESIGN: This study used cross-sectional data from the 2009-2014 National Immunization Survey for children aged 19-35 months (n = 98,186) in the United States. METHODS: The outcome variable was receipt of influenza vaccination (yes/no) and exposure variable was race/ethnicity. Weighted multivariate logistic regression was used to estimate the odds ratio and 95% confidence intervals (CIs) for the effect of race/ethnicity on receipt of the influenza vaccine. RESULTS: The overall vaccination rates were 81.6% for non-Hispanic whites, 79.2% for Hispanics, 80.5% for non-Hispanic blacks, and 80.7% for non-Hispanic mixed/other. In the adjusted model, compared with non-Hispanic white children, Hispanic children were 13% less likely to receive influenza vaccination within the last 12 months (adjusted odds ratio [aOR] = 0.87; 95% CI: 0.80-0.94). In addition, children aged 24-29 months (aOR = 0.48; 95% CI: 0.44-0.52) and 30-35 months (aOR = 0.33; 95% CI: 0.30-0.36) were significantly less likely to receive influenza vaccination within the last 12 months compared with those who were 19-23 months old. CONCLUSIONS: There were differences in influenza vaccination rates among different racial groups. Hispanic children had the lowest vaccination rates. Findings from our study have significant implications for targeted interventions to increase the overall vaccination rate for children in the United States. PMID- 29524611 TI - Increasing inequality in childhood obesity in primary schools in a northern English town. AB - OBJECTIVE: To undertake an analysis of National Child Measurement Programme (NCMP) data to quantify the obesity prevalence gap over time between children in primary schools in the most and least deprived areas of Doncaster. STUDY DESIGN: The research design for this study was retrospective quantitative analysis of secondary data. METHODS: The study undertook secondary analysis of NCMP data on obesity prevalence in children in Reception Year and Year 6 in primary schools in Doncaster for the period 2006-2007 to 2014-2015. Data were combined into three 3 year periods (2006-2007 to 2008-2009; 2009-2010 to 2011-2012; and 2012-2013 to 2014-2015), and schools were grouped by deprivation based on the national Indices of Multiple Deprivation 2015. Analysis was undertaken to assess whether there is a difference in obesity prevalence for Reception Year and Year 6 children in schools in the most deprived areas compared with the least deprived (prevalence gap), over time. RESULTS: The difference in obesity prevalence between children attending schools in the most and least deprived areas has increased over time. For Reception Year children, the prevalence gap has widened from a difference of 1.01% higher in the most deprived schools in 2006-2007 to 2008-2009 to 3.64% higher in 2012-2013 to 2014-2015. In the same time periods, for Year 6 children, the obesity prevalence gap has also increased over time from 2.82% to 5.08%. CONCLUSIONS: There is inequality in relation to obesity in primary school children in Doncaster with those in schools in the most deprived areas carrying the greatest burden. Research is needed to understand why the plateau seen nationally is not reaching the most deprived children. PMID- 29524613 TI - Whole-exome sequencing identifies rare compound heterozygous mutations in the MYBPC3 gene associated with severe familial hypertrophic cardiomyopathy. AB - Most patients with hypertrophic cardiomyopathy have single-gene autosomal dominant mutations in loci that encode for sarcomeric proteins. The aim of this study was to determine whether pathogenic mutations were present by whole-exome sequencing (WES) in two families with hypertrophic cardiomyopathy (HCM) that presented during adolescence. Blood samples and clinical data were collected from individuals in two families with HCM. DNA was extracted. Mutations were identified using whole-exome sequencing (WES), and the genotypes of family members were identified using Sanger sequencing. Compound heterozygous mutations in the MYBPC3 gene (c.659A > G, p.Tyr220Cys; c.772G > A, p.Glu258Lys,NM_000256, Family 1), (c.873delG, p. Ile292PhefsTer8; c.3G > A, p.Met1?, NM_000256, Family 2) were identified by WES. Patient 1 carried the maternally inherited c.659A > G mutation and the paternally inherited c.772G > A mutation. Patient 2 carried the maternally inherited frameshift mutation c.873delG and the paternally inherited mutation c.3G > A. Two families with HCM presenting during adolescence (age of onset is about 11 years old) demonstrated compound heterozygous mutations in the MYBPC3 gene. These findings suggested an association of MYBPC3 mutations with the early onset of symptoms and worsened prognoses. Our study highlights the importance of genetic screening of all family members in cases of HCM. PMID- 29524612 TI - Transcriptional regulation mediated by H2A.Z via ANP32e-dependent inhibition of protein phosphatase 2A. AB - The mechanisms that regulate H2A.Z and its requirement for transcription in differentiated mammalian cells remains ambiguous. In this study, we identified the interaction between the C-terminus of ANP32e and N-terminus of H2A.Z in a yeast two-hybrid screen. Knockdown of ANP32e resulted in proteasomal degradation and nuclear depletion of H2A.Z or of a chimeric green florescence protein fused to its N-terminus. This effect was reversed by inhibition of protein phosphatase 2A (PP2A) and, conversely, reproduced by overexpression of its catalytic subunit. Accordingly, knockdown of ANP32e inhibited phosphorylation of H2A.Z, whereas a mutation of serine-9 proved its requirement for both the protein's stability and nuclear localization, as did knockdown of the nuclear mitogen and stress-induced kinase 1. Moreover, ANP32e's knockdown also revealed its differential requirement for cell signaling and gene expression, whereas, genome-wide binding analysis confirmed its co-localization with H2A.Z at transcription start sites, as well as, gene bodies of inducible and tissue-specific genes. The data also suggest that H2A.Z restricts transcription, which is moderated by ANP32e at the promoter and gene bodies of expressed genes. Thus, ANP32e, through inhibition of PP2A, is required for nucleosomal inclusion of H2A.Z and the regulation of gene expression. PMID- 29524614 TI - Protein/polyelectrolyte coacervation: Investigating its occurrence in the lysozyme- carboxymethylcellulose system. AB - The coacervation of carboxymethylcellulose (CMC) and hen egg white lysozyme (HEWL) was investigated. The work focused on the effects of pH, ionic strength, I, temperature, T, and mass fraction of the macromolecular components on the coacervation process by spectrophotometry, and on characteristics of the resulting coacervate phase by rheology in the linear and non-linear regimes. Coacervation was found to be highest at HEWL mass fraction ~0.25 with very slight dependence on pH in the range from 5 to 9. The process was favored at I < 0.075 mol.L-1 for NaCl, KCl and NaBr. For BaCl2, the dependence was markedly distinct, reflecting differences brought about by a bivalent cation on the Debye length of the electric double layer. The coacervation process has been characterized as endothermic and entropically driven. Rheological analysis of the coacervates indicated a rather low limit of the linear viscoelastic region (0.1% strain) and the prevalence of the elastic over the viscous contribution (G' > G''). Despite configuring rather fragile structures, the presence of a network of strong interactions has been inferred from the observed pattern of variation of the moduli with frequency. In the non-linear regime, pseudoplasticity was observed, pointing out to the capacity of these structures in complying with the flow lines of the circumventing environment. Both apparently opposed characteristics suggest a possible evolutionary advantage of such structures in the prebiotic era. PMID- 29524615 TI - Identification of broadly reactive epitopes targeting major glycoproteins of Herpes simplex virus (HSV) 1 and 2 - An immunoinformatics analysis. AB - Infections due to both HSV-1 and HSV-2 constitute an enormous health burden worldwide. Development of vaccine against herpes infections is a WHO supported public health priority. The viral glycoproteins have always been the major hotspots for vaccine designing. The present study was aimed to identify the conserved T and B cell epitopes in the major glycoproteins of both HSV-1 and HSV 2 via rigorous computational approaches. Identification of promiscuous T cell epitopes is of utmost importance in vaccine designing as such epitopes are capable of binding to several allelic forms of HLA and could generate effective immune response in the host. The criteria designed for identification of T and B cell epitopes was that it should be conserved in both HSV-1 and 2, promiscuous, have high affinity towards HLA alleles, should be located on the surface of glycoproteins and not be present in the glycosylation sites. This study led to the identification of 17 HLA Class II and 26 HLA Class I T cell epitopes, 9 linear and some conformational B cell epitopes. The identified T cell epitopes were further subjected to molecular docking analysis to analyze their binding patterns. Altogether we have identified 4 most promising regions in glycoproteins (2-gB, 1-gD, 1-gH) of HSV-1 and 2 which are promiscuous to HLA Class II alleles and have overlapping HLA Class I and B cell epitopes, which could be very useful in generating both arms of immune response in the host i.e. adaptive as well as humoral immunity. Further the authors propose the cross-validation of the identified epitopes in experimental settings for confirming their immunogenicity to support the present findings. PMID- 29524616 TI - Stress From Uncertainty and Resilience Among Depressed and Burned Out Residents: A Cross-Sectional Study. AB - BACKGROUND: Depression and burnout are highly prevalent among residents, but little is known about modifiable personality variables, such as resilience and stress from uncertainty, that may predispose to these conditions. Residents are routinely faced with uncertainty when making medical decisions. OBJECTIVE: To determine how stress from uncertainty is related to resilience among pediatric residents and whether these attributes are associated with depression and burnout. METHODS: We surveyed 86 residents in pediatric residency programs from 4 urban freestanding children's hospitals in North America in 2015. Stress from uncertainty was measured with the use of the Physicians' Reaction to Uncertainty Scale, resilience with the use of the 14-item Resilience Scale, depression with the use of the Harvard National Depression Screening Scale; and burnout with the use of single-item measures of emotional exhaustion and depersonalization from the Maslach Burnout Inventory. RESULTS: Fifty out of 86 residents responded to the survey (58.1%). Higher levels of stress from uncertainty correlated with lower resilience (r = -0.60; P < .001). Five residents (10%) met depression criteria and 15 residents (31%) met burnout criteria. Depressed residents had higher mean levels of stress due to uncertainty (51.6 +/- 9.1 vs 38.7 +/- 6.7; P < .001) and lower mean levels of resilience (56.6 +/- 10.7 vs 85.4 +/- 8.0; P < .001) compared with residents who were not depressed. Burned out residents also had higher mean levels of stress due to uncertainty (44.0 +/- 8.5 vs 38.3 +/- 7.1; P = .02) and lower mean levels of resilience (76.7 +/- 14.8 vs 85.0 +/- 9.77; P = .02) compared with residents who were not burned out. CONCLUSIONS: We found high levels of stress from uncertainty, and low levels of resilience were strongly correlated with depression and burnout. Efforts to enhance tolerance of uncertainty and resilience among residents may provide opportunities to mitigate resident depression and burnout. PMID- 29524617 TI - Progress in the Management of Malignant Pleural Mesothelioma in 2017. AB - Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored. PMID- 29524618 TI - The influence of surface active l-leucine and 1,2-dipalmitoyl-sn-glycero-3 phosphatidylcholine (DPPC) in the improvement of aerosolization of pyrazinamide and moxifloxacin co-spray dried powders. AB - Pharmacotherapy of tuberculosis is potentially more efficient when delivered by the inhaled route than by the current oral and/or parenteral routes due to the higher concentration of drug reaching the primary region of infection in the lungs. This study investigated the influence of the amino acid l-leucine alone and in combination with the phospholipid, 1,2-dipalmitoyl-sn-glycero-3 phosphatidylcholine (DPPC), on the aerosolization behaviour of the anti-TB drugs, pyrazinamide and moxifloxacin HCl. Spray dried powders of pyrazinamide (P), moxifloxacin (M) alone and in combination with 10% l-leucine (PL and ML) and 10% DPPC (PLD and MLD) were produced. The particle sizes of all powders except P were in the inhalable size range (<5 um) but differ in their morphology in presence of the excipients. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed the migration of surface active l-leucine and DPPC onto the surface of the particles during the spray drying process. The aerosolization from a dry powder inhaler, Aerolizer(r), using a Next Generation Impactor revealed fine particle fraction (FPF) values for P, PL and PLD of 18.7 +/- 3.4%, 53.0 +/- 3.2% and 74.5 +/- 5.3% respectively while FPF values for M, ML and MLD were 55.6 +/- 3.3%, 74.7 +/- 4.7% and 74.1 +/- 1.3% respectively. In conclusion, the differences in the aerosolization behaviours of the pyrazinamide and moxifloxacin spray dried powders with and without excipients was a combination of difference in the surface morphology and surface composition. PMID- 29524619 TI - In situ monitoring of cocrystals in formulation development using low-frequency Raman spectroscopy. AB - In recent years, to guarantee a quality-by-design approach to the development of pharmaceutical products, it is important to identify properties of raw materials and excipients in order to determine critical process parameters and critical quality attributes. Feedback obtained from real-time analyses using various process analytical technology (PAT) tools has been actively investigated. In this study, in situ monitoring using low-frequency (LF) Raman spectroscopy (10-200 cm 1), which may have higher discriminative ability among polymorphs than near infrared spectroscopy and conventional Raman spectroscopy (200-1800 cm-1), was investigated as a possible application to PAT. This is because LF-Raman spectroscopy obtains information about intermolecular and/or lattice vibrations in the solid state. The monitoring results obtained from Furosemide/Nicotinamide cocrystal indicate that LF-Raman spectroscopy is applicable to in situ monitoring of suspension and fluidized bed granulation processes, and is an effective technique as a PAT tool to detect the conversion risk of cocrystals. LF-Raman spectroscopy is also used as a PAT tool to monitor reactions, crystallizations, and manufacturing processes of drug substances and products. In addition, a sequence of conversion behaviors of Furosemide/Nicotinamide cocrystals was determined by performing in situ monitoring for the first time. PMID- 29524620 TI - One-pot synthesis of dopamine-conjugated hyaluronic acid/polydopamine nanocomplexes to control protein drug release. AB - The self-organizing complexes with hyaluronic acid (HA) and polydopamine (PDA), an adhesion mediator via hydrogen bonding, were investigated for use as protein drug carriers. The complexes were prepared with HA of different molecular weights (20 kDa and 200 kDa) and various molar ratios of dopamine and lysozyme, a model protein. Dopamine-conjugated HA (HADA)/PDA complexes were prepared by one-pot synthesis by relying on the self-polymerization of dopamine under oxidative, weakly basic conditions. Lysozyme was bound via coacervation and hydrogen bonding into HADA/PDA complexes. Complex diameters were 100-300 nm, based on transmission electron microscopy image and dynamic light scattering findings. Circular dichroism and differential scanning calorimetry showed that a stable protein formulation was obtained without degradation while preserving the thermal characteristics of lysozyme. Transition temperature (Tm) of the HADA/PDA/lysozyme complex (1:10:0.05 ratio) was 72.45 degrees C, which is close to the Tm of the native lysozyme (72.46 degrees C). The efficacy of complexes was also evaluated to protect the structural stability of lysozyme. Lysozyme (0.33 mol) was complexed with HA monomer; consequently, lysozyme activity in the HADA/PDA complex was not affected from short-term degradation. Protein encapsulation and efficacy of the formulations showed successful complexation as protein carriers, thus suggesting an effective combinatory protein delivery system. PMID- 29524621 TI - Gamma-hydroxybutyrate increases brain resting-state functional connectivity of the salience network and dorsal nexus in humans. AB - According to the triple network hypothesis the brain is equipped with three core neurocognitive networks: the default mode (DMN), the salience (SN), and the central executive (CEN) network. Moreover, the so called dorsal nexus, has met growing interest as it is a hub region connecting these three networks. Assessment of resting-state functional connectivity (rsFC) of these networks enables the elucidation of drug-induced brain alterations. Gamma-hydroxybutyrate (GHB) is a GHB/GABA-B receptor agonist that induces a paradoxical state of mixed stimulation and sedation at moderate doses, which makes it a valuable tool to investigate neural signatures of subjective drug effects. Employing a placebo controlled, double-blind, randomized, cross-over design, we assessed the effects of GHB (35 mg/kg p. o.) in 19 healthy male subjects on DMN-, SN-, CEN-, and dorsal nexus-rsFC measured by functional magnet resonance imaging and applying independent component as well as seed-based analyses, while subjective drug effects were investigated using visual analog scales (VAS). Subjectively, GHB increased VAS ratings of a general drug effect, stimulation, and sedation. Intrinsic DMN-, and CEN-rsFC remained largely unchanged under GHB, but the drug increased SN-DMN-rsFC and SN-dorsal nexus-rsFC, while dorsal nexus-rsFC was reciprocally increased to both the SN (right anterior insula) and to the CEN (right middle frontal gyrus). Increased sedation significantly predicted the observed SN-dorsal nexus-rsFC. In conclusion, GHB generates a unique stimulant/sedative subjective state that is paralleled by a complex pattern of increased functional connectivity encompassing all three core neurocognitive networks of the brain, while increased SN-dorsal nexus-rsFC was demonstrated to be a potential signature of the sedative component of the drug effect. PMID- 29524622 TI - Disclosing large-scale directed functional connections in MEG with the multivariate phase slope index. AB - The phase slope index (PSI) is a method to disclose the direction of frequency specific neural interactions from magnetoencephalographic (MEG) time series. A fundamental property of PSI is that of vanishing for linear mixing of independent neural sources. This property allows PSI to cope with the artificial instantaneous connectivity among MEG sensors or brain sources induced by the field spread. Nevertheless, PSI is limited by being a bivariate estimator of directionality as opposite to the multidimensional nature of brain activity as revealed by MEG. The purpose of this work is to provide a multivariate generalization of PSI. We termed this measure as the multivariate phase slope index (MPSI). In order to test the ability of MPSI in estimating the directionality, and to compare the MPSI results to those obtained by bivariate PSI approaches based on maximizing imaginary part of coherency and on canonical correlation analysis, we used extensive simulations. We proved that MPSI achieves the highest performance and that in a large number of simulated cases, the bivariate methods, as opposed to MPSI, do not detect a statistically significant directionality. Finally, we applied MPSI to assess seed-based directed functional connectivity in the alpha band from resting state MEG data of 61 subjects from the Human Connectome Project. The obtained results highlight a directed functional coupling in the alpha band between the primary visual cortex and several key regions of well-known resting state networks, e.g. dorsal attention network and fronto-parietal network. PMID- 29524623 TI - Cortical and subcortical responses to biological motion. AB - Using fMRI and multivariate analyses we sought to understand the neural representations of articulated body shape and local kinematics in biological motion. We show that in addition to a cortical network that includes areas identified previously for biological motion perception, including the posterior superior temporal sulcus, inferior frontal gyrus, and ventral body areas, the ventral lateral nucleus, a presumably motoric thalamic area is sensitive to both form and kinematic information in biological motion. Our findings suggest that biological motion perception is not achieved as an end-point of segregated cortical form and motion networks as often suggested, but instead involves earlier parts in the visual system including a subcortical network. PMID- 29524624 TI - MIDAS: Regionally linear multivariate discriminative statistical mapping. AB - Statistical parametric maps formed via voxel-wise mass-univariate tests, such as the general linear model, are commonly used to test hypotheses about regionally specific effects in neuroimaging cross-sectional studies where each subject is represented by a single image. Despite being informative, these techniques remain limited as they ignore multivariate relationships in the data. Most importantly, the commonly employed local Gaussian smoothing, which is important for accounting for registration errors and making the data follow Gaussian distributions, is usually chosen in an ad hoc fashion. Thus, it is often suboptimal for the task of detecting group differences and correlations with non-imaging variables. Information mapping techniques, such as searchlight, which use pattern classifiers to exploit multivariate information and obtain more powerful statistical maps, have become increasingly popular in recent years. However, existing methods may lead to important interpretation errors in practice (i.e., misidentifying a cluster as informative, or failing to detect truly informative voxels), while often being computationally expensive. To address these issues, we introduce a novel efficient multivariate statistical framework for cross sectional studies, termed MIDAS, seeking highly sensitive and specific voxel-wise brain maps, while leveraging the power of regional discriminant analysis. In MIDAS, locally linear discriminative learning is applied to estimate the pattern that best discriminates between two groups, or predicts a variable of interest. This pattern is equivalent to local filtering by an optimal kernel whose coefficients are the weights of the linear discriminant. By composing information from all neighborhoods that contain a given voxel, MIDAS produces a statistic that collectively reflects the contribution of the voxel to the regional classifiers as well as the discriminative power of the classifiers. Critically, MIDAS efficiently assesses the statistical significance of the derived statistic by analytically approximating its null distribution without the need for computationally expensive permutation tests. The proposed framework was extensively validated using simulated atrophy in structural magnetic resonance imaging (MRI) and further tested using data from a task-based functional MRI study as well as a structural MRI study of cognitive performance. The performance of the proposed framework was evaluated against standard voxel-wise general linear models and other information mapping methods. The experimental results showed that MIDAS achieves relatively higher sensitivity and specificity in detecting group differences. Together, our results demonstrate the potential of the proposed approach to efficiently map effects of interest in both structural and functional data. PMID- 29524625 TI - Altered temporal stability in dynamic neural networks underlies connectivity changes in neurodevelopment. AB - Network connectivity is an integral feature of human brain function, and characterising its maturational trajectory is a critical step towards understanding healthy and atypical neurodevelopment. Here, we used magnetoencephalography (MEG) to investigate both stationary (i.e. time averaged) and rapidly modulating (dynamic) electrophysiological connectivity, in participants aged from mid-childhood to early adulthood (youngest participant 9 years old; oldest participant 25 years old). Stationary functional connectivity (measured via inter-regional coordination of neural oscillations) increased with age in the alpha and beta frequency bands, particularly in bilateral parietal and temporo-parietal connections. Our dynamic analysis (also applied to alpha/beta oscillations) revealed the spatiotemporal signatures of 8 dynamic networks; these modulate on a ~100 ms time scale, and temporal stability in attentional networks was found to increase with age. Significant overlap was found between age modulated dynamic networks and inter-regional oscillatory coordination, implying that altered network dynamics underlie age related changes in functional connectivity. Our results provide novel insights into brain network electrophysiology, and lay a foundation for future work in childhood disorders. PMID- 29524626 TI - Altered organization of the visual cortex in FHONDA syndrome. AB - A fundamental scheme in the organization of the early visual cortex is the retinotopic representation of the contralateral visual hemifield on each hemisphere. We determined the cortical organization in a novel congenital visual pathway disorder, FHONDA-syndrome, where the axons from the temporal retina abnormally cross to the contralateral hemisphere. Using ultra-high field fMRI at 7 T, the population receptive field (pRF) properties of the primary visual cortex were modeled for two affected individuals and two controls. The cortical activation in FHONDA was confined to the hemisphere contralateral to the stimulated eye. Each cortical location was found to contain a pRF in each visual hemifeld and opposing hemifields were represented as retinotopic cortical overlays of mirror-symmetrical locations across the vertical meridian. Since, the enhanced crossing of the retinal fibers at the optic chiasm observed in FHONDA has been previously assumed to be exclusive to the pigment-deficiency in albinism, our direct evidence of abnormal mapping in FHONDA highlights the independence of pigmentation and development of the visual cortex. These findings thus provide fundamental insights into the developmental mechanisms of the human visual system and underline the general relevance of the interplay of subcortical stability and cortical plasticity. PMID- 29524627 TI - Calcium-activated SK potassium channels are key modulators of the pacemaker frequency in locus coeruleus neurons. AB - The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early stages of neurodegenerative diseases. Therefore, identifying ion channels mediating the intrinsic pacemaking mechanism of LC neurons, which is in turn directly coupled to Ca2+ homeostasis and cell survival signaling pathways, can help to foster our understanding of the vulnerability of these neurons in neurodegenerative diseases. Small-conductance Ca2+-activated K+ (SK) channels regulate the intrinsic firing patterns in different central neurons and are essential regulators of the intracellular Ca2+ homeostasis. However, the role of SK channels for the intrinsic pacemaking of LC neurons in mice is still unclear. Therefore we performed qPCR expression analysis as well as patch clamp recordings of in vitro brainstem slices, for instance testing SK channel blockers and activators like apamin and NS309, respectively. Although we found a transcriptional expression of SK1, SK2 and SK3 channels, SK2 was the predominantly expressed subunit in mouse LC neurons. Using perforated-patch clamp experiments, we found that SK channels are essential regulators of the intrinsic pacemaking of LC neurons, mediating a large fraction of the afterhyperpolarization (AHP) in these cells. Consistent with a previous observation that a concerted action of L- and T-type Cav channels is essential for the pacemaking of LC neurons, we found that SK channel activation, and the respective AHP amplitude, is primarily coupled to Ca2+ influx via these types of Ca2+ channels. Our study identified SK2 channels as drug targets for the tuning of the pacemaker frequency in disorders involving a dysregulation of the LC. PMID- 29524628 TI - Assessment of metal concentrations in the SOD1G93A mouse model of amyotrophic lateral sclerosis and its potential role in muscular denervation, with particular focus on muscle tissue. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is among the most common of the motor neuron diseases, and arguably the most devastating. During the course of this fatal neurodegenerative disorder, motor neurons undergo progressive degeneration. The currently best-understood animal models of ALS are based on the over-expression of mutant isoforms of Cu/Zn superoxide dismutase 1 (SOD1); these indicate that there is a perturbation in metal homeostasis with disease progression. Copper metabolism in particular is affected in the central nervous system (CNS) and muscle tissue. METHODS: This present study assessed previously published and newly gathered concentrations of transition metals (Cu, Zn, Fe and Se) in CNS (brain and spinal cord) and non-CNS (liver, intestine, heart and muscle) tissues from transgenic mice over-expressing the G93A mutant SOD1 isoform (SOD1G93A), transgenic mice over-expressing wildtype SOD1 (SOD1WT) and non transgenic controls. RESULTS: Cu accumulates in non-CNS tissues at pre symptomatic stages in SOD1G93A tissues. This accumulation represents a potentially pathological feature that cannot solely be explained by the over expression of mSOD1. As a result of the lack of Cu uptake into the CNS there may be a deficiency of Cu for the over-expressed mutant SOD1 in these tissues. Elevated Cu concentrations in muscle tissue also preceded the onset of symptoms and were found to be pathological and not be the result of SOD1 over-expression. CONCLUSIONS: It is hypothesized that the observed Cu accumulations may represent a pathologic feature of ALS, which may actively contribute to axonal retraction leading to muscular denervation, and possibly significantly contributing to disease pathology. Therefore, it is proposed that the toxic-gain-of-function and dying-back hypotheses to explain the molecular drivers of ALS may not be separate, individual processes; rather our data suggests that they are parallel processes. PMID- 29524629 TI - Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease. AB - Microfibril-associated glycoproteins 1 and 2 (MAGP-1, MAGP-2) are protein components of extracellular matrix microfibrils. These proteins interact with fibrillin, the core component of microfibrils, and impart unique biological properties that influence microfibril function in vertebrates. MAGPs bind active forms of TGFbeta and BMPs and are capable of modulating Notch signaling. Mutations in MAGP-1 or MAGP-2 have been linked to thoracic aneurysms and metabolic disease in humans. MAGP-2 has also been shown to be an important biomarker in several human cancers. Mice lacking MAGP-1 or MAGP-2 have defects in multiple organ systems, which reflects the widespread distribution of microfibrils in vertebrate tissues. This review summarizes our current understanding of the function of the MAGPs and their relationship to human disease. PMID- 29524632 TI - Copper and ceruloplasmin dyshomeostasis in serum and cerebrospinal fluid of multiple sclerosis subjects. AB - Although many studies have been carried out in order to understand the implication of copper (Cu) in the pathogenesis of multiple sclerosis (MS), the exact role that this metal plays in the disease is not still clear. Because of the lack of information in this subject, the present study compared the serum and cerebrospinal (CSF) levels of copper in MS patients in respect to a control group, matched for age and sex, finding a significant increase of metal concentrations, in both biological fluids of MS subjects. To confirm the possible impairment of Cu metabolism, we analyzed ceruloplasmin (Cp) level and activity, seeing as this protein is an established peripheral marker in diseases associated with Cu imbalance. By comparing these two parameters between control and MS subjects, we found an increase of Cp levels, associated with a decrease in Cp activity, in the second group. By analysing these data, free copper levels were calculated, significantly increased in serum of MS subjects; the increase in free copper could be one of the predisposing factors responsible for the Cu altered levels in CSF of MS patients. At the same time, this alteration could be attributable to the inability to incorporate Cu by Cp, probably due to the high oxidative environment found in serum of MS patients. Overall, all these copper alterations may play a role in MS pathogenesis. PMID- 29524633 TI - The yeast replicative aging model. AB - It has been nearly three decades since the budding yeast Saccharomyces cerevisiae became a significant model organism for aging research and it has emerged as both simple and powerful. The replicative aging assay, which interrogates the number of times a "mother" cell can divide and produce "daughters", has been a stalwart in these studies, and genetic approaches have led to the identification of hundreds of genes impacting lifespan. More recently, cell biological and biochemical approaches have been developed to determine how cellular processes become altered with age. Together, the tools are in place to develop a holistic view of aging in this single-celled organism. Here, we summarize the current state of understanding of yeast replicative aging with a focus on the recent studies that shed new light on how aging pathways interact to modulate lifespan in yeast. PMID- 29524631 TI - HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo resistance of OS, and could be used as potential therapeutic targets in OS. PMID- 29524634 TI - Impaired Fast Network Oscillations and Mitochondrial Dysfunction in a Mouse Model of Alpha-synucleinopathy (A30P). AB - Intracellular accumulation of alpha-synuclein (alpha-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal alpha-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant alpha-syn (A30P). We found an age-dependent reduction in the power of the gamma (20-80 Hz) frequency oscillations in slices taken from mice aged 9-16 months (9+A30P), that was not present in either young 2-6 months old (2+A30P) mice, or in control mice at either age. The mitochondrial blockers potassium cyanide and rotenone both reduced network oscillations in a concentration-dependent manner in aged A30P mice and aged control mice but slices from A30P mice showed a greater reduction in the oscillations. Histochemical analysis showed an age-dependent reduction in cytochrome c oxidase (COX) activity, suggesting a mitochondrial dysfunction in the 9+A30P group. A deficit in COX IV expression was confirmed by immunohistochemistry. Overall, our data demonstrate an age-dependent impairment in mitochondrial function and gamma frequency activity associated with the abnormal expression of alpha-syn. These findings provide mechanistic insights into the consequences of over-expression of alpha-syn which might contribute to cognitive decline. PMID- 29524635 TI - Vestibular-Evoked Responses Indicate a Functional Role for Intrinsic Foot Muscles During Standing Balance. AB - Maintaining standing balance involves multisensory processing and integration to produce dynamic motor responses. Electrical vestibular stimulation (EVS) delivered over the mastoid processes can be used to explore the vestibular control of balance. The purpose of this study was to determine whether intrinsic foot muscles exhibit vestibular-evoked balance responses and to characterize the traits associated with these responses. Electromyography (EMG) of the abductor hallucis (AH), abductor digiti minimi (ADM) and medial gastrocnemius (MG) and anterior-posterior (AP) forces were sampled while quietly standing participants were subjected to a random continuous EVS signal (peak-to-peak amplitude = +/-3 mA). The relationship between EVS input and motor output was characterized in both the frequency (coherence) and time (cumulant density) domains. When head orientation was rotated in yaw from left to right, the biphasic cumulant density function was inverted for all muscle (EVS-EMG) and whole-body (EVS-AP forces) balance responses. When vision was occluded, the EVS-EMG and EVS-AP forces coherence function amplitude increased at low frequencies (<2 Hz) and was accompanied by a heightened medium-latency peak amplitude for all muscles as well as the whole-body balance response (AP forces) compared to when static visual cues were present. The enhanced coherence amplitudes at lower frequencies may highlight a mechanism for the increase in postural sway from vision to occluded vision. The current findings indicate that the vestibular control of standing balance can be represented by the intrinsic foot muscles and implicate a postural role for these muscles in modulating quiet standing. PMID- 29524636 TI - Reply to Comment on "Role of Choroid Plexus in Cerebrospinal Fluid Hydrodynamics". PMID- 29524630 TI - Extracellular matrix in lung development, homeostasis and disease. AB - The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases. PMID- 29524637 TI - Autophagy- and MMP-2/9-mediated Reduction and Redistribution of ZO-1 Contribute to Hyperglycemia-increased Blood-Brain Barrier Permeability During Early Reperfusion in Stroke. AB - Post-stroke hyperglycemia during early reperfusion increases blood-brain barrier (BBB) permeability and subsequently aggravates brain injury and clinical prognosis. The decreased level of tight junction proteins (TJPs) has been reported but the underlying mechanism remains largely elusive. Herein we designed to investigate the detailed molecular events in brain microvascular endothelial cells (BMECs) ex and in vivo. After oxygen-glucose deprivation (OGD) for 90 min and reperfusion with 8 or 16 mM glucose for 30 min, glucose at 16 mM caused significant decrease in the TJP expression and particularly ZO-1 redistribution from membrane to cytoplasm of BMECs. High glucose also markedly promoted the secretion of MMP-2/9 and oxidative/nitrosative stress, enhanced autophagy and increased the Caveolin-1 and LAMP-2 expression. Moreover, in vivo experiments demonstrated that rapamycin-enhanced autophagy further caused ZO-1 reduction and the increased BBB permeability. Therefore, high-glucose exposure in the early reperfusion causes the BBB disruption, with MMP-2/9-mediated extracellular degradation, caveolin-1-mediated intracellular translocation and autophagy lysosome-mediated degradation of ZO-1 protein all together involved in the process. The role of MMP-2/-9 and autophagy in the modulation of paracellular permeability was confirmed by pharmacological inhibition. Therefore, our findings may provide new insights into targeting ZO-1 regulation for the purpose of significantly improving the clinical prognosis of ischemic stroke. PMID- 29524638 TI - Steroid Receptor Coactivator-1 Knockdown Decreases Synaptic Plasticity and Impairs Spatial Memory in the Hippocampus of Mice. AB - Steroids have been demonstrated to play profound roles in the regulation of hippocampal function by acting on their receptors, which need coactivators for their transcriptional activities. Previous studies have shown that steroid receptor coactivator-1 (SRC-1) is the predominant coactivator in the hippocampus, but its exact role and the underlying mechanisms remain unclear. In this study, we constructed SRC-1 RNA interference (RNAi) lentiviruses, injected them into the hippocampus of male mice, and then examined the changes in the expression of selected synaptic proteins, CA1 synapse density, postsynaptic density (PSD) thickness, and in vivo long-term potentiation (LTP). Spatial learning and memory behavior changes were investigated using the Morris water maze. We then transfected the lentiviruses into cultured hippocampal cells and examined the changes in synaptic protein and phospho-cyclic AMP response element-binding protein (pCREB) expression. The in vivo results showed that SRC-1 knockdown significantly decreased the expression of synaptic proteins and CA1 synapse density as well as PSD thickness; SRC-1 knockdown also significantly impaired in vivo LTP and disrupted spatial learning and memory. The in vitro results showed that while the expression of synaptic proteins was significantly decreased by SRC 1 knockdown, pCREB expression was also significantly decreased. The above results suggest a pivotal role of SRC-1 in the regulation of hippocampal synaptic plasticity and spatial learning and memory, strongly indicating SRC-1 may serve as a novel therapeutic target for hippocampus-dependent memory disorders. PMID- 29524639 TI - Intrinsic Neural Linkage between Primary Visual Area and Default Mode Network in Human Brain: Evidence from Visual Mental Imagery. AB - Previous studies have reported the essence of the sensory-based properties of human brain function, in which mental imagery is of great importance. In this study, we explored the association between the activities of two special regions, i.e., the primary visual area (PVA), which is the classically dominant sensory region, and the default mode network (DMN), which is the classical supra-sensory region, with a focus on their linkage in visual mental imagery. For this purpose, we collected fMRI data from 30 healthy participants (15 males; 22.37 +/- 2.52 years) during the resting state and a mental rotation task state. By using a critical time point analysis (CTPA), we investigated the association between the activities of the PVA and the DMN. As the results showed, there existed a PVA related (i.e., prefrontal cortex, DMN, sensorimotor areas and medial temporal lobe (MTL)) and a DMN-related neural association pattern (i.e., PVA, prefrontal cortex and the MTL) in the human brain. Furthermore, the results showed the steady and tight intrinsic association between the activities of the PVA and the DMN, with the prefrontal cortex and the MTL regions being found to be consistently involved in the resting-state brain. It also was suggested that the observed association between the PVA and the DMN was highly reproducible for the mental rotation task. Together, these observations, from the perspective of visual mental imagery, provided experimental evidence for the robustness and stability of the detailed map of the associations between the activities of the PVA and the DMN. PMID- 29524640 TI - The Sport Expert's Attention Superiority on Skill-related Scene Dynamic by the Activation of left Medial Frontal Gyrus: An ERP and LORETA Study. AB - Extensive studies have shown that a sports expert is superior to a sports novice in visually perceptual-cognitive processes of sports scene information, however the attentional and neural basis of it has not been thoroughly explored. The present study examined whether a sport expert has the attentional superiority on scene information relevant to his/her sport skill, and explored what factor drives this superiority. To address this problem, EEGs were recorded as participants passively viewed sport scenes (tennis vs. non-tennis) and negative emotional faces in the context of a visual attention task, where the pictures of sport scenes or of negative emotional faces randomly followed the pictures with overlapping sport scenes and negative emotional faces. ERP results showed that for experts, the evoked potential of attentional competition elicited by the overlap of tennis scene was significantly larger than that evoked by the overlap of non-tennis scene, while this effect was absent for novices. The LORETA showed that the experts' left medial frontal gyrus (MFG) cortex was significantly more active as compared to the right MFG when processing the overlap of tennis scene, but the lateralization effect was not significant in novices. Those results indicate that experts have attentional superiority on skill-related scene information, despite intruding the scene through negative emotional faces that are prone to cause negativity bias toward their visual field as a strong distractor. This superiority is actuated by the activation of left MFG cortex and probably due to self-reference. PMID- 29524641 TI - Comparative application of IS711-based polymerase chain reaction (PCR) and loop mediated isothermal amplification (LAMP) for canine brucellosis diagnosis. AB - Canine brucellosis is caused by Brucella canis, a gram negative and facultative intracellular bacterium that is commonly associated with reproductive failures in dogs. The accurate diagnosis of the infection relies on the use of serological tests associated with blood culturing to guarantee sensitivity. The polymerase chain reaction (PCR) can replace the culturing procedure for the direct diagnosis of the infection because of its speed, high specificity and sensitivity values; however, it depends on some laboratory infrastructure to be conducted. The loop mediated isothermal amplification (LAMP) may be an alternative method for DNA amplification in a shorter period, using simpler equipment, and with a lower cost. This study evaluated the potential of molecular tools based on PCR and LAMP using primers targeting the insertion sequence IS711 for Brucella detection in three groups of dogs (infected, non-infected and suspected of brucellosis), which were determined according to the results of blood culturing and clinical examination. The performance of the three diagnostic tests was also determined using McNemar test and Kappa coefficient. The proportion of positive samples detected by blood culturing, PCR and LAMP was respectively 31.57% (18/57), 33.34% (19/57), and 14.03% (8/57). The agreement between blood culturing and PCR was almost perfect, while the agreement of PCR and blood culturing compared to LAMP was fair. The diagnostic sensitivity of PCR and LAMP was respectively 100% (18/18) and 44.44% (8/18), while the diagnostic specificity of both tests was 100% (21/21). LAMP performance was not satisfactory for canine brucellosis diagnosis because of the low diagnostic sensitivity of the test. The IS711 based PCR, otherwise, showed high values of sensitivity and specificity, which makes it a good alternative for use for the rapid diagnosis of canine brucellosis. PMID- 29524642 TI - Development and validation of pan-Leptospira Taqman qPCR for the detection of Leptospira spp. in clinical specimens. AB - BACKGROUND: Early diagnosis of leptospirosis is important for ensuring better clinical management and achieving better outcomes. Currently, serological assays suffer from inconsistent performance and are less useful for early diagnosis of leptospirosis. As an alternative, qPCR is more sensitive, specific and able to detect the presence of leptospiral DNA during the acute phase of the infection. Meanwhile, most molecular assays do not detect the non-pathogenic group of Leptospira, even though these groups may also infect humans, although less frequently and less severely. METHODS: A set of primers and probe targeting rrs genes of 22 Leptospira spp. were designed and evaluated on 31 Leptospira isolates, 41 other organisms and 65 clinical samples from suspected patients. RESULTS: The developed assay was able to detect as low as 20 fg Leptospira DNA per reaction (equivalent to approximately 4 copies) and showed high specificity against the tested leptospiral strains. No cross amplification was observed with the other organisms. During the evaluation of the confirmed clinical specimens, the developed assay was able to correctly identify all positive samples (n = 10/10). One amplification was observed in a negative sample (n = 1/55). The sequencing of the PCR product of the discordant sample revealed that the sequences were similar to those of L. interrogans and L. kirschneri. CONCLUSION: The findings suggest that the developed Taqman qPCR assay is sensitive, specific and has potential to be applied in a larger subsequent study. PMID- 29524643 TI - Sequential variation in brain functional magnetic resonance imaging after peripheral nerve injury: A rat study. AB - Although treatment protocols are available, patients experience both acute neuropathic pain and chronic neuropathic pain, hyperalgesia, and allodynia after peripheral nerve injury. The purpose of this study was to identify the brain regions activated after peripheral nerve injury using functional magnetic resonance imaging (fMRI) sequentially and assess the relevance of the imaging results using histological findings. To model peripheral nerve injury in male Sprague-Dawley rats, the right sciatic nerve was crushed using an aneurysm clip, under general anesthesia. We used a 7.04T MRI system. T2* weighted image, coronal slice, repetition time, 7 ms; echo time, 3.3 ms; field of view, 30 mm * 30 mm; pixel matrix, 64 * 64 by zero-filling; slice thickness, 2 mm; numbers of slices, 9; numbers of average, 2; and flip angle, 8 degrees . fMR images were acquired during electrical stimulation to the rat's foot sole; after 90 min, c-Fos immunohistochemical staining of the brain was performed in rats with induced peripheral nerve injury for 3, 6, and 9 weeks. Data were pre-processed by realignment in the Statistical Parametric Mapping 8 software. A General Linear Model first level analysis was used to obtain T-values. One week after the injury, significant changes were detected in the cingulate cortex, insular cortex, amygdala, and basal ganglia; at 6 weeks, the brain regions with significant changes in signal density were contracted; at 9 weeks, the amygdala and hippocampus showed activation. Histological findings of the rat brain supported the fMRI findings. We detected sequential activation in the rat brain using fMRI after sciatic nerve injury. Many brain regions were activated during the acute stage of peripheral nerve injury. Conversely, during the chronic stage, activation of the amygdala and hippocampus may be related to chronic-stage hyperalgesia, allodynia, and chronic neuropathic pain. PMID- 29524644 TI - Dopamine suppresses persistent firing in layer III lateral entorhinal cortex neurons. AB - Persistent firing in layer III entorhinal cortex neurons that can be evoked during muscarinic receptor activation may contribute to mechanisms of working memory. The entorhinal cortex receives strong dopaminergic inputs which may modulate working memory for motivationally significant information. We used whole cell recordings in in vitro rat brain slices to assess the effects of dopamine on persistent firing in layer III neurons initiated by depolarizing current injection. Persistent firing during pharmacological block of ionotropic excitatory and inhibitory synaptic transmission, and in the presence of the cholinergic agonist carbachol (10 MUM), was observed in 39% of layer III pyramidal cells. Addition of 1 MUM dopamine suppressed the incidence of persistent firing and similarly reduced the mean probability of induction of persistent firing at each current step, without significantly affecting the latency, duration, plateau potential, or frequency of persistent firing that was induced. These results indicate that dopamine can result in a suppression of the induction of persistent firing in layer III entorhinal neurons, while still being permissive of persistent firing once it is initiated. PMID- 29524645 TI - Inhibitory effect of several sphingolipid metabolites on calcineurin. AB - Neurons have well-developed membrane microdomains called "rafts" that are recovered as a detergent-resistant membrane microdomain fraction (DRM). NAP-22 is one of the major protein components of neuronal DRM. In a previous study, we showed that DRM-derived NAP-22 binds ganglioside and the inhibitory effect of ganglioside to calcineurin (CaN), a neuron-enriched calmodulin-regulated phosphoprotein phosphatase. Considering the important roles of CaN in neurons, identification of other cellular regulators of CaN could be a good clue to understand the molecular background of neuronal function. In this study, we screened the effect of several membrane lipid-derived molecules on the CaN activity and found sphingosine and some sphingosine-derived metabolites such as sphingosylphosphorylcholine, galactosylsphingosine (psychosine), and glucosylsphingosine, have inhibitory effect on CaN through the interaction with calmodulin. PMID- 29524646 TI - Cigarette smoke constituents cause endothelial nitric oxide synthase dysfunction and uncoupling due to depletion of tetrahydrobiopterin with degradation of GTP cyclohydrolase. AB - Cigarette smoking (CS) is a well-established risk factor for cardiovascular disease (CVD). Endothelial dysfunction (ED) with loss of nitric oxide (NO) production is a central mechanism leading to the advent of CVD. Despite many prior studies of this major health problem, the exact mechanism by which CS induces ED is not well understood. This study examines the mechanism by which CS induces ED with altered endothelial NO synthase (eNOS) function in aortic endothelial cells (AECs). Exposure of AECs to cigarette smoke extract (CSE) resulted in a marked decrease in NO production with concomitant increase in superoxide (O2.-) generation and accumulation of 4-hydroxy-2-nonenal protein adducts. CSE exposure led to depletion of the essential eNOS cofactor tetrahydrobiopterin (BH4) as well as total biopterin levels and decreased the expression level of guanosine triphosphate cyclohydrolase (GTPCH), the rate limiting enzyme in BH4 biosynthesis. Moreover, exposure of AECs to CSE increased the level of ubiquitinated proteins and increased 26 S proteasomal activity in a concentration-dependent manner. Pre-treatment with MG132, a 26 S proteasome inhibitor, partially prevented CSE-induced loss of BH4, total biopterin, GTPCH, and increased NO production following CSE exposure, indicating a role of the ubiquitin-proteasome system in CSE-induced eNOS dysfunction. In conclusion, CSE induced eNOS dysfunction and uncoupling occurs due to BH4 depletion with BH4de novo synthesis limited by diminished GTPCH expression. PMID- 29524647 TI - Urinary candidate biomarkers in an experimental autoimmune myocarditis rat model. AB - : Urine is a better source than plasma for biomarker studies, as it can accumulate all changes in the body. Various candidate urinary biomarkers of physiological condition, kidney disease and even brain dysfunction, have been detected in urine; however, urine has rarely been used to reflect cardiac diseases. In this study, urine at day 0, 14, 21 and 28 were collected from the myosin-induced autoimmune myocarditis rat models. The candidate urinary biomarkers were then characterized using the isobaric tandem mass tag labeling approach coupled with offline two-dimensional reverse-phase liquid chromatography and high-resolution mass spectrometry. Compared with controls, forty-six urinary proteins were significantly changed in the myocarditis rats; among them, ten had previously been associated with myocarditis, twelve corresponding gene products had annotated as mainly cardiovascular network genes by the Ingenuity Pathway Analysis, four urinary proteins were validated by western blot, thirteen were reported in previous urine proteome studies of other diseases and twenty-six were reported the first time to be related to myocarditis. SIGNIFICANCE: This is the first study to use isobaric tandem mass tag labeling approach in the urine proteome analysis of experimental autoimmune myocarditis. These findings may provide clues for the pathogenesis of myocarditis. And the study showed that urine can be a good source of myocarditis biomarkers. PMID- 29524648 TI - Integrated omics profiling identifies hypoxia-regulated genes in HCT116 colon cancer cells. AB - : Hypoxia is associated with poor prognosis in most solid tumors due to its multiple effects on therapy resistance, angiogenesis, apoptotic resistance, and tumor invasion/metastasis. Here we used a comprehensive omics profiling to investigate hypoxia-regulated gene expression in HCT116 colon cancer cells. Quantitative analyses of proteome and secretome were performed in HCT116 cells cultured under hypoxic or normoxic conditions. A total of 5700 proteins were quantified in proteome analysis and 722 proteins were quantified in secretome analysis. Both datasets were combined with the transcriptome and translatome datasets for further analysis. Verification of candidate proteins/genes in this integrated omics analysis was performed using immunoblotting and quantitative real-time RT-PCR analyses. We also performed polysome profiling to assess changes in translational efficiency of hypoxia-induced genes. Notably, several genes were differently regulated at the transcriptional and translational levels in HCT116 cells during hypoxia. Bioinformatics analysis suggested that hypoxia regulates translation of genes involved in extracellular matrix organization, extracellular exosomes, and protein processing in endoplasmic reticulum. Aberrations in these metabolic pathways appear to be correlated with an increased risk of tumor invasion/metastasis. BIOLOGICAL SIGNIFICANCE: This study integrates transcriptome/translatome and proteome/secretome to analyze gene expression changes in human colon cancer cells under hypoxic conditions. Candidate proteins/genes in this integrated omics analysis were further validated by immunoblotting, quantitative real-time RT-PCR, and polysome profiling. The datasets would be useful to uncover the molecular mechanisms of hypoxia-induced gene regulation in colorectal cancer. PMID- 29524649 TI - The Intronic cis Element SE1 Recruits trans-Acting Repressor Complexes to Repress the Expression of ELONGATED UPPERMOST INTERNODE1 in Rice. AB - Plant height has a major effect on grain yield in crops such as rice (Oryza sativa), and the hormone gibberellic acid (GA) regulates many developmental processes that feed into plant height. Rice ELONGATED UPPERMOST INTERNODE1 (Eui1) encodes a GA-deactivating enzyme governing elongation of the uppermost internode. The expression of Eui1 is finely tuned, thereby maintaining homeostasis of endogenous bioactive GA and producing plants of normal plant height. Here, we identified a dominant dwarf mutant, dEui1, caused by the deletion of an RY motif containing cis-silencing element (SE1) in the intron of Eui1. Detailed genetic and molecular analysis of SE1 revealed that this intronic cis element recruits at least one trans-acting repressor complex, containing the B3 repressors OsVAL2 and OsGD1, the SAP18 co-repressor, and the histone deacetylase OsHDA710, to negatively regulate the expression of Eui1. This complex generates closed chromatin at Eui1, suppressing Eui1 expression and modulating GA homeostasis. Loss of SE1 or dysfunction of the complex components impairs histone deacetylation and H3K27me3 methylation of Eui1 chromatin, thereby increasing Eui1 transcription and decreasing bioactive GA, producing dwarfism in rice. Together, our results reveal a novel silencing mechanism in which the intronic cis element SE1 negatively regulates Eui1 expression via repressor complexes that modulate histone deacetylation and/or methylation. PMID- 29524650 TI - HMOD: An Omics Database for Herbal Medicine Plants. PMID- 29524651 TI - West meets East: How do rainforest beetles become circum-Pacific? Evolutionary origin of Callipogon relictus and allied species (Cerambycidae: Prioninae) in the New and Old Worlds. AB - The longhorn beetle genus Callipogon Audinet-Serville represents a small group of large wood-boring beetles whose distribution pattern exhibits a unique trans Pacific disjunction between the East Asian temperate rainforest and the tropical rainforest of the Neotropics. To understand the biogeographic history underlying this circum-Pacific disjunct distribution, we reconstructed a molecular phylogeny of the subfamily Prioninae with extensive sampling of Callipogon using multilocus sequence data of 99 prionine and four parandrine samples (ingroups), together with two distant outgroup species. Our sampling of Callipogon includes 18 of the 24 currently accepted species, with complete representation of all species in our focal subgenera. Our phylogenetic analyses confirmed the purported affinity between the Palearctic Callipogon relictus and its Neotropical congeners. Furthermore, based on molecular dating under the fossilized birth-death (FBD) model with comprehensive fossil records and probabilistic ancestral range reconstructions, we estimated the crown group Callipogon to have originated in the Paleocene circa 60 million years ago (Ma) across the Neotropics and Eastern Palearctics. The divergence between the Palearctic C. relictus and its Neotropical congeners is explained as the result of a vicariance event following the demise of boreotropical forest across Beringia at the Eocene-Oligocene boundary. As C. relictus represents the unique relictual species that evidentiates the lineage's expansive ancient distribution, we evaluated its conservation importance through species distribution modelling. Though we estimated a range expansion for C. relictus by 2050, we emphasize a careful implementation of conservation programs towards the protection of primary forest across its current habitats, as the species remains highly vulnerable to habitat disturbance. PMID- 29524653 TI - Population genetic dynamics of Himalayan-Hengduan tree peonies, Paeonia subsect. Delavayanae. AB - According to the present taxonomical treatment, Paeonia subsect. Delavayanae consists of only two species (P. delavayi and P. ludlowii) endemic to the Himalayan-Hengduan Mountains. Although P. ludlowii can be distinguished from P. delavayi on the basis of a series of morphological characters, the species delimitation remains controversial because the more widespread one, P. delavayi, exhibits considerable morphological diversity. Both chloroplast DNA markers and nuclear microsatellites or simple sequence repeats (nSSR) are used herein to reveal genetic diversity and relationships of the two taxa included in this subsection, and ecological niche modeling (ENM) is employed to get insights into their paleodistribution. Our results show that genetic boundaries between the two currently recognized species are unclear, probably due to recent divergence. Paeonia ludlowii is budding from P. delavayi, probably by genetic isolation but also by shifting its niche to the harsher upland Tibetan conditions. Paeonia delavayi itself would be, however, under active speciation, showing significant genetic differentiation and morphological diversity. Whereas P. ludlowii would have endured the Pleistocene glacial periods by in situ persistence in local, small refugia, a 'dual' model seems to apply for P. delavayi (in situ persistence and retreat to refugia). The rarity of P. ludlowii and high evolutionary potential of P. delavayi imply high priority for in situ conservation of both taxa. The Himalayan-Hengduan Mountains are an ideal arena for differentiation within subsect. Delavayanae of Paeonia, by means of expansions/contractions/displacements, vertical migrations, and local survival/extinctions in response to the Neogene climate fluctuations and geological changes. PMID- 29524654 TI - Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. AB - Clostridium difficile infection causes antibiotics-associated diarrhea and pseudomembranous colitis. Major virulence factors of C. difficile are the Rho glucosylating toxins TcdA and TcdB. In addition, many, so-called hypervirulent C. difficile strains produce the binary actin-ADP-ribosylating toxin CDT. CDT causes depolymerization of F-actin and rearrangement of the actin cytoskeleton. Thereby, many cellular functions, which depend on actin, are altered. CDT disturbs the dynamic balance between actin and microtubules in target cells. The toxin increases microtubule polymerization and induces the formation of microtubule based protrusions at the plasma membrane of target cells. Moreover, CDT causes a redistribution of vesicles from the basolateral side to the apical side, where extracellular matrix proteins are released. These processes may increase the adherence of clostridia to target cells. Here, we review the effects of the action of CDT on the actin cytoskeleton and on the microtubule system. PMID- 29524655 TI - The burden of ischemic heart disease related to ambient air pollution exposure in a coastal city in South China. AB - OBJECTIVE: Air pollution is considered one of the most important risk factors for ischemic heart disease (IHD), which is a major public health concern. The disease burden of IHD has continued to rise in China in the past two decades. However, epidemiological studies examining the associations between air pollution and IHD have been scarce in China, and the only studies were conducted in severe air pollution areas, where air pollution levels seriously exceed the World Health Organization Air Quality Guidelines. Whether the influence of air pollution on IHD in areas with relatively low levels of air pollution differs from the influence of high pollution levels in heavily studied areas was unknown until now. Furthermore, the estimation of the disease burden of IHD related to air pollution has been very limited. METHODS: We conducted a time-series study to estimate the short-term burden of ambient air pollution on IHD using the indicator of years of life lost (YLL), based on 10 322 IHD deaths from 2011 to 2015 in Ningbo, a coastal city in South China. RESULTS: The mean concentrations of fine particle (PM2.5), sulfur dioxide (SO2) and nitrogen dioxide (NO2) were 49.58 MUg/m3, 21.34 MUg/m3 and 43.41 MUg/m3, respectively. A 10 MUg/m3 increase in PM2.5, SO2 and NO2 was associated with changes in YLL of 0.71 (95%CI: - 0.21,1.64), 3.31 (95%CI: 0.78, 5.84), and 2.27 (95%CI: 0.26, 4.28) years, respectively. Relatively stronger impacts were found for gaseous pollutants than PM2.5. A larger increase in YLL was found in the younger population than in the older population for NO2 exposure. In addition, estimations of the effects of SO2 and NO2 on YLL were higher for males than females. SO2 exposure was positively associated with YLL in widowed group. CONCLUSIONS: The findings highlighted the importance of stringent air pollution control, especially for gaseous pollutants. Furthermore, using the indicator of YLL, considering the occurrence of death at different ages, provided more information for resource allocation and protection of vulnerable populations. PMID- 29524652 TI - A biting commentary: Integrating tooth characters with molecular data doubles known species diversity in a lineage of sea slugs that consume "killer algae". AB - Predicting biotic resistance to highly invasive strains of "killer algae" (Caulerpa spp.) requires understanding the diversity and feeding preferences of native consumers, including sea slugs in family Oxynoidae. Past studies reported low algal host specificity for Oxynoe (6 spp.) and Lobiger (4 spp.), but these taxonomically challenging slugs may represent species complexes of unrecognized specialists that prefer different Caulerpa spp. Here, we assess global diversity of these genera by integrating gene sequences with morphological data from microscopic teeth and internal shells, the only hard parts in these soft-bodied invertebrates. Four delimitation methods applied to datasets comprising mtDNA and/or nuclear alleles yielded up to 16 species hypotheses for samples comprising five nominal taxa, including five highly divergent species in Lobiger and five in Oxynoe. Depending on the analysis, a further four to six species were recovered in the O. antillarum-viridis complex, a clade in which mitochondrial divergence was low and nuclear alleles were shared among lineages. Bayesian species delimitation using only morphological data supported most candidate species, however, and integrative analyses combining morphological and genetic data fully supported all complex members. Collectively, our findings double the recognized biodiversity in Oxynoidae, and illustrate the value of including data from traits that mediate fast-evolving ecological interactions during species delimitation. Preference for Caulerpa spp. and radular tooth characteristics covaried among newly delimited species, highlighting an unappreciated degree of host specialization and coevolution in these taxa that may help predict their role in containing outbreaks of invasive algae. PMID- 29524656 TI - Current trends in the surgical management of blister aneurysms. An illustrative case series. AB - Blister aneurysms are rare lesions characterized by a bleb-like appearance in combination with prominent fragility. They mainly affect the supraclinoid internal carotid artery and they are often thought of as dissecting or even false lesions. Treatment of such lesions has been a matter of debate during the past few years with authors competing, in an ever changing field, for best results. Both surgical and endovascular modalities have been tried, with every technique having though its own limitations and pitfalls. Our article presents a small series of five blister cases, all treated by surgical means (clipping). We also review the relevant literature presenting a brief overview of available surgical options. PMID- 29524657 TI - Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia. AB - Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders characterized primarily by a pyramidal syndrome with lower limb spasticity, which can manifest as pure HSP or associated with a number of neurological or non-neurological signs (i.e., complicated HSPs). The clinical variability of HSPs is associated with a wide genetic heterogeneity, with more than eighty causative genes known. Recently, next generation sequencing (NGS) has allowed increasing genetic definition in such a heterogeneous group of disorders. We report on a 56- year-old man affected by sporadic complicated HSP consisting of a pyramidal syndrome, cerebellar ataxia, congenital cataract, pes cavus, axonal sensory-motor peripheral neuropathy and cognitive decline. Brain MRI showed cerebellar atrophy and thin corpus callosum. By NGS we found a novel homozygous biallelic c.452-1G > C mutation in the b-glucosidase 2 gene (GBA2), known to be causative for autosomal recessive hereditary spastic paraplegia type 46 (SPG46). The rarity of this inherited form besides reporting on a novel mutation, expands the genetic and clinical spectrum of SPG46 related HSP. PMID- 29524658 TI - Novel XK mutation in a McLeod patient diagnosed after heart transplant. PMID- 29524659 TI - Roles of the Skn7 response regulator in stress resistance, cell wall integrity and GA biosynthesis in Ganoderma lucidum. AB - The transcription factor Skn7 is a highly conserved fungal protein that participates in a variety of processes, including oxidative stress adaptation, fungicide sensitivity, cell wall biosynthesis, cell cycle, and sporulation. In this study, a homologous gene of Saccharomyces cerevisiae Skn7 was cloned from Ganoderma lucidum. RNA interference (RNAi) was used to study the functions of Skn7, and the two knockdown strains Skn7i-5 and Skn7i-7 were obtained in G. lucidum. The knockdown of GlSkn7 resulted in hypersensitivity to oxidative and cell wall stresses. The concentrations of chitin and beta-1,3-glucan distinctly decreased in the GlSkn7 knockdown strains compared with those of the wild type (WT). In addition, the expression of cell wall biosynthesis related genes was also significantly down-regulated and the thickness of the cell wall also significantly reduced in the GlSkn7 knockdown strains. The intracellular reactive oxygen species (ROS) content and ganoderic acids biosynthesis increased significantly in the GlSkn7 knockdown strains. Interestingly, the level of intracellular ROS and the content of ganoderic acids decreased after N-acetyl-L cysteine (NAC), an ROS scavenger, was added, indicating that GlSkn7 might regulate ganoderic acids biosynthesis via the intracellular ROS level. The transcript level of GlSkn7 were up-regulated in osmotic stress, heat stress and fungicide condition. At the same time, the content of ganoderic acids in the GlSkn7 knockdown strains also changed distinctly in these conditions. Overall, GlSkn7 is involved in stress resistance, cell wall integrity and ganoderic acid biosynthesis in G. lucidum. PMID- 29524660 TI - Response to Letter to the Editor: 'Subchondral tibial bone texture predicts the incidence of radiographic knee osteoarthritis: data from the osteoarthritis initiative: methodological issues'. PMID- 29524661 TI - Army General Surgery's Crisis of Conscience. PMID- 29524662 TI - Break Scrub to Take That Phone Call? AB - BACKGROUND: The American College of Surgeons reports that 60% of the hundreds of thousands of surgical site infections occurring annually are preventable. The practice of surgeons taking phone calls while remaining sterile in the operating field is often accomplished by interposing a sterile disposable towel between the phone and their glove. After completing the call, surgeons resume operating. The purpose of our study was to test the conceptual idea of whether bacteria transmit from an inanimate object, such as a telephone, to the gloves of a surgeon through a sterile disposable towel. STUDY DESIGN: Glo Germ (Glo Germ Co), an ultraviolet light-enhanced particle powder sized to mimic bacteria, was placed on an inanimate surface and held with a sterile disposable operating room towel covering a sterile surgical glove. The glove was then inspected for Glo Germ using an ultraviolet light. Additionally, 18 operating room telephones were cultured and then held with a Sterile Disposable OR Towel (Medline Industries Inc) covering a sterile surgical glove. The surgical gloves were then cultured to determine if bacteria had transmitted from the telephone through the towel and onto the sterile glove. RESULTS: The Glo Germ powder readily transmitted through the towel to the gloves. Median colony-forming units (CFU) on the cultured telephones for the 17 samples was 10, ranging from 1 to 35 CFUs. Of these 17 samples, 47% had transmission from the telephone to the glove, which was significantly greater than 0% (95% CI 26% to 69%, p < 0.001). CONCLUSIONS: Sterile disposable operating room towels do not provide an effective barrier between bacteria present on operating room telephones and the otherwise sterile gloves of a surgeon. PMID- 29524663 TI - Does Improved Mortality at Low- and Medium-Volume Hospitals Lead to Attenuation of the Volume to Outcomes Relationship for Major Visceral Surgery? AB - BACKGROUND: Regionalization of complex visceral surgery across the US has followed identification of a volume to outcomes association. However, a simultaneous trend toward improved surgical outcomes might have attenuated this relationship. We hypothesize that the difference in adjusted postoperative mortality between low- (LV), medium- (MV), and high-volume (HV) hospitals has decreased over time. STUDY DESIGN: The National Inpatient Sample (NIS) was used to identify patients undergoing bladder, esophageal, pancreatic, liver, lung, and rectal surgery from 2003 to 2011. Hospitals were divided into LV (<33rd centile), MV (34th to 66th), and HV (>67th centile) groups. Annual organ-specific adjusted in-hospital mortality (AIHM) for each volume strata was calculated and the difference in AIHM between volume strata was plotted over time. RESULTS: The proportion of hospitals classified as HV was 6% for lung; 5% for rectal; 3% for esophageal, pancreatic, and bladder; and 2% for liver surgery patients. The AIHM after operation was higher in LV compared with HV hospitals in 2003 to 2005 for all visceral resections except liver surgery. The difference in AIHM between LV, MV, and HV hospitals showed a decreasing trend from 2003 to 2005 to 2009 to 2011 for pancreatic, esophageal, bladder, and lung surgery. For patients undergoing rectal resections, the difference in AIHM was low and stable, and increased for liver resections only. CONCLUSIONS: A reduction in the differences in AIHM among LV, MV, and HV hospitals for 5 of 6 organs studied suggests attenuation of the volume to outcomes relationship with time. This is likely due to system-wide improvements in surgical care. PMID- 29524664 TI - Do All Positive Margins in Breast Cancer Patients Undergoing a Partial Mastectomy Need to Be Resected? AB - BACKGROUND: Positive margins have been reported in 20% to 40% of patients undergoing a partial mastectomy, often resulting in re-excision. How often the re excision yields additional cancer and whether there are predictors of residual disease remain unknown. STUDY DESIGN: Patients who had a positive margin (defined as tumor at ink for patients with invasive disease or within 1 mm for patients with ductal carcinoma in situ) in the SHAVE (A Randomized Controlled Trial of Routine Shave Margins Versus Standard Partial Mastectomy in Breast Cancer Patients) trial before randomization were evaluated to determine the rate of additional disease either in cavity shave margins or at re-excision. Details of the SHAVE trial can be found elsewhere. RESULTS: Of the 235 patients in the trial, 82 (34.9%) had a positive margin before randomization; 58 of these patients underwent either cavity shave margins excision or a re-excision of the positive margin(s). Twenty-one (36.2%) patients had residual disease. On bivariate analysis, residual disease was associated with younger patient age (median 51 vs 62 years; p = 0.007), and the presence of high-grade ductal carcinoma in situ (57.1% vs 31.3% for grade 2 and 0% for grade 1; p = 0.025). The following factors were not associated with further disease: patient race; ethnicity; BMI; volume of resection; number of positive margins; extent of ductal carcinoma in situ; and extent, grade, and histologic subtype of invasive cancer. On multivariate analysis, only patient age younger than 60 years remained a significant predictor of residual disease (odds ratio 3.920; 95% CI 1.081 to 14.220; p = 0.038). CONCLUSIONS: Positive margins are associated with further disease in more than one-third of patients and, aside from young age, there are no predictors of this. These findings support continued re-excision of positive margins, particularly in patients younger than 60 years of age. PMID- 29524665 TI - Synthesis of N'-phenyl-N-hydroxyureas and investigation of their inhibitory activities on human carbonic anhydrases. AB - A series of N'-phenyl-N-hydroxyureas has been prepared by reacting hydroxylamine with aromatic isocyanates. These compounds were investigated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1), considering four physiologically relevant isoforms, the cytosolic isoforms hCA I and II, and tumor associated, transmembrane isoforms hCA IX and XII. The new compounds reported here did not inhibit the widespread cytosolic isoforms hCA I and II, but they inhibited the tumor associated isoforms with interesting potencies. The most effective inhibitors showed KIs ranging between 72.8 and 78.9 nM against hCA IX and between 6.9 and 7.2 against hCA XII, making them of interest as candidates for antitumor studies. PMID- 29524666 TI - Design, synthesis and biological activity of 4-(4-benzyloxy)phenoxypiperidines as selective and reversible LSD1 inhibitors. AB - Lysine specific demethylase 1 (LSD1) plays a vital role in epigenetic regulation of gene activation and repression in several human cancers and is recognized as a promising antitumor therapeutic target. In this paper, a series of 4-(4 benzyloxy)phenoxypiperidines were synthesized and evaluated. Among the tested compounds, compound 10d exhibited the potent and reversible inhibitory activity against LSD1 in vitro (IC50 = 4 MUM). Molecular docking was conducted to predict its binding mode. Furthermore, 10d displayed it could inhibit migration of HCT 116 colon cancer cells and A549 lung cancer cells. Taken together, 10d deserves further investigation as a hit-to-lead for the treatment of LSD1 associated tumors. PMID- 29524667 TI - Composite measures of watershed health from a water quality perspective. AB - Water quality data at gaging stations are typically compared with established federal, state, or local water quality standards to determine if violations (concentrations of specific constituents falling outside acceptable limits) have occurred. Based on the frequency and severity of water quality violations, risk metrics such as reliability, resilience, and vulnerability (R-R-V) are computed for assessing water quality-based watershed health. In this study, a modified methodology for computing R-R-V measures is presented, and a new composite watershed health index is proposed. Risk-based assessments for different water quality parameters are carried out using identified national sampling stations within the Upper Mississippi River Basin, the Maumee River Basin, and the Ohio River Basin. The distributional properties of risk measures with respect to water quality parameters are reported. Scaling behaviors of risk measures using stream order, specifically for the watershed health (WH) index, suggest that WH values increased with stream order for suspended sediment concentration, nitrogen, and orthophosphate in the Upper Mississippi River Basin. Spatial distribution of risk measures enable identification of locations exhibiting poor watershed health with respect to the chosen numerical standard, and the role of land use characteristics within the watershed. PMID- 29524668 TI - Anoxic denitrification of BTEX: Biodegradation kinetics and pollutant interactions. AB - Anoxic mineralization of BTEX represents a promising alternative for their abatement from O2-deprived emissions. However, the kinetics of anoxic BTEX biodegradation and the interactions underlying the treatment of BTEX mixtures are still unknown. An activated sludge inoculum was used for the anoxic abatement of single, dual and quaternary BTEX mixtures, being acclimated prior performing the biodegradation kinetic tests. The Monod model and a Modified Gompertz model were then used for the estimation of the biodegradation kinetic parameters. Results showed that both toluene and ethylbenzene are readily biodegradable under anoxic conditions, whereas the accumulation of toxic metabolites resulted in partial xylene and benzene degradation when present both as single components or in mixtures. Moreover, the supplementation of an additional pollutant always resulted in an inhibitory competition, with xylene inducing the highest degree of inhibition. The Modified Gompertz model provided an accurate fitting for the experimental data for single and dual substrate experiments, satisfactorily representing the antagonistic pollutant interactions. Finally, microbial analysis suggested that the degradation of the most biodegradable compounds required a lower microbial specialization and diversity, while the presence of the recalcitrant compounds resulted in the selection of a specific group of microorganisms. PMID- 29524669 TI - Identifying phosphorus hot spots: A spatial analysis of the phosphorus balance as a result of manure application. AB - In this paper, we analyze the phosphorus balance as a result of manure application on the parish level for Denmark and investigate its local geographic distribution. For our analysis, we determine phosphorus loads for the five main animal groups and the phosphorus demand of the fifteen major crop categories. Our results show that there is a large variability in the phosphorus balance within Denmark. Due to industry agglomeration statistically significant hot spots appear mainly along the west coast, while cold spots are predominantly present on southern and eastern coasts towards the Baltic Sea. The proximity of oversupply areas to water bodies and other environmentally sensitive areas reinforces the need for further phosphorus regulation. Our findings show the importance of a combined spatially targeted regulation, which allows different levels of phosphorus application depending on local economic and environmental circumstances in combination with subsidizing manure processing technologies in phosphorus hot spots. PMID- 29524670 TI - Analysis of antibiotic multi-resistant bacteria and resistance genes in the effluent of an intensive shrimp farm (Long An, Vietnam). AB - In Vietnam, intensive shrimp farms heavily rely on a wide variety of antibiotics (ABs) to treat animals or prevent disease outbreak. Potential for the emergence of multi-resistant bacteria is high, with the concomitant contamination of adjacent natural aquatic habitats used for irrigation and drinking water, impairing in turn human health system. In the present study, quantification of AB multi-resistant bacteria was carried out in water and sediment samples from effluent channels connecting a shrimp farming area to the Vam Co River (Long An Province, Vietnam). Bacterial strains, e.g. Klebsiella pneumoniae and Aeromonas hydrophila, showing multi-resistance traits were isolated. Molecular biology analysis showed that these strains possessed from four to seven different AB resistance genes (ARGs) (e.g. sul1, sul2, qnrA, ermB, tetA, aac(6)lb, dfrA1, dfr12, dfrA5), conferring multidrug resistance capacity. Sequencing of plasmids present within these multi-resistant strains led to the identification of a total of forty-one resistance genes, targeting nine AB groups. qPCR analysis on the sul2 gene revealed the presence of high copy numbers in the effluent channel connecting to the Vam Co River. The results of the present study clearly indicated that multi-resistant bacteria present in intensive shrimp cultures may disseminate in the natural environment. This study offered a first insight in the impact of plasmid-born ARGs and the related pathogenic bacteria that could emerged due to inappropriate antibiotic utilization in South Vietnam. PMID- 29524671 TI - Large scale treatment of total petroleum-hydrocarbon contaminated groundwater using bioaugmentation. AB - Bioaugmentation or the addition of microbes to contaminated sites has been widely used to treat contaminated soil or water; however this approach is often limited to laboratory based studies. In the present study, large scale bioaugmentation has been applied to total petroleum hydrocarbons (TPH)-contaminated groundwater at a petroleum facility. Initial TPH concentrations of 1564 mg L-1 in the field were reduced to 89 mg L-1 over 32 days. This reduction was accompanied by improved ecotoxicity, as shown by Brassica rapa germination numbers that increased from 52 at day 0 to 82% by the end of the treatment. Metagenomic analysis indicated that there was a shift in the microbial community when compared to the beginning of the treatment. The microbial community was dominated by Proteobacteria and Bacteroidetes from day 0 to day 32, although differences at the genus level were observed. The predominant genera at the beginning of the treatment (day 0 just after inoculation) were Cloacibacterium, Sediminibacterium and Brevundimonas while at the end of the treatment members of Flavobacterium dominated, reaching almost half the population (41%), followed by Pseudomonas (6%) and Limnobacter (5.8%). To the author's knowledge, this is among the first studies to report the successful large scale biodegradation of TPH-contaminated groundwater (18,000 L per treatment session) at an offshore petrochemical facility. PMID- 29524672 TI - Hydroxyapatite nanobelt/polylactic acid Janus membrane with osteoinduction/barrier dual functions for precise bone defect repair. AB - : Controllable osteoinduction maintained in the original defect area is the key to precise bone repair. To meet the requirement of precise bone regeneration, a hydroxyapatite (HAp) nanobelt/polylactic acid (PLA) (HAp/PLA) Janus membrane has been successfully prepared in this study by coating PLA on a paper-like HAp nanobelt film by a casting-pervaporation method. The Janus membrane possesses dual functions: excellent osteoinduction from the hydrophilic HAp nanobelt side and barrier function originating from the hydrophobic PLA film. The cell viability and osteogenic differentiation ability of human adipose-derived stem cells (hADSCs) on the Janus membrane were assessed. The in vitro experimental results prove that the HAp nanobelt side presents high cell viability and efficient osteoinduction without any growth factor and that the PLA side can prohibit cell attachment. The in vivo repair experiments on a rat mandible defect model prove that the PLA side can prevent postoperative adhesion between bone and adjacent soft tissues. Most importantly, the HAp side has a strong ability to promote defect repair and bone regeneration. Therefore, the HAp/PLA Janus membrane will have wide applications as a kind of tissue engineering material in precise bone repair because of its unique dual osteoinduction/barrier functions, biocompatibility, low cost, and its ability to be mass-produced. STATE OF SIGNIFICANCE: Precise bone defect repair to keeping tissue integrity and original outline shape is a very important issue for tissue engineering. Here, we have designed and prepared a novel HAp/PLA Janus membrane using a casting pervaporation method to form a layer of PLA film on paper-like HAp nanobelt film. HAp nanobelt side of the Janus membrane can successfully promote osteogenic differentiation. PLA side of the Janus membrane exhibits good properties as a barrier for preventing the adhesion of cells in vitro. Mandible repair experiments in vivo have shown that the HAp/PLA Janus membrane can promote rat mandible repair on the HAp side and can successfully prevent postoperative adhesion on the PLA side at the same time. Therefore, the HAp/PLA Janus membrane with its osteoinduction/barrier dual functions can be applied to repair bone defect precisely. PMID- 29524674 TI - Beyond the protein corona - lipids matter for biological response of nanocarriers. AB - : The interaction of nanocarriers with blood plasma components influences the biological response, and therefore, it needs to be controlled. Whereas protein adsorption to nanocarriers has been investigated to a large extent, the role of lipid interaction for drug delivery and its biological effect is not yet clear. However, lipids represent an important constituent of blood plasma and are usually bound in the form of lipoproteins. Because already for many nanocarrier systems an enrichment of apolipoproteins in their protein corona was reported, we examine the interaction of lipoproteins with nanocarriers. If interaction occurs in terms of lipoprotein adsorption, two scenarios are possible: adsorption of intact lipoprotein complexes or disintegration of the complexes with adsorption of the single components. To investigate the interaction and clarify which scenario occurs, polymeric model nanoparticles and different lipoprotein types have been studied by isothermal titration calorimetry, transmission electron microscopy, and other methods. Our data indicate that upon contact with polymeric nanoparticles, disintegration of lipoproteins and adsorption of lipids occurs. Further, the effect of lipoprotein adsorption on cell uptake has been examined, and a major effect of the lipoproteins has been found. STATEMENT OF SIGNIFICANCE: It is now well accepted that nanomaterials developed as diagnostic or therapeutic carrier systems need to be well characterized in terms of biological responses inside an organism. Many studies have already shown that proteins adsorb to the surface of a nanomaterial and create a new interface that define the identity of the material. However, the presence of other surface-active components of the blood plasma and how they interact with nanomaterials has been much less investigated. Thus, this study aims at providing a significant contribution to understanding the interaction mechanism between lipoproteins and nanomaterials. Since lipoproteins transport a high amount of lipids, which are surface-active molecules, the demonstrated interactions can go as far as complete lipoprotein disintegration. PMID- 29524673 TI - Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior. AB - : Ocular hypertension is a causal risk-factor to developing glaucoma. This is associated with stiffening of the trabecular meshwork (TM), the primary site of resistance to aqueous-humor-outflow. The mechanisms underlying this stiffening or how pathologic extracellular matrix (ECM) affects cell function are poorly understood. It is recognized that mechanotransduction systems allow cells to sense and translate the intrinsic biophysical properties of ECM into intracellular signals to control gene transcription, protein expression, and cell behavior. Using an anterior segment perfusion model, we document that there are significantly more low flow regions that are much stiffer, and fewer high flow regions that are less stiff in glaucomatous TM (GTM) when compared to non glaucomatous TMs (NTM). GTM tissue also has fewer cells overall when compared with NTM tissue. In order to study the role of pathologic ECM in glaucoma disease progression, we conducted studies using cell derived matrices (CDM). First, we characterized the mechanics, composition and organization of fibronectin in ECM deposited by GTM and NTM cells treated with glucocorticosteroids. Then, we determined that these GTM-derived ECM are able to induce stiffening of normal NTM cells, and alter their gene/protein expression to resemble that of a glaucomatous phenotype. Further, we demonstrate that GTM-derived ECM causes endoplasmic reticular stress in NTM. They also became resistant to being reorganized by these NTM cells. These phenomena were exacerbated by ECMs obtained from steroid treated glaucoma model groups. Collectively, our data demonstrates that CDMs represent a novel tool for the study of bidirectional interactions between TM cells and their immediate microenvironment. STATEMENT OF SIGNIFICANCE: Extracellular matrix (ECM) changes are prevalent in a number of diseases. The precise mechanisms by which changes in the ECM contribute to disease progression is unclear, primarily due to absence of appropriate models. Here, using glaucoma as a disease model, we document changes in cell derived matrix (CDM) and tissue mechanics that contribute to the pathology. Subsequently, we determine the effect that ECMs from diseased and healthy individuals have on healthy cell behaviors. Data emanating from this study demonstrate that CDMs are a potent tool for the study of cell-ECM interactions. PMID- 29524675 TI - Exogenous stromal derived factor-1 releasing silk scaffold combined with intra articular injection of progenitor cells promotes bone-ligament-bone regeneration. AB - : Anterior cruciate ligament (ACL) is one of the most difficult tissues to heal once injured. Ligament regeneration and tendon-bone junction healing are two major goals of ACL reconstruction. This study aimed to investigate the synergistic therapeutic effects of Stromal cell-derived factor 1 (SDF-1) releasing collagen-silk (CSF) scaffold combined with intra-articular injection of ligament-derived stem/progenitor cells (LSPCs) for ACL regeneration and the amelioration in the long-term complication of osteoarthritis (OA). The stem cell recruitment ability of CSF scaffold and the multipotency, particularly the tendon forming ability of LSPCs from rabbits were characterized in vitro, while the synergistic effect of the CSF scaffold and LSPCs for ACL regeneration and OA amelioration were investigated in vivo at 1, 3, and 6 months with a rabbit ACL reconstruction model. The CSF scaffold was used as a substitute for the ACL, and LSPCs were injected into the joint cavity after 7 days of the ACL reconstruction. CSF scaffold displayed a controlled release pattern for the encapsulated protein for up to 7 days with an increased stiffness in the mechanical property. LSPCs, which exhibited highly I Collagen and CXCR4 expression, were attracted by SDF-1 and successfully relocated into the CSF scaffold at 1 month in vivo. At 3 and 6 months post-treatment, the CSF scaffold combined with LSPCs (CSFL group) enhanced the regeneration of ACL tissue, and promoted bone tunnel healing. Furthermore, the OA progression was impeded efficiently. Our findings here provided a new strategy that using stem cell recruiting CSF scaffold with tissue-specific stem cells, could be a promising solution for ACL regeneration. STATEMENT OF SIGNIFICANCE: In this study, we developed a silk scaffold with increased stiffness and SDF-1 controlled release capacity for ligament repair. This advanced scaffold transplantation combined with intra-articular injection of LSPCs (which was isolated from rabbit ligament for the first time in this study) promoted the regeneration of both the tendinous and bone tunnel portion of ACL. This therapeutic strategy also ameliorated cartilage degeneration and reduced the severity of arthrofibrosis. Hence, combining LSPCs injection with SDF-1-releasing silk scaffold is demonstrated as a therapeutic strategy for ACL regeneration and OA treatment in the clinic. PMID- 29524676 TI - Are dental providers the next line of HPV-related prevention? Providers' perceived role and needs. AB - The rise in HPV-related oropharyngeal cancer incidence necessitates novel prevention efforts including multiple provider types. Although dental providers screen for HPV-related oropharyngeal cancers, little is known about their needs to advance "primordial prevention," or interventions at the earliest possible stage, to prevent HPV-related cancers. This study assessed dentists' and dental hygienists' perceived roles and needs regarding HPV-related primordial prevention. We conducted a mixed-method study with data from focus groups with dentists (n= 33) and dental hygienists (n= 48) and surveys from both provider types (n= 203) among providers from a diverse set of practice settings and geographic communities. Data were analyzed using qualitative thematic analysis and chi square tests. Participants affirmed dental professionals' roles in preventing HPV-related cancers and identified needs to overcome barriers to fulfilling prevention objectives. Barriers included: (1) practice environment and patient characteristics, and (2) the sensitive topic of HPV. Further, participants identified needs to improve HPV-related cancer prevention. Findings from this study suggest that dental providers may become the next line of prevention for HPV-related cancers. Dental providers' professional associations have provided guidance on HPV and oropharyngeal cancers, but our study reveals dental providers' needs for following professional organizations' guidance to advance prevention efforts and reduce HPV-related cancer incidence. PMID- 29524678 TI - The periosteum-like effect of fresh human amniotic membrane on bone regeneration in a rabbit critical-sized defect model. AB - OBJECTIVE: The purpose of this study was to investigate the effect of fresh human amniotic membrane (FHAM) as a substitute of periosteum to enhance bone regeneration in critical-sized defects. METHODS: Tibial diaphyseal bone defects were created in forty New Zealand white rabbits and treated with FHAM or left empty. Treatment groups consisted of: FHAM implanted in the place of removed periosteum (FHAMP group); FHFAM implanted to fill the entire defect (FHAMF group) compared to negative control group; empty defect with removing the periosteum (NC group) and positive control group; and empty defect without removing the periosteum (PC group). Bone regeneration was evaluated by radiographic, micro computed tomography (MU-CT) and histological analyses at 4 and 8weeks post surgery. RESULTS: Radiographic and MU-CT analysis demonstrated clearly enhanced new bone formation in positive control group (PC) and FHAMP group compared to negative control group (NC) and FHAMF group. Histological staining exhibited remaining woven bones and cartilage matrix in the FHAMP group, immature lamellar bone with medellury cavity and marrow bone formation in PC group from 4weeks post operatively. For FHAMF group, a little new bone formation was detected only from 8weeks post-operatively, and an absence of any sign of healing in NC group at both time points. CONCLUSION: The results provide that FHAM increases bone regeneration in critical-sized defects when it is implanted in the place of the removed periosteum, but its additive effect does not have the same effect of the natural periosteum. PMID- 29524677 TI - HPV vaccination in male physicians: A survey of gynecologists and otolaryngology surgeons' attitudes towards vaccination in themselves and their patients. AB - OBJECTIVE: Attitudes and barriers towards HPV vaccination were explored in a population of male surgeons in Gynecology and Otolaryngology in Ontario, Canada. MATERIALS/METHODS: An internet-based survey was distributed to male residents and physicians affiliated with the departments of Obstetrics and Gynecology, and Otolaryngology at six Ontario universities. The survey consisted of 16 questions (3 demographic, 3 workplace exposure, 6 regarding personal vaccination, and 3 regarding patient vaccination). Subgroup analyses examined differences between residents versus staff physicians and gynecologists versus otolaryngologists. RESULTS: Most respondents (51/63, 81.0%) had not been vaccinated against HPV, yet would consider vaccination in the future (41/51, 80.4%). Significantly more residents would consider vaccination compared to staff physicians (p = .03). Personal protection from benign HPV disease was the most common motivating factor (25/59, 42.4%) among participants. A notable barrier to vaccination was "age over recommendations" (9/44, 20.4%). Most participants would recommend the HPV vaccine to both male patients (49/62, 79.0%) and male partners of female patients (47/62, 75.8%). CONCLUSIONS: This study demonstrates male gynecologists and otolaryngologists had largely favorable attitudes towards HPV vaccination though few had received vaccination. These findings may be used to increase HPV vaccine uptake among male health care professionals and their patients. PMID- 29524679 TI - Subjective randomness as statistical inference. AB - Some events seem more random than others. For example, when tossing a coin, a sequence of eight heads in a row does not seem very random. Where do these intuitions about randomness come from? We argue that subjective randomness can be understood as the result of a statistical inference assessing the evidence that an event provides for having been produced by a random generating process. We show how this account provides a link to previous work relating randomness to algorithmic complexity, in which random events are those that cannot be described by short computer programs. Algorithmic complexity is both incomputable and too general to capture the regularities that people can recognize, but viewing randomness as statistical inference provides two paths to addressing these problems: considering regularities generated by simpler computing machines, and restricting the set of probability distributions that characterize regularity. Building on previous work exploring these different routes to a more restricted notion of randomness, we define strong quantitative models of human randomness judgments that apply not just to binary sequences - which have been the focus of much of the previous work on subjective randomness - but also to binary matrices and spatial clustering. PMID- 29524680 TI - What do nursing home residents with mental-physical multimorbidity need and who actually knows this? A cross-sectional cohort study. AB - OBJECTIVE: Aging societies will bring an increase in the number of long-term care residents with mental-physical multimorbidity. To optimize care for these residents, it is important to study their care needs, since unmet needs lower quality of life. To date, knowledge about care needs of residents with mental physical multimorbidity is limited. The aim of this study was to explore (un)met care needs of residents with mental-physical multimorbidity and determinants of unmet needs. METHODS: Cross-sectional cohort study among 141 residents with mental-physical multimorbidity without dementia living in 17 geronto-psychiatric nursing home units across the Netherlands. Data collection consisted of chart review, semi-structured interviews, (brief) neuropsychological testing, and self report questionnaires. The Camberwell Assessment of Need for the Elderly (CANE) was used to rate (un)met care needs from residents' and nursing staff's perceptions. Descriptive and multivariate regression analyses were conducted. RESULTS: Residents reported a mean number of 11.89 needs (SD 2.88) of which 24.2% (n = 2.88, SD 2.48) were unmet. Nursing staff indicated a mean number of 14.73 needs (SD 2.32) of which 10.8% (n = 1.59, SD 1.61) were unmet. According to the residents, most unmet needs were found in the social domain as opposed to the psychological domain as reported by the nursing staff. Different opinions between resident and nursing staff about unmet needs was most common in the areas accommodation, company, and daytime activities. Further, nearly half of the residents indicated 'no need' regarding behavior while the nursing staff supposed that the resident did require some kind of support. Depression, anxiety and less care dependency were the most important determinants of unmet needs. CONCLUSIONS: Systematic assessment of care needs showed differences between the perspectives of resident and nursing staff. These should be the starting point of a dialogue between them about needs, wishes and expectations regarding care. This dialogue can subsequently lead to the most optimal individually tailored care plan. To achieve this, nurses with effective communication and negotiation skills, are indispensable. PMID- 29524681 TI - Can perceptual grouping unfold in the absence of awareness? Comparing grouping during continuous flash suppression and sandwich masking. AB - In this study we examined whether grouping by luminance similarity and grouping by connectedness can occur in the absence of visual awareness, using a priming paradigm and two methods to render the prime invisible, CFS and sandwich masking under matched conditions. For both groupings, significant response priming effects were observed when the prime was reported invisible under sandwich masking, but none were obtained under CFS. These results provide evidence for unconscious grouping, converging with previous findings showing that visual awareness is not essential for certain perceptual organization processes to occur. They are also consistent with findings indicating that processing during CFS is limited, and suggest the involvement of higher visual areas in perceptual organization. Moreover, these results demonstrate that whether a process can occur without awareness is dependent on the level at which the suppression induced by the method used for rendering the stimulus inaccessible to awareness takes place. PMID- 29524682 TI - Cadmium treatment induces echinocytosis, DNA damage, inflammation, and apoptosis in cardiac tissue of albino Wistar rats. AB - Cadmium (Cd), a potent carcinogen present in almost all foods, poses a major health risk to humans. Major routes of exposure to Cd for humans are occupation, diet, and tobacco use. Cd elicits various deleterious effects on cellular molecules mainly by causing oxidant-antioxidant imbalance. Cd has been implicated in the pathogenesis of many cancers, Itai-itai disease, diabetic nephropathy, hypertension, peripheral artery disease, and myocardial infarction. This study was designed to investigate the effects of Cd intake on erythrocytes and cardiac tissue in male albino Wistar rats. We treated male albino Wistar rats with cadmium chloride (CdCl2) by intra-gastric administration for 30 days and examined Cd burden and changes in blood constituents and antioxidant status of blood and cardiac tissue. We also studied the structural alterations in the erthrocytes, elemental changes and Cd burden in cardiac tissue using scanning electron microscope (SEM/EDX). Inflammation and apoptosis were analysed in the cardiac tissue by polymerase chain reaction (PCR), western blotting, and DNA fragmentation assay. Cd treatment resulted in echinocytosis of erythrocytes and distorted myofibrils arrangement, vacuolization and congestion in the vessels. Cd administration has also induced inflammation and apoptosis in the cardiac tissue. At molecular level, Cd administration caused oxidative damage to DNA, lipids, and proteins and diminished the activities of various antioxidants. The present study provides a compelling evidence of Cd-induced imbalance in oxidant-antioxidant system with damage to erythrocytes and cardiac tissue that may contribute to various cardiac diseases. PMID- 29524683 TI - Highly sensitive and specific on-site detection of serum cocaine by a low cost aptasensor. AB - Cocaine is one of the most used illegal recreational drugs. Developing an on-site test for cocaine use detection has been a focus of research effort, since it is essential to the control and legal action against drug abuse. Currently most of cocaine detection methods are time-consuming and require special or expensive equipment, and the detection often suffers from high cross-reactivity with cocaine metabolites and relative low sensitivity with the best limit of detection reported at sub nanomolar (nM) level. In this work, an aptasensor has been developed using capacitive monitoring of sensor surface incorporating alternating current electrokinetics effects to speed up molecular transport and minimize matrix effects. The aptasensor is rapid, low cost, highly sensitive and specific as well as simple-to-use for the detection of cocaine from serum. The assay has a sample-to-result time of 30 s, a limit of detection of 7.8 fM, and a linear response for cocaine ranging from 14.5fM to 14.5pM in standard buffer, which are great improvements from other reported cocaine sensors. Special buffer is used for serum cocaine detection, and a limit of detection of 13.4 fM is experimentally demonstrated for cocaine spiked in human serum (equivalent to 1.34pM cocaine in neat serum). The specificity of the biosensor is also demonstrated with structurally similar chemicals, ecgonine ethyl ester and methylecgonidine. This biosensor shows high promise in detection of low levels of cocaine from complex matrices. PMID- 29524684 TI - Thermokinetic analysis and product characterization of Medium Density Fiberboard pyrolysis. AB - This study investigates the pyrolysis of Medium Density Fiberboard (MDF) as a potential waste management solution. Thermal behaviour of MDF was analysed via TG/DSC. The primary decomposition step occurred between 190 degrees C and 425 degrees C. Evolved gaseous products over this step were evaluated by a FTIR spectrometer coupled with TGA. Peaks for phenolic, alcohols and aldehydes were detected at the maximum decomposition temperature. Py-GC/MS analysis revealed phenols, ketones and cyclic compounds as the primary non-condensable pyrolysis products. The kinetics of pyrolysis were investigated by the widely applied Distributed Activation Energy Model, resulting in an average activation energy and pre-exponential factor of 127.40 kJ mol-1 and 8.4E+11. The results of this study suggest that pyrolyzing MDF could potentially provide renewable fuels and prevent environmental problems related with MDF disposal. PMID- 29524685 TI - Assessment of hydrothermal carbonization and coupling washing with torrefaction of bamboo sawdust for biofuels production. AB - Two kinds of biofuels were produced and compared from hydrothermal carbonization (HTC) and coupling washing with torrefaction (CWT) processes of bamboo sawdust in this study. The mass and energy yields, mass energy density, fuel properties, structural characterizations, combustion behavior and ash behavior during combustion process were investigated. Significant increases in the carbon contents resulted in the improvement of mass energy density and fuel properties of biofuels obtained. Both HTC and CWT improved the safety of the biofuels during the process of handling, storing and transportation. The ash-related issues of the biofuels were significantly mitigated and combustion behavior was remarkably improved after HTC and CWT processes of bamboo sawdust. In general, both HTC and CWT processes are suitable to produce biofuels with high fuel quality from bamboo sawdust. PMID- 29524686 TI - Characterized hydrochar of algal biomass for producing solid fuel through hydrothermal carbonization. AB - The aim of this work was to study the characterized hydrochar of algal biomass to produce solid fuel though hydrothermal carbonization. Hydrothermal carbonization conducted at temperatures ranging from 180 to 270 degrees C with a 60 min reaction improved the upgrading of the fuel properties and the dewatering of wet basis biomasses such as algae. The carbon content, carbon recovery, energy recovery, and atomic C/O and C/H ratios in all the hydrochars in this study were improved. These characteristic changes in hydrochar from algal biomass are similar to the coalification reactions due to dehydration and decarboxylation with an increase in the hydrothermal reaction temperature. The results of this study indicate that hydrothermal carbonization can be used as an effective means of generating highly energy-efficient renewable fuel resources using algal biomass. PMID- 29524687 TI - Enhanced electricity generation performance and dye wastewater degradation of microbial fuel cell by using a petaline NiO@ polyaniline-carbon felt anode. AB - A new electrode which embedded polyaniline (PANI) in petaline NiO (NiO@PANI-CF) was prepared through in-situ growth and in-situ polymerization. The NiO@PANI-CF integrated the high capacitive character of NiO and the high conductivity of PANI, which effectively increased electricity generation capacity of NiO@PANI MFC. The maximum output power density and the charge transfer resistance of NiO@PANI-MFC were 1078.8 mW.m-2 and 10.4 Omega respectively, which were 6.6 times and 68% lower than that of CF-MFC respectively. Moreover, NiO@PANI-MFC could effectively biodegrade dye wastewater due to high biocompatibility of NiO@PANI CF. The color and COD removal efficiencies of Reactive Brilliant Red X-3B reached 95.94% and 64.24% at 48 h respectively. The results demonstrate that the NiO@PANI CF has the advantage of high conductivity, high capacitance, high specific surface area, super hydrophilicity, low polarization performance, low charge transfer resistance, high biocompatibility and high stablity. PMID- 29524688 TI - Use of tannery wastewater as an alternative substrate and a pre-treatment medium for biogas production. AB - This study investigated biogas production as an alternative treatment of tannery wastewater (TWW) and its use as a pre-treatment medium to increase CH4 yield from anaerobic digestion (AD) of wheat straw. The TWW had high levels of sulfate and chloride, so biochemical CH4 potential could be estimated only when the TWW was diluted. Untreated straw yielded 255 NL CH4 (kg VS)-1, whereas straw that had been pre-treated with TWW yielded 314 NL CH4 (kg VS)-1 (35% increase). Treatment of TWW by AD with a co-substrate might be possible using a controlled feedstock mixing ratio. Use of TWW as a pre-treatment medium by simple co-storage before AD would be beneficial as an inexpensive treatment of lignocellulosic biomass. PMID- 29524689 TI - The carbon dioxide gasification characteristics of biomass char samples and their effect on coal gasification reactivity during co-gasification. AB - The carbon dioxide gasification characteristics of three biomass char samples and bituminous coal char were investigated in a thermogravimetric analyser in the temperature range of 850-950 degrees C. Char SB exhibited higher reactivities (Ri, Rs, Rf) than chars SW and HW. Coal char gasification reactivities were observed to be lower than those of the three biomass chars. Correlations between the char reactivities and char characteristics were highlighted. The addition of 10% biomass had no significant impact on the coal char gasification reactivity. However, 20 and 30% biomass additions resulted in increased coal char gasification rate. During co-gasification, chars HW and SW caused increased coal char gasification reactivity at lower conversions, while char SB resulted in increased gasification rates throughout the entire conversion range. Experimental data from biomass char gasification and biomass-coal char co-gasification were well described by the MRPM, while coal char gasification was better described by the RPM. PMID- 29524690 TI - The inhibition of hemicellulosic sugars on cellulose hydrolysis are highly dependant on the cellulase productive binding, processivity, and substrate surface charges. AB - In this study, the influence of major hemicellulosic sugars (mannose and xylose) on cellulose hydrolysis and major enzyme activities were evaluated by using both commercial enzyme cocktail and purified cellulase monocomponents over a "library" of cellulosic substrates. Surprisingly, the results showed that unlike glucose, mannose/xylose did not inhibit individual cellulase activities but significantly decreased their hydrolytic performance on cellulose substrates. When various enzyme-substrate interactions (e.g. adsorption/desorption, productive binding, and processive moving) were evaluated, it appeared that these hemicellulosic sugars significantly reduced the productive binding and processivity of Cel7A, which in turn limited cellulase hydrolytic efficacy. Among a range of major cellulose characteristics (e.g. crystallinity, degree of polymerization, accessibility, and surface charges), the acid group content of the cellulosic substrates seemed to be the main driver that determined the extent of hemicellulosic sugar inhibition. Our results provided new insights for better understanding the sugar inhibition mechanisms of cellulose hydrolysis. PMID- 29524691 TI - Comparative study of wet and dry torrefaction of corn stalk and the effect on biomass pyrolysis polygeneration. AB - Wet torrefaction (WT) possesses some advantages over dry torrefaction (DT). In this study, a comparative analysis of torrefied corn stalk from WT and DT was conducted along with an investigation of their pyrolysis properties under optimal conditions for biomass pyrolysis polygeneration. Compared with DT, WT removed 98% of the ash and retained twice the amount of hydrogen. The impacts of DT and WT on the biomass macromolecular structure was also found to be different using two dimensional perturbation correlation infrared spectroscopy (2D-PCIS). WT preserved the active hydroxyl groups and rearranged the macromolecule structure to allow cellulose to be more ordered, while DT removed these active hydroxyl groups and formed inter-crosslinking structures in macromolecules. Correspondingly, the bio-char yield after WT was lower than DT but the bio-char quality was upgraded due to high ash removal. Furthermore, higher bio-oil yield, higher sugar content, and higher H2 generation, were obtained after WT. PMID- 29524692 TI - Microwave-assisted co-pyrolysis of pretreated lignin and soapstock for upgrading liquid oil: Effect of pretreatment parameters on pyrolysis behavior. AB - The co-pyrolysis of pretreated lignin and soapstock was carried out to upgrade vapors under microwave irradiation. Results showed that the yield of 29.92-42.21 wt% of upgraded liquid oil was achieved under varied pretreatment conditions. Char yield decreased from 32.44 wt% for untreated control to 24.35 wt% for the 150 degrees C pretreated samples. The increased temperature, irradiation time and acid concentration were conducive to decrease the relative contents of phenols and oxygenates in liquid oils. The main components of the liquid oil were gasoline fraction (mono-aromatics and C5-C12 aliphatics), which ranged from 57.38 to 71.98% under various pretreatment conditions. Meanwhile, the diesel fraction (C12+ aliphatics) ranged from 13.16 to 22.62% from co-pyrolysis of pretreated lignin and soapstock, comparing with 10.18% of C12+ aliphatics from co-pyrolysis of non-pretreated lignin and soapstock. A possible mechanism was proposed for co pyrolysis of pretreated lignin and soapstock for upgraded liquid oils. PMID- 29524693 TI - Determination of acetyl coenzyme A in human whole blood by ultra-performance liquid chromatography-mass spectrometry. AB - Acetyl coenzyme A is involved in several key metabolic pathways. Its concentration can vary considerably in response to physiological or pathological conditions making it a potentially valuable biomarker. However, little information about the measurement and concentration of acetyl CoA in human whole blood is found in the literature. The aim of this study was the development of an accurate method for the determination of acetyl CoA in human whole blood by LC MS/MS. The method, involving extraction from whole blood by a rapid protein precipitation procedure was thoroughly validated: limit of quantitation was 3.91 ng mL-1. Accuracy and precision were calculated at five concentrations and were within +/-15%. The average endogenous level of acetyl CoA in human whole blood was determined in 17 healthy individuals to be 220.9 ng mL-1 (ranging from 124.0 to 308.0 ng mL-1). This represents, to our knowledge, the first report of acetyl CoA levels in human whole blood, and the first practical and reliable method for its determination. PMID- 29524694 TI - Factors affecting the separation performance of proteins in capillary electrophoresis. AB - Capillary electrophoresis (CE) is an effective tool for protein separation and analysis. Compared with capillary gel electrophoresis (CGE), non-gel sieving capillary electrophoresis (NGSCE) processes the superiority on operation, repeatability and automaticity. Herein, we investigated the effect of polymer molecular weight and concentration, electric field strength, and the effective length of the capillary on the separation performance of proteins, and find that (1) polymer with high molecular weight and concentration favors the separation of proteins, although concentrated polymer hinders its injection into the channel of the capillary due to its high viscosity. (2) The resolution between the adjacent proteins decreases with the increase of electric field strength. (3) When the effective length of the capillary is long, the separation performance improves at the cost of separation time. (4) 1.4% (w/v) hydroxyethyl cellulose (HEC), 100 V/cm voltage and 12 cm effective length offers the best separation for the proteins with molecular weight from 14,400 Da to 97,400 Da. Finally, we employed the optimal electrophoretic conditions to resolve Lysozyme, Ovalbumin, BSA and their mixtures, and found that they were baseline resolved within 15 min. PMID- 29524695 TI - Metabolomics-assisted metabolite profiling of itraconazole in human liver preparations. AB - Itraconazole (ITZ) is a first-generation triazole-containing antifungal agent that effectively treats various fungal infections. As ITZ has a better safety profile than that of ketoconazole (KCZ), ITZ has been used worldwide for over 25 years. However, few reports have explored the metabolic profile of ITZ, and the underlying mechanism of ITZ-induced liver injury is not clearly understood. In the present study, we revisited ITZ metabolism in humans, using a non-targeted metabolomics approach, and identified several novel metabolic pathways including O-dearylation, piperazine oxidation, and piperazine-N,N'-deethylation. Furthermore, we explored the formation of reactive ITZ metabolites using trapping agents as surrogates, to assess the possibility of metabolism-mediated toxicity. We found that ITZ and its metabolites did not form any adducts with nucleophiles including glutathione, potassium cyanide, and semicarbazide. The present study expands our knowledge of ITZ metabolism and supports the suggestion that ITZ has a better safety profile than that of KCZ in terms of metabolism-mediated toxicity. PMID- 29524696 TI - Green gas chromatographic stability-indicating method for the determination of Lacosamide in tablets. Application to in-vivo human urine profiling. AB - A direct, eco-friendly, stability-indicating GC method was developed for the determination of Lacosamide (LCM) in tablet dosage forms in presence of its degradation products as well as in human urine in presence of the co-administered drug Zonisamide (ZON). The assay method in tablets was validated according to the ICH guidelines, while the method for determination of LCM in urine was validated according to FDA; Bioanalytical Method Validation guidance. Linear response (r = 0.9998) was observed over the range of 20-280 MUg/mL of LCM, with detection and quantitation limits of 5.871 and 19.57 MUg/mL, respectively for the tablet assay method. While (r = 0.9999) was observed over the range of 0.5-20 MUg/mL of LCM, with detection and quantitation limits of 67 and 233 ng mL-1, respectively for the urine analysis method. Under various stress conditions, the investigation of LCM forced degradation behaviour was carried out. Furthermore, monitoring of the drug in urine followed by construction of its urine profile was done after the administration of 50 mg tablet of LCM to three healthy volunteers so as to prove the ability of the method to be applied in assaying LCM in human urine. The method showed also successful separation of LCM and the co-administered drug ZON in urine. Finally, the greenness of the method was assessed using National Environmental Methods Index label and Eco scale methods. PMID- 29524697 TI - UPLC-ESI-MS/MS method for the quantitative measurement of aliphatic diamines, trimethylamine N-oxide, and beta-methylamino-l-alanine in human urine. AB - This work describes a quantitative high-throughput analytical method for the simultaneous measurement of small aliphatic nitrogenous biomarkers, i.e., 1,6 hexamethylenediamine (HDA), isophoronediamine (IPDA), beta-methylamino-l-alanine (BMAA), and trimethylamine N-oxide (TMAO), in human urine. Urinary aliphatic diamines, HDA and IPDA, are potential biomarkers of environmental exposure to their corresponding diisocyanates. Urinary BMAA forms as a result of human exposure to blue-green algae contaminated food. And, TMAO is excreted in urine due to the consumption of carnitine- and choline-rich diets. These urinary biomarkers represent classes of small aliphatic nitrogen-containing compounds (N compounds) that have a high aqueous solubility, low logP, and/or high basic pKa. Because of the highly polar characteristics, analysis of these compounds in complex sample matrices is often challenging. We report on the development of ion pairing chemistry based ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method for the simultaneous measurement of these biomarkers in human urine. Chromatographic separation was optimized using heptafluorobutyric acid-(HFBA-) based mobile phase and a reversed phase C18 column. All four analytes were baseline separated within 2.6 min with an overall run time of 5 min per sample injection. Sample preparation involved 4 h of acid hydrolysis followed by automated solid phase extraction (SPE) performed using strong cation exchange sorbent bed with 7 N ammonia solution in methanol as eluent. Limits of detection ranged from 0.05 ng/mL to 1.60 ng/mL. The inter-day and intra-day accuracy were within 10%, and reproducibility within 15%. The method is accurate, fast, and well-suited for biomonitoring studies within targeted groups, as well as larger population-based studies such as the U. S. National Health and Nutrition Examination Survey (NHANES). PMID- 29524698 TI - Recanalized Left Internal Carotid Artery Bifurcation Aneurysm with Adherent Thrombus at Aneurysm Neck and M1 Origin Diagnosed on 2-Dimensional Angiography Cause of Embolic Stroke. AB - We report a unique case of recanalized left internal carotid artery aneurysm with thrombus adherent to the aneurysm neck and M1 origin diagnosed on 2-dimensional angiography causing embolic stroke in a 66-year-old female who was successfully treated with stent-assisted coiling. This is important to recognize as a cause of embolic stroke. PMID- 29524699 TI - The Effects of Smad3 on Adrenocorticotropic Hormone-Secreting Pituitary Adenoma Development, Cell Proliferation, Apoptosis, and Hormone Secretion. AB - OBJECTIVE: Down-regulation of mothers against decapentaplegic homolog 3 (Smad3) results in the formation of tumors both in vivo and in vitro. However, little is known about the effect of Smad3 on adrenocorticotropic hormone-secreting pituitary adenomas (ACTH-PAs). Our objective was to study the expression and effect of Smad3 in ACTH-PAs and its possible mechanisms. METHODS: Smad3, COOH terminally phosphorylated mothers against decapentaplegic homolog 3 (pSmad3), and mothers against decapentaplegic homolog 2 proteins (Smad2) were detected in samples from 5 normal anterior pituitaries and 18 ACTH-PAs by Western blot and immunohistochemical analysis. Then, Smad3 expression was up-regulated by Smad3 CMV plasmid or down-regulated by small interfering RNA in ACTH tumor cells (AtT 20) in vitro. Cell proliferation, apoptosis, ACTH level, and pSmad3, B-cell lymphoma/lewkmia-2 (BCL-2), and pro-opiomelanocortin (POMC) protein expression in the AtT-20 cells were measured to investigate the antitumor effects of Smad3. RESULTS: Reduced expression of Smad3 and pSmad3 but unchanged Smad2 levels were found in ACTH-PAs compared with normal pituitaries. In vitro, the overexpression of Smad3 inhibited cell proliferation, promoted cell apoptosis, and decreased ACTH secretion; in contrast, Smad3 knockdown increased cell proliferation and decreased cell apoptosis but had no significant effect on ACTH secretion. At the same time, overexpression of Smad3 increased pSmad3 but inhibited BCL-2 and POMC protein expression. On the contrary, underexpression of Smad3 inhibited pSmad3 but promoted BCL-2 and POMC protein expression. CONCLUSIONS: Smad3 is underexpressed in ACTH-PAs. Reversing the expression of Smad3 in AtT-20 cells could suppress cell growth, promote tumor apoptosis, and decrease ACTH secretion. Tumor suppression was possibly mediated by the promotion of pSmad3 and the reduction of BCL-2 and POMC expression. PMID- 29524700 TI - Analysis of Morphometric Parameters in Cervical Canal Stenosis on Neutral and Dynamic Magnetic Resonance Imaging. AB - OBJECTIVE: A dynamic compression injury of the cervical spinal cord (SC) is widely accepted in the pathophysiology of cervical myelopathy. Flexion/extension magnetic resonance imaging (MRI) provides information on the dynamic cervical injury. We sought to compare morphometric parameters on neutral and flexion/extension MRI in cervical spondylotic myelopathy. METHODS: Patients with cervical canal stenosis who had MRI in neutral, flexion, and extension positions were reviewed retrospectively. A morphometric comparison of following parameters at compression level was performed: SC area, cerebrospinal fluid (CSF) area, and CSF reserve ratio (CSF/CSF plus SC). Patients were classified according to the presence of high signal (HS) in SC, and predictors of HS were calculated by the use of logistic regression analysis. RESULTS: In total, 55 patients, 26 men, with mean age of 57 +/- 13 were analyzed. Significant difference was found in mean CSF reserve ratio between flexion and extension (0.47 +/- 0.18 vs. 0.40 +/- 0.21, P < 0.05). SC area was significantly smaller in flexion (58.8 +/- 13.3 mm2) than in both neutral (66.9 +/- 22.3 mm2) and extension (68.3 +/- 19.1 mm2). HS was found in 22 cases, and predictors of HS were smaller SC area on extension (odds ratio 1.46; 95% confidence interval 1.07-1.84) and smaller CSF plus SC area on flexion (OR 1.32; 95% confidence interval 1.06-1.45). Cut-off values on the receiver operating characteristic curve were 55 mm2 for SC and 99 mm2 for CSF plus SC area. CONCLUSIONS: Application of dynamic MRI in cervical stenosis reveals significant differences of both SC and CSF reserve ratio in flexion/extension and neutral positions. Patients with smaller SC area in extension and smaller CSF plus SC area in flexion have greater risk of HS on MRI. PMID- 29524701 TI - Surgical Resection of Pineal Epidermoid Cyst Contributed to Relieving Schizophrenia Symptoms. AB - BACKGROUND: The pineal gland has been demonstrated to be involved in the development of mood and psychotic disorders. However, few studies have looked at the relationship between pineal region tumors and psychiatric disorders. Intracranial epidermoid cysts usually arise in the cerebellopontine angle area and are extremely rare in the pineal region. The case of pineal epidermoid cyst presenting as schizophrenia has never been reported before. CASE PRESENTATION: We described the case of a 23-year-old man who presented to the hospital with symptoms suggestive of schizophrenia. During work-up, he was found to have a pineal lesion on brain magnetic resonance imaging. Total resection of the tumor was subsequently performed, and pathology confirmed an epidermoid cyst. One month after surgery, the patient's psychotic symptoms significantly improved free of drug and fully returned to work 3 months postoperatively. CONCLUSIONS: This case highlights the importance of including mass lesions of the pineal region in the differential diagnosis of psychotic disorders. It also provides further support that the pineal region may play a role in the pathophysiology of psychiatric diseases, although more studies will be needed to elucidate this interesting connection. PMID- 29524702 TI - A Longitudinal Mapping Study on Cortical Plasticity of Peripheral Nerve Injury Treated by Direct Anastomosis and Electroacupuncture in Rats. AB - OBJECTIVE: We used functional magnetic resonance imaging to provide a longitudinal description of cortical plasticity caused by electroacupuncture (EA) of sciatic nerve transection and direct anastomosis in rats. METHODS: Sixteen rats in a sciatic nerve transection and direct anastomosis model were randomly divided into intervention and control groups. EA intervention in the position of ST-36, GB-30 was conducted continuously for 4 months in the intervention group. Functional magnetic resonance imaging and gait assessment were performed every month after intervention. RESULTS: The somatosensory area was more activated in the first 2 months and then deactivated in the rest 2 months when EA was applied. The pain-related areas had the same activation pattern as the somatosensory area. The limbic/paralimbic areas fluctuated more during the EA intervention, which was not constantly activated or deactivated as previous studies reported. We attributed such changes in somatosensory and pain-related areas to the gradual reduction of sensory afferentation. The alterations in limbic/paralimbic system might be associated with the confrontation between the upregulating effect of paresthesia or pain and the downregulating effect of EA intervention through the autonomic nerve system. The gait analysis showed significantly higher maximum contact mean intensity in the intervention group. CONCLUSIONS: The alterations in the brain brought about by the long-term therapeutic effect of EA could be described as a synchronized activation pattern in the somatosensory and pain related areas and a fluctuating pattern in the limbic/paralimbic system. PMID- 29524703 TI - Neurologic Deterioration Due to Brain Sag After Bilateral Craniotomy for Subdural Hematoma Evacuation. AB - BACKGROUND: Intracranial hypotension from cerebrospinal fluid (CSF) hypovolemia resulting in cerebral herniation is a rare but known complication that can occur after neurosurgical procedures, usually encountered in correlation with perioperative placement of a lumbar subarachnoid drain. Decrease in CSF volume resulting in loss of buoyancy results in downward herniation of the brain without contributing mass effect, causing a phenomenon known as brain sag. Unreported previously is brain sag occurring without concomitant occult CSF leak or lumbar drainage. CASE DESCRIPTION: This case report describes a patient who underwent bilateral craniotomies for subacute on chronic subdural hematoma with successful decompression but experienced acute neurologic deterioration secondary to brain sag. Despite an initial improvement in neurologic function, he subsequently experienced progressive neurologic deterioration with evidence of cerebral herniation on neuroimaging, without evidence of continued mass effect on the brain parenchyma. After a diagnosis of brain sag was determined based on imaging criteria, the patient was placed in a flat position, which resulted in rapid improvement in his neurologic function without any further intervention. CONCLUSIONS: This case is unique in comparison with previous reports of intracranial hypotension after craniotomy in that the symptoms were completely reversed with positioning alone, without any evidence of active or occult CSF drainage. This report emphasizes that the diagnosis of brain sag should be taken into consideration when there is an unknown reason for neurologic decline after craniotomy, particularly bilateral craniotomies, if the imaging indicates herniation with imaging findings consistent with intracranial hypotension, without evidence of overlying mass effect. PMID- 29524704 TI - Endoscopic Endonasal Surgery Treatment Strategies for Invasive Pituitary Adenoma: Analysis of Four Approaches. AB - OBJECTIVE: To explore the surgical methods and clinical effect of endoscopic endonasal approaches for the treatment of invasive pituitary adenomas (IPAs). METHODS: A retrospective analysis was made of the clinical data of 74 patients (75 procedures) with IPAs treated by different endoscopic endonasal approaches at the Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University from May 2014 to August 2017. The data include clinical manifestation, imaging features, surgical methods and complications, resection rate, cure rate, prognosis, and complications in different Knosp classifications and Hardy stages. The transcavernous approach was used in 47 patients, the lateral-cavernous approach was used in 14 patients, the tuberculum sella planum approach was used in 8 patients, and the diaphragma sellae open or dorsum sellae cut approach was used in 6 patients. RESULTS: The gross total resection (GTR) rate was 70.7% (53 patients) and tumor residue rate was 29.3% (22 patients). GTR rate for pituitary adenoma according to Knosp classification was 89.3% in grade 3 and 28.6% in grade 4. The biology cure rate was 75.0% and 23.8%, respectively. There was significance between them (P < 0.05). In addition, the GTR rate of Hardy stage was 90.5% in stage C, 90.0% in stage D, 26.1% in stage E, and the biology cure rate was 80.1%, 75.0%, and 13.0%, respectively. There was significance among them (P < 0.05) Postoperative severe complications included 9 patients (12.0%) with cerebrospinal fluid leaks, 26 patients (34.7%)with electrolyte imbalance, 36 patients (48.0%) with transient diabetes insipidus, 22 patients (29.3%) with hypopituitarism, 2 patients (2.7%) with permanent hypopituitarism, and 2 patients (2.7%)with epistaxis. The follow-up lasted 2-41 months (average, 19.3 months). No patient experienced recurrence after GTR, 1 patient undergoing subtotal experienced recurrence and underwent reoperation, 3 patients underwent postoperative Gamma Knife treatment, and 2 patients with refractory IPA were given temozolomide and metformin chemotherapy. CONCLUSIONS: According to the invasiveness of IPA, choosing the appropriate endoscopic surgical approach is helpful in removing tumors and reducing complications. PMID- 29524705 TI - Is Low-Lying Optic Chiasm an Obstacle to an Endoscopic Endonasal Approach for Retrochiasmatic Craniopharyngiomas? (Korean Society of Endoscopic Neurosurgery 003). AB - OBJECTIVE: Despite advances in endoscopic techniques, retrochiasmatic craniopharyngiomas (CPs) are difficult to remove completely, because the low lying optic chiasm often provides an obstacle to an endoscopic endonasal approach. This study aimed to identify the endoscopic surgical outcomes of the retrochiasmatic CP and resolve the issues related to low-lying optic chiasm. METHODS: We reviewed 154 consecutive patients with CP who underwent endonasal endoscopic resection from February 2009 to April 2017 at 2 independent institutions. The topographic relationship of the tumor with the third ventricle, stalk, and optic chiasm and clinical outcomes were investigated. RESULTS: Retrochiasmatic CPs were found in 142 of 154 patients (92.2%). The median follow up time was 25 months. Gross total resection and near-total resection were achieved in 113 patients (79.6%) and 21 patients (13.8%), respectively. Postoperative cerebrospinal fluid leaks were found in 16 patients (11.3%). Low lying and high-lying chiasms were found in 44 patients (31.0%) and 98 patients (69.0%), respectively. Low-lying chiasm did not affect clinical outcomes including the extent of resection. Patients with low-lying chiasm showed a marginal trend for postoperative visual deterioration. The ventricular growth pattern representing the origin of the tumor and previous surgery were significantly associated with the position of the optic chiasm (P = 0.007 and 0.001, respectively). CONCLUSIONS: An endoscopic endonasal approach is an effective surgical approach for retrochiasmatic CP, even in tumors with low-lying chiasm. However, a thorough and careful dissection is necessary to prevent visual deterioration. PMID- 29524706 TI - Higher Improvement in Patient-Reported Outcomes Can Be Achieved After Transforaminal Lumbar Interbody Fusion for Clinical and Radiographic Degenerative Spondylolisthesis Classification Type D Degenerative Lumbar Spondylolisthesis. AB - BACKGROUND: Clinical and radiographic degenerative spondylolisthesis (CARDS) classification defines a distinct subset of patients with kyphotic angulation at the involved segment (type D). Research using CARDS classification to investigate motion characteristics at involved segments or patient-related outcomes (PROs) following surgical intervention is sparse. We investigated the relationship between CARDS type D spondylolisthesis and dynamic instability and PROs in type D versus non-type D spondylolisthesis. METHODS: We reviewed consecutive patients who received transforaminal lumbar interbody fusion for L4-5 spondylolisthesis between 2009 and 2015. Patients were assigned into type D and non-type D groups. Translational motion was determined by upright lumbar lateral radiography with supine sagittal magnetic resonance imaging or flexion and extension radiography. Demographics, radiographic parameters, and PROs were evaluated. RESULTS: Type D and non-type D groups comprised 34 and 163 patients, respectively. Compared with non-type D, type D group was characterized by lordotic angulation loss and higher degree of olisthesis on upright radiographs and demonstrated higher translational motion on upright lumbar lateral radiography with supine sagittal magnetic resonance imaging analysis. After surgery, mean reduction rate was significantly higher in type D group; type D had less slippage, but differences in slip angle and disc height were not significant. Preoperative Oswestry Disability Index and visual analog scale for back pain scores were higher in type D group. Type D spondylolisthesis and dynamic instability were associated with achieving minimal clinically important differences in PROs. CONCLUSIONS: CARDS type D spondylolisthesis is a distinct subset associated with dynamic instability and worse PROs. Higher improvement in PROs can be achieved in CARDS type D spondylolisthesis after surgery. PMID- 29524707 TI - Pediatric Case of Xanthogranuloma in the Sellar Region Presenting a Visual Disturbance Successfully Treated with Endoscopic Endonasal Surgery. AB - BACKGROUND: Xanthomatous pituitary diseases rarely occur in childhood. We report a rare pediatric case of a xanthogranuloma that developed in the sellar region, resulting in a visual disturbance that was treated successfully with endoscopic endonasal surgery. CASE DESCRIPTION: A 13-year-old boy came to us with a headache and visual disturbance that occurred 1 month prior. Clinical examination findings showed that he was alert with signs of bitemporal hemianopsia. An endocrinologic examination showed partial hypopituitarism, and brain magnetic resonance imaging revealed a cystic mass in the sellar turcica compressing the optic apparatus. Endoscopic endonasal surgery was performed to decompress the optic apparatus, and the mass was removed. Histopathologic analysis of the tumor demonstrated granulomatous tissue with cholesterol clefts, foamy macrophages, and multinucleated giant cells, with no epithelial component. The diagnosis was xanthogranuloma of the sellar region. The patient gradually recovered from the visual disturbance and was free from any neurologic signs or symptoms 6 months after surgery. CONCLUSIONS: Xanthogranuloma, although rare, should be considered as a differential diagnosis of a sellar or suprasellar lesion, even in children. PMID- 29524708 TI - A New Approach for Photorealistic Visualization of Rendered Computed Tomography Images. AB - OBJECTIVE: Classical single-colored or multicolored 3-dimensional (3D) visualization of sectional images lacked in being realistic and revealed limited anatomical discrimination. Recently, a new technique called cinematic volume rendering for 3D reconstruction of computed tomography has been developed. The aim of this study was to analyze this new visualization algorithm from a technical perspective and to investigate potential benefits for neurosurgical applications. METHODS: A standard test in computer graphics called Cornell Box was adapted and applied for reproducibility of light effects in cinematic rendering opposed to classic rendering methods. Simulation of distinct camera effects such as variable apertures, exposition time, optics, and surface refinements are presented in a human skull, respectively. Postprocessing capabilities allow for immediate clinical use. RESULTS: This volume-rendering technique generates cadaver-like 3D reconstructions. By considering complex interactions between a scanned object and dynamic light patterns, a cinematic illumination of a 3D surface reconstruction can be achieved. A spinal tumor case and a complex intracranial carotid artery aneurysm are presented, comparing all available rendering techniques. Cinematic rendering results in greater spatial discrimination of neighboring anatomical structures. CONCLUSIONS: This technical and clinical description focuses on the neurosurgical relevance of a new rendering technique. Considering the improved image impression of cinematic rendering and viewers' perception, it seems likely that the technique will gain wide acceptance in the clinical routine. PMID- 29524709 TI - The History and Evolution of Internal Maxillary Artery Bypass. AB - Internal maxillary artery (IMA) bypass has gained momentum in the last 5 years for the treatment of complex cerebrovascular disorders and skull base tumors. However, some issues regarding this treatment modality have been proposed. As one of the most experienced neurosurgical teams to perform internal maxillary artery bypass in the world (>100 clinical cases), we reviewed the literature in aspects of basic anatomy of maxillary artery with its variations to the lateral pterygoid muscle, initial anastomosis modalities, and subsequent exposure techniques in cadaver studies, preoperative arterial evaluation methods, optimal interposed graft selections, and surgical outcome in the management of complex aneurysms, skull base tumors, and steno-occlusive disorders. PMID- 29524710 TI - Technical Modification of Amygdalo-Hippocampectomy in Temporal Lobe Epilepsy Surgery to Further Reduce Severe Neurological Complications: A Clinical Anatomical Study. AB - BACKGROUND: Temporal lobe resection (TLR) including amygdalohippocampectomy (AHE) is the most frequent performed procedure in epilepsy surgery. Owing to the close anatomic relationship of the mesial temporal structures and the midbrain and choroidal fissure, the incidence of severe complications, such as postoperative stroke, is as high as 2.5%. METHODS: We developed a modification of the classical technique for AHE that involves entering the choroidal fissure early via the anterior part of the frontomesial temporal horn cleft to identify the crus cerebri, posterior cerebri artery, and oculomotor nerve. In a second step, after visualization of the cleavage plane between the midbrain and middle cerebral artery, the uncus and amygdala are removed. RESULTS: A total of 81 patients (47 females and 34 males; mean age at surgery, 40 years) underwent TLR including AHE with our surgical modification to treat heterogeneous pathologies. The cohort included 45 patients with hippocampal sclerosis, 11 with ganglioglioma, 2 with dysembryoplastic neuroepithelioma, 2 with diffuse glioma, and 21 with other pathologies, including cavernoma, scar tissue, and mild cortical dysplasia, among others. In all patients, anterior temporal resection was performed via AHE using our modified technique. Seizure outcome was favorable after a mean follow-up of 27 months (range, 3-56 months); 64% of the patients were completely seizure-free (Engel class 1A), and 75% had an Engel class 1 outcome. There was no mortality or permanent severe neurologic complications, and the rate of surgical complications was 3.7%. CONCLUSIONS: Our modified AHE technique is associated with a low rate of complications in TLR for medically refractory temporal lobe epilepsy, and helps avoid permanent severe neurologic complications. PMID- 29524711 TI - Retrograde Snare-Assisted Rescue via Anterior Communicating Artery for Lost Access During Multiple Overlapping Pipeline Embolization Device Placement. AB - BACKGROUND: The Pipeline embolization device (PED; ev3, Irvine, California, USA) has been used to divert flow away from an aneurysm sac. The risk of complications may increase for flow diversion with giant aneurysms because these cases may require multiple overlapping PEDs, which makes the technique highly complex. CASE DESCRIPTION: We report a rescue technical strategy for lost access during multiple overlapping PED placement for a giant, fusiform cavernous aneurysm. CONCLUSIONS: By using the collateral circulation as an alternative rescue route, intraprocedural loss of distal access may be salvaged. PMID- 29524712 TI - Percutaneous Endoscopic Spine Minimally Invasive Technique for Decompression Therapy of Thoracic Myelopathy Caused by Ossification of the Ligamentum Flavum. AB - BACKGROUND: The percutaneous endoscopic technique through an interlaminar approach is a commonly used minimally invasive procedure in the treatment of lumbar disc herniation, even lumbar spinal stenosis. This report describes complete decompression with the percutaneous endoscopic technique for patients with thoracic ossification of the ligamentum flavum (OLF). CASE DESCRIPTION: We performed surgical decompression in of 2 patients with thoracic myelopathy caused by OLF using percutaneous endoscopic surgery through an interlaminar approach. After surgery, the patients described significant improvement in their preoperative neurologic symptoms. Postoperative thoracic computed tomography showed that the ossification of ligaments was completely removed. CONCLUSION: We applied the percutaneous endoscopic technique for the treatment of thoracic OLF accomplished direct decompression of the ossified ligaments with minimal trauma and instability. This technique could be used as an alternative choice. However, the fused types should be performed prudently because of the difficulties of the operation. PMID- 29524713 TI - Osteodiskitis of Lumbar Spine Due to Migrated Fractured Inferior Vena Cava Filter. AB - BACKGROUND: Venous thromboembolism can be a significant cause of morbidity in the trauma population. Medical and surgical specialties have been pushing the indication for prophylactic filter placement. CASE DESCRIPTION: A 36-year-old man presented with axial lower back pain with a radicular right L2 component after lifting a heavy object. He had a history of penetrating brain trauma 3 years prior, with placement of a prophylactic inferior vena cava filter. His radiograph, computed tomography, and magnetic resonance imaging of the lumbar spine showed fracture of his filter, with migration of the fractured fragment through the inferior vena cava and into the L2-L3 disk space, and surrounding bony lysis and severe osteodiskitis. He was treated medically with intravenous and then oral antibiotics and improved clinically and radiographically. CONCLUSIONS: Conservative use of filter devices and early retrieval once their indication expires are paramount to avoid unnecessary complications. PMID- 29524714 TI - Comparison of Mobi-C Cervical Disc Arthroplasty Versus Fusion for the Treatment of Symptomatic Cervical Degenerative Disc Disease. AB - OBJECTIVE: Mobi-C cervical disc arthroplasty (MCDA) is an alternative to anterior cervical discectomy and fusion (ACDF). This study evaluated the effectiveness and safety of MCDA and ACDF for symptomatic cervical degenerative disc disease. METHODS: Databases were systematically searched for randomized controlled trials. Studies were included based on eligibility criteria. Risk of bias assessment and quality of evidence assessment were performed. RESULTS: Four studies with 785 patients were included. For clinical outcomes, MCDA were superior to ACDF with fewer subsequent surgical interventions (P < 0.00001), lower neck pain scores (P = 0.01), lower incidences of adjacent segment degeneration at both superior and inferior levels (P = 0.0003 and P = 0.01, respectively), greater range of motion of the operated segment (P < 0.0001), and higher patient satisfaction (P = 0.007). No significant differences were observed between groups regarding operative time, blood loss, duration of hospitalization, and neck disability index and arm pain scores (P > 0.05). Subgroup analyses indicated that for patients with 2-level cervical degenerative disc disease, MCDA demonstrated lower neck disability index and arm pain scores and higher patient satisfaction (P < 0.05) compared with ACDF. CONCLUSIONS: MCDA had fewer subsequent surgical interventions, lower neck pain scores, lower incidences of adjacent segment degeneration at superior and inferior levels, greater range of motion, and higher patient satisfaction scores than ACDF. MCDA was similar to ACDF regarding operative time, blood loss, duration of hospitalization, and neck disability index and neck pain scores. PMID- 29524715 TI - Surgeon Annual and Cumulative Volumes Predict Early Postoperative Outcomes After Brain Tumor Resection. AB - OBJECTIVE: Surgeon volume has been previously shown to affect patient outcomes. However, data related to neuro-oncologic surgery are limited and do not include neurologic morbidities as an outcomes measure. In this study, we aimed to determine if 5-year surgeon cumulative and annual volumes predict early postoperative outcomes in patients after brain tumor surgery. METHODS: A population-based cohort of patients (n = 10,258) undergoing brain tumor resection between 2005 and 2014 were included for study using the New York Statewide Planning and Research Cooperation System. Surgeons were categorized by their cumulative and annual surgical volume. RESULTS: Patients treated by high cumulative/high annual (HC/HA) volume surgeons had shorter length of stay (median, 5 days vs. 8 days vs. 8 days vs. 6 days, respectively; P < 0.01), lower charges (median, 70,025 vs. $77,043 vs. $93,715 vs. $77,018 respectively; P < 0.01) and less nonroutine discharge (41% vs. 48% vs. 50.9% vs. 43.9% respectively; P < 0.01) compared with patients treated by surgeons from the low cumulative/low annual (LC/LA), LC/HA, HC/LA groups. Similarly, HC/HA volume surgeons also had lower rate of hydrocephalus (9.9% vs. 10.4% vs. 13.7% respectively; P = 0.02), medical complications (6.9% vs. 11.2% vs. 11.5% respectively; P < 0.01), neurologic complications (44.1% vs. 46.8% vs. 48.1% respectively; P = 0.03), 30-day reoperation (5.1% vs. 6.9% vs. 7.1% respectively; P < 0.01) and 30-day death (3.3% vs. 5.4% vs. 5.2%; P < 0.01) compared with LC/LA and LC/HA volume surgeons. CONCLUSIONS: There is some evidence for improved postoperative outcomes when surgery is performed by HC and HA volume surgeons. This finding suggests that subspecialization in surgical neuro-oncology should be considered. PMID- 29524716 TI - Patients with Moderate and Severe Traumatic Brain Injury: Impact of Preinjury Platelet Inhibitor or Warfarin Treatment. AB - OBJECTIVE: We aimed to examine the effect of preinjury antithrombotic medication on clinical and radiologic neuroworsening in traumatic brain injury (TBI) and study the effect on outcome. METHODS: A total of 184 consecutive patients >=50 years old with moderate and severe TBI admitted to a level 1 trauma center were included. Neuroworsening was assessed clinically by using the Glasgow Coma Scale (GCS) score and radiologically by using the Rotterdam CT score on repeated time points. Functional outcome was assessed with the Glasgow Outcome Scale Extended 6 months after injury. RESULTS: The platelet inhibitor group (mean age, 77.3 years; n = 43) and the warfarin group (mean age, 73.2 years; n = 20) were significantly older than the nonuser group (mean age, 63.7 years; n = 121; P <= 0.001). In the platelet inhibitor group 74% and in the warfarin group, 85% were injured by falls. Platelet inhibitors were not significantly associated with clinical or radiologic neuroworsening (P = 0.37-1.00), whereas warfarin increased the frequency of worsening in GCS score (P = 0.001-0.028) and Rotterdam CT score (P = 0.004). In-hospital mortality was higher in the platelet inhibitor group (28%; P = 0.030) and the warfarin group (50%; P < 0.001) compared with the nonuser group (13%). Platelet inhibitors did not predict mortality or worse outcome after adjustment for age, preinjury disability, GCS score, and Rotterdam CT score, whereas warfarin predicted both mortality and worse outcome. CONCLUSIONS: In this study of patients with moderate and severe TBI, preinjury platelet inhibitors did not cause neuroworsening or predict higher mortality or worse outcome. In contrast, preinjury warfarin caused neuroworsening and was an independent risk factor for mortality and worse outcome at 6 months. Hence, fall prevention and liberal use of computed tomography examinations is important in this patient group. PMID- 29524717 TI - Clinical Characteristics and Prognostic Analysis of Glioma in Human Immunodeficiency Virus-Infected Patients. AB - OBJECTIVE: To perform a survival analysis of human immunodeficiency virus (HIV) patients with glioma and to assess the relationship between various prognostic factors and overall survival (OS). METHODS: We reported in detail the management and prognosis of 2 HIV-infected patients with glioma in our hospital and performed a quantitative and comprehensive systematic literature review of patients with HIV-associated glioma. We combined our treatment experience with retrospectively obtained treatment information and studied the survival time to statistically analyze whether age, sex, World Health Organization (WHO) grade, surgery, radiotherapy, chemotherapy, and combined radiotherapy and chemotherapy could predict patient survival. RESULT: The study included 34 cases, including our own 2 cases. The median survival was 9 months. On survival analysis, among the aforementioned parameters, WHO grade (low-grade glioma/high-grade glioma), surgery (surgical resection/stereotactic biopsy), and radiotherapy showed a significant association with OS by univariate analysis. Multivariate analysis showed WHO grade and surgery were significant predictors of OS. CONCLUSIONS: Most patients had astrocytoma or high-grade glioma. The median survival of all HIV infected patients with gliomas was shorter than that of GBM patients with glioblastoma multiforme. Surgery and WHO grade were independent prognostic factors for OS. PMID- 29524718 TI - Early Postoperative Perils of Intraventricular Tumors: An Observational Comparative Study. AB - BACKGROUND: Early postoperative patient surveillance after removal of intraventricular tumors is often hindered by delayed awakening and prolonged somnolence. The objective of this study was to analyze the incidence of early critical postoperative events after elective craniotomy for intraventricular tumors in adults compared with extraventricular lesions. METHODS: An observational comparative study was conducted on adult patients who had undergone first-time elective craniotomy between November 2011 and August 2016. Patients were stratified into extraventricular lesions (group 1) and intraventricular tumors (group 2). The rates of late extubation, early postoperative seizures, emergency head computed tomography (CT) scans, and urgent surgical intervention within 48 hours and mortality within 30 days of surgery were analyzed from a prospective database. RESULTS: A total of 977 elective craniotomies were analyzed, including 951 (97.3%) in group 1 and 26 (2.7%) in group 2. Emergency CT scans were ordered significantly more frequently in group 2 (34.6% vs. 8.4%; odds ratio, 5.76; 95% confidence interval [CI], 2.49-13.35; P = 0.0002), and the incidence of urgent surgical intervention was significantly higher in group 2 (11.5% vs. 0.8%; odds ratio, 15.38; 95% CI, 3.83-61.72; P = 0.002). The main reason for urgent surgical intervention in group 2 was acute obstructive hydrocephalus. Overall surgical mortality after 30 days was 0.3% (3 cases in group 1, no cases in group 2). CONCLUSIONS: Intraventricular tumors are at significantly higher risk for early emergency head CT and urgent surgical intervention. This patient cohort might benefit from routine intraoperative and early postoperative imaging, as well as intraoperative extraventricular drain placement. PMID- 29524719 TI - Morphological Parameters Related to Aneurysm Wall Enhancement in Patients with Multiple Intracranial Aneurysms. AB - BACKGROUND: Vessel wall magnetic resonance imaging (MRI) has been suggested as a potential in vivo method to detect inflammation of aneurysm wall and identify unruptured intracranial aneurysm (UIA) at high risk for rupture. This study aims to investigate the correlation between aneurysm wall enhancement (AWE) on vessel wall MRI and rupture-related morphological parameters in patients with multiple UIAs. METHODS: Clinical data and vessel wall MRI images were reviewed in 14 patients with 30 multiple UIAs. The AWE was defined as enhancement of the aneurysm wall in postcontrast vessel wall MRI using the precontrast MRI as a reference. Morphological parameters, including aneurysm size, aspect ratio, size ratio, bottleneck factor, height-to-width ratio, nonsphericity index (NSI), and inflow angle, were measured using 3-dimensional rotation angiography. Univariate and multivariate analyses were performed to evaluate the correlations between morphological parameters and the presence of AWE. RESULTS: Sixteen of the 30 multiple UIAs presented with AWE on vessel wall MRI. On univariate analyses, UIAs with AWE were significantly larger (P = 0.001) and had significantly higher aspect ratio (P = 0.047), size ratio (P = 0.003), bottleneck factor (P = 0.007), and NSI (P = 0.007) values. Further multivariate logistic regression showed that aneurysm size (odds ratio, 3.54; 95% confidence interval, 1.10-11.35; P = 0.033) and NSI (odds ratio, 3.53; 95% confidence interval, 1.06-11.80; P = 0.040) were independently associated with the presence of AWE in multiple UIAs. CONCLUSIONS: The presence of AWE on vessel wall MRI was significantly correlated with conventional morphological rupture risk factors in patients with multiple UIAs, which might indicate AWE as a potential radiologic predictor for UIAs with high rupture risk. PMID- 29524720 TI - Lessons to Be Remembered from a Dural Arteriovenous Fistula Mimicking Medulla and High Cervical Cord Glioma. AB - The radiological signs of intracranial dural arteriovenous fistulas (ICDAVFs) are heterogenous. While it is commonly accepted that hyper intense T2 wedge magnetic resonance imaging of the brainstem and cervical cord mainly concern gliomas, it is so far uncommon and probably unknown that ICDAVFs can imitate similar radiological pattern, especially with gadolinium contrast enhancement and cord enlargement. Thus the angiography is poorly documented in the diagnostic workup. We report the unusual history of ICDAVFs, revealed by clinical and radiological features that mimicked a medulla or cervical spinal cord glioma. This observation provides information on the management of atypical lesions mimicking medulla or cervical cord glioma and arguments for a careful radiological study. Looking for dilated veins around the brainstem and the cord is mandatory in the workup of a supposed infiltrating brainstem or spinal cord lesion, in order to rule out an ICDAVF. Even if the hyperintense T2 images associated with contrast enhancement is in favor of a brainstem or spinal cord glioma, additional cerebral angiography should be mandatory. Moreover, this clinical case highlights the need for a multidisciplinary approach including neuroradiologist, oncologist and neurosurgeon. PMID- 29524721 TI - Noninvasive Intracranial Pressure Monitoring for Severe Traumatic Brain Injury in Children: A Concise Update on Current Methods. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality worldwide and intracranial pressure (ICP) monitoring plays a crucial role in its management. Based on existing literature, we review the current practicing noninvasive ICP monitoring devices and their accuracy in predicting increased ICP in pediatric TBI. METHODS: A thorough literature search was conducted on PubMed, Medline, and the Cochrane database, articles were selected systematically and reviewed completely, and relevant data were summarized and discussed. RESULTS: A total of 27 articles pertaining to pediatric TBI were included and reviewed. We found various modalities of noninvasive ICP monitoring devices used over the last few years. The noninvasive modalities so far attempted in pediatric TBI and so reviewed here are transcranial Doppler, optic nerve sheath diameter, otoacoustic emission, near-infrared spectroscopy, contrast-enhanced ultrasonography, and quantitative pupillometry. CONCLUSIONS: Invasive monitoring methods are the current gold standard for monitoring ICP; however, complications caused by their invasive nature are of concern. Of all the noninvasive methods based on the literature, we found transcranial Doppler and optic nerve sheath diameter assessment to be the best tools to monitor ICP in pediatric TBI. The promising results and developments of noninvasive ICP monitoring modalities with its ideal features of high sensitivity, diagnostic accuracy, and simple acquisition technique may make it the future of neurointensive monitoring in pediatric TBI. PMID- 29524722 TI - Is Anatomic Reduction Better Than Partial Reduction in Patients with Vertical Atlantoaxial Dislocation? AB - OBJECTIVE: To describe lower cranial nerve (CN) palsy following vertical overdistraction when performing occipitocervical fusion (OCF) to treat vertical atlantoaxial dislocation (AAD) and basilar invagination (BI) and investigate its possible causes. METHODS: We report 4 cases with vertical AAD and BI who presented postoperatively with neurogenic dysphagia, dysarthria, and bucking after undergoing anatomic reduction. RESULTS: Patients underwent revision surgery to achieve partial reduction and demonstrated remarkable recovery of CN IX, X, and XI deficits. CONCLUSIONS: Performing OCF in the overdistraction position to treat vertical AAD may caudally displace the brainstem relative to the cranial base, resulting in traction injury to the CN IX, X, and XI where they exit the skull base through the jugular foramen. PMID- 29524723 TI - Hysteroscopic Diagnosis of Omentum Incarceration Subsequent to an Iatrogenic Uterine Perforation. AB - STUDY OBJECTIVE: To present and discuss the hysteroscopic aspects of incarcerated omentum through uterine perforation caused by previous dilation and curettage (D&C) for an incomplete first-trimester abortion. DESIGN: A case report. SETTING: Constantine University Hospital, Constantine, Algeria. PATIENT: A 40-year-old, gravida 3, para 2 patient, with a history of an incomplete first-trimester spontaneous abortion treated 6 months before by D&C requiring medical assistance because of moderate, chronic pelvic pain. No other clinical or biological alteration was found. The ultrasound showed intracavitary hyperechogenic formation infiltrating the myometrium posteriorly. INTERVENTIONS: Hysteroscopy revealed a fatlike lesion arousing suspicion of a residual trophoblast; the differential diagnosis included intramyometrial fat metaplasia as well [1]. A mechanical cold loop resection was initiated. Instrumental manipulation of the mass released yellow drops, probably of lipid nature, subsequently leading to the discovery of a uterine perforation giving passage to the omentum. Histologic examination confirmed fat tissue. There was immediate resolution of symptoms. Laparoscopic repair was subsequently performed and consisted of suturing the defect. There were no further complications. MEASUREMENTS AND MAIN RESULTS: Few cases of omentum incarceration in a perforated uterus diagnosed during laparotomy or by magnetic resonance imaging have previously been reported [2-4]. To our knowledge, this is the first case revealed through hysteroscopy. CONCLUSION: In women with a history of intracavitary interventions such as D&C, omentum incarceration should be considered when hysteroscopy demonstrates a fatlike formation and yellow droplets released by pressing or mobilizing the formation. Surgeons should be cautious, never using electrosurgery on formations whose origin arouses suspicion. PMID- 29524724 TI - A Survey of Public Opinion in the United States Regarding Uterine Transplantation. AB - STUDY OBJECTIVE: To evaluate the opinions and attitudes of the general public regarding uterine transplantation (UTx) in the United States. DESIGN: A cross sectional study (Canadian Task Force classification II-2). SETTING: A Web-based survey. PATIENTS: A nationally representative sample of adult US residents by age and sex. INTERVENTIONS: A Web-based questionnaire administered in November 2016. MEASUREMENTS AND MAIN RESULTS: Respondents who supported UTx were compared with those who were opposed using log binomial regression to calculate relative risk ratios and 95% confidence intervals. Of the 1444 respondents recruited, 1337 (93%) completed the survey. Ninety respondents (6%) disagreed with the use of in vitro fertilization for any indication and were excluded. Of the remaining 1247 respondents, 977 (78%) supported and 48 (4%) opposed allowing women to undergo UTx. Respondents with higher yearly incomes and education level were more likely to agree that "taking the uterus from one person and putting it into another person is ethical." Respondents who answered that UTx is safe for the donor, recipient, and baby were more likely to believe that UTx is an acceptable, ethical alternative to a gestational carrier. Forty-five percent of respondents believed that UTx should be covered by insurance, whereas 24% did not. CONCLUSION: The majority of respondents in a sample of US residents support UTx, find it ethical, and believe that it is an acceptable alternative to a gestational carrier although support varies. These findings suggest that the US public is in favor of uterine transplantation as a treatment for uterine factor infertility. PMID- 29524725 TI - Validation of the Simulated Vaginal Hysterectomy Trainer. AB - STUDY OBJECTIVE: To establish construct validity of the simulated vaginal hysterectomy trainer (SimVaHT). DESIGN: A cross-sectional validation study (Canadian Task Force classification II-2). SETTING: A single academic medical center in the United States. SUBJECTS: Fourteen residents in obstetrics and gynecology (4 postgraduate year [PGY] 1, 4 PGY-2, 3 PGY-3 and 3 PGY-4). PGY-1 and PGY-2 residents were grouped to form the "junior level" cohort, whereas PGY-3 and PGY-4 residents comprised the "senior level" cohort. INTERVENTIONS: Each participant underwent surgical skill simulation by performing a simulated vaginal hysterectomy on a practical, inexpensive vaginal hysterectomy trainer. MEASUREMENTS AND MAIN RESULTS: The primary outcome was resident surgical skill as assessed by the Objective Structured Assessment of Technical Skills Global Rating Scale (GRS). All obstetrics and gynecology residents were videotaped performing a simulated vaginal hysterectomy on the SimVaHT. The tapes were reviewed independently by 2 blinded urogynecology experts, each of whom provided a GRS score. The primary outcome was overall GRS scores. The secondary outcome was time to complete the exercise. GRS scores were compared between junior- and senior level residents. Senior-level residents scored significantly higher on the GRS overall compared with junior-level residents (p = .008). CONCLUSION: Construct validity was demonstrated for the SimVaHT. The SimVaHT is a practical and inexpensive tool that may improve resident vaginal surgical skills before their first case in the operating room. PMID- 29524726 TI - Structure and genetics of a glycerol 2-phosphate-containing O-specific polysaccharide of Escherichia coli O33. AB - An O-specific polysaccharide was isolated by mild acid degradation of the lipopolysaccharide of Escherichia coli O33 followed by gel-permeation chromatography on Sephadex G-50. The polysaccharide was found to contain glycerol 2-phosphate (Gro-2-P), and the following structure of its tetrasaccharide repeat was established by sugar analysis, dephosphorylation, and 1D and 2D 1H and 13C NMR spectroscopy: The O33-antigen gene cluster was analyzed and found to be essentially consistent with the O-polysaccharide structure. PMID- 29524727 TI - Full structure and insight into the gene cluster of the O-specific polysaccharide of Yersinia intermedia H9-36/83 (O:17). AB - Lipopolysaccharide was isolated from bacteria Yersinia intermedia H9-36/83 (O:17) and degraded with mild acid to give an O-specific polysaccharide, which was isolated by GPC on Sephadex G-50 and studied by sugar analysis and 1D and 2D NMR spectroscopy. The polysaccharide was found to contain 3-deoxy-3-[(R)-3 hydroxybutanoylamino]-d-fucose (d-Fuc3NR3Hb) and the following structure of the heptasaccharide repeating unit was established: The structure established is consistent with the gene content of the O-antigen gene cluster. The O polysaccharide structure and gene cluster of Y. intermedia are related to those of Hafnia alvei 1211 and Escherichia coli O:103. PMID- 29524728 TI - Novel hybrids of brefeldin A and nitrogen mustards with improved antiproliferative selectivity: Design, synthesis and antitumor biological evaluation. AB - A series of novel conjugates of brefeldin A (11a-c, 12a-c and 13a-c) were obtained by introducing a variety of nitrogen mustards at 4-OH or 7-OH position to explore more efficacious and less toxic antitumor agents. The antiproliferative activities were tested against three cancer cell lines (HL-60, PC-3 and Bel-7402) and one multidrug resistant cell line Bel-7402/5-FU. Among them, compound 11a was the strongest derivative with IC50 values of 4.48, 9.37, 0.2 and 0.84 MUM, respectively, and more potent than nitrogen mustards. Though the antiproliferative potency was weaker than the lead compound brefeldin A, 11a displayed lower toxicity than brefeldin A (IC50 < 0.001 MUM) with an IC50 of 9.74 MUM against normal human liver L-O2 cells, showing good selectivity between normal and malignant liver cells. The mechanism studies confirmed that 11a could induce apoptosis, arrest cell cycle at the G1 phase and lead to mitochondrial dysfunction in Bel-7402 cells at submicromolar concentrations. Furthermore, 11a induced the intrinsic apoptotic mitochondrial pathway in Bel-7402 cells, evidenced by the enhanced expression of the pro-apoptotic protein Bax, cyto-c and p53, and the reduced expression of the anti-apoptotic protein Bcl-2. The caspase 9 and -3 levels were also up-regulated. PMID- 29524729 TI - Photophysical properties and photocytotoxicity of free and liposome-entrapped diazepinoporphyrazines on LNCaP cells under normoxic and hypoxic conditions. AB - 5,7-Diaryl-substituted symmetrical diazepinoporphyrazine and tribenzodiazepinoporphyrazine were synthesized and characterized using UV-Vis, MS MALDI, and various NMR techniques. The expected photosensitizing potentials of these porphyrazines were evaluated by measuring their abilities to generate singlet oxygen in organic solvents and by comparing them with that of the recently obtained dendrimeric G1-type diazepinoporhyrazine. Absorbance and fluorescence measurements were performed to study the aggregation properties of the novel macrocycles. The photocytotoxicity of tribenzodiazepinoporphyrazine towards LNCaP cells in its free form and after its incorporation into liposomes was examined using MTT assay under normoxic and hypoxic conditions. It is interesting that all tested liposome formulations maintained their phototoxic activity in hypoxia. Also, tribenzodiazepinoporphyrazine incorporated into liposomes revealed better photocytotoxic effect (IC50 values of 0.600 +/- 0.357 MUM and 0.378 +/- 0.002 MUM) than its free form (IC50 values of 3.135 +/- 0.156 MUM). Following the in vitro experiments, the most promising liposomal formulation containing l-alpha-phosphatidyl-DL-glycerol for tribenzodiazepinoporphyrazine was found. Moreover, tribenzodiazepinoporphyrazine incorporated into liposomes containing 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt) revealed moderate phototoxicity at 5 * 10-5 MUM for antibacterial photodynamic therapy. It was established that an irradiation of planktonic bacterial strains significantly reduced CFUs of Staphylococcus aureus ATCC 25923 in comparison to tribenzodiazepinoporphyrazine containing l-alpha-phosphatidyl-DL glycerol liposomes. PMID- 29524730 TI - Antitumor activity and carrier properties of novel hemocyanins coupled to a mimotope of GD2 ganglioside. AB - Conjugation to carrier proteins is a way to improve the immunogenicity of peptides. Such is the case for peptides mimicking carbohydrate tumor-associated antigens in cancer vaccine development. The most used protein for this purpose is the keyhole limpet hemocyanin (KLH) from Megathura crenulata. Its limited bioavailability has prompted interest in finding new candidates; nevertheless, it is not known whether other hemocyanins might be equally efficient as carrier of carbohydrate peptide mimotopes to promotes anti-tumor responses. Here, we evaluated the carrier and antitumor activity of novel hemocyanins with documented immunogenicity obtained from Concholepas concholepas (CCH) and Fissurella latimarginata (FLH), coupled through sulfo-SMCC to P10, a mimetic peptide of GD2, the major ganglioside constituent of neuroectodermal tumors, and incorporating AddaVax as an adjuvant. The humoral immune responses of mice showed that CCH-P10 and FLH-P10 conjugates elicited specific IgM and IgG antibodies against P10 mimotope, similar to those obtained with KLH-P10, which was used as a positive control. The CCH-P10 and FLH-P10 antisera, exhibited cross-reactivity with murine and human melanoma cells, like anti-CCH and anti-FLH sera suggesting a cross reaction of CCH and FLH glycosylations with carbohydrate epitopes on the tumor cell surfaces, similar to the KLH antisera. When mice were primed with each hemocyanin-P10 and challenged with melanoma cells, better antitumor effects were observed for FLH-P10 than for CCH-P10 and, as for KLH-P10, irrespective of conjugation. These data demonstrate that CCH and FLH are useful carriers of carbohydrate mimotopes; however, the best antitumor activity of FLH preparations, indicate that is a suitable candidate for further cancer vaccines research. PMID- 29524731 TI - Development of Piperazinediones as dual inhibitor for treatment of Alzheimer's disease. AB - Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50 = 32.45 +/- 0.044, 28.65 +/- 0.029, BuChE, IC50 = 157.95 +/- 0.264, 160.58 +/- 0.082 and MMP-2, IC50 = 36.83 +/- 0.015, 19.57 +/- 0.005 (nM). In the enzyme kinetics study, lead molecule 46 showed non-competitive inhibition of AChE with Ki = 7 nM and competitive inhibition of MMP-2 with Ki = 20 nM. Compounds 52 and 46 inhibited AChE-induced Abeta aggregation at 20 MUM. The compounds also exhibited in-vitro antioxidant potential in DPPH assay. Further, compound 46 was found to be a promising neuroprotective agent in MC65 cells. Lead molecule 46 significantly enhanced working memory in scopolamine induced amnesia animal model at dose of 5 mg/kg dose. The mitochondrial membrane potential was restored in animals when treated with compounds 52 and 46. PMID- 29524732 TI - Feasibility study on medical isotope production using a compact neutron generator. AB - Compact neutron generators can provide high flux of neutrons with energies ranging from thermal (0.025 eV) to 14 MeV. Recent measurements demonstrated high neutron yields from the D-7Li fusion reaction at an interaction energy of 500 keV. Using the D-7Li reaction and applying new advancements in high flux neutron generator technology along with the commercial availability of high voltage DC power supplies enables the production of useful quantities of radioisotopes for medical applications. Using the known neutron reaction cross-sections, it has been estimated that hundreds-to-thousands MBq (or tens-to-hundreds mCi) of 99Mo, 225Ac, 64Cu and 67Cu can be obtained from a compact high flux neutron generator. PMID- 29524734 TI - Effects of naloxone distribution to likely bystanders: Results of an agent-based model. AB - BACKGROUND: Opioid overdose deaths in the US rose dramatically in the past 16 years, creating an urgent national health crisis with no signs of immediate relief. In 2017, the President of the US officially declared the opioid epidemic to be a national emergency and called for additional resources to respond to the crisis. Distributing naloxone to community laypersons and people at high risk for opioid overdose can prevent overdose death, but optimal distribution methods have not yet been pinpointed. METHODS: We conducted a sequential exploratory mixed methods design using qualitative data to inform an agent-based model to improve understanding of effective community-based naloxone distribution to laypersons to reverse opioid overdose. The individuals in the model were endowed with cognitive and behavioral variables and accessed naloxone via community sites such as pharmacies, hospitals, and urgent-care centers. We compared overdose deaths over a simulated 6-month period while varying the number of distribution sites (0, 1, and 10) and number of kits given to individuals per visit (1 versus 10). Specifically, we ran thirty simulations for each of thirteen distribution models and report average overdose deaths for each. The baseline comparator was no naloxone distribution. Our simulations explored the effects of distribution through syringe exchange sites with and without secondary distribution, which refers to distribution of naloxone kits by laypersons within their social networks and enables ten additional laypersons to administer naloxone to reverse opioid overdose. RESULTS: Our baseline model with no naloxone distribution predicted there would be 167.9 deaths in a six month period. A single distribution site, even with 10 kits picked up per visit, decreased overdose deaths by only 8.3% relative to baseline. However, adding secondary distribution through social networks to a single site resulted in 42.5% fewer overdose deaths relative to baseline. That is slightly higher than the 39.9% decrease associated with a tenfold increase in the number of sites, all distributing ten kits but with no secondary distribution. This suggests that, as long as multiple kits are picked up per visit, adding secondary distribution is at least as effective as increasing sites from one to ten. Combining the addition of secondary distribution with an increase in sites from one to ten resulted in a 61.1% drop in deaths relative to the baseline. Adding distribution through a syringe exchange site resulted in a drop of approximately 65% of deaths relative to baseline. In fact, when enabling distribution through a clean-syringe site, the secondary distribution through networks contributed no additional drops in deaths. CONCLUSION: Community-based naloxone distribution to reverse opioid overdose may significantly reduce deaths. Optimal distribution methods may include secondary distribution so that the person who picks up naloxone kits can enable others in the community to administer naloxone, as well as targeting naloxone distribution to sites where individuals at high-risk for opioid overdose death are likely to visit, such as syringe-exchange programs. This study design, which paired exploratory qualitative data with agent-based modeling, can be used in other settings seeking to implement and improve naloxone distribution programs. PMID- 29524733 TI - A fragmented code: The moral and structural context for providing assistance with injection drug use initiation in San Diego, USA. AB - BACKGROUND: Injection drug use initiation is shaped by social networks and structural contexts, with people who inject drugs often assisting in this process. We sought to explore the norms and contexts linked to assisting others to initiate injection drug use in San Diego, USA, to inform the development of structural interventions to prevent this phenomenon. METHODS: We undertook qualitative interviews with a purposive sample of people who inject drugs and had reported assisting others to initiate injection (n = 17) and a sub-sample of people who inject drugs (n = 4) who had not reported initiating others to triangulate accounts. We analyzed data thematically and abductively. RESULTS: Respondents' accounts of providing initiation assistance were consistent with themes and motives reported in other contexts: of seeking to reduce harm to the 'initiate', responding to requests for help, fostering pleasure, accessing resources, and claims that initiation assistance was unintentional. We developed analysis of these themes to explore initiation assistance as governed by a 'moral code'. We delineate a fragmented moral code which includes a range of meanings and social contexts that shape initiation assistance. We also show how assistance is happening within a structural context that limits discussion of injection drug use, reflecting a prevailing silence on drug use linked to stigma and criminalization. CONCLUSIONS: In San Diego, the assistance of others to initiate injection drug use is governed by a fragmented moral code situated within particular social norms and contexts. Interventions that address the social and structural conditions shaped by and shaping this code may be beneficial, in tandem with efforts to support safe injection and the reduction of injection related harms. PMID- 29524735 TI - A qualitative examination of the effects of international counter-drug interdictions. AB - BACKGROUND: The purpose of this study is to utilize unique qualitative data to determine the effects of sporadic international drug interdictions on drug trafficking, and to assess whether the responses of drug traffickers align with rational choice theory. METHODS: Qualitative data obtained from 23 high-level United States Drug Enforcement Administration (DEA) informants, who are embedded in international drug trafficking groups, are examined to identify common responses to drug interdiction operations. RESULTS: The findings indicate that sporadic counter-drug interdictions do not a have permanent deterrent effect on transnational drug smuggling operations. However, these types of law enforcement operations produce temporary alterations in drug trafficking, as traffickers adopted a variety of methods to thwart the efforts of law enforcement-often by relying on information acquired from corrupt local law enforcement. The results also indicate that while interdiction operations displaced trafficking activities (temporally, spatially, and methodological), there is little evidence that drug traffickers responded to such operations by moving into new areas (i.e., malign spatial displacement). CONCLUSION: Sporadic international drug interdiction programs do little to deter drug trafficking organizations (DTOs) from engaging in their illicit trade. Instead, DTOs adjust in a calculating manner to these operations to ensure that their illegal products reach consumer marketplaces, which is congruent with the rational choice theoretical perspective. PMID- 29524736 TI - Harnessing the language of overdose prevention to advance evidence-based responses to the opioid crisis. AB - Language has significant implications for how we view and respond to public health issues. Conventional moralistic messaging around drug use stigmatizes people who use drugs and inhibits the implementation of evidence-based harm reduction interventions that do not condemn drug use. However, within the context of the unprecedented North American opioid overdose crisis, we argue that shifting conventional moral messaging around overdose prevention and response strategies is key to supporting the rapid roll-out of evidence-based harm reduction interventions. Reframing overdose prevention to highlight the imperative to address the ongoing public health emergency is an important first step in implementing urgently needed response strategies. PMID- 29524737 TI - Heroic journeys through sobriety: How temporary alcohol abstinence campaigns portray participant experiences. AB - BACKGROUND: In Australia, recent years have seen a rise in the popularity of temporary abstinence campaigns, in which people pledge to abstain from alcohol for a month while raising funds for charity. In addition to their fundraising aims, such initiatives have been viewed as tools for broader behavioural and cultural change around alcohol, encouraging participants to reflect on their drinking and make longer-term changes to their behaviour. The extent to which these initiatives promote enduring change may depend on how they portray the experience of temporarily abstaining from alcohol, and how they position participants. METHOD: We conducted a thematic discourse analysis of e-mails and website content from the 2016 editions of Dry JulyTM and OcsoberTM, two Australian temporary abstinence campaigns. RESULTS: Both campaigns featured an overarching portrayal of participation as a hero's journey through sobriety, with participants embarking on a quest to fundraise for their cause, and returning from their experience transformed. However, the campaigns differed in the way they positioned participants. Dry JulyTM consistently positioned participants as heroes, promoting both fundraising and reflection on longer-term behaviour changes. In contrast, OcsoberTM offered varied and inconsistent positions which were less likely to engage participants or prompt enduring changes in behaviour, for example positioning participants as alcohol abusers or on a detox. CONCLUSION: Our findings emphasise the need to attend to how campaigns materials position participants in order to strengthen the effectiveness of such campaigns as health promotion tools. PMID- 29524738 TI - A critical analysis of the implementation of a legal regulated market for new psychoactive substances ("legal highs") in New Zealand. AB - BACKGROUND: In July 2013 New Zealand passed the Psychoactive Substances Act (PSA) to establish the world's first regulated legal market for new psychoactive substances (NPS) ("legal highs"). AIM: To critically analyse the implementation of the PSA. METHODS: Synthesis of findings from interviews with 30 key informants (i.e. politicians, civil servants, legal high industry actors, toxicologists, NGO representatives and drug policy academics), analysis of relevant laws and policy documents, and a review of academic and grey literature on the PSA. FINDINGS: Key challenges experienced during the implementation of the PSA included the harmfulness of interim approved products, the slowness in withdrawing products which caused adverse effects, enforcing retail restrictions, price competition by retailers, judicial challenges by the "legal high" industry, and growing opposition to the regime from local communities and key stakeholders (including local councils). The PSA lacks a tax on products and restrictions on retail opening hours which likely contributed to the problems above. The implementation of the PSA also appeared to suffer from a rushed legislative process and resource constraints on the regulatory agency which led to delays in the development of the full regulatory framework, including the product testing requirements, and issues with enforcing retail regulation, such as the minimum age of purchase. The decline in public support for the PSA regime reflected problems with communicating the aims of the policy to the general public. CONCLUSIONS: The troubled implementation of the PSA underlines a number of important lessons for consideration when developing a regulated legal drug market, including advanced development of regulatory systems, ensuring the sale of low risk products, adequately resourcing regulatory agencies and related enforcement activity, detailed regulation of retail outlets, establishing price controls, and ongoing engagement with stakeholders and the general public. PMID- 29524739 TI - Interpretation of clinical endpoints in trials of acute myeloid leukemia. AB - Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified alpha and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial's statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data. PMID- 29524740 TI - Intolerance of uncertainty as a vulnerability factor for excessive and inflexible avoidance behavior. AB - Recent studies have shown that avoidance behavior may become excessive and inflexible (i.e., detached from its incentive value and resistant to extinction). On the other hand, prospective intolerance of uncertainty (P-IU) has been defined as a factor leading to excessive responding in uncertain situations. Thus, uncertain avoidance situations may be taken as a relevant scenario to examine the role of intolerance of uncertainty as a factor that facilitates excessive and inflexible avoidance behavior. In our experiment, we tested the hypothesis that P IU is associated with excessive and inflexible avoidance in an outcome devaluation paradigm. Specifically, healthy participants learned in a free operant discriminative task to avoid an aversive sound, and were tested in extinction to measure the sensitivity of avoidance responses to the devaluation of the sound aversiveness. The results showed that an increase in P-IU was positively associated to an increase in insensitivity to the devaluation. Moreover, P-IU was also related to an increase in the frequency of avoidance responses during the instrumental learning phase, and to resistance to extinction. Interestingly, these associations involving P-IU were still significant when trait anxiety was controlled for. The pattern of results suggests that P-IU may be a vulnerability factor for excessive and inflexible avoidance, which, in turn, has been found to be associated with several mental disorders. PMID- 29524741 TI - Impact of one-step luminescent cyanoacrylate treatment on subsequent DNA analysis. AB - Fingermarks can be exploited for both their ridge detail and touch DNA. One-step luminescent cyanoacrylate (CA) fuming techniques used for fingermark enhancement, such as PolyCyano UV (Foster+Freeman Ltd) and LumicyanoTM (Crime Science Technology), claim to be compatible with DNA analysis as they reduce the need for post-staining to increase contrast of the developed fingermark. The aim of this study was to determine the impact that these one-step luminescent cyanoacrylates have on DNA analysis and how they compare to conventional CA techniques. Four donors each deposited five sets of natural fingermarks, to which a known amount of washed saliva cells was dispensed onto half of each set of fingermarks. Each set was treated with either a conventional CA technique or a one-step luminescent CA technique prior to collection and processing of DNA, with one set left as a non-fumed control. It was found that DNA was still recoverable and detectable following each of the treatments. LumicyanoTM had a similar impact on DNA profiles as conventional CA fuming and with post-stain, however, the degradation effect of PolyCyano UV on DNA was greater than the conventional treatments. For quantities of DNA such as that from touch DNA, the use of PolyCyano UV to enhance fingermarks may impact subsequent DNA analysis by causing allele drop out at larger fragment sizes. PMID- 29524742 TI - Early life stages of Northern shrimp (Pandalus borealis) are sensitive to fish feed containing the anti-parasitic drug diflubenzuron. AB - Increasing use of fish feed containing the chitin synthesis inhibiting anti parasitic drug diflubenzuron (DFB) in salmon aquaculture has raised concerns over its impact on coastal ecosystems. Larvae of Northern shrimp (Pandalus borealis) were exposed to DFB medicated feed under Control conditions (7.0 degrees C, pH 8.0) and under Ocean Acidification and Warming conditions (OAW, 9.5 degrees C and pH 7.6). Two weeks' exposure to DFB medicated feed caused significantly increased mortality. The effect of OAW and DFB on mortality of shrimp larvae was additive; 10% mortality in Control, 35% in OAW, 66% in DFB and 92% in OAW + DFB. In OAW + DFB feeding and swimming activity were reduced for stage II larvae and none of the surviving larvae developed to stage IV. Two genes involved in feeding (GAPDH and PRLP) and one gene involved in moulting (DD9B) were significantly downregulated in larvae exposed to OAW + DFB relative to the Control. Due to a shorter intermoult period under OAW conditions, the OAW + DFB larvae were exposed throughout two instead of one critical pre-moult period. This may explain the more serious sub-lethal effects for OAW + DFB than DFB larvae. A single day exposure at 4 days after hatching did not affect DFB larvae, but high mortality was observed for OAW + DFB larvae, possibly because they were exposed closer to moulting. High mortality of shrimp larvae exposed to DFB medicated feed, indicates that the use of DFB in salmon aquaculture is a threat to crustacean zooplankton. PMID- 29524744 TI - Employing a hydrazine linked asymmetric double naphthalene hybrid for efficient naked eye detection of F-: Crystal structure with real application for F. AB - An asymmetric hydrazide, (12E, 13E)-2-((naphthalen-1-yl) methylene)-1-(1-(2 hydroxynaphthalen-6-yl) ethylidene) hydrazine (abbreviated as AH) is synthesized and characterized by standard techniques and crystal structure of AH has been obtained. The naked eye detection of F- in aqueous acetonitrile (acetonitrile: water=7:3/v:v) by AH has been investigated by UV-Visible titration and in presence of other anions, the limit of detection being 1.31*10-6(M). The mechanism of F- sensing has been explored by 1H NMR titration. AH undergoes hydrogen bonding with F- followed by deprotonation. The practical utility of AH has been explored by successful test kit response and color change in toothpaste solution. PMID- 29524743 TI - Nrf2a modulates the embryonic antioxidant response to perfluorooctanesulfonic acid (PFOS) in the zebrafish, Danio rerio. AB - The glutathione redox system undergoes precise and dynamic changes during embryonic development, protecting against and mitigating oxidative insults. The antioxidant response is coordinately largely by the transcription factor Nuclear factor erythroid-2 (Nrf2), an endogenous sensor for cellular oxidative stress. We have previously demonstrated that impaired Nrf family signaling disrupts the glutathione redox system in the zebrafish embryo, and that impaired Nrf2 function increases embryonic sensitivity to environmental toxicants. Here, we investigated the persistent environmental toxicant and reported pro-oxidant perfluorooctanesulfonic acid (PFOS), and its impact on the embryonic glutathione mediated redox environment. We further examined whether impaired Nrf2a function exacerbates PFOS-induced oxidative stress and embryotoxicity in the zebrafish, and the potential for Nrf2-PPAR crosstalk in the embryonic adaptive response. Wild-type and nrf2afh318-/- mutant embryos were exposed daily to 0 (0.01% v/v DMSO), 16, 32, or 64 MUM PFOS beginning at 3 h post fertilization (hpf). Embryonic glutathione and cysteine redox environments were examined at 72 hpf. Gross embryonic toxicity, antioxidant gene expression, and apoptosis were examined at 96 hpf. Mortality, pericardial edema, and yolk sac utilization were increased in wild-type embryos exposed to PFOS. Embryonic glutathione and cysteine redox couples and gene expression of Nrf2 pathway targets were modulated by both exposure and genotype. Apoptosis was increased in PFOS-exposed wild-type embryos, though not in nrf2a mutants. In silico examination of putative transcription factor binding site suggested potential crosstalk between Nrf2 and PPAR signaling, since expression of PPARs and gene targets was modulated by both PFOS exposure and Nrf2a genotype. Overall, this work demonstrates that nrf2a modulates the embryonic response to PFOS, and that PPAR signaling may play a role in the embryonic adaptive response to PFOS. PMID- 29524745 TI - Optical absorption and fluorescence spectroscopy studies of Artepillin C, the major component of green propolis. AB - The bioactivity of propolis against several pathogens is well established, leading to the extensive consumption of that bee product to prevent diseases. Brazilian green propolis, collected by the species Apis mellifera, is one of the most consumed in the world. The chemical composition of green propolis is complex and it has been shown that it displays antioxidant, antimicrobial, anti inflammatory and antitumor activities, especially due to the high content of Artepillin C. The molecule is a derivative of cinnamic acid with two prenylated groups, responsible for the improvement of the affinity of the compound for lipophilic environment. A carboxylic group (COOH) is also present in the molecule, making it a pH-sensitive compound and the pH-dependent structure of Artepillin C, may modulate its biological activity related to interactions with the cellular membrane of organisms and tissues. Molecular properties of Artepillin C on aqueous solution were examined by optical absorption, steady state and time-resolved fluorescence spectroscopies. Acid-base titration based on the spectral position of the near UV absorption band, resulted in the pKa value of 4.65 for the carboxylic group in Artepillin C. In acidic pH, below the pKa value, an absorption band raised around 350nm at Artepillin C concentration above 50MUM, due to aggregation of the molecule. In neutral pH, with excitation at 310nm, Artepillin C presents dual emission at 400 and 450nm. In pH close to the pKa, the optical spectra show contribution from both protonated and deprotonated species. A three-exponential function was necessary to fit the intensity decays at the different pHs, dominated by a very short lifetime component, around 0.060ns. The fast decay resulted in emission before fluorescence depolarization, and in values of fluorescence anisotropy higher than could be expected for monomeric forms of the compound. The results give fundamental knowledge about the protonation-deprotonation state of the molecule, that may be relevant in processes mediated by biological membranes. PMID- 29524746 TI - Predicting extractives content of Eucalyptus bosistoana F. Muell. Heartwood from stem cores by near infrared spectroscopy. AB - Time and resource are the restricting factors for the wider use of chemical information of wood in tree breeding programs. NIR offers an advantage over wet chemical analysis in these aspects and is starting to be used for tree breeding. This work describes the development of a NIR-based assessment of extractive content in heartwood of E. bosistoana, which does not require milling and conditioning of the samples. This was achieved by applying the signal processing algorithms (external parameter orthogonalisation (EPO) and significance multivariate correlation (sMC)) to spectra obtained from solid wood cores, which were able to correct for moisture content, grain direction and sample form. The accuracy of extractive content predictions was further improved by variable selection, resulting in a root mean square error of 1.27%. Considering the range of extractive content in E. bosistoana heartwood of 1.3 to 15.0%, the developed NIR calibration has the potential to be used in an E. bosistoana breeding program or to assess the special variation in extractive content throughout a stem. PMID- 29524747 TI - Physiological response of Arundo donax to cadmium stress by Fourier transform infrared spectroscopy. AB - The present paper deals with the physiological response of the changes in chemical contents of the root, stem and leaf of Arundo donax seedlings stressed by excess cadmium using Fourier transform infrared spectroscopy technique, cadmium accumulation in plant by atomic absorption spectroscopy were tested after different concentrations cadmium stress. The results showed that low cadmium concentrations (<1.0mg/L) the root tissue of Arundo donax uses osmosis of organic substances (e.g. carbohydrates and amino acids) to improve cadmium tolerance. Organic substances (e.g. carbohydrates) that contain a lot of OH in leaf were transported to the root firstly and then could chelate cadmium, but no obvious changes in stems were noted. The cadmium in the shoots (stem and leaf) usually increased with increasing cadmium concentration. These studies demonstrate the potential of Fourier transform infrared spectroscopy technique for the non invasive and rapid monitoring of the plants stressed with heavy metals, Arundo donax is suitable for phytoremediation of cadmium -contaminated wetland. PMID- 29524748 TI - A methodological approach to study the stability of selected watercolours for painting reintegration, through reflectance spectrophotometry, Fourier transform infrared spectroscopy and hyperspectral imaging. AB - The aim of this work is to investigate the stability to simulated solar radiation of some paintings samples through a new methodological approach adopting non invasive spectroscopic techniques. In particular, commercial watercolours and iron oxide based pigments were used, these last ones being prepared for the experimental by gum Arabic in order to propose a possible substitute for traditional reintegration materials. Reflectance spectrophotometry in the visible range and Hyperspectral Imaging in the short wave infrared were chosen as non invasive techniques for evaluation the stability to irradiation of the chosen pigments. These were studied before and after artificial ageing procedure performed in Solar Box chamber under controlled conditions. Data were treated and elaborated in order to evaluate the sensitivity of the chosen techniques in identifying the variations on paint layers, induced by photo-degradation, before they could be observed by eye. Furthermore a supervised classification method for monitoring the painted surface changes adopting a multivariate approach was successfully applied. PMID- 29524749 TI - Differential prevalence and demographic and clinical correlates of antidepressant use in American bipolar I versus bipolar II disorder patients. AB - AIMS: Antidepressant use is controversial in bipolar disorder (BD) due to questionable efficacy/psychiatric tolerability. We assessed demographic/clinical characteristics of baseline antidepressant use in BD patients. METHODS: Prevalence and correlates of baseline antidepressant use in 503 BD I and BD II outpatients referred to the Stanford Bipolar Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. RESULTS: Antidepressant use was 39.0%, overall, and was higher in BD II versus BD I (46.9% versus 30.5%, p = 0.0002). Both BD I and BD II antidepressant compared to non-antidepressant users had higher rates of complex pharmacotherapy (>= 4 mood stabilizers, antipsychotics, and/or antidepressants) and use of other psychotropics. Antidepressant use in BD II versus BD I was higher during euthymia (44.0% vs. 28.0%) and subsyndromal symptoms (56.1% vs. 28.6%), but not depression or mood elevation. LIMITATIONS: American tertiary BD clinic referral sample receiving open naturalistic treatment. CONCLUSIONS: In our sample, antidepressant use was higher in BD II versus BD I patients, and was associated with markers of heightened illness severity in both BD I and BD II patients. Additional research is warranted to investigate these complex relationships. PMID- 29524750 TI - Determinants of access to health care for depression in 49 countries: A multilevel analysis. AB - BACKGROUND: The relative importance of individual and country-level factors influencing access to diagnosis and treatment for depression across the world is fairly unknown. METHODS: We analysed cross-national data from the WHO World Health Surveys. Depression diagnosis and access to health care were ascertained using a structured interview. Logistic Bayesian Multilevel analyses were performed to establish individual and country level factors associated with: (1) receiving a diagnosis and (2) accessing treatment for depression if a diagnosis was ascertained. RESULTS: The sample included 7870 individuals from 49 countries who met ICD-10 criteria for depressive episode in the past 12 months. A third (32%) of these individuals had ever been diagnosed with depression in their lifetime. Among those diagnosed with depression, 66% reported to have ever received treatment for depression. Although individual factors were more important determinants of access to treatment for depression, country-level factors explained 27.6% of the variance in access to diagnosis and 24.1% in access to treatment. Access to treatment for depression improved with increasing country income. Female gender, better education, the presence of physical co morbidity, more material assets, and living in urban areas were individual level determinants of better access. LIMITATIONS: Data on other contextual factors was not available. Unmet need was likely underestimated, since only lifetime treatment data was available. CONCLUSION: This study highlights major inequalities in access to a diagnosis and treatment of depression. Unlike the prevalence of depression, where contextual factors have shown to have less importance, a significant proportion of the variance in access to depression care was explained by country-level income. PMID- 29524751 TI - Generalized anxiety disorder in urban China: Prevalence, awareness, and disease burden. AB - INTRODUCTION: Limited published research has quantified the Generalized Anxiety Disorder (GAD) prevalence and its burden in China. This study aimed to fill in the knowledge gap and to evaluate the burden of GAD among adults in urban China. METHODS: This study utilized existing data from the China National Health and Wellness Survey (NHWS) 2012-2013. Prevalence of self-reported diagnosed and undiagnosed GAD was estimated. Diagnosed and undiagnosed GAD respondents were compared with non-anxious respondents in terms of health-related quality of life (HRQoL), resource utilization, and work productivity and activity impairment using multivariate generalized linear models. A multivariate logistic model assessed the risk factors for GAD. RESULTS: The prevalence of undiagnosed/diagnosed GAD was 5.3% in urban China with only 0.5% of GAD respondents reporting a diagnosis. Compared with non-anxious respondents, both diagnosed and undiagnosed GAD respondents had significantly lower HRQoL, more work productivity and activity impairment, and greater healthcare resource utilization in the past six months. Age, gender, marital status, income level, insurance status, smoking, drinking and exercise behaviors, and comorbidity burdens were significantly associated with GAD. LIMITATIONS: This was a patient reported study; data are therefore subject to recall bias. The survey was limited to respondents in urban China; therefore, these results focused on urban China and may be under- or over-estimating GAD prevalence in China. Causal inferences cannot be made given the cross-sectional nature of the study. CONCLUSIONS: GAD may be substantially under-diagnosed in urban China. More healthcare resources should be invested to alleviate the burden of GAD. PMID- 29524752 TI - Correlates of sedentary behavior in 2,375 people with depression from 6 low- and middle-income countries. AB - OBJECTIVE: Sedentary behaviour (SB) is harmful for health and well-being and may be associated with depression. However, little is known about the correlates of SB in people with depression. Thus, we investigated SB correlates among community dwelling adults with depression in six low- and middle-income countries. METHODS: Cross-sectional data from the World Health Organization's Study on Global Ageing and Adult Health were analyzed. The analysis was restricted to those with DSM-IV Depression or receiving depression treatment in the last 12 months. Self-reported time spent sedentary per day was the outcome. High SB was defined as >=8 hours of SB per day. The correlates (sociodemographic and health-related) of SB were estimated by multivariable linear and logistic regression analyses. RESULTS: In 2375 individuals with depression (mean age=48.0 years; 60.7% female), the prevalence of high SB was 11.1% (95%CI=8.2%-14.9%), while the mean (+/-SD) time spent sedentary was 215 (+/-192) minutes per day. Socio-demographic factors significantly associated with high SB were older age and being unmarried, being male and being unemployed. In other domains, no alcohol consumption, current smoking, mild cognitive impairment, bodily pain, arthritis, stroke, disability, and lower levels of social cohesion, COPD, visual impairment, and poor self-rated health was associated with greater time spent sedentary. CONCLUSION: Our data suggest that future interventions seeking to reduce SB among individuals with depression may target at risk groups based on identified sociodemographic correlates while the promotion of social cohesion may have the potential to increase the efficacy of future public health initiatives. From a clinical perspective, bodily pain and somatic co-morbidities need to be taken into account. PMID- 29524753 TI - Nature of bonding and cooperativity in linear DMSO clusters: A DFT, AIM and NCI analysis. AB - This study aims to cast light on the nature of interactions and cooperativity that exists in linear dimethyl sulfoxide (DMSO) clusters using dispersion corrected density functional theory. In the linear DMSO, DMSO molecules in the middle of the clusters are bound strongly than at the terminal. The plot of the total binding energy of the clusters vs the cluster size and mean polarizabilities vs cluster size shows an excellent linearity demonstrating the presence of cooperativity effect. The computed incremental binding energy of the clusters remains nearly constant, implying that DMSO addition at the terminal site can happen to form an infinite chain. In the linear clusters, two sigma-hole at the terminal DMSO molecules were found and the value on it was found to increase with the increase in cluster size. The quantum theory of atoms in molecules topography shows the existence of hydrogen and SO?S type in linear tetramer and larger clusters. In the dimer and trimer SO?OS type of interaction exists. In 2D non-covalent interactions plot, additional peaks in the regions which contribute to the stabilization of the clusters were observed and it splits in the trimer and intensifies in the larger clusters. In the trimer and larger clusters in addition to the blue patches due to hydrogen bonds, additional, light blue patches were seen between the hydrogen atom of the methyl groups and the sulphur atom of the nearby DMSO molecule. Thus, in addition to the strong H bonds, strong electrostatic interactions between the sulphur atom and methyl hydrogens exists in the linear clusters. PMID- 29524754 TI - Bond strength enhancement of zirconia-porcelain interfaces via Nd:YAG laser surface structuring. AB - OBJECTIVES: The aim of this study was to evaluate the effect of laser surface structuring on the bond strength of feldspar-based porcelain to zirconia, as compared to conventional sandblasting treatment. MATERIALS AND METHODS: Thirty cylindrical zirconia substrates, previously sintered, were divided in three groups according to the type of surface conditioning: 1) sandblasting with 50 um Al2O3; 2) laser structuring (O25 um holes); and 3) laser structuring (O50 um holes). Porcelain was injected onto the zirconia substrates. X-ray diffractometry (XRD) was used to evaluate the influence of the laser treatment on zirconia crystallographic phases. Shear bond strength test was performed. Micrographs using SEM were used to evaluate the zirconia surface after each surface treatment and to evaluate the fracture surface after the shear test. RESULTS: The laser structured groups presented the highest shear bond strength (65 +/- 16 MPa and 65 +/- 11 MPa, for the 25 um and 50 um holes, respectively). The sandblasting samples presented shear bond strength of 37 +/- 16 MPa. XRD analysis showed that there was no phase transformation on the thermally affected surface due to laser action. Microcracks were created at some holes due to the high temperature gradient generated by laser. SIGNIFICANCE: Laser structuring significantly increased (up to 75%) the shear bond strength of zirconia to veneering porcelain as compared to conventional sandblasting treatment. Therefore, laser structuring arises as a surface conditioning method for producing stronger and long lasting zirconia-porcelain interfaces. PMID- 29524755 TI - Effects of sterilization on the mechanical properties of poly(methyl methacrylate) based personalized medical devices. AB - BACKGROUND: Nowadays, personalized medical devices are frequently used for patients. Due to the manufacturing procedure sterilization is required. How different sterilization methods affect the mechanical behavior of these devices is largely unknown. MATERIALS AND METHODS: Three poly(methyl methacrylate) (PMMA) based materials (Vertex Self-Curing, Palacos R+G, and NextDent C&B MFH) were sterilized with different sterilization methods: ethylene oxide, hydrogen peroxide gas plasma, autoclavation, and gamma-irradiation. Mechanical properties were determined by testing the flexural strength, flexural modulus, fracture toughness, and impact strength. RESULTS: The flexural strength of all materials was significantly higher after gamma-irradiation compared to the control and other sterilization methods, as tested in a wet environment. NextDent C&B MFH showed the highest flexural and impact strength, Palacos R+G showed the highest maximum stress intensity factor and total fracture work. CONCLUSION: Autoclave sterilization is not suitable for the sterilization of PMMA-based materials. Ethylene oxide, hydrogen peroxide gas plasma, and gamma-irradiation appear to be suitable techniques to sterilize PMMA-based personalized medical devices. PMID- 29524756 TI - Quantification of glutathione transverse relaxation time T2 using echo time extension with variable refocusing selectivity and symmetry in the human brain at 7 Tesla. AB - Glutathione (GSH) is an endogenous antioxidant implicated in numerous biological processes, including those associated with multiple sclerosis, aging, and cancer. Spectral editing techniques have greatly facilitated the acquisition of glutathione signal in living humans via proton magnetic resonance spectroscopy, but signal quantification at 7 Tesla is still hampered by uncertainty about the glutathione transverse decay rate T2 relative to those of commonly employed quantitative references like N-acetyl aspartate (NAA), total creatine, or water. While the T2 of uncoupled singlets can be derived in a straightforward manner from exponential signal decay as a function of echo time, similar estimation of signal decay in GSH is complicated by a spin system that involves both weak and strong J-couplings as well as resonances that overlap those of several other metabolites and macromolecules. Here, we extend a previously published method for quantifying the T2 of GABA, a weakly coupled system, to quantify T2 of the strongly coupled spin system glutathione in the human brain at 7 Tesla. Using full density matrix simulation of glutathione signal behavior, we selected an array of eight optimized echo times between 72 and 322 ms for glutathione signal acquisition by J-difference editing (JDE). We varied the selectivity and symmetry parameters of the inversion pulses used for echo time extension to further optimize the intensity, simplicity, and distinctiveness of glutathione signals at chosen echo times. Pairs of selective adiabatic inversion pulses replaced nonselective pulses at three extended echo times, and symmetry of the time intervals between the two extension pulses was adjusted at one extended echo time to compensate for J-modulation, thereby resulting in appreciable signal-to-noise ratio and quantifiable signal shapes at all measured points. Glutathione signal across all echo times fit smooth monoexponential curves over ten scans of occipital cortex voxels in nine subjects. The T2 of glutathione was calculated to be 145.0 +/- 20.1 ms (mean +/- standard deviation); this result was robust within one standard deviation to changes in metabolite fitting baseline corrections and removal of individual data points on the signal decay curve. The measured T2 of NAA (222.1 +/- 24.7 ms) and total creatine (153.0 +/- 19.9 ms) were both higher than that calculated for GSH. Apparent glutathione concentration quantified relative to both reference metabolites increased by up to 32% and 6%, respectively, upon correction with calculated T2 values, emphasizing the importance of considering T2 relaxation differences in the spectroscopic measurement of these metabolites, especially at longer echo times. PMID- 29524757 TI - High-precision measurement of the electron spin g factor of trapped atomic nitrogen in the endohedral fullerene N@C60. AB - The electronic g factor carries highly useful information about the electronic structure of a paramagnetic species, such as spin-orbit coupling and dia- or paramagnetic (de-)shielding due to local fields of surrounding electron pairs. However, in many cases, a near "spin-only" case is observed, in particular for light elements, necessitating accurate and precise measurement of the g factors. Such measurement is typically impeded by a "chicken and egg situation": internal or external reference standards are used for relative comparison of electron paramagnetic resonance (EPR) Larmor frequencies. However, the g factor of the standard itself usually is subject to a significant uncertainty which directly limits the precision and/or accuracy of the sought after sample g factor. Here, we apply an EPR reference-free approach for determining the g factor of atomic nitrogen trapped within the endohedral fullerene C60:N@C60 in its polycrystalline state by measuring the 1H NMR resonance frequency of dispersing toluene at room temperature. We found a value of g=2.00204(4) with a finally reached relative precision of ~20 ppm. This accurate measurement allows us to directly compare the electronic properties of N@C60 to those found in atomic nitrogen in the gas phase or trapped in other solid matrices at liquid helium temperature. We conclude that spin-orbit coupling in N@C60 at room temperature is very similar in magnitude and of same sign as found in other inert solid matrices and that interactions between the quartet spin system and the C60 molecular orbitals are thus negligible. PMID- 29524758 TI - A presentation of ulcerative colitis after rituximab therapy in a patient with multiple sclerosis and literature review. AB - Multiple sclerosis (MS) is one of the most important demyelinating diseases that affects the central nervous system. Its treatment often involves a long-term disease modifying therapy. According to some studies, the prevalence of autoimmune disorders, such as autoimmune hepatitis (AIH) and ulcerative colitis (UC) is higher in MS patients than in the normal population. There are also few studies that have reported the onset of UC after rituximab therapy. The present study presents a report of a 31-years old female patient suffering from aggressive multiple sclerosis, which developed into autoimmune hepatitis during the MS therapy. Thereafter, she received rituximab for the treating both MS and AIH. One week after the third cycle of rituximab (6 doses of 1000 mg), she experienced abdominal pain, fever, and severe bloody diarrhea; finally, she was diagnosed with ulcerative colitis (UC). It seems that the administration of certain immunomodulators or immunosuppressive drugs may have a main role in the exacerbation of some autoimmune diseases. PMID- 29524759 TI - Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: A multicenter retrospective observational study (STRATEGY). AB - BACKGROUND: Delayed-release dimethyl fumarate (DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding predictors of favorable treatment outcomes in patients switching from natalizumab to DMF. Clinical practices and sequencing protocols vary. Herein, we present the clinical results, including annualized relapse rate (ARR) and risk of relapse, of a phase 4 retrospective observational study of patients with RRMS who switched from natalizumab to DMF in a community practice setting (STRATEGY). METHODS: STRATEGY was performed through a single time point medical record abstraction; no study visits or procedures were required. Key inclusion criteria included age >= 18 years, RRMS diagnosis (McDonald criteria, 2010 revised), >= 12 months of continuous treatment with natalizumab monotherapy before DMF initiation, and initiation of DMF >= 12 months before enrollment. Patients were eligible to enroll regardless of current DMF use. RESULTS: A total of 530 patients at 45 US sites enrolled, and 506 met the inclusion criteria and were included in the modified evaluable population for analysis. Mean (SD) age at DMF initiation was 47.0 (10.9) years, with a mean (SD) of 12.7 (7.2) years since MS diagnosis. The mean (SD) duration of natalizumab treatment was 3.4 (1.9) years, and the mean (SD) washout from natalizumab discontinuation to DMF initiation (n = 502) was 101.6 (164.0) days. Overall risk of relapse 12 months after DMF initiation was 19.6%. Overall unadjusted ARR was higher during the 12 months following initiation of DMF treatment compared with the 12 months following initiation of natalizumab treatment (rate ratio, 2.32 [95% CI, 1.69 3.18]; p < 0.0001), but was lower compared with that observed in the year before initiation of natalizumab (rate ratio, 0.51 [95% CI, 0.40-0.64]; p < 0.0001). At 1 year following initiation of DMF treatment, the relapse rate was lower for patients who did not experience a relapse during 1 year following initiation of natalizumab treatment than for those who did (rate ratio for relapse rate, 0.47 [95% CI, 0.16-1.38]; p = 0.1664). The relapse rate for patients who did not relapse during natalizumab treatment was significantly lower with a washout period of <= 90 days as compared with a washout period of > 90 days (rate ratio for relapse rate, 0.49 [95% CI, 0.26-0.90]; p = 0.0216). A total of 42 (8%) patients reported >= 1 adverse event leading to DMF discontinuation during the study; the most commonly reported events were gastrointestinal disorders (n = 21; 4%). CONCLUSIONS: Results from this multicenter retrospective observational study suggest that DMF may be an effective treatment option for patients who discontinue natalizumab in routine clinical practice. ARR was lower in patients who initiated DMF within 90 days of natalizumab discontinuation compared with patients who initiated DMF after 90 days of natalizumab discontinuation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02159573. PMID- 29524760 TI - New clinical implications of anti-myelin oligodendrocyte glycoprotein antibodies in children with CNS demyelinating diseases. AB - Acquired demyelinating CNS syndromes include a broad spectrum of clinical phenotypes and different entities can overlap. Therefore, differential diagnosis is still challenging. A humoral immune reaction against myelin oligodendrocyte glycoprotein (MOG) is present in a subgroup of these patients, particularly in children. Anti-MOG antibodies indicate a non-multiple sclerosis disease course. Indeed, early publications have suggested that anti-MOG antibodies argue for a monophasic course; recently an association with a high risk for recurrent non-MS disease has been shown. According new data, antibody analysis was included in a diagnostic algorithm for the diagnosis of acquired demyelinating CNS syndromes in children. Here, recent data from the implementation of anti-MOG antibodies in daily clinical practice are reviewed. PMID- 29524761 TI - The recognition of child abuse and the perceived need for intervention by school personnel of primary schools: Results of a vignette study on the influence of case, school personnel, and school characteristics. AB - In 2015, 523 reports of suspected child abuse and neglect (CAN) were brought to the attention of the Confidential Center of Child Abuse and Neglect (CCCAN) of Brussels. Around 38% of these reports came from school personnel. This study investigated which factors affect the recognition of CAN by school personnel of Dutch-speaking primary education in Brussels and their intervention need. Two hundred seventy-nine staff members of 16 schools professionally working with children, filled in a Questionnaire Assessment of Situations of CAN. The instrument consists of 24 vignettes describing CAN. Respondents were asked questions regarding recognition and intervention need about each vignette. Detection, severity assessment, the need for professional help, the need for referral to a CCCAN and the need to involve judicial authorities were mainly associated with case characteristics. Although most situations of CAN were detected, situations of emotional abuse were less often recognized. Situations involving non-Western victims were considered to be more severe and the perceived need for involvement of professional help, CCCAN and judicial authorities was larger. Ethnic stereotypes affect the actions undertaken in case of CAN. Awareness of these reactions may result in equal treatment for all victims. Staff characteristics were little associated with detection and intervention need. PMID- 29524762 TI - Urbanicity matters in self-reported child maltreatment prevalence: Findings from a nationally representative study. AB - Despite indications that there are differences in rates of child maltreatment (CM) cases in the child protection system between urban and rural areas, there are no published studies examining the differences in self-reported CM prevalence and its correlates by urbanicity. The present study aimed to: (1) identify the distribution of self-reported childhood experiences of maltreatment by urbanicity, (2) assess whether differences by urbanicity persist after adjusting for known risk factors, and (3) explore whether the associations between these risk factors and CM are modified by urban-rural designation. Using nationally representative data from waves I and III of the National Longitudinal Study of Adolescent to Adult Health, the prevalence of six maltreatment outcomes was estimated for rural, minor urban, and major urban areas (N = 14,322). Multivariable logistic models were estimated identifying if risk associated with urbanicity persisted after adjusting for other risk factors. Interactions between urbanicity and main effects were explored. Prevalence estimates of any CM, poly victimization, supervision neglect, and physical abuse were significantly higher in major urban areas. Those from major urban areas were more likely to report any maltreatment and supervision neglect even after adjusting for child and family risk factors. The association between race/ethnicity, welfare receipt, low parental educational attainment, and disability status and CM were modified by urbanicity. Significant differences in the prevalence and correlates of CM exist between urban and rural areas. Future research and policy should use self reported prevalence, in conjunction with official reports, to inform child maltreatment prevention and intervention. PMID- 29524763 TI - Glucocorticoid-endocannabinoid uncoupling mediates fear suppression deficits after early - Life stress. AB - Early-life stress (ELS) creates life-long vulnerability to stress-related anxiety disorders through altering stress and fear systems in the brain. The endocannabinoid system has emerged as an important regulator of the stress response through a crosstalk with the glucocorticoid system, yet whether it plays a role in the persistent effects of ELS remains unanswered. By combining, behavioral, pharmacological and biochemical approaches in adult male rats, we examined the impact of ELS on the regulation of endocannabinoid function by stress and glucocorticoids. We employed a postnatal limited-nesting/bedding induced ELS between postnatal days 2-9 in rats. Exposure to postnatal ELS compromised the ability of both acute stress and glucocorticoid administration to mobilize the endocannabinoid ligand 2-arachidonoyl glycerol (2-AG) in the hippocampus of adult male rats. These findings suggest that ELS compromises the coupling of the glucocorticoid and endocannabinoid systems in the hippocampus. Since 2-AG signaling is essential in mediating glucocorticoid-induced suppression of fear recall, we further examined the impact of ELS on the ability of glucocorticoids to suppress fear memory recall. While ELS did not affect normative fear recall, it impaired the ability of glucocorticoids to dampen fear recall. Notably, bypassing glucocorticoids and directly amplifying hippocampal 2 AG signaling with a monoacyl glycerol lipase inhibitor produced a suppression of fear memory recall in animals exposed to ELS. These findings suggest that ELS results in an uncoupling of glucocorticoid-endocannabinoid signaling in the hippocampus, which, in turn, relates to alterations in stress regulation of memory recall. These data provide compelling evidence that ELS-induced deficits in the glucocorticoid-endocannabinoid coupling following stress could predispose susceptibility to stress-related psychopathology. PMID- 29524764 TI - Non-monotonic convergence of online learning algorithms for perceptrons with noisy teacher. AB - Learning curves of simple perceptron were derived here. The learning curve of the perceptron learning with noisy teacher was shown to be non-monotonic, which has never appeared even though the learning curves have been analyzed for half a century. In this paper, we showed how this phenomenon occurs by analyzing the asymptotic property of the perceptron learning using a method in systems science, that is, calculating the eigenvalues of the system matrix and the corresponding eigenvectors. We also analyzed the AdaTron learning and the Hebbian learning in the same way and found that the learning curve of the AdaTron learning is non monotonic whereas that of the Hebbian learning is monotonic. PMID- 29524765 TI - Neural robust stabilization via event-triggering mechanism and adaptive learning technique. AB - The robust control synthesis of continuous-time nonlinear systems with uncertain term is investigated via event-triggering mechanism and adaptive critic learning technique. We mainly focus on combining the event-triggering mechanism with adaptive critic designs, so as to solve the nonlinear robust control problem. This can not only make better use of computation and communication resources, but also conduct controller design from the view of intelligent optimization. Through theoretical analysis, the nonlinear robust stabilization can be achieved by obtaining an event-triggered optimal control law of the nominal system with a newly defined cost function and a certain triggering condition. The adaptive critic technique is employed to facilitate the event-triggered control design, where a neural network is introduced as an approximator of the learning phase. The performance of the event-triggered robust control scheme is validated via simulation studies and comparisons. The present method extends the application domain of both event-triggered control and adaptive critic control to nonlinear systems possessing dynamical uncertainties. PMID- 29524766 TI - Inter-class sparsity based discriminative least square regression. AB - Least square regression is a very popular supervised classification method. However, two main issues greatly limit its performance. The first one is that it only focuses on fitting the input features to the corresponding output labels while ignoring the correlations among samples. The second one is that the used label matrix, i.e., zero-one label matrix is inappropriate for classification. To solve these problems and improve the performance, this paper presents a novel method, i.e., inter-class sparsity based discriminative least square regression (ICS_DLSR), for multi-class classification. Different from other methods, the proposed method pursues that the transformed samples have a common sparsity structure in each class. For this goal, an inter-class sparsity constraint is introduced to the least square regression model such that the margins of samples from the same class can be greatly reduced while those of samples from different classes can be enlarged. In addition, an error term with row-sparsity constraint is introduced to relax the strict zero-one label matrix, which allows the method to be more flexible in learning the discriminative transformation matrix. These factors encourage the method to learn a more compact and discriminative transformation for regression and thus has the potential to perform better than other methods. Extensive experimental results show that the proposed method achieves the best performance in comparison with other methods for multi-class classification. PMID- 29524767 TI - Target capture enrichment of nuclear SNP markers for massively parallel sequencing of degraded and mixed samples. AB - DNA from biological forensic samples can be highly fragmented and present in limited quantity. When DNA is highly fragmented, conventional PCR based Short Tandem Repeat (STR) analysis may fail as primer binding sites may not be present on a single template molecule. Single Nucleotide Polymorphisms (SNPs) can serve as an alternative type of genetic marker for analysis of degraded samples because the targeted variation is a single base. However, conventional PCR based SNP analysis methods still require intact primer binding sites for target amplification. Recently, probe capture methods for targeted enrichment have shown success in recovering degraded DNA as well as DNA from ancient bone samples using next-generation sequencing (NGS) technologies. The goal of this study was to design and test a probe capture assay targeting forensically relevant nuclear SNP markers for clonal and massively parallel sequencing (MPS) of degraded and limited DNA samples as well as mixtures. A set of 411 polymorphic markers totaling 451 nuclear SNPs (375 SNPs and 36 microhaplotype markers) was selected for the custom probe capture panel. The SNP markers were selected for a broad range of forensic applications including human individual identification, kinship, and lineage analysis as well as for mixture analysis. Performance of the custom SNP probe capture NGS assay was characterized by analyzing read depth and heterozygote allele balance across 15 samples at 25 ng input DNA. Performance thresholds were established based on read depth >=500X and heterozygote allele balance within +/-10% deviation from 50:50, which was observed for 426 out of 451 SNPs. These 426 SNPs were analyzed in size selected samples (at <=75 bp, <=100 bp, <=150 bp, <=200 bp, and <=250 bp) as well as mock degraded samples fragmented to an average of 150 bp. Samples selected for <=75 bp exhibited 99-100% reportable SNPs across varied DNA amounts and as low as 0.5 ng. Mock degraded samples at 1 ng and 10 ng exhibited >90% reportable SNPs. Finally, two-person male-male mixtures were tested at 10 ng in contributor varying ratios. Overall, 85-100% of alleles unique to the minor contributor were observed at all mixture ratios. Results from these studies using the SNP probe capture NGS system demonstrates proof of concept for application to forensically relevant degraded and mixed DNA samples. PMID- 29524768 TI - Assessing the functionality and genetic diversity of lactococcal prophages. AB - Lactococcus lactis is a lactic acid bacterium that is intensively and globally exploited in commercial dairy food fermentations. Though the presence of prophages in lactococcal genomes is widely reported, only limited studies pertaining to the stability of prophages in lactococcal genomes have been performed. The current study reports on the complete genome exploration of thirty lactococcal strains for the presence of potentially intact prophages, so as to assess their genomic diversity and the associated risk or benefit of harbouring such prophages. Genomic predictions partnered with mitomycin C inductions and flow cytometric analysis of the induced cell lysates confirmed that only four strains consistently produced intact phage particles, thus indicating a relatively low risk associated with prophage induction in the fermentation setting. Our analysis revealed the widespread presence of putative phage resistance systems encoded by lactococcal prophages, thus highlighting the potential benefits for host fitness. Many of the identified lactococcal prophages belong to the so-called P335 phage group, while a large group of phage remnants bear similarity to members of the 936 phage group. The P335 phage group was recently shown to encompass four distinct genetic lineages. Our study identified an additional lineage, thus expanding the diversity of this industrially significant phage group. PMID- 29524769 TI - Exposure to antimicrobial-resistant Escherichia coli through the consumption of ground beef in Western Canada. AB - Emergence and dissemination of antimicrobial resistance (AMR) in food-borne bacteria is a public health issue. Retail meat is considered an important carrier for antimicrobial-resistant Escherichia coli. Currently, resistance of E. coli strains to third generation cephalosporins are of particular concern, with significant potential animal and public health consequences. Resistance to tetracyclines is also a concern, due to high prevalence of this resistance and important co-resistance patterns. However, the actual likelihood of exposure to antimicrobial-resistant bacteria via the consumption of retail meats, beyond the simple frequencies of resistance found in samples of meat at the grocery store, in Canada remains to be investigated. This study was conducted to estimate the potential human exposure to ceftriaxone- and tetracycline-resistant E.coli (CREC and TREC; the hazards of interest) through the consumption of ground beef in Western Canada. Our exposure assessment simulation model included five modules: 1) estimation of prevalence and concentration of the hazards of interest in retail ground beef samples collected by the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS), 2011-2014; 2) potential growth of the hazards during transportation from retail to home; 3) potential growth or reduction of the hazards during home storage; 4) thermal inactivation of the hazards due to cooking; and 5) consumption. The outputs of the model were presented as the probability of consumers' exposure to various threshold levels of the hazards [10 to 106 colony forming units (CFU)] in one serving of cooked ground beef. Overall, the probabilities of exposure to high threshold levels of the hazards (>4 log10 CFU/serving) were estimated to be lower than 0.12% in the study population (2011-2014). The mean probabilities of exposure to at least 1 log10 CFU CREC and TREC in a single meal containing cooked ground beef were 0.067% (SD: 0.001%) and 1.20% (SD: 0.02%), respectively. This probability substantially decreased as the threshold level of exposure increased to >=6 log10 CFU. The probability of exposure to TREC was consistently greater than that for CREC. Cooking led to a prominent drop in the mean concentration of the hazards (4.7 log10 CFU/g). The findings from this research could inform the policy-making process and provide suggestions for adjustments in future retail surveillance plans. In addition, important knowledge gaps in this area have been highlighted. PMID- 29524770 TI - Following-up skin penetration of lidocaine from different vehicles by Raman spectroscopic mapping. AB - The application of local anesthetics, usually administered by subcutaneous injection, is common in the course of diagnostic, therapeutic, and cosmetic dermatology procedures. The effective dermal delivery of lidocaine could offer a solution to many adverse effects caused by needle insertion, such as pain, local reactions or toxicity, and additionally, it avoids the disruption of anatomical landmarks. Therefore, novel dermal formulations of local anesthetics are needed to overcome the barrier function of the skin and provide sufficient and prolonged anesthesia. In our study, we aimed to investigate and compare the penetration profiles of four different lidocaine containing formulations (hydrogel, oleogel, lyotropic liquid crystal and nanostructured lipid carrier) by Raman microscopic mapping of the drug. The application of Raman spectroscopy provided information about the spatial distribution of lidocaine in the skin ex vivo. The penetration of lidocaine from lyotropic liquid crystal and nanostructured carrier reached deeper skin layers and a higher amount of the drug was diffused into the skin, compared with hydrogel and oleogel. This study confirmed that nanostructured carriers can improve skin penetration properties of lidocaine and proved the applicability of Raman spectroscopy in the research of dermatological preparations ex vivo as a nondestructive, relatively easy and fast technique. PMID- 29524771 TI - Proposal of degradation pathway with toxicity prediction for hydrolytic and photolytic degradation products of timolol. AB - Timolol (TIM) is a potent beta-adrenergic blocker, useful in treatment of ocular hypertension or open-angle glaucoma. Development and validation of stability indicating LCMS assay method for TIM was accomplished coherent with ICH guideline. Successful chromatographic separation of TIM with its four degradation products was attained by using gradient elution mode on reverse phase column using ammonium acetate buffer, pH 4.6 as mobile phase A and organic solvent as the mobile phase B. Chromatographic conditions were set such as 1.0 mL min-1 flow rate, 20 MUL injection volume, 30 degrees C column temperature and 320 nm detection wavelength. Four major degradation products obtained from hydrolysis and photolysis, were identified and characterized with the combination of liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS/MS) and accurate mass measurements. Degradation pathways were identified based on a comparison of the fragmentation pattern of the [M+H]+ ions of TIM and its degradation products. The method validation was performed as per ICH guideline Q2 (R1). PMID- 29524772 TI - 'A worse nightmare than expected' - a Swedish qualitative study of women's experiences two months after obstetric anal sphincter muscle injury. AB - OBJECTIVE: this study explores women's experiences of the first two months after obstetric anal sphincter injury (OASIS) during childbirth with a focus on problematic recovery. METHODS: this qualitative study used inductive qualitative content analysis to investigate open-ended responses from 1248 women. The data consists of short and comprehensive written responses to open-ended questions focusing on recovery in the national quality register, the Perineal Laceration Register, two months after OASIS at childbirth. RESULTS: the theme 'A worse nightmare than expected' illustrated women's experiences of their life situation. Pain was a constant reminder of the trauma, and the women had to face physical and psychological limitations as well as crushed expectations of family life. Furthermore, navigating healthcare services for help added further stress to an already stressful situation. CONCLUSIONS: we found that women with problematic recovery two months after OASIS experienced their situation as a worse nightmare than expected. Extensive pain resulted in physical and psychological limitations, and crushed expectations of family life. Improved patient information for women with OASIS regarding pain, psychological and personal aspects, sexual function, and subsequent pregnancy delivery is needed. Also, there is a need for clear organizational structures and information to guide help-seeking women to needed care. PMID- 29524773 TI - Antidepressants during pregnancy: Guideline adherence and current practice amongst Dutch gynaecologists and midwives. AB - BACKGROUND AND OBJECTIVES: prescription rates of antidepressants during pregnancy range from 2-3% in The Netherlands to 6.2% in the USA. Inconclusive evidence about harms and benefits of antidepressants during pregnancy leads to variation in advice given by gynaecologists and midwives. The objective was to investigate familiarity with, and adherence to the Dutch multidisciplinary guideline on Selective Serotonin Reuptake Inhibitor (SSRI) use during pregnancy by gynaecologists and midwives in the Netherlands. METHODS: an online survey was developed and send to Dutch gynaecologists and midwives. The survey consisted mainly of multiple-choice questions addressing guideline familiarity and current practice of the respondent. Also, caregiver characteristics associated with guideline adherence were investigated. FINDINGS: a total of 178 gynaecologists and 139 midwives responded. Overall familiarity with the Dutch guideline was 92.7%. However, current practice and advice given to patients by caregivers differed substantially, both between gynaecologists and midwives as well as within both professions. Overall guideline adherence was 13.9%. Multivariable logistic regression showed that solely caregiver profession was associated with guideline adherence, with gynaecologists having a higher adherence rate (OR 2.10, 95%CI 1.02-4.33) than midwives. KEY CONCLUSION: although reported familiarity with the guideline is high, adherence to the guideline is low, possibly resulting in advice to patients that is inconsistent with guidelines and unwanted variation in current practice. IMPLICATIONS FOR PRACTICE: further implementation of the recommendations as given in the guideline should be stimulated. Additional research is needed to examine how gynaecologists and midwives can be facilitated to follow the recommendations of the clinical guideline on SSRI use during pregnancy. PMID- 29524774 TI - Teaching Guatemalan traditional birth attendants about obstetrical emergencies. AB - INTRODUCTION: Guatemala's Maternal Mortality Rate is 65th highest in the world at 120 deaths per 100,000 births. Contributing to the problem is traditional birth attendants (TBAs) attend most births yet lack knowledge about obstetrical emergencies. Government trainings in existence since 1955 have not changed TBA knowledge. Government trainings are culturally insensitive because they are taught in Spanish with written material, even though most TBAs are illiterate and speak Mayan dialects. The purpose of the observational study was to evaluate the effect of an oral training, that was designed to be culturally sensitive in TBAs' native language, on TBAs' knowledge of obstetrical emergencies. METHODS: one hundred ninety-one TBAs participated. The study employed a pretest-posttest design. A checklist was used to compare TBAs' knowledge of obstetrical emergencies before and after the training. FINDINGS: the mean pretest score was 5.006+/-SD 0.291 compared to the mean posttest score of 8.549+/-SD 0.201. Change in knowledge was a P value of 0.00. DISCUSSION: results suggest an oral training that was designed to be culturally sensitive in the native language improved TBAs' knowledge of obstetrical emergencies. Future trainings should follow a similar format to meet the needs of illiterate audiences in remote settings. PMID- 29524775 TI - Achieving competency in vaginal examinations: The challenge of balancing student learning needs with best practice in maternity care. AB - Assessment of labor progress through vaginal digital examination (VE) remains one of the most challenging skills for midwifery students. As VE during labor has become a less frequent occurrence there are less opportunities for student midwives to gain mastery of the skill. Best practices for teaching and evaluating VE involve a step-wise, multi modal approach. More research is needed on how to standardize teaching for this essential skill. PMID- 29524776 TI - Study circles in hospitals' obstetrics centers as a teaching-learning strategy in midwifery education. AB - We describe the experience of study circles on the theme 'good obstetrics practices backed by scientific evidence' and argue that they prepared midwifery students to dialogue with hospital staff and empowered them in the process of negotiating the implementation of practices put forward by the International Confederation of Midwives (ICM). We conclude that study circles are an efficient strategy of preparing midwifery students to be active participants in the maternity care team and lead discussions of evidenced-based practice. PMID- 29524777 TI - Ketogenic diet therapy in infants less than two years of age for medically refractory epilepsy. AB - PURPOSE: The Ketogenic Diet (KD) is a well-established treatment for epilepsy in children and adults. We describe our 10-year KD experience in children less than two years of age diagnosed with medically refractory epilepsy. METHODS: We conducted a retrospective case-note review of infants managed with KD at our centre between 2006 and 2016. RESULTS: Twenty-nine children between 21/2 weeks and 23 months of age were identified, with mixed epilepsy aetiologies. Ninety three percent had daily seizures and 82% were on two or more anti-epilepsy drugs (AEDs) at the time of KD commencement. KD was continued for more than four weeks in 86%. Based on a combination of parental reports, hospital observations and seizure diaries, two of 29 became seizure free, seven demonstrated >50% seizure reduction, and eight showed a decrease in seizure intensity/frequency. No adverse effects were observed in 45% patients, and dietary therapy was stopped in only two because of poor tolerability. CONCLUSION: We conclude that KD can be utilised and is generally well tolerated in infants with severe epilepsies. In addition, our experience suggests efficacy with improved seizure frequency/severity in around 50% without adverse effects on developmental outcome. PMID- 29524778 TI - Squamocin induce histological and ultrastructural changes in the midgut cells of Anticarsia gemmatalis (Lepidoptera: Noctuidae). AB - Annonaceous acetogenins (Annona squamosa Linnaeus) comprises of a series of natural products which are extracted from Annonaceae species, squamocin proved to be highly efficient among those agents. Squamocin is mostly referred as a lethal agent for midgut cells of different insects, with toxic effects when tested against larva of some insects. In present study, LC50 and LC90 of squamocin for A. gemmatalis Hubner (Lepidoptera: Noctuidae) were calculated using probit analysis. Morphological changes in midgut cells were analyzed under light, fluorescence and transmission electron microscopes when larvae were treated with LC50 and LC90 of squamocin for 24, 48 and 72 h. Results revealed that the maximum damage to midgut cells was found under LC90 where it showed digestive cells with enlarged basal labyrinth, highly vacuolated cytoplasm, damaged apical surface, cell protrusions to the gut lumen, autophagy and cell death. The midgut goblet cells showed a strong disorganization of their microvilli. Likewise, in insects treated with squamocin, mitochondria were not marked with Mitotracker fluorescent probe, suggesting some molecular damage in these organelles, which was reinforced by decrease in the respiration rate in these insects. These results demonstrate that squamocin has potential to induce enough morphological changes in midgut through epithelial cell damage in A. gemmatalis. PMID- 29524779 TI - Transcriptomic analyses of tributyltin-induced sexual dimorphisms in rare minnow (Gobiocypris rarus) brains. AB - The brain of fish displays sexual dimorphisms and exhibits remarkable sexual plasticity throughout their life span. Although reproductive toxicity of tributyltin (TBT) in fish is well documented in fish, it remains unknown whether TBT interrupts sexual dimorphisms of fish brains. In this work, brain transcriptomic profiles of rare minnow (Gobiocypris rarus) was characterized and sex-biased genes were identified using RNA sequencing. Functional annotation and enrichment analysis were performed to reveal differences of gene products and pathways between the brains of male and female fish. Furthermore, transcriptomic responses of male and female brains to TBT at 10 ng/L were also investigated to understand effects of TBT on brain sexual dimorphisms. Only 345 male-biased and 273 female-biased genes were found in the brains. However, significant female biased pathways of circadian rhythm and phototransduction were identified in the brains by enrichment analysis. Interestingly, following TBT exposure in the female fish, the circadian rhythm pathway was significantly disrupted based on enrichment analysis, while in the male fish, the phototransduction pathway was significantly disrupted. In the female fish, expression of genes (Per, Cry, Rev Erb alpha, Ror, Dec and CK1delta/epsilon) in the circadian rhythm pathway was down-regulated after TBT exposure; while in the male fish, expression of genes (Rec, GNAT1_2, GNGT1, Rh/opsin, PDE and Arr) in the phototransduction pathway was up-regulated after TBT exposure. Overall, our results not only provide key data on the molecular basis of brain sexual dimorphisms in fish, but also offer valuable resources for investigating molecular mechanisms by which environmental chemicals might influence brain sexual plasticity. PMID- 29524780 TI - Exposure to chlorpyrifos induces morphometric, biochemical and lipidomic alterations in green beans (Phaseolus vulgaris). AB - Chlorpyrifos (CPF) is a worldwide used pesticide that raises concerns from the environmental and human health perspectives. The presence of pesticides such as CPF in edible vegetables has been already reported, but little is known about the effects induced by this pesticide stress on the morphology, oxidative response and lipid composition of treated plants. In this work, green bean plants (Phaseolus vulgaris) were exposed to increasing concentrations of CPF and the different plant parts (roots, stem bases, stem, leaves, pods and beans) were subjected to different analyses. First, morphometric parameters and the oxidative response caused by CPF were explored. In a second phase of the study, an untargeted lipidomic analysis of the different tissue extracts was performed and MALDI-TOF mass spectrometry images of pods and beans were recorded and analysed to illustrate the spatial distribution of the changes observed. As a result of CPF treatment, plants showed a significant decrease in their height, leaf length, and pod number. The biochemical analysis showed lipid peroxidation and the activation of antioxidant mechanisms in roots, stem and leaves. Regarding the lipidomic results, changes in lipid levels were observed, mainly in leaves, pods and seeds. The main changes observed were a reduction of photosynthetic pigments and lipids in leaves and a decrease of triacylglycerols levels in pods and seeds. This last point was confirmed by the analysis of mass spectrometry images of the pods. These observations suggest that CPF would affect the yield of green bean crops as well as the nutritional value of pods and beans. This work represents a step forward in the knowledge of the effects of CPF, one of the most used pesticides worldwide, in plants. PMID- 29524781 TI - Effects of a herbicide and copper mixture on the quality of marine plankton. AB - Pesticides and metals are often used in agriculture and are therefore often simultaneously discharged to nearby estuarine and marine areas. The effects of this organic-inorganic chemical mixture on food quality of aquatic organisms are currently unknown. In this study we test if a mixture of copper (inorganic) and the herbicide Primextra(r) Gold TZ (organic) affects the quality of the diatom Thalassiosira weissflogii and the copepod Acartia tonsa - two key species that fuel the local food-web. We quantified quality (i.e. energy content as food for the next trophic level) in terms of fatty acids, proteins and thiobarbituric acid reacting substances. We found non-additive effects (positive and negative) of the metal-herbicide mixture on the diatom and copepod species. In general, nutritionally important biochemical parameters of Acartia tonsa were most sensitive to the chemical stressors. PMID- 29524782 TI - Treatment with medium chain fatty acids milk of CD36-deficient preschool children. AB - OBJECTIVE: CD36 deficiency is characterized by limited cellular long chain fatty acid uptake in the skeletal and cardiac muscles and often causes energy crisis in these muscles. However, suitable treatment for CD36 deficiency remains to be established. The aim of this study was to evaluate the clinical and metabolic effects of medium chain triacylglycerols (MCTs) in two CD36-deficient preschool children who often developed fasting hypoglycemia and exercise-induced myalgia. METHODS: Fasting blood glucose, total ketone bodies, and free fatty acids were examined and compared for usual supper diets and for diets with replacement of one component with 2 g/kg of 9% MCT-containing milk (MCT milk). Changes in serum creatine kinase and alanine aminotransferase levels, resulting from replacement of glucose water intake with 1 g/kg of MCT milk and determined by using bicycle pedaling tasks, were examined and compared. Hypoglycemic and/or myalgia episodes in daily life were also investigated. RESULTS: Biochemically, participants' blood glucose and total ketone bodies levels after overnight fasting substantially increased after dietary suppers containing MCT milk. Increases in serum creatine kinase and alanine aminotransferase levels resulting from the bicycle pedaling task were suppressed by MCT milk. Hypoglycemia leading to unconsciousness and tachycardia before breakfast decreased after introduction of dietary suppers containing MCT milk. Occurrence of myalgia in the lower limbs also decreased after intakes of MCT milk before long and/or strenuous exercising. CONCLUSION: Our results suggest that MCTs can prevent fasting hypoglycemia and exercise induced myalgia in CD36-deficient young children. PMID- 29524783 TI - Resveratrol promotes the arcuate nucleus architecture remodeling to produce more anorexigenic neurons in high-fat-diet-fed mice. AB - OBJECTIVE: Adult hypothalamic neurogenesis has been considered a central regulator of energy balance. Resveratrol (RSV), a natural polyphenol, influences the body fat mass and reduces the amount of adipose tissue. The present study was designed to evaluate the effect of RSV on dynamic of hypothalamic neurons in a diet-induced obesity model of mice. METHODS: Apoptosis, neurogenesis, the expression of the main trophic factors, and the fate of newborn cells were evaluated in the hypothalamus of adult male C57 BL/6 J mice fed a normal diet, a high-fat (HF) diet, or an HF diet supplemented with 400 mg/kg RSV (HF + RSV) for 6 wk. RESULTS: The HF diet caused an increase in neuronal apoptosis in the hypothalamus, which coincided with an increase in the number of newborn cells in the arcuate nucleus, suggesting that compensatory mechanisms developed to overcome deleterious effects of the HF diet. Addition of RSV to the HF diet enhanced the production of newborn cells in all studied regions of the hypothalamus. These changes were paralleled by enhancement of the expression of ciliary neurotrophic factor. Interestingly, a considerable proportion of newborn cells expressed neuropeptide Y in the arcuate nucleus of the HF group, and conversely, most of them differentiated to proopiomelanocortin neurons in HF + RSV mice. CONCLUSIONS: Diets rich in fat changed hypothalamic neuronal balance toward orexigenic versus anorexigenic neurons. Administration of RSV to the HF diet reversed this balance toward generation of anorexigenic neurons. These data point to the potential for RSV in regulation of body weight, possibly via modulation of hypothalamic neurogenesis. PMID- 29524784 TI - Psoriasis image representation using patch-based dictionary learning for erythema severity scoring. AB - Psoriasis is a chronic skin disease which can be life-threatening. Accurate severity scoring helps dermatologists to decide on the treatment. In this paper, we present a semi-supervised computer-aided system for automatic erythema severity scoring in psoriasis images. Firstly, the unsupervised stage includes a novel image representation method. We construct a dictionary, which is then used in the sparse representation for local feature extraction. To acquire the final image representation vector, an aggregation method is exploited over the local features. Secondly, the supervised phase is where various multi-class machine learning (ML) classifiers are trained for erythema severity scoring. Finally, we compare the proposed system with two popular unsupervised feature extractor methods, namely: bag of visual words model (BoVWs) and AlexNet pretrained model. Root mean square error (RMSE) and F1 score are used as performance measures for the learned dictionaries and the trained ML models, respectively. A psoriasis image set consisting of 676 images, is used in this study. Experimental results demonstrate that the use of the proposed procedure can provide a setup where erythema scoring is accurate and consistent. Also, it is revealed that dictionaries with large number of atoms and small patch sizes yield the best representative erythema severity features. Further, random forest (RF) outperforms other classifiers with F1 score 0.71, followed by support vector machine (SVM) and boosting with 0.66 and 0.64 scores, respectively. Furthermore, the conducted comparative studies confirm the effectiveness of the proposed approach with improvement of 9% and 12% over BoVWs and AlexNet based features, respectively. PMID- 29524785 TI - Breast lesions diagnosed by ultrasound-guided core needle biopsy: Can shearwave elastography predict histologic upgrade after surgery or vaccuum assisted excision? AB - PURPOSE: To compare breast stiffness based on shear-wave elastography (SWE) quantitative parameters with histopathologic results diagnosed by ultrasound (US) guided core needle biopsy (CNB) to determine their association with upgrade rates after surgical excision or follow-up US as well as clinico-radiologic differences between upgrade and non-upgrade groups. MATERIALS AND METHODS: This retrospective study enrolled 225 breast lesions from 225 patients, including 159 benign lesions, 38 high risk lesions and 28 ductal carcinoma in situ (DCIS) diagnosed by US-guided CNB. Quantitative SWE parameters of breast lesions were measured before CNB and compared according to histopathologic results (benign, high risk and DCIS) and lesion size (<20 mm and >20 mm). Clinico-radiologic and pathologic factors were compared between upgrade and non-upgrade groups after surgical excision or follow-up US. RESULTS: After surgical excision or follow-up US after more than one year, 29 lesions were upgraded for an overall upgrade rate of 12.9% (29/225). There were significant differences between upgrade and non-upgrade groups in age, mammographic category, US category, and sonographic features, including shape, margin, orientation, imaging-histologic correlation and E ratio. Patients with lesion upgrade were much older and had lesions characterized by significantly higher mammographic and US category (>4b), irregular shape, nonparallel orientation, microlobulated or angular margin, calcification in a mass, larger size on US (>20 mm) and greater imaging-histologic discordance. Multivariate analysis showed only mean and minimum elasticity values displayed a borderline association with histologic underestimation. CONCLUSION: Upgrade of breast lesions diagnosed by US-guided CNB can be predicted using Emean and Emin among quantitative SWE parameters. PMID- 29524786 TI - The unique associations of self-criticism and shame-proneness to symptoms of disordered eating and depression. AB - This study examined the unique associations of shame-proneness and self-criticism to symptoms of disordered eating and depression among 186 undergraduate students. The study also tested the degree to which self-criticism and shame-proneness accounted for the association between disordered eating and depressive symptoms. Both shame-proneness and self-criticism were significantly related to disordered eating and depressive symptoms. Self-criticism was significantly associated with disordered eating and depressive symptoms, over-and-above shame-proneness, but the reverse was not true. Controlling for shame-proneness, self-criticism also accounted for a significant proportion of the covariance between disordered eating and depressive symptoms, suggesting that self-criticism could account for some of the comorbidity between depression and eating disorders. Findings suggest that self-criticism may have incremental utility above-and-beyond shame-proneness as part of a transdiagnostic underlying cognitive substrate for depression and disordered eating. Implications emerge for future research and clinical practice. PMID- 29524787 TI - Relationship between severity of periodontitis and masseter muscle activity during waking and sleeping hours. AB - OBJECTIVE: This study was conducted to investigate whether the masseter muscle activity shows any specific pattern in relation to the severity of periodontitis. DESIGN: Sixteen subjects with no or mild periodontitis (NMP group) and 15 subjects with moderate or severe periodontitis (MSP group) were enrolled. Plasma IgG antibody titer was examined using Porphyromonas gingivalis as a bacterial antigen. Surface electromyography (EMG) of the masseter muscles was continuously recorded using an ambulatory surface EMG recording device while patients were awake and asleep. Masseter muscle activity was analyzed using intensities of 5% 10% maximal voluntary clenching (MVC), 10%-20% MVC, and >20% MVC. Furthermore, EMG levels of 20% MVC were adopted as the threshold for analysis of phasic, tonic, and mixed EMG activities. The cumulative duration of masseter muscle activity and bruxism episodes was calculated as duration per hour. RESULTS: There was no significant difference in plasma IgG antibody titers against P. gingivalis between the NMP and MSP groups (p = 0.423). During waking hours, the duration of masseter muscle activity with an intensity of >20% MVC was significantly longer in the MSP group than in the NMP group (p = 0.037). During sleeping hours, the duration of masseter muscle activity at all MVC intensities was significantly longer in the MSP group than in the NMP group (all p < 0.05). Additionally, the duration of phasic and mixed episodes was significantly longer in the MSP group than those in the NMP group while both awake and asleep (all p < 0.05). CONCLUSIONS: The results of this study suggested that masseter muscle activity might be related to the severity of periodontitis. PMID- 29524788 TI - Functional and molecular characterization of transmembrane intracellular pH regulators in human dental pulp stem cells. AB - OBJECTIVE: Homeostasis of intracellular pH (pHi) plays vital roles in many cell functions, such as proliferation, apoptosis, differentiation and metastasis. Thus far, Na+-H+ exchanger (NHE), Na+-HCO3- co-transporter (NBC), Cl-/HCO3- exchanger (AE) and Cl-/OH- exchanger (CHE) have been identified to co-regulate pHi homeostasis. However, functional and biological pHi-regulators in human dental pulp stem cells (hDPSCs) have yet to be identified. DESIGN: Microspectrofluorimetry technique with pH-sensitive fluorescent dye, BCECF, was used to detect pHi changes. NH4Cl and Na+-acetate pre-pulse were used to induce intracellular acidosis and alkalosis, respectively. Isoforms of pHi-regulators were detected by Western blot technique. RESULTS: The resting pHi was no significant difference between that in HEPES-buffered (nominal HCO3--free) solution or CO2/HCO3-buffered system (7.42 and 7.46, respectively). The pHi recovery following the induced-intracellular acidosis was blocked completely by removing [Na+]o, while only slowed (-63%) by adding HOE694 (a NHE1 specific inhibitor) in HEPES-buffered solution. The pHi recovery was inhibited entirely by removing [Na+]o, while adding HOE 694 pulse DIDS (an anion-transporter inhibitor) only slowed (-55%) the acid extrusion. Both in HEPES-buffered and CO2/HCO3 buffered system solution, the pHi recovery after induced-intracellular alkalosis was entirely blocked by removing [Cl-]o. Western blot analysis showed the isoforms of pHi regulators, including NHE1/2, NBCe1/n1, AE1/2/3/4 and CHE in the hDPSCs. CONCLUSIONS: We demonstrate for the first time that resting pHi is significantly higher than 7.2 and meditates functionally by two Na+-dependent acid extruders (NHE and NBC), two Cl--dependent acid loaders (CHE and AE) and one Na+-independent acid extruder(s) in hDPSCs. These findings provide novel insight for basic and clinical treatment of dentistry. PMID- 29524789 TI - pH changes of mixed biofilms of Streptococcus mutans and Candida albicans after exposure to sucrose solutions in vitro. AB - OBJECTIVE: This study aimed to standardize an in vitro experimental model able to reproduce the pH changes that occur in dental biofilm under in vivo conditions, using a mixed biofilm of Streptococcus mutans and Candida albicans. DESIGN: Biofilms were developed for 96 h, and exposed to three different concentrations of sucrose (10, 20 or 30%) during 1, 3 or 5 min. The pH was measured before exposure to sucrose, immediately after its removal from the biofilms, and at 1, 3, 5 and 10 min after removal. RESULTS: Sucrose solutions at 10 and 20% required 1 min to significantly reduce the biofilm pH, while for 30% sucrose a significant reduction was already seen immediately after its removal, even for the shortest exposure time. For an exposure of 3 min to 20% sucrose, the biofilm pH attained the critical value for hydroxyapatite dissolution when measured 1 min after sucrose removal, followed by a recovery phase. CONCLUSIONS: A mixed biofilm of S. mutans and C. albicans exposed to a 20% sucrose solution for 3 min exhibited a pattern of pH change similar to that observed in vivo, despite at a higher speed when compared to in vivo conditions. PMID- 29524790 TI - Cannabis-related psychotic disorder upon relapse to cannabis use: A case series and possible neurobiological implications. PMID- 29524791 TI - Polybacterial stimulation suggests discrete IL-6/IL-6R signaling in human fetal membranes: Potential implications on IL-6 bioactivity. AB - The polybacterial invasion of the amniotic cavity and risk of preterm birth is often due to cervicovaginal bacteria such as genital mycoplasmas (Mycoplasma hominis and Ureaplasma urealyticum) and Gardnerella vaginalis. The most studied biomarker associated with preterm birth is interleukin-6 (IL-6), a pleiotropic cytokine that performs different functions based on classical or trans-signaling mechanisms. This study evaluated the changes in IL-6 and IL-6 function associated accessory molecules by human fetal membranes to determine the functional availability of IL-6 assessment in an in vitro model of polybacterial infection. Fetal membranes were treated with LPS or heat-inactivated genital mycoplasmas and G. vaginalis alone or in combination. IL-6 and its soluble receptors (sgp130, sIL 6R) were assessed in conditioned medium by immunoassays and membrane-bound receptors were evaluated in the tissue using immunohistochemistry and RT-PCR. Data from protein and gene expression were evaluated using linear mixed effects models. Data from immunohistochemistry were evaluated using one-way analysis of variance followed by the Tukey test. Genital mycoplasmas alone, or in combination, inhibited IL-6 trans-signaling with increased sgp130 production. G. vaginalis activated the classical IL-6 signaling pathway, as did LPS. Polybacterial treatment resulted in a balanced response with neither pathway being favored. The increase in IL-6 production by fetal membranes in response to infection is likely a non-specific innate response and not an indicator of a functional mediator of any labor-inducing pathways. This suggests that correlating the risk of adverse pregnancy outcomes and designing interventions based on IL-6 levels without considering soluble receptors may be an ineffective strategy. PMID- 29524792 TI - Getting a healthy start: The effectiveness of targeted benefits for improving dietary choices. AB - There is growing policy interest in encouraging better dietary choices. We study a nationally-implemented policy - the UK Healthy Start scheme - that introduced vouchers for fruit, vegetables and milk. We show that the policy has increased spending on fruit and vegetables and has been more effective than an equivalent value cash benefit. We also show that the policy improved the nutrient composition of households' shopping baskets, with no offsetting changes in spending on other foodstuffs. PMID- 29524793 TI - Giving and promising gifts: Experimental evidence on reciprocity from the field. AB - We test the value of unconditional non-monetary gifts as a way to improve health worker performance in a low income country health setting. We randomly assigned health workers to different gift treatments within a program that visited health workers, measured performance and encouraged them to provide high quality care for their patients. We show that unconditional non-monetary gifts improve performance by 20 percent over a six-week period, compared to the control group. We compare the impact of the unconditional gift to one in which a gift is offered conditional on meeting a performance target and show that only the unconditional gift results in a statistically significant improvement. This demonstrates that organizations can improve the performance of health workers in the medium term without using financial incentives. PMID- 29524794 TI - Design, synthesis and perception of fluorescently labeled isoprenoid cytokinins. AB - Isoprenoid cytokinins play a number of crucial roles in the regulation of plant growth and development. To study cytokinin receptor properties in plants, we designed and prepared fluorescent derivatives of 6-[(3-methylbut-2-en-1 yl)amino]purine (N6-isopentenyladenine, iP) with several fluorescent labels attached to the C2 or N9 atom of the purine moiety via a 2- or 6-carbon linker. The fluorescent labels included dansyl (DS), fluorescein (FC), 7 nitrobenzofurazan (NBD), rhodamine B (RhoB), coumarin (Cou), 7 (diethylamino)coumarin (DEAC) and cyanine 5 dye (Cy5). All prepared compounds were screened for affinity for the Arabidopsis thaliana cytokinin receptor (CRE1/AHK4). Although the attachment of the fluorescent labels to iP via the linkers mostly disrupted binding to the receptor, several fluorescent derivatives interacted well. For this reason, three derivatives, two rhodamine B and one 4 chloro-7-nitrobenzofurazan labeled iP were tested for their interaction with CRE1/AHK4 and Zea mays cytokinin receptors in detail. We further showed that the three derivatives were able to activate transcription of cytokinin response regulator ARR5 in Arabidopsis seedlings. The activity of fluorescently labeled cytokinins was compared with corresponding 6-dimethylaminopurine fluorescently labeled negative controls. Selected rhodamine B C2-labeled compounds 17, 18 and 4 chloro-7-nitrobenzofurazan N9-labeled compound 28 and their respective negative controls (19, 20 and 29, respectively) were used for in planta staining experiments in Arabidopsis thaliana cell suspension culture using live cell confocal microscopy. PMID- 29524795 TI - Sit-to-stand ground reaction force characteristics in blind and sighted female children. AB - BACKGROUND: The association between visual sensory and sit-to-stand ground reaction force characteristics is not clear. Impulse is the amount of force applied over a period of time. Also, free moment represents the vertical moment applied in the center of pressure (COP). RESEARCH QUESTION: How the ground reaction force components, vertical loading rate, impulses and free moment respond to long and short term restricted visual information? METHODS: Fifteen female children with congenital blindness and 45 healthy girls with no visual impairments participated in this study. The girls with congenital blindness were placed in one group and the 45 girls with no visual impairments were randomly divided into three groups of 15; eyes open, permanently eyes closed, and temporary eyes closed. The participants in the permanently eyes closed group closed their eyes for 20 min before the test, whereas temporary eyes closed group did tests with their eyes closed throughout, and those in the eyes open group kept their eyes open. RESULTS: Congenital blindness was associated with increased vertical loading rate, range of motion of knee and hip in the medio-lateral plane. Also, medio-lateral and vertical ground reaction force impulses. Similar peak negative and positive free moments were observed in three groups. SIGNIFICANCE: In conclusion, the results reveal that sit-to-stand ground reaction force components in blind children may have clinical importance for improvement of balance control of these individuals. PMID- 29524796 TI - A comparison of gait one year post operation in an RCT of robotic UKA versus traditional Oxford UKA. AB - Robot-assisted unicompartmental knee surgery has been shown to improve the accuracy of implant alignment. However, little research has been conducted to ascertain if this results in a measureable improvement in knee function post operatively and a more normal gait. The kinematics of 70 OA knees were assessed using motion analysis in an RCT (31 receiving robotic-assisted surgery, and 39 receiving traditional manual surgery) and compared to healthy knees. Statistically significant kinematic differences were seen between the two surgical groups from foot-strike to mid-stance. The robotic-assisted group achieved a higher knee excursion (18.0 degrees , SD 4.9 degrees ) compared to the manual group (15.7 degrees , SD 4.1 degrees ). There were no significant difference between the healthy group and the robotic assisted group, however there was a significant difference between the healthy group and the manual group (p < 0.001). Hence robotically-assisted knee replacement with Mako Restoris Implants appears to lead not only to better implant alignment but also some kinematic benefits to the user during gait. PMID- 29524797 TI - Trunk involvement in performing upper extremity activities while seated in neurological patients with a flaccid trunk - A review. AB - BACKGROUND: Trunk control is essential during seated activities. The trunk interacts with the upper extremities (UE) and head by being part of a kinematic chain and by providing a stable basis. When trunk control becomes impaired, it may have consequences for the execution of UE tasks. AIM: To review trunk involvement in body movement and stability when performing seated activities and its relation with UE and head movements in neurological patients with a flaccid trunk, with a focus on childhood and development with age. METHODS AND PROCEDURES: A search using PubMed was conducted and 32 out of 188 potentially eligible articles were included. OUTCOMES AND RESULTS: Patients with a flaccid trunk (e.g. with spinal cord injury or cerebral palsy) tend to involve the trunk earlier while reaching than healthy persons. Different balance strategies are observed in different types of patients, like using the contralateral arm as counterweight, eliminating degrees of freedom, or reducing movement speed. CONCLUSIONS AND IMPLICATIONS: The key role of the trunk in performing activities should be kept in mind when developing interventions to improve seated task performance in neurological patients with a flaccid trunk. PMID- 29524798 TI - The relationship between foot posture and plantar pressure during walking in adults: A systematic review. AB - BACKGROUND: Foot posture is a risk factor for some lower limb injuries, however the underlying mechanism is not well understood. Plantar pressure analysis is one technique to investigate the interaction between foot posture and biomechanical function of the lower limb. RESEARCH QUESTION: The aim of this review was to investigate the relationship between foot posture and plantar pressure during walking. METHODS: A systematic database search was conducted using MEDLINE, CINAHL, SPORTDiscus and Embase to identify studies that have assessed the relationship between foot posture and plantar pressure during walking. Included studies were assessed for methodological quality. Meta-analysis was not conducted due to heterogeneity between studies. Inconsistencies included foot posture classification techniques, gait analysis protocols, selection of plantar pressure parameters and statistical analysis approaches. RESULTS: Of the 4213 citations identified for title and abstract review, sixteen studies were included and underwent quality assessment; all were of moderate methodological quality. There was some evidence that planus feet display higher peak pressure, pressure-time integral, maximum force, force-time integral and contact area predominantly in the medial arch, central forefoot and hallux, while these variables are lower in the lateral and medial forefoot. In contrast, cavus feet display higher peak pressure and pressure-time integral in the heel and lateral forefoot, while pressure-time integral, maximum force, force-time integral and contact area are lower for the midfoot and hallux. Centre of pressure was more laterally deviated in cavus feet and more medially deviated in planus feet. Overall, effect sizes were moderate, but regression models could only explain a small amount of variance in plantar pressure variables. SIGNIFICANCE: Despite these significant findings, future research would benefit from greater methodological rigour, particularly in relation to the use of valid foot posture measurement techniques, gait analysis protocols, and standardised approaches for analysis and reporting of plantar pressure variables. PMID- 29524799 TI - Genome-wide profiling of expression and biochemical functions of the Medicago glutathione S-transferase gene family. AB - Glutathione S-transferases are ubiquitous enzyme in plants, playing vital roles in several physiological and developmental processes. In this study we identified 73 GST genes from the genome of Medicago truncatula. The Medicago GSTs were divided to eight classes with tau and phi being the most numerous. Six clusters were found on four Medicago chromosomes. The local gene duplication mainly contributed to the expansion of this large gene family. Functional divergence was found in their gene structures, gene expression patterns, and enzyme properties. A genomic comparative analysis revealed lineage-specific loss/gain events between Medicago and Glycine. This study offered new insights into the evolution of gene family between closely related species. PMID- 29524800 TI - Metabolomics analysis of 'Housui' Japanese pear flower buds during endodormancy reveals metabolic suppression by thermal fluctuation. AB - Dormancy is a complex phenomenon that allows plants to survive the winter season. Studies of dormancy have recently attracted more attention due to the expansion of temperate fruit production in areas under mild winters and due to climate changes. This study aimed to identify and characterize the metabolic changes induced by chilling temperatures, as well as during thermal fluctuation conditions that simulate mild winter and/or climate change scenarios. To do this, we compared the metabolic profile of Japanese pear flower buds exposed to constant chilling at 6 degrees C and thermal fluctuations of 6 degrees C/18 degrees C (150 h/150 h) during endodormancy. We detected 91 metabolites by gas chromatography paired with time-of-flight mass spectrometry (GC-TOF-MS) that could be classified into eight groups: amino acids, amino acid derivatives, organic acids, sugars and polyols, fatty acids and sterols, phenol lipids, phenylpropanoids, and other compounds. Metabolomics analysis revealed that the level of several amino acids decreased during endodormancy. Sugar and polyol levels increased during endodormancy during constant chilling and might be associated with chilling stress tolerance and providing an energy supply for resuming growth. In contrast, thermal fluctuations produced low levels of metabolites related to the pentose phosphate pathway, energy production, and tricarboxylic acid (TCA) cycle in flower buds, which may be associated with failed endodormancy release. This metabolic profile contributes to our understanding of the biological mechanism of dormancy during chilling accumulation and clarifies the metabolic changes during mild winters and future climate change scenarios. PMID- 29524801 TI - Active proton efflux, nutrient retention and boron-bridging of pectin are related to greater tolerance of proton toxicity in the roots of two Erica species. AB - BACKGROUND AND AIMS: Tolerance to soil acidity was studied in two species of Ericaceae that grow in mine-contaminated soils (S Portugal, SW Spain) to find out if there are interspecific variations in H+ tolerance which might be related to their particular location. METHODS: Tolerance to H+ toxicity was tested in nutrient solutions using seeds collected in SW Spain. Plant growth and nutrient contents in leaves, stems and roots were determined. Viability tests and proton exchange were studied in roots exposed, short-term, to acidic conditions. Membrane ATPase activity and the cell-wall pectic polysaccharide domain rhamnogalacturonan-II (RG-II) were analysed to find out interspecific differences. RESULTS: Variation in survival, growth and mineral composition was found between species. The H+-tolerant species (Erica andevalensis) showed greater concentration of nutrients than E. australis. Very low pH (pH 2) produced a significant loss of root nutrients (K, P, Mg) in the sensitive species. Root ATPase activity was slightly higher in the tolerant species with a correspondingly greater H+ efflux capacity. In both species, the great majority of the RG-II domains were in their boron-bridged dimeric form. However, shifting to a medium of pH 2 caused some of the boron bridges to break in the sensitive species. CONCLUSIONS: Variation in elements linked to the cell wall-membrane complex and the stability of their components (RG-II, H+-ATPases) are crucial for acid stress tolerance. Thus, by maintaining root cell structure, active proton efflux avoided toxic H+ build-up in the cytoplasm and supported greater nutrient acquisition in H+-tolerant species. PMID- 29524802 TI - Soil amendment as a strategy for the growth of young vines when replanting vineyards in soils with high copper content. AB - Soil contamination with copper (Cu)-based agrochemicals used in vineyards for pest control is a growing problem. In this context, the application of soil amendment to limit Cu toxicity, especially for young plants after the replanting of vineyards, has been a concern for winemakers. Therefore, the aim of this study was to evaluate how different amendments can contribute to the decrease in Cu availability in areas vocated to viticulture. Furthermore, the aim was to evaluate to the effect of Cu on the biochemical and physiological changes in the development of the young vine plants, both at the shoot and the root level. Vine plants were grown in a greenhouse using a Typic Hapludalf soil characterized by 87.5 mg of Cu kg-1 (control). Three different amendments were applied to the soil: limestone (3 Mg ha-1), calcium silicate (3 Mg ha-1) and vermicompost (30 g of C kg-1). The amendment with vermicompost and calcium silicate caused a significant alkalization of the soil solution. Moreover, specifically for the treatment with vermicompost, the levels of Cu2+ in the soil solution were consistently diminished with a clear benefit for plants (+89% biomass accumulation at the shoot level). In addition, this soil amendment led to a higher photosynthetic rate, lower superoxide dismutase (SOD, EC 1.15.1.1) and guaiacol peroxidase (POD, EC 1.11.1.7) activity and a higher percentage of fine roots with diameter between 0 < L >= 0.2 mm (particularly active in water and nutrient acquisition). In conclusion, results showed that vermicompost effectively reduced Cu phytotoxicityin young vines grown in soils with high Cu contents. Furthermore, this amendment might be an asset in enhancing the availability of other important micronutrients such as iron. PMID- 29524803 TI - beta-Glucosidase activity in almond seeds. AB - Almond bitterness is the most important trait for breeding programs since bitter kernelled seedlings are usually discarded. Amygdalin and its precursor prunasin are hydrolyzed by specific enzymes called beta-glucosidases. In order to better understand the genetic control of almond bitterness, some studies have shown differences in the location of prunasin hydrolases (PH, the beta-glucosidase that degrades prunasin) in sweet and bitter genotypes. The aim of this work was to isolate and characterize different PHs in sweet- and bitter-kernelled almonds to determine whether differences in their genomic or protein sequences are responsible for the sweet or bitter taste of their seeds. RNA was extracted from the tegument, nucellus and cotyledon of one sweet (Lauranne) and two bitter (D05 187 and S3067) almond genotypes throughout fruit ripening. Sequences of nine positive Phs were then obtained from all of the genotypes by RT-PCR and cloning. These clones, from mid ripening stage, were expressed in a heterologous system in tobacco plants by agroinfiltration. The PH activity was detected using the Feigl Anger method and quantifying the hydrogen cyanide released with prunasin as substrate. Furthermore, beta-glucosidase activity was detected by Fast Blue BB salt and Umbelliferyl method. Differences at the sequence level (SNPs) and in the activity assays were detected, although no correlation with bitterness was found. PMID- 29524804 TI - Fully automatic liver segmentation in CT images using modified graph cuts and feature detection. AB - PURPOSE: Liver segmentation from CT images is a fundamental step in trajectory planning for computer-assisted interventional surgery. In this paper, we present a fully automatic procedure using modified graph cuts and feature detection for accurate and fast liver segmentation. METHODS: The initial slice and seeds of graph cuts are automatically determined using an intensity-based method with prior position information. A contrast term based on the similarities and differences of local organs across multi-slices is proposed to enhance the weak boundaries of soft organs and to prevent over-segmentation. The term is then integrated into the graph cuts for automatic slice segmentation. Patient-specific intensity and shape constraints of neighboring slices are also used to prevent leakage. Finally, a feature detection method based on vessel anatomical information is proposed to eliminate the adjacent inferior vena cava with similar intensities. RESULTS: We performed experiments on 20 Sliver07, 20 3Dircadb datasets and local clinical datasets. The average volumetric overlap error, volume difference, symmetric surface distance and volume processing time were 5.3%, -0.6%, 1.0 mm, 17.8 s for the Sliver07 dataset and 8.6%, 0.7%, 1.6 mm, 12.7 s for the 3Dircadb dataset, respectively. CONCLUSIONS: The proposed method can effectively extract the liver from low contrast and complex backgrounds without training samples. It is fully automatic, accurate and fast for liver segmentation in clinical settings. PMID- 29524805 TI - Noninvasive pulmonary arterial pressure estimation using a logistic-based systolic model. AB - RATIONALE: A hemodynamic relationship of pulmonary artery pressure (PAP) to pulmonary acceleration time (PAcT) has not yet been explicitly presented. OBJECTIVE: We employed a logistic-based systolic model with a subtle modification for pulmonary circulation and provided a logical ground for the relationship between systolic PAP and PAcT using transthoracic echocardiography. Additionally, the logistic-based PAP estimation equation was deduced from the model to relate systolic PAP and PAcT. METHODS AND RESULTS: This equation was statistically tested in comparison to existing PAP estimation equations. Results showed that the logistic-based PAP estimation equation was at least as accurate as previous equations with respect to previously published mean PAP versus PAcT values. After the subtle pulmonary modification of the model, the pulmonary blood flow velocity and pressure not only well reflected the underlying pulmonary circulation physiology, but could also be presented in harmony with systemic circulation physiology. CONCLUSIONS: A future clinical study with actual systolic PAP versus PAcT measurements is needed to test the application of the logistic-based PAP estimation equation. PMID- 29524806 TI - Polymer adhesion predictions for oral dosage forms to enhance drug administration safety. Part 3: Review of in vitro and in vivo methods used to predict esophageal adhesion and transit time. AB - The oral cavity is frequently used to administer pharmaceutical drug products. This route of administration is seen as the most accessible for the majority of patients and supports an independent therapy management. For current oral dosage forms under development, the prediction of their unintended mucoadhesive properties and esophageal transit profiles would contribute for future administration safety, as concerns regarding unintended adhesion of solid oral dosage forms (SODF) during oro-esophageal transit still remain. Different in vitro methods that access mucoadhesion of polymers and pharmaceutical preparations have been proposed over the years. The same methods might be used to test non-adhesive systems and contribute for developing safe-to-swallow technologies. Previous works have already investigated the suitability of non animal derived in vitro methods to assess such properties. The aim of this work was to review the in vitro methodology available in the scientific literature that used animal esophageal tissue to evaluate mucoadhesion and esophageal transit of pharmaceutical preparations. Furthermore, in vivo methodology is also discussed. Since none of the in vitro methods developed are able to mimic the complex swallowing process and oro-esophageal transit, in vivo studies in humans remain as the gold standard. PMID- 29524807 TI - A comprehensive literature review of guidelines facilitating transition of newly graduated nurses to professional nurses. AB - Literature shows that successful transition of newly graduate nurses to professional nurses is imperative but does not always take place, resulting in difficulty in performance, cognizance or behaviour of a role as a nurse, affecting the quality of patient care negatively. No integrative literature review could be found to summarize available guidelines facilitating transition of final year nursing students to professional nurses. An extensive search of the literature by means of an integrative literature review was conducted in 2014 and updated in June 2017, following a five-step process. All relevant studies were subsequently appraised for rigour and quality using the AGREE II tool by two independent reviewers. Eight (n = 8) guidelines on transitions were independently extracted. After thematic analysis was done, three factors to facilitate transition of final year nursing students to professional nurses were found: 1) support for new graduates, 2) the graduate's need for socialization and belonging, and 3) a positive clinical learning environment. The availability and implementation of guidelines on transition of final year nursing students by educational institutions and healthcare facilities could ease the transition from being final year nursing students to becoming professional nurses as well as improve retention of newly qualified professional nurses. PMID- 29524808 TI - Identification of type A spermatogonia in turbot (Scophthalmus maximus) using a new cell-surface marker of Lymphocyte antigen 75 (ly75/CD205). AB - Turbot (Schophthalmus maximus) is one of the most important economic marine flatfish species. However, due to rapid development of the industry, genetic resource recession has brought down the efficiency of aquaculture. Therefore, conservation of the genetic resource is increasingly demanded. Recent research proved that type A spermatogonia possesses the properties of spermatogonia stem cell, and it might provide an ideal solution. Therefore, it is necessary to develop an appropriate molecular marker on type A spermatogonia to further isolate and purify of type A spermatogonia in turbot. In this study, turbot lymphocyte antigen 75 (smly75) gene was identified and its localizations of expressions and the temporal transcription patterns were evaluated qualitatively and semiquantitatively. Investigation in testes of development of spermatogonia showed that smly75 mRNA, contrast with vasa and dnd mRNA, was exclusively localized in type A spermatogonia and not detected in type B spermatogonia, spermatocytes or gonadal somatic cells by in situ hybridization. Thus, the smly75 could be a new and convincing molecular marker on identification of type A spermatogonia. In addition, specifically to development pattern of type A spermatogonia, from 7- to 14- month testes, spermatogonia were dominated and the number of type A spermatogonia was increased, corresponding that smly75 expression was up-regulated gradually, while, in 16 month testes, accompanied by that several spermatogonia differentiated into primary spermatocytes, the smly75 expression down-regulated. Finally, broaden in the whole reproductive cycle, the smly75 transcription significantly variated with the differentiation of germ cells and in accordance with the number of type A spermatogonia. It is suggested that testes from 8 to 14 month old males could be used for further isolation and purification of type A-SG. These results will not only help to better understand type A spermatogonia, but also further facilitate type A spematogonia-mediated germ cell manipulation in turbot. PMID- 29524809 TI - Anti-Mullerian hormone and antral follicle count are more effective for selecting ewes with good potential for in vivo embryo production than the presence of FecGE mutation or eCG pre-selection tests. AB - This study aims to compare four different methods for selecting high responding sheep donors for in vivo embryo production. These methods include a pre-selection eCG test (eCG), antral follicle count (AFC), plasma anti-Mullerian hormone measurement (AMH) and genotyping for the presence of the FecGE mutation (a polymorphism in the GDF9 gene associated with increased ovulation rate). Santa Ines ewe lambs (n = 25) underwent superovulation (SOV) with 800 IU equine chorionic gonadotropin (eCG) and the corpus luteum (CL) count was recorded by laparoscopy after eight days. At the D0eCG, blood samples for AMH and genotyping analysis were collected. Twenty-one days after the end of the eCG test, the same animals underwent SOV with 200 mg of FSH, administered in six decreasing doses, and then naturally mated. Immediately before the beginning of the FSH protocol (D0FSH), and at the moment of the first FSH dose (D9FSH), the AFC was assessed. Plasma AMH was again determined at the D9FSH. After each screening process, animals were classified as having a high (HR), or low (LR), potential of response (using specific thresholds for each method). Then, the ewes' response to SOV and embryo yield for each screening method, classified as HR or LR, were compared. Animals classified as HR by AFC (HRAFC) and by AMH concentration (HRAMH) at the D9FSH, produced more viable embryos than those classified as LRAFC and LRAMH (HRAFC 6.2 +/- 3.2 vs LRAFC 2.8 +/- 3.0 and HRAMH 6.6 +/- 3.6 vs LRAMH 3.0 +/- 2.9). Pre-selection tests with eCG and different FecGE genotypes, either heterozygous (+/E) or wild type (+/+), were unable to discriminate HR or LR animals. A tendency (P = 0.06) to have lower plasma AMH was observed in heterozygous FecGE (+/E) ewes. In conclusion, both AFC and plasma AMH can be used to select donor ewes with a higher potential of response for in vivo embryo production. PMID- 29524810 TI - The association of fruit and vegetable consumption with changes in weight and body mass index in Chinese adults: a cohort study. AB - OBJECTIVES: Findings regarding the benefits of fruit and vegetables (FV) on weight control are inconsistent and little is known among Chinese populations. Therefore, we examined the relationship between change in FV consumption, weight, and change in body mass index (BMI) among Chinese adults, participants of the China Health and Nutrition Survey (CHNS). STUDY DESIGN: A prospective cohort study. METHODS: Two waves of CHNS conducted in 2006 and 2011 were used. Continuous FV consumption increase was considered as the exposure and changes in weight and BMI as outcomes. Change in FV consumption was categorized into quintiles. Analysis of covariance and multiple linear regression models, after controlling for potential confounders such as energy intake, physical activity, and smoking, were used to describe the relationship between change in FV consumption and change in weight and BMI. RESULTS: A total of 4357 participants aged 18-65 years were included in this study. The respective weight and BMI gains in male individuals were 1.81 kg and 0.73 kg/m2 in the fifth quintile of FV change relative to individuals in the first quintile (3.67 kg for weight gain and 1.48 kg/m2 for BMI gain). An increase in FV consumption by 100 g was associated with a 211 g weight loss (B = -2.11; 95% confidence interval [CI], -3.34, -0.89, P < 0.001) and a decrease in BMI by 0.94 kg/m2 (B = -0.94; 95% CI, -1.36, -0.46, P < 0.001) in men; and a 140 g weight loss (B = -0.14; 95% CI, -0.97, 0.69, P = 0.74) and a decrease in BMI by 0.29 kg/m2 BMI (B = -0.29; 95% CI, -0.63, 0.06, P = 0.11) in women. CONCLUSIONS: Increase in FV consumption was associated with statistically significant weight loss and decrease in BMI among Chinese men, and, although suggested, weight loss among women was not significant. Considering the protective effect of FV on human health, increasing FV consumption in the Chinese population is recommended. PMID- 29524811 TI - The age pattern of social inequalities in health at older ages: are common measures of socio-economic status interchangeable? AB - OBJECTIVES: Social inequalities in health have been largely documented in social science research. Members of the most disadvantaged groups experience worse health and higher mortality from birth throughout adulthood. However, it is not clear whether this association persists at older ages. Some studies have found a narrowing of the social gradient in health, at least when 'traditional' measures of socio-economic status (SES)-income, education, and occupation-are used. The main goal of the article is to highlight similarities and discrepancies in the age trend of social inequalities in health that arise when multiple measures of SES are considered. STUDY DESIGN: The present study uses a longitudinal sample of over 7000 individuals age 50+ from the Survey of Health, Ageing, and Retirement in Europe to examine the age trend of social inequalities in health. METHODS: By using growth curve models, individual trajectories of self-rated health and physical functioning were analyzed. SES is measured through wealth, income, and education. RESULTS: The findings show that for both health outcomes, the choice of the indicator of SES is very consequential, as the age trend of social inequalities in health is substantially different for different measures of SES. CONCLUSION: Using multiple measures of SES is recommended, as using only one measure would give only a partial account of the age trend of social inequalities in health. In particular, wealth seems to better capture individual's socio economic position, as it is able to detect health gradients even where education and income fail to do so. PMID- 29524812 TI - Implementing national strategies on antimicrobial resistance in Thailand: potential challenges and solutions. AB - BACKGROUND: Thailand has developed a national strategic plan on antimicrobial resistance (NSP-AMR) and endorsed by the Cabinet in August 2016. This study reviewed the main contents of the NSP-AMR and the mandates of relevant implementing agencies and identified challenges and recommends actions to mitigate implementation gaps. METHODS: This study analysed the contents of NSP AMR, reviewed institutional mandates and assessed the implementation gaps among agencies responsible for NSP-AMR. RESULTS: Two of six strategies are related to monitoring and surveillance of AMR and antimicrobial consumption in human and animal. Two other strategies aim to improve antibiotic stewardship and control the spread of AMR in both clinical and farm settings. The remaining two strategies aim to increase knowledge and public awareness on AMR and establish national governance for inter-sectoral actions. Strategies to overcome implementation challenges are sustaining cross-sectoral policy commitments, effective cross-sectoral coordination using One Health approach, generating evidence which guides policy implementation, and improving enforcement capacities in regulatory authorities. CONCLUSIONS: To address AMR, Thailand requires significant improvements in implementation capacities in two dimensions. First, technical capacities among implementing agencies are needed to translate policies into practice. Second, governance and organizational capacities enable effective multi-sectoral actions across human, animal, and environmental sectors. PMID- 29524813 TI - Ethnic and sex differences in E-cigarette use and relation to alcohol use in California adolescents: the California Health Interview Survey. AB - OBJECTIVES: E-cigarette use is not only prevalent among adolescents but is growing at an alarming rate. This study sought to determine e-cigarette use prevalence and its relation to alcohol use as a potential gateway drug, and how this may differ by sex and ethnicity in a multi-ethnic sample of California adolescents. STUDY DESIGN: Cross-sectional survey. METHODS: We included data from 1806 adolescents (weighted to 3.0 million) aged 12-17 in the 2014 and 2015 California Health Interview Survey (CHIS) cycles. The prevalence of e-cigarette use was calculated within sex and ethnic groups and the prevalence of alcohol use according to e-cigarette use was also examined with sample weighting providing population estimates. Multiple logistic regression models were built to predict the odds of using alcohol from e-cigarette use status adjusted for sociodemographic and other characteristics. RESULTS: The prevalence of e cigarette use was 9.1% (projected to 0.3 million) overall in California adolescents but highest in boys among non-Hispanic Whites (15.1%) and in Asian girls (13.3%). Among e-cigarette users, 61.3% of boys and 71.0% of girls reported using alcohol as well. The logistic regression odds of alcohol use, adjusted for age, ethnicity, body mass index, cigarette smoking status, socioeconomic status, parents' education level, and insurance status among e-cigarettes users (compared with non-users) was 9.2 in girls and 3.1 in boys (both P < 0.01). Asians/others, non-Hispanic whites and Hispanics were similarly at increased odds: 17.8, 5.4, and 3.0, respectively (P < 0.01 for Asians/others and for whites) of using alcohol compared with their non-e-cigarette using counterparts, respectively. CONCLUSION: Attention needs to be paid to the high prevalence of e-cigarette smoking as well as its potential as a gateway drug for alcohol drinking in adolescents, especially among girls and Asians. PMID- 29524814 TI - Response of ginger growth to a tetracycline-contaminated environment and residues of antibiotic and antibiotic resistance genes. AB - The presence of antibiotic residues in vegetables has been highlighted as a risk to human health; antibiotics not only cause toxic effects to plants but can also induce antibiotic resistance gene (ARG) expression. Using a soil-free approach, this study aimed to explore the response of ginger growth to tetracycline (TC) pollution and to assess the levels of antibiotic residues in different plant organs and the presence of ARGs in the rhizome. Ginger growth in a highly TC contaminated environment was remarkably inhibited. Photosynthetic parameters, fluorescence parameters, and some physiological indicators (oxidative substances, photosynthetic pigments, enzyme activity, etc.) were negatively influenced by TC contamination. Although the superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activity levels significantly increased, their effects appear to be limited. The accumulation of TC in the rhizome (28.1 mg kg-1) was greater than that in the roots, stem, or leaves. All tested antibiotic resistance genes except for tetL were detectable in the rhizome, and their relative abundance was in the order integron1>tetG > tetA > tetC > tetB > tetM. The level of TC in ginger rhizomes was much higher than the maximum residue limits. The potential dose of TC acquired from the consumption of ginger grown in a highly TC-contaminated environment poses no obvious risk to adults but may be a threat to children. PMID- 29524815 TI - Benzene induced resistance in exposed Drosophila melanogaster: Outcome of improved detoxification and gene modulation. AB - Adaptive behaviour of an organism has relevance towards developing better resistance in subsequent generations following xenobiotic exposures. Using a genetically tractable and functional insect model, Drosophila melanogaster, we aimed to examine the resistance of the organism against repeated exposures of benzene, an industrial and environmental-chemical and a class I human carcinogen. While 100 mM benzene exposure to one-day old flies for seven days caused ~95% mortality (F0), its exposure to subsequent generations of flies led a significant decrease in mortality with maximum survival (~85%) as evident at F28 generation. While burden of benzene and its toxic metabolites was higher in initial generations, in latter generations (F24-F28), concentrations of less toxic metabolites were higher. In parallel, improved metabolism, less oxidative stress, less induction of hsp60 and hsp70 and higher induction of hsp26 and hsp27 along with increased gene dose ratio of three genes (cyp6g1, mrp1, and cyp12d1) were observed in latter generations of benzene exposed flies with maximum benefit accrued in F28 generation. The resistance developed in flies of F28 generation had a negative impact on reproduction which might be due to a cost against selection. The study demonstrates development of benzene resistance in Drosophila with permanent genetic changes. PMID- 29524816 TI - Concentrations of imidacloprid and thiamethoxam in pollen, nectar and leaves from seed-dressed cotton crops and their potential risk to honeybees (Apis mellifera L.). AB - Neonicotinoid insecticides (NIs) have recently been recognized as co-factors in the decline of honeybee colonies because most neonicotinoids are systemic and can transfer into the pollen and nectar of many pollinated crops. In this study, we collected pollen, nectar and leaves from a cotton crop treated with imidacloprid and thiamethoxam to measure the residue levels of these two NIs at different application doses during the flowering period. Then, the residual data were used to assess the risk posed by the systemic insecticides to honeybees following mandated methods published by the European Food Safety Authority (EFSA), and a highly toxic risk to honeybees was highlighted. Imidacloprid was found in both pollen and nectar samples, whereas thiamethoxam was found in 90% of pollen samples and over 60% of nectar samples. Analysis of the pollen and nectar revealed residual amounts of imidacloprid ranging from 1.61 to 64.58 ng g-1 in the pollen and from not detected (ND) to 1.769 ng g-1 in the nectar. By comparison, the thiamethoxam concentrations in pollen and nectar ranged from ND to 14.521 ng g-1 and from ND to 4.285 ng g-1, respectively. The results of this study provide information on the transfer of two NIs from seed treatment to areas of the plant and provides an understanding of the potential exposure of the bee and other pollinators to systemic insecticides. PMID- 29524817 TI - Further insight into the roles of the chemical composition of dissolved organic matter (DOM) on ultrafiltration membranes as revealed by multiple advanced DOM characterization tools. AB - This study assessed the relative contributions of different constitutes in dissolved organic matter (DOM) with two different sources (i.e., urban river and effluent) to membrane fouling on three types of ultrafiltration (UF) membranes via excitation emission matrix - parallel factor analysis (EEM-PARAFAC), size exclusion chromatography (SEC), and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). Two polyethersulfone membranes with different pore sizes and one regenerated cellulose membrane were used as representative hydrophobic (HPO) and hydrophilic (HPI) UF membranes, respectively. Although size exclusion effect was found to be the most prevailing rejection mechanism, the behaviors of individual fluorescent components (one tryptophan-like, one microbial-humic-like, and terrestrial humic-like) and different size fractions upon the UF filtration revealed that chemical interactions (e.g., hydrophobic interactions and hydrogen bonding) between DOM and membrane might play important roles in UF membrane fouling, especially for small sized DOM molecules. Based on the molecular level composition determined by FT-ICR-MS, the CHOS formula group showed a greater removal tendency toward the HPO membrane, while the CHONS group was prone to be removed by the HPI membrane. The changes in the overall molecular composition of DOM upon UF filtration were highly dependent on the sources of DOM. The molecules of more acidic nature tended to remain in the permeate of effluent DOM, while the river DOM was shifted into more nitrogen-enriched composition after filtration. Regardless of the DOM sources, the HPO membrane with a smaller pore size led to the most pronounced changes in the molecular composition of DOM. PMID- 29524818 TI - A simultaneous determination of anti-cancer drugs in hospital effluent by DLLME HPLC-FLD, together with a risk assessment. AB - Currently, there is an increasing use of anti-cancer drugs, and hence their occurrence in the environment must be properly managed, in particular, in the light of their high degree of toxicity. In this study, analytical methods using HPLC-FLD assisted by microextraction and solid phase extraction, were developed and validated for the determination of doxorubicin, daunorubicin, epirubicin and irinotecan in hospital effluent. The validation results show determination coefficients (r2) higher than 0.99 and recovery values between 74% and 105%, with an intraday precision of <15%.The limit of quantification was 1.0 MUg L- 1 and there were almost no matrix effects. The methods proposed were employed for the determination of the named chemotherapeutics in effluent samples of the University Hospital of Santa Maria, Brazil and quantified in the range of >=LOQ 6.22 MUg L-1. A preliminary ecotoxicological risk assessment showed values that were potentially very harmful, and thus, the treatment of the hospital effluents requires special attention. PMID- 29524819 TI - Insights into influencing factor, degradation mechanism and potential toxicity involved in aqueous ozonation of oxcarbazepine (CHEM46939R1). AB - Oxcarbazepine (OXC), as a potent antiepileptic drug, is widely used in recent years, but its residue is potentially harmful to the environment. Although ozonation is a high-efficient technology for chemical oxidation during water treatment, it cannot completely mineralize organic matters, but partially transforms them into some unidentified by-products. In order to provide more insight into OXC ozonation process, the influencing factor, transformation mechanism and potential toxicity were comprehensively investigated in this study. The results showed that the optimal ozonation temperature was 20 degrees C with a pseudo-first-order reaction rate constant of 0.161 min-1. The increase of pH significantly enhanced OXC degradation, while the presence of bicarbonate caused a remarkable negative effect, manifesting that hydroxyl radical (OH) oxidation should play an important role in OXC ozonation. Moreover, transformation mechanism was further elucidated based on the identification of ten OXC-related by-products using UPLC-Q-TOF-MSn, which mainly consisted of electrophilic substitution, N-heterocyclic ring cleavage and re-arrangement, hydroxylation, carbonylation, demethoxylation and deamidation, etc. The toxicity evaluation, using US Environmental Protection Agency Toxicity Estimation Software Tool (US EPA TEST), suggested that most identified by-products were probably more toxic than OXC itself. Besides, further experiments, by measuring inhibitory effect of ozonated mixture on Vibrio fischeri bioluminescence, demonstrated that by products with higher toxicity tended to be accumulated under a short reaction time. Taken together, the present investigation provided valuable information for further understanding OXC ozonation process, and suggested that special attention should be paid to the control and elimination of toxic transformation by-products in future studies. PMID- 29524820 TI - Visible-light-driven photocatalytic activation of peroxymonosulfate by Cu2(OH)PO4 for effective decontamination. AB - The advanced oxidation process (AOP) based on SO4- radicals draws an increasing interest in water and wastewater treatment. Producing SO4- radicals from the activation of peroxymonosulfate (PMS) by transition metal ions or oxides may be problematic due to high operational cost and potential secondary pollution caused by metal leaching. To address this challenge, the present study reports the efficient production of SO4- radicals through visible-light-driven photocatalytic activation (VL-PCA) of PMS by using Cu2(OH)PO4 single crystal for enhanced degradation of a typical recalcitrant organic pollutant, i.e., 2,4-dichlorophenol (2,4-DCP). It took only 7 min to achieve almost 100% removal of 2,4-DCP in the Cu2(OH)PO4/PMS system under visible-light irradiation and pH-neutral condition. The 2,4-DCP degradation was positively correlated to the amount of Cu2(OH)PO4 and PMS. Both OH and SO4- radicals were responsible for enhanced degradation performance, indicated by radical scavenger experiments and electron spin resonance (ESR) measurements. The Cu2(OH)PO4 single crystal exhibited good cyclic stability and negligible metal leaching. According to density functional theory (DFT) calculations, the visible-light-driven transformation of two copper states between trigonal bipyramidal sites and octahedral sites in the crystal structure of Cu2(OH)PO4 facilitates the generation of OH and SO4- radicals from the activation of PMS and cleavage of O-O bonds. This study provides the proof-in concept demonstration of activation of PMS driven by visible light, making the SO4- radicals-based AOPs much easier, more economical and more sustainable in engineering applications for water and wastewater treatment. PMID- 29524821 TI - High activity of g-C3N4/multiwall carbon nanotube in catalytic ozonation promotes electro-peroxone process. AB - Three kinds of graphitic carbon nitride materials (bulk, porous and nanosheet g C3N4) were composited with a multiwall carbon nanotube (MWCNT) by a hydrothermal method, and the obtained b-C3N4/CNT, p-C3N4/CNT and n-C3N4/CNT materials were used in the electrodes for electro-peroxone process. It was found that the n C3N4/CNT composite exhibited the highest efficiency in oxalate degradation, though it performed the worst in the oxygen-reduction reaction for H2O2 production. The n-C3N4/CNT composite exhibited higher activity than CNT and other composites in catalytic ozonation experiments, due to the higher pyrrolic-N content modified on the CNT surface and higher surface area. It also has higher electron transfer ability, which benefited to the electro-reduction of both O2 and O3. The result confirmed that catalytic ozonation process was an important means to enhance the degradation efficiency in the electro-peroxone process, besides peroxone process and O3-electrolysis. PMID- 29524822 TI - Bisphenols: Application, occurrence, safety, and biodegradation mediated by bacterial communities in wastewater treatment plants and rivers. AB - Numerous data indicate that most of bisphenols (BPs) are endocrine disrupters and exhibit cytotoxicity, neurotoxicity, genotoxicity and reproductive toxicity against vertebrates. Nevertheless, they are widely applied in material production what result in their ubiquitous occurrence in ecosystems. While BPA is the most frequently detected in environment, BPAF, BPF and BPS are also often found. Ecosystem particularly exposed to BPs pollution is industrial and municipal wastewater being a common source of BPA in river waters. Different techniques to remove BPs from these ecosystems have been applied, among which biodegradation seems to be the most effective. In this review the current state of knowledge in the field of BPs application, distribution in the environment, effects on animal and human health, and biodegradation mediated by bacterial populations in wastewater treatment plants and rivers is presented. PMID- 29524823 TI - Phototransformation of estrogens mediated by Mn(III), not by reactive oxygen species, in the presence of humic acids. AB - Photodegradation of pollutants is classically explained by reaction with reactive oxygen species. However Mn(III) may also remove pollutants, but direct evidence is actually lacking. Here we investigated the role of soluble Mn(III) on phototransformation of four typical estrogens, namely estrone (E1), 17beta estradiol (E2), estriol (E3), and 17alpha-ethynylestradiol (EE2), in the presence of Mn(II) and humic acid. Conversion rates of 60.2%, 89.0%, 87.6%, and 80.2% were achieved for E1, E2, E3, and EE2, respectively, after 72 h visible light irradiation. A detailed quenching experiments revealed that soluble Mn(III), and not reactive oxygen species, was the oxidant responsible for estrogen removal. The determination of Mn(III) concentration provided direct proof of the role of Mn(III)-based oxidizers in the conversion of estrogens. Soluble Mn(III) can form complexes with humic acid, and about 6.51 MUM of Mn(III)-humic acid was formed from 20 MUM of Mn(II) in the presence of 5 mg/L of humic acid. Furthermore, product identification and theoretical computation demonstrated that estrogens are mainly converted into oligomers (dimers, trimers, tetramers, etc.) via a single-electron process. According to these results, the oxidation of Mn(II) to Mn(III) is initiated by superoxide ion (O2*-) generated from dissolved oxygen in the presence of humic acid under visible light irradiation. The formed soluble Mn(III) strips the estrogens of a single electron to generate phenoxyl radicals, which undergo oligomerization, while leads to regeneration of Mn(II). Hence, the photochemical Mn(II)-Mn(III) redox cycling may significantly influence the fate and transformation of estrogens in waters. PMID- 29524824 TI - Pollution, ecological-health risks, and sources of heavy metals in soil of the northeastern Qinghai-Tibet Plateau. AB - The Qinghai-Tibet Plateau, especially the northeastern region, is not a pure land any more due to recently increasing anthropogenic activities. This study collected soil samples from 70 sites of the northeastern Qinghai-Tibet Plateau to evaluate pollution, ecological-health risks, and possible pollution sources of heavy metals. The concentrations of heavy metals in soil were relatively high. Values of geo-accumulation index exhibited that Hg pollution was the most serious meanwhile Hg possessed the strongest enrichment feature based on enrichment factor values. The modified degrees of contamination showed that about 54.3% and 17.1% of sampling sites were at moderate and high contamination degree while pollution load indexes illustrated that 72.9% and 27.1% of sampling sites possessed moderate and high contamination level, respectively. Ecological risk indexes of heavy metals in soil ranged from 234.6 to 3759.0, suggesting that most of sites were under considerable/very high risks. Cancer risks for adults and children were determined as high and high-very high levels while non-cancer risks for children were high although those for adults were low. Industrial source contributed to the main fraction of ecological and health risks. Summarily speaking, heavy metals in soil of the study area has caused significantly serious pollution and exerted high potential ecological and health risks, especially for children who are more susceptible to hurt from pollutants. Therefore, more efficient and strict pollution control and management in study area should be put out as soon as possible. PMID- 29524825 TI - Characterization of metals in PM1 and PM10 and health risk evaluation at an urban site in the western Mediterranean. AB - PM1 and PM10 samples collected in the urban center of Elche during two years were analyzed by Energy Dispersive X-Ray Fluorescence in order to determine the concentrations of the following metals: K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Sr and Ba. The influence of traffic and Saharan dust intrusions on PM levels and metal content was studied in this work. The results indicate that the coarse fraction was affected more by variations in traffic intensity than the submicron fraction. The concentrations of Ca, commonly used as a tracer of road dust, showed the highest decreases during the weekends due to the reduction in traffic induced resuspension. In contrast, Saharan events had a greater impact on the levels of other metals such as Ti and Fe, significantly affecting their seasonal variability. High concentrations of V and Ni compared with the values found at larger urban areas were observed. This could be attributed to a significant contribution from soils, Saharan dust and even ship emissions. Enrichment factors calculated using Ti as a reference element indicate that Zn and Cu are predominantly emitted by anthropogenic activities. In fact, Saharan dust intrusions had a minor influence on the average concentrations of these metals. Non-carcinogenic health hazards associated with exposure to airborne metals were lower than the safety threshold (hazard quotient < 1). Carcinogenic risks for Cr (VI) and Ni were between 10-6 and 10-4 and, therefore, within the range considered acceptable by the US EPA. PMID- 29524826 TI - Determination of phthalic acid esters in water samples by hollow fiber liquid phase microextraction prior to gas chromatography tandem mass spectrometry. AB - A new hollow fiber liquid-phase microextraction (HF-LPME) method has been developed for the extraction of a group of phthalic acid esters (PAEs) of interest from different water samples prior to gas chromatography tandem mass spectrometry analysis. HF-LPME was carried out using 1-octanol as extraction solvent followed by a back extraction step with cyclohexane. The different parameters that affect HF-LPME such as sample pH, ionic strength, extraction time, stirring rate, extraction temperature and back extraction conditions were investigated. The optimized conditions involved the extraction of 10 mL of sample without pH adjustment or addition of salt during 75 min under a stirring of 850 rpm at 60 degrees C and subsequent desorption with 200 MUL of cyclohexane for 10 min in an ultrasonic bath. The method was validated in terms of calibration and recovery studies using dibutyl phthalate-d4 as internal standard. The developed procedure gave satisfactory recovery (74-120%) and relative standard deviation values (<20%) for the studied PAEs in mineral, tap, pond and waste water samples. PMID- 29524827 TI - Serial fiber optic bronchoscopy (FOB) to predict the need of tracheostomy in tracheomalacia after thyroidectomy in long standing goiter. PMID- 29524828 TI - Inhibition of pMAPK14 Overcomes Resistance to Sorafenib in Hepatoma Cells with Hepatitis B Virus. AB - Hepatitis B virus (HBV) targets the liver and is a major driver for liver cancer. Clinical data suggest that HBV infection is associated with reduced response to treatment with the multi-kinase inhibitor sorafenib, the first available molecularly targeted anti-hepatocellular carcinoma (HCC) drug. Given that Raf is one of the major targets of sorafenib, we investigated the activation state of the Raf-Mek-Erk pathway in the presence of HBV and in response to sorafenib. Here we show that hepatoma cells with replicating HBV are less susceptible to sorafenib inhibitory effect as compared to cells in which HBV expression is suppressed. However, although HBV replication is associated with increased level of pErk, its blockade only modestly augments sorafenib effect. In contrast, the phosphorylated form of the pro-oncogenic Mitogen-Activated Protein Kinase 14 (pMAPK14), a protein kinase that was recently linked to sorafenib resistance, is induced in sorafenib-treated hepatoma cells in association with HBV X protein expression. Knocking down pMAPK14 results in augmentation of the therapeutic efficacy of sorafenib and largely alleviates resistance to sorafenib in the presence of HBV. Thus, this study suggests that HBV promotes HCC resistance to sorafenib. Combining pMAPK14 inhibitors with sorafenib may be beneficial in patients with HBV-associated HCC. PMID- 29524829 TI - The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors. AB - Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors. PMID- 29524830 TI - Tumstatin, a Matrikine Derived from Collagen Type IValpha3, is Elevated in Serum from Patients with Non-Small Cell Lung Cancer. PMID- 29524831 TI - Dose-Dependent Relationship Between Metformin and Colorectal Cancer Occurrence Among Patients with Type 2 Diabetes-A Nationwide Cohort Study. AB - BACKGROUND: Increasing bodies of evidence suggest that metformin may be beneficial in the primary prevention of colorectal cancer (CRC), and a dose response relationship has been reported. However, long-term epidemiological observations between the treatment period, cumulative dose, and intensity of metformin and CRC are rarely reported. The aim of this study was to identify the association between the effect of metformin and CRC development in a nationwide cohort study. METHODS: This nationwide population-based study examined a cohort of 1,000,000 patients randomly sampled from individuals enrolled in the Taiwan National Health Insurance system. Patients with newly diagnosed type 2 diabetes mellitus (DM) between 1997 and 2007 were enrolled. A statistical variables, including the demographic data, treatment period, cumulative dose, and intensity of metformin use, was compared between patients developing CRC and those without CRC. RESULTS: This study included 47,597 patients. The mean follow-time was 7.17 +/- 3.21 years. After adjustment, metformin use was an independent protective factor against CRC development (P < .001). Although the protective ability of metformin against CRC development was reduced during long-term therapy, the risk of CRC decreased progressively with a higher cumulative dose or higher intensity of metformin use (both P < .001). CONCLUSION: This study revealed that metformin use significantly reduced the risk of CRC in a dose-dependent manner in patients with type 2 DM in the Taiwanese population. However, a gradual decline in medication adherence may reduce the protective ability of metformin against CRC development during long-term therapy. PMID- 29524832 TI - Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors. AB - OBJECTIVE: Chlamydia trachomatis (C. trachomatis) infection has been suggested to promote epithelial ovarian cancer (EOC) development. This study sought to explore the presence of C. trachomatis DNA and chlamydial heat shock protein 60 (chsp60) in ovarian tissue, as well as anti-chlamydial IgG antibodies in plasma, in relation to subtypes of EOC. METHODS: This cross-sectional cohort consisted of 69 women who underwent surgery due to suspected ovarian pathology. Ovarian tissue and corresponding blood samples were collected at the time of diagnosis. In ovarian tumor tissue, p53, p16, Ki67 and chsp60 were analyzed immunohistochemically, and PCR was used to detect C. trachomatis DNA. Plasma C. trachomatis IgG and cHSP60 IgG were analyzed with a commercial MIF-test and ELISA, respectively. RESULTS: Eight out of 69 women had C. trachomatis DNA in their ovarian tissue, all were invasive ovarian cancer cases (16.7% of invasive EOC). The prevalence of the chsp60 protein, C. trachomatis IgG and cHSP60 IgG in HGSC, compared to other ovarian tumors, was 56.0% vs. 37.2% P = .13, 15.4% vs. 9.3% P = .46 and 63.6% vs. 45.5% P = .33 respectively. None of the markers of C. trachomatis infection were associated with p53, p16 or Ki67. CONCLUSIONS: C. trachomatis was detected in invasive ovarian cancer, supporting a possible role in carcinogenesis of EOC. However, there were no statistically significant associations of chsp60 in ovarian tissue, or plasma anti-chlamydial IgG antibodies, with any of the subtypes of ovarian tumors. PMID- 29524833 TI - Ablation of aberrant neurogenesis fails to attenuate cognitive deficit of chronically epileptic mice. AB - Pilocarpine-induced acute seizures strongly induce aberrant hippocampal neurogenesis, characterized by increased proliferation of neural progenitors and abnormal integrations of newly generated granule cells - hilar ectopic granule cells (EGCs), mossy fibre sprouting (MFS), and hilar basal dendrites (HBDs), which may disturb hippocampal neuronal circuits and thus contribute to cognitive impairment in temporal lobe epilepsy (TLE) patients and animal models. Previous studies via ablating hippocampal neurogenesis after acute seizures produced inconsistent results regarding the development of long-term cognitive impairment. Furthermore, a sufficient decrease of subsequent abnormal integrations in chronically epileptic hippocampus was not well-established in these studies. Therefore, the link between seizure-induced aberrant hippocampal neurogenesis and cognitive decline associated with epilepsy is still in need to be clarified. In this study, the mice were injected with methylazoxymethanol acetate (MAM) both before and after pilocarpine-induced status epilepticus (SE) to achieve an overall ablation of newborn cells contributing to the pathological recruitment. In addition, a protracted time point was chosen for behavioral testing considering it takes a fairly long time for newborn granule cells to adequately develop abnormal integrations, especially MFS. Although an overall reduction of abnormal integrations, including EGCs, MFS and HBDs was confirmed following the ablation regime, the performance of ablated and non-ablated mice in the Morris Water Maze (MWM) task did not differ. The current findings therefore provide novel evidences that ablation of neurogenesis with an overall decrease of abnormal integrations cannot attenuate subsequent cognitive impairment at least in the model used in this study. PMID- 29524834 TI - Differential phosphorylation and n-terminal configuration of capsid subunits in parvovirus assembly and viral trafficking. AB - The T1 parvovirus Minute Virus of Mice (MVM) was used to study the roles that phosphorylation and N-terminal domains (Nt) configuration of capsid subunits may play in icosahedral nuclear viruses assembly. In synchronous MVM infection, capsid subunits newly assembled as two types of cytoplasmic trimeric intermediates (3VP2, and 1VP1:2VP2) harbored a VP1 phosphorylation level fivefold higher than that of VP2, and hidden Nt. Upon nuclear translocation at S phase, VP1-Nt became exposed in the heterotrimer and subsequent subviral assembly intermediates. Empty capsid subunits showed a phosphorylation level restored to VP1:VP2 stoichiometry, and the Nt concealed in their interior. However ssDNA filled virus maturing at S/G2 lacked VP1 phosphorylation and one major VP2 phosphopeptide, and exposed VP2-Nt. Endosomal VP2-Nt cleavage resulted in VP3 subunits devoid of any phospholabel, implying that incoming viral particles specifically harbor a low phosphorylation status. Phosphorylation provides a mechanistic coupling of parvovirus nuclear assembly to the cell cycle. PMID- 29524835 TI - Characterization of H9N2 avian influenza viruses from the Middle East demonstrates heterogeneity at amino acid position 226 in the hemagglutinin and potential for transmission to mammals. AB - Next-generation sequencing (NGS) technologies are a valuable tool to monitor changes in viral genomes and determine the genetic heterogeneity of viruses. In this study, NGS was applied to clinical poultry samples from Jordan to detect eleven H9N2 low pathogenic avian influenza viruses (LPAIV). All of the viruses tested belonged to Middle East A genetic group of G1 lineage. Deep sequencing demonstrated a high degree of heterogeneity of glutamine and leucine residues at position 226 in the hemagglutinin (HA) gene, which increases specificity to either avian or mammalian-type receptors. Moreover, additional amino acid changes in PB1, PA, M1, M2, and NS1 were identified among the viruses tested. Compared to single gene amplification, application of NGS for surveillance and characterization of H9N2 LPAIV provides a complete genetic profile of emerging isolates and better understanding of the potential of zoonotic transmissions to mammals. PMID- 29524836 TI - Disaster education and preparedness in the acute care setting: A cross sectional survey of operating theatre nurse's disaster knowledge and education. AB - BACKGROUND: Operating theatre services can be heavily relied upon during mass casualty disaster events, which require nurses to have adequate training and education of hospital disaster management plans to respond appropriately. The evidence-base of disaster preparedness in the acute setting is limited, particularly with regard to operating theatre nurses. OBJECTIVES: Explore operating theatre nurse's disaster knowledge of their role in a mass casualty event, and identify the preferred mode of disaster education and training to improve disaster preparedness. DESIGN: A cross-sectional research design was employed with data collected using a survey tool. SETTINGS: The research was undertaken on operating theatre nurses in a tertiary hospital in Victoria, Australia. PARTICIPANTS: The participants in this research included 53 operating theatre nurses, 51 Registered Nurses and 2 Enrolled Nurses. METHODS: The survey was based on a disaster questionnaire for emergency department nurses from South Australia, exploring knowledge and preparedness for disaster response in the acute setting, and altered to be specific and relevant to the operating theatre environment and broadened to focus on the training needs of perioperative nurses. RESULTS: The survey of 53 operating theatre nurses identified that few had previous disaster experience (19.9%). The majority of respondents were aware of their disaster management policy (Code Brown policy) (94.1%), of reporting lines, and appropriate triage (80.4%). However, a significant number of nurses (50.9%) stated that in the event of a disaster they would "call work to see if [they needed] additional assistance" compared with 43.4% of respondents "wait to be contacted by a manager/floor coordinator" as was policy. Finally, disaster nursing general knowledge amongst staff was poor; a mean of 1.79 (SD = 1.20) correct answers out of a possible 7. CONCLUSIONS: This study highlights that disaster education and training methods for disasters be specific to the role required by nurses and all staff during a disaster activation; training drills are preferred although face-to-face education is practical. PMID- 29524837 TI - In defence of the viva voce: Eighteen candidates' voices. AB - BACKGROUND: The doctoral viva voce is an under-researched field, particularly from the point of view of doctoral candidates. With increasing numbers of health care professionals undertaking doctoral study, we can develop practice by listening to their 'living voices'. OBJECTIVE: To explore doctoral candidates' experiences of their viva. DESIGN AND METHODS: Using exploratory research and purposive sampling, eighteen participants who had undergone examination of their doctorate within the last five years were identified. Semi-structured interviews were used to explore these participants' experiences of their viva. RESULTS: Thematic analysis of the data demonstrated that: Candidates wanted to engage in academic argument but were not always provided the opportunity to do so; the viva voce examination was frequently an emotional experience, even for candidates who did not regard themselves as subject to such emotions, examiners were sometimes able to moderate the effect of these emotions; practical aspects of the examination were not always considered; issues of fairness were raised, both by successful candidates and by those who were required to resubmit. CONCLUSIONS: The viva voce examination, as experienced by candidates, is not always a fair one. We recommend engagement of the academic community to promote best practice in the "living voice" examination. PMID- 29524838 TI - In the shadow of the ivory tower: Experiences of midwives and nurses undertaking PhDs. AB - AIMS: The aims of this study were to gain an understanding of the experiences of nurses and midwives enrolled in a PhD, explore any barriers that PhD students encounter whilst completing the degree, and develop recommendations for consideration in formulating support strategies to encourage completion for nurses and midwives enrolled on a PhD degree. BACKGROUND: It is important to understand what is happening at doctoral level education for nurses and midwives, and how those enrolled on PhD courses can successfully complete their studies, transition learning, and acquire the ability to undertake research into the clinical environments. DESIGN: The criteria for inclusion into the study was that participants were either a Registered Nurse or Registered Midwife enrolled in a PhD degree. METHODS: A mixed methodology, non-experimental design approach was used with purposive sampling in an anonymous survey, that included both qualitative and quantitative questions to collect data in 2017. FINDINGS: Supervisors and supervision were the focus of the participant's responses, and issues were identified in negotiating the right supervisors for nurse/midwife PhD students. PhD students would benefit from specific teaching and the opportunity to discuss issues that occur as part of the PhD process. CONCLUSION: Academia needs to consider new approaches to more effectively integrate teaching time into supervision, thereby optimising PhD completion for nursing and midwifery PhD students. PMID- 29524839 TI - The effect of in silico targeting Pseudomonas aeruginosa patatin-like protein D, for immunogenic administration. AB - The vaccine candidates that have been introduced for immunization against Pseudomonas aeruginosa (P. aeruginosa) strains are quite diverse. In fact, there has been no proper antigen to act as an effective immunogenic substance against this ubiquitous pathogen in the market as yet. The complications caused by this bacterium due to the rapid development of multiple drug resistant strains have led to clinical problems worldwide. P. aeruginosa encodes many specific virulence elements that could be used as appropriate vaccine candidates. Type Vd secretion system, also known as patatin-like protein D, is a novel P. aeruginosa auto transporter system. It is known that cellular or humoral immune responses could be elevated by chimeric proteins carrying epitopes. It has been recognized that in silico tools are essential for the evaluation of new chimeric antigens. In this study, we have considered the patatin-like protein D (PlpD) molecule from P. aeruginosa and predicted some immunogenic properties of this strong cytotoxic phospholipase A2 with the use of in-depth computational and immunoinformatics assessment methods The novelty of our in silico study is the modeling and assessment of both humoral and cellular immune potential against the PlpD molecule. The molecule was considered by multiple sequence alignment and homology valuation. The extremely conserved regions in the PlpD were predicted. The allergenic and physicochemical property predictions on the PlpD state that the molecule is a non-allergic and stable molecule. High-resolution secondary and tertiary conformations were created. Indeed, the B-cell and T-cell epitope mapping on the chimeric target protein confirmed that the engineered protein contained a tremendous number of both B-cell and T-cell corresponding epitopes. This investigation magnificently attained the chimeric molecule as being a potent lipolytic enzyme composed of numerous B-cell and T-cell restricted epitopes and could induce both humoral and cellular immune responses. The results indicated that this molecule has therapeutic potential against several potent pathogenic P. aeruginosa strains. PMID- 29524840 TI - Computational analysis for the determination of deleterious nsSNPs in human MTHFR gene. AB - Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism and plays a central role in DNA methylation and biosynthesis. MTHFR mutations may alter the cellular folate supply which in turn affects nucleic acid synthesis, DNA methylation and chromosomal damage. The identification of number of SNPs in the human genome growing nowadays and hence, the evaluation of functional & structural consequences of these SNPs is very laborious by means of experimental analysis. Therefore, in the present study, recently developed various computational algorithms have been used which can predict the functional and structural consequences of the SNPs. Various computational tools like SIFT, PolyPhen2, PROVEAN, SNAP2, nsSNPAnalyzer, SNPs&GO, PhD-SNP, PMut, I-Mutant, iPTREE-STAB and MUpro were used to predict most deleterious SNPs. Additionally, ConSurf was used to find amino acids conservation and NCBI conserved domain search tool to find conserved domains in MTHFR. Post translational modification sites were predicted using ModPred. SPARKS-X was used to generate 3D structure of the native and mutant MTHFR protein, ModRefiner for further refinement, Varify3D and RAMPAGE to validate structure. Ligand binding sites were predicted using FTsite, RaptorX binding and COACH. Three SNPs i.e. R157Q, L323P and W500C predicted the most deleterious in all the tools used for functional and stability analysis. Moreover, both residues R157, L323 and W500 were predicted highly conserved, buried and structural residues by ConSurf. Post translational modification sites were also predicted at R157 and W500. The ligand binding sites were predicted at R157, L323 and W500. PMID- 29524841 TI - Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress. AB - Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity. Furthermore, dioscin significantly inhibited myocardial oxidative insult through adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px in vitro and in vivo. Our data also indicated that dioscin activated Nrf2 and Sirt2 signaling pathways, and thereby affected the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a through decreasing miR-140-5p expression level. In addition, the level of intracellular ROS was significantly increased in H9C2 cells treated by DOX after miR-140-5p mimic transfection, as well as the down-regulated expression levels of Nrf2 and Sirt2, which were markedly reversed by dioscin. In conclusion, our data suggested that dioscin alleviated DOX-induced cardiotoxicity through modulating miR-140-5p mediated myocardial oxidative stress. This natural product should be developed as a new candidate to alleviate cardiotoxicity caused by DOX in the future. PMID- 29524842 TI - Insights into the HyPer biosensor as molecular tool for monitoring cellular antioxidant capacity. AB - Aerobic metabolism brings inexorably the production of reactive oxygen species (ROS), which are counterbalanced by intrinsic antioxidant defenses avoiding deleterious intracellular effects. Redox balance is the resultant of metabolic functioning under environmental inputs (i.e. diet, pollution) and the activity of intrinsic antioxidant machinery. Monitoring of intracellular hydrogen peroxide has been successfully achieved by redox biosensor advent; however, to track the intrinsic disulfide bond reduction capacity represents a fundamental piece to understand better how redox homeostasis is maintained in living cells. In the present work, we compared the informative value of steady-state measurements and the kinetics of HyPer, a H2O2-sensitive fluorescent biosensor, targeted at the cytosol, mitochondrion and endoplasmic reticulum. From this set of data, biosensor signal recovery from an oxidized state raised as a suitable parameter to discriminate reducing capacity of a close environment. Biosensor recovery was pH-independent, condition demonstrated by experiments on pH-clamped cells, and sensitive to pharmacological perturbations of enzymatic disulfide reduction. Also, ten human cell lines were characterized according their H2O2-pulse responses, including their capacity to reduce disulfide bonds evaluated in terms of their migratory capacity. Finally, cellular migration experiments were conducted to study whether migratory efficiency was associated with the disulfide reduction activity. The migration efficiency of each cell type correlates with the rate of signal recovery measured from the oxidized biosensor. In addition, HyPer-expressing cells treated with N-acetyl-cysteine had accelerated recovery rates and major migratory capacities, both reversible effects upon treatment removal. Our data demonstrate that the HyPer signal recovery offers a novel methodological tool to track the cellular impact of redox active biomolecules. PMID- 29524843 TI - Regulation of the mechanism of Type-II NADH: Quinone oxidoreductase from S. aureus. AB - Type-II NADH:quinone oxidoreductases (NDH-2s) are membrane proteins involved in respiratory chains and the only enzymes with NADH:quinone oxidoreductase activity expressed in Staphylococcus aureus (S. aureus), one of the most common causes of clinical infections. NDH-2s are members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, having a flavin adenine dinucleotide, FAD, as prosthetic group and NAD(P)H as substrate. The establishment of a Charge-Transfer Complex (CTC) between the isoalloxazine ring of the reduced flavin and the nicotinamide ring of NAD+ in NDH-2 was described, and in this work we explored its role in the kinetic mechanism using different electron donors and electron acceptors. We observed that CTC slows down the rate of the second half reaction (quinone reduction) and determines the effect of HQNO, an inhibitor. Also, protonation equilibrium simulations clearly indicate that the protonation probability of an important residue for proton transfer to the active site (D302) is influenced by the presence of the CTC. We propose that CTC is critical for the overall mechanism of NDH-2 and possibly relevant to keep a low quinol/quinone ratio and avoid excessive ROS production in vivo. PMID- 29524846 TI - Improving stomach content based death time determination by maximum probability estimation. AB - Stomach content based death time estimation (SCE), is a well-known technique in forensic sciences. Among more qualitatively oriented approaches the content percentage based method SCE by Troger, Baur and Spann yields quantitative results and gives stochastic error measures for its outputs. This is possible since the methods estimator, which we call transformed expectation estimator (TEE) as well as the probability distribution of the time between last meal and death are determined numerically, though in SCE the estimator and confidence intervals are presented graphically only. Our articles outcomes are. PMID- 29524844 TI - Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide. AB - : Insufficient hydrogen sulfide (H2S) has been implicated in Type 2 diabetic mellitus (T2DM) and hyperhomocysteinemia (HHcy)-related cardiovascular complications. We investigated the role of H2S in T2DM and HHcy-induced endothelial dysfunction in small mesenteric artery (SMA) of db/db mice fed a high methionine (HM) diet. HM diet (8 weeks) induced HHcy in both T2DM db/db mice and non-diabetic db/+ mice (total plasma Hcy: 48.4 and 31.3 uM, respectively), and aggravated the impaired endothelium-derived hyperpolarization factor (EDHF) induced endothelium-dependent relaxation to acetylcholine (ACh), determined by the presence of eNOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) and prostacyclin (PGI2) inhibitor indomethacin (INDO), in SMA from db/db mice but not that from db/+ mice. A non-selective Ca2+-active potassium channel (KCa) opener NS309 rescued T2DM/HHcy-impaired EDHF-mediated vascular relaxation to ACh. EDHF-induced relaxation to ACh was inhibited by a non-selective KCa blocker TEA and intermediate-conductance KCa blocker (IKCa) Tram-34, but not by small conductance KCa (SKCa) blocker Apamin. HHcy potentiated the reduction of free sulfide, H2S and cystathionine gamma-lyase protein, which converts L-cysteine to H2S, in SMA of db/db mice. Importantly, a stable H2S donor DATS diminished the enhanced O2- production in SMAs and lung endothelial cells of T2DM/HHcy mice. Antioxidant PEG-SOD and DATS improved T2DM/HHcy impaired relaxation to ACh. Moreover, HHcy increased hyperglycemia-induced IKCa tyrosine nitration in human micro-vascular endothelial cells. EDHF-induced vascular relaxation to L-cysteine was not altered, whereas such relaxation to NaHS was potentiated by HHcy in SMA of db/db mice which was abolished by ATP-sensitive potassium channel blocker Glycolamide but not by KCa blockers. CONCLUSIONS: Intermediate HHcy potentiated H2S reduction via CSE-downregulation in microvasculature of T2DM mice. H2S is justified as an EDHF. Insufficient H2S impaired EDHF-induced vascular relaxation via oxidative stress and IKCa inactivation in T2DM/HHcy mice. H2S therapy may be beneficial for prevention and treatment of micro-vascular complications in patients with T2DM and HHcy. PMID- 29524845 TI - EEG beta desynchronization during hand goal-directed action observation in newborn monkeys and its relation to the emergence of hand motor skills. AB - Previous developmental research suggests that motor experience supports the development of action perception across the lifespan. However, it is still unknown when the neural mechanisms underlying action-perception coupling emerge in infancy. The goal of this study was to examine the neural correlates of action perception during the emergence of grasping abilities in newborn rhesus macaques. Neural activity, recorded via electroencephalogram (EEG), while monkeys observed grasping actions, mimed actions and means-end movements during the first (W1) and second week (W2) of life was measured. Event-related desynchronization (ERD) during action observation was computed from the EEG in the alpha and beta bands, two components of the sensorimotor mu rhythm associated with activity of the mirror neuron system (MNS). Results revealed age-related changes in the beta band, but not the alpha band, over anterior electrodes, with greater desynchronization at W2 than W1 for the observation of grasping actions. Additionally, desynchronization to observed grasping actions at W2 was associated with infants' motor skills - measured by a separate behavioral task - such that more grasping attempts were associated to greater beta ERD. These findings suggest the emergence of an early action-perception system, that relies on motor experience, shortly after birth. PMID- 29524847 TI - Current and emerging neuromodulation therapies for addiction: insight from pre clinical studies. AB - Neuromodulation therapies such as deep brain stimulation or transcranial magnetic stimulation have shown promise in reducing symptoms of addiction when applied to the prefontal cortex, nucleus accumbens or subthalamic nucleus. Pre-clinical investigations implicate modulation of the cortico-basal ganglia network in these therapeutic effects, and this mechanistic understanding is necessary to optimize stimulation paradigms. Recently, the principle that neuromodulation can reverse drug-evoked synaptic plasticity and reduce behavioral symptoms of addiction has inspired novel stimulation paradigms that have long-term effects in animal models. Pre-clinical studies have also raised the possibility that tailoring neuromodulation protocols can modulate distinct symptoms of addiction. Combining mechanistic knowledge of circuit dysfunction with emerging technologies for non invasive neuromodulation holds promise for developing therapies for addiction and related disorders. PMID- 29524848 TI - Neurocircuitry of aggression and aggression seeking behavior: nose poking into brain circuitry controlling aggression. AB - Aggression is an innate behavior that helps individuals succeed in environments with limited resources. Over the past few decades, neurobiologists have identified neural circuits that promote and modulate aggression; however, far less is known regarding the motivational processes that drive aggression. Recent research suggests that aggression can activate reward centers in the brain to promote positive valence. Here, we review major recent findings regarding neural circuits that regulate aggression, with an emphasis on those regions involved in the rewarding or reinforcing properties of aggressive behavior. PMID- 29524849 TI - Branched poly (lactic acid) microparticles for enhancing the 5-aminolevulinic acid phototoxicity. AB - An innovative microcarrier based on a carboxy-enriched and branched polylactic acid derivative was developed to enhance the in vitro phototoxicity of the photosensitizer and prodrug 5-aminolevulinic. Microparticles, prepared by double emulsion technique and loaded with the prodrug were carefully characterized and the effect of the polymer structure on the chemical, physical and biological properties of the final product was evaluated. Results showed that microparticles have a spherical shape and ability to allocate up to 30 MUg of the photosensitizer per mg of carrier despite their difference in solubility. Release studies performed in various simulated physiological conditions demonstrate the influence of the branched structure and the presence of the additional carboxylic groups on the release rate and the possibility to modulate it. In vitro assays conducted on human epithelial adenocarcinoma cells proved the not cytotoxicity of the carriers in a wide range of concentrations. The hemocompatibility and surface proteins adsorption were evaluated at different microparticles concentrations to evaluate the safety and estimate the possible microparticles residential time in the bloodstream. The advantages, of loading 5-aminolevulinic acid in the prepared carrier has been deeply described in terms of enhanced phototoxicity, compared to the free 5-aminolevulinic acid formulation after irradiation with light at 635 nm. The obtained results demonstrate the advantages of the prepared derivative compared to the linear polylactide for future application in photodynamic therapy based on the photosensitizer 5-aminolevulinic acid. PMID- 29524850 TI - Visible light-induced insulin aggregation on surfaces via photoexcitation of bound thioflavin T. AB - Insulin is known to form amyloid aggregates when agitated in a hydrophobic container. Amyloid aggregation is routinely measured by the fluorescence of the conformational dye thioflavin T, which, when incorporated into amyloid fibers, fluoresces at 480 nm. The kinetics of amyloid aggregation in general is characterized by an initial lag-phase, during which aggregative nuclei form on the hydrophobic surface. These nuclei then lead to the formation of fibrils presenting a rapid growth during the elongation phase. Here we describe a novel mechanism of insulin amyloid aggregation which is surprisingly devoid of a lag time for nucleation. The excitation of thioflavin T by visible light at 440 nm induces the aggregation of thioflavin T-positive insulin fibrils on hydrophobic surfaces in the presence of strong agitation and at physiological pH. This process is material surface-induced and depends on the fact that surface-adsorbed insulin can bind thioflavin T. Light-induced insulin aggregation kinetics is thioflavin T-mediated and is based on an energy transfer from visible light to the protein via thioflavin T. It relies on a constant supply of thioflavin T and insulin from the solution to the aggregate. The growth rate increases with the irradiance and with the concentration of thioflavin T. The supply of insulin seems to be the limiting factor of aggregate growth. This light-induced aggregation process allows the formation of local surface-bound aggregation patterns. PMID- 29524851 TI - Gait strategies to reduce the dynamic joint load in the lower limbs during a loading response in young healthy adults. AB - Reducing external joint moments during gait can lead to a reduction in dynamic joint load. There has yet to be a detailed investigation of gait strategies that can reduce external joint moments by decreasing the magnitude of ground reaction force (GRF) without reducing the walking speed. The objectives of this study were to verify whether it is possible to reduce external joint moments by decreasing the GRF magnitude without reducing the walking speed and to identify the alternative walking strategy involved in young healthy adults. This study included 14 young healthy subjects. They performed two types of walking: normal and impact reduction walking. For impact reduction walking, the subjects walked in a manner that reduced the impact upon foot contact. Cadence and step length were unified between the two conditions. The walking speed, peak value of vertical GRF, braking-accelerating force, loading rate, joint angle, and external joint moments of the two conditions were recorded and compared. No significant difference was noted in the walking speed. However, the first peak of vertical GRF, braking force, and loading rate during loading response were significantly reduced during impact reduction walking, and external joint moments in the hip, knee, and ankle joints were reduced. In contrast, the second peak of vertical GRF, hip extension angle, and external ankle dorsiflexion moment were significantly increased during terminal stance. Our data imply that the ankle joint function during the terminal stance is important in reducing the dynamic joint load in the contralateral leg during the loading response. PMID- 29524852 TI - Light touch leads to increased stability in quiet and perturbed balance: Equivalent effects between post-stroke and healthy older individuals. AB - Cerebral damage provoked by stroke may lead to deficits of quiet balance control and of the recovery of body equilibrium following an unanticipated postural perturbation. In this investigation we aimed to evaluate the effect of light touch (LT) of an earth-fixed surface on balance stability in individuals with post-stroke hemiparesis, taking performance of age-matched healthy participants as reference. Evaluations were made in conditions of full and no visual information. Analysis of quiet balance showed that LT induced higher balance stability, with reduced amplitude and velocity of postural sway. Evaluation of the effect of LT on automatic postural responses was made in the task of recovering body equilibrium following a mechanical perturbation of balance leading to fast forward body sway. Results showed that LT led to reduced amplitude of center of mass displacement following the perturbation, in addition to reduced amplitude and velocity of center of pressure under the feet, and lower activation of the lower legs muscles. Those effects of LT were observed in both the post-stroke and control groups, and did not interact with vision availability. Our results indicated then that individuals who suffered a cerebral stroke can stabilize perturbed and non-perturbed postural responses by lightly touching a stable surface to a similar extent of healthy older individuals. PMID- 29524853 TI - A novel technique for determination of the fructose, glucose and sucrose distribution in nectar from orchids by HPLC-ELSD. AB - The dominant components in floral nectar is fructose, glucose and sucrose. The concentration and the ratio between the sugars are indicative for plant species and play an important part in the interplay between plants and pollinators. In this paper we present a novel HPLC-ELSD based analytical method for sugar characterization of nectar from orchids. Nectar was collected on Whatman No. 1 paper and preserved in the field by 70 v/v% ethanol. The analytical method had a linear range up to at least 3000 mg L-1 for all 3 sugars with a precision of 1.5 1.7%. Correlation coefficients were 0.9999 to 1.0000. The LOD of all sugars were 5-7 mg L-1 and the LOQ were 17-19 mg L-1. Field samples were stable for min. 7 weeks at -18 degrees C. The technique was applied to two species of Platanthera (Orchidaceae) in order to test whether species-related differences in sugar composition could be observed. No differences were found between the two species, which were sucrose-dominant (53.5-100%) though with high variation within species and between individual flowers. PMID- 29524854 TI - An adult ureterocele complicated by a large stone: A case report. AB - INTRODUCTION: Ureterocele is a cystic dilatation of the lower part of the ureter. It is a congenital anomaly that is associated with other anomalies such as a duplicated system, and other diseases. It poses a great challenge owing to its numerous types and clinical presentations. Its incidence is 1 in every 4000 individuals. One of its presentations in the adult population is the presence of a stone, usually a solitary stone, inside the ureterocele. CASE PRESENTATION: We are reporting a case of an adult ureterocele complicated by a large calculus; managed endoscopically with transurethral deroofing of the ureterocele followed by cystolitholapaxy. A literature review was also conducted. DISCUSSION: The pathogenesis of ureteroceles is not well understood, however many proposed mechanisms exist with the incomplete dissolution of chwalla membrane being the most accepted one. The type of ureterocele and age at presentation will help guide the appropriate investigation and management, nevertheless certain goals of treatment should apply to all cases. Adult ureterocele is usually clinically silent but it may co-exist with other conditions such as a ureteral calculus and in these conditions it can be managed endoscopically. CONCLUSION: Ureteroceles complicated by stones can be effectively managed with endoscopic resection or incision of the ureterocele coupled with stone removal, however long term follow up is required to monitor for hydronephrosis and iatrogenic vesicoureteric reflux. PMID- 29524855 TI - Melena as an unusual presentation of gastrointestinal stromal tumour, a case report. AB - INTRODUCTION: Gastrointestinal Stromal Tumors (GISTs) are a rare slow growing malignancy, accounting for less than 1% of all gastrointestinal (GI) tract tumors. These tumors are usually discovered incidentally by endoscopy, surgery or radiology. However on occasions they may present with significant symptoms including GI blood loss. This case report discusses an atypical presentation of a GIST in a 57-year-old female. CASE PRESENTATION: A 57-year-old woman presented to the emergency department following one episode of melena. This occurred on a background of two previous presentations with melena over a 10-year period. She had a preceding surgery for a Meckel's Diverticulum. She was admitted for monitoring and investigation. An emergency upper endoscopy showed no upper gastrointestinal pathology to account for the bleeding. Her condition deteriorated with development of hypovolemic shock, requiring blood transfusion. An urgent CT angiogram identified a large mass in the distal ileum. The patient underwent an emergency laparotomy, where a 9.1 cm tumor located on the distal one third of the ileum was resected. Histopathology confirmed the mass was a GIST. The patient had a successful post-operative period and subsequent treatment with Imatinib. DISCUSSION: The majority of GISTs are found incidentally. This case report describes an unusual presentation of a GIST in which the tumor bled into the intestinal lumen causing significant melena and life threatening hemorrhage. CONCLUSION: We conclude that GIST should be considered as a possible differential in rare cases of GI bleeding where more common causes have been ruled out. PMID- 29524857 TI - An unusual localization of seven months delayed pelvic lymphocele following radical retropubic prostatectomy: Case report and literature review. AB - INTRODUCTION: A pelvic lymphocele is a collection of lymphatic fluid that develops after extensive lymphadenectomies in surgeries such as urological malignancies or renal transplantation. Pelvic lymphoceles may cause complications such as fever, abdominal pain, leg swelling, genital swelling and flank pain. This report summarizes the management of a pelvic lymphocele after open radical retropubic prostatectomy with bilateral lymphadenectomy. PRESENTATION OF CASE: Herein, we present a case in which a pelvic lymphocele developed seven months post-radical open retropubic prostatectomy and through this patient we discussed the lymphocele following radical prostatectomy. The pelvic lymphocele occurred along the sciatic nerve from the sciatica foramen to the intergluteal muscles. The patient was treated with three drainage catheters. This localization is an atypical and unusual for lymphocele after radical retropubic prostatectomy. DISCUSSION: Lymphocele formation that leads to major complications after radical prostatectomy is rare. Lymphocele formation is most commonly seen in the early postoperative period, but it should be considered in patients with fever, abdominal pain or leg swelling during the late postoperative period. Lymphocele formation was the most common cause of hospital readmission after radical prostatectomy. CONCLUSION: Lymphocele formation can be seen in atypical regions and can lead to unexpected complications after radical prostatectomy. Therefore, it should be brought to mind when complaints such as fever and lower extremity swelling occurred in patients underwent extensive lymph node dissection. Surgical treatment options are available, but percutaneous interventions can also be used. PMID- 29524856 TI - Successful laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy for gastric duplication cyst connecting with the pancreatic tail. AB - INTRODUCTION: Gastrointestinal duplication cyst is a congenital rare disease that may occur in any region from mouth to anus. Among them, gastric duplication cysts are very rare. CASE REPORT: Here we report A 23-year-old Japanese man who visited our hospital to evaluate an abdominal tumor. Abdominal computed tomography showed a well-circumscribed homogenous low-density mass measuring 6.2 * 6.0 cm between the pancreatic tail and the upper posterior wall on the gastric greater curvature, and the mass seemed to originate from the pancreatic tail. We found intraoperatively that the mass adhered to the stomach and pancreatic tail strongly, so we performed laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy. Pathological findings showed that the lining epithelium of the cystic mass consisted of the gastric foveolar epithelium with fundic glands. Furthermore, the pancreatic tissue of the pancreatic tail and the muscular layer of the cystic mass were intermingled. DISCUSSION: GDCs are usually diagnosed at a younger age and in adults, they are very rare. Therefore, surgical resection is considered to be the best treatment due to the difficulty of diagnosis, and also that it mimics a pancreatic cystic tumor, and malignant transformation. Complete resection of the cyst is the ideal technique and laparoscopic surgery should be selected whenever possible. CONCLUSION: We experienced a case of GDC continuous to both stomach and pancreatic tail. Laparoscopic surgery is safety and useful even if GDC is continuous with both the stomach and the pancreas. PMID- 29524859 TI - Topographical differences of frontal-midline theta activity reflect functional differences in cognitive control abilities. AB - Electrophysiological oscillations are assumed to be the core mechanism for large scale network communication. The specific role of frontal-midline theta oscillations as cognitive control mechanism is under debate. According to the dual mechanisms of control framework, cognitive control processes can be divided into proactive and reactive control. The present study aimed at investigating the role of frontal-midline theta activity by assessing oscillations in two tasks varying in the type of cognitive control needed. More specifically, a delayed match to sample (DMTS) task requiring proactive control and a color Stroop task recruiting reactive control processes were conducted within the same group of participants. Moreover, both tasks contained conditions with low and high need for cognitive control. As expected larger frontal-midline theta activity was found in conditions with high need for cognitive control. However, theta activity was focally activated at frontal sites in the DMTS task whereas it had a broader topographical distribution in the Stroop task, indicating that both proactive and reactive control are reflected in frontal-midline theta activity but reactive control is additionally characterized by a broader theta activation. These findings support the conclusion that frontal-midline theta acts functionally different depending on task requirements. PMID- 29524858 TI - Specific and total N-nitrosamines formation potentials of nitrogenous micropollutants during chloramination. AB - N-nitrosamines are a group of potent human carcinogens that can be formed during oxidative treatment of drinking water and wastewater. Many tertiary and quaternary amines present in consumer products (e.g., pharmaceuticals, personal care and household products) are known to be N-nitrosodimethylamine (NDMA) precursors during chloramination, but the formation of other N-nitrosamines has been rarely studied. This study investigates the specific and total N-nitrosamine (TONO) formation potential (FP) of various precursors from nitrogen-containing micropollutants (chlorhexidine, metformin, benzalkonium chloride and cetyltrimethylammonium chloride) and tertiary and quaternary model amines (trimethyl amine, N,N-dimethylbutyl amine, N,N-dimethylbenzyl amine and tetramethyl ammonium). All the studied nitrogenous micropollutants displayed quantifiable TONO FP, with molar yields in the range 0.04-11.92%. However, the observed TONO pools constituted mostly of uncharacterized species, not included in US-EPA 8270 N-nitrosamines standard mix. Only the quaternary ammonium compound benzalkonium chloride showed quantifiable NDMA FP (0.56% molar yield), however, explaining only a minor fraction of the observed TONO FP. The studied model amines showed molar NDMA yields from 0.10% (trimethyl amine) to 5.05% (N,N dimethylbenzyl amine), very similar to the molar TONO yields. The comparison of the FPs of micropollutants and model compounds showed that the presence of electron donating functional groups (such as a benzyl group) in tertiary and quaternary amine precursors leads to a higher formation of NDMA and uncharacterized N-nitrosamines, respectively. LC-qTOF screening of a list of proposed N-nitrosamine structures has enabled to identify a novel N-nitrosamine (N-nitroso-N-methyldodecylamine) from the chloramination of benzalkonium chloride. This finding supports the hypothesis that different functional groups in quaternary amines can act as leaving groups during chloramination and form differing N-nitrosamine structures at significant yield. Molar TONO yields determined for micropollutants were finally validated under experimental conditions closer to real water matrices, confirming their representativeness also for lower concentration ranges. PMID- 29524860 TI - Carotid atherosclerosis and risk for ischemic stroke in patients with atrial fibrillation on oral anticoagulant treatment. AB - BACKGROUND AND AIMS: Whether carotid atherosclerosis is associated with an increased risk for ischemic stroke in patients with atrial fibrillation (AF) on anticoagulant treatment is undefined. To explore this association, patients with AF on treatment with vitamin K antagonists were included in a multicenter, prospective study. METHODS: At inclusion in the study, patients underwent Doppler ultrasonography for the assessment of carotid atherosclerosis and then were prospectively followed. Ischemic stroke or transient ischemic attack (TIA) were the primary study outcomes; death and its causes were reported. RESULTS: Overall, 587 patients were included in the study. At ultrasonography, 380 patients had carotid atherosclerosis (64.7%) and 45 internal carotid (ICA) stenosis >=50% (7.7%). During a mean follow-up of 41 +/- 15 months, 30 patients had an ischemic stroke or TIA (1.49% per patient-year, 95% CI 0.96-2.03) and 81 patients died (4.01% per patient-year, 95% CI 3.16-4.86). Carotid atherosclerosis was associated with a significant increase in the risk for the composite of ischemic stroke or TIA or death after adjusting for CHA2DS2VASc (6.0% vs. 3.1% patient year; HR 1.60, 95% CI 0.99-2.59; p = 0.05). ICA >=50% was associated with a not significant increase in the risk of ischemic stroke or TIA (2.05% vs. 1.45% patient-year; HR 1.39, 95% CI 0.42-4.58) or all-cause death (6.1% vs. 3.8% patient-year; HR 1.66, 95% CI 0.83-3.32). CONCLUSIONS: In patients with AF, carotid atherosclerosis is a predictor for the composite of cerebrovascular events or death while on anticoagulant therapy. In patients with AF and carotid atherosclerosis, the clinical benefit of a more intense antithrombotic treatment should be evaluated. PMID- 29524861 TI - Abnormal acetylation of FOXP3 regulated by SIRT-1 induces Treg functional deficiency in patients with abdominal aortic aneurysms. AB - BACKGROUND AND AIMS: Acetylation levels of FOXP3 could influence its expression level and SIRT1 is a deacetylase, which could regulate the acetylation level of FOXP3. We aimed to investigate the mechanism of Treg dysfunction, which might be caused by abnormal acetylation of FOXP3 regulated by SIRT1 in abdominal aortic aneurysm (AAA) patients. METHODS: Peripheral CD4+ T cells from AAA patients, abdominal aortic atherosclerotic occlusive disease (AOD) patients, and healthy donors (HC) were analyzed by flow cytometry to determine the percentage of CD4+CD25+ Tregs and CD4+CD25+FOXP3+ T cells in CD4+ T cells. Expression of FOXP3 and SIRT1 was analyzed by Western Blot. Cultured CD4+ T cells were treated with SIRT1 specific inhibitor EX-527 or left untreated. Acetylation expression of FOXP3 in CD4+ T cells was analyzed by immunoprecipitation and Western Blot. The suppressive function of Treg was analyzed by CFSE-assay. RESULTS: AAA patients had significantly lower CD4+CD25+FOXP3+ T cells. Western blot results showed that AAA CD4+ T cells had significantly less FOXP3 expression but significantly higher SIRT1 expression. After EX-527 treatment, CD4+CD25+FOXP3+ T cells and FOXP3 expression in the AAA group were significantly increased. FOXP3 acetylation level in the AAA group was lower than in control groups. After EX-527 treatment, it was significantly increased. AAA Tregs exhibited less suppressive activity, EX-527 treatment significantly increased the suppressive activity of AAA Tregs. CONCLUSIONS: Our data demonstrate that reduced FOXP3 expression and Treg function in AAA patients are regulated by SIRT1-induced FOXP3 deacetylation. EX-527 could up-regulate FOXP3 acetylation and increase number and suppressive function of Treg in AAA patients. PMID- 29524862 TI - Interleukin-32 upregulates the expression of ABCA1 and ABCG1 resulting in reduced intracellular lipid concentrations in primary human hepatocytes. AB - BACKGROUND AND AIMS: The role of interleukin (IL-)32 in inflammatory conditions is well-established, however, the mechanism behind its role in atherosclerosis remains unexplained. Our group reported a promoter single nucleotide polymorphism in IL-32 associated with higher high-density lipoprotein (HDL) concentrations. We hypothesize that endogenous IL-32 in liver cells, a human monocytic cell line and carotid plaque tissue, can affect atherosclerosis by regulating (HDL) cholesterol homeostasis via expression of cholesterol transporters/mediators. METHODS: Human primary liver cells were stimulated with recombinant human (rh)TNFalpha and poly I:C to study the expression of IL-32 and mediators in cholesterol pathways. Additionally, IL-32 was overexpressed in HepG2 cells and overexpressed and silenced in THP-1 cells to study the direct effect of IL-32 on cholesterol transporters expression and function. RESULTS: Stimulation of human primary liver cells resulted in induction of IL-32alpha, IL-32beta and IL-32gamma mRNA expression (p < 0.01). A strong correlation between the expression of IL-32gamma and ABCA1, ABCG1, LXRalpha and apoA1 was observed (p < 0.01), and intracellular lipid concentrations were reduced in the presence of endogenous IL-32 (p < 0.05). Finally, IL32gamma and ABCA1 mRNA expression was upregulated in carotid plaque tissue and when IL-32 was silenced in THP-1 cells, mRNA expression of ABCA1 was strongly reduced. CONCLUSIONS: Regulation of IL-32 in human primary liver cells, HepG2 and THP-1 cells strongly influences the mRNA expression of ABCA1, ABCG1, LXRalpha and apoA1 and affects intracellular lipid concentrations in the presence of endogenous IL-32. These data, for the first time, show an important role for IL32 in cholesterol homeostasis. PMID- 29524863 TI - The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity. AB - Cardiovascular disease associated with obesity and autoimmunity is the leading cause of death in these populations and significant residual risk remains despite current treatment approaches. Obesity, type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are linked to chronic inflammation, and subjects with these disorders have characteristic shifts in their gut microbiome composition. Recent data suggest that alterations in gut microbial and metabolic composition may be responsible, in part, for induction of chronic inflammation, thus promoting cardiovascular disease. Common microbiome changes observed in obesity, T1DM, RA, and SLE include a decrease in the ratio of bacteria, such as Gram-positive Firmicutes to Gram-negative Bacteroidetes, as well as an overabundance or depletion of certain species, including Prevotella copri. The consequent effects of these shifts include alterations in the metabolic composition of the gut, hyper-activation of toll like receptor 4 (TLR-4), upregulation of inflammatory pathways, e.g. c-Jun N terminal kinase and nuclear factor-kappa B (NFkappaB), increased intestinal permeability, increased C-reactive protein, and increased levels of trimethylamine N-oxide (TMAO). Differential microbiome compositions may also explain sex differences observed in autoimmunity, where a male gut microbiome promotes anti-inflammatory processes as compared to a female pro-inflammatory gut microbiome. Intervention at the level of the microbiota appears to attenuate symptoms in these inflammatory syndromes with probiotic treatment, such as Lactobacilli, playing a uniquely beneficial role in restoring intestinal health, decreasing inflammation, and reducing cardiovascular disease. This review will discuss obesity, T1DM, RA, and SLE in the context of how each unique microbiome profile contributes to elevated cardiovascular risk. PMID- 29524864 TI - Subclinical impairment of myocardial and endothelial functionality in very early psoriatic and rheumatoid arthritis patients: Association with vitamin D and inflammation. AB - BACKGROUND AND AIMS: Cardiovascular (CV) morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas increased prevalence of subclinical atherosclerosis has been reported in these conditions, whether an early myocardial functionality is also impaired remains unknown. The aim of this study was to evaluate the myocardial functionality by speckle-tracking echocardiography (STE) in recent onset RA and PsA patients and its potential associations with the levels of circulating CD34 + cells, vitamin D, and with disease activity. METHODS: STE was used to assess the myocardial functionality in patients with very early RA (n = 41) and PsA (n = 35) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) was estimated. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were measured as surrogate markers of atherosclerosis. Circulating CD34 + counts were evaluated by flow cytometry and vitamin D levels were quantified by HPLC. Disease activity was assessed by Disease Activity Score-28 (DAS28). RESULTS: RA patients exhibited impaired GLS and GCS (both p < 0.001) as compared to HC, GLS being also altered in PsA (p = 0.020 vs. HC). DAS28 was correlated to GLS (r = 0.908, p < 0.001) and GCS (r = 0.868, p < 0.001) in RA, these findings being confirmed by multivariate regression analyses adjusted for confounders and Principal Component Analyses. GLS and GCS were impaired in PsA patients with high disease activity as compared to HC, and GLS was found to be a predictor of cIMT in this condition. On the other hand, vitamin D was negatively associated with cIMT in HC (r = -0.308, p = 0.026) but not in PsA or RA, although decreased levels were observed (both p < 0.001). Vitamin D was an independent predictor of decreased CD34 + levels in PsA and RA. CD34 + counts negatively correlated DAS28, GLS and GCS in RA. CONCLUSIONS: Subclinical myocardial dysfunction is observed in IJD patients with preserved left-ventricular function and without traditional CV risk factors. Subclinical myocardial dysfunction was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Interestingly, myocardial function was altered and associated with cIMT also in PsA patients with high disease activity. PMID- 29524865 TI - Is the lower risk of venous thromboembolism with statins related to low-density lipoprotein reduction? A network meta-analysis and meta-regression of randomised controlled trials. AB - BACKGROUND AND AIMS: Meta-analyses of randomised controlled trials (RCTs) have suggested a possible benefit of statin treatment on the risk of venous thromboembolism (VTE), with potential differences by type and dose of statins. We aimed to assess differences among statins and to investigate the relationship between risk of VTE and reduction of LDL-cholesterol (LDL-c) levels. METHODS: We electronically searched, through November 29, 2017, RCTs comparing a statin with either placebo or another statin treatment, including 100 or more adult participants, and lasting at least 24 weeks. Data on first VTE events and LDL-c was analysed with a network meta-analysis and a meta-regression. RESULTS: Thirty RCTs (159,058 participants; 1431 events) were included, with 28 reporting LDL-c data. Network meta-analysis indicated a larger benefit for rosuvastatin compared to placebo and other statins; 50% of the effect of statins on VTE risk reduction, however, was explained by their different potencies in lowering LDL-c. The risk reduction in VTE was proportional to LDL-c decrease (37% relative lower risk per each 1 mmol/L reduction in LDL-c), without an apparent threshold. A reduction of 1 mmol/L in LDL-c would translate in 37 less VTE events per year in 100,000 people in UK, corresponding to 3162 prevented episodes per year in people between 50 and 59 years. CONCLUSIONS: In RCTs with statin treatment, the reduction of VTE risk was only partially related to LDL-c reduction and the benefit was larger than that observed for atherothrombotic risk. Further RCTs are warranted to clarify the relationship between statin, lipid modifications, and VTE risk. PMID- 29524866 TI - Feasibility and preliminary safety of nitric oxide releasing solution as a treatment for bovine mastitis. AB - Nitric oxide-releasing solution (NORS) is a liquid formulation that releases nitric oxide, a broad spectrum antimicrobial, single electron nitroxide radical. This solution was investigated as a potential antimicrobial treatment for bovine mastitis (BM). Three experiments were performed: a) NORS' effect on Staphylococcus aureus and Escherichia coli in an in vitro model; b) NORS' effect on milk obtained from dairy cows showing symptoms of clinical mastitis; and c) the consequences of administering NORS to healthy milking cattle using a dose escalating in vivo study. Metabolite concentrations were estimated in their blood for methaemoglobin and nitrite; also, milk nitrite concentration and somatic cell count (SCC) were measured to study possible mammary gland inflammation following treatment. NORS lowered the bacterial concentration in all infected samples, in a time- and milk-diluted dependant fashion. Blood methemoglobin concentrations following treatment were all within the normal range for cattle. However, blood and milk nitrite concentrations increased initially but, during the next 24 h, returned to normal range, as did SCC, without any clinical signs of mammary gland inflammation. NORS, if shown to be effective, could be an alternative treatment for mastitis with a shorter clearance time. PMID- 29524867 TI - Low-intensity violence and the social determinants of adolescent health among three East African pastoralist communities. AB - Recently, strong pleas have emerged to place the health of adolescents on the global health agenda. To reposition adolescence front and center, scholars argue that we must work toward a richly contextualized approach that considers the role that social environments play in shaping the final stages of growth and development. We aim to contribute to this deeper understanding of the social determinants of global adolescent health by offering a case study of three nomadic pastoralist communities from northern Kenya. In addition to noteworthy political and economic marginalization, East African pastoralist communities also contend with chronic, low intensity intercommunity conflict. Data collected over five extensive visits from 2008 to 2011, include the 10-19 year olds from 215 randomly sampled Pokot, Samburu, and Turkana households. Using a case/control design, we sampled two sites per ethnic community: one directly affected and one less affected by intercommunity violence. Our nutritional findings indicate that teens ages 15-19 years old had significantly higher anthropometric values compared to younger teens. Living in a wealthier household is associated with greater height, body mass indices, and summed skinfolds for boys but not for girls. Anthropometric measures were influenced by household and community variation in the mixed-effects, multi-level regression models. The Self-Report Questionnaire (SRQ-20) was used to assess psychosocial health, with higher scores associated with living in a community directly affected by violence and having lost a loved one due to violence. Our findings highlight the unique nature of adolescent health challenges but also the central role even subtle differences across communities and households play in shaping young people's experiences. With few studies to document the lived experience of pastoralist youth as they move toward adulthood, examining how such challenging socioeconomic environment shapes health seems long overdue. PMID- 29524868 TI - Brokerage in commercialised healthcare systems: A conceptual framework and empirical evidence from Uttar Pradesh. AB - In many contexts there are a range of individuals and organisations offering healthcare services that differ widely in cost, quality and outcomes. This complexity is exacerbated by processes of healthcare commercialisation. Yet reliable information on healthcare provision is often limited, and progress to and through the healthcare system may depend on knowledge drawn from prior experiences, social networks and the providers themselves. It is in these contexts that healthcare brokerage emerges and third-party actors facilitate access to healthcare. This article presents a novel framework for studying brokerage of access to healthcare, and empirical evidence on healthcare brokerage in urban slums in Lucknow, Uttar Pradesh. The framework comprises six areas of interest that have been derived from sociological and political science literature on brokerage. A framework approach was used to group observational and interview data into six framework charts (one for each area of interest) to facilitate close thematic analysis. A cadre of women in Lucknow's urban slums performed healthcare brokerage by encouraging use of particular healthcare services, organising travel, and mediating communications and fee negotiations with providers. The women emphasised their personal role in facilitating access to care and encouraged dependency on their services by withholding information from users. They received commission payments from healthcare programmes, and sometimes from users and hospitals as well, but were blamed for issues beyond their control. Disruption to their ability to facilitate low-cost healthcare meant some women lost their positions as brokers, while others adapted by leveraging old and new relationships with hospital managers. Brokerage analysis reveals how people capitalise on the complexity of healthcare systems by positioning themselves as intermediaries. Commercialised healthcare systems offer a fertile environment for such behaviours, which can undermine attainment of healthcare entitlements and exacerbate inequities in healthcare access. PMID- 29524869 TI - The role of place on healthcare quality improvement: A qualitative case study of a teaching hospital. AB - This article examines how the built environment impacts, and is impacted by, healthcare staff day to day practice, care outcomes and the design of new quality and patient safety (Q&PS) projects. It also explores how perceptions of the built environment affect inter-professional dynamics. In doing so, it contributes to the overlooked interplay between the physical, social, and symbolic dimensions associated with a hospital's place. The study draws on 46 in-depth semi structured interviews conducted at a large teaching hospital in Portugal formed by two buildings. Interview transcripts were analysed inductively using thematic analysis. The major contribution of this study is to advance the understanding of the interactions among the different dimensions of place on Q&PS improvement. For example, findings indicate that some of the characteristics of the physical infrastructure of the hospital have a negative impact on the quality of care provided and/or significantly limit the initiatives that can be implemented to improve it, including refurbishment works. However, decisions on refurbishment works were also influenced by the characteristics of the patient population, hospital budget, etc. Likewise, clinicians' emotional reactions to the limitations of the buildings depended on their expectations of the buildings and the symbolic projections they attributed to them. Nevertheless, differences between clinicians' expectations regarding the physical infrastructure and its actual features influenced clinicians' views on Q&PS initiatives designed by non clinicians. PMID- 29524870 TI - "What is meant by public?": Stakeholder views on strengthening impacts of public reporting of hospital performance data. AB - Public reporting of hospital performance data is a developing area that is gaining increased attention. This is the first study to explore a range of stakeholder opinions on how such public reporting could be strengthened in Australia. Thirty-four semi-structured interviews were conducted with a purposive sample of expert healthcare consumer, provider and purchaser informants who worked in a variety of senior roles and had knowledge of or involvement in public reporting of hospital data within the public or private healthcare sectors. Informants from all Australian states, territory and national jurisdictions participated. Thematic analysis was used to gain an overview of experts' opinions to inform policy and systems-development for strengthening foundational frameworks for public reporting of health services performance. Themes arising were synthesised to generate explanatory figures to highlight key areas for strengthening public reporting. Our findings suggest that in Australia there is a lack of agreement on what the objectives and who the audience are for public reporting of hospital performance data. Without this shared understanding it is difficult to strengthen frameworks and impacts of public reporting. When developing frameworks for public reporting of hospital data in Australia, more explicit definition of what or who are the 'public' is needed along with identification of barriers, desired impacts, data needs, and data collection/reporting/feedback mechanisms. All relevant stakeholders should be involved in design of public reporting frameworks. Offering multiple systems of public reporting, each tailored to particular audiences, might enable greater impact of reporting towards improved hospital quality and safety, and consumer knowledge to inform treatment decisions. This study provides an overview of perspectives, but further research is warranted to develop PR frameworks that can generate greatest impacts for the needs of various audiences. PMID- 29524871 TI - Ownership and hospital behaviour: Employment and local unemployment. AB - In this paper, we address two issues: i) how hospital employment changes with local unemployment, according to the type of hospital ownership, and ii) whether this relationship changed after the implementation of a pro-competitive reform that made hospitals more similar. A 2006-2010 French panel of 1695 hospitals over five waves allows us to consider within-hospital employment changes. We first find that higher local unemployment is associated with greater employment in State-owned hospitals, but not for any other hospital ownership type: French local authorities then seem to respond to depressed local labour markets by increasing employment in State-owned hospitals. After the full implementation of the pro-competitive reform hospital funding became based only on activity and no longer on some historical budget. Theoretically, the new reimbursement system should break the relationship between public-hospital employment and local unemployment. Our results reveal that the reform worked as expected in less deprived areas: reducing employment and eliminating the correlation between local unemployment and State-owned hospital employment. However, in higher-unemployment areas, public-hospital employment remains counter-cyclical. Poor local labour market health then seems to trump financial incentives in determining employment in public hospitals. PMID- 29524872 TI - Illegal drug use and its correlates in San Juan, Puerto Rico. AB - BACKGROUND: Data on the prevalence and correlates of illegal drug use in Puerto Rico are now almost 20 years old. OBJECTIVES: This study sought to estimate the 12-month prevalence of illegal and non-prescribed medical drug use in San Juan, Puerto Rico and identify sociodemographic correlates of use. METHODS: Data are from a random household sample of 1510 individuals, 18-64 years of age in San Juan, Puerto Rico. RESULTS: The 12-month prevalence of any illegal or non prescribed drug use was 16.5%. Prevalence among men (20.7%) was higher than among women (12.9%; chi2 = 16.308; df = 1; p < .01). Prevalence for specific drugs ranged from 11.2% for marijuana to 0.2% for methadone. RESULTS: of the multiple logistic regression analysis showed that male gender (OR = 1.67, 95CI = 1.21-2.3; p < .01), age 18-29 (OR = 2.39; 95CI = 1.35-4.23; p < .01), age 30-39 (OR = 1.93; 95CI = 1.01-3.69; p < .05), low (OR = 2.03; 95CI = 1.36-3.02; p < .001) and medium (OR = 1.50; 95CL = 1.01-2.23; p < .05) family cohesion/pride, and no religious preference (OR = 1.99; 95CI = 1.23-3.22; p < .01) increased the odds of drug use. Annual family income of $40,000-$60,000 (OR = 0.45; 95CI = 0.21-0.93; p < .05) and $60,001 and more (OR = 0.35; 95CI = 0.13-0.94; p > .05) were negatively associated with drug use compared to annual income up to $10,000. CONCLUSIONS: As in many other places in the U.S., drug use in San Juan, Puerto Rico is high, affecting about 1 in 6 adults in the population. The highest prevalence is for marijuana use, which cannot be medically prescribed and of which recreational use is illegal on the island. PMID- 29524873 TI - Child injury deaths linked with adult alcohol consumption: A time series analysis. AB - OBJECTIVE: This paper aims to quantify the population-level associations between child injury deaths and adult (aged 15+ years) per capita alcohol consumption (PCC) and between child injury deaths and the impact of major alcohol and safety policy changes in Australia. METHODS: All child deaths due to external causes during 1910-2013, and child deaths due specifically to road crashes, assaults, suicide and other external causes, were obtained from the Australian Institute of Health and Welfare. Child (0-14 year) mortality rates were analysed in relation to PCC using an Autoregressive Integrated Moving Average model. RESULTS: A positive association between PCC and overall child external mortality was identified. The estimated coefficient was 0.326 (p = .002), indicating that a 10% decrease in PCC was associated with a 3.3% reduction in child injury mortality. A positive association was identified for road traffic and other child injury mortality, but not assault injuries. The introduction of compulsory seatbelt legislation in combination with random breath testing was associated with a reduction in overall injury and road traffic child mortality. Decreasing the legal drinking age was associated with an increase in the rate of other external cause child mortality. CONCLUSION: Reducing PCC in Australia is likely to result in a small but significant reduction in the injury mortality rate of children aged 0-14 years. PMID- 29524874 TI - The national implementation of Contingency Management (CM) in the Department of Veterans Affairs: Attendance at CM sessions and substance use outcomes. AB - BACKGROUND: In 2011, the Department of Veterans Affairs launched an initiative to expand patients' access to contingency management (CM) for the treatment of substance use disorders, particularly stimulant use disorder. This study evaluates the uptake and effectiveness of the VA initiative by presenting data on participation in coaching, fidelity to key components of the CM protocol, and clinical outcomes (CM attendance and substance use). METHODS: Fifty-five months after the first VA stations began offering CM to patients in June 2011, 94 stations had made CM available to 2060 patients. As those 94 VA stations began delivering CM to Veterans, their staff participated in coaching calls to maintain fidelity to CM procedures. As a part of the CM coaching process, those 94 implementation sites provided data describing the setting and structure of their CM programs as well as their fidelity practices. Additional data on patients' CM attendance and urine test results also were collected from the 94 implementation sites. RESULTS: The mean number of coaching calls the 94 programs participated in was 6.5. The majority of sites implemented CM according to recommended standard guidelines and reported high fidelity with most CM practices. On average, patients attended more than half their scheduled CM sessions, and the average percent of samples that tested negative for the target substance was 91.1%. CONCLUSION: The VA's CM implementation initiative has resulted in widespread uptake of CM and produced attendance and substance use outcomes comparable to those found in controlled clinical trials. PMID- 29524875 TI - The simultaneous capture of mercury and fine particles by hybrid filter with powder activated carbon injection. AB - The hybrid filter (HF) was newly designed and operated with powder activated carbon (PAC) injection to capture mercury and fine particulate matter in the coal power plant. With PAC injection in HF operation, the capture efficiency of elemental mercury was clearly enhanced. When the injection rate of PAC increased from 0 to 20 mg/m3, the speciation fraction of elemental mercury significantly decreased from 85.19% to 3.76% at the inlet of the hybrid filter. The speciation fraction of oxidized mercury did not vary greatly, whereas the particulate mercury increased from 1.31% to 94.04%. It was clearly observed that the HF played a role in the capture of mercury and fine PM by leading the conversion of elemental mercury as particulate mercury and the growth of PM via electrode discharge in the HF operation with PAC injection. PMID- 29524876 TI - Molecular markers of benzene polycarboxylic acids in describing biochar physiochemical properties and sorption characteristics. AB - Biochar function in soil is based on properties such as sorption characteristics, and these are expected to change throughout the life cycle of the biochar. Because biochar particles cannot easily be separated from soil particles, this change is seldom investigated. Biochar-related molecular markers, such as benzene polycarboxylic acids (BPCAs) are promising tools for studying the properties of biochars in complex environmental matrices. In this study, biochars were derived from corn straw and pine wood sawdust at 200-500 degrees C, and their aging was simulated with NaClO. Biochar properties were characterized by elemental analysis, BET surface characterization and BPCA molecular marker analysis. Chemical oxidation decreased the surface area (SA) but increased the O content of biochars. The oxidation decreased the amount of biochars, with a mass loss in the range of 10-55%. A similar mass loss was also observed for BPCAs and was negatively related to both the pyrolysis temperature and the extent of the condensed structure (higher aromaticity). The biochar amounts were calculated quantitatively using the sum of BPCA contents, with a conversion factor (the ratio of biochar amount to BPCA content) in the range of 3.3-5.5, and were negatively related to the B5CA content. Three model pollutants, namely, bisphenol A (BPA), sulfamethoxazole (SMX), and phenanthrene (PHE), were chosen to study the sorption characteristics of biochar before and after oxidation. Chemical oxidation generally increased SMX sorption but decreased PHE sorption. The nonlinear factor n, based on Freundlich equation modeling, was negatively related to B6CA for all three chemicals. The BPCA molecular markers, especially B5CA and B6CA, were correlated to the biochar properties before and after oxidation and are thus a potentially useful technique for describing the characteristics of biochar in the environment. PMID- 29524877 TI - Impact of inorganic ions and pH variations on toxicity and endocrine potential of selected environmentally relevant pharmaceuticals. AB - Assessment of the impact of pharmaceutical residues on living organisms is a very complex subject. Apart from taking into account the toxicity of individual compounds, environmental factors should also be taken into account. In this paper, attempts were made to assess the impact of coexisting inorganic ions and changes in pH on the toxicity of ten selected pharmaceuticals. Two bioassays were used to measure the estrogenic and androgenic effects (XenoScreen YES/YAS - Saccharomyces cerevisiae) and acute toxicity (Microtox(r) - Vibrio fischeri). The Microtox(r) test gave the most definitive outputs concerning the determination of interaction type between drugs and chemical species. Synergism was proven for almost all drugs and chemical species, and only two cases of antagonism were found. Significant drug/pH interactions were rare. Regarding the XenoScreen YES/YAS bioassay, when estrogenic and androgenic agonistic effects (YES+ and YAS+, respectively) were studied, many cases of well-expressed synergism for all inorganic ions with limited number of drugs (diazepam, fluoxetine, estrone, chloramphenicol for the YES+ test and diazepam, progesterone, androstenedione, and estrone for the YAS+ test) were found. Antagonism was also proven for the YES+ test, especially for diclofenac and androstenedione interacting with cations. On the other hand, the YES- and YAS- tests (estrogenic and androgenic, respectively, antagonistic effects) did not indicate cases of synergetic interaction except for the couples Br-/diazepam and NH4+/ketoprofen. Antagonistic drug/ion interactions were detected only with diclofenac and fluoxetine. It is interesting that well-expressed (antagonism or synergism) drug/pH interactions were rare. Both tests were found utilizable in performing studies on impact of ions/pH fluctuations on drugs mixtures' toxicity confirming in most cases synergic impact of parameters studied on toxicity. The approach proposed in the paper seems to be proven as a reliable tool in assessing impact of abiotic factors on toxicity and endocrine potential of complex mixtures of pharmaceuticals' mixtures. PMID- 29524878 TI - Risk of breast cancer and residential proximity to industrial installations: New findings from a multicase-control study (MCC-Spain). AB - Breast cancer is the most frequent tumor in women worldwide, although well established risk factors account for 53%-55% of cases. Therefore, other risk factors, including environmental exposures, may explain the remaining variation. Our objective was to assess the relationship between risk of breast cancer and residential proximity to industries, according to categories of industrial groups and specific pollutants released, in the context of a population-based multicase control study of incident cancer carried out in Spain (MCC-Spain). Using the current residence of cases and controls, this study was restricted to small administrative divisions, including both breast cancer cases (452) and controls (1511) in the 10 geographical areas recruiting breast cancer cases. Distances were calculated from the respective woman's residences to the 116 industries located in the study area. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (between 1 km and 3 km) to industrial plants, adjusting for matching variables and other confounders. Excess risk (OR; 95%CI) of breast cancer was found near industries overall (1.30; 1.00-1.69 at 3 km), particularly organic chemical industry (2.12; 1.20-3.76 at 2.5 km), food/beverage sector (1.87; 1.26-2.78 at 3 km), ceramic (4.71; 1.62-13.66 at 1.5 km), surface treatment with organic solvents (2.00; 1.23 3.24 at 3 km), and surface treatment of plastic and metals (1.51; 1.06-2.14 at 3 km). By pollutants, the excess risk (OR; 95%CI) was detected near industries releasing pesticides (2.09; 1.14-3.82 at 2 km), and dichloromethane (2.09; 1.28 3.40 at 3 km). Our results suggest a possible increased risk of breast cancer in women living near specific industrial plants and support the need for more detailed exposure assessment of certain agents released by these plants. PMID- 29524879 TI - Chemosensitizing effect of Alpinia officinarum rhizome extract in cisplatin treated rats with hepatocellular carcinoma. AB - This study was conducted to estimate the preventing and sensitizing efficiency of Alpinia officinarum rhizome extract (AORE) in an experimental model of hepatocellular carcinoma (HCC) +/- cisplatin. HCC was induced by a single intraperitoneal (i.p) dose of diethylnitrosamine (DENA, 200mg/kg). After 14 days, phenobarbitone (PB, 0.05%) was added to drinking water for 14 weeks to promote hepatocarcinogenesis. Cisplatin (CP) was given in a dose of 1.5 mg/kg (i.p), twice a week, alone or with AORE (400 mg/kg daily, orally) for 21 days. AORE was tried as a protective before the induction of HCC for three weeks as well. Results revealed that DENA/PB elevated hepatic indices as ALT and AST and total bilirubin with declining serum total protein. It increased oxidative stress, as hepatic malondialdehyde (MDA) with depressed hepatic reduced glutathione (GSH) contents, superoxide dismutase (SOD) and catalase activities. This was accompanied by an increase in hepatic expression of antioxidant genes (thioredoxin and glutaredoxin). Hepatocarcinogenesis was detected by histopathological changes in liver sections and the elevation of serum alpha fetoprotein (AFP) level. Treatment with CP partially restored altered hepatic functions and oxidative stress markers. It also showed a partial decrease in the expression of antioxidant genes, improving histopathological changes in the liver and AFP level in serum. The treatment with AORE alone or AORE+CP enhanced hepatic function and oxidative stress markers. It also caused a decrease in the expression of antioxidant genes and improved histopathological changes in liver and serum AFP level. This effect is more potent than the treatment with CP alone. Our study suggested that AORE can be used as a promising natural chemoprevention or a chemosensitizing agent against hepatocarcinogenesis. PMID- 29524880 TI - Isoorientin triggers apoptosis of hepatoblastoma by inducing DNA double-strand breaks and suppressing homologous recombination repair. AB - Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo. Mechanistic studies showed that Iso triggered cell apoptosis by inducing DNA double-stranded breaks and blocking the initiation process of homologous recombination repair, which was related to the attenuation of ataxia telangiectasia mutated (ATM) activation and inhibiting the binding of phosphorylated ataxia telangiectasia mutated (pATM) and the MRE11-RAD50-NBS1 (MRN) complex. Furthermore, Iso markedly sensitized HB cells to the anti proliferative effects of the poly ADP-ribose polymerase (PARP) inhibitor olaparib both in vivo and in vitro. Taken together, our study first showed that Iso was a DNA-damage agent, and the combination of Iso with a PARP inhibitor might be a promising strategy for treating HB patients. PMID- 29524881 TI - Human umbilical cord mesenchymal stem cells improve irradiation-induced skin ulcers healing of rat models. AB - Irradiation-induced skin ulcers can be resultant from nuclear accident or reaction to radiation therapy of tumor and is intractable for healing. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been considered to be the potential therapeutic tools for tissue regeneration. However, the underlying mechanisms are still not well understood. This study aims to investigate the effects of hUC-MSCs on irradiation-induced skin ulcers healing and the related mechanisms. The ulcers were induced by irradiating the skin of adult SD rats. The ulcers of SD rats were treated with vehicle or hUC-MSCs donated from mother giving birth. The ulcer healing was measured by imaging the healing rate and the H&E staining. CD31 and VEGF expression was measured with immunohistochemistry assay. iTRAQ proteomics analysis was used to analyze the signaling pathway. The results showed that hUC-MSCs improved healing of irradiation-induced skin ulcers in vivo using a rat model of skin ulcer. Transplantation of hUC-MSCs promoted keratin generation and keratinocytes proliferation of ulcer areas. Furthermore, the results demonstrated that hUC-MSCs increased expression of CD31 and VEGF in ulcers and promoted neovascularization. iTRAQ proteomics analysis results indicated that PI3K/Akt signaling pathway involved in hUC-MSCs-mediated repairing of irradiation-induced skin ulcer. In conclusion, human umbilical cord mesenchymal stem cells promoted neovascularization and re-epithelization, and improved healing of irradiation-induced skin ulcers. This healing improvement may be conducted through activating the PI3K/Akt signaling pathway, however, which needs to be proven by the further investigations. PMID- 29524882 TI - Phenolic acids potentiate colistin-mediated killing of Acinetobacter baumannii by inducing redox imbalance. AB - Phenolic acids with catechol groups are good prooxidants because of their low redox potential. In this study, we provided data showing that phenolic acids, caffeic acid, gallic acid and protocatechuic acid, enhanced colistin-mediated bacterial death by inducing redox imbalance. The minimum inhibitory concentrations of these phenolic acids against Acinetobacter baumannii AB5075 were considerably lowered for DeltasodB and DeltakatG mutants. Checkerboard assay shows synergistic interactions between colistin and phenolic acids. The phenolic acids exacerbated colistin-induced oxidative stress in A. baumannii AB5075 through increased superoxide anion generation, NAD + /NADH and ADP/ATP ratio. In parallel, the level of reduced glutathione was significantly lowered. We conclude that phenolic acids potentiate colistin-induced oxidative stress in A. baumannii AB5075 by increasing ROS generation, energy metabolism and electron transport chain activity with a concomitant decrease in glutathione. PMID- 29524883 TI - Halofuginone attenuates intervertebral discs degeneration by suppressing collagen I production and inactivating TGFbeta and NF-kB pathway. AB - Most low back pain is caused by intervertebral discs (IVD) degeneration, a disease that prevalence is increasing with age. Halofuginone, an analog of ferbrifugine isolated from plant Dichroa febrifuga, has drawn much attention in recent years for the wide range of bioactivities in malaria, cancer, fibrotic and autoimmune diseases. In this study, we evaluated the benefit effects of halofuginone in IVD degeneration treatment in a validated rabbit puncture model. Halofuginone treatment could attenuate disc degeneration by suppressing the decrease of discs height and nucleus pulposus signal strength. Besides, halofuginone treatment could suppress mRNA and protein expression of collagen I in nucleus pulposus. This might possibly due to the inactivation of transform growth factor-beta (TGFbeta) signal pathway by down-regulating p-Samd3 and up regulating inhibitory Smad7. Then, we evaluated the effects of halofuginone treatment on nuclear factor of kappa B (NF-kappaB) signal pathway and its downstream pro-inflammatory cytokines. The level of p-p65 and p-IkappaBalpha was down-regulated in halofuginone treated group, indicating the inactivation of NF kappaB signal pathway. The mRNA expression of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 8 (IL-8) was decreased in nucleus pulposus too, indicating the down-regulation of pro inflammatory cytokines. In conclusion, halofuginone treatment could attenuate IVD degeneration and this was possibly due to suppressing of collagen I production and inactivation of TGFbeta and NF-kappaB signal pathway in nucleus pulposus of degenerated discs. These results suggest that halofuginone has the potential for IVD degeneration treatment, but more research is needed to validate this. PMID- 29524884 TI - Steviol slows renal cyst growth by reducing AQP2 expression and promoting AQP2 degradation. AB - Overexpression of aquaporin 2 (AQP2) was observed and suggested to be involved in fluid secretion leading to cyst enlargement in polycystic kidney disease (PKD). The cyst expansion deteriorates the renal function and, therefore, therapies targeting cyst enlargement are of clinical interest. Of note, inhibition of vasopressin function using vasopressin 2 receptor (V2R) antagonist which decreased cAMP production along with AQP2 production and function can slow cyst growth in ADPKD. This finding supports the role of AQP2 in cyst enlargement. Steviol, a major metabolite of the sweetening compound stevioside, was reported to retard MDCK cyst growth and enlargement by inhibiting CFTR activity. Interestingly, its efficacy was found to be higher than that of CFTRinh-172. Since steviol was also found to produce diuresis in rodent, it is likely that steviol might have an additional effect in retarding cyst progression, such as inhibition of AQP2 expression and function. Here, we investigated the effect of steviol on AQP2 function and on cyst growth using an in vitro cyst model (MDCK and Pkd1-/- cells). We found that steviol could markedly inhibit cyst growth by reducing AQP2 expression in both Pkd1-/- and MDCK cells. Real-time PCR also revealed that steviol decreased AQP2 mRNA expression level as well. Moreover, a proteasome inhibitor, MG-132, and the lysosomotropic agent, hydroxychloroquine (HCQ) were found to abolish the inhibitory effect of steviol in Pkd1-/- cells. Increased lysosomal enzyme marker (LAMP2) expression following steviol treatment clearly confirmed the involvement of lysosomes in steviol action. In conclusion, our finding showed for the first time that steviol slowed cyst growth, in part, by reducing AQP2 transcription, promoted proteasome, and lysosome-mediated AQP2 degradation. Due to its multiple actions, steviol is a promising compound for further development in the treatment of PKD. PMID- 29524885 TI - MiR-149 suppresses the inflammatory response of chondrocytes in osteoarthritis by down-regulating the activation of TAK1/NF-kappaB. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that with the complication of disability, while inflammation is the important response of OA. MiR-149 was down-regulated in the OA tissues, while the potential mechanism of miR-149 in OA is unclear. METHODS: A total of 20 OA patients and 20 healthy persons were enrolled in the present study. Real-time PCR was used to detect miR 149 and the mRNA expression of TAK1, western blot was used to detect the protein expression of TAK1. Luciferase reporter assay was performed to identify the targeting relationship between miR-149 and TAK1. Elisa assay was used to identify the level of several pro-inflammatory cytokines. RESULTS: MiR-149 was down regulated in both OA tissues and IL-1beta-induced chondrocytes, while the expression of TAK1 was opposite. TAK1 was the target gene miR-149 targets TAK1 to regulate its expression. Human normal chondrocytes subjected to IL-1beta significantly promoted the inflammatory response, and also accelerated the activation of NF-kappaB signaling pathway, while alternatively si-TAK1, miR-149 mimic or PDTC reversed the effects of IL-1beta. Cells transfected with miR-149 inhibitor promotes the level of inflammation cytokines, as well as the activation of NF-kappaB, while cells co-transfected with si-TAK1 and miR-149 inhibitor abolishes the effects of miR-149 inhibitor. CONCLUSION: MiR-149 targets TAK1 to regulate the pathogenesis of OA, among which TAK1/NF-kappaB signaling acted as an important pathway in the inflammatory response that induced by IL-1beta. PMID- 29524886 TI - Long non-coding RNA Linc00675 suppresses cell proliferation and metastasis in colorectal cancer via acting on miR-942 and Wnt/beta-catenin signaling. AB - Substantial evidence has demonstrated the involvement of long non-coding RNAs (lncRNAs) in the development and progression of colorectal cancer (CRC) via their regulation on cancer cell proliferation, apoptosis, invasion and metastasis pathways. The current study aimed to understand the role of lncRNA Linc00675 in the progression and metastasis of CRC and to identify the potential lncRNA-miRNA interactions and signaling pathways underlying the mechanisms of action of Linc00675 in CRC. Our data firstly demonstrated the down-regulation of Linc00675 in both CRC cells and clinical CRC tissues. Expression of Linc00675 was also relatively low in metastatic tumors and advanced tumors. Further studies also showed that overexpression of Linc00675 inhibited the proliferation, invasion and migration of CRC cells. In addition, our data also revealed the negative regulation of miR-942 by Linc00675 and the relatively higher expression of miR 942 in clinical CRC tissues. More importantly, the inhibitory effect of Linc00675 on proliferation, invasion and migration of HCT116 cells was also significantly attenuated in the presence of miR-942 mimic, suggesting that down-regulation of miR-942 represented one of the mechanisms by which Linc00675 inhibited the proliferation and metastasis of CRC. Furthermore, we also demonstrated the inhibition of Wnt/beta-catenin signaling in the Linc00675/miR-942 regulated pathway in CRC cells. Taken together, our findings suggested Linc00675 as a potential molecular marker and target for the diagnosis and treatment of CRC and enhanced the current understanding on the mechanisms of action of Linc00675 in CRC. PMID- 29524887 TI - LC-MS/MS determination of antiretroviral drugs in influents and effluents from wastewater treatment plants in KwaZulu-Natal, South Africa. AB - South Africa has the largest occurrence of the human immune deficiency virus (HIV) in the world but has also implemented the largest antiretroviral (ARV) treatment programme. It was therefore of interest to determine the presence and concentrations of commonly used antiretroviral drugs (ARVDs) and, also, to determine the capabilities of wastewater treatment plants (WWTPs) for removing ARVDs. To this end, a surrogate standard based LC-MS/MS method was optimized and applied for the detection of thirteen ARVDs used in the treatment and management of HIV/acquired immune deficiency syndrome (HIV/AIDS) in two major and one modular WWTP in the eThekwini Municipality in KwaZulu-Natal, South Africa. The method was validated and the detection limits fell within the range of 2-20 ng L 1. The analytical recoveries for the ARVDs were mainly greater than 50% with acceptable relative standard deviations. The concentration values ranged from 0.2MUm particles. This strongly implied that the particulate DMA+ and TMA+ at <0.2MUm size range overwhelmingly existed in the liquid organic phase as unprotonated TMA and DMA, but those at the >0.2MUm size range mainly existed in the aqueous (or solid) phase where the dominance of gas-aerosol equilibria would cause the ratios to be almost size-independent. The size-dependent phase states corresponded to their various formation pathways. PMID- 29524891 TI - Sustainability assessment of alternative end-uses for disused areas based on multi-criteria decision-making method. AB - The main aim of this study was to define and apply a multidisciplinary and multi criteria approach to sustainability in evaluating alternative end-uses for disused areas. Taking into account the three pillars of sustainability (social, economic and environmental dimension) as well as the need for stakeholders to have new practical instruments, the innovative approach consists of four modules stated (i) sociological, (ii) economic, (iii) environmental and (iv) multi criteria assessment. By means of a case study on a small Municipality in Southern Italy, three end-uses alternatives, representing three essential services for citizens, were selected: Municipal gym; Market area; Municipal Solid Waste (MSW) separate collection centre. The sociological module was useful to select the most socially sound alternative by means of a consultative referendum, simulated with the use of a structured questionnaire administered to a sample of the population. The economic evaluation was conducted defining the bill of quantities with regarding to six main items (soil handling, landfill disposal tax, public services, structure and services, completion work, equipment and furnishings). The environmental evaluation was performed applying the Delphi method with local technicians who were involved in a qualitative-quantitative evaluation of the three alternatives with regarding to eight possible environmental impacts (landscape impact, soil handling, odour, traffic, noise, atmospheric pollution, wastewater, waste). Finally, the Simple Additive Weighting was used as multi criteria technique to define alternatives priorities. The obtained results showed how the multi-criteria analysis is a useful decision support tool able to identify transparently and efficiently the most sustainable solutions to a complex social problem. PMID- 29524892 TI - A novel method of simultaneous NH4+ and NO3- removal using Fe cycling as a catalyst: Feammox coupled with NAFO. AB - The feasibility of using Feammox coupled with nitrate-dependent Fe(II) oxidizing (NAFO) to cause the simultaneous conversion of NH4+ and NO3- was explored by inoculation with Feammox sludge and the use Fe cycling as catalyst. After 61days operation, the simultaneous conversion of NO3- and NH4+ occurred with the presence of interconversion between Fe(III) and Fe(II). The conversion ratio of NH4+ to NO3- stabilized at 0.9-1. The results of isotopic tracing and microbial diversity analysis indicated that NH4+ was first oxidized to NO2- by Fe(III), then NO3- was reduced to NO2- and N2 by the Fe(II) produced in Feammox process, and finally, the NO2- produced in NAFO process underwent an Anammox process with the remaining NH4+ to yield N2. The results showed the simultaneous continuous conversion process of NO3- and NH4+ with limited Fe as a catalyst was a coupled process of Feammox, Anammox, and NAFO under the anaerobic conditions. PMID- 29524893 TI - Formation of organobromine and organoiodine compounds by engineered TiO2 nanoparticle-induced photohalogenation of dissolved organic matter in environmental waters. AB - There are increasing concerns about the adverse effects of released engineered nanoparticles and photochemically formed organohalogen compounds (OHCs) on human health and the environment. Herein, we report that titanium dioxide nanoparticles (TiO2 NPs) can photocatalytically halogenate dissolved organic matter (DOM) to form a large number of organobromine compounds (OBCs) and organoiodine compounds (OICs), as characterized by negative ion electrospray ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry. Compared with no OHCs produced in control samples in darkness and/or without TiO2 NPs under sunlight irradiation, various OBCs and OICs were detected in freshwater and seawater under sunlight irradiation for 12h and 24h even in the presence of 1mgL 1 TiO2 NPs, indicating the photocatalytic roles TiO2 NPs played in DOM halogenation. Furthermore, TiO2 NPs could result in the photodegradation of newly formed OHCs, as evidenced by the intensity and the number of some OHCs decreased with reaction time. In addition, many TiO2 NP-induced OBCs contained two or three bromine atoms, and/or nitrogen and sulfur elements, belonging to lignin-like, tannin-like, unsaturated hydrocarbon and aliphatic compounds. While the OICs were primarily contained one iodine, and very few consisted of nitrogen and sulfur elements, most were lignin-like and tannin-like compounds. Finally, the OBCs in freshwater were found to be formed mainly via a substitution reaction or addition reaction and were accompanied by other reactions such as photooxidation, while the OBCs in seawater and OICs were formed primarily via substitution reactions. Given the abundance of produced OHCs and their toxicity, our findings call for further studies on the exact structure and toxicity of the formed OHCs, taking account the TiO2 NP-induced DOM photohalogenation in aquatic environments during the evaluation of the environmental effects of engineered TiO2 NPs. PMID- 29524894 TI - Occurrence of pesticide residues in fish from south American rainfed agroecosystems. AB - Environmental sustainability of South American rainfed agroecosystems is of current concern. In this work, we evaluate the occurrence of multiple pesticide residues in muscle tissue of wild fish species from two large rivers in South America (Uruguay and Negro Rivers). Two sampling campaigns (representing summer and winter crops) were performed during 2015 targeting a wide biodiversity of fish species used for human consumption (ranging from migratory to non-migratory and from detritivorous to top-predators). Three different localities associated to rainfed agriculture were assessed, two of them enclosed to a RAMSAR site (National Park "Esteros de Farrapos e Islas del Rio Uruguay"). Pesticide residues occurred in muscle tissue of 143 from 149 sampled fishes (96%). Thirty different pesticides were detected at concentrations from <1 to 194MUgkg-1. Incidence of pesticides in fish were tightly related to: i) features of the contaminant: (Kow, environmental persistence and mobility) and ii) intensity of use of particular pesticides and land dedicated to rainfed agriculture. Trifloxystrobin, metolachlor and pyraclostrobin showed the highest rates of occurrence. Of great concern is that strobirulins have highest toxicity to fish from those detected compounds. From the pattern of pesticides occurring for non-migratory fish species it was possible to trend important spatial differences related to the intensity of rainfed agriculture. Results suggest a regular exposition of aquatic wild biota to sublethal concentrations of multiple semi-polar pesticides. PMID- 29524895 TI - Spatial and temporal variation of sources contributing to quasi-ultrafine particulate matter PM0.36 in Augsburg, Germany. AB - OBJECTIVE: to study the sources contributing to quasi-ultrafine particle (UFP) organic carbon and the spatial temporal variability of the sources. METHOD: 24h quasi-UFP (particulate matter <0.36MUm in this study) was sampled at a reference site continuously and at one of 5 other sites (T1, T2, T3, T4 and B1) in parallel in Augsburg, Germany from April 11th, 2014 to February 22nd, 2015, attempting to conduct 2-week campaigns at each site in 3 different seasons. Positive matrix factorization (PMF) was applied to measured organic tracers for source apportionment analyses. Pearson correlation coefficient r and coefficient of divergence (COD) were calculated to investigate spatial temporal variation of source contributions. RESULT: 5 sources were identified comprising biomass burning (BB), traffic emissions (Traffic), biogenic secondary organic aerosol (bioSOA), isoprene originated secondary organic aerosol (isoSOA) and biomass burning related secondary organic aerosol (bbSOA). In general, good temporal correlation and uniform distribution within the study area are found for bioSOA and bbSOA, probably resulting from regional formation/transport. Lower temporal correlation and spatial heterogeneity of isoSOA were found at the city background site with local influence from green space and less traffic impact. BB demonstrated very good temporal correlation, but higher contributions at sites influenced by local residential heating emissions were observed. Traffic showed the least seasonality and lower correlation over time among the sources. However, it demonstrated low spatial heterogeneity of absolute contribution, and only a few days of elevated contribution was found at T3 when wind came directly from the street nearby. CONCLUSION: temporal correlation and spatial variability of sources contributing to the organic fraction of quasi-UFP vary among sites and source types and show source-specific characteristics. Therefore, caution should be taken when using one monitor site measurement to assess human exposure in health effect studies of quasi-UFP. PMID- 29524896 TI - Water quality assessment and catchment-scale nutrient flux modeling in the Ramganga River Basin in north India: An application of INCA model. AB - The present study analyzes the water quality characteristics of the Ramganga (a major tributary of the Ganga river) using long-term (1991-2009) monthly data and applies the Integrated Catchment Model of Nitrogen (INCA-N) and Phosphorus (INCA P) to the catchment. The models were calibrated and validated using discharge (1993-2011), phosphate (1993-2010) and nitrate (2007-2010) concentrations. The model results were assessed based on Pearson's correlation, Nash-Sutcliffe and Percentage bias statistics along with a visual inspection of the outputs. The seasonal variation study shows high nutrient concentrations in the pre-monsoon season compared to the other seasons. High nutrient concentrations in the low flows period pose a serious threat to aquatic life of the river although the concentrations are lowered during high flows because of the dilution effect. The hydrological model is satisfactorily calibrated with R2 and NS values ranging between 0.6-0.8 and 0.4-0.8, respectively. INCA-N and INCA-P successfully capture the seasonal trend of nutrient concentrations with R2>0.5 and PBIAS within +/-17% for the monthly averages. Although, high concentrations are detected in the low flows period, around 50% of the nutrient load is transported by the monsoonal high flows. The downstream catchments are characterized by high nutrient transport through high flows where additional nutrient supply from industries and agricultural practices also prevail. The seasonal nitrate (R2: 0.88-0.94) and phosphate (R2: 0.62-0.95) loads in the catchment are calculated using model results and ratio estimator load calculation technique. On average, around 548tonnes of phosphorus (as phosphate) and 77,051tonnes of nitrogen (as nitrate) are estimated to be exported annually from the Ramganga River to the Ganga. Overall, the model has been able to successfully reproduce the catchment dynamics in terms of seasonal variation and broad-scale spatial variability of nutrient fluxes in the Ramganga catchment. PMID- 29524897 TI - Comparative ecotoxicity of potential biofuels to water flea (Daphnia magna), zebrafish (Danio rerio) and Chinese hamster (Cricetulus griseus) V79 cells. AB - The ecotoxicity of two biofuel candidates (1-octanol and 2-butanone) was investigated by an integrative test strategy using three bioassays: the acute immobilisation test with water flea (D. magna), the fish embryo acute toxicity test with zebrafish (Danio rerio) and the in vitro micronucleus assay with Chinese hamster (Cricetulus griseus) V79 cells. The median effective concentration (EC50) values were 14.9+/-0.66mgL-1 for 1-octanol, and 2152.1+/ 44.6mgL-1 for 2-butanone in the D. magna test. Both 1-octanol and 2-butanone caused teratogenic and lethal effects on zebrafish embryos, while exposure to 1 octanol significantly induced these effects at concentrations >=2.0mgL-1. These results indicate that 1-octanol exert much higher ecotoxicity than 2-butanone to D. magna and zebrafish embryos. Moreover, both 1-octanol and 2-butanone did not cause significant genotoxic effects, while their metabolites significantly induced micronuclei in V79 cells. The present study proposed an integrative test approach to evaluate the potential ecotoxicity of biofuels using simple, quick and inexpensive bioassays. PMID- 29524898 TI - Ecotoxicoparasitology of the gastrointestinal tracts of pinnipeds: the effect of parasites on the potential bioavailability of total mercury (THg). AB - Acanthocephalans, cestodes, and some species of nematodes acquire nutrients from the lumen contents in the gastrointestinal (GI) tract of their definitive host. These parasites are exposed to toxicants, such as mercury (Hg), through passive or active feeding mechanisms; therefore, the focus of this study was to determine if there is an effect of parasites on the dietary availability of total mercury (THg) within piscivorous pinniped hosts. THg concentrations ([THg]) in selected host tissues, parasites, and GI lumen contents from 22 California sea lions (Zalophus californianus), 15 ringed seals (Phoca hispida), and 4 spotted seals (Phoca largha) were determined. Among all pinnipeds, [THg] in acanthocephalans of the large intestine were significantly higher than concentrations in other samples (host lumen contents, other parasites and host intestinal wall), irrespective of location within the host GI tract. delta15N values of parasites depended both on parasite group and location within the GI tract. delta15N values were consistently higher in parasites inhabiting the large intestine, compared to elsewhere in the GI tract, for both sea lions and seals. delta13C values in parasites did not differ significantly from host GI tissues. Based on both [THg] and stable isotope values, parasites are likely affecting the Hg bioavailability within the GI lumen contents and host tissues, and toxicant-parasite interactions appear to depend on both parasitic taxon as well as their location within the host intestine. PMID- 29524899 TI - Transplacental transfer of persistent organic pollutants in La Plata dolphins (Pontoporia blainvillei; Cetartiodactyla, Pontoporiidae). AB - Persistent organic pollutants (POPs) accumulate in the fat tissue of living organisms and are found in relatively high concentrations in animals at the top of the food chain, such as dolphins. The ability of these compounds to interact with the endocrine system of marine mammals constitutes a risk for the reproduction and conservation of species. The La Plata dolphin, Pontoporia blainvillei, is exclusive to the southwestern Atlantic Ocean and is classified on the IUCN red list as a vulnerable species. Blubber, liver, kidney and muscle samples from four P. blainvillei mother-fetus pairs were analyzed to evaluate the transfer of POPs to fetal tissues through the placenta. The presence of POPs in fetal tissues indicates the maternal transfer of compounds. In the pregnant females, blubber was the tissue with POP highest concentration, followed by the liver, kidneys and muscles. In the fetuses, POP accumulation mainly occurred in the blubber followed by the muscles, liver and kidneys. Polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDTs) were found in all tissues analyzed and had the highest concentrations among all compounds. The main PCB congeners in the fetal samples had five to seven chlorine atoms. The only polybrominated diphenyl ether (PBDE) in the fetal samples was 47 and was found only in blubber. The main DDT metabolite in the fetuses was p,p'-DDE. POP transfer via the placenta occurs in the first months of gestation and increases with fetal development, according to fetus/mother (F/M) ratio: HCB>DDT>PCB>PBDE>Mirex, which may follow the order of the octanol/water partition coefficient (Kow) values. PMID- 29524900 TI - Feasible policy development and implementation for the destruction of endocrine disruptors in wastewater. AB - Endocrine disruptors when introduced to waterways have many adverse health effects on wildlife and humans. These health effects vary from neurological, immune, carcinogenic and reproductive disorders. Currently, there are few wastewater treatment facilities that are purposefully treating endocrine disruptors as part of the normal wastewater treatment process. Current literature has shown that endocrine disruptors can be treated using conventional methods. These conventional methods are centered around the denitrification process, which is rarely adopted in Canada. This paper investigates the current wastewater effluent regulations and guidelines in Canada, Ontario and the European Union. The research identifies a policy strategy that would include denitrification in the wastewater treatment process to help eliminate endocrine disruptors and acutely toxic nitrogen based compounds. Our emphasis here is on action possible in the Province of Ontario Canada, give the context of the Great Lakes basin and the potential for early action to stimulate other jurisdictions to follow. Our recommendations while aimed at one jurisdiction, have broad application globally. PMID- 29524901 TI - Nonlocal dispersal of dengue in the state of Bahia. PMID- 29524902 TI - Ambient air pollutants are associated with newly diagnosed tuberculosis: A time series study in Chengdu, China. AB - Although a few studies have analyzed the associations between ambient air pollutants and the development of tuberculosis (TB), most have been conducted in the core countries with inconsistent results. In this study, we used a distributed lag non-linear model to investigate the associations between the newly diagnosed TB cases and daily exposure to particulate matter with an aerodynamic diameter of <10MUm (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) in Chengdu, a severely polluted city. There were 36,108 newly diagnosed active TB cases from January 1, 2010 to December 31, 2015 in Chengdu. In a single pollutant model, the cumulative relative risk of active TB cases was 1.06 [lag of 0 to 21days, 95% confidence interval (CI): 1.01-1.11] for each 10MUg/m3 increase in PM10 above the threshold of 70MUg/m3; 1.06 (lag of 0 to 2days, 95% CI: 1.03 1.09) for each 10MUg/m3 increase in NO2 above the threshold of 40MUg/m3; and 1.07 (lag of 0 to 2days, 95% CI: 1.02-1.12) for each 10MUg/m3 increase in SO2 above the threshold of 60MUg/m3. Meanwhile, we found a positive association in males after exposure to a 10MUg/m3 increase in SO2 above the threshold of 60MUg/m3 at a lag of 0 to 2days. Exposure to PM10, NO2, and SO2 was associated with an increment in the incidence of active TB cases. PMID- 29524903 TI - Biological toxicity response of Asian Clam (Corbicula fluminea) to pollutants in surface water and sediment. AB - As a typical test species, Asian Clam (Corbicula fluminea) is widely used in the identification and evaluation of freshwater toxicity. This study provides a summary of the research published from 1979 to 2018. The focus was on the bioaccumulation, morphological and behavioral changes, and biochemical index alterations of Corbicula fluminea to target pollutants (i.e., ammonia, metal(loid)s, and organic chemicals) in surface water and sediment. The applications on the evaluation of actual aquatic pollution, determination of toxicological mechanisms, prediction of toxicity, and bioremediation are also specifically discussed. The primary purpose is to facilitate the comprehensive understanding and accurate application of Corbicula fluminea in freshwater ecotoxicological studies. PMID- 29524904 TI - Vulnerability and risk of deltaic social-ecological systems exposed to multiple hazards. AB - Coastal river deltas are hotspots of global change impacts. Sustainable delta futures are increasingly threatened due to rising hazard exposure combined with high vulnerabilities of deltaic social-ecological systems. While the need for integrated multi-hazard approaches has been clearly articulated, studies on vulnerability and risk in deltas either focus on local case studies or single hazards and do not apply a social-ecological systems perspective. As a result, vulnerabilities and risks in areas with strong social and ecological coupling, such as coastal deltas, are not fully understood and the identification of risk reduction and adaptation strategies are often based on incomplete assumptions. To overcome these limitations, we propose an innovative modular indicator library based approach for the assessment of multi-hazard risk of social-ecological systems across and within coastal deltas globally, and apply it to the Amazon, Ganges-Brahmaputra-Meghna (GBM), and Mekong deltas. Results show that multi hazard risk is highest in the GBM delta and lowest in the Amazon delta. The analysis reveals major differences between social and environmental vulnerability across the three deltas, notably in the Mekong and the GBM deltas where environmental vulnerability is significantly higher than social vulnerability. Hotspots and drivers of risk vary spatially, thus calling for spatially targeted risk reduction and adaptation strategies within the deltas. Ecosystems have been identified as both an important element at risk as well as an entry point for risk reduction and adaptation strategies. PMID- 29524905 TI - The health risk levels of different age groups of residents living in the vicinity of municipal solid waste incinerator posed by PCDD/Fs in atmosphere and soil. AB - In our study, health risk levels of different age groups of residents living in the vicinity of a municipal solid waste incinerator (MSWI) posed by polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in atmosphere and soil were evaluated. The toxic equivalent concentrations of PCDD/Fs (TEQ) in surrounding atmosphere and soil of studied MSWI were 0.05-0.12 pg I-TEQ Nm-3 and 7.622-15.450 ng I-TEQ kg-1, respectively. The PCDFs/PCDDs (F/D) values of PCDD/Fs in surrounding atmosphere of studied MSWI ranged from 0.40 to 5.90 with a mean of 1.80, suggesting that the PCDD/Fs mainly came from combustion sources and studied MSWI could be a key source of PCDD/Fs in surrounding atmosphere. The F/D ratios of PCDD/Fs in surrounding soil ranged from 0.18 to 1.81 with a mean of 0.90, suggesting combustion is not the mainly sources of PCDD/Fs in surrounding soil, and studied MSWI may have limited influence on PCDD/Fs in surrounding soil. O8CDD and 2,3,4,7,8-P5CDF could be the total PCDD/Fs and TEQ indicators in surrounding atmosphere of studied MSWI, respectively. The carcinogenic risk (CR) values of PCDD/Fs in surrounding atmosphere and soil for children, teens and adults were 1.24E-06, 9.06E-07 and 4.41E-06, respectively, suggesting that the potential cancer risk occurred but the risk was at acceptable levels for both children and adults (<1.00E-05), and the cancer risk for teens was negligible (<1.00E-06). The non-carcinogenic risk (non-CR) values of three age groups were lower than 1, indicating that no obvious non-carcinogenic effects occurred. Inhalation of air was the largest contributor of health risk (both CR and non-CR) for three age groups. In addition, a comparison of the health risk between PCDD/Fs and other emerging contaminants and traditional pollutants in soil and atmosphere was performed, which will help us have a good view of the health risk levels of PCDD/Fs in surrounding environment of MWSI. PMID- 29524906 TI - An inhalation-ingestion bioaccessibility assay (IIBA) for the assessment of exposure to metal(loid)s in PM10. AB - Although metal(loid) bioaccessibility of ambient particulate matter, with an aerodynamic diameter of <10MUm (PM10), has recently received increasing attention, limited research exists into standardising in-vitro methodologies using simulated lung fluid (SLF). Contradictions exist regarding which assay parameters should be adopted. Additionally, potential continuation of metal(loid) dissolution once PM10 is cleared from the lungs and passed through the gastro intestinal tract (GIT) has rarely been addressed. The objective of this study was to assess parameters that influence inhalation bioaccessibility in order to develop a conservative assay that is relevant to a human inhalation scenario. To achieve this aim, the effect of solid to liquid (S/L) ratio, extraction time, agitation and five major SLF compositions on the bioaccessibilities of arsenic (As) and lead (Pb) was investigated using PM10 from three Australian mining/smelting impacted regions. Using the biologically relevant parameters that resulted in the most conservative outcomes, bioaccessibility of metal(loid)s in PM10 was assessed in SLF, followed by simulated GIT solutions. Results from this study revealed that fluid composition and S/L ratio significantly affected metal(loid) dissolution (p<0.05). The highest Pb bioaccessibility resulted using simulated lung-gastric solution, while that of As resulted using simulated lung gastric-small intestinal tract solutions. Compared to SLF alone, metal(loid) dissolution using the inhalation-ingestion bioaccessibility assay (IIBA) was significantly higher (p<0.05) for all PM10 samples. PMID- 29524907 TI - Targeting the link between loneliness and paranoia via an interventionist-causal model framework. AB - Targeting the antecedents of paranoia may be one potential method to reduce or prevent paranoia. For instance, targeting a potential antecedent of paranoia - loneliness - may reduce paranoia. Our first research question was whether loneliness heightens subclinical paranoia and whether negative affect may mediate this effect. Second, we wondered whether this potential effect could be targeted via two interventionist pathways in line with an interventionist-causal model approach: (1) decreasing loneliness, and (2) intervening on the potential mediator - negative affect. In Study 1 (N = 222), recollecting an experience of companionship reduced paranoia in participants high in pre-manipulation paranoia but not in participants low in pre-manipulation paranoia. Participants recollecting an experience of loneliness, on the other hand, exhibited increased paranoia, and this effect was mediated by negative affect. In Study 2 (N = 196), participants who utilized an emotion-regulation strategy, cognitive reappraisal, to regulate the negative affect associated with loneliness successfully attenuated the effect of loneliness on paranoia. Targeting the effect of loneliness on paranoia by identifying interventionist pathways may be one promising route for reducing and preventing subclinical paranoia. PMID- 29524908 TI - Going direct to the consumer: Examining treatment preferences for veterans with insomnia, PTSD, and depression. AB - Inclusion of consumer preferences to disseminate evidence-based psychosocial treatment (EBPT) is crucial to effectively bridge the science-to-practice quality chasm. We examined this treatment gap for insomnia, posttraumatic stress disorder (PTSD), depression, and comorbid symptoms in a sample of 622 young adult veterans through preference in symptom focus, treatment modality, and related gender differences among those screening positive for each problem. Data were collected from veteran drinkers recruited through targeted Facebook advertisements as part of a brief online alcohol intervention. Analyses demonstrated that veterans reported greater willingness to seek insomnia-focused treatment over PTSD- or depression-focused care. Notably, even when participants screened negative for insomnia, they preferred sleep-focused care to PTSD- or depression-focused care. Although one in five veterans with a positive screen would not consider care, veterans screening for both insomnia and PTSD who would consider care had a preference for in-person counseling, and those screening for both insomnia and depression had similar preferences for in-person and mobile app-based/computer self-help treatment. Marginal gender differences were found. Incorporating direct to-consumer methods into research can help educate stakeholders about methods to expand EBPT access. Though traditional in-person counseling was often preferred, openness to app-based/computer interventions offers alternative methods to provide veterans with EBPTs. PMID- 29524909 TI - Shoulder range of motion and strength in young competitive tennis players with and without history of shoulder problems. AB - OBJECTIVE: To assess the effect of a history of shoulder problems on the shoulder flexibility and strength in young competitive tennis players. DESIGN: Cross sectional study. PARTICIPANTS: Ninety-one competitive and asymptomatic tennis players aged between 8 and 15 years old were divided into two groups according to the presence or absence of a history of shoulder problems. OUTCOME MEASURES: Glenohumeral joint ranges of motion and the strength of eight shoulder muscles were bilaterally assessed. Five agonist/antagonist muscle strength ratios were also reported. Ranges of motion, strengths and strength ratios were bilaterally compared between the two groups. RESULTS: Players with a history of shoulder problems presented a higher total arc of rotation for both glenohumeral joints (p = 0.02) and a lower external/internal glenohumeral rotator muscle strength ratio (p = 0.02) for both sides. They also presented stronger upper trapezius (p = 0.03) and dominant serratus anterior (p = 0.008) muscles than players without a history of shoulder problems. CONCLUSION: Having a history of shoulder problems may alter the balance between mobility and stability within the shoulder complex suggesting that particular attention should be given to dominant and non-dominant shoulder functions by coaches and clinicians. PMID- 29524911 TI - Mixotrophic and heterotrophic production of lipids and carbohydrates by a locally isolated microalga using wastewater as a growth medium. AB - The biomass production and changes in biochemical composition of a locally isolated microalga (Chlorella sp.) were investigated in autotrophic, mixotrophic and heterotrophic conditions, using glucose or glycerol as carbon sources and municipal wastewater as the growth medium. Both standard methods and Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) analysis of data acquired by Fourier-transform IR (FTIR) spectrometry showed that autotrophic and mixotrophic conditions promoted carbohydrate accumulation, while heterotrophic conditions with glycerol resulted in the highest lipid content and lowest carbohydrate content. Heterotrophic conditions with glycerol as a carbon source also resulted in high oleic acid (18:1) contents and low linolenic acid (18:3) contents, and thus increasing biodiesel quality. The results also show the utility of MCR-ALS for analyzing changes in microalgal biochemical composition. PMID- 29524910 TI - Comparison of the effects of fatigue on kinematics and muscle activation between men and women after anterior cruciate ligament reconstruction. AB - OBJECTIVES: Studies comparing the effects of fatigue between men and women after anterior cruciate ligament (ACL) reconstruction are lacking. The purpose of this study was to compare the effects of muscle fatigue on trunk, pelvis and lower limb kinematics and on lower limb muscle activation between male and female athletes who underwent ACL reconstruction. DESIGN: Cross-sectional study. SETTING: Laboratory setting. PARTICIPANTS: Fourteen recreational athletes (7 males and 7 females) with unilateral ACL reconstruction participated of this study. MAIN OUTCOME MEASURES: Trunk, pelvis and lower limb kinematics and muscle activation of the vastus lateralis, gluteus medius and gluteus maximus were evaluated during a single-leg drop vertical jump landing before and after a fatigue protocol. RESULTS: Females had greater peak knee abduction after fatigue in relation to before fatigue (P = 0.008), and in relation to men after fatigue (P = 0.011). Also, in females, peak knee abduction was greater in the reconstructed limb in relation to the non-reconstructed limb after fatigue (P = 0.029). Males showed a greater mean amplitude of activation of the vastus lateralis muscle after fatigue in relation to before fatigue (P < 0.001). CONCLUSIONS: Muscle fatigue produced kinematic alterations that have been shown to increase the risk for a second ACL injury in female athletes. PMID- 29524912 TI - Sulfur-based denitrification treating regeneration water from ion exchange at high performance and low cost. AB - Autotrophic denitrification with sulfur is an underexplored alternative to heterotrophic denitrification to remove nitrate from wastewater poor in organics. The application on ion exchange regeneration water (19.4-32.1 mS cm-1) is novel. Three fixed bed reactors were tested at 15 degrees C for >4 months, inoculated with activated sludge from sewage treatment. All were fast in start-up (<10 days) with high performance (94 +/- 2% removal efficiency). pH control with NaOH rendered higher nitrate removal rates than limestone addition to the bed (211 +/- 13 vs. 102 +/- 13 mg N L-1 d-1), related to higher pH (6.64 vs. 6.24) and sulfur surface area. Bacterial communities were strongly enriched in Sulfurimonas (63 67%) and Thiobacillus (24-26%). In an economic comparison, sulfur-based denitrification (?5.3 kg-1 N) was 15% cheaper than methanol-based denitrification (?6.22 kg-1 N) and both treatments were opex dominated (85.9 vs. 86.5%). Overall, the technological and economic feasibility should boost further implementation of sulfurotrophic denitrification. PMID- 29524913 TI - Dawson-type polyoxometalate nanoclusters confined in a carbon nanotube matrix as efficient redox mediators for enzymatic glucose biofuel cell anodes and glucose biosensors. AB - Two new inorganic-organic hybrid materials based on heteropolyoxometalates (POMs): (C4H10N)6[P2Mo18O62].4H2O (P2Mo18) and (C6H8NO)4[H2P2W18O62].6H2O (P2W18) are reported as mediators for electron transfer between FAD-dependent glucose dehydrogenase (FAD-GDH) and a multiwalled carbon nanotube (MWCNT) matrix for glucose biofuel cell and biosensor applications. These polyoxometalates were chosen due to their promising redox behavior in a potential range for mediated electron transfer with the glucose oxidizing enzyme, FAD-GDH. P2Mo18 and P2W18 were immobilized on 1-pyrenemethylamine (PMA) functionalized MWCNT deposits. After immobilization of FAD-GDH, the P2W18-modified MWCNT electrode demonstrated mediated electron transfer and provided a catalytic current density of 0.34 mA cm 2 at 0.2 V vs SCE with an open circuit potential (OCP) of -0.08 V vs SCE. A 10 fold increase in catalytic current to 4.7 mA cm-2 at 0.2 V vs SCE and a slightly lower OCP of -0.10 V vs SCE was observed for an equivalent electrode modified with P2Mo18.The apparent superiority of P2Mo18 is related, at least in part, to its improved incorporation in the MWCNT matrix compared to P2W18. Both POM modified bioanodes showed exceptional stabilities with 45% of their initial performances remaining after 15 days. The mediated electron transfer capacities of the POMs were also evaluated in a glucose sensor setup and showed very satisfying performances for glucose detection, including a sensitivity of 0.198 mA mol L-1 cm-2, a satisfying linear range between 1 mmol L-1 and 20 mmol L-1, and good reproducibility for the P2Mo18 electrode. PMID- 29524914 TI - Recent progresses in DNA nanostructure-based biosensors for detection of tumor markers. AB - DNA has emerged as a promising biomaterial for assembling a variety of nanostructures based on its programmable base pairing. It also has other remarkable properties including stability, prominent biocompatibility, and can easily be modified with functional groups for further applications. In the past few decades, researchers have established various design rules and assembly technologies to improve the stability and complexity of DNA nanostructures. The detection of cancer-associated biomarkers has significant importance in identifying patients with different clinical stages and also in developing adaptive therapeutic strategies. Due to their unique advantages, DNA nanostructures can be designed to serve as universal units to form biosensors for the detection of tumor biomarkers. In this review, we first present a brief introduction of the development of structural DNA nanotechnology. Then we summarize recent strategies for DNA nanostructure-based optical, electrochemical and mass sensitive biosensors in cancer detection. Finally, we discuss the challenges and opportunities these technologies provide. PMID- 29524915 TI - A universal and label-free impedimetric biosensing platform for discrimination of single nucleotide substitutions in long nucleic acid strands. AB - We report a label-free universal biosensing platform for highly selective detection of long nucleic acid strands. The sensor consists of an electrode immobilized universal stem-loop (USL) probe and two adaptor strands that form a 4J structure in the presence of a specific DNA/RNA analyte. The sensor was characterized by electrochemical impedance spectroscopy (EIS) using K3[Fe(CN)6]/K4[Fe(CN)6] redox couple in solution. An increase in charge transfer resistance (RCT) was observed upon 4J structure formation, the value of which depends on the analyte length. Cyclic voltammetry (CV) was used to further characterize the sensor and monitor the electrochemical reaction in conjunction with thickness measurements of the mixed DNA monolayer obtained using spectroscopic ellipsometry. In addition, the electron transfer was calculated at the electrode/electrolyte interface using a rotating disk electrode. Limits of detection in the femtomolar range were achieved for nucleic acid targets of different lengths (22 nt, 60 nt, 200 nt). The sensor produced only a background signal in the presence of single base mismatched analytes, even in hundred times excess in concentration. This label-free and highly selective biosensing platform is versatile and can be used for universal detection of nucleic acids of varied lengths which could revolutionize point of care diagnostics for applications such as bacterial or cancer screening. PMID- 29524916 TI - Impact of long term care and mortality risk in community care and nursing homes populations. AB - OBJECTIVES: To identify the survival time, the mortality risk factors and the individuals' characteristics associated with cognitive and physical status at discharge, among the Portuguese long-term care (LTC) populations. SETTINGS: Home and-Community-Based Services (HCBS) and three types of Nursing Homes (NH). PARTICIPANTS: 20,984 individuals admitted and discharged in 2015. MEASUREMENTS: The Kaplan-Meier survival analysis and the Cox Proportional Hazards Models were used to study the mortality risk; the Wilcoxon signed-rank test to identify the number of individuals with cognitive and physical changes between admission and discharge; two cumulative odds ordinal logistic regressions to predict the cognitive and physical dependence levels at discharge RESULTS: The mortality rate at HCBS was 30%, and 17% at the NH, with a median survival time of 173 and 200 days, respectively. The main factors associated with higher mortality were older age, male gender, family/neighbour support, neoplasms and cognitive/physical dependence at admission. In NH/HCBS, 26%/18% of individuals improve their cognitive status, while in physical status the proportion was 38%/27%, respectively. Finally, older age, being illiterate and being classified at the lowest cognitive and physical status at admission decrease the likelihood of achieving a higher level of cognitive and physical independence at discharge. CONCLUSIONS: The adoption of a robust and complete assessment tool, the definition of guidelines to enable a periodical assessment of individuals' autonomy and the adoption of benchmark metrics allowing the comparison of results between similar units are some of the main goals to be taken into account for future developments of this care in Portugal. PMID- 29524918 TI - Impaired regulation of emotional distractors during working memory load in schizophrenia. AB - Schizophrenia (SZ) patients exhibit deficits in emotion regulation that affect their daily functioning. There is evidence that the prefrontal cortex plays an important role in emotion regulation. However, it remains unclear how this brain region is involved in emotion regulation deficits in SZ, and how such deficits impact performance on cognitively demanding tasks. We examined how happy and fearful emotional distractors impact performance on working memory (WM) tasks of varying difficulty (0-back, 2-back), and brain activity using fMRI. Participants were 20 patients with SZ and 20 healthy controls (HC) matched on age, sex, race, and IQ. A significant 3-way interaction showed that SZ patients had lower performance compared to HC when exposed to fearful and happy distractors, but only during the 2-back task. Second-level fMRI between-group analysis revealed that compared to SZ patients, HC showed significantly greater increase in brain activity with WM load in the left IFG (BA 45) when exposed to fearful distractors. Less brain activity in this region was also associated with reduction in SZ patients' performance during higher WM load and the presence of fearful distractors. SZ patients had difficulty in performing a WM task when regulating emotions, and they failed to show the emotion-specific modulation of the left IFG observed in HC. These results suggest that SZ patients have difficulty with emotion regulation demands during effortful cognitive tasks. This also provides us with potential insight on how emotion regulation could be rehabilitated in SZ using cognitive training. PMID- 29524917 TI - Efficacy of a tool to predict short-term mortality in older people presenting at emergency departments: Protocol for a multi-centre cohort study. AB - BACKGROUND: Prognostic uncertainty inhibits clinicians from initiating timely end of-life discussions and advance care planning. This study evaluates the efficacy of the CriSTAL (Criteria for Screening and Triaging to Appropriate aLternative care) checklist in emergency departments. METHODS: Prospective cohort study of patients aged >=65 years with any diagnosis admitted via emergency departments in ten hospitals in Australia, Denmark and Ireland. Electronic and paper clinical records will be used to extract risk factors such as nursing home residency, physiological deterioration warranting a rapid response call, personal history of active chronic disease, history of hospitalisations or intensive care unit admission in the past year, evidence of proteinuria or ECG abnormalities, and evidence of frailty to be concurrently measured with Fried Score and Clinical Frailty Scale. Patients or their informal caregivers will be contacted by telephone around three months after initial assessment to ascertain survival, self-reported health, post-discharge frailty and health service utilisation since discharge. Logistic regression and bootstrapping techniques and AUROC curves will be used to test the predictive accuracy of CriSTAL for death within 90 days of admission and in-hospital death. DISCUSSION: The CriSTAL checklist is an objective and practical tool for use in emergency departments among older patients to determine individual probability of death in the short-term. Its validation in this cohort is expected to reduce clinicians' prognostic uncertainty on the time to patients' death and encourage timely end-of-life conversations to support clinical decisions with older frail patients and their families about their imminent or future care choices. PMID- 29524919 TI - Placental circadian pathway methylation and in utero exposure to fine particle air pollution. AB - In mammals, a central clock maintains the daily rhythm in accordance with the external environment. At the molecular level, the circadian rhythm is maintained by epigenetic regulation of the Circadian pathway. Here, we tested the role of particulate matter with an aerodynamic diameter <= 2.5 MUm (PM2.5) exposure during gestational life on human placental Circadian pathway methylation, as an important molecular target for healthy development. In 407 newborns, we quantified placental methylation of CpG sites within the promoter regions of the following genes: CLOCK, BMAL1, NPAS2, CRY1-2 and PER1-3 using bisulfite-PCR pyrosequencing. Daily PM2.5 exposure levels were estimated for each mother's residence, using a spatiotemporal interpolation model. We applied mixed-effects models to study the methylation status of the Circadian pathway genes and in utero PM2.5 exposure, while adjusting for a priori chosen covariates. In a multi gene model, placental Circadian pathway methylation was positively and significantly (p < 0.0001) associated with 3rd trimester PM2.5 exposure. Consequently, the single-gene models showed relative methylation differences [Log(fold change)] in placental NPAS2 (+0.16; p = 0.001), CRY1 (+0.59; p = 0.0023), PER2 (+0.36; p = 0.0005), and PER3 (+0.42; p = 0.0008) for an IQR increase (8.9 MUg/m3) in 3rd trimester PM2.5 exposure. PM2.5 air pollution, an environmental risk factor leading to a pro-inflammatory state of the mother and foetus, is associated with the methylation pattern of genes in the Circadian pathway. The observed alterations in the placental CLOCK epigenetic signature might form a relevant molecular mechanism through which fine particle air pollution exposure might affect placental processes and foetal development. PMID- 29524920 TI - Levels, variability and determinants of environmental phenols in pairs of Norwegian mothers and children. AB - BACKGROUND: Exposure to environmental phenols including parabens, bisphenols (BPs), oxybenzone/benzophenone-3 (BP-3) and triclosan (TCS) is ubiquitous. Due to evidence of their estrogenic activity, they have been considered as chemicals of concern. The exposure of the Norwegian population to these compounds is presently unknown. AIMS: To measure urinary levels of twelve different environmental phenols including four emerging bisphenols: S, F, B and AF (abbreviated as BPS, BPF, BPB and BPAF, respectively) in a healthy Norwegian population. We have calculated short-term variability, estimated daily intakes and investigated important determinants of exposure. METHODS: Urine samples were collected from mothers (n = 48) and their children (n = 56) during spring/summer 2012 in two counties in Norway. RESULTS: Six environmental phenols namely methyl, ethyl and propyl paraben, BPA, BP-3 and TCS were detected in almost 100% of the urine samples. Among the emerging bisphenols, BPS was detected most frequently in the urine samples (42-48%) followed by BPF (4-15%). Parabens were positively and significantly correlated to each other in both mothers and children. Levels of parabens and BP-3 were higher in mothers compared to children. All mothers and children had lower estimated daily intakes (back calculated from the urinary concentrations) of parabens and BPA than the respective acceptable and tolerable daily intakes (ADIs and TDIs) established by the European Food Safety Authority (EFSA). Observed intraclass correlation coefficients (ICCs) indicated moderate to high reliability of spot urine measurements for all the environmental phenols (ICCs: 0.70-0.97). Use of hair products, deodorants, face and hand creams were significantly associated with higher urinary levels of parabens. CONCLUSIONS: Occurrence of environmental phenols in healthy Norwegian women and children is abundant. Among emerging bisphenols, there is widespread exposure to BPS. A single spot urine sample can be used for estimating short-term exposures of environmental phenols. Urinary levels of parabens were associated with use of PCPs. PMID- 29524921 TI - Diesel exhaust exposure, its multi-system effects, and the effect of new technology diesel exhaust. AB - Exposure to diesel exhaust (DE) from vehicles and industry is hazardous and affects proper function of organ systems. DE can interfere with normal physiology after acute and chronic exposure to particulate matter (PM). Exposure leads to potential systemic disease processes in the central nervous, visual, hematopoietic, respiratory, cardiovascular, and renal systems. In this review, we give an overview of the epidemiological evidence supporting the harmful effects of diesel exhaust, and the numerous animal studies conducted to investigate the specific pathophysiological mechanisms behind DE exposure. Additionally, this review includes a summary of studies that used biomarkers as an indication of biological plausibility, and also studies evaluating new technology diesel exhaust (NTDE) and its systemic effects. Lastly, this review includes new approaches to improving DE emissions, and emphasizes the importance of ongoing study in this field of environmental health. PMID- 29524922 TI - Substantial reductions in ambient PAHs pollution and lives saved as a co-benefit of effective long-term PM2.5 pollution controls. AB - Under great efforts in fighting against serious haze problem of China since 2013, decreasing of air pollutants especially for fine particles (PM2.5) has been revealed for several key regions. This study tried to answer whether the reduction of PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) was coincident with PM2.5 because of long-term pollution control measures (PCM), and to assess source-oriented health risks associated with inhalation exposure to PAHs. Field measurements were carried out before and after the publishing of local air pollution protection plan for Nanjing, a mega-city in east China. Results indicated that the air quality was substantially improving, with a significant reduction in annual average PM2.5 by 34%, and moreover, PM2.5-bound PAHs significantly reduced by 63% (p < 0.001). The remarkable reduction was mainly attributable to the change of emission sources, compared to the influence of atmospheric circulation patterns, surface meteorological conditions, and atmospheric chemical reaction. Four PAHs sources including coal combustion (CC), petroleum and oil burning (PO), wood burning (WB) and vehicle emission (VE) were identified. On an annual basis, contributions to ambient PM2.5-PAHs from WB, PO, CC and VE sources in the period before the action of control measures were 2.26, 2.20, 1.96 and 5.62 ng m-3, respectively. They reduced to 1.09, 0.37, 1.31 and 1.77 ng m-3 for the four source types, with the reduction percentages as 51, 83, 33 and 68%, respectively. The estimated reduction in lifetime lung cancer risk was around 61%. The study that firstly assessed the health effects of PAHs reduction as a co-benefit raised by air PCM sustained for a long period is believed to be applicable and referential for other mega-cities around the world for assessing the benefits of PCM. PMID- 29524923 TI - Petrol and diesel exhaust particles accelerate the horizontal transfer of plasmid mediated antimicrobial resistance genes. AB - Particles exhausted from petrol and diesel consumptions are major components of urban air pollution that can be exposed to human via direct inhalation or other routes due to atmospheric deposition into water and soil. Antimicrobial resistance is one of the most serious threats to modern health care. However, how the petrol and diesel exhaust particles affect the development and spread of antimicrobial resistance genes (ARGs) in various environments remain largely unknown. This study investigated the effects and potential mechanisms of four representative petrol and diesel exhaust particles, namely 97 octane petrol, 93 octane petrol, light diesel oil, and marine heavy diesel oil, on the horizontal transfer of ARGs between two opportunistic Escherichia coli (E. coli) strains, E. coli S17-1 (donor) and E. coli K12 (recipient). The results demonstrated that these four representative types of nano-scale particles induced concentration dependent increases in conjugative transfer rates compared with the controls. The underlying mechanisms involved in the accelerated transfer of ARGs were also identified, including the generation of intracellular reactive oxygen species (ROS) and the consequent induction of oxidative stress, SOS response, changes in cell morphology, and the altered mRNA expression of membrane protein genes and those involved in the promotion of conjugative transfer. The findings provide new evidences and mechanistic insights into the antimicrobial resistance risks posed by petrol and diesel exhaust particles, and highlight the implications and need for stringent strategies on alternative fuels to mitigate air pollution and health risks. PMID- 29524924 TI - Adverse health effects of ferronickel manufacturing factory on local residents: An interrupted time series analysis. AB - The first ferronickel manufacturing factory of the Republic of Korea was opened in Gwangyang City on October, 23rd, 2008. There has been public concern regarding heavy metal dust blown from the factory and slag disposal site. Therefore, we evaluated the health impact of the ferronickel factory on Gwangyang City residents by using interrupted time series analysis. We analyzed the monthly incidence patterns of asthma, allergic rhinitis, and dermatitis in Gwangyang City residents from 2004 to 2014. Data were gathered from the National Health Insurance Service database which covers all the hospital use data of entire city residents. Seasonality adjusted quasi-Poisson regression model was used to evaluate whether the operation of the ferronickel factory was associated with the immediate changes in the monthly disease incidence patterns. We set a control region, Yeosu City, near Gwangyang City to ensure that the changes in the disease incidence were specific to Gwangyang City. We conducted sub-regional level analysis to evaluate whether the disease incidence patterns were affected by the distance from the ferronickel factory. The risk estimates after operation of the ferronickel factory showed an abrupt increase in the monthly incidence of unspecified dermatitis [RR (95% CI), 1.75 (1.17-2.60)] and vasomotor and allergic rhinitis [RR (95% CI), 1.23 (1.08-1.39)] in men, and pruritus [RR (95% CI), 1.95 (1.51-2.52)], unspecified dermatitis [RR (95% CI), 1.65 (1.04-2.60)], and vasomotor and allergic rhinitis [RR (95% CI), 1.17 (1.04-1.31)] in women. These findings were significant even after accounting for the changes of the corresponding disease incidence of the comparison city, Yeosu. The effects were greater in young children (aged 0-9) and sub-regions near the ferronickel factory. Our study suggests possible association between the operation of the ferronickel factory and an abrupt increase of pruritus, unspecific dermatitis, and vasomotor and allergic rhinitis in Gwangyang City residents. PMID- 29524925 TI - The Effect of Language on Economic Behavior: Evidence from Savings Rates, Health Behaviors, and Retirement Assets. AB - Languages differ widely in the ways they encode time. I test the hypothesis that the languages that grammatically associate the future and the present, foster future-oriented behavior. This prediction arises naturally when well-documented effects of language structure are merged with models of intertemporal choice. Empirically, I find that speakers of such languages: save more, retire with more wealth, smoke less, practice safer sex, and are less obese. This holds both across countries and within countries when comparing demographically similar native households. The evidence does not support the most obvious forms of common causation. I discuss implications for theories of intertemporal choice. PMID- 29524926 TI - Health Care Usage and Health Status of Immigrant Children: The Effects of Nativity versus Citizenship. PMID- 29524927 TI - HIV Risk and Adolescent Behaviors in Africa. PMID- 29524928 TI - Do Sex Workers Respond to Disease? Evidence from the Male Market for Sex. PMID- 29524929 TI - Inheritances, Intergenerational Transfers, and the Accumulation of Health. PMID- 29524930 TI - Adult Antiretroviral Therapy and Child Health: Evidence from Scale-up in Zambia. PMID- 29524931 TI - SSI for Disabled Immigrants: Why Do Ethnic Networks Matter? PMID- 29524932 TI - Boys' Cognitive Skill Formation and Physical Growth: Long-Term Experimental Evidence on Critical Ages for Early Childhood Interventions. PMID- 29524933 TI - Trade Agreements and Direct-to-Consumer Advertising of Pharmaceuticals. AB - There is growing international concern about the risks posed by direct-to consumer advertising (DTCA) of prescription pharmaceuticals, including via the internet. Recent trade agreements negotiated by the United States, however, incorporate provisions that may constrain national regulation of DTCA. Some provisions explicitly mention DTCA; others enable foreign investors to seek compensation if new regulations are seen to harm their investments. These provisions may thus prevent countries from restricting DTCA or put them at risk of expensive legal action from companies seeking damages due to restrictions on advertising. While the most recent example, the Trans-Pacific Partnership Agreement (TPP), collapsed following US withdrawal in January 2017, early indications of the Trump Administration's trade policy agenda signal an even more aggressive approach on the part of the United States in negotiating advantages for American businesses. Furthermore, the eleven remaining TPP countries may decide to proceed with the agreement in the absence of the United States, with most of the original text (including the provisions relevant to DTCA) intact. PMID- 29524934 TI - What Enables and Constrains the Inclusion of the Social Determinants of Health Inequities in Government Policy Agendas? A Narrative Review. AB - BACKGROUND: Despite decades of evidence gathering and calls for action, few countries have systematically attenuated health inequities (HI) through action on the social determinants of health (SDH). This is at least partly because doing so presents a significant political and policy challenge. This paper explores this challenge through a review of the empirical literature, asking: what factors have enabled and constrained the inclusion of the social determinants of health inequities (SDHI) in government policy agendas? METHODS: A narrative review method was adopted involving three steps: first, drawing upon political science theories on agenda-setting, an integrated theoretical framework was developed to guide the review; second, a systematic search of scholarly databases for relevant literature; and third, qualitative analysis of the data and thematic synthesis of the results. Studies were included if they were empirical, met specified quality criteria, and identified factors that enabled or constrained the inclusion of the SDHI in government policy agendas. RESULTS: A total of 48 studies were included in the final synthesis, with studies spanning a number of country-contexts and jurisdictional settings, and employing a diversity of theoretical frameworks. Influential factors included the ways in which the SDHI were framed in public, media and political discourse; emerging data and evidence describing health inequalities; limited supporting evidence and misalignment of proposed solutions with existing policy and institutional arrangements; institutionalised norms and ideologies (ie, belief systems) that are antithetical to a SDH approach including neoliberalism, the medicalisation of health and racism; civil society mobilization; leadership; and changes in government. CONCLUSION: A complex set of interrelated, context-dependent and dynamic factors influence the inclusion or neglect of the SDHI in government policy agendas. It is better to think about these factors as increasing (or decreasing) the 'probability' of health equity reaching a government agenda, rather than in terms of 'necessity' or 'sufficiency.' Understanding these factors may help advocates develop strategies for generating political priority for attenuating HI in the future. PMID- 29524935 TI - Towards Patient-Centered Conflicts of Interest Policy. AB - Financial conflicts of interest exist between industry and physicians, and these relationships have the power to influence physicians' medical practice. Transparency about conflicts matters for ensuring adequate informed consent, controlling healthcare expenditure, and encouraging physicians' reflection on professionalism. The US Centers for Medicare & Medicaid Services (CMS) launched the Open Payments Program (OPP) to publicly disclose and bring transparency to the relationships between industry and physicians in the United States. We set out to explore user awareness of the database and the ease of accessibility to disclosed information, however, as we show, both awareness and actual use are very low. Two practical policies can greatly enhance its intended function and help alleviate ethical tension. The first is to provide data for individual physicians not merely in absolute terms, but in meaningful context, that is, in relation to the zip code, city, and state averages. The second increases access to the OPP dataset by adding hyperlinks from physicians' professional websites directly to their Open Payments disclosure pages. These changes considerably improve transparency and the utility of available data, and can furthermore enhance professionalism and accountability by encouraging physicians to reflect more actively on their own practices. PMID- 29524936 TI - Measuring the Benefits of Healthcare: DALYs and QALYs - Does the Choice of Measure Matter? A Case Study of Two Preventive Interventions. AB - BACKGROUND: The measurement of health benefits is a key issue in health economic evaluations. There is very scarce empirical literature exploring the differences of using quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) as benefit metrics and their potential impact in decision-making. METHODS: Two previously published models delivering outputs in QALYs, were adapted to estimate DALYs: a Markov model for human papilloma virus (HPV) vaccination, and a pneumococcal vaccination deterministic model (PNEUMO). Argentina, Chile, and the United Kingdom studies were used, where local EQ-5D social value weights were available to provide local QALY weights. A primary study with descriptive vignettes was done (n = 73) to obtain EQ-5D data for all health states included in both models. Several scenario analyses were carried-out to evaluate the relative importance of using different metrics (DALYS or QALYs) to estimate health benefits on these economic evaluations. RESULTS: QALY gains were larger than DALYs avoided in all countries for HPV, leading to more favorable decisions using the former. With discounting and age-weighting - scenario with greatest differences in all countries - incremental DALYs avoided represented the 75%, 68%, and 43% of the QALYs gained in Argentina, Chile, and United Kingdom respectively. Differences using QALYs or DALYs were less consistent and sometimes in the opposite direction for PNEUMO. These differences, similar to other widely used assumptions, could directly influence decision making using usual gross domestic products (GDPs) per capita per DALY or QALY thresholds. CONCLUSION: We did not find evidence that contradicts current practice of many researchers and decision-makers of using QALYs or DALYs interchangeably. Differences attributed to the choice of metric could influence final decisions, but similarly to other frequently used assumptions. PMID- 29524937 TI - Managing In- and Out-Migration of Health Workforce in Selected Countries in South East Asia Region. AB - BACKGROUND: There is an increasing trend of international migration of health professionals from low- and middle- income countries to high-income countries as well as across middle-income countries. The WHO Global Code of Practice on the International Recruitment of Health Personnel was created to better address health workforce development and the ethical conduct of international recruitment. This study assessed policies and practices in 4 countries in South East Asia on managing the in- and out-migration of doctors and nurses to see whether the management has been in line with the WHO Global Code and has fostered health workforce development in the region; and draws lessons from these countries. METHODS: Following the second round of monitoring of the Global Code of Practice, a common protocol was developed for an in-depth analysis of (a) destination country policy instruments to ensure expatriate and local professional quality through licensing and equal practice, (b) source country collaboration to ensure the out-migrating professionals are equally treated by destination country systems. Documents on employment practice for local and expatriate health professionals were also reviewed and synthesized by the country authors, followed by a cross-country thematic analysis. RESULTS: Bhutan and the Maldives have limited local health workforce production capacities, while Indonesia and Thailand have sufficient capacities but are at risk of increased out-migration of nurses. All countries have mandatory licensing for local and foreign trained professionals. Legislation and employment rules and procedures are equally applied to domestic and expatriate professionals in all countries. Some countries apply mandatory renewal of professional licenses for local professionals that require continued professional development. Local language proficiency required by destination countries is the main barrier to foreign professionals gaining a license. The size of outmigration is unknown by these 4 countries, except in Indonesia where some formal agreements exist with other governments or private recruiters for which the size of outflows through these mechanisms can be captured. CONCLUSION: Mandatory professional licensing, employment regulations and procedures are equally applied to domestic and foreign trained professionals, though local language requirements can be a barrier in gaining license. Source country policy to protect their out-migrating professionals by ensuring equal conditions of practice by destination countries is hampered by the fact that most out-migrating professionals leave voluntarily and are outside government to government agreements. This requires more international solidarity and collaboration between source and destination countries, for which the WHO Global Code is an essential and useful platform. PMID- 29524938 TI - Including Health in Environmental Assessments of Major Transport Infrastructure Projects: A Documentary Analysis. AB - BACKGROUND: Transport policy and practice impacts health. Environmental Impact Assessments (EIAs) are regulated public policy mechanisms that can be used to consider the health impacts of major transport projects before they are approved. The way health is considered in these environmental assessments (EAs) is not well known. This research asked: How and to what extent was human health considered in EAs of four major transport projects in Australia. METHODS: We developed a comprehensive coding framework to analyse the Environmental Impact Statements (EISs) of four transport infrastructure projects: three road and one light rail. The coding framework was designed to capture how health was directly and indirectly included. RESULTS: We found that health was partially considered in all four EISs. In the three New South Wales (NSW) projects, but not the one South Australian project, this was influenced by the requirements issued to proponents by the government which directed the content of the EIS. Health was assessed using human health risk assessment (HHRA). We found this to be narrow in focus and revealed a need for a broader social determinants of health approach, using multiple methods. The road assessments emphasised air quality and noise risks, concluding these were minimal or predicted to improve. The South Australian project was the only road project not to include health data explicitly. The light rail EIS considered the health benefits of the project whereas the others focused on risk. Only one project considered mental health, although in less detail than air quality or noise. CONCLUSION: Our findings suggest EIAs lag behind the known evidence linking transport infrastructure to health. If health is to be comprehensively included, a more complete model of health is required, as well as a shift away from health risk assessment as the main method used. This needs to be mandatory for all significant developments. We also found that considering health only at the EIA stage may be a significant limitation, and there is a need for health issues to be considered when earlier, fundamental decisions about the project are being made. PMID- 29524939 TI - Public Health Policy and Experience of the 2009 H1N1 Influenza Pandemic in Pune, India. AB - BACKGROUND: Prior experience and the persisting threat of influenza pandemic indicate the need for global and local preparedness and public health response capacity. The pandemic of 2009 highlighted the importance of such planning and the value of prior efforts at all levels. Our review of the public health response to this pandemic in Pune, India, considers the challenges of integrating global and national strategies in local programmes and lessons learned for influenza pandemic preparedness. METHODS: Global, national and local pandemic preparedness and response plans have been reviewed. In-depth interviews were undertaken with district health policy-makers and administrators who coordinated the pandemic response in Pune. RESULTS: In the absence of a comprehensive district-level pandemic preparedness plan, the response had to be improvised. Media reporting of the influenza pandemic and inaccurate information that was reported at times contributed to anxiety in the general public and to widespread fear and panic. Additional challenges included inadequate public health services and reluctance of private healthcare providers to treat people with flu-like symptoms. Policy-makers developed a response strategy that they referred to as the Pune plan, which relied on powers sanctioned by the Epidemic Act of 1897 and resources made available by the union health ministry, state health department and a government diagnostic laboratory in Pune. CONCLUSION: The World Health Organization's (WHO's) global strategy for pandemic control focuses on national planning, but state-level and local experience in a large nation like India shows how national planning may be adapted and implemented. The priority of local experience and requirements does not negate the need for higher level planning. It does, however, indicate the importance of local adaptability as an essential feature of the planning process. Experience and the implicit Pune plan that emerged are relevant for pandemic preparedness and other public health emergencies. PMID- 29524940 TI - An Evaluation of the Role of an Intermediate Care Facility in the Continuum of Care in Western Cape, South Africa. AB - BACKGROUND: A comprehensive primary healthcare (PHC) approach requires clear referral and continuity of care pathways. South Africa is a lower-middle income country (LMIC) that lacks data on the role of intermediate care (IC) services in the health system. This study described the model of service provision at one facility in Cape Town, including reason for admission, the mix of services and skills provided and needed, patient satisfaction, patient outcome and articulation with other services across the spectrum of care. METHODS: A multi method design was used. Sixty-eight patients were recruited over one month in mid 2011 in a prospective cohort. Patient data were collected from clinical record review and an interviewer-administered questionnaire, administered shortly after admission to assess primary and secondary diagnosis, referring institution, knowledge of and previous use of home based care (HBC) services, reason for admission and demographics. A telephonic questionnaire at 9-weeks post-discharge recorded their vital status, use of HBC post-discharge and their satisfaction with care received. Staff members completed a self-administered questionnaire to describe demographics and skills. Cox regression was used to identify predictors of survival. RESULTS: Of the 68 participants, 38% and 24% were referred from a secondary and tertiary hospital, respectively. Stroke (35%) was the most common single reason for admission. The three most common reasons reported why care was better at the IC facility were staff attitude, the presence of physiotherapy and the wound care. Even though most patients reported admission to another health facility in the preceding year, only 13 patients (21%) had ever accessed HBC and only 25% (n=15) of discharged patients used HBC post-discharge. Of the 57 patients traced on follow-up, 21(37%) had died. The presence of a Care-plan was significantly associated with a 62% lower risk of death (hazard ratio: 0.38; CI 0.15-0.97). Notably, 46% of staff members reported performing roles that were outside their scope of practice and there was a mismatch between what staff reported doing and their actual tasks. CONCLUSION: Clients understood this service as a caring environment primarily responsible for rehabilitation services. A Care-plan beyond admission could significantly reduce mortality. There was poor referral to and poor articulation with HBC services. IC services should be recognised as an integral part of the health system and should be accessible. PMID- 29524941 TI - Community Psychology as a Process of Citizen Participation in Health Policy Comment on "The Rise of Post-truth Populism in Pluralist Liberal Democracies: Challenges for Health Policy". AB - This brief commentary discusses a recent paper by Speed and Mannion that explores "The Rise of post truth populism in liberal democracies: challenges for health policy." It considers their assertion that through meaningful democratic engagement in health policy, some of the risks brought about by an exclusionary populist politics can be mediated. With an overview of what participation means in modern healthcare policy and implementation, the field of community psychology is presented as one way to engage marginalized groups at risk of exploitation or exclusion by nativist populist policy. PMID- 29524942 TI - It Takes Two to Tango: Customization and Standardization as Colluding Logics in Healthcare Comment on "(Re) Making the Procrustean Bed Standardization and Customization as Competing Logics in Healthcare". AB - The healthcare context is characterized with new developments, technologies, ideas and expectations that are continually reshaping the frontline of care delivery. Mannion and Exworthy identify two key factors driving this complexity, 'standardization' and 'customization,' and their apparent resulting paradox to be negotiated by healthcare professionals, managers and policy makers. However, while they present a compelling argument an alternative viewpoint exists. An analysis is presented that shows instead of being 'competing' logics in healthcare, standardization and customization are long standing 'colluding' logics. Mannion and Exworthy's call for further sustained work to understand this complex, contested space is endorsed, noting that it is critical to inform future debates and service decisions. PMID- 29524943 TI - The Conceptualization of Value in the Value Proposition of New Health Technologies Comment on "Providing Value to New Health Technology: The Early Contribution of Entrepreneurs, Investors, and Regulatory Agencies". AB - Lehoux et al provide a highly valid contribution in conceptualizing value in value propositions for new health technologies and developing an analytic framework that illustrates the interplay between health innovation supply-side logic (the logic of emergence) and demand-side logic (embedding in the healthcare system). This commentary brings forth several considerations on this article. First, a detailed stakeholder analysis provides the necessary premonition of potential hurdles in the development, implementation and dissemination of a new technology. This can be achieved by categorizing potential stakeholder groups on the basis of the potential impact of future technology. Secondly, the conceptualization of value in value propositions of new technologies should not only embrace business/economic and clinical values but also ethical, professional and cultural values, as well as factoring in the notion of usability and acceptance of new technology. As a final note, the commentary emphasises the point that technology should facilitate delivery of care without negatively affecting doctor-patient communications, physical examination skills, and development of clinical knowledge. PMID- 29524944 TI - The WHO Tobacco Convention: A New Dawn in the Implementation of International Health Instrument? Comment on "The Legal Strength of International Health Instruments - What It Brings to Global Health Governance?" AB - The Tobacco Convention was adopted by the World Health Organization (WHO) in 2003. Nikogosian and Kickbusch examine the five potential impacts of the Tobacco Convention and its Protocol on public health. These include the adoption of the Convention would seem to unlock the treaty-making powers of WHO; the impact of the Convention in the global health architecture has been phenomenal globally; the Convention has facilitated the adoption of further instruments to strengthen its implementation at the national level; the Convention has led to the adoption of appropriate legal framework to combat the use of tobacco at the national level and that the impact of the Convention would seem to go beyond public health but has also led to the adoption of the Protocol to Eliminate Illicit Trade in Tobacco. However, the article by Nikogosian and Kickbusch would seem to overlook some of the challenges that may militate against the effective implementation of international law, including the Tobacco Convention, at the national level. PMID- 29524945 TI - The Magic Pudding Comment on "Four Challenges That Global Health Networks Face". AB - This commentary reflects on the contribution of this editorial and its "Three Challenges That Global Health Networks Face" to the totality of the framework developed over the past decade by Shiffman and his collaborators. It reviews the earlier works to demonstrate that the whole is greater than the sum of the parts in providing a package of tools for analysis of network effectiveness.Additionally the assertion is made that the framework can be utilised in reverse to form a map for action planning for network activity around a potential health policy issue. PMID- 29524946 TI - The Far Right Challenge Comment on "The Rise of Post-truth Populism in Pluralist Liberal Democracies: Challenges for Health Policy". AB - Speed and Mannion make a good case that the rise of populism poses significant challenges for health policy. This commentary suggests that the link between populism and health policy should be further nuanced in four ways. First, a deconstruction of the term populism itself and a focus on the far right dimension of populist politics; second, a focus on the supply side and more specifically the question of nationalism and the 'national preference'; third, the dynamics of party competition during economic crisis; and fourth the question of policy, and more specifically the extent to which certain labour market policies are able to mediate demand for the far right. PMID- 29524947 TI - Tackling HIV in MENA: Talk Is Not Enough-It Is Time for Bold Actions: A Response to Recent Commentaries. PMID- 29524948 TI - BRIC Health Systems and Big Pharma: A Challenge for Health Policy and Management. AB - BRIC nations - Brazil, Russia, India, and China - represent 40% of the world's population, including a growing aging population and middle class with an increasing prevalence of chronic disease. Their healthcare systems increasingly rely on prescription drugs, but they differ from most other healthcare systems because healthcare expenditures in BRIC nations have exhibited the highest revenue growth rates for pharmaceutical multinational corporations (MNCs), Big Pharma. The response of BRIC nations to Big Pharma presents contrasting cases of how governments manage the tensions posed by rising public expectations and limited resources to satisfy them. Understanding these tensions represents an emerging area of research and an important challenge for all those who work in the field of health policy and management (HPAM). PMID- 29524949 TI - The Urgency to Mitigate the Spread of Hepatitis C in Pakistan Through Blood Transfusion Reform. AB - Blood transfusions are contributing to a higher rate of hepatitis C virus (HCV) in Pakistan. Half of all blood transfusions in Pakistan are not screened for hepatitis C, hepatitis B or HIV. Family members donate blood that is likely not tested due to social stigma attached to HCV. Paid donations are also quite common in the country, especially by people who inject drugs (PWID), which increases the population's exposure to HCV. Most of the population utilizes the private sector for their health needs; this sector has lax regulation due to the lack of oversight by the government or any other regulatory body. In addition, groups who are at most need for blood transfusions, such as hemophiliacs and those with thalassemia, have a higher rate of hepatitis C. This fact reinforces the need for blood transfusion reform in Pakistan, which includes improving oversight, upgrading infrastructure and promoting health literacy through cultural norms, according to the World Health Organization (WHO) recommendations. The lessons learned in Pakistan can be adapted to countries facing similar issues. PMID- 29524950 TI - Human Dignity as Leading Principle in Public Health Ethics: A Multi-Case Analysis of 21st Century German Health Policy Decisions. AB - BACKGROUND: There is ample evidence that since the turn of the millennium German health policy made a considerable step towards prevention and health promotion, putting the strategies of 'personal empowerment' and 'settings based approach' high on the federal government's agenda. This phenomenon has challenged the role of ethics in health policy. Concurrently, increasing relevance of the Concept of Human Dignity for health and human rights has been discussed. However, a direct relationship between Human Dignity and Public Health Ethics (PHE) has surprisingly not yet been established. METHODS: We here conduct a systematic ethical analysis of eminent German health prevention policy case-examples between the years 2000-2016. Specifically, our analysis seeks to adapt and apply the principalism (autonomy, beneficence, justice)-based Concept of Human Dignity of Italian philosopher Corrado Viafora, contextualizing it with the emerging field of PHE. To further inform this health policy analysis, index databases (PubMed, Google Scholar) were searched to include relevant published and grey literature. RESULTS: We observe a systematic approach of post-millennial health policy decisions on prevention and on defined health targets in Germany, exemplified by (1) the fostering of the preparedness against pandemic infectious diseases, (2) the development and implementation of the first cancer vaccination, (3) major legal provisions on non-smokers protection in the public domain, (4) acts to strengthen long term care (LTC) as well as (5) the new German E-Health legislation. The ethical analysis of these health prevention decisions exhibits their profound ongoing impact on social justice, probing their ability to meet the underlying Concept of Human Dignity in order to fulfill the requirements of the principle of non-maleficence. CONCLUSION: The observed health policy focus on prevention and health promotion has sparked new public debates about the formation of/compliance with emerging standards of PHE in Germany. We believe that the overall impact of this novel policy orientation will gradually show over mid- and long-term periods, both in terms of improvements in health system performance and concurrently in diagnostics, therapies and health outcome on individual patient level. The Concept of Human Dignity may soon play an even greater role in European PHE debates to come. PMID- 29524952 TI - Using Complexity and Network Concepts to Inform Healthcare Knowledge Translation. AB - Many representations of the movement of healthcare knowledge through society exist, and multiple models for the translation of evidence into policy and practice have been articulated. Most are linear or cyclical and very few come close to reflecting the dense and intricate relationships, systems and politics of organizations and the processes required to enact sustainable improvements. We illustrate how using complexity and network concepts can better inform knowledge translation (KT) and argue that changing the way we think and talk about KT could enhance the creation and movement of knowledge throughout those systems needing to develop and utilise it. From our theoretical refinement, we propose that KT is a complex network composed of five interdependent sub-networks, or clusters, of key processes (problem identification [PI], knowledge creation [KC], knowledge synthesis [KS], implementation [I], and evaluation [E]) that interact dynamically in different ways at different times across one or more sectors (community; health; government; education; research for example). We call this the KT Complexity Network, defined as a network that optimises the effective, appropriate and timely creation and movement of knowledge to those who need it in order to improve what they do. Activation within and throughout any one of these processes and systems depends upon the agents promoting the change, successfully working across and between multiple systems and clusters. The case is presented for moving to a way of thinking about KT using complexity and network concepts. This extends the thinking that is developing around integrated KT approaches. There are a number of policy and practice implications that need to be considered in light of this shift in thinking. PMID- 29524951 TI - Prevalence of HAV Ab, HEV (IgG), HSV2 IgG, and Syphilis Among Sheltered Homeless Adults in Tehran, 2012. AB - BACKGROUND: This study investigated the prevalence for hepatitis A virus (HAV), hepatitis E virus (HEV), herpes simplex virus type 2 (HSV2) and syphilis among homeless in the city of Tehran. METHODS: In this cross-sectional study, 596 homeless were recruited in Tehran. A researcher-designed questionnaire was used to study demographic data. Using enzyme-linked immunoassay, and rapid plasma reagin (RPR) test, we evaluated the seroprevalence of HAV anti-body, HEV IgG, herpes, HSV2 IgG, and syphilis among sheltered homeless in Tehran. The associations between the participant's characteristics and infections were evaluated using logistic regression and chi-square. RESULTS: A total of 569 homeless, 78 women (13.7%) and 491 men (86.3%) were enrolled into the study from June to August 2012. Their age mean was 42 years and meantime of being homeless was 24 months. Seroprevalence of syphilis, HEV IgG, HSV2 IgG and HAV Ab was 0.55%, 24.37%, 16.48%, and 94.34%, respectively. History of drug abuse was reported in 77.70%; 46.01% of them were using a drug during the study and 26.87% of them had history of intravenous drug abuse. Among people who had intravenous drug abuse, 48.25% had history of syringe sharing. CONCLUSION: The prevalence of HAV, HEV and HSV2 were higher than the general population while low prevalence of syphilis was seen among homeless peoples who are at high risk of sexually transmitted infection (STD). Our findings highlighted that significant healthcare needs of sheltered homeless people in Tehran are unmet and much more attention needs to be paid for the health of homeless people. PMID- 29524953 TI - A Critical Analysis of Purchasing Arrangements in Kenya: The Case of the National Hospital Insurance Fund. AB - BACKGROUND: Purchasing refers to the process by which pooled funds are paid to providers in order to deliver a set of health care interventions. Very little is known about purchasing arrangements in low- and middle-income countries (LMICs), and certainly not in Kenya. This study aimed to critically analyse purchasing arrangements in Kenya, using the National Hospital Insurance Fund (NHIF) as a case study. METHODS: We applied a principal-agent relationship framework, which identifies three pairs of principal-agent relationships (government-purchaser, purchaser-provider, and citizen-purchaser) and specific actions required within them to achieve strategic purchasing. A qualitative case study approach was applied. Data were collected through document reviews (statutes, policy and regulatory documents) and in-depth interviews (n=62) with key informants including NHIF officials, Ministry of Health (MoH) officials, insurance industry actors, and health service providers. Documents were summarised using standardised forms. Interviews were recorded, transcribed verbatim, and analysed using a thematic framework approach. RESULTS: The regulatory and policy framework for strategic purchasing in Kenya was weak and there was no clear accountability mechanism between the NHIF and the MoH. Accountability mechanisms within the NHIF have developed over time, but these emphasized financial performance over other aspects of purchasing. The processes for contracting, monitoring, and paying providers do not promote equity, quality, and efficiency. This was partly due to geographical distribution of providers, but also due to limited capacity within the NHIF. There are some mechanisms for assessing needs, preferences, and values to inform design of the benefit package, and while channels to engage beneficiaries exist, they do not always function appropriately and awareness of these channels to the beneficiaries is limited. CONCLUSION: Addressing the gaps in the NHIF's purchasing performance requires a number of approaches. Critically, there is a need for the government through the MoH to embrace its stewardship role in health, while recognizing the multiplicity of actors given Kenya's devolved context. Relatively recent decentralisation reforms present an opportunity that should be grasped to rewrite the contract between the government, the NHIF and Kenyans in the pursuit of universal health coverage (UHC). PMID- 29524954 TI - Comparing the Income Elasticity of Health Spending in Middle-Income and High Income Countries: The Role of Financial Protection. AB - BACKGROUND: As middle-income countries become more affluent, economically sophisticated and productive, health expenditure patterns are likely to change. Other socio-demographic and political changes that accompany rapid economic growth are also likely to influence health spending and financial protection. METHODS: This study investigates the relationship between growth on per-capita healthcare expenditure and gross domestic product (GDP) in a group of 27 large middle-income economies and compares findings with those of 24 high-income economies from the Organization for Economic Cooperation and Development (OECD) group. This comparison uses national accounts data from 1995-2014. We hypothesize that the aggregated income elasticity of health expenditure in middle-income countries would be less than one (meaning healthcare is a normal good). An initial exploratory analysis tests between fixed-effects and random-effects model specifications. A fixed-effects model with time-fixed effects is implemented to assess the relationship between the two measures. Unit root, Hausman and serial correlation tests are conducted to determine model fit. Additional explanatory variables are introduced in different model specifications to test the robustness of our regression results. We include the out-of-pocket (OOP) share of health spending in each model to study the potential role of financial protection in our sample of high- and middle-income countries. The first-difference of study variables is implemented to address non-stationarity and cointegration properties. RESULTS: The elasticity of per-capita health expenditure and GDP growth is positive and statistically significant among sampled middle-income countries (51 per unit-growth in GDP) and high-income countries (50 per unit growth in GDP). In contrast with previous research that has found that income elasticity of health spending in middle-income countries is larger than in high income countries, our findings show that elasticity estimates can change if different criteria are used to assemble a more homogenous group of middle-income countries. Financial protection differences between middle- and high-income countries, however, are not associated with their respective income elasticity of health spending. CONCLUSION: The study findings show that in spite of the rapid economic growth experienced by the sampled middleincome countries, the aggregated income elasticity of health expenditure in them is less than one, and equals that of high-income countries. PMID- 29524955 TI - Adopting New International Health Instruments - What Can We Learn From the FCTC? Comment on "The Legal Strength of International Health Instruments - What It Brings to Global Health Governance?" AB - This Commentary forms a response to Nikogosian's and Kickbusch's forward-looking perspective about the legal strength of international health instruments. Building on their arguments, in this commentary we consider what we can learn from the Framework Convention on Tobacco Control (FCTC) for the adoption of new legal international health instruments. PMID- 29524956 TI - Populism, Exclusion, Post-truth. Some Conceptual Caveats Comment on "The Rise of Post-truth Populism in Pluralist Liberal Democracies: Challenges for Health Policy". AB - In their editorial, Speed and Mannion identify two main challenges "the rise of post-truth populism" poses for health policy: the populist threat to inclusive healthcare policies, and the populist threat to well-designed health policies that draw on professional expertise and research evidence. This short comment suggests some conceptual clarifications that might help in thinking through more profoundly these two important issues. It argues that we should approach right wing populism as a combination of a populist down/up (people/elite) axis with an exclusionary nationalist in/out (member/non-member) axis. And it raises some questions regarding the equation between populism, demagogy and the rejection of expertise and scientific knowledge. PMID- 29524957 TI - Toward Customized Care Comment on "(Re) Making the Procrustean Bed? Standardization and Customization as Competing Logics in Healthcare". AB - Patients want their personal needs to be taken into account. Accordingly, the management of care has long involved some degree of personalization. In recent times, patients' wishes have become more pressing in a moving context. As the population ages, the number of patients requiring sophisticated combinations of longterm care is rising. Moreover, we are witnessing previously unvoiced demands, preferences and expectations (eg, demand for information about treatment, for care complying with religious practices, or for choice of appointment dates). In view of the escalating costs and the concerns about quality of care, the time has now come to rethink healthcare delivery. Part of this reorganization can be related to customization: what is needed is a customized business model that is effective and sustainable. Such business model exists in different service sectors, the customization being defined as the development of tailored services to meet consumers' diverse and changing needs at near mass production prices. Therefore, its application to the healthcare sector needs to be seriously considered. PMID- 29524958 TI - State Support: A Prerequisite for Global Health Network Effectiveness Comment on "Four Challenges that Global Health Networks Face". AB - Shiffman recently summarized lessons for network effectiveness from an impressive collection of case-studies. However, in common with most global health governance analysis in recent years, Shiffman underplays the important role of states in these global networks. As the body which decides and signs international agreements, often provides the resourcing, and is responsible for implementing initiatives all contributing to the prioritization of certain issues over others, state recognition and support is a prerequisite to enabling and determining global health networks' success. The role of states deserves greater attention, analysis and consideration. We reflect upon the underappreciated role of the state within the current discourse on global health. We present the tobacco case study to illustrate the decisive role of states in determining progress for global health networks, and highlight how states use a legitimacy loop to gain legitimacy from and provide legitimacy to global health networks. Moving forward in assessing global health networks' effectiveness, further investigating state support as a determinant of success will be critical. Understanding how global health networks and states interact and evolve to shape and support their respective interests should be a focus for future research. PMID- 29524959 TI - Health Services Research Spending and Healthcare System Impact Comment on "Public Spending on Health Service and Policy Research in Canada, the United Kingdom, and the United States: A Modest Proposal". AB - The challenges associated with translating health services and policy research (HSPR) evidence into practice are many and long-standing. Indeed, those challenges have themselves spawned new areas of research, including knowledge translation and implementation science. These sub-disciplines have increased our understanding of the critical success factors associated with the uptake of research evidence into (system) practice. Engaging those for whom research evidence is likely to help solve implementation and/or policy problems, and ensuring that they are key partners throughout the research life-cycle, appear to us (based on current evidence) to be the most direct and effective paths to improved knowledge translation. In that regard, building on Canada's recent Strategy for Patient Oriented Research (SPOR) would seem to offer considerable promise. The "modest" proposals offered by Thakkar and Sullivan seem less likely to bear fruit. PMID- 29524960 TI - Challenges Facing Global Health Networks: The NCD Alliance Experience Comment on "Four Challenges that Global Health Networks Face". AB - Successful prevention and control of the epidemic of noncommunicable diseases (NCDs) cannot be achieved by the health sector alone: a wide range of organisations from multiple sectors and across government must also be involved. This requires a new, inclusive approach to advocacy and to coordinating, convening and catalysing action across civil society, best achieved by a broad based network. This comment maps the experience of the NCD Alliance (NCDA) on to Shiffman's challenges for global health networks - framing (problem definition and positioning), coalition-building and governance - and highlights some further areas overlooked in his analysis. PMID- 29524961 TI - Why Learning How to Chase Butterflies Matters: A Response to Recent Commentaries. PMID- 29524962 TI - How Political Science Can Contribute to Public Health: A Response to Gagnon and Colleagues. PMID- 29524963 TI - Coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma with antecedent chronic lymphocytic leukemia: a case report and review of the literature. AB - BACKGROUND: Chronic lymphocytic leukemia and chronic myeloid leukemia are the most common types of adult leukemia. However, it is rare for the same patient to suffer from both. Richter's transformation to diffuse large B-cell lymphoma is frequently observed in chronic lymphocytic leukemia. Purine analog therapy and the presence of trisomy 12, and CCND1 gene rearrangement have been linked to increased risk of Richter's transformation. The coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma in the same patient is extremely rare, with only nine reported cases. Here, we describe the first reported case of concurrent chronic myeloid leukemia and diffuse large B-cell lymphoma in a background of chronic lymphocytic leukemia. CASE PRESENTATION: A 60-year-old Saudi man known to have diabetes, hypertension, and chronic active hepatitis B was diagnosed as having Rai stage II chronic lymphocytic leukemia, with trisomy 12 and rearrangement of the CCND1 gene in December 2012. He required no therapy until January 2016 when he developed significant anemia, thrombocytopenia, and constitutional symptoms. He received six cycles of fludarabine, cyclophosphamide, and rituximab, after which he achieved complete remission. One month later, he presented with progressive leukocytosis (mostly neutrophilia) and splenomegaly. Fluorescence in situ hybridization from bone marrow aspirate was positive for translocation (9;22) and reverse transcription polymerase chain reaction detected BCR-ABL fusion gene consistent with chronic myeloid leukemia. He had no morphologic or immunophenotypic evidence of chronic lymphocytic leukemia at the time. Imatinib, a first-line tyrosine kinase inhibitor, was started. Eight months later, a screening imaging revealed new liver lesions, which were confirmed to be diffuse large B-cell lymphoma. CONCLUSIONS: In chronic lymphocytic leukemia, progressive leukocytosis and splenomegaly caused by emerging chronic myeloid leukemia can be easily overlooked. It is unlikely that chronic myeloid leukemia arose as a result of clonal evolution secondary to fludarabine treatment given the very short interval after receiving fludarabine. It is also unlikely that imatinib contributed to the development of diffuse large B-cell lymphoma; rather, diffuse large B-cell lymphoma arose as a result of Richter's transformation. Fludarabine, trisomy 12, and CCND1 gene rearrangement might have increased the risk of Richter's transformation in this patient. PMID- 29524964 TI - Airway surface liquid from smokers promotes bacterial growth and biofilm formation via iron-lactoferrin imbalance. AB - BACKGROUND: Smoking is a leading cause of respiratory infections worldwide. Tobacco particulate matter disrupts iron homeostasis in the lungs and increases the iron content in the airways of smokers. The airway epithelia secrete lactoferrin to quench iron required for bacteria to proliferate and cause lung infections. We hypothesized that smokers would have increased bacterial growth and biofilm formation via iron lactoferrin imbalance. METHODS: We collected bronchoalveolar lavage (BAL) samples from non-smokers and smokers. We challenged these samples using a standard inoculum of Staphylococcus aureus and Pseudomonas aeruginosa and quantified bacterial growth and biofilm formation. We measured both iron and lactoferrin in the samples. We investigated the effect of supplementing non-smoker BAL with cigarette smoke extract (CSE) or ferric chloride and the effect of supplementing smoker BAL with lactoferrin on bacterial growth and biofilm formation. RESULTS: BAL from smokers had increased bacterial growth and biofilm formation compared to non-smokers after both S. aureus and P. aeruginosa challenge. In addition, we found that samples from smokers had a higher iron to lactoferrin ratio. Supplementing the BAL of non-smokers with cigarette smoke extract and ferric chloride increased bacterial growth. Conversely, supplementing the BAL of smokers with lactoferrin had a concentration dependent decrease in bacterial growth and biofilm formation. CONCLUSION: Cigarette smoking produces factors which increase bacterial growth and biofilm formation in the BAL. We propose that smoking disrupts the iron-to-lactoferrin in the airways. This finding offers a new avenue for potential therapeutic interventions to prevent respiratory infections in smokers. PMID- 29524966 TI - Resistance to change. Resistance is futile. Change is inevitable. So why is it so challenging? PMID- 29524967 TI - Legends in Urology. PMID- 29524965 TI - The neural correlates of mental arithmetic in adolescents: a longitudinal fNIRS study. AB - BACKGROUND: Arithmetic processing in adults is known to rely on a frontal parietal network. However, neurocognitive research focusing on the neural and behavioral correlates of arithmetic development has been scarce, even though the acquisition of arithmetic skills is accompanied by changes within the fronto parietal network of the developing brain. Furthermore, experimental procedures are typically adjusted to constraints of functional magnetic resonance imaging, which may not reflect natural settings in which children and adolescents actually perform arithmetic. Therefore, we investigated the longitudinal neurocognitive development of processes involved in performing the four basic arithmetic operations in 19 adolescents. By using functional near-infrared spectroscopy, we were able to use an ecologically valid task, i.e., a written production paradigm. RESULTS: A common pattern of activation in the bilateral fronto-parietal network for arithmetic processing was found for all basic arithmetic operations. Moreover, evidence was obtained for decreasing activation during subtraction over the course of 1 year in middle and inferior frontal gyri, and increased activation during addition and multiplication in angular and middle temporal gyri. In the self-paced block design, parietal activation in multiplication and left angular and temporal activation in addition were observed to be higher for simple than for complex blocks, reflecting an inverse effect of arithmetic complexity. CONCLUSIONS: In general, the findings suggest that the brain network for arithmetic processing is already established in 12-14 year-old adolescents, but still undergoes developmental changes. PMID- 29524968 TI - Letter to the Editor. PMID- 29524969 TI - Identifying and managing the risks of medical ionizing radiation in endourology. AB - INTRODUCTION: The risks of exposure to medical ionizing radiation is of increasing concern both among medical professionals and the general public. Patients with nephrolithiasis are exposed to high levels of ionizing radiation through both diagnostic and therapeutic modalities. Endourologists who perform a high-volume of fluoroscopy guided procedures are also exposed to significant quantities of ionizing radiation. The combination of judicious use of radiation based imaging modalities, application of new imaging techniques such as ultra-low dose computed tomography (CT) scan, and modifying use of current technology such as increasing ultrasound and pulsed fluoroscopy utilization offers the possibility of significantly reducing radiation exposure. We present a review of the literature regarding the risks of medical ionizing radiation to patients and surgeons as it pertains to the field of endourology and interventions that can be performed to limit this exposure. MATERIALS AND METHODS: A review of the current state of the literature was performed using MEDLINE and PubMed. Interventions designed to limit patient and surgeon radiation exposure were identified and analyzed. Summaries of the data were compiled and synthesized in the body of the text. RESULTS: While no level 1 evidence exists demonstrating the risk of secondary malignancy with radiation exposure, the preponderance of evidence suggests a dose and age dependent increase in malignancy risk from ionizing radiation. Patients with nephrolithiasis were exposed to an average effective dose of 37mSv over a 2 year period. Multiple evidence-based interventions to limit patient and surgeon radiation exposure and associated risk were identified. CONCLUSION: Current evidence suggest an age and dose dependent risk of secondary malignancy from ionizing radiation. Urologists must act in accordance with ALARA principles to safely manage nephrolithiasis while minimizing radiation exposure. PMID- 29524970 TI - Analysis of bladder cancer subtypes in neurogenic bladder tumors. AB - INTRODUCTION: To establish if the validated tumor biomarkers of luminal and basal bladder cancers in non neuro-urological patients are applicable to a neuro urological population. MATERIALS AND METHODS: We retrieved bladder cancer samples from neuro-urological patients (n = 20) and non-neurological controls (n = 40). The expression of GATA3 and CK5/6 was analyzed using immunohistochemistry of microarray tissue sections. We also assessed the correlation between previous biomarker expression, gender, age, tumor stage (non-muscle-invasive bladder cancer (NMIBC)/muscle-invasive bladder cancer (MIBC)), squamous-cell differentiation and basal/luminal subtypes using Pearson's correlation coefficient (r). RESULTS: Mean age at diagnosis of bladder cancer in neuro urological patients was 53.2 years (min 41-max 73). MIBC was found in 13 neuro urological patients (65%). The luminal subtype was identified in 7 samples (35%, all urothelial differentiation). The basal subtype was found in 13 samples (65%): 12 squamous-cell and 1 sarcomatoid differentiation. GATA3 and CK5/6 were expressed in 6 (30%) neuro-urological patients. A significant positive correlation was found between GATA3 expression and the luminal subtype (p = 0.00001, r = 0.5676). This was not the case with the neuro-urological status (r = -0.307). A poor correlation was found between CK5/6 expression and the neuro urological status (r = 0.471 and -0.471), squamous-cell differentiation (r = 0.092), tumor stage NMIBC/MIBC (r = -0.118 and 0.118) and basal/luminal subtypes (r = -0.157 and 0.194). CONCLUSION: In summary, the expression of GATA3 and CK5/6 could not differentiate the different subtypes of bladder cancer in neuro urological patients. This implies that their specific histopathological signature is distinct from non neuro-urological patients. Additional pathways may be involved to explain their urothelial carcinogenesis mechanism. PMID- 29524971 TI - Analysis of evidence within the AUA's clinical practice guidelines. AB - INTRODUCTION: Surgical subspecialty societies release clinical practice guidelines (CPGs) to provide topic-specific recommendations to healthcare providers. We hypothesize that there may be significant differences in statement strength and evidence quality both within the American Urological Association (AUA) guidelines and compared to those published by the American Academy of Orthopedic Surgeons (AAOS) and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). MATERIALS AND METHODS: CPGs issued through 2017 were extracted from the AUAnet.org. Statements were characterized by evidence basis, strength, and evidence quality. CPGs were compared among urologic subspecialties and to those from the AAOS and AAO-HNS. Analysis used Fisher's exact tests and Student's t-tests with significance p < 0.05. RESULTS: A total of 25 AUA CPGs (672 statements) were reviewed and 34.6% were non-evidence based with the highest proportions in pediatrics (47.5%) and sexual medicine (46.5%). The AUA has published over twice as many statements as the AAOS and quadruple that of the AAO HNS. A smaller proportion of the AUA statements were evidence-based (65.4%) compared to the AAOS (80.5%, p < 0.001) and AAO-HNS (99.8%, p < 0.001), and fewer used "high" quality evidence (AUA 7.2% versus AAOS 21.2%, p < 0.001; versus AAO HNS 16.1%, p < 0.001). CONCLUSIONS: The AUA has published broad CPGs that far exceed those from the AAOS and AAO-HNS. The AUA has utilized extensive resources to provide guidance to help standardize care among urologists. The AAOS and AAO HNS may not provide guidelines when evidence is limited. With the continued increase of high quality clinical trials, the AUA will be able to continue improving its robust set of evidence-based CPGs. PMID- 29524972 TI - Sociodemographic and survival disparities for histologic variants of bladder cancer. AB - INTRODUCTION: To investigate the impact of perioperative factors on overall survival among patients with histologic variants of bladder cancer treated with radical cystectomy. MATERIALS AND METHODS: The National Cancer Data Base was utilized to identify patients diagnosed with muscle-invasive bladder cancer (cT2 4, N0, M0) from 2004-2013. Variant histology bladder cancers (non-mucinous adenocarcinoma, mucinous/signet ring adenocarcinoma, micropapillary urothelial carcinoma, small cell carcinoma, and squamous cell carcinoma) were compared to urothelial carcinoma with respect to overall survival. Adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were calculated from a multivariable Cox regression model to examine factors affecting overall survival, T upstaging, N upstaging, and positive surgical margins. Median survival was calculated using Kaplan-Meier analysis. RESULTS: A total of 5,856 patients were included in this study. Significant predictors of worse overall survival included: African American ancestry (aHR = 1.24, 95%CI: 1.03-1.48, p = 0.021), age (1.03, 1.02 1.03, p < 0.001), comorbidity (1.30, 1.20-1.40, p < 0.001), cT3 stage (1.41, 1.26 1.57, p < 0.001), and cT4 stage (1.59, 1.38-1.84, p < 0.001). Small cell carcinoma (2.10, 1.44-3.06, p < 0.001) and non-mucinous adenocarcinoma (1.59, 1.15-2.20, p = 0.005) were significant predictors of worse overall survival compared to urothelial carcinoma. Small cell carcinoma had the worst 5 year overall survival (15.5%, 95% CI: 5.2%-30.9%) compared to urothelial carcinoma (48.7%, 95% CI: 47.2%-50.2%). Micropapillary urothelial carcinoma was a significant predictor of increased progression to node positivity and positive margin status after radical cystectomy compared to urothelial carcinoma (6.01, 3.11-11.63, p < 0.001; 4.38, 2.05-9.38; p < 0.001). CONCLUSIONS: Among bladder cancer patients with equal treatment and staging, small cell carcinoma and non mucinous adenocarcinoma variant histologies were predictive of worse overall survival compared to urothelial carcinoma. Patient demographics such as African American ancestry and age were also predictive of worse overall survival among variant histology bladder cancer and urothelial carcinoma. PMID- 29524973 TI - Implications of postoperative pulmonary aspiration following major urologic surgery. AB - INTRODUCTION: The purpose of this article is to assess the incidence of pulmonary aspiration following major urologic surgery, predictors of an aspiration event, and subsequent clinical outcomes. MATERIALS AND METHODS: The Healthcare Cost and Utilization Project State Inpatient Database for California between 2007-2011 was used to identify cystectomy, prostatectomy, partial and radical nephrectomy patients. Aspiration events were identified within 30 days of surgery. The primary outcome was 30 day mortality and secondary outcomes included total length of stay, discharge location, and diagnoses of acute renal failure, pneumonia or sepsis. Descriptive statistics were performed. A multivariable logistic regression was performed to determine independent predictors of an aspiration event. A separate nonparsimonious logistic regression was fit to determine the independent effect of an aspiration event on 30 day mortality. RESULTS: Of 84,837 major urologic surgery patients 319 (0.4%) had an aspiration event. Risk factors for aspiration included ileus, congestive heart failure, paraplegia, chronic lung disease, and age = 80 years (all p < 0.01). Aspiration patients had higher rates of renal failure (36.1% versus 2.5%), pneumonia (36.1% versus 2.5%), sepsis (35.7% versus 0.7%), a prolonged length of stay (17 days versus 3 days), and discharge to nursing facility(26.3% vs 2.3%) (all p<0.001). The 30 day mortality rate following aspiration was 20.7% compared to 0.8% (p < 0.001). Aspiration independently increases the risk of 30 day mortality (OR 3.1 (95%CI 2.2-4.5). CONCLUSIONS: Postoperative aspiration following major urologic surgery is a devastating complication and precautions must be undertaken in high risk patient populations to avoid such an event. PMID- 29524974 TI - African-American men with prostate cancer have larger tumor volume than Caucasian men despite no difference in serum prostate specific antigen. AB - INTRODUCTION: Prior studies suggest that among men with low grade prostate cancer, African Americans (AA) produce less prostate-specific antigen (PSA) than Caucasians. We investigated racial differences in PSA, PSA density (PSAD), and tumor volume among men with prostate cancer, regardless of tumor grade. These racial differences, if present, would suggest that AA men may benefit from different screening, surveillance, and treatment regiments compared to Caucasians. MATERIALS AND METHODS: We identified men from our institutional prostate cancer database that underwent radical prostatectomy between 2012 and 2015. Clinicopathologic parameters were compared by race. Multivariable linear regression was then performed to identify factors associated with PSA, PSAD, and tumor volume, adjusting for race, age, body mass index, and pathologic parameters. RESULTS: A total of 255 men were included in the analysis, including 182 (71.4%) Caucasian and 73 (28.6%) AA. PSA (10.2 versus 8.1, p = 0.13) and PSAD (0.23 versus 0.22, p = 0.73) did not differ significantly between AA and Caucasian men. In contrast, tumor volume was significantly greater in AA men (13.4 versus 9.6 grams, p = 0.01). In multivariable linear regression analysis, AA race was not associated with PSA (p = 0.80) or PSAD (p = 0.41), but was significantly associated with increased tumor volume (p < 0.01). CONCLUSIONS: AA men who underwent radical prostatectomy in this analysis had larger tumor volume than Caucasian men despite having similar PSA levels. This association suggests that prostate cancers in AA men may produce less PSA than in Caucasian men. These findings have implications for prostate cancer screening and treatment, as PSA may underestimate the presence or extent of cancer in AA men. PMID- 29524975 TI - Urine kidney injury markers do not increase following gastric bypass: a multi center cross-sectional study. AB - INTRODUCTION: To determine if markers of kidney injury correlate with urinary oxalate excretion. If so, such biomarkers might be early predictors of oxalate nephropathy. Gastric bypass surgery for obesity is known to be associated with postoperative hyperoxaluria, which can lead to urolithiasis and kidney damage. MATERIALS AND METHODS: Patients were recruited from four large academic centers > 6 months following completion of gastric bypass surgery. Patients provided a spot urine sample for analysis of three markers of kidney injury: 8-iso-Prostaglandin F2 alpha, N-acetyl- beta -D-Glucosaminidase, and Neutrophil gelatinase-associated lipocalin. Patients also provided 24 hour urine samples for stone risk analysis. RESULTS: A total of 46 study patients provided samples, the average age was 48.4 +/- 11.3. There were 40 women and 6 men. There was no difference in the level of any of the three inflammatory markers between the study group and the reference range generated from healthy non-hyperoxaluric subjects. Neither oxalate excretion nor supersaturation of calcium oxalate correlated with any of the injury markers. There was no difference noted between those with hyperoxaluria (n = 17) and those with normoxaluria (n = 29) with respect to any of the injury markers. CONCLUSIONS: Though hyperoxaluria was common after bypass surgery, markers of kidney injury were not elevated after surgery. No correlation was found between urine oxalate excretion and any of the injury markers. PMID- 29524976 TI - Fluoroless-ureteroscopy for definitive management of distal ureteral calculi: randomized controlled trial. AB - INTRODUCTION: To assess the conversion rate during fluoroless-ureteroscopy (URS) and evaluate the feasibility, safety, and efficacy of fluoroless-URS as a definitive management of distal ureteral calculi. MATERIAL AND METHODS: Between May 2013 and August 2015, patients with radio-opaque distal ureteral calculi of <= 1 cm in size were randomized to undergo fluoroless-URS or standard URS. Patients with previous ureteral surgery, ureteral kinking, ureteral stricture, single kidney, additional proximal ureteral or renal calculi, uncontrolled coagulopathy, and/or congenital anomalies of the urinary tract were excluded. Patients' demographics, stone characteristics, operative data, stone free status, and complications were compared between both groups. RESULTS: Seventy-four cases in the fluoroless-URS group were compared with 80 cases in the standard-URS group. There was no significant difference in the baseline characteristics between both groups in terms of the mean patient's age (28.8 +/- 13.3 versus 29.5 +/- 14.6 years; p = 0.76), body mass index (28.2 +/- 33 versus 27.6 +/- 2.3 kg/m2; p = 0.19), and stone size (7.2 +/- 1.5 versus 7.3 +/- 1.7 mm; p = 0.70), respectively. Furthermore, there was no significant difference in the outcome parameters between both groups in terms of operative time (42.4 +/- 8.3 versus 40.3 +/- 6.5 min; p = 0.08), stone free rate (93.2% versus 95%; p = 0.06), and overall complications (12.2% versus 8.75%; p = 0.08), respectively. There was significant difference between both techniques in terms of fluoroscopy time (p < 0.001). However, 6 (7.5%) fluoroless-URS cases necessitated the use of fluoroscopy intraoperatively. CONCLUSION: Ureteroscopic management of distal ureteral stones using fluoroless-URS technique could be feasible and safe, without radiation exposure for patients and medical personnel. However, fluoroscopy should always be available during fluoroless-URS. PMID- 29524977 TI - Retroperitoneal Leydig cell tumor recurrence presenting 14 years after orchiectomy. AB - Malignant Leydig cell tumor is a rare entity that has been previously described as rapidly progressive and uniformly fatal. We present the case of a malignant Leydig cell tumor that presented 14 years after orchiectomy with an isolated retroperitoneal metastasis. Our patient underwent a retroperitoneal lymph node dissection and has been free of recurrence or progression at 12 months of follow up. Additionally, we describe the symptomatic hormone dysfunction experienced by our patient as a result of his tumor. PMID- 29524978 TI - T4 urothelial carcinoma in undiagnosed closed bladder exstrophy in a post menopausal female. AB - It is rare to see an adult presenting with exstrophy of the bladder. Malignant conversion in exstrophy occurs in 4%, with adenocarcinoma as the most common histopathology. We report the first case of metastatic high grade urothelial carcinoma with squamous and sarcomatoid differentiation arising from undiagnosed, closed bladder exstrophy in a female at advanced age with associated bilateral deep vein thrombosis and clot retention. The patient developed clinical progression of disease despite neoadjuvant gemcitabine-cisplatin and salvage (or palliative) radiotherapy. To the best of our knowledge, this is the first reported case of a primary urothelial malignancy in occult bladder exstrophy. PMID- 29524979 TI - Bilateral hydronephrosis and acute kidney injury secondary to pelvis lipomatosis. AB - A 57-year-old African American male presented with vague abdominal pain and bilateral flank pain. The patient was found to have bilateral hydronephrosis and significant renal function impairment secondary to pelvic lipomatosis. Pelvic lipomatosis represents a clinically-diagnosed unique cause of ureteral obstruction and subsequent renal impairment. We present a case report of newly diagnosed pelvic lipomatosis, the clinical and imaging characteristics for diagnosis, and its conservative management with serial ureteral stent exchanges. PMID- 29524980 TI - Reminiscences of a JNE Editor. PMID- 29524981 TI - Children's Food Preferences and Education Programs. PMID- 29524982 TI - An Exploration of How Fathers Attempt to Prevent Childhood Obesity in Their Families. AB - OBJECTIVE: To understand how fathers of preschool-aged children define overweight and obesity in children, investigate how fathers influence or attempt to influence their child's nutrition and physical activity behavior, and explore the father's perceived role in making decisions regarding his child's weight status. METHODS: Explorative study using an online survey, with 9 open-ended questions. Content analysis using constant comparative method was applied to data. A total of 117 US fathers (35.6 +/- 5.55 years, 85% white; 82% had a 4-year degree or more) of preschoolers were included in the final analysis. RESULTS: Four themes emerged from the responses: (1) causes of childhood obesity, (2) prevention and/or treatment strategies, (3) recognition of child excess weight, and (4) barriers to changing behavior. CONCLUSIONS AND IMPLICATIONS: Although qualitative studies with a more representative sample are needed, practitioners could engage both fathers and mothers in interventions aimed at improving a child's health. PMID- 29524983 TI - Spotlight Education Prompts Intent to Change Dietary Behaviors. PMID- 29524984 TI - A Comment on Scherr et al "A Multicomponent, School-Based Intervention, the Shaping Healthy Choices Program, Improves Nutrition-Related Outcomes". PMID- 29524985 TI - Response to "A Comment on Scherr et al 'A Multicomponent, School-Based Intervention, the Shaping Healthy Choices Program, Improves Nutrition-Related Outcomes'". PMID- 29524986 TI - Can the combination of ablation and immunomodulation become the breakthrough of cancer treatment? PMID- 29524987 TI - Creation of an educational quality improvement program for radiation oncology residents. AB - PURPOSE: Quality improvement (QI) is a pillar of good clinical governance and is at the center of modern health care. The Royal College of Physicians and Surgeons of Canada mandated, in CanMeds 2015, that QI should be taught and the competencies assessed in all postgraduate residency programs. The objective is to report on the feasibility and impact of teaching QI to radiation oncology residents at a single institution. METHODS AND MATERIALS: A QI team consisting of a clinical fellow, 3 staff physicians, and an expert in QI methods was created within our Department of Radiation Oncology. QI teaching took place in a longitudinal manner, with approximately 12 hours of direct faculty teaching. A mandatory curriculum divided into foundation and intermediate and advanced competencies was devised. Phase 1 teaching, delivered during 2 academic half days, consisted of didactic lectures, practical workshops, and self-directed online modules. Phase 2 required intermediate-year residents to complete a 9 month QI project. A QI day hosted by the department invited QI experts to teach and enabled residents to present their work, with merit prizes awarded. Our program evaluation used validated assessment tools (self-assessment, QI knowledge based assessments, and balanced score cards) before and after curriculum implementation and answers quantified using satisfaction indices (SI). RESULTS: Subjective and objective assessments demonstrated improvements in residents' QI knowledge acquisition following curriculum implementation. Those who had completed a project (n = 4) had greater confidence with QI methodology compared with those who had completed phase 1 alone (n = 2) (mean SI, 53% precurriculum to 66.5% and 90%). The majority lacked previous QI teaching and knowledge, but learner attitudes improved (SI, 50%-70%) and 91% of colleagues were enthusiastic about the program being implemented. CONCLUSION: We have demonstrated that implementation of a QI curriculum for radiation oncology residents is feasible and that early results suggesting improvements of attitude and knowledge are positive. We anticipate that the QI skills gained will enable the residents to elevate the quality of their practice throughout their subsequent careers. PMID- 29524988 TI - Journal editors as curators of scholarship: A case study in repairing the scientific record. PMID- 29524989 TI - Retraction notice to "Attractive Names Sustain Increased Vegetable Intake in Schools" [Prev. Med. 55/4 (2012) 330 - 332]. PMID- 29524990 TI - The Role of Food Challenges in Clinical Practice. AB - Food challenges are the criterion standard for establishing the presence or absence of food allergy. However, they remain underused because of their resource intensive nature, inadequate reimbursement, and concern for the risk of anaphylaxis. Here, we review indications for performing food challenges, including scenarios of uncertain diagnosis, quality-of-life effects following food challenges, and the impact on office practice including coding and reimbursement issues. Demand for food challenges is likely to increase and allergists should be capable of providing this service to their patients when indicated. PMID- 29524991 TI - Unproven Diagnostic Tests for Adverse Reactions to Foods. AB - Patients often seek opinions from allergists regarding unconventional testing for adverse reactions to foods. These tests include flow cytometry to measure the change in white blood cell volumes after incubation with foods, measurement of serum IgG or IgG4 antibodies directed against foods, intradermal provocation neutralization with food allergens, hair analysis, electrodermal testing, and applied kinesiology. In some cases, although the laboratory methods may be valid, there are no studies showing correlation with disease. In other cases, blinded, controlled studies have shown a lack of reproducibility and a lack of correlation with disease. Most of the tests lack biologic plausibility. By understanding the methodology of these tests and the lack of evidence supporting their utility, allergists can provide knowledgeable, evidence-based information to patients who inquire about them. PMID- 29524993 TI - The Consequences of Precautionary Allergen Labeling: Safe Haven or Unjustifiable Burden? AB - Precautionary allergen labeling (PAL) also known as "may contain" labeling has been applied to many packaged food products around the world. PAL is a voluntary form of labeling whose original intent was to help ensure that packaged foods were as safe as possible for allergic consumers by alerting them to the possible presence of allergen residues resulting from the use of shared processing equipment, shared processing facilities, or other industry practices. However, the proliferation of PAL and the myriad of various phrasing used as PAL statements are confusing to consumers and serve to diminish their quality of life. Thus many allergic consumers are known to ignore PAL statements. Analytical surveys indicate that many PAL products contain no detectable allergen residues and are likely safe for allergic consumers. However, up to 8% of allergic consumers report having had reactions to the ingestion of PAL products. Clearly a better approach to labeling is needed that balances the health and safety considerations of allergic consumers with their desire to enjoy the widest possible array of foods available in the marketplace. This article presents an overview and discussion of the shortcomings of the current PAL system and explores why a new approach is required. PMID- 29524992 TI - Primary Prevention of Food Allergy: Translating Evidence from Clinical Trials to Population-Based Recommendations. AB - Given the prevalence and impact of childhood food allergy, there is increasing interest in interventions targeting disease prevention. Although interventions such as early introduction of dietary peanut have demonstrated efficacy in a small number of well-conducted randomized clinical trials, evidence for broader effectiveness and successful implementation at a population level is still lacking, although epidemiological data suggest that such strategies are likely to be successful, at least for peanut. In this commentary, we explore the issues of translating evidence of efficacy studies (performed under optimal conditions) to make policy recommendations at a population level, and highlight potential benefits, harms, and unintended consequences of making population-based recommendations on the basis of randomized controlled trials. We discuss the complexity and barriers to effective primary and secondary prevention intervention implementation in resource-poor settings. PMID- 29524994 TI - Food Allergy: What's on the Menu in 2018? PMID- 29524995 TI - Getting to the Root of the Food Allergy "Epidemic". PMID- 29524996 TI - Preliminary Development of the Food Allergy Coping and Emotions Questionnaires for Children, Adolescents, and Young People: Qualitative Analysis of Data on IgE Mediated Food Allergy from Five Countries. AB - BACKGROUND: We have previously developed a food allergy-specific developmental model, that explained emotions and coping styles, among children aged 6 to 15years in Ireland. OBJECTIVE: The objective of this study was to investigate the usefulness of the developmental model in a large multicountry data set, including any mediators of coping style, and to use the findings to generate an item pool that will form the basis for 3 age-appropriate self-report questionnaires to measure coping and emotions. METHODS: We conducted deductive thematic analysis on secondary data from interviews with 274 participants aged 6 to 23 years, and 119 parents from Australia, Ireland, Italy, the UK, and the USA. Analysis was undertaken across the entire data set. RESULTS: The Food Allergy Coping and Emotions (FACE) model has 5 major themes: (1) experiences and emotions, (2) search for normality, (3) management and coping, (4) "external mediators," and (5) "internal mediators" (between emotions and coping). These themes were present across countries, but differed according to age. CONCLUSIONS: Early-life experiences provide the foundation for later cognitions and behaviors. The expanded FACE developmental model is useful in explaining emotions and coping styles across different age groups and countries. These data will also be used to generate an age-specific bank of items for the development of 3 (age-specific self-report, and parent proxy) questionnaires to assess emotions and coping in food allergy. Findings provide insight into how particular styles of coping develop and vary from patient to patient and may also guide clinician-patient communication and the development of individualized management strategies. PMID- 29524997 TI - Exercise Lowers Threshold and Increases Severity, but Wheat-Dependent, Exercise Induced Anaphylaxis Can Be Elicited at Rest. AB - BACKGROUND: Wheat-dependent, exercise-induced anaphylaxis (WDEIA) is a severe form of allergy in which exercise is being considered as mandatory. The diagnosis is often complex and the clinical reproducibility low. OBJECTIVE: The aims of this study were to establish a standardized challenge method for the diagnosis of WDEIA and to investigate whether exercise is an essential trigger factor or alternatively an augmentation factor able to lower threshold and increase severity. METHODS: We investigated 71 patients (age, 18.6-73.7 years) with a case history of WDEIA. Skin prick test (SPT) and measurement of specific IgE (sIgE) were followed by an oral food challenge with gluten at rest and in combination with treadmill exercise. RESULTS: A clinical reaction was elicited in 47 of 71 (66%), and in 26 of these (37%) the reaction could be elicited at rest. The median dose required at rest was 48 g (8-80 g) and in combination with exercise 24 g (4-80 g). Severity was significantly higher with exercise (2.3) than at rest (1.1) using Sampson severity score. In the challenge, SPT was positive to wheat in 93.6% (44 of 47) and to gluten in 95.7% (45 of 47). sIgE to wheat, gliadin, and omega-5 gliadin was present in 78.7% (37 of 47), 76.5% (36 of 47), and 91.4% (43 of 47) of the patients. Receiver operating characteristic-curve analysis for sIgE to omega-5 gliadin, a component of the gluten fraction and the major allergen in WDEIA, showed best sensitivity (91%) and specificity (92%) when gluten was combined with exercise. CONCLUSIONS: A challenge test with gluten at rest and combined exercise is a safe confirmatory test for WDEIA. A reaction can be elicited at rest (without exercise), but exercise is able to lower the threshold and increase the severity. PMID- 29524998 TI - Asthma Step-Down Strategies: Perhaps the Patient Should Decide? PMID- 29524999 TI - The Occasional Ebb and Flow between Eosinophilic Esophagitis and IgE-Mediated Food Allergy. PMID- 29525000 TI - Epidermal Necrolysis, Ocular Complications, and "Cold Medicines". PMID- 29525001 TI - Refutation is a strong word for partial evidence in ASIA. PMID- 29525002 TI - ASIA, chronic fatigue syndrome, and selective low dose neurotoxicity of aluminum adjuvants. PMID- 29525003 TI - Reply to Crepeaux et al and Blasco. PMID- 29525004 TI - ? PMID- 29525005 TI - ? PMID- 29525006 TI - [Certification assessment and quality and risk management]. AB - Organised by the French National Health Authority (HAS), certification is an external assessment process which is obligatory for all public and private health facilities, whatever their size or activity. The aim is to independently evaluate the quality of the health care provision of hospitals and clinics in France. This article looks at the investigation methods and the procedure used during the certification assessment of Henri Mondor University Hospitals in 2016. PMID- 29525008 TI - [Rolling out the quality policy within a healthcare facility]. AB - A nurse hygienist, a senior health care manager within her hospital, describes the V2014 certification quality policy. The Hygiene, Epidemiology, Infection vigilance and Prevention theme forms part of the hospital's priorities. PMID- 29525007 TI - [Certification, being observed by others]. AB - The process of certification of a healthcare facility means being assessed by one's peers. The person being assessed and the person carrying out the assessment are both health professionals. It is important to recognise the Other, to help him or her progress, keep a professional distance and demonstrate compassion, while also learning from him or her. More than a performance assessment, care is centred on the human relationship. PMID- 29525009 TI - [Experience of the hospital at home service]. AB - A doctor coordinator within the Nancy hospital at home service shares his experience of the assessment by the National Health Authority, carried out as part of the V2014 certification process, in February 2016. This 'adventure' sparked in him the desire to become an assessor. PMID- 29525010 TI - [Certification, on-the-ground experience of a manager and his team]. AB - The certification assessment is an important stage in the life of a healthcare facility. However, instilling a quality culture within a team to lead it towards performance is a long-term endeavour. This cannot work without the existence of a partnership between the paramedical and medical teams, nor without the support of the hospital led by senior quality managers. The challenge is to not limit the quality culture to the certification assessment, which aims to highlight the areas in which the institution conforms and those in which it is failing, but rather to adopt a continuous improvement approach. PMID- 29525011 TI - [Community health and interculturality]. AB - An interventional research study in public health was carried out with populations originating from sub-Saharan Africa living in France. With the aim of acting on health inequalities through health education, the researchers focused notably on the links between intercultural relationships and the improvement of health promotion actions. PMID- 29525012 TI - [Developing the valuable contribution of the nursing role in a palliative care mobile team]. AB - A Swiss palliative care mobile team shares its atypical experience resulting from the lack of a permanent doctor within the team because of recruitment difficulties, over a 16-month period. The positive result of this situation was the development of the nursing team's expertise and the experience of a remote constructive cross-discipline approach. PMID- 29525013 TI - [Crushing or opening medication: what practices, what risks?] AB - The practice of crushing tablets or opening up capsules to be taken orally, when it is not prescribed, can affect the efficacy of a treatment, or even cause an adverse event. A survey carried out in 2016 revealed that this is a common practice, especially among elderly people. However, alternative forms exist and can be prescribed. PMID- 29525014 TI - [Mobilising the team and the patient to prevent pressure ulcers]. AB - The occurrence of a pressure ulcer can be considered as an avoidable adverse event. Its consequences are not only very harmful for the patient, but also in terms of the costs induced and for the nursing teams faced with the failure of the prevention treatment. For these reasons, nurses, nurse assistants and the multidisciplinary team must work together around a pressure ulcer prevention strategy. PMID- 29525015 TI - [Meaning and humanity in care]. AB - Nursing practice is founded on numerous theories. While life sciences use evidence to design the most effective practices from a biomedical point of view, human sciences sometimes struggle to corroborate the perception of patients as caregivers in their humanised practice. This article presents a perspective of care in a resolutely human dimension, where the main objective is to be of use to the person. PMID- 29525016 TI - [Communication at the heart of effective group work]. AB - Nursing students conducted a study into the meaning of group work. Based on the experience they gained from their practice placements, as well as their trip organised as part of their optional learning unit, they scrutinised the conditions favourable to the effective functioning of a working group and the pitfalls to avoid. It equipped them with useful references with which to approach their first job. PMID- 29525017 TI - ? PMID- 29525018 TI - ? PMID- 29525019 TI - ? PMID- 29525020 TI - ? PMID- 29525021 TI - Shoulder Instability: Common Problems and Solutions. AB - Operative treatment of the unstable shoulder historically has a high success rate. However, the complication rate has risen. This article reviews the pearls and pitfalls to attempt to elucidate the etiology for these complications and failures. Preoperative assessment of the unstable shoulder ultimately is critical to avoid complications, including history, physical examination, and key radiographic features. Intraoperative techniques include appropriate soft tissue mobilization, multiple points of fixation, avoidance of hardware-related problems, and appropriate management of the capsule and bone defects. Finally, postoperative rehabilitation is equally important to regain physiologic range of motion in a safe, supervised fashion. PMID- 29525022 TI - Shoulder Rotator Cuff Pathology: Common Problems and Solutions. AB - Rotator cuff repair is an increasingly common orthopedic procedure. As with any surgical procedure, the complications can be potentially devastating when they do happen to occur. This review attempts to summarize the most frequently encountered complications, including retear, failure to heal, stiffness, missed concomitant pathology, and infection. Also included are several cases that outline the diagnosis and management of these complications. PMID- 29525023 TI - Shoulder Acromioclavicular and Coracoclavicular Ligament Injuries: Common Problems and Solutions. AB - Injuries to the acromioclavicular joint and coracoclavicular ligaments are common. Many of these injuries heal with nonoperative management. However, more severe injuries may lead to continued pain and shoulder dysfunction. In these patients, surgical techniques have been described to reconstruct the function of the coracoclavicular ligaments to provide stable relationship between the clavicle and scapula. These surgeries have been fraught with high complication rates including clavicle and coracoid fractures, infection, loss of reduction and fixation, hardware migration, and osteolysis. This article reviews common acromioclavicular and coracoclavicular repair and reconstruction techniques and associated complications, and provides recommendations for prevention and management. PMID- 29525024 TI - Elbow Injuries: Common Problems and Solutions. AB - The elbow is one of the more difficult joints in which to obtain good results. Common issues include placement of correct portals, neuropraxia, ankylosis, heterotopic bone formation, and simple failure of the procedure. Common solutions include portal placement safeguards, nerve protection, early motion and cryocompression, oral or injectable steroids, radiation therapy, secure stabilization, and postoperative protection and rehabilitation based on available evidence and imaging. PMID- 29525025 TI - Hand and Wrist Injuries: Common Problems and Solutions. AB - Injuries to the hands and wrist are common in athletes. Injuries include acute fractures, dislocations, ligamentous, and tendon injuries, as well as more chronic injuries such as sprains and strains. Complications in the treatment of sports injuries of the hand and wrist may be divided into 2 categories: incorrect or delayed diagnosis and iatrogenic injury related to treatment. This article highlights common sports injuries of the hand and wrist and their complications, and includes tips for successful management. PMID- 29525026 TI - Hip Arthroscopy: Common Problems and Solutions. AB - The use of hip arthroscopy continues to expand. Understanding potential pitfalls and complications associated with hip arthroscopy is paramount to optimizing clinical outcomes and minimizing unfavorable results. Potential pitfalls and complications are associated with preoperative factors such as patient selection, intraoperative factors such as iatrogenic damage, traction-related complications, inadequate correction of deformity, and nerve injury, or postoperative factors such as poor rehabilitation. This article outlines common factors that contribute to less-than-favorable outcomes. PMID- 29525027 TI - Knee Anterior Cruciate Ligament Injuries: Common Problems and Solutions. AB - Anterior cruciate ligament (ACL) reconstruction is one of the most commonly performed procedures in the United States. Although complications are rare in ACL surgery, failure to appreciate them can lead to significant patient morbidity in the short and long terms. More common complications in ACL reconstruction include tunnel malposition, infection, tunnel osteolysis, fixation failure, fracture, arthrofibrosis, graft site morbidity, and deep vein thrombosis or pulmonary embolism. Tunnel malposition is the most common technical error in ACL reconstruction leading to failure. Proper planning during the index surgery can help prevent these complications, especially when related to tunnel malposition. PMID- 29525028 TI - Knee MLI Injuries: Common Problems and Solutions. AB - The multiple ligament injured knee presents a challenge with regard to management and treatment. Immediate management of the acute injury requires special attention and thorough examination because knee dislocations have been associated with significant complications. Treatment options range from closed reduction and immobilization to surgical repair and/or reconstruction of the injured ligaments. This article focuses on complications that may result from surgical treatments of the multiple ligament injured knee and ways of prevention. These complications include vascular and neurologic complications, venous thromboembolic events, arthrofibrosis, compartment syndrome, wound problems, heterotopic ossification, fractures and avascular necrosis, tunnels positioning complications, and malalignment. PMID- 29525029 TI - Knee Meniscus Injuries: Common Problems and Solutions. AB - The rates of arthroscopic meniscus repair continue to increase with excellent reported outcomes. Complications, sometimes catastrophic, following meniscus repair may occur. The rate of postoperative complications may be reduced by adequate diagnosis, appropriate patient selection, meniscus repair selection, surgical techniques, and postoperative management. When complications occur, the provider must identify and take steps to rectify as well as prevent further complications from occurring. The purpose of this article is to detail the common diagnostic, technical, and postoperative pitfalls that may result in poor patient outcomes. PMID- 29525030 TI - Knee Cartilage Repair and Restoration: Common Problems and Solutions. AB - Focal cartilage defects in the knee are commonly found on MRI and arthroscopically. When these lesions are symptomatic and fail nonoperative management several surgical strategies are available. Common surgical techniques include reparative (ie, microfracture) and restorative procedures (ie, autologous chondrocyte implantation, particulated juvenile allograft cartilage, osteochondral autograft transfer, and osteochondral allograft). Each of these surgical procedures have shared and novel complications associated with their use. This article provides a detailed, case-based discussion of common complications encountered in surgical procedures for focal cartilage defects of the knee, highlighting causes, clinical recognition, and how to address and avoid these complications. PMID- 29525031 TI - Foot and Ankle Surgery: Common Problems and Solutions. AB - Participation in sports activity has increased significantly during the last several decades. This phenomenon has exposed orthopedic sports medicine surgeons to new challenges regarding the diagnosis and management of common sport-related injuries. Arthroscopy is becoming more commonly used in many of the surgical procedures for these injuries and carries the risk of complications. Wound and nerve complications make up the bulk of complications in most procedures. This article describes these complications associated with the common surgical procedures related to foot and ankle sport-related injuries and how to address and prevent them. PMID- 29525032 TI - Pediatric Sports Medicine Injuries: Common Problems and Solutions. AB - The treatment of sports injuries in the skeletally immature has a unique set of complications. Growth deformity may occur after anterior cruciate ligament reconstruction; therefore, skeletal age is used to help guide the choice between physeal sparing and transphyseal techniques. Arthrofibrosis after tibial spine fracture fixation can be reduced by initiating immediate range of motion, and should be treated early and cautiously to avoid iatrogenic fracture. Nonunions of medial epicondyle elbow fractures are more common with nonoperative treatment, but seldom lead to clinical problems outside of certain athletes. Risks of OCD fixation are specific to the material of screw used. PMID- 29525033 TI - Rehabilitation: Common Problems and Solutions. AB - There are numerous complications that can occur following a musculoskeletal injury or surgery in the sporting population. Prevention of the most frequent complications is the key in any successful rehabilitation program, but occasionally problems do occur. A thorough well-designed postoperative or postinjury rehabilitation program may prevent these problems. However, if complications do arise, a team approach among the parties involved in the process to develop an evidenced-based treatment program designed for the underlying complication can successfully treat these issues. The authors discuss the complications seen in sports injuries to the knee, shoulder, elbow, and foot/ankle joints of the body. PMID- 29525034 TI - Common Procedures-Common Problems: It's Complicated. PMID- 29525035 TI - Cytotoxic activities and effects of atractylodin and beta-eudesmol on the cell cycle arrest and apoptosis on cholangiocarcinoma cell line. AB - Cholangiocarcinoma (CCA) is the cancer of bile duct with high mortality rate particularly in Thailand. The clinical efficacy of the standard chemotherapeutics remains unsatisfactory, and therefore, discovery and development of the new alternative drugs with high efficacy and tolerability is needed. The aim of the study was to investigate cytotoxic activity as well as the underlying mechanisms through which atractylodin and beta-eudesmol exert their activities on CCA cell growth inhibition, cell cycle arrest, and cell apoptosis. Effects of the compounds on cell cytotoxicity, cell cycle arrest, and cell apoptosis were analyzed using MTT assay, BD CycletestTM Plus DNA kit, and FITC Annexin V Apoptosis Detection Kit I, respectively. The cytotoxic activities of both compounds were concentration- and time-dependent. The IC50 [mean (SD)] of atractylodin and beta-eudesmol were 41.66 (2.51) and 39.33 (1.15) MUg/ml respectively. Both promoted cell cycle arrest at G1 phase, and induced cell apoptosis through activation of caspase-3/7. The highest activity was observed at 48 h of exposure. Results suggest that these mechanisms are at least in part, explain the cell cytotoxic and anti-CCA activity of atractylodin and beta eudesmol shown in vitro and in vivo models. PMID- 29525036 TI - Corrigendum to 'Benzene and childhood acute leukemia in Oklahoma'. PMID- 29525037 TI - Association of vitamin D status with multiple sclerosis in a case-control study from Morocco. AB - BACKGROUND: Growing evidence suggests that hypovitaminosis D contributes to the pathogenesis of multiple sclerosis (MS). OBJECTIVE: This study aimed to evaluate whether vitamin D levels are associated with having MS and some of its characteristics in the Moroccan population. METHODS: Using liquid chromatography tandem mass spectrometry, the 25(OH)D3 metabolite was measured to quantify vitamin D serum levels (DSLs) in 113 patients with MS and 146 healthy controls matched for gender and age. DSLs were then compared between patients and controls, with correlations sought between DSLs and gender, age at onset, disease duration, MS type, degree of disability (EDSS score) and disease severity (MSSS) in patients. RESULTS: Hypovitaminosis D (DSL<30ng/mL) was observed in 97.3% of MS patients and in 98.6% of controls. Although the mean DSL was slightly lower in patients (11.69+/-6.97ng/mL) than in controls (12.98+/-6.58ng/mL), there was no significant association between DSL and MS status (P=0.131). Similarly, among patients, no apparent association was found between DSL and MS type (P=0.214), EDSS score (P=0.076) or MSSS (P=0.772). CONCLUSION: Our study suggests that DSL is not associated with having MS nor with MS type, degree of disability or disease severity in the Moroccan population. On the other hand, DSL was lower in women and decreased with age. PMID- 29525038 TI - Modeling the influence of coupled mass transfer processes on mass flux downgradient of heterogeneous DNAPL source zones. AB - Sequestered mass in low permeability zones has been increasingly recognized as an important source of organic chemical contamination that acts to sustain downgradient plume concentrations above regulated levels. However, few modeling studies have investigated the influence of this sequestered mass and associated (coupled) mass transfer processes on plume persistence in complex dense nonaqueous phase liquid (DNAPL) source zones. This paper employs a multiphase flow and transport simulator (a modified version of the modular transport simulator MT3DMS) to explore the two- and three-dimensional evolution of source zone mass distribution and near-source plume persistence for two ensembles of highly heterogeneous DNAPL source zone realizations. Simulations reveal the strong influence of subsurface heterogeneity on the complexity of DNAPL and sequestered (immobile/sorbed) mass distribution. Small zones of entrapped DNAPL are shown to serve as a persistent source of low concentration plumes, difficult to distinguish from other (sorbed and immobile dissolved) sequestered mass sources. Results suggest that the presence of DNAPL tends to control plume longevity in the near-source area; for the examined scenarios, a substantial fraction (43.3-99.2%) of plume life was sustained by DNAPL dissolution processes. The presence of sorptive media and the extent of sorption non-ideality are shown to greatly affect predictions of near-source plume persistence following DNAPL depletion, with plume persistence varying one to two orders of magnitude with the selected sorption model. Results demonstrate the importance of sorption controlled back diffusion from low permeability zones and reveal the importance of selecting the appropriate sorption model for accurate prediction of plume longevity. Large discrepancies for both DNAPL depletion time and plume longevity were observed between 2-D and 3-D model simulations. Differences between 2- and 3 D predictions increased in the presence of sorption, especially for the case of non-ideal sorption, demonstrating the limitations of employing 2-D predictions for field-scale modeling. PMID- 29525039 TI - Longitudinal associations between biomarkers of inflammation and changes in depressive symptoms in patients with type 1 and type 2 diabetes. AB - BACKGROUND: Depressive disorders represent a frequent comorbidity of type 1 diabetes (T1D) and type 2 diabetes (T2D). Subclinical inflammation increases the risk of depressive symptoms in the general population, but the relationship appears complex and bidirectional, and longitudinal data from patients with diabetes are lacking. Therefore, this study aimed to analyse associations between changes in depressive symptoms and changes in biomarkers of inflammation in patients with T1D and T2D and to investigate the hypothesis that higher baseline levels of biomarkers of inflammation are related to a less pronounced reduction of depressive symptoms over time. METHODS: Depressive symptoms and systemic levels of six biomarkers of inflammation were assessed in 168 individuals with T1D and 103 individuals with T2D who participated in baseline and 1-year follow up examinations. Data were obtained from two matching randomised controlled trials addressing diabetes distress and depressive symptoms. Longitudinal associations between biomarkers and depressive symptoms were estimated using linear regression models adjusting for multiple confounders. RESULTS: In patients with T2D, reductions in depressive symptoms were associated with reductions in high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-18 and IL-1 receptor antagonist (IL-1RA) (P <= 0.016), whereas no associations were seen for IL-6, CCL2 and adiponectin. Higher CCL2 levels at baseline were associated with lower subsequent reduction in depressive symptoms (P = 0.018). Neither baseline levels nor changes in biomarkers in subclinical inflammation were associated with changes in depressive symptoms in patients with T1D. CONCLUSIONS: Reductions of depressive symptoms were longitudinally associated with reductions in biomarkers of inflammation in patients with T2D. Higher baseline CCL2 levels were related with lower reduction of depressive symptoms in this group. No such associations were observed in patients with T1D, suggesting that risk factors and pathomechanisms linking inflammation and depression may differ between diabetes types. PMID- 29525041 TI - Beyond Fetal Aneuploidy: A Call For A Contemporary Canadian Approach To Prenatal Screening. PMID- 29525040 TI - A Mitochondrial Health Index Sensitive to Mood and Caregiving Stress. AB - BACKGROUND: Chronic life stress, such as the stress of caregiving, can promote pathophysiology, but the underlying cellular mechanisms are not well understood. Chronic stress may induce recalibrations in mitochondria leading to changes either in mitochondrial content per cell, or in mitochondrial functional capacity (i.e., quality). METHODS: Here we present a functional index of mitochondrial health (MHI) for human leukocytes that can distinguish between these two possibilities. The MHI integrates nuclear and mitochondrial DNA-encoded respiratory chain enzymatic activities and mitochondrial DNA copy number. We then use the MHI to test the hypothesis that daily emotional states and caregiving stress influence mitochondrial function by comparing healthy mothers of a child with an autism spectrum disorder (high-stress caregivers, n = 46) with mothers of a neurotypical child (control group, n = 45). RESULTS: The MHI outperformed individual mitochondrial function measures. Elevated positive mood at night was associated with higher MHI, and nightly positive mood was also a mediator of the association between caregiving and MHI. Moreover, MHI was correlated to positive mood on the days preceding, but not following the blood draw, suggesting for the first time in humans that mitochondria may respond to proximate emotional states within days. Correspondingly, the caregiver group, which had higher perceived stress and lower positive and greater negative daily affect, exhibited lower MHI. This effect was not explained by a mismatch between nuclear and mitochondrial genomes. CONCLUSIONS: Daily mood and chronic caregiving stress are associated with mitochondrial functional capacity. Mitochondrial health may represent a nexus between psychological stress and health. PMID- 29525042 TI - Au-dela de l'aneuploidie : pour une approche canadienne moderne en matiere de depistage prenatal. PMID- 29525043 TI - Excerpts from the World Medical Literature. PMID- 29525044 TI - Extraits de le litterature mondiale. PMID- 29525045 TI - No. 155-Guidelines for Vaginal Birth After Previous Caesarean Birth. AB - OBJECTIVE: To provide evidence-based guidelines for the provision of a trial of labour (TOL) after Caesarean section. OUTCOME: Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. EVIDENCE: MEDLINE database was searched for articles published from January 1, 1995, to February 28, 2004, using the key words "vaginal birth after Caesarean (Cesarean) section." The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: VALIDATION: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada. PMID- 29525046 TI - N degrees 155-Directive clinique sur l'accouchement vaginal chez les patientes ayant deja subi une cesarienne. PMID- 29525047 TI - No. 230-Initial Evaluation and Referral Guidelines for Management of Pelvic/Ovarian Masses. AB - OBJECTIVES: To optimize the management of adnexal masses and to assist primary care physicians and gynaecologists determine which patients presenting with an ovarian mass with a significant risk of malignancy should be considered for gynaecologic oncology referral and management. OPTIONS: Laparoscopic evaluation, comprehensive surgical staging for early ovarian cancer, or tumour debulking for advanced stage ovarian cancer. OUTCOMES: To optimize conservative versus operative management of women with possible ovarian malignancy and to optimize the involvement of gynaecologic oncologists in planning and delivery of treatment. EVIDENCE: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and the Cochrane Library, using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified by searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. RECOMMENDATIONS: PMID- 29525048 TI - N degrees 230-Prise en charge des masses pelviennes / ovariennes : Evaluation initiale et lignes directrices quant a l'orientation des patientes. PMID- 29525049 TI - No. 286-Surgical Safety Checklist in Obstetrics and Gynaecology. AB - OBJECTIVE: To provide guidance on the implementation of a surgical safety checklist in the practice of obstetrics and gynaecology. OUTCOMES: Outcomes evaluated include the impact of the surgical safety checklist on surgical morbidity and mortality. EVIDENCE: Medline databases were searched for articles on subjects related to "surgical safety checklist" published in English from January 2001 to January 2011. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to January 2012. VALUES: The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described by the Task Force (Table). BENEFITS, HARMS, AND COSTS: Implementation of the guideline recommendations will improve the health and well-being of women undergoing obstetrical or gynaecologic surgery. SUMMARY STATEMENTS: RECOMMENDATIONS. PMID- 29525050 TI - N degrees 286-Liste de controle de la securite chirurgicale en obstetrique gynecologie. PMID- 29525051 TI - Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions. AB - BACKGROUND: The dissociative anesthetic agent ketamine is increasingly being utilized to treat depression, despite not having FDA (Food and Drug Administration) approval for this indication. There are many questions about the potential risks of this treatment and hence the proper setting and degree of monitoring required to ensure patient safety. There is limited data about the cardiovascular safety of ketamine when administered at subanesthetic doses to treat depression. METHODS: 66 patients in the Department of Psychiatry at Emory University received a total of 684 ketamine infusions between 2014 and 2016. Ketamine was dosed at 0.5 mg/kg body weight and infused over 40 min. Blood pressure was measured every 10 min during the infusions and every 15 min thereafter. RESULTS: Mean age of the patients was 56.7 years, 87.9% had unipolar depression and 36.1% had essential hypertension. No infusions were discontinued due to instability of vital signs, adverse physiological consequences or acute psychotomimetic effects. The biggest increases in blood pressure were measured at 30 min (systolic 3.28 mmHg, diastolic 3.17 mmHg). Hypertensive patients had higher blood pressure peaks during the infusions. Blood pressures returned to baseline during post-infusion monitoring. There was no development of tolerance to the blood pressure elevating effects of ketamine between the first and sixth infusions. LIMITATIONS: This is a single site, retrospective analysis, of patients who were spontaneously seeking clinical care. CONCLUSIONS: The blood pressure changes observed when ketamine is administered over 40 min at 0.5 mg/kg for the treatment of depression are small, well tolerated and clinically insignificant. PMID- 29525052 TI - Are individuals diagnosed with social anxiety disorder successful in regulating their emotions? A mixed-method investigation using self-report, subjective, and event-related potentials measures. AB - BACKGROUND: Models of social anxiety emphasize the role of emotion dysregulation, but the nature of these impairments needs clarification. METHODS: We utilized a mixed-method approach to examine impairments in cognitive reappraisal and expressive suppression in social anxiety disorder. Forty nine treatment-seeking individuals diagnosed with social anxiety disorder and 35 healthy controls completed self-reports and a lab-based task of suppression and reappraisal. Unpleasantness ratings and event-related potentials (ERPs) were collected while participants regulated their emotions in response to shame-arousing pictures. ERP analyses focused on the late positive potential, a measure of increased attention to emotional stimuli that is reduced during emotion regulation. RESULTS: Participants with social anxiety reported less frequent and effective use of reappraisal and more frequent and effective use of suppression than controls. Counter to most models and our hypotheses, participants with social anxiety were more successful than controls in lab-based reappraisal as measured by unpleasantness ratings, but no differences emerged for ERPs. No differences were found in measures of lab-based suppression. LIMITATIONS: Use of standardized, and not participant-generated, materials in the lab-based task of emotion regulation may limit the generalizability of the findings. CONCLUSIONS: Subjective appraisals of self-efficacy and frequency suggest strong impairments in emotion regulation in social anxiety that are not revealed in the laboratory. Models and treatment protocols should specify the exact nature of emotion dyregulation in social anxiety, highlighting difficulties in implementation of potentially intact emotion regulation abilities. PMID- 29525053 TI - [Predictive biomarkers of response to immune checkpoint inhibitors]. AB - PD-1 checkpoint inhibitors are becoming the reference treatment for several types of cancers. Many patients show remarkable efficacy and low toxicity. However, some patients have a better outcome than others with PD-1 checkpoint inhibitors. So, it is crucial to identify biomarkers of response. We review here the available data of several potential biomarkers of efficacy. The expression of PD L1, detected by immunohistochemistry on tumor cells and immune cells is a good predictive biomarker of response for some cancers; however, this method is not standardized, and there are different antibodies, different cut-off values, and different targets (tumor or microenvironment). Moreover, the expression of PD-L1 is dynamic and heterogeneous within the tumor: expression is discordant between primary tumor and metastasis or between biopsy and surgical specimen. Peripheral blood lymphocytes also can be informative, especially the baseline neutrophil to lymphocyte ratio which is easy to measure in daily practice. High rate of neoantigens is also associated with improved response. Therefore, mutation burden can be predictive of response and this explains why tumors with microsatellites instability have an enhanced response. Similarly, genetic signatures are linked with resistance or response to treatment. Gut microbiota is associated with improved antitumor immune response although the underlying mechanism is not well understood so far. Lastly, it seems that cytokines, mediators of immunity may play a role in the response to immunotherapy and so, constitute an interesting biomarker. Several potential biomarkers are identified but none is prospectively validated so far. PMID- 29525054 TI - [Body image disorder in 100 Tunisian female breast cancer patients]. AB - INTRODUCTION: This study aimed at tracking the prevalence of body image disorder in a population of Tunisian women followed for breast cancer and the factors associated with it. PATIENTS END METHODS: The cross-sectional study was conducted at Salah-Azaiez Institute in Tunis, over a period of four months. One hundred outpatients followed for confirmed breast cancer were recruited. The questionnaire targeted the women's sexuality and their couple relationships, along with their socio-demographic, clinical, and therapeutic characteristics. The scales used were BIS, HADS, and FSFI. RESULTS: The prevalence of body image disorder according to BIS was 45% with an average of 11.5+/-11.2 among the interrogated patients, 24.7% of which reported an alteration in their couple relationships and 47% in their sexual relations. In univariate analysis, body image disorder was associated with family support, change in couple relationship, depression and anxiety. Body image disorder and sexual dysfunction were interrelated: each of them fostered the prevalence of the other. Multivariate analysis showed that occupational activity was an independent predictor and the absence of anxiety an independent protective factor. Body image disorder was an independent predictive factor of depression and anxiety. DISCUSSION: The quality of couple relation and sexuality, along with the impact of the patient's surrounding are decisive for the protection or alteration of her body image. PMID- 29525055 TI - Geriatric (G60) trauma patients with severe rib fractures: Is muscle sparing minimally invasive thoracotomy rib fixation safe and does it improve post operative pulmonary function? AB - BACKGROUND: Patient outcomes after muscle sparing minimally invasive thoracotomy rib fixation (MSMIT-ORF) in geriatric G60 trauma patients remain poorly studied. This study determined the effect of MSMIT-ORF on pulmonary function (PFT). Non operatively managed (NOM) patients were also described. METHODS: Medical records of G60 patients with severe rib fractures with PFTs measured before and after MSMIT-ORF were examined. Patient outcomes (MSMIT-ORF vs NOM) were adjusted in a multivariate logistic regression model. RESULTS: 64 patients underwent MSMIT-ORF, 135 were NOM patients. MSMIT-ORF treated patients showed improvements in PFTs on postoperative day 5, p = 0.001. After adjustment analysis, MSMIT-ORF was associated with increased hospital length of stay (OR 44.9; 95% CI, 9.8-205, p < 0.001), but a more favorable discharge disposition. There was no difference in the rates of pneumonia (p = 0.996) or death (p = 0.140). CONCLUSIONS: MSMIT-ORF is safe and improves pulmonary function in G60 trauma patients diagnosed with severe rib fractures. Future randomized control studies are needed for confirmation. PMID- 29525056 TI - The influence of stress responses on surgical performance and outcomes: Literature review and the development of the surgical stress effects (SSE) framework. AB - BACKGROUND: Surgical adverse events persist despite several decades of system based quality improvement efforts, suggesting the need for alternative strategies. Qualitative studies suggest stress-induced negative intraoperative interpersonal dynamics might contribute to performance errors and undesirable patient outcomes. Understanding the impact of intraoperative stressors may be critical to reducing adverse events and improving outcomes. DATA SOURCES: We searched MEDLINE, psycINFO, EMBASE, Business Source Premier, and CINAHL databases (1996-2016) to assess the relationship between negative (emotional and behavioral) responses to acute intraoperative stressors and provider performance or patient surgical outcomes. RESULTS/CONCLUSIONS: Drawing on theory and evidence from reviewed studies, we present the Surgical Stress Effects (SSE) framework. This illustrates how emotional and behavioral responses to stressors can influence individual surgical provider (e.g. surgeon, nurse) performance, team performance, and patient outcomes. It also demonstrates how uncompensated intraoperative threats and errors can lead to adverse events, highlighting evidence gaps for future research efforts. PMID- 29525057 TI - Single-case synthesis tools II: Comparing quantitative outcome measures. AB - Varying methods for evaluating the outcomes of single case research designs (SCD) are currently used in reviews and meta-analyses of interventions. Quantitative effect size measures are often presented alongside visual analysis conclusions. Six measures across two classes-overlap measures (percentage non-overlapping data, improvement rate difference, and Tau) and parametric within-case effect sizes (standardized mean difference and log response ratio [increasing and decreasing])-were compared to determine if choice of synthesis method within and across classes impacts conclusions regarding effectiveness. The effectiveness of sensory-based interventions (SBI), a commonly used class of treatments for young children, was evaluated. Separately from evaluations of rigor and quality, authors evaluated behavior change between baseline and SBI conditions. SBI were unlikely to result in positive behavior change across all measures except IRD. However, subgroup analyses resulted in variable conclusions, indicating that the choice of measures for SCD meta-analyses can impact conclusions. Suggestions for using the log response ratio in SCD meta-analyses and considerations for understanding variability in SCD meta-analysis conclusions are discussed. PMID- 29525058 TI - How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review. AB - Fragile X Syndrome (FXS) appears to be associated with an increased risk for engaging in challenging behaviour, particularly self-injury, relative to those with mixed aetiology learning disabilities. Such behavioural issues are reported to be of high concern for those providing support. As such, this systematic review aimed to gain further epidemiological data regarding challenging behaviours in individuals with FXS, including: self-injurious behaviour (SIB), hand-biting as a specific topography of SIB, aggression and property destruction. Twenty eight manuscripts were identified which reported the prevalence of a relevant topography of behaviour, with widely varying prevalence estimates. Weighted averages of the prevalence of behaviours were calculated across studies. Comparison of proportions revealed significant gender differences and differences in the prevalence of types of behaviour. It is hoped that this comprehensive overview of data on this clinically significant topic will help to inform and drive future investigation to understand and provide effective intervention for the benefit of those with FXS. PMID- 29525059 TI - Trends in Utilization, Mortality, Major Complications, and Cost After Left Ventricular Assist Device Implantation in the United States (2009 to 2014). AB - The utilization of contemporary continuous-flow left ventricular assist device (CF-LVADs) has increased, accounting for >90% of implants from 2009 to 2014. The present study aimed to identify the annual national estimates in utilization, in hospital mortality, and major complications with CF-LVAD using data from the National Inpatient Sample, the largest all-payer inpatient data set in the United States, and the US Census Bureau, for the years 2009 to 2014. Participants included all adult patients who received CF-LVADs from 2009 to 2014. End points included in-hospital mortality, in-hospital complications, length of stay, cost, and disposition at the time of discharge. A total of 3,572 (weighted = 17,552) patients with left ventricular assist device (LVAD) implants were analyzed. LVAD implants increased significantly, with average annual change (%) of +12.6% (p <0.001). Rates of in-hospital mortality decreased by average annual rate of -5.3% (p = 0.02). The rates of major complications including ischemic stroke, major bleeding, and cardiac tamponade did not change significantly over the study period. However, we found a significant decrease in postoperative infections (p = 0.001) and respiratory complications (p = 0.03). Although the length of stay and disposition patterns did not change over time, we found a significant decrease in cost of hospitalization (p = 0.001). In conclusion, from 2009 to 2014, utilization of LVADs increased with concomitant decrease in in-hospital mortality rates, without significant changes in major complications. PMID- 29525060 TI - Usefulness of Lipoprotein-Associated Phospholipase A2 Activity and C-Reactive Protein in Identifying High-Risk Smokers for Atherosclerotic Cardiovascular Disease (from the Atherosclerosis Risk in Communities Study). AB - Despite the causal role of cigarette smoking in atherosclerotic cardiovascular disease (ASCVD), the underlying mechanisms are not fully understood. We evaluated the joint relation between smoking and inflammatory markers with ASCVD risk. We tested cross-sectional associations of self-reported smoking status (never, former, current) and intensity (packs/day) with lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and high-sensitivity C-reactive protein (hsCRP) in 10,506 Atherosclerosis Risk in Communities participants at Visit 4 (1996 to 1998). Using Cox hazard models adjusted for demographic and traditional ASCVD risk factors, we examined the associations of smoking status and intensity with incident adjudicated ASCVD events (n = 1,745 cases) over an average of 17 years, stratified by Lp-PLA2 and hsCRP categories. Greater packs/day smoked was linearly associated with higher levels of both Lp-PLA2 and hsCRP among current smokers. Compared with never smokers, the hazard ratio for incident ASCVD in current smokers was 2.04 (95% CI 1.76 to 2.35). Among current smokers, the risk for ASCVD per 1 pack/day greater was 1.39 (1.10 to 1.76). Both Lp-PLA2 activity >=253 nmol/min/ml and hsCRP >3 mg/L identified current smokers at the highest risk for incident ASCVD, with similar hazard ratios. hsCRP risk-stratified current smokers better based on intensity. Among current smokers, hsCRP improved ASCVD prediction beyond traditional risk factors better than Lp-PLA2 (C-statistic 0.675 for hsCRP vs 0.668 for Lp-PLA2, p = 0.001). In this large cohort with long follow-up, we found a dose-response relation between smoking intensity with Lp PLA2 activity, hsCRP, and ASCVD events. Although both Lp-PLA2 activity and hsCRP categories identified high risk among current smokers, hsCRP may better stratify risk of future ASCVD. PMID- 29525061 TI - Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction. AB - Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction <=40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF. PMID- 29525062 TI - Prognostic Value of Improved Kidney Function After Transcatheter Aortic Valve Implantation for Aortic Stenosis. AB - Transcatheter aortic valve implantation (TAVI) is associated with acute kidney injury (AKI), but can also improve the kidney function (IKF). We assessed the effects of kidney function changes in relation to baseline kidney function on 2 year clinical outcomes after TAVI. In total, 639 consecutive patients with aortic stenosis who underwent TAVI were stratified into 3 groups according to the ratio of serum creatinine post- to pre-TAVI: IKF (<=0.80; n = 95 [15%]), stable kidney function (0.80 to 1.5; n = 477 [75%]), and AKI (>=1.5; n = 67 [10%]). Different AKI risk scores were compared using receiving-operator characteristics. Median follow-up was 24 (8 to 44) months. At 3 months, the increase in estimated glomerular filtration rate in the IKF group remained, and the decreased estimated glomerular filtration rate in the AKI group recovered. Compared with a stable kidney function, AKI showed a higher 2-year mortality rate (adjusted hazard ratio [HR] 3.69, 95% confidence interval [CI] 2.43 to 5.62) and IKF a lower mortality rate (adjusted hazard ratio 0.53, 95% CI 0.30 to 0.93). AKI also predicted major and life-threatening bleeding (adjusted odds ratio 2.94, 95% CI 1.27 to 6.78). Independent predictors of AKI were chronic kidney disease and pulmonary hypertension. Independent predictors of IKF were female gender, a preserved kidney function, absence of atrial fibrillation, and hemoglobin level. Established AKI risk scores performed moderately and did not differentiate between AKI and IKF. In conclusion, AKI is transient and is independently associated with a higher mortality rate, whereas IKF is sustained and is associated with a lower mortality rate. These effects are independent of baseline kidney function. Further studies are warranted to investigate the role of IKF and generate a dedicated prediction model. PMID- 29525063 TI - Diagnostic Accuracy of a Novel Mobile Phone Application for the Detection and Monitoring of Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults, associated with significant morbidity, increased mortality, and rising health-care costs. Simple and available tools for the accurate detection of arrhythmia recurrence in patients after electrical cardioversion (CV) or ablation procedures for AF can help to guide therapeutic decisions. We conducted a prospective, single-center study to evaluate the accuracy of Cardiio Rhythm Mobile Application (CRMA) for AF detection. Patients >18 years of age who were scheduled for elective CV for AF were enrolled in the study. CRMA finger pulse recordings, utilizing an iPhone camera, were obtained before (pre-CV) and after (post-CV) the CV. The findings were validated against surface electrocardiograms. Ninety-eight patients (75.5% men), mean age of 67.7 +/- 10.5 years, were enrolled. No electrocardiogram for validation was available in 1 case. Pre-CV CRMA readings were analyzed in 97 of the 98 patients. Post-CV CRMA readings were analyzed for 92 of 93 patients who underwent CV. One patient left before the recording was obtained. The Cardiio Rhythm Mobile Application correctly identified 94 of 101 AF recordings (93.1%) as AF and 80 of 88 non-AF recordings (90.1%) as non-AF. The sensitivity was 93.1% (95% confidence interval [CI] = 86.9% to 97.2%) and the specificity was 90.9% (95% CI = 82.9% to 96.0%). The positive predictive value was 92.2% (95% CI = 85.8% to 95.8%) and the negative predictive value was 92.0% (95% CI = 94.8% to 95.9%). In conclusion, the CRMA demonstrates promising potential in accurate detection and discrimination of AF from normal sinus rhythm in patients with a history of AF. PMID- 29525064 TI - Inhaled Methane Protects Rats Against Neurological Dysfunction Induced by Cerebral Ischemia and Reperfusion Injury: PI3K/Akt/HO-1 Pathway Involved. AB - BACKGROUND AND AIMS: Cerebral ischemia and reperfusion (I/R) could produce excess reactive oxygen species (ROS), which in turn induce neurological dysfunction and inflammation in cerebral tissues. This study was designed to study the effect of methane on cerebral I/R injury. METHODS: Fifty Sprague-Dawley (SD) rats were used to induce an animal model of cerebral I/R injury. Methane was mixed with air to achieve a final concentration of 2.2%. Rats started to inhale methane-air mixture after ischemia and continued it during the reperfusion. The neurological deficits, malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-alpha) in the brain tissue were examined. The protein kinase B (Akt) phosphorylation and heme oxygenase-1 (HO-1) expression was measured by Western Blot. The neurological deficits were re-measured after rats were treated with the HO-1 inhibitor Zinc protoporphyrin IX (ZnPP-IX), phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and Akt inhibitor triciribine. RESULTS: Cerebral I/R induced neurological deficit, which was significantly decreased by methane. MDA and TNF alpha levels were significantly enhanced by cerebral I/R, while methane caused significant reduction of MDA and TNF-alpha levels. Methane significantly increased Akt phosphorylation and HO-1 expression. The HO-1 inhibitor ZnPP-IX, PI3K inhibitor LY294002 and Akt inhibitor triciribine all significantly abolished the effect of methane on neurological deficit. CONCLUSIONS: This finding suggests the possible application of methane for cerebral I/R injury and PI3K/Akt/HO-1 dependent antioxidant pathway may be involved. PMID- 29525065 TI - [Angina bullosa haemorragica]. PMID- 29525066 TI - [Diffuse hypertrichosis revealing non-classical congenital adrenal hyperplasia]. AB - BACKGROUND: Non-classical congenital adrenal hyperplasia (NC-CAH) is a recessive autosomal disease caused by a deficiency of adrenal steroidogenesis enzymes. It must be distinguished from classical CAH, either simple virilising or salt wasting, diagnosed during the neonatal period and responsible for potentially lethal disorders of sexual differentiation. NC-CAH presents a simpler and less specific clinical picture. Herein, we present two cases comprising twin girls consulting for diffuse hypertrichosis. PATIENTS AND METHODS: Two 5-year-old twin girls were seen at our consultation for increased pilosity on all four limbs, but with no facial pilosity or synophrys, as well as comedones on the chin. Their height and weight and psychomotor development was normal, with no signs of precocious puberty and no clitoral hypertrophy. Levels of 17OH-P and SDHA were high, while FSH and LH were low and IGF1 and TSH were normal. Analysis of gene CYP21 associated with NC-CAH showed mutations p.V281L and IVS2-13A/C>G. Mutation p.V281L was present in the heterozygous state in the older sister and the father, together with moderate hyperpilosity but without hirsutism or acne. No mutations were found in the mother, indicating either de novo appearance of mutation IVS2 13A/C>G in the twins or germline mosaicism in the mother. DISCUSSION: We diagnosed NC-CAH as the cause of diffuse hypertrichosis in these twins. This disease is not rare, with a prevalence of 1/1000 to 1500 among peoples of European descent. It is often diagnosed late since routine neonatal screening is not performed. In some cases, NC-CAH remains asymptomatic. The appearance of pubic hair at around 5 to 7 years is the initial reason for consultation, particularly with a dermatologist. Hyperandrogenism varies, involving hirsutism, acne, fertility disorders and premature ageing of bone. Cortisol and aldosterone levels are generally normal. The risk of acute adrenal insufficiency is extremely low. Differential diagnosis concerns ovarian or adrenal tumors and polycystic ovary syndrome. 21-OH deficiency results in defective cortisol and aldosterone synthesis, and thus in raised ACTH, leading to increased adrenal androgen secretion. The early appearance of secondary sexual characteristics is associated with a gradual accumulation of 17-OHP. Depending on severity, hydrocortisone or anti-androgens may be given, or where treatment fails, aesthetic measures such as epilation or hair discolouration may be performed. CONCLUSION: In children presenting NC-CAH, the appearance of pubic hair and hirsutism often constitute the initial reasons for consultation, including with dermatologists. However, hypertrichosis may occur in isolation. It is important that these abnormalities be clearly known to enable early diagnosis and rapid initiation of simple and readily accessible treatment. PMID- 29525067 TI - Applying current normative data to prognosis in heart failure: The Fitness Registry and the Importance of Exercise National Database (FRIEND). AB - INTRODUCTION: Percent of predicted peak VO2 (ppVO2) is considered a standard measure for establishing disease severity, however, there are known limitations to traditional normative values. This study sought to compare ppVO2 from the newly derived "Fitness Registry and the Importance of Exercise: a National Database" (FRIEND) registry equation to conventional prediction equations in a clinical cohort of patients undergoing cardiopulmonary exercise testing (CPX). METHODS AND RESULTS: We selected 1094 patients referred for evaluation of heart failure (HF) symptoms who underwent CPX. ppVO2 was calculated using the FRIEND, Wasserman/Hansen and Jones equations. Participants were followed for a median of 4.5 years [Interquartile range 3.5-6.0] for the composite endpoint of death, advanced HF therapy, or acute decompensated HF requiring hospital admission. Mean age was 48 +/- 15 years and 62% were female. The FRIEND registry equation predicted the lowest ppVO2 (measured/predicted; 71 +/- 31%), compared to the Wasserman/Hansen (74 +/- 29%) and Jones equations (83 +/- 33%) (p < 0.001). All expressions of peak VO2 were significant as univariate predictors of outcome with no significant differences between equations on pairwise analysis of receiver operating characteristic curves. When compared at a similar threshold of ppVO2 the event rate was significantly lower in the FRIEND registry equation versus the currently used Wasserman and Jones equations. CONCLUSION: The use of the newly derived FRIEND registry equation predicts HF outcomes; however, it appears to predict a higher predicted VO2; the clinical implication being a lower threshold of percent predicted peak VO2 should be considered when risk stratifying patients with HF. PMID- 29525068 TI - Longitudinal profile of NT-proBNP levels in ischemic heart failure patients undergoing surgical ventricular reconstruction: The Biomarker Plus study. AB - BACKGROUND: Plasma concentrations of natriuretic peptides have been shown to predict prognosis in heart failure (HF) patients with left ventricle (LV) dysfunction. It is still unclear if measurements after cardiac surgery are associated with any effect on the outcome. We aimed to prospectively investigate the longitudinal profile of serial evaluations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in ischemic HF patients undergoing Surgical Ventricular Reconstruction (SVR) and how NT-proBNP levels at different time-points are associated with the outcome. METHODS: One hundred and forty-three patients (122 men, 64 +/- 9 years old) with post-infarction LV remodeling referred to our Center for SVR had an assessment of NT-proBNP levels before surgery and 6, 12 and 18 months after surgery. The analysis was performed using the logarithm of the biomarker and joint modeling of serial measurements through mixed models together with Cox regression to analyze time to event data. RESULTS: The average level of the biomarker decreased by about 50% during the first year after the operation. Time-varying NT-proBNP levels were associated with the hazard of: 1% increase in NT-proBNP during the follow-up was associated with 1.5% increase of the risk of the composite event (95% CI: 1.0%, 2.6%) and with 4.2% increase of the risk of death (95% CI: 2.2%, 8.2%). CONCLUSIONS: Serial profiles (either in increasing or in decreasing) at different time points are associated with a modulation of the risk of adverse events and, therefore, are important indicators for monitoring the evolution of the disease, even after cardiac surgery. PMID- 29525069 TI - Red cell distribution width in adults with congenital heart disease: A worldwide available and low-cost predictor of cardiovascular events. AB - BACKGROUND: Red cell distribution width (RDW) is a standard component of the automated blood count, and is of prognostic value in heart failure and coronary heart disease. We investigated the association between RDW and cardiovascular events in patients with adult congenital heart disease (ACHD). METHODS AND RESULTS: In this prospective cohort study, 602 consecutive patients with ACHD who routinely visited the outpatient clinic were enrolled between 2011 and 2013. RDW was measured in fresh venous blood samples at inclusion in 592 patients (median age 33 [IQR 25-41] years, 58% male, 90% NYHA I) and at four annual follow-up visits. During 4.3 [IQR 3.8-4.7] years of follow-up, the primary endpoint (death, heart failure, hospitalization, arrhythmia, thromboembolic events, cardiac intervention) occurred in 196 patients (33%). Median RDW was 13.4 (12.8-14.1)% versus 12.9 (12.5-13.4)% in patients with and without the primary endpoint (P < 0.001). RDW was significantly associated with the endpoint when adjusted for age, sex, clinical risk factors, CRP, and NT-proBNP (HR 1.20; 95% CI 1.06-1.35; P = 0.003). The C-index of the model including RDW was slightly, but significantly (P = 0.005) higher than the model without (0.74, 95% CI 0.70-0.78 versus 0.73, 95% CI 0.69-0.78). Analysis of repeated RDW measurements (n = 2449) did not show an increase in RDW prior to the occurrence of the endpoint. CONCLUSIONS: RDW is associated with cardiovascular events in patients with ACHD, independently of age, sex, clinical risk factors, CRP, and NT-proBNP. This readily available biomarker could therefore be considered as an additive biomarker for risk stratification in these patients. PMID- 29525070 TI - Infant Weight and Length Growth Trajectories Modeled Using Superimposition by Translation and Rotation Are Differentially Associated with Body Composition Components at 3 and 7 Years of Age. AB - OBJECTIVE: To evaluate how infant weigh and length growth trajectories associate with body composition at 3 and 7 years because previous studies have noted that rapid infant weight gain increases risk for high body mass index (BMI) in children. STUDY DESIGN: There were 322 children enrolled at 3 years of age with dual x-ray absorptiometry body composition data and pediatrician growth data for 0-2 years of age who were included in analysis. Superimposition by translation and rotation modeling was used to characterize infant weight and length trajectories in terms of size, tempo and velocity measures. Associations of these measures with fat mass, lean mass, percent body fat, bone mineral content, BMI z score, and overweight prevalence at 3 and 7 years of age were determined. RESULTS: Infant growth trajectories differed by sex, race, and breastfeeding status. Higher overall weight size and weight velocity from 0 to 2 years of age were associated positively with all age 3 body composition and anthropometry outcomes. However, longer length size from 0 to 2 years of age was associated independently with higher bone mineral content and lean mass, but lower percent body fat, BMI z-score, and a lower odds of overweight at 3 years of age. By 7 years of age, later than average infant weight tempo was also associated with lower fat mass, lean mass, and BMI z-score. CONCLUSIONS: Greater average weight size and greater weight velocity in infancy are markers for greater overall body size at 3 and 7 years of age. However, longer average lengths and later weight gain tempo between 0 and 2 years of age may help to establish a leaner body composition by 3 and 7 years of age. PMID- 29525071 TI - Trends in Teenagers' Nonopiod Substance Exposures Reported to Poison Control Centers, 2010-2015. AB - OBJECTIVE: To describe current trends in nonopioid substance exposures and associated outcomes among teenagers nationwide. STUDY DESIGN: In this cross sectional study, we used 2010-2015 data from the American Association of Poison Control Centers' National Poison Data System and Poisson tests to document trends in the rate of calls to poison control centers involving adolescents stratified by sex, exposures by substance category, proportion of intentional exposures, and severity of exposures. RESULTS: The number of calls per 1000 persons increased from 5.7 to 6.8 for teenage girls and decreased from 4.7 to 4.3 for boys. Reported exposures to prescription and over-the-counter medications and illicit street drugs increased between 24% and 73%, and reported opioid exposures decreased by 16%. Among teenage girls, intentional exposures increased from 57% to 68%, with cases increasingly managed in health care facilities and more likely to result in worse health outcomes. CONCLUSIONS: The increase in intentional nonopioid substance exposures among teenage girls, with serious and potentially life-threatening consequences, is a matter of serious concern. Similar trends were not observed among teenage boys. PMID- 29525072 TI - Factors Influencing Pediatric Resident Exposure to Adolescents in their Continuity Clinic. AB - Adequate training in adolescent primary care is a challenge for pediatric residency programs. We examined residents' pediatric continuity clinic exposure to and comfort with adolescents, and their knowledge about best practices. Comfort was predicted by patient numbers, training level, and completing the adolescent rotation. Knowledge was predicted by completing the adolescent rotation. PMID- 29525073 TI - Paracetamol Serum Concentrations in Neonates Treated Enterally for Ductal Closure: A Pilot Study. AB - We determined serum paracetamol concentrations 4 hours after the eighth dose in infants treated enterally for ductal closure. Serum paracetamol concentrations correlated (P = .0026) with ductal response. No patent ductus arteriosus in a baby with paracetamol levels <20 mg/L closed in response to treatment. Paracetamol levels also correlated (P = .046) with postnatal age. PMID- 29525075 TI - Vocal Acoustic and Auditory-Perceptual Characteristics During Fluctuations in Estradiol Levels During the Menstrual Cycle: A Longitudinal Study. AB - Estradiol production varies cyclically, changes in levels are hypothesized to affect the voice. The main objective of this study was to investigate vocal acoustic and auditory-perceptual characteristics during fluctuations in the levels of the hormone estradiol during the menstrual cycle. A total of 44 volunteers aged between 18 and 45 were selected. Of these, 27 women with regular menstrual cycles comprised the test group (TG) and 17 combined oral contraceptive users comprised the control group (CG). The study was performed in two phases. In phase 1, anamnesis was performed. Subsequently, the TG underwent blood sample collection for measurement of estradiol levels and voice recording for later acoustic and auditory-perceptual analysis. The CG underwent only voice recording. Phase 2 involved the same measurements as phase 1 for each group. Variables were evaluated using descriptive and inferential analysis to compare groups and phases and to determine relationships between variables. Voice changes were found during the menstrual cycle, and such changes were determined to be related to variations in estradiol levels. Impaired voice quality was observed to be associated with decreased levels of estradiol. The CG did not demonstrate significant vocal changes during phases 1 and 2. The TG showed significant increases in vocal parameters of roughness, tension, and instability during phase 2 (the period of low estradiol levels) when compared with the CG. Low estradiol levels were also found to be negatively correlated with the parameters of tension, instability, and jitter and positively correlated with fundamental voice frequency. PMID- 29525074 TI - Nanoscale artificial antigen presenting cells for cancer immunotherapy. AB - Exciting developments in cancer nanomedicine include the engineering of nanocarriers to deliver drugs locally to tumors, increasing efficacy and reducing off-target toxicity associated with chemotherapies. Despite nanocarrier advances, metastatic cancer remains challenging to treat due to barriers that prevent nanoparticles from gaining access to remote, dispersed, and poorly vascularized metastatic tumors. Instead of relying on nanoparticles to directly destroy every tumor cell, immunotherapeutic approaches target immune cells to train them to recognize and destroy tumor cells, which, due to the amplification and specificity of an adaptive immune response, may be a more effective approach to treating metastatic cancer. One novel technology for cancer immunotherapy is the artificial antigen presenting cell (aAPC), a micro- or nanoparticle-based system that mimics an antigen presenting cell by presenting important signal proteins to T cells to activate them against cancer. Signal 1 molecules target the T cell receptor and facilitate antigen recognition by T cells, signal 2 molecules provide costimulation essential for T cell activation, and signal 3 consists of secreted cues that further stimulate T cells. Classic microscale aAPCs present signal 1 and 2 molecules on their surface, and biodegradable polymeric aAPCs offer the additional capability of releasing signal 3 cytokines and costimulatory molecules that modulate the T cell response. Although particles of approximately 5-10 MUm in diameter may be considered the optimal size of an aAPC for ex vivo cellular expansion, nanoscale aAPCs have demonstrated superior in vivo pharmacokinetic properties and are more suitable for systemic injection. As sufficient surface contact between T cells and aAPCs is essential for activation, nano-aAPCs with microscale contact surface areas have been created through engineering approaches such as shape manipulation and nanoparticle clustering. These design strategies have demonstrated greatly enhanced efficacy of nano aAPCs, endowing nano-aAPCs with the potential to be among the next generation of cancer nanomedicines. PMID- 29525077 TI - Chronic Infarcts Predict Poor Clinical Outcome in Mechanical Thrombectomy of Sexagenarian and Older Patients. AB - BACKGROUND: The impact of lacunar and cortical chronic ischemic lesions (CILs) on the clinical outcome of mechanical thrombectomy (MT) has been little studied. Clinical trials suggest that older patients benefit from MT. We investigated the effect of CILs on the clinical outcome of sexagenarian and older patients with acute middle cerebral artery (MCA) or distal internal carotid artery (ICA) stroke who received MT to treat large-vessel occlusion (LVO). METHODS: We prospectively collected the clinical and imaging data of 130 consecutive MT patients of which 68 met the inclusion criteria. We limited the analysis to sexagenarian and older subjects and occlusions no distal than the M2 segment. Baseline clinical, procedural and imaging variables, technical outcome, 24-hour imaging outcome, and the clinical outcome were recorded. Differences between patients with and without CILs were studied with appropriate statistical tests and binary logistic regression analysis. RESULTS: Twenty-one patients (31%) had at least 1 CIL. Thirty-eight percent of patients with CIL(s) compared with 62% without (P = .06) experienced good clinical outcome (3-month modified Rankin Scale <= 2). A similar nonsignificant trend was seen when lacunar lesions, lesion multiplicity, and chronic white matter lesions were examined separately. Absence of CIL increased the odds of good clinical outcome 3.7-fold (95% confidence interval 1.0-10.7, P = .05) in logistic regression modeling. CONCLUSIONS: Chronic cortical and lacunar infarcts in admission imaging are associated with poor clinical outcome in sexagenarian and older patients treated with MT for LVO of the MCA or distal ICA. PMID- 29525076 TI - Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial. AB - BACKGROUND: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. RESULTS: Mean age was 66.9 +/- 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. CONCLUSIONS: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research. PMID- 29525078 TI - Accuracy of the Blend Sign on Computed Tomography as a Predictor of Hematoma Growth after Spontaneous Intracerebral Hemorrhage: A Systematic Review. AB - BACKGROUND: Hematoma growth is a strong independent predictor of poor outcome after intracerebral hemorrhage. However, there is no gold standard to accurately predict hematoma growth. Several noncontrast computed tomographic markers associated with hematoma growth have been reported recently. Blend sign, which is a new marker, has been reported in several studies and seems a particularly promising marker but lacks a standardized evaluation so far. METHODS: A systematic review of published literature on blend sign and hematoma growth and clinical outcomes was conducted. Systematic review of best practices was followed, and study quality was assessed. RESULTS: The 6 studies involved 1573 participants in this review. The prevalence of blend sign ranged from 8.70% to 38.46%. The sensitivity of blend sign to predict hematoma growth varied from 13.0% to 42.86%; the specificity varied from 88.51% to 95.5%. Blend sign showed lower sensitivity but superior specificity for prediction of hematoma growth. Four studies indicated that the presence of blend sign was an independent predictor of hematoma growth. Four studies showed that the prevalence of blend sign was significantly higher in patients with hematoma growth compared with those without hematoma growth (odds ratio, 9.33; 95% confidence interval, 5.20 16.74). CONCLUSION: There was an association between blend sign and hematoma growth, but this finding is tentative in light of the fact that the number of included studies was relatively small. PMID- 29525079 TI - Comparison of Clinical Characteristics among Subtypes of Visual Symptoms in Patients with Transient Ischemic Attack: Analysis of the PROspective Multicenter registry to Identify Subsequent cardiovascular Events after TIA (PROMISE-TIA) Registry. AB - BACKGROUND: A transient visual symptom (TVS) is a clinical manifestation of transient ischemic attack (TIA). The aim of this study was to investigate differences in clinical characteristics among subtypes of TVS using multicenter TIA registry data. MATERIALS AND METHODS: Patients with TIA visiting within 7 days of onset were prospectively enrolled from 57 hospitals between June 2011 and December 2013. Clinical characteristics were compared between patients with 3 major subtypes of TVS (transient monocular blindness [TMB], homonymous lateral hemianopia [HLH], and diplopia). RESULTS: Of 1365 patients, 106 (7.8%) had TVS, including 40 TMB (38%), 34 HLH (32%), 17 diplopia (16%), and 15 others/unknown (14%). Ninety-one patients with 1 of the 3 major subtypes of TVS were included. Symptoms persisted on arrival in 12 (13%) patients. Isolated TVS was significantly more common in TMB than in HLH and diplopia (88%, 62%, and 0%, respectively; P < .001). Duration of symptoms was shorter in patients with TMB than those with HLH (P = .004). The ABCD2 score was significantly lower in patients with TMB compared with those with HLH and diplopia (median 2 [interquartile range 2-3] versus 3 [2-4] and 4 [2-5], respectively; P = .005). Symptomatic extracranial internal carotid artery stenosis or occlusion was seen in 14 (16%) patients, and was more frequent in TMB than in HLH and diplopia (28%, 9%, and 0%, respectively; P = .015). CONCLUSIONS: TVS was an uncommon symptom in our TIA multicenter cohort. Some differences in clinical characteristics were found among subtypes of TVS. PMID- 29525081 TI - Effects of Pretreatment Cerebral Blood Volume and Time to Recanalization on Clinical Outcomes in Endovascular Thrombectomy for Acute Ischemic Stroke. AB - BACKGROUND: Faster time to recanalization leads to better clinical outcomes in patients treated with endovascular thrombectomy. Whether the association between time to recanalization and clinical outcomes depends on cerebral blood volume (CBV) obtained from pretreatment computed tomography (CT) perfusion (CTP) imaging was investigated. METHODS: In consecutive patients with acute ischemic stroke who achieved recanalization by endovascular thrombectomy for intracranial internal carotid artery or M1 occlusion, the effects on clinical outcome of time to recanalization and the relative CBV value (rCBV) assessed by pretreatment CTP were evaluated. The patient population was divided into 2 groups according to rCBV: normal rCBV group (rCBV >= .9) and low rCBV group (rCBV < .9). In each group, time to recanalization was compared between the good and the poor clinical outcome groups. RESULTS: Sixty-four patients were eligible for this study. Twenty six patients (40.6%) achieved good clinical outcomes. In the normal rCBV group, no association was found between clinical outcome and time to recanalization. In the low rCBV group, time to recanalization from CTP (101 minutes versus 136 minutes, P = .040) was significantly shorter in the good clinical outcome group. On binary logistic regression modeling, CTP to recanalization time (odds ratio 1.035 [1.004-1.067], P = .025) was an independent predictor of good clinical outcome only in the low rCBV group. CONCLUSIONS: The association between time to recanalization and clinical outcomes depends on rCBV obtained from pretreatment CTP. Time to recanalization is more important for good clinical outcomes in patients with low rCBV than in patients with normal rCBV. PMID- 29525080 TI - The Synergistic Neuroprotective Effects of Combined Rosuvastatin and Resveratrol Pretreatment against Cerebral Ischemia/Reperfusion Injury. AB - BACKGROUND: It is well accepted that both rosuvastatin and resveratrol exert neuroprotective effects on cerebral ischemia/reperfusion injury through some common pathways. Resveratrol has also been demonstrated to protect against cerebral ischemia/reperfusion injury through enhancing autophagy. Thus, we hypothesized that combined rosuvastatin and resveratrol pretreatment had synergistic effects on cerebral ischemia/reperfusion injury. MATERIALS AND METHODS: Adult male Sprague Dawley rats receiving middle cerebral artery occlusion surgery as animal model of cerebral ischemia/reperfusion injury were randomly assigned to 4 groups: control, resveratrol alone pretreatment, rosuvastatin alone pretreatment, and combined rosuvastatin and resveratrol pretreatment. Rosuvastatin (10 mg/kg) or resveratrol (50 mg/kg) was administrated once a day for 7 days before cerebral ischemia onset. RESULTS: We found that combined rosuvastatin and resveratrol pretreatment not only significantly decreased the neurologic defective score, cerebral infarct volume, the levels of caspase-3, and Interleukin-1beta (IL-1beta) but also significantly increased the ratios of Bcl-2/Bax and LC3II/LC3I, as well as the level of Becline-1, compared with resveratrol alone or rosuvastatin alone pretreatment group. Rosuvastatin alone pretreatment significantly increased the ratio of LC3II/LC3I and the level of Beclin-1. However, there were no significant differences in the neurologic defective score, cerebral infarct volume, the levels of caspase-3, IL-1beta, and Beclin-1, and the ratios of Bcl-2/Bax and LC3II/LC3I between resveratrol pretreatment group and rosuvastatin pretreatment group. CONCLUSIONS: Synergistically enhanced antiapoptosis, anti-inflammation, and autophagy activation might be responsible for the synergistic neuroprotective effects of combining rosuvastatin with resveratrol on cerebral ischemia/reperfusion injury. PMID- 29525082 TI - Successful Tissue Plasminogen Activator for a Patient with Stroke After Stanford Type A Aortic Dissection Treatment. AB - Some stroke patients with the acute aortic dissection receiving thrombolysis treatment resulted in fatalities. Thus, the concurrent acute aortic dissection is the contraindication for the intravenous recombinant tissue-type plasminogen activator. However, the safety and the effectiveness of the intravenous recombinant tissue-type plasminogen activator therapy are not known in patients with stroke some days after acute aortic dissection treatment. Here, we first report a case of a man with a cardioembolism due to the nonvalvular atrial fibrillation, who received the intravenous recombinant tissue-type plasminogen activator therapy 117 days after the traumatic Stanford type A acute aortic dissection operation. Without the intravenous recombinant tissue-type plasminogen activator therapy, the prognosis was expected to be miserable. However, the outcome was good with no complication owing to the intravenous recombinant tissue type plasminogen activator therapy. Our case suggests the effectiveness and the safety of the intravenous recombinant tissue-type plasminogen activator therapy to the ischemic stroke some days after acute aortic dissection treatment. PMID- 29525083 TI - The origin and migration of the dissolved sulfate from precipitation in Seoul, Korea. AB - This study incorporated stable isotope analyses with chemical analyses to determine the origin and migration of sulfur sources in East Asia, and these findings were compared with our decadal research from 2000 to 2001 and 2002 to 2003. The multiple sulfur isotope composition (32S, 33S and 34S) of the dissolved sulfate in precipitation was first measured from 2011 to 2013 in Seoul, South Korea. The delta34Snss values were -1.10/00 to 7.90/00 (avg. 3.60/00), strongly suggesting that sulfur derived from the combustion of Chinese coal is the predominant source of sulfate in the Seoul region. Low NO3/SO42- ratios in the precipitation samples indicated an insignificant effect of sulfur from vehicle exhaust. The seasonal variation of delta34Snss values appears to be caused by increasing biogenic sulfur activity during the spring and summer seasons. The some Delta33S values (0.130/00-0.160/00) measured in the three samples were sufficiently small; thus, whether these values can be attributed to mass independent fractionation remains unclear. Measuring the Delta33S anomalies in dissolved sulfate provides valuable insights for identifying the sources of sulfur transferred from the stratosphere to the troposphere and upper troposphere. PMID- 29525084 TI - Characterization, antioxidant and antimicrobial activities of green synthesized silver nanoparticles from Psidium guajava L. leaf aqueous extracts. AB - The green synthesis of nanoparticles has become increasingly promising due to their potential applications in nanomedicine and materials science. In this study, silver nanoparticles (P-AgNPs) were synthesized from aqueous extracts of P. guajava L. leaf. The synthesized silver nanoparticles were confirmed by UV-vis spectrophotometry at 438 nm. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and zetasizer analyses showed that the average sizes of the P-AgNPs were 20-35 nm, 25 nm, and 25-35 nm, respectively. Element mapping analyses of the P-AgNPs were confirmed by X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDX) analyses. Moreover, FTIR spectra of the synthesized P-AgNPs showed the presence of phyto constituents as capping agents. Zeta potential measurements (-20.17 mV) showed that the synthesized P-AgNPs had reasonably good stability. The in vitro antioxidant properties of the P-AgNPs were evaluated using two different methods. A highly efficient radical scavenging activity of P-AgNPs possessing IC50 values of 52.53 +/- 0.31 MUg/mL (DPPH) and 55.10 +/- 0.29 MUg/mL (ABTS+) were confirmed. At a concentration of 100 MUg/mL, antimicrobial activity assays of the P-AgNPs showed significant inhibition against selected bacteria, S. cerevisiae, A. niger and R. oryzae, especially against Alcaligenes faecalis and Escherichia coli. The present study revealed that the low-cost and environmentally friendly synthesis of P-AgNPs can be widely used in biomedicine, water treatment or purification, and nanobiotechnology. PMID- 29525085 TI - Antimicrobial activity of new materials based on the blends of collagen/chitosan/hyaluronic acid with gentamicin sulfate addition. AB - In this study polymeric blends based on collagen, chitosan and hyaluronic acid in the form of thin films with the addition of gentamicin sulfate were obtained. Surface morphology of films was evaluated based on atomic force microscopy images. Surface free energy was measured and its polar and dispersive components were calculated. Moreover, oxygen and water vapor permeability through the material were measured as well as the water content in materials was studied. Thermal stability was determined by differential scanning calorimetry. Microbiological tests were performed to evaluate the diffusion of the drug from matrixes. The results showed that thin films based on collagen, chitosan and hyaluronic acid enriched in gentamicin sulfate inhibit the growth of both, Gram negative bacteria (E. coli and P. aeruginosa) and Gram positive ones (S. aureus). PMID- 29525086 TI - Introducing an attractive method for total biomimetic creation of a synthetic biodegradable bioactive bone scaffold based on statistical experimental design. AB - A new total biomimetic technique based on both the water uptake and degradation processes is introduced in this study to provide an interesting procedure to fabricate a bioactive and biodegradable synthetic scaffold, which has a good mechanical and structural properties. The optimization of effective parameters to scaffold fabrication was done by response surface methodology/central composite design (CCD). With this method, a synthetic scaffold was fabricated which has a uniform and open-interconnected porous structure with the largest pore size of 100-200MUm. The obtained compressive ultimate strength of ~35MPa and compression modulus of 58MPa are similar to some of the trabecular bone. The pore morphology, size, and distribution of the scaffold were characterized using a scanning electron microscope and mercury porosimeter. Fourier transform infrared spectroscopy, EDAX and X-ray diffraction analyses were used to determine the chemical composition, Ca/P element ratio of mineralized microparticles, and the crystal structure of the scaffolds, respectively. The optimum biodegradable synthetic scaffold based on its raw materials of polypropylene fumarate, hydroxyethyl methacrylate and nano bioactive glass (PPF/HEMA/nanoBG) as 70/30wt/wt%, 20wt%, and 1.5wt/wt% (PHB.732/1.5) with desired porosity, pore size, and geometry were created by 4weeks immersion in SBF. This scaffold showed considerable biocompatibility in the ranging from 86 to 101% for the indirect and direct contact tests and good osteoblast cell attachment when studied with the bone-like cells. PMID- 29525087 TI - Tricalcium phosphate-Fluorapatite as bone tissue engineering: Evaluation of bioactivity and biocompatibility. AB - Biocomposites consisting of beta Tricalcium phosphate (beta-TCP) with 26.52% Fluorapatite (Fap) were elaborated and characterized in order to evaluate it potential application in bone graft substitute. Bioactivity was determined with in vitro tests by immersion of samples in simulated fluid body for several periods of times. The SEM, EDS and Atomic Absorption Spectroscopy showed the deposition of apatite layer on the surface of samples showing a good bioactivity. However, after 6days of soaking, the dissolution rate of Ca2+ and PO43- decreased which due probably to the improvement of crystallization of the apatite layer. These findings agree with those observed after 6weeks postimplantation of prepared macroporous scaffolds in rabbits. All histological observations of the preliminary in vivo study in the tibia of rabbits proved the biocompatibility and the resorption of the investigated bioceramic. In contrast, the implantation period will have to be optimized by further extensive animal experiments. PMID- 29525088 TI - An overview of polymeric dosage forms in buccal drug delivery: State of art, design of formulations and their in vivo performance evaluation. AB - Owing to the ease of the administration, the oral cavity is an attractive site for the delivery of drugs. The main difficulty for administration via the buccal route is an effective physiological removal mechanism of the oral cavity that takes way the formulation from the buccal site and decreases the bioavailability of drugs. The use of mucoadhesive polymers in buccal drug delivery shows assessing buccal drug permeation and absorption, however some studies bring an in vivo performance. This review points to the use of polymers in the manufacture of drug delivery systems (hydrogels, films and tablets) and shows the results of their in vivo performance tests. PMID- 29525089 TI - Polyhydroxyalkanoates (PHA) for therapeutic applications. AB - As intracellular carbon and energy storage materials, polyhydroxyalkanoates (PHA) are a diverse biopolyesters synthesized by many bacteria. PHA have been produced in large quantity for various application research including medical implants for approximately 30years. Many studies demonstrated that PHA are promising implant materials due to their diverse and ascendant mechanical, biodegradable and tissue compatible properties. Importantly, common PHA biodegradation products including oligomers and monomers are also not toxic to the cells and tissues. Pharmaceutical applications of some PHA degradation products also have been reported. So far, no study has been reported to have any carcinogenesis result induced by any PHA or their biodegradation products. All results suggest that PHA could be developed into various bio-implant products. PMID- 29525090 TI - Advancing the frontiers of silk fibroin protein-based materials for futuristic electronics and clinical wound-healing (Invited review). AB - The present review will introduce the basic concepts of silk-based electronics/optoelectronics including the latest technological advances on the use of silk fibroin in combination with other functional components, with an emphasis on improving the performance of next-generation silk-based materials. It also highlights the patterning of silk fibroin to produce micro/nano-scale features, as well as the functionalization of silk fibroin to impart antimicrobial (i.e. antibacterial) properties. Silk-based bioelectronics have great potential for advanced or futuristic bio-applications including e-skins, e bandages, biosensors, wearable displays, implantable devices, artificial muscles, etc. Notably, silk-based organic field-effect transistors have highly promising applications in e-skins and biosensors; silk-based electrodes/antennas are used for in vivo bioanalysis or sensing purpose (e.g., measurement of neurotransmitter such as dopamine) in addition to their use as food sensors; silk-based diodes can be applied as light sources for wound healing or tissue engineering, e.g., in cutaneous wound closure or induction of photothrombosis of corneal neovascularization; silk-based actuators have promising applications as artificial muscles; whereas silk-based memristors have exciting applications as logic or synaptic network for realizing e-skins or bionic brains. PMID- 29525091 TI - Graphene oxide: An efficient material and recent approach for biotechnological and biomedical applications. AB - The two-dimensional (2D) derivative of graphite termed graphene has widespread applications in various frontiers areas of nanoscience and nanotechnologies. Graphene in its oxidized form named as graphene oxide (GO) has a mixed structure equipped with various oxygen containing functional groups (epoxy, hydroxyl, carboxylic and carbonyl etc.) provides attachment sites to various biological molecules including protein, deoxyribonucleic acid (DNA), ribonucleic acid (RNA) etc. The attached biological molecules with the help of functional groups make it a promising candidate in research field of biotechnological and biomedical applications. The ease of processability and functionalization in aqueous solution due to available functional groups, amphiphilicity, better surface enhanced Raman scattering (SERS), fluorescence and its quenching ability better than graphene make GO a promising candidate for various biological applications. The amphipathetic nature and high surface area of the GO not only prepare it as a biocompatible, soft and flexible intra/inter cellular carrier but also provides long-term biocompatibility with very low cytotoxicity. Inspite of this, still we lack a very recent review for advanced biological applications of graphene oxide. This review deals the bio application of GO and the recent advancement as a biosensors, antibacterial agent, early detection of cancer, cancer cell imaging/mapping, targeted drug delivery and gene therapy etc. PMID- 29525092 TI - A novel layer-structured scaffold with large pore sizes suitable for 3D cell culture prepared by near-field electrospinning. AB - Electrospinning is a powerful method for preparing porous materials that can be applied as biomedical materials for implantation or tissue engineering or as scaffolds for 3D cell culture experiments. However, this technique is limited in practical applications because the pore size of 3D scaffolds directly prepared by conventional electrospinning is usually less than several tens of micrometres, which may not be suitable for 3D cell culture and tissue growth. To allow for satisfactory 3D cell culture and tissue engineering, the pore size of the scaffold should be controllable according to the requirement of the specific cells to be cultured. Here, we show that layer-structured scaffolds with pore sizes larger than 100MUm can be obtained by stacking meshes prepared by direct writing using the near-field electrospinning (NFES) technique. In the study, we prepared composite scaffolds made of polycaprolactone (PCL) and hydroxyapatite (HAp) via the above-mentioned method and tested the effectiveness of the novel scaffold in cell culture using mouse pre-osteoblast cells (MC3T3-E1). The pore size and the degradability of the PCL/HAp scaffolds were characterized. The results showed that the average pore size of the scaffolds was 167MUm, which was controllable based on the required application; the degradation rate was controllable depending on the ratio of PCL to HAp. The biocompatibility of the scaffolds in vitro was studied, and it was found that the scaffolds showed no toxicity and that the cells could effectively attach, proliferate, and differentiate in the 3D skeleton of the scaffolds. Our studies showed that a simple modification of the preparation procedure can lead to a new way to fabricate novel layer-structured 3D scaffolds with controllable structures and pore sizes suitable for practical applications in implantation, tissue engineering and 3D cell culture. PMID- 29525093 TI - Corrigendum to "Innovative superparamagnetic iron-oxide nanoparticles coated with silica and conjugated with linoleic acid: Effect on tumor cell growth and viability" [Mater. Sci. Eng. C 76 (2017) 439-447]. PMID- 29525094 TI - A novel self-assembled nanoparticle platform based on pectin-eight-arm polyethylene glycol-drug conjugates for co-delivery of anticancer drugs. AB - The application of non-toxic carriers to increase drug loading, multi-drug delivery, and extremely small size of nano-drugs to construct a tremendous transmission system is the goal for all researchers to be pursued. The proposal of natural pectin nano-platform for delivery of multiple drugs is critical for biomedical research, especially a particle size of below 100nm with high yield. Here we design a new core-shell structure pectin-eight-arm polyethylene glycol ursolic acid/hydrooxycampothecin nanoparticle (Pec-8PUH NPs) through a special self-assembly method for stabilizing and dispersing particles, improving water solubility, and achieving drug controlled release. The obtained Pec-8PUH NPs possessed appropriate size (~91nm), drug-loaded efficiency and encapsulation efficiency through the regulation of eight-arm polyethylene glycol. In addition, Pec-8PUH NPs could enhance cell cytotoxicity, shorten blood retention time (7.3 fold UA, 7.2-fold HCPT) and more effective cellular uptake than free drugs, which exhibited an obvious synergistic effect of UA and HCPT by the co-delivery. 4T1 tumor-bearing mice also showed a higher survival rate than free UA and free HCPT. The result further shows that this novel drug delivery system has a promising potential for anti-cancer combination therapy. PMID- 29525095 TI - Mg-based bone implants show promising osteoinductivity and controllable degradation: A long-term study in a goat femoral condyle fracture model. AB - In this work, the in vivo biocompatibility and biodegradation behavior of Mg-Nd Zn-Zr alloy (denoted as JDBM) screws were studied using a goat femoral condyle fracture model. Blood analysis indicates that the liver and kidney functions of goats were not affected by JDBM, JDBM coated with brushite (denoted as JDBM-DCPD) and PLA implants. Radiographic analysis shows that JDBM-DCPD screw has lower degradation rate than JDBM. Histological images show that compared with PLA, JDBM and JDBM-DCPD show superior effect to promote more new bone formation. JDBM-DCPD group has more new bone formation than JDBM group, indicating good osteoinductivity of DCPD coating. JDBM group show higher osteogenic factors level (BMP2, ALP and OC) in peri-implant callus tissue than PLA group. Long-term (18months) in vivo implants Micro-CT result shows that the degradation of JDBM DCPD screw may be slower than desirable, and the thickness of DCPD coating could be further adjusted to match the degradation to the bone recovery. PMID- 29525096 TI - Preparation and characterization of a novel host-guest complex based on folate modified beta-cyclodextrin and artesunate. AB - The purpose of this study was to develop a novel folate-modified host-guest complex to enhance antitumor activity of the artesunate and improve the solubility and stability by encapsulated in beta-cyclodextrin and linked with folate. In this work, we designed and prepared the inclusion complex of adamantanamine conjugated artesunate (AD-ATS) with folic acid-ethylenediamine beta-cyclodextrin (FA-EN-beta-CD). This material was characterized by 1D and 2D NMR, XRD, TG and SEM. The results suggested that AD-ATS was encapsulated within the FA-EN-beta-CD cavity to form host-guest inclusion complex, and the water solubility of AD-ATS was improved in the form of inclusion complex with FA-EN beta-CD. The assessment of antitumor activity showed that cytotoxicity of AD ATS/FA-EN-beta-CD complex was significantly enhanced in comparison to free AD ATS, ATS/beta-CD inclusion complex and ATS/FA-EN-beta-CD inclusion complex. PMID- 29525097 TI - One-step synthesis of NaLu80-xGdxF4:Yb183+/Er23+(Tm3+) upconversion nanoparticles for in vitro cell imaging. AB - Upconversion nanoparticles (UCNPs) possess a unique type of photoluminescence (PL) in which lower-energy excitation is converted into higher-energy emission via multi-photon absorption processes. In this work, we have used a facile one step hydrothermal method promoted water solubility to synthesis NaLuGdF4:Yb3+/Er3+(Tm3+) UCNPs coated with malonic acid (MA). Scanning electron microscopy images and X-ray diffraction patterns reveal sphere-shaped UCNPs with an average size of ~80nm crystallized in the cubic NaLuF4 structure. The characteristic vibrations of cubic UCNPs have been taken into account by using Fourier-transform infrared spectroscopy. Based on PL studies, we have determined an optimal concentration of Gd3+ doping. The dependence of upconversion PL intensity on Gd3+ concentration is discussed via the results of magnetization measurements, which is related to the coupling/uncoupling of Gd3+ ions. Particularly, our study reveals that carboxyl-functionalized NaLuGdF4:Yb3+/Er3+(Tm3+) UCNPs have a relatively high cell viability with HeLa cells. PMID- 29525098 TI - Immobilization of antibacterial metallic cations (Ga3+, Zn2+ and Co2+) in a polypyrrole coating formed on Nitinol. AB - Gallium, zinc and cobalt species were immobilized in hollow rectangular-sectioned microtubes of polypyrrole (PPy) electrosynthesized on Nitinol (NiTi) alloy by means of two different methods. One of them involved the immobilization after the PPy electropolymerization and the other one during the electrosynthesis process. The antibacterial activity of the coating against Escherichia coli (E. coli) was evaluated and the best results were obtained with gallium species. Characterization results demonstrated that gallium is incorporated into the PPy matrix as Ga3+ ions. The PPy film with gallium species incorporated during the electropolymerization exhibited a good corrosion protection performance. PMID- 29525099 TI - Tuning biological properties of poly (vinyl alcohol) with amino acids and studying its influence on osteoblastic cell adhesion. AB - A new class of bio composite materials for orthopedic applications were prepared by blending polyvinyl alcohol (PVA) with certain amino acids (AA) such as glycine, lysine and phenyl alanine followed by in-situ cross-linking with citric acid (CT). CT cross-linked PVA offers sufficient chemical, thermal, and morphological stability by establishing intermolecular interaction. These biocomposite films were characterized for mechanical and thermal behaviors as well as analyzed through SEM, TGA and AFM studies. Zwitterionic characteristics of AA create cell-adhesive hydrophilic domains that act as potential cell adhesion sites and facilitate osteointegration. Biocompatibility studies proved that PVA-AA/CT is non-toxic and exhibits good anti-bacterial activity. In-vitro bioactivity test and cell adhesion results predict that presence of AA is advantageous to enhance apatite growth and promote cell-substrate binding through modulating cellular activity of PVA polymer. Hydrophilicity of AA zwitterions significantly facilitates cell-substrate binding and CA cross-linking helps osteoblastic integration of PVA-AA/CT bio composite films. The rational design of microstructure with zwitterionic-hydrophilic domains is a key to enhance cell substrate interaction of PVA-AAs/CT bio composites. PMID- 29525100 TI - Preparation and characterization of gelatin-chitosan-nanobeta-TCP based scaffold for orthopaedic application. AB - The primary aim of this study was to fabricate gelatin/chitosan/beta-TCP (GCT) composite scaffold to improve its compressive mechanical behaviour and in-vivo biocompatibility with predictable degradation rate. Beta tricalcium phosphate (beta-TCP) powder was synthesized in size range between 70-100 nm using aqueous precipitation route at a fixed Ca/P molar ratio of 1.5:1 at pH 10 and after subsequent heat treatment of as precipitated powder at 800 degrees C for 4 hours. The composite scaffolds were fabricated using solid-liquid phase separation of the slurry containing gelatin, chitosan, beta-tricalcium phosphate in varying proportion and subsequent lyophilisation of the phase separated mixture. The prepared scaffolds exhibited high porosity (>80%) with pore sizes ranging between 78-382 MUm as determined using Hg-porosimetry. SEM result revealed that incorporation of beta-TCP to the extent of 30 wt% resulted in well shaped and uniformly distributed interconnected pores of average pore size of 120 +/- 18.6 MUm in it. Compressive strength of the scaffolds was increased from 0.8 MPa to 2.45 MPa on increase in beta-TCP content from 10 wt%-30 wt% in the prepared scaffold. Human Umbilical Cord derived mesenchymal stem cells (MSCs) exhibited higher degree of lamellopodia and fillopodia extensions and better spreading behaviour onto GCT30 scaffold. MTT assay and immunocytochemistry studies with cultured MSCs revealed that GCT30 scaffolds were more conducive to MSC's proliferation and differentiation into osteoblast lineage. In vivo implantation of GCT30 scaffold subcutaneously into mice did not indicate any significant inflammatory reaction, but ongoing vascularization. PMID- 29525101 TI - Antimicrobial and bioactive phosphate-free glass-ceramics for bone tissue engineering applications. AB - Glasses with composition 55SiO2-10K2O-(35-x)CaO-xMgO (x = 5, 10, 15 up to 35) were prepared via conventional melt-quench technique. The glasses were converted to glass-ceramics by controlled heat-treatment at 850 degrees C. Higher content of MgO instead of CaO prevents the devitrification of the glasses. The in-vitro bioactivity of the glasses/glass-ceramics was evaluated in simulated body fluid (SBF). Glasses exhibited better bioactivity than the glass-ceramics. The weight loss and ions leaching profiles (especially potassium ions) of the samples played crucial role in formation of hydroxyapatite layer and its morphology. Hydroxyapatite had Ca/P ratio close to that for natural bone. However, it could not crystallize within experimental time and exhibited amorphous nature in X-ray diffraction. Microhardness of the glasses/glass-ceramics before and after immersion in SBF is also given. Microbial tests reveal that these glasses/glass ceramics are effective in inhibiting the growth of fungi and do not affect the normal functioning of the antimicrobial drugs. PMID- 29525102 TI - An efficient method to prepare magnetic hydroxyapatite-functionalized multi walled carbon nanotubes nanocomposite for bone defects. AB - Hydroxyapatite-functionalized multi-walled carbon nanotube (HA-fMWCNT) magnetic nanocomposite was successfully prepared using a novel slurry-compounding method. The prepared HA-fMWCNT nanocomposite with the addition of small amount (0.5 wt%) of fMWCNT exhibited much greater improvement in mechanical properties due to strong interfacial adhesion between acid-treated MWCNTs fillers and HA matrix, thus efficient stress transfer to nanotubes from the matrix. The nanocomposite exhibited excellent haemocompatibility. Fractographic analysis was performed in order to understand the fracture behavior and toughening mechanisms. The fracture mechanisms and micro-deformation were examined by studying the microstructure of arrested crack tips using field emission scanning electron microscopy (FESEM). The origination and formation of micro-cracks are the dominant fracture mechanisms and micro-deformation in the HA-fMWCNTs nanocomposite. The developed new method enables to the fabrication of magnetic HA-fMWCNTs nanocomposite with superior mechanical performance may be potential for application as high load bearing bone implants in the biomedical field. PMID- 29525103 TI - Optimization of oxygenation during ex vivo lung perfusion-Best basic science article in 2017. PMID- 29525104 TI - Complement in stem cells and development. AB - From its discovery in the late nineteenth century, as a 'complement' to the cellular immune response, the complement system has been widely affirmed as a powerful controller of innate and adaptive immune responses. In recent decades however, new roles for complement have been discovered, with multiple complement proteins now known to function in a broad array of non-immune systems. This includes during development, where complement exerts control over stem cell populations from fertilization and implantation throughout embryogenesis and beyond post-natal development. It is involved in processes as diverse as cell localisation, tissue morphogenesis, and the growth and refinement of the brain. Such physiological actions of complement have also been described in adult stem cell populations, with roles in proliferation, differentiation, survival, and regeneration. With such a broad range of complement functions now described, it is likely that current research only describes a fraction of the full reach of complement proteins. Here, we review how complement control of physiological cell processes has been harnessed in stem cell populations throughout both development and in adult physiology. PMID- 29525105 TI - Cycling injuries and alcohol. AB - BACKGROUND: Most of the cycling accidents that occur in Finland do not end up in the official traffic accident statistics. Thus, there is minimal information on these accidents and their consequences, particularly in cases in which alcohol was involved. The focus of the present study is on cycling accidents and injuries involving alcohol in particular. METHODS: Data on patients visiting the emergency department at North Kymi Hospital because of a cycling accident was prospectively collected for two years, from June 1, 2004 to May 31, 2006. Blood alcohol concentration (BAC) was measured on admission with a breath analyser. The severity of the cycling injuries was classified according to the Abbreviated Injury Scale (AIS). RESULTS: A total of 217 cycling accidents occurred. One third of the injured cyclists were involved with alcohol at the time of visiting the hospital. Of these, 85% were males. A blood alcohol concentration of >= 1.2 g/L was measured in nearly 90% of all alcohol-related cases. A positive BAC result was more common among males than females (p < 0.001), and head injuries were more common among cyclists where alcohol was involved (AI) (60%) than among sober cyclists (29%) (p < 0.001). Two thirds (64%) of the cyclists with AI were not wearing a bicycle helmet. The figure for serious injuries (MAIS >= 3) was similar in both groups. Intoxication with an alcohol level of more than 1.5 g/L and the age of 15 to 24 years were found to be risk factors for head injuries. The mean cost of treatment was higher among sober cyclists than among cyclists with AI (?2143 vs. ?1629), whereas in respect of the cost of work absence, the situation was the opposite (?1348 vs. ?1770, respectively). CONCLUSIONS: Cyclists involved with alcohol were, in most cases, heavily intoxicated and were not wearing a bicycle helmet. Head injuries were more common among these cyclists than among sober cyclists. As cycling continues to increase, it is important to monitor cycling accidents, improve the accident statistics and heighten awareness of the risks of head injuries when cycling under the influence of alcohol. PMID- 29525106 TI - Radiocesium contamination of the moss Hypnum plumaeforme caused by the Fukushima Dai-ichi Nuclear Power Plant accident. AB - We investigated 134Cs and 137Cs activity concentrations in the common Japanese moss species Hypnum plumaeforme collected from 32 sites within ca. 100 km radius of the Fukushima Dai-ichi Nuclear Power Plant. A total of 32 samples of H. plumaeforme were collected during the field surveys from November 2013 to September 2014. The maximum radiocesium activity concentrations in H. plumaeforme were 60.9 +/- 1.8 kBq kg-1 for 134Cs and 123 +/- 2.3 kBq kg-1 for 137Cs. The mean value for the 134Cs/137Cs was 1.17 +/- 0.05, and the mean Tag value was 0.09 +/- 0.13. Positive correlations were obtained between total 134Cs + 137Cs activity concentrations in H. plumaeforme and the air dose rate with a correlation coefficient (r) of 0.55 (P = 0.001), and between 137Cs activity concentration in H. plumaeforme and 137Cs deposition density on soil with r of 0.55 (P = 0.001). These results suggest that the perennial moss species H. plumaeforme could be more suitable and useful as a qualitative indicator for the radiocesium pollution compared to vascular plants spreading over the lowlands including human habitation in Fukushima Prefecture. PMID- 29525107 TI - Radionuclide distribution in soil and undecayed vegetative litter samples in a riparian system at the Savannah River Site, SC. AB - The aim of this study is to comprehensively investigate radionuclide concentrations in surface soil and un-decayed vegetative litter along four stream systems (i.e. Fourmile Branch, Lower Three Runs, Pen Branch, and Steel Creek) at the Savannah River Site (SRS), Aiken, South Carolina. Soil and litter samples from systematically spaced 12 pairs (contaminated or uncontaminated) of plots along the four streams were analyzed for 16 distinct radionuclide activities. Lower radionuclide concentrations were observed in soil and litter samples collected along Pen Branch compared to the other 3 streams. The anthropogenic radionuclide with the highest activity was 137Cs in soil (10.6-916.9 Bq/kg) and litter (8.0-222.3 Bq/kg), while the naturally occurring radionuclides possessing the highest concentration in the samples were 40K (33.5-153.7 Bq/kg and 23.1-56.0 Bq/kg in soil and litter respectively) and 226Ra (55.6-159.9 Bq/kg and 30.2-101.8 Bq/kg in soil and litter respectively). A significant difference (p < 0.05) of radionuclide concentrations between paired-plots across four streams was observed for 241Am, 137Cs, 238Pu, 239Pu, and 226Ra in both contaminated and non contaminated samples. 137Cs and uranium isotopes had the highest litter-to-soil correlation in contaminated (rho = 0.70) and uncontaminated plots (rho = 0.31 0.41), respectively. 90Sr was the only radionuclide with higher radioactive concentrations in litter (12.65-37.56 Bq/kg) compared to soil (1.61-4.79 Bq/kg). The result indicates that 1) historical discharges of anthropogenic 137Cs was the most important contributor of radiation contamination in the riparian environment at SRS, 2) 90Sr was the only radionuclide with higher concentration in litter than in soil, and 3) no apparent pattern in deposition density in soil or litter along downstream was observed for the radionuclides measured in this study. PMID- 29525109 TI - The marine kd and water/sediment interaction problem. AB - The behavior of marine distribution coefficients is analyzed with the help of numerical experiments and analytical solutions of equations describing kinetic models for uptake/release of radionuclides. The difficulties in measuring true kd in a marine environment perturbed by an external radionuclide source are highlighted. Differences between suspended matter and bed sediment kd are analyzed. The performances of different kinetic models (1-step/2step; single layer/multi-layer) are studied in model/model and model/experiment comparisons. Implications for the use of models to assess radioactive contamination after an emergency are given; as well as recommendations when kd data are compiled in order to create a useful database. PMID- 29525108 TI - International challenge to model the long-range transport of radioxenon released from medical isotope production to six Comprehensive Nuclear-Test-Ban Treaty monitoring stations. AB - After performing a first multi-model exercise in 2015 a comprehensive and technically more demanding atmospheric transport modelling challenge was organized in 2016. Release data were provided by the Australian Nuclear Science and Technology Organization radiopharmaceutical facility in Sydney (Australia) for a one month period. Measured samples for the same time frame were gathered from six International Monitoring System stations in the Southern Hemisphere with distances to the source ranging between 680 (Melbourne) and about 17,000 km (Tristan da Cunha). Participants were prompted to work with unit emissions in pre defined emission intervals (daily, half-daily, 3-hourly and hourly emission segment lengths) and in order to perform a blind test actual emission values were not provided to them. Despite the quite different settings of the two atmospheric transport modelling challenges there is common evidence that for long-range atmospheric transport using temporally highly resolved emissions and highly space resolved meteorological input fields has no significant advantage compared to using lower resolved ones. As well an uncertainty of up to 20% in the daily stack emission data turns out to be acceptable for the purpose of a study like this. Model performance at individual stations is quite diverse depending largely on successfully capturing boundary layer processes. No single model-meteorology combination performs best for all stations. Moreover, the stations statistics do not depend on the distance between the source and the individual stations. Finally, it became more evident how future exercises need to be designed. Set-up parameters like the meteorological driver or the output grid resolution should be pre-scribed in order to enhance diversity as well as comparability among model runs. PMID- 29525110 TI - New evaluated radioxenon decay data and its implications in nuclear explosion monitoring. AB - This work presents the last updated evaluations of the nuclear and decay data of the four radioxenon isotopes of interest for the Comprehensive Nuclear-Test-Ban Treaty (CTBT): Xe-131 m, Xe-133, Xe-133 m and Xe-135. This includes the most recent measured values on the half-lives, gamma emission probabilities (Pgamma) and internal conversion coefficients (ICC). The evaluation procedure has been made within the Decay Data Evaluation Project (DDEP) framework and using the latest available versions of nuclear and atomic data evaluation software tools and compilations. The consistency of the evaluations was confirmed by the very close result between the total available energy calculated with the present evaluated data and the tabulated Q-value. The article also analyzes the implications on the variation of the activity ratio calculations from radioxenon monitoring facilities depending on the nuclear database of reference. PMID- 29525111 TI - Challenges and complexities in remediation of uranium contaminated soils: A review. AB - Uranium contamination of soil has been a major concern with respect to its toxicity, accumulation in the food chain and persistence in the environment. Owing to these problems, remediation of uranium-contaminated soils has been investigated by various techniques. This review focuses on the challenges and complexities associated with the remediation of uranium-contaminated soil at field level. Therefore, laboratory studies have been excluded from this review. Challenges faced during remediation of uranium-contaminated soil using various techniques such as microbial/phyto/chemical/material based strategies have been discussed with suitable examples. Various factors that have a major influence on uranium decontamination process in soil such as soil type, uranium speciation, the presence of coexisting ions and organics, etc., have been highlighted. This review brings out the significance of the integrated role of various factors which determine the efficiency of the uranium decontamination process. PMID- 29525112 TI - Reply. PMID- 29525113 TI - Unilateral renal agenesis and abrupt onset diabetes: an unfrequent form of MODY type diabetes. AB - INTRODUCTION: MODY diabetes encompasses heterogeneous group of monogenic forms of diabetes with low prevalence. It is not easily diagnosed because of the increase in obesity and family history of diabetes in the general population. PATIENTS AND METHODS: We present a clinical case with cardinal symptoms, diabetes,renal insufficiency with no acidosis and with a family history of diabetes and renal agenesis. RESULTS: Distinguishing MODY diabetes from DM1 and DM2 is very important to ensure optimal treatment, and because the risk of complications depends on each genetic defect. A proper diagnosis needs a detailed medical history. DISCUSSION: An earlier identification of family members at risk and a correct and individualised treatment could be possible. Many of these patients can be managed successfully in monotherapy without insulin therapy. PMID- 29525114 TI - Comorbidity associated to segmental neurofibromatosis. PMID- 29525115 TI - Prevalence of chronic obstructive pulmonary disease (COPD) not diagnosed in a population with cardiovascular risk factors. AB - BACKGROUND AND OBJECTIVE: The magnitude of undiagnosed COPD in our population with cardiovascular risk factors (CVRF) is unknown. The objective of this study was to estimate the prevalence of undiagnosed COPD and its specific characteristics in a population with CVRF. MATERIALS AND METHODS: Study the prevalence of COPD in patients with CVRF. Spirometry was performed between 01/01/2015 and 12/31/2016 and the percentage of patients with COPD, who had not previously been diagnosed, was determined. Each patient's variables of interest were recorded; the records of patients who had spirometry showing COPD were checked to confirm whether a diagnosis had been recorded or not. The association of undiagnosed COPD with different independent variables was determined with adjusted odds ratio (aOR) by non conditional logistic regression models. RESULTS: 2,295 patients with CVRF were studied. The overall prevalence of COPD was 14.5%. An underdiagnosis of 73.3% was observed. Newly diagnosed COPD vs. undiagnosed COPD showed to be higher in women (74.1% vs. 36.0%; P=.081), non-smokers (21.3% vs. 12.4%; P=.577), mild cases (GOLD1) (42.6% vs. 32.4%, P=.008) and cases with lower than average HbA1c (5.5% vs. 5.6%; P=.008) and uric acid (5.1mg/dL vs. 5.6mg/dL; P=.011). The variables associated with undiagnosed COPD were: women (aOR=1.27; 95%CI: 0.74-2.17; P=.383); age (aOR=0.94; 95%CI: 0.87-0.99; P=.018); smokers (smoker/non-smoker) (aOR=0.47; 95%CI: 0.22-1.01; P=.054) and HbA1c (%) (aOR=0.45; 95%CI: 0.23-0.88; P=.019). CONCLUSIONS: The under-diagnosis of COPD is very high. The contact patients aged between 50 and 65 years-old who have CVRF with their health system should be reassessed, and they need to ask for a spirometry. PMID- 29525116 TI - Anticholinergic drugs and cognitive impairment in the elderly. AB - OBJECTIVE: Describe the prevalence of the anticholinergic drugs (AD) used in patients who consult in regard to loss of memory. Assess the cognitive and functional repercussion of these drugs. PATIENTS AND METHODS: Retrospective review of the clinic history of the patients who consulted the clinic in 2015 and 2016. We used the Anticholinergic Cognitive Burden Scale. We explored cognition with the Mini Mental State Examination (MMSE) and function with the Barthel Index and the Lawton and Brody Scale. We compared the difference of scale scores between the patients exposed and not exposed to AD. RESULTS: Sample size of 610 patients (mean age=81.1years), 71% female. 37.2% of patients took AD. The mean (SD) difference between exposed and not exposed patients and the year-on-year worsening rate of the Barthel Index and the Lawton and Brody Scale and MMSE were 4 (4.5), -0.3 (0.4) and -1 (0.9), respectively. CONCLUSIONS: One third of patients who consulted for cognitive loss are taking AD. Patients exposed to AD show a greater tendency to impairment. PMID- 29525117 TI - Kounis syndrome induced by ranitidine. PMID- 29525118 TI - Fellows' perspective of HPB training programs in North America: results of a survey. AB - BACKGROUND: Sixteen hepatopancreatobiliary fellowship programs in North America are accredited by the Fellowship Council. This study aims to assess fellows' perceptions of their training program. METHODS: A multiple-choice questionnaire was sent to 35 fellows to assess how they perceived their training: academics, research, operative experiences, autonomy, mentorship, program quality and weaknesses. The survey was developed using the SurveyMonkey(r) tool. RESULTS: Twenty-four of 35 fellows completed the survey. Sixteen fellows reported structured didactics; 10 reported mandatory research. As to operative experiences; 9 fellows reported exposure to minimally-invasive liver surgery; 5 reported exposure to robotics. Fourteen fellows reported using ablation; 5 reported using ablation laparoscopically; 8 reported using mostly radiofrequency ablation; 1 reported using irreversible electroporation. Eighteen fellows reported excellent training; 20 reported mentorship; 19 reported operative autonomy. Limited exposure to medical oncology/multidisciplinary care, portal hypertension surgery, and robotics surgery were perceived as program weaknesses by 7, 9, and 7 fellows, respectively. CONCLUSION: Most fellows ranked their program quality and academic content as excellent, but they perceived a need for more exposure to medical oncology, portal hypertension surgery, and minimally invasive surgery, with an emphasis on robotics. Fellowship training may need to integrate fellows' desires for enhanced proficiency in these clinical areas. PMID- 29525119 TI - Survivability of Existing Peripheral Intravenous Access Following Blood Sampling in a Pediatric Population. AB - PURPOSE: Although pediatric patients report venipuncture as their most feared experience during hospitalization, blood sampling from peripheral intravenous accesses (PIVs) is not standard of care. Blood sampling from PIVs has long been considered by healthcare personnel to harm the access. In an effort to minimize painful procedures, pediatric nursing staff conducted a prospective, observational study to determine if blood sampling using existing PIVs resulted in the loss of the access. The ability to obtain the sample from the PIV was measured along with patient and PIV characteristics. DESIGN AND METHODS: Specimen collection using 100 existing PIVs was attempted on pediatric inpatients. Each PIV was observed for functionality, infiltration, occlusion, and dislodgement following collection and again in 4h. Frequencies of PIV loss and successful blood sampling were calculated. Patient age, PIV gauge, access site, and PIV age were evaluated for associations with successful sampling using chi-square tests, Fisher's exact tests, and logistic regression. RESULTS: PIV survivability was reported at 99%. The ability to obtain a complete specimen was reported at 76% and found to be significantly related to PIV age and site. Size of PIV and patient's age were not significantly related to successful sampling. CONCLUSIONS: Encouraging rates of PIV survivability and collectability suggest blood sampling from PIVs to be a valuable technique to minimize painful and distressful procedures. PRACTICE IMPLICATIONS: Nursing practice was changed in this pediatric department. Patients and families are saved the pain and distress of venipuncture. Nurses reported saving time and personal distress by avoiding the venipuncture procedure. PMID- 29525120 TI - Treatment algorithm for anal fissure. Consensus document of the Spanish Association of Coloproctology and the Coloproctology Division of the Spanish Association of Surgeons. AB - The Spanish Association of Coloproctology and the Coloproctology Division of the Spanish Association of Surgeons propose this consensus document with a treatment algorithm for anal fissure that could be used for decision making. Non-surgical therapy and surgical treatment of anal fissure are explained, and the recommended algorithm is provided. The methodology used was: creation of a group of experts; search in PubMed, MEDLINE and the Cochrane Library for publications from the last 10 years about anal fissure; presentation at the 21st National Meeting of the Spanish Association of Coloproctology Foundation 2017 with voting for/against each conclusion by the attendees and review by the scientific committee of the Spanish Association of Coloproctology. PMID- 29525121 TI - Intestinal obstruction secondary to hypogastric artery aneurysm. PMID- 29525122 TI - Bilateral retroperitoneal hibernoma identified by I-MIBG SPECT/CT in a patient with single pheochromocytoma. PMID- 29525123 TI - Treatment of Fistula-in-ano With OTSC(r) Proctology Clip Device: Short-term Results. AB - INTRODUCTION: The treatment of anal fistula with the OTSC(r) (over-the-scope clip) proctology device involves the placement of an elastic alloy clip called Nitinol on the internal fistula opening to achieve fistula healing. The aim of this study was to analyze preliminary results of this technique in a case series. METHODS: This was a retrospective analysis of patients who underwent OTSC(r) clip placement for fistula-in-ano treatment between June 2015 and March 2017 at a specialized colorectal unit. Patients with simple and complex fistulae, either previously treated or not, were included in the study. Both cryptoglandular and stable Crohn's disease fistulae were considered for this approach. Technique failure was determined by the re-appearance of anorectal suppuration or in clip related complications. RESULTS: Ten patients were treated surgically for anal fistula with a median age of 54 years (range: 41-70years). The etiology of the fistulae was mainly cryptoglandular. Three patients had simple fistulae, whereas seven had complex disease. 80% of the patients had already undergone previous fistula surgery. No events occurred during the procedure. The success rate for healing was 60%, with a median follow-up of 15months (range: 6-26months). Three patients developed suppuration relapse and one patient required clip extraction due to invalidating anal pain. No fecal incontinence was recorded after the procedure. CONCLUSIONS: The treatment of anal fistulae with the OTSC(r) device is a safe sphincter-saving technique in the short term. PMID- 29525124 TI - Sensitive determination of brassinosteroids by solid phase boronate affinity labeling coupled with liquid chromatography-tandem mass spectrometry. AB - Brassinosteroids (BRs) are regarded as the sixth plant hormone that is widely distributed in the plant kingdom. Sensitive quantification of BRs will be greatly benefit to illuminate the detail mechanisms about how BRs play crucial role in plant developmental processes such as cell division, cell expansion, cytodifferentiation, seed germination, vegetative growth and resisting biological or abiotic stress. In the current study, we developed a method for rapid and sensitive determination of endogenous BRs in plant tissues by combining LC-MS and a novel sample preparation strategy, in which the plant tissue extract was supplied to solid phase boronate affinity labeling and extraction, followed by desorption and salt-induced phase transition extraction for further purification. Under the optimized conditions, good linearity was obtained for 6 BR with correlation coefficients (r) ranging from 0.9988 to 0.9999. The limits of detection (LODs, S/N = 3) ranged from 1.4 to 2.8 pg mL-1. The recoveries were between 93.4% and 116.2% with the relative standard deviations (RSDs) ranging from 2.8% to 15.8%. Finally, the developed method was successfully applied to the analysis of 6 endogenous BR in various plant tissues including 20 mg FW Oryza sativa shoot, 10 mg FW Oryza sativa root, 20 mg FW Arabidopsis thaliana shoot, 4 Arabidopsis thaliana flowers (2.8 mg) and one Brassica napus stamen (3.0 mg) with concentration ranging from 0.26 to 157.28 ng g-1 FW. PMID- 29525125 TI - Optimized anion exchange column isolation of zirconium-89 (89Zr) from yttrium cyclotron target: Method development and implementation on an automated fluidic platform. AB - Zirconium-89 (89Zr), produced by the (p, n) reaction from naturally monoisotopic yttrium (natY), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new 89Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization. The separation of Zr from dissolved Y metal targets was evaluated using several anion exchange resins. Each resin was evaluated against its ability to quantitatively capture Zr from a load solution high in dissolved Y. The most appropriate anion exchange resin for this application was identified, and the separation method was optimized. The method is capable of a high Y decontamination factor (>105) and has been shown to remove Fe, an abundant contaminant in Y foils, from the 89Zr elution fraction. Finally, the method was evaluated using cyclotron bombarded Y foil targets; the method was shown to achieve >95% recovery of the 89Zr present in the foils. The anion exchange column method described here is intended to be the first 89Zr isolation stage in a dual column purification process. PMID- 29525126 TI - QuEChERS and ultra-high performance liquid chromatography-tandem mass spectrometry method for the determination of parabens and ultraviolet filters in human milk samples. AB - Concerns are growing about human exposure to endocrine disrupting chemicals (EDCs), especially during developmental stages. Parabens (PBs) and ultraviolet filters (UVFs) are prevalent EDCs widely used as additives in cosmetics and personal care products (PCPs). The objective of this study was to develop a method to determine four PBs and ten UVFs in human milk using QuEChERS treatment and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS). Multivariate strategies were applied to optimize experimental parameters. Limits of quantification ranged from 0.1 to 0.2 ng mL-1 and inter-day variability (evaluated as relative standard deviation) from 6% to 13%. The method was validated using matrix-matched standard calibration followed by a recovery assay with spiked samples. Recovery percentages ranged from 87% to 112%. The method was satisfactorily applied to assess target compounds in human milk samples from 15 donors. This analytical procedure can provide information on newborn exposure to these EDCs. PMID- 29525127 TI - Modeling and simulation of protein elution in linear pH and salt gradients on weak, strong and mixed cation exchange resins applying an extended Donnan ion exchange model. AB - Process development and characterization based on mathematic modeling provides several advantages and has been applied more frequently over the last few years. In this work, a Donnan equilibrium ion exchange (DIX) model is applied for modelling and simulation of ion exchange chromatography of a monoclonal antibody in linear chromatography. Four different cation exchange resin prototypes consisting of weak, strong and mixed ligands are characterized using pH and salt gradient elution experiments applying the extended DIX model. The modelling results are compared with the results using a classic stoichiometric displacement model. The Donnan equilibrium model is able to describe all four prototype resins while the stoichiometric displacement model fails for the weak and mixed weak/strong ligands. Finally, in silico chromatogram simulations of pH and pH/salt dual gradients are performed to verify the results and to show the consistency of the developed model. PMID- 29525128 TI - Great moments in evolution: the conquest of land by plants. AB - 500Ma ago the terrestrial habitat was a barren, unwelcoming place for species other than, for example, bacteria or fungi. Most probably, filamentous freshwater algae adapted to aerial conditions and eventually conquered land. Adaptation to a severely different habitat apparently included sturdy cell walls enabling an erect body plan as well as protection against abiotic stresses such as ultraviolet radiation, drought and varying temperature. To thrive on land, plants probably required more elaborate signaling pathways to react to diverse environmental conditions, and phytohormones to control developmental programs. Many such plant-typical features have been studied in flowering plants, but their evolutionary origins were long clouded. With the sequencing of a moss genome a decade ago, inference of ancestral land plant states using comparative genomics, phylogenomics and evolutionary developmental approaches began in earnest. In the past few years, the ever increasing availability of genomic and transcriptomic data of organisms representing the earliest common ancestors of the plant tree of life has much informed our understanding of the conquest of land by plants. PMID- 29525129 TI - The C/S1 bZIP Network: A Regulatory Hub Orchestrating Plant Energy Homeostasis. AB - Sustaining energy homeostasis is crucial to every living being. To balance energy supply and demand, plants make use of an evolutionarily conserved management system consisting of two counteracting kinases, TOR (TARGET OF RAPAMYCIN) and SnRK1 (Snf1-RELATED PROTEIN KINASE 1). SnRK1 is involved in reorganizing enzymatic and transcriptional responses to survive energy-limiting conditions. Recently, members of the bZIP (basic leucine zipper) transcription factor family have been established as SnRK1 downstream mediators. We review here current knowledge on the functional impact of these group C and S1 bZIPs, and analyze their regulation by environmental and endogenous cues. Given their specific homo- and heterodimerization, the so-called C/S1 bZIP network is proposed to act as a signaling hub that coordinates plant development and stress responses. PMID- 29525130 TI - The Hidden Face of Rubisco. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) fixes atmospheric CO2 into organic compounds and is composed of eight copies each of a large subunit (RbcL) and a small subunit (RbcS). Recent reports have revealed unusual RbcS, which are expressed in particular tissues and confer higher catalytic rate, lesser affinity for CO2, and a more acidic profile of the activity versus pH. The resulting Rubisco was proposed to be adapted to a high CO2 environment and recycle CO2 generated by the metabolism. These RbcS belong to a cluster named T (for trichome), phylogenetically distant from cluster M, which gathers well characterized RbcS expressed in mesophyll or bundle-sheath tissues. Cluster T is largely represented in different plant phyla, including pteridophytes and bryophytes, indicating an ancient origin. PMID- 29525131 TI - NUCare: Advancing research on technological integration for self-management in the aging population. AB - BACKGROUND: The Center for Technology in Support of Self-Management and Health (NUCare) is an exploratory research center funded by the National Institute of Nursing Research's P20 mechanism positioned to conduct rigorous research on the integration of technology in the self-management of the older adult population. PURPOSE: The purpose of this paper is to describe the development and application of an evaluation plan and preliminary evaluation results from the first year of implementation. METHODS: This evaluation plan is derived from and is consistent with Dorsey et al.'s (2014) logic model. Dorsey's model provided guidelines for evaluating sustainability, leveraging of resources, and interdisciplinary collaboration within the center. DISCUSSION: Preliminary results and strategies for addressing findings from the first year of evaluation are discussed. A secondary aim of this paper is to showcase the relevance of this center to the advancement and maintenance of health in the aging population. PMID- 29525132 TI - Corrigendum to "Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome" [Free Radic. Biol. Med. 114 (2018) 122-130]. PMID- 29525133 TI - Long-Term Follow-up of Adults Following the Atrial Switch Operation for Transposition of the Great Arteries - A Contemporary Cohort. AB - BACKGROUND: The atrial switch operation for transposition of the Great Arteries (TGA) (Mustard or Senning Procedure) provides excellent short-term survival. Significant long-term concerns exist for these patients, however, including the ability of the right ventricle to maintain systemic perfusion and the risk of arrhythmia. We seek to describe long-term mortality and morbidity of this group of adult patients. METHODS: Consecutive patients who had undergone an atrial switch procedure, who were aged over 16 years and who were followed up at our tertiary level adult congenital heart disease (ACHD) service in Sydney, Australia since 2000 were included. We documented mortality using a National Death Index and analysed the prospectively defined composite endpoint of "Serious Adverse Events" including death, heart failure hospitalisation and/or documented ventricular arrhythmia. RESULTS: There were 83 patients included; mean age at most recent follow-up was 35 +/- 5 years. Overall survival was 82% at 35 years and 22% of patients experienced a serious adverse event. Atrial and ventricular arrhythmias occurred in 45% and 7% of patients respectively. Eighteen (22%) patients required a pacemaker and six (7%) required implantable cardiac defibrillator (ICD) implantation. Significant right ventricular dysfunction was present in 26% of patients on their most recent visit and this, or requirement for permanent pacing, was associated with an increased risk of serious adverse events (OR 10.22, p<0.001), (OR 4.998, p=0.04) respectively. CONCLUSIONS: Significant mortality and morbidity accrues by mid-adult life after an atrial procedure for TGA. Right ventricular dysfunction and permanent pacing are associated with serious adverse events. PMID- 29525134 TI - Thoracoscopic Sympathectomy for Long QT Syndrome. Literature Review and Case Study. AB - BACKGROUND: Multiple case studies have suggested that video-assisted thoracoscopic sympathectomy (VATS) reduces the occurrence and frequency of symptoms in long QT syndrome (LQTS) [1,2,3]. To date there has not been a literature review to report on the short-term and long-term outcomes of this procedure. Our primary aims are to review the literature findings on the clinical outcomes of VATS sympathectomy for long QT and present a local centre case report on the outcomes of T2-T5 sympathectomy. METHODS: Relevant articles were identified by a systematic search of PubMed, Cochrane and Scopus databases, from November 1985 to October 2015. A total of 520 patients from 21 publications were included for analysis and discussion in three main areas: presenting symptoms and indication for surgery, perioperative complications, and patient quality of life following surgery. Our case study reviews a 49-year-old female with recently diagnosed long QT syndrome and intolerance to beta blocker therapy successfully managed with T2-T5 thoracic sympathectomy. RESULTS: The most common presenting indication for operative management of long QT syndrome was syncope (208/520 patients) and tachyarrhythmia (207/520 patients). T1-T5 left sympathectomy was performed in 15/21 published reports (332/520 patients) with partial stellate removal or in its entirety. Follow-up of patients ranged from 1 month to 11 years. Four patients died in the postoperative period, from fatal arrhythmias. The most common postoperative findings were no symptoms (64/520 patients); tachyarrhythmia (55/520 patients), syncope (45/520 patients), and Horner's syndrome (13/520 patients with 27 patients reporting associated symptoms). Thirteen cases reported on the QTc changes post sympathectomy and 9/13 cases involving 220/520 patients showed marked QTc reduction following surgery. Mean preoperative QTc was 558ms and median 559ms. Mean postoperative QTc was 476ms and median 466ms. Our patient showed a marked reduction in QTc following surgery, with no evidence of arrhythmias and reduced beta blocker dependence. CONCLUSIONS: Surgical management of LQTS has historically involved a left cervicothoracic stellectomy removing stellate ganglia and typically part of the left thoracic sympathetic chain resulting in reduction in symptoms but increasing the risk of Horner's syndrome and intermittent temperature changes [4,5]. Surgical resection of the thoracic ganglia alone for management of LQTS is scarce in the literature. Short-term follow-up in our case study following a T2-T5 sympathectomy revealed reduction in symptoms, no requirement for beta blocker therapy and reduced QTc interval. Further follow-up using greater patient numbers will further support T2 T5 sympathectomy as an option for surgical management of LQTS. PMID- 29525135 TI - Donor Lung Procurement by Surgical Fellow With an Expectation of High Rate of Lung Utilisation. AB - There is an ever increasing demand for donor lungs in patients waiting for transplantation. Lungs of many potential donors will be rejected if the standard criteria for donor assessment are followed. We have expanded our donor lung pool by accepting marginal donors and establishing a donation after circulatory death program. We have achieved comparable results using marginal donors and accepting donor lungs following donation after circulatory death. We present our assessment and technical guidelines on lung procurement taking into consideration an increasingly complex cohort of lung donors. These guidelines form the basis of the lung procurement training program involving surgical Fellows at the Alfred Hospital in Melbourne, Australia. PMID- 29525136 TI - Erythematous Papules on the Dorsum of the Hand. PMID- 29525137 TI - Design of Polymeric Gene Carriers for Effective Intracellular Delivery. AB - Polymeric carriers have emerged as major non-viral alternatives for gene delivery due to their lower immunogenicity and pathogenicity. However, during intracellular delivery of these carriers, multiple barriers have to be overcome or the efficiency of gene delivery will be impeded. A thorough understanding of these cellular impediments is pivotal to optimizing the efficiency of polymer based gene delivery. This review delineates the major barriers encountered during intracellular delivery of polyplexes and discusses possible molecular designs to overcome these barriers. Based on a review of the latest strategies to enhance the intracellular delivery process, we provide insights into the further development of polymeric carriers with enhanced efficiency in transfection. PMID- 29525138 TI - Does blindness affect ocular vestibular evoked myogenic potentials? AB - OBJECTIVE: The aim of the present study was to investigate the influence of blindness on ocular vestibular evoked myogenic potentials (oVEMP) responses. METHODS: Thirty-one subjects with unilateral blindness (UB group) and 25 age and sex-matched healthy subjects (control group) were recruited for the present study. The oVEMP responses including latency, amplitude and amplitude asymmetry ratio (AR) were measured and compared between the blind side, the contralateral eye of the UB group and the control subjects. RESULTS: Ocular VEMP recordings were obtained from 29 of 31 patients (93.5%) for the blind side of the UB group. There was no significant difference in terms of latency, amplitude and AR value between the blind side and the contralateral eye of the UB group and the control subjects. CONCLUSION: Clear oVEMP recordings can be elicited as long as the eyeball and extraocular muscles are preserved in a blind eye. PMID- 29525139 TI - Transoral robotic excision of laryngeal papillomas with Flex(r) Robotic System - A novel surgical approach. AB - INTRODUCTION: Recurrent respiratory papillomatosis results in hoarseness, stridor and airway obstruction. Management is surgical, with most surgeons using microdebrider or laser. Transoral robotic surgery (TORS) has been successfully utilised for the excision of oropharyngeal malignancies and paediatric airway surgery. This is the first case report of TORS being used for the excision of laryngeal papillomas. CASE REPORT: A 36 year old Chinese female was diagnosed with juvenile onset recurrent respiratory papillomatosis. She had 4 previous laryngeal surgeries. She was pregnant in her 2nd trimester and experienced rapid progression of her disease, leading to impending airway compromise. At her latest surgery (2 years ago), poor laryngeal exposure was encountered during laryngoscopy which made the surgery technically challenging. Thus, a flexible robotic system (Flex(r) Robotic System, Medrobotics Corporation, Raynham, Massachusetts, USA) was utilised with the aim of providing better surgical exposure. During surgery, laryngeal intubation was not possible and her airway was secured with needle cricothyroidotomy followed by tracheotomy. Transoral robotic excision of laryngeal papillomas was performed successfully. Complete excision of obstructing papillomas was achieved with postoperative restoration of airway and voice. DISCUSSION: Utilisation of TORS improved visualisation, dexterity and access. Drawbacks include cost, set up time, requirement for special equipment and advanced training. TORS approach can be considered as an alternative to the usual laryngoscopic technique, especially in cases where difficult anatomy and poor laryngeal exposure is anticipated. PMID- 29525140 TI - Neuromuscular function of the soft palate and uvula in snoring and obstructive sleep apnea: A systematic review. AB - OBJECTIVE: A collapsible upper airway is a common cause of obstructive sleep apnea. The exact pathophysiology leading to a more collapsible airway is not well understood. A progressive neuropathy of the soft palate and pharyngeal dilators may be associated with the progression of snoring to OSA. The purpose of this study is to systematically review the international literature investigating the neurophysiologic changes in the soft palate and uvula that contribute to progression from snoring to OSA. METHODS: PubMed/MEDLINE and 4 other databases were systematically searched through July 4, 2017. Eligibility: (1) Patients: controls, snoring or OSA patients (2) Intervention: neuromuscular evaluation of the palate and/or uvula (3) Comparison: differences between controls, snoring and OSA patients (4) Outcomes: neuromuscular outcomes (5) Study design: Peer reviewed publications of any design. RESULTS: 845 studies were screened, 76 were downloaded in full text form and thirty-one studies met criteria. Histological studies of the soft palate demonstrated diffuse inflammatory changes, muscular changes consistent with neuropathy, and neural aberrancies. Sensory testing studies provided heterogeneous outcomes though the majority favored neuronal dysfunction. Studies have consistently demonstrated that increasing severity of snoring and sleep apnea is associated with worsening sensory nerve function of the palate in association with atrophic histological changes to the nerves and muscle fibers of the soft palate and uvula. CONCLUSIONS: Recent evidence highlighted in this systematic review implicates the role of neurogenic pathology underlying the loss of soft palate and/or uvular tone in the progression of snoring to sleep apnea. PMID- 29525141 TI - Dynamic imaging with sialography combined with sialendoscopy to manage a foreign body in Stensen's duct. AB - OBJECTIVE: We describe sialography as a dynamic imaging modality useful in establishing the diagnosis and planning for treatment of a parotid gland ductal foreign body. METHODS: Chart and radiographic imaging review of a 75 year-old male who had obstructive sialadenitis symptoms two years after welding slag pierced the cheek skin and identified as a 'piece of steel stuck in his cheek'. RESULTS: Sialography was used to demonstrate a foreign body adjacent to the parotid gland to indicate its presence as a mobile element within the ductal system associated with marked pre-obstructive duct dilation. Sialendoscopy was used to successfully remove the foreign body. CONCLUSIONS: In selected cases, the management of obstructive sialadenitis can be improved with sialography in permitting dynamic imaging of salivary duct anatomy. Although ultrasound has evolved as a standard component of salivary gland assessment, sialography may complement imaging with ultrasound (or CT as in this case) to offer the highest acuity definition of the salivary ducts. PMID- 29525142 TI - Who's distressed? A comparison of diabetes-related distress by type of diabetes and medication. AB - OBJECTIVE: We hypothesized that diabetes-related distress would vary by type of diabetes and medication regimen [Type 1 diabetes (T1DM), Type 2 diabetes with insulin use (T2DM-i), Type 2 diabetes without insulin use (T2DM)]. Thus, the aim of this study was to identify groups with elevated diabetes-related distress. METHODS: We administered the 17-item Diabetes-related Distress Scale (DDS-17) to 585 patients. We collected demographics, medications, and lab results from patient records. RESULTS: Patients were categorized by type of diabetes and medication: T1DM (n = 149); T2DM-i (n = 333); and T2DM (n = 103). ANOVA revealed significant differences in sample characteristics. ANCOVA were conducted on all four DDS-17 domains [Emotional Burden (EB); Physician-related Distress (PD); Regimen-related Distress (RD); and Interpersonal Distress (ID)]; covariates included in the models were sex, age, duration of diabetes, BMI, and HbA1c. EB was significantly lower in T1DM than T2DM-i, p < 0.05. In addition, RD was significantly lower in T1DM than either T2DM-i, p < 0.05 and T2DM, p < 0.05. CONCLUSIONS: EB and RD are higher for those with type 2 diabetes. Thus, interventions to reduce EB and RD need to be considered for patients with type 2 diabetes. IMPLICATIONS: DDS-17 is useful in identifying diabetes-related distress in patients with diabetes. Efforts need to be made to reduce EB and RD. PMID- 29525143 TI - Evaluation of a patient-centered after visit summary in primary care. AB - OBJECTIVE: To test the impact of a redesigned, patient-centered after visit summary (AVS) on patients' and clinicians' ratings of and experience with the document. METHODS: We conducted a difference-in-differences (DiD) evaluation of the impact of the redesigned AVS before and after its introduction in an academic primary care practice compared to a concurrent control practice. Outcomes included ratings of the features of the AVS. RESULTS: The intervention site had 118 and 98 patients in the pre- and post-intervention periods and the control site had 99 and 105, respectively. In adjusted DiD analysis, introduction of the patient-centered AVS in the intervention site increased patient reports that the AVS was an effective reminder for taking medications (p = .004) and of receipt of the AVS from clinicians (p = .002). However, they were more likely to perceive it as too long (p = .04). There were no significant changes in overall rating of the AVS by clinicians or their likelihood of providing it to patients. CONCLUSIONS: A patient-centered AVS increased the number of patients receiving it and reporting that it would help them remember to take their medications. PRACTICE IMPLICATIONS: Improvements in the patient-centeredness of the AVS may improve its usefulness as a document to support self-management in primary care. PMID- 29525144 TI - Methylation analysis of polysaccharides: Technical advice. AB - Glycosyl linkage (methylation) analysis is used widely for the structural determination of oligo- and poly-saccharides. The procedure involves derivatisation of the individual component sugars of a polysaccharide to partially methylated alditol acetates which are analysed and quantified by gas chromatography-mass spectrometry. The linkage positions for each component sugar can be determined by correctly identifying the partially methylated alditol acetates. Although the methods are well established, there are many technical aspects to this procedure and both careful attention to detail and considerable experience are required to achieve a successful methylation analysis and to correctly interpret the data generated. The aim of this article is to provide the technical details and critical procedural steps necessary for a successful methylation analysis and to assist researchers (a) with interpreting data correctly and (b) in providing the comprehensive data required for reviewers to fully assess the work. PMID- 29525145 TI - Enzymatic depolymerization of the GY785 exopolysaccharide produced by the deep sea hydrothermal bacterium Alteromonas infernus: Structural study and enzyme activity assessment. AB - Polysaccharides have attracted much attention due to their interesting physico chemical and also biological properties that are explored in food, cosmetic and pharmaceutical industries. GY785 exopolysaccharide (EPS) presenting an unusual structure is secreted by the deep-sea hydrothermal bacterium, Alteromonas infernus. Low-molecular weight (LMW) derivatives obtained by chemical depolymerization of the native high molecular weight (HMW) EPS were previously shown to exhibit biological properties similar to glycosaminoglycans (GAG). In the present study, in order to generate well defined derivatives with a better control of the depolymerization, an enzymatic approach was applied for the first time. Various commercially available enzymes were firstly screened for their depolymerizing activities, however none of them was able to degrade the polysaccharide. Enzymatic assays performed with A. infernus protein extracts have shown that the bacterium produces by itself endogenous enzymes able to depolymerize its own EPS. The oligosaccharides released by the enzymes were analyzed and their structures allowed to assess that the protein extract contains several depolymerizing activities. PMID- 29525146 TI - Laminated chitosan-based composite sponges for transmucosal delivery of novel protamine-decorated tripterine phytosomes: Ex-vivo mucopenetration and in-vivo pharmacokinetic assessments. AB - In the current study, laminated chitosan (CS):hydroxypropyl methylcellulose (HPMC) composite sponges were exploited as solid matrices for buccal delivery of tripterine phytosomes functionalized with novel mucopenetrating protamine layer (PRT-TRI-PHY). Tripterine (TRI) is a herbal drug widely investigated as a potential anticancer candidate against various types of cancers. However, clinical use of TRI is handicapped by its low oral bioavailability. To surmount TRI pharmaceutical obstacles, TRI phytosomes (TRI-PHY) were prepared using solvent evaporation technique then coated with a protamine layer via electrostatic assembly process. The developed PRT-TRI-PHY showed a nano-metric size of 250 nm and positive zeta potential (+21.6 mV). Sponges loaded with PRT TRI-PHY demonstrated a sustained release profile with superior mucoadhesion characteristics compared with the counterparts loaded with uncoated TRI-PHY. The ex-vivo permeation study via chicken pouch mucosa revealed that sponges loaded with PRT-TRI-PHY demonstrated 2.3-folds higher flux value compared with sponges loaded with uncoated TRI-PHY. Additionally, in-vivo pharmacokinetic study in healthy rabbits revealed the significantly higher bioavailability of PRT-TRI-PHY compared with TRI-PHY with relative bioavailability of 244%. Conclusively, mucoadhesive CS-HPMC sponges loaded with a novel mucopenetrating nanocarrier, PRT TRI-PHY, could significantly improve the absorption of tripterine via buccal mucosa which would be of prime importance for its clinical utility. PMID- 29525147 TI - Rheological properties of nanocomposite-forming solutions and film based on montmorillonite and corn starch with different amylose content. AB - Nanoparticles (montmorillonite, MMT) can enhance biopolymer-based film properties. The structure-property relationship between polymers and nanoparticles may be explained by the rheological tests of nanocomposite forming solutions (NFS). The aim of this work was to study the effect of MMT concentration and amylose content on the rheological properties of NFS based on corn starch and glycerol following two preparation methods, through steady shear and dynamic tests. The organization level of NFS was influenced by the addition order of the components. Decreasing in flow index behavior when increasing amylose content was attributed to interactions between the starch components. In all NFS, G' was higher than G" indicating a gel-like behavior and suggesting that the MMT reinforced the starch matrix as observed by the increase in the storage modulus of films with MMT. Films obtained from method 2 have better mechanical properties probably due to the starch-MMT interactions. PMID- 29525148 TI - Fabrication of UV-absorbent cellulose-rosin based thermoplastic elastomer via "graft from" ATRP. AB - Cellulose-rosin based thermoplastic elastomers with UV absorption properties were fabricated by a combination of rosin, poly(butyl acrylate) (PBA) and ethyl cellulose (EC) via "graft from" ATRP with the aid of EC-rosin macroinitiator (EC g-(DA)-Br) prepared by a simple esterification reaction between EC, dehydroabietic acid (DA, one of rosin's resin acids) and 2-bromoisobutylryl bromide. The introduction of rosin affords these elastomers with UV absorption property. And the glass transition temperature of these EC-rosin grafted copolymers could be tuned by changing the content of PBA. Moreover, the introduction of PBA to EC endowed EC-g-(DA)-g-PBA with a good film-forming property and excellent thermoplastic elastomer behavior. All of these EC-rosin grafted copolymers showed an excellent UV absorption performance, and maintained outstanding UV absorption capability after continuous UV-irradiation or being heated to 115 degrees C for 1 h. As a result, these EC-rosin grafted copolymers have a potential application in coating materials with UV absorption property. PMID- 29525149 TI - Durable pectin/chitosan membranes with self-assembling, water resistance and enhanced mechanical properties. AB - Processing water-soluble polysaccharides, like pectin (PT), into materials with desirable stability and mechanical properties has been challenging. Here we report a new method to create water stable and mechanical resistant polyelectrolyte complex (PEC) membranes from PT and chitosan (CS) assemblies, without covalent crosslinking. This new method overcomes challenges of obtaining stable and durable complexes, by performing the complexation at low pH, enabling complex formation even when using an excess of PT, and when using PT with high degree of O-methoxylation. By performing the complexation at low pH, the complexes form with a high degree of intermolecular association, instead of forming by electrostatic complexation. This method avoids precipitation, and overcomes the aqueous instability typical of PT/CS complexes. After neutralization, the PEC membranes display features characteristic of a high degree of intermolecular association because of the self-assembling of polymer chains. The PT/CS ratio can be tuned to enhance the mechanical strength (sigma = 39 MPa) of the membranes. These polysaccharide-based materials can demonstrate advantages over synthetic materials for technological applications. PMID- 29525150 TI - Chitin/clay microspheres with hierarchical architecture for highly efficient removal of organic dyes. AB - Numerous adsorbents have been reported for efficient removal of dye from water, but the high cost raw materials and complicated fabrication process limit their practical applications. Herein, novel nanocomposite microspheres were fabricated from chitin and clay by a simple thermally induced sol-gel transition. Clay nanosheets were uniformly embedded in a nanofiber weaved chitin microsphere matrix, leading to their hierarchical architecture. Benefiting from this unique structure, microspheres could efficiently remove methylene blue (MB) through a spontaneous physic-sorption process which fit well with pseudo-second-order and Langmuir isotherm models. The maximal values of adsorption capability obtained by calculation and experiment were 152.2 and 156.7 mg g-1, respectively. Chitin/clay microspheres (CCM2) could remove 99.99% MB from its aqueous solution (10 mg g-1) within 20 min. These findings provide insight into a new strategy for fabrication of dye adsorbents with hierarchical structure from low cost raw materials. PMID- 29525151 TI - The hydration mechanism and hydrogen bonding structure of 6-carboxylate chitooligosaccharides superabsorbent material prepared by laccase/TEMPO oxidation system. AB - 6-carboxylate chitooligosaccharides (6-CCOS), as a superabsorbent material, were prepared by way of the laccase/TEMPO oxidation system. It exhibited a higher moisture-absorption ability and stronger affinity for water. To understand the real reasons for this, the hydrogen bonding structure of 6-CCOS and the hydration mechanism of the molecule were investigated using infrared (IR), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). It was found that the introduction of a strongly hydrophilic carboxylate ion on the C6 site of chitooligosaccharides molecule was conducive to the enhancement of the interaction between polysaccharide polymers and water molecules. The most important was the formation of hydrogen bonds connected between carboxylate ion and residual water. In addition, the hydration mechanism of 6-CCOS molecules was presumed to be that more water molecules from outside were incorporated into the already embedded water molecules within the polymer. The whole molecule was woven into a huge water-polymer network structure through intermolecular hydrated hydrogen bonds. PMID- 29525152 TI - A redox strategy to tailor the release properties of Fe(III)-alginate aerogels for oral drug delivery. AB - Iron(III)-crosslinked alginate aerogel beads (d = 3-5 mm) were prepared and loaded with ibuprofen by using the technique of adsorptive deposition from supercritical CO2. Additional formulations were prepared where the aerogels were co-impregnated by ibuprofen and ascorbic acid. The release of ibuprofen from the Fe(III)-alginate is much faster in pH = 7.4 (PBS) than in pH = 2.0 (HCl), which can be explained by the faster dissolution and higher swelling of the alginate matrix in PBS. By decreasing the size of the beads and using a higher G content alginate the release rate could be slightly increased. A marked acceleration of drug release was achieved in both HCl and PBS by incorporating ascorbic acid into the Fe(III)-alginate aerogel preparations. The explanation is that in aqueous media ascorbic acid in situ reduces the crosslinking Fe(III) to Fe(II). The latter does not interact strongly with alginate, which promotes the hydration of the chains, thus the erosion and dissolution of the carrier matrix. PMID- 29525153 TI - Synthesis of methylcellulose/cellulose nano-crystals nanocomposites: Material properties and study of sustained release of ketorolac tromethamine. AB - Non-toxic nanocomposites based bio-films obtained from methylcellulose (MC) can reduce environmental problems associated with synthetic polymers. A new facile route for the isolation of cellulose nano-crystals (CNC) from jute waste is successfully utilized here. The fabrication of CNC reinforced MC nanocomposites by film casting technique and the studies of the effect of CNC on the properties of the MC based nanocomposites have been reported. The synthesized nanocomposites have shown improved UV resistance, mechanical, barrier, and thermal properties. FTIR results established the physicochemical compatibility between the drug, MC and CNC in nanocomposites. In vitro permeation studies performed by using Franz diffusion cell revealed diffusion mediated sustained drug release from the devices due to the presence of interaction between MC and CNC through H-bonding, electrostatic interaction between the hydrophilic polymer/CNC chains with the drug and the formation of tortuous path. The nanocomposites can be used for edible packaging and transdermal drug delivery. PMID- 29525154 TI - In vitro digestibility and prebiotic potential of curdlan (1 -> 3)-beta-d-glucan oligosaccharides in Lactobacillus species. AB - Prebiotic effects of curdlan (1 -> 3)-beta-d-glucan oligosaccharides (GOS) were examined. GOS was tolerant against simulated gastrointestinal digestion, as well as low pH, thermal, and Maillard reaction conditions likely occurred during food processing. Growth of tested Lactobacillus (L.) strains was improved by GOS except L. brevis NRRL B-4527. E. coli did not grow on GOS as the only carbon source. In vitro batch fermentation using human faecal microbiota showed that GOS significantly increased the population of Lactobacillus sp. followed by Bifidobacterium sp. and Bacteroides sp. Growth of L. strains on GOS produced lactic acid, acetic, and propionic acid with decreased culture medium pH. Utilization pattern of GOS by representative L. strains was strain dependent. GOS with degree of polymerization (DP) of 2 and 3 were readily consumed. Findings here indicated that curdlan GOS (DP = 2 and 3) are promising physiologically active prebiotics for improvement of human intestinal health. PMID- 29525155 TI - Structure of New Zealand sweetpotato starch. AB - New Zealand sweetpotatoes (kumara) (Ipomoea batatas) represent unique genetic resources for sweetpotato diversity, though they are much under-studied. In this study, 7 New Zealand sweetpotato varieties with commercial significance were collected for the characterization of the molecular and granular structure of the starches. In particular, the internal molecular structure of the amylopectins was detailed by chromatographic and enzymatic techniques. Maize and potato starches with normal amylose contents, which are among the most important commercial starch sources, were employed for comparison. The results revealed a degree of diversity in amylose composition, unit and internal chain composition, granule size distribution, and degree of crystallinity among the 7 sweetpotato starches. All the sweetpotato starches showed CA-type polymorph. The sweetpotato amylopectins have intermediate amounts of both short and long internal unit chains among amylopectins of different botanical sources. The differences in the structure of sweetpotato starches suggest differences in physicochemical properties. PMID- 29525156 TI - Effect of electrohydrodynamic technique as a complementary process for cellulose extraction from bagasse: Crystalline to amorphous transition. AB - Electrohydrodynamic technique (EHD) has lately received considerable attention as an important non-thermal method used for food processing. In this work the effect of EHD on physicochemical properties of cellulose extracted from bagasse was investigated. A three-step process was chosen to extract cellulose fibers, which was performed under a high voltage electric field at the beginning of each step. The cellulose fibers were then characterized using Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), and Thermogravimetric Analysis (TGA). The morphological evaluation revealed that the cellulose fibers have smaller diameter and larger length compared to the microcrystalline cellulose. Moreover, according to the XRD patterns and FTIR spectrum, EHD-treated fibers mainly showed an amorphous structure, and contained a low crystalline fraction. The amorphous structure of cellulose fibers was confirmed by TGA analysis which revealed the presence of higher proportion of amorphous cellulose fraction causes early onset of thermal decomposition. PMID- 29525157 TI - Experimental design data for the zinc ions adsorption based on mesoporous modified chitosan using central composite design method. AB - In the present study, new generation of silica-based mesoporous adsorbents were introduced for the removal of heavy metals with the aim of developing new adsorption technologies in water treatment. The magnetic nanoadsorbent, prepared by modification of SBA-15 with [3-(2-Aminoethylamino) propyl] trimethoxysilane (AEAPTMS)-functionalized chitosan, was applied for the removal of Zn2+ from aqueous solution. The synthesized Fe2O3@SBA-15-CS-AEAPTMS nanoadsorbent was thoroughly characterized using XRD, TEM, FTIR and BET analysis. In order to determine the optimum condition of Zn2+ adsorption on Fe2O3@SBA-15-CS-AEAPTMS (3 ml), the experiments were performed based on central composite design in a response surface methodology method. The obtained results were further studied using adsorption kinetic, isotherm and thermodynamic relations which revealed that Zn2+ adsorption was spontaneous and endothermic with enhanced adsorption efficiency achieved for higher contents of functional groups. In addition, according to the results, the adsorption process was best conformed to Langmuir isotherm (with R2 > 0.99 and qmax = 107.21 mg g-1) and pseudo second-order kinetic model (with R2 > 0.999). The values of standard entropy (DS degrees ) and activation energy (Ea) reduced as the initial concentration was increased and the dominant mechanism was found to be chemisorption. PMID- 29525158 TI - Continuous flow adsorption of ciprofloxacin by using a nanostructured chitin/graphene oxide hybrid material. AB - A novel nanostructured material was successfully developed by combining a chitin matrix with graphene oxide nanosheets (Chi:nGO) and then used for the continuous flow adsorption of ciprofloxacin. The spectroscopic characterization indicated that none covalent interaction between both components would be occurring and the introduction of nGO did not interfere in chitin nanostructure rearrangement during gelling and later drying. SEM images and Mercury Intrusion Porosimetry results showed a wide pore size distribution ranging from nano to micrometers. The continuous flow adsorption was observed to be dependent on the pH which affects the electrostatic interaction. The flow rate, Na+ concentration and water hardness were evaluated to describe the adsorption process. The resistance to alkali allowed to regenerate and reuse the column for subsequent adsorption cycles. Finally, ciprofloxacin spiked real water samples were assessed and the results confirmed that the medium pH was the main parameter that defines the adsorption behavior. PMID- 29525159 TI - Bleaching of cotton fabric with tetraacetylhydrazine as bleach activator for H2O2. AB - Tetraacetylhydrazine (TH) as bleach activator for H2O2 cotton bleaching was synthesized and characterized by 1H NMR, 13C NMR and MS spectra. TH has better solubility than that of TAED. The CIE whiteness index (WI), H2O2 decomposition rate and bursting strength were employed to investigate the performance of H2O2/TH bleaching system. By addition of TH, WI and H2O2 decomposition rate increased significantly at 70 degrees C. Bleaching temperature, NaHCO3 concentration and bleaching time were also discussed in detail and the loss of bursting strength is not clear. By using benzenepentacarboxylic acid (BA) as a fluorescent probe for hydroxyl radical detection, the bleaching process of H2O2/TH system was investigated. Acetylhydrazine and diacetylhydrazine were also utilized to further confirm the process. In addition, bimolecular decomposition was investigated by using 9,10-dimethylanthracene (DMA) as fluorescent probe of 1O2. Based on these experimental results, the bleaching mechanism of H2O2/TH system was proposed. PMID- 29525160 TI - Multi-scale structural changes in lintnerized starches from three coloured potatoes. AB - Three kinds of potato starch were treated with 2.2 N HCl at 35 degrees C for 40 days, and their susceptibility to acid hydrolysis and the resulting structural changes were evaluated. Red potato starch was more susceptible to acid hydrolysis and presented highest rate of hydrolysis. Lintnerized starches had relatively low average molecular weights and z-average radius of gyration. HPAEC analyses showed three lintners presented different molecular size distributions. Lintnerized yellow potato starch had few chains of DP <= 12 (2.58 mol%) and more chains of DP >= 37 (8.16 mol%). Furthermore, the similarities of the branch-chain length distributions before and after debranching indicated the lintners consisted primarily of linear molecules. After lintnerization, most starch granules were degraded, and the birefringence disappeared from some granules. X-ray diffraction patterns revealed that the relative crystallinity significantly increased after lintnerization. DSC analyses showed that lintners displayed broader thermal transitions. PMID- 29525161 TI - Purification, characterization and immunomodulatory activity of polysaccharides from stem lettuce. AB - Stem lettuce has a long history of cultivation in China and possesses high nutritional and medicinal value. In our previous studies, extraction optimization, characterization, and bioactivities of stem lettuce polysaccharides (SLP) were investigated. In this study, SLP were further separated into two purified polysaccharides, SLP-1 and SLP-2, by anion exchange chromatography followed by size exclusion chromatography. SLP-1, with a molecular weight of 90 KDa, was mainly composed of galacturonic acid, galactose and arabinose in a molar ratio of 17.6:41.7:33.9. SLP-2, with a molecular weight of 44 KDa, was mainly composed of mannose, galacturonic acid, galactose and arabinose in a molar ratio of 11.5:69.5:9.3:8.2. In addition, both purified polysaccharides contain sulphate radicals, have triple helical structures and can promote macrophage proliferation without cytotoxicity. SLP-2 was better able to stimulate phagocytic and nitric oxide production than SLP-1. The results suggest that polysaccharides from stem lettuce could be explored as immunomodulatory agents in the field of pharmaceuticals and functional foods. PMID- 29525162 TI - Improving the stability of thyme essential oil solid liposome by using beta cyclodextrin as a cryoprotectant. AB - The objective of this study was to investigate the preparation of the freeze dried epsilon-polylysine (epsilon-PLY)-coated thyme essential oil (TEO) liposome, and its application in vegetable juices to control the Escherichia coli O157:H7 growth. Firstly, the solid liposomes (SLP) were obtained via freeze-drying in the presence of beta-cyclodextrins as cryoprotectant under different ratios of beta cyclodextrin: lipid (w/w) (2:1, 4:1, 6:1 and 8:1). The ultraviolet visible and fourier transformed infrared spectrograms results indicated the presence of TEO and epsilon-PLY in SLPs. Subsequently, the morphology, antioxidant activity, digestibility, release rate and phase inversion temperature of SLPs were measured respectively. The SLP powders and re-hydrated SLP solutions exhibited the optimal physical and chemical properties when the ratio of beta-cyclodextrin: lipid was 6:1. In addition, SLPs stored at 4 degrees C and 12 degrees C possessed favorable particle size, PDI and zeta potential. Finally, the desired antibacterial effects of SLPs on Escherichia coli O157:H7 in 4 vegetable juices were achieved at a concentration of 5 mg/mL. PMID- 29525163 TI - pH-responsive prodrug nanoparticles based on xylan-curcumin conjugate for the efficient delivery of curcumin in cancer therapy. AB - In the present study, novel pH-responsive prodrug nanoparticles based on xylan curcumin (xyl-cur) conjugate were developed to enhance the therapeutic efficacy of curcumin in cancer therapy. The synthesis of xyl-cur conjugate (prodrug) was confirmed by FT-IR, 1H NMR, UV-vis and fluorescence spectroscopy. The xyl-cur prodrug was subsequently self-assembled in to nanoparticles (xyl-cur prodrug NPs) in an aqueous medium with the average particle size 253 nm and the zeta potential of -18.76 mV. The xyl-cur prodrug NPs were highly pH-sensitive in nature and most of the drug was released at lower pH. The interaction of the xyl-cur prodrug NPs with blood components was tested by hemolysis study. The cytotoxic activity of the xyl-cur prodrug NPs against human colon cancer cells (HT-29, HCT-15) demonstrated that the prodrug NPs exhibits greater cytotoxic effect than curcumin. Therefore, these results reveal that xyl-cur prodrug NPs could be a promising candidate for improving the intracellular delivery of curcumin in cancer therapy. PMID- 29525164 TI - Stability, microstructure and rheological behavior of konjac glucomannan-zein mixed systems. AB - This study aims to investigate the stability, microstructure and rheological properties of konjac glucomannan (KGM)/zein mixed systems in different mixing ratios. A phase diagram was established by centrifugation and visual observation. KGM/zein could form a stable homogeneous dispersion with appropriate mixing formula, and the particle size in mixed systems increased with increasing zein content. During storage, zein particles increased in size but were homogeneously distributed in the continuous phase of KGM without flocculation as observed by confocal light scanning microscopy. The rate of particle size change slowed down with increasing concentration of KGM. Transmission electron microscopy and atomic force microscopy images showed that zein particles were distributed in the KGM molecular network. The mixed systems showed shear-thinning behavior, and the temperature dependence of the viscosity was well-fitted by the Arrhenius equation. Based on dynamic viscoelasticity analysis, the mixed systems showed typical behaviors for entangled polymer solutions. The shift of cross-over frequency of storage (G') and loss (G") moduli to higher frequencies with increasing concentration of zein implied the shortening of the lifetime of the temporary entangled junction in the mixed systems. PMID- 29525165 TI - Chitosan nanogels condensed to ferulic acid for the essential oil of Lippia origanoides Kunth encapsulation. AB - In order to enable the applicability of the essential oil of Lippia origanoides Kunth, increasing its stability and dispersion in aqueous base, were prepared nanogels of chitosan modified with ferulic acid to be used in their encapsulation. The results obtained by FTIR and 13C SSNMR revealed the formation of CS-FA link in the different synthesized nanogels, while the studied by DLS showed particles with varied sizes and positive charge. A satisfactory encapsulation capacity of the essential oil was obtained for the nanogels. However, the nanogel synthesized with the highest proportion of ferulic acid in relation to chitosan 0.760 g of ferulic acid (CF1) showed the highest encapsulation efficiency of 20%. The results indicate the CF1 nanogel potential to encapsulate important components of the essential oil of L. origanoides, being able to guarantee the constituents, preservation, moreover facilitate the dispersion and release, expanding its use. PMID- 29525166 TI - A physically crosslinked polydopamine/nanocellulose hydrogel as potential versatile vehicles for drug delivery and wound healing. AB - In this study, we reported a pH/near-infrared (NIR)-responsive hydrogel for on demand drug delivery and wound healing. Cellulose nanofibrils (TOCNFs) were produced by 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation method. Polydopamine (PDA) was introduced into TOCNFs network to fabricate a PDA/TOCNFs hydrogel through ion-crosslinking with calcium ion as a crosslinker. Then, tetracycline hydrochloride (TH) which loaded on PDA could be released from the prepared hydrogels in an on-demand fashion under NIR exposure or at lower pH conditions. In addition, the in vivo skin defect experiments illustrated that the resultant composite hydrogel had a synergistic effect on promoting wound healing. Therefore, owing to the unique pH/NIR responsiveness, long time period drug releasing property, antibacterial and mechanical properties, together with their biodegradability and biocompatibility, the prepared PDA/TOCNFs hydrogel is highly promising as a new drug delivery vehicle, offering simple and safe alternatives to the conventional systems based on the petroleum-based polymers. PMID- 29525167 TI - Design of polygalacturonate hydrogels using iron(II) as cross-linkers: A promising route to protect bioavailable iron against oxidation. AB - We designed stable and highly reproducible hydrogels by external unidirectional diffusion of Fe2+ ions into aqueous solutions of polygalacturonate (polyGal) chains. The Fe2+ ions act as cross-linkers between the Gal units in such a way that both the molar ratio R ([Fe2+]/[Gal units] = 0.25) and the mesh size of the polyGal network at the local scale (xi = 75 +/- 5 A) have constant values within the whole gel, as respectively determined by titration and Small Angle Neutron Scattering. From macroscopic point of view, there is a progressive decrease of polyGal concentration from the part of the gel formed in the early stages of the gelation process, which is homogeneous, transparent and whose Young modulus has a high value of ~105 Pa, up to the part of the gel formed in the late stages, which is heterogeneous, highly turbid and has a much lower Young modulus of ~103 Pa. Since the local organization of the polyGal chains remains identical all along the hydrogels, this macroscopic concentration gradient originates from the formation of heterogeneities at a mesoscopic length scale during the gelation process. In addition, X-ray Absorption Spectroscopy measurements remarkably reveal that Fe2+ ions keep their +II oxidation state in the whole gels once they have cross-linked the Gal units. These polyGal hydrogels thus protect iron against oxidation and could be used for iron fortification. PMID- 29525168 TI - Corrigendum to "Efficient removal of malachite green dye using biodegradable graft copolymer derived from amylopectin and poly (acrylic acid)" [Carbohydr. Polym. 111 (2014) 108-115]. PMID- 29525169 TI - Surface modification of PES membrane via aminolysis and immobilization of carboxymethylcellulose and sulphated carboxymethylcellulose for hemodialysis. AB - Sulphated carboxymethylcellulose (SCMC) was synthesized and characterized via FT IR and CHNS analysis. The PES membranes were prepared and modified via surface amination with an aminolysis reaction and amount of amino groups was measured. The carboxymethylcellulose (CMC) and SCMC were immobilized on the surface of the aminated PES membranes (PES-NH2) via amide bonds to synthesize PES-CMC and PES SCMC membranes, respectively, and the concentration of immobilized CMC and SCMC was determined. The unmodified PES, PES-CMC, and PES-SCMC membranes were characterized in terms of morphology, overall porosity, mean pore size, zeta potential, tensile strength, contact angle, protein adsorption and platelet adhesion. The results showed a decrease in contact angle, protein adsorption and platelet adhesion in the case of PES-CMC and PES-SCMC compared to unmodified PES membranes, which supported the increased hemocompatibility of the modified membranes especially for the PES-SCMC membrane. Moreover, the PES-CMC and PES SCMC membranes displayed good antifouling properties, especially for PES-SCMC. PMID- 29525170 TI - Transforming fish scale waste into an efficient filler for starch foam. AB - In this work modified fish scale waste (FS) was used as a filler in order to improve the properties of starch foam prepared by a baking process. The FS was modified under two calcination conditions: at 500 degrees C for 5 h and at 700 degrees C for 3 h. The FS powder calcined at 700 degrees C for 3 h (FS700-3) had higher Ca content and lower protein content and was the filler chosen for experimental study of the effects of its addition on the properties of the starch foam. The addition of FS700-3 to the starch foam produced a more expanded structure due to FS700-3 efficiently supported the growth of existing cells during nucleation and bubble growth. Moreover, the flexural stress at maximum load of the starch foam increased from 1.03 MPa to 1.54 MPa after adding FS700-3 at 10 wt% because of the good adhesion between the two components. PMID- 29525171 TI - The combination between cations and sulfated polysaccharide from abalone gonad (Haliotis discus hannai Ino). AB - Effects of cations (Na+, K+, Ca2+, Mg2+) on the structure of abalone gonad sulfated polysaccharide (AGSP) were studied by means of Congo red test, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). The results showed that the local ordered helical conformation was observed in AGSP. The cations could combine with anionic groups in AGSP by ionic bonds, which caused the weakening of electrostatic repulsion and crosslinking of molecular chains. Furthermore, the effects of divalent cations on the conformation were more obvious than that of monovalent cations, and divalent cations led to the aggregation of AGSP due to the more interaction sites. In short, AGSP molecular chains were crosslinked through ionic bonds after adding cations, and, divalent cations could induce the aggregation of AGSP by electrostatic interactions. This study will provide valuable insights for the further research on AGSP conformation. PMID- 29525172 TI - Effect of natural flocculants on purity and properties of beta-glucan extracted from barley and oat. AB - In this study, beta-glucan was extracted from wholegrain oat and barley flours by a novel extraction and purification method employing natural flocculants (chitosan, guar gum and gelatin). The use of flocculants decreased the total amount of extracted gum, which was highest in control samples (9.07 and 7.9% for oat and barley, respectively). The beta-glucan specific yield, however, increased with the use of chitosan and guar gum, which were able to remove protein and ash impurities resulting in gums with a higher purity.The highest concentration of chitosan (0.6 %) resulted in gums with the highest beta-glucan content (82.0 +/- 0.23 and 79.0 +/- 0.19 for barley and oat, respectively) and highest beta-glucan specific yield (96.9 and 93.3 % for oat and barley, respectively). Explanation is in R&D section. The use of gelatin was not successful. All gum samples had a high content of total dietary fiber (>74%) and a high water holding capacity (4.6-7.4 g/g), but differed in apparent viscosity, which was highest for the oat sample extracted with 0.6% chitosan. This sample also showed the highest beta-glucan molecular weight among the oat samples, which were in general 10-fold higher than for the barley samples. Among the barley samples, beta-glucan molecular weight was highest for the control. PMID- 29525173 TI - Indigestible pyrodextrins prepared from corn starch in the presence of glacial acetic acid. AB - This study was conducted to evaluate the feasibility of using acetic acid (0 2.5%) as the catalyst in the production of pyrodextrins from corn starch at 140 180 degrees C, and to elucidate the effects of catalyst concentration and pyrolytic temperature on the characteristics of indigestible pyrodextrins. In the absence of acetic acid, noticeable changes to the loss of birefringence, increased solubility, plateau of molecular weight reduction, decreased reducing sugar content and digestibility were observed at 180 degrees C. By using catalyst, the alterations in the aforementioned characteristics of pyrodextrins were intensified. Moreover, by using 0.5-1.0% catalyst, the substantial alterations in birefringence, solubility and molecular weight were observed concurrently for pyrodextrins formed at 170 degrees C. Further increasing the concentration of acetic acid to 1.0-2.5% decreased the intervening temperature to 160 degrees C. The findings suggest that indigestible pyrodextrins with desired characteristics could be tailored via using various combinations of catalyst concentration and pyrolytic temperature. PMID- 29525174 TI - Improved hydroxypropyl methylcellulose (HPMC) films through incorporation of amylose-sodium palmitate inclusion complexes. AB - Polymer film blends of hydroxypropyl methylcellulose (HPMC) and amylose-sodium palmitate inclusion complexes (Na-Palm) were produced with no plasticizer, and were observed to have improved physical and gas barrier properties as compared with pure HPMC. The crystalline amylose helices incorporating the hydrophobic sodium palmitate ligand decreased the water vapor permeability of a 50/50% blended film of HPMC/Na-Palm by 40% and decreased oxygen permeability by 96%. The incorporation of 25% Na-Palm into HPMC films resulted in improved elongation, Young's modulus and toughness. Addition of the amylose-complexes produced relatively smooth, high clarity films which had reduced solubility in neutral and acidic solutions. Increasing concentrations of Na-Palm increased film thermal resilience and increased storage modulus at high temperatures. The heat deflection temperature of the films also increased with increasing concentrations of amylose-complex; HPMC/Na-Palm film blends with >50% Na-Palm displayed almost no material deformation up to 250 degrees C. PMID- 29525175 TI - Adsorption of AgNO3 onto bamboo hemicelluloses in aqueous medium. AB - An insight into the adsorption behavior between hemicellulose biomass and metal ions is important to utilize hemicelluloses as adsorbent. In this study, bamboo hemicelluloses were used as adsorbent for AgNO3 in aqueous medium. The adsorption amount of AgNO3 onto hemicelluloses was determined through an inductively coupled plasma-atomic emission spectrometer (ICP-AES). The morphology and the elemental composition of the recovered hemicelluloses were characterized using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) techniques, respectively. The filtrate after removing undissolved hemicelluloses was analyzed by ultraviolet-visible spectroscopy (UV-vis). Results demonstrated that the obtained highest adsorption amount of AgNO3 onto hemicelluloses was 42.82 mg/g under the conditions discussed. Some Ag+ was in situ reduced by hemicelluloses to form silver nanoparticles. Ag+ and the formed silver nanoparticles possibly destroyed the hydrogen-bonding network of hemicelluloses, resulting in the stretch of molecules and formed rod-like agglomerates with irregular length. Even an agglomerate with the length of 420 nm was found. The side chains and the newly formed carboxyl groups through oxidation of hemicelluloses by silver ions removed away from the hemicelluloses during adsorption. A part of Ag+ and silver nanoparticles were adsorbed on the unresolved hemicelluloses, and the other part was dispersed in the aqueous solution. PMID- 29525176 TI - Extraction and characterization of cellulose single fibers from native african napier grass. AB - With increasing awareness of protecting the environment, the demand for renewable and environmental materials is increasing. In this work, the cellulose single fibers (CSFs) were extracted from the African native Napier grass fibers (NGFs) by chemical process. NGFs and CSFs were characterized for their chemical composition, structure, morphology, crystallinity and thermal properties using, chemical analysis, FTIR, 13C CP/MAS NMR, SEM, XRD and TGA techniques. The resulted CSFs had higher alpha-cellulose content, crystallinity and thermal stability than the pristine NGFs. SEM images showed cleaner and rough surfaces for the CSFs when compared to those of NGFs. About 69% of the extracted CSFs showed a diameter range between 4 and 10 MUm. FTIR and 13C CP/MAS NMR spectra confirmed the removal of lignin and hemicellulose components after chemical treatments. PMID- 29525177 TI - The preparation of hyaluronic acid grafted pullulan polymers and their use in the formation of novel biocompatible wound healing film. AB - A series of hyaluronic acid grafted pullulan (HA-g-Pu) polymers with different hyaluronic acid (HA) moieties degrees of substitution (DS) were synthesized and characterized by fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR) and differential scanning calorimetry measurement (DSC). Compared to pure HA, HA-g-Pu polymers obtained better anti-enzymatic degradation ability in vitro, and the degradation rate of HA-g-Pu polymers depended on their different DS of HA moieties. The HA-g-Pu films were made of leaf-shape cascading arrangement with many small porous ranging from 0 to 100 MUm in diameter when observed by scanning electron microscopy (SEM). Therefore, HA-g-Pu films have a higher swelling ratio than that of the pullulan/or HA films. HA-g-Pu films could absorb much liquid, effectively protect the wound bed from accumulation of exudates and reduce the frequency of replacement. Moreover, the good biocompatibility of HA-g-Pu polymers were confirmed by skin irritation, cytotoxicity, cell proliferation and hemolysis test. Compared with the natural healing, the HA-g-Pu films promoted the wound healing. HA of HA-g-Pu polymers played an important role in the wound healing response. Furthermore, the HA-g-Pu polymers appeared a certain coagulation function and obtained a relative rapid hemostasis ability which might be attribute to heal wound. PMID- 29525178 TI - Twenty years of molecular analyses in amyotrophic lateral sclerosis: genetic landscape of Italian patients. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a heterogeneous genetic background. Because mutation analysis by Sanger sequencing is costly and time-consuming, in recent years, next-generation sequencing (NGS) techniques have become of much interest. This study analyses the results of 20 years of molecular analyses in ALS patients in our laboratory using traditional methods and NGS. Almost 300 ALS patients underwent genetic analysis with Sanger sequencing of 7 genes or with an NGS panel of 23 genes. The C9orf72 expansion was tested by fragment size analysis. Sanger sequencing revealed mutations in 23.8% of familial and 3.8% of sporadic cases, whereas NGS detected potentially pathogenic variants in 45.5% of familial and 5.4% of sporadic cases and variants of unknown significance in 30.3% of patients. In 11.8% of patients, potentially causative mutations were found in 2 or more ALS genes. Compared to traditional methods, NGS is more effective in revealing possibly causal variants, but counseling patients becomes more complicated due to frequent variants of unknown significance and potentially oligogenic cases. PMID- 29525181 TI - Heat shock factor 1 suppresses the HIV-induced inflammatory response by inhibiting nuclear factor-kappaB. AB - The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4+ T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-kappaB (NF-kappaB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS. PMID- 29525180 TI - Identification of rare genetic variants in Italian patients with dementia by targeted gene sequencing. AB - Genetics is intricately involved in the etiology of neurodegenerative dementias. The incidence of monogenic dementia among all neurodegenerative forms is unknown due to the lack of systematic studies and of patient/clinician access to extensive diagnostic procedures. In this study, we conducted targeted sequencing in 246 clinically heterogeneous patients, mainly with early-onset and/or familial neurodegenerative dementia, using a custom-designed next-generation sequencing panel covering 27 genes known to harbor mutations that can cause different types of dementia, in addition to the detection of C9orf72 repeat expansions. Forty nine patients (19.9%) carried known pathogenic or novel, likely pathogenic, variants, involving both common (presenilin 1, presenilin 2, C9orf72, and granulin) and rare (optineurin, serpin family I member 1 and protein kinase cyclic adenosine monophosphate (cAMP)-dependent type I regulatory subunit beta) dementia-associated genes. Our results support the use of an extended next generation sequencing panels as a quick, accurate, and cost-effective method for diagnosis in clinical practice. This approach could have a significant impact on the proportion of tested patients, especially among those with an early disease onset. PMID- 29525182 TI - Low-dose thiopurine with allopurinol co-therapy overcomes thiopurine intolerance and allows thiopurine continuation in inflammatory bowel disease. AB - AIMS: To assess the utility and tolerability of thiopurine-allopurinol co-therapy in inflammatory bowel disease (IBD) patients with intolerance to thiopurine monotherapy. METHODS: A retrospective observational study assessed cases of thiopurine intolerance then switched to thiopurine allopurinol co-therapy between 2011 and 2015 at two centres. Indications for switch, dosing and subsequent clinical outcomes (including thiopurine persistence) were recorded. RESULTS: Of 767 patients on thiopurines for IBD, 89 (12%) were switched to co-therapy for intolerance. 64/89 (72%) had Crohn's disease, 38 (43%) were males, median age at switch was 40y (range 17-78), median IBD duration 6y (0-29). Median follow-up was 1.9y (0-5). Reasons for switching to co-therapy included fatigue (37%), hepatotoxicity (23%), nausea (23%), arthralgia (10%), headache (12%) and hypersensitivity reaction (4%). Overall, 66 (74%) patients remained on co-therapy until most recent review and achieved a clinical response. High rates of overcoming intolerance (62-100%) occurred with co-therapy for all reasons above, although fatigue was less amenable to switching than non-fatigue indications (62% vs 91%, p = <0.001). Of 34 patients not escalated to biologics with endoscopic data, 15 were in remission (44%) at most recent review. CONCLUSION: Low-dose thiopurine combined with allopurinol appears safe and effective in overcoming intolerances to thiopurine monotherapy in many cases. PMID- 29525179 TI - Genetic markers of dopaminergic transmission predict performance for older males but not females. AB - Mobility and memory declines with aging can limit independence. Several single nucleotide polymorphisms have been associated with cognitive performance, but studies investigating motor function are scant. We examined 4 single-nucleotide polymorphisms involved in dopaminergic metabolism: BDNF (Val66Met), DRD3 (Ser9Gly), DBH (C>T), and COMT (Val158Met) for their relationship to motor and cognitive function in healthy older adults (n = 4605 and n = 7331) who participated in the U.S. Health and Retirement Study. Individuals with genotypes associated with reduced dopamine metabolism exhibited poorer balance and memory. We found the most pronounced effects in the oldest participants (aged 85+ years), supporting the notion that age-related declines in dopamine availability contribute to magnified genotype effects with advancing age. Moreover, males demonstrated stronger associations than did females between a number of beneficial dopamine alleles and cognitive scores, suggesting that sex differences in dopaminergic transmission interact with genotype to influence performance. These findings point to common genetic variants related to dopaminergic metabolism that characterizes individual differences in motor and cognitive function in older adults. PMID- 29525183 TI - LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways. AB - Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutieres syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1. The mechanism of immune activation in AGS patients has not been thoroughly elucidated to date. In this study, we report that endogenous LINE1 components trigger IFNbeta production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential. LINE1 triggered immune activation could be suppressed by diverse LINE1 inhibitors, including AGS-associated proteins targeting LINE1 RNA or proteins. However, AGS associated ADAR1 or TREX1 mutants were defective in suppressing LINE1 retrotransposition or LINE1-triggered immune activation. Therefore, we have revealed a new function for LINE1 as an endogenous trigger of innate immune activation, which is important for understanding the molecular basis of IFN-based autoimmune diseases and may offer new intervention strategies. PMID- 29525184 TI - [Hospital costs estimation by micro and gross-costing approaches]. AB - Cost analysis has become increasingly commonplace in healthcare facilities in recent years. Regardless of the aim, the first consideration for a hospital costing process is to determine the point of view, or perspective, to adopt. Should the cost figures reflect the healthcare facility's point of view or enlighten perspectives for the public health insurance system? Another consideration is in regard to the method to adopt, as there are several. The two most widely used methods to determine the costs of hospital treatments in France are the micro-costing method and the gross-costing method. The aims of this work are: (1) to describe each of these methods (e.g. data collection, assignment of monetary value to resource consumption) with their advantages and shortcomings as they relate to the difficulties encountered with their implementation in hospitals; (2) to present a review of the literature comparing the two methods and their possible combination; and (3) to propose ways to address the questions that need to be asked before compiling resource consumption data and assigning monetary value to hospital costs. A final diagram summarizes methodologies to be preferred according to the evaluation strategy and the impact on patient care. PMID- 29525185 TI - [Evidence-based ways of colorectal anastomotic complications prevention in the setting of digestive deep endometriosis resection: CNGOF-HAS Endometriosis Guidelines]. AB - Management of deep pelvic and digestive endometriosis can lead to colorectal resection and anastomosis. Colorectal anastomosis carries risks for dreaded infectious and functional morbidity. The aim of the study was to establish, regarding the published data, the role of the three most common used surgical techniques to prevent such complications: pelvic drainage, diverting stoma, epiplooplasty. Even if many studies and articles have focused on colorectal anastomotic leakage prevention in rectal cancer surgery data regarding this topic in the setting of endometriosis where lacking. Due to major differences between the two situations, patients, diseases the use of the conclusions from the literature have to be taken with caution. In 4 randomized controlled trials the usefulness of systematic postoperative pelvic drainage hasn't been demonstrated. As this practice is not systematically recommended in cancer surgery, its interest is not demonstrated after colorectal resection for endometriosis. There is a heavy existing literature supporting systematic diverting stoma creation after low colorectal anastomosis for rectal cancer. Keeping in mind the important differences between the two situations, the conclusions cannot be directly extrapolated. In endometriosis surgery after low rectal resection, stoma creation must be discussed and the patient must be informed and educated about this possibility. Even if widely used there is no data supporting the role of epiplooplasty in colorectal anastomotic complication prevention? The place for epiplooplasty in preventing rectovaginal fistula occurrence in case of concomitant resection hasn't been studied. PMID- 29525186 TI - Efficient synthesis of a 6-deoxy-talose containing tetrasccharide found in Franconibacter helveticus LMG23732T. AB - Synthesis of the 6-deoxy-talose (6-dTal) containing tetrasaccharide, naturally found in Franconibacter helveticus LMG23732T, has been described. The synthetic method utilized an allyloxyethylidene group for protecting the 1-OH and 2-OH groups of rhamnopyranose and a redox reaction for synthesizing 6-deoxy talose, which eventually formed a disaccharide containing alpha-Glcp-(1->2)-6dTalp configured glycosidic bonds using a [2 + 2] synthetic strategy. PMID- 29525187 TI - Local Anesthetic Systemic Toxicity Induced Cardiac Arrest After Topicalization for Transesophageal Echocardiography and Subsequent Treatment With Extracorporeal Cardiopulmonary Resuscitation. PMID- 29525188 TI - Lung Transplantation: Can PiCCO2 Navigate Perioperative Safe Harbor? PMID- 29525189 TI - Intraoperative Massive Carbon Dioxide Embolism Captured with Transesophageal Echocardiography in a Patient with a Rare Vena Cava Anomaly. PMID- 29525190 TI - Pro: In Favor of More Generalized Use of del Nido Cardioplegia in Adult Patients Undergoing Cardiac Surgery. PMID- 29525191 TI - The Ross Operation in the Adult: What, Why, and When? AB - The normal aortic valve is a sophisticated and dynamic structure whose equal replacement has not yet been actualized by modern technology. The use of the pulmonary autograft as a substitute for a diseased aortic valve (the Ross procedure) has been in practice for several decades in many types of patient. In the adult, it has not been adopted widely due to concerns about its technical challenge, complex perioperative care, the development of pulmonic valve disease, and concerns about long-term dilatation of the neo-aortic root, among others. There has been a substantial body of data showing excellent long-term survival, freedom from reoperation, and quality of life, in contradistinction to these preconceptions. The authors review the available data pertinent to these questions to further define the role of the Ross procedure in the adult cardiac surgery patient. PMID- 29525192 TI - The Sign of Things to Come: Who Calls the Shots? PMID- 29525193 TI - Cardiovascular Collapse During Liver Transplantation-Echocardiographic-Guided Hemodynamic Rescue and Perioperative Management. PMID- 29525194 TI - Less Invasive, More Informative: A New Mathematical Model of Oxygen Kinetics of Bidirectional Glenn Circulation. PMID- 29525195 TI - Advanced Age Attenuates Left Ventricular Filling Efficiency Quantified Using Vortex Formation Time: A Study of Octogenarians With Normal Left Ventricular Systolic Function Undergoing Coronary Artery Surgery. AB - OBJECTIVE: Blood flow across the mitral valve during early left ventricular (LV) filling produces a 3-dimensional rotational fluid body, known as a vortex ring, that enhances LV filling efficiency. Diastolic dysfunction is common in elderly patients, but the influence of advanced age on vortex formation is unknown. The authors tested the hypothesis that advanced age is associated with a reduction in LV filling efficiency quantified using vortex formation time (VFT) in octogenarians undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Observational study. SETTING: Veterans Affairs medical center. PARTICIPANTS: After institutional review board approval, octogenarians (n = 7; 82 +/- 2 year [mean +/- standard deviation]; ejection fraction 56% +/- 7%) without valve disease or atrial arrhythmias undergoing CABG were compared with a younger cohort (n = 7; 55 +/- 6 year; ejection fraction 57% +/- 7%) who were undergoing coronary revascularization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were monitored using radial and pulmonary arterial catheters and transesophageal echocardiography. Peak early LV filling (E) and atrial systole (A) blood flow velocities and their corresponding velocity-time integrals were obtained using pulse-wave Doppler echocardiography to determine E/A, atrial filling fraction (beta), and E wave deceleration time. Pulse-wave Doppler also was used to measure pulmonary venous blood flow during systole and diastole. Mitral valve diameter (D) was calculated as the average of major and minor axis lengths obtained in the midesophageal LV bicommissural and long-axis transesophageal echocardiography imaging planes, respectively. VFT was calculated as 4 * (1 - beta) * SV/(piD3), where SV is the stroke volume measured using thermodilution. Systemic and pulmonary hemodynamics, LV diastolic function, and VFT were determined during steady-state conditions 30 minutes before cardiopulmonary bypass. A delayed relaxation pattern of LV filling (E/A 0.81 +/- 0.16 v 1.29 +/- 0.19, p = 0.00015; beta 0.44 +/- 0.05 v 0.35 +/- 0.03, p = 0.0008; E wave deceleration time 294 +/- 58 v 166 +/- 28 ms, p < 0.0001; ratio of peak pulmonary venous systolic and diastolic blood flow velocity 1.42 +/- 0.23 v 1.14 +/- 0.20, p = 0.0255) was observed in octogenarians compared with younger patients. Mitral valve diameter was similar between groups (2.7 +/- 0.2 and 2.6 +/- 0.2 cm, respectively, in octogenarians v younger patients, p = 0.299). VFT was reduced in octogenarians compared with younger patients (3.0 +/- 0.9 v 4.5 +/ 1.2; p = 0.0171). An inverse correlation between age and VFT was shown using linear regression analysis (VFT = -0.0627 * age + 8.24; r2 = 0.408; p = 0.0139). CONCLUSION: The results indicate that LV filling efficiency quantified using VFT is reduced in octogenarians compared with younger patients undergoing coronary artery bypass grafting. PMID- 29525196 TI - Pharmacokinetics and Pharmacodynamics of Nebulized and Intratracheal Milrinone in a Swine Model of Hypercapnia Pulmonary Hypertension. AB - OBJECTIVES: Milrinone pulmonary administration is used currently for the treatment of pulmonary hypertension. Several methods are available: simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. The aim of this study was to explore the concentration effect relationship of milrinone for each of these methods. DESIGN: Observational open-label pharmacokinetic/pharmacodynamics cohort study. SETTING: Single-center, hospital animal laboratory. PARTICIPANTS: Twelve swine. INTERVENTIONS: After hypercapnia pulmonary hypertension, swine were administered equivalent inhaled milrinone doses of 15 or 50 ug/kg through simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. MEASUREMENTS AND MAIN RESULTS: Blood and urine samples were taken up to 360 minutes postadministration. The ratio of mean systemic arterial pressure to mean pulmonary arterial pressure was monitored continuously. Right heart echographies were taken before and after hypercapnia and after drug administration. Mean elimination half-lives were similar for the 4 administrations. Mean percent changes in the ratio were of 37 (60%), 18 (31%), 17 (36%), and 20 (20%), for simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization, respectively. Mean maximum plasma concentrations for intratracheal administrations were reached at 8 and 45 min for atomization and instillation, respectively. Significant increases in right atrial diameter and right ventricular end-diastolic area were witnessed during pulmonary hypertension as well as a return to baseline values after milrinone administration. CONCLUSIONS: The intratracheal methods, particularly intratracheal atomization, showed less hemodynamic effect than nebulizations and, in the case of intratracheal instillation, unpredictable drug exposure. Nebulization methods on the other hand, especially simple jet nebulization, suggest better efficacy and sensitivity but are less fit for emergency situations. PMID- 29525197 TI - Perioperative Management of Pregnant Women With Idiopathic Pulmonary Arterial Hypertension: An Observational Case Series Study From China. AB - OBJECTIVES: The mortality of pregnant women with idiopathic pulmonary arterial hypertension (PAH) is very high. There are limited data on the management of idiopathic PAH during pregnancy. The authors aimed to examine systematically the characteristics of parturient women with idiopathic PAH, to explore the adverse effects of idiopathic PAH on pregnancy outcomes, and to report the multidisciplinary perioperative management strategy from the largest comprehensive cardiac hospital in China. DESIGN: Observational case series study. SETTING: Tertiary referral acute care hospital in Beijing, China. PARTICIPANTS: The cases of 17 consecutive pregnant idiopathic PAH patients undergoing abortion or parturition at Anzhen Hospital were reviewed retrospectively. INTERVENTIONS: Preoperative characteristics, anesthesia method, intensive care management, PAH specific therapy, and maternal and neonatal outcomes were analyzed in this case series study. MEASURES AND MAIN RESULTS: Maternal and neonatal outcomes were the main measures. The mean ages of the 17 parturient women with idiopathic PAH were 28.3 +/- 5.4 years, and the mean systolic pulmonary arterial pressure was 97.9 +/ 18.6 mmHg. Fifteen patients (88.2%) received PAH-specific therapy before delivery, including sildenafil, iloprost, and treprostinil. All except 1 parturient received epidural anesthesia for surgery due to an emergency Caesarean section. Three patients experienced pulmonary hypertension crisis that necessitated conversion to general anesthesia. Ten parturients underwent Caesarean delivery at a median gestational age of 31 weeks. Three patients developed acute pulmonary hypertensive crisis intraoperatively. Two patients underwent cardiopulmonary resuscitation and extracorporeal membrane oxygenation support. The maternal mortality was 17.6% (3/17). Of the 10 delivered neonates, 9 (90.0%) survived. CONCLUSIONS: The maternal mortality of the idiopathic PAH parturient was high in this case series from China. The authors applied epidural anesthesia, early management with multidisciplinary approaches, PAH-specific therapy, avoidance of oxytocin, and timely delivery or pregnancy termination to improve maternal and neonatal outcomes. PMID- 29525198 TI - Prophylactic Intra-aortic Balloon Counterpulsation-Still Searching for Answers. PMID- 29525199 TI - SAM: An Unwelcome Guest in the OR. PMID- 29525200 TI - Early clinical results of total hip arthroplasty assessed with the 25-question Geriatric Locomotive Function Scale and muscle strength testing. AB - BACKGROUND: We think that it is necessary to evaluate whether the patient after total hip arthroplasty has achieved age-appropriate locomotor ability by improvement in hip joint function. The 25-question Geriatric Locomotive Function Scale (GLFS-25) have been determined age-specific standard values for the general population. The aim of this study was to compare postoperative hip muscle strength and functional performance at 3 months after THA with preoperative levels, and to compare the outcomes at 3 months after THA with the function of age-matched adults without hip disease. METHODS: The GLFS-25 scores and muscle strength were investigated before THA and 3 months after surgery in 12 men and 75 women who underwent total hip arthroplasty. RESULTS: The mean preoperative and postoperative GLFS-25 score was 55.4 and 19.1, respectively. With regard to the influence of age, the mean scores before and after THA were respectively 52.0 versus 18.2 for patients aged 60-69 years and 61.2 versus 17.3 for those aged 70 79 years in the normal/mild OA group. When female patients from the normal/mild OA group and the implant group classified into levels 4-7 after THA were combined (n = 15), their mean preoperative and postoperative straight leg raising (SLR) strength was 0.56 Nm/kg and 0.75 Nm/kg, respectively. On the other hand, the mean preoperative and postoperative SLR strength was respectively 0.54 Nm/kg and 0.86 Nm/kg for patients classified into levels 1-3 after THA (n = 45). CONCLUSION: Before THA, 90% of the patients who has severe hip disturbance were in need of nursing care (levels 4-7), while the percentage decreased to 30% after surgery. There was a difference of SLR muscle strength between the patients in levels 4-7 and those in levels 1-3 after THA, suggesting that achieving levels 1-3 postoperatively might depend on whether SLR muscle strength shows improvement. PMID- 29525201 TI - Glenohumeral joint translation and muscle activity in patients with symptomatic rotator cuff pathology: An ultrasonographic and electromyographic study with age matched controls. AB - OBJECTIVES: To determine whether patients with symptomatic rotator cuff pathology had more glenohumeral joint translation and different patterns of rotator cuff muscle activity compared to controls. DESIGN: Repeated measurements of glenohumeral translation and muscle activity in two positions and six testing conditions in two groups. METHODS: Twenty participants with a symptomatic and diagnosed rotator cuff tear and 20 age, and gender matched controls were included. Neuromuscular activity was tested by inserting intramuscular electrodes in the rotator cuff muscles. Anterior and posterior glenohumeral translations were measured using real time ultrasound in testing conditions (with and without translation force, with and without isometric internal and external rotation), in two positions (shoulder neutral, 90 degrees of abduction) and two force directions (anterior, posterior). RESULTS: Symptomatic pathology group demonstrated increased passive glenohumeral translation with posterior translation force (p<0.05). Overall, rotator cuff muscle contraction in the pathology group limited joint translation in a similar manner to the control group, but they did not show the normal direction specific pattern in the neutral posterior position (p<0.03). The pathology group demonstrated reduced EMG activity in the upper infraspinatus muscle relative to the reference position (p<0.02) with anterior translation force and in the supraspinatus (p<0.05) muscle with anterior and posterior translation force in the abducted position. CONCLUSIONS: Symptomatic pathology resulted in increased passive glenohumeral joint translation. Although there were some reductions in muscle activity with injury, their rotator cuff still controlled glenohumeral translation. These results highlight the need to consider joint translation in the assessment and management of patients with rotator cuff injury. PMID- 29525202 TI - A comparison of the acute physiological responses to BODYPUMPTM versus iso caloric and iso-time steady state cycling. AB - OBJECTIVES: Given apparent consumer interest in calorie counting and arguably inadequate understanding of the differential effects of exercise modality despite equivalent caloric expenditure, we sought to quantify and compare the acute physiological responses within and between a BODYPUMPTM (BP) group-fitness class and steady-state cycling (CARDIO), matched for caloric cost (iso-caloric) and time (iso-time). DESIGN: Acute cross-over study design. METHODS: Twelve healthy recreationally active females (30.1+/-5.8 years [mean+/-SD]) completed cardiorespiratory fitness and strength tests. Subsequently, BP and CARDIO were performed on separate days in randomized order, during which heart rate was monitored continuously, and rating of perceived exertion solicited. Blood samples were collected immediately pre- and post-trial and at 45min post-trial for determination of human growth hormone (HGH), interleukin 6 (IL-6), and cortisol. Lactate (BL) was determined from capillary blood. All outcome measures were analyzed for within-, and between-trial differences. RESULTS: HGH, IL-6 and BL were significantly elevated immediately post-trial for both BP and cycling; the elevation for HGH and BL was significantly greater for BP than CARDIO. IL6 remained elevated at 45min post-trial for both exercise modes, but there was no significant between trial difference. Mean heart rate for both trials was 68% of individually determined maximum heart rate, and predicted VO2 during BP was 14.9+/-5.2mlkgmin, or 46.7+/-19.4%VO2peak. Mean load self-selected by participants during BP ranged from 21+/-7%1RM to 32+/-9%1RM across four exercises. CONCLUSIONS: These results indicate that BP provided some more potent acute physiological effects than iso-caloric and iso-time steady-state cycling. PMID- 29525203 TI - Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions. AB - Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. Here, we make use of a framework that treats intracellular signal transduction networks as "black boxes" with characterized input-to-output response relationships. We study simple cell-to-cell communication circuit motifs and find conditions that generate bimodal responses in time, as well as mechanisms for independently controlling synchronization and delay of cell population responses. We apply our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. Our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps. PMID- 29525204 TI - A High-Throughput Mutational Scan of an Intrinsically Disordered Acidic Transcriptional Activation Domain. AB - Transcriptional activation domains are essential for gene regulation, but their intrinsic disorder and low primary sequence conservation have made it difficult to identify the amino acid composition features that underlie their activity. Here, we describe a rational mutagenesis scheme that deconvolves the function of four activation domain sequence features-acidity, hydrophobicity, intrinsic disorder, and short linear motifs-by quantifying the activity of thousands of variants in vivo and simulating their conformational ensembles using an all-atom Monte Carlo approach. Our results with a canonical activation domain from the Saccharomyces cerevisiae transcription factor Gcn4 reconcile existing observations into a unified model of its function: the intrinsic disorder and acidic residues keep two hydrophobic motifs from driving collapse. Instead, the most-active variants keep their aromatic residues exposed to the solvent. Our results illustrate how the function of intrinsically disordered proteins can be revealed by high-throughput rational mutagenesis. PMID- 29525206 TI - Colloid centrifugation of fresh semen improves post-thaw quality of cryopreserved dromedary camel spermatozoa. AB - Colloids have been successfully used in a number of species to improve sperm populations for IVF and for cryopreservation The usefulness of Single Layer Centrifugation (SLC) for freezing dromedary camel spermatozoa in two different extenders was evaluated by examining the motility, viability, acrosome status, DNA integrity, and ability of cryopreserved sperm to penetrate oocytes in vitro in a heterologus IVF system. Two ejaculates from each of five males were divided into four aliquots: two were processed by SLC (selected) while two were centrifuged without colloid (control). Pellets were cryopreserved in Green Buffer or INRA-96(r) containing 3% glycerol and evaluated at 0 and 1 h post thawed. The SLC improved post-thaw total and progressive motility at 0 (both P < 0.0001) and 1 (P < 0.001; P < 0.01, respectively) h, and STR (both P < 0.05) and BCF (both P < 0.001) at 0 h. Sperm viability and acrosome integrity (both P < 0.001) were improved at both time points. Sperm frozen in Green Buffer had greater total and progressive motilities at 0 (both P < 0.001) and 1 (both P < 0.001) h than INRA 96(r) samples. Spermatozoa in Green Buffer also had a greater VAP, VCL and VSL at 0 h and improved viability and acrosome integrity at 0 h (P < 0.05; P = 0.001, respectively) and 1 h (P < 0.05; P < 0.001, respectively). Viability of SLC spermatozoa was improved in Green Buffer at 1 h (P < 0.05). Oocyte penetration (P < 0.05) and pronuclear formation (P < 0.01) were greater with SLC-selected spermatozoa than non-selected spermatozoa, regardless of extender. No difference was observed between treatments or extenders in the mean number of spermatozoa per oocyte penetrated. The SLC spermatozoa had less (P < 0.01) DNA fragmentation compared to controls. The DNA fragmentation was moderately and negatively correlated with penetration (r = -0.4162; P = 0.02) and pronuclear formation (r = -0.3390; P < 0.01). In conclusion, colloid centrifugation of spermatozoa and cryopreservation in Green Buffer improves post thaw motility variables and IVF performance of dromedary camel spermatozoa. PMID- 29525205 TI - The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy. AB - Cancer chronotherapy, treatment at specific times during circadian rhythms, endeavors to optimize anti-tumor effects and to lower toxicity. However, comprehensive characterization of clock genes and their clinical relevance in cancer is lacking. We systematically characterized the alterations of clock genes across 32 cancer types by analyzing data from The Cancer Genome Atlas, Cancer Therapeutics Response Portal, and The Genomics of Drug Sensitivity in Cancer databases. Expression alterations of clock genes are associated with key oncogenic pathways, patient survival, tumor stage, and subtype in multiple cancer types. Correlations between expression of clock genes and of other genes in the genome were altered in cancerous versus normal tissues. We identified interactions between clock genes and clinically actionable genes by analyzing co expression, protein-protein interaction, and chromatin immunoprecipitation sequencing data and also found that clock gene expression is correlated to anti cancer drug sensitivity in cancer cell lines. Our study provides a comprehensive analysis of the circadian clock across different cancer types and highlights potential clinical utility of cancer chronotherapy. PMID- 29525207 TI - Comparative effects of zinc oxide, zinc oxide nanoparticle and zinc-methionine on hatchability and reproductive variables in male Japanese quail. AB - The objective was to examine the effect of different dietary zinc sources on reproduction of male Japanese quail. A total of 512 quail chicks (day-old) were divided into four groups with four replications for a period of 42 days. After this period, excess chicks were removed to attain the ratio of one male to three females and 16 quail in each subgroup. At 52 to 60 d of age, the eggs were collected and incubated. The basal diet (control) contained no zinc and the other three experimental diets were supplemented with 25 and 50 mg/kg zinc from zinc oxide (ZnO), zinc oxide nanoparticles (ZnONP) and zinc-methionine (Zn-Met) for 1 to 35 and 36 to 60 days, respectively. On day 42, two males from each replicate were euthanized. Males from the ZnO and Zn-Met treatments had an increase (P < 0.05) in seminiferous tubule diameters (STD) and germinal epithelium thickness (GET) compared with the control and ZnONP treatments. Cloacal gland index (CGI) was greatest (P < 0.05) for the Zn-Met compared with the other groups. Testosterone concentration was greater (P < 0.05) in the ZnO and Zn-Met compared with the other groups. Addition of Zn-Met to the diet enhanced (P < 0.05) fertility, hatchability and hatched chick weight compared with the other groups. Early and late embryonic death was greater (P < 0.05) in the control and ZnONP groups, respectively, compared with the other groups. This study indicated that supplementing diets with the Zn-Met source improves male Japanese quail reproductive performance and hatchability traits while zinc oxide nanoparticles have detrimental effects on male Japanese quail reproduction and reduces hatchability. PMID- 29525208 TI - Exogenous melatonin influences distribution of French Alpine buck spermatozoa in morphometrically distinct subpopulations during the non-breeding season. AB - The aim of this study was to establish subpopulations of spermatozoa in bucks using the principal component (PC) and cluster analysis according to morphometric head and tail variables, and to determine differences in proportions of subpopulations between exogenous melatonin-treated and control bucks. The bucks (n = 12) were assigned to two groups comprising six bucks each. By the end of March, four melatonin implants were inserted in the bucks in the experimental group. Semen was collected weekly using an artificial vagina from March to May (the non-breeding season). Analyses were performed in stained smears by SFORM computer-assisted program for eight head and five tail variables. The PC analysis revealed four components with the most important value for each (head outline, head ellipticity, mid-piece length and width). Cluster analysis indicated there were three subpopulations (average-sized spermatozoa- C_1; small and less elliptic - C_2; big and elliptic - C_3). Melatonin-treated bucks had a greater proportion of C_1 spermatozoa and a lesser proportion of C_2 spermatozoa during May (P < 0.05). To the best of our knowledge, this is the first study where PC and cluster analyses were performed on buck semen with head and tail variables analyzed together, in the same analysis, to evaluate spermatozoa population. Also, this is the first analysis of morphometric variables for assessing the influence of melatonin on spermatozoa subpopulations. The positive effect of melatonin on the proportions of spermatozoa in subpopulations could have been a consequence of the decreasing the proportion of the subpopulation with the least head and tail sizes and ellipticity. PMID- 29525209 TI - Could a bovine pregnancy rapid test be an alternative to a commercial pregnancy associated glycoprotein ELISA test in dairy cattle? AB - The aim of the present study was to compare a Bovine Pregnancy Rapid Test (Ubio quickVET; BPRT) with a commercial ELISA-PAG test (Bovine Pregnancy Test DG29(r)) for early pregnancy diagnosis based on the presence of the PAG (pregnancy associated glycoprotein) in dairy cattle between 30 and 40 days after artificial insemination (AI). Blood samples were collected from 212 cows between 30 and 40 days after artificial insemination (AI) to quantify the concentrations of PAG in each sample. Transrectal ultrasonography (TRUS) diagnosis of pregnancy was conducted at day 45 +/- 3 after AI as the reference standard for the two PAG tests. The results indicated the sensitivity (Se) of the BPRT and DG29 for diagnosing pregnant cattle were 89.4% and 100%, respectively while the specificity (Sp) of the two tests for diagnosis of non-pregnant animals was 89.8% and 81.3%, respectively. Based on these results, the BPRT has a slightly lesser sensitivity and greater specificity than the DG29 test. Moreover, the accuracy of both tests was 94% and 90% respectively for DG29 and BPRT. This implies that the BPRT test could be considered an accurate test when compared to PAG-ELISA test and TRUS at days 30-40 after AI. The BPRT test, therefore, can be used as an alternative to the PAG-ELISA test with some constraints that need to be considered with its use. PMID- 29525210 TI - Pediatric Vascular Access Peripheral IV Algorithm Success Rate. AB - PURPOSE: Determine if the pediatric peripheral vascular access algorithm (PPVAA) led to differences in first-attempt and overall peripheral intravenous (PIV) success, staff attempting PIV access per episode and overall attempts and first PIV attempt success by provider. DESIGN/METHODS: A two-cohort pre-/post implementation comparative design involved pediatric nurses and patients. The PPVAA included four components: a patient comfort plan, PIV grading score, nurses' self-assessed IV access capability and nurse decision to stop-the-line. Two sample t-test or Wilcoxon rank sum test and Pearson's chi-square test were used to evaluate differences between groups and measures. RESULTS: Healthcare providers (N=96) attempted 721 PIV insertions (pre-PPVAA, n=419 and post-PPVAA, n=302). Of 78 nurse providers, mean (SD) age was 37.4 (11.0) years and 20.0% self assessed PIV capability as expert. Of children, mean age was 8.3 (7.0) years. Post-PPVAA, first-attempt (p=0.86) and overall (p=0.21) success did not change, though fewer staff were needed per episode to initiate PIV; p=0.017. Overall rate of success after one attempt in the post-PPVAA period compared to pre-PPVAA was reduced (p=0.002), reflecting greater awareness to stop-the-line. Compared to pre PPVAA, advanced practice nurses and non-clinician providers were more likely to achieve success on first attempt. CONCLUSIONS: The PPVAA did not increase first attempt or overall PIV success; however, it decreased overall IV attempts and the number of staff attempting access per episode. PRACTICE IMPLICATIONS: The multi component PPVAA provided a guide for nurses during PIV and assisted decision making to stop attempts in difficult cases. PMID- 29525211 TI - Children's Early Disruptive Behavior Predicts Later Coercive Behavior and Binge Drinking by Mothers. AB - PURPOSE: We examined the prospective influence of early child problematic behavior on later coercive interactions and binge drinking by mothers. DESIGN AND METHODS: Canadian participants are from the Quebec Longitudinal Study of Child Development, born between spring 1997 and 1998, which allowed a longitudinal birth cohort design. At the 41months, 628 parents reported on children's oppositional, aggressive, turbulent, and inattentive/hyperactive behavior. Mothers then reported on their own coercive and binge drinking behavior at the 60month follow-up. RESULTS: We estimated a series of ordinary least-squares regressions to examine the relationship between early child behavior problems and later parental coercion and binge drinking, above and beyond many key pre existing/concurrent confounding factors including prior parenting stress and binge alcohol use. Oppositional, aggressive, and turbulent child behaviors at 41months predicted harsh, negative parenting at 60months. Early inattentive/hyperactive child behavior also forecasted later binge alcohol use by mothers within the same time frame. CONCLUSION: Negative preschool behavior predicted harsh, negative maternal behavior kindergarten entry. Early inattentive/hyperactive behavior also forecasted later binge alcohol use by mothers. Coercive parenting and alcohol use are clinically signs of adult distress. Such parents might use alcohol excessively because of its perceived stress-dampening effects and mental evasion from their life difficulties and frustration experiences. PRACTICE IMPLICATIONS: Problematic preschool behavior can lead to less effective child-rearing and unhealthy parental behavior. Such at risk mothers would benefit from professional caring practices. Practitioners can inspire change, especially using interaction interventions which encourage positive parent-child relations that, in turn, diminish parental distress. PMID- 29525212 TI - The Effect of High Fidelity Simulators on Knowledge Retention and Skill Self Efficacy in Pediatric Advanced Life Support Courses in a Rural State. AB - PURPOSE: Rural health care providers (HCPs) care for millions of Americans despite challenges. Pediatric Advanced Life Support (PALS) provides rural HCPs training in assessment and interventions for critically ill/injured pediatric patients (American Heart Association, 2015). The purpose of this study was to determine the effects of integration of high fidelity simulators into PALS courses in a rural setting. DESIGN AND METHODS: Participants were randomized by course to control or experimental PALS conditions where the control group received PALS with low fidelity static manikins (LFM) and the experimental group received PALS with high-fidelity simulators (HFS). Multiple level modeling (MLM) was used to examine participants time-to-task on pre-identified skills on PALS core case scenarios during testing on the last day of the course. MLM also was used to examine the differences in PALS knowledge and skills self-efficacy (SEI) between control and experimental groups at course end and six months later. RESULTS: The experimental and control groups had similar scores on the PALS post course knowledge exam, however the skill performance of the experimental group on time-to-task in core case scenarios was significantly better when compared to the control group (p=0.05). A decrease in knowledge exam scores and SEI scores occurred in both groups over time, however the control group had significantly greater declines in PALS written exam (p=0.042) and SEI (p=0.003). CONCLUSIONS AND PRACTICE IMPLICATIONS: Integration of HFS into PALS may increase HCPs' ability to recall valuable knowledge when seconds matter most. Further research in long-term recall of knowledge and retention of skills following PALS training is needed. PMID- 29525213 TI - No Evidence to Support Number of Clinical Hours Necessary for Nursing Competency. AB - INTRODUCTION: Direct patient care across the lifespan has been the standard for nursing clinical experiences over the past several years. Recently, the Ohio Board of Nursing ruled that 100% of pediatric clinical hours could be replaced with simulation. PURPOSE: Make a recommendation for the number of direct patient care clinical hours in pediatrics that are needed to meet the pediatric nursing competencies. METHOD: All fifty United States Boards of Nursing prelicensure nursing education requirements were reviewed to identify the number of required clinical hours and definitions for clinical experience. In addition, the Society of Pediatric Nurses members were surveyed to identify the number of direct pediatric clinical hours needed to achieve the Society of Pediatric Nurses pediatric pre-licensure competencies. RESULTS: Only ten states outline any requirements regarding the required number of clinical hours for prelicensure nursing education and twenty-six states incorporate language that defines clinical experiences. CONCLUSION: All prelicensure students take the standardized National Council Licensure Examination (NCLEX), therefore, a consensus among the state boards of nursing outlining the minimum number of clinical hours required to reach nursing competency is needed. PRACTICE IMPLICATIONS: Based on the survey results of the Society of Pediatric Nurses' members and expert opinion of the pediatric authors, a minimum of 61 to 80 clinical hours in direct care of pediatric patients is necessary for nursing students to meet the Society of Pediatric Nurses' recommended pediatric nursing content, obtain pediatric nursing competency, and be able to care for pediatric patients and their families. PMID- 29525214 TI - Reasons for Stopping Exclusive Breastfeeding Between Three and Six Months: A Qualitative Study. AB - PURPOSE: Scant published qualitative literature exists focusing on why exclusive breastfeeding rates decline between three and six months. This study aims to develop an understanding of why exclusive breastfeeding tails off so dramatically between three and six months after birth in New Zealand. DESIGN AND METHODS: A generic qualitative methodology was employed in this study and social constructionism selected as the main epistemological framework underpinning the research. This study was carried out between September 2013 and July 2014, involving face-to-face interviews with 30 women who were characterised as highly motivated to complete six months exclusive breastfeeding prior to the birth of their child. In order to gain an in-depth understanding of the research material, thematic analysis of the interview transcripts was completed using manual coding techniques. RESULTS: After thematic analysis of the data four key themes were identified: 1) The good employee/good mother dilemma. 2) Breastfeeding is lovely, but six months exclusively is demanding. 3) Exclusive breastfeeding recommendations should be individualised. 4) Introducing solids early as a cultural practice. CONCLUSIONS: Most studies have linked barriers to six months exclusive breastfeeding to difficulties within the mother-infant dyad, as well as negative maternal socioeconomic and socio-demographic characteristics. However, this study has shown that the maintenance of six months exclusive breastfeeding is also challenging for this group of mothers who were socially advantaged, well educated and highly motivated to breastfeed their babies exclusively for six months. PMID- 29525215 TI - Social Support Provision: Perspective of Fathers With Preterm Infants. AB - PURPOSE: Today's social support systems for parents of preterm infants tend to pay more attention to mothers than fathers. As a father also plays a critical role in caring for a preterm infant, there is a need to advance understanding of paternal concerns and needs about social supports that should better support fathers. DESIGN AND METHODS: Interviews were conducted with 18 parents of preterm infants (i.e., 10 mothers and 8 fathers) who have been discharged from the NICU to home. All interviews were audio-recorded and subsequently transcribed verbatim for analysis. RESULTS: The fathers' primary resources are healthcare professionals, their partners, and peer fathers of preterm infants. The fathers expressed various social support needs associated with informational, belonging, and emotional supports. CONCLUSIONS: It is recommended that a social support system be customized accordingly to better accommodate paternal needs. PRACTICE IMPLICATIONS: Healthcare professionals may refer to the study results in designing the educational materials for fathers of preterm infants. PMID- 29525216 TI - Multi-Site Comparison of Patient, Parent, and Pediatric Provider Perspectives on Transition to Adult Care in IBD. AB - PURPOSE: This multi-site study examines patient, parent, and pediatric provider perspectives on what is most important for successful transition. DESIGN AND METHODS: Using the Transition Readiness Assessment Questionnaire, 190 participants recruited from two pediatric IBD centers selected the top five skills they considered "most important for successful transition." Rankings were summarized and compared by group. RESULTS: While patients, parents, and clinicians all identified "calling the doctor about unusual changes in health" and "taking medications correctly and independently" as being important, each stakeholder group qualitatively and statistically differed in terms of transition readiness skills emphasized. Patients endorsed "calling the doctor about unusual changes in health" and "being knowledgeable about insurance coverage," as being most important to successful transition while parents emphasized health monitoring and problem solving. Pediatric providers emphasized adherence to treatment and reporting unusual changes in health. There were statistically significant differences in endorsement rates across participants for seven transition readiness skills. Patients agreed with providers 80% of the time and with their parents 40% of the time. Parent-provider agreement was 60%. CONCLUSIONS: Although there was some overlap across groups, areas of emphasis differed by informant. Patients emphasized skills they need to learn, parents emphasized skills they most likely manage for their children, and providers emphasized skills that directly impact their provision of care. PRACTICE IMPLICATIONS: Patient, parent, and provider beliefs all need to be considered when developing a comprehensive transition program. Failure to do so may result in programs that do not meet the needs of youth with IBD. PMID- 29525217 TI - Completeness of Human Papilloma Virus Vaccination: A Systematic Review. AB - PROBLEM: It has been reported that some adolescents and young women who started taking human papillomavirus (HPV) vaccination are not completing all three doses. The aim of this study was to systematically review intervention studies on HPV vaccination completion. ELIGIBILITY CRITERIA: Intervention studies with a comparison group that assessed HPV vaccination completion rate as the primary outcome variable in adolescents and adults younger than 26years of age, and published in English from 2006 to 2016, were eligible for review. SAMPLE: Five studies from a literature search of CINAHL, EMBASE, PsycARTICLES, PubMed, SCOPUS, and Web of Science databases were included in this review. RESULTS: The overall quality of the reviewed studies was moderate, and the studies have mainly been conducted in a high-income country. Intervention strategies were DVD-based education on HPV and reminders that were delivered via either electronic or non electronic methods. Some studies used fixed type of electronic reminders. Others chose preference-based electronic reminders, allowing participants to select one or two delivery options from e-mail, text message, automated telephone message, or Facebook message. Non-electronic reminders were letters sent by standard mail. CONCLUSIONS: The rates of HPV vaccination completeness increased with the interventions. However, the completeness rate of HPV vaccination remained unsatisfactory and lower than its initiation rate. IMPLICATIONS: Educational and reminder interventions for HPV vaccination could contribute to HPV vaccination completion. However, this review highlights the need for more high-quality studies to identify the best way to promote vaccination completion. PMID- 29525218 TI - Identification of caffeoylquinic acid derivatives as natural protein tyrosine phosphatase 1B inhibitors from Artemisia princeps. AB - Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1-10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC50 11.1 MUM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B. Furthermore, compound 3 showed remarkable selectivity against four homologous PTPs. According to these findings, compound 3 might be potentially valuable for further drug development. PMID- 29525219 TI - Design, synthesis and biological evaluation of spiropyrimidinetriones oxazolidinone derivatives as antibacterial agents. AB - Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5] hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome. PMID- 29525220 TI - Two new lathyrane-type diterpenoid glycosides with IL-6 production inhibitory activity from the roots of Euphorbia kansui. AB - As part of our ongoing search for anti-inflammatory compounds from higher plants, we isolated and elucidated two new diterpenoid glycosides, kansuingol A (1) and kansuingol B (2), from the roots of Euphorbia kansui. These structures were elucidated by extensive spectroscopic methods such as NMR and MS. Compounds were assessed for their IL-6 production inhibitory activity in PMA + A23187-stimulated HMC-1 cells. As a result, compounds 1 and 2 exerted inhibitory activities in the production of IL-6 with IC50 values of 2.96, and 1.94 MUM, respectively. Further, kansuingol A (1) decreased mRNA expressions of TNF-alpha and IL-6. PMID- 29525221 TI - 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus. AB - Herein, we report the synthesis and evaluation of 3-hydroxy-1,5-dihydro-2H-pyrrol 2-ones as antibacterial agents against methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE). Lead compound 38 showed minimum inhibitory concentrations (MICs) of 8 and 4 MUg/mL against MRSA and MRSE, respectively. Furthermore, compound 38 displayed a MIC of 8-16 MUg/mL against linezolid-resistant MRSA. These molecules, previously underexplored as antibacterial agents, serve as a new scaffold for antimicrobial development. PMID- 29525222 TI - Corrigendum to "Population genetic data of 38 insertion-deletion markers in South East Spanish population" [Forensic Sci. Int.: Genet. (2014) 236-238]. PMID- 29525223 TI - Lipoprotein-associated phospholipase A2 activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia. AB - BACKGROUND AND AIM: Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a key role in atherosclerosis development. It is considered a marker of increased risk of cardiovascular disease (CVD) and plaque vulnerability. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol and a higher prevalence of early CVD. Our aim was to evaluate the differences in Lp-PLA2 activity in a population of hypercholesterolemic patients with and without definite FH. METHODS AND RESULTS: Hypercholesterolemic patients were consecutively recruited. Definite FH was defined according to Dutch Lipid Clinic Network criteria >=8. All patients underwent routine clinical examination and biological assessments and Lp-PLA2 activity was measured in blood samples. Among 469 patients, 118 had a definite diagnosis of FH. Lp-PLA2 activity was significantly higher in definite FH patients compared to non-definite FH patients (206.5 +/- 54.5 vs. 180.8 +/- 48.4 nmol/min/mL, p < 0.0001). Lp-PLA2 positively correlated with total cholesterol, LDL-C and apolipoprotein B and negatively with HDL-C and apolipoprotein A-1. In multivariate analysis, definite FH diagnosis, LDL-C, HDL-C and statin treatment remained correlates of Lp-PLA2 independently of systolic blood pressure. CONCLUSIONS: Lp-PLA2 activity was higher in definite FH than in non-definite FH patients independently of LDL-C levels and statin treatment. These results highlight the particular phenotype of FH subjects among hypercholesterolemic patients. As increased Lp-PLA2 activity suggests, FH patients exhibit higher arterial inflammation that may contribute to their high cardiovascular risk. Our results reinforce the potential beneficial role of statins pleiotropic effects and the need for proper identification and treatment of FH patients. PMID- 29525224 TI - Redefining target omega-3 index levels: The Japan Public Health Center Study. PMID- 29525226 TI - An artificial bee colony optimization based matching pursuit approach for ultrasonic echo estimation. AB - Ultrasonic echo estimation is important in ultrasonic non-destructive evaluation and material characterization. Matching pursuit is one of the most popular methods for the purpose of estimating ultrasonic echoes. In this paper, an artificial bee colony optimization based matching pursuit approach (ABC-MP) is proposed specifically for ultrasonic signal decomposition by integrating the artificial bee colony algorithm into the matching pursuit method. The optimal atoms are searched from a continuous parameter space over a tailored Gabor dictionary in ABC-MP instead of a discrete parameter space in matching pursuit. As a result, echoes characterized by a set of physical parameters can be estimated accurately and efficiently. The performance of ABC-MP is tested using both simulated signals and real ultrasonic signals, and compared with matching pursuit. Results clearly demonstrate the superior performance of the proposed ABC MP approach over matching pursuit in ultrasonic echo estimation in terms of the shape and amplitude of the recovered echoes and the reconstructed signal, and the residue signal. PMID- 29525225 TI - Durability of protective effect of dulaglutide on pancreatic beta-cells in diabetic mice: GLP-1 receptor expression is not reduced despite long-term dulaglutide exposure. AB - AIMS: It is well-known that chronic exposure to large amounts of ligand leads to downregulation of its receptor. It is not known, however, whether a GLP-1R agonist downregulates its receptor. For this reason, our study examined whether GLP-1R expression is reduced after long-term exposure to dulaglutide (Dula) in non-diabetic and diabetic mice. METHODS: Seven-week-old male db/db and db/m mice were given either Dula (0.6mg/kg*2/week) or a control vehicle (CTL) for 17 weeks. Various metabolic parameters, such as glucose-stimulated insulin secretion (GSIS), insulin and TG content in islets, were evaluated after the intervention. beta-cell-related gene expression was also analyzed by real-time RT-PCR. RESULTS: In db/m mice, GLP-1R expression in beta-cells did not decrease, not even after long-term administration of Dula, compared with control mice, while GLP-1R expression in 24-week-old db/db mice treated with Dula was augmented, rather than downregulated, compared with 24-week-old CTL db/db mice. This was probably due to improved glycaemic control. In db/db mice treated with Dula, food intake and blood glucose levels were significantly decreased up to 24 weeks of age compared with CTL db/db mice, and their expression levels of various beta-cell-related genes, insulin content and GSIS were also enhanced. In contrast, oxidative and endoplasmic reticulum stress, inflammation, fibrosis and apoptosis were suppressed with Dula treatment. CONCLUSION: Dula exerts beneficial effects on glycaemic control and has long-lasting protective effects on pancreatic beta cells. GLP-1R expression levels were not reduced at all in non-diabetic as well as diabetic mice despite long-term dulaglutide exposure. PMID- 29525227 TI - Silicone-based composite materials simulate breast tissue to be used as ultrasonography training phantoms. AB - A silicone-based composite breast phantom is fabricated to be used as an education model in ultrasonography training. A matrix of silicone formulations is tracked to mimic the ultrasonography and tactile response of human breast tissue. The performance of two different additives: (i) silicone oil and (ii) vinyl terminated poly (dimethylsiloxane) (PDMS) are monitored by a home-made acoustic setup. Through the use of 75 wt% vinyl-terminated PDMS in two-component silicone elastomer mixture, a sound velocity of 1.29 +/- 0.09 * 103 m/s and an attenuation coefficient of 12.99 +/- 0.08 dB/cm-values those match closely to the human breast tissue-are measured with 5 MHz probe. This model can also be used for needle biopsy as well as for self-exam trainings. Herein, we highlight the fabrication of a realistic, durable, accessible, and cost-effective training platform that contains skin layer, inner breast tissue, and tumor masses. PMID- 29525228 TI - Editor's Perspectives - March 2018. PMID- 29525229 TI - Automated geometric optimization for robotic HIFU treatment of liver tumors. AB - BACKGROUND: High intensity focused ultrasound (HIFU) represents a non-invasive method for the destruction of cancerous tissue within the body. Heating of targeted tissue by focused ultrasound transducers results in the creation of ellipsoidal lesions at the target site, the locations of which can have a significant impact on treatment outcomes. Towards this end, this work describes a method for the optimization of lesion positions within arbitrary tumors, with specific anatomical constraints. MATERIALS & METHODS: A force-based optimization framework was extended to the case of arbitrary tumor position and constrained orientation. Analysis of the approximate reachable treatment volume for the specific case of treatment of liver tumors was performed based on four transducer configurations and constraint conditions derived. Evaluation was completed utilizing simplified spherical and ellipsoidal tumor models and randomly generated tumor volumes. The total volume treated, lesion overlap and healthy tissue ablated was evaluated. Two evaluation scenarios were defined and optimized treatment plans assessed. RESULTS: The optimization framework resulted in improvements of up to 10% in tumor volume treated, and reductions of up to 20% in healthy tissue ablated as compared to the standard lesion rastering approach. Generation of optimized plans proved feasible for both sub- and intercostally located tumors. CONCLUSIONS: This work describes an optimized method for the planning of lesion positions during HIFU treatment of liver tumors. The approach allows the determination of optimal lesion locations and orientations, and can be applied to arbitrary tumor shapes and sizes. PMID- 29525230 TI - Seroprevalence of Leptospirosis in Working Dogs. AB - Working dogs are canine animals that have been trained to assist human beings in carrying out various tasks. They help in guarding property, performing rescues, assisting the visually impaired or physically handicapped, searching for drugs, explosives, and others. Leptospirosis is one of the most widespread zoonotic diseases in the world and a commonly occurring disease of the tropics and subtropics. In Malaysia, all working dogs are normally vaccinated with serovars, Pomona, Icterohaemorrhagiae, Canicola, and Grippotyphosa based on protocols recommended from other countries. The duration of immunity in vaccinated dogs for Leptospira can last up to 13 months; however, there is no full crossprotection between the different serovars. Five representative canine units from different government agencies in Malaysia (n = 96 dogs) were recruited in this study. For detection, the microscopic agglutination test was performed by incubating the serum from dogs with various serovars of leptospires, namely, Icterohaemorrhagiae, Canicola, Pomona, Grippotyphosa, Australis, Bataviae, Javanica, Tarassovi, Hebdomadis, Lai, and Pyrogenes. The plasma obtained was used for polymerase chain reaction (PCR) analysis, for the detection of 16S rRNA, and lipL 32 genes of Leptospira. Out of the 96 dogs sampled, only 3 dogs were positive toward serovars, Australis, Bataviae, and Javanica, based on the cutoff point at 1:80. The seroprevalence of canine leptospirosis in this population was 3.1% (n = 3/96). However, all 96 blood samples of working dogs tested negative for both pathogenic and nonpathogenic Leptospira genes. The results revealed that, by vaccination alone, working dogs were not fully protected against leptospirosis and could pose a risk to dog handlers. A preventative and control protocol for leptospirosis is warranted, and its implementation should be monitored and improved accordingly from time to time, in order to maintain a healthy condition in both working dogs and their handlers. PMID- 29525231 TI - Effect of an Oral Joint Supplement When Compared to Carprofen in the Management of Hip Osteoarthritis in Working Dogs. AB - The goal of this study was to evaluate the effectiveness of an oral joint supplement in working dogs with hip osteoarthritis compared with a positive control group (CG). Fifteen animals were divided in treatment group (TG, n = 10) and CG (n = 5). To TG a commercially available joint supplement, containing glucosamine HCl, chondroitin sulphate, and hyaluronic acid was given for 40 days and a 70-day course of a placebo, to be administered as if it was carprofen. The CG received carprofen for 70 days, and a placebo to be administered as the joint supplement. Response to treatment, measured by the canine brief pain inventory (CBPI) and the Hudson visual analog scale, was evaluated before treatment (T0), after 15 days (T1) and 1 (T2), 2 (T3), 3 (T4), 4 (T5), and 5 (T6) months. With CBPI, no differences were found in pain interference score and pain severity score between TG and CG throughout or when comparing results within groups. Individual results were considered successful in a maximal of three dogs of the TG by T3 (30%) and 1 in CG (25%). With Hudson visual analog scale, improvements where registered with individual results, for 40%-50% of the animals in TG and 60%-80% of cases in CG. The oral joint supplement and carprofen produced some improvements in individual scores but where unable to do so when overall results were considered. Each of these options may not be able, by itself, to fully address the demands of a working dog with joint disease and related pain. PMID- 29525232 TI - Why Owners Choose an Orthosis Over Stifle Surgery for Canine Cranial Cruciate Ligament Deficiency. AB - The objective of this study was to describe the patient population of dogs with cranial cruciate ligament (CrCL) deficiency that were prescribed a stifle orthosis. A total of 215 client-owned dogs with previously diagnosed CrCL deficiency were prescribed a stifle orthosis at a veterinary pain management and mobility clinic. Patient intake data collected included dog signalment, chief medical complaint, home environment and activity description, medical and surgical history, and diagnosing veterinarian. An orthopedic examination was conducted to assess pelvic limb function and determine pelvic limb morphologic measures. Spayed females (57.2%) were most common in our sample. Median age, body weight, and body condition score were 9.00 +/- 3.23 years, 32.98 +/- 13.37kg, and 6.00 +/- 1.04, respectively. Most common breeds prescribed stifle orthoses included Labrador Retriever, Golden Retriever, and German Shepherd. Right and left limbs were equally affected, and 19.5% of dogs previously had stifle stabilization surgery. Primary reasons for seeking a stifle orthosis consultation were surgical concerns, advanced age, and surgery cost. Most common chief complaints included altered gait, decreased weight bearing, and pain following activity. Reduced stifle extension, increased cranial drawer score, and decreased 3-leg stance time characterized the CrCL-deficient stifle. Stifle orthosis represents an alternative approach to surgical stabilization and management of CrCL deficiency. CrCL-deficient dogs prescribed stifle orthoses were generally large breeds of advanced age with above ideal body condition score. Owners commonly sought a stifle orthosis for CrCL deficiency due to reservations regarding surgical management. PMID- 29525233 TI - Small Animal Massage Therapy: A Brief Review and Relevant Observations. AB - Massage therapy is becoming increasingly popular in human and animal physiotherapy and rehabilitation. Wider application of the technique led to research efforts aimed at providing scientific support to anecdotal beneficial effects, particularly pain relief. Recent studies have shown that massage therapy alters dopamine and serotonin levels, decreases noradrenaline levels, and modulates the immune system. Psychological effects such as reduction of stress and anxiety, with improvement of depressive patients, have been reported in humans. This article set out to review the major aspects of massage therapy based on recent publications on the topic, and to extrapolate concepts and practical aspects described in human physiotherapy to the veterinary patient, particularly the applicability of different techniques in Small Animal Medicine. Indications of massage therapy in small animals include pain relief, orthopedic rehabilitation, Canine Sports Medicine, intensive care, and management of nonspecific edema. Techniques described in this article were originally intended for use in humans and scientific data supporting anecdotal, beneficial effects in domestic animals are still lacking; this fruitful area for research is therefore open to veterinary professionals. PMID- 29525234 TI - Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Mini-Breed Puppy Associated With Aspiration Pneumonia. AB - A 3-month-old intact male Prague ratter was presented to the emergency service for evaluation of progressive lethargy, weakness, coughing and labour breathing after an episode of resistance to oral deworming. The patient exhibited depression, increased respiratory effort and cyanosis at initial presentation. Results of first diagnostic work-up (complete blood cell count, biochemistry panel and thoracic x-rays) were all consistent with aspiration pneumonia. The puppy was initially treated with balanced isotonic crystalloids, broad spectrum antibiotics, nebulization with thoracic coupage and was transferred to an infant incubator with a sustained FiO2 of 40-50%. Twenty-four hours after ICU admission the patient's condition suffered a worsening and the dog was orthopneic, severely depressed with episodes of intermittent dysphoria and seizuring. New thoracic radiographs and several samples of blood and urine were collected to go further in the diagnostic workup revealing severe hyponatremia, severe plasma hypotonicity, high natriuresis and metabolic acidosis with a worsening of the radiological pulmonary pattern. Based on these new clinical findings a diagnosis of SIADH was established. Emergency treatment with hypertonic 3% saline solution and loop diuretics was started like a sodium supplement and to inhibit water resorption in renal tubules, thus reducing the volume overload. The goal of this treatment was to achieve a progressive and controlled increase of plasma sodium concentration and promoting the excretion of positive body water imbalance. The patient's condition improved clinically over the following days, treatment was progressively discontinued and the dog was discharged 7 days after admission. To the author's knowledge this is the first report of a puppy younger than 12 weeks with respiratory distress developing SIADH associated to aspiration pneumonia. PMID- 29525235 TI - Optimising cost-effectiveness of freedom from disease surveillance-Bluetongue Virus Serotype 8 as an example. AB - The aim of this study was to propose a procedure for optimising the cost effectiveness of vector borne disease surveillance using a scenario tree model and cost-effectiveness analysis. The surveillance systems for Bluetongue Virus serotype 8 (BTV-8) implemented in Switzerland and Belgium were used as examples. In twenty four different, simulated population structures, passive surveillance and five designs of active surveillance were investigated. The influence of surveillance system design and parameters such as farmer disease awareness, veterinary disease awareness, herd and within-herd design prevalence on the overall surveillance system sensitivity were assessed. Furthermore, the cost effectiveness of mandatory and voluntary vaccination regimes in relation to disease surveillance was investigated. Under the assumption that BTV-8 manifests clinically, freedom from disease in a population can be established with almost certainty over the period of one year using clinical surveillance alone. Additional investment in active surveillance would therefore economically only be justified, if no clinical manifestation is suspected or other surveillance objectives are to be provided such as early detection. The best cost effectiveness is obtained by sampling more herds rather than more animals within a herd. Mandatory vaccination reduces the cost of surveillance by 0.26 ? per vaccine and voluntary vaccination only marginally reduces the cost of risk-based surveillance, by reducing the population at risk. Finally, in populations with predominantly dairy cattle, bulk-tank milk testing is the method of choice to actively demonstrate freedom from disease. PMID- 29525236 TI - Anodal transcranial direct current stimulation (tDCS) boosts dominant brain oscillations. PMID- 29525237 TI - Comparison of cortical responses to the activation of retina by visual stimulation and transcorneal electrical stimulation. AB - BACKGROUND: Electrical stimulation has been widely used in many ophthalmic diseases to modulate neuronal activities or restore partial visual function. Due to the different processing pathways and mechanisms, responses to visual and electrical stimulation in the primary visual cortex and higher visual areas might be different. This differences would shed some light on the properties of cortical responses evoked by electrical stimulation. OBJECTIVE: This study's goal was to directly compare the cortical responses evoked by visual and electrical stimulation and investigate the cortical processing of visual information and extrinsic electrical signal. METHODS: Optical imaging of intrinsic signals (OIS) was used to probe the cortical hemodynamic responses in 11 cats. Transcorneal electrical stimulation (TES) through an ERG-jet contact lens electrode was used to activate visual cortices. Full-field and peripheral drifting gratings were used as the visual stimuli. RESULTS: The response latency evoked by TES was shorter than that responding to visual stimulation (VS). Cortical responses evoked by VS were retinotopically organized, which was consistent with previous studies. On the other hand, the cortical region activated by TES was preferentially located in the secondary visual cortex (Area 18), while the primary visual cortex (Area 17) was activated by a higher current intensity. Compared with the full-field VS, the cortical response in Area 18 to TES with a current intensity above 1.2 mA was significantly stronger. CONCLUSION: According to our results, we provided some evidence that the cortical processing of TES was influenced by the distribution of the electrical field in the retina and the activating threshold of different retinal ganglion cells. PMID- 29525238 TI - Frequent methodological errors in clinical research. AB - Several errors that are frequently present in clinical research are listed, discussed and illustrated. A distinction is made between what can be considered an "error" arising from ignorance or neglect, from what stems from a lack of integrity of researchers, although it is recognized and documented that it is not easy to establish when we are in a case and when in another. The work does not intend to make an exhaustive inventory of such problems, but focuses on those that, while frequent, are usually less evident or less marked in the various lists that have been published with this type of problems. It has been a decision to develop in detail the examples that illustrate the problems identified, instead of making a list of errors accompanied by an epidermal description of their characteristics. PMID- 29525239 TI - Atezolizumab in Japanese Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis of the Phase 3 OAK Study. AB - INTRODUCTION: Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) agent, is effective and well tolerated in patients with pretreated advanced non-small-cell lung cancer (NSCLC). We assessed its efficacy and safety in Japanese patients through subgroup analyses of the phase 3 OAK study (NCT02008227). PATIENTS AND METHODS: Key eligibility criteria of this randomized, controlled, open-label, international study include locally advanced/metastatic NSCLC, >= 1 prior platinum-based chemotherapy, age >= 18 years, measurable disease (Response Evaluation Criteria in Solid Tumors v1.1), and Eastern Cooperative Oncology Group performance status 0 or 1. Atezolizumab 1200 mg or docetaxel 75 mg/m2 was provided intravenously every 3 weeks. Co-primary end points were overall survival (OS) in the intention-to-treat (ITT) population and those with >= 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC; TC1/2/3 or IC1/2/3). RESULTS: Sixty-four ITT patients were Japanese; 19 had TC1/2/3 or IC1/2/3 status. In Japanese ITT patients, median OS in the atezolizumab arm (n = 36) was longer than the docetaxel arm (n = 28; 21.3 months [95% confidence interval (CI), 11.0-not estimable (NE)] versus 17.0 months [95% CI, 12.5-NE], respectively; hazard ratio 0.80 [95% CI, 0.41-1.57]). In the TC1/2/3 or IC1/2/3 population, median OS was 21.3 months (95% CI, 15.0-NE) and NE in the atezolizumab (n = 11) and docetaxel (n = 8) groups, respectively (hazard ratio, 0.81 [95% CI, 0.22-3.05]). Atezolizumab was generally well tolerated, with no treatment-related deaths. CONCLUSION: Atezolizumab was effective and well tolerated in pretreated Japanese patients with NSCLC. Results are consistent with the primary analysis of OAK. PMID- 29525240 TI - Estimation of unmeasured ground reaction force data based on the oscillatory characteristics of the center of mass during human walking. AB - To enhance the wearability of portable motion-monitoring devices, the size and number of sensors are minimized, but at the expense of quality and quantity of data collected. For example, owing to the size and weight of low-frequency force transducers, most currently available wearable gait measurement systems provide only limited, if any, elements of ground reaction force (GRF) data. To obtain the most GRF information possible with a minimal use of sensors, we propose a GRF estimation method based on biomechanical knowledge of human walking. This includes the dynamics of the center of mass (CoM) during steady human gait resembling the oscillatory behaviors of a mass-spring system. Available measurement data were incorporated into a spring-loaded inverted pendulum with translating pivot. The spring stiffness and simulation parameters were tuned to match, as accurately as possible, the available data and oscillatory characteristics of walking. Our results showed that the model simulation estimated reasonably well the unmeasured GRF. Using the vertical GRF and CoP profile for gait speeds ranging from 0.93 to 1.89 m/s, the anterior-posterior (A P) GRF was estimated and resulted in an average correlation coefficient of R = 0.982 +/- 0.009. Even when the ground contact timing and gait speed information were alone available, our method estimated GRFs resulting in R = 0.969 +/- 0.022 for the A-P and R = 0.891 +/- 0.101 for the vertical GRFs. This research demonstrates that the biomechanical knowledge of human walking, such as inherited oscillatory characteristics of the CoM, can be used to gain unmeasured information regarding human gait dynamics. PMID- 29525241 TI - Continuous hypergravity alters the cytoplasmic elasticity of MC3T3-E1 osteoblasts via actin filaments. AB - Osteoblasts are sensitive to altered gravity conditions, displaying changes in RNA and protein expression, proliferation, and differentiation; however, the effect of hypergravity on the mechanical properties of osteoblasts remains unclear. In this study, atomic force microscopy (AFM) was used to evaluate the effect of hypergravity on the elasticity of osteoblasts. We demonstrate that a continuous hypergravitational environment increased the elasticity of the cytoplasm, but not the nuclei zone, of MC3T3-E1 osteoblasts. Actin filaments, but not microtubules, dominated in the increased elasticity. These findings provide new insights on cellular gravity-sensing mechanisms. PMID- 29525242 TI - Could lowering the tackle height in rugby union reduce ball carrier inertial head kinematics? AB - There is mounting evidence of reduced long-term cognitive ability in rugby players, even in those without a reported history of concussion. The tackle height law is an area of controversy. However, little is known about the effects of repetitive inertial head loading in rugby. Furthermore, the magnitude and influencing factors for head kinematics are generally unknown. In this exploratory study, 45 multibody front-on shoulder tackles simulated with the MADYMO pedestrian model and 20 staged rugby tackles executed by professional rugby players in a marker-based 3D motion laboratory were used to assess the effect of tackle height on ball carrier head kinematics. The peak resultant head linear accelerations, angular accelerations and change in angular velocities were measured and examined. The results suggest that tackle height strongly affects the head kinematics experienced by the ball carrier. In particular, higher ball carrier head kinematic values were identified for upper trunk tackles compared to mid/lower trunk tackles in both the multibody simulations and the staged rugby tackles. Average ball carrier peak resultant head linear acceleration, angular acceleration and change in angular velocity values for upper trunk tackles were greater than for mid/lower trunk tackles by a factor of 1.5, 2.5 and 1.7, in the multibody simulations, respectively, and 1.8 (p = 0.102), 2.2 (p = 0.025) and 2.3 (p = 0.004), in the staged tackles, respectively. The results of the study support the proposition of lowering the current tackle height laws to below the chest. PMID- 29525243 TI - Multiple functions of alpha-catenin beyond cell adhesion regulation. AB - alpha-Catenin is known to play a pivotal role in cell-cell adhesion as a cytoplasmic partner for the cadherin adhesion receptors that are essential for tissue organization. The action of cadherins to firmly connect cells together depends on alpha-catenin; without alpha-catenin, cells tend to disperse. Despite this established role of alpha-catenin in cell junction formation, evidence has accumulated that it also plays extra-junctional roles, regulating various cell behaviors such as cell motility and polarity. Moreover, alpha-catenin has also been detected in non-metazoan organisms that lack cadherins, suggesting that its ancient role may not be related to cell adhesion. This article provides an overview of recent findings of such cadherin-independent functions of alpha catenin, and discusses how these functions can be performed. PMID- 29525244 TI - An unusual case of posterior elbow dislocation with proximal radioulnar translocation. AB - We present a 9-year-old girl who suffered a posterior dislocation of the right elbow with a proximal translocation between the ulna and the radius. It is a type of exceptional dislocation which in our case was not accompanied by lesions of the joint surfaces of the elbow unlike most cases already published. This article stresses the importance of making an early diagnosis of this variety of dislocation; this is the best way to prevent it from going unnoticed. The use of Computed Tomography (CT) helped this early diagnosis, enabling an immediate closed orthopaedic reduction and achieving a cure without sequelae. PMID- 29525245 TI - Calciphylaxis. PMID- 29525246 TI - Evaluation and Management of Aortic Stenosis for the Emergency Clinician: An Evidence-Based Review of the Literature. AB - INTRODUCTION: Aortic stenosis is a common condition among older adults that can be associated with dangerous outcomes, due to both the disease itself and its influence on other conditions. OBJECTIVE: This review provides an evidence-based summary of the current emergency department (ED) evaluation and management of aortic stenosis. DISCUSSION: Aortic stenosis refers to significant narrowing of the aortic valve and can be caused by calcific disease, congenital causes, or rheumatic valvular disease. Symptoms of advanced disease include angina, dyspnea, and syncope. Patients with these symptoms have a much higher mortality rate than asymptomatic patients. Initial evaluation should include an electrocardiogram, complete blood count, basic metabolic profile, coagulation studies, troponin, brain natriuretic peptide, type and screen, and a chest radiograph. Transthoracic echocardiogram is the test of choice, but point-of-care ultrasound has been found to have good accuracy when a formal echocardiogram is not feasible. Initial management should begin with restoring preload and ensuring a normal heart rate, as both bradycardia and tachycardia can lead to clinical decompensation. For patients with high blood pressure and heart failure symptoms, nitrate agents may be reasonable, but hypotension should be avoided. Dobutamine can increase inotropy. For hypotensive patients, vasopressors should be used at the lowest effective dose. The treatment of choice is valve replacement, but extracorporeal membrane oxygenation and percutaneous balloon dilatation of the aortic valve have been described as temporizing measures. CONCLUSION: Aortic stenosis is an important condition that can lead to dangerous outcomes and requires prompt recognition and disease-specific management in the ED. PMID- 29525247 TI - American Tegumentary Leishmaniasis. PMID- 29525248 TI - The introduction of a midwife-led obstetric triage system into a regional referral hospital in Ghana. AB - OBJECTIVE: to introduce and embed a midwife-led obstetric triage system in a busy labour ward in Accra, Ghana to improve the quality of care and to reduce delay. DESIGN: the study utilized a participatory action research design. Local staff participated in baseline data collection, the triage training course design and delivery, and post-training monitoring and evaluation. SETTING: a regional referral hospital in Accra, Ghana undertaking 11,032 deliveries in 2012. PARTICIPANTS: all midwives and medical staff. MEASUREMENTS: measurements included maternal health outcomes, observations of labour ward activity, structured assessments of midwife actions during admission, waiting times, focus group discussions, and learning needs assessments which informed the course content. During training, two quality improvement tools were developed; coloured risk acuity wristbands and a one page triage assessment form. Participants measured compliance and accuracy in the use of these tools following course completion. FINDINGS: initially, no formal triage system was in place. The environment was chaotic with poor compliance to existing protocols. Sixty-two midwives received triage training between 2013 and 2014. Two Triage Champions became responsible for triage implementation, monitoring and further training. Following training, the 'in-charge' midwives recorded a cumulative average of 83.4% of women wearing coloured wristbands. A separate audit by the Triage Champions found that 495/535 (93%) of the wristbands were correctly applied based on the diagnosis. Quarterly monitoring of the triage assessment forms by Kybele trainers, showed that 92% recorded the risk acuity colour, 85% a 'working diagnosis' and 82% a 'plan.' Median (interquartile range) waiting times were reduced from 40 (15-100) to 29 (11-60) minutes (p = 007). Twenty of 25 of the staff reported that the wristbands were helpful. CONCLUSIONS: an interactive triage training course led to the development of a triage assessment form and the use of coloured patient wristbands which resulted in delay reduction and improved quality of maternity care. PMID- 29525249 TI - Prevalence and Predictive Value of Microvascular Flow Abnormalities after Successful Contemporary Percutaneous Coronary Intervention in Acute ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Although microvascular flow abnormalities have been observed following epicardial recanalization in acute ST-segment elevation myocardial infarction (STEMI), the prevalence and severity of these abnormalities in the current era of rapid percutaneous coronary intervention (PCI) has not been evaluated. The objective of this study was to assess microvascular perfusion (MVP) following successful primary PCI in patients with STEMI and how it affects clinical outcome. METHODS: In this single-center, retrospective study, 170 patients who successfully underwent emergent PCI for STEMI were assessed using real-time myocardial contrast echocardiography using a continuous infusion of intravenous commercial microbubbles (3% Definity). Three patterns of myocardial contrast replenishment were observed following intermittent high-mechanical index impulses: infarct zone replenishment within 4 sec (normal MVP), delays in contrast replenishment but normal plateau intensity (delayed MVP [dMVP]), and both delays in replenishment and reduced plateau intensity (microvascular obstruction [MVO]). Changes in left ventricular ejection fraction at 6 months and clinical event rate at 12 months (death, recurrent infarction, need for defibrillator placement, or heart failure admission) were compared. RESULTS: Normal MVP was seen in 62 patients (36%), dMVP in 49 (29%), and MVO in 59 (35%). Left anterior descending coronary artery infarct location was the only parameter independently associated with dMVP or MVO, independent of age, cardiac risk factors, door-to-dilation time, pre-PCI Thrombolysis In Myocardial Infarction flow grade, and thrombus burden. A dMVP pattern had a similar reduction in left ventricular ejection fraction as MVO at hospital discharge but had recovery of left ventricular ejection fraction at 6 months and a greater than fourfold lower event rate than the MVO group (P < .001). CONCLUSIONS: MVO and dMVP are frequently seen following contemporary successful PCI for STEMI, especially following left anterior descending coronary artery infarction. Despite a similar area at risk, a dMVP pattern has better functional recovery and clinical outcome than MVO. PMID- 29525250 TI - Right Ventricular Longitudinal Strain Reproducibility Using Vendor-Dependent and Vendor-Independent Software. AB - BACKGROUND: Right ventricular peak systolic longitudinal strain (RVLS) has emerged as an approach for quantifying right ventricular function in diseases such as pulmonary hypertension and congenital heart disease. A major limitation in applying RVLS is that strain imaging and analysis are proprietary, which may result in systematic differences from vendor to vendor. The goal of this study was to test the reproducibility of right ventricular strain analysis among selected vendor-specific software (VSS) and vendor-independent software (VIS) on images obtained from different ultrasound scanners, as would be common in clinical practice or in a multicenter clinical trial. METHODS: In this prospective, single-center study, 35 patients (5 healthy subjects and 30 with pulmonary hypertension) each underwent two echocardiographic scans, one using GE (Vivid E9) and the other using Philips (iE33) ultrasound systems. Images were analyzed using both VSS and VIS (TomTec) software for determination of RVLS. A repeated-measures analysis of variance was used to assess for any systematic differences among methods, as well as effects of scanner and software and a possible interaction between scanner and software for each strain measurement. RESULTS: Differences for global strains were not statistically significant among VSS packages (P >= .05), but some differences were noted between VSS and VIS. Wide variability between regional peak strain measurements was noted, but no systematic differences were found. CONCLUSIONS: Global RVLS values between VSS systems are not significantly different but may differ slightly from VIS. When comparing regional strain between VSS and VIS analyses, there is widespread variability without clear systematic differences. PMID- 29525252 TI - The revolution and evolution of mechanical valves: The ball has left the cage. PMID- 29525251 TI - Transapical simultaneous edge-to-edge neochord repair: A new way to manage bileaflet prolapse? PMID- 29525253 TI - To cut or not to cut: When is the pill mightier than the scalpel? PMID- 29525254 TI - Laser speckle flow graph-assisted sympathetic gangliectomy for treatment of facial blushing: Can technology aid psychology? PMID- 29525256 TI - Early-stage (cT2N0) esophageal cancer: Should induction therapy be a standard? PMID- 29525255 TI - Transapical transcatheter aortic valve replacement for aortic regurgitation with a second-generation heart valve. AB - OBJECTIVE: To report on the Chinese multicenter study of the J-Valve transcatheter heart valve for treatment of predominant aortic regurgitation. METHODS: Transapical transcatheter aortic valve replacement with the J-Valve for treating high-risk severe aortic regurgitation was performed in 43 patients in 3 Chinese centers. The study was registered with the Chinese Clinical Trial Registry (ChiCTR-OPC-15006354). Procedural results and clinical outcomes up to 1 year were analyzed using Valve Academic Research Consortium 2 criteria. RESULTS: All patients (mean age, 73.9 +/- 5.7 years) were considered at prohibitive or high risk for surgical valve replacement (logistic European System for Cardiac Operative Risk Evaluation, 20.0% to 44.4%; mean, 25.5% +/- 5.3%) after evaluation by an interdisciplinary heart team. Transapical implantation was successful in 42 patients (97.7%). The 1-year outcomes included all-cause mortality (4.7%), disabling stroke (2.3%), new permanent pacemaker (4.7%), and valve-related reintervention (7.0%). At the 1-year follow-up, postprocedural paravalvular regurgitation was none/trace in 30 of 39 patients and mild in 8 of 39 patients, and the mean transvalvular gradient after valve implantation was favorable at 10.4 +/- 4.5 mm Hg. CONCLUSIONS: After an initial demonstration of feasibility, this multicenter study shows that the J-Valve transcatheter heart valve system is a reasonable option for patients with predominant aortic regurgitation. PMID- 29525257 TI - Atrial fibrillation and coronary artery bypass grafting: The question is no longer why, but why not? PMID- 29525258 TI - One-year outcomes with the HeartMate 3 left ventricular assist device. AB - BACKGROUND: The HeartMate 3 (HM3; Abbott Laboratories, Lake Forest, Ill) left ventricular assist device (LVAD) received its Conformite Europeenne mark for Europe in October 2015 and is currently under investigation of the Food and Drug Administration to gain approval in the United States. Within this study, we present the first real-world experiences, 1-year outcomes, and adverse events of a single-center cohort treated with the HM3. METHODS: We prospectively studied midterm results of 27 consecutive patients receiving the HM3 at a single institution. After HM 3 implantation, survival, causes of death, and complications were recorded for all patients. Follow up was 100% complete. RESULTS: Twenty-seven patients were enrolled into the study. Within 1 year after HM3 implantation, 3 patients underwent heart transplantation and 3 patients died. Thirty-day survival was 88.9%, 6-month 85.2%, and 1-year survival 85.2%. No pump thrombosis and no strokes were observed within the study group. One incident of gastrointestinal bleeding was observed (3.7%). Right heart failure was diagnosed in 1 patient after HM3 implantation (3.7%). No technical complications of the pump were documented. No pump exchanges were necessary. The main complication was LVAD-related infection (22.2%). CONCLUSIONS: The novel LVAD HM3 has already shown excellent Conformite Europeenne mark trial results. Within this cohort, 1-year survival after HM3 implantation was 85%. The HM3 showed excellent midterm results with 0% stroke and 0% pump thrombosis rates 1 year after implantation. PMID- 29525259 TI - Powering the heart to recovery? PMID- 29525260 TI - Sympathetic ganglionectomy for facial blushing using application of laser speckle flow graph. AB - OBJECTIVE: Endoscopic thoracic sympathectomy at the second rib level is considered effective as a therapeutic treatment for facial blushing. However, 10% to 15% of patients do not benefit from this intervention. No additional procedure has been developed for this disorder. Recently, ganglionectomy using application of laser speckle flow graph has been evaluated for the treatment of compensatory sweating. We report our results of ganglionectomy for facial blushing as a redo surgery. METHODS: Between August 2012 and April 2017, 8 patients with facial blushing who underwent an initial sympathectomy reported symptom recurrence. Seven patients had undergone transection of the sympathetic trunk at the second rib and 1 patient had undergone transection of the sympathetic trunk at the second and third ribs. These patients were treated using ganglionectomy guided by application of laser speckle flow graph. After temporary decreases in facial skin blood perfusion were confirmed by stimulating the sympathetic ganglions, ganglionectomy was performed. RESULTS: All patients' symptoms improved. There were no side effects, including deterioration of compensatory sweating, worsening of gustatory sweating, or Horner syndrome. There were no cases of mortality or conversion to open surgery. CONCLUSIONS: This study shows the effectiveness of ganglionectomy for the treatment of facial blushing, representing a new treatment option for this condition. Considering the mechanism of facial blushing, it is important to recognize that ganglionectomy is effective after the interception of the sympathetic trunk on the cranial side. PMID- 29525261 TI - Postoperative outcomes in bariatric surgical patients participating in an insurance-mandated preoperative weight management program. AB - BACKGROUND: Many insurance companies require patient participation in a medically supervised weight management program (WMP) before offering approval for bariatric surgery. Clinical data surrounding benefits of participation are limited. OBJECTIVE: To evaluate the relationship between preoperative insurance-mandated WMP participation and postoperative outcomes in bariatric surgery patients. SETTING: Regional referral center and teaching hospital. METHODS: A retrospective review of patients who underwent vertical sleeve gastrectomy or Roux-en-Y gastric bypass between January 2014 and January 2016 was performed. Patients (N = 354) were divided into 2 cohorts and analyzed according to presence (n = 266) or absence (n = 88) of an insurance-mandated WMP requirement. Primary endpoints included rate of follow-up and percent of excess weight loss (%EWL) at postoperative months 1, 3, 6, and 12. All patients, regardless of the insurance mandated WMP requirement, followed a program-directed preoperative diet. RESULTS: The majority of patients with an insurance-mandated WMP requirement had private insurance (63.9%). Both patient groups experienced a similar proportion of readmissions and reoperations, rate of follow-up, and %EWL at 1, 3, 6, and 12 months (P = NS). Median operative duration and hospital length of stay were also similar between groups. Linear regression analysis revealed no significant improvement in %EWL at 12 months in the yes-WMP group. CONCLUSION: These data show that patients who participate in an insurance-mandated WMP in addition to completing a program-directed preoperative diet experience no significant benefit to rate of readmission, reoperation, follow-up, or %EWL up to 12 months postoperation. Our findings suggest that undergoing bariatric surgery without completing an insurance-mandated WMP is safe and effective. PMID- 29525262 TI - Bad words: why language counts in our work with bariatric patients. AB - Language is powerful. Our words convey our impressions, attitudes, and worldview. Language not only reflects, but also shapes, the way that we think. In the field of bariatric-metabolic surgery, it is critical for clinicians to choose our language thoughtfully. In this paper, we demonstrate the importance of language choices in our clinical work and our professional communications; explore the potential pitfalls of words and phrases commonly used in the field of obesity; and encourage the use of more productive language choices in our communications with patients and professional colleagues, both within and outside of our field. PMID- 29525263 TI - Modeling suture patterns for endoscopic gastrojejunostomy revision: Analyzing a technique to address weight regain after gastric bypass. AB - BACKGROUND: Weight regain after Roux-en-Y gastric bypass affects up to 30% of individuals. A dilated gastrojejunostomy contributes to regain through decreased restriction. Endoscopic gastrojejunostomy revision is a safe alternative to revisional surgery. There is evidence that technique affects outcome, but the mechanical properties of various sutured repairs have not been evaluated. OBJECTIVE: To compare different suture patterns for endoscopic gastrojejunostomy revision using an ex vivo porcine model. SETTING: University hospital, United States; surgical laboratory. METHODS: Gastrojejunostomoies were created between porcine stomach and a small intestine with a circular stapler. The gastrojejunostomy was revised with 1 of 5 suture patterns: simple-interrupted, vest-over-pants, figure-of-eight, purse-string, or hairpin. After revision, the stomachs were pressurized with water under continuous manometric monitoring. Failure pressure was recorded when either the hardware or the tissue became compromised. RESULTS: Procedure time, failure type, and pressure were recorded for 8 trials per pattern. Average failure pressures from lowest to highest were simple interrupted, vest-over-pants, figure-of-eight, purse-string, and hairpin. By analysis of variance, the failure pressures were different (P<.01). The suture anchor connection failed 16 times, the tissue tore 24 times, and failure pressure of the former was lower (P<.01). Failure pressure was moderately correlated with number of bites-per-suture. The purse-string pattern was the fastest to perform (P<.05). CONCLUSION: This study successfully used an ex vivo porcine model to compare performance of suture patterns used for endoscopic gastrojejunostomy revision. More bites-per-suture seems to improve durability by reducing tension on the suture-anchor. For this reason, the interrupted technique is inferior and should likely be abandoned in favor of patterns with more bites-per-suture. PMID- 29525264 TI - Engineering spheroids potentiating cell-cell and cell-ECM interactions by self assembly of stem cell microlayer. AB - Numerous methods have been reported for the fabrication of 3D multi-cellular spheroids and their use in stem cell culture. Current methods typically relying on the self-assembly of trypsinized, suspended stem cells, however, show limitations with respect to cell viability, throughput, and accurate recapitulation of the natural microenvironment. In this study, we developed a new system for engineering cell spheroids by self-assembly of micro-scale monolayer of stem cells. We prepared synthetic hydrogels with the surface of chemically formed micropatterns (squares/circles with width/diameter of 200 MUm) on which mesenchymal stem cells isolated from human nasal turbinate tissue (hTMSCs) were selectively attached and formed a monolayer. The hydrogel is capable of thermally controlled expansion. As the temperature was decreased from 37 to 4 degrees C, the cell layer detached rapidly (<10 min) and assembled to form spheroids with consistent size (~100 MUm) and high viability (>90%). Spheroidization was significantly delayed and occurred with reduced efficiency on circle patterns compared to square patterns. Multi-physics mapping supported that delamination of the micro-scale monolayer may be affected by stress concentrated at the corners of the square pattern. In contrast, stress was distributed symmetrically along the boundary of the circle pattern. In addition, treatment of the micro-scale monolayer with a ROCK inhibitor significantly retarded spheroidization, highlighting the importance of contraction mediated by actin stress fibers for the stable generation of spheroidal stem cell structures. Spheroids prepared from the assembly of monolayers showed higher expression, both on the mRNA and protein levels, of ECM proteins (fibronectin and laminin) and stemness markers (Oct4, Sox2, and Nanog) compared to spheroids prepared from low-attachment plates, in which trypsinized single cells are assembled. The hTMSC spheroids also presented enhanced expression levels of markers related to tri-lineage (osteogenic, chondrogenic and adipogenic) differentiation. The changes in microcellular environments and functionalities were double-confirmed by using adipose derived mesenchymal stem cells (ADSCs). This spheroid engineering technique may have versatile applications in regenerative medicine for functionally improved 3D culture and therapeutic cell delivery. PMID- 29525265 TI - Injectable and detachable heparin-based hydrogel micropatches for hepatic differentiation of hADSCs and their liver targeted delivery. AB - A micropatterned heparin-based hydrogel system that can provide sustained release of multiple growth factors upon one time loading was prepared via photopolymerization and lithography and it was employed as a culture matrix for differentiating hADSCs into hepatic lineage. Mature differentiation of hADSCs into hepatic lineage in terms of gene expression and immunofluorostaining of hepatic markers, and functional characteristics such as glycogen storage ability and production of albumin and urea was observed on the soft hydrogel (~400 Pa) when the gel elasticity was modulated. This optimal heparin-based hydrogel was used to prepare micropatches containing hepatic-differentiated cells by 1) micropatterning of the gel on a polyelectrolyte multilayer (PEM), 2) seeding of hADSCs and inducing hepatic differentiation, and 3) electrochemical retrieval of cell-attached micropatches. Upon i.v. injection, the retrieved cell micropatches showed a prolonged retention in the liver and promoted function compared to single cell injection in a rat model. In conclusion, this injectable and detachable miropatterned heparin-based hydrogel system could serve as a total platform for the stem cell differentiation under well-controlled microenvironment in vitro and for targeted delivery of the differentiated cells in vivo. PMID- 29525266 TI - Assessing the influence of a passive, upper extremity exoskeletal vest for tasks requiring arm elevation: Part II - "Unexpected" effects on shoulder motion, balance, and spine loading. AB - Adopting a new technology (exoskeletal vest designed to support overhead work) in the workplace can be challenging since the technology may pose unexpected safety and health consequences. A prototype exoskeletal vest was evaluated for potential unexpected consequences with a set of evaluation tests for: usability (especially, donning & doffing), shoulder range of motion (ROM), postural control, slip & trip risks, and spine loading during overhead work simulations. Donning/doffing the vest was easily done by a wearer alone. The vest reduced the max. shoulder abduction ROM by ~10%, and increased the mean center of pressure velocity in the anteroposterior direction by ~12%. However, vest use had minimal influences on trip-/slip-related fall risks during level walking, and significantly reduced spine loadings (up to ~30%) especially during the drilling task. Use of an exoskeletal vest can be beneficial, yet the current evaluation tests should be expanded for more comprehensiveness, to enable the safe adoption of the technology. PMID- 29525267 TI - Are gestures worth a thousand words? Verbal and nonverbal communication during robot-assisted surgery. AB - Communication breakdowns in the operating room (OR) have been linked to errors during surgery. Robot-assisted surgery (RAS), a new surgical technology, can lead to new challenges in communication owing to the remote location of the surgeon away from the patient and bedside assistants. Nevertheless, few studies have studied communication strategies during RAS. In this study, 11 robot-assisted radical prostatectomies were recorded and the interaction events between the surgeon and two bedside surgical team members were categorized by modality (verbal/nonverbal), topic, and pair (sender and receiver). Both verbal and nonverbal modalities were used by all pairs. The percentage of nonverbal interactions differed significantly by pair: 66% for the Surgeon-Physician Assistant, 50% for the Physician Assistant-Scrub Nurse, and 25% for the Surgeon Scrub Nurse, indicating different communication strategies across pairs. In addition, there was a significant dependence between topic and the percentages of verbal and nonverbal events for all pairs. Strategies to improve team communication during RAS should take into account the use of verbal and nonverbal communication means and the variation in interaction strategies based on the topic of communication. PMID- 29525269 TI - Fusarium riograndense sp. nov., a new species in the Fusarium solani species complex causing fungal rhinosinusitis. AB - Invasive fusariosis has a high mortality and is predominantly observed in patients with leukemia. We report the first case of a novel species of Fusarium, Fusarium riograndense sp. nov, isolated from a lesion in the nasal cavity lesion of a patient with acute lymphoblastic leukemia. The etiological agent was identified by Multilocus Sequencing Typing (MLST), including RPB2, TEF-1alpha, and ITS-LSU sequences, the gold standard technique to identify new species of Fusarium. MLST and phenotypic data strongly supported its inclusion in the F. solani species complex (FSSC). The new species produced a red pigment in the Sabouraud Dextrose Agar similar to other members of the complex. The macroconiodia developed from phialides on multibranched conidiophores which merge to form effuse sporodochia with a basal foot-cell instead of papilla in basal cell shape. The microconidia were ellipsoidal, 0-1-septated, produced from long monophialides. Chlamydospores were produced singly or in pairs. Amphotericin B (MIC 1MUg/mL) was the most active drug, followed by voriconazole (MIC 8MUg/mL). The patient was successfully treated with voriconazole. Our findings indicate another lineage within FSSC capable causing of invasive human infection. PMID- 29525268 TI - Assessing the influence of a passive, upper extremity exoskeletal vest for tasks requiring arm elevation: Part I - "Expected" effects on discomfort, shoulder muscle activity, and work task performance. AB - Use of exoskeletal vests (designed to support overhead work) can be an effective intervention approach for tasks involving arm elevation, yet little is known on the potential beneficial impacts of their use on physical demands and task performance. This laboratory study (n = 12) evaluated the effects of a prototype exoskeletal vest during simulated repetitive overhead drilling and light assembly tasks. Anticipated or expected benefits were assessed, in terms of perceived discomfort, shoulder muscle activity, and task performance. Using the exoskeletal vest did not substantially influence perceived discomfort, but did decrease normalized shoulder muscle activity levels (e.g., <= 45% reduction in peak activity). Drilling task completion time decreased by nearly 20% with the vest, but the number of errors increased. Overall, exoskeletal vest use has the potential to be a new intervention for work requiring arm elevation; however, additional investigations are needed regarding potential unexpected or adverse influences (see Part II). PMID- 29525270 TI - Evaluation of murine lung epithelial cells (TC-1 JHU-1) line to develop Th2 promoting cytokines IL-25/IL-33/TSLP and genes Tlr2/Tlr4 in response to Aspergillus fumigatus. AB - OBJECTIVE: The aims of this study were to determine the role of live and heat killed Aspergillus fumigatus conidia in releasing interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP) and to express Toll-like receptor (Tlr)2 and Tlr4 genes. MATERIALS AND METHODS: Murine lung epithelial cells were incubated with live and heat-killed A. fumigatus conidia at 37 degrees C for 6, 24 and 48h. After treatments, ELISA was performed to measure the concentrations of IL-25, IL 33 and TSLP in the supernatants. Quantitative real-time PCR (qPCR) was performed to assess the expression levels of Tlr2 and Tlr4 genes. RESULTS: The concentrations of IL-25 and IL-33 significantly increased after exposure to live and heat-killed conidia for various times when compared with untreated control (P<0.05). The secretion of TSLP at different concentrations of heat-killed conidia was significantly higher than both live conidia and untreated control (P<0.05). qRT-PCR results indicated a up-regulation from 1.08 to 3.60-fold for Tlr2 gene expression and 1.20 to 1.80-fold for Tlr4 gene expression exposed to heat-killed conidia. CONCLUSION: A. fumigatus has a potential ability to stimulate murine lung epithelial cells to produce IL-25/IL-33/TSLP, as well as to express Tlr2/Tlr4 genes, indicating an important role of lung epithelial cells in innate immune responses to A. fumigatus interaction. PMID- 29525271 TI - The (un)habitual geographies of Social Anxiety Disorder. AB - This article investigates experiences of Social Anxiety Disorder ('social anxiety') with reference to recent geographical debates on habit. It considers how habit simultaneously captures (un)reflective modes of being in the world and the foreboding disruptive capacity of uncertainty as people attempt to adapt to, negotiate and manage everyday life with social anxiety. Drawing on lived accounts from online questionnaires and online interviews with people diagnosed, or self diagnosing, with social anxiety, it uncovers the relational and embodied practices-and the inherent spatialities of such practices-that enable individuals to (re)gain control of their socio-spatial surroundings. It also considers the capacity for habits to become disrupted and displaced through pervasive anxieties and persistent rumination and anticipation, situated within the context of participants' everyday lives. This analysis highlights the social, spatial and temporal dimensions of socially anxious experiences. Overall, by interpreting lived experience in this way, this article introduces a socio-spatial dynamic to otherwise extremely limited accounts of social anxiety found outside of the dominant biomedical framework. PMID- 29525272 TI - Bracing of pectus carinatum: A quantitative analysis. AB - BACKGROUND/PURPOSE: Primary treatment of pectus carinatum (PC) is performed with an external brace that compresses the protrusion. Patients are 'prescribed' a brace tightening force. However, no visual guides exist to display this force magnitude. The purpose of this study was to determine the repeatability of patients in applying their prescribed force over time and to determine whether the protrusion stiffness influences the patient-applied forces and the protrusion correction rate. METHODS: Twenty-one male participants (12-17years) with chondrogladiolar PC were recruited at the time of brace fitting. Participants were evaluated on three visits: fitting, one month postfitting, and two months postfitting. Differences between prescribed force and patient-applied force were evaluated. Relationships of patient-applied force and correction rate with protrusion stiffness were assessed. RESULTS: Majority of individuals followed for two months (75%) had a significantly different patient-applied force (p<0.05) from their prescribed force. Protrusion stiffness had a positive relationship with patient-applied force, but no relationship with correction rate. CONCLUSION: Patients did not follow their prescribed force. Magnitudes of these differences require further investigation to determine clinical significance. Patient-applied forces were influenced by protrusion stiffness, but correction rate was not. Other factors may influence these variables, such as patient compliance. LEVEL OF EVIDENCE: Treatment Study - Level IV. PMID- 29525273 TI - Appropriate use of total parenteral nutrition in children with perforated appendicitis. AB - BACKGROUND: Total parenteral nutrition (TPN) is often used in children with perforated appendicitis, despite the absence of clear indications. We assessed the validity of specific clinical indications for initiation of TPN in this patient cohort. METHODS: Data were gathered prospectively on duration of nil per os (NPO) status and TPN use in a cohort of children treated under a perforated appendicitis protocol during a 19-month period. TPN was started in the immediate postoperative period in patients who had generalized peritonitis and severe intestinal dilatation at operation, or later per the discretion of the attending surgeon. At discharge, TPN was considered to have been used appropriately, according to consensus guidelines, if the patient was NPO>=7days or received TPN>=5days. RESULTS: During the study period, TPN was initiated in 31 (25.4%) of 122 patients operated for perforated appendicitis. Sixteen (51.6%) received TPN per operative finding indications and 15 (48.4%) for prolonged ileus. The operative indications demonstrated 47% sensitivity, 86% specificity, a positive predictive value (PPV) of 35%, and a negative predictive value (NPV) of 91%, when adherence to TPN consensus guidelines was considered the gold standard. CONCLUSION: Patients without severe intestinal dilatation and generalized peritonitis at operation should not be placed on TPN in the immediate postoperative period. Refinement of selection criteria is necessary to further decrease inappropriate TPN use in children with perforated appendicitis. TYPE OF STUDY: Diagnostic Test. LEVEL OF STUDY: II. PMID- 29525274 TI - Emergency pediatric surgery: Comparing the economic burden in specialized versus nonspecialized children's centers. AB - BACKGROUND: The American College of Surgeons has developed a verification program for children's surgery centers. Highly specialized hospitals may be verified as Level I, while those with fewer dedicated resources as Level II or Level III, respectively. We hypothesized that more specialized children's centers would utilize more resources. STUDY DESIGN: We performed a retrospective study of the Maryland Health Services Cost Review Commission (HSCRC) database from 2009 to 2013. We assessed total charge, length of stay (LOS), and charge per day for all inpatients with an emergency pediatric surgery diagnosis, controlling for severity of illness (SOI). Using published resources, we assigned theoretical level designations to each hospital. RESULTS: Two hospitals would qualify as Level 1 hospitals, with 4593 total emergency pediatric surgery admissions (38.5%) over the five-year study period. Charges were significantly higher for children treated at Level I hospitals (all P<0.0001). Across all SOI, children at Level I hospitals had significantly longer LOS (all P<0.0001). CONCLUSION: Hospitals defined as Level II and Level III provided the majority of care and were able to do so with shorter hospitalizations and lower charges, regardless of SOI. As care shifts towards specialized centers, this charge differential may have significant impact on future health care costs. LEVEL OF EVIDENCE: Level III Cost Effectiveness Study. PMID- 29525275 TI - A 15-long non-coding RNA signature to improve prognosis prediction of cervical squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs), which have little or no protein-coding capacity, caught a particular interest since their potential roles in the cancer paradigm. As the most common cancer in women, cervical squamous cell carcinoma remains one of the leading causes of deaths from cancer. However, limited evidence is available to determine the role of lncRNAs in the prognosis of cervical squamous cell carcinoma. In this study, we collected lncRNA expression profiling to identify prognosis related lncRNAs for cervical squamous cell carcinoma from TCGA database. In addition, we developed a 15-lncRNA signature based risk score to comprehensively assess the prognostic function of lncRNA. Furthermore, we performed a ROC analysis to identify the optimal cut-off point for classification risk level of the patients. Univariate Cox regression models were used to assess the association between lncRNAs and prognosis of patients with cervical squamous cell carcinoma. A 15-lncRNA based risk score was developed based on the Cox co efficient of the individual lncRNAs. The prognostic value of this risk score was validated in the complete set and internal testing set. In summary, a 15-lncRNA expression signature (BAIAP2-AS1, RP11-203J24.8, LINC01133, RP1-7G5.6, RP11 147L13.15, SERHL, CTC-537E7.3, RP11-440L14.1, RP11-131N11.4, ILF3-AS1, RP11 80H18.4, RP11-1096G20.5, CTD-2192J16.26, RP11-621L6.3, and RP11-571M6.18) were identified and validated which can predict cervical cancer patient survival. The potential functions of this 15-lncRNA expression signature and individual lncRNAs as prognostic targets of cervical cancer were revealed by this study. Furthermore, these findings may have important implications in the understanding of the potential therapeutic method for the cervical squamous cell carcinoma patients. PMID- 29525276 TI - Meigs to modern times: The evolution of debulking surgery in advanced ovarian cancer. AB - Joe V. Meigs was a visionary clinician and an early adopter of radical techniques in the surgical treatment of ovarian cancer. His 1934 textbook "Tumors of the Female Pelvic Organs", consolidated his approach to this "hopeless" disease, with pearls on diagnosis, outcomes, and even speculations about the benefits of minimally invasive surgery. Decades before adjuvant chemotherapy would prove of value, and in an era when sophisticated statistics were unheard of, he nonetheless tried to eke out what benefits he could using the methods available in his time. We transition his original findings and observations through the advent of platinum-based chemotherapy, retrospective cohort studies supporting the benefits of primary debulking, and finally the long-awaited randomized controlled trial. We aim to provide historical context for the underpinnings of how cytoreductive surgery has evolved into its current role in the treatment of advanced ovarian cancer. PMID- 29525277 TI - Assessment of the safety of Bacillus Calmette-Guerin vaccine administered orally to badgers (Meles meles). AB - European badgers (Meles meles) are a wildlife reservoir for Mycobacterium bovis (M. bovis) in parts of England, Wales and Ireland, constituting a potential source of tuberculosis (TB) infection for cattle. Vaccination of badgers against TB is one of the tools available for helping reduce the prevalence of bovine TB in badgers, made possible by the licensing in 2010 of Bacillus Calmette-Guerin (BCG) vaccine for intramuscular administration to badgers (BadgerBCG). However, practical limitations associated with administering an injected vaccine to wild animals make an oral, bait-delivered form of the vaccine highly desirable. Evaluation of the safety of oral BCG to badgers and the environment is a mandatory step on the road to licensing an oral vaccine. This study had the following objectives: (a) to determine whether adverse effects followed the oral administration of BCG vaccine to badgers; (b) to measure the quantity and frequency of BCG excreted in the faeces of vaccinated badgers; and (c) to assess whether there was evidence of the vaccine spreading to unvaccinated, 'sentinel' badgers sharing the same environment as vaccinated animals. We report here that the oral administration per badger of >=6.4 * 109 cfu BCG, followed 14 days later by a single oral dose of >=6.4 * 107 cfu BCG caused no adverse physical effects and did not affect the social behaviour and feeding habits of the vaccinated animals. BCG was cultured from the faeces of two of nine vaccinated animals (372 cfu/g and 996 cfu/g, respectively) approximately 48 h after the higher dose of BCG was administered and by one of the nine vaccinated animal (80 cfu/g) approximately 24 h after receiving the lower dose of BCG. We found no evidence for the transmission of BCG to unvaccinated, sentinel, badgers housed with the vaccinated animals despite the occasional excretion of BCG in faeces. PMID- 29525278 TI - African horse sickness virus (AHSV) with a deletion of 77 amino acids in NS3/NS3a protein is not virulent and a safe promising AHS Disabled Infectious Single Animal (DISA) vaccine platform. AB - African horse sickness virus (AHSV) is a virus species in the genus Orbivirus of the family Reoviridae. Currently, nine serotypes have been defined showing limited cross neutralization. AHSV is transmitted by species of Culicoides biting midges and causes African Horse Sickness (AHS) in equids with a mortality up to 95% in naive domestic horses. AHS has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates are competent vectors of closely related bluetongue virus. AHS outbreaks cause huge economic losses in developing countries. In the developed world, outbreaks will result in losses in the equestrian industry and will have an enormous emotional impact on owners of pet horses. Live-attenuated vaccine viruses (LAVs) have been developed, however, safety of these LAVs are questionable due to residual virulence, reversion to virulence, and risk on virulent variants by reassortment between LAVs or with field AHSV. Research aims vaccines with improved profiles. Reverse genetics has recently being developed for AHSV and has opened endless possibilities including development of AHS vaccine candidates, such as Disabled Infectious Single Animal (DISA) vaccine. Here, virulent AHSV5 was recovered and its high virulence was confirmed by experimental infection of ponies. 'Synthetically derived' virulent AHSV5 with an in-frame deletion of 77 amino acids codons in genome segment 10 encoding NS3/NS3a protein resulted in similar in vitro characteristics as published NS3/NS3a knockout mutants of LAV strain AHSV4LP. In contrast to its highly virulent ancestor virus, this deletion AHSV5 mutant (DISA5) was completely safe for ponies. Two vaccinations with DISA5 as well as two vaccinations with DISA vaccine based on LAV strain AHSV4LP showed protection against lethal homologous AHSV. More research is needed to further improve efficacy, to explore the AHS DISA vaccine platform for all nine serotypes, and to study the vaccine profile in more detail. PMID- 29525279 TI - Assessment of temporally-related acute respiratory illness following influenza vaccination. AB - BACKGROUND: A barrier to influenza vaccination is the misperception that the inactivated vaccine can cause influenza. Previous studies have investigated the risk of acute respiratory illness (ARI) after influenza vaccination with conflicting results. We assessed whether there is an increased rate of laboratory confirmed ARI in post-influenza vaccination periods. METHODS: We conducted a cohort sub-analysis of children and adults in the MoSAIC community surveillance study from 2013 to 2016. Influenza vaccination was confirmed through city or hospital registries. Cases of ARI were ascertained by twice-weekly text messages to household to identify members with ARI symptoms. Nasal swabs were obtained from ill participants and analyzed for respiratory pathogens using multiplex PCR. The primary outcome measure was the hazard ratio of laboratory-confirmed ARI in individuals post-vaccination compared to other time periods during three influenza seasons. RESULTS: Of the 999 participants, 68.8% were children, 30.2% were adults. Each study season, approximately half received influenza vaccine and one third experienced >=1 ARI. The hazard of influenza in individuals during the 14-day post-vaccination period was similar to unvaccinated individuals during the same period (HR 0.96, 95% CI [0.60, 1.52]). The hazard of non-influenza respiratory pathogens was higher during the same period (HR 1.65, 95% CI [1.14, 2.38]); when stratified by age the hazard remained higher for children (HR 1.71, 95% CI [1.16, 2.53]) but not for adults (HR 0.88, 95% CI [0.21, 3.69]). CONCLUSION: Among children there was an increase in the hazard of ARI caused by non-influenza respiratory pathogens post-influenza vaccination compared to unvaccinated children during the same period. Potential mechanisms for this association warrant further investigation. Future research could investigate whether medical decision-making surrounding influenza vaccination may be improved by acknowledging patient experiences, counseling regarding different types of ARI, and correcting the misperception that all ARI occurring after vaccination are caused by influenza. PMID- 29525280 TI - Vaccination of sheep with Quil-A(r) adjuvant expands the antibody repertoire to the Fasciola MF6p/FhHDM-1 antigen and administered together impair the growth and antigen release of flukes. AB - Fasciolosis continues to be a major cause of economic losses in the livestock industry and a growing threat to humans. The limited spectrum of effective anthelmintics and the appearance of resistances urge the need for developing an effective vaccine. Most studies have been focused on the use of TH1-polarizing adjuvants and the use of recombinant Fasciola critical molecules and, despite the efforts, no reproducible protections have been achieved. The F. hepatica MF6p/FhHDM-1 protein is a heme-binding protein also reported to have immunomodulatory properties, constituting a promising target for vaccination and/or as target for the development of new flukicides. Thus, in this study, we investigated the effects of the TH1-polarizing adjuvant Quil A(r) on sheep immune response to MF6p/FhHDM-1, and the vaccine potential of both native and synthetic forms of this protein against ovine fasciolosis. Subcutaneous injection of Quil A(r) alone, i.e., without co-injecting any antigen, expands the antibody repertoire to MF6p/FhHDM-1 triggered by a subsequent primoinfection with metacercariae. This effect was not observed with aluminum hydroxide, the most frequently adjuvant used in commercial vaccines. On the other hand, vaccination with synthetic MF6p/FhHDM-1 in Quil A(r) prompted a 2-4-week delay in the antibody response induced in sheep by a challenge experimental infection. Moreover, fluke populations stablished showed stunted growth and low antigen release probably due to reduced metabolic activity. These observations suggest that primary circulating antibodies induced by the immunization had harmful effects on fluke development. Such effects could not be demonstrated to be associated to TH1 immune response linked events (production of IgG2 isotype antibodies and IFN-gamma). PMID- 29525281 TI - A large-scale field randomized trial demonstrates safety and efficacy of the vaccine LetiFend(r) against canine leishmaniosis. AB - Canine leishmaniosis is a zoonotic disease caused by Leishmania infantum. Extensive research is currently ongoing to develop safe and effective vaccines to protect from disease development. The European Commission has granted a marketing authorization for LetiFend(r), a new vaccine containing recombinant Protein Q. The efficacy of LetiFend(r) vaccination in a large-scale dog population of both sexes, different breeds and ages in endemic areas is reported in this multicenter, randomized, double-blind, placebo-controlled field trial. Dogs (n = 549) living in France and Spain were randomly selected to receive a single subcutaneous dose of LetiFend(r) or placebo per year, and were naturally exposed to two L. infantum transmission seasons. Clinical examinations, blood and lymphoid organ sampling to evaluate serological, parasitological and disease status of the dogs were performed at different time points during the study. LetiFend(r) was very well tolerated and clearly reduced the incidence of clinical signs related to leishmaniosis. The number of confirmed cases of leishmaniosis was statistically significantly lower in the vaccine group. The number of dogs with parasites was close to be significantly reduced in the vaccine group (p = 0.0564). Re-vaccination of seropositive dogs demonstrated to be safe and not to worsen the course of the disease. The likelihood that a dog vaccinated with LetiFend(r) develops a confirmed case or clinical signs of leishmaniosis in areas with high pressure is, respectively, 5 and 9.8 time less than that for an unvaccinated dog. Thus, the overall efficacy of the LetiFend(r) vaccine in the prevention of confirmed cases of leishmaniosis in endemic areas with high disease pressure was shown to be 72%. In conclusion, this field trial demonstrates that LetiFend(r) is a novel, safe and effective vaccine for the active immunization of non-infected dogs from 6 months of age in reducing the risk of developing clinical leishmaniosis after natural infection with Leishmania infantum. PMID- 29525282 TI - Characterization of the immune response elicited by the vaccinia virus L3 protein delivered as naked DNA. AB - Poxviruses are complex dsDNA viruses with over 200 genes, many of them with unknown role in the stimulation of immune responses. Among these, the vaccinia virus (VACV) L3L ORF encodes an essential protein for the transcription of the VACV early genes. To the best of our knowledge, the immune response elicited by L3 has not been characterized. In this regard, our data describes a DNA L3-coding plasmid (pL3L) that stimulates both, humoral- and cell-mediated immune responses in a mouse model. Cell-mediated immune responses were measured by IFN-gamma and IL-4 ELISPOT assays. We performed CD8+ cells depletion and flow cytometry analysis to account for the contribution of cytotoxic T lymphocytes in the IFN gamma production. Moreover, results from ELISPOT were confirmed by measuring the concentration of IL-4 and IFN-gamma in supernatant of antigen-stimulated splenocytes by cytokine ELISA. Additionally, dominant antigenic regions of L3 protein were identified by epitope mapping analysis. Humoral immune responses were assessed by ELISA. Specifically, the production of total IgG, IgG1 (TH-2) and IgG2a (TH-1) were determined one week after the final immunization. Our ELISPOT data shows pL3L-immunized animals to produce significantly higher frequencies of IFN-gamma Spot-Forming Cells (SFC) versus controls. IL-4 levels remained unchanged in all three groups, demonstrating the increase in antigen specific IFN-gamma releasing cells. Flow cytometry assay results showed that CD8+ T cells are a major contributor to the production of IFN-gamma. Moreover, our formulation enhances the production of total IgG, predominantly IgG2a isotype. Immunization with pL3L promotes a robust cytotoxic immune response, crucial against viral pathogens. In addition, our vaccine candidate promotes an increase in IgG levels, especially IgG2a (TH-1 type). Our data encourages further studies of L3 as a novel antigen in vaccine development against poxviruses. PMID- 29525283 TI - Clinical development and regulatory points for consideration for second generation live attenuated dengue vaccines. AB - Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines. PMID- 29525284 TI - Effectiveness of parental cocooning as a vaccination strategy to prevent pertussis infection in infants: A case-control study. AB - BACKGROUND: During a pertussis epidemic in 2009, the Department of Health, Victoria, Australia, implemented a cocoon program offering parents of new babies a funded-dose of pertussis-containing vaccine. We assessed vaccine effectiveness (VE) of the program in reducing pertussis infection in infants. METHODS: Using a matched case-control design, infants aged <12 months that were notified with pertussis between 1 January 2010 and 31 December 2011, and born during the time that the cocoon program was in place, were identified. Controls were matched by area of residence and date of birth. Telephone interviews we conducted to ascertain parents' vaccination status, and if vaccinated, timing of vaccination receipt relative to the birth of their baby. Odds ratios (ORs) were calculated for the association between vaccination and pertussis infection, with VE calculated as (1 - OR) * 100%. RESULTS: The study recruited 215 cases and 240 controls (response rates 67% and 25% of eligible participants, respectively). Vaccination of both parents after delivery of the infant and >=28 days prior to illness onset reduced pertussis infection by 77% (Vaccine Effectiveness [VE] = 77% (confidence interval [95% CI], 18-93%). After adjusting for maternal education, presence of a sibling within the household, and the infants' primary course vaccination status, the adjusted VE was 64% (95% CI, -58-92%). CONCLUSIONS: Although not reaching statistical significance, our results demonstrated that cocoon immunisation - where both parents are vaccinated in the post-partum period - may offer some protection again infant pertussis infection. Cocoon immunisation could be considered in circumstances where antenatal vaccination of the mother has not occurred. PMID- 29525285 TI - Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) has increased in prevalence in the past decade. Studies attempting to identify a specific genetic component have not been able to account for much of the heritability of ADHD, indicating there may be gene-environment interactions underlying the disorder, including early exposure to environmental chemicals. Based on several relevant studies, we chose to examine bisphenol A (BPA) as a possible contributor to ADHD in humans. BPA is a widespread environmental chemical that has been shown to disrupt neurodevelopment in rodents and humans. OBJECTIVES: Using the Office of Health Assessment and Translation (OHAT) framework, a systematic review and meta analysis was designed to determine the relationship between early life exposure to BPA and hyperactivity, a key diagnostic criterion of ADHD. DATA SOURCES: Searches of PubMed, Web of Science, and Toxline were completed for all literature to January 1, 2017. STUDY ELIGIBILITY CRITERIA: For inclusion, the studies had to publish original data, be in the English language, include a measure of BPA exposure, and assess if BPA exposure affected hyperactive behaviors in mice, rats or humans. Exposure to BPA had to occur at <3 months of age for humans, up to postnatal day 35 for rats and up to postnatal day 40 for mice. Exposure could occur either gestationally (via maternal exposure) or directly to the offspring. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were evaluated using the OHAT risk of bias tool. The effects in humans were assessed qualitatively. For rodents exposed to 20 MUg/kg/day BPA, we evaluated the study findings in a random effects meta-analytical model. RESULTS: A review of the literature identified 29 rodent and 3 human studies. A random effects meta-analysis showed significantly increased hyperactivity in male rodents. In humans, early BPA exposure was associated with hyperactivity in boys and girls. LIMITATIONS, CONCLUSIONS, AND IMPLICATIONS OF KEY FINDINGS: We concluded that early life BPA exposure is a presumed human hazard for the development of hyperactivity. Possible limitations of this systematic review include deficiencies in author reporting, exclusion of some literature based on language, and insufficient similarity between human studies. SRs that result in hazard-based conclusions are the first step in assessing and mitigating risks. Given the widespread exposure of BPA and increasing diagnoses of ADHD, we recommend immediate actions to complete such risk analyses and take next steps for the protection of human health. In the meantime, precautionary measures should be taken to reduce exposure in pregnant women, infants and children. The present analysis also discusses potential mechanisms by which BPA affects hyperactivity, and the most effective avenues for future research. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not available. PMID- 29525286 TI - Socioeconomic Development and Cardiovascular Disease. PMID- 29525287 TI - Relationship between nocturnal blood pressure profiles and the presence and severity of hypertensive retinopathy. AB - INTRODUCTION: Non-dipper and extreme dipper blood pressure (BP) profiles are associated with a worse cardiovascular prognosis. The relationship between nocturnal BP profile and hypertensive retinopathy (HR) is not fully established. AIM: To assess the association between the prevalence and severity of HR and nocturnal BP. METHODS: We prospectively studied hypertensive patients who underwent 24-hour ambulatory BP monitoring. The population was divided into two groups according to the presence or absence of lesions and compared according to baseline characteristics, nocturnal BP profile (dippers, non-dippers, inverted dippers/risers and extreme dippers) and mean nocturnal systolic (SBP) and diastolic (DBP) BP values. The presence and severity of HR were assessed using the Scheie classification. The relationship between nocturnal SBP and DBP values (and nocturnal BP profile) and the prevalence and severity of HR was determined. RESULTS: Forty-six patients (46% male, aged 63+/-12 years) were analyzed, of whom 91% (n=42) were under antihypertensive treatment. Seventy percent (n=33) had uncontrolled BP. HR was diagnosed in 83% (n=38). Patients with HR had higher mean systolic nocturnal BP (151+/-23 vs. 130+/-13 mmHg), p=0.008). Patients with greater HR severity (Scheie stage >=2) had higher nocturnal BP (153+/-25 vs. 140+/-16 mmHg, p=0.04). There was no statistically significant association between DBP and nocturnal BP patterns and HR. CONCLUSIONS: The prevalence and severity of HR were associated with higher nocturnal SBP. No relationship was observed between nocturnal BP profile and the presence of HR. PMID- 29525288 TI - Cardiac channelopathies: The role of sodium channel mutations. AB - INTRODUCTION AND OBJECTIVES: The importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations (inherited or de novo) in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome (LQTS). The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies, namely at the level of diagnosis, risk stratification, prognosis, screening of family members and treatment. METHODS: The online Pubmed(r) database was used to search for articles published in this field in indexed journals. The MeSH database was used to define the following query: "Mutation [Mesh] AND Sodium Channels [Mesh] AND Heart Diseases [Mesh]", and articles published in the last 15 years, written in English or Portuguese and referring to research in human beings were included. CONCLUSIONS: In the past few years, significant advances have been made to clarify the genetic and molecular basis of these syndromes. A greater understanding of the underlying pathophysiological mechanisms showed the importance of the relationship between genotype and phenotype and led to progress in the clinical approach to these patients. However, it is still necessary to improve diagnostic capacity, optimize risk stratification, and develop new specific treatments according to the genotype-phenotype binomial. PMID- 29525289 TI - The Stability of Intimate Partner Violence Perpetration From Adolescence to Emerging Adulthood in Sexual Minorities. AB - PURPOSE: The objective of this study was to examine the stability of physical and sexual intimate partner violence (IPV) perpetration from adolescence to emerging adulthood among sexual minorities. METHODS: Adolescents who identified as a sexual minority (N = 135; 71.1% female; mean age = 15.02, standard deviation=.77; 34.1% African-American/black, 26.7% white, 22.2% Hispanic) from southeast Texas were assessed annually for 6 years on their IPV perpetration. RESULTS: Structural equation modeling demonstrated that physical IPV perpetration was modestly stable across years 1-4 (24.6%, 24.6%, 26.4%, and 21.6%, respectively), decreased in year 5 (18.6%), and increased in year 6 (24.5%). The stability of sexual IPV perpetration was high across all 6 years (14.3%, 13%, 14.9%, 10.8%, 12.4%, and 14.4%). CONCLUSIONS: This is the first study to examine the stability of IPV perpetration among sexual minority adolescents. Findings suggest that the development of interventions for IPV among sexual minority adolescents is needed, as IPV is unlikely to desist from adolescence to emerging adulthood. PMID- 29525290 TI - Sex as a Moderator of Adolescents' Weight Loss Treatment Outcomes. AB - PURPOSE: Weight loss treatments targeting adolescents often occur in mixed-sex contexts and produce variable outcomes. Sex considerations may be of particular importance, especially given differences in social relating. This study aggregated data from two randomized controlled trials of a peer-enhanced intervention compared with a standard cognitive-behavioral weight loss intervention to test the hypothesis that adolescent girls may demonstrate greater benefit than boys from a peer-enhanced weight loss intervention. METHODS: Participants were 193 adolescents with overweight/obesity (age M = 14.4 years, standard deviation = .99) from two randomized clinical trials comparing a peer enhanced intervention with an active cognitive-behavioral weight loss intervention. Adolescents' percent over body mass index (percent greater than the 50th percentile for age and sex) was measured at baseline, end of treatment, and approximately 6 months post treatment. Multilevel modeling was used to test hypotheses. RESULTS: Findings suggested different weight change trajectories from baseline to end of treatment, and from end of treatment to follow-up. On average, all participants demonstrated weight loss from baseline to end of treatmentm and there was evidence that adolescent boys in the peer-enhanced condition may have benefited the most. On average, weight was maintained from end of treatment to follow-up. CONCLUSION: Adolescent males may particularly benefit from weight loss interventions that incorporate a team component to supervised physical activity. PMID- 29525291 TI - Immune thrombocytopenic purpura associated with Crohn's disease with complete response to infliximab. PMID- 29525293 TI - Minimally-invasive operations on the temporomandibular joint with a new retractor: technical note. PMID- 29525292 TI - Effects of balance and proprioceptive training on total hip and knee replacement rehabilitation: A systematic review and meta-analysis. AB - BACKGOUND: Balance and proprioceptive deficits are frequently persistent after total joint replacement, limiting functionality and involving altered movement patterns and difficulties in walking and maintaining postural control among patients. RESEARCH QUESTION: The goal of this systematic review was to evaluate the short- and mid-term effects of proprioceptive and balance training for patients undergoing total knee and hip replacement. METHODS: This is a systematic review of literature. MEDLINE, Embase, Cochrane Library, PEDro, and Scopus were the databases searched. The review included randomized clinical trials in which the experimental groups underwent a training aimed at improving balance and proprioception, in addition to conventional care. The studies had to assess at least one of the following outcomes: self-reported functionality or balance (primary outcomes), knee function, pain, falls, or quality of life. RESULTS: Eight trials were included, involving 567 participants. The quantitative synthesis found a moderate to high significant effect of balance and proprioceptive trainings on self-reported functionality and balance after total knee replacement. The effects were maintained at mid-term in terms of balance alone. Conversely, preoperative training did not enhance outcomes after total hip arthroplasty. SIGNIFICANCE: The synthesis showed that, in clinical terms, balance trainings are a convenient complement to conventional physiotherapy care to produce an impact on balance and functionality after knee replacement. If outcomes such as improvement in pain, knee range of movement, or patient quality of life are to be promoted, it would be advisable to explore alternative proposals specifically targeting these goals. Further research is needed to confirm or discard the current evidence ultimately, predominantly in terms of the effects on the hips and those yielded by preoperative interventions. PMID- 29525294 TI - Bifurcation of the inferior dental nerve canal: an anatomical study. AB - The aims of this study were to find the incidence of bifurcation of the inferior dental nerve (IDN) canal, to describe the characteristics of this variant, and to examine the sensitivity and specificity of dental panoramic tomography to identify it. We classified bifurcations by size and position relative to the main canal and the lower third molar using cone-beam computed tomography (CT) and dental panoramic tomography. In our study of 281 patients, 106 (38%) had bifurcations, and in one quarter, these were classified as large accessory canals. Bifurcations were most commonly found posterior to the lower third molar (n=64, 57%) or within 2mm of the roots of the third molar (n=40, 38%). The sensitivity and specificity of dental panoramic tomography to identify all bifurcations was 11% (95% CI: 5.67 to 17.97) and 91% (95% CI: 85.58 to 94.68), respectively; this was 33% (95% CI: 15.63 to 55.32) and 94% (95% CI: 90.34 to 96.50), respectively, for large bifurcations. Our use of cone-beam CT suggested an incidence of bifid canals of 38%, with a variation in size and distribution in relation to the lower third molar. It also showed that the sensitivity of panoramic radiography to identify them was poor. PMID- 29525295 TI - Research in oral and maxillofacial surgery: infrastructure and innovation. PMID- 29525296 TI - Further evidence for a distinctive atypical degenerative parkinsonism in the Caribbean: A new cluster in the French West Indian Island of Martinique. AB - BACKGROUND: A high prevalence of an atypical levodopa-resistant parkinsonism has been reported in the Caribbean island of Guadeloupe. These seminal observations have not been replicated or extended to neighbouring populations who share genetic and environmental characteristics. METHODS: To further characterise this atypical parkinsonism we prospectively investigated 305 consecutive patients with neurodegenerative parkinsonism in a community-based population from Guadeloupe and Martinique, a neighbouring French Caribbean island where the population has similar environmental and genetic backgrounds. The aims of this study were to confirm the frequency of atypical parkinsonism within this cohort and to precisely define its clinical phenotype. RESULTS: A high frequency (66%) of atypical parkinsonism was identified in both Guadeloupe and Martinique. The clinical phenotype consisted of a levodopa-resistant parkinsonism with postural instability (72%), early dementia (58%), dysautonomia (58%), rapid-eye-movement sleep behavioural disorder (53%), hallucinations (43%), and supranuclear gaze palsy (29%). A low educational level was identified as a major risk factor for developing atypical parkinsonism (p < .001). CONCLUSION: Our findings support the existence of a distinctive atypical parkinsonism - Caribbean Parkinsonism - within the French Caribbean Islands. This could either correspond to a single entity or reflect a propensity for developing more widespread and rapidly progressive lesions in Caribbean patients with parkinsonism. In both cases, genetic susceptibility and/or environmental exposure may be involved. PMID- 29525297 TI - Hysteria in ancient civilisations: A neurological review: Possible significance for the modern disorder. AB - The word hysteria originated in the Corpus Hippocraticum (c420 BCE) as a natural explanation for a variety of diseases in women linked in the Greco-Roman mind to an animate or inanimate womb, but which in the last five centuries has evolved to describe an elusive disorder of brain +/- mind in men and women, currently referred to by neurologists as "functional neurological disorder". The Babylonians, Assyrians and Egyptians had no knowledge of brain or psychological function. Babylonian and Assyrian descriptions of disease and behaviour include only rare examples suggestive of modern hysteria. An earlier suggestion that the Greek concept of hysteria was transmitted from Egypt is not supported by recent evidence. The Greco-Roman civilisations had some knowledge of neuroanatomy, but little of nervous system function, conceived in terms of humors. The examples cited here suggestive of modern hysteria are relatively infrequent and fragmentary. The most plausible are attempts to separate the "sacred disease" from other causes of loss of consciousness. The great achievement of Greco-Roman medicine was in introducing natural causation, including causation linked to the womb, rather than gods or evil spirits. Nevertheless medicine, magic and religion have remained intertwined to varying degrees in all cultures up to the present time, despite the growth of modern scientific medicine. The study of hysteria in ancient civilisations adds interesting insight into the evolution of thinking about brain, psyche, mind and self. Babylonian and Egyptian medical and behavioural descriptions are based on observation. Greek and Roman accounts include some subjective aspects, probably linked to early attempts to understand identity, the psyche, intellectual and emotional functions. The great philosophical debate whether the latter resided in the head/brain (Plato) or the heart (Aristotle) has only been settled in the last few centuries, during which hysteria also became linked to brain +/- mind. Our more recent increasing knowledge of brain function has also been accompanied by increasing interest in subjective feelings, thoughts, the inner life and subconscious mechanisms, suggesting we may have become more self-aware than in earlier civilisations, which in turn may perhaps influence the clinical presentation of hysteria. The study of hysteria may be one of the keys to a greater understanding of the relationship between brain and mind. PMID- 29525298 TI - Severe multiple sclerosis reactivation after gonadotropin treatment. AB - Several reports indicate increased disease activity in patients with multiple sclerosis (MS) undergoing assisted reproductive techniques (ART), in the form of gonadtopin releasing hormone (GnRH) agonists. Other forms of ART treatments, like gonadotropin-treatment, have therefore been considered a safer option for MS patients. We present a patient who despite being completely clinically and radiologically stable for eight years during disease modifying therapy experienced a nearly fulminant disease course almost immediately after starting gonadotropin-treatment, indicating that this form of follicle stimulating treatment could also be a major risk factor for MS disease activity. PMID- 29525299 TI - Factors associated with profitability in pasture-based systems of milk production. AB - The global dairy industry needs to reappraise the systems of milk production that are operated at farm level with specific focus on enhancing technical efficiency and competitiveness of the sector. The objective of this study was to quantify the factors associated with costs of production, profitability, and pasture use, and the effects of pasture use on financial performance of dairy farms using an internationally recognized representative database over an 8-yr period (2008 to 2015) on pasture-based systems. To examine the associated effects of several farm system and management variables on specific performance measures, a series of multiple regression models were developed. Factors evaluated included pasture use [kg of dry matter/ha and stocking rate (livestock units/ha)], grazing season length, breeding season length, milk recording, herd size, dairy farm size (ha), farmer age, discussion group membership, proportion of purchased feed, protein %, fat %, kg of milk fat and protein per cow, kg of milk fat and protein per hectare, and capital investment in machinery, livestock, and buildings. Multiple regression analysis demonstrated costs of production per hectare differed by year, geographical location, soil type, level of pasture use, proportion of purchased feed, protein %, kg of fat and protein per cow, dairy farm size, breeding season length, and capital investment in machinery, livestock, and buildings per cow. The results of the analysis revealed that farm net profit per hectare was associated with pasture use per hectare, year, location, soil type, grazing season length, proportion of purchased feed, protein %, kg of fat and protein per cow, dairy farm size, and capital investment in machinery and buildings per cow. Pasture use per hectare was associated with year, location, soil type, stocking rate, dairy farm size, fat %, protein %, kg of fat and protein per cow, farmer age, capital investment in machinery and buildings per cow, breeding season length, and discussion group membership. On average, over the 8-yr period, each additional tonne of pasture dry matter used increased gross profit by ?278 and net profit by ?173 on dairy farms. Conversely, a 10% increase in the proportion of purchased feed in the diet resulted in a reduction in net profit per hectare by ?97 and net profit by ?207 per tonne of fat and protein. Results from this study, albeit in a quota limited environment, have demonstrated that the profitability of pasture-based dairy systems is significantly associated with the proportion of pasture used at the farm level, being cognizant of the levels of purchased feed. PMID- 29525300 TI - Invited review: Effectiveness of precalving treatment on postcalving udder health in nulliparous dairy heifers: A systematic review and meta-analysis. AB - Clinical mastitis affects 3% of primiparous dairy cattle (heifers) in the first month after calving. Additionally, the prevalence of intramammary infection (IMI) in the months before first calving is high, resulting in a high prevalence of heifers calving with IMI. Precalving therapy is an accepted recommendation for reducing mastitis in multiparous cows, but prophylactic treatment for heifers is uncommon in North America. Objectives of this study were to (1) quantify changes in postcalving udder health in heifers following application of a precalving treatment; (2) compare effectiveness among various types of treatments; and (3) compare effectiveness of various types of treatments against specific pathogens. A systematic review was conducted comparing interventions aimed at improving udder health in heifers. Of 62 included studies, 48 clinical trials were used in a meta-analysis. Data were synthesized using a random effects model for meta analysis, followed by sub-group analyses comparing treatment types, and specific pathogens with statistical testing using meta-regression. Occurrence of mastitis (defined as elevated somatic cell count, clinical mastitis, and IMI) was reduced in treated heifers compared with untreated controls with a pooled risk ratio of treated to untreated heifers of 0.56 (95% confidence interval: 0.47 to 0.67). Upon stratification by treatment types, teat sealants and combination therapies (vaccines and antimicrobials; antimicrobials and teat sealants; and all 3) were most effective at improving udder health with pooled risk ratios of 0.40 (95% confidence interval: 0.30 to 0.52) and 0.34 (95% confidence interval: 0.25 to 0.45), respectively. Antimicrobials and vaccines also reduced occurrence of IMI and subclinical and clinical mastitis when compared with untreated heifers. Although variation was observed in the pathogen-specific effectiveness of treatments at reducing rates of disease, antimicrobials, teat sealants, and combinations of vaccines or teat sealants with antimicrobials were consistently effective, whereas vaccines were only effective for contagious pathogens. Recommendations for use of antibiotics should consider their relative benefit while also considering potential for increasing antimicrobial resistance. PMID- 29525301 TI - Invited review: Genetics and claw health: Opportunities to enhance claw health by genetic selection. AB - Routine recording of claw health status at claw trimming of dairy cattle has been established in several countries, providing valuable data for genetic evaluation. In this review, we examine issues related to genetic evaluation of claw health; discuss data sources, trait definitions, and data validation procedures; and present a review of genetic parameters, possible indicator traits, and status of genetic and genomic evaluations for claw disorders. Different sources of data and traits can be used to describe claw health. Severe cases of claw disorders can be identified by veterinary diagnoses. Data from lameness and locomotion scoring, activity information from sensors, and feet and leg conformation traits are used as auxiliary traits. The most reliable and comprehensive information is data from regular hoof trimming. In genetic evaluation, claw disorders are usually defined as binary traits, based on whether or not the claw disorder was present (recorded) at least once during a defined time period. The traits can be specific disorders, composite traits, or overall claw health. Data validation and editing criteria are needed to ensure reliable data at the trimmer, herd, animal, and record levels. Different strategies have been chosen, reflecting differences in herd sizes, data structures, management practices, and recording systems among countries. Heritabilities of the most commonly analyzed claw disorders based on data from routine claw trimming were generally low, with ranges of linear model estimates from 0.01 to 0.14, and threshold model estimates from 0.06 to 0.39. Estimated genetic correlations among claw disorders varied from -0.40 to 0.98. The strongest genetic correlations were found among sole hemorrhage (SH), sole ulcer (SU), and white line disease (WL), and between digital/interdigital dermatitis (DD/ID) and heel horn erosion (HHE). Genetic correlations between DD/ID and HHE on the one hand and SH, SU, or WL on the other hand were, in most cases, low. Although some of the studies were based on relatively few records and the estimated genetic parameters had large standard errors, there was, with some exceptions, consistency among studies. Various studies evaluate the potential of various data soureces for use in breeding. The use of hoof trimming data is recommended for maximization of genetic gain, although auxiliary traits, such as locomotion score and some conformation traits, may be valuable for increasing the reliability of genetic evaluations. Routine genetic evaluation of direct claw health has been implemented in the Netherlands (2010); Denmark, Finland, and Sweden (joint Nordic evaluation; 2011); and Norway (2014), and other countries plan to implement evaluations in the near future. PMID- 29525302 TI - Invited review: Incidence, risk factors, and effects of clinical mastitis recurrence in dairy cows. AB - Clinical mastitis (CM) is one of the most frequent and costly diseases in dairy cows. A frustrating aspect of CM is its recurrent nature. This review was conducted to synthesize knowledge on risk of repeated cases of CM, effects of recurrent CM cases, and risk factors for CM recurrence. A systematic review methodology was used to identify articles for this narrative review. Searches were performed to identify relevant scientific literature published after 1989 in English or French from 2 databases (PubMed and CAB Abstracts) and 1 search platform (Web of Science). Fifty-seven manuscripts were selected for qualitative synthesis according to the inclusion criteria. Among the 57 manuscripts selected in this review, a description of CM recurrence, its risk factors, and effects were investigated and reported in 33, 37, and 19 selected manuscripts, respectively. Meta-analysis and meta-regression analyses were used to compute risk ratio comparing risk of CM in cows that already had 1 CM event in the current lactation with risk of CM in healthy cows. For these analyses, 9 manuscripts that reported the total number of lactations followed and the number of lactations with <=1 and <=2 CM cases were used. When summarizing results from studies requiring >=5 d between CM events to consider a CM event as a new case, we observed no significant change in CM susceptibility following a first CM case (risk ratio: 0.99; 95% confidence interval: 0.86-1.14). However, for studies using a more liberal CM recurrence definition (i.e., only 24 h between CM events to consider new CM cases), we observed a 1.54 times greater CM risk (95% confidence interval: 1.20-1.97) for cows that already had 1 CM event in the current lactation compared with healthy cows. The most important risk factors for CM recurrence were parity (i.e., higher risk in older cows), a higher milk production, pathogen species involved in the preceding case, and whether a bacteriological cure was observed following the preceding case. The most important effects of recurrent CM were the milk yield reduction following a recurrent CM case, which was reported to be similar to that of the first CM case, and the increased risk of culling and mortality, which were reported to surpass those of first CM cases. PMID- 29525303 TI - Molecular characterization of non-aureus Staphylococcus spp. from heifer intramammary infections and body sites. AB - The purpose of this study was to investigate non-aureus Staphylococcus spp. intramammary infections (IMI) in periparturient heifers and determine the relationship of precalving body site isolation with precalving IMI and postcalving IMI using molecular speciation and strain-typing methods. Primiparous heifers were enrolled at approximately 14 d before expected calving date. Precalving mammary quarter secretions and body site swabbing samples (teat skin, inguinal skin, muzzle, and perineum) were collected. Postcalving, mammary quarter milk samples were collected for culture and somatic cell counting. Precalving body site samples were cultured, and up to 10 staphylococcal colonies were saved for characterization. Staphylococcal isolates were speciated using matrix assisted laser/desorption ionization time-of-flight mass spectrometry or sequencing of rpoB or tuf. Pulsed-field gel electrophoresis was used to strain type a subset of isolates. Overall, Staphylococcus chromogenes, Staphylococcus agnetis, and Staphylococcus simulans were the most common species identified in precalving mammary secretions, whereas S. chromogenes, Staphylococcus xylosus, and S. agnetis were the most common species found in postcalving milk samples. The most common species identified from body site samples were S. chromogenes, S. xylosus, and Staphylococcus haemolyticus. Mammary quarters that had a precalving mammary secretion that was culture positive for S. agnetis, S. chromogenes, or Staphylococcus devriesei had increased odds of having an IMI with the same species postcalving. A S. chromogenes IMI postcalving was associated with higher somatic cell count when compared with postcalving culture-negative quarters. Among heifers identified with a non-aureus Staphylococcus spp. IMI either precalving or postcalving, heifers that had S. agnetis or S. chromogenes isolated from their teat skin had increased odds of having the same species found in their precalving mammary secretions, and heifers with S. chromogenes, S. simulans, and S. xylosus isolated from their teat skin precalving were at increased odds of having an IMI with the same species postcalving. Overall, 44% of all heifers with a S. chromogenes IMI around the time of parturition had the same strain isolated from a body site. Based on pulsed-field gel electrophoresis, a high level of strain diversity was found. PMID- 29525304 TI - Effect of replacing calcium salts of palm oil with camelina seed at 2 dietary ether extract levels on digestion, ruminal fermentation, and nutrient flow in a dual-flow continuous culture system. AB - Camelina is a drought- and salt-tolerant oil seed, which in total ether extract (EE) contains up to 74% polyunsaturated fatty acids. The objective of this study was to assess the effects of replacing calcium salts of palm oil (Megalac, Church & Dwight Co. Inc., Princeton, NJ) with camelina seed (CS) on ruminal fermentation, digestion, and flows of fatty acids (FA) and AA in a dual-flow continuous culture system when supplemented at 5 or 8% dietary EE. Diets were randomly assigned to 8 fermentors in a 2 * 2 factorial arrangement of treatments in a replicated 4 * 4 Latin square design, with four 10-d experimental periods consisting of 7 d for diet adaptation and 3 d for sample collection. Treatments were (1) calcium salts of palm oil supplementation at 5% EE (MEG5); (2) calcium salts of palm oil supplementation at 8% EE (MEG8); (3) 7.7% CS supplementation at 5% EE (CS5); and (4) 17.7% CS supplementation at 8% EE (CS8). Diets contained 55% orchardgrass hay, and fermentors were fed 72 g of dry matter/d. On d 8, 9, and 10 of each period, digesta effluent samples were taken for ruminal NH3, volatile fatty acids, nitrogen metabolism analysis, and long-chain FA and AA flows. Statistical analysis was performed using the MIXED procedure (SAS Institute Inc., Cary, NC). We detected an interaction between FA source and dietary EE level for acetate, where MEG8 had the greatest molar proportion of acetate. Molar proportions of propionate were greater and total volatile fatty acids were lower on CS diets. Supplementation of CS decreased overall ruminal nutrient true digestibility, but dietary EE level did not affect it. Diets containing CS had greater biohydrogenation of 18:2 and 18:3; however, biohydrogenation of 18:1 was greater in MEG diets. Additionally, CS diets had greater ruminal concentrations of trans-10/11 18:1 and cis-9,trans-11 conjugated linoleic acid. Dietary EE level at 8% negatively affected flows of NH3-N (g/d), nonammonia N, and bacterial N as well as the overall AA outflow. However, treatments had minor effects on individual ruminal AA digestibility. The shift from acetate to propionate observed on diets containing CS may be advantageous from an energetic standpoint. Moreover, CS diets had greater ruminal outflow of trans-10/11 18:1 and cis 9,trans-11 conjugated linoleic acid than MEG diets, suggesting a better FA profile available for postruminal absorption. However, dietary EE at 8% was deleterious to overall N metabolism and AA outflow, indicating that CS can be fed at 5% EE without compromising N metabolism. PMID- 29525305 TI - Evaluation of creatinine as a urine marker and factors affecting urinary excretion of magnesium by dairy cows. AB - Nutrient balance studies require measuring urine volume, and urinary excretion can be used to assess Mg bioavailability. A less laborious method than total collection of urine could make balance studies more feasible and expand the utility of using urinary Mg as an index of bioavailability, but the method needs to be accurate and sensitive. Sampling interval can affect accuracy because excretion must be at steady state. Two experiments were conducted to (1) determine whether urinary creatinine could be used to accurately estimate urinary output of nutrients markedly excreted via urine (N, K, Na, S, and Mg; experiment 1) and (2) determine the appropriate sampling schedule to evaluate Mg excretion after abrupt diet changes (experiment 2). Experiment 1 was originally designed to evaluate the interaction of monensin [0 vs. 14 mg of monensin/kg of dry matter (DM)] and Mg source (MgO vs. MgSO4; total diet Mg: 0.36% of DM) under antagonism from increased dietary K (2.11% of DM) on urinary Mg excretion. Experiment 2 evaluated the interaction of Mg concentration (basal vs. supplemental MgO; total diet Mg: 0.20 vs. 0.42% of DM) and K (basal vs. supplemental K2CO3; total diet K: 1.60 vs. 2.57% of DM) on urinary Mg excretion over time. Using 4-d composite samples from total collection of urine (n = 34 cow-periods), the average daily excretion of creatinine was similar to previous estimates (29.0 +/- 1.16 mg of creatinine/kg of body weight) but was variable among cows (root mean squared error = 2,980 mg/d; 14% of mean). Treatment-average estimated excretion of urine and urinary N, K, Na, S, and Mg were similar to actual values; however, differences between actual and estimated values could be substantial for individual cows. Using the mean creatinine excretion per kilogram of body weight for all cows to estimate urine eliminates the lack of fit variance resulting in artificially low within-treatment variation for estimated urine volume. The standard error of the mean for estimated urine volume was 23% less (1.93 vs. 2.51) than that for actual urine production. This inflated the type I error rate, and, consequently, statistical inferences on N and K excretion differed when urine output was estimated rather than measured. The standard error of the mean for excretion of Mg calculated with actual or estimated urine production were almost identical (0.92 vs. 0.97); however, similar standard error of the mean was likely caused by differences in the covariance of urinary Mg concentration with estimated or actual urine output. Based on spot sampling (experiment 2), urinary Mg reached steady state by 2 d following an increase in dietary K regardless of Mg level, whereas excretion of urinary Mg following an increase in dietary Mg continued to increase through 7 d. Estimating nutrient excretion with urinary creatinine and body weight on average is accurate, but variance is likely underestimated. Knowing the time course of urinary Mg excretion will improve the value of using urinary Mg concentration to assess diet adequacy or Mg bioavailability. PMID- 29525306 TI - Improving accuracy of bulls' predicted genomic breeding values for fertility using daughters' milk progesterone profiles. AB - The main objective of this study was to investigate the benefit of accuracy of genomic prediction when combining records for an intermediate physiological phenotype in a training population with records for a traditional phenotype. Fertility was used as a case study, where commencement of luteal activity (C-LA) was the physiological phenotype, whereas the interval from calving to first service and calving interval were the traditional phenotypes. The potential accuracy of across-country genomic prediction and optimal recording strategies of C-LA were also investigated in terms of the number of farms and number of repeated records for C-LA. Predicted accuracy was obtained by estimating population parameters for the traits in a data set of 3,136 Holstein Friesian cows with 8,080 lactations and using a deterministic prediction equation. The effect of genetic correlation, heritability, and reliability of C-LA on the accuracy of genomic prediction were investigated. When the existing training population was 10,000 bulls with reliable estimated breeding value for the traditional trait, predicted accuracy for the physiological trait increased from 0.22 to 0.57 when 15,000 cows with C-LA records were added to the bull training population; but, when the interest was in predicting the traditional trait, we found no benefit from the additional recording. When the genetic correlation was higher between the physiological and traditional traits (0.7 instead of 0.3), accuracy increased less when adding the 15.000 cows with C-LA (from 0.51 to 0.63). In across-country predictions, we observed little to no increase in accuracy of the intermediate physiological phenotype when the training population from Sweden was large, but when accuracy increased the training population was small (200 cows), from 0.19 to 0.31 when 15,000 cows were added from the Netherlands (genetic correlation of 0.5 between countries), and from 0.19 to 0.48 for genetic correlation of 0.9. The predicted accuracy initially increased substantially when recording on the same farm was extended and multiple C-LA records per cow were used in prediction compared with single records; that is, accuracy increased from 0.33 with single records to 0.38 with multiple records (on average 1.6 records per cow) from 2 yr of recording C-LA. But, when the number C-LA per cow increased beyond 2 yr of recording, we noted no substantial benefit in accuracy from multiple records. For example, for 5 yr of recording (on average 2.5 records per cow), accuracy was 0.47; on doubling the recording period to 10 yr (on average 3.1 records per cow), accuracy increased by 0.07 units, whereas when C-LA was recorded for 15 yr (on average 3.3 records per cow) accuracy increased only by 0.05 units. Therefore, for genomic prediction using expensive equipment to record traits for training populations, it is important to optimize the recording strategy. The focus should be on recording more cows rather than continuous recording on the same cows. PMID- 29525307 TI - Characterization of semipurified enterocins produced by Enterococcus faecium strains isolated from raw camel milk. AB - Food safety has become an issue of great interest worldwide. Listeria monocytogenes is a food-borne pathogen that causes listeriosis and is difficult to control in the dairy industry. The use of lactic acid bacteria (LAB) and their antimicrobial substances against Listeria is promising in food applications. Here, we report the isolation from raw camel milk of LAB displaying antilisterial activity. Two isolates were selected for their secretion of bacteriocin(s) and identified by 16S rRNA sequencing as Enterococcus faecium S6 and R9. The produced bacteriocins were partially purified by ammonium sulfate precipitation and then biochemically characterized. Antimicrobial activity was estimated to be 6,400 and 400 AU (arbitrary units)/mL for E. faecium S6 and R9, respectively. The proteinaceous nature of the bacteriocins was confirmed via enzymatic reactions. Moreover, lipolytic and glycolytic enzymes completely inactivated the antimicrobial effect of the bacteriocins. These bacteriocins were heat-resistant and stable over a wide range of pH (2.0 to 10.0). To confirm its inactivation by lipolytic and glycolytic enzymes, the bacteriocin of E. faecium S6 was further purified by gel filtration, which suggested the existence of carbohydrate and lipid moieties. In addition, enterocin-coding genes were identified by PCR, showing DNA fragments corresponding in size to enterocins A, B, and P for E. faecium S6 and to enterocins B and P for E. faecium R9. In conclusion, these results indicate that partially purified bacteriocins from E. faecium S6 and R9 may be beneficial in controlling Listeria in the dairy industry. PMID- 29525308 TI - Short communication: Is hair cortisol a potential indicator for stress caused by chronic lameness in dairy cows? AB - The objective of this study was to evaluate hair cortisol concentration as an indicator for stress caused by chronic lameness in dairy cows. Sixty-eight cows were scored for lameness for 4 consecutive weeks. The hair of the tail switch was clipped at the beginning of the study and regrown hair was clipped after 4 wk. Hair samples were analyzed for cortisol concentration. Animals with 2 consecutive locomotion scores >=3 or with an overall mean score >1.5 were classified as lame. After pair matching lame and nonlame cows, considering days in milk, lactation number, and milk yield, and excluding cows with less than 20 mg hair sample for analysis, 21 lame and 21 nonlame cows were included in the analysis. The mean hair cortisol concentration in this study was 2.32 +/- 0.35 pg/mg (mean +/- standard deviation). Cortisol concentration from hair regrown in the study period was 2.38 +/- 0.95 and 2.26 +/- 1.35 pg/mg for lame and nonlame cows (n = 21), respectively; we found no difference in mean cortisol level of primiparous and multiparous cows. Based on these data, hair cortisol concentration was not a useful indicator to differentiate cows with chronic lameness and healthy cows. PMID- 29525309 TI - Phenotypically divergent classification of preweaned heifer calves for feed efficiency indexes and their correlations with heat production and thermography. AB - The aims of this study were (1) to assess if there is phenotypical divergence for feed efficiency (FE) during the preweaning phase; (2) if FE is correlated with heat production (HP) measured by the face mask method or (3) by surface skin temperature via thermography, and (4) whether these methods are applicable to preweaned calves. Holstein * Gyr heifer calves (n = 36, birth body weight = 32.4 +/- 6.6 kg) were enrolled and on trial between 4 and 12 wk of age and were classified into 2 residual feed intake (RFI) and residual body weight gain (RG) groups: high efficiency (HE; RFI, n = 10; and RG, n = 9) and low efficiency (LE; RFI, n = 10; and RG, n = 8). Calves were fed milk (6 L/d) and solid feed (95% starter and 5% chopped Tifton 85 hay, as fed). Growth was monitored weekly and feed intake (milk and solid feed) daily, during the whole period. Gas exchanges (O2 consumption and production of CO2 and CH4) were obtained using a face mask at 45 +/- 5 d of age and HP was estimated. Maximum temperatures were measured at 7 sites with an infrared camera at 62 +/- 7 d of age. There was divergence in RFI and RG. Respectively, HE and LE calves had RFI of -0.14 and 0.13 kg/d, and RG of 0.05 and -0.07 kg/d. Dry matter intake was 15% lower in HE-RFI compared with LE RFI, but no differences were observed in average daily weight gain. Within the RG test, no differences were observed in dry matter intake or average daily gain. The HE-RFI calves consumed less O2 (L/d) and produced less CO2 (L/d). Heart rate and HP were lower for HE-RFI calves compared with LE-RFI. Residual feed intake was correlated with HP (r = 0.48), O2 consumption (r = 0.48), CO2 production (r = 0.48), and heart rate (r = 0.40). No differences were observed in HP and gas exchanges between RG groups. Methane production was null in both groups. Eye temperature measured by thermography was 0.5 degrees C greater in HE-RG than LE RG calves. Differences in skin temperature between HE and LE calves were not observed at the other sites. These results support the hypothesis that calves are divergent for RFI, RG, and FE during preweaning and divergence tests are applicable during this phase. The face mask method described here is a useful tool for estimating differences in HP among phenotypically divergent RFI calves. Eye temperature measured by infrared thermography may have potential to screen phenotypically divergent RG calves. PMID- 29525310 TI - Invited review: Use of butyrate to promote gastrointestinal tract development in calves. AB - Promotion of microbial butyrate production in the reticulorumen is a widely used method for enhancing forestomach development in calves. Additional acceleration of gastrointestinal tract (GIT) development, both the forestomach and lower parts of the GIT (e.g., abomasum, intestine, and also pancreas), can be obtained by dietary butyrate supplementation. For this purpose, different sources (e.g., butyrate salts or butyrins), forms (e.g., protected or unprotected), methods (e.g., in liquid feed or solid feed), and periods (e.g., before or after weaning) of butyrate administration can be used. The aim of this paper was to summarize the knowledge in the field of butyrate supplementation in feeds for newborn calves in practical situations, and to suggest directions of future studies. It has been repeatedly shown that supplementation of unprotected salts of butyrate (primarily sodium salt) in milk replacer (MR) stimulates the rumen, small intestine, and pancreas development in calves, with a supplementation level equating to 0.3% of dry matter being sufficient to exert the desired effect on both GIT development and growth performance. On the other hand, the effect of unprotected butyrins and protected forms of butyrate supplementation in MR has not been extensively investigated, and few studies have documented the effect of butyrate addition into whole milk (WM), with those available focusing mainly on the growth performance of animals. Protected butyrate supplementation at a low level (0.3% of protected product in DM) in solid feed was shown to have a potential to enhance GIT development and performance of calves fed MR during the preweaning period. Justification of this form of butyrate supplementation in solid feed when calves are fed WM or after weaning needs to be documented. After weaning, inclusion of unprotected butyrate salts in solid feed was shown to increase solid feed intake, but the effect on GIT development and function has not been determined in detail, and optimal levels of supplementation are also difficult to recommend based on available reports. Future studies should focus on comparing different sources (e.g., salts vs. esters), forms (e.g., protected vs. unprotected), and doses of supplemental butyrate in liquid feeds and solid feeds and their effect not only on the development of rumen, abomasum, and small intestine but also the omasum and large intestine. Furthermore, the most effective source, form, and dose of supplemental butyrate in solid feed depending on the liquid feed program (e.g., MR or WM), stage of rearing (e.g., pre- or postweaning), and solid composition (e.g., lack or presence of forage in the diet) need to be determined. PMID- 29525311 TI - The effect of lung consolidation, as determined by ultrasonography, on first lactation milk production in Holstein dairy calves. AB - Bovine respiratory disease (BRD) is a complex disease process and many reports emphasize the negative implications of clinical BRD in dairy calves. Early diagnosis can be difficult because of inconsistent or absent clinical signs; however, the use thoracic ultrasonography has the potential to improve detection of respiratory disease. Earlier detection of BRD may result in actions to improve calf welfare and production. The objective of this prospective cohort study was to determine if lung consolidation (LC) in young dairy calves influenced age at first calving (AFC), first-lactation milk production, and survival to the end of first lactation. A total of 215 female calves from 3 dairy herds in southwestern Ontario were enrolled and assessed weekly during their first 8 wk of life for evidence of LC using thoracic ultrasonography (Ibex Pro, Loveland, CO). Consolidation was measured, using gridlines on the screen of the ultrasound, in the first 10 intercostal spaces on both sides of the thorax. Calves were considered LC positive if >=3 cm of consolidated lung was present. Multivariable linear regression models were used to identify risk factors associated with AFC and first-lactation 305-d milk production. A survival analysis was conducted to determine differences in survival from enrolment until the end of first lactation between calves with and without consolidation. In the study population, the following calfhood conditions were detected: twins (4%; n = 8), diarrhea in the first 21 d of life (31%; n = 66), rib fractures (7%; n = 14), lung abscesses (3%; n = 6), and at least one diagnosis of LC (57%; n = 123). Overall, 7% (n = 15) of calves died, and 18% (n = 38) of animals were sold before the end of first lactation. The presence of LC, at least once in the first 8 wk of life, did not influence AFC, but did result in a 525 kg (95% confidence interval: -992.81 to 60.25) decrease in first-lactation 305-d milk production. No difference in survival was detected between LC groups. These results indicate that LC during the first 56 d of life has a long-term effect on dairy calves, manifested as reduced milk production during first lactation. PMID- 29525312 TI - Technical note: Simultaneous carotenoid and vitamin analysis of milk from total mixed ration-fed cows optimized for xanthophyll detection. AB - Concentrations of retinol, alpha-tocopherol, and major carotenoids in dairy products are often determined simultaneously by liquid chromatography. These compounds have different polarity and solubility; thus, extracting them simultaneously can be difficult and inefficient. In milks with low carotenoid concentrations, the xanthophylls lutein and zeaxanthin may not be completely resolved using common extraction techniques. A simplified method was developed to optimize extraction efficiency and the limit of detection and limit of quantification (LoQ) of lutein and zeaxanthin in bovine milk without decreasing sensitivity to other vitamins or carotenoids. The developed method evaluates lutein, zeaxanthin, beta-carotene, retinol, and alpha-tocopherol simultaneously by ultra-high performance liquid chromatography-photodiode array detection. Common saponification temperatures (40-60 degrees C) and concentrations of KOH in water (10-50% KOH wt/vol) were evaluated. Multiple solvents were evaluated for optimal xanthophyll extraction (diethyl ether, dichloromethane, hexane, and tetrahydrofuran) following saponification. The limit of detection and LoQ were defined as 3:1 and 10:1 signal-to-noise ratio, respectively. All experiments were performed in triplicate. The optimal saponification procedure was a concentration of 25% KOH at either 40 or 50 degrees C. Saponified extracts solubilized in solutions containing diethyl ether had greater concentrations of lutein- than hexane- or tetrahydrofuran-based solutions, with peak areas above LoQ values. The solution containing diethyl ether solubilized similar concentrations of retinol, alpha-tocopherol, and beta-carotene when compared with other solutions. The proposed optimized method allows for the simultaneous determination of carotenoids from milk with increased lutein and zeaxanthin sensitivity without sacrificing recovery of retinol, alpha-tocopherol, and beta-carotene. PMID- 29525313 TI - Estimation of relative economic weights and the marginal willingness to pay for breeding traits of Brown Swiss cattle using discrete choice experiments. AB - Breeding traits are usually combined in a total merit index according to their economic weights to maximize genetic gain based on economic merit. However, this maximization may not always be the aim of the selection decisions by farm managers. A discrete choice experiment was used to evaluate the importance of traits in terms of the selection decisions of farm managers operating in different environments. Six trait complexes, the semen price, the interactions between these traits, and significant characteristics of the farms were included in a conditional logit model to estimate relative economic weights and the marginal willingness to pay for all traits. Milk value, conformation/udder, and fitness were the most important traits for the farmers, and significant interactions indicated that fitness is of greater importance on organically managed farms than on conventional farms. Farm managers with an advanced education placed more weight on the milk value trait than farm managers without advanced education. On conventional farms, managers weighted the traits milk value and conformation/udder highly. The conformation/udder and fitness trait complexes were important on organic farms. A new trait called perinatal sucking behavior of newborn calves should be included in the total merit index. PMID- 29525314 TI - Development of an isothermal amplification-based assay for the rapid detection of Cronobacter spp. AB - Cronobacter spp. is an opportunistic pathogen that is associated with rare but life-threatening neonatal infections resulting from the consumption of contaminated powdered infant formula milk (PIF). In the present study, we developed recombinase polymerase amplification (RPA) and real-time RPA for the detection of Cronobacter spp. in PIF for the first time by targeting the ompA gene. The specificity and sensitivity of the RPA and real-time RPA were validated and the practical applicability of these methods for the detection of Cronobacter spp. in artificially contaminated PIF samples was proved by comparing their reaction time, sensitivity, and efficacy with those of real-time PCR and the Chinese traditional method. The RPA and real-time RPA assays reduced the analysis time to less than 15 min and the results were as reliable as those of real-time PCR. Taken together, the RPA and real-time RPA assays served as fast, reliable, and sensitive techniques for the detection of Cronobacter spp. PMID- 29525315 TI - Inclusion of brown midrib dwarf pearl millet silage in the diet of lactating dairy cows. AB - Brown midrib brachytic dwarf pearl millet (Pennisetum glaucum) forage harvested at the flag leaf visible stage and subsequently ensiled was investigated as a partial replacement of corn silage in the diet of high-producing dairy cows. Seventeen lactating Holstein cows were fed 2 diets in a crossover design experiment with 2 periods of 28 d each. Both diets had forage:concentrate ratios of 60:40. The control diet (CSD) was based on corn silage and alfalfa haylage, and in the treatment diet, 20% of the corn silage dry matter (corresponding to 10% of the dietary dry matter) was replaced with pearl millet silage (PMD). The effects of partial substitution of corn silage with pearl millet silage on dry matter intake, milk yield, milk components, fatty acid profile, apparent total tract digestibility of nutrients, N utilization, and enteric methane emissions were analyzed. The pearl millet silage was higher in crude protein and neutral detergent fiber and lower in lignin and starch than the corn silage. Diet did not affect dry matter intake or energy-corrected milk yield, which averaged 46.7 +/- 1.92 kg/d. The PMD treatment tended to increase milk fat concentration, had no effect on milk fat yield, and increased milk urea N. Concentrations and yields of milk protein and lactose were not affected by diet. Apparent total-tract digestibility of dry matter decreased from 66.5% in CSD to 64.5% in PMD. Similarly, organic matter and crude protein digestibility was decreased by PMD, whereas neutral- and acid-detergent fiber digestibility was increased. Total milk trans fatty acid concentration was decreased by PMD, with a particular decrease in trans-10 18:1. Urinary urea and fecal N excretion increased with PMD compared with CSD. Milk N efficiency decreased with PMD. Carbon dioxide emission was not different between the diets, but PMD increased enteric methane emission from 396 to 454 g/d and increased methane yield and intensity. Substituting corn silage with brown midrib dwarf pearl millet silage at 10% of the diet dry matter supported high milk production in dairy cows. When planning on farm forage production strategies, brown midrib dwarf pearl millet should be considered as a viable fiber source. PMID- 29525316 TI - trans-10,cis-12 conjugated linoleic acid alters lipid metabolism of goat mammary epithelial cells by regulation of de novo synthesis and the AMPK signaling pathway. AB - The trans-10,cis-12 isomer of conjugated linoleic acid (t10c12-CLA) is a biohydrogenation intermediate in the rumen and has been shown to cause milk fat depression in dairy goats. However, few studies have focused on the in vitro molecular mechanisms involved in the response of the goat mammary gland to t10c12 CLA. In the present study, RNA sequencing technology was used to investigate the effects of t10c12-CLA on goat mammary epithelial cells. From the data, 25,153 annotated transcripts were obtained, and differentially expressed genes were selected based on a false discovery rate <0.05. Candidate genes and potent cellular signaling pathways were identified through Gene Ontology (GO) and pathway analysis. Next, real-time quantitative PCR and Western blot analyses were used to verify the results of the RNA sequencing data. The results indicated that t10c12-CLA inhibits fatty acid synthesis through downregulation of genes involved in de novo fatty acid synthesis, and this process is likely correlated with the activation of the AMP-activated protein kinase signaling pathways. PMID- 29525317 TI - Short communication: Lysine retained among 2 lipid-coated lysine products after exposure to alfalfa or corn silage with different amounts of acidity. AB - We conducted 2 experiments to determine lysine loss from 2 lipid-coated lysine products after mixing with silage. In our first experiment, we mixed 2 lipid coated lysine products, crystalline lysine or crystalline lysine and amounts of lipid identical to amounts included in lipid-coated lysine products, with alfalfa or corn silage that had 2 different amounts of acidity. Lysine appeared to disassociate from lipid-coated lysine products in a nonlinear manner after mixing with either alfalfa or corn silage at different amounts of acidity. Additionally, silage source and acidity affected amounts of lysine released from lipid-coated lysine products after mixing. In a corresponding experiment, in vitro estimates of lysine available to ruminal microbiota after mixing with alfalfa or corn silage at different amounts of acidity were measured by ammonia release. In vitro measures were conducted with or without monensin to allow estimates of effects of monensin on amounts of lysine released from the 2 lipid-coated lysine products. It is unclear whether in vitro estimates of lysine fermentation from lipid-coated lysine are truly reflective of ruminal degradation of lysine from lipid-coated lysine because amounts of time needed to measure differences between different lysine sources were greater than typical estimates of mean ruminal particulate retention time. Nonetheless, monensin apparently reduced ammonia release from lysine, but ammonia release from lipid-coated lysine did not differ from crystalline lysine. Clearly, methods of manufacture together with physical and chemical characteristics of diet can affect amounts of lysine provided from lipid coated lysine products to ruminants. PMID- 29525318 TI - Fuels derived from starch digestion have different effects on energy intake and metabolic responses of cows in the postpartum period. AB - Absorbed fuels from the digestion of starch include propionic acid (PA) produced by ruminal fermentation and glucose (GLU) from intestinal digestion, which may be partially metabolized to lactic acid (LA) by intestinal tissues. Our objective was to evaluate the effects of these fuels on dry matter intake (DMI) and feeding behavior of cows in the postpartum period. We hypothesized that these fuels affect feed intake differently and that their effects are related to differences in their hepatic metabolism. Glucose was expected to have little effect on feed intake because little or no GLU is extracted from the blood by the liver. Whereas both LA and PA are anaplerotic and can stimulate oxidation of acetyl CoA in hepatocytes, hepatic extraction of PA is greater than LA, which depends on cytosolic redox state. Continuous isoenergetic infusions (150 kcal of ME/h) of PA, LA, or GLU or no infusion were administered abomasally to 8 ruminally cannulated multiparous Holstein cows (12.4 +/- 6.2 d postpartum) in a duplicate 4 * 4 Latin square design experiment, with four 1-d infusion periods, balanced for carry-over effects. Treatment sequences were assigned to cows randomly, and treatments included control (CON, no infusion), PA (0.41 mol/h), LA (0.46 mol/h), and GLU (0.22 mol/h). Solutions containing treatments were infused at 500 mL/h for 22 h/d and provided ~3.3 Mcal/d. Feeding behavior was recorded by a computerized data acquisition system. Gross energy digestibility of the diet was determined for each cow and used to calculate metabolizable energy intake (MEI) from the diet. Total MEI was calculated as the sum of MEI from the diet plus energy from infusions. Data were analyzed statistically with a mixed model including the fixed effect of treatment and random effects of block and cow within block. Each treatment was compared with CON by contrasts. Compared with CON, PA decreased DMI by 24% (14.3 vs. 18.9 kg/d) and total MEI by 13% (34.8 vs. 40.2 Mcal/d) with a tendency to decrease meal frequency. Lactic acid decreased DMI by 14% (16.3 vs. 18.9 kg/d) compared with CON by decreasing meal size 20% but did not affect MEI. Glucose infusion did not affect DMI or MEI. Treatment effects on DMI and MEI were consistent with their expected effects on hepatic oxidation. Depression of feed intake in diets containing highly fermentable starch is likely because of differences in hepatic metabolism. PMID- 29525319 TI - Dairy farmers with larger herd sizes adopt more precision dairy technologies. AB - An increase in the average herd size on Australian dairy farms has also increased the labor and animal management pressure on farmers, thus potentially encouraging the adoption of precision technologies for enhanced management control. A survey was undertaken in 2015 in Australia to identify the relationship between herd size, current precision technology adoption, and perception of the future of precision technologies. Additionally, differences between farmers and service providers in relation to perception of future precision technology adoption were also investigated. Responses from 199 dairy farmers, and 102 service providers, were collected between May and August 2015 via an anonymous Internet-based questionnaire. Of the 199 dairy farmer responses, 10.4% corresponded to farms that had fewer than 150 cows, 37.7% had 151 to 300 cows, 35.5% had 301 to 500 cows; 6.0% had 501 to 700 cows, and 10.4% had more than 701 cows. The results showed that farmers with more than 500 cows adopted between 2 and 5 times more specific precision technologies, such as automatic cup removers, automatic milk plant wash systems, electronic cow identification systems and herd management software, when compared with smaller farms. Only minor differences were detected in perception of the future of precision technologies between either herd size or farmers and service providers. In particular, service providers expected a higher adoption of automatic milking and walk over weighing systems than farmers. Currently, the adoption of precision technology has mostly been of the type that reduces labor needs; however, respondents indicated that by 2025 adoption of data capturing technology for monitoring farm system parameters would be increased. PMID- 29525321 TI - Midwives and clinical investigation: A review of the literature. AB - BACKGROUND: An allegation of negligence or an adverse outcome during childbirth can lead to clinical investigation of a midwife's practice. Anecdotal evidence suggests midwives find this stressful and disturbing. AIM: Synthesise the evidence relating to midwives' experiences of investigation and the effects on clinical practice and personal wellbeing. METHODS: Two database searches were conducted between 2015 and 2016 to identify primary research published between 1990 and 2016. Studies were evaluated for quality using standard instruments. FINDINGS: Despite numerous references to 'litigation' in peer-reviewed journals, little substantive research related specifically to midwives. 11 inclusions comprised three qualitative studies (one with two publications), reporting litigation experiences of midwives and seven quantitative studies (four research groups), identifying risk liability through cyclic surveys of midwives and law reports. Failure to identify deterioration in foetal well-being was a common finding among researchers examining reasons for litigation. Experienced midwives were at highest risk of litigation. Researchers found high levels of distress and abreaction among participants who either stopped working in birth suite or left midwifery. They also identified a level of ambiguity around defensive practices associated with fear of litigation. CONCLUSION: There is little research regarding experiences of midwives and clinical investigation. Midwives under investigation need appropriate support. Continuing to work during prolonged investigative processes is stressful as reported by midwives who described being "ill-equipped" and "unprepared." Midwives in the review preferred the support of colleagues over counsellors. Educators, employers and regulators need to work collaboratively and incorporate reflective practice in targeted support. PMID- 29525320 TI - Effect of increasing amounts of olive crude phenolic concentrate in the diet of dairy ewes on rumen liquor and milk fatty acid composition. AB - Agro-industrial by-products contain several secondary plant metabolites, such as polyphenols, tannins, saponins, and essential oils. The effects of these compounds on animal metabolism may vary significantly according to the dose, the chemical nature of the molecules, and the overall composition of the diet. In the Mediterranean area, the olive oil extraction is associated with 2 by-products: olive pomace and wastewater, both rich in polyphenols. In particular, wastewater may be further processed to obtain olive crude phenolic concentrate (OCPC). An experiment was carried out aiming to evaluate animal performance, milk fatty acid (FA) profile, diversity of rumen microbial population, and rumen liquor FA profile in dairy ewes fed diets containing extruded linseed (EL) and increasing doses of OCPC. Twenty-eight Comisana ewes in mid lactation were allotted to 4 experimental groups. The experiment lasted 5 wk after 3 wk of adaptation. Diets were characterized by lucerne hay administrated ad libitum and by 800 g/ewe and day of 4 experimental concentrates containing 22% of EL on dry matter and increasing dose of OCPC: 0 (L0), 0.6 (L0.6), 0.8 (L0.8), and 1.2 (L1.2) g of OCPC/kg of dry matter. Milk yield was daily recorded and milk composition was analyzed weekly. At the beginning and at the end of the experiment, samples of rumen liquor were collected to analyze FA profile, changes in rumen microbial population, and dimethylacetal (DMA) composition. The inclusion of OCPC did not affect milk yield and gross composition, whereas milk from L0.8 and L1.2 sheep contained higher concentrations of linoleic (+18%) and alpha-linolenic acid (+24%) and lower concentration of the rumen biohydrogenation intermediates. A similar pattern was observed for rumen liquor FA composition. No differences were found in the diversity of the rumen microbial population. Total amount of DMA did not differ among treatments, whereas significant differences were found in the concentration of individual DMA; in the diet with a higher amount of OCPC, DMA 13:0, 14:0, 15:0, and 18:0 increased, whereas DMA 16:0 decreased. Probably the presence of polyphenols in the diet induced a rearrangement of bacteria membrane phospholipids as a response to the rumen environment stimulus. Overall, the use of OCPC allowed a significant increase in the polyunsaturated FA content of milk, probably due to a perturbation of the rumen biohydrogenation process. Further studies are needed to understand the correlation between diet composition and the pattern of DMA in rumen liquor. PMID- 29525323 TI - In Reply to 'Stepwise Attempts on the Forearm Protect Against Exhaustion of Vascular Access Options'. PMID- 29525322 TI - Laryngeal nerve morbidity in 1.273 central node dissections for thyroid cancer. AB - AIM: We assess the prevalence and mechanism of recurrent laryngeal nerve (RLN) injury in central neck dissection (CND) for thyroid cancer. METHODS: CND with intraoperative neural monitoring was outlined in 1.273 nerves at risk (NAR). RLN lesions were stratified according to: timing (during thyroidectomy versus CND), segmental vs. diffuse injury, mechanism, severity, location, number of lymph nodes dissected and metastastatic. EMG parameters were recorded. RESULTS: 49/1.273NAR (3,8%) documented RLN palsy. 25 nerves were injured during thyroidectomy, 8 while CND. In 16 no precise moment or mechanism of injury was identified. A disrupted point could be identified in 19/25 (76%) and 7/8 (87%) respectively for thyroidectomy and CND steps. Diffuse injury, occurred in 24% and 12,5% respectively for thyroidectomy and CND. Nerves were injured in the all cervical nerve course without any major location for incidence for CND; for thyroidectomy most nerves were injured in the last 1 cm course. Traction (36%) was the leading cause of RLN injury for thyroidectomy. For solely CND, traction, entrapment and thermal injuries were equally frequent. Permanent vs. transient injuries were respectively 8% (4/49) and 92% (n.45/49), overall. Permanent lesions were equally distributed. CONCLUSIONS: During CND, RLN palsy still occurs with routine exposure of the nerve even combined with IONM. The incidence of nerve lesions during thyroidectomy is higher than that of CND. PMID- 29525324 TI - Residential Area Life Expectancy: Association With Outcomes and Processes of Care for Patients With ESRD in the United States. AB - BACKGROUND: The effects of underlying noncodified risks are unclear on the prognosis of patients with end-stage renal disease (ESRD). We aimed to evaluate the association of residential area life expectancy with outcomes and processes of care for patients with ESRD in the United States. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult patients with incident ESRD between 2006 and 2013 recorded in the US Renal Data System (n=606,046). PREDICTOR: The primary exposure was life expectancy in the patient's residential county estimated by the Institute for Health Metrics and Evaluation. OUTCOMES: Death, placement on the kidney transplant wait list, living and deceased donor kidney transplantation, and posttransplantation graft loss. RESULTS: Median life expectancies of patients' residences were 75.6 (males) and 80.4 years (females). Compared to the highest life expectancy quintile and adjusted for demographic factors, disease cause, and multiple comorbid conditions, the lowest quintile had adjusted HRs for mortality of 1.20 (95% CI, 1.18-1.22); placement onto the waiting list, 0.68 (95% CI, 0.67-0.70); living donor transplantation, 0.53 (95% CI, 0.51-0.56); posttransplantation graft loss, 1.35 (95% CI, 1.27-1.43); and posttransplantation mortality, 1.29 (95% CI, 1.19-1.39). Patients living in areas with lower life expectancy were less likely to be informed about transplantation, be under the care of a nephrologist, or receive an arteriovenous fistula as the initial dialysis access. Results remained consistent with additional adjustment for zip code-level median income, population size, and urban-rural locality. LIMITATIONS: Potential residual confounding and attribution of effects to individuals based on residential area-level data. CONCLUSIONS: Residential area life expectancy, a proxy for socioeconomic, environmental, genetic, and behavioral factors, was independently associated with mortality and process-of care measures for patients with ESRD. These results emphasize the underlying effect on health outcomes of the environment in which patients live, independent of patient-level factors. These findings may have implications for provider assessments. PMID- 29525325 TI - Stepwise Attempts on the Forearm Protect Against Exhaustion of Vascular Access Options. PMID- 29525326 TI - Narrowing the Disparities in Heart Failure: Treat the Event or Try to Prevent? PMID- 29525327 TI - Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2. AB - Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The features of this syndrome appear to be related (in part) to the overproduction of adipocyte derived cell-signaling molecules, including aldosterone and neprilysin. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis. Inhibitors of aldosterone, neprilysin, and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors and is being further tested in an ongoing large-scale trial of neprilysin inhibition. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that physicians might finally have a phenotype of HFpEF that they can understand and treat. PMID- 29525328 TI - Is Time of the Essence? The Impact of Time of Hospital Presentation in Acute Heart Failure: Insights From ASCEND-HF Trial. AB - OBJECTIVES: As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF. BACKGROUND: Time of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized. METHODS: A post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation. RESULTS: Overall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40). CONCLUSIONS: In this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials. PMID- 29525329 TI - Diastole Tracks Cardiometabolic Risk. PMID- 29525331 TI - "Recovering" the Recognition for VO2 Kinetics During Exercise Recovery in Heart Failure: A Good Practice in Need of More Exercise. PMID- 29525330 TI - Post-Exercise Oxygen Uptake Recovery Delay: A Novel Index of Impaired Cardiac Reserve Capacity in Heart Failure. AB - OBJECTIVES: This study sought to characterize the functional and prognostic significance of oxygen uptake (VO2) kinetics following peak exercise in individuals with heart failure (HF). BACKGROUND: It is unknown to what extent patterns of VO2 recovery following exercise reflect circulatory response during exercise in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). METHODS: We investigated patients (30 HFpEF, 20 HFrEF, and 22 control subjects) who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and a second distinct HF cohort (n = 106) who underwent noninvasive cardiopulmonary exercise testing with assessment of long term outcomes. Fick cardiac output (CO) and cardiac filling pressures were measured at rest and throughout exercise in the initial cohort. A novel metric, VO2 recovery delay (VO2RD), defined as time until post-exercise VO2 falls permanently below peak VO2, was measured to characterize VO2 recovery kinetics. RESULTS: VO2RD in patients with HFpEF (median 25 s [interquartile range (IQR): 9 to 39 s]) and HFrEF (28 s [IQR: 2 to 52 s]) was in excess of control subjects (5 s [IQR: 0 to 7 s]; p < 0.0001 and p = 0.003, respectively). VO2RD was inversely related to cardiac output augmentation during exercise in HFpEF (rho = -0.70) and HFrEF (rho = -0.73, both p < 0.001). In the second cohort, VO2RD predicted transplant-free survival in univariate and multivariable Cox regression analysis (Cox hazard ratios: 1.49 and 1.37 per 10-s increase in VO2RD, respectively; both p < 0.005). CONCLUSIONS: Post-exercise VO2RD is an easily recognizable, noninvasively derived pattern that signals impaired cardiac output augmentation during exercise and predicts outcomes in HF. The presence and duration of VO2RD may complement established exercise measurements for assessment of cardiac reserve capacity. PMID- 29525332 TI - Worsening Heart Failure During the Use of DPP-4 Inhibitors: Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications. AB - Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction. PMID- 29525333 TI - Innovation in Heart Failure Treatment: Life Expectancy, Disability, and Health Disparities. AB - OBJECTIVES: The goal of this study was to illustrate the potential benefit of effective congestive heart failure (CHF) treatment in terms of improved health, greater social value, and reduced health disparities between black and white subpopulations. BACKGROUND: CHF affects 5.7 million Americans, costing $32 billion annually in treatment expenditures and lost productivity. CHF also contributes to health disparities between black and white Americans: black subjects develop CHF at a younger age and are more likely to be hospitalized and die of this disease. Improved CHF treatment could generate significant health benefits and reduce health disparities. METHODS: We adapted an established economic-demographic microsimulation to estimate scenarios in which a hypothetical innovation eliminates the incidence of CHF and, separately, 6 other diseases in patients 51 to 52 years of age in 2016. This cohort was followed up until death. We estimated total life years, quality-adjusted life years, and disability-free life years with and without the innovation, for the population overall and for race- and sex-defined subpopulations. RESULTS: CHF prevalence among 65- to 70-year-olds increased from 4.3% in 2012 to 8.5% in 2030. Diagnosis with CHF coincided with significant increases in disability and medical expenditures, particularly among black subjects. Preventing CHF among those 51 to 52 years of age in 2016 would generate nearly 2.9 million additional life years, 1.1 million disability-free life years, and 2.1 million quality-adjusted life years worth $210 to $420 billion. These gains are greater among black subjects than among white subjects. CONCLUSIONS: CHF prevalence will increase substantially over the next 2 decades and will affect black Americans more than white Americans. Improved CHF treatment could generate significant social value and reduce existing health disparities. PMID- 29525334 TI - Comorbidities and Cardiometabolic Disease: Relationship With Longitudinal Changes in Diastolic Function. AB - OBJECTIVES: This study sought to evaluate the course, correlates, and prognosis of longitudinal changes in left ventricular (LV) diastolic dysfunction (DD) in the community-based Framingham Heart Study. BACKGROUND: Relationships of clinical risk factors to longitudinal progression of DD are incompletely understood. METHODS: Diastolic function was assessed by echocardiography performed at consecutive examinations (visits 1 and 2, mean interval 5.6 years) in 1,740 participants (64 +/- 8 years of age at visit 1, 59% women) with normal LV systolic function and no atrial fibrillation. RESULTS: Of 1,615 individuals with normal-to-mild DD at visit 1, 198 (12%) progressed to >= moderate DD at visit 2. Progression was more likely in women and with advancing age (p < 0.0001). Of 125 individuals with >= moderate DD at visit 1, 25 (20%) regressed to normal-to-mild DD by visit 2. Regression of DD was associated with younger age (p < 0.03). In stepwise regression models, age, female sex, baseline and changes in systolic blood pressure, diastolic blood pressure, body mass index, serum triglycerides, and diabetes were positively associated with worsening diastolic function (all p < 0.05). Noncardiac comorbidity tracked with progressive DD. Cardiovascular disease (CVD) or death events occurred in 44 of 1,509 participants free of CVD at visit 2, during 2.7 +/- 0.6 years of post-visit 2 follow-up. Presence of >= moderate DD was associated with higher risk (age- and sex-adjusted hazard ratio for CVD or death: 2.14; 95% confidence interval: 1.06 to 4.32; p = 0.03). CONCLUSIONS: In a community-based cohort of middle-aged to older adults, cardiometabolic risk factors and noncardiac comorbidities were associated with DD progression. Moderate or worse DD was associated with higher risk of CVD or death. PMID- 29525335 TI - Design and synthesis of estrogen receptor ligands with a 4-heterocycle-4 phenylheptane skeleton. AB - The estrogen receptor (ER), a member of the nuclear receptor (NR) family, is involved in the regulation of physiological effects such as reproduction and bone homeostasis. Approximately 70% of human breast cancers are hormone-dependent and ERalpha-positive, and, thus, ER antagonists are broadly used in breast cancer therapy. We herein designed and synthesized a set of ER antagonists with a 4 heterocycle-4-phenylheptane skeleton. PMID- 29525336 TI - Sulfamic acid promoted one-pot synthesis of phenanthrene fused-dihydrodibenzo quinolinones: Anticancer activity, tubulin polymerization inhibition and apoptosis inducing studies. AB - A facile one-pot method for the synthesis of new phenanthrene fused dihydrodibenzo-quinolinone derivatives has been successfully accomplished by employing sulfamic acid as catalyst. These new compounds were evaluated for their in vitro cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MCF-7) and colon (HT-29 and HCT-116) cancer cell lines. Among all the tested compounds, one of the derivatives 8p showed good anti-proliferative activity against A549 lung cancer cell line with an IC50 of 3.17 +/- 0.52 uM. Flow cytometric analyses revealed that compound 8p arrested both Sub G1 and G2/M phases of cell cycle in a dose dependent manner. The compound 8p also displayed significant inhibition of tubulin polymerization and disruption of microtubule network (IC50 of 5.15 +/- 0.15 uM). Molecular docking studies revealed that compound 8p efficiently interacted with critical amino acid Cys241 of the alpha/beta-tubulin by a hydrogen bond (SH...O = 2.4 A). Further, the effect of 8p on cell viability was also studied by AO/EB, DCFDA and DAPI staining. The apoptotic characteristic features revealed that 8p inhibited cell proliferation effectively through apoptosis by inducing the ROS generation. Analysis of mitochondrial membrane potential through JC-1 staining and annexin V binding assay indicated the extent of apoptosis in A549 cancer cells. PMID- 29525337 TI - Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2 (pyrimidin-2-yl)thiazole derivatives. AB - Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4 (aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site. PMID- 29525338 TI - Fused Frontal Lobes on Prenatal Magnetic Resonance Imaging. PMID- 29525339 TI - The Role of National and International Neurology Societies in Global Health. PMID- 29525340 TI - Incidence and Risk Factors for Blood Transfusion in Simultaneous Bilateral Total Joint Arthroplasty: A Multicenter Retrospective Study. AB - BACKGROUND: The aim of this study was to identify the incidence and risk factors for blood transfusion in patients undergoing simultaneous bilateral total hip arthroplasty (SBTHA) and simultaneous bilateral total knee arthroplasty (SBTKA). METHODS: We identified 414 SBTHA and 1147 SBTKA procedures, and separated the patients into those who did and did not require allogeneic blood transfusion. A multivariate logistic regression model was used to identify independent risk factors for transfusion. RESULTS: The transfusion rate after SBTHA was 50.0%, and significant risk factors for transfusion were female gender (odds ratio [OR] = 2.612), lower body mass index (OR = 1.093), inflammatory arthritis (OR = 1.970), American Society of Anesthesiologists (ASA) class >=3 (OR = 3.477), drain use (OR = 4.607), and increased intraoperative bleeding. We also found that higher preoperative hemoglobin (Hb) and tranexamic acid use decreased the risk of transfusion. The transfusion rate after SBTKA was 29.1%, and significant risk factors for transfusion were ASA class >=3 (OR = 8.959), tourniquet use (OR = 2.129), drain use (OR = 4.970), and increased intraoperative bleeding. A higher preoperative Hb was the only protective factor for transfusion. CONCLUSION: For SBTHA, the risk factors included female gender, lower body mass index, inflammatory arthritis, ASA class >=3, drain use, and increased intraoperative bleeding, while for SBTKA, risk factors were ASA class >=3, tourniquet use, drain use, and increased intraoperative bleeding. Increasing the preoperative Hb level may decrease transfusion risk. In addition, tranexamic acid was encouraged to use to decrease transfusion need in SBTHA. PMID- 29525341 TI - Constrained Acetabular Liners. AB - BACKGROUND: Dislocation remains one of the most common complications after total hip arthroplasty. Constrained acetabular liners were developed to address the problem of recurrent instability. They have been in clinical use since the mid 1980s and function by capturing the femoral head. METHOD: The aim of this review is to highlight the mechanism of action, development, and advances in constrained liner design, together with an emphasis on the modes of failure and the authors' opinion on the current indications for the use of these implants. RESULTS: A systematic review of the literature summarizes the current body of published evidence on the results of constrained liners. Overall, at best level III evidence is available. In the 38 studies included, this study considered a total of 2852 constrained liners with a mean follow-up 4.3 years (range 0.8-20 years), which had a mean dislocation and/or constrained failure rate of 11.4% (95% confidence interval 10.3-12.6). CONCLUSION: Constrained acetabular liners remain an important option in the armamentarium of the revision hip surgeon. At this point in time with current designs and published results, they should remain a salvage device. The implantation of a constrained liner should be considered when all other factors related to the total hip arthroplasty have been optimized, especially component malposition. PMID- 29525342 TI - Revision of Unicompartmental to Total Knee Arthroplasty: Does the Unicompartmental Implant (Metal-Backed vs All-Polyethylene) Impact the Total Knee Arthroplasty? AB - BACKGROUND: The aim of this study is to investigate differences in implant requirement, outcomes, and re-revision when total knee arthroplasty (TKA) was performed following unicompartmental knee arthroplasties (UKAs) with metal-backed (MB) compared to all-polyethylene (AP) tibial components. METHODS: Retrospective study of 60 UKAs converted to 60 TKAs at mean 7.3 years (0.1 to 17) after implantation in 55 patients (mean age, 64 [49-83]; 44% male): 44 MB and 16 AP. TKA implant requirement was investigated in addition to mode of failure, Oxford Knee Score, and TKA survival at mean 5.4 years (0.5 to 17). RESULTS: Progression of osteoarthritis was the commonest mode of failure in MB UKAs (P = .03) and unexplained pain in AP (P = .011) where revisions were performed earlier (4.8 +/- 3.2 vs 8.2 +/- 4.5, P = .012). In 56 of 60 (93%) cases, unconstrained TKA implants were used. The use of standard cruciate-retaining TKAs without augments or stems was less likely following MB UKA compared to AP (12 of 38 [32%] vs 10/14 [71%], P = .013). Specifically MB UKA implants were associated with more tibial stem use (P = .04) and more use of cruciate-substituting polyethylene (P = .05). There was no difference in the use of constrained implants. Multivariate analysis showed tibial resection depth to predict stem requirement. Seven were re-revised giving 7-year TKA survival: from MB UKA 70.3 (95% CI, 47.0 to 93.6) and from AP UKA 87.5 (95% CI, 64.6 to 100; P = .191). CONCLUSION: MB UKA implants increase the chances of a complex revision requiring tibial stems and cruciate substitution but reduce the chances of early revision compared to AP UKA which often fail early with pain. PMID- 29525343 TI - Lessons Learned from Effective Models of Joint Replacement Care in the United States. PMID- 29525344 TI - Prevention of Dislocation After Total Hip Arthroplasty. AB - BACKGROUND: Prevention of dislocation after primary total hip arthroplasty (THA) begins with patient preoperative assessment and planning. METHODS: We performed a literature search to assess historical perspectives and current strategies to prevent dislocation after primary THA. The search yielded 3458 articles, and 154 articles are presented. RESULTS: Extremes of age, body mass index >30 kg/m2, lumbosacral pathology, surgeon experience, and femoral head size influence dislocation rates after THA. There is mixed evidence regarding the effect of neuromuscular disease, sequelae of pediatric hip conditions, and surgical approach on THA instability. Sex, simultaneous bilateral THA, and restrictive postoperative precautions do not influence the dislocation rates of THA. Navigation, robotics, lipped liners, and dual-mobility acetabular components may improve dislocation rates. CONCLUSIONS: Risks for dislocation should be identified, and measures should be taken to mitigate the risk. Reliance on safe zones of acetabular component positioning is historical. We are in an era of bespoke THA surgery. PMID- 29525345 TI - Incise Draping Reduces the Rate of Contamination of the Surgical Site During Hip Surgery: A Prospective, Randomized Trial. AB - BACKGROUND: Iodophor-impregnated adhesive incise drapes are widely used during surgeries for reducing surgical site contamination. There is little evidence to support the latter belief. This study evaluated the efficacy of iodophor impregnated adhesive drapes for reducing bacterial contamination and counts at the incision site during hip surgery. METHODS: In this prospective, randomized clinical trial, we enrolled 101 patients undergoing open joint preservation procedure of the hip. Half the patients had the adhesive drape applied to the skin prior to incision, while the remainder underwent the same surgery without a drape. Culture swabs were taken from the surgical site at 5 points (preskin preparation, after skin preparation, postincision, before subcutaneous closure, prior to dressing application) and sent for culture and colony counts. Mixed effects logistic regressions were used to estimate effects of time and drape application on contamination rate. RESULTS: At the conclusion of surgery, 12.0% of incisions with adhesive drapes and 27.4% without adhesive drapes were positive for bacterial colonization. When controlling for preoperative colonization and other factors, patients without adhesive drapes were significantly more likely to have bacteria present at the time of skin closure, and at all time points when swab cultures were taken. CONCLUSION: It appears that the iodophor-impregnated adhesive draping significantly reduces bacterial colonization of the incision. Bacterial count at the skin was extremely high in some patients in whom adhesive drapes were not used, raising the possibility that a subsequent surgical site infection or periprosthetic joint infection could arise had an implant been utilized. PMID- 29525346 TI - NKG2D and its ligands in cancer. AB - NKG2D is an activating immune receptor expressed by NK and effector T cells. Induced expression of NKG2D ligand on tumor cell surface during oncogenic insults renders cancer cells susceptible to immune destruction. In advanced human cancers, tumor cells shed NKG2D ligand to produce an immune soluble form as a means of immune evasion. Soluble NKG2D ligands have been associated with poor clinical prognosis in cancer patients. Harnessing NKG2D pathway is considered a viable avenue in cancer immunotherapy over recent years. In this review, we will discuss the progress and perspectives. PMID- 29525347 TI - Metabolites, genome organization, and cellular differentiation gene programs. AB - The nutrient environment and metabolism play a dynamic role in cellular differentiation and research is elucidating the mechanisms that contribute to this process. Metabolites serve as an effective bridge that helps to translate information about nutrient states into specific interpretations of the genome. Part of this activity relates to the role for metabolites in regulating epigenetic processes as well as a newly appreciated role for metabolites in the regulation of genome organization. In this review, we will highlight recent research that has defined roles for metabolism in the organization and interpretation of the genome and how this influences cellular differentiation decisions. We will integrate information about how nutrients, such as glutamine, regulate metabolites, such as alpha-ketoglutarate, and highlight how these pathways influence epigenetic states as well as CTCF association and genome organization. We will also discuss mechanistic similarities and differences between normal differentiation states associated with embryonic stem (ES) cells and T cells and how this might relate to dysregulated states such as those associated with tumor infiltrating lymphocytes. PMID- 29525348 TI - Synthesis, molecular docking study and thymidine phosphorylase inhibitory activity of 3-formylcoumarin derivatives. AB - Thymidine phosphorylase (TP) over expression plays role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. The inhibitor of this enzyme plays an important role in preventing the serious threat due to over expression of TP. In this regard, a series of seventeenanalogs of 3-formylcoumarin (1-17) were synthesized, characterized by 1HNMR and EI-MS and screened for thymidine phosphorylaseinhibitory activity. All analogs showed a variable degree of thymidine phosphorylase inhibition with IC50 values ranging between 0.90 +/- 0.01 and 53.50 +/- 1.20 MUM when compared with the standard inhibitor 7-Deazaxanthine having IC50 value 38.68 +/- 1.12 MUM. Among the series, fifteenanalogs such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16 and 17 showed excellent inhibition which is many folds better than the standard 7-Deazaxanthine whiletwo analogs 13 and 14 showed good inhibition. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl ring. Molecular docking study was carried out to understand the binding interaction of the most active analogs. PMID- 29525349 TI - High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma. AB - BACKGROUND: A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied. PATIENTS AND METHODS: Clinical data and formalin-fixed paraffin-embedded tissues of pT1 UBC treated with an organ preserving approach was analyzed retrospectively. Total RNA was isolated using commercial RNA extraction kits and mRNA expression of CDKN2A/p16 and FGFR3 was measured using single step reverse transcription quantitative real time polymerase chain reaction using RNA-specific TaqMan assays. RESULTS: Data from 296 patients (79.4% male; median age: 72 years) could be used for the final evaluation. Spearman correlation revealed a statistically significant negative correlation between mRNA expression of CDKN2A/p16 and FGFR3. There was a positive correlation between CDKN2A/p16 and G3 tumors (rho = 0.1875; P = .0012) and associated carcinoma in situ (rho = 0.1703, P = .0033) and a negative correlation between FGFR3 and these factors (rho = -0.2791, P < .0001 and rho = -0.2182, P = .0002). High CDKN2A/p16 expression (>=38.04) and low FGFR3 expression (<39.14) were statistically significantly associated with worse progression-free survival (PFS; P = .0194 and P = .0089). Multivariate Cox regression analysis could identify patients with low FGFR3 and high CDKN2A/p16 expression (log rank (LR) chi2 = 10.69; P = .0048) as well as tumor size >=3 cm (LR chi2 = 6.03; P = .0141) as independent predictors for PFS. CONCLUSION: High expression of CDKN2A/p16 and low expression of FGFR3 show a correlation with established prognostic features for non-muscle-invasive bladder cancer and can predict progression of stage pT1 UBC. PMID- 29525350 TI - Genome-wide QTL analysis for anxiety trait in bipolar disorder type I. AB - BACKGROUND: Genetic studies have been consistent that bipolar disorder type I (BPI) runs in families and that this familial aggregation is strongly influenced by genes. In a preliminary study, we proved that anxiety trait meets endophenotype criteria for BPI. METHODS: We assessed 619 individuals from the Central Valley of Costa Rica (CVCR) who have received evaluation for anxiety following the same methodological procedure used for the initial pilot study. Our goal was to conduct a multipoint quantitative trait linkage analysis to identify quantitative trait loci (QTLs) related to anxiety trait in subjects with BPI. We conducted the statistical analyses using Quantitative Trait Loci method (Variance components models), implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR), using 5606 single nucleotide polymorphism (SNPs). RESULTS: We identified a suggestive linkage signal with a LOD score of 2.01 at chromosome 2 (2q13-q14). LIMITATIONS: Since confounding factors such as substance abuse, medical illness and medication history were not assessed in our study, these conclusions should be taken as preliminary. CONCLUSIONS: We conclude that region 2q13-q14 may harbor a candidate gene(s) with an important role in the pathophysiology of BPI and anxiety. PMID- 29525351 TI - The prevalence and correlates of severe depression in a cohort of Mexican teachers. AB - BACKGROUND: Depression is among the 10 major causes of disability in Mexico. Yet, local contextual factors associated to the disorder remain poorly understood. We measured the impact of several factors on severe depression such as demographics, pharmacotherapy, multimorbidity, and unhealthy behaviors in Mexican teachers. METHODS: A total of 43,845 Mexican female teachers from 12 Mexican states answered the Patient Health Questionnaire (PHQ9). Data were part the Mexican Teacher's Cohort prospective study, the largest ongoing cohort study in Latin America. Unadjusted and adjusted estimates assessed the impact of several contextual factors between severe versus mild-no depression cases. RESULTS: In total 7026 teachers (16%) had a PHQ9 score compatible with severe depression. From them, only 17% received psychotropics, compared to 60% for those with a formal diagnosis. Less than 5% of teachers with PHQ9 scores compatible with severe depression had a formal diagnosis. Adjusted analysis reported higher odds of pharmacotherapy, having >= 3 comorbidities, higher levels of couple, family and work stress, fewer hours of vigorous physical activity, higher alcohol consumption, and smoking as risk factors for severe depression. Also, rural residents of northern and center states appeared more severely depressed compared to their urban counterparts. On average, the PHQ9 scores differed by ~ 10 points between severe and mild-no depressed teachers. LIMITATIONS: A cross-sectional design. Also, the study focused on female teachers between ages 25 and 74 years old, reducing the generalizability of the estimates. CONCLUSION: Under-diagnosis of clinical depression in Mexican teachers is concerning. Unhealthy behavior is associated with severe depression. The information collected in this study represents an opportunity to build prevention mechanisms of depression in high risk subgroups of female educators and warrants improving access to mental care in Mexico. PMID- 29525352 TI - Mortality risk associated with psychological distress and major depression: A population-based cohort study. AB - BACKGROUND: Few studies have examined the impact of psychological distress on mortality. We aimed to estimate mortality rates of psychological distress and major depressive disorder (MDD) compared to a referent group with no MDD or psychological distress. METHODS: Our study population (N = 10 181) consisted of respondents from the Canadian Community Health Survey Cycle 1.2 linked to Ontario health administrative databases followed for up to 11 years. We used Cox proportional hazards models to assess overall, sex-specific, as well as short term (within two years of follow-up) and long-term (follow-up >= two years) mortality among those with DSM-criteria MDD and psychological distress independent of MDD adjusted for socio-demographic, lifestyle and clinical factors. RESULTS: Individuals with psychological distress (n = 666) had a similar mortality rate as those with MDD (n = 428) and significantly greater adjusted hazards of death than the referent group (hazard ratio = 1.57, 95% CI = 1.14 2.15). The risk of death was greatest in the short-term among those with MDD, however, we observed a persistent 1.6-fold increased risk in both the short- and long-term among those with psychological distress compared to the referent. Women with MDD had the greatest mortality rate and died a median of 15 years earlier than women in the referent group. LIMITATIONS: Psychological distress and MDD were ascertained at baseline with small number of deaths in the early follow-up period. Survey variables were prone to self-report bias with a possibility of residual confounding. CONCLUSIONS: Focused longitudinal research and targeted management strategies for those with psychological distress and women with MDD are warranted. PMID- 29525353 TI - Response pattern of depressive symptoms among college students: What lies behind items of the Beck Depression Inventory-II? AB - BACKGROUND: This study examines the response pattern of depressive symptoms in a nationwide student sample, through item analyses of a rating scale by both classical test theory (CTT) and item response theory (IRT). METHODS: The 21-item Beck Depression Inventory-II (BDI-II) was administered to 12,711 college students. First, the psychometric properties of the scale were described. Thereafter, the endorsement probability of depressive symptom in each scale item was analyzed through CTT and IRT. Graphical plots depicted the endorsement probability of scale items and intensity of depression. Three items of different difficulty level were compared through CTT and IRT approach. RESULTS: Four in five students reported the presence of depressive symptoms. The BDI-II items presented good reliability and were distributed along the symptomatic continuum of depression. Similarly, in both CTT and IRT approaches, the item 'changes in sleep' was easily endorsed, 'loss of interest' moderately and 'suicidal thoughts' hardly. Graphical representation of BDI-II of both methods showed much equivalence in terms of item discrimination and item difficulty. The item characteristic curve of the IRT method provided informative evaluation of item performance. LIMITATION: The inventory was applied only in college students. CONCLUSION: Depressive symptoms were frequent psychopathological manifestations among college students. The performance of the BDI-II items indicated convergent results from both methods of analysis. While the CTT was easy to understand and to apply, the IRT was more complex to understand and to implement. Comprehensive assessment of the functioning of each BDI-II item might be helpful in efficient detection of depressive conditions in college students. PMID- 29525354 TI - Clinical and psychopathological features associated with treatment-emergent mania in bipolar-II depressed outpatients exposed to antidepressants. AB - BACKGROUND: Treatment-emergent affective switch (TEAS), including treatment emergent mania (TEM), carry significant burden in the clinical management of bipolar depression, whereas the use of antidepressants raises both efficacy, safety and tolerability concerns. The present study assesses the prevalence and clinical correlates of TEM in selected sample of Bipolar Disorder (BD) Type-II (BD-II) acute depression outpatients. METHODS: Post-hoc analysis of the clinical and psychopathological features associated with TEM among 91 BD-II depressed outpatients exposed to antidepressants. RESULTS: Second-generation antipsychotics (SGA) (p = .005), lithium (<= .001), cyclothymic/irritable/hyperthymic temperaments (p = <= .001; p = .001; p = .003, respectively), rapid-cycling (p = .005) and depressive mixed features (p = .003) differed between TEM+ cases vs. TEM- controls. Upon multinomial logistic regression, the accounted psychopathological features correctly classified as much as 88.6% of TEM+ cases (35/91 overall sample, or 38.46% of the sample), yet not statistically significantly [Exp(B) = .032; p = ns]. Specifically, lithium [B = - 2.385; p = .001], SGAs [B = - 2.354; p = .002] predicted lower rates of TEM+ in contrast to the number of lifetime previous psychiatric hospitalizations [B = 2.380; p = .002], whereas mixed features did not [B = 1.267; p = ns]. LIMITATIONS: Post-hoc analysis. Lack of systematic pharmacological history record; chance of recall bias and Berkson's biases. Permissive operational criterion for TEM. Relatively small sample size. CONCLUSIONS: Cyclothymic temperament and mixed depression discriminated TEM+ between TEM- cases, although only lithium and the SGAs reliably predicted TEM+/- grouping. Larger-sampled/powered longitudinal replication studies are warranted to allow firm conclusions on the matter, ideally contributing to the identification of clear-cut sub-phenotypes of BD towards patient-tailored-pharmacotherapy. PMID- 29525356 TI - Looking back on the alternative complement pathway. AB - The alternative pathway of complement originated from the Properdin pathway originally described by the Pillemer laboratory in the 1950s. This work generated great controversy and it took several decades for a consensus on its components, its reaction sequence and its functions to emerge. This paper reviews this history and attempts to clarify some of the ambiguities that remain. PMID- 29525355 TI - Tracking intracellular uptake and localisation of alkyne tagged fatty acids using Raman spectroscopy. AB - Intracellular uptake, distribution and metabolism of lipids are tightly regulated characteristics in healthy cells. An analytical technique capable of understanding these characteristics with a high level of species specificity in a minimally invasive manner is highly desirable in order to understand better how these become disrupted during disease. In this study, the uptake and distribution of three different alkyne tagged fatty acids in single cells were monitored and compared, highlighting the ability of Raman spectroscopy combined with alkyne tags for better understanding of the fine details with regard to uptake, distribution and metabolism of very chemically specific lipid species. This indicates the promise of using Raman spectroscopy directly with alkyne tagged lipids for cellular studies as opposed to subsequently clicking of a fluorophore onto the alkyne for fluorescence imaging. PMID- 29525357 TI - Freshly-mixed and setting calcium-silicate cements stimulate human dental pulp cells. AB - OBJECTIVES: To evaluate the effect of the eluates from 3 freshly-mixed and setting hydraulic calcium-silicate cements (hCSCs) on human dental pulp cells (HDPCs) and to examine the effect of a newly developed hCSC containing phosphopullulan (PPL) on HDPCs. METHODS: Human dental pulp cells, previously characterized as mesenchymal stem cells, were used. To collect the eluates, disks occupying the whole surface of a 12-well plate were prepared using an experimental hCSC containing phosphopullulan (GC), Nex-Cem MTA (GC), Biodentine (Septodont) or a zinc-oxide (ZnO) eugenol cement (material-related negative control). Immediately after preparing the disks (non-set), 3ml of Dulbecco's Modified Eagle Medium (DMEM) with 10% fetal bovine serum (FBS) were added. The medium was left in contact with the disks for 24h before being collected. Four different dilutions were prepared (100%, 50%, 25% and 10%) and cell-cytotoxicity, cell-proliferation, cell-migration and odontogenic differentiation were tested. The cell-cytotoxicity and cell-proliferation assays were performed by XTT colorimetric assay at different time points. The cell-migration ability was tested with the wound-healing assay and the odontogenic differentiation capacity of hCSCs on HDPCs was tested with RT-PCR. RESULTS: Considering all experimental data together, the eluates from 3 freshly-mixed and setting hCSCs appeared not cytotoxic toward HDPCs. Moreover, all three cements stimulated proliferation, migration and odontogenic differentiation of HDPCs. SIGNIFICANCE: The use of freshly-mixed and setting hCSCs is an appropriate approach to test the effect of the materials on human dental pulp cells. The experimental material containing PPL is non-cytotoxic and positively stimulates HDPCs. PMID- 29525358 TI - Acidic pH weakens the bonding effectiveness of silane contained in universal adhesives. AB - OBJECTIVES: Some silane-containing universal adhesives were introduced that a separate ceramic primer was unnecessary to glass-ceramic bonding because of incorporated silane. We aimed to investigate the effectiveness of silane in universal adhesives with acidic media. METHODS: A functional gamma methacryloxypropyltrimethoxysilane (gamma-MPTS) was used, and its pH value was adjusted to 2.7 by adding hydrochloric acid (HCl) or 10-methacryloxydecyl phosphate (MDP). The prepared acidic silane solutions after 2h or 10d storage were characterized by Fourier transform infrared spectroscopy (FTIR), 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. Micro-shear bond strength (MUSBS) was used to evaluate the bonding performance of glass ceramics. Two silane containing and two silane-free universal adhesives were included. Field-emission scanning electron microscopy fractography analysis was also performed. RESULTS: FTIR, 1H and 13C NMR revealed that the hydrolysis of gamma-MPTS and the self condensation reaction of silanol groups occurred over time under acidic conditions (HCl or MDP solution). This reaction formed the siloxane oligomers. For glass-ceramic bonding, the MUSBS of acidic silane after 10 d storage was lower than that of silane stored for 2h storage (p<0.05), although the difference among the MUSBS of the four universal adhesives were nonsignificant (p>0.05). Additionally, cohesive failure was the main fracture pattern of universal adhesive bonding. SIGNIFICANCE: The effectiveness of silane contained in low pH universal adhesives can be weakened by dehydration self-condensation and consequently became unstable. For the enhancement of glass-ceramic bonding efficiency with universal adhesives, a separate ceramic primer was recommended. PMID- 29525359 TI - The effect of ultraviolet induced fluorescence on visually perceived tooth color under normal light conditions. AB - OBJECTIVE: Restorative and prosthetic materials should provide an appearance similar to natural teeth under all light conditions, including UV-rich environments and daylight. Various studies claim that UV-induced fluorescence makes teeth whiter and brighter in daylight. The aim of this paper is to determine experimentally the significance of tooth fluorescence in natural sunlight on perceived tooth color. METHODS: A total of 35 extracted, hydrated teeth without restorations or endodontic treatments were evaluated in an experimental setup. A UV/VIS spectrometer using a reflectance/backscattering probe was used to collect the reflected spectrum. Unfiltered and filtered sunlight was used for irradiation of the samples so as to use the combined ultraviolet and visible spectrum (UV/VIS) and the visible spectrum (VIS) exclusively. Color coordinates for each group were measured using the CIE L*a*b* 1976 system, averaged, and compared. RESULTS: The average color difference between both groups (UV/VIS and UV) was DeltaE* 0.527. The average tooth color for the VIS group was L*VIS 72.21, a*VIS -2.42, and b*VIS 22.35, and for the UV/VIS group was L*UV/VIS 72.00, a*UV/VIS -2.47, and b*UV/VIS 22.44. SIGNIFICANCE: UV induced fluorescence from sunlight does not make teeth whiter and brighter. PMID- 29525360 TI - Identifying a typology of men who use anabolic androgenic steroids (AAS). AB - BACKGROUND: Despite recognition that the Anabolic Androgenic Steroid (AAS) using population is diverse, empirical studies to develop theories to conceptualise this variance in use have been limited. METHODS: In this study, using cluster analysis and multinomial logistic regression, we identify typologies of people who use AAS and examine variations in motivations for AAS use across types in a sample of 611 men who use AAS. RESULTS: The cluster analysis identified four groups in the data with different risk profiles. These groups largely reflect the ideal types of people who use AAS proposed by Christiansen et al. (2016): Cluster 1 (You Only Live Once (YOLO) type, n = 68, 11.1%) were younger and motivated by fat loss; Cluster 2 (Well-being type, n = 236, 38.6%) were concerned with getting fit; Cluster 3 (Athlete type, n = 155, 25.4%) were motivated by muscle and strength gains; Cluster 4 (Expert type, n = 152, 24.9%) were focused on specific goals (i.e. not 'getting fit'). CONCLUSION: The results of this study demonstrate the need to make information about AAS accessible to the general population and to inform health service providers about variations in motivations and associated risk behaviours. Attention should also be given to ensuring existing harm minimisation services are equipped to disseminate information about safe intra muscular injecting and ensuring needle disposal sites are accessible to the different types. PMID- 29525361 TI - Federal funding for syringe exchange in the US: Explaining a long-term policy failure. AB - BACKGROUND: The United States prohibited federal funding for syringe exchange programs for people who inject drugs nearly continuously from 1988 to 2015, despite growing scientific evidence, diminishing AIDS-related controversy, and tens of thousands of deaths from injection-related AIDS. This study investigates the political and institutional bases of this long-term failure to support lifesaving public policy. METHODS: This study draws on national, regional, and local media coverage, archival sources, and semi-structured, in-depth interviews with 6 long-time syringe exchange researchers and activists from California. I use case-oriented process tracing methods to explain the persistence and reform of the federal funding ban. RESULTS: Though previous studies focus on the symbolic clash between conservative morality and empirical science, I find that changing demographic and regional inequalities in the effects of the AIDS epidemic and dynamics produced by the federal structure of US government were more important factors in the creation and persistence of the funding ban. CONCLUSION: The persistence and eventual repeal of the ban on federal funding for syringe exchange was a product of the changing demographic, geographic, and political effects of the AIDS epidemic within the federal structure of US government, rather than a consequence of intractable morality politics. These contextual dynamics continue to shape AIDS and public health policy at all levels of government. PMID- 29525362 TI - Assessment of quality of life in patients who underwent breast reduction using BREAST-Q. PMID- 29525363 TI - Foot reconstruction using a free proximal peroneal artery perforator flap: Anatomical study and clinical application. AB - BACKGROUND: When a small, thin, and durable flap is required for coverage of the foot, the proximal peroneal artery perforator (PPAP) free flap may be a novel option. However, few clinical results and anatomical studies on the PPAP flap have been published. METHODS: A total of 24 PPAP flaps used in 22 patients from January 2013 to December 2016 were analyzed. All flaps were elevated in the subfascial plane based on a single perforator from the peroneal artery between the soleus and peroneus muscles. RESULTS: The average harvested flap size was 18.9 cm2 (range, 9-40 cm2), pedicle length was 4.3 cm (range, 3.1-5.5 cm), and pedicle artery diameter was 1.1 mm (range, 0.8-1.5 mm). Twenty-three of the 24 PPAP flaps survived. Average time to harvest the flap was 35 minutes (range, 20 55 minutes). Perforator location (ratio by fibula length) was confirmed at the 0.32 site (standard deviation, +/-0.04) from the fibular head. Percentages of septocutaneous and musculocutaneous types were 42% (10/24) and 58% (14/24), respectively, for perforator vessel course; average intramuscular course was 1.3 cm (range, 0.7-2.4 cm). Vessel graft was conducted in four cases, with an average length of 2.2 cm (range, 1.5-3.0 cm). CONCLUSIONS: The PPAP flap is one of the thinnest flaps available and is relatively easy to elevate. Moreover, it can be elevated in the same operative field as the foot, and primary closure is available for the donor site. Thus, the PPAP flap may be a good surgical option for soft tissue coverage of the foot. PMID- 29525364 TI - Screening and isolation of potential neuraminidase inhibitors from leaves of Ligustrum lucidum Ait. based on ultrafiltration, LC/MS, and online extraction separation methods. AB - Ultrafiltration liquid chromatography-mass spectrometry (ultrafiltration LC/MS) is introduced as an efficient method that can be applied to rapidly screen and identify ligands from the leaves of Ligustrum lucidum Ait. Using this method, we identified 13 compounds, including organic acids, flavonoids, and glycosides, as potent neuraminidase inhibitors. A continuous online method, employing pressurized liquid extraction followed by parallel centrifugal partition chromatography and preparative liquid chromatography PLE-(parallel-CPC/PLC), was developed for the efficient, scaled-up production of 12 compounds with high purities. The bioactivities of the separated compounds were assessed by an in vitro enzyme inhibition assay. The use of ultrafiltration LC/MS combined with PLE (parallel-CPC/PLC), and an in vitro enzyme inhibition assay facilitated the efficient screening and isolation of neuraminidase inhibitors from complex samples, and could serve as an important platform for the large-scale production of functional ingredients. PMID- 29525366 TI - Comparison of complications in midlines versus central venous catheters: Are midlines safer than central venous lines? AB - BACKGROUND: With the rising use of midline catheters (MCs), validation of their safety is essential. Our study aimed to evaluate the incidence of bloodstream infections (BSIs) and other complications related to the use of MCs and central venous catheters (CVCs). METHODS: A retrospective cohort study was performed at a tertiary care hospital in Detroit, Michigan, from March-September 2016. Adult patients with either MC or CVC were included. Outcomes assessed were catheter related BSI (CRBSI), mechanical complications, hospital length of stay, readmission within 90 days of discharge (RA), and mortality. Statistical analysis was performed using SAS software. RESULTS: A total of 411 patients with MC and 282 patients with CVC were analyzed. More CRBSIs were seen in patients with CVC (10/282) than MC (1/411) (3.5% vs 0.2%, respectively; P = .0008). More mechanical complications were seen in patients with MC (2.6%) than CVC (0.3%; P = .03). Patients with CVC had a higher crude mortality (17.3% vs 5.3%; P < .0001), RA (58% vs 35%; P <= .0001), line-related RA (2.8% vs 0.2%; P = .0041), and transfer to intensive care unit after line placement (9% vs 5%; P = .01). CVC was a significant exposure for a composite of mortality, CRBSI, mechanical issues, thrombosis, and readmission because of a line-related complication (odds ratio, 3.2; 95% confidence interval, 1.8-5.8). CONCLUSIONS: Our findings show use of MC is safer than CVC, but larger studies are needed to confirm our findings. PMID- 29525367 TI - Update to the Centers for Disease Control and Prevention and the Healthcare Infection Control Practices Advisory Committee Guideline for the Prevention of Surgical Site Infection (2017): A summary, review, and strategies for implementation. AB - Surgical site infections remain a common cause of morbidity, mortality, and increased length of stay and cost amongst hospitalized patients in the United States. This article summarizes the evidence used to inform the Centers for Disease Control and Prevention and the Healthcare Infection Control Practices Advisory Committee Guideline for the Prevention of Surgical Site Infection (2017), and highlights key updates and new recommendations. We also present specific suggestions for how infection preventionists can play a central role in guideline implementation by translating these recommendations into evidence-based policies and practices in their facility. PMID- 29525365 TI - Intestinal absorption differences of major bioactive compounds of Gegenqinlian Decoction between normal and bacterial diarrheal mini-pigs in vitro and in situ. AB - Intestinal condition plays an important role in drug absorption and metabolism, thus the effects of varied gastrointestinal diseases such as infectious diarrhea on the intestinal function are crucial for drug absorption. However, due to the lack of suitable models, the differences of absorption and metabolism of drugs between the diarrheal and normal intestines are rarely reported. Thus, in this study, Escherichia coli diarrhea model was induced in mini-pigs and single-pass intestinal perfusion and intestinal mucosal enzyme metabolism experiments were conducted. A simple and rapid ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to determine the concentrations of 9 major components in Gegen Qinlian decoction (GQD). Samples were pretreated by protein precipitation with methanol and naringin and prednisolone were used as internal standards. The validated method demonstrated adequate sensitivity, selectivity, and process efficiency for the bioanalysis of 9 compounds. Results of intestinal perfusion showed that puerarin, daidzein, daidzin and baicalin and berberine were absorbed faster in diarrheal jejunum than in normal intestines (p < 0.05). However, puerarin, daidzin and liquiritin were metabolized more slowly in diarrheal intestine after incubation compared with the normal group (p < 0.05). The concentrations of daidzein in both perfusion and metabolism and wogonin in metabolism were significantly increased (p < 0.05). In conclusion, absorption and metabolism of GQD were significantly different between the diarrheal and normal intestines, which suggest that bacterial diarrheal mini pigs model can be used in the intestinal absorption study and is worthy to be applied in the other intestinal absorption study of anti- diarrheal drugs. PMID- 29525368 TI - The relationship between a single-patient-use electrocardiograph cable and lead system and coronary artery bypass graft surgical site infection within a Medicare population. AB - Surgical site infection incidence following coronary artery bypass graft surgery was observed across 27,296 procedures within a Medicare population. A facility level case-control claims analysis demonstrated a significant 25% reduction (P = .04) in suspected surgical site infection at 90 days after coronary artery bypass graft surgery at facilities utilizing a single-patient-use electrocardiography cable and lead wire system. PMID- 29525369 TI - Spanish translation, adaptation and validation of the Hypoglycemia Fear Survey in adults with type 1 diabetes in the Community of Madrid. AB - BACKGROUND AND OBJECTIVE: The negative impact of hypoglycemia on patients with type 1 diabetes mellitus (T1DM) may lead to development of fear of hypoglycemia. In this study, the original Hypoglycemia Fear Survey (HFS) questionnaire was translated into Spanish, adapted and validated, and variables associated to fear of hypoglycemia in T1DM were analyzed. MATERIAL AND METHODS: The HFS was translated and adapted to Spanish using the forward-backward translation method. The resulting questionnaire, EsHFS, was administrated to a population with T1DM. The following parameters of the questionnaire were analyzed: feasibility, reliability (Cronbach's alpha), content validity (correlating EsHFS and EsDQOL [Diabetes Quality of Life] questionnaire), and stability (by means of test-retest correlation). RESULTS: The EsHFS questionnaire consists of 24 items and three subscales including: subscale 1 on worry; subscale 2 on hypoglycemia-avoidant behavior, and subscale 3 on hyperglycemia-influenced behavior. STUDY POPULATION: 163 subjects, with a mean aged (SD) of 36 (10.5) years, 24% on continuous subcutaneous insulin infusion. Of these, 99.8% completed the EsHFS questionnaire in less than 10minutes. Cronbach's alpha for global EsHFS was 0.92. EsHFS and its subscales correlated with EsDQOL. Test-retest correlation (Pearson) was r=0.92. Age, female sex, lower educational level, living alone, frequency of daily self monitoring and non-severe hypoglycemia, and history of severe and/or asymptomatic hypoglycemia were independently associated to the result of EsHFS. CONCLUSIONS: The Spanish version of the HFS, EsHFS, has good psychometric properties and may be a useful tool to assess fear of hypoglycemia in Spanish-speaking patients with T1DM. PMID- 29525370 TI - Impact of uric acid levels on the risk of long-term cardiovascular mortality in patients with type 2 diabetes mellitus. AB - BACKGROUND: Hyperuricemia is associated to cardiovascular disease. However, the contribution of uric acid (UA) to cardiovascular mortality in diabetic patients is controversial. OBJECTIVE: To assess the impact of UA levels on the risk of cardiovascular mortality risk in a cohort of patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: A prospective cohort study on outpatients with T2DM. The clinical endpoint was cardiovascular death. Anthropometric, demographic, clinical, and biochemical variables were collected, including UA levels, urinary albumin excretion and estimated glomerular filtration rate. The independent contribution of UA levels to cardiovascular mortality was assessed using multivariate Cox regression models, progressively adjusted for potential confounders. RESULTS: A total of 452 patients with a mean age of 65.9 (SD 9.5) years were enrolled. Mean UA level was 4.2mg/dL. Quartiles of UA levels were Q1 < 3.3; Q2: 3.3-4.2; Q3: 4.3-5.1; Q4 > 5.1mg/dL. UA levels significantly correlated with estimated glomerular filtration rate (Rho=-0.227; p<0.001). During a median follow-up time of 13 years, cardiovascular mortality rates were higher in Q4 of the UA distribution (Q1: 10.7; Q2: 11.7; Q3: 10.7; Q4: 21.6 per 1000 patient years; p = 0.027). UA was a predictor of cardiovascular mortality in the univariate analysis (HR1mg/dL = 1.30; p=0.002), but not in a multivariate analysis adjusted for urinary albumin excretion and eGFR (HR1mg/dL=1.20; p=0.12). DISCUSSION AND CONCLUSIONS: High UA levels are associated to cardiovascular mortality in patients with T2DM. However, the role of UA may be mediated by impaired kidney function in patients with hyperuricemia. PMID- 29525371 TI - Tick vectors and tick borne illnesses overview. PMID- 29525372 TI - EMERGING INFECTIOUS DISEASES - OVERVIEW. PMID- 29525374 TI - Evaluation and management of lower gastrointestinal bleeding. AB - Lower gastrointestinal bleeding (LGIB) is a common cause of presentation to the emergency department and hospital admissions. The incidence of LGIB increases with age and the most common etiologies are diverticulosis, angiodysplasia, malignancy and anorectal diseases. Foremost modality for evaluation and treatment of LGIB is colonosopy. Other diagnostic tools such as nuclear scintigraphy, computed tomography, angiography and capsule endoscopy are also frequently used in the workup of LGIB. Choice of treatment modality depends on the hemodynamic status of the patient, rate of bleeding, expertise and available resources. We present a comprehensive review of the evaluation and management of LGIB. PMID- 29525375 TI - Evaluation and management of Non-variceal upper gastrointestinal bleeding. AB - Non-variceal upper gastrointestinal bleeding continues to be an important cause of morbidity and mortality. The most common causes include peptic ulcer disease, Mallory-Weiss syndrome, erosive gastritis, duodenitis, esophagitis, malignancy, angiodysplasias and Dieulafoy's lesion. Initial assessment and early aggressive resuscitation significantly improves outcomes. Upper gastrointestinal endoscopy continues to be the gold standard for diagnosis and treatment. We present a comprehensive review of literature for the evaluation and management of non variceal upper gastrointestinal bleeding. PMID- 29525376 TI - Evaluation and management of variceal bleeding. AB - Acute variceal bleeding is one of the most fatal complications of cirrhosis and is responsible for about one-third of cirrhosis-related deaths. Therefore, every effort should be made to emergently resuscitate the patients, start pharmacotherapy as soon as possible and do endoscopic therapy in a timely manner. Despite the recent advances in treatment, mortality rate is still high. We provide a comprehensive review of evaluation and management of variceal bleeding. PMID- 29525377 TI - Surgical decompression of Wirsung duct reduces serum concentration of SPINK1 in patients with chronic pancreatitis. AB - OBJECTIVES: The primary aim of this study was to determine the blood levels of SPINK1 in patients with chronic pancreatitis (CP) submitted to surgical or endoscopic decompression of pancreatic duct (PD). Additionally, we measured trypsin activity levels. METHODS: Two groups were identified, surgical (group A) and endoscopic (group B). Levels of SPINK1 and trypsin activity were measured at baseline and 6 months after pancreatic duct decompression and then compared within the groups. SPINK1 levels were determined with Human ELISA Kit. RESULTS: Group A and B were made up of 30 and 28 patients, respectively. Baseline features of the groups were similar. A decrease in SPINK1 levels was significant only in group A 46.88 to 16.10 ng/mL (p = 0.001). On the contrary, trypsin activity changed significantly in group B 40.01 to 34.92 mU/mL (p = 0.01). Patients of group A showed a significant increase in BMI, before and after treatment. The pain score pre- and post-treatment reduced significantly in both groups (p < 0.001). CONCLUSIONS: We demonstrate for the first time a significant decrease of SPINK1 levels after surgical decompression of PD and a reduction of trypsin activity analysis after endoscopic decompression. The meaning of this phenomena is yet to be explained and it should be further explored. PMID- 29525379 TI - Average middle ear frequency response curves with preservation of curve morphology characteristics. AB - For the validation of modelling results or the comparison of middle ear interventions, such as prostheses placement, average responses of middle ear vibrations are needed. One such response is the amplitude and phase of the vibration of the stapes footplate as a function of frequency. Average responses and their standard deviation are commonly obtained by calculating the mean of a number of measured responses at each frequency. A typical middle ear magnitude response curve shows a number of distinct peaks, and the location of these peaks varies between ears. By simply taking an average along the magnitude or phase response axis, the typical fine structure of the response curve is flattened out, delivering an average curve which no longer has the typical morphology of an individual response curve. This paper introduces methods to avoid this problem by first aligning the typical curve features along the frequency axis prior to calculating the average along the magnitude or phase axis, resulting in average magnitude and phase curves which maintain the typical morphology of the curve obtained for an individual ear. In the method, landmark points on the response magnitude curves are defined and the frequencies at which these points occur are averaged. Next, these average frequencies are used to align the landmark points between curves, prior to averaging values along the magnitude or phase axes. Methods for semi-automatic and manual assignment of landmark points and curve alignment are presented. After alignment, the correspondence between the original landmark frequencies and aligned frequencies is obtained together with the warping function which maps each original magnitude curve to its aligned version. The phase curves are aligned using the warping functions determined from the corresponding magnitude curves. Finally, a method is proposed to compare the data set of an individual measurement or model result to an aligned average curve in terms of magnitude and frequency by applying the alignment procedure to the individual curve. PMID- 29525378 TI - Celecoxib suppresses proliferation and metastasis of pancreatic cancer cells by down-regulating STAT3 / NF-kB and L1CAM activities. AB - OBJECTIVE: To explore the molecular mechanisms of celecoxib-induced pancreatic cancer suppression in vivo and in vitro. METHODS: The anti-pancreatic cancer activities of celecoxib (0, 20, 60 and 100 MUmol/L) were investigated by cell viability and migration of Panc-1 and Bxpc-3 cells in vitro. The expression of L1CAM in pancreatic cancer and adjacent tissues was compared using immunohistochemistry. The expressions of L1CAM, STAT3, p-STAT3, NF-kappaB, p-NF kappaB were determined by western blotting, and cell invasive ability was determined by wound healing assay in L1CAM-silenced and over-expressed Panc-1and Bxpc-3 cells. RESULTS: The expression of L1CAM in pancreatic carcinoma was stronger than that in the adjacent tissues and L1CAM could increase the growth and invasion of pancreatic cancer cells. Over-expression of L1CAM activated the STAT3/NF-kappaB signaling pathway in Panc-1 and Bxpc-3 pancreatic cancer cells and celecoxib inhibited their viability and the expressions of STAT3, p-STAT3, NF kappaB, p-NF-kappaB as well as full length L1CAM in a concentration dependent manner. CONCLUSIONS: L1CAM was highly expressed in pancreatic cancer tissue and positively correlated with age, TNM staging and tumor differentiation. L1CAM activated the STAT/NF-kappaB signaling pathway and celecoxib could inhibit the activity of L1CAM, STAT3 and the NF-kappaB signaling pathway resulting in decreased growth and invasion of pancreatic cancer cells. PMID- 29525380 TI - Prognostic Effect of FGFR Mutations or Gene Fusions in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Results from a Large, Single-institution Cohort. AB - : FGFR gene alterations represent a target for treatment in clinical trials of urothelial carcinoma (UC). Little is known about their prognostic effect in patients with metastatic UC. We analyzed data for 112 patients treated with platinum-based first-line chemotherapy at our center between October 2011 and March 2017 and who were screened for the presence of FGFR mutations or gene fusions within multiple clinical trials with pan-FGFR inhibitors. Centralized targeted exome sequencing analyses were performed to detect multiple FGFR mutations and fusions. Cox regression analyses were performed, adjusting for recognized prognostic factors. Thirty-seven patients (33%) had upper tract UC (UTUC). A total of 22 patients (19.6%) had FGFR alterations and ten (8.9%) received salvage pan-FGFR inhibitor therapy. Thirty-two patients (45.4%) received salvage treatment with an immune checkpoint inhibitor. FGFR alterations were more frequently observed in UTUC versus bladder UC (p=0.017). On multivariable analyses, FGFR alterations were not significantly associated with OS (p=0.860) or PFS (p=0.147) after first-line chemotherapy. PATIENT SUMMARY: In an original single-center study, FGFR gene alterations were not prognostic for either progression-free survival or overall survival in patients receiving first-line chemotherapy for metastatic urothelial carcinoma. These results will be useful in interpreting findings from future clinical trials. PMID- 29525381 TI - Long-term Outcomes of Follow-up for Initially Localised Clear Cell Renal Cell Carcinoma: RECUR Database Analysis. AB - BACKGROUND: Optimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. OBJECTIVE: To analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. DESIGN, SETTING, AND PARTICIPANTS: Nonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). INTERVENTION: Primarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. RESULTS AND LIMITATION: Of 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n=53), intermediate- (n=105), and high-risk (n=128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p=0.004). Median OS was longer in PC compared with that in PI patients (p<0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. CONCLUSIONS: Low-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score dependent FU approach is suggested. PATIENT SUMMARY: We analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies. PMID- 29525382 TI - Prostate Indeterminate Lesions on Magnetic Resonance Imaging-Biopsy Versus Surveillance: A Literature Review. AB - CONTEXT: The indeterminate multiparametric prostate magnetic resonance image (mpMRI) lesion is one which cannot be classified as "positive" or "negative" for suspected cancer. Currently, there is no consensus on how to manage patients with indeterminate mpMRIs where areas cannot be classified as positives or negatives (Prostate Imaging Reporting and Data System [PI-RADS] 3 or Likert 3). OBJECTIVE: To define the concept of indeterminate lesion and describe the management strategies that may be adopted for these patients. EVIDENCE ACQUISITION: A literature search of the PubMed database was performed including the search terms "prostate indeterminate lesions", "PI-RADS 3", "Likert 3", "magnetic resonance imaging", and "prostate cancer". EVIDENCE SYNTHESIS: There is no universally accepted definition of what constitutes an indeterminate lesion on mpMRI. This is partly due to the experience of the reporting radiologist and their willingness to call a lesion indeterminate, knowing that this may have consequences for biopsy decisions. This is also partly due to the significant variation in mpMRI acquisition parameters used between different sites. Strategies for managing the indeterminate lesion include: (1) biopsy, where there is a highly variable prevalence of prostate cancer (PCa), reflecting the differences in clinically significant PCa definitions, mpMRI protocols and interobserver variability in characterization of indeterminate lesions and (2) surveillance, where early results suggest that this strategy may be of value for some selected patients with prostate-specific antigen (PSA) monitoring and/or interval mpMRI. The use of prebiopsy MRI, in conjunction with traditional clinical parameters and secondary biomarkers-nomograms, may allow a more accurate selection of patients who can avoid biopsy. CONCLUSIONS: A strategy of close surveillance based on PSA monitoring and interval mpMRI is a feasible management option for motivated patients with indeterminate mpMRI. This surveillance strategy could result in fewer men needing to undergo biopsy, and although early results are promising, long-term results for such a strategy are awaited. PATIENT SUMMARY: In some patients who have an MRI scan of their prostate, the scan may identify an area which may or may not contain cancer. This area is typically called the "indeterminate" lesion. In this report, we attempted to define the concept of indeterminate lesion on multiparametric magnetic resonance (mpMRI) and described the strategies that may be performed for these patients. The use of mpMRI in conjunction with traditional clinical parameters may allow more accurate risk stratification and assessment of the need for prostate biopsy. PMID- 29525383 TI - Update on off label use of metformin for obesity. PMID- 29525384 TI - Re: Letter to the Editor of public health in response to 'Human Papillomavirus vaccine initiation in Asian Indians and Asian Subpopulations: A case for examining disaggregated data in public health research'. PMID- 29525385 TI - A successful catheter ablation of a ventricular fibrillation. AB - Malignant ventricular arrhythmias are challenging to manage, requiring a multidisciplinary approach. The mechanism, which triggers ventricular fibrillation (VF) associated with ventricular extrasystoles has not been clarified yet, however, abolishing ventricular extrasystoles may stop ventricular fibrillation in these patients. By this case presentation, we aimed to present a successful treatment of an electrical storm (ES), which developed after an acute myocardial infarction, by catheter ablation. PMID- 29525386 TI - Cardiac resynchronization therapy with His bundle pacing as a method of treatment of chronic heart failure in patients with permanent atrial fibrillation and left bundle branch block. AB - CRT is a therapeutic option for patients with heart failure, sinus rhythm, prolonged QRS complex duration and reduced ejection fraction. We present a case of 71-year-old woman with dilated cardiomyopathy, NYHA functional class III and AF. We implanted CRT combined with direct His-bundle pacing. The indication for such a therapy was a left bundle branch block with a QRS complex of 178ms and a left ventricular EF of 15%, left ventricular end-diastolic diameter (LVEDD) of 75mm. After 8months of follow-up the LVEDD was 60mm with EF 35-40%. PMID- 29525388 TI - Global Hearing Loss Prevention. AB - Hearing loss is the fourth leading contributor to years lived with a disability worldwide. Most recent estimates indicate that one-half of a billion people suffer from disabling hearing loss worldwide. The social and economic burden is significant. When attributing monetary value to years lived with disability owing to hearing loss, there is greater than $US750 billion lost each year globally. There are numerous contributors to hearing loss, including congenital, infectious, noise exposure, age-related, traumatic, and immune-mediated causes. Understanding the pathophysiology of these factors allows for the development of preventative and treatment strategies specific to the underlying cause. PMID- 29525389 TI - Workforce Considerations, Training, and Certification of Physicians in Europe. AB - Following recent geopolitical events and unification of Europe, the European Union (EU) is currently confronted with health care workforce shortage and insufficient uniform access to quality care. Aging population, difficulties with physician retention, and mobility of health care professionals are thought to contribute to this problem. Because of the differences in medical education and residency curriculum across the European countries, there is a need for a standardized training and certification. Current government initiatives are geared toward developing common policies and programs across the EU countries to address health care access. PMID- 29525390 TI - Management of Chronic Suppurative Otitis Media and Otosclerosis in Developing Countries. AB - Chronic ear disease is a major cause of acquired hearing loss in the developing world. It is prevalent on every continent, but occurs more commonly in poorer nations owing to a lack of preventative measures. This article outlines the particular challenges in treating this disease in the developing world, including a discussion of surgical management and special situations. Otosclerosis is another surgically treatable cause of hearing loss that is found throughout the developing world. Surgeons working in these environments should be prepared to deal with advanced otosclerotic disease. PMID- 29525387 TI - Intracranial Electrophysiology of the Human Default Network. AB - The human default network (DN) plays a critical role in internally directed cognition, behavior, and neuropsychiatric disease. Despite much progress with functional neuroimaging, persistent questions still linger concerning the electrophysiological underpinnings, fast temporal dynamics, and causal importance of the DN. Here, we review how direct intracranial recording and stimulation of the DN provides a unique combination of high spatiotemporal resolution and causal information that speaks directly to many of these outstanding questions. Our synthesis highlights the electrophysiological basis of activation, suppression, and connectivity of the DN, each key areas of debate in the literature. Integrating these unique electrophysiological data with extant neuroimaging findings will help lay the foundation for a mechanistic account of DN function in human behavior and cognition. PMID- 29525391 TI - An Evidence-Based Practical Approach to Pediatric Otolaryngology in the Developing World. AB - Despite humanitarian otolaryngology groups traveling in record numbers to resource-limited areas treating pediatric otolaryngology disease processes and training local providers, there remains a large burden of unmet needs. There is a meager amount of published information that comes from the developing world from an otolaryngology standpoint. As would be expected, the little information that does comes involves some of the most common pediatric otolaryngology diseases and surgical burdens including childhood hearing loss, otitis media, adenotonsillectomies, airway obstructions requiring tracheostomies, foreign body aspirations, and craniomaxillofacial surgeries, including cleft lip and palate. PMID- 29525392 TI - Educational Resources for Global Health in Otolaryngology. AB - Advances in modern communications and information technology have helped to improve access to, and quality of, health care and education. These enhancements include a variety of World Wide Web-based and mobile learning platforms, such as eLearning, mLearning, and open education resources. This article highlights the innovative approaches that have fostered improved collaboration and coordination of global health efforts in otolaryngology. PMID- 29525393 TI - Incidence, predictors and therapeutic consequences of hypocalcemia in patients treated with cinacalcet in the EVOLVE trial. AB - The calcimimetic cinacalcet is used to treat secondary hyperparathyroidism in patients receiving dialysis, and asymptomatic hypocalcemia is often observed following its initiation. Here we investigated the incidence, predictors and therapeutic consequences of hypocalcemia by a post hoc analysis of the randomized, double-blind, placebo-controlled EValuation Of Cinacalcet Hydrochloride Therapy to Lower CardioVascular Events (EVOLVE) trial. Hypocalcemia was classified as mild (total serum calcium 8.0-8.39 mg/dL), moderate (7.5-7.99 mg/dL) or severe (under 7.5 mg/dL). At least one episode of hypocalcemia developed within 16 weeks after the first administered dose among 58.3% of 1938 patients randomized to cinacalcet versus 14.9% of 1923 patients randomized to placebo. Hypocalcemia in the cinacalcet group was severe in 18.4% of the patients versus 4.4% in the placebo group. Severe hypocalcemia following administration of cinacalcet was associated with higher baseline plasma parathyroid hormone, lower corrected total serum calcium, higher serum alkaline phosphatase, geographic region (patients from Latin America and Russia had a higher risk relative to the United States) and higher body mass index. The median cinacalcet dose immediately prior to the first hypocalcemic episode was 54-58 mg/day and similar in the three hypocalcemia categories. In the majority of patients, hypocalcemia resolved spontaneously within 14 days without modification of background therapy. Among patients who received an intervention, the most common was an increase in the active vitamin D sterol dose. Thus, the occurrence of hypocalcemia is frequent following initiation of cinacalcet and the likelihood of developing hypocalcemia was related to the severity of secondary hyperparathyroidism. Hypocalcemia was generally asymptomatic and self-limited. PMID- 29525394 TI - A population-based cohort study defines prognoses in severe chronic kidney disease. AB - In older people with chronic kidney disease (CKD) and comorbidities, the risk of death or disability may overshadow the risk of kidney failure. To help refine this we did a retrospective population-based cohort study to evaluate the relative likelihood of adverse outcomes as functions of age and comorbidity burden among 47,228 adults with severe non-dialysis dependent CKD. We identified comorbidities using 29 validated algorithms applied to administrative data and assessed death, end-stage renal disease (ESRD), cardiovascular disease (CVD) events, and long-term care. Over five years of follow-up, 53.4% of participants died, 24.1% had a CVD event, 14.3% were placed into long-term care and 5.3% developed ESRD. Death was 145 times more likely and 11 times more likely than ESRD for participants aged 80 years or more and 60-79 years, respectively; long term care was 30 times more likely and 1.7 times as likely as ESRD for participants aged 80 years or more and 60-79 years, respectively. Increasing comorbidity burden was similarly associated with increased risk of death and long term care placement but reduced the likelihood of ESRD, and the risks of increasing age were similarly incremental. Thus, among patients with severe CKD, older age and/or higher comorbidity burden, death and long-term care placement are markedly more likely than ESRD. Hence, clinicians, patients and families should all consider the relative magnitude of these risks when making decisions about renal replacement. PMID- 29525395 TI - Isolated pseudotumoural demyelination: A focal, monophasic autoimmune encephalitis? PMID- 29525396 TI - Use of commercial video games to improve postural balance in patients with multiple sclerosis: A systematic review and meta-analysis of randomised controlled clinical trials. AB - INTRODUCTION: Commercial video games are considered an effective tool to improve postural balance in different populations. However, the effectiveness of these video games for patients with multiple sclerosis (MS) is unclear. OBJECTIVES: To analyse existing evidence on the effects of commercial video games on postural balance in patients with MS. MATERIAL AND METHOD: We conducted a systematic literature search on 11 databases (Academic-Search Complete, AMED, CENTRAL, CINAHL, WoS, IBECS, LILACS, Pubmed/Medline, Scielo, SPORTDiscus, and Science Direct) using the following terms: "multiple sclerosis", videogames, "video games", exergam*, "postural balance", posturography, "postural control", balance. Risk of bias was analysed by 2 independent reviewers. We conducted 3 fixed effect meta-analyses and calculated the difference of means (DM) and the 95% confidence interval (95% CI) for the Four Step Square Test, Timed 25-Foot Walk, and Berg Balance Scale. RESULTS: Five randomized controlled trials were included in the qualitative systematic review and 4 in the meta-analysis. We found no significant differences between the video game therapy group and the control group in Four Step Square Test (DM: -.74; 95% CI, -2.79-1.32; P=.48; I2=0%) and Timed 25-Foot Walk scores (DM: .15; 95% CI, -1.06-.76; P=.75; I2=0%). We did observe intergroup differences in BBS scores in favour of video game therapy (DM: 5.30; 95% CI, 3.39 7.21; P<.001; I2=0%), but these were not greater than the minimum detectable change reported in the literature. CONCLUSIONS: The effectiveness of commercial video game therapy for improving postural balance in patients with MS is limited. PMID- 29525397 TI - Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia. AB - Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i)develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii)evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM). We allocated 21 male Wistar rats into 3 groups: intact controls, lesioned rats (with neurotoxin 6-OHDA), and dyskinetic rats (injected with L-DOPA for 19 days). Sensorimotor impairment was assessed with behavioural tests. Dyskinetic rats gradually developed AIMs during the treatment period; front leg AIMs were more severe and locomotor AIMs less severe (P<.05). All AIMs were significantly evident from day 5 and persisted until the last day of injection. D2R density was greater in the striatum and the medial anterior brain of the lesioned and dyskinetic rats than in those of controls. Our results suggest an association between D2R expression and locomotor AIMs. We conclude that RD2 is involved in L-DOPA-induced dyskinesia. PMID- 29525398 TI - Temporal lobe encephalocele, a subtle structural lesion that can be associated with temporal lobe epilepsy. PMID- 29525399 TI - Manual therapy in adults with tension-type headache: A systematic review. AB - INTRODUCTION: Tension-type headache is the most common primary headache, with a high prevalence and a considerable socioeconomic impact. Manual physical therapy techniques are widely used in the clinical field to treat the symptoms associated with tension-type headache. This systematic review aims to determine the effectiveness of manual and non-invasive therapies in the treatment of patients with tension-type headache. DEVELOPMENT: We conducted a systematic review of randomised controlled trials in the following databases: Brain, PubMed, Web of Science, PEDro, Scopus, CINAHL, and Science Direct. Ten randomised controlled trials were included for analysis. According to these studies, manual therapy improves symptoms, increasing patients' well-being and improving the outcome measures analysed. CONCLUSIONS: Manual therapy has positive effects on pain intensity, pain frequency, disability, overall impact, quality of life, and craniocervical range of motion in adults with tension-type headache. None of the techniques was found to be superior to the others; combining different techniques seems to be the most effective approach. PMID- 29525400 TI - Safety and effectiveness of surgery for epilepsy in children. Experience of a tertiary hospital in Ecuador. AB - INTRODUCTION: There is sufficient evidence on the usefulness of surgery as a therapeutic alternative for patients with drug-resistant epilepsy; however this treatment is underutilized, especially in developing countries. METHODS: We describe the outcomes of epilepsy surgery in 27 paediatric patients at Hospital Baca Ortiz in Quito, Ecuador. Our analysis considered the following variables: reduction in seizure frequency, surgery outcome according to the Engel classification, improvement in quality of life, and serious complications due to surgery. RESULTS: 21 corpus callosotomies and 6 resective surgeries were performed. The mean seizure frequency decreased from 465 per month before surgery to 37.2 per month thereafter (p<.001); quality of life scale scores increased from 12.6 to 37.2 (p<.001), and quality of life improved in 72.7% of patients. Regarding resective surgery, 2 patients with temporal lobe epilepsy and one with posterior quadrant epilepsy achieved Engel class IA, and one patient undergoing hemispherotomy due to Rasmussen encephalitis achieved Engel class IIA. Two patients underwent surgery for hypothalamic hamartoma: one achieved Engel III and the other, Engel IA; however, the latter patient died in the medium term due to a postoperative complication. The other major complication was a case of hydrocephalus, which led to the death of a patient with refractory infantile spasms who underwent corpus callosotomy. CONCLUSIONS: Favourable outcomes were observed in 92.5% of patients. PMID- 29525401 TI - Targeting immune checkpoints in non small cell lung cancer. AB - Cancers have the ability to disrupt immune response by interfering with adaptive immunity. Blocking checkpoint pathways has become a target for pharmacological research in lung cancer with particular focus on peptides PD-1 and CTLA-4. A number of immune check-point inhibitors (ICIs) targeting both PD-1 and CTLA-4 pathways are under investigation within clinical trials, of which Nivolumab, Pembrolizumab and Atezolizumab have already been approved for lung cancer treatment by both FDA and EMA. Employed as single-agents in current practice for the treatment of advanced non-small cell lung cancer (NSCLC) ICIs have exhibited advantages in terms of overall survival and response rate with some responses being durable. Evaluating combinations of different inhibitors, dosing and sequencing within a multimodal therapy approach, together with better management of toxicity represents a new challenge for future research of therapy targeting immune check-points. PMID- 29525402 TI - Biometric correspondence between reface computerized facial approximations and CT derived ground truth skin surface models objectively examined using an automated facial recognition system. AB - This study employed an automated facial recognition system as a means of objectively evaluating biometric correspondence between a ReFace facial approximation and the computed tomography (CT) derived ground truth skin surface of the same individual. High rates of biometric correspondence were observed, irrespective of rank class (Rk) or demographic cohort examined. Overall, 48% of the test subjects' ReFace approximation probes (n=96) were matched to his or her corresponding ground truth skin surface image at R1, a rank indicating a high degree of biometric correspondence and a potential positive identification. Identification rates improved with each successively broader rank class (R10=85%, R25=96%, and R50=99%), with 100% identification by R57. A sharp increase (39% mean increase) in identification rates was observed between R1 and R10 across most rank classes and demographic cohorts. In contrast, significantly lower (p<0.01) increases in identification rates were observed between R10 and R25 (8% mean increase) and R25 and R50 (3% mean increase). No significant (p>0.05) performance differences were observed across demographic cohorts or CT scan protocols. Performance measures observed in this research suggest that ReFace approximations are biometrically similar to the actual faces of the approximated individuals and, therefore, may have potential operational utility in contexts in which computerized approximations are utilized as probes in automated facial recognition systems. PMID- 29525403 TI - The degree of overlap between the follicular dendritic cell meshwork and tumor cells in mantle cell lymphoma is associated with prognosis. AB - This study concerning mantle cell lymphoma (MCL) investigated retrospectively an association between patient prognosis and the percentage of the total number of lymphoma cells found in the follicular dendritic cell (FDC) meshwork, that is, the degree of overlap of lymphoma cells. Two hundred and nine MCL patients were apportioned to grades I-III, in which the CD21-positive FDC meshwork covered <=50%, 51%-89%, and >=90% of the tumor area, respectively. Significant differences among the grades (all, P < 0.01) were found in the following: duration of disease (from onset of clinical manifestation to diagnosis); clinical staging; extranodal involvement (non-lymphoid organs); histological subtype; and Ki-67 proliferation index (PI). After removing the aggressive variants, the overall survival rates of grade I (n = 92) and II (n = 57) patients were similar. The overall survival rates of grade III (n = 46) patients differed from that of grade I + II patients (P < 0.01). The grades negatively correlated with the Ki-67 PI value (r = -0.234, P = 0.001). At each grade the OSR of patients with Ki-67 PI <=30% was similar to that of patients with Ki-67 >30%. In the Ki-67 PI <=30% group, the OSRs of the patients differed significantly among the grades. In the Ki-67 >30% group the OSRs of the grades were similar. The results of multivariate Cox regression analysis showed that the degree of overlap, age and Ki-67 PI was the independent prognostic factors of the OSRs of MCL patients. Our data suggests that MCL patients in whom there was a high degree of overlap between the FDC meshwork and tumor area have a better clinical prognosis. The degree of overlap correlates well with the Ki-67 PI, which can be used to predict the prognosis of patients. PMID- 29525404 TI - Association between NME1 polymorphisms and cancer susceptibility: A meta-analysis based on 1644 cases and 2038 controls. AB - The association between polymorphisms in the nucleoside diphosphate kinase 1 (NME1) gene and overall risk of cancer remains to be elucidated. Here, we performed a meta-analysis of the association between rs16949649, rs2302254, and rs34214448 polymorphisms in the NME1 gene and cancer risk. PubMed, Web of Science, and CNKI databases (as of June 6, 2017) were searched. Eight studies, encompassing 1644 cases and 2038 controls, were selected. The results revealed no significant relationship between NME1 polymorphisms and overall cancer susceptibility. Interestingly, the rs16949649 polymorphism was associated with increased susceptibility to gynecological cancer (heterozygous model: odds ratio [OR] = 1.74, 95% confidence interval [CI] = 1.06-2.86, P = 0.029). The rs2302254 polymorphism was linked to decreased susceptibility to gastric cancer in the other groups (recessive model: OR = 0.53, 95% CI = 0.28-0.98, P = 0.045). The rs34214448 polymorphism correlated significantly with increased susceptibility to non-small cell lung cancer according to all genetic models (P < 0.05) and was linked to decreased risk in cervical cancer (recessive model: OR = 0.51, 95% CI = 0.27-0.94, P = 0.031). Thus, our meta-analysis found rs16949649 associated with increased susceptibility to gynecological cancer and rs2302254 was linked to reduced gastric cancer risk; additional, larger studies are required to confirm these findings. PMID- 29525405 TI - Clinicopathological analysis of Large Cell Lung Carcinomas definitely diagnosed according to the New World Health Organization Criteria. AB - OBJECTIVE: The definition of large cell lung carcinoma (LCC) has undergone an extensive modification in the World Health Organization (WHO) Classification (2015). Present study aimed to investigate the clinicopathological characteristics of patients diagnosed as LCC according to current WHO criteria. METHODS: LCCs diagnosed based on the previous WHO classification were reevaluated, and 17 cases of LCC were finally identified at Peking Union Medical College Hospital and Beijing Chest Hospital between 2009 and 2015. The clinicopathologic features were examined and EGFR and KRAS mutations were tested. Survival of the patients was analyzed by Kaplan-Meier method. RESULTS: The median age of the patients was 64 years (range: 40-78). Most patients were male (64.7%) and about half of the patients were at TNM stage III (47.1%). Morphologically, most cases (70.6%) were classic LCC. All patients were treated by lobectomy plus lymph node dissection, 2 with bi-lobectomy and 1 with complex lobectomy, and the other 2 patients were further treated by partial pericardiotomy. Ten patients received postoperative chemotherapy, while only 3 patients were treated with radiotherapy after surgery. Molecular analysis showed two cases of EGFR mutation (L858R) but without non-overlapping KRAS mutation. The 3-year overall survival rate was 48.4 +/- 15.1%. Chemotherapy was the only predictive factor that is associated with the prognosis of the patients (P = 0.003). CONCLUSION: The clinicopathological characteristics of 17 cases of stringently diagnosed LCC were retrospectively analyzed. LCC in our study showed aggressive behavior with high recurrence and metastasis and poor prognosis. Chemotherapy was only predictive factor that is significantly associated with the prognosis of the patients. Future studies based on a larger series and long term follow-up are still needed to characterize it further. PMID- 29525406 TI - Sperm epigenetics and influence of environmental factors. AB - BACKGROUND: Developmental programming of the embryo is controlled by genetic information but also dictated by epigenetic information contained in spermatozoa. Lifestyle and environmental factors not only influence health in one individual but can also affect the phenotype of the following generations. This is mediated via epigenetic inheritance i.e., gametic transmission of environmentally-driven epigenetic information to the offspring. Evidence is accumulating that preconceptional exposure to certain lifestyle and environmental factors, such as diet, physical activity, and smoking, affects the phenotype of the next generation through remodeling of the epigenetic blueprint of spermatozoa. SCOPE OF REVIEW: This review will summarize current knowledge about the different epigenetic signals in sperm that are responsive to environmental and lifestyle factors and are capable of affecting embryonic development and the phenotype of the offspring later in life. MAJOR CONCLUSIONS: Like somatic cells, the epigenome of spermatozoa has proven to be dynamically reactive to a wide variety of environmental and lifestyle stressors. The functional consequence on embryogenesis and phenotype of the next generation remains largely unknown. However, strong evidence of environmentally-driven sperm-borne epigenetic factors, which are capable of altering the phenotype of the next generation, is emerging on a large scale. PMID- 29525408 TI - Report card shows gender is missing in global health. PMID- 29525409 TI - Female physicians nominated for the Nobel Prize 1901-50. PMID- 29525407 TI - Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity. AB - OBJECTIVE: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. METHODS: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. RESULTS: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). CONCLUSIONS: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. PMID- 29525410 TI - Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment. AB - BACKGROUND: Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients. METHODS: Pa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent). RESULTS: Forty seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 * 10-6 MUg/mL in Eradicated cases compared to 3 * 10-5 MUg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection. CONCLUSIONS: Pediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates. PMID- 29525411 TI - Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies. AB - In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals. The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2S,6S;2R,6R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis. We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine. PMID- 29525412 TI - Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study. AB - BACKGROUND AND PURPOSE: To determine the safety and tolerability of dose escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. MATERIALS AND METHODS: A sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with >=Grade 3 (G3) toxicity at 12 months post-treatment. RESULTS: Fifteen patients were recruited to DL1 and twenty nine to DL2. At 12 months >=G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, >=G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses. PMID- 29525413 TI - Discussion. PMID- 29525414 TI - Outcomes of reintervention for recurrent symptomatic disease after tibial endovascular intervention. AB - OBJECTIVE: Tibial interventions for critical limb ischemia are now commonplace. Restenosis and occlusion remain barriers to durability after intervention. The aim of this study was to examine the patient-centered outcomes of open and endovascular reintervention for symptomatic recurrent disease after a primary isolated tibial endovascular intervention. METHODS: A database of patients undergoing isolated primary lower extremity tibial endovascular interventions between 2006 and 2016 was retrospectively queried. Patients with recurrent critical ischemia (Rutherford 4 and 5) were identified. Outcomes in this cohort were analyzed, and three groups were defined: endovascular reintervention (ie, a repeated tibial or pedal endovascular intervention), bypass (bypass to a tibial or pedal vessel), and primary amputation (ie, above- or below-knee amputation) on the ipsilateral leg. Patient-oriented outcomes of clinical efficacy (absence of recurrent signs or symptoms of critical ischemia, maintenance of ambulation, and absence of major amputation), amputation-free survival (survival without major amputation), and freedom from major adverse limb events (above-ankle amputation of the index limb or major reintervention, such as new bypass graft or jump or interposition graft revision) were evaluated after the reintervention. RESULTS: There were 1134 patients (56% male; average age, 59 years) who underwent primary tibial intervention for critical ischemia, and 54% presented with symptomatic restenosis and occlusion. Of the 513 patients with recurrent disease, 58% presented with rest pain and the remainder with ulceration. A repeated tibial endovascular intervention was performed in 64%, open bypass in 19%, and below knee amputation in 17%. Bypass was employed in patients with a good target vessel, venous conduit, and good pedal runoff. Patient-centered outcomes were better in the bypass group compared with the reintervention group (amputation free survival, 45% +/- 9% vs 27% +/- 9% [P < .01]; major adverse limb events, 50% +/- 9% vs 31% +/- 9% [P < .05]; clinical efficacy, 60% +/- 7% vs 30% +/- 9% [P < .01], mean +/- standard error of the mean at 5 years). CONCLUSIONS: Tibial interventions for critical ischemia are associated with a high rate of reintervention. In patients with good target vessel, venous conduit, and good pedal runoff, bypass appears more durable than repeated tibial endovascular intervention. PMID- 29525415 TI - Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches. AB - INTRODUCTION: Immune Mediated Inner Ear Disease (IMIED) is a rare form of sensorineural bilateral hearing loss, usually progressing in weeks to months and responsive to immunosuppressive treatment. Despite recent advances, there is no consensus on diagnosis and optimal treatment. METHODS: A review of articles on IMIED from the last 10 years was conducted using PubMed(r) database. RESULTS: IMIED is a rare disease, mostly affecting middle aged women. It may be a primary ear disease or secondary to autoimmune systemic disease. A dual immune response (both cellular and humoral) seems to be involved. Cochlin may be the inner ear protein targeted in this disease. Distinction from other (core common) forms of neurosensory hearing loss is a challenge. Physical examination is mandatory for exclusion of other causes of hearing loss; audiometry identifies characteristic hearing curves. Laboratory and imaging studies are controversial since no diagnostic marker is available. CONCLUSION: Despite recent research, IMIED diagnosis remains exclusive. Steroids are the mainstay treatment; other therapies need further investigation. For refractory cases, cochlear implantation is an option and with good relative outcome. PMID- 29525416 TI - Neural cognitive control moderates the association between insular risk processing and risk-taking behaviors via perceived stress in adolescents. AB - Adolescence is a critical period for the initiation of risk-taking behaviors. We examined the longitudinal interplay between neural correlates of risk processing and cognitive control in predicting risk-taking behaviors via stress. The sample consisted of 167 adolescents (53% males) who were assessed twice (MAgeTime1 = 14.13, MAgeTime2 = 15.05). Neural risk processing was operationalized as blood oxygen-level-dependent (BOLD) responses in the anterior insula during a lottery choice task and neural cognitive control as BOLD responses during an inhibitory control task. Adolescents reported on perceived stress and risk-taking behaviors. Structural equation modeling analyses indicated that low insular risk processing predicted increases in perceived stress, while perceived stress did not predict changes in insular risk processing across one year. Moreover, significant moderation by neural cognitive control indicated that low insular risk processing predicted increases in risk-taking behaviors via increases in perceived stress among adolescents with poor neural cognitive control, but not among adolescents with good neural cognitive control. The results suggest that risk processing in the anterior insular cortex plays an important role in stress experience and risk taking behaviors particularly for vulnerable adolescents with poor neural cognitive control. PMID- 29525417 TI - The lifespan trajectory of neural oscillatory activity in the motor system. AB - Numerous studies connect beta oscillations in the motor cortices to volitional movement, and beta is known to be aberrant in multiple movement disorders. However, the dynamic interplay between these beta oscillations, motor performance, and spontaneous beta power (e.g., during rest) in the motor cortices remains unknown. This study utilized magnetoencephalography (MEG) to investigate these three parameters and their lifespan trajectory in 57 healthy participants aged 9-75 years old. Movement-related beta activity was imaged using a beamforming approach, and voxel time series data were extracted from the peak voxels in the primary motor cortices. Our results indicated that spontaneous beta power during rest followed a quadratic lifespan trajectory, while movement related beta oscillations linearly increased with age. Follow-on analyses showed that spontaneous beta power and the beta minima during movement, together, significantly predicted task performance above and beyond the effects of age. These data are the first to show lifespan trajectories among measures of beta activity in the motor cortices, and suggest that the healthy brain compensates for age-related increases in spontaneous beta activity by increasing the strength of beta oscillations within the motor cortices which, when successful, enables normal motor performance into later life. PMID- 29525419 TI - Infusion of in vivo expanded cord blood lymphocytes: A new strategy to control residual disease? PMID- 29525418 TI - [Tumor necrosis receptor associated periodic syndrome (TRAPS): State of the art]. AB - Tumour necrosis receptor associated periodic syndrome (TRAPS) is a rare cosmopolitan dominant autosomal disease that belongs to the group of recurrent autoinflammatory syndromes. TRAPS is characterized by recurrent bouts of fever lasting more than 7 days, with arthralgia, myalgia, abdominal pain, erythematous rash and sometimes ocular symptoms. During flares, raised inflammatory markers are constant. The age of onset may occur during childhood but also during adulthood. TRAPS is caused by mutations in the TNF receptor 1 (TNFRSF1A) gene that may occur in most of the populations over the world. In the majority of patients, history shows affected relatives, even if sporadic cases do exist. Management of TRAPS usually involves corticosteroid therapy during inflammatory flares. The most severe cases require a treatment with biological agents (mainly interleukin 1 inhibitors). The prognosis of TRAPS is overall good; the main risk is represented by the development of secondary inflammatory amyloidosis. This risk is greatest in patients with structural mutations leading to conformation abnormalities of the TNFRSF1A receptor. Regular clinical and biological monitoring is essential in the follow-up of TRAPS patients. PMID- 29525420 TI - X-linked hyper-IgM syndrome associated with pulmonary manifestations: A very rare case of functional mutation in CD40L gene in Iran. AB - Hyper IgM (HIGM) syndromes are a complex of primary immunodeficiency disorders. A 4-years-old boy with recurrent fever and chills, dyspnea, sort throat for a month was admitted to emergency department. In the current case, whole exome sequencing followed by Sanger sequencing were employed in order to screen probable functional mutations. Molecular analysis revealed a functional mutation across the CD40L gene (NM_000074: exon5: c.T464C) resulted in amino acid change p.L155P attributed to X-linked hyper IgM syndrome. The findings of the current study signify the critical role of microbial infection as well as XHIGM screening, particularly in those children cases with respiratory symptoms. PMID- 29525421 TI - Towards Understanding MCR-like Colistin Resistance. AB - Antibiotic resistance has become a global public health priority. Polymyxins, a family of cationic polypeptide antibiotics, act as a final line of refuge against severe infections by Gram-negative pathogens with pan-drug resistance. Unfortunately, this last-resort antibiotic has been challenged by the emergence and global spread of mobilized colistin resistance determinants (mcr). Given the fact that it has triggered extensive concerns worldwide, we present here an updated view of MCR-like colistin resistance. These studies provide a basic framework for understanding the molecular epidemiology and resistance mechanism of MCR-like genes. However, further large-scale epidemiology and functional studies are urgently needed to better understand the biology of this clinically important antibiotic resistance. PMID- 29525422 TI - [What does the Internet teach the obstetric patient about labor analgesia?] AB - BACKGROUND AND OBJECTIVES: It has been observed a general public increased search on the Internet for health information, including Anesthesiology. The objective of this study was to evaluate the information available to the lay person in Portuguese on the internet about labor analgesia for the Brazilian population. METHOD: Using the term "labor anesthesia", the first 20 sites found on Google in November 2014 were evaluated by two resident physicians and classified as medical and non-medical. Legibility and Design - accessibility, reliability and navigability-were compared using Flesch Reading Ease Score (FRESH) and Minervation validation tool for healthcare websites (LIDA) tools. The websites' content was confronted with that of the medical literature. RESULTS: Medical and non-medical websites were considered difficult to read according to FRESH. Regarding the design, there was no difference between groups regarding navigability, however, accessibility was considered superior in non-medical websites (p = 0.042); while reliability was higher in medical websites (p = 0.019). CONCLUSIONS: With the increased search for health information on the Internet and concern about improving the quality of childbirth care, it is fundamental that the content available to the layperson about labor analgesia is of quality and well understood. This study demonstrated that both medical and non medical websites are difficult to read and that non-medical websites are more accessible while the medical ones are more accurate. PMID- 29525423 TI - Investigation of fMRI Analysis Method to Visualize the Difference in the Brain Activation Timing. AB - RATIONALE AND OBJECTIVES: In general functional magnetic resonance imaging (fMRI) analysis, the task onset time of the statistical model is typically set according to the timing of stimulation. In this study, using a high temporal resolution fMRI data, we examined the way of dynamically visualizing the difference in the activation timing between the brain activation areas by analyzing the task onset time of the statistical model shifted from the actual stimulation timing. MATERIALS AND METHODS: fMRI data with high temporal resolution was acquired using 3 T magnetic resonance imaging for 10 right-handed healthy volunteers. While being scanned, the volunteers completed a task that comprised two sets of a rest and right hand grip movement task. Statistical Parametric Mapping 12 (SPM12) software was used to analyze fMRI data. After preprocessing, statistical analyses were performed by shifting the task onset time on the statistical model by about 1 second forward or backward from the actual stimulation timing. Activation maps of multiple time phases were then created. RESULTS: Activity was observed to the left of the primary motor area and the supplementary motor area and to the right of the cerebellum (familywise error rate, P < .05). In the right hand grip movement, the primary motor area and the supplementary motor area were activated from 1.12 to 4.48 seconds earlier than the cerebellum. CONCLUSIONS: Using this analysis method, we visualized the differences in activation timings of different areas of the brain. PMID- 29525424 TI - Magnetic Resonance Imaging Parameters in Predicting the Treatment Outcome of High intensity Focused Ultrasound Ablation of Uterine Fibroids With an Immediate Nonperfused Volume Ratio of at Least 90. AB - RATIONALE AND OBJECTIVES: We aimed to investigate the role of magnetic resonance imaging parameters in predicting the treatment outcome of high-intensity focused ultrasound (HIFU) ablation of uterine fibroids with a nonperfused volume (NPV) ratio of at least 90%. MATERIAL AND METHODS: A total of 120 women who underwent HIFU treatment were divided into groups 1 (n = 72) and 2 (n = 48), comprising patients with an NPV ratio of at least 90% and less than 90%, respectively. Multivariate logistic regression analyses were carried out to investigate the potential predictors of the NPV ratio of at least 90%. The NPV ratios immediately post-treatment, therapeutic efficacy at 6 months' follow-up, and safety in terms of adverse effects and changes in anti-Mullerian hormone level were assessed. RESULTS: By introducing multiple predictors obtained from multivariate analyses into a generalized estimating equation model, the results showed that the thickness of the subcutaneous fat layer in the anterior abdominal wall, peak enhancement of fibroid, time to peak of fibroid, and the ratio of area under the curve of fibroid to myometrium were statistically significant, except T2 signal intensity ratio of fibroid to myometrium, hence predicting an NPV ratio of at least 90%. No serious adverse effects and no significant difference between the anti-Mullerian hormone levels before or 6 months post-treatment were reported. CONCLUSIONS: The findings in this study suggest that the achievement of NPV ratio of at least 90% in magnetic resonance imaging-guided HIFU treatment of uterine fibroids based on prediction model appears clinically possible without compromising the safety of patients. PMID- 29525425 TI - Effects of Ag and Ag2S nanoparticles on denitrification in sediments. AB - The widespread use of commercial silver nanoparticles (Ag NPs) inevitably results in their increased release into natural waters and subsequent deposition in sediments, requiring the environmental impact of such deposition to be closely investigated. Hence, the effects of Ag NPs, polyvinylpyrrolidone (PVP)-Ag NPs, and sliver sulfide nanoparticles (Ag2S NPs) on denitrification-induced gas production (N2O and 15N-N2), and denitrifying microbes in freshwater sediments were investigated. Slurry experiments (8 h) combined with a 15NO3- addition technique were performed to determine the gaseous production. The abundance of relative functional genes (nirK, nirS and nosZ) and the composition of functional community were determined through RT-PCR and high-throughput sequencing, respectively. The obtained results showed that the toxicity of NPs on denitrification depended on their type (Ag+ > Ag NPs > PVP-Ag NPs > Ag2S NPs) and concentration, e.g., all 1 mg/L NPs exhibited no effects on denitrification, whereas evident hormesis effect-induced acceleration was observed in the case of Ag+. Conversely, 10 mg/L Ag+ and Ag NPs significantly inhibited the release rates of N2O and N2 by decreasing the abundance of functional genes (nirK and/or nirS) and the predominant bacteria Paracoccus. PVP-Ag and Ag2S NPs had no effects on N2 release rates and the composition of denitrifiers, however, inhibited the emission of N2O (by reducing the abundance of nirK), suggesting that normal denitrification-induced N2 formation in sediments could still be sustained when the N2O production decrease lied within a certain range. Further, the inhibiting ability of Ag-containing NPs was caused by their intrinsic nanotoxicity to functional microbes rather than by the general toxicity of Ag+. Besides, Ag2S NPs (as a main detoxification form of AgNPs) were revealed to be intrinsically nanotoxic to denitrifiers, albeit showing the lowest inhibitory effect among the three tested NPs. Thus, this study demonstrated that the inhibitory effect of Ag containing NPs on denitrification in sediments depends on their morphology and type, implying that the stability and toxicity of Ag-containing NPs should be considered with caution. PMID- 29525426 TI - Enhanced Fe(III)-mediated Fenton oxidation of atrazine in the presence of functionalized multi-walled carbon nanotubes. AB - In this study we reported that the presence of functionalized multi-walled carbon nanotubes (FCNT-H) would greatly enhance the degradation of atrazine (ATZ), a model contaminant, in the Fe(III)-mediated Fenton-like system. Efficient ATZ degradation (>90%) was achieved within 30 min in the presence of 20 mg.L-1 FCNT H, 2.0 mg.L-1 Fe(III), and 170 mg.L-1 H2O2, whereas negligible ATZ degradation occurred in FCNT-H free system. The structure and surface chemistry of FCNT-H and other CNTs were well characterized. The formed active species were determined based on ESR analysis, and the mass balance of Fe species during the reaction was monitored. In particular, a new method based on ferrozine complexation was proposed to track the formed Fe(II). The results indicated that ATZ was mainly degraded by the generated hydroxyl radical (HO.), and Fe(III)/Fe(II) cycling was still the rate-limiting step. Besides a small fraction of Fe(III) reduced by FCNT H, a new pathway was revealed for fast reduction of most Fe(III), i.e., reaction of FCNT-H-Fe(III) complexes with H2O2. Comparison of different CNTs-mediated Fe(III)/H2O2 systems indicated that such enhanced effect of CNTs mainly resulted from the surface carboxyl group instead of hydroxyl and carbonyl group. Combined with X-ray photoelectron spectroscopy (XPS) analysis, the electron density migration from Fe(III) to FCNT-H possibly resulted in the fast reduction of FCNT H-Fe(III) complexes by H2O2. This study enables better understanding the enhanced Fe(III)-mediated Fenton-like reaction in the presence of MWCNTs and thus, will shed new light on how to develop more efficient similar Fenton systems via Fe(III) complexation. PMID- 29525427 TI - Antifouling paint particles: Sources, occurrence, composition and dynamics. AB - Sources, occurrence, composition and dynamics of antifouling paint particles (APPs) were assessed in Patos Lagoon estuary (PLE), Southern Brazil. Ten areas including boatyards, a marina and artisanal fishing harbors were identified in the estuarine system as potential sources of APPs. The APPs generated in these areas were highly heterogeneous considering the size, shape and composition. Based on an estimate of antifouling paint usage and amount of boats in each studied area, artisanal fishing harbors could be the main source of particles to PLE. However, relatively high amounts of APPs, which ranged from 130 to 40,300 MUg g-1, were detected in sediments collected in front of boatyards and a marina. The uneven distribution of APPs levels among the sediment samples were probably due to the presence of diffuse sources (fishing harbors) associated to "hotspots" (boatyards and marina) along the study area. Additionally, data of settling experiment indicate that size, shape and density of APPs, combined to local hydrodynamics, appears to contribute to the mobility of these residues within the estuary. In the main channel of PLE, smaller particles tend to be transported to adjacent coastal zone while particles tend to be deposited in the sediment surface of sheltered areas. Since different trace metals, and booster biocides were detected in APPs that were not correctly disposed, these particles can be considered as an important source of contamination to aquatic environments. The present data suggest that APPs represent an environmental problem for aquatic systems in Brazil, since the country lacks legislation in addition to inefficient control mechanisms. An improvement in boat maintenance processes are urgently needed to avoid this continuous release of APPs into the aquatic systems. PMID- 29525428 TI - Circulating pathogen-specific plasmablasts in female patients with upper genital tract infection. AB - Mucosal antibodies constitute the first line of adaptive immune defence against invaders in the female genital tract (FGT), yet the sequence of events leading to their production is surprisingly poorly characterized. We explored the induction of pathogen-specific antibody-secreting cells (ASC) as a response to an acute infection in the upper FGT. We recruited 12 patients undergoing surgery due to an upper FGT infection (7/12 blood culture positive, 5/12 negative) and six healthy controls. Pathogens were sampled during surgery and PBMC collected in the acute phase of the disease (days 7-10). We searched by ELISPOT circulating pathogen specific ASC and explored their frequency, immunoglobulin isotype distribution, and expressions of homing receptors (alpha4beta7, L-selectin, and CLA). All patients had circulating ASC specific to the infective bacteria; the geometric mean was 434 (95%CI 155-1234) ASC (IgA + IgG + IgM)/106 PBMC. IgA ASC predominated in 7/12, IgG ASC in 3/12, and IgM ASC in 2/12 cases. Of all the pathogen-specific ASC, 60% expressed alpha4beta7, 67% L-selectin, and 9% CLA. This study is the first to show induction of pathogen-specific ASC in the peripheral blood in bacterial infection in the human FGT. Our findings reveal that such FGT-originating pathogen-specific ASC are predominated by IgA ASC and exhibit a homing receptor profile resembling that of ASC in acute urinary tract infection. The data thus suggest a characteristic profile shared by the urogenital tract. PMID- 29525429 TI - The Relationship Between 6 Polymorphisms of Caveolin-1 Gene and the Risk of Breast Cancer. AB - BACKGROUND: Caveolae play a role in cell signal transduction, kinetic regulation of transport vesicles, and cellular physiology. In this study, we evaluated the role of caveolin-1 (CAV-1) genotypes in the risk of breast cancer. PATIENTS AND METHODS: We evaluated 6 single nucleotide polymorphisms of the CAV-1 gene in a sample size of 406 participants. Six polymorphisms-G32124A (rs3807992), T29107A (rs7804372), T28608A (rs3757733), G21985A (rs12672038), G14713A (rs3807987), and C521A (rs1997623)-were assessed using restriction fragment length polymorphism polymerase chain reaction. RESULTS: Regarding the distribution of genotypes, the relationship between cases and controls was significant for T29107A, G21985A, G14713A, and C521A polymorphisms, among which only C521A showed a significant difference in body mass index between the 2 groups. Moreover, the age of the 2 groups was significant in the case of G32124A and T28608A polymorphisms. CONCLUSION: Our results showed that genetic changes of CAV-1 might modify the risk for breast cancer and point out the importance of more studies for variants of this gene in breast cancer. PMID- 29525430 TI - The Global Need for a Trastuzumab Biosimilar for Patients With HER2-Positive Breast Cancer. AB - Trastuzumab improves survival outcomes for patients with HER2-positive (HER2+) breast cancer, yet not all such women receive this important therapy. Trastuzumab was approved by the US Food and Drug Administration in 1998 and the European Medicines Agency in 2000 as treatment for HER2+ metastatic breast cancer (MBC). Observational studies between 2000 and 2015 in patients with HER2+ MBC suggest that nearly 12% in the United States, 27% to 54% in Europe, and 27.1% to 49.2% in China did not receive trastuzumab or any other HER2-targeted agent as first- and/or later-line for treatment of metastatic disease. In 2006, both agencies approved trastuzumab as adjuvant therapy for patients with HER2+ early breast cancer (EBC). Observational studies on real-world treatment patterns for HER2+ EBC between 2005 and 2015 suggest that 19.1% to 59.5% of patients across regions of North America, Europe, Australia, New Zealand, and China did not receive (neo)adjuvant trastuzumab. Data suggest that some patient subgroups, including older patients, those with HER2+/hormone receptor-positive disease, and women with small and/or node-negative HER2+ tumors, were less likely to receive anti HER2 therapy. Barriers to accessing trastuzumab are multifactorial and include issues related to drug funding and high treatment costs for patients that have been reported worldwide. Herein, we review available literature on the use of, and barriers to, treatment with trastuzumab in patients with HER2+ breast cancer. We also discuss how the availability of safe and effective biosimilars might increase access to trastuzumab and allow greater use of anti-HER2 therapy, potentially improving patient outcomes. PMID- 29525431 TI - Discovery of tetrahydrocarbazoles with potent hypoglycemic and hypolipemic activities. AB - A series of tetrahydrocarbazole derivatives was designed and synthesized on the basis of the AMP-activated protein kinase activator GY3. All the synthesized compounds were screened in HepG2 cell lines for glucose consumption activity and several of them showed potent glucose decreasing activity. In vivo evaluation of the hypoglycemic and hypolipemic effects indicated that 7a exhibited comparable activity with pioglitazone, but with a weaker body-weight increasing effect. The pharmacokinetic profiles of 7a were also investigated. PMID- 29525432 TI - Marliolide inhibits skin carcinogenesis by activating NRF2/ARE to induce heme oxygenase-1. AB - Heme oxygenase-1 (HO-1) catalyzes the enzymatic degradation of heme to produce three anti-oxidant molecules: carbon monoxide (CO), ferrous ion (Fe2+), and biliverdin. Induction of HO-1 is currently considered as a feasible strategy to treat oxidative stress-related diseases. In the present study, we identified marliolide as a novel inducer of HO-1 in human normal keratinocyte HaCaT cells. Mechanism-based studies demonstrated that the induction of HO-1 by marliolide occurred through activation of NRF2/ARE via direct binding of marliolide to KEAP1. Structure-activity relationship revealed chemical moieties of marliolide critical for induction of HO-1, which renders a support for Michael reaction as a potential mechanism of action. Finally, we observed that marliolide significantly inhibited the papilloma formation in DMBA/TPA-induced mouse skin carcinogenesis model and this event was closely associated with lowering the formation of 8-OH-G and 4-HNE in vivo. Together, our study provides the first evidence that marliolide might be effective against oxidative stress-related skin disorders. PMID- 29525433 TI - The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside like agonists of the human adenosine A2B receptor. AB - A new series of amino-3,5-dicyanopyridines (3-28) as analogues of the adenosine hA2B receptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA2B adenosine receptor display EC50 values in the range 9 350 nM behaving as partial agonists, with the only exception being the 2-{[4-(4 acetamidophenyl)-6-amino-3,5-dicyanopyridin-2-yl]thio}acetamide (8) which shows a full agonist profile. Moreover, the 2-[(1H-imidazol-2-yl)methylthio)]-6-amino-4 (4-cyclopropylmethoxy-phenyl)pyridine-3,5-dicarbonitrile (15) turns out to be 3 fold more active than 1 although less selective. This result can be considered a real breakthrough due to the currently limited number of non-adenosine hA2B AR agonists reported in literature. To simulate the binding mode of nucleoside and non-nucleoside agonists at the hA2B AR, molecular docking studies were performed at homology models of this AR subtype developed by using two crystal structures of agonist-bound A2A AR as templates. These investigations allowed us to represent a hypothetical binding mode of hA2B receptor agonists belonging to the amino-3,5-dicyanopyridine series and to rationalize the observed SAR. PMID- 29525434 TI - Metallomics for Alzheimer's disease treatment: Use of new generation of chelators combining metal-cation binding and transport properties. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting tens of million people. Currently marketed drugs have limited therapeutic efficacy and only slowing down the neurodegenerative process. Interestingly, it has been suggested that biometal cations in the amyloid beta (Abeta) aggregate deposits contribute to neurotoxicity and degenerative changes in AD. Thus, chelation therapy could represent novel mode of therapeutic intervention. Here we describe the features of chelators with therapeutically relevant mechanism of action. We have found that the tested compounds effectively reduce the toxicity of exogenous Abeta and suppress its endogenous production as well as decrease oxidative stress. Cholyl hydrazones were found to be the most active compounds. In summary, our data show that cation complexation, together with improving transport efficacy may represent basis for eventual treatment strategy in AD. PMID- 29525435 TI - Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups. AB - Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9, 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 MUM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors. PMID- 29525436 TI - Inhibition of methionine gamma lyase deaminase and the growth of Porphyromonas gingivalis: A therapeutic target for halitosis/periodontitis. AB - BACKGROUND AND OBJECTIVES: Pathogenic infections caused by Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia can result in the production of volatile sulfur compounds (VSC's) and other toxic compounds from methionine catabolism that can lead to halitosis and periodontitis. Our aim is to block the activity of methionine gammalyase-deaminase (Mgld) of methionine catabolism to prevent halitosis/periodontitis. DESIGNS: Cloned, expressed, Mgld protein was tested for purity by SDS-PAGE and western blotting. Mgld activity was tested by UV-vis spectroscopy and DTNB assay. Effects of Mgld inhibitor propargylglycine (PGLY) was tested on P. gingivalis growth by turbidity measurements. The effects of PGLY on oral epithelial and periodontal ligament cells in culture at different concentrations and time were tested for cell viability by MTT and Live-Dead assays. Amino acid comparisons of Mgld from different oral pathogens were done using standard bioinformatics program. RESULTS: Propargylglycine (PGLY) inhibited purified Mgld activity completely. In vivo, PGLY is a potent inhibitor on the growth of the P. gingivalis over 24 h, grown at 25 degrees C and 37 degrees C. Correspondingly in vivo Mgld activity was also affected by PGLY. Amino acid comparisons of oral pathogens showed 100% identity on the key residues of Mgld catalysis. Mammalian oral cell lines with PGLY, showed no difference in cell death over untreated controls assessed by MTT and Live-Dead assays. CONCLUSIONS: PGLY arrest's VSC's production by P. gingivalis. Since initial Mgld activity is inhibited subsequent enzymatic and nonenzymatic products formed will be prevented. PGLY showed no toxicity towards cultured mammalian oral cells. Thus, PGLY can serve as a mouthwash ingredient to prevent halitosis/periodontitis. PMID- 29525438 TI - How Do You Design Undergraduate Genetics Laboratory Courses? PMID- 29525437 TI - Pathophysiology of endometriosis-associated pain: A review of pelvic and central nervous system mechanisms. AB - Although pain is one of the main symptoms women with endometriosis present with, there is poor correlation between symptom severity and disease burden and the underlying biological mechanisms by which pain arises are still only poorly understood. We briefly review the neurobiology of pain before considering mechanisms that may be specifically relevant in the context of endometriosis. The role of pelvic factors such as new nerve fibre growth, peritoneal fluid and inflammation is explored with a particular focus on studies where these factors have been associated with pain symptoms rather than just being compared between women with endometriosis and disease-free controls. We then consider the role of the central nervous system and associated systems, including the stress axis and psychological factors, in the modulation of pain. The potential for changes in these systems to be a cause and/or a consequence of the pain and how they might explain some of the known associations between endometriosis and other somatic symptoms is discussed. The chapter concludes by considering the implications of these mechanisms on treatment strategies for these women. PMID- 29525439 TI - Can we base the indication of early cystectomy on more than clinical-pathological characteristics? PMID- 29525440 TI - Learning curve for the management of tyrosine kinase inhibitors as the first line of treatment for patients with metastatic renal cancer. AB - OBJECTIVES: To analyse the learning curve for the management of tyrosine kinase inhibitors as the first line of treatment for patients with metastatic renal cancer. MATERIAL AND METHODS: We evaluated 32 consecutive patients treated in our department for metastatic renal cancer with tyrosine kinase inhibitors (pazopanib or sunitinib) as first-line treatment between September 2012 and November 2015. We retrospectively analysed this sample. We measured the time to the withdrawal of the first-line treatment, the time to progression and overall survival using Kaplan-Meier curves. The learning curve was analysed with the cumulative sum (CUSUM) methodology. RESULTS: In our series, the median time to the withdrawal of the first-line treatment was 11 months (95% CI 4.9-17.1). The mean time to progression was 30.4 months (95% CI 22.7-38.1), and the mean overall survival was 34.9 months (95% CI 27.8-42). By applying the CUSUM methodology, we obtained a graph for the CUSUM value of the time to withdrawal of the first-line treatment (CUSUM TW), observing 3 well-differentiated phases: phase 1 or initial learning phase (1-15), phase 2 (16-26) in which the management of the drug progressively improved and phase 3 (27-32) of maximum experience or mastery of the management of these drugs. The number of treated patients needed to achieve the proper management of these patients was estimated at 15. CONCLUSIONS: Despite the limitations of the sample size and follow-up time, we estimated (in 15 patients) the number needed to reach the necessary experience in the management of these patients with tyrosine kinase inhibitors. We observed no relationship between the time to the withdrawal of the first-line treatment for any cause and progression. PMID- 29525441 TI - Exogenous nitric oxide pretreatment protects Brassica napus L. seedlings from paraquat toxicity through the modulation of antioxidant defense and glyoxalase systems. AB - To investigate the physiological and biochemical mechanisms of nitric oxide (NO) induced paraquat (PQ) tolerance in plants, we pretreated a set of 10-day-old Brassica napus seedlings with 500 MUM sodium nitroprusside (SNP - a NO donor) for 24 h. Then, three doses of PQ (62.5, 125 and 250 MUM) were applied separately, as well as to SNP-pretreated seedlings, and the seedlings were allowed to grow for an additional 48 h. The seedlings treated with PQ showed clear, dose-dependent signs of oxidative stress, with elevated levels of lipid peroxidation (MDA, malondialdehyde), H2O2 and O2- generation, and lipoxygenase (LOX) activity. Paraquat treatment disrupted pools of water-soluble antioxidants (ascorbate-AsA and reduced glutathione-GSH). Paraquat had different effects on the activities of antioxidant enzymes. The activities of glutathione reductase (GR) and catalase (CAT) decreased after PQ treatment in a dose-dependent manner, while the activities of ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR) and glyoxalase (Gly I and Gly II) decreased only with high doses of PQ (125 and 250 MUM). By contrast, the activities of monodehydroascorbate reductase (MDHAR), glutathione S-transferase (GST) and glutathione peroxidase (GPX) increased after PQ treatment. A higher dose of PQ reduced chlorophyll and leaf water content but increased the methylglyoxal (MG) and proline (Pro) content. Compared to PQ alone, PQ supplemented with exogenous NO reduced LOX activity, the AsA-GSH pool, and the activities of APX, DHAR, GR, GPX, Gly I and Gly II. These effects helped to reduce oxidative stress and MG toxicity and were accompanied by reduced chlorosis and increased relative water content. Given these results, exogenous NO was found to be a key player in the mitigation of PQ toxicity in plants. PMID- 29525442 TI - Metabolomics and its physiological regulation process reveal the salt-tolerant mechanism in Glycine soja seedling roots. AB - Wild soybean (Glycine soja) is an excellent germplasm resource and has strong resistance and wide adaptability to different environments. Hence, the physiology and metabolomics characteristics of wild soybean under different types of salt stress were determined to improve understanding of salt-tolerant mechanisms of wild soybean in the field. Two types of wild soybean seedlings were exposed to two different types of salt stress for 14 d. The photosynthesis of wild soybean seedling extracts were analyzed using metabolomics based on gas chromatography mass spectrometry. The wild soybean root extracts used metabolomics to quantify the metabolic changes and ion contents. The assimilative function of photosynthesis in salt-tolerant wild soybean was less inhibited than in common wild soybean, and it regulated accumulation of toxic ions and maintained the accumulation of K+ and Mg2+ to alleviate salt stress. Moreover, in resisting salt stress the salt-tolerant wild soybean has showed improved amino acid and carbohydrate and polyol metabolisms under neutral-salt stress and organic acid, amino acid and tricarboxylic acid metabolisms under alkali-salt stress. Our results provide valuable insights into the response of salt-tolerant wild soybean to two types of salt stress by linking stress-related physiological responses to changes in metabolites. PMID- 29525443 TI - The Artemisia annua FLOWERING LOCUS T Homolog 2, AaFT2, is a key regulator of flowering time. AB - Artemisia annua is a typical short-day photoperiod (SD) and belongs to Asteraceae family. FLOWERING LOCUS T Homolog genes play important roles in regulation of flowering time. Two FT-like genes AaFT1 and AaFT2 were isolated from cDNA libraries constructed from leaves of A. annua. The gene expression analysis revealed that AaFT1 and AaFT2 mRNAs were expressed predominantly in leaves and could be induced by GA3. Subcellular localization results indicated that AaFT1 and AaFT2 proteins were both localized to the nuclei and cytoplasm. The Y2H assay results indicated that AaFT1 and AaFT2 could interact with a bZIP transcription factor, AaFD. AaFT2 was induced by SDs condition and may play an important role in modulation of flowering. In the present study, we performed RNA interference (RNAi) experiments to inhibit the mRNA level of AaFT2 in A. annua for detecting AaFT2 gene function. Our findings suggest that inhibition of AaFT2 may delay the flowering time and increase the accumulation of artemisinin (ART) in transgenic A. annua. Collectively, these results indicate that AaFT2 is a key regulator of regulation flowering time and can be used for genetic engineering to improve artemisinin yield. PMID- 29525444 TI - A peptidogalactomannan isolated from Cladosporium herbarum induces defense related genes in BY-2 tobacco cells. AB - Cladosporium herbarum is a plant pathogen associated with passion fruit scab and mild diseases in pea and soybean. In this study, a peptidogalactomannan (pGM) of C. herbarum mycelium was isolated and structurally characterized, and its role in plant-fungus interactions was evaluated. C. herbarum pGM is composed of carbohydrates (76%) and contains mannose, galactose and glucose as its main monosaccharides (molar ratio, 52:36:12). Methylation and 13C-nuclear magnetic resonance (13C-NMR) spectroscopy analysis have shown the presence of a main chain containing (1 -> 6)-linked alpha-D-Manp residues, and beta-D-Galf residues are present as (1 -> 5)-interlinked side chains. beta-Galactofuranose containing similar structures were characterized by our group in A. fumigatus, A. versicolor, A. flavus and C. resinae. Tobacco BY-2 cells were used as a model system to address the question of the role of C. herbarum pGM in cell viability and induction of the expression of plant defense-related genes. Native and partially acid hydrolyzed pGMs (lacking galactofuranosyl side-chain residues) were incubated with BY-2 cell suspensions at different concentrations. Cell viability drastically decreased after exposure to more than 400 MUg ml-1 pGM; however no cell viability effect was observed after exposure to a partially acid hydrolyzed pGM. BY-2 cell contact with pGM strongly induce the expression of plant defense-related genes, such as phenylalanine ammonia lyase (PAL) and lipoxygenase (LOX), as well as the pathogen-related PR-1a, PR-2 and PR-3 genes, suggesting that pGM activates defense responses in tobacco cells. Interestingly, contact with partially hydrolyzed pGM also induced defense-related gene expression at earlier times than native pGM. These results show that the side chains of the (1 -> 5)-linked beta-D-galactofuranosyl units from pGM play an important role in the first line fungus-plant interactions mediating plant responses against C. herbarum. In addition, it was observed that pGM and/or C. herbarum conidia are able to induced HR when in contact with tobacco leaves and in vitro plantlets roots, producing necrotic lesions and peroxidase and NO burst, respectively. PMID- 29525445 TI - Alirocumab in high-risk patients: Observations from the open-label expanded use program. AB - BACKGROUND: The alirocumab expanded use program provided open-label access to alirocumab before its commercial availability to patients with severe hypercholesterolemia not controlled with maximally tolerated doses of standard-of care lipid-lowering therapy. OBJECTIVE: To describe the safety and lipid-lowering efficacy of alirocumab in high-risk patients who were likely to be early users of proprotein convertase subtilisin/kexin type 9 inhibitors after approval. METHODS: Patients with heterozygous familial hypercholesterolemia (HeFH) and/or coronary heart disease (CHD) and baseline low-density lipoprotein cholesterol (LDL-C) of >=160 mg/dL on maximally tolerated lipid-lowering therapy were enrolled and received alirocumab 150 mg every 2 weeks for 24 weeks. Patients were permitted use of all available statins; those not taking any dose of statin could also be enrolled. RESULTS: Of 100 enrolled patients, 93 were white, 62 were women, and overall mean age was 58 years; 61 had HeFH, 3 had unknown type of familial hypercholesterolemia, 66 had CHD, and 30 had both familial hypercholesterolemia and CHD. Sixty-four patients were identified by their providers to have some level of statin intolerance; of these, 47 were not on statin. Alirocumab reduced LDL-C on average from 221 mg/dL at baseline to 102 mg/dL by week 24 (-55%). Treatment-emergent adverse events were experienced in 61% of patients and treatment-emergent adverse events leading to permanent treatment discontinuation in 3% of patients; no deaths occurred. CONCLUSIONS: Safety and efficacy observations from the open-label alirocumab expanded use program of very high risk patients with HeFH and/or CHD and baseline LDL-C of >=160 mg/dL uncontrolled by maximally tolerated lipid-lowering therapy were consistent with those in the placebo/ezetimibe-controlled ODYSSEY trials. PMID- 29525446 TI - Alanine and glycine conjugates of (2S,4R)-4-[18F]fluoroglutamine for tumor imaging. AB - INTRODUCTION: Glutamine is an essential source of energy, metabolic substrates, and building block for supporting tumor proliferation. Previously, (2S,4R)-4 [18F]fluoroglutamine (4F-Gln) was reported as a glutamine-related metabolic imaging agent. To improve the in vivo kinetics of this radiotracer, two new dipeptides, [18F]Gly-(2S,4R)4-fluoroglutamine (Gly-4F-Gln) and [18F]Ala-(2S,4R)4 fluoroglutamine (Ala-4F-Gln) were investigated. METHODS: Radiolabeling was performed via 2-steps 18F-fluorination. Cell uptake studies of Gly-4F-Gln and Ala 4F-Gln were investigated in 9 L cell lines. In vitro and in vivo metabolism studies were carried out in Fisher 344 rats. Biodistribution and microPET imaging studies were performed in 9 L tumor-bearing rats. RESULTS: In vitro incubation of these [18F]dipeptides in rat and human blood showed a rapid conversion to (2S,4R) 4-[18F]fluoroglutamine (t1/2 = 2.3 and 0.2 min for [18F]Gly-4F-Gln and [18F]Ala 4F-Gln, respectively for human blood). Biodistribution and PET imaging in Fisher 344 rats bearing 9 L tumor xenografts showed that these dipeptides rapidly localized in the tumors, comparable to that of (2S,4R)-4-[18F]fluoroglutamine (4F Gln). CONCLUSIONS: The results support that these dipeptides, [18F]Gly-4F-Gln and [18F]Ala-4F-Gln, are prodrugs, which hydrolyze in the blood after an iv injection. They appear to be selectively taken up and trapped by tumor tissue in vivo. The dipeptide, [18F]Ala-4F-Gln, may be suitable as a PET tracer for imaging glutaminolysis in tumors. PMID- 29525447 TI - [Epidemiology and associated factors with depression among people suffering from epilepsy: A transversal French study in a tertiary center]. AB - OBJECTIVES: The occurrence of depression in people with epilepsy is almost twice as common as in the general population. Furthermore, depression is the first cause of lower quality of life among those patients. Which is why the main goal of this study was to assess the epidemiology of depression and its associated factors among the patients from the tertiary department of epileptology in Rennes. METHODS/RESULTS: The subjects were included prospectively and consecutively at the moment of their consultation or hospitalisation in the department. Personal data about the socio-economic status and the type of epilepsy was collected. The subjects filled validated self-assessment of depression (NDDIE), anxiety (GAD-7) and quality of life (QOLIE-10). Thanks to the NDDIE, the patients were divided into: "depressed" and "not depressed"; and the two groups were compared with univariate and multivariate models. Of the 322 patients followed-up in the department between the 17th of June and the 9th of September 2016 223 of them were included in the study. According to the NDDIE, 22.6% suffered from depression; according to the GAD-7, 46.4% suffered from anxiety. In the "depressed" group, 82% were not under anti-depressant medication. In the univariate model, depression was associated with: anxiety, suicidal ideations, lower quality of life, vague nervus stimulation treatment, anticonvulsant benzodiazepine medication or psychiatric medication, and last of all bitherapy or polytherapy antiepileptic medication compared to monotherapy. In the multivariate model, depression was significantly related to anxiety (OR: 8.86 [3.00; 26.19] p=0.0001), suicidal ideas (OR: 7.43 [2.93; 18.81] p<0.0001), anticonvulsant benzodiazepine medication (OR: 3.31 [1.16; 9.49] p=0.0255), and lower quality of life (OR: 1.09 [1.02; 1.17] p=0.0087). Generalised epilepsy was a protective factor with uni and multivariate models (OR: 0.34 [0.11; 1.00] p=0.0492). CONCLUSIONS: In the tertiary epileptic department of Rennes, more than 20% of patients with epilepsy suffered from depression during the inclusion period according to the NDDIE. Among those "depressed" subjects, fewer than one out of five seemed to receive proper psychiatric care. Which is why this study highlights the importance of interdisciplinary cooperation between neurologists and psychiatrists in order to aim at better management of epileptic patients as a whole. PMID- 29525448 TI - Interventions for post-stroke fatigue: A Cochrane review summary. PMID- 29525449 TI - Rehabilitation following carpal tunnel release: A Cochrane review summary. PMID- 29525450 TI - Assistive devices, hip precautions, environmental modifications and training to prevent dislocation and improve function after hip arthroplasty: A Cochrane review summary. PMID- 29525451 TI - Production of highly efficient activated carbons from industrial wastes for the removal of pharmaceuticals from water-A full factorial design. AB - The wide occurrence of pharmaceuticals in aquatic environments urges the development of cost-effective solutions for their removal from water. In a circular economy context, primary paper mill sludge (PS) was used to produce activated carbon (AC) aiming the adsorptive removal of these contaminants. The use of low-cost precursors for the preparation of ACs capable of competing with commercial ACs continues to be a challenge. A full factorial design of four factors (pyrolysis temperature, residence time, precursor/activating agent ratio, and type of activating agent) at two levels was applied to the production of AC using PS as precursor. The responses analysed were the yield of production, percentage of adsorption for three pharmaceuticals (sulfamethoxazole, carbamazepine, and paroxetine), specific surface area (SBET), and total organic carbon (TOC). Statistical analysis was performed to evaluate influencing factors in the responses and to determine the most favourable production conditions. Four ACs presented very good responses, namely on the adsorption of the pharmaceuticals under study (average adsorption percentage around 78%, which is above that of commercial AC), and SBET between 1389 and 1627 m2 g-1. A desirability analysis pointed out 800 degrees C for 60 min and a precursor/KOH ratio of 1:1 (w/w) as the optimal production conditions. PMID- 29525453 TI - Expression of complement receptor 3 (CR3) and regulatory protein CD46 on dendritic cells of antiretroviral naive and treated HIV-1 infected individuals: Correlation with immune activation status. AB - During infection and budding, human immunodeficiency virus-1 (HIV-1) acquires regulators of Complement Activation (RCAs) along with the host cell membrane on the viral envelope. Activation of host complement system results in opsonization of virus by complement fragments, however the virus evades complement mediated lysis (CoML) by virtue of the RCAs on the viral envelope. The RCAs on HIV-1 envelope process complement protein C3 into various fragments that promote viral entry and infection of cells through different complement receptors. Complement opsonized HIV-1 has been shown in vitro to infect dendritic cells (DCs) in a CR3 dependent manner, although the role of CR3 and CD46 in natural HIV-1 infection is not clear. Surface expression of CR3 and CD46 on DC subsets of 30 antiretroviral naive, 31 treated (cART) HIV-1 infected individuals and 30 seronegative controls was measured by flow cytometry and plasma levels of cytokines and complement activity (C3c levels) were quantitated by sandwich ELISA. Significantly lower surface expression of CR3 and CD46 was observed on DC subsets in naive and treated HIV-1 infected individuals compared to controls. Significantly higher complement activation and plasma levels of IL-4, IL-8, IL-10 and IFN-gamma were observed in treatment naive HIV-1 infected individuals than controls. Significantly lower plasma levels of IL-4, IL-6, IL-8 and IL-10 were observed in treated vs. naive HIV-1 infected individuals. Our findings suggest that alterations in expression of CR3 and CD46 on DCs along with complement activity could be factors that influence viral persistence and HIV-1 disease progression and need to be further evaluated. PMID- 29525454 TI - A novel multi-peptide subunit vaccine admixed with AddaVax adjuvant produces significant immunogenicity and protection against Proteus mirabilis urinary tract infection in mice model. AB - Proteus mirabilis is a common pathogen in urinary tract infections (UTIs). There is no vaccine against P. mirabilis, thus a novel multi-peptide vaccine of MrpA, UcaA and Pta factors of P. mirabilis we designed and a mice model was used to evaluate its efficacy in combination with AddaVax adjuvant. According to the bioinformatics studies, 7 fragments of MrpA (31-75, 112-146), UcaA (68-117, 132 156) and Pta (210-265, 340-400, 496-570) with B and T cell epitope regions were selected for fusion construction. Mice subcutaneously vaccinated with the fusion MrpA.Pta.UcaA induced a significant increase in serum and mucosal IgG and IgA responses. The fusion also showed a significant induction in cellular responses (Th1 and Th2). The addition of AddaVax to fusion and the mixture of MrpA, UcaA, and Pta (MUP) improved the humoral and cellular responses, especially the IgG2a and IFN-gamma (Th1 responses) levels. Fusion with and without AddaVax and MUP + AddaVax could maintain significant humoral responses until 6 months after the first vaccine dose. All vaccine combinations with and without adjuvant showed high effectiveness in the protection of the bladder and kidney against experimental UTI; this could be attributed to the significant humoral and cellular responses. The present study suggests that the AddaVax-based vaccine formulations especially the fusion Pta.MrpA.UcaA admixed with AddaVax as potential vaccine candidates for protection against P. mirabilis. Furthermore, AddaVax could be considered as an effective adjuvant in designing other vaccines against UTI pathogens. PMID- 29525452 TI - Adolescent neurocognitive development and impacts of substance use: Overview of the adolescent brain cognitive development (ABCD) baseline neurocognition battery. AB - Adolescence is characterized by numerous social, hormonal and physical changes, as well as a marked increase in risk-taking behaviors. Dual systems models attribute adolescent risk-taking to tensions between developing capacities for cognitive control and motivational strivings, which may peak at this time. A comprehensive understanding of neurocognitive development during the adolescent period is necessary to permit the distinction between premorbid vulnerabilities and consequences of behaviors such as substance use. Thus, the prospective assessment of cognitive development is fundamental to the aims of the newly launched Adolescent Brain and Cognitive Development (ABCD) Consortium. This paper details the rationale for ABC'lected measures of neurocognition, presents preliminary descriptive data on an initial sample of 2299 participants, and provides a context for how this large-scale project can inform our understanding of adolescent neurodevelopment. PMID- 29525455 TI - Transluminal Approach with Bubble-Seeded Histotripsy for Cancer Treatment with Ultrasonic Mechanical Effects. AB - Bubble-seeded histotripsy (BSH) is a newly developed ultrasound-based mechanical fractionation technique using locally injected phase change nanodroplets (PCNDs) as sensitizers. The PCNDs are a kind of microbubble precursor compressed into submicron-size in droplets form, which were designed for local administration and will expand into microbubbles under ultrasound exposure. Previously, we reported that a combination of PCNDs injection and pulsed high-intensity focused ultrasound (pHIFU) with an acoustic intensity as low as about 3 kW/cm2 at 1.1 MHz, which is similar to the acoustic intensity of currently available HIFU coagulation therapy, was enough to induce tissue fractionation after significant antitumor effects in an in vivo study. Toward therapeutic application of BSH to deep-seated tissues such as the pancreas, the transluminal approach, using endoscopic ultrasound was thought to be ideal. Therefore, for a preliminary examination, we developed a new transducer with a small aperture (20- * 20-mm square) and long focal length (35 mm), operating at 2.1 MHz that could be attached to an EUS-mimicking probe. With the newly developed transducer and locally injected PCNDs, predictable tissue mechanical fractionation was observed in both ex vivo and in vivo studies at acoustic intensities that were too low to induce any significant bioeffects (around 4 kW/cm2) without using PCNDs. For in situ monitoring of the treatment site during a procedure, the degree of attenuation of microbubble motions after exposing the microbubbles to pHIFU was monitored, using ultrafast echographic imaging. Microbubble movements were observed to be largest at 25-30 s after pHIFU exposure. On the contrary, after 40 s, the movement of microbubbles decreased to the same level as at the start of the procedure, suggesting that an overdose of pHIFU exposure causes coagulation attributable to the thermal effect caused by absorption of the energy. Those results were promising for expanding the application of BSH for a transluminal approach, using a small transducer under real-time monitoring. PMID- 29525456 TI - Influence of Acoustic Reflection on the Inertial Cavitation Dose in a Franz Diffusion Cell. AB - The exposure of the skin to low-frequency (20-100 kHz) ultrasound is a well established method for increasing its permeability to drugs. The mechanism underlying this permeability increase has been found to be inertial cavitation within the coupling fluid. This study investigated the influence of acoustic reflections on the inertial cavitation dose during low-frequency (20 kHz) exposure in an in vitro skin sonoporation setup. This investigation was conducted using a passive cavitation detector that monitored the broadband noise emission within a modified Franz diffusion cell. Two versions of this diffusion cell were employed. One version had acoustic conditions that were similar to those of a standard Franz diffusion cell surrounded by air, whereas the second was designed to greatly reduce the acoustic reflection by submerging the diffusion cell in a water bath. The temperature of the coupling fluid in both setups was controlled using a novel thermoelectric cooling system. At an ultrasound intensity of 13.6 W/cm2, the median inertial cavitation dose when the acoustic reflections were suppressed, was found to be only about 15% lower than when reflections were not suppressed. PMID- 29525458 TI - Ultrasound-Guided Percutaneous Needle Biopsy for Peripheral Pulmonary Lesions: Diagnostic Accuracy and Influencing Factors. AB - A retrospective study was carried out to evaluate the diagnostic accuracy and the factors influencing the diagnostic accuracy of 648 procedures of ultrasound guided percutaneous needle biopsy (PNB) for peripheral pulmonary lesions (PPLs). We reviewed the histopathology results, the clinical records and the procedure reports of these 648 biopsies and the final diagnoses of 637 PPLs to determine the diagnostic accuracy of ultrasound-guided PNB. Factors that influenced the diagnostic accuracy were assessed by analysis of the biopsy procedures, which were classified as diagnostic cases (true-positive and true-negative) and non diagnostic cases (false-positive, false-negative and indeterminate). Statistical analyses of factors that related to patient demographic characteristics, lesion characteristics and biopsy details were performed to determine possible effects on diagnostic accuracy. Biopsies were successfully performed in all cases, and 11 patients underwent second biopsies for the same lesions. Among the 637 PPLs, there were 326 (51.2%) malignant lesions, 272 (42.7%) benign lesions and 39 (6.1%) indeterminate lesions. Of the 272 benign lesions, 114 (41.9%) were found to be tuberculous. The overall diagnostic accuracy was 81.8%, and the rates of hemoptysis, symptomatic pneumothorax and chest-tube insertion were 8.0%, 1.7% and 0.9%, respectively. Lesions sizes were divided into 3 groups according to the measurement by ultrasound. For lesions that measured <=20 mm, 21-49 mm and >=50 mm, the diagnostic accuracy was 72.0%, 86.8% and 79.7%, while sensitivity and specificity were 54.3%-79.2%, 88.3%-90.7% and 79.4%-89.5% and 77.3%-100%, 96.8% 100% and 58.6%-100%, respectively. Diagnostic accuracy was significantly affected by lesion size when lesion size was measured by ultrasound (p = 0.006) and computed tomography (CT) (p = 0.001). In the 3 lesion groups of <=20 mm, 21-49 mm or >=50 mm, diagnostic accuracy among each group was significantly different (p <0.001). When lesion size was measured by ultrasound (p <0.001) and CT (p <0.001) and the 3 groups were analyzed (p <0.001), there was a statistically significant relationship between lesion size and the presence of necrosis. The rates of the presence of necrosis in lesions that measured <=20 mm, 21-49 mm and >=50 mm were 3.9%, 11.7% and 28.8%, respectively. No significance was found for age (p = 0.119), gender (p = 0.25), lesion location (p = 0.55), the presence of necrosis (p = 0.226), patient position (p = 0.25), needle size (p = 0.26), puncture angle (p = 0.34) and needle passes (p = 0.21). Ultrasound-guided PNB is an effective and safe diagnostic method for PPLs; the diagnostic accuracy is significantly affected by lesion size and decreases in smaller (<=20 mm) and larger (>=50 mm) lesions. PMID- 29525457 TI - Activation of Piezo1 but Not NaV1.2 Channels by Ultrasound at 43 MHz. AB - Ultrasound (US) can modulate the electrical activity of the excitable tissues, but the mechanisms underlying this effect are not understood at the molecular level or in terms of the physical modality through which US exerts its effects. Here, we report an experimental system that allows for stable patch-clamp recording in the presence of US at 43 MHz, a frequency known to stimulate neural activity. We describe the effects of US on two ion channels proposed to be involved in the response of excitable cells to US: the mechanosensitive Piezo1 channel and the voltage-gated sodium channel NaV1.2. Our patch-clamp recordings, together with finite-element simulations of acoustic field parameters indicate that Piezo1 channels are activated by continuous wave US at 43 MHz and 50 or 90 W/cm2 through cell membrane stress caused by acoustic streaming. NaV1.2 channels were not affected through this mechanism at these intensities, but their kinetics could be accelerated by US-induced heating. PMID- 29525459 TI - Schizophrenia and dissociation: Its relation with severity, self-esteem and awareness of illness. AB - This article describes the conclusions of an investigation done with 120 Spanish patients: the finding of a new psychopathological profile within a subgroup of patients suffering from schizophrenia. The patients were evaluated through different questionnaires about sociodemographic data, traumatic events, the severity index (both clinical and psychopathological), self-esteem and consciousness of the illness. From the scores obtained on a scale of dissociative experiences, they were classified into two groups: high dissociative symptomatology or HD, and low dissociative symptomatology or LD. The HD group contained 44 patients (36.7% of the total population). The groups LD and HD show meaningful differences with respect to dissociative symptomatology levels, general psychopathology and level of traumatic events suffered. The percentage of patients with low self-esteem was higher in group HD than in group LD (M=25.52 front 28.76 of group LD; t (118)=2.94, p=.00). In addition, the group HD was more conscious of having a mental disorder, of the beneficial effects of medication and of the social consequences of their illness: F (1)=10.929, p=.001; n2pt=0.083; 1-beta=0.907. The results show the existence of a subgroup of schizophrenic patients with higher levels of dissociation and trauma that were related with higher levels of symptomatology, lower self-esteem and higher consciousness of the illness, building a population of higher severity in which it would make sense to implement coadjutant treatments specifically oriented to these variables and, in addition, opening a therapeutic possibility for the patients with refractory schizophrenia. PMID- 29525461 TI - Paranoid beliefs and realistic expectations of victimization: Data from the survey of police-public encounters. AB - BACKGROUND: The anticipation of threat or victimization is a core feature of paranoia. Cognitive theories of paranoia suggest that paranoid thoughts may arise as a psychological response to trauma exposure, which likewise may lead to greater anticipation of subsequent victimization. Little is known, however, about the relation between paranoid beliefs and anticipated victimization when accounting for past victimization experience. The present study aimed to address whether the experiences of past victimization contribute to the link between paranoid beliefs and the anticipation of threat or victimization, with a particular focus on exposure to police violence. METHODS: Data were collected through the Survey of Police-Public Encounters (N=1615), a cross-sectional, general population survey study conducted in four Eastern U.S. cities. Associations between paranoia and anticipated victimization were assessed using linear regression models, with and without adjustment for past victimization exposure. RESULTS: Paranoid beliefs were positively associated with police victimization expectations (beta=0.19, p<0.001), but these associations were statistically better explained by past exposures to similar victimization such that paranoia was no longer associated with anticipated victimization in adjusted models (beta=0.02, p=0.451). To assess for the specificity of past exposures to victimization, adjusting for past exposure to intimate partner violence (as a control condition) did not eliminate the association between paranoia and expected police victimization. CONCLUSIONS: The overall findings are consistent with cognitive theories of paranoia in which paranoid beliefs may be a severe but normative reaction to past victimization exposures in some cases. PMID- 29525460 TI - Sensorimotor gating deficits in schizophrenia: Advancing our understanding of the phenotype, its neural circuitry and genetic substrates. PMID- 29525462 TI - Considerations for the development and implementation of brief screening tools in the identification of early psychosis. PMID- 29525463 TI - Clozapine use in early psychosis. AB - BACKGROUND: The superior efficacy of clozapine in treatment resistant schizophrenia has been clearly demonstrated, yet there are often delays in the commencement of clozapine. In this study, we aimed to determine; the proportion of young people with a first episode of psychosis (FEP) who would be considered eligible for clozapine treatment, the theoretical delay in commencing clozapine and to compare the outcomes of those treated with clozapine to those who were eligible but not treated with clozapine. METHODS: This study was conducted at Orygen Youth Health (OYH), a youth mental health service for young people aged 15 24. All clients who were treated at the Early Psychosis Prevention and Intervention Centre (EPPIC) clinic between 01.01.2011 and 31.12.2013 were included. RESULTS: 544 young people presented with a FEP in the study period and 9.4% (N = 51) subsequently fulfilled criteria for treatment-resistant schizophrenia. Of these individuals, thirty (58.8%) were commenced on clozapine, in addition to a further eleven. The median delay to the commencement of clozapine was 42 weeks (I.Q.R. = 7.5-64). Of those commenced on clozapine, 76.6% achieved remission of positive psychotic symptoms and 50% were in employment or education by the time of discharge or transfer to the adult mental health services. The rate of discontinuation of clozapine was 24.4% and 60.0% of discontinuations were due to cardiac complications and the remainder were due to non-compliance. CONCLUSIONS: These findings suggest that early intervention for psychosis services have a crucial role in ensuring timely initiation of clozapine in individuals with a diagnosis of treatment-resistant schizophrenia. PMID- 29525464 TI - Management of positive margins after initial lumpectomy in elderly women with breast cancer. AB - INTRODUCTION: It is unknown whether the treatment disparity observed between young and elderly women extends to the management of positive margins after initial lumpectomy. The primary aim was to evaluate the management of positive margins after initial lumpectomy in elderly women. METHODS: Women >=50 y who underwent lumpectomy for stage I-III tumors were identified. Tumor and treatment characteristics were collected across two subgroups: young (50-69 y) and elderly (>=70 y). Univariate comparisons were done using chi-square and Wilcoxon Rank Sum test. A multivariable logistic regression was used to evaluate factors associated with reoperation. Incidence of overall recurrence was compared between young and elderly women by plotting the cumulative incidence function of overall recurrence and death without recurrence. RESULTS: Of 1670 women identified, 29.5% were elderly. Compared to young women, tumors in elderly patients were more frequently invasive lobular carcinoma, larger, low grade and lymphovascular negative. Positive margins were less common in elderly than young women (10.8% versus 16.2%, unadjusted OR 0.60, 95% CI 0.42-0.86). Compared to young women, elderly women were less likely to undergo reoperation (84.9% versus 100%, p < 0.001), adjuvant chemotherapy (5.7% versus 46.6%, p < 0.0001), and adjuvant radiation therapy (69.8% versus 83.9%, p = 0.04). Five-year disease free survival (DFS) was similar between age groups (86% versus 86%, p = 0.8). CONCLUSIONS: Elderly women with positive margins after initial lumpectomy were treated differently than younger women as shown by a lower rate of reoperation and adjuvant radiation therapy. Despite these treatment variations there was no impact on overall recurrence and DFS. PMID- 29525465 TI - Enucleation of pancreatic solid pseudopapillary neoplasm: Short-term and long term outcomes from a 7-year large single-center experience. AB - BACKGROUND: Enucleation is increasingly used for pancreatic solid pseudopapillary neoplasm (SPN) to preserve function of the pancreas. The data was limited due to rarity of this low-grade neoplasm. We sought to describe the indications, operative technique, short and long-term outcomes after enucleation with largest series of enucleated SPNs. METHODS: Data collected retrospectively from 110 patients with SPN who underwent pancreatectomy between 2009 and 2016 in our institution were reviewed. Thirty-one patients underwent enucleation were identified for analysis, and compared with the 70 patients underwent conventional pancreatic resection. RESULTS: Of the 31 patients, 27 (87.1%) were women, and the mean age was 29.8 years (range, 11-49 years). Enucleated SPNs were mostly located in the head/uncinate process of the pancreas (38.7%). Overall morbidity was 25.8%, mainly due to POPF (19.4%), and severe morbidity was only 6.5% with no death. Compared with conventional pancreatic resection, enucleation had a shorter duration of surgery (P < 0.001), less blood loss (P < 0.001), lower rate of exocrine insufficiency (P = 0.033) and comparable morbidity (P = 1), with no increased risk of tumor recurrence (P = 1). The rate of endocrine insufficiency after enucleation seemed lower (Nil vs. 4.5%, P = 0.55). CONCLUSIONS: Enucleation of SPN of the pancreas appears to be feasible and safe for preserving exocrine and endocrine function of the gland. Enucleation with negative surgical margin seems adequate with no increased risk of tumor recurrence. Enucleation could be seriously considered as an alternative to conventional resection for this frequently young population. PMID- 29525466 TI - Hepatectomy increases metastatic graft and growth in an immunocompetent murine model of peritoneal metastases. AB - BACKGROUND: Curative surgery of synchronous peritoneal metastases (PM) and colorectal liver metastases (LM) has been recently investigated as feasible option. When synchronous peritoneal and liver resection is not achievable, the sequence of the surgery remains unknown. Our hypothesis was that liver resection (LR) promotes peritoneal growth resulting in a non-resectable PM. We sought to analyse the effects of major LR and liver regeneration after hepatectomy in a murine model of PM and the associated angiogenesis. METHODS: Murine model of colorectal PM in Balb/C mice was developed by intraperitoneal injection of different CT-26 tumour cell concentrations. Five days after the injection, mice were randomized into three groups: 68% hepatectomy group, sham laparotomy and control group without surgery. On post-operative days 1, 5 and 20, PM was evaluated macroscopically, tumour growth and liver regeneration by immunohistochemistry, and angiogenesis by immunofluorescence. Circulating progenitor cells, plasmatic cytokines and digestive arterial blood flow velocity measurements were also analysed. RESULTS: Reproducible murine model of limited colorectal PM was obtained. Surgery induced PM increases and promoted neo angiogenesis. Major hepatectomy influence the tumour growth in the late phase after surgery, the extent of extra-peritoneal metastasis and the increase of Ki 67 expression in the remnant liver. CONCLUSIONS: This animal model confirms the pro-tumoural and pro-angiogenic role of surgery, laparotomy and major LR, which promotes the increase of angiogenic factors and their participation in PM growth. These results suggest that peritoneal resection should be first step in the case of two-step liver and peritoneal surgery for patients with colorectal PM and LM. PMID- 29525467 TI - Role of the anterior fissure vein in ventral or dorsal resection at Segment 8 of liver. AB - BACKGROUND: The vein that runs between ventral and dorsal Segment 8 is called the anterior fissure vein (AFV). AFV is sometimes needed as a boundary for Subsegmentectomy in Segment 8. The aim of the present study was to investigate the AFV to determine whether the AFV can be used a landmark for subsegmentectomy of the liver at Segment 8. METHODS: We analyzed data from 151 patients who had undergone abdominal computed tomographic (CT) examinations. The position of the AFV is identified by determining whether the AFV drains flows into the proximal, medial, or distal portion of the middle hepatic vein (MHV) or right hepatic vein (RHV). Furthermore, the proximal region is divided into 2 halves; the proximal portion is designated as P1 and the distal portion is designated as P2. RESULTS: The AFV could be identified in 78.8% (119/151) of the patients. The AFV flowed into the MHV in 84.9% of the patients and into the RHV in 15.1%. Among the former, the AFV flowed into the proximal MHV in 69.7% of the patients. CONCLUSIONS: Although the AFV might not be easily identifiable, the AVF can be used to determine the border between the ventral and dorsal portions of Segment 8. The AFV should thus be used as a landmark for Subsegmentectomy. PMID- 29525468 TI - ECCO essential requirements for quality cancer care for melanoma: Defining how to organise care. PMID- 29525469 TI - Direct oral anticoagulants after bariatric surgery: To use or not to use. PMID- 29525470 TI - Management of peri-operative anaemia in a patient with rare alloantibodies scheduled for oesophagectomy. AB - A description is presented on the management of a patient with an oesophageal neoplasm scheduled for oesophagectomy. Alloantibodies were detected during a blood components reservation procedure, which made it almost impossible to obtain compatible blood. Peri-operative anaemia management or "Patient Blood Management" should be routinely performed in all patients at transfusion risk. This strategy has been considered as one of the actions to bear in mind in fast-track surgery or enhanced recovery after surgery. PMID- 29525471 TI - Exposure of human melanocytes to UVB twice and subsequent incubation leads to cellular senescence and senescence-associated pigmentation through the prolonged p53 expression. AB - BACKGROUND: Ultraviolet radiation (UVR) is a well-known factor in skin aging and pigmentation, and daily exposure to subcytotoxic doses of UVR might accelerate senescence and senescence-associated phenomena in human melanocytes. OBJECTIVE: To establish an in vitro melanocyte model to mimic the conditions of repeated exposure to subcytotoxic doses of UVB irradiation and to investigate key factor(s) for melanocyte senescence and senescence-associated phenomena. METHODS: Human epidermal melanocytes were exposed twice with 20 mJ/cm2 UVB over a 24-h interval and subsequently cultivated for 2 weeks. Senescent phenotypes were addressed morphologically, and by measuring the senescence-associated beta galactosidase (SA-beta-Gal) activity, cell proliferation capacity with cell cycle analysis, and melanin content. RESULTS: The established protocol successfully induced melanocyte senescence, and senescent melanocytes accompanied hyperpigmentation. Prolonged expression of p53 was responsible for melanocyte senescence and hyperpigmentation, and treatment with the p53-inhibitor pifithrin alpha at 2-weeks post-UVB irradiation, but not at 48 h, significantly reduced melanin content along with decreases in tyrosinase levels. CONCLUSION: Melanocyte senescence model will be useful for studying the long-term effects of UVB irradiation and pigmentation relevant to physiological photoaging, and screening compounds effective for senescence-associated p53-mediated pigmentation. PMID- 29525472 TI - Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats. AB - Hyperphagia triggers and accelerates diabetes, and prevents proper dietary control of glycemia. Inversely, the impact of hyperglycemia on hyperphagia and possible mechanistic cause common for these two metabolic disorders in type 2 diabetes are less defined. The present study examined the precise developmental process of hyperglycemia and hyperphagia and explored the alterations in the hypothalamic arcuate nucleus (ARC), the primary feeding and metabolic center, in Goto-Kakizaki (GK) rats with type 2 diabetes and nearly normal body weight. At mid 3 to 4 weeks of age, GK rats first exhibited hyperglycemia, and then hyperphagia and reduced mRNA expressions for anorexigenic pro-opiomelanocortin (POMC) and glucokinase in ARC. Furthermore, [Ca2+]i responses to high glucose in ARC POMC neurons were impaired in GK rats at 4 weeks. Treating GK rats from early 3 to mid 6 weeks of age with an anti-diabetic medicine miglitol not only suppressed hyperglycemia but ameliorated hyperphagia and restored POMC mRNA expression in ARC. These results suggest that the early hyperglycemia occurring in weaning period may lead to impaired glucose sensing and neuronal activity of POMC neurons, and thereby induce hyperphagia in GK rats. Correction of hyperglycemia in the early period may prevent and/or ameliorate the progression of hyperphagia in type 2 diabetes. PMID- 29525473 TI - Utility of lung radiodensity ratios in diagnosis of radiolucent foreign body aspiration in children: a practical approach. AB - OBJECTIVE: To evaluate the utility of radiodensity ratio between lungs on chest X ray for the diagnosis of radiolucent foreign body aspiration (FBA) in children. METHODS: X-rays of 33 patients with confirmed diagnosis of FBA by bronchoscopy were compared to 66 control patients. We divided the study group into three subgroups: symmetric (13-patients), right-oblique (RO;12-patients) and left oblique (LO;8-patients). RESULTS: When we compared FBA-symmetric-subgroup to symmetric-control-group, FBA-RO-subgroup to RO-control-group and FBA-LO-subgroup to LO-control-group, radiodensity ratios were significantly higher in the FBA subgroups. CONCLUSION: The calculated radiodensity ratio between lungs on X-ray would be a useful and practical tool for the diagnosis of radiolucent FBA in children. PMID- 29525475 TI - Anaphase: a fortune-teller of genomic instability. AB - The anaphase of mitosis is one of the most critical stages of the cell division cycle in that it can reveal precious information on the fate of a cell lineage. Indeed, most types of nuclear DNA segregation defects visualized during anaphase are manifestations of genomic instability and augur dramatic outcomes, such as cell death or chromosomal aberrations characteristic of cancer cells. Although chromatin bridges and lagging chromatin are always pathological (generating aneuploidy or complex genomic rearrangements), the main subject of this article, the ultrafine anaphase bridges, might, in addition to potentially driving genomic instability, play critical roles for the maintenance of chromosome structure in rapidly proliferating cells. PMID- 29525474 TI - Medical Care Tasks among Spousal Dementia Caregivers: Links to Care-Related Sleep Disturbances. AB - OBJECTIVE: Medical care tasks are commonly provided by spouses caring for persons living with dementia (PLWDs). These tasks reflect complex care demands that may interfere with sleep, yet their implications for caregivers' sleep outcomes are unknown. The authors evaluated the association between caregivers' medical/nursing tasks (keeping track of medications; managing tasks such as ostomy care, intravenous lines, or blood testing; giving shots/injections; and caring for skin wounds/sores) and care-related sleep disturbances. METHODS: A retrospective analysis of cross-sectional data from the 2011 National Health and Aging Trends Study and National Study of Caregiving was conducted. Spousal caregivers and PLWDs/proxies were interviewed by telephone at home. The U.S. sample included 104 community-dwelling spousal caregivers and PLWDs. Caregivers reported on their sociodemographic and health characteristics, caregiving stressors, negative caregiving relationship quality, and sleep disturbances. PLWDs (or proxies) reported on their health conditions and sleep problems. RESULTS: Caregivers who performed a higher number of medical/nursing tasks reported significantly more frequent care-related sleep disturbances, controlling for sociodemographic and health characteristics, caregiving stressors, negative caregiving relationship quality, and PLWDs' sleep problems and health conditions. Post hoc tests showed that wound care was independently associated with more frequent care-related sleep disturbances after accounting for the other medical/nursing tasks and covariates. CONCLUSION: Spousal caregivers of PLWDs who perform medical/nursing tasks may be at heightened risk for sleep disturbances and associated adverse health consequences. Interventions to promote the well being of both care partners may benefit from directly addressing caregivers' needs and concerns about their provision of medical/nursing care. PMID- 29525476 TI - A portrait of patients who die in-hospital from acute pulmonary embolism. PMID- 29525477 TI - Impact of scribe utilization on resident education and fatigue mitigation. PMID- 29525478 TI - CPR feedback/prompt device improves the quality of hands-only CPR performed in manikin by laypersons following the 2015 AHA guidelines. AB - PURPOSE: We investigated the effects of a cardiopulmonary resuscitation (CPR) feedback/prompt device on the quality of chest compression (CC) during hands-only CPR following the 2015 AHA guidelines. METHODS: A total of 124 laypersons were randomly assigned into three groups. The first (n=42) followed the 2010 guidelines, the second (n=42) followed the 2015 guidelines with no feedback/prompt device, the third (n=40) followed the 2015 guidelines with a feedback/prompt device (2015F). Participants underwent manual CPR training and took a written basic life support examination, then required to perform 2min of hands-only CPR monitored by a CPR feedback/prompt device. The quality of CPR was quantified as the percentage of correct CCs (mean CC depth and rate, complete recoil and chest compression fraction (CCF)) per 20s, as recorded by the CPR feedback/prompt device. RESULTS: Significantly higher correct ratios of CC, CC depth, and rate were achieved in the 2010 group in each minute vs the 2015 group. The greater mean CC depth and rate were observed in the 2015F group vs the 2015 group. The correct ratio of CC was significantly higher in the 2015F group vs the 2015 group. CCF was also significantly higher in the 2015F group vs the 2015 group in the last 20s of CPR. CONCLUSIONS: It is difficult for a large percentage of laypersons to achieve the targets of CC depth and rate following the 2015 AHA guidelines. CPR feedback/prompt devices significantly improve the quality of hands-only CPR performance by laypersons following the standards of the 2015 AHA guidelines. PMID- 29525479 TI - A pilot, prospective, randomized trial to evaluate the influence of telemedicine training on the CPR quality provided by the nurses. PMID- 29525480 TI - Safety of reassessment-and-release practice for mental health patients boarded in the emergency department. AB - OBJECTIVES: Among emergency department (ED) mental health and substance abuse (MHSA) patients, we sought to compare mortality and healthcare utilization by ED discharge disposition and inpatient bed request status. METHODS: A retrospective cohort study of 492 patients was conducted at a single University ED. We reviewed three groups of MHSA patients including ED patients that were admitted, ED patients with a bed request that were discharged from the ED, and ED patients with no bed request that were discharged from the ED. We identified main outcomes as ED return visit, re-hospitalization and mortality within 12months based on chart review and reference from the National Death Index. RESULTS: The average age of patients presenting was 30.5 (SD16.4) years and 251 (51.0%) were female patients. Of these patients, 216 (43.9%) presented with mood disorder and 93 (18.9%) with self-harm. The most common reason for discharge from the ED after an admission request was placed was from stabilization of the patient (n=138). An ED revisit within 12months was significantly higher among patients discharged who had a bed request in place prior to departure (54.0%, p<0.001), than those discharged from the ED (40.9%) or admitted to inpatient care (30.5%). The rate of suicide attempt and death did not show statistical significance (p=0.55 and p=0.88). CONCLUSION: MHSA patients who were discharged from ED after bed requests were placed were at greater risk for return visits to the ED. This implicates that these patients require outpatient planning to prevent further avoidable healthcare utilization. PMID- 29525481 TI - Spontaneous bilateral quadriceps tendon rupture. AB - Spontaneous bilateral quadriceps tendon rupture is a rare finding in emergency departments. Thus, the pathophysiology is not well understood. Imaging for improved speed of diagnosis is rarely considered. We present a case of non traumatic spontaneous bilateral quadriceps tendon rupture and examine current literature on the pathophysiology and imaging guidelines on the topic. The patient is a 49-year-old male that presented to the emergency department with bilateral thigh pain. He had been seen earlier with similar pain, but now presents with increased difficulty ambulating. The patient was found to have spontaneous rupture of bilateral quadriceps tendon. He was treated surgically and has been following with Orthopedic Surgery. Imaging in the emergency department included an ultrasound that showed tendon rupture. Spontaneous bilateral quadriceps tendon rupture is an uncommon finding in medicine and the emergency department. MRI remains the gold standard. However, clinical exam and ultrasound should be utilized for diagnosis of tendon rupture to hasten treatment. PMID- 29525482 TI - Expanded buprenorphine prescribing privileges: Sandbagging in the midst of the flood? PMID- 29525483 TI - An opioid dispensing and misuse prevention algorithm for community pharmacy practice. AB - BACKGROUND: Prescription opioid abuse has rapidly increased in recent years and is now considered a national epidemic by the United States government. Community pharmacies are at the forefront of opioid abuse, given their role in dispensing opioid prescriptions. Despite this role, however, there are few known guidelines to help community pharmacists navigate the process of detecting and managing prescription opioid abuse. OBJECTIVES: To develop and evaluate a candidate guideline, based on clinical experience and existing literature, to help community pharmacists monitor and manage potential opioid prescription abuse. METHODS: We developed an algorithm based on literature and expert advice. The algorithm was reviewed by two discussion groups and six community pharmacy stakeholders through in-depth interviews, and revised based on feedback. RESULT: Key themes identified from the discussions were that the algorithm should encompass the following: (1) start with ensuring authenticity of the prescription; (2) employ state prescription drug monitoring program (PDMP) as a primary screening tool to detect those at risk for prescription opioid abuse; (3) employ the additional abuse detection steps of clinical profile review and observation of the person picking up the prescription; (4) involve protocols of sharing concerns with the patient, making contact with the prescriber, and/or return of the prescription if appropriate, and (5) be easy to follow and significantly enhanced through color coding. CONCLUSION: Future steps should explore the feasibility of using the algorithm in different community settings, and determine the algorithm's impact on the number of prescription opioids dispensed and the number of individuals referred to prescribers for discussions about possible prescription opioid abuse. PMID- 29525484 TI - The Cytokinin-Activating LOG-Family Proteins Are Not Lysine Decarboxylases. AB - A conserved PGGxGTxxE motif misleads the cytokinin (CK) converting LONELY GUY enzymes to be wrongly annotated as lysine decarboxylases (LDCs). However, so far PGGxGTxxE motif-containing LDCs do not show any LDC activity. Instead, they show phosphoribohydrolase activity by converting inactive CK nucleotides into active free-base forms to invoke CK responses. PMID- 29525485 TI - Interest in medical health care for foreign residents among Japanese nursing students in areas of varying ethnic diversity. AB - BACKGROUND: Exposure of nursing students to foreign residents may improve cultural understanding. Nursing students are expected to have differing rates of contact with foreign residents, depending on how many foreign residents live in their municipality where they study in. Those in areas densely populated by foreign residents are more likely to encounter foreigners, and to have favorable views of them than students in areas with sparser foreign-resident populations. As of 2015, 2.23 million foreign residents lived in Japan, equaling 1.76% of the population; however, Japan still has fewer foreign-born residents compared to other countries. Therefore, interest in Medical Health Care for Foreign Residents (MHCFR) may be greater in students in ethnically diverse areas. While nursing students may have different levels of recognition of foreign nationals as potential clients and interest in MHCFR, no research validates this assumption. OBJECTIVES: This study aimed to clarify the association between proximity to foreign nationals and interest in MHCFR among Japanese nursing students. The secondary purpose was to describe knowledge and interest regarding MHCFR among students. To elucidate these topics, education and development of human resources in MHCFR should be considered. RESEARCH DESIGN AND METHOD: The study design was cross-sectional. A self-administered questionnaire survey was conducted with 143 nursing students. RESULTS: Most students understood the likelihood of providing nursing care to foreigners; however, knowledge and interest were low, regardless of whether lectures on MHCFR were provided. Knowledge of MHCFR, recognition of providing care to foreign nationals, and level of contact experiences with foreign nationals were significantly associated with students' level of interest in MHCFR. DISCUSSION: Nursing students in ethnically diverse areas tend to show greater interest in MHCFR in Japan. To foster global health perspectives, including MHCFR, in nursing students studying in ethnically diverse areas, contact experiences with foreigners and acceptance of international students by universities might be effective. PMID- 29525486 TI - The effectiveness of evidence-based nursing on development of nursing students' critical thinking: A meta-analysis. AB - OBJECTIVES: The aim of this meta-analysis was to assess the effectiveness of evidence-based nursing (EBN) on the development of critical thinking for nursing students. DESIGN: A systematic literature review of original studies on randomized controlled trials was conducted. DATA SOURCES: The relevant randomized controlled trials were retrieved from multiple electronic databases including Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health (CINAHL), Chinese BioMed Database (CBM), China National Knowledge Infrastructure (CNKI), and WanFang Database. REVIEW METHODS: In order to make a systematic evaluation, studies were selected according to inclusion and exclusion criteria, and then according to extracted data and assessed quality. The data extraction was completed by two independent reviewers, and the methodological quality assessment was completed by another two reviewers. All of the data was analyzed by the software RevMan5.3. RESULTS: A total of nine studies with 1079 nursing students were chosen in this systematic literature review. The result of this meta-analysis showed that the effectiveness of evidence-based nursing was superior to that of traditional teaching on nursing students' critical thinking. CONCLUSION: The results of this meta-analysis indicate that evidence-based nursing could help nursing students to promote their development of critical thinking. More researches with higher quality and larger sample size can be analyzed in the further. PMID- 29525487 TI - Self-knowledge of health teachers: A qualitative exploratory study. AB - BACKGROUND: Specific pedagogical training for teaching in the area of health emerges with the goal of creating critical and reflective professionals and as a necessary challenge to university teaching, where there is reflection on self awareness, consciousness, and the incompleteness of being. OBJECTIVES: This study aims to understand how Freire's critical consciousness is expressed in the pedagogical practice of health teachers. DESIGN: This study is a qualitative study that is descriptive, exploratory, and analytical. PARTICIPANTS AND SETTINGS: Twenty-one teachers from a public university in southern Brazil participated. METHODS: Data were collected using open-ended, in-person interviews held from May to December 2013. Data systematization was based on Minayo's operative proposal. RESULTS: The analysis yielded 2 main categories, including the naive critical consciousness of health teachers, i.e., education as a practice of oppression, and the epistemological critical consciousness of health teachers, i.e., education as a practice of freedom. The results revealed the teachers' self-knowledge, including the reasoning and motivations that made them become teachers, the characteristics considered necessary to be a teacher, the teachers' feelings in their teaching practice, and the teaching preparation required for being in the classroom from the perspective of naive and epistemological critical consciousness. CONCLUSIONS: The study shows that the self-knowledge that emerged from the teachers' reports encourages new perspectives in the construction of the teacher, raising the challenge of development and transformation from naive consciousness to epistemological consciousness, and thus contributing to a breakthrough with respect to critical and creative teacher training. PMID- 29525488 TI - Questioning the Alienation of Native Species from Invasion Ecology: A Reply to Tong et al. PMID- 29525489 TI - Identification of Cha o 3 homolog Cry j 4 from Cryptomeria japonica (Japanese cedar) pollen: Limitation of the present Japanese cedar-specific ASIT. AB - BACKGROUND: About one-third of the Japanese population suffers from Japanese cedar pollinosis, which is frequently accompanied by Japanese cypress pollinosis. Recently, a novel major Japanese cypress pollen allergen, Cha o 3, was discovered. However, whether a Cha o 3 homolog is present in Japanese cedar pollen remains to be determined. METHODS: Western blot analysis was performed using Cha o 3-specific antiserum. In addition, cloning of the gene encoding Cry j 4 was conducted using total cDNA from the male flower of Japanese cedar trees. Allergen potency and cross-reactivity were investigated using a T-cell proliferation assay, basophil activation test, and ImmunoCAP inhibition assay. RESULTS: A low amount of Cha o 3 homolog protein was detected in Japanese cedar pollen extract. The deduced amino acid sequence of Cry j 4 showed 84% identity to that of Cha o 3. Cross-reactivity between Cry j 4 and Cha o 3 was observed at the T cell and IgE levels. CONCLUSIONS: Cry j 4 was discovered as a counterpart allergen of Cha o 3 in Japanese cedar pollen, with a relationship similar to that between Cry j 1-Cha o 1 and Cry j 2-Cha o 2. Our findings also suggest that allergen-specific immunotherapy (ASIT) using Japanese cedar pollen extract does not induce adequate immune tolerance to Cha o 3 due to the low amount of Cry j 4 in Japanese cedar pollen. Therefore, ASIT using Cha o 3 or cypress pollen extract coupled with Japanese cedar pollen extract is required in order to optimally control allergy symptoms during Japanese cypress pollen season. PMID- 29525490 TI - Mobile technology and telemedicine for shoulder range of motion: validation of a motion-based machine-learning software development kit. AB - BACKGROUND: Mobile technology offers the prospect of delivering high-value care with increased patient access and reduced costs. Advances in mobile health (mHealth) and telemedicine have been inhibited by the lack of interconnectivity between devices and software and inability to process consumer sensor data. The objective of this study was to preliminarily validate a motion-based machine learning software development kit (SDK) for the shoulder compared with a goniometer for 4 arcs of motion: (1) abduction, (2) forward flexion, (3) internal rotation, and (4) external rotation. METHODS: A mobile application for the SDK was developed and "taught" 4 arcs of shoulder motion. Ten subjects without shoulder pain or prior shoulder surgery performed the arcs of motion for 5 repetitions. Each motion was measured by the SDK and compared with a physician measured manual goniometer measurement. Angular differences between SDK and goniometer measurements were compared with univariate and power analyses. RESULTS: The comparison between the SDK and goniometer measurement detected a mean difference of less than 5 degrees for all arcs of motion (P > .05), with a 94% chance of detecting a large effect size from a priori power analysis. Mean differences for the arcs of motion were: abduction, -3.7 degrees +/- 3.2 degrees ; forward flexion, -4.9 degrees +/- 2.5 degrees ; internal rotation, -2.4 degrees +/- 3.7 degrees ; and external rotation -2.6 degrees +/- 3.4 degrees . DISCUSSION: The SDK has the potential to remotely substitute for a shoulder range of motion examination within 5 degrees of goniometer measurements. An open source motion-based SDK that can learn complex movements, including clinical shoulder range of motion, from consumer sensors offers promise for the future of mHealth, particularly in telemonitoring before and after orthopedic surgery. PMID- 29525491 TI - Correlating the depth of compensation to the 3-D shape of the breast to achieve homogeneous dose distribution using the electronic tissue compensation treatment technique. AB - Our study aimed to correlate the overall 3-dimensional (3-D) shape of the breast to the compensation depth to produce a homogeneous dose distribution using the electronic tissue compensation (ECOMP) treatment technique. The study involved creating a number of semioval water phantoms with the diameter of the larger axis representing the breast separation and the shorter axis representing the distance from the chest wall to the apex of the breast. Multiple plans with 2 tangential fields were created for each phantom using different transmission penetration depths (TPDs) to determine the optimum TPD value based on the evaluation of dose uniformity and maximum hot spot. Optimum TPD values from the semioval water phantom plans were plotted on a graph as a function of separation and radius and were used as guidelines to choose the optimum TPD for the breast patient's cases. A total of 10 patients who had been treated with radiation therapy using ECOMP tangential fields were randomly selected. The separation and the radius of the breast were measured for 3 regions (superior, middle, and inferior) to retrospectively determine the optimum TPD from the graph for each region. These TPD values were then used to plan the breast cases. For all the patients studied, the optimized TPD technique produced a lower average homogeneity index (HI) value of 0.658 than the standard ECOMP technique of 0.856. These results showed that optimized TPD technique produced a more homogeneous dose distribution than the standard ECOMP technique. By measuring the breast size based on breast separation and the chest wall-to-apex distance at different locations along the superior inferior axis of the breast, the optimum TPD can be determined at each location to provide a homogeneous dose distribution. A module can be created within the planning system to automatically assign the optimum TPD for both tangential fields so uniform fluence maps can be achieved throughout the whole breast volume. This method can serve as a guideline in ECOMP during the treatment planning to obtain a homogeneous dose distribution. PMID- 29525493 TI - Riluzole, disease stage and survival in ALS. PMID- 29525492 TI - Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. AB - BACKGROUND: Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose ranging clinical trial of riluzole. METHODS: In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research Council score for muscle strength, El Escorial category, vital capacity, and gastrostomy insertion data. The lowest allocated stage was 2 because the original trial only included patients with probable or definite ALS. We used a chi2 test to assess the independence of stage at trial enrolment and treatment group, Kaplan-Meier product limit distribution to test the transition from each stage to subsequent stages, and Cox regression to confirm an effect of treatment group on time in stage, controlling for covariates. We did sensitivity analyses by combining treatment groups, using alternative strategies to stage, stratifying by stage at trial enrolment, and using multistate outcome analysis of treatments (MOAT). FINDINGS: We analysed the case records of all 959 participants from the original dose-ranging trial, 237 assigned to 50 mg/day riluzole, 236 to 100 mg/day, 244 to 200 mg/day, and 242 to daily placebo. Clinical stage at enrolment did not significantly differ between treatment groups (p=0.22). Time in stage 4 was longer for patients receiving 100 mg/day riluzole than for those receiving placebo (hazard ratio [HR] 0.55, 95% CI 0.36-0.83; log-rank p=0.037). Combining treatment groups and stratifying by stage at enrolment showed a similar result (HR 0.638, 95% CI 0.464-0.878; p=0.006), as did analysis with MOAT where the mean number of days spent in stage 4 was numerically higher for patients given riluzole at higher doses compared with patients receiving placebo. Time from stages 2 or 3 to subsequent stages or death did not differ between riluzole treatment groups and placebo (p=0.83 for stage 2 and 0.88 for stage 3). INTERPRETATION: We showed that riluzole prolongs survival in the last clinical stage of ALS; this finding needs to be confirmed in a prospective study, and treatment effects at stage 1 still need to be analysed. The ALS stage at which benefit occurs is important for counselling of patients before starting treatment. Staging should be used in future ALS clinical trials to assess the stage at which survival benefit occurs, and a similar approach could be used for other neurodegenerative diseases. FUNDING: NIHR Maudsley Biomedical Research Centre, The European Union Joint Programme on Neurodegeneration, and the King's Summer Undergraduate Studentship. PMID- 29525494 TI - Impact of Cardiovascular Risk on the Relative Benefit and Harm of Intensive Treatment of Hypertension. AB - BACKGROUND: The lower rate of primary outcome events in the intensive treatment group in SPRINT (Systolic Pressure Intervention Trial) was associated with increased clinically significant serious adverse events (SAEs). In 2017, the American College of Cardiology/American Heart Association issued risk-based blood pressure treatment guidelines. The authors hypothesized that stratification of the SPRINT population by degree of future cardiovascular disease (CVD) risk might identify a group which could benefit the most from intensive treatment. OBJECTIVES: This study investigated the effect of baseline 10-year CVD risk on primary outcome events and all-cause SAEs in SPRINT. METHODS: Stratifying by quartiles of baseline 10-year CVD risk, Cox proportional hazards models were used to examine the associations of treatment group with the primary outcome events and SAEs. Using multiplicative Poisson regression, a predictive model was developed to determine the benefit-to-harm ratio as a function of CVD risk. RESULTS: Within each quartile, there was a lower rate of primary outcome events in the intensive treatment group, with no differences in all-cause SAEs. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause SAEs increased from 62 to 250. The predictive model demonstrated significantly increasing benefit-to-harm ratios (+/- SE) of 0.50 +/- 0.15, 0.78 +/- 0.26, 2.13 +/- 0.73, and 4.80 +/- 1.86, for the first, second, third, and fourth quartile, respectively (p for trend <0.001). All possible pairwise comparisons of between quartile mean values of benefit-to-harm ratios were significantly different (p < 0.001). CONCLUSIONS: In SPRINT, those with lower baseline CVD risk had more harm than benefit from intensive treatment, whereas those with higher risk had more benefit. With the 2017 American College of Cardiology/American Heart Association blood pressure treatment guidelines, this analysis may help providers and patients make decisions regarding the intensity of blood pressure treatment. PMID- 29525495 TI - Clinical Precision in the Management of Hypertension: Improving Upon the "One Size-Fits-All" Approach. PMID- 29525496 TI - High numbers of firework related injury referrals to the London Burns Service during the recent 'Bonfire night' period, is it time for new regulations? PMID- 29525497 TI - Response to Letter to the Editor: 'Experience with NexoBrid(r) in enzymatic debridement of facial burns'. PMID- 29525498 TI - Comments on "Diabetes mellitus after injury in burn and non-burned patients: A population based retrospective cohort study". PMID- 29525499 TI - A quality improvement project incorporating preoperative warming to prevent perioperative hypothermia in major burns. AB - BACKGROUND: Patients with extensive burn injuries are susceptible to a host of accompanying adverse effects should they develop perioperative hypothermia, which occurs in up to 1/4 of all major burn cases. This quality improvement project aimed to reduce the incidence of perioperative hypothermia to below 10% of cases in patients with major burn (Total Body Surface Area [TBSA] >15%), within a one year period. METHODS: A baseline diagnostic phase was undertaken to provide a greater understanding of the incidence, natural history and risk factors of perioperative hypothermia. We also reviewed and reinforced intraoperative measures in current use, including preemptive adjustment of the ambient temperature, underbody warming mattress use, warming blanket application over areas not operated, regular temperature monitoring, and discussion at the WHO surgical checklist. Preoperative forced air warming with a 'Bair Hugger'TM was identified as a sound change initiative, a strategy applied to good effect in other surgical settings. The primary outcome measure was the percentage of cases of perioperative hypothermia (<36 degrees C), utilizing a time series design for the period between 1 November 2016 and 31 October 2017. RESULTS: 53 patients with burn greater than 15% TBSA were admitted over the one year period. Of these, 40 patients required 127 operative procedures. Their mean age was 48.23 years, their mean TBSA was 27.65% (range 15-75%), and their mean length of hospital stay was 31.2 days. After the introduction of pre-warming, the proportion of cases of inadvertent hypothermia reduced to 13.77% (n=14/102), with special cause variation, from 24% (n=6/25) in the baseline data collection period. The final temperature correlated with the lowest temperature recorded in only 32% of cases. Based on stakeholder feedback and consensus from the literature, an algorithm was developed which forms the basis for a medical directive for preoperative warming for eligible patients. No significant balancing measures were identified, nor any undue costs incurred. DISCUSSION: The inevitable drop in temperature is ameliorated by sound perioperative practices, rather than just intraoperative ones. This initiative demonstrated the potential benefits of, and motivates for, the broad application of preoperative warming in the context of major acute burn surgery. Further investigations include PDSA cycles to determine whether the duration or degree of intraoperative hypothermia is more virulent. To consolidate the pre-warming initiative, we have introduced a standard order within our admission order sets to include preoperative warming for all eligible patients. PMID- 29525500 TI - A flexible nonvolatile resistive switching memory device based on ZnO film fabricated on a foldable PET substrate. AB - In this work, a flexible resistive switching memory device based on ZnO film was fabricated using a foldable Polyethylene terephthalate (PET) film as substrate while Ag and Ti acts top and bottom electrode. Our as-prepared device represents an outstanding nonvolatile memory behavior with good "write-read-erase-read" stability at room temperature. Finally, a physical model of Ag conductive filament is constructed to understanding the observed memory characteristics. The work provides a new way for the preparation of flexible memory devices based on ZnO films, and especially provides an experimental basis for the exploration of high-performance and portable nonvolatile resistance random memory (RRAM). PMID- 29525501 TI - The isotopic exchangeability of phosphate in Mg-Al layered double hydroxides. AB - Layered double hydroxides (LDH) of Mg/Al are anion exchangers that are candidate materials for phosphate (PO4) recovery and recycling from waste streams. However, PO4 recycling in agriculture might be limited by incomplete desorption of PO4 from the minerals. This study was set up to identify the factors explaining irreversible PO4 sorption ("fixation") on LDHs by comparing the isotopic exchangeability (33PO4) with the PO4 desorption from LDH materials and from boehmite as a P fixing reference mineral. Six different Mg-Al LDH materials were synthesized, by varying the synthesis pH and exposing obtained materials to hydrothermal (HT) treatment. Phase pure LDH materials were obtained from syntheses at pH 10 and 12, while at pH 8 Al-rich phase impurities such as a boehmite or gibbsite were formed. Crystallite size increased significantly during HT treatment. The LDHs were first loaded with PO4 prior to 33PO4 isotopic exchange (0-20 days, 1 mM NaHCO3) or PO4 desorption (0-20 days, NaHCO3 concentrations increasing from 0 to 20 mM). The isotopic PO4 exchangeability was 85-95% of total PO4 after 72 h in the phase pure LDHs with intercalated PO4 whereas this value was 40-54% in the presence of Al-rich phase impurities in non HT treated materials and in boehmite. In contrast, the maximally desorbed PO4 fractions were only 55-63% for the phase pure LDHs, indicating that not all of the isotopically exchangeable PO4 can be desorbed. Samples at different stages of desorption (different initial NaHCO3 concentrations) were subjected to isotopic exchange after desorption. In the LDHs with PO4 intercalation, PO4 was increasingly less isotopically exchangeable as the initial NaHCO3 concentrations increased, while this trend was not observed for samples without intercalated PO4. This suggests that PO4 becomes increasingly less accessible for isotopic exchange as the fraction binding sites occupied with HCO3- increases. The interlayer outward diffusion of PO4 might be increasingly rate limited upon H2PO4 /HCO3- exchange, which explains the PO4 fixation in LDHs. PMID- 29525502 TI - Yolk-shell structured composite for fast and selective lithium ion sieving. AB - Yolk-shell structured C@Li4Ti5O12 microspheres composed of carbon core (ca. 500 nm) and sea urchin-like Li4Ti5O12 shell (ca. 400-500 nm) are formed by hydrothermally treating the core-shell structured C@TiO2 in the EtOH/H2O solution of LiOH and calcining it in N2 atmosphere. Yolk-shell structured TiO2-type lithium ion sieve is further transformed from C@Li4Ti5O12 through the acid treatment, which have a high specific surface area of 201.74 m2/g. The composite shows adsorption capacity towards Li+ proportional to the pH value in the range of 7-13. The adsorption reaches equilibrium within 2 h with a high equilibrium adsorption capacity of 28.46 mg/g under alkaline conditions, which is ca. 8 times the value of ordinary TiO2 lithium ion sieve with comparable size and surface area, demonstrating the enhanced adsorption is attributed to the generation of more accessible surficial voids by replacing internal part with light carbon core. The adsorption follows Freundlich and pseudo-second-order kinetic models with a high rate constant of 0.015 g/(mg.min). The selective adsorption to Li+ is verified in the presence of K+, Na+, Ca2+ and Mg2+. PMID- 29525503 TI - The importance of pKa in an analysis of the interaction of compounds with DNA. AB - pKa of a compound is crucial for determining the contributions of different forms of it towards overall binding with DNA. Hence it is important to use correct pKa values in DNA interaction studies. This study takes a look at the importance of pKa values to realize binding of compounds with DNA. Since pKa of a compound determined in the presence of DNA is quite different from that determined in its absence hence, presence of different forms of a compound during interaction with DNA is different from that realized if the determination of pKa is done in normal aqueous solution in absence of DNA. Hence, calculations determining contributions of different forms of a compound interacting with DNA are affected accordingly. Two simple analogues of anthracyclines, alizarin and purpurin, were used to investigate the influence DNA has on pKa values. Indeed, they were different in presence of DNA than when determined in normal aqueous solution. pKa1 for alizarin and purpurin determined in the absence and presence of calf thymus DNA were used in equations that determine contributions of two forms (neutral and anionic) towards overall binding with DNA. The study concludes that correct pKa values, determined correctly i.e. under appropriate conditions, must be used for DNA binding experiments to evaluate contributions of individual forms. PMID- 29525504 TI - Short questionnaire on Burnout, an appropriate choice? PMID- 29525505 TI - Pregnancy and perinatal outcomes after transfer of binucleated or multinucleated frozen-thawed embryos: a case-control study. AB - Blastomere multinucleation in human embryos is a common phenomenon, but data on its effect on pregnancy outcome and the health of newborns are scarce. In this case-control study, we assessed pregnancy and perinatal outcomes from 136 binucleated and multinucleated frozen-thawed embryo transfer cycles against a control group of 136 non-binucleated and multinucleated frozen embryo transfer cycles. Clinical pregnancy and live birth rates were lower among the case group (29.4% versus 44.1%, P = 0.012; 22.1% versus 36.0%, P = 0.011, respectively), but perinatal outcomes (gestational week at delivery, birth weight, placental weight and occurrence of congenital anomalies) were similar. Live birth rates among patients receiving embryos with multinucleation compared with binucleation was not significantly different (24.7% versus 13.2%). Consequently, frozen-thawed cleavage-stage embryos with bi- or multinucleation have lower than normal but still acceptable implantation potential and ability to produce healthy pregnancies and newborns. The study is limited by its retrospective nature. Time lapse monitoring would be a more sensitive method of detecting multinucleation. Controls and cases were matched only by age at the time of oocyte retrieval, and other characteristics were only interpreted statistically. Although larger than previously reported, the number of cases is limited. PMID- 29525506 TI - Brain derived neurotrophic factor (BDNF) and suicidal behavior: A review of studies from Asian countries. AB - The biological basis of suicide and suicidal behavior is actively researched. Recently, the role of Brain Derived Neurotropic Factor (BDNF) in suicidal behavior has gained attention and significant results are observed. In this review, we aimed to focus on the studies from Asian countries that have explored the role of BDNF and suicidal behavior. The review highlights the findings from these studies and discusses the possible avenues that should be explored in future studies from Asian countries to understand more on suicidal behavior and possible prevention. PMID- 29525507 TI - Experimentation of 2.0 telemedicine in elderly patients with chronic heart failure: A study prospective in 175 patients. PMID- 29525508 TI - Autonomic dysfunction and cardiovascular risk in patients with atherosclerotic renal artery stenosis: A pilot study. PMID- 29525509 TI - Violaceous papules on the legs of an elderly Mediterranean man. PMID- 29525510 TI - DFT results against experimental data for electronic properties of C60 and C70 fullerene derivatives. AB - Some electronic properties of different C60 and C70 derivatives were evaluated using 20 density functionals (the B3LYP, BHANDH, PBE0, HSE06, CAM-B3LYP, omegaB97X-D, BMK, PBEPBE, M06-L, M06, M06-2X, M06-HF, PW91PW91, BLYP, B97D, HCT407, tau-HCTH, tau-HCTHhyb, TPSS, and LSDA), and some of the results were compared with the available experimental data. Unlike in Hartree-Fock (HF) method, the orbital relaxation is not the origin of the violation of DFT from the Koopmans' theorem. For most of functionals, the HOMO-LUMO gap (Eg) is more sensitive to the functional compared to the optical gap. The functionals with a large %HF exchange significantly overestimate the Eg, and are not suggested for electronic calculations. All non-hybrid functionals underestimate the value of |HOMO| in comparison to the experimental ionization potential (IPe). In the hybrid functionals, the HOMO level becomes more stable by increasing %HF exchange and even in some functionals with a large %HF, |HOMO| overestimates the IPe. PMID- 29525511 TI - Mortality risk factors after percutaneous gastrostomy: Who is a good candidate? AB - BACKGROUND: The percutaneous gastrostomy tube (PG) is an effective and safe way for the delivery of enteral nutrition. The aim of this study was to identify predictive factors for mortality after PG placement. MATERIAL AND METHODS: An observational and analytical cohort study was conducted. All endoscopic or radiological percutaneous gastrostomy tubes placed between January 2009 and July 2016 were evaluated. Mortality was the dependent variable. Initial clinical and analytical patient features and the development of complications during follow-up were recorded. Cox regression models were used to evaluate the risk of mortality associated to the studied variables. Hazard ratios with the corresponding 95% confidence intervals were retrieved from these models. RESULTS: A total of 289 patients underwent PG placement (57% male). The mean age was 70.1 (SD 13.6) years. The median follow-up period was 8.7 (IQR 18) months. One hundred and seventy-four patients died during the follow-up period. The overall mortality rate was 4.8 per 100 patients-month. The highest mortality rate was during the first month after PG placement (13.2 per 100 patients-month), subsequently decreasing. Multivariate regression analysis showed that age (HR1year = 1.01; p = 0.015), Charlson comorbidity index >=4 (HR = 1.69; p = 0.011), the presence of degenerative neurological disease (HR = 1.69; p = 0.012) or malignancy (HR = 2.02; p = 0.012) and the development of aspiration pneumonia during the follow-up period (HR = 3.29; p = 0.001) were statistically significant independent predictive risk factors associated with mortality. A model to predict survival probability prior to placing the PG was developed from the variables of the multivariate analysis. CONCLUSION: Mortality after PG placement is high. Older age, higher comorbidity and the development of aspiration pneumonia are predictive factors for mortality. A more careful selection of candidates for PG placement should be done to improve the patient prognosis after the procedure. PMID- 29525512 TI - Bioimpedance analysis is safe in patients with implanted cardiac electronic devices. AB - BACKGROUND & AIMS: There is an increase in the number of patients worldwide with cardiac implantable electronic devices (CIEDs). Current medical practice guidelines warn against performing bioimpedance analysis (BIA) in this group of patients in order to avoid any electromagnetic interference. These recommendations restrict using the BIA in patients undergoing heart failure or with nutrition disorders in whom BIA could be of major interest in detecting peripheral congestion and to help guide treatment. The present study was conducted to evaluate whether BIA caused electromagnetic interference in patients having CIEDs. METHODS: Patient enrollment was conducted during routine face-to face consultations for scheduled CIEDs interrogations. Device battery voltage, lead impedance, pacing thresholds and device electrograms were recorded before and after each BIA measurement to detect any electromagnetic interference or oversensing. RESULTS: A total of 200 patients were enrolled. During BIA, no significant changes in battery voltage, lead impedance or pacing thresholds were detected, nor were there any inappropriate over- or undersensing observed in intracardiac electrograms. Furthermore, 6- and 12-month follow-up did not reveal any changes in CIEDs. CONCLUSIONS: This study shows no interference in patients equipped with CIEDs and suggests that BIA can be securely performed in these patients. Trial registered under the identifier NCT03045822. PMID- 29525513 TI - Metabolically healthy obesity, vitamin D, and all-cause and cardiometabolic mortality risk in NHANES III. AB - BACKGROUND & AIMS: Previous studies assessing the prognosis of metabolically healthy obesity (MHO) have been limited by a lack of a harmonized definition of MHO phenotype. Furthermore, obesity is a risk factor for vitamin D deficiency and low vitamin D status has been associated with a higher risk of mortality; however, few studies have evaluated the joint association between vitamin D, metabolic health phenotype, and mortality risk. Using a harmonized definition, we investigated whether MHO is associated with subsequent all-cause and cardiometabolic mortality, and whether serum 25-hydroxyvitamin D [25(OH)D] modifies these associations. METHODS: This study included participants aged >=20 years from the Third National Health and Nutrition Examination Survey (NHANES III). MHO phenotype was defined as a combination of obesity (>=30 kg/m2) and zero component of metabolic syndrome. Multivariable Cox regression was used to assess the risk of mortality across metabolic phenotypes, and the joint association between metabolic phenotype and 25(OH)D. Fine and Gray regression was performed to account for competing risk events. RESULTS: Among 11,333 participants, a total of 2980 deaths (937 cardiometabolic death outcomes) occurred during a median follow-up of 19.1 years. In the absence of any metabolic abnormality, obesity (MHO) was not associated with a higher risk of all-cause (hazard ratio [HR], 0.89 [95% CI, 0.52-1.51]) or cardiometabolic mortality (cause-specific HR, 1.21 [95% CI 0.33-4.46]). Similar results were obtained from competing risk analysis. No significant differences in average 25(OH)D levels were observed between MHO and non-MHO participants; however, there was a significant interaction between metabolic health phenotype and serum 25(OH)D in relation to cardiometabolic mortality such that levels of serum 25(OH)D < 50 nmol/L were associated with increased risk of cardiometabolic mortality, particularly in participants within the normal-weight and obese BMI ranges. CONCLUSIONS: Our results support the hypothesis that MHO phenotype is a benign health condition. Vitamin D deficiency may exacerbate the risk of cardiometabolic death outcomes associated with metabolic dysfunction in normal weight and obese individuals. Further research is warranted to validate our findings. PMID- 29525514 TI - New approach of ultra-focal brachytherapy for low- and intermediate-risk prostate cancer with custom-linked I-125 seeds: A feasibility study of optimal dose coverage. AB - PURPOSE: To present the feasibility study of optimal dose coverage in ultra-focal brachytherapy (UFB) with multiparametric MRI for low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: UFB provisional dose plans for small target volumes (<7 cc) were calculated on a prostate training phantom to optimize the seeds number and strength. Clinical UFB consisted in a contour-based nonrigid registration (MRI/Ultrasound) to implant a fiducial marker at the location of the tumor focus. Dosimetry was performed with iodine-125 seeds and a prescribed dose of 160 Gy. On CT scans acquired at 1 month, dose coverage of 152 Gy to the ultra focal gross tumor volume was evaluated. Registrations between magnetic resonance and CT scans were assessed on the first 8 patients with three software solutions: VariSeed, 3D Slicer, and Mirada, and quantitative evaluations of the registrations were performed. Impact of these registrations on the initial dose matrix was performed. RESULTS: Mean differences between simulated dose plans and extrapolated Bard nomogram for UFB volumes were 36.3% (26-56) for the total activity, 18.3% (10-30) for seed strength, and 22.5% (16-38) for number of seeds. Registration method implemented in Mirada performed significantly better than VariSeed and 3D Slicer (p = 0.0117 and p = 0.0357, respectively). For dose plan evaluation between Mirada and VariSeed, D100% (Gy) for ultra-focal gross tumor volume had a mean difference of 28.06 Gy, mean values being still above the objective of 152 Gy. D90% for the prostate had a mean difference of 1.17 Gy. For urethra and rectum, dose limits were far below the recommendations. CONCLUSIONS: This UFB study confirmed the possibility to treat with optimal dose coverage target volumes smaller than 7 cc. PMID- 29525515 TI - CT features differentiating pre- and minimally invasive from invasive adenocarcinoma appearing as mixed ground-glass nodules: mass is a potential imaging biomarker. AB - AIM: To investigate the differential diagnosis value of preoperative computed tomography (CT) features between pre/minimally invasive and invasive adenocarcinoma in pulmonary mixed ground glass nodules (mGGNs). MATERIALS AND METHODS: The histopathological data and CT images of 146 mGGNs in 141 patients were reviewed retrospectively. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed to identify the CT features differentiating between pre/minimally invasive and invasive adenocarcinoma and to evaluate their accuracy. RESULTS: In univariate analysis, there were significant differences (p<0.05) in the nodule diameter, volume, density, mass, solid portion volume, shape, margin, air bronchogram, and pleural retraction between pre/minimally invasive and invasive adenocarcinoma. Multivariate logistic regression analyses revealed that nodule mass and volume were statistically significant independent differentiators. ROC curve analysis was performed to evaluate the differentiators. According to the corresponding ROC curve, the optimal cut-off mass to differentiate pre/minimally invasive adenocarcinoma from invasive adenocarcinoma was 254.87 mg, with a sensitivity of 84.52%, a specificity of 88.71%, and an accuracy of 86.30%. Compared with the area under the ROC curve (AUC) for mass, volume, and diameter, the differential diagnosis value of mass was higher than those of volume and diameter. CONCLUSION: Nodule mass and volume were significant differentiators of pre/minimally invasive adenocarcinoma from invasive adenocarcinoma in mGGN, and mass had a higher differential diagnosis value. PMID- 29525516 TI - [Management of drug-resistant epilepsy]. AB - Epilepsy is considered as drug-resistant when seizures persist despite the administration of 2 antiepileptic drugs adapted to the patient's needs, with an effective dosage, well-tolerated, whether as a single agent or in combination. Any patient suffering from drug-resistant focal epilepsy should be evaluated at least once in a tertiary epilepsy centre to discuss the appropriateness of a pre surgical work-up. In drug-resistant epilepsy, the determinants of quality of life are multifactorial and not exclusively linked to the seizure frequency. Anticipating the side effects of treatments is a key element during management of polytherapy. Screening for psychiatric and cognitive comorbidities must be systematic. PMID- 29525517 TI - Retained products of conception: What is the risk for recurrence on subsequent pregnancies? AB - OBJECTIVE: To investigate whether women who were surgically treated for retained products of conception (RPOC) by either suction curettage or hysteroscopy are at risk for recurrent RPOC on their subsequent pregnancies. STUDY DESIGN: Retrospective analysis of 442 women surgically treated for RPOC following delivery or abortion by suction curettage (N = 63, 14.3%) or hysteroscopy (N = 379, 85.7%). Information on subsequent pregnancies and their outcomes was available for 161 (36.4%) women. RESULTS: One or more live births were reported for 150 (93.2%) of the women for whom information on subsequent pregnancies was available. The overall rate of spontaneous abortions was 31/161 (19.3%). Recurrent RPOC were diagnosed in 25 (15.5%) cases, while third stage of labor placental problems (including retained placenta or cotyledons and placenta accreta) were found in 44 (27.3%) cases. Recurrent RPOC was associated with treatment by suction curettage compared with hysteroscopy for the initial RPOC on multivariate logistic regression analysis (Odds Ratio [OR] = 3.6, 95% Confidence Interval [CI]1.3-10.5, p = 0.01) and with the initial RPOC occurring after delivery compared with after abortion (OR = 8.4, 95%CI 1.8-39.5, p = 0.006). CONCLUSION: Women treated for RPOC are at risk for recurrent RPOC and for third stage of labor placental problems on their subsequent pregnancies, especially those who had been managed by suction curettage in comparison with operative hysteroscopy. Clinical and ultrasound follow-up in the early and late postpartum period should be considered in women with a history of RPOC. PMID- 29525518 TI - Obstetric and neonatal outcome in women aged 50 years and up: A collaborative, Nordic population-based study. AB - OBJECTIVES: Childbearing at extremely advanced maternal age is a globally increasing trend, but only a few studies have described the outcomes of these pregnancies. The aim of this study was to describe the occurrence of childbearing at age 50 and up in the Nordic countries, as well as to examine the frequency of adverse obstetric and neonatal outcomes. STUDY DESIGN: A descriptive population based study was designed. Data from 1991 to 2013 were collected from the Medical Birth Registries in Denmark, Finland, Norway and Sweden. We investigated the occurrence of antepartum, delivery and neonatal outcomes. RESULTS: A total of 170 deliveries, in 141 singleton and 29 multiple pregnancies, were identified in mothers aged 50 and up. The highest frequency during this period was 6 per 100,000 deliveries. The prevalence for selected adverse outcomes in singleton pregnancies were: intrauterine fetal death (IUFD) 6%, preeclampsia 4%, preterm delivery 14%, gestational diabetes 8% and cesarean delivery 50%. In multiple pregnancies, the respective prevalence were: IUFD 2%, preeclampsia 22%, preterm delivery 57%, gestational diabetes 10% and cesarean delivery 79%. Pregnancy after assisted reproductive technologies was frequent (29% of singleton and 50% of multiple pregnancies). CONCLUSIONS: This study found high frequency of obstetric and neonatal complications at extremely advanced maternal age. Despite a high prevalence of stillbirth in singleton pregnancies in the studied Nordic countries, other complications were less frequent than those previously reported in different populations. Adequate preconception consultation concerning maternal and neonatal hazards is highly recommended in this group of women. PMID- 29525519 TI - High resolution global chromosomal aberrations from spontaneous miscarriages revealed by low coverage whole genome sequencing. AB - OBJECTIVE: Chromosome aberrations are generally considered as one of the most substantial causative factors contributing to spontaneous miscarriages. Cytogenetic analyses like G-banded karyotype and chromosomal microarray analyses are often performed to further investigate the chromosome status of a miscarried fetus. STUDY DESIGN: Here, we describe a novel method, AnnoCNV, to detect DNA copy number variations (CNVs) using low coverage whole genome sequencing (WGS). We investigated the overall frequency of chromosomal abnormalities in 149 miscarriage specimens using AnnoCNV. RESULTS: Among 149 fetal miscarriage samples, more than two fifths of them (42.95%, 64) carried at least one chromosomal abnormality, and a subset (40) was identified as autosomal trisomy which account for 26.84% of all samples. We have also developed a robust algorithm in AnnoCNV, which is able to differentiate specifically karyotype 69,XXY from sex chromosomal aneuploidy 45,X, and to identify 45,X/46,XX mosaicism. Lastly, across the whole genome AnnoCNV identifies CNVs, which are associated with both reported symptoms and unknown clinical conditions. CONCLUSION: This cost-effective strategy reveals genome wide discovery of chromosome aberrations at higher resolution, which are consistent with parallel investigation conducted by SNP based assay. PMID- 29525520 TI - Role of male genetic factors in recurrent pregnancy loss in Northeast China. AB - OBJECTIVE: This study aimed to investigate the roles of male genetic factors, including Y chromosome microdeletions and chromosomal heteromorphism, in recurrent pregnancy loss (RPL) in Northeast China. STUDY DESIGN: We evaluated 1072 male patients from Northeast China whose wives had a history of two or more consecutive miscarriages. We also selected 971 infertile and 200 fertile men as control groups. Semen analysis was carried out by computer-assisted sperm analysis. Y chromosome microdeletions were detected by polymerase chain reaction and chromosomes were evaluated by karyotype analysis. RESULTS: There were no microdeletions in the RPL and fertile control groups, but 112 of the infertile men had Y chromosome microdeletions. Chromosomal heteromorphism was detected in all the groups. Patients in the infertile control group had a significantly higher percentage (2.16%) of Y variation (Yqh+/-) heteromorphism compared with the RPL group, but there were no significant differences in the incidences of chromosomal heteromorphism among the other groups. CONCLUSION: Y chromosome microdeletions and chromosomal heteromorphism are not associated with RPL in Northeast China. Some RPL males had structural chromosome anomalies, all of which were reciprocal translocations. We suggest that it may not be necessary to detect Y chromosome microdeletions in RPL males with Yqh+/-. PMID- 29525522 TI - Physical Symptom Burden and Its Association With Distress, Anxiety, and Depression in Breast Cancer. AB - BACKGROUND: Physical symptom burden and psychologic symptoms are highly prevalent in women with breast cancer. The Distress Thermometer and Problem List (DT&PL) is commonly used in oncology clinics to screen for distress and its accompanying Physical Problem List (PPL) identifies pertinent physical symptoms. OBJECTIVE: We sought to identify physical symptoms found on the PPL and evaluate whether they are associated with psychologic symptoms in women with breast cancer. METHODS: Patients (n=125) with breast cancer (Stage 0-IV) completed the DT&PL and the Hospital Anxiety and Depression Scale. They reported bother from any of 22 PPL items on the DT&PL. PPL items were assessed for their associations with distress, Hospital Anxiety and Depression Scale-anxiety, and Hospital Anxiety and Depression Scale-depression. The total number of PPL items endorsed per patient was evaluated for associations with psychologic outcomes, controlling for relevant demographic factors. RESULTS: Most physical problems were associated with depression (n = 13, 87%), and anxiety (n = 8, 53%), but fewer were associated with distress (n = 4, 27%). In multivariate analyses, a higher total number of problems was associated with younger age (p = 0.03) and more depressive symptoms (p < 0.001). CONCLUSION: Physical symptom burden detected by the DT&PL co-occurs with depression most commonly and to a lesser extent anxiety and distress in women with breast cancer. Depression is associated with more types of physical symptoms and a total number of physical symptoms. The endorsement of multiple PPL items on the DT&PL should prompt an evaluation for depression. Similarly, depression should prompt the evaluation and treatment of physical symptom burden. PMID- 29525521 TI - Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability. AB - Although interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) inhibit infection of many viruses by recognizing their RNA, the regulatory mechanisms involved remain unclear. Here we report a crystal structure of cap 0 (m7GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending the half-life of IFIT1 and thereby increasing its steady-state amounts in cells; and (2) allosterically regulating the IFIT1 RNA-binding channel, thereby enhancing the specificity of recognition for cap 0 but not cap 1 (m7GpppNm) or 5'-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse Ifit1. The IFIT3 interaction with IFIT1 is important for restricting infection of viruses lacking 2'-O methylation in their RNA cap structures. Our experiments establish differences in the regulation of IFIT1 orthologs and define targets for modulation of human IFIT protein activity. PMID- 29525524 TI - Pattern and Management of Recurrence of Mid-Low Rectal Cancer After Neoadjuvant Intensity-Modulated Radiotherapy: Single-Center Results of 687 Cases. AB - BACKGROUND: The purpose of this study was to retrospectively analyze the pattern and the management of recurrence of rectal cancer treated with 22-fraction intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS: This study included patients who underwent IMRT with gross tumor volume of 50.6 Gy in 22 fractions with concurrent capecitabine treatment over a period of 30 days, after which the patients underwent total mesorectal excision at Peking University Cancer Hospital (2007-2015). Study end points were local recurrence-free survival (LRFS), local disease-free survival (LDFS), disease-free survival (DFS), and cancer-specific survival (CSS). RESULTS: A total of 687 patients were included in our analysis. The median age was 57 years (range, 21-87 years), and 66.4% of the patients were male. The estimated 5-year LRFS and 5-year LDFS rates were 94.4% (95% confidence interval [CI], 92.1%-96.7%) and 96.1% (95% CI, 94.1%-98.1%), respectively. The estimated 3-year DFS and 5-year CSS rates were 77.5% (95% CI, 74.1%-80.9%) and 84.7% (95% CI, 80.9%-88.4%), respectively. Overall, 33.3% of patients (9 of 27) who developed local recurrence, 35.8% of patients (19 of 53) who developed lung metastasis, and 60% of patients (15 of 25) who developed liver metastasis received curative treatment after recurrence. The estimated 3-year survival after recurrence rates of patients who received curative versus palliative treatment were significantly different (87.8% vs. 15.3%, P = .000). CONCLUSION: Rectal cancer treated with the 22-fraction IMRT regimen provides good local control. More than one-fourth of patients who develop recurrence have the chance to receive curative treatment with the incorporation of a multidisciplinary team and achieves excellent survival after recurrence. PMID- 29525523 TI - Anxiety and Depression in Young Women With Metastatic Breast Cancer: A Cross Sectional Study. AB - BACKGROUND: Young adults with cancer experience disruptions in their normal developmental trajectories and commonly experience psychologic distress related to their diagnoses. Young women with metastatic breast cancer (MBC) are at particular risk of adverse mental health outcomes. OBJECTIVE: We sought to determine the prevalence of and factors associated with anxiety and depression symptoms in young women with newly diagnosed de novo MBC. METHODS: A total of 54 women with newly diagnosed de novo MBC were identified from an ongoing, prospective, multicenter cohort of women diagnosed with breast cancer at age <40. Depression and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Items assessing socio-demographics, physical symptom burden, social support, and disease and treatment history, with complementary medical record review, were used to assess variables potentially associated with anxiety and depression symptoms. RESULTS: Mean HADS Depression score was 4.4 (standard deviation = 3.7) and mean HADS Anxiety score was 7.9 (standard deviation = 5.0). Eleven (20%) women scored >=8 on the HADS Depression subscale, the suggested threshold for depression/anxiety screening, and 24 (44%) women scored >=8 on the HADS Anxiety subscale. In a multivariable model of anxiety, higher physical symptom scores (odds ratio = 4.41, p = 0.005) was significantly associated with higher anxiety scores. None of the other variables improved the model fit. CONCLUSION: In this study, a considerable proportion of young women with newly diagnosed MBC experienced anxiety symptoms, although depression was less common. Future strategies focused on distress reduction in young MBC patients should focus on physical symptom management as well as anxiety identification and management. PMID- 29525526 TI - All gender inequality is not equal. PMID- 29525525 TI - Self-Perceived Cooking Skills in Emerging Adulthood Predict Better Dietary Behaviors and Intake 10 Years Later: A Longitudinal Study. AB - OBJECTIVE: To determine whether perceived cooking skills in emerging adulthood predicts better nutrition a decade later. METHODS: Data were collected as part of the Project Eating and Activity in Teens and Young Adults longitudinal study. Participants reported on adequacy of cooking skills in 2002-2003 (age 18-23 years) and subsequently reported on nutrition-related outcomes in 2015-2016 (age 30-35 years) (n = 1,158). Separate regression models were used to examine associations between cooking skills at age 18-23 years and each subsequent outcome. RESULTS: One fourth of participants described their cooking skills as very adequate at 18-23 years, with no statistically significant differences by sociodemographic characteristics. Reports of very adequate cooking skills at age 18-23 years predicted better nutrition-related outcomes 10 years later, such as more frequent preparation of meals including vegetables (P < .001) and less frequent fast food consumption (P < .001). CONCLUSIONS AND IMPLICATIONS: Developing adequate cooking skills by emerging adulthood may have long-term benefits for nutrition over a decade later. Ongoing and new interventions to enhance cooking skills during adolescence and emerging adulthood are warranted but require strong evaluation designs that observe young people over a number of years. PMID- 29525527 TI - African women working in global health: closing the gender gap in Africa? PMID- 29525528 TI - Are older women forgotten in the fight against sexual violence? PMID- 29525529 TI - AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of beta-catenin activation. AB - BACKGROUND & AIMS: The Wnt/beta-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/beta-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/beta-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations. We aimed to elucidate the relationship between CTNNB1 mutations, AXIN1 mutations and the activation level of the Wnt/beta-catenin program. METHODS: We evaluated two independent human HCC datasets for the expression of a 23-beta-catenin target genes program. We modeled Axin1 loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling. RESULTS: Based on gene expression, we defined three levels of beta catenin program activation: strong, weak or no activation. While more than 80% CTNNB1-mutated tumors were found in the strong or in the weak activation program, most of the AXIN1-mutated tumors (>70%) were found in the subgroup with no activation. We validated this result by demonstrating that mice with a hepatocyte specific AXIN1 deletion developed HCC in the absence of beta-catenin induction. We defined a 329-gene signature common in human and mouse AXIN1 mutated HCC that is highly enriched in Notch and YAP oncogenic signatures. CONCLUSIONS: AXIN1 mutated HCCs occur independently of the Wnt/beta-catenin pathway and involve Notch and YAP pathways. These pathways constitute potentially interesting targets for the treatment of HCC caused by AXIN1 mutations. LAY SUMMARY: Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/beta-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/beta-catenin pathway. PMID- 29525530 TI - Sulforaphane epigenetically demethylates the CpG sites of the miR-9-3 promoter and reactivates miR-9-3 expression in human lung cancer A549 cells. AB - Increasing evidence suggests that epigenetic aberrations contribute to the development and progression of cancers such as lung cancer. The promoter region of miR-9-3 was recently found to be hypermethylated in lung cancer, resulting in down-regulation of miR-9-3 and poor patient prognosis. Sulforaphane (SFN), a natural compound that is obtained from cruciferous vegetables, has potent anticancer activities. In this study, we aimed to investigate the effect of SFN on restoring the miR-9-3 level in lung cancer A549 cells through epigenetic regulation. DNA methylation of the miR-9-3 promoter was examined using bisulfite genomic sequencing and methylated DNA immunoprecipitation analysis. The expression levels of miR-9-3 and several epigenetic modifying enzymes were measured using quantitative real-time polymerase chain reaction and Western blotting, respectively. The transcriptional activity of the miR-9-3 promoter was evaluated by patch methylation, and histone modifications were analyzed using chromatin immunoprecipitation (ChIP) assays. We found that CpG methylation was reduced in the miR-9-3 promoter and that miR-9-3 expression was increased after 5 days of treatment with SFN. In vitro methylation analysis showed that the methylated recombinant construct exhibited lower luciferase reporter activity than the unmethylated counterpart. ChIP assays revealed that SFN treatment increased H3K4me1 enrichment at the miR-9-3 promoter. Furthermore, SFN treatment attenuated enzymatic DNMT activity and DNMT3a, HDAC1, HDAC3, HDAC6 and CDH1 protein expression. Taken together, these findings indicate that SFN may exert its chemopreventive effects partly through epigenetic demethylation and restoration of miR-9-3. PMID- 29525531 TI - Raspberry ketone induces brown-like adipocyte formation through suppression of autophagy in adipocytes and adipose tissue. AB - Promoting white adipose tissue (WAT) to acquire brown-like characteristics is a promising approach for obesity treatment. Although raspberry ketone (RK) has been reported to possess antiobesity activity, its effects on the formation of brown like adipocytes remain unclear. Therefore, we investigated the effects and underlying mechanism of RK on WAT browning in 3T3-L1 adipocytes and rats with ovariectomy (Ovx)-induced obesity. RK (100 MUM) significantly induced browning of 3T3-L1 cells by increasing mitochondrial biogenesis and the expression of browning-specific proteins (PR domain containing 16, PRDM16; peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1alpha; uncoupling protein-1, UCP-1) and lipolytic enzymes (hormone-sensitive lipase and adipose triglyceride lipase). RK significantly reduced the expression of the autophagy related protein Atg12 and increased the expression of p62 and heme oxygenase 1 (HO-1). Additionally, these effects of RK were reversed by the HO-1 inhibitor SnPP (20 MUM). In addition, RK (160 mg/kg, gavage, for 8 weeks) significantly reduced body weight gain (Ovx+RK, 191.8 +/- 4.6 g vs. Ovx, 223.6 +/- 5.9; P < .05), food intake, the amount of inguinal adipose tissue (Ovx+RK, 9.05 +/- 1.1 g vs Ovx, 12.9 +/- 0.92 g; P < .05) and the size of white adipocytes in Ovx rats. Moreover, compared to expression in the Ovx group, the levels of browning specific proteins were significantly higher and the levels of autophagy-related proteins were significantly lower in the Ovx+RK group. Therefore, this study elucidated the mechanism associated with RK-induced WAT browning and thus provides evidence to support the clinical use of RK for obesity treatment. PMID- 29525532 TI - Developmental programming of vascular dysfunction by prenatal and postnatal zinc deficiency in male and female rats. AB - Micronutrient malnutrition during intrauterine and postnatal growth may program cardiovascular diseases in adulthood. We examined whether moderate zinc restriction in male and female rats throughout fetal life, lactation and/or postweaning growth induces alterations that can predispose to the onset of vascular dysfunction in adulthood. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. After weaning, offspring were fed either a low- or a control zinc diet until 81 days. We evaluated systolic blood pressure (SBP), thoracic aorta morphology, nitric oxide (NO) system and vascular reactivity in 6- and/or 81-day-old offspring. At day 6, zinc-deficient male and female offspring showed a decrease in aortic NO synthase (NOS) activity accompanied by an increase in oxidative stress. Zinc-deficient 81-day-old male rats exhibited an increase in collagen deposition in tunica media, as well as lower activity of endothelial NOS (eNOS) that could not be reversed with an adequate zinc diet during postweaning life. Zinc deficiency programmed a reduction in eNOS protein expression and higher SBP only in males. Adult zinc deficient rats of both sexes showed reduced vasodilator response dependent on eNOS activity and impaired aortic vasoconstrictor response to angiotensin-II associated with alterations in intracellular calcium mobilization. Female rats were less sensitive to the effects of zinc deficiency and exhibited higher eNOS activity and/or expression than males, without alterations in SBP or aortic histology. This work strengthens the importance of a balanced intake of micronutrients during perinatal growth to ensure adequate vascular function in adult life. PMID- 29525533 TI - Maternal green tea polyphenol intake during lactation attenuates kidney injury in high-fat-diet-fed male offspring programmed by maternal protein restriction in rats. AB - Maternal malnutrition is known to increase the risk of obesity in offspring. We investigated whether green tea extract (GTE) intake during lactation affects obesity-related fibrosis and inflammation in the kidney of high-fat-diet-fed adult offspring of protein-restricted-diet-fed dams during pregnancy and lactation. Pregnant Wistar rats received diets containing 20% (normal-protein, NP) or 8% (low-protein, LP) casein, and they received 0%-, 0.12%- or 0.24%-GTE containing LP diets (LP/LP, LP/LGT and LP/HGT, respectively) during lactation. At weaning, the pups that received a diet providing 13% (normal-fat, NF) or 45% (high-fat, HF) energy from fat were divided into five groups: NP/NP/NF, LP/LP/NF, LP/LP/HF, LP/LGT/HF and LP/HGT/HF. At week 45, the degree of fibrosis; macrophage infiltration; protein expression levels of TGF-beta; and mRNA levels of TNF alpha, DNMT, UHRF1 and histone lysine methyltransferase (G9a) in the kidneys of male offspring were examined. The area of fibrosis and TGF-betalevels increased in the LP/LP/HF group. Conversely, the fibrotic areas and TGF-beta levels in the LP/HGT/HF group decreased (33% and 31%, respectively) compared with those in the LP/LP/HF group. The number of macrophages and mRNA levels of TNF-alpha in the LP/HGT/HF group decreased (34% and 29%, respectively) compared with those in the LP/LP/HF group. DNMT1, UHRF1 and G9a mRNA levels in the LP/HGT/HF group decreased compared with those in the LP/LP/HF group. In conclusion, GTE intake during lactation attenuated tubulointerstitial fibrosis and macrophage infiltration by down-regulating epigenetic modulators such as DNMT1, UHRF1 and G9a in the kidney of HF-diet-fed adult offspring programmed by maternal protein restriction. PMID- 29525534 TI - The evaluation of three comorbidity indices in predicting postoperative complications and readmissions in pediatric urology. AB - INTRODUCTION: The surgical comorbidity assessment is important for patient risk stratification, counseling, and research. In adults, risk assessment indices, such as the Charlson Co-morbidity Score (CCS) or Van Walraven Index (VWI), are well established. In pediatrics, however, risk assessment indices are scarce. Recently, a pediatric-specific risk assessment index, the Rhee index, was developed to discriminate mortality for pediatric general surgery patients. Currently, there is no validated risk assessment tool in pediatric urology. OBJECTIVE: We compared the performance of the CCS, VWI, and Rhee Index in discriminating postoperative complications and readmissions to the emergency room/inpatient unit after pediatric urological procedures. METHODS: We analyzed the Nationwide Readmissions Database (NRD), State Inpatient Databases (SID), and State Emergency Department Databases (SEDD). We included patients (<18 years) who underwent the following urological procedures: ureteroneocystostomy, ureteroureterostomy, radical/partial nephrectomy, pyeloplasty, appendicovesicostomy, enterocystoplasty, vesicostomy, and bladder neck sling. Complications were identified based on definitions in the National Surgical Quality Improvement Program (NSQIP). Thirty-day emergency room admission and inpatient readmissions were extracted. Comorbidity scores were calculated using each of the three indices. We compared the performance of each index in discriminate primarily postoperative complications in the NRD and both admission types in the SID/SEDD by constructing a receiver operating characteristics (ROC). AUCs were compared using the Delong method. This protocol was reviewed by our Institutional Review Board and deemed to be exempt. RESULTS: We identified a total of 8006 patients in NRD and 6236 patients in SID/SEDD. The Rhee index had the best performance for discriminating postoperative complications (AUC = 0.67, 95% CI 0.64-0.70) compared to CCS (AUC = 0.62, 95% CI 0.60-0.65) and VWI (AUC = 0.62, 95% CI 0.59-0.65); p < 0.01. The CCS had the best performance for discriminating 30-day inpatient readmissions (AUC = 0.63, 95% CI 0.61-0.66) than VWI (AUC = 0.54, 95% CI 0.52-0.57), and Rhee Index (AUC = 0.56, 95% CI 0.54 0.59); p < 0.0001. All three indices had similarly poor discrimination for 30-day ER admissions: CCS (AUC = 0.52), VWI (AUC = 0.51), and Rhee Index (AUC = 0.50); p = 0.5 (see Table). DISCUSSION: The Rhee Index had the best performance for discriminating postoperative complications, while the CCS was superior for discriminating inpatient readmissions among the three indices. Limitations to our study include inpatient-only procedures, inability to identify complications managed in clinics, omission of secondary operations, accounting for parental anxiety, and the generalizability of SID. CONCLUSIONS: The three comorbidity indices evaluated are poor discriminators for postoperative complications, 30-day inpatient readmissions or 30-day ER admissions. A new index is needed for pediatric urology patients. PMID- 29525535 TI - Long-term urinary symptoms in adolescent and adult women with congenital adrenal hyperplasia. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition resulting in excess androgen production. Females are typically born with ambiguous genitalia and often undergo feminising genitoplasty in infancy or childhood. Recently, there has been considerable international debate as to whether distressing urinary symptoms in CAH patients are truly present and, if so, whether these urinary problems are a consequence of the feminising genitoplasty. OBJECTIVE: To identify and assess any urinary symptoms in an Australian cohort of adolescent and adult women with CAH who have undergone feminising genitoplasty in infancy, childhood or adolescence as a part of their management. STUDY DESIGN: Females with CAH aged 12-40 years, who had undergone feminising genitoplasty, and were identified from a hospital database (n = 72). Those aged 12-15 years were assessed using the Paediatric Incontinence Symptom Index questionnaire in conjunction with sections of the Bristol Female Lower Urinary Tract Symptoms Scored Form questionnaire. Those aged 16-40 years were assessed using the Bristol Female Lower Urinary Tract Symptoms Scored Form questionnaire. Uroflowmetry studies and post-void residual volume ultrasounds were also conducted. Previously published normative data were used for the control population. RESULTS: Responses to the questionnaire indicated that CAH patients had a higher incidence of urgency, frequency, urge incontinence, unexplained incontinence and nocturnal incontinence, when compared to previously published control data. Average and maximum urine flow rates measured by uroflowmetry were within normal range; however, the 16-40-year-old age group had significantly increased mean post-void residual volumes (P < 0.001) (Summary table). DISCUSSION: The presence of lower urinary tract symptoms in these patients has previously been interpreted as a direct outcome of feminising genitoplasty; however, these results could also be accounted for by the virilisation of pelvic floor musculature. Androgens have been shown to increase skeletal muscle mass, but their exact impact on the pelvic floor musculature requires further research. Three previous studies have measured post-void residual volumes in patients with CAH, all of which found it them be raised. CONCLUSIONS: Patients with CAH appeared to have overall normal urinary flow but increased post-void residual volumes. The data suggested that this population of patients has an increased probability of incontinence, urgency, and frequency when compared to a control population. These results confirmed findings of other small studies; however, it remains unclear if these changes reflected the underlying diagnosis or were a consequence of management. PMID- 29525536 TI - Response to "Re. Extraordinary daytime only urinary frequency in childhood: prevalence, diagnosis and management". PMID- 29525537 TI - Response to "Re: Non-stented versus stented urethroplasty for distal hypospadias repair: A systematic review and meta-analysis". PMID- 29525538 TI - Response to "Re. A simple technique for small diameter urethrocutaneous fistula repair: Ligation". PMID- 29525539 TI - Dynamic Penile Corpora Cavernosa Reconstruction Using Bilateral Innervated Gracilis Muscles: A Preclinical Investigation. AB - INTRODUCTION: Prosthesis-assisted penile reconstruction has been performed extensively to restore a cosmetically acceptable phallus. However, a large number of patients will undergo revision surgery for various prosthesis-related complications. AIM: To develop a 1-stage prosthesis-free dynamic cavernosa reconstruction method using bilateral innervated gracilis muscles and to investigate the feasibility and reliability of the surgical design. METHODS: 10 fresh cadavers were dissected to assess the availability of bilateral gracilis muscles for functional cavernosa rebuilding. 11 mongrel female dogs were involved in the penile reconstruction surgery. The neophallus consisted of bilateral gracilis muscles as the neo-cavernosa, a right gracilis skin flap as the neourethra, and a lower abdominal flap with an anterior rectus sheath as the skin envelope and neo-tunica albuginea. The function and structure of the neo-phalli were assessed 7 months postoperatively. MAIN OUTCOME MEASURES: The neurovascular pedicle length of the gracilis muscles and the volume of the gracilis venter musculi were measured in the cadaveric investigation. The average dimensions of the canine neo-phalli at rest and during electrostimulated erection were obtained and the muscular fatigue-resistant curve was drawn. Histologic evaluations also were performed. RESULTS: The neurovascular pedicle length and volume of the gracilis muscles were sufficient to yield a nearly normal appearance of the neo cavernosa in the cadaveric and animal studies. The muscular fatigue-resistant curve demonstrated adequate length, stiffness, and duration of erection of the neo-phalli to accomplish normal coitus. Histologic evaluations showed an intact neourethra and nearly normal muscle structure in the inner layer of the canine neo-cavernosa, except for significantly increased amount of collagen fibers and type I/III collagen ratio in the outer layer of the neo-cavernosa. The percentage of type II (fatigue-prone) muscle fibers did not change significantly. CONCLUSION: Our preclinical investigation proves that corpora cavernosa reconstruction using bilateral innervated gracilis muscles is technically feasible and functionally efficacious. Yin Z, Liu L, Xue B, et al. Dynamic Penile Corpora Cavernosa Reconstruction Using Bilateral Innervated Gracilis Muscles: A Preclinical Investigation. Sex Med 2018;6:162-170. PMID- 29525540 TI - Large hepatocellular carcinoma: Does fibrosis really impact prognosis after resection? AB - BACKGROUND: Hepatectomy remains the standard treatment for large hepatocellular carcinoma (LHCC) >=5cm. Fibrosis may constitute a contraindication for resection because of high risk of post-hepatectomy liver failure, but its impact on patient outcome and cancer recurrence remains ill defined. Our aim was to compare predictors of survival in patients with and without cirrhosis following hepatectomy for LHCC. METHODS: The data on consecutive patients undergoing hepatectomy for LHCC in two tertiary centres between 2012 and 2016 were reviewed. The outcomes of cirrhotic (F4) and non-cirrhotic (F0-F3) patients were compared. Patients with perioperative medical (sorafenib) or radiological (transarterial chemoembolization, radiofrequency) treatments were excluded. RESULTS: Sixty patients were included. Preoperative and intraoperative features were identical between both groups. Cirrhotics (n=15) presented more satellite nodules on specimens (73% vs. 44%; P=0.073) but better differentiated lesions than non cirrhotics (P=0.041). The median overall survival of cirrhotics was 34 vs. 29months for non-cirrhotics (P=0.8), and their disease-free survival was 14 versus 18 months (P=0.9). Fibrosis stage did not impact overall (P=0.2) nor disease-free survivals (P=0.6). CONCLUSION: Hepatectomy for LHCC in cirrhotics can achieve acceptable oncological results when compared to non-cirrhotic patients. Curative resection of LHCC should be attempted if liver function is acceptable, whatever the fibrosis stage. PMID- 29525541 TI - Answering Questions and Questioning Answers: More Evidence To Guide Decision making About Chemohormonal Therapy in Metastatic Prostate Cancer. PMID- 29525542 TI - Prognosis of anatomic coronary artery disease without myocardial ischemia: Coronary computed tomography angiography detects high-risk patients even in cases of negative single-photon emission computed tomography findings. AB - BACKGROUND: While coronary computed tomography angiography (CCTA) provides comprehensive anatomic evaluation of coronary artery disease (CAD) with prognostic implications, clinically, the focus is usually placed on presence or absence of functionally significant CAD. Herein, we aimed to suggest a new risk stratification strategy using CCTA in patients with anatomic CAD but without myocardial ischemia on single-photon emission computed tomography (SPECT). METHODS: Consecutive patients (n=798) with CAD on CCTA who underwent SPECT for evaluation of myocardial ischemia were retrospectively evaluated. The primary outcome was the occurrence of adverse cardiac events, including cardiac death, nonfatal myocardial infarction, unstable angina, and late revascularization. RESULTS: Of the enrolled patients, 542 (68%) showed no perfusion defect (PD) on SPECT. During the follow-up (median, 22.6 months), adverse cardiac events occurred in 23 patients without PD (4.6%). Presence of plaque in >=4 coronary segments, plaque in the left main or proximal left anterior descending coronary artery, and partially calcified plaque presence were independent predictors of adverse events. When we defined the CCTA score based on these 3 predictors (0-3 points), the annualized event rates increased with increasing CCTA scores. Patients with a CCTA score of 3 were associated with a 23-fold risk increase (adjusted HR 23.18; p=0.003) and showed unfavorable event-free survival, comparable to those with PD on SPECT (p=0.191). CONCLUSION: Anatomic CAD patients without evidence of myocardial ischemia on SPECT but with high-risk characteristics on CCTA showed unfavorable outcomes, comparable to those with PD. CCTA allows further risk stratification even in patients with negative SPECT findings. PMID- 29525543 TI - Exaptation of transposable element coding sequences. AB - Transposable elements (TEs) are mobile genetic elements that were once perceived as merely selfish, but are now recognized as potent agents of adaptation. One way TEs contribute to genome evolution is through TE exaptation, a process whereby TEs, which usually persist by replicating in the genome, transform into novel host genes, which thereafter persist by conferring phenotypic benefits. Exapted TEs are known to contribute diverse and vital functions, and may facilitate punctuated equilibrium, yet we have little understanding about the process of TE exaptation. In order to facilitate our understanding of how TE coding sequences may become exapted, here we incorporate the findings of recent publications into a framework and six-step model. PMID- 29525544 TI - Transposable elements, genome evolution and transgenerational epigenetic variation. AB - Although transposable elements (TEs) have been regarded as genomic parasites, accumulating evidence suggests that they can also have beneficial roles in evolution of diverse biological processes. In this review, we focus on epigenetic control of TEs as sources of selectable phenotypic variation, with an emphasis on their connections to defense responses. PMID- 29525546 TI - Polyethylene liner dislocation of fixed-bearing medial oxinium unicompartmental arthroplasty with severe metallosis. AB - The case of an atraumatic dislocation of a fixed bearing in a medial unicompartmental arthroplasty with an oxinium femoral component is presented. A review of the literature pertaining to knee arthroplasty locking mechanisms is discussed. Potential modes of locking mechanisms failure are reviewed including the recognition of such failures in the clinical setting. This is the first report of a dislocated fixed-bearing medial oxinium unicompartmental arthroplasty and consequent metal arthrogram. PMID- 29525545 TI - Time between anterior cruciate ligament injury and reconstruction and cartilage metabolism six-months following reconstruction. AB - BACKGROUND: To determine the association between time from injury to ACL reconstruction (TimeInjury-ACLR) and biochemical markers of cartilage metabolism and inflammation six months following ACL reconstruction (ACLR). METHODS: Individuals with a unilateral ACL injury were enrolled at initial presentation in the orthopedic clinic; blood was collected six months following ACLR. Enzyme linked immunosorbent assays were used to analyze the ratio of serum concentrations of type-II collagen breakdown (C2C) to synthesis (CPII), plasma matrix metalloproteinase-3 (MMP-3), interleukin-6 (IL-6), and serum aggrecan neoepitope (ARGS). We used separate linear regressions to assess associations between biochemical markers and TimeInjury-ACLR. RESULTS: Twenty-two participants (50% females, mean [SD], age 21.9 [4.5] years old; BMI 23.8 [2.6] kg/m2) completed the study. TimeInjury-ACLR ranged from nine to 67days (31.0 [14.4days]). Greater TimeInjury-ACLR predicted greater serum C2C:CPII ratios six months following ACLR (C2C:CPII=0.15 [0.02], R2=0.213, P=0.030). Males (R2=0.733, P=0.001) but not females (R2=0.030, P=0.609) demonstrated a significant association between greater C2C:CPII and TimeInjury-ACLR at the six-month follow up exam. TimeInjury-ACLR did not associate with IL-6, MMP-3, or ARGS at six months. CONCLUSIONS: Greater time between injury and ACL reconstruction was associated with greater serum C2C:CPII six months following ACLR in males but not females, and IL-6, MMP-3, and ARGS levels were not associated with TimeInjury ACLR in males or females. The time between ACL injury and ACLR may affect collagen metabolism in males and should be further investigated in a larger study along with other patient-relevant outcomes. PMID- 29525547 TI - Interactive effect of femoral posterior condylar offset and tibial posterior slope on knee flexion in posterior cruciate ligament-substituting total knee arthroplasty. AB - BACKGROUND: This work aimed to evaluate the changes in the femoral posterior condylar offset (PCO) and tibial slope after posterior cruciate ligament (PCL) substituting total knee arthroplasty (TKA), and to address the presence of any interactive effect between the two on knee flexion. METHODS: Fifty-two PCL substituting TKAs were performed using a posterior referencing system. Three dimensional reconstructed computed tomographic (CT) images were used to evaluate PCO and tibial slope before and after arthroplasty. Range of motion and clinical scores were evaluated at a mean of 3.1years postoperatively. Multivariate linear model with interaction terms was used to evaluate and compare the relationships among changes in PCO, tibial slope, and postoperative knee flexion angles. RESULTS: The degree of change in PCO was greater in the lateral condyle than in the medial condyle (3.1+/-2.5mm and -0.5+/-2.8mm, respectively). Postoperative medial and lateral tibial slopes were 1.4 degrees +/-1.8 and 1.4 degrees +/-2.0, respectively. The mean degree of postoperative knee flexion was 125 degrees . Analysis with interaction terms and covariate adjustment demonstrated that medial PCO and tibial slope were significantly related to knee flexion with interactive effect (P=0.011). In cases with <3 degrees posterior tibial slope, the postoperative PCO was positively correlated to the degree of knee flexion angle. However, in cases with >3 degrees tibial slope, PCO was negatively correlated to knee flexion. CONCLUSION: Medial femoral PCO and tibial slope showed interactive effect on knee flexion after PCL-substituting TKAs. Reconstitution of the proper PCO and avoiding excessive tibial slope may be necessary. PMID- 29525548 TI - Curve analyses reveal altered knee, hip, and trunk kinematics during drop-jumps long after anterior cruciate ligament rupture. AB - BACKGROUND: Anterior cruciate ligament (ACL) ruptures may lead to knee dysfunctions later in life. Single-leg tasks are often evaluated, but bilateral movements may also be compromised. Our aim was to use curve analyses to examine double-leg drop-jump kinematics in ACL-reconstructed, ACL-deficient, and healthy knee cohorts. METHODS: Subjects with unilateral ACL ruptures treated more than two decades ago (17-28years) conservatively with physiotherapy (ACLPT, n=26) or in combination with reconstructive surgery (ACLR, n=28) and healthy-knee controls (n=25) performed 40-cm drop-jumps. Three-dimensional knee, hip, and trunk kinematics were analyzed during Rebound, Flight, and Landing phases. Curves were time-normalized and compared between groups (injured and non-injured legs of ACLPT and ACLR vs. non-dominant and dominant legs of controls) and within groups (between legs) using functional analysis of variance methods. RESULTS: Compared to controls, ACL groups exhibited less knee and hip flexion on both legs during Rebound and greater knee external rotation on their injured leg at the start of Rebound and Landing. ACLR also showed less trunk flexion during Rebound. Between leg differences were observed in ACLR only, with the injured leg more internally rotated at the hip. Overall, kinematic curves were similar between ACLR and ACLPT. However, compared to controls, deviations spanned a greater proportion of the drop-jump movement at the hip in ACLR and at the knee in ACLPT. CONCLUSIONS: Trunk and bilateral leg kinematics during double-leg drop-jumps are still compromised long after ACL-rupture care, independent of treatment. Curve analyses indicate the presence of distinct compensatory mechanisms in ACLPT and ACLR compared to controls. PMID- 29525549 TI - Comparative postural stability in patients with lateral meniscus versus medial meniscus tears. AB - BACKGROUND: Types of mechanoreceptors may differ between the medial and lateral menisci, suggesting that postural stability may differ between patients with medial and lateral meniscus tears. However, to date, postural stability has not been compared in patients with medial and lateral meniscus tears. This study used stabilometry to compare postural stability in patients with medial and lateral meniscus tears. METHODS: Postural stability and thigh muscle strength were assessed in 24 patients with medial and 18 patients with lateral meniscus tears. Postural stability was determined by measuring the anteroposterior (APSI), mediolateral (MLSI), and overall (OSI) stability indices using stabilometry. Maximal torque (60 degrees /s) of the quadriceps and hamstring was evaluated using an isokinetic testing device. RESULTS: The three stability indices, OSI, APSI, and MLSI, in both involved and uninvolved knees were all significantly greater in patients with lateral than with medial meniscus tears. (P<0.001 for all OSI, APSI, and MLSI in both involved and uninvolved knees, except for P=0.005 for MLSI of involved knees). In patients with medial meniscus tears, both OSI (1.4+/-0.4 vs. 1.1+/-0.4, P=0.037) and MLSI (0.9+/-0.3 vs. 0.8+/-0.3, P=0.041) were significantly higher on the injured than the uninjured side. In patients with lateral meniscus tears, none of the stability indices differed significantly between injured and uninjured knee joints. CONCLUSION: Postural stability of both the injured and uninjured knee joints was poorer in patients with lateral than with medial meniscus tears. PMID- 29525550 TI - Ultrasound evaluation of infrapatellar fat pad impingement: An exploratory prospective study. AB - BACKGROUND: We sought to determine whether there are ultrasound parameters that differ between knees with symptomatic fat pad synovial impingement and asymptomatic knees. METHODS: A prospective study was performed in patients with clinical signs and symptoms of fat pad synovial impingement and asymptomatic controls. Eleven symptomatic knees and 10 asymptomatic controls were evaluated. Ultrasound imaging was performed before and after exercise. Evaluated parameters included largest fat lobule compressibility, subjective assessment of vascularity, largest vessel diameter, and subjective assessment of dynamic fat pad motion during flexion and extension. Receiver operating characteristic (ROC) curve analysis was used to assess whether changes in these parameters were different between symptomatic and asymptomatic knees. RESULTS: Change in the largest vessel diameter was greater and trended toward dilation in asymptomatic knees compared to symptomatic knees (mean: 0.83 vs. -0.02; P<0.001). No significant differences were observed between symptomatic and asymptomatic knees with respect to pre-exercise versus post-exercise states in subjective assessment of vascularity (P=0.131), fat pad motion (P=0.115), or percent change of the largest fat lobule (P=0.241). However, overall compressibility of the fat pad lobule was significantly diminished in the pre-exercise state in symptomatic knees compared to asymptomatic controls. CONCLUSIONS: This study demonstrated a statistically significant change in the largest vessel diameter from pre- to post exercise states between symptomatic and asymptomatic knees, as well as abnormal pre-exercise fat lobule compressibility in symptomatic knees. These findings show promise that with further research, ultrasound could have clinical utility in diagnosing infrapatellar fat pad impingement. PMID- 29525551 TI - A nine-legged tick: Report of a morphological anomaly in the blacklegged tick, Ixodes scapularis (Acari: Ixodidae) from the northeastern United States. AB - Morphological anomalies have been reported in the blacklegged tick, Ixodes scapularis (Acari: Ixodidae), from the northeastern and upper Midwestern United States, complicating identification of this important vector of human pathogens. Here, we report a case of a local morphological anomaly in I. scapularis, parasitizing a human living in Connecticut. We used a dichotomous morphological key, high-resolution and scanning electron microscopy images, as well as DNA sequencing for identification. The specimen was identified as an adult female I. scapularis with the left leg II split at the trochanter, resulting in two complete legs from the femur to pretarsus giving the appearance of five legs on the left side versus four on the right side. Here we discuss recent reports of morphological anomalies in I. scapularis, and highlight the need for further studies of teratology in this important tick species and its potential implications. PMID- 29525552 TI - Isolation and whole-genome sequencing of a Crimean-Congo hemorrhagic fever virus strain, Greece. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) was isolated from a pool of two adult Rhipicephalus bursa ticks removed from a goat in 2015 in Greece. The strain clusters into lineage Europe 2 representing the second available whole-genome sequenced isolate of this lineage. CCHFV IgG antibodies were detected in 8 of 19 goats of the farm. Currently CCHFV is not associated with disease in mammals other than humans. Studies in animal models are needed to investigate the pathogenicity level of lineage Europe 2 and compare it with that of other lineages. PMID- 29525553 TI - Tick host specificity: An analysis based on host phylogeny and tick ecological features using Amblyomma triste and Amblyomma tigrinum immature stages. AB - Here we have evaluated tick host specificity with two different methodological approaches considering Amblyomma tigrinum and Amblyomma triste immatures as targets. Firstly, the Std* index was applied, which considers host phylogenetic relationships weighted by the prevalence of the parasite; followed by generalized linear models to explore associations between different host species and burdens and prevalence of larvae and nymphs, independently. The Std* index showed that A. tigrinum larvae and nymphs infest host species belonging to different orders and classes, respectively; while A. triste immatures fed on hosts that belong to different tribes, showing that both tick species have low specificity and thus, a generalist behavior. When analyzing prevalence and burdens, we found that both tick species infest some hosts more heavily compared with the rest. Even though immature stages of A. triste and A. tigrinum are generalists, the level of infestation within the range of usual hosts of these two species is uneven. This shows that a generalist behavior may result in dissimilar levels of infestation across a range of usual hosts. PMID- 29525554 TI - Personality and Parkinson's disease: A meta-analysis. PMID- 29525555 TI - Reply to Zappia et al.'s comment on personality and Parkinson's Disease: A meta analysis. PMID- 29525556 TI - Neurite orientation dispersion and density imaging of the nigrostriatal pathway in Parkinson's disease: Retrograde degeneration observed by tract-profile analysis. AB - INTRODUCTION: Parkinson's disease (PD) is marked by the degeneration of dopaminergic neurons in the nigrostriatal pathway (NSP). We aimed to identify the microstructural changes in the NSP of PD patients using neurite orientation dispersion and density imaging (NODDI). METHODS: NSPs of 29 PD patients, who were retrospectively selected from patients previously admitted to our institution, and 29 age- and gender-matched healthy controls were isolated via deterministic tractography. The NODDI indices, intracellular volume fraction (Vic), orientation dispersion index (OD), and isotropic volume fraction (Viso) were compared between the two groups. The significant results were assessed with a tract-profile analysis. The correlation between indices and disease duration or motor symptom severity was evaluated with the Pearson's correlation test. RESULTS: The contralateral distal Vic (p = 0.00028) of the nigrostriatal pathway was significantly lower in PD patients than in healthy controls. No correlations were detected between any of the indices and disease duration or motor symptom severity. CONCLUSIONS: NODDI can be used to identify retrograde degeneration of the NSP in PD patients and might be useful for monitoring the disease progression of PD. PMID- 29525557 TI - Absence of a neutralizing antibody response to humanized cobra venom factor in mice. AB - Cobra venom factor (CVF) is the complement-activating protein in cobra venom. Humanized CVF (hCVF) is a human C3 derivative where the C-terminal 168 amino acid residues were replaced with the homologous sequence from CVF. hCVF has been shown in multiple models of disease with complement pathology to be a promising therapeutic agent, with no observed adverse effects. Here we describe the antibody response to hCVF in two different strains of mice. hCVF was able to repeatedly decomplement the mice after four injections in weekly intervals, demonstrating the absence of a neutralizing antibody response. In contrast, natural CVF caused decomplementation in all mice only after the first administration. After two additional administrations of natural CVF, decomplementation was inconsistent and varied tremendously from mouse to mouse. After the fourth administration, natural CVF was essentially unable to deplete complement, consistent with the known generation of a neutralizing antibody response. We also analyzed the IgG antibody response to hCVF. There was great variation, with approximately one quarter of the mice exhibiting non-detectable levels of anti-hCVF IgG, and another quarter very low levels. The levels of anti hCVF IgG did not correlate with the levels of remaining C3. The anti-hCVF antibodies cross-reacted with natural CVF, recombinant CVF, and human C3. Whereas overall the level of anti-hCVF IgG cross-reacting with human C3 was lower compared to rCVF or nCVF, mice with higher levels of anti-hCVF IgG exhibited higher binding to CVF and human C3, excluding the possibility that higher antibody levels reflect preferential immunogenicity of CVF-specific or human C3 specific epitopes. PMID- 29525558 TI - Outcomes of rotational atherectomy in patients with severe left ventricular dysfunction without hemodynamic support. AB - INTRODUCTION: Elective insertion of a percutaneous circulatory assist device (PCAD) in high-risk patients is considered a reasonable adjunct to percutaneous coronary intervention (PCI). There is limited data examining the safety and efficacy of rotational atherectomy (RA) without hemodynamic support in patients with reduced left ventricular ejection fraction (LVEF). METHODS: We retrospectively identified 131 consecutive patients undergoing RA without elective PCAD over a three-year period. Patients were categorized into three groups: LVEF <=30%, LVEF 31-50%, and LVEF >50%. The incidence of procedural hypotension, major adverse cardiac events (MACE), and mortality were recorded. RESULTS: Statistical analysis included 18, 42, and 71 patients with LVEF <=30%, 31-50%, and >50%, respectively. Bailout hemodynamic support was required in four cases. Analysis revealed a significant trend as bailout hemodynamic support was required in 11.1% vs 2.4% (P = 0.1551) in the <=30% vs 31-50% and 11.1% vs 1.4% (P = 0.0416) in the <=30% vs >50% subgroups. Combined subgroup analysis also demonstrated statistical significance 11.1% vs 1.8% (P = 0.0324) in the <=30% vs >30% subgroups. No-reflow phenomenon was more prevalent in patients with reduced LVEF (LVEF <=30%: 11.1%, LVEF 31-50%: 2.4%, LVEF >50%: 0%; P = 0.0190). Otherwise, no significant differences in in-hospital MACE, or mortality were observed. CONCLUSION: RA can be effectively utilized in patients with severely reduced LVEF; however, these patients are at increased risk of prolonged procedural hypotension requiring bailout hemodynamic support. If indicated, prompt implementation of hemodynamic support mitigated any impact of procedural hypotension on in-hospital MACE and mortality. PMID- 29525560 TI - Combined modalities of surgery, radiotherapy, radiosurgery and chemotherapy for invasive pituitary carcinoma. PMID- 29525559 TI - Personality traits and facets linked with self-reported alcohol consumption and biomarkers of liver health. AB - INTRODUCTION: This study examines whether the association between Five Factor Model personality traits and alcohol consumption extends beyond self-report to biomarkers of alcohol consumption. METHODS: Community-dwelling adults from Sardinia (N = 5380), Italy, completed the revised NEO Personality Inventory and reported on alcohol consumption, while traditional biomarkers of heavy drinking, such as gamma-glutamyl transferase (GGT), were assayed from blood samples. RESULTS: Associations between self-report measures were modest but consistent with previous findings on the link between personality and alcohol use. For instance, higher scores on the order and self-discipline facets of conscientiousness were associated with reduced risk of heavy alcohol consumption. Personality was also associated with GGT, though effects were small. Personality was unrelated to other biomarkers of liver health. CONCLUSIONS: This study adds multi-method evidence in support of a link between personality and health behaviors. PMID- 29525561 TI - Secreting ectopic adrenal adenoma: A rare condition to be aware of. AB - Ectopic adrenal adenoma causing chronic Cushing's syndrome (CS) is a rare phenomenon. Diagnosis is usually made years after disease onset because of the insidious nature of the ectopic adrenal gland and because it overlaps with common symptoms, such as overweight and hypertension, in the general population (Kreitschmann-Andermahr et al., 2015). Here, we report the case of a 46-year-old male with a 15-year history of severe hypertension, facial plethora, and centripetal obesity. During treatment for herpes zoster, the patient presented with severe hypokalemia and flaccid paralysis, characteristic changes associated with CS. The serum cortisol level was elevated and baseline adrenocorticotrophic hormone (ACTH) was suppressed. After administration of the low-dose overnight dexamethasone suppression test, plasma cortisol was 38.9MUg/dL. A contrast computed tomography (CT) scan revealed normal adrenal glands and significant tumor adjacent to the right renal hilum measuring ~3.6*2.3cm. The tumor was removed through retroperitoneoscopy, and pathological examination confirmed adrenocortical adenoma and myelolipoma metaplasia. The serum potassium level gradually became normal after surgical removal of the mass. In the current report, we have reviewed the pertinent literature and highlighted the importance of considering ectopic adrenal adenoma in the differential diagnosis of chronic CS with nonspecific symptoms. PMID- 29525562 TI - A hierarchical classification approach for recognition of low-density (LDPE) and high-density polyethylene (HDPE) in mixed plastic waste based on short-wave infrared (SWIR) hyperspectral imaging. AB - The aim of this work was to recognize different polymer flakes from mixed plastic waste through an innovative hierarchical classification strategy based on hyperspectral imaging, with particular reference to low density polyethylene (LDPE) and high-density polyethylene (HDPE). A plastic waste composition assessment, including also LDPE and HDPE identification, may help to define optimal recycling strategies for product quality control. Correct handling of plastic waste is essential for its further "sustainable" recovery, maximizing the sorting performance in particular for plastics with similar characteristics as LDPE and HDPE. Five different plastic waste samples were chosen for the investigation: polypropylene (PP), LDPE, HDPE, polystyrene (PS) and polyvinyl chloride (PVC). A calibration dataset was realized utilizing the corresponding virgin polymers. Hyperspectral imaging in the short-wave infrared range (1000 2500nm) was thus applied to evaluate the different plastic spectral attributes finalized to perform their recognition/classification. After exploring polymer spectral differences by principal component analysis (PCA), a hierarchical partial least squares discriminant analysis (PLS-DA) model was built allowing the five different polymers to be recognized. The proposed methodology, based on hierarchical classification, is very powerful and fast, allowing to recognize the five different polymers in a single step. PMID- 29525563 TI - Theoretical study of chromophores for biological sensing: Understanding the mechanism of rhodol based multi-chromophoric systems. AB - Development of two-photon fluorescent probes can aid in visualizing the cellular environment. Multi-chromophore systems display complex manifolds of electronic transitions, enabling their use for optical sensing applications. Time-Dependent Density Functional Theory (TDDFT) methods allow for accurate predictions of the optical properties. These properties are related to the electronic transitions in the molecules, which include two-photon absorption cross-sections. Here we use TDDFT to understand the mechanism of aza-crown based fluorescent probes for metals sensing applications. Our findings suggest changes in local excitation in the rhodol chromophore between unbound form and when bound to the metal analyte. These changes are caused by a charge transfer from the aza-crown group and pyrazol units toward the rhodol unit. Understanding this mechanism leads to an optimized design with higher two-photon excited fluorescence to be used in medical applications. PMID- 29525564 TI - Selective detection of Co2+ by fluorescent nano probe: Diagnostic approach for analysis of environmental samples and biological activities. AB - Nowadays scientist over the world are engaging to put forth improved methods to detect metal ion in an aqueous medium based on fluorescence studies. A simple, selective and sensitive method was proposed for detection of Co2+ ion using fluorescent organic nanoparticles. We synthesized a fluorescent small molecule viz. 4,4'-{benzene-1,4-diylbis-[(Z)methylylidenenitrilo]}dibenzoic acid (BMBA) to explore its suitability as sensor for Co2+ ion and biocompatibility in form of nanoparticles. Fluorescence nanoparticles (BMBANPs) prepared by simple reprecipitation method. Aggregation induced enhanced emission of BMBANPs exhibits the narrower particle size of 68nm and sphere shape morphology. The selective fluorescence quenching was observed by addition of Co2+ and does not affected by presence of other coexisting ion solutions. The photo-physical properties, viz. UV-absorption, fluorescence emission, and lifetime measurements are in support of ligand-metal interaction followed by static fluorescence quenching phenomenon in emission of BMBANPs. Finally, we develop a simple analytical method for selective and sensitive determination of Co2+ ion in environmental samples. The cell culture E. coli, Bacillus sps., and M. tuberculosis H37RV strain in the vicinity of BMBANPs indicates virtuous anti-bacterial and anti-tuberculosis activity which is of additional novel application shown by prepared nanoparticles. PMID- 29525565 TI - Raman spectroscopy analysis of dental enamel treated with whitening product - Influence of saliva in the remineralization. AB - In this work we present the analysis of dental enamel treated with an over-the counter whitening product, bought in e-commerce at a very low cost, used without medical supervision in an abusive manner, in order to evaluate its demineralization action. Moreover, we studied the influence of renewal or non renewal of saliva solution in which the specimens were stored throughout the study. The Degree of Demineralization was determined through the evaluation of the PO43- symmetric stretching band (~959cm-1) in Raman spectra of the specimens in different days during the course of the study. Results showed that a maximum of demineralization occurred between days 27 and 34 of application. Titration of the whitening product revealed a content of hydrogen peroxide 170-fold higher than what is allowed in Europe, according with legislation. Despite this extreme concentration of hydrogen peroxide, the demineralization was not as great as could be expected suggesting an important role of the pH of the solution in this demineralization mechanism. PMID- 29525566 TI - The role of metals and dithiolate ligands on structural, electronic and optical properties of [M(bipyridine)(dithiolate)] complexes: A theoretical study. AB - A series of [M(diimine)(dithiolate)] complexes of general formula [M(bpy)(dithiolate)] {bpy=2,2'-bipyridine;dithiolate=1,2-benzenedithiolate (bdt2 ), 3,4-toluenedithiolate (tdt2-) and 4-cyanobenzene-1,2-dithiolate (cbdt2-); M=Ni(II), Pd(II) and Pt(II)} have been studied by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations. The geometries, stabilities, electronic structures, optical absorption spectra in different phases as well as thermodynamic parameters are explored. The changes of metal ion center and dithiolate ligands on some molecular properties are also discussed. These calculated results are in good agreement with the experimental data. The bonding analyses show that the MS bond is covalent so that always polarized towards sulfur atom, whereas the MN bond exhibits a considerable amount of electrostatic interaction. Detailed NBO analysis indicates that these complexes can be easily oxidized than reduced, and acts as the reducing agent. The HOMO-LUMO energy gaps of all complexes under study are founded about 2eV and the strong absorption from 400 to 700nm which match with the solar spectra very well. Besides, the simulated absorption spectra are in accordance with the trends of energy gaps. Comparison of the absorption spectra in dichloromethane solution with those in gas phase show that the solvatochromic effect. The order of magnitude for light harvesting efficiencies (LHE) of all complexes is Pt>Pd>Ni and cbdt2->bdt2->tdt2-. Our results confirm the effect and role of metals and dithiolate ligands on enhancing the optical properties of these complexes. Thus, the result of this work can serve as a rational tool for the design and synthesis of diimine-dithiolate complexes and broadens the scope for further investigations into potential dyes for use in the field of dye-sensitized solar cells (DSSC). PMID- 29525567 TI - Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics. AB - Nanoparticles create exciting platforms for anticancer immunotherapy and vaccination, though their inherent immunomodulatory properties have remained underexploited. Ammonio methacrylate copolymers (AMC) are well-established excipients in pharmaceutical industry and components of controlled-release oral formulations. Here, we demonstrate that nanoscaling of type A and B AMC (Eudragit(r) RL and RS) endows these inactive ingredients immunostimulatory properties exploitable for cancer therapy. The particles induce the secretion of various pro-inflammatory cytokines and chemokines from the cells of innate immunity. Though the underlying mechanisms are not fully uncovered, the current work established the partial involvement of Toll-like Receptor 4 (TLR4) and Nuclear factor kappaB (NF-kappaB). The size and charge-dependency of the particles' pro-inflammatory properties and cytokine/chemokine induction profile was also demonstrated. Within the context of cancer immunotherapy, biweekly peritumoral nanoparticle injection led to a complete regression of the syngeneic colorectal tumor, or a significant growth retardation thereof, considerably extending the survival of tumor-bearing animals. Additionally, presence of the immunological memory in treated animals was established. Given their better economical and relatively safer profile compared to well-established chemo- and immunotheraputics, and their ability to serve as carriers for drug targeting, vaccination and combination therapy, AMC nanoparticles (AMCNP) are fascinating subjects for further research in the field of cancer therapy. PMID- 29525568 TI - A new assay for global fibrinolysis capacity (GFC): Investigating a critical system regulating hemostasis and thrombosis and other extravascular functions. AB - For many years, the importance of fibrinolysis has been recognized, first for its intravascular antithrombotic action, and more recently for its many extravascular activities, associated with matrix degradation and tissue remodeling. In the blood circulation system, fibrinolysis prevents thrombosis, and is associated with various biological and clinical situations: risk factors for cardio-vascular diseases in high risk clinical situations (type II diabetes, hypertension, triglycerides, high BMI, elevated glucose, etc.), probably resulting from a significant reduction of the fibrinolysis potential, and elevation of PAI-1. Noteworthy, t-PA is mainly present as an inactive complex with PAI-1, and its concentration in plasma tends to follow that of PAI-1, but in a lesser extent. Hypofibrinolysis can favor the occurrence of thrombotic events, and possibly other biological dysfunctions. Fibrinolysis activity is however difficult to evaluate as it has a delayed activity after clot formation, is initiated and regulated after fibrin generation, and conversely to clotting, its action is delayed (long lag phase) and slow, before being dramatically amplified leading to rapid clot dissolution. We have designed a new assay for evaluating the global fibrinolytic capacity (GFC) in the body. Reagents are used in association with a specific instrument, which can be connected to any computer, and dedicated software is used for analyzing clot lysis kinetics. The assay is performed in a micro-cuvette, introduced into one of the instrument wells at 37 degrees C, and light transmittance is continuously measured. Assayed plasma is first supplemented with a limited and constant amount of t-PA with silica and is then clotted with thrombin and calcium. Clot dissolution (measurement of turbidity change) is recorded over time using the dedicated instrument (Lysis Timer), and clot lysis kinetics are analyzed with the associated software: primary and secondary derivatives of the light transmission curve give information on kinetics and completion of clot dissolution. Total assay time is about 1 h (but in the presence of hypofibrinolysis it can be prolonged). The concentration of t PA used for the assay has been adjusted (100 ng/ml) to obtain an optimal sensitivity to hypofibrinolysis within a short time interval, and clot dissolution occurs within about 45 min for normal individuals, with a broad range from 30 min to 60 min, with some samples presenting a clot dissolution time >60 min (hypofibrinolysis). This new assay is performed with the tested plasma intrinsic factors, especially its own fibrinogen, and only exogeneous t-PA is added. GFC is highly sensitive to PAI-1 activity, but other factors regulating fibrinolysis contribute to the clot dissolution kinetics. Freshly prepared or frozen and thawed citrated plasma can be used. The usefulness of this assay for clinical applications is under investigation. Although fibrinolysis is mainly initiated in the body upon stimulation or blood clotting, and rapidly diluted and inhibited in the circulation, evaluation of its "residual" activity in plasma is expected to reflect its global body potential. PMID- 29525569 TI - Use of red blood cell exchange for treating acute complications of sickle cell disease. AB - Sickle cell disease (SCD) is a life-threatening chronic condition primarily caused by genetic mutation. The disease is characterized by intermittent vaso occlusive events and chronic hemolytic anemia. Acute complications in patients with SCD are difficult to manage due to the pathophysiological nature of the disease. Transfusion therapy is the cornerstone of management of acute complications and significantly reduces SCD morbidity and mortality. Red cell exchange (RCE), which is characterized by low iron accumulation and volume overload, has been widely used for transfusion therapy in recent years. PMID- 29525570 TI - Knowledge and attitude towards the Middle East respiratory syndrome coronavirus among healthcare personnel in the southern region of Saudi Arabia. AB - INTRODUCTION: Middle East respiratory syndrome coronavirus (MERS-CoV) belongs to the family Coronaviridae, and is named for the crown-like spikes on its surface. The clinical presentation of MERS-CoV infection ranges from asymptomatic to very severe disease, and the classical presentation includes fever, cough chills, sore throat, myalgia, and arthralgia. METHODS: A cross-sectional study of 339 healthcare personnel was conducted over an 8-month period in the Aseer region of Saudi Arabia using a structured survey that included demographic information and questions testing participant's knowledge. RESULTS: Approximately two-thirds of the respondents properly identified the causative agent of MERS-CoV as an RNA virus (66.4%, n=225) that is enveloped (68.1%, n=231). On the other hand, few respondents identified the proper number of strains or the genus (16.5% and 17.4%, respectively). More than half of the study sample identified the disease as zoonotic (57.2%, n=194). Similarly, 89.1% (n=302) identified that camels and bats are prone to infection with coronaviruses. Only 23.9% (n=81) properly identified March through May as the season with the highest transmission rate. There was a massive lack of adequate knowledge regarding prevalence of antibodies. Only 18.3% (n=62) of respondents identified PCR as the proper diagnostic confirmatory test for MERS-CoV infection. Regarding MERS-CoV clinical features, 76.4% (n=259) recognized the presence of sub-clinical infection, 64.7% (n=218) indicated that cases should be immediately isolated, and 46.9% (n=159) identified the main cause of mortality as respiratory failure. CONCLUSIONS: There is limited microbiological and virological knowledge of MERS-CoV infection among healthcare personnel in the southern region of Saudi Arabia, although the clinical aspects are known. PMID- 29525571 TI - Vaccination coverage among children and adolescents below 18 years of age in French Guiana: inventory and determinant factors. AB - OBJECTIVE: The purpose of this study was to estimate the vaccination coverage (VC) rate in persons aged from 9 months to 18 years and to describe it according to the predictive factors of good vaccination status. STUDY DESIGN: Descriptive and etiological study. METHODS: The study involved 1332 persons aged below 18 years and members of 521 representative households in French Guiana. VC was estimated by the proportion of people with complete immunization for 13 vaccines (four mandatory, seven recommended, and two specific). This vaccination status was described in terms of sociodemographic characteristics. The relationship between vaccination status and predictive factors was analyzed in a hierarchical mixed, polytomic, and ordered regression model. RESULTS: For compulsory vaccination, VC was 81.2% for yellow fever, 63.4% for diphtheria, 61.7% for tetanus, and 61.6% for poliomyelitis. The proportion of people with complete immunization for recommended vaccines remains well below 50% (11.7% for pneumococcus and 6.2% for meningitis). Regardless of the vaccine, respondents aged 3-7 years were 2.5 times more likely to have an up-to-date vaccination compared to respondents younger than 3 years of age (P < 0.001). CONCLUSION: The VC observed in this study is still below the departmental objectives. The link between age and vaccination status could be explained by the efforts of the national education authorities to systematically check health cards for preschool and school enrollment. PMID- 29525573 TI - Vaccines for Improved Cellular Immunity to Influenza. PMID- 29525572 TI - Endogenous Mobilization of Bone-Marrow Cells Into the Murine Retina Induces Fusion-Mediated Reprogramming of Muller Glia Cells. AB - Muller glial cells (MGCs) represent the most plastic cell type found in the retina. Following injury, zebrafish and avian MGCs can efficiently re-enter the cell cycle, proliferate and generate new functional neurons. The regenerative potential of mammalian MGCs, however, is very limited. Here, we showed that N methyl-d-aspartate (NMDA) damage stimulates murine MGCs to re-enter the cell cycle and de-differentiate back to a progenitor-like stage. These events are dependent on the recruitment of endogenous bone marrow cells (BMCs), which, in turn, is regulated by the stromal cell-derived factor 1 (SDF1)-C-X-C motif chemokine receptor type 4 (CXCR4) pathway. BMCs mobilized into the damaged retina can fuse with resident MGCs, and the resulting hybrids undergo reprogramming followed by re-differentiation into cells expressing markers of ganglion and amacrine neurons. Our findings constitute an important proof-of-principle that mammalian MGCs retain their regenerative potential, and that such potential can be activated via cell fusion with recruited BMCs. In this perspective, our study could contribute to the development of therapeutic strategies based on the enhancement of mammalian endogenous repair capabilities. PMID- 29525575 TI - Signal propagation along the axon. AB - Axons link distant brain regions and are usually considered as simple transmission cables in which reliable propagation occurs once an action potential has been generated. Safe propagation of action potentials relies on specific ion channel expression at strategic points of the axon such as nodes of Ranvier or axonal branch points. However, while action potentials are generally considered as the quantum of neuronal information, their signaling is not entirely digital. In fact, both their shape and their conduction speed have been shown to be modulated by activity, leading to regulations of synaptic latency and synaptic strength. We report here newly identified mechanisms of (1) safe spike propagation along the axon, (2) compartmentalization of action potential shape in the axon, (3) analog modulation of spike-evoked synaptic transmission and (4) alteration in conduction time after persistent regulation of axon morphology in central neurons. We discuss the contribution of these regulations in information processing. PMID- 29525576 TI - Use of the LUS in sequence allele designations to facilitate probabilistic genotyping of NGS-based STR typing results. AB - Some of the expected advantages of next generation sequencing (NGS) for short tandem repeat (STR) typing include enhanced mixture detection and genotype resolution via sequence variation among non-homologous alleles of the same length. However, at the same time that NGS methods for forensic DNA typing have advanced in recent years, many caseworking laboratories have implemented or are transitioning to probabilistic genotyping to assist the interpretation of complex autosomal STR typing results. Current probabilistic software programs are designed for length-based data, and were not intended to accommodate sequence strings as the product input. Yet to leverage the benefits of NGS for enhanced genotyping and mixture deconvolution, the sequence variation among same-length products must be utilized in some form. Here, we propose use of the longest uninterrupted stretch (LUS) in allele designations as a simple method to represent sequence variation within the STR repeat regions and facilitate - in the nearterm - probabilistic interpretation of NGS-based typing results. An examination of published population data indicated that a reference LUS region is straightforward to define for most autosomal STR loci, and that using repeat unit plus LUS length as the allele designator can represent greater than 80% of the alleles detected by sequencing. A proof of concept study performed using a freely available probabilistic software demonstrated that the LUS length can be used in allele designations when a program does not require alleles to be integers, and that utilizing sequence information improves interpretation of both single-source and mixed contributor STR typing results as compared to using repeat unit information alone. The LUS concept for allele designation maintains the repeat based allele nomenclature that will permit backward compatibility to extant STR databases, and the LUS lengths themselves will be concordant regardless of the NGS assay or analysis tools employed. Further, these biologically based, easy-to derive designations uphold clear relationships between parent alleles and their stutter products, enabling analysis in fully continuous probabilistic programs that model stutter while avoiding the algorithmic complexities that come with string based searches. Though using repeat unit plus LUS length as the allele designator does not capture variation that occurs outside of the core repeat regions, this straightforward approach would permit the large majority of known STR sequence variation to be used for mixture deconvolution and, in turn, result in more informative mixture statistics in the near term. Ultimately, the method could bridge the gap from current length-based probabilistic systems to facilitate broader adoption of NGS by forensic DNA testing laboratories. PMID- 29525574 TI - Basolateral amygdala circuitry in positive and negative valence. AB - All organisms must solve the same fundamental problem: they must acquire rewards and avoid danger in order to survive. A key challenge for the nervous system is therefore to connect motivationally salient sensory stimuli to neural circuits that engage appropriate valence-specific behavioral responses. Anatomical, behavioral, and electrophysiological data have long suggested that the amygdala plays a central role in this process. Here we review experimental efforts leveraging recent technological advances to provide previously unattainable insights into the functional, anatomical, and genetic identity of neural populations within the amygdala that connect sensory stimuli to valence-specific behavioral responses. PMID- 29525577 TI - Cost-effectiveness analysis of intensive hypertension control in China. AB - China has the largest population of adults with hypertension in the world. Recent clinical trials have shown that intensive hypertension control can help patients achieve lower blood pressure and reduce the incidence of major cardiovascular disease (CVD) events, but this level of hypertension control also incurs additional costs to patients and society and may result in a substantial increase in adverse events. The objective of this study is to assess the cost effectiveness of intensive hypertension control to inform health policymakers and health care delivery systems in China in their decision-making regarding hypertension treatment strategies. We developed a Markov based simulation model of hypertension to assess the impact of intensive and standard hypertension control strategies for the Chinese population who are diagnosed with hypertension. Model parameters were estimated based on the best available data and the literature. We projected that intensive hypertension control would avert about 2.2 million coronary heart disease events and 4.4 million stroke events for all hypertensive patients in China in 10 years compared to standard hypertension control. The incremental cost-effectiveness ratio (ICER) for intensive hypertension control was estimated at 7876 CNY per quality-adjusted life year (QALY) compared to standard hypertension control. Intensive hypertension control would be more cost-effective than standard hypertension control in China. Our findings indicated that China should consider expanding intensive hypertension control among hypertensive patients given its great potential in preventing CVD. PMID- 29525579 TI - The application of frontal sinus index and frontal sinus area in sex estimation based on lateral cephalograms among Han nationality adults in Xinjiang. AB - The frontal sinus, due to its unique anatomical features, has become an important element in research for individual identification. Previous studies have demonstrated the use of frontal sinus as an indicator for sex discrimination; however, the sex discrimination rate using frontal sinus was lower compared to that using the traditional morphological methods. In order to improve the sex discrimination percentage, we developed a new method involving the measurement of the frontal sinus index and frontal sinus area from lateral cephalogram radiographs. In this study, 475 digital lateral cephalograms of adult Han citizens from Xinjiang were included. The maximum height, depth, and area of the frontal sinus were calculated using the NemoCeph NX software. The frontal sinus index (ratio of the maximum height to the depth of frontal sinus) was also computed. Statistical analysis results showed significant differences in the frontal sinus index and area between males and females. Discriminant function equation derived from this study differentiated between sexes with 76.6% accuracy. The results demonstrated that the use of frontal sinus index and area for sex discrimination was more accurate than using the frontal sinus index alone. PMID- 29525578 TI - Taking on the stress-depression link: Meaning as a resource in adolescence. AB - We investigated how meaning in life affects the link between stress and depression symptoms in adolescents. Adolescents (N = 177; 58.4% female, mean age = 14.75 years) reported on their meaning in life, exposure to stressors, and depression symptomatology. Higher meaning in life predicted lower depression symptoms. Importantly, meaning in life moderated the relationship between stress exposure and depressive symptoms: stress exposure was associated with higher depression when meaning in life was low, when meaning in life was high, there was no association between stressors and depression. These findings indicate the importance of having a sense of meaning in life adolescence. A positive relationship was found between stress exposure and depression symptomatology levels at a time-point seven months earlier. This lends a longitudinal perspective; meaning in life moderated a relationship that had been present for seven months. Therapeutic implications for protecting at-risk youth are discussed. PMID- 29525580 TI - Paraphilic infantilism, diaperism and pedophilia: A review. AB - Paraphilic disorders range from nearly normal behaviour to a behaviour which may be considered as destructive or menacing to the society at large. In accordance with Diagnostic and Statistical Manual of Mental Disorders-V, the terms Paraphilia and Paraphilic disorders, denote different interpretations. Multiple paraphilias connected to childhood either directly or indirectly has been documented in scientific literature. Paraphilic Infantilism, Diaperism and Pedophilia constitute major portion among them. Paraphilic infantilism denotes paraphilic desire of being a baby. Diaperism deals with fetishistic behaviour in relation to diapers and pedophilia stands for sexual attraction towards children. Behaviourally these three paraphilias do share some characteristics and show overlapping of certain features, but psychologically they are diverse. In a number of literature on digital media, the terms have been used interchangeably or are described in a manner that creates confusion. However, when described individually they are precisely written, hence it necessitates to be elaborated collectively to surpass the current trends of mixing them. The review focuses on behavioral, developmental, psychological and legal aspects of these paraphilias. PMID- 29525581 TI - Paraquat poisoning calls to the Malaysia National Poison Centre following its ban and subsequent restriction of the herbicide from 2004 to 2015. AB - This study analyses the incidences and patterns of paraquat poisoning from calls received at the Malaysia National Poison Centre (NPC) since 2004 following the ban of the herbicide (2004-2006) and subsequent restriction up to year 2015. Related reported cases to the centre over twelve years (2004-2015) were retrieved and studied in respect to socio-demographic characteristics, mode and type of poisonings, exposure routes and location of incident. Ages of poisoned victims range from 10 months old to 98 years with males being intoxicated more frequently than females (ratio male to female = 2.7). The age group mainly involved in the poisoning was 20-39 years. The most common mode was intentional (62.8%) followed by unintentional (36.9%). Among the 1232 reported cases, suicidal poisoning was the highest (57.2%); accidental poisoning (30.8%) and occupational poisoning (3.3%). The findings showed an upward trend of suicidal poisoning over the years, clearly emphasizing the need for more stringent and effective enforcement to ensure the safe use of paraquat. PMID- 29525582 TI - Annual variation in decomposition and insect succession at a periurban area of central Iberian Peninsula. AB - The variation in decomposition and insect succession among the four seasons of one year was studied for the first time in a periurban area of central Spain. During the winter trial, the carcasses showed corification, a cadaveric preservation phenomenon which apparently leaded to a significant delay in decomposition processes. The composition of the insect fauna breeding on carcasses changed significantly between trials. Active decay was mainly driven by Calliphoridae (Diptera) larvae in every season except in winter trial, when larvae of Thanatophilus species (Coleoptera: Silphidae) were the main consumers of soft tissues. Advanced decay was characterized by the occurrence of Dermestidae, Silphidae, Cleridae, Nitidulidae (Coleoptera) and Piophilidae (Diptera) larvae. Differences in the species composition in comparison with other regions of the Iberian Peninsula were also observed. The current paper provides baseline and preliminary information on the insect succession on carrion in central Spain, as well as a starting point for further research on forensic entomology in this region. PMID- 29525583 TI - A comparative analysis of suicides in Greece's main port city area of Piraeus before (2006-2010) and during (2011-2015) the country's severe economic crisis. AB - We investigated all cases of completed suicide in the city area of Piraeus -the largest port in Greece- for the years 2006 up to 2015. We searched, among others, parameters regarding the victims' psychiatric medication intake and drug and alcohol use that -to the best of our knowledge- had never been investigated before by a study on suicides in Greece within the crisis' years. We documented variations before (2006-2010) and during (2011-2015) crisis. Information was provided by the victims' forensic records at the Piraeus Department of Forensic Medicine. During the period of the study 435 individuals died by suicide. "Before" crisis: 227 cases, 77,1% males, mean age 48.6 years (SD:19.8), 85% Greek. "During": 208 cases, 79,8% males, mean age 51.4 years (SD:17.7), 83.2% Greek. Psychiatric medication intake: "Before"-"During": 16.3%-29.8% (p=0.003), males: 16.1%-31.7%, females: 19.6%-27.5% (p=0.003). Drug use: opioids 2.7%(5.5%), cannabis 1.4%(5.5%), cocaine 0(1.5%), alcohol 14.5%(13.4%). Significant seasonality was observed only for suicides by jumping with a peak late in the month of July in the "Before" group. There were no significant differences regarding suicide method, place of suicide or place of death. The slight decrease in suicides within the crisis' years, together with the higher medication intake observed within the same period, could imply that more individuals were willing to accept their psychological difficulties and/or to commence treatment. Probably the stigma of psychiatric illness is somewhat lower after the beginning of the crisis and/or non-psychiatrists became more aware of the psychological origins of some of their patients' problems. Our findings tentatively suggest that, as the crisis persists, adaptive mechanisms have been set in motion. PMID- 29525584 TI - Unusual head injury by a forklift vehicle. AB - A case of an unusual head injury by a forklift vehicle is presented. PMID- 29525585 TI - Hypothalamus-Pituitary-Adrenal-axis activity and cognitive functioning in older adults. AB - Inconsistent results are found in the involvement of the Hypothalamus-Pituitary Adrenal (HPA)-axis in cognitive functioning. This study examined the association between various saliva cortisol measures (the 1-h awakening cortisol, evening cortisol, diurnal change, and cortisol suppression) and cognitive functioning (episodic memory, processing speed, interference control, and working memory). Participants were older adults, between 60 and 93 years with (N = 328) and without (N = 119) a depressive disorder from the Netherlands Study of Depression in Older adults. No significant associations between cortisol and cognitive functioning were observed in the total sample. Only in non-depressed older adults, higher total cortisol secretion over the first hour after awakening and worse episodic memory, higher cortisol levels at awakening and better working memory, and higher diurnal change and better processing speed were significantly associated. Cortisol was not associated with cognitive functioning in depressed older adults. In older adults, the association between depression and cognitive functioning is likely the consequence of other biological or psychological mechanisms. PMID- 29525586 TI - Depressive symptoms in obesity: Relative contribution of low-grade inflammation and metabolic health. AB - BACKGROUND: Recent reports suggest that the risk of depressive symptoms in obesity is potentiated in subjects presenting a metabolically unhealthy phenotype. Inflammation is often considered a defining criteria of metabolic health. However, this factor may drive the association of metabolic health with depressive symptoms given its well-known role in the pathophysiology of depression. This study aimed at determining the relative contribution of inflammation and metabolic abnormalities to depressive symptoms in obesity. METHODS: One-hundred severely obese adults (BMI >= 35-40 kg/m2) and 25 non-obese control individuals (BMI < 30 kg/m2) were recruited. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and Mini International Neuropsychiatric Interview (MINI). Serum high-sensitive C-reactive protein (hs-CRP) was measured as a marker of systemic inflammation. Metabolically unhealthy obesity was defined as obesity associated with two or more metabolic alterations, including low high-density lipoprotein cholesterol, hypertriglyceridemia, high fasting glucose and hypertension. RESULTS: Total MADRS scores were significantly higher in obese subjects with significant inflammation (hs-CRP >= 5 mg/L) compared to those with low inflammation (hs-CRP < 5 mg/L) and non-obese controls. Interestingly, hs-CRP levels significantly predicted MADRS scores in the whole population under study and in the group of obese subjects. Overall, no association was found between MADRS scores and individual metabolic alterations or the composite measure of metabolically unhealthy obesity. Similarly, the association of hs-CRP with MADRS scores in obese patients was not modulated by metabolic health factors. CONCLUSIONS: These results indicate that systemic inflammation represents a stronger contributor of obesity-related depressive symptoms than metabolic health per se. This supports the notion that inclusion of inflammation in the definition of metabolically unhealthy obesity drives the association found between poor metabolic health and depressive symptoms. PMID- 29525587 TI - Impacts of zero valent iron, natural zeolite and Dnase on the fate of antibiotic resistance genes during thermophilic and mesophilic anaerobic digestion of swine manure. AB - This study investigated the fate of antibiotic resistance genes (ARGs) during mesophilic (mAD) and thermophilic digestion (tAD) of swine manure through zero valent iron (ZVI), natural zeolite and Dnase addition. Changes of microbial community, intI1, heavy metal resistance genes (MRGs) and virulence factors (VFs) were followed to clarify the influencing factors to ARGs reduction. Results showed that AD could realize ARGs reduction with tAD superior to mAD, and ZVI and natural zeolite could further enhance the reduction, especially for natural zeolite addition at mAD. The reduction efficiency of the relative abundance of ARGs was increased by 33.3% and 138.5% after ZVI and natural zeolite addition, respectively, but Dnase deteriorated ARGs reduction at mAD. Most of ARGs could be reduced effectively except sulII and tetM. Network analysis and partial redundancy analysis indicated that co-occurrence of MRGs followed by microbial community contributed the most to the variation of ARGs fate among treatments. PMID- 29525588 TI - Evaluation of process performance, energy consumption and microbiota characterization in a ceramic membrane bioreactor for ex-situ biomethanation of H2 and CO2. AB - The performance of a pilot ceramic membrane bioreactor for the bioconversion of H2 and CO2 to bioCH4 was evaluated in thermophilic conditions. The loading rate was between 10 and 30 m3 H2/m3reactor d and the system transformed 95% of H2 fed. The highest methane yield found was 0.22 m3 CH4/m3 H2, close to the maximum stoichiometric value (0.25 m3 CH4/m3 H2) thus indicating that archaeas employed almost all H2 transferred to produce CH4. kLa value of 268 h-1 was reached at 30 m3 H2/m3reactor d. DGGE and FISH revealed a remarkable archaeas increase related to the selection-effect of H2 on community composition over time. Methanothermobacter thermautotrophicus was the archaea found with high level of similarity. This study verified the successful application of membrane technology to efficiently transfer H2 from gas to the liquid phase, the development of a hydrogenotrophic community from a conventional thermophilic sludge and the technical feasibility of the bioconversion. PMID- 29525589 TI - Computational Fluid Dynamics simulation of hydrothermal liquefaction of microalgae in a continuous plug-flow reactor. AB - Computational Fluid Dynamics (CFD) technique is used in this work to simulate the hydrothermal liquefaction of Nannochloropsis sp. microalgae in a lab-scale continuous plug-flow reactor to understand the fluid dynamics, heat transfer, and reaction kinetics in a HTL reactor under hydrothermal condition. The temperature profile in the reactor and the yield of HTL products from the present simulation are obtained and they are validated with the experimental data available in the literature. Furthermore, the parametric study is carried out to study the effect of slurry flow rate, reactor temperature, and external heat transfer coefficient on the yield of products. Though the model predictions are satisfactory in comparison with the experimental results, it still needs to be improved for better prediction of the product yields. This improved model will be considered as a baseline for design and scale-up of large-scale HTL reactor. PMID- 29525590 TI - Hydrothermal liquefaction of high- and low-lipid algae: Mass and energy balances. AB - Hydrothermal liquefaction (HTL) of high-lipid microalgae Nannochloropsis salina (N. salina) and low-lipid microalgae Galdieria sulphuraria (G. sulphuraria) were run under subcritical conditions (310-350 degrees C and 10-17 MPa) in a 1.8 L batch autoclave system. HTL mass and energy balances for both species were compared under different operating conditions to predict the optimum reaction conditions for new algae strains based on their feedstock composition. Bio-crude oils and chars were characterized by bomb calorimetry, elemental analysis, inductively coupled plasma optical emission spectrometry (ICP-OES), and thermogravimetric analysis (TGA). Under the optimized conditions, 59 wt% and 31 wt% bio-crude oil yields were obtained from HTL of N. salina and G. sulphuraria, while 85% and 59% of the feedstock energy were partitioned into N. salina-derived and G. sulphuraria-derived bio-crude oils, respectively. More favorable energy balances were related to shorter reaction times and higher algal solid contents. PMID- 29525591 TI - Performance and microbial community analysis of bio-electrocoagulation on simultaneous nitrification and denitrification in submerged membrane bioreactor at limited dissolved oxygen. AB - A pair of Fe-C electrodes was installed in a traditional submerged membrane bioreactor (MBR, Rc), and a novel asynchronous periodic reversal bio electrocoagulation system (Re) was developed. The simultaneous nitrification and denitrification (SND) performance was discussed under limited dissolved oxygen (DO). Results showed that electrocoagulation enhanced total nitrogen (TN) removal from 59.48% to 75.09% at 1.2 mg/L DO. Additionally, Fe electrode could increase sludge concentration, particle size, and enzyme activities related to nitrogen removal. The enzyme activities of Hydroxylamine oxidoreductase (HAO), Nitrate Reductase (NAR), nitric oxide reductase NOR and nitrous oxide reductase (N2OR) in Re were 38.35%, 21.59%, 89.96% and 38.64% higher than Rc, respectively. Moreover, electrocoagulation was advantageous for nitrite accumulation, indicating partial nitrification and denitrification were more easily achieved in Re. Besides, results from high throughput sequencing analysis revealed that electrocoagulation increased the relative abundance of most genera related to nitrogen removal, including Nitrosomonas, Comamonadaceae_unclassified, Haliangium and Denitratisoma. PMID- 29525592 TI - Influence of electric field and iron on the denitrification process from nitrogen rich wastewater in a periodic reversal bio-electrocoagulation system. AB - This study proposed a periodic reversal bio-electrocoagulation system (PRBES) with Fe-C electrodes and three other control systems and explored their denitrification mechanism. The experimental results illustrated that iron ions contributed to increasing biomass and denitrifying bacteria and that the electric field may enhance the nitrogen transfer rate and enzyme activities. The dominant bacterial genera in the four systems were the Enterobacter (32.75%), Thauera (9.29%), Paracoccus (8.54%), Hyphomicrobium (5.01%) and Saccharibacteria_genera (10.57%). The sum of the relative abundance of the first four bacteria, which were the major microorganisms in the denitrification process in this study, was 64.61%, 55.40%, 61.19% and 47.08%, respectively, in PRBES and the three other control systems at 10 degrees C. Additionally, compared to the conventional SBR, there was a 65.48% decrease in N2O in PRBES at 10 degrees C. This study provided a meaningful and significant understanding of denitrification in PRBES when treating nitrogen-rich wastewater. PMID- 29525593 TI - Microbial community evolution of black and stinking rivers during in situ remediation through micro-nano bubble and submerged resin floating bed technology. AB - Microbes play important roles during river remediation and the interaction mechanism illustration between microorganisms and sewage is of great significance to improve restoration technology. In this study, micro-nano bubble and submerged resin floating bed composite technology (MBSR) was firstly used to restore two black and stinking urban rivers. After restoration, the water pollution indices such as dissolved oxygen (DO), ammonia nitrogen (NH4+-N), total phosphorous (TP), chemical oxygen demand (CODCr), water clarity, and the number of facial coliform were significantly improved. Microbial community composition and relative abundance both varied and more aerobic microbes emerged after remediation. The microbial changes showed correlation with DO, NH4+-N, TP and CODCr of the rivers. In summary, the MBSR treatment improved the physiochemical properties of the two black and stinking urban rivers probably through oxygen enrichment of micro-nano bubble and adsorption of submerged resin floating bed, which thereby stimulated functional microbes to degrade pollutants. PMID- 29525594 TI - Improvement of biochar and bacterial powder addition on gaseous emission and bacterial community in pig manure compost. AB - Effect of bamboo biochar (BC) combined with two bacterial powders (B) on gaseous emission and variety of bacterial community during pig manure (PM) composting was investigated. The results showed that treatments of BC, BC + B1 and BC + B2 can reduce peak gaseous emission by 54%, 80% and 69% for CH4, respectively, while 37%, 45% and 45% for N2O, respectively, and 13%, 19% and 26% for NH3, respectively. The evolution of the bacterial community quantified with 16S rDNA analysis showed that in the thermophile stage, total relative abundance percentage of bacterial phyla of Firmicutes and Proteobacteria reached 97%, 97%, 93% and 96% for CK, BC, BC + B1 and BC + B2, respectively. Effects of BC on the compost bacterial community variation analysis proved bacterial activity in the thermophile stage was controlled by the content of dissolved organic carbon and temperature of the compost mixture, while electrical conductivity and total kjeldahl nitrogen also influenced compost maturity stage. PMID- 29525595 TI - Spontaneous and applied potential driven indium recovery on carbon electrode and crystallization using a bioelectrochemical system. AB - Indium removal and recovery on a carbon electrode under a microbial fuel cell (MFC)-based oxidation/reduction reaction were examined using synthetic wastewater. More than 90% of In3+ ions were removed after continuous operation of the MFC for 14 days with an average current generation of ~50 MUA. During operation, indium particulates formed on the cathode carbon electrode. Scanning electron microscopy equipped with X-ray energy dispersive spectroscopy showed that they were composed of amorphous and crystalline indium hydroxides (In(OH)3 and In(OH).H2O). When the current flow was reversed to drive the oxidation of the particles to recover the indium from indium hydroxides, a few indium oxide (In2O3) nanocrystals with a rectangular platelet shape formed on the electrode, while the majority of the amorphous and crystalline indium hydroxides re dissolved into the aqueous environment. Overall, these results demonstrate a feasible route towards the MFC-based recovery of indium with the simultaneous generation of bioelectricity. PMID- 29525596 TI - Effect of temperature on microbial diversity and nitrogen removal performance of an anammox reactor treating anaerobically pretreated municipal wastewater. AB - The effects of temperature reduction (from 35 degrees C to 20 degrees C) on nitrogen removal performance and microbial diversity of an anammox sequencing batch reactor were evaluated. The reactor was fed for 148 days with anaerobically pretreated municipal wastewater amended with nitrite. On average, removal efficiencies of ammonium and nitrite were high (96%) during the enrichment period and phases 1 (at 35 degrees C) and 2 (at 25 degrees C), and slightly decreased (to 90%) when the reactor was operated at 20 degrees C. Deep sequencing analysis revealed that microbial community structure changed with temperature decrease. Anammox bacteria (Ca. Brocadia and Ca. Anammoximicrobium) and denitrifiers (Burkholderiales, Myxococcales, Rhodocyclales, Xanthomonadales, and Pseudomonadales) were favoured when the temperature was lowered from 35 degrees C to 25 degrees C, while Anaerolineales and Clostridiales were negatively affected. The results support the feasibility of using the anammox process for mainstream nitrogen removal from anaerobically pretreated municipal wastewater at typical tropical temperatures. PMID- 29525597 TI - Mitigation of membrane biofouling by a quorum quenching bacterium for membrane bioreactors. AB - In this study, a quorum-quenching (QQ) bacterium named HEMM-1 was isolated at a membrane bioreactor (MBR) plant. HEMM-1 has diplococcal morphology and 99% sequence identity to Enterococcus species. The HEMM-1 cell-free supernatant (CFS) showed higher QQ activities than the CFS of other QQ bacteria, mostly by degrading N-acyl homoserine lactones (AHLs) with short acyl chains. Instrumental analyses revealed that HEMM-1 CFS degraded AHLs via lactonase activity. Under static, flow, and shear conditions, the HEMM-1 CFS was effective in reducing bacterial and activated-sludge biofilms formed on membrane surfaces. In conclusion, the HEMM-1 isolate is a QQ bacterium applicable to the control of biofouling in MBRs via inhibition of biofilm formation on membrane surfaces. PMID- 29525598 TI - Elimination of pyraclostrobin by simultaneous microbial degradation coupled with the Fenton process in microbial fuel cells and the microbial community. AB - The elimination of pyraclostrobin by simultaneous microbial degradation and Fenton oxidation was achieved in a microbial fuel cell (MFC) system. After 12 h of incubation, the removal rate of pyraclostrobin was 1.4 mg/L/h at the anode and 1.7 mg/L/h at the cathode. The pyraclostrobin concentration was less than the detection limit (0.1 mg/L) after 72 h at the anode and 24 h at the cathode. The air flow rate, temperature, and pH of the catholyte had significant effects on the generation of H2O2. The maximum production of H2O2 was 1.2 mg/L after reaction for 20 h during the Fenton process. Microbial community analysis indicated that functional bacteria in the genera Chryseobacterium, Stenotrophomonas, Arcobacter, and Comamonas were predominant in the anodic biofilm. In conclusion, the MFC-Fenton system provides an effective approach for treating environmental contaminants. PMID- 29525599 TI - Optimized co-production of lipids and carotenoids from Ettlia sp. by regulating stress conditions. AB - This study used a single strain Ettlia sp. YC001 and two stages to optimize the production of three materials: lipids, lutein, and beta-carotene. In the cultivation stage for lutein production, different temperatures, light qualities, and intensities were applied. The highest biomass was obtained at 35 degrees C, but the maximum lutein productivity of 6.1 mg/L/d achieved at 25 degrees C. In the stress stage for lipids and beta-carotene production, UV-A and nitrogen starvation were applied. While UV stress increased the chlorophyll-a and beta carotene content. The beta-carotene, oleic acid, and lipids significantly increased under nitrogen starvation with a high light intensity of 1200 umol/m2/s, plus the Ettlia sp. changed from green to red. The results showed that Ettlia sp. can be an effective microalga for the co-production of lutein, beta carotene, and biodiesel. PMID- 29525600 TI - An autologous tumor vaccine for CLL. AB - Chronic Lymphocytic Leukemia B cells (CLL) are malignant cells which retain at least some functions of normal B cells. Paramount amongst the latter is that when such cells are appropriately stimulated, they are able to present antigens, including any potential tumor antigens, making them excellent choices as a candidate tumor vaccine. We show that following stimulation of CLL cells with Phorbol myristic acetate, IL-2, the TLR7 agonist imiquimod (P2I) and ionomycin (P2Iio), markedly increased expression of CD54 and CD83 was seen, indicative of B cell activation and a transition to antigen-presenting cells. However, this occurred in the context of augmented expression of the known immunoregulatory molecule, CD200. Accordingly we explored the effect of stimulation of CLL cells with P2Iio, followed by coating of cells with a non-depleting anti-CD200mAb, on the ability of those cells to immunize PBL in vitro to become cytotoxic to CLL cells, or to protect NOD-SCIDgammacnull (NSG) mice from subsequent CLL tumor challenge. Our data indicate that this protocol is effective in inducing CD8+ CTL able to lyse CLL cells in vitro, and decrease tumor burden in vivo in spleen and marrow of mice injected with CLL cells. Pre-treatment of mice with a CD8 depleting antibody before vaccination with P2Iio/anti-CD200 coated cells abolished any protection seen. These data suggest a potential role for blockade of CD200 expression on CLL cells as a component of a tumor vaccination strategy. PMID- 29525601 TI - Functional brain connectivity when cooperation fails. AB - Functional connectivity during cooperative actions is an important topic in social neuroscience that has yet to be answered. Here, we examined the effects of administration of (fictitious) negative social feedback in relation to cooperative capabilities. Cognitive performance and neural activation underlying the execution of joint actions was recorded with functional near-infrared spectroscopy (fNIRS) on prefrontal regions during a task where pairs of participants received negative feedback after their joint action. Performance (error rates (ERs) and response times (RTs)) and intra- and inter-brain connectivity indices were computed, along with the ConIndex (inter-brain/intra brain connectivity). Finally, correlational measures were considered to assess the relation between these different measures. Results showed that the negative feedback was able to modulate participants' responses for both behavioral and neural components. Cognitive performance was decreased after the feedback. Moreover, decreased inter-brain connectivity and increased intra-brain connectivity was induced by the feedback, whereas the cooperative task pre feedback condition was able to increase the brain-to-brain coupling, mainly localized within the dorsolateral prefrontal cortex (DLPFC). Finally, the presence of significant correlations between RTs and inter-brain connectivity revealed that ineffective joint action produces the worst cognitive performance and a more 'individual strategy' for brain activity, limiting the inter-brain connectivity. The present study provides a significant contribution to the identification of patterns of intra- and inter-brain functional connectivity when negative social reinforcement is provided in relation to cooperative actions. PMID- 29525603 TI - Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS. AB - Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-kappaB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio sensitization by melatonin may have clinical benefits in thyroid cancer. PMID- 29525605 TI - Treatment and clinical outcomes of elderly idiopathic membranous nephropathy: A multicenter cohort study in Korea. AB - Idiopathic membranous nephropathy (MN) is the most common glomerulonephritis in elderly patients showing nephrotic syndrome. However, little is known about its treatment options and outcomes in elderly MN patients at long term follow-up. We retrospectively enrolled patients with biopsy-proven MN between April 1990 and December 2015 from eight tertiary hospitals in Korea. Among them, we excluded patients who had secondary causes of MN and subnephrotic-range proteinuria. We evaluated the presenting features and clinical outcomes and analyzed the all cause mortality, renal outcomes, infection, and remission with respect to age. During the median follow-up at 77.2 months, 198 younger patients (<65 years) and 133 elderly patients (>=65 years) were enrolled. Age was an independent risk factor for all-cause mortality, renal outcome, and infection (for all P < 0.05) except remission. In elderly patients, there was no significant factor associated with mortality rate. The use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) was significantly associated with renal outcome and infection (renal outcome, hazard ration [HR] 0.06, 95% confidence intervals [CI] 0.01-0.36, P = 0.003; infection, HR 0.20, 95% CI 0.04-0.94, P = 0.041). Immunosuppressant therapy significantly increased renal outcome (P = 0.045) and infection (P = 0.029) compared with conservative therapy. In conclusion, old age is one of the clinically important predictors for MN patients. Among the treatment of elderly MN patients, only ACEI or ARB was associated with beneficial effects on renal outcome and infection. Elderly MN patients need a more tailored regimen considering their comorbidities and condition. PMID- 29525604 TI - Astroglial DJ-1 over-expression up-regulates proteins involved in redox regulation and is neuroprotective in vivo. AB - DJ-1, a Parkinson's disease-associated protein, is strongly up-regulated in reactive astrocytes in Parkinson's disease. This is proposed to represent a neuronal protective response, although the mechanism has not yet been identified. We have generated a transgenic zebrafish line with increased astroglial DJ-1 expression driven by regulatory elements from the zebrafish GFAP gene. Larvae from this transgenic line are protected from oxidative stress-induced injuries as caused by MPP+, a mitochondrial complex I inhibitor shown to induce dopaminergic cells death. In a global label-free proteomics analysis of wild type and transgenic larvae exposed to MPP+, 3418 proteins were identified, in which 366 proteins were differentially regulated. In particular, we identified enzymes belonging to primary metabolism to be among proteins affected by MPP+ in wild type animals, but not affected in the transgenic line. Moreover, by performing protein profiling on isolated astrocytes we showed that an increase in astrocytic DJ-1 expression up-regulated a large group of proteins associated with redox regulation, inflammation and mitochondrial respiration. The majority of these proteins have also been shown to be regulated by Nrf2. These findings provide a mechanistic insight into the protective role of astroglial up-regulation of DJ-1 and show that our transgenic zebrafish line with astrocytic DJ-1 over-expression can serve as a useful animal model to understand astrocyte-regulated neuroprotection associated with oxidative stress-related neurodegenerative disease. PMID- 29525606 TI - Nursing students' perceptions of a collaborative clinical placement model: A qualitative descriptive study. AB - Clinical placements are specifically designed to facilitate authentic learning opportunities and are an integral component of undergraduate nursing programs. However, as academics and clinicians frequently point out, clinical placements are fraught with problems that are long-standing and multidimensional in nature. Collaborative placement models, grounded in a tripartite relationship between students, university staff and clinical partners, and designed to foster students' sense of belonging, have recently been implemented to address many of the challenges associated with clinical placements. In this study a qualitative descriptive design was undertaken with the aim of exploring 14 third year third year nursing students' perceptions of a collaborative clinical placement model undertaken in an Australian university. Students participated in audio recorded focus groups following their final clinical placement. Thematic analysis of the interview data resulted in identification of six main themes: Convenience and Camaraderie, Familiarity and Confidence, Welcomed and Wanted, Belongingness and Support, Employment, and The Need for Broader Clinical Experiences. The clinical collaborative model fostered a sense of familiarity for many of the participants and this led to belongingness, acceptance, confidence and meaningful learning experiences. PMID- 29525607 TI - Raspberry promotes brown and beige adipocyte development in mice fed high-fat diet through activation of AMP-activated protein kinase (AMPK) alpha1. AB - Development of brown and beige/brite adipocytes increases thermogenesis and helps to reduce obesity and metabolic syndrome. Our previous study suggests that dietary raspberry can ameliorate metabolic syndromes in diet-induced obese mice. Here, we further evaluated the effects of raspberry on energy expenditure and adaptive thermogenesis and determined whether these effects were mediated by AMP activated protein kinase (AMPK). Mice deficient in the catalytic subunit of AMPKalpha1 and wild-type (WT) mice were fed a high-fat diet (HFD) or HFD supplemented with 5% raspberry (RAS) for 10 weeks. The thermogenic program and related regulatory factors in adipose tissue were assessed. RAS improved the insulin sensitivity and reduced fat mass in WT mice but not in AMPKalpha1-/- mice. In the absence of AMPKalpha1, RAS failed to increase oxygen consumption and heat production. Consistent with this, the thermogenic gene expression in brown adipose tissue and brown-like adipocyte formation in subcutaneous adipose tissue were not induced by RAS in AMPKalpha1-/- mice. In conclusion, AMPKalpha1 is indispensable for the effects of RAS on brown and beige/brite adipocyte development, and prevention of obesity and metabolic dysfunction. PMID- 29525608 TI - Beneficial effects of white wine polyphenols-enriched diet on Alzheimer's disease like pathology. AB - The development of effective medicines to break or delay the progressive brain degeneration underlying cognitive decline and dementia that characterize Alzheimer's disease (AD) is one of the greatest challenges of our time. In the present work, a selective pool of polyphenols, obtained from the white wine by adsorption to polyvinylpyrrolidone polymer (PVPP), was used to prepare a polyphenols-enriched diet, supplementing the drinking water with 100 mg/L (expressed as gallic acid equivalent) of wine polyphenolic extract. The impact of the daily consumption of water supplemented with polyphenols for 2 months on brain of 10-month-old 3xTg-AD and NonTg mice was evaluated, considering effects on the redox state of cells, levels of amyloid-beta peptides, mitochondrial bioenergetics and fatty acid profile of whole membrane phospholipids. The polyphenols-enriched diet promotes brain accumulation of catechin and hydroxybenzoic acid derivatives, and modulates the redox state of 3xTg-AD brain cells, increasing both glutathione/glutathione disulfide ratio and catalase activity and decreasing membrane lipids oxidation. Additionally, the functional diet decreases the 3xTg-AD brain levels of both amyloid-beta peptides, Abeta1-40 and Abeta1-42. However, the brain mitochondrial bioenergetic dysfunction of 3xTg AD animals was not attenuated by the polyphenols-enriched diet. Lipidomic studies showed that this functional diet modulates membrane lipid composition of brain cells, increasing C22:6n-3 (docosahexanoic acid) and decreasing C20:4n-6 (arachidonic acid) levels, which may have beneficial impact on the chronic inflammatory process associated with AD pathology. Altogether, these results indicate that the oral administration of this polyphenols-enriched diet promotes significant benefits in multiple aspects of the pathophysiological cascade associated with the neuropathology developed by 3xTg-AD mice. PMID- 29525609 TI - Differential effect of dietary vitamin D supplementation on natural killer cell activity in lean and obese mice. AB - Vitamin D has an immunoregulatory effect on both innate and adaptive immunity. Contradictory results regarding vitamin D and natural killer (NK) cell functions have been reported with in vitro studies, but little is known about this in vivo. We investigated whether vitamin D levels (50, 1000 or 10,000 IU/kg of diet: DD, DC or DS) affect NK cell functions in mice fed a control or high-fat diet (10% or 45% kcal fat: CD or HFD) for 12 weeks. The splenic NK cell activity was significantly higher in the CD-DS group than the HFD-DS group, and the CD-DS group showed significantly higher NK cell activity compared with the CD-DD and CD DC groups. However, no difference in NK cell activity was observed among the HFD groups fed different levels of vitamin D. The splenic population of NK cells was significantly higher in the CD-DS group than the HFD-DS group. There was no difference in the intracellular expression of IFN-gamma and the surface expression of NKG2D and CD107a in NK cells by both dietary fat and vitamin D content. The splenic mRNA expression of Ifng and Ccl5 was significantly lower in the HFD groups compared with the CD groups, but there was no difference in the mRNA levels of Vdup1 and Vdr among the groups. Taken together, these results suggest that dietary vitamin D supplementation can modulate innate immunity by increasing NK activity in control mice but not in obese mice. This effect might be mediated through alternation of the splenic NK cell population. PMID- 29525610 TI - Arctigenin protects against steatosis in WRL68 hepatocytes through activation of phosphoinositide 3-kinase/protein kinase B and AMP-activated protein kinase pathways. AB - Arctigenin (ATG), a lignin extracted from Arctium lappa (L.), exerts antioxidant and anti-inflammatory effects. We hypothesized that ATG exerts a protective effect on hepatocytes by preventing nonalcoholic fatty liver disease (NAFLD) progression associated with lipid oxidation-associated lipotoxicity and inflammation. We established an in vitro NAFLD cell model by using normal WRL68 hepatocytes to investigate oleic acid (OA) accumulation and the potential bioactive role of ATG. The results revealed that ATG inhibited OA-induced lipid accumulation, lipid peroxidation, and inflammation in WRL68 hepatocytes, as determined using Oil Red O staining, thiobarbituric acid reactive substance assay, and inflammation antibody array assays. Quantitative RT-PCR analysis demonstrated that ATG significantly mitigated the expression of acetylcoenzyme A carboxylase 1 and sterol regulatory element-binding protein-1 and significantly increased the expression of carnitine palmitoyltransferase 1 and peroxisome proliferator-activated receptor alpha. The 40 targets of the Human Inflammation Antibody Array indicated that ATG significantly inhibited the elevation of the U937 lymphocyte chemoattractant, ICAM-1, IL-1beta, IL-6, IL-6sR, IL-7, and IL-8. ATG could activate the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK) pathways and could increase the phosphorylation levels of Akt and AMPK to mediate cell survival, lipid metabolism, oxidation stress, and inflammation. Thus, we demonstrated that ATG could inhibit NAFLD progression associated with lipid oxidation-associated lipotoxicity and inflammation, and we provided insights into the underlying mechanisms and revealed potential targets to enable a thorough understanding of NAFLD progression. PMID- 29525611 TI - Potato phenolics impact starch digestion and glucose transport in model systems but translation to phenolic rich potato chips results in only modest modification of glycemic response in humans. AB - Beneficial effects of some phenolic compounds in modulation of carbohydrate digestion and glycemic response have been reported, however effects of phenolics from processed potato products on these endpoints are not well known. The aims of this study were to characterize phenolic profiles of fresh potatoes (purple, red, or white fleshed; 2 varieties each) and chips, and to examine the potential for potato phenolic extracts (PPE) to modulate starch digestion and intestinal glucose transport in model systems. Following in vitro assessment, a pilot clinical study (n=11) assessed differences in glycemic response and gastric emptying between chips from pigmented and white potatoes. We hypothesized that phenolics from pigmented potato chips would be recovered through processing and result in a reduced acute glycemic response in humans relative to chips made from white potatoes. PPEs were rich in anthocyanins (~98, 11 and ND mg/100 g dw) and chlorogenic acids (~519, 425 and 157 mg/100 g dw) for purple, red and white varieties respectively. While no significant effects were observed on starch digestion by alpha-amylase and the alpha-glucosidases, PPEs significantly (p<0.05) decreased the rate of glucose transport, measured following transport of 1,2,3,4,5,6,6-d7 -glucose (d7-glu) across Caco-2 human intestinal cell monolayers, by 4.5-83.9%. Consistent with in vitro results, consumption of purple potato chips modestly but significantly (p<0.05) decreased blood glucose at 30 and 60 minutes post consumption compared to white chips without impacting gastric emptying. These results suggest that potato phenolics may play a modest role in modulation of glycemic response and these effects may result in subtle differences between consumer products. PMID- 29525612 TI - A novel combined interventional radiologic and hepatobiliary surgical approach to a complex traumatic hilar biliary stricture. AB - INTRODUCTION: Benign strictures of the biliary system are challenging and uncommon conditions requiring a multidisciplinary team for appropriate management. PRESENTATION OF CASE: The patient is a 32-year-old male that developed a hilar stricture as sequelae of a gunshot wound. Due to the complex nature of the stricture and scarring at the porta hepatis a combined interventional radiologic and surgical approach was carried out to approach the hilum of the right and left hepatic ducts. The location of this stricture was found by ultrasound guidance intraoperatively using a balloon tipped catheter placed under fluoroscopy in the interventional radiology suite prior to surgery. This allowed the surgeons to select the line of parenchymal transection for best visualization of the stricture. A left hepatectomy was performed, the internal stent located and the right hepatic duct opened tangentially to allow a side-to side Roux-en-Y hepaticojejunostomy (a Puestow-like anastomosis). DISCUSSION: Injury to the intrahepatic biliary ductal confluence is rarely fatal, however, the associated injuries lead to severe morbidity as seen in this example. Management of these injuries poses a considerable challenge to the surgeon and treating physicians. CONCLUSION: Here we describe an innovative multi disciplinary approach to the repair of this rare injury. PMID- 29525613 TI - Reverse Argentinean flag sign: Intraoperative complication during capsulorhexis. AB - We report a case of iatrogenic creation of an excessive anterior-to-posterior gradient in the setting of an open anterior capsule during capsulorhexis. This complication shows the inverse mechanism of that observed in the Argentinean flag sign. An excessive anterior-to-posterior gradient from an exuberant ophthalmic viscosurgical device fill of the anterior chamber caused radialization of the anterior capsule during creation of a continuous curvilinear capsulorhexis in a nonintumescent lens. We describe this complication as the reverse Argentinean flag sign. PMID- 29525614 TI - Intraocular lens power adjustment by a femtosecond laser: In vitro evaluation of power change, modulation transfer function, light transmission, and light scattering in a blue light-filtering lens. AB - PURPOSE: To evaluate intraocular lens (IOL) power, modulation transfer function (MTF), light transmission, and light scattering of a blue light-filtering IOL before and after power adjustment by a femtosecond laser obtained through increased hydrophilicity of targeted areas within the optic, creating the ability to build a refractive-index-shaping lens within an existing IOL. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Ten CT Lucia 601PY single-piece yellow hydrophobic acrylic IOLs were used in this study. The IOL power and MTF were measured with a power and modulation transfer function device. Light transmission was measured using a Lambda 35 UV-VIS spectrophotometer. Backlight scattering was assessed with a Scheimpflug camera within the IOL substance. All measurements were done with hydrated IOLs. The IOLs were also evaluated under light microscopy (LM) before and after laser adjustment. RESULTS: After laser adjustment, a mean power change of -2.037 diopters was associated with a MTF change of -0.064 and a light transmittance change of -1.4%. Backlight scattering increased within the IOL optic in the zone corresponding to the laser treatment at levels that are not expected to be clinically significant. Treated areas within the optic could be well appreciated under LM without damage to the IOLs. CONCLUSION: Power adjustment of a commercially available hydrophobic acrylic blue light-filtering IOL by a femtosecond laser produced an accurate change in dioptric power while not significantly affecting the quality of the IOL. PMID- 29525615 TI - Intraoperative hyphema in Descemet membrane endothelial keratoplasty alone or combined with phacoemulsification. AB - PURPOSE: To identify whether intraoperative hyphema from the peripheral iridotomy during Descemet membrane endothelial keratoplasty (DMEK) is associated with anticoagulant or antiplatelet use, age, combined phacoemulsification, or adverse outcomes. SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Retrospective case series. METHODS: Data were obtained from consecutive DMEK cases with an intraoperative iridotomy from July 2015 through July 2016. Hyphema was classified as negative or positive (small or large). Associations with possible risk factors and with transplant outcomes were assessed. RESULTS: Of 445 cases, 262 (59%) were negative for hyphema and 183 (41%) were positive. The proportion of patients who used preoperative anticoagulant or antiplatelet medication did not differ significantly with the hyphema classification (negative hyphema 42%, small hyphema 34%, large hyphema 46%) (P = .31). Likewise, recipient age was not a risk factor for hyphema (P = .085). Hyphema was more likely in cases combined with phacoemulsification than in single DMEK procedures (relative risk, 1.5 [95% confidence interval, 1.2-1.9]). Hyphema was not associated with postoperative rebubbling rates (negative hyphema 10.5%, small hyphema 10.3%, large hyphema 8.0%) (P = .33), 6-month endothelial cell loss (mean = 29%, P = .19), or 6-month visual acuity (mean = 20/25 Snellen in all hyphema groups, P = .98). CONCLUSIONS: Preoperative anticoagulant or antiplatelet use was not a significant risk factor for hyphema. The risk for hyphema was increased somewhat when DMEK was combined with cataract surgery. Intraoperative hyphema did not significantly affect the rebubbling rate, endothelial cell loss, or visual acuity outcomes. PMID- 29525616 TI - Racial/ethnic differences in rates of complex cataract surgery among United States Medicare beneficiaries. AB - PURPOSE: To determine racial/ethnic differences in rates of complex cataract surgery among United States Medicare beneficiaries. SETTING: Departments of Ophthalmology and Health Science Research, Mayo Clinic, Rochester, Minnesota, USA. DESIGN: Retrospective case series. METHODS: The U.S. Medicare 5% Limited Data Set, representing a 5% sample of over 28 million fee-for-service Medicare beneficiaries predominantly aged 65 years and older, were analyzed for rates of complex cataract surgery (Current Procedural Terminology [CPT] code 66982) among all beneficiaries who had cataract surgery (CPT codes 66982, 66984), stratified by race/ethnicity between January 1, 2014, and December 31, 2014. Associations were tested by using multivariate regression analysis. RESULTS: Data from approximately 1 087 680 Medicare beneficiaries were analyzed. After adjustment for age and sex, the likelihood of complex cataract surgery was significantly higher in African Americans (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.75-2.08), Asians (OR, 1.57; 95% CI, 1.34-1.85), and Hispanics (OR, 1.42; 95% CI, 1.18-1.71) than in whites among fee-for-service Medicare beneficiaries. Complex cataract surgery was more likely in men (OR, 1.83; 95% CI, 1.73-1.92) than in women, and the likelihood of complex cataract surgery increased in the elderly, with beneficiaries older than 84 years more likely to have complex surgery (OR, 2.68, 95% CI, 2.45-2.93) than beneficiaries aged 65 to 69 years. CONCLUSION: There were racial/ethnic differences in the likelihood of complex cataract surgery among fee-for-service Medicare beneficiaries; racial/ethnic minorities (Hispanics, Asians, and African Americans) were 42% to 90% more likely to have complex cataract surgery than whites. PMID- 29525617 TI - Intraocular pressure elevation after cataract surgery and its prevention by oral acetazolamide in eyes with pseudoexfoliation syndrome. AB - PURPOSE: To examine whether intraocular pressure (IOP) increases immediately after cataract surgery in eyes with pseudoexfoliation (PXF) syndrome and to assess whether orally administered acetazolamide can prevent the IOP elevation. SETTING: Hayashi Eye Hospital, Fukuoka, Japan. DESIGN: Prospective case series. METHODS: Patients with PXF syndrome scheduled for phacoemulsification were randomly assigned to 1 of 3 groups: (1) oral acetazolamide administered 1 hour preoperatively (preoperative administration group), (2) administered 3 hours postoperatively (postoperative administration group), and (3) not administered (no administration group). The IOP was measured using a rebound tonometer 1 hour preoperatively, upon completion of surgery, and at 1, 3, 5, 7, and 24 hours postoperatively. RESULTS: The study comprised 96 patients (96 eyes). The mean IOP increased at 3, 5, and 7 hours postoperatively in all groups. At 1 hour and 3 hours postoperatively, the IOP was significantly lower in the preoperative administration group than in the postoperative group and no administration group (P <= .001). At 5, 7, and 24 hours postoperatively, the IOP was significantly lower in the preoperative group and postoperative administration group than in the no administration group (P <=. 045). An IOP spike higher than 25 mm Hg occurred less frequently in the preoperative administration group than in the postoperative administration group and the no administration group (P = .038). CONCLUSIONS: Intraocular pressure increased at 3, 5, and 7 hours after cataract surgery in eyes with PXF syndrome. Oral acetazolamide administered 1 hour preoperatively reduced the IOP elevation throughout the 24-hour follow-up; acetazolamide administered 3 hours postoperatively reduced the elevation at 5 hours postoperatively and thereafter. PMID- 29525618 TI - New algorithm for toric intraocular lens power calculation considering the posterior corneal astigmatism. AB - PURPOSE: To assess the accuracy of toric intraocular lens (IOL) power calculations of a new algorithm that incorporates the effect of posterior corneal astigmatism (PCA). SETTING: Abbott Medical Optics, Inc., Groningen, the Netherlands. DESIGN: Retrospective case report. METHODS: In eyes implanted with toric IOLs, the exact vergence formula of the Tecnis toric calculator was used to predict refractive astigmatism from preoperative biometry, surgeon-estimated surgically induced astigmatism (SIA), and implanted IOL power, with and without including the new PCA algorithm. For each calculation method, the error in predicted refractive astigmatism was calculated as the vector difference between the prediction and the actual refraction. Calculations were also made using postoperative keratometry (K) values to eliminate the potential effect of incorrect SIA estimates. RESULTS: The study comprised 274 eyes. The PCA algorithm significantly reduced the centroid error in predicted refractive astigmatism (P < .001). With the PCA algorithm, the centroid error reduced from 0.50 @ 1 to 0.19 @ 3 when using preoperative K values and from 0.30 @ 0 to 0.02 @ 84 when using postoperative K values. Patients who had anterior corneal against-the-rule, with the-rule, and oblique astigmatism had improvement with the PCA algorithm. In addition, the PCA algorithm reduced the median absolute error in all groups (P < .001). CONCLUSIONS: The use of the new PCA algorithm decreased the error in the prediction of residual refractive astigmatism in eyes implanted with toric IOLs. Therefore, the new PCA algorithm, in combination with an exact vergence IOL power calculation formula, led to an increased predictability of toric IOL power. PMID- 29525619 TI - The bacterial biota of laboratory-reared edible mealworms (Tenebrio molitor L.): From feed to frass. AB - Tenebrio molitor represents one of the most popular species used for the large scale conversion of plant biomass into protein and is characterized by high nutritional value. In the present laboratory study, the bacterial biota characterizing a pilot production chain of fresh T. molitor larvae was investigated. To this end, different batches of fresh mealworm larvae, their feeding substrate (wheatmeal) and frass were analyzed by viable microbial counts, PCR-DGGE and Illumina sequencing. Moreover, the occurrence of Coxiella burnetii, Pseudomonas aeruginosa and Shiga toxin-producing E. coli (STEC) was assessed through qualitative real-time PCR assays. Microbial viable counts highlighted low microbial contamination of the wheatmeal, whereas larvae and frass were characterized by high loads of Enterobacteriaceae, lactic acid bacteria, and several species of mesophilic aerobes. Spore-forming bacteria were detected to a lesser extent in all the samples. The combined molecular approach used to profile the microbiota confirmed the low microbial contamination of wheatmeal and allowed the detection of Enterobacter spp., Erwinia spp., Enterococcus spp. and Lactococcus spp. as dominant genera in both larvae and frass. Moreover, Klebsiella spp., Pantoea spp., and Xenorhabdus spp. were found to be in the minority. Entomoplasmatales (including Spiroplasma spp.) constituted a major fraction of the microbiota of one batch of larvae. From the real-time PCR assays, no sample was positive for either C. burnetii or STEC, whereas P. aeruginosa was detected in one sample of frass. Based on the overall results, two sources of microbial contamination were hypothesized, namely feeding with wheatmeal and vertical transmission of microorganisms from mother to offspring. Since mealworms are expected to be eaten as a whole, the overall outcomes collected in this laboratory study discourage the consumption of fresh mealworm larvae. Moreover, microbial loads and the absence of potential pathogens known to be associated with this insect species should be carefully assessed in order to reduce the minimum risk for consumers, by identifying the most opportune processing methods (e.g., boiling, frying, drying, etc.). PMID- 29525620 TI - Simultaneous use of a crossflow filtration membrane as microbial fuel cell anode Permeate flow leads to 4-fold increased current densities. AB - A new concept for the combination of membrane bioreactors and microbial fuel cells is introduced, that aims at the production of electricity for reducing the overall energy consumption of wastewater treatment. In contrast to previous approaches, the anode is integrated as microfiltration membrane in sidestream crossflow configuration. Using a stainless steel filtration membrane with G. sulfurreducens and an acetate-based synthetic medium, up to 4-fold higher current densities are achieved. In a standard setup without filtration, a membrane of filter grade 1 um shows current densities of 5.8 A m-2 +/- 0.5 A m-2 compared to >11 A m-2 when it is used simultaneously as membrane filter. With smaller pore sizes of filter grade 0.5 um, 4.4 A m-2 +/- 0.5 A m-2 in a standard setup and >15 A m-2 in a filtration setup are achieved. The permeate flow was identified as the main parameter leading to increased current densities. PMID- 29525621 TI - Lipid-mediated mode of action of local anesthetics on lipid pores induced by polyenes, peptides and lipopeptides. AB - The effects of local anesthetics (LAs), namely, lidocaine (LDC), prilocaine (PLC), mepivacaine (MPV), bupivacaine (BPV), procaine (PC), and tetracaine (TTC), on the steady-state transmembrane conductance induced by the cis-side addition of the antifungal polyene macrolide antibiotic, nystatin (NYS), in planar lipid bilayers were studied. The addition of TTC to model membranes comprising DOPC and cholesterol (33 mol%) led to a nearly twenty-fold increase in the steady-state NYS-induced membrane conductance. BPV slightly enhanced the channel-forming activity of polyene. LDC, PLC, MPV, and PC did not affect the NYS-induced transmembrane current. We concluded that the effects of LAs on the channel forming activity of NYS were in agreement with their effects on the elastic properties of model membranes. The ability of aminoamide LAs to promote calcein leakage from large unilamellar DOPC-vesicles was decreased in the following order: BPV >> LDC ~ PLC ~ MPV. LDC, PLC, and MPV produced a graded leakage of fluorescent marker from liposomes, up to 10-13%. A initial sharp jump in fluorescence after the introduction of BPV was attributed to the solubilization of liposomes and the formation of mixed DOPC:BPV-micelles. Differential scanning microcalorimetry (DSC) of large unilamellar DPPC-vesicles showed that the main transition temperature (Tm) is continuously decreased upon increasing concentrations of TTC. A sharp drop in the enthalpy of the transition at higher TTC concentrations indicated a formation of anesthetic/lipid mixed micelles. In contrast to TTC, PC slightly decreased Tm, broadened the DSC signal and did not provoke vesicle-to-micelle transition. Both the calcein leakage and DSC data together with the results of measurements of threshold voltages that are required to cause the lipid bilayer breakdown might indicate an alteration in the curvature lipid packing stress, induced by BPV and TTC. The data presented here lend support to a lipid-mediated mode of LAs action on NYS pores via an alteration in curvature stress near the trans-mouth. Similar results were obtained for several lipid pores, formed by polyene amphotericin B, lipopeptide syringomycin E, and the peptides magainin and melittin. This finding further developed the concept of non-specific regulation of lipid pores by LAs. In conclusion, the combination of nystatin with LAs could be a novel treatment for efficient therapy of superficial and mucosal candidiasis. PMID- 29525622 TI - Polymer adhesion predictions for oral dosage forms to enhance drug administration safety. Part 2: In vitro approach using mechanical force methods. AB - Predicting the potential for unintended adhesion of solid oral dosage forms (SODF) to mucosal tissue is an important aspect that should be considered during drug product development. Previous investigations into low strength mucoadhesion based on particle interactions methods provided evidence that rheological measurements could be used to obtain valid predictions for the development of SODF coatings that can be safely swallowed. The aim of this second work was to estimate the low mucoadhesive strength properties of different polymers using in vitro methods based on mechanical forces and to identify which methods are more precise when measuring reduced mucoadhesion. Another aim was to compare the obtained results to the ones achieved with in vitro particle interaction methods in order to evaluate which methodology can provide stronger predictions. The combined results correlate between particle interaction methods and mechanical force measurements. The polyethylene glycol grades (PEG) and carnauba wax showed the lowest adhesive potential and are predicted to support safe swallowing. Hydroxypropyl methylcellulose (HPMC) along with high molecular grades of polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) exhibited strong in vitro mucoadhesive strength. The combination of rheological and force tensiometer measurements should be considered when assessing the reduced mucoadhesion of polymer coatings to support safe swallowing of SODF. PMID- 29525623 TI - Starch nanoparticle as a vitamin E-TPGS carrier loaded in silk fibroin-poly(vinyl alcohol)-Aloe vera nanofibrous dressing. AB - Core-sheath nanofibrous mat as a new vitamin E (VE) delivery system based on silk fibroin (SF)/poly(vinyl alcohol) (PVA)/aloe vera (AV) was successfully prepared by the electrospinning method. Initially, VE-loaded starch nanoparticles were produced and then incorporated into the best beadless SF-PVA-AV nanofibers. The successful loading of VE in starch nanoparticles was proved by Fourier-transform infrared spectroscopy. The scanning electron microscopy and transmission electron microscopy indicated that spherical nanoparticles were successfully embedded within the nanofibers. In vitro release studies demonstrated that the release of VE was controlled by Fickian diffusion and was faster in samples containing more nanoparticles. Fibroblast attachment, proliferation, and collagen secretion were enhanced after adding AV and VE to the SF-PVA nanomatrix. Moreover, the incorporation of VE into the nanocomposite dressing enhanced antioxidant activity, which can have a positive effect on wound healing process by protecting the cells from toxic oxidation products. PMID- 29525624 TI - Presence, mobility and bioavailability of toxic metal(oids) in soil, vegetation and water around a Pb-Sb recycling factory (Barcelona, Spain). AB - The work was conducted to establish contamination from improper disposal of hazardous wastes containing lead (Pb) and antimony (Sb) into nearby soils. Besides other elements in the affected area, the biological role of Sb, its behaviour in the pedosphere and uptake by plants and the food chain was considered. Wastes contained 139532 +/- 9601 mg kg-1 (~14%) Pb and 3645 +/- 194 mg kg-1 (~0.4%) Sb respectively and variability was extremely high at a decimetre scale. Dramatically high concentrations were also found for As, Cd, Cu, Mn, Ni, Sn and Zn. In adjacent natural soils metal(oid)s amounts decreased considerably (Pb 5034 +/- 678 mg kg-1, Sb 112 mg kg-1) though largely exceeded the directives for a given soil use. Metal(oid)s potential mobility was assessed by using H2O >KNO3->EDTA sequential extractions, and EDTA extracts showed the highest concentration suggesting stable humus-metal complexes formation. Nevertheless, selected plants showed high absorption potential of the investigated elements. Pb and Sb values for Dittrichia viscosa grown in wastes was 899 +/- 627 mg kg-1 and 37 +/- 33 mg kg-1 respectively. The same plant showed 154 +/- 99 mg kg-1 Pb and 8 +/- 4 mg kg-1 Sb in natural soils. Helichrysum stoechas had 323 +/- 305 mg kg-1 Pb, and 8 +/- 3 mg kg-1 Sb. Vitis vinifera from alongside vineyards contained 129 +/- 88 mg kg-1 Pb and 18 +/- 9 mg kg-1 Sb, indicating ability for metal uptake and warning on metal diffusion through the food chain. The biological absorption coefficient (BAC) and the translocation factor (TF) assigned phytoextraction potential to Dittrichia viscosa and Foeniculum vulgare and phytostabilization potential to Helichrysum stoechas. Dissolved metal (oid)s in the analysed water strongly exceeded the current directive being a direct threat for livings. Data warned against the high contamination of the affected area in all its compartments. Even though native plants growing in metal-contaminated sites may have phytoremediation potential, high risk of metal diffusion may threat the whole ecosystem. PMID- 29525625 TI - Prenatal exposure to polychlorinated biphenyl and umbilical cord hormones and birth outcomes in an island population. AB - Prenatal exposure to polychlorinated biphenyl (PCB) is suspected to interfere with fetal development including reproductive and thyroid function and birth outcomes, but published evidence are still sparse. We designed a cross-sectional study to analyze the associations between PCB levels in umbilical cord sera and hormones and birth outcomes of mothers and newborns who are residents from an island. Seven indicator-PCB (PCB-28, 52, 101, 118, 138, 153, 180), and five reproductive hormones including luteotropic hormones (LH), estradiol (E2), testosterone (T), follicle-stimulating hormones (FSH) and anti-Mullerian hormones (AMH), and three thyroid hormones including tri-iodothyronine (T3), tetra iodothyronine (T4) and thyroid stimulating hormones (TSH) were measured in 106 cord sera specimens. Birth outcomes include birth weight, length, head circumference, and gestational age. Multiple linear regression and quartile regression were used to analyze the associations between PCB and each of the hormones and birth outcomes, adjusting for selected potential confounders. The median value of total PCB in umbilical cord sera was 2.02 MUg L-1 (IQR, 1.13 4.64). Several negative associations between PCB exposure and reproductive hormones were found. Among them, the beta value of PCB-101 for FSH reached -0.38 (95%CI, -0.69, -0.07; p = 0.02). Moreover, we also found some sex-specific associations i.e. PCB-28 was negatively correlated with LH and T and PCB-118 was negatively correlated with T in male newborns but not in female newborns. The associations between PCB and birth outcomes seem to differ by molecular weight of the PCB congeners i.e. the low-chlorinated PCB congeners were negatively associated with gestational age and head circumference while high-chlorinated PCB congeners were positively associated birth weight and gestational age. In this study, we found that PCB congeners with different molecular weight has different associations with hormones and birth outcomes, and future studies are recommended to investigate underlying mechanisms of these associations. PMID- 29525626 TI - Effects on IL-1beta signaling activation induced by water and organic extracts of fine particulate matter (PM2.5) in vitro. AB - Fine particulate matter (PM2.5) air pollution poses a major risk to human health worldwide, and absorbed chemicals play a key role in determining the toxicity of PM2.5. After inhalation and entry into the lungs, PM2.5 components induce pro inflammatory cytokines (e.g., interleukin (IL)-1beta) in pulmonary cells. To test whether PM2.5 components induce IL-1beta through signing pathways that include the toll-like receptor 4 (TLR4)/nuclear factor-kappa-gene binding (NF-kappaB), nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3), we exposed the mouse macrophage cell-line RAW264.7 to both water and organic extracts of PM2.5 sampled over a 1-year period in Beijing, China. Varying degrees of oxidative stress and inflammatory responses were induced following exposure, while organic extracts of PM2.5 collected during the heating season induced more significant responses. This response is attributed to high concentrations of polycyclic aromatic hydrocarbons (PAHs) originating from coal combustion and biomass burning for domestic heating. The inhibition of signaling molecules suggested that increased IL-1beta was associated with the TLR4/NF-kappaB pathway and NLRP3 inflammasome activation, with a slightly difference between water and organic extracts exposure groups, which was likely the result of different chemical components. Our study elucidated a potentially important mechanism by which PM2.5 components could trigger pulmonary inflammation, thus improving our understanding of the deleterious effects of this important and prevalent form of air pollution. PMID- 29525627 TI - Plastic litter from shotgun ammunition on Danish coastlines - Amounts and provenance. AB - Plastic litter in the marine environment is a major global issue. Discarded plastic shotgun ammunition shells and discharged wads are an unwelcome addition and feature among the top ten litter items found on reference beaches in Denmark. To understand this problem, its scale and origins, collections were made by volunteers along Danish coastal shorelines. In all 3669 plastic ammunition items were collected at 68 sites along 44.6 km of shoreline. The collected items were scored for characteristic variables such as gauge and length, shot type, and the legibility of text, the erosion, and the presence of metallic components. Scores for characteristics were related to the site, area, and season and possible influences discussed. The prevalence of collected plastic shotgun litter ranges from zero to 41 items per 100 m with an average of 3.7 items per 100 m. Most ammunition litter on Danish coasts originates from hunting on Danish coastal waterbodies, but a small amount may come from further afield. North Sea coasts are the most distinctive suggesting the possible contribution of long distance drift as well as the likelihood that such litter can persist in marine habitats for decades. The pathway from initial discard to eventual wash-up and collection depends on the physical properties of plastic components, marine tides and currents, coastal topography and shoreline vegetation. Judging from the disintegration of the cartridge and the wear and decomposition of components, we conclude that there is a substantial supply of polluting plastic ammunition materials that has and will accumulate. These plastic items pose a hazard to marine ecosystems and wash up on coasts for many years to come. We recommend that responsible managers, hunters and ammunition manufacturers will take action now to reduce the problem and, thereby, protect ecosystems, wildlife and the sustainability of hunting. PMID- 29525628 TI - Use of biomarkers to evaluate the ecological risk of xenobiotics associated with agriculture. AB - This research aimed to evaluate the ecological risk of xenobiotics associated with agricultural activities by determining metal contents and biomarker responses using tucunare (Cichla sp.) as a bioindicator. The work was conducted in the southwest region of the state of Tocantins, in the cities of Lagoa da Confusao and Pium. Water samples and specimens of Cichla sp. were collected in the Javaes and Formoso Rivers at three collection points (A, B and C). The concentrations of Cd, Pb, Cu, Cr, Mn, Ni and Zn in water and fish were analyzed. In fish, genotoxic, biochemical (glucose serum levels, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and histological (gills and liver) biomarkers were assessed. In the water, the Cr and Mn concentrations at the three collection points exceeded the values for Class 1 rivers. In the muscle, Cr was above the maximum limit allowed for human consumption at the three collection points, although the values at Points B and C were not significantly different from that at Point A (p > 0.05). At the three collection points, the micronucleus test revealed a low frequency of micronuclei. Significant hyperglycemia and a decrease in the AST activity of the fish collected at Point C was observed. In the gills, the most frequent alterations were at Stages I and II, which indicated mild to moderate damage, and epithelial detachment was the most frequent variation. In the liver tissue, the most frequently observed histological changes were at Stages I and II and included cytoplasmic vacuolization, nuclear hypertrophy, dilated sinusoids and bile stagnation. The integrated evaluation of these biomarkers indicated that fish collected from areas with intense agricultural activities presented adaptive responses that were likely caused by the availability and bioaccumulation of certain xenobiotics in the environment. PMID- 29525602 TI - Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema. AB - PURPOSE: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS: Participants with available plasma samples (N = 436). METHODS: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30+/-0.61 pg/ml, -0.31+/-0.54 pg/ml, and -0.02+/-0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and 0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was 0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted. PMID- 29525629 TI - Household air pollution and personal exposure to air pollutants in rural China - A review. AB - Solid fuels, an important source of severe Household Air Pollution (HAP) linked to many adverse health outcomes, has been widely consumed around the world. China consumes large amounts of solid fuels and suffers from serious indoor and outdoor air pollution. Though global HAP issues had been reviewed in previous literatures, peer-reviewed Chinese publications were seldom included in those reviews. We conducted a literature review on the studies of HAP and personal exposure in rural China with inputs from peer-reviewed publications in both English and Chinese. A total of 36,572 articles were retrieved, 294 were read in full text, of which 92 were included in final data extraction and in-depth analysis. Although HAP is a very serious issue in China, studies on either HAP or personal exposure assessment were very limited. From existing studies, levels of air pollutants including carbon monoxide, sulfur dioxide, particulate matter (PM), organic carbon, elemental carbon, polycyclic aromatic hydrocarbons (PAHs), etc., in indoor and ambient air were analyzed for their temporal and spatial variations, and the differences across different fuel types were compared. The studies showed that PM and PAHs levels in most rural homes exceeded the World Health Organization (WHO) and Chinese National Standards, especially during the heating season in northern China. Replacing traditional fuels with cleaner ones (such as liquid petroleum gas (LPG), biogas or electricity) was considered as the most appropriate way to mitigate HAP. The daily exposure to PM and PAHs from using LPG, biogas or electricity was considerably lower than that from using traditional solid fuels. However, the level was still higher than the guideline values for PM and PAHs set by WHO to protect human health. To achieve a more effective control, the current data gap need to be closed and suggestions for future research were discussed in this review. PMID- 29525630 TI - Risk analysis of heavy metal concentration in surface waters across the rural urban interface of the Wen-Rui Tang River, China. AB - Heavy metal pollution is a major concern in China because of its serious effects on human health. To assess potential human health and ecological risks of heavy metal pollution, concentration data for seven heavy metals (As, Pb, Cd, Cr, Hg, Cu, Zn) from 14 sites spanning the rural-urban interface of the Wen-Rui Tang River watershed in southeast China were collected from 2000 to 2010. The heavy metal pollution index (HPI), hazard index (HI) and carcinogenic risk (CR) metrics were used to assess potential heavy metal risks. Further, we evaluated the uncertainty associated with the risk assessment indices using Monte Carlo analysis. Results indicated that all HPI values were lower than the critical level of 100 suggesting that heavy metal levels posed acceptable ecological risks; however, one site having an industrial point-source input reached levels of 80-97 on several occasions. Heavy metal concentrations fluctuated over time, and the decrease after 2007 is due to increased wastewater collection. The HI suggested low non-carcinogenic risk throughout the study period (HI < 1); however, nine sites showed CR values above the acceptable level of 10-4 for potential cancer risk from arsenic in the early 2000s. Uncertainty analysis revealed an exposure risk for As at all sites because some CR values exceeded the 10-4 level of concern; levels of Cd near an old industrial area also exceeded the Cd exposure standard (2.6% of CR values > 10-4). While most metrics for human health risk did not exceed critical values for heavy metals, there is still a potential human health risk from chronic exposure to low heavy metal concentrations due to long-term exposure and potential metal interactions. Results of this study inform water pollution remediation and management efforts designed to protect public health in polluted urban area waterways common in rapidly developing regions. PMID- 29525631 TI - Comparison of the SuperARMS and Droplet Digital PCR for Detecting EGFR Mutation in ctDNA From NSCLC Patients. AB - BACKGROUND: Liquid biopsy is emerging as an important approach for tumor genotyping in non-small cell lung cancer, ddPCR and SuperARMS are both methods with high sensitivity and specificity for detecting EGFR mutation in plasma. We aimed to compare ddPCR and SuperARMS to detect plasma EGFR status in a cohort of advanced NSCLC patients. METHOD: A total of 79 tumor tissues and paired plasma samples were collected. The EGFR mutation status in tissue was tested by ADx ARMS, matched plasma was detected by ddPCR and SuperARMS, respectively. RESULTS: The EGFR mutation rates were identified as 64.6% (tissue, ARMS), 55.7% (plasma, ddPCR), and 49.4% (plasma, Super ARMS), respectively. The sensitivity of ddPCR was similar with Super-ARMS in plasma EGFR detection (80.4% vs 76.5%), as well as the specificity (89.3% vs 100%). And the McNemar's test showed there was no significant difference (P = .125). The concordance rate between SuperARMS and ddPCR was 91.1%. A significant interaction was observed between cfDNA EGFR mutation status and EGFR-TKIs treatment tested by both methods. CONCLUSION: Super ARMS and ddPCR share the similar accuracy for EGFR mutation detection in plasma biopsy; both methods predicted well the efficacy of EGFR-TKIs by detecting plasma EGFR status. PMID- 29525632 TI - CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage. AB - Spontaneous tumor hemorrhage (TH) is frequently observed in solid tumors including human hepatocellular carcinoma (HCC). TH implies fast-growing and worse tumor immunological microenvironment; however, the underlying mechanism remains largely unknown. CLEC1B is a signature gene highly associated with tumor progression. PD-L1 expression is a key biomarker predictive of immune checkpoint therapies, which showed astonishing effect on various types of tumor. We assume that, in HCC, TH may closely associate with the expression of these two molecules. In this study, 136 patients with HCC were enrolled. qRT-PCR showed that CLEC1B expression is significantly lower in HCC tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that PD-L1high and CLEC1Blow expressions were significantly correlated with TH and clinicopathological features indicating worse HCC progression. According to univariate/multivariate analysis, a combination of PD-L1high and CLEC1Blow expression was an independent prognostic factor indicating the poor outcome. The prognostic value of PD-L1high and CLEC1Blow was validated by Cox proportional hazard analyses. Collectively, tumor with TH is closely associated with CLEC1Blow & PD-L1high expression, which may imply high response of PD-L1/PD-1 immune checkpoint therapies. CLEC1B may be a potential therapeutic target for PD-L1/PD-1 immunotherapy. PD-L1high and CLEC1Blow can be a valuable prognosis factor implying worse clinical outcomes. PMID- 29525633 TI - Association of PD-L1 and HIF-1alpha Coexpression with Poor Prognosis in Hepatocellular Carcinoma. AB - OBJECTIVE: To investigate the correlation between the expression of PD-L1 and HIF 1alpha in hepatocellular carcinoma (HCC) tissue and further analyze the association with clinical parameters and the prognostic value of coexpression in HCC patients. METHODS: We assessed the expression of PD-L1 and HIF-1alpha by immunohistochemistry in tumor tissue from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: PD-L1 and HIF-1alpha exhibited in tumor tissue high expression rates of 41.11% (37/90) and 43.33% (43/90), respectively, and their expressions were positively correlated (r = 0.563, P < .01). High expression of PD-L1 was significantly associated with low albumin levels (P < .05); high expression of HIF-1alpha was significantly correlated with high alpha-fetoprotein (AFP) levels and low albumin levels (P < .05); high expression of both PD-L1 and HIF-1alpha was also significantly associated with high AFP levels and low albumin levels (P < .05). High expression of PD-L1, HIF-1alpha, as well as both PD-L1 and HIF-1 alpha was respectively significantly associated with worse overall survival (OS) and disease-free survival (DFS) (P < .05). Patients with co-overexpression of PD-L1 and HIF-1alpha had the worst prognosis compared with other groups. Additionally, multivariate Cox regression models suggested that high expression of PD-L1, HIF-1alpha, as well as both PD-L1 and HIF-1alpha was an independent prognostic factor for OS and DFS (P < .05). Furthermore, the positive correlation and prognostic values of PD-L1 and HIF-1alpha were validated in an independent data set. CONCLUSION: We demonstrated that HCC patients with co-overexpression of PD-L1 and HIF-1alpha in tumor tissue had a significantly higher risk of recurrence or metastasis and death compared with others. Therefore, more frequent follow-up is needed for patients with co-overexpression of PD-L1 and HIF-1alpha. At the same time, a combinational therapy with HIF-1alpha inhibitors in conjunction with PD-L1 blockade may be beneficial for HCC patients with co overexpression in the future. PMID- 29525634 TI - Performance of the OraQuick Hepatitis C virus antibody test in oral fluid and fingerstick blood before and after treatment-induced viral clearance. AB - BACKGROUND: A reliable population screening strategy for hepatitis C virus (HCV) infection may be based in easy-to-use point-of-care (POC) tests for HCV antibodies, but validation data is needed before their potential widespread use in primary care or outreach practice. Besides, the sensitivity of these POC tests in patients with spontaneous or treatment-induced viral clearance is unknown. OBJECTIVES: To test the performance of a non-invasive POC anti-HCV test (OraQuick HCV rapid test) in oral mucosal transudate (OMT) and fingerstick blood from patients with known anti-HCV serostatus and with or without active viremia (after treatment-induced clearance). STUDY DESIGN: A risk factor questionnaire was collected from 317 consecutive patients (anti-HCV positive/HCV-RNA positive n = 107; anti-HCV positive/HCV-RNA negative after antiviral treatment n = 107; anti HCV negative with other liver diseases n = 109) before performing the OraQuick HCV rapid test in OMT (n = 317) and fingerstick blood (n = 251). We calculated the sensitivity and specificity of the test by using anti-HCV serostatus as the reference gold-standard. RESULTS: Among all anti-HCV seropositive patients, the clinical sensitivity and specificity of the OraQuick HCV rapid test in OMT was 89.9% and 100%, respectively. In fingerstick blood, the sensitivity improved to 98.8%. The sensitivity was higher in OMT (97.2%) in anti-HCV seropositive patients who were viremic as compared to that in non-viremic individuals (82.2%). In contrast, there were no significant differences in sensitivity between viremic and non-viremic individuals when testing fingerstick blood. Finally, extension of the read time to 40 min enhanced the sensitivity, especially in OMT (up to 94.7%) and in the subgroup of non-viremic, anti-HCV-positive patients (up to 90.1%). CONCLUSIONS: The OraQuick HCV rapid test in OMT has a high sensitivity and specificity for detecting active HCV infection that decreases substantially in anti-HCV positive/HCV-RNA negative patients with treatment-induced viral clearance. For these individuals, extension of read times and testing fingerstick blood showed improved sensitivity. PMID- 29525635 TI - Primary Epstein-Barr virus infection. AB - Epstein-Barr virus (EBV) infects about 90% of adults worldwide. It is the main cause of infectious mononucleosis, which is observed most frequently in adolescents. The disease can last several weeks and is characterized by lymphocytosis, sore throat, lymphadenopathy, and fatigue. Exposure to oral secretions during deep kissing has been identified as the major source for primary EBV infection in adolescents. Oral secretions are also thought to be the source for younger children through intimate intact or sharing food and eating utensils, although this has not been confirmed. Unlike most acute viral illnesses such as influenza, the incubation period of symptomatic primary EBV infection is unusually long, lasting about six weeks. Diagnosis is typically made by heterophile antibody tests and/or EBV-specific antibody tests. Long-term consequences may result from acquisition of the virus, including nasopharyngeal carcinoma and lymphomas. Nevertheless, there remains a surprising dearth of knowledge regarding the establishment of an immune response to persistent EBV infection, especially during the incubation period. This lack of knowledge has impaired our ability to develop an effective prophylactic EBV vaccine, despite various attempts. Our greatest challenges in EBV research are to develop a prophylactic vaccine and devise treatment strategies for persons already infected with EBV. PMID- 29525636 TI - Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018. AB - Nowadays, due to the development of potent Direct-Acting Antiviral Agents (DAAs) that specifically target NS3, NS5A and NS5B viral proteins, several new and highly efficacious options to treat chronic Hepatitis C virus (HCV) infection are available. The natural presence of resistance associated substitutions (RASs), as well as their rapid emergence during incomplete drug-pressure, are intrinsic characteristics of HCV that greatly affect treatment outcome and the chances to achieve a virolgical cure. To date, a high number of RASs in NS3, NS5A, and NS5B have been associated in vivo and/or in vitro with reduced susceptibility to DAAs, but no comprehensive RASs list is available. This review thus provides an updated, systematic overview of the role of RASs to currently approved DAAs or in phase II/III of clinical development against HCV-infection, discriminating their impact in different HCV-genotypes and DAAs, providing assistance for a fruitful use of HCV resistance testing in clinical practice. PMID- 29525637 TI - A man with Garrod's pads and camptodactyly. PMID- 29525638 TI - In vitro osteogenic potential of collagen/chitosan-based hydrogels-silica particles hybrids in human bone marrow-derived mesenchymal stromal cell cultures. AB - The aim of this study was to assess osteogenic potential of three groups of biopolymeric hydrogel-based surfaces made of plain collagen, chitosan or collagen/chitosan, crosslinked with genipin or all three biopolymers modified with silica particles of two sizes (S1=240nm and S2=450nm). Biocompatibility and osteoinductive properties of the resulting composites were analyzed in the human bone marrow-derived mesenchymal stromal cells (hBMSCs) in vitro cultures. It was revealed that all tested materials are biocompatible and significantly enhance ALP activity in hBMSCs which was particularly pronounced for collagen/chitosan based hybrids. Gene expression (RUNX-2, COL-I, OC and VEGF mRNA) analyses performed in hBMSCs cultured at collagen/chitosan materials showed that ColChS1 hybrid the most effectively promotes osteogenic differentiation of hBMSCs. SEM and EDS analyses of materials carried out after 20days of hBMSCs culturing on ColCh-based hydrogels revealed that the hybrid materials enhanced hBMSCs-mediated mineralization of ECM. Our studies revealed that collagen/chitosan hydrogels modified with silica particles of smaller sizes (ColChS1) exhibit high pro osteogenic properties without the need of applying any additional osteogenic inducers. That suggests that ColChS1 having the intrinsic osteoinductive activity holds great potential as material of choice for bone regeneration procedures, especially in regeneration of small bone losses. PMID- 29525639 TI - Concentrations of organophosphate flame retardants and plasticizers in urine from young children in Queensland, Australia and associations with environmental and behavioural factors. AB - In recent years, the production and usage volumes of organophosphate flame retardants (OPFRs) has increased substantially. Certain OPFRs are suspected reproductive toxins, carcinogenic, and neurotoxic. Insufficient information is available on human exposure pathways to these chemicals, particularly in Australia. We aim to assess the association between OPFR concentrations in the urine of children to environmental and behavioural risk factors. Concentrations of eight OPFRs and eleven metabolites were measured in the urine of 51 children, aged 3-29 months, in Southeast Queensland, Australia and compared to their behavioural and environmental risk factor data obtained by an online questionnaire. Of the 11 OPFR metabolites analysed, 55% were frequently detected in the majority (> 80%) of samples. The most frequently detected metabolite was bis(1,3-dichloroisopropyl) phosphate (BDCIPP) (detected in 100% of samples), followed by 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) (96%), diphenyl phosphate (DPHP) (94%) and bis(1-chloroisopropyl) phosphate (BCIPP) (86%). In multivariable modelling, age was positively associated with concentrations of bis(2-butoxyethyl) phosphate (BBOEP) and negatively associated with concentrations of BCIPP and BCIPHIPP. Other non-age related factors, including vacuuming frequency, hand-washing frequency and presence and number of some electrical appliances in the home were also associated with concentrations of OPFR metabolites. PMID- 29525640 TI - The association of visually-assessed quality of movement during jump-landing with ankle dorsiflexion range-of-motion and hip abductor muscle strength among healthy female athletes. AB - OBJECTIVE: To explore the association between ankle dorsiflexion (DF) range of motion (ROM), and hip abductor muscle strength, to visually-assessed quality of movement during jump-landing. DESIGN: Cross-sectional. SETTING: Gymnasium of participating teams. PARTICIPANTS: 37 female volleyball players. MAIN OUTCOME MEASURES: Quality of movement in the frontal-plane, sagittal-plane, and overall (both planes) was visually rated as "good/moderate" or "poor". Weight-bearing Ankle DF ROM and hip abductor muscle strength were compared between participants with differing quality of movement. RESULTS: Weight-bearing DF ROM on both sides was decreased among participants with "poor" sagittal-plane quality of movement (dominant side: 50.8 degrees versus 43.6 degrees , P = .02; non-dominant side: 54.6 degrees versus 45.9 degrees , P = .01), as well as among participants with an overall "poor" quality of movement (dominant side: 51.8 degrees versus 44.0 degrees , P < .01; non-dominant side: 56.5 degrees versus 45.1 degrees , P < .01). Weight-bearing ankle DF on the non-dominant side was decreased among participants with a "poor" frontal-plane quality of movement (53.9 degrees versus 46.0 degrees , P = .02). No differences in hip abductor muscle strength were noted between participants with differing quality of movement. CONCLUSIONS: Visual assessment of jump-landing can detect differences in quality of movement that are associated with ankle DF ROM. Clinicians observing a poor quality of movement may wish to assess ankle DF ROM. PMID- 29525641 TI - Epidemiology and Clinical Aspects of Genetic Cardiomyopathies. AB - Cardiomyopathies (CMPs) are an increasingly recognized cause of heart failure and sudden death, particularly in young patients. Since their original description, major advances were achieved in the phenotype knowledge, natural history, and nosography of CMPs leading to different classification systems and therapies. However, a deeper knowledge of different causes, genotype-phenotype link, and natural history in different disease stages (preclinical, overt disease, and end stage disease) according to a recognized standard of care (ie, international guidelines) is needed. Clinical registries can fill gaps in our knowledge regarding the uncovered issues on cause, clinical course, and management of CMPs. PMID- 29525642 TI - Genetic Testing for Cardiomyopathies in Clinical Practice. AB - Cardiac genetic testing for inherited cardiomyopathies has become a routine aspect of care. Advances in genetic testing technologies have made testing more comprehensive and affordable. With this increase come greater understanding of the genetic basis of these diseases, but also shines a light on the challenges. Ability to ascertain whether a rare variant is causative of disease is problematic. A genetic diagnosis in a family can offer an invaluable tool for cascade genetic testing of at-risk relatives and avenues for reproductive testing options. A careful approach to cardiac genetic testing that recognizes where there is potential for harm ensures the best possible outcomes for families. PMID- 29525643 TI - Genetic Pathogenesis of Hypertrophic and Dilated Cardiomyopathy. AB - Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of preclinical mutation carriers has yielded insights into the earliest biomechanical defects that link pathogenic variants to cardiac dysfunction. Understanding this early molecular pathophysiology can illuminate modifiable pathways to reduce the emergence of overt cardiomyopathy and curb adverse outcomes. Here, the authors review current understandings of how human hypertrophic cardiomyopathy- and hypertrophic dilated cardiomyopathy-linked mutations disrupt the normal structure and function of the sarcomere. PMID- 29525645 TI - Clinical and Molecular Aspects of Cardiomyopathies: Emerging Therapies and Clinical Trials. AB - Cardiomyopathies are diseases of the myocardium, often genetically determined, associated with heterogeneous phenotypes and clinical manifestations. Despite significant progress in the understanding of these conditions, available treatments mostly target late complications, whereas approaches that promise to interfere with the primary mechanisms and natural history are just beginning to surface. The last decade has witnessed the establishment of large international cardiomyopathy registries, paralleled by advances in cardiac imaging and genetic testing, deeper understanding of the pathophysiology and growing involvement by the pharmaceutical industry. As a result, the number of molecular interventions under scrutiny is increasing sharply. PMID- 29525644 TI - Biophysical Derangements in Genetic Cardiomyopathies. AB - This article focuses on three "bins" that comprise sets of biophysical derangements elicited by cardiomyopathy-associated mutations in the myofilament. Current therapies focus on symptom palliation and do not address the disease at its core. We and others have proposed that a more nuanced classification could lead to direct interventions based on early dysregulation changing the trajectory of disease progression in the preclinical cohort. Continued research is necessary to address the complexity of cardiomyopathic progression and develop efficacious therapeutics. PMID- 29525647 TI - Controversies Surrounding Exercise in Genetic Cardiomyopathies. AB - Exercise and sports are an integral part of daily life for millions of Americans, with 16% of the US population older than age 15 years engaged in sports or exercise activities (Bureau of Labor statistics). The physical and psychological benefits of exercise are well-recognized. However, high-profile cases of athletes dying suddenly on the field, often due to undiagnosed genetic cardiomyopathies, raise questions about the risks and benefits of exercise for those with cardiomyopathy. PMID- 29525646 TI - Gene Editing and Gene-Based Therapeutics for Cardiomyopathies. AB - With an increasing understanding of genetic defects leading to cardiomyopathy, focus is shifting to correcting these underlying genetic defects. One approach involves treating mutant RNA through antisense oligonucleotides; the first drug has received regulatory approval to treat specific mutations associated with Duchenne muscular dystrophy. Gene editing is being evaluated in the preclinical setting. For inherited cardiomyopathies, genetic correction strategies require tight specificity for the mutant allele. Gene-editing methods are being tested to create deletions that may be useful to restore protein expression by through the bypass of mutations that restore protein production. Site-specific gene editing, which is required to correct many point mutations, is a less efficient process than inducing deletions. PMID- 29525648 TI - Diagnostic Criteria, Genetics, and Molecular Basis of Arrhythmogenic Cardiomyopathy. AB - Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease characterized by myocardial atrophy and fibrofatty replacement of the ventricular myocardium, at risk of sudden cardiac death, particularly in the young and athletes. Because there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined, including imaging, electrocardiographic changes, arrhythmias, tissue characterization, and family history. However, the routine use of contrast-enhanced cardiac magnetic resonance increasingly revealed left dominant AC, a variant that is not well addressed in the diagnostic criteria and still escapes clinical identification. PMID- 29525650 TI - Clinical Presentation and Natural History of Hypertrophic Cardiomyopathy in RASopathies. AB - RASopathies are a heterogeneous group of genetic syndromes characterized by mutations in genes that regulate cellular processes, including proliferation, differentiation, survival, migration, and metabolism. Excluding congenital heart defects, hypertrophic cardiomyopathy is the most frequent cardiovascular defect in patients affected by RASopathies. A worse outcome (in terms of surgical risk and/or mortality) has been described in a specific subset of Rasopathy patients with early onset, severe hypertrophic cardiomyopathy presenting with heart failure. New short-term therapy with a mammalian target of rapamycin inhibitor has recently been used to prevent heart failure in these patients with a severe form of hypertrophic cardiomyopathy. PMID- 29525649 TI - Genetic Infiltrative Cardiomyopathies. AB - Infiltrative cardiomyopathies are characterized by abnormal accumulation or deposition of substances in cardiac tissue leading to cardiac dysfunction. These can be inherited, resulting from mutations in specific genes, which engender a diverse array of extracardiac features but overlapping cardiac phenotypes. This article provides an overview of each inherited infiltrative cardiomyopathy, describing the causative genes, the pathologic mechanisms involved, the resulting cardiac manifestations, and the therapies currently offered or being developed. PMID- 29525651 TI - On the Road from Gene to Therapy in Inherited Cardiomyopathies. PMID- 29525652 TI - In vivo visual reporter system for estrogenic contaminant exposure using transgenic see-through Japanese medaka Oryzias latipes. AB - Estrogenic contaminants are commonly detected in water bodies and can result in reproductive effects of aquatic organisms. This necessitates the development of time and cost effective tools to screen chemicals for estrogenic potential. Our objective was to develop a novel in vivo visual reporter system for rapid detection of estrogenic contaminants. We developed a Japanese medaka (Oryzias latipes) transgenic line (pOSP1-AcGFP), which expresses Aequorea coerulescens green florescence protein (AcGFP) under the control of ovarian structural protein 1 (osp1) promoter region. Osp1 is a gene with early female-specific expression that is highly responsive to hormonal exposure. Next, we conducted 24 h exposure of 30 dph pOSP1-AcGFP larvae to successfully detect estrogenic activity of contaminants. Our results support the hypothesis that molecular biomarkers are sensitive tools for early detection of the effects of estrogenic contaminants. PMID- 29525654 TI - Dispersibility and dispersion stability of carbon nanotubes in synthetic aquatic growth media and natural freshwater. AB - The dispersion behavior of carbon nanotubes (CNTs) is influenced by both their physicochemical properties and by the aqueous media properties (e.g. ionic strength, presence of divalent cations and natural organic matter) in which they are dispersed. In the current study, the dispersibility and dispersion stability of four multi-walled CNTs (MWCNT) and a single walled CNT (SWCNT) with different physicochemical properties were investigated in three freshwater growth media (with and without natural organic matter; NOM) used in algae and daphnia ecotoxicity studies. CNT dispersion behavior was also investigated in a natural freshwater for comparison. SWCNTs and non-functionalized MWCNTs showed similar dispersibility irrespective of the media type (SWCNTs = 0.5-0.9 mg/L; MWCNTs = 1.5-2.8 mg/L). Functionalized MWCNTs exhibited higher dispersion concentrations, but were more dependent upon the ionic strength and divalent cation concentration of each media (MWCNT-COOH = 3.0-6.6 mg/L). In contrast, CNT surface oxygen content had no influence on CNT dispersibility in the natural water (all MWCNTs = 0.9-1.4 mg/L). Functionalized MWCNTs were affected more by the differences in media properties than non-functionalized MWCNTs. The dispersed CNT concentration decreased over time for all CNT types and in all media due to sedimentation, but was influenced by both CNT and media properties. The study shows how a complex interplay between CNT and media properties can influence the environmental fate of CNTs. Furthermore, the study demonstrates how different CNT types and/or ecotoxicological media in aquatic tests influences the dispersion behavior of the CNTs, and thus their exposure and toxicity to aquatic organisms. PMID- 29525653 TI - A real scale phytoremediation of multi-metal contaminated e-waste recycling site with Eucalyptus globulus assisted by electrical fields. AB - The combined utilization of direct or alternating electric fields and phytoremediation was designed to decontaminate multi-metal polluted soil at a field scale e-waste recycling impacted site. Eucalyptus globulus was chosen for metal purification for its resilient and unpalatable nature. Biomass production, metal concentration and water use efficiency of the species under direct current (DC) and alternating current (AC) fields with various voltages were investigated. DC and AC fields stimulated the growth of the plant, except for DC field with high voltage (10 V). Metal concentrations increased in plant tissues under the influence of AC or DC fields irrespective of voltages. DC fields elevated the root and shoot metal contents of plants in equal proportions and AC fields tended to migrate metals from roots to the aboveground parts of the species. Compared to the control, soil moisture of various soil layers at the planted site was significantly lower and subsequently leading to the decrease of metal leaching. In soil profile metal distributes differently between DC and AC treatments. Compared to AC field, more metals tended to accumulate in soil surface under the influence of DC fields due to the stable converse gravitational pathway of metals. Considering decontamination efficiency, leaching interception and energy consumption, DC field with moderate voltage was a suitable candidate for real scale multi-metal polluted soil phytoremediation. PMID- 29525655 TI - Assessing biochar applications and repeated Brassica juncea L. production cycles to remediate Cu contaminated soil. AB - Copper contamination and toxicity in soils is a worldwide problem, especially in areas where copper-based fungicides are applied. Indian mustard (Brassica juncea L.) plants are used in phytoremediation and are also edible crops commonly cultivated in organic agricultural areas. Application of biochar to Cu contaminated soils may reduce Cu availability and uptake, thereby allowing for greater Indian mustard production. A (3 * 2) + 1) experiment in a randomized complete block design was used to evaluate the effect of three different biochars (coconut shell, orange bagasse and sewage sludge) and two application rates (30 and 60 t ha-1) on Cu uptake by Indian mustard during three successive growth cycles and Cu immobilization in soil, under greenhouse conditions. Coconut husk biochar did not influence available soil Cu; however, its presence increased shoot Cu uptake by 117% and 38% in the two last growth cycles. Orange bagasse biochar, at the 60 t ha-1 application rate, reduced Cu availability, but it was not effective in reducing Cu uptake. Sewage sludge biochar did not affect Cu availability and caused an approximated 100% increase in shoot Cu uptake at the highest application rate. Therefore, the orange bagasse biochar is the most effective whereas the sewage sludge biochar is the least in Cu immobilization. None of the biochars was shown to be suitable as soil amendment to reduce the uptake of Cu by Indian mustard. However, coconut shell and sewage sludge biochar can be effectively applied to soil as an auxiliary tool to remediate Cu contaminated soils. PMID- 29525656 TI - Toxicity evaluation of lignocellulose-derived phenolic inhibitors on Saccharomyces cerevisiae growth by using the QSTR method. AB - Quantitative Structure-toxicity Relationship (QSTR) models were built to evaluate the toxicity of lignocellulose-derived phenolic inhibitors on the growth of Saccharomyces cerevisiae in a bioethanol production process. The established models were proved to be reliable after rigorous validation and showed values of R2 > 0.6 and Q2LOO > 0.5. They could provide accurate guidance for alleviating the most toxic inhibitors in pretreated lignocellulosic hydrolysates, thus facilitating bioethanol production. The results showed that the inhibitors that possessed unsaturated bonds, formyl groups and carbonyl group substituents showed obvious toxicity effects. The toxicity of the inhibitors with ortho-electron withdrawing substituents was stronger than that of metra- or para-electron donating substituents. Ferulic acid was chosen to analyze its toxicity in practical alkali-pretreated rice straw hydrolysates because of its strong toxicity and high concentration. The results showed that its toxicity was up to 82%, which was suggested to be dominantly detoxified in the bioethanol production process. PMID- 29525657 TI - Transcriptome analysis reveals the role of nitric oxide in Pleurotus eryngii responses to Cd2+ stress. AB - Pleurotus eryngii is widely cultivated in China. However, our understanding of its transcriptional response to heavy metal stress and the underlying mechanism of nitric oxide (NO) in enhancing its tolerance to heavy metals is limited. In the present study, RNA-seq was used to generate large transcript sequences from P. eryngii exposed to cadmium chloride (CdCl2) and exogenous NO. A total of 45,833 unigenes were assembled from the P. eryngii transcriptome, of which 32,333 (70.54%) unigenes matched known proteins in the nr database. Transcriptional analysis revealed that putative genes encoding heat shock proteins (HSPs) and genes participating in glycerolipid metabolism and steroid biosynthesis were significantly up-regulated in P. eryngii exposed to 50 MUM Cd (P < 0.05). P. eryngii mycelia exposed to extremely high levels of heavy metals showed an increase in biomass when exogenous NO was added to the culture. The collaboration of putative oxidoreductase, dehydrogenase, reductase, transferase genes and transcription factors such as "GTPase activator activity", "transcription factor complex", "ATP binding", "GTP binding", and "enzyme activator activity", which were significantly up-regulated in samples induced by exogenous NO, contributed to the enhancement of P. eryngii tolerance to extremely high levels of heavy metals. The study provides a new insight into the transcriptional response of P. eryngii to extremely high levels of heavy metals and the mechanism of NO in enhancing heavy metal tolerance. PMID- 29525658 TI - Removal of perfluorooctanoic acid in simulated and natural waters with different electrode materials by electrocoagulation. AB - Increasing attentions have been paid on widespread perfluorooctanoic acid (PFOA) contaminations in the environment globally, especially in the industrial wastewaters and natural water bodies. In order to perform the treatment of PFOA simulated solution effectively with periodically reverse electrocoagulation (PREC), intensive studies were implemented on the conditions of treatment and adsorption mechanism. The optimal conversion rate of 1 mg L-1 PFOA treatment could be achieved 99.6% with Al-Zn electrode, when the voltage and stirring speed were set to 9 V and 500 rmp. The energy consumption of treating PFOA simulated aqueous solution at 20 min using Al-Zn electrodes was 43.93 kWh kg-1. In addition, the PREC technique was further applied to eliminate the PFOA contaminations in the natural groundwater, generating the conversion rate up to 79.4% at 60 min. Moreover, it was verified that PFOA contamination was adsorbed on the flocs of Zn0.61Al0.39(OH)2(CO3)0.195.xH2O by the detection of X-ray diffraction spectra (XRD) and Fourier transform infrared (FTIR) spectrum, the mainly mechanism was adsorption bringing and enmeshment, primarily resulting from the hydrophobic interaction of PFOA and Al-Zn hydroxide flocs. PMID- 29525659 TI - Occurrence of benzothiazole and its derivates in tire wear, road dust, and roadside soil. AB - Benzothiazole (BT) and its derivates are commonly used as vulcanization accelerators in rubber production. Information on the occurrence of BTs in road dust (RD) and on human exposure to these compounds is very limited. BT and its six derivates in tire wear particles (TWPs) and RD were determined in this study. Samples were extracted using solid-liquid extraction, purified by a HLB SPE column, and determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). All seven BTs were found in 17 TWPs samples from different tire brands. The mass fractions of all seven BTs (?BTs) in TWPs ranged from 46.93 to 215 MUg/g with an average concentration of 99.32 MUg/g. Benzothiazole and 2-hydroxybenzothiazole (2-OH-BT) were the two major compounds, accounting for 56%-89% of the total. The seven BTs were also found in all 36 sets of RD samples (each set included one sample of TSP (particles < 75 MUm in diameter), PM10 (particles < 10 MUm in diameter) and PM2.5 (particles < 2.5 MUm in diameter)) fractions of RD. The median ?BTs concentration was highest in PM2.5 (26.62 MUg/g), followed by PM10 (22.03 MUg/g), and TSP (0.68 MUg/g). Of the seven BTs, BT, 2-aminobenzothiazole (2-NH2-BT), 2-mercaptobenzothiazole (MBT), and 2 (methylthio)benzothiazole (MTBT) were distributed in PM2.5 and 2-OH-BT was distributed in PM2.5-10 of RD. Based on the mass fractions of BTs in the TSP, PM10, and PM2.5 fractions of RD, human exposure via ingestion, inhalation and dermal absorption were evaluated. Ingestion was found to be the main exposure pathway in humans, and daily intake of BTs in PM2.5 was highest, followed by PM10 and TSP, respectively. Children may suffer more health risks than adults when exposed to RD. PMID- 29525660 TI - Kinetic and mechanistic study of the gas-phase reaction of CxF2x+1CHCH2 (x=1, 2, 3, 4 and 6) with O3 under atmospheric conditions. AB - The relative-rate technique has been used to determine the rate coefficient for the reaction of CxF2x+1CHCH2 (x = 1, 2, 3, 4 and 6) with ozone at (298 +/- 2) K and (720 +/- 5) Torr of air by FTIR (Fourier Transform Infrared Spectroscopy) and by GC-MS/SPME (Gas Chromatography-Mass Spectroscopy with Solid Phase Micro Extraction) in two different atmospheric simulation chambers. The following rate coefficients, in units of 10-19 cm3 molecule-1 s-1, were obtained: (3.01 +/- 0.10) for CF3CHCH2, (2.11 +/- 0.35) for C2F5CHCH2, (2.34 +/- 0.42) for C3F7CHCH2, (2.05 +/- 0.31) for C4F9CHCH2 and (2.07 +/- 0.39) for C6F13CHCH2, where uncertainties represent +/-2sigma statistical error. The atmospheric lifetime of CxF2x+1CHCH2 due to reaction with ozone was estimated from the reported rate coefficients. Additionally, the gaseous products formed in these reactions were investigated in the presence of synthetic air simulating a clean atmosphere. Perfluoroaldehydes, CxF2x+1C(O)H (PFALs), formaldehyde, formic acid and CF2O were identified as reaction products in the investigated reactions. The identified products made possible to propose a reaction mechanism that justifies the observed products. The atmospheric implications of these results are discussed in terms of the potential contribution of the atmospheric degradation of these species to PFAL and PFCA burden. PMID- 29525661 TI - Phosphorus transformations at the sediment-water interface in shallow freshwater ecosystems caused by decomposition of plant debris. AB - We studied the processes and mechanisms that drove phosphorus (P) release and transformations at the sediment-water interface (SWI) because of the decomposition of plant debris. The results showed that, as the simulation time increased, the pH, dissolved oxygen (DO), and oxidation reduction potential (ORP) in Duckweed+Sediment+Water (DWS) and Duckweed+Water (DW) initially decreased and then increased before stabilizing. Changes in the physicochemical characteristics affect the microhabitat and the release and transformations of P at the SWI. The initial flux of total P (TP), total dissolved phosphorus (TDP), and soluble reactive phosphorus (SRP) was 886, 515, and 441 mg m-2 d-1 in DWS and 626, 376, and 330 mg m-2 d-1 in DW, respectively. As the plant debris decomposed, the fluxes of TP, TDP, and SRP decreased, and after 11 days, the fluxes remained at around 0 mg m-2 d-1. The dissolved organic phosphorus (DOP) flux followed different trends in DWS and DW, and increased first to a maximum of 285 and 109 mg m-2 d-1, respectively, by day 6. The results of this study indicate that plant debris decomposition drive P transformations at the SWI in shallow freshwater ecosystems. Therefore, to control internal sources and transformations of P, plant debris should be removed and harvested. This study also indicates that intervention is needed to ensure the health of freshwater ecosystems, and we cannot hope to get satisfactory results from only improving the national wastewater discharge standards. PMID- 29525662 TI - Modeling avian exposures to perfluoroalkyl substances in aquatic habitats impacted by historical aqueous film forming foam releases. AB - Releases of Perfluoroalkyl and Polyfluoroalkyl Substances (PFASs) associated with Aqueous Film Forming Foams (AFFFs) have the potential to impact on-site and downgradient aquatic habitats. Dietary exposures of aquatic-dependent birds were modeled for seven PFASs (PFHxA, PFOA, PFNA, PFDA, PFHxS, PFOS, and PFDS) using five different scenarios based on measurements of PFASs obtained from five investigations of sites historically-impacted by AFFF. Exposure modeling was conducted for four avian receptors representing various avian feeding guilds: lesser scaup (Aythya affinis), spotted sandpiper (Actitis macularia), great blue heron (Ardea herodias), and osprey (Pandion haliaetus). For the receptor predicted to receive the highest PFAS exposure (spotted sandpiper), model predicted exposure to PFOS exceeded a laboratory-based, No Observed Adverse Effect Level exposure benchmark in three of the five model scenarios, confirming that risks to aquatic-dependent avian wildlife should be considered for investigations of historic AFFF releases. Perfluoroalkyl sulfonic acids (PFHxS, PFOS, and PFDS) represented 94% (on average) of total PFAS exposures due to their prevalence in historical AFFF formulations, and increased bioaccumulation in aquatic prey items and partitioning to aquatic sediment relative to perfluoroalkyl carboxylic acids. Sediment-associated PFASs (rather than water associated PFASs) were the source of the highest predicted PFAS exposures, and are likely to be very important for understanding and managing AFFF site-specific ecological risks. Additional considerations for research needs and site-specific ecological risk assessments are discussed with the goal of optimizing ecological risk-based decision making at AFFF sites and prioritizing research needs. PMID- 29525663 TI - Evaluation of toxicity, mutagenicity and carcinogenicity of samples from domestic and industrial sewage. AB - Physico-chemical and toxicological analyses are of fundamental importance to determine water quality. The objectives of the present study were to evaluate the toxicity, mutagenicity and carcinogenicity of samples from the Mumbuca Stream and the Perdizes River, through both SMART and the wts test, respectively, in somatic cells of Drosophila melanogaster and to quantify the amount of heavy metals and other pollutants, which are indicative of environmental quality. Water samples were collected (M1, M2, P1, P2 and MP) and submitted to physico-chemical analysis, calculating the water quality index for each sampling site. In order to evaluate the toxicity, mutagenicity and carcinogenicity of the samples, third instar larvae descended from the crossing between virgin female wts/TM3, sb1 and mwh/mwh males (wts test) and ST and HB (SMART) crosses were treated with samples from P1, P2, M1, M2 and MP sites. The physico-chemical analysis and the biological assay allowed us to conclude that undetected values for heavy metals and the low frequency of mutant spots (SMART) and epithelial tumor (wts) in treated flies from the Mumbuca Stream and Perdizes River may be due to the reduction of ceramic activities in the municipality. The physico-chemical analyzes identified altered the environmental quality parameters, which directly influenced the survival of D. melanogaster treated with samples of M2 and MP, which according to the WQI were classified as regular and poor environmental quality, respectively. The altered parameters may be due to clandestine domestic sewage sent downstream of the effluent. PMID- 29525664 TI - Development of a new ecotoxicological assay using the testate amoeba Euglypha rotunda (Rhizaria; Euglyphida) and assessment of the impact of the herbicide S metolachlor. AB - An ever-increasing diversity of potentially toxic chemical compounds are being developed and released into the environment as a result of human activities (e.g. agriculture, drugs, and cosmetics). Among these, pesticides have been shown to affect non-targeted wildlife since the 1960s. A range of ecotoxicological tests are used to assess the toxicity of pesticides on various model organisms. However most model organisms are metazoans, while the majority of Eukaryotes are unicellular microorganisms known as protists. Protists are ubiquitous organisms of key functional roles in all ecosystems but are so far little studied with respect to pesticide impact. To fill this gap, we developed a new ecotoxicological test based on Euglypha rotunda, a common soil amoeba, grown in culture flask with Escherichia coli as sole food source. We tested this assay with the herbicide S-metolachlor, which is known to affect cell division in seedling shoots and roots of weeds. Reproducible growth conditions were obtained for E. rotunda. The growth of E. coli was not affected by the herbicide. The growth of E. rotunda was affected by the herbicide in a non-linear way, growth being significantly reduced at ca. 15 MUg/L, but not at 150 MUg/L. Our results show the potential for using soil protists in ecotoxicology and adds to the growing body of evidence for non-linear impacts of pesticides on non-target organisms. With the acquisition of additional data, the protocol should be suitable for standard ecotoxicological tests. PMID- 29525665 TI - 4-Chlorophenol degradation using ultrasound/peroxymonosulfate/nanoscale zero valent iron: Reusability, identification of degradation intermediates and potential application for real wastewater. AB - In this study, nanoscale-zero valent iron (nZVI) was synthesized and its function was assessed in ultrasound (US)/peroxymonosulfate (PMS)/nZVI process to degrade 4 chlorphenol (4-CP). The influential operation parameters of US/PMS/nZVI were evaluated on 4-CP degradation. 95% of 4-CP was degraded during 30 min under the conditions of pH = 3.0, nZVI = 0.4 g/L, PMS = 1.25 mM, US power = 200 W. The rate constants of 4-CP degradation for US/PMS/nZVI, PMS/nZVI, US/PMS and US/nZVI were 0.1159, 0.03, 0.0134 and 0.0088 min-1 respectively. Simultaneous application of US and nZVI synergistically increased 4-CP degradation and PMS activation. nZVI was compared with Fe2+, Fe3+ and micro-ZVI and their results indicated high performance of nZVI compared to others. Reusability of nZVI was examined in four cycles. nZVI exhibited that reusability was acceptable in three runs. The results of effect of anions showed that phosphate had significant inhibitory effect on 4 CP degradation in US/PMS/nZVI process. The scavenging experiments indicated that hydroxyl radical had more contribution compared to sulfate radical. Intermediates of 4-CP degradation were identified including five aromatic compounds. Reaction pathway of 4-CP degradation was proposed. Finally, the performance of US/PMS/nZVI process was evaluated on real petrochemical wastewater. The results showed that US/PMS/nZVI can be a suitable pretreatment for biological treatment. PMID- 29525666 TI - Dissolution and redistribution of trace elements and nutrients during dredging of iron monosulfide enriched sediments. AB - The increased use of estuarine waters for commercial and recreational activities is one consequence of urbanisation. Western Australia's Peel-Harvey Estuary highlights the impacts of urbanisation, with a rapidly developing boating industry and periodic dredging activity. The aim of this research is to evaluate the potential mobility of nutrients and trace elements during dredging, and the influence of flocculation on iron and sulfur partitioning in iron monosulfide enriched sediments. Our findings indicate a short-term increase in nitrate, phosphate and ammonium, during dredging through the resuspension of sediments. However, no increase in metal mobilisation during dredging was observed except copper (Cu) and zinc (Zn). Flocculant addition increased the release of nutrients, zinc (Zn) and arsenic (As) from sediments, had no effect on acid volatile sulfides and pyritic sulfur, but corresponded with an initial sharp rise in elemental sulfur concentrations. The run-off water from geofabric bags should be treated to decrease the concentrations of Zn and As to their background levels before releases into the estuary. Long-term impact of dredging on organic matter mineralisation and its subsequent effect on nutrients and trace elements dynamics needs further investigation. PMID- 29525667 TI - Effect of fatigue protocols on flexural strength of lithium disilicate bars with clamped-ends. AB - The aim of this study was compare the effect of two in vitro ageing protocols to intraoral aging on the flexural strength of a lithium disilicate (LD) ceramic bars with clamped ends. After polishing and crystallization, the both ends of the bars were cemented to a metallic device and subjected to mechanical cycling, thermomechanical cycling, or intraoral ageing. Ten volunteers used an intraoral device - similar to an occlusal splint with a balanced contact condition on the occlusal surface of the ceramic bar - during 8 h night time / 30 days. Both in vitro and intraoral ageing decreased the flexural residual strength of LD, with the lowest values obtained after intraoral ageing. Thus, the in vitro ageing protocols tested in this study revealed to be less deleterious than intraoral ageing of LD. PMID- 29525669 TI - Molecular recognition by synthetic receptors: Application in field-effect transistor based chemosensing. AB - Molecular recognition, i.e., ability of one molecule to recognize another through weak bonding interactions, is one of the bases of life. It is often implemented to sensing systems of high merits. Preferential recognition of the analyte (guest) by the receptor (host) induces changes in physicochemical properties of the sensing system. These changes are measured by using suitable signal transducers. Because of possibility of miniaturization, fast response, and high sensitivity, field-effect transistors (FETs) are more frequently being used for that purpose. A FET combined with a biological material offers the potential to overcome many challenges approached in sensing. However, low stability of biological materials under measurement conditions is a serious problem. To circumvent this problem, synthetic receptors were integrated with the gate surface of FETs to provide robust performance. In the present critical review, the approach utilized to devise chemosensors integrating synthetic receptors and FET transduction is discussed in detail. The progress in this field was summarized and important outcome was provided. PMID- 29525668 TI - Study of inflammatory factors' effect on the endothelial barrier using piezoelectric biosensor. AB - This paper used piezoelectric sensor to study the dysfunction of endothelial cell monolayer barrier caused by inflammatory factors. The biocompatible conductive polymer membrane of pPy[pGlu]-pLys was prepared on the surface of the ITO work electrode to improve the interface between the endothelial cell and the electrode. Both the impedance analysis data and the stable plateau stage of sensor's frequency shift indicated that endothelial cells formed a good monolayer barrier on this polymer surface. The response frequency shifts of lipopolysaccharide (LPS)- and histamine-induced endothelial barrier dysfunction were different, which distinguished their different stimulation mechanism. It provided a valuable analysis method for detecting the endothelial barrier function affected by inflammatory factor, and could further promote the application of piezoelectric sensor in cell biology and toxicology research. PMID- 29525671 TI - Enhancement of safety and immunogenicity of the Chinese Hu191 measles virus vaccine by alteration of the S-adenosylmethionine (SAM) binding site in the large polymerase protein. AB - The live-attenuated measles virus (MV) vaccine based on the Hu191 strain has played a significant role in controlling measles in China. However, it has considerable adverse effects that may cause public health burden. We hypothesize that the safety and efficacy of MV vaccine can be improved by altering the S adenosylmethionine (SAM) binding site in the conserved region VI of the large polymerase protein. To test this hypothesis, we established an efficient reverse genetics system for the rMV-Hu191 strain and generated two recombinant MV-Hu191 carrying mutations in the SAM binding site. These two mutants grew to high titer in Vero cells, were genetically stable, and were significantly more attenuated in vitro and in vivo compared to the parental rMV-Hu191 vaccine strain. Importantly, both MV-Hu191 mutants triggered a higher neutralizing antibody than rMV-Hu191 vaccine and provided complete protection against MV challenge. These results demonstrate its potential for an improved MV vaccine candidate. PMID- 29525670 TI - Cellular Hsp27 interacts with classical swine fever virus NS5A protein and negatively regulates viral replication by the NF-kappaB signaling pathway. AB - Classical swine fever virus (CSFV) nonstructural protein NS5A is a multifunctional protein functioning in regulation of viral genome replication, protein translation and assembly by interaction with viral or host proteins. Here, heat shock protein 27 (Hsp27) has been identified as a novel binding partner of NS5A by using His tag "pull down" coupled with shotgun LC-MS/MS, with interaction of both proteins further confirmed by co-immunoprecipitation and laser confocal assays. In PK-15 cells, silencing of Hsp27 expression by siRNA enhanced CSFV replication, and upregulation of Hsp27 inhibited viral proliferation. Additionally, we have shown that overexpression of Hsp27 increased NF-kappaB signaling induced by TNFalpha. Blocking NF-kappaB signaling in PK-15 cells overexpressing Hsp27 by ammonium pyrrolidinedithiocarbamate (PDTC) eliminated the inhibition of CSFV replication by Hsp27. These findings clearly demonstrate that the inhibition of CSFV replication by Hsp27 is mediated via the NF-kappaB signaling pathway. PMID- 29525672 TI - Isoferulic acid attenuates methylglyoxal-induced apoptosis in INS-1 rat pancreatic beta-cell through mitochondrial survival pathways and increasing glyoxalase-1 activity. AB - Methylglyoxal (MG) is a reactive precursor to advanced glycation end-products (AGEs), which exert deleterious effects on cells and tissues. MG also causes pancreatic beta-cell dysfunction and apoptosis. Isoferulic acid (IFA), a naturally occurring cinnamic acid derivative, is considered to be an antiglycating agent. However, the effect of IFA on MG-induced pancreatic beta cell dysfunction remains unknown. The objective of this study was to determine the protective effect of IFA against MG-induced mitochrondrial dysfunction and apoptosis in INS-1 pancreatic beta-cells. The results showed that pretreatment of INS-1 cells with 100 MUM IFA for 48 h prevented MG-induced decrease in cell viability and impairment of glucose-stimulated insulin secretion (GSIS). In addition, 100 MUM IFA pretreatment also decreased MG-induced generation of reactive oxygen species (ROS) and upregulation of mitochondrial uncoupling protein 2 (Ucp2) mRNA expression. Furthermore, IFA pretreatment reduced MG induced increase in caspase-3 activity, suggesting a reduction of apoptotic cell death. IFA (50-100 MUM) itself markedly increased the activity of glyoxalase 1 (GLO1), a major enzyme for the detoxification of MG. The results showed that 100 MUM IFA protected MG-induced loss of GLO1 activity in INS-1 cells. These findings suggest that IFA pretreatment attentuates MG-induced dysfunction and apoptosis in INS-1 pancreatic beta-cells through mitochondrial survival pathway and increasing GLO1 activity. PMID- 29525673 TI - Corrigendum to "double sword role of EZH2 in leukemia" [Biomed. Pharmacother. 98 (2018) 626-635]. PMID- 29525674 TI - In renal hypertension, Cirsium japonicum strengthens cardiac function via the intermedin/nitric oxide pathway. AB - Cirsium japonicum, a constituent of traditional Chinese medicine, has been shown to exert inflammatory effects as well as to improve the circulation and thus to counteract hematologic stasis. Studies have demonstrated that intermedin (IMD) has protective effects on hypertension in rats by regulating the Ang/NO metabolic pathway. In this study, we investigated whether by regulating the expression of IMD, Cirsium japonicum could improve cardiac function in rats with 2k1c-induced renal hypertension. Renal hypertension was induced in Sprague-Dawley rats by occluding the renal artery. The rats were maintained on a normal diet and randomly divided into four groups: sham, 2k1c, 2k1c with Cirsium japonicum (1.8 g/kg per day) and 2k1c with IMD (n = 10 in each group). Cardiac function, plasma angiotensin II (Ang II), IMD, serum nitric oxide (NO) and nitric oxide synthase (NOS), as well as the expression of IMD and adrenomedullin (ADM) in the aorta and left ventricle were analyzed. Administration of Cirsium japonicum or IMD significantly strengthened cardiac function in 2k1c-induced rats, increased serum NO and NOS levels, reduced plasma Ang II, and upregulated IMD expression in the aorta and left ventricle. These results demonstrate that Cirsium japonicum has cardioprotective effects on 2k1c-induced renal hypertension in rats via the IMD/NO pathway. PMID- 29525675 TI - Reduction in nitric oxide bioavailability shifts serum lipid content towards atherogenic lipoprotein in rats. AB - Nitric oxide (NO) is major endothelial relaxing factor and reduction in its bioavailabilty has been linked to hypertension. Furthermore, high lipid content is a strong risk factor predisposing to cardiovascular diseases. The principal focus of this study was to investigate the effect of blockade of nitric oxide synthase (NOS) on serum lipid content in rats. Male Wistar rats (150-170 g, n = 15) were randomly divided into two groups designated control (n = 5), and L-Name group (n = 10) and were gavage with distilled water and 60 mg/kg of L-NAME respectively daily for three weeks. After 3 weeks, the L-NAME group was sub divided into two sub-groups (n = 5 each): L-NAME (60 mg/kg of L-NAME), and L-NAME plus ramipril (LR) (60 mg/kg of L-NAME plus 20 mg/kg of ramipril) and were treated daily for another three weeks. The blood pressure (BP) of the conscious rats was measured by tail-cuff method at the onset, at the third and at the sixth weeks of the experiment; while serum lipid contents and NO were measured at the third and sixth weeks. At the end of the experiment blood sample was drawn by ocular puncture for evaluation of lipid profile and NO, and the animals were later euthanized by overdose of anaesthesia. Data were analyzed using ANOVA at p < 0.05. There was a significant increase in BP, triglyceride, total cholesterol, low density lipoprotein-cholesterol, and atherogenic indices in L-NAME group compared to the control and LR group (p < 0.05); NO and high density lipoprotein cholesterol was significant lower in the L-NAME group compared to control and LR (p < 0.05). In conclusion, reduction in NO bioavailability alters lipid metabolism, which was rectified by ramipril. PMID- 29525676 TI - Adiponectin as a potential therapeutic target for the treatment of restenosis. AB - Restenosis is a pathologic re-narrowing of a coronary artery lesion after mechanical injury. Its pathophysiological mechanisms have not been fully elucidated at present, but are thought to include inflammation, vascular smooth muscle cell (VSMC) proliferation, and matrix remodeling, beginning with insufficient endothelium healing. Restenosis presents with angina symptoms or acute coronary syndromes and lead to a revascularization, either with coronary artery bypass or repeat percutaneous coronary intervention. Some studies have reported that hypoadiponectinemia has been an independent risk factor for the onset of acute coronary syndromes and restenosis. Accumulating evidence shows that low concentrations of adiponectin may be involved in impairing endothelium functions, inflammation, and VSMC proliferation that lead to restenosis. Preclinical studies have proven that adiponectin promotes endothelium healing, effectively inhibits inflammation, and maintains contractile phenotypes of VSMCs, indicating that it may be developed as a new therapeutic target for the treatment of restenosis. PMID- 29525677 TI - An in vitro comparative study of the antioxidant activity and SIRT1 modulation of natural compounds. AB - Oxidative stress arises from an imbalance between the production of free radicals and antioxidant defences. Several studies have suggested that dietary antioxidants (such as polyphenols and berberine) may counteract oxidative stress through the involvement of the Sirtuin 1/Adenosine Monophosphate-Activated Protein Kinase (SIRT1/AMPK) pathway. The aim of this study was to evaluate the direct and specific antioxidant activity of some natural compounds, as well as their ability to modulate the expression of SIRT1 and the activation of AMPK. Quercetin, tyrosol, ferulic acid, catechin, berberine and curcumin were evaluated for their specific and direct antioxidant activity with TOSC assay. Their ability to modulate SIRT1 and AMPK was assessed by immunoblotting assay, while their cytotoxicity by CellTiter-Blue Cell Viability Assay. No statistically significant decrease (p > 0.05) in the number of viable cells was found upon challenging with the natural compounds. Quercetin exhibited the highest antioxidant activity against peroxyl radical and peroxinitrate derivates, while curcumin showed the best anti-hydroxyl activity with respect to the other compounds and, most importantly, respect to the reference antioxidants. Finally, all the tested compounds significantly increased the SIRT1 expression and the activation of AMPK. Our results clearly disclose the specific antioxidant activity of these natural compounds and their ability to increase SIRT1 expression and AMPK activation. PMID- 29525678 TI - Corrigendum to "Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review" [Biomed. Pharmacother. 92 (2017) 681-689]. PMID- 29525679 TI - The IL-10-1082 (rs1800896) G allele is associated with a decreased risk of developing premature coronary artery disease and some IL-10 polymorphisms were associated with clinical and metabolic parameters. The GEA study. AB - Interleukin 10 (IL-10) is an anti-inflammatory cytokine with a protective role in the formation and the development of the atherosclerotic plaque. The aim of the present study was to establish if IL-10 gene polymorphisms are associated with the development of premature coronary artery disease (pCAD) and cardiovascular risk factors in Mexican individuals. Three IL-10 gene polymorphisms [-592C/A (rs1800872), -819C/T (rs1800871), and -1082 A/G (rs1800896)] and IL-10 plasma levels were analyzed in 2266 individuals (1160 pCAD patients and 1106 healthy controls). Under recessive and co-dominant2 models, the -1082 A/G (rs1800896) G allele was associated with decreased risk of developing pCAD (OR = 0.572, Prec = 0.022 and OR = 0.567, Pcod2 = 0.023). In pCAD patients, the polymorphisms were associated with hyperinsulinemia, small and dense LDLs, hypertension, and diabetes mellitus. In the control group, the polymorphisms were associated with hypertension, hyperuricemia, and small and dense LDLs. pCAD patients have significantly higher IL-10 plasma levels than healthy controls [0.91 (0.55-1.67) pg/mL vs 0.45 (0.24-0.98) pg/mL, respectively, P < 0.0001]. Nevertheless, these levels were not associated with the genotypes analyzed in the present study. The results suggest that the IL-10-1082 A/G (rs1800896) G allele is associated with a decreased risk of developing pCAD. In patients and controls, the polymorphisms analyzed were associated with some cardiovascular risk factors. Although, in pCAD patients the IL-10 plasma levels were higher, they were not associated with the genotypes of the polymorphisms examined. PMID- 29525680 TI - I see neither your Fear, nor your Sadness - Interoception in adolescents. AB - Interoception describes the mapping of the body's internal landscape and has been connected to greater intensity of emotional experience. The goal of the current study was to explore the relationship between interoception and emotion face recognition in healthy adolescents. The heartbeat perception task was used to assess interoceptive accuracy(IAC) and participants were asked to recognize different facial expressions. EEG activity was recorded, providing data for the P100, the N170 and the P300 ERP components. Results indicated high sensitivity to negative affect, as well as low accuracy in the recognition of fear and sadness among adolescents high in IAC, reflected by amplitude modulations in the N170 and the P300. The interpretation of these results focus on the intensity experienced in negative facial emotions, modified by IAC, as well as on emotional valence and arousal. These findings emphasize the dynamic integration of body and mind for shaping emotion recognition in adolescence. PMID- 29525681 TI - Gut microbiota dysbiosis is associated with Henoch-Schonlein Purpura in children. AB - BACKGROUND: Alterations in the intestinal microbiota have been associated with the development of allergic diseases, such as asthma and food allergies. However, there is no report detailing the role of microbiota alterations in Henoch Schonlein Purpura (HSP) development. METHOD: A total of 85 children with HSP and 70 healthy children were recruited for this study. Intestinal microbiota composition was analyzed by 16S rRNA gene-based pyrosequencing. Fecal microbial diversity and composition were compared. RESULT: We compared the gut microbiota of 155 subjects and found that children with HSP exhibited gut microbial dysbiosis. Lower microbial diversity and richness were found in HSP patients when compared to the control group. Based on an analysis of similarities, the composition of the microbiota in HSP patients was also different from that of the control group (r = 0.306, P = 0.001). The relative abundance of the bacterial genera Dialister (P < 0.0001), Roseburia (P < 0.0001), and Parasutterella (P < 0.0001) was significantly decreased in HSP children, while the relative abundance of Parabacteroides (P < 0.006) and Enterococcus (P < 0.0001) in these children was significantly increased. Based on Spearman correlation analysis, the LOS showed a significant negative (P < 0.05) correlation with the genera Paraprevotella and Roseburia. Meanwhile, IgA levels exhibited a significant negative (P < 0.01) correlation with the genus Bifidobacterium. CONCLUSIONS: Our results indicate that HSP is associated with significant compositional and structural changes in the gut microbiota. These results enhance the potential for future microbial-based therapies to improve the clinical outcome of HSP in children. PMID- 29525682 TI - S-allylmercaptocysteine attenuates posaconazole-induced adverse effects in mice through antioxidation and anti-inflammation. AB - Posaconazole is a broad-spectrum antibacterial drug for the treatment of invasive fungal infections. However, its clinical usage is limited by a lot of adverse reactions such as diarrhea. S-allylmercaptocysteine (SAMC), a garlic organosulfur compound, has a strong antioxidative and anti-inflammatory activity. This study aimed to examine the protective effects of SAMC on posaconazole-induced adverse effects. Mice were treated with the blank control, enteric coated posaconazole microparticles (POS group) and its combination with SAMC (Combination group). Oxidative stress markers, antioxidative activities and histological changes in the study mice were investigated. We found that the percentage of mice diarrhea was reduced by 20% in the combination group after administration for 1 week. The results reveal that the levels of TNF-alpha (p < 0.05), IL-1beta (p < 0.01) and IL-6 (p < 0.01) in the serum of the POS group were significantly higher compared to the control group while the combination group decreased the POS-induced cytokine elevations (p < 0.05). The MDA content in colon tissues of the POS group increased distinctly (p < 0.01) compared with the control group. The combination groups dosed with the low and high strengths of SAMC decreased the MDA level about 20% and 30%, respectively, compared to the POS group. The histopathological results display that the colonic tissues of the combination groups had significant improvement in mucosal adhesions and inflammatory infiltration versus the POS group. Briefly, SAMC could alleviate the POS-induced adverse reactions by the mechanisms of antioxidation and anti-inflammation. PMID- 29525683 TI - Maternal dietary exposure to selenium nanoparticle led to malformation in offspring. AB - Selenium (Se) is an essential element and its biological activity is related to its speciation. It is also well-known that in excess it can cause teratogenesis in fish and birds. In this study we compared dietary toxicity of elemental selenium nanoparticles (SeNPs) with selenite and selenomethionine (Se-Met). Japanese medaka (Oryzias latipes) was used as a laboratory model to determine Se effects on adults and their offspring. Adult females were individually exposed using a dry diet fortified with 0, 10 or 20 ug/g of the three Se species for 7 days and then allowed to breed for 3 days. Fertilization rate and the proportion of malformed offspring were examined. The three Se diets led to significant increase in maternal tissue Se concentration in the order of Se-Met >>selenite > SeNP. However, in terms of proportion of malformed offspring, the effect of Se Met = selenite > SeNP. The malformations included pericardial edema and craniofacial changes, which were typical for Se toxicity. The mismatch of maternal ovary Se concentration and proportion of malformed offspring suggested total Se concentration is a poor predictor of toxicity and teratogenesis. Comparing expression of four genes related to oxidative stress in maternal tissue also showed that there were significant differences in expression patterns between three Se diets in the order of selenite = SeNP > Se-Met. Our results showed that SeNPs cause similar toxicity as other Se species but require further study to elucidate the underlying mechanism. PMID- 29525684 TI - Biochemical responses of Gammarus pulex to malachite green solutions decolorized by Coriolus versicolor as a biosorbent under batch adsorption conditions optimized with response surface methodology. AB - The current study was aimed to investigate the detoxifying and antioxidant enzyme response of Gammarus pulex exposed to malachite green (MG) after decolorization by Coriolus versicolor. Response surface methodology (RSM) was utilized to optimize the decolorization conditions of MG synthetic solutions by C. versicolor. Glutathione (GSH), malondialdehyde (MDA) levels and glutathione peroxidase (GPX), catalase (CAT), superoxide dismutase (SOD), glutathione S transferase (GST), cytochrome P450 1A1 (CYP1A1) activities in G. pulex exposed to undecolorized (A1) and decolorized (A2) MG synthetic solution during 24 and 96 h were tested by using ELISA method. SOD and GPX enzyme activity was increased after decolorization (p > 0.05). CAT enzyme activity was increased in A2 group during 24 h (p > 0.05) but decreased during 96 h (p < 0.05). GSH levels were increased in A2 group during 24 and 96 h (p < 0.05). GST, CYP1A1 enzyme activity and MDA levels were decreased after decolorization during 96 h (p < 0.05). In this study, GSH levels, CAT, GST and CYP1A1 activities in G. pulex approved the capability of C. versicolor in MG decolorization, optimized with RSM. PMID- 29525685 TI - Involvement of neuronal nitric oxide synthase in cross-sensitization between chronic unpredictable stress and ethanol in adolescent and adult mice. AB - The peculiar neurochemical profile of the adolescent brain renders it differently susceptible to several stimuli, including stress and/or drug exposure. Among several stress mediators, nitric oxide (NO) has a role in stress responses. We have demonstrated that adolescent mice are less sensitive to ethanol-induced sensitization than adult mice. The present study investigated whether chronic unpredictable stress (CUS) induces behavioral sensitization to ethanol in adolescent and adult Swiss mice, and investigated the influence of Ca2+-dependent nitric oxide synthase (NOS) activity in the phenomenon. Adolescent and adult mice were exposed to repeated 1.8 g/kg ethanol or CUS and challenged with saline or ethanol. A neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7NI), was administered along with ethanol and CUS to test its effects on behavioral sensitization. Both adolescent and adult mice displayed cross sensitization between CUS and ethanol in adult mice, with adolescents showing a lower degree of sensitization than adults. nNOS inhibition by 7NI reduced both ethanol sensitization and cross-sensitization. All age differences in the Ca2+ dependent NOS activity in the hippocampus and prefrontal cortex were in the direction of greater activity in adults than in adolescents. Adolescents showed lower sensitivity to cross-sensitization between CUS and ethanol, and the nitric oxide (NO) system seems to have a pivotal role in ethanol-induced behavioral sensitization and cross-sensitization in both adolescent and adult mice. PMID- 29525686 TI - Gestational carrier use in assisted reproductive technology: what can it tell us about the uterine role in infertility? PMID- 29525687 TI - Ovarian reserve in polycystic ovary syndrome: more, but for how long? PMID- 29525688 TI - Comparing the risk of adverse pregnancy outcomes of Chinese patients with polycystic ovary syndrome with and without antiandrogenic pretreatment. AB - OBJECTIVE: To evaluate the prevalence of adverse pregnancy outcomes in healthy Chinese women and to investigate whether these outcomes could be decreased in patients with polycystic ovary syndrome (PCOS) by ethinylestradiol/cyproterone acetate (EE/CPA) pretreatment. DESIGN: Retrospective study. SETTING: Medical university. PATIENT(S): Six thousand healthy women (group A) were selected from 24,566 pregnant women by randomized sampling. Four hundred forty-eight patients with PCOS without EE/CPA pretreatment were assigned to group B, and 222 patients with PCOS with 3 months of pretreatment to group C. All patients with PCOS had biochemical and/or clinical hyperandrogenism and conceived within 3 monthly ovulation inductions using clomiphene. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), premature delivery (PD), and neonatal birth weight. RESULT(S): The prevalence of GDM, PIH, and PD was higher in group B than in groups A and C (A vs. B vs. C: GDM, 21.2% vs. 35.0% vs. 22.5%; PIH, 6.5% vs. 14.1% vs. 7.7%; PD, 5.4% vs. 8.6% vs. 6.8%). No significant difference was found in neonatal birth weight. After adjusting for age, pregestational body mass index, education level, and employment status, PCOS without pretreatment increased the risk of GDM (adjusted odds ratio [aOR] = 1.666; 95% confidence interval [CI], 1.340-2.072), PIH (aOR = 1.487; 95% CI, 1.093-2.023), and PD (aOR = 1.522; 95% CI 1.051-2.205), compared with healthy women. No increased risk was found in group C. CONCLUSION(S): In our highly selected study population, patients with PCOS are more likely to develop GDM, PIH, and PD. Pretreatment with EE/CPA was associated with a lower risk of GDM, PIH, and PD. PMID- 29525689 TI - High number of endometrial polyps is a strong predictor of recurrence: findings of a prospective cohort study in reproductive-age women. AB - OBJECTIVE: To compare the incidence of recurrence between a cohort with a high number (>=6) of endometrial polyps (EPs) and a single-EP cohort among reproductive-age patients after polypectomy. DESIGN: Prospective observational cohort study. SETTING: Single university center. PATIENT(S): Premenopausal women who underwent hysteroscopic endometrial polypectomy were recruited. INTERVENTION(S): Patients underwent a transvaginal ultrasound scan every 3 months after polypectomy to detect EP recurrence. Kaplan-Meier and Cox regression models were used to compare the risk of recurrence between the two cohorts and analyze the potential risk factors for EP recurrence. MAIN OUTCOME MEASURE(S): EP recurrence rate. RESULT(S): The study enrolled 101 cases with a high number of EP and 81 cases with a single EP. All baseline parameters were similar except that the high number of EP cohort had a slightly lower mean age than the single EP cohort (33.5 [range 30.0-39.0] vs. 36.0 [30.5-43.0] years). The risk of recurrence in the high number of EP cohort was 4.08 (95% confidence interval [CI] 1.89-8.81) times higher than that in the single-EP cohort 1 year after polypectomy, with a recurrence rate of 45.5% versus 13.4%, respectively. A high number of EPs, endometriosis, and previous polypectomy history were independently associated with polyp recurrence. CONCLUSION(S): The high number of EP cohort was much more prone to recurrence than the single-EP cohort. A high number of EPs, endometriosis, and previous polypectomy history were independent risk factors for recurrence. A high number of EPs is suggested to be a distinct subgroup with different pathogenesis, which warrants frequent monitoring and prevention. PMID- 29525690 TI - Ulipristal acetate decreases transforming growth factor beta3 serum and tumor tissue concentrations in patients with uterine fibroids. AB - OBJECTIVE: To evaluate and compare transforming growth factor beta3 (TGF-beta3) serum concentration in patients with uterine fibroids (UFs) without hormone treatment, treated with ulipristal acetate (UPA), and controls; to evaluate TGF beta3 concentrations in UF tissue in patients without hormone treatment and those treated with UPA; and to evaluate the correlations of age and body mass index (BMI) with TGF-beta3 serum and UF tissue levels between the groups. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENT(S): A total of 141 patients divided into three groups: UFs non-UPA, UFs, and UPA, controls. INTERVENTION(S): Medical history and examination, genital ultrasound scan, blood and tissue sampling, and measurement of TGF-beta3 serum and tissue concentrations. MAIN OUTCOME MEASURE(S): Evaluation of the impact of UPA (3 months treatment), age and BMI on TGF-beta3 serum and UF tissue levels. RESULT(S): The values of TGF-beta3 serum and tissue concentrations statistically significantly differed between the non-UPA and UPA groups. The mean TGF-beta3 serum concentrations were non-UPA group 32.24 +/- 34.55 pg/mL, UPA group 10.88 +/ 7.15 pg/mL, and controls 11.97 +/- 10.30 pg/mL. The mean TGF-beta3 tissue concentrations were non-UPA group 171.29 +/- 91.81 pg/mg and UPA group 99.99 +/- 60.63 pg/mg. Statistically significantly lower mean TGF-beta3 serum and tissue concentrations were observed in patients treated with UPA. No statistically significant correlations between TGF-beta3 concentrations and age or BMI were found. CONCLUSION(S): Reduction of serum and tissue TGF-beta3 concentrations in UFs may be an important component of the effect of UPA on UF biology. Further research in this area is necessary. PMID- 29525691 TI - Impact of transfer time on pregnancy outcomes in frozen-embryo transfer cycles. AB - OBJECTIVE: To identify the impact of embryo transfer time (total seconds from the loading of the transfer catheter to the expulsion of the embryo(s) into the uterine cavity) on clinical pregnancy (CPR), implantation (IR), and live birth (LBR) rates. DESIGN: Retrospective cohort study. SETTING: Academic hospital practice. PATIENT(S): A total of 465 women undergoing 571 frozen-embryo transfers with the use of cryopreserved blastocysts in a single academic institution from 2007 through 2014. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): CPR, IR, and LBR. RESULT(S): The cohort was divided into tertiles according to transfer time in seconds (T1: 33-55; T2: 57-81; T3: 82-582) with mean (SD) transfer times of 47.4 (5.7), 67.1 (7.3), and 121.9 (55.1) seconds, respectively. Crude CPRs were 43.9%, 48.7%, and 48.7% among the respective tertiles, crude IRs were 36.9%, 39.9%, and 38.6%, and crude LBRs were 34.8%, 39.6%, and 36.0%. In univariate analysis, inferior cohort score, blood inside catheter, difficult mock transfer, and use of an outer sheath were negatively associated with CPR. No association was seen between physician performing the transfer (including fellows) and CPR. In multivariate regression, longer transfer time was not associated with CPR. With T1 as reference, adjusted odds ratios (95% confidence interval) were 1.28 (0.77-2.11) and 1.52 (0.85-2.71) for transfer time groups T2 and T3, respectively. CONCLUSION(S): After adjusting for potential confounders, this analysis found that contrary to commonly held belief, longer embryo transfer times do not negatively affect CPR, IR, or LBR. PMID- 29525692 TI - Reversing the similarity effect: The effect of presentation format. AB - A context effect is a change in preference that occurs when alternatives are added to a choice set. Models of preferential choice that account for context effects largely assume a within-dimension comparison process. It has been shown, however, that the format in which a choice set is presented can influence comparison strategies. That is, a by-alternative or by-dimension grouping of the dimension values encourage within-alternative or within-dimension comparisons, respectively. For example, one classic context effect, the compromise effect, is strengthened by a by-dimension presentation format. Extrapolation from this result suggests that a second context effect, the similarity effect, will actually reverse when stimuli are presented in a by-dimension format. In the current study, we presented participants with a series of apartment choice sets designed to elicit the similarity effect, with either a by-alternative or by dimension presentation format. Participants in the by-alternative condition demonstrated a standard similarity effect; however, participants in the by dimension condition demonstrated a strong reverse similarity effect. The present data can be accounted for by Multialternative Decision Field Theory (MDFT) and the Multiattribute Linear Ballistic Accumulator (MLBA), but not Elimination by Aspects (EBA). Indeed, when some weak assumptions of within-dimension processes are met, MDFT and the MLBA predict the reverse similarity effect. These modeling results suggest that the similarity effect is governed by either forgetting and inhibition (MDFT), or attention to positive or negative differences (MLBA). These results demonstrate that flexibility in the comparison process needs to be incorporated into theories of preferential choice. PMID- 29525693 TI - Mucosal fixed drug eruption due to mefenamic acid: Report of a case and a review. PMID- 29525694 TI - Gradient coatings of strontium hydroxyapatite/zinc beta-tricalcium phosphate as a tool to modulate osteoblast/osteoclast response. AB - The chemistry, structure and morphology of the implant surface have a great influence on the integration of an implant material with bone tissue. In this work, we applied Combinatorial Matrix-Assisted Pulsed Laser Evaporation (C-MAPLE) to deposit gradient thin films with variable compositions of Sr-substituted hydroxyapatite (SrHA) and Zn-substituted beta-tricalcium phosphate (ZnTCP) on Titanium substrates. Five samples with different SrHA/ZnTCP composition ratios were fabricated by a single step laser procedure. SrHA was synthesized in aqueous medium, whereas ZnTCP was obtained by reaction at high temperature. Both powders were separately suspended in deionized water, frozen at liquid nitrogen temperature and used as targets for C-MAPLE experiments, which proceed via simultaneous laser vaporization of two distinct material targets. X-ray diffraction, scanning electron microscopy and energy dispersive X-ray spectroscopy analyses confirmed that the coatings contain the same crystalline phases as the as-prepared powder samples, with a homogeneous distribution of the two phosphates along deposited thin films. Human osteoclast precursor 2T-110 and human osteoblast-like cells MG63 were co-cultured on the coatings. The results indicate that osteoblast viability and production of osteocalcin were promoted by the presence of ZnTCP. On the other hand, SrHA inhibited osteoclastogenesis and osteoclast differentiation, as demonstrated by the observed increase of the osteoprotegerin/RANKL ratio and decrease of the number of TRAP-positive multinucleated cells when increasing SrHA amount in the coatings. The results indicate that the possibility to tailor the composition of the coatings provides materials able to modulate bone growth and bone resorption. PMID- 29525695 TI - 5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride (FeTPPS), a peroxynitrite decomposition catalyst, catalyzes protein tyrosine nitration in the presence of hydrogen peroxide and nitrite. AB - 5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride (FeTPPS) is a water-soluble heme analog, which has been used as a scavenger of peroxynitrite in many studies. Similar to heme, it may also possess pseudo-peroxidase activity that could cause protein tyrosine nitration through the peroxidase-H2O2-NO2- pathway. In this paper, we used western blotting and spectrophotometry analysis to study the capability of FeTPPS in catalyzing protein tyrosine nitration. Furthermore, the capability of FeTPPS in catalyzing protein nitration in tissue homogenate and cultured cells was also investigated. Our results showed that FeTPPS induced bovine serum albumin (BSA) nitration in the presence of H2O2 and NaNO2, and the reaction was dose-, time- and pH-dependent. In acidic condition, more protein was nitrated by FeTPPS than heme, which corresponded to their peroxidase activities. Meanwhile, our results also confirmed the catalytic effect of FeTPPS on protein tyrosine nitration in rat brain homogenate and human hepatocellular carcinoma (HepG2) cells. At the end of this study, we used liquid chromatography (LC)-tandem mass spectrometry (MS/MS) to investigate differences of site selectivity between heme and FeTPPS catalyzed protein tyrosine nitration. The result indicated that FeTPPS tended to catalyze tyrosine residues locating in more hydrophilic sites, whereas heme was more likely to induce nitration of tyrosine residues locating in relatively hydrophobic environment. Taken together, this is the first report that FeTPPS is an effective and convenient nitration catalyzer in vitro, and this study confirms that the hydrophilicity of the nitrating agents would play an important role in nitration site selection. PMID- 29525696 TI - Insights into gliadin supramolecular organization at digestive pH 3.0. AB - Alpha-gliadin is a highly immunogenic protein from wheat, which is associated with many human diseases, like celiac disease and non-celiac gluten sensitivity. Because of that, gliadin solution is subject to intense biomedical research. However, the physicochemical nature of the employed gliadin solution at physiological pH is not understood. Herein, we present a supramolecular evaluation of the alpha-gliadin protein in water at pH 3.0 by dynamic light scattering (DLS), cryo-transmission electron microscopy (cryo-TEM) and small angle-.X-ray scattering (SAXS). We report that at 0.5 wt% concentration (0.1 mg/ml), gliadin is already a colloidal polydisperse system with an average hydrodynamic radius of 30 +/- 10 nm. By cryo-TEM, we detected mainly large clusters. However, it was possible to visualise for the first time prolate oligomers of around 68 nm and 103 nm, minor and major axis, respectively. SAXS experiments support the existence of prolate/rod-like structures. At 1.5 wt% concentration gliadin dimers, small oligomers and large clusters coexist. The radius of gyration (Rg1) of gliadin dimer is 5.72 +/- 0.23 nm with a dimer cross section (Rc) of 1.63 nm, and an average length of around 19 nm, this suggests that gliadin dimers are formed longitudinally. Finally, our alpha-gliadin 3D model, obtained by ab initio prediction and analysed by molecular dynamics (MD), predicts that two surfaces prone to aggregation are exposed to the solvent, at the C-terminus. We hypothesise that this region may be involved in the dimerisation process of alpha-gliadin. PMID- 29525697 TI - Multifunctional fluorescent iron quantum clusters for non-invasive radiofrequency ablationof cancer cells. AB - This work reports the potential of iron quantum clusters (FeQCs) as a hyperthermia agent for cancer, by testing its in-vitro response to shortwave (MHz range), radiofrequency (RF) waves non-invasively. Stable, fluorescent FeQCs of size ~1 nm prepared by facile aqueous chemistry from endogenous protein haemoglobin were found to give a high thermal response, with a DeltaT ~50 degrees C at concentrationsas low as165 MUg/mL. The as-prepared nanoclusters purified by lyophilization as well as dialysis showed a concentration, power and time-dependent RF response, with the lyophilized FeQCs exhibiting pronounced heating effects. FeQCs were found to be cytocompatible to NIH-3T3 fibroblast and 4T1 cancer cells treated at concentrations upto 1000 MUg/mL for 24 h. Upon incubation with FeQCs and exposure to RF waves, significant cancer cell death was observed which proves its therapeutic ability. The fluorescent ability of the clusters could additionally be utilized for imaging cancer cells upon excitation at ~450 nm. Further, to demonstrate the feasibility of imparting additional functionality such as drug/biomolecule/dye loading to FeQCs, they were self assembled with cationic polymers to form nanoparticles. Self assembly did not alter the RF heating potential of FeQCs and additionally enhanced its fluorescence. The multifunctional fluorescent FeQCs therefore show good promise as a novel therapeutic agent for RF hyperthermia and drug loading. PMID- 29525699 TI - Types of violence and psychiatric symptoms among women survivors of violence in Bangladesh. PMID- 29525700 TI - Craniofacial asymmetry as a marker of socioeconomic status among undocumented Mexican immigrants in the United States. AB - This study examines levels of fluctuating asymmetry (FA) in Mexican residents, U.S. residents, and undocumented border crossers (UBCs) from Mexico to the United States. Craniofacial structures develop symmetrically under ideal circumstances; however, during periods of developmental stress random deviations from perfect symmetry, or FA, can occur. It is hypothesized that the UBC sample would represent individuals of a lower socioeconomic status (SES) who experienced higher stress levels during development, and that these individuals would consequently have higher levels of FA. Three-dimensional cranial landmarks were collected from 509 individuals representing the three resident groups. Geometric morphometric methods were used to calculate an FA score for each individual. The FA score provides a distance measure that is a scalar measure of the magnitude of FA in each individual. The results show that the difference in the means of the FA scores between UBCs and U.S. residents is 0.43 (p = 0.02), with UBCs showing significantly higher levels of FA compared to U.S. residents. Moreover, Mexican residents' FA levels are intermediate between and not significantly different from the other two samples. These results suggest that levels of FA may prove useful for reconstructing individuals' social and economic circumstances, and that craniofacial asymmetry provides a suitable biological marker for analyzing differences in SES among different groups. PMID- 29525698 TI - Self-medication of mood and anxiety disorders with marijuana: Higher in states with medical marijuana laws. AB - BACKGROUND: Self-medication with drugs or alcohol is commonly reported among adults with mood or anxiety disorders, and increases the risk of developing substance use disorders. Medical marijuana laws (MML) may be associated with greater acceptance of the therapeutic value of marijuana, leading individuals to self-medicate. METHODS: The study utilized data from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (2004-2005). Participants were sampled from households in the general population and included adults with a mood or anxiety disorder in the past 12 months (n = 7418), and the subset of those who used marijuana and no other drug (n = 314). Weighted logistic regression models predicted the prevalence of self-medication with drugs in U.S. states with and without MML, adjusting for individual and state-level covariates. As a negative control, analyses were repeated for self-medication with alcohol. RESULTS: Overall, self-medication with drugs was 3.73 percentage points higher (95% confidence interval [CI]: 0.93-6.53) among those living in MML states (p = 0.01). For the subpopulation that only used marijuana, self-medication with drugs was 21.22 percentage points higher (95% CI: 3.91-38.53) among those living in MML states (p = 0.02). In contrast, self-medication with alcohol had nearly identical prevalence in MML and non-MML states, overall and for drinkers. CONCLUSIONS: Among adults with mood or anxiety disorders, living in a medical marijuana law state is associated with self-medication with marijuana. While additional research is needed to determine the reasons for this association, clinical screening for self-medication with marijuana may be particularly important in states with medical marijuana laws. PMID- 29525701 TI - Contrast-enhanced swallow study sensitivity for anastomotic leak detection in post-esophagectomy patients. AB - INTRODUCTION AND AIMS: Esophagectomy is a highly invasive surgery and one of its postoperative complications is anastomotic leakage, occurring in 53% of cases. The aim of the present study was to determine the sensitivity of the contrast enhanced swallow study as a method for diagnosing anastomotic leak in patients that underwent esophagectomy. MATERIAL AND METHODS: The present retrospective study included the case records of patients that underwent esophagectomy with reconstruction and cervical anastomosis at the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran within the time frame of January 1, 2000 and May 31, 2016. Demographic, clinical, and laboratory data emphasizing clinical and radiographic anastomotic leak detection were identified. Descriptive statistics were carried out and contrast-enhanced swallow study sensitivity for diagnosing leakage was calculated. RESULTS: Seventy patients were included in the analysis. The mean age of the patients was 50.6 years, 51 of the patients were men (72.86%), and 19 were women (27.14%). Indications for surgery were benign lesion in 29 patients (41.4%) and malignant lesion in 41 (58.6%). A total of 44.3% of the patients presented with a comorbidity, with diabetes mellitus and high blood pressure standing out. Thirty patients (42.85%) presented with anastomotic leak. Contrast-enhanced swallow study sensitivity for leak detection was 43.33%. CONCLUSIONS: The diagnostic sensitivity of the contrast-enhanced swallow study was very low. Therefore, we recommend the discontinuation of its routine use as a method for diagnosing anastomotic leaks. PMID- 29525702 TI - Seasonal dynamics of transparent exopolymer particles (TEP) and their drivers in the coastal NW Mediterranean Sea. AB - Transparent Exopolymer Particles (TEPs) are a subclass of organic particles with high impact in biogeochemical and ecological processes, such as the biological carbon pump, air-sea interactions, or the microbial loop. However, the complexity in production and consumption makes TEP dynamics hardly predictable, calling for the need of descriptive studies about the in situ dynamics of these particles. We followed monthly TEP dynamics and combined them with a dataset of environmental variables during three years in a coastal site of the oligotrophic North Western Mediterranean (Blanes Bay). TEP concentration, ranging from 11.3 to 289.1MUgXGeqL 1 (average 81.7+/-11.7MUgXGeqL-1), showed recurrent peaks in early summer (June July). TEP were temporally disconnected from chlorophyll a maxima, that occurred in late winter and early spring (maxima 1.21MUgL-1), but they were significantly related to the abundance of specific phytoplankton groups (diatoms and dinoflagellates) and also coincided with periods of low nutrient concentrations. The fraction of particulate organic carbon in the form of TEP (the TEP:POC and TEP:PM ratios) were also highest in early summer, indicating that TEP-enriched particles of low density accumulate in surface waters during stratified periods. We hypothesize that the accumulation of these particles affects the microbial food web by enhancing the activity of specific prokaryotic extracellular enzymes (esterase, beta-glucosidase and alkaline phosphatase) and promoting the abundance of heterotrophic nanoflagellates. PMID- 29525703 TI - Restoring water quality in the polluted Turag-Tongi-Balu river system, Dhaka: Modelling nutrient and total coliform intervention strategies. AB - River water quality in rapidly urbanising Asian cities threatens to damage the resource base on which human health, economic growth and poverty reduction all depend. Dhaka reflects the challenges and opportunities for balancing these dynamic and complex trade-offs which goals can be achieved through effective policy interventions. There is a serious problem of water pollution in central Dhaka, in the Turag-Tongi-Balu River system in Bangladesh with the river system being one of the most polluted in the world at the moment. A baseline survey of water chemistry and total coliforms has been undertaken and shows dissolved oxygen close to zero in the dry season, high organic loading together with extreme levels of Ammonium-N and total coliform in the water. Models have been applied to assess hydrochemical processes in the river and evaluate alternative strategies for policy and the management of the pollution issues. In particular models of flow, Nitrate-N, Ammonium-N and indicator bacteria (total coliforms) are applied to simulate water quality in the river system. Various scenarios are explored to clean up the river system, including flow augmentation and improved effluent treatment. The model results indicate that improved effluent treatment is likely to have a more significant impact on reducing Ammonium-N and total coliforms than flow augmentation, but a combined strategy would greatly reduce the pollution problems in the Turag-Tongi-Balu River System. PMID- 29525704 TI - Translocation, accumulation and bioindication of trace elements in wetland plants. AB - This study aimed to shed further light on the capacity of macrophytes to translocate, accumulate and bioindicate the levels of trace elements present in contaminated water and sediments. Specifically, this study aimed to find evidence whether translocation, accumulation and bioindication are dependent on the kind of trace element and plant species. To investigate the correlation between trace elements in plants and in the environment, the concentrations of As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, and Zn were analyzed in twenty different wetland plants, and in water and sediments from a wetland area affected by urban and industrial pollutants. Results showed that wetland plants share some common characteristics such as high tolerance to toxic element levels, capacity of phytostabilization and different element concentrations in the various organs. Moreover, element translocation from sediments to roots seems more influenced by the kind of plant species and trace element, whereas translocation across the various organs seems mainly species-specific. No clear patterns of trace element translocation were identified according to plant life forms. PMID- 29525706 TI - Mercury speciation and distribution in a glacierized mountain environment and their relevance to environmental risks in the inland Tibetan Plateau. AB - Glacierized mountain environments can preserve and release mercury (Hg) and play an important role in regional Hg biogeochemical cycling. However, the behavior of Hg in glacierized mountain environments and its environmental risks remain poorly constrained. In this research, glacier meltwater, runoff and wetland water were sampled in Zhadang-Qugaqie basin (ZQB), a typical glacierized mountain environment in the inland Tibetan Plateau, to investigate Hg distribution and its relevance to environmental risks. The total mercury (THg) concentrations ranged from 0.82 to 6.98ng.L-1, and non-parametric pairwise multiple comparisons of the THg concentrations among the three different water samples showed that the THg concentrations were comparable. The total methylmercury (TMeHg) concentrations ranged from 0.041 to 0.115ng.L-1, and non-parametric pairwise multiple comparisons of the TMeHg concentrations showed a significant difference. Both the THg and MeHg concentrations of water samples from the ZQB were comparable to those of other remote areas, indicating that Hg concentrations in the ZQB watershed are equivalent to the global background level. Particulate Hg was the predominant form of Hg in all runoff samples, and was significantly correlated with the total suspended particle (TSP) and not correlated with the dissolved organic carbon (DOC) concentration. The distribution of mercury in the wetland water differed from that of the other water samples. THg exhibited a significant correlation with DOC as well as TMeHg, whereas neither THg nor TMeHg was associated with TSP. Based on the above findings and the results from previous work, we propose a conceptual model illustrating the four Hg distribution zones in glacierized environments. We highlight that wetlands may enhance the potential hazards of Hg released from melting glaciers, making them a vital zone for investigating the environmental effects of Hg in glacierized environments and beyond. PMID- 29525705 TI - CeO2 nanoparticles attenuate airway mucus secretion induced by TiO2 nanoparticles. AB - Nanotoxicity studies associated with various nanoparticles (NPs) have attracted intense research interest due to the broader applications of nanoparticles in our daily lives. The exposure of nanoparticles can lead to hypersecretion and accumulation of airway mucus which are closely associated with many respiratory diseases. Titanium dioxide (TiO2), one of the PM10 components, is a major NP that is widely utilized in many commercial products. Our previous study established the connection between induced airway mucus secretion and TiO2 NPs. However, the countermeasure to reduce the harmful effects of TiO2 NPs, especially airway mucus secretion, remains unexplored. One of the potential candidates to reduce airway mucus secretion is cerium oxide (CeO2) NPs. It has been reported that CeO2 NPs can protect cells by diminishing ROS and inflammatory responses. Herein, our study shows that CeO2 NPs are able to reduce cytosolic Ca2+ changes and mitochondrial damage caused by TiO2 NPs. Our results provide the evidence that hypersecretion of mucus and apoptosis progression induced by TiO2 NPs can be attenuated by CeO2 NPs. This study highlights the potential capacity of CeO2 NPs as a supplementary material for TiO2 NPs applications in the future. PMID- 29525707 TI - Integrating global land-cover and soil datasets to update saturated hydraulic conductivity parameterization in hydrologic modeling. AB - Soil properties play an important role in watershed hydrology and environmental modeling. In order to model realistic hydrologic processes, it is necessary to obtain compatible soil data. This study introduces a new method that integrates global soil databases with land use/land cover (LULC) databases to better represent saturated hydraulic conductivity (Ks) which is one of the most important soil properties in hydrologic modeling. The Ks is modified by means of uniting physical infiltration mechanisms with hydrologic soil-LULC complexes from lookup tables from USDA-SCS (1985). This approach enables assimilation of available coarse resolution soil parameters by the finer resolution global LULC datasets. In order to test the performance of the proposed approach, it has been incorporated into the Watershed Environmental Hydrology (WEHY) model to simulate hydrologic conditions over the Cache Creek Watershed (CCW) and Shasta Dam Watershed (SDW) in Northern California by means of different soil datasets. Soil dataset S1 was obtained from the local soil database including SSURGO (Web soil survey, USDA). The second soil dataset (S2) is the global ISRIC soil data SoilGrids-1km obtained from World Soil Information. Soil dataset S4 is global FAO soil data. The third (S3) and fifth (S5) soil datasets were calculated by integrating the LULC into global soil datasets (S2, S4), respectively. The results of this study suggest that the proposed approach can provide a fine resolution soil dataset through integration of LULC and soil data, which can improve the estimation of soil hydraulic parameters and the performance of hydrologic modeling over the target watersheds. Within this framework, the new approach of this study can be applied widely in many parts of the world by means of the global soil and LULC databases. PMID- 29525708 TI - Effect of loss of plant functional group and simulated nitrogen deposition on subalpine ecosystem properties on the Tibetan Plateau. AB - Biodiversity loss impacts on ecosystem functioning can vary greatly among ecosystems types and different ecosystem processes can respond differently. Here we conducted a plant functional group removal experiment with and without nitrogen (N) addition (5gNm-2year-1) to examine the effects of plant functional group types presence, nitrogen deposition and their interaction effects on plant diversity, aboveground biomass, soil nutrients, soil microbial biomass and soil enzyme activity. After 4years, the removal of dominant grass did increase subordinates, forb richness, and decreased total aboveground biomass significantly. However, the removal of forb resulted in a rapid decline in species richness, which did not change strongly the aboveground biomass, regardless of N addition. This pattern suggests that the dominant grass can compensate for the loss of forb removal with respect to production, but cannot compensate with respect to species loss. Forb cannot compensate for grass removal with respect to production, but can compensate with respect to species loss. Nitrogen addition only has a small effect on species richness, and also not enhances aboveground biomass. In addition, the majority of soil properties did not respond to either plant functional group removal, or N addition. Only soil CO2 efflux and soil NO3--N content significantly changed with plant functional group removal. Soil respiration rate was positively correlated with both plant species richness (R2=0.97) and aboveground biomass (R2=0.64). Our results show that the short-term losses of plant functional group have significant effects on plant diversity and productivity, and only minor impact on soil properties. PMID- 29525709 TI - Assessment of the disinfection capacity and eco-toxicological impact of atmospheric cold plasma for treatment of food industry effluents. AB - Generation of wastewater is one of the main environmental sustainability issues across food sector industries. The constituents of food process effluents are often complex and require high energy and processing for regulatory compliance. Wastewater streams are the subject of microbiological and chemical criteria, and can have a significant eco-toxicological impact on the aquatic life. Thus, innovative treatment approaches are required to mitigate environmental impact in an energy efficient manner. Here, dielectric barrier discharge atmospheric cold plasma (ACP) was evaluated for control of key microbial indicators encountered in food industry effluent. This study also investigated the eco-toxicological impact of cold plasma treatment of the effluents using a range of aquatic bioassays. Continuous ACP treatment was applied to synthetic dairy and meat effluents. Microbial inactivation showed treatment time dependence with significant reduction in microbial populations within 120 s, and to undetectable levels after 300 s. Post treatment retention time emerged as critical control parameter which promoted ACP bacterial inactivation efficiency. Moreover, ACP treatment for 20 min achieved significant reduction (>=2 Log10) in Bacillus megaterium endospores in wastewater effluent. Acute aquatic toxicity was assessed using two fish cell lines (PLHC-1 and RTG-2) and a crustacean model (Daphnia magna). Untreated effluents were toxic to the aquatic models, however, plasma treatment limited the toxic effects. Differing sensitivities were observed to ACP treated effluents across the different test bio-assays in the following order: PLHC-1 > RTG-2 >= D. magna; with greater sensitivity retained to plasma treated meat effluent than dairy effluent. The toxic effects were dependent on concentration and treatment time of the ACP treated effluent; with 30% cytotoxicity in D. magna and fish cells observed after 24 h of exposure to ACP treated effluent for concentrations up to 5%. The findings suggest the need to employ wider variety of aquatic organisms for better understanding and complete toxicity evaluation of long-term effects. The study demonstrates the potential to tailor ACP system parameters to control pertinent microbial targets (mono/poly-microbial, vegetative or spore form) found in complex and nutritious wastewater effluents whilst maintaining a safe eco-toxicity profile for aquatic species. PMID- 29525710 TI - Understanding and application of an electroplating sludge-derived catalyst with an active texture for improved NO reduction. AB - Industrial sludge has been shown to be a valuable source of transition metals and to be effective in NO reduction. This research has further revealed a characteristic texture (O-Me-C) that promotes effective NO reduction and supports its existence in a sludge-derived catalyst. HRTEM exhibited that the O-Me-C consisted of multi-metal-oxide core, carbon shell and their binding interfaces. Furthermore, pre-treatment of the sludge with aromatic containing wastewater produced a more active texture (O-Me-GOL), characterized by the presence of multi metal-oxide core, graphene oxide-like carbon and highly active interfaces (EELS, Mossbauer and Raman). As a result, the hybrid with O-Me-GOL exhibited enhanced activity and was able to remove >45% of NO (1000 ppm) at 200 degrees C and >99% at 400 degrees C over a much longer period (from 25 to 180 min) with an hourly gas space velocity of 14,400 h-1. Besides, the hybrid showed excellent resistance to both SO2 and O2. Therefore, the present work promoted the high value-added utilization of environment waste, and produced efficient catalyst in favor of sustainable development. PMID- 29525711 TI - Demographic, endocrine and behavioral responses to mirex in the South polar skua. AB - Population consequences of chronic exposure to multiple pollutants at low environmental doses remain speculative, because of the lack of appropriate long term monitoring surveys. This study integrates proximate and ultimate aspects of persistent organic pollutants (POP) burden in free-living vertebrates, by coupling hormonal and behavioral endpoints, life-history traits, and population dynamics. Blood samples (N=70) were collected in South polar skuas during two breeding periods, in 2003 and 2005, and individuals were annually monitored until 2011. Multi-state mark recapture models were used to test the effects of POP levels on demographic traits. Survival rate and long-term breeding probability were not related to individual POP levels, whereas long-term breeding success significantly decreased with increasing blood levels of mirex, an organochlorine insecticide. At the proximate level, corticosterone (stress hormone) and prolactin (parental care hormone) levels were not linked to individual POP burden. Nest defense in 2005 was significantly less intensive in chick-rearing skuas bearing higher mirex levels, suggesting reproductive behavioral impairment. Matrix population models were then built to project the rate of population decline according to increasing mirex burden. Although mirex levels were 2.8 times higher in 2003 than in 2005, the population-level effect of mirex was only detected in 2005, the year of higher corticosterone levels. The combination of endocrine traits with demographic analysis thereby enables to provide new support of synergistic interactions between pollutants and stress levels on long-term breeding outputs and population dynamics. PMID- 29525712 TI - Tidal variability of CO2 and CH4 emissions from the water column within a Rhizophora mangrove forest (New Caledonia). AB - We performed a preliminary study to quantify CO2 and CH4 emissions from the water column within a Rhizophora spp. mangrove forest. Mean CO2 and CH4 emissions during the studied period were 3.35+/-3.62mmolCm-2h-1 and 18.30+/-27.72MUmolCm-2h 1, respectively. CO2 and CH4 emissions were highly variable and mainly driven by tides (flow/ebb, water column thickness, neap/spring). Indeed, an inverse relationship between the magnitude of the emissions and the thickness of the water column above the mangrove soil was observed. delta13CO2 values ranged from 26.880/00 to -8.60/00, suggesting a mixing between CO2-enriched pore waters and lagoon incoming waters. In addition, CO2 and CH4 emissions were significantly higher during ebb tides, mainly due to the progressive enrichment of the water column by diffusive fluxes as its residence time over the forest floor increased. Eventually, we observed higher CO2 and CH4 emissions during spring tides than during neap tides, combined to depleted delta13CO2 values, suggesting a higher contribution of soil-produced gases to the emissions. These higher emissions may result from higher renewable of the electron acceptor and enhanced exchange surface between the soil and the water column. This study shows that CO2 and CH4 emissions from the water column were not negligible and must be considered in future carbon budgets in mangroves. PMID- 29525713 TI - Assessing combined impacts of agrochemicals: Aquatic macroinvertebrate population responses in outdoor mesocosms. AB - Agricultural ditches host a diverse community of species. These species often are unwarrantedly exposed to fertilizers and a wide-array of pesticides (hereafter: agrochemicals). Standardized ecotoxicological research provides valuable information to predict whether these pesticides possibly pose a threat to the organisms living within these ditches, in particular macro-invertebrates. However, knowledge on how mixtures of these agrochemicals affect macro invertebrates under realistic abiotic conditions and with population and community complexity is mostly lacking. Therefore we examined here, using a full factorial design, the population responses of macroinvertebrate species assemblages exposed to environmentally relevant concentrations of three commonly used agrochemicals (for 35days) in an outdoor experiment. The agrochemicals selected were an insecticide (imidacloprid), herbicide (terbuthylazine) and nutrients (NPK), all having a widespread usage and often detected together in watersheds. Effects on species abundance and body length caused by binary mixture combinations could be described from single substance exposure. However, when agrochemicals were applied as tertiary mixtures, as they are commonly found in agricultural waters, species' abundance often deviated from expectations made based on the three single treatments. This indicates that pesticide-mixture induced toxicity to population relevant endpoints are difficult to extrapolate to field conditions. As in agricultural ditches often a multitude (approx. up to 7) of agrochemicals residues are detected, we call other scientist to verify the ecological complexity of non-additive induced shifts in natural aquatic invertebrate populations and aquatic species assemblages. PMID- 29525714 TI - Contamination source apportionment and health risk assessment of heavy metals in soil around municipal solid waste incinerator: A case study in North China. AB - Few studies have comprehensively taken into account the source apportionment and human health risk of soil heavy metals in the vicinity of municipal solid waste incinerator (MSWI) in high population density area. In this study, 8 elements (Cr, Pb, Cu, Ni, Zn, Cd, Hg, and As) in fly ash, soil samples from different functional areas and vegetables collected surrounding the MSWI in North China were determined. The single pollution index, integrated Nemerow pollution index, principal component analysis (PCA), absolute principle component score-multiple linear regression (APCS-MLR) model and dose-response model were used in this study. The results showed that the soils around the MSWI were moderately polluted by Cu, Pb, Zn, and Hg, and heavily polluted by As and Cd. MSWI had a significant influence on the distribution of soil heavy metals in different distances from MSWI. The source apportionment results showed that MSWI, natural source, industrial discharges and coal combustion were the four major potential sources for heavy metals in the soils, with the contributions of 36.08%, 29.57%, 10.07%, and 4.55%, respectively. MSWI had a major impact on Zn, Cu, Pb, Cd, and Hg contamination in soil. The non-carcinogenic risk and carcinogenic risk posed by soil heavy metals surrounding the MSWI were unacceptable. The soil heavy metals concentrations and health risks in different functional areas were distinct. MSWI was the predominate source of non-carcinogenic risk with the average contribution rate of 36.99% and carcinogenic risk to adult male, adult female and children with 4.23*10-4, 4.57*10-4, and 1.41*10-4 respectively, implying that the impact of MSWI on human health was apparent. This study provided a new insight for the source apportionment and health risk assessment of soil heavy metals in the vicinity of MSWI. PMID- 29525715 TI - Graphene oxide-facilitated transport of Pb2+ and Cd2+ in saturated porous media. AB - This paper provides an overview of the effect of graphene oxide (GO) on sorption, transport, and remobilization of Pb2+ and Cd2+ ions in saturated porous media. The affinity of GO to Pb2+ and Cd2+ ions was investigated via kinetic and isothermal sorption experiments. Laboratory packed-column experiments were also conducted to investigate the cotransport of Pb2+ and Cd2+ ions with GO across a quartz sand matrix. In addition, the Pb2+- and Cd2+-preequilibrated sand column was sequentially flushed with GO to test its remobilization effect on these ions. GO exhibited a high affinity toward both Pb2+ and Cd2+ ions with maximum sorption capacities of 1428.57 and 911.43mgg-1, respectively. On the other hand, while GO improved the transport ability of Pb2+ and Cd2+, both ions reduced the mobility of GO in saturated porous media. Data from the elution experiment revealed that the high affinity of GO toward the metal ions led to the remobilization of the presorbed Pb2+ and Cd2+ ions onto the quartz sand surfaces and their concurrent migration across the sand column. XDLVO (Extended Derjaguin-Landau-Verwey Overbeek) calculations were employed to interpret the GO transport behavior in the column wells. The cotransport of Pb2+ and Cd2+ ions with GO in the saturated quartz sand was successfully simulated by the advection-dispersion-reaction equation. Findings from this study provide an insight on the potential implications of remobilization and spread of pollutants by nanomaterials existing in vulnerable ecosystems. PMID- 29525716 TI - Accounting for the measurement error of spectroscopically inferred soil carbon data for improved precision of spatial predictions. AB - Spatial modelling of environmental data commonly only considers spatial variability as the single source of uncertainty. In reality however, the measurement errors should also be accounted for. In recent years, infrared spectroscopy has been shown to offer low cost, yet invaluable information needed for digital soil mapping at meaningful spatial scales for land management. However, spectrally inferred soil carbon data are known to be less accurate compared to laboratory analysed measurements. This study establishes a methodology to filter out the measurement error variability by incorporating the measurement error variance in the spatial covariance structure of the model. The study was carried out in the Lower Hunter Valley, New South Wales, Australia where a combination of laboratory measured, and vis-NIR and MIR inferred topsoil and subsoil soil carbon data are available. We investigated the applicability of residual maximum likelihood (REML) and Markov Chain Monte Carlo (MCMC) simulation methods to generate parameters of the Matern covariance function directly from the data in the presence of measurement error. The results revealed that the measurement error can be effectively filtered-out through the proposed technique. When the measurement error was filtered from the data, the prediction variance almost halved, which ultimately yielded a greater certainty in spatial predictions of soil carbon. Further, the MCMC technique was successfully used to define the posterior distribution of measurement error. This is an important outcome, as the MCMC technique can be used to estimate the measurement error if it is not explicitly quantified. Although this study dealt with soil carbon data, this method is amenable for filtering the measurement error of any kind of continuous spatial environmental data. PMID- 29525717 TI - Outdoor human thermal perception in various climates: A comprehensive review of approaches, methods and quantification. AB - Over the past century, many research studies have been conducted in an attempt to define thermal conditions for humans in the outdoor environment and to grade thermal sensation. Consequently, a large number of indices have been proposed. The examination of human thermal indices by thermal subjective perception has become recently a methodical issue to confirm the accuracy, applicability and validation of human thermal indices. The aims of this study are: (a) to review studies containing both calculated human thermal conditions and subjective thermal perception in the outdoor environment (b) to identify the most used human thermal indices for evaluating human thermal perception (c) to examine the relation between human thermal comfort range and outdoor thermal environment conditions and (d) to compare between categories of thermal sensation in different climatic zones based on subjective perception and levels of thermal strain. A comprehensive literature review identified 110 peer-reviewed articles which investigated in-situ thermal conditions versus subjective thermal perception during 2001-2017. It seems that out of 165 human thermal indices that have been developed, only 4 (PET, PMV, UTCI, SET*) are widely in use for outdoor thermal perception studies. Examination of the relation between human thermal comfort range and outdoor thermal environment conditions for selective indices in different climatic zones shows that the range of the thermal comfort or dis comfort is affected by the outdoor thermal environment. For the PET index, the "neutral" range for hot climates of 24-26 degrees C is agreed by 95% of the studies where for cold climate, the "neutral" range of 15-20 degrees C is agreed by 89% of the studies. For the UTCI, the "no thermal stress" category is common to all climates. The "no stress category" of 16-23 degrees C is agreed by 80% of the case studies, while 100% of the case studies agreed that the range is between 18 and 23 degrees C. PMID- 29525719 TI - Type 1 metabotropic glutamate receptor and its signaling molecules as therapeutic targets for the treatment of cerebellar disorders. AB - Neurodegenerative diseases such as spinocerebellar ataxias and autoantibody associated disorders of the central nervous system often affect the cerebellum, resulting in motor deficits. Recent studies have revealed that most of these disorders impair type 1 metabotropic glutamate receptor (mGluR1) and/or the closely associated signaling molecules in cerebellar Purkinje cell. Since the signaling pathway triggered by mGluR1 activation in Purkinje cell plays a pivotal role in coordinated movements and motor learning, pharmacological repair of aberrant mGluR1 signaling in Purkinje cell is critical for mitigation of cerebellar symptoms. Here we review recently identified pathophysiology underlying the neurodegenerative and autoimmune diseases affecting mGluR1 signaling in Purkinje cell and possible therapeutic interventions. PMID- 29525718 TI - Modelling crop land use change derived from influencing factors selected and ranked by farmers in North temperate agricultural regions. AB - To develop meaningful land use scenarios, drivers that affect changes in the landscape are required. In this study, driving factors that influence farmers to change crops on their farm were determined. A questionnaire was administered to four independent groups of farmers who identified and ranked influencing factors pertaining to their choices of crops. The farmers were located in two mid latitude agricultural watersheds (in Germany and Canada). The ranked influencing factors were used to develop a "farmer driven" scenario to 2040 in both watersheds. Results showed that the most important influencing factors for farmers to change crops were the "economic return of the crop" and "market factors". Yet, when the drivers of crop land use change were grouped into two categories of "financial" and "indirectly-related financial" factors, the "financial" factors made up approximately half of the influencing factors. For some responses, the "indirectly-related financial" factors (i.e. "access to farm equipment", the "farm experience", and "climate") ranked higher than or just as high as the financial factors. Overall, in the four farmer groups the differences between the rankings of the influencing factors were minor, indicating that drivers may be transferable between farms if the farmers are full-time and the farming regions have comparable growing seasons, access to markets, similar technology, and government programs for farm income. In addition to the "farmer driven" scenario, a "policy driven" scenario was derived for each watershed based only on available information on the financial incentives provided to farmers (i.e. agricultural subsidies, income support, crop insurance). The influencing factors ranked by the farmers provided in-depth information that was not captured by the "policy driven" scenario and contributed to improving predictions for crop land use development. This straight-forward method to rank qualitative data provided by farmers can easily be replicated in other watersheds to improve environmental impact modelling. PMID- 29525720 TI - Targeting metabotropic glutamate receptors in the treatment of primary brain tumors. AB - In spite of the recent advancement in the molecular characterization of malignant gliomas and medulloblastomas, the treatment of primary brain tumors remains suboptimal. The use of small molecule inhibitors of intracellular signaling pathways, inhibitors of angiogenesis, and immunotherapic agents is limited by systemic adverse effects, limited brain penetration, and, in some cases, lack of efficacy. Thus, adjuvant chemo-therapy and radiotherapy still remain the gold standard in the treatment of grade-IV astrocytoma (glioblastoma multiforme) and medulloblastoma. We review evidence that supports the development of mGlu3 receptor antagonists as add-on drugs in the treatment of malignant gliomas. These drugs appear to display pleiotropic effect on tumor cells, affecting proliferation, differentiation, and response to chemotherapy. mGlu1 and mGlu4 receptors could also be targeted by potential anticancer agents in the treatment of malignant gliomas and medulloblastoma, but extensive research is required for target validation. PMID- 29525721 TI - Electrocorticographic high gamma language mapping: Mind the pitfalls of comparison with electrocortical stimulation. PMID- 29525722 TI - A self-completed questionnaire study of attitudes and perceptions of paramedic and prehospital practitioners towards acute seizure care in Northern Ireland. AB - INTRODUCTION: Paramedics are increasingly expected to take on wider roles in the management of epilepsy in the community by making nonconveyance decisions after patients have had seizures. Studies have identified barriers to the successful implementation of this clinical role. We sought to determine levels of confidence, training, perceived barriers, and self-identified learning needs and methods to address these needs regarding seizure management. METHODS AND MATERIALS: A questionnaire was developed by consensus and administered to 63 paramedic and prehospital clinicians at various mandatory training days occurring at the central headquarters of the regional ambulance service in Northern Ireland. Participants had no foreknowledge of the questionnaire, which was self completed and returned immediately. RESULTS: A 75% return rate was obtained after 63 questionnaires were distributed. Paramedics had a mean of 11.5years of experiences, and 49% had treated 1-10 seizures in the last year. The Joint Royal Colleges Ambulance Liaison Committee guideline on seizure management is the most commonly utilized clinical guideline (100%). All could recall formal training on seizures in their qualification course. They identified a need to develop their knowledge in certain aspects of drug management and seizure subtype identification, including nonepileptic attack disorder (NEAD). Seventy percent of paramedics had a limited understanding of NEAD. Overall, paramedics rated their confidence as higher in drug treatment and the process of managing a seizure but rated their confidence lower in recognizing different seizure types as well as making nonconveyance decisions. The two factors which were cited as instilling high confidence included clinical experience and good use of provided protocols. Other barriers identified included lack of access to intramuscular midazolam, poor information availability in the prehospital setting, and a lack of a feedback mechanism to ensure follow-up. The methods by which learning needs would be addressed included tutorials, e-Learning, and simulation, with 30% preferring a combination of these methods. CONCLUSIONS: We identified that the paramedic workforce feels a reasonable to high level of confidence in the management of acute seizures. However, there are areas where they experience less confidence including making nonconveyance decisions and the identification of nontonic clonic seizure subtypes. PMID- 29525723 TI - Corrigendum to "Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study" [Epilepsy Behav. Oct 2017; 75C:151-157]. PMID- 29525725 TI - Percutaneous Closure of a Left Ventricular Outflow Tract Pseudoaneurysm. PMID- 29525724 TI - Invasive Versus Conservative Strategy in Frail Patients With NSTEMI: The MOSCA FRAIL Clinical Trial Study Design. AB - INTRODUCTION AND OBJECTIVES: Although clinical guidelines recommend invasive management in non-ST-segment elevation myocardial infarction (NSTEMI), this strategy is underused in frail elderly patients in the real world. Furthermore, these patients are underrepresented in clinical trials and therefore the evidence is scarce. Our hypothesis is that an invasive strategy will improve prognosis in elderly frail patients with NSTEMI. METHODS: This will be a prospective, multicenter, randomized trial, in which the conservative and invasive strategies will be compared in patients meeting all of the following inclusion criteria: NSTEMI diagnosis, age >= 70 years, and frailty defined by a category >= 4 in the Clinical Frailty Scale. Participants will be randomized to an invasive (coronary angiogram and revascularization if anatomically amenable) or conservative (medical treatment and coronary angiogram only if persistent clinical instability) strategy. The primary endpoint will be the number of days alive out of hospital during the first year. The coprimary endpoint will be the time until the first cardiac event (cardiac death, reinfarction or postdischarge revascularization). We estimate a sample size of 178 patients (89 per arm), considering an increase of 20% in the proportion of days alive out of hospital with the invasive management. RESULTS: The results of this study will add important knowledge to inform the management of frail elderly patients hospitalized with NSTEMI. CONCLUSIONS: We hypothesize that the invasive strategy will improve outcomes in frail elderly patients with NSTEMI. If this is confirmed, frailty status should not dissuade physicians from implementing an invasive management strategy.This trial was registered at ClinicalTrials.gov (Identifier: NCT03208153). PMID- 29525726 TI - 18F-FDG Pitfall due to Atrial Appendages Uptake. PMID- 29525727 TI - Endomyocardial biopsy in differential diagnosis between arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy: an in vitro simulated study. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), despite being two dramatically different entities, have overlapping phenotypes. As it is easy to misdiagnose between ARVC and DCM, there is a need to establish a new differential diagnostic parameter to differentiate the two. We investigated the utility of endomyocardial biopsy (EMB) for the differential diagnosis, and our study had three aims. The first was to verify the EMB high diagnostic efficacy. The second was to investigate the EMB perforation risk at the right ventricle (RV) free wall of end-stage ARVC. The third was to determine the best EMB sampling site in differential diagnosis between ARVC and DCM. Transmural tissues were sampled at six sites on the ventricular free walls and interventricular septum of recipient hearts (35 ARVCs and 35 DCMs). Participants with wall thickness <1.7 mm were included in the subgroup with high perforation risk, and the rest were included in a subgroup with low perforation risk. The best EMB sampling site was determined by the largest area under curve (AUC) among receiver operating characteristic curves. We found significant differences (P<.01) in percentages of tissue components in transmural sections between ARVC and DCM. In the subgroup with high perforation risk, there were 12 ARVCs and no DCMs, and paper-like RV walls and transmural fat replacement were their features in the cardiac enhancement computed tomography images. In the subgroup with low perforation risk, the largest AUC was on the myocardium at the ARV: AUC=0.839, cutoff=74.76%, sensitivity=73.68%, specificity=97.14%. We conclude that EMB high differential diagnostic efficacy is a meaningful fact regardless of limited sampling range, that EMB perforation risk at the RV free wall of end-stage ARVC cannot be neglected, and that the best EMB sampling site is the ARV. Among participants with low perforation risk, ARV is still recommended as an EMB sampling site with good differential diagnostic efficacy. PMID- 29525728 TI - Papillary muscles of right ventricle-morphological variations and its clinical relevance. AB - INTRODUCTION: Papillary muscle plays an important role in stabilizing the position of the tricuspid valve. Several pathologies can result in anatomical and functional abnormalities of the papillary muscles. The aim of the study is to deliberate the morphometry of papillary muscles in tricuspid valve and to analyze with the eminent research works previously done. MATERIALS AND METHODS: The study was carried out in 52 formalin-fixed adult apparently normal cadaveric hearts belonging to either sex obtained from the Department of Anatomy. These hearts were dissected carefully to open the right ventricle and to expose the papillary muscles. Different morphological features of papillary muscles were noted, and measurements were taken. RESULT: The classical picture of three papillary muscles existed in 23.07% of the specimens. Anterior papillary muscle was in all hearts, but posterior and septal muscle was off in 15.38% and 55.76%, respectively. Double and triple papillary muscles were seen too. Anterior and posterior muscle appeared predominantly flat-top and arose from the middle third (mostly), while septal muscle was chiefly conical and originated basically from the upper third of the ventricular wall. Chordopapillary relationship with tricuspid valve leaflets was beyond conventional. Mean length and breadth of anterior muscle were 2.19+/-0.59 cm and 0.76+/-0.26 cm, those of posterior muscle were 1.39+/-0.63 cm and 0.67+/-0.43 cm, and those of septal papillary muscle were 0.95+/-0.38 cm and 0.59+/-0.09 cm. CONCLUSIONS: Detailed knowledge of normal and variable anatomy of papillary muscles is not only necessary for better understanding of tricuspid pathologies but also valuable for successful newer surgical approaches in cardiac treatment. PMID- 29525729 TI - Immunophenotypic analysis of the chronological events of tissue repair in aortic medial dissections. AB - Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections. PMID- 29525730 TI - A comparison of two stroke cohorts cared for by two different specialties in a practice-based tele-stroke population. AB - OBJECTIVES: Neurologists have continually led the assessment and management of Acute Ischemic Stroke(AIS) by use of IV-rtPA, anti-platelet therapy, antihypertensives, and other pharmacologic agents. Since the advent of mechanical thrombectomy(MT) and its proven efficacy, neurovascular surgeons(NS) are playing an increasingly important role in the management and overall care of AIS. We assessed outcomes of AIS patients managed by NS, who have been traditionally managed by neurologists. PATIENTS AND METHODS: Outcomes of AIS patients who presented to the telestroke system, over a 5-year period, were assessed. NIHSS and mRS stroke scales were used as outcome metrics. Multivariate analysis was conducted to compare outcomes of patients treated by neurovascular surgeons and those treated by neurologists. RESULTS: 1353 AIS patients were identified. 21.6% received care from neurosurgeons and 78.4% received care from neurologists. Of the neurologist-managed group: 7.8% received MT and were followed by NS, 34% received IVrt-PA, average discharge NIHSS = 9.0 (SD = 8.42), latest follow-up mRS < 2 = 57.5% and mortality rate = 9.4%. Of the neurovascular surgeon-managed group: 7.4% patients received MT, 20% received IVrt-PA, average discharge NIHSS = 0.14(SD = 0.72), latest follow-up mRS <=2 = 98.6% and mortality rate = 8.3%. There were no significant differences between groups in MT use (OR 1.22; CI95%, 0.971-2.09; p = 0.464), IVrt-PA administration (OR 0.98; CI95%, 0.70-1.38; p = 0.924), mortality rate (OR 1.21; 0.71-2.03; p = 0.483) and patients' latest mRS, p = 0.873. CONCLUSIONS: AIS requires multidisciplinary management. Care provided by neurosurgeons has similar efficacy and patient outcomes as the care provided by neurologists. These findings support the role and ability of neurosurgeons to manage and care for these patients. PMID- 29525731 TI - Atypical presentation of probable Creutzfeldt-Jakob disease associated with anti Zic4 antibody: Literature review of neuronal antibodies in Creutzfeldt-Jakob disease. AB - INTRODUCTION: Sporadic Creutzfeldt-Jakob disease is a prion disease characterized by rapidly progressive dementia, ataxia and myoclonus. Atypical phenotype masquerading as stroke, movement disorders or autoimmune encephalitis have been described. Here, I report a probable case of sCJD with an atypical presentation associated with anti-Zic4 antibody and review the literature of neuronal antibodies in CJD. CASE REPORT: A 70 year-old gentleman is admitted with a 2 month history of recurrent stroke-like symptoms associated with behavioral disturbances, gait ataxia and rapidly progressive dementia. His initial examination demonstrated akinetic mutism, diffuse rigidity, dysautononia, and Cheyne-Stokes respiration. Over the following weeks his condition progressed to profound coma. A comprehensive infectious, metabolic, inflammatory and autoimmune work-up yielded negative results. Empiric immunosuppressive therapy ensued. He expired three months after symptoms onset. Autopsy was not performed. After his demise, prion tests came back abnormal for elevated 14-3-3 protein, total tau and positive RTQuIC. Later on, anti-Zic4 antibodies were found in serum. CONCLUSION: This case underscores the importance of a high index of suspicion for CJD even in case of atypical features or the concurrence of neuronal antibodies. Further larger prospective studies on the prevalence of these neuronal antibodies in CJD and the contribution of these autoantibodies to disease pathophysiology are necessary. PMID- 29525732 TI - Progression of vestibular schawnnoma after GammaKnife radiosurgery: A challenge for microsurgical resection. AB - OBJECTIVE: We aimed to evaluate the outcome of patients who underwent salvage microsurgery for vestibular schwannoma (VS) that failed primary Gammaknife radiosurgery (GKS). PATIENTS AND METHODS: Among the 1098 patients who received GKS for the treatment of VS in our center between January 2004 and December 2012, the follow-up was organized in our institution for 290 patients who lived in our recruitment area. Tumor progression was noted in 23 patients. A salvage microsurgical resection was performed in 11 patients, who were included in our study. Grading of facial function was done according to the House & Brackman scale. RESULTS: The mean age at diagnosis was 50.2 years (19-68 years) and the mean follow-up was 9.4 years (4-13 years). The mean dose was 11.8 Gy (11-12 Gy) and the mean volume was 922 mm3 (208-2500 mm3). The mean period between GKS and diagnosis of tumor progression was 32 months (18-72 months). Concerning salvage microsurgery, complete resection was obtained in 8 patients. Small residual tumor on the facial nerve was deliberately left in 3 patients and no tumor progression was noted with a mean follow-up of 26 months. At last follow-up, facial nerve function was grade 1 in 4 patients, grade 2 in 3 patients, grade 3 in 1 patient and grade 4 in 3 patients. CONCLUSION: Salvage surgery of recurrent vestibular schwannoma after failed initial GKS remains a good treatment. However, facial nerve preservation is more challenging in this case and small tumor remnant could be sometimes deliberately left. PMID- 29525733 TI - Lacunar implementation of the critical view of safety technique for laparoscopic cholecystectomy: Results of a nationwide survey. AB - BACKGROUND: Bile duct injury remains a dilemma in laparoscopic cholecystectomy, with an incidence still higher than in conventional cholecystectomy. The Critical View of Safety technique is used as one of the important operating technique to reduce bile duct injury incidence. The objective of this study was to determine current practices in laparoscopic cholecystectomy and the use of the Critical View of Safety technique among surgeons and residents in surgical training. METHODS: We conducted an electronic survey among all affiliated members of the Association of Surgeons of the Netherlands containing questions regarding the current practice of laparoscopic cholecystectomy, essential steps of the Critical View of Safety technique, reasons for conversion to open cholecystectomy, and the use of other safety techniques. RESULTS: The response rate was 37% (766/2,055). In the study, 610 completed surveys were analyzed. Of the respondents, 410 (67.2%) were surgeons and 200 (32.8%) were residents in surgical training. Furthermore, 98.2% of the respondents indicated incorporating the Critical View of Safety technique into current practice. However, only 72% of respondents performed the essential steps of the Critical View of Safety technique frequently. Subsequently, half of respondents were able to identify the corresponding steps of the Critical View of Safety technique, and only 16.9% were able to distinguish these adequately from possible harmful steps. Furthermore, 74.9% selected >=1 possible harmful steps as part of this technique. Residents significantly performed and selected the essential steps of the Critical View of Safety technique more often than surgeons. Intraoperative cholangiography, intraoperative ultrasound, and fluorescence cholangiography are seldom used. Bail out techniques such as subtotal cholecystectomy, fundus first dissection, and leaving the gallbladder in situ are familiar to the majority of respondents. CONCLUSION: Responses indicate that practically all Dutch surgeons and residents claim to use the Critical View of Safety technique. The majority of surgeons and residents are unable to discern correctly the essential steps of the Critical View of Safety technique from actions not part of the technique and even potentially harmful. Residents' current knowledge regarding the Critical View of Safety technique is superior to those of surgeons. PMID- 29525734 TI - Retracted articles in surgery journals. What are surgeons doing wrong? AB - BACKGROUND: Retraction of previously published scientific articles is an important mechanism to preserve the integrity of scientific work. This study analyzed retractions of previously published articles from surgery journals. METHODS: We searched for retracted articles in the 100 surgery journals with the highest SJR2 indicator grades. RESULTS: We found 130 retracted articles in 49 journals (49%). Five or more retracted articles were published in 8 journals (8%). The mean time between publication and retraction was 26 months (range 1 to 158 months). The United States, China, Germany, Japan, and the United Kingdom accounted for more than 3 out of 4 of the retracted articles. The greatest number of retractions came from manuscripts about orthopedics and traumatology, general surgery, anesthesiology, cardiothoracic surgery, and plastic surgery. Nonsurgeons were responsible for 16% of retractions in these surgery journals. The main reasons for retraction were duplicate publication (42%), plagiarism (16%), absence of proven integrity of the study (14%), incorrect data (13%), data published without authorization (12%), violation of research ethics (11%), documented fraud (11%), request of an author(s) (5%), and unknown (3%). In 25% of the retracted articles, other publications by the same authors also had been retracted. CONCLUSION: Retraction of published articles does not occur frequently in surgery journals. Some form of scientific misconduct was present in the majority of retractions, especially duplication of publication and plagiarism. Retractions of previously published articles were most frequent from countries with the greatest number of publications; some authors showed recidivism. PMID- 29525735 TI - Outcomes in real-world practice are different than cooperative trial for elderly patients with early breast cancer treated with adjuvant radiation therapy. AB - BACKGROUND: The Cancer and Leukemia Group B 9,343 demonstrated that postoperative radiation can be safely omitted in women >=70 years who underwent breast conserving therapy for clinical stage I (T1N0M0) estrogen receptor positive breast cancer treated with antihormonal therapy. Whether such results are observed in real-world population is unknown. In this hospital-based data, we report the survival outcomes of patients who received adjuvant radiation therapy versus those who did not. METHODS: Using the National Cancer Data Base, we evaluated a cohort of 47,358 women with newly diagnosed breast cancer between 2004 and 2011 who underwent a lumpectomy and antihormonal therapy with the following criteria: age >=70 years, clinical stage I, estrogen receptor positive, and negative margins. Patients were stratified into 2 groups: (1) radiation therapy and (2) no radiation therapy. Propensity score matching was used to compensate for differences in demographic and clinical characteristics of the patients. Univariate and multivariable survival analysis were employed to determine factors associated with overall survival. RESULTS: The 5-year overall survival after propensity score matching was 87.2% for radiation therapy and 79.4% for no radiation therapy (P < .0001). The median survival time was 113.7 months for radiation therapy and 105.2 months for no radiation therapy. After adjusting for sociodemographic and clinical factors, the risk of overall deaths was significantly higher for those not receiving radiation therapy (hazard ratio = 1.66; 95% confidence interval, 1.54-1.79). Other significant adjusted predictors (P < .05) of poor overall survival were, advanced age, comprehensive community cancer program, facility location, poorly differentiated tumor, and high comorbidity index. CONCLUSION: Patients who received radiation therapy had better survival outcomes than those who did not, revealing discordance between results of randomized trials and real-world setting. PMID- 29525736 TI - Mortality and morbidity after hepatic resection in patients undergoing hemodialysis: analysis of a national inpatient database in Japan. AB - BACKGROUND: Whether patients undergoing hemodialysis have greater risks of mortality and morbidity after hepatic resection remains unclear. METHODS: We used the Diagnosis Procedure Combination database, a national inpatient database in Japan, to identify patients who underwent hepatic resection from July 2010 to March 2014. Propensity scorematching analysis was performed to compare morbidity and mortality between patients with and without hemodialysis. RESULTS: Of 53,651 eligible patients, 498 (0.93%) underwent hemodialysis. Propensity score-matching analysis indicated greater in-hospital mortality in patients with than without hemodialysis (8.6% vs 2.0%; P < .001). Patients undergoing hemodialysis had more postoperative major complications than did patients not undergoing hemodialysis (18.1% vs 7.4%; P < .001). In the subgroup analyses for in-hospital mortality, the odds ratio of hemodialysis was 2.36 (95% confidence interval, 0.78-6.59; P = .067) in limited resection, 4.61 (95% confidence interval, 1.90-11.2; P < .001) in segmentectomy or sectoriectomy, and 5.58 (95% confidence interval, 3.40-14.9; P < .001) in bisectoriectomy or trisectoriectomy. In the age subgroup analyses, the odds ratio of hemodialysis was 4.38 (95% confidence interval, 2.66-7.21; P < .001) in patients aged <80 years and 7.20 (95% confidence interval, 1.55-36.7; P = .0011) in those aged >=80 years. CONCLUSION: Patients undergoing hemodialysis had a substantially increased risk of mortality and morbidity after hepatic resection. Surgical indications for major hepatectomy in patients undergoing hemodialysis who are >=80 years of age may be limited and require careful scrutiny. PMID- 29525737 TI - Factors associated with negative observer responses towards individuals with visible differences: A scoping review. AB - People with visible differences are often confronted with negative observer responses, including stares, disgust, and avoidance. Characteristics of negative observer responses are well-documented, but less is known about associated factors. We conducted a scoping review to map what is known about factors associated with negative observer responses. Web of Science, PubMed, PsycINFO, and CINAHL databases were searched, and 16 articles met inclusion criteria. Two general categories of factors were identified: (1) observer characteristics, including age, sex, and socioeconomic status, experiences with disfigurements, and personal beliefs or attitudes related to visible differences; and (2) evolved internal mechanisms, including threat-detection, disgust, and disease avoidance. Additionally, there was evidence that lack of anonymity influences lower reporting of observer reactions. Efforts that increase exposure to individuals with visible differences may ameliorate adverse reactions; however, due to the limited nature of evidence reviewed, further research is needed before more concrete recommendations can be made. PMID- 29525738 TI - Labelling fashion magazine advertisements: Effectiveness of different label formats on social comparison and body dissatisfaction. AB - The experiment investigated the impact on women's body dissatisfaction of different forms of label added to fashion magazine advertisements. Participants were 340 female undergraduate students who viewed 15 fashion advertisements containing a thin and attractive model. They were randomly allocated to one of five label conditions: no label, generic disclaimer label (indicating image had been digitally altered), consequence label (indicating that viewing images might make women feel bad about themselves), informational label (indicating the model in the advertisement was underweight), or a graphic label (picture of a paint brush). Although exposure to the fashion advertisements resulted in increased body dissatisfaction, there was no significant effect of label type on body dissatisfaction; no form of label demonstrated any ameliorating effect. In addition, the consequence and informational labels resulted in increased perceived realism and state appearance comparison. Yet more extensive research is required before the effective implementation of any form of label. PMID- 29525739 TI - Mechanisms of functional improvement through cognitive rehabilitation in schizophrenia. AB - Whereas the efficacy of cognitive rehabilitation in schizophrenia is widely known, studies examining mechanisms for functional improvement are still scarce. The aim of the study was to examine the mediational mechanisms through which cognitive rehabilitation improves functioning in schizophrenia. One hundred and eleven schizophrenia patients were randomly assigned to either a 4-month cognitive rehabilitation group or an active control group. Patients underwent a neurocognitive battery (including processing speed, verbal memory, working memory and executive functioning) and social cognition assessment (emotion perception, theory of mind and social perception). Functioning was assessed by the combined use of a performance-based instrument, the UCSD Performance-based Skills Assessment (UPSA) and an observer-rated instrument, the Global Assessment of Functioning (GAF). The trial was registered in clinicaltrials.gov (NCT02796417). Multiple mediational analyses revealed that the effect of cognitive rehabilitation on functional improvement was partially mediated by changes in processing speed and verbal memory, but not by the domains of social cognition and negative symptoms. More specifically, verbal memory partially mediated the treatment's effect on performance-based functioning (UPSA), whereas processing speed acted as a partial mediator for observer-rated functioning (GAF). The effect of rehabilitation on functioning did not take place through all the domains that showed significant improvement. Verbal memory and processing speed emerged as the most crucial factors. However, these complex interactions need further research. PMID- 29525740 TI - Major Sources of Bias. PMID- 29525741 TI - Editor's Choice - Spinal Cord Ischaemia in Endovascular Thoracic and Thoraco abdominal Aortic Repair: Review of Preventive Strategies. AB - INTRODUCTION: The incidence of spinal cord ischaemia (SCI) and subsequent paraplegia after thoracic endovascular aneurysm repair (TEVAR) and thoraco abdominal endovascular aneurysm repair is estimated to be between 2.5% and 8%. The aim of this review is to provide an overview of SCI preventive strategies in TEVAR and thoraco-abdominal repair and recommend an optimal strategy. METHODS: Medline, Embase, and the Cochrane Library were searched for studies on TEVAR, thoraco-abdominal endovascular repair, and the use of SCI preventive measures. The review was reported according to the PRISMA statement. RESULTS: The final analysis included 43 studies (7168 patients). All studies are cohort studies (non comparative cohorts n = 37, comparative cohorts n = 6) and largely performed retrospectively (n = 27). The included studies had an average MINORS score of 9 (range 6-13) for non-comparative studies and 15.5 (range 12-18) for comparative studies. Transient SCI occurred in 5.7% (450/7,168, 95% CI 4.5-6.9%), permanent SCI in 2.2% (232/7,168, 95% CI 1.6-2.8%). There was a trend towards increased SCI incidence for more "high risk" cohorts. Avoidance of hypotension resulted in a slightly lower permanent SCI rate 1.8% (102/4216, 95% CI 1.2-2.3%) than the overall cohort. A very low SCI estimate (transient and permanent) was found in the subgroup of studies (2 studies, n = 248) using (mild) peri-operative hypothermia (transient SCI 0.8%, permanent SCI 0.4%). In the subgroup using temporary permissive endoleak, there was a transient SCI estimate (15.4%), with a permanent SCI estimate of 4.8%. The remaining preventive measures did not significantly impact transient or permanent SCI estimates. CONCLUSION: Low overall transient and permanent SCI rates are achieved during endovascular thoracic and thoraco-abdominal aortic repair. Based on the presented data, the use of selective spinal fluid drainage in high risk patients seems justified. Peri-operative hypotension should be avoided and treated where possible. The use of mild hypothermia is promising in small cohorts, but requires further evaluation. Further high quality data are essential to establish a definitive preventive strategy. PMID- 29525742 TI - Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development. AB - Abdominal aortic aneurysm (AAA) is an often deadly disease without medical, non invasive treatment options. The upregulation of vascular cell adhesion molecule-1 (VCAM-1) on aortic endothelium provides an early target epitope for a novel biotechnological theranostic approach. MicroRNA-126 was used as a therapeutic agent, based on its capability to downregulate VCAM-1 expression in endothelial cells and thereby reduces leukocyte adhesion and exerts anti-inflammatory effects. Ultrasound microbubbles were chosen as carriers, allowing both molecular imaging as well as targeted therapy of AAA. Microbubbles were coupled with a VCAM 1-targeted single-chain antibody (scFvmVCAM-1) and a microRNA-126 mimic (M126) constituting theranostic microbubbles (TargMB-M126). TargMB-M126 downregulates VCAM-1 expression in vitro and in an in vivo acute inflammatory murine model. Most importantly, using TargMB-M126 and ultrasound-guided burst delivery of M126, the development of AAA in an angiotensin-II-induced mouse model can be prevented. Overall, we describe a unique biotechnological theranostic approach with the potential for early diagnosis and long-sought-after medical therapy of AAA. PMID- 29525744 TI - Outcomes of postoperative radiation therapy for breast cancer in older women according to age and comorbidity status: An observational retrospective study in 752 patients. AB - OBJECTIVES: The aim of this study was to assess efficacy, tolerability, and the impact of comorbidities on outcomes in older women treated by radiation therapy (RT) for non-metastatic breast cancer. MATERIALS AND METHODS: Women aged >=70 years at diagnosis who received postoperative RT for primary non-metastatic BC between 2003 and 2009 were retrieved from the Institut Curie registry. We calculated the Charlson Comorbidity Index (CCI) for each patient. We analyzed overall survival (OS), progression free survival (PFS), and acute and late toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. RESULTS: A total of 752 patients were included in this study. Median age at diagnosis was 75 years [70-93.3]. With a median follow-up of 7.3 years [0.4-12.9], OS and PFS at 5 years were 87.2% CI95%[84.8-89.8] and 85.7% CI95%[83.1-88.3], respectively. OS at 5 years was statistically different according to the CCI: 90.7% CI95%[87.6-93.9] for a CCI of 0, 85.8% CI95%[81.8 90.1] for a CCI of 1, and 79.1% CI95%[71.1-87.9] for a CCI >= 2 (p < 0.01, log rank test), respectively. Similar results were found for PFS (p < 0.05, log-rank test). Most (23.3%) of the patients had no toxicities; of those who experienced side-effects, the majority were grade I or II (96.9%). CONCLUSION: Postoperative RT for non-metastatic BC in older women is effective and well-tolerated. Outcome is impacted by age and comorbidities, which are clear independent prognostic factors. PMID- 29525743 TI - miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance. AB - This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR 296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3 kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC. PMID- 29525745 TI - Applicability of electrochemical wastewater treatment system powered by temperature difference energy. AB - In this research, an electrochemical wastewater treatment system, powered through the conversion of temperature difference into energy, was designed. The wastewater treatment system was applied to drainage flowing from two different mines, one contaminated by arsenic (As), the other ferrous iron (Fe2+). Arsenic was adsorbed on, or co-precipitated with, iron hydroxide generated from iron electrodes. A pseudo second order model well described the tendency for As removal. Ferrous iron oxidation occurred directly on graphite electrodes and followed a first order reaction model. The efficiency of As and Fe2+ removal was up to 99.7% and 97.9%, respectively. The rate constants for each model were proportional to given temperature differences, as the relationship between current generation and temperature difference was linear. Economic evaluation of the wastewater treatment system was performed by comparing the predicted cost of the thermocouples under particular environmental conditions. The thermocouple technology currently available could be applied to wastewater treatment for hot springs with high temperatures and high As concentrations. The applicability of the system to low temperature wastewaters will expand as energy production capacity per unit cost of thermocouples increases, as occurred with the photovoltaic and heat pump systems currently in use. PMID- 29525746 TI - Impact of styrenic polymer one-step hyper-cross-linking on volatile organic compound adsorption and desorption performance. AB - A novel one-step hyper-cross-linking method, using 1,2-dichloroethane (DCE) and 1,6-dichlorohexane (DCH) cross-linkers, expands the micropore volume of commercial styrenic polymers. Performance of virgin and modified polymers was evaluated by measuring hexane, toluene, and methyl-ethyl-ketone (MEK) adsorption capacity, adsorption/desorption kinetics, and desorption efficiency. Hyper-cross linked polymers have up to 128% higher adsorption capacity than virgin polymers at P/P0 = 0.05 due to micropore volume increases up to 330%. Improvements are most pronounced with the DCE cross-linker. Hyper-cross-linking has minimal impact on hexane adsorption kinetics, but adsorption rates for toluene and MEK decrease by 6-41%. Desorption rates decreased (3-36%) for all materials after hyper-cross linking, with larger decreases for DCE hyper-cross-linked polymers due to smaller average pore widths. For room temperature desorption, 20-220% more adsorbate remains in hyper-cross-linked polymers after regeneration compared to virgin materials. DCE hyper-cross-linked polymers have 13-92% more residual adsorbate than DCH counterparts. Higher temperatures were required for DCE hyper-cross linked polymers to completely desorb VOCs compared to the DCH hyper-cross-linked and virgin counterparts. Results show that the one-step hyper-cross-linking method for modifying styrenic polymers improves adsorption capacity because of added micropores, but decreases adsorption/desorption kinetics and desorption efficiency for large VOCs due to a decrease in average pore width. PMID- 29525747 TI - Dilute-and-shoot enhances sensitivity of phthalate urinary concentrations for assessing the exposure in children. AB - Phthalates are not covalently bound to plastics. They can leach from experimental plastic devices. Due to the development of sensitive techniques, exogenous sources that interfere with the accuracy of phthalate monoester analysis can be easily detected. Here, we propose the simple and rapid dilute-and-shoot method to minimize sample handling and limit contact with laboratory apparatus, which efficiently reduced phthalate interferences mainly from experimental plasticware and improved the accuracy of analysis. Chemical additives in the mobile phase and modifiers in reconstituted solution were evaluated to improve peak shape and liquid chromatography separation. Under optimal conditions, the limit of detection ranged from 0.01 to 0.5 ng/mL. No phthalate monoesters were detected above the limit of detection in blank water while the leached concentrations of MMP, MEP, MiBP, MnBP and MEHP from the conventional solid phase extraction procedure were 1.9, 2.7, 0.9, 2.0 and 1.1 ng/mL, respectively. In 304 samples collected from primary school- children aged 9-10 years, we observed a positive association between body mass index (BMI) and urinary MMP and MiBP concentrations in boys, while MEOHP and MEHHP were inversely related to BMI in girls. Furthermore, detectable phthalate monoesters may be considered potential chemical obesogens related to BMI in children. PMID- 29525748 TI - Effects of salicylic acid, Fe(II) and plant growth-promoting bacteria on Cd accumulation and toxicity alleviation of Cd tolerant and sensitive tomato genotypes. AB - In this study, we investigated the ameliorative effects of salicylic acid (SA), metal ion (Fe(II)), and plant growth-promoting bacteria Burkholderia sp. D54 (B) on two tomato genotypes with different Cd tolerances under Cd stress, viz. Liger (Cd tolerant) and Tabd (Cd sensitive). The plant biomass, Cd accumulation, antioxidative response, pigment content and photosynthetic performance were determined. According to the results, exogenous application of SA, Fe(II) and Burkholderia sp. D54 or their complex effectively reduced Cd accumulation and increased biomass of root, stem and leaves in both Cd sensitive and Cd tolerant genotypes. Among all treatments, SA+Fe+B exerted the best performance. Burkholderia sp. D54 effectively alleviated Cd-induced oxidative toxicity in both tomato genotypes, while SA ameliorated oxidative stress in Cd sensitive genotype. Photosynthetic pigment content and photosynthetic rate of Cd tolerant genotype was increased by all treatments, but only SA and Burkholderia sp. D54 treatment increased pigment contents and photosynthetic performance in Cd sensitive genotypes. All treatments significantly decreased Cd accumulation in both tomato genotypes. The effect of Cd reduction was Fe+SA+B>SA>Fe>B. Taken together, our results indicated that exogenous application of SA, Fe(II) and Burkholderia sp. D54 could alleviate the Cd toxicity in both Cd sensitive and Cd tolerant genotypes, although the extent varies. PMID- 29525749 TI - Minimizing the risk to human health due to the ingestion of arsenic and toxic metals in vegetables by the application of biochar, farmyard manure and peat moss. AB - Mining activity releases toxic metals (TMs) into the soil ecosystem and creates serious problems for the environment and human beings due to their adverse eco toxilogical impacts. Currently, several remediation techniques can be used to immobilize TMs within contaminated soil. The present study focuses on the application of different organic amendments biochar (B), farmyard manure (FYM) and peat moss (PTM) - at different application rates (1%, 2% and 5%) in mining impacted agricultural soil to immobilize TMs (Ni, Cr, As, Zn, Cd and Pb) and minimize their bioaccumulation in pea (Pisum sativum) and chili (Capsicum annuum) and the associated human health risk. Among the organic amendments, the treatments at the 5% application rate of B, FYM and PTM significantly (p <= 0.001) reduced the bioavailability of TM concentrations in amended soil and increased pea and chili plants' and fruits' biomasses when compared with the control. Moreover, risk assessments showed that B, FYM and PTM decreased the daily intake and health risk associated with the consumption of vegetables effectively for individual TMs compared with the control. The highest application rate of 5% significantly (p <= 0.001) reduced the average daily intake of TMs and their health risk, as compared to 1% and 2%, for both adults and children. The health risk index (HRI ? 1) values were lower (and within safety limits) for adults and children consuming vegetables grown on organic-amended soils. The results indicate that the B5% treatment of this mining-impacted agricultural soil was the most efficient at increasing plant and fruit biomasses and reducing the bioavailability, bioaccumulation and daily intake of TMs and their potential health risk through consumption of vegetables such as pea and chili, as compared to FYM, PTM and the control treatment. PMID- 29525750 TI - Biological denitrification from mature landfill leachate using a food-waste derived carbon source. AB - The mature landfill leachate containing high ammonia concentration (>1000 mg/L) is a serious threat to environment; however, the low COD to TN ratio (C/N, <3) strongly inhibits the denitrification process and poses a severe obstacle for efficient treatment. Herein, two kinds of acidogenic liquids, fermented from oil removed food waste and oil-added food waste, were first applied as external carbon sources for the biological nitrogen removal from mature landfill leachate in an aerobic/anoxic membrane bioreactor. "Acidogenic liquid b" served quite better than commercial sodium acetate, considering the higher denitrification efficiency and the slightly rapider denitrification rate. The effect of C/N and temperature were investigated under hydraulic retention time (HRT) of 7 d, which showed that C/N >= 7 (25 degrees C) was enough to meet the general discharge standards of NH4+-N, TN and COD in China. Even for some special areas of China, the more stringent discharge standards (NH4+-N <= 8 mg/L, TN <= 20 mg/L) could also be achieved under longer HRT of 14 d and C/N >= 6. Notably, the COD concentration in effluent could also be well reduced to 50-55 mg/L, without further physical-chemical treatment. This proposed strategy, involving the high value utilization of food waste, is thus promising for efficient nitrogen removal from mature landfill leachate. PMID- 29525751 TI - Effects of storage environment on the moisture content and microbial growth of food waste. AB - Food waste (FW) has become a critical issue in sustainable development as the world's population has increased. Direct incineration of FW remains the primary treatment option. The moisture content of FW may affect the energy efficiency of incineration. In Taiwan, FW, which includes raw (r-FW) and post-consumer (p-FW) waste, is often stored in freezers before pretreatment. This study evaluated the effects of storage environment on the moisture content and microbial growth of FW. Storage at 263 K was associated with the largest reduction in moisture content in both r-FW and p-FW. At 263 K, the moisture content of r-FW and p-FW was lowest at 96 and 72 h, respectively. The E.coli and total bacteria counts were steady over 120 h when stored at 263 K. Storage at 253 K required the greatest electricity consumption, followed by 263 K and 258 K. Based on the reduction of moisture content and increase in energy efficiency, it is suggested that FW is placed in temporary storage at 263 K before (pre)treatment. The results of this study will help waste-to-energy plants, incinerators, and waste management enterprises to implement proper (pre)treatment of FW for sustainable waste management. PMID- 29525752 TI - Measuring the sustainability of a natural system by using multi-criteria distance function methods: Some critical issues. AB - There is an important body of literature using multi-criteria distance function methods for the aggregation of a battery of sustainability indicators in order to obtain a composite index. This index is considered to be a proxy of the sustainability goodness of a natural system. Although this approach has been profusely used in the literature, it is not exempt from difficulties and potential pitfalls. Thus, in this paper, a significant number of critical issues have been identified showing different procedures capable of avoiding, or at least of mitigating, the inherent potential pitfalls associated with each one. The recommendations made in the paper could increase the theoretical soundness of the multi-criteria distance function methods when this type of approach is applied in the sustainability field, thus increasing the accuracy and realism of the sustainability measurements obtained. PMID- 29525753 TI - Desorption and mobility mechanisms of co-existing polycyclic aromatic hydrocarbons and heavy metals in clays and clay minerals. AB - The effects of soil components such as clay minerals and as humic acids, as well as co-existing metals and polycyclic aromatic hydrocarbons, on desorption and mobility are examined. Three types of artificially blended clay and clay mineral mixtures (pure kaolinite, kaolinite + sand and kaolinite + sand + bentonite), each with different humic acid content, were tested for desorption and mobility of acenaphthene, fluorene and fluoranthene by three extracting solutions CaCl2 (0.01 M) and EDTA (0.01M) with non-ionic surfactants (Tween 80 and Triton X100). Heavy metals (Ni, Pb and Zn) were also studied for desorption and mobility. The influence of co-present metals on simultaneous desorption and mobility of PAHs was investigated as well. The results showed that <10% of metals in the clay mineral mixtures were mobile. Combined EDTA and non-ionic solutions can enhance the desorption and mobility of PAHs to >80% in clay mineral mixtures containing no sand, while in the same soils containing ~40% sand, the desorption exceeded 90%. Heavy metals, as well as increasing humic acids content in the clay mineral mixtures, decreased the desorption and mobility of PAHs, especially for soils containing no sand, and for fluoranthene compared with fluorene and acenaphthene. PMID- 29525754 TI - Computing the effective diffusion coefficient of solutes in a multi-salts solutions during forward osmosis (FO) membrane filtration: Experiments and mathematical modelling. AB - Diffusion coefficient of solutes through a porous membrane media is different from diffusion coefficient through a free homogenous media. Porosity, tortuosity and the thickness of the membrane significantly affect the diffusion through a specific thickness of a membrane and therefore it is termed as effective diffusion coefficient (Deff) which is lower than the actual diffusion coefficient, D. The Deff of single or dual solutes through a porous membrane layer are well documented but not for multiple salts. Therefore, in this study, single, dual and multiple salt mixtures were passed through a flat sheet cellulose triacetate Forward Osmosis (FO) membrane to obtain a semi-empirical relationship with the Deff and its water flux. This will allow computing the structural coefficient of FO membranes. Research community have spent tremendous efforts in membrane modification to reduce the structural coefficient to improve FO process efficiency. Our finding suggests that optimising the draw solution chemistry can achieve this goal. PMID- 29525755 TI - Neoadjuvant chemotherapy or primary debulking surgery in FIGO IIIC and IV patients; results from a survey study in the Netherlands. AB - INTRODUCTION: Primary debulking surgery (PDS) followed by adjuvant chemotherapy is historically recommended as first line treatment for advanced stage ovarian cancer. Two randomized controlled trials, however, showed similar efficacy and reduced toxicity with neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS). Nevertheless, uptake of NACT-IDS varies widely between hospitals, which cannot be explained by difference in patient populations. In this survey, we therefore aimed to evaluate the views on NACT-IDS among all Dutch gynaecologists and medical oncologists involved in the treatment of ovarian cancer. STUDY DESIGN: An e-mail link to the online questionnaire was sent to all medical oncologists and gynaecologists in the Netherlands, regardless of their (sub)specializations. The data was analysed using descriptive statistics and chi square tests were used to analyse differences between groups. RESULTS: Three hundred-forty physicians were invited to fill out the questionnaire. After two reminders, 167 of them responded (49%). Among the responders, 82% of the gynaecologists versus 93% of the medical oncologists considered the available evidence sufficiently convincing to treat advanced stage ovarian cancer patients with NACT-IDS (p = 0.076). Moreover, 33% of gynaecologists and 62% of medical oncologists preferred NACT-IDS to PDS as first line treatment (p = 0.001). While most responders (86%) indicated that selecting the right patients for NACT-IDS is difficult, those with bulky disease, FIGO stage IV or metastases near the porta hepatica were most likely to undergo NACT-IDS. CONCLUSION: The majority of Dutch gynaecologists and medical oncologists adopted NACT-IDS as an alternative treatment approach for advanced stage primary ovarian cancer. About two-thirds of medical oncologists and one-third of gynaecologists prefer NACT-IDS to PDS as first line treatment in this setting. Improving patient selection is considered of paramount importance. PMID- 29525756 TI - The novel use of botulinum toxin A for the treatment of Raynaud's phenomenon in the toes. AB - Raynaud's phenomenon is a vasospastic disorder of the digital vessels triggered by exposure to cold or stress. It is most commonly observed in the hands, but also frequently affects the toes. We present three cases of patients with severe Raynaud's phenomenon in the toes, secondary to scleroderma. The diagnosis of Raynaud's syndrome and scleroderma was established according to the 2010 American College of Rheumatology and European League Against Rheumatism criteria. Patients were treated with 10 units of botulinum toxin injected into each foot. Two millilitres was injected into the base of each toe in both the left and right feet. Six weeks postinjection into the toes, patients reported an improvement of cold intolerance, colour change and frequency and severity of Raynaud's attacks. The effects were reported to last up to 5 months. To our knowledge, these are the first reported cases of the treatment of Raynaud's phenomenon in the toes with botulinum toxin A. PMID- 29525757 TI - Renocolic fistula secondary to urothelial carcinoma. AB - A 77-year-old man presented with watery, bloody diarrhoea, symptomatic anaemia and signs of sepsis. He was well known to our unit with a history of extensive low-grade urothelial carcinoma involving a solitary kidney. CT performed on admission demonstrated a new finding of renocolic fistula. Due to his multiple medical and surgical comorbidities conservative management was elected. He passed away after 1 year of follow-up. PMID- 29525759 TI - Spontaneous renal infarct heralding bowel ischaemia in an adult male: lessons to learn from a rare clinical association. AB - Spontaneous renal artery dissection (SRAD) is a rare entity with less than 200 cases reported in literature. It usually affects middle-aged men and the clinical presentation is non-specific. Many times it is associated with conditions such as hypertension, fibromuscular dysplasia or vasculitides. We report the case of a patient who initially had renal infarct due to SRAD and then progressed to have bowel ischaemia. The renal infarct preceded bowel ischaemia in this patient and to the best of our knowledge this is the first such association reported in literature. Our report emphasises the point that whenever this condition is diagnosed in a patient one should be vigilant for other vascular disorders. PMID- 29525758 TI - Atrial myxoma presenting as infective endocarditis. AB - A 23-year-old Asian student presented to our service with a 1-month history of fever, weight loss of 10 kg, night sweats, fatigue and general malaise. He was previously well with no significant medical or family history. He had a low-grade pyrexia and cardiac auscultation revealed a diastolic murmur consistent with 'tumour plop'. He had no sequelae of endocarditis. He had low-grade pyrexia of 37.7 degrees C, and ECG showed sinus tachycardia at 130 bpm. He had raised inflammatory markers and was started on broad spectrum antibiotics. Blood cultures grew Streptococcus viridans twice. Transthoracic and transo-oesophageal echocardiography revealed a large mobile mass attached to the interatrial septum, suspicious for atrial myxoma, flopping into the left ventricle but not causing left ventricular outflow tract obstruction. All valves looked normal in appearance. He was treated with antibiotics for 2 weeks until inflammatory markers normalised. The patient was referred for cardiothoracic surgery where a large atrial myxoma (5 cm*3 cm) was excised just superior to the mitral valve. It had areas of necrosis and was colonised with S. viridans He had an unremarkable postoperative course and made a complete recovery. PMID- 29525760 TI - Pancytopenia: a rare complication of Graves' disease. AB - A 27-year-old male patient who presented to the emergency room with complaints of sweating, palpitations, heat intolerance, insomnia and weight loss for the last 3 months. His medical history was significant for hypertension. On examination, he was tachycardic, hypertensive, had tremors of the upper extremities and a smooth goitre with a thyroid bruit. Laboratory assessment revealed a suppressed thyroid stimulating hormone, high free thyroxine and positive thyroid receptor antibodies. Complete blood count showed pancytopenia. As part of the work-up for pancytopenia, haptoglobin, ferritin, Coombs test, reticulocyte count hepatitis B and C antibodies were done, all of which were normal. Patient was started on methimazole, propranolol and hydrocortisone. His symptoms improved through the hospital course and he was subsequently discharged. Thyroidectomy was done once the patient's hyperthyroidism was controlled. Levothyroxine was started for the control of postsurgical hypothyroidism. Six months after thyroidectomy, the patient was euthyroid and the pancytopenia resolved. PMID- 29525761 TI - Rare case of thoracic endometriosis presenting with lung nodules and pneumothorax. AB - We present the case of a 34-year-old Nigerian woman who was referred to the Respiratory team with a 12-month history of breathlessness. She was concurrently being investigated for an abdominal mass and rectal and vaginal bleeding. Consequently, she underwent cross-sectional imaging of her chest, abdomen and pelvis, revealing a small right-sided pneumothorax and right lower lobe pleural based lesion. Shortly thereafter, she was admitted to the hospital with chest pain and required chest drain insertion. This partially treated her pneumothorax but she required referral to a cardiothoracic centre for definitive diagnosis and to manage her non-resolving pneumothorax. Biopsies from the video-assisted thoracoscopic surgery confirmed the very rare diagnosis of thoracic endometriosis. PMID- 29525762 TI - Lactate gap as a tool in identifying ethylene glycol poisoning. AB - Ethylene glycol toxicity is a known cause of anion gap metabolic acidosis, with the presence of an osmolar gap and the right clinical context suggesting to the diagnosis. Rapid recognition and early treatment is crucial. Unfortunately, ethylene glycol levels are not readily available and must be performed at a reference laboratory. We present a case where recognising the significance of the 'lactate gap' assisted in identifying ethylene glycol poisoning. PMID- 29525763 TI - Different doses of Pilates-based exercise therapy for chronic low back pain: a randomised controlled trial with economic evaluation. AB - OBJECTIVES: To evaluate the effectiveness and cost-utility of the addition of different doses of Pilates to an advice for non-specific chronic low back pain (NSCLBP) from a societal perspective. DESIGN: Randomised controlled trial with economic evaluation. SETTING: Physiotherapy clinic in Sao Paulo, Brazil. PARTICIPANTS: 296 patients with NSCLBP. INTERVENTIONS: All patients received advice and were randomly allocated to four groups (n=74 per group): booklet group (BG), Pilates once a week (Pilates group 1, PG1), Pilates twice a week (Pilates group 2, PG2) and Pilates three times a week (Pilates group 3, PG3). MAIN OUTCOME MEASURES: Primary outcomes were pain and disability at 6-week follow-up. RESULTS: Compared with the BG, all Pilates groups showed significant improvements in pain (PG1, mean difference (MD)=-1.2, 95% CI -2.2 to -0.3; PG2, MD=-2.3, 95% CI -3.2 to -1.4; PG3, MD=-2.1, 95% CI -3.0 to -1.1) and disability (PG1, MD=-1.9, 95% CI 3.6 to -0.1; PG2, MD=-4.7, 95% CI -6.4 to -3.0; PG3, MD=-3.3, 95% CI -5.0 to 1.6). Among the different doses, PG2 showed significant improvements in comparison with PG1 for pain (MD=-1.1, 95% CI -2.0 to -0.1) and disability (MD= 2.8, 95% CI -4.5 to -1.1). The cost-utility analysis showed that PG3 had a 0.78 probability of being cost-effective at a willingness-to-pay of L20 000 per quality-adjusted life-year gained. CONCLUSIONS: Adding two sessions of Pilates exercises to advice provided better outcomes in pain and disability than advice alone for patients with NSCLBP; non-specific elements such as greater attention or expectation might be part of this effect. The cost-utility analysis showed that Pilates three times a week was the preferred option. TRIAL REGISTRATION NUMBER: NCT02241538, Completed. PMID- 29525764 TI - Hospital Readmission After Perioperative Acute Myocardial Infarction Associated With Noncardiac Surgery. AB - BACKGROUND: Acute myocardial infarction (AMI) is a major cardiovascular complication of noncardiac surgery. We aimed to evaluate the frequency, causes, and outcomes of 30-day hospital readmission after perioperative AMI. METHODS: Patients who were diagnosed with AMI during hospitalization for major noncardiac surgery were identified using the 2014 US Nationwide Readmission Database. Rates, causes, and costs of 30-day readmissions after noncardiac surgery with and without perioperative AMI were identified. RESULTS: Among 3 807 357 hospitalizations for major noncardiac surgery, 8085 patients with perioperative AMI were identified. A total of 1135 patients (14.0%) with perioperative AMI died in-hospital during the index admission. Survivors of perioperative AMI were more likely to be readmitted within 30 days than surgical patients without perioperative AMI (19.1% versus 6.5%, P<0.001). The most common indications for 30-day rehospitalization were management of infectious complications (30.0%), cardiovascular complications (25.3%), and bleeding (10.4%). In-hospital mortality during hospital readmission in the first 30 days after perioperative AMI was 11.3%. At 6 months, the risk of death was 17.6% and >=1 hospital readmission was 36.2%. CONCLUSIONS: Among patients undergoing noncardiac surgery who develop a perioperative MI, ~1 in 3 suffer from in-hospital death or hospital readmission in the first 30 days after discharge. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted. PMID- 29525765 TI - Spinal meningioma, aortic aneurysms and the missing link of observation: the anchoring heuristic approach. AB - Over the last three decades, the development of systematic and protocol-based algorithms, and advances in available diagnostic tests have become the indispensable parts of practising medicine. Naturally, despite the implementation of meticulous protocols involving diagnostic tests or even trials of empirical therapies, the cause of one's symptoms may still not be obvious. We herein report a case of chronic back pain, which took about 5 years to get accurately diagnosed. The case challenges the diagnostic assumptions and sets ground of discussion for the diagnostic reasoning pitfalls and heuristic biases that mislead the caring physicians and cost years of low quality of life to our patient. This case serves as an example of how anchoring heuristics can interfere in the diagnostic process of a complex and rare entity when combined with a concurrent potentially life-threatening condition. PMID- 29525766 TI - Internet-based programmes on weight loss appear to be effective for low-income postpartum women. PMID- 29525767 TI - Effectiveness of evidence-based treatments of fetal alcohol spectrum disorders in children and adolescents: a systematic review protocol. AB - INTRODUCTION: The aim of this paper is to provide a protocol for a systematic review assessing the effectiveness of evidence from randomised controlled trials comparing fetal alcohol spectrum disorders pharmacological and non pharmacological interventions with placebo/dummy interventions or usual standards of care in children and adolescents (<18 years old). METHODS AND ANALYSIS: The following electronic databases will be searched: Medline (Ovid), Cumulative Index of Nursing and Allied Health Plus with Full text (EBSCO), Cochrane Central Register of Controlled Trials (Cochrane Library-Wiley), PsycINFO (ProQuest) and Proquest DissertationsandTheses will be searched from inception to March 2017 for relevant citations of published trials using individualised search strategies prepared for database. We will also search the reference lists of relevant articles and conference proceedings. Two reviewers will independently assess each study against predetermined inclusion/exclusion criteria and extract data including population characteristics, types and duration of interventions and outcomes from included trials. Internal validity will be assessed using the Cochrane Risk of Bias Tool. Primary outcome measures will be improvements in symptoms, including: hyperactivity, impulsivity and attention as measured by standard rating scales. Secondary outcome measures will include improvements in physical and mental health domains, as well as cognitive, behavioural, social and educational skills as measured by rating scales, standardised psychometric tests of IQ and memory, grade repetition, literacy tests and diagnosis of mental health disorder. ETHICS AND DISSEMINATION: Ethical approval will not be obtained since it is not required for systematic reviews as there are no concerns regarding patient privacy. The results of this review will be disseminated through publication in a peer-review journal and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42013005996. PMID- 29525768 TI - Using an internet intervention to support self-management of low back pain in primary care: findings from a randomised controlled feasibility trial (SupportBack). AB - OBJECTIVE: To determine the feasibility of a randomised controlled trial of an internet intervention for low back pain (LBP) using three arms: (1) usual care, (2) usual care plus an internet intervention or (3) usual care plus an internet intervention with additional physiotherapist telephone support. DESIGN AND SETTING: A three-armed randomised controlled feasibility trial conducted in 12 general practices in England. PARTICIPANTS: Primary care patients aged over 18 years, with current LBP, access to the internet and without indicators of serious spinal pathology or systemic illness. INTERVENTIONS: The 'SupportBack' internet intervention delivers a 6-week, tailored programme, focused on graded goal setting, self-monitoring and provision of tailored feedback to encourage physical activity. Additional physiotherapist telephone support consisted of three brief telephone calls over a 4-week period, to address any concerns and provide reassurance. OUTCOMES: The primary outcomes were the feasibility of the trial design including recruitment, adherence and retention at follow-up. Secondary descriptive and exploratory analyses were conducted on clinical outcomes including LBP-related disability at 3 months follow-up. RESULTS: Primary outcomes: 87 patients with LBP were recruited (target 60-90) over 6 months, and there were 3 withdrawals. Adherence to the intervention was higher in the physiotherapist-supported arm, compared with the stand-alone internet intervention. Trial physiotherapists adhered to the support protocol. Overall follow-up rate on key clinical outcomes at 3 months follow-up was 84%. CONCLUSIONS: This study demonstrated the feasibility of a future definitive randomised controlled trial to determine the clinical and cost-effectiveness of the SupportBack intervention in primary care patients with LBP. TRIAL REGISTRATION NUMBER: ISRCTN31034004; Results. PMID- 29525769 TI - Healthcare use for children with complex needs: using routine health data linked to a multiethnic, ongoing birth cohort. AB - OBJECTIVES: Congenital anomaly (CA) are a leading cause of disease, death and disability for children throughout the world. Many have complex and varying healthcare needs which are not well understood. Our aim was to analyse the healthcare needs of children with CA and examine how that healthcare is delivered. DESIGN: Secondary analysis of observational data from the Born in Bradford study, a large prospective birth cohort, linked to primary care data and hospital episode statistics. Negative binomial regression with 95% CIs was performed to predict healthcare use. The authors conducted a subanalysis on referrals to specialists using paper medical records for a sample of 400 children. SETTING: Primary, secondary and tertiary healthcare services in a large city in the north of England. PARTICIPANTS: All children recruited to the birth cohort between March 2007 and December 2011. A total of 706 children with CA and 10 768 without CA were included in the analyses. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare use for children with and without CA aged 0 to <5 years was the primary outcome measure after adjustment for confounders. RESULTS: Primary care consultations, use of hospital services and referrals to specialists were higher for children with CA than those without. Children in economically deprived neighbourhoods were more likely to be admitted to hospital than consult primary care. Children with CA had a higher use of hospital services (beta 1.48, 95% CI 1.36 to 1.59) than primary care consultations (beta 0.24, 95% CI 1.18 to 0.30). Children with higher educated mothers were less likely to consult primary care and hospital services. CONCLUSIONS: Hospital services are most in demand for children with CA, but also for children who were economically deprived whether they had a CA or not. The complex nature of CA in children requires multidisciplinary management and strengthened coordination between primary and secondary care. PMID- 29525770 TI - Steps Towards Alcohol Misuse Prevention Programme (STAMPP): a school-based and community-based cluster randomised controlled trial. AB - OBJECTIVES: To assess the effectiveness of a combined classroom curriculum and parental intervention (the Steps Towards Alcohol Misuse Prevention Programme (STAMPP)), compared with alcohol education as normal (EAN), in reducing self reported heavy episodic drinking (HED) and alcohol-related harms (ARHs) in adolescents. SETTING: 105 high schools in Northern Ireland (NI) and in Scotland. PARTICIPANTS: Schools were stratified by free school meal provision. Schools in NI were also stratified by school type (male/female/coeducational). Eligible students were in school year 8/S1 (aged 11-12 years) at baseline (June 2012). INTERVENTION: A classroom-based alcohol education intervention, coupled with a brief alcohol intervention for parents/carers. PRIMARY OUTCOMES: (1) The prevalence of self-reported HED in the previous 30 days and (2) the number of self-reported ARHs in the previous 6 months. Outcomes were assessed using two level random intercepts models (logistic regression for HED and negative binomial for number of ARHs). RESULTS: At 33 months, data were available for 5160 intervention and 5073 control students (HED outcome), and 5234 and 5146 students (ARH outcome), respectively. Of those who completed a questionnaire at either baseline or 12 months (n=12 738), 10 405 also completed the questionnaire at 33 months (81.7%). Fewer students in the intervention group reported HED compared with EAN (17%vs26%; OR=0.60, 95% CI 0.49 to 0.73), with no significant difference in the number of self-reported ARHs (incident rate ratio=0.92, 95% CI 0.78 to 1.05). Although the classroom component was largely delivered as intended, there was low uptake of the parental component. There were no reported adverse effects. CONCLUSIONS: Results suggest that STAMPP could be an effective programme to reduce HED prevalence. While there was no significant reduction in ARH, it is plausible that effects on harms would manifest later. TRIAL REGISTRATION NUMBER: ISRCTN47028486; Post-results. PMID- 29525771 TI - Impact of particulate matter on mothers and babies in Antwerp (IPANEMA): a prospective cohort study on the impact of pollutants and particulate matter in pregnancy. AB - INTRODUCTION: Air pollution is a hot topic and is known to cause multiple health issues. Especially pregnant women seem to be vulnerable to environmental issues. There are data suggesting that exposure contributes to hypertensive disorders.This study aims to evaluate the effects of exposure to particulate matter (PM) and outdoor air pollutants on the clinical pregnancy outcome for mother and child and to determine which biochemical changes in maternal, placental and cord blood best explain this effect. METHODS AND ANALYSIS: This study is a prospective cohort study. We aim to recruit 200 pregnant women. The outcome measurements will include maternal parameters, labour parameters and neonatal parameters.Multiple samples will be analysed such as maternal urine samples (8-oxo-deoxyguanosine), maternal blood samples (routine blood sampling, biomarkers of pre-eclampsia and transcript markers), maternal hair samples, neonatal blood samples (transcript markers) combined with extensive questionnaires. ETHICS AND DISSEMINATION: We obtain informed consent from each participant prior to enrolment in the study.The study has received approval by the Ethical Committee of the Antwerp University Hospital (14/40/411).IPANEMA is the first prospective study to assess the impact of PM on mothers and babies in Antwerp, Belgium.Findings from this study will contribute to improve knowledge on the impact of exposure to air pollution on mothers and babies and will also define biomarkers as predictors for pregnant women at risk. TRIAL REGISTRATION: ClinicalTrials.gov: 14/40/411. Registered 22-10-2015. PMID- 29525772 TI - Consumption of ultra-processed foods and associated sociodemographic factors in the USA between 2007 and 2012: evidence from a nationally representative cross sectional study. AB - OBJECTIVES: To compare ultra-processed food consumption across sociodemographic groups and over time (2007-2008, 2009-2010, 2011-2012) in the USA. DESIGN: Cross sectional study. SETTING: National Health and Nutrition Examination Survey (NHANES) 2007-2012. PARTICIPANTS: All individuals aged >=2 years with at least one 24-hour dietary recall were included (n=23 847). MAIN OUTCOME MEASURES: Average dietary contribution of ultra-processed foods (expressed as a percentage of the total caloric value of the diet), obtained after classifying all food items according to extent and purpose of industrial food processing using NOVA classification. DATA ANALYSIS: Linear regression was used to evaluate the association between sociodemographic characteristics or NHANES cycles and dietary contribution of ultra-processed foods. RESULTS: Almost 60% of calories consumed in the period 2007-2012 came from ultra-processed foods. Consumption of ultra processed foods decreased with age and income level, was higher for non-Hispanic whites or non-Hispanic blacks than for other race/ethnicity groups and lower for people with college than for lower levels of education, all differences being statistically significant. Overall contribution of ultra-processed foods increased significantly between NHANES cycles (nearly 1% point per cycle), the same being observed among males, adolescents and high school education-level individuals. CONCLUSIONS: Ultra-processed food consumption in the USA in the period 2007-2012 was overall high, greater among non-Hispanic whites or non Hispanic blacks, less educated, younger, lower-income strata and increased across time. PMID- 29525773 TI - Evaluation of the district health management fellowship training programme: a case study in Iran. AB - OBJECTIVE: To evaluate the district health management fellowship training programme in the north-west of Iran. DATA SOURCES/STUDY SETTING: The programme was introduced to build the managerial capacity of district health managers in Iran. Eighty-nine heads of units in the province's health centre, district health managers and the health deputies of the district health centres in the north-west provinces of Iran had registered for the district health management fellowship training programme in Tabriz in 2015-2016. STUDY DESIGN: This was an educational evaluation study to evaluate training courses to measure participants' reactions and learning and, to a lesser extent, application of training to their job and the organisational impact. DATA COLLECTION/EXTRACTION METHODS: Valid and reliable questionnaires were used to assess learning techniques and views towards the fellowship, and self-assessment of health managers' knowledge and skills. Also, pretest and post-test examinations were conducted in each course and a portfolio was provided to the trainees to be completed in their work settings. PRINCIPAL FINDINGS: About 63% of the participants were medical doctors and 42.3% of them had over 20 years of experience. Learning by practice (scored 18.37 out of 20) and access to publications (17.27) were the most useful methods of training in health planning and management from the participants' perspective. Moreover, meeting peers from other districts and the academic credibility of teachers were the most important features of the current programme. Based on the managers' self assessment, they were most skilful in quality improvement, managing, planning and evaluation of the district. The results of the post-test analysis on data collected from district health managers showed the highest scores in managing the district (77 out of 100) and planning and evaluation (69) of the courses. CONCLUSION: The results of this study indicated that training courses, methods and improvement in managers' knowledge about the health system and the skills necessary to manage their organisation were acceptable. PMID- 29525774 TI - Organisational perspectives on addressing differential attainment in postgraduate medical education: a qualitative study in the UK. AB - OBJECTIVES: To explore how representatives from organisations with responsibility for doctors in training perceive risks to the educational progression of UK medical graduates from black and minority ethnic groups (BME UKGs), and graduates of non-UK medical schools (international medical graduates (IMGs)). To identify the barriers to and facilitators of change. DESIGN: Qualitative semistructured individual and group interview study. SETTING: Postgraduate medical education in the UK. PARTICIPANTS: Individuals with roles in examinations and/or curriculum design from UK medical Royal Colleges. Employees of NHS Employers. RESULTS: Representatives from 11 medical Royal Colleges (n=29) and NHS Employers (n=2) took part (55% medically qualified, 61% male, 71% white British/Irish, 23% Asian/Asian British, 6% missing ethnicity). Risks were perceived as significant, although more so for IMGs than for BME UKGs. Participants based significance ratings on evidence obtained largely through personal experience. A lack of evidence led to downgrading of significance. Participants were pessimistic about effecting change, two main barriers being sensitivities around race and the isolation of interventions. Participants felt that organisations should acknowledge problems, but felt concerned about being transparent without a solution; and talking about race with trainees was felt to be difficult. Participants mentioned 63 schemes aiming to address differential attainment, but these were typically local or specialty-specific, were not aimed at BME UKGs and were largely unevaluated. Participants felt that national change was needed, but only felt empowered to effect change locally or within their specialty. CONCLUSIONS: Representatives from organisations responsible for training doctors perceived the risks faced by BME UKGs and IMGs as significant but difficult to change. Strategies to help organisations address these risks include: increased openness to discussing race (including ethnic differences in attainment among UKGs); better sharing of information and resources nationally to empower organisations to effect change locally and within specialties; and evaluation of evidence-based interventions. PMID- 29525775 TI - Is it feasible to conduct a randomised controlled trial of pretransplant exercise (prehabilitation) for patients with multiple myeloma awaiting autologous haematopoietic stem cell transplantation? Protocol for the PREeMPT study. AB - INTRODUCTION: While myeloma is an incurable malignancy, developments in disease management have led to increased life expectancy in recent years. Treatment typically involves stem-cell transplantation. Increased survival rates equate to more patients living with the burden of both the disease and its treatment for increasing number of years, rendering myeloma a long-term condition.Evidence exists to demonstrate the benefits of exercise for patients recovering from stem cell transplantation, and prehabilitation-exercise before treatment-has been shown to be effective in other disease areas. To date there has been no research into prehabilitation in patients with myeloma awaiting transplantation treatment.Our objective is to determine whether it is feasible to conduct a randomised controlled trial into pretransplant exercise for patients with multiple myeloma who are awaiting autologous stem-cell transplantation. METHODS AND ANALYSIS: This mixed methods study identifies patients with diagnosis of multiple myeloma who have been assigned to the autologous transplantation list and invites them to participate in six weekly sessions of individualised, supervised exercise while awaiting transplantation.Quantitative data to determine feasibility targets include rates of recruitment, adherence and adverse events, and outcome measures including 6 min walking distance test and quality of life.Qualitative interviews are undertaken with a purposive sample of patients to capture their experiences of the study and the intervention. ETHICS AND DISSEMINATION: Ethics committee approval has been obtained. Dissemination will be through open-access publications and presentations and will seek to reach multiprofessional bases as well as patients and carer groups, addressing the widespread interest in this area of research. TRIAL REGISTRATION NUMBER: NCT03135925; Pre-results. PMID- 29525777 TI - Common language description of the term rheumatic and musculoskeletal diseases (RMDs) for use in communication with the lay public, healthcare providers and other stakeholders endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). AB - A European League Against Rheumatism-American College of Rheumatology working group consisting of practising and academic rheumatologists, a rheumatology researcher and a patient representative created a succinct general statement describing rheumatic and musculoskeletal diseases (RMDs) in adults and children in language that can be used in conversations with the lay public, media, healthcare providers and other stakeholders. Based on the literature review, several elements were deemed important for inclusion in the description of RMDs. First, RMDs encompass many different diseases that can affect individuals at any age, including children. Second, there are various pathophysiological pathways underlying different RMDs. Third, the impact of RMDs on individuals and society should be emphasised. The working group agreed that the language should be comprehensible to the lay public. Thus, the following description of RMDs has been developed: 'Rheumatic and musculoskeletal diseases (RMDs) are a diverse group of diseases that commonly affect the joints, but can affect any organ of the body. There are more than 200 different RMDs, affecting both children and adults. They are usually caused by problems of the immune system, inflammation, infections or gradual deterioration of joints, muscles and bones. Many of these diseases are long term and worsen over time. They are typically painful and limit function. In severe cases, RMDs can result in significant disability, having a major impact on both quality of life and life expectancy.' This description can be used by rheumatology groups, researchers and those who work in advocacy and education related to RMDs. PMID- 29525776 TI - Determinants of psychological well-being in axial spondyloarthritis: an analysis based on linked claims and patient-reported survey data. AB - OBJECTIVES: The aim of this study was to assess the psychological well-being and to analyse factors associated with depressive symptoms in axial spondyloarthritis (axSpA). METHODS: A stratified random sample of subjects with a diagnosis of axSpA (International Classification of Diseases, Tenth Revision, German Modification M45) was drawn from health insurance data in Germany. These persons received a postal questionnaire on disease-related, psychological and lifestyle factors as well as socioeconomic status. Additional information to verify the axSpA diagnosis was also collected. The psychological well-being was assessed by means of the 5-item WHO Well-Being Index (WHO-5), which is considered a screening tool for depression. The following established cut-offs on the WHO-5 were applied: >50: good well-being, no depressive symptoms; 29-50: mild depressive symptoms; <=28: moderate-to-severe depressive symptoms. Information on comorbidities, drug prescriptions and non-pharmacological treatment was retrieved from claims data and linked to the questionnaire data. RESULTS: A total of 1736 persons with a confirmed axSpA diagnosis were included. Using the cut-offs on the WHO-5, 533 persons (31%) were found to have moderate-to-severe depressive symptoms, 479 (28%) had mild depressive symptoms and 724 (42%) had a good well being. Multivariable logistic regression revealed that higher disease activity, higher level of functional impairment, lower income, self-reported stress and lack of exercise, and younger age represent factors associated with moderate-to severe depressive symptoms. CONCLUSIONS: The prevalence of depressive symptoms in axSpA subjects is high and associated with disease-related parameters, socioeconomic status and lifestyle factors. These findings highlight the need for the careful evaluation of depressive symptoms as a part of the management strategy for axSpA. PMID- 29525778 TI - Provider Specialty, Anticoagulation Prescription Patterns, and Stroke Risk in Atrial Fibrillation. AB - BACKGROUND: Differences in anticoagulation rates and direct oral anticoagulant use by provider specialty may identify an area of practice improvement to reduce future stroke events in patients with atrial fibrillation (AF). METHODS AND RESULTS: We examined anticoagulant prescription fills in 388 045 (mean age, 68+/ 15 years; 59% male) patients with incident AF from the MarketScan databases between 2009 and 2014. Provider specialty and filled anticoagulant prescriptions around the time of AF diagnosis (3 months before through 6 months after) were obtained from outpatient services and pharmacy claims. We estimated the association of provider specialty (cardiology versus primary care) with filling oral anticoagulant prescriptions, adjusting for patient characteristics. The risk of stroke and bleeding events also was explored. A total of 235 739 patients (61%) had a cardiology provider claim, whereas 152 306 (39%) were exclusively managed by primary care. Patients seen by cardiology providers were more likely to fill anticoagulant prescriptions than those seen by primary care (39% versus 27%; relative risk, 1.39; 95% confidence interval [CI], 1.37-1.40). Differences were observed for direct oral anticoagulants (relative risk, 1.74; 95% CI, 1.71 1.78) and warfarin (relative risk, 1.24; 95% CI, 1.22-1.26). A reduced risk of stroke events was observed among those seen by cardiology providers (hazard ratio, 0.90; 95% CI, 0.86-0.94) compared with primary care, without an increased bleeding risk (hazard ratio, 1.03; 95% CI, 0.98-1.07). CONCLUSIONS: Patients seen by an outpatient cardiology provider shortly after AF diagnosis were more likely to initiate oral anticoagulation and were at lower risk of future stroke events without a higher rate of bleeding. Early referral to cardiology specialists may increase initiation of anticoagulant therapies and improve outcomes in AF. PMID- 29525779 TI - Non-ST-Segment-Elevation Myocardial Infarction Among Patients With Chronic Kidney Disease: A Propensity Score-Matched Comparison of Percutaneous Coronary Intervention Versus Conservative Management. AB - BACKGROUND: Chronic kidney disease (CKD) remains an independent predictor of cardiovascular morbidity and mortality. CKD complicates referral for percutaneous coronary intervention (PCI) in non-ST-segment-elevation myocardial infarction (NSTEMI) patients because of the risk for acute kidney injury and the need for dialysis, with American College of Cardiology/American Heart Association guidelines underscoring the limited data on these patients. METHODS AND RESULTS: Using the National Inpatient Sample to analyze hospitalizations in the United States from 2004 to 2014, we sought to assess PCI utilization and in-hospital outcomes in NSTEMI admissions with CKD. NSTEMI admissions were identified by International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) code 410.7. CKD admissions were identified by ICD-9-CM code 585. Propensity score-matched cohorts of patients with NSTEMI were matched for age, sex, comorbidities, race, median household income, primary payer status, and hospital characteristics. Of 4 488 795 hospitalizations for NSTEMI, 31% underwent PCI. Overall, 89% of admissions had no CKD. In addition, 32% of NSTEMI admissions with no CKD and 23%, 14%, and 22% with CKD stages 3, 4, and 5 underwent PCI, respectively. Hospitalized NSTEMI patients with CKD stages 4 and 5 had 41% and 20% less likelihood, respectively, of undergoing PCI compared with those with no CKD. Among hospitalized NSTEMI patients with no CKD or CKD stage 3, 4, or 5, PCI treated groups had 63%, 57%, 39%, and 59% lower likelihood, respectively, of all cause, in-hospital mortality compared with propensity score-matched medically managed groups. CONCLUSIONS: PCI use decreased among hospitalized NSTEMI patients as CKD severity increased, and all-cause, in-hospital mortality was greater for NSTEMI patients admitted with more severe CKD regardless of treatment strategy. PMID- 29525780 TI - Cognitive Function Before and After Left Heart Catheterization. AB - BACKGROUND: Hospital procedures have been associated with cognitive change in older patients. This study aimed to document the prevalence of mild cognitive impairment in individuals undergoing left heart catheterization (LHC) before the procedure and the incidence of cognitive decline to 3 months afterwards. METHODS AND RESULTS: We conducted a prospective, observational, clinical investigation of elderly participants undergoing elective LHC. Cognition was assessed using a battery of written tests and a computerized cognitive battery before the LHC and then at 3 months afterwards. The computerized tests were also administered at 24 hours (or discharge) and 7 days after LHC. A control group of 51 community participants was recruited to calculate cognitive decline using the Reliable Change Index. Of 437 participants, mild cognitive impairment was identified in 226 (51.7%) before the procedure. Computerized tests detected an incidence of cognitive decline of 10.0% at 24 hours and 7.5% at 7 days. At 3 months, written tests detected an incidence of cognitive decline of 13.1% and computerized tests detected an incidence of 8.5%. Cognitive decline at 3 months using written tests was associated with increasing age, whereas computerized tests showed cognitive decline was associated with baseline amnestic mild cognitive impairment, diabetes mellitus, and prior coronary stenting. CONCLUSIONS: More than half the patients aged >60 years presenting for LHC have mild cognitive impairment. LHC is followed by cognitive decline in 8% to 13% of individuals at 3 months after the procedure. Subtle cognitive decline both before and after LHC is common and may have important clinical implications. CLINICAL TRIAL REGISTRATION INFORMATION: URL: www.anzctr.org.au. Unique identifier: ACTRN12607000051448. PMID- 29525781 TI - Does Cardiac Catheterization Accelerate Decline in Cognitive Function or Serve as an Inflection Point for Evaluation? PMID- 29525782 TI - Relations of Sex to Diagnosis and Outcomes in Acute Coronary Syndrome. AB - BACKGROUND: The atypical presentation of women with acute coronary syndrome (ACS) has been related to delayed diagnosis and treatment, which may explain worse outcome compared with men. METHODS AND RESULTS: We analyzed pooled data of 2520 patients of 2 prospective cohorts in terms of differences in presentation and management of women and men suggestive of ACS. Using logistic regression, we established 2 diagnostic models and tested their diagnostic performance in both sexes separately. Sex-specific differences in management of patients with ACS were ascertained and a 2-year follow-up was performed. Women were older than men (median 67 versus 61 years, P=0.001), had more often dyspnea (22% versus 18%, P=0.024), nausea or vomiting (26% versus 16%, P=0.001) and radiating chest pain (47% versus 40%, P=0.001). Classical risk factors (smoking, diabetes mellitus, dyslipidemia or known coronary artery disease) were less frequent in women. Diagnostic models showed no significant sex-related differences in diagnostic performance in a "first contact" setting (medical history and symptoms) or after "complete triage" (including ECG and biomarkers). Women with ACS underwent coronary angiography (73.8% versus 84.3%, P<0.001) and revascularization (53.8% versus 70.1%, P<0.001) less frequently. Two-year incidence of myocardial infarction and death was similar in both sexes, but revascularization and cardiac rehospitalization were more frequent in men. CONCLUSIONS: In a large cohort of patients with suspected ACS, sex differences in clinical presentation did not impair diagnostic accuracy. Two-year outcomes were comparable. Our findings suggest a benefit of chest pain units to minimize sex differences in ACS management and prognosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02355457 (BACC), NCT03227159 (stenoCardia). PMID- 29525784 TI - Clinical Outcomes After Cardiac Stress Testing Among US Patients Younger Than 65 Years. AB - BACKGROUND: Scientific statements have championed the measurement of clinical outcomes after cardiac stress testing to better define their value. Using contemporary national data, we sought to describe the characteristics of patients who experience outcomes after stress testing. METHODS AND RESULTS: Using administrative claims from a large national private insurer, we conducted an observational cohort study of patients without cardiovascular disease aged 25 to 64 years who underwent stress testing from 2006 to 2011 and had at least 1 year of membership in the insurance company before and after testing. We used Kaplan Meier time-to-event analyses to determine rates of acute myocardial infarction (AMI), elective coronary revascularization, and coronary angiography without revascularization in the year following testing. We used logistic regression to determine factors associated with outcomes, and stratified the cohort into quintiles based on likelihood of experiencing AMI and/or revascularization to describe the characteristics of patients at highest and lowest risk. Among 553 027 patients who underwent stress testing (mean age 50 years, 49% women, 73% white), 0.8% were hospitalized for AMI, 1.8% underwent elective coronary revascularization, and 2.5% underwent coronary angiography without revascularization within 1 year. Patients who were older, male, and white were more likely to undergo subsequent revascularization. Patients in the lowest likelihood quintile were young (mean age 40 years), frequently women (84.7%), had a low incidence of coexisting conditions (5.2% with diabetes mellitus), and had a 0.5% rate of AMI and/or revascularization. CONCLUSIONS: The proportion of US patients younger than 65 who had AMI and/or coronary revascularization after stress testing was low. Assessing risk of subsequent outcomes may be useful in improving patient referrals for stress testing. PMID- 29525783 TI - Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80+Clec4f+Vsig4+Ly6C- Kupffer Cell Subsets. AB - BACKGROUND: Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. METHODS AND RESULTS: In CETP-transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C-type lectin domain family 4, member f (Clec4f) and V set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high-density lipoprotein cholesterol over non-high-density lipoprotein-cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double-immunofluorescence staining showed that CETP co localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor-mediated CETP expression. CONCLUSIONS: Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C-). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high-density lipoprotein (HDL) cholesterol. This sequence of events is consistent with the anti-inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections. PMID- 29525785 TI - Predictive Value of the Sequential Organ Failure Assessment Score for Mortality in a Contemporary Cardiac Intensive Care Unit Population. AB - BACKGROUND: Optimal methods of mortality risk stratification in patients in the cardiac intensive care unit (CICU) remain uncertain. We evaluated the ability of the Sequential Organ Failure Assessment (SOFA) score to predict mortality in a large cohort of unselected patients in the CICU. METHODS AND RESULTS: Adult patients admitted to the CICU from January 1, 2007, to December 31, 2015, at a single tertiary care hospital were retrospectively reviewed. SOFA scores were calculated daily, and Acute Physiology and Chronic Health Evaluation (APACHE)-III and APACHE-IV scores were calculated on CICU day 1. Discrimination of hospital mortality was assessed using area under the receiver-operator characteristic curve values. We included 9961 patients, with a mean age of 67.5+/-15.2 years; all-cause hospital mortality was 9.0%. Day 1 SOFA score predicted hospital mortality, with an area under the receiver-operator characteristic curve value of 0.83; area under the receiver-operator characteristic curve values were similar for the APACHE-III score, and APACHE-IV predicted mortality (P>0.05). Mean and maximum SOFA scores over multiple CICU days had greater discrimination for hospital mortality (P<0.01). Patients with an increasing SOFA score from day 1 and day 2 had higher mortality. Patients with day 1 SOFA score <2 were at low risk of mortality. Increasing tertiles of day 1 SOFA score predicted higher long term mortality (P<0.001 by log-rank test). CONCLUSIONS: The day 1 SOFA score has good discrimination for short-term mortality in unselected patients in the CICU, which is comparable to APACHE-III and APACHE-IV. Advantages of the SOFA score over APACHE include simplicity, improved discrimination using serial scores, and prediction of long-term mortality. PMID- 29525786 TI - Safety and Effectiveness of Direct Oral Anticoagulants Versus Vitamin K Antagonists: Pilot Implementation of a Near-Real-Time Monitoring Program in Italy. AB - BACKGROUND: Real-time monitoring is used to the ends of postmarketing observational research on newly marketed drugs. We implemented a pilot near-real time monitoring program on the test case of oral anticoagulants. Specifically, we evaluated the safety and effectiveness of direct oral anticoagulants compared to vitamin K antagonists in nonvalvular atrial fibrillation secondary prevention during 2013-2015 in the Lazio Region, Italy. METHODS AND RESULTS: A cohort study was conducted using a sequential propensity-score-matched new user parallel cohort design. Sequential analyses were performed using Cox models. Overall, 10 742 patients contributed to the analyses. Compared with vitamin K antagonists, direct oral anticoagulant use was associated with a reduction of all-cause mortality (0.81; 95% confidence interval [CI] 0.66-0.99), cardiovascular mortality (0.71; 95% CI 0.54-0.93), myocardial infarction (0.67; 95% CI 0.43 1.04), ischemic stroke (0.87; 95% CI 0.52-1.45), hemorrhagic stroke (0.25; 95% CI 0.07-0.88), and with a nonsignificant increase of gastrointestinal bleeding (1.26; 95% CI 0.69-2.30). CONCLUSIONS: The present pilot study is a cornerstone to develop real-time monitoring for new drugs in our region. PMID- 29525787 TI - Intraoperative Inducibility of Atrial Fibrillation Does Not Predict Early Postoperative Atrial Fibrillation. AB - BACKGROUND: Early postoperative atrial fibrillation (EPoAF) is associated with thromboembolic events, prolonged hospitalization, and development of late PoAF (LPoAF). It is, however, unknown if EPoAF can be predicted by intraoperative AF inducibility. The aims of this study are therefore to explore (1) the value of intraoperative inducibility of AF for development of both EPoAF and LPoAF and (2) the predictive value of de novo EPoAF for recurrence of LPoAF. METHODS AND RESULTS: Patients (N=496, 75% male) undergoing cardiothoracic surgery for coronary and/or valvular heart disease were included. AF induction was attempted by atrial pacing, before extracorporeal circulation. All patients were on continuous rhythm monitoring until discharge to detect EPoAF. During a follow-up period of 2 years, LPoAF was detected by ECGs and Holter recordings. Sustained AF was inducible in 56% of patients. There was no difference in patients with or without AF before surgery (P=0.159), or between different types of surgery (P=0.687). In patients without a history of AF, incidence of EPoAF and LPoAF was 37% and 2%, respectively. EPoAF recurred in 58% patients with preoperative AF, 53% developed LPoAF. There were no correlations between intraoperative inducibility and EPoAF or LPoAF (P>0.05). EPoAF was not correlated with LPoAF in patients without a history of AF (P=0.116), in contrast to patients with AF before surgery (P<0.001). CONCLUSIONS: Intraoperative AF inducibility does not predict development of either EPoAF or LPoAF. In patients with AF before surgery, EPoAF is correlated with LPoAF recurrences. This correlation is absent in patients without AF before surgery. PMID- 29525788 TI - Long-term stability of glucose: glycolysis inhibitor vs. gel barrier tubes. AB - BACKGROUND: Measuring the glucose concentration in whole blood samples is critical due to unsatisfactory glycolysis inhibition. Previous studies showed that Terumo tubes were superior, but they were taken off the European market in 2016 and alternatives were required. This initiated the present evaluation of glucose stability in five available tube types. METHODS: Venous blood samples were collected from 61 healthy volunteers to test tubes supplied by Terumo (two sets), Greiner FC-Mix, BD FX-Mixture and BD serum. After sampling, the contents were thoroughly mixed and centrifuged within an hour. The glucose concentrations were determined and the samples resuspended except for BD serum tubes (gel barrier). The first 30 samples were stored at room temperature and the remaining 31 at 4 degrees C. After 24, 48, 72 and 96 h, all tubes were (re)centrifuged, and glucose concentration measurements were repeated. RESULTS: Changes in glucose concentrations over time differed significantly between the investigated tube types and to a certain extent between the two storing conditions. Glycolysis was most evident in the BD FX-mixture tubes. Good glucose stability was observed in samples retrieved form BD serum and Greiner tubes. The stability in both Terumo tubes was comparable to that in other studies. Although Greiner and both Terumo tubes are supposed to contain the same glycolysis inhibitor, glucose stability differed between these tubes. CONCLUSIONS: We showed that Greiner is an acceptable alternative to Terumo and that glucose in serum that was rapidly separated from corpuscles by a gel barrier is stable for an extended time. PMID- 29525789 TI - A Novel PORCN Frameshift Mutation Leading to Focal Dermal Hypoplasia: A Case Report. AB - Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is a rare, multisystemic, X-linked dominant genodermatosis characterized by defective development of mesodermal and ectodermal tissues. Major clinical features of the disorder are skin manifestations, skeletal defects, and developmental eye abnormalities. FDH is caused by heterozygous mutations in the PORCN gene located at Xp11.23, and 90% of individuals with FDH are females. Here, we report a female patient with cutaneous changes, multiple eye anomalies, short stature, and ectrodactyly of the right foot. These clinical findings were compatible with the diagnosis of FDH, and a novel mutation, NM_022825.3:c.488delG was found in the PORCN gene causing a premature stop codon. PMID- 29525792 TI - New insights into classification, epidemiology and microbiology of SSTIs, including diabetic foot infections. AB - Skin and soft tissue infections (SSTIs) involve a heterogeneous group of entities with different clinical presentations classified according to several specific criteria. Because of their great variability, their incidence and prevalence is difficult to accurately determine. Yet it is generally thought that the rate of SSTIs is globally increasing due to an aging population, strictly associated with the increase in the number of critical and immunocompromised patients. The aetiology of SSTIs is also extremely variable, reflecting the noteworthy heterogeneity of their clinical presentations and their epidemiology. Gram positive are far more prevalently than Gram-negative cocci responsible for STTIs globally considered including both aerobe and anaerobe microorganisms. The emergence of multidrug-resistance bacteria represents a serious public health threat which is making antimicrobial therapy less efficacious and more challenging by the day. PMID- 29525790 TI - Race/Ethnicity, Dietary Acid Load, and Risk of End-Stage Renal Disease among US Adults with Chronic Kidney Disease. AB - BACKGROUND: Dietary acid load (DAL) contributes to the risk of CKD and CKD progression. We sought to determine the relation of DAL to racial/ethnic differences in the risk of end-stage renal disease (ESRD) among persons with CKD. METHODS: Among 1,123 non-Hispanic black (NHB) and non-Hispanic white (NHW) National Health and Nutrition Examination Survey III participants with estimated glomerular filtration rate 15-59 mL/min/1.73 m2, DAL was estimated using the Remer and Manz net acid excretion (NAEes) formula and 24-h dietary recall. ESRD events were ascertained via linkage with Medicare. A competing risk model (accounting for death) was used to estimate the hazard ratio (HR) for treated ESRD, comparing NHBs with NHWs, adjusting for demographic, clinical and nutritional factors (body surface area, total caloric intake, serum bicarbonate, protein intake), and NAEes. Additionally, whether the relation of NAEes with ESRD risk varied by race/ethnicity was tested. RESULTS: At baseline, NHBs had greater NAEes (50.9 vs. 44.2 mEq/day) than NHWs. It was found that 22% developed ESRD over a median of 7.5 years. The unadjusted HR comparing NHBs to NHWs was 3.35 (95% CI 2.51-4.48) and adjusted HR (for factors above) was 1.68 (95% CI 1.18 2.38). A stronger association of NAE with risk of ESRD was observed among NHBs (adjusted HR per mEq/day increase in NAE 1.21, 95% CI 1.12-1.31) than that among NHWs (HR 1.08, 95% CI 0.96-1.20), p interaction for race/ethnicity * NAEes = 0.004. CONCLUSIONS: Among US adults with CKD, the association of DAL with progression to ESRD is stronger among NHBs than NHWs. DAL is worthy of further investigation for its contribution to kidney outcomes across race/ethnic groups. PMID- 29525793 TI - Zero surgical site infection in primary knee arthroplasty with multidisciplinary intervention: is it possible? AB - Surgical site infections (SSI) are among the most important complications in knee arthroplasty. In this article we aim to retrospectively evaluate effects of preoperative multidisciplinary assessment and treatment of focal infections in primary knee arthroplasty patients operated by a single surgeon in a single center. A total of 93 patients undergoing 120 primary knee arthroplasty operations were included in the study. In the preoperative assessment all patients were consulted by infectious diseases, otorhinolaryngology (ENT) and dentistry departments, and female patients additionally by gynecology departments to evaluate and treat possible focal infections. Decolonization protocols were implemented for the bacterial growths detected in nasal and urine cultures. Patients received one of four surgical interventions, namely unilateral total knee arthroplasty (TKA), unilateral robotic-assisted unicompartmental knee arthroplasty (RUKA), bilateral RUKA or unilateral TKA and unilateral RUKA. No patients received bilateral TKA in a single session. Out of 93 patients 70 (75.3%) were female, mean age was 67.7 +/- 9.9 years, and American Society of Anesthesiologists (ASA) scores were < 3 for 93.5% of the study group. Fifty-two (55.9%) of the patients received RUKA. Mean value for the duration of operations was 150.7 +/- 67 minutes, for hospitalization it was 5.9 +/- 2.8 days, and postoperative follow-up was 25.7 +/- 8.8 months. None of the patients developed SSI in the follow-up period. Many factors are associated with SSI after knee arthroplasty. Total absence of SSI in our study group may be attributable to meticulous patient selection, multidisciplinary preoperative assessment, and the performance of RUKA by a single surgeon in a single center. PMID- 29525794 TI - Prevalence of diabetes mellitus (DM) in tuberculosis (TB) patients: clinical and radiologic features in the TB-DM association based on a five-year hospital study. AB - A previously known association of tuberculosis (TB), now a global emergency, with diabetes mellitus (DM), a chronic disease of increasing prevalence worldwide, has resurfaced. DM is a recognised TB risk factor and M. tuberculosis infection usually disturbs glycoregulation. We aimed to estimate DM prevalence among TB patients and to analyse clinical and radiologic manifestations of TB in this group. The cross-sectional study included 1017 patients discharged with a TB diagnosis from a tertiary level facility in a five-year period. After exclusion of 128 patients with TB sequelae, we selected 889 patients with confirmed active TB, and the final selection led to 88 subjects with both active TB and DM. DM was found in 9.89% of active TB patients. Testing hypotheses for single-sample proportions showed that the prevalence was significantly higher than the prevalence in the general population (p<0.01). The average patient age was 60.47+/-14.88 years (range: 20-88), while the male/female ratio was 2.26. We found pulmonary TB in 96.3% of the 88 subjects, and extrapulmonary in 3.4%, the latter more frequently in women (p=0.08). Cavities were more frequently found in tobacco smokers compared to non-smokers (p=0.002) and in patients living in rural settings (p=0.002); haemoptysis was detected more frequently in men compared to women (p=0.044). Half of the patients had no fever at all, and only 14.8% had tachycardia. Auscultatory findings were positive in 57 (64.8%) patients. Radiographic changes were atypical in 17/88 (19.3%) patients and included pulmonary bases in seven patients, upper lobe anterior segment, and disseminated miliary pattern in two patients. DM prevalence is significantly higher among TB patients compared to the general population. The mean age of TB patients with DM is significantly higher than expected in TB patients alone. Knowledge of TB clinical and radiologic variations in this group of patients may reduce the delay in TB diagnosis with its clinical and epidemiologic consequences. PMID- 29525795 TI - Research trends in Carrion's disease in the last 60 years. A bibliometric assessment of Latin American scientific production. AB - Carrion's disease is a major re-emerging and occupational health disease. This bibliometric study aimed to evaluate scientific production on this disease both globally and in Latin America. SCI-E, MEDLINE/GoPubMed, SCOPUS, ScIELO, and LILACS databases were searched for Carrion's disease-related articles. They were classified according to publication year, type, city and institution of origin, international cooperation, scientific journal, impact factor, publication language, author(s), and H-index. There were 170 articles in SCI-E. The USA was the largest contributor (42.9%), followed by Peru (24.1%) and Spain (12.4%). Latin American publications were cited 811 times (regional H-index=18). There were 335 articles in SCOPUS: 25.9%, 11.6%, and 8.3% were published by the USA, Peru, and Spain, respectively. Latin American publications were cited 613 times (H-index=12): Peru, Colombia, and Brazil received the most citations (n=395, H index=10; n=61, H-index=1; and n=54, H-index=4, respectively). The most scientifically productive American institution was the University of Montana (2.9% of American production). In Peru, it was the Institute of Tropical Medicine Alexander von Humboldt of Peruvian University Cayetano Heredia (6.5% of Peruvian scientific production). There were 3,802 articles in Medline (1.2% were Peruvian), 35 in SciELO (94.3% were from Peru), and 168 in LILACS (11% were published in 2010-2014; only one article was published in 2015). Scientific production worldwide is led by the USA, and, in Latin America, by Peru and Brazil. However, Latin American scientific production in bibliographic databases is much lower than in other regions, despite being an endemic area for Carrion's disease. PMID- 29525796 TI - Epidemiological profile of malaria among various socio-demographic groups in a western district of Odisha, India. AB - A retrospective analysis of malaria incidence, patterns and trends in Bargarh, a western district of Odisha, India, over five consecutive years (2012 to 2016) among various socio-demographic components was established from the National Vector Borne Disease Control Programme (NVBDCP), Bargarh, as well as from district survey reports. The increasing trend in malariometric indices such as the Annual Blood Examination Rate (ABER), the Annual Parasite index (API) as well as the Total Positive Rate (TPR) reveals a better surveillance activity but an alarming situation for malaria. The trend for P. falciparum and P. vivax infection is found to be zigzagging or fluctuating for the five years in question, with the preponderance of P. falciparum infection. Malaria in Bargarh district is age-specific where there is a strong positive correlation between the age factor and malaria morbidity, but it is gender-blind. The incidence of malaria is increasing among deprived communities as well as pregnant women in the district. The community perception study reveals the knowledge level regarding cause, prevention and treatment for malaria, which is lower among deprived communities than more progressive communities. The overall epidemiological study highlights the dynamics of disease transmission among various demographic members in Bargarh district, whilst evaluating awareness of current malaria endemicity. PMID- 29525797 TI - Hepatitis A outbreak in men who have sex with men (MSM) in Brescia (Northern Italy), July 2016-July 2017. AB - Since June 2016, an outbreak of hepatitis A has been reported in Europe. Here we report the HAV outbreak in Brescia (Northern Italy) from July 2016 to July 2017. We actively recorded all HAV cases defined by detection of HAV IgM antibodies in serum. Data on sexual behaviour, travel attitudes, concomitant sexually transmitted diseases (STDs), clinical presentation and laboratory results were collected. Forty-two confirmed cases were recorded: 25 (60%) were MSM and reported sexual contact at risk of STDs. Compared to 2015 and the first half of 2016, when only three hepatitis A cases were recorded, in the 12 months in question the number of cases rose 14-fold. Among 25 MSM, 14 were HIV-infected. Hepatitis A is usually a self-limiting disease, but it could be more serious in the case of HIV co-infection, immunosuppression and chronic hepatitis. HAV infection has a high outbreak potential in MSM because of more common oro-anal practices compared to HS, a high interconnectedness global network, chemsex practices and a new tendency to travel abroad to attend group sex events. In our experience, most cases occurred in MSM and 56% of them were HIV-infected, suggesting the need to promote active screening, immunization and education in this population. PMID- 29525798 TI - Beta-tubulin gene in the differentiation of Fusarium species by PCR-RFLP analysis. AB - Fusarium species belong to one of the most important fungal groups in the medical, agricultural, and veterinary fields. This study aimed to evaluate the efficiency of PCR-RFLP analysis of the beta (beta)-tubulin region for differentiating Fusarium species. A total of 107 strains of Fusarium spp. were studied, including isolates from environmental, clinical, and reference sources. The beta-tubulin genes of all isolates were successfully amplified with primer pairs (T1 and T22). A PCR product of approximately 1400 base pairs was generated for each Fusarium sp. After evaluation of various enzymes, three restriction enzymes, namely Ban II, BsaWI, and HincII, were selected. Based on the selected enzymes, the isolated Fusarium spp. were categorized into 24 groups. In this study we were able to identify F. graminearum, F. culmorum, and F. cerealis through the proposed analyses as well as other pathogenically important species such as F. oxysporum and F. solani. Unlike all other similar previous studies, this study was able to differentiate among F. graminearum, F. culmorum, and F. cerealis. However, we were unable to differentiate F. armeniacum and F. acuminatum or F. sportrichioides from F. langsethiae. Hence, it is recommended that other genes must be evaluated to overcome the limitations of the ?-tubulin gene in differentiating the above species. PMID- 29525799 TI - Determination of antibiotic resistance pattern and prevalence of OXA-type carbapenemases among Acinetobacter baumannii clinical isolates from inpatients in Isfahan, central Iran. AB - Acinetobacter baumannii is one of the most important bacterial species with the ability to produce OXA-type carbapenemases. We aimed to evaluate the prevalence of OXA-type carbapenemases among clinical isolates of A. baumannii in three major hospitals of Isfahan. In this cross-sectional descriptive study, 153 non-repeated strains of A. baumannii were isolated from various clinical samples of hospitalized patients in Al-Zahra, Imam Mousa Kazem, and Shariati hospitals from October 2015 to October 2016. Antimicrobial susceptibility testing for imipenem, meropenem, ertapenem, cefepime, ceftazidime, ceftriaxone, piperacillin tazobactam, gentamicin, amikacin, ciprofloxacin, and tetracycline was performed using the disk diffusion method. In order to identify bla-oxa genes, a multiplex polymerase chain reaction was used. The resistance rates in A. baumannii isolates to beta-lactam antibiotics including imipenem, ertapenem, meropenem, cefepime, ceftazidime, ceftriaxone, and piperacillin/tazobactam were 100%, 100%, 99.3%, 97.4%, 96.7%, 97.4%, and 98.6%, respectively. PCR assay showed the presence of bla-oxa genes in all isolates. The bla-oxa-51 gene was recognized in all (100%) isolates, 90.8% and 62.1% of isolates possessed the bla-oxa-23 and bla-oxa-24 genes, respectively, while the bla-oxa-58 gene was not detected in any of the isolates. Also, 56.2% of isolates had both the bla-oxa-23 and bla-oxa-24 genes simultaneously. We found that the prevalence of OXA-type carbapenemases among carbapenem-resistant A. baumannii isolates is high in Isfahan, with OXA-23 being the major carbapenemase mechanism responsible for the resistance phenotype. PMID- 29525800 TI - Molecular characteristics of multiple and extensive drug-resistant Acinetobacter baumannii isolates obtained from hospitalized patients in Southwestern Iran. AB - The emergence of multiple drug-resistant (MDR) Acinetobacter baumannii strains has become a global problem. This study aimed to evaluate the occurrence of antibiotic resistance and to investigate the presence of antibiotic resistance determinants among A. baumannii isolates obtained from hospitalized patients in Iran. This cross-sectional study was performed on 92 A. baumannii isolates in the years 2015-2016. Antimicrobial susceptibility testing was carried out by the disk diffusion method. The presence of antibiotic resistance determinants was detected by the PCR method. All the A. baumannii isolates were resistant to tested carbapenems, fluoroquinolones and sulfonamide agents, and susceptible to polymixins. Of the isolates 92.4% were extensive drug-resistant (XDR) and 7.6% were MDR. PCR screening for the presence of integron genes revealed that class 1 integron presented in 46.7% of isolates and class 2 in 18.5% isolates. Of the investigated antibiotic resistance genes, bla vim, bla imp, bla spm, sul1 and sul2 were positive in 75%, 12%, 12%, 47.8%, and 67.4% of isolates, respectively. The high prevalence of metallo-beta-lactamase (MBL) and sul genes in our results may indicate the importance of these genes in the dissemination of carbapenem- and sulfonamide-resistant A. baumannii isolates. Rational and restricted prescription of carbapenems may be an effective way to minimize the emergence and spread of MBL-harboring strains. PMID- 29525801 TI - Trombiculiasis: an underreported ectoparasitosis in Sicily. AB - Trombiculiasis is a common but underreported ectoparasitosis characterized by an infestation of the skin by the larval stage of various species of mites belonging to the phylum Arthropoda, class Arachnida, subclass Acarina. Clinical manifestations consist of pruritic erythematous and urticarial macules and papules located on covered thin and glabrous skin. In recent studies Neotrombicula autumnalis larvae have been described as the possible vectors of pathogens such as Borrelia burgdorferi and Anaplasma phagocytophilum. Few reports of trombiculosis have been collected in the medical literature to date. We report a typical case of trombiculosis induced by trombiculid larvae of N. autumnalis, which are habitual parasites of various endo- and ectothermic vertebrates. PMID- 29525802 TI - Respiratory syncytial virus bronchiolitis and hypertransaminasemia. AB - Bronchiolitis is the most common disease of the lower respiratory tract occurring in children during their first year of life, becoming the most frequent cause of hospitalization. Although the disease can also be caused by other viruses, more than 70% of bronchiolitis cases are caused by respiratory syncytial virus (RSV). RSV bronchiolitis clinically presents rhinitis, coughing, increased breathing and eating difficulties; the symptoms are usually mild, but in some cases may be so severe as to require hospitalization. Diagnosis is mainly clinical and is based on a thorough medical history and a physical examination. Therapy is substantially of support, and has the aim of ensuring alimentation/hydration and optimal oxygenation. It has been recently noted that RSV infections may cause extra-pulmonary manifestations, including liver problems, as rarely described in the literature. The aim of this paper is to present three cases of RSV bronchiolitis in children with elevated transitory transaminase levels. PMID- 29525803 TI - Report on three cases of pertussis in the Urbino area (Italy). AB - Pertussis is a contagious, infectious disease that affects mainly children and is caused by Bordetella pertussis. The pertussis vaccine has changed the epidemiology of the disease up to the point when it almost vanished, with a minimum number of cases recorded in Italy (2008) when vaccination coverage was 97%. For the same reason the natural history of the disease was also modified. Indeed, in high-income countries the lack of immunity acquired with the vaccine causes adolescents and adults to become an important source of infection for unvaccinated subjects, the newborn and children who have not completed their primary education. The reduction in the vaccinated pediatric population and the loss of acquired immunity could be the cause of the re-emergence of a disease which, in developing countries, has a 4% mortality rate among children under one year of age. In this work we describe three cases of pertussis that are apparently unrelated. They occurred in the area of Urbino in a period of slightly under a month. Italy is going through a historical moment of great suspicion regarding pediatric vaccination, despite scientific evidence that should allay such suspicion. To increase people's awareness of vaccinations with a view to comments made regarding older children and adults it is our view that more effective intervention methods are needed. PMID- 29525804 TI - Giardiasis and subsequent diagnosis of HIV infection in a patient with persistent diarrhoea: a case report. AB - Although its prevalence in resource-rich countries is not precisely estimated, persistent diarrhoea is not a common event if extreme ages are excluded. Enteric pathogens, of various underlying aetiologies, often cause major diarrhoeal syndromes, especially in immunocompromised adults. While there is a rich medical literature regarding HIV-related infections, information about the diagnosis of HIV-infection from diarrhoea as a presenting complaint is scarce. Our case report focuses on a 29-year-old Italian male with persistent diarrhoea who was diagnosed with Giardiasis and subsequently tested for HIV infection, resulting positive. In approaching young adults with persistent diarrhoea, lowering the threshold of suspicion for HIV infection proves useful. PMID- 29525805 TI - Congenital Chagas disease in a Bolivian newborn in Bergamo (Italy). AB - Chagas disease (CD) is an uncommon disease in Europe. Its epidemiology has changed because of mass migration from Latin America to Europe. Herein we describe a congenital case of CD in a Bolivian newborn in Bergamo, the main city of residence for the Bolivian community in Italy. At delivery, serological analyses evidenced IgG antibodies against Trypanosoma cruzi both in the child and mother, as expected. Hemoscopic analyses on peripheral blood were repeatedly negative during the first months of life. Eventually, thanks to T. cruzi Real Time polymerase chain reaction (RT-PCR) positivity on peripheral blood and development of progressive anemia in the following weeks, congenital Chagas disease was diagnosed and benznidazole-based therapy started. A progressive antibodies' index decrease was observed till negativity (306 days apart). RT-PCR was negative at the end of treatment. Our case is instructive and management of congenital CD is discussed from the perspective of a non-endemic country. PMID- 29525806 TI - Spanish flu in Italy: new data, new questions. AB - This paper proposes a new estimate for the number of victims of Spanish flu in Italy and highlights some aspects of mortality closely linked to the First World War. The sources used are official death statistics and the Albo d'oro, a roll of honor of the Italians fallen in the First World War. The new estimate of deaths from the flu is 410,000 for 1918, which should be raised to 466,000 when the numbers are taken up to 1920. Deaths from Spanish flu among the military were about 70,000. The time sequence of deaths recognizes two distinct peaks, one in October and one in November 1918. Between these two peaks, the lowest number of deaths falls in the week of the armistice between Italy and Austria-Hungary (signed 4 November 1918). This suggests links between Spanish flu and WWI that cannot be merely explained in terms of movement of people and contagion. PMID- 29525807 TI - The treatment of latent TB infection in HIV-positive people: the Verona experience. AB - Not available. PMID- 29525808 TI - Effects of 12C6+ Heavy Ion Radiation on Dendritic Cells Function. AB - BACKGROUND Carbon ion radiotherapy has been shown to be more effective in cancer radiotherapy than photon irradiation. Influence of carbon ion radiation on cancer microenvironment is very important for the outcomes of radiotherapy. Tumor infiltrating dendritic cells (DCs) play critical roles in cancer antigen processing and antitumor immunity. However, there is scant literature covering the effects of carbon ion radiation on DCs. In this study, we aimed to uncover the impact of carbon ion irradiation on bone marrow derived DCs. MATERIAL AND METHODS Bone marrow cells were co-cultured with GM-CSF and IL-4 for seven days, and the population of DCs was confirmed with flow cytometry. We used an Annexin V and PI staining method to detect cell apoptosis. Endocytosis assay of DCs was determined by using a flow cytometry method. DCs migration capacity was tested by a Transwell method. We also used ELISA assay and western blotting assay to examine the cytokines and protein expression, respectively. RESULTS Our data showed that carbon ion radiation induced apoptosis in both immature and mature DCs. After irradiation, the endocytosis and migration capacity of DCs was also impaired. Interestingly, carbon irradiation triggered a burst of IFN-g and IL-12 in LPS or CpG treated DCs, which provide novel insights into the combination of immunotherapy and carbon ion radiotherapy. Finally, we found that carbon ion irradiation induced apoptosis and migration suppression was p38 dependent. CONCLUSIONS Our present study demonstrated that carbon ion irradiation induced apoptosis in DCs, and impaired DCs function mainly through the p38 signaling pathway. Carbon ion irradiation also triggered anti-tumor cytokines secretion. This work provides novel information of carbon ion radiotherapy in DCs, and also provides new insights on the combination of immune adjuvant and carbon ion radiotherapy. PMID- 29525809 TI - Proliferation of Bilateral Nerve Fibers Following Thalamic Infarction Contributes to Neurological Function Recovery: A Diffusion Tensor Imaging (DTI) Study. AB - BACKGROUND The aim of this study was to investigate the reorganization in ipsilesional and contralesional thalamic radiation fibers after unilateral focal thalamic stroke in sensory disturbance patients. MATERIAL AND METHODS We recruited 12 patients with acute unilateral thalamic infarction and sensory disturbance and 12 healthy age- and sex-matched controls. All patients underwent diffusion tensor imaging (DTI) and were assessed with National Institutes of Health stroke scale (NIHSS), Barthel index (BI), and paragraph 8 of NIHSS (NIHSS8) at 1 week (W1), 4 weeks (W4), 3 months (M3), and 6 months (M6) after thalamic infraction. The relationship between FA changes and the clinical scores changes were then examined. RESULTS NIHSS and NIHSS8 scores decreased while BI scores increased gradually from W1 to M6 in patients, but not in controls. FA values of the patients gradually increased in ipsilesional and contralesional thalamic radiation fibers from W1 to M6. In addition, the FA values in patients were significantly higher at M3 and M6 compared to W1. No significant changes were observed in the controls. Regarding the relationship between FA changes and the clinical scores changes, the FA increases were negatively correlated with NIHSS and NIHSS8 decrease while FA increases were positively correlated with BI increases. CONCLUSIONS Our results indicate that reorganization occurred after unilateral focal thalamic infarct not only in ipsilesional, but also in contralesional thalamic radiation fibers in patients with sensory disturbance. In addition, the results suggested that the reorganization can support and promote stroke restoration. PMID- 29525810 TI - Glucocorticoid-Induced Myopathy in a Patient with Systemic Lupus Erythematosus (SLE): A Case Report and Review of the Literature. AB - BACKGROUND Chronic intake of high-dose corticosteroids is associated with multiple adverse clinical effects, including hypertension, insulin resistance, impaired wound healing, immunosuppression, myopathy, and osteoporosis. In cases of autoimmune disease, use of steroid-sparing treatment modalities is preferred over chronic steroid therapy to limit these side effects. Glucocorticoid-induced myopathy is a less common side effect of chronic steroid use in patients treated with <10 mg/day of prednisone. However, doses exceeding 40-60 mg/day can induce clinically significant myopathy and weakness. CASE REPORT A 35-year-old woman with a past medical history of hypothyroidism, systemic lupus erythematosus (SLE), and end-stage renal disease secondary to lupus nephritis, on hemodialysis, presented to the local emergency department with progressive bilateral proximal lower extremity weakness. Three months before admission, when her insurance company prematurely discontinued her monthly cyclophosphamide injections, at which time, she was treated with prednisone 60 mg daily. Two months before hospital admission, she reported increasing fatigue, weight gain, difficulty in standing from a seated position and climbing stairs. CONCLUSIONS Elucidating the etiology of progressive neuromotor deficit in immunosuppressed patients can be difficult. The management of SLE and other autoimmune diseases with chronic high dose steroids is associated with recognized side effects. Differentiating natural disease progression from iatrogenic etiologies is important in this subset of patients, particularly to reduce prolonged clinical management and hospital admissions. PMID- 29525811 TI - [Dissertations 25 years after date 49. A biomechanical analysis of bone around dental implants in an edentulous mandible]. AB - Changes in the bone around permucosal endosseous implants can be caused by biomechanical factors. Computer models are used to calculate the location and magnitude of stresses in the bone. The finite element method is used for the construction and calculation of models. The ongoing development of software and hardware 25 years ago made it possible to construct more complex 3-dimensional models. The general aim of the dissertation was to develop a state-of-the-art computer model of an edentulous mandible with dental implants and then to calculate the influence of a number of parameters on the location and magnitude of stresses in the bone. Conspicuous results were that there is hardly any difference between 2 and 4 implants in the interforaminal region and that the length of implants has a negligible effect on the magnitude of stresses. Clinical studies have subsequently demonstrated that these results are in line with reality. PMID- 29525812 TI - [Dental visits among people over 65; a study in a general dental clinic in Drenthe, the Netherlands]. AB - In this study, factors that may influence the dental visiting patterns of people over 65 living independently were investigated. The results of a questionnaire (n = 164; 53% response) revealed that 89% of them regularly visited the dentist for a check-up. Factors affecting dental visits were: whether or not one had difficulty planning a visit, whether or not one was motivated to make an appointment and actually made one, the condition of one's teeth; whether or not one had dental insurance and whether or not one reacted to a dental reminder (post)card. Mobility played no greater role among non-regular dental visitors than among regular visitors. Anticipating the possibility of an older patient living independently might fail to show by means of an active call policy seems more relevant than organising transport. PMID- 29525813 TI - [Active oxygen in the treatment of (root) caries and its suitability for frail older people]. AB - In 2000 it was suggested that there was a new, fast and simple way to treat dental caries based on the outcomes of an in vitro study of the antimicrobial effect of ozone, a form of active oxygen, on caries lesions in dental roots. The aim of the review of literature described in this article was to determine the effectiveness of active oxygen in the treatment of dental (root) caries as demonstrated by in vivo research of frail older people'. From the results it became clear that the quality of the various trials is not very high and that there is, at least at the present time, an insufficient solid scientific evidence base that the use of ozone is an effective treatment for dental (root) caries. It is, however, still too early to conclude that active oxygen, in whatever form, cannot contribute positively to the fight against caries. PMID- 29525814 TI - [A phd completed. The effect of radiotherapy on oral mucosa cell morphology.] AB - The treatment of oral cancer usually consists of surgical removal of the tumour, possibly followed by radiotherapy. The purpose of this dissertation research was to investigate the effects of radiotherapy on the oral tissues, in particular the superficially positioned epithelial cells in the oral mucosa. Earlier studies with electron microscopy revealed that unradiated oral mucosa cells, when observed at high magnification, contain microplicae (ridges or folds). Together with various saliva components, these microplicae form a protective layer that offers defence against, for instance, microorganisms. Radiotherapy damages these microplicae and may even destroy them altogether. Studies have shown that this effect of radiation can be observed in animals as well as in humans. As the radiation dose increased (50 Gy or more) the destruction of the microplicae was more severe. With a dose of 60 Gy or more the microplicae completely disappeared. This process may play an important role in the occurrence of osteoradionecrosis in the jaw and failure of dental implants placed after radiotherapy. PMID- 29525815 TI - [Series: Caries prevention in a historical perspective. Food]. AB - Different ideas on the impact of diet on the occurrence of dental caries that have been of influence during the last 125 years are discussed. The initial premise was that deficits in calcium and vitamins during the formation phase of the teeth were the cause of their high caries susceptibility. That idea has been abandoned. The frequency with which someone eats or drinks after the eruption of the teeth and the avoidance of quickly degradable carbohydrates in the diet now appear to be the most important factors for the development of caries lesions. The question whether nutrition education is still needed now that caries can be prevented by cleaning teeth with fluoride toothpaste, is discussed. PMID- 29525816 TI - ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study. AB - Importance: A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial. Objective: To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high risk vascular disease. Design, Setting, and Participants: A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017. Exposures: Evacetrapib, 130 mg, or matching placebo. Main Outcomes and Measures: The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. Results: For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59. Conclusions and Relevance: Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib. PMID- 29525817 TI - Pharmacogenetics and the Promise of Personalized Medicine. PMID- 29525818 TI - Trends in Use and Expenditures of Brand-name Atorvastatin After Introduction of Generic Atorvastatin. PMID- 29525819 TI - Lipid Lowering in Acute Coronary Syndrome: Is Treatment Early Enough? PMID- 29525820 TI - The TREAT Trial-Moving ST-Elevation Myocardial Infarction Care Forward, With More to Do. PMID- 29525821 TI - Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial. AB - Importance: The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective: To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions: Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures: The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results: Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, -0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance: Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration: clinicaltrials.gov Identifier: NCT01448642. PMID- 29525822 TI - Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST Elevation Myocardial Infarction: A Randomized Clinical Trial. AB - Importance: The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain. Objective: To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy. Design, Setting and Participants: We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%. Interventions: Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel. Main Outcomes and Measures: The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days. Results: The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, 0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). Conclusions and Relevance: In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. Trial Registration: clinicaltrials.gov Identifier: NCT02298088. PMID- 29525823 TI - Topical blood stopper agents during adenoid surgery in young children; a prospective randomized controlled trial. AB - OBJECTIVE: To investigate the safety and efficacy of two topical blood stopper modulators; Ankaferd blood stopper (ABS) and feracrylum 1% solution (FS) during adenoid surgery. STUDY DESIGN: Prospective randomized trial. METHODS: Two hundred and twenty five consecutive pediatric adenoid patients aged from 9 months to 2 years old were studied. Patients were randomly allocated into two haemostatic groups; (ABS, FS) and normal saline (control group). RESULTS: ABS and FS groups showed a significantly less intra operative blood loss (16.4 +/- 2.6/22 +/- 6.2), operative time (9.31 +/- 1.9/11.2 +/- 1.6 min), use of cautery (10.6/25.3%), postoperative analgesics (3 +/- 1.1/3.8 +/- 1.2), duration to return normal diet (2.4 +/- 1.2/3.9 +/- 0.9) and operating theatre cost (233 +/- 48$ and 279 +/- 40$) than the control group. CONCLUSION: AFS and FS are easy, safe, and reliable topical haemostatic modulators that could be used in adenoid surgery. PMID- 29525824 TI - Snail immunohistochemical overexpression correlates to recurrence risk in non muscle invasive bladder cancer: results from a longitudinal cohort study. AB - The current WHO/ISUP classification and grading system subdivides urothelial tumours into prognostically distinct categories. Understanding the molecular pathways involved in bladder cancer development can improve patient stratification and management. This study aims to investigate the relationship between Snail, Slug and E-cadherin expressions and clinico-pathological features of non-muscle invasive bladder carcinoma (NMIBC). All patients attending the same urological centre from January to May 2002, who were pathologically diagnosed with NMIBC, were enrolled in this longitudinal cohort study. E-cadherin, Snail and Slug protein expressions were assessed by immunohistochemical analysis and compared with follow-up data. The main outcome measures were recurrence and progression rates. The cohort under investigation included 43 patients (38 men and 5 women, mean age 67.7 +/- 10.6 years). High-grade (HG) carcinomas were 20/43, with 10 invasive cases (pT1). Low-grade (LG) carcinomas were 23/43, with no invasive cases (pTa). Among the eight HGpTa cases with recurrence, strong Snail expression was detected in six (75%). Out of the 17 LGpTa patients who experienced recurrence, 12 (70.6%) showed strong positivity for Snail. Among the 10 HGpT1 cases, recurrence was observed in 4, of which, 3 (75%) stained intensely for Snail. The Kaplan-Meier curves showed significantly different recurrence rates for patients with strong or weak Snail reactivity (p = 0.027). E-cadherin and Slug expression did not correlate with any of the parameters considered. On multivariate analysis, Snail expression was recognised as an independent prognostic factor for tumour recurrence (p = 0.003). In our study population, Snail immunohistochemical overexpression proved to be related to tumour recurrence in patients affected by NMIBC. PMID- 29525825 TI - Calcium mishandling impairs contraction in right ventricular hypertrophy prior to overt heart failure. AB - Currently, there are no tailored therapies available for the treatment of right ventricular (RV) hypertrophy, and the cellular mechanisms that underlie the disease are poorly understood. We investigated the cellular changes that occur early in the progression of the disease, when RV hypertrophy is evident, but prior to the onset of heart failure. Intracellular Ca2+ ([Ca2+]i) handling was examined in a rat model of monocrotaline (MCT)-induced pulmonary hypertension and subsequent RV hypertrophy. [Ca2+]i and stress production were measured in isolated RV trabeculae under baseline conditions (1-Hz stimulation, 1.5 mM [Ca2+]o, 37 degrees C), and in response to inotropic interventions (5-Hz stimulation or 1-MUM isoproterenol). Under baseline conditions, MCT trabeculae had impaired Ca2+ release in response to stimulation with a 45% delay in the time to-peak Ca2+, but there was no difference in the amplitude and decay of the Ca2+ transient, or active stress relative to RV trabeculae from normotensive hearts (CON). Increasing stimulation frequency from 1 to 5 Hz increased stress in CON, but not MCT trabeculae. Similarly, beta-adrenergic stimulation with isoproterenol increased Ca2+ transient amplitude and active stress in CON, but not in MCT trabeculae, despite accelerating Ca2+ transient decay in trabeculae from both groups. During isoproterenol treatment, MCT trabeculae showed increased diastolic Ca2+ leak, which may explain the blunted inotropic response to beta-adrenergic stimulation. Confocal imaging of trabeculae fixed following functional measurements showed that myocytes were on average wider, and transverse-tubule organisation was disrupted in MCT which provides a mechanism to explain the observed slower release of Ca2+. PMID- 29525826 TI - The growth-promoting effects of endophytic bacteria on Phyllostachys edulis. AB - The research results of the growth-promoting effects of endophytic bacteria on Phyllostachys edulis indicated that the growth-promoting endophytic bacteria could improve photosynthesis in P. edulis leaves. The photosynthetic rate, transpiration rate, and the stomatal conductance in P. edulis treated with endophytic bacteria were all higher than in the control group. Endophytic bacteria could also increase the chlorophyll content and the protective enzyme activities in P. edulis, improving their reactions to the adverse environmental conditions. Through injection treatments with growth-promoting endophytic bacteria, the catalase, superoxide dismutase (SOD), peroxidase activity, soluble protein content, and soluble sugar content in P. edulis were all higher than in the control group, except for the malondialdehyde content, which was lower than in the control group. PMID- 29525827 TI - Antibacterial activity of monoacetylated alkyl gallates against Xanthomonas citri subsp. citri. AB - Asiatic citrus canker (ACC) is an incurable disease of citrus plants caused by the Gram-negative bacterium Xanthomonas citri subsp. citri (X. citri). It affects all the commercially important citrus varieties in the major orange producing areas around the world. Control of the pathogen requires recurrent sprays of copper formulations that accumulate in soil and water reservoirs. Here, we describe the improvement of the alkyl gallates, which are potent anti-X. citri compounds, intended to be used as alternatives to copper in the control of ACC. Acetylation of alkyl gallates increased their lipophilicity, which resulted in potentiation of the antibacterial activity. X. citri exposed to the acetylated compounds exhibited increased cell length that is consistent with the disruption of the cell division apparatus. Finally, we show that inhibition of cell division is an indirect effect that seemed to be caused by membrane permeabilization, which is apparently the primary target of the acetylated alkyl gallates. PMID- 29525830 TI - PTSD of rape after IS ("Islamic State") captivity. AB - Research into the psychological consequences of rape on women in war and warlike situations is limited. The aims of this study were (a) to describe the prevalence and the nature of PTSD symptoms among Yazidi women reporting rape during IS captivity, (b) to describe comorbidity of other psychological disorders, and (c) to examine the risk factors associated with posttraumatic stress disorder.The study included 296 Yazidi women survivors of rape and has been conducted in Germany since January 2016 as part of a special-quota project in the German region of Baden-Wuerttemberg, designed to support the women and children who have escaped after being held hostage by IS.The survivors were recruited into a retrospective, cross-sectional study. Interviews in Germany were done through trained personnel to evaluate the mental health status of raped women.All the investigated women had been raped many times during IS captivity. About 82% of the women were also physically tortured. Of the sample, 67% suffered from somatoform disorder, 53% suffered from depression, 39% from anxiety, and 28% from dissociation. The prevalence of PTSD in those with rape events of more than 20 times was 57% (95% CI = 35.1-65.9%), less than 20 times was 41% (95%, CI = 28.7 4.8% and less than 10 times 39% [95% CI = 28.2-41.8%], respectively.The IS captivity and wartime rapes had deep immediate and long-term consequences on the mental health of women survivors. The high prevalence of PTSD emphasizes the need for culturally sensitive diagnostic and therapeutic services to address the intermediate and long-term consequences of wartime rape. PMID- 29525828 TI - Exercise Training and Cardiovascular Health in Cancer Patients. AB - PURPOSE OF REVIEW: Cancer patients nearly universally experience a decline in quality of life, with fatigue and reduced exercise tolerance as cardinal reflections. A routine exercise program can improve these signs and symptoms as well as overall outcomes. The review provides an updated overview of the field and its translation to clinical practice. RECENT FINDINGS: A wealth of clinical studies have documented the safety and benefits of exercise after and during cancer therapy, and pilot and larger-scale studies are currently ongoing to integrate exercise into the treatment program for cancer patients undergoing active therapy (EXACT pilot, OptiTrain, and TITAN study). More recently, efforts have emerged to commence exercise programs before the start of cancer therapy, so called pre-habilitation. The concept of increasing the cardiovascular reserve beforehand is intuitively attractive. In agreement, preclinical studies support exercise as an effective preventive means before and during cardiotoxic drug exposure. Assuming that a pronounced drop in exercise tolerance will occur during cancer therapy, pre-habilitation can potentially curtail or raise the nadir level of exercise tolerance. Furthermore, such efforts might serve as pre-conditioning efforts in reducing not only the nadir, but even the magnitude of drop in cardiovascular reserve. Initiated beforehand, cancer patients are also more likely to continue these efforts during cancer therapy. Finally, an active exercise routine (>= 150 min/week moderate intensity or >= 75 min/week vigorous intensity or combination) in conjunction with the other six American Heart Association's cardiovascular health metrics (BMI < 25 kg/m2, blood pressure < 120/80 mmHg, fasting plasma glucose < 100 mg/dL, total cholesterol < 200 mg/dL, 4 5 component healthy diet, no smoking) reduces not only the cardiovascular but also the cancer disease risk. Exercise can reduce the risks of developing cancer, the detrimental effects of its treatment on the cardiovascular system, and overall morbidity and mortality. Exercise should become an integral part of the care for every cancer patient. PMID- 29525829 TI - Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain. AB - Somatic symptoms are a robust, transdiagnostic risk factor for pain conditions. However, the extent to which somatic symptoms contribute to the manifestation of the women's pain syndromes, such as dysmenorrhea and noncyclic pelvic pain (NCPP), is unclear due to high rates of co-occurrence. Therefore, the present study investigated the primary hypothesis that somatic symptoms would be elevated in NCPP and distinctly influence the relationship between dysmenorrhea and co occurring NCPP. A secondary analysis was performed on cross-sectional questionnaire data from 1012 nonpregnant reproductive-aged women. Eligible analyzed participants (n = 834) were categorized into four groups: healthy, dysmenorrhea, NCPP, and NCPP with co-occurring dysmenorrhea (NCPP+dysmenorrhea). A parallel mediation analysis was run to evaluate the primary hypothesis that somatic symptoms are the primary factor associated with increased NCPP accounting for dysmenorrhea. The NCPP+dysmenorrhea group had higher somatic, anxiety, and depression symptom T-scores (respectively 61, 61, 60) compared to the healthy controls (46, 51, 51; p's < .001) and the dysmenorrhea group (50, 53, 54; p's < .001). The pain and psychological symptoms were significantly correlated across the entire sample (r's = .29, - .64, p's < .01). Results from parallel mediation analysis showed that somatic symptoms were distinctly associated with NCPP+dysmenorrhea. Women with NCPP+dysmenorrhea have increased psychological and somatic symptoms compared to women with dysmenorrhea alone. Given that NCPP often co-occurs with dysmenorrhea, failure to account for comorbidity in previous studies has likely led to an overestimation of psychological symptoms in dysmenorrhea. Future studies should evaluate whether somatic sensitivity is a modifiable risk factor for NCPP. PMID- 29525831 TI - Comparison of ultrasonography and computed tomography for diagnosing diffuse thyroid disease: a multicenter study. AB - PURPOSE: To compare the diagnostic performance of ultrasonography (US) and computed tomography (CT) for diagnosing incidentally detected diffuse thyroid disease (DTD) in patients who underwent thyroid surgery using multicenter data. METHODS: Between July and December 2016, a total of 177 patients who underwent preoperative thyroid US and neck CT, and subsequent thyroid surgery at 4 participating institutions, were reviewed. US and CT images in each case were retrospectively reviewed by a radiologist at each institution, and classified into one of the following four categories based on US and CT features: no DTD; indeterminate; suspicious for DTD; and DTD. The diagnostic accuracy of US and CT were calculated at each institution by comparison with histopathological results. RESULTS: Respective US and CT classifications in the 177 patients were no DTD in 75 and 71, indeterminate in 46 and 34, suspicious for DTD in 28 and 31, and DTD in 28 and 41. Among the histopathological results, 113 patients had normal thyroid parenchyma, 23 had Hashimoto thyroiditis, 36 had non-Hashimoto lymphocytic thyroiditis, and 5 had diffuse hyperplasia. The presence of >= 2 US and CT features of DTD, which was classified as suspicious for DTD or DTD, had the largest area under the receiver operating characteristic curve (0.866 and 0.893, respectively), with sensitivity and specificity of 71.9 and 91.2% in US, and 84.4 and 84.1% in CT, respectively. However, there was no statistically significant difference between readers' experience and their diagnostic performance. CONCLUSION: US and CT imaging may be helpful for detecting incidental DTD. PMID- 29525833 TI - Three new 5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone derivatives enantiomeric to agarotetrol from agarwood. AB - Agarwood (jinkoh in Japanese) is a resinous wood from Aquilaria species of the family Thymelaeaceae and has been used as incense and in traditional medicines. Characteristic chromone derivatives such as agarotetrol have been isolated from agarwood. In previous study, we isolated two new 2-(2-phenylethyl)chromones together with six known compounds from MeOH extract of agarwood. Further chemical investigation of the MeOH extract led to isolation of eighteen 2-(2 phenylethyl)chromones, including three new 5,6,7,8-tetrahydroxy-5,6,7,8 tetrahydrochromones with stereochemistry enantiomeric to agarotetrol-type, viz. (5R,6S,7S,8R)-2-[2-(3'-hydroxy-4'-methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy 5,6,7,8-tetrahydrochromone (2), (5R,6S,7S,8R)-2-[2-(4'-methoxyphenyl)ethyl] 5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone (6), and (5R,6S,7S,8R)-2-[2-(4' hydroxy-3'- methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone (13). The absolute configurations of the new compounds were determined by exciton chirality method. All isolated compounds were tested for their phosphodiesterase (PDE) 3A inhibitory activity by fluorescence polarization method. Compounds 8, 12 15, 21-24 showed moderate PDE 3A inhibitory activity. PMID- 29525832 TI - Analysis of the DNA methylation patterns and transcriptional regulation of the NB LRR-encoding gene family in Arabidopsis thaliana. AB - KEY MESSAGE: The relationships between transcription and methylation were revealed in Arabidopsis thaliana NB-LRR-encoding genes in wild type (Col-0) and different mutants. Plant nucleotide-binding, leucine-rich repeat (NB-LRR) proteins constitute a large family that plays predominant roles in disease resistance. However, the regulation of NB-LRR-encoding genes at the transcriptional level is still poorly understood. Recently, DNA cytosine methylation in eukaryotes has been described as serving an important function in regulating gene expression. Here, we analysed the DNA methylation patterns of NB LRR-encoding genes in Arabidopsis thaliana in samples from a wild type (Col-0) and ago4, met1, cmt3, drm1/2, and ddm1 mutants. Our results revealed that the vast majority of the NB-LRR-encoding genes in Col-0 were methylated, and the DNA methylation occurred predominantly in the CG sequence context. Moreover, DNA methylation was widely distributed in both the promoters and the bodies of most NB-LRR-encoding genes. Our results also showed that the loss of AGO4, MET1, CMT3, DRM1/2 or DDM1 functions generally led to decreased cytosine methylation in the NB-LRR-encoding genes. Analysis of the available transcriptome data from the wild type and the met1, cmt3, drm1/2 and ddm1 mutants revealed that differences in the transcription levels between the wild type and mutants were statistically significant for 63 of the NB-LRR-encoding genes. Of these genes, 38 were significantly upregulated, and the other 25 were significantly downregulated. Some NB-LRR-encoding genes with differential expression levels, which were revealed by the mRNA-Seq data, were confirmed to be significantly upregulated or downregulated in the mutants compared to the wild type by using quantitative RT PCR. These data suggest that some Arabidopsis NB-LRR-encoding genes are likely to be regulated by altered DNA methylation patterns. PMID- 29525834 TI - Tree community structure reflects niche segregation of three parapatric squirrel monkey species (Saimiri spp.). AB - Integration between ecology and biogeography provides insights into how niche specialization affects the geographical distribution of species. Given that rivers are not effective barriers to dispersal in three parapatric species of squirrel monkeys (Saimiri vanzolinii, S. cassiquiarensis and S. macrodon) inhabiting floodplain forests of Central Amazonia, we tested whether forest structure and tree diversity may explain species differences in niche specialization and spatial segregation. We sampled 6617 trees of 326 species in three habitats (high varzea, low varzea and chavascal) used by three Saimiri species, and estimated tree species richness in each of them. For each tree, we measured variables known to influence habitat use in primates, such as crown area and presence of lianas, epiphytes and hemi-epiphytes. We used ANOVA to compare these variables and performed multivariate analyses (NMDS, ANOSIM and SIMPER) to evaluate dissimilarities in forest structure among each habitat inhabited by the three Saimiri species. We identified differences in the tree species richness, crown area and presence of lianas, epiphytes and hemi-epiphytes between the three habitats for all Saimiri species. NMDS demonstrated that areas of high and low varzeas occupied by S. vanzolinii were clearly separated from the other species. We also found that different plant species contributed to dissimilarity among Saimiri ranges. Our findings support the hypothesis that tree community structure may promote niche specialization and spatial segregation among primates. We discuss how these patterns could have been favored by historical changes in forest flood patterns, the evolutionary history of Saimiri spp., and past competition. PMID- 29525836 TI - Monitoring and management of autoimmunity in multiple sclerosis patients treated with alemtuzumab: practical recommendations. AB - Alemtuzumab is a humanized anti-CD52 monoclonal antibody approved in more than 65 countries for the treatment of relapsing-remitting multiple sclerosis (RRMS). Compared with subcutaneous interferon-beta-1a, alemtuzumab significantly reduced clinical disease activity and the rate of brain volume loss, and improved disability outcomes in patients with active RRMS who were either treatment naive (CARE-MS I study) or who had an inadequate response (>= 1 relapse after >= 6 months of treatment) to prior therapy (CARE-MS II study). Adverse events (AEs) associated with alemtuzumab include infusion-associated reactions, infections, and autoimmunity. The most commonly reported autoimmune AEs observed with alemtuzumab involve the thyroid gland, followed by immune thrombocytopenia and nephropathies. A monitoring program was designed and implemented to facilitate the early detection of autoimmune events to ensure timely and adequate management. The aim of this article is to provide physicians (including neurologists, general practitioners, endocrinologists, hematologists, and nephrologists who may be less familiar with the symptoms and treatment of autoimmune events), with practical real-world recommendations for the monitoring and management of autoimmunity associated with alemtuzumab treatment. PMID- 29525837 TI - Morphological and molecular characterisation of digenean parasites of the Galapagos sheephead Semicossyphus darwini (Jenyns) with the re-description of Labrifer secundus Manter, 1940 (Lepidapedidae) from the Humboldt Current Large Marine Ecosystem. AB - The Humboldt Current Large Marine Ecosystem (HCLME) is recognised as one of the largest and most productive marine ecosystems. The estimated number of teleost fish species for the Chilean coast influenced by the HCLME reaches c.1,030 but digeneans have been reported for 39 teleost species, i.e. less than 4% of the potential hosts. During a survey of parasites of the Galapagos sheephead wrasse Semicossyphus darwini (Jennyns) (Perciformes: Labridae) from off northern Chile, we obtained representatives of three digenean species, Helicometrina nimia Linton, 1910 (Opecoelidae), Proctoeces humboldti George-Nascimento & Quiroga, 1983 (Fellodistomidae) and Labrifer secundus Manter, 1940 (Lepidapedidae). Labrifer secundus, originally described from Semicossyphus pulcher (Ayres, 1854) off the coast of Baja California, Mexico is re-described. Helicometrina nimia is a common parasite from littoral fishes in the HCLME. Semicossyphus darwini is a new host for these three digenean species. PMID- 29525835 TI - Antimicrobial resistance (AMR) nanomachines-mechanisms for fluoroquinolone and glycopeptide recognition, efflux and/or deactivation. AB - In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics-the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins. Expression of efflux systems is regulated by GntR-like (S. aureus NorG), MarR like (MgrA, MepR) regulators or a two-component signal transduction system (TCS) (S. aureus ArlSR). Resistance to the glycopeptide antibiotic teicoplanin occurs via efflux regulated by the TcaR regulator in S. aureus. Resistance to vancomycin occurs through modification of the D-Ala-D-Ala target in the cell wall peptidoglycan and removal of high affinity precursors, or by target protection via cell wall thickening. Of the six Van resistance types (VanA-E, VanG), the VanA resistance type is considered in this review, including its regulation by the VanSR TCS. We describe the recent application of biophysical approaches such as the hydrodynamic technique of analytical ultracentrifugation and circular dichroism spectroscopy to identify the possible molecular effector of the VanS receptor that activates expression of the Van resistance genes; both approaches demonstrated that vancomycin interacts with VanS, suggesting that vancomycin itself (or vancomycin with an accessory factor) may be an effector of vancomycin resistance. With 16 and 19 proteins or protein complexes involved in fluoroquinolone and glycopeptide resistances, respectively, and the complexities of bacterial sensing mechanisms that trigger and regulate a wide variety of possible resistance mechanisms, we propose that these antimicrobial resistance mechanisms might be considered complex 'nanomachines' that drive survival of bacterial cells in antibiotic environments. PMID- 29525838 TI - Long-term database analysis of conventional and accelerated crosslinked keratoconic mid-European eyes. AB - PURPOSE: To investigate the long-term efficacy of accelerated corneal collagen cross-linking (CXL) in a large mid-European cohort with progressive keratoconus. METHODS: Four hundred thirteen eyes of 316 patients with progressive keratoconus were enrolled and treated with conventional (group A) or accelerated (group B) CXL. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), slit lamp, and Pentacam(r) examinations were performed before and 12, 24, and 36 months after surgery. Maximum and mean anterior keratometry (Kmax, Kmf), corneal topography indices, and corneal pachymetry (TCT) were examined within each group and between groups. Further subgroup analysis of mild and moderate keratoconic eyes was performed. RESULTS: One hundred thirty-one eyes of 101 patients were treated in group A, 282 eyes of 215 patients in group B. (UDVA, CDVA) and Kmax improved within each group, but not statistically significantly between groups after 36 months (p = 0.081, p = 0.344, p = 0.113, respectively). Kmf remained stable in both groups. TCT decreased significantly in group A (p = 0.014), but remained stable in group B (p = 0.063). Subgroup analysis showed similar results with improvement in visual acuity and keratometry and decrease of TCT. Corneal topography indices showed no differences between the groups after 36 months, but developed differently in the subgroup analysis. No correlation was detected between the change of corneal topography indices and TCT with regard to preoperative Kmax. CONCLUSION: In a large mid-European study population including subgroup analysis of mild and moderate keratoconus, accelerated CXL showed similar results to conventional CXL regarding keratometry, corneal topography indices, and CDVA, but further improvement of UDVA. Preoperative Kmax did not affect the postoperative course of corneal topography indices and TCT. PMID- 29525839 TI - Ocular manifestation in Marfan syndrome: corneal biomechanical properties relate to increased systemic score points. AB - PURPOSE: To evaluate corneal deformation to an air puff as a new noninvasive tool to document disease status in Marfan syndrome (MFS) METHODS: Prospective observational cohort study. We included patients diagnosed with MFS who had their routine cardiovascular follow-up and applied the revised Ghent nosology to define two subgroups according to a high (>= 7) and a low (< 7 points) systemic score. Dynamic Scheimpflug-based biomechanical analyses (CorvisST(r) [CST; Oculus GmbH]) were performed. The main outcome measure was the displacement of the corneal apex as given by the parameters highest concavity (HC; in ms), peak distance (PD; in mm), and highest concavity deformation amplitude (DA; mm). RESULTS: Forty-three eyes of 43 individuals (19 female, 24 male; mean age 42.0 +/- 12.0 years, range 18-67 years) diagnosed with MFS were included. Applying the Ghent criteria, 21 patients had an advanced systemic score of >= 7, and 22 had score points < 7. There were no differences in age or sex between both groups. In contrast, HC was faster (P = 0.004), and PD (P < 0.001) was longer in those individuals with systemic score >= 7; maximum DA did not result in a statistically significant difference between the groups (P = 0.250). CONCLUSIONS: In vivo noninvasive biomechanical analyses with CST offer a new, non-invasive method to identify pathologic corneal deformation responses in adults with MFS. In the future, corneal deformation to an air puff could thus assist early identification of patients with high Ghent score as an adjunct to existing diagnostic tests. PMID- 29525840 TI - Reply to the letter to the editor: Aflibercept in diabetic macular edema refractory to previous bevacizumab: outcomes and predictors of success. PMID- 29525841 TI - A brief psychoeducational intervention improves memory contentment in breast cancer survivors with cognitive concerns: results of a single-arm prospective study. AB - PURPOSE: One in three breast cancer survivors experiences persistent cognitive changes that can negatively impact daily functioning and quality of life. In our cancer center, the largest tertiary cancer center in Canada, patients with self reported cancer-related cognitive dysfunction (CRCD) are offered psychoeducation intended to reduce distress about CRCD symptoms and improve everyday cognitive performance, but evidence regarding this intervention's impact is lacking. Here, we assess whether a 1-hour (h), individual psychoeducational intervention designed to promote self-management of CRCD symptoms can improve attitudes and coping with memory-related difficulties in women with breast cancer. METHODS: Breast cancer survivors with self-reported CRCD (N = 100) were assessed immediately before, immediately after, and 6 weeks following the intervention. Participants' memory contentment, knowledge of CRCD, symptom distress, and self efficacy to cope with symptoms were measured. RESULTS: Participants showed improvements in memory contentment immediately after the intervention (Cohen's d effect size and 95% CI = 0.87 [0.58, 1.16]) and 6 weeks later (d = 0.77 [0.48, 1.05]). Significant improvements in secondary study outcomes, including knowledge of CRCD (d = 1.32 [1.01, 1.63]), symptom distress (d = - 0.82 [- 1.11, - 0.53]), and self-efficacy to cope with cognitive symptoms (d = 1.45 [1.14, 1.76]), were also observed. CONCLUSIONS: A single, 1-hour psychoeducational intervention can achieve lasting and improved adjustment to memory symptoms in breast cancer survivors with self-reported CRCD. Further investigation using a randomized controlled study design is warranted. Comparisons with previously reported psychoeducational interventions for CRCD are made, and next steps for this research are discussed. PMID- 29525842 TI - Correction to: ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease. AB - The original version of this article, unfortunately, contained errors. Figure citation, caption, image and updated sentence in the Result section are now presented correctly in this article. PMID- 29525843 TI - Proteomic analysis of plasma from rheumatoid arthritis patients with mild cognitive impairment. AB - Rheumatoid arthritis (RA) patients may suffer from comorbid neuropsychiatric symptoms including mild cognitive impairment (MCI). Although comorbidity of MCI is common, there are currently no validated plasma biomarkers to aid MCI diagnosis. This study screened plasma from patients with RA with and without comorbid MCI to identify potential biomarkers useful in the differential diagnosis of comorbid MCI. Plasma samples were collected from patients with RA without comorbid MCI, with comorbid MCI, and from healthy controls. Plasma samples were examined by tandem mass tags (TMT) combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MSMS) to analyze protein expression. Differentially expressed proteins were identified by bioinformatics and validated by enzyme-linked immunosorbent assay (ELISA). A total of 746 reliable proteins and 158 differentially expressed proteins were identified. Fourteen patients with RA-MCI showed differential protein expression (six proteins upregulated and eight proteins downregulated) compared with those patients without MCI and with healthy controls. Bioinformatics analysis showed that the differentially expressed proteins were primarily involved in biological processes, such as cell adhesion, coagulation, apoptosis, and body fluid regulation. The results of the ELISA experiments, similar to those of the proteomic analysis, demonstrated that sonic hedgehog (SHH) was upregulated and serum paraoxonase (TTR) was downregulated in patients with RA-MCI. These results indicate that SHH and TTR may be candidate plasma biomarkers that could be used to distinguish patients with RA and comorbid MCI from those without comorbid MCI. PMID- 29525844 TI - Influence of the different "patient global assessment" formulations on disease activity score by different indices in rheumatoid arthritis. AB - Patient global assessment (PGA) is included in almost all rheumatoid arthritis (RA) composite disease activity indices and definitions of remission. However, different PGA formulations exist and are used interchangeably in research and clinical practice. We investigated how five different PGA formulations used in four disease indices affect the remission rates. This was an ancillary analysis of data from a cross-sectional study in patients with RA. The data comprised the following: 28-joint counts, C-reactive protein, and five PGA formulations. Remission rate variation was assessed using five PGA formulations in each index (ACR/EULAR Boolean, CDAI, SDAI, and DAS28-CRP). PGA agreement was assessed by the following: Pearson's correlation; Bland-Altman plots; paired samples t test; and establishing the proportion of patients who scored (i) all formulations within an interval of 20 mm and (ii) each formulation <= 10 mm. This analysis included 191 patients. PGA formulations presented good correlations (>= 0.65), but Bland Altman plots showed clinically significant differences, which were statistically confirmed by comparison of means. Just over a half (51.8%) of patients scored all PGA formulations within a 20-mm interval. The proportion of those scoring <= 10 mm varied from 11.5 to 16.2%. When different formulations of PGA were used in each index, remission differences of up to 4.7, 4.7, 6.3, and 5.2% were observed. When formulations were used in their respective indices, as validated, the remission rates were similar (13.1, 13.6, 14.1, and 18.3%). Using PGA formulations interchangeably may have implications in the assessment of disease activity and in the attainment of remission, and this can impact upon management decisions. PMID- 29525845 TI - Anti-neutrophil cytoplasmic antibodies and their clinical significance. AB - Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies that cause systemic vascular inflammation by binding to target antigens of neutrophils. These autoantibodies can be found in serum from patients with systemic small-vessel vasculitis and they are considered as a biomarker for ANCA associated vasculitis (AAV). A conventional screening test to detect ANCA in the serum is indirect immunofluorescence study, and subsequently confirmed by enzyme linked immunosorbent assay. A positive staining of ANCA can be classified into three main categories based on the staining patterns: cytoplasmic, perinuclear, and atypical. Patients with granulomatosis with polyangiitis (GPA) mostly have a positive cytoplasmic staining pattern (c-ANCA) whilst a perinuclear pattern (p ANCA) is more common in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) patients. Atypical pattern (a-ANCA) is rarely seen in patients with systemic small-vessel vasculitis but it can be found in other conditions. Here, techniques for ANCA detection, ANCA staining patterns and their clinical significances are reviewed. PMID- 29525846 TI - Evaluation of work disability in Japanese patients with rheumatoid arthritis: from the TOMORROW study. AB - : To evaluate work disability and associated factors in patients with rheumatoid arthritis (RA) who participated in the TOMORROW study, a 10-year cohort study in Japan. Subjects in this cross-sectional analysis comprised 191 RA patients and 191 age- and sex-matched non-RA individuals. Work-related outcomes were measured using the Work Productivity and Activity Impairment questionnaire by employment status (full-time worker (FTW), employed >= 35 h/week; part-time worker (PTW), < 35 h/week; home worker (HW), non-employed). In addition, we assessed the EuroQol 5 Dimensions (EQ-5D) and Health Assessment Questionnaire (HAQ) to evaluate quality of life and activities of daily living. No significant differences were evident between groups in percentages of participants in each employment status (p = 0.11), percentages of absenteeism (FTW, p = 1.00; PTW, p = 0.29), presenteeism (FTW, p = 0.23; PTW, p = 0.54), overall work impairment (FTW, p = 0.23; PTW, p = 0.73), or percentage of activity impairment (AI) (FTW, p = 0.62; PTW, p = 0.60). In the HW group, percentage of AI was higher in RA patients than that in non-RA patients (p < 0.01). Among RA patients, HW showed lower EQ-5D and higher HAQ than FTW or PTW (p < 0.001 each). Higher disease activity was observed in HW than FTW (p < 0.01). In terms of the effect of biological disease-modifying anti-rheumatic drugs, no significant differences in work-related outcomes, health status, or daily activity were evident between users and non-users. No significant differences in employment status or work impairment were seen between RA and non-RA groups among paid workers. HW with RA showed more impaired daily activity and higher disease activity compared to working RA patients. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000003876 . Registered 1 Jun 2010. PMID- 29525848 TI - Trace Elements and Paraoxonase-1 Activity in Lower Extremity Artery Disease. AB - Oxidative stress and inflammation are candidate mechanisms to explain the potential role of exposure to metals and reduced activity of paraoxonase-1 (PON1) in age-related diseases. Both may be risk factors contributing to atherosclerosis. In the present study, inductively coupled mass spectrometry was used to explore multiple trace elements, while in-house methods were employed to measure PON1-related variables in patients with lower extremity artery disease (LEAD). Healthy controls were matched for sex, age, body weight, and relevant genotype variants. Serum concentrations of As, Ba, Cu, and Sr were higher in patients than those in controls, with a strong predictive ability to discriminate between groups. Differences in serum Pb, Cd, and Zn were negligible. Serum Cu increased when the disease was more severe, but a negative trend was noted for serum As, B, Ba, and Zn. The only variable associated with ankle-brachial index was serum Zn. Serum PON1 activity was significantly lower in LEAD patients. When the ability of serum trace elements to modulate PON1 activity was explored, the analysis revealed a unique association with serum Zn. The current results strongly suggest that Zn may have a protective effect in non-coronary atherosclerosis and indicate that this element may exert its anti-inflammatory and antioxidant functions through interactions with PON1 activity. These findings deserve confirmation and further research. In particular, the periodic evaluation of serum trace elements and the prescription of Zn supplements are easy measures to implement and that can improve the treatment of patients with LEAD. PMID- 29525847 TI - Ultrasound characterization of cutaneous ulcers in systemic sclerosis. AB - Skin ulcers in scleroderma (SSc) patients are considered a major challenge, both in clinical assessment and treatment decisions. The objective of our study is to assess ultrasonographic (US) morphology of skin ulcers in SSc patients and evaluate if US will be of value in enhancing our clinical information and influence our management plans. We examined a convenience sample of 21 skin ulcers reported in 10 SSc patients by US. We used a previously published US definition of normal skin and developed a preliminary US definition of skin ulcer. Skin ulcers were evaluated by gray scale (GS) and power Doppler (PD) and separated into ulcer and non-ulcer lesions; pain and ulcer measures were obtained using visual analogue scales (VAS). Lesions were characterized and ulcers were clinically and sonographically measured. Ten patients presenting with 21 skin lesions were examined by US. Applying our US definition of skin ulcer, all ulcers were available to measure by ultrasound. Eight lesions were sonographically defined as ulcers, and 13 lesions as non-ulcer lesions. Three ulcers had high PD signals suggestive of infection requiring antibiotic treatment and were monitored for 2 weeks showing a decrease of the pain, VAS, and PD signals. Five lesions showed subclinical calcinosis. This is the first study to show the promising role of US in defining skin ulcers of SSc patients. US may support the assessment of morphology and extent of skin ulcers in SSc and can be a helpful tool for detecting underlying pathology. PMID- 29525849 TI - Association of Periodontitis with the Concentration Levels of Germanium and Tin in Hair. AB - The purpose of this study was to investigate whether or not the concentration levels of certain kinds of trace elements in hair are associated with periodontitis. We studied a total of 109 participants, which are composed of 25 participants with periodontitis and 84 participants without periodontitis. Periodontal conditions were assessed by measuring the periodontal clinical attachment loss and pocket depth, which were determined at six sites of all teeth. Periodontitis was defined according to the criteria of periodontitis proposed by CDC-AAP. The hair samples were washed with acetone, water, and extran (1%v/v), and then aliquots of hair samples were wet-ashed. This sample solution was analyzed by Perkin-Elmer Mass Spectrometer. The odds ratios and 95% confidence intervals of the concentration levels of trace elements for periodontitis were calculated by multivariate logistic regression analysis. After adjusting all confounders, it was found that the higher concentration level of germanium in hair was significantly and positively associated with periodontitis (odds ratio [OR] 7.12; 95% confidential interval [CI] 2.03-25.00). The higher concentration level of tin in hair was significantly and negatively associated with periodontitis (OR 0.27; 95% CI 0.08-0.94). It was concluded that there was a significant relationship between periodontitis and the concentration level of germanium and tin in hair. PMID- 29525850 TI - Intramyocardial dissecting hematoma of right ventricle following a myocardial infarction. PMID- 29525851 TI - Effect of an Exercise Program on Lymphocyte Proliferative Responses of COPD Patients. AB - Exercise training has been shown to reduce symptoms and exacerbations in COPD patients; however, the exercise effect on patients' immune response is poorly known. We thus verified if an exercise program (EP) impacted on proliferative T cell response of COPD patients. Fourteen non-O2 dependent COPD patients on standard treatment were studied. EP consisted in 24 sessions of aerobic and muscular training. Peripheral blood mononuclear cells were stimulated with the mitogen phytohemagglutinin and antigens from Haemophilus influenzae and cytomegalovirus, and the lymphocyte proliferative response (LPR) was assessed through the expression of Ki67 before and after the EP. The Quality of life [COPD assessment test (CAT)], dyspnea [(modified Medical Research Council scale (mMRC)], and 6-min walk distance were also assessed. The EP program increased significantly the LPR of TCD4+ lymphocytes to phytohemagglutinin and cytomegalovirus and H. influenzae antigens, but with TCD8+ lymphocytes the increase was less marked. Consistent with this, a higher proportion of TCD8+ than TCD4+ cells did not express the costimulatory molecule CD28. The EP also resulted in improvement of the quality of life, dyspnea, and physical capacity. The improvement in TCD4+ cell function may represent an additional mechanism through which the EP results in less exacerbations and hospitalizations. PMID- 29525852 TI - Biocatalytic production of mandelic acid and analogues: a review and comparison with chemical processes. AB - The aim of this study is to summarize the current progress in the design of biocatalytic processes applicable for the production of optically pure mandelic acids and their analogues. These compounds are used as building blocks for pharmaceutical chemistry and as chiral resolving agents. Their enzymatic syntheses mainly employed nitrile hydrolysis with nitrilases, ester hydrolysis, ammonolysis or esterification with lipases or esterases, and ketone reduction or alcohol oxidation with dehydrogenases. Each of these methods will be characterized in terms of its product concentrations, enantioselectivities, and the types of catalysts used. This review will focus on the dynamic kinetic resolution of mandelonitrile and analogues by nitrilases resulting in the production of high concentrations of (R)-mandelic acid or (R)-2-chloromandelic acid with excellent e.e. Currently, there is no comparable process for (S) mandelic acids. However, the coupling of the S-selective cyanation of benzaldehyde with the enantioretentive hydrolysis of (S)-mandelonitrile thus obtained is a promising strategy. The major product can be changed from (S)-acid to (S)-amide using nitrilase mutants. The competitiveness of the biocatalytic and chemical processes will be assessed. This review covers the literature published within 2003-2017. PMID- 29525853 TI - APC:T1556fs and STK11 mutations in duodenal adenomas and adenocarcinomas. AB - PURPOSE: Duodenal adenoma and adenocarcinoma (AC) are rare tumors, and few studies have examined their genetic features. We aimed to determine the key genetic changes in duodenal adenoma and AC, and to clarify the possible involvement of the adenoma-carcinoma sequence in duodenal tumor carcinogenesis. METHODS: Nineteen duodenal tumors collected by endoscopic mucosal resection or surgical resection were classified as AC, adenoma with high-grade dysplasia (HGD), or adenoma with low-grade dysplasia (LGD) per the World Health Organization tumor classification. When a tumor contained two or more components with different dysplasia grades, the highest grade was assigned as the tumor grade. Representative areas of these components with different grades were microdissected and evaluated by a genomic analysis. Mutational hotspots involving 50 oncogenes and tumor suppressor genes were analyzed by next-generation sequencing, and their association with the dysplasia grade was investigated. RESULTS: We analyzed 27 tumor components of AC or adenoma, with 11 normal mucosal samples obtained from 19 patients with duodenal tumors. The most prevalent abnormality among 50 genes tested was the KRAS mutation, which was detected in 12/19 (63.2%) patients, followed by APC and TP53 mutations (47.4 and 36.8%, respectively). According to the tumor dysplasia grading of each component, KRAS mutations were found in 5/8 (62.5%) tumors with AC components, 6/9 (66.7%) tumors with HGD components, and 3/10 (30.0%) tumors with LGD components. TP53 mutations were found in 4/8 (50.0%) tumors with AC components, 3/9 (33.3%) tumors with HGD components, and 1/10 (10.0%) tumors with LGD components. APC mutations were found in 2/8 (25.0%) tumors with AC components, 6/9 (66.7%) tumors with HGD components, and 5/10 (50.0%) tumors with LGD components. Notably, an APC:T1556fs mutation was detected in six cases (31.6%), five of which were adenoma cases. Furthermore, STK11 mutations were confirmed in 2/8 (25.0%) AC cases and in 1/11 (9.1%) adenoma cases. CONCLUSION: APC:T1556fs and STK11 mutations found in duodenal adenomas/ACs highlight the importance of proteins encoded by these genes in tumor development. APC mutations were identified in duodenal adenomas more frequently than in duodenal ACs, which differed from the observations of typical adenoma-carcinoma sequences seen in colorectal cancer, suggesting the limited involvement of this mechanism in duodenal cancer development. PMID- 29525854 TI - The allometry of the arcuate body in the postembryonic development of the giant house spider Eratigena atrica. AB - The brain of arachnids contains a special neuropil area called the arcuate body (AB), whose function has been widely discussed. Its growth and proportion in the brain volume during postembryogenesis have been investigated only in several spider species. Our allometric study is aimed at determining to what extent the development of the AB in Eratigena atrica, a spider with unique biology and behaviour, is similar to the development of this body in other species. We put forward a hypothesis of allometric growth of this body in relation to the volume of the central nervous system (CNS) and its neuropil as well as in relation to the volume of the brain and its neuropil. The analysis of paraffin embedded, H + E stained histological preparations confirmed our hypothesis. The AB developed more slowly than the CNS and the neuropil of both the brain and the CNS. In contrast, it exhibited positive allometry in relation to the volume of the brain. This body increased more than nine times within the postembryonic development. Its proportion in the brain volume varied; the lowest was recorded in larvae and nymphs I; then, it increased in nymphs VI and decreased to 2.93% in nymphs X. We conclude that in Eratigena atrica, the AB develops differently that in orb-weaver and wandering spiders. There is no universal model of the AB development, although in adult spiders, regardless of their behaviour, the proportion of this area in the brain volume is similar. PMID- 29525855 TI - Association between exercise intensity and renal blood flow evaluated using ultrasound echo. AB - BACKGROUND: High-intensity exercise reduces renal blood flow (RBF) and may transiently exacerbate renal dysfunction. RBF has previously been measured invasively by administration of an indicator material; however, non-invasive measurement is now possible with technological innovations. This study examined variations in RBF at different exercise intensities using ultrasound echo. METHODS: Eight healthy men with normal renal function (eGFRcys 114 +/- 19 mL/min/1.73 m2) participated in this study. Using a bicycle ergometer, participants underwent an incremental exercise test using a ramp protocol (20 W/min) until exhaustion in Study 1 and the lactate acid breaking point (LaBP) was calculated. Participants underwent a multi-stage test at exercise intensities of 60, 80, 100, 120, and 140% LaBP in Study 2. RBF was measured by ultrasound echo at rest and 5 min after exercise in Study 1 and at rest and immediately after each exercise in Study 2. To determine the mechanisms behind RBF decline, a catheter was placed into the antecubital vein to study vasoconstriction dynamics. RESULTS: RBF after maximum exercise decreased by 51% in Study 1. In Study 2, RBF showed no significant decrease until 80% LaBP, and showed a significant decrease (31%) at 100% LaBP compared with at rest (p < 0.01). The sympathetic nervous system may be involved in this reduction in RBF. CONCLUSIONS: RBF showed no significant decrease until 80% LaBP, and decreased with an increase in blood lactate. Reduction in RBF with exercise above the intensity at LaBP was due to decreased cross-sectional area rather than time-averaged flow velocity. PMID- 29525856 TI - Early renoprotection by anemia correction. PMID- 29525857 TI - Health status, mental health and air quality: evidence from pensioners in Europe. AB - Environmental quality is an important determinant of individuals' well-being and one of the main concerns of the governments is the improvement on air quality and the protection of public health. This is especially the case of sensitive demographic groups, such as the old aged people. However, the question this study attempts to answer is how do individuals value the effects on the environment. The study explores the effects of old and early public pension schemes, as well as the impact of air pollution on health status of retired citizens. The empirical analysis relies on detailed micro-level data derived from the Survey of Health, Ageing and Retirement in Europe (SHARE). As proxies for health, we use the general health status and the Eurod mental health indicator. We examine two air pollutants: the sulphur dioxide (SO2) and ground-level ozone (O3). Next, we calculate the marginal willingness-to-pay (MWTP) which shows how much the people are willing to pay for improvement in air quality. We apply various quantitative techniques and approaches, including the fixed effects ordinary least squares (OLS) and the fixed effects instrumental variables (IV) approach. The last approach is applied to reduce the endogeneity problem coming from possible reverse causality between the air pollution, pensions and the health outcomes. For robustness check, we apply also a structural equation modelling (SEM) which is proper when the outcomes are latent variables. Based on our favoured IV estimates and the health status, we find that the MWTP values for one unit decrease in SO2 and O3 are respectively ?221 and ?88 per year. The respective MWTP values using the Eurod measure are ?155 and ?68. Overall, improvement of health status implies reduction in health expenditures, and in previous literature, ageing has been traditionally considered the most important determinant. However, this study shows that health lifestyle and socio-economic status, such as education and marital status, are more important, and furthermore, air pollution cannot be ignored in the agenda of policy makers. PMID- 29525858 TI - Toxicity bioassays with concentrated cell culture media-a methodology to overcome the chemical loss by conventional preparation of water samples. AB - The use of in vitro bioassays for studies of toxic activity in environmental water samples is a rapidly expanding field of research. Cell-based bioassays can assess the total toxicity exerted by a water sample, regardless whether the toxicity is caused by a known or unknown agent or by a complex mixture of different agents. When using bioassays for environmental water samples, it is often necessary to concentrate the water samples before applying the sample. Commonly, water samples are concentrated 10-50 times. However, there is always a risk of losing compounds in the sample in such sample preparation. We have developed an alternative experimental design by preparing a concentrated cell culture medium which was then diluted in the environmental water sample to compose the final cell culture media for the in vitro assays. Water samples from five Swedish waste water treatment plants were analyzed for oxidative stress response, estrogen receptor (ER), and aryl hydrocarbon receptor (AhR) activity using this experimental design. We were able to detect responses equivalent to 8.8-11.3 ng/L TCCD for AhR activity and 0.4-0.9 ng/L 17beta-estradiol for ER activity. We were unable to detect oxidative stress response in any of the studied water samples. In conclusion, we have developed an experimental design allowing us to examine environmental water samples in toxicity in vitro assays at a concentration factor close to 1, without the risk of losing known or unknown compounds during an extraction procedure. PMID- 29525859 TI - On the flocculation and settling characteristics of low- and high-concentration sediment suspensions: effects of particle concentration and salinity conditions. AB - It remains unclear how the primary particle concentration and salinity conditions influence the flocculation and settling characteristics of water-sediment suspensions. In this study, two sets of experiments were performed to examine the flocculation and settling properties of low- and high-concentration sediment suspensions. In low-concentration suspensions, the sediment concentration undergoes a rapid initial decrease followed by a slow decrease until it approaches zero with increasing flocculation time. Increases in salinity or the valence of cations from the saline solution added to the suspension lead to a more rapidly decreasing sediment concentration with flocculation time. The valence of cations from the saline solution has a larger influence on the flocculation-settling behaviours of the suspension than the salinity. In high concentration sediment suspensions, the height of the clear water-turbid water interface in the water-sediment suspension experiences an initial, rapidly decreasing phase followed by a slowly decreasing phase with increasing flocculation time. Increasing the primary particle concentration, salinity or valence of cations from the saline solution added to the suspension causes the height reduction of the clear water-turbid water interface to become gentler. Finally, the valence of cations from the saline solution has a greater influence on the settling characteristics of the high-concentration water-sediment suspension than the salinity. PMID- 29525860 TI - Improved isolation of cadmium from paddy soil by novel technology based on pore water drainage with graphite-contained electro-kinetic geosynthetics. AB - Novel soil remediation equipment based on electro-kinetic geosynthetics (EKG) was developed for in situ isolation of metals from paddy soil. Two mutually independent field plot experiments A and B (with and without electric current applied) were conducted. After saturation using ferric chloride (FeCl3) and calcium chloride (CaCl2), soil water drainage capacity, soil cadmium (Cd) removal performance, energy consumption as well as soil residual of iron (Fe) and chloride (Cl) were assessed. Cadmium dissolved in the soil matrix and resulted in a 100% increase of diethylenetriamine-pentaacetic acid (DTPA) extracted phyto available Cd. The total soil Cd content reductions were 15.20% and 26.58% for groups A and B, respectively, and electric field applications resulted in a 74.87% increase of soil total Cd removal. The electric energy consumption was only 2.17 kWh/m3 for group B. Drainage by gravity contributed to > 90% of the overall soil dewatering capacity. Compared to conventional electro-kinetic technology, excellent and fast soil water drainage resulted in negligible hydrogen ion (H+) and hydroxide ion (OH-) accumulation at nearby electrode zones, which addressed the challenge of anode corrosion and cathode precipitation of soil metals. External addition of FeCl3 and CaCl2 caused soil Fe and Cl residuals and led to 4.33-7.59% and 139-172% acceptable augments in soil total Fe and Cl content, correspondingly, if compared to original untreated soils. Therefore, the novel soil remediation equipment developed based on EKG can be regarded as a promising new in situ technology for thoroughly isolating metals from large-scale paddy soil fields. PMID- 29525861 TI - Mortality assessment attributed to long-term exposure to fine particles in ambient air of the megacity of Tehran, Iran. AB - Few studies regarding the health effects of long-term exposure to particulate matter with an aerodynamic diameter of 2.5 MUm or less (PM2.5) have been carried out in Asia or the Middle East. The objective of our study was to assess total, lung cancer and chronic obstructive pulmonary disease (COPD) mortality attributed to long-term exposure to PM2.5 among adults aged over 30 years in Tehran from March 2013 to March 2016 using AirQ+ software. AirQ+ modeling software was used to estimate the number of deaths attributed to PM2.5 concentrations higher than 10 MUg m-3. Air quality data were obtained from the Department of Environment (DOE) and Tehran Air Quality Control Company (TAQCC). Only valid stations with data completeness of 75% in all 3 years were selected for entry into the model. The 3-year average of the 24-h concentrations was 39.17 MUg m-3. The results showed that the annual average concentration of PM2.5 in 2015-2016 was reduced by 13% compared to that in 2013-2014. The annual average number of all natural, COPD, and lung cancer deaths attributable to long-term exposure to PM2.5 in adults aged more than 30 years was 5073, 158, and 142 cases, respectively. The results of all three health endpoints indicate that the mortality attributable to PM2.5 decreased yearly from 2013 to 2016 and that the reduced mortality was related to a corresponding reduction in the PM2.5 concentration. Considering these first positive results, the steps that have been currently taken for reducing air pollution in Tehran should be continued to further improve the already positive effects of these measures on reducing health outcomes. PMID- 29525862 TI - Effect of microalgae storage conditions on methane yields. AB - During the last decade, a lot of research has been focused on identifying the methane yields achievable when using microalgae biomass (fresh and pretreated) as a substrate in anaerobic digestion. Encountered differences are frequently attributed to the different microalgae strains (cell walls and macromolecular profiles) or the different metabolic activities of anaerobic sludge used as inoculum. Nevertheless, under the hypothesis that the state of microalgae upon biomass storage may also play a significant role, this study was designed to evaluate the effect of biomass processing and storage on methane yields and hydrolysis kinetics in batch mode assays. Slight changes in the macromolecular profile distribution of the different tested biomass were observed. Regardless of the time that the biomass was stored, results revealed that frozen biomass doubled the hydrolysis constant and enhanced methane yield by 1.56-fold compared to fresh microalgae biomass (82.4 mL CH4 g COD in-1). Similar enhancement was obtained with the freeze-dried biomass, and slightly lower values were obtained (1.34-fold) for the biomass kept at 4 degrees C longer than a week. Likewise, the semi-continuously operated reactor fed with microalgae biomass stored for 28 days at 4 degrees C did not show any effect in terms of methane production, although nitrogen mineralization was higher than expected. Remarkably, the initial stage of the biomass should be carefully considered for comparison purposes with the available literature on batch mode assays. This study highlights the importance of considering how the biomass is stored before the anaerobic digestion process to avoid misleading conclusions. PMID- 29525863 TI - Nano-MnO2-mediated transformation of triclosan with humic molecules present: kinetics, products, and pathways. AB - It has been shown that manganese dioxide (MnO2) can mediate transformation of phenolic contaminants to form phenoxyl radical intermediates, and subsequently, these intermediates intercouple to form oligomers via covalent binding. However, the reaction kinetics and transformation mechanisms of phenolic contaminants with humic molecules present in nano-MnO2-mediated systems were still unclear. In this study, it was proven that nano-MnO2 were effective in transforming triclosan under acidic conditions (pH 3.5-5.0) during manganese reduction, and the apparent pseudo first-order kinetics rate constants (k = 0.0599-1.5314 h-1) increased as the pH decreased. In particular, the transformation of triclosan by nano-MnO2 was enhanced in the presence of low-concentration humic acid (1-10 mg L-1). The variation in the absorption of humic molecules at 275 nm supported possible covalent binding between humic molecules and triclosan in the nano-MnO2-mediated systems. A total of four main intermediate products were identified by high resolution mass spectrometry (HRMS), regardless of humic molecules present in the systems or not. These products correspond to a suite of radical intercoupling reactions (dimers and trimers), ether cleavage (2,4-dichlorophenol), and oxidation to quinone-like products, triggered by electron transfer from triclosan molecules to nano-MnO2. A possible reaction pathway in humic acid solutions, including homo-coupling, decomposition, oxidation, and cross-coupling, was proposed. Our findings provide valuable information regarding the environmental fate and transformation mechanism of triclosan by nano-MnO2 in complex water matrices. PMID- 29525864 TI - Development of an in vitro toxicological test system based on zebrafish (Danio rerio) sperm analysis. AB - The effect of seven heavy metals on the motility parameter of zebrafish sperm was tested in order to develop an in vitro toxicological test system as an alternative to live animal testing. In vitro test systems are currently preferred in ecotoxicology due to their practical and ethical advantages and fish sperm can be a suitable model. A number of studies had been carried out previously on this topic, but the described methods had not been standardized in numerous aspects (donor species, measured endpoint, etc.). In this study, heavy metals (mercury, arsenic, chromium, zinc, nickel, copper, cadmium) were used as reference toxicants with known toxicity to develop a standardized fish sperm in vitro assay. The tested concentrations were determined based on preliminary range finding tests. The endpoints were progressive motility (PMOT, %), curvilinear velocity (VCL, MUm/s), and linearity (LIN, %) measured by a computer-assisted sperm analysis (CASA) system. According to our results, PMOT was the most sensitive of the three investigated parameters: dose-response curves were observed for each metal at relatively low concentrations. VCL values were less sensitive: higher concentrations were needed to observe changes. Of the three parameters, LIN was the least affected: dose-response relationship was observed only in the case of mercury (e.g., lowest observed effect concentration (LOEC) of Hg at 120 min: 1 mg/L for PMOT, 2.5 mg/L for VCL, 5 mg/L for LIN; LOEC of Cu at 120 min: 1 mg/L for PMOT, 5 mg/L for VCL, any for LIN). The order of toxicity as determined by PMOT was as follows: Hg2+ > As3+ > Cd2+ > Cu2+ > Zn2+ > Cr3+ > Ni2+. In conclusion, we found that PMOT of zebrafish sperm was an accurate and fast bioindicator of heavy metal load. Sperm analysis can be adopted to estimate the possible toxic effects of various chemicals in vitro. Future investigations should concentrate on the applicability of this assay to other contaminants (e.g., organic pollutants). PMID- 29525865 TI - Surfactant-enhanced biodegradation of crude oil by mixed bacterial consortium in contaminated soil. AB - This study evaluated the effects of two surfactants (i.e., Tween 80 and SDS) on biodegradation of crude oil by mixed bacterial consortium in soil-aqueous system. The mixed bacterial consortium was domesticated from the activated sludge of cooking plant through a progressive domestication process. High-throughput sequencing analysis revealed that Rhodanobacter sp. was the dominant bacteria. The higher CMCeff value for two surfactants was observed in soil-aqueous system compared with that in aqueous system, which was likely due to their adsorption onto soil particles. Either Tween 80 or SDS can be utilized as carbon source and promote the growth of mixed bacterial consortium. Further findings evidenced that the degradation of crude oil can be enhanced by adding either Tween 80 or SDS. The performance of Tween 80 was generally superior to SDS for the crude oil degradation. The highest crude oil degradation efficiency was 42.2 and 31.0% under the conditions of 5 CMCeff of Tween 80 and 2 CMCeff of SDS, respectively. Furthermore, the degradation efficiency of crude oil in remediation experiment (i.e., 77%) evidenced that the integration of adding Tween 80 and inoculating mixed bacterial consortium was effective for crude oil-contaminated soil decontamination. PMID- 29525866 TI - Evaluation of cationic polyacrylamide-based hybrid coagulation for the removal of dissolved organic nitrogen. AB - Dissolved organic nitrogen (DON) is an important component of aquatic environment of which amount impacts water quality. Thus, removal of DON has attracted wide attention. At present, it is difficult for common coagulation to remove DON from the aquatic environment. The cationic polymers can help to improve the removal efficiency of DON to some extent, but the underlying mechanism of the ascension is not clear. In order to grasp its removal behavior and further improve the removal efficiency of DON in the future, we evaluated the effect of a hybridized coagulant of polyacrylamide with iron-based coagulant on removal of aquatic DON. A higher floc growth rate (119.82 MUm/min) and recovery factors (26.96) were found in the hybrid coagulation. The parameters affecting the DON and the dissolved organic carbon (DOC) included the molar ratio of Zn to Fe (nZn/nFe), CPAM content, and molar ratio of OH to Fe (nOH/nFe): nZn/nFe had a larger influence in DON removal than CPAM content; CPAM had a larger influence in the DOC removal; nOH/nFe played a moderate effect between CPAM and nZn/nFe. Mutual effect of hybrid coagulants indicated the colloidal species to be helpful in enhancing DOC and DON removal. Other parameters affecting coagulation performance included the pH: the estimated maximum DON removal efficiency occurred at pH 6, DOC removal efficiency at pH 8. The above results found in this study showed that DON removal was affected by the ingredient and the species composition of the hybrid coagulant, and the water environmental parameter. The enhanced efficiency of DON removal in the presence of CPAM was mainly attributed to the increased adsorption-bridging and sweep-floc. PMID- 29525867 TI - Trace analysis of parabens preservatives in drinking water treatment sludge, treated, and mineral water samples. AB - Parabens have been widely used as antimicrobial agents, mainly in food products, pharmaceuticals, and cosmetics. Although they are known as safe preservatives, they also cause some harm to human health, which has been discussed lately. Therefore, the aim of this study was to evaluate the occurrence of nine parabens (including isomers) in mineral and drinking waters, besides in drinking water treatment sludge (DWTS) samples with determination by liquid chromatography tandem mass spectrometry (LC-MS/MS). Both methods solid phase extraction (SPE) and QuEChERS were validated. Calibration curves showed a correlation coefficient of 0.99 for all compounds. LOQ values ranged from 0.04 to 4 MUg L-1 in aqueous matrices and from 5 to 500 ng g-1 in DWTS. Recoveries between 70 and 115% were reached with RSD below 20% for all compounds in SPE whereas recoveries between 62 and 119% were found with RSD below 20% for almost all compounds in QuEChERS. Matrix effect had low values (< 20%); it was only above 20% for methylparaben in the SPE and for pentylparaben in the QuEChERS. Using a quick and simple extraction procedures with SPE, QuEChERS, and LC-MS/MS analyses, these methods proved to be selective and sensitive. They were successfully applied to real samples (treated water, mineral water, and sludge), and methylparaben was detected at concentration levels below 0.242 MUg L-1 in mineral and treated water samples and 10 ng g-1 in DWTS samples. PMID- 29525868 TI - Simultaneous oxidation of Hg0 and NH3-SCR of NO by nanophase Ce x Zr y Mn z O2 at low temperature: the interaction and mechanism. AB - Simultaneous oxidation of Hg0 and NH3-SCR of NO by catalyst is one of the key methods for co-purification of coal-fired flue gas. Till now, the interaction between the oxidation of Hg0 and NH3-SCR of NO and its mechanism have not clarified. In this study, a series of nanophase Ce x Zr y Mn z O2 was prepared for the simultaneous oxidation of Hg0 and NH3-SCR of NO at low temperature. The catalysts were characterized using surface area analysis, X-ray diffraction, temperature-programmed techniques, and several types of microscopy and spectroscopy. The experimental results indicated that the Ce0.47Zr0.22Mn0.31O2 exhibited superior Hg0 removal efficiency (> 99%) and NO conversion efficiency (> 90%) even at 150 degrees C, and it also exhibited a good durability in the presence of SO2 and H2O. The excellent performance of Ce0.47Zr0.22Mn0.31O2 on co purifying Hg0 and NO was due to the stronger synergistic effects of Ce-Zr-Mn in Ce0.47Zr0.22Mn0.31O2 than that of the others, which was illustrated by the characterization results of XPS, XRD, and FT-IR. Moreover, it was found that the NO conversion of Ce0.47Zr0.22Mn0.31O2 could be slightly influenced by Hg0 and was decreased about 4% to the max, while that of Hg0 could rarely be affected by the selected catalytic reduction process of NO. It might be due to the co purification mechanism of NO and Hg0. The mechanism of the simultaneous oxidation of Hg0 and NH3-SCR of NO was mainly due to the synergetic effect on the mobility of surface oxygen and the activation of lattice oxygen of Ce0.47Zr0.22Mn0.31O2. The effect of the oxidation of Hg0 on the NH3-SCR of NO was mainly due to the absorbed Hg0/Hg2+ on the surface of Ce0.47Zr0.22Mn0.31O2, which attenuated the formation of NH3(ad), -NH2(ad), and NH4+ on its acid sites. Similarly, the NH3 SCR of NO process could hardly influence the oxidation of Hg0 when NO and Hg0 were co-purified. PMID- 29525869 TI - Growth and nutrition of Agelastica coerulea (Coleoptera: Chrysomelidae) larvae changed when fed with leaves obtained from an O3-enriched atmosphere. AB - A series of laboratory no-choice assays were performed to test changes in the feeding, growth, and nutrition of leaf beetle (Agelastica coerulea) larval instars on O3-treated leaves of Japanese white birch (Betula platyphylla var. japonica). Larvae fed with O3-treated leaves grew and developed significantly faster throughout their developmental cycle than the corresponding controls. The growth rate (GR) and consumption index (CI) were mostly decreased with age for both control and O3-treated leaves. Efficiency of conversion of both ingested and digested food (ECI, ECD) showed an increase from the 2nd to the 4th instar, after which they decreased significantly and reached the lowest value in the last larval instars (7th). GR, CI, ECI, and ECD were greater and approximate digestibility (AD) was lower in larvae fed with O3-treated leaves than those fed with control leaves. This indicated that the greater rate of growth on fumigated leaves was due primarily to a greater rate of consumption (i.e., O3 increased the "acceptability" of the host more than "suitability") and efficiency in converting food into body mass. Overall, larval performance seemed to have improved when fed with O3-treated leaves in these assays. This study suggests that insects may be more injurious to O3-treated plants and warrants further investigations on birch beetle interactions under field conditions. PMID- 29525870 TI - High-performance for hydrogen evolution and pollutant degradation of reduced graphene oxide/two-phase g-C3N4 heterojunction photocatalysts. AB - We have successfully synthesized the composites of two-phase g-C3N4 heterojunction photocatalysts by one-step method. And the reduced graphene oxide/two-phase g-C3N4 heterojunction photocatalyst was fabricated via a facile hydrothermal reduction method. The characterization results indicated that the two-phase g-C3N4 was integrated closely, and the common phenomenon of agglomeration for g-C3N4 was significantly reduced. Moreover, the oxidized graphene was reduced successfully in the composites and the graphene was overlaid on the surface or the interlayers of g-C3N4 heterojunction composite uniformly. In addition, we have carried out the photocatalytic activity experiments by H2 evolution and rhodamine B removal, tetracycline removal under the visible light irradiation. The results revealed that the composite has improved the separation efficiency a lot than the pure photocatalyst. The photocurrent test demonstrated that the recombination of electrons and holes were efficiently inhibited as well as enhanced the photocatalytic activity. The 0.4% rGO loaded samples, 0.4% rGOCN2, own the best performance. Its rate of H2 evolution was 15 times as high as that of the pure g-C3N4. PMID- 29525871 TI - Study on turbulence characteristics and sensitivity of quadrant analysis to threshold level in Lake Taihu. AB - The identification of coherent structures is very important in investigating the sediment transport mechanism and controlling the eutrophication in shallow lakes. This study analyzed the turbulence characteristics and the sensitivity of quadrant analysis to threshold level. Simultaneous in situ measurements of velocities and suspended sediment concentration (SSC) were conducted in Lake Taihu with acoustic Doppler velocimeter (ADV) and optical backscatter sensor (OBS) instruments. The results show that the increase in hole size makes the difference between dominant and non-dominant events more distinct. Wind velocity determines the frequency of occurrence of sweep and ejection events, which provide dominant contributions to the Reynolds stress. The increase of wind velocity enlarges the magnitude of coherent events but has little impact on the events frequency with the same hole size. The events occurring within short periods provide large contributions to the momentum flux. Transportation and diffusion of sediment are in control of the intermittent coherent events to a large extent. PMID- 29525872 TI - The regulatory role of endogenous iron on greenhouse gas emissions under intensive nitrogen fertilization in subtropical soils of China. AB - Anaerobic batch experiments were conducted to study the regulatory role of endogenous iron in greenhouse gas emissions under intensive nitrogen fertilization in subtropical soils of China. Fe2+, Fe3+, and NO3--N dynamics and N2O, CH4, and CO2 emissions, as well as the relationships between N fertilizer, endogenous iron, and greenhouse gas emissions were investigated. The emissions of N2O increased to different extents from all the test soils by N1 (260 mg N kg-1) application compared with N0. After 24 days of anaerobic incubation, the cumulative emissions of N2O from red soils in De'an (DR) were significantly higher than that from paddy soils in De'an (DP) and Qujialing (QP) under N1. However, N application enhanced CH4 and CO2 emissions from the red soils slightly but inhibited the emissions from paddy soils. The maximal CH4 and CO2 emission fluxes occurred in DP soil without N input. Pearson's correlation analysis showed that there were significant correlations (P < 0.01) between Fe2+ and Fe3+, NO3- N, (N2O + N2)-N concentrations in DP soil, implying that Fe2+ oxidation was coupled with nitrate reduction accompanied by (N2O + N2)-N emissions and the endogenous iron played a regulatory role in greenhouse gas emissions mainly through the involvement in denitrification. The proportion of the electrons donated by Fe2+ used for N2O production in denitrification in DP soil was approximately 37.53%. Moreover, positive correlations between Fe2+ and CH4, CO2 were found in both DR and QP soils, suggesting that endogenous iron might regulate the anaerobic decomposition of organic carbon to CH4 and CO2 in the two soils. Soil pH was also an important factor controlling greenhouse gas emissions by affecting endogenous iron availability and C and N transformation processes. PMID- 29525873 TI - Retinal findings in a patient of French ancestry with CABP4-related retinal disease. AB - INTRODUCTION: CABP4-related retinal dysfunction is a cone-rod synaptic transmission disorder with electronegative electroretinogram (ERG) waveform. It is a rare retinal dysfunction that can be classified into the incomplete form of congenital stationary night blindness. Absent foveal reflex and overall foveal thinning were previously reported, but in most cases the fundus appearance was described as nearly normal. We report here peculiar macular changes in a patient of French ancestry harbouring CABP4 mutations. METHODS: Complete ocular examination and full-field ERG were performed at the initial presentation and follow-up. Multimodal fundus imagining, including spectral-domain optical coherence tomography, colour, infrared reflectance and short-wavelength autofluorescence photographs, was performed during follow-up visits. RESULTS: A 7 month-old infant was addressed to our department for visual unresponsiveness and nystagmus. ERG had an electronegative waveform, even for light-adapted stimuli, thus supporting the diagnosis of photoreceptor-bipolar cell transmission disorder. Genetic investigations discovered a compound heterozygous mutation in CABP4: c.646C > T, p.Arg216*/c.673C > T, p.Arg225*. Multimodal fundus imaging, performed at follow-up visits, showed fine radial folds at the vitreomacular interface and dark foveal dots in both eyes. Optic coherence tomography revealed a focal foveal ellipsoid zone gap. DISCUSSION: Initial presentation was misleading with Leber congenital amaurosis. The electronegative ERG waveform reoriented the genetic investigations and thus establishing a correct diagnosis. To the best of our knowledge, the peculiar fundus changes observed in our patient were never reported before. We hypothesized that a foveal ellipsoid zone interruption discovered in our patient could reflect mostly a cone dysfunction. It was unclear whether the fine radial folds in both maculae were linked with high hyperopia or were an intrinsic feature of the retinal disease. CONCLUSION: CABP4-related retinal disease is a cone-rod system disorder with possible foveal abnormalities. PMID- 29525875 TI - Imaging following renal ablation: what can we learn from recurrent tumors? AB - PURPOSE: The purpose of the study was to evaluate the post-contrast appearance of local tumor progression (LTP) following renal ablation to better understand patterns of tumor recurrence and to optimize follow-up imaging protocols. METHODS: From 2002 to 2015, 913 patients underwent 988 renal ablation procedures for treatment of 1064 tumors. LTP was identified in 24 (2.6%) patients during median imaging follow-up of 30 months (range 0-139). One patient with LTP was followed with non-contrast MRI only and was excluded from evaluation. Three body radiologists reviewed the contrast-enhanced CT and/or MRI follow-up imaging in the remaining 23 patients to determine the timing and imaging appearance of the recurrent tumor. RESULTS: Local tumor progression was identified on contrast enhanced CT or MRI at median 11 months (range 1 and 68) after renal ablation. Corticomedullary phase imaging was performed in 16/23 (70%) patients. LTP was identified on the corticomedullary phase in all cases, and was most conspicuous on the corticomedullary phase compared to any other phase of imaging in 15/16 (94%) patients. No cases of LTP were best visualized on non-contrast or excretory phase images. CONCLUSIONS: Delayed recurrence following renal ablation is possible; therefore, extended follow-up is indicated in ablation patients. Almost all cases of LTP were best visualized on the corticomedullary phase of imaging, which should be included in any post-ablation imaging protocol. Excretory phase images were not required to diagnose LTP in any case and could be excluded from routine post-ablation follow-up. PMID- 29525874 TI - Dissecting the individual contribution of conserved cysteines to the redox regulation of RubisCO. AB - Oxidation of the cysteines from ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) leads to inactivation and promotes structural changes that increase the proteolytic sensitivity and membrane association propensity related to its catabolism. To uncover the individual role of the different cysteines, the sequential order of modification under increasing oxidative conditions was determined using chemical labeling and mass spectrometry. Besides, site-directed RubisCO mutants were obtained in Chlamydomonas reinhardtii replacing single conserved cysteines (Cys84, Cys172, Cys192, Cys247, Cys284, Cys427, Cys459 from the large and sCys41, sCys83 from the small subunit) and the redox properties of the mutant enzymes were determined. All mutants retained significant carboxylase activity and grew photoautotrophically, indicating that these conserved cysteines are not essential for catalysis. Cys84 played a noticeable structural role, its replacement producing a structurally altered enzyme. While Cys247, Cys284, and sCys83 were not affected by the redox environment, all other residues were oxidized using a disulfide/thiol ratio of around two, except for Cys172 whose oxidation was distinctly delayed. Remarkably, Cys192 and Cys427 were apparently protective, their absence leading to a premature oxidation of critical residues (Cys172 and Cys459). These cysteines integrate a regulatory network that modulates RubisCO activity and conformation in response to oxidative conditions. PMID- 29525876 TI - The stack of coins sign in scleroderma. PMID- 29525877 TI - Renal epithelioid angiomyolipoma: magnetic resonance imaging characteristics. AB - OBJECTIVE: The aim of the study was to analyze MR imaging features of renal epithelioid angiomyolipoma (EAML). METHODS: This study included 17 patients with histopathologically confirmed renal EAML who underwent renal MRI scanning before radical or partial nephrectomy. MR images were retrospectively reviewed and correlated with pathological findings. RESULT: Fifteen lesions (88.2%) appeared as round or oval. The tumor-kidney interface was round in 14 lesions (82.4%). Fifteen tumors (88.2%) presented mainly isointensity on T1WI, and eleven tumors (64.7%) presented mainly hypointensity on T2WI. Twelve lesions (70.6%) showed restricted diffusion on DWI, and the mean ADC value was 1.23 +/- 0.28 * 10 3mm2/s. Minimal fat component was identified as loss of signal intensity on opposed-phase MR images in 6 cases (35.3%). Sixteen lesions (100%) demonstrated inhomogeneous enhancement, and 7 of 16 masses (43.8%) showed reticular enhancement. Rapid wash-in and wash-out enhancement was seen in 13 masses (81.3%). In the corticomedullary phase, the mass showed markedly enhancement in 14 cases (87.5%). The irregular vessels and hemorrhage were detected in 4 cases (23.5%) and 7 cases (41.2%), respectively. One patient (5.9%) had a lymph node involvement at initial diagnosis, and showed distant metastasis after operation. In the immunohistochemical analysis, 15 tumors (88.2%) were positive for melanocytic marker (HMB45 or Melan-A), and all cases (100%) were negative for epithelial-associated markers (CK or AE1/AE3). CONCLUSION: The presence of hypointensity on T2WI, restricted diffusion on DWI, round tumor-kidney interface, reticular, and marked enhancement (rapid wash-in and wash-out) should further raise suspicion for renal EAML. The diagnosis may be confirmed by pathological analysis. PMID- 29525878 TI - The celiac seagull. PMID- 29525879 TI - The Champagne sign. PMID- 29525880 TI - Germline VHL gene variant in patients with von Hippel-Lindau disease does not predict renal tumor growth. AB - PURPOSE: To determine whether the type of VHL gene pathogenic variant influences the growth rate or CT enhancement values of renal lesions in VHL patients. MATERIALS AND METHODS: Thirty-two VHL patients (19 male) were selected from a prospectively maintained imaging database for patients that underwent surgical tumor resection between 2014 and 2016. One hundred and eleven VHL lesions were marked for resection and pathology analysis. Whole lesion volumetric segmentation was performed on nephrographic phase of the two most recent contrast-enhanced CT scans before surgery. Intensity distribution curves were obtained from segmentations. A linear mixed model, accounting for within-patient correlations, was used to compare the growth and enhancement differences between different germline pathogenic variant types. RESULTS: There was no significant difference for the lesions' total growth between different germline pathogenic variants (P value = 0.78). The median growth rate for all lesions was 1.7 cc/year (IQR 0.5, 3.9) with a baseline median size of 4.1 cm3 (IQR 1.7, 11.7). In complex lesions, the solid portion of the tumor demonstrated a higher growth rate (1.6 cc/year) than cystic portions (0.02 cc/year) which stayed relatively unchanged. Only one pathogenic variant (Splice donor) showed some levels of difference in its relative enhancement from other subtypes. CONCLUSION: The type of germline pathogenic variant on the VHL gene does not affect the growth rate or CT enhancement values of renal lesions in patients with VHL. The absolute growth rate of these tumors may be used in the scheduling of follow-up studies. PMID- 29525881 TI - The skinny on skin: MRI features of cutaneous and subcutaneous lesions detected on body MRI studies. AB - The skin and subcutaneous tissues are inevitably imaged as part of most body MRI studies. Incidental or even symptomatic skin lesions may, therefore, be detected and present a diagnostic challenge for the radiologist. We aim to provide a comprehensive review, with illustrative examples, of the skin abnormalities encountered on body MRI studies in our busy academic radiology department. PMID- 29525882 TI - The cluster sign. PMID- 29525883 TI - Intravoxel incoherent motion (IVIM) at 3.0 T: evaluation of early renal function changes in type 2 diabetic patients. AB - PURPOSE: The purpose of this study was to evaluate the utility of intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) parameters in identifying early renal function changes in diabetics. METHODS: A total of 40 patients with type 2 diabetes mellitus and 20 healthy control subjects underwent multiple b value DWI. The diabetic patients were stratified into two groups based on albuminuria category: NAU (normal to mildly increased albuminuria; ACR < 30 mg/g) and MAU (moderately increased albuminuria; 30 <= ACR < 300 mg/g). The mean cortical and medullary IVIM parameters (D, D*, f, and ADC) were calculated and compared among the different groups, and the correlation of ACR and eGFR was also calculated. RESULTS: The present study revealed the limited water molecule diffusion and hyperperfusion of renal cortex and medulla in diabetic patients before proteinuria detection. Mean cortical and medullary D values negatively correlated with the ACR values in diabetics with 30 <= ACR < 300 mg/g, whereas no correlation was found between ACR values and other IVIM parameters. CONCLUSION: IVIM DWI might be helpful in noninvasively identifying early-stage DN. The IVIM parametric values are more sensitive than the ACR in detecting early-stage kidney changes. PMID- 29525884 TI - The Potential of Stem Cells and Stem Cell-Derived Exosomes in Treating Cardiovascular Diseases. AB - In recent years, the cardiac protective mechanisms of stem cells have become a research focus. Increasing evidence has suggested that stem cells release vesicles, including exosomes and micro-vesicles. The content of these vesicles relies on an extracellular stimulus, and active ingredients are extensively being studied. Previous studies have confirmed that stem cell-derived exosomes have a cardiac protective function similar to that of stem cells, and promote angiogenesis, decrease apoptosis, and respond to stress. Compared to stem cells, exosomes are more stable without aneuploidy and immune rejection, and may be a promising and effective therapy for cardiovascular diseases. In this review, the biological functions and molecular mechanisms of stem cells and stem cell-derived exosomes are discussed. PMID- 29525885 TI - Utilization Patterns of Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus in Italy: A Retrospective Cohort Study. AB - INTRODUCTION: Real-world evidence on glucagon-like peptide-1 receptor agonist (GLP-1 RAs) usage is emerging in different European countries but is lacking in Italy. This retrospective cohort study aimed to describe the real-world drug utilization patterns in patients initiating GLP-1 RAs for treating T2DM in Italy. METHODS: Adults aged >= 20 years and with >= 1 oral antidiabetic drug (alone or in combination with insulin) other than GLP-1 RAs in the 6 months prior to initiating exenatide twice daily (exBID), exenatide once weekly (exQW), dulaglutide once weekly (DULA), liraglutide once daily (LIRA) or lixisenatide once daily (LIXI) between March and July 2016 were retrospectively identified in the Italian IMS LifeLinkTM longitudinal prescriptions database (retail pharmacy data). Patients with >= 6-month follow-up (defined as evidence of any prescription activity) were included. Proportions of patients who remained persistent (continued treatment until discontinuation/switch) in the first 6 months and of those who discontinued or switched to a different GLP-1 RA over the entire follow-up were recorded. For each treatment, the average daily/weekly dosage (ADD/AWD) while persistent during the available follow-up was calculated. RESULTS: We identified 7319 patients: 92 exBID, 970 exQW, 3368 DULA, 2573 LIRA and 316 LIXI. Across treatments, 89% patients were >= 50 years old, 54% were males, and the median follow-up duration ranged between 8.1 and 8.7 months. At 6 months, 35% exBID, 47% exQW, 62% DULA, 50% LIRA and 40% LIXI patients remained persistent. Over the entire follow-up, median persistence days varied from 73 (exBID) to > 300 days (DULA). The mean +/- SD ADD/AWD was exBID: 17.7 +/- 2.1 ug/day; exQW: 2.1 +/- 0.1 mg/week; DULA: 1.5 +/- 0.2 mg/week; LIRA: 1.5 +/- 0.2 mg/day; LIXI: 21.0 +/- 5.5 ug/day. CONCLUSIONS: This real-world analysis suggests differences exist in persistence between patients treated with various GLP-1 RAs. Among the investigated treatments, patients prescribed exBID recorded the lowest and those prescribed DULA the highest persistence with therapy. FUNDING: Eli Lilly and Co., Indianapolis, IN, USA. PMID- 29525886 TI - Assessment of contamination, environmental risk, and origin of heavy metals in soils surrounding industrial facilities in Vojvodina, Serbia. AB - Content of potentially toxic elements was examined in soils from Srem (Vojvodina), to evaluate industrial facilities as pollution sources. Based on the distribution of the elements, the results of sequential extraction, enrichment factor (EF), ecological risk factor (Er), ecological risk index (RI), and statistical analysis, the current ecological status of the soils was determined. Elements in soils around the industrial facilities can be grouped into the five significant components derived by the principal component analysis (PCA), which explains 78.435% of the total variance. Al, Fe and Mg, and K and Mn are associated with two lithogenic components, respectively. Anthropogenic origin is identified for Hg and Cd. Mixed sources, geogenic and anthropogenic, are identified within two PCA components; one wich includes As, Pb, B, Zn, and the other: K and Cr, Ni and Cu. Cluster analysis (CA) corroborated the results obtained by PCA. The preliminary results revealed that the soils studied in a vicinity of industrial facilities in Srem have been exposed to different degrees of pollution. Among the characterized studied elements, Pb, Cd, Hg, Cu, Ni, and Cr are the main contaminants. Based on calculated EF, the studied soils show minor to severe enrichment with heavy metals. Ecological risk assessment results indicate that Cd and Hg carry the highest ecological risk level, and Zn and Cr the lowest. PMID- 29525887 TI - The neural correlates of arithmetic difficulty depend on mathematical ability: evidence from combined fNIRS and ERP. AB - Mathematical abilities are essential for an individual, as they predict career prospects among many other abilities. However, little is known about whether neural correlates of arithmetic problem difficulty differ between individuals with high and low math ability. For instance, the difficulty of two-digit addition and subtraction increases whenever a carry or borrow operation is required. Therefore, we systematically investigated the spatial and temporal neural correlates of the carry and borrow effects for high and low performers in a written production paradigm using combined functional near-infrared spectroscopy (fNIRS) and event-related potential (ERP) measurements. Effects of arithmetic difficulty interacted with an individual's math ability. High performers showed increased frontal activation especially in the left inferior frontal gyrus associated with the carry and borrow effects, whereas low performers did not. Furthermore, high and low performers even differed in their early processing of the borrow effect, as reflected by differences in slow waves at 1000-1500 ms at frontal sites. We conclude that the processing of arithmetic difficulty relies on an individual's mathematical ability, and suggest that individual differences should be taken into account when investigating mental arithmetic in an ecologically valid assessment. PMID- 29525889 TI - Nobiletin acts anti-inflammatory on murine IL-10-/- colitis and human intestinal fibroblasts. AB - PURPOSE: Inflammatory bowel disease (IBD) shows increasing prevalence over the last years. We propose that anti-inflammatory plant substances could be used as additional or alternative agents with good compliance in prevention and/or therapy of IBD and its complication intestinal fibrosis. We could recently show that the citrus flavonoid nobiletin acts anti-inflammatory on activation of intestinal mast cells. Here, we analysed the effects of nobiletin on inflammation and fibrosis in IL-10-/- colitis. METHODS: IL-10-/- and wild-type (WT) mice were orally treated with/without vehicle or nobiletin. Clinical symptoms of colitis and disease activity index (DAI) were assessed, and colon tissue was analysed for tissue damage, cellular infiltration, bowel wall thickness, mast cell number and degranulation, as well as collagen deposition as marker for fibrosis. Human intestinal fibroblasts (hiFB) were treated with nobiletin and the expression of collagen and pro-inflammatory cytokines was measured. RESULTS: Nobiletin treatment of IL-10-/- mice resulted in a reduction of clinical colitis symptoms and a longer survival time. In addition, histological scores of colitis were reduced compared to control groups. Mast cell number and degranulation was lower in nobiletin treated IL-10-/- mice, and correlated positively with DAI. As well, fibrotic marker of collagen deposition was reduced by nobiletin. In hiFB, the expression of collagen as well as of pro-inflammatory cytokines IL-6, TNF and CCL2 was down-regulated by nobiletin treatment. CONCLUSIONS: Nobiletin decreases inflammatory symptoms and markers in murine colitis as well as fibrotic collagen deposition and expression. Thus, nobiletin could be a potential new agent in therapy of chronic colitis. PMID- 29525888 TI - Effect of preameloblast-conditioned medium and CPNE7 on root surfaces in dogs: a histologic and histomorphometric evaluation. AB - Preameloblast-conditioned medium (PACM) has been reported as a potent dentin regenerative material, but its effects as a mixture on periodontal regeneration and the role of CPNE7 in PACM are not known. The purpose of this study is to evaluate the histologic and histomorphometric effects of preameloblast conditioned medium (PACM) and CPNE7 on periodontal tissue healing in dogs. Seventy-two mandibular premolar roots from ten dogs were extracted and randomly divided into six groups (n = 12 each): (1) positive control group; (2) negative control group; (3) cementum-removed and PACM-treated group; (4) cementum preserved and PACM-treated group; (5) CPNE7-inactivated PACM-treated group; and (6) recombinant CPNE7-treated group. The extracted roots were replanted into extraction sockets for 4 and 8 weeks and analyzed histologically. Most of the root surfaces in the negative control group showed ankylosis; and those in the experimental groups showed newly formed PDL-like and cementum-like tissues. Histomorphometric analysis of horizontal sections showed that the mean length of the PDL on the roots of the positive controls was similar to those in cementum removed or -preserved and PACM-treated group at 8 weeks (p = 1.08). Sagittal sections showed that the mean length of the new cementum on the roots in cementum removed and PACM-treated group was significantly greater than that in CPNE7 inactivated PACM-treated group (p = 0.037). The mean length of the newly formed PDL on the roots in CPNE7- inactivated PACM-treated and rCPNE7-treated groups was significantly greater than that in the negative controls at 8 weeks (p = 0.037, p = 0.036). The use of PACM and CPNE7 in tooth replantation resulted in increased PDL and cementum formation, suggesting the beneficial role of PACM and CPNE7 in periodontal tissue healing. PMID- 29525890 TI - Prospective associations of dietary carbohydrate, fat, and protein intake with beta-cell function in the CODAM study. AB - PURPOSE: Type 2 diabetes mellitus (T2DM) is characterized by both impaired pancreatic beta-cell function (BCF) and insulin resistance. In the etiology of T2DM, BCF basically determines whether a person with a certain degree of insulin resistance develops T2DM, as beta-cells are able to compensatorily increase insulin secretion. The effects of dietary intake on BCF are largely unknown. Our study aim was to investigate whether dietary macronutrient intake predicts BCF. METHODS: Prospective data (median follow-up 7 years) of 303 individuals recruited from the CODAM study population (aged 40-70 years, 39% women) were analyzed. BCF was measured by C-peptide deconvolution and physiological modeling of data from a 5-point, 75-g, 2-h oral glucose tolerance test. Macronutrient intake was estimated by a 178-item Food Frequency Questionnaire. RESULTS: Associations adjusted for relevant covariates of baseline macronutrient intake with model derived parameters describing BCF (glucose sensitivity, rate sensitivity or potentiation) or C-peptidogenic index were detected for trans fat [standardized regression coefficient (95%-CI) glucose sensitivity - 0.14 (- 0.26, - 0.01)] per g, cholesterol [potentiation 0.20 (0.02, 0.37)] per 100 mg, dietary fiber [glucose sensitivity 0.21 (0.08, 0.33)] per 10 g, MUFA glucose sensitivity 0.16 (0.02, 0.31) per 10 g, and polysaccharide [potentiation - 0.24 (- 0.43, - 0.05), C-peptidogenic index - 0.16 (- 0.29 - 0.03); odds ratio lowest versus highest tertile (95%-CI) rate sensitivity 1.51 (1.06, 2.15)) per 50 g. CONCLUSIONS: In this population at high risk for developing T2DM, polysaccharide and trans fat intake were associated with worse BCF, whereas increased intake of MUFA, dietary cholesterol, and fiber were associated with better BCF. PMID- 29525891 TI - A Review of the Role of Non-Vitamin K Oral Anticoagulants in the Acute and Long Term Treatment of Venous Thromboembolism. AB - Venous thromboembolism (VTE), which includes both deep vein thrombosis and pulmonary embolism (PE), is a very common disorder with high risk for recurrence and is associated with significant morbidity and mortality. The non-vitamin K oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, have been shown to be noninferior to conventional anticoagulant therapy for the prevention of recurrent VTE and are associated with more favorable bleeding risk. Evidence from the treatment of VTE with traditional therapy (low molecular weight heparin and vitamin K antagonists) implies that extended or indefinite treatment reduces risk of recurrence. Recently, mounting evidence suggests a role for the extended use of NOACs to reduce the risk of VTE recurrence. This review summarizes the existing evidence for the extended use of NOACs in the treatment of VTE from phase III extension studies with dabigatran, rivaroxaban, and apixaban. Additionally, it examines and discusses the major society guidelines and how these recommendations may change physician practices in the near future. PMID- 29525892 TI - When the Ends Are Really the Beginnings: Targeting Telomerase for Treatment of GBM. AB - PURPOSE OF REVIEW: High-throughput genomic sequencing has identified alterations in the gene encoding human telomerase reverse transcriptase (TERT) as points of interest for elucidating the oncogenic mechanism of multiple different cancer types, including gliomas. In gliomas, the TERT promoter mutation (TPM) and resultant overexpression of TERT are observed mainly in the most aggressive (primary glioblastoma/grade IV astrocytoma) and the least aggressive (grade II oligodendroglioma) cases. This article reviews recent research on (1) the mechanism of TERT activation in glioma, (2) downstream consequences of TERT overexpression on glioma pathogenesis, and (3) targeting TPMs as a therapeutic strategy. RECENT FINDINGS: New molecular classifications for gliomas include using TPMs, where the mutant group demonstrates the worst prognosis. Though a canonical function of TERT is established in regard to telomere maintenance, recent studies on non-canonical functions of TERT explore varied roles of telomerase in tumor progression and maintenance. Somatic alterations of the TERT promoter present a promising target for novel therapeutics development in primary glioma treatment. PMID- 29525893 TI - Children's Demonstrative Comprehension and the Role of Non-linguistic Cognitive Abilities: A Cross-Linguistic Study. AB - Previous studies have shown that young children often fail to comprehend demonstratives correctly when they are uttered by a speaker whose perspective is different from children's own, and instead tend to interpret them with respect to their own perspective (e.g., Webb and Abrahamson in J Child Lang 3(3):349-367, 1976); Clark and Sengul in J Child Lang 5(3):457-475, 1978). In the current study, we examined children's comprehension of demonstratives in English (this and that) and Mandarin Chinese (zhe and na) in order to test the hypothesis that children's non-adult-like demonstrative comprehension is related to their still developing non-linguistic cognitive abilities supporting perspective-taking, including Theory of Mind and Executive Function. Testing 3 to 6-year-old children on a set of demonstrative comprehension tasks and assessments of Theory of Mind and Executive Function, our findings revealed that children's successful demonstrative comprehension is related to their development of Theory of Mind and Executive Function, for both of the language groups. These findings suggest that the development of deictic expressions like demonstratives may be related to the development of non-linguistic cognitive abilities, regardless of the language that the children are acquiring. PMID- 29525894 TI - Surgical Correction of Pectus Excavatum by the Nuss Procedure: A 15-Year Experience Study. AB - Pectus excavatum is the most common congenital deformity of the chest. The Nuss procedure is minimally invasive surgical correction of this defect, using retrosternal metal bars. The purpose of the present study was to describe a 15 year experience with the Nuss surgery, and to evaluate the long-term clinical results of the procedure. We retrospectively evaluated 239 patients, aged 14-34, who underwent the Nuss surgery in the years 2002-2016. Postoperative complications were observed in 40/236 (16.9%) patients. The most common complication was pneumothorax in 14/239 patients. Less common were the following: wound infection in 4, pleural effusion in 3, allergy to nickel in 1, lung atelectasis in 1, and ventricular failure in 1 patient. Three patients were treated because of severe postoperative pain, and in one case the implant had to be removed. Postoperative complications associated with the number of bars inserted, but not with the patient age or gender. A satisfactory and long lasting corrective effect of surgery was observed in 231/239 (96.7%) of patients. There was no perioperative mortality. We conclude that the Nuss surgery is a safe surgery that demonstrates excellent and long-lasting esthetic results, with a low risk of severe complications. PMID- 29525895 TI - The Enduring Influence of a Dangerous Narrative: How Scientists Can Mitigate the Frankenstein Myth. AB - Reflecting the dangers of irresponsible science and technology, Mary Shelley's Frankenstein quickly became a mythic story that still feels fresh and relevant in the twenty-first century. The unique framework of the Frankenstein myth has permeated the public discourse about science and knowledge, creating various misconceptions around and negative expectations for scientists and for scientific enterprises more generally. Using the Frankenstein myth as an imaginative tool, we interviewed twelve scientists to explore how this science narrative shapes their views and perceptions of science. Our results yielded two main conclusions. First, the Frankenstein myth may help scientists identify popular concerns about their work and offer a framework for constructing a more positive narrative. Second, finding optimistic science narratives may allow scientists to build a better relationship with the public. We argue that by showing the ethical principles and social dimensions of their work, scientists could replace a negative Frankenstein narrative with a more optimistic one. PMID- 29525896 TI - Radiation dose rates of differentiated thyroid cancer patients after 131I therapy. AB - Postoperative 131I treatment for differentiated thyroid cancer (DTC) can create a radiation hazard for nearby persons. The present prospective study aimed to investigate radiation dose rates in 131I-treated DTC patients to provide references for radiation protection. A total of 141 131I-treated DTC patients were enrolled, and grouped into a singular treatment (ST) group and a repeated treatment (RT) group. The radiation dose rate of 131I-treated patients was measured. The rate of achieving discharge compliance and restricted contact time were analyzed based on Chinese regulations. Multivariate logistic regression analysis was used to analyze the independent factors associated with the clearance of radioiodine. The rate of achieving discharge compliance (131I retention < 400 MBq) was 79.8 and 93.7% at day 2 (D2) for the ST and RT groups, respectively, and reached 100% at D7 and D4, respectively. The restricted contact time with 131I-treated patients at 0.5 m for medical staff, caregivers, family members, and the general public ranged from 4 to 7 days. Multivariate logistic regression analysis showed that the 24-h iodine uptake rate was the only significant factor associated with radioiodine clearance. For the radiation safety of 131I-treated DTC patients, the present results can provide radiometric data for radiation protection. PMID- 29525897 TI - Unmet supportive care needs of haematological cancer survivors: rural versus urban residents. AB - Due to fewer cancer services in rural locations, rural survivors may have unique unmet needs compared to urban survivors. This study compared among rural and urban haematological cancer survivors the most common "high/very high" unmet supportive care needs and the unmet need scores for five domains (information, financial concerns, access and continuity of care, relationships and emotional health). Survivors' socio-demographics, rurality, cancer history and psychological factors associated with each unmet need domain were also explored. A total of 1511 haematological cancer survivors were recruited from five Australian state cancer registries and 1417 (1145 urban, 272 rural) allowed extraction of their residential postcode from registry records. A questionnaire that contained the Survivor Unmet Needs Survey was mailed to survivors. Dealing with feeling tired was the most common "high/very high" unmet need for rural (15.2%) and urban (15.5%) survivors. The emotional health domain had the highest mean unmet need score for rural and urban survivors. Rurality was associated with a decreased unmet emotional health domain score whereas travelling for more than 1 h to treatment was associated with increased unmet financial concerns and unmet access and continuity of care. Depression, anxiety and stress were associated with increased unmet need scores for all five domains. Unmet need domain scores generally did not differ by rurality. Travelling for more than 1 h to treatment was associated with increased unmet need scores on two domains. Telemedicine and increased financial assistance with travel and accommodation may help those travelling long distances for treatment. PMID- 29525898 TI - Transition of Children with Neurological Disorders. AB - PURPOSE OF THE REVIEW: The goal of the article is to describe a systematic approach through core principles and steps for the transition of the patient with a neurological disorder to the adult model of care, to provide steps and principles to help receiving providers successfully integrate the patient into their practice, and to discuss cultural, systemic, and discipline-based barriers to transition. RECENT FINDING: The literature has expanded rapidly. The recent publications help define the barriers to the process and are currently exploring the best methods to evaluate readiness, needs, barriers, and develop solutions for best practices. There is a consensus that there is a need for a systematic approach to transition and integration of the patient with a neurological disorder. The transition of the child and youth with special health care needs (CYSHCN) is complex with multiple barriers. An important concept is that these patients, their families, and medical care providers all benefit from a coordinated and collaborative methodology. PMID- 29525899 TI - Preventing Smoking Progression in Young Adults: the Concept of Prevescalation. AB - As adolescents cross the threshold to young adulthood, they encounter more opportunities to engage in or accelerate previously discouraged or prohibited behaviors. Young adults, therefore, are more apt to initiate cigarette smoking and, more importantly, to accelerate their use if they tried and experimented as an adolescent. Preventing the escalation and entrenchment of smoking in the young adult years is critically important to reducing tobacco's long-term health toll. However, traditional interventions for youth have focused on preventing smoking initiation, and interventions for adults have focused on smoking cessation; both have failed to address the needs of young adults. We introduce the concept of "prevescalation" to capture the need and opportunity to prevent the escalation of risk behaviors that typically occur during young adulthood, with a focus on the example of cigarette smoking. Prevescalation negates the notion that prevention has failed if tobacco experimentation occurs during adolescence and focuses on understanding and interrupting transitions between experimentation with tobacco products and established tobacco use that largely occur during young adulthood. However, since risk behaviors often co-occur in young people, the core concept of prevescalation may apply to other behaviors that co-occur and become harder to change in later adulthood. We present a new framework for conceptualizing, developing, and evaluating interventions that better fit the unique behavioral, psychosocial, and socio-environmental characteristics of the young adult years. We discuss the need to target this transitional phase, what we know about behavioral pathways and predictors of cigarette smoking, potential intervention considerations, and research challenges. PMID- 29525900 TI - Medical cyber-physical systems: A survey. AB - Medical cyber-physical systems (MCPS) are healthcare critical integration of a network of medical devices. These systems are progressively used in hospitals to achieve a continuous high-quality healthcare. The MCPS design faces numerous challenges, including inoperability, security/privacy, and high assurance in the system software. In the current work, the infrastructure of the cyber-physical systems (CPS) are reviewed and discussed. This article enriched the researches of the networked Medical Device (MD) systems to increase the efficiency and safety of the healthcare. It also can assist the specialists of medical device to overcome crucial issues related to medical devices, and the challenges facing the design of the medical device's network. The concept of the social networking and its security along with the concept of the wireless sensor networks (WSNs) are addressed. Afterward, the CPS systems and platforms have been established, where more focus was directed toward CPS-based healthcare. The big data framework of CPSs is also included. PMID- 29525901 TI - Perianal minimally invasive surgery (PAMIS) for rectal stump resection after previous colectomy. AB - PURPOSE: Resection of a long rectal stump after previous colectomy or Hartmann procedure often requires a combined transperitoneal and transperineal approach because of limited access through a perineal incision alone. Risks associated with this procedure include iatrogenic injury to bowels, nerves, ureters, vessels and sexual organs. This study reports on the feasibility and safety of perianal minimally invasive surgery (PAMIS) for the resection of long rectal stumps that would otherwise require a combined transperitoneal and perianal approach. METHODS: PAMIS utilizes standard laparoscopic equipment and a single access port to dissect the rectal stump following the mesorectal fascia into the pelvis after excision of the anal canal. Three PAMIS procedures were performed between February and April 2016. Feasibility, safety and outcome were analysed. RESULTS: Three patients with previous colectomy and ostomy creation due to colitis ulcerosa (n = 2) and idiopathic enteropathy (n = 1) underwent PAMIS. The rectal stump length ranged between 10 and 19 cm. The median postoperative length of stay was 9 (range 6 to 11) days and the median operating time was 90 (range 80 to 120) min. There were no perioperative complications. CONCLUSION: PAMIS is a feasible, safe and efficient procedure for rectal stump resection avoiding the transperitoneal approach for pelvic dissection. PMID- 29525902 TI - Quality of life after laparoscopic sigmoid resection for uncomplicated diverticular disease. AB - PURPOSE: The study aimed to evaluate the QoL in patients who underwent elective surgery for uncomplicated diverticulitis using a recently developed diverticulitis quality of life questionnaire (DV-QoL). METHODS: All consecutive patients who underwent surgery for uncomplicated diverticulitis or who were hospitalized and treated conservatively for acute uncomplicated diverticulitis episodes in three referral centers, in a 5-year period, were included in the study. The 36-Item Short Form Survey and the DV-QoL were administered to the patients to assess their QoL before and after treatment of diverticular disease. RESULTS: Ninety-seven patients who underwent surgery, 44 patients who were treated conservatively, and 44 healthy volunteers were included in the study. DV QoL scores correlated with SF-36 scores (p < 0.0001). The surgically treated patients reported a worse quality of life before treatment with respect to the patients treated conservatively (mean 21.12 surgical vs 15.41 conservative, p = 0.0048). The surgically treated patients presented better post-treatment global scores with respect to the conservatively treated patients (mean: 6.90 surgical vs 10.61 conservative, p = 0.0186). Covariance analysis confirmed that the differences between the pre- and post-treatment DV-QoL scores were significantly higher in the surgical (p = 0.0002) with respect to the non-surgical patients. As far as single items were concerned, differences between the two groups were found in the pre- and post-treatment "concerns" and "behavioral changes" DV-QoL items. CONCLUSIONS: Sigmoidectomy reduces concerns about diverticulitis and behavioral changes due to the disease. Quality of life should be considered when referring patients with uncomplicated diverticulitis to surgery. Prospective studies are required to confirm this result. PMID- 29525904 TI - Decompression retinochoroidopathy: a unique presentation post-trabeculectomy. AB - PURPOSE: To present a unique case of decompression retinochoroidopathy presenting with intraretinal, subretinal and preretinal hemorrhages. METHODS: A 65-year-old hypertensive female presented with diminution of vision in right eye of 1-week duration. She had been a known case of primary open-angle glaucoma and had undergone trabeculectomy with mitomycin C in right eye 1 week back. Her day 1 postoperative intraocular pressure was 6 mmHg. Her left eye had undergone Ahmed glaucoma valve surgery for the same 2 years back. RESULT: Right eye vision at 1 week of presentation was 6/36, N36 and left eye hand movements. Both eyes were pseudophakic. Intraocular pressure in right eye was 35 mmHg with nonfunctional bleb and in left eye 15 mmHg. Right eye fundus shows multiple subretinal, intraretinal, preretinal and some white-centered blot hemorrhage in all the four quadrants including the posterior pole. Disk had glaucomatous cupping with no dilatation or tortuosity of retinal blood vessels. Left eye had total glaucomatous optic atrophy. CONCLUSION: Old hypertensive females may not tolerate hemodynamic changes in retinal and choroidal vasculature so well, and if the autoregulation of retinal capillaries and choriocapillaris fails because of IOP spikes or rise of IOP to high levels in a relatively short duration, sudden lowering of IOP after trabeculectomy may cause decompression retinopathy and choroidopathy. PMID- 29525903 TI - Intraoperative Completion Angiogram May Be Superior to Transesophageal Echocardiogram for Detection of Pulmonary Artery Residual Lesions in Congenital Heart Surgery. AB - The purpose of this study was to assess the diagnostic capabilities of transesophageal echocardiography (TEE) compared to completion angiography for detection of residual post-operative pulmonary artery lesions. This is a retrospective review of 19 consecutive surgical cases involving the pulmonary arteries that had post-operative TEE and completion angiography from 2014 to 2017. The echocardiograms were reviewed by 2 blinded examiners and categorized as adequate or inadequate visualization of the surgical repair. Based on TEE images, the surgical repair was graded as no revision necessary, residual lesion present requiring revision, or unable to assess. TEE was compared to completion angiography to determine the ability of each method to detect residual pulmonary artery lesions. Fifty-three percent of TEE imaging was graded as inadequate. Based on TEE, surgical revision was indicated in 2 of 19 cases. Completion angiography documented 4 additional residual lesions resulting in surgical revision in 6 of 19 patients. TEE sensitivity for detecting residual pulmonary artery lesions was 40%. One Glenn patient with adequate image quality and repair by TEE had moderate left pulmonary artery stenosis by completion angiography. All other discrepancies occurred in patients with inadequate TEE imaging. No patient with pulmonary artery abnormalities had hemodynamic instability or excessive desaturations. Completion angiography-related complications included three transient arrhythmias with no increased incidence of acute kidney injury. Completion angiography may be more effective than TEE at detecting post-operative pulmonary artery lesions even in patients not manifesting clinical symptoms. Documentation of residual lesions with completion angiography allows immediate surgical revision potentially limiting necessity for future interventions. PMID- 29525905 TI - Interactions among competing nematode species affect population growth rates. AB - Investigations of the interplay of organisms in an ecological community are a prerequisite to understanding the processes that shape the structures of those communities. Among several types of interactions, interest in the positive interactions of species that compete for the same resource has grown, as they may provide a mechanism enabling coexistence. In the laboratory experiment described herein, the effects of interspecific interaction on the population growth of two bacterial-feeding nematode species, Panagrolaimus cf. thienemanni and Poikilolaimus cf. regenfussi, were investigated. Specifically, we asked: (1) whether there is an interspecific interaction between organisms competing for a mutual resource and (2) whether these interactions are altered by the competitors' initial densities and (3) their variable growth rates (induced by different food supplies). Each treatment initially contained 48 nematode individuals, but at different species ratios (48:0; 32:16; 24:24; 16:32; 0:48). The populations were provided with three different bacterial densities (108, 109, and 1010 cells ml-1) as food. The data were analyzed using a generalized linear mixed model. The best-fitting model revealed a significant decline in population growth rates with an increasing species ratio, but depending on the food density and species. These results provide strong evidence for positive interspecific interactions that vary with both species density and food-supply level. They also suggest important roles for positive interspecific interactions in habitat colonization and in maintaining the coexistence of species in the same trophic group. PMID- 29525907 TI - Autologous platelet-rich plasma and triamcinolone acetonide intralesional injection in the treatment of oral erosions of pemphigus vulgaris: a pilot study. AB - Oral erosions of pemphigus vulgaris (PV) represent a therapeutic challenge. In this work we compared intralesional injection of steroids (ILS) and autologous platelet-rich plasma (PRP) treatment of oral erosions of PV. In this split-mouth randomized double blind study, one side of the buccal mucosa of 11 PV patients was injected with 10 mg/ml triamcinolone and the opposite side was injected with 1 millilitre of autologous PRP every 14 days for 3 months. The percentage of clinical improvement, pemphigus disease area index and pain score were recorded before and after therapy. Out of 11 recruited patients, only 9 completed the study. Seven out of the nine patients (78%) showed improvement in PDAI and/or pain score. The mean oral PDAI of the steroid injected sides decreased from 2.3 to 0.9. The mean oral PDAI of the PRP injected sides decreased from 2.6 to 1.0. No significant difference was detected in clinical improvement, PDAI and pain score between autologous PRP and ILS in the treatment of oral erosions of PV. Autologous PRP can be used for the treatment of resistant oral erosions of PV when ILS is contraindicated. PMID- 29525908 TI - Treating Type 1 Diabetes Mellitus with a Rapid-Acting Analog Insulin Regimen vs. Regular Human Insulin in Germany: A Long-Term Cost-Effectiveness Evaluation. AB - OBJECTIVE: The aim of the present study was to evaluate the cost effectiveness of rapid-acting analog insulin relative to regular human insulin in adults with type 1 diabetes mellitus in Germany. METHODS: The PRIME Diabetes Model, a patient level, discrete event simulation model, was used to project long-term clinical and cost outcomes for patients with type 1 diabetes from the perspective of a German healthcare payer. Simulated patients had a mean age of 21.5 years, duration of diabetes of 8.6 years, and baseline glycosylated hemoglobin of 7.39%. Regular human insulin and rapid-acting analog insulin regimens reduced glycosylated hemoglobin by 0.312 and 0.402%, respectively. Compared with human insulin, hypoglycemia rate ratios with rapid-acting analog insulin were 0.51 (non severe nocturnal) and 0.80 (severe). No differences in non-severe diurnal hypoglycemia were modeled. Discount rates of 3% were applied to future costs and clinical benefits accrued over the 50-year time horizon. RESULTS: In the base case analysis, rapid-acting analog insulin was associated with an improvement in quality-adjusted life expectancy of 1.01 quality-adjusted life-years per patient (12.54 vs. 11.53 quality-adjusted life-years). Rapid-acting analog insulin was also associated with an increase in direct costs of ?4490, resulting in an incremental cost-effectiveness ratio of ?4427 per quality-adjusted life-year gained vs. human insulin. Sensitivity analyses showed that the base case was driven predominantly by differences in hypoglycemia; abolishing these differences reduced incremental quality-adjusted life expectancy to 0.07 quality-adjusted life-years, yielding an incremental cost-effectiveness ratio of ?74,622 per quality-adjusted life-year gained. CONCLUSIONS: Rapid-acting analog insulin is associated with beneficial outcomes in patients with type 1 diabetes and is likely to be considered cost effective in the German setting vs. regular human insulin. PMID- 29525906 TI - Mild Cognitive Impairment in Parkinson's Disease-What Is It? AB - PURPOSE OF REVIEW: Mild cognitive impairment is a common feature of Parkinson's disease, even at the earliest disease stages, but there is variation in the nature and severity of cognitive involvement and in the risk of conversion to Parkinson's disease dementia. This review aims to summarise current understanding of mild cognitive impairment in Parkinson's disease. We consider the presentation, rate of conversion to dementia, underlying pathophysiology and potential biomarkers of mild cognitive impairment in Parkinson's disease. Finally, we discuss challenges and controversies of mild cognitive impairment in Parkinson's disease. RECENT FINDINGS: Large-scale longitudinal studies have shown that cognitive involvement is important and common in Parkinson's disease and can present early in the disease course. Recent criteria for mild cognitive impairment in Parkinson's provide the basis for further study of cognitive decline and for the progression of different cognitive phenotypes and risk of conversion to dementia. Improved understanding of the underlying pathology and progression of cognitive change are likely to lead to opportunities for early intervention for this important aspect of Parkinson's disease. PMID- 29525909 TI - Prenatal care and socioeconomic status: effect on cesarean delivery. AB - Cesarean deliveries are widely used in many high- and middle-income countries. This overuse both increases costs and lowers quality of care and is thus a major concern in the healthcare industry. The study first examines the impact of prenatal care utilization on cesarean delivery rates. It then determines whether socioeconomic status affects the use of prenatal care and thereby influences the cesarean delivery decision. Using exclusive French delivery data over the 2008 2014 period, with multilevel logit models, and controlling for relevant patient and hospital characteristics, we show that women who do not participate in prenatal education have an increased probability of a cesarean delivery compared to those who do. The study further indicates that attendance at prenatal education varies according to socioeconomic status. Low socioeconomic women are more likely to have cesarean deliveries and less likely to participate in prenatal education. This result emphasizes the importance of focusing on pregnancy health education, particularly for low-income women, as a potential way to limit unnecessary cesarean deliveries. Future studies would ideally investigate the effect of interventions promoting such as care participation on cesarean delivery rates. PMID- 29525911 TI - Management of a posterior gunshot injury with a floating pedicle and cerebrospinal fluid leak. AB - PURPOSE: Gunshot injury to the spine can be devastating, and it has increased in the civilian population during the last decade. METHODS: We present the case of a 30-year-old male, who received a bullet in his back after exchange of fire with the police. Initial assessment revealed paraparesis with cerebrospinal fluid leak (CSF) from the bullet entry hole, CT scan showed metal debris with two bullet fragments in the L5/S1 right foramen and lateral recess, and another fragment in the central canal posteriorly, and also it revealed two fracture lines creating a right L5 "floating pedicle". RESULTS: The patient was taken to the operating room and underwent L5/S1 posterior approach with right L5 pedicle stabilization with a pedicle screw, removal of the bullet fragments, dural repair with a patch, L5/S1 posterolateral fusion, and insertion of a lumbar CSF drain. The patient could walk with a walking frame on day 7 with a satisfactory radiological result at 1 year but with a remaining partial motor deficit of both ankles, mainly on the right side. CONCLUSION: Literature contains a lot of controversies regarding the management of spinal gunshot injuries. The current case shows that early surgical management, when partial neurological deficit with a CSF leak is noted, could improve the clinical outcome and prevent related complications. PMID- 29525912 TI - Dialytic interval and the timing of electrocardiographic screening for subcutaneous cardioverter-defibrillator placement in chronic hemodialysis patients. AB - BACKGROUND: Hemodialysis (HD) patients have a high risk of sudden death but limited vascular access and high complication rates from transvenous implantable cardioverter-defibrillators (ICDs). Subcutaneous ICDs (S-ICD) may be an alternative, but dynamic ECG changes may result in inappropriate shocks. This study aims to define the screen failure rate for S-ICD in patients pre- and post HD. METHODS: ECG waveforms were obtained using electrodes mimicking the S-ICD sensing vectors in an unselected test group of chronic HD patients and a control group of ICD-eligible non-dialysis patients. Participants passed screening if their QRS and T-waves fit within the screening template in supine and standing positions in any lead. Test group participants were screened before and after HD and control group patients were screened at two separate time points. HD patients were stratified into the four following groups: (A) passed screening before and after HD, (B) failed screening before but passed after HD, (C) passed screening before but failed after HD, and (D) failed screening before and after HD. Patients in group A passed the screening for ICD implantation, and patients in groups B, C, and D failed the screening for ICD implantation. Control patients were similarly classified by pass/fail status at the two assessment points. RESULTS: Of the 76 patients enrolled, 51 were HD patients and 25 were controls. Of the 51 HD patients, 43 (84%) were in group A, four participants (8%) were in group B, one (2%) was in group C, and three participants (6%) were in group D. There were no differences in any of the clinical or demographic variables between the pass and fail test HD groups. None of the 25 controls failed the screening at either time point (p = 0.047 vs HD patients). CONCLUSIONS: Overall, HD patients were more likely to fail S-ICD screening compared to non-HD patients (16 v 0%, p = 0.047) and are more likely to do so prior to HD. Patients on HD should be screened at multiple time points around the dialytic interval to reduce the risk of inappropriate shocks. PMID- 29525910 TI - Insights into the Mechanisms That May Clarify Obesity as a Risk Factor for Multiple Sclerosis. AB - PURPOSE OF REVIEW: The proportion to which genetic and environmental factors contribute to the etiology of multiple sclerosis (MS) is still incompletely understood. An interesting association between MS etiology and obesity has recently been shown although the mechanisms underlying this association are still unknown. We propose deregulated gut microbiota and increased leptin levels as possible mechanisms underlying MS etiology in obese individuals. RECENT FINDINGS: Alterations in the human gut microbiota and leptin levels have recently been established as immune modulators in both MS patients and obese individuals. A resemblance between pro-inflammatory bacterial profiles in MS and obese individuals was observed. Furthermore, elevated leptin levels push the immune system towards a more pro-inflammatory state and inhibit the regulatory immune response. Deregulated gut microbiota and elevated leptin levels may explain the increased risk of developing MS in obese individuals. Further research to confirm causality is warranted. PMID- 29525913 TI - Percutaneous Left Atrial Appendage Closure with WATCHMANTM device: peri procedural and mid-term outcomes from the TRAPS Registry. AB - PURPOSE: The WATCHMAN device for Left Atrial Appendage Occlusion (LAAO) has proven to be an effective alternative to oral anticoagulation (OAC) in patients with atrial fibrillation (AF), and has now been adopted in clinical practice. In the present study, we analyzed the safety and efficacy profile of the LAAO procedure at mid-term follow-up. METHODS: The TRAPS Registry is an observational, multicenter registry involving four Italian centers. Consecutive patients who had undergone LAAO with WATCHMAN device were enrolled. Clinical, demographic, and procedural data were collected at the time of implantation, and follow-up data were collected to assess the clinical outcome. RESULTS: A total of 151 patients were included in the Registry from May 2012 to October 2015. Implantation of the device was successful in 150/151 patients, with no or minimal (< 5 mm) leakage as assessed by peri-procedural transesophageal echo. In the remaining patient, early device embolization was reported, with no sequelae. Overall, intra-procedural events were reported in 5 (3.3%) patients. During a median follow-up of 16 months (25th and 75th percentile, 10-25), 5 patients died of any cause. The annual rate of all-cause stroke was 2.2% (95% CI, 0.7-5.1), the rate of transient ischemic attack was 1.3% (95% CI, 0.3-3.8), and that of major bleeding 0.4% (95% CI, 0.01 2.4). CONCLUSIONS: LAAO for stroke prevention was safely and effectively achieved by implantation of the WATCHMAN device in patients with non-valvular AF. Moreover, regardless of the risk profile of the population, we observed low rates of death and thromboembolic and bleeding events over a median follow-up of 16 months. These findings were obtained in an unselected group of consecutive patients who were variably eligible for chronic OAC therapy. PMID- 29525915 TI - Depression During Pregnancy and Its Association with Birth Outcomes. PMID- 29525914 TI - Re-admissions treble the risk of late mortality after primary total hip arthroplasty. AB - BACKGROUND: Following a total hip arthroplasty (THA), early hospital re-admission rates of 3-11% are considered as 'acceptable' in terms of medical care cost policies. Surprisingly, the impact of re-admissions on mortality has not been priorly portrayed. Therefore, we sought to determine the mortality rate after 90 day re-admissions following a THA in a series of patients from a captive medical care program. PATIENTS AND METHODS: We prospectively analysed 90-day readmissions of 815 unilateral, elective THA patients operated upon between 2010 and 2014 whose medical care was the one offered by our institution. We stratified our sample into readmitted and non-readmitted cohorts. Through a Cox proportional hazards model, we compared demographic characteristics, clinical comorbidities, surgical outcomes and laboratory values between both groups in order to determine association with early and late mortality. RESULTS: We found 37 (4.53%) re admissions at a median time of 40.44 days (IQR 17.46-60.69). Factors associated with re-admission were hospital stay (p = 0.00); surgical time (p = 0.01); chronic renal insufficiency (p = 0.03); ASA class 4 (p = 0.00); morbid obesity (p = 0.006); diabetes (p = 0.04) and a high Charlson index (p = 0.00). Overall mortality rate of the series was 3.31% (27/815). Median time to mortality was 455.5 days (IQR 297.58-1170.65). One-third (11/37) of the re-admitted patients died, being sepsis non-related to the THA the most common cause of death. After adjusting for confounders, 90-day re-admissions remained associated with mortality with an adjusted HR of 3.14 (CI95% 1.05-9.36, p = 0.04). CONCLUSIONS: Unplanned re-admissions were an independent risk factor for future mortality, increasing three times the risk of mortality. PMID- 29525916 TI - Transformation of a Pediatric Primary Care Waiting Room: Creating a Bridge to Community Resources. AB - Introduction Children and families living in poverty frequently encounter social risks that significantly affect their health and well-being. Physicians' near universal access to at-risk children and their parents presents opportunities to address social risks, but time constraints frequently interfere. We sought to redesign our waiting room to create a clinic-to-community bridge and evaluate the impact of that redesign on family-centered outcomes. Methods We conducted a pre post study of a waiting room redesign at a large, academic pediatric primary care center. Design experts sought input about an optimal waiting room from families, community partners and medical providers. Family caregivers were surveyed before and after redesign regarding perceived availability of help with social needs and access to community resources, and hospitality and feelings of stress. Pre-post differences were assessed using the Chi square or Wilcoxon rank sum test. Results The key redesign concepts that emerged included linkages to community organizations, a welcoming environment, and positive distractions for children. A total of 313 caregiver surveys were completed (pre-160; post-153). Compared to pre-redesign, caregivers surveyed post-redesign were significantly more likely to perceive the waiting room as a place to obtain help connecting to community resources and find information about clinical and educational resources (both p < 0.05). Families were also significantly more likely to report the waiting room as more welcoming and relaxing, with sufficient privacy and space (all p < 0.05). Discussion Waiting rooms, typically a place of wasted time and space, can be redesigned to enhance families' engagement and connection to community resources. PMID- 29525917 TI - Domestic horses (Equus ferus caballus) fail to intuitively reason about object properties like solidity and weight. AB - From early infancy, humans reason about the external world in terms of identifiable, solid, cohesive objects persisting in space and time. This is one of the most fundamental human skills, which may be part of our innate conception of object properties. Although object permanence has been extensively studied across a variety of taxa, little is known about how non-human animals reason about other object properties. In this study, we therefore tested how domestic horses (Equus ferus caballus) intuitively reason about object properties like solidity and height, to locate hidden food. Horses were allowed to look for a food reward behind two opaque screens, only one of which had either the proper height or inclination to hide food rewards. Our results suggest that horses could not intuitively reason about physical object properties, but rather learned to select the screen with the proper height or inclination from the second set of 5 trials. PMID- 29525918 TI - Spectrum of concepts associated with the term "biodiversity": a case study in a biodiversity hotspot in South America. AB - In most conservation programs that include public participation, the word "biodiversity" is used. However, many variables influence the public understanding of the term and determine what biodiversity means to local stakeholders. Those representations of the concept must be addressed and included in conservation actions. We asked 47 local stakeholders in a biosphere reserve (BR) located in a biodiversity hotspot in South America, for whom the conservation of biodiversity is not the main focus of interest, to explain how they understand the term "biodiversity." Twenty-two different definitions were provided, ranging from purely ecological concepts to the human dimension. Although the diversity of animals and plants was the most frequently mentioned concept, the variety of concepts that emerged suggested that more explicit examples of social constructions must be considered in public participatory projects and environmental education programs. Actors living in a close relationship with nature provide a greater diversity of elements in defining biodiversity, visualizing ecological but also instrumental values. PMID- 29525919 TI - Investigating the nutritional value of foods targeting children. AB - PURPOSE: This study aimed to investigate the nutritional values of some low nutrition packaged foods widely sold in supermarkets and encouraged for consumption. METHODS: The study used 435 packaged foods from six hypermarkets with high sale capacities in Ankara to analyze their contents of energy/total fat/saturated fat/carbohydrate/sugar/salt based on label information. RESULTS: Among the products in the scope of the study, the highest values were found in chocolates for fat (33.0 +/- 4.28/100 g) and sugar (45.6 +/- 5.95/100 g), wafers for saturated fat (19.2 +/- 3.89/100 g), and crackers for sodium (0.9 +/- 0.23/100 g). Among the 435 packaged foods investigated in the study, the products exceeded the limits designated in the health codes declared by the Turkish Food Codex Labeling Directive in 83.4% of the instances in terms of sugar, 93.7% of the instances in terms of total fat, 92.4% of the instances in terms of saturated fat, and 70.3% of the instances in terms of sodium. CONCLUSION: Energy/fat/sugar/salt contents were high in the packaged products that are especially targeted for children for higher consumption. Children's frequent and excessive consumption of these products contribute to the prevalence of childhood obesity and increase in related health risks. LEVEL OF EVIDENCE: Level V, descriptive study. PMID- 29525920 TI - Lack of association between FTO gene variations and metabolic healthy obese (MHO) phenotype: Tehran Cardio-metabolic Genetic Study (TCGS). AB - BACKGROUND: Obesity is currently an international epidemic and metabolic derangements pose these individuals at greater risk for future morbidity and mortality. Genetics and environmental factors have undeniable effects and among genetic risk factors, FTO/CETP genes are important. The current study examines the interaction between obesity phenotypes and FTO/CETP SNPs and their effects on lipid profile changes. MATERIALS AND METHODS: We selected 954 adult subjects from TCGS (47.9% male). Participants were stratified according to their BMI and presence of metabolic syndrome according to the Joint Interim Statement (JIS) definition. Nine selected polymorphisms from FTO/CETP genes were genotyped using Tetra ARMS-PCR method. After age and sex adjustment the interaction of 9 markers with lipid profiles among phenotypes were tested by PASW. RESULTS: In three main groups, HDL_C level had a strong significant association with CETP markers: (rs3764261, beta(95% CI) - 0.48(- 0.61 to - 0.35), P = 1.0 * 10-11), (rs1800775, beta(95% CI) 0.5(0.36;0.65), P = 1.0 * 10-6) and (rs1864163, beta(95% CI) 0.3(0.16;0.43), P = 9.1 * 10-5). This association was also seen in rs7202116 within the total population. In only unhealthy metabolic obese (MUHO) subgroups four new FTO markers (rs1421085, rs1121980, rs1558902 and rs8050136) (P value < 0.01) demonstrated significant association, even after lipid profile adjustment. CONCLUSION: In the present study, we investigated the association between obesity phenotypes and some variations in FTO/CETP genes for the first time. Our study showed that four markers in the first intron of the FTO gene should be the risk marker in MUHO participants. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 29525921 TI - Shaping ability of rotary or reciprocating systems for oval root canal preparation: a micro-computed tomography study. AB - OBJECTIVES: To evaluate the shaping ability and cleaning after oval root canal preparation using one or more instruments in reciprocating or rotary motion. MATERIALS AND METHODS: Oval-shaped mandibular incisors were selected, based on the radiographic diameter (2 <= diameter ratio <= 4), and assigned according to root canal preparation (n = 18): single-file (Reciproc R40); two reciprocating files (Unicone size 20 and 40, .06 taper) or Mtwo rotary files until a size 40, .06 taper instrument. Root canal preparations were performed using an open root canal model. Scanning was performed before and after preparation using SkyScan 1176 with a voxel size of 17.42 MUm. Volume, percentage of debris, and percentage of uninstrumented surface were analyzed in the entire root canal and in each root canal third. Data were compared using ANOVA and Tukey or Kruskal-Wallis and Dunn tests (alpha = 5%). RESULTS: The initial volume were similar among the groups (p > .05). Unicone preparation was associated with higher debris, increase in root canal volume and uninstrumented surface in entire root canal and in the middle third (P < .05). Mtwo was associated with lower uninstrumented surface in the entire root canal and in the cervical third. The apical third were similar for the three preparations. CONCLUSIONS: Unicone system using two instruments in reciprocating motion resulted in higher increase in volume. However, less remaining debris was observed when Reciproc single-file and Mtwo rotary systems were used. CLINICAL RELEVANCE: A preparation that volumetrically increases the root canal is not necessarily associated with better cleaning. Shaping and hard tissue debris removal depends on root canal anatomy, kinematics, number of instruments, and instrument design. PMID- 29525922 TI - Resorptive potential of impacted mandibular third molars: 3D simulation by finite element analysis. AB - OBJECTIVES: Previous studies have suggested a relationship between resorption in second molars and pressure from the eruptive force of the third molar. The aim of this study was to simulate functional forces in a mandible model by means of finite element analysis and then assess the biomechanical response produced by impacted third molars on the roots of the second molar. MATERIALS AND METHODS: A cone beam computed tomography scan presenting an impacted mandibular third molar was segmented (Mimics V17 software). The modeling process was performed using the reverse engineering technique provided by the Rhinoceros 3D 5.0 software. The third molar position was changed in order to produce different inclinations of the impacted tooth. Bite forces were simulated to evaluate total deformation, the equivalent von Mises stress, minimum principal stress on hard tissue, and equivalent elastic strain on soft tissue. RESULTS: Areas of high energy dissipation and compression stress were detected in the second molar root, independently of the inclination of the impacted third molar. In general, the horizontal position was the situation in which major stress and the amount of deformation occurred in the second and third molar regions. CONCLUSION: Impacted third molars in close proximity with the adjacent tooth can generate areas of compression concentrated at the site of contact, which suggests an involvement of mechanical factors in the triggering of resorption lesions. CLINICAL RELEVANCE: The results of these computational experiments contribute to the understanding of the triggering and progression of resorptive lesions in the adjacent second molar. PMID- 29525923 TI - Single tooth anesthesia versus conventional anesthesia: a cross-over study. AB - OBJECTIVES: The aim of the present study was to compare an electronic device, the Wand Injection System (Milestone Scientific Livingstone), with conventional anesthesia in terms of the following: pain sensation during anesthetic injection; effectiveness in achieving adequate anesthesia for a complete painless dental treatment; post-operative discomfort; and patient's anxiety toward dental treatment. MATERIALS AND METHODS: Eighty adults from 18 to 70 years were enrolled in this cross-over study. Each patient served as his/her own control being subject to two anesthesia techniques: conventional and Single Tooth Anesthesia (STA) performed with the Wand. A split-mouth design was adopted in which each tooth undergoing conservative restorative or endodontic treatment received anesthesia with both techniques at 1-week interval. Before anesthetic administration, the patients' anxiety levels were determined. Physiological parameteres were measured before, during, and after the two injection procedures, and the Visual Analogue Scale (VAS) was used to assess pain of injection, discomfort, and anesthetic efficacy. Differences in assessment of pain's injection, discomfort, anesthetic efficacy, vital parameters (heart rate, blood pressure, and oxygen saturation), and state anxiety levels were analyzed using Student's t test (p value < 0.001). RESULTS: The mean injection pain and post operative discomfort ratings with Wand were lower than those with conventional syringe (p = 0.022 and p < 0.001, respectively). No differences were found in the assessment of anesthetic efficacy. Blood pressure and heart rate mean values were lower during the anesthesia performed with the Wand than with the conventional syringe (p < 0.001). The anxiety level was higher during the first appointment, independently from the device used for the injections. CONCLUSION: The STA technique resulted in lower pain, discomfort, and lower intensity of physiological parameters. CLINICAL RELEVANCE: Single Tooth Anesthesia could be an efficacious alternative to conventional procedures. PMID- 29525925 TI - Outcomes of autotransplanted teeth and prognostic factors: a 10-year retrospective study. AB - OBJECTIVES: This retrospective study aimed to investigate the clinical outcome of tooth autotransplantation and related prognostic factors. MATERIALS AND METHODS: Eighty-two cases of transplanted teeth from March 2006 to December 2016 were retrospectively investigated by medical records and radiographs. The clinical outcomes of transplanted teeth, which included tooth survival, inflammatory root resorption (IRR), ankylosis, and marginal bone loss (MBL), and the related prognostic factors were assessed via survival analysis. RESULTS: The cumulative survival rate of transplanted teeth was 74% at 10 years after autotransplantation. According to Cox proportional hazards regression analysis, the eruption state of the donor tooth, recipient position, and postoperative MBL were significantly related to tooth survival. The donor tooth position was significantly associated with IRR, the recipient position and the timing of orthodontic initiation with ankylosis, and the recipient position with MBL. CONCLUSIONS: Fully erupted donor teeth and a bounded recipient site were significantly associated with longer tooth survival. Periodontal healing and management to prevent postoperative MBL were as important for successful autotransplantation. CLINICAL RELEVANCE: Knowledge about the prognostic factors that are significantly associated with each particular clinical outcome may guide clinicians to achieve predictable and successful outcomes after tooth transplantation. PMID- 29525926 TI - Detection accuracy of maxillary sinus floor septa in panoramic radiographs using CBCT as gold standard: a multi-observer receiver operating characteristic (ROC) study. AB - OBJECTIVES: To investigate diagnostic accuracy of panoramic radiography in detecting maxillary sinus floor septa by means of a multi-observer receiver operating characteristic (ROC) analysis and a standardized protocol for reporting (STARD protocol; Clin Chem 49(1):1-6, 2003). MATERIAL AND METHODS: From our database, 25 cone beam computed tomographies (CBCTs) were selected with one maxillary sinus floor septum (height >= 2.5 mm). For the same patient, a recent panoramic radiograph (PAN) had to be available in the database. As controls, 28 CBCTs plus corresponding PANs without evidence of a sinus septum were selected. Using the CBCTs as ground truth, 17 observers from our dental school on a five point confidence scale rated both sinuses in all 53 PANs with respect to presence/absence of a sinus septum. Areas beneath ROC curves (Az-values), sensitivity/specificity (SNT/SPF), positive/negative predictive values (PPV, NPV), and positive/negative likelihood ratios (LR+, LR-) were computed for each observer and pooled over all observers. Inter-rater reproducibility was assessed by means of the intraclass coefficient (ICC) using a two-way random effects model. RESULTS: A pooled Az-value of 0.839 was observed (SNT 84.6%, SPF 73.5%). PPV ranged between 0.492 and 0.824 (median 0.627) and NPV between 0.838 and 0.976 (median 0.917). A median LR+ of 3.567 was computed (LR- median 0.193). Inter rater reliability revealed an ICC of 0.55 (95% confidence interval 0.48 to 0.62). CONCLUSIONS: Our results indicate that PAN is a moderately accurate method for sinus elevation planning for the purpose of septum detection. Ruling out a septum by PAN seems to work more accurately than ruling in. CLINICAL RELEVANCE: For the purpose of maxillary sinus floor septa detection, panoramic radiography can be relatively safely advocated, particularly for judgment of a septum-free sinus. PMID- 29525924 TI - Autotransplantation of teeth with incomplete root formation: a systematic review and meta-analysis. AB - OBJECTIVES: The objective of this systematic review and meta-analysis was to determine the rates of survival and success and the complications related to autotransplantation of teeth with incomplete root formation. Additionally, we attempted to identify the prognostic factors that influence the outcome of tooth autotransplantation. MATERIALS AND METHODS: A literature search for all data published until July 2016 was conducted. Inclusion and exclusion criteria were specified. Risk of bias was assessed with the Newcastle checklist. Meta-analysis was performed by using the DerSimonian-Laird random effect model. The 1-, 5-, and 10-year survival rates and the weighted estimated survival, success, and complication rates per year were calculated. RESULTS: Thirty-two studies were included for analysis. The survival rates reported after 1, 5, and 10 years were 97.4, 97.8, and 96.3%, respectively. The annual weighted estimated survival rate (98.2%), success rate (96.6%), and complication rates in terms of ankylosis (2.0%), root resorption (2.9%), and pulp necrosis (3.3%) were analyzed. No firm conclusions could be drawn with respect to the prognostic factors due to insufficient evidence of high quality. CONCLUSION: The survival and success rates of autotransplantation of teeth with incomplete root formation were high (> 95%), with a low rate of complications (< 5%). CLINICAL RELEVANCE: Current evidence from the literature on autotransplantation of teeth with incomplete root formation shows favorable survival and success rates and low complication rates, indicating it is a reliable treatment option. PMID- 29525927 TI - Frequent ploidy changes in growing yeast cultures. AB - Ploidy is considered a very stable cellular characteristic. Although rare, changes in ploidy play important roles in the acquisition of long-term adaptations. Since these duplications allow the subsequent loss of individual chromosomes and accumulation of mutations, changes in ploidy can also cause genomic instability, and have been found to promote cancer. Despite the importance of the subject, measuring the rate of whole-genome duplications has proven extremely challenging. We have recently measured the rate of diploidization in yeast using long-term, in-lab experiments. We found that spontaneous diploidization occurs frequently, by two different mechanisms: endoreduplication and mating type switching. Despite its common occurrence, spontaneous diploidization is usually selected against, although it can be advantageous under some stressful conditions. Our results have implications for the understanding of evolutionary processes, as well as for the use of yeast cells in biotechnological applications. PMID- 29525928 TI - Correction to: Anti-inflammatory, anti-rheumatic and analgesic activities of 2-(5 mercapto-1,3,4-oxadiazol-2-yl)-N-propylbenzenesulphonamide (MOPBS) in rodents. AB - Unfortunately, Fig. 1 was incorrectly published in the original publication. The corrected Fig. 1 is given as below. PMID- 29525929 TI - Perceived Need for Treatment and Engagement in Mental Health Services Among Community-Referred Racial/Ethnic Minority Adolescents. AB - This study examines clinical and family predictors of perceived need for treatment and engagement in mental health treatment services among community referred racial/ethnic minority adolescents and their primary caregivers. Findings indicated that the majority of families perceived a need for treatment, but that perceived need was not associated with treatment engagement. Family factors (i.e., low cohesion and high conflict within the family) predicted perceived need for treatment among adolescents, whereas clinical factors (i.e., adolescent internalizing and externalizing symptomatology) predicted caregiver perceived need for adolescent treatment. Neither clinical nor family factors predicted treatment engagement. PMID- 29525930 TI - Exploring the Issues Surrounding Clinical Exome Sequencing in the Prenatal Setting. AB - Exome sequencing is a clinical diagnostic test offered primarily for children and adults with suspected genetic conditions. The purpose of this study was to explore issues related to exome sequencing in a reproductive clinical setting. This was a qualitative study using semi-structured interviews. Participants were professionals drawn from four key stakeholder groups-healthcare providers, laboratory/industry, ethics, and government. Transcribed interviews were analyzed for emergent themes. Most participants saw potential clinical utility in offering prenatal exome sequencing for diagnostic purposes as opposed to screening. Participants expressed similar challenges already encountered with using exome sequencing in a pediatric setting, such as difficulty interpreting results and voiced many of the same concerns posed by prenatal testing, such as adequate pretest counseling. While previously reported issues and challenges were mentioned, participants agreed those difficulties are anticipated to be much greater with prenatal exome sequencing because of the scope of testing and the option for pregnancy decision-making. The results of this study help gain a better understanding of the implications of using exome sequencing in a prenatal setting. Development of guidelines is also warranted to aid clinical practice and laboratory standards for reporting prenatal results. PMID- 29525931 TI - A Commentary on Opportunities for the Genetic Counseling Profession through Genomic Variant Interpretation: Reflections from an Ex-Lab Rat. AB - The genetic counseling profession continues to expand and respond to the changing landscape of genomic medicine. "Non-traditional" genetic counseling roles have become more commonplace and the transferability of the genetic counselor skill set has been widely acknowledged, particularly in genetic laboratory settings. As these expanding roles continue to mature, all genetic counselors can benefit by learning and adopting clinically relevant skills, such as genomic variant interpretation, which can be applied to direct patient care. These skills can enrich our patients' understanding of their test results, help ensure quality patient care, and could be useful in positioning genetic counselors as critical members in the medical team as we continue to fully transition into the genomic medicine era. PMID- 29525932 TI - Attitudes Toward and Uptake of Prenatal Genetic Screening and Testing in Twin Pregnancies. AB - The rate of twinning is rising and since the introduction of non-invasive prenatal testing, interest in and uptake of genetic screening and testing in twin pregnancies has not been investigated. This study aimed to explore the attitudes toward and uptake of current prenatal genetic screening and diagnostic testing options for fetal aneuploidy in twin pregnancies. Women being seen for genetic counseling with twin gestations were recruited for participation in a descriptive study with questionnaire (n = 42) and semi-structured phone interview (n = 15). Women were significantly more in favor of screening than diagnostic testing (p = 0.049). Sixty-nine (n = 25) percent elected screening, while one participant had a diagnostic procedure. Women were interested in screening for preparation or reassurance despite having concerns about accuracy and uncertainty. Most women (86%) felt they would make the same decision in a singleton pregnancy. Despite this, 48% cited twin pregnancy as influential to some degree. Information learned from providers, past experiences, and family and friends were also cited as influencing and anchoring factors, suggesting that tailoring prenatal genetic counseling sessions for twins might parallel that of singletons. No significant differences between natural and assisted conception patients were found. Although it did not alter patient decisions, genetic counseling was used as a platform to raise concerns and gather information. PMID- 29525933 TI - American Academy of Dermatology Annual Meeting: San Diego, CA, USA, 16-20 Feb 2018. PMID- 29525935 TI - Selective Vagotomy Worsens Glucose Control After Ileal Transposition. AB - PURPOSES: Our aim was to investigate the effects of selective celiac branch vagotomy on food intake and glycemic control after ileal transposition (IT) and the possible roles of the vagus on the improvement of diabetes. MATERIALS AND METHODS: Forty non-obese rats with diabetes underwent either IT, IT + celiac branch vagotomy (ITV), sham IT (SI), or sham IT + celiac branch vagotomy (SIV). They were pair fed, and the food intake, body weight, fasting plasma glucose, and glucagon-like peptide 1 (GLP-1) level were monitored. The number of activated pro opiomelanocortin (POMC) neurons and POMC-derived peptides were measured after sacrifice. RESULTS: The fasting glucose level of the ITV group was higher (7.0 +/ 0.7 mmol/L vs. 5.7 +/- 0.3, P = 0.01), and the area under the curve of the oral glucose tolerance test (AUCOGTT) value was greater than that of the IT group (1101.8 +/- 90.3 (mmol/l) min vs. 986.9 +/- 47.7 (mmol/l) min, P = 0.01). There was no significant difference in the postprandial GLP-1 level between these two groups, but the number of activated neurons in the ITV group was less than that of the IT group (10.3 +/- 2.1 vs. 14.9 +/- 2.3, P < 0.01), while the relative content level of POMC-derived peptides in the ITV group was half that of the IT group (P < 0.01). CONCLUSIONS: The celiac branches of the vagus might contribute to less eating and improvement of diabetes after IT. The activating vagus strategy might be a goal for the treatment of diabetes. PMID- 29525934 TI - Pleiotropic Anti-atherosclerotic Effects of PCSK9 InhibitorsFrom Molecular Biology to Clinical Translation. AB - PURPOSE OF REVIEW: Clinical trials with PCSK9 inhibitors have shown a robust decrease in plasma LDL levels and a significant reduction in the incidence of cardiovascular atherosclerotic events. However, the role of PCSK9 in atherosclerosis is not well investigated and it remains unclear whether PCSK9 inhibition has direct, LDL-independent, anti-atherosclerotic effects. This review outlines the molecular pathways and targets of PCSK9 in atherosclerosis and summarizes the experimental and clinical data supporting the anti-atherosclerotic (pleiotropic) actions of PCSK9 inhibitors. RECENT FINDINGS: PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g., endothelial cell, smooth muscle cell, and macrophage) and is detected inside human atherosclerotic plaque. Preclinical studies have shown that inhibition of PCSK9 can attenuate atherogenesis and plaque inflammation. Besides increasing plasma LDL, PCSK9 appears to promote the initiation and progression of atherosclerosis. Inhibition of PCSK9 may confer atheroprotection that extends beyond its lipid-lowering effects. PMID- 29525936 TI - Attrition after Acceptance onto a Publicly Funded Bariatric Surgery Program. AB - BACKGROUND: Factors such as ethnicity, gender, and socioeconomic status may play a role in both access to and attrition from bariatric programs before surgery is undertaken. New Zealand (NZ) has high rates of obesity in its Pacific population and the indigenous Maori. These groups also experience poorer health outcomes and therefore have the greatest need for surgery. METHODOLOGY: A retrospective cross sectional study of 704 people referred for and accepted onto a publicly funded bariatric surgery from 2007 to 2016. The demographic and clinical features of two groups were compared: those that completed surgery successfully (n = 326) and those that dropped out of the program before surgery (n = 378). We also attempted to identify factors associated with attrition. RESULTS: The attrition rate was high (54%), with a significant difference according to gender (men 66% vs 45% women, p < 0.001) and ethnicity (39% in NZ Europeans, 50% in Maori, and 73% in Pacific patients, p < 0.001). Two out of three European women proceeded to surgery, but fewer than one in seven Pacific men. Attrition was associated with having a higher mean BMI and being a smoker. Logistic regression modeling showed that while employment seemed to be protective against attrition for NZ Europeans (p < 0.004), it was not for Pacific patients. CONCLUSIONS: While there was no obvious bias in rates of referral, there is clearly a need for better ways to support Maori and Pacific people, and men in particular, to complete bariatric surgery. Further research is needed to clarify the socio-economic and cultural barriers that underlie this phenomenon. PMID- 29525937 TI - Bariatric Surgery in the Elderly Is Associated with Similar Surgical Risks and Significant Long-Term Health Benefits. AB - PURPOSE: Older age (> 60) has been considered a relative contraindication for bariatric surgery due to increased complication risk. This study examined the risks and benefits of bariatric surgery for patients older than 60 years in Canadian population. METHODS: This was a retrospective cohort study of the Ontario Bariatric Registry: a database recording peri-operative and post operative outcomes of publicly funded bariatric surgeries across the province. Patients who completed 1 year follow-up, who underwent laparoscopic gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) between January 2010 and May 2013, were divided into older (> 60) and younger (> 60) cohorts, and outcomes were compared. RESULTS: Between January 2010 and May 2013, 3166 registry patients underwent LRYGB or LSG and completed 1-year follow-up. Of these, 204 (6.5%) were older than 60 years, with 175 (85.8%) undergoing LRYGB and 29 (14.2%) LSG. Demographics were similar, except for a higher number of males in the older group (59 (28.9%) versus 452 (15.3%) (p < 0.001)). No significant difference in complication rate was noted (15% for younger cohort versus 13.8% (p = 0.889)). The average percentage of excess weight loss was significantly higher in the younger population (60.72% versus 56.25% (p < 0.05)) overall, however not significantly in the LSG group. Reduction in medication use post-surgery for management of co-morbidities was significantly higher in the older patients (- 0.91 versus - 2.03 (p < 0.001)). CONCLUSION: The older cohort who underwent LRYGB or LSG was at no greater risk for intra-operative and post-operative complications and showed greater reduction in medication use post-surgery when compared to the younger cohort. PMID- 29525938 TI - A Screening Study of Potential Carcinogen Biomarkers After Surgical Treatment of Obesity. AB - BACKGROUND: Obesity has been associated with the development of various types of cancer. Biomarker studies may provide molecular level knowledge of the factors involved in this association, improving clinical practice through new methods of prevention and treatment. PURPOSE: The present study aimed to analyze proteins found in the plasma of obese patients prior to and 6 months after bariatric surgery, using body mass index (BMI) and percentage total weight loss (%TWL) to evaluate, in a prospective manner, the effects of weight loss on the regulation of proteins related to the appearance of tumors. MATERIAL AND METHODS: This was a cohort study designed to compare parameters before and after intervention. A total of 40 patients were divided into two groups: control (n = 10) and obese (n = 30). The latter group was stratified according to surgical technique used (Roux en-Y gastric bypass (RYGB) n = 11 and sleeve gastrectomy (SG) n = 19) to remove confounding variables. Blood samples were collected for plasma protein studies using two-dimensional electrophoresis. RESULTS: Six proteins related to carcinogenesis were hyperexpressed in the obese patients but were absent in the control group and following surgery. These proteins were the beta-receptor of derived growth factor platelet, the receptor of apolipoprotein B, thrombospondin 2, the low-density lipoprotein receptor, transthyretin, and podoplanin. CONCLUSION: The current preliminary study thus identified potentially carcinogenic proteins in obese patients. Surgical weight loss resulted in the not detection of these proteins. PMID- 29525939 TI - Identification of service improvement opportunities in an Australian community transition care program. AB - BACKGROUND: Transition care programs (TCPs) are designed to optimise functional recovery and independence in older adults post-hospitalisation. These programs are under high demand, and understanding inefficiencies in patient flow are a key step towards service improvement. AIMS: To identify service improvement opportunities in an Australian community TCP service. METHODS: An in-depth retrospective study of 113 community TCP clients. RESULTS: TCP occupancy was high (94%) and client functional level improved across the program. Inefficiencies experienced included: admission delays to the program; low completion rates (61%) predominantly due to re-hospitalisation; variable response times by Allied Health services (5-20 days); and discharge delays-the latter attributed to waiting for services such as Home Care Packages through Non-Government Organisations. DISCUSSION: This study identified several opportunities for service improvement in a community TCP service. Health practitioners should be regularly provided with up-to-date information on efficiency of TCP services. PMID- 29525940 TI - Mash1-expressing cells could differentiate to type III cells in adult mouse taste buds. AB - The gustatory cells in taste buds have been identified as paraneuronal; they possess characteristics of both neuronal and epithelial cells. Like neurons, they form synapses, store and release transmitters, and are capable of generating an action potential. Like epithelial cells, taste cells have a limited life span and are regularly replaced throughout life. However, little is known about the molecular mechanisms that regulate taste cell genesis and differentiation. In the present study, to begin to understand these mechanisms, we investigated the role of Mash1-positive cells in regulating adult taste bud cell differentiation through the loss of Mash1-positive cells using the Cre-loxP system. We found that the cells expressing type III cell markers-aromatic L-amino acid decarboxylase (AADC), carbonic anhydrase 4 (CA4), glutamate decarboxylase 67 (GAD67), neural cell adhesion molecule (NCAM), and synaptosomal-associated protein 25 (SNAP25) were significantly reduced in the circumvallate taste buds after the administration of tamoxifen. However, gustducin and phospholipase C beta2 (PLC beta2)-markers of type II taste bud cells-were not significantly changed in the circumvallate taste buds after the administration of tamoxifen. These results suggest that Mash1-positive cells could be differentiated to type III cells, not type II cells in the taste buds. PMID- 29525941 TI - Peri- and postoperative management and outcomes of morbidly obese patients (BMI > 40 kg/m2) with gynaecological disease. AB - INTRODUCTION: For the last two decades, obesity rates have been increasing in both developed and developing countries, with the number of obese women roughly doubling during this period (Stevens et al. in Popul Health Metr 10(1):33, 2012). Obesity represents one of the biggest epidemics of the 21st century. The aim of this retrospective study is to characterise the outcomes of gynaecologic surgeries in cases of extremely obese women with a body mass index (BMI) over 40 kg/m2. METHODS: This study is a retrospective case control study in a single centre setting. Our clinical database was searched for gynaecological operations performed on morbidly obese patients (BMI > 40 kg/m2) between 2009 and 2014 in the Department of Gynaecology and Obstetrics at Hannover Medical School. We matched these results with random patients of normal body weight who had similar surgical procedures and diseases. RESULTS: We included 97 obese patients in our case group and 99 patients in the control group. We found an association between a strongly elevated BMI and peri- and postoperative morbidity. Both intraoperative and postoperative complications are significantly increased in morbid obesity with a BMI over > 40 kg/m2. We observed intraoperative complications in 55.6% and postoperative complications in 50.5% of patients with extreme obesity. In contrast, the complication rate in the control group with a normal BMI was 11% intraoperatively (p = 0.0001) and 3% postoperatively (p = 0.0001). The data showed that perioperative and postoperative morbidity could be reduced by laparoscopic surgery in many cases, with a significant lower rate of difficulties with closing the wound, a significant shorter duration of surgery and a significant lower rate of infections combined with a significant lower reoperation rate and shorter hospital stay. In gynaecological-oncological diseases, we could demonstrate a reduced radicality during the operative procedure due to extreme obesity. DISCUSSION: Dealing with the growing number of obese patients is essential, because the problems emerging from obesity are manifold for the treating hospitals as well as the general health system. For this high-risk patient group, it is indispensable to obtain a thorough overview of the patient's overall situation preoperatively to ensure good perioperative care and complications management. PMID- 29525942 TI - The association of CCAT2 rs6983267 SNP with MYC expression and progression of uterine cervical cancer in the Polish population. AB - PURPOSE: Previous studies have reported a significant contribution of NC_000008.10:g.128413305 G>T (rs6983267) single-nucleotide polymorphism (SNP) in the MYC enhancer region to the susceptibility of various cancers. However, the role of rs6983267 SNP in cervical cancer (CC) development and progression has not been demonstrated to date. Therefore, we evaluated the role of rs6983267 SNP in MYC expression in cervical cancers and non-cancerous cervical tissues. In addition, we assessed the role of this SNP in the development and progression of CC. METHODS: Using high-resolution melting analysis, we evaluated rs6983267 SNP frequency in women diagnosed with cervical squamous cell carcinoma (SCC) (n = 481) and controls (n = 502) in a Polish Caucasian population. Logistic regression analysis was employed to adjust for the effects of age, parity, oral contraceptive use, tobacco smoking, and menopausal status. RESULTS: Dividing patients based on clinical characteristics demonstrated an association of the rs6983267 genotype with tumor stage III and grade of differentiation G2 and G3. The p trend value calculated for the rs6983267 SNP in patients with stage III was 0.0006. We also observed a significant contribution of rs6983267 SNP to tumor grade of differentiation G2 and G3. Additional contributors were oral contraceptive use, smoking, and postmenopausal age. We found statistically significant increase of MYC transcript levels in cervical SCC tissues from carriers of the GG vs. T/T (p < 0.00001), G/T vs. T/T (p = 0.0002), and in the non-cancerous cervical tissues from carriers of the GG vs. T/T (p = 0.00046). CONCLUSION: The rs6983267 SNP may contribute to the increased MYC expression as well as the spread and rapid growth of cervical SCC as compared to lower grade carcinomas. PMID- 29525943 TI - Pelvic floor muscle activity during jumps in continent and incontinent women: an exploratory study. AB - PURPOSE: Stress urinary incontinence (SUI) symptoms can be provoked during impact loads such as vertical jumps. To investigate and compare pelvic floor muscle (PFM) activity in women with SUI and continent women (CON) during drop jumps (DJ) and counter movement jumps (CMJ) could clarify the activity of the PFMs during impact loads. METHODS: A tripolar vaginal probe was used to record surface electromyographic (EMG) activity of the PFMs during DJ and CMJ. Time intervals of 30 ms were used to parameterize data from 30 ms before (pre-activity) to 150 ms after (reflex activity) ground contact on a force plate during the landing and take-off phase. EMG signals were normalized to the mean of the peak values of two maximal voluntary contractions (MVC) and expressed in percentage (% MVC). RESULTS: For all time intervals during the landing and take-off phase, no statistically significant differences could be found between women with SUI and CON. EMG values exceeded 100% MVC for all time intervals during all landing and take-off phases. Maximal PFM activation was measured during the first landing of DJ and was 404.1% MVC for SUI and 370.2% MVC for CON. CONCLUSIONS: Vertical jumps seem to stimulate pre-activity before and reflex activity after ground contact during the landing phase and activate PFMs up to 400% MVC. Jumping stimuli inducing involuntary PFM contraction could show a beneficial factor to be integrated in a PFM rehabilitation program. PMID- 29525944 TI - Giant periosteal aggressive epithelioid osteoblastoma: 21-year-old male presents case in the midshaft of his femur. AB - We report a rare case of giant periosteal osteoblastoma in the femur of a 21-year old male. The patient presented with a painful, firm, non-tender mass in his left thigh. The pain was worse at night and was temporarily relieved with NSAIDS. He had no fevers, night sweats, or weight loss. The patient underwent preoperative radiological studies including plain radiographs, MRI, bone scan, and CT scan. An open biopsy was subsequently performed that was consistent with an aggressive, epithelioid osteoblastoma. Pathology demonstrated a neoplasm characterized by cohesive sheets of epithelioid osteoblasts, mixed with areas of conventional osteoblastoma displaying prominent osteoblastic rimming of woven bone trabeculae in a fibrovascular stroma. The patient subsequently underwent resection, cryosurgery, fixation, and bone grafting with cortical strut allografts. At final follow-up, 32 months postoperatively, there was no evidence of local recurrence. The patient had resumed all his normal activities. He could run without pain and had no restrictions with activities. The goal of this case report is to aid professionals in the diagnosis and treatment of highly uncommon aggressive osteoblastomas. PMID- 29525945 TI - Measuring Plant Root Traits Under Controlled and Field Conditions: Step-by-Step Procedures. AB - In this chapter, we present methods that we routinely use to measure plant root traits in the field and under controlled environmental conditions (using rhizoboxes). We describe procedures to (1) collect, wash, and store root samples, (2) acquire images of washed root samples, and (3) measure root traits using image analysis. In addition, we also describe sampling methods for studying belowground productivity, soil exploration, and root distribution in the first soil layers at the community level (soil coring and ingrowth core method). Because the use of rhizoboxes allows a nondestructive and dynamic measurement of traits hardly accessible in the field, a section of this chapter is devoted to the acquisition and analysis of images of roots growing in rhizoboxes. PMID- 29525946 TI - Phenotyping Crop Root Crowns: General Guidance and Specific Protocols for Maize, Wheat, and Soybean. AB - Root crown phenotyping allows measuring many parameters that describe the top portion of crop root systems and can be used for the basis of genome-wide association studies, QTL analysis, and physiology studies. Root crown phenotyping is a relatively simple process, with the major steps being excavation, transport, soil removal, and measurements. On the other hand, all steps require substantial manual labor and occur outside in challenging environments, and many factors influence the ultimate success of applying this methodology to research questions. Here, general guidance is given for how to optimize root crown phenotyping for unique research questions, and specific protocols are given for acquiring images of root crowns of three crop species: maize, wheat, and soybean. PMID- 29525947 TI - Developmental Analysis of Arabidopsis Root Meristem. AB - Plant postembryonic development takes place in region called meristems that represent a reserve of undifferentiated cells. In the root meristem of Arabidopsis thaliana, all tissues originate from a stem-cell niche. Stem-cell daughters undergo a finite number of cell divisions until they reach the transition zone where divisions cease and cells start to differentiate. For meristem maintenance, and therefore continuous root growth, the rate of cell differentiation must equal the rate of generation of new cells. How this balance is achieved is a central question in plant biology. In this chapter we described protocols to help the operator in approaching developmental studies on the Arabidopsis root meristem. PMID- 29525948 TI - Genetic and Phenotypic Analysis of Lateral Root Development in Arabidopsis thaliana. AB - Root system formation to a great extent depends on lateral root (LR) formation. In Arabidopsis thaliana, LRs are initiated within a parent root in pericycle that is an external tissue of the stele. LR initiation takes place in a strictly acropetal pattern, whereas posterior lateral root primordium (LRP) formation is asynchronous. In this chapter, we focus on methods of genetic and phenotypic analysis of LR initiation, LRP morphogenesis, and LR emergence in Arabidopsis. We provide details on how to make cleared root preparations and how to identify the LRP stages. We also pay attention to the categorization of the LRP developmental stages and their variations and to the normalization of the number of LRs and LRPs formed, per length of the primary root, and per number of cells produced within a root. Hormonal misbalances and mutations affect LRP morphogenesis significantly, and the evaluation of LRP abnormalities is addressed as well. Finally, we deal with various molecular markers that can be used for genetic and phenotypic analyses of LR development. PMID- 29525949 TI - Adapting the Lateral Root-Inducible System to Medicago truncatula. AB - Almost all legume plants have the capacity to form two types of root organs: lateral roots and nodules (that will host rhizobia that fix nitrogen). Transcriptomic analyses are useful to understand both the similarities and differences between nodule and LR formation and to compare the LR developmental programs used by Arabidopsis and model legumes such as Medicago truncatula. However, in M. truncatula as in Arabidopsis, root cells "committed" to LR formation programs are scattered along the primary root and localized in the inner most layers of the root. To gain access to these cells, a lateral root inducible system (LRIS) was first developed in Arabidopsis. This LRIS was recently shown to be effective in maize as well. Here we present a LRIS protocol adapted to the model legume Medicago truncatula. Using the same auxin transporter inhibitor and permeant auxin molecules used for Arabidopsis and maize but with slight modifications in their concentrations, we obtained very efficient enrichment and synchronization in LR development stages in M. truncatula. PMID- 29525950 TI - Characterization of Root Epidermal Cell Patterning and Differentiation in Arabidopsis. AB - The root epidermis of Arabidopsis thaliana has been established as a model system for elucidating the mechanisms which govern the spatial patterningAbstract and morphogenesis of plant cells. Investigations into root hairs focus on various aspects of the biology of epidermal cells, using methods specifically developed to dissect the biological question under study. Despite the large number of studies related to epidermal cell differentiation, a survey of methods to analyze the phenotypic readout resulting from environmental conditions or the genetic background of the plant has not been provided so far. This protocol describes how to analyze the spatial arrangement and morphologic characteristics of cells in the root epidermis based on whole mount roots or cross sections, using confocal, scanning electron and light microscopy. This comparison of methods aids in selecting the most suitable strategy to examine the differentiation of root epidermal cells at different developmental stages. PMID- 29525951 TI - In Vitro Assay for Induction of Adventitious Rooting on Intact Arabidopsis Hypocotyls. AB - Adventitious roots (AR) are de novo formed roots that emerge from any part of the plant or from callus in tissue culture, except root tissue. The plant tissue origin and the method by which they are induced determine the physiological properties of emerged ARs. Hence, a standard method encompassing all types of AR does not exist. Here we describe a method for the induction and analysis of AR that emerge from the etiolated hypocotyl of dicot plants. The hypocotyl is formed during embryogenesis and shows a determined developmental pattern which usually does not involve AR formation. However, the hypocotyl shows propensity to form de novo roots under specific circumstances such as removal of the root system, high humidity or flooding, or during de-etiolation. The hypocotyl AR emerge from a pericycle-like cell layer surrounding the vascular tissue of the central cylinder, which is reminiscent to the developmental program of lateral roots. Here we propose an easy protocol for in vitro hypocotyl AR induction from etiolated Arabidopsis seedlings. PMID- 29525952 TI - Root Gravitropism: Quantification, Challenges, and Solutions. AB - Better understanding of root traits such as root angle and root gravitropism will be crucial for development of crops with improved resource use efficiency. This chapter describes a high-throughput, automated image analysis method to trace Arabidopsis (Arabidopsis thaliana) seedling roots grown on agar plates. The method combines a "particle-filtering algorithm with a graph-based method" to trace the center line of a root and can be adopted for the analysis of several root parameters such as length, curvature, and stimulus from original root traces. PMID- 29525953 TI - Calcium Ion Dynamics in Roots: Imaging and Analysis. AB - Calcium sensors are indispensable tools to study the role of Ca2+ and visualize Ca2+ dynamics during biological processes. Over the past years, the field of Ca2+ imaging has strongly expanded by the development of a wide palette of sensors and optimization of sample handling. Here, we provide guidelines for imaging of the Ca2+ sensor R-GECO1 in Arabidopsis thaliana roots which can be interpolated to other intensiometric Ca2+ sensors. Furthermore, we demonstrate a procedure for image analysis of the acquired time-lapse recordings. PMID- 29525954 TI - Optimized Whole-Mount In Situ Immunolocalization for Arabidopsis thaliana Root Meristems and Lateral Root Primordia. AB - Immunolocalization is a valuable tool for cell biology research that allows to rapidly determine the localization and expression levels of endogenous proteins. In plants, whole-mount in situ immunolocalization remains a challenging method, especially in tissues protected by waxy layers and complex cell wall carbohydrates. Here, we present a robust method for whole-mount in situ immunolocalization in primary root meristems and lateral root primordia in Arabidopsis thaliana. For good epitope preservation, fixation is done in an alkaline paraformaldehyde/glutaraldehyde mixture. This fixative is suitable for detecting a wide range of proteins, including integral transmembrane proteins and proteins peripherally attached to the plasma membrane. From initiation until emergence from the primary root, lateral root primordia are surrounded by several layers of differentiated tissues with a complex cell wall composition that interferes with the efficient penetration of all buffers. Therefore, immunolocalization in early lateral root primordia requires a modified method, including a strong solvent treatment for removal of hydrophobic barriers and a specific cocktail of cell wall-degrading enzymes. The presented method allows for easy, reliable, and high-quality in situ detection of the subcellular localization of endogenous proteins in primary and lateral root meristems without the need of time-consuming crosses or making translational fusions to fluorescent proteins. PMID- 29525955 TI - Light Sheet Fluorescence Microscopy Optimized for Long-Term Imaging of Arabidopsis Root Development. AB - Light sheet fluorescence microscopy (LSFM) allows sustained and repeated optical sectioning of living specimens at high spatial and temporal resolution, with minimal photodamage. Here, we describe in detail both the hardware and the software elements of a live imaging method based on LSFM and optimized for tracking and 3D scanning of Arabidopsis root tips grown vertically in physiological conditions. The system is relatively inexpensive and with minimal footprint; hence it is well suited for laboratories of any size. PMID- 29525956 TI - Histological Profiling Over Time to Optimize Root Cell Type-Specific Reporter Lines for Cell Sorting. AB - Cell type-specific marker lines expressing fluorophores such as GFP or GUS can be used as starting material from which single cell types can be isolated by fluorescence-activated cell sorting (FACS) and/or for the study of root development. Establishing the stability of these lines is an essential step prior to further study to ensure that marker expression and localization is stable over time and during environmental perturbations of interest to researchers applying these lines as treatments. Here, we detail the use of root cross sectioning to investigate marker expression throughout the length and width of the root using the model legume Medicago truncatula as an example. In order to deal with the fact that plant cell walls are highly autofluorescent, we also describe the usage of confocal microscopy to conduct a lambda scan to discriminate autofluorescence from marker molecule expression. PMID- 29525957 TI - Long-Term In Vivo Imaging of Luciferase-Based Reporter Gene Expression in Arabidopsis Roots. AB - Plants have an amazing capacity to adjust their growth to environmental limitations. This is particularly relevant for the root system that tunes its developmental pattern to mine the soil for water and nutrients while avoiding patches of soil that contain biotic and abiotic stress agents. Because most developmental processes are taking place gradually while roots are growing, it is often difficult to correlate gene expression events with specific developmental processes that are not necessarily coinciding in time and space. Therefore, in vivo detection and quantification of gene expression over a long period under gravitational conditions can be instrumental in dissecting complex processes in the root. Here, we describe a method for long-term imaging of luciferase dynamics in growing Arabidopsis roots that express a luciferase gene driven by the auxin output reporter DR5, in the context of lateral root development. PMID- 29525958 TI - Cortical Cell Length Analysis During Gravitropic Root Growth. AB - The typical parameter used to evaluate the root growth response to gravity is the degree of root bending in time. This employs the quantification of the root tip angle toward gravity and, hence, does not directly assess the actual differential growth process. Here, we describe the cortical cell length as a parameter to quantify cell elongation during the gravitropic response, using median longitudinal confocal sections. This analysis depicts that root organ bending is a consequence of differential cellular elongation on the upper versus lower side of the gravistimulated root. Moreover, we introduce here a simple mounting setup that is suitable to gravistimulate and subsequently image seedlings on upright microscopes. PMID- 29525959 TI - Growth Rate Normalization Method to Assess Gravitropic Root Growth. AB - Time-lapse imaging of roots is highly suitable for depicting gravitropic growth behaviors. However, roots may show faster or slower bending kinetics when compared to control as a result of differences in overall root growth. Accordingly, conditions that cause differential organ growth require growth rate normalization to compare gravitropic curvature. Here, we describe a simple normalization method for gravitropic root growth evaluation. We exemplify this method by exposing seedlings to distinct environmental conditions or disturbing the cellular auxin contents. This data shows that the method is suitable to discriminate between gravitropic and overall organ growth defects. PMID- 29525960 TI - Immunoprecipitation of Membrane Proteins from Arabidopsis thaliana Root Tissue. AB - Here, we present different methods for immunoprecipitating membrane proteins of Arabidopsis thaliana root material. We describe two extraction methods for the precipitation either for an integral membrane protein of the endoplasmic reticulum (ER) or a peripheral membrane protein partially localized at the plasma membrane, where we precipitate the protein out of the total membrane as well as total cytosolic fractions. PMID- 29525961 TI - Monitoring Transcriptomic Changes in Soil-Grown Roots and Shoots of Arabidopsis thaliana Subjected to a Progressive Drought Stress. AB - Numerous experiments have been performed in Arabidopsis to monitor changes in gene expression that occur in response to a variety of abiotic and biotic stresses, different growth conditions, and at various developmental stages. In addition, gene expression patterns have also been characterized among wild-type and mutant genotypes. Despite these numerous reports, transcriptional changes occurring in roots of soil-grown plants subjected to a progressive drought stress have remained undocumented. To fill this gap, we established a system that allows one to establish water-deficit conditions and to collect root and shoot samples with minimal damage to the root system. Arabidopsis plants are grown in a ceramic based granular soil and subjected to progressive drought stress by withholding water. Root and shoot samples were collected separately, RNA was purified, and a microarray analysis of drought-stressed roots and shoots was performed at 0, 1, 3, 5, 7, and 9 days after the onset of drought stress treatment. Here, we describe the detailed protocol used to analyze the transcriptomic changes occurring in roots and shoots of soil-grown Arabidopsis subjected to a progressive drought stress. PMID- 29525962 TI - Chromatin Immunoprecipitation Sequencing (ChIP-Seq) for Transcription Factors and Chromatin Factors in Arabidopsis thaliana Roots: From Material Collection to Data Analysis. AB - Chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) is a powerful technique to investigate in vivo transcription factor (TF) binding to DNA, as well as chromatin marks. Here we provide a detailed protocol for all the key steps to perform ChIP-seq in Arabidopsis thaliana roots, also working on other A. thaliana tissues and in most non-ligneous plants. We detail all steps from material collection, fixation, chromatin preparation, immunoprecipitation, library preparation, and finally computational analysis based on a combination of publicly available tools. PMID- 29525963 TI - MUChIP-Seq for Genome-Wide Mapping of In Vivo TF-DNA Interactions in Arabidopsis Root Protoplasts. AB - Chromatin immunoprecipitation (ChIP) is a widely used method to map the position of DNA-binding proteins such as histones and transcription factors (TFs) upon their interaction with particular regions of the genome. To examine the genomic distribution of a TF in specific cell types in response to a change in nitrogen concentration, we developed a micro-ChIP (MUChIP) protocol that requires only ~5000 Arabidopsis cells transiently expressing the Arabidopsis TF Basic Leucine Zipper 1 (bZIP1) fused to the glucocorticoid receptor (GR) domain that mediates nuclear import in the presence of dexamethasone. The DNA fragments obtained from the immunoprecipitation of bZIP1-DNA complexes were analyzed by next-generation sequencing (ChIP-seq), which helped uncover genome-wide associations between a bZIP1 and its targets in plant cells upon fluctuations in nitrogen availability. PMID- 29525964 TI - Proteome Analysis of Arabidopsis Roots. AB - Plant health and development are directly depending on a plant's ability to react to a constantly changing environment. Sensing of water and nutrition levels and of the biotic environment is vital for a plant, making the root one of the key plant organs. Proteins are the key molecules that play numerous roles in a cell's everyday life. Quantitative proteome profiling of roots can provide a global overview on the molecular regulatory mechanisms and networks involved in plant growth and development and abiotic and biotic stress responses. Here, we provide a detailed proteomics workflow on Arabidopsis thaliana roots from plant growth up to proteomics data analysis. PMID- 29525965 TI - Step-by-Step Construction of Gene Co-expression Networks from High-Throughput Arabidopsis RNA Sequencing Data. AB - The rapid increase in the availability of transcriptomics data generated by RNA sequencing represents both a challenge and an opportunity for biologists without bioinformatics training. The challenge is handling, integrating, and interpreting these data sets. The opportunity is to use this information to generate testable hypothesis to understand molecular mechanisms controlling gene expression and biological processes (Fig. 1). A successful strategy to generate tractable hypotheses from transcriptomics data has been to build undirected network graphs based on patterns of gene co-expression. Many examples of new hypothesis derived from network analyses can be found in the literature, spanning different organisms including plants and specific fields such as root developmental biology.In order to make the process of constructing a gene co-expression network more accessible to biologists, here we provide step-by-step instructions using published RNA-seq experimental data obtained from a public database. Similar strategies have been used in previous studies to advance root developmental biology. This guide includes basic instructions for the operation of widely used open source platforms such as Bio-Linux, R, and Cytoscape. Even though the data we used in this example was obtained from Arabidopsis thaliana, the workflow developed in this guide can be easily adapted to work with RNA-seq data from any organism. PMID- 29525966 TI - GWA-Portal: Genome-Wide Association Studies Made Easy. AB - Genome-wide association studies (GWAS) are an effective method for investigating the genetics of natural phenotypic variation in many different model organisms.Here we present GWA-Portal, an interactive web application that enables researchers to upload their phenotypes and easily carry out GWAS directly in the browser. We will present all the steps needed-from uploading the phenotype to interpreting the results-using a published root phenotype. PMID- 29525967 TI - Serum levels of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in predicting the severity of acute pancreatitis. AB - INTRODUCTION: Acute pancreatitis (AP) is a severe disease associated with significant morbidity and mortality. The overall outcome has improved, but specific treatment(s) remains elusive. The challenge is the early identification and treatment of patients who will develop severe acute pancreatitis. Therefore, the aim of the present study is to investigate plasma levels of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the initial phase of predicted severe acute pancreatitis. METHODS: Between June 2014 and January 2016, 64 patients with acute pancreatitis and 36 healthy individuals were included to study. Four blood samples, for serum TWEAK measurement, were taken from each individual in each group. The first measurement was taken from the admission blood sample. The subsequent three samples were taken at 12, 24, and 48 h after the hospital admission. RESULTS: Serum TWEAK levels were significantly higher in patients with acute pancreatitis when compared with healthy controls. TWEAK plasma concentrations in severe pancreatitis patients were significantly higher than in mild pancreatitis patients. CONCLUSION: Serum TWEAK levels increase progressively with the severity of acute pancreatitis and TWEAK might be a novel early marker of severity in acute pancreatitis. PMID- 29525968 TI - Informing prehospital care planning using pilot trauma registry data in Yaounde, Cameroon. AB - INTRODUCTION: About 54% of deaths in low- and middle-income countries (LMICs) are attributable to lack of prehospital care. The single largest contributor to the disability-adjusted life years due to poor prehospital care is injury. Despite having disproportionately high injury burdens, most LMIC trauma systems have little prehospital organization. An understanding of existing prehospital care patterns in LMICs is warranted as a precursor to strengthening prehospital systems. METHODS: In this retrospective pilot study, we collected demographic and injury characteristics, therapeutic itinerary, and transport data of patients that were captured by the trauma registry at the Central Hospital of Yaounde (CHY) from April 15, 2009 to October 15, 2009. Bivariate and multivariate regression analyses were used to explore relationships between care-seeking behavior, method of transport, and predictor variables. RESULTS: The mean age was 30.2 years (95% CI [29.7, 30.7]) and 73% were male. Therapeutic itinerary was available for 97.5% of patients (N = 2855). Nearly 18.7% of patients sought care elsewhere before CHY and 82% of such visits were at district hospitals or health clinics. Moderately (OR 1.336, p = 0.009) and severely (OR 1.605, p = 0.007) injured patients were more likely to seek care elsewhere before CHY and were less likely to be discharged home after their emergency ward visit as opposed to being admitted to the hospital for further treatment (OR 0.462, p < 0.001). Commercial vehicles provided most prehospital transport (65%), while police or ambulance transported few injured patients (7%). CONCLUSIONS: Possible areas for prehospital trauma care strengthening include training lay commercial vehicle drivers in trauma care and formalizing triage, referral, and communication protocols for prehospital care to optimize timely transfer and care while minimizing secondary injury to patients. PMID- 29525969 TI - Time trend tendency (1988-2014 years) of organochlorine pesticide levels in the adipose tissue of Veracruz inhabitants. AB - The population that lives in areas where organochlorine pesticides were spread in the past is still exposed to them through contaminated food, particulate matter, and vapors. Due to their lipophilic properties and resistance to metabolic reactions, they accumulate in tissues and fluids rich in lipids. The aim of the study was to monitor the concentrations of organochlorine pesticides in forensic adipose tissue samples of adult inhabitants of Veracruz City, Mexico, and compare their time trend levels from 1988 to 2014. During the study, hexachlorobenzene (HCB); lindane; beta-hexachorocyclohexane; p,p'-dichlorodiphenyldichloroethylene (pp'DDE); p,p'-dichlorodiphenyldichloroethane (p,p'-DDT); and o,p' dichlorodiphenyldichloroethane (o,p'-DDT) were determined. Our survey was divided into two periods: first, from the years 1988 to 1999, during which DDT was allowed to fight malaria and dengue vectors and the second from the years 2001 to 2014, after the DDT ban. A total of 1435 samples were analyzed. There were substantial differences in the forecasted time trend values of p,p'-DDE and p,p' DDT in human adipose tissue samples in the two different periods. During the first period, p,p'-DDE decrease time trend was 1.198 mg/kg on lipid base per year; for the second one, decrease was 0.128 mg/kg on lipid base per year. p,p' DDT decreased 0.507 mg/kg on lipid base during the first period and 0.039 mg/kg on lipid base for the second. The different concentrations may be explained by the cessation of fresh exposure after the first period and a more equilibrated decontamination tendency during the second period. This model was useful to show the decrease in the concentration of pesticides in human adipose tissue samples. PMID- 29525970 TI - Effects of discontinuing oral bisphosphonate treatments for postmenopausal osteoporosis on bone turnover markers and bone density. AB - : The antiresorptive potency varies between different bisphosphonates. We investigated the effect of stopping oral bisphosphonate treatment for postmenopausal osteoporosis (ibandronate, alendronate, risedronate) on BTMs and BMD. After stopping treatment, all three groups showed an increase in BTMs and a decrease in hip BMD; however, none returned to pre-treatment baseline values. INTRODUCTION: Bisphosphonates (BPs) continue to suppress bone turnover markers (BTMs) after treatment has stopped, leading to the suggestion that a pause in treatment could be considered for low-risk patients. Indirect comparisons suggest that after cessation of treatment, the effects on bone may differ between drugs. We investigated the effects of stopping oral BP treatments for postmenopausal osteoporosis on BTMs and bone mineral density (BMD). METHODS: We studied postmenopausal osteoporotic women who had previously taken part in a 2-year randomised study of three oral BPs (ibandronate, alendronate, or risedronate). At the end of the study, women with hip BMD T-score > - 2.5 and considered clinically appropriate to discontinue treatment were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs, and BMD was measured by dual-energy X-ray absorptiometry. RESULTS: All BTMs increased after treatment withdrawal but remained below the pre-treatment baseline with less suppression of BTMs for the risedronate group compared to alendronate and ibandronate up to 48 weeks. There was no difference between the BP groups 96 weeks after stopping treatment. The change in BMD during the 96 weeks after stopping treatment was - 1.6% (95% CI - 1.9 to - 1.2, P < 0.001) for the total hip and - 0.6% (95% CI - 1.1 to - 0.2, P = 0.17) at the lumbar spine with no difference between the three BP groups (P = 0.85 and P = 0.48, respectively). CONCLUSION: For all treatment groups, there was an increase in BTMs and a decrease in hip BMD after stopping BPs for 2 years; however, none returned to pre-treatment baseline values. PMID- 29525972 TI - Positron emission tomography of sodium glucose cotransport activity in high grade astrocytomas. AB - A novel glucose transporter, the sodium glucose cotransporter 2 (SGLT2), has been demonstrated to contribute to the demand for glucose by pancreatic and prostate tumors, and its functional activity has been imaged using a SGLT specific PET imaging probe, alpha-methyl-4-[F-18]fluoro-4-deoxy-D-glucopyaranoside (Me-4FDG). In this study, Me-4FDG PET was extended to evaluate patients with high-grade astrocytic tumors. Me-4FDG PET scans were performed in four patients diagnosed with WHO Grade III or IV astrocytomas and control subjects, and compared with 2 deoxy-2-[F-18]fluoro-D-glucose (2-FDG) PET and magnetic resonance imaging (MRI) of the same subjects. Immunocytochemistry was carried out on Grade IV astrocytomas to determine the cellular location of SGLT proteins within the tumors. Me-4FDG retention was pronounced in astrocytomas in dramatic contrast to the lack of uptake into the normal brain, resulting in a high signal-to-noise ratio. Macroscopically, the distribution of Me-4FDG within the tumors overlapped with that of 2-FDG uptake and tumor definition using contrast-enhanced MRI images. Microscopically, the SGLT2 protein was found to be expressed in neoplastic glioblastoma cells and endothelial cells of the proliferating microvasculature. This preliminary study shows that Me-4FDG is a highly sensitive probe for visualization of high-grade astrocytomas by PET. The distribution of Me 4FDG within tumors overlapped that for 2-FDG, but the absence of background brain Me-4FDG resulted in superior imaging sensitivity. Furthermore, the presence of SGLT2 protein in astrocytoma cells and the proliferating microvasculature may offer a novel therapy using the SGLT2 inhibitors already approved by the FDA to treat type 2 diabetes mellitus. PMID- 29525971 TI - Identifying characteristics of an effective fracture liaison service: systematic literature review. AB - Fracture liaison services (FLS) have been demonstrated to improve outcomes following osteoporotic fracture. The aim of this systematic literature review (SLR) was to determine the characteristics of an FLS that lead to improved patient outcomes. We conducted a SLR, including articles published between 2000 and February 2017, using global (Medline, EMBASE, PubMed and Cochrane Library) and local databases. Studies including patients aged >= 50 years with osteoporotic fractures enrolled in an FLS were assessed. Information extracted from each article included key person coordinating the FLS (physician, nurse or other healthcare professional), setting (hospital vs community), intensity (single vs multiple), duration (long vs short term), fracture type and gender. A meta-analysis of randomised controlled trials was conducted based on the key person coordinating the FLS. Out of 7236 articles, 57 were considered to be high quality and identified for further analysis. The SLR identified several components which contributed to FLS success, including multidisciplinary involvement, driven by a dedicated case manager, regular assessment and follow up, multifaceted interventions and patient education. Meta-analytic data confirm the effectiveness of an FLS following an osteoporotic fracture: approximate 27% increase in the likelihood of BMD testing and up to 21% increase in the likelihood of treatment initiation compared with usual care. The balance of evidence indicates that the multifaceted FLS and dedicated coordination are important success factors that contribute to effective FLS interventions which reduce fracture-related morbidity and mortality. PMID- 29525973 TI - Laser-cut paper-based device for the detection of dengue non-structural NS1 protein and specific IgM in human samples. AB - The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical areas worldwide, affecting hundreds of millions of people each year. Dengue viruses are typically transmitted by mosquitoes and can cause a wide range of symptoms from flu-like fever to organ impairment and death. Although conventional diagnostic tests can provide early diagnosis of acute dengue infections, access to these tests is often limited in developing countries. Consequently, there is an urgent need to develop affordable, simple, rapid, and robust diagnostic tools that can be used at 'Point of Care' settings. Early diagnosis is crucial to improve patient management and reduce the risk of complications. In the present study, a novel laser-cut device made of glass-fiber paper was designed and tested for the detection of the dengue Non Structural 1 (NS1) viral protein and specific IgM in blood and plasma. The device, called PAD, was able to detect around 25 ng/mL of NS1 protein in various sample types in 8 minutes, following a few simple steps. The PAD was also able to detect specific IgM in human plasmas in less than 10 minutes. The PAD appears to have all the potential to assist health workers in early diagnosis of dengue fever or other tropical fevers caused by flaviviruses. PMID- 29525974 TI - Complete nucleotide sequence of a new carlavirus in chrysanthemums in China. AB - A new virus causing a serious stunt disease of chrysanthemum was identified in China by high-throughput sequencing (HTS) and named chrysanthemum virus R (CVR). The complete sequence of CVR was determined by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The genomic RNA of CVR consists of 8,874 nucleotides (nt), excluding the poly(A) tail, contains six putative open reading frames (ORFs), and has a genomic organization typical of members of the genus Carlavirus. BLAST analysis of the full genome sequence showed low similarity (38%-56% sequence identity) to other members of the genus Carlavirus. BLAST analysis and phylogenetic analysis based on the amino acid (aa) sequences of the CVR replicase and coat protein (CP) confirmed that CVR is a distinct member of the genus Carlavirus. PMID- 29525976 TI - Investigating the mechanical response of paediatric bone under bending and torsion using finite element analysis. AB - Fractures of bone account 25% of all paediatric injuries (Cooper et al. in J Bone Miner Res 19:1976-1981, 2004. https://doi.org/10.1359/JBMR.040902 ). These can be broadly categorised into accidental or inflicted injuries. The current clinical approach to distinguish between these two is based on the clinician's judgment, which can be subjective. Furthermore, there is a lack of studies on paediatric bone to provide evidence-based information on bone strength, mainly due to the difficulties of obtaining paediatric bone samples. There is a need to investigate the behaviour of children's bones under external loading. Such data will critically enhance our understanding of injury tolerance of paediatric bones under various loading conditions, related to injuries, such as bending and torsional loads. The aim of this study is therefore to investigate the response of paediatric femora under two types of loading conditions, bending and torsion, using a CT-based finite element approach, and to determine a relationship between bone strength and age/body mass of the child. Thirty post-mortem CT scans of children aged between 0 and 3 years old were used in this study. Two different boundary conditions were defined to represent four-point bending and pure torsional loads. The principal strain criterion was used to estimate the failure moment for both loading conditions. The results showed that failure moment of the bone increases with the age and mass of the child. The predicted failure moment for bending, external and internal torsions were 0.8-27.9, 1.0-31.4 and 1.0-30.7 Nm, respectively. To the authors' knowledge, this is the first report on infant bone strength in relation to age/mass using models developed from modern medical images. This technology may in future help advance the design of child, car restrain system, and more accurate computer models of children. PMID- 29525977 TI - Personal Transformation Process of Mental Health Relief Workers in Sichuan Earthquake. AB - After Sichuan earthquake, a few dedicated teams of psychological volunteers have been committed to helping the survivors of the disaster for a long period. Their personal transformation experiences were absent in the literatures. The purpose of this qualitative research was to adopt a qualitative research to examine individuals' lived experiences of personal transformation after long-term disaster mental health services. The study interviewed 10 psychological counselors, 3 psychiatric nurses, 4 psychiatrist, and 6 social workers. We built an explorative model to understand disaster relief workers personal transformation after long-term periods in disaster settings. The model proposes that existential learning is a key mediator factor from negative transformation to positive transformation. Cultivating the existential learning though training, caring and support involves a number of processes that includes acceptance, being authentic, and being mindful of here and now, which can transform their suffering to growth. PMID- 29525975 TI - Prognostic Value of EEG in Patients after Cardiac Arrest-An Updated Review. AB - PURPOSE OF REVIEW: This paper aims to review and summarize the key contributions of EEG to prognostication after cardiac arrest (CA). RECENT FINDINGS: While there are more EEG patterns predicting poor than good outcome, even EEG patterns previously considered to be "very malignant" may result in survival with a meaningful neurological outcome depending on their underlying etiology as well as the continuity and reactivity of the EEG background. Regardless of the potentially confounding factors, EEG patterns are highly specific with a relatively low false-positive rate. The development of more complex and comprehensive approaches to quantitative EEG analysis could help improve the prognostic value of EEG, but this approach has its own limitations. Seizures and status epilepticus in the setting of CA predict poor outcomes, but it is not clear whether treating them prevents additional brain damage and results in improved outcome. Either continuous EEG or frequent intermittent EEGs should be obtained within the first 12-24 h of return of spontaneous circulation in order to capture highly dynamic and prognostic patterns. Even though EEG has high predictive value for outcomes after cardiac arrest, it should not be the only prognostic tool. Rather, to improve prognostication, EEG should be used in combination with the neurological examination and other ancillary tests. PMID- 29525978 TI - Mental Footnotes. Knowledge Constructivism From Logical Thinking and Personal Beliefs to Social Rationality and Spiritual Freedom. AB - Cognition is an efficient but limited system that deals with mundane tasks. Daily life demands the system to save energy in order to be able to solve other more relevant tasks. Reasoning out every single problem would immeasurably increase our mental load and fatigue. Our minds avoid this waste of resources by taking shortcuts when reasoning. Outputs from previous episodes of reasoning turn into pieces of implicit information. These outputs go on to constitute the meanings that we give to things or circumstances, which in turn become the general framework where other reasonings occur. These implicit meanings determine the manner in which we represent our social environment and, therefore, our emotions and behaviors. These "mental footnotes" set the way in which we contemplate and conceive the world and deal with reality. World order capitalizes on the mechanisms of the mind to control and guide humanity. The better we understand these processes, the better we can control and restructure them. Academic psychology often ignores the power of the discipline to set humankind free from those meanings that restrict spiritual and human development. PMID- 29525979 TI - Effects on proprioception by Kinesio taping of the knee after anterior cruciate ligament rupture. AB - INTRODUCTION: The use of Kinesio tape (KT) to improve proprioception is a matter of considerable debate. In comparison, the rupture of the anterior cruciate ligament is a sufficiently well-investigated injury with a proven compromise of proprioception. The objective of the present study was to assess a supportive effect on proprioception after KT application, taking the anterior cruciate ligament (ACL) rupture as an example. MATERIALS AND METHODS: Forty-eight patients who had suffered an ACL rupture, confirmed clinically and by magnetic resonance imaging, and who were treated conservatively or were awaiting surgery were included in this study. In all patients, a gait analysis was performed on the affected leg before and after KT application. In addition, the IKDC score, the Lysholm score, stability using the Rolimeter, and the angle reproduction test were determined. RESULTS: Thirty-nine men and nine women who had had an ACL rupture for at least 3 weeks were included in the study. Significant improvements were achieved on the affected knee joint for the gait analysis parameters touchdown and unrolling, cadence, stability and stance phase as well as an extension of the hip joint. The Lysholm score improved from 79.3 to 85.8 (p < 0.001) and the IKDC score from 60.2 to 71.3 points (p < 0.001). Significant improvements were achieved in the Rolimeter and angle reproduction test. CONCLUSIONS: The use of KT has a positive effect on proprioception in patients with an anterior cruciate ligament rupture. Therefore, the application may improve gait pattern as well as the subjective function of the affected knee joint. PMID- 29525980 TI - Preoperative embolization and local hemostatic agents in palliative decompression surgery for spinal metastases of renal cell carcinoma. AB - BACKGROUND: Intraoperative hemorrhage can sometimes be massive in patients with spinal metastasis of renal cell carcinoma (MRCC). Preoperative embolization and local hemostatic agents are routinely use in spinal tumor surgery, but there have been no comparisons between these methods. This report compares the efficiency of various methods of bleeding control and their influence on outcome and survival after decompression procedures for MRCC. MATERIALS AND METHODS: This was a retrospective case-control study of 54 patients with hypervascular extraosseous MRCC. All patients underwent palliative decompression procedures. We compared two groups of patients stratified by methods of bleeding control. The first group (EMB) included 32 patients who underwent preoperative embolization of a tumor. The second group (HEM) consisted of 22 patients, treated surgically using intraoperative local hemostatic agents. The parameters under evaluation were blood loss volume, drainage loss, possible complications, time of hospital stay and survival. RESULTS: The median intraoperative blood loss for EMB group [1275 (95% CI 1175-1500) mL] was slightly less than the median in HEM group [1400 (95% CI 1050-1725) mL] without significant differences (p = 0.681). The postoperative drainage loss in HEM group [250 (95% CI 140-325) mL] was significantly less than that in EMB group [500 (95% CI 425-550) mL] (p = 0.013). The complication rate (infections, hematomas, neurological deficit) was nearly equal in all groups. No statistically significant difference in overall survival was found between groups: EMB-26 months (1 year-93.3%, 3 years-26.7%) and HEM-24 months (1 year 95.2%, 3 years-16.3%) (p = 0.360). CONCLUSION: Our results suggest that not all patients with MRCC require preoperative embolization, because usage of modern hemostatic agents can be an alternative bleeding control method. PMID- 29525981 TI - NeuroPP: A Tool for the Prediction of Neuropeptide Precursors Based on Optimal Sequence Composition. AB - Neuropeptides (NPs) are short secreted peptides produced mainly in the nervous system and digestive system. They activate signaling cascades to control a wide range of biological functions, such as metabolism, sensation, and behavior. NPs are typically produced from a larger NP precursor (NPP) which includes a signal peptide sequence, one or more NP sequences, and other sequences. With the drastic growth of unknown protein sequences generated in the post-genomic age, it is highly desired to develop computational methods for identifying NPP rapidly and efficiently. In this article, we developed a predictor for NPPs based on optimized sequence composition of single amino acid, dipeptide, and tripeptide. Evaluated with independent data set, the predictor showed excellent performance that achieved an accuracy of 88.65% with AUC of 0.95. The corresponding web server was developed, which is freely available at http://i.uestc.edu.cn/neuropeptide/neuropp/home.html . It can help relevant researchers to screen candidate NP precursor, shorten experimental cycle, and reduce costs. PMID- 29525982 TI - Concurrence of multiple CNS complications in a post-irradiated nasopharyngeal cancer patient. PMID- 29525984 TI - Switching from Glargine to Degludec is not associated with an overt change in glucose control in a cohort of patients with type 1 diabetes: a CGM analysis. PMID- 29525983 TI - Identification of novel mutations in FFPE lung adenocarcinomas using DEPArray sorting technology and next-generation sequencing. AB - Formalin-fixed paraffin-embedded (FFPE) tissues are utilized as the standard diagnostic method in pathology laboratories. However, admixture of unwanted tissues and shortage of normal samples, which can be used to detect somatic mutation, are considered critical factors to accurately diagnose cancer. To explore these challenges, we sorted the pure tumor cells from 22 FFPE lung adenocarcinoma tissues via Di-Electro-Phoretic Array (DEPArray) technology, a new cell sorting technology, and analyzed the variants with next-generation sequencing (NGS) for the most accurate analysis. The allele frequencies of the all gene mutations were improved by 1.2 times in cells sorted via DEPArray (tumor suppressor genes, 1.3-10.1 times; oncogenes, 1.3-2.6 times). We identified 16 novel mutations using the sequencing from sorted cells via DEPArray technology, compared to detecting 4 novel mutation by the sequencing from unsorted cells. Using this analysis, we also revealed that five genes (TP53, EGFR, PTEN, RB1, KRAS, and CTNNB1) were somatically mutated in multiple homogeneous lung adenocarcinomas. Together, we sorted pure tumor cells from 22 FFPE lung adenocarcinomas by DEPArray technology and identified 16 novel somatic mutations. We also established the precise genomic landscape for more accurate diagnosis in 22 lung adenocarcinomas with mutations detected in pure tumor cells. The results obtained in this study could offer new avenues for the treatment and the diagnosis of squamous cell lung cancers. PMID- 29525985 TI - Random Migration Assays of Mammalian Cells and Quantitative Analyses of Single Cell Trajectories. AB - Cell migration is essential to many biological processes such as embryonic development, immune surveillance and wound healing. Random cell migration refers to the intrinsic ability of cells to migrate, often called cell motility. This basal condition contrasts with directed cell migration, where cells migrate toward a chemical or physical cue. Unlike Brownian particles, however, randomly migrating cells exhibit a directional persistence, i.e., they are more likely to sustain the movement in the direction they previously took than to change, even if this direction is randomly chosen in an isotropic environment. Here we describe how to set up time-lapse recording of mammalian cells freely moving on a two-dimensional surface coated with extracellular matrix proteins, how to acquire single cell trajectories from movies and how to extract key parameters that characterize cell motility, such as cell speed, directionality, mean square displacement, and directional persistence. PMID- 29525986 TI - Directional Collective Migration in Wound Healing Assays. AB - Cell migration is suppressed by confluence in a process called contact inhibition. Relieving contact inhibition upon scratching is one of the simplest ways to induce cell migration in a variety of cell types. Wound healing is probably most relevant to epithelial monolayers, because epithelial cells generally assume a barrier function, which must be restored as fast as possible by the healing process. This versatile assay, however, can also be applied to fibroblasts and to tumor cell types. Furthermore, assessing the cell response to scratch wounding requires no special equipment or reagents. It is one of the few cell migration assays, which can even be performed without videomicroscopy, since the closure of the wound can be estimated at fixed time points. Several hours after wounding, directional collective migration is easily assessed and quantified. However, cell proliferation, which is also induced by the relief of contact inhibition, is one of the confounding factors of wound healing assays that must be taken into account. A recent alternative to the scratch-induced wound is to use special inserts to seed cells into closely spaced chambers. When the insert is removed, contact inhibition is relieved, similar to the scratch induced wound. In this chapter, we provide the protocol of the two methods and compare their advantages and disadvantages. We also provide a protocol to estimate cell proliferation upon wound healing based on the incorporation of the nucleotide analog EdU. PMID- 29525987 TI - An In Vitro System to Study the Mesenchymal-to-Amoeboid Transition. AB - During the last few years, significant attention has been given to the plasticity of cell migration, i.e., the ability of individual cell to switch between different motility modes, in particular between mesenchymal and amoeboid motilities. This phenomenon is called the mesenchymal-to-amoeboid transition (MAT). Such a plasticity of cell migration is a mechanism, by which cancer cells can adapt their migration mode to different microenvironments and thus it may promote tumor dissemination. It was shown that interventions at certain regulatory points of mesenchymal motility as well as alterations of environmental conditions can trigger MAT. One of the approaches to induce MAT is to mechanically confine cells and one of the simplest ways to achieve this is to cultivate cells under agarose. This method does not require any special tool, is easily reproducible and allows cell tracking by videomicroscopy. We describe here a protocol, where MAT is associated with chemotaxis. PMID- 29525988 TI - An In Vitro System to Study the Epithelial-Mesenchymal Transition In Vitro. AB - The epithelial-mesenchymal transition (EMT) plays an important role in development and cancer progression. Upon EMT, epithelial cells lose stable cell cell adhesions and reorganize their cytoskeleton to acquire migratory activity. Recent data demonstrated that EMT drives cancer cells from the epithelial state to a hybrid epithelial/mesenchymal phenotype with retention of some epithelial markers (in particular, E-cadherin), which is important for cancer cell dissemination. In vitro studies of the effect of growth factors (in particular, epidermal growth factor (EGF)) on cultured cells can be highly advantageous for understanding the details of the early stages of EMT. The methods described in this chapter are intended for studying intermediate phenotypes of EMT. Time-lapse DIC microscopy is used for visualization of changes in morphology and motility of the cells stimulated with EGF. The transwell migration assay allows the evaluation of the migratory activity of the cells. Studying of dynamics of a fluorescently labeled actin-binding protein F-tractin-tdTomato using confocal microscopy allows detection of EGF-induced changes in the organization of the actin cytoskeleton. Live-cell imaging of cells stably expressing GFP-E-cadherin visualizes reorganization of stable tangential E-cadherin-based adherens junctions (AJs) into unstable radial AJs during the early stages of EMT. PMID- 29525989 TI - Detection of Migrasomes. AB - The migrasome is a newly discovered, migration-dependent membrane-bound cellular organelle. It functions in the active release of intracellular contents into the external environment and in cell-cell communications. Migrasomes have characteristic morphological features compared with intracellular organelles and extracellular vesicles. This unit describes methods for visualizing migrasomes by fluorescence microscopy and electron microscopy. PMID- 29525990 TI - 3D Endothelial Cell Migration. AB - Endothelial cells have the capacity to shift between states of quiescence and angiogenesis. The early stage of angiogenesis, sprouting, occurs with the synchronized activities of tip cells, which lead the migration of the sprout, and stalk cells, which elongate this vessel sprout. Here, we describe a method to study in vitro this early and rapid stage of sprouting angiogenesis. PMID- 29525991 TI - Transmigration of Leukocytes Across Epithelial Monolayers. AB - Migration of leukocytes through epithelial monolayers represents an essential step in the generation of an inflammatory response and is often seen in inflammatory conditions such as Crohn's disease (Matthews et al., Toxicol Pathol 42:91-98, 2014) and asthma (Lambrecht and Hammad, Nat Med 18:684-692, 2012). Transepithelial migration involves adhesion to the basal surface of the epithelium before migration through the epithelial cell layer to the apical surface. Analyzing this process can present a technical challenge due to complications of using a coculture model and trying to recapitulate an intact monolayer. Here we describe two methods of assessing transepithelial migration based on a Transwell assay, the first of which measures the apical-basal migration of epithelial cells and the second "Inverted" transwell assay that measures basal-apical transmigration of leukocytes and therefore more closely mimics the in vivo process. PMID- 29525992 TI - Evaluation of Tumor Cell Invasiveness In Vivo: The Chick Chorioallantoic Membrane Assay. AB - Metastases is largely responsible for the mortality among cancer patients. Metastasis formation is a complex multistep process, which results from the propagation of cancer cells from the primary tumor to distant sites of the body. Research on cancer metastasis aims to understand the mechanisms involved in the spread of cancer cells through the development of in vivo assays that assess cell invasion. Here we describe the use of the chick chorioallantoic membrane to evaluate cancer cell invasiveness in vivo. The chick chorioallantoic membrane assay is based on the detection and quantification of disseminated human tumor cells in the chick embryo femurs by real-time PCR amplification of human Alu sequences. PMID- 29525993 TI - Analysis of Invasion Dynamics of Matrix-Embedded Cells in a Multisample Format. AB - In vitro tests of cancer cell invasion are the "first line" tools of preclinical researchers for screening the multitude of chemical compounds or cell perturbations that may aid in halting or treating cancer malignancy. In order to have predictive value or to contribute to designing personalized treatment regimes, these tests need to take into account the cancer cell environment and measure effects on invasion in sufficient detail. The in vitro invasion assays presented here are a trade-off between feasibility in a multisample format and mimicking the complexity of the tumor microenvironment. They allow testing multiple samples and conditions in parallel using 3D-matrix-embedded cells and deal with the heterogeneous behavior of an invading cell population in time. We describe the steps to take, the technical problems to tackle and useful software tools for the entire workflow: from the experimental setup to the quantification of the invasive capacity of the cells. The protocol is intended to guide researchers to standardize experimental set-ups and to annotate their invasion experiments in sufficient detail. In addition, it provides options for image processing and a solution for storage, visualization, quantitative analysis, and multisample comparison of acquired cell invasion data. PMID- 29525994 TI - Using Systems Microscopy to Understand the Emergence of Cell Migration from Cell Organization. AB - Cell migration is a dynamic process that emerges from fine-tuned networks coordinated in three-dimensional space, spanning molecular, subcellular, and cellular scales, and over multiple temporal scales, from milliseconds to days. Understanding how cell migration arises from this complexity requires data collection and analyses that quantitatively integrate these spatial and temporal scales. To meet this need, we have combined quantitative live and fixed cell fluorescence microscopy, customized image analysis tools, multivariate statistical methods, and mathematical modeling. Collectively, this constitutes the systems microscopy strategy that we have applied to dissect how cells organize themselves to migrate. In this overview, we highlight key principles, concepts, and components of our systems microscopy methodology, and exemplify what we have learnt so far and where this approach may lead. PMID- 29525995 TI - Neuronal Precursor Migration in Ex Vivo Brain Slice Culture. AB - Neuronal migration during fetal brain development is a well-coordinated process between the migrating neurons and their substrates, the basal processes of the radial glial cells (RGCs). The progeny-progenitor relationship between the migrating neurons and the RGCs in the developing fetal brain may make interpretations of the results difficult, because the variable in question may affect both the RGCs and the migrating neurons in different ways. A transplantation assay combining migrating cells and the scaffolding tissue from two different sources may circumvent this issue. We developed an ex vivo brain slice transplantation assay that allows recording of migrating neurons in real time. PMID- 29525996 TI - In Vitro Models to Analyze the Migration of MGE-Derived Interneurons. AB - In the developing brain, MGE-derived interneuron precursors migrate tangentially long distances to reach the cortex in which they later establish connections with the principal cortical cells to control the activity of adult cortical circuits. Interneuron precursors exhibit complex morphologies and migratory properties, which are difficult to study in the heterogeneous and uncontrolled in vivo environment. Here, we describe two in vitro models in which the migration environment of interneuron precursors is significantly simplified and where their migration can be observed for one to 3 days. In one model, MGE-derived interneuron precursors are cultured and migrate on a flat synthetic substrate. In the other model, fluorescent MGE-derived interneuron precursors migrate on a monolayer of dissociated cortical cells. In both models, cell movements can be recorded by time-lapse microscopy for dynamic analyses. PMID- 29525997 TI - Cell Migration in Tissues: Explant Culture and Live Imaging. AB - Cell migration is a process that ensures correct cell localization and function in development and homeostasis. In disease such as cancer, cells acquire an upregulated migratory capacity that leads to their dissemination throughout the body. Live imaging of cell migration allows for better understanding of cell behaviors in development, adult tissue homeostasis and disease. We have optimized live imaging procedures to track cell migration in adult murine tissue explants derived from: (1) healthy gut; (2) primary intestinal carcinoma; and (3) the liver, a common metastatic site. To track epithelial cell migration in the gut, we generated an inducible fluorescent reporter mouse, enabling us to visualize and track individual cells in unperturbed gut epithelium. To image intratumoral cancer cells, we use a spontaneous intestinal cancer model based on the activation of Notch1 and deletion of p53 in the mouse intestinal epithelium, which gives rise to aggressive carcinoma. Interaction of cancer cells with a metastatic niche, the mouse liver, is addressed using a liver colonization model. In summary, we describe a method for long-term 3D imaging of tissue explants by two-photon excitation microscopy. Explant culturing and imaging can help understand dynamic behavior of cells in homeostasis and disease, and would be applicable to various tissues. PMID- 29525998 TI - Intravital Imaging of Tumor Cell Motility in the Tumor Microenvironment Context. AB - Cancer cell motility and invasion are key features of metastatic tumors. Both are highly linked to tumor microenvironmental parameters, such as collagen architecture or macrophage density. However, due to the genetic, epigenetic and microenvironmental heterogeneities, only a small portion of tumor cells in the primary tumor are motile and furthermore, only a small portion of those will metastasize. This creates a challenge in predicting metastatic fate of single cells based on the phenotype they exhibit in the primary tumor. To overcome this challenge, tumor cell subpopulations need to be monitored at several timescales, mapping their phenotype in primary tumor as well as their potential homing to the secondary tumor site. Additionally, to address the spatial heterogeneity of the tumor microenvironment and how it relates to tumor cell phenotypes, large numbers of images need to be obtained from the same tumor. Finally, as the microenvironment complexity results in nonlinear relationships between tumor cell phenotype and its surroundings, advanced statistical models are required to interpret the imaging data. Toward improving our understanding of the relationship between cancer cell motility, the tumor microenvironment context and successful metastasis, we have developed several intravital approaches for continuous and longitudinal imaging, as well as data classification via support vector machine (SVM) algorithm. We also describe methods that extend the capabilities of intravital imaging by postsacrificial microscopy of the lung as well as correlative immunofluorescence in the primary tumor. PMID- 29525999 TI - Using the Zebrafish Embryo to Dissect the Early Steps of the Metastasis Cascade. AB - Most cancers end up with the death of patients caused by the formation of secondary tumors, called metastases. However, how these secondary tumors appear and develop is only poorly understood. A fine understanding of the multiple steps of the metastasis cascade requires in vivo models allowing high spatiotemporal analysis of the behavior of metastatic cells. Zebrafish embryos combine several advantages such as transparency, small size, stereotyped anatomy, and easy handling, making it a very powerful model for cell and cancer biology, and in vivo imaging analysis. In the following chapter, we describe a complete procedure allowing in vivo imaging methods, at high throughput and spatiotemporal resolution, to assess the behavior of circulating tumor cells (CTCs) in an experimental metastasis assay. This protocol provides access, for the first time, to the earliest steps of tumor cell seeding during metastasis formation. PMID- 29526000 TI - Analysis of In Vivo Cell Migration in Mosaic Zebrafish Embryos. AB - Being optically clear, the zebrafish embryo is a nice model system to analyze cell migration in vivo. This chapter describes a combination of injection and cell transplant procedures that allows creation of mosaic embryos, containing a few cells labeled differently from their neighbors. Rapid 5D confocal imaging of these embryos permits to simultaneously track and quantify the movement of large cell groups, as well as analyze the cellular or subcellular dynamics of transplanted cells during their migration. In addition, expression of a candidate gene can be modified in transplanted cells. Comparing behavior of these cells to control or neighboring cells allows determination of the role of the candidate gene in cell migration. We describe the procedure, focusing on one specific cell population during gastrulation, but it can easily be adapted to other cell populations and other migration events during early embryogenesis. PMID- 29526001 TI - Analysis of Cell Shape and Cell Migration of Drosophila Macrophages In Vivo. AB - The most abundant immune cells in Drosophila are macrophage-like plasmatocytes that fulfill central roles in morphogenesis, immune and tissue damage response. The various genetic tools available in Drosophila together with high-resolution and live-imaging microscopy techniques make Drosophila macrophages an excellent model system that combines many advantages of cultured cells with in vivo genetics. Here, we describe the isolation and staining of macrophages from larvae for ex vivo structured illumination microscopy (SIM), the preparation of white prepupae for in vivo 2D random cell migration analysis, and the preparation of pupae (18 h after puparium formation, APF) for in vivo 3D directed cell migration analysis upon wounding using spinning disk microscopy. PMID- 29526002 TI - Migration of Q Cells in Caenorhabditis elegans. AB - During C. elegans larval development, the Q neuroblasts produce their lineage by three rounds of divisions along with continuous cell migrations. Their neuronal progeny is dispersed from the pharynx to the anus. This in vivo system to study cell migration is appealing for several reasons. The lineage development is stereotyped; functional analysis and genomic screens are rendered easy and powerful thanks to powerful tools; transgenic manipulations and genome engineering are efficient and can be conveniently combined with live-cell imaging. Here we describe a series of protocols in Q cell migration studies, including quantifications of progeny position, genetic screening strategies, preparation of migration mutants or transgenic worms expressing related fluorescent proteins, multipositional time-lapse tracking of Q cell migration using confocal microscopy and image analyses of single cell movements and dynamics. PMID- 29526003 TI - Imaging the Molecular Machines That Power Cell Migration. AB - Animal cell migration constitutes a complex process involving a multitude of forces generated and maintained by the actin cytoskeleton. Dynamic changes of the cell surface, for instance to effect cell edge protrusion, are at the core of initiating migratory processes, both in tissue culture models and whole animals. Here we sketch different aspects of imaging representative molecular constituents in such actin-driven processes, which power and regulate the polymerisation of actin filaments into bundles and networks, constituting the building blocks of such protrusions. The examples presented illustrate both the diversity of subcellular distributions of distinct molecular components, according to their function, and the complexity of dynamic changes in protrusion size, shape, and/or orientation in 3D. Considering these dynamics helps mechanistically connecting subcellular distributions of molecular machines driving protrusion and migration with their biochemical function. PMID- 29526004 TI - A Biologist-Friendly Method to Analyze Cross-Correlation Between Protrusion Dynamics and Membrane Recruitment of Actin Regulators. AB - During mesenchymal cell motility, various actin regulators are recruited to the leading edge with exquisite precision in time and space to generate protrusion and retraction cycles. We present here an automated method, named CorRecD (from Correlation Recruitment Dynamics), which quantifies cell edge dynamics, protein recruitment and analyze their cross-correlation. The Wave Regulatory Complex (WRC), a master driver of protrusions, is used as a case-of-study. This biologist friendly method relies on free software tools and can be applied to any fluorescently tagged protein of interest. PMID- 29526005 TI - Using Single-Protein Tracking to Study Cell Migration. AB - To get a complete understanding of cell migration, it is critical to study its orchestration at the molecular level. Since the recent developments in single molecule imaging, it is now possible to study molecular phenomena at the single molecule level inside living cells. In this chapter, we describe how such approaches have been and can be used to decipher molecular mechanisms involved in cell migration. PMID- 29526006 TI - Optogenetic Control of Cell Migration. AB - Subcellular optogenetics allows specific proteins to be optically activated or inhibited at a restricted subcellular location in intact living cells. It provides unprecedented control of dynamic cell behaviors. Optically modulating the activity of signaling molecules on one side of a cell helps optically control cell polarization and directional cell migration. Combining subcellular optogenetics with live cell imaging of the induced molecular and cellular responses in real time helps decipher the spatially and temporally dynamic molecular mechanisms that control a stereotypical complex cell behavior, cell migration. Here we describe methods for optogenetic control of cell migration by targeting three classes of key signaling switches that mediate directional cellular chemotaxis-G protein coupled receptors (GPCRs), heterotrimeric G proteins, and Rho family monomeric G proteins. PMID- 29526007 TI - Electrotaxis: Cell Directional Movement in Electric Fields. AB - Electrotaxis plays an important role during embryogenesis, inflammation, wound healing, and tumour metastasis. However, the mechanisms at play during electrotaxis are still poorly understood. Therefore intensive studies on signaling pathways involved in this phenomenon should be carried out. In this chapter, we described an experimental system for studying electrotaxis of Amoeba proteus, mouse embryonic fibroblasts (MEF), Walker carcinosarcoma cells WC256, and bone marrow adherent cells (BMAC). PMID- 29526008 TI - Analysis of Random Migration of Dictyostelium Amoeba in Confined and Unconfined Environments. AB - Dictyostelium discoideum has proven to be an excellent model to study amoeboid cell migration. During their life cycle, Dictyostelium cells exhibit distinct modes of motility. Individual growth-phase cells explore new territories by random cell migration using the core cell motility machinery, but they can also hunt bacteria by detection and chemotaxis toward the by-product folate. After depletion of nutrients, the cells initiate a developmental program allowing streaming of the cells into aggregation centers by chemotaxis toward cAMP and by cell-to-cell adhesion. Subsequent development is associated with complex rotational movement of the compacted aggregates to drive cell type specific sorting, which in turn is necessary for terminal culmination and formation of fruiting bodies. Here we describe a protocol for the analyses of cell motility of vegetative Dictyostelium cells in unconfined and mechanically confined settings. PMID- 29526009 TI - Neutrophil Chemotaxis in One Droplet of Blood Using Microfluidic Assays. AB - Neutrophils are the most abundant leukocytes in blood serving as the first line of host defense in tissue damage and infections. Upon activation by chemokines released from pathogens or injured tissues, neutrophils migrate through tissues toward sites of infections along the chemokine gradients, in a process named chemotaxis. Studying neutrophil chemotaxis using conventional tools, such as a transwell assay, often requires isolation of neutrophils from whole blood. This process requires milliliters of blood, trained personnel, and can easily alter the ability of chemotaxis. Microfluidics is an enabling technology for studying chemotaxis of neutrophils in vitro with high temporal and spatial resolution. In this chapter, we describe a procedure for probing human neutrophil chemotaxis directly in one droplet of whole blood, without neutrophil isolation, using microfluidic devices. The same devices can be applied to the study the chemotaxis of neutrophils from small animals, e.g., mice and rats. PMID- 29526010 TI - Leukocyte Migration and Deformation in Collagen Gels and Microfabricated Constrictions. AB - In multicellular organisms, cell migration is a complex process. Examples of this are observed during cell motility in the interstitial space, full of extracellular matrix fibers, or when cells pass through endothelial layers to colonize or exit specific tissues. A common parameter for both situations is the fast adaptation of the cellular shape to their irregular landscape. In this chapter, we describe two methods to study cell migration in complex environments. The first one consists in a multichamber device for the visualization of cell haptotaxis toward the collagen-binding chemokine CCL21. This method is used to study cell migration as well as deformations during directed motility, as in the interstitial space. The second one consists in microfabricated channels connected to small constrictions. This procedure allows the study of cell deformations when single cells migrate through small holes and it is analogous to passage of cells through endothelial layers, resulting in a simplified system to study the mechanisms operating during transvasation. Both methods combined provide a powerful hub for the study of cell plasticity during migration in complex environments. PMID- 29526011 TI - Microfluidic Devices for Examining the Physical Limits of Migration in Confined Environments. AB - Cell migration plays a key role in many physiological and pathological conditions during which cells migrate primarily in the 3D environments formed by tissues. Microfluidics enables the design of simple devices that can mimic in a highly controlled manner the geometry and dimensions of the interstices encountered by cells in the body. Here we describe the design, fabrication, and implementation of an array of channels with a range of cross sections to investigate migration of cells and cell clusters through confined spaces. By combining this assay with a motorized microscope stage, image data can be acquired with high throughput to determine the physical limits of migration in confined environments and their biological origin. PMID- 29526012 TI - Controlling Confinement and Topology to Study Collective Cell Behaviors. AB - Confinement and substrate topology strongly affect the behavior of cell populations and, in particular, their collective migration. In vitro experiments dealing with these aspects require strategies of surface patterning that remain effective over long times (typically several days) and ways to control the surface topology in three dimensions. Here, we describe protocols addressing these two aspects. High-resolution patterning of a robust cell-repellent coating is achieved by etching the coating through a photoresist mask patterned directly on the coated surface. Out-of-plane curvature can be controlled using glass wires or corrugated "wavy" surfaces. PMID- 29526013 TI - Correction to: Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer. AB - Following the publication from the original article, it came to our attention that we unintentionally neglected to acknowledge some text overlap with previous publications. PMID- 29526014 TI - Judaism as a Group Evolutionary Strategy : A Critical Analysis of Kevin MacDonald's Theory. AB - MacDonald argues that a suite of genetic and cultural adaptations among Jews constitutes a "group evolutionary strategy." Their supposed genetic adaptations include, most notably, high intelligence, conscientiousness, and ethnocentrism. According to this thesis, several major intellectual and political movements, such as Boasian anthropology, Freudian psychoanalysis, and multiculturalism, were consciously or unconsciously designed by Jews to (a) promote collectivism and group continuity among themselves in Israel and the diaspora and (b) undermine the cohesion of gentile populations, thus increasing the competitive advantage of Jews and weakening organized gentile resistance (i.e., anti-Semitism). By developing and promoting these movements, Jews supposedly played a necessary role in the ascendancy of liberalism and multiculturalism in the West. While not achieving widespread acceptance among evolutionary scientists, this theory has been enormously influential in the burgeoning political movement known as the "alt-right." Examination of MacDonald's argument suggests that he relies on systematically misrepresented sources and cherry-picked facts. It is argued here that the evidence favors what is termed the "default hypothesis": Because of their above-average intelligence and concentration in influential urban areas, Jews in recent history have been overrepresented in all major intellectual and political movements, including conservative movements, that were not overtly anti Semitic. PMID- 29526015 TI - Allele frequencies of 18 autosomal STR loci in the Uyghur population living in Kashgar Prefecture, Northwest China. AB - There is currently no large population data-based data set in Kashgar Prefecture Uyghur. The allele frequencies of 18 autosomal short tandem repeat (STR) loci included in the DNATyperTM 19 kit were evaluated in 2600 Uyghur individuals living in Kashgar Prefecture, Northwest China. The values of combined power of discrimination (CPD) and combined probability of exclusion (CPE) of all 18 autosomal STR loci were 0.99999999999999999998235 and 0.99999998670, respectively. Phylogenetic analyses revealed that the Uyghur population has a closer relationship with the Xinjiang-Kazakh, Inner Mongolia-Mongolian, and other three Uyghur populations. In addition, our results are consistent with the hypothesis that Uyghur population is an admixture of Eastern Asian and European populations. PMID- 29526018 TI - A Review of the Chemistry, Pesticide Use, and Environmental Fate of Sulfur Dioxide, as Used in California. AB - Sulfur dioxide (SO2) is an atmospheric pollutant that is moderately persistent in the atmosphere and highly water soluble. When applied as a pesticide, SO2 may be transported, deposited, or transformed in various chemical reactions. SO2 participates in the sulfur biogeochemical cycle, which involves complex reactions of sulfur-containing compounds between abiotic and biotic components of ecosystems. The main degradation route of SO2 is atmospheric oxidation, and sulfur oxides may undergo long-distance transport prior to removal from the atmosphere by wet or dry deposition. According to the Pesticide Use Reporting (PUR) database maintained by the California Department of Pesticide Regulation (DPR), SO2 use in California from 2010 to 2015 was primarily for fumigations (96%), including treatments of postharvest grape products and winery equipment sterilizations. Other site uses contributed less than 5% of reported statewide SO2 use from 2010 to 2015. A slight increasing trend in use of SO2 as a pesticide was observed from 2010 to 2015, with the highest reported uses of SO2 within California counties during the months of July-November. Although the primary sources of SO2 in the environment are anthropogenic emissions from the combustion of fossil fuels, emissions of SO2 from pesticide uses have the potential to contribute to the environmental and public welfare impacts of SO2 pollution. Oxidation of atmospheric SO2 may contribute to the negative environmental and public welfare impacts of acid rain, which include toxicity to aquatic organisms, fish, and terrestrial vegetation, and corrosion of man-made materials. PMID- 29526017 TI - Resveratrol Prevents the Cellular Damages Induced by Monocrotophos via PI3K Signaling Pathway in Human Cord Blood Mesenchymal Stem Cells. AB - The role of resveratrol (RV) as a neuroprotectant is well recognized, and cellular molecules involved in imparting the physiological effect have been well illustrated. However, some ambiguity still prevails as the specific receptor, and downstream signaling molecules are not yet clearly stated. So, we investigated the signaling pathway(s) involved in its cellular protection in the human umbilical cord blood mesenchymal stem cell (hUCB-MSC) derived neuronal cells. The mesenchymal stem cells were exposed to various concentrations (10, 100, 1000 MUM) of monocrotophos (MCP), a known developmental neurotoxic organophosphate pesticide, for a period of 24 h. The MAPK signaling pathways (JNK, p38, and ERK) known to be associated with MCP-induced damages were also taken into consideration to identify the potential connection. The biological safe dose of RV (10 MUM) shows a significant restoration in the MCP-induced alterations. Under the specific growth conditions, RV exposure was found to promote neuronal differentiation in the hUCB-MSCs. The exposure of cells to a specific pharmacological inhibitor (LY294002) of PI3K confirms the significant involvement of PI3K-mediated pathway in the ameliorative responses of RV against MCP exposure. Our data identifies the substantial role of RV in the restoration of MCP-induced cellular damages, thus proving to have a therapeutic potential against organophosphate pesticide-induced neurodegeneration. PMID- 29526019 TI - Systematic versus sentinel-lymph-node-driven axillary-lymph-node dissection in clinically node-negative patients with operable breast cancer. Results of the GF GS01 randomized trial. AB - PURPOSE: Sentinel-lymph-node (SLN) resection seems to minimize systematic axillary-lymph-node dissection (sALND) side effects in operated breast cancer patients. We explored whether SLN resection achieves similar therapeutic outcomes as sALND but with fewer side effects. METHODS: A randomized, controlled, open label trial with parallel-group design compared sALND restricted to cases with positive SLN biopsy (test arm, n = 774) versus SLN biopsy followed by sALND (control arm, n = 770). RESULTS: The five-year overall survivals in control and test arms were 96.42 and 95.64% (P = 0.2925). The estimated difference was nearly zero (precisely, - 0.79%, one-tailed 95% confidence interval (CI) limit - 2.44%). In a multivariate Cox model, the adjusted hazard ratio in the test arm was HR 0.81 (upper 95% CI limit 1.17). Advanced age (HR 1.05 per additional year, CI [1.03-1.08]), negative progesterone receptor (HR 2.17 [1.35-3.45]), SLN metastasis (HR 1.69 [1.03-2.79]), and only one SLN identification technique (HR 4.14 [1.21-14.18]) were associated with lower survival. Patients with >= 1 severe side effect at 1 month in control and test arms were 173/703 = 24.6% [21.5-28.0%] and 91/693 = 13.1% [10.7-15.9%] (P < 0.001). The estimated sensitivity of SLN biopsy (control arm) was 145/178 = 81.5% [74.8-86.7%]. CONCLUSIONS: Restricting ALND to cases with positive SLN biopsy does not affect the overall survival but reduces by 11.5% [7.5-15.6%] (P < 0.001) the risk of severe short-time side effects of sALND. PMID- 29526020 TI - Disparities in Oral Cancer Awareness: a Population Survey in Tehran, Iran. AB - Oral cancer is a life-threatening disease with low survival rates, especially when diagnosed in an advanced stage. Lack of awareness about this cancer among the population is proposed as a possible reason for this diagnostic delay. The aim of this study was to evaluate oral cancer awareness, as well as the association of this with sociodemographic status in Tehran. In this cross sectional population-based survey, 1800 self-administered questionnaires (collecting sociodemographic data, questions regarding oral cancer awareness and the source of information) were distributed through multistage stratified random sampling. Scores for questions ranged from 0 to 4, and totals were summed. The outcome of question responses was also analyzed separately. In total, 1312 questionnaires were available for analysis, from 788 females and 489 males (37.8 +/- 9.02 years). Only 30% of the respondents were aware of oral cancer. The average score for awareness was 1.09 +/- 1.6 with no significant differences between age groups and genders. Almost 6.5% of participants had complete awareness about oral cancer. A significant difference was found between mean scores in different levels of education and occupation (p = 0.0001). From 585 responses to the "source of information" question, "public media" was the most important source (almost 50%). Only 2% mentioned "dentists" as a source of information. This study indicated an alarming lack of oral cancer awareness and literacy in Tehran, Iran. Dentists should be obliged to practice their pivotal role in informing the public about oral cancer. PMID- 29526016 TI - Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington's Disease. AB - Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington's disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington's disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD. PMID- 29526021 TI - Assessing Key Stakeholders' Knowledge, Needs, and Preferences for Head and Neck Cancer Survivorship Care Plans. AB - Cancer survivorship care plans (SCPs) are endorsed to support quality care for cancer survivors, but uptake is slow. We assessed knowledge, needs, and preferences for SCP content and delivery from a wide variety of stakeholders. We focused SCP content for head and neck cancer as it is a disease prone to long term side effects requiring management from multiple providers. We conducted telephone-based, qualitative interviews. We purposively sampled head and neck cancer survivors (n = 4), primary care physicians in the community (n = 5), and providers affiliated with a large academic medical center (n = 5) who treat head and neck cancer, cancer specialists (n = 6), and nurse practitioners/supportive care staff (n = 5). Interviews were recorded, transcribed, and analyzed using direct content analysis. Few participants reported personal experience with SCPs, but most supported the concept. Several key themes emerged: (1) perceived ambiguity regarding roles and responsibilities for SCPs, (2) a need to tailor the content and language based on the intended recipient, (3) documentation process should be as automated and streamlined as possible, (4) concerns about using the SCP to coordinate with outside providers, and (5) that SCPs would have added value as a "living document." We also report SCP-related issues that are unique to serving patients diagnosed with head and neck cancer. Effort is needed to tailor SCPs for different recipients and optimize their potential for successful implementation, impact on care outcomes, and sustainability. Many cancer survivors may not receive a SCP as part of routine care. Survivors could engage their health care team by requesting a SCP. PMID- 29526023 TI - Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol. AB - Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders. PMID- 29526022 TI - Volatiles of Grape Inoculated with Microorganisms: Modulation of Grapevine Moth Oviposition and Field Attraction. AB - Semiochemicals released by plant-microbe associations are used by herbivorous insects to access and evaluate food resources and oviposition sites. Adult insects may utilize microbial-derived nutrients to prolong their lifespan, promote egg development, and offer a high nutritional substrate to their offspring. Here, we examined the behavioral role of semiochemicals from grape microbe interactions on oviposition and field attraction of the grapevine moth Lobesia botrana (Denis & Schiffermuller). The volatile constituents released by grape inoculated with yeasts (Hanseniaspora uvarum (Niehaus), Metschnikowia pulcherrima (Pitt.) M.W. Miller, Pichia anomala, Saccharomyces cerevisiae Meyen ex E.C. Hansen, and Zygosaccharomyces rouxii (Boutroux) Yarrow), sour rot bacteria (Acetobacter aceti (Pasteur) Beijerinck and Gluconobacter oxydans (Henneberg) De Ley), and a fungal pathogen (Botrytis cinerea Pers.) all endemic of the vineyard were sampled by solid-phase microextraction and analyzed by gas chromatography coupled with mass spectrometry. Ethanol, 3-methyl-1-butanol, and ethyl acetate were the most common volatiles released from all microbe-inoculated grapes. In addition, acetic acid was released at a substantial amount following bacteria inoculation and in a three-way inoculation with yeasts and the fungus. 2 phenylethanol, a compound reported to attract tortricid moths when used in combination with acetic acid, was found at a relatively low level in all microbial combinations as well as in the control grape. While grapes inoculated with a consortium of yeasts stimulated oviposition in comparison with uninoculated berries, the phytopathogenic fungus deterred egg-laying. Nonetheless, the highest preference to lay eggs was measured when the yeasts were co-inoculated with the fungus. The lowest preference was obtained when grapes were inoculated with sour rot bacteria and their binary co-inoculation with yeasts and the fungus. Interestingly, oviposition on berries simultaneously inoculated with all the three microbial groups was unaffected. Lures loaded with either acetic acid or 2-phenylethanol were not attractive when placed in traps as single component in vineyards, but a binary blend attracted both sexes of grapevine moth in significant numbers. Further addition of the three most common volatiles released by infected berries (ethanol, 3-methyl-1-butanol, and ethyl acetate) did not significantly increase moth catch with this binary blend. The ecological implications of the grape-microorganism and grapevine moth interaction as well as the possibility to develop a pest monitoring system based on microbial volatiles are discussed. PMID- 29526024 TI - Comparative study between Larval Packet Test and Larval Immersion Test to assess the effect of Metarhizium anisopliae on Rhipicephalus microplus tick larvae. AB - Entomopathogenic fungi, such as Metarhizium anisopliae, for the control of arthropods, have been studied for more than 20 years. The aim of this study was to determine the best methodology to evaluate the in vitro effect of the fungus M. anisopliae on Rhipicephalus microplus tick larvae. We compared a modified Larval Packet Test (LPT) and a Larval Immersion Test (LIT). For the LPT filter papers were impregnated with 1 mL of M. anisopliae suspension in Triton X-100 at 0.02%, in concentrations of 106, 107 and 108 conidia/mL and subsequently folded to include the larval ticks. LIT was performed by immersing the larvae in M. anisopliae suspensions for 5 min using the same three concentrations, then the larvae were placed on filter paper clips. For LPT, the LT50 values obtained were 134.6, 27.2 and 24.8 days for concentrations of 106, 107 and 108 conidia/mL; and the mortality after 21 days was 17.3, 17.6 and 38%, respectively. The LT50 values of LIT were 24.5, 20 and 9.2 days with mortality after 21 days of 50.5, 64.7 and 98% for 106, 107 and 108 conidia/mL, respectively. For the same conidia concentration, LIT showed a higher mortality in a shorter time interval when compared with LPT. These differences between the methods tested must be taking into account in further screening and effect studies with M. anisopliae. The set of results shown here could optimize the protocol used to identify M. anisopliae strains pathogenic against R. microplus. PMID- 29526025 TI - Sensitivity to house dust mite allergens and prevalence of allergy-causing house dust mite species in Pothwar, Pakistan. AB - This study is the first report on the epidemiological status of house dust mite (HDM) allergy in Pothwar, Pakistan. Allergy data of 2087 symptomatic patients were obtained, of whom 1706 (81.7%) patients were skin-prick-test positive for HDM allergens. This percentage was significantly higher than for pollen and food allergens. In the results of this study Dermatophagoides farinae (61%) and D. pteronyssinus (29%) were the predominant species in the study area. Besides these pyroglyphids, predatory Cheyletus sp. (10%) and an oribatid mite sp. (1%) were also observed. Random and patients' houses showed 87.4 and 87.1% positive mite infestation, respectively. Mean (+/- SEM) D. farinae counts per g of dust in random samples was 235.4 +/- 7.93 compared to 274.7 +/- 10.78 from patients' homes. Mean D. pteronyssinus counts from random houses compared to patients' houses were 115.0 +/- 4.57 and 124.6 +/- 5.76, respectively. Mite counts depicted seasonal variation, with peaks during monsoon season. ELISA results of dust samples demonstrated that of the dust samples with > 10 ug/g of dust, the threshold value described as a risk factor for developing asthma, 57.6% had Der f1 and 20% Der p1 allergen load. Mean Der f1 burden was significantly higher than Der p1, with maximum levels during monsoon and autumn seasons. This research established a better awareness about the epidemiological status of HDM allergy and prevalence of allergy causing HDM species in Pakistan. PMID- 29526027 TI - An insider's view on how Ki-67, the bright beacon of cell proliferation, became very popular. A tribute to Johannes Gerdes (1950-2016). PMID- 29526026 TI - CXCL5 regulation of proliferation and migration in human non-small cell lung cancer cells. AB - Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the subgroup of CXC-type chemokine family, is an inflammatory factor involved in the progression of lung cancer, but the underlying mechanism remains unclear. In this study, we investigated the effects of CXCL5 on proliferation and migration in non-small cell lung cancer (NSCLC) using tissue microarrays from NSCLC patients and H460 cells transfected with a CXCL5-interfered lentivirus vector or stimulated with recombinant CXCL5. We observed that the expression of CXCL5 was significantly higher in lung cancer cell lines, and high CXCL5 was associated with high chemokine (C-X-C motif) receptor 2 expression and was significantly associated with poor differentiation. The high expression of CXCL5 was associated with poor NSCLC prognosis and was an independent predictive factor. Furthermore, downregulation of CXCL5 in H460 cells significantly reduced proliferation and migration. Recombinant CXCL5 promoted H460 cell proliferation and movement by activating MAPK/ERK1/2 and PI3K/AKT signaling. Our study elucidates the important role of CXCL5 in the progression and prognosis of NSCLC. These findings suggested that CXCL5 might be a potential biomarker and novel therapeutic target for lung cancer. PMID- 29526028 TI - Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses. AB - BACKGROUND: In addition to the extent of atypical keratinocytes throughout the epidermis, actinic keratoses (AKs) are histologically characterized by downward directed basal-layer expansion. It is not known whether this growth pattern correlates with the risk of developing invasive squamous cell carcinoma (iSCC). OBJECTIVES: To characterize the prevalence of downward-directed basal-layer expansion of AKs adjacent to iSCC. METHODS: The epidermis overlying and adjacent to iSCCs was assessed histologically. We determined the histological grade (AK I III), basal growth pattern (PRO I-III) and accompanying parameters such as adnexal involvement. RESULTS: Among 307 lesions, 52.4% of AKs were histologically classified as AK grade I, 38.1% as AK II and 6.8% as AK III (chi2 -test, P < 0.001). Only 2.6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25.7%, PRO II in 31.9% and PROIII in 39.4% of cases. Only 2.9% of AKs showed no basal growth (chi2 -test, P < 0.001). In total 118 AKs (48.8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18.6% of cases, PRO II in 30.5% and PRO III in 50.8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0.42). CONCLUSIONS: Basal proliferative AKs, as well as atypical keratinocytes restricted to the lower third of the epidermis, are most commonly seen adjacent to iSCC, with less evidence for full-thickness epidermal dysplasia. Our study supports the important role of dysplastic keratinocytes in the epidermal basal layer and their potential association with iSCC. PMID- 29526029 TI - Cascaded systems analysis of charge sharing in cadmium telluride photon-counting x-ray detectors. AB - PURPOSE: Single-photon-counting (SPC) and spectroscopic x-ray detectors are under development in academic and industry laboratories for medical imaging applications. The spatial resolution of SPC and spectroscopic x-ray detectors is an important design criterion. The purpose of this article was to extend the cascaded systems approach to include a description of the spatial resolution of SPC and spectroscopic x-ray imaging detectors. METHODS: A cascaded systems approach was used to model reabsorption of characteristic x rays, Coulomb repulsion, and diffusion in SPC and spectroscopic x-ray detectors. In addition to reabsorption, diffusion, and Coulomb repulsion, the model accounted for x-ray conversion to electron-hole (e-h) pairs, integration of e-h pairs in detector elements, electronic noise, and energy thresholding. The probability density function (PDF) describing the number of e-h pairs was propagated through each stage of the model and was used to derive new theoretical expressions for the large-area gain and modulation transfer function (MTF) of CdTe SPC x-ray detectors, and the energy bin sensitivity functions and MTFs of CdTe spectroscopic detectors. Theoretical predictions were compared with the results of MATLAB-based Monte Carlo (MC) simulations and published data. Comparisons were also made with the MTF of energy-integrating systems. RESULTS: Under general radiographic conditions, reabsorption, diffusion, and Coulomb repulsion together artificially inflate count rates by 20% to 50%. For thicker converters (e.g. 1000 MUm) and larger detector elements (e.g. 500 MUm pixel pitch) these processes result in modest inflation (i.e. ~10%) in apparent count rates. Our theoretical and MC analyses predict that SPC MTFs will be degraded relative to those of energy-integrating systems for fluoroscopic, general radiographic, and CT imaging conditions. In most cases, this degradation is modest (i.e., ~10% at the Nyquist frequency). However, for thicker converters, the SPC MTF can be degraded by up to 25% at the Nyquist frequency relative to EI systems. Additionally, unlike EI systems, the MTF of spectroscopic systems is strongly dependent on photon energy, which results in energy-bin-dependent spatial resolution in spectroscopic systems. CONCLUSIONS: The PDF-transfer approach to modeling signal transfer through SPC and spectroscopic x-ray imaging systems provides a framework for understanding system performance. Application of this approach demonstrated that charge sharing artificially inflates the SPC image signal and degrades the MTF of SPC and spectroscopic systems relative to energy-integrating systems. These results further motivate the need for anticharge-sharing circuits to mitigate the effects of charge sharing on SPC and spectroscopic x-ray image quality. PMID- 29526030 TI - Superior vena cava stenosis due to lipomatosis of the right atrium. PMID- 29526031 TI - Novel compound heterozygous mutations in KREMEN1 confirm it as a disease gene for ectodermal dysplasia. PMID- 29526032 TI - PAR1 contribution in acute electrophysiological properties of oral anticoagulants in rabbit pulmonary vein sleeve preparations. AB - Whether oral anticoagulants, vitamin K antagonists (VKAs), and nonvitamin K oral anticoagulant (NOACs) frequently prescribed to atrial fibrillation (AF) patients, do themselves have a pro- or anti-arrhythmic effect have never been addressed. Transmembrane action potentials were recorded in an acute rabbit model of superfused pulmonary veins (PVs) sleeves preparations using standard microelectrode technique. Fluindione 10 MUm (n = 6) increased the AP (action potential) duration (APD), induced a significantly Vmax depression (from 95 +/- 14 to 53 +/- 5 V/s, P < 0.05), and 2 : 1 blocks during rapid atrial pacing thus evoking class I anti-arrhythmic properties, and prevented spontaneous trigger APs. Apixaban 10 MUm (n = 6) increased the APD, significantly prolonged the effective refractory period (from 56.3 +/- 4.2 to 72.0 +/- 8.6 ms, P < 0.05), and prevented triggered APs occurrence. Fluindione and apixaban effects were suppressed with the addition of the protease-activated receptors 1 (PAR 1) agonist SFLLR-NH2 . Warfarin 10 MUm (n = 6) significantly abbreviated the early refractory period (from 56.3 +/- 4.2 to 45.0 +/- 2.2 ms, P < 0.05) and increased triggered APs occurrence that were successfully prevented by nifedipine but not by the addition of the protease-activated receptors 1 agonist SFLLR-NH2 . In this acute rabbit PVs model, VKAs and NOACs, at physiological concentrations, exhibited very different pharmacological properties that influence PVs electrophysiology, implying PAR1, with fluindione and apixaban which exhibited more anti-arrhythmic properties, whereas warfarin exhibited more pro-arrhythmic properties. PMID- 29526033 TI - Land use intensity, rather than plant species richness, affects the leaching risk of multiple nutrients from permanent grasslands. AB - The intensification of land use constitutes one of the main drivers of global change and alters nutrient fluxes on all spatial scales, causing landscape-level eutrophication and contamination of natural resources. Changes in soil nutrient concentrations are thus indicative for crucial environmental issues associated with intensive land use. We measured concentrations of NO3 -N, NH4 -N, P, K, Mg, and Ca using 1,326 ion-exchange resin bags buried in 20 cm depth beneath the main root zone in 150 temperate grasslands. Nutrient concentrations were related to land use intensity, that is, fertilization, mowing, grazing intensities, and plant diversity by structural equation modeling. Furthermore, we assessed the response of soil nutrients to mechanical sward disturbance and subsequent reseeding, a common practice for grassland renewal. Land use intensity, especially fertilization, significantly increased the concentrations of NO3 -N, NH4 -N, K, P, and also Mg. Besides fertilization (and tightly correlated mowing) intensity, grazing strongly increased NO3 -N and K concentrations. Plant species richness decreased P and NO3 -N concentrations in soil when grassland productivity of the actual year was statistically taken into account, but not when long-term averages of productivity were used. Thus, we assume that, in the actual study year, a distinct drought period might have caused the observed decoupling of productivity from fertilization and soil nutrients. Breaking up the grassland sward drastically increased NO3 -N concentrations (+146%) but reduced NH4 -N, P, and K concentrations, unbalancing soil nutrient stoichiometry and boosting the risk of N leaching. Reseeding the sward after disturbance did not have a short-term effect on nutrient concentrations. We conclude that renewal of permanent grassland should be avoided as far as possible and future grassland management has to strongly rise the effectiveness of fertilization. Additionally, grassland management might have to increasingly taking care of periods of drought, in which nutrient additions might not increase plant growth but potentially only facilitate leaching. PMID- 29526035 TI - Trends and characteristics of maxillofacial fractures sustained during sports activities in Japan. AB - BACKGROUND/AIM: Sports activity increases the risk of maxillofacial fractures. The aim of this study was to analyze trends and characteristics of maxillofacial fractures sustained during sports activity to develop more effective treatments and possibly to prevent injury. MATERIALS AND METHODS: Data of 248 patients with maxillofacial fractures sustained during sports activity were retrospectively analyzed based on their clinical records and radiographs. RESULTS: The patients were 226 males (91.1%) and 22 females (8.9%). Their ages ranged from 6 to 70 years and the majority were in their second decade. The fractures were sustained in various sports which included baseball in 85 patients (34.3%), rugby in 40 (16.1%), soccer in 30 (12.1%), softball in 22 (8.9%), golf in 10 (4.0%), hockey in 8 (3.2%), combat sports in 28 (11.3%), and others in 29 (11.7%). The cause of injuries was collision with another player in 97 patients (39.1%), hit by a ball in 89 (35.9%), intended attack in 20 (8.1%), hit by equipment of another player in 15 (6.0%), a fall in 14 (5.6%), and collision with ground equipment in 13 (5.2%). The site of fractures was the mandible in 145 patients (58.5%), midface in 100 (40.3%), and both in 3 (1.2%). Among 210 fracture sites in the mandible, 77 (36.6%) were in the angle, 68 (32.4%) in the symphysis, and 65 (30.9%) in others. Among 103 fractures in the midface, 58 (56.3%) were in the zygoma, 26 (25.2%) in alveolar bone, and 19 (18.4%) in others. Treatment was observation in 67 patients (27.0%), maxillomandibular fixation in 64 (25.8%), open reduction and internal fixation in 63 (25.4%), intramaxillary splinting in 40 (16.1%), transcutaneous reduction in 10 (4.0%), and other procedures in 4 (1.6%). CONCLUSION: Maxillofacial fractures sustained during sports activity showed characteristic features dependent on the type of sport and cause of injury. PMID- 29526034 TI - Dyssegmental dysplasia, Silverman-Handmaker type: A challenging antenatal diagnosis in a dizygotic twin pregnancy. AB - BACKGROUND: Dyssegmental dysplasia Silverman-Handmaker (DDSH; MIM 224410) type is an extremely rare skeletal dysplasia caused by functional null mutations in the perlecan gene. Less than forty cases are reported in the literature, of which only four were prenatally detected. METHODS: We report on a dizygotic twin pregnancy from consanguineous parents for which one of the twins presented prenatally with severe micromelia, limb bowing and scoliosis, and postnatally with clinical and radiological features compatible with a diagnosis of dyssegmental dysplasia. Molecular studies were undertaken to confirm the clinical diagnosis of DDSH. RESULTS: Molecular analysis results revealed a novel homozygous variant in the HSPG2 gene (MIM 142461), NM_005529.6(HSPG2):c.4029 + 1G>A, consistent with a diagnosis of DDSH. CONCLUSION: To the best of our knowledge, the current report is only the seventh molecularly confirmed case of DDSH. PMID- 29526036 TI - Differential blood cellular profile in patients with moderate-to-severe psoriasis treated with classical systemic therapies: a step forward in personalized medicine. PMID- 29526037 TI - On the Mechanism of Photodehydrogenation of Aryl(hetaryl)pyrazolines in the Presence of Perchloroalkanes. AB - New (1,5-diaryl-3-pyrazolinyl)coumarins have been synthesized. The compounds do not undergo keto-enol tautomeric transformations with changes in the solvent. (1,5-Diaryl-3-pyrazolinyl)coumarins provide dehydrogenation reaction under irradiation in the presence of perchloroalkanes and manifest themselves as effective photogenerators of acidity. Several aspects of photodehydrogenation mechanism have been studied. Oxygen is shown not be involved in the reaction. Polar solvents increase rate of the reaction. The measured rate constants of the photodehydrogenation reactions vary in a significant range according to the structure of pyrazoline. The data correlate with ionization potentials of pyrazolines available from DFT quantum chemical calculations. These results are discussed in terms of proposed scheme of mechanism of pyrazolines photodehydrogenation assuming formation of ion-radical and ion intermediates. PMID- 29526038 TI - Effect of mild exercise on glycemic and bodyweight control in Japanese type 2 diabetes patients: A retrospective analysis. AB - We retrospectively evaluated the effects of mild physical exercise (P) in a routine clinical setting on glycemic and bodyweight control in Japanese type 2 diabetes patients with and without individualized nutritional therapy (D). We analyzed 49 patients who participated in P that measured 2.5 metabolic equivalents and was held once every 2 weeks, compared with 83 non-participant controls, followed over a period of approximately 1.6 years. With a Cox model, the adjusted hazard ratio for improved glycated hemoglobin by numerical count of P was 1.03 (95% confidence interval [CI] 1.00-1.07; P = 0.025). Among four categories - with neither P nor D, only P, only D, and both P and D - the hazard ratios for reduced body mass index were 1.0, 0.87 (95% CI 0.46-1.67), 0.58 (95% CI 0.25-1.30) and 2.17 (95% CI 1.03-4.59), respectively. Even mild physical exercise contributed to glycemic control. The combination of P and D exerted beneficial effects on bodyweight control. PMID- 29526040 TI - Esophagojejunal anastomotic dehiscence successfully repaired by endoluminal suture and stent positioning: Report of a mini-invasive approach. PMID- 29526039 TI - Double helical suture for transaortic closure of the sinus of Valsalva aneurysm. PMID- 29526041 TI - Primary fallopian tube sex cord tumour: tubal counterpart of uterine tumour resembling ovarian sex cord tumour. PMID- 29526042 TI - Recurrent erysipelas of the face with hyperimmune reaction to group C streptococcus. PMID- 29526043 TI - Spinal Cord Stimulation: Clinical Efficacy and Potential Mechanisms. AB - Spinal cord stimulation (SCS) is a minimally invasive therapy used for the treatment of chronic neuropathic pain. SCS is a safe and effective alternative to medications such as opioids, and multiple randomized controlled studies have demonstrated efficacy for difficult-to-treat neuropathic conditions such as failed back surgery syndrome. Conventional SCS is believed mediate pain relief via activation of dorsal column Abeta fibers, resulting in variable effects on sensory and pain thresholds, and measurable alterations in higher order cortical processing. Although potentiation of inhibition, as suggested by Wall and Melzack's gate control theory, continues to be the leading explanatory model, other segmental and supraspinal mechanisms have been described. Novel, non standard, stimulation waveforms such as high-frequency and burst have been shown in some studies to be clinically superior to conventional SCS, however their mechanisms of action remain to be determined. Additional studies are needed, both mechanistic and clinical, to better understand optimal stimulation strategies for different neuropathic conditions, improve patient selection and optimize efficacy. PMID- 29526044 TI - Effects of personal air pollution exposure on asthma symptoms, lung function and airway inflammation. AB - BACKGROUND: There is evidence that air pollution increases the risk of asthma hospitalizations and healthcare utilization, but the effects on day-to-day asthma control are not fully understood. OBJECTIVE: We undertook a prospective single centre panel study to test the hypothesis that personal air pollution exposure is associated with asthma symptoms, lung function and airway inflammation. METHODS: Thirty-two patients with a clinical diagnosis of asthma were provided with a personal air pollution monitor (Cairclip NO2 /O3 ) which was kept on or around their person throughout the 12-week follow-up period. Ambient levels of NO2 and particulate matter were modelled based upon satellite imaging data. Directly measured ozone, NO2 and particulate matter levels were obtained from a monitoring station in central Leicester. Participants made daily electronic records of asthma symptoms, peak expiratory flow and exhaled nitric oxide. Spirometry and asthma symptom questionnaires were completed at fortnightly study visits. Data were analysed using linear mixed effects models and cross-correlation. RESULTS: Cairclip exposure data were of good quality with clear evidence of diurnal variability and a missing data rate of approximately 20%. We were unable to detect consistent relationships between personal air pollution exposure and clinical outcomes in the group as a whole. In an exploratory subgroup analysis, total oxidant exposure was associated with increased daytime symptoms in women but not men. CONCLUSIONS AND CLINICAL RELEVANCE: We did not find compelling evidence that air pollution exposure impacts on day-to-day clinical control in an unselected asthma population, but further studies are required in larger populations with higher exposure levels. Women may be more susceptible than men to the effects of air pollution, an observation which requires confirmation in future studies. PMID- 29526045 TI - Comparison of propofol monotherapy and propofol combination therapy for sedation during gastrointestinal endoscopy: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Previous randomized controlled trials have reported conflicting findings comparing propofol combination therapy (PCT) with propofol monotherapy (PMT) for sedation of patients undergoing gastrointestinal endoscopy. Therefore, a systematic review was carried out to compare the efficacy and safety of PCT and PMT in such patients. METHODS: We searched MEDLINE, EMBASE and CENTRAL databases to identify all randomized controlled trials that compared the efficacy and safety of PCT and PMT for sedation of patients undergoing gastrointestinal endoscopy. Primary endpoints were incidence of respiratory complications, hypotension and arrhythmia, dose of propofol used, and recovery time. Procedure duration and the satisfaction of patients and doctors were also evaluated. RESULTS: A total of 2250 patients from 22 studies were included in the final analysis. The combined analysis did not show any difference between PCT and PMT in the incidence of respiratory complications (risk ratio [RR], 0.80; 95% CI, 0.52 to 1.23; I2 = 58.34%), hypotension (RR, 1.06; 95% CI, 0.63 to 1.78; I2 = 72.13%), arrhythmia (RR,1.40; 95% CI, 0.74 to 2.64; I2 = 43.71%), recovery time (standardized mean difference [SMD], 0.16; 95% CI, -0.49 to 0.81; I2 = 95.9%), procedure duration (SMD, 0.04; 95% CI, -0.05 to 0.14; I2 = 0.0%), patient satisfaction (SMD, 0.13; 95% CI, -0.26 to 0.52; I2 = 89.63%) or doctor satisfaction (SMD, 0.01; 95% CI, -0.15 to 0.17; I2 = 0.00%). However, the dose of propofol used was significantly lower in PCT than in PMT (SMD, -1.38; 95% CI, 1.99 to -0.77; I2 = 97.70%). CONCLUSION: PCT showed comparable efficacy and safety to PMT with respect to respiratory complications, hypotension and arrhythmia, recovery time, procedure duration, patient satisfaction, and doctor satisfaction. However, the average dose of propofol used was higher in PMT. PMID- 29526046 TI - Transbronchial lung biopsy for the diagnosis of IgG4-related lung disease. AB - AIMS: The diagnosis of IgG4-related disease (IgG4-RD) requires a multidisciplinary approach, in which histology plays an important role. Although a diagnosis was previously established by the use of surgically resected specimens, there is increasing clinical demand to diagnose this systemic condition by the use of biopsies. The aim of the present study was to elucidate how useful transbronchial lung biopsies (TBLBs) are for this diagnostic purpose. METHODS AND RESULTS: The study cohort consisted of 20 consecutive patients diagnosed with IgG4-RD in other organs who underwent TBLB for potential pulmonary involvement. One case showing multiple granulomas suggestive of other conditions was excluded. Seven of the remaining 19 cases (37%) showed apparently normal lung tissue, indicating a sampling error, and 12 (63%) had microscopic abnormalities. Nine cases (47%) with a dense lymphoplasmacytic infiltrate met the number and ratio criteria for IgG4-positive plasma cell infiltration (>20 cells/high-power field, and an IgG4/IgG-positive plasma cell ratio of >40%). Obliterative phlebitis and storiform fibrosis were observed in one case each. In 43 control cases of various inflammatory conditions, tissue IgG4 elevations appeared to be uncommon, with only two cases (5%) each meeting the number or ratio criterion, and one case (2%) fulfilling both. All control cases with tissue IgG4 elevations were of eosinophilic pneumonia. CONCLUSIONS: Transbronchial lung biopsies provided histological findings that were supportive for the diagnosis of IgG4-RD in 47% of cases, with 98% diagnostic specificity. Therefore, they have potential as a useful and acceptable diagnostic approach for IgG4-related lung disease. PMID- 29526047 TI - Mycotic innominate artery aneurysm repair using a bovine pericardial bifurcation prosthesis. AB - We report the use of a bovine pericardial bifurcation prosthesis to repair a mycotic innominate artery aneurysm. PMID- 29526048 TI - Stunting, starvation and refeeding: a review of forgotten 19th and early 20th century literature. AB - AIM: To scrutinize to what extent modern ideas about nutrition effects on growth are supported by historic observations in European populations. METHOD: We reviewed 19th and early 20th century paediatric journals in the Staatsbibliothek zu Berlin, the third largest European library with an almost complete collection of the German medical literature. During a three-day visit, we inspected 15 bookshelf meters of literature not available in electronic format. RESULTS: Late 19th and early 20th century breastfed European infants and children, independent of social strata, grew far below World Health Organisation (WHO) standards and 15 30% of adequately-fed children would be classified as stunted by the WHO standards. Historic sources indicate that growth in height is largely independent of the extent and nature of the diet. Height catch-up after starvation was greater than catch-up reported in modern nutrition intervention studies, and allowed for unimpaired adult height. CONCLUSION: Historical studies are indispensable to understand why stunting does not equate with undernutrition and why modern diet interventions frequently fail to prevent stunting. Appropriateness and effect size of modern nutrition interventions on growth need revision. PMID- 29526049 TI - Population-based prevalence of eosinophilic fasciitis (Shulman syndrome): a capture-recapture study. PMID- 29526050 TI - The role of ungulates in nowadays temperate forests. A response to Flojgaard et al. (DOI:10.1111/gcb.14029). AB - In Boulanger et al. (2018), we investigated the effects of ungulates on forest plant diversity. By suggesting a revisit of our conclusions regarding ecosystem dynamics since the late Pleistocene, Flojgaard et al. (2018) came to the conclusion that moderate grazing in forest should be a conservation target. Since major points of our paper were mis- or over- interpreted, we put the record straight on our study system and on the scope of our conclusions. Finally, we advocate for an assessment of the conservation issues of ungulates in forests not only regarding hypothetical and still debated states of past ecosystems but also considering timely challenges for forest ecosystems. PMID- 29526051 TI - Central venous pressure monitoring in living donor kidney recipients does not affect immediate graft function: A propensity score analysis. AB - BACKGROUND: During kidney transplantation, intraoperative fluid management can affect post-transplant graft function. It is unclear whether or not central venous pressure (CVP) monitoring is required to guide fluid therapy during kidney transplantation. METHODS: We compared post-transplant graft function in recipients of living donor kidney transplants between August 2006 and March 2009 based on the use or absence of intraoperative CVP monitoring. Graft function, assessed using the creatinine reduction ratio on postoperative day 2 (CCR2), was evaluated by multivariable linear regression analysis and in a propensity-matched cohort. RESULTS: Two hundred and ninety patients were included in the analysis. Central venous pressure was monitored in 84 patients (29%). There was no difference in post-transplant graft function, as measured by CCR2, between patients with and without CVP monitoring in both unadjusted and multivariable adjusted analyses. There were also no statistically significant differences in CCR2, delayed graft function, or 3-month renal function between those monitored with CVP and those without, in the propensity-matched cohort. CONCLUSIONS: In this single-center analysis, immediate post-transplant renal function was not associated with the use of intraoperative CVP monitoring. PMID- 29526052 TI - Nursing students' understanding of the Fundamentals of Care: A cross-sectional study in five countries. AB - AIM AND OBJECTIVE: To explore the accuracy with which nursing students can identify the fundamentals of care. BACKGROUND: A challenge facing nursing is ensuring the fundamentals of care are provided with compassion and in a timely manner. How students perceive the importance of the fundamentals of care may be influenced by the content and delivery of their nursing curriculum. As the fundamentals of care play a vital role in ensuring patient safety and quality care, it is important to examine how nursing students identify these care needs. DESIGN: Cross-sectional descriptive design. METHODS: A total of 398 nursing students (pre- and postregistration) from universities in Sweden, England, Japan, Canada and Australia participated. The Fundamentals of Care Framework guided this study. A questionnaire containing three care scenarios was developed and validated. Study participants identified the fundamentals of care for each of the scenarios. All responses were rated and analysed using ANOVA. RESULTS: The data illustrate certain fundamentals of care were identified more frequently, including communication and education; comfort and elimination, whilst respecting choice, privacy and dignity were less frequently identified. The ability to identify all the correct care needs was low overall across the pre- and postregistration nursing programmes in the five universities. Significant differences in the number of correctly identified care needs between some of the groups were identified. CONCLUSIONS: Nursing students are not correctly identifying all a patient's fundamental care needs when presented with different care scenarios. Students more frequently identifying physical care needs and less frequently psychosocial and relational needs. The findings suggest educators may need to emphasise and integrate all three dimensions. RELEVANCE TO CLINICAL PRACTICE: To promote students' ability to identify the integrated nature of the fundamentals of care, practising clinicians and nurse educators need to role model and incorporate all the fundamental care needs for their patients. PMID- 29526053 TI - Splenic hematopoietic stem cells display a pre-activated phenotype. AB - Splenic hematopoiesis is crucial to the pathogenesis of diseases including myocardial infarction and atherosclerosis. The spleen acts as a reservoir of myeloid cells, which are quickly expelled out in response to acute inflammation. In contrast to the well-defined bone marrow hematopoiesis, the cellular and molecular components sustaining splenic hematopoiesis are poorly understood. Surprisingly, we found that, unlike quiescent bone marrow hematopoietic stem cells (HSC), most of splenic HSC are in the G1 phase in C57BL/6 mice. Moreover, splenic HSC were enriched for genes involved in G0-G1 transition and expressed lower levels of genes responsible for G1-S transition. These data indicate that, at steady state, splenic HSC are pre-activated, which may expedite their cell cycle entry in emergency conditions. Consistently, in the acute phase of septic shock induced by LPS injection, splenic HSC entered the S-G2-M phase, whereas bone marrow HSC did not. Mobilization and transplantation experiments displayed that bone marrow HSC, once in the spleen, acquired cell cycle status similar to splenic HSC, strongly suggesting that the splenic microenvironment plays an important role in HSC pre-activation. In addition, we found that myeloid translocation gene 16 (Mtg16) deficiency in C57BL/6 mice resulted in significantly increased S-G2-M entry of splenic but not bone marrow HSC, suggesting that Mtg16 is an intrinsic negative regulator of G1-S transition in splenic HSC. Altogether, this study demonstrates that compared to bone marrow, splenic HSC are in a pre-activated state, which is driven by extracellular signals provided by splenic microenvironment and HSC intrinsic factor Mtg16. PMID- 29526054 TI - Pulmonary function in patients with psoriasis: across-sectional population study. PMID- 29526055 TI - Knowledge and attitudes about sports-related dental injuries and mouthguard use in young athletes in four different contact sports-water polo, karate, taekwondo and handball. AB - BACKGROUND/AIMS: The increasing popularity of participating in sports activities among children and adolescents has increased the risk of sports-related orofacial and dental injuries. Therefore, it is important to establish efficient preventive strategies regarding sports-related dental trauma. The aim of this study was to evaluate the occurrence of sports-related dental injuries in young athletes and to compare the frequency of such injuries between high-risk and medium-risk sports, along with assessing athletes' attitudes and habits regarding mouthguard use. METHODS: A total of 229 young athletes from four different sports (water polo (n = 59), karate (n = 58), taekwondo (n = 57) and handball (n = 55)) participated in this study. A standardized questionnaire about the frequency of orofacial and dental injuries was used. Questions were also asked about athletes' habits related to mouthguard use. RESULTS: Mean age of the participants was 12.9 +/- 3.2 years, and the average time of playing experience was 4.8 +/- 3.1 years. Orofacial injury had been experienced by 58 athletes (25.3%), while 31 athletes (13.5%) suffered dental injury. Higher rate of dental injuries was observed in water polo (18.6%), karate (17.2%) and handball (21.8%) than in taekwondo (3.5%) (P = .035). Most participants were aware of mouthguards for dental trauma prevention and considered them efficient for preventing dental injuries during sports activities, but only 94 (41%) used them. There was a statistically significant difference in the use of mouthguards between taekwondo (73.7%) and karate (70.7%) players compared to handball (14.5%) and water polo players (5.1%) (P < .001). CONCLUSIONS: Handball and water polo had similarly high occurrence of dental trauma as karate, a high-risk martial art sport. Therefore, the classification of sports according to the risk of dental trauma should be reconsidered. It would be beneficial to make wearing a mouthguard mandatory in all high-risk sports, as well as in those with medium-risk for dental injuries. PMID- 29526056 TI - Contained myocardial abscess following a myocardial infarction. PMID- 29526057 TI - Epidemiologic characteristics of scrub typhus on Jeju Island. PMID- 29526059 TI - Restoration of Sagittal Balance in Spinal Deformity Surgery. AB - The prevalence of patients with adult spinal deformity (ASD) has been reported as high as 68%. ASD often leads to significant pain and disability. Recent emphasis has been placed on sagittal plane balance and restoring normal sagittal alignment with regards to the three dimensional deformity of ASD. Optimal sagittal alignment has been known to increase spinal biomechanical efficiency, reduce energy expenditure by maintaining a stable posture with improved load absorption, influence better bony union, and help to decelerate adjacent segment deterioration. Increasingly positive sagittal imbalance has been shown to correlate with poor functional outcome and poor self-image along with poor psychological function. Compensatory mechanisms attempt to maintain sagittal balance through pelvic rotation, alterations in lumbar lordosis as well as knee and ankle flexion at the cost of increased energy expenditure. Restoring normal spinopelvic alignment is paramount to the treatment of complex spinal deformity with sagittal imbalance. Posterior osteotomies including posterior column osteotomies, pedicle subtraction osteotomies, and posterior vertebral column resection, as well anterior column support are well known to improve sagittal alignment. Understanding of whole spinal alignment and dynamics of spinopelvic alignment is essential to restore sagittal balance while minimizing the risk of developing sagittal decompensation after surgical intervention. PMID- 29526060 TI - Straight-Forward versus Bicortical Fixation Penetrating Endplate in Lumbosacral Fixation-A Biomechanical Study. AB - OBJECTIVE: Many lumbosacral fixation techniques have been described to offer a more screw-bone purchase. The forward anatomical fixation parallel to the endplate is still the most preferred method. Literature revealed little knowledge regarding the mechanical stability of lumbosacral trans-endplate fixation compared to the traditional trans-pedicular screw fixation method. The aim of this study is to assess the pull-out strength of lumbosacral screws penetrating the end plate and comparing it to the conventional trans-pedicular screw insertion method. METHODS: Eight lumbar and eight sacral vertebrae, with average age 69.4 years, Left pedicles of the 5th lumbar vertebrae were used for trans endplate screw fixation, group 1A, right pedicles were used for anatomical trans pedicular screw fixation, group 1B. In the sacral vertebrae, the right side S1 pedicles were used for trans-endplate fixation, group 2A, left side pedicles were used for anatomical trans-pedicular screw fixation, group 2B. The biomechanical tests were performed using the axial compression testing machine. All tests were applied using 2 mm/min traction speed. RESULTS: The average pull-out strength values of groups 1A and 1B were 403.78+/-11.71 N and 306.26+/-17.55 N, respectively. A statistical significance was detected with p=0.012. The average pull-out strength values of groups 2A and 2B were 388.73+/-17.03 N and 299.84+/ 17.52 N, respectively. A statistical significance was detected with p=0.012. CONCLUSION: The trans-endplate lumbosacral fixation method is a trustable fixation method with a stronger screw-bone purchase and offer a good alternative for surgeons specially in patients with osteoporosis. PMID- 29526061 TI - Cold Allodynia after C2 Root Resection in Sprague-Dawley Rats. AB - OBJECTIVE: The purpose of this study was to evaluate pain-related behaviors after bilateral C2 root resection and change in pain patterns in the suboccipital region in rats. METHODS: Male Sprague-Dawley rats were randomly assigned to three groups (n=25/group); naive, sham, and C2 resection. Three, 7, 10, and 14 days after surgery, cold allodynia was assessed using 20 MUL of 99.7% acetone. c-Fos and c-Jun were immunohistochemically stained to evaluate activation of dorsal horn gray matter in C2 segments of the spinal cord 2 hours, 1 day, 7 days, and 14 days after surgery. RESULTS: Three days after surgery, the response to acetone in the sham group was significantly greater than in the naive group, and this significant difference between the naive and sham groups was maintained throughout the experimental period (p<0.05 at 3, 7, 10, and 14 days). Seven, 10, and 14 days after surgery, the C2 root resection group exhibited a significantly greater response to acetone than the naive group (p<0.05), and both the sham and C2 resection groups exhibited significantly greater responses to acetone compared with 3 days after surgery. No significant difference in cold allodynia was observed between the sham and C2 root resection groups throughout the experimental period. Two hours after surgery, both the sham and C2 root resection groups exhibited significant increases in c-Fos- and c-Jun-positive neurons compared with the naive group (p=0.0021 and p=0.0358 for the sham group, and p=0.0135 and p=0.014 for the C2 root resection group, respectively). One day after surgery, both the sham and C2 root resection groups exhibited significant decreases in c-Fos -positive neurons compared with two hours after surgery (p=0.0169 and p=0.0123, respectively), and these significant decreases in c-Fos immunoreactivity were maintained in both the sham and C2 root resection groups 7 and 14 days after surgery. The sham and C2 root resection groups presented a tendency toward a decrease in c-Jun-positive neurons 1, 7, and 14 days after surgery, but the decrease did not reach statistical significance. CONCLUSION: We found no significant difference in cold allodynia and the early expression of c Fos and c-Jun between the sham and C2 resection groups. Our results may support the routine resection of the C2 nerve root for posterior C1-2 fusion, but, further studies are needed. PMID- 29526062 TI - C2 Segmental-Type Vertebral Artery Diagnosed Using Computed Tomographic Angiography. AB - OBJECTIVE: Sometimes a vertebral artery (VA) enters the spinal canal via the C1-2 intervertebral space, a variation regarded as a C2 segmental-type VA. This paper describes the anatomy of the C2 segmental-type VA and reviews its clinical importance. METHODS: Between March 2014 and November 2015, 3386 patients underwent computed tomographic angiography. I identified C2 segmental-type VAs, associated vascular variation, the origin of ipsilateral posterior inferior cerebellar arteries (PICAs), and the clinical symptoms associated with C2 segmental-type VAs. The origin of an ipsilateral PICA is divided into 5 types. A type 1 PICA originates from ipsilateral VAs coursing suboccipitally (IVASO), a type 2 originates from ipsilateral proximal C2 segmental-type VAs, a type 3 originates from ipsilateral distal C2 segmental-type VAs. For type 4, the PICA does not originate from an ipsilateral VA. For type 5, the PICA is the terminal end of an ipsilateral C2 segmental-type VA. RESULTS: One hundred thirteen patients had 121 C2 segmental-type VAs; 47 were associated with an IVASO, and 74 were not. Four type 1, 13 type 2, 60 type 3, 42 type 4, and two type 5 PICAs were identified. Only one patient showed symptoms associated with a C2 segmental-type VA, being a 71-year-old man presenting with a C2 segmental-type VA infarction. CONCLUSION: For C2 segmental-type VAs, the ipsilateral IVASO and origin of the PICA are important for predicting the outcome of this type of VA infarction. PMID- 29526063 TI - Clopidogrel Response Variability in Unruptured Intracranial Aneurysm Patients Treated with Stent-Assisted Endovascular Coil Embolization : Is Follow-Up Clopidogrel Response Test Necessary? AB - OBJECTIVE: The purpose of this study was to analyze the variability of clopidogrel responses according to duration of a clopidogrel drug regimen after stent-assisted coil embolization (SAC), and to determine the correlation between the variability of clopidogrel responses and thromboembolic or hemorrhagic complications. METHODS: A total of 47 patients who underwent SAC procedures to treat unruptured intracranial aneurysms were enrolled in the study. Preoperatively, patients received more than seven days of aspirin (100 mg) and clopidogrel (75 mg), daily. P2Y12 reaction unit (PRU) was checked with the VerifyNow test one day before the procedure (pre-PRU) and one month after the procedure (post-PRU). PRU variability was calculated as the difference between the initial response and the follow-up response. Patients were sorted into two groups based on their response to treatment : responsive and hypo-responsive. RESULTS: PRU variability was significantly greater in the hypo-responsive group when compared to the responsive group (p=0.019). Pre-PRU and serum platelets counts were significantly correlated with PRU variation (p=0.005 and p=0.004, respectively). Although thromboembolic complication had no significant correlated factors, hemorrhagic complication was correlated with pre-PRU (p=0.033). CONCLUSION: In conclusion, variability of clopidogrel responses during clopidogrel medication was correlated to serum platelet counts and the initial clopidogrel response. Thromboembolic and hemorrhagic complications did not show correlation with the variability of clopidogrel response, or the clopidogrel response after one month of medication; however, hemorrhagic complication was associated with initial clopidogrel response. Therefore, it is recommended to test patients for an initial clopidogrel response only, as further tests would be insignificant. PMID- 29526064 TI - Management of Recurrent Cerebral Aneurysm after Surgical Clipping : Clinical Article. AB - OBJECTIVE: Surgical clipping of the cerebral aenurysm is considered as a standard therapy with endovascular coil embolization. The surgical clipping is known to be superior to the endovascular coil embolization in terms of recurrent rate. However, a recurrent aneurysm which is initially treated by surgical clipping is difficult to handle. The purpose of this study was to research the management of the recurrent cerebral aneurysm after a surgical clipping and how to overcome them. METHODS: From January 1996 to December 2015, medical records and radiologic findings of 14 patients with recurrent aneurysm after surgical clipping were reviewed retrospectively. Detailed case-by-case analysis was performed based on preoperative, postoperative and follow-up radiologic examinations and operative findings. All clinical variables including age, sex, aneurysm size and location, type and number of applied clips, prognosis, and time to recurrence are evaluated. All patients are classified by causes of the recurrence. Possible risk factors that could contribute to those causes and overcoming ways are comprehensively discussed. RESULTS: All recurrent aneurysms after surgical clipping were 14 of 2364 (0.5%). Three cases were males and 11 cases were females. Mean age was 52.3. At first treatment, nine cases were ruptured aneurysms, four cases were unruptured aneurysms, and one case was unknown. Locations of recurrent aneurysm were determined; anterior communicating artery (A com) (n=7), posterior communicating artery (P-com) (n=3), middle cerebral artery (n=2), anterior cerebral artery (n=1) and basilar artery (n=1). As treatment of the recurrence, 11 cases were treated by surgical clipping and three cases were treated by endovascular coil embolization. Three cases of all 14 cases occurred in a month after the initial treatment. Eleven cases occurred after a longer interval, and three of them occurred after 15 years. By analyzing radiographs and operative findings, several main causes of the recurrent cerebral aneurysm were found. One case was incomplete clipping, five cases were clip slippage, and eight cases were fragility of vessel wall near the clip edge. CONCLUSION: This study revealed main causes of the recurrent aneurysm and contributing risk factors to be controlled. To manage those risk factors and ultimately prevent the recurrent aneurysm, neurosurgeons have to be careful in the technical aspect during surgery for a complete clipping without a slippage. Even in a perfect surgery, an aneurysm may recur at the clip site due to a hemodynamic change over years. Therefore, all patients must be followed up by imaging for a long period of time. PMID- 29526065 TI - Nationwide Mortality Data after Flow-Diverting Stent Implantation in Korea. AB - OBJECTIVE: To investigate nationwide statistics on flow-diverting stent usage for cerebral aneurysm treatment and related mortality data. METHODS: We requested data extraction from the National Health Insurance Service claims database using electronic data interchange codes (J3207064, J3207073). Patient and hospital information as well as death statistics were collected from the database. RESULTS: A total of 169 procedures were performed using flow-diverting stents for cerebral aneurysm treatment from November 2014 to December 2016 in Korea. The majority of primary diagnosis was unruptured intracranial aneurysm. During the study period, nine subjects died, including one patient initially diagnosed with subarachnoid hemorrhage. The crude mortality rate was 5.3%. Five patients died within one month after the procedure; therefore, the estimated periprocedural mortality rate was 3.0+/-1.3%. The mortality rate as of the last day of 2016 was 6.3+/-2.1%. CONCLUSION: In a 171 person-year follow-up in a Korean series, nine deaths occurred after flow-diverting stent treatment. The crude mortality rate in Korea (5.3%) was higher than that reported in a previous meta-analysis (3.8%). PMID- 29526058 TI - Korean Clinical Practice Guidelines for Aneurysmal Subarachnoid Hemorrhage. AB - Despite advancements in treating ruptured cerebral aneurysms, an aneurysmal subarachnoid hemorrhage (aSAH) is still a grave cerebrovascular disease associated with a high rate of morbidity and mortality. Based on the literature published to date, worldwide academic and governmental committees have developed clinical practice guidelines (CPGs) to propose standards for disease management in order to achieve the best treatment outcomes for aSAHs. In 2013, the Korean Society of Cerebrovascular Surgeons issued a Korean version of the CPGs for aSAHs. The group researched all articles and major foreign CPGs published in English until December 2015 using several search engines. Based on these articles, levels of evidence and grades of recommendations were determined by our society as well as by other related Quality Control Committees from neurointervention, neurology and rehabilitation medicine. The Korean version of the CPGs for aSAHs includes risk factors, diagnosis, initial management, medical and surgical management to prevent rebleeding, management of delayed cerebral ischemia and vasospasm, treatment of hydrocephalus, treatment of medical complications and early rehabilitation. The CPGs are not the absolute standard but are the present reference as the evidence is still incomplete, each environment of clinical practice is different, and there is a high probability of variation in the current recommendations. The CPGs will be useful in the fields of clinical practice and research. PMID- 29526066 TI - Analysis of Factors Contributing to Repeat Surgery in Multi-Segments Cervical Ossification of Posterior Longitudinal Ligament. AB - OBJECTIVE: Cervical ossification of the posterior longitudinal ligament (OPLL) can be treated via anterior or posterior approach, or both. The optimal approach depends on the characteristics of OPLL and cervical curvature. Although most patients can be successfully treated by a single surgery with the proper approach, renewed or newly developed neurological deterioration often requires repeat surgery. METHODS: Twenty-seven patients with renewed or newly developed neurological deterioration requiring salvage surgery for multi-segment cervical OPLL were enrolled. Ten patients (group AP) underwent anterior approach, and 17 patients (group PA) underwent posterior approach at the initial surgery. Clinical and radiological data from initial and repeat surgeries were obtained and analyzed retrospectively. RESULTS: The intervals between the initial and repeat surgeries were 102.80+/-60.08 months (group AP) and 61.00+/-8.16 months (group PA) (p<0.05). In group AP, the main OPLL lesions were removed during the initial surgery. There was a tendency that the site of main OPLL lesions causing renewed or newly developed neurological deterioration were different from that of the initial surgery (8/10, p<0.05). Repeat surgery was performed for progressed OPLL lesions at another segment as the main pathology. In group PA, the main OPLL lesions at the initial surgery continued as the main pathology for repeat surgery. Progression of kyphosis in the cervical curvature (Cobb's angle on C2-7 and segmental angle on the main OPLL lesion) was noted between the initial and repeat surgeries. Group PA showed more kyphotic cervical curvature compared to group AP at the time of repeat surgery (p<0.05). CONCLUSION: The reasons for repeat surgery depend on the type of initial surgery. The main factors leading to repeat surgery are progression of remnant OPLL at a different segment in group AP and kyphotic change of the cervical curvature in group PA. PMID- 29526067 TI - Spinal Cord Subependymoma Surgery : A Multi-Institutional Experience. AB - OBJECTIVE: A spinal cord subependymoma is an uncommon, indolent, benign spinal cord tumor. It is radiologically similar to a spinal cord ependymoma, but surgical findings and outcomes differ. Gross total resection of the tumor is not always feasible. The present study was done to determine the clinical, radiological and pathological characteristics of spinal cord subependymomas. METHODS: We retrospectively reviewed the medical records of ten spinal cord subependymoma patients (M : F=4 : 6; median 38 years; range, 21-77) from four institutions. RESULTS: The most common symptoms were sensory changes and/or pain in eight patients, followed by motor weakness in six. The median duration of symptoms was 9.5 months. Preoperative radiological diagnosis was ependymoma in seven and astrocytoma in three. The tumors were located eccentrically in six and were not enhanced in six. Gross total resection of the tumor was achieved in five patients, whereas subtotal or partial resection was inevitable in the other five patients due to a poor dissection plane. Adjuvant radiotherapy was performed in two patients. Neurological deterioration occurred in two patients; transient weakness in one after subtotal resection and permanent weakness after gross total resection in the other. Recurrence or regrowth of the tumor was not observed during the median 31.5 months follow-up period (range, 8-89). CONCLUSION: Spinal cord subependymoma should be considered when the tumor is located eccentrically and is not dissected easily from the spinal cord. Considering the rather indolent nature of spinal cord subependymomas, subtotal removal without the risk of neurological deficit is another option. PMID- 29526068 TI - Comparison of Morphological Characteristics of the Subaxial Cervical Spine between Athetoid Cerebral Palsy and Normal Control. AB - OBJECTIVE: To compare the morphometry of subaxial cervical spine between cerebral palsy (CP) and normal control. METHODS: We retrospectively analyzed 72 patients with CP, as well as 72 patients from normal population. The two groups were matched for age, sex, and body mass index. Pedicle, lateral mass (LM), and vertebral foramen were evaluated using computed tomography (CT) imaging. Pedicle diameter, LM height, thickness, width and vertebral foramen asymmetry (VFA) were measured and compared between the two groups. Cervical dynamic motion, disc and facet joint degeneration were investigated. Additionally, we compared the morphology of LM between convex side and concave side with cervical scoliotic CP patients. RESULTS: LM height was smaller in CP group. LM thickness and width were larger in CP group at mid-cervical level. In 40 CP patients with cervical scoliosis, there were no height and width differences between convex and concave side. Pedicle outer diameter was not statistically different between two groups. Pedicle inner diameter was significantly smaller in CP group. Pedicle sclerosis was more frequent in CP patients. VFA was larger in CP group at C3, C4, and C5. Disc/facet degeneration grade was higher in the CP group. Cervical motion of CP group was smaller than those of the control group. CONCLUSION: LM morphology of CP patients was different from normal population. Sclerotic pedicles and vertebral foramen asymmetry were more commonly identified in CP patients. CP patients were more likely to demonstrate progressive disc/facet degeneration. This data may provide useful information on cervical posterior instrumentation in CP patients. PMID- 29526069 TI - Clinical and Radiological Outcomes of Posterior Vertebral Column Resection for Severe Spinal Deformities. AB - OBJECTIVE: The aim of this study was to investigate clinical and radiological outcomes of patients who underwent posterior vertebral column resection (PVCR) by a single neurosurgeon in a single institution. METHODS: Thirty-four consecutive patients with severe spinal deformities who underwent PVCR between 2010 and 2016 were enrolled. The radiographic measurements included a kyphotic angle of PVCR levels (VCR angle), sagittal vertical axis (SVA), thoracic kyphosis, lumbar lordosis (LL), and spinopelvic parameters. The data of surgical time, estimated blood loss, duration of hospital stay, complications, intraoperative neurophysiologic monitoring, and the Scoliosis Research Society (SRS)-22 questionnaire were collected using a retrospective review of medical records. RESULTS: The VCR angle, LL, and SVA values were significantly corrected after surgery. The VCR and LL angle were changed from the average of 38.4+/-32.1 degrees and -22.1+/-39.1 degrees to -1.7+/-29.4 degrees (p<0.001) and -46.3+/ 23.8 degrees (p=0.001), respectively. The SVA was significantly reduced from 103.6+/-88.5 mm to 22.0+/-46.3 mm (p=0.001). The clinical results using SRS-22 survey improved from 2.6+/-0.9 to 3.4+/-0.8 (p=0.033). There were no death and permanent neurological deficits after PVCR. However, complications occurred in 19 (55.9%) patients. Those patients experienced a total of 31 complications during- and after surgery. Sixteen reoperations were performed in twelve (35.3%) patients. The incidence of transient neurological deterioration was 5.9% (two out of 34 patients). CONCLUSION: Severe spinal deformities can be effectively corrected by PVCR. However, the PVCR technique should be utilized limitedly because surgery-related serious complications are relatively common. PMID- 29526070 TI - Sacral Insufficiency Fractures : How to Classify? AB - OBJECTIVE: The diagnosis of insufficiency fractures of the sacrum in an elder population increases annually. Fractures show very different morphology. We aimed to classify sacral insufficiency fractures according to the position of cortical break and possible need for intervention. METHODS: Between January 1, 2008 and December 31, 2014, all patients with a proven fracture of the sacrum following a low-energy or an even unnoticed trauma were prospectively registered : 117 females and 13 males. All patients had a computer tomography of the pelvic ring, two patients had a magnetic resonance imaging additionally : localization and involvement of the fracture lines into the sacroiliac joint, neural foramina or the spinal canal were identified. RESULTS: Patients were aged between 46 and 98 years (mean, 79.8 years). Seventy-seven patients had an unilateral fracture of the sacral ala, 41 bilateral ala fractures and 12 patients showed a fracture of the sacral corpus : a total of 171 fractures were analyzed. The first group A included fractures of the sacral ala which were assessed to have no or less mechanical importance (n=53) : fractures with no cortical disruption ("bone bruise") (A1; n=2), cortical deformation of the anterior cortical bone (A2; n=4), and fracture of the anterolateral rim of ala (A3; n=47). Complete fractures of the sacral ala (B; n=106) : parallel to the sacroiliac joint (B1; n=63), into the sacroiliac joint (B2; n=19), and involvement of the sacral foramina respectively the spinal canal (B3; n=24). Central fractures involving the sacral corpus (C; n=12) : fracture limited to the corpus or finishing into one ala (C1; n=3), unidirectional including the neural foramina or the spinal canal or both (C2; n=2), and horizontal fractures of the corpus with bilateral sagittal completion (C3; n=8). Sixty-eight fractures proceeded into the sacroiliac joint, 34 fractures showed an injury of foramina or canal. CONCLUSION: The new classification allowes the differentiation of fractures of less mechanical importance and a risk assessment for possible polymethyl methacrylate leaks during sacroplasty in the direction of the neurological structures. In addition, identification of instable fractures in need for laminectomy and surgical stabilization is possible. PMID- 29526071 TI - Safety and Efficacy of Hypothermia (34 degrees C) after Hemicraniectomy for Malignant MCA Infarction. AB - OBJECTIVE: The beneficial effect of hypothermia after hemicraniectomy in malignant middle cerebral artery (MCA) infarction has been controversial. We aim to investigate the safety and clinical efficacy of hypothermia after hemicraniectomy in malignant MCA infarction. METHODS: From October 2012 to February 2016, 20 patients underwent hypothermia (Blanketrol III, Cincinnati Sub Zero, Cincinnati, OH, USA) at 34 degrees C after hemicraniectomy in malignant MCA infarction (hypothermia group). The indication of hypothermia included acute cerebral infarction >2/3 of MCA territory and a Glasgow coma scale (GCS) score <11 with a midline shift >10 mm or transtentorial herniation sign (a fixed and dilated pupil). We retrospectively collected 27 patients, as the control group, who had undergone hemicraniectomy alone and simultaneously met the inclusion criteria of hypothermia between January 2010 and September 2012, before hypothermia was implemented as a treatment strategy in Dong-A University Hospital. We compared the mortality rate between the two groups and investigated hypothermia-related complications, such as postoperative bleeding, pneumonia, sepsis and arrhythmia. RESULTS: The age, preoperative infarct volume, GCS score, National institutes of Health Stroke Scale score, and degree of midline shift were not significantly different between the two groups. Of the 20 patients in the hypothermia group, 11 patients were induced with hypothermia immediately after hemicraniectomy and hypothermia was initiated in 9 patients after the decision of hypothermia during postoperative care. The duration of hypothermia was 4+/-2 days (range, 1 to 7 days). The side effects of hypothermia included two patients with arrhythmia, one with sepsis, one with pneumonia, and one with hypotension. Three cases of hypothermia were discontinued due to these side effects (one sepsis, one hypotension, and one bradycardia). The mortality rate of the hypothermia group was 15.0% and that of the control group was 40.7% (p=0.056). On the basis of the logistic regression analysis, hypothermia was considered to contribute to the decrease in mortality rate (odds ratio, 6.21; 95% confidence interval, 1.04 to 37.05; p=0.045). CONCLUSION: This study suggests that hypothermia after hemicraniectomy is a viable option when the progression of patients with malignant MCA infarction indicate poor prognosis. PMID- 29526072 TI - Additional Surgical Method Aimed to Increase Distractive Force during Occipitocervical Stabilization : Technical Note. AB - OBJECTIVE: Craniovertebral junctional anomalies constitute a technical challenge. Surgical opening of atlantoaxial joint region is a complex procedure especially in patients with nuchal deformity like basilar invagination. This region has actually very complicated anatomical and functional characteristics, including multiple joints providing extension, flexion, and wide rotation. In fact, it is also a bottleneck region where bones, neural structures, and blood vessels are located. Stabilization surgery regarding this region should consider the fact that the area exposes excessive and life-long stress due to complex movements and human posture. Therefore, all options should be considered for surgical stabilization, and they could be interchanged during the surgery, if required. METHODS: A 53-year-old male patient applied to outpatients' clinic with complaints of head and neck pain persisting for a long time. Physical examination was normal except increased deep tendon reflexes. The patient was on long-term corticosteroid due to an allergic disease. Magnetic resonance imaging and computed tomography findings indicated basilar invagination and atlantoaxial dislocation. The patient underwent C0-C3-C4 (lateral mass) and additional C0-C2 (translaminar) stabilization surgery. RESULTS: In routine practice, the sites where rods are bound to occipital plates were placed as paramedian. Instead, we inserted lateral mass screw to the sites where occipital screws were inserted on the occipital plate, thereby creating a site where extra rod could be bound. When C2 translaminar screw is inserted, screw caps remain on the median plane, which makes them difficult to bind to contralateral system. These bind directly to occipital plate without any connection from this region to the contralateral system. Advantages of this technique include easy insertion of C2 translaminar screws, presence of increased screw sizes, and exclusion of pullout forces onto the screw from neck movements. Another advantage of the technique is the median placement of the rod; i.e., thick part of the occipital bone is in alignment with axial loading. CONCLUSION: We believe that this technique, which could be easily performed as adjuvant to classical stabilization surgery with no need for special screw and rod, may improve distraction force in patients with low bone density. PMID- 29526073 TI - True Aneurysms of the Extracranial Carotid Artery : An Evaluation of Two "Giant Aneurysms" and the Current Literature. AB - True extracranial carotid artery aneurysms (ECCAs) are uncommon. Atherosclerosis is the most common etiological factor. Neck pain, a pulsatile mass and murmur at auscultation are the most common symptoms. ECCAs may exhibit severe clinical manifestations due to complications. Cases of rupture can be fatal. There is a risk of distal embolization and stroke in thrombosed cases. We discuss two cases of enlarged ECCA treated surgically in the light of the most recent literature. PMID- 29526074 TI - Erratum to "Retrospective Analysis of Cerebrospinal Fluid Profiles in 228 Patients with Leptomeningeal Carcinomatosis : Differences According to the Sampling Site, Symptoms, and Systemic Factors" by Shim Y, et al. (J Korean Neurosurg Soc 59 : 570-576, 2016). AB - [This corrects the article on p. 570 in vol. 59.]. PMID- 29526075 TI - Inverse Correlation between Methylation and Expression of the Delta-like Ligand 1 Gene in Gastric Cancer. AB - Notch signaling is a candidate pathway that transmits environmental information into the celland interferes with the epigenome of gastric cancer. This study aimed to explore if the Notch pathwaywas abnormally regulated during gastric tumorigenesis. To achieve the goal, Delta-like ligand 1 (DLL1)gene expression, Notch upstream signal, promoter methylation and its correlation with DLL1expression were examined by methylation-specific polymerase chain reaction (PCR) and real-timePCR (RT-PCR) in cultured gastric cancer cell lines or gastric cancer patient samples. Immunostainingsand tissue arrays (n = 40) were used to confirm the DLL1 expression was down-regulated in cancer cells.Transient or stable Notch1 active domain (NICD)-overexpression suppressed proliferation of thegastric cells but the in vivo tumor growth was enhanced. The results of abnormal DLL1 methylationand expression observed in early gastric lesions and in gastric cancers may be relevant to thepathogenesis of gastric cancer. PMID- 29526076 TI - Semen Parameter Alteration, Histological Changes and Role of Oxidative Stress in Adult Rat Epididymis on Exposure to Electronic Cigarette Refill Liquid. AB - Electronic cigarettes (e-cigarettes) are devices intended to substitute conventional cigarettes, withthe aim of being less harmful. In a previous report, we showed that intraperitoneal (i.p.) injectionof e-cigarette liquid (E-liquid), with or without nicotine, induced toxicity in the testes of Wistar ratsby disrupting oxidative balance and steroidogenesis. In the present work, we further evaluatedthe impact of e-liquid with or without nicotine on the epididymis of rats using the same procedure.Results showed that e-liquid treatments led to alteration of semen parameters, with a significant dropof at least 50% in sperm vitality, a significant increase of morphologically abnormal spermatozoaand an imbalance of redox status in comparison to the control group. A significant raise of 1.4 fold,compared to the untreated rats, in myeloperoxidase (MPO) granules after both treatments wasrecorded, suggesting an inflammatory state. Histopathological examination confirmed a markedreduction in sperm count in the cauda epididymis. Data of this study suggest that the pro-oxidantproperties of e liquid with or without nicotine, in addition to testicular defects, could lead to aninflammatory state in the epididymis, causing alterations in the semen parameters. These dataprovide additional information on the impact of e-liquid on the reproductive system. PMID- 29526077 TI - Sex Differences in the Age of Peak Marathon Race Time. AB - Recent studies showed that women were older than men when achieving their fastest marathonrace time. These studies, however, investigated a limited sample of athletes. We investigated the age ofpeak marathon performance in a large sample of female and male marathon finishers by using datafrom all finishers. We analyzed the age of peak marathon performance in 1-year and 5-year ageintervals of 451,637 runners (i.e. 168,702 women and 282,935 men) who finished the 'New York CityMarathon' between 2006 and 2016, using analysis of variance and non linear regression analysis.During these 11 years, men were faster and older than women, the participation of women increaseddisproportionately to that of men resulting in a decrease of the male-to-female ratio, and relativelymore women participated in the younger age groups. Most women were in the age group 30-34 yearsand most men in the age group 40-44 years. The fastest race time was shown at 29.7 years in womenand 34.8 years in men in the 1-year age intervals, and in age group 30-34 years in women and 35-39years in men in the 5-year age intervals. In contrast to existing findings reporting a higher age ofpeak marathon performance in women compared to men, we found that women achieved their bestmarathon race time ~5 years earlier in life than men in both 1-year and 5 year age intervals. Femaleathletes and their coaches should plan to achieve their fastest marathon race time at the age of ~30years. PMID- 29526078 TI - Hot Water Bathing Impairs Training Adaptation in Elite Teen Archers. AB - Despite heat imposes considerable physiological stress to human body, hot water immersionremains as a popular relaxation modality for athletes. Here we examined the lingering effect ofhot tub relaxation after training on performance associated measures and dehydroepiandrosteronesulfate (DHEA-S) in junior archers. Ten national level archers, aged 16.6 +/- 0.3 years (M = 8, F =2), participated in a randomized counter-balanced crossover study after baseline measurements.In particular, half participants were assigned to the hot water immersion (HOT) group, whereasanother halves were assigned to the untreated control (CON) group. Crossover trial was conductedfollowing a 2-week washout period. During the HOT trial, participants immersed in hot water for30 min at 40 degrees C, 1 h after training, twice a week (every 3 days) for 2 weeks. Participants duringCON trial sat at the same environment without hot water after training. Performance associatedmeasures and salivary DHEA-S were determined 3 days after the last HOT session. We found thatthe HOT intervention significantly decreased shooting performance (CON: -4%; HOT: -22%, P <0.05), postural stability (CON: +15%; HOT: 16%, P < 0.05), and DHEA-S levels (CON: -3%; HOT:-60%, P < 0.05) of archers, compared with untreated CON trial. No group differences were foundin motor unit recruitment (root mean square electromyography, RMS EMG) of arm muscles duringaiming, autonomic nervous activity (sympathetic and vagal powers of heart rate variability, HRV),and plasma cortisol levels after treatments. Our data suggest that physiological adaptation againstheat exposure takes away the sources needed for normal training adaptation specific to shootingperformance in archers. PMID- 29526080 TI - Conjugated Polymer Nanoparticles Based Fluorescent Electronic Nose for the Identification of Volatile Compounds. AB - A fluorescence sensing array (or fluorescent electronic nose) is designed on a disposable paper card using 36 sets of soluble conjugated polymeric nanoparticles (SCPNs) as sensors to easily identify wide ranges of volatile analytes, including explosives and toxic industrial chemicals (amines and pungent acids). A 108 dimensional vector obtained from the fluorescent color change in the sensing array is defined and directly treated as an index in a standard chemical library (30 kinds of volatile analytes and a control group). Hierarchical clustering analysis (HCA) and principal component analysis (PCA) indicated the diversity in electronic structures; saturated vapor pressure and miscibility of analytes are keys in differentiating the analytes, with electron-rich arenes and alkylamines enhancing fluorescence and electron-deficient analytes attenuating fluorescence. A support vector machine (SVM) works well to predict an unknown sample, reaching 99.5% accuracy. The excellent fluorescence stability (no fluorescence quenching after being exposed in air for one month) and high sensitivity (emission color changes within minutes when exposed to analytes) suggest that the fluorescent polymer-based electronic nose will play an important role in field detection and identification of a wide spreading of hazardous substances. PMID- 29526079 TI - Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type I interferon signaling. AB - BACKGROUND/AIMS: Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy. METHODS: A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-beta and its downstream interferon stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs. RESULTS: The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-beta. After DAA treatment, a significant decrease in the expression levels of IFN-beta, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-beta and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation. CONCLUSION: Pretreatment activation of IFN-beta response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA induced alleviation of extrahepatic manifestation of chronic HCV infection. PMID- 29526081 TI - Iron Catalyzed Hydroformylation of Alkenes under Mild Conditions: Evidence of an Fe(II) Catalyzed Process. AB - Earth abundant, first row transition metals offer a cheap and sustainable alternative to the rare and precious metals. However, utilization of first row metals in catalysis requires harsh reaction conditions, suffers from limited activity, and fails to tolerate functional groups. Reported here is a highly efficient iron catalyzed hydroformylation of alkenes under mild conditions. This protocol operates at 10-30 bar syngas pressure below 100 degrees C, utilizes readily available ligands, and applies to an array of olefins. Thus, the iron precursor [HFe(CO)4]-[Ph3PNPPh3]+ (1) in the presence of triphenyl phosphine catalyzes the hydroformylation of 1-hexene (S2), 1-octene (S1), 1-decene (S3), 1 dodecene (S4), 1-octadecene (S5), trimethoxy(vinyl)silane (S6), trimethyl(vinyl)silane (S7), cardanol (S8), 2,3-dihydrofuran (S9), allyl malonic acid (S10), styrene (S11), 4-methylstyrene (S12), 4- iBu-styrene (S13), 4- tBu styrene (S14), 4-methoxy styrene (S15), 4-acetoxy styrene (S16), 4-bromo styrene (S17), 4-chloro styrene (S18), 4-vinylbenzonitrile (S19), 4-vinylbenzoic acid (S20), and allyl benzene (S21) to corresponding aldehydes in good to excellent yields. Both electron donating and electron withdrawing substituents could be tolerated and excellent conversions were obtained for S11-S20. Remarkably, the addition of 1 mol % acetic acid promotes the reaction to completion within 16-24 h. Detailed mechanistic investigations revealed in situ formation of an iron dihydride complex [H2Fe(CO)2(PPh3)2] (A) as an active catalytic species. This finding was further supported by cyclic voltammetry investigations and intermediacy of an Fe(0)-Fe(II) species was established. Combined experimental and computational investigations support the existence of an iron-dihydride as the catalyst resting state, which then follows a Fe(II) based catalytic cycle to produce aldehyde. PMID- 29526082 TI - Immunostimulatory CpG on Carbon Nanotubes Selectively Inhibits Migration of Brain Tumor Cells. AB - Even when treated with aggressive current therapies, patients with glioblastoma usually survive less than two years and exhibit a high rate of recurrence. CpG is an oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9) activation. Injection of CpG into glioblastoma tumors showed promise as an immunotherapy in mouse models but proved disappointing in human trials. One aspect of glioma that is not addressed by CpG therapy alone is the highly invasive nature of glioma cells, which is associated with resistance to radiation and chemotherapy. Here, we demonstrate that single-walled carbon nanotubes noncovalently functionalized with CpG (SWNT/CpG), which retain the immunostimulatory property of the CpG, selectively inhibit the migration of glioma cells and not macrophages without affecting cell viability or proliferation. SWNT/CpG also selectively decreased NF-kappaB activation in glioma cells, while activating macrophages by induction of the TLR9/NF-kappaB pathway, as we have previously reported. The migration inhibition of glioma cells was correlated with selective reduction of intracellular levels of reactive oxygen species (ROS), suggesting that an antioxidant-based mechanism mediates the observed effects. To the best of our knowledge, SWNT/CpG is the first nanomaterial that inhibits the migration of cancer cells while stimulating the immune system. PMID- 29526083 TI - At the Intersection of Urbanization, Water, and Food Security: Determination of Select Contaminants of Emerging Concern in Mussels and Oysters from Hong Kong. AB - Aquaculture, which is growing 3-5 times faster than terrestrial agriculture, will play an important role to meet future global food production needs. However, over 80% of global sewage production is returned to the environment untreated or poorly treated. In developing nations, these nontraditional waters of diverse quality are being recycled for aquaculture, yet chemical residues are differentially studied. Here, we examined pharmaceuticals, pesticides, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), and flame retardants in marine bivalves using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) and low-pressure gas chromatography-tandem mass spectrometry (LP GC-MS/MS). Green lipped mussels from the field and oysters from aquaculture net pens, which are harvested as food products, were collected adjacent to point source municipal wastewater and landfill leachate effluent discharges, respectively, in Hong Kong, the fourth most densely populated country in the world. Multiple classes of pharmaceutical, pesticides, PAHs, and phosphorus-based flame retardants were detected at low MUg/kg levels. Acceptable servings per week indicated minimal risk for a number of chemicals; however, such calculations could not be performed for other contaminants of emerging concern. Future efforts are needed to better understand contaminant influences on marine bivalve populations and aquaculture product safety, particularly in rapidly urbanizing regions of developing countries with limited wastewater infrastructure. PMID- 29526084 TI - Positive Aspects of Cane Sugar and Sugar Cane Derived Products in Food and Nutrition. AB - Recently, as previously for fat and protein, there has been negative discussion about carbohydrate, including blaming it for the rise of obesity and related metabolic conditions, even though overconsumption and sedentary lifestyles are more defined contributors. In many parts of the world, natural sugar (sucrose) from sugar cane is the main dietary source of carbohydrate. Considerable misinformation about sugar is in the public domain with the average consumer being unaware of (i) the critical need of body cells, particularly brain cells, for sugar to function, (ii) the multitude of functionalities other than sweetening that sugar imparts, and (iii) micronutrients delivered with many sugar products. PMID- 29526085 TI - Arsenic Speciation and Accumulation in Selected Organs after Oral Administration of Rice Extracts in Wistar Rats. AB - Despite its nutritional values, rice also contains arsenic. There has been increasing concern about health implications associated with exposure to arsenic through rice consumption. The present study evaluated arsenic accumulation and its speciation in selected organs of Wistar rats after 28 day repeated oral administrations of polished or unpolished rice and their control arsenic compounds (sodium arsenite or dimethylarsinic acid; DMA). Only the treatment of sodium arsenite (2 MUg/kg body weight), significantly increased total arsenic concentrations in blood when compared to the distilled water control group. In all groups, total arsenic concentrations were highest in kidney (1.54-1.90 mg/kg) followed by liver (0.85-1.52 mg/kg), and the predominant arsenic form in these organs was DMA. However, there was no significant difference in arsenic accumulation in the measured organs among the control and rice-treated groups. Therefore, the repeated 28 day administration of arsenic-contaminated rice did not cause significant arsenic accumulation in the animal organs. PMID- 29526086 TI - Flavonoid Glycosides from Fenugreek Seeds Regulate Glycolipid Metabolism by Improving Mitochondrial Function in 3T3-L1 Adipocytes in Vitro. AB - Fenugreek is a well known annual herb widely used in both medicine and food. Four flavonoid glycosides have been separated from fenugreek seeds in our previous study. In this study, the effects of the four flavonoid glycosides on regulating glycolipid metabolism and improving mitochondrial function were investigated. Isoorientin showed a very significant activity among these flavonoid glycosides. First, isoorientin decreased the accumulation of lipid droplets in 3T3-L1 preadipocytes by reducing the expression of adipokines including PPARgamma, C/EBPalpha, and FAS. Second, isoorientin restored insulin-stimulated glucose uptake in dexamethasone-induced insulin-resistant 3T3-L1 adipocytes by reactivating Akt and AMPK. Finally, isoorientin improved mitochondrial dysfunction induced by dexamethasone in 3T3-L1 adipocytes. Isoorientin also reversed dexamethasone-induced decrease in mitochondrial membrane potential (MMP) and intracellular ATP production, reduced accumulation of intracellular reactive oxygen species (ROS), and protected mitochondrial DNA (mtDNA) from oxidative damage. At the same time, mitochondrial biogenesis is promoted. Therefore, isoorientin may be an attractive candidate as a glucose-lowering and insulin resistance-improving agent for the treatment of diabetes. PMID- 29526087 TI - PhotooxidationEffect in Liquid Lipid Matrices: Answers from an Innovative FTIR Spectroscopy Strategy with "Mesh Cell" Incubation. AB - Developing new approaches to evaluate the stability of edible oils under moderate conditions is highly demanded today to avoid accelerated experiments that are not well correlated with actual shelf life. In particular, low intensity of visible light (photooxidation) needs to be integrated in stability studies, together with mild temperature. Thus, in this work, a strategy based on a "mesh cell"-FTIR to monitor chemical changes in lipid matrices using a combination of light and mild heating was applied. The results were compared with those obtained for the stability of triolein used as a molecular model. The study showed that the moderate light intensity (400 lx) at a low temperature (23 degrees C) has an early effect on the degradation of lipid matrices that is not observed when they are stored at 35 degrees C in the absence of light. Thus, the results proved that the exposure to light (400 lx) was more relevant than mild heating (35 degrees C) in monounsaturated lipid matrices, while polyunsaturated lipid matrices were more sensitive to mild heating. PMID- 29526088 TI - Characterization of 1,2-Propanediol Dehydratases Reveals Distinct Mechanisms for B12-Dependent and Glycyl Radical Enzymes. AB - Propanediol dehydratase (PD), a recently characterized member of the glycyl radical enzyme (GRE) family, uses protein-based radicals to catalyze the chemically challenging dehydration of ( S)-1,2-propanediol. This transformation is also performed by the well-studied enzyme B12-dependent propanediol dehydratase (B12-PD) using an adenosylcobalamin cofactor. Despite the prominence of PD in anaerobic microorganisms, it remains unclear if the mechanism of this enzyme is similar to that of B12-PD. Here we report 18O labeling experiments that suggest PD and B12-PD employ distinct mechanisms. Unlike B12-PD, PD appears to catalyze the direct elimination of a hydroxyl group from an initially formed substrate-based radical, avoiding the generation of a 1,1- gem diol intermediate. Our studies provide further insights into how GREs perform elimination chemistry and highlight how nature has evolved diverse strategies for catalyzing challenging reactions. PMID- 29526089 TI - Fatty Acid Profile and the sn-2 Position Distribution in Triacylglycerols of Breast Milk during Different Lactation Stages. AB - Fatty acid (FA) is the major energy resource in breast milk, which is important for infant development. FAs profiles with sn-2 positional preference were an important part of triacylglycerols due to their better availability. This profile is still not replicated in artificial formulas. This study quantified the FAs profile of total and sn-2 position in human breast milk samples from 103 healthy volunteers during colostrum, transitional, and mature stages. Multicomponent analysis showed significant differences in FAs profiles of different lactation periods, due to that with relative percentage less than 1%. Linoleic acid (LA), mostly located at the sn-1,3 positions of TAGs, was more common in the milk of Chinese women than in western women. The majority of the breast milk did not meet the standard for the ratio of LA/alpha-linolenic acid for infant formula. FAs related to brain development, mainly at sn-2 in TAGs, were enriched in colostrum. Capric and lauric acids were enriched in transitional and mature breast milk, and capric acid showed sn-1,3 selectivity in TAGs. This study will aid the development of infant formula containing TAGs more similar to human breast milk. PMID- 29526090 TI - A Comparative Study on Formation of Polar Components, Fatty Acids and Sterols during Frying of Refined Olive Pomace Oil Pure and Its Blend Coconut Oil. AB - The frying performance of pure refined olive-pomace oil (ROPO) and blended with refined coconut oil (RCO) (80:20) was compared during a frying operation of French fries at 180 degrees C. Blending polyunsaturated oils with highly saturated or monounsaturated oils has been studied extensively, however in literature there is no study has been reported so far on blending ROPO (rich in monounsaturated fatty acids) with RCO (rich in saturated fatty acids) to formulate new frying oils. At the end of the frying process, the blend of ROPO/RCO exhibited a higher chemical stability than the pure ROPO based on total polar compounds (TPC), and polymers. The rate of TPC formation was achieved 23.3% and 30.6% for the blend and the pure oil, respectively. Trans and free fatty acids content, as well as anisidine value were also observed to be the highest in the pure ROPO. This study evaluated the frying performance in the search for appropriate frying oils to deliver healthy fried products with optimized nutritional qualities. PMID- 29526091 TI - Evaluation of Nonvolatile Chemistry Affecting Sensory Bitterness Intensity of Highly Hopped Beers. AB - The range of different nonvolatile constituents extracted from hops in highly hopped beers suggests that isohumulones may not be the sole contributor to beers' bitterness. Among brewers producing hop-forward beer styles, there is concern that the bitterness unit (BU) is no longer an accurate predictor of beer bitterness. This study examined factors within the beer matrix that influence sensory bitterness perception in highly hopped beers. Over 120 commercial beers were evaluated using sensory and instrumental techniques. Chemical analysis consisted of the BU via spectrophotometry, hop acids via high-performance liquid chromatography, total polyphenols via spectrophotometry, and alcohol content plus real extract via an Alcolyzer. Sensory analysis was conducted over two studies, and the beers' overall bitterness intensities were rated using a 0-20 scale. This study identified that the BU measurement predicts sensory bitterness with a nonlinear response, and it proposed an alternative approach to predicting bitterness based on isohumulones, humulinones, and ethanol concentrations. The study also revealed the importance of oxidized hop acids, humulinones, as a significant contributor to beer bitterness intensity. PMID- 29526092 TI - Improved Analytical Method for Determination of Cholesterol-Oxidation Products in Meat and Animal Fat by QuEChERS Coupled with Gas Chromatography-Mass Spectrometry. AB - Cholesterol is widely present in animal fats and meat products and can undergo oxidation to form cholesterol-oxidation products (COPs) during heating. The objective of this study was to develop a QuEChERS method for the determination of COPs in edible animal fats and meat products via gas chromatography-mass spectrometry in which the required solvent volume and extraction time were reduced. By employing a DB-5MS capillary column (30 m * 0.25 mm i.d., 0.25 MUm film thickness) and a temperature-programming method, seven COPs, cholesterol, and the internal standard 5alpha-cholestane could be separated within 19 min. The limits of detection and limits of quantitation based on the COP standards ranged from 0.16 to 180 ng/mL and from 0.32 to 400 ng/mL, respectively, and the recoveries ranged from 89.1 to 107.6% for boiled pork and from 80.5 to 105.6% for lard. The intraday variabilities for boiled pork and lard ranged from 2.27 to 6.87% and from 1.52 to 9.78%, respectively, whereas the interday variabilities ranged from 1.81 to 7.89% and from 3.57 to 9.26%, respectively. Among the various meat samples, fish showed the highest level of COPs (31.84 MUg/g). For the edible fats, the COP contents in tallow (22.79-60.15 MUg/g) were much higher than those in lard (0.152-2.55 MUg/g) and butter (0.526-1.36 MUg/g). Collectively, this method can be applied to determine COPs in cholesterol-containing foodstuffs. PMID- 29526093 TI - Antioxidant Protection of Nobiletin, 5-Demethylnobiletin, Tangeretin, and 5 Demethyltangeretin from Citrus Peel in Saccharomyces cerevisiae. AB - Aging and oxidative-related events are closely associated with the oxidative damages induced by excess reactive oxygen species (ROS). The phytochemicals nobiletin (NBT) and tangeretin (TAN) and their 5-demethylated derivatives 5 demethylnobiletin (5-DN) and 5-demethyltangeretin (5-DT) are the representative polymethoxyflavone (PMF) compounds found in aged citrus peels. Although the health benefits from PMFs due to their antioxidant activities have been well documented, a systematic assessment regarding the antioxidation process of PMFs is still lacking attention. Herein, we investigated the effects of the four PMFs subjected to oxidative stress including hydrogen peroxide, carbon tetrachloride, and cadmium sulfate using an emerging model organism Saccharomyces cerevisiae. As expected, all four of the PMFs exhibited improved cellular tolerance with decreasing lipid peroxidation and ROS. Furthermore, by using the mutant strains deficient in catalase, superoxide dismutase, or glutathione synthase, NBT, 5-DN, and TAN appear to contribute to the increased tolerance by activating cytosolic catalase under CCl4, while the antioxidant protection conferred by 5-DT against H2O2 and CdSO4 seems to require cytosolic catalase and glutathione, respectively. However, the involvement of Ctt1 and Sod1 is achieved neither by decreasing lipid peroxidation nor by scavenging intracellular ROS according to our results. In addition, a comparison of antioxidant capability of the four PMFs was conducted in this study. In general, this research tries to explore the antioxidant mechanism of PMFs in Saccharomyces cerevisiae, hoping to provide an example for developing more efficacious dietary antioxidants to battle against oxidative- or age-related illness. PMID- 29526094 TI - A Turn-On Fluorescent Probe for Detection of Sub-ppm Levels of a Sulfur Mustard Simulant with High Selectivity. AB - A new type of fluorescent probe capable of detecting a sulfur mustard (SM) simultant at a concentration of 1.2 MUM in solution and 0.5 ppm in the gas phase has been developed. Owing to its molecular structure with a thiocarbonyl component and two piperidyl moieties integrated into the xanthene molecular skeleton, this probe underwent a highly selective nucleophilic reaction with the SM simultant and generated a thiopyronin derivative emitting intensive pink fluorescence. The distinct difference in electronic structure between the probe and thiopyronin derivative generated a marked shift of the absorption band from 445 to 567 nm, which enabled an optimal wavelength propitious for exciting the thiopyronin derivative but adverse to the probe. Such efficient separation of the excitation wavelength and tremendous increase in fluorescence quantum yield, from less than 0.002 to 0.53, upon conversion from the probe to the thiopyronin derivative, jointly led to a distinct contrast in the beaconing fluorescence signal (up to 850-fold) and therefore the unprecedented sensitivity for detecting SM species. PMID- 29526095 TI - Women in Inorganic Chemistry: Synthetic Chemistry Addressing Challenges in Energy and the Environment. PMID- 29526096 TI - Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery. AB - To expand the range of functional polymer materials to include fully hydrolytically degradable systems that bear bioinspired phosphorus-containing linkages both along the backbone and as cationic side chain moieties for packaging and delivery of nucleic acids, phosphonium-functionalized polyphosphoester- block-poly(l-lactide) copolymers of various compositions were synthesized, fully characterized, and their self-assembly into nanoparticles were studied. First, an alkyne-functionalized polyphosphoester- block-poly(l-lactide) copolymer was synthesized via a one pot sequential ring opening polymerization of an alkyne-functionalized phospholane monomer, followed by the addition of l lactide to grow the second block. Second, the alkynyl side groups of the polyphosphoester block were functionalized via photoinitiated thiol-yne radical addition of a phosphonium-functionalized free thiol. The polymers of varying phosphonium substitution degrees were self-assembled in aqueous buffers to afford formation of well-defined core-shell assemblies with an average size ranging between 30 and 50 nm, as determined by dynamic light scattering. Intracellular delivery of the nanoparticles and their effects on cell viability and capability at enhancing transfection efficiency of nucleic acids (e.g., siRNA) were investigated. Cell viability assays demonstrated limited toxicity of the assembly to RAW 264.7 mouse macrophages, except at high polymer concentrations, where the polymer of high degree of phosphonium functionalization induced relatively higher cytotoxicity. Transfection efficiency was strongly affected by the phosphonium-to phosphate (P+/P-) ratios of the polymers and siRNA, respectively. The AllStars Hs Cell Death siRNA complexed to the various copolymers at a P+/P- ratio of 10:1 induced comparable cell death to Lipofectamine. These fully degradable nanoparticles might provide biocompatible nanocarriers for therapeutic nucleic acid delivery. PMID- 29526097 TI - SWNT Anchored with Carboxylated Polythiophene "Links" on High-Capacity Li-Ion Battery Anode Materials. AB - Conjugated polymers possessing polar functionalities were shown to effectively anchor single-walled carbon nanotubes (SWNTs) to the surface of high-capacity anode materials and enable the formation of electrical networks. Specifically, poly[3-(potassium-4-butanoate) thiophene] (PPBT) served as a bridge between SWNT networks and various anode materials, including monodispersed Fe3O4 spheres (sFe3O4) and silicon nanoparticles (Si NPs). The PPBT pi-conjugated backbone and carboxylate (COO-) substituted alkyl side chains, respectively, attracted the SWNT pi-electron surface and chemically interacted with active material surface hydroxyl (-OH) species to form a carboxylate bond. Beneficially, this architecture effectively captured cracked/pulverized particles that typically form as a result of repeated active material volume changes that occur during charging and discharging. Thus, changes in electrode thickness were suppressed substantially, stable SEI layers were formed, electrode resistance was reduced, and enhanced electrode kinetics was observed. Together, these factors led to excellent electrochemical performance. PMID- 29526098 TI - Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. AB - Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically. PMID- 29526099 TI - Design, Synthesis, and Biological Activity of New N-(Phenylmethyl)-benzoxazol-2 thiones as Macrophage Migration Inhibitory Factor (MIF) Antagonists: Efficacies in Experimental Pulmonary Hypertension. AB - Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent. Molecular docking studies helped to interpret initial SAR related to MIF tautomerase inhibition and propose preferred binding mode for 31 within the MIF tautomerase active site. Interestingly, daily treatment with 31 started 2 weeks after a subcutaneous monocrotaline injection regressed established pulmonary hypertension in rats. PMID- 29526100 TI - Analysis of Structural Stability of Chignolin. AB - We discuss the stability of an entire protein and the influence of main chains and side chains of individual amino acids to investigate the protein-folding mechanism. For this purpose, we calculated the solvation free-energy contribution of individual atoms using the three-dimensional reference interaction site model with the atomic decomposition method. We generated structures of chignolin miniprotein by a molecular dynamics simulation and classified them into six types: native 1, native 2, misfolded 1, misfolded 2, intermediate, and unfolded states. The total energies of the native (-171.1 kcal/mol) and misfolded (-171.2 kcal/mol) states were almost the same and lower than those of the intermediate ( 158.5 kcal/mol) and unfolded (-148.1 kcal/mol) states; however, their components were different. In the native state, the side-chain interaction between Thr6 and Thr8 is important for the formation of pi-turn. On the other hand, the hydrogen bonds between the atoms of the main chains in the misfolded state become stronger than those in the intermediate state. PMID- 29526101 TI - Antioxidants: Differing Meanings in Food Science and Health Science. AB - "Antioxidant" is a term commonly used in food science to describe compounds that block lipid peroxidation and other oxidative reactions, thereby maintaining freshness and prolonging the shelf lives of food products. Dietary antioxidants and antioxidant supplements are lauded as quenching reactive oxygen species and preventing different chronic diseases, but strong evidence for their beneficial effects is lacking. In addition to the essential antioxidant nutrients, vitamins E and C, there are several well-designed antioxidant and cytoprotective enzyme systems in the human body, which are more important than dietary non-nutrient antioxidants. At high concentrations, many antioxidants could act as pro oxidants, increasing oxidative stress and inducing toxicity. PMID- 29526102 TI - How Partial Atomic Charges and Bonding Orbitals Affect the Reactivity of Aluminum Clusters with Water? AB - We present here a further insight on the hydrogen evolution reactions (HER) of aluminum clusters with one and multiple water molecules. Along with natural bond orbital (NBO) and frontier molecular orbital (FMO) analysis, we compared the reactivities of both anionic and neutral Al13, Al12, Al7, and Al6 clusters with water in gas phase. It is found that electron flow interactions between these typical Al clusters and H2O initiate their reactions, allowing varied charge distribution on the cluster. With an emphasis on the typical Al6 cluster, we checked out the reactive intermediates, activated complexes, transition states, bond breaking and stereochemistry for it to react with two and four water molecules, respectively. The kinetic- and thermodynamic- allowed reaction pathways are coincident with the experimental observation of Al n(OH)4- being dominant products for Al n- clusters reacting with water. It is illustrated how additional water molecules function as catalysts enabling strengthened HER activity. PMID- 29526103 TI - Waking Up from Four Decades' Long Dream of Valorizing Agro-Food Byproducts: Toward Practical Applications of the Gained Knowledge. AB - The late 1970s was the onset of literature about the first research outputs on alternatives to create added-value to agro-food byproducts focused on the reduction of the dependency on raw materials and, simultaneously, helping to reduce the environmental impacts of the agricultural activities. This trend, increased over the years and during the past decade, has been boosted by the growing concern of the socio-economic impact of wastes from agro-food activities, however, with little success of the proposed applications. Throughout four decades an array of studies have emerged, aimed to gain evidence on the relevance of innovation in the agro-food industry, as well as to overcome this situation. To our knowledge, only a few cases, summarized in the present perspective, represent the main alternatives currently available for the valorization of agro food byproducts, with indications of some constraints that need to be addressed, in the coming years, to obtain a real profit from these products. PMID- 29526104 TI - Valine Supplementation in a Reduced Protein Diet Regulates Growth Performance Partially through Modulation of Plasma Amino Acids Profile, Metabolic Responses, Endocrine, and Neural Factors in Piglets. AB - The objective of this study was to investigate whether valine (Val) supplementation in a reduced protein (RP) diet regulates growth performance associated with the changes in plasma amino acids (AAs) profile, metabolism, endocrine, and neural system in piglets. Piglets or piglets with a catheter in the precaval vein were randomly assigned to two treatments, including two RP diets with standardized ileal digestible (SID) Val:Lysine (Lys) ratio of 0.45 and 0.65, respectively. The results indicated that piglets in the higher Val:Lys ratio treatment had higher average daily feed intake (ADFI) ( P < 0.001), average daily gain (ADG) ( P = 0.001), feed conversion ratio (FCR) ( P = 0.004), lower plasma urea nitrogen ( P = 0.032), expression of gastric cholecystokinin (CCK), and hypothalamic pro-opiomelanocortin (POMC). Plasma AAs profiles including postprandial plasma essential AAs (EAAs) profile and in serum, muscle, and liver involved in metabolism of AAs and fatty acids were significantly different between two treatments. In conclusion, Val influenced growth performance associated with metabolism of AAs and fatty acids and both endocrine and neural system in piglets. PMID- 29526105 TI - Excitonic Interactions in Bacteriochlorin Homo-Dyads Enable Charge Transfer: A New Approach to the Artificial Photosynthetic Special Pair. AB - Excitonically coupled bacteriochlorin (BC) dimers constitute a primary electron donor (special pair) in bacterial photosynthesis and absorbing units in light harvesting antenna. However, the exact nature of the excited state of these dyads is still not fully understood. Here, we report a detailed spectroscopic and computational investigation of a series of symmetrical bacteriochlorin dimers, where the bacteriochlorins are connected either directly or by a phenylene bridge of variable length. The excited state of these dyads is quenched in high dielectric solvents, which we attribute to photoinduced charge transfer. The mixing of charge transfer with the excitonic state causes accelerated (within 41 ps) decay of the excited state for the directly linked dyad, which is reduced by orders of magnitude with each additional phenyl ring separating the bacteriochlorins. These results highlight the origins of the excited-state dynamics in symmetric BC dyads and provide a new model for studying the primary processes in photosynthesis and for the development of artificial, biomimetic systems for solar energy conversion. PMID- 29526106 TI - Effect of Ethanolamines on the Electroless Deposition of Copper on Functionalized Organic Surfaces. AB - Electroless deposition (ELD) is widely used in industry to deposit metals because it is inexpensive and compatible with organic materials. The deposition rate and deposited film properties critically depend on the reducing agent, complexing agent, and bath pH and temperature as well as bath additives. We have investigated the role of ethanolamine additives in the ELD of copper using the reducing agent dimethylamine borane on -CH3- and -OH-terminated self-assembled monolayers (SAMs) adsorbed on gold. Three additives were studied: ethanolamine (EOA), diethanolamine (DEOA), and triethanolamine (TEOA). Both the chemical identity and concentration of the ethanolamine significantly affect the deposition process. We show that the Cu deposition rate is faster on -CH3 terminated surfaces than on -OH-terminated SAMs because of the stronger interaction of the ethanolamines with the hydroxyl terminal group. In contrast to physical vapor deposition and other ELD processes, Cu deposits atop methyl terminated SAMs using TEOA. However, using EOA and DEOA, copper penetrates through -CH3-terminated SAMs to the Au/S interface. For -OH-terminated SAMs, copper is observed to penetrate through the SAM for all ethanolamines investigated. The amount of copper penetration through the SAM to the Au/S interface increases with ethanolamine concentration. These effects are attributed to an adsorption-inhibition mechanism and differences in the chelation of Cu2+ in the deposition bath. PMID- 29526107 TI - Sputter Deposition toward Short Cationic Thiolated Fluorescent Gold Nanoclusters: Investigation of Their Unique Structural and Photophysical Characteristics Using High-Performance Liquid Chromatography. AB - We herein present the preparation of short, bulky cationic thiolate (thiocholine) protected fluorescent Au nanoclusters via sputter deposition over a liquid polymer matrix. The obtained Au nanoclusters showed near-infrared fluorescence and had an average core diameter of 1.7 +/- 0.6 nm, which is too large compared to that of the reported fluorescent Au nanoclusters prepared via chemical means. We revealed the mechanism of formation of this unique material using single particle electron microscopy, optical measurements, X-ray photoelectron spectroscopy (XPS), and high-performance liquid chromatography fractionations. The noncrystallized image was observed via single-particle high-angle annular dark-field scanning transmission electron microscopy observations and compared with chemically synthesized crystalline Au nanoparticle with the same diameter, which demonstrated the unique structural characteristic speculated via XPS. The size fractionation and size-dependent fluorescence measurement, together with other observations, indicated that the nanoclusters most probably contained a mixture of very small fluorescent species in their aggregated form and were derived from the sputtering process itself and not from the interaction between thiol ligands. PMID- 29526108 TI - Headgroup-Inversed Liposomes: Biointerfaces, Supported Bilayers and Applications. AB - Phospholipids are a major component of the cell membrane. In most natural phospholipids, the phosphate acts as a bridge, connecting the other portion of the polar headgroup with the hydrophobic tails. Such bridging phosphate is chemically quite inert. Synthetic lipids inversing the headgroup polarity of phosphocholine (PC) have been recently reported, and these are named CP lipids with a terminal phosphate, or CPe with the terminal phosphate capped by an ethyl group. This Feature Article summarizes the properties and applications of such inversed lipids. First, CPe liposomes were found to be highly resistant to protein adsorption with an even longer blood circulation time than PC liposomes, allowing for enhanced accumulation in tumor sites. CPe liposomes do not interact with PC liposomes either, and this observation was different from that reported using CP polymers, which adhere strongly to cells. Second, CP liposomes interact strongly with many metal oxide nanoparticles (but not silica) forming supported lipid bilayers, while PC liposomes only form supported bilayers on silica. Finally, CP liposomes are good metal ligands based on their exposed terminal phosphate. Zn2+ binds to CP liposomes so strongly that Zn2+ sandwiched multilayered lipid structures were observed. Aside from these fundamental aspects, the potential applications of these headgroup-inversed lipids in drug delivery and biosensor development have also been described, which in turn has promoted fundamental biointerface insights. PMID- 29526109 TI - Hyperbranched Poly(ether amine)@Poly(vinylidene fluoride) Hybrid Membrane with Oriented Nanostructures for Fast Molecular Filtration. AB - Porous membranes with uniform nanostructures and selective adsorption can realize molecular filtration with high flux and have gained great attention because of their wide application in water treatment and industrial separation. Herein, a novel hyperbranched poly(ether amine)@poly(vinylidene fluoride) (hPEA@PVDF) porous membrane with oriented nanostructures and selective adsorption of guest molecules was fabricated by applying the combined crystallization and diffusion method for the functionalization of the PVDF membrane. The resulting hPEA@PVDF porous membranes were fully characterized by scanning electron microscopy and X ray photoelectron spectra. The results indicated that the hPEA@PVDF membrane exhibited oriented open channel structure and high water flux up to 2116 L m-2 h 1, in which the PVDF skeleton was covered by the amphiphilic hPEA layer. The adsorption behavior of hPEA@PVDF porous membranes to 12 hydrophilic dyes including batch adsorption and molecular filtration was systematically investigated. The results revealed that the hPEA@PVDF membrane possessed high adsorption capacity toward erythrosin B (577 MUmol g-1) and eosin B (511 MUmol g 1), while low adsorption capacity toward calcein (76 MUmol g-1) and methylene blue (hardly adsorbed), indicating the selective adsorption behavior toward dyes in aqueous solution. On the basis of this selective property, the hPEA@PVDF could be used to separate the dye mixtures very efficiently through molecular filtration. In addition, the separation efficiency remained 100% after five adsorption-desorption cycles, indicating that it had great potential in practical applications. PMID- 29526113 TI - "There is a chain of connections": using syndemics theory to understand HIV treatment side effects. AB - Side effects are central to the experience of living longer with HIV but rarely have they been studied alone. Unlike other aspects of that experience, like quality of life, treatment adherence, chronicity, episodic disability, aging, health, and viral load suppression, side effects have not benefited from the same level of empirical and theoretical engagement from qualitative researchers. In this paper, we draw on syndemics theory and 50 qualitative interviews to better understand the experience of HIV treatment side effects. Two main categories were identified in the data: side effects as a product and side effects as a risk factor. The first category suggests that side effects are not just the product of taking antiretroviral drugs. They are also the product of particular conditions and tend to cluster with other health problems. The second category puts forward the idea that side effects can act as a syndemic risk factor by exposing PLWH to a greater risk of developing health problems and creating conditions in which psychosocial issues are more likely to emerge. The paper concludes by calling for more research on the complex nature of side effects and for the development of comprehensive approaches for the assessment and management of side effects. PMID- 29526115 TI - Sensory profiles are comparable in patients with distal and proximal entrapment neuropathies, while the pain experience differs. AB - OBJECTIVE: Distal and proximal entrapment neuropathies such as carpal tunnel syndrome (CTS) and cervical radiculopathy (CR) share similar etiologies. Experimental models suggest that, despite comparable etiology, pathomechanisms associated with injuries of the peripheral and central axon branches are distinct. This study therefore compared self-reported and elicited sensory profiles in patients with distal and proximal entrapment neuropathies. METHODS: Patients with electrodiagnostically confirmed CTS (n = 103) and patients with CR (n = 23) were included in this study. A group of healthy participants served as controls (n = 39). Symptoms and sensory profiles were evaluated using quantitative sensory testing (QST) and a self-reported neuropathic pain questionnaire (painDETECT). RESULTS: Both patient groups were characterized by a loss of function in thermal and mechanical detection in the main pain area and dermatome compared to healthy reference data (p < .001). There was no significant difference between patients with CTS and CR in pain and detection thresholds except for reduced vibration sense in the main pain area (p < .001) and reduced pressure pain sensitivity in the dermatome in patients with CR (p < .001). However, patients with CR reported higher pain intensities (p = .008), more severe pain attacks (p = .009) and evoked pain by light pressure (p = .002) compared to patients with CTS. CONCLUSION: While QST profiles were similar between patients with CTS and CR, self-reported pain profiles differed and may suggest distinct underlying mechanisms in these patient cohorts. PMID- 29526116 TI - Menopausal hormone therapy: a better and safer future. AB - Major advances in menopause hormone therapy (MHT) hold promise in the future of better and safer care for women at and after the menopause. The principal advances are: (1) the critical window or 'window of opportunity' in the 10 years or so after the menopause, during which the benefits of MHT in healthy women exceed any risks; (2) use of transdermal instead of oral administration of estrogen to reduce the risk of venous thromboembolism; (c) investigation of the use of oral micronized progesterone (MP) and vaginal MP to prevent endometrial hyperplasia and carcinoma without any increased risk of breast cancer and venous thromboembolism in postmenopausal women receiving estrogens; vaginal MP prevents endometrial proliferation in the short term but the long-term effects in MHT remain to be established; (4) investigation into the use of intrauterine levonorgestrel-releasing devices (LNG-IUDs), which are an attractive form of MHT in perimenopausal women, providing contraception and reducing uterine bleeding, although the risk of breast cancer with LNG-IUDs requires clarification. Women in the future can look forward to a symptom-free menopause and to safer and more beneficial MHT. PMID- 29526117 TI - Metabonomic analysis of the therapeutic effect of exendin-4 for the treatment of tBHP-induced injury in mouse glomerulus mesangial cells. AB - Although previous studies have reported the protective effect of glucagon-like peptide-1 (GLP-1) in diabetes nephropathy, the molecular mechanism such as nephroprotection remains elusive. In this study, we explored the molecular mechanism of exendin-4 as an GLP-1 receptor agonist for the treatment of tert butyl hydroperoxide (t-BHP)-induced injury in mouse glomerulus mesangial cells (SV40 MES 13 cells) via an NMR-based metabonomic analysis. We found that exendin 4 protected mesangial cells from t-BHP-mediated toxicity, decreased the percentage of t-BHP-treated cells undergoing apoptosis, and restored glucose consumption in the t-BHP-treated group. A supervised partial least-squares discriminant analysis (PLS-DA) revealed that the metabolic profiles could be distinguished between the control, t-BHP-treated, and exendin-4-pretreated groups. Our findings indicate that exendin-4 pretreatment can cause distinct changes in energy, glycerol phospholipid, and amino acid metabolism. Our study provides novel insight into the metabolic mechanism of exendin-4-mediated nephroprotective effects. PMID- 29526118 TI - First-line disease-modifying drugs in relapsing-remitting multiple sclerosis: an Italian real-life multicenter study on persistence. AB - OBJECTIVE: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing-remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation. METHODS: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued. RESULTS: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n = 62, 24%) or on injectable (n = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences. CONCLUSION: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS. PMID- 29526119 TI - Methylation levels of the TNFA gene are different between Graves' and Hashimoto's diseases and influenced by the TNFA polymorphism. AB - Graves' disease (GD) and Hashimoto's disease (HD) are different pathological types of autoimmune thyroid diseases (AITDs). However, the epigenetic differences between these diseases have not been elucidated. DNA methylation is one of the primary epigenetic modifications that reflect environmental influences on gene expression. In this study, we evaluated the methylation status of six CpG sites in the TNFA promoter using pyrosequencing and analyzed the data in combination with functional polymorphisms (-1031 T/C and +123 C/T) in the TNFA gene to clarify the role of gene methylation on the prognosis of AITDs. We examined the methylation pattern in 52 patients with GD, 60 patients with HD, and 29 healthy controls by pyrosequencing. Additionally, we also genotyped the polymorphisms from 163 patients with GD, 152 patients with HD, and 94 healthy controls using the restriction fragment length polymorphism (RFLP) method. Each proportion of subjects with low methylation of the -72 CpG site (<=11.9%), low methylation of the -49 CpG site (<=15.5%), and low methylation of the -38 CpG site (<=8.9%) was significantly increased in the groups with high concentration of TNF-alpha (>=0.134 pg/mL). The methylation level of the -72 CpG site was significantly higher in GD cases (10.7 +/- 4.9%) than in healthy controls (6.8 +/- 3.9%). The methylation level of the -49 and -38 CpG sites were significantly higher in patients with GD in remission (20.5 +/- 9.5%, 17.6 +/- 8.0%, respectively) than in healthy controls (13.0 +/- 7.6%, 7.9 +/- 7.3%, respectively). The frequency of the TNFA - 1031C carrier (CT + CC) is correlated with higher TNF-alpha production and was significantly higher in GD (35.0%) and HD (39.5%) cases than in controls (19.1%). In the subjects with the TNFA - 1031C carrier (CT + CC), the methylation level of the -72 CpG site was significantly higher in GD (11.5 +/- 5.7%) than in HD (6.0 +/- 3.4%). However, there was no difference between GD and HD in patients with the TT genotype. Cumulatively, our data indicate the methylation levels of CpG sites in the TNFA gene may be related to the difference between GD and HD in AITDs and may be influenced by the TNFA gene polymorphism. PMID- 29526120 TI - Discharge breastmilk feeding rates in asymptomatic term newborns admitted to the neonatal intensive care unit for maternal chorioamnionitis. AB - PURPOSE: To compare discharge breastmilk feeding rates among asymptomatic term newborns receiving 48-hour versus >48-hour antibiotics in the neonatal intensive care unit (NICU) and a cohort of well-baby nursery (WBN) newborns. MATERIALS AND METHODS: This retrospective review included asymptomatic term neonates admitted to the NICU due to maternal chorioamnionitis and a comparison group of WBN neonates between January 2012 and December 2015. Demographic, birth, feeding, and lactation consultant visit data were analyzed in univariate and multivariate models. RESULTS: Among 272 NICU neonates, 237 (87%) received 48-hour antibiotics versus 35 (13%) who received >48-hour (h) antibiotics; a cohort of 428 WBN neonates was studied for comparison. Exclusive breastmilk feeding was seen in 14% of NICU versus 35% of WBN neonates (p < .01). Among NICU newborns, 48 h versus >48 h antibiotics was not associated with altered discharge breastmilk feeding (14 versus 14%; p = .89). On multivariate logistic regression analysis among NICU subjects, older maternal age (p < .01), lower parity (p = .02), first-feed breastmilk (p < .01), and more lactation consultant visits (p = .012) were associated with increased discharge breastmilk feeding. CONCLUSIONS: NICU admission for presumed early-onset sepsis due to maternal chorioamnionitis was associated with reduced discharge breastmilk feeding in asymptomatic term neonates, but prolonged antibiotic exposure was not. We speculate that demographic factors, such as maternal age and parity, may aid in focusing lactation consultant efforts to potentially improve NICU exclusive discharge breastmilk feeding rates. PMID- 29526121 TI - Lymphopenia in atopic dermatitis patients treated with oral immunosuppressive drugs. AB - INTRODUCTION: Oral immunosuppressive drugs are commonly used in the treatment of atopic dermatitis (AD). In patients with autoimmune- and rheumatic diseases, these drugs have been associated with lymphopenia. Lymphopenia is related to an increased risk of opportunistic infections. The incidence of lymphopenia in patients with AD treated with oral immunosuppressive drugs is yet unknown. OBJECTIVE: To evaluate the occurrence of recurrent lymphopenia in patients with AD treated with oral immunosuppressive drugs and to make recommendations for screening in daily practice. METHODS: Patients with recurrent lymphopenia (i.e. >5 times lymphocyte counts below 0.8 * 109/L) during treatment with oral immunosuppressive drugs were included from our immunosuppressive drugs database and further analyzed. RESULTS: A total of 360 AD patients, treated with oral immunosuppressive drugs, were screened. A recurrent lymphopenia during treatment was found in 11 patients. In 8/11 patients, recurrent lymphopenia was observed during concomitant treatment with prednisone. No serious infections were observed. CONCLUSION: Lymphopenia is occasionally seen in AD patients treat with oral immunosuppressive drugs. Concomitant treatment with prednisone seems to be a risk factor. We suggest to include monitoring of lymphocyte counts in the standard follow-up for all AD patients treated with oral immunosuppressive drugs. PMID- 29526122 TI - Feasibility of incorporating functionally relevant virtual rehabilitation in sub acute stroke care: perception of patients and clinicians. AB - PURPOSE: To determine user satisfaction and safety of incorporating a low-cost virtual rehabilitation intervention as an adjunctive therapeutic option for cognitive-motor upper limb rehabilitation in individuals with sub-acute stroke. METHODS: A low-cost upper limb virtual rehabilitation application incorporating realistic functionally-relevant unimanual and bimanual tasks, specifically designed for cognitive-motor rehabilitation was developed for patients with sub acute stroke. Clinicians and individuals with stroke interacted with the intervention for 15-20 or 20-45 minutes, respectively. The study had a mixed methods convergent parallel design that included a focus group interview with clinicians working in a stroke program and semi-structured interviews and standardized assessments (Borg Perceived Exertion Scale, Short Feedback Questionnaire) for participants with sub-acute stroke undergoing rehabilitation. The occurrence of adverse events was also noted. RESULTS: Three main themes emerged from the clinician focus group and patient interviews: Perceived usefulness in rehabilitation, satisfaction with the virtual reality intervention and aspects to improve. All clinicians and the majority of participants with stroke were highly satisfied with the intervention and perceived its usefulness to decrease arm motor impairment during functional tasks. No participants experienced major adverse events. CONCLUSIONS: Incorporation of this type of functional activity game-based virtual reality intervention in the sub-acute phase of rehabilitation represents a way to transfer skills learned early in the clinical setting to real world situations. This type of intervention may lead to better integration of the upper limb into everyday activities. Implications for Rehabilitation * Use of a cognitive-motor low-cost virtual reality intervention designed to remediate arm motor impairments in sub-acute stroke is feasible, safe and perceived as useful by therapists and patients for stroke rehabilitation. * Input from end-users (therapists and individuals with stroke) is critical for the development and implementation of a virtual reality intervention. PMID- 29526123 TI - [The situation of pediatric patients' rights in the Transylvanian healthcare]. AB - This study summarizes the results of the author's PhD thesis presenting the research process and the most important findings regarding the situation of Transylvanian healthcare. Our data are based on the knowledge and compliance of pediatric patients' rights as they are seen by healthcare specialists, parents and children. A number of 751 persons were involved in the research: 200 healthcare specialists, 200 parents, 200 children aged from 7 to 17 years who have been experiencing health services at least three times over the past year and a control group of 151 children who did not have this kind of experience. Based on our data, it was possible to highlight the major problems encountered in children's healthcare. We found that children are treated by obsolete principles of medical practice despite the fact that the rights of pediatric patients are well known to doctors. Neither the parents nor the children themselves are sufficiently aware of their rights. Healthcare professionals are not prepared to overcome communication difficulties due to the age-specific characteristics of children, so the fundamental rights of children are just partially enforced: children are usually heard, but not properly informed, their medical decisions are usually not taken into account violating the right to self-determination. The chances to access adequate health services are lower for vulnerable children living in poverty. Orv Hetil. 2018; 159(11): 423-429. PMID- 29526124 TI - [Two years ago died the Hungarian pioneer of orthopedics-related biomechanics. Professor Gabor Krakovits (1934-2016)]. PMID- 29526126 TI - [Odontogenic foci and systemic diseases. A review]. AB - The aim of the present review is to provide an up-to-date picture of what we know about the connection between odontogenic foci and non-oral diseases. After a brief historical summary, we give an overview on how the odontogenic focus causes disease in distant areas of the body in general, and then we start the discussion of the particular conditions, such as cardiovascular diseases, pneumonia, diabetes mellitus, metabolic syndrome, rheumatoid arthritis and adverse pregnancy outcomes. The review is centered around the two main odontogenic foci: periodontitis and periapical periodontitis, the latter being a widely recognized but rarely discussed oral focus. Finally, we offer a few considerations that the practicing dentist may find useful when dealing with odontogenic foci. Orv Hetil. 2018; 159(11): 415-422. PMID- 29526127 TI - [Radiological forms of cerebral amyloid angiopathy]. AB - Cerebral amyloid angiopathy (CAA) is most commonly recognized by beta-amyloid deposition in the small and medium sized vessels of the brain. The 71-year-old female presented with a sudden onset of vertigo and headache. By native computer tomography (CT) examination we found cerebral atrophy and the sign of chronic vascular injury. The complaints of the patient worsened, thus magnetic resonance imaging (MRI) was performed. The MRI scan revealed a bleeding transformation of an ischemic lesion in the right occipital region. On the susceptibility weighted scans we could observe old microbleedings, thus we suspected CAA. The patient later re-presented at the clinic with a sudden onset of right sided hemiplegia. We performed a native CT scan which identified cerebral hemorrhage in atypical position confirming our diagnosis. CAA has many radiological presentations. The most important is the lobar cerebral hemorrhage. On the susceptibility weighted MRI scans, we could identify the microbleeds and the superficial siderosis by the deposition of the hemosiderin. The subarachnoid hemorrhage is a sign of bad outcome. In the white matter, we could detect the change of the related inflammation and the leukoaraiosis. Further, two not specific abnormalities can be important as well, such as extended ischemic lesions and perivascular space dilatation. CAA has various appearances on MRI. Repeated vascular events and dementia in old age patients draw attention to its presence. The correct diagnosis can be made with the right interpretation of the patient's complaints in combination with the radiological abnormalities. Orv Hetil. 2018; 159(11): 439 444. PMID- 29526128 TI - [Second breast conserving surgery and interstitial radiotherapy for the treatment of breast tumor local recurrences. Five-year results]. AB - INTRODUCTION AND AIM: To report the clinical outcomes of second breast-conserving therapy with perioperative interstitial radiotherapy for the treatment of ipsilateral breast tumor recurrences. METHOD: Between 1999 and 2015, 33 patients, presenting with an ipsilateral breast tumor recurrence after previous breast conserving therapy, were salvaged by re-excision and perioperative high-dose-rate interstitial brachytherapy. A median of 8 (range: 4-24) catheters were implanted into the tumor bed intraoperatively. A total dose of 22 Gy in 5 fractions of 4.4 Gy was delivered to the tumor bed with a margin of 1-2 cm, on 3 consecutive days. The adjuvant systemic treatments consisted of hormonal therapy for 24 patients (73%) and chemotherapy for 6 patients (18%). The survival results were estimated by the Kaplan-Meier method. Late side effects and cosmetic results were also registered. RESULTS: The median follow-up time following the second breast conserving therapy was 61 months (range: 26-189 months). During the follow-up, 4 patients (12.1%) developed second local recurrence. The five-year actuarial rates of the second local, regional and distant recurrence were 6.3%, 6.1%, and 14.9%, respectively. The five-year probabilities of disease-free, cancer-specific and overall survival were 76.2%, 92.4%, and 89.2%, respectively. Four (12%), 19 (58%), 4 (12%) and 6 (18%) patients had excellent, good, fair and poor cosmetic results, respectively. Grade 2 and 3 fibrosis developed in 9 (27%) and 1 (3%) patients. Asymptomatic fat necrosis was detected in 7 (21%) women. CONCLUSION: Second breast conserving therapy with perioperative high-dose-rate interstitial brachytherapy is a safe and feasible option for the management of ipsilateral breast tumor recurrences. Interstitial brachytherapy may decrease the risk of second local relapse with acceptable cosmetic results and low rate of late side effects. Hence, in selected cases it can provide a feasible alternative to salvage mastectomy. Orv Hetil. 2018; 159(11): 430-438. PMID- 29526129 TI - The effectiveness of iodine supplementation during pregnancies in geographical areas of high prevalence of iodine insufficiency. AB - The objective of this study was to determine the effectiveness of routine iodine supplementation among pregnant women in areas of high prevalence of an iodine insufficiency, using WHO criteria to determine the iodine status. A longitudinal study was conducted on pregnant women attending antenatal care at a tertiary hospital. The urine iodine concentration was measured in the first trimester and after 150 MUg of iodine supplementation in the third trimester. A total of 327 pregnant women met the inclusion criteria with a complete follow-up. The prevalence of an iodine insufficiency was significantly lower in the third trimester, when compared to the first trimester (21.41% vs 55.35%, p < .001). However, 21.4% of cases still had an iodine insufficiency and 35.17% had an 'above-requirement' in the third trimester. In the areas of high prevalence of iodine insufficiency, an iodine supplementation significantly reduces the number of women with insufficiency; however, it was associated with unnecessarily high UICs, leading to the risk of excess iodine. Impact statement What is already known on this subject: Iodine insufficiency is highly prevalent in many geographical areas. Half of the pregnant women in the northern part of Thailand had an iodine insufficiency in the first trimester. What do the results of this study add: Iodine supplementation (daily 150-mcg of potassium iodide) could significantly reduce the number of women with the insufficiency. About one-fifth of women still had an iodine insufficiency in spite of iodine supplementation. Universal supplementation could be associated with unnecessarily high UICs, potentially at risk of iodine excess. What are the implications of these findings for clinical practice and/or further research: Physicians should guard against the occurrence of adverse effect from an iodine excess when there is routine iodine supplementation for pregnant women. Further study is required to establish the best strategy for an iodine supplementation in pregnancy. PMID- 29526130 TI - Fatherhood during dabrafenib and trametinib therapy for metastatic melanoma. PMID- 29526131 TI - Effect of serum vitamin D level on endometrial thickness and parameters of follicle growth in infertile women undergoing induction of ovulation. AB - In this paper, 153 infertile women undergoing induction of ovulation at an academic tertiary care centre were included in a cross-sectional study. Serum Vitamin D level was measured and the rate of clinical pregnancy (defined as a sonographic presence of FHR of an intrauterine gestational sac) and patient and cycle parameters were determined. The results showed that a correlation exists between endometrial thickness as well as the number of antral follicles and replete level of Vitamin D. Interestingly, the median level of these two parameters was of upmost level in the most replete tertile of serum Vitamin D level. There was no correlation between the serum level of Vitamin D and pregnancy rate. Vitamin D status was associated with endometrial thickness and number of antral follicles, but this study did not find a pivotal effect of serum Vitamin D level on pregnancy rate. Impact statement What is already known on this subject? Literature reviews have indicated that a Vitamin D deficiency is directly responsible for a reduced fertility and reproduction capacity. Women with higher level of Vitamin D in serum and follicular fluid are more likely to become pregnant. What do the results of this study add? This study, assessing the effect of serum level of Vitamin D on endometrial thickness and parameters of follicle growth in infertile women undergoing induction of ovulation showed that a correlation exists between endometrial thickness as well as the number of antral follicles and replete level of Vitamin D. It can be concluded that a replete Vitamin D status is associated with a better state of endometrial thickness and a number of antral follicles, but this study did not find a pivotal effect of serum Vitamin D level on the pregnancy rate. What are the implications of these findings for clinical practice and further research? If a relationship would be proved between Vitamin D deficiency and endometrial thickness and parameters of follicle growth it is possible that with prescribing supplemental Vitamin D as a relatively inexpensive and safe way along with the other more complex and costly infertility treatments, achieving the pregnancy would be easier. PMID- 29526132 TI - Pregnancy outcomes of women with HIV in a district general hospital in the UK. AB - The aim of this study was to describe the obstetrical and virological outcomes in HIV-infected pregnant women who delivered at a district general hospital in south London in the period from 2008 to 2014. Our review identified 137 pregnancies; most (60%, 63/105) of them were unplanned. The commonest mode of delivery was spontaneous vaginal delivery (SVD) (42%, 48/114) followed by emergency Caesarean section (32%, 36/114). Gestational age at delivery was >=37 weeks in most (84%, 91/106) of the cases. Maternal HIV VL at or closest to delivery was undetectable (<40 copies/mL), <400 copies/mL and >1000 copies/mL in 73% (94/129), 90% (116/129) and 6% (8/129) of the pregnancies, respectively. None of the infants were infected with HIV making the rate of MTCT of HIV 0% (zero). Our study shows that favourable virological and obstetrical outcomes of HIV-infected pregnant women are achievable in non-tertiary HIV treatment centres. Impact Statement What is already known on this subject: Prevention of mother-to-child transmission (MTCT) of HIV has been one of the major public health successes in the last decades. This success was evident by the reduction of MTCT of HIV in the UK from 25.6% in the 1993 to only 0.46% in 2011. Furthermore, many reports from individual providers, mainly from tertiary centres, of HIV care in the UK also showed very low rates MTCT of HIV. What the results of this study add: Our study shows that favourable virological and obstetrical outcomes of HIV-infected pregnant women are achievable in non-tertiary HIV treatment centres. The MTCT of HIV rate in our hospital was zero in the period from 2008 to 2014. What the implications are of these findings for clinical practice and/or further research: Staff caring for pregnant HIV positive women in general hospitals and small-to medium HIV clinics should liaise closely with each other and utilise the skill mix within their hospital in order to provide a quality care that is similar to what is achieved in large teaching centres; however, a prompt referral to tertiary hospitals, when indicated, should be facilitated. PMID- 29526133 TI - Satisfaction and psychological after effects of legal abortion at a tertiary care teaching hospital of North India. AB - Psychological assessment using the Beck Depression Inventory II (BDI) on 196 eligible Medical Termination of Pregnancy (MTP) seekers showed that the depression rate prior to MTP was 12 (6.1%) and had increased to 21 (10.7%) 1 month after MTP. Risk factors included primipara, second-trimester abortion, MTP on humanitarian grounds (rape), foetal congenital anomalies and maternal illness. Psychological morbidity due to abortion greatly interferes with the interpersonal, spousal and mother-child relationships. This demands the need of counselling centres so that each MTP seeker could be counselled prior to and after MTP. Impact statement What is already known on this subject? The association between abortion and depression has already been established. But there is a scarcity of information about the association between the psychological morbidity of abortion seekers, prior to and after legal abortions at a tertiary hospital. What do the results of this study add? Our study has not only evaluated the depression rate, but also evaluated the various individual psychological parameters of women with mild mood disorders which might go unnoticed and which certainly interferes with their interpersonal relationships. What are the implications of these findings for clinical practice and/or further research? Early diagnosis and interventions could help these women to have sound interpersonal relations. PMID- 29526134 TI - Comparison of methods for estimating premorbid intelligence. AB - To evaluate impact of neurological injury on cognitive performance it is typically necessary to derive a baseline (or "premorbid") estimate of a patient's general cognitive ability prior to the onset of impairment. In this paper, we consider a range of common methods for producing this estimate, including those based on current best performance, embedded "hold/no-hold" tests, demographic information, and word reading ability. Ninety-two neurologically healthy adult participants were assessed on the full Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV; Wechsler, D. (2008). Wechsler Adult Intelligence Scale (4th ed.). San Antonio, TX: Pearson Assessment.) and on two widely used word reading tests: National Adult Reading Test (NART; Nelson, H. E. (1982). National Adult Reading Test (NART): For the assessment of premorbid intelligence in patients with dementia: Test manual. Windsor: NFER-Nelson.; Nelson, H. E., & Willison, J. (1991). National Adult Reading Test (NART). Windsor: NFER-Nelson.) and Wechsler Test of Adult Reading (WTAR; Wechsler, D. (2001). Wechsler Test of Adult Reading: WTAR. San Antonio, TX: Psychological Corporation.). Our findings indicate that reading tests provide the most reliable and precise estimates of WAIS-IV full scale IQ, although the addition of demographic data provides modest improvement. Nevertheless, we observed considerable variability in correlations between NART/WTAR scores and individual WAIS-IV indices, which indicated particular usefulness in estimating more crystallised premorbid abilities (as represented by the verbal comprehension and general ability indices) relative to fluid abilities (working memory and perceptual reasoning indices). We discuss and encourage the development of new methods for improving premorbid estimates of cognitive abilities in neurological patients. PMID- 29526135 TI - Physical Fitness Is Longitudinally Associated With Academic Performance During Childhood and Adolescence, and Waist Circumference Mediated the Relationship. AB - PURPOSE: The current investigation aimed to investigate the longitudinal association between physical fitness and academic performance over 3 years in adolescents. A secondary aim was to determine to what extent waist circumference mediated the association between physical fitness and academic performance. METHODS: For the current study, 1020 students from first grade [mean age: 7.87 (0.34) y] to fifth grade [mean age: 11.87 (0.37) y] were monitored annually for 3 years (2010-2013). Physical fitness was assessed using the Andersen test, 5 * 5-m shuttle run, jump height, and grip strength tests and by constructing a composite score combining all 4 fitness tests. Academic performance was assessed by national standardized tests in Danish language and math. Generalized structural equation modeling was used to evaluate the relationships between these variables. RESULTS: The Andersen test (standardized beta = 0.15 SD), shuttle run (beta = 0.18 SD), jump height (beta = 0.10 SD), and the fitness composite score (beta = 0.23 SD) were positively associated with academic performance over 3 years. In addition, waist circumference partially mediated the association between physical fitness and academic performance. CONCLUSION: Thus, physical fitness abilities should be stimulated during childhood and early adolescence because of their positive association with academic performance. PMID- 29526136 TI - Prenatally diagnosed infracardiac total anomalous pulmonary venous connection: from the two sides of the spectrum. PMID- 29526137 TI - Bowel ischaemia after endovascular aneurysm repair. AB - The aim of this review was to investigate presentation, aetiology, management, and outcomes of bowel ischaemia following EVAR. We present a case report and searched electronic bibliographic databases to identify published reports of bowel ischaemia following elective infra-renal EVAR not involving hypogastric artery coverage or iliac branch devices. We conducted our review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. In total, five cohort studies and three case reports were included. These studies detailed some 6,184 infra-renal elective EVARs, without procedure-related occlusion of the hypogastric arteries, performed between 1996 and 2014. Bowel ischaemia in this setting is uncommon with an incidence ranging from 0.5 to 2.8 % and includes a spectrum of severity from mucosal to transmural ischaemia. Due to varying reporting standards, an overall proportion of patients requiring bowel resection could not be ascertained. In the larger series, mortality ranged from 35 to 80 %. Atheroembolization, hypotension, and inferior mesenteric artery occlusion were reported as potential causative factors. Elderly patients and those undergoing prolonged procedures appear at higher risk. Bowel ischaemia is a rare but potentially devastating complication following elective infra-renal EVAR and can occur in the setting of patent mesenteric vessels and hypogastric arteries. Mortality ranges from 35 to 80 %. Further research is required to identify risk factors and establish prophylactic measures in patients that have an increased risk of developing bowel ischaemia after standard infra renal EVAR. PMID- 29526138 TI - Comparison between two doses of betamethasone administration with 12 hours vs. 24 hours intervals on prevention of respiratory distress syndrome: a randomised trial. AB - The purpose of the present study was to compare the effect of a two-dose administration of betamethasone with 12 hours interval vs. 24 hours interval on neonatal respiratory distress syndrome (RDS). The study was performed as a randomised clinical trial on 201 pregnant women with a gestational age of 26-34 weeks. In one group 12 mg of betamethasone every 12 hours for two doses and in the other group 12 mg of betamethasone every 24 hours for two doses were prescribed intramuscularly. There were no significant differences between the two groups according to maternal age, parity, gravidity, BMI, neonatal sex, need to surfactant, NICU admission, NICU stay, neonatal death, neonatal sepsis and Apgar score at minutes 1 and 5, but the gestational age at the beginning of the study and delivery receiving complete course of betamethasone and neonatal weight were lower in 24 hours group. RDS, necrotising enterocolitis, intra-ventricular haemorrhage and chorioamnionitis were more in the 24 hours' group. Multiple regression analysis showed that RDS and IVH (p = .022, RR = 0.07, CI95% 0.006 0.96 and p = .013; RR = 0.9, CI95% 0.1-0.89, respectively) were more in the 24 hours group and neonatal death (p = .034, RR = 4.7, CI95% 1.07-16.2) and NEC (p = 0.038, RR = 2.5, CI95% 1.7-3.7), were more in the 12 hours group. In conclusion, it seems that 12 hours interval betamethasone therapy may be considered as an alternative treatment in the case of preterm labour for acceleration of lung maturity; however, it is suggested that more studies should be performed on this issue and various morbidities. IMPACT STATEMENT What is already known on this subject: Administration of a single course of corticosteroids in all women with a gestational age of 24-34 weeks of pregnancy who are at risk for preterm labour and delivery has been recommended. The accepted regimen by National Institutes of Health (NIH) is an injection of betamethasone for two doses with 24 hours interval. What do the results of this study add: Twelve hours interval betamethasone therapy may be considered as an alternative treatment in the cases of preterm labour for acceleration of lung maturity. What are the implications of these findings for clinical practice and/or further research: Prescription of two doses (complete regimen) is more important than the interval between two doses for obtaining the maximum effect in a preterm birth. PMID- 29526140 TI - Can anti-gravity running improve performance to the same degree as over-ground running? AB - This study examined the changes in running performance, maximal blood lactate concentrations and running kinematics between 85%BM anti-gravity (AG) running and normal over-ground (OG) running over an 8-week training period. Fifteen elite male developmental cricketers were assigned to either the AG or over-ground (CON) running group. The AG group (n = 7) ran twice a week on an AG treadmill and once per week over-ground. The CON group (n = 8) completed all sessions OG on grass. Both AG and OG training resulted in similar improvements in time trial and shuttle run performance. Maximal running performance showed moderate differences between the groups, however the AG condition resulted in less improvement. Large differences in maximal blood lactate concentrations existed with OG running resulting in greater improvements in blood lactate concentrations measured during maximal running. Moderate increases in stride length paired with moderate decreases in stride rate also resulted from AG training. The use of AG training to supplement regular OG training for performance should be used cautiously, as extended use over long periods of time could lead to altered stride mechanics and reduced blood lactate. PMID- 29526139 TI - Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure. AB - BACKGROUND: In an early analysis of this trial, use of a magnetically levitated centrifugal continuous-flow circulatory pump was found to improve clinical outcomes, as compared with a mechanical-bearing axial continuous-flow pump, at 6 months in patients with advanced heart failure. METHODS: In a randomized noninferiority and superiority trial, we compared the centrifugal-flow pump with the axial-flow pump in patients with advanced heart failure, irrespective of the intended goal of support (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke (with disabling stroke indicated by a modified Rankin score of >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove a malfunctioning device. The noninferiority margin for the risk difference (centrifugal-flow pump group minus axial-flow pump group) was -10 percentage points. RESULTS: Of 366 patients, 190 were assigned to the centrifugal-flow pump group and 176 to the axial-flow pump group. In the intention-to-treat population, the primary end point occurred in 151 patients (79.5%) in the centrifugal-flow pump group, as compared with 106 (60.2%) in the axial-flow pump group (absolute difference, 19.2 percentage points; 95% lower confidence boundary, 9.8 percentage points [P<0.001 for noninferiority]; hazard ratio, 0.46; 95% confidence interval [CI], 0.31 to 0.69 [P<0.001 for superiority]). Reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (3 patients [1.6%] vs. 30 patients [17.0%]; hazard ratio, 0.08; 95% CI, 0.03 to 0.27; P<0.001). The rates of death and disabling stroke were similar in the two groups, but the overall rate of stroke was lower in the centrifugal-flow pump group than in the axial-flow pump group (10.1% vs. 19.2%; hazard ratio, 0.47; 95% CI, 0.27 to 0.84, P=0.02). CONCLUSIONS: In patients with advanced heart failure, a fully magnetically levitated centrifugal-flow pump was superior to a mechanical-bearing axial-flow pump with regard to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755 .). PMID- 29526141 TI - The MRCGP Clinical Skills Assessment: an international perspective of evidence. PMID- 29526142 TI - SNAP-II for prediction of mortality and morbidity in extremely preterm infants. AB - OBJECTIVE: To determine the specific Score of Neonatal Acute Physiology (SNAP-II) cut-off scores associated with outcomes in extremely preterm infants, and to examine its contribution to predictive models that include nonmodifiable birth predictors. STUDY DESIGN: Retrospective observational study of 9240 infants born at 22-28 weeks' gestation and admitted to the Canadian Neonatal Network from 2010 to 2015. Outcomes included early and hospital mortality, composite of mortality/morbidity and individual morbidities. The SNAP-II cut-off to predict each outcome was determined using the Youden index. Additional contributions were evaluated using a base model that adjusted for gestational age, birth weight z score and sex and by comparing the area under the curve (AUC). RESULTS: The mortality/morbidity rate was 63% (5859/9240). Specific SNAP-II cut-offs ranged from 12 to 20 and were associated with each adverse outcome. Adding SNAP-II cut offs to predictive models that included birth variables significantly improved (p < .05) the prediction of early mortality (AUC 0.84 versus 0.79), hospital mortality (AUC 0.80 versus 0.78), mortality/morbidity (AUC 0.76 versus 0.75), and severe neurological injury (AUC 0.69 versus 0.66) but had little or no effect on predictive models for retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, and nosocomial infection. CONCLUSIONS: SNAP-II cut offs were independently associated with each adverse outcome and using the proposed SNAP-II cut-offs improved the performance of predictive models for certain short-term outcomes. PMID- 29526143 TI - Prevention practices of vaginitis among Malaysian women and its associated factors. AB - Information on vaginal-related issues among Malaysian women is very limited. This study aimed to explore factors associated with preventive practices of vaginitis among Malaysian women. A cross-sectional computer-assisted telephone interview survey of a representative sample of multi-racial Malaysian women aged 18-50 years old was conducted from January to April 2014. Women from 1446 households responded to the survey and nearly one-third (32.1%) reported to have experienced vaginitis. In multivariate analyses, respondents in the urban locality were more likely to practice vaginitis prevention (OR = 1.40, 95% CI = 1.06-1.84) compared with those in the rural areas. Respondents who perceived low susceptibility to vaginitis were less likely to practice vaginitis prevention (OR = 0.72, 95% CI = 0.57-0.91) compared with responders who highly perceive susceptibility. Respondents who had no formal education were less likely to practice vaginitis prevention (OR = 0.16, 95% CI = 0.05-0.48) compared with those with tertiary education. This study showed that comprehensive education and health programmes need to focus on women with a low educational level, living in rural areas and women with low perceived susceptibility to vaginitis. Impact statement What is already known on this subject? Little is known about vaginitis issues among women in Malaysia. This study provides information regarding vaginitis among Malaysian women by looking at the factors associated with prevention practices. What do the results of this study add? From our study, factors associated with prevention practices were found to be educational level, locality, and perceived susceptibility of vaginitis. Those who perform fewer vaginitis prevention practices were women with a low educational level and those who live in rural areas. From the Health Belief Model, women with a low perceived susceptibility of vaginitis were less likely to carry out vaginitis prevention practices. What are the implications of these findings for clinical practice and/or further research? The findings may provide additional insights for policy makers and healthcare providers to deliver effective approaches in order to improve prevention practices of vaginitis among women in multi-ethnic communities. This study has identified points of interest which need to be put in attention for women's health section which has been overlooked in Malaysia. PMID- 29526144 TI - Ulipristal acetate for uterine fibroids: 2 years of real world experience in a UK hospital. AB - Ulipristal acetate (UPA), is a selective progesterone-receptor modulator, it decreases fibroid size and reduces menstrual bleeding. We reviewed its use at the Heart of England Foundation Trust (HEFT), one of the largest prescribing trusts in the UK. The electronic records of patients treated with UPA from January 2013 to August 2015 were reviewed. One hundred and thirty four patients received UPA, 20 women (15%) received a second course. Eighty percent reported subjective global improvements in symptoms after the first course; 45.5% described amenorrhoea or light bleeding compared to 4.5% prior to treatment. Fewer patients were anaemic (Hb <11 g/dL) following treatment (8.2% versus 33.6%). The majority of fibroids (34%) reduced or remained the same size (25%). Two-thirds of women treated for symptom control avoided surgical intervention. UPA improves symptoms and modifies the use of surgery in treating fibroids. Correcting anaemia prior to major surgery reduces the risk of blood transfusion and optimises a patient's condition as part of an enhanced recovery pathway. Impact Statement What is already known on this subject: In women with heavy menstrual bleeding secondary to fibroids, UPA has been shown to reduce fibroid size and control uterine bleeding, inducing amenorrhoea in the majority. Initially, only licenced for pre operative use, an expansion of the licence has included on-going intermittent use for symptomatic fibroids. What the results of this study add: Our review is the largest published cohort of women treated with UPA. It demonstrates symptomatic improvements and advantageous modifications in fibroid size in women of all ethnicities and ages. Our inclusion of women with a uterine size greater than 16 weeks and fibroid diameter larger than 10 cm demonstrates the benefits of UPA with increased fibroid dimensions. What the implications are of these findings for clinical practice and/or further research: These findings can allow clinicians to consider alternative surgical interventions or even avoid surgery completely in a proportion of patients with fibroids. Correcting anaemia and optimising a patient's pre-operative condition reduces post-operative complications and ongoing morbidity. However, 25% of fibroids failed to respond to UPA treatment, further research into the characteristics of women and fibroids that show favourable clinical outcomes will allow identification of those women who are likely to benefit from treatment and prevent futile use in others. PMID- 29526145 TI - Observational prospective study on Lactobacillus plantarum P 17630 in the prevention of vaginal infections, during and after systemic antibiotic therapy or in women with recurrent vaginal or genitourinary infections. AB - We performed a prospective cohort parallel observational study on the use of Lactobacillus plantarum P 17630 in the prevention of vaginal infections. Eligible were women with a diagnosis of bacterial vaginosis (<15 days) and documented history of recurrent vaginal infections; and/or cystitis (<15 days); and/or treatment with antibiotics for bacterial respiratory tract infections during the week before the study entry. Study subjects were prescribed Lactobacillus plantarum P 17630 > 100.000.000 UFC one vaginal capsule per day for 6 days, then a capsule per week for 16 weeks. Eligible subjects were enrolled in two parallel cohorts: 85 women using (group A) and 39 not using (group B) Lactobacillus plantarum P 17630. The risk of recurrent infection within 4 months from the study entry, was higher among untreated women: multivariate OR 2.6 (95%CI 0.7-9.4). The modification of presence/intensity or symptoms was significant in both the study groups (p < .001). Impact statement What is already known on this subject? The Lactobacillus plantarum P 17630 has been shown to be active in the treatment of bacterial vaginosis and vaginal candidiasis. No data are available on its efficacy in the prevention of recurrent vaginal or urological infection or as a prevention strategy during systemic treatment with antibiotics. What do the results of this study add? This observational study suggests that Lactobacillus plantarum given for 4 months may lower the risk of recurrent infection in women with recurrent vaginal or genitourinary infection or after antibiotic systemic treatment for bacterial respiratory tract infection. The finding, however, is not statistically significant, possibly due to the lower than expected rate of infection observed in our population and consequently the limited power of the study. What are the implications of these findings for clinical practice and/or further research? New studies are needed in order to evaluate in different populations the role of Lactobacillus plantarum in lowering the risk of recurrent infection in a high-risk populations. PMID- 29526146 TI - A case report of complications following a combination of modulated B-lynch and Hwu sutures in postpartum haemorrhage: haematocele in the uterine cavity, hemoperitoneum and swelling and rupture of the fallopian tube. PMID- 29526147 TI - Educating the mind without educating the heart is no education at all. PMID- 29526148 TI - Utilisation of preconception care services and determinants of poor uptake among a cohort of women in Abakaliki Southeast Nigeria. AB - Preconception care (PCC) is a preventive strategy for maternal and perinatal morbidity and mortality. This study aimed to assess the level of awareness and utilisation of PCC services. A descriptive cross-sectional survey was conducted at a teaching hospital. Interviewer-administered questionnaires were used to extract information. A total of 450 participants responded; 44.2% (190/450) were aware, 31.7% (143/450) had good knowledge, while only 10.3% (46/450) received PCC. Health care providers were the main source of information (77.9%). There was statistically significant correlation between awareness and participants' level of education (p < .001) and residence (p < .001), as well as between utilisation and education (p < .001), and information from doctors (p < .001). There was a low level of awareness and poor utilisation of PCC, underpinning the need to scale up health education, establishment of functional PCC clinics and formulation of evidence-based guidelines to improve uptake and pregnancy outcome. Impact statement What is already known on the subject of the paper? PCC has been known in high-income countries as a prevention-based strategy, which aims at improving obstetric outcomes. However, the level of utilisation in low-income countries like Nigeria is either unknown or far too low. What do this study add? This work has provided local data on PCC; clearly indicating that the awareness and utilisation of PCC services in Abakaliki, Nigeria is very low when compared with other regions of the world, and this was influenced by the socio-demographic factors - particularly education and place of residence (for awareness), and level of education and information from health care providers (for utilisation), thus suggesting that enlightenment and improvement in social infrastructures could improve awareness, access and utilisation of PCC. What are the implications for clinical practice and/or further research? The implications of these findings in low resource settings like ours will include introducing interventions to scaling up health education, universal establishment of functional PCC units and formulation of evidence-based guidelines aimed at improving the uptake of PCC and pregnancy outcome. Further research will also be needed in future to assess the impact of such interventions and how to sustain potential benefits. PMID- 29526149 TI - Metastatic oesophageal cancer to the ovary: an unusual case. PMID- 29526150 TI - Maternal and neonatal hyponatremia during labor: a case series. AB - BACKGROUND: Hyponatremia during labor and delivery may result in severe maternal and neonatal sequelae. Our aim was to describe the direct effect of hyponatremia in labor on pregnancy outcome. METHODS: A case series of parturients diagnosed with hyponatremia during labor and their neonates. Clinical presentation, laboratory workup, and maternal and neonatal outcomes are presented. RESULTS: Four parturients and their corresponding six neonates were diagnosed with hyponatremia. Of these, two cases were caused by water intoxication and two were preeclampsia induced. While two were identified due to maternal or neonatal symptoms, two were diagnosed by routine laboratory testing. In all cases, low maternal sodium resulted in similarly low neonatal sodium. Neonatal symptoms included respiratory distress syndrome (RDS), lethargy, and jaundice. CONCLUSION: Psychogenic drinking during labor and preeclampsia may predispose to maternal hyponatremia, resulting in neonatal hyponatremia. Early recognition and treatment can prevent further maternal deterioration and adverse neonatal sequelae. PMID- 29526151 TI - Which articles do we prefer to publish? PMID- 29526152 TI - Comparison of different fixation methods of bicolumnar acetabular fractures. AB - OBJECTIVES: This study aims to investigate if the stabilization of iliac wing fractures influences the stability of the acetabular osteosynthesis, if surgical fixation is the choice of treatment, and which technique to be used. MATERIALS AND METHODS: In the study, measurements were performed with an improved finite element model. Tension and displacement values were measured in bicolumnar acetabular fractures in the following cases: combination of cranial and medial plate fixation through the linea terminalis, or combination of cranial plate and quadrilateral surface plates. The iliac wing fracture was either not fixed, or fixed with screws or with a plate. RESULTS: In cases where osteosynthesis was performed through the linea terminalis, 0.01 mm fracture gap displacement was observed with the use of a combination of cranial and quadrilateral surface plate fixations. In the combination of cranial and medial positioned plates, the displacement in the fracture gap was 0.088 mm. The fixation of the iliac wing fracture did not improve the stability of the osteosynthesis of the linea terminalis. Plate fixation of the iliac wing fracture was more stable than screw fixation alone. CONCLUSION: In double column fractures, if the reduction does not require an anterior approach, it is not necessary to fix the iliac wing fracture only to improve the stability of the fixation. If the reduction does require an anterior approach, it is worth fixing the iliac wing fracture with the technically less demanding screw fixation. PMID- 29526153 TI - Surgical reconstruction of hip subluxation and dislocation in children with cerebral palsy. AB - OBJECTIVES: This study aims to review the efficacy of femoral varus derotation osteotomy (VDRO) and Dega transiliac osteotomy in the treatment of hip subluxation and dislocation of cerebral palsy (CP) patients. PATIENTS AND METHODS: This retrospective study included 25 hips of 22 CP patients (9 males, 13 females; mean age 8.7 years; range 4 to 18 years) who were operated due to hip subluxation and dislocation between July 2010 and December 2015. The mean follow up period was 36.1+/-10.4 months (range, 20 to 65.6 months). Femoral VDRO and Dega transiliac osteotomy were performed in all cases. None of the patients were administered cast immobilization postoperatively. Patients were evaluated clinically with gross motor function classification system preoperatively and at the follow-up period. Acetabular index (AI), migration percentage (MP), and neck shaft angle (NSA) were measured and documented by pelvic radiographs taken pre- and postoperatively and at the follow-up period. Intra- and postoperative complications were recorded. RESULTS: Gross motor function classification system scores improved in 16 patients. Mean AI was 33.2 degrees preoperatively and 20.4 degrees postoperatively. In preoperative period, MP and NSA were 72.7% and 160 degrees , respectively, which improved to 24.3% and 130 degrees , respectively, postoperatively. The postoperative improvement in AI, NSA and MP were statistically significant (p<0.001). We performed revision surgery due to implant failure in two patients and detected hip subluxation due to increased pelvic obliquity in one patient who had thoracolumbar scoliosis. CONCLUSION: In CP patients, reconstruction of hip subluxation and dislocation with femoral VDRO and Dega transiliac osteotomy establish femoroacetabular congruency. Without any cast immobilization, early physical therapy is encouraged for immediate recovery. PMID- 29526154 TI - Effects of low molecular weight heparin and rivaroxaban on rat Achilles tendon healing. AB - OBJECTIVES: This study aims to compare the histopathological and biomechanical effects of low molecular weight heparin (LMWH) and rivaroxaban, which are frequently used in orthopedic surgery for thromboembolic prophylaxis, on rat Achilles tendon healing. MATERIALS AND METHODS: In the study, 36 adult, male Sprague Dawley rats weighing between 300 g and 400 g were used. Three groups were formed including 12 rats in each. Achilles tendons of all rats were cut and repaired. Nadroparin calcium was administered subcutaneously for 21 days at a dose of 170 IU AXa to the first group (LMWH group). Rivaroxaban was administered daily at a dose of 3 mg/kg for 21 days as gastric lavage to the second group (rivaroxaban group). The third group was identified as the control group and no medication was administered in this group. At the end of three weeks, tendons extracted from the groups were examined histopathologically and biomechanically. RESULTS: Bonar's and Movin's scores obtained as a result of histopathological examination were statistically significantly higher in the control group (p=0.003 and p=0.004, respectively) (high scores indicate that tendon healing is not sufficient). When type I and type III collagen ratios were examined, type I collagen ratio, which should be found at a higher ratio in mature tendon, was statistically significantly higher in rivaroxaban and LMWH groups compared with the control group (p=0.002). As a result of biomechanical examination, higher mean maximum force values were obtained from the rivaroxaban group compared with the LMWH group (p=0.31). Mean maximum force values obtained from the control group were higher than those obtained from the LMWH group (p=0.03) and the rivaroxaban group (p=0.18). CONCLUSION: Histopathological examination revealed that both LMWH and rivaroxaban have positive effects on tendon healing. However, the same positive effects were not detected in biomechanical examination. PMID- 29526155 TI - Local application of tranexamic acid affects tendon healing negatively in the late period. AB - OBJECTIVES: This study aims to evaluate the potential adverse effects of tranexamic acid (TA) on tendon healing. MATERIALS AND METHODS: Twelve male Wistar Albino rats (weighing 300 g to 350 g) were used in the study. Rats were divided into two groups. Right legs of the rats were determined as the TA group and left legs as the serum physiologic (SP) group. Bilateral Achilles tenotomy was performed and surgically repaired. For the right side, 1 mL of TA and for the left side, 1 mL of SP were applied. Half of the rats were sacrificed at the third week and the other half at the sixth week and tendon samples were collected from the extremities. Histological analyses were performed according to the tendon scoring system (Bonar classification). RESULTS: Tenocyte cell morphology was better in the third week in TA group than in SP group. In terms of colloidal organization, SP groups gave superior results in all weeks. An analysis of total tendon healing scores revealed that the results of the third week TA groups were superior to the results of the sixth week TA groups. Tenocyte morphology and total tendon healing scores of rats in the sixth week TA group were statistically significantly lower compared to the third week TA group (tenocyte morphology p=0.009, total score p=0.041). CONCLUSION: In this study, we detected that locally administered TA has an adverse effect on tendon healing in late period. However, further immunohistochemical and biomechanical studies are needed to support these results. PMID- 29526156 TI - Epidermoid cysts localized on extremities. AB - OBJECTIVES: This study aims to investigate the incidence, anatomic localization, relationship to trauma, treatment complications, relapse ratios after treatment, and factors affecting relapse of epidermoid cysts localized on the extremities. PATIENTS AND METHODS: The study evaluated retrospectively 120 patients (76 males, 44 females; mean age 41.8 years; range 9 to 76 years) diagnosed with and operated due to epidermoid cyst localized on the extremities between January 2012 and June 2017. Patients' age, gender, cyst's localization, anatomic localization, complaint duration, and trauma history were investigated as well as whether a cutaneous islet was left on the cyst and whether any cyst rupture occurred intraoperatively; and relapse and association of relapse ratios with these parameters. RESULTS: There was no statistically significant difference between patients with or without relapse in terms of age, gender distribution, or cyst size or localization (p>0.05). Relapse ratios were significantly lower in patients in whom a cutaneous islet was left intraoperatively (p<0.05). Relapse ratios were significantly higher in patients who developed intraoperative cyst rupture (p<0.05). There was no significant relationship between relapse and trauma history (p>0.05). Intraoperative cyst rupture ratios were significantly lower in patients in whom a cutaneous islet was left intraoperatively (p<0.05). CONCLUSION: Epidermoid cysts are most frequently localized on the hands. They may also be atypically localized with different dimensions and characteristics. Well definition of the cyst margins and characteristics and avoiding intraoperative rupture while excising the cyst together with the cutaneous islet are essential to reduce possible postoperative complications and relapse ratios. PMID- 29526157 TI - Chondrosarcomas of the phalanges of the hand. AB - OBJECTIVES: This study aims to evaluate the diagnosis and treatment approaches of the rarely seen chondrosarcomas of the phalanges of the hand. PATIENTS AND METHODS: Fifty-two patients (27 males, 25 females; mean age 41.2 years; range 12 to 70 years) with chondroid lesions localized in hand phalanges who were performed surgical treatment between December 2012 and September 2016 were retrospectively reviewed. The study included 62 phalangeal chondroid lesions. Patients' mean follow-up duration was 60.6 months (range 13 to 165 months). Incisional biopsy was performed for the diagnosis. One patient with bilateral and multiple involvement was performed tru-cut biopsy. Phalangeal chondrosarcoma was diagnosed in five patients (9.6%). RESULTS: Of the chondroid lesions, 37 were localized in proximal phalanges (59.6%), 16 in midphalanges (25.8%), and nine in distal phalanges (14.6%). Chondrosarcoma was detected in 15 phalanges of five patients. Of the two patients with Ollier disease, localization was detected in nine phalanges (four proximal, two mid, three distal phalanges) of one patient and in three phalanges (one proximal, two midphalanges) of the other patient. None of the patients had distant metastasis on diagnosis. Ray amputation was performed in two patients under general anesthesia and amputation was performed in one patient. One patient did not give consent for operation. The other patient with Ollier disease gave consent for amputation of only one finger. No local recurrence was seen. CONCLUSION: The hand localization of chondrosarcomas is rare with scarce information in the literature. Their metastasis potential is low but local recurrence rates are high after insufficient surgery. Amputation or ray amputation is the applicable treatment. PMID- 29526159 TI - Effects of a lateral row anchor position on the suture holding strength of a double-row knotless fixation in rotator cuff repair. AB - OBJECTIVES: This study aims to evaluate the effects of anchor positions on the suture holding strength of a double-row knotless fixation in rotator cuff repair. MATERIALS AND METHODS: Four different double-row fixation techniques were assessed. In group 1, a 15-mm-wide mattress suture was fixed using a knotless lateral row anchor, horizontal to the shaft. In group 2, the medial sutures were fixed with a 5-mm more lateral anchor that was placed at 45 degrees to the long axis of the humeral shaft. In group 3, different from group 2, medial sutures were fixed with a 30-mm mattress suture width. In group 4, the mattress sutures coming from the medial row anchors were fixed to the 10-mm more lateral row, vertical to the long axis of the humeral shaft. The specimens were cyclically loaded from 10 N to 30 N at 0.5 Hz for 50 cycles, and then loaded to failure. RESULTS: Group 4 had higher cyclic elongation values than group 1 (p=0.021) and group 3 (p=0.006). Group 1 had lower maximum load value than group 3 (p=0.011). Most of the specimens failed with suture ruptures. Unlike the other groups, none of the specimens in group 4 failed via a suture pull through the lateral anchor. CONCLUSION: A horizontal lateral row anchor positioned closer to the medial anchor resulted in less cyclic elongation when compared to a more vertically positioned lateral row anchor. The vertical or oblique positioning of the lateral row anchor did not result in any increase in the failure load value; however, the vertical placement prevented a suture pull through the lateral row anchor. PMID- 29526158 TI - Obese patients require higher, but not high pneumatic tourniquet inflation pressures using a novel technique during total knee arthroplasty. AB - OBJECTIVES: This study aims to investigate the effect of obesity on pneumatic tourniquet inflation pressures determined with a novel formula during total knee arthroplasty (TKA). PATIENTS AND METHODS: Data of 208 patients (19 males, 199 females; mean age 69.8 years; range, 53 to 84 years) who were performed TKA between January 2013 and December 2016 were evaluated prospectively. Patients were divided into two groups as non-obese (body mass index [BMI] <=30.0 kg/m2) and obese (BMI >30.0 kg/m2) according to BMI. Tourniquet inflation pressures were set using arterial occlusion pressure (AOP) estimation method and adding 20 mmHg of safety margin to AOP value. All patients were assessed intra- and postoperatively with outcome measures such as systolic blood pressure, AOP, tourniquet pressure and its effectiveness. The quality of the surgical field and complications were assessed by the surgical team in a blinded fashion. RESULTS: The study included 118 and 90 lower extremity operations in obese and non-obese groups, respectively. Compared to non-obese group; extremity circumference, initial and maximal systolic blood pressures, AOP values, initial and maximal tourniquet pressures were higher in obese group. The performance of the tourniquet was assessed as "excellent" and "good" at almost all stages of the surgical procedure in all patients in both groups. No complication occurred intra or postoperatively. CONCLUSION: Compared to non-obese patients, higher tourniquet inflation pressure is required in obese patients during TKA due to their wider extremity circumference and higher systolic blood pressure profile. PMID- 29526160 TI - Basic principles of fracture treatment in children. AB - This review aims to summarize the basic treatment principles of fractures according to their types and general management principles of special conditions including physeal fractures, multiple fractures, open fractures, and pathologic fractures in children. Definition of the fracture is needed for better understanding the injury mechanism, planning a proper treatment strategy, and estimating the prognosis. As the healing process is less complicated, remodeling capacity is higher and non-union is rare, the fractures in children are commonly treated by non-surgical methods. Surgical treatment is preferred in children with multiple injuries, in open fractures, in some pathologic fractures, in fractures with coexisting vascular injuries, in fractures which have a history of failed initial conservative treatment and in fractures in which the conservative treatment has no/little value such as femur neck fractures, some physeal fractures, displaced extension and flexion type humerus supracondylar fractures, displaced humerus lateral condyle fractures, femur, tibia and forearm shaft fractures in older children and adolescents and unstable pelvis and acetabulum fractures. Most of the fractures in children can successfully be treated by non surgical methods. PMID- 29526161 TI - Tumors and tumor-like lesions of infrapatellar fat pad and surrounding tissues: A review of the literature. AB - The infrapatellar fat pad (IFP) is an intracapsular structure with critical importance both mechanically and endocrinologically. Its dysfunction must be considered while clinically investigating the symptoms arising from the knee joint. Infrapatellar fat pad may be subject to trauma, impingement, inflammation or tumoral formations. Although tumors arising within or adjacent to IFP are not extremely rare, the literature can only provide limited information about them. This article aims to briefly review the current literature on tumors and tumor like lesions of the IFP and surrounding tissues; focusing on diagnosis and treatment management. PMID- 29526162 TI - Spontaneous regression of a primary squamous cell lung cancer following biopsy: a case report. AB - BACKGROUND: Spontaneous regression has been defined as occurring when the malignant tumor mass partially or completely disappears without any treatment or as a result of a therapy considered inadequate to influence systemic neoplastic disease. Recently, studies have implicated immunological responses as likely being involved. We report a case of a patient with squamous cell carcinoma of the lung who experienced spontaneous regression following biopsy without other intervention. CASE PRESENTATION: A 57-year-old white man was referred to our pulmonary clinic after an incidental finding of a nodule in the lower lobe of his left lung. Thoracic computed tomography revealed a 2.0 * 1.4 * 1.5 cm spiculated nodule in the superior segment of the left lower lobe. Workup identified the mass as a squamous cell carcinoma that was clinically staged as T1M0N0. The patient deferred treatment of this lesion. He undertook no significant lifestyle or medical changes. Three months later, computed tomography revealed that, compared with the initial study, the solitary mass had decreased in size to 1.6 * 0.9 * 0.9 cm. Follow-up computed tomography 1 year after the original workup demonstrated that the nodule had stabilized to its smaller size. CONCLUSIONS: Studies have shown that immunological response can be initiated by trauma to an area. Because the tumor regression became evident in our patient only after the tissue biopsy, his immune response to the surgical procedure seems to be a plausible contributor to the spontaneous regression. Further understanding of spontaneous regression can potentially impact the identification of neoplastic drug targets or even the course of a patient's treatment plan and goals. PMID- 29526164 TI - Influence of premium vs masked cigarette brand names on the experienced taste of a cigarette after tobacco plain packaging in Australia: an experimental study. AB - BACKGROUND: Few studies have experimentally assessed the contribution of branding to the experience of smoking a cigarette, compared with the inherent properties of the product. This study examined the influence of cigarette brand name on the sensory experience of smoking a cigarette. METHODS: Seventy-five Australian smokers aged 18-39 years smoked two 'premium' cigarettes, one with the brand variant name shown and one with the brand variant name masked (which provided 'objective' ratings). Unknown to participants, the two cigarettes were identical. At recruitment, participants rated their expected enjoyment, quality and harshness of several premium cigarette brands. RESULTS: Branded cigarettes were rated as having a significantly more favorable taste (M(SE) = 64.14(2.21)) than masked cigarettes (M(SE) = 58.53(2.26), p = .031). Branded cigarettes were also rated as being less stale (M(SE) = 36.04(2.62)) than masked cigarettes (M(SE) = 43.90(2.60), p = .011). Purchase intent tended to be higher among those shown the branded cigarette compared to the masked cigarette (chi2 (1) = 3.00, p = .083). Expected enjoyment and quality of the brand variant (enjoyment: b = 0.31, 95%CI = 0.11, 0.51, p < .01; quality: b = 0.46, 95%CI = 0.21, 0.72, p < .01) contributed to the perceived smoking experience more than the objective enjoyment and quality of the cigarette (enjoyment: b = 0.23, 95%CI = 0.05, 0.41, p < .05; quality: b = 0.08, 95%CI = - 0.13, 0.30, p > .05). This pattern was not observed for cigarette harshness. CONCLUSIONS: A premium brand variant name can enhance the subjective experience of a cigarette. Further, smokers' expectations of such brand variants contribute to the smoking experience as much, if not more than, the actual qualities of the product. PMID- 29526166 TI - Distinct genetic profiles of Leishmania (Viannia) braziliensis associate with clinical variations in cutaneous-leishmaniasis patients from an endemic area in Brazil. AB - American tegumentary leishmaniasis (ATL) samples obtained from the lesions of patients with typical (n = 25, 29%), atypical (n = 60, 69%) or both (n = 2%) clinical manifestations were analysed by multilocus enzyme electrophoresis, hsp70 restriction-fragment length polymorphism (PCR-RFLP), hsp70 sequencing and phylogenetics methods. The hsp70 PCR-RFLP analysis revealed two different profiles whose the most samples differed from those expected for Leishmania braziliensis and the other Leishmania species tested: of 39 samples evaluated, two (5%) had a restriction profile corresponding to L. braziliensis, and 37 (95%) had a restriction profile corresponding to a variant pattern. A 1300-bp hsp70 gene fragment was sequenced to aid in parasite identification and a phylogenetic analysis was performed including 26 consensus sequences from the ATL patient's samples and comparing to other Leishmania and trypanosomatids species. The dendrogram allowed to observe a potential population structure of L. braziliensis complex in the studied region, emphasizing that the majority of clinical samples presented a variant genetic profile. Of interest, the L. braziliensis diversity was associated with different clinical manifestations whose parasites with hsp70 variant profile were associated with atypical lesions. The results may be helpful to improve the diagnosis, treatment and control measures of the ATL in endemic areas. PMID- 29526163 TI - Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer. AB - BACKGROUND: Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. MAIN BODY: The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. CONCLUSION: Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers. PMID- 29526165 TI - Odon device for instrumental vaginal deliveries: results of a medical device pilot clinical study. AB - BACKGROUND: A prolonged and complicated second stage of labour is associated with serious perinatal complications. The Odon device is an innovation intended to perform instrumental vaginal delivery presently under development. We present an evaluation of the feasibility and safety of delivery with early prototypes of this device from an early terminated clinical study. METHODS: Hospital-based, multi-phased, open-label, pilot clinical study with no control group in tertiary hospitals in Argentina and South Africa. Multiparous and nulliparous women, with uncomplicated singleton pregnancies, were enrolled during the third trimester of pregnancy. Delivery with Odon device was attempted under non-emergency conditions during the second stage of labour. The feasibility outcome was delivery with the Odon device defined as successful expulsion of the fetal head after one-time application of the device. RESULTS: Of the 49 women enrolled, the Odon device was inserted successfully in 46 (93%), and successful Odon device delivery as defined above was achieved in 35 (71%) women. Vaginal, first and second degree perineal tears occurred in 29 (59%) women. Four women had cervical tears. No third or fourth degree perineal tears were observed. All neonates were born alive and vigorous. No adverse maternal or infant outcomes were observed at 6-weeks follow up for all dyads, and at 1 year for the first 30 dyads. CONCLUSIONS: Delivery using the Odon device is feasible. Observed genital tears could be due to the device or the process of delivery and assessment bias. Evaluating the effectiveness and safety of the further developed prototype of the BD Odon DeviceTM will require a randomized-controlled trial. TRIAL REGISTRATION: ANZCTR ACTRN12613000141741 Registered 06 February 2013. Retrospectively registered. PMID- 29526167 TI - Infection patterns and molecular data reveal host and tissue specificity of Posthodiplostomum species in centrarchid hosts. AB - Posthodiplostomum minimum utilizes a three-host life cycle with multiple developmental stages. The metacercarial stage, commonly known as 'white grub', infects the visceral organs of many freshwater fishes and was historically considered a host generalist due to its limited morphological variation among a wide range of hosts. In this study, infection data and molecular techniques were used to evaluate the host and tissue specificity of Posthodiplostomum metacercariae in centrarchid fishes. Eleven centrarchid species from three genera were collected from the Illinois portion of the Ohio River drainage and necropsied. Posthodiplostomum infection levels differed significantly by host age, host genera and infection locality. Three Posthodiplostomum spp. were identified by DNA sequencing, two of which were relatively common within centrarchid hosts. Both common species were host specialists at the genus level, with one species restricted to Micropterus hosts and the other preferentially infecting Lepomis. Host specificity is likely dictated by physiological compatibility and deviations from Lepomis host specificity may be related to host hybridization. Posthodiplostomum species also differed in their utilization of host tissues. Neither common species displayed strong genetic structure over the scale of this study, likely due to their utilization of bird definitive hosts. PMID- 29526168 TI - Has the Genetic Contribution to the Propensity to Gamble Increased? Evidence From National Twin Studies Conducted in 1962 and 2002. AB - Social changes, such as the expansion of legal forms of gambling, can influence not only the prevalence of gambling, but can also shape the relative importance of genetic and environmental contributions to individual differences in the propensity to gamble. In the present study, I examined differences in the prevalence and in the relative contribution of genetic and environmental factors to gambling involvement in the United States in 1962 versus 2002. The data came from two sources: (1) a survey of 839 17-year-old same-sex twin pairs from the National Merit Scholarship Qualifying Test twin study, and (2) an interview of 477 18- to 26-year-old same-sex twin pairs from Wave III of the National Longitudinal Study of Adolescent to Adult Health. Similar measures of gambling participation were included in the two studies. Evidence for a genotype-by-time interaction was evaluated by testing whether the contribution of genetic influences was greater in the more recently born cohort of twins. Despite the major changes in the gambling landscape over the intervening 40 years, there was no evidence for such an interaction. The contribution of genetic factors and environmental factors did not significantly differ and there was no evidence for genetic influences at either time point. Instead, the variation in the propensity to gamble was explained nearly equally by common and unique environmental factors. Explanations for this surprising finding are discussed. PMID- 29526169 TI - Factors associated with fatal outcome of children with enterovirus A71 infection: a case series. AB - Enterovirus A-71 (EV-A71) may be fatal, but the natural history, symptoms, and signs are poorly understood. This study aimed to examine the natural history of fatal EV-A71 infection and to identify the symptoms and signs of early warning of deterioration. This was a clinical observational study of fatal cases of EV-A71 infection treated at five Chinese hospitals between 1 January 2010 and 31 December 2012. We recorded and analysed 91 manifestations of EV-A71 infection in order to identify early prognosis indicators. There were 54 fatal cases. Median age was 21.5 months (Q1-Q3: 12-36). The median duration from onset to death was 78.5 h (range, 6 to 432). The multilayer perceptron analysis showed that ataxia respiratory, ultrahyperpyrexia, excessive tachycardia, refractory shock, absent pharyngeal reflex, irregular respiratory rhythm, hyperventilation, deep coma, pulmonary oedema and/or haemorrhage, excessive hypertension, tachycardia, somnolence, CRT extension, fatigue or sleepiness and age were associated with death. Autopsy findings (n = 2) showed neuronal necrosis, softening, perivascular cuffing, colloid and neuronophagia phenomenon in the brainstem. The fatal cases of enterovirus A71 had neurologic involvement, even at the early stage. Direct virus invasion through the neural pathway and subsequent brainstem damage might explain the rapid progression to death. PMID- 29526170 TI - Factors in the home environment associated with toddler diet: an ecological momentary assessment study. AB - OBJECTIVE: To identify home environment factors associated with toddler dietary behaviours using ecological momentary assessment (EMA). DESIGN: Home environment and toddler's diet were assessed by mothers through EMA (random beeps over <=8 d and a brief survey). Dietary outcomes were fruit/vegetable consumption, eating episode ('snack' v. 'meal') and sugar-sweetened beverage (SSB) consumption. Home environment factors included interacting with mother, eating alone/with others, eating in a high chair/chair at the table, watching television and movement/translocation. Multilevel logistic mixed-effects regression models assessed both within- (individual toddlers across time) and between- (toddlers-on average) subject effects. SUBJECTS: Low-income mother-toddler dyads (n 277). SETTING: Urban and suburban Maryland, USA. RESULTS: EMA captured eating/drinking episodes for 249/277 (89.9 %) toddlers (883 eating episodes, 1586 drinking episodes). Toddlers-on-average were more likely (adjusted OR, P value) to eat fruit/vegetables when not moving around (0.43, P=0.043), eat with the television off (0.33, P<0.001) and eat in a high chair/chair (3.38, P<0.001); no within subject effects were shown. For eating episodes, both toddlers-on-average and individual toddlers were more likely to eat snacks when not in a high chair/chair (0.13, P<0.001 and 0.06, P<0.001, respectively) and when eating alone (0.30, P<0.001 and 0.31, P<0.001, respectively). Also, individual toddlers were more likely to eat snacks when moving around (3.61, P<0.001). Toddlers-on-average were more likely to consume SSB when not in a high chair/chair (0.21, P=0.001), eating alone (0.38, P=0.047) or during a snacking episode (v. a meal: 3.96, P=0.012); no within-subject effects shown. CONCLUSIONS: Factors in the home environment are associated with dietary behaviours among toddlers. Understanding the interplay between the home environment and toddler diet can inform future paediatric dietary recommendations. PMID- 29526171 TI - The changing epidemiology of varicella and herpes zoster in Hong Kong before universal varicella vaccination in 2014. AB - In Hong Kong, universal varicella vaccination started in July 2014. Before this, children could receive varicella vaccine via the private market. We analysed the epidemiology of varicella and zoster before universal vaccination. We estimated varicella vaccination coverage through surveys in preschool children. We estimated the burden of varicella and zoster with varicella notifications from 1999/00 to 2013/14, Accident and Emergency Department (A&E) attendance and inpatient admissions to public hospitals from 2004/05 to 2013/14. We fitted a catalytic model to serological data on antibodies against varicella-zoster virus to estimate the force of infection. We found that varicella vaccination coverage gradually increased to about 50% before programme inception. In children younger than 5 years, the annual rate of varicella notifications, varicella admission and zoster A&E attendance generally declined. The annual notification, A&E attendance and hospitalisation rate of varicella and zoster generally increased for individuals between 10 and 59 years old. Varicella serology indicated an age shift during the study period towards a higher proportion of infections in slightly older individuals, but the change was most notable before vaccine licensure. In conclusion, we observed a shift in the burden of varicella to slightly older age groups with a corresponding increase in incidence but it cannot necessarily be attributed to private market vaccine coverage alone. Increasing varicella vaccination uptake in the private market might affect varicella transmission and epidemiology, but not to the level of interrupting transmission. PMID- 29526172 TI - Investigating ethnic variations in reporting of psychotic symptoms: a multiple group confirmatory factor analysis of the Psychosis Screening Questionnaire. AB - BACKGROUND: Epidemiological evidence suggests risk for psychosis varies with ethnicity in Western countries. However, there is little evidence to date on the cross-cultural validity of screening instruments used for such comparisons. METHODS: Combining two existing UK population-based cohorts, we examined risk for reporting psychotic symptoms across White British (n = 3467), White Irish (n = 851), Caribbean (n = 1899), Indian (n = 2590), Pakistani (n = 1956) and Bangladeshi groups (n = 1248). We assessed the psychometric properties of the Psychosis Screening Questionnaire (PSQ) with a multiple-group confirmatory factor analysis, assessing the equivalence of factor loadings, response thresholds and residual variances in an analysis of measurement non-invariance. RESULTS: Compared with prevalence among British Whites (5.4%), the prevalence of self reported psychotic symptoms was greater in the Caribbean group (12.7%, adjusted OR = 2.38 [95% CI 1.84-3.07]). Prevalence was also increased among Pakistani individuals (8.3%, adjusted OR = 1.36 [1.01-1.84]) although this difference was driven by a greater likelihood of reporting paranoid symptoms. PSQ items for thought interference, strange experience and hallucination were measured in equivalent ways across ethnic groups. However, our measurement models suggested that paranoid symptoms were measured less reliably among ethnic minorities than among British Whites and appeared to exaggerate latent differences between Pakistani and White British groups when measurement non-invariance was not accounted for. CONCLUSIONS: Notwithstanding evidence for measurement non invariance, the greater risk for reporting psychotic symptoms among Caribbean individuals is unlikely to be an artefact of measurement. Greater residual variance in the recording of paranoid symptoms among ethnic minority respondents warrants caution in using this item to investigate ethnic variation in psychosis risk. PMID- 29526173 TI - [China National Lung Cancer Screening Guideline with Low-dose Computed ?Tomography (2018 version)]. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related death in China. The results from a randomized controlled trial using annual low-dose computed tomography (LDCT) in specific high-risk groups demonstrated a 20% reduction in lung cancer mortality. The aim of tihs study is to establish the China National lung cancer screening guidelines for clinical practice. METHODS: The China lung cancer early detection and treatment expert group (CLCEDTEG) established the China National Lung Cancer Screening Guideline with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 2 medical oncologists, 2 pulmonologists, 2 pathologist, and 2 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with at risk for lung cancer. The expert group reviewed the literature, including screening trials in the United States and Europe and China, and discussed local best clinical practices in the China. A consensus based guidelines, China National Lung Cancer Screening Guideline (CNLCSG), was recommended by CLCEDTEG appointed by the National Health and Family Planning Commission, based on results of the National Lung Screening Trial, systematic review of evidence related to LDCT screening, and protocol of lung cancer screening program conducted in rural China. RESULTS: Annual lung cancer screening with LDCT is recommended for high risk individuals aged 50-74 years who have at least a 20 pack-year smoking history and who currently smoke or have quit within the past five years. Individualized decision making should be conducted before LDCT screening. LDCT screening also represents an opportunity to educate patients as to the health risks of smoking; thus, education should be integrated into the screening process in order to assist smoking cessation. CONCLUSIONS: A lung cancer screening guideline is recommended for the high-risk population in China. Additional research , including LDCT combined with biomarkers, is needed to optimize the approach to low-dose CT screening in the future. PMID- 29526175 TI - [Impact of Cystic Fibrosis Transmembrane Conductance Regulator on Malignant? Properties of KRAS Mutant Lung Adenocarcinoma A549 Cells]. AB - BACKGROUND: The incidence of lung cancer is gradually increased, and the cystic fibrosis transmembrane conductance regulator (CFTR) has recently demonstrated to have an implication in the deoncogenesis and malignant transformation of many types of cancers. The aim of this study is to investigate impacts of CFTR on the malignant features of lung adenocarcinoma A549 cells. METHODS: The capacity of cell proliferation, migration, invasion and clonogenicity of non-small cell lung cancer A549 cells were detected by CCK8 cell proliferation assay, cell scratch assay, Transwell cell invasion assay and clone formation assay, respectively. Meanwhile, the effect of CFTR gene on the expression of cancer stem cell related transcriptional factors was also detected by immunoblotting (Western blot) assay. RESULTS: An overexpression of CFTR gene in A549 cells significantly inhibited the malignant capacity of A549 cells, including potencies of cell proliferation, migration, invasion and colony formation; while knockdown of CFTR gene expression by RNA interference in A549 cells resulted in an opposite effect seen in above cells overexpressing CFTR gene. Mechanistically, immunoblotting assay further revealed that the ectopic expression of CFTR gene led an inhibitory expression of stem cell-related transcriptional factors SOX2 and OCT3/4, and cancer stem cell surface marker CD133 in A549 cells, while a knockdown of CFTR expression yielded a moderately increased expression of these gene. However, an alteration of CFTR gene expression had neither effect on the expression of putative lung cancer stem cell marker aldehyde dehydrogenase1 (ALDH1), nor the frequency of ALDH1A-positive cells in A549 cells, as ascertained by the immunoblotting assay and cytometry analysis, respectively. CONCLUSIONS: The CFTR exhibited an inhibitory role in the malignancy of lung adenocarcinoma A549 cells, suggesting that it may be a novel potential target for lung cancer treatment. However, its functions in other lung adenocarcinoma cell lines and its underlying molecular mechanisms require further investigation. PMID- 29526174 TI - [Expert Consensus for Image-guided Radiofrequency Ablation of Pulmonary Tumors (2018 Version)]. PMID- 29526176 TI - [The Initial Experience of Video-assisted Thoracic Surgery Segmentectomy for Early Stage Lung Cancer]. AB - BACKGROUND: Segmentectomy can retains more healthy lung tissue than lobectomy, but it remains controversial in oncology for early stage lung cancer. The aim of this study is to discuss the problems of video-assisted thoracic surgery (VATS) segmentectomy in early stage lung cancer, by analyzing the clinical and pathological data of 35 cases and reviewing the literature. METHODS: There were 35 patients who received segmentectomy by complete video-assisted thoracic surgery, from May 2013 to July 2017, in single operation group in the Third Hospital of Peking University. We analyzed the patient's clinical and pathological data, intraoperative and postoperative complications, lymph node number and metastasis its situation, and compared postoperative pathology and preoperative computed tomography (CT) imaging type. In 35 cases of segmentectomy, there were 11 males and 24 females, with an average age of 57.7 years old. The lesions located in the right upper lobe were 8 cases, in the right lower lobe were 8 cases, in the left upper lobe were 13 cases, in the left lower lobe were 6 cases. The mean maximum diameter of CT imaging was 12.7 mm, and the largest diameter of hilar and mediastinal lymph nodes was less than 10 mm. 23 of them were ground glass predominating and 12 were solid components predominating. RESULTS: All 35 cases were successfully completed VATS anatomical segmentectomy. The average operation time was 153 minutes, the amount of bleeding was 51 mL. There were 10 cases of air leakage after operation, all of which were not more than 3 days. There was contralateral atelectasis in 1 case, chylothorax in 1 case. The average length of hospitalization was 6.1 days. There was no other complications outpatient related to surgery, in 30 days after discharge. The pathological changes were as follow, 2 cases of metastatic tumor, 8 cases of benign lung disease and 25 cases of primary lung cancer. In the 25 cases of primary lung cancer, there were 14 cases of invasive lung adenocarcinoma (7 cases were groundglassopacity (GGO) predominating in CT imaging), 4 cases of micro invasive adenocarcinoma (3 cases were GGO predominating in CT imaging), 6 cases of adenocarcinoma in situ (all were pure GGO in CT imaging), 1 case of lung squamous cell carcinoma (mainly composed of solid in CT imaging). An average of 7.2 lymph nodes were removed in 25 cases of lung cancer, and all lymph nodes had no metastasis. CONCLUSIONS: VATS anatomical segmentectomy is technically safe and reliable, and the indications for lung cancer need to be strictly controlled. Its advantages still need to be confirmed by prospective randomized controlled trials. PMID- 29526177 TI - [Effect of Thoracic Surgeons on Lung Cancer Patients' Survival]. AB - BACKGROUND: Surgeons are the direct decision-makers and performers in the surgical treatment of patients with lung cancer. Whether the differences among doctors affect the survival of patients is unclear. This study analyzed the five year survival rates of different thoracic surgeries in patients undergoing surgery to assess the physician's impact and impact. METHODS: A retrospective analysis of five years between 2002-2007 in the Department of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, for surgical treatment of lung cancer patients. According to different surgeons grouping doctors to compare the basic information of patients, surgical methods, short-term results and long term survival differences. RESULTS: A total of 712 patients treated by 11 experienced thoracic surgeons were included in this study. The patients have nosignificant difference with gender, age, smoking, pathological type between groups. There were significant differences in clinical staging, surgery type, operation time, blood transfusion rate, number of lymph node dissection, palliative resection rate, postoperative complications and perioperative mortality. There was a significant difference in five-year survival rates among patients treated by different doctors. This difference can be seen in all clinical stage analyzes with consistency. In the multivariate analysis, it was suggested that surgeon was an independent factor influencing the prognosis of patients. CONCLUSIONS: Thoracic surgeon has a significant effect on the therapeutic effect of lung cancer patients. PMID- 29526178 TI - [Mechanisms of Resistance to the Third-generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer]. AB - Targeted therapy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has been the standard modality as first-line treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-TKIs has been approved to overcome the EGFR T790M mutation in patients resistant to the first-or second-generation TKIs, which brings more survival benefits for patients with advanced NSCLC. Unfortunately, acquired resistance inevitably develops after application of approximately 10 months. Heterogeneities of the tumor determines the diversity of resistance. Mechanisms of resistance to the third-generation TKIs includs EGFR-dependent pathway (such as new EGFR mutations, T790M reduction/disappearance and EGFR amplification, etc.) and EGFR-independent pathway (such as bypass pathway activation and histological transformation, etc.). In this paper, we reviewed principle mechanisms of acquired resistance to third-generation EGFR-TKIs. PMID- 29526179 TI - [Progress on the Study of Targeting FGFR in Squamous Non-small Cell Lung Cancer]. AB - Squamous cell lung cancer (SqCLC) is a unique clinical and histologic category of non-small cell lung cancer (NSCLC). Most of patients with SqCLC tend to be older, typically at advanced stage, associated with smoking and have more complications. With progress of targeted therapy of lung cancer, we identified several potential actionable genetic abnormalities such as FGFR. Several FGFR inhibitors have been approved for clinical use in different cancers. And some of these agents are currently under investigation in clinical trials for SqCLC. This article summarizes the current knowledge about FGFR aberrations, the relative inhibitors in development and clinical data in SqCLC. PMID- 29526180 TI - [Advances in Long Non-coding RNAs on Resistant to EGFR-TKIs ?in Non-small Cell Lung Cancer]. AB - Most non-small cell lung cancer patients with active epidermal growth factor receptor (EGFR) mutation will eventually acquire drug resistant to EGFR tyrosine kinase inhibitors, such as gefitinib, resulting in disease progression, which involves a variety of complex mechanisms. Up to now, the molecular mechanisms of long non-coding RNAs mediated EGFR-TKIs resistance remains poorly understood. This review aims to outline the current state of information on lncRNAs and progress on its role in EGFR-TKIs resistance in non-small cell lung cancer. PMID- 29526181 TI - [Research Advances of Pan-negative Type of Non-small Cell Lung Cancer]. AB - In recent years, series of driver genes, such as EGFR, KRAS/NRAS, BRAF, PIK3CA, ALK and ROS1 and so on, have been found in non-small cell lung cancer (NSCLC) one after another with the development of molecular detecting technology. Targeted drugs bring benefits for these NSCLC patients with driver gene variations. However, some NSCLC did not have any known driver gene variations; we called it pan-negative lung cancer. In this paper, we summarize the concept, clinical pathological characteristics, the epidemiological characteristics, treatment and prognosis of pan-negative NSCLC. PMID- 29526182 TI - Pulmonary Rehabilitation and Exercise Training in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common condition that is becoming increasingly prevalent. It affects 13.2% of the population over age 40 in Germany. In 2020, it will be the third most common cause of morbidity and mortality around the world. It markedly impairs the quality of life of those who suffer from it and presents a major economic challenge to the health-care system. METHODS: This review is based on pertinent publications retrieved by a selective literature search and on the authors' clinical experience. RESULTS: Pulmonary rehabilitation (PR) for patients with COPD is supported by evidence on the highest level. It is associated with statistically significant (p <0.001) and clinically relevant improvement in physical performance (6-minute walk distance: + 44 m; 95% confidence interval [33; 55]), shortness of breath (Chronic Respiratory Disease Questionnaire: +0.79 points [0.56; 1.03]), and the quality of life (Saint George's Respiratory Questionnaire: -6.9 points [-9.3; -4.5]). The benefits of PR are especially evident after an acute exacerbation of COPD: it significantly lowers the rate of readmission to the hospital (odds ratio 0.22 [0.08; 0.58], p = 0.002) and improves physical performance ability (6-minute walk distance: + 62 m [38; 86] and the quality of life (Saint George's Respiratory Questionnaire: -7.8 points [-12.1; -3.5]; p <0.001 for both). CONCLUSION: PR is an effective and cost-effective therapeutic intervention that improves physical performance ability, shortness of breath, and the quality of life in patients with COPD, but it has not yet been fully implemented as recommended in the relevant guidelines. There is a need for targeted, problem-oriented referral to a range of PR programs with problem-specific content. The necessary outpatient PR structures still need to be established in Germany. PMID- 29526183 TI - An Exotic Visitor. PMID- 29526184 TI - Chronic Heart Failure. AB - BACKGROUND: Chronic heart failure (CHF) is the most common reason for hospital admissions in Germany. For the National Disease Management Guideline (NDMG) on CHF, a multidisciplinary expert panel revised the chapters on drug therapy, invasive therapy, and care coordination, following the methods of evidence-based medicine. METHODS: Recommendations are based on international guideline adaptations or systematic literature search. They were developed by a multidisciplinary expert panel, approved in a formal consensus procedure, and tested in open consultation, as specified by the requirements for S3 guidelines. RESULTS: The pharmacological treatment is based on ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists as well as diuretics to treat fluid retention, if present. Sacubitril/Valsartan and ivabradine showed positive effects on mortality in large but methodologically limited RCT. They are recommended if established combination therapy is not sufficient for symptom control, or if drugs are not tolerated/contraindicated. The indications for pacemakers or defibrillators have been confined to patient subgroups in which clinical trials have shown a clear benefit. Moreover, the goals of treatment and the patient's expectations should be aligned with each other. Structured care programs, specialized nurses, remote, or telephone monitoring showed moderate effects on patient related outcomes in RCT. CONCLUSION: All patients with heart failure are suggested to be enrolled in a structured program (e.g., a disease management program) including coordinated multidisciplinary care and continuous educational interventions. In patients with a poor prognosis, more intensive care is recommended, e.g. specialized nurses, or telephone support. PMID- 29526185 TI - The Importance of Ergometry Was Underrated. PMID- 29526186 TI - Current Clinical Practice Is Different. PMID- 29526187 TI - In Reply. PMID- 29526189 TI - Incomplete and Curtailed Statements. PMID- 29526188 TI - Limitations of the Study. PMID- 29526190 TI - In Reply. PMID- 29526191 TI - Prevention of intimal hyperplasia by immobilized all-trans retinoic acid. PMID- 29526192 TI - Correction. PMID- 29526193 TI - Comparison of efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up noninferiority trial. PMID- 29526194 TI - Effectiveness of UV-C light assisted by mild heat on Saccharomyces cerevisiae KE 162 inactivation in carrot-orange juice blend studied by flow cytometry and transmission electron microscopy. AB - The aim of this study was to analyze the effectiveness of UV-C light (0-10.6 kJ/m2) assisted by mild heat treatment (50 degrees C) on the inactivation of Saccharomyces cerevisiae KE 162 in peptone water and fresh carrot-orange juice blend (pH: 3.8; 9.8 degrees Brix; 707 NTU; absorption coefficient: 0.17 cm-1). Yeast induced damage by single UV-C and mild heat (H) and the combined treatment UV-C/H, was investigated by flow cytometry (FC) and transmission electron microscopy (TEM). When studying induced damage by FC, cells were labeled with fluorescein diacetate (FDA) and propidium iodide (PI) to monitor membrane integrity and esterase activity. UV-C/H provoked up to 4.7 log-reductions of S. cerevisiae; whereas, only 2.6-3.3 log-reductions were achieved by single UV-C and H treatments. FC revealed a shift with treatment time from cells with esterase activity and intact membrane to cells with permeabilized membrane. This shift was more noticeable in peptone water and UV-C/H treated juice. In the UV-C treated juice, double stained cells were detected, suggesting the possibility of being sub-lethally damaged, with compromised membrane but still metabolically active. TEM images of treated cells revealed severe damage, encompassing coagulated inner content, disorganized lumen and cell debris. FC and TEM provided additional information regarding degree and type of damage, complementing information revealed by the traditional plate count technique. PMID- 29526195 TI - Different temperatures select distinctive acetic acid bacteria species and promotes organic acids production during Kombucha tea fermentation. AB - Kombucha is a traditional beverage produced by tea fermentation, carried out by a symbiotic consortium of bacteria and yeasts. Acetic Acid Bacteria (AAB) usually dominate the bacterial community of Kombucha, driving the fermentative process. The consumption of this beverage was often associated to beneficial effects for the health, due to its antioxidant and detoxifying properties. We characterized bacterial populations of Kombucha tea fermented at 20 or 30 degrees C by using culture-dependent and -independent methods and monitored the concentration of gluconic and glucuronic acids, as well as of total polyphenols. We found significant differences in the microbiota at the two temperatures. Moreover, different species of Gluconacetobacter were selected, leading to a differential abundance of gluconic and glucuronic acids. PMID- 29526196 TI - Antifungal activity of synthetic cowpea defensin Cp-thionin II and its application in dough. AB - Plant defensins are small, cysteine-rich antimicrobial peptides of the immune system found in several organs during plant development. A synthetic peptide, KT43C, a linear analogue of the native Cp-thionin II found in cowpea seeds, was evaluated for its antifungal potential. It was found that KT43C displayed antifungal activity against Fusarium culmorum, Penicillium expansum and Aspergillus niger. Like native plant defensins, KT43C showed thermostability up to 100 degrees C and cation sensitivity. The synthetic peptide decreased the fungal growth without inducing morphogenic changes in the fungal hyphae. Non inhibitory concentrations of the peptide induced permeabilization of the fungal membrane. In addition, high concentrations of KT43C induced the production of reactive oxygen species in the granulated cytoplasm. To investigate potential applications, the peptide was used as an additive in the preparation of dough which did not contain yeast. This peptide delayed the development of fungal growth in the dough by 2 days. Furthermore, KT43C did not induce red blood cell lysis up to a concentration of 200 MUg.ml-1. These results highlight the potential for the use of synthetic antimicrobial defensins for shelf-life extension of food products. PMID- 29526197 TI - Use of whole-genome sequencing for Campylobacter surveillance from NARMS retail poultry in the United States in 2015. AB - Whole genome sequencing (WGS) has become a rapid and affordable tool for public health surveillance and outbreak detection. In this study, we used the Illuminia MiSeq(r) to sequence 589 Campylobacter isolates obtained in 2015 from retail poultry meats as part of the National Antimicrobial Resistance Monitoring System (NARMS). WGS data were used to identify the Campylobacter species and to compare the concordance between resistance genotypes and phenotypes. WGS accurately identified 386 C. jejuni and 203 C. coli using gyrA sequence information. Ten resistance genes, including tetO, blaOXA-61, aph(2")-Ic, aph(2")-If, aph(2")-Ig, aph(3')-III, ant(6)-1a, aadE, aph(3")-VIIa, and Inu(C), plus mutations in housekeeping genes (gyrA at position 86, 23S rRNA at position 2074 and 2075), were identified by WGS analysis. Overall, there was a high concordance between phenotypic resistance to a given drug and the presence of known resistance genes. Concordance between both resistance and susceptible phenotypes and genotype was 100% for ciprofloxacin, nalidixic acid, gentamicin, azithromycin, and florfenicol. A few discrepancies were observed for tetracycline, clindamycin, and telithromycin. The concordance between resistance phenotype and genotype ranged from 67.9% to 100%; whereas, the concordance between susceptible phenotype and genotype ranged from 98.0% to 99.6%. Our study demonstrates that WGS can correctly identify Campylobacter species and predict antimicrobial resistance with a high degree of accuracy. PMID- 29526198 TI - Decontamination and survival of Enterobacteriaceae on shredded iceberg lettuce during storage. AB - Enterobacteriaceae family can contaminate fresh produce at any stage of production either at pre-harvest or post-harvest stages. The objectives of the current study were to i) identify Enterobacteriaceae species on iceberg lettuce, ii) compare the decontamination efficiency of water, sodium hypochlorite (free chlorine 200 ppm), peroxyacetic acid (PA 80 ppm; Kenocid 2100(r)) or their combinations and ionizing radiation against Enterobacteriaceae on shredded iceberg lettuce and iii) determine the survival of Enterobacteriaceae post treatment storage of shredded iceberg lettuce at 4, 10 and 25 degrees C, for up to 7 days. Klebsiella pneumonia spp. pneumonia, Enterobacter cloacae, Klebsiella oxytoca, Pantoea spp., Leclercia adecarboxylata and Kluyvera ascorbate were identified on iceberg lettuce. No significant difference (P>= 0.05) among Enterobacteriaceae survival after washing with water or sanitizing with sodium hypochlorite or Kenocid 2100(r) (reduction <= 0.6 log CFU/g) were found. Combined sanitizer treatments were more effective against Enterobacteriaceae than single washing/sanitizing treatments. Sanitization of iceberg lettuce with combined washing/sanitizing treatments reduced Enterobacteriaceae by 0.85-2.24 CFU/g. Post treatment growth of Enterobacteriaceae during storage on samples sanitized with sodium hypochlorite and Kenocid 2100(r) was more than on samples washed with water. The D10-value of Enterobacteriaceae on shredded iceberg lettuce was 0.21 KGy. The reduction of Enterobacteriaceae populations on iceberg after gamma radiation (0.6 KGy) was 3 log CFU/g, however, Enterobacteriaceae counts increased post-irradiation storage by 4-5 log CFU/g. Therefore, washing shredded iceberg lettuce with combined sanitizing treatment (sodium hypochlorite/sodium hypochlorite, sodium hypochlorite/Kenocid 2100(r), or Kenocid 2100(r)/Kenocid 2100(r)) for total time of 6 min or exposing it to gamma irradiation (0.6 KGy) can decrease the risk of Enterobacteriaceae (reduction >= 2 log). Post-washing storage of sliced iceberg lettuce (4, 10, 25 degrees C) could increase the risk of Enterobacteriaceae as their counts increased during storage even at low temperatures. PMID- 29526199 TI - Polyphasic identification of Penicillia and Aspergilli isolated from Italian grana cheese. AB - Penicillium and Aspergillus genera, both including mycotoxin producing species, were reported as associated to cheese and cheese working environment, but never studied in an extensive way in Italian grana cheese (Grana Padano and Parmigiano Reggiano). The aim of this work was to address the identification of Aspergilli and Penicillia associated to grana cheese in order to lay down the basis for risk assessment and safe processing for a high quality production. One hundred and four strains belonging to Aspergillus and Penicillium genera were obtained from cheese crust and from ripening room air (with the latter largely dominant), and identified following a polyphasic approach, strongly required for the identification at the species level. Morphological observation was used along with molecular techniques, RAPD-PCR fingerprinting and calmodulin gene sequencing (CaM), the former aimed to limit as much as possible the latter sequencing effort. Seventy four percent of the strains were assigned to Penicillium subgenus Penicillium, section Fasciculata. Main mycotoxin producing species identified were A. flavus, P. crustosum and P. verrucosum, while the dominant species in both air and cheese crust was P. solitum, which has never been so far reported as mycotoxigenic. Results obtained in this study confirmed that mycotoxin contamination is a possible issue to face during grana cheese making. PMID- 29526200 TI - Directed evolution of Oenococcus oeni strains for more efficient malolactic fermentation in a multi-stressor wine environment. AB - High concentrations of ethanol, low pH, the presence of sulfur dioxide and some polyphenols have been reported to inhibit Oenococcus oeni growth, thereby negatively affecting malolactic fermentation (MLF) of wine. In order to generate superior O. oeni strains that can conduct more efficient MLF, despite these multiple stressors, a continuous culture approach was designed to directly evolve an existing ethanol tolerant O. oeni strain, A90. The strain was grown for ~350 generations in a red wine-like environment with increasing levels of stressors. Three strains were selected from screening experiments based on their completion of fermentation in a synthetic wine/wine blend with 15.1% (v/v) ethanol, 26 mg/L SO2 at pH 3.35 within 160 h, while the parent strain fermented no more than two thirds of l-malic acid in this medium. These superior strains also fermented faster and/or had a larger population in four different wines. A reduced or equivalent amount of the undesirable volatile, acetic acid, was produced by the optimised strains compared to a commercial strain in Mouvedre and Merlot wines. These findings demonstrate the feasibility of using directed evolution as a tool to generate more efficient MLF starters tailored for wines with multiple stressors. PMID- 29526201 TI - Detection of Fusarium verticillioides by PCR-ELISA based on FUM21 gene. AB - Fusarium verticillioides is a primary corn pathogen and fumonisin producer which is associated with toxic effects in humans and animals. The traditional methods for detection of fungal contamination based on morphological characteristics are time-consuming and show low sensitivity and specificity. Therefore, the objective of this study was to develop a PCR-ELISA based on the FUM21 gene for F. verticillioides detection. The DNA of the F. verticillioides, Fusarium sp., Aspergillus sp. and Penicillium sp. isolates was analyzed by conventional PCR and PCR-ELISA to determine the specificity. The PCR-ELISA was specific to F. verticillioides isolates, showed a 2.5 pg detection limit and was 100-fold more sensitive than conventional PCR. In corn samples inoculated with F. verticillioides conidia, the detection limit of the PCR-ELISA was 1 * 104 conidia/g and was also 100-fold more sensitive than conventional PCR. Naturally contaminated corn samples were analyzed by PCR-ELISA based on the FUM21 gene and PCR-ELISA absorbance values correlated positively (p < 0.05) with Fusarium sp. counts (CFU/g). These results suggest that the PCR-ELISA developed in this study can be useful for F. verticillioides detection in corn samples. PMID- 29526202 TI - Inhibitory activity of propolis against Listeria monocytogenes in milk stored under refrigeration. AB - Propolis is a natural bee-product with documented antimicrobial properties in vitro. The objective of this study was to develop a protocol for adding propolis into milk and to determine whether the addition of propolis can confer anti listerial activity during the storage of milk under optimal or improper refrigeration conditions. Upon dissolving propolis ethanolic extract (PEE) into glycerol, the PEE-glycerol mixture contained no visible insoluble particles and could be dispersed evenly into milk, without leaving any insoluble material. PEE, with or without glycerol, was added into extended shelf-life milk, artificially contaminated with Listeria monocytogenes. The addition of PEE dissolved into glycerol resulted in a pronounced and dose-dependent anti-listerial effect in milk stored at 4 degrees C, with the higher concentration tested (4 mg of dry PEE per mL of milk) resulting in complete inhibition of L. monocytogenes growth throughout 30 days of storage. The combination of PEE with glycerol was also effective in significantly reducing the growth rate of the pathogen in milk stored under improper refrigeration (10 degrees C). Based on a patented PEE deodorization protocol, the addition of deodorized PEE into milk resulted in a product with average consumer acceptability. However, the PEE deodorization process resulted in reduction or even complete removal of propolis constituents with known antibacterial activity, with a concomitant significant reduction in its anti-listerial effect. Nonetheless, the data presented in this manuscript highlight the strong anti-listerial potential of propolis in milk and suggest that, upon further research on its deodorization and standardization, there may be room for the application of propolis as a natural preservative in dairy beverages. PMID- 29526203 TI - Staphylococcus aureus undergoes major transcriptional reorganization during growth with Enterococcus faecalis in milk. AB - Previous studies have demonstrated the antagonistic potential of lactic acid bacteria (LAB) present in raw milk microbiota over Staphylococcus aureus, albeit the molecular mechanisms underlying this inhibitory effect are not fully understood. In this study, we compared the behavior of S. aureus ATCC 29213 alone and in the presence of a cheese-isolated LAB strain, Enterococcus faecalis 41FL1 in skimmed milk at 30 degrees C for 24 h using phenotypical and molecular approaches. Phenotypic analysis showed the absence of classical staphylococcal enterotoxins in co-culture with a 1.2-log decrease in S. aureus final population compared to single culture. Transcriptional activity of several exotoxins and global regulators, including agr, was negatively impacted in co-culture, contrasting with the accumulation of transcripts coding for surface proteins. After 24 h, the number of transcripts coding for several metabolite responsive elements, as well as enzymes involved in glycolysis and acetoin metabolism was increased in co-culture. The present study discusses the complexity of the transcriptomic mechanisms possibly leading to S. aureus attenuated virulence in the presence of E. faecalis and provides insights into this interspecies interaction in a simulated food context. PMID- 29526204 TI - Sources and contamination routes of microbial pathogens to fresh produce during field cultivation: A review. AB - Foodborne illness resulting from the consumption of contaminated fresh produce is a common phenomenon and has severe effects on human health together with severe economic and social impacts. The implications of foodborne diseases associated with fresh produce have urged research into the numerous ways and mechanisms through which pathogens may gain access to produce, thereby compromising microbiological safety. This review provides a background on the various sources and pathways through which pathogenic bacteria contaminate fresh produce; the survival and proliferation of pathogens on fresh produce while growing and potential methods to reduce microbial contamination before harvest. Some of the established bacterial contamination sources include contaminated manure, irrigation water, soil, livestock/ wildlife, and numerous factors influence the incidence, fate, transport, survival and proliferation of pathogens in the wide variety of sources where they are found. Once pathogenic bacteria have been introduced into the growing environment, they can colonize and persist on fresh produce using a variety of mechanisms. Overall, microbiological hazards are significant; therefore, ways to reduce sources of contamination and a deeper understanding of pathogen survival and growth on fresh produce in the field are required to reduce risk to human health and the associated economic consequences. PMID- 29526205 TI - Variability within the dominant microbiota of sliced cooked poultry products at expiration date in the Belgian retail. AB - Sliced cooked poultry products are susceptible to bacterial spoilage, notwithstanding their storage under modified-atmosphere packaging (MAP) in the cold chain. Although the prevailing bacterial communities are known to be mostly consisting of lactic acid bacteria (LAB), more information is needed about the potential variation in species diversity within national markets. In the present study, a total of 42 different samples of sliced cooked poultry products were collected in the Belgian retail and their bacterial communities were analysed at expiration date. A total of 629 isolates from four different culture media, including plate count agar for the total microbiota and de Man-Rogosa-Sharpe (MRS), modified MRS, and M17 agar as three selective agar media for LAB, were subjected to (GTG)5-PCR fingerprinting and identification by gene sequencing. Overall, Carnobacterium, Lactobacillus, and Leuconostoc were the dominant genera. Within each genus, the most encountered isolates were Carnobacterium divergens, Lactobacillus sakei, and Leuconostoc carnosum. When comparing samples from chicken origin with samples from turkey-derived products, a higher dominance of Carnobacteria spp. was found in the latter group. Also, an association between the dominance of lactobacilli and the presence of added plant material and lactate salts was found. PMID- 29526206 TI - Quantitative physiology and aroma formation of a dairy Lactococcus lactis at near zero growth rates. AB - During food fermentation processes like cheese ripening, lactic acid bacteria (LAB) encounter long periods of nutrient limitation leading to slow growth. Particular LAB survive these periods while still contributing to flavour formation in the fermented product. In this study the dairy Lactococcus lactis biovar diacetylactis FM03-V1 is grown in retentostat cultures to study its physiology and aroma formation capacity at near-zero growth rates. During the cultivations, the growth rate decreased from 0.025 h-1 to less than 0.001 h-1 in 37 days, while the viability remained above 80%. The maintenance coefficient of this dairy strain decreased by a factor 7 at near-zero growth rates compared to high growth rates (from 2.43 +/- 0.35 to 0.36 +/- 0.03 mmol ATP.gDW-1.h-1). In the retentostat cultures, 62 different volatile organic compounds were identified by HS SPME GC-MS. Changes in aroma profile resembled some of the biochemical changes occurring during cheese ripening and reflected amino acid catabolism, metabolism of fatty acids and conversion of acetoin into 2-butanone. Analysis of complete and cell-free samples of the retentostat cultures showed that particular lipophilic compounds, mainly long-chain alcohols, aldehydes and esters, accumulated in the cells, most likely in the cell membranes. In conclusion, retentostat cultivation offers a unique tool to study aroma formation by lactic acid bacteria under industrially relevant growth conditions. PMID- 29526207 TI - Evaluation of the antimicrobial efficacy of neutral electrolyzed water on pork products and the formation of viable but nonculturable (VBNC) pathogens. AB - The goals of this study were to evaluate the antimicrobial efficacy of Neutral electrolyzed oxidizing (NEO) water on E. coli O157:H7, Salmonella Enteritidis and Yersinia enterocolitica in both pure culture and on inoculated pork chops and skin samples, and to investigate the formation of viable but nonculturable (VBNC) pathogens after treatments. Both the plate count method and flow cytometry were used to evaluate antimicrobial efficacy on pure cultures. Different concentrations of NEO water were prepared by diluting the original NEO water (100%) with sterilized deionized water. The antimicrobial efficacy increased as the concentrations of NEO water increased. The flow cytometry results showed that treating with diluted NEO water led to the formation of VBNC cells. No VBNC cells formed when treating pure cultures with 50% or 100% NEO water. Yersinia cultures were found to be more resistant to NEO treatments than Salmonella and E. coli O157:H7 cultures, with Yersinia cultures showing lower reductions and higher levels of VBNC cells after treatments. The antimicrobial efficacy of NEO water was significantly better on skin samples than on pork chops. The differences in protein content and structure between pork chops and skin samples serve as major factors impacting the NEO water's efficacy. PMID- 29526208 TI - Changes in microbial communities and quality attributes of white muscle and dark muscle from common carp (Cyprinus carpio) during chilled and freeze-chilled storage. AB - This study investigated sensory scores, quality attributes and microbial communities in white muscle and dark muscle of common carp (Cyprinus carpio) during chilled (4 degrees C) and freeze-chilled (-20 degrees C for 4 weeks prior to 4 degrees C) storage. Compared to the samples at the end of storage, fresh samples and frozen-thawed samples on day 0 showed greater bacterial diversity and more differences in microbiota. Initially, Aeromonas was the prevalent genus in fresh white muscle and dark muscle. As time progressed, Aeromonas followed by Pseudomonas predominated in white muscle, while Aeromonas, Pseudomonas, and Lactococcus dominated in dark muscle. Paenibacillus was identified as the largest population in frozen-thawed samples of both muscle types, but Pseudomonas increased dramatically to become dominant in the two spoiled samples. Volatile organic compounds (VOCs) of carp muscle consisted mainly of aldehydes and alcohols, and the percentage of ketones in both muscle types increased considerably after storage. Moreover, dark muscle showed more kinds of VOCs, and a slower rate of quality deterioration than white muscle. Based on sensory assessment, the shelf-life of white muscle and dark muscle of common carp for chilled storage was 8 days and 10 days, respectively, as well as 8 days together for freeze-chilled storage. PMID- 29526209 TI - Investigating on the fermentation behavior of six lactic acid bacteria strains in barley malt wort reveals limitation in key amino acids and buffer capacity. AB - Understanding lactic acid bacteria (LAB) fermentation behavior in malt wort is a milestone towards flavor improvement of lactic acid fermented malt beverages. Therefore, this study aims to outline deficiencies that may exist in malt wort fermentation. First, based on six LAB strains, cell viability and vitality were evaluated. Second, sugars, organic acids, amino acids, pH value and buffering capacity (BC) were monitored. Finally, the implication of key amino acids, fructose and wort BC on LAB growth was determined. Short growth phase coupled with prompt cell death and a decrease in metabolic activity was observed. Low wort BC caused rapid pH drop with lactic acid accumulation, which conversely increased the BC leading to less pH change at late-stage fermentation. Lactic acid content (<=3.9 g/L) was higher than the reported inhibitory concentration (1.8 g/L). Furthermore, sugars were still available but fructose and key amino acids lysine, arginine and glutamic acid were considerably exhausted (<=98%). Wort supplementations improved cell growth and viability leading to conclude that key amino acid depletion coupled with low BC limits LAB growth in malt wort. Then, a further increase in organic acid reduces LAB viability. This knowledge opens doors for LAB fermentation process optimization in malt wort. PMID- 29526210 TI - Rapid and sensitive detection of viable Listeria monocytogenes in food products by a filtration-based protocol and qPCR. AB - Listeria monocytogenes continues to be one of the most important foodborne pathogens worldwide, either due to its incidence and/or to its high mortality rate. In the present study, a filtration-based protocol was applied for the screening of viable bacteria. Additionally, a complete method (enrichment, filtration, DNA extraction and real-time PCR detection) was evaluated in order to determine the capacity of this protocol to detect viable L. monocytogenes in food samples. A new multiplex qPCR detection system was designed, including an internal amplification control, both targets were detected with hydrolysis probes. It was demonstrated that the method could reliably detect this pathogen, reaching a limit of detection of 9.5 cfu/25 g. The evaluation of the relative sensitivity, specificity, accuracy, positive and negative predictive values, as well as the index kappa of concordance obtained values higher than 90.0% after 24 h sample enrichment. Furthermore, it was demonstrated that with a secondary enrichment step, the limit of the detection could be further decreased to 4.6 cfu/25 g without significantly affecting the performance parameters. The present study demonstrates the reliability of the proposed methodology for the detection of viable L. monocytogenes, and the possibility of its direct implementation for routine analyses in the food industry. PMID- 29526211 TI - Molecular phylogeny and characterization of secondary metabolite profile of plant pathogenic Alternaria species isolated from basil. AB - Alternaria leaf-spot is a new disease recently reported on basil in Italy. The correct identification of Alternaria species has suffered from many reclassifications in function of morphological features and molecular data. In our study, we performed an overall approach to obtain a better characterization of basil Alternaria isolates. Morphological characteristics, seven-genome region phylogenic analysis, and secondary metabolite profile differentiated the majority of the isolates as A. alternata. OPA 1-3 and OPA 10-2 were the best molecular regions to discriminate among the isolates. Morphological characteristics and sporulation groups helped to discriminate A. tenuissima from A. alternata isolates. All isolates in the A. sect. Alternaria were mycotoxigenic and pathogenic on basil, the production of mycotoxins was enhanced on basil compared to in vitro conditions used in this work. PMID- 29526212 TI - Inactivation of Escherichia coli O157:H7 and Salmonella during washing of contaminated gloves in levulinic acid and sodium dodecyl sulfate solutions. AB - Field workers often wear gloves harvesting ready-to-eat produce; however, fields are not sterile environments and gloves may become contaminated numerous times during a working shift. This study explored the potential for inactivation of Escherichia coli O157:H7 and Salmonella when contaminated gloves were washed in levulinic acid (LV) and sodium dodecyl sulfate (SDS) solutions. Washing nitrile gloves with increasing concentrations of LV above 1.0% led to a decreased prevalence of glove contamination by Salmonella (P = 0.0000). A higher level of prevalence occurred for solid agar-cultured pathogens than liquid broth-cultured pathogens after nitrile gloves were washed in LV/SDS (P = 0.0000). Pathogens residing on latex gloves were more likely to be completely inactivated by washing in 0.5% LV/0.1% SDS solutions than nitrile or Canners gloves that exhibited inconsistent responses dependent on the pathogen strain. However, drying after washing nitrile gloves in 0.5% LV/0.1% SDS led to additional pathogen inactivation (P = 0.0394). Pathogen transfer from gloves to produce was implied as the pathogen prevalence on cantaloupe rind handled by LV/SDS-washed gloves was not statistically different from the prevalence on gloves (P = 0.7141). Hence, the risk of produce contamination may still exist but would be reduced by washing gloves in LV/SDS. PMID- 29526213 TI - Simultaneous and individual quantitative estimation of Salmonella, Shigella and Listeria monocytogenes on inoculated Roma tomatoes (Lycopersicon esculentum var. Pyriforme) and Serrano peppers (Capsicum annuum) using an MPN technique. AB - Simultaneous and individual enumeration of Salmonella, Shigella and Listeria monocytogenes was compared on inoculated Roma tomatoes and Serrano peppers using an Most Probable Number (MPN) technique. Samples consisting of tomatoes (4 units) or peppers (8 units) were individually inoculated with a cocktail of three strains of Salmonella, Shigella or L. monocytogenes, or by simultaneous inoculation of three strains of each pathogen, at low (1.2-1.7 log CFU/sample) and high (2.2-2.7 log CFU/sample) inocula. Samples were analyzed by an MPN technique using universal pre-enrichment (UP) broth at 35 degrees C for 24 +/- 2 h. The UP tubes from each MPN series were transferred to enrichment and plating media following adequate conventional methods for isolating each pathogen. Data were analyzed using multifactorial analysis of variance (p < 0.05) and LSD multiple rang test. There were differences (p < 0.05) in recovery of simultaneous and individual bacteria inoculated (individual > simultaneous), type of bacteria (Salmonella > Shigella and L. monocytogenes), type of sample (UP broth > pepper and tomato), and inoculum level (high > low). The MPN technique was effective for Salmonella on both commodities. Shigella counts were higher on tomatoes compared to peppers, (p < 0.05), and for L. monocytogenes on peppers (p < 0.05). PMID- 29526214 TI - Selection of indigenous lactic acid bacteria presenting anti-listerial activity, and their role in reducing the maturation period and assuring the safety of traditional Brazilian cheeses. AB - Artisanal raw milk cheeses are highly appreciated dairy products in Brazil and ensuring their microbiological safety has been a great need. This study reports the isolation and characterization of lactic acid bacteria (LAB) strains with anti-listerial activity, and their effects on Listeria monocytogenes during refrigerated shelf-life of soft Minas cheese and ripening of semi-hard Minas cheese. LAB strains (n = 891) isolated from Minas artisanal cheeses (n = 244) were assessed for anti-listerial activity by deferred antagonism assay at 37 degrees C and 7 degrees C. The treatments comprised the production of soft or semi-hard Minas cheeses using raw or pasteurized milk, and including the addition of selected LAB only [Lactobacillus brevis 2-392, Lactobacillus plantarum 1-399 and 4 Enterococcus faecalis (1-37, 2-49, 2-388 and 1-400)], L. monocytogenes only, selected LAB co-inoculated with L. monocytogenes, or without any added cultures. At 37 degrees C, 48.1% of LAB isolates showed anti-listerial capacity and 77.5% maintained activity at 7 degrees C. Selected LAB strains presented a bacteriostatic effect on L. monocytogenes in soft cheese. L. monocytogenes was inactivated during the ripening of semi-hard cheeses by the mix of LAB added. Times to attain a 4 log-reduction of L. monocytogenes were 15 and 21 days for semi-hard cheeses produced with raw and pasteurized milk, respectively. LAB with anti-listerial activity isolated from artisanal Minas cheeses can comprise an additional barrier to L. monocytogenes growth during the refrigerated storage of soft cheese and help shorten the ripening period of semi-hard cheeses aged at ambient temperature. PMID- 29526215 TI - Escherichia coli testing and enumeration in live bivalve shellfish - Present methods and future directions. AB - A wide variety of pathogenic agents such as bacteria, viruses and parasites can be greatly concentrated in filter feeding bivalve molluscan shellfish (BMS), that are grown in faecally contaminated waters. Human health risks associated with the consumption of BMS are also compounded by the traditional pattern of consuming them raw or lightly cooked. Because of these well-established food safety risks, food legislation such as that in Europe stipulates that BMS production areas are monitored for faecal contamination and classified accordingly. In this review we provide information regarding the background and use of methods for determining and quantifying Escherichia coli (E. coli) in shellfish matrices, focussing on the Most Probable Number (MPN) based approach. This review also discusses other techniques for determining E. coli in food matrices, as well as specific tests across a range of other food microbiology applications. This information draws on several sources: published peer-reviewed reports, data derived from proficiency testing/ring trials, depuration and challenge studies, as well as specific examples from BMS classification and long-term monitoring studies. We also provide a discussion on possible avenues for future direction regarding testing methods in this food microbiology sector. PMID- 29526216 TI - Shelf life evaluation of fresh-cut red chicory subjected to different minimal processes. AB - Microbiological, chemical and physical parameters of minimally processed red chicory (Cichorium intybus L.) subjected to two different transformation processes were investigated. A classic ready-to-eat (RTE) process (P1) and a production without cutting (P2) were monitored during refrigerated (4 degrees C) storage (15 d). Total mesophilic microorganisms, total psychrotrophic microorganisms and pseudomonads were detected at the highest cell densities in all samples. Presumptive Pseudomonas population dominated the cultivable microbial community of RTE red chicory and were characterized genetically. Twenty two randomly amplified polymorphic DNA (RAPD) types were investigated by 16S rRNA gene sequencing, resulting in members of Rahnella and Pseudomonas. The identification of Pseudomonas species was further determined by sequencing of gyrB, rpoB and rpoD genes resulting in 16 species. A highest visual quality and a lower weight loss and colour variation were registered for P2, while soluble solid, nitrate and ascorbic acid contents were not affected by processing and storage. The integrated microbiological, chemical and physical approach applied in this study demonstrated the longer shelf-life of P2 red chicory. PMID- 29526217 TI - Combined effects of oregano essential oil and salt on the growth of Escherichia coli in salad dressing. AB - There is a broad research interest in the search for alternatives to chemical additives for use as natural food preservatives. Although many natural compounds have biological in vitro properties evidenced, in situ studies are still scarce. This study evaluated the effect of oregano essential oil (OEO) and salt (NaCl) concentrations against Escherichia coli (ATCC 8739), in salad dressing, using the response surface methodology. The experiment included a 22 central composite rotatable design (CCRD) in a total of 11 formulations of salad dressings. Oregano essential oil was characterized by gas chromatography and salad dressings by ash, lipids, proteins and moisture. OEO was composed mainly by carvacrol (65.1%) and p cymene (12.0%). Salad dressings showed similar chemical profiles. A mathematical model for the prediction of the antibacterial activity in salad dressing was obtained. The results revealed that the interaction between OEO and salt showed effect on the bacterial count. However, the effect of salt was negative suggesting that the highest NaCl concentrations decreases the bacterial count. Therefore, within the parameters studied, the use of OEO to control E. coli in salad dressing can be considered promising and allows reduction in the levels of salt to be incorporated in food. PMID- 29526218 TI - The inhibitory effects of essential oil constituents against germination, outgrowth and vegetative growth of spores of Clostridium perfringens type A in laboratory medium and chicken meat. AB - C. perfringens type A is the causative agent of C. perfringens type A food poisoning (FP) and non-food-borne (NFB) human gastrointestinal diseases. Due to its ability to form highly heat-resistant spores, it is of great interest to develop strategies alternative to thermal processing to inactivate C. perfrinegens. Thus, in this study we evaluated the inhibitory effects of essential oil constituents (EOCs) (cinnamaldehyde, eugenol, allyl isothiocyanate (AITC), and carvacrol) against germination, outgrowth and vegetative growth of spores of C. perfringens FP and NFB disease isolates in laboratory medium and chicken meat. The cinnamaldehyde, eugenol and carvacrol, but not AITC, all at 0.05-0.1%, inhibited the germination of spores of all tested C. perfringens isolates in Tripticase-glucose-yeast extract (TGY) medium. Furthermore, all tested EOCs at 0.05-0.1% arrested the outgrowth and vegetative growth of C. perfringens spores in TGY, with AITC and carvacrol being the most effective. However, among four tested EOCs, only AITC (at 0.5%-2.0%) was able to inhibit the growth of C. perfringens spores in chicken meat and no such inhibitory effect was observed even with a 10-fold higher concentration (5%) of carvacrol. In conclusion, our current work identified AITC as an effective EOC to control spores and vegetative cells of C. perfringens isolates in laboratory medium and chicken meat. Further studies on evaluating the effectiveness of different combination of EOCs against C. perfringens spore growth in different meat products should establish an effective use of EOCs to control the risk of C. perfringens-mediated illnesses. PMID- 29526219 TI - Microbial diversity and chemical analysis of the starters used in traditional Chinese sweet rice wine. AB - Chinese sweet rice wine (CSRW) is a popular alcoholic drink in China. To investigate the effect of the microbial composition in CSRW starters on the final quality of the alcoholic drink, high-throughput sequencing on the fungal internal transcribed spacer II and bacterial 16S rRNA gene of the microflora in 8 starter samples was performed. The sequencing data analysis showed that 10 genera of yeasts and mold, and 11 genera of bacteria were identified. Fungal diversity analyses showed the significant variances in the fungal compositions among the starter samples. Starter microbiota were dominated by the Rhizopus genus in SZ5, LS6, NN8, QD9, DZ10 and DZ11, indicating its important role in starch hydrolysis during CSRW brewing. According to principal coordinate analyses, the bacterial composition had even less similarity among the 8 starter samples. The chemical determination of CSRW fermented with the 8 starters demonstrated that the CSRW quality and flavor were drastically influenced by the taxonomic composition and metabolism of the microbes in the starters. This study suggests it is necessary to standardize rice wine manufacturing and flavor classification by specifying starter and fermentation techniques. PMID- 29526220 TI - High survival rates of Campylobacter coli under different stress conditions suggest that more rigorous food control measures might be needed in Brazil. AB - Campylobacter spp. have been the most commonly reported gastrointestinal bacterial pathogen in many countries. Consumption of improperly prepared poultry meat has been the main transmission route of Campylobacter spp. Although Brazil is the largest exporter of poultry meat in the world, campylobacteriosis has been a neglected disease in the country. The aim of this study was to characterize 50 Campylobacter coli strains isolated from different sources in Brazil regarding the frequency of 16 virulence genes and their survival capability under five different stress conditions. All strains studied presented the cadF, flaA, and sodB genes that are considered essential for colonization. All strains grew at 4 degrees C and 37 degrees C after 24 h. High survival rates were observed when the strains were incubated in BHI with 7.5% NaCl and exposed to acid and oxidative stress. In conclusion, the pathogenic potential of the strains studied was reinforced by the presence of several important virulence genes and by the high growth and survival rates of the majority of those strains under different stress conditions. The results enabled a better understanding of strains circulating in Brazil and suggest that more rigorous control measures may be needed, given the importance of contaminated food as vehicles for Campylobacter coli. PMID- 29526221 TI - Temperature impacts the sporulation capacities and spore resistance of Moorella thermoacetica. AB - Temperatures encountered in cannery allow growth of thermophilic spore-forming bacteria, including the strictly anaerobe Moorella thermoacetica, which grows optimally from 55 degrees C to 65 degrees C and is the main cause of spoilage of low-acid canned foods (LACFs) at high temperature. Resistance to wet-heat, biocides and UV-C of spores formed at different temperatures was assessed either for a selection of M. thermoacetica strains or for the strain M. thermoacetica ATCC 39073. Spores formed at 45 degrees C were significantly more sensitive to wet-heat than spores produced at 55 degrees C, while spores produced at 65 degrees C were as heat-resistant as spores produced at 55 degrees C. Spores of M. thermoacetica ATCC 39073 produced at 45 degrees C were significantly less resistant to peracetic acid than spores formed at 55 degrees C, while no difference in sensitivity to H2O2 or to UV-C treatment was observed whatever the sporulation temperature. However, both types of treatment enabled at least a 3.3 log CFU/mL reduction of M. thermoacetica ATCC 39073 spores. M. thermoacetica spores thus showed higher resistance properties when sporulation temperature was close to optimal growth temperature. These findings suggest food spoilage due to M. thermoacetica species could be controllable by holding temperatures below optimal growth temperature from the blanching step to the can filling step. PMID- 29526222 TI - Fermentation of enset (Ensete ventricosum) in the Gamo highlands of Ethiopia: Physicochemical and microbial community dynamics. AB - Enset (Ensete ventricosum) provides staple food for 15 million people in Ethiopia after fermentation into kocho. The fermentation process has hardly been investigated and is prone to optimization. The aim of this study was to investigate the physicochemical and microbial dynamics of fermentation practices in the Gamo highlands. These practices show local variation, but two steps were omnipresent: scraping of the pseudostem and fermenting it in a pit or a bamboo basket. Enset plants were fragmented and fermented for two months in order to investigate the physicochemical (temperature, moisture content, pH and titratable acidity) and microbial dynamics (total viable aerobic counts, counts of Enterobacteriaceae, lactic acid bacteria, yeasts and moulds and Clostridium spores counts, and Illumina Miseq sequencing). Samples were taken on days 1, 7, 15, 17, 31 and 60. The pH decreased, whereas the titratable acidity increased during fermentation. Of all counts those of lactic acid bacteria and Clostridium spores increased during fermentation. Leuconostoc mesenteroides initiated the fermentation. Later on, Prevotella paludivivens, Lactobacillus sp. and Bifidobacterium minimum dominated. These three species are potential candidates for the development of a starter culture. PMID- 29526223 TI - Oxygen and diverse nutrients influence the water kefir fermentation process. AB - Eight water kefir fermentation series differing in the presence of oxygen, the nutrient concentration, and the nutrient source were studied during eight consecutive backslopping steps. The presence of oxygen allowed the proliferation of acetic acid bacteria, resulting in high concentrations of acetic acid, and decreased the relative abundance of Bifidobacterium aquikefiri. Low nutrient concentrations resulted in slow water kefir fermentation and high pH values, which allowed the growth of Comamonas testosteroni/thiooxydans. Further, low nutrient concentrations favored the growth of Lactobacillus hilgardii and Dekkera bruxellensis, whereas high nutrient concentrations favored the growth of Lactobacillus nagelii and Saccharomyces cerevisiae. Dried figs, dried apricots, and raisins resulted in stable water kefir fermentation. Water kefir fermentation with dried apricots resulted in the highest pH and water kefir grain growth, whereas that with raisins resulted in the lowest pH and water kefir grain growth. Further, water kefir fermentation with raisins resembled fermentations with low nutrient concentrations, that with dried apricots resembled fermentations with normal nutrient concentrations, and that with fresh figs or a mixture of yeast extract and peptone resembled fermentations with high nutrient concentrations. PMID- 29526224 TI - Response of Leuconostoc strains against technological stress factors: Growth performance and volatile profiles. AB - The ability of twelve strains belonging to three Leuconostoc species (Leuconostoc mesenteroides, Leuconostoc lactis and Leuconostoc pseudomesenteroides) to grow under diverse sub-lethal technological stress conditions (cold, acidic, alkaline and osmotic) was evaluated in MRS broth. Two strains, Leuconostoc lactis Ln N6 and Leuconostoc mesenteroides Ln MB7, were selected based on their growth under sub-lethal conditions, and volatile profiles in RSM (reconstituted skim milk) at optimal and under stress conditions were analyzed. Growth rates under sub-lethal conditions were strain- and not species-dependent. Volatilomes obtained from the two strains studied were rather diverse. Particularly, Ln N6 (Ln. lactis) produced more ethanol and acetic acid than Ln MB7 (Ln. mesenteroides) and higher amounts and diversity of the rest of volatile compounds as well, at all times of incubation. For the two strains studied, most of stress conditions applied diminished the amounts of ethanol and acetic acid produced and the diversity and levels of the rest of volatile compounds. These results were consequence of the different capacity of the strains to grow under each stress condition tested. PMID- 29526225 TI - The carbon consumption pattern of the spoilage yeast Brettanomyces bruxellensis in synthetic wine-like medium. AB - The wine matrix contains limited carbon compounds to sustain microbial life. Brettanomyces bruxellensis is one of very few yeast species that has adapted to this environment. Indeed, the presence of growth-inhibiting compounds and conditions do not prevent its proliferation. Literature regarding the nutritional requirements of this yeast is surprisingly poor, given the observation that B. bruxellensis produces biomass with apparently less nutrients than other yeasts. In this study, various carbon sources were screened in a synthetic wine medium, under anaerobic and semi-aerobic growth conditions, in order to determine which compounds B. bruxellensis assimilates. Slight differences were observed between strains but overall, B. bruxellensis produced biomass from limited nutrients consumed in a specific order regardless of the oxygen conditions. Upon initial consumption of the simple sugars, B. bruxellensis was able to remain viable, by concurrently utilising ethanol (only in the presence of oxygen) and malic acid. Although initially beneficial, oxygen was found detrimental in the long term. Formation of volatile phenols occurred during the consumption of the sugars but not as a mechanism to help correct the redox imbalance. The study confirms that B. bruxellensis is able to survive using limited amount of nutrients, making this yeast a challenge for winemakers. PMID- 29526226 TI - Structure of association networks in food bacterial communities. AB - The structure of microbial association networks was investigated for seventeen studies on food bacterial communities using the CoNet app. The results were compared with those for host and environmental microbiomes. Microbial association networks of food bacterial communities shared several properties with those of host microbiomes, although they were less complex and lacked a scale-free, small world structure that is characteristic of environmental microbial communities. This may depend on both the initial contamination pattern, whose main source is the raw material microbiome, and on the copiotrophic nature of food environments, with lack of well defined, specific niches. The selective factors which are characteristic of fermentation and spoilage drastically simplified microbial association networks and showed the emergence of negative hubs. Co-presence and mutual exclusion networks had a radically different structure, with high clustering coefficient in the first and high heterogeneity in the latter. Node properties (degree, positive degree, betweenness centrality, abundance) can be combined in plots, which allow a rapid identification of hub species. The combined use of three network inference tools (CoNet, SparCC, and SPIEC-EASI) confirmed that microbial association network detection is method specific, but several coherent copresence or mutual exclusion relationships were detected by at least two different methods. PMID- 29526227 TI - Use of acetic and citric acids to inhibit Escherichia coli O157:H7, Salmonella Typhimurium and Staphylococcus aureus in tabbouleh salad. AB - The objective of the current study was to evaluate the antimicrobial action of different concentrations of acetic (0.3% and 0.4%) or citric (1% and 1.4%) acids and their combinations (1% citric acid plus 0.4% acetic acid and 1.4% citric acid plus 0.3% acetic acid) against Salmonella Typhimurium, Escherichia coli O157:H7 and Staphylococcus aureus in tabbouleh salad stored at 21, 10 and 4 degrees C. Acetic acid was more inhibitory toward S. Typhimurium and E. coli O157:H7 than citric acid at 21 degrees C; S. Typhimurium and E. coli O157:H7 cells were not detected in tabbouleh treated with 0.4% acetic acid after 5 and 7 days, respectively. The combined effect of acetic and citric acid was synergistic against S. Typhimurium, and E. coli O157:H7, but not against S. aureus. The combinations of acetic and citric acids reduced S. Typhimurium, and E. coli O157:H7 to below the detection levels after 2 and 3 days at 21 degrees C, respectively. However, these treatments significantly reduced S. aureus numbers compared to the control at tested temperatures by the end of storage. Acetic and citric acids have the potential to be used in tabbouleh salad to reduce the risk from S. Typhimurium, E. coli O157:H7 and S. aureus. PMID- 29526228 TI - Factors influencing autolysis of Saccharomyces cerevisiae cells induced by pulsed electric fields. AB - The influence of temperature (7-43 degrees C), pH (3.5-7.0) and ethanol concentration (6-25%) on PEFinduced autolysis and the release of mannose from Saccharomyces cerevisiae was investigated. Changes in the release of intracellular compounds absorbing at 260 nm and 280 nm depended on storage conditions and differed among untreated and PEF-treated cells. For untreated cells, the increase of the Abs260 and Abs280 values during 3 weeks of storage was very low when incubated in media of different pH, different ethanol concentrations, or at 7 degrees and 25 degrees C. Conversely, Abs260 and Abs280 values progressively increased for PEF-treated cells stored under the same conditions. Although the PEF treatment intensity was the same in all cases, the amount of intracellular material released depended on incubation conditions. Except for cells stored at 43 degrees C, for which the concentration of mannose in the media after 21 days was around 90 mg L-1, the amount of mannose released from untreated cells after 21 days of storage was lower than 60 mg L-1 under all other conditions assayed. After the same incubation time, the amount of mannose released from PEF treated cells ranged from 80 mg L-1, when they were stored in media with 25% ethanol, to 190 mg L-1 when they were stored at 43 degrees C. Interaction among assayed factors affecting mannose release was investigated in a medium containing 10% ethanol (v/v) and pH 3.5 for 21 days. Although the interaction of both factors delayed mannose release, the medium containing PEF treated yeasts had approximately twice the amount of mannoproteins as those containing untreated yeasts. PMID- 29526229 TI - Shifts in spinach microbial communities after chlorine washing and storage at compliant and abusive temperatures. AB - Fresh produce, like spinach, harbors diverse bacterial populations, including spoilage and potentially pathogenic bacteria. This study examined the effects of produce washing in chlorinated water and subsequent storage on the microbiota of spinach. Baby spinach leaves from a commercial fresh-cut produce processor were assessed before and after washing in chlorinated water, and then after one week's storage at 4, 10, and 15 degrees C. Microbial communities on spinach were analyzed by non-selective plating, qPCR, and 16S rDNA amplicon sequencing. Bacterial populations on spinach, averaging 6.12 +/- 0.61 log CFU/g, were reduced by 1.33 +/- 0.57 log after washing. However, populations increased by 1.77-3.24 log after storage, with larger increases occurring at higher temperature (15 > 10 > 4 degrees C). The predominant phylum identified on unwashed spinach leaves was Proteobacteria; dominant genera were Pseudomonas and Sphingomonas. Bacterial communities shifted significantly after chlorine washing and storage. Several Proteobacteria species, such as Stenotrophomonas sp. and Erwinia sp., were relatively tolerant of chlorine treatment, while species of Flavobacterium and Pedobacter (phylum Bacteroidetes) grew rapidly during storage, especially at abusive temperatures. Cupriavidus sp. and Ralstonia sp. showed significant increases after washing. After storage, microbial communities on spinach appeared to shift back toward the pre-washing distributions. PMID- 29526230 TI - Development of a rapid method for the detection of Yersinia enterocolitica serotype O:8 from food. AB - In this study, a new and alternative method based on monoclonal antibodies (MAbs) for the rapid detection of Yersinia enterocolitica O:8 was developed. This microorganism is an emerging foodborne pathogen causing gastrointestinal disease in humans. The transmission can occur through contaminated food such as raw or undercooked meat, milk and dairy products, water and fresh vegetables. Nine MAbs (46F7, 54B11, 54C11, 62D10, 64C7, 64C10, 72E8, 72E10, 72G6) were characterized and selected versus Y. enterocolitica O:8, and only 2 of them showed also a weak cross-reaction with Campylobacter jejuni. The MAb 54B11 was used for the development of Y. enterocolitica capture-ELISA in food matrices, i.e. meat and dairy products (n = 132). The method was validated by ISO 16140:2003 and compared with the official method for the detection of presumptive pathogenic Y. enterocolitica (ISO 10273:2003). Relative accuracy, sensitivity and specificity corresponded to 100%. The selectivity was evaluated on other food samples (n = 126) showing a lower confidence limit of 90.3% and an upper confidence limit of 100%. The results from this study demonstrated that the developed method was rapid and cheap, specific and sensitive for the screening of the pathogen in food. PMID- 29526231 TI - Fungi in spices and mycotoxigenic potential of some Aspergilli isolated. AB - The aim of this study was to identify fungal species present in 200 samples of rosemary, fennel, cinnamon, clove, pepperoni, black and white pepper and oregano and evaluate the mycotoxigenic potential of the some Aspergilli isolated. Clove, black and white peppers were analyzed by direct plating. For rosemary, cinnamon, fennel, pepperoni pepper and oregano samples were used spread plate. Mycotoxigenic capacity was verified by the agar plug method. With the exception of clove, all the spices showed high fungal contamination, especially by Aspergillus sp., Penicillium sp. and Cladosporium sp. Frequency of toxigenic Aspergillus spp. was intense in white and black peppers, with presence of Aspergillus flavus (up to 32%), Aspergillus nomius (up to 12%), Aspergillus parasiticus (up to 4%), Aspergillus niger complex (up to 52%), Aspergillus ochraceus (up 12%) and Aspergillus carbonarius (up to 4%). 14,2% of A. flavus isolated from black pepper were aflatoxins producers. In the white pepper, 66.7% of A. flavus isolates and 100% of A. nomius were aflatoxigenic. Oregano showed the highest number of A. niger complex isolates (49), however, only 2.04% produced ochratoxin A. This study showed a huge fungal presence in spices, which could compromise the sensorial quality of these products and represent a hazard for consumers. PMID- 29526232 TI - Comparison of advanced whole genome sequence-based methods to distinguish strains of Salmonella enterica serovar Heidelberg involved in foodborne outbreaks in Quebec. AB - Salmonella enterica serovar Heidelberg (S. Heidelberg) is one of the top serovars causing human salmonellosis. This serovar ranks second and third among serovars that cause human infections in Quebec and Canada, respectively, and has been associated with severe infections. Traditional typing methods such as PFGE do not display adequate discrimination required to resolve outbreak investigations due to the low level of genetic diversity of isolates belonging to this serovar. This study evaluates the ability of four whole genome sequence (WGS)-based typing methods to differentiate among 145 S. Heidelberg strains involved in four distinct outbreak events and sporadic cases of salmonellosis that occurred in Quebec between 2007 and 2016. Isolates from all outbreaks were indistinguishable by PFGE. The core genome single nucleotide variant (SNV), core genome multilocus sequence typing (MLST) and whole genome MLST approaches were highly discriminatory and separated outbreak strains into four distinct phylogenetic clusters that were concordant with the epidemiological data. The clustered regularly interspaced short palindromic repeats (CRISPR) typing method was less discriminatory. However, CRISPR typing may be used as a secondary method to differentiate isolates of S. Heidelberg that are genetically similar but epidemiologically unrelated to outbreak events. WGS-based typing methods provide a highly discriminatory alternative to PFGE for the laboratory investigation of foodborne outbreaks. PMID- 29526233 TI - Effects of laying on of hands with and without a spiritual context on pain and functionality of older women with knee osteoarthritis: study protocol for a randomized controlled trial. AB - BACKGROUND: Laying on of hands (LooH) is a culturally-accepted therapy in several traditions. In Brazil, "Spiritism" (third-largest religious tradition in number of followers) uses LooH with the name of "Spiritist Passe" (SP). However, there are few studies assessing SP's role in medical outcomes. The present study aims to investigate the effects of LooH, with and without a spiritual context, on pain, joint stiffness, and functional capacity of older women (>=60 years old) with knee osteoarthritis (KOA). METHODS/DESIGN: In this triple-blind, prospective randomized controlled trial, older women with KOA are assigned to three groups: LooH with a spiritual context group, LooH group without a spiritual context, and a control group receiving no intervention. Patients are assessed by a blinded researcher at baseline, 8 weeks, and 16 weeks. Pain, joint stiffness, and functional capacity are assessed using Western Ontario and McMaster Universities Osteoarthritis Index. Other measures such as anxiety, depression, gait speed, and quality of life will also be assessed. To detect differences between groups, a post-intervention comparison between the three groups and a mean change (post pre) comparison among the three groups will be done using analysis of variance. All statistical analyses will be performed using an intention-to-treat approach and a per-protocol analysis. DISCUSSION: A pragmatic design using SP, LooH without spiritual context, and no LooH may provide further scientific evidence on SP's feasibility and efficacy for KOA patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02917356. PMID- 29526234 TI - Awareness, practice and views about integrating AYUSH in allopathic curriculum of allopathic doctors and interns in a tertiary care teaching hospital in New Delhi, India. AB - OBJECTIVE: To assess the knowledge, attitude, perception and practice of Ayurveda, yoga, Unani, Siddha, homeopathy and naturopathy (AYUSH) among allopathic doctors and interns and determine their opinion regarding integration of AYUSH education within the allopathic curriculum. METHODS: This prospective, cross sectional study was conducted in a tertiary care teaching Hospital, New Delhi, India, from March 2016 to March 2017. A survey of 500 allopathic doctors and 150 interns was performed using a structured questionnaire. RESULTS: A majority of doctors (95.2%) were aware of the term AYUSH and had knowledge of yoga (70.6%), homeopathy (55.6%), Ayurveda (50.3%), Siddha (47.8%), naturopathy (32.9%) and Unani (28.9%). Most of the participants (63.0%) felt that therapies under AYUSH are effective. A majority (84.0%) of the doctors were of the view that more research is required in the field of AYUSH. While homeopathy (44.0%) was the most common system used by doctors for themselves, yoga was the therapy most commonly (60.0%) recommended to patients. Nearly half of the doctors (46.7%) recommended AYUSH to their patients, mainly for chronic illness (74.0%). A majority (77.5%) of the respondents agreed that students of allopathic medicine should be familiarized with AYUSH. The modes of incorporation of AYUSH into the medical curriculum most commonly suggested by respondents were optional courses (54.5%) and introductory lectures (42.3%). CONCLUSION: Doctors and interns of allopathic medicine are aware of AYUSH systems. They use it for themselves and recommend it to patients. They believe that familiarization of Bachelor of Medicine and Bachelor of Surgery students with AYUSH therapies and their integration with allopathic medicine may help in improving patient care. PMID- 29526235 TI - Effects of aromatherapy with Rosa damascena on nulliparous women's pain and anxiety of labor during first stage of labor. AB - BACKGROUND: Reducing labor pain and anxiety is one of the most important goals of maternity care. OBJECTIVE: This study aimed to assess the effects of aromatherapy with Rosa damascena on pain and anxiety in the first stage of labor among nulliparous women. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This was a randomized clinical trial of 110 nulliparous women. The eligible participants were randomly assigned to two groups of aromatherapy and control in an Iranian maternity hospital. The participants received 0.08 mL of Rosa damascena essence in the aromatherapy group and 0.08 mL of normal saline in the control group, every 30 min. Pain was measured 3 times, once each at three stages of cervical dilation (4-5, 6-7, and 8-10 cm). Anxiety was measured twice, once each at two stages of cervical dilation (4-7 and 8-10 cm). The tools for data collection were the Spielberger anxiety questionnaire, numerical pain rating scale, demographic and obstetric questionnaire, and an observational checklist. Data analyses included the t-test, Mann-Whitney U test and Chi-square test. MAIN OUTCOME MEASURES: Severity of labor pain and severity of anxiety were used as primary outcome measures. Labor and delivery characteristics (including number of contractions, duration of contractions in second stage, Bishop score, augmentation by oxytocin, Apgar score, and mode of delivery), demographic characteristics, and fertility information were used as secondary outcome measures. RESULTS: Pain severity in the group receiving aromatherapy with R. damascena was significantly lower than in the control group after treatment at each pain assessment (cervical dilation of 4-5, 6-7, and 8-10 cm; P < 0.05). Anxiety levels were also significantly lower in the treatment group than in the control group after treatment at each time of measurement (cervical dilation of 4 7 and 8-10 cm; P < 0.05). CONCLUSION: Aromatherapy with R. damascena reduced the severity of pain and anxiety in the first stage of labor. Aromatherapy with R. damascena is a convenient and effective method for pain and anxiety reduction during the first stage of labor. TRIAL REGISTRATION: Iranian Registry of Clinical Trial: IRCT201306258801N3. PMID- 29526236 TI - Efficacy and safety of Amla (Phyllanthus emblica L.) in non-erosive reflux disease: a double-blind, randomized, placebo-controlled clinical trial. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal complaints. GERD, caused by the reflux of stomach contents into the esophagus, leads to troublesome symptoms such as heartburn and regurgitation. It is classified into two types: erosive esophagitis, characterized by visible esophageal mucosa erosion in endoscopy, and non-erosive reflux disease (NERD). GERD is a chronic and recurrent disease that impairs the quality of life and imposes socioeconomic and therapeutic burdens to both patients and society. OBJECTIVE: Due to the failure of the conventional treatments for GERD and to the traditional use of Amla (Phyllanthus emblica L.), in addition to beneficial effects shown in recent studies, we evaluated the safety and efficacy of Amla tablet for improvement of symptoms of patients with NERD. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: We designed a double-arm, randomized, double blind, placebo-controlled clinical trial. Sixty-eight patients who had classic symptoms of GERD (heartburn, regurgitation and epigastralgia) for at least three months before the start of the trial were randomized in two parallel groups. Patients in the Amla group received two 500 mg Amla tablets twice a day, after meals, for 4 weeks. In the control group, patients received placebo tablets similar to the Amla prescription. MAIN OUTCOME MEASURES: The patients were visited at baseline, and at the end of the 2nd and 4th weeks of intervention; their symptoms were measured on a frequency and severity scale for the symptoms of NERD, according to the quality of life in reflux-associated disease questionnaire. RESULTS: Frequencies of heartburn and regurgitation in both groups of the study were significantly reduced after intervention (P < 0.001). Repeated measures logistic regression analysis showed that, in the Amla group, there was a more significant reduction in regurgitation frequency, heartburn frequency, regurgitation severity and heartburn severity during the study period, compared with the placebo group (P < 0.001). CONCLUSION: This randomized double-blind, placebo-controlled clinical trial demonstrated that Amla could reduce frequencies of heartburn and regurgitation and improve heartburn and regurgitation severity in patients with NERD. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT2016061428469N1. PMID- 29526237 TI - Medicinal properties of Ocotea bullata stem bark extracts: phytochemical constituents, antioxidant and anti-inflammatory activity, cytotoxicity and inhibition of carbohydrate-metabolizing enzymes. AB - OBJECTIVE: This study evaluates the phytochemical constituents, antioxidant and anti-inflammatory activity, cytotoxicity, and inhibitory activity against carbohydrate metabolism of extracts from Ocotea bullata stem bark. METHODS: Hexane, ethyl acetate, methanol and water were used to extract the air-dried sample. The phytochemical investigation and antioxidant assays were carried out on the extracts using standard procedures. The antidiabetic and anti-inflammatory potentials were evaluated using alpha-amylase, alpha-glucosidase and 5 lipoxygenase enzymes respectively. Vero cells were employed to determine the cytotoxicity of the extracts. RESULTS: The ethyl acetate extract showed higher phenolic contents (8.97 mg/g gallic acid) while methanol displayed higher flavonoid (36.06 mg/g quercetin) and flavonol (153.44 mg/g rutin) contents than other extracts. Hexane extract had the greatest capacity to scavenge 1,1-diphenyl 2-picryl-hydrazyl (0.19 mg/mL), hydroxyl (25.77 mg/mL) and 2,2-azino-bis(3 ethylbenzothiazoline)-6-sulfonic acid (0.07 mg/mL) radicals, while ethyl acetate extract exhibited stronger inhibition (P < 0.05) against superoxide anion (0.41 mg/mL) and ferric ion-reducing power (2.36 mg/mL) compared to other extracts and standards. Aqueous extract (27.02 mg/mL) exhibited strong metal-chelating activity (P < 0.05) compared to other extracts and gallic acid. The aqueous extract demonstrated the greatest inhibition of alpha-glucosidase (1.45 mg/mL) and alpha-amylase (2.43 mg/mL) compared to other extracts and acarbose. There were no significant differences (P < 0.05) in half-maximum inhibitory concentration (IC50) values of all tested extracts and indomethacin in the inhibition of 5-lipoxygenase activity. The aqueous extract was nontoxic to Vero cells with an IC50 value of 0.38 mg/mL. CONCLUSION: O. bullata stem bark contains active phytochemicals with diverse pharmacological potentials that could be beneficial in managing diabetes and inflammation. PMID- 29526238 TI - Integrative medicine is an evolving field and the future of healthcare: a summary of the 2017 Integrative Medicine Shanghai Forum. PMID- 29526239 TI - Arnica montana experimental studies: confounders and biases? AB - Arnica montana is a popular traditional remedy widely used in complementary and alternative medicine, in part for its wound-healing properties. The authors recently showed that this plant extract and several of its homeopathic dilutions are able to modify the expression of a series of genes involved in inflammation and connective tissue regeneration. Their studies opened a debate, including criticisms to the "errors" in the methods used and the "confounders and biases". Here the authors show that the criticisms raised on methodology and statistics are not consistent and cannot be considered pertinent. The present comment also updates and reviews information concerning the action of A. montana dilutions in human macrophage cells while summarizing the major experimental advances reported on this interesting medicinal plant. PMID- 29526240 TI - The medieval Persian manuscript of Afyunieh: the first individual treatise on the opium and addiction in history. AB - According to historical evidence, the abuse of opium has been reported all over the globe-specifically throughout Eastern nations-since the sixteenth century. Before that, opium had mostly been applied as medication. Reference has been made in traditional Persian medical literature to the method of cultivation, properties, side effects and toxicity. In sixteenth century Iran, during the reign of the Safavids, opium abuse began. It was from then that prominent Persian scholars started to think of solutions to this societal problem. One of the most famous scholars was Imad al-Din Mahmud ibn Mas'ud Shirazi, who composed a book concerning addiction-Afyunieh, a comprehensive book on the topic of opium and all issues of opium. Furthermore, he recommended methods for reducing opium dose as well as substitution with other medications that had a narrower range of side effects, in order to eradicate dependency upon opium and opium-derived materials. This is most likely the first book that comprehensively addressed opium and discussed drug rehabilitation methodology, in traditional Persian medical literature. In this historical review, the authors have introduced the book Afyunieh, which presents methods for treating addiction to and giving up opium; the text comprises a synthesis of the author's opinions, professional experience and references to the work of other famous physicians. PMID- 29526241 TI - Occupational hand injuries: a current review of the prevalence and proposed prevention strategies for physical therapists and similar healthcare professionals. AB - Hand injury is the second most common work-related musculoskeletal injury among physical therapists (PTs) and other manual therapy professionals such as osteopaths, physiotherapists, chiropractors, acupuncturists and massage therapists. However, the nature and extent of this problem have not been fully explored yet. Therefore, the objective of this study was to review the existing literature published on the prevalence, risk factors, consequences, and prevention of hand injuries among PTs and similar healthcare professionals. The lifetime prevalence of hand injuries was about 15%-46%, and the annual prevalence was reported as 5%-30%. Thumb injuries were found to be the most prevalent of all injuries, accounting more than 50% of all hand-related problems. The most significant risk factors for job-related hand injuries were performing manual therapy techniques, repetitive workloads, treating many patients per day, continued work while injured or hurt, weakness of the thumb muscles, thumb hypermobility, and instability at the thumb joints. PTs reported modifying treatment technique, taking time off on sick leave, seeking intervention, shifting the specialty area, and decreasing patient contact hours as the major consequences of these injuries. The authors recommend that PTs should develop specific preventive strategies and put more emphasis on the use of aids and equipment to reduce the risk of an unnecessary injury. PMID- 29526242 TI - Traditional and modern aspects of hemorrhoid treatment in Iran: a review. AB - Hemorrhoidal disease is a prevalent anorectal condition which is generally not managed well with current pharmacologic interventions. However, in Iranian traditional medicine (ITM) there are numerous plants with hemorrhoid-healing properties. The present research assembled plants with hemorrhoid-healing properties in ITM; their related pharmacological effects, phytochemical constituents and mechanisms of action in the modern medicine were also gathered. For this purpose, leading ITM textbooks were searched for plants with hemorrhoid healing effects. Further, in vitro, in vivo and clinical studies on the most cited species were considered using scientific databases. Studying ITM textbooks revealed 37 medicinal plants with hemorrhoid-healing effects. Among the mentioned herbal medicines, six species, including Allium ampeloprasum, Phyllanthus emblica, Aloe vera, Terminalia chebula, Vitis vinifera and Commiphora mukul, had the largest number of related pharmacological effects documented in scientific databases. These herbs from ITM should be considered as important resources for producing novel drugs for hemorrhoid treatment. PMID- 29526243 TI - An integrative Tai Chi program for patients with breast cancer undergoing cancer therapy: study protocol for a randomized controlled feasibility study. AB - BACKGROUND: Breast cancer patients experience various side effects during cancer therapy, often resulting in reduced quality of life and poor adherence to treatment. A limited range of proven interventions has been developed to target such side effects. While Tai Chi offers benefits for the health and well-being of breast cancer survivors, the effectiveness of Tai Chi across the treatment continuum has not been evaluated. Improved patient education and support has been suggested as a priority for breast cancer care. This pilot study assesses the feasibility of a randomized controlled trial (RCT) to evaluate the effectiveness of "an integrative Tai Chi" (ANITA) program for breast cancer patients undergoing cancer therapy. METHODS/DESIGN: This is a single-centre, two-arm feasibility RCT. Twenty-four patients with breast cancer who have undergone surgical treatment will be recruited from the Dunedin Hospital (New Zealand) over a 12-month period (from August 2017 to July 2018). Subject to informed consent, patients will be randomized to receive standard cancer treatment alone or standard cancer treatment plus the ANITA program, consisting of peer support, health education, and Tai Chi Ruler exercise. The program runs alongside the patient's adjuvant cancer therapy, which may include chemotherapy, radiation therapy, antibody treatment, and/or antihormonal therapy. Analysis in this study will focus on process evaluation of participant recruitment, retention, treatment fidelity, acceptability of the program, and occurrence of adverse events. Clinical outcomes (i.e., fatigue, sleep quality, anxiety and depression and quality of life) will be assessed at baseline, and at 12 weeks and 24 weeks post-randomization. DISCUSSION: Outcomes from this study will inform the feasibility and methodology for a future fully-powered RCT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry with the identifier ACTRN12617000975392. PMID- 29526244 TI - Corrections. PMID- 29526245 TI - Progress of health care is closely connected with innovation of research methodology. PMID- 29526246 TI - High pressure-elevated temperature x-ray micro-computed tomography for subsurface applications. AB - Physical, chemical and mechanical pore-scale (i.e. micrometer-scale) mechanisms in rock are of key importance in many, if not all, subsurface processes. These processes are highly relevant in various applications, e.g. hydrocarbon recovery, CO2 geo-sequestration, geophysical exploration, water production, geothermal energy production, or the prediction of the location of valuable hydrothermal deposits. Typical examples are multi-phase flow (e.g. oil and water) displacements driven by buoyancy, viscous or capillary forces, mineral-fluid interactions (e.g. mineral dissolution and/or precipitation over geological times), geo-mechanical rock behaviour (e.g. rock compaction during diagenesis) or fines migration during water production, which can dramatically reduce reservoir permeability (and thus reservoir performance). All above examples are 3D processes, and 2D experiments (as traditionally done for micro-scale investigations) will thus only provide qualitative information; for instance the percolation threshold is much lower in 3D than in 2D. However, with the advent of x-ray micro-computed tomography (MUCT) - which is now routinely used - this limitation has been overcome, and such pore-scale processes can be observed in 3D at micrometer-scale. A serious complication is, however, the fact that in the subsurface high pressures and elevated temperatures (HPET) prevail, due to the hydrostatic and geothermal gradients imposed upon it. Such HPET-reservoir conditions significantly change the above mentioned physical and chemical processes, e.g. gas density is much higher at high pressure, which strongly affects buoyancy and wettability and thus gas distributions in the subsurface; or chemical reactions are significantly accelerated at increased temperature, strongly affecting fluid-rock interactions and thus diagenesis and deposition of valuable minerals. It is thus necessary to apply HPET conditions to the aforementioned MUCT experiments, to be able to mimic subsurface conditions in a realistic way, and thus to obtain reliable results, which are vital input parameters required for building accurate larger-scale reservoir models which can predict the overall reservoir-scale (hectometer-scale) processes (e.g. oil production or diagenesis of a formation). We thus describe here the basic workflow of such HPET-MUCT experiments, equipment requirements and apparatus design; and review the literature where such HPET-MUCT experiments were used and which phenomena were investigated (these include: CO2 geo-sequestration, oil recovery, gas hydrate formation, hydrothermal deposition/reactive flow). One aim of this paper is to give a guideline to users how to set-up a HPET-MUCT experiment, and to provide a quick overview in terms of what is possible and what not, at least up to date. As a conclusion, HPET-MUCT is a valuable tool when it comes to the investigation of subsurface micrometer-scaled processes, and we expect a rapidly expanding usage of HPET-MUCT in subsurface engineering and the subsurface sciences. PMID- 29526247 TI - Burn injury mortality in patients with preexisting and new onset renal disease. AB - INTRODUCTION: We sought to examine the impact of preexisting and new onset renal disease on burn injury mortality. METHODS: Retrospective analysis of patients admitted to a regional burn center from 2002-2012 was performed. Variables analyzed included demographics, burn mechanism, inhalation injury status, and % TBSA. Poisson regression was performed to estimate risk of in-hospital burn mortality. RESULTS: There were a total of 7640 patients over the study period. The adjusted 60-day risk of in-hospital mortality in patients with preexisting renal disease (PRD was 3 times higher compared to patients with no preexisting renal disease (IRR = 3.22, 95% CI = 1.26-8.25). The adjusted 60-day risk of mortality is 2 times higher for patients with new onset renal disease compared to those without (IRR = 2.11, 95% CI = 1.55-2.87). CONCLUSION: Preexisting and new onset renal disease results in a significantly higher risk of mortality following burn injury compared to patients without renal disease. Prevention of new onset renal injury and careful management of patients with preexisting renal disease to prevent exacerbation should be pursued. PMID- 29526249 TI - Functional Mitral Regurgitation Repair: Earlier Is Better. PMID- 29526248 TI - Predictive factors of endocrine and exocrine insufficiency after resection of a benign tumour of the pancreas. AB - BACKGROUND: The aim of the present study is to evaluate the risk factors of endocrine and exocrine insufficiency occurring few years after pancreatic resections in a consecutive series of patients who underwent pancreatoduodenectomy (PD), left pancreatectomy (LP) or enucleation for benign neoplasms at a referral centre. METHODS: Pancreatic exocrine insufficiency (PEI) was defined by the onset of steatorrhea associated with weight loss, and endocrine insufficiency was determinate by fasting plasma glucose. Association between pancreatic insufficiency and clinical, pathological, and perioperative features was studied using univariate and multivariate Cox regression analysis. RESULTS: A prospective cohort of 92 patients underwent PD (48%), LP (44%) or enucleation (8%) for benign tumours, from 2005 to 2016 in the University Hospital in Poitiers (France). The median follow-up was 68.6+/-42.4months. During the following, 54 patients developed exocrine insufficiency whereas 32 patients presented endocrine insufficiency. In the Cox model, a BMI>28kg/m2, being a man and presenting a metabolic syndrome were significantly associated with a higher risk to develop postoperative diabetes. The risks factors for the occurrence of PEI were preoperative chronic pancreatitis, a BMI<18.5kg/m2, tumours located in the pancreatic head, biological markers of chronic obstruction and fibrotic pancreas. Undergoing LP or enucleation were protective factors of PEI. Histological categories such as neuroendocrine tumours and cystadenomas were also associated with a decreased incidence of PEI. CONCLUSION: Men with metabolic syndrome and obesity should be closely followed-up for diabetes, and patients with obstructive tumours, pancreatic fibrosis or chronic pancreatitis require a vigilant follow up on their pancreatic exocrine function. PMID- 29526250 TI - Emotional reaction evaluation provoked by the vestibular caloric test through physiological variables monitoring. AB - INTRODUCTION AND OBJECTIVES: The emotional evaluation of the causes of vertigo is made using the clinical records and several subjective questionnaires. The aim of the present study is to evaluate the emotional response objectively, in normal subjects, during an induced vertigo crisis. MATERIAL AND METHOD: A caloric vestibular test with cold water was performed on 30 healthy subjects. The following physiological parameters were monitored during the 60seconds prior to and the 60seconds after the stimulation: Skin Conductivity, Peripheral Pulse Volume, Body Temperature, Muscle Contraction, Heart Rate, and Respiratory Rate. The maximum angular speed of the nystagmus slow phase at each stimulation was assessed. RESULTS: Skin conductance presented a statistically significant increase during the vertigo crisis in relation to the prior period while the peripheral pulse volume presented a statistically significant decrease. There was no relationship between the slow phase of the provoked nystagmus angular speed and skin conductance and peripheral pulse volume changes. The decrease in peripheral pulse volume was significantly higher in the second vertigo crisis. CONCLUSIONS: Skin conductance and peripheral pulse volume changed significantly during a vertigo crisis. There was no relation between the provoked vertiginous crisis intensity and the changes produced in those variables. The stress generated by the caloric stimulation is higher in the second crisis, when the subject has experience of the vertigo caused by the stimulation. PMID- 29526251 TI - Robot-assisted pudendal neurolysis in the treatment of pudendal nerve entrapment syndrome. AB - INTRODUCTION: Pudendal nerve entrapment syndrome (PNE) is characterised by the presence of neuropathic pain in the pudendal nerve (PN) territory, associated or not with urinary, defecatory and sexual disorders. Surgical PN decompression is an effective and safe alternative for cases when conservative treatment fails. The aim of this study is to describe the first robot-assisted pudendal neurolysis procedure performed in our country. MATERIAL AND METHODS: We describe step by step the technique of robot-assisted laparoscopic neurolysis of the left PN performed with intraoperative neurophysiological monitoring on a 60-year-old patient diagnosed with left PNE. RESULTS: The procedure was performed satisfactorily without complications. After 24h, the patient was discharged from the hospital. We observed a 50% reduction in pain measured using the visual analogue scale 2 weeks after the procedure, which remained after 10 weeks of the neurolysis. CONCLUSIONS: Robot-assisted neurolysis of the PN constitutes a feasible and safe approach, enabling better visualisation and accuracy in the dissection of the PN. Intraoperative neurophysiological monitoring is useful for locating the PN and for detecting intraoperative changes after the release of the nerve. PMID- 29526252 TI - LAMPs: Shedding light on cancer biology. AB - Lysosomes are important cytoplasmic organelles whose critical functions in cells are increasingly being understood. In particular, despite the long-standing accepted concept about the role of lysosomes as cellular machineries solely assigned to degradation, it has been demonstrated that they play active roles in homeostasis and even in cancer biology. Indeed, it is now well documented that during the process of cellular transformation and cancer progression lysosomes are changing localization, composition, and volume and, through the release of their enzymes, lysosomes can also enhance cancer aggressiveness. LAMPs (lysosome associated membrane proteins) represent a family of glycosylated proteins present predominantly on the membrane of lysosomes whose expression can vary among different tissues, suggesting a separation of functions. In this review we focus on the functions and roles of the different LAMP family members, with a particular emphasis on cancer progression and metastatic spread. LAMP proteins are involved in many different aspects of cell biology and can influence cellular processes such as phagocytosis, autophagy, lipid transport, and aging. Interestingly, for all the five members identified so far (LAMP1, LAMP2, LAMP3, CD68/Macrosialin/LAMP4, and BAD-LAMP/LAMP5), a role in cancer has been suggested. While this is well documented for LAMP1 and LAMP2, the involvement of the other three proteins in cancer progression and aggressiveness has recently been proposed and remains to be elucidated. Here we present different examples about how LAMP proteins can influence and support tumor growth and metastatic spread, emphasizing the impact of each single member of the family. PMID- 29526253 TI - The prodigious network of chromosome 17 miRNAs regulating cancer genes that influence the hallmarks of cancer. AB - Chromosome 17 (Chr17) harbors crucial genes that encode proteins implicated in a variety of cancers, including some that guard cancer cells from genomic instability and others that interfere with metastasis. Included amongst the genes on chr17 that regulate biological processes fundamental to the genesis of cancer are TP53, BRCA1, CCL5, NF-1, and GRB7. As many as 50% of all human tumors and at least 30% of breast carcinomas contain p53 mutations, while 30%-40% of breast cancers have defective BRCA1. A large number of proteins regulate the expression of these cancer genes on chr17 with miRNAs, the most widely studied class of regulatory RNAs, playing a major role in epigenetically controlling the gene expression programs, thereby managing various cellular functions. This review provides information on the genes transcribed from chr17, and their regulation by miRNAs in the context to tumorigenesis located on chr17, along with an analysis of the receptor status (estrogen, progesterone, and Her2/Neu) from the miRNA prediction data of miRNA genes located on chr17. PMID- 29526254 TI - The Sunshine Act and oncology: Lessons learned from urology. AB - INTRODUCTION: The Physician Payment Sunshine Act was enacted to increase the transparency of financial relationships between physicians and the pharmaceutical industry. These financial relationships are prevalent in the field of oncology, as they are in other fields of medicine. We explored the relationship between industry and urologists for compensations associated with the treatment of urologic malignancies. METHODS: The publicly available Open Payments database was obtained from the Centers for Medicare & Medicaid Services. We performed a descriptive analysis of payments made to urologists for drugs associated with urologic malignancies. RESULTS: In total, 44,334 payments, summing to $ 4,638,856, were made to 5,666 urologists for drugs used to treat urologic cancers. The median payment per transaction was $14, and most (74.3%) were L $20. Of the transactions, 39,368 (88.8%) were associated with drugs for prostate cancer, 3,475 (7.8%) for bladder cancer, and 1,491 (3.4%) for kidney cancer. Most payments were made the form of food or beverage (89%), equating to $826,667. CONCLUSIONS: For urologists, industry payments associated with cancer treatment are prevalent. Treatments for prostate cancer are associated with the most financial relationships, followed by bladder cancer and kidney cancer. Payments are small in amount, and are commonly in the form of food or beverage. PMID- 29526255 TI - Male Breast Cancer: Epidemiology and Risk Factors. AB - Male breast cancer is a rare malignancy that accounts for less than 1% of all cancers in men and less than 1% of all breast cancers. But the incidence is rising and in some patient groups reaching 15% over the course of their lives. The major risk factors for the development of male breast cancer include advancing age, hormonal imbalance, radiation exposure, and a family history of breast cancer. Regarding the latter, incidence can be linked to mutations in high or low-penetrance genes. The most relevant risk factor for the development of male breast cancer is a mutation in the BRCA2 gene. Most cases present late because of a lack of awareness of the existence of such a malignancy in males and ignorance of the related risk factors. Additionally, males with breast cancer are at special risk for developing a second cancer. This in depth review highlights the epidemiology and risk factors for the development of male breast cancer. PMID- 29526256 TI - Revisiting the Role of Bevacizumab in the Treatment of Breast Cancer. AB - Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF) that interferes with VEGF binding to its receptor on vascular endothelium. Bevacizumab has been approved for the treatment of various malignant tumors, and has been studied in combination with several cytotoxic agents in the treatment of breast cancer. In 2008, the US Food and Drug Administration granted accelerated approval for the use of bevacizumab in combination with weekly paclitaxel for first-line treatment of HER2-negative metastatic breast cancer. However, this approval was later reversed in 2010 because of concerns for safety and lack of improvement in overall survival in randomized clinical trials. In this review, we summarize relevant clinical studies conducted to investigate the role of bevacizumab in the management of breast cancer, both in the early stage and in the metastatic disease settings. We also provide commentary regarding the future of this agent in breast cancer treatment. PMID- 29526257 TI - Bevacizumab in breast cancer: a targeted therapy still in search of a target population. PMID- 29526258 TI - Comparative aspects of canine and human inflammatory breast cancer. AB - Inflammatory breast cancer (IBC) in humans is the most aggressive form of mammary gland cancer and shares clinical, pathologic, and molecular patterns of disease with canine inflammatory mammary carcinoma (CIMC). Despite the use of multimodal therapeutic approaches, including targeted therapies, the prognosis for IBC/CIMC remains poor. The aim of this review is to critically analyze IBC and CIMC in terms of biology and clinical features. While rodent cancer models have formed the basis of our understanding of cancer biology, the translation of this knowledge into improved outcomes has been limited. However, it is possible that a comparative "one health" approach to research, using a natural canine model of the disease, may help advance our knowledge on the biology of the disease. This will translate into better clinical outcomes for both species. We propose that CIMC has the potential to be a useful model for developing and testing novel therapies for IBC. Further, this strategy could significantly improve and accelerate the design and establishment of new clinical trials to identify novel and improved therapies for this devastating disease in a more predictable way. PMID- 29526259 TI - Leveraging Comparative Oncology in the Hopes of Improving Therapies for Breast Cancer. PMID- 29526260 TI - Pay-for-performance incentive program in a large dental group practice. AB - BACKGROUND: Dentists increasingly are employed in large group practices that use financial incentive systems to influence provider performance. The authors describe the design and initial implementation of a pay-for-performance (P4P) incentive program for a large capitated Oregon group dental practice that cares primarily for patients receiving Medicaid. The authors do not assess the effectiveness of the incentive system on provider and staff member performance. METHODS: The data come from use of care files and integrated electronic health records, provider and staff member surveys, and interviews and community surveys from 6 counties. Quarterly individual- and team-level incentives focused on 3 performance metrics. RESULTS: The program was challenged by many complex administrative issues. The key issues included designing a P4P system for different types of providers and administrative staff members who were employed centrally and in different communities, setting realistic performance metrics, building information systems that provided timely information about performance, and educating and gaining the support of a diverse workforce. Adjustments are being made in the incentive scheme to meet these challenges. CONCLUSIONS: This is the first report of a P4P compensation system for dental care providers and supporting staff members. The complex administrative challenges will require several years to address. PRACTICAL IMPLICATIONS: Large, capitated dental practice organizations will employ more dental care providers and administrative staff members to care for patients who receive Medicaid and patients who are privately insured. It is critical to design and implement a P4P system that the workforce supports. PMID- 29526261 TI - Corrigendum to "Rescuing infusion of miRNA-1 prevents cardiac remodeling in a heart-selective miRNA deficient mousetitle of article" [Biochem. Biophys. Res. Commun. 495(1) (2018) 607-613]. PMID- 29526262 TI - A comparison of penetration and damage caused by different types of arrowheads on loose and tight fit clothing. AB - Bows and arrows are used more for recreation, sport and hunting in the Western world and tend not to be as popular a weapon as firearms or knives. Yet there are still injuries and fatalities caused by these low-velocity weapons due to their availability to the public and that a licence is not required to own them. This study aimed to highlight the penetration capabilities of aluminium arrows into soft tissue and bones in the presence of clothing. Further from that, how the type and fit of clothing as well as arrowhead type contribute to penetration capacity. In this study ballistic gelatine blocks (non-clothed and loose fit or tight fit clothed) were shot using a 24lb weight draw recurve bow and aluminium arrows accompanied by four different arrowheads (bullet, judo, blunt and broadhead). The penetration capability of aluminium arrows was examined, and the depth of penetration was found to be dependent on the type of arrowhead used as well as by the type and fit or lack thereof of the clothing covering the block. Loose fit clothing reduced penetration with half of the samples, reducing penetration capacity by percentages between 0% and 98.33%, at a range of 10m. While the remaining half of the samples covered with tight clothing led to reductions in penetration of between 14.06% and 94.12%. The damage to the clothing and the gelatine (puncturing, cutting and tearing) was affected by the shape of the arrowhead, with the least damaged caused by the blunt arrowheads and the most by the broadhead arrows. Clothing fibres were also at times found within the projectile tract within the gelatine showing potential for subsequent infection of an individual with an arrow wound. Ribs, femur bones and spinal columns encased in some of the gelatine blocks all showed varying levels of damage, with the most and obvious damage being exhibited by the ribs and spinal column. The information gleaned from the damage to clothing, gelatine blocks and bones could potentially be useful for forensic investigators, for example, when a body has been discovered with no weapons or gunshot residue present. PMID- 29526263 TI - A study of the intermolecular interactions of lipid components from analogue fingerprint residues. AB - A compositionally simplified analogue of a latent fingermark was created by combining single representatives of each major component of a natural fingermark. Further modified analogues were also produced each having one component removed. The aim of this study was to investigate the intermolecular interactions that occurred within these analogue samples using Fourier Transform Infrared (FT-IR) Microspectroscopy. FT-IR microspectroscopy showed that the absence of squalene and cholesterol significantly restricted the interactions between the other organic constituents within the analogue samples. Investigating the intermolecular interactions of organic compounds within a simplified analogue solution could indicate corresponding interactions that occur within natural fingermarks. These potential interactions could go on to be the target of further investigation of latent fingermark chemistry, and ultimately contribute to a better understanding of the aging processes and degradation mechanisms that take place post-deposition. PMID- 29526264 TI - A systematic analysis of misleading evidence in unsafe rulings in England and Wales. AB - Evidence has the potential to be misleading if its value when expressing beliefs in hypotheses is not fully understood or presented. Although the knowledge base to understand uncertainties is growing, a challenge remains to prioritise research and to continuously assess the magnitude and consequences of misleading evidence in criminal cases. This study used a systematic content analysis to identify misleading evidence, drawing information from case transcripts of rulings argued unsafe by the Court of Appeal of England and Wales. In the 7-year study period, 218 applications were successful on appeal, containing 235 cases of misleading evidence. The majority (76%) of successful appeals were based upon the same materials available in the original trial, rather than the presentation of new relevant information. Witness (39%), forensic (32%), and character evidence (19%) were the most commonly observed evidence types, with the validity of witnesses (26%), probative value of forensic evidence (12%), and relevance of character evidence (10%) being the most prevalent combinations of identified issues. Additionally, the majority (66%) of misleading evidence types relate to their interpretation at activity level. The findings suggest that many of these misleading aspects could have been prevented by providing more transparency in the relationship between evidence and hypotheses. Generally, the results contribute to gaining a more complete picture of the role of misleading evidence in the criminal justice system. PMID- 29526265 TI - Soil forensics: How far can soil clay analysis distinguish between soil vestiges? AB - Soil traces are useful as forensic evidences because they frequently adhere to individuals and objects associated with crimes and can place or discard a suspect at/from a crime scene. Soil is a mixture of organic and inorganic components and among them soil clay contains signatures that make it reliable as forensic evidence. In this study, we hypothesized that soils can be forensically distinguished through the analysis of their clay fraction alone, and that samples of the same soil type can be consistently distinguished according to the distance they were collected from each other. To test these hypotheses 16 Oxisol samples were collected at distances of between 2m and 1.000m, and 16 Inceptisol samples were collected at distances of between 2m and 300m from each other. Clay fractions were extracted from soil samples and analyzed for hyperspectral color reflectance (HSI), X-ray diffraction crystallographic (XRD), and for contents of iron oxides, kaolinite and gibbsite. The dataset was submitted to multivariate analysis and results were from 65% to 100% effective to distinguish between samples from the two soil types. Both soil types could be consistently distinguished for forensic purposes according to the distance that samples were collected from each other: 1000m for Oxisol and 10m for Inceptisol. Clay color and XRD analysis were the most effective techniques to distinguish clay samples, and Inceptisol samples were more easily distinguished than Oxisol samples. Soil forensics seems a promising field for soil scientists as soil clay can be useful as forensic evidence by using routine analytical techniques from soil science. PMID- 29526266 TI - Novel messenger RNAs for body fluid identification. AB - In forensic investigations, the identification of the cellular or body fluid source of biological evidence can provide crucial probative information for the court. Messenger RNA (mRNA) profiling has become a valuable tool for body fluid and cell type identification due to its high sensitivity and compatibility with DNA analysis. However, using a single marker to determine the somatic origin of a sample can lead to misinterpretation as a result of cross-reactions. While false positives may be avoided through the simultaneous detection of multiple markers per body fluid, this approach is currently limited by the small number of known differentially expressed mRNAs. Here we characterise six novel mRNAs, partly identified from RNA-Seq, which can supplement existing markers for the detection of circulatory blood, semen (with and without spermatozoa), and menstrual fluid: HBD and SLC4A1 for blood, TNP1 for spermatozoa, KLK2 for seminal fluid, and MMP3 and STC1 for menstrual fluid. Respective expression profiles were evaluated by singleplex endpoint reverse transcription polymerase chain reaction (RT-PCR). HBD, SLC4A1, and KLK2 were specific to their target body fluids. TNP1, MMP3, and STC1 each cross-reacted with two non-target samples; however, these signals were below 350RFU, not reproducible, and likely resulted from large body fluid inputs. All candidates were more sensitive for the detection of their target body fluids than corresponding well-known mRNAs, in particular those for menstrual fluid. The increased sensitivities were statistically significant, except for KLK2. Thus, the new mRNAs introduced here are promising new targets for improved body fluid profiling. PMID- 29526267 TI - Massively parallel sequencing and the emergence of forensic genomics: Defining the policy and legal issues for law enforcement. AB - Use of DNA in forensic science will be significantly influenced by new technology in coming years. Massively parallel sequencing and forensic genomics will hasten the broadening of forensic DNA analysis beyond short tandem repeats for identity towards a wider array of genetic markers, in applications as diverse as predictive phenotyping, ancestry assignment, and full mitochondrial genome analysis. With these new applications come a range of legal and policy implications, as forensic science touches on areas as diverse as 'big data', privacy and protected health information. Although these applications have the potential to make a more immediate and decisive forensic intelligence contribution to criminal investigations, they raise policy issues that will require detailed consideration if this potential is to be realised. The purpose of this paper is to identify the scope of the issues that will confront forensic and user communities. PMID- 29526268 TI - Analysing and exemplifying forensic conclusion criteria in terms of Bayesian decision theory. AB - There is ongoing discussion in forensic science and the law about the nature of the conclusions reached based on scientific evidence, and on how such conclusions - and conclusion criteria - may be justified by rational argument. Examples, among others, are encountered in fields such as fingermarks (e.g., 'this fingermark comes from Mr. A's left thumb'), handwriting examinations (e.g., 'the questioned signature is that of Mr. A'), kinship analyses (e.g., 'Mr. A is the father of child C') or anthropology (e.g., 'these are human remains'). Considerable developments using formal methods of reasoning based on, for example (Bayesian) decision theory, are available in literature, but currently such reference principles are not explicitly used in operational forensic reporting and ensuing decision-making. Moreover, applied examples, illustrating the principles, are scarce. A potential consequence of this in practical proceedings, and hence a cause of concern, is that underlying ingredients of decision criteria (such as losses quantifying the undesirability of adverse decision consequences), are not properly dealt with. There is merit, thus, in pursuing the study and discussion of practical examples, demonstrating that formal decision-theoretic principles are not merely conceptual considerations. Actually, these principles can be shown to underpin practical decision-making procedures and existing legal decision criteria, though often not explicitly apparent as such. In this paper, we will present such examples and discuss their properties from a Bayesian decision-theoretic perspective. We will argue that these are essential concepts for an informed discourse on decision-making across forensic disciplines and the development of a coherent view on this topic. We will also emphasize that these principles are of normative nature in the sense that they provide standards against which actual judgment and decision-making may be compared. Most importantly, these standards are justified independently of peoples' observable decision behaviour, and of whether or not one endorses these formal methods of reasoning. PMID- 29526269 TI - The effect of antifreeze (ethylene glycol) on the survival and the life cycle of two species of necrophagous blowflies (Diptera: Calliphoridae). AB - Entomotoxicology involves the analysis of the presence and the effects of toxicological substances in necrophagous insects. Results obtained by entomotoxicological studies may assist in the investigation of both the causes and the time of death of humans and animals. Ethylene glycol (EG) is easy to purchase, sweet and extremely toxic. It may be consumed accidentally or purposefully, in an attempt to cause death for suicidal or homicidal intent. Several cases report fatalities of humans and animals. The present study is the first to examine the effects of EG on the survival, developmental rate and morphology of two blowfly species, (Diptera: Calliphoridae) typically found on corpses and carcasses: Lucilia sericata (Meigen) and L. cuprina (Wiedemann). Both species were reared on substrates (beef liver) spiked with three different concentrations of EG that could cause death in either a human or cat: 1/2LD50 (T1), LD50 (T2), 2LD50 (T3), in addition to a control treatment (C) with no EG. Results of this research show that: a) both species are unable to survive if reared on a food substrate spiked with the highest concentration of EG (T3), while lower and medium concentrations (T1, T2) affect, but not prevent, the survival and the completion of the life cycle of such species; b) adults of L. sericata eclose only in C and T1, while adults of L. cuprina in both C, T1, T2; however, c) the developmental time of both species reared in T1 and T2 is statistically slower than the control; d) the body length of the immatures of both of the species reared in T1 and T2 is statistically smaller than the control. PMID- 29526270 TI - Changes in illicit cocaine hydrochloride processing identified and revealed through multivariate analysis of cocaine signature data. AB - For nearly 30years, the methods utilized in illicit cocaine hydrochloride production have remained relatively consistent. Cocaine hydrochloride is typically produced one kilogram at a time. As a result, each individual kilogram is unique and distinct from other kilograms in any particular seizure based on the total alkaloid profile, occluded solvent profile, and isotopic signature. Additionally, multi-kilogram cocaine seizures are often comprised of cocaine from several different coca growing regions. There has been a documented shift in this type of processing based on the recent analysis of a large cocaine seizure in the Eastern Pacific. Signature analyses of samples from 21kg randomly selected from a 517kg seizure were virtually identical. Triplicate analyses of each sample via gas chromatography with flame ionization detection, static headspace gas chromatography mass spectrometry, and isotope ratio mass spectrometry were completed. An initial outlier evaluation of the data and an in-depth univariate analysis indicated there was no statistically significant difference among the 21 samples at the 95% confidence interval. Principal components analysis did reveal consistent minor deviations between the samples and known authentic data from the Narino coca growing region of Colombia. These deviations were only observed on the latter principal components and could be explained by differences in solvent selection during cocaine hydrochloride processing. Chemical analyses in addition to a thorough statistical evaluation suggest a shift in the traditional small batch method of cocaine processing to a multi-kilogram, high throughput approach. PMID- 29526271 TI - Profiling the scent of weathered training aids for blood-detection dogs. AB - At outdoor crime scenes, cadaver-detection and blood-detection dogs may be tasked with locating blood that is days, weeks or months old. Although it is known that the odour profile of blood will change during this time, it is currently unknown how the profile changes when exposed to the environment. Such variables must be studied in order to understand when the odour profile is no longer detectable by the scent-detection dogs and other crime scene tools should be implemented. In this study, blood was deposited onto concrete and varnished wood surfaces and weathered in an outdoor environment over a three-month period. Headspace samples were collected using solid phase microextraction (SPME) and analysed using comprehensive two-dimensional gas chromatography - time-of-flight mass spectrometry (GC*GC-TOFMS). The chemical odour profiles were compared with the behavioural responses of cadaver-detection and blood-detection dogs during training. Data interpretation using principal component analysis (PCA) and hierarchical cluster analysis (HCA) established that the blood odour could no longer be detected using SPME-GC*GC-TOFMS after two months of weathering on both surfaces. Conversely, the blood-detection dogs had difficulty locating the blood samples after one month of weathering on concrete and after one week of weathering on varnished wood. The scent-detection dogs evaluated herein had not been previously exposed to environmentally weathered blood samples during training. Given that this study was conducted to test the dogs' baseline abilities, it is expected that with repeated exposure, the dogs' capabilities would likely improve. The knowledge gained from this study can assist in providing law enforcement with more accurate training aids for blood-detection dogs and can improve their efficiency when deployed to outdoor crime scenes. PMID- 29526272 TI - Different perspectives on predictability and preventability of surgical readmissions. AB - BACKGROUND: Although unscheduled readmissions are increasingly being used as a quality indicator, only few readmission studies have focused on surgical patient populations. METHODS: An observational study "CURIOS@" was performed at three centers in the Netherlands. Readmitted patients and treating doctors were surveyed to assess the discharge process during index admission and their opinion on predictability and preventability of the readmission. Risk factors associated with predictability and preventability as judged by patients and their doctor were identified. Cohen's kappa was calculated to measure pairwise agreement of considering readmission as predictable/preventable. PRISMA root cause categories were used to qualify the reasons for readmission. RESULTS: In 237 unscheduled surgical readmissions, more patients assessed their readmissions to be likely preventable compared with their treating doctors (28.7% versus 6.8%; kappa, 0.071). This was also reflected in poor consensus about risk factors and root causes of these readmissions. When patients reported that they did not feel ready for discharge or requested their doctor to allow them to stay longer at discharge during index admission, they deemed their readmission more likely predictable and preventable. Doctors focused on measurable factors such as the clinical frailty scale and biomarkers during discharge process. Health-care worker failures were strongly associated with preventable readmissions. CONCLUSIONS: There is no consensus between readmitted patients and treating doctors about predictability and preventability of readmissions, nor about associated risk factors and root causes. Patients should be more effectively involved in their discharge process, and the relevance of optimal communication between them should be emphasized to create a safe and efficient discharge process. PMID- 29526273 TI - Relation of Body Mass Index to Development of Atrial Fibrillation in Hispanics, Blacks, and Non-Hispanic Whites. AB - No previous studies have examined the interaction between body mass index (BMI) and race/ethnicity with the risk of atrial fibrillation (AF). We retrospectively followed 48,323 persons free of AF (43% Hispanic, 37% black, and 20% white; median age 60 years) for subsequent incident AF (ascertained from electrocardiograms). BMI categories included very severely underweight (BMI <15 kg/m2), severely underweight (BMI 15.1 to 15.9 kg/m2), underweight (BMI 16 to 18.4 kg/m2), normal (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25.0 to 29.9 kg/m2), moderately obese (BMI 30 to 34.9 kg/m2), severely obese (BMI 35 to 39.9 kg/m2), and very severely obese (BMI >40 kg/m2). Cox regression analysis controlled for baseline covariates: heart failure, gender, age, treatment for hypertension, diabetes, PR length, systolic blood pressure, left ventricular hypertrophy, socioeconomic status, use of beta blockers, calcium channel blockers, and digoxin. Over a follow-up of 13 years, 4,744 AF cases occurred. BMI in units of 10 was associated with the development of AF (adjusted hazard ratio 1.088, 95% confidence interval 1.048 to 1.130, p <0.01). When stratified by race/ethnicity, non-Hispanic whites compared with blacks and Hispanics had a higher risk of developing AF, noted in those whom BMI classes were overweight to severely obese. In conclusion, our study demonstrates that there exists a relation between obesity and race/ethnicity for the development of AF. Non Hispanic whites had a higher risk of developing AF compared with blacks and Hispanics. PMID- 29526274 TI - Patent Foramen Ovale Closure-When Number Needed to Treat and Number Needed to Harm Do Not Tell the Whole Story. PMID- 29526275 TI - Smoking Cessation in Patients With Acute Coronary Syndrome. AB - Over 30% of the nearly 1 million North Americans hospitalized annually with an acute coronary syndrome (ACS) are smokers. Despite a substantially increased risk of morbidity and mortality, 2/3 of patients who quit smoking after ACS return to smoking within 1 year. To summarize the evidence of smoking cessation in patients hospitalized after ACS, we systematically reviewed all randomized controlled trials of pharmacologic and behavioral smoking cessation therapies in patients with ACS. In addition, we reviewed the clinical considerations surrounding the use of smoking cessation therapies, including their broad mechanisms of action and possible alternative treatments, including cardiac rehabilitation programs and electronic cigarettes. A total of 7 randomized controlled trials met our inclusion criteria (4 pharmacotherapies and 3 behavioral therapies). In pharmacologic trials, only varenicline increased point prevalence abstinence at 12 months. Behavioral interventions produced significantly improved abstinence rates at 6 and 12 months. However, these studies had substantial limitations affecting their generalizability. Overall, currently available smoking cessation therapies are limited in their efficacy in patients hospitalized after ACS. Because of the relative scarcity of data and the urgency of establishing clinical guidelines, there is a critical need to continue examining the efficacy and safety of smoking cessation interventions in patients hospitalized after ACS. PMID- 29526276 TI - Usefulness of the CHA2DS2-VASc and HAS-BLED Scores in Predicting the Risk of Stroke Versus Intracranial Bleeding in Patients With Atrial Fibrillation (from the FibStroke Study). AB - CHA2DS2-VASc and HAS-BLED scores stratify the risk of thromboembolic and bleeding events respectively in patients with atrial fibrillation. There is only little information on how they differentiate which of the 2 clinically most important complications (ischemic stroke [IS] or an intracranial bleeding [IB]) the patient is more prone to suffer. We evaluated both scores in patients with either of these major complications. The FibStroke Study collected data on all patients with atrial fibrillation with either an IS or an IB event between 2003 and 2012 in 4 Finnish hospital districts. Individual electronic patient records were manually reviewed to collect the study data. To assess the relative risk of IS and IB, an IS/IB-ratio was calculated by dividing the absolute number of ISs with the absolute number of IBs within each score category. A total of 3,816 (82.7%) ISs and 798 (17.3%) IBs were detected in 3,909 patients. In general, ISs occurred more often than IBs in patients on oral anticoagulation in each score category (ratio 1.6 to 5.1). The ratio decreased below 1, however, only with very high HAS BLED scores (>4). Moreover, 221 ISs and 53 IBs occurred in patients with HAS-BLED > CHA2DS2-VASc, of whom only 19.7% were on anticoagulation. In conclusion, IS was the predominant intracranial event irrespective of CHA2DS2-VASc score, HAS-BLED score <=4, or use of oral anticoagulation, also in patients with low estimated thromboembolic risk (CHA2DS2-VASc 0 to 1). Furthermore, the HAS-BLED score predicted the excess of IBs over ISs only at very high-risk levels. PMID- 29526277 TI - Idiopathic Restrictive Cardiomyopathy in Children and Young Adults. AB - Idiopathic restrictive cardiomyopathy (IRC) is a rare condition characterized by reduced ventricular compliance. Children with IRC have poor outcomes with most patients proceeding to cardiac transplantation. We sought to analyze our institutional experience and assess contemporary outcomes for children with IRC. We reviewed the medical record for patients (<21 years old) evaluated for a primary diagnosis of IRC between 1975 and 2013 at our institution. Demographic, clinical, echocardiographic, and catheterization data were abstracted. The patients were divided into 2 groups comprising a historical cohort (HC) (diagnosis: 1975 to 1993, n = 8) and a contemporary cohort (CC) (diagnosis: 1994 to 2013, n = 12). Twenty children were identified with IRC (mean age at presentation 9.7 +/- 6.5 years, 55% female). Mean length of follow-up was 6.5 +/- 8.4 years (range 0.1 to 35.6 years). In the CC, 7 of 12 patients (58%) progressed to cardiac transplantation (mean age of 9 +/- 4 years at transplant, mean interval from diagnosis of IRC: 1.5 +/- 0.9 years). Overall survival was improved significantly in the CC compared with the HC (80% vs. 38%, p = 0.02), but transplantation free survival was no different between the CC and HC over 5 years (38% vs 38%, p = 0.65). In the CC, elevation of mitral valve Doppler E/e' ratio on echocardiography was associated with increased mortality (p = 0.01). In conclusion, IRC continues has a poor prognosis. Early referral for transplantation was associated with improved overall survival in the modern era. Patients with markedly elevated E/e' ratio may have increased risk of death. PMID- 29526278 TI - Identification and Rescue of Splice Defects Caused by Two Neighboring Deep Intronic ABCA4 Mutations Underlying Stargardt Disease. AB - Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ~40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep intronic ABCA4 variants (c.4539+2001G>A and c.4539+2028C>T) result in a retina specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs*36), likely due to the creation of exonic enhancers. Administration of antisense oligonucleotides (AONs) targeting the 345-nt pseudoexon can significantly rescue the splicing defect observed in PPCs of two individuals with these mutations. Intriguingly, an AON that is complementary to c.4539+2001G>A rescued the splicing defect only in PPCs derived from an individual with STGD1 with this but not the other mutation, demonstrating the high specificity of AONs. In addition, a single AON molecule rescued splicing defects associated with different neighboring mutations, thereby providing new strategies for the treatment of persons with STGD1. As many genes associated with human genetic conditions are expressed in specific tissues and pre-mRNA splicing may also rely on organ-specific factors, our approach to investigate and treat splicing variants using differentiated cells derived from individuals with STGD1 can be applied to any tissue of interest. PMID- 29526279 TI - Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase. AB - Five classical designations of sickle haplotypes are made on the basis of the presence or absence of restriction sites and are named after the ethno-linguistic groups or geographic regions from which the individuals with sickle cell anemia originated. Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p.Glu7Val] in HBB). We investigated the origins of the sickle mutation by using whole-genome-sequence data. We identified 156 carriers from the 1000 Genomes Project, the African Genome Variation Project, and Qatar. We classified haplotypes by using 27 polymorphisms in linkage disequilibrium with rs334. Network analysis revealed a common haplotype that differed from the ancestral haplotype only by the derived sickle mutation at rs334 and correlated collectively with the Central African Republic (CAR), Cameroon, and Arabian/Indian haplotypes. Other haplotypes were derived from this haplotype and fell into two clusters, one composed of Senegal haplotypes and the other composed of Benin and Senegal haplotypes. The near-exclusive presence of the original sickle haplotype in the CAR, Kenya, Uganda, and South Africa is consistent with this haplotype predating the Bantu expansions. Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation. The posterior distribution of the ancestral recombination graph yielded a sickle mutation age of 259 generations, corresponding to 7,300 years ago during the Holocene Wet Phase. These results clarify the origin of the sickle allele and improve and simplify the classification of sickle haplotypes. PMID- 29526282 TI - A History of Percutaneous Left Atrial Appendage Occlusion with the PLAATO Device. AB - Percutaneous left atrial appendage occlusion was introduced as an alternative method for prevention of thromboembolism in patients with nonvalvular atrial fibrillation after extensive animal work in 2001. The first device was named Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) and patented by the company Appriva. The device was invented by Michael Lesh, MD. PMID- 29526281 TI - Outcomes of Counseling after Education about Carrier Results: A Randomized Controlled Trial. AB - In-person education and counseling for all people receiving genetic results is the predominant model of disclosure but is challenged by the growing volume of low-impact results generated by sequencing. Evidence suggests that web-based tools may be as effective as in-person counseling at educating individuals about their low-impact results. However, the effects of counseling have not been assessed. To evaluate its utility, carrier results were returned to 459 post reproductive participants from the ClinSeq cohort within a randomized controlled trial. Participants received education and were randomized to receive counseling or not. Primary outcomes included risk worry, test-related positive experiences, attitudes, and decisional conflict. Secondary outcomes were satisfaction, preferences, and counseling value. There were no differences between participants who received counseling and those who did not in the primary outcomes. Participants who received counseling were more satisfied than those who did not (x- = 10.2 and 9.5, respectively, p < 0.002, range: 3-12), although overall satisfaction was high. Most participants (92%) randomized to counseling preferred it and valued it because it provided validation of their reactions and an opportunity for interpersonal interaction. Web-based tools address the challenge of returning low-impact results, and these data provide empiric evidence that counseling, although preferred and satisfying, is not critical to achieving desired outcomes. PMID- 29526283 TI - A History of Left Atrial Appendage Occlusion. AB - A new era in antiembolic therapy has been initiated by the growing numbers of device-based therapies. Early concerns surrounding eliminating this enigmatic structure have not proven true. Other benefits are being further evaluated. Many other questions remain, such as whether there is a device-specific outcome effect or whether it is a class effect. Other questions include other devices, what head to-head studies will show, and the impact of residual leak. Left atrial appendage using the Watchman ablation strategy can reduce cardioembolic stroke, with comparable or fewer adverse effects by device technology than obtained by long term anticoagulation with its attendant bleeding risks. PMID- 29526284 TI - History of Percutaneous Left Atrial Appendage Occlusion with AMPLATZER Devices. AB - AMPLATZER devices preceded WATCHMAN occluder in 2002 for catheter-based left atrial appendage occlusion. The AMPLATZER technique facilitates simultaneous closure of atrial shunts using two devices through one gear. Randomized WATCHMAN follow-up data showed a mortality benefit over warfarin. AMPLATZER data make this likely valid for the strategy. Particularly young people with atrial fibrillation should be offered left atrial appendage occlusion because the risk is confined to the intervention and early postintervention period. Guidelines should be adapted to make this progress in prevention of stroke and bleeding in patients with atrial fibrillation accessible for all, in the sense of a mechanical vaccination. PMID- 29526280 TI - Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity. AB - Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (>=50 copies) of a non coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease. PMID- 29526285 TI - Left Atrial Appendage Occlusion: Data Update. AB - Resection of the left atrial appendage (LAA) to prevent recurrent arterial emboli in patients with atrial fibrillation was first suggested more than 60 years ago. Longer-term follow-up from randomized studies of the safety and efficacy of transcatheter LAA occlusion has recently been completed; data from large, observational cohorts are being reported. These recent data provide further insights into procedural safety with current techniques and the ability of LAA closure to reduce thromboembolic stroke compared with warfarin anticoagulation. This review summarizes the latest data regarding transcatheter LAA occlusion, focusing on larger prospective studies and further analyses of seminal clinical trials. PMID- 29526286 TI - Indication, Patient Selection, and Referral Pathways for Left Atrial Appendage Closure. AB - Left atrial appendage closure (LAAC) has emerged as a viable option for stroke prevention, especially in those intolerant of or not suitable for long-term oral anticoagulation therapy. This article describes the clinical characteristics, indications, and a proposed referral system for potential LAAC patients. Patient selection remains a challenge because of the paradox between the available randomized data on this intervention and the actual patient population who may gain maximum benefit. Further investigations comparing different LAAC devices with each other and with novel oral anticoagulants are needed. Also, the optimal antithrombotic regimen post-procedure has yet to be determined. PMID- 29526287 TI - Anatomy and Physiologic Roles of the Left Atrial Appendage: Implications for Endocardial and Epicardial Device Closure. AB - The left atrial appendage has been implicated as a major nidus for thrombus formation, particularly in atrial fibrillation. This discovery has prompted substantial interest in the development of left atrial appendage exclusion devices aimed at decreasing systemic thromboembolism risk. Its deceptively simple appearance belies the remarkable complexity that characterizes its anatomy and physiology. We highlight the key anatomic features and variations of the left atrial appendage as well as its relationships with surrounding structures. We also summarize crucial anatomic factors that should be taken into account by the interventional cardiologist when planning for or performing left atrial appendage exclusion procedures. PMID- 29526288 TI - The WATCHMAN Left Atrial Appendage Closure Device: Technical Considerations and Procedural Approach. AB - Randomized clinical trials have demonstrated that left atrial appendage (LAA) closure with the WATCHMAN device provides stroke prevention in nonvalvular atrial fibrillation while significantly reducing morality and major bleeding. Technical and procedural considerations are paramount for the therapeutic success. Maximizing procedural safety is critical. Optimal LAA sealing is required. Improvements in procedural technique and operator training have resulted in a marked reduction in adverse procedural events, which should increase the absolute long-term clinical benefit. This article outlines the key aspects of patient workup and procedural technique for the best possible outcome. PMID- 29526289 TI - The Amplatzer Amulet Device: Technical Considerations and Procedural Approach. AB - Percutaneous left atrial appendage occlusion (LAAO) for stroke prevention in patients with atrial fibrillation has significantly advanced in the past 2 decades. LAAO has emerged as a feasible and safe alternative to oral anticoagulants in patients who are deemed high risk for bleeding or are ineligible to receive anticoagulation. Herein, the authors review the main design features of the AMPLATZER Amulet device and describe step-by-step technical considerations for implantation of this LAAO device. PMID- 29526290 TI - Echocardiographic Imaging for Left Atrial Appendage Occlusion: Transesophageal Echocardiography and Intracardiac Echocardiographic Imaging. AB - Left atrial appendage occlusion (LAAO) is a rapidly evolving technology. Multi modality imaging and understanding of left atrial appendage anatomy are sure to advance. Two-dimensional and 3-dimensional transesophageal echocardiography with fluoroscopy are the mainstay for LAAO image-guided therapy. Key to successful LAAO is an understanding of the transseptal puncture, LAAO size selection for the device-specific landing zone, and postdeployment evaluation for leak and complications. With advancements in computed tomography, there may be a greater role for intracardiac echocardiographic imaging in specific types of LAAO anatomy and devices. PMID- 29526291 TI - Cardiac Computed Tomography for Left Atrial Appendage Occlusion: Acquisition, Analysis, Advantages, and Limitations. AB - Transcatheter left atrial appendage occlusion is increasingly used for stroke prevention in atrial fibrillation. The technique has proven effective and safe in randomized trials and multiple observational studies. The procedure is challenging due to the complex anatomy of the left atrial appendage; accurate cardiac imaging is essential for procedural guidance. Transesophageal echocardiography is the gold standard, but cardiac computed tomography (CT) has gained increasing interest within recent years. Cardiac CT offers high-resolution imaging allowing for preprocedural anatomic evaluation and device sizing, but may also be useful for exclusion of left atrial appendage thrombus, and follow-up assessment of residual peri-device leaks. PMID- 29526292 TI - Incidence, Prevention, and Management of Periprocedural Complications of Left Atrial Appendage Occlusion. AB - Major procedural complications related to left atrial appendage occlusion (LAAO) are relatively infrequent but may be associated with major morbidity and mortality. LAAO operators should be knowledgeable about these potential complications. Prompt recognition and treatment are necessary to avoid rapid deterioration and dire consequences. With stringent guidelines on operator training, competency requirements, and procedural-technical refinements, LAAO can be performed safely with low complication rates. This article focuses on commonly used devices, as well as prevention, treatment, and management of complications of LAOO. PMID- 29526293 TI - Left Atrial Appendage Occlusion: The Current Device Landscape and Future Perspectives. AB - Since the first percutaneous left atrial appendage occlusion (LAAO), many studies have shown the safety and efficacy of this technique to prevent embolic strokes in nonvavular atrial fibrillation. The design, characteristics, and clinical data of the most frequently used devices for LAAO are reviewed, including the Amplatzer cardiac plug and Amulet (Abbott Vascular), the Watchman (Boston Scientific), and the LARIAT device (SentreHEART). Similarly, newer closer devices, such as Ultraseal (Cardia), LAmbre (Lifetech), and Coherex WaveCrest (Johnson & Johnson), are also discussed. Finally, new technologies still in the stage of preclinical study or in the initial clinical experience are also reviewed. PMID- 29526294 TI - Left Atrial Appendage Occlusion, Shared Decision-Making, and Comprehensive Atrial Fibrillation Management. AB - The epidemic of atrial fibrillation (AF) requires a comprehensive management strategy that uses the full force of available data and technology, including anticoagulation, ablative therapy, and left atrial appendage occlusion. Patient centered care with an emphasis on shared decision-making is particularly relevant to the authors' understanding of the complexity of AF and has helped them tailor therapy in this ever-growing patient population. PMID- 29526295 TI - Left Atrial Appendage Occlusion for Stroke Prevention in Patients with Atrial Fibrillation. PMID- 29526296 TI - A packet-based dual-rate PID control strategy for a slow-rate sensing Networked Control System. AB - This paper introduces a packet-based dual-rate control strategy to face time varying network-induced delays, packet dropouts and packet disorder in a Networked Control System. Slow-rate sensing enables to achieve energy saving and to avoid packet disorder. Fast-rate actuation makes reaching the desired control performance possible. The dual-rate PID controller is split into two parts: a slow-rate PI controller located at the remote side (with no permanent communication to the plant) and a fast-rate PD controller located at the local side. The remote side also includes a prediction stage in order to generate the packet of future, estimated slow-rate control actions. These actions are sent to the local side and converted to fast-rate ones to be used when a packet does not arrive at this side due to the network-induced delay or due to occurring dropouts. The proposed control solution is able to approximately reach the nominal (no-delay, no-dropout) performance despite the existence of time-varying delays and packet dropouts. Control system stability is ensured in terms of probabilistic Linear Matrix Inequalities (LMIs). Via real-time control for a Cartesian robot, results clearly reveal the superiority of the control solution compared to a previous proposal by authors. PMID- 29526297 TI - Tuning strategy for dynamic matrix control with reduced horizons. AB - In Dynamic Matrix Control (DMC) algorithm, the control signal is computed optimally based on the process model. In effect, the DMC algorithm allows for obtaining a better quality of control than conventional controllers, especially for plants with large time delays. However, in spite of these advantages, there are still some difficulties that can appear in the implementation of DMC in local control loops. This is due to limitations of the computational resources in industrial devices (e.g., Programmable Logic Controllers). To overcome these difficulties, we propose a tuning strategy for the DMC algorithm with reduced horizons. It is shown that a reduction in the length of prediction and dynamic horizons can reduce the required memory in industrial controllers without degrading the quality of control. PMID- 29526298 TI - A CAD-CAM technique for conversion of interim-to-definitive restoration in patients with complete edentulism. AB - An interim restoration is a prototype for the definitive prosthesis and preserves the occlusal information and the original vertical dimension of the occlusion. Several techniques have been developed to transfer the information from implant supported fixed interim to definitive restoration. However, these conventional techniques have limitations, and they are time-consuming, require making impressions and stone casts, and mounting in an articulator. The purpose of this article was to describe a digital technique to accurately transfer the information from complete-arch implant interim restoration to definitive restorations without using definitive casts. PMID- 29526299 TI - Fabricating a custom zirconia post-and-core without a post-and-core pattern or a scan post. AB - Due to the increased esthetic demands, custom zirconia post-and-cores have recently become popular. A post-and-core pattern with acrylic resin or wax is scanned using a laboratory scanner for the design of a definitive post-and-core restoration. This procedure requires additional time and material handling experience. If a scan post is used for an intracanal digital scan, substantial initial investments for hardware and software are required. This article introduces an alternative technique for fabricating a custom zirconia post-and core with a conventional impression. By using this technique, a properly fitted zirconia post-and-core is quickly and easily fabricated with less human error. PMID- 29526300 TI - Defining centric relation. AB - STATEMENT OF PROBLEM: Multiple definitions of centric relation (CR) have evolved over time that may have created confusion or impeded understanding. A recent attempt to achieve a singular definition by surveying the members of the Academy of Prosthodontics (AP) did not achieve majority consensus. PURPOSE: The purpose of this study was to identify those aspects or attributes within the existing definitions of CR in which there was agreement or disagreement among the members of the AP. MATERIAL AND METHODS: After pretesting and institutional review board approval, a second survey of the AP membership was performed using both email and postal mail survey methods of contact. The CR Attributes Survey separated and stratified the previous definitions of CR into 5 domains: spatial relationship, condylar position, articular disks, mandibular movement, and recording. Each domain attribute was evaluated by agree-uncertain-disagree assessments. Also recorded were demographics, perception of scientific evidence, and open comments. RESULTS: Of the total 146 fellows, 100 completed the survey for an overall response rate of 68.5%. The query completion rate ranged from 96% to 98%. The CR Attributes Survey revealed those components within each domain in which there was strong agreement, disagreement, or uncertainty. The survey assessment of those queries with a moderate to strong agreement were that CR is a "spatial relationship" that is (1) a clinically determined relationship of the mandible to the maxilla, (2) a repeatable position, (3) is independent of tooth contact, and (4) is a physiologic position. Relative to "disks," the condyles articulate with the thinnest avascular intermediate zone of their respective disks; however, there is a lack of sufficient evidence to determine the position of the disks and the condyles. Relative to "mandibular movement," CR is (1) a starting point for vertical, lateral, or protrusive movements, (2) is where the individual can make to and from lateral movements, and (3) is restricted to pure rotary movement about a transverse horizontal axis. Relative to "recording CR" (1) it can be determined in patients without pain or derangement of the temporomandibular joints (TMJs), (2) but may not be recordable in the presence of dysfunction of the masticatory system, or (3) due to the neuromuscular influence or proprioception from the dentition, (4) is a clinical useful repeatable reference position for mounting casts, or (5) for developing a functional treatment occlusion, (6) at an established vertical dimension, and (7) may vary slightly by recording method. CONCLUSIONS: The CR Attributes Survey revealed a majority agreement or consensus for various CR attributes that should be considered for defining the term 'centric relation.' In contrast, those CR attributes with a plurality agreement, disagreement, or uncertainty outcomes should be considered for exclusion. The evaluated weakness of these latter attributes indicates the need for further research and reassessment. PMID- 29526301 TI - Digital design of patient-specific abutments for the retention of implant retained facial prostheses. AB - The present report describes the digital design of patient-specific milled abutments for the retention of osseointegrated facial prostheses by using digital technology. Patient imaging including surface scans of the patient's head, scans of the patient's definitive cast, and digitally designed prosthesis prototypes were combined to create a digital simulation of the patient. Using this simulation, patient-specific abutments were digitally designed, printed in 3 dimensions (3D), and finally copy-milled in titanium. This process provided the patient with an optimal abutment design for prosthetic retention, hygiene control, and skin emergence profile. PMID- 29526302 TI - Effect of number of pontics and impression technique on the accuracy of four-unit monolithic zirconia fixed dental prostheses. AB - STATEMENT OF PROBLEM: Because of their relatively small scanning area, intraoral scanners may result in less accurate fixed dental prostheses (FDPs) than do laboratory scanners. PURPOSE: The purpose of this in vitro study was to evaluate the accuracy of monolithic zirconia FDPs with different numbers of pontics fabricated with different impression techniques. MATERIAL AND METHODS: The mandibular right premolars and molars of an acrylic resin model were prepared to receive 4-unit FDPs. Three master models were fabricated with epoxy resin: model NP, no pontic; model 1P, 1 pontic; and model 2P, 2 pontics. Each master model was scanned by using direct (DD) and indirect digitalization (ID). Four-unit monolithic zirconia FDPs were fabricated and divided into 3 groups (groups NP, 1P, and 2P) and then subdivided according to the digitalization technique (group DD and ID; n=10). The FDPs were also evaluated based on the presence (Po) or absence (NPo) of an adjacent pontic. The marginal, axial, and occlusal gap widths of each FDP were measured, and statistical analyses were performed to evaluate and compare the amount of gap present (alpha=.05). RESULTS: For direct digitalization, group 2P had significantly greater marginal (69.4 MUm versus 60.9 MUm or 62.3 MUm; P<.001) and axial gap widths (127.1 MUm versus 108.9 MUm or 110.4 MUm; P<.001) than group NP or 1P. Group DD resulted in significantly smaller gaps compared with group ID at marginal (64.8 MUm versus 73.6 MUm), axial (114.8 MUm versus 124.3 MUm), and occlusal (172.6 MUm versus 184.1 MUm) measurement locations (P<.001). Greater marginal and axial gaps were noted in group Po than NPo (P<.001). CONCLUSIONS: The length of the edentulous area significantly influenced the extent of the marginal and internal gap with the use of direct digitalization. Direct digitalization resulted in significantly smaller gap widths in all measurement areas than indirect digitalization; however, the mean differences were less than 12 MUm, which is considered clinically insignificant. The presence of an adjacent pontic had a significant effect on the adjacent marginal and axial gap widths. PMID- 29526303 TI - A technique to facilitate ceramic veneer cementation. AB - This report describes a technique to facilitate ceramic veneer cementation. By stabilizing a ceramic veneer in its fully seated position with miniature wooden spring clips before resin polymerization, excess luting resin cement can be removed from ceramic veneer margins without the risk of veneer dislodgement or fracture. PMID- 29526304 TI - Corrigendum to "Single-Molecule Fluorescence Reveals the Oligomerisation and Folding Steps Driving the Prion-like Behaviour of ASC" [J. Mol. Biol. 430 (4) (February 16, 2018) 491-508]. PMID- 29526305 TI - Editorial overview: Biocatalysis and biotransformation: The golden age of biocatalysis. PMID- 29526306 TI - Editorial overview: Bioinorganic chemistry: Bio-medicinal functions of metal complexes. PMID- 29526307 TI - Effectiveness in the treatment of solar urticaria with omalizumab: Report of 7 cases. PMID- 29526308 TI - Primary bone lymphoma: report of 7 cases. PMID- 29526309 TI - Primary biliary cholangitis. AB - Primary cholangitis (cirrhosis) is a chronic cholestatic disease with an unquestionable female predominance. It is characterised by inflammation of the small and medium size bile ducts, and can eventually progress to cirrhosis. Most patients remain asymptomatic and are diagnosed by the casual finding of an anicteric biochemical cholestasis with increased alkaline phosphatase. The pathogenesis is unknown and of presumed autoimmune origin in genetic susceptible subjects. M2-type antimitochondrial antibodies, and specific antinuclear antibodies (gp210 and Sp100) are typical and specific of the disease. The positivity of these antibodies and a biochemical cholestasis are sufficient for diagnosis, without the need for liver biopsy. Ursodeoxycholic acid is the specific treatment with an excellent response in more than 60% of patients. When this optimal response is not observed, it can be combined with new agents, but those that have shown to be effective are those that improve cholestasis such as fibrates and obeticholic acid. PMID- 29526310 TI - Pulmonary arterial hypertension associated to systemic erythematosus lupus: molecular characterization of 3 cases. AB - BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension associated with systemic lupus erythematosus (PAH-SLE) is a rare disease with a low incidence rate. In this study, PAH related genes and genetic modifiers were characterised molecularly in patients with PAH-SLE. PATIENTS AND METHODS: Three patients diagnosed with PAH-SLE and 100 control individuals were analysed after signing an informed consent. RESULTS: Two out of the three analysed patients with PAH-SLE were carriers of pathogenic mutations in the genes BMPR2 and ENG. After an in silico analysis, pathogenic mutations were searched for in control individuals and different databases, with negative results, and they were thus functionally analysed. The third patients only showed polymorphisms in the genes BMPR2, ACVRL1 and ENG. Several genetic variants and genetic modifiers were identified in the three analysed patients. These modifiers, along with the pathogenic mutations, could lead to a more severe clinical course in patients with PAH. CONCLUSIONS: We present, for the first time, patients with PAH-SLE carrying pathogenic mutations in the main genes related to PAH and alterations in the genetic modifiers. PMID- 29526311 TI - Ischaemic stroke in a post-surgical patient after replacement of a parenteral nutrition bag. PMID- 29526312 TI - Guillain-Barre syndrome and hyponatraemia. PMID- 29526313 TI - Alzheimer disease triggered by reversible posterior leukoencephalopathy syndrome. PMID- 29526314 TI - A novel pathogenic variant of the SPAST gene in a Spanish family with hereditary spastic paraplegia. PMID- 29526315 TI - Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients. AB - INTRODUCTION: Numerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis. METHODS: We performed a case-control study of consecutive ischaemic stroke survivors aged <= 45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction-restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4G/5G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke. RESULTS: 204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P=.03), tobacco use (P=.02), and the polymorphisms Glu298Asp (genotype: P=.001, allele frequency: P=.001) and C677T (genotype: P=.01); the Ala147Thr, Thr325IIe, 4G/5G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P=.03) and T (P=.01) alleles, hypertension (P=.03), tobacco use (P=.01) and family history of stroke (P=.04) were identified as independent risk factors. CONCLUSIONS: The polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4G/5G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors. PMID- 29526316 TI - Echocardiographic parameters of atrial cardiopathy and the detection of atrial fibrillation in patients with cryptogenic stroke. PMID- 29526317 TI - Hyperuricaemia as a prognostic factor for acute ischaemic stroke. AB - INTRODUCTION: Recent studies on uric acid as a biomarker for the prognosis of acute stroke have found conflicting results. METHODS: We collected blood samples from 600 consecutively admitted patients at our tertiary hospital and analysed the relationship between uric acid levels and functional prognosis (measured using the modified Rankin Scale [mRS]). Patients who had received reperfusion therapy were excluded since this may have influenced uric acid levels. RESULTS: A total of 73% of patients had mRS scores <=2; the mean uric acid level was 5.22mg/dL. We found a nonlinear relationship between functional prognosis at discharge and serum uric acid levels at admission when the National Institutes of Health Stroke Scale score was excluded from the analysis. CONCLUSIONS: Serum uric acid levels in patients with acute ischaemic stroke are significantly associated with functional prognosis at discharge, although this relationship is nonlinear. In fact, poorer prognosis is associated both with very low and with very high concentrations of uric acid. This suggests a dual role of uric acid in relation to stroke: on the one hand, as an associated risk factor, and on the other, as a possible neuroprotective factor due to its antioxidant effect. PMID- 29526318 TI - A comparative study of melatonin and immunomodulatory therapy with interferon beta and glatiramer acetate in a mouse model of multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system causing neuroinflammation. Experimental autoimmune encephalitis (EAE) is a model of the disease. MS is classically treated with interferon beta (IFN-beta) and glatiramer acetate (GA). Melatonin (MLT) has been reported to modulate immune system responses. The aim of the present study is to analyse the effects of MLT administration in comparison with the first-line treatments for MS (IFN-beta and GA). METHODS: EAE was induced in male Sprague-Dawley rats; the animals subsequently received either IFN-beta, GA, or MLT. Cerebrospinal fluid (CSF) samples were analysed by multiplex assay to determine the levels of proinflammatory cytokines. The neurological evaluation of EAE was also recorded. RESULTS: All immunised animals developed EAE. We evaluated the first relapse-remission cycle, observing that IFN-beta and GA had better results than MLT in the clinical evaluation. Neither EAE nor any of the treatments administered modified CSF IL-1beta and IL-12p70 concentrations. However, IFN-beta and MLT did decrease CSF TNF-alpha concentrations. CONCLUSIONS: Further studies are needed to evaluate the molecular mechanisms involved in the behaviour of MLT in EAE, and to quantify other cytokines in different biological media in order for MLT to be considered an anti-inflammatory agent capable of regulating MS. PMID- 29526319 TI - Consensus on the diagnosis, treatment and follow-up of patients with Duchenne muscular dystrophy. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is the most common myopathy in children, with a worldwide prevalence of approximately 0.5 cases per 10,000 male births. It is characterised by a progressive muscular weakness manifesting in early childhood, with the subsequent appearance of musculoskeletal, respiratory, and cardiac complications, causing disability, dependence, and premature death. Currently, DMD is mainly managed with multidisciplinary symptomatic treatment, with favourable results in terms of the progression of the disease. It is therefore crucial to establish clear, up-to-date guidelines enabling early detection, appropriate treatment, and monitoring of possible complications. DEVELOPMENT: We performed a literature search of the main biomedical databases for articles published in the last 10years in order to obtain an overview of the issues addressed by current guidelines and to identify relevant issues for which no consensus has yet been established. The degree of evidence and level of recommendation of the information obtained were classified and ordered according to the criteria of the American Academy of Neurology. CONCLUSIONS: DMD management should be multidisciplinary and adapted to the patient's profile and the stage of clinical progression. In addition to corticotherapy, treatment targeting gastrointestinal, respiratory, cardiac, and orthopaedic problems, as well as physiotherapy, should be provided with a view to improving patients' quality of life. Genetic studies play a key role in the management of the disease, both in detecting cases and potential carriers and in characterising the mutation involved and developing new therapies. PMID- 29526320 TI - Optic neuritis in paediatric patients: Experience over 27 years and a management protocol. AB - INTRODUCTION AND OBJECTIVE: In this article, we present our experience on optic neuritis (ON) and provide a diagnostic/therapeutic protocol, intended to rule out other aetiologies (particularly infection), and a fact sheet for parents. MATERIAL AND METHODS: We conducted a descriptive, retrospective study of patients with ON over a 27-year period (1990-2017). A review of the available scientific evidence was performed in order to draft the protocol and fact sheet. RESULTS: Our neuropaediatrics department has assessed 20,744 patients in the last 27 years, of whom 14 were diagnosed with ON: 8 had isolated ON, 1 had multiple sclerosis (MS), 1 had clinically isolated syndrome (CIS), 3 had acute disseminated encephalomyelitis, and 1 had isolated ON and a history of acute disseminated encephalomyelitis one year previously. Patients' age range was 4-13 years; 50% were boys. Eight patients were aged over 10: 7 had isolated ON and 1 had MS. Nine patients had bilateral ON, and 3 had retrobulbar ON. MRI results were normal in 7 patients and showed involvement of the optic nerve only in 2 patients and optic nerve involvement + central nervous system demyelination in 5. Thirteen patients received corticosteroids. One patient had been vaccinated against meningococcus-C the previous month. Progression was favourable, except in the patient with MS. A management protocol and fact sheet are provided. CONCLUSIONS: ON usually has a favourable clinical course. In children aged older than 10 years with risk factors for MS or optic neuromyelitis (hyperintensity on brain MRI, oligoclonal bands, anti-NMO antibody positivity, ON recurrence), the initiation of immunomodulatory treatment should be agreed with the neurology department. The protocol is useful for diagnostic decision-making, follow-up, and treatment of this rare disease with potentially major repercussions. The use of protocols and fact sheets is important. PMID- 29526321 TI - Incidence of Guillain-Barre syndrome during the Zika virus outbreak. PMID- 29526322 TI - Glycosylation controls sodium-calcium exchanger 3 sub-cellular localization during cell cycle. AB - The Na+/Ca2+ exchanger (NCX) is a membrane antiporter that has been identified in the plasma membrane, the inner membrane of the nuclear envelope and in the membrane of the endoplasmic reticulum (ER). In humans, three genes have been identified, encoding unique NCX proteins. Although extensively studied, the NCX's sub-cellular localization and mechanisms regulating the activity of different subtypes are still ambiguous. Here we investigated the subcellular localization of the NCX subtype 3 (NCX3) and its impact on the cell cycle. Two phenotypes, switching from one to the other during the cell cycle, were detected. One phenotype was NCX3 in the plasma membrane during S and M phase, and the other was NCX3 in the ER membrane during resting and interphase. Glycosylation of NCX3 at the N45 site was required for targeting the protein to the plasma membrane, and the N45 site functioned as an on-off switch for the translocation of NCX3 to either the plasma membrane or the membrane of the ER. Introduction of an N glycosylation deficient NCX3 mutant led to an arrest of cells in the G0/G1 phase of the cell cycle. This was accompanied by accumulation of de-glycosylated NCX3 in the cytosol (that is in the ER), where it transported calcium ions (Ca2+) from the cytosol to the ER. These results, obtained in transfected HEK293T and HeLa and confirmed endogenously in SH-SY5Y cells, suggest that cells can use a dynamic Ca2+ signaling toolkit in which the NCX3 sub-cellular localization changes in synchrony with the cell cycle. PMID- 29526323 TI - Narrative review of pediatric critical care humanization: Where we are? AB - The humanization of care emerges as a response to something that seems indisputable: the scientific and technological developments in Intensive Care Units. Such development has improved the care of the critically ill patient in quantitative terms, but has perhaps caused the emotional needs of patients, families and professionals to be regarded as secondary concerns. The humanization of healthcare should be discussed without confusing or discussing the humanity displayed by professionals. In this paper we review and describe the different strategic lines proposed in order to secure humanized care, and adopt a critical approach to their adaptation and current status in the field of pediatric critical care. PMID- 29526324 TI - Morphologic, digestive enzymes and immunological responses of intestine from Litopenaeus vannamei after lipopolysaccharide injection. AB - The shrimp intestine barrier serves as the first line of the host defense against pathogen infection. Lipopolysaccharide (LPS) is the cell wall component of gram negative bacteria, which known as endotoxin and induce the intestine inflammation. In this study, the acute toxicity effects of LPS injection on the morphology, digestive enzymes and immunological responses of intestine from Litopenaeus vannamei was investigated. HE stain showed that LPS injection damaged the intestine connective and epithelium tissue. Specifically, a decrease in the activities of digestive enzymes including of amylase, lipase, trypsin and pepsin was observed. Moreover, LPS injection increased the content of oxidative stress parameters (O2- generation capacity, LPO, MDA and PC), and the expression of HIF 1alpha gene. Alternatively, the antibacterial activities (PO and T-NOS), and the expression of the antibacterial genes (proPO, ALF, Toll and Imd) and pathogen pattern recognition genes (LGBP and Lec) increased at first and then decreased. Significant variations in anitioxidant enzyme activity of T-AOC, and the expression of the anitioxidant-related genes (SOD, HSP70 and Trx). These results revealed that LPS injection harmed the intestine barrier of L. vannamei by damaging intestine mucosal structure, increasing oxidative stress, and suppressing the digestive and immune status. PMID- 29526325 TI - Prevention and treatment of the chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon and late complication of pulmonary embolism resulting from misguided remodelling of residual pulmonary thromboembolic material and small-vessel arteriopathy. CTEPH is the only form of pulmonary hypertension (PH) potentially curable by pulmonary endarterectomy (PEA). Unfortunately, several patients have either an unacceptable risk-benefit ratio for undergoing the surgical intervention or develop persistent PH after PEA. Novel medical and endovascular therapies can be considered for them. The soluble guanylate cyclase stimulator riociguat is recommended for the treatment of patients with inoperable disease or with recurrent/persistent PH after PEA. Other drugs developed for the treatment of other forms of PH, as prostanoids, phosphodiesterase-5 inhibitors and endothelin receptor antagonists have been used in the treatment of CTEPH, with limited benefit. Balloon pulmonary angioplasty is a novel and promising technique and is progressively emerging from the pioneering phase. Highly specialized training level and complex protocols of postoperative care are mandatory to consolidate the technical success of the surgical and endovascular intervention. PMID- 29526326 TI - [Authors' response]. PMID- 29526327 TI - [Induced drug uveitis and drug side effects in ophthalmology]. AB - Ocular drug side effects are very varied and can affect all the structures of the eye. The purpose of this review is to help clinicians: (i) to evoke this drug induced toxicity yearly in the course of an unexplained ocular injury, before its damage become irreversible, (ii) to be able to recognize induced paradoxical ocular inflammation, mimicking an inflammatory pathology flare-up, especially in patient under anti-TNF regimen and (iii) to propose a more in-depth knowledge on recently described ocular toxicities from targeted cancer therapy, mainly the tyrosine kinase inhibitors. PMID- 29526328 TI - [Gastroparesis may be the cause of unexplained dyspepsia in patients with primary Sjogren syndrome]. AB - INTRODUCTION: Upper digestive symptoms may be present in up to 50% of patients with primary Sjogren syndrome (pSS). We report a retrospective cohort of gastroparesis in a population of pSS presenting unexplained dyspepsia. Delayed gastric emptying was defined by a gastric emptying time above 113min or by a retention percentage at 4h more than 10% on scintigraphy. RESULTS: Eleven patients with primary Sjogren syndrome and gastroparesis were included in a retrospective study. Every patients were women of age 48+/-18y. The average time of gastric emptying was 725,18+/-704,45min. 64% of patients had abdominal pain or gastric heaviness. A central or peripheral neurologic involvement was described in respectively 9 and 27% of cases. The diagnostic delay of gastroparesis was higher than 24 months. CONCLUSION: In primary Sjogren syndrome, gastroparesis should be suspected in case of unexplained dyspepsia, and a scintigraphy performed to prove the diagnosis. A neurologic involvement could explain gastroparesis, but prospective studies are needed for a better understanding of this disorder. PMID- 29526329 TI - [Familial Mediterranean fever]. AB - Familial Mediterranean Fever (FMF) is the most frequent monogenic auto inflammatory disease. FMF is an autosomal recessive disease, which affects populations from Mediterranean origin and is associated with MEFV gene mutations encoding for the protein pyrin. Pyrin activation enhances the secretion of interleukin 1 by myelo-monocytic cells. Main features of the disease are acute attacks of serositis mainly located on the abdomen, less frequently on chest and joints, accompanied by fever and biological inflammatory markers elevation. Usually attacks last 1 to 3 days and spontaneously stop. A daily oral colchicine intake of 1 to 2mg/day is able to prevent attack's occurrence, frequency, intensity and duration among most patients. Colchicine is also able to prevent the development of inflammatory amyloidosis, the most severe complication of FMF. This state of the art article will focus on the diagnosis of FMF, the treatment and an update on the pathophysiology including the recent described dominant form of MEFV-associated new auto-inflammatory diseases. PMID- 29526330 TI - Reducing Hypotension and Acute Kidney Injury in the Elective Total Joint Arthroplasty Population: A Multi-Disciplinary Approach. AB - BACKGROUND: When critically analyzing our hospital system's rate of hypotension and acute kidney injury (AKI) after total joint arthroplasty, our incidence rates (14.54%, 6.02%) were much higher than our peers (7.17%, 2.03%) and national rates (2.0%, 3.3%). We present a multi-disciplinary management intervention that aimed to decrease overall complication rates. METHOD: A multi-disciplinary team implemented a protocol at our suburban hospital to limit complication rates after joint replacement surgery. Hypotension, AKI, length of stay (LOS), re-admission rates, and mortality rates were compared before the protocol was implemented, after protocol implementation, and after protocol integration into our EMR (electronic medical record). RESULTS: In total, 1233 patients over 36 months were followed. Hypotension rates after protocol implementation into EMR (group 3) were significantly lower than rates before the protocol (group 1) (P = .002), with rates after protocol implementation without EMR (group 2) trending toward a significant decrease from group 1 (P = .064). AKI rates in group 3 were significantly lower than group 1 (P = .000) and group 2 (P = .006). No difference was seen in hypotension rates between group 2 and 3 (P = .792) or AKI rates between group 1 and 2 (P = .533). Finally, no significant difference was seen between groups in LOS (P = .560), re-admission rates (P = .378), and mortality rates (all 0.0%). CONCLUSION: By implementing a comprehensive electronic protocol consisting of pre-operative risk stratification, multi-disciplinary medical optimization, and an evolving post-operative management plan, significant decreases in hypotension and AKI can be seen. PMID- 29526331 TI - Nephrotoxicity After the Treatment of Periprosthetic Joint Infection With Antibiotic-Loaded Cement Spacers. AB - BACKGROUND: Treatment of periprosthetic joint infections commonly involves insertion of an antibiotic-loaded cement spacer (ACS). The risk for acute kidney injury (AKI) related to use of antibiotic spacers has not been well defined. We aimed to identify the incidence of and risk factors for AKI after placement of an ACS. METHODS: We performed a prospective cohort study of patients with an infected primary total hip or knee arthroplasty treated with ACSs with vancomycin, gentamicin, and tobramycin. Serum creatinine and glomerular filtration rate data were collected at baseline and weekly intervals for 8 weeks. Patients were classified into Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) stages to determine incidence of AKI. Risk factors for kidney injury were identified via regression analysis. RESULTS: A total of 37 patients (20 total knee arthroplasty and 17 total hip arthroplasty) were included. During the 8 weeks after ACS placement, 10 patients (27%) fit RIFLE criteria for kidney injury and 2 patients (5%) fit RIFLE criteria for kidney failure. No baseline patient characteristics were associated with development of AKI. CONCLUSION: Patients should be monitored closely for development of AKI after placement of ACSs for the treatment of periprosthetic joint infection. Further research into minimizing risk for AKI is warranted. PMID- 29526332 TI - Total Joint Arthroplasty in Patients With Schizophrenia: How Much Does It Increase the Risk of Complications? AB - BACKGROUND: Mental illness is an often overlooked comorbidity in the total joint arthroplasty (TJA) population. The purpose of this study was to evaluate the risk of schizophrenia on the outcomes of TJA. METHODS: The nationwide inpatient sample was used to identify a cohort of 505,840 patients having total hip arthroplasty between 2009 and 2012, of which 953 patients (0.2%) had been diagnosed with schizophrenia. Multivariate logistic regression was used to identify the impact of schizophrenia on short-term medical and surgical complications. Differences in length of stay and discharge disposition were also compared. RESULTS: Schizophrenic patients are 15 times more likely to have pulmonary insufficiency after surgery (odds ratio [OR] 15.1, P = .0133). Patients were 11 times more likely to have mental status changes (OR 11.1, P = .0002), 3 times more likely to have a mechanical complication of the implant (OR 3.2, P = .0031), and 2 times more likely to require a transfusion (OR 2.4, P < .0001). All-cause medical (OR 2.2, P < .0001) and surgical (OR 1.5, P < .0001) complications were higher in schizophrenic patients. Patients stayed 0.63 days longer in the hospital (P < .0001), and were 3 times more likely to discharge to a facility (OR 2.7, P < .0001). CONCLUSIONS: TJA in patients with schizophrenia had markedly increased complications. Particularly, pulmonary complications, mechanical complications of the implant, mental status changes, and transfusion rates were higher. Future risk adjustment models should include schizophrenia as a major contributor to increased complications. PMID- 29526333 TI - Incidence and Circumstances of Falls in Women Before and After Total Hip Arthroplasty: A Prospective Cohort Study. AB - BACKGROUND: We investigated the incidence and circumstances related to falls in patients before and after total hip arthroplasty (THA), and compared them with those in an age-matched control group. METHODS: This is a prospective cohort study. A total of 140 women with severe hip osteoarthritis (OA) who underwent THA (OA group) and a control cohort of 319 age-matched healthy women were analyzed. We investigated the incidence and circumstances of falls before THA and during the first year after surgery. We assessed the Harris Hip Score and investigated hip pain and ambulatory ability using a self-administered questionnaire. RESULTS: The incidence of at least one fall during the first year after THA in the OA group (30.0%) was significantly higher than that in the control group (13.5%) (P < .001), as were the rates of indoor falls (50.0%) and falls during daytime (66.2%). Although the incidence of fall-induced injuries after THA (37.8%) was significantly lower than that in the control group (62.5%), 5.9% of patients who experienced a fall developed a fracture. No significant differences were found in the number and circumstances of falls before and after THA, with 31.4% and 30.0% of the OA group reporting at least one fall in the 12 months before and after surgery, respectively. Self-reported pain, ambulation, and Harris Hip Score significantly improved after THA. CONCLUSION: Women undergoing THA have an increased risk of falls during the first year after surgery. Clinicians should suggest preventive measures during rehabilitation to prevent falling in post-THA women. PMID- 29526334 TI - Higher Prevalence of Mixed or Solid Pseudotumors in Metal-on-Polyethylene Total Hip Arthroplasty Compared With Metal-on-Metal Total Hip Arthroplasty and Resurfacing Hip Arthroplasty. AB - BACKGROUND: Pseudotumors are a common finding in metal-on-metal (MoM) total hip arthroplasty (THA) and resurfacing hip arthroplasty (RHA). However, information on pseudotumors in metal-on-polyethylene (MoP) THA is limited. METHODS: One hundred eleven patients with 148 hip articulations-30 MoM THA, 47 MoM RHA, and 71 MoP THA-participated in a cross-sectional study at mean 7.1 (range: 0.2-21.5) years postoperatively. Patients were evaluated with metal artifact reducing sequence magnetic resonance imaging, measurements of metal ions, clinical scores of Harris Hip Score, Oxford Hip Score, the Copenhagen Hip and Groin Outcome Score, and conventional radiographs. RESULTS: Pseudotumors were present in 13 of 30 (43%) MoM THA, 13 of 47 (28%) MoM RHA, and 29 of 71 (41%) MoP THA patients, which was a similar prevalence (P = .10). The prevalence of mixed or solid pseudotumors was significantly higher in patients with MoP THA (n = 10) compared to MoM THA (n = 3) and MoM THA (n = 0), (P = .01). Hips with a mixed or solid pseudotumor had significantly poorer scores of Harris Hip Score (P = .01) and OHS (P = .002) and higher metal ion levels of cobalt (P = .0009) compared to hips without a pseudotumor or with a cystic pseudotumor. CONCLUSION: Pseudotumors have primarily been associated with MoM hip articulations, but we found a similar pseudotumor prevalence in MoP THA, which is the most common bearing worldwide. Mixed or solid pseudotumors were more often seen in MoP THA compared with MoM hip articulations, and patients with a mixed or solid pseudotumor had poorer clinical scores and higher metal ion levels than patients without a pseudotumor or with a cystic pseudotumor. PMID- 29526335 TI - Ninety-Day Costs, Reoperations, and Readmissions for Primary Total Knee Arthroplasty Patients With Varying Body Mass Index Levels. AB - BACKGROUND: We compared 90-day costs and outcomes for primary total knee arthroplasty patients among nonobese (body mass index [BMI] 18.5-24.9), overweight (25-29.9), obese (30-34.9), severely obese (35-39.9), morbidly obese (40-49.9), and super-obese (50+) cohorts. METHODS: We conducted a retrospective review of an institutional database of total knee arthroplasty patients from 2006 to 2013 with a minimum of 3-year follow-up. Sixty-five super-obese patients were identified, and five other cohorts were randomly selected in a 2:1 ratio (total, n = 715). Demographics, 90-day outcomes (costs, reoperations, and readmissions), and outcomes after 3 years (revisions and change scores for Short-Form Health Survey [SF-12], Knee Society Scores, and Western Ontario and McMaster Universities Arthritis Index) were aggregated. RESULTS: The 90-day costs were significantly greater in the morbidly obese ($11,568 +/- $1,960) and super-obese ($14,021 +/- $7,903) cohorts relative to the smaller BMI cohorts ($9,938 - $10,352). The increased cost from readmissions was the main driver of costs. The outcome change scores were similar across all the BMI cohorts for Knee Society Scores, SF-12 Mental Health Composite Score, and Western Ontario and McMaster Universities Arthritis Index, but not for the SF-12 Physical Health Composite Score. At the midterm follow-up, there was no statistical difference in repeat surgery or aseptic revision rates. Septic revisions were significantly greater in the super-obese cohort relative to the other cohorts (6.2% vs 0.8-3.1%). CONCLUSION: Health-care policy based purely on the economic costs may place morbidly obese and super-obese patients at risk of losing arthroplasty care, thereby denying them access to the comparable quality of life improvements. PMID- 29526336 TI - Do Mortality and Complication Rates Differ Between Periprosthetic and Native Hip Fractures? AB - BACKGROUND: Epidemiological estimates indicate a rising incidence of periprosthetic hip fractures. While native hip fractures are known to be a highly morbid condition, a significant body of research has led to improved outcomes and decreased complications following these injuries. Comparatively, little research has evaluated the relative morbidity and mortality of periprosthetic hip fractures. The purpose of this study was to compare the morbidity and mortality of periprosthetic vs native hip fractures. METHODS: Using the National Surgical Quality Improvement Program (NSQIP) database, 523 periprosthetic hip fractures were matched to native hip fractures using propensity scores. The 30-day rates of complications were compared using McNemar's test. A multivariate regression was then used to determine independent risk factors for mortality following periprosthetic fracture. RESULTS: Mortality was similar between groups (periprosthetic: 2.7% vs native: 3.4%; P = .49). Periprosthetic fractures exhibited a greater rate of overall (63.1% vs 38.6%; P < .001) and minor complications (59.1% vs 34.4%; P < .001). There was an increased rate of return to the operating room (7.8% vs 3.1%; P < .001) and blood transfusion in the periprosthetic group (54.9% vs 30.2%; P = .001). Age greater than 85 (odds ratio 9.21) and dependent functional status (odds ratio 5.38) were both independent risk factors for mortality following periprosthetic fracture. CONCLUSIONS: While native hip fractures are known to be highly morbid, our findings suggest that periprosthetic hip fractures have a similar mortality with significantly higher short-term morbidity. Future research is warranted to better understand risk factors and prevention strategies for complications in this subset of patients. PMID- 29526337 TI - Effect of age of red cells for transfusion on patient outcomes: a systematic review and meta-analysis. AB - Longer storage duration of red blood cell (RBC) units prior to transfusion has been associated with worse outcomes in observational studies. We performed a systematic review, including recently published randomized trials, to determine if storage age of RBCs is associated with mortality, morbidity or adverse events in patients. Searches were performed up to 21st July 2017 in Medline (OvidSP), 20 July in EMBASE (OvidSP) and June 2017 in Cochrane Library. Eligible studies were randomized controlled trials comparing transfusion of fresher or freshest available with older or standard issue RBCs. Human volunteer and autologous RBC transfusion studies were excluded. Data were extracted from published reports independently by 2 authors and strength of evidence assessed according to GRADE criteria. The primary outcome was latest-reported mortality. Sixteen trials randomizing 31,359 patients were identified. Transfusion with fresher compared with older RBC was not associated with risk of death (relative risk [RR] 1.04, 95% CI 0.98-1.09; P=.20, I2=0%, high quality evidence), but was associated with higher risk of transfusion reactions (RR 1.35, 95% CI 1.04-1.76; P=.02; I2=0%; high quality evidence) and infection (RR 1.08, 95% CI 1.00-1.17; P=.05; I2=0%, moderate evidence). Trial sequential analysis showed required information size has now been reached to exclude a 10% relative risk increase or decrease in mortality. Transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection. The current evidence does not support a change from current usual transfusion practice. PMID- 29526338 TI - Comparative analysis of clinical outcomes of a monofocal and an extended-range-of vision intraocular lens in eyes with previous myopic laser in situ keratomileusis. AB - PURPOSE: To compare the clinical outcomes after cataract surgery with implantation of a monofocal or an extended-range-of-vision intraocular lens (IOL). SETTING: Hospital da Luz, Lisbon Portugal. DESIGN: Prospective case series. METHODS: Patients who previously had myopic laser in situ keratomileusis (LASIK) had cataract surgery with bilateral implantation of an extended-range-of vision IOL (Tecnis Symfony) or a monofocal IOL (Tecnis ZCB00). Visual acuity, refraction, defocus curve, contrast sensitivity, photic phenomena, spectacle independence, and patient satisfaction were evaluated at 4 months postoperatively. RESULTS: The study comprised 44 patients (88 eyes), with 22 patients in each IOL group. No significant differences between groups were found postoperatively for most visual and refractive parameters (all P >= .27). However, binocular uncorrected intermediate and near visual acuities were significantly better in the extended-range-of-vision group (P < .01). The defocus curve of both IOLs differed more with increasing negative defocus (P < .01). No significant differences between IOLs were found in contrast sensitivity for any spatial frequency evaluated (P >= .05). Most of the patients did not perceive photic phenomena with either IOL. Mild glare was reported in 22.7% of the extended-range-of-vision patients and 9.1% of the monofocal group; mild halos were comparable with 13.6% in both groups. Spectacle dependence for intermediate vision and near vision was higher in the monofocal IOL group. CONCLUSION: The extended-range-of-vision IOL was a useful option to restore visual function after cataract surgery in eyes that previously had myopic LASIK surgery, offering levels of visual quality comparable to those achieved with the monofocal IOL. PMID- 29526339 TI - Quantitative analysis of corneal stromal riboflavin concentration without epithelial removal. AB - PURPOSE: To compare the corneal stromal riboflavin concentration and distribution using 2 transepithelial corneal crosslinking (CXL) systems. SETTING: Absorption Systems, San Diego, California, USA. DESIGN: Experimental study. METHODS: The stromal riboflavin concentration of 2 transepithelial CXL systems was compared in rabbit eyes in vivo. The systems were the Paracel/Vibex Xtra, comprising riboflavin 0.25% solution containing TRIS and ethylenediaminetetraacetic acid and an isotonic solution of riboflavin 0.25%, (Group 1) and the CXLO system (Group 2). Manufacturers' Instructions For Use were followed. The intensity of riboflavin fluorescence by slitlamp observation 10, 15, and 20 minutes after instillation was graded on a scale of 0 to 5. The animals were humanely killed and the corneal stromal samples analyzed with liquid chromatography and mass spectrometry. RESULTS: The mean riboflavin fluorescence intensity grades in Group 1 (4 eyes) were 3.8, 4.8, and 4.8 at 10, 15, and 20 minutes, respectively. The mean grades in Group 2 (3 eyes) were 2.0, 2.3, and 2.0, respectively. The riboflavin distribution was uniform in Group 1 but not in Group 2. The mean riboflavin concentration by liquid chromatography and mass spectrometry was 27.0 MUg/g stromal tissue in Group 1 and 6.7 MUg/g in Group 2. A stromal riboflavin concentration theoretically adequate for CXL, 15 MUg/g, was achieved in all eyes in Group 1 and no eyes in Group 2. Slitlamp grading correlated well with liquid chromatography and mass spectrometry concentration (R2 = 0.940). CONCLUSIONS: The system used in Group 1 produced corneal riboflavin concentrations that were theoretically adequate for effective transepithelial CXL (>=15 MUg/g), while the system in Group 2 did not. Slitlamp grading successfully estimated the corneal riboflavin concentration and can be used to ensure an adequate concentration of riboflavin in the cornea for transepithelial CXL. PMID- 29526340 TI - Key features of bone and joint infections following the implementation of reference centers in France. AB - OBJECTIVES: French reference centers for bone and joint infections (BJI) were implemented from 2009 onwards to improve the management of complex BJIs. This study compared BJI burden before and after the implementation of these reference centers. PATIENTS AND METHODS: BJI hospital stays were selected from the 2008 and 2013 national hospital discharge database using a validated algorithm, adding the new complex BJI code created in 2011. Epidemiology and economic burden were assessed. RESULTS: BJI prevalence increased in 2013 (70 vs. 54/100,000 in 2008). Characteristics of BJI remained similar between 2008 and 2013: septic arthritis (50%), increasing prevalence with age and sex, case fatality 5%, mean length of stay 17.5 days, rehospitalization 20%. However, device-associated BJIs increased (34 vs. 26%) as well as costs (?421 million vs. ?259 in 2008). Similar device associated BJI characteristics between 2008 and 2013 were: septic arthritis (70%), case fatality (3%), but with more hospitalizations in reference centers (34 vs. 30%) and a higher cost per stay. Among the 7% of coded complex BJIs, the mean length of stay was 22.2 days and mean cost was ?11,960. CONCLUSIONS: BJI prevalence highly increased in France. Complex BJI prevalence assessment is complicated by the absence of clinical consensus and probable undercoding. A validation of clinical case definition of complex BJI is required. PMID- 29526341 TI - Randomised feasibility study to compare the use of Therabite(r) with wooden spatulas to relieve and prevent trismus in patients with cancer of the head and neck. AB - Our aim was to compare the efficacy of the Therabite(r) jaw motion rehabilitation system (Atos Medical) with that of wooden spatulas to relieve and prevent trismus in patients who have had radiotherapy for stage three and four oral and oropharyngeal cancer. Secondary aims were to assess the feasibility and the impact of exercise on health-related quality of life (QoL), and the use of health services after treatment. We designed a randomised, open-label, controlled, three centre feasibility study to compare the effectiveness and cost of the Therabite(r) and wooden spatulas. We studied compliance with exercises and health related QoL, assessed cost using three health economics measures, and conducted semistructured interviews with patients. Patients were randomised into two groups: the Therabite(r) group (n=37) and the wooden spatula group (n=34). All patients had some sense of jaw tightening before the study started. Mean mouth opening after six months increased in both groups, but the difference between the groups was not significant (p=0.39). Completion rates for the three economic measures were good. There was no significant difference between the two groups in frequency of contact with care services or in QoL. Exercises during and after radiotherapy can ameliorate trismus in patients with stage three and four oral and oropharygeal cancers, but differences between groups in efficacy, compliance, QoL, or use of hospital or community health services, were not significant. PMID- 29526342 TI - Current thinking about the management of recurrent pleomorphic adenoma of the parotid: a structured review. AB - Pleomorphic adenoma is the most common tumour of the parotid gland, and can recur after excision. Recurrent pleomorphic adenoma can be a challenge to treat, and has variable outcomes. The aim of this review was to summarise current thinking in its management, which may be helpful to clinical teams and could improve patients' health-related quality of life. We searched several online databases using the key terms pleomorphic adenoma, recurrent pleomorphic adenoma, parotid gland tumours, parotid surgery, radiotherapy and parotid pleomorphic adenoma, and parotid surgery outcomes. Information collected included sample size, recurrence rate, condition of the facial nerve, type of operation, adjuvant treatments associated with recurrence, and clinical outcome. We screened 2301 papers, of which 49 were eligible. There was no consensus among authors about management. There are few if any randomised studies, and so conclusions in most papers were based on coherent arguments. Pleomorphic adenomas of the parotid tend to recur after long intervals, with a propensity towards multifocal disease, and the risk of recurrence (which depends on the initial surgical technique) is higher when the initial operation was done at a young age, after enucleation, and if the initial margins were invaded. Published conclusions suggest that the accepted management varies from observation in selected cases to total parotidectomy with or without postoperative radiotherapy. PMID- 29526343 TI - [Non-small lung cancer, ECCO/ESMO congres 2017]. AB - During the esmo congress that took place from 08 to 12 September 2017 in Madrid, non-small cell lung cancer (NSCLC) was the subject of various communications and posters. We selected the most innovative and most likely to change our daily practice These updates presented concerned both localized and metastatic lung cancers. For completely resected localized stages minimal monitoring by annual CT scan is recommended, in stage III after radio chemotherapy durvalumab treatment provides better progression-free survival (PFS). For metastatic stages, pembroluzumab immunotherapy plus platinum-based chemotherapy in first-line is superior to chemotherapy alone in terms of response rate, second-line treatment with nivolumab provides better overall survival (OS) at 3years, the duration of 1year is characterized by a PFS lower than a continuous treatment. In EGFR mutated NSCLCs, the best choice between 3rd and 1st generation EGFR antigen has generated a lot of debate after the interesting results in terms of progression free survival (PFS) of osamertinib in 1st metastatic line as well as for NSCLC with ALK rearrangement, alectinib was superior to crizotinib in the first metastatic line even in the presence of brain metastases. PMID- 29526344 TI - Perinatal Case Fatality Rate Related to Congenital Zika Syndrome in Brazil: A Cross-Sectional Study. PMID- 29526345 TI - Improving Folic Acid Supplementation Rates in Women of Childbearing Age With Epilepsy. AB - BACKGROUND: This study aims to improve the rate of folic acid supplementation to adolescent women with epilepsy on an antiepileptic drug (AED) regimen seen by the pediatric neurology providers at the Children's Hospital at Montefiore, in compliance with the 2009 American Academy of Neurology and American Epilepsy Society practice parameter. METHODS: We designed a quality improvement study with implementation of a series of interventions and compared folic acid supplementation rates before and after intervention. We made additional comparisons based on specific age groups (12 to 15 years and 16 to 21 years) and a diagnosis with or without developmental impairment. RESULTS: A review of 1850 charts from 2004 to 2015 showed an average folic acid prescription rate of 41%. Supplementation rates gradually increased to 52.2%, 58.5%, 60.3%, and finally up to 81.6% after this respective intervention: initial email reminder, provider education, posting signs in examination rooms, and implementation of an electronic medical record best practice advisory. There was improvement across all categories, in both age groups (12 to 15 years and 16 to 21 years) and in those with or without developmental impairment. There was a trend for higher compliance rates in adolescents without developmental impairment. CONCLUSIONS: Our interventions resulted in an increase in folic acid supplementation rates of adolescent women with epilepsy. These results are encouraging. We plan to extend education about the recommendations for folic acid supplementation to non neurology providers, as well as expand to apply our interventions and assess adherence to other defined epilepsy quality measures. PMID- 29526346 TI - Childhood Stroke and Vision: A Review of the Literature. AB - OBJECTIVE: Here we review the current literature regarding visual outcome after perinatal and childhood stroke. BACKGROUND: Visual deficits following stroke in adults are common and have been previously reviewed. Less is known about visual deficits following stroke in neonates and older children. Most of the literature regarding this subject has focused on preterm infants, or on other types of brain injury. This review summarizes the types of visual deficits seen in term infants following perinatal stroke and children following childhood stroke and predictors of outcome. This review suggests areas for future research. METHODS: We performed Ovid MEDLINE searches regarding visual testing in children, vision after childhood stroke, neuroplasticity of vision, treatment of visual impairment after stroke, and driving safety concerns after stroke. RESULTS: Visual field defects were the most commonly reported visual deficits after perinatal and childhood stroke. There is a significant lack of literature on this subject, and most is in the form of case reports and case series. Children can experience significant visual morbidity after stroke, and have the potential to show some recovery, but guidelines on assessment and treatment of this population are lacking. CONCLUSIONS: There were limitations to this study, given the small amount of literature available. Although stroke in children can result in severe visual deficits, most children regain at least a portion of their vision. However, more research is needed regarding visual assessment of this population, long-term visual outcomes, specific predictors of recovery, and treatment options. PMID- 29526347 TI - Surgical treatment for partial rupture of the distal biceps tendon using palmaris longus tendon graft: A case report. AB - We report a case of a partial rupture of the distal biceps tendon that was surgically treated using a palmaris longus tendon graft. A 58-year-old man complained of increasing pain with resisted elbow flexion and supination in the antecubital fossa. Magnetic resonance imaging revealed the irregularity of a distal attachment of the biceps brachii and peripheral signal changes. We diagnosed a partial rupture of the distal biceps tendon. Because conservative treatment failed, surgical treatment was performed through a single anterior approach. The insertion of the tendon was partially ruptured at the radial tuberosity. After the involved site was debrided, the palmaris longus tendon was grafted with suture anchors to reinforce the remaining tendon. Postoperative immobilization was not performed, and all moves were freed after 3 weeks. At the 6-year postoperative follow-up, the patient no longer experienced pain and returned to his original job without any limitations. PMID- 29526348 TI - Interventions in the operating room for children near end of life: A multidisciplinary approach. AB - INTRODUCTION: Pediatric surgeons are often involved in the management of severely or terminally ill patients. However, articles addressing their specific roles in the context of palliative care are almost inexistent. We sought to characterize the involvement of pediatric surgeons caring for children near end of life. METHODS: Chart review of children who had a procedure under general anesthesia within 6months of their death over a five-year period at a tertiary children's hospital (excluding traumas and neonatology cases). In addition to demographic and clinical data, we recorded the aim of the procedures performed, the involvement of the palliative care service, and presence of DNAR orders. RESULTS: The analysis included 83 patients (mean age: 8years). Forty-four children had more than one procedure (range 2-10). Pediatric palliative care service was involved in 66 cases (80%). A majority of patients had cancer (50%), and the most frequent cause of death was oncologic progression (46%). Ten patients died of a complication following their intervention. The aim of the procedure was palliative in 48 cases (29 for symptoms control and 19 to facilitate care), diagnostic in 16, and curative in 19. Forty-five procedures were performed urgently and 14 despite DNAR orders. CONCLUSION: Surgeon involvement with children near end of life is not infrequent. The procedures performed are varied and can be categorized according to their aim. Lack of formal palliative care training by surgeons highlights the need for increased collaboration with palliative care services to provide children optimal care when they need it most. LEVEL OF EVIDENCE: IV. PMID- 29526349 TI - Necrotizing enterocolitis in patients with congenital heart disease: A single center experience. AB - PURPOSE: The purpose of this study was to evaluate the characteristics of patients with congenital heart disease (CHD) who developed necrotizing enterocolitis (NEC). METHODS: A retrospective review of neonates with CHD at a tertiary care center between January 2006 and January 2016 was performed. Diagnosis of NEC was based on modified Bell's criteria. Patients were grouped by Risk Adjustment for Congenital Heart Surgery (RACHS-1) or by ductal-dependent (DD) lesions that require a patent ductus arteriosus to supply pulmonary or systemic circulation. RESULTS: Of 1811 neonates with CHD, 3.4% (n=61) developed NEC. Eighteen (30%) of these required surgical management. The rate of NEC among DD patients was 5% (n=33/653), compared to 2.4% (n=28/1158) in the non-DD group (p=0.003). RACHS-1 score>2 had a higher rate of NEC 6.2% (41/658) compared to RACHS-1<=2 cases, 1.7% (20/1153) (p=0.005). DD patients and complex patients with RACHS-1>2 were more likely to develop NEC after cardiac surgery. Hypoplastic left heart syndrome patients had a rate of 9% (n=16/185). Surgical NEC was more prevalent in the non-DD group. Mortality was similar among groups. CONCLUSION: CHD patients with ductal-dependent lesions or complex cases (RACHS-1 score>2) have higher rates of NEC than non-ductal-dependent patients or RACHS-1 score of 2 or less. Mortality is similar regardless of ductal dependence, but surgical NEC was more prevalent in non-DD patients. LEVEL OF EVIDENCE: Level IIb. PMID- 29526350 TI - Racial disparity in an outreach pediatric surgical service. AB - AIM: The aim of this study was to investigate whether racial disparities in healthcare exist within a New Zealand pediatric surgical outreach service in a high indigenous Maori population. METHODOLOGY: This retrospective study assessed all pediatric surgical procedures performed within a secondary center in New Zealand between May 2014 and May 2016. The days between the date of surgery booking on the waiting list and actual date of surgery were calculated and compared to their corresponding elective surgery waiting target times set by the New Zealand Ministry of Health (MoH). Patient demographic data were collated to then identify any discrepancy between ethnic groups. RESULTS: A total of 203 pediatric surgical procedures were performed on 193 patients. Of the 194 (95%) procedures that were included in the study, 30 breached a maximum waiting time. Though this represented a small proportion of patients, Maori were significantly over represented in this group. CONCLUSION: The majority of our patients with delayed elective surgery were of Maori ethnicity, for reasons not entirely accounted for by common socioeconomic determinants of health. Our study suggests the possibility of innate systemic causes not detected by standard models of health. However, further research with larger cohorts is needed. LEVEL OF EVIDENCE: III. PMID- 29526351 TI - Replacing gastrostomy tubes with collapsible bumpers in pediatric patients: Is it safe to "cut" the tube and allow the bumper to pass enterally? AB - PURPOSE: The "cut and push" technique for removal of percutaneous endoscopic gastrostomy (PEG) tubes with collapsible bumpers offers an alternative to the standard traction method of removal. This study compared the outcomes of these techniques. METHODS: We completed a research ethics board-approved retrospective cohort study, identifying all patients less than 18years of age who underwent PEG tube removal at a children's hospital between December 2013 and December 2016. Outcomes included need for sedation and complications. RESULTS: We identified 127 children who had PEG tubes removed. Significantly fewer children required sedation with the cut and push group (1.1% vs. 60.6%, p<=0.001). Ten complications occurred, including 9 in the cut and push group (9.6% vs. 3%, p=0.23). Mean age at time of complication was significantly younger in the cut and push group (2.2 vs. 6.3years p=0.004). CONCLUSION: This is the largest reported series comparing the cut and push vs. traction removal methods. The cut and push technique significantly reduced the need for procedural sedation but was associated with increased risk of complications. While these data suggest that the technique is safe in older children, caution should be taken in younger children who appear to be more likely to vomit the residual bumper. LEVELS OF EVIDENCE: Level III-Treatment study, Retrospective comparative study. PMID- 29526352 TI - A retrospective explanatory case study of the implementation of a bleeding management quality initiative, in an Australian cardiac surgery unit. AB - BACKGROUND: Bleeding management in cardiac surgery is challenging. Many guidelines exist to support bleeding management; however, literature demonstrates wide variation in practice. In 2012, a quality initiative was undertaken at The Prince Charles Hospital, Australia to improve bleeding management for cardiac surgery patients. The implementation of the quality initiative resulted in significant reductions in the incidence of blood transfusion, re-exploration for bleeding; superficial leg and chest wound infections; length of hospital stay, and cost. Given the success of the initiative, we sought to answer the question; "How and why was the process of implementing a bleeding management quality initiative in the cardiac surgery unit successful, and sustainable?" METHODS: A retrospective explanatory case study design was chosen to explore the quality initiative. Analysis of the evidence was reviewed through phases of the 'Knowledgeto Action' planned change model. Data was derived from: (1) document analysis, (2) direct observation of the local environment, (3) clinical narratives from interviews, and analysed with a triangulation approach. The study period extended from 10/2011 to 6/2013. RESULTS: Results demonstrated the complexity of changing practice, as well as the significant amount of dedicated time and effort required to support individual, department and system wide change. Results suggest that while many clinicians were aware of the potential to apply improved practice, numerous barriers and challenges needed to be overcome to implement change across multiple disciplines and departments. CONCLUSIONS: The key successful components of the QI were revealed through the case study analysis as: (1) an appropriately skilled project manager to facilitate the implementation process; (2) tools to support changes in workflow and decision making including a bleeding management treatment algorithm with POCCTs; (3) strong clinical leadership from the multidisciplinary team and; (4) the evolution of the project manager position into a perpetual clinical position to support sustainability. PMID- 29526353 TI - Adipose tissue macrophages and their polarization in health and obesity. AB - Adipose tissue is a special tissue environment due to its high lipid content. Adipose tissue macrophages (ATMs) help maintain adipose tissue homeostasis in steady state by clearing dead adipocytes. However, adipose tissue changes drastically during obesity, resulting in a state of chronic low grade inflammation and a shift in the adipose immune landscape. In this review we will discuss how these changes influence the polarization of ATMs. PMID- 29526355 TI - Enhancing oleanolic acid production in engineered Saccharomyces cerevisiae. AB - Oleanolic acid is a plant-derived pentacyclic triterpenoid compound with various biological activities. Recently, biosynthesis of oleanolic acid in microbes has been demonstrated as a promising and green way, but the production is too low for industrialization. To improve oleanolic acid production, this study constructed a novel pathway for biosynthesis of oleanolic acid in Saccharomyces cerevisiae by improving the pairing efficiency between cytochrome P450 monooxygenase and reductase. Furthermore, to improve the transcriptional efficiency of heterologous genes, the cellular galactose regulatory network was reconstructed by knocking out galactose metabolic genes GAL80 and GAL1. Finally, the 3-hydroxy-3 methylglutaryl-CoA reductase, squalene synthase and 2,3-oxidosqualene synthase were further overexpressed, increasing oleanolic acid production up to 186.1 +/- 12.4 mg/L in flask shake. Combined with fermentation optimization, the final oleanolic acid production was 606.9 +/- 9.1 mg/L with a yield of 16.0 +/- 0.8 mg/g DCW which was 7.6-fold higher than the reported maximum production. PMID- 29526354 TI - Heart Disease and Relaxin: New Actions for an Old Hormone. AB - The hormone relaxin has long been recognized for its involvement in maternal adaptation during pregnancy. However, discoveries during the past two decades on the mechanism of action of relaxin, its family of receptors, and newly described roles in attenuating ischemia/reperfusion (I/R) injury, inflammation, and arrhythmias have prompted vast interest in exploring its therapeutic potential in cardiovascular disease. These observations inspired recently concluded clinical trials in patients with acute heart failure. This review discusses our current understanding of the protective signaling pathways elicited by relaxin in the heart, and highlights important new breakthroughs about relaxin signaling that may pave the way to more carefully designed future trials. PMID- 29526357 TI - Dislocation of a sutureless prosthesis after type I bicuspid aortic valve replacement. PMID- 29526356 TI - [Standard or specific unit costs: Which criteria for choosing an economic evaluation of health strategies in multicentric studies?] AB - The question of what monetary value should be assigned to consumed resources, that is to say the choice of the unit cost, is a major consideration in terms of impact on the cost analysis results. To date, no agreement has been reached regarding this methodological question. The choices made by methodologists and the subsequent impact on the results of the analysis are only rarely put forward. This work addresses the theoretical framework of health strategy evaluations that can be carried out either in the normative framework of the conventional economic approach of well-being, referred to as welfarist, or in that of an approach referred to as extra-welfarist. It also provides elements that help clarify the choice of the hospital unit costs used to calculate the cost of health strategies, so as to reconcile the use of such studies and improve their comparability. What is preferable, opting for specific per hospital unit costs or applying a standard unit cost to all facilities? How should a standard cost be calculated? Is it appropriate to calculate an average of the unit costs, as recommended by certain guidelines? The advantages and the limitations of the various modes of assessing hospital resources in the setting of multicentric trials are discussed. PMID- 29526359 TI - Discussion. PMID- 29526360 TI - Rapid-deployment bioprosthetic aortic valve replacement; There is a flag on the field! PMID- 29526358 TI - Patients with anomalous aortic origin of the coronary artery remain at risk after surgical repair. AB - OBJECTIVES: Anomalous aortic origin of a coronary artery (AAOCA) from the opposite sinus of Valsalva is a rare cardiac anomaly associated with sudden cardiac death (SCD). Single-center studies describe surgical repair as safe, although medium- and long-term effects on symptoms and risk of SCD remain unknown. We sought to describe outcomes of surgical repair of AAOCA. METHODS: We reviewed institutional records for patients who underwent AAOCA repair, from 2001 to 2016, at 2 affiliated institutions. Patients with associated heart disease were excluded. RESULTS: In total, 60 patients underwent AAOCA repair. Half of the patients (n = 30) had an anomalous left coronary artery arising from the right sinus of Valsalva and half had an anomalous right. Median age at surgery was 15.4 years (interquartile range, 11.9-17.9 years; range, 4 months to 68 years). The most common presenting symptoms were chest pain (n = 38; 63%) and shortness of breath (n = 17; 28%); aborted SCD was the presenting symptom in 4 patients (7%). Follow-up data were available for 54 patients (90%) over a median of 1.6 years. Of 53 patients with symptoms at presentation, 34 (64%) had complete resolution postoperatively. Postoperative mild or greater aortic insufficiency was present in 8 patients (17%) and moderate supravalvar aortic stenosis in 1 (2%). One patient required aortic valve replacement for aortic insufficiency. Two patients required reoperation for coronary stenosis at 3 months and 6 years postoperatively. CONCLUSIONS: Surgical repair of AAOCA is generally safe and adverse events are rare. Restenosis, and even sudden cardiac events, can occur and long-term surveillance is critical. Multi-institutional collaboration is vital to identify at-risk subpopulations and refine current recommendations for long-term management. PMID- 29526361 TI - Enhanced exposure of subvalvular structures during mitral valve repair with a novel flexible and reusable leaflets retractor. PMID- 29526362 TI - To reattach or not to reattach, that is not the question. PMID- 29526363 TI - Cost reduction in left ventricular assist device therapy: An elusive paradigm. PMID- 29526364 TI - Surgical strategies for zone 2/3 pathologies of the thoracic aorta: Resolve or prepare? PMID- 29526365 TI - ARID1B: From the Garden of Eden to the Sahara. PMID- 29526366 TI - Association between single nucleotide polymorphisms in estrogen receptor 1/2 genes and symptomatic severity of autism spectrum disorder. AB - BACKGROUND: Previous studies on etiology of autism spectrum disorders (ASD) have shown strong contribution of hereditary factors. On the basis the heterogeneity in ASD symptoms, it is highly possible that each independent domain of ASD symptom is linked to a different set of genetic risk factors. However, few empirical investigations have been carried out to examine this hypothesis. AIMS: The aim of the present study was to investigate the association between single nucleotide polymorphisms (SNPs) in estrogen receptor genes, which several previous studies have identified as potential risk factors of ASD, and the severity of each independent aspect of ASD symptom within an Asian clinical sample. METHOD AND PROCEDURES: We investigated the association between severities of four ASD symptoms (Social Communication, Social Interaction, Stereotypies and Sensory Abnormalities, and Emotional Regulation) measured by childhood autism rating scale and SNPs in genes of estrogen receptor 1 and 2, ESR1 rs11155819 and ESR2 rs1152582, in 96 Japanese individuals with ASD. OUTCOMES AND RESULTS: The analysis revealed that severities in the impairment of social interaction and emotional regulation were linked to SNPs in ESR1 rs11155819 and ESR2 rs1152582, respectively. The effect of genotype was not observed for the other aspects of ASD symptoms. CONCLUSIONS AND IMPLICATIONS: These findings support our contention that the severity of each ASD symptom domain is determined by a distinct set of genetic risk factors. PMID- 29526367 TI - Multicenter comprehensive methodological and technical analysis of 832 pressurized intraperitoneal aerosol chemotherapy (PIPAC) interventions performed in 349 patients for peritoneal carcinomatosis treatment: An international survey study. AB - BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method offered in selected patients suffering from non-resectable peritoneal carcinomatosis (PC). As reported experience is still limited, we conducted a survey among active PIPAC centers aiming to report their technical approach and clinical findings. METHODS: An online survey was sent to active PIPAC centers worldwide. The questionnaire consisted of 34 closed questions and was conducted over a period of 3 months beginning in March 2017. RESULTS: Nine out of 15 contacted centers completed the questionnaire totaling 832 PIPAC procedures in 349 patients. Most common indications for PIPAC were PC from gastric, ovarian and colorectal origin. The mean time between each PIPAC procedure was 6-8 weeks. Seven of nine (77.8%) centers evaluate the PCI at every PIPAC procedure. At least four tissue samples for histopathology analysis were retrieved in 5 (55.6%). All centers (100%) use the same chemotherapy protocol: oxaliplatin at a dosage of 92mg/m2 for PC of colorectal origin and a combination of cisplatin and doxorubicin at a dosage of 7.5mg/m2 and 1.5mg/m2, respectively, for other types of PC. Eight centers (88.9%) perform routine radiological evaluation before first PIPAC and after third PIPAC. CONCLUSION: These data confirm that PIPAC procedures are homogeneously performed in established centers. Standardization of the procedure will facilitate future international multicenter prospective clinical trials. PMID- 29526368 TI - Prognostic role of splenic vessel infiltration in distal pancreatic adenocarcinoma: Comment on: Systematic review and meta-analysis of prognostic role of splenic vessels infiltration in resectable pancreatic cancer. PMID- 29526369 TI - Evidence-based data and rare cancers: The need for a new methodological approach in research and investigation. AB - Rare cancers are not so rare, their incidence is increasing and, as a group, they have worse survival than the common cancers. These factors emphasise the societal need to ensure sufficient focus on research into their biological basis, aetiological factors, new more effective therapies and organisation of healthcare to improve access to best practice and innovation. Accuracy of diagnosis is one of the first hurdles to be overcome, with around one third of tumours being reclassified - by type or risk group - when subject to a centralised pathology review process. Timely access to appropriate expert knowledge is a second challenge for patients - in Europe this is being addressed by the establishment of European Reference Networks (ERNs) as part of the EU cross border healthcare initiative. There are ERNs for adult solid and haematological cancers and childhood cancers, all of which are individually rare. These ERNs will facilitate creation of large databases of rare tumours that will incorporate knowledge of their molecular features and build an evidence base for the effectiveness of innovative, biology-directed therapies. With an increasing focus on 'real world' outcome data, research methodologies are evolving, to include randomised registry trials and data linkage approaches that exploit the ever-richer information held on patients in routine health care data. The inclusion of genomic analysis into cancer diagnosis, treatment and risk prediction raises many issues for the conduct of clinical research and cohort studies and personal data sharing. Sophisticated means of pseudonymisation, together with full involvement of affected and 'at risk' patients, are supporting novel research designs and access to data that will continue to build the evidence base to improve outcomes for patients with rare cancers. PMID- 29526371 TI - Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland. AB - BACKGROUND: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types). METHODS: We used data on IPD from the national, population based surveillance. A target cohort of vaccine-eligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. For the indirect effect, another cohort of older PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of season- and age matched reference cohorts before NVP introduction. RESULTS: Among vaccine eligible children, the incidence of all IPD decreased by 79% (95% CI 74-83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant. In the unvaccinated older children, the incidence of all IPD decreased by 33% (95% CI 8-52%) compared to the reference cohort, and there was no impact on serotype 6A or 19A IPD. CONCLUSION: Overall, the impact of PCV10 vaccination on IPD was high in vaccine eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained. PMID- 29526373 TI - MMRV vaccine safety. PMID- 29526372 TI - Rotavirus genotypes circulating in Ontario, Canada, before and after implementation of the rotavirus immunization program. AB - BACKGROUND AND OBJECTIVES: Ontario introduced a universal publicly-funded group A rotavirus (RVA) immunization program in August 2011, using monovalent vaccine. RVA immunization programs have decreased the incidence of RVA acute gastroenteritis in many countries but it is unclear if it will contribute to the emergence of certain genotypes. We monitored RVA trends and genotypes in Ontario before and after implementation of the publicly-funded immunization program. METHODS: RVA detection was conducted at Public Health Ontario Laboratories from January 2009 to December 2011 (pre-program period) and January 2012 to October 2015 (publicly-funded RVA immunization program period) and number of RVA-positive specimens and percent positivity were analysed. A convenience sample of RVA positive stool specimens, from September 2010 to December 2011 (pre-program period) and January 2012 to June 2013 (program period), were genotyped using heminested PCR. A literature review on the burden of illness from emergent genotype was performed. RESULTS: Stool specimens showed a significant decrease in RVA percent positivity from the 36 month pre-program period (14.4%; 1537/10700) to the 46 month program period (6.1%; 548/9019). An increase in the proportion of RVA G10 among genotyped specimens, associated with five different P genotypes, from the pre-program (6.3%; 13/205) to the program (31.5%; 40/127) period was observed. Our literature review identified approximately 200 G10-positive human stool specimens from 16 different countries. CONCLUSIONS: This study documented a decrease in the number of RVA-positive specimens and percent positivity after implementation of the immunization program. An unexpected increase in the proportion of RVA G10 was detected following program introduction. Ongoing RVA surveillance is important in evaluating both the long-term impact of immunization and emergence of RVA genotypes. PMID- 29526374 TI - Independent association of arteriovenous ratio index on the primary functional maturation of autologous radiocephalic arteriovenous fistula. AB - OBJECTIVE: It has been hypothesized that a novel measurement technique of arteriovenous ratio (AVR) index obtained from inflow (radial artery diameter) to that of outflow (cephalic vein diameter) and its application through the Bernoulli effect has no impact on the primary functional maturation (FM) of autogenous radiocephalic arteriovenous fistula (RCAVF). METHODS: A prospective consecutive single-center cohort study with intention to treat of 324 patients undergoing RCAVF during a period of 4 years was conducted. Variables of demographics, anatomic factors, laterality, comorbidities, anesthesia type, presence of intraoperative thrill, angle of anastomosis, and AVR index were assessed through univariate and multivariate logistic regression analysis on the end point of FM. The AVR was subjected to three decimal points to ensure maximal accuracy for best sensitivity and 1 - specificity by receiver operating characteristic curve. The chi2 (subgroup) analyses were undertaken to investigate the differences in FM incidence within different ranges of AVR. Test of probability (P value) was considered to be significant with P < .05. Effect sizes were reported as odds ratio with their measure of uncertainty at 95% confidence intervals. RESULTS: Among all variables, the AVR index remained the only independent factor associated with FM (66%; n = 214/324) of RCAVFs (P = .001; 95% confidence interval, 0.08-0.26). AVR of 1 to 1.06 was associated with 100% FM in RCAVFs. Decrease or increase of this index was associated with stepwise reduction in FM of RCAVFs (P < .05). CONCLUSIONS: The suggested novel measurement technique (AVR index) is an independent predictor of FM in RCAVFs. This study implies that minimal diameter (ie, inflow artery dimeter to outflow cephalic vein diameter) mismatch (AVR, 1-1.06) irrespective of other variables remains crucial for optimal hemodynamics (pressure and velocity) of RACVFs and their primary FM. PMID- 29526370 TI - Testicular germ-cell tumours and penile squamous cell carcinoma: Appropriate management makes the difference. AB - Germ-cell tumours (GCT) of the testis and penile squamous cell carcinoma (PeSCC) are a rare and a very rare uro-genital cancers, respectively. Both tumours are well defined entities in terms of management, where specific recommendations - in the form of continuously up-to-dated guide lines-are provided. Impact of these tumour is relevant. Testicular GCT affects young, healthy men at the beginning of their adult life. PeSCC affects older men, but a proportion of these patients are young and the personal consequences of the disease may be devastating. Deviation from recommended management may be a reason of a significant prognostic worsening, as proper treatment favourably impacts on these tumours, dramatically on GCT and significantly on PeSCC. RARECAREnet data may permit to analyse how survivals may vary according to geographical areas, histology and age, leading to assume that non-homogeneous health-care resources may impact the cure and definitive outcomes. In support of this hypothesis, some epidemiologic datasets and clinical findings would indicate that survival may improve when appropriate treatments are delivered, linked to a different accessibility to the best health institutions, as a consequence of geographical, cultural and economic barriers. Finally, strong clues based on epidemiological and clinical data support the hypothesis that treatment delivered at reference centres or under the aegis of a qualified multi-institutional network is associated with a better prognosis of patients with these malignancies. The ERN EURACAN represents the best current European effort to answer this clinical need. PMID- 29526375 TI - Gore Iliac Branch Endoprosthesis for treatment of bilateral common iliac artery aneurysms. AB - OBJECTIVE: The Gore Iliac Branch Endoprosthesis (IBE; W. L. Gore & Associates, Flagstaff, Ariz) has recently been approved by the Food and Drug Administration for treatment of common iliac artery (CIA) aneurysms. Despite early excellent results in clinical trial, none of 63 patients were treated for bilateral iliac aneurysms. The goal of this study was to examine real-world experience using the Gore IBE for bilateral CIA aneurysms. METHODS: A retrospective review of an international multicenter (16 U.S., 8 European) experience using the Gore IBE to treat bilateral CIA aneurysms was performed. Cases were limited to those occurring after Food and Drug Administration approval (February 2016) in the United States and after CE mark approval (November 2013) in Europe. Demographics of the patients, presentation, anatomic characteristics, and procedural details were captured. RESULTS: There were 47 patients (45 men; mean age, 68 years; range, 41-84 years) treated with bilateral Gore IBEs (27 U.S., 20 European). Six patients (12.7%) were symptomatic and 12 (25.5%) patients were treated primarily for CIA aneurysm (aorta <5.0 cm). Mean CIA diameter was 40.3 mm. Four patients had aneurysmal internal iliac arteries (IIAs). Two of these were sealed proximally at the IIA aneurysm neck and two required coil embolization of IIA branches to achieve seal in the largest first-order branches. Technical success was achieved in 46 patients (97.9%). No type I or type III endoleaks were noted. There was no significant perioperative morbidity or mortality. IIA branch adjunctive stenting was required in four patients (one IIA distal dissection, three kinks). On follow-up imaging available for 40 patients (85.1%; mean, 6.5 months; range, 1-36 months), 12 type II endoleaks (30%) and no type I or type III endoleaks were detected. Two of 80 (2.5%) IIA branches imaged were occluded; one was intentionally sacrificed perioperatively. CONCLUSIONS: Preservation of bilateral IIAs in repair of bilateral CIA aneurysms can be performed safely with excellent technical success and short-term patency rates using the Gore IBE device. Limb and branch occlusions are rare, usually are due to kinking, and can almost always be treated successfully with stenting. PMID- 29526376 TI - Clinical effectiveness of open thrombectomy for thrombosed autogenous arteriovenous fistulas and grafts. AB - OBJECTIVE: Arteriovenous (AV) fistulas are the preferred hemodialysis access for patients with end-stage renal disease, although multiple interventions are typically needed to maintain patency. When AV fistulas thrombose, however, there is debate as to whether open thrombectomy should be attempted, particularly for salvage of upper arm fistulas. This study was designed to evaluate outcomes after open thrombectomy of upper arm and forearm AV fistulas compared with AV grafts. METHODS: We identified all patients who underwent an open thrombectomy procedure for a thrombosed AV fistula or graft at a single academic medical center between January 2006 and March 2017. The specific type of AV fistula or graft was evaluated, as were the patients' demographics, comorbidities, medications, adjunctive procedures during thrombectomy, and secondary interventions. The primary outcome measures, postintervention primary patency and postintervention secondary patency, were analyzed using Kaplan-Meier curves and Cox regression models for risk adjustment. RESULTS: During the study period, 209 open thrombectomy procedures were performed in 139 patients; 73 (35%) were undertaken in AV fistulas and 136 (65%) in grafts. Patients with upper arm fistulas (n = 52; 54% brachiocephalic, 46% brachiobasilic) and forearm fistulas (n = 16) were more likely to be male but less likely to have cerebrovascular disease or ischemic heart disease and to be receiving anticoagulation therapy compared with graft patients. After thrombectomy, the majority of patients underwent dialysis successfully (70% upper arm fistulas, 56% forearm fistulas, 63% grafts; P > .05), and 1-year survival rates were similar in all three cohorts. Postintervention primary patency at 1 year was significantly higher for AV fistulas vs grafts (33% for upper arm fistulas and 25% for forearm fistulas vs 9% for grafts; P < .05), which was confirmed in multivariate analysis, where upper arm AV fistulas had a 46% lower risk of recurrent thrombosis or secondary intervention (hazard ratio, 0.56; 95% confidence interval, 0.35-0.85; P < .05). Postintervention secondary patency at 1 year was similar between AV fistulas and grafts (44% for upper arm fistulas vs 43% for forearm fistulas vs 31% for grafts; P = .16), but in multivariate analysis, upper arm fistulas were significantly less likely to fail (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .05). CONCLUSIONS: Our data suggest that AV fistula thrombectomy is successful in up to 70% of cases, with significantly improved risk-adjusted 1-year primary and secondary patency rates for upper arm fistulas compared with grafts. Whereas the risk of access failure is high after thrombectomy, efforts to salvage upper arm AV fistulas are effective in most patients and should be undertaken when feasible. PMID- 29526377 TI - Short-term and midterm survival of ruptured abdominal aortic aneurysms in the contemporary endovascular era. AB - OBJECTIVE: Endovascular aneurysm repair (EVAR) has been shown to reduce mortality in the emergent repair of ruptured abdominal aortic aneurysms (AAAs). However, long-term survival data for this group of patients are lacking with contemporary endovascular endografts. The purpose of this study was to evaluate both 30-day mortality rates and 1-year survival in patients undergoing emergent EVAR in a 43 facility hospital system with a quaternary referral center with an established ruptured aneurysm protocol. METHODS: Retrospective analysis of patients captured prospectively in an Institutional Review Board-approved registry for patients treated emergently for AAA were reviewed between 2012 and 2017 was conducted. Primary outcome measures were 30-day mortality and 1-year survival for the entire group as well as for symptomatic and ruptured aneurysms. Data were analyzed using logistic regression survival curves, and a log-rank test was performed to compare survival between open and endovascular repair. Patients were evaluated on an intent-to-treat basis, and outcomes were evaluated in a multivariate model. RESULTS: A total of 249 patients were referred as part of the protocol. Of these, 102 (41%) were treated emergently. Kaplan-Meier estimates of 30-day and 1-year survival were 64% and 53% for all patients, 58% and 46% for ruptured patients, and 86% and 81% for symptomatic patients. EVAR resulted in improved 30-day survival (64% vs 31%; odds ratio, 4.0; P = .03) and 1-year survival (40% vs 23%; odds ratio, 2.3; P = .4) over open repair. Significant predictors for 30-day mortality included hypotension (P = .0003), blood transfusion (P < .0001), length of stay (P = .0005), extravasation (P = .01), preoperative cardiopulmonary resuscitation (P = .04), open repair (P = .007), aortouni-iliac reconstruction (P = .008), and abdominal compartment syndrome (P = .007). Significant predictors for 1-year mortality included advanced age (P = .04), hypotension (P = .01), blood transfusion (P = .006), extravasation (P = .03), reintubation (P = .03), and abdominal compartment syndrome (P = .03). There were no differences in outcomes based on race, gender, or outside transfer. Peripheral arterial disease (P = .04), hypertension (P = .04), coronary artery disease (P = .03), and familial history of aneurysms (P = .05) were related to increased 30-day mortality. Peripheral arterial disease (P = .06) and coronary artery disease (P = .07) were nearly significant, with increased 1-year mortality. CONCLUSIONS: EVAR is associated with improved survival compared with open repair in patients requiring emergent AAA repair. However, in the first year, there is a significant risk of death based on initial presentation as well as underlying comorbidities. To improve long-term survival, aggressive medical management and medical surveillance are warranted. PMID- 29526378 TI - Successful percutaneous access for endovascular aneurysm repair is significantly cheaper than femoral cutdown in a prospective randomized trial. AB - OBJECTIVE: Because of its minimally invasive nature, percutaneous femoral access for endovascular aneurysm repair (pEVAR) is currently undergoing rapid popularization. Compared with surgical cutdown for femoral access (cEVAR), it offers the advantage of faster recovery after surgery as well as a reduction in wound complications. Despite proposed advantages, the method is largely considered uneconomical because of its reliance on costly closure devices. METHODS: There were 50 patients undergoing EVAR who were enrolled in this randomized prospective single-center trial. Each patient randomly received percutaneous access in one groin and surgical access in the other. The primary end points were access duration and cost. Secondary end points were wound complications and the postoperative pain levels. RESULTS: Surgery was performed per protocol in 44 patients. Mean access times for pEVAR and cEVAR were 11.5 +/- 3.4 minutes and 24.8 +/- 12.1 minutes (P < .001), respectively. Total access costs were ?559.65 +/- ?112.69 for pEVAR and ?674.85 +/- ?289.55 for cEVAR (P = .016). Eight complications in six patients were attributed to cutdown, none to pEVAR (P = .02). The percutaneously accessed groin was significantly less painful at day 1 and day 5 after surgery (P < .001). An intention-to-treat analysis (N = 50 patients) included six cases of pEVAR conversion due to technical failure in three patients (6%) and change of the operative strategy in another three patients (eg, aortouni-iliac stent graft followed by crossover bypass). The intention-to-treat analysis showed shorter mean overall access time for pEVAR (pEVAR, 14.65 +/- 10.20 minutes; cEVAR, 25.12 +/- 11.77 minutes; P < .001) and no cost difference between the two methods (pEVAR, ?651.29 +/- ?313.49; cEVAR, ?625.53 +/- ?238.29; P = .65). CONCLUSIONS: Our data confirm proposed potential benefits attributable to the minimally invasive nature of pEVAR while demonstrating cost-effectiveness despite the additional cost of closure devices. Taking into account pEVAR failures still does not increase pEVAR costs over cEVAR. Further considering reduced postoperative pain and wound complications, the technique deserves consideration in suitable patients. PMID- 29526379 TI - An immunohistochemical and ultrastructural analysis of the retina in tadalafil (Cialis) treated rats. AB - Tadalafil (Cialis) is one of the most commonly used phosphodiesterase type5 (PDE5) inhibitors. This work aimed to analyze the histological and ultrastructural changes provoked by chronic tadalafil administration in the rat retina, correlate between such changes and PDE5 immunoexpression and to evaluate the possible reversibility of these changes. Thirty Sprague Dawley male rats were randomly distributed into 3 groups. Control group; given 1 ml distilled water daily for 6 weeks. Tadalafil group; given tadalafil in a daily dose of 2.6 mg/kg for 6 weeks. Withdrawal group; given tadalafil 2.6 mg/kg daily for 6 week followed by a withdrawal period of 4 weeks. Retinal specimens were prepared for histological, ultrastructural and immunohistochemical study using anti-PDE5 and anti-Bcl-2 antibodies. Morphometric and statistical studies were performed. Tadalafil group displayed a significant reduction in retinal thickness, diminished cell population of outer and inner nuclear layers, dilated blood capillaries and a significant decline in the number of ganglion cells. Significant reductions of both PDE5 and Bcl-2 immunoexpression were observed. At the ultrastructural level, the photoreceptors showed spacing of outer segments and disorganized membranous discs. Retinal neurons showed ultrastructural degenerative changes in the form of shrunken irregular nuclei, dilated rER, and disrupted mitochondria. Withdrawal group revealed preservation of histological structure and partial restoration of retinal thickness, retinal cells ultrastructure, and PDE5 and Bcl-2 immunoexpressions. In conclusion, chronic use of tadalafil could induce reversible apoptotic and degenerative changes in retinal neurons due to its inhibitory effect on PDE5 expression which affects the metabolism and viability of retinal cells. PMID- 29526380 TI - The clinical value of the RGB value of an image of the interarytenoid area for diagnosis of laryngopharyngeal reflux. PMID- 29526382 TI - Neonatal nonpolio enterovirus and parechovirus infections. AB - Nonpolio enteroviruses and parechoviruses are frequent causes of neonatal infection. Clinical manifestations of infection range from asymptomatic infection to mild infection without sequelae to septic shock with muiltiorgan failure. Neonates with clinically apparent infection typically have mothers and/or other contacts with recent symptoms consistent with a viral illness. Severe neonatal infection with nonpolio enterovirus or parechovirus cannot be differentiated clinically from serious bacterial infection. The preferred method for diagnosing neonatal nonpolio enterovirus or parechovirus infection is PCR as it is rapid, sensitive, specific, and commercially available for the detection of virus from various clinical specimens. Investigational agents such as the capsid inhibitors pleconaril and pocapavir show promise for treatment of neonatal enterovirus infections, and other investigational agents are being developed. This review focuses on the epidemiology, diagnosis, and treatment of neonatal nonpolio enterovirus and parechovirus infections. PMID- 29526381 TI - Bioglass reconstruction of posterior meatal wall after canal wall down mastoidectomy. AB - BACKGROUND: Canal wall down (CWD) mastoidectomy has many drawbacks including chronic otorrhea, granulations, dizziness on exposure to cold or hot water and tendency of debris accumulation in the mastoid cavity demanding periodic cleaning. Many of these problems can be solved by reconstruction of the posterior meatal wall (PMW). OBJECTIVES: To assess the results of PMW reconstruction after CWD mastoidectomy for cholesteatoma using bioactive glass (BAG) that is fabricated and built up intraoperatively. PATIENTS AND METHODS: This study was applied on 20 patients had atticoantral chronic suppurative otitis media. All cases were subjected to CWD mastoid surgery with complete elimination of the disease and reconstruction of the PMW by BAG that was prepared and built up intraoperatively. All patients were exposed to full preoperative evaluation and full postoperative assessment of complications, appearance of the external auditory canal contour, and the hearing gain expressed by the change of the air bone gap postoperatively. RESULTS: During a follow up of 12 to 36 months, postoperative appearance of external auditory canal contour was found smooth without hidden pouches, irregularities nor stenosis in all cases. No registered granulation, foreign body reaction, nor extrusion and/or displacement of the BAG material. No reported facial palsy or recurrent cholesteatoma. Significant hearing improvement was statistically reported (p = 0.0006). CONCLUSION: Surgical reconstruction of the PMW using BAG that operatively fashioned immediately after CWD mastoidectomy appears to be reliable without considerable complications giving smooth appearance of the PMW and improving the hearing. PMID- 29526384 TI - Introduction. PMID- 29526383 TI - Update on the management of hepatitis B and C infections in the neonatal period. AB - Hepatitis B virus and hepatitis C virus have received a significant amount of attention in recent years, and both viruses share a significant amount of similarities with one another beyond just that they both primarily target the liver. In recent years, cases of both infections have been fueled by a nationwide epidemic of injection drug use. Most relevant to this audience, they are both transmitted from mother to child. The increased cases in young adults combined with mother to child transmission translate into more exposed infants that will need to be managed and followed. Screening of pregnant women for hepatitis B infection coupled with appropriate treatment and prophylaxis measures are incredibly effective to preventing transmission. Prevention of hepatitis C infection is not yet possible, but advances in antiviral therapy make interruption of transmission a future possibility. PMID- 29526385 TI - Editorial overview: Neurobiology of behavior. PMID- 29526386 TI - Systematic alphanumeric-coded endoscopy versus chromoendoscopy for the detection of precancerous gastric lesions and early gastric cancer in subjects at average risk for gastric cancer. AB - INTRODUCTION AND AIMS: Gastric cancer is one of the main causes of cancer worldwide, but there is currently no global screening strategy for the disease. Endoscopy is the screening method of choice in some Asian countries, but no standardized technique has been recognized. Systematic alphanumeric-coded endoscopy can increase gastric lesion detection. The aim of the present article was to compare the usefulness of systematic alphanumeric-coded endoscopy with conventional endoscopy for the detection of premalignant lesions and early gastric cancer in subjects at average risk for gastric cancer. MATERIALS AND METHODS: A cross-sectional, comparative, prospective, randomized study was conducted on patients at average risk for gastric cancer (40-50 years of age, no history of H. pylori infection, intestinal metaplasia, gastric atrophy, or gastrointestinal surgery). Before undergoing endoscopy, the patients had gastric preparation (200mg of oral acetylcysteine or 50mg of oral dimethicone). Conventional chromoendoscopy was performed with indigo carmine dye for contrast enhancement. RESULTS: Fifty consecutive cases (mean age 44.4 +/- 3.34 years, 60% women, BMI 27.6 +/- 5.82 kg/m2) were evaluated. Endoscopic imaging quality was satisfactory in all the cases, with no differences between methods (p = 0.817). The detection rate of premalignant lesions and early gastric cancer was 14% (6 cases of intestinal metaplasia and one case of gastric adenocarcinoma). Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 100, 95, 80, 100 and 96%, respectively, for systematic alphanumeric-coded endoscopy, and 100, 45, 20, 100, and 52%, respectively, for conventional endoscopy. Lesion detection through systematic alphanumeric-coded endoscopy was superior to that of conventional endoscopy (p = 0.003; OR = 12). CONCLUSION: Both techniques were effective, but systematic alphanumeric-coded endoscopy significantly reduced the false positive rate. PMID- 29526387 TI - Infections Diagnosed after Admission to a Stroke Unit and Their Impact on Hospital Mortality in Poland from 1995 to 2015. AB - BACKGROUND: Implementation of modern stroke unit care might have attenuated the negative effect of infections on stroke outcome. Our aim was to investigate changes in the occurrence of pneumonia and urinary infections diagnosed after admission to experienced Polish stroke center between 1995 and 2015, and their association with hospital mortality. MATERIALS AND METHODS: This is a retrospective registry-based analysis of consecutive patients with acute stroke from highly urbanized area (Warsaw, Poland) in years 1995-2015. A total of 5174 patients were divided to 4 time periods: 1995-2000 (n = 883), 2001-2006 (n = 1567), 2006-2010 (n = 1539), and 2011-2015 (n = 1183). Odds ratios (ORs) for hospital death were calculated after adjustment for age, congestive heart failure, preexisting disability, stroke type, and baseline neurological deficit, separately in years 1995-2015, 1995-2000, and 2011-2015. RESULTS: Over time there was a significant decrease in the proportion of patients diagnosed with pneumonia (20%, 19%, 9%, and 15%, respectively) or urinary tract infection (29%, 21%, 24%, and 18%, respectively) and in the proportion of patients having body temperature of 38.0 degrees C or higher at least once within first 7 days of hospital stay (20%, 20%, 13%, and 13%, respectively), without significant change in the use of antibiotics (range 35%-37%). Hospital mortality was strongly predicted by pneumonia (OR 3.6-4.2) and fever (OR 2.7-4.7) but not urinary infections. CONCLUSIONS: Over the last 2 decades there was a decrease in the proportion of patients with acute stroke diagnosed with pneumonia or urinary tract infection during stroke unit stay. Hospital death was strongly predicted by pneumonia and fever but no by urinary infections. PMID- 29526388 TI - Managing challenging interactions with family caregivers in the cancer setting: Guidelines for clinicians (TRIO Guidelines-2). AB - OBJECTIVE: Family caregivers can, at times, add complexity to clinical encounters. Difficult family caregivers and dynamics may: derail consultation communication, reduce patient autonomy, and compromise effective clinical care. A paucity of practical strategies guiding effective clinician-family communication exists. This study aimed to develop and evaluate the first comprehensive, evidence-based guidelines (the TRIO guidelines) for oncology physicians and nurses to better manage several complex/challenging situations involving family members. METHODS: TRIO Guidelines were based on a comprehensive review of literature, relevant guidelines, and feedback from an expert advisory group (n = 10). Draft guidelines underwent two rounds of evaluation via an online Delphi consensus process involving international experts (n = 35). RESULTS: Guidelines incorporate topic areas, strategies, and sub-strategies on managing challenging family involvement (7 topics). Example wording, behaviours and level of evidence are provided. CONCLUSION: Challenging triadic interactions require skillful navigation, and the TRIO Guidelines provide clear, specific, and evidence-based strategies for clinicians to utilise in these potentially stressful encounters. Training based on these guidelines may improve both patient care and clinician confidence. PRACTICE IMPLICATIONS: Implementation of these guidelines into medical/nursing curricula and as a component of continuing professional development programs will likely be highly beneficial. PMID- 29526389 TI - Facilitating collaborative and effective family involvement in the cancer setting: Guidelines for clinicians (TRIO Guidelines-1). AB - OBJECTIVE: Family caregivers regularly attend medical consultations and are often involved in decision-making; however, there are few practical strategies to guide effective communication for the clinician-patient-family trio. We aimed to develop and evaluate the first comprehensive guidelines for oncology physicians and nurses, on how to positively and effectively involve family caregivers of adult patients in consultations and patient care (TRIO Guidelines-1) and how to manage challenging interactions with family caregivers (TRIO Guidelines-2). METHODS: The TRIO Guidelines were based on a comprehensive literature review and input from an expert advisory group (n = 10). They underwent two rounds of formal evaluation via an online Delphi consensus process involving international experts (n = 35), and a subset were piloted with 24 breast cancer clinicians in a workshop format. RESULTS: TRIO Guidelines-1 incorporate strategies and sub strategies on facilitating collaborative and effective family involvement (6 topics). Example wording, behaviours, and level of evidence are provided throughout. All 24 clinicians rated the guidelines as helpful after the pilot workshop. CONCLUSION: These guidelines will be a useful educational tool for clinicians and medical/nursing students. PRACTICE IMPLICATIONS: By equipping clinicians with strategies to facilitate effective and collaborative family engagement, the TRIO Guidelines have the potential to transform communication in clinical practice. PMID- 29526390 TI - Promoting men's knowledge of cancer risk reduction: A systematic review of interventions. AB - OBJECTIVE: To critically appraise and discuss evidence from interventions designed to increase men's knowledge about cancer risk reduction. METHODS: A systematic review was conducted. Six electronic databases were searched for interventions published between January 1st 2006 and May 30th 2016 in English. Studies were included if they used an experimental design, included adult males (>=18 years), and had a primary focus on the acquisition and utilisation of information on cancer risk reduction. The methodological quality of the included studies was appraised. RESULTS: A total of 25 studies met the inclusion criteria, 23 of which involved prostate cancer risk reduction. Twenty-one studies reported knowledge gain among the men. Three studies found that knowledge gain was associated with health literacy. CONCLUSIONS: Interventions aiming to improve men's knowledge about cancer risk reduction require a multimodal approach. Findings highlight the need to design and measure the impact of interventions for men on wider cancer risk reduction topics, while accounting for different socio demographic and ethnic groups, literacy and health literacy levels. PRACTICE IMPLICATIONS: More research is warranted into the development and evaluation of theoretically-driven multimodal community-based approaches to information dissemination for men taking into account their daily information spheres such as workplaces and community environs. PMID- 29526391 TI - Colorectal adenoma risk in childhood cancer survivors. PMID- 29526392 TI - Dasatinib in paediatric chronic myeloid leukaemias. PMID- 29526393 TI - Introduction to disease vectors. PMID- 29526394 TI - Renal complications during pregnancy: In the hypertension spectrum. PMID- 29526395 TI - Up-regulation of HO-1 by Nrf2 activation protects against palmitic acid-induced ROS increase in human neuroblastoma BE(2)-M17 cells. AB - Saturated fatty acids (SFAs) induce reactive oxygen species (ROS) production in neurons. Extracellular signal regulated kinase (ERK)/nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) is a ROS response pathway. Therefore, high ROS is always accompanied by increase of HO-1, an anti-oxidative enzyme; but it remains unknown why there is no significant reduction of ROS with the increase of HO-1 in SFAs-treated neurons. We hypothesized that the up regulation of HO-1 is compensatory for response to fatty acid-induced oxidative stress but not enough to reduce ROS levels. We evaluated the anti-ROS effect of HO-1 and the involved pathway in palmitic acid (PA)-treated human neuroblastoma BE(2)-M17 cells. As expected, PA-induced ROS increase was accompanied by activation of the ERK-Nrf2-HO-1 pathway, as demonstrated by an increase in ERK phosphorylation, Nrf2 phosphorylation and nuclear accumulation, and HO-1 expression at the mRNA and protein levels, in a PA-dose-dependent manner. In contrast, administration of the ROS scavenger NAC significantly reduced the levels of PA-regulated ROS and HO-1 protein. However, the ERK inhibitor U0126 not only reversed the activating effect of PA on the ERK-Nrf2-HO-1 pathway but also aggravated PA-induced ROS. Furthermore, the Nrf2-specific activator NK-252 significantly increased PA-up-regulated HO-1 protein and alleviated PA-induced ROS. Therefore, our results suggest that up-regulation of HO-1 in PA-treated neurons is a compensatory response to ROS increase and that increasing HO-1 expression by Nrf2 activation can prevent the process of ROS production in PA treated neurons. PMID- 29526396 TI - Unexplained pain following total knee arthroplasty: Is rotational malalignment the problem? AB - BACKGROUND: Malrotation of tibial and femoral components is a potential source of pain following total knee arthroplasty (TKA). This study aimed to 1) compare component rotation in TKA patients with unexplained pain versus a control group with well-functioning TKAs and 2) investigate the relationship between TKA component rotation and pain. METHODS: Seventy one patients with unexplained pain after primary TKA were compared to a control cohort of 41 well functioning TKA patients. Both groups underwent post-operative computed tomography (CT) scans to assess component rotation. Findings were compared between the painful and control TKA groups. RESULTS: We found no difference in femoral component rotation between the painful and control groups (mean 0.6 degrees vs 1.0 degrees external rotation (ER), p=0.4), and no difference in tibial component rotation (mean 11.2 degrees vs 9.5 degrees internal rotation (IR), p=0.3). Also, there was no difference in combined mal-rotation (tibial+femoral rotation) between the groups (mean 10.5 degrees vs 8.5 degrees IR, p=0.25). Fifty-nine percent of patients in the painful group had tibial component rotation >9 degrees IR vs 49% in the control group. CONCLUSION: In the largest study yet on component rotation after TKA, we found no difference in the incidence of tibial, femoral, or combined component mal-rotation in painful versus well-functioning TKAs. Tibial component IR relative to the junction of the medial to middle thirds of the tibial tubercle appears to be common in patients with well-functioning TKAs. The significance of slight tibial IR should be interpreted with caution when evaluating the painful TKA. Level III retrospective case-control study. PMID- 29526397 TI - Peptidergic signaling in the tadpole shrimp Triops newberryi: A potential model for investigating the roles played by peptide paracrines/hormones in adaptation to environmental change. AB - Peptides are the largest/most diverse class of molecules used by animals for chemical communication, and with their cognate receptors, are key players in modulating physiological/behavioral control systems, including those involved in adaptation to environmental change. Crustaceans have long served as models for investigating peptidergic control of physiology/behavior, and members of Notostraca, an ancient branchiopod order, have recently been proposed as models for investigating the genetic/physiological underpinnings of ecoresponsiveness; nothing is currently known about the genes/proteins underlying peptidergic signaling in any member of this crustacean taxon. Transcriptome mining is a powerful tool for peptidome prediction in crustaceans, and all large-scale discovery of crustacean peptide receptors has been achieved via transcriptomics. Here, in silico transcriptome mining was used to elucidate the peptidergic signaling systems of the tadpole shrimp Triops newberryi, a member of Notostraca. Transcripts encoding putative precursor proteins and/or receptors for 28 peptide families were identified within the T. newberryi dataset. The deduced precursor proteins included those for allatostatin A, allatostatin B, allatostatin C, allatotropin, bursicon, CCHamide, crustacean cardioactive peptide, crustacean hyperglycemic hormone, diuretic hormone 44, ecdysis-triggering hormone, eclosion hormone, elevenin, FMRFamide-like peptide, glycoprotein hormone, GSEFLamide, inotocin, insulin-like peptide, neuroparsin, neuropeptide F, orcokinin/orcomyotropin, proctolin, pyrokinin/periviscerokinin, SIFamide, sulfakinin and tachykinin-related peptide; 117 distinct mature peptides were predicted from the collective set of deduced pre/preprohormones. Transcripts encoding putative receptors for most of the abovementioned peptide groups were also identified from the T. newberryi assembly, as were those for several families for which no precursors were found, i.e., corazonin, RYamide and short neuropeptide F. This is the first description of a peptidome and peptide receptors from any member of the Notostraca, and as such, provide a foundation for beginning to investigate the roles played by peptidergic signaling systems in T. newberryi and other notostracans, including how they may contribute to modulating organism-environment interactions. PMID- 29526398 TI - Human sperm proteins identified by 2-dimensional electrophoresis and mass spectrometry and their relevance to a transcriptomic analysis. AB - The aim of this study was to identify and analyse human sperm proteins from normozoospermic men using 2-dimensional electrophoresis (2-DE) and mass spectrometry (MS). We identified 73 different sperm proteins, including two less characterized human sperm proteins, Annexin A7 (ANXA7) and c14orf105. Bioinformatic analysis of detected sperm proteins revealed new carbohydrate and lipid metabolic pathways, which supply energy to motile sperm. A comparison of our data with available mRNA microarray data from the human testis allows for validation of identified sperm proteins and aids in the recognition of their physiological pathways. PMID- 29526399 TI - Corrigendum to "Global variations in pesticide regulations and health risk assessment of maximum concentration levels in drinking water" [J. Environ. Manag. 212 (15 April 2018) 384-394]. PMID- 29526400 TI - Loa loa: More Than Meets the Eye? PMID- 29526401 TI - Parasites and Their Impact on Ecosystem Nutrient Cycling. AB - Consumer species alter nutrient cycling through nutrient transformation, transfer, and bioturbation. Parasites have rarely been considered in this framework despite their ability to indirectly alter the cycling of nutrients via their hosts. A simple mathematical framework can be used to assess the relative importance of parasite-derived nutrients in an ecosystem. PMID- 29526402 TI - Transgenic Mosquitoes - Fact or Fiction? AB - Technologies for controlling mosquito vectors based on genetic manipulation and the release of genetically modified mosquitoes (GMMs) are gaining ground. However, concrete epidemiological evidence of their effectiveness, sustainability, and impact on the environment and nontarget species is lacking; no reliable ecological evidence on the potential interactions among GMMs, target populations, and other mosquito species populations exists; and no GMM technology has yet been approved by the WHO Vector Control Advisory Group. Our opinion is that, although GMMs may be considered a promising control tool, more studies are needed to assess their true effectiveness, risks, and benefits. Overall, several lines of evidence must be provided before GMM-based control strategies can be used under the integrated vector management framework. PMID- 29526403 TI - Schistosome-Induced Fibrotic Disease: The Role of Hepatic Stellate Cells. AB - Hepatic fibrosis is a common pathology in various liver diseases. Hepatic stellate cells (HSCs) are the main cell type responsible for collagen deposition and fibrosis formation in the liver. Schistosomiasis is characterised by granulomatous fibrosis around parasite eggs trapped within the liver and other host tissues. This response is facilitated by the recruitment of immune cells and the activation of HSCs. The interactions between HSCs and schistosome eggs are complex and diverse, and a better understanding of these interactions could lead to improved resolution of fibrotic liver disease, including that associated with schistosomiasis. Here, we discuss recent advances in HSC biology and the role of HSCs in hepatic schistosomiasis. PMID- 29526404 TI - Learning from Noise: How Observing Stochasticity May Aid Microbiology. AB - For many decades, the wedding of quantitative data with mathematical modeling has been fruitful, leading to important biological insights. Here, we review some of the ongoing efforts to gain insights into problems in microbiology - and, in particular, cell-cycle progression and its regulation - through observation and quantitative analysis of the natural fluctuations in the system. We first illustrate this idea by reviewing a classic example in microbiology - the Luria Delbruck experiment - and discussing how, in that case, useful information was obtained by looking beyond the mean outcome of the experiment, but instead paying attention to the variability between replicates of the experiment. We then switch gears to the contemporary problem of cell cycle progression and discuss in more detail how insights into cell size regulation and, when relevant, coupling between the cell cycle and the circadian clock, can be gained by studying the natural fluctuations in the system and their statistical properties. We end with a more general discussion of how (in this context) the correct level of phenomenological model should be chosen, as well as some of the pitfalls associated with this type of analysis. Throughout this review the emphasis is not on providing details of the experimental setups or technical details of the models used, but rather, in fleshing out the conceptual structure of this particular approach to the problem. For this reason, we choose to illustrate the framework on a rather broad range of problems, and on organisms from all domains of life, to emphasize the commonality of the ideas and analysis used (as well as their differences). PMID- 29526405 TI - Impact of Time to Treatment Initiation in Patients with Human Papillomavirus positive and -negative Oropharyngeal Squamous Cell Carcinoma. AB - AIMS: The distinct difference in disease phenotype of human papillomavirus positive (HPV+) and -negative (HPV-) oropharyngeal squamous cell cancer (OPSCC) patients might also be apparent when assessing the effect of time to treatment initiation (TTI). We assessed the overall survival and progression-free survival (PFS) effect from increasing TTI for HPV+ and HPV- OPSCC patients. MATERIALS AND METHODS: We examined patients who received curative-intended therapy for OPSCC in eastern Denmark between 2000 and 2014. TTI was the number of days from diagnosis to the initiation of curative treatment. Overall survival and PFS were measured from the start of treatment and estimated with the Kaplan-Meier estimator. Hazard ratios and 95% confidence intervals were estimated with Cox proportional hazard regression. RESULTS: At a median follow-up of 3.6 years (interquartile range 1.86 6.07 years), 1177 patients were included (59% HPV+). In the adjusted analysis for the HPV+ and HPV- patient population, TTI influenced overall survival and PFS, most evident in the HPV- group, where TTI >60 days statistically significantly influenced overall survival but not PFS (overall survival: hazard ratio 1.60; 95% confidence interval 1.04-2.45; PFS: hazard ratio 1.46; 95% confidence interval 0.96-2.22). For patients with a TTI >60 days in the HPV+ group, TTI affected overall survival and PFS similarly, with slightly lower hazard ratio estimates of 1.44 (95% confidence interval 0.83-2.51) and 1.15 (95% confidence interval 0.70 1.88), respectively. CONCLUSION: For patients treated for a HPV+ or HPV- OPSCC, TTI affects outcome, with the strongest effect for overall survival among HPV- patients. Reducing TTI is an important tool to improve the prognosis. PMID- 29526407 TI - The therapeutic effect of anti-CD52 treatment in murine experimental autoimmune encephalomyelitis is associated with altered IL-33 and ST2 expression levels. AB - Experimental autoimmune encephalomyelitis (EAE) mice were administered with murine anti-CD52 antibody to investigate its therapeutic effect and whether the treatment modulates IL-33 and ST2 expression. EAE severity and central nervous system (CNS) inflammation were reduced following the treatment, which was accompanied by peripheral T and B lymphocyte depletion and reduced production of various cytokines including IL-33, while sST2 was increased. In spinal cords of EAE mice, while the number of IL-33+ cells remained unchanged, the extracellular level of IL-33 protein was significantly reduced in anti-CD52 antibody treated mice compared with controls. Furthermore the number of ST2+ cells in the spinal cord of treated EAE mice was downregulated due to decreased inflammation and immune cell infiltration in the CNS. These results suggest that treatment with anti-CD52 antibody differentially alters expression of IL-33 and ST2, both systemically and within the CNS, which may indicate IL-33/ST2 axis is involved in the action of the antibody in inhibiting EAE. PMID- 29526406 TI - Morphine-potentiated cognitive deficits correlate to suppressed hippocampal iNOS RNA expression and an absent type 1 interferon response in LP-BM5 murine AIDS. AB - Opioid use accelerates neurocognitive impairment in HIV/AIDS patients. We assessed the effect of chronic morphine treatment and LP-BM5/murine AIDS (MAIDS) infection on cognition, cytokine production, and type 1 interferon (IFN) expression in the murine CNS. Morphine treatment decreased expression of pro inflammatory factors (CCL5, iNOS) and reduced cognitive performance in LP-BM5 infected mice, correlating to increased hippocampal viral load and a blunted type 1 IFN response. In the striatum, morphine reduced viral load while increasing IFN alpha RNA expression. Our results suggest that differentially regulated type 1 IFN responses may contribute to distinct regional outcomes in the hippocampus and striatum in LP-BM5/MAIDS. PMID- 29526408 TI - An 8-year study of people with multiple sclerosis in Isfahan, Iran: Association between environmental air pollutants and severity of disease. AB - The evidence for an impact of ambient air pollution on the incidence and severity of multiple sclerosis (MS) is still limited. In the present study, we assessed the association between daily air pollution levels and MS prevalence and severity in Isfahan city, Iran. Data related to MS patients has been collected from 2008 to 2016 in a referral university clinic. The air quality index (AQI) data, were collected from 6 monitoring stations of Isfahan department of environment. The distribution map presenting the sites of air pollution monitoring stations as well as the residential address of MS patients was plotted on geographical information system (GIS). An increase in AQI level in four areas of the city (north, west, east and south) was associated with higher expanded disability status scale (EDSS) of MS patients[logistic regression odds ratio = 1.01 (95% CI = 1.008,1.012)]. Moreover, significant inverse association between the complete remission after the first attack with AQI level in total areas [logistic regression odds ratio = 0.987 (95% CI = 0.977, 0.997)] was found in crude model. However, after adjustment for confounding variables through multivariate logistic regression, AQI level was associated with degree of complete remission after first attack 1.005 (95% CI = 1.004, 1.006). The results of our study suggest that air pollution could play a role in the severity and remission of MS disease. However, more detailed studies with considering the complex involvement of different environmental factors including sunlight exposure, diet, depression and vitamin D are needed to determine the outcome of MS. PMID- 29526409 TI - Marked asymmetry in vertical force (but not contact times) during running in ACL reconstructed athletes <9 months post-surgery despite meeting functional criteria for return to sport. AB - OBJECTIVES: Compare maximum plantar force (Fmax) during running in soccer players following anterior cruciate ligament reconstruction (ACLR) as they pass return to sport (RTS) criteria. DESIGN: Case control study. METHODS: Soccer players after ACLR (n=16) and matched healthy controls (n=16) ran on a treadmill at 12, 14 and 16km/h while plantar loading data was measured using an in-shoe pressure system (Pedar-X, Novel). Fmax and contact time of the injured and uninjured limbs in athletes <9months post-ACLR and those >=9months ACLR were compared to healthy players (no ACLR). RESULTS: Significant differences with large effect sizes in Fmax asymmetry were seen at all running speeds for the athletes <9months ACLR compared to those >=9months, and the healthy subjects. Fmax difference peaked at 16km/h; 32+/-11%BW in <9months ACLR group compared to 6+/-5%BW in >=9months group; ES=1.67, p<0.01. There was a non-significant trend for increasing asymmetry with increasing speed for subjects who were <9months after ACLR while the reverse was true for those >=9 months and the healthy subjects. CONCLUSIONS: Relatively large unloading of the ACLR limb (but not differences in contact times) are seen during running for athletes <9months post-ACLR despite having completed functional criteria required to permit RTS training. These asymmetries appear to slightly increase with increasing speed, and the reverse is true for healthy controls and those >=9months after ACLR surgery. PMID- 29526410 TI - Impingement-type bony morphology was related to cartilage defects, but not pain in professional ballet dancers' hips. AB - OBJECTIVES: Professional ballet dancers may have hip bony morphology that predisposes them to cartilage or labral injury. However, the relationship between bony morphology and pathology has not been investigated in ballet. This study investigates associations between bony morphology, chondrolabral defects and hip pain in ballet dancers. DESIGN: Cross-sectional study. METHODS: 33 male and female professional ballet dancers, (mean age 27 years (range 19-39)), completed questionnaires with hip pain measured on a visual analogue scale; and underwent 3.0-T magnetic resonance imaging (3T MRI) to measure lateral centre edge angles (LCEA), alpha angles in the anterior and superior position, femoral neck-shaft angles (NSA) and acetabular version angles; and to detect acetabular labral tear and articular cartilage defects. RESULTS: Seventeen dancers (51.5%) had impingement-type (alpha angle>50.5 degrees or acetabular version <10 degrees or >20 degrees ) and 19 (58%) had instability-type (LCEA<25 degrees or NSA>135 degrees ) bony morphology. Cartilage defect prevalence was higher in dancers with impingement-type bony morphology (n=14) compared to those without impingement type morphology (n=4, p=0.001). There was no relationship between instability type bony morphology and cartilage defects (p>0.05). There was no relationship between labral tears and bony morphology (p>0.05). Neither chondrolabral pathology nor any morphological feature were associated with hip pain (p>0.05 for all). CONCLUSIONS: Impingement-type bony morphology was related to cartilage defects, but not labral tear. Hip pain was not associated with pathology or bony morphology. Longitudinal studies are warranted to determine if bony features, such as cam morphology, acetabular retroversion or anteversion, are precursors to symptomatic hip joint injury or osteoarthritis. PMID- 29526411 TI - Bone mineral density in pre-professional female ballet dancers: A systematic review and meta-analysis. AB - OBJECTIVES: To quantitatively compare bone mineral density (BMD) outcomes between pre-professional female adolescent ballet dancers and control populations. DESIGN: Systematic review and meta-analysis. METHODS: Six electronic databases and relevant journals were systematically searched up to August 2017. Included articles examined BMD in adolescent females undergoing pre-professional ballet training and healthy age-matched controls with an available English full text. Dancers were aged 15-19 years and trained in ballet at least 10h per week. BMD data were analysed via standardized mean difference to account for differences in reporting methods RESULTS: From 3984 potential articles, 8 cross-sectional studies were accepted for inclusion, which compared 293 dancers (16.9+/-0.8 years) to 333 controls (16.9+/-0.9 years). No data were available from longitudinal studies. Dancers displayed lower BMD at the radius and higher BMD at the femoral neck, femoral trochanter and Ward's triangle. No significant differences were observed in the lumbar spine or tibia. The overall study quality was low and heterogeneity was present in some analyses. CONCLUSIONS: This meta analysis indicates that there may be a site-specific osteogenic effect of pre professional classical ballet training in adolescent females, with a notable and concerning finding of reduced upper limb BMD compared to age-matched controls. Longitudinal cohort studies are required to confirm the effects of pre professional ballet training on BMD during adolescence. PMID- 29526413 TI - Assessment of tumor margins in head and neck cancer using a 3D-navigation system based on PET/CT image-fusion - A pilot study. AB - OBJECTIVES: Determination of tumor margins in patients with squamous cell carcinoma of the head and neck (SCCHN) is mostly based on preoperative magnetic resonance imaging (MRI) or computed tomography scans (CT). Local recurrence of disease is often correlated with the presence of positive resection margins after surgical treatment. Positron emission tomography/computed tomography (PET/CT) imaging plays a crucial role in the assessment of patients with SCCHN. The purpose of this study was to determine whether PET/CT could predict tumor extension. METHODS: In 12 patients who underwent surgical treatment of primary SCCHN (Stage III-IV) F18-FDG PET/CT image-fusion was performed on a 3D navigation system based workstation. Image-guided needle biopsies were obtained from four different, color-coded metabolic areas within the tumor. The histopathological findings were correlated with findings on corresponding PET/CT scans. RESULTS: 81.3% of biopsies from the central area were positive. Specimens taken from the outer metabolic zone were positive in 66.7% of the patients. The highest incidence of positive biopsies was found in the zone adjacent to the outermost area. There was a statistically significant difference in positive tumor histopathology when comparing the various metabolic zones (p = 0.03). CONCLUSION: Exact determination of tumor is an important research topic, although results remain controversial. The results of this study suggest that in some cases PET scans may overestimate tumor extension. PMID- 29526412 TI - Current concepts in cleft care: A multicenter analysis. AB - The current surgical techniques used in cleft repair are well established, but different centers use different approaches. To determine the best treatment for patients, a multi-center comparative study is required. In this study, we surveyed all craniofacial departments registered with the German Society of Maxillofacial Surgery to determine which cleft repair techniques are currently in use. Our findings revealed much variation in cleft repair between different centers. Although most centers did use a two-stage approach, the operative techniques and timing of lip and palate closure were different in every center. This shows that a retrospective comparative analysis of patient outcome between the participating centers is not possible and illustrates the need for prospective comparative studies to establish the optimal technique for reconstructive cleft surgery. PMID- 29526414 TI - Experiences with a modified preauricular mini incision with subdermally dissection in condylar and subcondylar fractures of the mandible. AB - OBJECTIVE: Condylar and subcondylar fractures (CSFs) are among the most common mandible fractures. If reduction of these fractures is not carried out correctly, serious complications can result, including infection, damage to temporomandibular joint (TMJ) function, malocclusion, nonunion, malunion, and ankylosis of the TMJ. METHODS: We used a preauricular, mini-incision, open technique (PMIOT) for CSF of the mandible. 66 patients (48 males, 18 females), with a total of 72 CSFs of the mandible, were repaired with PMIOT between 2011 and 2016. Average age was 37.8 years (range: 8-78). CSFs were located on the right side, left side, and bilaterally in 21, 27 and six patients, respectively. We used only one mini incision of length 2 cm for non-displaced subcondylar fractures. However, we had to perform a second mini incision for condylar fractures displaced by more than 45 degrees , where subcondylar fractures overlapped, or where there was deep surgical exposure and difficulty with reduction. RESULTS: No early complications, such as bleeding, hematoma, seroma, infection, or parotid fistula, were seen in any patients. Temporary facial nerve paresis was reported in three patients, but these recovered spontaneously with conservative treatment within 15 days. Permanent facial nerve paralysis occurred in none of the patients. CONCLUSION: We believe that PMIOT is an effective, reliable, and feasible method for repair of CSF. It does not need any expensive and sophisticated tools, and has low complication rates. The mini incision used in our technique results in both a hidden scar and protection of essential structures in the region. PMID- 29526415 TI - Corrigendum to "Anxiety, neuroinflammation, cholinergic and GABAergic abnormalities are early markers of Gulf War illness in a mouse model of the disease" [Brain Res. 1681 (2018) 34-43]. PMID- 29526416 TI - Comparison of Magnetic Resonance Analysis of Myocardial Scarring With Biomarker Release Following S-T Elevation Myocardial Infarction. AB - BACKGROUND: Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) is commonly assumed to represent myocardial fibrosis; however, comparative human histological data are limited, and there is no consensus on the most accurate method for LGE quantitation. We evaluated the relationship between CMR assessment of regional fibrosis and infarct size assessment using serial biomarkers after ST elevation acute myocardial infarction (STEMI). METHODS: Ninety-three patients treated for STEMI (59+/-10 years, 86% male) underwent CMR 6 months after infarction. Infarct size was quantified by CMR-LGE using manual and range of semi-automated thresholds (range: 2-10 standard deviations [SD]) above reference myocardium and the full width-half maximum (FWHM) technique, and compared with the rise in serum biomarkers. The agreement between CMR and biomarker in the identification of large infarcts based on peak troponin (TnI) levels was also analysed. RESULTS: Quantification methods had a strong influence on the infarct size assessment with CMR-LGE. Significant correlations were observed between LGE and biomarkers across all of the signal intensity thresholds. Whilst there was a wide variation with respect to the estimation of total LGE size (from 6.8+/-7.7 to 32.1+/-11.3 grams), the variation in the correlation with peak troponin level was much smaller (r-values ranging from 0.670 to 0.876). There was good agreement between CMR-LGE and biomarker assessment of infarct size; the best agreement between CMR-LGE and large infarction using a threshold of 8SD for peak TnI>50ng/mL (Cohen's kappa (kappa)=0.722), and a threshold of 4SD for peak TnI >95ng/mL (kappa=0.761). CONCLUSIONS: The correlation between CMR-LGE quantification of infarct size and biomarker release following STEMI at a range of semi-automated thresholds was consistently strong, with good agreement between measures across a range of thresholds. PMID- 29526417 TI - Comparison of CRUSADE and ACUITY-HORIZONS Bleeding Risk Scores in Patients with Acute Coronary Syndromes. AB - BACKGROUND: Compare the discriminative performance of two validated bleeding risk models for in-hospital bleeding events in a non-selected cohort of acute coronary syndrome (ACS) patients. METHODS: CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) and ACUITY-HORIZONS (Acute Catheterization and Urgent Intervention Triage strategY-Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) scores were calculated in 501 consecutive patients (median age 68 years (IQR 57-77), 31% female) admitted for ACS to the coronary care unit (CCU) of San Paolo Hospital in Milan (Italy). In-hospital haemorrhagic events and mortality were recorded and calibration and discrimination of the two risk models were evaluated using the Hosmer-Lemeshow test and the C-statistic, respectively. RESULTS: Overall bleeding events were observed in 32 patients and major bleedings in 11 (with an incidence of 6.4% and 2.2%, respectively). In-hospital mortality was 2.6%. Regarding major bleedings both risk scores demonstrated an adequate calibration (H-L test p>0.20) and a moderate discrimination with no significant difference in predictive accuracy between the two models (C-statistic 0.69 for CRUSADE and 0.73 for ACUITY HORIZONS). We also tested the performance of the two risk models in predicting in hospital mortality, showing an adequate calibration and a very good discrimination (C-statistic 0.88 and 0.89 for the CRUSADE and ACUITY-HORIZONS scores, respectively), with no significant difference in predictive accuracy. CONCLUSIONS: In our ACS population the CRUSADE and the ACUITY-HORIZONS risk scores showed a fairly good and comparable predictive accuracy regarding in hospital bleeding events and they appeared to be very good predictors of in hospital mortality. PMID- 29526418 TI - Resistant Hypertension: Which Agent? AB - Resistant hypertension is commonly defined as office blood pressure above recommended target despite the use of optimal doses of at least three antihypertensive drugs including a diuretic. Australian guidelines recommend combination of blockers of the renin-angiotensin system, either ACE inhibitors or angiotensin receptor blockers, with calcium channel blockers and diuretics as the preferred triple therapy. A substantial proportion of hypertensive patients will require additional pharmacotherapy to achieve or get close to target blood pressure levels. Here we briefly review the evidence currently available to provide guidance on the most appropriate choice for additional antihypertensive pharmacotherapy and touch on interventional approaches that may be considered in some patients. PMID- 29526419 TI - Physical model of qualitative cognition: Comment on "Physics of mind: Experimental confirmations of theoretical predictions" by F. Schoeller, L. Perlovsky and D. Arseniev. PMID- 29526420 TI - A sadness-independent account of the enjoyment of music-evoked sadness: Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29526421 TI - The need to consider pluralistic functions of music from a global perspective: Comment on "Physics of mind: Experimental confirmations of theoretical predictions" by Felix Schoeller et al. PMID- 29526422 TI - How much free energy is absorbed upon breaking DNA base pairs?: Comment on "DNA melting and energetics of the double helix" by Maxim Frank-Kamenetskii et al. PMID- 29526423 TI - The nature of music-induced sadness and the role of kama muta: Comment on "An integrative review of the enjoyment of sadness associated with music" by Eerola et al. PMID- 29526424 TI - [Specific aspects of the management of women with epilepsy]. AB - Catamenial epilepsy, defined as the exacerbation of the frequency of seizures in a given phase of the menstrual cycle, affects 35% of women. In women with catamenial epilepsy with perimenstrual seizures, progesterone therapy may be effective. In case of enzyme inducer AEDs, hormonal contraception is deprecated (estroprogestative or progestative pill, progestative implant, patches or hormonal rings). Because of its high malformative teratogenic potential, its possible depressive cognitive effects and the autistic risk, sodium valproate is not indicated during pregnancy. To date, the most recommended AEDs for pregnancy are lamotrigine and levetiracetam. Plasma drug monitoring is recommended during pregnancy. The decision to breastfeed remains individual depending mainly on the term of delivery and the type of antiepileptic treatment. PMID- 29526425 TI - Lichenoid drug eruption associated with rifampicin. PMID- 29526426 TI - [Beware of back pain]. PMID- 29526427 TI - [Acute aortic syndromes]. AB - Acute aortic syndromes include aortic dissections, intramural hematomas, penetrating ulcers, ruptured or contained ruptured aortic aneurysms. In presence of acute thoracic or dorsal pain, elevated D-Dimers and if acute coronary artery syndrome has been ruled out, additional imaging should be performed to detect acute aortic pathologies. Acute type A dissections involve the ascending aorta. Emergent open repair is the preferred treatment. Acute type B dissections involve the thoracic descending aorta. Endovascular treatment using thoracic stent grafts is indicated in complicated cases (malperfusion, rupture, uncontrolled hypertension) or in cases where risk factors of aortic degeneration are identified. Regarding ruptured abdominal aortic aneurysms, optimization techniques recently led to a reduced postoperative mortality. They include adequate treatment of abdominal compartment syndrome, use of aortic stent grafts, endovascular balloon occlusion and permissive hypotension. Symptomatic complex aneurysms encompass renal and visceral arteries. Nowadays, they can be treated in an urgent setting using new endovascular techniques, such as "off-the shelf" branched stent grafts, parallel techniques, home made or in situ fenestrations of standard stent grafts. PMID- 29526428 TI - [Status epilepticus: Recent advances]. AB - About half of status epilepticus (SE) occur in patients without epilepsy. An EEG has to be performed quickly in any patient who remains unconscious after the end of convulsions with the aim to detect a subtle status. An EEG should be performed as soon as possible in case of suspicion of non-convulsive status epilepticus, or in case of a confusional state whose origin remains unknown. The realization of a cerebral imaging is very often necessary in case of inaugural SE, as soon as the patient's condition allow it. It is also often indicated in case of known epilepsy. The main differential diagnosis of convulsive SE is psychogenic non epileptic status. In non-convulsive status epilepticus, the use of anesthetic agents should be considered only rarely, as the risks of such an approach are often greater than the expected benefits. PMID- 29526429 TI - [Diagnosis and management of de novo epilepsy]. AB - The diagnosis of de novo epilepsy is complex. An accurate diagnostic approach has to be followed based on specific key steps. Epileptic seizure or non-epileptic malaise: risk of diagnosis error around 20%. Facing a first unprovoked seizure, the practitioner has to know the risk factors specifically linked to an increase risk of seizure recurrence. In presence of these factors, an antiepileptic drug would be indicated. The first antiepileptic drug has to be highly selected according to the epilepsy type and causes but also to the patient characteristics (sex, age, comorbidities, associated drugs, profession, and way of life...) An exhaustive patient Education needs to support the first antiepileptic drug prescription: (sleep and nutritional advices, benefit of observance, antiepileptic drugs features and side effects, follow-up, prognosis...) A regular follow-up is essential to control the observance, tolerability and efficacy of the antiepileptic drug, and to control also the good acceptance of the disease. A systematic research of common comorbidities may be also performed. Electroencephalogram and antiepileptic drugs levels are unnecessary in the classical follow up of known epileptic patients (except specific cases). PMID- 29526430 TI - [Autopsy legal under the law]. AB - Only a physician specialized in forensic medicine is allowed to process a autopsy legal. The 2011 reform of forensic medicine aimed to homogenize and enhance thanatological practices over French state territory. According to the law, biological samples withdrawn during an autopsy can't be given back to the families after analysis(art. 230-30 CPP). Respecting the human body and restoring their physical aspect are mandatory by law (art. 230-29 CPP). After a autopsy legal, dead bodies must be given back to their relatives as soon as possible. PMID- 29526431 TI - Structural Insights into the Inhibition of Zika Virus NS2B-NS3 Protease by a Small-Molecule Inhibitor. AB - Zika virus (ZIKV) infection has become a global public health concern. The viral NS2B-NS3 protease is an attractive antiviral target because of its role in maturation of viral non-structural proteins. Substrate-derived protease inhibitors have been investigated, but it remains challenging to develop them into drugs. Small-molecule inhibitors are of great interest in antiviral drug development. Here we report the structure and dynamics of ZIKV NS2B-NS3 protease covalently bound to a small-molecule inhibitor. Our crystallographic and NMR studies demonstrate that the inhibitor further stabilizes the closed conformation of ZIKV protease. Upon hydrolysis in situ into two fragments, the benzoyl group of the inhibitor forms a covalent bond with the side chain of catalytic residue S135, whereas the second fragment exhibits no obvious molecular interactions with the protease. This study provides a detailed mechanism of action for a covalent inhibitor, which will guide further development of ZIKV protease inhibitors. PMID- 29526432 TI - Cork-in-Bottle Occlusion of Fluoride Ion Channels by Crystallization Chaperones. AB - Crystallization of dual-topology fluoride (Fluc) channels requires small, soluble crystallization chaperones known as monobodies, which act as primary crystal lattice contacts. Previous structures of Flucs have been solved in the presence of monobodies that inhibit fluoride currents in single-channel electrophysiological recordings. These structures have revealed two-fold symmetric, doubly bound arrangements, with one monobody on each side of the membrane. The combined electrophysiological and structural observations raise the possibility that chaperone binding allosterically closes the channel, altering the structure from its conducting form. To address this, we identify and solve the structure with a different monobody that only partially blocks fluoride currents. The structure of the channel-monobody complex is asymmetric, with monobody bound to one side of the channel only. The channel conformation is nearly identical on the bound and uncomplexed sides, and to all previously solved structures, providing direct structural evidence that monobody binding does not induce local structural changes. PMID- 29526433 TI - Anticalins Reveal High Plasticity in the Mode of Complex Formation with a Common Tumor Antigen. AB - We describe the comparative X-ray structural analysis of three Anticalin proteins directed against the extra-domain B (ED-B) of oncofetal fibronectin (Fn), a validated marker of tumor neoangiogenesis. The Anticalins were engineered from the human lipocalin 2 (Lcn2) scaffold via targeted randomization of the structurally variable loop region and selection by phage display, resulting in 15 19 exchanged residues. While the four reshaped loops exhibit diverse conformations (with shifts in Calpha positions up to 20.4 A), the beta-barrel core of the lipocalin remains strongly conserved, thus confirming the extraordinary robustness of this scaffold. All three Anticalins bind the cc' hairpin loop of ED-B, the most exposed motif in the context of its neighboring Fn domains, but reveal entirely different binding modes, with orientations differing by up to 180 degrees . Hence, each Anticalin recognizes its molecular target in an individual manner, in line with the distinct epitope specificities previously seen in binding experiments. PMID- 29526434 TI - Unique Substrate Specificity of SplE Serine Protease from Staphylococcus aureus. AB - Staphylococcus aureus is a dangerous human pathogen characterized by alarmingly increasing antibiotic resistance. Accumulating evidence suggests the role of Spl proteases in staphylococcal virulence. Spl proteases have restricted, non overlapping substrate specificity, suggesting that they may constitute a first example of a proteolytic system in bacteria. SplA, SplB, and SplD were previously characterized in terms of substrate specificity and structural determinants thereof. Here we analyze the substrate specificity of SplE documenting its unique P1 preference among Spl proteases and, in fact, among all chymotrypsin-like (family S1) proteases characterized to date. This is interesting since our understanding of the general aspects of proteolysis is based on seminal studies of S1 family members. To better understand the molecular determinants of the unusual specificity of SplE, the crystal structure of the protein is determined here. Conclusions from structural analysis are evaluated by successful grafting of SplE specificity on the scaffold of SplB protease. PMID- 29526435 TI - Structural and Functional Insights into Bacillus subtilis Sigma Factor Inhibitor, CsfB. AB - Global changes in bacterial gene expression can be orchestrated by the coordinated activation/deactivation of alternative sigma (sigma) factor subunits of RNA polymerase. Sigma factors themselves are regulated in myriad ways, including via anti-sigma factors. Here, we have determined the solution structure of anti-sigma factor CsfB, responsible for inhibition of two alternative sigma factors, sigmaG and sigmaE, during spore formation by Bacillus subtilis. CsfB assembles into a symmetrical homodimer, with each monomer bound to a single Zn2+ ion via a treble-clef zinc finger fold. Directed mutagenesis indicates that dimer formation is critical for CsfB-mediated inhibition of both sigmaG and sigmaE, and we have characterized these interactions in vitro. This work represents an advance in our understanding of how CsfB mediates inhibition of two alternative sigma factors to drive developmental gene expression in a bacterium. PMID- 29526437 TI - Multilayered and versatile inhibition of cellular antiviral factors by HIV and SIV accessory proteins. AB - HIV-1, the main causative agent of AIDS, and related primate lentiviruses show a striking ability to efficiently replicate throughout the lifetime of an infected host. In addition to their high variability, the acquisition of several accessory genes has enabled these viruses to efficiently evade or counteract seemingly strong antiviral immune responses. The respective viral proteins, i.e. Vif, Vpr, Vpu, Vpx and Nef, show a stunning functional diversity, acting by various mechanisms and targeting a large variety of cellular factors involved in innate and adaptive immunity. A focus of the present review is the accumulating evidence that Vpr, Vpu and Nef not only directly target cellular antiviral factors at the protein level, but also suppress their expression by modulating the activity of immune-regulatory transcription factors such as NF-kappaB. Furthermore, we will discuss the ability of accessory proteins to act as versatile adaptors, removing antiviral proteins from their sites of action and/or targeting them for proteasomal or endolysosomal degradation. Here, the main emphasis will be on emerging examples for functional interactions, synergisms and switches between accessory primate lentiviral proteins. A better understanding of this complex interplay between cellular immune defense mechanisms and viral countermeasures might facilitate the development of effective vaccines, help to prevent harmful chronic inflammation, and provide insights into the establishment and maintenance of latent viral reservoirs. PMID- 29526438 TI - Let me in: Control of HIV nuclear entry at the nuclear envelope. AB - The nuclear envelope is a physical barrier that isolates the cellular DNA from the rest of the cell, thereby limiting pathogen invasion. The Human Immunodeficiency Virus (HIV) has a remarkable ability to enter the nucleus of non dividing target cells such as lymphocytes, macrophages and dendritic cells. While this step is critical for replication of the virus, it remains one of the less understood aspects of HIV infection. Here, we review the viral and host factors that favor or inhibit HIV entry into the nucleus, including the viral capsid, integrase, the central viral DNA flap, and the host proteins CPSF6, TNPO3, Nucleoporins, SUN1, SUN2, Cyclophilin A and MX2. We review recent perspectives on the mechanism of action of these factors, and formulate fundamental questions that remain. Overall, these findings deepen our understanding of HIV nuclear import and strengthen the favorable position of nuclear HIV entry for antiviral targeting. PMID- 29526439 TI - Single-energy non-contrast hepatic steatosis criteria applied to virtual non contrast images: is it still highly specific and positively predictive? AB - AIM: To determine the sensitivity, specificity, and predictive values of single energy non-contrast hepatic steatosis criteria on dual-energy virtual non contrast (VNC) images. MATERIALS AND METHODS: Forty-eight computed tomography (CT) examinations, which included single-energy non-contrast (TNC) and contrast enhanced dual-energy CT angiography (CTA) of the abdomen, were enrolled. VNC images were reconstructed from the CTA. Region of interest (ROI) attenuations were measured in the right and left hepatic lobes, spleen, and aorta on TNC and VNC images. The right and left hepatic lobes were treated as separate samples. Steatosis was diagnosed based on TNC liver attenuation of <=40 HU or liver attenuation index (LAI) of <=-10 HU, which are extremely specific and predictive for moderate to severe steatosis. The sensitivity, specificity, and predictive values of VNC images for steatosis were calculated. VNC-TNC deviations were correlated with aortic enhancement and patient water equivalent diameter (PWED). RESULTS: Thirty-two liver ROIs met steatosis criteria based on TNC attenuation; VNC attenuation had sensitivity, specificity, and a positive predictive value of 66.7%, 100%, and 100%, respectively. Twenty-one liver ROIs met steatosis criteria based on TNC LAI. VNC LAI had sensitivity, specificity, and positive predictive values of 61.9%, 90.7%, and 65%, respectively. Hepatic and splenic VNC-TNC deviations did not correlate with one another (R2=0.08), aortic enhancement (R2<0.06) or PWED (R2 <0.09). CONCLUSIONS: Non-contrast hepatic attenuation criteria is extremely specific and positively predictive for moderate to severe steatosis on VNC reconstructions from the arterial phase. Hepatic attenuation performs better than LAI criteria. VNC deviations are independent of aortic enhancement and PWED. PMID- 29526436 TI - Integrated Structural Biology for alpha-Helical Membrane Protein Structure Determination. AB - While great progress has been made, only 10% of the nearly 1,000 integral, alpha helical, multi-span membrane protein families are represented by at least one experimentally determined structure in the PDB. Previously, we developed the algorithm BCL::MP-Fold, which samples the large conformational space of membrane proteins de novo by assembling predicted secondary structure elements guided by knowledge-based potentials. Here, we present a case study of rhodopsin fold determination by integrating sparse and/or low-resolution restraints from multiple experimental techniques including electron microscopy, electron paramagnetic resonance spectroscopy, and nuclear magnetic resonance spectroscopy. Simultaneous incorporation of orthogonal experimental restraints not only significantly improved the sampling accuracy but also allowed identification of the correct fold, which is demonstrated by a protein size-normalized transmembrane root-mean-square deviation as low as 1.2 A. The protocol developed in this case study can be used for the determination of unknown membrane protein folds when limited experimental restraints are available. PMID- 29526440 TI - Energy drinks, alcohol and cardiovascular functioning. PMID- 29526441 TI - Airborne particle dispersion to an operating room environment during sliding and hinged door opening. AB - BACKGROUND: Operating rooms (ORs) are usually over-pressurized in order to prevent the penetration of contaminated air and the consequent risk of surgical site infection. However, a door-opening can result in the rapid disappearance of pressure and contaminants can then easily penetrate into the surgical zone. Therefore, a broad knowledge and understanding of OR ventilation systems and their protective potential is essential for optimizing the surgical environment. OBJECTIVES: This study investigated the air quality and level of airborne particles during a single and multiple door-opening cycles in an operating room supplied by a turbulent-mixing ventilation system. METHODS: The exploration was carried out numerically using computational fluid dynamics. Model validation was performed to ensure the validity of the achieved results. The OR was initially over-pressurized by approximately 15Pa, relative to the adjacent corridors. Both sliding and hinged doors were simulated and compared. RESULTS: Penetration of bacteria carrying particles from the corridors to the OR can be successfully restricted by using a positive-pressure system. However, the results clearly indicate that frequent door opening can interfere with airflow ventilation systems, alter the pressure gradient, and increase the infection risk for the patient undergoing surgical intervention. Door-opening disturbs the airflow field and could result in containment failure. PMID- 29526444 TI - Healthcare predictive analytics: An overview with a focus on Saudi Arabia. AB - Despite a newfound wealth of data and information, the healthcare sector is lacking in actionable knowledge. This is largely because healthcare data, though plentiful, tends to be inherently complex and fragmented. Health data analytics, with an emphasis on predictive analytics, is emerging as a transformative tool that can enable more proactive and preventative treatment options. This review considers the ways in which predictive analytics has been applied in the for profit business sector to generate well-timed and accurate predictions of key outcomes, with a focus on key features that may be applicable to healthcare specific applications. Published medical research presenting assessments of predictive analytics technology in medical applications are reviewed, with particular emphasis on how hospitals have integrated predictive analytics into their day-to-day healthcare services to improve quality of care. This review also highlights the numerous challenges of implementing predictive analytics in healthcare settings and concludes with a discussion of current efforts to implement healthcare data analytics in the developing country, Saudi Arabia. PMID- 29526442 TI - Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia. AB - BACKGROUND: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. METHODS: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. RESULTS: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval -5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p=0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR)=1.2; 95% CI, 0.3-4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR)=5.4; 95% CI, 1.1-26.8). CONCLUSION: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections. PMID- 29526445 TI - Hypoxemia After Percutaneous Mitral Valve Replacement: Management. PMID- 29526443 TI - Diagnostic performance of the RT-qPCR method targeting 85B mRNA in the diagnosis of pulmonary Mycobacterium tuberculosis infection. AB - BACKGROUND: Several nucleic acid amplification techniques (IS6110, 16S rRNA, and 85B mRNA) were developed for the rapid, direct detection of Mycobacterium tuberculosis. We aimed to assess the diagnostic performance of 85B mRNA-based RT qPCR by comparing with the real-time PCR COBAS TaqMan MTB Kit while using the BACTEC MGIT 960 method as the gold standard. METHODS: 60 patients with confirmed pulmonary TB and 60 individuals without TB were included as the study and control groups, respectively. Sputum specimens were cultured using LJ and BACTEC MGIT 960 systems. Extracted DNA was used for COBAS PCR in a CONAS TaqMan 48 analyzer. 85B mRNA detection was performed by RT-qPCR. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of COBAS TaqMan MTB Test were detected as 93.3%, 83.3%, 84.8%, 92.6%, and 88.3%, respectively. The same diagnostic parameters of RT-qPCR were: 98.3%, 95.0%, 95.2%, 98.3%, and 96.7%, respectively. According to the binary logistic regression analysis, RT-qPCR (OR: 19,924, p<0.001) was identified as the more optimal test. CONCLUSION: RT-qPCR targeting the 85B gene of M. tuberculosis seems to be a more useful and rapid technique than DNA-based methods for detecting live M. tuberculosis bacilli from sputum specimens. PMID- 29526447 TI - Computerized tomographic evaluation of supraorbital notches and foramen in patients with frontal migraine headaches and correlation with clinical symptoms. AB - PURPOSE: To correlate the location and size of supraorbital notches (SON) and foramen (SOF) with migraine headache symptoms in a migraine patient population. METHODS: A retrospective review was performed on consecutive patients who were candidates for frontal migraine surgery with available preoperative computed tomography (CT) images of the face/perinasal sinuses. The supraorbital anatomy from CT images was analyzed and correlated with presenting migraine headache symptoms. To assess for anatomic variations associated with migraine headaches, normative anatomic data were obtained by performing a meta-analysis. RESULTS: Fifty-six patients were included, 95% were female, aged 17-80 (mean = 47) years. Bilateral SON were present in 58.9% patients, combination of SON/SOF in 25%, and bilateral SOF in 16.1%. SOF mean diameter (1.22 mm) was 45% smaller than SON (2.20 mm, p < 0.0001). The mean lateral distance from midline for SOF (2.74 cm) was ~0.5 cm farther than SON (2.25 cm, p < 0.0001). Migraine patients with SOF had 178.6% longer mean migraine headache duration (p = 0.0020), 9.8% higher intensity (p = 0.0052), and 91.4% greater migraine headache index (p = 0.0498) compared to those without SOF. Compared to normative patient data, migraine patients are more likely to have SON/SOF (100% vs. 83%, p = 0.0047) and have mean SON and SOF diameters that are 34.3-41.5% smaller (p < 0.0001). DISCUSSION: Nerve compression at SON and especially SOF contributes significantly to migraine headache symptoms, and these structures (if present) should be released during frontal migraine surgery. Given the variable presence and location of SON/SOF, analysis of available face/perinasal sinus CT images helps preoperative planning for foraminotomy and band release. PMID- 29526446 TI - Analytical Comparability Assessments of 5 Recombinant CRM197 Proteins From Different Manufacturers and Expression Systems. AB - Cross-reacting material 197 (CRM197), a single amino acid mutant of diphtheria toxoid, is a commonly used carrier protein in commercial polysaccharide protein conjugate vaccines. In this study, CRM197 proteins from 3 different expression systems and 5 different manufacturers were obtained for an analytical comparability assessment using a wide variety of physicochemical and in vitro antigenic binding assays. A comprehensive analysis of the 5 CRM197 molecules demonstrate that recombinant CRM197's expressed in heterologous systems (Escherichia coli and Pseudomonas fluorescens) are overall highly similar (if not better in some cases) to those expressed in the traditional system (Corynebacterium diphtheriae) in terms of primary sequence/post-translational modifications, higher order structural integrity, apparent solubility, physical stability profile (vs. pH and temperature), and in vitro antigenicity. These results are an encouraging step to demonstrate that recombinant CRM197 expressed in alternative sources have the potential to replace CRM197 expressed in C diphtheriae as a source of immunogenic carrier protein for lower cost polysaccharide conjugate vaccines. The physicochemical assays established in this work to monitor the key structural attributes of CRM197 should also prove useful as complementary characterization methods (to routine quality control assays) to support future process and formulation development of lower cost CRM197 carrier proteins for use in various conjugate vaccines. PMID- 29526448 TI - S. aureus endocarditis: Clinical aspects and experimental approaches. AB - Infective endocarditis (IE) is a life-threatening disease, caused by septic vegetations and inflammatory foci on the surface of the endothelium and the valves. Due to its complex and often indecisive presentation the mortality rate is still about 30%. Most frequently bacterial microorganisms entering the bloodstream are the underlying origin of the intracardiac infection. While the disease was primarily restricted to younger patients suffering from rheumatic heart streptococci infections, new at risk categories for Staphylococcus (S.) aureus infections arose over the last years. Rising patient age, increasing drug resistance, intensive treatment conditions such as renal hemodialysis, immunosuppression and long term indwelling central venous catheters but also the application of modern cardiac device implants and valve prosthesis have led to emerging incidences of S. aureus IE in health care settings and community. The aetiologic change has impact on the pathophysiology of IE, the clinical presentation and the overall patient management. Despite intensive research on appropriate in vitro and in vivo models of IE and gained knowledge about the fundamental mechanisms in the formation of bacterial vegetations and extracardiac complications, improved understanding of relevant bacterial virulence factors and triggered host immune responses is required to help developing novel antipathogenic treatment strategies and pathogen specific diagnostic markers. In this review, we summarize and discuss the two main areas affected by the changing patient demographics and provide first, recent knowledge about the pathogenic strategies of S. aureus in the induction of IE, including available experimental models of IE used to study host-pathogen interactions and diagnostic and therapeutic targets. In a second focus we present diagnostic (imaging) regimens for patients with S. aureus IE according to current guidelines as well as treatment strategies and surgical recommendations. PMID- 29526449 TI - Longevity promoting efficacies of different plant extracts in lower model organisms. AB - Past investigations have shown that various plant extracts are capable of promoting longevity in lower model organisms like Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, Bombyx mori etc. Longevity studies on such organisms provide a foundation to explore anti-aging efficacies of such plant extracts in higher organisms. Plant extracts of acai palm, apple, asparagus, blueberry, cinnamon, cocoa, Damnacanthus, maize, milk thistle, mistletoe, peach, pomegranate, Rhodiola, rose, Sasa, turmeric, and Withania have extended lifespan in lower model organisms via diverse mechanisms like insulin like growth factor (IGF) signaling pathway, and antioxidant defense mechanisms. Knowledge of pathways altered by the extracts can be investigated as potential drug-targets for natural anti-aging interventions. Thus, the aim of the review is to scrutinize longevity promoting efficacies of various plant extracts in lower model organisms. PMID- 29526450 TI - Value of blood culture time to positivity in identifying complicated nontyphoidal Salmonella bacteremia. AB - Few studies analyzed the association between blood culture time to positivity (TTP) and risk of complicated nontyphoidal Salmonella (NTS) bacteremia. We conducted a retrospective study of 206 patients (aged 60.4 +/- 17.4 years) with NTS bacteremia during a 30-month period. Complicated NTS bacteremia was defined as the presence of 30-day mortality, complicated infection requiring surgery or abscess drainage, or requirement of intensive care unit admission. Serogroup D (75.7%) was the predominant isolates. Malignancy (44.7%) was the most prevalent comorbidity. Patients with rapid TTP (<10 h) were more likely to have thrombocytopenia, septic shock, persistent bacteremia, complicated infection, and a higher intensive care unit admission rate. In multivariate logistic regression model, a TTP <10 h was an independent predictor for complicated NTS bacteremia (adjusted odd ratio, 5.683, 95% confidence interval, 2.396-13.482). Our study showed that blood culture TTP provides important diagnostic and prognostic information in the treatment of NTS bacteremia patients. PMID- 29526451 TI - Impaired reward responsiveness in schizophrenia. AB - BACKGROUND: Anhedonia is a core negative symptom of schizophrenia. Schizophrenia patients report largely intact pleasure in consuming rewards, but have impairments in generating motivated behavior to pursue rewards, and show reduced fMRI activation of the reward pathway during presentation of rewarded stimuli. A computer based task measuring the development of a response bias in favor of rewarded stimuli permits assessment of reward-induced motivation. We hypothesized that subjects with schizophrenia would be impaired on this task. METHODS: 58 schizophrenia subjects (SCZ) and 52 healthy controls (CON) were studied with a signal detection task to assess reward responsiveness. In multiple trials over three blocks subjects were asked to correctly identify two stimuli that were paired with unequal chance of monetary reward. The critical outcome variable was response bias, the development of a greater percent correct identification of the stimulus that was rewarded more often. RESULTS: An ANOVA on response bias with Block as a repeated-measures factor and Diagnosis as a between-group factor indicated that SCZ subjects achieved a lower bias to rewarded stimuli than CON subjects (F(1,105)=8.82, p=0.004, eta2=0.078). Post hoc tests indicated that SCZ subjects had significantly impaired bias in Block 1 (p=0.002) and Block 2 (p=0.05), indicating that SCZ were slower to achieve normal levels of bias during the session. CONCLUSIONS: SCZ subjects were slower to develop response bias to rewarded stimuli than CON subjects. This finding is consonant with the hypothesis that people with schizophrenia have a blunted capacity to modify behavior in response to reward. PMID- 29526452 TI - Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGBeta4 gene in schizophrenia and bipolar disorder. AB - Recent results imply that rare variants contribute to the risk of schizophrenia. Exome sequence data from the UK10K project was used to identify three rare, amino acid changing variants in the ITGB4 gene which segregated with schizophrenia in two families: rs750367954, rs147480547 and rs145976111. Association analysis was carried out in the exome-sequenced Swedish schizophrenia study and in UCL schizophrenia and bipolar cases and controls genotyped for these variants. A gene wise weighted burden test was performed on a trio sample of schizophrenia cases and their parents. rs750367954 was seen in two Swedish cases and in no controls. The other two variants were commoner in cases than controls in both Swedish and UCL cohort samples and an overall burden test was significant at p=0.0000031. The variants were not observed in the trio sample but ITGB4 was most highly ranked out of 14,960 autosomal genes in a gene-wise weighted burden test. The effect of rs147480547 and rs145976111 was studied in human neuroblastoma SH-SY5Y cells. Cells transfected with both variants had increased proliferation at both 24 and 48h (p=0.013 and p=0.05 respectively) compared to those with wild-type ITGB4. Taken together, these results suggest that rare variants in ITGB4 which affect function may contribute to the aetiology of schizophrenia and bipolar disorder. PMID- 29526454 TI - Chronotropic incompetence of the heart is associated with exercise intolerance in patients with schizophrenia. AB - The elevated cardiovascular risk of patients with schizophrenia contributes to a reduced life expectancy of 15-20years. This study investigated whether cardiac autonomic dysfunction (CADF) in schizophrenia is related to chronotropic incompetence, an established cardiovascular risk marker. We investigated thirty two patients suffering from paranoid schizophrenia and thirty-two control subjects matched for age, sex, body mass index and fat free mass. A cardiopulmonary exercise test (CPET) was performed to study heart rate responses to exercise as well as submaximal (ventilatory threshold 1, VT1) and maximal endurance capacities (peak oxygen consumption, VO2peak; peak power output, Ppeak). In addition, epinephrine and norepinephrine levels were assessed in a subset of patients. Fitness parameters were significantly reduced in all patients. Most investigated physiological parameters were significantly different at rest as well as during peak exercise being in line with previously described CADF in schizophrenia. In particular, 14 out of 32 patients were classified as chronotropically incompetent whereas no control subject was below the cut-off value. In addition, a positive correlation of a slope reflecting chronotropic incompetence with peak oxygen uptake (p<0.001) was observed in patients only indicating a close correlation to the lack of physical fitness. The catecholamine increase was reduced in patients after exercise. This study identified a novel cardiac risk factor in patients with schizophrenia. Moreover, it seems to be associated with reduced physical fitness and indicates targets for exercise intervention studies. Future studies are warranted to elucidate pathophysiological mechanisms of this cardiac condition. PMID- 29526455 TI - Glucocorticoids and the risk of schizophrenia spectrum disorder in childhood and adolescence - A Danish nationwide study. AB - Glucocorticoids can have psychosis as a potential side effect, but have also been suggested to yield protective effects due to anti-inflammatory properties. Nonetheless, knowledge is sparse on the association between glucocorticoid treatment and development of psychosis, which we aimed to study in this first large-scale longitudinal study. Among all individuals born in Denmark 1995-2003 (n=597,257), we compared individuals who had redeemed >=1 prescription for glucocorticoids to an active comparator group and a non-exposed group concerning subsequent development of schizophrenia spectrum disorders until 2013. Hazard rate ratios (HRR) were estimated using Cox regression adjusted for calendar year, age, gender, urbanization, somatic diseases, parental educational level and psychiatric history. The risk for a subsequent diagnosis of early-onset schizophrenia spectrum disorder (N=1141) was increased after exposure to both non systemic (HRR=1.47; 95%-CI=1.25-1.73; N=371) and systemic glucocorticoids (HRR=1.66; 95%-CI=1.13-2.43; N=34), when compared to non-exposed individuals. Similar elevated risks were observed when comparing to the active comparator group, for schizophrenia and acute psychosis, and within an older cohort. The risk of psychosis was elevated the most within the first year after exposure to glucocorticoids (P<0.001) without any indication for a dose-response association. However, in individuals with asthma, exposure to glucocorticoids did not further increase the risk of psychosis. Glucocorticoid exposure was associated with an increased risk for psychotic disorders, which may be explained by an effect of the underlying somatic disease, such as asthma. A potential beneficial effect of glucocorticoids on psychotic symptoms should be investigated in clinical trials. PMID- 29526453 TI - Association between sleep, childhood trauma and psychosis-like experiences. AB - Psychosis-like experiences (PLEs), or attenuated positive symptoms of psychosis, present along a severity continuum and have been associated with distressing thoughts and impairments in functioning. Although knowledge of the clinical importance of PLEs is expanding, risk factors for their expression are still poorly understood. Sleep disturbances are one known factor that exacerbate PLEs expression and distress, and trauma exposure is associated with occurrence of PLEs, as well as increased risk of later sleep difficulties. This study examined the joint influences of sleep and trauma on PLEs in an undergraduate sample. Self report questionnaires on presence and distress of PLEs, sleep problems, and occurrence of previous traumatic experiences were completed by participants (N=409). In order to determine the unique impact of sleep on PLEs, three sets of predictors: sociodemographic, psychosocial (including trauma), and sleep were entered in steps into a hierarchical multiple regression model. In the final model, specific sleep domains uniquely predicted PLEs, while previous trauma exposure, which was a significant predictor when entered in step two with other psychosocial variables, was no longer a significant predictor. Results suggest the possibility that disruptions in sleep following or occurring alongside a traumatic experience may somehow contribute to, or exacerbate the presence of PLEs. PMID- 29526456 TI - Early treatment resistance in a Latin-American cohort of patients with schizophrenia. AB - BACKGROUND: Failure to respond to antipsychotic medication in schizophrenia is a common clinical scenario with significant morbidity. Recent studies have highlighted that many patients present treatment-resistance from disease onset. We here present an analysis of clozapine prescription patterns, used as a real world proxy marker for treatment-resistance, in a cohort of 1195 patients with schizophrenia from a Latin-American cohort, to explore the timing of emergence of treatment resistance and possible subgroup differences. METHODS: Survival analysis from national databases of clozapine monitoring system, national disease notification registers, and discharges from an early intervention ward. RESULTS: Echoing previous studies, we found that around 1 in 5 patients diagnosed with schizophrenia were eventually prescribed clozapine, with an over-representation of males and those with a younger onset of psychosis. The annual probability of being prescribed clozapine was highest within the first year (probability of 0.11, 95% confidence interval of 0.093-0.13), compared to 0.018 (0.012-0.024) between years 1 and 5, and 0.006 (0-0.019) after 5years. Age at psychosis onset, gender, dose of clozapine used, and compliance with hematological monitoring at 12months, was not related to the onset of treatment resistance. A similar pattern was observed in a subgroup of 230 patients discharged from an early intervention ward with a diagnosis of non-affective first episode of psychosis. CONCLUSIONS: Our results highlight that treatment resistance is frequently present from the onset of psychosis. Future studies will shed light on the possible different clinical and neurobiological characteristics of this subtype of psychosis. PMID- 29526457 TI - Changes in plasma levels of nitric oxide metabolites and negative symptoms after 16-week minocycline treatment in patients with schizophrenia. AB - OBJECTIVE: This study examined the effect of adjunctive minocycline on psychopathology and possibly relevant biomarkers in patients with schizophrenia. METHOD: In a 16-week randomized, double-blind, placebo-controlled study, subjects received either minocycline (200mg per day) or placebo. Psychopathology was assessed using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS) at baseline and week 16. Plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin-1 beta (IL-1beta) and nitric oxide metabolites were assessed at both time points. RESULTS: Fifty five patients completed the study (27 in the minocycline group, 28 in the placebo group). The minocycline group had significant decreases in the SANS total sore, the PANSS total score and the PANSS negative symptoms score at week 16 compared to the placebo group. In addition, the minocycline group had a significant decrease in plasma levels of nitric oxide metabolites, but no significant difference in changes in plasma levels of IL-1beta or TNF-alpha, compared to the placebo group at week 16. Further, the more decrease in plasma levels of nitric oxide metabolites was associated with less improvement in negative symptoms. CONCLUSION: The beneficial effect of adjunctive minocycline treatment on negative symptoms might be through mechanisms other than the nitric oxide pathway. The implications for future studies were discussed. PMID- 29526458 TI - Pupillary responses to a cognitive effort task in schizophrenia. AB - Effort-based decision making paradigms are increasingly utilized to gain insight into the nature of motivation deficits. Although these tasks are being used to assess effort and motivation in schizophrenia, little work has been done to confirm that effort-based decision making tasks validly manipulate effort. In the current study, we adapted the effort component a cognitive effort-based decision making task (the Deck Choice Effort Task) for use with pupillometric assessment. We sought to confirm with psychophysiology that cognitive effort is manipulated. We also examined correlations between physiological indicators of effort exertion and cognition and negative symptoms. The results confirmed manipulation of cognitive effort: there was a significant difference in pupillary responses between easy and difficult task conditions. Pupillary responses were also correlated with cognitive ability, and with negative symptoms when controlling for cognition. Thus, our findings offer physiological validation of an effort manipulation included in a cognitive effort-based decision making task for schizophrenia. PMID- 29526459 TI - Local and global measurements show that damage initiation in articular cartilage is inhibited by the surface layer and has significant rate dependence. AB - Cracks in articular cartilage are a common sign of joint damage, but failure properties of cartilage are poorly understood, especially for damage initiation. Cartilage failure may be further complicated by rate-dependent and depth dependent properties, including the compliant surface layer. Existing blunt impact methods do not resolve local cartilage inhomogeneities and traditional fracture mechanics tests induce crack blunting and may violate underlying assumptions of linear elasticity. To address this knowledge gap, we developed and applied a method to indent cartilage explants with a sharp blade and initiate damage across a range of loading rates (strain rates 0.5%/s-500%/s), while recording local sample deformation and strain energy fields using confocal elastography. To investigate the importance of cartilage's compliant surface, we repeated the experiment for samples with the surface removed. Bulk data suggest a critical force at which the tissue cuts, but local strains reveals that the deformation the sample can sustain before reaching this force is significantly higher in the surface layer. Bulk and local results also showed significant rate dependence, such that samples were easier to cut at faster speeds. This result highlights the importance of rate for understanding cracks in cartilage and parallels recent studies of rate-dependent failure in hydrogels. Notably, local sample deformation fields were well fit by classical Hookean elasticity. Overall, this study illustrates how local and global measurements surrounding the initiation of damage in articular cartilage can be combined to reveal the importance of cartilage's zonal structure in protecting against failure across physiologically relevant loading rates. PMID- 29526460 TI - Orofacial and thumb-index finger ramp-and-hold isometric force dynamics in young neurotypical adults. AB - The relation among several parameters of the ramp-and-hold isometric force contraction (peak force and dF/dtmax during the initial phase of force recruitment, and the proportion of hold-phase at target) was quantified for the right and left thumb-index finger pinch, and lower lip midline compression in 40 neurotypical right-handed young adults (20 female/20 males) using wireless force sensors and data acquisition technology developed in our laboratory. In this visuomotor control task, participants produced ramp-and-hold isometric forces as 'rapidly and accurately' as possible to end-point target levels at 0.25, 0.5, 1 and 2 Newtons presented to a computer monitor in a randomized block design. Significant relations were found between the parameters of the ramp-and-hold lip force task and target force level, including the peak rate of force change (dF/dtmax), peak force, and the criterion percentage of force within +/-5% of target during the contraction hold phase. A significant performance advantage was found among these force variables for the thumb-index finger over the lower lip. The maximum voluntary compression force (MVCF) task revealed highly significant differences in force output between the thumb-index fingers and lower lip (~4.47 4.70 times greater for the digits versus lower lip), a significant advantage of the right thumb-index finger over the non-dominant left thumb-index finger (12% and 25% right hand advantage for males and females, respectively), and a significant sex difference (~1.65-1.73 times greater among males). PMID- 29526461 TI - A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux. AB - Endogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults/therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila "blood"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends on a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires cyclically expressed gap junctions. Specifically, during nighttime, gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system. PMID- 29526463 TI - Chromatin Accessibility Landscape in Human Early Embryos and Its Association with Evolution. AB - The dynamics of the chromatin regulatory landscape during human early embryogenesis remains unknown. Using DNase I hypersensitive site (DHS) sequencing, we report that the chromatin accessibility landscape is gradually established during human early embryogenesis. Interestingly, the DHSs with OCT4 binding motifs are enriched at the timing of zygotic genome activation (ZGA) in humans, but not in mice. Consistently, OCT4 contributes to ZGA in humans, but not in mice. We further find that lower CpG promoters usually establish DHSs at later stages. Similarly, younger genes tend to establish promoter DHSs and are expressed at later embryonic stages, while older genes exhibit these features at earlier stages. Moreover, our data show that human active transposons SVA and HERV-K harbor DHSs and are highly expressed in early embryos, but not in differentiated tissues. In summary, our data provide an evolutionary developmental view for understanding the regulation of gene and transposon expression. PMID- 29526464 TI - Inhibitory effects of colchicine on inflammasomes. PMID- 29526462 TI - Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity. AB - Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to beta cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to beta cell failure. PMID- 29526465 TI - Effects of altering total mixed ration conservation method when feeding dry rolled versus steam-flaked hulled rice on lactation and digestion in dairy cows. AB - We evaluated the effects of different methods of conserving the total mixed ration (TMR) and processing hulled rice (Oryza sativa L.) on intake, digestion, ruminal fermentation, lactation performance, and nitrogen utilization in dairy cows. Eight multiparous Holstein cows (126 +/- 19 d in milk) were used in a replicated 4 * 4 Latin square design with a 2 * 2 factorial arrangement of dietary treatments. The experimental diets used fresh TMR and ensiled TMR containing either dry-rolled (DR) hulled rice or steam-flaked (SF) hulled rice. The fresh TMR was prepared every morning. The ensiled TMR was prepared by baling fresh TMR and then sealing it with a bale wrapper; this was stored outdoors at 10 to 30 degrees C for >4 mo. The method of grain processing did not affect the dry matter (DM) intake. The DM intake tended to be greater for ensiled TMR than for fresh TMR. Apparent total-tract DM digestibility and milk yield were increased by feeding ensiled TMR instead of fresh TMR and by replacing DR with SF. An interaction effect between the TMR conservation method and the grain processing method was detected for DM digestibility and milk yield; replacing DR with SF increased the DM digestibility and milk yield in cows fed fresh TMR, but this did not affect the cows fed ensiled TMR. The milk fat and lactose contents did not differ among dietary treatments. The milk protein concentration was higher for the cows fed SF processed hulled rice than those fed DR, but it was not influenced by the TMR conservation method. The ruminal total volatile fatty acid concentration was higher for the cows fed ensiled TMR compared with those fed fresh TMR, but it was not affected by the grain processing method. The molar proportion of acetate was decreased and propionate was increased by feeding ensiled TMR instead of fresh TMR and by replacing DR with SF. The concentrations of rumen ammonia N and plasma urea N were higher for the cows fed ensiled TMR than fresh TMR and were lower for SF than DR. Feeding ensiled TMR instead of fresh TMR increased the cows' urinary N excretion and decreased the retention N. Replacing DR with SF decreased the urinary N excretion, increased the milk N secretion, and then improved the nitrogen efficiency. These results show that feeding ensiled TMR instead of fresh TMR has an adverse effect on N utilization, but it increases digestion and milk production. Replacing DR with SF also increases digestion, milk yield, and milk protein content, and the improvement of milk yield by replacing DR with SF was prominent in the cows fed fresh TMR. PMID- 29526466 TI - Preoperative biliary drainage in resectable pancreatic cancer: a systematic review and network meta-analysis. AB - BACKGROUND: Controversy remains about the best pre-operative management of jaundice in patients with resectable pancreatic head cancer (RPC) undergoing planned pancreaticoduodenectomy (PD). OBJECTIVE: The aim of this study was to compare rates of post-operative complications in patients undergoing four pre operative approaches (POA): preoperative biliary drainage with plastic stent (PBD PS), metal stent (PBD-MS), and percutaneous transhepatic drain (PBD-PT), or no pre-operative biliary drainage (NPBD). METHOD: A study was included in the systematic review if it assessed the effects of PBD on post-operative outcomes in jaundiced patients with RPC. Endpoints were the rate of any post-operative complication, wound infection, intra-abdominal infection and post-operative bleeding. A network meta-analysis (NMA) was performed to rank the POAs from the best to worst, for each outcome. RESULTS: Thirty-two studies were included in the systematic review. Ten out of 32 studies included in the systematic review reported at least one of the 4 outcomes of interest and thus were used for NMA. The calculated odds ratios and P-scores ranked NPBD as the best approach. There was insufficient evidence to determine the best modality of PBD among PBD-PS, PBD MS and PBD-PT. CONCLUSIONS: No preoperative biliary drainage may be the best management of preoperative jaundice in patients with RPC before PD. Further studies are needed to determine the best modality in patients that need PBD. PMID- 29526467 TI - Unique predictors and economic burden of superficial and deep/organ space surgical site infections following pancreatectomy. AB - BACKGROUND: Surgical site infections (SSIs) are common following pancreatectomy and associated with significant morbidity and economic burden. We sought to identify distinct predictors for superficial versus deep/organ space SSIs and their effects on surgical outcomes. METHODS: ACS-NSQIP targeted pancreatectomy 2014 and 2015 databases were queried. Univariate and multivariate models were developed for both types of SSI, length of stay (LOS), and readmission. Costs were estimated based on Centers for Medicare & Medicaid Services (CMS) recommendations. RESULTS: Of 8093 patients, there were 422 (5.2%) superficial and 1005 (12.4%) deep/organ space SSIs. On multivariate analyses, preoperative biliary stenting was predictive only for superficial SSI (OR: 2.21), while BMI of 25-29.9 (OR: 1.25) and BMI >=30 kg/m2 (OR: 1.53), pancreatic duct size <3 mm (OR: 1.30), and intermediate (OR: 1.67) versus hard gland texture were predictors of deep/organ-space SSI. Superficial and deep/organ space SSIs were independent predictors of prolonged LOS (OR: 1.74 vs 1.80) and readmission (OR: 2.59 vs 6.57). Additional readmission costs per patient secondary to superficial SSI and deep/organ space SSI were $7661.37 and $18,409.42, respectively. CONCLUSION: Deep/organ space SSI contributes more profoundly to prolonged hospital stay, readmission, and additional costs, suggesting that strategies should focus on preferential prevention of deep/organ space infections. PMID- 29526468 TI - Long term effectiveness of RA-1 as a monotherapy and in combination with disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis. AB - BACKGROUND: Data on long term use of Ayurvedic drugs is sparse. They may prove useful if combined with modern medicine in certain clinical situations (integrative medicine). We present the results of a long term observational study of RA-1 (Ayurvedic drug) used in the treatment of rheumatoid arthritis (RA). OBJECTIVE: The objective was to study safety of long term use of RA-1 for treatment of rheumatoid arthritis (RA). MATERIALS AND METHODS: On completion of a 16 week randomized controlled study, 165 consenting volunteer patients were enrolled into a three year open label phase (OLP) study. Patients were symptomatic with persistent active disease and naive for disease modifying anti rheumatic drugs (DMARD). 57 patients were on fixed low dose prednisone. Patients were examined every 10-14 weeks in a routine rheumatology practice using standard care norms. They continued RA-1 (Artrex TM, 2 tablets twice daily) throughout the study period and were generally advised to lead a healthy life style. Based on clinical judgment, rheumatologist added DMARD and/or steroids (modified if already in use) to patients with inadequate response; chloroquine and/or methotrexate commonly used. Treatment response was assessed using American College of Rheumatology (ACR) efficacy measures and ACR 20% improvement index standard update statistical software (SAS and SPSS) were used; significant at p < 0.05. RESULTS: 158, 130 and 122 patients respectively completed evaluations at 1, 2 and 3 year primary end point. The ACR 20 response (range 34-40%) remained stable over three years (p = 0.33). Patients improved optimum for several measures by one year (p < 0.05) and this was sustained. The use of steroids varied from 42 to 49% patients at yearly end points (mean daily dose 5 mg prednisone); correspondingly the use of DMARD varied from 20 to 34% patients. 40% patients on RA-1 did not require DMARD/steroids for control of disease. 77% patients reported adverse events, albeit mild and mostly gut related, and not causing withdrawal. Several study limitations (especially self-selection) were reduced by the high patient retention and consistency in drug use. CONCLUSION: RA 1 is safe and effective in the long term management of symptomatic active chronic RA. DMARDs and/or steroids can be used judiciously along with RA-1 to treat difficult disease/flares. Further studies are required to evaluate RA-1 in early RA. This paves way for research and application of integrative therapeutic approach in clinical medicine. PMID- 29526469 TI - [Calciphylaxis in hemodialysis patients: 8 cases treated with sodium thiosulfate]. PMID- 29526470 TI - Associations of Childhood Maltreatment with Single and Multiple Suicide Attempts among Older Chinese Adolescents. AB - OBJECTIVES: To test, among older Chinese adolescents, the associations of childhood maltreatment with single and multiple suicide attempts and whether these associations vary in relation to the presence of sleep disturbance. STUDY DESIGN: We analyzed data collected from 10th to 12th graders from 7 randomly selected provinces of China in the 2015 School-based Chinese Adolescents Health Survey. There were 83 200 students who were invited to participate, and 75 715 students' questionnaires were completed and qualified for the survey. Adjusted multinomial logistic regression models were conducted to evaluate the associations of childhood maltreatment with suicide attempts. RESULTS: Compared with no suicide attempts, each type of adjusted childhood maltreatment (physical abuse, emotional abuse, sexual abuse, physical neglect, or emotional neglect) was associated with an increased risk of single and multiple suicide attempts (P < .05). The magnitude of the aORs in multiple suicide attempters was greater than those in single suicide attempters. Moreover, the adjusted interaction effects for a single suicide attempt between each type of childhood maltreatment and sleep disturbance were all statistically significant in the multivariable multinomial logistic regression models (P < .001). However, the adjusted interaction effects for multiple suicide attempts were not significant (P > .05). CONCLUSIONS: Maltreatment during one's childhood is associated with an increased risk of single and multiple suicide attempts among older Chinese adolescents. Sleep disturbances play a moderating role in these associations for a single suicide attempt. PMID- 29526471 TI - Refining the Use of Nasal High-Flow Therapy as Primary Respiratory Support for Preterm Infants. AB - OBJECTIVE: To identify clinical and demographic variables that predict nasal high flow (nHF) treatment failure when used as a primary respiratory support for preterm infants. STUDY DESIGN: This secondary analysis used data from a multicenter, randomized, controlled trial comparing nHF with continuous positive airway pressure as primary respiratory support in preterm infants 28-36 completed weeks of gestation. Treatment success or failure with nHF was determined using treatment failure criteria within the first 72 hours after randomization. Infants in whom nHF treatment failed received continuous positive airway pressure, and were then intubated if failure criteria were again met. RESULTS: There were 278 preterm infants included, with a mean gestational age (GA) of 32.0 +/- 2.1 weeks and a birth weight of 1737 +/- 580 g; of these, nHF treatment failed in 71 infants (25.5%). Treatment failure was moderately predicted by a lower GA and higher prerandomization fraction of inspired oxygen (FiO2): area under a receiver operating characteristic curve of 0.76 (95% CI, 0.70-0.83). Nasal HF treatment success was more likely in infants born at >=30 weeks GA and with prerandomization FiO2 <0.30. CONCLUSIONS: In preterm infants >=28 weeks' GA enrolled in a randomized, controlled trial, lower GA and higher FiO2 before randomization predicted early nHF treatment failure. Infants were more likely to be successfully treated with nHF from soon after birth if they were born at >=30 weeks GA and had a prerandomization FiO2 <0.30. However, even in this select population, continuous positive airway pressure remains superior to nHF as early respiratory support in preventing treatment failure. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000303741. PMID- 29526472 TI - Conversion of primary endoluminal endoscopic surgery to laparoscopic Roux-en-Y gastric bypass. Appearance of anastomotic ulcer 3 months after surgery. PMID- 29526473 TI - A geriatric assessment followed by geriatric intervention is essential for elderly hospitalized patients. PMID- 29526474 TI - Yoga improves quality of life and fall risk-factors in a sample of people with chronic pain and Type 2 Diabetes. AB - OBJECTIVE: Assess pre to-post outcomes for people with chronic pain and Type 2 Diabetes Mellitus (T2DM) randomized to an 8-week yoga intervention or usual care. METHODS: Participants were included if they self-reported: chronic pain; T2DM; >18 years old; no exercise restrictions or consistent yoga; and consented to the study. RESULTS: After yoga, there were significant improvements in: Brief Pain Inventory pain interference (49 +/- 15.00 vs. 41.25 +/- 19.46, p = .034); Fullerton Advanced Balance scale (14.2 +/- 14.1 vs. 20.4 +/- 13.5, p = .03); upper extremity strength (7.7 +/- 6.3 vs.10.8 +/- 6.5, p = .02); lower extremity strength (4.1 +/- 3.8 vs. 6.7 +/- 4.8, p = .02); and RAND 36-item Health Survey quality of life scores (81.1 +/- 7.7 vs. 91.9 +/- 8.9, p = .04). Balance scores became significantly worse during the 8 weeks for people randomized to the control (27.1 +/- 9.9 vs. 21.7 +/- 13.4, = p.01). CONCLUSION: Data from this small RCT indicates yoga may be therapeutic and may improve multiple outcomes in this seemingly at-risk population. CLINICAL TRIALS NUMBER: NCT03010878. PMID- 29526475 TI - Sexual harassment in the work place: Its impact on gynecologic oncology and women's health. AB - For the last few months, media and news outlets have exposed prominent professionals in many settings who have taken advantage of their status of power and influence to engage in sexual harassment and discrimination in the workplace. In medicine, harassment may include many types of health professionals including physicians, nurses, medical students, colleagues and even patients. Programs for sexual harassment prevention, education and training vary between industries, workplaces, medical schools and hospitals. It is imperative to engage men and women in awareness, education, empowerment of the bystander and movement for cultural change. A grass roots effort should be started by each of us to reach out to our academic institutions, health systems and private practices to review policy, education and codes of conduct. We have the ability to embrace improvement around gender and diversity in our words and actions. PMID- 29526476 TI - Introduction: Uterine adenomyosis, another enigmatic disease of our time. AB - Like endometriosis, uterine adenomyosis is another enigmatic disease and remains a source of controversy. Uterine adenomyosis is characterized by the presence of endometrial glands in the myometrium. Two main theories may explain its pathogenesis: adenomyosis may arise from invagination of the myometrial basalis into the myometrium; or an alternative theory maintains that it may result from metaplasia of displaced embryonic pluripotent mullerian remants or differentiation of adult stem cells. Uterine adenomyosis is responsible for pelvic pain, abnormal bleeding, and infertility. Its diagnosis may be improved by high quality imaging. This issue's Views and Reviews, authors stress the urgent need to establish some systematic classification. Medical and surgical strategies are discussed. It should be emphasized that treatment should be designed according to a patient's symptoms and an individual's needs. Surgical treatment remains a matter of debate. Indeed, the risk of uterine rupture during pregnancy after adenomyomectomy is a reality. Therefore, continued research into new molecules based on the pathogenic mechanisms is vital. PMID- 29526477 TI - Uterine architecture: building the foundation for a healthy pregnancy. AB - "The hardest thing to explain is the glaringly evident which everybody has decided not to see." - Ayn Rand, The Fountainhead. PMID- 29526478 TI - Addressing challenges in developing and implementing successful in vitro fertilization in endangered species: an opportunity for humanity to "give back". PMID- 29526479 TI - Statistical methods to the control of the production of blood components: principles and control charts for variables. AB - General quality control good practices require the control of the production of blood components using statistical techniques, such as mandatory by the European Commission Directives and the American Association of Blood Banks standards. Sometimes, the control procedure is exclusively in favor of the compliance verification with specifications per individual component or to compute the number of defective parts usually on a monthly basis. However, this is a critical restriction to detect unnatural patterns such as to guarantee that the production has a non-significance chance to manufacturing nonconforming components. Therefore, a crucial issue in Blood Establishments is the application of a reliable statistical process control methodology to assure products reliable and consistent to specifications. Statistical principles and control charts for variables are reviewed, discussed and recommended, based on current good practices. The empirical data demonstrate the consistency of these models on blood establishment routine. A flowchart to select the type of control chart is suggested. PMID- 29526480 TI - Evaluating a point-of-care circulating cathodic antigen test (POC-CCA) to detect Schistosoma mansoni infections in a low endemic area in north-eastern Brazil. AB - Schistosomiasis is still a public health problem in Brazil. The Kato-Katz test is the most frequently used diagnostic method for Schistosoma mansoni infection. However, it lacks sensitivity in areas of low prevalence. We have assessed the positivity rate of S. mansoni infection in Bananeiras, a village on Capistrano, Ceara, Brazil by performing a point-of-care test in urine to determine the circulating cathodic antigens (POC-CCA), and we compared the findings with those of the Kato-Katz technique for egg detection in stool and an enzyme-linked immunosorbent assay for specific antibodies against adult worms (SWAP-ELISA) in serum before treatment (baseline). Additionally, the POC-CCA and Kato-Katz test results were compared at one and two years post-treatment, and only POC-CCA strips were utilised for follow-up testing on urine samples at 3-6 weeks. Only one sample of stool and urine was collected per event. Overall, 258 individuals were investigated at the baseline. The POC-CCA test detected 10 (3.9%) positive cases; however, this amount increased to 30 (11.6%) when considering trace readings as positive (t + ), whereas the Kato-Katz method found only 4 (1.6%) positive cases and the SWAP-ELISA detected 105 (40.7%) positive cases. The consistency observed between a single POC-CCA (t + ) or (t-) and the Kato-Katz (three slides) was poor (Kappa indexes <0.20). The highest positivity rate as determined by CCA and Kato-Katz was found in adults. At the baseline, a praziquantel treatment was administered to all individuals regardless of their infection status. According to the POC-CCA test, 93% of the previous positive cases became negative by the third week after the treatment; this rate reached 100% at the sixth week assessment. The follow-up showed that of the 175 individuals evaluated at one year post-treatment, only one (0.6%) showed 'trace' results, and all the individuals were negative for eggs in the stool. At two years, all 185 examined individuals were negative by the Kato-Katz method, and 11 (5.9%) presented traces by POC-CCA. Our results indicate that a single POC-CCA test reveals a significantly higher number of positive cases than the Kato-Katz technique for diagnosing S. mansoni in a low endemic setting, when trace results are considered as positive cases. Nevertheless, the true significance of the trace is not clear. These findings reinforce the need to associate different tools for improved schistosomiasis diagnosis in individuals with low parasite burdens. PMID- 29526481 TI - Proposition of decision limits for serum lipids in Brazilian children aged one to 13 years. AB - OBJECTIVE: To determine decision limits for total cholesterol, LDL-cholesterol, non-HDL cholesterol, HDL-cholesterol, and triglycerides in healthy children and adolescents from Cuiaba, Brazil. METHODS: This was a cross-sectional study of 1866 healthy children and adolescents randomly selected from daycare centers and public schools in Cuiaba. The desirable levels of serum lipids were defined using the classic criteria, i.e., total cholesterol, LDL-cholesterol, non-HDL cholesterol, and triglycerides levels below the P75 percentile, and HDL-c above the P10 percentile. RESULTS: For CT, P75 was: 160mg/dL for the age range of 1 to <3 years, 170mg/dL for >=3 to <9 years, and 176mg/dL for >=9 to <13 years. For non-HDL cholesterol, it was 122mg/dL for the age range of 1 to <13 years. For LDL c, it was 104mg/dL at the age range of 1 to <9 years and 106mg/dL from >=9 to <13 years. For TG, it was 127mg/dL from 1 to <2 years; 98mg/dL from >=2 to <6 years; and 92mg/dL from >=6 to <13 years. As for HDL-cholesterol, P10 was 24mg/dL, 28mg/dL, 32mg/dL, and 36mg/dL, for the age ranges of 1 to <2 years, >=2 to <3 years, >=3 to <4 years, and >=4 to <13 years, respectively. CONCLUSION: The decision limits for the serum lipid levels defined in this study differed from those observed in the current Brazilian and North-American guidelines, especially because it differentiates between the age ranges. Using these decision limits in clinical practice will certainly contribute to improve the diagnostic accuracy for dyslipidemia in this population group. PMID- 29526482 TI - Telephone counseling for young Brazilian cocaine and/or crack users. Who are these users? AB - OBJECTIVE: To describe the users' drug abuse characteristics, problematic behaviors associated with addiction, the motivation of teenagers and young adults to quit cocaine and/or crack abuse, and then compare these characteristics. METHODS: A cross-section study was conducted with 2390 cocaine/crack users (teenagers from 14 to 19 years of age, and young adults from 20 to 24 years of age); 1471 were young adults and 919 were teenagers who had called a phone counseling service between January 2006 and December 2013. Semi-structured interviews were performed via phone calls. The questionnaires included sociodemographic information; assessment of the characteristics of cocaine/crack abuse; assessment of the problematic behaviors; also, the Contemplation Ladder was used to evaluate the stages of readiness to cease substance abuse. RESULTS: Participants reported using cocaine (48.2%), crack and other smoking forms (36.7%) and combined consumption of both drugs (15%). Young adults were more prone to using crack or crack associated with cocaine (OR=1.9; CI 95%=1.05-1.57) and they were exposed to substance abuse for longer than two years (OR=3.45; CI 95%=2.84-4.18), when compared to teenagers. On the other hand, they showed higher readiness to quit. CONCLUSION: Data shows important differences in drug abuse characteristics, problematic behaviors and motivation to cease substance abuse between teenager and young adult cocaine and/or crack users. Behaviors displayed by young adults involve greater physical, mental and social health damages. These findings reinforce the importance of public policy to act on prevention and promoting health, to increase protection factors among teenagers and lower risks and losses during adult life. PMID- 29526483 TI - Gene Golden Age paradox and its partial solution. AB - The prevalence of purifying selection in the nature suggests that larger organisms bear a higher number of slightly deleterious mutations because of smaller populations and therefore weaker selection. In this work redistribution of purifying selection in favor of information genes, pathways and processes was found in primates compared with treeshrew and rodents on the ground of genome wide analysis. The genes which are more favored in primates belong mainly to regulation of gene expression and development, in treeshrew and rodents, to metabolism, transport, energetics, reproduction and olfaction. The former occur predominantly in the nucleus, the latter, in the cytoplasm and membranes. Thus, although purifying selection is on average weaker in the primates, it is stronger concentrated on the "information technology" of life (regulation of gene expression and development). Increased accuracy of information processes probably allows escaping "error catastrophes" in spite of more complex organization, larger body size and higher longevity. PMID- 29526485 TI - Melanogenesis inhibitory pregnane glycosides from Cynanchum atratum. AB - Bioassay-guided fractionation of the methanolic extract from the roots of Cynanchum atratum has resulted in the isolation of three new pregnane glycosides (1-3) along with four known compounds (4-7). Their structures were identified by analysis of the spectroscopic data including extensive 2D NMR. All of the isolates were evaluated for their potential to inhibit the melanin production in alpha-melanocyte stimulating hormone (alpha-MSH)-activated B16 melanoma cells. Of these, compounds 4-7 dose-dependently inhibited the melanin production with the IC50 values ranging from 4 MUM to 33 MUM. PMID- 29526484 TI - De novo sequencing and initial annotation of the Mongolian gerbil (Meriones unguiculatus) genome. AB - : The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals. ACCESSION NUMBER: The Whole Genome Shotgun sequence data from this project has been deposited at DDBJ/ENA/GenBank under the accession NHTI00000000. The version described in this paper is version NHTI01000000. The fragment reads, and mate pair reads have been deposited in the Sequence Read Archive under BioSample accession SAMN06897401. PMID- 29526486 TI - Midwifery students' experiences of problem solving based interprofessional learning: A qualitative study. AB - BACKGROUND: Interprofessional learning is identified as one of the most innovative ways to encourage students of different disciplines to communicate with each other in interprofessional teams. A review of existing studies identified that inter-professional learning with nursing and midwifery students learning together had not previously been reported. AIM: This qualitative study sought to explore perceptions and experiences of midwifery students from interprofessional learning with nursing students. METHODS: This study was an exploratory qualitative study employing focus groups. Participants were 30 female students in the fourth year Bachelor of Midwifery at one university in Iran who undertook the surgical training course in midwifery in their seventh semester by inter-professional learning based on problem solving. Data were analysed according to the six steps of the concurrent thematic analysis method. FINDINGS: One main theme of challenging approach in learning emerged and two sub-themes 1) being challenged in a simulated clinical situation and 2) demonstrating professional knowledge. CONCLUSION: Interprofessional learning by challenging students of various professions during shared interprofessional learning can be followed by positive outcomes such as improved critical thinking, interprofessional communication, teaching-learning motivation and independent learning. PMID- 29526488 TI - Erratum to "Selecting the right defibrillator in the younger patient: Transvenous, epicardial or subcutaneous?" [Int. J. Cardiol. 250 (2018) 133-138]. PMID- 29526489 TI - MACRA in the era of big data: Implications for clinical practice. PMID- 29526487 TI - Innate Antiviral Immunity in the Skin. AB - Barrier sites such as the skin play a critical role in immune defense. They must maintain homeostasis with commensals and rapidly detect and limit pathogen invasion. This is accomplished in part through the production of endogenous antimicrobial peptides and proteins, which can be either constitutive or inducible. Here, we focus particularly on the control of innate antiviral proteins and present the basic aspects of their regulation in the skin by interferons (IFNs), IFN-independent immunity, and environmental factors. We also discuss the activity and (dys-)function of antiviral proteins in the context of skin-tropic viruses and highlight the relevance of the innate antiviral pathway as a potential therapeutic avenue for vulnerable patient populations and skin diseases with high risk for virus infections. PMID- 29526490 TI - Erratum to "Vigorous exercise in hypertrophic cardiomyopathy: Benefits may outweigh the risks" [Int. J. Cardiol. 250 (2018) 229-230]. PMID- 29526491 TI - Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction. AB - 12/15 lipoxygenase (LOX) directs inflammation and lipid remodeling. However, the role of 12/15LOX in post-myocardial infarction (MI) left ventricular remodeling is unclear. To determine the role of 12/15LOX, 8-12 week-old C57BL/6 J wild-type (WT; n = 93) and 12/15LOX-/- (n = 97) mice were subjected to permanent coronary artery ligation and monitored at day (d)1 and d5 post-operatively. Post-MI d28 survival was measured in male and female mice. No-MI surgery mice were maintained as d0 naive controls. 12/15LOX-/- mice exhibited higher survival rates with lower cardiac rupture and improved LV function as compared with WT post-MI. Compared to WT, neutrophils and macrophages in 12/15LOX-/- mice were polarized towards N2 and M2 phenotypes, respectively, with increased of expression mrc-1, ym-1, and arg-1 post-MI. 12/15LOX-/- mice exhibited lower levels of pro-inflammatory 12-(S) hydroperoxyeicosatetraenoic acid (12(S)-HETE) and higher CYP2J-derived epoxyeicosatrienoic acids (EETs) levels. CYP2J-derived 5,6-, 8,9-, 11,12-, and 14,15-EETs activated macrophage-specific hemeoxygenase (HO)-1 marked with increases in F4/80+/Ly6Clow and F4/80+/CD206high cells at d5 post-MI in 12/15LOX /- mice. In contrast, inhibition of HO-1 led to total mortality in 12/15LOX-/- mice by post-MI d5. 12/15LOX-/- mice exhibited reduced collagen density and lower alpha-smooth muscle actin (SMA) expression at d5 post-MI, indicating delayed or limited fibroblast-to-myofibroblast differentiation. In conclusion, genetic deletion of 12/15LOX reduces 12(S)-HETE and activates CYP2J-derived EETs to promote effective resolution of inflammation post-MI leading to reduced cardiac rupture, improved LV function, and better survival. PMID- 29526492 TI - Fast and robust adaptation of organs-at-risk delineations from planning scans to match daily anatomy in pre-treatment scans for online-adaptive radiotherapy of abdominal tumors. AB - PURPOSE: To validate a novel deformable image registration (DIR) method for online adaptation of planning organ-at-risk (OAR) delineations to match daily anatomy during hypo-fractionated RT of abdominal tumors. MATERIALS AND METHODS: For 20 liver cancer patients, planning OAR delineations were adapted to daily anatomy using the DIR on corresponding repeat CTs. The DIR's accuracy was evaluated for the entire cohort by comparing adapted and expert-drawn OAR delineations using geometric (Dice Similarity Coefficient (DSC), Modified Hausdorff Distance (MHD) and Mean Surface Error (MSE)) and dosimetric (Dmax and Dmean) measures. RESULTS: For all OARs, DIR achieved average DSC, MHD and MSE of 86%, 2.1 mm, and 1.7 mm, respectively, within 20 s for each repeat CT. Compared to the baseline (translations), the average improvements ranged from 2% (in heart) to 24% (in spinal cord) in DSC, and 25% (in heart) to 44% (in right kidney) in MHD and MSE. Furthermore, differences in dose statistics (Dmax, Dmean and D2%) using delineations from an expert and the proposed DIR were found to be statistically insignificant (p > 0.01). CONCLUSION: The validated DIR showed potential for online-adaptive radiotherapy of abdominal tumors as it achieved considerably high geometric and dosimetric correspondences with the expert-drawn OAR delineations, albeit in a fraction of time required by experts. PMID- 29526493 TI - Phosphorylation of p70 Ribosomal Protein S6 Kinase beta-1 is an Independent Prognostic Parameter in Metastatic Colorectal Cancer. AB - BACKGROUND: Deregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes. PATIENTS AND METHODS: A prospectively studied cohort of 160 patients with metastatic CRC was included. Standard diagnostic workup included mutational analyses of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v Raf murine sarcoma viral oncogene homolog B (BRAF). In addition, markers of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mammalian target of rapamycin pathway activation (phosphorylation of extracellular signal-regulated kinase [ERK], AKT, and p70 ribosomal protein S6 kinase beta-1 [p70S6K]) were studied using standardized immunohistochemistry. RESULTS: There was a significant correlation between markers of ERK and AKT activation in the full cohort. In addition, phosphorylation of p70S6K correlated strongly with ERK and AKT phosphorylation and primary tumor localization in the right colon. Subgroup analyses specified these correlations to patients with all-RAS wild type tumors. In contrast, tumors harboring RAS mutations predominantly exhibited ERK phosphorylation. Interestingly, patients with CRC showing high p70S6K phosphorylation (highest quartile) had a significantly inferior overall survival (hazard ratio [HR], 2.4; P = .002) irrespective of RAS mutational status. This effect remained significant in multivariate analysis (P = .002). A patient subgroup characterized by high p70S6K phosphorylation and right-sided primary tumors had a particularly poor prognosis with a dramatically inferior overall survival (HR, 5.2; P < .001). Patients with right-sided primary tumor and low p70S6K phosphorylation had responses to anti-epidermal growth factor receptor antibody-based therapies and overall survival similar to patients with left-sided primary tumors. CONCLUSION: High phosphorylation of p70S6K is a novel, independent biomarker for poor prognosis, in particular in patients with right-sided primary tumors. PMID- 29526494 TI - Ancient DNA: a history of the science before Jurassic Park. PMID- 29526495 TI - Automated detection of radioisotopes from an aircraft platform by pattern recognition analysis of gamma-ray spectra. AB - A generalized methodology was developed for automating the detection of radioisotopes from gamma-ray spectra collected from an aircraft platform using sodium-iodide detectors. Employing data provided by the U.S Environmental Protection Agency Airborne Spectral Photometric Environmental Collection Technology (ASPECT) program, multivariate classification models based on nonparametric linear discriminant analysis were developed for application to spectra that were preprocessed through a combination of altitude-based scaling and digital filtering. Training sets of spectra for use in building classification models were assembled from a combination of background spectra collected in the field and synthesized spectra obtained by superimposing laboratory-collected spectra of target radioisotopes onto field backgrounds. This approach eliminated the need for field experimentation with radioactive sources for use in building classification models. Through a bi-Gaussian modeling procedure, the discriminant scores that served as the outputs from the classification models were related to associated confidence levels. This provided an easily interpreted result regarding the presence or absence of the signature of a specific radioisotope in each collected spectrum. Through the use of this approach, classifiers were built for cesium-137 (137Cs) and cobalt-60 (60Co), two radioisotopes that are of interest in airborne radiological monitoring applications. The optimized classifiers were tested with field data collected from a set of six geographically diverse sites, three of which contained either 137Cs, 60Co, or both. When the optimized classification models were applied, the overall percentages of correct classifications for spectra collected at these sites were 99.9 and 97.9% for the 60Co and 137Cs classifiers, respectively. PMID- 29526496 TI - Dispersive liquid-liquid microextraction and gas chromatography accurate mass spectrometry for extraction and non-targeted profiling of volatile and semi volatile compounds in grape marc distillates. AB - The suitability of dispersive liquid-liquid microextraction (DLLME) and gas chromatography accurate mass spectrometry (GC-MS), based on a time-of-flight (TOF) MS analyzer and using electron ionization (EI), for the characterization of volatile and semi-volatile profiles of grape marc distillates (grappa) are evaluated. DLLME conditions are optimized with a selection of compounds, from different chemical families, present in the distillate spirit. Under final working conditions, 2.5 mL of sample and 0.5 mL of organic solvents are consumed in the sample preparation process. The absolute extraction efficiencies ranged from 30 to 100%, depending on the compound. For the same sample volume, DLLME provided higher responses than solid-phase microextraction (SPME) for most of the model compounds. The GC-EI-TOF-MS records of grappa samples were processed using a data mining non-targeted search algorithm. In this way, chromatographic peaks and accurate EI-MS spectra of sample components were linked. The identities of more than 140 of these components are proposed from comparison of their accurate spectra with those in a low resolution EI-MS database, accurate masses of most intense fragment ions of known structure, and available chromatographic retention index. The use of chromatographic and spectral data, associated to the set of components mined from different grappa samples, for multivariate analysis purposes is also illustrated in the study. PMID- 29526497 TI - A non-targeted metabolomic approach to identify food markers to support discrimination between organic and conventional tomato crops. AB - In the last decade, the consumption trend of organic food has increased dramatically worldwide. However, the lack of reliable chemical markers to discriminate between organic and conventional products makes this market susceptible to food fraud in products labeled as "organic". Metabolomic fingerprinting approach has been demonstrated as the best option for a full characterization of metabolome occurring in plants, since their pattern may reflect the impact of both endogenous and exogenous factors. In the present study, advanced technologies based on high performance liquid chromatography-high resolution accurate mass spectrometry (HPLC-HRAMS) has been used for marker search in organic and conventional tomatoes grown in greenhouse under controlled agronomic conditions. The screening of unknown compounds comprised the retrospective analysis of all tomato samples throughout the studied period and data processing using databases (mzCloud, ChemSpider and PubChem). In addition, stable nitrogen isotope analysis (delta15N) was assessed as a possible indicator to support discrimination between both production systems using crop/fertilizer correlations. Pesticide residue analyses were also applied as a well-established way to evaluate the organic production. Finally, the evaluation by combined chemometric analysis of high-resolution accurate mass spectrometry (HRAMS) and delta15N data provided a robust classification model in accordance with the agricultural practices. Principal component analysis (PCA) showed a sample clustering according to farming systems and significant differences in the sample profile was observed for six bioactive components (L-tyrosyl-L-isoleucyl-L threonyl-L-threonine, trilobatin, phloridzin, tomatine, phloretin and echinenone). PMID- 29526498 TI - Synthesis of high generation thermo-sensitive dendrimers for extraction of rivaroxaban from human fluid and pharmaceutic samples. AB - In this present study, poly (N-isopropylacrylamide) as a thermo-sensitive agent was grafted onto magnetic nanoparticles, then ethylenediamine and methylmethacrylate were used to synthesize the first generation of poly amidoamine (PAMAM) dendrimers successively and the process continued alternatively until the ten generations of dendrimers. The synthesized nanocomposite was investigated using Fourier transform infrared spectrometry, thermalgravimetry analysis, X-ray diffractometry, elemental analysis and vibrating-sample magnetometer. The particle size and morphology were characterized using dynamic light scattering, field emission scanning electron microscopy and transmission electron microscopy. Batch experiments were conducted to investigate the parameters affecting adsorption and desorption of rivaroxaban by synthesized nanocomposite. The maximum sorption of rivaroxaban by the synthesized nanocomposite was obtained at pH of 8. The resulting grafted magnetic nanoparticle dendrimers were applied for extraction of rivaroxaban from biologic human liquids and medicinal samples. The specifications of rivaroxaban sorbed by a magnetic nanoparticle dendrimer showed good accessibility and high capacity of the active sites within the dendrimers. Urine and drug matrix extraction recoveries of more than 92.5 and 99.8 were obtained, respectively. PMID- 29526499 TI - Response to Comment on salt-assisted dispersion effects in dispersive liqud liquid microextraction of haloacetonitriles. PMID- 29526500 TI - Adjuvant Chemotherapy for Prostate Cancer: The Long and Winding Road. PMID- 29526501 TI - Does Preoperative Troponin Level Impact Outcomes After Coronary Artery Bypass Grafting? AB - BACKGROUND: As a marker of myocardial injury, troponin level correlates with adverse outcomes after myocardial infarction (MI). We hypothesized that patients with a higher preoperative troponin level would have increased morbidity and mortality after coronary artery bypass grafting (CABG). METHODS: Preoperative troponin measurements were available for 1,272 patients who underwent urgent or emergent isolated CABG at our institution from 2002 to 2016. Logistic regression assessed the risk-adjusted effect of peak troponin level on morbidity and mortality. Long-term survival analysis was performed with Kaplan-Meier and Cox proportional hazards models. RESULTS: Preoperative troponin was positive in 835 patients (65.6%). The median peak troponin for this group was 3.2 ng/mL (interquartile range, 0.6 to 11.9 ng/mL), with a median time from peak troponin to the operation of 3 days (interquartile range, 1 to 4 days). Positive troponin was associated with more significant comorbid conditions and more extensive coronary artery disease. Operative mortality (3.7% versus 1.1%, p = 0.009), major morbidity (11.7% versus 3.9%, p < 0.001), and long-term mortality (median survival 12.5 years versus 13.6 years, p = 0.01) were increased in the positive troponin group. After risk adjustment, positive troponin was not independently associated with increased operative mortality (odds ratio, 2.61; p = 0.053). Adjusted and unadjusted analysis showed the peak preoperative troponin level did not independently predict death at any time point (all odds ratios, 1.0; p > 0.05). CONCLUSIONS: A positive preoperative troponin correlates with worse outcomes after CABG, but risk adjustment eliminates much of the short-term predictive value of this biomarker. Peak troponin level does not influence outcomes after CABG and is a poor predictor of events when The Society of Thoracic Surgeons predictive models are used. PMID- 29526502 TI - Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. AB - Individuals with chronic kidney disease are at increased risk of premature cardiovascular disease. Among them, many with elevated low-density lipoprotein cholesterol (LDL-C) are unable to achieve optimal LDL-C on statins and require additional lipid-lowering therapy. To study this, we compared the LDL-C-lowering efficacy and safety of alirocumab in individuals with hypercholesterolemia with impaired renal function, defined as eGFR 30-59 ml/min/1.73 m2, to those without impaired renal function eGFR >=60 ml/min/1.73 m2. A total of 4629 hypercholesterolemic individuals without or with impaired renal function, pooled from eight phase 3 ODYSSEY trials (double-blind treatments of 24-104 weeks), were on alirocumab 150 mg or 75/150 mg every two weeks vs. placebo or ezetimibe. Overall, 10.1% had impaired renal function and over 99% were receiving statin treatment. Baseline LDL-C in alirocumab and control groups was comparable in subgroups analyzed. LDL-C reductions at week 24 ranged from 46.1 to 62.2% or 48.3 to 60.1% with alirocumab among individuals with or without impaired renal function, respectively. Similar reductions were observed for lipoprotein (a), non high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Safety data were similar in both treatment subgroups, regardless of the degree of CKD. Renal function did not change over time in response to alirocumab. This post hoc efficacy analysis is limited by evaluation of alirocumab treatment effects on renal and lipid parameters by serum biochemistry. Thus, alirocumab consistently lowered LDL-C regardless of impaired renal function, with safety comparable to control, among individuals with hypercholesterolemia who nearly all were on statin treatment. PMID- 29526503 TI - Engineering the immune system with particles, step-by-step. AB - Biomaterials-based strategies to engineer the immune system have gathered considerable attention the past decade and have opened new avenues for vaccine delivery and for modulating the immune system to fight cancer. This review highlights some of these strategies that involve well-defined particle-based delivery systems that are constructed in a multistep fashion. Particular attention is devoted to the design of micro and nanoparticles to deliver antigen and molecular adjuvants to antigen presenting immune cell subsets in lymphatic tissue. PMID- 29526504 TI - Efficient hydroxylation of cycloalkanes by co-addition of decoy molecules to variants of the cytochrome P450 CYP102A1. AB - The wild-type cytochrome P450 (CYP) monooxygenase enzyme CYP102A1 (P450Bm3) has low activity for cycloalkane oxidation. The oxidation of these substrates by variants of this enzyme in combination with perfluorinated decoy molecules (PFCs) was investigated to improve productivity. The use of rate accelerating variants, which have mutations located outside of the substrate binding pocket as well as an active site variant of CYP102A1 (A74G/F87V/L188Q) all enhanced cycloalkane oxidation (C5 to C10). The addition of the decoy molecules to the wild-type and the rate accelerating mutants of CYP102A1 boosted the substrate oxidation rates even further. However, the levels of cycloalkanol product decreased with the larger alkanes when the decoy molecules were used with the variant A74G/F87V/L188Q, which contained mutations within the substrate binding pocket. For the majority of the enzymes and PFC decoy molecule combinations the highest levels of oxidation were obtained with cyclooctane. When larger second generation decoy molecules, based on modified amino acids were utilised there was a significant improvement in the oxidation of the smaller cycloalkanes by the wild type enzyme and one other variant. This resulted in significant improvements in biocatalytic oxidation of cyclopentane and cyclohexane. However, the use of these optimised decoy molecules did not significantly improve cycloalkane oxidation over the fluorinated fatty acid derivatives when combined with the best rate accelerating variant, R47L/Y51F/I401P. Overall our approach enabled the cycloalkanes to be oxidised 300- to 8000-fold more efficiently than the wild-type enzyme at product formation rates in excess of 500 and up to 1700 nmol.nmol-CYP 1.min-1. PMID- 29526505 TI - Biochemical and thermodynamic comparison of the selenocysteine containing and non containing thioredoxin glutathione reductase of Fasciola gigantica. AB - The thiol-disulfide redox metabolism in platyhelminth parasites depends entirely on a single selenocysteine (Sec) containing flavoenzyme, thioredoxin glutathione reductase (TGR) that links the classical thioredoxin (Trx) and glutathione (GSH) systems. In the present study, we investigated the catalytic and structural properties of different variants of Fasciola gigantica TGR to understand the role of Sec. The recombinant full-length Sec containing TGR (FgTGRsec), TGR without Sec (FgTGR) and TGRsec without the N-terminal glutaredoxin (Grx) domain (?NTD FgTGRsec) were purified to homogeneity. Biochemical studies revealed that Sec597 is responsible for higher thioredoxin reductase (TrxR) and glutathione reductase (GR) activity of FgTGRsec. The N-terminal Grx domain was found to positively regulate the DTNB-based TrxR activity of FgTGRsec. The FgTGRsec was highly sensitive to inhibition by auranofin (AF). The structure of FgTGR was modeled, and the inhibitor AF was docked, and binding sites were identified. Unfolding studies suggest that all three proteins are highly cooperative molecules since during GdnHCl-induced denaturation, a monophasic unfolding of the proteins without stabilization of any intermediate is observed. The Cm for GdnHCl induced unfolding of FgTGR was higher than FgTGRsec and ?NTD-FgTGRsec suggesting that FgTGR without Sec was more stable in solution than the other protein variants. The free energy of stabilization for the proteins was also determined. To our knowledge, this is also the first report on unfolding and stability analysis of any TGR. PMID- 29526506 TI - Imaging linear and circular polarization features in leaves with complete Mueller matrix polarimetry. AB - Spectropolarimetry of intact plant leaves allows to probe the molecular architecture of vegetation photosynthesis in a non-invasive and non-destructive way and, as such, can offer a wealth of physiological information. In addition to the molecular signals due to the photosynthetic machinery, the cell structure and its arrangement within a leaf can create and modify polarization signals. Using Mueller matrix polarimetry with rotating retarder modulation, we have visualized spatial variations in polarization in transmission around the chlorophyll a absorbance band from 650 nm to 710 nm. We show linear and circular polarization measurements of maple leaves and cultivated maize leaves and discuss the corresponding Mueller matrices and the Mueller matrix decompositions, which show distinct features in diattenuation, polarizance, retardance and depolarization. Importantly, while normal leaf tissue shows a typical split signal with both a negative and a positive peak in the induced fractional circular polarization and circular dichroism, the signals close to the veins only display a negative band. The results are similar to the negative band as reported earlier for single macrodomains. We discuss the possible role of the chloroplast orientation around the veins as a cause of this phenomenon. Systematic artefacts are ruled out as three independent measurements by different instruments gave similar results. These results provide better insight into circular polarization measurements on whole leaves and options for vegetation remote sensing using circular polarization. PMID- 29526508 TI - Risk factors associated with post-loading implant loss of removable and fixed implant-supported prostheses in edentulous jaws. AB - PURPOSE: This study analyzed risk factors for post-loading implant loss in cases of implant-supported prostheses applied to edentulous jaws of Japanese patients. METHODS: In total, 245 dental implant fixtures placed in 54 edentulous jaws of 46 patients performed at Niigata University Hospital were retrospectively analyzed. Kaplan-Meier curves were used to estimate the cumulative survival rate (SR) of implants, and multiple Cox regression analysis was used to identify predictive factors of implant loss. The following risk factors for implant failure were examined: age, sex, survival time, implant length, implant location, smoking habit, bone density, bone augmentation, opposing dentition, loading period, and type of final restoration. The Cochran-Mantel-Haenszel test was used to examine difference in survival curves of the extracted predictors. RESULTS: Sixteen implants failed during the observation period (SR=92.8 %). Multiple Cox regression analysis revealed that male sex [hazard ratio (HR)=16.1; p=0.007] and use of maxillary removable restorations (HR=12.7; p<0.000) were risk factors for implant failure. Other factors had no significant effect on implant failure. The SR of implants for males (SR=86.9%) was significantly lower than that for females (SR=99.1%). The SR of implants for maxillary removable restorations (SR=76.4%) was significantly lower than for maxillary fixed restorations (SR=99.1%) and mandibular fixed restorations (SR=97.8%). CONCLUSIONS: Maxillary implants with removable restorations and male sex were risk factors for implant failure among Japanese edentulous patients. PMID- 29526509 TI - Availability of cosmetic treatment using novel cosmetics-based material on patients with craniofacial concavity. AB - PURPOSE: Patients treated with maxillofacial prosthetics often experience emotional problems because of the remaining facial skin concavity such as a surgical scar. In such cases, cosmetic treatment can potentially correct their skin tone imperfections and deformities. This study aimed to evaluate the clinical availability of novel cosmetics-based material for craniofacial small concavity by initiating a cosmetic treatment in a preliminary case. METHODS: Eighteen patients with aesthetic problems such as craniofacial deformities, small defects, and concavities on their faces underwent cosmetic treatment that was performed by makeup practitioners. Data were collected from the patient's charts and a survey questionnaire. A visual analog scale was used to conduct a survey regarding the satisfaction levels of the patients following cosmetic treatment with a novel cosmetics-based material. The cosmetic treatment was performed for a concavity on the left midface of a 67-year-old woman with partial maxillectomy. The novel cosmetics-based material was manufactured from a semi-translucent oil base. RESULTS: The satisfaction level of the patient increased after undergoing the cosmetic treatment. Regarding clinical applications, the novel cosmetics based material can help reduce their cosmetic disturbance and restore the small deformity. CONCLUSIONS: These results suggest that the cosmetic treatment with the novel cosmetics-based material can be used as a subsidiary method for facial prostheses or an independent new method for correcting patients' small craniofacial concavity and for reducing visible deformity. PMID- 29526507 TI - Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells. AB - BACKGROUND: Impairment in mitochondrial biogenesis and function plays a key role in depression and anxiety, both of which being associated with changes in fatty acid and phospholipid metabolism. The antidepressant effects of (R,S)-ketamine have been linked to its conversion into (2S,6S;2R,6R)-hydroxynorketamine (HNK); however, the connection between structure and stereochemistry of ketamine and HNK in the mitochondrial homeostatic response has not yet been fully elucidated at a metabolic level. METHODS: We used a multi-platform, non-targeted metabolomics approach to study the change in mitochondrial metabolome of PC-12 cells treated with ketamine and HNK enantiomers. The identified metabolites were grouped into pathways in order to assess global responses. RESULTS: Treatment with (2R,6R)-HNK elicited the significant change in 49 metabolites and associated pathways implicated in fundamental mitochondrial functions such as TCA cycle, branched chain amino acid biosynthetic pathway, glycoxylate metabolic pathway, and fatty acid beta-oxidation. The affected metabolites included glycerate, citrate, leucine, N,N-dimethylglycine, 3-hexenedioic acid, and carnitine and attenuated signals associated with 9 fatty acids and elaidic acid. Important metabolites involved in the purine and pyrimidine pathways were also affected by (2R-6R)-HNK. This global metabolic profile was not as strongly impacted by treatment with (2S,6S)-HNK, (R)- and (S)-ketamine and in some instances opposite effects were observed. CONCLUSIONS: The present data provide an overall view of the metabolic changes in mitochondrial function produced by (2R,6R)-HNK and related ketamine compounds and offer an insight into the source of the observed variance in antidepressant response elicited by the compounds. PMID- 29526510 TI - The Correlation of Prostate Volume and Prostate-specific Antigen Levels With Positive Bacterial Prostate Tissue Cultures. AB - OBJECTIVE: To compare prostate volume and prostate-specific antigen (PSA) levels with bacterial growth in prostate tissue cultures. MATERIALS AND METHODS: Fifty male patients who underwent transurethral prostate resection were investigated prospectively. Resection chips from the prostate gland were added to brain-heart infusion medium and incubated. PSA levels were determined preoperatively at our urology ward. The prostate gland volume was estimated by transabdominal ultrasound examination preoperatively. RESULTS: Persons with positive bacterial prostate tissue cultures have a greater prostate volume. This is significant in patients with and without histopathologic signs of prostatitis. Persons with positive bacterial prostate tissue cultures have higher PSA values. This is significant in patients without histopathologic signs of prostatitis. CONCLUSION: People with positive bacterial prostatic tissue culture have a higher prostate volume in comparison with patients with negative culture findings and show a tendency toward increased PSA levels as well. PMID- 29526511 TI - In vitro studies of heparin-coated magnetic nanoparticles for use in the treatment of neointimal hyperplasia. AB - Restenosis by neointimal hyperplasia is still an ongoing concern in endovascular surgery. Slowing vascular smooth muscle cell (VSMC) proliferation by reversing the phenotype change, would allow vessel healing and re-endotheliazation. To accomplish this, we have developed heparin-coated magnetic nanoparticles for targeted drug therapy of neointimal hyperplasia. Iron oxide nanoparticles were modified with a poly (ethylene oxide) based coating and then further functionalized with heparin. In vitro experiments were conducted to observe changes in phenotype, metabolic activity, and viability of three relevant cell lines including VSMC, endothelial cells and fibroblasts. Inhibition of proliferation of VSMCs was observed with doses as low as 1 MUg/mL Fe of heparin loaded nanoparticle where endothelial cells showed an increase in proliferation in response to treatment. Fibroblasts showed relatively low response. Results suggest proliferation suppression of VSMCs due to phenotype coupled with the increase in endothelial cell proliferation at low doses of heparin coated nanoparticles. PMID- 29526512 TI - Influence of estrous cycle and gestation on cardiovascular system of bitches. AB - The purpose of this study was to evaluate the consequences of the estrous cycle and gestation on the cardiovascular system of bitches evaluated through echocardiographic assessment. Fifteen healthy pregnant bitches aged 2 to 6 years and weighing 8.8 +/- 2.5 kg were included in the study. Heart rate and blood pressure were clinically evaluated. M-mode, spectral, and tissue Doppler echocardiography assessments were performed during the anestrous and estrous stages, every 15 days during pregnancy (15, 30, 45, and 60 days), and 45 days postpartum. The data for evaluated variables were submitted for statistical analysis. Heart rate (P = 0.286) and systolic blood pressure (P = 0.686) were not changed as a result of pregnancy or estrus, while ejection fraction (P = 0.0016) and fractional shortening (P = 0.00004) changed. The variables transmitral flow, isovolumetric relaxation time, aortic and pulmonary flow, and some variables related to myocardium movement obtained via tissue Doppler assessment varied (P < 0.05) among the reproductive periods studied. In conclusion, gestation resulted in changes in echocardiography variables, and consequently, on maternal hemodynamics, with myocardial contractility increasing during pregnancy, resulting in greater systolic efficiency and ventricular compliance. PMID- 29526513 TI - Correlation between ubiquitination and defects of bull spermatozoa and removal of defective spermatozoa using anti-ubiquitin antibody-coated magnetized beads. AB - Ubiquitination is an important cellular process in spermatogenesis and involves the regulation of spermatid differentiation and spermiogenesis. In the current study, the correlation between bull sperm ubiquitination and sperm defects was analyzed, and the feasibility using anti-ubiquitin specific antibody immobilized magnetic beads to remove the spermatozoa with defects was assessed. A total of nine bulls were examined, and the amount of sperm ubiquitination ranged from 55 to 151. Correspondingly, the percentage of sperm deformity ranged from 9.3% to 28.1%. The coefficient of correlation was r = 0.92, indicating a significant correlation between the percentage of sperm deformity and the amount of ubiquitination (P < 0.05). The results from use of fluorescence staining and single-channel flow cytometry indicated there was a significant correlation between the sperm deformity and amount of ubiquitination (r = 0.86, P < 0.05). Results gained by use of the TUNEL and ubiquitination assays by double-channel flow cytometry indicated that the proportion of genetically defective spermatozoa with ubiquitination in Q3 and Q2 quartiles was markedly greater than that of spermatozoa with ubiquitination in Q1 and Q4 quartiles (82.1% compared with 17.9%). All these results confirmed that sperm ubiquitination is associated with genetic DNA defects (P < 0.01). Furthermore, nine semen samples with sperm motility of less than 50% (minimal motility), 50% to 70% (moderate motility) and greater than 70% (greatest motility) were selected for sorting defective spermatozoa using anti-ubiquitin specific antibody-coated magnetic beads. Strikingly, the percentage of sperm deformity significantly decreased from 18.8%, 19.0% and 17.1% to 11.7%, 11.0% and 11.0%, respectively (P < 0.05), suggesting that this method might be a feasible technology to improve the productivity via removal of the defective spermatozoa from bull semen. PMID- 29526514 TI - Facilitation of antagonist motor output through short-latency sensory pathways during postnatal development in the mouse. AB - Reciprocal inhibition of motor neurons via Ia inhibitory interneurons recruited by stimulation of proprioceptive afferents supplying antagonist muscles has been well described. Changes in the efficacy of inhibition, and sometimes even a switch from inhibition to facilitation, have been reported in the literature after disruption of descending pathways. We sought to test whether such facilitation could be expressed in normal animals by evaluating the presence of facilitation in acute preparations from uninjured animals. Using an isolated spinal cord preparation from neonatal mice, changes in the monosynaptic stretch reflex response in knee flexor motor neurons (posterior biceps semitendinosus; PBST) were monitored following conditioning stimulation of proprioceptive sensory afferents in other muscle nerves. As expected for reciprocal inhibition, conditioning by stimulation of quadriceps (knee extensors and PBST antagonists) sensory afferents resulted in inhibition of the stretch reflex response. Facilitation, however, of the stretch reflex response by quadriceps conditioning stimulation was observed when the glycinergic reciprocal inhibitory pathway was blocked by application of strychnine. Facilitation was elicited by low-threshold proprioceptive afferents and occurred at latencies consistent with a disynaptic circuit. The magnitude of facilitation was larger at birth than at one week postnatal. Our results also suggest reciprocal facilitation is restricted to antagonist muscle pairs, as facilitation of PBST responses was not observed when conditioned with the obturator nerve supplying the adductor muscles. Overall, these data suggest the efficacy of facilitation is modulated during the first postnatal week, while the specificity of facilitation is already established by birth. PMID- 29526515 TI - Unique expression pattern of KIBRA in the enteric nervous system of APP/PS1 mice. AB - KIBRA has been recognized as a memory-related gene, which is abundant in the brain and kidney of mammals. However, the expression pattern of KIBRA in the "second brain"-enteric nervous system (ENS) is still unknown, especially in neurodegenerative disorders. In this study, we aimed to investigate the detailed expression pattern of KIBRA in the intestinal myenteric nerve plexus of APP/PS1 and wild type mice by whole mount staining technology. The deposition of Abeta and increased levels of phosphorylated Tau (p-Tau) and total Tau (T-Tau) protein were observed in the intestinal myenteric nerve plexus of APP/PS1 mice. Interestingly, the amount of Tuj+ cells remained unchanged between these two groups. Compared to the control mice, the protein levels of KIBRA significantly increased in the jejunal myenteric plexus of APP/PS1 mice, and the proportion of KIBRA+ GABAergic neurons in both the jejunal myenteric nerve plexus and the cortex was much higher in the APP/PS1 mice. But there was no significant difference in the number of KIBRA+ cholinergic neurons and KIBRA+ nitrergic neurons between APP/PS1 and wild type mice. In summary, our study further confirmed that typical pathology features of Alzheimer's disease (AD) not only existed in the central nervous system but also in the ENS. PMID- 29526516 TI - Translational view: Ablative methods in in vivo epilepsy models. AB - New treatment approaches in epilepsy - such as novel antiepileptic drugs and neurostimulation - generally at first are assessed in animal models in regard to feasibility, efficacy and safety. The aim of this review was to elucidate and summarize the available literature on in vivo experimental studies on radiofrequency thermoablation and laser interstitial thermal therapy. We have found two in vivo studies on radiofrequency ablation of an acute seizure focus, one assessed the conventional transcranial and the other one a transvenous approach. All other studies focused on technical issues of functional ablation of brain structures assessing parameters such as maximal temperature and duration of thermal ablation as well as electrode devices. As the concept of functional ablation is evident - destruction of the epileptogenic focus as performed in "open" resective surgery - general "proof of concept" experiments do not seem to be necessary. PMID- 29526518 TI - Obesity and place: Chronic disease in the 500 largest U.S. cities. AB - OBJECTIVES: Extant research clearly points to a correlation between place and health, specifically as it pertains to chronic diseases like obesity. The present study examines this relationship among a diverse set of compositional place indicators and obesity rates across census tracts in the 500 largest cities in the United States. METHODS: Using data compiled from the Robert Wood Johnson Foundation 500 Cities project and the Census' American Community Survey, the analyses examined aggregate relationships between sociodemographic, socioeconomic, and housing characteristics of census tracts and crude prevalence obesity rates in over 27,000 census tracts located in the 500 largest cities in the United States. RESULTS: Multivariate analysis confirms the place-chronic health connection. Regardless of variable groups, deteriorating places with higher concentrations of low-income, minority populations reported more obesity prevalence. CONCLUSIONS: Place matters. The continuing burden of zip code in the United States for disenfranchised populations will likely continue to force policymakers to examine the role that place-based prevention and place-focused medical care plays in the future health and well-being of U.S. residents. PMID- 29526517 TI - Identification of sleep hypoventilation in young individuals with Becker muscular dystrophy: A pilot study. AB - AIM: To report on sleep hypercapnia in Becker muscular dystrophy (BMD) at earlier stages than ever recognized. SUBJECTS AND METHODS: This retrospective study examined nocturnal hypercapnia in six young Becker muscular dystrophy (BMD) patients with deletions of one or more exons of DMD gene. Clinical information, consecutive data on forced vital capacity (FVC%), forced expiratory volume in one second (FEV1%), peak expiratory flow (PEF%), peak cough flow (PCF), average PCO2 in all-night monitoring, and left ventricular ejection fraction (LVEF) were reviewed. RESULTS: In five BMD patients, including three who were still ambulant, nocturnal average PCO2 was elevated to >45 mmHg at 12-31 years of age. Noninvasive positive pressure ventilation was initiated in four patients. Gradual declines in FVC% and PEF% were evident in one BMD patient with exon 3-7 deletion, whereas these functions did not change in the remaining BMD patients. PCF, FEV1%, and LVEF were less informative for the assessment of respiratory function in this patient series. CONCLUSION: Sleep hypercapnia was present in certain BMD patients, which was unexpected from the routine pulmonary function tests. Individualized assessment of nocturnal PCO2, partly based on the deletion types, should be further explored in the clinical practice of BMD patients. PMID- 29526519 TI - Editorial Comment. PMID- 29526520 TI - Trauma, traumatisation, and functional neurological symptom disorder-what are the links? PMID- 29526521 TI - Stressful life events and maltreatment in conversion (functional neurological) disorder: systematic review and meta-analysis of case-control studies. AB - BACKGROUND: Stressful life events and maltreatment have traditionally been considered crucial in the development of conversion (functional neurological) disorder, but the evidence underpinning this association is not clear. We aimed to assess the association between stressors and functional neurological disorder. METHODS: We systematically reviewed controlled studies reporting stressors occurring in childhood or adulthood, such as stressful life events and maltreatment (including sexual, physical abuse, and emotional neglect) and functional neurological disorder. We did a meta-analysis, with assessments of methodology, sources of bias, and sensitivity analyses. FINDINGS: 34 case-control studies, with 1405 patients, were eligible. Studies were of moderate-to-low quality. The frequency of childhood and adulthood stressors was increased in cases compared with controls. Odds ratios (OR) were higher for emotional neglect in childhood (49% for cases vs 20% for controls; OR 5.6, 95% CI 2.4-13.1) compared with sexual abuse (24% vs 10%; 3.3, 2.2-4.8) or physical abuse (30% vs 12%; 3.9, 2.2-7.2). An association with stressful life events preceding onset (OR 2.8, 95% CI 1.4-6.0) was stronger in studies with better methods (interviews; 4.3, 1.4-13.2). Heterogeneity was significant between studies (I2 21.1-90.7%). 13 studies that specifically ascertained that the participants had not had either severe life events or any subtype of maltreatment all found a proportion of patients with functional neurological disorder reporting no stressor. INTERPRETATION: Stressful life events and maltreatment are substantially more common in people with functional neurological disorder than in healthy controls and patient controls. Emotional neglect had a higher risk than traditionally emphasised sexual and physical abuse, but many cases report no stressors. This outcome supports changes to diagnostic criteria in DSM-5; stressors, although relevant to the cause in many patients, are not a core diagnostic feature. This result has implications for ICD-11. FUNDING: None. PMID- 29526522 TI - A heterozygous mutation in the SAM domain of p63 underlies a mild form of ectodermal dysplasia. PMID- 29526524 TI - Implications of the Research Domain Criteria project for childhood anxiety and its disorders. AB - Anxiety disorders are among the most prevalent psychiatric disorders in youth; however, progress in treatment for childhood anxiety has stalled over the past decade. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) project represents a shift toward a dimensional and interdisciplinary approach to psychiatric disorders; this shift can reframe developmental psychopathology for childhood anxiety and facilitate novel advances in its classification and treatment. Here we highlight constructs in the Systems for Social Processes and the Negative Valence System domains of RDoC, as they relate to childhood anxiety disorders. Childhood anxiety relates to both RDoC domains. In terms of social processes, through natural reliance on parents to reduce children's fear, attachment represents one particular social process, which plays a central role in anxiety among youth. In terms of negative valence, considerable research links threat conditioning to pediatric anxiety. Finally, fronto-amygdala circuitry relates to all three entities, as it has been shown to underly both attachment processes and threat learning, while it also has been consistently implicated in anxiety disorders across development. Through integrative and translational approaches, RDoC provides unique opportunities and simultaneous challenges for advancing the understanding and treatment of childhood anxiety disorders. PMID- 29526523 TI - Efficient isolation and high yield of epidermal cells from foreskin biopsies by dynamic trypsinization. AB - Cultured keratinocytes play important roles in burn wound healing and scientific research studies. We aimed to modify the isolation method to avoid over digestion, maximize the number of isolated epidermal cells and establish a more efficient and innocuous way of cell isolation. Compared to the conventional method, the modified method combines the more dynamic process of enzymatic digestion with multiple harvestings of dissociated cells via digestion. The cells from each harvesting were immediately re-suspended in culture medium with serum to avoid extended trypsinization and then pooled for further analysis. The number of viable cells isolated per gram of adult foreskin epidermis was (18.88+/ 13.22)*106 cells in the control group and (67.34+/-30.66)*106 cells in the modified group (p<0.001). No significant differences were observed in the proportion of CD49f-positive cells between the two groups (p>0.05). The modified method was significantly more efficient in dissociating keratinocytes from each unit of skin biopsy, which is particularly important for treating severe burns when donor skin is limited. PMID- 29526527 TI - In Reply to 'Attempts to Change the Globally Accepted Term, CKDu, to KDUCAL, NUCAL, or CINAC Are Inappropriate'. PMID- 29526525 TI - Analysis of 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (DTMBA) as a new potential biomarker of exposure to vinclozolin in urine. AB - Vinclozolin (V) is a fungicide with anti-androgenic properties whose metabolism is not fully understood, and data on urinary elimination of either V or its metabolites are limited. Therefore the kinetics of urinary elimination of V and its metabolites, after an oral dose in adult male rats were investigated. A single oral dose of V (100 mg/kg) suspended in corn oil was administered to male adult Wistar rats, and urine was collected at different times after dosing. V and its metabolites were extracted from urine, then enzymatically hydrolyzed using beta-glucuronidase/sulfatase of H. pomatia, and analyzed by HPLC/DAD. Urinary pharmacokinetic parameters were calculated using the analyte concentrations adjusted by creatinine levels. V and its metabolites 3',5'-dichloro-2,3,4 trihydroxy-2-methylbutylanilide (DTMBA, formerly denoted as M5), 2-[[(3,5 dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), 3,5-dichloroaniline (M3), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2) were efficiently detected. The mean urine concentrations of V and M1 metabolite were fitted to a two-compartmental model for pharmacokinetic analysis. DTMBA approximately represented 88% of the total excreted metabolites, it was easily detected up to 168 h after dosing and its half-lives were 21.5 and 74.1 h, respectively. M1 was the second most abundant metabolite and was detected up to 144 h after being void. V and M3 were detected before 48 h, and M2 exhibited the lowest levels during the first 8 h after dosing. DTMBA, the most abundant V metabolite is quickly eliminated by urine, it is chemically stable, specific and could represent a useful alternative to be used as a biomarker of exposure to V. PMID- 29526526 TI - The dual role of mitochondrial superoxide in arsenite toxicity: Signaling at the boundary between apoptotic commitment and cytoprotection. AB - Arsenite toxicity is in numerous cellular systems dependent on the formation of reactive oxygen and or nitrogen species. This is also true in U937 cells in which the metalloid selectively promotes the formation of mitochondrial superoxide (mitoO2-) rapidly converted to diffusible H2O2. We tested the hypothesis that, under the same conditions, mitoO2- also mediates the triggering of a parallel survival signaling. We found that a low concentration of the metalloid causes an early activation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), and a downstream signaling leading to enhanced GSH biosynthesis, via a mechanism sensitive to various treatments/strategies selectively preventing mitoO2- formation. Under the same conditions, the toxic effects mediated by arsenite, leading to delayed mitochondrial permeability transition (MPT)-dependent apoptosis, were also prevented. Additional studies revealed remarkable similarities in the kinetics of mitoO2- formation, MPT induction, Nrf2 activation and GSH biosynthesis, prior to the onset of apoptosis in a small portion of the cells. Importantly, mitoO2- formation, as well as the ensuing toxic events, were significantly potentiated and anticipated under conditions associated with inhibition of de novo GSH biosynthesis triggered by the metalloid through Nrf2 activation. We conclude that, in the arsenite toxicity paradigm under investigation, mitoO2- represents the only trigger of two opposite pathways leading to activation of the Nrf2 signaling and/or to a MPT-dependent apoptotic death. The first pathway, through enhanced GSH biosynthesis, mitigates the extent of further mitoO2- formation, thereby limiting and delaying an otherwise rapid and massive apoptotic death. PMID- 29526528 TI - Attempts to Change the Globally Accepted Term, CKDu, to KDUCAL, NUCAL, or CINAC Are Inappropriate. PMID- 29526529 TI - Flower Kidney: The Gift of Giving. PMID- 29526530 TI - Accidental Injection of Freund Complete Adjuvant With Mycobacterium Tuberculosis. AB - Accidental needlestick injuries are common in laboratory and health care workers. Injection of atypical pathogens, such as those encountered in the animal laboratory setting, may pose considerable problems at the site of inoculation. We present the case of an otherwise healthy laboratory worker who accidentally self injected Freund complete adjuvant with heat-killed Mycobacterium tuberculosis into her hand, requiring multiple debridement operations over a prolonged treatment course. PMID- 29526531 TI - Non-small-cell Lung Cancer With Brain Metastasis at Presentation. AB - BACKGROUND: Data on the prevalence of brain metastases at presentation in patients with non-small-cell lung cancer (NSCLC) are limited. We queried the National Cancer Data Base to determine prevalence, clinical risk factors, and outcomes of patients with NSCLC presenting with brain metastases. PATIENTS AND METHODS: Patients with NSCLC diagnosed between 2010 and 2012 were identified using the National Cancer Data Base. The risk of brain metastases for individual variables was summarized by odds ratios and calculated using logistic regression analysis. The Kaplan-Meier product limit method was used to calculate the median and 1-, 2-, and 3-year overall survival (OS). RESULTS: Brain metastases were observed in 47,546 (10.4%) of the 457,481 patients with NSCLC overall. The prevalence of brain metastases was much higher (26%) in patients with stage IV disease at presentation. On multivariate analysis, younger age, adenocarcinoma or large cell histology, tumor size > 3 cm, tumor grade >= II, and node-positive disease were associated with brain metastases. The prevalence of brain metastases ranged from as low as 0.57% in patients with only 1 risk factor to as high as 22% in patients with all 5 risk factors. The median and 1-, 2-, and 3-year OS for patients with brain metastases were 6 months and 29.9%, 14.3%, and 8.4%, respectively, with the 3-year OS increasing to 36.2% in those with T1/2 and N0/1 undergoing surgery for the primary site. CONCLUSIONS: In patients with NSCLC, the risk of brain metastases at presentation may be calculated based on 5 clinical variables. Selected patients with brain metastases at presentation may achieve prolonged benefit. PMID- 29526532 TI - Fatal Radiation Pneumonitis in Patients With Subclinical Interstitial Lung Disease. PMID- 29526533 TI - Type 2 diabetes-related proteins derived from an in vitro model of inflamed fat tissue. AB - Currently, there is a worldwide increase of patients with type 2 diabetes (T2D). During the progression of healthy obese to T2D status, there is an influx of immune cells, in particular macrophages, into visceral adipose tissue, accompanied by an increase of inflammatory cytokines, such as, IL6, TNFalpha and Hp. To get a better insight in the underlying mechanisms, we performed a quantitative LCMS analysis on a modified in vitro assay, combining 3T3L1 adipocytes and activated RAW264.7 macrophages, thus mimicking inflamed adipose tissue. Clinically known proteins, e.g. IL6, TNFalpha, AdipoQ, complement factor C3, B and D were identified, thus confirming the assay. In addition, we found 54 new proteins that can potentially be used for research into the mechanism of T2D. Comparison of our results to a study on human visceral fat of obese non-diabetic and obese diabetic subjects, indicated that AUH, NAGK, pCYT2, NNMT, STK39 and CSNK2A2 might indeed be linked to insulin resistance in humans. Moreover, the expression of some of these genes was also altered in human blood samples at early or later stages of insulin desensitization. Overall, we conclude that the direct contact co-culture of 3T3L1 adipocytes with activated macrophages could be a mechanistically relevant and partially translational model of inflamed visceral adipose tissue. PMID- 29526534 TI - Inferior Vena Cava Filter Malpractice Litigation: Damned if You Do, Damned if You Don't. AB - BACKGROUND: The aim of this study was to analyze malpractice litigation trends and to better understand the causes and outcomes of suits involving inferior vena cava filters (IVCF) to prevent future litigation and improve physician education. METHODS: Jury verdict reviews from the Westlaw database from January 1, 2000, to December 31, 2015, were reviewed. The search term "inferior vena cava filter" was used to compile data on the demographics of the defendant, plaintiff, allegation, complication, and verdict. RESULTS: A total of 156 cases were identified. Duplicates and cases in which the IVCF was incidentally included were excluded from the analysis. Forty-nine cases involving either failure to place or a complication of IVCF placement were identified. Throughout the last 15 years, there has been increased number of jury verdicts toward IVCF. The most frequent defendants were internal medicine physicians (38%), vascular surgeons (19%), and cardiothoracic surgeons (12%). The most frequent claims were denied treatment or delay in treatment (in 35% of cases), negligent surgery (in 24% of cases), and failure to diagnose and treat complications (in 24% of cases). Of these, the most frequent specific claims were failure to place IVC filter (41%), implantation failure such as misplacement and/or misaligned implant (24%), erosion of IVC/retroperitoneal bleed (6%), and discontinuation of anticoagulation prematurely (6%). Seventeen cases (35%) were found for the plaintiff, with median awards worth of $1,092,500. In the 21 cases where pulmonary embolism (PE) was involved (43% of cases), 19 were fatal (90%). Of the fatal PE cases, 8 cases ended with verdicts in favor of the plaintiff (42%). Both nonfatal PE cases were won by the defense. CONCLUSIONS: IVCF placement with subsequent PE and death results in verdicts that favor the plaintiffs. This study emphasizes that adequate and transparent communication regarding preoperative planning, decision for IVCF placement, and informed consent may reduce the frequency of litigation. Public awareness of complications related to the placement of IVCF is increasing largely and spurned by aggressive advertising and marketing by plaintiff attorneys. Conditions for which IVCF placement is contemplated carry significant risk of malpractice litigation. PMID- 29526535 TI - Loss of LCAT activity in the golden Syrian hamster elicits pro-atherogenic dyslipidemia and enhanced atherosclerosis. AB - OBJECTIVE: Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in HDL metabolism but its influence on atherosclerosis remains controversial for decades both in animal and clinical studies. Because lack of cholesteryl ester transfer protein (CETP) is a major difference between murine and humans in lipoprotein metabolism, we aimed to create a novel Syrian Golden hamster model deficient in LCAT activity, which expresses endogenous CETP, to explore its metabolic features and particularly the influence of LCAT on the development of atherosclerosis. METHODS: CRISPR/CAS9 gene editing system was employed to generate mutant LCAT hamsters. The characteristics of lipid metabolism and the development of atherosclerosis in the mutant hamsters were investigated using various conventional methods in comparison with wild type control animals. RESULTS: Hamsters lacking LCAT activity exhibited pro-atherogenic dyslipidemia as diminished high density lipoprotein (HDL) and ApoAI, hypertriglyceridemia, Chylomicron/VLDL accumulation and significantly increased ApoB100/48. Mechanistic study for hypertriglyceridemia revealed impaired LPL-mediated lipolysis and increased very low density lipoprotein (VLDL) secretion, with upregulation of hepatic genes involved in lipid synthesis and transport. The pro-atherogenic dyslipidemia in mutant hamsters was exacerbated after high fat diet feeding, ultimately leading to near a 3- and 5-fold increase in atherosclerotic lesions by aortic en face and sinus lesion quantitation, respectively. CONCLUSIONS: Our findings demonstrate that LCAT deficiency in hamsters develops pro-atherogenic dyslipidemia and promotes atherosclerotic lesion formation. PMID- 29526536 TI - The BACE1 product sAPPbeta induces ER stress and inflammation and impairs insulin signaling. AB - OBJECTIVE: beta-secretase/beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPbeta (sAPPbeta), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. MATERIALS/METHODS: Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1-/-mice and mice treated with sAPPbeta and adipose tissue and plasma from obese and type 2 diabetic patients. RESULTS: We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator-Activated Receptor gamma Co activator 1alpha (PGC-1alpha) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1alpha down-regulation, and fatty acid oxidation were mimicked by soluble APPbeta in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1alpha mRNA levels and by an increase in sAPPbeta plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPbeta administration to mice reduced PGC-1alpha levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. CONCLUSIONS: Collectively, these findings indicate that the BACE1 product sAPPbeta is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver. PMID- 29526537 TI - Body weight regulation, socioeconomic status and epigenetic alterations. AB - Obesity is a complex disease which has reached epidemic dimensions. Thus, prevention of excessive weight gain and associated metabolic and cardiovascular diseases has to start as early in life as possible. The impact of epigenetic mechanisms on the regulation of genes involved in obesity is increasingly recognized. On the other hand, it is well known that socioeconomic factors influence the risk for obesity. These factors can also have an impact on epigenetic gene regulation. There is increasing body of evidence that several factors and interventions addressing extragenetic causes of obesity may not only improve individual health, but also the health of future generations by epigenetic alterations. Our current understanding of epigenetic changes has shown that many of them are potentially reversible, i.e. by physical exercise, by pharmacological treatment, by environmental factors or nutrition, or even by influencing socioeconomic factors, which might have impact on improving health in future generations by avoiding epigenetic dysregulation. In this review we present the current state of the art with regard to the interplay between social determinants, weight status and epigenetic alterations. PMID- 29526538 TI - Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-kappaB pathway. AB - BACKGROUND: AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-kappaB is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS: The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-kappaB signaling pathway. Rat cardiac myoblast H9c2 cells were subjected to hypoxia and/or reoxygenation to investigate the signal transduction that occurred during myocardial ischemia/reperfusion. Mitochondrial function was measured by the Seahorse XF24 V7 PS system. Hypoxia treatment triggered AMPK activation in H9c2 cells in a time dependent manner. The inhibition of hypoxic AMPK activation through a pharmacological approach (Compound C) or siRNA knockdown of AMPK alpha catalytic subunits caused dramatic augmentation in JNK activation, inflammatory NF-kappaB phosphorylation, and apoptosis during hypoxia and reoxygenation. Inhibition of AMPK activation significantly impaired mitochondrial function and increased the generation of reactive oxygen species (ROS) during hypoxia and reoxygenation. In contrast, pharmacological activation of AMPK by metformin significantly inhibited mitochondrial permeability transition pore (mPTP) opening and ROS generation. Moreover, AMPK activation significantly attenuated the JNK-NF-kappaB signaling cascade and inhibited mRNA and protein levels of pro-inflammatory cytokines, such as TNF-alpha and IL-6, during hyopoxia/reoxygenation in H9c2 cells. Intriguingly, both pharmacologic inhibition of JNK by JNK-IN-8 and siRNA knockdown of JNK signaling pathway attenuated NF-kappaB phosphorylation and apoptosis but did not affect AMPK activation in response to hypoxia and reoxygenation. CONCLUSIONS: AMPK activation modulates JNK-NF-kappaB signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults. PMID- 29526539 TI - Buthus lienhardi venom and pathophysiological effects at the histological, hematological, biochemical and motor skills levels. AB - The present study investigated the toxic effects of B. lienhardi venom, at the histological, hematological, biochemical and motor skill levels following a subcutaneous injection of different doses of venom. The LD50 of B. lienhardi scorpion venom was found to be 0.27 mg/Kg by subcutaneous injection route. The results clearly indicate that B. lienhardi venom induces massive tissue damages in the organs, such as lungs, heart, kidneys and liver together with hematological impairments manifested by decreased levels of both red and white series. We further demonstrated that scorpion venom is able to alter motor system by inducing motor incoordination and reducing muscle strength. The overall results confirm that the venom from B. lienhardi primarily is a highly toxic agent and has cardiotoxic, nephrotoxic, hepatotoxic and pneumotoxic activity. PMID- 29526540 TI - Dendritic cell-based cancer immunotherapy for pancreatic cancer. AB - Pancreatic cancer (PC) is a lethal disease and remains one of the most resistant cancers to traditional therapies. New therapeutic modalities are urgently needed, particularly immunotherapy, which has shown promise in numerous animal model studies. Dendritic cell (DC)-based immunotherapy has been used in clinical trials for various cancers, including PC, because DCs are the most potent antigen presenting cell (APC), which are capable of priming naive T cells and stimulating memory T cells to generate antigen-specific responses. In this paper, we review the preclinical and clinical efforts towards the application of DCs for PC. PMID- 29526541 TI - Effectiveness and Safety of Rivaroxaban Versus Warfarin in Frail Patients with Venous Thromboembolism. AB - PURPOSE: Frailty predicts poorer outcomes in patients receiving anticoagulation. We assessed the effectiveness and safety of rivaroxaban vs warfarin in frail patients experiencing venous thromboembolism. METHODS: Using US MarketScan claims data from January 2012-December 2016, we identified frail patients (using the Johns Hopkins Claims-Based Frailty Indicator score) who had >=1 primary hospitalization/emergency department visit diagnosis codes for venous thromboembolism, received rivaroxaban or warfarin as their first outpatient oral anticoagulant within 30 days of the index event, and had >=12 months of insurance prior to the index venous thromboembolism. Differences in baseline covariates between cohorts were adjusted using inverse probability of treatment weights based on propensity scores. The primary endpoint was the composite of recurrent venous thromboembolism or major bleeding. Patient claims were tracked for up to 12 months after the index venous thromboembolism or until endpoint occurrence oral anticoagulant discontinuation/switch, insurance disenrollment, or end of follow-up. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of 58,089 incident venous thromboembolism patients identified, 6869 (1365 rivaroxaban and 5504 warfarin users) were classified as frail. Rivaroxaban reduced patients' hazard of the composite of recurrent venous thromboembolism or major bleeding (HR 0.75; 95% CI, 0.57-0.98) and recurrent venous thromboembolism alone (HR 0.65; 95% CI, 0.44-0.97) compared with warfarin. No significant difference in major bleeding was observed between cohorts (HR 0.88; 95% CI, 0.61-1.27). CONCLUSIONS: Frail patients experiencing a venous thromboembolism and given rivaroxaban experience less recurrent venous thromboembolism, with at least as good bleeding outcomes, as patients prescribed warfarin. PMID- 29526542 TI - Looking Beyond the Obvious: Eosinophilic Enterocolitis. PMID- 29526543 TI - Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment. AB - The lung presents a highly oxidative environment, which is tolerated through engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH associated protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation. Notably, metabolites identified in the plasma of Keap1f/f/Ptenf/f tumor-bearing mice indicate that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumor regression was achieved utilizing immune checkpoint inhibition. Thus, our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung tumors harboring KEAP1/NRF2 pathway alterations. PMID- 29526544 TI - Molecular characterization of the histiocytoses: Neoplasia of dendritic cells and macrophages. AB - The systemic histiocytoses encompass a clinically heterogeneous group of disorders leading to tissue damage secondary to the accumulation and infiltration of pathological cells thought to be derived from the dendritic or monocytic lineages with accompanying inflammation. For decades, whether or not the histiocytoses were inflammatory or neoplastic disorders was unclear, and their cellular origins have long been obscure and heavily debated. However, the rise of the molecular era led to the discovery of recurrent BRAFV600E mutations in approximately 50% of patients with Langerhans cell and non-Langerhans cell histiocytoses, which provided the first convincing evidence that these are indeed histiocytic neoplasms. This also supplied a molecular biomarker for potentially mapping the cell(s)-of-origin of these neoplasms. The purpose of this review will be to highlight the barrage of recent molecular advancements in the histiocytic neoplasms and discuss the impact these insights have had on our understanding of the molecular pathophysiology and cellular origins of these rare, enigmatic diseases. PMID- 29526545 TI - Community-Based Acupunch Exercise Program Improves Physical Health and Quality of Sleep in Taiwanese Older Adults. PMID- 29526546 TI - The new MTV generation: Using methamphetamine, TruvadaTM, and ViagraTM to enhance sex and stay safe. AB - INTRODUCTION: Gay and bisexual men (GBM) often use illicit drugs to enhance sexual pleasure, commonly referred to as 'chemsex' or 'party n play'. In particular, the use of methamphetamine and ViagraTM, and other erectile dysfunction medications, both together and separately are strongly predictive of subsequent HIV infection. TruvadaTM, as pre-exposure prophylaxis (PrEP), virtually eliminates HIV transmission during condomless anal intercourse (CLAI). HIV-negative GBM in intensive sex partying networks may be adding PrEP to their drug regimen to actively reduce the possibility of HIV transmission during chemsex. AIM: We describe the prevalence and context of concurrent use of methamphetamine, TruvadaTM (or its generic formulations), and ViagraTM or other erectile dysfunction medication (collectively, MTV). METHOD: The Following Lives Undergoing Change study is an online prospective observational study of licit and illicit drug use among Australian GBM. Between January and July 2017, 1831 GBM provided details about their use of MTV. Binary logistic multiple regression analysis were used to estimate adjusted odds ratios (aOR) and associated 95% confidence intervals (95%CI). RESULTS: Concurrent MTV use was reported by 6.0% of participants; 3.1% used methamphetamine and ViagraTM or other erectile dysfunction medication ('MV only') and 11.2% used TruvadaTM as PrEP ('T only'). In multivariate analysis, compared to use of 'MV only', MTV was independently associated with CLAI with casual partners (aOR = 6.78;95%CI = 1.42-32.34) and 'fuckbuddies' (aOR = 3.47;95%CI = 1.41-8.56) in the previous six months. Compared to use of 'T only', MTV was independently associated with being older (aOR = 3.95;95%CI = 1.55-10.03) and engaging in group sex (aOR = 3.31;95%CI = 1.82 6.00). Greater social engagement with other gay men (aOR = 1.44;95%CI = 1.18 1.76) and having more sexual partners (aOR = 2.30;95%CI = 1.10-4.82) were independently associated with use of MTV compared to use of 'MV only' or 'T only'. CONCLUSION: GBM in intensive sex partying networks are increasingly adding PrEP alongside other drugs they use to enhance sexual experiences. Interventions that promote the use of PrEP during chemsex could mitigate HIV risk. PMID- 29526547 TI - Huntingtin protein: A new option for fixing the Huntington's disease countdown clock. AB - Huntington's disease is a dreadful, incurable disorder. It springs from the autosomal dominant mutation in the first exon of the HTT gene, which encodes for the huntingtin protein (HTT) and results in progressive neurodegeneration. Thus far, all the attempted approaches to tackle the mutant HTT-induced toxicity causing this disease have failed. The mutant protein comes with the aberrantly expanded poly-glutamine tract. It is primarily to blame for the build-up of beta amyloid-like HTT aggregates, deleterious once broadened beyond the critical ~35 37 repeats threshold. Recent experimental findings have provided valuable information on the molecular basis underlying this HTT-driven neurodegeneration. These findings indicate that the poly-glutamine siding regions and many post translation modifications either abet or counter the poly-glutamine tract. This review provides an overall, up-to-date insight into HTT biophysics and structural biology, particularly discussing novel pharmacological options to specifically target the mutated protein and thus inhibit its functions and toxicity. PMID- 29526548 TI - Breast Cancer Molecular Subtype Prediction by Mammographic Radiomic Features. AB - RATIONALE AND OBJECTIVES: This study aimed to investigate whether quantitative radiomic features extracted from digital mammogram images are associated with molecular subtypes of breast cancer. MATERIALS AND METHODS: In this institutional review board-approved retrospective study, we collected 331 Chinese women who were diagnosed with invasive breast cancer in 2015. This cohort included 29 triple-negative, 45 human epidermal growth factor receptor 2 (HER2)-enriched, 36 luminal A, and 221 luminal B lesions. A set of 39 quantitative radiomic features, including morphologic, grayscale statistic, and texture features, were extracted from the segmented lesion area. Three binary classifications of the subtypes were performed: triple-negative vs non-triple-negative, HER2-enriched vs non-HER2 enriched, and luminal (A + B) vs nonluminal. The Naive Bayes machine learning scheme was employed for the classification, and the least absolute shrink age and selection operator method was used to select the most predictive features for the classifiers. Classification performance was evaluated by the area under receiver operating characteristic curve and accuracy. RESULTS: The model that used the combination of both the craniocaudal and the mediolateral oblique view images achieved the overall best performance than using either of the two views alone, yielding an area under receiver operating characteristic curve (or accuracy) of 0.865 (0.796) for triple-negative vs non-triple-negative, 0.784 (0.748) for HER2 enriched vs non-HER2-enriched, and 0.752 (0.788) for luminal vs nonluminal subtypes. Twelve most predictive features were selected by the least absolute shrink age and selection operator method and four of them (ie, roundness, concavity, gray mean, and correlation) showed a statistical significance (P <.05) in the subtype classification. CONCLUSIONS: Our study showed that quantitative radiomic imaging features of breast tumor extracted from digital mammograms are associated with breast cancer subtypes. Future larger studies are needed to further evaluate the findings. PMID- 29526549 TI - Fluctuating periodic solutions and moment boundedness of a stochastic model for the bone remodeling process. AB - In this work, we model osteoclast-osteoblast population dynamics with random environmental fluctuations in order to understand the random variations of the bone remodeling process in real life. For this purpose, we construct a stochastic differential model for the interactions between the osteoclast and osteoblast cell populations using the parameter perturbation technique. We prove the existence of a globally attractive positive unique solution for the stochastically perturbed system. Also, the stochastic boundedness of the solution is demonstrated using its p-th order moments for p >= 1. Finally, we show that the introduction of noise in the deterministic model provides a fluctuating periodic solution. Numerical evidence supports our theoretical results and a discussion of the results is carried out. PMID- 29526550 TI - A geometrical model for diffusion of hydrophilic compounds in human stratum corneum. AB - A three-dimensional diffusion model with either hexagonal or cylindrical symmetry has been constructed to simulate desorption profiles of hydrophilic chemicals from the topmost layer of human skin (the stratum corneum) as measured in ex vivo studies. The tissue is pierced by skin appendages - sweat glands and hair follicles - which in this particular scenario are considered to be perfect sinks. Desorption profiles of nine test permeants covering a wide range of lipophilicity were analyzed. By optimizing transverse and lateral diffusion coefficients to match these profiles, it was found that the lateral diffusivity values exceeded the transverse values by average factors ranging from 45 (hexagon model) to 71 (cylinder model). However, transverse clearance exceeded lateral clearance by factors ranging from 8 to 27 (cylinder model); these values were strongly influenced by the thickness of the individual tissue samples, as expected. The results confirm the validity of earlier estimates of transverse diffusivity of hydrophilic compounds in human stratum corneum based on purely one-dimensional models. They furthermore confirm that transcellular transport is an important component of the stratum corneum's polar pathway, in addition to the already recognized appendageal transport mechanism. PMID- 29526551 TI - Impact of disposing stray dogs on risk assessment and control of Echinococcosis in Inner Mongolia. AB - Echinococcosis has been recognized as one of the most important helminth zoonosis in China. Available models always consider dogs as the mainly definitive hosts. However, such models ignore the distinctions between domestic dogs and stray dogs. In this study, we propose a 10-dimensional dynamic model distinguishing stray dogs from domestic dogs to explore the special role of stray dogs and potential effects of disposing stray dogs on the transmission of Echinococcosis. The basic reproduction number R0, which measures the impact of both domestic dogs and stray dogs on the transmission, is determined to characterize the transmission dynamics. Global dynamic analysis of the model reveals that, without disposing the stray dogs, the Echinococcosis becomes endemic even the domestic dogs are controlled. Moreover, due to the difficulties in estimating the parameters involved in R0 with real data and the limitation of R0 in real-world applications, a new risk assessment tool called relative risk index Irisk is defined for the control of zoonotic diseases, and the studies of the risk assessment for Echinococcosis infection show that it is essential to distinguish stray dogs from domestic dogs in applications. PMID- 29526552 TI - On structural identifiability analysis of the cascaded linear dynamic systems in isotopically non-stationary 13C labelling experiments. AB - The isotopically non-stationary 13C labelling experiments, as an emerging experimental technique, can estimate the intracellular fluxes of the cell culture under an isotopic transient period. However, to the best of our knowledge, the issue of the structural identifiability analysis of non-stationary isotope experiments is not well addressed in the literature. In this work, the local structural identifiability analysis for non-stationary cumomer balance equations is conducted based on the Taylor series approach. The numerical rank of the Jacobian matrices of the finite extended time derivatives of the measured fractions with respect to the free parameters is taken as the criterion. It turns out that only one single time point is necessary to achieve the structural identifiability analysis of the cascaded linear dynamic system of non-stationary isotope experiments. The equivalence between the local structural identifiability of the cascaded linear dynamic systems and the local optimum condition of the nonlinear least squares problem is elucidated in the work. Optimal measurements sets can then be determined for the metabolic network. Two simulated metabolic networks are adopted to demonstrate the utility of the proposed method. PMID- 29526553 TI - ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism. AB - Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity. PMID- 29526555 TI - Systematic review identifies six metrics and one method for assessing literature search effectiveness but no consensus on appropriate use. AB - OBJECTIVES: To identify the metrics or methods used by researchers to determine the effectiveness of literature searching where supplementary search methods are compared to bibliographic database searching. We also aimed to determine which metrics or methods are summative or formative and how researchers defined effectiveness in their studies. STUDY DESIGN AND SETTING: Systematic review. We searched MEDLINE and Embase to identify published studies evaluating literature search effectiveness in health or allied topics. RESULTS: Fifty studies met full text inclusion criteria. Six metrics (sensitivity, specificity, precision, accuracy, number needed to read, and yield) and one method (capture recapture) were identified. CONCLUSION: Studies evaluating effectiveness need to identify clearly the threshold at which they will define effectiveness and how the evaluation they report relates to this threshold. Studies that attempt to investigate literature search effectiveness should be informed by the reporting of confidence intervals, which aids interpretation of uncertainty around the result, and the search methods used to derive effectiveness estimates should be clearly reported and validated in studies. PMID- 29526554 TI - Differential Control of Axonal and Somatic Resting Potential by Voltage-Dependent Conductances in Cortical Layer 5 Pyramidal Neurons. AB - Voltage-dependent conductances not only drive action potentials but also help regulate neuronal resting potential. We found differential regulation of resting potential in the proximal axon of layer 5 pyramidal neurons compared to the soma. Axonal resting potential was more negative than the soma, reflecting differential control by multiple voltage-dependent channels, including sodium channels, Cav3 channels, Kv7 channels, and HCN channels. Kv7 current is highly localized to the axon and HCN current to the soma and dendrite. Because of impedance asymmetry between the soma and axon, axonal Kv7 current has little effect on somatic resting potential, while somatodendritic HCN current strongly influences the proximal axon. In fact, depolarizing somatodendritic HCN current is critical for resting activation of all the other voltage-dependent conductances, including Kv7 in the axon. These experiments reveal complex interactions among voltage dependent conductances to control region-specific resting potential, with somatodendritic HCN channels playing a critical enabling role. PMID- 29526556 TI - Quality assessment versus risk of bias in systematic reviews: AMSTAR and ROBIS had similar reliability but differed in their construct and applicability. AB - OBJECTIVES: The objective of the study was to assess the inter-rater reliability (IRR) of AMSTAR and ROBIS in judging individual domains and overall methodological quality/risk of bias of systematic reviews, the concurrent validity of the tools, and the time required to apply them. STUDY DESIGN AND SETTING: This is a cross-sectional study. Five raters independently read 31 systematic reviews and applied AMSTAR and ROBIS. Fleiss' k for multiple raters for individual domains and overall methodological quality/risk of bias was calculated. Similar domains assessed by both tools and final scores were matched to explore the concurrent validity, using the Kendall tau correlation. RESULTS: IRR ranged from fair to perfect for AMSTAR and from moderate to substantial for ROBIS. Kappa for overall quality/risk of bias was 0.73 (95% confidence interval [CI] 0.65-0.81) for AMSTAR and 0.64 (95% CI 0.54-0.74) for ROBIS. We judged most of the reviews at intermediate quality with AMSTAR (53%), while judgments were split in high (53%) and low (47%) risk of bias with ROBIS. The correlation between judgments on similar domains ranged from moderate to high, while it was fair on the overall judgment (K = 0.35, 95% CI 0.21-0.49). The mean time to complete ROBIS was about double that for AMSTAR. CONCLUSION: AMSTAR and ROBIS offer similar IRR but differ in their construct and applicability. PMID- 29526557 TI - Intracystic papillary carcinoma of the breast: Experience of a major Chinese cancer center. AB - BACKGROUND: Intracystic papillary carcinoma (IPC) is a rare breast neoplasm. There are few studies focusing on its clinical features and limited data about its preoperative diagnosis,treatment and outcomes. The purpose of this study is to explore specific characteristics of patients with IPC, investigate its clinicopathological features, prognosis in China and confirm its surgery management. METHODS: We identified 111 patients with IPC from the registry of Tianjin Medical University Cancer Institute and Hospital between 2004 and 2017. Follow-up of cases dating back to January 1, 2004 was obtained from retrospective chart review and patient questionnaires. Differences in clinical features and survival of patients were assessed using the Kaplan-Meier method. RESULTS: The median tumor size was 2.25 cm. Median age was 62 years. In the cases of axillary lymph node dissection(ALND), only 1.1% (1/85) of patients with axillary lymph node metastasis were found. The diagnostic accuracy of preoperative Color Doppler ultrasound and Mammograms for IPC was 62.0% (62/100) and 63.5% (54/85) respectively. The median follow-up period was 52 (range2-149) months. The overall survival rate was 98.9%, 92.2%,and 85.6% at 2,5,and 10 years and the relapse-free rate was 99.1%,97.2%,and 92.0% at 2,5, and 10 years, respectively. The disease specific survival rate was 100%. CONCLUSION: Overall, we report some unique features of IPC in the Chinese population. The patients of IPC of the breast in China have more excellent prognosis than in Caucasian and other races. The diagnostic accuracy of imaging was low, and was easily misinterpreted as a cyst or benign disease. Preoperative core needle biopsies are very difficult for accurate pathological diagnosis of IPC. IPC is a localized disease with a low frequency of axillary lymph node involvement, rare distant metastases and excellent survival. The low incidence of axillary lymph node metastasis suggests that quadrectomy + sentinel lymph node biopsy (SLNB) and breast-conserving surgery is recommended for IPC. PMID- 29526558 TI - High TRIM44 expression in endometrial carcinoma is associated with a poorer patient outcome. AB - BACKGROUND: Tripartite motif-containing protein 44 (TRIM44) has been recently identified as a novel oncogene that is overexpressed in several types of human cancers; however, its role in endometrial cancer (EC) remains unknown. The purpose of the current study was to investigate the TRIM44 protein expression and clinicopathological significance of TRIM44 in EC. METHODS: Paraffin-embedded surgical specimens were collected from 143 patients with EC for the immunohistochemical analysis of TRIM44 expression. Western blotting was performed to evaluate differences in TRIM44 protein expression in EC and normal endometrial tissues. RESULTS: TRIM44 expression was low in normal tissues and high in EC tissues (P < 0.001). TRIM44 overexpression was significantly associated with the Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, depth of myometrial invasion and lymph node metastasis (P < 0.05). Moreover, TRIM44 expression was an independent prognostic factor for both overall survival and disease-free survival in patients with EC (both P < 0.05). CONCLUSIONS: The present study provides evidence that TRIM44 predicts the risk of development and prognosis of EC, highlighting its potential application as a therapeutic target for this malignancy. PMID- 29526559 TI - Role of upregulated miR-136-5p in lung adenocarcinoma: A study of 1242 samples utilizing bioinformatics analysis. AB - BACKGROUND: It is generally acknowledged that miRNAs play pivotal roles in the initiation and development of cancer. The aim of the current study is to investigate the clinicopathological role of miR-136-5p in lung adenocarcinoma and its underlying molecular mechanism. MATERIALS AND METHODS: Data of a cohort of 1242 samples were provided by the Gene Expression Omnibus and The Cancer Genome Atlas to evaluate miR-136-5p expression in lung adenocarcinoma. A comprehensive meta-analysis integrating the expression data from all sources was performed, followed by a summary receiver operating curve plotted to appraise the upregulated expression of miR-136-5p in lung adenocarcinoma. Candidate targets of miR-136-5p were launched by the intersection of differentially expressed genes in The Cancer Genome Atlas and genes predicted by 12 web-based platforms. Then, hub genes were illustrated by a protein-protein interaction network. Furthermore, Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Protein Analysis Through Evolutionary Relationships analyses of potential target genes were carried out via bioinformatics tools. RESULTS: MiR-136-5p expression was upregulated in lung adenocarcinoma versus normal tissues (standard mean difference = 0.43, 95% confidence interval: 0.27-0.58). The summary receiver operating characteristic curve further verified the upregulation of miR-136-5p in lung adenocarcinoma (area under curve = 0.7459). A total of 311 candidate target genes of miR-136-5p were gathered to create a protein-protein interaction network. Molecular mechanism analysis unveiled the potential miR-136-5p target genes participated in cell adhesion molecules, focal adhesion, complement and coagulation cascades and blood coagulation. CONCLUSION: MiR-136-5p is overexpressed in lung adenocarcinoma and is involved in the molecular mechanism of lung adenocarcinoma via suppressing the expressions of downstream targets, especially claudin-18, sialophorin and syndecan 2 that participate in cell adhesion. PMID- 29526561 TI - The psychosocial impact of orofacial pain in trigeminal neuralgia patients: a systematic review. AB - Trigeminal neuralgia (TN) is characterized by sharp, electric shock-like pain, which can be triggered by trivial stimuli. Although medical and surgical treatments are available for TN, some patients experience refractory pain, which has a significant impact on their quality of life. The aim of this systematic review was to determine the psychosocial impact of orofacial pain in patients with diagnosed TN. A search was initiated in three electronic databases (Embase, MEDLINE, PubMed) to identify potential studies for inclusion in the review. All types of study published in English that reported psychosocial measures using validated psychometric questionnaires were included. A total of 585 articles were retrieved from the search. These were screened thoroughly, leading to the selection of 13 articles for data extraction and final analysis. The results show the chronic overwhelming nature of TN, with pain levels varying from mild to severe. Psychometric scores indicated mild to moderate depression, moderate to severe anxiety, and moderate to severe functional limitation of daily life activities in TN patients. Therefore, psychological support within a multidisciplinary team is recommended for TN patients to help them cope better with their chronic disorder and to improve the efficacy of treatment. PMID- 29526560 TI - Biomechanical simulation of temporomandibular joint replacement (TMJR) devices: a scoping review of the finite element method. AB - The aim of this study was to perform a literature review on the use of finite element modeling (FEM) for the evaluation of the biomechanical behavior of temporomandibular joint replacement (TMJR) devices. An electronic search of online medical and scientific literature database was conducted using selected search terms. The search identified 307 studies, of which 19 were considered relevant to this study. Of the 19 selected studies, 10 (52.6%) investigated the influence of geometry and fixation methods, while two (10.5%) evaluated the behavior of artificial condyle-fossa structures. The TMJR devices assessed in these studies included TMJ Inc. (aka Christensen; 63.2%), Zimmer Biomet (15.7%), Stryker (10.5%), and a theoretical intramedullary condylar component (5.3%); 26.3% of the studies evaluated custom TMJR devices. Such studies provided important data on the distribution of strain and stress through TMJR structural components and surrounding bone by using different software systems and methods. The mean stress values were lower on a custom TMJR condyle-ramus component and the supporting bone than on the stock device. FEM proved to be an accurate and valuable biomechanical simulation tool for studying the current TMJR devices and should be considered a useful tool for the improvement and development of future joint replacement devices. PMID- 29526562 TI - Endoscopic pericranial flap design for the restoration of nasal mid-vault lining defects. AB - Despite progress made in nasal reconstruction, the restoration of a large defect, including the whole septum and mid-nasal vault structures, remains a challenge. The pericranial flap (PCF) is used widely for the reconstruction of anterior cranial fossa defects. This article presents a surgical technique for nasal lining restoration with an endoscopic PCF design. This technique was used in patients with huge intranasal tumours. Two patients with nasal eosinophilic angiocentric fibrosis were treated. The structural involvement was similar in each case. The tumour was resected completely by combined endoscopic and external methods through an open rhinoplasty approach. The resulting defect included the whole nasal septum, bilateral upper lateral cartilage, and the entire mid-nasal vault mucosal lining. Reconstruction was achieved by endoscopic PCF design for internal lining reconstruction and rib cartilage for framework repair. The first patient was followed up for 18months and the second for 8months. No infection occurred in the postoperative period. Framework stability and texture were good, and both nasal shapes were acceptable. In conclusion, this endoscopic PCF approach for restoring the internal nasal lining appears to be a good choice in selected cases. PMID- 29526563 TI - Dobutamine Stress Echocardiography Unmasks Early Left Ventricular Dysfunction in Asymptomatic Patients with Uncomplicated Type 2 Diabetes: A Comprehensive Two Dimensional Speckle-Tracking Imaging Study. AB - BACKGROUND: Discrepancies are present in the literature on resting myocardial mechanics in patients with uncomplicated type 2 diabetes mellitus (T2DM). Data are noticeably sparse regarding circumferential function and torsional mechanics. Resting deformation imaging may not be sensitive enough to detect subtle dysfunctions. The aim of this study was thus to comprehensively evaluate myocardial mechanics in patients with T2DM at rest and to investigate whether dobutamine stress echocardiography could unmask functional alterations that would remain otherwise subtle at rest. METHODS: Forty-four patients with T2DM and 35 healthy control subjects of similar age and sex were prospectively recruited. After conventional echocardiography, myocardial mechanics was evaluated at rest and during low-dose dobutamine stress echocardiography (target heart rate, 110 beats/min). RESULTS: Patients with T2DM presented with altered global diastolic function but preserved systolic function. Deformation imaging indexes were similar between groups at rest, but significant differences were noticed under dobutamine infusion for longitudinal strain (-21.2 +/- 2.4% vs -24.2 +/- 2.5%, P < .001), circumferential strain (apex, -32.3 +/- 5.3% vs -36.3 +/- 5.3%, P = .002; papillary muscle, -25.6 +/- 3.2% vs -28.0 +/- 3.6%, P = .001; base, -23.2 +/- 3.6% vs -25.3 +/- 3.8%, P = .03), apical (11.2 +/- 4.4 degrees vs 14.1 +/- 6.3 degrees , P = .020) and basal (-12.2 +/- 3.3 degrees vs -14.3 +/- 3.9 degrees , P = .021) rotation, and twist (21.9 +/- 5.9 degrees vs 26.8 +/- 8.3 degrees , P = .007). Multivariate analysis identified epicardial fat, dyslipidemia, and fasting glycaemia as significant contributors to the changes from rest to dobutamine. CONCLUSIONS: These findings demonstrate the usefulness of dobutamine stress echocardiography in establishing impairments in myocardial mechanics in patients with uncomplicated T2DM. Systemic metabolic disturbances and epicardial fat act as the main contributors to the blunted response to dobutamine stress in these patients. PMID- 29526564 TI - Normative Data for Left and Right Ventricular Systolic Strain in Healthy Caucasian Italian Children by Two-Dimensional Speckle-Tracking Echocardiography. AB - BACKGROUND: There is an increasing interest in echocardiographic strain (epsilon) measurements for the assessment of ventricular myocardial function in children; however, pediatric nomograms remain limited. Our aim was to establish pediatric nomograms for the left ventricular (LV) and the right ventricular (RV) epsilon measured by two-dimensional speckle-tracking echocardiography (2D-STE) in a large cohort of healthy children prospectively enrolled. METHODS: Echocardiographic measurements included STE LV longitudinal and circumferential and RV longitudinal global end-systolic epsilon. Age, weight, height, heart rate (HR), and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement. Echocardiograms were performed by Philips-iE33 systems (Philips, Bothell, WA) and offline measurements on Philips-Q Lab-9. RESULTS: In all, 721 subjects (age 31 days to 17 years; 48% female) were studied. Low coefficients of determination (R2) were noted among all of the epsilon parameters evaluated and adjusted for age, weight, height, BSA, and HR (i.e., R2 all <= 0.10; range, 0.01-0.088). This hampered the possibility of performing z-scores with a sufficient reliability. Thus, we are limited to presenting data as mean values (+/-SD) stratified for age groups and divided by gender. LV longitudinal epsilon values decreased with age (P < .001), while no significant age-related variations were noted for RV longitudinal epsilon. A significant base-to-apex (lowest to highest) gradient in circumferential LV epsilon values was noted at all ages (P < .001). CONCLUSIONS: We report pediatric echocardiographic normative data for 2D-STE for the LV and RV epsilon by using vendor-specific software. Our results confirm previous observations, showing only little variations of strain parameters with age and gender. PMID- 29526565 TI - Attenuation of quorum sensing controlled virulence factors and biofilm formation in Pseudomonas aeruginosa by pentacyclic triterpenes, betulin and betulinic acid. AB - The production of virulence determinants and biofilm formation in numerous pathogens is regulated by the cell-density-dependent phenomenon, Quorum sensing (QS). The QS system in multidrug resistant opportunistic pathogen, P. aeruginosa constitutes of three main regulatory circuits namely Las, Rhl, and Pqs which are closely linked to its pathogenicity and establishment of chronic infections. In spite intensive antibiotic therapy, P. aeruginosa continue to be an important cause of nosocomial infections and also the major cause of mortality in Cystic Fibrosis patients with 80% of the adults suffering from chronic P. aeruginosa infection. Hence, targeting QS circuit offers an effective intervention to the ever increasing problem of drug resistant pathogens. In the present study, the pentacyclic triterpenes i.e. Betulin (BT) and Betulinic acid (BA) exhibited significant attenuation in production of QS-regulated virulence factors and biofilm formation in P. aeruginosa, at the sub-lethal concentration. The test compound remarkably interfered in initial stages of biofilm development by decreasing the exopolysaccharide production and cell surface hydrophobicity. Based on the in vivo studies, the test compounds notably enhanced the survival of Caenorhabditis elegans infected with P. aeruginosa. Furthermore, molecular docking analysis revealed that BT and BA can act as a strong competitive inhibitor for QS receptors, LasR and RhlR. The findings suggest that BT and BA can serve as potential anti-infectives in the controlling chronic infection of P. aeruginosa. PMID- 29526566 TI - Impact of cell-free hemoglobin on contracting skeletal muscle microvascular oxygen pressure dynamics. AB - Free hemoglobin (Hb) associated with hemolysis extravasates into vascular tissue and depletes nitric oxide (NO), which leads to impaired vascular function and could impair skeletal muscle metabolic control during exercise. We tested the hypothesis that: 1) free Hb would extravasate into skeletal muscle tissue, reducing the contracting skeletal muscle O2 delivery/O2 utilization ratio (microvascular PO2, PO2mv) to a similar extent as that observed following NO synthase (NOS) blockade, and 2) that the Hb scavenging protein haptoglobin (Hp) would prevent Hb extravasation and inhibit these skeletal muscle tissue effects. PO2mv was measured in eight rats (phosphorescence quenching) at rest and during 180 s of electrically induced (1-Hz) twitch spinotrapezius muscle contractions (experiment 1). A second group of seven rats was also used to investigate the effects of Hb + Hp (experiment 2). For both experiments, measurements were made: 1) during control conditions, 2) following a bolus infusion of either Hb (50 mg/kg) or Hb + Hp (50 mg/kg), and 3) following local superfusion of NG-nitro-l arginine methyl ester (L-NAME; 10 mg/kg). Additional experiments were completed to visualize Hb extravasation into the muscular tissue using Click chemistry techniques. There were no significant differences in the PO2mv observed at rest for any condition in either experiment (p > 0.05 for all). In experiment 1, both Hb and L-NAME reduced the PO2mv significantly during the steady-state of muscle contractions when compared to control conditions with no differences between Hb and L-NAME (control: 24 +/- 1, Hb: 21 +/- 1, L-NAME: 20 +/- 1 mmHg, p < 0.05). In experiment 2, only L-NAME resulted in a significantly lower PO2mv during the steady-state of muscle contractions (control: 25 +/- 1, Hb + Hp: 22 +/- 2, L NAME: 18 +/- 1 mmHg, p < 0.05). Free Hb lowered the blood-myocyte O2 driving force to a level not significantly different from L-NAME. However, infusing Hb bound to Hp resulted in no significant differences in steady-state PO2mv during muscle contractions when compared to control. Surprisingly, we did not observe Hb accumulation in skeletal muscle tissue. Taken together these data suggests that free Hb impairs O2 delivery/utilization via a NO scavenging effect. Furthermore, the unchanged PO2mv steady-state observed following Hb + Hp further indicates that vascular compartmentalization of Hb by the scavenger protein haptoglobin may improve skeletal muscle metabolic control and potentially exercise tolerance in those afflicted with hemolytic diseases. PMID- 29526567 TI - Exhaled NO as a predictor of exercise-induced asthma in cold air. AB - PURPOSE: Physical activity is an important part of life, and exercise-induced asthma (EIA) can reduce the quality of life. A standardized exercise challenge is needed to diagnose EIA, but this is a time consuming, effortful and expensive method. Exhaled nitric oxide (eNO) as a marker of eosinophil inflammation is determined rapidly and easily. The aim of this study was to investigate eNO as surrogate marker for predicting a positive reaction in an exercise challenge in a cold chamber (ECC). METHODS: A total of 143 subjects aged 6-45 years with suspected EIA were recruited for the study. The subjects underwent an eNO measurement, an ECC and a skin prick test (SPT). To define the sensitivity and specificity of eNO as predictor, a receiver-operating characteristic (ROC) curve was plotted. The individual probability of the occurrence of a positive reaction after ECC based on an eNO value was calculated using a logistic regression model. RESULTS: An eNO cut-off value of 18.5 ppb (area under the curve (AUC) 0.71, p < 0.001) showed the best combination of sensitivity and specificity for a positive reaction (forced expiratory volume in 1 s (FEV1) decrease >= 10% after ECC) for the whole group. An eNO cut-off value of 46.0 ppb had a specificity of 100.0% to predict a significant FEV1 decrease and may save exercise testing in 22.4% of patients. A negative predictive level with a high sensitivity and negative predictive value (NPV) could not be defined. In the subgroup that was house dust might (HDM) allergy positive (HDM pos; n = 68, 45.5% of all subjects), an eNO cut off value of 35.5 ppb (AUC 0.79, p < 0.01) showed the best combination of sensitivity and specificity for a positive reaction after the ECC with a specificity 100.0% and may save exercise testing in 45.6% of HDM pos patients. Using logistic regression, a 95% probability for a positive FEV1 decrease after ECC was estimated at 53 ppb for the whole group and at 47 ppb for the HDM pos subgroup. CONCLUSIONS: Exhaled NO measurement is a screening tool for EIA, especially in HDM pos subjects. In a real-life setting, a cut-off value of 46.0 ppb detects EIA at 100% in all suspected patients, and a cut-off level of 35.5 ppb is valuable marker of EIA in patients with an HDM allergy. These levels can save time and costs in a large proportion of patients and will be helpful for clinicians. PMID- 29526568 TI - E2F1 promotes hepatic gluconeogenesis and contributes to hyperglycemia during diabetes. AB - OBJECTIVE: Aberrant hepatic glucose production contributes to the development of hyperglycemia and is a hallmark of type 2 diabetes. In a recent study, we showed that the transcription factor E2F1, a component of the cell cycle machinery, contributes to hepatic steatosis through the transcriptional regulation of key lipogenic enzymes. Here, we investigate if E2F1 contributes to hyperglycemia by regulating hepatic gluconeogenesis. METHODS: We use different genetic models to investigate if E2F1 regulates gluconeogenesis in primary hepatocytes and in vivo. We study the impact of depleting E2F1 or inhibiting E2F1 activity in diabetic mouse models to evaluate if this transcription factor contributes to hyperglycemia during insulin resistance. We analyze E2F1 mRNA levels in the livers of human diabetic patients to assess the relevance of E2F1 in human pathophysiology. RESULTS: Lack of E2F1 impaired gluconeogenesis in primary hepatocytes. Conversely, E2F1 overexpression increased glucose production in hepatocytes and in mice. Several genetic models showed that the canonical CDK4 RB1-E2F1 pathway is directly involved in this regulation. E2F1 mRNA levels were increased in the livers from human diabetic patients and correlated with the expression of the gluconeogenic enzyme Pck1. Genetic invalidation or pharmacological inhibition of E2F1 improved glucose homeostasis in diabetic mouse models. CONCLUSIONS: Our study unveils that the transcription factor E2F1 contributes to mammalian glucose homeostasis by directly controlling hepatic gluconeogenesis. Together with our previous finding that E2F1 promotes hepatic steatosis, the data presented here show that E2F1 contributes to both hyperlipidemia and hyperglycemia in diabetes, suggesting that specifically targeting E2F1 in the liver could be an interesting strategy for therapies against type 2 diabetes. PMID- 29526569 TI - Elevated levels of follicular T helper cells and their association with therapeutic effects in patients with chronic lymphocytic leukaemia. AB - Chronic lymphocytic leukaemia (CLL) is characterized by an abnormal expansion of mature B cells with variable progression. Follicular T helper (Tfh) cells help B cells differentiate into plasma cells or long-lived memory B cells in germinal centres (GCs). However, the role of Tfh cells in CLL is poorly understand, and whether it plays a critical role in disease progression in vivo is lacking. In this study, we investigate the dynamic change of circulating Tfh cells in peripheral blood from patients with CLL during the treatment periods to evaluate their utility to predict disease progression. Our findings revealed the expansion of circulating CD4+CXCR5+, CD4+ICOS+, CD4+PD-1+ and CD4+CXCR5+ICOS+PD-1+ (Tfh) cells but lower serum IL-21 levels and CD4+ T cell polarization not only to Tfh2 subtypes but also to Tfh17 subtypes in patients with CLL at pretreatment compared to patients with monoclonal B cell lymphocytosis (MBL) and healthy individuals, especially in those with advanced stage, which indicate these Tfh cells could be employed as a novel indicator for disease progression. Moreover, we observed significant correlations of Tfh17 and immunoglobulin heavy chain variable region (IGHV) mutation. Importantly, significantly decreased CD4+ICOS+, CD4+PD-1+ and Tfh cells were found after effective treatments, whereas a significantly high CD4+ICOS+, CD4+PD-1+ and Tfh cells were still found in those with progressive disease after treatments, suggesting that circulating CD4+ICOS+, CD4+PD-1+, Tfh cells could predict therapeutic effects. PMID- 29526570 TI - An in vitro cytotoxicities comparison of 16 priority polycyclic aromatic hydrocarbons in human pulmonary alveolar epithelial cells HPAEpiC. AB - In present study, we compared for the first time the cytotoxicities of the 16 priority polycyclic aromatic hydrocarbons (PAHs) in human pulmonary alveolar epithelial cells HPAEpiC. Moreover, we examined the effects of each PAH on oxidative stress (SOD, GSH, and ROS), cell viability, extracellular LDH, and apoptosis. The 16 priority PAHs were classified into four levels of cytotoxicity: (1) high cytotoxicity, BkF, BaP, and DBA; (2) moderate cytotoxicity, BbF, IND, BghiP, BaA, and CHR; (3) low cytotoxicity, PA, FL, and Pyr; and (4) mild cytotoxicity, Nap, AcPy, Acp, Flu, and Ant. Most of the PAHs showed benzene-ring related cytotoxicity, except PA with 3-ring structure, cytotoxicity of which is similar to those of FL and Pyr with 4-ring structure. Results indicated the need for more studies on DBA, IND, and BghiP, among others, which are rarely investigated. PA, FL, and Pyr with little carcinogenicity should also be evaluated. This study will provide useful references for studies on the effects of PAHs on different cells or animal models. PMID- 29526571 TI - Dibutyl phthalate exposure aggravates type 2 diabetes by disrupting the insulin mediated PI3K/AKT signaling pathway. AB - Epidemiological studies suggest a positive relationship between phthalate exposure and diabetes. However, little is known about the impact of dibutyl phthalate (DBP) exposure on the development of diabetes. To determine the role of DBP exposure on the development of type 2 diabetes, mice were orally exposed to DBP dosages of 0.5, 5, 50 mg/kg/day for 7 weeks, combined with a high fat diet and injections of a low dose of streptozotocin (STZ). The results showed that exposure to 50 mg/kg/day DBP alone induced a marked decrease in insulin secretion and glucose intolerance, but had no influence on insulin resistance. However, combined with a high fat diet and STZ treatment, DBP exposure markedly aggravated glucose intolerance, insulin tolerance and insulin resistance and induced lesions in the pancreas and kidney. Investigation of the role of DBP on the insulin signaling pathway, we found that DBP exposure could disrupt the PI3K expression and AKT phosphorylation, and decrease the level of GLUT-2 in the pancreas. Administering demethylasterriquinone B1, significantly increased the level of PI3K, AKT phosphorylation and GLUT-2 expression, effectively inhibiting the aggravation of diabetes. Our results suggested that DBP aggravated type 2 diabetes by disrupting the insulin signaling pathway and impairing insulin secretion. PMID- 29526573 TI - Genetic diversity analysis of PvCSP and its application in tracking of Plasmodium vivax. AB - BACKGROUND: Plasmodium vivax remains a potential cause of morbidity and mortality for people living where it is endemic. Understanding the regional genetic diversity of P. vivax is valuable for studying population dynamics and tracing the origins of parasites. The Plasmodium vivax circumsporozoite gene (PvCSP) is highly polymorphic and has been used previously as a marker in P. vivax population studies. The aim of this study is to investigate the genetic diversity of the PvCSP, to provide more genetic polymorphism data for further studies on P. vivax population structure, and tracking of the origin of clinical cases. METHODS: Nested PCR and DNA sequencing of the PvCSP were performed to obtain nucleotide sequences of P. vivax isolates collected from Zhejiang province, China, between 2006 and 2014. To investigate the genetic diversity of PvCSP, the nucleotide sequences and amino acid sequences of the PvCSP were analyzed using DNAstar, Mega software and the phylogenetic tree constructed. The relatedness between the polymorphism and infection source were also analyzed using the SPSS software. RESULTS: The 66 P. vivax isolates collected from Zhejiang province were either indigenous cases or cases imported from different regions of the world. All 66 P. vivax isolates belonged to the VK210 variant. Fourteen different Peptide Repeat Motifs (PRMs) were detected in the Central Repeat Region (CRR) of PvCSP, among which, two PRMs of GDRADGQPA and GDRAAGQPA were widely distributed in all isolates. Several polymorphic characteristics of the VK210 variant were observed, including the insertion sequence of 12 peptides, the frequency of the GGNA repeat, the frequency of the PRMs repeat in CRR, and the frequency of the PRM of GNGAGGQAA repeat, which were indicative for tracking the parasite. CONCLUSION: This study presents abundant genetic diversity in the PvCSP marker among P. vivax strains around the world. The genetic data are valuable to expand the polymorphism information on P. vivax, which could be helpful for further study on population dynamics and tracking the origin of P. vivax. PMID- 29526574 TI - Molecular and biochemical characterization of natural and recombinant phosphoglycerate kinase B from Trypanosoma rangeli. AB - T. rangeli epimastigotes contain only a single detectable phosphoglycerate kinase (PGK) enzyme in their cytosol. Analysis of this parasite's recently sequenced genome showed a gene predicted to code for a PGK with the same molecular mass as the natural enzyme, and with a cytosolic localization as well. In this work, we have partially purified the natural PGK from T. rangeli epimastigotes. Furthermore, we cloned the predicted PGK gene and expressed it as a recombinant active enzyme. Both purified enzymes were kinetically characterized and displayed similar substrate affinities, with KmATP values of 0.13 mM and 0.5 mM, and Km3PGA values of 0.28 mM and 0.71 mM, for the natural and recombinant enzyme, respectively. The optimal pH for activity of both enzymes was in the range of 8 10. Like other PGKs, TrPGK is monomeric with a molecular mass of approximately 44 kDa. The enzyme's kinetic characteristics are comparable with those of cytosolic PGK isoforms from related trypanosomatid species, indicating that, most likely, this enzyme is equivalent with the PGKB that is responsible for generating ATP in the cytosol of other trypanosomatids. This is the first report of a glycolytic enzyme characterization from T. rangeli. PMID- 29526572 TI - Chronic intermittent hypoxia induces hormonal and male sexual behavioral changes: Hypoxia as an advancer of aging. AB - Sleep apnea is a common sleep disorder characterized by intermittent periods of low blood oxygen levels. The risk for sleep apnea increases with age and is more prevalent in men than women. A common comorbidity of sleep apnea includes male sexual dysfunction, but it is not clear if a causal relationship exists between sleep apnea and sexual dysfunction. Possible mechanisms that link these two disorders include oxidative stress and testosterone. Oxidative stress is elevated in clinical patients with sleep apnea and in rodents exposed to chronic intermittent hypoxia (CIH), an animal model for apnea-induced hypopnea. Further, oxidative stress levels increase with age. Therefore, age may play a role in sleep apnea-induced sexual dysfunction and oxidative stress generation. To investigate this relationship, we exposed gonadally intact 3 (young) and 12 (middle-aged) month old male F344/BN F1 hybrid male rats to 8 days of CIH, and then examined male sexual function. Plasma was used to assess circulating oxidative stress and hormone levels. Middle-aged male rats had lower testosterone levels with increased sexual dysfunction and oxidative stress, independent of CIH. However, CIH decreased testosterone levels and increased sexual dysfunction and oxidative stress only in young gonadally intact male rats, but not in gonadectomized young rats with physiological testosterone replacement. In sum, CIH had a greater impact on younger gonadally intact animals, with respect to sexual behaviors, testosterone, and oxidative stress. Our data indicate CIH mimics the effects of aging on male sexual behavior in young gonadally intact male rats. PMID- 29526575 TI - First description of clonal lineage type II (genotype #1) of Toxoplasma gondii in abortion outbreak in goats. AB - The purpose of this study was to perform genotypic characterization and to evaluate the virulence of Toxoplasma gondii obtained from aborted fetuses in an abortion outbreak in goats from northeastern Brazil. Brain samples from 32 fetuses were submitted to mouse bioassay for T. gondii isolation. Two isolates were obtained and subjected to genotypic characterization. Isolate virulence was evaluated using murine model in different doses (from 105 to 101 tachyzoites/mL). In genotyping, both isolates were classified as clonal lineage type II (genotype #1 ToxoDB) and showed to be virulent for mice. This is the first description of genotype #1 in cases of goat abortion, showing the circulation of virulent T. gondii isolate producing reproductive disorders in pregnant goat. PMID- 29526576 TI - An invertebrate beta-integrin mediates coelomocyte phagocytosis via activation of septin2 and 7 but not septin10. AB - We have previously confirmed that beta-integrin from Apostichopus japonicus (designated AjITGB) binds LPS and mediates the immune response. In this study, we found that AjITGB positively promoted the echinoderm immune cells located in the coelomic cavity (designated as coelomocyte) phagocytic activities. Flow cytometry assay indicated that the phagocytic percentage was significantly decreased, by a 37.3% and 41.36%, after AjITGB siRNA inference in vitro and in vivo, respectively, a result consistent with the decrease observed with an anti-AjITGB antibody blocking treatment. These decreased phagocytic activities were partially recovered by rAjITGB supplementation. To better understand the molecular mechanism underlying this phagocytosis, three phagocytic-related proteins, including Ajseptin2, Ajseptin7 and Ajseptin10, were cloned and further characterized. Completely consistent expression profiles were detected between AjITGB and Ajseptin2/7, at both the mRNA and protein levels, in V. splendidus challenged sea cucumber. Furthermore, Ajseptin2/7 expression levels were significantly down-regulated in the AjITGB silencing group and could be partially recovered to its original level after rAjITGB administration. However, Ajseptin10 displayed no significant change in the same condition. A phagocytic assay further indicated that Ajseptin2/7, but not Ajseptin10, was crucial in mediating coelomocyte phagocytosis. The knockdown of the three genes by specific siRNAs indicated that Ajseptin2/7 significantly decreased coelomocyte phagocytosis, and this decrease was completely recovered after rAjITGB supplementation. There was no significant change in the phagocytosis rate in both the AjSEPT10 siRNA interference and rAjITGB supplementation groups. All our results confirmed that AjITGB modulates coelomocyte phagocytosis via the activation of Ajseptin2/7 but not AjSEPT10 and further supported the divergent roles of Ajseptins in AjITGB mediated phagocytosis. PMID- 29526578 TI - Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia. AB - PURPOSE: Refractory epilepsies in children present a major burden for patients and their families. Cannabidiol (CBD) has been suggested as a potential treatment for refractory epilepsies. The aim of this study was to evaluate the effectiveness of add-on therapy with CBD for the treatment of refractory childhood epilepsies. METHOD: Patients with childhood-onset refractory epilepsy, treated at the tertiary epilepsy center of the University Children's Hospital Ljubljana, Slovenia, were included in the study. Add-on therapy with CBD was initiated once the child's epilepsy was categorized as pharmacoresistant to other antiepileptic drugs/therapies. The dosage of CBD was gradually increased to at least 8mg/kg/day. The effect of CBD treatment was evaluated by the reduction in seizure burden and presence of side effects (positive and negative). Serial electroencephalography was performed in some children. RESULTS: Sixty-six patients were included in the analysis. Thirty-two (48.5%) patients had a more than 50% improvement regarding seizure burden, 14 of whom (21.2%) became seizure free. None of the patients reported worsening of seizure frequency, but CBD had no effect in 15 (22.7%) patients. Some patients reported less vigorous seizures, shorter duration of seizures, shorter time to recovery, and other positive side effects of CBD treatment. Adverse effects were reported in 5/66 children. CONCLUSIONS: In our cohort of patients, CBD was found to have potential benefits as add-on therapy for refractory childhood epilepsies, mainly by reducing seizure burden. PMID- 29526579 TI - The role of stereoelectroencephalography (SEEG) in reevaluation of epilepsy surgery failures. AB - Management of patients after initial epilepsy surgical failure is challenging. In this study, we report our experience in using the stereoelectroencephalography (SEEG) method in the reevaluation of patients after initial epilepsy surgical failure. We selected 28 patients examined through SEEG in our department for drug resistant focal epilepsy following initial epilepsy surgical failure. For each patient, the residual seizure onset zone (rSOZ) as defined by SEEG was classified as either contiguous if the seizure onset zone (SOZ) was focal and close to the surgical cavity (same lobe) or noncontiguous in cases where the SOZ included site(s) distant from the surgical cavity. The rSOZ was defined according to visual analysis of SEEG traces completed by an estimation of the epileptogenicity index (EI). A second surgical procedure was performed in 12 patients (45%). A favorable outcome (Engel class I or II) was obtained in 9/12 patients (6 in Engel class I, 50%). The proportion of patients that had reoperation was higher in the contiguous group (80%) than in the noncontiguous group (22%) (p=0.02). A rSOZ localized in close relation to the initial surgical resection zone (contiguous group) was found in 10 patients (35%). Among them, 8 have since undergone reoperation, and a good outcome (Engel class I) was achieved in 5/8 (63%). A rSOZ involving a distant region from the first surgery was observed in 18 patients (65%) (noncontiguous group). Among them, only 4 have undergone reoperation, leading to a failure in 2 (Engel class III or IV) and a good outcome in 2 (IA). Ten patients had a first standard temporal lobectomy, and in 50% of these cases, the insula was involved in the rSOZ. Stereoelectroencephalography offers a unique way to evaluate the rSOZ at the individual level and thus guide further surgical decision-making. The best results are observed in patients having a focal rSOZ close to the site of the surgical resection in the first surgery. PMID- 29526580 TI - Home particle repositioning maneuver to prevent the recurrence of posterior canal BPPV. AB - OBJECTIVE: To check the value of home particle repositioning maneuver in the prevention of the recurrence of posterior canal benign paroxysmal positional vertigo (pc-BPPV). METHODS: In this study, patients diagnosed as unilateral posterior canal BPPV were selected following an accurate evaluation using video goggle VNG system. All patients were managed by particle repositioning maneuver (PRM). Patients were instructed to do home PRM once weekly for five years. Then, they were divided into two groups (according to choice of patient to do PRM). The first group (control group) consisted of 144 patients who did not do home PRM; whereas the second group (study group) included 165 patients who performed home PRM. All patients (control & study groups) were followed up every four months for five years. RESULTS: The study found out that the recurrence rate of pc-BPPV in control group was 33 patients in the first year (27.2%), 11 patients in second year (9%), 5 patients in third year (4%), 3 patients in fourth year (2.5%) and 3 patients in fifth year (2.5%). The recurrence of pc-BPPV in the treated side (study group) of patients was reported as 5 patients in the first year (3.5%), 3 patients in the second year (2%), 2 patients in the third year (1.4%), 2 patients in the fourth year (1.4%), and 1 patient in the fifth year (0.7%). There was statistically significant difference between the control and the study groups regarding the recurrence rates in the first year follow up which was the highest in first four months. CONCLUSION: Home particle repositioning maneuver has the capacity to prevent the recurrence of pc-BPPV. It proved to be more successful and functional in minimizing the recurrence of the disease in the study than in the control group. Hence, home particle repositioning maneuver is highly recommended for one year at least in pc-BPPV. PMID- 29526581 TI - [The dimethyl sulfoxide under general anesthesia: An alternative after failure without anesthesia in the painful bladder syndrome/interstitial cystitis?] AB - INTRODUCTION: The intravesical instillation of dimethyl sulfoxide (iDMSO), performed without anesthestic, is a therapeutic option for the painful bladder syndrome/interstial cystitis (PBS/IC). Some patients are against those iDMSO because of bad tolerance. Our study evaluates the tolerance and the outcome of the iDMSO under general anesthetic (GA) after the failure of the iDMSO without anesthetic. PATIENTS AND METHODS: From May 2013 to April 2016, 11 patients with a PBS, 9 women (81.8 %), have been treated by iDMSO without anesthetic, without improvement because of bad tolerance and no possibility to have a one hour contact between the bladder and the DMSO. The 11 patients were evaluated by mictional calendar and Sant O'Leary score. All the patients had a hydrodistension and a per os treatment without improvement. OUTCOMES: Six new iDMSO were performed under general anesthetic in ambulatory surgery with good tolerance for the 11 patients. The frequency and the nocturia before iDMSO without anesthetic and after iDMSO under general anesthetic were 32.2minutes [15; 60] and 6.3 per night [3; 10] and 126.9minutes [25; 240] and 3 per night [2; 6], so a variation respectively of 96.4minutes [0; 180] and of 3.75 per night [2; 6]. The symptom score and the problem index were 17.5 [13; 20] and 15.5 [13; 16] before and 13.5 [4; 20] and 12 [1; 16] after iDMSO under general anesthetic; a variation of 3.2 [0; 9] and 4 [0; 12]. CONCLUSION: The iDMSO under general anesthetic seems to improve objectively and subjectively the patients who are not improved by the instillations without anesthetic because of bad tolerance. LEVEL OF EVIDENCE: 4. PMID- 29526577 TI - Obesity and Cancer: Existing and New Hypotheses for a Causal Connection. AB - Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers. PMID- 29526582 TI - Discovery and identification of quality markers of Chinese medicine based on pharmacokinetic analysis. AB - BACKGROUND: Quality control of Chinese medicine (CM) is an effective measure to ensure the safety and efficacy of CM in clinical practice, which is also a key factor to restrict the modernization process of CM. Various chemical components exist in CM and the determination of several chemical components is the main approach for quality control of vast majority of CM in the present. However, many components determined lack not only specificity, but also biological activities. This is bound to greatly reduce the actual value of quality standard of CM. PURPOSE: Professor Changxiao Liu proposed the "quality marker" (Q-marker) concept to ensure the standardization and rationalization for the quality control of CM. As we all know, CMs are taken orally in most cases and could be extensively metabolized in vivo. Both prototype components and the metabolites could be the actual therapeutic material basis. Pharmacokinetic studies could benefit the elucidation of actual therapeutic material basis which is closely related to the identification of Q-markers. Therefore, a new strategy about Q-marker was proposed based on the pharmacokinetic analysis of CM, hoping to provide some ideas for the discovery and identification of Q-marker. METHODS: The relationship between pharmacokinetic studies and the identification of Q-markers was demonstrated in this review and a new strategy was proposed. Starting from the pharmacokinetic analysis, reverse tracing of the prototype active components and the potential prodrugs in CM were conducted first and the therapeutic material basis were identified as Q-markers. Then, modern analytical techniques and methods were applied to obtain comprehensive quality control for these constituents. Several CMs including gingko biloba, ginseng, Periplocae Cortex, Mori Cortex, Bupleuri Radix and Scutellariae Radix were listed as examples to clarify how the new strategy could be applied. CONCLUSION: Pharmacokinetic studies play an important role for the elucidation of therapeutic material basis of CM and the identification of Q-markers and it should be taken into account during the process of the investigation of Q-marker. PMID- 29526583 TI - Identifying potential quality markers of Xin-Su-Ning capsules acting on arrhythmia by integrating UHPLC-LTQ-Orbitrap, ADME prediction and network target analysis. AB - BACKGROUND: Quality marker (Q-markers) has been proposed as a novel concept for quality evaluation and standard elaboration of traditional Chinese medicine (TCM). Xin-Su-Ning capsule (XSNC) has been extensively used for the treatment of arrhythmia with the satisfactory therapeutic effects in clinics. However, it is lack of reliable and effective Q-markers of this prescription. PURPOSE: To identify potential Q-markers of XSNC against arrhythmia. STUDY DESIGN: An integrative pharmacology-based investigation was performed. METHODS: Ultra-high pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap) was performed to identify the preliminary chemical profile of XSNC in a rapid and high-throughput manner. Then, in silico Absorption-Distribution-Metabolism-Excretion (ADME) models were utilized to screen candidate active chemical compounds characterized by drug-likeness features. In addition, drug target-disease gene interaction network was constructed, and network features were calculated to identify key candidate targets and the potential Q-markers of XSNC against arrhythmia. RESULTS: A total of 41 chemical compounds with good drug-likeness and more chances to be absorbed into body were identified as the candidate bioactive chemical compounds which might offer contributions to the therapeutic effects of XSNC against arrhythmia in vivo. Following the prediction of 921 XSNC putative targets and the construction of XSNC putative target-known therapeutic target of arrhythmia interaction network, 315 hub nodes with high connectivity were selected. Functionally, the hub nodes were involved into modulation of cardiac sympatho vagal balance, regulation of energy production and metabolism, as well as angiogenesis and vascular circulation during the development and progression of arrhythmia. Moreover, 63 major hubs with network topological importance were chosen as XSNC candidate targets against arrhythmia. Furthermore, berberine, palmatine, scopoletin, liquiritigenin, naringenin, formononetin, nobiletin, tangeretin, 5-demethylnobiletin, kushenol E and kurarinone hitting the corresponding XSNC candidate targets were screened out to be the potential Q markers of XSNC against arrhythmia. CONCLUSION: Our integrative pharmacology based approach combining UHPLC-LTQ-Orbitrap, in silico ADME prediction and network target analysis may be efficient to identify potential Q-markers of TCM prescriptions. Our data showed that berberine, palmatine, scopoletin, liquiritigenin, naringenin, formononetin, nobiletin, tangeretin, 5 demethylnobiletin, kushenol E and kurarinone might function as candidate markers for qualitative evaluation of XSNC. PMID- 29526585 TI - Repeated Diversification of Ecomorphs in Hawaiian Stick Spiders. AB - Insular adaptive radiations in which repeated bouts of diversification lead to phenotypically similar sets of taxa serve to highlight predictability in the evolutionary process [1]. However, examples of such replicated events are rare. Cross-clade comparisons of adaptive radiations are much needed to determine whether similar ecological opportunities can lead to the same outcomes. Here, we report a heretofore uncovered adaptive radiation of Hawaiian stick spiders (Theridiidae, Ariamnes) in which different species exhibit a set of discrete ecomorphs associated with different microhabitats. The three primary ecomorphs (gold, dark, and matte white) generally co-occur in native forest habitats. Phylogenetic reconstruction mapped onto the well-known chronosequence of the Hawaiian Islands shows both that this lineage colonized the islands only once and relatively recently (2-3 mya, when Kauai and Oahu were the only high islands in the archipelago) and that the distinct ecomorphs evolved independently multiple times following colonization of new islands. This parallel evolution of ecomorphs matches that of "spiny-leg" long-jawed spiders (Tetragnathidae, Tetragnatha), also in Hawaii [2]. Both lineages are free living, and both have related lineages in the Hawaiian Islands that show quite different patterns of diversification with no evidence of deterministic evolution. We argue that repeated evolution of ecomorphs results from a rugged adaptive landscape, with the few peaks associated with camouflage for these free-living taxa against the markedly low diversity of predators on isolated islands. These features, coupled with a limited genetic toolbox and reduced dispersal between islands, appear to be common to situations of repeated evolution of ecomorphs. PMID- 29526584 TI - A systematic review of pharmacokinetic studies on herbal drug Fuzi: Implications for Fuzi as personalized medicine. AB - BACKGROUND: Fuzi, which is the processed lateral roots of Aconitum carmichaeli Debx. (Ranunculaceae), is a traditional herbal medicine that is well known for its excellent pharmacological effects and acute toxicity. Aconitum alkaloids are responsible for its pharmacological activity and toxicity. Although a large number of studies on Fuzi have been reported, no comprehensive review on its pharmacokinetics has yet been published. PURPOSE: This paper seeks to present a comprehensive review regarding the phytochemistry, pharmacokinetic features and toxicity of Fuzi. The regulation of drug-metabolizing enzymes (DMEs) and efflux transporters (ETs) by Fuzi is also concluded. Additionally, the use of Fuzi as a personalized medicine based on the bioavailability barrier (BB), which mainly comprises DMEs and ETs, is discussed. METHODS: All available information on Fuzi was collected by searching for key words in PubMed, ScienceDirect, CNKI, Google Scholar, Baidu Scholar, and Web of Science. RESULTS: Aconitum alkaloids, which mainly include diester-diterpene alkaloids (DDAs), monoester-diterpene alkaloids (MDAs) and unesterified-diterpene alkaloids (UDAs), could be detected after Fuzi ingestion in vivo. The Aconitum alkaloids are rapidly absorbed in the intestine and extensively distributed in the body. DMEs, especially CYP3A4/5, are responsible for various types of metabolic reactions of the Aconitum alkaloids. ETs, including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), are involved in the efflux of the DDAs and MDAs. The kidney is the most important organ involved in the excretion of the Aconitum alkaloids. DDAs are the main toxic compounds present in Fuzi, and their acute toxicity is mainly due to their effects on the voltage dependent sodium channels. Furthermore, Fuzi can substantially regulate DMEs and ETs. CONCLUSIONS: The toxicity of DDAs is acute. However, further investigations are necessary to determine the exact toxicological mechanisms. The significant impact of Fuzi on DMEs and ETs suggests that the co-administration of Fuzi with drugs that are substrates of DMEs and/or ETs may cause herb-drug interactions (HDIs). The BB network controlled exposure to the Aconitum alkaloids in vivo. Polymorphisms of DMEs and ETs in different individuals contribute to the differences in the efficacy and toxicity of Fuzi ingestion. In the future, the use of Fuzi as personalized medicine based on the BB network is necessary and practical to achieve ideal therapeutic efficacy with minimal toxicity. PMID- 29526586 TI - The Arabidopsis SPIRAL2 Protein Targets and Stabilizes Microtubule Minus Ends. AB - The contribution of microtubule tip dynamics to the assembly and function of plant microtubule arrays remains poorly understood. Here, we report that the Arabidopsis SPIRAL2 (SPR2) protein modulates the dynamics of the acentrosomal cortical microtubule plus and minus ends in an opposing manner. Live imaging of a functional SPR2-mRuby fusion protein revealed that SPR2 shows both microtubule plus- and minus-end tracking activity in addition to localization at microtubule intersections and along the lattice. Analysis of microtubule dynamics showed that cortical microtubule plus ends rarely undergo catastrophe in the spr2-2 knockout mutant compared to wild-type. In contrast, cortical microtubule minus ends in spr2-2 depolymerized at a much faster rate than in wild-type. Destabilization of the minus ends in spr2-2 caused a significant decrease in the lifetime of microtubule crossovers, which dramatically reduced the microtubule-severing frequency and inhibited light-induced microtubule array reorientation. Using in vitro reconstitution experiments combined with single-molecule imaging, we found that recombinant SPR2-GFP intrinsically localizes to microtubule minus ends, where it binds stably and inhibits their dynamics. Together, our data establish SPR2 as a new type of microtubule tip regulator that governs the length and lifetime of microtubules. PMID- 29526587 TI - Parasitoids Turn Herbivores into Mutualists in a Nursery System Involving Active Pollination. AB - Nursery pollination involves pollinators that lay eggs on the flowers they pollinate and have their brood fed on flower parts or developing ovules [1-4]. Active pollination, a ritualistic behavioral sequence shown by nursery pollinators when transferring pollen from anthers to stigmas, is known in only four plant lineages [5-8], including the classical examples of fig trees-fig wasps and yuccas-yucca moths [5, 6]. We report in detail a system in which weevils actively pollinate orchids prior to having their larvae fed on the developing fruits. Sampling over five years revealed that although weevils trigger fruit set, this interaction is negative for the plant as weevil larvae often consume all contents of infested fruits. However, part of weevil-infested fruits is often "rescued" by parasitoid wasps, which kill the weevil larvae before all fruit content is consumed (Figure 1). "Rescued" fruits present high seed viability and biomass similar to that of non-infested fruits, much higher than that of fruits with weevils only. Hence, parasitoids mediate the fitness consequences of the interaction between the plant and its parasitic pollinator. Weevils constitute a megadiverse group of herbivores commonly reported as florivores [9] but are also appreciated as flower-ovipositing pollinators of cycads and palms [4, 10-13] and were previously recorded carrying orchid pollinaria [14-16]. The orchid-weevil system presented here shows that plant floral visitor interaction outcome can be mediated by a third party (parasitoids) and illustrates a way by which the biological context may allow the emergence and persistence of active nursery pollination behavior in nature. PMID- 29526588 TI - Rapid Global Spread of wRi-like Wolbachia across Multiple Drosophila. AB - Maternally transmitted Wolbachia, Spiroplasma, and Cardinium bacteria are common in insects [1], but their interspecific spread is poorly understood. Endosymbionts can spread rapidly within host species by manipulating host reproduction, as typified by the global spread of wRi Wolbachia observed in Drosophila simulans [2, 3]. However, because Wolbachia cannot survive outside host cells, spread between distantly related host species requires horizontal transfers that are presumably rare [4-7]. Here, we document spread of wRi-like Wolbachia among eight highly diverged Drosophila hosts (10-50 million years) over only about 14,000 years (5,000-27,000). Comparing 110 wRi-like genomes, we find <=0.02% divergence from the wRi variant that spread rapidly through California populations of D. simulans. The hosts include both globally invasive species (D. simulans, D. suzukii, and D. ananassae) and narrowly distributed Australian endemics (D. anomalata and D. pandora) [8]. Phylogenetic analyses that include mtDNA genomes indicate introgressive transfer of wRi-like Wolbachia between closely related species D. ananassae, D. anomalata, and D. pandora but no horizontal transmission within species. Our analyses suggest D. ananassae as the Wolbachia source for the recent wRi invasion of D. simulans and D. suzukii as the source of Wolbachia in its sister species D. subpulchrella. Although six of these wRi-like variants cause strong cytoplasmic incompatibility, two cause no detectable reproductive effects, indicating that pervasive mutualistic effects [9, 10] complement the reproductive manipulations for which Wolbachia are best known. "Super spreader" variants like wRi may be particularly useful for controlling insect pests and vector-borne diseases with Wolbachia transinfections [11]. PMID- 29526589 TI - Repellent and Attractant Guidance Cues Initiate Cell Migration by Distinct Rear Driven and Front-Driven Cytoskeletal Mechanisms. AB - Attractive and repulsive cell guidance is essential for animal life and important in disease. Cell migration toward attractants dominates studies [1-8], but migration away from repellents is important in biology yet relatively little studied [5, 9, 10]. It is widely held that cells initiate migration by protrusion of their front [11-15], yet this has not been explicitly tested for cell guidance because cell margin displacement at opposite ends of the cell has not been distinguished for any cue. We argue that protrusion of the front, retraction of the rear, or both together could in principle break cell symmetry and start migration in response to guidance cues [16]. Here, we find in the Dictyostelium model [6] that an attractant-cAMP-breaks symmetry by causing protrusion of the front of the cell, whereas its repellent analog-8CPT-breaks symmetry by causing retraction of the rear. Protrusion of the front of these cells in response to cAMP starts with local actin filament assembly, while the delayed retraction of the rear is independent of both myosin II polarization and of motor-based contractility. On the contrary, myosin II accumulates locally in the rear of the cell in response to 8CPT, anticipating retraction and required for it, while local actin assembly is delayed and couples to delayed protrusion at the front. These data reveal an important new concept in the understanding of cell guidance. PMID- 29526590 TI - A Single-Neuron Chemosensory Switch Determines the Valence of a Sexually Dimorphic Sensory Behavior. AB - Biological sex, a fundamental dimension of internal state, can modulate neural circuits to generate behavioral variation. Understanding how and why circuits are tuned by sex can provide important insights into neural and behavioral plasticity. Here we find that sexually dimorphic behavioral responses to C. elegans ascaroside sex pheromones are implemented by the functional modulation of shared chemosensory circuitry. In particular, the sexual state of a single sensory neuron pair, ADF, determines the nature of an animal's behavioral response regardless of the sex of the rest of the body. Genetic feminization of ADF causes males to be repelled by, rather than attracted to, ascarosides, whereas masculinization of ADF has the opposite effect in hermaphrodites. When ADF is ablated, both sexes are weakly repelled by ascarosides. Genetic sex modulates ADF function by tuning chemosensation: although ADF is functional in both sexes, it detects the ascaroside ascr#3 only in males, a consequence of cell autonomous action of the master sexual regulator tra-1. This occurs in part through the conserved DM-domain gene mab-3, which promotes the male state of ADF. The sexual modulation of ADF has a key role in reproductive fitness, as feminization or ablation of ADF renders males unable to use ascarosides to locate mates. Our results reveal an economical mechanism in which sex-specific behavioral valence arises through the cell-autonomous regulation of a chemosensory switch by genetic sex, allowing a social cue with salience for both sexes to elicit navigational responses commensurate with the differing needs of each. PMID- 29526592 TI - Diversification Patterns of Lanternfishes Reveal Multiple Rate Shifts in a Critical Mesopelagic Clade Targeted for Human Exploitation. AB - The mesopelagic (midwater) and deep-sea environments together comprise over 90% of the volume of the world ocean [1] and provide services that are only recently becoming recognized [2]. One of the most significant of these services relates to midwater fish biomass, recently estimated to be two orders of magnitude larger than the current worldwide fisheries catch [3, 4]. Calls to exploit midwater fish biomass have increased despite warnings about the unknown recovery potential of such organisms [2] and despite existing data suggesting that deep-sea fishes could be classified as endangered [5]. Here, to provide a null model for the respondability of midwater fishes, I use lanternfishes-which comprise the majority of worldwide midwater fish biomass [6]-to examine the diversification response of a critical midwater clade to oceanic changes over evolutionary timescales, including several extinction and turnover events. Using a time calibrated molecular phylogeny based on seven autosomal protein-coding loci, with over 50% species sampling and three ingroup node calibrations, I show that lanternfishes exhibit a continuously increasing diversification rate, consistent with nonequilibrium speciation dynamics, and three major evolutionary rate shift locations with timing that is similar to those of marine clades in more well known environments. These results suggest that lanternfish diversification patterns overlapped with major events in the physical partitioning of the ocean volume and that the clade has responded positively to a range of pre-Anthropocene extinction drivers [7]. However, lanternfish respondability to modern extinction drivers-habitat loss and overexploitation-is best addressed with populational and ecological data and remains largely unknown. PMID- 29526593 TI - Distinct Contributions of Mesencephalic Locomotor Region Nuclei to Locomotor Control in the Freely Behaving Mouse. AB - The mesencephalic locomotor region (MLR) has been initially identified as a supraspinal center capable of initiating and modulating locomotion. Whereas its functional contribution to locomotion has been widely documented throughout the phylogeny from the lamprey to humans, there is still debate about its exact organization. Combining kinematic and electrophysiological recordings in mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus initiate locomotion and induce running gaits, whereas glutamatergic and cholinergic neurons of the pedunculopontine nucleus modulate locomotor pattern and rhythm, contributing to slow-walking gaits. By initiating, modulating, and accelerating locomotion, our study identifies and characterizes distinct neuronal populations of this functional region important to locomotor command. PMID- 29526591 TI - Architecture of Lipid Droplets in Endoplasmic Reticulum Is Determined by Phospholipid Intrinsic Curvature. AB - Lipid droplets (LDs) store fats and play critical roles in lipid and energy homeostasis. They form between the leaflets of the endoplasmic reticulum (ER) membrane and consist of a neutral lipid core wrapped in a phospholipid monolayer with proteins. Two types of ER-LD architecture are thought to exist and be essential for LD functioning. Maturing LDs either emerge from the ER into the cytoplasm, remaining attached to the ER by a narrow membrane neck, or stay embedded in the ER and are surrounded by ER membrane. Here, we identify a lipid based mechanism that controls which of these two architectures is favored. Theoretical modeling indicated that the intrinsic molecular curvatures of ER phospholipids can determine whether LDs remain embedded in or emerge from the ER; lipids with negative intrinsic curvature such as diacylglycerol (DAG) and phosphatidylethanolamine favor LD embedding, while those with positive intrinsic curvature, like lysolipids, support LD emergence. This prediction was verified by altering the lipid composition of the ER in S. cerevisiae using mutants and the addition of exogenous lipids. We found that fat-storage-inducing transmembrane protein 2 (FIT2) homologs become enriched at sites of LD generation when biogenesis is induced. DAG accumulates at sites of LD biogenesis, and FIT2 proteins may promote LD emergence from the ER by reducing DAG levels at these sites. Altogether, our findings suggest that cells regulate LD integration in the ER by modulating ER lipid composition, particularly at sites of LD biogenesis and that FIT2 proteins may play a central role in this process. PMID- 29526594 TI - Memory Consolidation Is Linked to Spindle-Mediated Information Processing during Sleep. AB - How are brief encounters transformed into lasting memories? Previous research has established the role of non-rapid eye movement (NREM) sleep, along with its electrophysiological signatures of slow oscillations (SOs) and spindles, for memory consolidation [1-4]. In related work, experimental manipulations have demonstrated that NREM sleep provides a window of opportunity to selectively strengthen particular memory traces via the delivery of auditory cues [5-10], a procedure known as targeted memory reactivation (TMR). It has remained unclear, however, whether TMR triggers the brain's endogenous consolidation mechanisms (linked to SOs and/or spindles) and whether those mechanisms in turn mediate effective processing of mnemonic information. We devised a novel paradigm in which associative memories (adjective-object and adjective-scene pairs) were selectively cued during a post-learning nap, successfully stabilizing next-day retention relative to non-cued memories. First, we found that, compared to novel control adjectives, memory cues evoked an increase in fast spindles. Critically, during the time window of cue-induced spindle activity, the memory category linked to the verbal cue (object or scene) could be reliably decoded, with the fidelity of this decoding predicting the behavioral consolidation benefits of TMR. These results provide correlative evidence for an information processing role of sleep spindles in service of memory consolidation. PMID- 29526595 TI - Mechanisms of Tissue Injury in Lupus Nephritis. AB - Disease heterogeneity remains a major challenge for the understanding of systemic lupus erythematosus (SLE). Recent work has revealed the important role of nonimmune factors in the development of end-organ damage involvement, shifting the current paradigm that views SLE as a disease inflicted by a disturbed immune system on passive target organs. Here, we discuss the pathogenesis of lupus nephritis in a comprehensive manner, by incorporating the role that target organs play by withstanding and modulating the local inflammatory response. Moreover, we consider the effects that genetic variants exert on immune and nonimmune cells in order to shape the phenotype of the disease in each affected individual. PMID- 29526596 TI - Age-related hearing loss and communication at a PACE Day Health Center. PMID- 29526597 TI - Research on Frailty: Continued Progress, Continued Challenges. PMID- 29526598 TI - Disturbed functional connectivity within the left prefrontal cortex and sensorimotor areas predicts impaired cognitive speed in patients with first episode schizophrenia. AB - This study aimed at identifying abnormal cortico-cortical functional connectivity patterns that could predict cognitive slowing in patients with schizophrenia. A group of thirty-two patients with the first-episode schizophrenia and comparable healthy controls underwent resting-state qEEG and cognitive assessment. Phase Lag Index (PLI) was applied as a connectivity index and the synchronizations were analyzed in six frequencies. Pairs of electrodes were grouped to separately cover frontal, temporal, central, parietal and occipital regions. PLI was calculated for intra-regional connectivity and between-regions connectivity. Computer version processing speed tests were applied to control for possible fluctuations in cognitive efficiency during the performance of the tasks. In the group of patients, in comparison to healthy controls, significantly higher PLI values were recorded in theta frequency, especially in the posterior areas and decreased PLI in low-alpha frequency within the frontal regions. Mean PLI in gamma frequency was also lower in the patients group. Regression analysis showed that lower intra regional PLI for left frontal cortex and higher PLI within somatosensory cortex in theta band, together with the duration of untreated psychosis, proved to be significant predictors of impaired processing speed in first-episode patients. Our investigation confirmed that disrupted cortico-cortical synchronization contributes to cognitive slowing in schizophrenia. PMID- 29526599 TI - Prostate cancer management choices in patients undergoing multiparametric magnetic resonance imaging/ultrasound fusion biopsy compared to systematic biopsy. AB - OBJECTIVES: To assess management choices in patients who undergo magnetic resonance imaging (MRI)/ultrasound (MRI/US) fusion-guided prostate biopsy compared to patients who undergo systematic biopsy. METHODS: We compared men who underwent MRI/US fusion-guided prostate biopsy to those who underwent systematic 12-core biopsy from 2014 to 2016. Patient demographics and pathologic findings were reviewed. The highest grade group per case was considered for analysis. RESULTS: Follow-up was available on 133 patients who underwent MRI/US targeted biopsy and 215 patients who underwent systematic biopsy. There was no difference in prebiopsy prostate-specific antigen (PSA) (10.1 +/- 10.0 vs. 12.9 +/- 20.5, P = 0.11) between the 2 cohorts. Patients in the MRI cohort were more likely to have had a previous prostate biopsy (P<0.0001). Overall, more patients in the MRI cohort choose active surveillance compared to the standard cohort (49.6% vs. 24.2%, P<0.0001), confirmed on multivariate logistic regression model adjusting for age, PSA density, prior biopsy history, race, grade group, and provider (P = 0.013). This finding held true independently for patients with grade groups 1 and 2 tumors (P = 0.02 and P = 0.005, respectively) and in a multivariate logistic regression model adjusting for grade group 1 and 2 tumors (P = 0.0051). In the standard cohort, more patients chose radiation over prostatectomy (47.2% vs. 24.4%, P<0.0001). On multivariate analysis, race was an independent predictor of active surveillance, with African Americans less likely to undergo active surveillance. CONCLUSIONS: Patients who undergo MRI/US targeted biopsy are more likely to choose active surveillance over early definitive treatment compared to men diagnosed on systematic biopsy when adjusting for tumor grade, PSA density, prior biopsy history, race, and provider. PMID- 29526600 TI - Five-year minimum clinical and radiographic outcomes of total shoulder arthroplasty using a hybrid glenoid component with a central porous titanium post. AB - BACKGROUND: To determine the effectiveness of hybrid glenoid components in reducing the frequency of glenoid component loosening, we evaluated clinical and radiographic outcomes at a minimum 5-year follow-up in 45 shoulders that underwent total shoulder arthroplasty (TSA) using a system with a central porous titanium post to augment the cemented peripheral pegs. METHODS: Function and pain were evaluated with the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment score, visual analog scale, active shoulder range of motion, and strength. Postoperative radiographs were analyzed for radiolucent lines, progressive loosening, and at-risk signs. RESULTS: The mean American Shoulder and Elbow Surgeons score improved from 40.4 to 83.7 (P < .0001) and the mean visual analog scale from 5.9 to 0.8 (P < .0001). Forward elevation improved from 113 degrees to 151 degrees (P < .001), internal rotation from 49 degrees to 60 degrees (P = .035), and mean external rotation from 36 degrees to 50 degrees (P = .0006). Radiographs showed glenoid component radiolucency in 29 shoulders. Radiolucencies were confined to the area under the glenoid faceplate in 6 and were only around the central post in 13. Nine TSAs (20%) demonstrated 2 or more columns of involvement but were not judged to be at-risk. One implant (2.2%) had glenoid component failure and was revised to a hemiarthroplasty. CONCLUSION: Anatomic TSA using a hybrid glenoid component with a central porous titanium post demonstrated a low rate of mechanical failure and a rate of radiolucent lines comparable to reports of all polyethylene implants. Further evaluations are needed to demonstrate the long-term durability of these implants and to determine the significance and fate of the radiolucent lines, particularly relative to the central post. PMID- 29526601 TI - Association between serotonin 2A receptor genetic variations, stressful life events and suicide. AB - AIM: Life events are series of events that disrupt a person's psychological equilibrium and may enhance the development of a disorder such as suicide. Several studies have assessed a relationship between 5-hydroxytryptamine (serotonin) 2A receptor (5-HTR2A) gene polymorphisms with an increased risk of suicide. However, there has been no study about the association between three 5 HTR2A gene polymorphisms, A1438G (rs6311), T102C (rs6313) and C1354T (rs6314), suicide, stressful life, and loss events in a same time. METHODS: Relatives of 191 suicide victims were interviewed using a semi-structured questionnaire designed according to Iranian culture. Venous blood was taken from all subjects for DNA isolation. 5-HTR2A polymorphisms in a total of 191 suicide victims and 218 healthy controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Chi-squared and Fisher's exact tests were used to compare genotype and allele frequencies between suicide and control groups. Correction for multiple comparisons was calculated using Bonferroni correction. RESULTS: There was a significant association between the 102 C/C genotype of 5-HTR2A gene and suicide (k2 = 8.700, P = 0.012). Furthermore, we found that suicide victims with a 102 C/C genotype had a significantly higher number of stressful life and loss events (P < 0.05). Genotype and allele distributions of A1438G (rs6311) and C1354T (rs6314) polymorphisms of 5-HTR2A gene showed no differences between suicide victims and control participants and there was no association between genotype distribution and higher number of stressful life and loss events (P > 0.05). CONCLUSION: Our results suggest that C102T (rs6313) polymorphism of 5-HTR2A gene may be involved in the susceptibility to suicide, higher number of stressful life and loss events, but A1438G (rs6311) and C1354T (rs6314) polymorphisms of 5-HTR2A gene were not associated with suicide, higher number of stressful life and loss events. PMID- 29526602 TI - Epigenome-wide study for the offspring exposed to maternal HBV infection during pregnancy, a pilot study. AB - BACKGROUND & AIM: Hepatitis B virus (HBV) can be transmitted to infants, and is related to infants' later disease risk. Epigenetic change (such as DNA methylation) may be mechanism underlying the relationship. In this study, we aimed to investigate whether prenatal HBV infection could alter DNA methylation status in newborns. METHOD: We selected 12 neonates with intrauterine HBV infection whose mothers were HBsAg-positive during pregnancy, relative to 12 HBV free neonates with HBsAg-negative mothers. The pattern of genome-wide DNA methylation in the umbilical cord blood was investigated by Illumina Infinium Human Methylation 450K BeadChip. RESULT: The average level of global methylation in infected neonates exposed to maternal HBV infection was not significantly different from controls. However, after adjusting for multiple comparisons, we found differential significance in the cases group compared to the controls for 663 CpG sites, associated with 534 genes. Among these sites, 53.85% (357/663) had decreased methylation (DeltaM < 0) and 46.15% (306/663) had increased methylation (DeltaM > 0). The average percentage change (Deltabeta) in methylation ranged from -46% to 36%. Validated by pyrosequencing, we identified 4 significantly differentially methylated CpG sites in the KLHL35 gene and additional CpGs for the CPT1B gene. These genes play a role in the development of hepatocellular and colorectal carcinoma and fatty acid oxidation, suggesting the candidature of these genes in HBV related disease. CONCLUSION: Prenatal HBV exposure, even without malformation or preterm birth, may alter the epigenome profile in newborns. We identified a set of genes with differentially methylated CpG sites presented in the cord blood of HBV-infected newborns with HBsAg-positive mothers, demonstrating that DNA methylation status at birth can be used as a biomarker of prenatal exposure. These DNA methylation differences suggest a possible role for epigenetic processes in neonatal development in response to prenatal HBV exposure. PMID- 29526604 TI - Erratum. PMID- 29526603 TI - Association Between Psychiatric Disorders, Substance Use, and Sexual Risk Behaviors in Perinatally HIV-Exposed Youth. AB - As youth with perinatally acquired HIV infection age, there is a need for studies that identify predictors and correlates of sexual risk behaviors. We examined the association between psychiatric disorders and substance use disorders (SUD) with sexual risk behaviors in youth with perinatally acquired HIV infection and perinatally HIV-exposed but uninfected youth. Participants were recruited from four medical centers in New York City. The Diagnostic Interview Schedule for Children and the Adolescent Sexual Behavior Assessment were administered to assess psychiatric disorders and sexual behaviors, respectively. SUD and behavior disorders were correlated with either ever having had penetrative sex or recent condomless sex for participants with perinatally acquired HIV infection only. Results suggest that clinicians should screen and treat patients for SUD and behavioral disorders to reduce sexual risk behaviors in youth with perinatally acquired HIV infection. PMID- 29526605 TI - Comparison of two closed carriers for vitrification of human blastocysts in a donor program. AB - The survival of human blastocysts to vitrification with two different carriers is compared. Both vitrification carriers used in this study are in the category of closed carriers, as they completely isolate the samples from direct contact with liquid nitrogen or its vapours during cooling and storage, until warming. This characteristic is appealing because it reduces or eliminates the theoretical risk of cross-contamination during that period of time. The two closed vitrification systems used present very different design and features: in the High Security Vitrification device, the carrier straw containing the embryos is encapsulated inside an external straw before plunging in liquid nitrogen, resulting in thermal insulation during cooling. On the other hand, in the SafeSpeed carrier embryos are loaded in a thin-walled, narrow capillary designed to maximize the thermal transference. Both closed carriers achieved comparable outcomes in terms of survival of blastocysts to the vitrification process, with 97.5% vs. 96.1% survival with HSV and SafeSpeed, respectively. In conclusion, the cooling and warming rates at which these carriers operate, in combination with the cytosolic solute concentration in the cells of the cryopreserved blastocysts attained after a cryoprotectant-loading protocol, result in successful vitrification of human blastocysts for human assisted reproduction. PMID- 29526606 TI - Population pharmacokinetics of vancomycin in critically ill patients receiving prolonged intermittent renal replacement therapy. AB - OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury. METHODS: Critically ill patients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics(r). The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC0-24)/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC0-24 700 for toxicity. RESULTS: Eleven critically ill patients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean +/- standard deviation (SD) age, weight and body mass index (BMI) were 57 +/- 13 years, 98 +/- 43 kg and 31 +/- 9 kg/m2, respectively. A two-compartment linear model adequately described the data. The mean +/- SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 +/- 1.99 L/h, non-PIRRT CL 2.15 +/- 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 +/- 24.33 L, distribution rate constant from central to peripheral compartment 5.97 +/- 7.93 per h and from peripheral to central compartment 5.29 +/- 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. CONCLUSIONS: This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring. PMID- 29526607 TI - Prospective cross-sectional study of tuberculosis screening in United Arab Emirates. AB - OBJECTIVES: Intense migrations from tuberculosis endemic areas to Gulf countries create special risks for people in the region. The purpose of this study was to provide data that could justify implementing universal, regular TB screening in UAE. DESIGN: This prospective, cross-sectional study used interferon-gamma release assay (IGRA) to screen for TB among Emirati citizens between August-2016 and May-2017; expatriates were not included in this study. Participants were recruited from Emiratis attending Tawam Hospital Polyclinics for problems unrelated to TB risk assessment. IGRA was requested for all enrolled participants. A risk-assessment questionnaire was completed by all participants. In addition, a retrospective review of IGRA results (January-2011 to April-2016) was conducted to compare prevalence of positive IGRA in the 'prospective sample' with that in 'patients screened in the past'. RESULTS: Four hundred fifty-five participants (69% females) were enrolled in this study. Participants' age (mean+/ SD) was 42+/-16y. The majority of participants had traveled to or had helpers from TB-endemic areas. Two hundred forty (53%) participants had IGRA test. Forty five (18.8%) participants had positive IGRA, similar to the retrospective results of 12.4% to 23.5%. CONCLUSIONS: The prevalence of positive-IGRA in this study is high. PMID- 29526609 TI - Assessing effects of behavioral intervention on treatment outcomes among patients initiating HIV care: Rationale and design of iENGAGE intervention trial. AB - During the initial year of HIV diagnosis, while patients are often overwhelmed adjusting to this life changing diagnosis, they must develop self-care behaviors for attending regular medical care visits and antiretroviral therapy (ART) adherence to achieve and sustain viral suppression (VS). Maintaining "HIV adherence" and integrating it into one's daily life is required to sustain VS over time. The HIV care continuum or "treatment cascade," an epidemiological snapshot of the national epidemic in the United States (US), indicates that a minority of persons living with HIV (PLWH) have achieved VS. Little evidence exists regarding the effects of interventions focusing on PLWH newly initiating outpatient HIV care. An intervention that focuses on both retention in care and ART adherence skills delivered during the pivotal first year of HIV care is lacking. To address this, we developed a theory-based intervention evaluated in the Integrating Engagement and Adherence Goals upon Entry (iENGAGE) study, a National Institute of Allergy and Infectious Diseases (NIAID) funded randomized behavioral intervention trial. Here we present the study objectives, design and rationale, as well as the intervention components, targeting rapid and sustained VS through retention in HIV care and ART adherence during participants' first year of HIV care. The primary outcome of the study is 48-week VS (<200 c/mL). The secondary outcomes are retention in care, including HIV visit adherence and visit constancy, as well as ART adherence. PMID- 29526610 TI - Personalized Pain Goal as an Outcome Measure in Routine Cancer Pain Assessment. AB - BACKGROUND: There is currently no universally accepted outcome measure in cancer pain management. The personalized pain goal (PPG) has been shown to be a relevant outcome measure. We examined its use in routine outpatient practice and compared it with the clinically important difference (CID, >=2 points or 30%), a pain outcome measure frequently used in several clinical studies. MEASURES: Initial and follow-up clinical information of outpatients with advanced cancer pain were retrospectively reviewed. PPG response was defined as pain <= PPG and CID response as >=30% or >=2-point decrease in pain intensity at follow-up. OUTCOMES: PPG was successfully completed in 375 of 387 eligible patients (97%) with cancer pain. The median baseline PPG was three for all patients and remained unchanged at follow-up. One hundred thirty-two of 375 (35%) had a PPG response and 243 of 375 (65%) were non-responders. The odds ratio for PPG non-response was 1.01 for each milligram increase in morphine equivalent daily dose (P = 0.001), 1.46 for each point increase in the number of adjuvant analgesics (P = 0.006), 2.63 for severe pain (P = 0.002), and 2.55 for moderate depression (P = 0.006). Using PPG response as the gold standard for pain relief, the overall sensitivity and specificity of CID response were 83% and 77%, respectively. CONCLUSION: PPG was successfully completed in the vast majority of patients, suggesting its feasibility as a pain outcome measure in routine clinical practice. Higher baseline pain intensity, depression, opioid dose, and number of adjuvant analgesics were independent predictors of poor pain relief. Further research is needed to further evaluate its clinical importance in cancer pain management. PMID- 29526608 TI - The VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention (VITAL-DEP): Rationale and design of a large-scale ancillary study evaluating vitamin D and marine omega-3 fatty acid supplements for prevention of late-life depression. AB - RATIONALE: Depression is a leading cause of disease burden and disability for older adults; thus, prevention is a priority. Biologic and observational data support potential mental health benefits of vitamin D and omega-3 fatty acids; however, it is unclear whether these supplements can prevent late-life depression. DESIGN: We describe the novel methodology of a large-scale study: VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention), an ancillary to the VITAL trial. Primary Aims of VITAL-DEP are to determine effects on prevention of depression and on trajectory of mood symptoms of long-term (mean=5years) supplementation with vitamin D (vitamin D3 [cholecalciferol], 2000IU/day) and marine omega-3 fatty-acids (eicosapentaenoic acid + docosahexaenoic acid, 1g/day), in a 2*2 factorial design, among 25,874 older adults. Secondary Aims will evaluate: vitamin D's effects among African-Americans (an at-risk group for vitamin D deficiency); both agents' effects among those with high-risk factors or sub-syndromal depression in a sub-set of ~1000 participants with detailed examinations at baseline and 2-year follow-up; whether baseline nutrient levels influence depression risk and/or modify agents' effects. Additional planned analyses will use pre-randomization blood samples available in ~17,000 participants to address whether key biomarkers and factors influence long term mood and depression risk and/or the agents' effects. CONCLUSION: VITAL-DEP applies all modalities of state-of-the-art prevention research - universal, selective and indicated. VITAL-DEP will clarify effects of supplemental vitamin D and/or omega-3 on mood, and inform clinical care and public health guidelines on the use of these agents for prevention of depression in mid-life and older adults. PMID- 29526611 TI - A Palliative Radiation Oncology Consult Service Reduces Total Costs During Hospitalization. AB - CONTEXT: Palliative radiation therapy (PRT) is a highly effective treatment in alleviating symptoms from bone metastases; however, currently used standard fractionation schedules can lead to costly care, especially when patients are treated in an inpatient setting. The Palliative Radiation Oncology Consult (PROC) service was developed in 2013 to improve appropriateness, timeliness, and care value from PRT. OBJECTIVES: Our primary objective was to compare total costs among two cohorts of inpatients with bone metastases treated with PRT before, or after, PROC establishment. Secondarily, we evaluated drivers of cost savings including hospital length of stay, utilization of specialty-care palliative services, and PRT schedules. METHODS: Patients were included in our observational cohort study if they received PRT for bone metastases at a single tertiary care hospital from 2010 to 2016. We compared total costs and length of stay using propensity score-adjusted analyses. Palliative care utilization and PRT schedules were compared by chi2 and Mann-Whitney U tests. RESULTS: We identified 181 inpatients, 76 treated before and 105 treated after PROC. Median total hospitalization cost was $76,792 (range $6380-$346,296) for patients treated before PROC and $50,582 (range $7585-$620,943) for patients treated after PROC. This amounted to an average savings of $20,719 in total hospitalization costs (95% CI [$3687, $37,750]). In addition, PROC was associated with shorter PRT schedules, increased palliative care utilization, and an 8.5 days reduction in hospital stay (95% CI [3.2,14]). CONCLUSION: The PROC service, a radiation oncology model integrating palliative care practice, was associated with cost savings, shorter treatment courses and hospitalizations, and increased palliative care. PMID- 29526612 TI - Psychiatric Comorbidity, Health-Related Quality of Life, and Mental Health Service Utilization Among Patients Awaiting Liver Transplant. AB - CONTEXT: The prevalence of psychiatric disorders and mental health service utilization among patients with end-stage liver disease awaiting transplant remains understudied. OBJECTIVES: This study assessed the prevalence of psychological disorders and symptoms with the use of a structured diagnostic interview and self-report measures, and examined patient-reported mental health service utilization and barriers to care. METHODS: Waitlisted liver transplant candidates (N = 120) completed assessments during routine clinic appointments at a single time point. RESULTS: Participants endorsed moderate-to-severe levels of depression (19.2%), anxiety (26.7%), and Post Traumatic Stress Disorder (PTSD) (23.3%). Forty-three percent had received some form of mental health treatment in the recent past, and a range of barriers to accessing mental health services were endorsed. In a subset of 39 participants who received a structure diagnostic assessment, there was a high prevalence of current (51.3%) and past (82.1%) psychiatric disorders. Elevated scores on depression, anxiety, and PTSD measures were associated with significant decrements in health-related quality of life, but were not differentially associated with mental health service utilization. CONCLUSION: There are a significant number of end-stage liver disease patients who could benefit from intervention who are not currently connected to treatment. Many patients do not see the need for accessing services, perhaps because of a lack of insight or knowledge about the benefits of mental health treatment. Future research should determine optimal treatment and service delivery methods for this vulnerable population. PMID- 29526613 TI - Correlates of Patterns of Health Values of African Americans Living With HIV/AIDS: Implications for Advance Care Planning and HIV Palliative Care. AB - CONTEXT: Advance care planning rates remain low, especially among people who are HIV positive, disadvantaged, and African American. Although advance care planning can be a sensitive topic for clinicians and patients to discuss, health values clarification can be an important initial step. OBJECTIVES: The purpose of the study was to explore health values of African Americans living with HIV/AIDS and to examine correlates of these values. METHODS: Data were from the first 325 participants in the AFFIRM Care study, which enrolled adults living with HIV/AIDS in Baltimore, Maryland, who had histories of illicit drug use. Respondents were asked whether (yes/no) they thought any of six health states would be worse than death: severe unremitting pain, total dependency on others, irreversible coma, being on mechanical ventilation, nursing home residence, and severe dementia. Latent class analysis was used to group individuals by their pattern of responses, interpretable as preference for aggressive (life-sustaining) or nonaggressive (palliative) end-of-life care. Latent class regression analysis was used to examine associations between class membership and background, health status, and social variables. RESULTS: We found statistical support for a three class latent class analysis model: 1) the nonaggressive treatment class, comprising 43% of cases, in which members perceived that every state was worse than death; 2) the aggressive treatment class, comprising 33% of cases, in which members perceived that none of the states was worse than death; and 3) the mixed class (24% of cases), in which members perceived that only four of the six states were worse than death. CONCLUSION: Three-quarters of participant response patterns had clear preferences for treatment decisions. Further research is needed to ensure inclusion of end-of-life scenarios relevant to this population. PMID- 29526614 TI - Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment. AB - Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced >=1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. PMID- 29526615 TI - Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy. AB - Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2S. Patients are typically identified after the onset of clinical symptoms and there is limited information about long term response to treatment. We report the findings of two unrelated patients with EE, identified through newborn screening, who were managed with conventional treatment (NAC, metronidazole alternated with neomycin) and in patient 2, a novel dietary treatment restricting sulfur containing amino acids. Pathogenic mutations were confirmed in the ETHE1 gene (homozygous splice site mutation in patient 1, c.505 + 1G > A; compound heterozygous mutations in patient 2, c.131_132delAG + c.566delG). Both patients were started on metronidazole and NAC by 10 weeks of age and treated for 23 months. Patient 1 did not accept the metabolic formula due to palatability and parental refusal for gastrostomy tube placement. She demonstrated improved biomarkers (EMA, lactic acid and thiosulfate) and an attenuated clinical course. Patient 2 was started on a low methionine and cysteine diet at 8 months of age utilizing SOD Anamix(r) Early Years, (Nutricia). Baseline EMA levels were (642 mg/g Cr; n = 2) and decreased with medical treatment by 38% to a mean of 399 (n = 4, SD = 71, p 0.0013). With dietary treatment EMA levels were further reduced by 42% to a mean of 233 (n = 8, SD = 52, p 0.0030). Lactic acid, thiosulfates and clinical outcomes were also improved. Our long-term follow-up confirms previous reports of clinical improvement with NAC and metronidazole treatment. Additionally, our studies suggest that a diet restricted in sulfur-containing amino acids results in further improvement in clinical outcomes and biochemical markers. PMID- 29526617 TI - Development of pectin microparticles by using ionotropic gelation with chlorhexidine as cross-linking agent. AB - Having previously highlighted the gelation of pectin with chlorhexidine (CX), pectinate microparticles were prepared here by vibrational prilling using CX, not only as an active ingredient encapsulated but also as a cross-linking agent. CX amount required for pectin gelation was smaller than usual dications (Ca2+, Zn2+) used as cross-linking agent for pectin ionotropic gelation: CX seemed to bind more easily to pectin chains that could be explained by its large molecular size. Three batches of CX microparticles with different mean size were prepared. Whatever the droplet mean diameter, similar particle characteristics in terms of encapsulation efficiency, CX encapsulation yield and drug release were observed. The encapsulation efficiency was about 5.5%, the CX encapsulation yield was approximately 44% and the maximal amount of CX released after 6 h was about 7%. Finally, zinc diacetate was added to the formulation as a competitive pectin cross-linking agent in order to limit CX binding to pectin and to improve CX release. The influence of CX and Zn2+ concentrations on the particles properties was studied by the means of a Doehlert design. Results showed the interest of such a mixture since the competition between both cations led to more or less structured and large microparticles, some of them having promoted the quantity of CX released. PMID- 29526616 TI - N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease. AB - Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease. PMID- 29526618 TI - Lamination of biconvex tablets: Numerical and experimental study. AB - Capping and lamination are common industrial problems during the manufacturing of pharmaceutical tablets. Even if they are commonly treated together, these phenomena correspond to different failure patterns of the tablet and, as a consequence, to different mechanisms of cracking. In this work, a specific case of lamination of biconvex tablets was studied. It corresponds to a breakage into two parts of the tablets along a failure plan normal to the compression direction and located approximately at the center of the tablet band. Simulation with finite element method made it possible to propose that this kind of failure is promoted by tensile stresses localized at the center of the tablet that are induced by the residual die wall pressure and the tablet shape. Moreover, these stresses are favored by a small band thickness. Experimental results confirmed these hypotheses and also showed that this kind of lamination was favored by a high compaction pressure. As the crack is formed at the center of the tablet, it may not propagate until the tablet band. Failure may thus remain undetected by external visual examination. X-ray tomography made it possible to observe central cracks inside the tablet without tablet breakage. The possibility to have such cracks inside the tablet must be considered during tablet development as, even if not detected just after compression, they could lead to tablet failure during post compaction events. PMID- 29526619 TI - Improving in vivo conversion of oleuropein into hydroxytyrosol by oral granules containing probiotic Lactobacillus plantarum 299v and an Olea europaea standardized extract. AB - This study reports novel food-grade granules for co-delivery of L. plantarum 299v and a standardized extract of Olea europaea leaves (Phenolea(r)) as oral carrier of probiotics and hydroxytyrosol. Different granule formulations containing either L. plantarum 299v (Lac), or the olive leave extract (Phe) or their combination (Lac-Phe) have been successfully produced through wet granulation employing excipients generally regarded as safe as granulating/binding agents. L. plantarum cells withstood the manufacturing process and were stable upon storage at 4 degrees C for more than 6 months. In vitro dissolution studies in simulated gastro-intestinal fluids showed the capability of the granules to rapidly dissolve and deliver both olive leave phenols and living L. plantarum cells. In simulated digestion conditions, Lac and Lac-Phe granules protected L. plantarum against the harsh environment of the gastro-intestinal tract. Co-administration of Lac and Phe oral granules to healthy mice provided for higher amounts of hydroxytyrosol in urines as compared to Phe granules alone, suggesting that L. plantarum 299v boosted in vivo conversion of oleuropein to hydroxytyrosol. On the other hand, PCR-assisted profiling of the Lactobacillus population in faeces obtained from mice treated with Lac or Lac plus Phe confirmed that the probiotic arrived alive to colon and was there able to exert a sort of perturbing effect on the climax colonic microflora. Overall, these results pave the way towards the development of a nutraceutical useful for combined delivery of bioactive hydroxytyrosol and probiotics to colon site. PMID- 29526620 TI - Endothelial progenitor cell secretome delivered by novel polymeric nanoparticles in ischemic hindlimb. AB - Endothelial progenitor cells (EPCs) contribute to ischemic tissue repair by paracrine secretion up-regulated by hypoxia. In this study we use novel nanoparticles (NPs) as carriers for a controlled release of EPC secretome (CM) to improve their angiogenic properties. The in vivo effect in ischemic hindlimb rat model was evaluated, comparing hypoxic EPC-CM-NPs with hypoxic EPC-CM alone. A proteomic characterization of hypoxic CM and the in vitro effect on endothelial cells (HUVECs) were also performed. Up to 647 protein, 17 of which with angiogenic properties, were upregulated by hypoxia. Moreover, hypoxic EPC-CM significantly promoted capillary-like structures on Matrigel. A significant increase of blood perfusion in ischemic limbs at 2 weeks with EPC-CM-loaded NPs as compared to both EPC-CM and control and a significant increase of capillary formation were observed. The use of EPC-CM-NPs significantly improved neoangiogenesis in vivo, underlining the advantages of controlled release in regenerative medicine. PMID- 29526621 TI - Development of itaconic acid-based molecular imprinted polymers using supercritical fluid technology for pH-triggered drug delivery. AB - A novel pH-responsive molecularly imprinted polymer (MIP) based on Itaconic acid:Ethylene glycol dimethacrylate was developed as a potential body-friendly oral drug delivery system for metronidazole (MZ), a pH-independent drug. MIP performance was evaluated in a simulated oral administration situation, at pHs 2.2 and 7.4. Itaconic acid-based copolymers were synthesized using two different molar ratios of template:monomer:crosslinker (T:M:C), 1:5:25 and 1:5:50, in supercritical carbon dioxide (scCO2) in high yields. Further, impregnation of MZ was performed in scCO2 environment. Morphological and chemical properties of the copolymers produced were assessed by SEM, Morphologi G3 and FTIR analyses. Non molecularly imprinted polymer (NIP) matrices presented swelling over time in opposition to the molecularly imprinted ones. In the scCO2-impregnation process, MIPs showed a significant molecular recognition towards MZ, presenting higher drug uptake ability with MZ loading of 18-61 wt% in MIPs, compared to 7-20 wt% in NIPs. In vitro drug release experiments presented different release profiles at the different pHs, where MZ-MIPs could release higher amounts of MZ at the lowest pH than at pH 7.4. PMID- 29526622 TI - Zaleplon loaded bi-layered chronopatch: A novel buccal chronodelivery approach to overcome circadian rhythm related sleep disorder. AB - The aim of this study was to develop a novel buccal bi-layered chronopatch capable of eliciting pulsatile release pattern of drugs treating diseases with circadian rhythm related manifestation. Zaleplon (ZLP) was used as a model drug intended to induce sleep and to treat middle of night insomnia. The chronopatch was prepared adopting double casting technique. The first layer was composed of a controlled release patch containing ZLP-Precirol melt granules intended to release ZLP in a sustained manner to maintain sleep and to prevent early morning awakening. The second layer was composed of a fast release lyophilized buccal disc containing ZLP loaded SNEDDS (Z-SNEDDS) intended for rapid sleep induction. Pharmacokinetic parameters of ZLP from the chronopatch were compared to those of the immediate release capsule, Siesta(r), as reference in Mongrel dogs using a randomized crossover design. The appearance of two peaks having two Cmax and Tmax proved the pulsatile release pattern. The increase in relative bioavailability of ZLP from the chronopatch was 2.63 folds. The results revealed the ability of the developed ZLP loaded bi-layered chronopatch to be a candidate for overcoming early morning awakening without middle of night dose administration. PMID- 29526623 TI - Dual-responsive drug delivery systems prepared by blend electrospinning. AB - To prepare temperature and pH dual-responsive drug delivery systems, the thermosensitive polymer poly(N-isopropylacrylamide) (PNIPAAm) was first synthesized by free-radical polymerization. It was then co-dissolved with the pH sensitive polymer Eudragit(r) L100-55 (EL100-55) and processed into fibers using electrospinning. Ketoprofen (KET), a model drug, was also incorporated into the composite fibers, and fibers based on a single polymer additionally prepared. The fibers had smooth cylindrical morphologies, and no obvious phase separation could be seen. Using X-ray diffraction, KET was determined to be present in the amorphous state in the fiber matrix. FTIR spectroscopy also indicated the successful incorporation of amorphous KET in the fibers. In vitro drug release studies in media at different pH (4.5 or 7.4) or temperature (25 and 37 degrees C) showed that the release of KET from the blend PNIPAAm/EL100-55 fibers was dependent both on environmental temperature and pH, reflecting the dual responsive properties of the fibers. The MTT assay was used to explore the biocompatibility of the PNIPAAm/EL100-55 composite fibers towards L929 fibroblasts. Viability was always found to be >80%, even at polymer concentrations of 100 mg/L. Therefore, the fibers prepared here could lead to the development of multi-responsive materials for drug delivery and tissue engineering. PMID- 29526624 TI - An expanded prevention quality diabetes composite: Quantifying the burden of preventable hospitalizations for older adults with diabetes. AB - AIM: To expand the existing United States Agency for Health Research and Quality (AHRQ) Diabetes composite (AHRQ-DC) to include additional preventable hospitalizations specific or relevant to diabetes. METHODS: A cross-sectional analysis of 834,696 veteran patients with diabetes aged >=65 years in 2012. An Expanded Diabetes Composite (Expanded-DC) was developed utilizing: (1) the diabetes-specific category: the AHRQ-DC (short-term and long-term complications, uncontrolled diabetes, lower extremity amputations) and two proposed conditions: hypoglycemia and lower extremity ulcers/inflammation/infections (LEU) and (2) the diabetes-relevant category: the AHRQ-Acute Composite (dehydration, pneumonia, urinary tract infections) and one proposed condition, acute kidney injury (AKI). RESULTS: The study population was 98% male, 80% White, 10% Black, and 5% Hispanic; 71% had complex comorbidities. There were 64,243 (77.0 admissions/1000 patients) hospitalizations in the Expanded-DC, compared to 13,523 (16.2) in the AHRQ-DC, a 4.7 fold increase. Hospitalizations from AHRQ-Acute Composite and the three proposed conditions added 79% to the Expanded-DC. LEU and hypoglycemia added 39% to the diabetes-specific category. AKI added 18% to the diabetes relevant category. Blacks incurred more preventable hospitalizations (85.9) than Whites (74.7); as did patients with complex comorbidities (93.6) versus those without (34.6). CONCLUSION: The AHRQ-DC substantially underestimates rates of clinically important preventable hospitalizations in older diabetes patients. PMID- 29526625 TI - Legacy effect in combined diabetic-renal multifactorial intervention in patients with advanced diabetic nephropathy. AB - AIM: Evaluate legacy effect on renal outcomes after the end of a multifactorial multidisciplinary intervention in patients with advanced diabetic nephropathy (ADN trial) CKD 3-4. METHODS: A retrospective electronic review was conducted of 72 patients who completed the ADN trial ESRD-free with subsequent follow-up of two years or until ESRD development. RESULTS: At baseline, reflecting ADN trial end, 38 post-intervention and 34 post-control patients were similar except for lower HbA1c, SBP and age in the post-intervention group. In post-trial follow-up, ESRD developed in both groups at similar rates (23 vs 20%). ESRD occurred mainly in baseline CKD 4 (75%). In CKD 3, only those in post-control developed ESRD (28.6%, p = 0.067). A significant decline in eGFR occurred within both groups. In multivariate analyses, ESRD was associated with baseline yearly eGFR decline. Greater yearly eGFR decline was associated with higher albumin/creatinine ratio at follow-up, lower age, and baseline SBP not being at target (p = 0.005, with an R2 of 0.197). CONCLUSIONS: There was no significant post-intervention effect on ESRD progression in the two groups. Minimal legacy effect was observed in less advanced nephropathy (CKD 3). These renal and risk outcomes emphasize the importance and potential benefits of continuous and long-term multifactorial care. PMID- 29526626 TI - Serum concentrations of fatty acid-binding protein 4 in Chinese children with type 1 diabetes mellitus. AB - OBJECTIVE: The aim of this study was to test the serum concentrations of fatty acid-binding protein 4(FABP4) in children with type 1 diabetes mellitus (T1DM) and to determine the relationship between patients with good and poor glycaemic control who were classified according to their glycated hemoglobin A1c (HbA1c) levels. METHODS: Children with T1DM were selected consecutively from our department from May 2016 to May 2017. For comparison, the same non-diabetic, age, sex, BMI and pubertal stage-matched healthy children were selected consecutively among non-diabetic children. Serum levels of FABP4 were batch analyzed using a commercially available ELISA assay. Patients were categorized into two groups according to their glycaemic control (Poor glycaemic control is HbA1c>7.0% and good is <=7.0%). RESULTS: In this study, 118 children with T1DM and 118 control cases were included. The mean serum FABP4 concentrations were significantly (P<.001) higher in T1DM as compared to controls. There was a modest correlation between serum concentrations of FABP4 and duration of diabetes (r=0.484, P<.001). Fifty-two patients were defined as poor glycaemic control (HbA1c>7.0%). The mean serum FABP4 concentrations were significantly (P=.002) higher in the poor glycaemic control as compared to the good glycaemic control. After adjusting for all other predictors, FABP4 remained an independent poor glycaemic control indictor with an adjusted OR of 1.07 (95% CI, 1.01-1.13; P=.03). CONCLUSIONS: The present results indicated that FABP4 concentrations were increased and independently associated with the poor glycaemic control in Chinese children with T1DM. PMID- 29526627 TI - Cryoglobulins: An update on detection, mechanisms and clinical contribution. AB - Cryoglobulins are immunoglobulins precipitating in cold condition. They are classified in 3 types according to the Brouet classification and may lead to vasculitis of small and medium size vessels. Vasculitis is related to vessel obstruction by monoclonal cryoglobulin aggregates in type I cryoglobulins and immune complex deposition in type II and III mixed cryoglobulins. This phenomenon is favored by low temperature, especially in skin, joints, and peripheral nerves, or increased cryoglobulin concentration in kidneys. For their detection, collection and clotting at 37 degrees C are critical pre-analytical conditions. Cryoglobulin characterization and quantification are important to identify the underlying disease. Since detection and identification of cryoglobulins lack standardization, a protocol for such detection, characterization and quantification is proposed. PMID- 29526628 TI - The role of capillaroscopy and thermography in the assessment and management of Raynaud's phenomenon. AB - Most patients with Raynaud's phenomenon (RP) have "benign" primary RP (PRP), but a minority have an underlying cause, for example a connective tissue disease such as systemic sclerosis (SSc). Secondary RP can be associated with structural as well as functional digital vascular changes and can be very severe, potentially progressing to digital ulceration or gangrene. The first step in management is to establish why the patient has RP. This short review discusses the role of nailfold capillaroscopy and thermography in the assessment of RP. Nailfold capillaroscopy examines microvascular structure, which is normal in PRP but abnormal in most patients with SSc: the inclusion of abnormal nailfold capillaries into the 2013 classification criteria for SSc behoves clinicians diagnosing connective tissue disease to be familiar with the technique. For those without access to the gold standard of high magnification videocapillaroscopy, a low magnification dermatoscope or USB microscope can be used. Thermography measures surface temperature and is therefore an indirect measure of blood blow, assessing digital vascular function (abnormal in both PRP and SSc). Until now, the use of thermography has been mainly confined to specialist centres and used mainly in research: this may change with development of mobile phone thermography. PMID- 29526629 TI - Letter to the Editor: Autoimmune pathogenic mechanisms in Amyotrophic Lateral Sclerosis. PMID- 29526630 TI - The value of Autoimmune Syndrome Induced by Adjuvant (ASIA) - Shedding light on orphan diseases in autoimmunity. AB - Autoimmune Syndrome Induced by Adjuvant (ASIA) is a definition aimed to describe the common etiological process at the root of five clinical entities sharing similar symptomatology: macrophagic myofasciitis syndrome (MMF), Gulf War Syndrome (GWS), sick building syndrome (SBS), siliconosis, and post vaccination autoimmune phenomena. ASIA illustrates the role of environmental immune stimulating agents, or adjuvants, in the instigation of complex autoimmune reactions among individuals bearing a genetic preponderance for autoimmunity. The value of ASIA lies first in the acknowledgment it provides for patients suffering from these as yet ill-defined medical conditions. Equally important is the spotlight it sheds for further research of these poorly understood conditions sharing a common pathogenesis. In this article we elaborate on the significance of ASIA, review the current evidence in support of the syndrome, and address recent reservations raised regarding its validity. PMID- 29526631 TI - A methodological review of induced animal models of autoimmune diseases. AB - Autoimmune disorders are characterized by a loss of immune tolerance and consequent autoimmunity-mediated disease manifestation. Experimental models are invaluable research tools helping us to understand disease pathogenesis and to search for novel therapeutics. Animal models of autoimmune diseases consist of two groups, spontaneous and induced models. In this review article, we focus on the induced models of autoimmune diseases. Due to the complex nature of autoimmune disorders, many strategies have been applied for the induction of corresponding experimental models in animals like monkeys, rabbits, rats, and mice. Methodologically, these strategies can be categorized into three categories, namely immunization with autoantigen, transfer of autoimmunity, and induction by environmental factors. In this review article, we aim to provide a comprehensive overview of the field of induced experimental autoimmune diseases. On the one hand, we describe and summarize the different strategies used for induction of experimental autoimmune disease. On the other hand, we discuss how to select a strategy for modeling human disease, including the choice of an appropriate species and method for such an approach. PMID- 29526632 TI - Contribution of sex steroids and prolactin to the modulation of T and B cells during autoimmunity. AB - In this review we discuss how sex steroids and prolactin affect regulation and responsiveness of B and T cells. Sex hormones exert profound effects on several physiological processes of non- reproductive tissues. In the immune system, several studies with experimental models for SLE have shown a noticeable pro inflammatory role for ERalpha, contributing to disease development reflected in proteinuria and renal pathology. On the other hand, ERbeta appears to have an anti- inflammatory and immunosuppressive effect. Estrogen/ERalpha signaling induced an increase of Th17 cells in lymph nodes as well as the expression of its correspondent chemokine receptor CCR6 during collagen induced arthritis acute phase. High levels of anti- DNA antibodies and increased mortality was observed when given high E and prolactin doses to NZB/NZW mice, as compared with mice receiving low E and prolactin doses, or high E and low prolactin doses. Intracellular progesterone receptors have been detected in TCD4+ cells but in contrast as observed with ERs, it suppresses T cell dependent responses. Progestagen administration on female NZB/NZW mice decreased anti DNA IgG, improved survival, decreased glomerulonephritis and proteinuria. PMID- 29526633 TI - Association between allelic variants of the human glucocorticoid receptor gene and autoimmune diseases: A systematic review and meta-analysis. AB - INTRODUCTION: The human glucocorticoid receptor gene (NR3C1) is considered to play a role in the differences and sensitivities of the glucocorticoid response in individuals with autoimmune diseases. The objective of this study was to examine by means of a systematic review previous findings regarding allelic variants of NR3C1 in relation to the risk of developing systemic autoimmune diseases. METHODS: Studies that analysed the genotype distribution of NR3C1 allelic variants among patients with systemic autoimmune diseases were retrieved. A meta-analysis was conducted with a random effects model. Odds ratios (ORs) and their confidence intervals (CIs) were calculated. In addition, sub-analysis by ethnicity, sensitivity analysis and tests for heterogeneity of the results were performed. RESULTS: Eleven studies met the inclusion criteria for meta-analysis. We found no evidence that the analysed NR3C1 polymorphisms, rs6198, rs56149945, and rs6189/rs6190, modulate the risk of developing a systemic autoimmune disease. Nonetheless, a protective role for the minor allele of rs41423247 was found among Caucasians (OR=0.78; 95% CI: 0.65, 0.92; P=0.004). A subgroup analysis according to underlying diseases revealed no significant association either for Behcet's disease or rheumatoid arthritis, while correlations between NR3C1 polymorphisms and disease activity or response to glucocorticoids could not be evaluated due to insufficient data. CONCLUSIONS: There is no clear evidence that the analysed NR3C1 allelic variants confer a risk for developing systemic autoimmune diseases although the minor G allele of rs41423247 may be protective among Caucasians. PMID- 29526634 TI - Solid phase assays versus automated indirect immunofluorescence for detection of antinuclear antibodies. AB - Solid phase assays (SPAs) and automated microscope systems are increasingly used to screen for antinuclear antibodies (ANAs). The goal of this study was to evaluate the performance of three automated ANA screening assays; NOVA Lite HEp-2 using NOVA View(r) (NV, Inova Diagnostics), an automated indirect immunofluorescence method, EliATM CTD Screen (Fluorescence Enzyme Immunoassay, FEIA; Thermo Fisher) and QUANTA Flash(r) CTD Screen Plus (Chemiluminescence immunoassay, CIA; Inova Diagnostics). The assays were performed on 480 diagnostic samples from patients with an ANA-associated rheumatic disease (AARD; systemic lupus erythematosus, primary Sjogren's syndrome, systemic sclerosis, inflammatory myopathy, mixed connective tissue disease) and on 767 samples from diseased and healthy controls. Using cut-offs proposed by the manufacturers, the sensitivity was 95%, 80.5% and 86% for NV, FEIA and CIA, respectively. The corresponding specificity was 61% (NV), 97.5% (FEIA) and 88% (CIA). The sensitivity associated with a specificity of ~95% was 79%, 82% and 78% for NV, FEIA, and CIA, respectively. Receiver operating characteristics (ROC) curve analysis revealed no differences in area under the curve (AUC) between the 3 assays when all diseases were grouped. For Sjogren's syndrome, the AUC was higher for SPAs than for NV, whereas for systemic sclerosis, the AUC was higher for NV than for CIA. For all assays, the likelihood ratio for AARD increased with increasing antibody levels and for double positivity of NV with SPA. In conclusion, the performance of automated SPA and IIF was assay- and disease-dependent. Taking into account antibody levels and combining IIF with SPA adds value. PMID- 29526635 TI - Perspective: Scientific and ethical concerns pertaining to animal models of autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). AB - The autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was first described in 2011. The aluminium containing adjuvants of vaccines were stated to be one of the main causes of the condition. Other disorders associated with ASIA include siliconosis, Gulf war syndrome, sick building syndrome and the macrophagic myositis syndrome. We have recently reviewed ASIA as defined by its authors. We have shown that the definition of ASIA is imprecise and includes all patients with an autoimmune disorder as well as potentially the entire population. Application of the Bradford Hill criteria for causality does not support ASIA as an outcome of exposure to aluminium containing adjuvants in vaccines. The advocates of ASIA highlight animal models as evidence for the existence of the disorder. However, as this review will demonstrate, animal models purporting to support the existence of ASIA have methodological, analytical and ethical flaws which, in our view, refute the existence of the condition. Three publications by the advocates of ASIA were recently retracted from peer-reviewed journals. We call for an immediate moratorium on animal experiments of ASIA until an independent inquiry has been conducted to determine the existence of a clinically relevant syndrome, identifiable as ASIA in humans. PMID- 29526636 TI - Optimizing conventional DMARD therapy for Sjogren's syndrome. PMID- 29526637 TI - Clinical and experimental evidence for targeting CD6 in immune-based disorders. AB - CD6 is a cell surface glycoprotein expressed by most T cells and a subset of B cells that has incompletely-defined roles in regulation of lymphocyte development, selection, activation and differentiation. The two main known mammalian CD6 ligands, CD166/ALCAM and the very recently reported CD318, are widely expressed by both immune cells and a wide range of other cell types, including various epithelial and mesenchymal cell types, as well as many neoplasms. Moreover, CD6 is also a receptor for several pathogen- and damage associated molecular patterns. Further layers of complexity of CD6 function are implied by the existence of multiple CD6 isoforms generated by alternative splicing of CD6 transcripts and soluble forms of CD6 released by proteases from the lymphocyte surface. Multiple lines of evidence are now emerging to implicate CD6 and its ligands in the pathogenesis and potentially the treatment of human autoimmune diseases, such as multiple sclerosis and psoriasis. CD6 is an important multiple sclerosis risk gene, and mice genetically deficient in CD6 or CD318, or treated with antibodies or chimerical proteins that interfere with CD6 ligand interactions, are protected from experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. CD6 deficient mice also show reduced TH17 differentiation and protection from disease in a moue model of psoriasis, providing a foundation for successful clinical trials of an anti-CD6 monoclonal antibody (Itolizumab) in psoriasis. Here we review current knowledge about CD6 and its ligands, and consider its potential value as a therapeutic target in a range of immune-mediated disorders. PMID- 29526638 TI - Skeletal muscle cells actively shape (auto)immune responses. AB - Histopathological analyses of muscle specimens from myositis patients indicate that skeletal muscle cells play an active role in the interaction with immune cells. Research over the last few decades has shown that skeletal muscle cells exhibit immunobiological properties that perfectly define them as non professional antigen presenting cells. They are able to present antigens via major histocompatibility complex molecules, exhibit costimulatory molecules and secrete soluble molecules that actively shape the immune response in an either pro- or anti-inflammatory manner. Skeletal muscle cells regulate both innate and adaptive immune responses and are essentially involved in the pathophysiological processes of idiopathic inflammatory myopathies. Understanding the role of skeletal muscle cells might help to identify new therapeutic targets for these devastating diseases. This review summarizes the immunobiological features of skeletal muscle cells, especially in the context of idiopathic inflammatory myopathies, and discusses shortcomings and limitations in skeletal muscle related research providing potential perspectives to overcome them in the future. PMID- 29526639 TI - The effect of interbody fusion cage design on the stability of the instrumented spine in response to cyclic loading: an experimental study. AB - BACKGROUND CONTEXT: In the lumbar spine, end plate preparation for the interbody fusion cages may critically affect the cage's long-term performance. This study investigated the effect of the interbody cage design on the compliance and cage subsidence of instrumented spines under cyclic compression. PURPOSE: We aimed to quantify the role of cage geometry and bone density on the stability of the spinal construct in response to cyclic compressive loads. STUDY DESIGN: Changes in the cage-bone interface and the effect of bone density on these changes were evaluated in a human cadaveric model for three intervertebral cage designs. METHODS: The intervertebral space of 27 functional cadaveric spinal units was instrumented with bilateral linear cages, single anterior conformal cages, or single unilateral oblique cages. Once augmented with a pedicle screw fixation system, the instrumented spine unit was tested under cyclic compression loads (400-1,200 N) to 20,000 cycles at a rate of 2 Hz. Compliance of the cage-bone interface and cage subsidence was computed. Two-way repeated multivariate analysis of variance was used to test the effects of cage design and bone density on the compliance and subsidence of the cages. RESULTS: The anterior conformal shaped cage showed reduced interface stiffness (p<.01) and higher hysteresis (p<.01) and subsidence rate (10%-30%) than the bilateral linear and unilateral oblique-shaped cages. Bone density was not associated with the initial compliance of the cage-bone interface or the rate of cage subsidence. Higher bone density did decrease the rate of reduction in cage-bone interface stiffness under higher cyclic loads for the anterior conformal shaped and unilateral oblique cages. CONCLUSIONS: Cage design and position significantly affected the degradation of the cage-bone interface under cyclic loading. Comparisons of subsidence rate between the different cage designs suggest the peripheral location of the cages, using the stronger peripheral subchondral bone of the apophyseal ring, to be advantageous in preventing the subsidence and failure of the cage-bone interface. PMID- 29526640 TI - Effect of posterior instrumented fusion on three-dimensional volumetric growth of cervical ossification of the posterior longitudinal ligament: a multiple regression analysis. AB - BACKGROUND CONTEXT: Despite the fact that ossification of posterior longitudinal ligament (OPLL) is a three-dimensional disease, conventional studies have focused mainly on a two-dimensional measurement, and it is difficult to accurately determine the volume of OPLL growth and analyze the factors affecting OPLL growth after posterior decompression (laminoplasty or laminectomy and fusion). PURPOSE: The present study aimed to investigate the factors affecting OPLL volume growth using a three-dimensional measurement. STUDY DESIGN/SETTING: This was a retrospective case study. PATIENT SAMPLE: Eighty-three patients with cervical OPLL who were diagnosed as having multilevel cervical OPLL of more than three levels on cervical computed tomography (CT) scans were retrospectively reviewed from June 1, 1998, to December 31, 2015. OUTCOME MEASURES: The OPLL volume from the C1 vertebrae to the C7 vertebrae was measured on preoperative and the most recent follow-up CT scans. METHODS: Eighty-three patients were retrospectively examined for age, gender, body mass index, hypertension, diabetes, type of OPLL, surgical method, preoperative cervical curvature, and preoperative and postoperative cervical range of motion. Preoperative cervical CT and the most recent follow-up cervical CT scans were converted to Digital Imaging and Communications in Medicine data, and the OPLL volume was three-dimensionally measured using the Mimics program (Materialise, Leuven, Belgium). The OPLL volume growth was analyzed using univariate and multivariate analyses. RESULTS: The average follow-up period was 32.36 (+/-23.39) months. Patients' mean age was 54.92 (+/-8.21) years. In univariate analysis, younger age (p=.037) and laminoplasty (p=.012) were significantly associated with a higher mean annual growth rate of OPLL (%/y). In multivariate analysis, only laminoplasty (p=.027) was significantly associated with a higher mean annual growth rate of OPLL (%/y). The mean annual growth rate of OPLL was about seven times faster with laminoplasty (8.00+/-13.06%/y) than with laminectomy and fusion (1.16+/-9.23%/y). CONCLUSIONS: Posterior instrumented fusion has the effect of reducing OPLL growth rate compared with motion-preserving laminoplasty. Patients' age and the surgical method need to be considered in surgically managing the multilevel OPLL. PMID- 29526641 TI - Relative pelvic version: an individualized pelvic incidence-based proportional parameter that quantifies pelvic version more precisely than pelvic tilt. AB - BACKGROUND CONTEXT: Pelvic tilt (PT) is used as an indicator of pelvic version with increased values indicating retroversion and disability. The concept of using PT solely as an absolute numerical value can be misleading, especially for the patients with pelvic incidence (PI) values near the upper and lower normal limits. Relative pelvic version (RPV) is a PI-based individualized measure of the pelvic version. Relative pelvic version indicates the individualized spatial orientation of the pelvis relative to the ideal sacral slope as defined by the magnitude of PI. PURPOSE: The aim of this study was to compare RPV and PT for their ability to predict mechanical complications and their correlations with health-related quality of Life (HRQoL) scores. STUDY DESIGN: A retrospective analysis of a prospectively collected data of adult spinal deformity patients was carried out. Mechanical complications (proximal junctional kyphosis or proximal junctional failure, distal junctional kyphosis or distal junctional failure, rod breakage, and implant-related complications) and HRQoL scores (Oswestry Disability Index [ODI], Core Outcome Measures Index [COMI], Short Form-36 Physical Component Summary [SF-36 PCS], and Scoliosis Research Society 22 Spinal Deformity Questionnaire [SRS-22]) were used as outcome measures. METHODS: Inclusion criteria were >=4 levels fusion, and >=2-year follow-up. Correlations between PT, RPV, PI, and HRQoL were analyzed using Pearson correlation coefficient. Pelvic incidence values and mechanical complication rates in RPV subgroups for each PT category were compared using one-way analysis of variance, Student t test, and chi-squared tests. Predictive models for mechanical complications with RPV and PT were analyzed using binomial logistic regressions. RESULTS: A total of 222 patients (168 women, 54 men) met the inclusion criteria. Mean age was 52.2+/-19.3 (18-84) years. Mean follow-up was 28.8+/-8.2 (24-62) months. There was a significant correlation between PT and PI (r=0.613, p<.001), threatening the use of PT to quantify pelvic version for different PI values. Relative pelvic version was not correlated with PI (r=-0.108, p>.05), being able to quantify pelvic version for all PI values. Compared with PT, RPV had stronger partial correlations with ODI, COMI, SF-36 PCS, and SRS-22 scores (p<.05). Discrimination performance assessed by area under the curve, percentage accuracy in classification, true positive rate, true negative rate, and positive and negative predictive values was better for the model with RPV than for PT. For average PI sizes, the agreement between RPV and PT were moderate (0.609, p<.001), whereas the agreement in small and large PI sizes were poor (0.189, p>.05; 0.098, p>.496, respectively). When analyzed by RPV, each PT "0," "+," and "++" category was further divided into two or three distinct subgroups of patients having different PI values (p=.000, p=.000, and p=.029, respectively). Relative pelvic version subgroups within the same PT category displayed different mechanical complication rates (p=.000, p=.020, and p=.019, respectively). CONCLUSIONS: Pelvic tilt may be insufficient or misleading in quantifying normoversion for the whole spectrum of PI values when used as an absolute numeric value in conjunction with previously reported population-based average thresholds of 20 and 30 degrees. Relative pelvic version offers an individualized quantification of ante-, normo-, and retroversion for all PI sizes. Schwab PT groups were found to constitute inhomogeneous subgroup of patients with different mean PI values and mechanical complication rates. Compared with PT, RPV showed a greater association with both mechanical complications and HRQoL. PMID- 29526642 TI - Empirical reproducibility, sensitivity, and optimization of acquisition protocol, for Neurite Orientation Dispersion and Density Imaging using AMICO. AB - Neurite Orientation Dispersion and Density Imaging (NODDI) has been gaining prominence for estimating multiple diffusion compartments from MRI data acquired in a clinically feasible time. To establish a pathway for adoption of NODDI in clinical studies, it is important to understand the sensitivity and reproducibility of NODDI metrics on empirical data in the context of acquisition protocol and brain anatomy. Previous studies addressed reproducibility across the 3 T scanners and within session and between subject reproducibility at 1.5 T and 3 T. However, empirical reproducibility on the performance of NODDI metrics based on b-value and diffusion-sensitized directions has not yet been addressed. In this study, we investigate a high angular resolution dataset with 11 repeats of a study with five b-values shells (1000, 1500, 2000, 2500 and 3000 s/mm2) and 96 directions per shell on a single subject. We validated the findings with a dataset from second subject with 10 repeats and 3 b-value shells (1000, 2000, 3000 s/mm2). The NODDI model was estimated using Accelerated Microstructure Imaging via Convex Optimization (AMICO) for different b-values and gradient directions on two-shell High Angular Resolution Density Imaging (HARDI) data fixing the lower shell at b = 1000 s/mm2. NODDI model applied to all acquired imaging data was used as a baseline gold standard for comparison. Additionally, we characterize orientation dispersion index (ODI) reproducibility using single shell data. The experimental findings confirmed the sensitivity of intracellular volume fraction (Vic) with the choice of outer shell b-value more than with the choice of gradient directions. On the other hand, ODI is more sensitive to the number of gradient directions compared to b-value selection. Single-shell results for ODI are more comparable to 2-shell data at lower b-values than higher b values. Recommended settings by region of interest and acquisition time are reported for the researchers considering using NODDI in human studies and/or comparing results across acquisition protocols. PMID- 29526643 TI - Theoretical analysis and optimization of ultrashort echo time (UTE) imaging contrast with off-resonance saturation. AB - PURPOSE: Off-resonance saturation (ORS) is a tool which can be used in ultrashort echo time (UTE) magnetic resonance imaging to selectively reduce short T2 signals. When these ORS prepared UTE images are subtracted from a non-suppressed UTE acquisition, the short T2 signals are highlighted. The aim of this paper is to develop a theoretical ORS model and optimize short T2 contrast. THEORY: Using a theoretical model the sequence parameters such as saturation flip angle and off resonance frequency were optimized to maximize short T2 contrast. Bloch simulations were performed to demonstrate the accuracy of the theoretical model. METHODS: Volunteer imaging was performed on the knee using different saturation flip angles and off-resonance frequencies using a Fermi RF pulse with a 3D UTE Cones acquisition. RESULTS: The off-resonance saturation method showed good long T2 suppression, and highlighted short T2 signals such as the patella tendon. The theoretical signal curves generally agreed with simulated and experimentally measured signals. CONCLUSION: Off-resonance saturation 3D UTE imaging can be used to effectively suppress long T2 signals and highlight short T2 signals. Theoretical modeling can be used to optimize sequence parameters to maximize long T2 suppression and short T2 contrast. Experimental results confirmed the theoretical predictions. PMID- 29526644 TI - A novel approach for accelerating mouse abdominal MRI by combining respiratory gating and compressed sensing. AB - PURPOSE: To combine the technique of respiratory gating and compressed sensing (CS) with the objective of accelerating mouse abdominal magnetic resonance imaging (MRI). MATERIALS AND METHODS: To obtain the maximum acceleration, phase encoding data from a phantom and mouse were obtained on a 4.7 Tesla scanner using the respiratory gating technique. The fully sampled data (FSD) were used to construct reference images and to provide samples to simulate retrospective undersampled data (UD) acquisition using respiratory gating. The UD and 95% of the UD on acceleration 2-5 rates were acquired and used for image reconstruction by CS. Quantitative assessment of reconstructed images was performed by structural similarity index (SSIM), peak signal-to-noise ratio (PSNR) and root mean square error (RMSE). RESULTS: The proposed method can accelerate phantom and mouse abdominal MRI acquisition between 2 and 4 rates by reducing the amount of FSD. For phantom UD acquisition, the mean time was reduced in 45.9% and for the acquisition of 95% of UD in 67.8%. For mouse abdominal image UD acquisition, the mean time was reduced in 44.6% and for the acquisition of 95% of UD in 62.5%. The metrics results show that the reconstructed image from UD and 95% of UD by using CS maintains an optimal agreement with their reference images (similarity above 0.88 for phantom and 0.93 for mouse). CONCLUSION: This study presents a novel approach to accelerate mouse abdominal MRI combining respiratory gating technique and CS without the use of expensive hardware and capable of achieving up to 4 acceleration rate without image degradation. PMID- 29526645 TI - Low dose bisphenol S or ethinyl estradiol exposures during the perinatal period alter female mouse mammary gland development. AB - Throughout life, mammary tissue is strongly influenced by hormones. Scientists have hypothesized that synthetic chemicals with hormonal activities could disrupt mammary gland development and contribute to breast diseases and dysfunction. Bisphenol S (BPS) is an estrogenic compound used in many consumer products. In this study, CD-1 mice were exposed to BPS (2 or 200 MUg/kg/day) during pregnancy and lactation. Mice exposed to 0.01 or 1 MUg/kg/day ethinyl estradiol (EE2), a pharmaceutical estrogen, were also evaluated. Mammary glands from female offspring were collected prior to the onset of puberty, during puberty, and in early adulthood. Growth parameters, histopathology, cell proliferation and expression of hormone receptors were quantified. Our evaluations revealed age- and dose-specific effects of BPS that were different from the effects of EE2, and distinct from the effects of BPA that have been reported previously. These assessments suggest that individual xenoestrogens may have unique effects on this sensitive tissue. PMID- 29526646 TI - Inactivation of Fgfr2 gene in mouse secondary palate mesenchymal cells leads to cleft palate. AB - Numerous studies have been conducted to understand the molecular mechanisms controlling mammalian secondary palate development such as growth, reorientation and fusion. However, little is known about the signaling factors regulating palate initiation. Mouse fibroblast growth factor (FGF) receptor 2 gene (Fgfr2) is expressed on E11.5 in the palate outgrowth within the maxillary process, in a region that is responsible for palate cell specification and shelf initiation. Fgfr2 continues to express in palate on E12.5 and E13.5 in both epithelial and mesenchymal cells, and inactivation of Fgfr2 expression in mesenchymal cells using floxed Fgfr2 allele and Osr2-Cre leads to cleft palate at various stages including reorientation, horizontal growth and fusion. Notably, some mutant embryos displayed no sign of palate shelf formation suggesting that FGF receptor 2 mediated FGF signaling may play an important role in palate initiation. PMID- 29526647 TI - Neural mechanisms of two different verbal working memory tasks: A VLSM study. AB - Currently, a distributed bilateral network of frontal-parietal areas is regarded as the neural substrate of working memory (WM), with the verbal WM network being more left-lateralized. This conclusion is based primarily on functional magnetic resonance imaging (fMRI) data that provides correlational evidence for brain regions involved in a task. However, fMRI cannot differentiate the areas that are fundamentally required for performing a task. These data can only come from brain injured individuals who fail the task after the loss of specific brain areas. In addition to the lack of complimentary data, is the issue of the variety in the WM tasks used to assess verbal WM. When different tasks are assumed to measure the same behavior, this may mask the contributions of different brain regions. Here, we investigated the neural substrate of WM by using voxel-based lesion symptom mapping (VLSM) in 49 individuals with stroke-induced left hemisphere brain injuries. These participants completed two different verbal WM tasks: complex listening span and a word 2-back task. Behavioral results indicated that the two tasks were only slightly related, while the VLSM analysis revealed different critical regions associated with each task. Specifically, significant detriments in performance on the complex span task were found with lesions in the inferior frontal gyrus, while for the 2-back task, significant deficits were seen after injury to the superior and middle temporal gyri. Thus, the two tasks depend on the structural integrity of different, non-overlapping frontal and temporal brain regions, suggesting distinct neural and cognitive mechanisms triggered by the two tasks: rehearsal and cue-dependent selection in the complex span task, versus updating/auditory recognition in the 2-back task. These findings call into question the common practice of using these two tasks interchangeably in verbal WM research and undermine the legitimacy of aggregating data from studies with different WM tasks. Thus, the present study points out the importance of lesion studies in complementing functional neuroimaging findings and highlights the need to consider task demands in neuroimaging and neuropsychological investigations of WM. PMID- 29526648 TI - The role of vacuum assisted thrombectomy (AngioVac) in treating chronic venous thromboembolic disease. Systematic review and a single center's experience. AB - BACKGROUND: Beyond medical therapy, the role of endovascular approach for the management of chronic Venous Thromboembolic (VTE) disease is yet to be defined. To our knowledge, no systematic reviews or guidelines are available that provide information on how to manage this chronic condition. This paper represents the first systematic review of published reports on the use of vacuum-assisted thrombectomy (AngioVac) in treating chronic VTE disease. METHODS: A systematic review of published case-series, individual case-reports, and review articles in MEDLINE, PubMed, and Google Scholar was conducted. Keywords used for the search were: "vacuum assisted thrombectomy", "AngioVac", "thrombectomy", and "chronic venous thrombosis". Inclusion criteria were a diagnosis of chronic DVT (>28 days) and the use of vacuum-assisted thrombectomy device (AngioVac) with or without additional endovascular therapy. Our selection process followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. The literature search was conducted through June 2017. RESULTS: The initial search yielded 51 publications of which 18 reported the use of vacuum assisted thrombectomy (AngioVac) in treatment of venous thrombosis but only 7 reports (13 patients) met our inclusion criteria. Similarly, 5 patients representing our center's experience were included in the analysis. Patients' demographics, admission diagnoses, risk factors, and procedural success were individually reported. Procedural success (both partial and complete resolution of thrombus burden) was achieved in 15 of the 18 cases (83%). Failure to re-canalize or significantly improve venous flow was seen in only 3 cases. No procedural mortality was reported. However, in-hospital and long-term mortality rates were not reported. CONCLUSION: Vacuum-assisted thrombectomy using the AngioVac system is a minimally invasive alternative to surgical thrombectomy for chronic VTE management. The use of this device in iliocaval thrombosis appears to be safe and effective compared to other anatomical locations. Further outcome studies are needed to define long-term benefits of mechanical thrombectomy in treating chronic VTE diseases. PMID- 29526649 TI - 2015 Evidence Analysis Library Systematic Review on Advanced Technology in Food Production. AB - In the late 20th century, plant breeders began using molecular biology techniques such as recombinant DNA, also known as genetic engineering, along with traditional cross-breeding. Ten plant and one animal food have been approved for commercialization in the United States. Today, foods and ingredients from genetically engineered (GE) crops are present throughout the food supply, which has led to varying levels of acceptance. Much discussion exists among consumers and health professionals about the believability of statements made regarding benefits or risks of GE foods. The aim of this systematic review was to examine the evidence on the association of consumption of GE foods and ingredients derived from them on human health, specifically allergenicity, food safety, pesticide consumption, nutrient adequacy, inflammation, and antibiotic resistance. An expert panel conducted a systematic review on advanced technology in food production. The 30 developed questions focused on effects of human consumption of GE foods and the effects of human consumption of foods containing pesticide residues on human health. Primary research published from 1994 to 2014 were identified using PubMed and Agricultural Online Access databases. Additional studies were identified by searching references of review articles. Twenty-one studies met the inclusion criteria. Relevant research addressed five of 30 questions. Four questions focused on food allergenicity, the fifth on nutrient adequacy, and all received a Grade III (limited/weak) rating. No human studies addressed 25 questions on the consumption of foods produced using genetic engineering technologies on gene translocation, cancer, food safety, phenotype expression, inflammation and inflammatory markers, or antibiotic resistance. These questions received a Grade V (grade not assignable). Evidence from human studies did not reveal an association between adverse health effects and consumption of foods produced using genetic engineering technologies. Although the number of available human studies is small, they support that there are no clear adverse health effects-as they relate to allergenicity and nutrient adequacy-associated with consumption of GE foods. The present systematic review is aligned with a recent report by the National Academy of Sciences that included human and animal research. PMID- 29526651 TI - Accounting for frailty when treating chronic diseases. AB - Chronic diseases are considered to be major determinants of frailty and it could be hypothesized that their treatment may counteract the development of frailty. However, the hypothesis that intensive treatment of chronic diseases might reduce the progression of frailty is poorly supported by existing studies. In contrast, some evidence suggests that intensive treatment of chronic diseases may increase negative health outcomes in frail older adults. In particular, if treatment of symptoms related to chronic diseases (i.e. pain in osteoarthritis, dyspnoea in respiratory disease, motor symptoms in Parkinson disease) might potentially reverse frailty, the benefits related to preventive pharmacological treatment of chronic diseases (i.e. antihypertensive treatment) in patients with prevalent frailty is not certain. In particular, several factors might alter the risk/benefit ratio of a given treatment in persons with frailty. These include: exclusion of frail persons from clinical studies, reduced life expectancy in frail persons, increased susceptibility to iatrogenic events, and functional deficits associated with frailty. Therefore, frailty acts as an effect modifier, by modifying the risks and benefits of chronic disease treatments. This hypothesis must be considered and tested in future clinical intervention studies and clinical guidelines should provide specific recommendations for the treatment of frail people, underlining the pros and the cons of pharmacological treatment and possible targets for therapy in this population. Meanwhile, in older patients, the prescribing process should be individualized and flexible. PMID- 29526650 TI - miRNAs Targeting ICP4 and Delivered to Susceptible Cells in Exosomes Block HSV-1 Replication in a Dose-Dependent Manner. AB - miRNAs are potent tools that in principle can be used to control the replication of infectious agents. The objectives of the studies reported here were to design miRNAs that can block the replication of herpes simplex virus 1 and which could be delivered to infected cells via exosomes. We report the following: (1) We designed three miRNAs targeting the mRNA encoding ICP4, an essential viral regulatory protein. Of the three miRNAs, one miRNA401 effectively blocked ICP4 accumulation and viral replication on transfection into susceptible cells. (2) To facilitate packaging of the miRNA into exosomes, we incorporated into the sequence of miRNA401 an exosome-packaging motif. miRNA401 was shown to be packaged into exosomes and successfully delivered by exosomes to susceptible cells, where it remained stable for at least 72 hr. Finally, the results show that miRNA401 delivered to cells via exosomes effectively reduced virus yields in a miRNA401 dose-dependent fashion. The protocol described in this report can be applied to study viral gene functions without actually deleting or mutagenizing the gene. PMID- 29526652 TI - Diagnosing catheter-associated urinary tract infection: Still a matter of concern. PMID- 29526654 TI - Understanding Confounding in Observational Studies. PMID- 29526653 TI - Deep Vein Thrombosis Exhibits Characteristic Serum and Vein Wall Metabolic Phenotypes in the Inferior Vena Cava Ligation Mouse Model. AB - OBJECTIVES: Deep vein thrombosis (DVT) is a major health problem, responsible for significant morbidity and mortality. The identification of a simple and effective diagnostic biomarker of DVT remains a challenge. Metabolomics have recently emerged as a new powerful scientific tool to characterise metabolic phenotypes of complex diseases and investigate small molecules in biofluids. The aim of the study was to identify the blood and vein wall metabolomic signature of DVT in a murine experimental model. METHODS: An established inferior vena cava ligation mouse model of DVT (n=10) was used and compared with sham surgery controls (n=10). Comprehensive untargeted metabolic profiling of serum and vein wall extracts was undertaken using liquid chromatography coupled mass spectrometry (LC MS) and nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Multivariate and univariate statistical analysis demonstrated a differential metabolic profile when comparing DVT mice and control animals. Serum from DVT mice was characterised by differential concentrations of adenosine (decreased in DVT mice 9.6 fold), adenine (decreased 10.6 fold), and tricyclic acid cycle (TCA) intermediates, including citrate, succinate, and fumarate (1.5, 2.3, and 2.8 fold decreases, respectively). l-carnitine was found to be of greater abundance in the serum of DVT animals (67.0 fold change). A number of lipid moiety classes, including sphingomyelins, phosphatidylcholines, and triglycerides, were differentially abundant. Several metabolites were found in vein wall, including acetylcarnitine (increased in DVT mice 1.9 fold), adenosine (increased 2.2 fold), and ceramide (increased 2.7 fold). Correlation analysis illustrated the biochemical relationships between assigned metabolites, with the discriminatory molecules being highly correlated with each other, in both serum and vein wall. CONCLUSIONS: The present findings demonstrate that metabolic dysregulations in DVT centre on energy metabolism, sphingolipid, and adenosine metabolism, representing a DVT specific metabolite signature in a murine experimental model. PMID- 29526655 TI - Preventing EVAR Associated Acute Kidney Injury: The Optimal Strategy Remains Elusive. PMID- 29526656 TI - Systematic review and meta-analysis in GI endoscopy: Why do we need them? How can we read them? Should we trust them? PMID- 29526657 TI - Effect of striatal dopamine depletion on cognition in de novo Parkinson's disease. AB - INTRODUCTION: To investigate the relationship between the sub-regional pattern of striatal dopamine depletion and cognitive impairment in early-stage Parkinson's disease (PD), and determine the effect of striatal dopamine density on cognitive prognosis. METHODS: Patients with drug-naive non-demented PD were divided into mild cognitive impairment (PD-MCI; n = 129) and cognitively normal (PD-CogN; n = 182) groups. Using quantification of the dopamine transporter (DAT) availability in each striatal sub-region with 18F-FP-CIT PET scans, we performed inter-group comparative analysis of DAT availability and multivariate linear regression analysis to assess the association between DAT availability and cognitive performance. Additionally, the effect of baseline DAT availability on the cognitive decline across time as well as on changes in the cognitive status was estimated. RESULTS: The PD-MCI group exhibited more severely decreased DAT availability in all the striatal sub-regions compared to the PD-CogN group, although there was no significant difference in PD duration. The DAT availability in the caudate, anterior putamen, and ventral striatum was directly associated with attention/working memory, frontal/executive, and visuospatial functions, while the DAT availability of the posterior putamen was not. However, the baseline DAT availability of the striatal sub-regions did not influence the cognitive decline or cognitive status in the longitudinal cognitive assessment. CONCLUSION: Our results suggest that striatal DAT availability may determine MCI in patients with de novo PD. Dopamine loss in the associative and limbic striatum is closely linked to cognitive deficits in early-stage PD, although it does not affect cognitive prognosis. PMID- 29526658 TI - Long term outcomes of simple clinical risk stratification in management of differentiated thyroid cancer. AB - OBJECTIVE: To establish the long term outcomes of risk stratified management of differentiated thyroid cancer (DTC). BACKGROUND: Guidelines for management of DTC lack a strong evidence base and expose patients to overtreatment. This prospective study of patients diagnosed with DTC between 1977 and 2012 describes the long term outcomes of a conservative risk stratified (AMES) management policy. METHODS: Outcomes were analysed around patient and tumour characteristics, primary intervention (surgery +/- radioiodine (RAI)), in terms of mortality, recurrence and reintervention. RESULTS: Median follow-up in 348 patients was 14 years: mean age 48 (range 10-91) years, 257 (73.9%) female, 222 (68.3%) papillary cancer, tumour size 3.4 +/- 2.0 cm (mean +/- SD). 89 (25.6%) AMES high risk, 116 (33.3%) TNM stage III/IV and 16 (4.6%) had distant metastases. Primary surgery comprised lobectomy in 189 (54.3%): 11 (5.8%) patients had subsequent completion total thyroidectomy with cancer present in five. Primary nodal surgery was performed in 142 (40.8%) patients. 35 (13.5%) low and 43 (48.3%) high risk patients received RAI following initial surgery. Overall disease specific survival (DSS) was 92.1% at 10 years and 90.7% at 20 years. DSS at 20 years was 99.2% in low risk cases. AMES risk scoring predicted both survival and recurrence. Patients receiving RAI and AMES high risk were significantly associated with increased risk of death and recurrence. CONCLUSIONS: Routine total thyroidectomy and RAI are not justifiable for low risk DTC. Treatment should be tailored to risk and AMES risk stratification remains a simple reliable clinical tool. PMID- 29526659 TI - Capnographic identification of end-expiratory flow limitation. AB - Patients with end-expiratory flow limitation (eEFL) demonstrate a terminal rise in capnography slope. The high slope could represent phase 5, a phenomenon described for single breath N2 tests but previously unreported during capnography. This study evaluated 6 healthy subjects exhaling from total lung capacity to residual volume at several set constant rates. We measured the volumes of flow limitation (VFL) and phase 5 (VP5) for CO2 and N2. A distinct phase 5 occurred shortly after eEFL for both gases. Increased expiratory flow rate resulted in parallel increases in VFL and VP5. The two quantities differed on average by the volume of dead space. These data suggest that phase 5 on capnography identifies eEFL with a small delay resulting from transit of expired gas through dead space. Following phase 5 by volumetric capnography could be useful for monitoring anesthetized patients, who in some circumstances may have lung volumes close to residual volume. eEFL could be treated with lung volume increasing maneuvers, such as positive end-expiratory pressure. PMID- 29526660 TI - Modulation-demodulation hypothesis of periodic breathing in human respiration. AB - Periodic breathing (PB) is a diseased condition of the cardiorespiratory system, and mathematically it is modelled as an oscillation. Modeling approaches replicate periodic oscillation in the minute ventilation due to a higher than normal gain of the feedback signals from the chemoreceptors coupled with a longer than normal latency in feedback, and do not consider the waxing-waning pattern of the oronasal airflow. In this work, a noted regulation model is extended by integrating respiratory mechanics and respiratory central pattern generator (rCPG) model, using modulation-demodulation1 hypothesis. This is a top-down modeling approach, and it is assumed that the sensory feedback signal from the chemoreceptors modulates the output of the rCPG model. It is also assumed that the brainstem network is responsible for the demodulation process. The respiratory mechanics is modeled as a multi-input multi-output (MIMO) system, where modulated and demodulated neural signals are applied as input and the minute ventilation and the oronasal airflow are specified as output. The minute ventilation signal drives the regulation model, completing the feedback loop. The proposed model is validated by comparing the model output with the clinical data. Using the modulation-demodulation hypothesis, a respiratory mechanics model is formulated in the form of a linear state-space model, which can be useful for providing assisted ventilation in clinical conditions. PMID- 29526661 TI - Mobile Apps for the Dietary Approaches to Stop Hypertension (DASH): App Quality Evaluation. AB - OBJECTIVE: To identify the availability and quality of apps supporting Dietary Approaches to Stop Hypertension (DASH) education. METHODS: The researchers identified DASH apps over 1 month in the Apple App Store. Five registered dietitians used the App Quality Evaluation (AQEL) to evaluate app quality on 7 domains. Interrater reliability was tested using intraclass correlations. RESULTS: One paid and 3 free DASH apps were evaluated. Interrater reliability (n = 5) was good for 3 apps and fair for 1 app. Only the paid app scored high (>8 of 10) on most AQEL quality domains. CONCLUSIONS AND IMPLICATIONS: Based on lower quality found among the included free apps, further development of free apps is warranted. Whereas the paid app may be useful in supporting DASH education, future research should determine whether improvements in clinical outcomes are found and whether this app should be improved to address AQEL domains better. PMID- 29526662 TI - Administration of temozolomide: Comparison of conventional and metronomic chemotherapy regimens. AB - PURPOSE: We compare the Maximum Tolerated Dose (MTD) and Metronomic Chemotherapy (MC) protocols for temozolomide administration. We develop an innovative methodology for characterizing optimal chemotherapy regimens. METHODS: We use a PK/PD model based on Faivre et al. (2013) for the pharmacokinetics of temozolomide, as well as the pharmacodynamics of its efficacy. For toxicity, which is measured by the nadir of the normalized absolute neutrophil count, we formalize the myelosuppression effect of temozolomide with the physiological model of Panetta et al. (2003b). We introduce a multi-criteria tool for comparing protocols along their efficacy and toxicity dimensions. RESULTS: We show that the toxicity of the MC regimen proposed by Faivre et al. (2013) can greatly be reduced without affecting its efficacy, while the standard MTD protocol efficacy cannot be improved without impairing its toxicity. We also show that for any acceptable toxicity level, the optimal protocol remains closely related to standard MTD. CONCLUSIONS: Overall, our new method enables a rich comparison between protocols along multiple dimensions. We can rank protocols for temozolomide administration. It is a first step toward building optimal individual protocols. PMID- 29526663 TI - What causes the spatial heterogeneity of bacterial flora in the intestine of zebrafish larvae? AB - Microbial flora in the intestine has been thoroughly investigated, as it plays an important role in the health of the host. Jemielita et al. (2014) showed experimentally that Aeromonas bacteria in the intestine of zebrafish larvae have a heterogeneous spatial distribution. Although bacterial aggregation is important biologically and clinically, there is no mathematical model describing the phenomenon and its mechanism remains largely unknown. In this study, we developed a computational model to describe the heterogeneous distribution of bacteria in the intestine of zebrafish larvae. The results showed that biological taxis could cause the bacterial aggregation. Intestinal peristalsis had the effect of reducing bacterial aggregation through mixing function. Using a scaling argument, we showed that the taxis velocity of bacteria must be larger than the sum of the diffusive velocity and background bulk flow velocity to induce bacterial aggregation. Our model and findings will be useful to further the scientific understanding of intestinal microbial flora. PMID- 29526664 TI - A systematic review of measures of medication adherence in consumers with unipolar depression. AB - OBJECTIVE: To identify and evaluate the range of adherence measures used to assess different phases of medication adherence (initiation, implementation, and discontinuation) to antidepressants, including the psychometric properties of the measures. METHODS: This systematic review followed the PRISMA statement. Medline, Embase, International Pharmaceutical Abstracts, CINAHL and PsychINFO were searched (1994-2015) for articles which reviewed or reported the psychometric properties of adherence measures in adults with unipolar depression without co morbidity. Included articles were reviewed for the reliability and validity of their adherence measures. RESULTS: 26 studies met the inclusion criteria. Most assessed medication adherence at implementation and/or discontinuation phases. Self-report measures were the most frequently used, followed by electronic lid devices and pharmacy records. Standardized self-report measures such as Morisky, Green, and Levine Self-Reported Medication Taking Scale (MGLS) and Antidepressant Adherence Scale (AAS) demonstrated acceptable reliability and validity, while medication claims data showed good reliability as a long-term measure. CONCLUSIONS: Although the psychometric properties of various measures have been evaluated across the three phases of adherence, a standout measure with strong reliability and validity was not apparent. No single measure demonstrated reliability and validity throughout the adherence process. A range of different subjective and objective adherence measures is recommended to assess medication adherence across the different phases. PMID- 29526666 TI - Hysteroscopic Management of Endometrial Smooth Muscle Metaplasia: A Rare Cause of Abnormal Uterine Bleeding. PMID- 29526665 TI - The metabolic capacity of lipid droplet localized acyl-CoA synthetase 3 is not sufficient to support local triglyceride synthesis independent of the endoplasmic reticulum in A431 cells. AB - ACSL3 is the only long chain fatty acyl-CoA synthetase consistently found on growing and mature lipid droplets (LDs), suggesting that this specific localization has biological relevance. Current models for LD growth propose that triglycerides are synthesized by enzymes at the LD surface, with activated fatty acids provided by LD localized ACSL3, thus allowing growth independent of the ER. Here, we tested this hypothesis by quantifying ACSL3 on LDs from human A431 cells. RNAi of ACSL3 reduced the oleoyl-CoA synthetase activity by 83%, suggesting that ACSL3 is by far the dominant enzyme of A431 cells. Molar quantification revealed that there are 1.4 million ACSL3 molecules within a single cell. Metabolic labeling indicated that each ACSL3 molecule contributed a net gain of 3.1 oleoyl-CoA/s. 3D reconstruction of confocal images demonstrated that 530 individual lipid droplets were present in an average oleate fed A431 cell. A representative single lipid droplet with a diameter of 0.66 MUm contained 680 ACSL3 molecules on the surface. Subcellular fractionation showed that at least 68% of ACSL3 remain at the ER even during extensive fatty acid supplementation. High resolution single molecule microscopy confirmed the abundance of cytoplasmic ACSL3 outside of LDs. Model calculations for triglyceride synthesis using only LD localized ACSL3 gave significant slower growth of LDs as observed experimentally. In conclusion, although ACSL3 is an abundant enzyme on A431 LDs, the metabolic capacity is not sufficient to account for LD growth solely by the local synthesis of triglycerides. PMID- 29526667 TI - In vitro performance of the DIAGNOcam for detecting proximal carious lesions adjacent to composite restorations. AB - OBJECTIVES: To assess the accuracy of near-infrared-light transillumination (DIAGNO) compared to visual-tactile (VT) and radiographic (RA) evaluation of proximal carious lesions adjacent to composite restorations in vitro. METHODS: Two hundred extracted posterior permanent human teeth with occluso-proximal composite restorations were allocated to 50 groups of four posterior teeth, and mounted in a pilot-tested diagnostic model in a dummy head. The teeth were independently assessed by two examiners. Transverse microradiography and visual assessment served as reference tests to detect any lesions (prevalence 24%) and cavitated lesions (18%), respectively, adjacent to restorations. Sensitivity, specificity, positive and negative predictive values and the area under the receiver-operating-characteristics curve (AUC) were calculated. RESULTS: To detect any proximal carious lesions adjacent to composite, the mean sensitivity/specificity were 0.63/0.95 for DIAGNO, 0.70/0.88 for RA when lesions radiographically extending into enamel and dentin were considered, 0.26/0.98 for RA when only lesions extending into dentin were considered, and 0.31/0.96 for VT. For cavitated lesions adjacent to proximal composite restorations, these values were RA (enamel and dentin) 0.84/0.88, RA (dentin) 0.34/0.99, DIAGNO 0.69/0.94 and VT 0.40/0.97. AUC did not differ significantly between RA and DIAGNO, while VT showed significantly lower values (p < 0.05). CONCLUSION: Within the limitations of this study, DIAGNO seems useful for detecting proximal carious lesions adjacent to restorations. CLINICAL RELEVANCE: Near-infrared-light transillumination could be used as a radiation-free adjunct or alternative to RA for detecting carious lesions adjacent to composite restorations. PMID- 29526668 TI - Novel rechargeable calcium phosphate nanocomposite with antibacterial activity to suppress biofilm acids and dental caries. AB - OBJECTIVE: Rechargeable calcium phosphate (CaP) composites were developed recently. However, none of the rechargeable CaP composites was antibacterial. The objectives of this study were to develop the first rechargeable CaP composite that was antibacterial, and to investigate the effects of adding dimethylaminohexadecyl methacrylate (DMAHDM) into rechargeable CaP composite on ion rechargeability and re-release as well as biofilm properties. METHODS: DMAHDM was synthesized via a Menschutkin reaction. Nanoparticles of amorphous calcium phosphate (NACP) were synthesized using a spray-drying technique. The resin contained ethoxylated bisphenol A dimethacrylate (EBPADMA) and pyromellitic glycerol dimethacrylate (PMGDM). Two composites were fabricated: rechargeable NACP composite, and rechargeable NACP-DMAHDM composite. Mechanical properties and ion release and recharge were measured. A dental plaque microcosm biofilm model using saliva was tested. RESULTS: Flexural strength and elastic modulus of rechargeable NACP and NACP-DMAHDM composites matched commercial control composite (p > 0.1). NACP-DMAHDM inhibited biofilm metabolic activity and lactic acid, and reduced biofilm colony-forming units (CFU) by 3-4 log. NACP and NACP-DMAHDM showed similar Ca and P ion recharge and re-release (p > 0.1). Therefore, adding DMAHDM did not compromise the ion rechargeability. One recharge yielded continuous release for 42 d. The release was maintained at the same level with increasing number of recharge cycles, indicating long-term ion release and remineralization capability. CONCLUSIONS: The first CaP rechargeable and antibacterial composite was developed. Adding DMAHDM into the rechargeable NACP composite did not adversely affect the Ca and P ion release and recharge, and the composite had much less biofilm growth and lactic acid production, with CFU reduction by 3-4 log. CLINICAL SIGNIFICANCE: This novel CaP rechargeable composite with long-term remineralization and antibacterial properties is promising for tooth restorations to inhibit caries. PMID- 29526670 TI - [Cardiovascular disease in lupus nephritis: An underestimated risk]. PMID- 29526669 TI - Chronic Pain, TBI, and PTSD in Military Veterans: A Link to Suicidal Ideation and Violent Impulses? AB - : The polytrauma clinical triad refers to the co-occurrence of chronic pain, traumatic brain injury (TBI), and posttraumatic stress disorder (PTSD). Despite research implicating dyadic relationships between these conditions and adverse outcomes, scant research has examined the polytrauma clinical triad's relation to suicide or violence. The present cross-sectional study was designed to examine whether this complex clinical presentation increases risk of suicidal ideation and violent impulses after accounting for other established risk factors. Veterans who served in the military since September 11, 2001 (N = 667) who reported chronic pain completed an interview and self-report battery. Bivariate analyses showed that suicidal ideation and violent impulses both correlated with PTSD, TBI+PTSD, pain intensity and interference, drug abuse, and major depressive disorder (MDD). Multiple regression analyses showed that: 1) race, chronic pain with PTSD, alcohol abuse, and MDD significantly predicted suicidal ideation, 2) pain interference, chronic pain with TBI, chronic pain with PTSD, chronic pain with TBI+PTSD, drug abuse, and MDD significantly predicted violent impulses, and 3) pain interference was a more critical predictor of suicidal and violent ideation than pain intensity. Implications for risk assessment and treatment are discussed. PERSPECTIVE: This article presents results from a study examining predictors of suicide and violence risk among a sample of post-9/11 U.S. Veterans with chronic pain. Health care professionals should assess for pain interference, TBI, PTSD, depression, and alcohol/drug abuse when conducting risk assessments with this population. PMID- 29526671 TI - Response to Paired Editorial. PMID- 29526672 TI - Prediction of type 2 diabetes remission after metabolic surgery: a comparison of the individualized metabolic surgery score and the ABCD score. AB - BACKGROUND: Metabolic surgery has become increasingly accepted for the treatment of type 2 diabetes (T2D). However, there is limited evidence regarding the optimal candidate and surgical procedure. Although a new individualized metabolic surgery (IMS) score was recently proposed for procedure selection, it has yet to be validated. OBJECTIVE: To validate the IMS score with regard to remission of T2D after metabolic surgery and compare it with the age, body mass index, C peptide level, and duration of T2D (ABCD) score. SETTING: Hospital-based bariatric center. METHODS: A total of 310 T2D patients who underwent gastric bypass and sleeve gastrectomy at an academic center in Taiwan and had a minimum 5 year follow-up (2004-2012) were examined for the predictive power of complete remission using the IMS and the ABCD scoring systems. RESULTS: At the 5-year follow-up, weight loss was 27.5%, with mean body mass index decreasing from 37.8 to 27.9 kg/m2, mean glycated hemoglobin decreased from 8.6% to 6.1%, and prolonged remission of T2D achieved in 224 (72.3%) T2D patients. Remission rates were higher in patients who underwent gastric bypass than in those who underwent sleeve gastrectomy (73.6% versus 66.1%; P = .04), regardless of T2D severity, and were 96%, 68%, and 16% in patients with IMS mild, moderate, and severe scores, respectively. Although both scores predicted the success of surgery, the ABCD was better in patients with IMS moderate scores. CONCLUSION: Metabolic surgery is an option for T2D patients with obesity. The ABCD score may be better at predicting T2D remission after metabolic surgery compared with the IMS score. PMID- 29526673 TI - Are we really assessing safety and efficacy of bariatric surgery in patients suffering from bipolar disorder? PMID- 29526674 TI - Defining permissible limits for the combined uncertainty budget in the implementation of metrological traceability. AB - In addition to the correct implementation of calibration traceability, the definition and the achievement of an appropriate analytical performance specification for the total uncertainty budget (GU) is essential to ensure that laboratory measurements are clinically usable. To understand if it is possible to fulfil these specifications, limits for combined uncertainty across the entire metrological traceability chain should be defined. We recommended that no more than one third of GU should be consumed by the uncertainty of higher order references and <=50% of GU by the combined measurement uncertainty at the manufacturer's calibration level. The remaining allowable uncertainty should be available for random sources, i.e. for the imprecision of the commercial measuring system (including the reagent batch-to-batch variation) and the individual laboratory performance, as a safety margin to fulfil GU. Based on this approach, it is of interest to assess for each analyte measured in the clinical laboratory the status of the uncertainty budget of its measurement associated with the selected metrological traceability chain. Accordingly, we report three didactic cases that could occur in the clinical practice. This approach is very helpful to identify those analytes for which further technological improvements are probably needed to reduce uncertainty associated with their measurement. PMID- 29526675 TI - Glycosylated and non-glycosylated NT-IGFBP-4 in circulation of acute coronary syndrome patients. AB - BACKGROUND: N-terminal and C-terminal proteolytic fragments of IGF binding protein 4 (NT-IGFBP-4 and CT-IGFBP-4) were recently shown to predict adverse cardiac events in acute coronary syndrome (ACS) patients. NT-IGFBP-4 and CT-IGFBP 4 are products of the pregnancy-associated plasma protein-A (PAPP-A)-mediated cleavage of IGFBP-4. It has been demonstrated that circulating IGFBP-4 is partially glycosylated in its N-terminal region, although the influence of this glycosylation on PAPP-A-mediated proteolysis and the ratio of glycosylated/non glycosylated IGFBP-4 fragments in human blood remain unrevealed. The aims of this study were to investigate i) the presence of glycosylated NT-IGFBP-4 in the circulation, ii) the influence of the glycosylation of IGFBP-4 on its susceptibility to PAPP-A-mediated cleavage, and iii) the influence of glycosylation on NT-IGFBP-4 immunodetection. METHODS: Affinity purification was used for the extraction of IGFBP-4 and NT-IGFBP-4 from plasma samples. Purified proteins were quantified by Western blotting and specific sandwich immunoassays, while molecular masses were determined using mass spectrometry. RESULTS: Glycosylated NT-IGFBP-4 was identified in the blood of ACS patients. The fraction of glycosylated NT-IGFBP-4 in individual plasma samples was 9.8%-23.5% of the total levels of NT-IGFBP-4. PAPP-A-mediated proteolysis of glycosylated IGFBP-4 was 3-4 times less efficient (p < 0.001) than proteolysis of non-glycosylated protein. A sandwich fluoroimmunoassay that was designed for quantitative NT-IGFBP 4 measurements recognized both protein forms with the same efficiency. CONCLUSIONS: Although glycosylation suppresses PAPP-A-mediated IGFBP-4 cleavage, a considerable amount of glycosylated NT-IGFBP-4 is present in blood. Glycosylation does not influence NT-IGFBP-4 measurements using a specific sandwich immunoassay. PMID- 29526676 TI - Livedoid vasculopathy in a patient with bullous pemphigoid and primary Sjogren's syndrome. PMID- 29526677 TI - Epithelial Paradox: Clinical Significance of Coexpression of E-cadherin and Vimentin With Regard to Invasion and Metastasis of Breast Cancer. AB - BACKGROUND: E-cadherin and vimentin are regarded as major conventional canonical markers of the epithelial-mesenchymal transition. It is commonly assumed that E cadherin is uniformly lost during the process of epithelial-mesenchymal transition. Breast tumor cells typically invade as a cohesive multicellular unit in a process called collective invasion. The aim of this study was to reveal the clinical importance of the expression pattern of E-cadherin and vimentin in breast cancer. METHODS: E-cadherin and vimentin protein expression was evaluated by immunohistochemistry in 176 invasive breast cancer samples. Among these, E cadherin and vimentin expression were evaluated in the set of primary site and metastatic lymph nodes in 65 cases. In addition, E-cadherin and vimentin expression were analyzed by confocal laser scanning microscopy to see E-cadherin and vimentin localization in the breast cancer cells. RESULTS: Both at the primary site and metastatic lymph nodes, both E-cadherin- and vimentin-positive tumors had the worst disease-free and overall survival among all cases. In addition, E-cadherin and vimentin protein is colocalized within the same tumor cells in a human breast cancer specimen. CONCLUSION: Our present data suggest the existence of an aggressive subpopulation in the primary tumor nest of breast cancer. PMID- 29526678 TI - Physiologic response to pre-arrest bolus dilute epinephrine in the pediatric intensive care unit. AB - AIM: To quantify the physiologic effects of pre-arrest bolus dilute epinephrine in the pediatric intensive care unit. METHODS: Patients <18 years old and >=37 weeks gestation who received an intravenous bolus of dilute epinephrine (10 mcg/mL) in the pediatric intensive care units at our institution from January 2011 to March 2017 were retrospectively identified. Patients were excluded if doses exceeded 20 mcg/kg, or under the following circumstances: orders limiting resuscitation, extracorporeal membrane oxygenation, active chest compressions, simultaneous administration of other blood pressure-altering interventions or documented normotension prior to epinephrine. The primary outcome was change in systolic blood pressure within 5 min of epinephrine. Patients were categorized as non-responders if the change in systolic blood pressure was <=10 mmHg. RESULTS: One hundred forty-four patients were analyzed. The median index dose was 0.7 mcg/kg (IQR, 0.3-2.0), and the mean increase in systolic blood pressure was 31 mmHg (95% CI, 25-36; P < 0.001). Thirty-nine (27%) patients were classified as non-responders. Compared to responders, non-responders had higher rates of cardiac arrest or extracorporeal membrane oxygenation within 6 h (26% vs 10%; relative risk, 2.69; 95% CI, 1.21-5.97; P = 0.03), and had higher in-hospital mortality (51% vs 21%; relative risk, 2.45; 95% CI, 1.51-3.96; P < 0.001). CONCLUSIONS: In the majority of pre-arrest pediatric patients, bolus dilute epinephrine resulted in an increase in systolic blood pressure, and lack of blood pressure response was associated with poor outcomes. Optimal dosing of dilute epinephrine remains unclear. PMID- 29526679 TI - Impact of cancer diagnosis on persistence of oral antidiabetic drugs. AB - AIMS: The purpose of this study was to determine the effects of cancer occurrence on persistence of oral antidiabetic drugs (OAD) in France. METHODS: A retrospective cohort including incident OAD users between 2006 and 2011 was set up using a permanent sample of health insurance beneficiaries (Echantillon Generaliste de Beneficiaires, EGB). A Cox model was used to assess the association between cancer occurrence and OAD persistence. Non-persistence was defined as a gap in OAD treatment coverage between the end of a given prescription and a new one greater than or equal to 90 days. Cancer occurrence was studied as a time-dependent variable. RESULTS: The study included 13,943 OAD users. Median follow-up was 760 days. After adjustment for age, sex, first OAD used, type of prescriber and polypharmacy, non-persistence risk was higher after a diagnosis of cancer: (HR: 1.93 and IC 95% 1.69; 2.21). Subgroup analyses according to cancer localization found a higher risk of non-persistence for lung cancer (HR: 2.66 and IC 95% 1.68; 4.23) and colorectal cancer (HR: 2.02 and IC 95% 1.40; 2.91). CONCLUSIONS: Our findings indicate there is an association between cancer diagnosis and OAD non-persistence. Additional studies of this type would be useful to evaluate the association between cancer diagnosis and persistence of treatment of other chronic diseases. PMID- 29526680 TI - Endothelial dysfunction of coronary arteries in subjects without diabetes: An association with both insulin resistance and impaired insulin secretion response. AB - AIMS: This study was aimed to compare insulin sensitivity and secretion response, lipoprotein and plasminogen activator inhibitor 1 (PAI-1) levels between the subjects with and without coronary artery endothelial dysfunction (ED). METHODS: ED was detected by intracoronary injection of acetylcholine (ACh) in 47 nondiabetes subjects without stenotic coronary arteries, selected from 316 consecutive patients with coronary angiography performed for suspected coronary artery disease. The subjects were divided into two groups: presence of ACh induced coronary spasm (group ED+, N = 30) and absence of ACh-induced coronary spasm (group ED-, N = 17). Insulin sensitivity (Si) was evaluated by frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis and by HOMA-IR, insulin secretion by acute insulin response (AIR) (calculated from the first 8 min of FSIGTT) and by disposition index (DI) (Si * AIR). Lipids and PAI-1 levels were determined enzymatically, and LDL particle size by gradient gel electrophoresis. RESULTS: Si was significantly lower (4.22 +/- 0.62 vs 6.98 +/- 1.47 min-1/mU/l * 104; p < 0.05) while HOMA-IR was significantly higher in ED + group vs ED- group (2.8 +/- 0.3 vs 1.7 +/- 0.2; p < 0.05). Simultaneously, AIR and DI was significantly lower in ED + vs ED- groups (p < 0.05 and p < 0.01, respectively). Investigated groups did not differ in fasting lipid levels but ED+ group had significantly smaller LDL particles (p < 0.01) and higher PAI-1 levels (p < 0.05). Regression analysis shown that DI was a strong independent predictor of appearance of ED, together with PAI-1 and LDL particle size. CONCLUSIONS: Both insulin resistance and impairment in insulin secretion response strongly correlate with coronary ED in subjects without diabetes. PMID- 29526681 TI - Sleep duration, obesity and insulin resistance in a multi-ethnic UK population at high risk of diabetes. AB - AIMS: Investigating the association between sleep duration, obesity, adipokines and insulin resistance (via Leptin:Adiponectin ratio (LAR)), in those at high risk of type 2 diabetes mellitus (T2DM). METHODS: Adults with impaired glucose regulation (IGR) were included. Fasting bloods for inflammatory biomarkers and glycaemic status, 2-h glucose, anthropometrics, objective physical activity, and self-reported sleep were collected. The average number of hours slept in a 24 h period was categorised as <=5.5, 6-6.5, 7-7.5, 8-8.5, and >=9 h. Regression models were fitted with sleep (linear and quadratic) and logistic regression used for IGR and adjusted for age, sex, ethnicity, body mass index, waist circumference and objective physical activity. RESULTS: 2848 participants included (593 with inflammatory marker data). Short sleep and long sleep duration were significantly independently associated with higher body mass index (P < 0.001), body weight (P < 0.01), and waist circumference (P < 0.001). 6-7 h of sleep/24 h is associated with the lowest obesity measures. Fasting insulin and LAR were positively associated with sleep duration. Adiponectin levels were negatively associated with sleep duration. CONCLUSIONS: These results support the evidence of an association between short and long sleep duration and indices of obesity. We demonstrate an independent relationship between long sleep duration and insulin resistance. PMID- 29526682 TI - The prevalence of gestational diabetes mellitus amongst black South African women is a public health concern. AB - AIMS: This study aimed to determine the prevalence of gestational diabetes mellitus (GDM) amongst black South African women, describe GDM-associated risk factors and clinical management, and evaluate the efficacy of the fasting plasma glucose reading in diagnosing GDM. METHODS: A cross-sectional screening study was performed. Pregnant women were recruited from the Chris Hani Baragwanath Academic Hospital in Johannesburg. A total of 1906 women underwent a two-hour 75 g oral glucose tolerance test at 24-28 weeks gestation. The World Health Organization's 2013 criteria were used to diagnose GDM. RESULTS: A total of 174/1906 (9.1% (95% confidence interval (CI) 7.9, 10.5)) women were diagnosed with GDM. These women had significantly higher weights and body mass indexes (BMIs), were significantly older, of higher household socioeconomic status, more likely to report a family history of diabetes, and more likely to be diagnosed with anaemia than women without GDM. An age of >=35 years, BMI >= 30 kg/m2, and a family history of diabetes were significant risk factors. The fasting plasma glucose reading had a high sensitivity (83.3% (95% CI 77.0, 88.5)) in diagnosing GDM and 56.9% of the women with GDM were managed by diet therapy alone. CONCLUSION: This is the largest GDM prevalence study in South Africa to date. A diagnosis of GDM increases the risk of both mother and child developing Type 2 diabetes which causes further health complications, decreases longevity, and burdens a country's healthcare system. Therefore, a GDM prevalence of 9.1% is concerning and warrants further discussion around current GDM screening policies. PMID- 29526683 TI - Hyperglycemia in pregnancy among South Asian women: A single tertiary care center experience from Colombo, Sri Lanka. AB - AIM: To study case mix, risk factors, adverse outcomes and associations of hyperglycemia in pregnancy in a cohort of Sri Lankans. METHODS: Prospective observational study, from April 2011-October 2015 at a tertiary care referral center, Colombo, Sri Lanka. Data from first trimester to delivery of HIP was analyzed. Three subgroups were defined: Diabetes in pregnancy (DIP), Hyperglycemia in early Pregnancy (HIEP) [<24 weeks] and Gestational diabetes (GDM) [>24 weeks]. RESULTS: Of 782 patients 572 (73.1%) had complete data. Case mix: 137(24.0%) DIP, 331(57.9%) GDM and 104 (18.2%) HIEP. Primigravidae commoner in GDM (<0.05). DIP older - mean 33.3 +/- 5.5 years (<0.01). Previous GDM commoner and pharmacological interventions needed in DIP and HIEP. Majority GDM (66.8%) required Medical Nutrition Therapy (MNT) alone. There was no difference in pregnancy outcomes between the 3 subgroups. Macrosomia significantly greater in HIEP (33.7%); neonatal cardiac defects more in DIP and HIEP. CONCLUSIONS: Increasing maternal age is a significant risk for DIP, while previous GDM is a risk for DIP and HIEP and neonatal congenital cardiac defects in subsequent pregnancies of South Asian women. We recommend preconception screening for glucose intolerance and achieving normoglycaemia among South Asian women with advanced maternal age and previous GDM. PMID- 29526684 TI - Beneficial effect of baicalin on insulin sensitivity in adipocytes of diet induced obese mice. AB - AIMS: Although baicalin has been shown to increase glucose uptake and insulin sensitivity in skeletal muscle of mice, there is no literature available about the effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice. METHODS: In the present study, diet-induced obese mice were given 50 mg/kg baicalin intraperitoneally (i.p.) once a day for 21 days, and 3T3-L1 cells were treated with 100, 200, 400 MUM baicalin for 3 h. Then insulin resistance indexes and insulin signal protein levels were examined to elucidate whether baicalin increased glucose uptake and GLUT4 translocation in adipocytes of diet-induced obese mice. RESULTS: The present findings showed that administration of baicalin decreased food intake, body weight, HOMA-IR and p-p38 MAPK and pERK levels, but enhanced pAKT and PGC-1alpha contents, as well as GLUT4 mRNA, PGC-1alpha mRNA expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalin treatment increased GLUT4 concentration in plasma membranes of adipocytes. CONCLUSIONS: These data demonstrated that baicalin accelerated GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. Baicalin plays a significant role in elevation of glucose uptake and insulin sensitivity to promote glucose clearance. PMID- 29526685 TI - Murine remote preconditioning increases glucose uptake and suppresses gluconeogenesis in hepatocytes via a brain-liver neurocircuit, leading to counteracting glucose intolerance. AB - AIMS: Our previous study revealed that cyclic hindlimb ischaemia-reperfusion (IR) activates cardiac acetylcholine (ACh) synthesis through the cholinergic nervous system and cell-derived ACh accelerates glucose uptake. However, the mechanisms regulating glucose metabolism in vivo remain unknown. We investigated the effects and mechanisms of IR in mice under pathophysiological conditions. METHODS: Using IR-subjected male C57BL/6J mice, the effects of IR on blood sugar (BS), glucose uptake, central parasympathetic nervous system (PNS) activity, hepatic gluconeogenic enzyme expression and those of ACh on hepatocellular glucose uptake were assessed. RESULTS: IR decreased BS levels by 20% and increased c-fos immunoreactivity in the center of the PNS (the solitary tract and the dorsal motor vagal nucleus). IR specifically downregulated hepatic gluconeogenic enzyme expression and activities (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) and accelerated hepatic glucose uptake. Transection of a hepatic vagus nerve branch decreased this uptake and reversed BS decrease. Suppressed gluconeogenic enzyme expression was reversed by intra-cerebroventricular administration of a choline acetyltransferase inhibitor. Moreover, IR significantly attenuated hyperglycaemia in murine model of type I and II diabetes mellitus. CONCLUSIONS: IR provides another insight into a therapeutic modality for diabetes mellitus due to regulating gluconeogenesis and glucose-uptake and advocates an adjunctive mode rectifying disturbed glucose metabolism. PMID- 29526686 TI - Percutaneous Closure of Pseudoaneurysm After Rastelli Surgery. PMID- 29526687 TI - Correlation between venous pressure gradients and intravascular ultrasound in the diagnosis of iliac vein compression syndrome. AB - OBJECTIVE: The objective of this study was to evaluate the correlation between venous pressure gradients (VPGs) and intravascular ultrasound (IVUS) for the diagnosis of caval-iliac venous obstructions in patients with advanced chronic venous insufficiency. METHODS: Fifty patients with advanced chronic venous insufficiency symptoms (Clinical, Etiology, Anatomy, and Pathophysiology class 3 to 6) were prospectively submitted to multiplanar venography (MV) with intravenous pressure measurements and IVUS. The patients' lower limbs were divided accordingly: group I, limbs with <50% obstruction on IVUS (n = 49); and group II, limbs with >=50% obstruction on IVUS (n = 51). Receiver operating characteristic curves compared the diagnostic performance of the VPGs. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy assessed the performance of VPGs in categories to determine the presence of significant obstruction. Logistic regression assessed the capacity of the VPGs to identify significant obstruction. RESULTS: The most frequent point of venous compression according to IVUS was the proximal left common iliac vein (70%; P < .05). Group II showed a greater prevalence of transpelvic (group I, 8.2%; group II, 74.5%; P < .001) and paravertebral collaterals (group I, 4.1%; group II, 45.1%; P < .001) on MV. The femoral vein pressures at rest and after reactive hyperemia as well as the femorocaval gradient after reactive hyperemia (FCG-rh) and the femoral gradient after reactive hyperemia were significantly higher in group II (P = .001, P < .001, P = .002, and P = .006). The FCG-rh and the femoral gradient after reactive hyperemia presented the best diagnostic performance among the VPGs (P = .004 and P = .007) in the receiver operating characteristic curve analysis, although no significant differences between them were found. All the gradients presented low values of sensitivity (<40%), negative predictive value (<60%), and accuracy (<30%). Logistic regression showed that FCG-rh was significantly independent of MV (OR, 8.1; P = .011) in identifying significant obstructions. CONCLUSIONS: There is correlation between the VPGs and significant obstructions with IVUS. However, this correlation does not translate to a good diagnostic performance of these VPGs. Only the FCG-rh added significant information to MV in identifying significant caval-iliac vein obstructions. PMID- 29526689 TI - Brain Response to Injuries: When Microglia Go Sexist. AB - Microglia are the principle immune cells of the brain. Once activated, microglial cells may exhibit a wide repertoire of the context-dependent profiles ranging from highly neurotoxic to more protective and pro-regenerative cellular phenotypes. While to date the mechanisms involved in the molecular regulation of the microglia polarization phenotypes remain elusive, growing evidence suggests that gender may markedly affect the inflammatory and/or glial responses following brain injuries. In the recent years, special attention has been given to the role of microglia in sexual dimorphism, both in healthy brain and diseased brain. Here, we review recent advances revealing microglia as an important determinant of gender differences under physiological conditions and in injured brain. We also discuss how microglia-driven innate immunity and signaling pathways might be involved in the sex-dependent responses following brain ischemic injury. Finally we describe how advanced methods such as live imaging techniques may help elucidate the role of microglia in the modulation of immune responses and gender difference after stroke. PMID- 29526688 TI - The Lipase Activity of Phospholipase D2 is Responsible for Nigral Neurodegeneration in a Rat Model of Parkinson's Disease. AB - Phospholipase D2 (PLD2), an enzyme involved in vesicle trafficking and membrane signaling, interacts with alpha-synuclein, a protein known to contribute in the development of Parkinson disease (PD). We previously reported that PLD2 overexpression in rat substantia nigra pars compacta (SNc) causes a rapid neurodegeneration of dopamine neurons, and that alpha-synuclein suppresses PLD2 induced nigral degeneration (Gorbatyuk et al., 2010). Here, we report that PLD2 toxicity is due to its lipase activity. Overexpression of a catalytically inactive mutant (K758R) of PLD2 prevents the loss of dopaminergic neurons in the SNc and does not show signs of toxicity after 10 weeks of overexpression. Further, mutant K758R does not affect dopamine levels in the striatum. In contrast, mutants that prevent PLD2 interaction with dynamin or growth factor receptor bound protein 2 (Grb2) but retained lipase activity, continued to show rapid neurodegeneration. These findings suggest that neither the interaction of PLD2 with dynamin, which has a role in vesicle trafficking, nor the PLD2 interaction with Grb2, which has multiple roles in cell cycle control, chemotaxis and activation of tyrosine kinase complexes, are the primary cause of neurodegeneration. Instead, the synthesis of phosphatidic acid (the product of PLD2), which is a second messenger in multiple cellular pathways, appears to be the key to PLD2 induced neurodegeneration. The fact that alpha-synuclein is a regulator of PLD2 activity suggests that regulation of PLD2 activity could be important in the progression of PD. PMID- 29526691 TI - Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas. AB - BACKGROUND & AIMS: Cellular and nuclear material from tumors disseminates into the bloodstream (tumoremia), but it is not clear whether medical procedures cause release of this material or contribute to formation of metastases. We performed a prospective study of blood samples from patients with pancreatic adenocarcinoma (PDAC) to determine whether endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) associates with markers of tumoremia. METHODS: We obtained peripheral blood from 104 patients (35 with PDAC) before and after EUS-FNA of primary tumors; blood samples from 69 healthy individuals were used as controls. Plasma concentrations of cell-free DNA (cfDNA) were measured, and cfDNA and primary tumor samples were analyzed to detect activating mutations in KRAS. Potential development of tumoremia was defined by an increase in cfDNA of 2-fold or more, and/or detection of mutant KRAS in samples collected after FNA from patients whose blood samples did not contain detectable mutant KRAS before FNA. RESULTS: Peripheral blood concentrations of cfDNA were 1200 ng/ml (500-3300 ng/ml) before FNA vs 1400 ng/ml (900-4000 ng/ml) after FNA (P = .391). Tumoremia was detected in 10/35 patients (28.6%): 7 patients had a >=2-fold increase in cfDNA concentration (20.6%) and 3 patients had circulating tumor DNA with KRAS mutations after FNA that were not detected before FNA (8.8%). New distant metastases were detected in 1.3 +/- 0.82 patients with tumoremia vs 0.64 +/- 0.81 without (P = .0375). Overall mortality did not differ significantly between patients with tumoremia (10/10 deaths, 100%) vs those without (19/25 deaths, 76%) nor did survival times of deceased patients (13.3 months for patients with tumoremia; range, 5.8-14.9 months vs 11.1 months for patients without tumoremia; range, 5.5-14.5 months). However, 6 patients without tumoremia were alive at a mean 23.9 months after EUS-FNA (range, 19.9-25 months after EUS-FNA) vs none of the patients with tumoremia. CONCLUSION: In patients with PDAC, EUS-FNA associates with increased plasma concentration of cfDNA and increased detection of mutant KRAS after the procedure (markers of tumoremia and possible new distant metastasis). Although levels of cfDNA and activating mutations in KRAS are logical markers of tumoremia, they may not serve as the ideal biomarkers of this process. These findings are preliminary and do not indicate a need to modify current practice, yet further studies are needed. PMID- 29526690 TI - Validation of refraction and anterior segment parameters by a new multi diagnostic platform (VX120). AB - BACKGROUND: The VX120 (Visionix Luneau, France) is a novel multi-diagnostic platform that combines Hartmann-Shack based autorefraction, Placido-disk based corneal-topography and anterior segment measurements made with a stationary Scheimpflug camera. We investigate the agreement between different parameters measured by the VX120 with accepted or gold-standard techniques to test if they are interchangeable, as well as to evaluate the repeatability and reproducibility. METHODS: The right-eyes of healthy subjects were included in the study. Autorefraction of the VX120 was compared to subjective refraction. Agreement of anterior segment parameters was compared to the Sirius (CSO, Italy) including autokeratometry, central corneal thickness (CCT), iridiocorneal angle (IA). Inter and intra-test repeatability of the above parameters was assessed. Results were analyzed using Bland and Altman analyses. RESULTS: A total of 164 eyes were evaluated. The mean difference between VX120 autorefraction and subjective refraction for sphere, spherical equivalent (SE), and cylinder was 0.01+/-0.43D, 0.14+/-0.47D, and -0.26+/-0.30D, respectively and high correlation was found to all parameter (r>0.75) except for J45 (r=0.61). The mean difference between VX120 and the Sirius system for CCT, IA, and keratometry (k1 and k2) was 3.51+/-8.64MUm, 7.6+/-4.2 degrees , 0.003+/-0.06mm and 0.004+/-0.04mm, respectively and high correlation was found to all parameter (r>0.97) except for IA (r=0.67). Intrasession repeatability of VX120 refraction, CCT, IA and keratometry yielded low within-subject standard deviations. Inter-session repeatability showed no statistically significant difference for most of the parameters measured. CONCLUSIONS: The VX120 provides consistent refraction and most anterior segment measurements in normal healthy eyes, with high levels of intra and inter-session repeatability. PMID- 29526692 TI - Rituximab Maintenance Therapy Reduces Rate of Relapse of Pancreaticobiliary Immunoglobulin G4-related Disease. AB - BACKGROUND & AIMS: IgG4-related disease (IgG4-RD), a multi-organ fibroinflammatory syndrome, typically responds to steroids. However, some cases are steroid resistant, and pancreaticobiliary IgG4-RD commonly relapses after steroid withdrawal. Rituximab induces remission of IgG4-RD, but the need for and safety of maintenance rituximab treatment are unknown. We compared outcomes of patients with pancreaticobiliary IgG4-RD treated with or without maintenance rituximab therapy. METHODS: We performed a retrospective study of patients with pancreaticobiliary IgG4-RD treated with rituximab at the Mayo Clinic in Rochester, Minnesota, from January 2005 through December 2015. The cohort was divided into patients who received only rituximab induction therapy (group 1, n = 14) and patients who received rituximab induction followed by maintenance therapy (group 2, n = 29). We collected data on recurrence of IgG4-RD symptoms and findings, as well as information on evaluations, treatment, and adverse events. RESULTS: Median follow-up times were similar between group 1 (34 mo) and group 2 (27 mo) (P = .99). Thirty-seven patients (86%) were in steroid-free remission 6 months after rituximab initiation. A higher proportion of patients in group 1 had disease relapse (3-year event rate, 45%) than in group 2 (3-year event rate, 11%) (P = .034). Younger age, higher IgG4 responder index score after induction therapy, and increased serum levels of alkaline phosphatase at baseline or after rituximab induction were associated with relapse. Infections developed in 6 of 43 patients, all in group 2 (P = .067 vs group 1); all but 1 occurred during maintenance therapy. CONCLUSIONS: In a retrospective study of patients with pancreaticobiliary IgG4-RD, we found rituximab maintenance therapy prolongs remission. Relapses are uncommon among patients receiving maintenance therapy, but maintenance therapy may increase risk of infection. Patients with factors that predict relapse could be candidates for rituximab maintenance therapy. PMID- 29526693 TI - Beverages containing low energy sweeteners do not differ from water in their effects on appetite, energy intake and food choices in healthy, non-obese French adults. AB - The usefulness of replacement of caloric sugars by low-calorie sweeteners (LCS) for weight management has been questioned on the grounds that the uncoupling of LCS sweet taste and dietary energy may confuse physiological mechanisms, leading potentially to higher energy and sugar intake. The aim of the present study was to determine whether LCS beverages compared to water, when consumed with meals, differ in their effects on energy and food intake in acute trials and after long term habituation. Ad libitum food intake of 166 (80 women; 86 men) healthy non obese adults (BMI between 19 and 28 kg/m2), infrequent consumers of LCS was measured in four 2-consecutive-day testing sessions (Day 1 in the laboratory, Day 2 free-living). During the first 3 sessions, held one-week apart, participants were required to drink either water or commercial non-carbonated LCS lemonade (330 ml) with their main meals (randomised cross-over design). On Day 1, motivational ratings were obtained using visual analogue scales and ad libitum food intakes (amounts and types of foods selected) were measured using the plate waste method. On Day 2, participants reported their ad libitum intakes using a food diary. After Session 3, participants were randomly assigned to the LCS habituation group or to the water control group. The habituation (660 ml LCS lemonade daily vs 660 ml water) lasted 5 weeks. The fourth and final test session measured food intakes and motivational ratings after habituation. Water and LCS beverage did not differ in their effects on total energy intake, macronutrient intakes or the selection of sweet foods and on motivational ratings. Similar results were obtained in both LCS-naive and LCS-habituated individuals. PMID- 29526694 TI - Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. AB - Under stress, certain eukaryotic proteins and RNA assemble to form membraneless organelles known as stress granules. The most well-studied stress granule components are RNA-binding proteins that undergo liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by intrinsically disordered low complexity domains (LCDs). Here we show that stress granules include proteasomal shuttle factor UBQLN2, an LCD-containing protein structurally and functionally distinct from RNA-binding proteins. In vitro, UBQLN2 exhibits LLPS at physiological conditions. Deletion studies correlate oligomerization with UBQLN2's ability to phase-separate and form stress-induced cytoplasmic puncta in cells. Using nuclear magnetic resonance (NMR) spectroscopy, we mapped weak, multivalent interactions that promote UBQLN2 oligomerization and LLPS. Ubiquitin or polyubiquitin binding, obligatory for UBQLN2's biological functions, eliminates UBQLN2 LLPS, thus serving as a switch between droplet and disperse phases. We postulate that UBQLN2 LLPS enables its recruitment to stress granules, where its interactions with ubiquitinated substrates reverse LLPS to enable shuttling of clients out of stress granules. PMID- 29526695 TI - The 3.5-A CryoEM Structure of Nanodisc-Reconstituted Yeast Vacuolar ATPase Vo Proton Channel. AB - The molecular mechanism of transmembrane proton translocation in rotary motor ATPases is not fully understood. Here, we report the 3.5-A resolution cryoEM structure of the lipid nanodisc-reconstituted Vo proton channel of the yeast vacuolar H+-ATPase, captured in a physiologically relevant, autoinhibited state. The resulting atomic model provides structural detail for the amino acids that constitute the proton pathway at the interface of the proteolipid ring and subunit a. Based on the structure and previous mutagenesis studies, we propose the chemical basis of transmembrane proton transport. Moreover, we discovered that the C terminus of the assembly factor Voa1 is an integral component of mature Vo. Voa1's C-terminal transmembrane alpha helix is bound inside the proteolipid ring, where it contributes to the stability of the complex. Our structure rationalizes possible mechanisms by which mutations in human Vo can result in disease phenotypes and may thus provide new avenues for therapeutic interventions. PMID- 29526696 TI - LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. AB - The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. We also found that MEF2C-dependent leukemias are sensitive to on target chemical inhibition of SIK activity. This study reveals a chemical strategy to block MEF2C function in AML, highlighting how an oncogenic TF can be disabled by targeting of upstream kinases. PMID- 29526698 TI - Regeneration of coelomocytes after evisceration in the sea cucumber, Apostichopus japonicus. AB - Sea cucumber, Apostichopus japonicus, is one of the most important holothurian species cultured in China. Severe evisceration induced by various natural and artificial factors commonly occurs during transport and culture of A. japonicus. Evisceration causes higher mortality and lower yield. Along with the visceral regeneration process, sea cucumbers also regenerate coelomocytes in order to recover immune function. In this study, evisceration of A. japonicus was induced by intracoelomic injection of 0.35 M KCl. Regeneration of coelomocytes was investigated by time course cell counting as well as detection of DNA replication by the EdU labeling technique. Coelomic fluid volume was restored to the pre evisceration level within 2 h after evisceration. Total coelomocyte count (TCC) reached a peak at 6 h post-evisceration, followed decreased and then increased with a slight fluctuation, restored to the pre-evisceration level at 35 d post evisceration. The change in different subtypes of coelomocytes was consistent with that of total coelomocytes. However, there were some variations in the regeneration of coelomocyte subtypes. At the end of the study, only the counts of amoebocytes and morula cells recovered to the pre-evisceration level. DNA replication assay showed EdU-positive cells accounted for 9.5% before evisceration and 4.7% at 6 h post-evisceration. However, the percentage of EdU positive cells significantly increased, reaching 18.6% at 3 d after evisceration, then declined. Therefore, we analyzed the observed increase in coelomocytes at 6 h post-evisceration, which may be due to coelomocyte migration from the water vascular system into the coelom rather than de novo cell proliferation. PMID- 29526697 TI - Inter-chromosomal Contact Properties in Live-Cell Imaging and in Hi-C. AB - Imaging (fluorescence in situ hybridization [FISH]) and genome-wide chromosome conformation capture (Hi-C) are two major approaches to the study of higher-order genome organization in the nucleus. Intra-chromosomal and inter-chromosomal interactions (referred to as non-homologous chromosomal contacts [NHCCs]) have been observed by several FISH-based studies, but locus-specific NHCCs have not been detected by Hi-C. Due to crosslinking, neither of these approaches assesses spatiotemporal properties. Toward resolving the discrepancies between imaging and Hi-C, we sought to understand the spatiotemporal properties of NHCCs in living cells by CRISPR/Cas9 live-cell imaging (CLING). In mammalian cells, we find that NHCCs are stable and occur as frequently as intra-chromosomal interactions, but NHCCs occur at farther spatial distance that could explain their lack of detection in Hi-C. By revealing the spatiotemporal properties in living cells, our study provides fundamental insights into the biology of NHCCs. PMID- 29526700 TI - Macrophage sphingolipids are essential for the entry of mycobacteria. AB - Mycobacteria are intracellular pathogens that can invade and survive within host macrophages. Mycobacterial infections remain a major cause of mortality and morbidity worldwide, with serious concerns of emergence of multi and extensively drug-resistant tuberculosis. While significant advances have been made in identifying mycobacterial virulence determinants, the detailed molecular mechanism of internalization of mycobacteria into host cells remains poorly understood. Although several studies have highlighted the crucial role of sphingolipids in mycobacterial growth, persistence and establishment of infection, the role of sphingolipids in the entry of mycobacteria into host cells is not known. In this work, we explored the role of host membrane sphingolipids in the entry of Mycobacterium smegmatis into J774A.1 macrophages. Our results show that metabolic depletion of sphingolipids in host macrophages results in a significant reduction in the entry of M. smegmatis. Importantly, the entry of Escherichia coli into host macrophages under similar conditions remained invariant, implying the specificity of the requirement of sphingolipids in mycobacterial entry. To the best of our knowledge, our results constitute the first report demonstrating the role of host macrophage sphingolipids in the entry of mycobacteria. Our results could help in the development of novel therapeutic strategies targeting sphingolipid-mediated entry of mycobacteria into host cells. PMID- 29526699 TI - Characterization and expression analysis of g- and c-type lysozymes in Dabry's sturgeon (Acipenser dabryanus). AB - Dabry's sturgeon (Acipenser dabryanus) is mainly distributed in the upper Yangtze River. Although extensively farmed, little information is available on its innate immune system. In this study, we conducted de novo transcriptome assembly of the head kidney to create a comprehensive dataset for A. dabryanus. A total of 51,324,686 high quality reads were obtained from head kidney cDNA library by the Illumina sequencing platform and 131,261 unigenes were determined to contain complete ORFs. The complete coding sequences of g- and c-type lysozymes were identified from unigenes, and designated as ADLysG and ADLysC. Aeromonas hydrophila infection of Dabry's sturgeon caused a significant increase (P < 0.05) in blood for both lysozyme types, confirming their active defensive role against bacterial infections. This research provides the first characterization of these enzymes in an ancestral chondrostean. These data suggest that ADLysG and ADLysC have the potential for immune defense system against bacterial infection. PMID- 29526701 TI - Early Surgical Intervention May Be More Likely to Cause Complications in Patients with Male Lower Urinary Tract Symptoms than To Prevent Them. AB - There is no evidence that early surgical intervention will prevent complications due to bladder outlet obstruction, and a high likelihood that the surgery will bring its own complications. PMID- 29526702 TI - Protein network module-based identification of key pharmacological pathways of Curcuma phaeocaulis Val. acting on hepatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma phaeocaulis Val. (CP), as the vital medicines for blood-breaking and disorder-eliminating, has been widely used for hepatitis with good curative effects. Owing to the complexity of traditional Chinese medicine, the pharmacological mechanism of CP remains unclear. To solve this problem, a protein network module-based approach was proposed in this study. MATERIALS AND METHODS: Firstly, the content of active components of CP was detected based on HPLC-DAD. Then the liver protection of CP on Con A-induced hepatitis was validated via the analysis of serum levels of ALT, AST and LDH and histological findings. Next, the targets of CP components obtained from TCMD database were predicted by STITCH and ChEMBL retrieval. In addition, the protein interaction network (PIN) of CP was constructed by Cytoscape based on protein protein interaction of targets obtained from STRING database. Following the topological analysis of CP PIN, it showed to exhibit the properties of scale free, small world, and modularity matched with the property of complex biological networks. Finally, the functional modules were identified by gene ontology enrichment analysis based on Molecular Complex Detection algorithm. RESULTS: The functional modules indicated that the mechanism of CP acting on the hepatitis is significantly associated with NF-kappaB and TGF-beta signaling pathway. More interestingly, curcumin, demethoxycurcumin and bisdemethoxycurcumin were the main active components of CP acting on the hepatitis, which were demonstrated to be associated with the inflammatory process that occurs during the progression of hepatitis. CONCLUSION: The protein network module-based approach is an efficient way to investigate the pharmacological mechanisms of CP. PMID- 29526704 TI - Long-term Effect of Scleral Encircling on Axial Elongation. AB - PURPOSE: To determine the long-term effect of scleral encircling on the progression of myopia. DESIGN: Retrospective clinical cohort study. METHODS: Setting: Single-center academic hospital (Severance Hospital). STUDY POPULATION: The study included 76 eyes of 38 patients (mean age 37.21 +/- 15.76) who had undergone retinal detachment surgery with scleral encircling. Observational Procedures: Axial length was measured preoperatively, at 6 months after surgery, and at the most recent visit. Patients were followed up for at least 12 months. MAIN OUTCOME MEASURE: The changes of axial length per month between operated eyes and contralateral eyes (control group). RESULTS: The operated group showed more rapid changes in axial length from 6 months after surgery to the time of the last follow-up than did the control group (0.020 +/- 0.033 mm/month vs 0.002 +/- 0.002 mm/month, P = .002; mean follow-up, 26.05 +/- 11.39 months). Similar trends were observed during the entire follow-up period (0.065 +/- 0.062 mm/month vs 0.008 +/ 0.020 mm/month, P < .001). Subgroup analysis showed that both the myopic and highly myopic group showed no significant difference of change in rate of axial length during the first 6 postoperative months (P = .267), from 6 months after surgery to the final assessment point (P = .144), or over the entire observation period (P = .507). CONCLUSIONS: Encircling the sclera may accelerate progression of myopia by significantly increasing axial length. The degree of myopia itself does not contribute to a significant difference in the increased axial length. PMID- 29526703 TI - The chemistry and pharmacology of Ligularia przewalskii: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ligularia przewalskii (Maxim.) Diels (LP) (called zhangyetuowu in Chinese), is generally found in moist forest areas in the western regions of China. The root, leaves and flower of LP are utilized as a common traditional medicine in China. It has been utilized conventionally in herbal remedies for the remedy of haemoptysis, asthma, pulmonary phthisis, jaundice hepatitis, food poisoning, bronchitis, cough, fever, wound healing, measles, carbuncle, swelling and phlegm diseases. AIM OF THE STUDY: The review aims to provide a systematic summary of LP and to reveal the correlation between the traditional uses and pharmacological activities in order to provide updated, comprehensive and categorized information and identify the therapeutic potential for its use as a new medicine. MATERIALS AND METHODS: The relevant data were searched by using the keywords "Ligularia przewalskii" "phytochemistry", "pharmacology", "Traditional uses", and "Toxicity" in "Scopus", "Scifinder", "Springer", "Pubmed", "Wiley", "Web of Science", "China Knowledge Resource Integrated databases (CNKI)", "Ph.D." and "M.Sc. dissertations", and a hand search was done to acquire peer-reviewed articles and reports about LP. The plant taxonomy was validated by the databases "The Plant List", "Flora Reipublicae Popularis Sinicae", "A Collection of Qinghai Economic Plants", "Inner Mongolia plant medicine Chi", Zhonghua-bencao and the Standard of Chinese herbal medicine in Gansu. RESULTS: Based on the traditional uses, the chemical nature and biological effects of LP have been the focus of research. In modern research, approximately seventy-six secondary metabolites, including thirty-eight terpenoids, nine benzofuran derivatives, seven flavonoids, ten sterols and others, were isolated from this plant. They exhibit anti-inflammatory, antioxidative, anti-bacterial and anti-tumour effects, and so on. Currently, there is no report on the toxicity of LP, but hepatotoxic pyrrolizidine alkaloids (HPA) were first detected with LC/MSn in LP, and they have potential hepatotoxicity. CONCLUSIONS: The lung-moistening, cough-relieving and phlegm resolving actions of the root of LP are attributed to the anti-inflammatory properties of flavonoids and terpenoids. The heat-clearing, dampness-removing and gallbladder-normalizing (to cure jaundice) actions of the flowers of LP are based on the anti-inflammatory, antioxidant and hepatoprotective activity properties of terpenoids, flavonoids and sterols. The Traditional Chinese Medicine (TCM) characteristics of LP (bitter flavour) corroborate its potent anti-inflammatory effects. In addition, the remarkable anti-inflammatory and antioxidant capacities of LP contribute to its anti-tumour and antitussive activities. Many conventional uses of LP have now been validated by modernized pharmacological research. For future research, further phytochemical and biological studies need to be conducted on LP, In particular, the safety, mechanism of action and efficacy of LP could be of future research interest before beginning clinical trials. More in vivo experiments and clinical studies are encouraged to further clarify the relation between traditional uses and modern applications. Regarding the roots, leaves and flowers of LP, their chemical compositions and clinical effects should be compared. The information on LP will be helpful in providing and identifying its therapeutic potential and economic value for its use as a new medicine in the future. PMID- 29526705 TI - Glucocorticoids induce apoptosis and matrix metalloproteinase-13 expression in chondrocytes through the NOX4/ROS/p38 MAPK pathway. AB - Based on the results from our previous study, dexamethasone (Dex) increases reactive oxygen species (ROS) levels and subsequently induces cell death and matrix catabolism in chondrocytes. Nevertheless, the mechanism underlying this phenomenon remains unclear. Nicotinamide adenine dinucleotide (phosphate) (NADPH) oxidase 4 (NOX4) is one of the major enzymes responsible for intracellular ROS production during the inflammatory process. The objective of the current study was to investigate the role of NOX4 in Dex-induced ROS over-production. Healthy chondrocytes were harvested from the cartilage debris from 6 female patients. NOX4 and p38 mitogen-activated protein kinase (MAPK) expression levels in these cells were evaluated in the presence of Dex. Changes in the number of apoptotic and viable Dex-treated chondrocytes were recorded after the cells were treated with NOX and p38 MAPK inhibitors. Changes in matrix metalloproteinase 13 (MMP-13) expression levels in Dex-treated chondrocytes were also investigated. The Dex treatment increased NOX4 expression via the glucocorticoid receptor (GR). Treatment of cells with apocynin, a NOX inhibitor, decreased intracellular ROS levels and inhibited p38 MAPK activation. Treatment of cells with a ROS scavenger also reduced p38 MAPK expression. Treatment of cells with a NOX inhibitor, ROS scavenger and p38 MAPK inhibitor rescued chondrocytes from Dex-induced apoptosis. Moreover, treatment of cells with these agents blocked MMP-13 expression in Dex treated chondrocytes. NOX4 silencing also suppressed p38 MAPK and MMP-13 expression. Dex triggered apoptosis and MMP-13 expression through the NOX4/ROS/p38 MAPK signaling pathway. NOX4 may be a therapeutic target in the management of Dex-induced complications. PMID- 29526706 TI - DMPA self-administration can improve contraceptive access, continuation, and autonomy. PMID- 29526707 TI - Effect of self-administration versus provider-administered injection of subcutaneous depot medroxyprogesterone acetate on continuation rates in Malawi: a randomised controlled trial. AB - BACKGROUND: Injectable contraceptives are popular in sub-Saharan Africa but have high discontinuation rates due partly to the need for provider-administered re injection. We compared continuation rates of women who self-injected subcutaneous depot medroxyprogesterone acetate (DMPA-SC) and women who received DMPA-SC from a health-care provider, including community health workers (CHWs). METHODS: We did an open-label randomised controlled trial based at six Ministry of Health clinics in rural Mangochi District, Malawi. Health-care providers recruited adult women who presented at the six clinics or to CHWs in rural communities in the clinic catchment areas. Participants received DMPA-SC and were randomised (1:1) to receive provider-administered injections or training in how to self-inject DMPA SC. Randomisation was done via a computer-generated block randomisation schedule with block sizes of four, six, and eight and stratified by study site, generated by an independent statistician. Self-injectors administered the first injection under observation and were sent home with three doses, written instructions, and a calendar. The provider-administered group received a DMPA-SC injection and a calendar, and were asked to return for subsequent injections. Data collectors contacted participants after the 14-week re-injection window at 3, 6, and 9 months to collect continuation data. At 12 months after enrolment or early discontinuation, women had their final interview, which included pregnancy testing. The primary outcome was discontinuation of DMPA-SC, as assessed in the intention-to-treat population. We used Kaplan-Meier methods to estimate the probabilities of continuation and a log-rank test to compare groups. Safety was assessed in the as-treated population, which consisted only of participants who successfully received at least one DMPA-SC injection after randomisation. This trial is registered with ClinicalTrials.gov, number NCT02293694. FINDINGS: This study lasted from Sept 17, 2015, to Feb 21, 2017. 731 women underwent randomisation, with 364 assigned to the self-administered group and 367 to the provider-administered group. One woman in the self-injection group withdrew at month 0. Treatment was discontinued by 99 women in the self-administered group and 199 women in the provider-administered group. The 12 month continuation rate was 73% in the self-injection group and 45% in the provider-administered group, giving an incidence rate ratio of 0.40 (95% CI 0.31-0.51; p<0.0001). Adverse events deemed to potentially be treatment-related were reported by ten women (20 events) in the self-administered group and 17 women (28 events) in the provider administered group. Five serious adverse events were reported during the trial by four women; two events related to DMPA-SC (menorrhagia and anaemia requiring hospital admission) were reported by the same woman in the provider-administered group and resolved without sequelae. The other serious adverse events, including one death, were deemed to be unrelated to DMPA-SC. INTERPRETATION: Women who self injected DMPA-SC had significantly higher rates of continuation than those receiving provider-injected DMPA-SC. Community-based provision of injectable contraception for self-injection in low-resource settings seems to be safe and feasible. Self-administration of DMPA-SC should be made widely available. FUNDING: United States Agency for International Development and Children's Investment Fund Foundation. PMID- 29526708 TI - Aggregation kinetics in the presence of brain lipids of Abeta(1-40) cleaved from a soluble fusion protein. AB - The cleavage of the amyloid precursor protein by beta- and gamma-secretases is a key event in Alzheimer's disease. A fusion protein was constructed to investigate the cleavage rate and aggregation kinetics of amyloid-beta (1-40) (Abeta(1-40)) peptides. The peptide was expressed with a Small Ubiquitin-Like Modifier (SUMO) on the N-terminus and cleaved by a SUMO protease Ulp1. The time course of the cleavage reaction was monitored by SDS-PAGE gel with 100:1 or 1000:1 SUMO-Abeta(1 40) to Ulp1 molar ratio and in the presence of brain total lipid extract unilamellar vesicles. Similarly, the aggregation of Abeta(1-40) peptides upon cleavage was monitored by thioflavin T fluorescence assays and by circular dichroism. The cleavage reaction was modulated by the concentration of Ulp1, with fast release of Abeta(1-40) peptides producing shorter lag time before fibril formation, but with similar elongation rate. The presence of lipids significantly reduced the cleavage completion at 1000:1, but reduced the lag time before fibril formation, while at 100:1 similar cleavage and aggregation kinetics were observed compared to the lipid-free condition. Overall, the results showed that the fusion protein SUMO-Abeta(1-40) is a means to study the cleavage and aggregation of amyloid peptides and that the presence of lipids and the fast release rate accelerated the aggregation of Abeta(1-40) peptides. PMID- 29526710 TI - A Split-Luciferase-Based Trimer Formation Assay as a High-throughput Screening Platform for Therapeutics in Alport Syndrome. AB - Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen alpha3-alpha5 chains (alpha3-alpha5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of alpha3/alpha4/alpha5 chain is a feasible therapeutic approach, but is hindered by lack of information on the regulation of intracellular alpha(IV) chain and the absence of high-throughput screening (HTS) platforms to assess alpha345(IV) trimer formation. Here, we developed sets of split NanoLuc fusion alpha345(IV) proteins to monitor alpha345(IV) trimerization of wild-type and clinically associated mutant alpha5(IV). The alpha345(IV) trimer assay, which satisfied the acceptance criteria for HTS, enabled the characterization of intracellular- and secretion-dependent defects of mutant alpha5(IV). Small interfering RNA-based and chemical screening targeting the ER identified several chemical chaperones that have potential to promote alpha345(IV) trimer formation. This split luciferase-based trimer formation assay is a functional HTS platform that realizes the feasibility of targeting alpha345(IV) trimers to treat Alport syndrome. PMID- 29526711 TI - Unmasking Fucosylation: from Cell Adhesion to Immune System Regulation and Diseases. AB - Fucosylation is a biological process broadly observed in vertebrates, invertebrates, plants, bacteria, and fungi. Fucose moieties on cell-surface glycans are increasingly recognized as critical to many cell-cell interaction and signaling processes. One of the characteristic roles of fucose is its regulation of selectin-dependent leukocyte adhesion that has been well studied over the last two decades. Recent studies of fucose in immune cell development and function regulation have significantly expanded the contemporary understanding of fucosylation. From cellular adhesion to immune regulation, herein we discuss the use of gene knockout studies, competitive inhibitors of fucose-containing glycan, and metabolic inhibitors of fucose biosynthesis to probe fucosylated glycan biosynthesis and signaling and its functional consequences. Promising clinical and preclinical applications in sickle cell disease, rheumatoid arthritis, tumor inhibition, metastasis prevention, antibody-dependent cell-mediated cytotoxicity, chemoresistance reversal, and in improving chemotherapy-related side effects and recovery are reviewed. PMID- 29526709 TI - Cause and consequence of Abeta - Lipid interactions in Alzheimer disease pathogenesis. AB - Self-templating propagation of protein aggregate conformations is increasingly becoming a significant factor in many neurological diseases. In Alzheimer disease (AD), intrinsically disordered amyloid-beta (Abeta) peptides undergo aggregation that is sensitive to environmental conditions. High-molecular weight aggregates of Abeta that form insoluble fibrils are deposited as senile plaques in AD brains. However, low-molecular weight aggregates called soluble oligomers are known to be the primary toxic agents responsible for neuronal dysfunction. The aggregation process is highly stochastic involving both homotypic (Abeta-Abeta) and heterotypic (Abeta with interacting partners) interactions. Two of the important members of interacting partners are membrane lipids and surfactants, to which Abeta shows a perpetual association. Abeta-membrane interactions have been widely investigated for more than two decades, and this research has provided a wealth of information. Although this has greatly enriched our understanding, the objective of this review is to consolidate the information from the literature that collectively showcases the unique phenomenon of lipid-mediated Abeta oligomer generation, which has largely remained inconspicuous. This is especially important because Abeta aggregate "strains" are increasingly becoming relevant in light of the correlations between the structure of aggregates and AD phenotypes. Here, we will focus on aspects of Abeta-lipid interactions specifically from the context of how lipid modulation generates a wide variety of biophysically and biochemically distinct oligomer sub-types. This, we believe, will refocus our thinking on the influence of lipids and open new approaches in delineating the mechanisms of AD pathogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29526713 TI - Stereoacuity outcomes following surgical correction of the nonaccommodative component in partially accommodative esotropia. AB - BACKGROUND: Previous studies of partially accommodative esotropia (PAET) have assessed factors requiring surgery and alignment outcomes. The purpose of the present study was to additionally evaluate stereoacuity in patients who required surgery for their nonaccommodative component. METHODS: The medical records of consecutive patients with PAET who underwent bilateral medial rectus recession from April 1990 to July 2010 to treat the nonaccommodative component were reviewed retrospectively. Preoperative data included visual acuity, stereoacuity, cycloplegic refraction, deviation at distance and near, and age at surgery. The primary outcomes were stereoacuity and alignment. RESULTS: A total of 84 patients were included. Stereopsis by the Titmus StereoTest was demonstrated in 51 (61%) by the final visit. The average follow-up time was 4.4 +/- 2.8 years (range, 0.8 11.0 years). Fine stereopsis (100 arcsec or better) was appreciated in 29 patients (35%, 57% of those with stereopsis). Of those with residual esotropia, 11 (50%) demonstrated stereopsis, and 7 (32%) appreciated fine stereoacuity. No exotropic patient had stereopsis. There was a statistically significant correlation between age at time of surgery and stereopsis at 1 year (rho = 0.233; P = 0.033) but not at the final visit (rho = 0.106, P = 0.34). Of the 84 patients, 56 (67%) had a favorable alignment (within 10Delta of orthotropia) at the final visit; 22 (26%) had residual esotropia; and 6 (7%) had consecutive exotropia. CONCLUSIONS: In this subset of esotropic patients who required surgery for their nonaccommodative component, favorable sensory outcomes can be achieved. Furthermore, favorable stereoacuity can be found even when there is a residual esodeviation. PMID- 29526712 TI - The Dolphin Proline-Rich Antimicrobial Peptide Tur1A Inhibits Protein Synthesis by Targeting the Bacterial Ribosome. AB - Proline-rich antimicrobial peptides (PrAMPs) internalize into susceptible bacteria using specific transporters and interfere with protein synthesis and folding. To date, mammalian PrAMPs have so far been identified only in artiodactyls. Since cetaceans are co-phyletic with artiodactyls, we mined the genome of the bottlenose dolphin Tursiops truncatus, leading to the identification of two PrAMPs, Tur1A and Tur1B. Tur1A, which is orthologous to the bovine PrAMP Bac7, is internalized into Escherichia coli, without damaging the membranes, using the inner membrane transporters SbmA and YjiL/MdM. Furthermore, like Bac7, Tur1A also inhibits bacterial protein synthesis by binding to the ribosome and blocking the transition from the initiation to the elongation phase. By contrast, Tur1B is a poor inhibitor of protein synthesis and may utilize another mechanism of action. An X-ray structure of Tur1A bound within the ribosomal exit tunnel provides a basis to develop these peptides as novel antimicrobial agents. PMID- 29526714 TI - The clinical effect of surgical timing in infantile exotropia. AB - PURPOSE: To review the association of postoperative ocular alignment, sensory outcomes, and need for reoperation after surgical management of infantile exotropia. METHODS: The clinical records of patients who presented with constant infantile exotropia of >25Delta and subsequently underwent strabismus surgery at a single center from 2004 to 2014 were reviewed retrospectively. Postoperative binocular sensory status was assessed using Worth 4-Dot and Titmus stereoacuity tests. Patients with postoperative exotropia of >10Delta or esotropia of >5Delta were advised to undergo additional surgery. RESULTS: A total of 49 cases were included (28 boys; age at diagnosis, 1-12 months). The patients who underwent reoperation were younger at the time of first surgery (mean age, 13.15 +/-1.68 vs 18.58 +/- 0.92 months [P = 0.005]). Patients who developed consecutive esotropia were younger at the time of initial operation (P = 0.039). Among 20 patients who were testable for sensory outcome assessment, only 4 patients developed stereopsis, whereas 15 patients achieved bifixation by Worth 4-Dot test. All of the 4 patients with measurable postoperative stereoacuity had initial surgery after 1 year of age. CONCLUSIONS: In this patient cohort, earlier surgery did not necessarily lead to better sensory outcomes, and reoperation was associated with younger age at time of first surgery. PMID- 29526715 TI - A novel pharmacodynamic model in rats for preventing vascular dementia from maintaining neurovascular coupling sensitivity. AB - Vascular dementia (VaD) is the common cognitive disorder derived mainly from lacunar stroke. The neurovascular coupling (NVC) dysfunction involves in its pathogenesis. VaD lacks suitable animal models for developing preventive therapies. This study aimed to confirm a model for preventing VaD via maintaining NVC sensitivity in rats. The model was replicated with autologous microthrombi against the background of hypercholesterolemia. A phosphodiesterase inhibitor (pentoxyfylline) was preventively administrated to confirm the role of NVC sensitivity. Cognitive function was evaluated as exploratory, learning and memorizing abilities. NVC sensitivity was defined as the ratio of microcirculative cerebral blood flow (?CBF) to the quantitative electroencephalograph (?qEEG) before and after penicillin stimulation. The pathogenesis of NVC dysfunction was explored as expressions of neuronal (nNOS), inducible (iNOS) and endothelial nitric oxide synthase (eNOS) in cerebral cortex. The model rats showed cognitive impairment, microvascular edema (2.54 +/- 0.30%, P < 0.01), neuronal edema (1.24 +/- 0.48%, P < 0.01) and nissl body loss (0.03 +/ 0.003%, P < 0.01) in cerebral cortex, and neuronal necrosis in hippocampal CA1 region (neuronal cell number 41.76 +/- 10.04 cells, P < 0.01) compared with sham group. The NVC dullness in model rats was confirmed as significantly decreased ratio of ?CBF/?qEEG (0.05 +/- 0.02%, P < 0.01) compared with sham group (0.20 +/- 0.06%). The underlying mechanism of NVC dysfunction was found as imbalanced NOS expressions (decreased nNOS and eNOS, while increased iNOS levels in cerebral cortex). The NVC dullness was significantly relieved in pentoxyfylline administrated rats (0.12 +/- 0.06%, P < 0.01). It indicated that this model was suitable to evaluate candidates for preventing VaD via maintaining NVC sensitivity. PMID- 29526716 TI - Inhibition of protein tyrosine phosphatase 1B in spinal cord dorsal horn of rats attenuated diabetic neuropathic pain. AB - Protein tyrosine phosphatase 1B (PTP1B) has been shown to dephosphorylate and inactivate insulin receptors, which contributes to the pathogenesis of diabetes. Neuropathic pain is one of the severe complications that results from diabetic neuropathy. However, whether PTP1B was involved in the development of diabetic neuropathic pain is largely unknown. The current study illustrated that PTP1B was located in spinal cord dorsal horn neurons of Sprague-Dawley rats. Western blot analysis demonstrated that the diabetic neuropathic pain induced by intraperitoneal injection of streptozotocin was associated with an increased protein expression and a dynamic redistribution of spinal PTP1B into excitatory glutamatergic synapses. We found that PTP1B operated to stimulate Src kinase and enhance the tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The siRNA-mediated knockdown of PTP1B in streptozotocin injected rats repressed Src activity, decreased NMDA receptor phosphorylation and alleviated the thermal hyperalgesia and mechanical allodynia. A similar analgesia against diabetic neuropathic pain was also achieved when PTP1B activity was manipulated by a chemical PTP Inhibitor or PTP1B(C215S) mutant. These data revealed a regulated expression of PTP1B in spinal cord dorsal horn of rats after diabetic neuropathy, and demonstrated that inhibition of PTP1B was beneficial for the treatment of pain hypersensitivity related to diabetes. PMID- 29526717 TI - Biogenic amine signaling systems in the red imported fire ant, Solenopsis invicta - Possible contributors to worker division of labor. AB - The red imported fire ant, Solenopsis invicta Buren, is a dangerous invasive pest in the United States, China and other countries. Efficient division of labor is one of the main reasons for the success of this social insect. Biogenic amines are important regulators of worker division of labor in this eusocial insect, but the related molecular mechanisms are largely unknown. In this study, we identified 10 candidate biogenic amine synthetic enzyme genes and 17 candidate biogenic amine receptor genes in the genome of S. invicta. Quantitative real-time PCR results indicated that foragers had higher head transcripts levels of all the tested enzyme genes than nurses did. In the abdomen, only the rate-limiting enzyme genes for the biosynthesis of serotonin and dopamine were higher in foragers than in nurses. Among the tested serotonin receptors, only the expression of 5-HT2A gene showed significant difference between foragers and nurses. In the head, more abundant 5-HT2A transcripts were detected in foragers than in nurses. Foragers expressed higher Octbeta4R than nurses in the head and abdomen. However, much lower mRNA levels of Dop3 receptor gene were detected in both body regions of foragers than nurses. Several other octopamine and tyramine receptor genes were also differentially expressed between foragers and nurses in the head and/or in the abdomen. Our results will improve the understanding of molecular mechanisms underlying biogenic amine modulation of the worker division of labor in S. invicta. PMID- 29526718 TI - Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17alpha-ethinyl estradiol. AB - 17alpha-Ethinylestradiol (EE2) is a ubiquitous aquatic contaminant shown to decrease fish fertility at low concentrations, especially in fish exposed during development. The mechanisms of the decreased fertility are not fully understood. In this study, we perform transcriptome analysis by RNA sequencing of testes from zebrafish with previously reported lowered fertility due to exposure to low concentrations of EE2 during development. Fish were exposed to 1.2 and 1.6 ng/L (measured concentration; nominal concentrations 3 and 10 ng/L) of EE2 from fertilization to 80 days of age, followed by 82 days of remediation in clean water. RNA sequencing analysis revealed 249 and 16 genes to be differentially expressed after exposure to 1.2 and 1.6 ng/L, respectively; a larger inter-sample variation was noted in the latter. Expression of 11 genes were altered by both exposures and in the same direction. The coding sequences most affected could be categorized to the putative functions cell signalling, proteolysis, protein metabolic transport and lipid metabolic process. Several homeobox transcription factors involved in development and differentiation showed increased expression in response to EE2 and differential expression of genes related to cell death, differentiation and proliferation was observed. In addition, several genes related to steroid synthesis, testis development and function were differentially expressed. A number of genes associated with spermatogenesis in zebrafish and/or mouse were also found to be differentially expressed. Further, differences in non coding sequences were observed, among them several differentially expressed miRNA that might contribute to testis gene regulation at post-transcriptional level. This study has generated insights of changes in gene expression that accompany fertility alterations in zebrafish males that persist after developmental exposure to environmental relevant concentrations of EE2 that persist followed by clean water to adulthood. Hopefully, this will generate hypotheses to test in search for mechanistic explanations. PMID- 29526719 TI - Identification and characterization of two novel Gammapapillomavirus genomes in skin of an immunosuppressed Epidermodysplasia Verruciformis patient. AB - Two novel human gamma-papillomavirus genomes (HPV_MTS3, and HPV_MTS4) were isolated from the skin of an immunosuppressed, late-onset Epidermodysplasia Verruciformis patient and fully cloned. The L1 open reading frames of HPV_MTS3 and HPV_MTS4 were 77% and 91% identical to their closest HPV full genome isolates w18c39 and EV03c60, which belong to the species gamma-22and gamma-7 of the genus Gammapapillomavirus, respectively. PMID- 29526720 TI - Leptospirosis in Spanish travelers returning from Chiang Mai: A case series. AB - BACKGROUND: Leptospirosis is an important zoonosis worldwide, nevertheless is often poor recognized in non tropical settings. In Thailand is becoming an emerging disease and Chiang Mai could become a popular spot to acquire the disease amongst travelers. METHODS: We describe three cases of imported leptospirosis undifferentiated fever after travelling to Thailand during the summer of 2015 diagnosed at two Spanish hospitals. RESULTS: Our three patients probably acquired leptospirosis while swimming in freshwater around Chiang Mai, a Thailand's northern region with moderate incidence of leptopirosis. Travelers had normal white blood cell counts and low platelets, suggesting leptospirosis after ruling out other imported diseases such as malaria, dengue or typhoid. CONCLUSION: As recent findings point out, low platelets and normal white blood cell counts are clinical features that could help the clinician to suspect Leptospirosis infection. It should be always considered as a cause of fever, particularly if travelers come from a tropical country and have had contact with water or flooding, especially during rainy season. PMID- 29526721 TI - Reply. PMID- 29526722 TI - Reply. PMID- 29526723 TI - Reply. PMID- 29526724 TI - Nonalcoholic Fatty Liver Disease in Alcohol Users: An Oxymoron? PMID- 29526725 TI - Colon Cancer Survival and Statins: What More Evidence Do We Need? PMID- 29526726 TI - The Elevation of Hepatic Venous Pressure Gradient After Sustained Virologic Response in Hepatitis C Virus-Related Cirrhosis. PMID- 29526727 TI - Low FODMAP Diet for IBS. PMID- 29526728 TI - Monitoring the Evolution of Portal Hypertension After Sustained Virologic Response. PMID- 29526729 TI - Reply. PMID- 29526730 TI - Biomarkers for Nonalcoholic Steatohepatitis. PMID- 29526731 TI - Risk of Hepatocellular Carcinoma After Cure of Hepatitis C Virus. PMID- 29526732 TI - High Accumulation of Metformin in Colonic Tissue of Subjects With Diabetes or the Metabolic Syndrome. PMID- 29526733 TI - New Insights for Controversial Issues of miR-122 in Hepatic Lipid Metabolism. PMID- 29526734 TI - Combined Loss of JMJD1A and JMJD1B Reveals Critical Roles for H3K9 Demethylation in the Maintenance of Embryonic Stem Cells and Early Embryogenesis. AB - Histone H3 lysine 9 (H3K9) methylation is unevenly distributed in mammalian chromosomes. However, the molecular mechanism controlling the uneven distribution and its biological significance remain to be elucidated. Here, we show that JMJD1A and JMJD1B preferentially target H3K9 demethylation of gene-dense regions of chromosomes, thereby establishing an H3K9 hypomethylation state in euchromatin. JMJD1A/JMJD1B-deficient embryos died soon after implantation accompanying epiblast cell death. Furthermore, combined loss of JMJD1A and JMJD1B caused perturbed expression of metabolic genes and rapid cell death in embryonic stem cells (ESCs). These results indicate that JMJD1A/JMJD1B-meditated H3K9 demethylation has critical roles for early embryogenesis and ESC maintenance. Finally, genetic rescue experiments clarified that H3K9 overmethylation by G9A was the cause of the cell death and perturbed gene expression of JMJD1A/JMJD1B depleted ESCs. We summarized that JMJD1A and JMJD1B, in combination, ensure early embryogenesis and ESC viability by establishing the correct H3K9 methylated epigenome. PMID- 29526735 TI - Modeling Down Syndrome with Patient iPSCs Reveals Cellular and Migration Deficits of GABAergic Neurons. AB - The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum. Gene expression profiling revealed altered cell migratory pathways, and correction of the PAK1 pathway mitigated the cell migration deficit in vitro. These results suggest that impaired migration of DS GABAergic neurons may contribute to the reduced number of interneurons in the cerebral cortex and hippocampus in DS patients. PMID- 29526736 TI - miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation. AB - The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA) cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons. PMID- 29526737 TI - KLF4 Nuclear Export Requires ERK Activation and Initiates Exit from Naive Pluripotency. AB - Cooperative action of a transcription factor complex containing OCT4, SOX2, NANOG, and KLF4 maintains the naive pluripotent state; however, less is known about the mechanisms that disrupt this complex, initiating exit from pluripotency. We show that, as embryonic stem cells (ESCs) exit pluripotency, KLF4 protein is exported from the nucleus causing rapid decline in Nanog and Klf4 transcription; as a result, KLF4 is the first pluripotency transcription factor removed from transcription-associated complexes during differentiation. KLF4 nuclear export requires ERK activation, and phosphorylation of KLF4 by ERK initiates interaction of KLF4 with nuclear export factor XPO1, leading to KLF4 export. Mutation of the ERK phosphorylation site in KLF4 (S132) blocks KLF4 nuclear export, the decline in Nanog, Klf4, and Sox2 mRNA, and differentiation. These findings demonstrate that relocalization of KLF4 to the cytoplasm is a critical first step in exit from the naive pluripotent state and initiation of ESC differentiation. PMID- 29526738 TI - Gene Correction Reverses Ciliopathy and Photoreceptor Loss in iPSC-Derived Retinal Organoids from Retinitis Pigmentosa Patients. AB - Retinitis pigmentosa (RP) is an irreversible, inherited retinopathy in which early-onset nyctalopia is observed. Despite the genetic heterogeneity of RP, RPGR mutations are the most common causes of this disease. Here, we generated induced pluripotent stem cells (iPSCs) from three RP patients with different frameshift mutations in the RPGR gene, which were then differentiated into retinal pigment epithelium (RPE) cells and well-structured retinal organoids possessing electrophysiological properties. We observed significant defects in photoreceptor in terms of morphology, localization, transcriptional profiling, and electrophysiological activity. Furthermore, shorted cilium was found in patient iPSCs, RPE cells, and three-dimensional retinal organoids. CRISPR-Cas9-mediated correction of RPGR mutation rescued photoreceptor structure and electrophysiological property, reversed the observed ciliopathy, and restored gene expression to a level in accordance with that in the control using transcriptome-based analysis. This study recapitulated the pathogenesis of RPGR using patient-specific organoids and achieved targeted gene therapy of RPGR mutations in a dish as proof-of-concept evidence. PMID- 29526739 TI - Insights into maleimide-thiol conjugation chemistry: Conditions for efficient surface functionalization of nanoparticles for receptor targeting. AB - Maleimide-thiol chemistry is widely used for the design and preparation of ligand decorated drug delivery systems such as poly(lactide-co-glycolide) (PLGA) based nanoparticles (NPs). While many publications on nanocarriers functionalized exploiting this strategy are available in the literature, the conditions at which this reaction takes place vary among publications. This paper presents a comprehensive study on the conjugation of the peptide cRGDfK and the nanobody 11A4 (both containing a free thiol group) to maleimide functionalized PLGA NPs by means of the maleimide-thiol click reaction. The influence of different parameters, such as the nanoparticles preparation method and storage conditions as well as the molar ratio of maleimide to ligand used for conjugation, on the reaction efficiency has been evaluated. The NPs were prepared by a single or double emulsion method using different types and concentrations of surfactants and stored at 4 or 20 degrees C before reaction with the targeting moieties. Several maleimide to ligand molar ratios and different reaction times were studied and the conjugation efficiency was determined by quantification of the not-bound ligand by liquid chromatography. The kind of emulsion used to prepare the NPs as well as the type and concentration of surfactant used had no effect on the conjugation efficiency. Reaction between the maleimide groups present in the NPs and cRGDfK was optimal at a maleimide to thiol molar ratio of 2:1, reaching a conjugation efficiency of 84 +/- 4% after 30 min at room temperature in 10 mM HEPES pH 7.0. For 11A4 nanobody the optimal reaction efficiency, 58 +/- 12%, was achieved after 2 h of incubation at room temperature in PBS pH 7.4 using a 5:1 maleimide to protein molar ratio. Storage of the NPs at 4 degrees C for 7 days prior to their exposure to the ligands resulted in approximately 10% decrease in the reactivity of maleimide in contrast to storage at 20 degrees C which led to almost 40% of the maleimide being unreactive after the same storage time. Our findings demonstrate that optimization of this reaction, particularly in terms of reactant ratios, can represent a significant increase in the conjugation efficiency and prevent considerable waste of resources. PMID- 29526740 TI - Polymer-based gadolinium oxide nanocomposites for FL/MR/PA imaging guided and photothermal/photodynamic combined anti-tumor therapy. AB - Recently, ultrasmall gadolinium oxide (Gd2O3) nanoparticles with high longitudinal relaxation rate have received enormous attention. However, it can't be concentrated in tumor site through intravenous administration due to its ultrasmall size. In this project, we coated ultrasmall Gd2O3 nanoparticles with a near-infrared (NIR) light-absorbing polymer polypyrrole (PPy), modifying with hyaluronic acid (HA) and loaded aluminum phthalocyanine (AlPc), the Gd2O3@PPy/AlPc-HA nanoparticles could be used for fluorescence (FL)/magnetic resonance (MR)/photoacoustic (PA) imaging guided as well as remotely controlled PTT/PDT combined anti-tumor therapy. Polymerized PPy with high photothermal conversion efficiency was introduced to assemble the ultrasmall Gd2O3 nanoparticles which have high longitudinal relaxation rate and signal-to-noise ratio, thus obtaining Gd2O3@PPy nanoparticles which possess a larger particle size and can be more suitable for tumor targeting based on the EPR effect. HA and AlPc were adsorbed on PPy for HA-mediated tumor targeting and photodynamic therapy respectively. The in vivo triple-modal imaging revealed that Gd2O3@PPy/AlPc-HA nanoparticles possess enhanced tumor uptake effect after intravenous injection. More importantly, the nanoparticles exhibited an obvious photothermal effect, which can trigger the release and de-quench of AlPc. The anti-tumor efficiency further corroborated that the combined therapy achieved an excellent tumor inhibition therapeutic effect which was much better than any other mono-therapy. Consequently, our work encouraged further exploration of polymer-based multifunctional theranostic nanoparticles for cancer combination therapy under remote near-infrared (NIR) light controls. PMID- 29526741 TI - Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat. AB - Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5 HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy. 5-HT, 5-HT2AR, 5 HT1AR, and dendritic densities were quantified both early (1 week) and late (9 weeks) after SCI, and also following therapeutic interventions (5-HT pharmacotherapy, bike therapy, or a combination). Interestingly, chronic 5-HT pharmacotherapy largely normalized spinal 5-HTR upregulation following injury. Improvement in locomotor behavior was not correlated to 5-HTR density. These results support the hypothesis that chronic 5-HT pharmacotherapy can mediate recovery following SCI, despite acting on largely normal spinal 5-HTR levels. We next assessed spinal dendritic plasticity and its potential role in locomotor recovery. Single therapies did not normalize the loss of dendritic density after SCI. Groups displaying significantly atrophied dendritic processes were rarely able to achieve weight supported open-field locomotion. Only a combination of 5 HT pharmacotherapy and bike therapy enabled significant open-field weigh supported stepping, mediated in part by restoring spinal dendritic density. These results support the use of combined therapies to synergistically impact multiple markers of spinal plasticity and improve motor recovery. PMID- 29526743 TI - Distinct criticality of phase and amplitude dynamics in the resting brain. AB - Converging research suggests that the resting brain operates at the cusp of dynamic instability, as signified by scale-free temporal correlations. We asked whether the scaling properties of these correlations differ between amplitude and phase fluctuations, which may reflect different aspects of cortical functioning. Using source-reconstructed magneto-encephalographic signals, we found power-law scaling for the collective amplitude and for phase synchronization, both capturing whole-brain activity. The temporal changes of the amplitude comprise slow, persistent memory processes, whereas phase synchronization exhibits less temporally structured and more complex correlations, indicating a fast and flexible coding. This distinct temporal scaling supports the idea of different roles of amplitude and phase fluctuations in cortical functioning. PMID- 29526742 TI - Low Rank plus Sparse decomposition of ODFs for improved detection of group-level differences and variable correlations in white matter. AB - A novel approach is presented for group statistical analysis of diffusion weighted MRI datasets through voxelwise Orientation Distribution Functions (ODF). Recent advances in MRI acquisition make it possible to use high quality diffusion weighted protocols (multi-shell, large number of gradient directions) for routine in vivo study of white matter architecture. The dimensionality of these data sets is however often reduced to simplify statistical analysis. While these approaches may detect large group differences, they do not fully capitalize on all acquired image volumes. Incorporation of all available diffusion information in the analysis however risks biasing the outcome by outliers. Here we propose a statistical analysis method operating on the ODF, either the diffusion ODF or fiber ODF. To avoid outlier bias and reliably detect voxelwise group differences and correlations with demographic or behavioral variables, we apply the Low-Rank plus Sparse (L+S) matrix decomposition on the voxelwise ODFs which separates the sparse individual variability in the sparse matrix S whilst recovering the essential ODF features in the low-rank matrix L. We demonstrate the performance of this ODF L+S approach by replicating the established negative association between global white matter integrity and physical obesity in the Human Connectome dataset. The volume of positive findings p<0.01,227cm3, agrees with and expands on the volume found by TBSS (17 cm3), Connectivity based fixel enhancement (15 cm3) and Connectometry (212 cm3). In the same dataset we further localize the correlations of brain structure with neurocognitive measures such as fluid intelligence and episodic memory. The presented ODF L+S approach will aid in the full utilization of all acquired diffusion weightings leading to the detection of smaller group differences in clinically relevant settings as well as in neuroscience applications. PMID- 29526744 TI - Applying dimension reduction to EEG data by Principal Component Analysis reduces the quality of its subsequent Independent Component decomposition. AB - Independent Component Analysis (ICA) has proven to be an effective data driven method for analyzing EEG data, separating signals from temporally and functionally independent brain and non-brain source processes and thereby increasing their definition. Dimension reduction by Principal Component Analysis (PCA) has often been recommended before ICA decomposition of EEG data, both to minimize the amount of required data and computation time. Here we compared ICA decompositions of fourteen 72-channel single subject EEG data sets obtained (i) after applying preliminary dimension reduction by PCA, (ii) after applying no such dimension reduction, or else (iii) applying PCA only. Reducing the data rank by PCA (even to remove only 1% of data variance) adversely affected both the numbers of dipolar independent components (ICs) and their stability under repeated decomposition. For example, decomposing a principal subspace retaining 95% of original data variance reduced the mean number of recovered 'dipolar' ICs from 30 to 10 per data set and reduced median IC stability from 90% to 76%. PCA rank reduction also decreased the numbers of near-equivalent ICs across subjects. For instance, decomposing a principal subspace retaining 95% of data variance reduced the number of subjects represented in an IC cluster accounting for frontal midline theta activity from 11 to 5. PCA rank reduction also increased uncertainty in the equivalent dipole positions and spectra of the IC brain effective sources. These results suggest that when applying ICA decomposition to EEG data, PCA rank reduction should best be avoided. PMID- 29526745 TI - Integrated models of neurovascular coupling and BOLD signals: Responses for varying neural activations. AB - A state-of-the-art integrated model of neurovascular coupling (NVC) (Dormanns et al., 2015b; Dormanns et al., 2016; Kenny et al., 2018) and the BOLD response (Mathias et al., 2017a; Mathias et al., 2017b) is presented with the ability to simulate the fMRI BOLD responses due to continuous neuronal spiking, bursting and cortical spreading depression (CSD) along with the underlying complex vascular coupling. Simulated BOLD responses are compared to experimental BOLD signals observed in the rat barrel cortex and in the hippocampus under seizure conditions showing good agreement. Bursting phenomena provides relatively clear BOLD signals as long as the time between bursts is not too short. For short burst periods the BOLD signal remains constant even though the neuron is in a predominantly bursting mode. Simulation of CSD exhibits large negative BOLD signals. Visco elastic effects of the capillary bed do not seem to have a large effect on the BOLD signal even for relatively high values of oxygen consumption. While the results of the model suggests that potassium ions released during neural activity could act as the main mediator in NVC, it suggests the possibility of other mechanisms that can coexist and increase blood flow such as the arachidonic acid to epoxyeicosatrienoic acid (EET) pathway. The comparison with experimental cerebral blood flow (CBF) data indicates the possible existence of multiple neural pathways influencing the vascular response. Initial negative BOLD signals occur for all simulations due to the rate at which the metabolic oxygen consumption occurs relative to the dilation of the perfusing cerebro-vasculature. However it is unclear as to whether these are normally seen clinically due to the size of the magnetic field. Experimental comparisons for different animal experiments may very well require variation in the model parameters. The complex integrated model is believed to be the first of its kind to simulate both NVC and the resulting BOLD signal. PMID- 29526746 TI - Arsenic impairs insulin signaling in differentiated neuroblastoma SH-SY5Y cells. AB - A strong correlation between chronic arsenic exposure and neuropsychological disorders leads to a growing concern about a potential risk of arsenic related neurodegeneration. Evidently, brain insulin signaling contributes to physiological effects, including energy homeostasis, and learning and memory. Arsenic has been shown to impair insulin signaling in adipocytes and myocytes, however, this impairment has not yet been explored in neurons. Here we showed that NaAsO2 caused significant reduction in basal levels of glucose, plasma membrane glucose transporter, GLUT 3 and Akt phosphorylation in differentiated human neuroblastoma SH-SY5Y cells. NaAsO2 significantly decreased insulin mediated glucose uptake, as well as GLUT1 and 3 membrane translocation. Furthermore, the ability of insulin to increase Akt phosphorylation, a well recognized insulin signaling response, was significantly lessened by NaAsO2 treatment. In addition, the classical tyrosine phosphorylation response of insulin was reduced by NaAsO2, as evidenced by reduction of insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1(IRS-1). Moreover, NaAsO2 lowered the ratio of p110, a catalytic subunit to p85, a regulatory subunit of PI3K causing an imbalance between p110 and p85, the conditions reported to contribute to insulin sensitivity. Additionally, increment of IRS-1 interaction with GSK3beta, and p85-PI3K were observed in NaAsO2 treated cells. These molecular modulations may be mechanistically attributed to neuronal insulin signaling impairment by arsenic. PMID- 29526747 TI - Perfluorooctanesulfonate induces neuroinflammation through the secretion of TNF alpha mediated by the JAK2/STAT3 pathway. AB - Perfluorooctanesulfonate (PFOS)-containing compounds are widely used in all aspects of industrial and consumer products. Recent studies indicated that PFOS is ubiquitous in environments and is considered to be a new type of persistent organic pollutant (POP). This has raised concerns regarding its adverse effects on human health. The nervous system is regarded as a sensitive target of environmental contaminants, including PFOS. Previous findings showed that PFOS can induce neurobehavioral deficits. However, the molecular mechanism underlying PFOS neurotoxicity remains obscure. Astrocyte activation and the resulting pro inflammatory cytokine release play an integral role in protecting neurons from neurotoxin-mediated damage. If uncontrolled, sustained astrocyte activation may cause the secretion of excessive levels of pro-inflammatory cytokines that exacerbate the initial damage. In this study, we showed that PFOS could promote excessive secretion of tumor necrosis factor-alpha (TNF-alpha) in dose- and time dependent manners in astrocytes. Furthermore, PFOS exposure could induce the phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). This suggests that the JAK2/STAT3 signal transduction pathway is involved in PFOS-mediated astrocyte activation and secretion of TNF alpha. Indeed, targeted blockage of the JAK2/STAT3 pathway prevented the phosphorylation of JAK and STAT3, and it also caused abnormal expression of TNF alpha. Finally, we demonstrated that SH-SY5Y neuronal cells underwent rapid apoptosis via a TNF-alpha-dependent mechanism after exposure to PFOS-treated astrocyte-conditioned medium. In summary, our findings reveal that PFOS mediates a rapid activation of JAK2/STAT3 signal transduction in C6 astrocytes, which plays a pivotal role in the initiation of PFOS-mediated neurotoxicity. PMID- 29526748 TI - Detection of qnrVC6, within a new genetic context, in an NDM-1-producing Citrobacter freundii clinical isolate from Uruguay. AB - OBJECTIVES: The objective of this study was to characterise the mechanisms underlying quinolone and oxyimino-cephalosporin resistance in a Citrobacter freundii clinical isolate obtained from the ICU in a university hospital in Uruguay. METHODS: Citrobacter freundii strain CF638 was isolated from a urine culture. Identification was performed using a VITEK(r)2 system, and antimicrobial susceptibility was established by MIC determination and disk diffusion assay. Resistance genes and mobile genetic elements were identified by PCR and sequencing. Plasmid transfer was assessed by conjugation and the plasmid size was estimated by S1-PFGE. Plasmid incompatibility (Inc) group and toxin-antitoxin systems were sought by PCR. RESULTS: Strain CF638 showed a multidrug-resistant profile, including resistance to carbapenems and quinolones. Transconjugant TcCF638, harbouring an ca. 200-kb IncA/C plasmid, also showed resistance to all beta-lactams (except aztreonam) and diminished susceptibility to ciprofloxacin. PCR was positive for blaNDM-1 and qnrVC in CF638 and TcCF638. Two different class 1 integrons were detected (In127 and In907). In127 featured the genetic array aadA2-ltr2. Conversely, complex In907 featured two variable regions (VRs); VR-1 consisted of aadB-blaOXA-10-aadA1cc, whereas VR-2 featured a qnrVC6 gene 108bp downstream from ISCR1 and 45bp upstream from qacEDelta1. Expression of qnrVC6 was due to a putative promoter region, detected using the Neural Network Promoter Prediction program. CONCLUSION: To the best of our knowledge, this constitutes the first report of qnrVC within a complex class 1 integron, as well as the first report of the occurrence of such a gene in an NDM-1-producing enterobacterial clinical isolate. PMID- 29526749 TI - The effect of oxytocin on group formation and strategic thinking in men. AB - Decision-making in groups is a remarkable and decisive element of human societies. Humans are able to organize themselves in groups, engage in collaborative decision-making processes and arrive at a binding agreement, even in the absence of unanimous consent. However, the transfer of decision-making autonomy requires a willingness to deliberately expose oneself to the decisions of others. A lack of trust in the abilities of others or of the underlying decision-making process, i.e. public trust, can lead to a breakdown of organizations in political or economic domains. Recent studies indicate that the biological basis of trust on an individual level is related to Oxytocin, an endogenous neuropeptide and hormone, which is also associated with pro-social behavior and positive conflict resolution. However, little is known about the effects of Oxytocin on the inclination of individuals to form or join groups and to deliberately engage in collaborative decision-making processes. Here, we show that intranasal administration of Oxytocin (n = 60) compared to placebo (n = 60) in males causes an adverse effect on the choice for forming groups in the presence of a competitive environment. In particular, Oxytocin negatively affects the willingness to work collaboratively in a p-Beauty contest game, whereas the effect is most pronounced for participants with relatively high strategic sophistication. Since our data provide initial evidence that Oxytocin has a positive effect on strategic thinking and performance in the p-Beauty contest game, we argue that the adverse effect on group formation might be rooted in an enhanced strategic sophistication of participants treated with Oxytocin. PMID- 29526750 TI - The ghrelin paradox in the control of equine chondrocyte function: The good and the bad. AB - Increasing evidence suggests a role for ghrelin in the control of articular inflammatory diseases like osteoarthritis (OA). In the present study we examined the ability of ghrelin to counteract LPS-induced necrosis and apoptosis of chondrocytes and the involvement of GH secretagogue receptor (GHS-R)1a in the protective action of ghrelin. The effects of ghrelin (10-7-10-11 mol/L) on equine primary cultured chondrocytes viability and necrosis in basal conditions and under LPS treatment (100 ng/ml) were detected by using both acridine orange/propidium iodide staining and annexin-5/propidium iodide staining. The presence of GHS-R1a on chondrocytes was detected by Western Blot. The involvement of the GHS-R1a in the ghrelin effect against LPS-induced cytotoxicity was examined by pretreating chondrocytes with D-Lys3-GHRP-6, a specific GHS-R1a antagonist, and by using des-acyl ghrelin (DAG, 10-7 and 10-9 mol/L) which did not recognize the GHS-R 1a. Low ghrelin concentrations reduced chondrocyte viability whereas 10-7 mol/L ghrelin protects against LPS-induced cellular damage. The protective effect of ghrelin depends on the interaction with the GHS R1a since it is significantly reduced by D-Lys3-GHRP-6. The negative action of ghrelin involves caspase activation and could be due to an interaction with a GHS R type different from the GHS-R1a recognized by both low ghrelin concentrations and DAG. DAG, in fact, induces a dose-dependent decrease in chondrocyte viability and exacerbates LPS-induced damage. These data indicate that ghrelin protects chondrocytes against LPS-induced damage via interaction with GHS-R1a and suggest the potential utility of local GHS-R1a agonist administration to treat articular inflammatory diseases such as OA. PMID- 29526751 TI - Enoyl coenzyme A hydratase 1 protects against high-fat-diet-induced hepatic steatosis and insulin resistance. AB - Metabolic disorders, including obesity, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and diabetes, are complex and progressive diseases. Enoyl coenzyme A hydratase 1 (Ech1) is an enzyme that participates in mitochondrial fatty acid beta-oxidation; however, little is known regarding the significance of Ech1 in the pathogenesis of metabolic disorders. Here, we report that high-fat-diet (HFD)-induced and genetic obesity could increase Ech1 expression in mouse liver. The overexpression of Ech1 using adeno-associated virus (AAV2/8) ameliorated HFD-induced liver lipid accumulation and accompanying liver injury. Additionally, Ech1 overexpression resulted in improved dyslipidemia and insulin resistance in HFD-fed mice. Further, the studies revealed that Ech1 could directly inhibit lipogenesis gene expressions and attenuate the insulin pathway induced by an HFD. Together, our results demonstrate that Ech1 protects against HFD-induced hepatic steatosis and insulin resistance and that its inhibitory effects on lipogenesis and insulin signaling may partly explain its role in metabolic disorders. PMID- 29526752 TI - Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non small cell lung cancer. AB - Immunotherapy targeting the programmed cell death-1/programmed death ligand 1(PD L1) pathway has shown promising antitumor activity in brain metastases (BMs) of non-small cell lung cancer (NSCLC) patients with an acceptable safety profile; however, the response rates often differ between primary lesions and intracranial lesions. Studies are necessary to identify detailed characterizations of the response biomarkers. In this study, we aimed to compare the differences of PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density, two major response biomarkers of PD-1/PD-L1 blockade, between paired primary and brain metastatic lesions in advanced NSCLC. We observed that among primary lesions or BMs, only a small number of patients harbored common PD-L1 expression on both tumor cells and tumor-infiltrating immune cells. Additionally, we found that the numbers of CD8+ TILs were significantly fewer in BMs than in primary lung cancers. Low stromal CD8+ TIL numbers in BMs were associated with significantly shorter overall survival compared to high stromal CD8+ TIL counts. Notably, we demonstrated a discrepancy in PD-L1 expression and CD8+ TIL density between primary lung cancers and their corresponding BMs. Such heterogeneities are significantly associated with the time at which BMs occurred. Our study emphasizes the spatial and temporal heterogeneity of biomarkers for anti-PD-1/PD L1 therapy, which should be concerned in clinical practice. PMID- 29526753 TI - MFAP5 promotes tumor progression and bone metastasis by regulating ERK/MMP signaling pathways in breast cancer. AB - Breast cancer accounts for about 30% of all cancers in women, while approximately 70% breast cancer patients developed bone metastases throughout the course of their disease, highlighting the importance of exploring new therapeutic targets. Microfibrillar-associated protein 5 (MFAP5) is a component of extracellular elastic microfibril which has been confirmed to function in tissue development and cancer progression. But the role of MFAP5 in breast cancer remains unclear. The present study demonstrated that MFAP5 was up-regulated in breast cancers compared with that in normal breast tissues, and further increased in breast cancer bone metastasis. Functionally, MFAP5 overexpression accelerated breast cancer cell proliferation and migration, while an opposite effect was observed when MFAP5 was knocked down. In addition, up-regulation of MFAP5 increased the expression of MMP2 and MMP9 and activated the ERK signaling pathway. Conversely, inhibition of MFAP5 suppressed the expression of MMP2, MMP9, p-FAK, p-Erk1/2 and p-cJun. These findings may provide a better understanding about the mechanism of breast cancer and suggest that MFAP5 may be a potential prognostic biomarker and therapeutic target for breast cancer, especially for bone metastasis of breast cancer. PMID- 29526754 TI - Structure of a [NiFe] hydrogenase maturation protease HycI provides insights into its substrate selectivity. AB - The immature large subunit of [NiFe] hydrogenases undergoes C-terminal cleavage by a specific protease in the final step of the post-translational process before assembly with other subunits. It has been reported that the [NiFe] hydrogenase maturation protease HycI from Thermococcus kodakarensis (TkHycI) has the catalytic ability to target the membrane-bound hydrogenase large subunit MbhL from T. kodakarensis. However, the detailed mechanism of its substrate recognition remains elusive. We determined the crystal structure of TkHycI at 1.59 A resolution to clarify how TkHycI recognizes its own substrate MbhL. Although the overall structure of TkHycI is similar to that of its homologous protease TkHybD, TkHycI adopts a larger loop than TkHybD, thereby creating a broad and deep cleft. We analyzed the structural properties of the TkHycI cleft probably involved in its substrate recognition. Our findings provide novel and profound insights into the substrate selectivity of TkHycI. PMID- 29526755 TI - Circular RNA expression profiles in placental villi from women with gestational diabetes mellitus. AB - Circular RNAs (circRNAs) have recently been shown to exert their effects on multiple pathological processes by acting as microRNA (miRNA) sponges. However, the roles of circRNAs in gestational diabetes mellitus (GDM) are largely unknown. This study aimed to identify the circRNAs involved in GDM and predict their potential biological functions. We first performed next-generation sequencing (NGS) to generate unbiased placental villi circRNA expression profiles of GDM and normal controls. In total, 48,270 circRNAs from the placental villi of the two groups were sequenced. Of these, 227 circRNAs were significantly up-regulated and 255 circRNAs were significantly down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses demonstrated that glycometabolism and lipometabolism processes, which are important in GDM development, were significantly enriched. Further analysis showed that most of the circRNAs harbored miRNA binding sites, and some were associated with GDM. These results showed that circRNAs are aberrantly expressed in the placental villi of GDM patients and play potential roles in the development of GDM. PMID- 29526756 TI - Structural insights into the apo-structure of Cpf1 protein from Francisella novicida. AB - Clustered regularly interspaced short palindromic repeats (CRISPRs) from Prevotella and Francisella 1 (Cpf1) are RNA-guided endonucleases that produce cohesive double-stranded breaks in DNA by specifically recognizing thymidine-rich protospacer-adjacent motif (PAM) sequences. Cpf1 is emerging as a powerful genome editing tool. Despite previous structural studies on various Cpf1 proteins, the apo-structure of Cpf1 remains unknown. In the present study, we determined the solution structure of the Cpf1 protein from Francisella novicida (FnCpf1) with and without CRISPR RNA (crRNA) using small-angle X-ray scattering, providing the insights into the apo-structure of FnCpf1. The apo-structure of FnCpf1 was also visualized using negative staining electron microcopy. When we compared the apo structure of FnCpf1 with crRNA-bound structure, their overall shapes (a closed form) were similar, suggesting that conformational change upon crRNA binding to FnCpf1 is not drastic, but a local induced fit might occur to recognize PAM sequences. In contrast, the apo Cpf1 from Moraxella bovoculi 237 (MbCpf1) was analyzed as an open form, implying that a large conformational change from an open to a closed form might be required for crRNA binding to MbCpf1. These results suggested that the crRNA-induced conformational changes in Cpf1 differ among species. PMID- 29526757 TI - Oncostatin M induces tumorigenic properties in non-transformed human prostate epithelial cells, in part through activation of signal transducer and activator of transcription 3 (STAT3). AB - Prostate cancer is one of the most common types of cancer in men in Western countries. Chronic inflammation in the prostate, regulated by a complex network of factors including inflammatory cytokines, is one of the established risk factors for development of prostate cancer. Interleukin-6 (IL-6) is a well-known promoter of inflammation-induced carcinogenesis and disease progression in prostate cancer. Presence in the prostate and possible roles in tumor development by other members of the IL-6 family of cytokines have, however, been less studied. Here we show that the IL-6-type cytokine oncostatin M (OSM) indeed induce cellular properties associated with tumorigenesis and disease progression in non-transformed human prostate epithelial cells, including morphological changes, epithelial-to-mesenchymal transition (EMT), enhanced migration and pro invasive growth patterns. The effects by OSM were partly mediated by activation of signal transducer and activator of transcription 3 (STAT3), a transcription factor established as driver of cancer progression and treatment resistance in numerous types of cancer. The findings presented here further consolidate IL-6 type cytokines and STAT3 as promising future treatment targets for prostate cancer. PMID- 29526758 TI - A potential risk factor of essential hypertension in case-control study: Circular RNA hsa_circ_0037911. AB - BACKGROUND: Essential hypertension (EH) is a high prevalence with multifactorial diseases. Human studies on the impact of genes on this disease are just in the initial stage, the mechanism of gene regulation is still remains unclear. Circular RNAs (circRNAs) as a continuous cycle of covalent closure, RNA molecules added to the 3'-5' end covalently bound by the formation of incidental event. CircRNAs may be an important biomolecule in revealing the molecule regulate mechanisms of EH. METHODS: The circRNAs were selected and validated with qRT-PCR followed. Our experiment was conducted with case-control studies among 200 EH participants. The t-test was used to evaluate the different expression of circRNAs and miRNAs, the significance of which was set as p < 0.05. RESULTS: The hsa_circ_0037911 expression level in EH cases were significantly higher than healthy controls (p = 0.005). There was still important significance when adjusted by logistic regression (adjusted p = 0.026). We also found that hsa_circ_0037911 was an effective marker of EH (area under curve = 0.627; p = 0.002). The levels of hsa_circ_0037911 were significantly differences in gender, BMI, smoking and drinking among EH cases. There was a positive correlation between Serum creatinine (Scr) and hsa_circ_0037911. CONCLUSIONS: Our findings suggested that higher expression hsa_circ_0037911 may be key circRNAs for EH development by changing the concentration of Scr and could be a stable biomarker for early diagnosis of EH. PMID- 29526759 TI - Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain. AB - Excitatory amino acid transporters (EAATs) on cerebral vascular endothelial cells play an important role in maintaining glutamate homeostasis in the brain. The dysfunction of endothelial EAATs is an important reason for the dramatically elevated brain glutamate levels after brain injury, such as traumatic brain injury (TBI). The adenosine A2A receptor (A2AR) plays an important role in regulating the brain glutamate level after brain injury; however, researchers have not clearly determined whether this role was related to its ability to regulate endothelial EAATs. Activation of A2AR in vitro not only decreased the PKA- and glutamate level-dependent strengthening of the interaction between NKA alpha1 and the FXYD1 subunit and the subsequent decrease in the activity of Na+/K+-ATPases (NKAs) but also enhanced its interaction with EAATs and ultimately aggravated the reverse transport function of endothelial EAATs under oxygen glucose deprivation (OGD) conditions. Conversely, inhibition of A2AR restored the normal transport of EAAT. Moreover, A2AR inhibition increased NKA activity and decreased its interaction with EAATs in isolated brain capillaries after TBI, further confirming its role in endothelial EAATs in vivo. Based on our results, A2AR played an important role in regulating endothelial EAAT function, and strategies that restore the normal transport of endothelial EAATs through the inhibition of A2AR might serve as an effective treatment for brain injury. PMID- 29526760 TI - Dual Role of the Anaphase Promoting Complex/Cyclosome in Regulating Stemness and Differentiation in Human Primary Keratinocytes. AB - Cdc20 and Cdh1 activate the anaphase-promoting complex/cyclosome, a master cell cycle regulator. Although cell cycle modifications occur during differentiation of stem cells, a role for the anaphase-promoting complex/cyclosome on stem cell fate has not been established in embryonic or adult human tissues. We found that differentiated human primary keratinocytes from the skin express extremely low levels of Cdc20 compared with human primary keratinocyte stem cells (holoclones). In agreement with this, staining of human skin biopsies showed that Cdc20 is expressed in occasional cells from the basal and epibasal layers of the epidermis and is absent from the differentiated layers. Conversely, Cdh1 is preferentially expressed in differentiated cells. Interestingly, partial silencing of Cdc20 enhanced differentiation, indicating that loss of Cdc20 might be a cause rather than a consequence of terminal differentiation. By contrast, Cdh1 silencing induced the opposite cellular phenotype, which was characterized by an increase in stemness, cellular proliferation, and loss of differentiation markers. These data pinpoint the anaphase-promoting complex/cyclosome as a key regulator of adult stem cell fate. They also demonstrate the critical and opposing roles of Cdc20 and Cdh1 in controlling the balance between human primary keratinocyte proliferation and differentiation, and therefore in regulating skin homeostasis. PMID- 29526761 TI - Type I Immune Response Induces Keratinocyte Necroptosis and Is Associated with Interface Dermatitis. AB - Interface dermatitis is a characteristic histological pattern that occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different interface dermatitis positive skin diseases, lichen planus and lupus erythematosus. The shared transcriptome signature pointed toward a strong type I immune response, and biopsy-derived T cells were dominated by IFN-gamma and tumor necrosis factor alpha (TNF-alpha) positive cells. The transcriptome of keratinocytes stimulated with IFN-gamma and TNF-alpha correlated significantly with the shared gene regulations of lichen planus and lupus erythematosus. IFN-gamma, TNF-alpha, or mixed supernatant of lesional T cells induced signs of keratinocyte cell death in three-dimensional skin equivalents. We detected a significantly enhanced epidermal expression of receptor-interacting-protein-kinase 3, a key regulator of necroptosis, in interface dermatitis. Phosphorylation of receptor-interacting-protein-kinase 3 and mixed lineage kinase domain like pseudokinase was induced in keratinocytes on stimulation with T-cell supernatant-an effect that was dependent on the presence of either IFN-gamma or TNF-alpha in the T-cell supernatant. Small hairpin RNA knockdown of receptor-interacting-protein-kinase 3 prevented cell death of keratinocytes on stimulation with IFN-gamma or TNF-alpha. In conclusion, type I immunity is associated with lichen planus and lupus erythematosus and induces keratinocyte necroptosis. These two mechanisms are potentially involved in interface dermatitis. PMID- 29526763 TI - Lysosomes Support the Degradation, Signaling, and Mitochondrial Metabolism Necessary for Human Epidermal Differentiation. AB - Keratinocytes undergo significant structural remodeling during epidermal differentiation, including a broad transformation of the proteome coupled with a reduction in total cellular biomass. This suggests that intracellular digestion of proteins and organelles is necessary for keratinocyte differentiation. Here, we use both genetic and pharmacologic approaches to demonstrate that autophagy and lysosomal functions are required for keratinocyte differentiation in organotypic human skin. Lysosomal activity was required for mechanistic target of rapamycin signaling and mitochondrial oxidative metabolism. In turn, mitochondrial reactive oxygen species, produced as a natural byproduct of oxidative phosphorylation, were necessary for keratinocyte differentiation. Finally, treatment with exogenous reactive oxygen species rescued the differentiation defect in lysosome-inhibited keratinocytes. These findings highlight a reciprocal relationship between lysosomes and mitochondria, in which lysosomes support mitochondrial metabolism and the associated production of mitochondrial reactive oxygen species. The mitochondrial reactive oxygen species released to the cytoplasm in suprabasal keratinocytes triggers autophagy and lysosome-mediated degradation necessary for epidermal differentiation. As defective lysosome-dependent autophagy is associated with common skin diseases including psoriasis and atopic dermatitis, a better understanding of the role of lysosomes in epidermal homeostasis may guide future therapeutic strategies. PMID- 29526762 TI - Lack of Type 2 Innate Lymphoid Cells Promotes a Type I-Driven Enhanced Immune Response in Contact Hypersensitivity. AB - Allergic contact dermatitis and its animal model, contact hypersensitivity, are T cell-mediated inflammatory skin diseases that require activation of the innate immune system. Here we investigate the role of innate lymphoid cells (ILCs) during the elicitation phase of 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity using EomesGfp/+ x Rorc(gammat)-CreTg x Rosa26RYfp/+ reporter mice. Ear swelling responses, cutaneous ILC numbers, and cytokine production were determined at different time points. Functional analyses were performed in a CD90.1/.2 congenic adoptive transfer model that allowed selective antibody mediated depletion of ILCs before hapten challenge, and in Rorasg/floxIl7rCre/+ mice, which lack ILC2. Hapten challenge induced early increases of natural killer cells in skin and ear draining lymph nodes corresponding to the peak ear swelling response. In contrast, ILC1, 2, and 3 showed a delayed increase in numbers corresponding to the contact hypersensitivity resolution phase. Hapten challenge induced increased marker cytokines in all ILC subtypes and an activated phenotype in ILC2. Depletion of all ILC resulted in a significantly enhanced ear swelling response. Similarly, ILC2-deficient mice (Rorasg/floxIl7rCre/+) displayed increased ear swelling responses on hapten challenge, suggesting that ILC2 act as negative regulators in the type 1-dominated immune response of contact hypersensitivity. PMID- 29526764 TI - Dissociating meditation proficiency and experience dependent EEG changes during traditional Vipassana meditation practice. AB - Meditation, as taught by most schools of practice, consists of a set of heterogeneous techniques. We wanted to assess if EEG profiles varied across different meditation techniques, proficiency levels and experience of the practitioners. We examined EEG dynamics in Vipassana meditators (Novice, Senior meditators and Teachers) while they engaged in their traditional meditation practice (concentration, mindfulness and loving kindness in a structured manner) as taught by S.N. Goenka. Seniors and Teachers (vs Novices) showed trait increases in delta (1-4 Hz), theta-alpha (6-10 Hz) and low-gamma power (30-40 Hz) at baseline rest; state-trait increases in low-alpha (8-10 Hz) and low-gamma power during concentrative and mindfulness meditation; and theta-alpha and low gamma power during loving-kindness meditation. Permutation entropy and Higuchi fractal dimension measures further dissociated high proficiency from duration of experience as only Teachers showed consistent increase in network complexity from baseline rest and state transitions between the different meditation states. PMID- 29526765 TI - Pharmacometabolomics analysis of plasma to phenotype clopidogrel high on treatment platelets reactivity in coronary artery disease patients. AB - Dual antiplatelet therapy (DAPT) of clopidogrel and aspirin is crucial for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, some patients may endure clopidogrel high on treatment platelets reactivity (HTPR) which may cause thromboembolic events. Clopidogrel HTPR is multifactorial with some genetic and non-genetic factors contributing to it. We aimed to use nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis of plasma to investigate this multifactorial and identify metabolic phenotypes and pathways associated with clopidogrel HTPR. Blood samples were collected from 71 CAD patients planned for interventional angiographic procedure (IAP) before the administration of clopidogrel 600 mg loading dose (LD) and 6 h after the LD. Platelets function testing was done 6 h post-LD using VerifyNow(r) P2Y12 assay. Pre-dose and post-dose plasma samples were analysed using 1H NMR. Multivariate statistical analysis was used to indicate the discriminating metabolites. Two metabotypes, each with 34 metabolites (pre-dose and post-dose) were associated with clopidogrel HTPR. Pathway analysis of these metabotypes revealed that aminoacyl-tRNA biosynthesis, nitrogen metabolism and glycine-serine-threonine metabolism are the most perturbed metabolic pathways associated with clopidogrel HTPR. Furthermore, the identified biomarkers indicated that clopidogrel HTPR is multifactorial where the metabolic phenotypes of insulin resistance, type two diabetes mellitus, obesity, gut-microbiota and heart failure are associated with it. Pharmacometabolomics analysis of plasma revealed new insights on the implicated metabolic pathways and the predisposing factors of clopidogrel HTPR. PMID- 29526766 TI - Novel hGHRH homodimer promotes fertility of female infertile hamster by up regulating ovarian GHRH receptor without triggering GH secretion. AB - Extra-hypothalamic growth hormone-releasing hormone (GHRH) plays an important role in infertility. The female infertility models were formed by intraperitoneally injecting cyclophosphamide in 5-week-old Chinese hamster once in a week for 5 weeks. All the models mated with healthy male hamster in the ratio of 1:1 in the experimental 6-8th week and the couples were separated to breed in the 9-10th week. 20 mg/kg of cyclophosphamide induced temporary interference of reproduction and did not cause significant difference in the weight of body, bilateral ovaries, or liver. By intramuscularly injecting twice in a week during the experimental 4-10th week, 2, 4, 8 mg/kg of Grin induced 30, 42.9, 60% of total pregnancy rates in a dose-dependent manner whereas 200 U/kg of hMG induced 50% of total pregnancy rates. The single cyclophosphamide dose caused strongly eosinophilic ovarian cells, scattered early follicles, many atretic follicles, and no corpora luteum was observed. The hMG group individually presents many follicles at all levels, especially secondary ones in the ovarian cortex and medulla. Much of loose connective tissue, vacuoles, and sparse interstitial cells distribute in the medulla. Grin induced many follicles at all dose levels and corpora lutea in the cortex, and the compactly aligned interstitial cells occurred in the whole ovarian tissue. The less TUNEL staining and higher expression of ki67 showed the proliferation and protection effect of Grin on ovarian cells. Grin obviously promotes fertility by up-regulating ovarian GHRH receptor and strengthening the development and maturation of follicles without triggering central and ovarian GH secretion. PMID- 29526767 TI - Advances in cryo-electron tomography for biology and medicine. AB - Cryo-electron tomography (CET) utilizes a combination of specimen cryo-fixation and multi-angle electron microscopy imaging to produce three-dimensional (3D) volume reconstructions of native-state macromolecular and subcellular biological structures with nanometer-scale resolution. In recent years, cryo-electron microscopy (cryoEM) has experienced a dramatic increase in the attainable resolution of 3D reconstructions, resulting from technical improvements of electron microscopes, improved detector sensitivity, the implementation of phase plates, automated data acquisition schemes, and improved image reconstruction software and hardware. These developments also greatly increased the usability and applicability of CET as a diagnostic and research tool, which is now enabling structural biologists to determine the structure of proteins in their native cellular environment to sub-nanometer resolution. These recent technical developments have stimulated us to update on our previous review (Koning, R.I., Koster, A.J., 2009. Cryo-electron tomography in biology and medicine. Ann Anat 191, 427-445) in which we described the fundamentals of CET. In this follow-up, we extend this basic description in order to explain the aforementioned recent advances, and describe related 3D techniques that can be applied to the anatomy of biological systems that are relevant for medicine. PMID- 29526768 TI - Inducible glutathione S-transferase (IrGST1) from the tick Ixodes ricinus is a haem-binding protein. AB - Blood-feeding parasites are inadvertently exposed to high doses of potentially cytotoxic haem liberated upon host blood digestion. Detoxification of free haem is a special challenge for ticks, which digest haemoglobin intracellularly. Ticks lack a haem catabolic mechanism, mediated by haem oxygenase, and need to dispose of vast majority of acquired haem via its accumulation in haemosomes. The knowledge of individual molecules involved in the maintenance of haem homeostasis in ticks is still rather limited. RNA-seq analyses of the Ixodes ricinus midguts from blood- and serum-fed females identified an abundant transcript of glutathione S-transferase (gst) to be substantially up-regulated in the presence of red blood cells in the diet. Here, we have determined the full sequence of this encoding gene, ir-gst1, and found that it is homologous to the delta /epsilon-class of GSTs. Phylogenetic analyses across related chelicerates revealed that only one clear IrGST1 orthologue could be found in each available transcriptome from hard and soft ticks. These orthologues create a well-supported clade clearly separated from other ticks' or mites' delta-/epsilon-class GSTs and most likely evolved as an adaptation to tick blood-feeding life style. We have confirmed that IrGST1 expression is induced by dietary haem(oglobin), and not by iron or other components of host blood. Kinetic properties of recombinant IrGST1 were evaluated by model and natural GST substrates. The enzyme was also shown to bind haemin in vitro as evidenced by inhibition assay, VIS spectrophotometry, gel filtration, and affinity chromatography. In the native state, IrGST1 forms a dimer which further polymerises upon binding of excessive amount of haemin molecules. Due to susceptibility of ticks to haem as a signalling molecule, we speculate that the expression of IrGST1 in tick midgut functions as intracellular buffer of labile haem pool to ameliorate its cytotoxic effects upon haemoglobin intracellular hydrolysis. PMID- 29526769 TI - JH biosynthesis and hemolymph titers in adult male Aedes aegypti mosquitoes. AB - Juvenile hormone (JH) is a major hormonal regulator in insects. In Aedes aegypti females, JH signals the completion of the ecdysis to the adult stage and initiates reproductive processes. Although the regulation of JH synthesis and titer in Ae. aegypti females has been extensively studied, relatively little is known about changes of JH synthesis and titers in male mosquitoes, as well as on the roles of JH controlling male reproductive biology. A better understanding of male mosquito reproductive biology, including an improved knowledge of the hormonal control of reproduction, could increase the likelihood of success of male-targeting vector control programs. Using a high performance liquid chromatography coupled to electrospray tandem mass spectrometry method, we measured JH biosynthesis and hemolymph levels in male mosquitoes during pupal and adult stages. Our results revealed tightly concomitant changes in JH biosynthesis and JH hemolymph titers. Synthesis of JH III was very low in late pupae, significantly increased during the first 24 h after adult eclosion, and then remained relatively constant during the first six days after adult eclosion. Feeding high sugar diets resulted in an increase of JH synthesis and titers, and starvation significantly decreased JH synthesis, but this effect could be reversed by changing the males back to a high sugar diet. JH synthesis rates were similar in virgin and mated males, but hemolymph JH levels were different in well nourished virgin and mated males. Starvation resulted in a significant reduction in insemination rates; with well-nourished males inseminating 2 times more females than water-fed. Giving a 20% sugar meal for 24 h to those mosquitoes that were previously starved for 6 days, caused a significant rise in insemination rates, restoring them to levels similar to those recorded for 20% fed males. These results suggest that nutrition plays a role on male fecundity, and this effect might be mediated by JH. PMID- 29526770 TI - HR38, an ortholog of NR4A family nuclear receptors, mediates 20-hydroxyecdysone regulation of carbohydrate metabolism during mosquito reproduction. AB - The Aedes aegypti mosquito is the principal vector for many dangerous human viral diseases. Carbohydrate metabolism (CM) is essential for supplying the energy necessary for host seeking, blood digestion and rapid egg development of this vector insect. The steroid hormone 20-hydroxyecdysone (20E) and the ecdysone receptor (EcR) are important regulators of CM, coordinating it with female reproductive events. We report here that the NR4A nuclear receptor AHR38 plays a critical role in mediating these actions of 20E and EcR. AHR38 RNA interference (RNAi) depletion in female mosquitoes blocked the transcriptional activation of CM genes encoding phosphoglucomutase (PGM) and trehalose-6-phophate synthase (TPS); it caused an increase of glycogen accumulation and a decrease of the circulating sugar trehalose. This treatment also resulted in a dramatic reduction in fecundity. Considering that these phenotypes resulting from AHR38 RNAi depletion are similar to those of EcR RNAi, we investigated a possible connection between these transcription factors in CM regulation. EcR RNAi inhibits the AHR38 gene expression. Moreover, the 20E-induced EcR complex directly activates AHR38 by binding to the ecdysone response element (EcRE) in the upstream regulatory region of this gene. The present work has implicated AHR38 in the 20E-mediated control of CM and provided new insight into mechanisms of 20E regulation of metabolism during female mosquito reproduction. PMID- 29526771 TI - Targeting symbiosis-related insect genes by RNAi in the pea aphid-Buchnera symbiosis. AB - The growth and reproduction of phloem sap-feeding insects requires the sustained function of intracellular bacteria localized in specialized cells known as bacteriocytes, giving the potential to target the bacterial symbiosis as a novel strategy for controlling sap-feeding insect pests. We focused on two genes in the pea aphid Acyrthosiphon pisum, amiD and ldcA1, which were acquired horizontally from bacteria and have the annotated function to degrade immunogenic bacterial peptidoglycan. We hypothesized that AmiD and LdcA1 function to eliminate peptidoglycan fragments released by the bacterial symbiont Buchnera inhabiting the bacteriocytes, thereby protecting the Buchnera from host attack. Consistent with this hypothesis, expression of amiD and ldcA1 was enriched in bacteriocytes and varied significantly with aphid age, conforming to an inverse curvilinear relationship for amiD and negative linear relationship for ldcA1. RNAi against amiD and ldcA1 administered orally to larval pea aphids caused a significant reduction in Buchnera abundance and activity, accompanied by depressed aphid growth rates. For RNAi experiments, the aphids were co-administered with dsRNA against an aphid nuclease nuc1, protecting the dsRNA against non-specific degradation. These experiments demonstrate that selective suppression of insect symbiosis-related gene function can reduce the performance of an insect pest. Phylogenetic analysis identified amiD and ldcA1 in sequenced genomes of other aphid species, and amiD in related groups of phloem-feeding insects, offering the opportunity for specific controls against a range of insect pests. PMID- 29526773 TI - Altered brain functional connectivity and behaviour in a mouse model of maternal alcohol binge-drinking. AB - Prenatal and perinatal alcohol exposure caused by maternal alcohol intake during gestation and lactation periods can have long-lasting detrimental effects on the brain development and behaviour of offspring. Children diagnosed with Foetal Alcohol Spectrum Disorders (FASD) display a wide range of cognitive, emotional and motor deficits, together with characteristic morphological abnormalities. Maternal alcohol binge drinking is particularly harmful for foetal and early postnatal brain development, as it involves exposure to high levels of alcohol over short periods of time. However, little is known about the long-term effects of maternal alcohol binge drinking on brain function and behaviour. To address this issue, we used pregnant C57BL/6 female mice with time-limited access to a 20% v/v alcohol solution as a procedure to model alcohol binge drinking during gestation and lactational periods. Male offspring were behaviourally tested during adolescence (30 days) and adulthood (60 days), and baseline neural metabolic capacity of brain regions sensitive to alcohol effects were also evaluated in adult animals from both groups. Our results show that prenatal and postnatal alcohol exposure caused age-dependent changes in spontaneous locomotor activity, increased anxiety-like behaviour and attenuated alcohol-induced conditioned place preference in adults. Also, significant changes in neural metabolic capacity using cytochrome c oxidase (CCO) quantitative histochemistry were found in the hippocampal dentate gyrus, the mammillary bodies, the ventral tegmental area, the lateral habenula and the central lobules of the cerebellum in adult mice with prenatal and postnatal alcohol exposure. In addition, the analysis of interregional CCO activity correlations in alcohol-exposed adult mice showed disrupted functional brain connectivity involving the limbic, brainstem, and cerebellar regions. Finally, increased neurogenesis was found in the dentate gyrus of the hippocampus of alcohol-exposed offspring, suggesting neuroadaptive effects due to early alcohol exposure. Our results demonstrate that maternal binge-like alcohol drinking causes long-lasting effects on motor and emotional related behaviours associated with impaired neuronal metabolic capacity and altered functional brain connectivity. PMID- 29526772 TI - A deep insight into the male and female sialotranscriptome of adult Culex tarsalis mosquitoes. AB - Previously, a Sanger-based sialotranscriptome analysis of adult female Culex tarsalis was published based on ~2000 ESTs. During the elapsed 7.5 years, pyrosequencing has been discontinued and Illumina sequences have increased considerable in size and decreased in price. We here report an Illumina-based sialotranscriptome that allowed finding the missing apyrase from the salivary transcriptome of C. tarsalis, to determine several full-length members of the 34 62 kDa family, when a single EST has been found previously, in addition to identifying many salivary families with lower expression levels that were not detected previously. The use of multiple libraries including salivary glands and carcasses from male and female organisms allowed for an unprecedented insight into the tissue specificity of transcripts, and in this particular case permitting identification of transcripts putatively associated with blood feeding, when exclusive of female salivary glands, or associated with sugar feeding, when transcripts are found upregulated in both male and female glands. PMID- 29526774 TI - Analysis of relapse after transplantation in acute leukemia: A comparative on second allogeneic hematopoietic cell transplantation and donor lymphocyte infusions. AB - Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLIs) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT after receiving debulking therapy. In total, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4-66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI. The median follow-up of the cohort was 273 days (range 9-7013). Overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and cumulative incidence (CI) of relapse were calculated from DLI or second Allo-HCT date. In univariate analysis, second Allo-HCT was associated with higher OS (p = 0.021) and a trend to higher DFS (p = 0.097) and CI of relapse (p = 0.094) on univariate analysis. However, multivariate analysis showed comparable outcomes between DLI and second Allo-HCT, with the time interval to relapse before DLI or second Allo-HCT the only statistically significant factor with an impact on OS and DFS. Within the DLI cohort, T-cell-depleted Allo-HCT was associated with higher OS (p = 0.003) and DFS (p < 0.001) and lower CI of relapse (p = 0.002) than T-cell-replete Allo-HCT. Overall, in this cohort of AL patients, second Allo-HCT and DLI associated similar outcomes. As in other relapse studies, the length of remission (time to relapse) was identified as a factor with statistical impact on survival. Further studies are warranted. PMID- 29526775 TI - Planar lipid bilayers in recombinant ion channel research. AB - There are a number of methods of investigating the function of recombinant proteins such as ion channels. However, after channel purification there are few methods to guarantee that the protein still functions. For ion channels, reconstituting back into planar lipid bilayers and demonstrating preserved function is a convenient and trusted method. It is cell free and even inaccessible, intracellular ion channels can be studied. We have used this method to study the function of recombinant channels of known subunit composition and have found it convenient for investigating the mode of action of ion channel modulators. PMID- 29526776 TI - Sub-concussive trauma, acute concussion, and history of multiple concussions: Effects on quiet stance postural control stability. AB - Although balance control has been studied extensively following acute concussion, little is known regarding repetitive sub-concussive head impacts or chronic exposure to multiple concussive events. Quiet stance postural control was characterized in contact sport athletes at pre-season (n = 135) and post-season (n = 48) to evaluate the effects of subconcussive trauma to the head. To determine the impact of acute concussion on postural control, athletes diagnosed with a concussion during the season (n = 12) were tested at 72-h, 2-weeks, and 1 month post-injury. Because only 4 of the concussed athletes completed baseline testing, control athletes (n = 12) matched for sport, age, body mass index (BMI), and previous concussion history served as a comparison group. Finally, the effects of previous concussion history on quiet stance postural control were determined by comparing pre-season data in contact sport athletes with either zero (Hx0, n = 50) or three or more (Hx3+, n = 25) previous concussions. A force plate was used to compare changes in centre-of-pressure root-mean-square displacement (RMSdisp) and mean-velocity (COPvel) in the anterior/posterior (AP) and medial/lateral (ML) directions. One-minute trials were performed with feet hip-width apart, hands-on-hips, and A) eyes-open and B) eyes-closed. Biomechanical head-impact exposure (impacts over 10 g) was indexed over the season using mastoid-fixed impact sensors. In acutely injured athletes, repeated measures ANOVA revealed a significant effect of time for RMSdisp AP with increased displacement at 2 weeks compared to 72 h (p = 0.008, 95% CI: -0.180, 0.310 cm). No other COP variables were affected by acute concussion. Moreover, there was no effect of concussion history or repeated sub-concussive impacts on any quiet stance metric. Additionally, head-impact exposure metrics were not correlated with COP metrics. Taken together, the data suggests alterations in COP sway during quiet stance persist in the acute 2-week period after injury. These findings were not present with either a history of multiple concussions or exposure to sub-concussive head impacts indicating acute concussion does not have appear to have long term effects for these measures. PMID- 29526777 TI - Comparative proteomic analysis of chief and oxyphil cell nodules in refractory uremic hyperparathyroidism by iTRAQ coupled LC-MS/MS. AB - : SHPT is one of the most common complications of CKD-MBD. Recent studies indicate that oxyphil cell proliferation is related to SHPT progression, while not inhibited by current treatments. The aim of this study was to analyze the correlation between oxyphil cell and clinical indicators in SHPT, further explore the protein expression differences of oxyphil cell. Among 33 MHD patients, 84.8% patients have one or more oxyphil dominant glands and the overall oxyphil cells proportion was 39.5 +/- 16.3%. Univariate correlation and multivariable linear regression model showed that oral calcitriol dosage and treatment duration were independently correlated to oxyphil cell ratio. Proteomic study showed that mitochondrial protein, protein synthesis, and cell cycle regulation were significantly altered in oxyphil cell nodules. DBP was downregulated in oxyphil nodules on protein level, which may contribute to calcitriol resistance by reducing vitamin D transport. Through KEGG and PPI network analysis, Wnt signaling, TGF-beta, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules. Among which, MIF-CUL1 axis was significantly increased. These results suggest that the limitations of vitamin D in SHPT treatment is closely related to oxyphil cell and may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell. SIGNIFICANCE: Secondary hyperparathyroidism in end stage renal patients is one of the major challenges nephrology field faces. Emerging data indicate that oxyphil cell may participate in the pathophysiology of secondary hyperparathyroidism, while both calcimimetics and vitamin D receptor activators treatments are underperformed in controlling oxyphil cell proliferation. In the present study, we validated that the proliferation of oxyphil cells is associated with calcitriol treatment, and discovered that oxyphil cell nodules were significantly different from chief cells nodules in protein expression of mitochondria, protein synthesis and cell cycle regulation. It is noteworthy that DBP was downregulated in oxyphil nodules on protein level and may therefore participate in the resistance of calcitriol therapy by reducing the vitamin D transport capacity. Wnt signaling, TGF-beta, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules, among which, MIF-CUL1 axis may play an important role in the regulation of oxyphil proliferation and calcitriol resistance through ubiquitin mediated proteolysis. These results suggest that calcitriol treatment has limitations in oxyphil cell predominant SHPT, which may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell, and the influence of microenvironment in uremia status may be the underlying reason. PMID- 29526778 TI - Disseminated Oligodendroglial-like Leptomeningeal Tumor in the Adult: Case Report and Review of the Literature. AB - BACKGROUND: Diffuse leptomeningeal glioneuronal tumor (DLGNT) was recently added to the World Health Organization classification of central nervous system tumors. DLGNT is a rare entity that occurs more commonly in pediatric patients, but occasional cases have been reported in adults. This tumor has been recognized as a distinct pathologic entity; however, its biologic behavior remains unclear. It is considered an indolent neoplasm, although considerable morbidity has been reported. For this reason, further characterization and collection of evidence are crucial. METHODS: In this article, we reported a case of a 36-year-old woman with a DLGNT characterized by rapid, aggressive behavior. We also performed a review of the literature for reported cases of low-grade and high-grade forms involving adults and children. RESULTS: DLGNTs should no longer be considered only as low-grade tumors affecting pediatric patients. The spectrum of presentations also includes aggressive tumors affecting adults. CONCLUSIONS: Further clinical and pathologic data supported by cytogenetic and molecular investigations are mandatory to better characterize DLGNTs. PMID- 29526779 TI - Tuberculous Spondylolisthesis: A Reappraisal of the Clinicoradiologic Spectrum and Surgical Treatment Paradigm. AB - INTRODUCTION: Spinal tuberculosis (TB) is a common infectious disease prevalent in developing countries and an increasing issue in developed countries. The association of tuberculosis with spondylolisthesis is rarely reported in literature. The aim of our review is to analyze the clinical features and radiologic characteristics of TB spondylolisthesis and to provide a concise update on its surgical management, based on the literature. METHODS: A systematic review was performed after conducting a thorough search of the PubMed database. Articles were selected systematically and reviewed completely and relevant data were summarized and discussed. RESULTS: Nineteen articles were selected for the review. The most common clinical manifestation was focal back pain, followed by motor deficit. Most patients had grade 2 listhesis and associated tubercular abscess. The anterior as well as the posterior surgical approach have their own advantages and the choice of approach depends on the location of disease, ease of access, achievement of spinal stability, and avoidance of spread of contiguous infection. Although a posterior approach and fixation using pedicular screws and rods along with debridement of pus or granulation tissue is the favored approach in dorsolumbar TB, an anterior approach, corpectomy, and fusion are preferred in cervical TB. CONCLUSIONS: Treatment of TB spondylolisthesis encompasses a wide spectrum of surgical options. However, the mainstay of treatment is chemotherapy. The indications for which surgical management may have an upper hand over medical management are spinal cord compression, significant instability, large tubercular abscess, painful vertebral lesions, kyphosis, and infection by multidrug resistant TB or extreme drug-resistant TB, when medical management alone does not help. Surgery is effective in these situations by achieving radical debridement, permanent stability, prevention of further neurologic deterioration, and early recovery. Even although conservative management may help in certain cases, a posterior approach, decompression, and fusion are preferred for unstable dorsolumbar disease, whereas an anterior approach is preferred for cervical disease. Combined approaches can be considered in pediatric spinal TB for the correction of kyphotic deformity and its consequent maintenance. PMID- 29526780 TI - Subchondral bone microarchitecture in ACL reconstructed knees of young women: A comparison with contralateral and uninjured control knees. AB - Anterior cruciate ligament (ACL) tears are a common sports-related knee injury that increases the risk of developing post-traumatic osteoarthritis (OA). During OA progression bone microarchitecture changes in the affected knee, however, little is known about bone microarchitecture in knees with early stage OA. The purpose of this study is to investigate in a cohort of females predisposed to develop OA how bone microarchitecture in ACL reconstructed knees differs from uninjured contralateral knees as well as healthy control knees and how this relates to early changes in OA. Bone microarchitecture was directly assessed in ACL reconstructed knees of injured female participants (n=15) with a median age of 25.4years (age range: 22.5-28.5) and compared to their uninjured contralateral knees, as well as to a healthy age-matched female control sample (n=14) with a median age of 25.2years (age range: 22.2-27.1). ACL reconstructed knees had lower trabecular bone mineral density (compared to contralateral: -7.7% to -10.4%, p<0.05; control knees: -7.1% to -13.9%, p<0.05) and altered trabecular bone microarchitecture in the medial femur compared to contralateral and control knees. The subchondral bone plate in the lateral femur was thicker in ACL reconstructed knees compared to contralateral (29.6%, p=0.009) and control knees (47.9% to 53.7%, p<0.05). Contralateral knees did not differ from control knees. Loss of trabecular bone and increased subchondral bone plate thickness in the ACL reconstructed knees are consistent with changes associated with OA progression. Most differences in bone microarchitecture were found in the femur, with few differences in the tibia. The bone microarchitecture of contralateral knees did not differ from control knees in our participants, suggesting the potential to use them as control references in future longitudinal studies. PMID- 29526781 TI - Comparison of femoral strength and fracture risk index derived from DXA-based finite element analysis for stratifying hip fracture risk: A cross-sectional study. AB - BACKGROUND: Dual-energy X-ray absorptiometry (DXA)-based finite element analysis (FEA) has been studied for assessment of hip fracture risk. Femoral strength (FS) is the maximum force that the femur can sustain before its weakest region reaches the yielding limit. Fracture risk index (FRI), which also considers subject specific impact force, is defined as the ratio of von Mises stress induced by a sideways fall to the bone yield stress over the proximal femur. We compared risk stratification for prior hip fracture using FS and FRI derived from DXA-based FEA. METHODS: The study cohort included women aged >=65years undergoing baseline hip DXA, with femoral neck T-scores <-1 and no osteoporosis treatment; 324 cases had prior hip fracture and 655 controls had no prior fracture. Using anonymized DXA hip scans, we measured FS and FRI. Separate multivariable logistic regression models were used to estimate odds ratios (ORs), c-statistics and their 95% confidence intervals (95% CIs) for the association of hip fracture with FS and FRI. RESULTS: Increased hip fracture risk was associated with lower FS (OR per SD 1.36, 95% CI: 1.15, 1.62) and higher FRI (OR per SD 1.99, 95% CI: 1.63, 2.43) after adjusting for Fracture Risk Assessment Tool (FRAX) hip fracture probability computed with bone mineral density (BMD). The c-statistic for the model containing FS (0.69; 95% CI: 0.65, 0.72) was lower than the c-statistic for the model with FRI (0.77; 95% CI: 0.74, 0.80) or femoral neck BMD (0.74; 95% CI: 0.71, 0.77; all P<0.05). CONCLUSIONS: FS and FRI were independently associated with hip fracture, but there were differences in performance characteristics. PMID- 29526782 TI - Solution structure of an archaeal DUF61 family protein SSO0941 encoded by a gene in the operon of box C/D RNA protein complexes. AB - Domain of unknown function 61 (DUF61) family proteins widely exist in archaea and the genes of DUF61 proteins in crenarchaea are in an operon containing two genes of box C/D RNA protein complexes. Here we report the solution NMR structure of DUF61 family member protein SSO0941, from the hyperthermophilic archaeon Sulfolobus solfataricus. SSO0941 has a rigid core structure and flexible N- and C terminal regions as well as a negatively-charged independent C-terminal helix. The core structure consists of N- and C-terminal subdomains, in which the C terminal subdomain shows significant structural similarity with several nucleic acid binding proteins. The structure of SSO0941 is the first representative structure of DUF61 family proteins. PMID- 29526783 TI - Dickkopf-related protein 1 and gremlin 1 show different response than frizzled related protein in human synovial fluid following knee injury and in patients with osteoarthritis. AB - OBJECTIVE: To explore the involvement of the wingless-type MMTV integration site (WNT) and bone morphogenetic protein (BMP) antagonists dickkopf-related protein 1 (DKK1), frizzled-related protein (FRZB) and gremlin 1 (GREM1) in knee injury and osteoarthritis (OA). DESIGN: The antagonists were immunoassayed in synovial fluid from a cross-sectional cohort of nine knee healthy reference subjects, patients with recent (0-77 days, n = 158) or old (1-37 years, n = 50) knee injuries, and OA (n = 22). Cartilage (ARGS-aggrecan, cartilage oligomeric matrix protein and C2C type II collagen) and other biomarkers were assessed in synovial fluid in a subset of samples. Statistical analysis was by Kendall's tau (tau) correlation, Mann-Whitney U test, and linear regression analysis. RESULTS: Compared to references, median concentration of GREM1 (but not DKK1 and FRZB) was elevated 1.5-fold immediately after injury, and FRZB was reduced 1000-folds in OA. All three antagonists decreased with increasing time after injury as well as with increasing age, but the temporal change after injury was less accentuated for FRZB (peaked 8-22 days after injury) compared to that of DKK1 and GREM1 (peaked immediately after injury). In the recent injury group, there was a correlation between GREM1 and DKK1 (tau = 0.172); FRZB concentrations correlated with concentrations of cartilage biomarkers (tau between 0.257 and 0.369), while DKK1 and GREM1 were inversely correlated (tau between -0.177 and -0.217) with these markers. CONCLUSIONS: Our results indicate separate roles for the antagonists, where DKK1 and GREM1 had similarities in response to injury and in OA, with a different response for FRZB. PMID- 29526784 TI - Knee menisci segmentation using convolutional neural networks: data from the Osteoarthritis Initiative. AB - OBJECTIVE: To present a novel method for automated segmentation of knee menisci from MRIs. To evaluate quantitative meniscal biomarkers for osteoarthritis (OA) estimated thereof. METHOD: A segmentation method employing convolutional neural networks in combination with statistical shape models was developed. Accuracy was evaluated on 88 manual segmentations. Meniscal volume, tibial coverage, and meniscal extrusion were computed and tested for differences between groups of OA, joint space narrowing (JSN), and WOMAC pain. Correlation between computed meniscal extrusion and MRI Osteoarthritis Knee Score (MOAKS) experts' readings was evaluated for 600 subjects. Suitability of biomarkers for predicting incident radiographic OA from baseline to 24 months was tested on a group of 552 patients (184 incident OA, 386 controls) by performing conditional logistic regression. RESULTS: Segmentation accuracy measured as dice similarity coefficient was 83.8% for medial menisci (MM) and 88.9% for lateral menisci (LM) at baseline, and 83.1% and 88.3% at 12-month follow-up. Medial tibial coverage was significantly lower for arthritic cases compared to non-arthritic ones. Medial meniscal extrusion was significantly higher for arthritic knees. A moderate correlation between automatically computed medial meniscal extrusion and experts' readings was found (rho = 0.44). Mean medial meniscal extrusion was significantly greater for incident OA cases compared to controls (1.16 +/- 0.93 mm vs 0.83 +/- 0.92 mm; P < 0.05). CONCLUSION: Especially for medial menisci an excellent segmentation accuracy was achieved. Our meniscal biomarkers were validated by comparison to experts' readings as well as analysis of differences w.r.t groups of OA, JSN, and WOMAC pain. It was confirmed that medial meniscal extrusion is a predictor for incident OA. PMID- 29526785 TI - Role of AMPA glutamate receptors in the conditioned rewarding effects of MDMA in mice. AB - Currently, there is not an effective treatment for 3,4 methylenedioxymethamphetamine (MDMA) dependence but pharmacotherapies targeting glutamate neurotransmission are a promising strategy. Previously, we showed that blockade of glutamate NMDA and AMPA receptors impairs the conditioned rewarding effects of MDMA and cocaine, respectively. In this study we evaluated the role of AMPA receptors in the rewarding effects of MDMA in mice using the conditioned place preference (CPP) paradigm. Mice were conditioned with MDMA (1.25 mg/kg) 60 min after the treatment with saline or different doses (0.25, 1 and 5 mg/kg) of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Mice conditioned with MDMA acquired CPP while those treated with any dose of CNQX + MDMA did not. These results supported the involvement of the glutamatergic system in the rewarding properties of MDMA, and suggest that AMPA receptor blockade could be a new therapeutic option for the treatment of those individuals that develop MDMA dependence. PMID- 29526786 TI - Ultrastructural brain abnormalities and associated behavioral changes in mice after low-intensity blast exposure. AB - Explosive blast-induced mild traumatic brain injury (mTBI), a "signature wound" of recent military conflicts, commonly affects service members. While past blast injury studies have provided insights into TBI with moderate- to high-intensity explosions, the impact of primary low-intensity blast (LIB)-mediated pathobiology on neurological deficits requires further investigation. Our prior considerations of blast physics predicted ultrastructural injuries at nanoscale levels. Here, we provide quantitative data using a primary LIB injury murine model exposed to open field detonation of 350 g of high-energy explosive C4. We quantified ultrastructural and behavioral changes up to 30 days post blast injury (DPI). The use of an open-field experimental blast generated a primary blast wave with a peak overpressure of 6.76 PSI (46.6 kPa) at a 3-m distance from the center of the explosion, a positive phase duration of approximate 3.0 milliseconds (ms), a maximal impulse of 8.7 PSI * ms and a sharp rising time of 9 * 10-3 ms, with no apparent impact/acceleration in exposed animals. Neuropathologically, myelinated axonal damage was observed in blast-exposed groups at 7 DPI. Using transmission electron microscopy, we observed and quantified myelin sheath defects and mitochondrial abnormalities at 7 and 30 DPI. Inverse correlations between blast intensities and neurobehavioral outcomes including motor activities, anxiety levels, nesting behavior, spatial learning and memory occurred. These observations uncover unique ultrastructural brain abnormalities and associated behavioral changes due to primary blast injury and provide key insights into its pathogenesis and potential treatment. PMID- 29526787 TI - Chronic perinatal odour exposure with heptaldehyde affects odour sensitivity and olfactory system homeostasis in preweaning mice. AB - Exposure to specific odorants in the womb during pregnancy or in the milk during early nursing is known to impact morpho-functional development of the olfactory circuitry of pups. This can be associated with a modification in olfactory sensitivity and behavioural olfactory-based preferences to the perinatally encountered odorants measured at birth, weaning or adult stage. Effects depend on a multitude of factors, such as odorant type, concentration, administration mode and frequency, as well as timing and mice strain. Here, we examined the effect of perinatal exposure to heptaldehyde on the neuro-anatomical development of the olfactory receptor Olfr2 circuitry, olfactory sensitivity and odour preferences of preweaning pups using mI7-IRES-tau-green fluorescent protein mice. We found that perinatal odour exposure through the feed of the dam reduces the response to heptaldehyde and modulates transcript levels of neuronal transduction proteins in the olfactory epithelium of the pups. Furthermore, the number of I7 glomeruli related to Olfr2-expressing OSN is altered in a way similar to that seen with restricted post-natal exposure, in an age-dependent way. These variations are associated with a modification of olfactory behaviours associated with early post natal odour preferences at weaning. PMID- 29526788 TI - On the central noradrenergic mechanism underlying the social play-suppressant effect of methylphenidate in rats. AB - Social play behaviour is a vigorous, highly rewarding social activity abundant in the young of most mammalian species, including humans. Social play is thought to be important for social, emotional and cognitive development, yet its neural underpinnings are incompletely understood. We have previously shown that low doses of methylphenidate suppress social play behaviour through a noradrenergic mechanism of action, and that methylphenidate exerts its effect within the prefrontal cortex, amygdala and habenula. In the present study, we sought to reveal whether these regions work in parallel or in series to mediate the play suppressant effect of methylphenidate. To that aim, we tested whether infusion of the alpha2-adrenoceptor antagonist RX821002 into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala or habenula prevents the effect of methylphenidate on social play behaviour, or the psychomotor stimulant effect of methylphenidate. We found that the social play-suppressant effect of methylphenidate was not prevented by infusion of the alpha2-adrenoceptor antagonist into either region, or by infusion of RX821002 into both the anterior cingulate and infralimbic cortex. By contrast, RX821002 infusion into the anterior cingulate modestly enhanced social play, and infusion of the antagonist into the infralimbic cortex attenuated the psychomotor stimulant effect of methylphenidate. We conclude that there is redundancy in the neural circuitry that mediates the play-suppressant effect of methylphenidate, whereby prefrontal cortical and subcortical limbic mechanisms act in parallel. Moreover, our data support the notion that prefrontal noradrenergic mechanisms contribute to the locomotor enhancing effect of psychostimulant drugs. PMID- 29526790 TI - Selegiline increases on time without exacerbation of dyskinesia in 6 hydroxydopamine-lesioned rats displaying l-Dopa-induced wearing-off and abnormal involuntary movements. AB - 3,4-Dihydroxy-l-phenylalanine (l-Dopa) remains the most effective drug for treating the motor symptoms of Parkinson's disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l-Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l-Dopa induced motor fluctuations and exacerbated dyskinesia. Repeated administration of l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, twice daily for 22 days) progressively shortened rotational response duration (on time) and augmented peak rotation in lesioned rats. Single subcutaneous injection of selegiline (10 mg/kg) extended l-Dopa-induced shortened on time without augmenting peak rotation. Furthermore, l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, once daily for 7 days) progressively increased abnormal involuntary movements (l-Dopa-induced dyskinesia, LID) and peak rotation. Single subcutaneous injection of selegiline (10 mg/kg) did not exacerbate LID or alter mRNA expression of prodynorphin (PDy) and activity-regulated cytoskeleton-associated protein (Arc), both mRNAs associated with LID in the lesioned striatum. Despite undetectable plasma concentrations of selegiline and its metabolites at 24 h post-administration, these on time and LID effects did not decrease, suggesting involvement of irreversible mechanisms. Altogether, these results indicate that selegiline is effective in increasing on time without worsening dyskinesia. PMID- 29526789 TI - Lateral habenular norepinephrine contributes to states of arousal and anxiety in male rats. AB - Recent research has identified the lateral habenula (LHb) as a brain region playing an important role in the production of stressful and anxiogenic states. Additionally, norepinephrine (NE) has long been known to be involved in arousal, stress and anxiety, and NE projections to the LHb have been identified emanating from the locus coeruleus (LC). The current research was devised to test the hypothesis that NE release within the LHb contributes to the occurrence of anxiogenic behaviors. Male rats were implanted with bilateral guide cannula aimed at the LHb and subsequently treated with intracranial (IC) infusions of the selective alpha2 adrenergic autoreceptor agonist, dexmedetomidine (DEX) (0, 0.5, 1.0 MUg/side), prior to assessment of ambulatory and anxiogenic behavior in tests of spontaneous locomotion, open field behavior, and acoustic startle-response. Results demonstrated that DEX administration significantly reduced the overall locomotor behavior of subjects at both doses indicating that infusion of even small doses of this alpha2 agonist into the LHb can have profound effects on the subjects' general levels of alertness and activity. DEX was also found to attenuate anxiety as evidenced by a reduction in the magnitude of a startle response to an acoustic 110 dB stimulus. Taken together, these results identify a role for NE release within the LHb in both arousal and anxiety. PMID- 29526791 TI - An analysis of anterior segment development in the chicken eye. AB - Precise anterior segment (AS) development in the vertebrate eye is essential for maintaining ocular health throughout life. Disruptions to genetic programs can lead to severe structural AS disorders at birth, while more subtle AS defects may disrupt the drainage of ocular fluids and cause dysregulation of intraocular pressure homeostasis, leading to progressive vision loss. To date, the mouse has served as the major model to study AS development and pathogenesis. Here we present an accurate histological atlas of chick AS formation throughout eye development, with a focus on the formation of drainage structures. We performed expression analyses for a panel of known AS disorder genes, and showed that chick PAX6 was localized to cells of neural retina and surface ectoderm derived structures, displaying remarkable similarity to the mouse. We provide a comparison to mouse and humans for chick AS developmental sequences and structures and confirm that AS development shares common features in all three species, although the main AS structures in the chick are developed prior to hatching. These features enable the unique experimental advantages inherent to chick embryos, and we therefore propose the chick as an appropriate additional model for AS development and disease. PMID- 29526792 TI - [Urinary tract involvement by endometriosis. Techniques and outcomes of surgical management: CNGOF-HAS Endometriosis Guidelines]. AB - Urinary tract involvement by endometriosis is reported in 1% of endometriosis patients (NP3). Consequences range from pelvic pain for bladder localizations to silent kidney loss in case of chronic ureteral obstruction (NP3). The feasibility of laparoscopic management was widely proven (NP3) and may reduce hospital stay length (NP4). Radical surgery with partial cystectomy for bladder localizations was shown to significantly and durably reduce pain symptoms with low risk of a severe postoperative complications (NP3). Medical hormonal treatment also shows short-term reduction of pain symptoms (NP4). Transureteral resection of bladder endometriosis nodule is not recommended (grade C) because of a high postoperative recurrence rate (NP4). Given a high risk of silent kidney loss, it is recommended that patients with ureteral involvement by endometriosis are managed by a multidisciplinary team considering urinary and potential extra-urinary localizations of endometriosis (grade C). No recommendation can be made on which technique to prefer between conservative (ureterolysis) or radical surgical techniques or on benefit and length of ureteral stents in case of ureteral involvement. Surgical management of bladder and ureteral localizations of endometriosis do not seem to be associated with altered or improved postoperative fertility (NP4). Since late postoperative ureteral anastomosis stenosis were reported with silent kidney loss, repeated postoperative imaging monitoring is justified (expert opinion). PMID- 29526793 TI - [Strategies and surgical management of endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - The article presents French guidelines for surgical management of endometriosis. Surgical treatment is recommended for mild to moderate endometriosis, as it decreases pelvic painful complaints and increases the likelihood of postoperative conception in infertile patients (A). Surgery may be proposed in symptomatic patients with ovarian endometriomas which diameter exceeds 20mm. Cystectomy allows for better postoperative pregnancy rates when compared to ablation using bipolar current, as well as for lower recurrences rates when compared to ablation using bipolar current or CO2 laser. Ablation of ovarian endometriomas using bipolar current is not recommended (B). Surgery may be employed in patients with deep endometriosis infiltrating the colon and the rectum, with good impact on painful complaints and postoperative conception. In these patients, laparoscopic route increases the likelihood of postoperative spontaneous conception when compared to open route. When compared to conservative rectal procedures (shaving or disc excision), segmental colorectal resection increases the risk of postoperative stenosis, requiring additional endoscopic or surgical procedures. In large deep endometriosis infiltrating the rectum (>20mm length of bowel infiltration), conservative rectal procedures do not improve postoperative digestive function when compared to segmental resection. In patients with bowel anastomosis, placing anti-adhesion agents on contact with bowel suture is not recommended, due to higher risk of bowel fistula (C). Various other recommendations are proposed in the text, however, they are based on studies with low level of evidence. PMID- 29526794 TI - Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. AB - Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1). Given that SARM1 acts upstream of DLK/JNK signaling in axon degeneration, we tested whether SARM1 plays a similar role in RGC somal apoptosis in response to optic nerve injury. Using the mouse optic nerve crush (ONC) model, our results show that SARM1 is critical for RGC axonal degeneration and that axons rescued by SARM1 deficiency are electrophysiologically active. Genetic deletion of SARM1 did not, however, prevent DLK/JNK pathway activation in RGC somas nor did it prevent or delay RGC cell death. These results highlight the importance of SARM1 in RGC axon degeneration and suggest that somal activation of the DLK/JNK pathway is activated by an as-yet-unidentified SARM1-independent signal. PMID- 29526796 TI - Bilateral early activation of retinal microglial cells in a mouse model of unilateral laser-induced experimental ocular hypertension. AB - The immune system plays an important role in glaucomatous neurodegeneration. Retinal microglial reactivation associated with ganglion cell loss could reportedly contribute to the glaucoma progression. Recently we have described signs of microglia activation both in contralateral and ocular hypertension (OHT) eyes involving all retinal layers 15 days after OHT laser induction in mice. However, no works available have analyzed the microglial activation at earliest time points after OHT induction (24 h) in this experimental model. Thus, we seek to describe and quantify signs of microglia activation and differences depending on the retinal layer, 24 h after unilateral laser-induced OHT. Two groups of adult Swiss mice were used: age-matched control (naive) and lasered. In the lasered animals, OHT eyes as well as contralateral eyes were analyzed. Retinal whole-mounts were immunostained with antibodies against Iba-1 and MHC-II. We quantified the number of microglial cells in the photoreceptor layer (OS), outer plexiform layer (OPL), and inner plexiform layer (IPL); the number of microglial vertical processes connecting the OPL and OS; the area of the retina occupied by Iba-1+ cells (Iba1-RA) in the nerve fiber layer-ganglion cell layer (NFL-GCL), the total arbor area of microglial cells in the OPL and IPL and; Iba-1+ cell body area in the OPL, IPL and NFL-GCL. In contralateral and OHT eyes the morphological features of Iba-1+ cell activation were: migration, enlargement of the cell body, higher degree of branching and reorientation of the processes, radial disposition of the soma and processes toward adjacent microglial plexuses, and presence of amoeboid cells acting as macrophages. These signs were more pronounced in OHT eyes. Most of Iba-1+ cells did not express MHC-II; rather, only dendritic and rounded cells expressed it. In comparison with naive eyes, in OHT eyes and contralateral eyes no significant differences were found in the microglial cell number; but there was a significant increase in Iba1-RA. The total arbor area of microglial cells was significantly decreased in: i) OHT eyes with respect contralateral eyes and naive-eyes in IPL; ii) OHT eyes with respect to naive eyes in OPL. The number of microglial vertical processes connecting the OPL and OS were significantly increased in contralateral eyes compared with naive-eyes and OHT eyes. In OPL, IPL and NFL-GCL, the cell body area of Iba-1+ cells was significantly greater in OHT eyes than in naive and contralateral eyes, and greater in contralateral eyes than in naive eyes. A non-proliferative microglial reactivation was detected both in contralateral eyes and in OHT eyes in an early time after unilateral laser-induced OHT (24 h). This fast microglial activation, which involves the contralateral eye, could be mediated by the immune system. PMID- 29526797 TI - Melatonin resists oxidative stress-induced apoptosis in nucleus pulposus cells. AB - AIMS: Intervertebral disc degeneration (IVDD) is thought to be the major cause of low back pain (LBP), which is still in lack of effective etiological treatment. Oxidative stress has been demonstrated to participate in the impairment of nucleus pulposus cells (NPCs). As the most important neuroendocrine hormone in biological clock regulation, melatonin (MLT) is also featured by good antioxidant effect. In this study, we investigated the effect and mechanisms of melatonin on oxidative stress-induced damage in rat NPCs. MAIN METHODS: Cytotoxicity of H2O2 and protecting effect of melatonin were analyzed with Cell Counting kit-8 (CCK 8). Cell apoptosis rate was detected by Annexin V-FITC/PI staining. DCFH-DA probe was used for the reactive oxygen species (ROS) detection. The mitochondrial membrane potential (MMP) changes were analyzed with JC-1 probe. Intracellular oxidation product and reductants were measured through enzymatic reactions. Extracellular matrix (ECM) and apoptosis associated proteins were analyzed with Western blot assays. KEY FINDINGS: Melatonin preserved cell viability of NPCs under oxidative stress. The apoptosis rate, ROS level and malonaldehyde (MDA) declined with melatonin. MLT/H2O2 group showed higher activities of GSH and SOD. The fall of MMP receded and the expression of ECM protein increased with treatment of melatonin. The mitochondrial pathway of apoptosis was inhibited by melatonin. SIGNIFICANCE: Melatonin alleviated the oxidative stress-induced apoptosis of NPCs. Melatonin could be a promising alternative in treatment of IVDD. PMID- 29526795 TI - Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. AB - Cultured trabecular meshwork (TM) cells are a valuable model system to study the cellular mechanisms involved in the regulation of conventional outflow resistance and thus intraocular pressure; and their dysfunction resulting in ocular hypertension. In this review, we describe the standard procedures used for the isolation of TM cells from several animal species including humans, and the methods used to validate their identity. Having a set of standard practices for TM cells will increase the scientific rigor when used as a model, and enable other researchers to replicate and build upon previous findings. PMID- 29526798 TI - Effects of dehydroepiandrosterone on the ovarian reserve and pregnancy outcomes in perimenopausal rats (DHEA and fertility in perimenopausal rats). AB - BACKGROUND: Dehydroepiandrosterone (DHEA) is a weak androgen and a crucial precursor of sex steroids. Exogenous supplementation of DHEA is now being commonly used to augment ovarian stimulation in women with diminished ovarian reserve. However, the effects of DHEA are controversial. AIMS: This study verifies the effects of pharmacologic doses of DHEA on the ovarian reserve variables, follicular development, reproductive function, and pregnancy outcomes of perimenopausal rats. MAIN METHODS: The reproductive function was studied by monitoring the estrous cycle and hormones. The ovarian reserve was studied by testing the anti-mullerian hormone and ovarian histology. The follicular development was studied histologically and immunohistochemically. KEY FINDINGS: DHEA supplementation at a dose of at 50 mg/kg improved the ovarian reserve and pregnancy outcomes. Higher doses of DHEA caused PCOs-like symptoms manifested by the development of cystic follicles and low ovarian reserve and pregnancy outcomes. SIGNIFICANCE: DHEA is a promising treatment that improves the ovarian reserve parameters and pregnancy outcomes. Further studies are needed to determine the optimal dose and duration. PMID- 29526799 TI - Pharmacokinetics and pharmacodynamics of PEGylated truncated human cystathionine beta-synthase for treatment of homocystinuria. AB - AIMS: PEGylated human truncated cystathionine beta-synthase, lacking the C terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. In this communication, we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice, wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials. MAIN METHODS: Animal models received single or multiple doses of PEG-CBS. Activity of PEG-CBS and sulfur amino acid metabolites were determined in plasma and used to determine PK and PD. KEY FINDINGS: The plasma half-lives of PEG-CBS after a single subcutaneous (SC) injection were approximately 20, 44 and 73 h in mouse, rat and monkey, respectively. The SC administration of PEG-CBS resulted in a significant improvement or full correction of metabolic imbalance in both blood and tissues of homocystinuric mice. The PD of PEG-CBS in mouse was dose-dependent, but less than dose proportional, with the maximal efficacy achieved at 8 mg/kg. PEG-CBS was well tolerated in mice and monkeys, but resulted in dose-dependent minimal-to-moderate inflammation at the injection sites and vacuolated macrophages in rats. Allometric scaling of animal data was linear and the estimated human efficacious dose was determined as 0.66 mg/kg administered once a week. SIGNIFICANCE: These results provide critical preclinical data for the design of first-in-human PEG CBS clinical trial. PMID- 29526801 TI - BCL2-overexpressing prostate cancer cells rely on PARP1-dependent end-joining and are sensitive to combined PARP inhibitor and radiation therapy. AB - Here we report that BCL2 blocks DNA double strand break (DSB) repair via nonhomologous end-joining (NHEJ), through sequestration of KU80 protein outside the nucleus. We find that this effect is associated with a repair switch to the error-prone PARP1-dependent end-joining (PARP1-EJ). We present in-vitro proof-of concept for therapeutic targeting of this switch using PARP inhibitor to specifically enhance the radiosensitivity of BCL2-overexpressing cells. Given its erroneous behavior, PARP1-EJ might allow for the accumulation of genetic alterations and tumor progression. Consistently, we report an inverse correlation between BCL2 expression and biochemical recurrence-free survival of 10.259 prostate cancer (PCa) patients who underwent primary radical-prostatectomy for localized disease. Further, we evaluated retrospectively the impact of BCL2 expression on clinical outcome of 1.426 PCa patients, who had been given salvage radiotherapy at relapse after radical prostatectomy. In line with its role in blocking NHEJ, BCL2 over-expressers showed significantly better response to salvage radiotherapy compared to low-expressers. Collectively, our findings identify BCL2 status in PCa as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor olaparib as a radiosensitizing agent. PMID- 29526800 TI - Effects of Parkinson disease and antiparkinson medication on central adaptations to repetitive grasping. AB - Cortical activity during motor task performance is attenuated in individuals with Parkinson disease (PD) relative to age-matched adults without PD, and this activity is enhanced with antiparkinson medication. It remains unclear, however, whether the relative change in cortical activity over the duration of the task, i.e., central adaptation, is affected individuals with PD, and if so, whether medication corrects for any unique behaviors. Movement-related cortical potentials (MRCPs) were recorded from scalp electrode sites Cz and C1 during 150 repetitive handgrip contractions at 70% of maximal voluntary contraction, in individuals with PD (n = 10) both ON and OFF of their PD medication, and neurologically normal age- and sex-matched controls (n = 10). Repetitions were divided into two Blocks (Block 1 and 2: repetitions 1-60 and 91-150, respectively), and the composite MRCP slopes were calculated during periods representing movement initiation (-2 s to movement onset) and execution (movement onset to 1 s). No significant interactions were noted for either comparison (PD OFF vs. control; PD OFF vs. PD ON), irrespective of electrode site (Cz or C1) or movement period (initiation or execution). Despite similar MRCP slopes and task performance, PD OFF endorsed greater perceived exertion during task performance than controls. In the present study, we observed attenuated task-related cortical activity among individuals with PD OFF relative to controls, but a similar relative adaptive response to a fatiguing task. Additionally, although antiparkinson medication enhanced cortical activity (PD OFF vs. PD ON), central adaptation was similar. PMID- 29526802 TI - The poly(ADP-ribose) polymerase inhibitor olaparib induces up-regulation of death receptors in primary acute myeloid leukemia blasts by NF-kappaB activation. AB - Olaparib is a potent orally bioavailable poly(ADP-ribose) polymerase inhibitor (PARPi), approved for BRCA-mutated ovarian and breast cancers. We recently showed that olaparib at clinically achievable concentrations exerts anti-proliferative and pro-apoptotic effects in vitro as monotherapy against primary acute myeloid leukemia (AML) blasts, while sparing normal bone marrow (BM) hematopoietic cells. Since AML expresses low levels of death receptors that may contribute to apoptosis resistance, in this study we investigated whether the anti-leukemia activity of olaparib involves modulation of FAS and TRAIL receptors DR5 and DR4. Our data show that the primary AML samples tested express FAS and DR5 transcripts at levels lower than normal BM. In this context, apoptosis triggered by olaparib is associated with a dose-dependent up-regulation of death receptors expression and caspase 8 activation. Olaparib-mediated FAS up-regulation requires NF-kappaB activation, as indicated by the increase of p65 phosphorylation and decrease of IkappaBalpha. Moreover, FAS up-regulation is abrogated by pretreatment of AML cells with two different NF-kappaB inhibitors. These results indicate that NF kappaB activation and consequent induction of death receptor expression contribute to the anti-leukemia effect of olaparib in AML. PMID- 29526804 TI - Molecular phylogenetics and species limits in a cryptically coloured radiation of Australo-Papuan passerine birds (Pachycephalidae: Colluricincla). AB - Detailed knowledge of species limits is an essential component of the study of biodiversity. Although accurate species delimitation usually requires detailed knowledge of both genetic and phenotypic variation, such variation may be limited or unavailable for some groups. In this study, we reconstruct a molecular phylogeny for all currently recognized species and subspecies of Australasian shrikethrushes (Colluricincla), including the first sequences of the poorly known C. tenebrosa. Using a novel method for species delimitation, the multi-rate Poisson Tree Process (mPTP), in concordance with the phylogenetic data, we estimate species limits in this genetically diverse, but phenotypically subtly differentiated complex of birds. In line with previous studies, we find that one species, the little shrikethrush (C. megarhyncha) is characterized by deep divergences among populations. Delimitation results suggest that these clades represent distinct species and we consequently propose a new classification. Furthermore, our findings suggest that C. megarhyncha melanorhyncha of Biak Island does not belong in this genus, but is nested within the whistlers (Pachycephala) as sister to P. phaionota. This study represents a useful example of species delimitation when phenotypic variation is limited or poorly defined. PMID- 29526803 TI - Pancreatic DCLK1+ cells originate distinctly from PDX1+ progenitors and contribute to the initiation of intraductal papillary mucinous neoplasm in mice. AB - PanINs and IPMNs are the two most common precursor lesions that can progress to invasive pancreatic ductal adenocarcinoma (PDA). DCLK1 has been identified as a biomarker of progenitor cells in PDA progressed from PanINs. To explore the potential role of DCLK1-expressing cells in the genesis of IPMNs, we compared the incidence of DCLK1-positive cells in pancreatic tissue samples from genetically engineered mouse models (GEMMs) for IPMNs, PanINs, and acinar to ductal metaplasia by immunohistochemistry and immunofluorescence. Mouse lineage tracing experiments in the IPMN GEMM showed that DCLK1+ cells originated from a cell lineage distinct from PDX1+ progenitors. The DCLK1+ cells shared the features of tuft cells but were devoid of IPMN tumor biomarkers. The DCLK1+ cells were detected in the earliest proliferative acinar clusters prior to the formation of metaplastic ductal cells, and were enriched in the "IPMN niches". In summary, DCLK1 labels a unique pancreatic cellular lineage in the IPMN GEMM. The clustering of DCLK1+ cells is an early event in Kras-induced pancreatic tumorigenesis and may contribute to IPMN initiation. PMID- 29526805 TI - Multilocus phylogenetic analysis of the first molecular data from the rare and monotypic Amarsipidae places the family within the Pelagia and highlights limitations of existing data sets in resolving pelagian interrelationships. AB - The Pelagia is a recently delineated group of fishes, comprising fifteen families formerly placed in six perciform suborders. The Pelagia was lately recognized as it encompasses huge morphological diversity and only in the last few years have large-scale molecular phylogenetic studies been undertaken that could unite such morphologically disparate lineages. Due to the recent erection of Pelagia, the composition of the taxon is not entirely certain. Five families of the former perciform suborder Stromateoidei have been identified as pelagians. However, the sixth stromateoid subfamily Amarsipidae is a rare monotypic family that has distinctive meristic and morphological characteristics from that of other stromateoids such as the lack of a pharyngeal sac. We examine molecular data generated from the sole species in Amarsipidae, Amarsipus carlsbergi, and demonstrate that it is clearly nested within Pelagia. As with two previous studies that have the breadth of sampling to evaluate pelagian intra relationships, we find high support for monophyly of most family-level taxonomic units but statistical support for early-branching nodes in the pelagian tree is very low. We conduct the first analyses of Pelagia incorporating the multispecies coalescent and are limited by a high degree of missing loci, or, incomplete taxon sampling. The high degree of missing data across a complete sampling of pelagian lineages along with the deep time scale and rapid radiation of the lineage contribute to poor resolution of early-branching relationships within Pelagia that cannot be resolved with current data sets. Currently available data are either mitochondrial genomes or a super matrix of relatively few loci with a high degree of missing data. A new and independent dataset of numerous phylogenetic loci derived from high-throughput sequencing technology may reduce uncertainty within the Pelagia and provide insights into this adaptive radiation. PMID- 29526806 TI - Historical introgression among the species of Rodgersia (Saxifragaceae) in mountainous forests of southwest China. AB - In the present study, we used genetic data and ecological niche modelling to explore possible historical introgressions among the species of Rodgersia (Saxifragaceae) in central-southwest China. Markedly differentiated chloroplast haplotypes were found in R. aesculifolia, R. sambucifolia and the Lijiang (LJ) population of R. pinnata, respectively, and differentiated chloroplast haplotypes within each of them showed the closest relationships with haplotypes from different species. ITS cloning did not reveal any shared ribotype between R. aesculifolia and the remaining species. Historical introgression between R. aesculifolia and R. sambucifolia (or R. pinnata) seems to be the most plausible explanation according to the geographical pattern and derivative status of putative introgressed chloroplast haplotypes, and also from morphological evidence. Introgressions were also found among R. sambucifolia, R. pinnata, and R. henricii from Yunnan. Frequent gene exchanges may have promoted the diversity of leaf shapes in this genus. Ecological niche modelling indicated that past secondary contact following range shifts during Pleistocene cold periods may have provided opportunities for ancient introgression between R. aesculifolia and adjacent species. PMID- 29526807 TI - Oxidative stress and neurodegeneration: The possible contribution of quinone reductase 2. AB - There is increasing evidence that oxidative stress is involved in the etiology and pathogenesis of neurodegenerative disorders. Overproduction of reactive oxygen species (ROS) is due in part to the reactivity of catecholamines, such as dopamine, adrenaline, and noradrenaline. These molecules are rapidly converted, chemically or enzymatically, into catechol-quinone and then into highly deleterious semiquinone radicals after 1-electron reduction in cells. Notably, the overexpression of dihydronicotinamide riboside:quinone oxidoreductase (QR2) in Chinese hamster ovary (CHO) cells increases the production of ROS, mainly superoxide radicals, when it is exposed to exogenous catechol-quinones (e.g. dopachrome, aminochrome, and adrenochrome). Here we used electron paramagnetic resonance analysis to demonstrate that the phenomenon observed in CHO cells is also seen in human leukemic cells (K562 cells) that naturally express QR2. Moreover, by manipulating the level of QR2 in neuronal cells, including immortalized neuroblast cells and ex vivo neurons isolated from QR2 knockout animals, we showed that there is a direct relationship between QR2-mediated quinone reduction and ROS overproduction. Supporting this result, the withdraw of the QR2 co-factor (BNAH) or the addition of the specific QR2 inhibitor S29434 suppressed oxidative stress. Taken together, these data suggest that the overexpression of QR2 in brain cells in the presence of catechol quinones might lead to ROS-induced cell death via the rapid conversion of superoxide radicals into hydrogen peroxide and then into highly reactive hydroxyl radicals. Thus, QR2 may be implicated in the early stages of neurodegenerative disorders. PMID- 29526808 TI - Association of NOX2 subunits genetic variants with autoimmune diseases. AB - A single nucleotide polymorphism in Ncf1 has been found with a major effect on chronic inflammatory autoimmune diseases in the rat with the surprising observation that a lower reactive oxygen response led to more severe diseases. This finding was subsequently reproduced in the mouse and the effect operates in many different murine diseases through different pathogenic pathways; like models for rheumatoid arthritis, encephalomyelitis, lupus, gout, psoriasis and psoriatic arthritis. The human gene is located in an unstable region with many variable sequence repetitions, which means it has not been included in any genome wide associated screens so far. However, identification of copy number variations and single nucleotide polymorphisms has now clearly shown that major autoimmune diseases are strongly associated with the Ncf1 locus. In systemic lupus erythematosus the associated Ncf1 polymorphism (leading to an amino acid substitution at position 90) is the strongest locus and is associated with a lower reactive oxidative burst response. In addition, more precise mapping analysis of polymorphism of other NOX2 genes reveals that these are also associated with autoimmunity. The identified genetic association shows the importance of redox control and that ROS regulate chronic inflammation instead of promoting it. The genetic identification of Ncf1 polymorphisms now opens for relevant studies of the regulatory mechanisms involved, effects that will have severe consequences in many different pathogenic pathways and understanding of the origin of autoimmune diseases. PMID- 29526810 TI - Integrated physical map of bread wheat chromosome arm 7DS to facilitate gene cloning and comparative studies. AB - Bread wheat (Triticum aestivum L.) is a staple food for a significant part of the world's population. The growing demand on its production can be satisfied by improving yield and resistance to biotic and abiotic stress. Knowledge of the genome sequence would aid in discovering genes and QTLs underlying these traits and provide a basis for genomics-assisted breeding. Physical maps and BAC clones associated with them have been valuable resources from which to generate a reference genome of bread wheat and to assist map-based gene cloning. As a part of a joint effort coordinated by the International Wheat Genome Sequencing Consortium, we have constructed a BAC-based physical map of bread wheat chromosome arm 7DS consisting of 895 contigs and covering 94% of its estimated length. By anchoring BAC contigs to one radiation hybrid map and three high resolution genetic maps, we assigned 73% of the assembly to a distinct genomic position. This map integration, interconnecting a total of 1713 markers with ordered and sequenced BAC clones from a minimal tiling path, provides a tool to speed up gene cloning in wheat. The process of physical map assembly included the integration of the 7DS physical map with a whole-genome physical map of Aegilops tauschii and a 7DS Bionano genome map, which together enabled efficient scaffolding of physical-map contigs, even in the non-recombining region of the genetic centromere. Moreover, this approach facilitated a comparison of bread wheat and its ancestor at BAC-contig level and revealed a reconstructed region in the 7DS pericentromere. PMID- 29526809 TI - An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice. AB - Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient alpha-tocopherol (alpha-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of alpha-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by alpha-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-alpha (RORA), which is required for neural homeostasis. Thus we find that alpha-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration. PMID- 29526811 TI - The use of tail-flagging and white rump-patch in alarm behavior of goitered gazelles. AB - Tail signals and rump patch exposure in ungulates are well-documented phenomena, but there is no consensus about their functional significance, which has remained disputed. In addition, these patterns have been analyzed for only a limited number of ungulate species; and until now did not include goitered gazelles. This paper, then, will discuss these aspects of goitered gazelle antipredator behavior. I chose human harassments as predator threats and found that tail flagging, stotting and presentation of the white rump-patch were displayed mostly by adult females, less often by adult males, and least in sub-adults. Adult females used tail-flagging and rump-patch exposure primarily for communication with their fawns especially frequently in July when fawns finished their hiding period. In August, adult females further strengthened their alarm signals by frequent stotting. Unlike females, adult males displayed tail- flagging and stotting quite randomly over months, likely depending on frequencies of encountered threats. However, females and males both displayed tail-flagging significantly more frequently than stotting (with a few exceptions) suggesting that tail-flagging has an independent communicative function, even if one signal amplifies the other. Goitered gazelles used tail-flagging and white rump-patch exposure likely as an alarm and cohesive signal for conspecifics, and adult females communicated by these signals mostly with their fawns. PMID- 29526812 TI - To take or not to take the shortcut: Flexible spatial behaviour of rats based on cognitive map in a lattice maze. AB - To examine the flexibility of rats' spatial behaviour, we required rats to navigate to one of four boxes on the corners of a lattice maze. The maze consisted of five vertical and five horizontal corridors on a plane parallel to the ground and allowed us to design diverse routes. One box was set as goal and the other three were set as starting points. Both the time to arrive at the goal and the number of errors at the intersections on the route decreased, suggesting that the rats learned the route. As the goal boxes were successively changed, the decrease in the errors and the time to reach the goal became faster. This suggests that the rats learned the spatial layout of the maze, i.e., developed a cognitive map. We then carried out a shortcut test by removing one wall located near the centre of the maze. The rats took the shortcut route when passing through the location around the removed wall made the entire route shorter, but did not pass through the location when passing through the location made the entire route longer. These suggest that rats can flexibly utilize their internal representation of a spatial structure to respond to a change in a learned environment. PMID- 29526813 TI - Rare but evolutionarily consequential outcrossing in a highly inbred zoonotic parasite. AB - Recurrent self-mating can result in nearly clonal propagation of biological lineages, but even occasional outcrossing can serve to redistribute variation in future generations, providing cohesion among regional populations. The zoonotic parasite Trichinella spiralis has been suspected to undergo frequent inbreeding, resulting in genetically uniform larval cohorts which differ markedly from one another. Here, we explored the extent of inbreeding for this parasite by determining how genetic variation (at variable microsatellite markers) is distributed among 1379 larvae derived from 41 wild boars in Extremadura, Spain. In particular, we sought to determine how much of the genetic variation in this region's parasites occurs among the larvae of any given wild boar, and whether each derives from one, or more, parental lineages. We found strong evidence for inbreeding, resulting in genetically distinct parasite subpopulations among the parasites derived from many pairs of wild boar. Fully two-thirds of these parasite cohorts appear to derive from inbred parents; in 10% of the wild boars, parasites were so inbred as to become absolutely fixed in all of the assayed genetic loci. In spite of this, more than one pair of parents appear to have given rise to the infections in one-third of the sampled wild boars, resulting in mixed infections. These mixed infections should slow losses of heterozygosity and multi-locus polymorphism in any given parasite lineage. Such outcrossing should limit distinctions that would otherwise accumulate among transmission chains, thereby enforcing cohesion through the region's population in spite of its marked departure from panmixia. Conditions of transmission may differ in other regions, where such epidemiological features may engender different evolutionary outcomes. PMID- 29526814 TI - Integrating chemical, toxicological and clinical research to assess the potential of reducing health risks associated with cigarette smoking through reducing toxicant emissions. AB - The concept of a risk continuum for tobacco and nicotine products has been proposed, which differentiates products according to their propensity to reduce toxicant exposure and risk. Cigarettes are deemed the most risky and medicinal nicotine the least. We assessed whether a Reduced-Toxicant Prototype (RTP) cigarette could sufficiently reduce exposure to toxicants versus conventional cigarettes to be considered a distinct category in the risk continuum. We present findings from both pre-clinical and clinical studies in order to examine the potential for reduced smoke toxicant emissions to lower health risks associated with cigarette smoking. We conclude that current toxicant reducing technologies are unable to reduce toxicant emissions sufficiently to manifest beneficial disease-relevant changes in smokers. These findings point to a minimum toxicant exposure standard that future potentially reduced risk products would need to meet to be considered for full biological assessment. The RTP met WHO TobReg proposed limits on cigarette toxicant emissions, however the absence of beneficial disease relevant changes in smokers after six months reduced toxicant cigarette use, does not provide evidence that these regulatory proposals will positively impact risks of smoking related diseases. Greater toxicant reductions, such as those that can be achieved in next generation products e.g. tobacco heating products and electronic cigarettes are likely to be necessary to clearly reduce risks compared with conventional cigarettes. PMID- 29526815 TI - Weight Loss Trajectories and Adverse Childhood Experience among Obese Adolescents with Polycystic Ovary Syndrome. AB - STUDY OBJECTIVE: To examine the effect of childhood trauma and family history of psychiatric illness on weight loss trajectories of obese, female adolescents with polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: PCOS and adolescent medicine outpatient clinics. PARTICIPANTS: Participants were, on average, 15.8 years of age, 80% Caucasian (39/49 participants), and had a body mass index of 36.8 +/- 8.8. INTERVENTIONS: Healthy Bodies, Healthy Minds is an evidence-based one-on-one intervention consisting of 4 weekly sessions, 4 biweekly sessions, and 3 monthly booster sessions. Each session was 45-60 minutes long with 15-30 minutes of physical activity with a lifestyle coach. MAIN OUTCOME MEASURES: Paired sample t tests were used to assess group differences in pre- and post-treatment weight between participants reporting childhood trauma and body mass index-matched controls not endorsing trauma. One-way analysis of variance was performed to assess the influence of childhood trauma on weight loss between the 2 groups. RESULTS: Adolescents without a family history of psychiatric illness lost more weight (mean, -1.28 kg; SD, 6.89) than those who had a family history of psychiatric illness (mean, -0.64 kg; SD, 4.7) from baseline to booster session completion (6 months). However, results of independent t tests did not reveal statistically significant group differences in weight loss from baseline to booster session completion (t21 = 0.51; P = .6). CONCLUSION: Obese adolescents with PCOS who have experienced childhood trauma can lose weight and acquire its health benefits when enrolled in an intervention addressing weight, mood, and sleep. Family history of psychiatric illness emerged as a potential predictor of lesser weight loss. PMID- 29526816 TI - Elastic, dipole-dipole interaction and viscosity impact on vibrational properties of anisotropic hexagonal microtubule lattice. AB - The paper investigates microtubules lattice properties taking into consideration elastic, dipole-dipole interaction of tubulins and viscosity. A microtubule is modeled as a system of bound tubulins, forming a skewed hexagonal two-dimensional lattice. Wave frequencies and group velocities have been calculated. Calculations have been performed for various directions of wave front propagation: helix, along the protofilament, and anti-helix. Three different wave polarization directions have been considered. It has been shown that the direction of the wave polarization influences the frequency and wave group velocity values in the lattice considerably. The impact of dipole-dipole interaction greatly depends on the direction of the wave polarization; thus, it is only moderate for the longitudinally (LA) polarized waves while it is sufficient for the transversely (TA), and out-of-plane (ZA) polarized waves. Moreover dipole-dipole interaction may result in the waves which are able to cause the rupture of microtubules. With viscosity considered, lattice oscillations become harmonically damped only over a certain wavelength range when longitudinal polarization occurs. Out of this range as well as for the other polarization directions, lattice deviations from equilibrium are dampened exponentially. Taking viscosity into consideration also results in a noticeable decrease in frequency and increase in the group wave velocity when the waves are longitudinally polarized. Reverse wave domains which may be associated with a possible phenomenon of negative refraction have been determined for hexagonal microtubule lattice. PMID- 29526817 TI - Evaluation of spectral libraries and sample preparation for DIA-LC-MS analysis of host cell proteins: A case study of a bacterially expressed recombinant biopharmaceutical protein. AB - Recombinantly expressed biopharmaceutical proteins often undergo a series of purification steps with the aim of removing contaminating material. Depending on the application of the protein, there are various requirements for the degree of purity, but host cell proteins (HCPs) will in general remain in small amounts. LC MS has emerged as an orthogonal technique, capable of providing detailed information regarding the individual proteins. The aim of this case study was to characterize the HCPs associated with a biopharmaceutical protein, provided by Statens Serum Institut (DK), which is used in the field of tuberculosis and has not previously been studied by LC-MS. The developed method and acquired experiences served to develop a generalized strategy for HCP-characterization in our laboratory. We evaluated the use of different spectral libraries, recorded in data-dependent mode for obtaining the highest HCP coverage, combined with SWATH based absolute quantification. The accuracy of two label-free absolute quantification strategies was evaluated using stable isotope peptides. Two different sample preparation workflows were evaluated for optimal HCP yield. . The label-free strategy produced accurate quantification across several orders of magnitude, and the calculated purity was found to be in agreement with previously obtained ELISA data. PMID- 29526818 TI - Elucidation of photoautotrophic carbon flux topology in Synechocystis PCC 6803 using genome-scale carbon mapping models. AB - Completeness and accuracy of metabolic mapping models impacts the reliability of flux estimation in photoautotrophic systems. In this study, metabolic fluxes under photoautotrophic growth conditions in the widely-used cyanobacterium Synechocystis PCC 6803 are quantified by re-analyzing an existing dataset using genome-scale isotopic instationary 13C-Metabolic Flux Analysis (INST-MFA). The reconstructed carbon mapping model imSyn617 and implemented algorithmic updates afforded an approximately 48% reduction in computation time. The mapping model encompasses 18 novel carbon paths spanning Calvin-Benson-Bassham cycle, photorespiration, an expanded glyoxylate metabolism, and corrinoid biosynthetic pathways and 190 additional metabolites absent in core models currently used for MFA. Flux elucidation reveals that 98% of the fixed carbons is routed towards biomass production with small amounts diverted towards organic acids and glycogen storage. 12% of the fixed carbons are oxidized to CO2 in the TCA cycle and anabolic reactions in peripheral metabolism. Flux elucidation using instationary MFA reveals that these carbons are not re-fixed by RuBisCO and are instead off gassed as CO2. A newly discovered modality is the bifurcated topology of glycine metabolism using parts of photorespiration and the phosphoserine pathways to avoid carbon losses associated with glycine oxidation. The TCA cycle is shown to be incomplete with a bifurcated topology. Inactivity of futile cycles and alternate routes results in pathway usage and (in)dispensability predictions consistent with experimental findings. The resolved flux map is consistent with the maximization of biomass yield from fixed carbons as the cellular objective function. Flux prediction departures from the ones obtained with the core model demonstrate the importance of constructing mapping models with global coverage to reliably glean new biological insights using labeled substrates. PMID- 29526820 TI - Benzbromarone aggravates hepatic steatosis in obese individuals. AB - : As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD) induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group. The inflammatory and oxidative stress factors were also activated in the liver of benzbromarone treated DIO mice. In accordance with the in vivo results, an in vitro experiment using human hepatoma HepG2 cells also confirmed that benzbromarone promoted intracellular lipid accumulation under high free fatty acids (FFAs) conditions by regulating the expression of lipid metabolism genes. Importantly, prolonged treatment of benzbromarone significantly increased cell apoptosis in HepG2 cells in the presence of high FFAs. In addition, in benzbromarone-treated hyperuricemic patients, serum transaminase levels were positively correlated with patients' obesity level. CONCLUSION: This study demonstrated that benzbromarone aggravated hepatic steatosis in obese individuals, which could subsequently contribute to hepatic cell injury, suggesting a novel toxicological mechanism in benzbromarone induced hepatotoxicity. PMID- 29526821 TI - Heterodimer formation by Oct4 and Smad3 differentially regulates epithelial-to mesenchymal transition-associated factors in breast cancer progression. AB - The multifunctional cytokine TGF-beta crucially participates in breast cancer (BCa) metastasis and works differently in the disease stages, thus contributing in BCa progression. We address connections between TGF-beta and the stem cell related transcription factor (TF) Oct4 in BCa. In 147 BCa patients with infiltrating duct carcinoma, we identified a significantly higher number of cases with both moderate/high Oct4 expression and high TGF-beta in late stages compared to early stages of the disease. In vitro studies showed that TGF-beta elevated Oct4 expression, which in turn, regulated Epithelial-to-Mesenchymal transition (EMT)-regulatory gene (Snail and Slug) expression, migratory ability, chemotactic invasiveness and extracellular matrix (ECM) degradation potential of BCa cells. Putative binding sites for Oct4 on the snail, slug and cxcl13 promoters and for Smad3 on the snail and slug promoters were identified. Promoter activities of snail and slug were greater in dual-treated cells than only TGF-beta-treated or Oct4-overexpressing cells. CXCL13 mRNA fold changes, however, were low in cells induced with TGF-beta, compared to dual-treated or Oct4-overexpressing cells. Our co-IP studies confirmed that Oct4 and Smad3 form heterodimers that recognize specific promoter sequences to promote Snail and Slug expression, but which in turn, indirectly inhibits Smad3-mediated repression of CXCL13 expression, allowing Oct4 to act as a positive TF for CXCL13. Taken together, these data suggest that TGF-beta signaling and Oct4 cooperate to induce expression of EMT related genes Snail, Slug and CXCL13, which accelerates disease progression, particularly in the late stages, and may indicate a poor prognosis for BCa patients. PMID- 29526819 TI - Metabolic studies of a patient harbouring a novel S487L mutation in the catalytic subunit of AMPK. AB - AMP-activated protein kinase (AMPK) regulates many different metabolic pathways in eukaryote cells including mitochondria biogenesis and energy homeostasis. Here we identify a patient with hypotonia, weakness, delayed milestones and neurological impairment since birth harbouring a novel homozygous mutation in the AMPK catalytic alpha-subunit 1, encoded by the PRKAA1 gene. The homozygous mutation p.S487L in isoform 1 present in the patient is in a cryptic residue for AMPK activity. In the present study, we performed the characterization of mitochondrial respiratory properties of the patient, in comparison to healthy controls, through the culture of skin fibroblasts in order to understand some of the cellular consequences of the PRKAA1 mutation. In these assays, mitochondrial respiratory complex I showed lower activity, which was followed by a decrement in the mtDNA copy number, which is a probable consequence of the lower expression of PGC-1alpha and PRKAA1 itself as measured in our quantitative PCRs experiments. Confirming the effect of the patient mutation in respiration, transfection of patient fibroblasts with wild type PRKAA1 partially restore complex I level. The preliminary clinic evaluations of the patient suggested a metabolic defect related to the mitochondrial respiratory function, therefore treatment with CoQ10 supplementation dose started four years ago and a clear improvement in motor skills and strength has been achieved with this treatment. PMID- 29526822 TI - Breathprinting and Early Diagnosis of Lung Cancer. AB - The electronic nose (e-nose) is a promising technology as a useful addition to the currently available modalities to achieve lung cancer diagnosis. The e-nose can assess the volatile organic compounds detected in the breath and derived from the cellular metabolism. Volatile organic compounds can be analyzed to identify the individual chemical elements as well as their pattern of expression to reproduce a sensorial combination similar to a fingerprint (breathprint). The e nose can be used alone, mimicking the combinatorial selectivity of the human olfactory system, or as part of a multisensorial platform. This review analyzes the progress made by investigators interested in this technology as well as the perspectives for its future utilization. PMID- 29526823 TI - Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models. AB - INTRODUCTION: Osimertinib showed great clinical efficacy for activated-EGFR NCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody cetuximab or the MEK1/2-inhibitor selumetinib in EGFR-mutated NCLC in vivo models. METHODS: We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746 A759del/T790M-), H1975 (L858R/T790M+), and PC9-T790M (E746-A759del /T790M+) xenografts in second-line therapy after the development of resistance to osimertinib, and in first-line therapy, and we explored mechanisms of resistance to these treatments. RESULTS: The addition of selumetinib or cetuximab to osimertinib in second-line therapy reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50% to 80%, and a median progression-free survival (mPFS) of first- plus second-line of therapy of 28 weeks. The early use of combinations in first-line therapy increased the RR to 90%, with an mPFS not reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0.005) as compared to osimertinib, achieving in first-line therapy an mPFS time of 17 to 18 weeks. Moreover, in ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found Hedgehog pathway activation and we showed that therapy with an SMO inhibitor plus osimertinib and selumetinib inhibited proliferation and migratory and invasive properties of resistant cells. CONCLUSIONS: We showed that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated NCLC and that hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments. PMID- 29526824 TI - Immunohistochemical and Image Analysis-Based Study Shows That Several Immune Checkpoints are Co-expressed in Non-Small Cell Lung Carcinoma Tumors. AB - INTRODUCTION: The understanding of immune checkpoint molecules' co-expression in non-small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. METHODS: We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs - 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) - placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathologic features, TAICs, and molecular characteristics. RESULTS: Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current smokers than in never smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS-mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, T-cell immunoglobulin mucin family member 3, and IDO-1 in TAICs than wild type. Kaplan Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. CONCLUSIONS: We found frequent immunohistochemical co expression of immune checkpoints in surgically resected NCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status. PMID- 29526825 TI - The Role of Prophylactic Cranial Irradiation in Patients With Extensive Stage Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: The role of prophylactic cranial irradiation (PCI) is controversial in patients with extensive stage small cell lung cancer. The aim of this study was to determine the impact of PCI in these patients. METHODS: We performed a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic literature search was conducted in MEDLINE, EMBASE, and the Cochrane Central Register. The primary outcome was overall survival (OS). RESULTS: We identified five studies comprising 984 patients, of whom 448 received PCI and 536 did not receive PCI. In pooled estimates, PCI did not statistically improve OS compared with controls (hazard ratio [HR] = 0.82; 95% confidence interval [CI]: 0.60-1.11; I2 = 77%; p = 0.19). However, the PCI group had a significant advantage in 1-year survival compared to the no-PCI group (37.1% versus 27.1%; risk ratio = 0.87; 95% CI: 0.80 0.95; I2 = 47%; p = 0.002), and the pooled estimates indicated that progression free survival and the risk of brain metastasis were associated with significant benefit in the PCI group (HR = 0.83; 95% CI: 0.70-0.98; I2 = 22%; p = 0.03; and HR = 0.34; 95% CI: 0.23-0.50; I2 = 0%; p < 0.001, respectively). CONCLUSIONS: Our findings suggest that PCI in patients with extensive stage small cell lung cancer may lead to a significant benefit in 1-year survival, progression-free survival, and the risk of brain metastasis, despite the lack of a significant advantage in OS. PMID- 29526826 TI - Brain abscess and cervical lymphadenitis due to Paraclostridium bifermentans: A report of two cases. AB - Paraclostridium bifermentans (current nomenclature of Clostridium bifermentans since 2016) is a gram-positive, spore-forming anaerobic bacterium. Here, we describe two cases associated with this organism. The first, primarily a case of tubercular brain abscess where P. bifermentans was isolated as part of a polymicrobial flora, following a neurosurgical procedure for the same and the second, a case of cervical lymphadenitis from which it was isolated as the sole causative agent. There are only a few reported cases of P. bifermentans in literature and these cases illustrate the widening spectrum of infections related to it. PMID- 29526827 TI - Toxin profile of fecal Clostridium perfringens strains isolated from children with autism spectrum disorders. AB - Infectious factors are taken into consideration in pathophysiology of autism spectrum disorders (ASD). ASD patients often suffer from gastrointestinal disorders. The intestinal microbiota of autistic patients significantly differs from that in healthy individuals. The aim of the study was to compare the profile of toxins produced by C. perfringens strains isolated from feces of children with ASD, with healthy individuals and obese subjects. This study included 111 strains of C. perfringens: 49 isolates from 29 children with ASD, 30 - from 17 healthy individuals and 32 - from 24 young obese subjects. Alpha, beta, beta2, epsilon, iota and enterotoxin genes were detected using appropriate PCRs. The alpha toxin gene (cpa) was present in all 111 examined strains (100%). The beta2 gene (cpb2) was detected in 45/49 strains (91.8%) isolated from children with ASD, 17/30 (56.7%) isolates from healthy subjects, and 12 of 32 (37.5%) isolates from obese subjects. C. perfringens strains with cpb2 gene were detected in 27/29 ASD patients (93.1%), 10/17 healthy subjects (58.8%) and 11/24 (45.8%) obese subjects. Beta2 toxin encoding cpb2 gene was significantly more common in strains isolated from ASD patients, with no significant difference between control subjects regardless of diet. Further research to explain observed phenomena and pathomechanism of beta2 toxin is required. PMID- 29526828 TI - Controlled release of an HDAC inhibitor for reduction of inflammation in dry eye disease. AB - : Dry eye disease (DED), also known as keratoconjunctivitis sicca, is an ocular surface disease characterized by T-cell-mediated inflammation. Current therapeutics, such as immunosuppressive agents, act to suppress the clinical signs and inflammation. However, long-term usage of these treatments can cause severe side effects. In this study, we present an alternative therapeutic approach that utilizes a histone deacetylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. Specifically, HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs), enhancing FoxP3 acetylation and subsequently guarding the transcription factor from proteasomal degradation. Here, a specific HDACi known as SAHA (suberoylanilide hydroxamic acid) was formulated to controllably release in the lacrimal gland. Intralacrimal gland injection of PLGA-based SAHA microspheres prevented clinical signs of DED in mice with Concanavalin A-induced DED, reduced expression of pro-inflammatory cytokines, and increased expression of FoxP3 in the lacrimal glands. Murine T cell culture experiments also revealed that SAHA decreased effector T cell proliferation and enhanced suppressive function of Tregs in co-cultures of Tregs and effector T cells. STATEMENT OF SIGNIFICANCE: In this study, we demonstrate a therapeutic approach that utilizes a histone deactylase inhibitor (HDACi) to regulate transcription of a variety of immunomodulatory genes. HDACi have emerged as a potential anti-inflammatory agent, which can modulate the functions of a subset of suppressive T lymphocytes known as regulatory T cells (Tregs). Here, HDACi microspheres composed of a biocompatible and biodegradable polymer (poly(lactic-co-glycolic acid) (PLGA)), were able to locally release the HDACi and prevent clinical signs of DED. This work is timely given the recent shift in treatments of DED towards immunological based therapies to reduce ocular inflammation. However, notably, many of these treatments require large amounts of drug, and non-specifically suppress the immune system, leading to several systemic side effects. Instead of merely suppressing or blocking inflammation, the formulation described herein intends to balance the microenvironment promoting immunological homeostasis. This particular drug delivery system may also have broad implications in the field of inflammatory mediated ocular disorders such as uveitis, Sjogren's syndrome, allergic conjunctivitis. PMID- 29526829 TI - Mechanical stabilization of proteolytically degradable polyethylene glycol dimethacrylate hydrogels through peptide interaction. AB - : Balancing enhancement of neurite extension against loss of matrix support in synthetic hydrogels containing proteolytically degradable and bioactive signaling peptides to optimize tissue formation is difficult. Using a systematic approach, polyethylene glycol hydrogels containing concurrent continuous concentration gradients of the laminin derived bioactive signaling peptide, Ile-Lys-Val-Ala-Val (IKVAV), and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ, were fabricated and characterized. During proteolytic degradation of the concentration gradient hydrogels, the IKVAV and IWGQ cleavage fragment from GPQGIWGQ were found to interact and stabilize the bulk Young's Modulus of the hydrogel. Further testing of discrete samples containing GPQGIWGQ or its cleavage fragments, GPQG and IWGQ, indicates hydrophobic interactions between the peptides are not necessary for mechanical stabilization of the hydrogel, but changes in the concentration ratio between the peptides tethered in the hydrogel and salts and ions in the swelling solution can affect the stabilization. Encapsulation of human induced pluripotent stem cell derived neural stem cells did not reduce the mechanical properties of the hydrogel over a 14 day neural differentiation culture period, and IKVAV was found to maintain concentration dependent effects on neurite extension and mRNA gene expression of neural cytoskeletal markers, similar to previous studies. As a result, this work has significant implications for the analysis of biological studies in matrices, as the material and mechanical properties of the hydrogel may be unexpectedly temporally changing during culture due to interactions between peptide signaling elements, underscoring the need for greater matrix characterization during the degradation and cell culture. STATEMENT OF SIGNIFICANCE: Greater emulation of the native extracellular matrix is necessary for tissue formation. To achieve this, matrices are becoming more complex, often including multiple bioactive signaling elements. However, peptide signaling in polyethylene glycol matrices and amino acids interactions between peptides can affect hydrogel material and mechanical properties, but are rarely studied. The current study identifies such an interaction between laminin derived peptide, IKVAV, and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ. Previous studies using these peptides did not identify their interactions' ability to mechanically stabilize the hydrogel during degradation. This work underscores the need for greater matrix characterization and consideration of bioactive signaling element effects temporally on the matrix's material and mechanical properties, as they can contribute to cellular response. PMID- 29526830 TI - Inhibition of osteoclastogenesis by stem cell-derived extracellular matrix through modulation of intracellular reactive oxygen species. AB - : Decellularized extracellular matrix (ECM) derived from stem cells has been shown as a promising biomaterial for bone regeneration because of the promotion effect on osteogenesis in mesenchymal stem cells (MSCs). However, bone regeneration is also influenced by bone resorption and little is known about the effect of cell-derived ECM on osteoclast differentiation. In this study, ECM was deposited by MSCs and, after decellularization, the effect of ECM on osteoclastogenesis of bone marrow monocytes (BMMs) was investigated in comparison to standard tissue culture polystyrene. Our results showed that cell-derived ECM improved BMM proliferation but potently inhibited osteoclast differentiation, evidenced by down-regulation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells, areas of actin rings, and osteoclast-specific gene expression. ECM-mediated attenuation of intracellular reactive oxygen species (ROS) was suggested to play a rival role in the inhibition of osteoclastogenesis, because exogenous hydrogen peroxide supplementation partially rescued the ECM-inhibited osteoclastogenesis. Furthermore, rather than collagen type I, fibronectin in the ECM contributed to ECM-mediated anti osteoclastogenesis. In conclusion, stem cell-derived decellularized ECM significantly suppressed osteoclastogenesis via the attenuation of intracellular ROS. The anti-osteoclastogenic property of cell-derived ECM may benefit its clinical use for modulating bone remodeling and promoting bone tissue engineering. STATEMENT OF SIGNIFICANCE: Decellularized extracellular matrix (ECM) derived from stem cells has been shown as a promising biomaterial for bone regeneration; however, bone remodeling is influenced by bone resorption and little is known about the effect of cell-derived ECM on osteoclast differentiation. Cell-derived ECM improved BMM proliferation but potently inhibited osteoclast differentiation. ECM-mediated attenuation of intracellular reactive oxygen species was suggested to play a rival role in osteoclastogenesis. Fibronectin in cell-derived ECM also contributed to ECM-mediated anti osteoclastogenesis. The anti-osteoclastogenic property of cell-derived ECM may benefit clinically for modulating bone remodeling and promoting bone tissue engineering. PMID- 29526831 TI - Intravenous Dexketoprofen versus Intravenous Paracetamol for Dysmenorrhea: A Randomized Controlled Trial AB - BACKGROUND: Dysmenorrhea is one of the most common acute pain disorders among women of reproductive age. AIMS: To compare the effects of IV paracetamol with dexketoprofen in patients presenting with primary dysmenorrhea to the emergency department. STUDY DESIGN: Randomized controlled trial. METHODS: Patients over 18 years old presenting with pelvic pain related to menstruation were eligible for the study. Study patients received 1 g paracetamol or 50 mg dexketoprofen in 100 mL normal saline with a 4-5 minute infusion via the intravenous route. Pain intensity was measured by a visual analog scale at 15 and 30 minutes. Patients were randomized and assigned to either of two study arms via sealed envelopes. Study drugs were identical in color, and thus both personnel and patients were blinded to the study drug. The dexketoprofen group comprised 49 patients, and the paracetamol group had 50 patients in the final analysis. RESULTS: The mean age of the study subjects was 20.9+/-2.5 and the mean duration of the pain was 1.9+/-1.7 (median: 1, interquartile range: 1 to 2) hours. Both dexketoprofen (median change: 33, 95% CI: 24 to 38) and paracetamol (median change: 21, 95% CI: 12 to 32) effectively reduced the pain at 15 minutes, which was repeated at 30 minutes (median change: 63, 95% CI: 57 to 65 vs 55.5, 95% CI: 50 to 59, respectively). Pain improvement in the dexketoprofen group was better than in the paracetamol group at 15 (median difference: 8, 95% CI: 0 to 16, p=0.048) and 30 (median difference: 6, 95% CI: 1 to 12, p=0.028) minutes, which was statistically significant but not clinically significant. CONCLUSION: Dexketotoprofen has a better visual analogue scale score that is not clinically relevant compared to paracetamol. PMID- 29526832 TI - Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). AB - BACKGROUND : Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure and cardiovascular death overall, in those with and without a baseline history of heart failure, and in other participant subgroups. METHODS : The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized heart failure. RESULTS : Participants with a history of heart failure at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and beta-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized heart failure was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67 0.91), as was fatal or hospitalized heart failure (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized heart failure alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized heart failure may be greater in patients with a prior history of heart failure (HR, 0.61; 95% CI, 0.46-0.80) compared with those without heart failure at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without heart failure at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of heart failure (P=0.03). CONCLUSIONS : In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized heart failure across a broad range of different patient subgroups. Benefits may be greater in those with a history of heart failure at baseline. CLINICAL TRIAL REGISTRATION : URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754. PMID- 29526833 TI - Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease: Results of the SWAP-4 Study. AB - BACKGROUND: Switching between different classes of P2Y12 inhibitors, including de escalation from ticagrelor to clopidogrel, commonly occurs in clinical practice. However, the pharmacodynamic profiles of this strategy have been poorly explored. METHODS: This was a prospective, randomized, open-label study conducted in patients on maintenance dosing (MD) of aspirin (81 mg/d) and clopidogrel (75 mg/d). After a 7-day run-in with ticagrelor (180 mg loading dose [LD] followed by 90 mg twice daily MD), patients (n=80) were randomized into 1 of 4 groups: group A, clopidogrel 600 mg LD 24 hours after the last MD of ticagrelor (C-600 mg-24h); group B, clopidogrel 600 mg LD 12 hours after the last MD of ticagrelor (C-600 mg 12h); group C, clopidogrel 75 mg/d MD 24 hours after the last MD of ticagrelor (C 75 mg-24h); and group D, ticagrelor 90 mg twice daily MD (T-90 mg twice daily). MD of the randomized treatment was maintained for 10+/-3 days. Pharmacodynamic assessments were performed at baseline, after run-in, and at 2, 24, 48, and 72 hours and 10 days with P2Y12 reaction units by VerifyNow; platelet reactivity index was assessed by vasodilator-stimulated phosphoprotein; and maximal platelet aggregation was determined by light transmittance aggregometry. RESULTS: T-90 mg twice daily led to lower platelet reactivity than any clopidogrel regimen using all assays at all time points. P2Y12 reaction unit levels were similar between the C-600 mg-24h (group A) and the C-75 mg-24h (group C) (P=0.29), including at 48 hours (primary end point; least mean difference, -6.9; 95% confidence interval, -38.1 to 24.3; P=0.66). P2Y12 reaction unit levels were lower with C 600 mg-12h (group B) than with C-75 mg-24h (group C; P=0.024). Maximal platelet aggregation over time was lower with both C-600 mg-24h (group A; P=0.041) and C 600 mg-12h (group B; P=0.028) compared with C-75 mg-24h (group C). Platelet reactivity index profiles paralleled those observed with P2Y12 reaction units. There were no pharmacodynamic differences for all tests between C-600 mg-24h (group A) and C-600 mg-12h (group B). In group C (C-75 mg-24h), platelet reactivity increased compared with baseline as early as 24 hours, reaching statistical significance at 48 and 72 hours and up to 10 days. These pharmacodynamic findings were delayed and blunted in magnitude with the administration of an LD, regardless of the timing of administration. CONCLUSIONS: De-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity. The use of an LD before the initiation of an MD regimen of clopidogrel mitigates these observations, although this is not affected by the timing of its administration after ticagrelor discontinuation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02287909. PMID- 29526834 TI - Mobile Phone Detection of Atrial Fibrillation With Mechanocardiography: The MODE AF Study (Mobile Phone Detection of Atrial Fibrillation). PMID- 29526836 TI - Beamspace dual signal space projection (bDSSP): a method for selective detection of deep sources in MEG measurements. AB - OBJECTIVE: Magnetoencephalography (MEG) has a well-recognized weakness at detecting deeper brain activities. This paper proposes a novel algorithm for selective detection of deep sources by suppressing interference signals from superficial sources in MEG measurements. APPROACH: The proposed algorithm combines the beamspace preprocessing method with the dual signal space projection (DSSP) interference suppression method. A prerequisite of the proposed algorithm is prior knowledge of the location of the deep sources. The proposed algorithm first derives the basis vectors that span a local region just covering the locations of the deep sources. It then estimates the time-domain signal subspace of the superficial sources by using the projector composed of these basis vectors. Signals from the deep sources are extracted by projecting the row space of the data matrix onto the direction orthogonal to the signal subspace of the superficial sources. MAIN RESULTS: Compared with the previously proposed beamspace signal space separation (SSS) method, the proposed algorithm is capable of suppressing much stronger interference from superficial sources. This capability is demonstrated in our computer simulation as well as experiments using phantom data. SIGNIFICANCE: The proposed bDSSP algorithm can be a powerful tool in studies of physiological functions of midbrain and deep brain structures. PMID- 29526837 TI - Pain perception and low back pain functional disability after a 10-week core and mobility training program: A pilot study. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the effects of a 10-week core and mobility training program on pain perception and low back disability score in professors, students and employees of a university. METHODS: Twenty-four individuals of a university who previously reported pain and low back disability were randomly assigned to an experimental group (EG; n= 8) that received 2 weekly sessions of 50 minutes of core and mobility training for 10 weeks; or to a control group (CG; n= 16). Both groups received a guideline to adopt ergonomic postures during work and activities of daily living. The visual analog pain scale (VAS) and the Roland-Morris questionnaire (RMQ) were applied pre- and post intervention. RESULTS: Significant reductions in the pain intensity perception (p= 0.014) and low back functional disability (p= 0.011) were noted in the EG pre- and post measures. However, no significant difference was observed in the CG. Thus, there was a significant difference between the EG and the CG in the post-intervention measures (p= 0.001). CONCLUSION: Core and mobility training and home-ergonomic instructions were effective to reduce the pain intensity perception and low back functional disability in the EG. PMID- 29526835 TI - Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. AB - OBJECTIVES: To design a questionnaire and use it to explore unmet needs with practical aspects of medicine taking after stroke, predictors of medicine taking and to estimate the proportion of survivors who get support with daily medication taking. DESIGN: Four workshops with stroke survivors and caregivers to design the questionnaire.A cross-sectional postal questionnaire in primary care. SETTING: 18 general practitioner practices in the East of England and London. Questionnaires posted between September 2016 and February 2017. PARTICIPANTS: 1687 stroke survivors living in the community outside institutional long-term care. PRIMARY OUTCOME MEASURES: The proportion of community stroke survivors receiving support from caregivers for practical aspects of medicine taking; the proportion with unmet needs in this respect; the predictors of experiencing unmet needs and missing taking medications. RESULTS: A five-item questionnaire was developed to cover the different aspects of medicine taking. 596/1687 (35%) questionnaires were returned. 56% reported getting help in at least one aspect of taking medication and 11% needing more help. 35% reported missing taking their medicines. Unmet needs were associated with receiving help with medications (OR 5.9, P<0.001), being on a higher number of medications (OR 1.2, P<0.001) and being dependent for activities of daily living (OR 4.9, P=0.001). Missing medication was associated with having unmet needs (OR 5.3, P<0.001), receiving help with medications (OR 2.1, P<0.001), being on a higher number of medicines (OR 1.1, P=0.008) and being older than 70 years (OR 0.6, P=0.006). CONCLUSIONS: More than half of patients who replied needed help with taking medication, and 1 in 10 had unmet needs in this regard. Stroke survivors dependent on others have more unmet needs, are more likely to miss medicines and might benefit from focused clinical and research attention. Novel primary care interventions focusing on the practicalities of taking medicines are warranted. PMID- 29526838 TI - Changes in the bioelectric activity of the trapezius muscle following the thermal effect of red light and infrared radiation. AB - BACKGROUND: The therapeutic effects of visible light and infrared is especially often used in physiotherapy. OBJECTIVE: The purpose of this study was to determine the effect of exposure to radiation on the motor units activity. METHODS: The study included 29 volunteers of whom the spontaneous and voluntary bioelectric activity of the trapezius muscle was evaluated using surface electromyography (value of average amplitude and frequency), before and immediately after a 15-minute irradiation. Additionally, the range of motion of the cervical spine and trigger points pain sensitivity to the pressure were assessed. RESULTS: No statistically significant changes in the pain sensitivity threshold and the range of motion after the irradiation was applied. On the other hand, a 15-minute exposure to radiation induced an increase in the value of average amplitude of rest-related as well as exercise-related potentials and an increase in the average value of frequency of the right side biopotentials at rest and of both sides for active elevation. CONCLUSIONS: Infrared radiation and visible red light have a stimulating effect on the muscle ability to develop active contraction. It is proposed that the observed changes are associated with the thermal effect of radiation as well as with the so-called extra-visual effects. PMID- 29526839 TI - Metatarsophalangeal joint flexion affects dorsiflexor activity in subjects with a dominant extensor hallucis longus. AB - BACKGROUND AND OBJECTIVES: Normal dorsiflexion (DF) required for normal gait is achieved through balance of the tibialis anterior (TA) and extensor hallucis longus (EHL). Imbalance may induce ankle and foot deformities and exacerbate pathology. EHL dominance is associated with progressive TA weakness, attributable to muscle non-use. When the EHL dominantly dorsiflexes the ankle, the big toe extends at the metatarsophalangeal joint (MTPJ) and pure ankle DF is absent. The effects of active MTPJ flexion on TA and EHL muscles, TA/EHL ratio, and the force applied during active DF in EHL-dominant (EHL-D) and EHL-non-dominant (EHL-ND) subjects were compared. METHODS: The 38 subjects were divided into EHL-D and EHL ND groups. All subjects performed active ankle DF with and without active MTPJ flexion. Surface electromyographic data, ankle active range of motion, and DF force were measured. Two-way mixed analysis of variance was used to evaluate differences in dependent variables. RESULTS: Compared to the EHL-ND group, the EHL-D group exhibited less TA activity, more EHL activity, and a reduced TA/EHL activity ratio. Active application of MTPJ flexion during DF significantly reduced muscle imbalance, whereas EHL activity decreased and the TA/EHL activity ratio increased. The DF force decreased significantly with MTPJ flexion in both groups. CONCLUSIONS: Active MTPJ flexion can reduce EHL and/or increase TA activity and increase the TA/EHL activity ratio during active ankle DF in both EHL-D and EHL-ND subjects. PMID- 29526840 TI - Feasibility of high intensity training in nonspecific chronic low back pain: A clinical trial. AB - BACKGROUND: Although low to moderate intensity exercise therapy is a predominant part of rehabilitation in nonspecific chronic low back pain (NSCLBP), effect sizes are small and optimal exercise modalities/intensities are unclear. Conversely, effects of high intensity training have not yet been investigated in this population. OBJECTIVE: The aim of this study is to investigate the feasibility of high intensity training (HIT) and to explore the magnitude of the effects of a HIT program on exercise capacity and disease related outcome measures compared to conventional therapy for persons with NSCLBP. METHODS: In this non-randomized controlled feasibility study, treatment satisfaction, adherence, disability, pain, physical activity, body composition, exercise capacity and self-reported motivation, were assessed in persons with NSCLBP, before (PRE) and after (POST) 6 weeks (12 sessions, 1.5 hours/session, 2 x/week) of high intensity cardiovascular (100% VO2Max) and high load resistance (80% 1RM) training (HIT, n= 10) and compared to average intensity/load (60% VO2max) conventional physical therapy (CON, n= 10). RESULTS: At PRE, CON and HIT did not differ, except for gender ratio and lean mass. Compared to CON, HIT retained motivation to rehabilitate better (HIT: +3%; CON: -25%) and had higher therapy adherence (+16%) during the study course. No adverse events were noted in both groups. Whereas disability reduced in both groups (HIT: -10.4%; CON: -8.3%), peak workload (+7.0%), time to exhaustion (+9.5%), and activity level (+5.6%) only improved in HIT. CONCLUSIONS: High intensity exercise therapy appears to be a feasible rehabilitation approach in NSCLBP. Outcomes improved following the HIT protocol, warranting the investigation of its effectiveness in future large scale RCT studies. PMID- 29526841 TI - Test-retest reliability of a handheld dynamometer for measurement of isometric cervical muscle strength. AB - BACKGROUND: There is a lack of test-retest reliability studies of measurements of cervical muscle strength, taking into account gender and possible learning effects. OBJECTIVE: To investigate test-retest reliability of measurement of maximal isometric cervical muscle strength by handheld dynamometry. METHODS: Thirty women (age 20-58 years) and 28 men (age 20-60 years) participated in the study. Maximal isometric strength (neck flexion, neck extension, and right/left lateral flexion) was measured on three separate days at least five days apart by one evaluator. RESULTS: Intra-rater consistency tended to improve from day 1-2 measurements to day 2-3 measurements in both women and men. In women, the intra class correlation coefficients (ICC) for day 2 to day 3 measurements were 0.91 (95% confidence interval [CI], 0.82-0.95) for neck flexion, 0.88 (95% CI, 0.76 0.94) for neck extension, 0.84 (95% CI, 0.68-0.92) for right lateral flexion, and 0.89 (95% CI, 0.78-0.95) for left lateral flexion. The corresponding ICCs among men were 0.86 (95% CI, 0.72-0.93) for neck flexion, 0.93 (95% CI, 0.85-0.97) for neck extension, 0.82 (95% CI, 0.65-0.91) for right lateral flexion and 0.73 (95% CI, 0.50-0.87) for left lateral flexion. CONCLUSION: This study describes a reliable and easy-to-administer test for assessing maximal isometric cervical muscle strength. PMID- 29526842 TI - Application of algometry in patients with cervical and lumbar radiculopathy. AB - BACKGROUND: Algometry, as a highly sensitive method, provides an objective insight into the degree of pain, while the use of questionnaires can estimate the patient's psychological status in a simple way. OBJECTIVE: This study was conducted in order to measure the pressure pain threshold in patients with cervical and lumbar radiculopathy and to find a possible association of pain with the anxiety and depression. METHODS: The study examined 60 hospitalized patients with cervical radiculopathy and 60 patients with lumbar radiculopathy before starting and after finishing kinesitherapy. The research was conducted using the digital algometry device and Hospital Anxiety and Depression Scale. RESULTS: There was no statistically significant difference in algometric values between the patients with cervical radiculopathy and the patients with lumbar radiculopathy. The program of rehabilitation did not lead to significant improvement in the level of pain. Females have a lower pressure pain threshold than males. Psychological factors greatly affect the pain. CONCLUSIONS: The applied methods will provide the implementation of appropriate therapy and would achieve better verification of the results in a rehabilitation program. Radiculopathy in conservative therapy should be treated in cervical-thoracic and lumbar region together. Rehabilitation period for patients with radiculopathy have to be longer. PMID- 29526844 TI - Effects of endurance training on hsa-miR-223, P2RY12 receptor expression and platelet function in type 2 diabetic patients. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with thrombotic events due to platelets' defects. OBJECTIVE: The aim of this study was to investigate the effects of endurance training on expressions of platelet hsa-miR-223 and P2RY12 receptor, as well as platelet function in T2DM patients. METHODS: Twenty female T2DM patients (age, 62.25+/-3.81 yr; weight, 73.53+/-9.04 kg; height, 154.7+/-4.3 cm) were randomly divided into two groups (Control (CONT) and endurance training (ET)). Subjects in ET group performed eight weeks of running on treadmill at 60-75% of VO2peak (moderate intensity), 3 sessions per week, while, the subjects in control group were not involved in any kind of exercise training. Two blood samples were taken before and 48 h after the training and were analyzed for platelet aggregation, and hsa-miR-223 and P2RY12 expressions. RESULTS: Although platelet aggregation decreased significantly in ET group (P < 0.05), these changes were not significantly different between two groups. Expression of platelet hsa-miR-223 increased and P2RY12 mRNA reduced following ET non-significantly. However, decreases in fasting blood glucose, glycated hemoglobin and body weight, and increases in VO2peak following ET were significantly different when compared to control group (P < 0.05). CONCLUSIONS: Short-term endurance training dose not induce up-regulation of hsa-miR-223 and down-regulation of P2RY12, while it has a positive impact on platelet function, glycemic indices, physical fitness and body composition in female T2DM patients. PMID- 29526843 TI - LncRNA AB209630 inhibits gemcitabine resistance cell proliferation by regulating PI3K/AKT signaling in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Recent study revealed that abnormal long noncoding RNAs (lncRNAs) expression are association with chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC). OBJECTIVE: The present study was aimed to investigate the effects of lncRNA AB209630 expression for gemcitabine resistance in PDAC cells. METHODS: In the study, increased expression of lncRNA AB209630 could suppress cell proliferation and cell colony formation ability in gemcitabine resistance cells of PDAC. Furthermore, western blot results demonstrated that upregulation of lncRNA AB209630 suppressed the PI3K/AKT signaling pathway in gemcitabine resistance cells. Besides, we found that lncRNA AB209630 expression was dramatically downregulated in PDAC tissues compared to adjacent normal tissues. Lower PDAC expression predicted a poor prognosis in PDAC patients. CONCLUSIONS: Thus, these results indicated that lncRNA AB209630 may be a potential target of PDAC. PMID- 29526845 TI - Polymorphism FSHR (-29G/A) as a genetic agent together with ESRI (XbaIG/A) in women with poor response to controlled ovarian hyperstimulation. AB - BACKGROUND: One of the major problems in IVF is the poor response of the ovary to gonadotropins. ESRI and FSHR are two effective genes on controlled ovarian hyperstimulation (COH). OBJECTIVES: Evaluating the correlation of alleles and genotypes of polymorphism (-29G/A) located in the FSH receptor gene and polymorphism (XbaI G/A) located in Estrogen receptor genes with the ovary's response would help to anticipate the results of ovulation in IVF cycles. METHODS: In the present study, two hundred (200) blood samples were taken from infertile women aged 20 to 39 who were under IVF therapy. After DNA extraction from the samples, real-time PCR was performed using a specific probe-primer. RESULTS: Statistical analysis revealed that the frequency of alleles and genotypes of polymorphisms (-29G/A) and (XbaI A/G) in women with normal to poor response did not have significant correlation. PMID- 29526846 TI - Cost-effective batch production process of scFv antibody in Escherichia coli. AB - BACKGROUND: Cost-effective production of antibody (Ab) fragments is of great interests of many pharmaceutical industries, in large part due to their high usages in research, diagnosis and therapy. Thus, the production of Abs necessitates accomplishment of the optimal strategies. OBJECTIVE: In this study, based on the induction start time using arabinose, we implemented a novel strategy for the cost-effective production of single chain variable fragment (scFv) in Escherichia coli (E. coli). METHODS: Complex and minimum media were used to investigate the batch fermentation in 50 mL batch tubes to find the optimum conditions for the production of a scFv in the Escherichia coli HB2151. RESULTS: Arabinose was used as an appropriate economical alternative of isopropyl beta-D-1-thiogalactopyranoside (IPTG) for the production of scFv antibody. The optimum concentration of arabinose as an inducer was 0.1% (w/w), while below this point the scFv production yield (YP/X) decreased significantly. The start time of the induction of E. coli HB2151 cells was adjusted to the stationary phase of the growth, and the results showed higher specific scFv production yields up to 0.9 mg scFv/g biomass in the minimum media. The optimum induction duration times for the complex and minimum media were about 12 and 24 hours, respectively. CONCLUSIONS: We propose this method to possibly be used for the large-scale production of recombinant proteins/peptides such as scFv and Fab antibodies. PMID- 29526847 TI - FOXP3 gene expression in the blood of Iranian multiple sclerosis patients. AB - INTRODUCTION: Multiple sclerosis (MS) is a heterogeneous disease with an unknown etiology. Both genetic and environmental factors lead to MS disease. Recent studies have revealed the inhibitory role of T regulatory cells in the MS disease. Forkhead box P3 (FOXP3) gene is a transcript of the CD4+CD25+FOXP3 and T regulatory cells that is recently introduced as a factor in determining the lineage of immune cells. Based on these assumptions we investigate the expression of this gene in the peripheral blood of fifty MS patients in comparison to fifty controls. MATERIAL AND METHODS: In this case-control study, we investigate the FOXP3 expression in fifty MS patients (30 females (60%) and 20 males (40%), mean age +/- SD: 33.3 +/- 5.4 years) in comparing to fifty healthy age and sex matched controls (30 females (60%) and 20 males (40%), mean age +/- SD: 34.2 +/- 4.8) using real-time quantitative reverse transcription-PCR (qRT-PCR) in order to explore any association between FOXP3 expression level and MS. RESULTS: The expression level of FOXP3 gene was not significantly different between MS patients and controls (p: 0.79). In addition the expression level of the gene was not significantly different between male and female (p: 0.8, p: 0.79, respectively). CONCLUSION: Although, the FOXP3 gene is one of the most important genes in the regulation of the immune cells, according to no significant results of this study it may concluded that the expression of the gene is not different between MS patients and healthy controls at least at mRNA level. So it seems that investigating the protein level of FOXP3, related LNCs and microRNAs could be useful to investigate the relation between this gene and the disease. However, the clinical relevance of FOXP3 in patients with regard to their therapy needs to be further explored by evaluation of genetic background in relation to immune responses in MS patients. PMID- 29526848 TI - White matter asymmetries in patients with cerebral small vessel disease. AB - White matter asymmetries of the human brain have been well documented using diffusion tensor imaging. The purpose of this study was to investigate white matter asymmetry across the whole brain in cerebral small vessel disease patients and evaluate the relation between the factors which often represent disease existence and white matter asymmetry. A total of 105 nondemented elderly subjects with cerebral small vessel disease aged between 60 and 85 years were included in this study. All subjects underwent T1 MPRAGE, fluid-attenuated inversion recovery, and diffusion tensor imaging scanning. With tract-based spatial statistics in diffusion tensor imaging, this study examined the white matter asymmetries and the correlations between white matter asymmetries and four distinct factors such as deep white matter hyperintensities score, periventricular hyperintensities score, cerebral microbleed number and lacune number. The study suggested the asymmetric microstructural change in small vessel disease patients involving the right side being more injured than the left. The four factors jointly affect right brain anisotropy decrease in the middle cerebellar peduncle, the cerebral peduncle, the pontine crossing tract, the corticospinal tract, the medial lemniscus, the posterior limb of internal capsule, and the frontal pattern of white matter. Results of the study demonstrated the lost right white matter may be the main origin of dysfunction in small vessel disease patients. This asymmetry should help with the evaluation of prognostic indicators of disease progression in lesion-based neuropathology.. PMID- 29526849 TI - Translaminar neuromorphotopological clustering and classification of dentate nucleus neurons. AB - Thisstudy aims to determine whether dentate neurons can be translaminarlyneuromorphotopologically classified as ventrolateral or dorsomedial type. Adulthuman dentate interneuron 2D binary images are analyzed. The analysis isperformed on both real and virtual neuron samples and 29 parameters are used.They are divided into the classes: neuron surface, shape, length, branching andcomplexity. Clustering is performed by an algorithm that employs predictor extraction (matrix attractor analysis/non-negative matrix factorization and cluster analysis of predictor factors - separate unifactor analysis/Student's t test and MANOVA) and multivariate cluster analysis (cluster analysis, principal component analysis, factor analysis with pro/varimax rotation, Fisher's linear discriminant analysis and feed-forward backpropagation artificial neural networks). The separate unifactor analysis extracted as significant the following predictors from the natural cell sample: the Npd (p< 0:05), and from the virtual cell sample: the Adt (p< 0.05),Do (p< 0.001), Ms (p< 0.01), Dwdth (p< 0:001), Npd (p< 0:05), Nsd (p< 0.001), Nt/hod (p< 0.001), Nmax (p< 0.01), Ds (p< 0.001), Cdf (Nt/hod)st (p< 0.05). For the multidimensional analysis, with the exception of the Fisher's linear discriminant analysis which gave a false positive result, all other analyses rejected the translaminar dentate neuron classification. Thus, dentate neurons cannot be classified into ventrolateral/dorsomedial neuromorphotopological subtypes. Although some differences were found to exist, they are not sufficient to carry this classification. The methods of multidimensional statistical analysis are again shown to be the best for such kinds of analysis. PMID- 29526850 TI - Transcranial direct current stimulation based on quantitative electroencephalogram combining positive psychotherapy for major depression. AB - Frontal cortex activity is reduced in the left hemisphere during depression. Transcranial direct current stimulation is a noninvasive neuromodulation technique that can increase frontal cortex activity. Therapy based on transcranial Direct Current Stimulation and positive psychology therapy was applied for improving patients' quality of life. The present study compared three conditions of subjects with clinical depression; (a) transcranial Direct Current Stimulation therapy, (b) positive psychotherapy, and(c) combined treatment. Hamilton Depression Rating Scale, Adult State Hope Scale and Optimism/Pessimism Scale was used at baseline, 2-week, 4-week, and 3-month follow-up. Combined condition participants showed greater reduction in depressed mood, improved hope and optimism after 4-weeks as well as during 3-month follow-up than the other conditions. Results are discussed in terms of additive or synergistic relation between transcranial direct current stimulation and positive psychology treatment. PMID- 29526851 TI - The effect of an exogenous magnetic field on neural coding in deep spiking neural networks. AB - A ten-layer feed forward network was constructed in the presence of an exogenous alternating magnetic field. Results indicate that for rate coding, the firing rate is increased in the presence of an exogenous alternating magnetic field and particularly with increasing enhancement of the alternating magnetic field amplitude. For temporal coding, in the presence of alternating magnetic field, the interspike intervals of the spiking sequence are decreased and the distribution of interspike intervals tends to be uniform. PMID- 29526852 TI - Plantar stimulation in parkinsonians: From biomarkers to mobility - randomized controlled trial. AB - BACKGROUND: The decrease of Brain-Derived Neurotrophic Factor (BDNF) serum levels has been related to the pathophysiology of several neurodegenerative diseases as well as to neural plasticity and rehabilitation. Automated Mechanical Peripheral Stimulation (AMPS) has been investigated as a complementary therapy for Parkinson Disease (PD). OBJECTIVES: (1) to investigate the effects of AMPS on BDNF and Cortisol serum levels of subjects with PD; (2) to evidence the interplay between BDNF and Cortisol serum levels and the functional mobility improvement after AMPS treatment. METHODS: Thirty-three subjects with PD were randomized into two groups: effective stimulation (AMPS, n = 16) or placebo stimulation (AMPS SHAM, n = 17). Fourteen healthy aged-matched subjects were included as a reference group. Each AMPS group received eight sessions of treatment using a commercial medical device (GondolaTM). BDNF and Cortisol serum levels, spatiotemporal gait parameters and TUG test were assessed at baseline and after eight sessions of treatment. RESULTS: After the treatment, AMPS group showed significantly higher levels of BDNF and lower levels of Cortisol compared to AMPS SHAM. AMPS group also showed a positive effect on gait pattern as a higher improvement on gait velocity, stride length, and TUG performance was shown. CONCLUSION: Effective AMPS treatment increased BDNF and decreased Cortisol serum levels and produced improvements in functional mobility. PMID- 29526853 TI - Axial diffusivity changes in the motor pathway above stroke foci and functional recovery after subcortical infarction. AB - BACKGROUND: Secondary degeneration of the fiber tract of the motor pathway below infarct foci and functional recovery after stroke have been well demonstrated, but the role of the fiber tract above stroke foci remains unclear. OBJECTIVE: This study aimed to investigate diffusion changes in motor fibers above the lesion and identify predictors of motor improvement within 12 weeks after subcortical infarction. METHODS: Diffusion tensor imaging and the Fugl-Meyer (FM) scale were conducted 1, 4, and 12 weeks (W) after a subcortical infarct. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Region of interest analysis was used to assess diffusion changes in the motor pathway above and below a stroke lesion. Multivariable linear regression was employed to identify predictors of motor improvement within 12 weeks after stroke. RESULTS: Axial diffusivity (AD) in the underlying white matter of the ipsilesional primary motor area (PMA) and cerebral peduncle (CP) in both proportional and poor recovery groups was lower at W1 compared to the controls and values in the contralesional PMA and CP (all P < 0.05). Subsequently, AD in the ipsilesional CP became relatively stable, while AD in the ipsilesional PMA significantly increased from W4 to W12 after stroke (P < 0.05). In all of the patients, changes in the FM scores were greater in those with higher changes in AD of the ipsilesional PMA. Only initial impairment or lesion volume was predictive of motor improvement within 12 weeks after stroke in patients with proportional or poor recovery. CONCLUSION: Increases of AD in the motor pathway above stroke foci may be associated with motor recovery after subcortical infarction. Early measurement of diffusion metrics in the ipsilesional non-ischemic motor pathway has limited value in predicting future motor improvement patterns (proportional or poor recovery). PMID- 29526854 TI - Neural Restoration Training improves visual functions and expands visual field of patients with homonymous visual field defects. AB - BACKGROUND: In recent years, the introduction of visual rehabilitation for patients with homonymous visual field defects has been met with both enthusiasm and caution. Despite the evidence that restitutive training results in expansion of the visual field, several concerns have been raised. OBJECTIVE: We tested the effectiveness of a new rehabilitative protocol called "Neuro Restoration Training" (NRT) in reducing visual field defects and in restituting visual functions in the restored hemianopic area. METHODS: Ten patients with homonymous visual field defects (lesion age >6 months) where trained in detecting low contrast Gabor patches randomly presented in the blind field, which refers to regions of 0 dB sensitivity, and along the hemianopic boundary between absolute (0 dB) and partial blindness (>0 dB). Training included static, drifting, and flickering Gabors in different blocks. Positions along the hemianopic boundary were systematically shifted toward the blind field according to the threshold reduction during the training. Before and after the training, we assessed visual field expansion and improvement in different high-level transfer tasks (i.e., letter identification and shape recognition) performed in the hemianopic boundary and in the blind field. RESULTS: NRT led to significant visual field enlargement (~5 deg), as indicated by the conventional Humphrey perimetry, and two custom made evaluations of visual field expansion with eye movement control (one static and one dynamic). The restored area acquired new visual functions such as small letter recognition and perception of moving shapes. Finally, for some patients, NRT also improved detection, either aware or not, of high contrast flickering grating and recognition of geometrical shapes entirely presented within the blind field. CONCLUSION: These results suggest that NRT may lead to visual field enlargement and translate into untrained visual functions. PMID- 29526855 TI - Potential benefits of a cognitive training program in mild cognitive impairment (MCI). AB - BACKGROUND: Dementia is a disease that is constantly evolving in older people. Its diverse symptoms appear with varying degrees of severity affecting the daily life of those who suffer from it. The rate in which dementia progresses depends on different aspects of the treatment, chosen to try to control and slow down the development of the illness. OBJECTIVE: The aim of this study is to assess the effectiveness of cognitive training through a Brain Computer Interface (BCI) and the NeuronUp platform in two age groups whose MMSE is between 18-23 MCI (mild dementia). METHOD: 32 subjects took part in the study. There were 22 subjects in Group 1 (61-69 years of age) and 10 subjects in Group 2 (70-81 years of age). The criterium for the selection of the groups was to identify the age range with greater improvements due to the training. In order to estimate neuropsychological performance, the subjects were evaluated with the Luria-DNA neuropsychological battery before and after training. This design enables us to evaluate five cognitive areas: visuospatial, spoken language, memory, intellectual processes and attention. RESULTS: After training, Group 1 showed significant improvements in almost all the variables measured when compared with Group 2. This reveals a significant increase in cognitive ability, the degree of which depends on the age. CONCLUSION: People with mild dementia may delay cognitive impairment with a suitable cognitive training program. PMID- 29526856 TI - A wearable resistive robot facilitates locomotor adaptations during gait. AB - BACKGROUND: Robotic-resisted treadmill walking is a form of task-specific training that has been used to improve gait function in individuals with neurological injury, such as stroke, spinal cord injury, or cerebral palsy. Traditionally, these devices use active elements (e.g., motors or actuators) to provide resistance during walking, making them bulky, expensive, and less suitable for overground or in-home rehabilitation. We recently developed a low cost, wearable robotic brace that generates resistive torques across the knee joint using a simple magnetic brake. However, the possible effects of training with this device on gait function in a clinical population are currently unknown. OBJECTIVE: The purpose of this study was to test the acute effects of resisted walking with this device on kinematics, muscle activation patterns, and gait velocity in chronic stroke survivors. METHODS: Six stroke survivors wore the resistive brace and walked on a treadmill for 20 minutes (4*5 minutes) at their self-selected walking speed while simultaneously performing a foot trajectory tracking task to minimize stiff-knee gait. Electromyography, sagittal plane gait kinematics, and overground gait velocity were collected to evaluate the acute effects of the device on gait function. RESULTS: Robotic-resisted treadmill training resulted in a significant increase in quadriceps and hamstring EMG activity during walking. Significant aftereffects (i.e., improved joint excursions) were also observed on the hip and knee kinematics, which persisted for several steps after training. More importantly, training resulted in significant improvements in overground gait velocity. These results were consistent in all the subjects tested. CONCLUSION: This study provides preliminary evidence indicating that robotic-resisted treadmill walking using our knee brace can result in meaningful biomechanical aftereffects that translate to overground walking. PMID- 29526857 TI - Combined effects of cerebellar transcranial direct current stimulation and transcutaneous spinal direct current stimulation on robot-assisted gait training in patients with chronic brain stroke: A pilot, single blind, randomized controlled trial. AB - BACKGROUND: Preliminary evidence showed additional effects of anodal transcranial direct current stimulation over the damaged cerebral hemisphere combined with cathodal transcutaneous spinal direct current stimulation during robot-assisted gait training in chronic stroke patients. This is consistent with the neural organization of locomotion involving cortical and spinal control. The cerebellum is crucial for locomotor control, in particular for avoidance of obstacles, and adaptation to novel conditions during walking. Despite its key role in gait control, to date the effects of transcranial direct current stimulation of the cerebellum have not been investigated on brain stroke patients treated with robot assisted gait training. OBJECTIVE: To evaluate the effects of cerebellar transcranial direct current stimulation combined with transcutaneous spinal direct current stimulation on robot-assisted gait training in patients with chronic brain stroke. METHODS: After balanced randomization, 20 chronic stroke patients received ten, 20-minute robot-assisted gait training sessions (five days a week, for two consecutive weeks) combined with central nervous system stimulation. Group 1 underwent on-line cathodal transcranial direct current stimulation over the contralesional cerebellar hemisphere + cathodal transcutaneous spinal direct current stimulation. Group 2 received on-line anodal transcranial direct current stimulation over the damaged cerebral hemisphere + cathodal transcutaneous spinal direct current stimulation. The primary outcome was the 6-minute walk test performed before, after, and at follow-up at 2 and 4 weeks post-treatment. RESULTS: The significant differences in the 6-minute walk test noted between groups at the first post-treatment evaluation (p = 0.041) were not maintained at either the 2-week (P = 0.650) or the 4-week (P = 0.545) follow up evaluations. CONCLUSION: Our preliminary findings support the hypothesis that cathodal transcranial direct current stimulation over the contralesional cerebellar hemisphere in combination with cathodal transcutaneous spinal direct current stimulation might be useful to boost the effects of robot-assisted gait training in chronic brain stroke patients with walking impairment. PMID- 29526858 TI - Paired associative stimulation modulates corticomotor excitability in chronic stroke: A preliminary investigation. AB - BACKGROUND: Paired associative stimulation (PAS) combining repeated pairing of electrical stimulation of a peripheral nerve with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) can induce neuroplastic adaptations in the human brain and enhance motor learning in neurologically intact individuals. However, the extent to which PAS is an effective technique for inducing associative plasticity and improving motor function in individuals post-stroke is unclear. OBJECTIVE: The objective of this pilot study was to investigate the effects of a single session of PAS to modulate corticomotor excitability and motor skill performance in individuals post-stroke. METHODS: Seven individuals with chronic stroke completed two separate visits separated by at least one week. We assessed general corticomotor excitability, intracortical network activity and behavioral outcomes prior to and at three time points following PAS and compared these outcomes to those following a sham PAS condition (PASSHAM). RESULTS: Following PAS, we found increased general corticomotor excitability but no significant difference in behavioral measures between PAS conditions. There was a relationship between PAS-induced corticomotor excitability increase and enhanced motor skill performance across post-PAS testing time points. CONCLUSION: These results provide preliminary evidence for the potential of PAS to increase corticomotor excitability that could favorably impact motor skill performance in chronic individuals post-stroke and are an important first step for future studies investigating the clinical application and behavioral relevance of PAS interventions in post stroke patient populations. PMID- 29526860 TI - Rehabilitation of stroke patients with plegic hands: Randomized controlled trial of expanded Constraint-Induced Movement therapy. AB - PURPOSE: To evaluate the efficacy of an expanded form of Constraint-Induced Movement Therapy (eCIMT) that renders CIMT, originally designed for treating mild to-moderate upper-extremity hemiparesis, suitable for treating severe hemiparesis. METHODS: Twenty-one adults >=1 year after stroke with severe upper extremity hemiparesis (with little or no capacity to make movements with the more affected hand) were randomly assigned to eCIMT (n = 10), a placebo-control procedure (n = 4), or usual care (n = 7). The participants who received usual care were crossed over to eCIMT four months after enrollment. The CIMT protocol was altered to include fitting of orthotics and adaptive equipment, selected neurodevelopmental techniques, and electromyography-triggered functional electrical stimulation. Treatment was given for 15 consecutive weekdays with 6 hours of therapy scheduled daily for the immediate eCIMT group and 3.5 hours daily for the cross-over eCIMT group. RESULTS: At post-treatment, the immediate eCIMT group showed significant gains relative to the combination of the control groups on the Grade-4/5 Motor Activity Log (MAL; mean = 1.5 points, P < 0.001, f = 4.2) and a convergent measure, the Canadian Occupational Performance Measure (COPM; mean = 2.3, P = 0.014, f = 1.1; f values >=0.4 are considered large, on the COPM changes >=2 are considered clinically meaningful). At 1-year follow-up, the MAL gains in the immediate eCIMT group were only 13% less than at post treatment. The short and long-term outcomes of the crossover eCIMT group were similar to those of the immediate eCIMT group. CONCLUSIONS: This small, randomized controlled trial (RCT) suggests that eCIMT produces a large, meaningful, and persistent improvement in everyday use of the more-affected arm in adults with severe upper-extremity hemiparesis long after stroke. These promising findings warrant confirmation by a large RCT. PMID- 29526859 TI - Sensorimotor integration in chronic stroke: Baseline differences and response to sensory training. AB - BACKGROUND: The integration of somatosensory information from the environment into the motor cortex to inform movement is essential for motor function. As motor deficits commonly persist into the chronic phase of stroke recovery, it is important to understand potential contributing factors to these deficits, as well as their relationship with motor function. To date the impact of chronic stroke on sensorimotor integration has not been thoroughly investigated. OBJECTIVES: The current study aimed to comprehensively examine the influence of chronic stroke on sensorimotor integration, and determine whether sensorimotor integration can be modified with an intervention. Further, it determined the relationship between neurophysiological measures of sensorimotor integration and motor deficits post stroke. METHODS: Fourteen individuals with chronic stroke and twelve older healthy controls participated. Motor impairment and function were quantified in individuals with chronic stroke. Baseline neurophysiology was assessed using nerve-based measures (short- and long-latency afferent inhibition, afferent facilitation) and vibration-based measures of sensorimotor integration, which paired vibration with single and paired-pulse TMS techniques. Neurophysiological assessment was performed before and after a vibration-based sensory training paradigm to assess changes within these circuits. RESULTS: Vibration-based, but not nerve-based measures of sensorimotor integration were different in individuals with chronic stroke, as compared to older healthy controls, suggesting that stroke differentially impacts integration of specific types of somatosensory information. Sensorimotor integration was behaviourally relevant in that it related to both motor function and impairment post-stroke. Finally, sensory training modulated sensorimotor integration in individuals with chronic stroke and controls. CONCLUSION: Sensorimotor integration is differentially impacted by chronic stroke based on the type of afferent feedback. However, both nerve-based and vibration-based measures relate to motor impairment and function in individuals with chronic stroke. PMID- 29526861 TI - Clinical features of patients who might benefit more from walking robotic training. AB - BACKGROUND: Robotic walking training improves probability to reach an autonomous walking in non-ambulant patients affected by subacute stroke. However, little information is available regarding the prognostic factors for identifying best responder patients. The purpose of the present study is therefore to investigate the clinical features of patients with subacute stroke that might benefit more from robotic walking therapy. METHODS: One hundred subacute inpatients randomized in robotic or conventional gait training were assessed at baseline and after 4 weeks of training performed 5 times per week. Forward Binary Logistic Regression was performed using functional ambulation category (FAC) as dependent variable and as independent variables: trunk function (trunk control test), global ability (Barthel Index), age, sex, time from stroke and beginning of rehabilitation, side and type of stroke, and in the first analysis also type of treatment. RESULTS: The parameters that have a significant effect on the FAC-score at discharge were a higher BI-score at admission, a higher TCT-score at admission, a short time from the ictus and a robotic therapy. The variance explained by these four factors was 78%. When the two groups were separately analysed for type of treatment, a higher BI-score and a short time from stroke resulted in good prognosis for conventional therapy, whereas only a high TCT-score improved efficacy of robotic training. CONCLUSION: Efficacy of robotic walking training was not associated with global ability at admission. Hence, more severely disabled patients may obtain greater benefit from robotic training, independently by other factors, except the need of a residual trunk control that was identified as a good prognostic factor for robotic walking training. PMID- 29526863 TI - Predicting body weight by measuring weight underneath the buttock in supine position: A quantitative observation study. AB - BACKGROUND: Measuring body weight (BW) for bedridden patients often presents difficulty and challenge. OBJECTIVES: The present study aimed at providing a self designed indirect method to predict BW by measuring weight underneath the buttock (WUB) of an individual in supine position, thereby providing an easy, safe and effective way of BW measurement for bedridden patients. METHODS: A total of 180 subjects participated in the present study and agreed to have their BW and WUB to be measured. BW was measured normally at the standing position through an electronic weighing machine without any special requirement. By placing the electronic weighing machine under the subject's buttock along with an additional hard board set under the electronic weighing machine, WUB was measured in subjects who were asked to assume a supine position in beds to simulate conditions of bedridden individuals. Measurement was repeated thrice to minimise the test error. RESULTS: Average BW (62.7 +/- 11.7 kg) was 2.0 +/- 0.1 (~ 2) folds of WUB (31.4 +/- 6.0 kg). Significant linear correlation was identified between BW and WUB in all subjects with a linear equation yielded (y= 1.8 x + 6.0). Further multiple regression analysis resulted in an equation of BW (kg) = 36.8 + 1.66*WUB (kg) + 29.0*height (m). Predicted BW (PBW) was calculated out based on the results described above: the multiple relationship (2 folds), the linear equation, and the multiple regression equation, and differed from the measured BW by 3.6 +/- 2.8, 3.5 +/- 2.7 and 4.2 +/- 3.1 kg respectively. CONCLUSIONS: Predicting BW through WUB in supine position is effective and reliable because the latter can be easily measured and features a strong linear relationship with BW. This method provides clinical staff with remarkable benefits in BW determination for bedridden patients. PMID- 29526862 TI - Robotic gaming prototype for upper limb exercise: Effects of age and embodiment on user preferences and movement. AB - BACKGROUND: Effective human-robot interactions in rehabilitation necessitates an understanding of how these should be tailored to the needs of the human. We report on a robotic system developed as a partner on a 3-D everyday task, using a gamified approach. OBJECTIVES: To: (1) design and test a prototype system, to be ultimately used for upper-limb rehabilitation; (2) evaluate how age affects the response to such a robotic system; and (3) identify whether the robot's physical embodiment is an important aspect in motivating users to complete a set of repetitive tasks. METHODS: 62 healthy participants, young (<30 yo) and old (>60 yo), played a 3D tic-tac-toe game against an embodied (a robotic arm) and a non embodied (a computer-controlled lighting system) partner. To win, participants had to place three cups in sequence on a physical 3D grid. Cup picking-and placing was chosen as a functional task that is often practiced in post-stroke rehabilitation. Movement of the participants was recorded using a Kinect camera. RESULTS: The timing of the participants' movement was primed by the response time of the system: participants moved slower when playing with the slower embodied system (p = 0.006). The majority of participants preferred the robot over the computer-controlled system. Slower response time of the robot compared to the computer-controlled one only affected the young group's motivation to continue playing. CONCLUSION: We demonstrated the feasibility of the system to encourage the performance of repetitive 3D functional movements, and track these movements. Young and old participants preferred to interact with the robot, compared with the non-embodied system. We contribute to the growing knowledge concerning personalized human-robot interactions by (1) demonstrating the priming of the human movement by the robotic movement - an important design feature, and (2) identifying response-speed as a design variable, the importance of which depends on the age of the user. PMID- 29526864 TI - An Internet of Things based physiological signal monitoring and receiving system for virtual enhanced health care network. AB - BACKGROUND: Wireless physiological signal monitoring system designing with secured data communication in the health care system is an important and dynamic process. OBJECTIVE: We propose a signal monitoring system using NI myRIO connected with the wireless body sensor network through multi-channel signal acquisition method. Based on the server side validation of the signal, the data connected to the local server is updated in the cloud. The Internet of Things (IoT) architecture is used to get the mobility and fast access of patient data to healthcare service providers. METHODS: This research work proposes a novel architecture for wireless physiological signal monitoring system using ubiquitous healthcare services by virtual Internet of Things. RESULTS: We showed an improvement in method of access and real time dynamic monitoring of physiological signal of this remote monitoring system using virtual Internet of thing approach. This remote monitoring and access system is evaluated in conventional value. This proposed system is envisioned to modern smart health care system by high utility and user friendly in clinical applications. CONCLUSION: We claim that the proposed scheme significantly improves the accuracy of the remote monitoring system compared to the other wireless communication methods in clinical system. PMID- 29526865 TI - Oxymatrine attenuates lipopolysaccharide-induced acute lung injury by activating the epithelial sodium channel and suppressing the JNK signaling pathway. AB - The epithelial sodium channel (ENaC) and mitogen-activated protein kinase (MAPK) pathway have been reported to be associated with the progression of acute lung injury (ALI). Oxymatrine (OMT) alone or combined with other drugs can ameliorate paraquat- or oleic acid-induced lung injury. However, the effect of OMT on lipopolysaccharide (LPS)-induced ALI remains unknown. The aim of the present study was to evaluate whether OMT can attenuate LPS-induced ALI through regulation of the ENaC and MAPK pathway using an ALI mouse model. Histological assessment of the lung and inflammatory cell counts in bronchoalveolar lavage fluid (BALF) were performed by H&E and Wright-Giemsa staining. The lung wet/dry (W/D) weight ratio and the levels of tumor necrosis factor-alpha (TNF-alpha), C reactive protein (CRP), ENaC subunits, and the MAPK pathway members were determined. Isolated type II rat alveolar epithelial cells were incubated with OMT 30 min before LPS stimulation to investigate the activation of ENaC and the MAPK pathway. The results showed that OMT remarkably alleviated histopathologic changes in lung and pulmonary edema, reduced inflammatory cell counts in BALF, and decreased TNF-alpha and CRP levels in a dose-dependent manner. OMT significantly increased the three subunits of ENaC proteins in vivo and in vitro, while it decreased p-ERK/ERK, p-p38/p38, and p-JNK/JNK ratios in vivo. However, only the JNK pathway was markedly inhibited in vitro following pretreatment with OMT. Collectively, the results suggested that OMT might alleviate LPS-induced ALI by elevating ENaC proteins and inhibiting the JNK signaling pathway. PMID- 29526866 TI - Relationship between morphological development and sex hormone receptor expression of mammary glands with age in male rats. AB - The aim of this study is to investigate the changes with age on morphology and sex hormone receptor expression in the mammary glands of male Sprague-Dawley rats, focusing on male-specific cells, "oxyphilic cells", observed after sexual maturity. The mammary glands of male rats at 14, 21, 35, 50, 75 and 100 days old were examined by gross observation, microscopic observation using whole mount specimens, histological and immunohistochemical sections. Grossly, mammary glands showed brown color at 50-100 days old. In whole mount specimens, terminal end buds (TEBs) were observed at 14-50 days old and the number of TEBs was highest at 35 days old. Histologically, the male mammary glands contained small epithelial cells with scanty cytoplasm at 14-35 days old while ductal and lobular epithelial cells were changed into oxyphilic cells with abundant cytoplasm at 50-100 days old. Immunohistochemicaly, androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PgR) expressions were found in both mammary glands found at a young age and oxyphilic cells. In oxyphilic cells, AR expression was dominant compared to ER and PgR expressions and increased with age. From these results, the development at 50-100 days old might be strongly related to AR. Ultrastructural observation of oxyphilic cells confirmed a number of lipid droplets, deformed and/or enlarged mitochondria, lysosomes and peroxisomes in their cytoplasm. PMID- 29526867 TI - Cervical ganglioneuroblastoma in a new born Japanese Black calf. AB - This case report describes a congenital ganglioneuroblastoma in a 38-day-old male Japanese Black calf. The cervical multinodular mass was present at birth and grew rapidly. The cut surface was pale gray-to-yellow and had a gelatinous appearance. Hemorrhagic cysts of various sizes were observed in the nodule. Histologically, the mass contained clusters of neuroblastic cells, ganglionic cells, and Schwann like cells. Immunohistochemically, the ganglionic cells showed strong positivity for neuron-specific enolase, neurofilament, synaptophysin, and chromogranin A, whereas the Schwann-like cells strongly expressed S-100, glial fibrillary acidic protein, and vimentin. Ultrastructurally, neurosecretory granules resembling catecholamine were observed in the neuroblastic and Schwann-like cells. Based on the pathology, the diagnosis was congenital cervical nodular ganglioneuroblastoma. PMID- 29526868 TI - The mechanisms underlying the effects of AMH on Mullerian duct regression in male mice. AB - Anti-Mullerian hormone (AMH) produced in the developing testis induces the regression of the Mullerian duct, which develops into the oviducts, uterus and upper vagina. In our true hermaphrodite mouse with an ovary on one side and a testis on the other (O/T), the oviduct and uterus are present only on the ovary side, and nothing derived from the Mullerian duct is present on the testis side. Here, we investigate the mechanism underlying the unilateral Mullerian duct regression and the mode of AMH signaling, by performing immunohistology, Western blotting, and organ culture analyses. The histological analysis revealed that during the start of the Mullerian duct regression, the duct in the O/T mice was clearly regressed on the AMH-positive testis side compared to the AMH-negative ovary side. The immunohistochemistry showed a diffuse immunoreaction of AMH in the interstitium surrounding the testis cord and boundary region between the testis and mesonephros, especially in the cranial portion. Western blotting revealed that the amount of AMH in the cranial half of the mesonephros was larger than that in the caudal half. AMH injected into the gonads in organ culture induced the regression of the Mullerian duct via the interstitium of the organ. These results suggest that AMH acts on the Mullerian duct in male mice by exuding into the interstitium surrounding the testis cord and infiltrating through the cranial region from the testis to the mesonephros. PMID- 29526869 TI - Improvement of the Sterol and Triacylglycerol Compositions of Chemlali Virgin Olive Oils through Controlled Crossing with Mediterranean Cultivars. AB - The chemical composition of extra virgin olive oils (EVOOs) from six new progenies, obtained through controlled crossings between the main Tunisian variety Chemlali and autochthonous (Chemcheli) and foreign cultivars (Sigoise, Coratina, Koroneiki, and Arbequina) used as pollen acceptor or pollinator, were compared with the EVOO of Chemlali cultivar known to be the main one cultivated in Tunisia as it is the most adapted to the arid climate. Several analytical determinations of major and minor components of EVOO were employed, especially triacylglycerol and sterol fractions. All the studied hybrid EVOOs showed an improvement in their chemical composition and stability by comparison with Chemlali EVOO. The main triacylglycerols were 1,2,3-trioleylglycerol (OOO), 2,3 dioleyl-1-palmitoylglycerol (POO), 2,3-dioleyl-1-linoleylglycerol (LOO) and 2,3 dioleyl-1-stearoylglycerol (SOO). beta-sitosterol, Delta5-avenasterol and campesterol were the principal sterols in all samples. Cholesterol, stigmasterol, clerosterol and Delta7-stigmastenol were also found in all samples. Oil samples examined showed inter-variability between the studied cultivars. Results of discriminant and principal component analyses appear to prove that genetic origin of the raw materials has a great influence on the final composition of the oil; especially triacylglycerol and sterol compositions. PMID- 29526870 TI - Pomegranate Seed Oil Enhances the Percutaneous Absorption of trans-Resveratrol. AB - Pomegranate seed oil (PSO) is primarily composed of unsaturated fatty acids, implying its potential application as a transdermal enhancer. In this study, the function of PSO in prompting the percutaneous absorption of resveratrol was examined and compared with isopropyl palmitate (IP). IP of 10% enhanced the cumulative permeation amount of resveratrol by 50% but did not influence the permeation velocity. Though 2.5% and 5.0% IP accelerated the penetration process of resveratrol, they had no discernable impact on total permeation amount. In contrast, the cumulative percutaneous amount of the drug with 2.5%, 5.0% and 10% PSO was 1.25, 2.25, and 3.14-fold that of resveratrol alone, respectively. Moreover, PSO of different concentrations speeded up resveratrol to permeate through skin in the whole process, exhibiting its superior capacity over IP in enhancing the transdermal absorption of resveratrol. IP of 2.5% substantially augmented resveratrol retention in stratum corneum (SC), epidermis, and dermis (p < 0.05) while 2.5% PSO only increased the drug detaining in SC. Involvement of oils also aided in resveratrol diffusion within skin. The study demonstrates that both IP and PSO prompted the percutaneous transport of resveratrol. PSO presents more promising opportunities in serving as a percutaneous enhancer for transdermal preparations. PMID- 29526871 TI - Chimyl Alcohol Suppresses PGE2 Synthesis by Human Epidermal Keratinocytes through the Activation of PPAR-gamma. AB - Alkyl glyceryl ethers (AKGs) are widely used as emulsion stabilizers, and their anti-inflammatory effects are well known. Daily exposure to environmental stresses, such as chemicals, low humidity and ultraviolet light (UV), can initiate and promote the development of various skin problems. Among those stresses, it has been established that UV induces skin pigmentation and accelerates premature skin aging due to the inflammation that results. Here, we investigated whether chimyl alcohol (CA), which is an AKG, suppresses the inflammatory process. The suppression of cell damage and the reduction of intracellular levels of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEKs) after UVB exposure was evaluated using the Neutral red (NR) and the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assays, respectively. Moreover, the expression levels of mRNAs and proteins related to inflammation were evaluated by Real-time RT-PCR and ELISA assays, respectively. CA suppressed prostaglandin E2 (PGE2) production in UVB-exposed NHEKs according to the down regulated expression level of cyclooxygenase-2 (COX-2) mRNA. Furthermore, CA up regulated the mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-gamma, nuclear factor E2-related factor 2 (Nrf2) and gamma glutamyl cysteine synthase (gamma-GCS) in NHEKs. Finally, we examined the effects of CA on siPPAR-gamma transfected NHEKs. siPPAR-gamma transfection of NHEKs abolished the mRNA expression levels of Nrf2 and UVB-stimulated PGE2 secretion that were regulated by CA. Hence, CA suppresses the UVB-induced COX-2 mRNA expression and PGE2 production through PPAR-gamma as an agonist. We conclude that CA provides useful protection and/or alleviation against UV damage. PMID- 29526872 TI - Activities of Endogenous Lipase and Lipolysis Oxidation of Low-Salt Lactic Acid Fermented Fish (Decapterus maruadsi). AB - There is increasing demand for low-salt meat products that retain traditional flavors. In this study, dry-salted fish (Decapterus maruadsi) were processed by 2 methods to obtain traditional salted fish (HS) and low-salt lactic acid-fermented fish (LAF). The relationship between lipolysis and lipid oxidation was investigated by evaluating changes in endogenous lipase (lipolytic enzymes; lipoxygenase, LOX), free fatty acid composition, thiobarbituric acid reactive substances (TBARS), and peroxide value (POV) during processing. Lipolytic enzyme activity showed a decreasing trend, in general. LOX activity initially increased and eventually decreased. Phospholipase, acid lipase, and neutral lipase activity was 0.33, 0.17, 0.57 (in HS) and 0.39, 0.25, 0.67 (in LAF) times in the final product than the activity levels observed in fresh fish. A principal component analysis indicated that phospholipase and neutral lipase play major roles in promoting lipid hydrolysis (in HS and LAF), the correlation between lipolytic activity and lipid oxidation in HS is greater than the correlation in LAF, and the contribution of LOX to lipid oxidation was minor in salted fish. PMID- 29526873 TI - Effects of beta-Sitosteryl Sulfate on the Phase Behavior and Hydration Properties of Distearoylphosphatidylcholine: a Comparison with Dipalmitoylphosphatidylcholine. AB - We have studied the phase behavior of distearoylphosphatidylcholine (DSPC) in the presence of sodium beta-sitosteryl sulfate (PSO4). PSO4 was found to induce sterol-rich and sterol-poor domains in the DSPC membrane. These two domains constitute a fluid, liquid ordered (Lo) phase and a gel (Lbeta) phase. PSO4 was less miscible in DSPC than in a dipalmitoylphosphatidylcholine (DPPC) membrane, as evidenced by its tendency to separate from the bilayer at a concentration of 50 mol%. This lack of miscibility was attributed to the greater van der Waals forces between the PC hydrocarbon chains. In addition to affecting the phase behavior, PSO4 also enhanced the hydration of the membrane. Despite its weaker interaction with DSPC compared to DPPC, its tendency to fluidize this phospholipid and enhance its hydration can be useful in formulating cosmetics and pharmaceutical products. PMID- 29526874 TI - Efficient Production of Acid-Form Sophorolipids from Waste Glycerol and Fatty Acid Methyl Esters by Candida floricola. AB - We discovered that Candida floricola ZM1502 is capable of selectively producing the promising hydrophilic biosurfactants, acid-form sophorolipids (SLs), from glycerol. However, productivity was very low (approximately 3.5 g L-1) under the initial culture conditions. Here, we describe the design of culture medium for abundant production of acid-form SLs by C. floricola ZM1502 using waste glycerol and hydrophobic substrates in order to develop a method for SL production and disposal of waste glycerol produced by oleo-chemical industries. Urea provided the best nitrogen source for acid-form SL production from glycerol among four nitrogen sources tested [urea, NaNO3, NH4NO3, and (NH4)2SO4]. Among carbon sources we compared, hydrophobic substrates (soybean oil and oleic acid) led to productivities of approximately 20 g L-1, indicating that hydrophobic substrates provided fatty acid moieties for SL production. Addition of olive oil and oleic acid to waste glycerol enhanced acid-form SL production to 42.1 +/- 0.9 and 37.5 +/- 3.4 g L-1, respectively. To develop a potential industrial process, we explored other suitable hydrophobic substrates for SL production, which were obtained on site from oleo-chemical industries. Alkyl C18 esters (Pastell M-182), along with waste glycerol, increased acid-form SL production to 48.0 +/- 3.4 g L 1 over a 7-d period. Furthermore, we demonstrated abundant production of acidic SLs at the mini-jar fermenter scale, obtaining 169 g L-1 over 180 h using a fed batch cultivation technique. Efficient acid-form SL production by C. floricola could have a great impact on the development of bio-industrial processes using waste glycerol as a substrate. PMID- 29526875 TI - Quality Characterization and Oxidative Stability of Camellia Seed Oils Produced with Different Roasting Temperatures. AB - In this study, the effects of roasting camellia (Camellia oleifera Abel.) seed oils at different temperatures (65 degrees C, 100 degrees C, 120 degrees C, and 140 degrees C) on the oxidative stability and composition of the oils were investigated. The results showed that, in terms of the quality of the oils, the roasting temperature influenced the total phenolic content (which ranged from 1.64~2.45 GAE mg/g for the different oils) and total flavonoid content (which ranged from 0.36~0.45 QE mg/g for the different oils), while the fatty acid profile and tocopherol content were not influenced by the roasting temperature. We also investigated the kinetic parameters of camellia seed oil during oxidation via Rancimat (at temperatures ranging from 110~140 degrees C). It turned out that the natural logarithms of the oxidative stability index (OSI) varied linearly with respect to temperature (R2: 0.958~0.997). This was done on the basis of the Arrhenius equation that indicates that the activation energies (Ea) for oxidative stability are 65.7~78.4 KJ/mol. Simultaneously, we found that increasing the roasting temperature could increase the antioxidant stability of Maillard reaction products in camellia seed oil. The effects of roasting include the assurance that the camellia seed oil so produced will comply with the relevant governmental health codes and standards and have a longer shelf life. PMID- 29526876 TI - Optimisation of Croton gratissimus Oil Extraction by n-Hexane and Ethyl Acetate Using Response Surface Methodology. AB - The extraction of oil from Croton gratissimus seeds was studied using the three factor five-level full-factorial central composite rotatable design (CCRD) of the response surface methodology (RSM). The effect of the three factors selected, viz., extraction time, extraction temperature and solvent-to-feed ratio on the extraction oil yield was investigated when n-hexane and ethyl acetate were used as extraction solvents. The coefficients of determination (R2) of the models developed were 0.98 for n-hexane extraction and 0.97 for ethyl acetate extraction. These results demonstrated that the models developed adequately represented the processes they described. From the optimized model, maximum extraction yield obtained from n-hexane and ethyl acetate extraction were 23.88% and 23.25%, respectively. In both cases the extraction temperature and solvent-to feed ratio were 35 degrees C and 5 mL/g, respectively. In n-hexane extraction the maximum conditions were reached only after 6 min whereas in ethyl acetate extraction it took 20 min to get the maximum extraction oil yield. Oil extraction of Croton gratissimus seeds, in this work, favoured the use of n-hexane as an extraction solvent as it offered higher oil yields at low temperatures and reduced residence times. PMID- 29526877 TI - Preparation of Copper (II) Containing Phosphomolybdic Acid Salt as Catalyst for the Synthesis of Biodiesel by Esterification. AB - Copper (II) containing phosphomolybdic acid (PMA) catalysts were synthesized by ion exchange method and characterization using various physico-chemical techniques such as X-ray diffraction (XRD), fourier transform infrared spectroscopy (FT-IR), thermogravimetric (TG) and scanning electron microscopy (SEM). The characterization results showed that the Keggin ions were retained in the catalysts and possessed well thermal stability. The catalytic esterification of lauric acid with methanol could be easily achieved about 78.7% conversion under optimum condition, the catalyst also contributed to the stability of the catalyst in which it can be reused for a certain time. This study demonstrated an alternative approach to biodiesel production with high efficiency by Cu (II) ion exchanged phosphomolybdic acid catalyst in the esterification catalytic. PMID- 29526878 TI - New Insights on Degumming and Bleaching Process Parameters on The Formation of 3 Monochloropropane-1,2-Diol Esters and Glycidyl Esters in Refined, Bleached, Deodorized Palm Oil. AB - This paper examines the interactions of degumming and bleaching processes as well as their influences on the formation of 3-monochloropropane-1,2-diol esters (3 MCPDE) and glycidyl esters in refined, bleached and deodorized palm oil by using D-optimal design. Water degumming effectively reduced the 3-MCPDE content up to 50%. Acid activated bleaching earth had a greater effect on 3-MCPDE reduction compared to natural bleaching earth and acid activated bleaching earth with neutral pH, indicating that performance and adsorption capacities of bleaching earth are the predominant factors in the removal of esters, rather than its acidity profile. The combination of high dosage phosphoric acid during degumming with the use of acid activated bleaching earth eliminated almost all glycidyl esters during refining. Besides, the effects of crude palm oil quality was assessed and it was found that the quality of crude palm oil determines the level of formation of 3-MCPDE and glycidyl esters in palm oil during the high temperature deodorization step of physical refining process. Poor quality crude palm oil has strong impact towards 3-MCPDE and glycidyl esters formation due to the intrinsic components present within. The findings are useful to palm oil refining industry in choosing raw materials as an input during the refining process. PMID- 29526879 TI - Optimization of Microencapsulation of Human Milk Fat Substitute by Response Surface Methodology. AB - Human milk fat substitutes (HMFS) are rich in polyunsaturated fatty acids which upon microencapsulation, can be used as a source of high quality lipids in infant formula. The response surface methodology (RSM) was employed to optimize the microencapsulation condition of HMFS as a functional product. The microencapsulation efficiency (MEE) of microencapsulated HMFS was investigated with respect to four variables including concentration of soy lecithin (A), ratio of demineralized whey powder to malt dextrin (B), HFMS concentration (C), and homogenizing pressure (D). The optimum conditions for efficient microencapsulation of HMFS by the spray drying technique were determined as follows: the amount of soybean lecithin-0.96%, ratio of desalted whey powder to malt dextrin-2.04:1, oil content-17.37% and homogeneous pressure-0.46MPa. Under these conditions, the MEE was 84.72%, and the basic indices of the microcapsules were good. The structure of the microcapsules, as observed by scanning electron microscopy (SEM), revealed spherical, smooth-surfaced capsules with diameters ranging between 10-50 MUm. Compared with HFMS, the peroxide value (POV) and acid value (AV) of the microcapsule were significantly lower during storage indicating that the microencapsulation process increases stability and shelf life. Infrared spectroscopic analyses indicated that HFMS had the same characteristic functional groups as the oil extracted from microcapsules. Simulated in vitro digestion revealed that the microcapsules were digested completely within 2h with maximum lipid absorption rate of 64%. Furthermore, these results advocate the embedding process of HFMS by RSM due to its efficacy. PMID- 29526880 TI - Emu Oil Reduces LPS-Induced Production of Nitric Oxide and TNF-alpha but not Phagocytosis in RAW 264 Macrophages. AB - Emu is the second-largest extant bird native to Australia. Emu oil, obtained from the emu's fat deposits, is used as an ingredient in cosmetic skincare products. Emu oil has been reported to improve several inflammatory symptoms; however, the mechanisms of these anti-inflammatory effects are largely unknown. This study investigated the effects of emu oil on the inflammatory macrophage response in vitro. A murine macrophage cell line, RAW 264, was incubated in culture media supplemented with or without emu oil and stimulated with lipopolysaccharide (LPS). We determined phagocytic activity by measuring the number of fluorescent microspheres taken up by the cells. The phagocytic activity of RAW 264 cells in the presence of LPS was unaffected by emu oil. We also determined production of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha in the culture medium using the Griess reaction and an enzyme-linked immunosorbent assay, respectively, and the protein expression of inducible NO synthase (iNOS) using western blotting. The results indicated that emu oil reduced the LPS-induced production of NO, TNF-alpha, and iNOS expression in a dose-dependent manner. The results suggested that emu oil does not reduce the phagocytic clearance rate of inflammatory matter; however, it does reduce the production of NO and TNF-alpha in macrophages. These latter products enhance the inflammatory response and emu oil thereby demonstrated anti-inflammatory properties. PMID- 29526882 TI - Thin-slice Free-breathing Pseudo-golden-angle Radial Stack-of-stars with Gating and Tracking T1-weighted Acquisition: An Efficient Gadoxetic Acid-enhanced Hepatobiliary-phase Imaging Alternative for Patients with Unstable Breath Holding. AB - PURPOSE: To compare four free-breathing scan techniques for gadoxetic acid enhanced hepatobiliary phase imaging with conventional breath-hold scans. MATERIALS AND METHODS: Gadoxetic acid-enhanced hepatobiliary phase imaging with six image acquisition sets performed in 50 patients. Image acquisition sets included fat-suppressed 3D T1-weighted turbo field echo with free-breathing pseudo-golden-angle radial stack-of-stars (FBRS) acquisition, FBRS with track (FBRST), FBRS with gate and track (FBRSG&T), thin-slice FBRS with gate and track (thin-slice FBRSG&T), free-breathing Cartesian acquisition (CartesianFB), and breath-hold Cartesian acquisition (CartesianBH). Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and image quality compared to the six-image acquisition sets. RESULTS: Signal-to-noise ratio and CNR were significantly higher in FBRS, FBRST, FBRSG&T, and thin-slice FBRSG&T than in CartesianFB and CartesianBH (P < 0.001). Based on sharpness, motion artifacts, visibility of intrahepatic vessels, and overall image quality, thin-slice FBRSG&T had the highest image quality followed by CartesianBH and FBRSG&T (P < 0.001). Severe motion artifacts were observed in 25 patients in CartesianFB and three patients in CartesianBH, whereas image quality remained above the acceptable range in FBRSG&T, FBRST, FBRS, and thin-slice FBRSG&T in all cases. CONCLUSION: Thin-slice FBRSG&T demonstrated excellent image quality compared with conventional CartesianBH in gadoxetic acid-enhanced hepatobiliary phase imaging. It can be apply to supplemental sequences of patients with unstable breath holding. PMID- 29526881 TI - Efficacy and Safety of REVIVE SE Thrombectomy Device for Acute Ischemic Stroke: River JAPAN (Reperfuse Ischemic Vessels with Endovascular Recanalization Device in Japan). AB - REVIVE SE (REVIVE) is a closed-ended, self-expanding stent retriever used in the RIVER JAPAN study. We present our early experience with REVIVE for revascularization of acute ischemic stroke (AIS) in patients who have failed or are ineligible for intravenous recombinant tissue plasminogen activator treatment. This prospective, single-arm, non-randomized, multicenter registry study followed up patients undergoing mechanical thrombectomy with REVIVE for 90 days. The primary endpoint was a post-procedure Thrombolysis in Cerebral Infarction (TICI) score >=2a. Secondary endpoints were clot migration/embolization; recanalization without symptomatic intracranial hemorrhage (ICH) at 24 h; symptomatic ICH; good neurological outcome (modified Rankin Scale score <=2 National Institute of Health Stroke Scale (NIHSS) score decrease >=10) at day 90; device- or procedure-related serious adverse events (SAEs) and mortality at day 90. To confirm non-inferiority of REVIVE, results were compared with historical data of the Merci Retriever. About 49 patients were enrolled (median age 73 years; males 46.9%; middle cerebral artery (MCA) occlusion 83.7%; median NIHSS score 17). A post-procedure TICI score >=2a was observed in 73.5% (36/49, 95% confidence interval [CI] 58.9-85.1) of patients. No post-procedural clot migration/embolization events occurred. Successful recanalization without symptomatic ICH was observed in 62.5% (30/48, 95% CI 47.4 76.0). The good neurological outcome was achieved in 66.7% (32/48) patients. Symptomatic ICH and device- or procedure-related SAEs were reported in 6.3% and 12.2% of patients, respectively. Two deaths were reported. REVIVE demonstrated equivalent efficacy and safety as the Merci Retriever. Results suggest that REVIVE is effective and safe in recanalizing occluded intracranial arteries in AIS. PMID- 29526883 TI - Ethyl Pyruvate Improves Pulmonary Function in Mice with Bleomycin-induced Lung Injury as Monitored with Hyperpolarized 129Xe MR Imaging. AB - PURPOSE: High Mobility Group Box1 (HMGB1), which is one of the damage-associated molecular pattern molecules relating to various inflammatory diseases, has gained interest as a therapeutic target because of its involvement in wound healing processes. In the present study, we investigated HMGB1 as a potential therapeutic target in a model of lung fibrosis using a preclinical hyperpolarized 129Xe (HPXe) MRI system. METHODS: Lung injury was induced by intra-peritoneal injection of bleomycin (BLM) in 19 mice. Three weeks post-injection (when fibrosis was confirmed histologically), administration of ethyl pyruvate (EP) and alogliptin (ALG), which are down- and up-regulators of HMGB1, respectively, was commenced in six and seven of the 19 mice, respectively, and continued for a further 3 weeks. A separate sham-instilled group was formed of five mice, which were administered with saline for 6 weeks. Over the second 3-week period, the effects of disease progression and pharmacological therapy in the four groups of mice were monitored by HPXe MRI metrics of fractional ventilation and gas-exchange function. RESULTS: Gas-exchange function in BLM mice was significantly reduced after 3 weeks of BLM challenge compared to sham-instilled mice (P < 0.05). Ethyl pyruvate was found to improve HPXe MRI metrics of both ventilation and gas exchange, and repair tissue damage (assessed histologically), to a similar level as sham-instilled mice (P < 0.05), whilst ALG treatment caused no significant improvement of pulmonary function. CONCLUSION: This study demonstrates the down-regulator of HMGB1, EP, as a potential therapeutic agent for pulmonary fibrosis, as assessed by a non invasive HPXe MRI protocol. PMID- 29526884 TI - Efficacy and Safety of Oxycodone Injection for Relieving Cancer Pain: A Study in Japan Consisting of Two Open Trials for Intravenous and Subcutaneous Administration. AB - Pure oxycodone injection became increasingly necessary after oral oxycodone was launched in Japan in 2003. However, trials clarifying the efficacy and safety of injection are rare. Therefore, a multicenter open study on injection was designed and carried out in 2010, resulting in the launch of injection therapy in 2012. As published domestic case reports on efficacy already show widespread prescription, this study aimed to provide useful information for cancer pain relief in Japan and other countries. Our oxycodone injection study consisted of two trials, one of intravenous (S#9131) and the other of subcutaneous (S#9132) administration. The minimum required number of enrolled patients suffering cancer pain was determined to be 70 in S#9131 and 20 in S#9132. These studies had the same dose titration protocol as the main endpoint, i.e., pain relief rate (PRR) defined as the rate of achieving adequate pain control (APC), as in prior oral oxycodone trials in Japan. In S#9131, PRR was 81.4% (95% confidence interval: 70.3-89.7%), therefore, the null hypothesis of PRR<70% was rejected using the binominal one sided test (p=0.0217). In S#9132, PRR was 73.7% also surpassing 70%. Safety was also assessed in the same way as in prior trials. The majority of adverse effects were moderate or mild and recovered with no sequelae. As shown above, the injection was considered to be effective and safe in cancer pain treatment. The details of these trials, particularly the dose-titration protocol for achieving APC and route switching information, are expected to enhance injection convenience for prescribers. PMID- 29526885 TI - In Vitro Anti-inflammatory Effects of the Phenylbutyric Acid Metabolite Phenylacetyl Glutamine. AB - Sodium 4-phenylbutyrate (PBA), which exerts a wide range of anti-inflammatory effects, is rapidly cleared from the body (approximately 98%) by urinary excretion by 24 h after oral treatment in humans. PBA was almost entirely excreted to urine as phenylacetyl glutamine (PAGln). However, no data describe the potential anti-inflammatory effects of PAGln. The purpose of this study was to evaluate the anti-inflammatory effects of PAGln on mouse spleen cells and peritoneal cavity cells, and explore the potential mechanism underlying this effect. PAGln was added to mouse spleen cell cultures stimulated by concanavalin A, or mouse peritoneal cavity cell cultures stimulated by lipopolysaccharide. After 72 h of culture, levels of inflammatory cytokines in culture supernatants were measured using a sandwich enzyme-linked immunosorbent assay system, and levels of inflammatory proteins were assessed by Western blotting. PAGln significantly inhibited inflammatory cytokine (interferon-gamma, interleukin-6, and tumor necrosis factor-alpha) production, decrease of cell number in the spleen cell, and suppressed the expression of inflammatory proteins (nuclear factor kappaB, and inducible nitric oxide synthase). These results suggest that PAGln possesses anti-inflammatory activity via inhibition of T cell activation and Toll-like receptor 4 signaling. This study of the anti-inflammatory mechanism of PAGln provides useful information about its potential for therapeutic applications. PMID- 29526886 TI - Wntless Is Highly Expressed in Advanced-Stage Intrahepatic Cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile duct, representing the second most common primary liver cancer. Wntless (Wls) is a highly conserved transmembrane protein that shuttles palmitoylated Wnt proteins from the endoplasmic reticulum to the plasma membrane. Wls is highly expressed in various types of cancers and is essential for cell proliferation, anti-apoptotic activity, and survival. The profile of Wls expression and its clinical significance has not been well clarified in ICC. In the present study, we analyzed Wls expression in a set of ICC tissues (n = 44) by immunohistochemistry and the relationship between Wls expression and clinicopathological parameters. Immunoreactive Wls was detected in normal cholangiocytes, but was undetectable in normal hepatocytes. The intensity for immunoreactive Wls was varied, depending on ICC specimens. The degree of Wls expression was scored as 0 or 1+ in 8 specimens (18.2%), 2+ in 24 (54.5%), and 3+ in 12 (27.3%) out of the 44 ICC specimens, based on the staining intensity and percentage of Wls-positive cells. In normal cholangiocytes, the scores were varied from 0 to 2+. The intensity of Wls expression was positively associated with tumor stage (T stage, P = 0.005, r = 0.413), tumor-node-metastasis stage (TNM stage, P = 0.000, r = 0.548), and lymphatic invasion (P = 0.000, r = 0.548). Our results show that Wls is differentially expressed in ICC tissues and positively related to tumor stage and lymphatic invasion. Wls is a potential marker for advanced tumor stage and metastasis in ICC. PMID- 29526887 TI - The Impact of Respiratory Events on the Autonomic Nervous System during Sleep. AB - Sleep apnea hypopnea syndrome (SAHS) is an independent risk factor for cardiovascular diseases. However, the pathophysiology between them is not yet clear. This paper seeks to understand how respiratory events impact the cardiovascular system by heart rate variability. We compared the differences between successional pathological respiratory events (PR) and pure normal respiration (NR) during sleep. The transitions between normal and pathological respiration (TR) were also analyzed. Thirteen patients who suffered moderate or severe SAHS were enrolled in this study. The results demonstrate that the beat-to beat interval (RR interval) mean value and sample entropy are significantly lower during PR than during NR. RR interval standard deviation, the power of very low frequency (VLF) and low frequency (LF), total power, and the low frequency/high frequency (LF/HF) ratio were significantly larger during PR than during NR. However, the high frequency (HF) power was not significantly different between normal and pathological respiration. Additionally, the trends during TR also supported these significant differences. The results indicate that during pathological respiration, as the heart rate and its volatility increase, the complexity of its rhythm decreases. We conclude that the energy of the autonomic nervous system rapidly increases during pathological respiration, especially at the beginning. The HF power does not significantly change to modulate the heart rhythm, but the activity of the sympathetic nervous system will significantly increase, resulting in the imbalance of the LF/HF ratio. In addition to these findings, this paper discusses the influence of arousal on these indices during TR. PMID- 29526890 TI - Carbon Nanomaterials in Analytical Chemistry. PMID- 29526888 TI - Congenital Absence of Left Atrial Appendage Diagnosed by Multimodality Imaging. AB - A 70-years-old male with a history of hypertension and drug resistant paroxysmal atrial fibrillation (AF) presented to our hospital for catheter ablation to his symptomatic AF. He had no prior surgical or percutaneous procedure to close or exclude the left atrial appendage (LAA). A transesophageal echocardiography (TEE) was performed to rule out intra-cardiac thrombus prior to the ablation procedure. Although the TEE imaging at multiple acquisition angles was obtained, the LAA could not be visualized and an absence of the LAA was suspected. An absence of the LAA was confirmed using cardiac computed tomography (CT), which included 3D reconstruction. Additionally, the LAA was not visualized with left atrium (LA) angiography. During the ablation procedure, 3D voltage mapping in LA was created and no low voltage area or abnormal potential was recorded around the usual root location of the LAA. Successful electrical pulmonary vein isolation was achieved with no major complications. After six months of follow-up, the patient remained in sinus rhythm without any antiarrhythmic drugs and showed no related clinical symptoms. He stopped his anticoagulation therapy due to lack of evidence of AF recurrence and an absence of LAA. Multimodality imaging allowed us to identify the congenital absence of LAA. PMID- 29526891 TI - A Label-free and Highly Sensitive Fluorescence Strategy for Mercury Ion Detection Based on Exonuclease III-aided Recycling Amplification. AB - In this paper, we describe a simple and highly sensitive fluorescence strategy of mercury ions based on exonuclease III (Exo III)-aided target recycling amplification to ensure sensitivity. With an ultra high sensitivity (1 pM), our strategy has been simple and cost-effective, which does not need any artificial modification fluorescence groups, and can be carried out in a pot. It also shows excellent selectivity. Therefore, our new method provides an effective platform for mercury-ion detection. PMID- 29526892 TI - Development of Technologies for Sensing Ozone in Ambient Air. AB - Ozone (O3) gas is widely used as a strong oxidizing agent for many purposes, such as the decomposition/removal of organic contaminants and photoresist, and the deodorization/disinfection of air and water. However, ozone is highly toxic to the human body when the air concentration exceeds about 1 ppm. Therefore, there is increasing demand for simple, sensitive, reliable, and cost-effective techniques for sensing ozone gas. This article describes the features, advantages, and disadvantages of the available, practical techniques for sensing ozone gas in ambient air. The advantages of optical gas sensors as next generation sensors is specifically introduced. The features of photoluminescent, semiconductor nanoparticles (quantum dots, QDs) as bright phosphors with the potential for various applications is further explored. Lastly, recent research results demonstrating the ozone sensitivity of photoluminescent CdSe-based core shell quantum dots are presented. These results strongly suggest that optical ozone sensing using photoluminescent quantum dots is a promising technique. PMID- 29526893 TI - In Vivo Molecular Imaging for Biomedical Analysis and Therapies. AB - In vivo molecular imaging is a powerful tool to analyze the human body. Precision medicine is receiving high attention these days, and molecular imaging plays an important role as companion diagnostics in precision medicine. Nuclear imaging with PET or SPECT and optical imaging technologies are used for in vivo molecular imaging. Nuclear imaging is superior for quantitative imaging, and whole-body analysis is possible even for humans. Optical imaging is superior due to its ease of use, and highly targeted specific imaging is possible with activatable agents. However, with optical imaging using fluorescence, it is difficult to obtain a signal from deep tissue and quantitation is difficult due to the attenuation and scattering of the fluorescent signal. Recently, to overcome these issues, optoacoustic imaging has been used in in vivo imaging. In this article, we review in vivo molecular imaging with nuclear and optical imaging and discuss their utility for precision medicine. PMID- 29526894 TI - Precolumn Derivatization with Bromine to Improve Separation and Detection Sensitivity of Triacylglycerols in Edible Oil by Reversed-Phase High Performance Liquid Chromatography. AB - The complexity of triacylglycerols (TAGs) in edible oils is largely due to the many similar unsaturated TAG compounds, which makes profiling TAGs difficult. In this study, precolumn derivatization with bromine (Br2) was used to improve the separation and detection sensitivity of TAGs in edible oils by RP-HPLC. Oil samples dissolved in n-hexane and TAGs were derived by reaction with a Br2-CCl4 (1:1, v/v) solution for 3 h at room temperature. The derivate product solution was stable and was best separated and detected by RP-HPLC using a C18 column, with a mobile phase of methanol-n-hexane (91.5:8.5, v/v) at 25 degrees C. A detection wavelength of 230 nm was used. The results showed that the approach enabled the separation and detection of more similar TAGs by RP-HPLC. The method was applied to profile 20 types of edible oil, and the results presented the differences in the TAG profiles of various edible oils, which may be useful in the identification of edible oils. PMID- 29526895 TI - Polyelectrolyte-protected Dual-color-quantum-dot Assembled Silica Nanoparticles and Their Application in Simultaneous Fluorescence Determination of e Antigen and Surface Antigen of Hepatitis B. AB - Cationic poly-diallyldimethylammonium (PDADMAC), green CdTe quantum dots (QDs) or red CdS coated CdTe QDs, and anionic polyacrylic acid (PAA) were respectively assembled on the nano-carrier SiO2 to prepare green fluorescence composite nanoparticles (GF-QDs) and red ones (RF-QDs) with the structure SiO2/PDADMAC/QD/PDADMAC/PAA. The sandwich structure "PDADMAC/QD/PDADMAC" on the nano-carrier not only realized the protection to fluorescence of QDs but also avoided the fluorescence shielding of silica shell for the assembled QDs. In 7 days, the diluent solutions of GF-QD and RF-QD all have a very stable fluorescence. On the contrary, the fluorescence of diluent solutions of red and green QDs reduced by 75.99 and 94.35%, respectively. Indeed, they have not fluorescent shielding and have a very slight fluorescent enhancement. Based on GF QD and RF-QD, the simultaneous determination of Hepatitis B e antigen and surface antigen has been established. Their determination in buffer and plasma all showed good precision and accuracy. PMID- 29526896 TI - Magnetic Dual-template Molecularly Imprinted Polymer Nanoparticles for the Simultaneous Determination of Acetaminophen and Codeine in Urine Samples by Ion Mobility Spectrometry. AB - Dual-template magnetic molecularly imprinted polymer nanoparticles were synthesized and used for the solid-phase extraction of acetaminophen and codeine before simultaneous determination by corona discharge ion mobility spectrometry. The magnetic molecularly imprinted polymer nanoparticles were prepared using silica-coated magnetic nanoparticles as supporters, acetaminophen and codeine as template molecules, 3-aminopropyltriethoxysilane and phenyltriethoxysilane as functional monomers, and tetraethoxysilane as a cross-linker. The obtained molecularly imprinted polymer was characterized by transmission electron microscopy, x-ray diffraction and Fourier-transform infrared spectroscopy. The adsorption performance of the imprinted polymers was studied by a series of experiments, indicating a satisfactory recognition ability of products for acetaminophen and codeine. The detection limits of 0.05 and 0.12 MUg mL-1, and the dynamic range of 0.20 - 2.0 and 0.40 - 3.0 MUg mL-1 were achieved for acetaminophen and codeine, respectively. The proposed method was used for simultaneous determinations of acetaminophen and codeine in urine samples, and the corresponding recoveries were calculated in the range of 87 - 94%. These satisfactory results revealed the ability of the method for a routine analysis of acetaminophen and codeine, simultaneously. PMID- 29526897 TI - Estimation of Cr(III) in Water with the Presence of Cr(VI) by Chlorophosphonazo I Color Reaction Spectrophotometry. AB - A method capable of accurately and selectively measuring Cr3+ in water is required and was therefore studied. The precision and reproducibility of chlorophosphonazo I color reaction spectrophotometry (CCRS) for the selective determination of Cr3+ was improved to be acceptable standards. The CCRS established is therefore an accurate, reproducible and inexpensive method. It also has reasonably good sensitivity and selectivity, and a high sample output. This method should be readily adapted for the routine and selective determination of Cr3+ in bottled mineral drinking water with (or without) the supplementation of Cr3+ or in natural water such as mineral or pipe water with the presence of Cr6+. PMID- 29526898 TI - Fabrication of Highly Uniform Gold Nanoparticles-Titanium Dioxide Nanotube Arrays for H2O2 Sensing. AB - This research was to prepare the titanium dioxide nanotube arrays (TiNT arrays) and deposit the Au nanoparticles on its surface using the pulse electrodeposition technique. The Au nanoparticles-TiNT arrays (AuNP-TiNT arrays) were characterized by field emission scanning electron microscopy (FESEM), X-ray diffraction, and cyclic voltammetry. The results showed that the Au nanoparticles were uniformly dispersed on the TiNT array surface. The size and loading of Au nanoparticles can be controlled by deposition time, deposition potential, and concentration of HAuCl4. The AuNP-TiNT arrays were then used as a working electrode for hydrogen peroxide (H2O2) detection. Compared with the pure TiNT array electrode, the AuNP TiNT array electrode had higher sensitivity for the detection of H2O2 and thus provided a simple, promising, and cost-effective sensing platform for the development of enzyme-based biosensors. PMID- 29526899 TI - A Sol-gel Integrated Dual-readout Microarray Platform for Quantification and Identification of Prostate-specific Antigen. AB - Here, we report a sol-gel integrated affinity microarray for on-chip matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) that enables capture and identification of prostate?specific antigen (PSA) in samples. An anti-PSA antibody (H117) was mixed with a sol?gel, and the mixture was spotted onto a porous silicon (pSi) surface without additional surface modifications. The antibody easily penetrates the sol-gel macropore fluidic network structure, making possible high affinities. To assess the capture affinity of the platform, we performed a direct assay using fluorescein isothiocyanate-labeled PSA. Pure PSA was subjected to on-chip MALDI-TOF-MS analysis, yielding three clear mass peptide peaks (m/z = 1272, 1407, and 1872). The sol-gel microarray platform enables dual readout of PSA both fluorometric and MALDI-TOF MS analysis in biological samples. Here we report a useful method for a means for discovery of biomarkers in complex body fluids. PMID- 29526900 TI - Development of a Simple Permeability Assay Method for Snake Venom-induced Vascular Damage. AB - We have developed a novel bioassay method for the detection of snake venom based on the permeability of endothelial cell monolayers cultured in Transwell cell culture inserts. This assay relies on the proteolytic degradation of capillary basement membrane proteins, a pathophysiological event that occurs due to snakebites in vivo. Transwell permeability assays with fluorescence measurements are advantageous with regard to ethical considerations for the use of animals. The assay time was reduced from 24 h for animal tests to 2 h, and many samples could be assayed easily. PMID- 29526901 TI - A Fluorescent Probe for Sensitive Detection of Hydrazine and Its Application in Red Wine and Water. AB - A fluorescent probe, 7-(diethylamino)-2-oxo-2H-chromene-4-carbaldehyde (probe 1), was designed and synthesized for the sensitive detection of hydrazine. The addition of N2H4 caused the fluorescence intensity of probe 1 to decrease. The probe's fluorescence was turn-off after adding N2H4, which could be observed under UV light at 365 nm. Moreover, once treated with different concentrations N2H4 solutions, the solution color change could be distinguished, which indicates that probe 1 could be used as a visual sensor for hydrazine. Moreover, probe 1 can be used as a signal tool to determine hydrazine levels in solutions, such as red wine and water. PMID- 29526902 TI - Sensitive Determination of Quinones by High-Performance Liquid Chromatography Electrospray Ionization-Tandem Mass Spectrometry with Methanol Derivatization. AB - Quinones are a class of compounds having substantial toxicity and pharmacological function. This work has produced a derivatization method for quinone detection with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS). Through introducing tags (methoxy) to the quinone structures, the ionization efficiencies of five quinones (p-benzoquinone (BQ), methyl-p-benzoquinone (MBQ), 1,4-naphthoquinone (1,4-NQ), 1,2-naphthoquinone (1,2 NQ), and 1,4-anthraquinones (AQ)) were greatly improved during ESI. The limit of detections (LODs) for quinone determination could be flexibly adjusted by changing the reaction time or the solvent composition. While lower LODs (<0.02 - 2.06 pg for five quinones) were achieved with methanol as the derivatization reagent, the reaction time was substantially shortened (from 27 to 3 h or 11 h) with methanol/water (v/v, 1:1) as the derivatization reagent. Finally, the proposed method was successfully used for quinone determination in airborne particulates. PMID- 29526903 TI - Metal-to-Ligand Charge-Transfer-based Visual Detection of Alkaline Phosphatase Activity. AB - The ability to directly detect alkaline phosphatase (ALP) activity in undiluted serum samples is of great importance for clinical diagnosis. In this work, we report the use of the distinctive metal-to-ligand charge-transfer (MLCT) absorption properties of the Cu(BCA)2+ (BCA = bicinchoninic acid) reporter for the visual detection of ALP activity. In the presence of ALP, the substrate ascorbic acid 2-phosphate (AAP) can be enzymatically hydrolyzed to release ascorbic acid (AA), which in turn reduces Cu2+ to Cu+. Subsequently, the complexation of Cu+ with the BCA ligand generates the chromogenic Cu(BCA)2+ reporter, accompanied by a color change of colorless-to-purple of the solution with a sharp absorption band at 562 nm. The underlying MLCT-based mechanism has been demonstrated on the basis of density functional theory (DFT) calculations. Needless of any sequential multistep operations and elaborately designed colorimetric probe, the proposed MLCT-based method allows for a fast and sensitive visual detection of ALP activity within a broad linear range of 20 - 200 mU mL-1 (R2 = 0.999), with a detection limit of 1.25 mU mL-1. The results also indicate that it is highly selective and has great potential for the screening of ALP inhibitors in drug discovery. More importantly, it shows a good analytical performance for the direct detection of the endogenous ALP levels of undiluted human serum samples. Owing to the prominent simplicity and practicability, it is reasonable to conclude that the proposed MLCT-based method has a high application prospect in clinical diagnosis. PMID- 29526904 TI - Determination of Caffeine and Its Metabolites in Wastewater Treatment Plants Using Solid-Phase Extraction and Liquid Chromatography-Tandem Mass Spectrometry. AB - For caffeine and its seven major metabolites (i.e., theobromine, theophylline, paraxanthine, 1-methylxanthine, 3-methylxanthine, 7-methylxanthine, and xanthine), an optimized analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for their detection in wastewater samples was developed in this study. Extraction of these compounds (recoveries ranged from 60.3 to 83.2%) was made possible by combining universal polymeric reversed-phase cartridge and polymeric strong cation exchange cartridge. This method was applied to the determination of caffeine and its metabolites in the influent and effluent of an anaerobic-anoxic-oxic (A2O) process. In the A2O influent, caffeine and its metabolites (except xanthine) ranged from 1.39 to 5.45 MUg/L, and their concentrations in the A2O effluent ranged from 10.2 to 171.3 ng/L. The mass load of caffeine was 14.9 g/day/1000 inhabitants, considering the population served by the target wastewater treatment plant (WWTP). The concentration of caffeine derivatives in wastewater influent is a tool for estimating the population size in the area served by WWTPs. PMID- 29526905 TI - Non-enzymatic Determination of L-Proline Amino Acid in Unprocessed Human Plasma Sample Using Hybrid of Graphene Quantum Dots Decorated with Gold Nanoparticles and Poly Cysteine: A Novel Signal Amplification Strategy. AB - An innovative electrochemical interface for quantitation of L-proline (L-Pro) based on ternary amplification strategy was fabricated. In this work, gold nanoparticles prepared by soft template methodology were immobilized onto green and biocompatible nanocomposite containing poly as a conductive matrix and graphene quantum dots as the amplification element. Therefore, a novel multilayer film based on poly-L-cysteine, graphene quantum dots (GQDs), and gold nanoparticles (GNPs) was exploited to develop a highly sensitive electrochemical sensor for the detection of L-Pro. Fully electrochemical methodology was used to prepare a new transducer on a glassy carbon electrode, which provided a high surface area towards sensitive detection of L-Pro. The prepared electrode was employed for the detection of L-Pro. Under optimized conditions, the calibration curve for L-Pro concentration was linear in 0.5 nM - 10 mM with a low limit of quantification of 0.1 nM. The practical analytical utility of the modified electrode was illustrated by determination of L-Pro in unprocessed human plasma samples. PMID- 29526906 TI - Surface Modification Enhanced Reflection Intensity of Quartz Crystal Microbalance Sensors upon Molecular Adsorption. AB - Molecular adsorption on a sensing surface involves molecule-substrate and molecule-molecule interactions. Combining optical systems and a quartz crystal microbalance (QCM) on the same sensing surface allows the quantification of such interactions and reveals the physicochemical properties of the adsorbed molecules. However, low sensitivity of the current reflection-based techniques compared to the QCM technique hinders the quantitative analysis of the adsorption events. Here, a layer-by-layer surface modification of a QCM sensor is studied to increase the optical sensitivity. The intermediate layers of organic-inorganic molecules and metal-metal oxide were explored on a gold (Au) surface of a QCM sensor. First, polyhedral oligomeric silsesquioxane-derivatives that served as the organic-inorganic intermediate layer were synthesized and modified on the Au QCM surface. Meanwhile, titanium oxide, fabricated by anodic oxidation of titanium, was used as a metal-metal oxide intermediate layer on a titanium-coated QCM surface. The developed technique enabled interrogation of the molecular adsorption owing to the enhanced optical sensitivity. PMID- 29526907 TI - Partition/Ion-Exclusion Chromatographic Ion Stacking for the Analysis of Trace Anions in Water and Salt Samples by Ion Chromatography. AB - A new analytical methodology for a simple and efficient on-line preconcentration of trace inorganic anions in water and salt samples prior to ion chromatographic determination is proposed. The preconcentration method is based on partition/ion exclusion chromatographic ion stacking (PIEC ion stacking) with a hydrophilic polymer gel column containing a small amount of fixed anionic charges. The developed on-line PIEC ion stacking-ion chromatography method was validated by recovery experiments for the determination of nitrate in tap water in terms of both accuracy and precision, and the results showed the reliability of the method. The method proposed was also successfully applied to the determination of trace impurity nitrite and nitrate in reagent-grade salts of sodium sulfate. A low background level can be achieved since pure water is used as the eluant for the PIEC ion stacking. It is possible to reach sensitive detection at sub-MUg L-1 levels by on-line PIEC ion stacking-ion chromatography. PMID- 29526908 TI - Thin Alginate Membranes Functionalized with Humic Acids for Removing Traces of Cu(II) from Contaminated Seawater. AB - Humic acid (HA) could become a useful agent for removing trace amounts of Cu(II) from contaminated seawater. This study reports on the use of a thin alginate membrane (TAM) containing immobilized HA as a Cu(II) binding agent for this purpose. The removal efficiency of Cu(II) by a TAM functionalized with HA was significantly increased compared to TAM alone. In this removal method, HA extracted from hardwood bark compost was more effective in removing Cu(II) than that from peat soil. PMID- 29526909 TI - Rapid Enzyme-linked Immunosorbent Assays for Diagnosis of Diabetes in a Compact Disc-shaped Microfluidic Device. AB - We have developed a compact disc (CD)-shaped microfluidic device for multiple, rapid enzyme-linked immunosorbent assays (ELISA). The device has a versatile design that can be adapted for the detection of various proteins by selecting the push-in-type reaction parts and appropriate reagents for each target. In this paper, we report the rapid quantification of insulin, adiponectin, and leptin, which can be used for the early diagnosis of diabetes, in human serum in only 16 min with our device. PMID- 29526910 TI - Determination of Sulfate Ion with 2-Aminoperimidine Hydrobromide Using an Optode Based on Tetrabromophenolphthalein Ethyl Ester Membrane. AB - An optode method for the determination of sulfate ion was developed. The optode membrane is 2-nitrophenyl octyl ether-plasticized poly(vinyl chloride) membrane containing tetrabromophenolphthalein ethyl ester. The method is based on formation of an ion associate between the excess of 2-aminoperimidine hydrobromide (Ap) and sulfate ion in the sample solution, and detection of the concentration of the remaining Ap ion by the optode. Under the optimal conditions, a good linear relationship was found to exist between the absorbance of the optode membrane, and concentrations of sulfate ion in a concentration range from 20 to 400 MUM. The developed optode method was applied to the determination of sulfate ion in environmental water samples. PMID- 29526911 TI - Sequential Injection Analysis System Exploiting On-line Solid-phase Extraction for the Determination of Strontium and Nickel by Microwave Plasma Atomic Emission Spectrometry. AB - A sequential flow-based analysis system with on-line solid-phase extraction (SPE) columns coupled to microwave plasma atomic emission spectrometry (MP-AES) was developed for strontium and nickel determination. Crown ether chromatographic resin and dimethylglyoxime polymethacrylate resin were used for strontium and nickel retention under acidic and basic conditions, respectively; eluted with a nitric acid solution in both cases followed by MP-AES detection. The calculated detection limits were 0.25 MUg L-1 for strontium and 3.56 MUg L-1 for nickel. PMID- 29526913 TI - Clinical Correlates and Prognostic Value of Elevated Right Atrial Pressure in Patients With Hypertrophic Cardiomyopathy. AB - BACKGROUND: The clinical characteristics associated with elevated right atrial pressure (RAP) in hypertrophic cardiomyopathy (HCM) are unknown. Few data exist as to whether elevated RAP has prognostic implications in patients with HCM. This study investigated the clinical correlates and prognostic value of elevated RAP in HCM.Methods and Results:This retrospective cohort study was performed on 180 patients with HCM who underwent right heart catheterization between 1997 and 2014. Elevated RAP was defined as >8 mmHg. Baseline characteristics, mean pulmonary artery pressure, and mean pulmonary capillary wedge pressure (PCWP) were assessed for association with elevated RAP. The predictive value of elevated RAP for all-cause mortality and the development of atrial fibrillation (AF), ventricular tachycardia/fibrillation (VT/VF), and stroke was evaluated. Elevated RAP was associated with higher New York Heart Association class, dyspnea on exertion, orthopnea, edema, jugular venous distention, larger left atrial size, right ventricular hypertrophy, higher pulmonary artery pressure, and higher PCWP. RAP independently predicted all-cause mortality (adjusted hazard ratio [aHR] 2.18 per 5-mmHg increase, 95% confidence interval [CI] 1.05-4.50, P=0.04) and incident AF (aHR 1.85 per 5-mmHg increase, 95% CI 1.20-2.85, P=0.005). Elevated RAP did not predict VT/VF (P=0.36) or stroke (P=0.28). CONCLUSIONS: Elevated RAP in patients with HCM is associated with left-sided heart failure and is an independent predictor of all-cause mortality and new-onset AF. PMID- 29526914 TI - Incidence and Risk Factors of Stroke or Systemic Embolism in Patients With Atrial Fibrillation and Heart Failure - The Fushimi AF Registry. AB - BACKGROUND: Heart failure (HF) is a heterogeneous syndrome, but the effect of the type and severity of HF on the incidence of stroke or systemic embolism (SE) in atrial fibrillation (AF) patients is unclear.Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 3,749 patients. We defined pre existing HF as having one of the following: prior hospitalization for HF, presence of HF symptoms (NYHA >=2), or reduced ejection fraction (<40%). At baseline, 1,008 (26.9%) patients had pre-existing HF. On multivariate analysis, the incidence of stroke/SE was not associated with pre-existing HF (hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.92-1.64) or each criterion for the definition of pre-existing HF, but was associated with high B-type natriuretic peptide (BNP) or N-terminal proBNP levels (above the median of the pre-existing HF group) at baseline (HR, 1.65; 95% CI, 1.06-2.53). Stroke/SE was markedly increased in the initial 30-day period following hospital admission for HF (HR, 12.0; 95% CI, 4.59-31.98). CONCLUSIONS: The effect of HF on the incidence of stroke/SE may depend on the stage or severity of HF in patients with AF. The incidence of stroke/SE was markedly increased in the 30 days after admission for HF, but compensated 'stable' HF did not appear to confer an independent risk. PMID- 29526915 TI - Aortic Dissection Resulting in Simultaneous Bilateral Coronary Invasion via Different Mechanisms on Intravascular Ultrasonography. PMID- 29526917 TI - [The critical role of autophagy in heart failure]. AB - Autophagy is an evolutionarily conserved process for degradation of long-lived proteins and organelles that govern a number of cardiac pathologies which cause heart failure. Indeed, recent investigations have uncovered pathways that regulate autophagy in the heart and underlying mechanisms by which alterations in this process affect cardiac function and structure. One of the major roles of autophagy in cardiomyocytes is the intracellular protein quality control (PQC). Impairment of autophagy causes aggregation of damaged and/or misfolded proteins in cardiomyocytes, thereby damaging the cells which, in turn leads to pathological cardiac remodeling. We have shown previously that the molecular mechanism of autophagy suppression in response to cardiac stress. Activation of mammalian Ste20-like kinase 1 (Mst1) by stress causes autophagy suppression below physiological levels and inhibits PQC, which in turn contributes to cardiac dysfunction. Specifically, Mst1 inhibits autophagy through phosphorylation of Beclin1, enhancement of Beclin1-Bcl-2 interaction and suppression of Vps34. Here, I show recent advances in understanding the role of autophagy in pathological cardiac remodeling and discuss the therapeutic potential of modulating autophagy in heart disease. PMID- 29526916 TI - Observational Evidence of the Association Between Handgrip Strength, Hand Dexterity, and Cognitive Performance in Community-Dwelling Older Adults: A Systematic Review. AB - BACKGROUND: Deterioration of hand motor function is a possible risk factor of cognitive impairment in older adults. Despite a growing body of research, a lack of clarity exists regarding the relationships. This review offers a synthesis of existing observational studies evaluating the associations of handgrip strength and hand dexterity with cognitive performance in community-dwelling older adults. METHODS: PubMed, PsycINFO, and ScienceDirect were systematically searched (search dates: 1990-2016), and relevant articles were cross-checked for related and relevant publications. RESULTS: Twenty-two observational studies assessed the association of handgrip strength or hand dexterity with cognitive performance; none evaluated handgrip strength and hand dexterity together. Handgrip strength was associated with global cognition, mostly assessed using the Mini-Mental State Examination, cross-sectionally and longitudinally. Also, one cross-sectional and three longitudinal studies found an association with cognitive domains, such as language, memory, visuospatial ability, working memory, and processing speed. Hand dexterity was only assessed cross-sectionally in four studies. These studies found an association with cognitive domains, such as executive function. CONCLUSIONS: Although handgrip strength was associated with cognitive performance, it is unclear which variable at baseline affects the other in the long-term. Cross-sectional studies indicate an association between hand dexterity and cognitive performance, yet longitudinal studies are needed to elucidate this association. The interaction effects of both decreased grip strength and hand dexterity on cognitive performance is still unclear; therefore, future studies will need to consider the interaction of the three variables cross-sectionally and longitudinally. PMID- 29526918 TI - [Basement membrane-derived matricryptins as a new target molecule for heart failure treatment]. AB - Extracellular matrix (ECM) is a complex of non-cellular macromolecules which is indispensable not only for maintaining tissue structure but also for regulating the functions of surrounding cells via cell-ECM interaction. Recently, a number of ECM fragments termed "matricryptins" have been identified as novel endogenous bioactive substances, which usually have different bioactivity from that of original ECM. Because most matricryptins derived from basement membrane have anti angiogenic and anti-tumor effects, they have been initially studied for developing anti-tumor agents. Meanwhile, there are several reports indicating that the expression of basement membrane-derived matricryptins changes in the heart tissue from experimental animal models as well as in the circulating blood from patients with cardiac diseases. Thus, it is logical to hypothesize that the basement membrane-derived matricryptins play roles in the development of cardiac diseases. In this article, we would like to introduce current findings on the functions of matricryptins including ours and discuss the possibility that they serve as a novel target for the treatment of heart failure. PMID- 29526919 TI - [Septic cardiomyopathy: pathophysiology and potential new therapeutic approaches]. AB - Sepsis is the leading cause of death in critically ill patients, and its incidence continues to rise. Sepsis was defined as a systemic inflammatory response syndrome with an identifiable focus of infection, but therapeutic strategies aimed at eliminating the inflammatory response have only modest clinical benefit. The development of a failure of one or more organs poses a major threat to the survival of patients with sepsis, and mortality in sepsis is most often attributed to multiple organ dysfunction. Accordingly, sepsis has been recently redefined as life-threatening organ dysfunction due to a dysregulated host response to infection. Cardiac dysfunction is a well-recognized important component of septic multiple organ failure and can compromise the balance between oxygen supply and demand, ultimately leading to the development of multiple organ failure. The existence of cardiac dysfunction in sepsis is associated with much higher mortality when compared with septic patients without heart problems. Dobutamine, a beta1-selective adrenoceptor agonist, has been used in septic shock for many years as an only inotrope, but limited clinical outcome measures have been provided as to advisability of the usefulness of dobutamine in septic shock management. Here we provide an overview on the possible mechanisms underlying intrinsic myocardial depression during sepsis and discuss the perspective of several inotropes for sepsis-associated cardiac dysfunction. PMID- 29526920 TI - [Current status of development for regenerative cell therapy, SB623]. AB - SanBio Co., Ltd. is developing regenerative medicine, SB623. SB623 secretes neurotrophic and growth factors, and can possibly show benefit in repair of the damaged brain after stroke. An open-label, single-arm phase I/IIa clinical study was conducted with 18 chronic ischemic stroke patients in the United States to evaluate the safety and clinical outcomes of surgical transplantation of SB623. Clinical evaluation for a one year follow-up period showed significant improvements with all mean scores on the European Stroke Scale, the National Institute of Health Stroke Scale, and on the basis of fugl-Meyer Assessment. All patients experienced neither side effects nor serious treatment-emergent adverse events related to cell treatments. These results suggest that SB623 cell transplantation is safe and effective for treating chronic ischemic stroke. Currently we are conducting clinical studies in Japan and the US, and are accelerating clinical development to provide our cells to patients under new regulation of regenerative medical product in Japan. PMID- 29526921 TI - [Romidepsin (Istodax(r) for intravenous injection 10 mg): pharmacokinetics, pharmacodynamics and clinical study outcome]. AB - Romidepsin (Brand name: ISTODAX(r) for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U.S. and other countries. Thereafter, domestic phase I/II studies were planned. The phase I study was designed to evaluate the tolerability of romidepsin in Japanese patients with relapsed or refractory PTCL/CTCL and thereby determine the recommended dose, as patients were administered romidepsin by intravenous infusion at a dose of 9 or 14 mg/m2 over 4 hours on days 1, 8 and 15 of each 28-day cycle, and 14 mg/m2 was determined as the recommended dose for phase II. While the phase II study was designed to include 40 Japanese patients with relapsed or refractory PTCL to evaluate the efficacy and safety of romidepsin. Treatment response was 42.5% and the most common AEs of Grade >= 3 were lymphopenia (74.0%), neutropenia (54.0%), leukocytopenia (46.0%) and thrombocytopenia (38.0%). The overall safety profile was considered to be within the acceptable range. On the basis of these result, romidepsin was approved in July 2017 for the treatment of relapsed or refractory PTCL in Japan. PMID- 29526922 TI - [The roles of IgE in allergic diseases]. PMID- 29526923 TI - [New aspects of poly(A) tail shortening of mRNA in controlling heart functions]. AB - Cardiovascular diseases are major increasing causes of death in developed countries. Coordinated transcriptional and post-transcriptional regulation of gene expression is crucial to maintain normal heart physiology. Dysregulation of these processes causes and/or accompanies multiple pathologies, such as cardiomyopathy and myocardial infarction. The exonuclease-mediated shortening of the mRNA poly(A) tail, a process called deadenylation, is a key step in regulated mRNA degradation, and deadenylation is mostly executed by the CCR4-NOT complex. CCR4-NOT complex is a multi-subunit protein complex, which controls gene expression in the levels from transcription through mRNA deadenylation and protein ubiquitination. We had previously identified CNOT3, a scaffold subunit of the CCR4-NOT complex, as a conserved regulator of heart function in Drosophila and mouse. Our recent genetic data of conditional Cnot3 knockout mice revealed unexpected association of poly(A) shortening and transcriptional activation, which is reprersented by Atg7 and p53. In this review, we introduce our recent progress in dissecting the mechanisms how poly(A) shortening contributes to controlling heart functions and overview new aspects of poly(A) regulation in maintaining cardiac homeostasis. PMID- 29526924 TI - gamma-aminobutyric acid accumulation enhances the cell growth of Candida glycerinogenes under hyperosmotic conditions. AB - gamma-aminobutyric acid (GABA) is an important non-protein amino acid involved in the response to various environmental stresses in plant cells. The objectives of this study was to test the hypothesis that intracellular accumulation of GABA improves osmotic tolerance in the unconventional yeast Candida glycerinogenes. In C. glycerinogenes, the expression of UGA4 encoding GABA-specific permease is highly induced by hyperosmotic stress. Exogenous GABA application enhanced intracellular GABA accumulation and promoted cell growth under hyperosmotic conditions. Overexpression of the glutamate decarboxylase gene GAD1 resulted in an increased intracellular GABA and improvement in cell growth under hyperosmotic conditions. These results indicated that improving intracellular GABA accumulation of C. glycerinogenes, either through exogenous application or cellular synthesis, is available for improving the tolerance to hyperosmotic stress. We demonstrate that GABA accumulation plays an important role in osmotic stress resistance of the unconventional yeast C. glycerinogenes. PMID- 29526925 TI - Involvement of the response regulator CtrA in the extracellular DNA production of the marine bacterium Rhodovulum sulfidophilum. AB - The marine bacterium Rhodovulum sulfidophilum is a nonsulfur phototrophic bacterium, which is known to produce extracellular nucleic acids in soluble form in culture medium. In the present paper, constructing the response regulator ctrA deficient mutant of R. sulfidophilum, we found that this mutation causes a significant decrease in the extracellular DNA production. However, by the introduction of a plasmid containing the wild type ctrA gene into the mutant, the amount of extracellular DNA produced was recovered. This is the first and clear evidence that the extracellular DNA production is actively controlled by the CtrA in R. sulfidophilum. PMID- 29526926 TI - Metagenomic insights into lignocellulose-degrading genes through Illumina-based de novo sequencing of the microbiome in Vietnamese native goats' rumen. AB - The scarcity of enzymes having an optimal activity in lignocellulose deconstruction is an obstacle for industrial-scale conversion of cellulosic biomass into biofuels. With the aim of mining novel lignocellulolytic enzymes, a ~9 Gb metagenome of bacteria in Vietnamese native goats' rumen was sequenced by Illumina platform. From the data, 821 ORFs encoding carbohydrate esterases (CEs) and polysaccharide lyases (PLs) serving for lignocellulose pre-treatment, 816 ORFs encoding 11 glycoside hydrolase families (GHs) of cellulases, and 2252 ORFs encoding 22 GHs of hemicellulases, were mined. The carbohydrate binding module (CBM) was also abundant with 763 ORFs, of which 480 ORFs are located with lignocellulolytic enzymes. The enzyme modularity analysis showed that CBMs are usually present in endoglucanase, endo 1,3-beta-D-glucosidase, and endoxylanase, whereas fibronectin 3-like module (FN3) mainly represents in GH3 and immunoglobulin-like domain (Ig) was located in GH9 only. Every domain located in each ORF was analyzed in detail to contribute enzymes' modularity which is valuable for modelling, to study the structure, and for recombinant production. With the aim of confirming the annotated results, a mined ORF encoding CBM63 was highly expressed in E. coli in soluble form. The purified recombinant CBM63 exhibited no cellulase activity, but enhanced a commercial cellulase activity in the destruction of a paper filter. PMID- 29526927 TI - Development and validation of a work-related low back pain risk-assessment tool for sugarcane farmers. AB - This cross sectional study developed and validated a LBP risk-factor screening scale for use with sugarcane farmers. The scale was developed from a synthesis of LBP risk factors, pretested with 30 sugarcane farmers and administered to five hundred and forty sugarcane farmers to test its psychometric properties. Results indicated construct validity for three factors; physical factors (19 items) with factor loadings of 0.406 to 0.881 and communalities between 0.471 and 0.991; psychological factors (7 items) with factor loadings of 0.635 to 0.821 and communalities between 0.444 and 0.714, and third, working environment factors (2 items), with factor loadings between 0.345 and 0.347 and communalities between 0.946 and 0.953. The content validity index was 0.90 with reliability index of 0.87. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 82.02%, 30.49%, 62.65% and 54.40% respectively. The area under the receiver operating characteristic was 0.56. The scale's high specificity and sensitivity and comprehensive three risk-factor dimensions should make it a very useful screening tool in primary health care for early detection of LBP and for LBP risk-reduction and prevention advice. Future studies could focus on confirming content and predictive validity in other settings to assess generality of its usage. PMID- 29526928 TI - Gastric Arteriovenous Malformation with Characteristic Endoscopic Findings. AB - Gastric arteriovenous malformation (AVM) is an uncommon cause of upper gastrointestinal bleeding, and the endoscopic findings are unclear. We herein describe a case of gastric AVM in a 28-year-old man. Esophagogastroduodenoscopy showed a Dieulafoy lesion surrounded by a red mucosa with a sharp margin, which implied blood vessel malformation. Computed tomography angiography and conventional angiography revealed aggregated vessels on the greater curvature. Partial gastrectomy was performed, with no recurrent bleeding postoperatively. The histopathological diagnosis was AVM. We conclude that gastric AVM should be considered in the differential diagnosis of patients who present with a Dieulafoy lesion surrounded by a red mucosa. PMID- 29526929 TI - Chronic Hepatitis C Treatment with Daclatasvir Plus Asunaprevir Does Not Lead to a Decreased Quality of Life. AB - Objective The aim of this study was to determine if direct-acting antiviral (DAA) treatment with daclatasvir (DCV) plus asunaprevir (ASV) for 24 weeks influenced the health-related quality of life (HRQOL) at 12 and 24 weeks after treatment initiation [end of treatment (EOT)]. Methods This was a prospective, longitudinal study comparing the HRQOL of patients receiving DAA treatment at 12 weeks after treatment initiation and EOT with the HRQOL at baseline. We used a Japanese validated version of the 8-item Short Form Health Survey (SF-8) to assess the HRQOL of patients. This score can be compared to the Japanese normative sample scores of SF-8. Wilcoxon signed-rank tests were used to compare the HRQOL before treatment, 12 weeks after treatment initiation, and at EOT. Patients We enrolled patients who received 24-week combination therapy using DCV and ASV for HCV at Saga University Hospital between November 2014 and July 2015. Those who discontinued treatment due to relapse or adverse reactions during the treatment period were excluded from the study. Results There were no significant changes in any of the SF-8 subscales, Physical component scores (PCS) or mental component scores (MCS) during the treatment period for both males and females. Conclusion Our study makes a significant contribution to the literature because 24-week DAA treatment with DCV plus ASV did not decrease the HRQOL at 12 or 24 weeks after treatment initiation. PMID- 29526931 TI - Severe Hyperkyphosis. PMID- 29526930 TI - Five Cases of Familial Mediterranean Fever in Japan: The Relationship with MEFV Mutations. AB - Familial Mediterranean fever (FMF) is the most common genetic autoinflammatory disease, but it has been considered a rare disease in Japan. We herein describe five patients with FMF who were diagnosed both clinically and genetically at a single Japanese institute. A genetic investigation of Mediterranean fever (MEFV) detected heterozygosity for the compound mutations L110P/E148Q (n=2) and L110P/148Q/P369S/R406Q (n=1), and heterozygosity for M694I (n=1) and S503C (n=1). Colchicine prevented febrile attacks and accompanying symptoms in four patients. One patient with an S503C mutation showed resistance. Physicians should be aware of the characteristic symptoms, as well as the more unusual symptoms such as headache, when diagnosing FMF. PMID- 29526932 TI - Erythema as a Visual Surrogate Marker of Glucagonoma. PMID- 29526933 TI - Endobronchial Mucosa-associated Lymphoid Tissue Lymphoma: A Report of Two Cases and a Review of the Literature. AB - Primary endobronchial mucosa-associated lymphoid tissue lymphoma (EML) is rare. We reviewed 20 cases of EML, including ours and case reports. We found that the location of tumor in 70% of these cases was limited to the trachea and main bronchus, and the form of tumor in 61% of these cases was several nodular protrusions. If a patient exhibits these characteristics, adequate specimen collection on bronchoscopy is important. Because the prognosis for patients with EML is good, tumors on the trachea and main bronchus should be treated, while those on the peripheral airway can be watched carefully. PMID- 29526936 TI - Gas-filled Cavities in the Liver. PMID- 29526934 TI - Can the Wish to Receive Intensive Treatment in Elderly Patients with Respiratory Tract Infection Be Predicted? AB - Objective Almost no Japanese elderly patients have an advance directive (AD). Our aim was to determine whether or not the wish to receive intensive care in elderly patients with respiratory tract infection could be predicted from the prehospital data. Methods In this retrospective study, we reviewed patients >=65 years of age with respiratory tract infection who had been transferred to our hospital by ambulance between September 2014 and August 2016. The patients were divided into two groups according to whether or not they wished to receive intensive treatment. We placed patients without a wish to receive intensive treatments (WITs) in Group A and patients with a WITs in Group B. We then analyzed parameters that could be determined in the prehospital phase and compared the findings between the groups. Results Thirty-seven patients were in Group A, and 67 patients were in Group B. None of the patients in this study had an AD. There were significant differences in the age, rate of residence in an extended care facility, frequency of inability to care for oneself fully, frequency of dementia, number of prescribed drugs, and Glasgow coma scale (GCS) on a univariate analysis. A logistic regression analysis showed that the inability to care for oneself fully [odds ratio (OR): 4.521, 95% confidence interval (CI): 2.024-10.096, p<0.001] and a low GCS (OR 0.885, 95%CI 0.838-0.935, p<0.001) were related to a WITs. Conclusion Elderly patients who are unable to care for themselves and who have a low GCS in the prehospital stage are likely not to want intensive treatment. PMID- 29526935 TI - Medical Attitudes Survey for Female Dystrophinopathy Carriers in Japan. AB - Objective This study attempted to clarify the current status of female dystrophinopathy carriers, including the numbers of patients, the status of genetic screening, the status of counseling, physicians' understanding, and barriers to registration. Methods We sent out questionnaires to 402 physicians registered in the Remudy dystrophinopathy registry. The total number of responses received was 130 (response rate: 32%). Result In total, 1,212 cases of Duchenne muscular dystrophy, 365 cases of Becker muscular dystrophy, and 132 cases of female dystrophinopathy with a confirmed genetic mutation were encountered, and genetic testing was performed in the mother in 137, 23, and 12 cases, respectively. With respect to the risk of the onset of health problems, 25% of physicians always explained, 29% usually explained, 29% sometimes explained, and 13% never explained the risk to the mothers and female siblings of dystrophinopathy patients. The most common reason for not explaining the risk was a lack of knowledge/information. Thirty-five percent were familiar with the guidelines for testing the heart function of carriers. Conclusion Fewer mothers of dystrophinopathy patients have undergone genetic testing in Japan than in other countries. A significant portion of doctors did not explain the risks of health problems due to a lack of knowledge. We hope this survey will lead to an increased discussion of female dystrophinopathy patients. PMID- 29526937 TI - Secondary Brain Neoplasm after Stereotactic Radiosurgery in Patients with Metastatic Non-small Cell Lung Cancer. AB - Stereotactic radiosurgery (SRS) using the Gamma Knife (GK) is now being increasingly utilized for the treatment of brain metastases. However, there are a few reported cases of SRS-induced brain neoplasms. We herein report the case of a Japanese woman with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR)-mutations who was treated four times with a GK for brain metastases. She developed glioblastoma 5.7 years after the initial GK surgery. Radiation-induced secondary neoplasms generally appear after a latency period of several years. Advances in cancer therapy have improved the survival of patients with NSCLC, providing enough time for secondary neoplasms to appear after SRS. PMID- 29526938 TI - Streptococcus Anginosus Group-associated Pyogenic Liver Abscess. PMID- 29526939 TI - Type 2 Autoimmune Pancreatitis with Crohn's Disease. AB - Autoimmune pancreatitis (AIP) is a distinct subtype of pancreatitis, which is classified into type 1 and 2 based on the clinicopathological features. According to the international consensus diagnostic criteria, pancreas resection or core biopsy specimens are recommended to make an accurate histological evaluation. However, the usefulness of endoscopic ultrasonography (EUS) guided fine needle aspiration (FNA) for histological evaluation has also been reported. Furthermore, the simultaneous presentation of type 2 AIP and Crohn's disease (CD) is very rare, especially in the Asian population. Therefore, we herein report a case of type 2 AIP with CD, which was diagnosed using EUS guided FNA with a 22-gauge needle. PMID- 29526940 TI - Emphysematous Osteomyelitis of the Spine: A Case Report and Literature Review. AB - Emphysematous osteomyelitis is a rare but potentially fatal infection. It is caused by gas-forming organisms and is characterized by the presence of intraosseous gas. A 75-year-old woman with untreated diabetes mellitus presented with difficulty in moving and anorexia. Laboratory studies revealed inflammation, a urinary infection, and diabetic ketoacidosis. Klebsiella pneumoniae was detected in both urine and blood cultures. Computed tomography and magnetic resonance imaging revealed emphysematous lesions in the paravertebral soft tissue, spinal canal, and iliopsoas muscle, with intraosseous gas at L1 and L2. These findings led to a diagnosis of emphysematous osteomyelitis. We herein review 35 reported cases of emphysematous osteomyelitis including our case. PMID- 29526941 TI - Late Onset of Non-islet Cell Tumor Hypoglycemia Managed via Multidisciplinary Treatment in a Patient with a Solitary Fibrous Tumor. AB - Solitary fibrous tumor (SFT) is a rare subtype of soft tissue sarcoma (STS). We herein describe a case of late onset of non-islet cell tumor hypoglycemia (NICTH) that was managed via multidisciplinary treatment in a patient with SFT. A 67-year old man previously diagnosed with SFT 4 years prior to this presentation and treated with several rounds of surgery, presented with massive tumors. Eighteen months following his prescribed chemotherapy, the patient developed hypoglycemia. He was diagnosed with NICTH, after confirming the presence of high molecular weight insulin-like growth factor-2. This case suggests that paraneoplastic syndrome can occur even in cases of rare cancers, such as STS. PMID- 29526942 TI - Successful Treatment of Intestinal Mycosis Caused by a Simultaneous Infection with Lichtheimia ramosa and Aspergillus calidoustus. AB - A 53-year-old woman was hospitalized due to septic shock after developing pneumococcal pneumonia after undergoing esophageal cancer surgery. Her transverse colon became perforated after receiving antimicrobial chemotherapy; therefore, emergency subtotal colectomy was performed. Fungi detected in both her colon tissue and a drainage sample indicated intestinal mucormycosis. Early intensive treatment with high-dose liposomal amphotericin B was successful, and she was subsequently discharged from the hospital. The fungal isolates were identified to be Lichtheimia ramosa and Aspergillus calidoustus via gene sequencing using panfungal primers as well as species-specific primers against elongation factor 1 and beta-tubulin for detecting Lichtheimia and Aspergillus, respectively. PMID- 29526943 TI - Usefulness of Aspergillus Galactomannan Antigen Testing and the Prediction of an Outbreak during Hospital Reconstruction. AB - Objective This study retrospectively evaluated fungal dissemination due to hospital reconstruction and explored effective methods of predicting an outbreak. Methods Patients suspected of having invasive aspergillosis were tested for Aspergillus galactomannan antigen before and after reconstruction, and the mean values of three months of testing for positive patients were determined. The characteristics of patients with aspergillosis during this period were also assessed. Results Forty-five patients were positive for Aspergillus antigen (>0.5 cut-off index) from January 2013 to December 2014. Mean Aspergillus antigen values significantly increased following reconstruction (p<0.05). Three patients developed pneumonia due to Aspergillus and were diagnosed with "probable" invasive aspergillosis according to the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. We also discovered that the anteroom to contain dust was not prefabricated and a negative pressure system to remove dust was not used. After construction of the unit, no new cases of aspergillosis were diagnosed. Conclusion Many Aspergillus spores may be transiently floating during hospital reconstruction. Therefore, monthly surveillance with frequent serum galactomannan antigen testing to predict outbreaks is necessary. Surveillance of all patients in the hematology ward is especially important. Reconsideration of prophylactic antifungals may also be necessary during hospital reconstruction. PMID- 29526944 TI - Posterior Reversible Encephalopathy Syndrome after a Variety of Combined Chemotherapies Containing Bevacizumab for Metastatic Colon Cancer. AB - A 44-year-old woman with advanced metastatic colon cancer received chemotherapies comprising oxaliplatin and capecitabine (XELOX), irinotecan hydrochloride, leucovorin calcium and fluorouracil irinotecan (FOLFIRI)/panitumumab and mFOLFOX6/bevacizumab. Fifteen months later, she presented with the acute onset of a headache, drowsiness and seizure with a fever and hypertension. Brain magnetic resonance imaging (MRI) indicated bilateral regions of signal hyperintensity in the white matter with spasms of bilateral cerebral arteries apparent on magnetic resonance angiography. Posterior reversible encephalopathy syndrome (PRES) was diagnosed, and treatments resulted in improvement of the MRI findings, but the patient experienced cerebral infarction and ultimately died of deterioration of cancer on day 26 after the onset of PRES. PMID- 29526945 TI - Anti-PL-7 Antisynthetase Syndrome with Eosinophilic Pleural Effusion. AB - A 68-year-old woman was admitted to our hospital with fever and pleural effusion. Her thoracentesis showed eosinophilic pleural effusion (EPE) without any evidence of malignancy, infection, or trauma. Pleural biopsy revealed pleuritis and intercostal myositis. Characteristic skin manifestations, including Gottron's sign, interstitial lung disease, and pericardial effusion, appeared later in the clinical course. She was finally diagnosed with anti-PL-7 antisynthetase syndrome (ASS) based on the presence of anti-PL-7 antibody, and she fulfilled the diagnostic criteria for dermatomyositis. These clinical manifestations improved with immunosuppressive therapy. EPE might therefore be one of the characteristic features of anti-PL-7 ASS. PMID- 29526946 TI - A Retrospective Study on the Epidemiological and Clinical Features of Emergency Patients with Large or Massive Consumption of Caffeinated Supplements or Energy Drinks in Japan. AB - Objective We conducted a retrospective study on the epidemiological and clinical features of patients with acute caffeine poisoning in Japan. Methods Letters requesting participation were sent to 264 emergency departments of hospitals, and questionnaires were mailed to those that agreed to participate. Patients Participants were patients transported to emergency departments of hospitals between April 2011 and March 2016 after consuming large or massive amounts of caffeinated supplements and/or energy drinks (caffeine dose >=1.0 g). Results We surveyed 101 patients from 38 emergency departments. Since April 2013, the number of patients has markedly increased. Of these young patients (median age, 25 years), 53 were men, and 97 had consumed caffeine in tablet form. Estimated caffeine doses (n=93) ranged from 1.2 to 82.6 g (median, 7.2 g). Serum caffeine levels on admission (n=17) ranged from 2.0 to 530.0 MUg/mL (median level, 106.0 MUg/mL). Common abnormal vital signs and laboratory data on admission included tachypnea, tachycardia, depressed consciousness, hypercreatinekinasemia, hyperglycemia, hypokalemia, hypophosphatemia, and hyperlactatemia. Common signs and symptoms in the clinical course included nausea, vomiting, excitement/agitation, and sinus tachycardia. Seven patients (6.9%) who had consumed >=6.0 g of caffeine, or whose serum caffeine levels on admission were >=200 MUg/mL, developed cardiac arrest. Ninety-seven patients (96.0%) recovered completely, but 3 patients (3.0%) died. Conclusion The present analysis of data from more than 100 emergency patients revealed clinical features of moderate to fatal caffeine poisoning. We recommend highlighting the toxicity risks associated with ingesting highly caffeinated tablets. PMID- 29526947 TI - Pylephlebitis: A Rare Complication of Diverticulitis. PMID- 29526948 TI - Rituximab-induced Acute Thrombocytopenia in Granulomatosis with Polyangiitis. AB - A 72-year-old Japanese woman diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was admitted to our hospital with hearing loss, temporal pain, and sudden blindness. We finally diagnosed recurrent granulomatosis with polyangiitis and initiated methyl-prednisolone pulse therapy (1,000 mg) followed by prednisolone (30 mg/day) and rituximab (RTX). After the third RTX administration, she developed bloody stools along with acute thrombocytopenia and low complement levels. We diagnosed rituximab-induced acute thrombocytopenia (RIAT), and her platelet counts spontaneously recovered. This case suggests that after RTX therapy RIAT may sometimes cause severe thrombocytopenia, and that monitoring the complements may be useful for making an early diagnosis of RIAT. PMID- 29526949 TI - A Japanese Encephalitis Patient Presenting with Parkinsonism with Corresponding Laterality of Magnetic Resonance and Dopamine Transporter Imaging Findings. AB - Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using 123I labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE. PMID- 29526950 TI - Pulmonary Adenocarcinoma, Harboring Both an EGFR Mutation and ALK Rearrangement, Presenting a Stable Disease to Erlotinib and a Partial Response to Alectinib. AB - A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor (EGFR) mutation and an anaplastic lymphoma kinase (ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents. PMID- 29526951 TI - IgG4-related Pleuritis with Elevated Adenosine Deaminase in Pleural Effusion. AB - An 81-year-old man was admitted with bilateral pleural effusion. A clinical examination showed lymphocytic pleura effusion and elevated serum IgG4 levels, so that IgG4-related disease was suggested, whereas tuberculous pleurisy was suspected because of high adenosine deaminase (ADA) levels in the pleural effusion. A surgical pleural biopsy revealed that there were large numbers of IgG4-positive cells and IgG4/IgG positive cell ratio exceeded 40% in several sites. Accordingly, we diagnosed IgG4-related pleuritis and treated with the patient with glucocorticoid therapy. The ADA levels in pleural effusion can increase in IgG4-related pleuritis, and it is therefore important to perform a pleural biopsy. PMID- 29526952 TI - Lambert-Eaton Myasthenic Syndrome Associated with Synchronous Double Cancer: A Combination of Small Cell Carcinoma of the Cervix and Breast Carcinoma. AB - Lambert-Eaton myasthenic syndrome (LEMS) is most commonly associated with small cell lung carcinoma, while it is rarely associated with gynecological and breast carcinoma. We herein report a case of LEMS associated with synchronous double cancer, which was a combination of small cell carcinoma of the cervix and breast carcinoma. The early diagnosis and treatment of LEMS are important for achieving a good outcome. The possibility of accompanying paraneoplastic neurological syndrome must be sufficiently considered in gynecology and breast cancer patients. To our knowledge, this is the first report of LEMS associated with synchronous double cancer. PMID- 29526953 TI - Budd-Chiari Syndrome and Esophageal Achalasia: Unrecognized Intrahepatic Cholangiocarcinoma Invading Multiple Organs. AB - Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver cancer, although its occurrence is relatively rare. Budd-Chiari syndrome (BCS) is characterized by outflow obstruction from the liver, with hepatocellular carcinoma being the most common cause of malignant BCS. In this case report, we describe the occurrence of an unrecognized ICC that induced BCS and esophageal achalasia. PMID- 29526954 TI - The Development of Acute Systemic Multiple Thrombosis after Achieving Remission during Systemic Glucocorticoid Therapy for Acquired Hemophilia A. AB - Acquired hemophilia A (AHA) is a hemorrhagic disorder. Whether or not severe thrombotic events can develop without the use of bypassing agents in AHA patients is unclear. An 80-year-old woman with AHA underwent immunosuppressive therapy with prednisolone at 1 mg/kg daily. After achieving remission, she suddenly developed multiple organ failure due to acute systemic thrombosis and died within a few hours of the diagnosis. Patients with AHA, especially those with risk factors for thrombosis, have a considerable risk of developing thrombosis during the recovery phase of factor VIII activity and should be carefully monitored by coagulation testing. PMID- 29526955 TI - Improvement of Proteinuria due to Combination Therapy with Daclatasvir and Asunaprevir in Hepatitis C Virus-associated Renal Disease without Cryoglobulinemia. AB - We herein report a unique case of hepatitis C virus (HCV)-associated renal disease without cryoglobulinemia that showed proteinuria, hypoproteinemia, ascites, and edema. Due to combination therapy with daclatasvir and asunaprevir, the patient achieved sustained virological response at week 24 of the therapy. Furthermore, the therapy caused marked amelioration of her proteinuria, ascites, edema, and hypoalbuminemia, and finally improved her estimated glomerular filtration rate. There were no adverse events, and the combination therapy was well-tolerated. We recommend that HCV eradication with antiviral therapy using direct-acting antiviral agents be attempted first for all renal disease with HCV infection, regardless of cryoglobulinemia, considering the existence of resistance-associated variants. PMID- 29526956 TI - Rhabdomyolysis Induced by Isoniazid in a Patient with Rheumatoid Arthritis and End-stage Renal Disease: A Case Report and Review of the Literature. AB - A 76-year-old man complicated with end-stage renal disease had latent tuberculosis infection (LTBI), and isoniazid (INH) 300 mg daily was started to prevent reactivation of LTBI before using biologic agents for rheumatoid arthritis. On the 8th day after administration of INH, he presented with a fever, petechiae, and myalgia. Serological studies revealed elevated myogenic enzymes and creatinine level. Based on the exclusion of other etiologies, rapid improvement with cessation of INH, and the recurrence of the fever and myalgia with re-administration of a reduced dose of INH, we diagnosed him with INH induced rhabdomyolysis. Physicians should be aware of rhabdomyolysis induced by INH at a therapeutic dose as an infrequent but potentially fatal adverse drug reaction. PMID- 29526958 TI - An Occluded Hooklet of an Embedded Inferior Vena Cava Filter. PMID- 29526957 TI - Efficacy of Oral Factor Xa Inhibitor for Venous Thromboembolism in a Patient with Antithrombin Deficiency. AB - A 19-year-old man was referred due to sudden onset of right foot pain and chest discomfort. Contrast-enhanced computed tomography revealed massive thrombi in the right pulmonary artery and femoral vein. The patient's father had experienced multiple recurrences of venous thromboembolism (VTE) and was diagnosed with inherited antithrombin deficiency by a genetic examination. The patient was administered the oral factor Xa inhibitor rivaroxaban (30 mg). After seven days, the thrombus disappeared. Rivaroxaban (15 mg) was continued for 6 months with no recurrence, indicating the efficacy of this factor Xa inhibitor for the treatment and prevention of VTE in patients with antithrombin deficiency. PMID- 29526959 TI - Infectious Hepatic Cyst: An Underestimated Complication. AB - Objective An infectious hepatic cyst (IHC) is a hepatic cyst complicated with secondary infection and is generally assumed to be rare. However, we have experienced no small number of patients with IHC in recent clinical practice. We therefore examined the incidence and clinical characteristics of IHC. Methods The medical records of patients with IHC who were hospitalized at our institution between January 2012 and December 2016 were retrospectively reviewed. Their demographic factors, biochemical, bacteriological, imaging, and treatment results were explored and compared with those of patients with pyogenic liver abscess (PLA). Patients Twelve patients with IHC and 39 with PLA were identified. Results The IHCs were significantly larger in diameters than the PLAs, and patients with IHCs tended to be older and more often women than those with PLAs. IHCs showed characteristic imaging features, including heterogeneous contents with occasional fluid-debris levels, a thickened cystic wall with rim enhancement, perilesional edema and hyperaemia. Patients with IHCs had a significantly shorter hospital stay than those with PLAs. Conclusion Physicians should note that IHCs are not rare. A careful imaging evaluation can suggest an IHC, and the timely aspiration of the content can lead to an accurate diagnosis. The cystic wall may keep the infectious material confined within the IHC, resulting in the observed good treatment outcome with catheter drainage. PMID- 29526960 TI - Saibokuto as a Possible Therapy for Type B Insulin Resistance Syndrome: The Disappearance of Anti-insulin Receptor Antibody and a Marked Amelioration of Glycemic Control by Saibokuto Treatment. AB - Type B insulin resistance syndrome is a rare autoimmune disease and no effective therapy has yet been established. On the other hand, it is known that Saibokuto, one type of Japanese Kampo medicine, may have beneficial effects on various symptoms associated with this disease and it is therefore occasionally prescribed for various immune disorders. We herein describe a case of type B insulin resistance syndrome in which anti-insulin receptor antibody disappeared and the patient's glycemic control markedly improved after the administration of Saibokuto. At first, we administered various anti-oral diabetic drugs and insulin therapy, but the patient's glycemic control became further aggravated. In addition, Helicobacter pylori eradication therapy was not effective, although its benefit has been reported. Interestingly, after the patient started taking Saibokuto, her glycemic control markedly improved. In addition, the patient's plasma insulin levels markedly decreased and anti-insulin receptor antibody became negative after taking Saibokuto. Taken together, there is a possibility that Saibokuto may one of the options for type B insulin resistance syndrome therapy. PMID- 29526961 TI - Choledochoduodenal Fistula during Chemotherapy with Brentuximab Vedotin for Methotrexate-associated Lymphoproliferative Disorder. AB - We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin. PMID- 29526962 TI - Successful Cord Blood Stem Cell Transplantation for Primary Cutaneous CD8 positive Aggressive Epidermotropic Cytotoxic T-cell Lymphoma Complicated with Cerebral Infiltration. AB - A 16-year-old boy, who had been initially examined for bilateral blepharedema and slight eruption, presented with rapidly deteriorating symptoms in associating with headache and consciousness disturbance. He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE CTL) by a biopsy of the skin and brain. After whole-brain radiation and some courses of chemotherapy, cord blood transplantation was performed with myeloablative conditioning. After transplantation, the cerebral dysfunction gradually improved. Disease remission was confirmed by the disappearance of any abnormal findings on electroencephalogram and magnetic resonance imaging. PCAE CTL is reported to be an extremely aggressive disease with a poor prognosis, but the timely performance of cord blood transplantation is considered to be a promising treatment strategy. PMID- 29526963 TI - Paraneoplastic Pemphigus Associated with B-cell Chronic Lymphocytic Leukemia Treated with Ibrutinib and Rituximab. AB - Paraneoplastic pemphigus (PNP) is a severe autoimmune blistering disease associated with an underlying malignancy, and its prognosis is poor. We herein report the first patient with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)-associated PNP successfully treated with the Bruton's tyrosine kinase inhibitor ibrutinib and rituximab. Although his PNP lesions did not improve with ibrutinib monotherapy, the combination of ibrutinib and rituximab was effective against B-CLL/SLL-associated PNP. This case suggests that ibrutinib plus rituximab may be a potent therapeutic option for B-CLL/SLL associated PNP that is hard to control with ibrutinib alone. PMID- 29526964 TI - Large Bowel Progressive Stricture after Infliximab Therapy for Crohn's Disease. AB - This case report refers to a 31-year-old patient with an 11-year history of Crohn's disease. The patient presented with an edematous elevated lesion in the splenic flexure. Two histological analyses revealed no signs of obvious dysplasia, and the patient subsequently began infliximab treatment. Nine months later, a worsening of the stricture of the edematous elevated lesion was observed in the splenic flexure, and transverse colonic resection was performed. A histological investigation of the lesion in the splenic flexure revealed advanced adenocarcinoma. Six months after the surgery, computed tomography revealed recurrent carcinoma and peritoneal metastases. The patient was administered palliative chemotherapy. PMID- 29526965 TI - Spontaneous Mesenteric-gonadal Shunt in a Patient without Cirrhosis. PMID- 29526966 TI - Effects of Systematic Intervention for Chronic Obstructive Pulmonary Disease on Follow-up and Smoking Cessation Rates and Changes of the Pulmonary Function: A 7 year Longitudinal Study in a Japanese Rural City. AB - Objective The early detection and treatment of chronic obstructive pulmonary disease (COPD) requires comprehensive follow-up over a long period. The aim of this study was to determine the effects of a comprehensive long-term intervention system developed by the COPD Task Force for a rural city in Japan during a 7-year period. Methods This prospective, community-based longitudinal study encompassed 2006-2013 in Matsuura City, Japan. Primary and secondary screenings were performed for the early diagnosis and treatment of COPD. Individuals diagnosed with COPD were managed by the COPD Task Force's comprehensive early intervention system. The outcomes of interest were the rate of continuous follow-up after the diagnosis of COPD, the smoking cessation rate, and changes in the pulmonary function during a 7-year period. Subjects The study included 8,878 residents of 50-89 years of age who resided in Matsuura in 2006. Results In total, 140 participants received definitive diagnoses of COPD in 2006. After 7 years of intervention, 34 patients withdrew; 78 (74%) patients continued with treatment in our intervention system. The rate of smoking cessation was significantly increased in the intervention group (from 30% to 68%; p<0.01) over the 7-year period. The change in forced expiratory volume in 1 second (FEV1) was -23.2 mL/year. Conclusion Our systematic longitudinal intervention system during a 7 year period led to high rates of follow-up and smoking cessation. Furthermore, our system may be able to prevent the decline of FEV1 in COPD patients. This intervention system may be effective in rural cities with few respiratory physicians. PMID- 29526967 TI - A Cluster Analysis of Bronchial Asthma Patients with Depressive Symptoms. AB - Objective Whether or not depression affects the control or severity of asthma is unclear. We performed a cluster analysis of asthma patients with depressive symptoms to clarify their characteristics. Methods Multiple medical institutions in Niigata Prefecture, Japan, were surveyed in 2014. We recorded the age, disease duration, body mass index (BMI), medications, and surveyed asthma control status and severity, as well as depressive symptoms and adherence to treatment using questionnaires. A hierarchical cluster analysis was performed on the group of patients assessed as having depression. Results Of 2,273 patients, 128 were assessed as being positive for depressive symptoms [DS(+)]. Thirty-three were excluded because of missing data, and the remaining 95 DS[+] patients were classified into 3 clusters (A, B, and C). The patients in cluster A (n=19) were elderly, had severe, poorly controlled asthma, and demonstrated possible adherence barriers; those in cluster B (n=26) were elderly with a low BMI and had no significant adherence barriers but had severe, poorly controlled asthma; and those in cluster C (n=50) were younger, with a high BMI, no significant adherence barriers, well-controlled asthma, and few were severely affected. The scores for depressive symptoms were not significantly different between clusters. Conclusion About half of the patients in the DS[+] group had severe, poorly controlled asthma, and these clusters were able to be distinguished by their Adherence Starts with Knowledge (ASK)-12 score, which reflects adherence barriers. The control status and severity of asthma may also be related to the age, disease duration, and BMI in the DS[+] group. PMID- 29526969 TI - Reversible Restrictive Lung Disease in Pseudomesotheliomatous Carcinoma in a Lung Harboring a HER2-mutation. AB - Pseudomesotheliomatous carcinoma of the lung is very rare, and reversible restrictive lung disease with pseudomesotheliomatous carcinoma has not yet been previously reported. We herein report a patient with HER2-positive non-small-cell lung cancer (NSCLC) showing pseudomesotheliomatous carcinoma who was successfully treated with bevacizumab combination chemotherapy. A 56-year-old Japanese woman with advanced NSCLC presented with dyspnea. We administered chemotherapy with cisplatin (75 mg/m2) plus pemetrexed (500 mg/m2) plus bevacizumab (15 mg/kg), followed by pemetrexed plus bevacizumab. After eight cycles of maintenance chemotherapy, chest CT demonstrated a marked tumor reduction and an improvement of the right lung volume. The vital capacity was thereafter found to have significantly increased according to pulmonary function tests. PMID- 29526968 TI - Advanced Lung Adenocarcinoma with Nivolumab-associated Dermatomyositis. AB - We herein report a 42-year-old man with advanced lung adenocarcinoma and nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is classified as an immune checkpoint inhibitor, often induces immune-related adverse events (irAEs). However, there have so far been no reports regarding nivolumab-associated dermatomyositis. This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration. It is important to consider drug associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment. PMID- 29526970 TI - Relationship between Impairment of the Vascular Endothelial Function and the CHA2DS2-VASc Score in Patients with Sinus Rhythm and Non-valvular Atrial Fibrillation. AB - Objective and methods There is little information concerning the influence of the heart rhythm on the vascular endothelial function in patients with non-valvular atrial fibrillation (AF) compared with studies concerning sinus rhythm (SR). The present study included paroxysmal (n=184) or chronic (n=53) AF patients without heart failure and control subjects with SR (n=79) matched for age, gender and the CHA2DS2-VASc score. Paroxysmal AF was defined as episodes that terminated spontaneously within 7 days, while chronic AF was defined as longstanding AF that was refractory to cardioversion for 12 months or longer. There were no significant differences in the numbers of patients receiving renin-angiotension aldosterone system inhibitors or statins among the three groups. Results Among the 237 AF patients (155 men, mean age 64+/-9 years, mean CHA2DS2-VASc score 1.8+/-1.4), the flow-mediated dilatation (FMD) was 5.4%+/-2.6% in the paroxysmal AF group, 4.3%+/-2.1% in the chronic AF group and 6.5%+/-3.5% in the SR group. There were significant differences among the 3 groups (all, p<0.05). Nitroglycerin-induced dilatation (NMD) was noted in 14.6%+/-6.5% of the paroxysmal AF group, 16.5%+/-9.1% of the chronic AF group and 12.7%+/-5.9% of the SR group, with no significant differences among the 3 groups. There was a significant negative correlation between the CHA2DS2-VASc scores and the FMDs value in all 3 groups (paroxysmal AF group:r=-0.322, p<0.01; chronic AF group:r= 0.291, p<0.05; SR group:r=-0.326, p<0.01). Conclusion In comparison with SR, the frequency and duration of AF episodes appear to cause deterioration of the vascular endothelial function. PMID- 29526971 TI - Risk of Heparin-induced Immediate-type Hypersensitivity during Arteriovenous Fistula Placement. AB - Heparin is commonly used to prevent clotting; however, severe hypersensitivity reactions during vascular access (VA) placement are rarely but occasionally reported. A 49-year-old man experienced a heparin-induced hypersensitivity reaction during VA placement. Severe side effects may occur even while placing the VA; therefore, we reconsidered the routine use of heparin, as the side effects are unpredictable. Physicians should be aware of the risk of heparin induced hypersensitivity and be ready to effectively manage it during VA placement. PMID- 29526972 TI - [Work accommodation at the time of Return-to-Work for workers on sick leave: a qualitative systematic review with recommendations for Return-to-work Guidance 2017]. AB - OBJECTIVE: We conducted a systematic review to determine whether work accommodation at the time of return-to-work (RTW) following a period of sick leave would improve work-related outcomes. Using a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, we developed recommendations applicable to the field of occupational health in Japan. METHOD: We approached our review question for "Evidence-based Return-to-work Guidance in Occupational Health 2017 (RTW 2017) " using a PICO framework (P: workers on sick leave; I: work accommodation; C: usual care; O: improvement of work-related outcomes, such as shortened sick leave period or lower rate of sick leave recurrence). To identify relevant intervention studies about work accommodation at the time of RTW, for example, modified work or partial RTW, we searched Cochrane Library, PubMed, and ICHUSHI Web using keywords/phrases such as workplace accommodation, partial RTW, rehabilitation, and modified work. Although we found no systematic reviews, we did identify 632 randomized controlled trials and cohort studies. Two researchers screened them independently using selection and exclusion criteria defined by the RTW guidance committee in the scope. For intervention studies, we extracted PICO and evaluated risk of bias using RevMan 5.3. For cohort studies, we applied the Newcastle-Ottawa scale for evaluation of risk of bias. We then evaluated the body of evidence based on risk of bias, indirectness, inconsistency, imprecision, and publication bias using GRADEPro GDT. Finally, we adopted Evidence to Decision from GRADE and developed recommendations based on anonymous panels' votes. RESULT: We identified three relevant studies, which were one randomized controlled trial and two cohort studies, on Partial RTW or modified work for musculoskeletal disorders. Although we could not conduct a meta-analysis, our qualitative systematic review of these studies led us to conclude that partial RTW could shorten the period of sick leave and modified work could lower the recurrence rates of sick leave. Therefore, "Work accommodation at the time of RTW could be provided for workers on sick leave for musculoskeletal disorders" was weakly recommended on the basis of low evidence. CONCLUSIONS: Our recommendation, though plausible, is weak, as it is based on evidence from a small number of studies of foreign occupational health systems. Development of robust recommendations will require accumulation of additional information on diverse factors, such as cost-effectiveness, and on other diseases, for example, mental health disorders or malignant diseases, in Japan. PMID- 29526975 TI - [Cutting edge of medical therapy to inflammatory bowel disease]. PMID- 29526973 TI - Kinetics of transmitter release at the calyx of Held synapse. AB - Synaptic contacts mediate information transfer between neurons. The calyx of Held, a large synapse in the mammalian auditory brainstem, has been used as a model system for the mechanism of transmitter release from the presynaptic terminal for the last 20 years. By applying simultaneous recordings from pre- and postsynaptic compartments, the calcium-dependence of the kinetics of transmitter release has been quantified. A single pool of readily releasable vesicles cannot explain the time course of release during repetitive activity. Rather, multiple pools of vesicles have to be postulated that are replenished with distinct kinetics after depletion. The physical identity of vesicle replenishment has been unknown. Recently, it has become possible to apply total internal reflection fluorescent microscopy to the calyx terminal. This technique allowed the visualization of the dynamics of individual synaptic vesicles. Rather than recruitment of vesicles to the transmitter release sites, priming of tethered vesicles in the total internal reflection fluorescent field limited the number of readily releasable vesicles during sustained activity. PMID- 29526976 TI - [Recent advances in the research of pathophysiology in inflammatory bowel disease and future perspectives]. PMID- 29526974 TI - Adjuvant immunotherapy for cancer: both dendritic cell-priming and check-point inhibitor blockade are required for immunotherapy. AB - The immune system eliminates advanced cancer when treated with programmed cell death protein-1 (PD-1) or its ligand (PD-L1) blockade, but PD-1 therapy is effective in only ~20% of patients with solid cancer. The PD-1 antibody mainly acts on the effector phase of cytotoxic T lymphocytes (CTLs) in tumors but induces no activation of the priming phase of antigen-presenting dendritic cells (DCs). It is reasonable that both DC-priming and PD-1/L1 blocking are mandatory for efficient CTL-mediated tumor cytolysis. For DC-priming, a therapeutic vaccine containing Toll-like receptor (TLR) agonists, namely a priming adjuvant, is a good candidate; however, a means for DC-targeting by TLR adjuvant therapy remains to be developed. TLR adjuvants usually harbor cytokine toxicity, which is a substantial barrier against drug approval. Here, we discuss the functional properties of current TLR adjuvants for cancer immunotherapy and introduce a TLR3 specific adjuvant (ARNAX) that barely induces cytokinemia in mouse models. PMID- 29526977 TI - [Endoscopic and imaging diagnosis and assessment of inflammatory bowel disease]. PMID- 29526978 TI - [Usefulness of biomarkers for disease activity and mucosal healing in patients with inflammatory bowel disease]. PMID- 29526979 TI - [Treatment strategy for inflammatory bowel disease with a focus on biologicals]. PMID- 29526980 TI - [Gastric type adenoma with submucosal invasive carcinoma:a case study]. AB - A 75-year-old woman visited our hospital for the examination of esophagogastroduodenoscopy (EGD) without any major complaint. The patient's medical history included hypertension, but no carcinoma. EGD revealed a 30-mm elevated lesion located in the anterior wall of the upper region of the stomach. The lesion, which was a 0-IIa+I type lesion with fading-like and light flare-like domains, was surgically removed using endoscopic submucosal dissection (ESD) and then the patient was diagnosed with gastric type adenoma with submucosal invasive carcinoma. To the best of our knowledge, this is the first report of a gastric type adenoma with submucosal invasive carcinoma and may therefore provide significant insights into the malignant potential of gastric type adenoma lesions. PMID- 29526981 TI - [Dihydropyrimidine dehydrogenase deficiency causes severe adverse effects of capecitabine]. AB - We report the case of a 61-year-old man who experienced severe adverse effects of capecitabine because of dihydropyrimidine dehydrogenase (DPD) deficiency. In 2016, he visited our hospital for adenocarcinoma of the gastroesophageal junction and was prescribed neoadjuvant chemotherapy with capecitabine, cisplatin, and trastuzumab. On day 14 of chemotherapy, he developed severe diarrhea, canker sores, enterocolitis, febrile neutropenia, and thrombocytopenia. He was then urgently hospitalized, and anticancer treatment was stopped. We administered antibiotics and G-CSF, and he gradually recovered. However, he complained of severe bloody stools due to hemorrhagic enteritis;hence, we performed a bowel resection. The level of DPD protein, which metabolizes 5-fluorouracil (FU), was very low (2.83U/mg). Therefore, he was diagnosed with DPD deficiency, based on DPD protein or urinary pyrimidine levels, which caused serious adverse effects of capecitabine. It is a rare condition, and 5-FU administration should be avoided in DPD deficiency cases. PMID- 29526982 TI - [Rhabdomyolysis associated with long-term treatment of esomeprazole]. AB - Proton pump inhibitors (PPIs) have been widely used in the treatment of gastroesophageal reflux disease and peptic ulcer disease. Although they have a potent acid suppressive effect and excellent efficacy in acid-related diseases, PPI-induced rhabdomyolysis has been reported. Here, we report the case of a patient with reflux esophagitis who developed rhabdomyolysis after esomeprazole treatment. A 67-year-old man with reflux esophagitis who had started esomeprazole treatment for the preceding 10 months complained of back and limb fatigue and myalgia. His serum creatinine kinase (CK) level was markedly elevated, and CK isozyme exhibited an MM pattern. He was diagnosed with rhabdomyolysis induced by esomeprazole. The cessation of esomeprazole rapidly improved his symptoms, and the serum CK level was normalized within 16 days. PPI-induced rhabdomyolysis is a rare complication. In most cases, PPI-induced rhabdomyolysis occurs within 3 months after starting PPIs. However, rhabdomyolysis occurred at 10 months after starting esomeprazole treatment in our patient. Early diagnosis of PPI-induced rhabdomyolysis is required even in long-term PPI users. PMID- 29526983 TI - [Case of main duct-intraductal papillary mucinous carcinoma (pancreatobiliary type) causing 4-mm dilatation of the pancreatic duct]. AB - A 77-year-old woman with mild dilatation (4mm) of the main pancreatic duct was referred to our hospital. Contrast-enhanced computed tomography revealed segmental dilatation of the main pancreatic duct in the pancreatic tail, but no mass was noted in the pancreas. Endoscopic ultrasonography showed low papillary lesions in the dilated pancreatic duct. Cytological analysis of the pancreatic juice revealed adenocarcinoma. Distal pancreatectomy was performed for a diagnosis of main duct-intraductal papillary mucinous cancer (MD-IPMC) of the pancreatic tail. Histological findings indicated pancreatobiliary (PB)-type non invasive IPMC. Although the patient did not meet the diagnostic criteria for intraductal papillary mucinous neoplasms (IPMNs), her final diagnosis was PB-type non-invasive IPMC. Because PB-type IPMNs display poor mucin production, pancreatic duct dilatation is sometimes mild and requires careful assessment for accurate diagnosis. PMID- 29526984 TI - Nationwide Survey of Palliative Care for Patients With Heart Failure in Japan. AB - BACKGROUND: Palliative care for heart failure (HF) patients is recommended in Western guidelines, so this study aimed to clarify the current status of palliative care for HF patients in Japan.Methods and Results:A survey was sent to all Japanese Circulation Society-authorized cardiology training hospitals (n=1,004) in August 2016. A total of 544 institutions (54%) returned the questionnaire. Of them, 527 (98%) answered that palliative care is necessary for patients with HF. A total of 227 (42%) institutions held a palliative care conference for patients with HF, and 79% of the institutions had <10 cases per year. Drug therapy as palliative care was administered at 403 (76%) institutions; morphine (87%) was most frequently used. Among sedatives, dexmedetomidine (33%) was administered more often than midazolam (29%) or propofol (20%). Regarding the timing of end-of-life care, most institutions (84%) reported having considered palliative care when a patient reached the terminal stage of HF. Most frequently, the reason for the decision at the terminal stage was "difficulty in discontinuing cardiotonics." A major impediment to the delivery of palliative care was "difficulty predicting an accurate prognosis." CONCLUSIONS: This large scale survey showed the characteristics of palliative care for HF in Japan. The present findings may aid in the development of effective end-of-life care systems. PMID- 29526985 TI - Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases. AB - Protein-coding genes account for less than 2% of the whole genome. However, the advances in RNA sequencing and genome-wide analysis have demonstrated that most of the genome is capable of being transcribed. Moreover, recent studies have suggested that long non-coding RNAs (lncRNAs) are critical regulators of gene expression and epigenesis in both physiological and disease states. Several lncRNAs are functionally involved in cardiovascular diseases and may be potential therapeutic targets. Here, we review the current strategies for the discovery of functional lncRNAs and recently discovered lncRNAs in the cardiovascular field, focusing on cardiac development, hypertrophy, heart failure, and atherosclerosis. We also discuss the therapeutic potentials of synthetic RNAs to modulate these lncRNAs and future directions in this research field. PMID- 29526986 TI - Towards Effective Cost-Effectiveness Analysis in Atherosclerotic Cardiovascular Disease Prevention. PMID- 29526987 TI - Obstacles to Optimal Lipid-Lowering Therapy - Any Solution? PMID- 29526988 TI - Rapid Publication and Announcement of the 2018 JCS Meeting Activities. PMID- 29526989 TI - Twelve-year trends of increasing overweight and obesity in patients with diabetes: the Shiga Diabetes Clinical Survey. AB - The prevalence of obesity is increasing globally in patients with diabetes. This study aimed to examine 12-year trends of increasing obesity in Japanese patients with diabetes, and their clinical features. The study used results of the Shiga Diabetes Clinical Survey, which recorded medical performance in diabetic patients in 2000, 2006 and 2012. Data were analyzed from 14,205, 14,407 and 21,449 adult patients in these three years, respectively. Overweight and obesity prevalence and the clinical features of diabetes patients were examined, stratified by body mass index (BMI) and age. The prevalence of overweight (BMI 25-30 kg/m2) and obesity (BMI >=30 kg/m2) were 27.0% and 5.1% in 2000, 28.9% and 7.3% in 2006 and 30.9% and 10.0% in 2012. Glycemic control, blood pressure and serum lipid profile improved over 12 years in all BMI categories. However, glycemic and triglyceride control were insufficient in obese patients aged <65 years (hemoglobin A1c 7.5 +/ 1.4%, triglyceride 197.7 +/- 178.4 mg/dL in 2012). The percentage of patients who used antihypertensive and lipid-lowering drugs increased and patients with higher BMI had increased frequency of using these drugs, both in young and old age groups. Higher BMI was significantly and positively associated with albuminuria. In summary, overweight and obesity have increased in Japanese diabetic patients, particularly for younger generations. Findings suggest that obesity may lead to poorer glycemic control, blood pressure and lipid profiles. Overweight and obesity are important modifiable risk factors for diabetes, suggesting that more active weight-control interventions are warranted. PMID- 29526990 TI - False-positive TSH receptor antibody-a pitfall of third-generation TSH receptor antibody measurements in neonates. AB - Maternal Graves' disease (GD) during pregnancy may influence thyroid function in fetuses. Neonates born to mothers with high serum TSH receptor antibody (TRAb) levels have been reported to develop 'neonatal GD'. Therefore, evaluations of serum thyroid hormone and TRAb levels in neonates upon birth are crucial for a prompt diagnosis. At delivery, we measured TRAb with third-generation TRAb test using an M22 human monoclonal antibody in neonates by collecting umbilical cord blood in a blood collection tube with lithium-heparin, which provides a whole blood/plasma sample. In recent years, we have encountered positive TRAb levels (more than 2.0 IU/L) in nineteen neonates born to mothers with GD whose thyroid hormone levels were almost within the reference range and serum TRAb levels were less than 10 IU/L. All the neonates with positive TRAb levels did not exhibit thyrotoxicosis. However, when we measured TRAb levels with serum sample in six out of the nineteen cases, their serum TRAb levels were all negative, suggesting a discrepancy of TRAb levels between in lithium-heparin plasma from umbilical cord blood and serum. Moreover, this discrepancy was observed in neonates born to euthyroid mothers, adult active GD patients and healthy volunteers. Since lithium heparin plasma from umbilical cord blood is widely used in laboratory tests at delivery, we may encounter 'false-positive' TRAb, which may, in turn, lead to a misdiagnosis of neonatal GD. This is a pitfall of third-generation TRAb measurements in neonates, particularly at delivery, and needs to be considered by obstetricians and neonatologists. PMID- 29526991 TI - Protective effects of astaxanthin on a combination of D-galactose and jet lag induced aging model in mice. AB - Oxidative stress caused free radical and mitochondrial damage plays a critical role in the progression of aging and age-related damage at the cellular and tissue levels. Antioxidant supplementation has received growing attention and the effects of antioxidant on aging are increasingly assessed in both animal and human studies. However, additional and more promising treatments that contribute to the expansion of anti-aging therapies are needed. Astaxanthin, a super antioxidant carotenoid and free radical scavenger, inhibits lipid peroxidation more potently than vitamin E. In the present study, we investigated the preventative effects of astaxanthin on aging using an accelerated aging model: mice chronically treated with a combination of D-galactose and jet lag. After 6 weeks of treatment, astaxanthin administration tended to protect the liver weight loss in aged mice. It is probably by upregulating the mRNA expression of galactose-1-phosphate uridyltransferase, which contribute to the enhancement of D galactose metabolism. Astaxanthin supplementation also improved muscle endurance of aged mice in a swimming test. These results were associated with reduced oxidative stress in serum and increased anti-oxidative enzymes activities and mRNA expression in vivo. Moreover, astaxanthin reversed the dysregulation of aging-related gene expression caused by the combination of D-galactose and jet lag in the liver and kidney of mice. In conclusion, astaxanthin prevents liver weight loss, ameliorates locomotive muscular function, exerts significant anti aging effects by reducing oxidative stress and improving the expression of age related genes in D-galactose and jet lag-induced aging model. PMID- 29526993 TI - [How to Use the Electronic Publishing of Our Journal]. PMID- 29526994 TI - [Notice on the Electronic Journal of JSMP]. PMID- 29526995 TI - [History in Management of Japanese Journal of Medical Physics]. PMID- 29526992 TI - Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan. AB - There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9 1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies. PMID- 29526997 TI - [Obtaining an Impact Factor: Radiological Physics and Technology]. PMID- 29526996 TI - [My Precious Memories in Preparation for RPT]. PMID- 29526998 TI - [Report of the 111th Scientific Meeting of the Japan Society of Medical Physics]. PMID- 29526999 TI - [Report of the 112th Scientific Meeting of the Japan Society of Medical Physics]. PMID- 29527000 TI - [Report of the 113th Scientific Meeting of the Japan Society of Medical Physics]. PMID- 29527001 TI - Looking Back on the 8th Japan-Korea Joint Meeting on Medical Physics. PMID- 29527003 TI - A Case of Carcinoid Syndrome Due to Malignant Metastatic Carcinoid Tumor with Carcinoid Heart Disease Involving Four Cardiac Valves. AB - BACKGROUND Carcinoid tumor, benign, low-grade malignant, and high-grade malignant, can be associated with the release of vasoactive substances that cause symptoms including cutaneous flushing, diarrhea, and bronchospasm. In 50-60% of patients with carcinoid syndrome, the vasoactive substances cause fibrosis of the pulmonary and tricuspid heart valves which lead to regurgitation and right-sided heart failure. The right side of the heart is usually affected because monoamine oxidases in the lungs usually inactivate the vasoactive substances. CASE REPORT A 62-year-old woman presented with a four-month history of diarrhea and abdominal discomfort. The patient had bilateral pelvic masses and elevated serum CA125 and an elevated urinary 5-hydroxyindoleacetic acid (5-HIAA). Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) identified a primary appendiceal carcinoid tumor with bilateral ovarian metastases. Post-operatively, a computed tomography (CT) scan showed cardiomegaly. Transthoracic echocardiography showed morphologic changes that affected all four heart valves, consistent with carcinoid heart disease but without a patent foramen ovale (PFO). The patient was evaluated for valve replacement surgery, but surgery was not performed due to the degree of heart failure. CONCLUSIONS This report describes a rare case of carcinoid heart disease with involvement of all four cardiac valves, but without the presence of a PFO, possibly due to a large amount of vasoactive substances in the patient's circulation, as supported by the patient's elevated urinary 5-HIAA. This rare presentation highlights the importance of early diagnosis and treatment with tumor resection and, if possible, Cardiac valve replacement to prevent irreversible heart failure. PMID- 29527002 TI - Sulforaphane, a Natural Isothiocyanate Compound, Improves Cardiac Function and Remodeling by Inhibiting Oxidative Stress and Inflammation in a Rabbit Model of Chronic Heart Failure. AB - BACKGROUND The aim of this study was to investigate the effects of sulforaphane (SFN), a natural isothiocyanate compound, in a rabbit ascending aortic cerclage model of chronic heart failure (CHF). MATERIAL AND METHODS Thirty New Zealand White rabbits were divided into the sham operation group (n=10), the CHF group (n=10), and the CHF + SFN group (n=10) treated with subcutaneous SFN (0.5 mg/kg) for five days per week for 12 weeks. After 12 weeks, echocardiography and biometric analysis were performed, followed by the examination of the rabbit hearts. Enzyme-linked immunosorbent assay (ELISA) and Western blot were used to detect levels of inflammatory cytokines, superoxide dismutase (SOD), and malondialdehyde (MDA). RESULTS In the CHF group, compared with the sham operation group, there was an increase in the heart weight to body weight ratio (HW/BW), the left ventricular weight to body weight ratio (LVW/BW), the left ventricular end diastolic diameter (LVEDD), the left ventricular end systolic diameter (LVESD), plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels, the cardiac collagen volume fraction (CVF), apoptotic index, expression levels of collagen I, collagen III, tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and malondialdehyde (MDA) in the myocardial tissue, and a decrease in the left ventricular shortening fraction (LVFS) and left ventricular ejection fraction (LVEF), and cardiac superoxide dismutase (SOD) activity. These changes were corrected in the SFN-treated group. CONCLUSIONS In a rabbit model of CHF, treatment with SFN improved cardiac function and remodeling by inhibiting oxidative stress and inflammation. PMID- 29527004 TI - microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer. AB - MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various biological processes including tumorigenesis. Here, we addressed the function of miR-155 using LC-MS/MS-based metabolic profiling of miR 155 deficient breast cancer cells. Our results revealed the loss of miR-155 hampers glucose uptake and glycolysis, via the down-regulation of glucose transporters and metabolic enzymes including HK2, PKM2, and LDHA. We showed this is due to the down-regulation of cMYC, controlled through phosphoinositide-3 kinase regulatory subunit alpha (PIK3R1)-PDK1/AKT-FOXO3a pathway. UTR analysis of the PIK3R1 and FOXO3a indicated miR-155 directly represses these genes. A stable expression of miR-155 in patient-derived cells (PDCs) showed activated glucose metabolism whereas a stable inhibition of miR-155 reduced in vivo tumor growth with retarded glucose metabolism. Furthermore, analysis of 50 triple-negative breast cancer (TNBC) specimens and specific uptake value (SUV) of PET images revealed a positive correlation between miR-155 level and glucose usage in human breast tumors via PIK3R1-PDK/AKT-FOXO3a-cMYC axis. Collectively, these data demonstrate the miR-155 is a key regulator of glucose metabolism in breast cancer. PMID- 29527005 TI - Autoimmunity: Increased PGD2 signalling in lupus pathogenesis. PMID- 29527006 TI - Genome-wide analyses of self-reported empathy: correlations with autism, schizophrenia, and anorexia nervosa. AB - Empathy is the ability to recognize and respond to the emotional states of other individuals. It is an important psychological process that facilitates navigating social interactions and maintaining relationships, which are important for well being. Several psychological studies have identified difficulties in both self report and performance-based measures of empathy in a range of psychiatric conditions. To date, no study has systematically investigated the genetic architecture of empathy using genome-wide association studies (GWAS). Here we report the results of the largest GWAS of empathy to date using a well-validated self-report measure of empathy, the Empathy Quotient (EQ), in 46,861 research participants from 23andMe, Inc. We identify 11 suggestive loci (P < 1 * 10-6), though none were significant at P < 2.5 * 10-8 after correcting for multiple testing. The most significant SNP was identified in the non-stratified analysis (rs4882760; P = 4.29 * 10-8), and is an intronic SNP in TMEM132C. The EQ had a modest but significant narrow-sense heritability (0.11 +/- 0.014; P = 1.7 * 10 14). As predicted, based on earlier work, we confirmed a significant female advantage on the EQ (P < 2 * 10-16, Cohen's d = 0.65). We identified similar SNP heritability and high genetic correlation between the sexes. Also, as predicted, we identified a significant negative genetic correlation between autism and the EQ (rg = -0.27 +/- 0.07, P = 1.63 * 10-4). We also identified a significant positive genetic correlation between the EQ and risk for schizophrenia (rg = 0.19 +/- 0.04; P = 1.36 * 10-5), risk for anorexia nervosa (rg = 0.32 +/- 0.09; P = 6 * 10-4), and extraversion (rg = 0.45 +/- 0.08; 5.7 * 10-8). This is the first GWAS of self-reported empathy. The results suggest that the genetic variations associated with empathy also play a role in psychiatric conditions and psychological traits. PMID- 29527007 TI - Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models. AB - BACKGROUND: Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells. METHODS: We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents. RESULTS: We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo. CONCLUSIONS: These findings may lead to the development of novel therapeutic strategies targeting DGC. PMID- 29527008 TI - Body mass index throughout adulthood, physical activity, and risk of multiple myeloma: a prospective analysis in three large cohorts. AB - BACKGROUND: Obesity is the only known modifiable multiple myeloma (MM) risk factor. However, the influence of obesity in earlier or later adulthood and the role of other energy balance correlates in MM development are unclear. METHODS: We leveraged repeatedly updated data from the Nurses' Health Study, Health Professionals Follow-up Study, and Women's Health Study cohorts to further explore energy balance measures in MM etiology. Exposures derived from questionnaires included young adult body mass index (BMI), cumulative average BMI, BMI change since young adulthood, and cumulative average physical activity and walking. We assessed MM risk related to those variables with Cox proportional hazard models. RESULTS: We observed 575 incident MM cases in over five million person-years of follow-up across the cohorts. In pooled analyses, MM risk increased 17% per 5 kg/m2 increase in cumulative average BMI (95% confidence interval (CI): 1.05, 1.29) and 28% per 5 kg/m2 increase in young adult BMI (CI: 1.12, 1.47); adjustment for BMI change since young adulthood did not affect either association. BMI change since young adulthood and cumulative average physical activity and walking were not significantly associated with MM risk. CONCLUSIONS: These findings suggest that a high BMI in early and later adulthood are risk factors for MM. PMID- 29527009 TI - Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study. AB - BACKGROUND: Advanced biliary tract cancers (BTCs) have a poor prognosis and limited treatment options. This exploratory phase II study aimed to evaluate the activity of the mTOR inhibitor everolimus in advanced BTC and explore prognostic biomarkers. METHODS: Patients with advanced BTCs, who had not received chemotherapy for advanced disease, were enroled to receive everolimus (10 mg daily). The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events. Activation status of the RAS and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways was assessed by DNA sequencing and immunohistochemistry on archival tumour tissue. RESULTS: The study enroled 27 patients and the DCR at 12 weeks was 48%. Median PFS was 5.5 months (95% confidence interval (CI): 2.1-10.0 months) and median OS was 9.5 months (95% CI: 5.5-16.6 months). DCR at 12 weeks was significantly worse for gall bladder carcinoma compared to other anatomical sites, and there was a trend towards a worsened PFS and OS. Treatment was well tolerated. KRAS (12%) and PIK3CA mutations (12%) were uncommon. Immunohistochemical staining for PI3K/AKT/mTOR pathways did not significantly correlate with outcome. CONCLUSION: In unselected patients, everolimus demonstrated clinical activity as first-line monotherapy in advanced BTC. PMID- 29527010 TI - A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours. AB - BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5 fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS: Ninety-two patients received >=1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination. PMID- 29527011 TI - Space flight-associated neuro-ocular syndrome (SANS). AB - Interesting novel and somewhat perplexing physiologic and pathologic neuro-ocular findings have been documented in astronauts during and after long duration space flight (LDSF). These findings collectively have been termed the "space flight associated neuro-ocular syndrome" (SANS). The National Aeronautics and Space Administration (NASA) in the United States has meticulously and prospectively documented the clinical, ultrasound, optical coherence tomography imaging, and radiographic findings of SANS including unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts (i.e., cotton wool spots). NASA and collaborating researchers continue to study SANS in preparation for future manned missions to space, including continued trips to the ISS, a return to the moon, or perhaps new voyages to the asteroid belt, or the planet, Mars. PMID- 29527012 TI - Accuracy of intraocular lens power calculation using three optical biometry measurement devices: the OA-2000, Lenstar-LS900 and IOLMaster-500. AB - PURPOSE: To compare ocular measurements of three optical biometry devices and their application in intraocular lens (IOL) power calculations. METHODS: One hundred and forty eyes which had undergone cataract extraction surgery with preoperative biometry with OA--2000, IOLMaster-500, and Lenstar-LS900 were enrolled. Biometry measurements of the three devices were compared. The deviation of the postoperative refraction from the preoperative refractive target was calculated with different formulas (Barrett Universal II, Hoffer Q, Holladay I, and SRK/T). Errors in the predicted astigmatism using the Barrett toric calculator were calculated for the toric IOLs. Additional 6465 eyes in which the IOLMaster-500 failed to measure axial length (AL) were reviewed. The percentage of successful measurements using the OA-2000 in those eyes was calculated. RESULTS: High agreement was found between the three devices for AL, anterior chamber depth, and average keratometry measurements (interclass correlation confidents: 1.000, 0.970, and 0.998, respectively, P < 0.001). The mean absolute prediction errors were similar using all formulas, ranging from 0.25 to 0.29 D, with no statistical significant difference between the three devices per each formula. The OA-2000 yielded a lower against-the-rule (ATR) centroid error in the predicted astigmatism than the IOLMaster-500 and Lenstar-LS900 (0.06 D +/- 0.59 at 13.4 degrees vs. 0.20 D +/- 0.61 at 14.8 degrees and 0.16 D +/- 0.55 at 21.4 degrees , respectively, P < 0.001, X-axis). Among 301 cases with unsuccessful AL readings using the IOLMaster-500, the OA-2000 had 284 (94.35%) successful measurements. CONCLUSIONS: The OA-2000 measurements showed good agreement with those of the IOLMaster-500 and Lenstar-LS900. Our results may suggest a potential advantage of the OA-2000 device in toric IOLs calculations and AL measurement success rate. PMID- 29527014 TI - Genetic engineering: Expanding the reach of Cas9. PMID- 29527013 TI - Trabeculectomy training in England: are we safe at training? Two year surgical outcomes. AB - OBJECTIVES: To define the safety profile of trainee trabeculectomy surgery in the United Kingdom. Surgical exposure for trainees in England is limited due to service requirements, the European working time directive constraints and increasing sub-specialisation of glaucoma surgery. Limited knowledge exists on the outcomes of supervised glaucoma surgery. The aim is to determine the safety of supervised trabeculectomy surgery performed by trainee ophthalmologists. METHODS: Retrospective case note review of all patients that had trabeculectomy surgery with MMC by consultant and trainee surgeons across multiple UK centres. All eyes have 2-year follow up. Success was determined using WGA guidelines. Two tailed p values were obtained using Fisher's exact test to ascertain statistical significance between groups. MAIN OUTCOME MEASURES: intraocular pressure, visual acuity, success and failure rates. RESULTS: 324 eyes were reviewed. 211 (66.4%) cases were performed by glaucoma consultants, 107(33.6%) by trainee ophthalmologists. The majority of eyes in each group were undergoing surgery for POAG. Post-operative IOP control showed no significant difference between consultant and trainee groups at year 1 and year 2. Success rates showed no significant difference between consultant and trainee cases. Failure rates at year 1 showed a significant difference between the two groups. No significant difference was seen at year 2. The trainee group had significantly more complications, when compared with the consultant group. Snellen visual acuity loss was not statistically significant between the two groups at the 2 year time point. CONCLUSIONS: The outcomes of supervised trainee trabeculectomy compare favourably with consultant cases after 2 year follow up. Trainee cases had higher complication rates than consultant cases. Bleb leaks are a common complication of trainee cases, where closer supervision may be required. There is potential for surgical simulation to help increase the success of such cases. These findings may encourage trainee participation in glaucoma surgery. PMID- 29527015 TI - The Epidemiologic Association Between Obesity and Heart Failure. PMID- 29527016 TI - Studying audience effects in animals: what we can learn from human language research. PMID- 29527018 TI - Quest for Excellence: The Journey Continues. PMID- 29527017 TI - Enhancement of microbial fuel cell performance by introducing a nano-composite cathode catalyst. AB - Iron aminoantipyrine (Fe-AAPyr), graphene nanosheets (GNSs) derived catalysts and their physical mixture Fe-AAPyr-GNS were synthesized and investigated as cathode catalysts for oxygen reduction reaction (ORR) with the activated carbon (AC) as a baseline. Fe-AAPyr catalyst was prepared by Sacrificial Support Method (SSM) with silica as a template and aminoantipyrine (AAPyr) as the organic precursor. 3D-GNS was prepared using modified Hummers method technique. The Oxygen Reduction Reaction (ORR) activity of these catalysts at different loadings was investigated by using rotating ring disk (RRDE) electrode setup in the neutral electrolyte. The performance of the catalysts integrated into air-breathing cathode was also investigated. The co-presence of GNS (2 mg cm-2) and Fe-AAPyr (2 mg cm-2) catalyst within the air-breathing cathode resulted in the higher power generation recorded in MFC of 235 +/- 1 MUW cm-2. Fe-AAPyr catalyst itself showed high performance (217 +/- 1 MUW cm-2), higher compared to GNS (150 +/- 5 MUW cm-2) while AC generated power of roughly 104 MUW cm-2. PMID- 29527020 TI - Recent Advances in Severe Cutaneous Adverse Drug Reaction. PMID- 29527019 TI - Consensus Statement for the Diagnosis and Treatment of Urticaria: A 2017 Update. AB - This article is developed by the Skin Allergy Research Society of India for an updated evidence-based consensus statement for the management of urticaria, with a special reference to the Indian context. This guideline includes updated definition, causes, classification, and management of urticaria. Urticaria has a profound impact on the quality of life and causes immense distress to patients, necessitating effective treatment. One approach to manage urticaria is by identification and elimination of the underlying cause(s) and/or eliciting trigger(s) while the second one is by treatment for providing symptomatic relief. This guideline recommends the use of second-generation nonsedating H1 antihistamines as the first-line treatment. The dose can be increased up to four times to meet the expected results. In case patients still do not respond, appropriate treatment options can be selected depending on the associated medical condition, severity of the symptoms, affordability of the drugs, and accessibility of modern biologics such as omalizumab. PMID- 29527021 TI - Causality or Relatedness Assessment in Adverse Drug Reaction and Its Relevance in Dermatology. AB - Causality assessment essentially means finding a causal association or relationship between a drug and drug reaction. Identifying the culprit drug or drugs can be lifesaving or helpful in preventing the further damage caused by the drug to our body systems. In dermatology practice, when it comes to cutaneous adverse drug reaction, this is much more important and relevant because many aetiologies can produce a similar cutaneous manifestation. There are multiple criteria or algorithms available as of now for establishing a causal relationship in cases of adverse drug reaction (ADR), indicating that none of them is specific or complete. Most of these causality assessment tools (CATs) use four cardinal principles of diagnosis of ADR such as temporal relationship of drug with the drug reaction, biological plausibility of the drug causing a reaction, dechallenge, and rechallenge. The present study reviews some of the established or commonly used CATs and its implications or relevance to dermatology in clinical practice. PMID- 29527022 TI - Acute Generalised Exanthematous Pustulosis: An Update. AB - Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction and is attributed to drugs in more than 90% of cases. It is a rare disease, with an estimated incidence of 1-5 patients per million per year. The clinical manifestations characterised by the rapid development of sterile pustular lesions, fever and leucocytosis. Number of drugs has been reported to be associated with AGEP, most common being the antibiotics. Histopathologically there is intraepidermal pustules and papillary dermal oedema with neutrophilic and eosinophilic infiltrations. Systemic involvement can be present in more severe cases. Early diagnosis with withdrawal of the causative drug is the most important step in the management. Treatment includes supportive care, prevention of antibiotics and use of a potent topical steroid. PMID- 29527023 TI - Drug Reaction with Eosinophilia and Systemic Symptoms: An Update and Review of Recent Literature. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is also known as drug induced hypersensitivity syndrome and by various other names. It is now recognised as one of the severe cutaneous adverse reaction (SCAR) and can be potentially life-threatening. Historically, it was most frequently linked with phenytoin and was initially described as phenytoin hypersensitivity syndrome. However, it was later found to be caused by various other medications. Anticonvulsants and sulfonamides are the most common offender. Characteristically DRESS has a latent period of 2 to 6 weeks. The pathophysiology remains incompletely understood but involves reactivation of viruses and activation of lymphocyte. It is manifested most commonly with a morbilliform cutaneous eruption with fever and lymphadenopathy. The severity of this syndrome is related to the systemic involvement, which can result in multi-organ failure. Most important step in the management of DRESS is early diagnosis and immediate cessation of the suspected offending drug. Patients of DRESS syndrome should be managed in an intensive care set up for appropriate supportive care and infection control. Topical corticosteroids can give symptomatic relief, but systemic therapy with steroid and other immunosuppressant is usually required. PMID- 29527024 TI - Cutaneous Adverse Reactions of Chemotherapy in Cancer Patients: A Clinicoepidemiological Study. AB - Background: The diagnosis of cutaneous adversities in the cancer patient is especially difficult, given the complexity of their illness and combination protocols used for the treatment. The present study was undertaken to know the spectrum of cutaneous adversities in patients undergoing chemotherapy and the drug(s) most commonly associated with it. Materials and Methods: A total of 1000 patients with malignancies under chemotherapy in the oncology ward and outpatient department were screened in this observational study from January 2013 to February 2015. Relevant investigations for diagnosis of malignancies under chemotherapy and dermatological disorders were carried out. Results: Three hundred and eighty-four patients presented with cutaneous adversities of chemotherapy. The most common was anagen effluvium (78.6%), followed by xerosis (4.4%), thrombophlebitis (3.1%), generalised pruritus (2.9%), melanonychia (2.9%), hand-foot syndrome (2.6%), extravasation reactions (1.8%), flagellate dermatosis (1.3%), prurigo nodularis (0.8%), exfoliation (0.5%), ichthyosis (0.5%), papulopustular rash (0.3%), bullous photodermatitis (0.3%), and Sweet's syndrome (0.3%). Chemotherapeutic drugs were mostly given in combinations. Most common drugs to cause anagen effluvium were alkylating agents in combinations, hand-foot syndrome by taxanes (docetaxel), flagellate dermatoses by antitumour antibiotics (bleomycin), and exfoliation by antimetabolites (methotrexate). The limitation of this study was to imply a specific drug as the causation of the cutaneous adversities since the chemotherapy mostly consisted of combination protocols. Therefore, we have tried to associate the drug combination itself. Conclusion: Chemotherapeutic drugs produce a range of cutaneous adversities, certain specific adversities pertaining to drugs, and their combinations have been implicated which should be looked for and managed accordingly. Knowledge of the adverse effects of anticancer drugs will help reduce the psychological trauma and improve the quality of life. PMID- 29527025 TI - Clinical and Histopathological Response to Multidrug Therapy in Paucibacillary Leprosy at the end of 6 Months: A Prospective Observational Study from Eastern India. AB - Background: At present, the WHO recommends fixed duration multidrug therapy (FD MDT) for the treatment of leprosy, in which treatment is provided for a fixed duration regardless of clearance of skin lesions or bacterial status of the patient. There is divided opinion regarding the efficacy of FD-MDT; especially for paucibacillary Hansen's disease, in which treatment is provided for 6 months. In addition, there is a paucity of literature on clinical and histopathological features of treated leprosy. Objectives: The objectives of this study were to prospectively observe the effects of MDT on clinical and histopathological features in paucibacillary leprosy and to assess the efficacy, safety and tolerability of MDT-paucibacillary (PB) regimen. Materials and Methods: A total of 52 new cases of PB leprosy diagnosed by clinicopathological correlation and slit skin smear were administered standard WHO PB-MDT for 6 months. Patients were reviewed at 3rd month and 6th month of therapy and 3 months posttherapy for their clinical and histopathological assessment. Results: Among 52 new cases of PB leprosy 43 patients (mean age 31.74 +/- 12.2 years, m:f 1.53:1) completed the study as per protocol. Fourteen percent patients recovered completely, 76.7% patients had a residual patch at the end. Number of lesions reduced significantly 2nd follow-up onwards while the lesional size showed significant decrease 1st follow-up onward. Nerve palpability also reduced significantly at treatment completion. Histological improvement was appreciable; lymphocytic infiltration reduced significantly 2nd follow-up onward and presence of granuloma 1st FU onward. Only four patients complained of occasional, uneventful epigastric pain during the study. Conclusion: Although the frequency of persistence of lesions after completion of therapy was high, histological evidence of activity was present in a minority (7%). Thus, the standard WHO MDT-PB regimen was found to be effective, safe and well-tolerated. PMID- 29527026 TI - A Comparative Study of Efficacy and Safety of Eberconazole versus Terbinafine in Patients of Tinea Versicolor. AB - Background: Tinea versicolor (TV) is characterised by the appearance of maculosquamous lesions sometimes associated with mild erythema and pruritus in characteristic areas of the body. Eberconazole and terbinafine though drugs of different classes provide both mycological and clinical cure. Aim: This study aims to compare the efficacy and safety of eberconazole versus terbinafine in patients of TV. Materials and Methods: An open-label, randomised, comparative clinical trial was conducted on 60 patients. The patients were randomly divided into two study groups. Group A: Eberconazole 1% cream once daily and Group B: Terbinafine 1% cream once daily for 2 weeks. Efficacy assessment was done by observing signs and symptoms, i.e., Physician assessment 4-point scale, microscopic KOH examination, Wood's lamp examination, global clinical response assessment, and patient's assessment on visual analog scale at the end of 2 weeks and subsequently patients were reassessed at the end of 4 and 8 weeks to check any relapse. Safety assessment was also done. Results: There was a significant improvement in all the parameters in both groups over a period of 2 weeks. Both the treatment groups, i.e., eberconazole and terbinafine were found to be safe and efficacious at the end of 2 weeks, and no statistically significant difference was observed between the two groups regarding complete cure, i.e., mycological and clinical cure (80% vs. 63.33%), respectively. However, early response (at the end of week 1) was observed with eberconazole. No relapse was seen with eberconazole, but one patient had relapse at 8 weeks with terbinafine. Both drugs had similar safety profile. Conclusion: Although both the drugs cured the disease, eberconazole showed better response as clinical cure and mycological cure were observed earlier and no patient relapsed in the follow-up. PMID- 29527027 TI - Palmoplantar Lesions of Lichen Planus. AB - Introduction: Palmoplantar lesions of lichen planus (LP) are uncommon and may not always have classical clinical features of LP. A variety of morphological types has been described in literature. Aim and Objectives: The aim was to study and classify the clinical variants into distinct easily recognisable categories for quick recognition and early treatment initiation. Methods: All patients diagnosed with LP over a period of 5 years were evaluated for palmoplantar lesions in our hospital. The clinical and histopathological features of the palmoplantar lesions were then studied. Results: Out of 424 patients of LP, 55 (12.9%) had palmoplantar lesions. Histopathology was consistent or at least compatible with LP in 44/55 patients. For the purpose of assessment, only patients with histopathology consistent with LP were included (n = 44) in the study. Just over half of the patients were male, with most patients (43.2%) having had LP lesions elsewhere for 6 months before palmoplantar lesions were noticed. Soles were more frequently involved than palms. The sites most often involved were the centre of the palms (45.2%), and the instep of the soles (63.9%). The predominant morphological presentation was psoriasiform (47.7%). One patient had ulcerative lesions of LP on both his soles which is a very rare variant. Notably, nearly half of the patients (20/44) had mucosal (mostly oral) lesions characteristic of LP. This was significant as typical oral lesions of LP help in identifying palmoplantar lesions that do not have classical lichenoid morphology. Conclusion: LP lesions on palms and soles need to be identified keeping a high index of suspicion and differentiated from other papulosquamous conditions so that specific treatment can be initiated early. PMID- 29527028 TI - Adverse Reactions Due to the Bacillus Calmette-Guerin Vaccine: Twenty Tunisian Cases. AB - Background: Bacillus Calmette-Guerin (BCG) vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear. Aims: We aim to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax. Patients and Methods: This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005-2015). Results: Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases. Conclusion: BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency. PMID- 29527029 TI - Omalizumab for Management of Refractory Urticaria: Experience of a Tertiary Care Centre in Eastern India. AB - Aim: To study the effects of omalizumab in chronic spontaneous urticaria in Indian patients. Setting and Design: The study was conducted in a tertiary care centre and it was retrospective and descriptive in nature. Material and Methods: We analysed the data of patients who were administered omalizumab between June 2014 and June 2015 for the management of refractory chronic spontaneous urticaria at our centre. Omalizumab was used in those patients who did not respond to updosing of antihistaminics and cyclosporine. Omalizumab was used in dose of 300 mg per month for 3 doses. Results: Twenty-four patients were administered omalizumab during the study period. Average age of the patients was 36.54 years, female:male ratio was 1.4:1, mean duration of disease was 20.66 months, and autologous serum skin test was positive in 33% of studied individuals. Ninety six percent of cases showed response to treatment in our study. Remission was seen in 25% of patients, 50% showed satisfactory response, and 20.83% showed partial response. Average UAS7 scoring before starting omalizumab in preceding week was 24.4. Average UAS7, 2 weeks after starting omalizumab was 4 in responsive patients. Conclusion: Omalizumab is safe and effective treatment for the management of chronic spontaneous urticaria. It can be used in Indian setting after failure to other third-line therapies such as addition of montelukast and cyclosporine due to high cost of treatment. PMID- 29527030 TI - Aceclofenac-Induced Erythema Annulare Centrifugum. AB - Erythema annulare centrifugum (EAC) is characterised by slowly enlarging annular erythematous lesions and is thought to represent a clinical reaction pattern to infections, medications, and rarely, underlying malignancy. Causative drugs include chloroquine, cimetidine, gold sodium thiomalate, amitriptyline, finasteride, etizolam etc. We present a case of 40-year-old woman who presented to us with a 10 days history of nonpruritic, peripherally growing annular erythematous eruption. She had a history of recent onset of joint pain, for which she was taking aceclofenac 90 mg once a day for 5 days prior to the onset of the rash. This was confirmed on biopsy as EAC. The rash promptly subsided after stopping the drug. We report this case as there was no previous report of aceclofenac induced EAC. PMID- 29527031 TI - Multiple Cutaneous and Uterine Leiomyomatosis with Renal Involvement: Report of a Rare Association. AB - Cutaneous leiomyomas (CLs) are uncommon benign smooth muscle tumours characterised by solitary or multiple painful nodules. Based on origin, three types are recognised, namely piloleiomyoma, dartoic leiomyoma, and angioleiomyoma, with piloleiomyomas being the commonest one. Reed's syndrome also known as multiple cutaneous and uterine leiomyomatosis (MCULs) is characterised by CLs in men and CLs and uterine fibroids in women. Association of Reed's syndrome with renal cell carcinoma is labelled as hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Both MCUL and HLRCC are caused by a heterozygous mutation in the fumarate hydratase gene. Besides renal cell carcinoma, there were extremely rare reports of association of MCUL with benign renal lesions. We report a case of a 55-year-old female with segmental tender papulonodular lesions suggestive of leiomyoma associated with uterine leiomyomas and unilateral renal cyst. The case is reported here for its rarity and uncommon association with asymptomatic benign renal cyst. PMID- 29527032 TI - H Syndrome: A Case Report and Review of Literature. AB - H syndrome is a rare autosomal recessive syndrome characterised by constellation of clinical features and systemic manifestations including cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, hyperglycaemia, low height, and hallux valgus. We report a case of this syndrome with typical clinical findings. We report this case citing the rarity of this uncommon entity. PMID- 29527034 TI - Critical Comment on "Vitamin D Level in Alopecia Areata". PMID- 29527033 TI - Autosomal-Recessive Hyper-IgE Syndrome. AB - The hyper-IgE syndrome (HIES) is a rare group of primary immunodeficiency characterised by recurrent infections, eczema, and elevated serum levels of IgE. Autosomal dominant HIES is caused by mutations in transcription factor - signal transducer and activator of transcription-3. Autosomal-recessive (AR) HIES was described in 2004 due to mutation of tyrosine kinase 2 gene, and subsequently, another mutation in dedicator of cytokinesis 8 gene was discovered in 2009. Although both the forms have many common clinical features, few characteristic findings help in differentiating them. AR-HIES is characterized by recurrent bacterial and viral infections, atopic eczema, and raised serum IgE levels. We report a case of a 4-year-old girl presenting with the features of AR-HIES to highlight the presentation of this rare disease. PMID- 29527035 TI - Authors' Reply to Critical Comment on "Vitamin D Level in Alopecia Areata". PMID- 29527036 TI - Generalised Lichenoid Drug Eruption Accompanied by Hand-foot Syndrome Due to Capecitabine. PMID- 29527037 TI - Serum Omentin-1 in Psoriasis. PMID- 29527038 TI - Utility of a Multispectral Dermatoscope in onychomycosis. PMID- 29527040 TI - MESSAGE FROM THE PRESIDENT. PMID- 29527039 TI - Anti-Programmed Cell Death-1-Induced Plaque and Guttate Psoriasis. PMID- 29527041 TI - MESSAGE FROM THE PRESIDENT ELECT. PMID- 29527042 TI - MESSAGE FROM THE GENERAL SECRETARY. PMID- 29527043 TI - Walk down the memory lane!!! PMID- 29527044 TI - Turning the pages, or why history is important to psychiatry. PMID- 29527045 TI - Reminiscences and reflections on growth of psychiatry in India. AB - The paper is an autobiographical account of growth of Psychiatry in India, during the last six decades. It highlights on the development of treatment modalities in psychiatry especially on psychopharmacological drugs. The establishment of general hospital psychiatry and manpower development in the field of mental health are other areas which are discussed. PMID- 29527046 TI - Kilpauk Mental Hospital: The Bethlem of South Asia - A recall of its history prior to 1970. AB - Period of Custodial Care Only: The magnificent "Institute of Mental Health" has its history almost from 1795 when the East India company appointed Surgeon Valentine Conolly to be in charge of a "House for accommodating persons of unsound mind." After a few transitions, backed by a government order for the construction of a lunatic asylum in a 66 1/2 acre site, the asylum started functioning from 1871. The period of about six decades from its inception could be referred to as "the period of custodial care." However, the quality of care for the general medical problems gradually improved with the creation of separate facilities for some common ailments and also one for seriously ill. Separate wards were also conceptualized for criminal patients and female inmates. Towards Modern Comprehensive Patient Care: Thanks to Government sanctions, the staff strength gradually increased with regularization of bed strength to 1800, and by 1948-1957, the hospital had 14 medical officers and a host of other staff. The period from 1939 to 1948 witnessed the introduction of electroconvulsive therapy and insulin coma therapy including the modified one and also insulin histamine therapy. During the prephenothiazine era, the drugs used were barbiturates, paraldehyde, opiates, and Rauwolfia serpentina, which were discontinued after the use of Chlorpromazine from 1954. Psychosurgery was also undertaken in selected cases from 1948, but the procedure went out of vogue soon due to the quality of outcome being poor and development of complications. Rehabilitation of patients got a fillip with the introduction of occupation therapy in 1949 and industrial therapy center in 1970. Extension of psychiatric services to general hospitals began from 1949. Advances in Academic Spheres And Research Activities: Regular training was imparted to paramedical and undergraduate medical students from 1948. The institute had the privilege of hosting the Annual National Conference of Indian Psychiatric Society - 1957. The institute also spearheaded in several pioneering researches such as insulin coma therapy, syphilis, and Alzheimer's dementia, to name a few. The pivotal role played by the State Psychiatric Institutes in patient care, training, and research, should speak for adequate empowerment of these government institutes. PMID- 29527047 TI - History of psychiatry in Bengal. AB - The history of psychiatry in Bengal mirrors the history of psychiatry in India. With Bengal being an important location for the East India Company, it became the locus for much infrastructure development, including the setting up of lunatic asylums. This article traces the development of psychiatric care in Bengal, from the early time of private asylums exclusively for Europeans, to psychiatric care in the present time. PMID- 29527048 TI - The development of mental hospitals in West Bengal: A brief history and changing trends. AB - The communication between G. S Bose and Sigmund Freud is a well-documented fact, and philosophical blend of rich cultural experiences is unique to modification of traditional psychoanalysis in the context of development of psychiatry in West Bengal. The Calcutta lunatic asylum was established at Bhowanipore, and first general hospital psychiatric unit was formed at R. G. Kar Medical College, Calcutta. Prof. Ajita Chakraborty was a pioneer to describe her struggling days in the early career and shared her views with experiences in her autobiography. The volume and quality of research work, especially in the field of epidemiology led by Dr. D. N. Nandi is worth mentioning. A jail had been converted to mental hospital which is the largest in terms of bed strength (n = 350) at Berhampore, Murshidabad district where Kazi Nazrul Islam and Netaji Subhas Chandra Bose had spent some period as prisoner during British rules. Bankura was the first district in West Bengal to start District Mental Health program. The various nongovernmental organizations are working together in public-private partnership model or indigenous ways in tandem over years for the betterment of mental health services both at institutional and community level. PMID- 29527049 TI - Ranchi Institute of Neuro-Psychiatry and Allied Sciences: A pioneer in the field of psychiatry in India. AB - Ranchi Institute of Neuro-Psychiatry and Allied Sciences (RINPAS; Ranchi Indian Mental Hospital; Ranchi Manasik Aryogyashala) traces its origin from a lunatic asylum for Indian soldiers established at Munghyr in Bihar in 1795 and thus is the first mental hospital in India established by the British purely for Indian patients as well as the second oldest functioning mental hospital in India. The hospital made great strides in improving patients care and using modern methods of assessment and treatment as well as education and research during the tenure of Dr J E Dhunjibhoy the first Indian medical superintendent. As a result the mortality rate was the lowest among the mental hospitals in Indian. There was a shift from custodial care to curative treatment. Since 1930s psychiatric training was given to undergraduate medical students of Patna Medical College and subsequently from Darbhanga and Cuttack. The Institute was affiliated to Universities of London and Edinburgh for Diploma in Psychological Medicine in 1936. The thesis work of the first Indian MD (Psychiatry) was done at this institute. Subsequently many psychiatrists completed their MD (Psychiatry) under the guidance of Dr L.P. Verma at this institute. A number of staff and alumini of the institute held the post of President and office bearers of Indian Psychiatric Society (IPS), starting with Dr J.E. Dhunjibhoy, the first president of the IPS. The Institute declined in the 1980s but after intervention of the Supreme Court it was transformed into an autonomous institute. Under the new dispensation the institution is regaining its vitality. Care and facilities for inpatients has greatly improved. Laboratory and imaging services have been updated. Modern facilities for eye and dental surgery are available. Attendance in outpatient department and especially in satellite clinics is increasing. Postgraduate training in psychiatry, clinical psychology, psychiatric social work and psychiatric nursing has started and research is once again a priority. PMID- 29527050 TI - The fractured history of the mental hospital in Delhi. AB - The history of the mental hospital in Delhi is a fascinating story. Set up in colonial times, the asylum in Delhi seems to reflect the tumultuous and chaotic history of the city itself. It was perhaps established in the early 19th century, and functions till 1857, when it is ransacked in the Mutiny. It is subsequently merged with the asylum at Lahore in 1861, set up again, and incredibly, closed again at the turn of the century. Subject to the whims of administrators and policy makers, the asylum then ceases to exist till the 1960s when a new avatar appears. In it's non continuity is the story of the neglect of mental illness. PMID- 29527051 TI - Psychiatry in Delhi: History and current status. AB - Delhi hasn't always enjoyed the status of the India's capital, but it has always played a pivotal role in the history of India as a gateway city. The same way, it received mental health services much later than the rest part of country, but it has witnessed an evolution from colonial era to the birth of state of art modern psychiatry services. Journey started with the landmark inaugural meeting in Delhi University of few visionaries paving the birth of Indian psychiatry society. Subsequently, it witnessed emergence of general hospital psychiatry units & saw their transformation to apex institutes of teaching and research like AIIMS and others. It saw an exemplary worth replicating transformation of hospital for mental diseases into the state of art neuropsychiatry center, IHBAS. Delhi of today represents a microcosm of psychiatry institutes offering entire range of therapeutic, rehabilitative and academic services with equally important share in policy making at national level. This article traces the trends and developments that happened in mental health services in last six decades. PMID- 29527052 TI - A journey from custodial to community-based care: Psychiatric Centre, Jodhpur. AB - Since 1979, consistent and untiring efforts of Dr. D.R. Purohit, Dr. Mahaveer Chand Jain and Dr. G. D. Koolwal against the odds have brought remarkable changes in the Psychiatric centre, Jodhpur. PMID- 29527053 TI - Golden roots to golden fruits of mental health in Gujarat. AB - Through the behavioral descriptions in age-old texts it is obvious that Mental Health problems exist since the existence of Homo Sapiens and humanity, with ever changing norms, contexts, definitions and hence their management. Gujarat state of India is one of the oldest land plateaus existing. It has been inhabited, ruled and governed by many different people, races, kings; and invaded through its longest sea-coast by Dutch, Portuguese, British. Even after freedom of India in 1947, Gujarat emerged as a separate state in 1960 only. The history of Mental Health, before being a separate state, could be summed up in 2 Mental Hospitals started by British governance and 2 very unique institutions. Post NMHP, there has been a tremendous growth in the sector, supported by many leaders in the governance. This is an attempt to review some documented and some gathered information from dependable sources, from pre-independence colonial era, post independence and post-statehood contemporary period. PMID- 29527054 TI - Historical aspects of the Institute of Psychiatry and Human Behavior, Goa. AB - Organized delivery of mental health services in Goa had its origin during the Portuguese regime. From the inception of a mental asylum in the 1500s, mental health services have come a long way. In post liberation period, after 1961, under the guidance of a WHO Consultant, Dr. Govindaswamy, a new mental hospital was built at Panaji, Goa and it was named as the Abbe de Faria Institute. The Department of Psychiatry in Goa Medical College was established in 1968, and unlike in most parts of the country, where Psychiatry was a part of Medicine; here in Goa, it enjoyed an independent departmental status. With the merger of Department of Psychiatry with the mental hospital, an independent Institute of Psychiatry and Human Behavior emerged in 1980, a status it continues to retain till date. In 2016, the Institute of Psychiatry and Human Behavior has been identified to become a "Centre of Excellence" by the Ministry of Health and Family Welfare, Government of India. PMID- 29527055 TI - Mental Hospitals in India: Reforms for the future. AB - Mental hospitals are an integral part of mental health services in India. It is an interesting story how mental hospitals have responded to the challenges of contemporary period they were built in. It is beyond doubt that it is a progressive journey along with advances in mental health both in India and internationally. As in other countries, mental hospitals in India have responded to the social challenges, disparities, and poor resources of workforce and fiscal investment. Historically, there have been changes and three major reforms are needed, namely attempt to facilitate discharge and placing patients back into the family, introducing teaching and research in mental hospitals, and accountability to civil rights as per the requirements of the National Human Rights Commission. In this review, we explore the brief history of mental hospitals in India and examine the reforms in the clinical, administrative, and psychosocial areas of these hospitals and progress in teaching and research. We finally summarize and conclude the necessity and the relevance of mental hospitals in India akin to modern psychiatric practice. We believe that mental hospitals have an important and perhaps a central role in mental health services in India. Its modernization to address issues of long-term stay, burden on caregivers, stigma, research and teaching including undergraduate and postgraduate training, new curriculum, and training for nonpsychiatric professionals and primary care physicians are necessary components of the role of mental hospitals and responsibilities of both government and nongovernmental sectors. Last but not the least, it is obligatory for mental hospitals to ensure that evidence-based treatments are implemented and that the standard of care and respect of civil and human rights of the patients and families are provided while involving the people's participation in its functioning. PMID- 29527056 TI - The role of work in psychiatry: Historical reflections. AB - Until recently, the role of patient work in the history of psychiatry has been a neglected dimension. Yet, in the psychiatric institutions that emerged across the world from the late eighteenth century onwards, work and work therapy were prominent features, culminating in the rise of a specialist profession affiliated to medicine - occupational therapy. This article explores the changing meanings of work within varied medical, social, and political contexts. PMID- 29527057 TI - Tracing the development of psychosocial rehabilitation from its origin to the current with emphasis on the Indian context. AB - Mental illness and mental health are concepts that have existed from time immemorial. In India, the Atharvaveda and Vedic texts and traditional medical systems such as Siddha, Unani, and Ayurveda have described mental health and disorders, in detail. The advent of the mental hospital brought in the 'chemical revolution' in psychiatric management. The early nineties witnessed the birth of psychiatric rehabilitation in India. These developments saw a shift from a biological to a biopsychosocial model. It embraced the individual, family, community and society into the treatment process. The present rehabilitation process is geared towards providing quality of life, community living, accessible and suitable care. PMID- 29527058 TI - General hospital psychiatry in India: History, scope, and future. AB - Background: General hospital psychiatry units (GHPUs) are the major providers of mental health services in India. Unlike in high-income countries, GHPUs in India are also the main training centers for providing postgraduate training in psychiatry and allied disciplines. Aim: This paper traces the history of the GHPUs in India from beginning to the present. Material and Methods: PubMed, old issues of the Indian Journal of Psychiatry and related sources were searched with key words general hospital and psychiatry both electronically and manually to look for the related literature. Results: The history of the development of GHPUs is discussed under 3 phases: beginning to the preindependence period, independence to the year of the launch of the National Mental Health Programme of India, and afterward. Contributions of the GHPUs towards service development, teaching, research, community awareness and reducing stigma, and their future scope are discussed. Conclusion: GHPUs have been a revolutionary development in India with great contribution in the field of mental heath. PMID- 29527059 TI - History of Child and Adolescent Psychiatry at Central Institute of Psychiatry: Journey of Erna Hoch Centre for Child and Adolescent Psychiatry. AB - Child and adolescent psychiatry has not been considered as an established field until the early 1900s till first such unit was started by Leo Kanner in 1930. In India, the first child guidance clinic was founded in 1938 in Mumbai by Dr. Clifford Manshardt. The child and adolescent Psychiatry unit at Central institute of Psychiatry has been into existence for the last 55 years and since then it has been an integral part of the institute in providing high-quality patient care, promoting substantial growth in research, and imparting education to the post graduate trainees and scholars in the field of child psychiatry. The journey embarked by it has been a phenomenal one and many laurels have already been achieved so far. PMID- 29527060 TI - Syphilis and psychiatry at the Mysore Government Mental Hospital (NIMHANS) in the early 20th century. AB - Prior to the advent of the Wasserman Test as a diagnostic tool for Syphilis, the identification rate for Syphilis at the Mysore Government Mental Hospital in Southern India was 1%. With the introduction of the test, there was a dramatic increase in the diagnosis of Syphilis, with 17% of the patients testing positive. This paper throws light on the early notions of Syphilis and GPI, societal responses to the disease, early misdiagnosis, the advent of the Wasserman test and treatment management as reflected in the records of the early 20th century at the Mysore Government Mental Hospital (currently known as NIMHANS). PMID- 29527061 TI - Global Pharma and Local Science: The Untold Tale of Reserpine. PMID- 29527062 TI - The brief existence of the Indian section of the royal medico-psychological association: A historical note. AB - Specialists in psychiatry, in the Indian sub-continent, were trained in the UK in the early 20th century. Just before Independence, an Indian branch of the Royal Medical Psychological Association was established. Many issues of contemporary concern were discussed, as also plans for the further development of psychiatry in the region. Soon after the Second World War, and the Independence of India, the association was disbanded. However, a large number of psychiatrists from south Asia now live and work in the UK, and the Indian Psychiatric society and the Royal College continue to have close links. PMID- 29527063 TI - Central Institute of Psychiatry: A fictional journey to past in a time machine. AB - A fictional journey was planned and carried out in a time machine, to know and understand the glorious past of Central Institute of Psychiatry (CIP), Ranchi. As Dr. Anand, the protagonist, went through different periods in the history of CIP, he narrated his experiences while meeting different peoples in different clinical settings. In this journey, he met Lt. Col Berkeley-Hill at European Mental Hospital, as it was in the 1930s. He tried to understand the relevance of Professor Mapother's report and its essence in relation to European and Indian psychiatric scenario during inter-war period, the significance of Moore-Taylor's report, and the direction of psychiatric training and teaching during postindependence era under Major RB Davis as the superintendent of Hospital for Mental Diseases (HMD). Here, Dr. Anand met the great rebel poet of Bengal (and the national poet of Bangladesh later), Kazi Nazrul Islam, who was here for a short period, before being shifted to Europe for further treatment. Dr. Anand also met other superintendents/directors of CIP during postindependence period and tried to understand the significance of those periods in the total journey of CIP till today. The journey started in the present and went back in time. Finally, a brief comparative analysis has been made regarding the status of CIP vis-a -vis other important psychiatric institutes/hospitals in the past and present. PMID- 29527064 TI - Population structure of the ash dieback pathogen, Hymenoscyphus fraxineus, in relation to its mode of arrival in the UK. AB - The ash dieback fungus, Hymenoscyphus fraxineus, a destructive, alien pathogen of common ash (Fraxinus excelsior), has spread across Europe over the past 25 years and was first observed in the UK in 2012. To investigate the relationship of the pathogen's population structure to its mode of arrival, isolates were obtained from locations in England and Wales, either where established natural populations of ash had been infected by wind-dispersed ascospores or where the fungus had been introduced on imported planting stock. Population structure was determined by tests for vegetative compatibility (VC), mating type and single-nucleotide polymorphisms (SNPs). VC heterogeneity was high at all locations, with 96% of isolate pairings being incompatible. Frequencies of the MAT1-1-1 and MAT1-2-1 idiomorphs were approximately equal, consistent with H. fraxineus being an obligate outbreeder. Most SNP variation occurred within study location and there was little genetic differentiation between the two types of location in the UK, or between pathogen populations in the UK and continental Europe. There was modest differentiation between UK subpopulations, consistent with genetic variation between source populations in continental Europe. However, there was no evidence of strong founder effects, indicating that numerous individuals of H. fraxineus initiated infection at each location, regardless of the route of pathogen transmission. The ssRNA virus HfMV1 was present at moderate to high frequencies in all UK subpopulations. The results imply that management of an introduced plant pathogen requires action against its spread at the continental level involving coordinated efforts by European countries. PMID- 29527065 TI - Cassava brown streak disease in Rwanda, the associated viruses and disease phenotypes. AB - Cassava brown streak disease (CBSD) was first observed on cassava (Manihot esculenta) in Rwanda in 2009. In 2014 eight major cassava-growing districts in the country were surveyed to determine the distribution and variability of symptom phenotypes associated with CBSD, and the genetic diversity of cassava brown streak viruses. Distribution of the CBSD symptom phenotypes and their combinations varied greatly between districts, cultivars and their associated viruses. The symptoms on leaf alone recorded the highest (32.2%) incidence, followed by roots (25.7%), leaf + stem (20.3%), leaf + root (10.4%), leaf + stem + root (5.2%), stem + root (3.7%), and stem (2.5%) symptoms. Analysis by RT-PCR showed that single infections of Ugandan cassava brown streak virus (UCBSV) were most common (74.2% of total infections) and associated with all the seven phenotypes studied. Single infections of Cassava brown streak virus (CBSV) were predominant (15.3% of total infections) in CBSD-affected plants showing symptoms on stems alone. Mixed infections (CBSV + UCBSV) comprised 10.5% of total infections and predominated in the combinations of leaf + stem + root phenotypes. Phylogenetic analysis and the estimates of evolutionary divergence, using partial sequences (210 nt) of the coat protein gene, revealed that in Rwanda there is one type of CBSV and an indication of diverse UCBSV. This study is the first to report the occurrence and distribution of both CBSV and UCBSV based on molecular techniques in Rwanda. PMID- 29527066 TI - Evaluating the potential of Unmanned Aerial Systems for mapping weeds at field scales: a case study with Alopecurus myosuroides. AB - Mapping weed densities within crops has conventionally been achieved either by detailed ecological monitoring or by field walking, both of which are time consuming and expensive. Recent advances have resulted in increased interest in using Unmanned Aerial Systems (UAS) to map fields, aiming to reduce labour costs and increase the spatial extent of coverage. However, adoption of this technology ideally requires that mapping can be undertaken automatically and without the need for extensive ground-truthing. This approach has not been validated at large scale using UAS-derived imagery in combination with extensive ground-truth data. We tested the capability of UAS for mapping a grass weed, Alopecurus myosuroides, in wheat crops. We addressed two questions: (i) can imagery accurately measure densities of weeds within fields and (ii) can aerial imagery of a field be used to estimate the densities of weeds based on statistical models developed in other locations? We recorded aerial imagery from 26 fields using a UAS. Images were generated using both RGB and Rmod (Rmod 670-750 nm) spectral bands. Ground-truth data on weed densities were collected simultaneously with the aerial imagery. We combined these data to produce statistical models that (i) correlated ground truth weed densities with image intensity and (ii) forecast weed densities in other fields. We show that weed densities correlated with image intensity, particularly Rmod image data. However, results were mixed in terms of out of sample prediction from field-to-field. We highlight the difficulties with transferring models and we discuss the challenges for automated weed mapping using UAS technology. PMID- 29527067 TI - Fully-coupled aeroelastic simulation with fluid compressibility - For application to vocal fold vibration. AB - In this study, a fully-coupled fluid-structure interaction model is developed for studying dynamic interactions between compressible fluid and aeroelastic structures. The technique is built based on the modified Immersed Finite Element Method (mIFEM), a robust numerical technique to simulate fluid-structure interactions that has capabilities to simulate high Reynolds number flows and handles large density disparities between the fluid and the solid. For accurate assessment of this intricate dynamic process between compressible fluid, such as air and aeroelastic structures, we included in the model the fluid compressibility in an isentropic process and a solid contact model. The accuracy of the compressible fluid solver is verified by examining acoustic wave propagations in a closed and an open duct, respectively. The fully-coupled fluid structure interaction model is then used to simulate and analyze vocal folds vibrations using compressible air interacting with vocal folds that are represented as layered viscoelastic structures. Using physiological geometric and parametric setup, we are able to obtain a self-sustained vocal fold vibration with a constant inflow pressure. Parametric studies are also performed to study the effects of lung pressure and vocal fold tissue stiffness in vocal folds vibrations. All the case studies produce expected airflow behavior and a sustained vibration, which provide verification and confidence in our future studies of realistic acoustical studies of the phonation process. PMID- 29527068 TI - SEMIPARAMETRIC EFFICIENT ESTIMATION FOR SHARED-FRAILTY MODELS WITH DOUBLY CENSORED CLUSTERED DATA. AB - In this paper, we investigate frailty models for clustered survival data that are subject to both left- and right-censoring, termed "doubly-censored data". This model extends current survival literature by broadening the application of frailty models from right-censoring to a more complicated situation with additional left censoring. Our approach is motivated by a recent Hepatitis B study where the sample consists of families. We adopt a likelihood approach that aims at the nonparametric maximum likelihood estimators (NPMLE). A new algorithm is proposed, which not only works well for clustered data but also improve over existing algorithm for independent and doubly-censored data, a special case when the frailty variable is a constant equal to one. This special case is well known to be a computational challenge due to the left censoring feature of the data. The new algorithm not only resolves this challenge but also accommodate the additional frailty variable effectively. Asymptotic properties of the NPMLE are established along with semi-parametric efficiency of the NPMLE for the finite dimensional parameters. The consistency of Bootstrap estimators for the standard errors of the NPMLE is also discussed. We conducted some simulations to illustrate the numerical performance and robustness of the proposed algorithm, which is also applied to the Hepatitis B data. PMID- 29527069 TI - Development and validation of the Single Item Trait Empathy Scale (SITES). AB - Empathy involves feeling compassion for others and imagining how they feel. In this article, we develop and validate the Single Item Trait Empathy Scale (SITES), which contains only one item that takes seconds to complete. In seven studies (N=5,724), the SITES was found to be both reliable and valid. It correlated in expected ways with a wide variety of intrapersonal outcomes. For example, it is negatively correlated with narcissism, depression, anxiety, and alexithymia. In contrast, it is positively correlated with other measures of empathy, self-esteem, subjective well-being, and agreeableness. The SITES also correlates with a wide variety of interpersonal outcomes, especially compassion for others and helping others. The SITES is recommended in situations when time or question quantity is constrained. PMID- 29527070 TI - Web of Science use in published research and review papers 1997-2017: a selective, dynamic, cross-domain, content-based analysis. AB - Clarivate Analytics's Web of Science (WoS) is the world's leading scientific citation search and analytical information platform. It is used as both a research tool supporting a broad array of scientific tasks across diverse knowledge domains as well as a dataset for large-scale data-intensive studies. WoS has been used in thousands of published academic studies over the past 20 years. It is also the most enduring commercial legacy of Eugene Garfield. Despite the central position WoS holds in contemporary research, the quantitative impact of WoS has not been previously examined by rigorous scientific studies. To better understand how this key piece of Eugene Garfield's heritage has contributed to science, we investigated the ways in which WoS (and associated products and features) is mentioned in a sample of 19,478 English-language research and review papers published between 1997 and 2017, as indexed in WoS databases. We offered descriptive analyses of the distribution of the papers across countries, institutions and knowledge domains. We also used natural language processingtechniques to identify the verbs and nouns in the abstracts of these papers that are grammatically connected to WoS-related phrases. This is the first study to empirically investigate the documentation of the use of the WoS platform in published academic papers in both scientometric and linguistic terms. PMID- 29527071 TI - Bias against research on gender bias. AB - The bias against women in academia is a documented phenomenon that has had detrimental consequences, not only for women, but also for the quality of science. First, gender bias in academia affects female scientists, resulting in their underrepresentation in academic institutions, particularly in higher ranks. The second type of gender bias in science relates to some findings applying only to male participants, which produces biased knowledge. Here, we identify a third potentially powerful source of gender bias in academia: the bias against research on gender bias. In a bibliometric investigation covering a broad range of social sciences, we analyzed published articles on gender bias and race bias and established that articles on gender bias are funded less often and published in journals with a lower Impact Factor than articles on comparable instances of social discrimination. This result suggests the possibility of an underappreciation of the phenomenon of gender bias and related research within the academic community. Addressing this meta-bias is crucial for the further examination of gender inequality, which severely affects many women across the world. PMID- 29527072 TI - Authorship identification of documents with high content similarity. AB - The goal of our work is inspired by the task of associating segments of text to their real authors. In this work, we focus on analyzing the way humans judge different writing styles. This analysis can help to better understand this process and to thus simulate/ mimic such behavior accordingly. Unlike the majority of the work done in this field (i.e. authorship attribution, plagiarism detection, etc.) which uses content features, we focus only on the stylometric, i.e. content-agnostic, characteristics of authors. Therefore, we conducted two pilot studies to determine, if humans can identify authorship among documents with high content similarity. The first was a quantitative experiment involving crowd-sourcing, while the second was a qualitative one executed by the authors of this paper. Both studies confirmed that this task is quite challenging. To gain a better understanding of how humans tackle such a problem, we conducted an exploratory data analysis on the results of the studies. In the first experiment, we compared the decisions against content features and stylometric features. While in the second, the evaluators described the process and the features on which their judgment was based. The findings of our detailed analysis could (1) help to improve algorithms such as automatic authorship attribution as well as plagiarism detection, (2) assist forensic experts or linguists to create profiles of writers, (3) support intelligence applications to analyze aggressive and threatening messages and (4) help editor conformity by adhering to, for instance, journal specific writing style. PMID- 29527073 TI - Plots for visualizing paper impact and journal impact of single researchers in a single graph. AB - In research evaluation of single researchers, the assessment of paper and journal impact is of interest. High journal impact reflects the ability of researchers to convince strict reviewers, and high paper impact reflects the usefulness of papers for future research. In many bibliometric studies, metrics for journal and paper impact are separately presented. In this paper, we introduce two graph types, which combine both metrics in a single graph. The graphs can be used in research evaluation to visualize the performance of single researchers comprehensively. PMID- 29527074 TI - High research productivity in vertically undifferentiated higher education systems: Who are the top performers? AB - The growing scholarly interest in research top performers comes from the growing policy interest in research top performance itself. A question emerges: what makes someone a top performer? In this paper, the upper 10% of Polish academics in terms of research productivity are studied, and predictors of entering this class are sought. In the science system (and Poland follows global patterns), a small number of scholars produce most of the works and attract huge numbers of citations. Performance determines rewards, and small differences in talent translate into a disproportionate level of success, leading to inequalities in resources, research outcomes, and rewards. Top performers are studied here through a bivariate analysis of their working time distribution and their academic role orientation, as well as through a model approach. Odds ratio estimates with logistic regression of being highly productive Polish academics are presented. Consistently across major clusters of academic disciplines, the tiny minority of 10% of academics produces about half (44.7%) of all Polish publications (48.0% of publications in English and 57.2% of internationally co authored publications). The mean research productivity of top performers across major clusters is on average 7.3 times higher than that of the other academics, and in terms of internationally co-authored publications, 12.07 times higher. High inequality was observed: the average research productivity distribution is highly skewed with a long tail on the right not only for all Polish academics but also for top performers. The class of top performers is as internally stratified as that of their lower-performing colleagues. Separate regression models for all academics, science, technology, engineering and mathematics academics, and social sciences and humanities academics are built based on a large national sample (2525 usable observations), and implications are discussed. PMID- 29527075 TI - Home institution bias in the New England Journal of Medicine? A noninferiority study on citation rates. AB - Recently, in the four top journals of humanities, an institutional bias towards publication of authors from Harvard and Yale was shown. The New England Journal of Medicine (NEJM) is today the highest ranked general medical journal. It is unknown if there exists institutional bias favoring publication of articles originating from Harvard University, since the NEJM is produced by the Massachusetts Medical Society with close connections to the Harvard University. We examined if studies originating from the Harvard University published in the NEJM were noninferior in terms of citation rates compared to articles with an origin outside Harvard University. We evaluated original research articles published in the NEJM in 2000 up until June 2001. A two-sample noninferiority test based on the primary endpoint of citations was performed. Twenty-two studies were affiliated to the Harvard University and 280 studies were not affiliated to the Harvard University. The mean number of citations for Harvard affiliated studies was 625 (95% CI 358-952, median 354) and for non-Harvard affiliated studies 493 (95% CI 421-569, median 303). The mean difference was not statistically different between affiliations, but fulfilled the requirements for noninferiority [132 (95% CI - 138-402, P = 0.343), Delta 200]. In summary, citation rates were comparable between studies origination from the Harvard University compared to non-Harvard Institutions. Based on these results there appears to be low risk of institutional bias in the publishing process of original studies in the NEJM. PMID- 29527076 TI - A Bilingual-Monolingual Comparison of Young Children's Vocabulary Size: Evidence from Comprehension and Production. AB - It is often assumed that young bilinguals are lexically delayed in comparison to monolinguals. A comprehensive comparison of comprehension and production vocabulary in 31 firstborn bilingual and 30 matched monolingual children fails to find empirical foundation for this assumption. Several raters completed Dutch and French adaptations of the MacArthur Communicative Development Inventories for children aged 13 and 20 months. At 13 months, bilinguals understood more words than monolinguals; at 20 months, monolinguals knew more Dutch words than bilinguals (combining comprehension and production). There were no group differences for word production or for Dutch word comprehension. Both groups understood and produced the same number of lexicalized meanings; ratios of word comprehension to word production did not differ; inter-individual variation was similar. This study underscores the importance of conducting bilingual monolingual comparisons with matched groups and suggests that if individual bilingual children appear to be slow in early vocabulary development, reasons other than their bilingualism should be investigated. PMID- 29527077 TI - A Comparison of Content-Balancing Procedures for Estimating Multiple Clinical Domains in Computerized Adaptive Testing: Relative Precision, Validity, and Detection of Persons With Misfitting Responses. AB - This simulation study sought to compare four different computerized adaptive testing (CAT) content balancing procedures designed for use in a multidimensional assessment with respect to measurement precision, symptom severity classification; validity of clinical diagnostic recommendations; and sensitivity to atypical responding. The four content balancing procedures were: (1) no content balancing, (2) Screener-based, (3) Mixed (Screener plus content balancing), and (4) Full content balancing. In Full content balancing and in Mixed content balancing following administration of the screener items, item selection was based on: (1) whether the target number of items for the item's subscale was reached, and (2) the item's information function. Mixed and Full content balancing provided the best representation of items from each of the main IMDS subscales. These procedures also resulted in higher CAT-to-full-scale correlations for the Trauma and Homicidal/Suicidal Thought subscales, and improved detection of atypical responding. PMID- 29527078 TI - The effect of perceived overqualification on job satisfaction and career satisfaction among immigrants: Does host national identity matter? AB - Overqualification is a form of person-job misfit that is common among those who reside in a foreign country. It is associated with poor work-related well-being and can inhibit full adjustment to the host society. The goal of our study is to examine the impact of perceived overqualification on job satisfaction and career satisfaction among immigrants. Furthermore, we investigated immigrants' host national identity as a moderator of the impact of perceived overqualification on job satisfaction and career satisfaction. We analysed longitudinal online survey data from 124 Italian and Spanish immigrants who migrated to Germany between 2000 and 2014. Regression analyses show that perceived overqualification is negatively associated with job satisfaction six months later. Furthermore, host national identity moderates the association between perceived overqualification and job satisfaction: low overqualification is beneficial for job satisfaction whereas high overqualification is a threat for job satisfaction, especially for immigrants who identify strongly with the host society. We do not find corresponding direct and moderating effects on career satisfaction. We conclude that indicators of acculturation, such as host national identity, are worth considering in order to understand the impact of person-job misfit on work related well-being among immigrants. PMID- 29527079 TI - Therapist Behaviors as Predictors of Immediate Homework Engagement in Cognitive Therapy for Depression. AB - Homework assignments are an integral part of cognitive therapy (CT) for depression, though facilitating homework engagement in patients with depression can be a challenge. We sought to examine three classes of therapist behaviors as predictors of homework engagement in early sessions of CT: therapist behaviors related to the review of homework, the assignment of homework, and efforts to help patients overcome obstacles to completing homework. In a sample of 66 depressed outpatients participating in CT, therapist behaviors involved in assigning homework predicted both CT-specific homework engagement and more general homework engagement. Therapist behaviors involved in homework review were not predictive of homework engagement. Our findings are consistent with the possibility that therapists' emphasis of key elements of the homework assignment process enhances patients' engagement in homework in early sessions of CT. PMID- 29527080 TI - Bidirectional Linkages between Emotion Recognition and Problem Behaviors in Elementary School Children. AB - Cross-sectional studies support negative associations between children's skills in recognizing emotional expressions and their problem behaviors. Few studies have examined these associations over time, however, precluding our understanding of the direction of effects. Emotion recognition difficulties may contribute to the development of problem behaviors; additionally, problem behaviors may constrain the development of emotion recognition skill. The present study tested the bidirectional linkages between children's emotion recognition and teacher reported problem behaviors in 1st and 3rd grade. Specifically, emotion recognition, hyperactivity, internalizing behaviors, and externalizing behaviors were assessed in 117 children in 1st grade and in 3rd grade. Results from fully cross-lagged path models revealed divergent developmental patterns: Controlling for concurrent levels of problem behaviors and first-grade receptive language skills, lower emotion recognition in 1st grade significantly predicted greater internalizing behaviors, but not hyperactivity or externalizing behaviors, in 3rd grade. Moreover, greater hyperactivity in 1st grade marginally predicted lower emotion recognition in 3rd grade, but internalizing and externalizing behaviors were not predictive of emotion recognition over time. Together, these findings extend previous research to identify specific developmental pathways, whereby emotion recognition difficulties contribute to the development of internalizing behaviors, and early hyperactivity may contribute to the development of emotion recognition difficulties, thus highlighting the importance of examining these processes and their mutual development over time. PMID- 29527081 TI - Pointing to Visible and Invisible Targets. AB - We investigated how the visibility of targets influenced the type of point used to provide directions. In Study 1, we asked 605 passersby in three localities for directions to well-known local landmarks. When that landmark was in plain view behind the requester, most respondents pointed with their index fingers, and few respondents pointed more than once. In contrast, when the landmark was not in view, respondents pointed initially with their index fingers, but often elaborated with a whole-hand point. In Study 2, we covertly filmed the responses from 157 passersby we approached for directions, capturing both verbal and gestural responses. As in Study 1, few respondents produced more than one gesture when the target was in plain view and initial points were most likely to be index finger points. Thus, in a Western geographical context in which pointing with the index finger is the dominant form of pointing, a slight change in circumstances elicited a preference for pointing with the whole hand when it was the second or third manual gesture in a sequence. PMID- 29527082 TI - Parental Educational Attainment and Offspring Subjective Well-being and Self Beliefs in Older Adulthood. AB - This research examines whether parental educational attainment and subjective childhood socioeconomic status (SES) is associated with adult offspring well being and self-beliefs (broadly defined). Participants from the Health and Retirement Study were included if they completed the leave-behind questionnaire in 2006 or 2008 (N=10,827; Mage=68.38; SD=9.81; range=50-101). Participants reported on their own and both parents educational attainment, subjective childhood financial situation, and financial difficulties in childhood at study entry and on well-being in 2006/2008. Linear regression was used to examine the association between offspring education, parental education, childhood SES and three aspects of well-being and self-beliefs: positive affect (e.g., positive emotions, optimism), negative affect (e.g., loneliness, hostility), and cognitive evaluation (e.g., life satisfaction). Participants with more education reported higher well-being (median beta=.12). Parental educational attainment, subjective childhood SES, and a significant financial event during childhood were associated with more positive affect, less negative affect, and higher life satisfaction (median beta=.05); these associations held controlling for offspring education. The educational and financial environment of childhood may hamper well-being into older adulthood; the offspring's own experiences and achievements do not completely attenuate the association with these aspects of the childhood environment. PMID- 29527083 TI - Links Between Remembered Childhood Emotion Socialization and Adult Adjustment: Similarities and Differences Between European American and African American Women. AB - The purpose of this paper was to examine whether recollections of mothers' emotion socialization practices during childhood are linked to adult emotional well-being as indexed by depression, trait anger, and cardiac vagal tone, and whether these effects vary for African American and European American women. Participants included 251 women (128 European American; 123 African American) who ranged in age from 18 to 44 years (M = 25 years). Multigroup confirmatory factor analyses indicated strong measurement and factor invariance across African American and European American participants. Remembered non-supportive emotion socialization was linked with elevated depressive symptoms for European American women, but not African American women and with elevated trait anger for both groups. Remembered supportive emotion socialization was linked with higher resting vagal tone for both groups. The results provide some support for the view that non-supportive emotion socialization may be more detrimental for European Americans than African Americans. PMID- 29527084 TI - Aggregation in particle rich environments: a textural study of examples from volcanic eruptions, meteorite impacts, and fluidized bed processing. AB - Aggregation is a common process occurring in many diverse particulate gas mixtures (e.g. those derived from explosive volcanic eruptions, meteorite impact events, and fluid bed processing). It results from the collision and sticking of particles suspended in turbulent gas/air. To date, there is no generalized model of the underlying physical processes. Here, we investigate aggregates from 18 natural deposits (16 volcanic deposits and two meteorite impact deposits) as well as aggregates produced experimentally via fluidized bed techniques. All aggregates were analyzed for their size, internal structuring, and constituent particle size distribution. Commonalities and differences between the aggregate types are then used to infer salient features of the aggregation process. Average core to rim ratios of internally structured aggregates (accretionary lapilli) is found to be similar for artificial and volcanic aggregates but up to an order of magnitude different than impact-related aggregates. Rim structures of artificial and volcanic aggregates appear to be physically similar (single, sub-spherical, regularly-shaped rims) whereas impact-related aggregates more often show multiple or irregularly shaped rims. The particle size distributions (PSDs) of all three aggregate types are similar (< 200 MUm). This proves that in all three environments, aggregation occurs under broadly similar conditions despite the significant differences in source conditions (particle volume fraction, particle size distribution, particle composition, temperature), residence times, plume conditions (e.g., humidity and temperature), and dynamics of fallout and deposition. Impact-generated and volcanic aggregates share many similarities, and in some cases may be indistinguishable without their stratigraphic context. PMID- 29527085 TI - The Greatest Right of Them All: The Debate on the Right to Petition in the Netherlands from the Dutch Republic to the Kingdom (c. 1750-1830). AB - Between 1750 and 1830 the Dutch state developed from an oligarchic republic into an enlightened autocratic monarchy via a brief experiment with representative democracy. During this period, there was an ongoing debate about the right to petition. Political actors and opinion-makers addressed the questions to what and to whom this right extended, and what it meant to have such a right. While theorists of the different types of government had sharply contrasting views on the place of the people in the political process, ideas about petitioning, which throughout the period under discussion remained the principal instrument for popular involvement in politics, stayed remarkably stable. Through an investigation of the debate on the right to petition in the crucial transitional phase from the Dutch Republic to the Kingdom of the Netherlands, this article contributes to bridging the divide between petition research of the early modern period and that of the modern era. PMID- 29527086 TI - Adolescent-Peer Relationships, Separation and Detachment from Parents, and Internalizing and Externalizing Behaviors: Linkages and Interactions. AB - Most research exploring the interplay between context and adolescent separation and detachment has focused on the family; in contrast, this investigation directs its attention outside of the family to peers. Utilizing a latent variable approach for modeling interactions and incorporating reports of behavioral adjustment from 14-year-old adolescents (N = 190) and their mothers, we examine how separation and detachment relate to adolescent peer relationships, and whether peer relationships moderate how separation and detachment relate to adolescent internalizing and externalizing behaviors. Positive peer relationships were both associated with lower detachment and sharply attenuated relations between detachment and higher adolescent internalizing and externalizing. Separation from parents was unrelated to peer relationships, and regardless of whether peer relationships were positive, separation was not related to adolescent internalizing and externalizing. We integrate these findings with those from family-focused investigations and discuss their substantive and clinical implications. PMID- 29527088 TI - Changes in Self-Rated Health During the Transition to Retiring Living Among Medicare Managed-Care Recipients. AB - Objectives: Moving into a retirement community may be precipitated by or bring about changes in health status. We hypothesized that moving into a retirement community would be associated with a decline in self-rated health (SRH), but that health-related factors would mitigate this association. Methods: We analyzed data from 58,272 participants in Cohort 3 of the Medicare Health Outcome Survey. Individuals answered questions regarding living status in 2000 and 2002. Those who moved into a retirement community were compared with those who did not. The primary outcome was change in SRH. We created adjusted and unadjusted models. Results: 2,520 (4.4%) individuals moved into retirement communities between 2000 and 2002. There were no substantial differences in the mean change in SRH between those who moved and those who did not. In adjusted and unadjusted models, moving was not significantly associated with changes in SRH. In an analysis stratified by SRH, only those with the best SRH had a significant decline in SRH during the move. Discussion: SRH mainly remained stable for most people regardless of moving into a retirement community. These findings argue against environmental context being a main determinant of self-perceived health status among older adults. PMID- 29527087 TI - The Influences of Described and Experienced Information on Adolescent Risky Decision Making. AB - Adolescents are known to take more risks than adults, which can be harmful to their health and well-being. However, despite age differences in real-world risk taking, laboratory risk-taking paradigms often do not evince these developmental patterns. Recent findings in the literature suggest that this inconsistency may be due in part to differences between how adolescents process information about risk when it is described (e.g., in a description-based classroom intervention) versus when it is experienced (e.g., when a teenager experiences the outcome of a risky choice). The present review considers areas of research that can inform approaches to intervention by deepening our understanding of risk taking in described or experienced contexts. We examine the literature on the description experience gap, which has generally been limited to studies of adult samples, but which highlights differential decision making when risk information is described versus experienced. Informed by this work, we then explore the developmental literature comparing adolescent to adult decision making, and consider whether inconsistencies in age-related findings might be explained by distinguishing between studies in which participants learn about decision outcomes through experience versus description. In light of evidence that studies using experience based tasks more often show age differences in risk taking, we consider the implications of this pattern, and argue that experience-based tasks may be more ecologically valid measures of adolescent risky decision making, in part due to the heightened affective nature of these tasks. Finally, we propose a model to integrate our findings with theories of adolescent risk-taking, and discuss implications for risk-reduction messaging. PMID- 29527089 TI - Using Infrared Thermography to Assess Emotional Responses to Infants. AB - Adult-infant interactions operate simultaneously across multiple domains and at multiple levels - from physiology to behavior. Unpackaging and understanding them, therefore, involves analysis of multiple data streams. In this study, we tested physiological responses and cognitive preferences for infant and adult faces in adult females and males. Infrared thermography was used to assess facial temperature changes as a measure of emotional valence, and we used a behavioral rating system to assess adults' expressed preferences. We found greater physiological activation in response to infant stimuli in females than males. As for cognitive preferences, we found greater responses to adult stimuli than to infant stimuli, both in males and females. The results are discuss in light of the Life History Theory. Finally, we discuss the importance of integrating the two data streams on our conclusions. PMID- 29527090 TI - Sexualizing Media Use and Self-Objectification: A Meta-Analysis. AB - Objectification theorists suggest that exposure to sexualizing media increases self-objectification among individuals. Correlational and experimental research examining this relation has received growing attention. The aim of this meta analysis was to investigate the influence of sexualizing media use on self objectification among women and men. For this purpose, we analyzed 54 papers yielding 50 independent studies and 261 effect sizes. The data revealed a positive, moderate effect of sexualizing media on self-objectification (r = .19). The effect was significant and robust, 95% CI [.15, .23], p < .0001. We identified a conditional effect of media type, suggesting that the use of video games and/or online media led to stronger self-objectification effects when compared to television use. Other sample characteristics or study characteristics did not moderate the overall effect. Thus, our findings highlight the importance of sexualizing media exposure on women's and men's objectified self-concept. We discuss future research directions and implications for practice. We hope that the article will stimulate researchers in their future work to address the research gaps outlined here. Moreover, we hope that the findings will encourage practitioners and parents to reflect on the role of the use of sexualizing media in the development of individuals' self-objectification. Additional online materials for this article are available on PWQ's website at http://journals.sagepub.com/doi/suppl10.1177/0361684317743019. PMID- 29527091 TI - Power generation in microbial fuel cells using platinum group metal-free cathode catalyst: Effect of the catalyst loading on performance and costs. AB - Platinum group metal-free (PGM-free) catalyst with different loadings was investigated in air breathing electrodes microbial fuel cells (MFCs). Firstly, the electrocatalytic activity towards oxygen reduction reaction (ORR) of the catalyst was investigated by rotating ring disk electrode (RRDE) setup with different catalyst loadings. The results showed that higher loading led to an increased in the half wave potential and the limiting current and to a further decrease in the peroxide production. The electrons transferred also slightly increased with the catalyst loading up to the value of ~3.75. This variation probably indicates that the catalyst investigated follow a 2x2e- transfer mechanism. The catalyst was integrated within activated carbon pellet-like air breathing cathode in eight different loadings varying between 0.1 mgcm-2 and 10 mgcm-2. Performance were enhanced gradually with the increase in catalyst content. Power densities varied between 90 +/- 9 MUWcm-2 and 262 +/- 4 MUWcm-2 with catalyst loading of 0.1 mgcm-2 and 10 mgcm-2 respectively. Cost assessments related to the catalyst performance are presented. An increase in catalyst utilization led to an increase in power generated with a substantial increase in the whole costs. Also a decrease in performance due to cathode/catalyst deterioration over time led to a further increase in the costs. PMID- 29527092 TI - LMFAO! Humor as a Response to Fear: Decomposing Fear Control within the Extended Parallel Process Model. AB - This study seeks to analyze fear control responses to the 2012 Tips from Former Smokers campaign using the Extended Parallel Process Model (EPPM). The goal is to examine the occurrence of ancillary fear control responses, like humor. In order to explore individuals' responses in an organic setting, we use Twitter data tweets-collected via the Firehose. Content analysis of relevant fear control tweets (N = 14,281) validated the existence of boomerang responses within the EPPM: denial, defensive avoidance, and reactance. More importantly, results showed that humor tweets were not only a significant occurrence but constituted the majority of fear control responses. PMID- 29527093 TI - Team Creative Environment as a Mediator Between CWX and R&D Team Performance and Moderating Boundary Conditions. AB - Purpose: The purpose of this study was to investigate how high-quality dyadic co worker relationships (CWXs) favour or hinder team performance. Specifically, we examine the role played by CWX, team creative environment, job complexity and task interdependence to achieve higher levels of team performance. Design/Methodology/Approach: We analyse data from 410 individuals belonging to 81 R&D teams in technology sciences to examine the quality of the dyadic relationships between team members under the same supervisor (co-workers) and team performance measured by the number of publications as their research output. Findings: Higher levels of team average CWX relationships are positively related to the establishment of a favourable creative team environment, ending into higher levels of team performance. Specifically, the role played by team average CWX in such relationship is stronger when job complexity and task interdependence are also high. Implications: Team's output not only depends on the leader and his/her relationships with subordinates but also on quality relationships among team members. CWXs contribute to creative team environments, but they are essential where jobs are complex and tasks are highly dependent. Originality/Value: This study provides evidence of the important role played by CWXs in determining a creative environment, irrespective of their leaders. Previous research has provided information about how leader's role affects team outcomes, but the role of dyadic co-worker relationships in a team remains still relatively unknown. Considering job complexity and task interdependence variables, the study provides with a better understanding about how and when high quality CWXs should be promoted to achieve higher team performance. PMID- 29527094 TI - A DISCRETE-EVENT SIMULATION APPROACH TO IDENTIFY RULES THAT GOVERN ARBOR REMODELING FOR BRANCHING CUTANEOUS AFFERENTS IN HAIRY SKIN. AB - In mammals, touch is encoded by sensory receptors embedded in the skin. For one class of receptors in the mouse, the architecture of its Merkel cells, unmyelinated neurites, and heminodes follow particular renewal and remodeling trends over hair cycle stages from ages 4 to 10 weeks. As it is currently impossible to observe such trends across a single animal's hair cycle, this work employs discrete event simulation to identify and evaluate policies of Merkel cell and heminode dynamics. Well matching the observed data, the results show that the baseline model replicates dynamic remodeling behaviors between stages of the hair cycle - based on particular addition and removal polices and estimated probabilities tied to constituent parts of Merkel cells, terminal branch neurites and heminodes. The analysis shows further that certain policies hold greater influence than others. This use of computation is a novel approach to understanding neuronal development. PMID- 29527095 TI - Aphids Playing Possum - Defensive or Mutualistic Response? AB - Paper presents the phenomenon of thanatosis or death-feigning in selected aphids species. This specific reaction was predominantly analysed on the example of aphid subfamily Lachninae. Individuals of this group were used in experiments, during which a thanatotic response was induced with various results. The response differed from prolonged thanatosis, lasting for several minutes (Eulachnus rileyi), through shrinking behaviour (e. g. in Stomaphis graffii) to non responsive species such as Cinara (Schizolachnus) pineti. The large interspecies variation of observed responses can be linked to other defensive mechanisms existing in the studied species, as well as to their mutualistic relationship with ants. The behaviour of shrinking is hypothesized to be the mutualistic response, developed from thanatosis, and being adapted to transportation by ant workers. PMID- 29527096 TI - Evaluation of the Ozone Fields in NASA's MERRA-2 Reanalysis. AB - We describe and assess the quality of the assimilated ozone product from the Modern-Era Retrospective Analysis for Research and Applications, Version 2 (MERRA 2) produced at NASA's Global Modeling and Assimilation Office (GMAO) spanning the time period from 1980 to present. MERRA-2 assimilates partial column ozone retrievals from a series of Solar Backscatter Ultraviolet (SBUV) radiometers on NASA and NOAA spacecraft between January 1980 and September 2004; starting in October 2004 retrieved ozone profiles from the Microwave Limb Sounder (MLS) and total column ozone from the Ozone Monitoring Instrument on NASA's EOS Aura satellite are assimilated. We compare the MERRA-2 ozone with independent satellite and ozonesonde data focusing on the representation of the spatial and temporal variability of stratospheric and upper tropospheric ozone and on implications of the change in the observing system from SBUV to EOS Aura. The comparisons show agreement within 10 % (standard deviation of the difference) between MERRA-2 profiles and independent satellite data in most of the stratosphere. The agreement improves after 2004 when EOS Aura data are assimilated. The standard deviation of the differences between the lower stratospheric and upper tropospheric MERRA-2 ozone and ozonesondes is 11.2 % and 24.5 %, respectively, with correlations of 0.8 and above, indicative of a realistic representation of the near-tropopause ozone variability in MERRA-2. The agreement improves significantly in the EOS Aura period, however MERRA-2 is biased low in the upper troposphere with respect to the ozonesondes. Caution is recommended when using MERRA-2 ozone for decadal changes and trend studies. PMID- 29527097 TI - Clinical and genetic aspects of Mayer-Rokitansky-Kuster-Hauser syndrome. AB - The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome [MIM 277000] is characterised by the absence of a uterus and vagina in otherwise phenotypically normal women with karyotype 46,XX. Clinically, the MRKH can be subdivided into two subtypes: an isolated or type I form can be delineated from a type II form, which is characterised by extragenital malformations. The so-called Mullerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia (MURCS) association can be seen as the most severe phenotypic outcome. The MRKH syndrome affects at least 1 in 4000 to 5000 female new-borns. Although most of the cases are sporadic, familial clustering has also been described, indicating a genetic cause of the disease. However, the mode of inheritance is autosomal-dominant inheritance with reduced penetrance. High-resolution array-CGH and MLPA analysis revealed recurrent aberrations in different chromosomal regions such as TAR susceptibility locus in 1q21.1, chromosomal regions 16p11.2, and 17q12 and 22q11.21 microduplication and deletion regions in patients with MRKH. Sequential analysis of the genes LHX1, TBX6 and RBM8A, which are located in chromosomal regions 17q12, 16p11.2 and 1q21.1, yielded in the detection of MRKH-associated mutations. In a subgroup of patients with signs of hyperandrogenaemia mutations of WNT4 have been found to be causative. Analysis of another member of the WNT family, WNT9B, resulted in the detection of some causative mutations in MRKH patients. PMID- 29527098 TI - Disorders of spermatogenesis: Perspectives for novel genetic diagnostics after 20 years of unchanged routine. AB - Infertility is a common condition estimated to affect 10-15% of couples. The clinical causes are attributed in equal parts to the male and female partners. Diagnosing male infertility mostly relies on semen (and hormone) analysis, which results in classification into the two major phenotypes of oligo- and azoospermia. The clinical routine analyses have not changed over the last 20 years and comprise screening for chromosomal aberrations and Y-chromosomal azoospermia factor deletions. These tests establish a causal genetic diagnosis in about 4% of unselected men in infertile couples and 20% of azoospermic men. Gene sequencing is currently only performed in very rare cases of hypogonadotropic hypogonadism and the CFTR gene is routinely analysed in men with obstructive azoospermia. Still, a large number of genes have been proposed to be associated with male infertility by, for example, knock-out mouse models. In particular, those that are exclusively expressed in the testes are potential candidates for further analyses. However, the genome-wide analyses (a few array-CGH, six GWAS, and some small exome sequencing studies) performed so far have not lead to improved clinical diagnostic testing. In 2017, we started to routinely analyse the three validated male infertility genes: NR5A1, DMRT1, and TEX11. Preliminary analyses demonstrated highly likely pathogenic mutations in these genes as a cause of azoospermia in 4 men, equalling 5% of the 80 patients analysed so far, and increasing the diagnostic yield in this group to 25%. Over the past few years, we have observed a steep increase in publications on novel candidate genes for male infertility, especially in men with azoospermia. In addition, concerted efforts to achieve progress in elucidating genetic causes of male infertility and to introduce novel testing strategies into clinical routine have been made recently. Thus, we are confident that major breakthroughs concerning the genetics of male infertility will be achieved in the near future and will translate into clinical routine to improve patient/couple care. PMID- 29527099 TI - Transition Manifolds of Complex Metastable Systems: Theory and Data-Driven Computation of Effective Dynamics. AB - We consider complex dynamical systems showing metastable behavior, but no local separation of fast and slow time scales. The article raises the question of whether such systems exhibit a low-dimensional manifold supporting its effective dynamics. For answering this question, we aim at finding nonlinear coordinates, called reaction coordinates, such that the projection of the dynamics onto these coordinates preserves the dominant time scales of the dynamics. We show that, based on a specific reducibility property, the existence of good low-dimensional reaction coordinates preserving the dominant time scales is guaranteed. Based on this theoretical framework, we develop and test a novel numerical approach for computing good reaction coordinates. The proposed algorithmic approach is fully local and thus not prone to the curse of dimension with respect to the state space of the dynamics. Hence, it is a promising method for data-based model reduction of complex dynamical systems such as molecular dynamics. PMID- 29527100 TI - Reduced Models for Ferromagnetic Thin Films with Periodic Surface Roughness. AB - We investigate the influence of periodic surface roughness in thin ferromagnetic films on shape anisotropy and magnetization behavior inside the ferromagnet. Starting from the full micromagnetic energy and using methods of homogenization and [Formula: see text]-convergence, we derive a two-dimensional local reduced model. Investigation of this model provides an insight into the formation mechanism of perpendicular magnetic anisotropy and uniaxial anisotropy with an arbitrary preferred direction of magnetization. PMID- 29527102 TI - RSSDI clinical practice recommendations for the management of type 2 diabetes mellitus 2017. PMID- 29527101 TI - [Stem cell-based strategies in vascular surgery]. AB - Critical chronic ischemia in patients with underlying arterial occlusive disease requires vascular reconstructive surgery. The limited supply of suitable small diameter autologous vascular grafts in many patients and obvious disadvantages of synthetic bypass material demand the development of clinically usable tissue engineered blood vessel substitutes. Despite substantial progress in the field over the last two decades, their implementation into the clinical routine has been challenging. The limited replicative life span of human adult vascular cells and their slow rate of collagenous matrix production in vitro have posed important problems in the development of mechanically robust and biologically functional engineered grafts. With recent advances in stem cell research, new cell sources for vascular tissue engineering have become available. In particular, the discovery of human induced pluripotent stem (iPS) cells derived from adult differentiated cells, as well as of human multipotent adult mesenchymal stem cells without gene modification requirements and related safety concerns, may advance the development of novel autologous cell-based tissue engineering approaches. Here we discuss recent developments in the field of vascular progenitor cells and opportunities and challenges for the clinical translation of stem cell-engineered vascular tissue substitutes. PMID- 29527103 TI - Some Wilker and Cusa type inequalities for generalized trigonometric and hyperbolic functions. AB - The authors obtain some Wilker and Cusa type inequalities for generalized trigonometric and hyperbolic functions and generalize some known inequalities. PMID- 29527104 TI - Interior regularity of obstacle problems for nonlinear subelliptic systems with VMO coefficients. AB - This article is concerned with an obstacle problem for nonlinear subelliptic systems of second order with VMO coefficients. It is shown, based on a modification of A-harmonic approximation argument, that the gradient of weak solution to the corresponding obstacle problem belongs to the Morrey space [Formula: see text]. PMID- 29527106 TI - Refining the COPES to Measure Social Climate in Therapeutic Residential Youth Care. AB - Background: Previous studies have shown that social climate in therapeutic residential youth care (TRC) is important to the welfare of residents, staff, and assessing treatment outcomes. The most influential theory on social climate in residential settings is the theory of Moos. The measurement of the concepts and aspects of this theory using the Community Oriented Programs Environment Scale (COPES) has repeatedly been criticized regarding usability, validity, and reliability, especially for TRC. Objective: To improve the usability and psychometric quality of the COPES by shortening and refining the original subscale structure for usage in TRC. Methods: Four-hundred adolescents living in Norwegian TRC participated. We supplemented confirmatory factor analysis (CFA) with item response theory (IRT) to evaluate model fit, investigate factor loadings, and shorten scales to improve their psychometric qualities and usability in describing social climate in TRC. Results: The original subscales were not acceptable as evaluated by the criteria for CFA and IRT. By removing psychometrically weak items, the instrument was shortened to 40 items within the original ten subscales. This short version showed acceptable psychometric qualities based on both CFA and IRT criteria and the instrument retained its content validity. Finally, the original three higher-order dimensions was not supported. Conclusions: Compared to the original instrument, the refined 40-item version of the COPES represents a more usable instrument for measuring social climate in TRC. Future studies are needed to confirm the multifaceted refined short version in comparable samples of youth and staff to further investigate predictive value and construct validity. PMID- 29527105 TI - Emotional Processes in Borderline Personality Disorder: An Update for Clinical Practice. AB - Despite prior assumptions about poor prognosis, the surge in research on borderline personality disorder (BPD) over the past several decades shows that it is treatable and can have a good prognosis. Prominent theories of BPD highlight the importance of emotional dysfunction as core to this disorder. However, recent empirical research suggests a more nuanced view of emotional dysfunction in BPD. This research is reviewed in the present article, with a view towards how these laboratory-based findings can influence clinical work with individuals suffering from BPD. PMID- 29527107 TI - Stability and Change of Adolescents' Aggressive Behavior in Residential Youth Care. AB - Background: Aggression in residential youth care institutions is a frequent problem. Objective: The present short-term longitudinal study examined individual and institutional predictors of aggression in a group of 198 adolescents placed in open, semi-secure and secure residential institutions from the perspective of the importation and deprivation model. Methods: A total of 198 adolescents in residential youth care filled in questionnaires regarding group climate and aggression with a 3 month interval. Hierarchical multiple regression analyses were performed to test the degree to which individual and contextual factors predict aggression. Results: Very limited support was found for the effect of contextual factors; only repression showed a trend, predicting direct aggression, while gender composition of the living groups yielded a small effect. Girls placed in same-gender groups showed lower levels of indirect (relational) aggression compared to adolescents placed in mixed-gender or boys-only groups, even when controlled for gender and initial levels of aggression. Type of institution (i.e., level of security) did not predict differences in aggression. In particular individual characteristics of the adolescents were associated with later aggression, including initial levels of aggression, showing substantial 3 months stability, age and gender of the adolescents. Conclusions: These findings are in line with research showing that aggression is relatively stable. Very limited support for environmental effects was found. PMID- 29527108 TI - Synthesis and antibacterial activities of enamine derivatives of dehydroacetic acid. AB - Dehydroacetic acid is a common pyrone derivative used commercially as an antibacterial and antifungal agent. Based on the synthesis of dehydroacetic acid (1) from N-hydroxysuccinimdyl acetoacetate, a novel series of enamine-based derivatives were synthesised in order to improve the antibacterial activity of dehydroacetic acid. The antibacterial activities of the synthesised analogues were evaluated against Escherichia coli and Staphylococcus aureus. Derivative 4d (N-Ph) was identified as the most potent inhibitor of S. aureus growth. Overall, derivative 4b (N-Me) showed the best broad-spectrum activity with five-fold greater minimum inhibitory concentration and 11-fold greater minimum biocidal concentration against E. coli when compared to dehydroacetic acid, in addition to improved antibacterial activity against S. aureus. PMID- 29527110 TI - Lost and misplaced items and assistive devices in nursing homes: Identifying problems and technological opportunities through participatory design research. AB - INTRODUCTION: Modern healthcare, including nursing home care, goes together with the use of technologies to support treatment, the provision of care and daily activities. The challenges concerning the implementation of such technologies are numerous. One of these emerging technologies are location technologies (RTLS or Real-Time Location Systems). that can be utilized in the nursing home for monitoring the use and location of assets. METHODOLOGY: This paper describes a participatory design study of RTLS based on context mapping, conducted in two nursing home organizations. Rather than investigating the technological possibilities, this study investigates the needs and wishes from the perspective of the care professional. RESULTS: The study identified semantic themes that relate to the practicalities of lost and misplaced items in the nursing home, as well as latent themes that cover the wishes regarding technology in the nursing homes. The organizational culture and building typology may play a role in losing items. CONCLUSION: The participants in this study indicated that RTLS can provide a solution to some of the challenges that they encounter in the workplace. However, the implementation of new technologies should be done with care and should be integrated into existing ICT systems in order to minimize additional training and posing a burden on the workload. PMID- 29527109 TI - An integrative review of information and communication technology based support interventions for carers of home dwelling older people. AB - BACKGROUND: A growing number of studies of informal carers of older people reveal positive results concerning support via Information and Communication Technologies (ICT). Systematic examination of factors that have a potential impact on carer outcomes are needed to inform future research. OBJECTIVE: To explore studies concerning ICT support of adult carers of older people and to identify study characteristics that have a potential impact on carer outcomes. METHODS: This integrative review includes 123 studies published since 2005. Fundamental questions for designing sensitive support interventions; 'who, what, and how' were applied to a synthesis of the results. RESULTS: Identified characteristics from the studies responding to the who question included variables of the carers, such as their relationship with the care recipient or their ethnicity. Characteristics related to the what question related to the types of interventions, and the how question concerned the different services or programs offered, the idiosyncratic needs of the carers, and the types of technologies used. CONCLUSION: Results are discussed according to micro, meso and macro levels of analysis. This extensive review can inform future studies and highlight the evidence in the area for decision makers, practitioners and/or NGOs working with innovative forms of support for carers of older people. PMID- 29527111 TI - Extending Working Life: Which Competencies are Crucial in Near-Retirement Age? AB - Nowadays, one of the most important economic and social phenomena is population ageing. Due to the low activity rate of older people, one of the most important challenges is to take various actions involving active ageing, which is supposed to extending working life, and along with it-improve the competencies of older people. The aim of this paper is to evaluate the relevance of different competencies for extending working life, with limiting the analysis for Poland. The paper also assesses the competencies of mature Polish people (aged 50+, but still in working age). In the statistical analysis, I used logistic regression, as well as descriptive statistics and appropriate statistical tests. The results show that among the actions aimed at extending working life, the most important are those related to lifelong learning, targeted at improving the competencies of the older generation. The competencies (both soft and hard) of people aged 50+ are more important than their formal education. PMID- 29527112 TI - The Academic Achievement of Limited English Proficient (LEP) Youth in New and Established Immigrant States: Lessons from the National Assessment of Educational Progress (NAEP). AB - The dramatic growth and dispersal of immigrant families has changed the face of public education at a time when states are experiencing increased school accountability pressures under the No Child Left Behind (NCLB) and its recent successor the Every Student Succeeds Act. Of particular concern is how these demographic shifts affect the academic well-being of Limited English Proficient (LEP) youth, the protected sub-group that most directly targets children from immigrant families. Using individual-level data from the National Association of Educational Progress, we examine how 8th grade test scores of LEP youth differ across new and established immigrant destination states. Results show that achievement for LEP youth is higher in new than in established immigrant states but that this advantage is not consistent across ethnic/racial groups. LEP youth in new immigrant states benefit from more favorable demographic characteristics and more family and school resources, but these differences only explain a small portion of the achievement gap. PMID- 29527113 TI - The Complex Relationship between Pain Intensity and Physical Functioning in Fibromyalgia: The Mediating Role of Depression. AB - PURPOSE: Fibromyalgia (FM) is typically associated with the experience of diffuse pain and physical impairment. Depression also commonly co-exists in patients with FM, and has been correlated with pain intensity and physical functioning. Previous research suggests an association between pain intensity and physical functioning; however, the direct causal relationship between improvements in pain intensity and in functioning is not observed in many FM patients. This may suggest that another factor such as depression is mediating this relationship. The present work examined mediating role of depression. METHODS: 216 patients with FM completed measures of pain intensity, depression, and physical function as part of a larger longitudinal study. Assessments were completed at baseline, 12, 24, and 36 weeks. RESULTS: Longitudinal mediational analyses indicated that depression is a partial mediator of the relationship between pain intensity and physical functioning at all four assessment points. Beta coefficients for the path from pain to physical functioning ranged from 0.18 - 0.36, with attenuated path coefficients ranging from 0.03 - 0.08, still showing significant but decreased associations when depression was added as a mediator. CONCLUSIONS: Clinical implication includes the importance of treating co-morbid depression in patients with fibromyalgia early in the course of treatment to prevent engagement in the cycle of disability. PMID- 29527114 TI - Examining the Etiology of Reading Disability as Conceptualized by the Hybrid Model. AB - A fairly recent definition of reading disability (RD) is that in the form of a hybrid model. The model views RD as a latent construct that is manifested through various observable unexpected impairments in reading related skills and through inadequate response to intervention. The current report evaluated this new conceptualization of RD from an etiological perspective. The sample consisted of 2737 twin pairs in first through fourth grade (Mage = 8.52) from the Florida Twin Project on Reading. Using twin analyses, results showed that a substantial proportion of genetic variance, a small proportion of shared environmental, and a small proportion of non-shared environmental variance was attributed to the RD factor. Findings suggest that the etiological architecture of RD closely mirrors the structure of the hybrid model of RD. PMID- 29527115 TI - Tacrolimus interacts with voriconazole to reduce the severity of fungal keratitis by suppressing IFN-related inflammatory responses and concomitant FK506 and voriconazole treatment suppresses fungal keratitis. AB - Purpose: To investigate the expression and roles of type I and II interferons (IFNs) in fungal keratitis, as well as the therapeutic effects of tacrolimus (FK506) and voriconazole on this condition. Methods: The mRNA and protein expression levels of type I (IFN-alpha/beta) and II (IFN-gamma) IFNs, as well as of related downstream inflammatory cytokines (interleukin (IL)-1alpha, IL-6, IL 12, and IL-17), were detected in macrophages, neutrophils, lymphocytes, and corneal epithelial cells (A6(1) cells) stimulated with zymosan (10 mg/ml) for 8 or 24 h. A fungal keratitis mouse model was generated through intrastromal injection of Aspergillus fumigatus, and the mice were then divided into four groups: group I, the PBS group; group II, the voriconazole group; group III, the FK506 group; and group IV, the voriconazole plus 0.05% FK506 group. Corneal damage was evaluated with clinical scoring and histological examination. In addition, the mRNA and protein expression levels of type I (IFN-alpha/beta) and type II (IFN-gamma) IFNs, as well as related inflammatory cytokines, were determined at different time points using quantitative real-time PCR (qRT-PCR) and western blotting. Results: After zymosan stimulation of mouse neutrophils, lymphocytes, macrophages, and A6(1) cells, the IFN mRNA and protein expression levels were markedly increased until 24 h, peaking at 8 h (p<0.001). The mRNA and protein expression levels of inflammatory cytokines (IL-1alpha, IL-6, IL-12, and IL-17) were also upregulated after zymosan stimulation. Moreover, type I (IFN alpha/beta) and type II (IFN-gamma) IFN expression levels were increased and positively correlated with the progression of fungal keratitis in vivo. FK506 administered with voriconazole reduced the pathological infiltration of inflammatory cells into the cornea and downregulated the expression levels of IFNs and related inflammatory cytokines. Conclusions: In conclusion, this study demonstrated that type I and II IFN levels were markedly increased in fungal keratitis and that FK506 combined with voriconazole decreased the severity of fungal keratitis by suppressing type I and II IFNs and their related inflammatory responses. PMID- 29527117 TI - Experimental Investigation of Aerodynamics of Feather-Covered Flapping Wing. AB - Avian flight has an outstanding performance than the manmade flapping wing MAVs. Considering that the feather is light and strong, a new type of the flapping wing was designed and made, whose skeleton is carbon fiber rods and covered by goose feathers as the skin. Its aerodynamics is tested by experiments and can be compared with conventional artificial flapping wings made of carbon fiber rods as the skeleton and polyester membrane as the skin. The results showed that the feathered wing could generate more lift than the membrane wing in the same flapping kinematics because the feathered wing can have slots between feathers in an upstroke process, which can mainly reduce the negative lift. At the same time, the power consumption also decreased significantly, due to the decrease in the fluctuating range of the periodic lift curve, which reduced the offset consumption of lift. At the same time, the thrusts generated by the feather wing and the membrane wing are similar with each other, which increases with the increase of flapping frequency. In general, the aerodynamic performances of the feather wing are superior to that of the membrane wings. PMID- 29527116 TI - Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. AB - Purpose: Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Methods: Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Results: Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. Conclusions: The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD. PMID- 29527118 TI - Dexmedetomidine to Help Nerve Regeneration in a Rat Sciatic Nerve Injury Model. AB - Background: Several studies have shown that dexmedetomidine (DXM), a selective alpha2-adrenoceptor agonist, also has neuroprotective effects. However, its effect on impaired peripheral nerve regeneration has not been studied. Materials and Methods: Forty-five Sprague-Dawley rats were randomly assigned to three groups: group 1 (control SHAM), group 2 (sciatic nerve injury + normal saline), and group 3 (sciatic nerve injury + DXM). The rats of group 3 were subdivided into the following three groups: DXM 0.5, 6, and 20 MUg.kg-1 (groups 3A, 3B, and 3C, resp.). The sciatic nerve injury was assessed for nerve regeneration at 2 and 6 weeks. Results: There were no differences between groups 2 and 3 in their sciatic functional index (SFI) values or histological findings at 2 weeks postinjury. However, SFI differences were statistically significant at 6 weeks postinjury in group 3. The gross findings with H&E staining showed that the number of axons was higher in group 3 than in group 2. There was no histological difference according to the DXM concentration. Conclusion: The coincidental functional and histological assessment results of this study suggest that DXM for 6 weeks positively affects damaged peripheral nerves. PMID- 29527119 TI - The importance of long-term experiments in agriculture: their management to ensure continued crop production and soil fertility; the Rothamsted experience. AB - : Long-term field experiments that test a range of treatments and are intended to assess the sustainability of crop production, and thus food security, must be managed actively to identify any treatment that is failing to maintain or increase yields. Once identified, carefully considered changes can be made to the treatment or management, and if they are successful yields will change. If suitable changes cannot be made to an experiment to ensure its continued relevance to sustainable crop production, then it should be stopped. Long-term experiments have many other uses. They provide a field resource and samples for research on plant and soil processes and properties, especially those properties where change occurs slowly and affects soil fertility. Archived samples of all inputs and outputs are an invaluable source of material for future research, and data from current and archived samples can be used to develop models to describe soil and plant processes. Such changes and uses in the Rothamsted experiments are described, and demonstrate that with the appropriate crop, soil and management, acceptable yields can be maintained for many years, with either organic manure or inorganic fertilizers. Highlights: Long-term experiments demonstrate sustainability and increases in crop yield when managed to optimize soil fertility.Shifting individual response curves into coincidence increases understanding of the factors involved.Changes in inorganic and organic pollutants in archived crop and soil samples are related to inputs over time.Models describing soil processes are developed from current and archived soil data. PMID- 29527120 TI - Resisting Urges to Self-Injure. AB - The present study explored whether and how self-injurers attempt to resist urges to harm themselves. Participants were 39 young adults with a history of skin cutting and other non-suicidal self-injurious behaviors. A structured interview assessed the prevalence and perceived helpfulness of 48 methods for resisting self-injurious urges. Ninety percent of participants indicated that they had made efforts to resist urges to self-injure. These individuals had used an average of 16 different methods, and reported that they were successful in resisting the urges most of the time. "Keeping busy" and "Being around friends" were the most common methods used to resist self-injurious urges. However, "Doing sports or exercise" and "Removing the means/instruments typically used to self-harm from the home" were rated as being the most helpful for resisting self-injurious urges. Findings have implications for enhancing treatment and guiding future research. PMID- 29527121 TI - Single-Centre Experience of Systemic Treatment with Vincristine, Ifosfamide, and Doxorubicin Alternating with Etoposide, Ifosfamide, and Cisplatin in Adult Patients with Ewing Sarcoma. AB - The treatment of Ewing sarcoma (ES) in adult patients requires a multidisciplinary approach. Systemic therapy remains an important component of clinical management of this disease. ES is extremely rare in adult patients. Due to the rarity of the disease, no standard of care in terms of chemotherapy for the adult population exists, and the level of evidence for individual agents or some multidrug combinations is limited. Most regimens that are used in both adults and children include anthracyclines, etoposide, vincristine, cyclophosphamide, and ifosfamide. In this report, we describe our experience with the alternating use of triple combination therapies based on vincristine, ifosfamide, and doxorubicin (VIA) and an etoposide, ifosfamide, and cisplatin combination (VIP). We retrospectively evaluated the response rates, outcome, and tolerance of adult patients (n = 64) treated with VIA/VIP between 1990 and 2014. The patients included were treated with perioperative chemotherapy (53.1% neoadjuvant therapy and 17.2% adjuvant therapy) or had synchronous metastases at diagnosis (29.7%). Five-year overall survival rate was 52.2% for all patients, 72.2% for patients with localized disease, and 5.3% in patients with synchronous metastases. Overall response rate (ORR) was 37% after 2 cycles of VIA and 2 cycles of VIP. There were no patients with progressive disease (PD). PMID- 29527122 TI - Influencing trade policy in a multi-level system - Understanding corporate political activity in the context of global value chains and regime complexity. PMID- 29527123 TI - Can disc diffusion susceptibility tests assess the antimicrobial activity of engineered nanoparticles? AB - The use of disc diffusion susceptibility tests to determine the antibacterial activity of engineered nanoparticles (ENPs) is questionable because their low diffusivity practically prevents them from penetrating through the culture media. In this study, we investigate the ability of such a test, namely the Kirby-Bauer disc diffusion test, to determine the antimicrobial activity of Au and Ag ENPs having diameters from 10 to 40 nm on Escherichia coli cultures. As anticipated, the tests did not show any antibacterial effects of Au nanoparticles (NPs) as a result of their negligible diffusivity through the culture media. Ag NPs on the other hand exhibited a strong antimicrobial activity that was independent of their size. Considering that Ag, in contrast to Au, dissolves upon oxidation and dilution in aqueous solutions, the apparent antibacterial behavior of Ag NPs is attributed to the ions they release. The Kirby-Bauer method, and other similar tests, can therefore be employed to probe the antimicrobial activity of ENPs related to their ability to release ions rather than to their unique size dependent properties. Graphical abstract?. PMID- 29527124 TI - Strategies for the Synthesis of the Halenaquinol and Xestoquinol Families of Natural Products. AB - The halenaquinol family of naphthoquinol natural products includes a few closely related polycyclic compounds that feature an activated, electrophilic furan ring. This motif is likely responsible for the rich biological activity attributed to these secondary metabolites. Their interesting structures-related via their electrophilic furan to the biologically important furanosteroids-and their activities prompted significant efforts by organic chemists that resulted in many strategically compelling laboratory syntheses of these targets. These different strategies are compared and contrasted in this Microreview, and the authors' recent work on the structurally different but biogenetically related natural product exiguaquinol is put into the context of the previous studies on halenaquinol-type targets. PMID- 29527125 TI - TMD splitting functions in [Formula: see text] factorization: the real contribution to the gluon-to-gluon splitting. AB - We calculate the transverse momentum dependent gluon-to-gluon splitting function within [Formula: see text]-factorization, generalizing the framework employed in the calculation of the quark splitting functions in Hautmann et al. (Nucl Phys B 865:54-66, arXiv:1205.1759, 2012), Gituliar et al. (JHEP 01:181, arXiv:1511.08439, 2016), Hentschinski et al. (Phys Rev D 94(11):114013, arXiv:1607.01507, 2016) and demonstrate at the same time the consistency of the extended formalism with previous results. While existing versions of [Formula: see text] factorized evolution equations contain already a gluon-to-gluon splitting function i.e. the leading order Balitsky-Fadin-Kuraev-Lipatov (BFKL) kernel or the Ciafaloni-Catani-Fiorani-Marchesini (CCFM) kernel, the obtained splitting function has the important property that it reduces both to the leading order BFKL kernel in the high energy limit, to the Dokshitzer-Gribov-Lipatov Altarelli-Parisi (DGLAP) gluon-to-gluon splitting function in the collinear limit as well as to the CCFM kernel in the soft limit. At the same time we demonstrate that this splitting kernel can be obtained from a direct calculation of the QCD Feynman diagrams, based on a combined implementation of the Curci-Furmanski Petronzio formalism for the calculation of the collinear splitting functions and the framework of high energy factorization. PMID- 29527126 TI - Suggestion, persuasion and work: Psychotherapies in communist Europe. AB - This article traces what recent research and primary sources tell us about psychotherapy in Communist Europe, and how it survived both underground and above the surface. In particular, I will elaborate on the psychotherapeutic techniques that were popular across the different countries and language cultures of the Soviet sphere, with a particular focus upon the Cold War period. This article examines the literature on the mixed fortunes of psychoanalysis and group therapies in the region. More specifically, it focuses upon the therapeutic modalities such as work therapy, suggestion and rational therapy, which gained particular popularity in the Communist countries of Central and Eastern Europe. The latter two approaches had striking similarities with parallel developments in behavioural and cognitive therapies in the West. In part, this was because clinicians on both sides of the 'iron curtain' drew upon shared European traditions from the late nineteenth and early twentieth centuries. Nevertheless, this article argues that in the Soviet sphere, those promoting these approaches appropriated socialist thought as a source of inspiration and justification, or at the very least, as a convenient political shield. PMID- 29527127 TI - Buddhism, Christianity, and psychotherapy: A three-way conversation in the mid twentieth century. AB - This article explores the scope of 'religion-psy dialogue' in the mid-twentieth century, via a case study from Japan: Kosawa Heisaku, a Buddhist psychoanalyst based in Tokyo. By putting this case study in brief comparative perspective, with the conversation that took place in 1965 between Paul Tillich and Carl Rogers, the article discusses both the promise and the pitfalls of the modern and contemporary world of 'religion-psy dialogue', alongside the means by which specialists in a variety of fields might investigate and hold it to account. PMID- 29527128 TI - Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy. VEGF monoclonal antibodies and VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are the main drugs used in anti-angiogenic therapy. However, crosstalk between VEGFR and other tyrosine kinase or downstream pathways produce resistance to TKI treatment, and the multi target inhibitors, HIF inhibitors or combination strategies are promising strategies for mRCC. HIFs are upstream of the crosstalk between the growth factors, and these factors may regulate the expression of VEGR, EGF, PDGF and other growth factors. The frequent VHL loss in ccRCC increases HIF expression, and HIFs may be an ideal candidate to overcome the TKI resistance. The combination of HIF inhibitors and immune checkpoint inhibitors is also anticipated. Various clinical trials of programmed cell death protein 1 inhibitors are planned. The present study reviews the effects of current and potential TKIs on mRCC, with a focus on VEGF/VEGFR and other targets for mRCC therapy. PMID- 29527130 TI - CLUSTERING OF INTERICTAL SPIKES BY DYNAMIC TIME WARPING AND AFFINITY PROPAGATION. AB - Epilepsy is often associated with the presence of spikes in electroencephalograms (EEGs). The spike waveforms vary vastly among epilepsy patients, and also for the same patient across time. In order to develop semi-automated and automated methods for detecting spikes, it is crucial to obtain a better understanding of the various spike shapes. In this paper, we develop several approaches to extract exemplars of spikes. We generate spike exemplars by applying clustering algorithms to a database of spikes from 12 patients. As similarity measures for clustering, we consider the Euclidean distance and Dynamic Time Warping (DTW). We assess two clustering algorithms, namely, K-means clustering and affinity propagation. The clustering methods are compared based on the mean squared error, and the similarity measures are assessed based on the number of generated spike clusters. Affinity propagation with DTW is shown to be the best combination for clustering epileptic spikes, since it generates fewer spike templates and does not require to pre-specify the number of spike templates. PMID- 29527129 TI - A critical appraisal on AIT in childhood asthma. AB - Abstract: Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous "generic class effect" evaluation, as testified by the numerous meta analyses, AIT is now considered a product-specific pathogenic-oriented treatment. Background: AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efficacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication. Conclusions: Given that some specific AIT products are effective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confirm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development. PMID- 29527131 TI - EPILEPTIFORM SPIKE DETECTION VIA CONVOLUTIONAL NEURAL NETWORKS. AB - The EEG of epileptic patients often contains sharp waveforms called "spikes", occurring between seizures. Detecting such spikes is crucial for diagnosing epilepsy. In this paper, we develop a convolutional neural network (CNN) for detecting spikes in EEG of epileptic patients in an automated fashion. The CNN has a convolutional architecture with filters of various sizes applied to the input layer, leaky ReLUs as activation functions, and a sigmoid output layer. Balanced mini-batches were applied to handle the imbalance in the data set. Leave one-patient-out cross-validation was carried out to test the CNN and benchmark models on EEG data of five epilepsy patients. We achieved 0.947 AUC for the CNN, while the best performing benchmark model, Support Vector Machines with Gaussian kernel, achieved an AUC of 0.912. PMID- 29527133 TI - Preoperative Hypertension. AB - Purpose of Review: This review will examine the implications for perioperative management of new hypertension guidelines and place these in the context of findings from recent large observational studies. Recent Findings: Recent hypertension guidelines highlight the role of ambulatory blood pressure measurement with the implication that isolated preoperative blood pressure measurements are of limited value. There is emerging evidence from large observational studies that both preoperative and intraoperative hypotension are associated with increased risk. It is not clear if this is a particular concern for hypertensive patients. Summary: Assessment of the hypertensive surgical patient should include blood pressure measurements taken using the correct technique. Preoperative blood pressures of less than 180/100 mmHg are not grounds for deferring surgery in the absence of active comorbid disease. Evidence to guide the perioperative management of patients with higher pressures is scanty and decisions should be made on a case-by-case basis. PMID- 29527132 TI - Risk Assessment. AB - Purpose of Review: The central question of preoperative assessment is not "What can be done?" but "What should be done and how?" Predicting a patient's risk of unwanted outcomes is vital to answering this question. This review discusses risk prediction tools currently available and anticipates future developments. Recent Findings: Simple, parsimonious risk scales and scores are being replaced by complex risk prediction models as high-capacity information systems become ubiquitous. The accuracy of risk estimation will be further increased by improved assessment of physical fitness, frailty, and incorporation of existing and novel biomarkers. However, the limitations of risk prediction for individual patient care must be recognized. Summary: Risk prediction is transforming from clinical estimation to statistical science. Predictions should be used within the context of a patient's baseline risk (life expectancy independent of surgery), personal circumstances, quality of life, their expectations and values, and consideration of outcomes that are meaningful for the patient. PMID- 29527134 TI - ADAPTIVE METHODS FOR STOCHASTIC DIFFERENTIAL EQUATIONS VIA NATURAL EMBEDDINGS AND REJECTION SAMPLING WITH MEMORY. AB - Adaptive time-stepping with high-order embedded Runge-Kutta pairs and rejection sampling provides efficient approaches for solving differential equations. While many such methods exist for solving deterministic systems, little progress has been made for stochastic variants. One challenge in developing adaptive methods for stochastic differential equations (SDEs) is the construction of embedded schemes with direct error estimates. We present a new class of embedded stochastic Runge-Kutta (SRK) methods with strong order 1.5 which have a natural embedding of strong order 1.0 methods. This allows for the derivation of an error estimate which requires no additional function evaluations. Next we derive a general method to reject the time steps without losing information about the future Brownian path termed Rejection Sampling with Memory (RSwM). This method utilizes a stack data structure to do rejection sampling, costing only a few floating point calculations. We show numerically that the methods generate statistically-correct and tolerance-controlled solutions. Lastly, we show that this form of adaptivity can be applied to systems of equations, and demonstrate that it solves a stiff biological model 12.28x faster than common fixed timestep algorithms. Our approach only requires the solution to a bridging problem and thus lends itself to natural generalizations beyond SDEs. PMID- 29527135 TI - Sediment-associated organic matter sources and sediment oxygen demand in a Special Area of Conservation (SAC): A case study of the River Axe, UK. AB - Oxygen demand in river substrates providing important habitats for the early life stages of aquatic ecology, including lithophilous fish, can arise due to the oxidation of sediment-associated organic matter. Oxygen depletion associated with this component of river biogeochemical cycling, will, in part, depend on the sources of such material. A reconnaissance survey was therefore undertaken to assess the relative contributions from bed sediment-associated organic matter sources potentially impacting on the River Axe Special Area of Conservation (SAC), in SW England. Source fingerprinting, including Monte Carlo uncertainty analysis, suggested that the relative frequency-weighted average median source contributions ranged between 19% (uncertainty range 0-82%) and 64% (uncertainty range 0-99%) for farmyard manures or slurries, 4% (uncertainty range 0-49%) and 35% (uncertainty range 0-100%) for damaged road verges, 2% (uncertainty range 0 100%) and 68% (uncertainty range 0-100%) for decaying instream vegetation, and 2% (full uncertainty range 0-15%) and 6% (uncertainty range 0-48%) for human septic waste. A reconnaissance survey of sediment oxygen demand (SOD) along the channel designated as a SAC yielded a mean SOD5 of 4 mg O2 g-1 dry sediment and a corresponding SOD20 of 7 mg O2 g-1 dry sediment, compared with respective ranges of 1-15 and 2-30 mg O2 g-1 dry sediment, measured by the authors for a range of river types across the UK. The findings of the reconnaissance survey were used in an agency (SW region) catchment appraisal exercise for informing targeted management to help protect the SAC. PMID- 29527136 TI - Noun and Verb Production in Maternal and Child Language: Continuity, Stability, and Prediction across the Second Year of Life. AB - The present study examined continuity/discontinuity and stability/instability of noun and verb production measures in 30 child-mother dyads observed at 16 and 20 months, and predictive relations with the acquisition of nouns and verbs at 24 months. Children exhibited significant discontinuity and robust stability in the frequency of nouns and verbs between 16 and 20 months (over and above the contribution of maternal measures). By contrast, mothers showed small, but significant, increases in the total number of nouns and the percentages of nouns located in the initial and final utterance positions, together with a decrease in the percentage of verbs located in the initial position. After removing the variance explained by child language, mothers' speech was stable only in the percentages of nouns located in the initial and final utterance positions. Finally, children's production of nouns at 24 months was predicted by the percentages of nouns located in the initial and final positions of maternal utterances at 16 months. Maternal measures at 20 months did not predict children's production of nouns nor for verbs at 24 months. Implications for language acquisition are discussed. PMID- 29527138 TI - Intrinsic 3D Dynamic Surface Tracking based on Dynamic Ricci Flow and Teichmuller Map. AB - 3D dynamic surface tracking is an important research problem and plays a vital role in many computer vision and medical imaging applications. However, it is still challenging to efficiently register surface sequences which has large deformations and strong noise. In this paper, we propose a novel automatic method for non-rigid 3D dynamic surface tracking with surface Ricci flow and Teichmuller map methods. According to quasi-conformal Teichmuller theory, the Techmuller map minimizes the maximal dilation so that our method is able to automatically register surfaces with large deformations. Besides, the adoption of Delaunay triangulation and quadrilateral meshes makes our method applicable to low quality meshes. In our work, the 3D dynamic surfaces are acquired by a high speed 3D scanner. We first identified sparse surface features using machine learning methods in the texture space. Then we assign landmark features with different curvature settings and the Riemannian metric of the surface is computed by the dynamic Ricci flow method, such that all the curvatures are concentrated on the feature points and the surface is flat everywhere else. The registration among frames is computed by the Teichmuller mappings, which aligns the feature points with least angle distortions. We apply our new method to multiple sequences of 3D facial surfaces with large expression deformations and compare them with two other state-of-the-art tracking methods. The effectiveness of our method is demonstrated by the clearly improved accuracy and efficiency. PMID- 29527137 TI - Effects of caffeine intake on muscle strength and power: a systematic review and meta-analysis. AB - Background: Caffeine is commonly used as an ergogenic aid. Literature about the effects of caffeine ingestion on muscle strength and power is equivocal. The aim of this systematic review and meta-analysis was to summarize results from individual studies on the effects of caffeine intake on muscle strength and power. Methods: A search through eight databases was performed to find studies on the effects of caffeine on: (i) maximal muscle strength measured using 1 repetition maximum tests; and (ii) muscle power assessed by tests of vertical jump. Meta-analyses of standardized mean differences (SMD) between placebo and caffeine trials from individual studies were conducted using the random effects model. Results: Ten studies on the strength outcome and ten studies on the power outcome met the inclusion criteria for the meta-analyses. Caffeine ingestion improved both strength (SMD = 0.20; 95% confidence interval [CI]: 0.03, 0.36; p = 0.023) and power (SMD = 0.17; 95% CI: 0.00, 0.34; p = 0.047). A subgroup analysis indicated that caffeine significantly improves upper (SMD = 0.21; 95% CI: 0.02, 0.39; p = 0.026) but not lower body strength (SMD = 0.15; 95% CI: -0.05, 0.34; p = 0.147). Conclusion: The meta-analyses showed significant ergogenic effects of caffeine ingestion on maximal muscle strength of upper body and muscle power. Future studies should more rigorously control the effectiveness of blinding. Due to the paucity of evidence, additional findings are needed in the female population and using different forms of caffeine, such as gum and gel. PMID- 29527139 TI - Transactional Pathways of Transgender Identity Development in Transgender and Gender Nonconforming Youth and Caregivers from the Trans Youth Family Study. AB - Background: A growing body of research has examined transgender identity development, but no studies have investigated developmental pathways as a transactional process between youth and caregivers, incorporating perspectives from multiple family members. The aim of this study was to conceptualize pathways of transgender identity development using narratives from both transgender and gender nonconforming (TGN) youth and their cisgender (non-transgender) caregivers. Methods: The sample included 16 families, with 16 TGN youth, ages 7 18 years, and 29 cisgender caregivers (N = 45 family members). TGN youth represented multiple gender identities, including trans boy (n = 9), trans girl (n = 5), gender fluid boy (n = 1), and girlish boy (n = 1). Caregivers included mothers (n = 17), fathers (n = 11), and one grandmother. Participants were recruited from LGBTQ community organizations and support networks for families with transgender youth in the Midwest, Northeast, and South regions of the United States. Each family member completed a one-time in-person semi-structured qualitative interview that included questions about transgender identity development. Results: Analyses revealed seven overarching themes of transgender identity development, which were organized into a conceptual model: Trans identity development, sociocultural influences/societal discourse, biological influences, family adjustment/impact, stigma/cisnormativity, support/resources, and gender affirmation/actualization. Conclusions: Findings underscore the importance of assessing developmental processes among TGN youth as transactional, impacting both youth and their caregivers. PMID- 29527140 TI - Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease. AB - Background: Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications. Methods: From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles. Results: Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen. Conclusions: The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles. PMID- 29527141 TI - Reproducible proteomics sample preparation for single FFPE tissue slices using acid-labile surfactant and direct trypsinization. AB - Background: Proteomic analyses of clinical specimens often rely on human tissues preserved through formalin-fixation and paraffin embedding (FFPE). Minimal sample consumption is the key to preserve the integrity of pathological archives but also to deal with minimal invasive core biopsies. This has been achieved by using the acid-labile surfactant RapiGest in combination with a direct trypsinization (DTR) strategy. A critical comparison of the DTR protocol with the most commonly used filter aided sample preparation (FASP) protocol is lacking. Furthermore, it is unknown how common histological stainings influence the outcome of the DTR protocol. Methods: Four single consecutive murine kidney tissue specimens were prepared with the DTR approach or with the FASP protocol using both 10 and 30 k filter devices and analyzed by label-free, quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS). We compared the different protocols in terms of proteome coverage, relative label-free quantitation, missed cleavages, physicochemical properties and gene ontology term annotations of the proteins. Additionally, we probed compatibility of the DTR protocol for the analysis of common used histological stainings, namely hematoxylin & eosin (H&E), hematoxylin and hemalaun. These were proteomically compared to an unstained control by analyzing four human tonsil FFPE tissue specimens per condition. Results: On average, the DTR protocol identified 1841 +/- 22 proteins in a single, non fractionated LC-MS/MS analysis, whereas these numbers were 1857 +/- 120 and 1970 +/- 28 proteins for the FASP 10 and 30 k protocol. The DTR protocol showed 15% more missed cleavages, which did not adversely affect quantitation and intersample comparability. Hematoxylin or hemalaun staining did not adversely impact the performance of the DTR protocol. A minor perturbation was observed for H&E staining, decreasing overall protein identification by 13%. Conclusions: In essence, the DTR protocol can keep up with the FASP protocol in terms of qualitative and quantitative reproducibility and performed almost as well in terms of proteome coverage and missed cleavages. We highlight the suitability of the DTR protocol as a viable and straightforward alternative to the FASP protocol for proteomics-based clinical research. PMID- 29527142 TI - Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides. AB - Abstract: Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include N methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism. Graphical Abstract: PMID- 29527143 TI - Strategies to assess and optimize stability of endogenous amines during cerebrospinal fluid sampling. AB - Introduction: Metabolic profiling of cerebrospinal fluid (CSF) is a promising technique for studying brain diseases. Measurements should reflect the in vivo situation, so ex vivo metabolism should be avoided. Objective: To investigate the effects of temperature (room temperature vs. 4 degrees C), centrifugation and ethanol, as anti-enzymatic additive during CSF sampling on concentrations of glutamic acid, glutamine and other endogenous amines. Methods: CSF samples from 21 individuals were processed using five different protocols. Isotopically labeled alanine, isoleucine, glutamine, glutamic acid and dopamine were added prior to sampling to trace any degradation. Metabolomics analysis of endogenous amines, isotopically-labeled compounds and degradation products was performed with a validated LC-MS method. Results: Thirty-six endogenous amines were quantified. There were no statistically significant differences between sampling protocols for 31 out of 36 amines. For GABA there was primarily an effect of temperature (higher concentrations at room temperature than at 4 degrees C) and a small effect of ethanol (lower concentrations if added) due to possible degradation. O-phosphoethanolamine concentrations were also lower when ethanol was added. Degradation of isotopically-labeled compounds (e.g. glutamine to glutamic acid) was minor with no differences between protocols. Conclusion: Most amines can be considered stable during sampling, provided that samples are cooled immediately to 4 degrees C, centrifuged, and stored at - 80 degrees C within 2 h. The effect of ethanol addition for more unstable metabolites needs further investigation. This was the first time that labeled compounds were used to monitor ex vivo metabolism during sampling. This is a useful strategy to study the stability of other metabolites of interest. PMID- 29527145 TI - Comparison of the Determinants of the Health Service System and the Health Status of the People in the Greater Mekong Subregion (GMS). AB - Background: Health is influenced by numerous factors that affect the health service system and health status of the people in every country. This article aims to compare the determinants of the health service system and the health status of the people in Thailand, the Lao PDR, Vietnam, and Cambodia; and to recommend policies that impact the population's health and the country's development. Methods: A comprehensive search of the literature from a variety of online search and academic databases, and synthesis of previous study was used in this paper. Data on country indicators were taken from published online databases of the Ministry of Public Health of Cambodia, Lao PDR, Thailand,and Vietnam; the World Health Organization, and the World Bank. Results: In Thailand, the determinants of the health service system and health status of the people are medical information and technology because of the government initiatives to improve the quality of healthcare services through the use of modern technology. In Vietnam, the society and culture, and the strengths and weaknesses of the hospital significantly affect the health status and health service system there because of the religious beliefs of the people. However, in Cambodia, the strengths and weaknesses of the hospital are the primary determinant of the health service system and health status of the people due to the condition of the hospitals, the availability of new medical devices, and the number of healthcare professionals. In the Lao PDR, trade and investment, and medical information and technology, significantly influence the health service system and health status of the people because of the government efforts to outsource capital expenditures and medical technology. Conclusion: The strengths and weaknesses of the hospital are the key determinants of the health service system and health status of the people in all GMS countries. Understanding the determinants of health is essential in order to develop policies and programs that impact the population's health and the country's development. PMID- 29527144 TI - Weight loss moderately affects the mixed meal challenge response of the plasma metabolome and transcriptome of peripheral blood mononuclear cells in abdominally obese subjects. AB - Introduction: The response to dietary challenges has been proposed as a more accurate measure of metabolic health than static measurements performed in the fasted state. This has prompted many groups to explore the potential of dietary challenge tests for assessment of diet and lifestyle induced shifts in metabolic phenotype. Objectives: We examined whether the response to a mixed-meal challenge could provide a readout for a weight loss (WL)-induced phenotype shift in abdominally obese male subjects. The underlying assumption of a mixed meal challenge is that it triggers all aspects of phenotypic flexibility and provokes a more prolonged insulin response, possibly allowing for better differentiation between individuals. Methods: Abdominally obese men (n = 29, BMI = 30.3 +/- 2.4 kg/m2) received a mixed-meal challenge prior to and after an 8-week WL or no-WL control intervention. Lean subjects (n = 15, BMI = 23.0 +/- 2.0 kg/m2) only received the mixed meal challenge at baseline to have a benchmark for WL-induced phenotype shifts. Results: Levels of several plasma metabolites were significantly different between lean and abdominally obese at baseline as well as during postprandial metabolic responses. Genes related to oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) were expressed at higher levels in abdominally obese subjects as compared to lean subjects at fasting, which was partially reverted after WL. The impact of WL on the postprandial response was modest, both at the metabolic and gene expression level in PBMCs. Conclusion: We conclude that mixed-meal challenges are not necessarily superior to measurements in the fasted state to assess metabolic health. Furthermore, the mechanisms accounting for the observed differences between lean and abdominally obese in the fasted state are different from those underlying the dissimilarity observed during the postprandial response. PMID- 29527146 TI - A Review of the Relationships among the Key Determinants Affecting the Mental Health Disorders of the People in Greater Mekong Subregion Countries. AB - Background: ASEAN integration aims to transform the GMS into a single market with free flows of products, services, and skilled labor, as well as investment openness, which will ultimately force regional economic growth. Therefore, this integration is likely to bring about a big change to this area in the new era; it can subsequently cause many problems as well, including mental health issues of the people in this region. The characteristic differences among the GMS member countries in terms of trade and investment, so-cial and cultural values, medical information and technology, and the living and working environment have become major problems affecting mental health disorders, which are usually identified as depression, stress, and substance abuse. Methods: This review paper is a literature review of the relationship of the determinants affecting GMS mental disorders conducted using the following strategies: 1) collecting data from previous qualitative and quantitative research studies, com-paratively analyzing the literature, articles, published papers, and reports relevant to the existing policies on economic, environmental, and healthcare issues obtained from the GMS; and 2) exchanging information from the institutions involved, including reports and papers regarding the determinants affecting mental health disorders of the people in the GMS, which were used to generate the synthesis of the existing knowledge of the mental health and to provide recommenda-tion programs for the GMS people. Results: Based on the reviewed literature there are four key factors affecting mental health, especially mental health in GMS populations: 1) the living and work environments; 2) trade and investment; 3) technology and medical information; and 4) social and cultural values. The study found that the increasing number of mental health dis-orders is a big burden for national healthcare spending. Financial issues have become a major key to the wide prevalence of mental disorders in the GMS. Health issues related to mental health disorders are also caused by the environment and other related factors and therefore a stable and a well-balanced environment is an indicator of healthy mental status. In addition, the environment is a way to pursue both physical and mental health because green spaces serve as a mood freshener and can al-leviate anxiety, stress, and depression. Conclusion: Globalization and urbanization should follow sustainable development instructions and concerns about the population's health, especially regarding mental health. These key determinants affect the people's life, especially in terms of mental health thus leading to mental health disorders. PMID- 29527147 TI - Mental Health and Mental Disorder Recommendation Programs. AB - Background: The characteristic differences among the Greater Mekong Subregion (GMS) countries in terms of trade and investment, society and cultural values, medical information and technology, and the living and working environment have become major health problems in terms of mental disorders. The purpose of this article is to identify the gaps in those aspects, to propose mental health and mental disorder recommendation programs, and to recommend policies for policy makers and research investors. Methods: A comparative analysis and literature review of existing policy, including overviews of previous research were used to generate a synthesis of the existing knowledge of the mental health and mental disorder recommendation programs. Results: The review results recommend mental health and mental disorder programs for policy makers, research investors, and stakeholders in order to strengthen the directions for implementing these programs in the future. Conclusion: The healthcare provision in each country will not be limited only to its citizens; the healthcare markets and target groups are likely to expand to the neighboring countries in the context of changes in domestic and international factors, which have both positive and negative impacts according to the political, economic, and social situations of the influencing countries. PMID- 29527149 TI - The Magnetohydrodynamic Effect and its Associated Material Designs for Biomedical Applications: A State-of-the-Art Review. AB - The presented article discusses recent advances in biomedical applications of classical Magnetohydrodynamics (MHD), with a focus on operating principles and associated material considerations. These applications address novel approaches to common biomedical problems from micro-particle sorting for lab-on-a-chip devices to advanced physiological monitoring techniques. 100 papers in the field of MHDs were reviewed with a focus on studies with direct biomedical applications. The body of literature was categorized into three primary areas of research including Material Considerations for MHD Applications, MHD Actuation Devices, and MHD Sensing Techniques. The state of the art in the field was examined and research topics were connected to provide a wide view of the field of biomedical MHDs. As this field develops, the need for advanced simulation and material design will continue to increase in importance in order to further expand its reach to maturity. As the field of biomedical MHDs continues to grow, advances towards micro-scale transitions will continue to be made, maintaining its clinically driven nature and moving towards real-world applications. PMID- 29527150 TI - Histological exhibition of the gastroprotective effect of Moringa oleifera leaf extract. AB - The gastroprotective activity of Moringa oleifera leaf extract against aspirin induced ulcers was investigated in rats. Thirty (30) rats under starvation but with access to drinking water for 48 h were divided into 6 groups of 5 animals each. Animals in groups 1 and 2 were pretreated with 0.2 ml normal saline via the oral route. Group 3 received 32 mg/kg cimetidine while those in groups 4, 5 and 6 received oral Moringa leaf extract treatments at doses 200, 400 and 800 mg/kg body weight respectively. Thirty minutes after treatment, all animals in groups 2 to 6 were given 800 mg/kg Aspirin to induce ulcer. Results obtained showed complete erosion of the superficial epithelium with complete loss of the mucus globules and sloughing off of immediate underlying cells and sparsely distributed intraepithelial lymphocytes in the stomach of rats in which no treatment was given and significantly differed from those of the normal control animals which were essentially intact. No significant gastroprotection was observed in rats pretreated with the lowest dose of the extract (200 mg/kg) as a high degree of intestinal mucosal lesions and complete erosion of the surface epithelium with intraepithelial haemorrhage, moderate inflammation and tissue oedema were observed. Pretreatment with 400 mg/kg, however, offered a mild degree of protection with patches of surface epithelial protection and mucus globules, even though there was still predominant disintegration and sloughing off of superficial and underlying epithelial cells. The level of protection was sufficiently increased in animals treated with 800 mg/kg Moringa extract as there was increased protection of surface epithelium with more mucus globules and compared favourably with the effect of Cimetidine in which patches of intact superficial cells were observed. Moringa leaf extract may contain active agents with gastroprotective and mucus enhancing activities and could be harnessed into safe and potent treatment agents for ulcer in addition to providing template for the development of new antiulcer agents. PMID- 29527148 TI - Toward Strong and Tough Glass and Ceramic Scaffolds for Bone Repair. AB - The need for implants to repair large bone defects is driving the development of porous synthetic scaffolds with the requisite mechanical strength and toughness in vivo. Recent developments in the use of design principles and novel fabrication technologies are paving the way to create synthetic scaffolds with promising potential for reconstituting bone in load-bearing sites. This article reviews the state of the art in the design and fabrication of bioactive glass and ceramic scaffolds that have improved mechanical properties for structural bone repair. Scaffolds with anisotropic and periodic structures can be prepared with compressive strengths comparable to human cortical bone (100-150 MPa), while scaffolds with an isotropic structure typically have strengths in the range of trabecular bone (2-12 MPa). However, the mechanical response of bioactive glass and ceramic scaffolds in multiple loading modes such as flexure and torsion - as well as their mechanical reliability, fracture toughness, and fatigue resistance has received little attention. Inspired by the designs of natural materials such as cortical bone and nacre, glass-ceramic and inorganic/polymer composite scaffolds created with extrinsic toughening mechanisms are showing potential for both high strength and mechanical reliability. Future research should include improved designs that provide strong scaffolds with microstructures conducive to bone ingrowth, and evaluation of these scaffolds in large animal models for eventual translation into clinical applications. PMID- 29527152 TI - Impairment in the Intention Formation and Execution Phases of Prospective Memory in Parkinson's Disease. AB - Objective: Patients with Parkinson's disease have prospective memory impairments. However, little is known about distinct phases of prospective memory in these patients. This study was designed to elucidate the specific phase(s) of prospective memory that are impaired in patients with Parkinson's disease. Methods: The study included 31 Parkinson's disease patients and 27 healthy controls. The four phases of prospective memory (intention formation, retention, initiation, and execution) were examined in a complex prospective memory task. In this task, the participants were asked to form a sophisticated plan for performing six subtasks to obtain the highest score, and then execute the plan following a cue embedded in a questionnaire. Global cognitive function and relevant cognitive abilities, including attention, short-term memory, working memory, and inhibition, were also evaluated during the retention phase of the prospective memory task. Results: Intention formation was impaired in Parkinson's disease patients (p < 0.001 vs. healthy controls). This impairment could not be attributed to deficits in other cognitive functions. The score of intention execution was also lower in Parkinson's disease patients (p = 0.004 vs. healthy controls). Such a difference was related to working memory deficits in Parkinson's disease. The intention retention and initiation were intact in Parkinson's disease patients. The score of intention execution correlated negatively with disease severity and disease duration. Conclusions: Prospective memory in Parkinson's disease patients is impaired at the phase of intention formation. The worsening performance of intention execution in Parkinson's disease may be related to working memory deficits. In addition, prospective memory impairment might progress with increasing disease duration and severity. PMID- 29527151 TI - Protective Effects of L-902,688, a Prostanoid EP4 Receptor Agonist, against Acute Blood-Brain Barrier Damage in Experimental Ischemic Stroke. AB - Ischemic stroke occurs when a clot forms in the brain vasculature that starves downstream tissue of oxygen and nutrients resulting in cell death. The tissue immediately downstream of the blockage, the core, dies within minutes, but the surrounding tissue, the penumbra is potentially salvageable. Prostaglandin E2 binds to four different G-protein coupled membrane receptors EP1-EP4 mediating different and sometimes opposing responses. Pharmacological activation of the EP4 receptor has already been established as neuroprotective in stroke, but the mechanism(s) of protection are not well-characterized. In this study, we hypothesized that EP4 receptor activation reduces ischemic brain injury by reducing matrix metalloproteinase (MMP)-3/-9 production and blood-brain barrier (BBB) damage. Rats underwent transient ischemic stroke for 90 min. Animals received an intravenous injection of either the vehicle or L-902,688, a highly specific EP4 agonist, at the onset of reperfusion. Brain tissue was harvested at 24 h. We established a dose-response curve and used the optimal dose that resulted in the greatest infarct reduction to analyze BBB integrity compared to vehicle-treated rats. The presence of IgG, a blood protein, in the brain parenchyma is a marker of BBB damage, and L-902,688 (1 mg/kg; i.v.) dramatically reduced IgG extravasation (P < 0.05). Consistent with these data, we assessed zona occludens-1 and occludin, tight junction proteins integral to the maintenance of the BBB, and found reduced degradation with L-902,688 administration. With immunoblotting, qRT-PCR, and/or a fluorescence resonance energy transfer (FRET)-based activity assay, we next measured MMP-3/-9 since they are key effectors of BBB breakdown in stroke. In the cerebral cortex, not only was MMP-3 activity significantly decreased (P < 0.05), but L-902,688 treatment also reduced MMP-9 mRNA, protein, and enzymatic activity (P < 0.001). In addition, post-ischemic administration of the EP4 agonist significantly reduced pro-inflammatory cytokines IL-1beta (P < 0.05) and IL-6 (P < 0.01) in the ischemic cerebral cortex. Most importantly, one injection of L-902,688 (1 mg/kg; i.v) at the onset of reperfusion significantly reduces neurological deficits up to 3 weeks later (P < 0.05). Our data show for the first time that pharmacological activation of EP4 with L-902,688 is neuroprotective in ischemic stroke by reducing MMP-3/-9 and BBB damage. PMID- 29527154 TI - Editorial: Gene Therapy for the Central and Peripheral Nervous System. PMID- 29527153 TI - Integrated Genetic Analysis of Racial Differences of Common GBA Variants in Parkinson's Disease: A Meta-Analysis. AB - Background: Numerous studies have indicated that there is a possible relationship between GBA variants and Parkinson's disease (PD), however, most of them focused on a few variants such as L444P, N370S. We performed a comprehensive pooled analysis to clarify the relationship between variations of GBA and the risk of PD in different racial groups. Methods: Standard meta-analysis was conducted, including generating inclusion and exclusion criteria, searching literature, extracting and analyzing data. Results: Fifty studies containing 20,267 PD patients and 24,807 controls were included. We found that variants 84insGG, IVS2+1G>A, R120W, H255Q, E326K, T369M, N370S, D409H, L444P, R496H and RecNciI increased the risk of PD in total populations (OR: 1.78-10.49; p: <0.00001, 0.00005, 0.0008, 0.005, <0.00001, 0.004, <0.00001, 0.0003, <0.00001, <0.0001, 0.0001). In subgroup analysis by ethnicity, in AJ populations, variants 84insGG, R496H, N370S increased the risk of PD (OR: 9.26-3.51; p: <0.00001, <0.0001, <0.00001). In total non-AJ populations, variants L444P, R120W, IVS2+1G>A, H255Q, N370S, D409H, RecNciI, E326K, T369M increased the risk of PD (OR: 8.66-1.89; p: <0.00001, 0.0008, 0.02, 0.005, <0.00001, 0.001, 0.0001, <0.00001, 0.002). Among the non-AJ populations, pooled analysis from five different groups were done separately. Variants L444P, N370S, H255Q, D409H, RecNciI, E326K increased risk of PD (OR: 6.52-1.84; p: <0.00001, <0.00001, 0.005, 0.005, 0.04, <0.00001) in European/West Asians while R120W and RecNciI in East Asians (OR: 14.93, 3.56; p: 0.001, 0.003). L444P increased the risk of PD in Hispanics, East Asians and Mixed populations (OR: 15.44, 12.43, 7.33; p: 0.00004, <0.00001, 0.009). Lacking of enough original studies, we failed to conduct quantitative analysis in Africa. Conclusions: Obvious racial differences were found for GBA variants in PD. 84insGG and R496H exclusively increased PD risks in AJ populations, so did L444P, R120W, IVS2+1G>A, H255Q, D409H, RecNciI, E326K, T369M in non-AJ populations. N370S increased the risk of PD in both ethnics. In non-AJ subgroup populations, N370S, H255Q, D409H, E326K exclusively increased PD risks in European/West Asians, as were R120W in East Asians. L444P increased the risk of PD in all groups in non-AJ ethnicity. These results will contribute to the future genetic screening of GBA gene in PD. PMID- 29527155 TI - Silencing a Multifunctional microRNA Is Beneficial for Stroke Recovery. AB - Stroke-induced endothelial cell injury leads to destruction of cerebral microvasculature and significant damage to the brain tissue. A subacute phase of cerebral ischemia is associated with regeneration involving the activation of vascular remodeling, neuroplasticity, neurogenesis, and neuroinflammation processes. Effective restoration and improvement of blood supply to the damaged brain tissue offers a potential therapy for stroke. microRNAs (miRNAs) are recently identified small RNA molecules that regulate gene expression and significantly influence the essential cellular processes associated with brain repair following stroke. A number of specific miRNAs are implicated in regulating the development and propagation of the ischemic tissue damage as well as in mediating post-stroke regeneration. In this review, I discuss the functions of the miRNA miR-155 and the effect of its in vivo inhibition on brain recovery following experimental cerebral ischemia. The article introduces new and unexplored approach to cerebral regeneration: regulation of brain tissue repair through a direct modulation of specific miRNA activity. PMID- 29527156 TI - Toward a Mechanistic Understanding of Color Vision in Insects. AB - Many visual animals exploit spectral information for seeking food and mates, for identifying preys and predators, and for navigation. Animals use chromatic information in two ways. "True color vision," the ability to discriminate visual stimuli on the basis of their spectral content independent of brightness, is thought to play an important role in object identification. In contrast, "wavelength-specific behavior," which is strongly dependent on brightness, often associates with foraging, navigation, and other species-specific needs. Among animals capable of chromatic vision, insects, with their diverse habitats, stereotyped behaviors, well-characterized anatomy and powerful genetic tools, are attractive systems for studying chromatic information processing. In this review, we first discuss insect photoreceptors and the relationship between their spectral sensitivity and animals' color vision and ecology. Second, we review recent studies that dissect chromatic circuits and explore neural mechanisms of chromatic information processing. Finally, we review insect behaviors involving "true color vision" and "wavelength-specific behaviors," especially in bees, butterflies, and flies. We include examples of high-order color vision, such as color contrast and constancy, which are shared by vertebrates. We focus on Drosophila studies that identified neuronal correlates of color vision and innate spectral preferences. We also discuss the electrophysiological studies in bees that reveal color encoding. Despite structural differences between insects' and vertebrates' visual systems, their chromatic vision appears to employ the same processing principles, such as color opponency, suggesting convergent solutions of neural computation to common problems. PMID- 29527158 TI - Is Smaller Better? A Proposal to Use Bacteria For Neuroscientific Modeling. AB - Bacteria are easily characterizable model organisms with an impressively complicated set of abilities. Among them is quorum sensing, a cell-cell signaling system that may have a common evolutionary origin with eukaryotic cell-cell signaling. The two systems are behaviorally similar, but quorum sensing in bacteria is more easily studied in depth than cell-cell signaling in eukaryotes. Because of this comparative ease of study, bacterial dynamics are also more suited to direct interpretation than eukaryotic dynamics, e.g., those of the neuron. Here we review literature on neuron-like qualities of bacterial colonies and biofilms, including ion-based and hormonal signaling, and a phenomenon similar to the graded action potential. This suggests that bacteria could be used to help create more accurate and detailed biological models in neuroscientific research. More speculatively, bacterial systems may be considered an analog for neurons in biologically based computational research, allowing models to better harness the tremendous ability of biological organisms to process information and make decisions. PMID- 29527159 TI - Muscle Synergies Control during Hand-Reaching Tasks in Multiple Directions Post stroke. AB - Purpose: A muscle synergies model was suggested to represent a simplifying motor control mechanism by the brainstem and spinal cord. The aim of the study was to investigate the feasibility of such control mechanisms in the rehabilitation of post-stroke individuals during the execution of hand-reaching movements in multiple directions, compared to non-stroke individuals. Methods: Twelve non stroke and 13 post-stroke individuals participated in the study. Muscle synergies were extracted from EMG data that was recorded during hand reaching tasks, using the NMF algorithm. The optimal number of synergies was evaluated in both groups using the Variance Accounted For (VAF) and the Mean Squared Error (MSE). A cross validation procedure was carried out to define a representative set of synergies. The similarity index and the K-means algorithm were applied to validate the existence of such a set of synergies, but also to compare the modulation properties of synergies for different movement directions between groups. The similarity index and hierarchical cluster analysis were also applied to compare between group synergies. Results: Four synergies were chosen to optimally capture the variances in the EMG data, with mean VAF of 0.917 +/- 0.034 and 0.883 +/- 0.046 of the data variances, with respective MSE of 0.007 and 0.016, in the control and study groups, respectively. The representative set of synergies was set to be extracted from movement to the center of the reaching space. Two synergies had different muscle activation balance between groups. Seven and 17 clusters partitioned the muscle synergies of the control and study groups. The control group exhibited a gradual change in the activation in the amplitude in the time domain (modulation) of synergies, as reflected by the similarity index, whereas the study group exhibited consistently significant differences between all movement directions and the representative set of synergies. The study findings support the existence of a representative set of synergies, which are modulated to execute movements in different directions. Conclusions: Post-stroke individuals differently modulate the activation of synergies to different movement directions than do non-stroke individuals. The conclusion was supported by different muscle activation balances, similarity values and different classifications of synergies among groups. PMID- 29527157 TI - Computational Neuropsychology and Bayesian Inference. AB - Computational theories of brain function have become very influential in neuroscience. They have facilitated the growth of formal approaches to disease, particularly in psychiatric research. In this paper, we provide a narrative review of the body of computational research addressing neuropsychological syndromes, and focus on those that employ Bayesian frameworks. Bayesian approaches to understanding brain function formulate perception and action as inferential processes. These inferences combine 'prior' beliefs with a generative (predictive) model to explain the causes of sensations. Under this view, neuropsychological deficits can be thought of as false inferences that arise due to aberrant prior beliefs (that are poor fits to the real world). This draws upon the notion of a Bayes optimal pathology - optimal inference with suboptimal priors - and provides a means for computational phenotyping. In principle, any given neuropsychological disorder could be characterized by the set of prior beliefs that would make a patient's behavior appear Bayes optimal. We start with an overview of some key theoretical constructs and use these to motivate a form of computational neuropsychology that relates anatomical structures in the brain to the computations they perform. Throughout, we draw upon computational accounts of neuropsychological syndromes. These are selected to emphasize the key features of a Bayesian approach, and the possible types of pathological prior that may be present. They range from visual neglect through hallucinations to autism. Through these illustrative examples, we review the use of Bayesian approaches to understand the link between biology and computation that is at the heart of neuropsychology. PMID- 29527160 TI - A Ternary Hybrid EEG-NIRS Brain-Computer Interface for the Classification of Brain Activation Patterns during Mental Arithmetic, Motor Imagery, and Idle State. AB - The performance of a brain-computer interface (BCI) can be enhanced by simultaneously using two or more modalities to record brain activity, which is generally referred to as a hybrid BCI. To date, many BCI researchers have tried to implement a hybrid BCI system by combining electroencephalography (EEG) and functional near-infrared spectroscopy (NIRS) to improve the overall accuracy of binary classification. However, since hybrid EEG-NIRS BCI, which will be denoted by hBCI in this paper, has not been applied to ternary classification problems, paradigms and classification strategies appropriate for ternary classification using hBCI are not well investigated. Here we propose the use of an hBCI for the classification of three brain activation patterns elicited by mental arithmetic, motor imagery, and idle state, with the aim to elevate the information transfer rate (ITR) of hBCI by increasing the number of classes while minimizing the loss of accuracy. EEG electrodes were placed over the prefrontal cortex and the central cortex, and NIRS optodes were placed only on the forehead. The ternary classification problem was decomposed into three binary classification problems using the "one-versus-one" (OVO) classification strategy to apply the filter-bank common spatial patterns filter to EEG data. A 10 * 10-fold cross validation was performed using shrinkage linear discriminant analysis (sLDA) to evaluate the average classification accuracies for EEG-BCI, NIRS-BCI, and hBCI when the meta classification method was adopted to enhance classification accuracy. The ternary classification accuracies for EEG-BCI, NIRS-BCI, and hBCI were 76.1 +/- 12.8, 64.1 +/- 9.7, and 82.2 +/- 10.2%, respectively. The classification accuracy of the proposed hBCI was thus significantly higher than those of the other BCIs (p < 0.005). The average ITR for the proposed hBCI was calculated to be 4.70 +/- 1.92 bits/minute, which was 34.3% higher than that reported for a previous binary hBCI study. PMID- 29527161 TI - Learning by Demonstration for Motion Planning of Upper-Limb Exoskeletons. AB - The reference joint position of upper-limb exoskeletons is typically obtained by means of Cartesian motion planners and inverse kinematics algorithms with the inverse Jacobian; this approach allows exploiting the available Degrees of Freedom (i.e. DoFs) of the robot kinematic chain to achieve the desired end effector pose; however, if used to operate non-redundant exoskeletons, it does not ensure that anthropomorphic criteria are satisfied in the whole human-robot workspace. This paper proposes a motion planning system, based on Learning by Demonstration, for upper-limb exoskeletons that allow successfully assisting patients during Activities of Daily Living (ADLs) in unstructured environment, while ensuring that anthropomorphic criteria are satisfied in the whole human robot workspace. The motion planning system combines Learning by Demonstration with the computation of Dynamic Motion Primitives and machine learning techniques to construct task- and patient-specific joint trajectories based on the learnt trajectories. System validation was carried out in simulation and in a real setting with a 4-DoF upper-limb exoskeleton, a 5-DoF wrist-hand exoskeleton and four patients with Limb Girdle Muscular Dystrophy. Validation was addressed to (i) compare the performance of the proposed motion planning with traditional methods; (ii) assess the generalization capabilities of the proposed method with respect to the environment variability. Three ADLs were chosen to validate the system: drinking, pouring and lifting a light sphere. The achieved results showed a 100% success rate in the task fulfillment, with a high level of generalization with respect to the environment variability. Moreover, an anthropomorphic configuration of the exoskeleton is always ensured. PMID- 29527162 TI - Long-Term Potentiation Enhances Neuronal Differentiation in the Chronic Hypoperfusion Model of Rats. AB - Several reports have shown that long-term potentiation (LTP) per se effectively enhances neurogenesis in the hippocampus of intact animals. If LTP can enhance neurogenesis in chronic hypoperfusion, this approach could potentially become a new therapeutic strategy for the restoration of cognitive function and for prevention from deterioration of mild cognitive impairment (MCI). Using an in vivo LTP model of rats, we examined whether LTP per se can enhance neurogenesis in hypoperfusion rats that underwent permanent bilateral common carotid artery occlusion (permanent 2-vessel occlusion, P2VO). High frequency stimulation (HFS) in the subacute phase after P2VO enhanced hippocampal cell proliferation and neurogenesis. However, most enhanced cell proliferation and neurogenesis was seen in the hypoperfusion rats that received HFS and for which LTP could finally be induced. In contrast, the same effect was not seen in the LTP induction in the chronic phase. The present findings, which reveal that most enhanced neurogenesis was seen in hypoperfusion rats for which LTP could be finally induced, could explain the ability of LTP-like activities such as learning paradigms and environmental stimuli to increase the rate of neurogenesis in the hippocampus even under hypoperfusion conditions. Moreover, the present findings, which reveal that LTP induction in the chronic phase after P2VO could not effectively enhance neurogenesis in the hypoperfusion rats, could indicate that patients with MCI and even middle-aged healthy control individuals should start LTP-like activities as early as possible and continue with these activities to prevent age-related deterioration of hippocampal function. PMID- 29527163 TI - When Cognitive Decline and Depression Coexist in the Elderly: CSF Biomarkers Analysis Can Differentiate Alzheimer's Disease from Late-Life Depression. AB - Late-life depression (LLD) and Alzheimer's Disease (AD) are the two most frequent neuropsychiatric disorders affecting elderly. LLD and AD may clinically present with depressive and cognitive symptoms. Therefore, when cognitive decline is coupled with depression in the elderly, the differential diagnosis between LLD and AD could be challenging. The aim of the present study was to evaluate in a population of elderly patients affected by depression and dementia the usefulness of CSF AD biomarkers (tau proteins and beta-amyloid42-Abeta42) and 2-[18F]fluoro 2-deoxy-d-glucose positron emission tomography (18FFDG-PET) in early differentiating LLD from AD. Two hundred and fifty-six depressed and demented patients, after performing CSF AD biomarkers and 18FFDG-PET, were distributed in two groups on the basis of the current diagnostic guidelines for AD (n = 201) and LLD (n = 55). Patients were then observed for 2 years to verify the early diagnosis. After the 2 year follow-up we compared AD and LLD patients' CSF and 18FFDG-PET data obtained at baseline to a group of age- and sex-matched controls. We found CSF Abeta42 levels significantly higher in LLD compared to AD patients. Remarkably, CSF Abeta42 levels of LLD patients (range between 550 and 1204 pg/mL) did not overlap with those of AD patients (range between 82 and 528 pg/mL). Moreover, we documented no differences in CSF AD biomarkers (Abeta42 and tau proteins) when comparing LLD patients to controls. In addition, AD patients showed the significant reduction of 18FFDG-PET uptake in temporo-parietal regions compared to both controls and LLD. Conversely, LLD and control groups did not differ at 18FFDG-PET analysis, although LLD patients showed heterogeneous patterns of glucose hypometabolism involving cortical and subcortical brain areas. It is noteworthy that at the end of the clinical follow-up, patients owing to AD group showed the expected significant decline of cognitive performances, whereas patients assigned to LLD group improved cognition as depressive symptoms recovered. Hence, in case of co-existence of cognitive impairment and depression in the elderly, we propose CSF AD biomarkers analysis to early differentiate LLD from AD and properly target the patient's therapeutic strategy and clinical follow-up. PMID- 29527164 TI - MicroRNA-455-3p as a Potential Biomarker for Alzheimer's Disease: An Update. AB - A non-invasive and early-detectable peripheral biomarker is urgently needed for Alzheimer's disease (AD). The present study is a step forward to verify the biomarker properties of human microRNA-455-3p (Hsa-miR-455-3p) in AD patients. Our previous findings on mild cognitive impaired subjects, AD patients and AD cells and mouse models unveiled the miR-455-3p as a potential peripheral biomarker for AD. In the current study, we verified the differential expression of miR-455-3p in postmortem AD brains obtained from NIH NeuroBioBank, and fibroblasts and B-lymphocytes from both familial and sporadic AD patients from Coriell Cell Repository of National Institutes on Aging. Total RNA was extracted from the fibroblasts, B-lymphocytes and AD postmortem brains, and expression of miR-455-3p was measured by real-time reverse-transcriptase RT-PCR. Our real-time RT-PCR analysis showed a significant (P = 0.0002) upregulation of miR-455-3p expression in AD postmortem brains compared to healthy control samples. Expression of miR-455-3p was also upregulated in the fibroblasts from AD patients, however a significant difference in miR-455-3p level was observed in the cells from sporadic AD patients (P = 0.014) compared to healthy controls. Similarly, in B-lymphocytes, miR-455-3p level was also higher (P = 0.044) especially in sporadic AD cases compared to controls. Receiver operating characteristic (ROC) curve analysis indicated the significant area under ROC curve (AUROC) value of miR-455-3p in AD postmortem brain (AUROC = 0.792; P = 0.001) and AD fibroblasts cells (AUROC = 0.861; P = 0.03), whereas in B lymphocytes AUROC value of miR-455-3p was not significant. Further, in-silico analysis for miRNA targets predictions showed the binding capacity of miR-455-3p with several AD associated key genes such as APP, NGF, USP25, PDRG1, SMAD4, UBQLN1, SMAD2, TP73, VAMP2, HSPBAP1, and NRXN1. Hence, these observations further revealed that miR-455-3p is a potential biomarker for AD and its possible therapeutic target for AD. PMID- 29527165 TI - Efficacy of Synthetic Peptide Corresponding to the ACTH-Like Sequence of Human Immunoglobulin G1 in Experimental Autoimmune Encephalomyelitis. AB - Peptide immunocortin sequence corresponds to the amino acid residues 11-20 of the variable part of human immunoglobulin G1 (IgG1) heavy chain. Since immunocortin was shown previously to inhibit phagocytosis in peritoneal macrophages and ConA induced T-lymphocytes proliferation in culture, we suggested that immunocortin administering may be of use for patients with self-immune syndrome. Immunocortin in concentration 10 MUM inhibited proliferation of both antigen (myelin)-induced and ConA-induced LN lymphocytes isolated from the lymph nodes of Dark Agouti (DA) rats immunized with chorda shear. The biological trials of the synthetic immunocortin were carried out on the DA rats with induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. These in vivo experiments have shown that intraperitoneal injections of immunocortin in a daily dosage 100 MUg per animal reduced symptoms of EAE in DA rats. PMID- 29527166 TI - Icariin Ameliorate Thiram-Induced Tibial Dyschondroplasia via Regulation of WNT4 and VEGF Expression in Broiler Chickens. AB - Tibial dyschondroplasia (TD) is main bone problem in fast growing poultry birds that effect proximal growth plate (GP) of tibia bone. TD is broadly defined as non-vascularized and non-mineralized, and enlarged GP with tibia bone deformation and lameness. Icariin (Epimedium sagittatum) is a traditional Chinese medicine, which is commonly practiced in the treatment of various bone diseases. Recently, many researcher reports about the beneficial effects of icariin in relation to various types of bone conditions but no report is available about promoting effect of icariin against TD. Therefore, current study was conducted to explore the ameliorating effect of icariin in thiram-induced TD chickens. A total of 180 broiler chicks were equally distributed in three groups; control, TD induced by thiram (50 mg/kg), and icariin group (treated with icariin @10 mg/kg). All groups were administered with normal standard diet ad libitum regularly until the end of experiment. The wingless-type member 4 (WNT4) and vascular endothelial growth factor (VEGF) genes and proteins expression were analyzed by quantitative real time polymerase chain reaction and western blot analysis respectively. Tibial bone parameters, physiological changes in serum, antioxidant enzymes, and chicken growth performance were determined to assess advantage and protective effect of the medicine in broiler chicken. The expression of WNT4 was decreased while VEGF increased significantly (P < 0.05) in TD affected chicks. TD enhanced the GP, lameness, and irregular chondrocytes, while reduced the liver function, antioxidant enzymes in liver, and performance of chickens. Icariin treatment up regulated WNT4 and down-regulated VEGF gene and protein expressions significantly (P < 0.05), restored the GP width, increased growth performance, corrected liver functions and antioxidant enzymes levels in liver, and mitigated the lameness in broiler chickens. In conclusion, icariin administration recovered GP size, normalized performance and prevented lameness significantly. Therefore, icariin treatments are encouraged to reduce the incidence of TD in broiler chickens. PMID- 29527167 TI - Polydopamine-Functionalized CA-(PCL-ran-PLA) Nanoparticles for Target Delivery of Docetaxel and Chemo-photothermal Therapy of Breast Cancer. AB - Current limitations of cancer therapy include the lack of effective strategy for target delivery of chemotherapeutic drugs, and the difficulty of achieving significant efficacy by single treatment. Herein, we reported a synergistic chemo photothermal strategy based on aptamer (Apt)-polydopamine (pD) functionalized CA (PCL-ran-PLA) nanoparticles (NPs) for effective delivery of docetaxel (DTX) and enhanced therapeutic effect. The developed DTX-loaded Apt-pD-CA-(PCL-ran-PLA) NPs achieved promising advantages, such as (i) improved drug loading content (LC) and encapsulation efficiency (EE) initiated by star-shaped copolymer CA-(PCL-ran PLA); (ii) effective target delivery of drugs to tumor sites by incorporating AS1411 aptamers; (iii) significant therapeutic efficacy caused by synergistic chemo-photothermal treatment. In addition, the pD coating strategy with simple procedures could address the contradiction between targeting modification and maintaining formerly excellent bio-properties. Therefore, with excellent bio properties and simple preparation procedures, the DTX-loaded Apt-pD-CA-(PCL-ran PLA) NPs effectively increased the local drug concentration in tumor sites, minimized side effects, and significantly eliminated tumors, indicating the promising application of these NPs for cancer therapy. PMID- 29527168 TI - Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats. AB - Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARgamma) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARgamma decreases in PAH, suggesting that screening of dual agonists of IP and PPARgamma might be an efficient method for drug discovery. Virtual screening (VS) of potential IP-PPARgamma dual targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARgamma antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARgamma agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARgamma that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH. PMID- 29527169 TI - Orthosiphon stamineus Leaf Extract Affects TNF-alpha and Seizures in a Zebrafish Model. AB - Epileptic seizures result from abnormal brain activity and can affect motor, autonomic and sensory function; as well as, memory, cognition, behavior, or emotional state. Effective anti-epileptic drugs (AEDs) are available but have tolerability issues due to their side effects. The Malaysian herb Orthosiphon stamineus, is a traditional epilepsy remedy and possesses anti-inflammatory, anti oxidant and free-radical scavenging abilities, all of which are known to protect against seizures. This experiment thus aimed to explore if an ethanolic leaf extract of O. stamineus has the potential to be a novel symptomatic treatment for epileptic seizures in a zebrafish model; and the effects of the extract on the expression levels of several genes in the zebrafish brain which are associated with seizures. The results of this study indicate that O. stamineus has the potential to be a novel symptomatic treatment for epileptic seizures as it is pharmacologically active against seizures in a zebrafish model. The anti convulsive effect of this extract is also comparable to that of diazepam at higher doses and can surpass diazepam in certain cases. Treatment with the extract also counteracts the upregulation of NF-kappaB, NPY and TNF-alpha as a result of a Pentylenetetrazol (PTZ) treated seizure. The anti-convulsive action for this extract could be at least partially due to its downregulation of TNF alpha. Future work could include the discovery of the active anti-convulsive compound, as well as determine if the extract does not cause cognitive impairment in zebrafish. PMID- 29527171 TI - Decreasing Compensatory Ability of Concentric Ventricular Hypertrophy in Aortic Banded Rat Hearts. AB - The cardiac system compensates for variations in physiological and pathophysiological conditions through a dynamic remodeling at the organ, tissue, and intracellular levels in order to maintain function. However, on longer time scales following the onset of ventricular pressure overload, such remodeling may begin to inhibit physiological function and ultimately lead to heart failure. This progression from compensatory to decompensatory behavior is poorly understood, in particular owing to the absence of a unified perspective of the concomitantly remodeling subsystems. To address this issue, the present study investigates the evolution of compensatory mechanisms, in response to overload, by integrating diffusion-tensor MRI, echocardiography, and intracellular and hemodynamic measurements within consistent computational simulations of aortic banded rat hearts. This approach allows a comparison of the relative leverage of different cardiac properties (geometry, passive mechanical stiffness, fiber configuration, diastolic and peak calcium concentrations, calcium-binding affinity, and aortic impedance) to affect cardiac contraction. Measurements indicate that, following aortic banding, an ejection fraction (EF) of 75% was maintained, relative to control rats, despite significant remodeling of the left ventricular wall thickness (increasing by ~90% over 4 weeks). Applying our framework, we identified the left-ventricular wall thickness (concentric hypertrophy) and the intracellular calcium dynamics as playing the dominant roles in preserving EF acutely, whereas the significance of hypertrophy decreased subsequently. This trend suggests an increasing reliance on intracellular mechanisms (average increase ~50%), rather than on anatomical features (average decrease ~60%), to achieve compensation of pump function in the early phase of heart failure. PMID- 29527172 TI - Inducing the Alternative Oxidase Forms Part of the Molecular Strategy of Anoxic Survival in Freshwater Bivalves. AB - Hypoxia in freshwater ecosystems is spreading as a consequence of global change, including pollution and eutrophication. In the Patagonian Andes, a decline in precipitation causes reduced lake water volumes and stagnant conditions that limit oxygen transport and exacerbate hypoxia below the upper mixed layer. We analyzed the molecular and biochemical response of the North Patagonian bivalve Diplodon chilensis after 10 days of experimental anoxia (<0.2 mg O2/L), hypoxia (2 mg O2/L), and normoxia (9 mg O2/L). Specifically, we investigated the expression of an alternative oxidase (AOX) pathway assumed to shortcut the regular mitochondrial electron transport system (ETS) during metabolic rate depression (MRD) in hypoxia-tolerant invertebrates. Whereas, the AOX system was strongly upregulated during anoxia in gills, ETS activities and energy mobilization decreased [less transcription of glycogen phosphorylase (GlyP) and succinate dehydrogenase (SDH) in gills and mantle]. Accumulation of succinate and induction of malate dehydrogenase (MDH) activity could indicate activation of anaerobic mitochondrial pathways to support anoxic survival in D. chilensis. Oxidative stress [protein carbonylation, glutathione peroxidase (GPx) expression] and apoptotic intensity (caspase 3/7 activity) decreased, whereas an unfolded protein response (HSP90) was induced under anoxia. This is the first clear evidence of the concerted regulation of the AOX and ETS genes in a hypoxia tolerant freshwater bivalve and yet another example that exposure to hypoxia and anoxia is not necessarily accompanied by oxidative stress in hypoxia-tolerant mollusks. PMID- 29527170 TI - Animal Toxins as Therapeutic Tools to Treat Neurodegenerative Diseases. AB - Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis. PMID- 29527174 TI - The Effects of Photobiomodulation of 808 nm Diode Laser Therapy at Higher Fluence on the in Vitro Osteogenic Differentiation of Bone Marrow Stromal Cells. AB - The literature has supported the concept of mesenchymal stromal cells (MSCs) in bone regeneration as one of the most important applications in oro-maxillofacial reconstructions. However, the fate of the transplanted cells and their effects on the clinical outcome is still uncertain. Photobiomodulation (PBM) plays an important role in the acceleration of tissue regeneration and potential repair. The aim of this in vitro study is to evaluate the effectiveness of PBM with 808 nm diode laser therapy, using a flat-top hand-piece delivery system at a higher fluence (64 J/cm2) irradiation (1 W, continuous-wave) on bone marrow stromal cells (BMSCs). The BMSCs of 3 old female Balb-c mice were analyzed. The cells were divided into two groups: irradiated group and control group. In the former the cells were irradiated every 24 h during 0 day (T0), 5 (T1), 10 (T2), and 15 (T3) days, whereas the control group was non-irradiated. The results have shown that the 64 J/cm2 laser irradiation has increased the Runt-related transcription factor 2 (Runx2). Runx2 is the most important early marker of osteoblast differentiation. The higher-fluence suppressed the synthesis of adipogenic transcription factor (PPARgamma), the pivotal transcription factor in adipogenic differentiation. Also, the osteogenic markers such as Osterix (Osx) and alkaline phosphatase (ALP) were upregulated with an increase in the matrix mineralization. Furthermore, western blotting data demonstrated that the laser therapy has induced a statistically valid increase in the synthesis of transforming growth factor beta1 (TGF-beta1) but had no effects on the tumor necrosis factor alpha (TNFalpha) production. The data has statistically validated the down-regulation of the important pro-inflammatory cytokines such as interleukin IL-6, and IL-17 after 808 nm PBM exposition. An increase in anti-inflammatory cytokines such as IL-1ralpha and IL-10 was observed. These in vitro studies provide for first time the initial proof that the PBM of the 808 nm diode laser therapy with flat-top hand-piece delivery system at a higher-fluence irradiation of 64 J/cm2 (1 W/cm2) can modulate BMSCs differentiation in enhancing osteogenesis. PMID- 29527175 TI - Cardiac Arrhythmias and Antiarrhythmic Drugs: An Autophagic Perspective. AB - Degradation of cellular material by lysosomes is known as autophagy, and its main function is to maintain cellular homeostasis for growth, proliferation and survival of the cell. In recent years, research has focused on the characterization of autophagy pathways. Targeting of autophagy mediators has been described predominantly in cancer treatment, but also in neurological and cardiovascular diseases. Although the number of studies is still limited, there are indications that activity of autophagy pathways increases under arrhythmic conditions. Moreover, an increasing number of antiarrhythmic and non-cardiac drugs are found to affect autophagy pathways. We, therefore, suggest that future work should recognize the largely unaddressed effects of antiarrhythmic agents and other classes of drugs on autophagy pathway activation and inhibition. PMID- 29527176 TI - Grip Force Adjustments Reflect Prediction of Dynamic Consequences in Varying Gravitoinertial Fields. AB - Humans have a remarkable ability to adjust the way they manipulate tools through a genuine regulation of grip force according to the task. However, rapid changes in the dynamical context may challenge this skill, as shown in many experimental approaches. Most experiments adopt perturbation paradigms that affect only one sensory modality. We hypothesize that very fast adaptation can occur if coherent information from multiple sensory modalities is provided to the central nervous system. Here, we test whether participants can switch between different and never experienced dynamical environments induced by centrifugation of the body. Seven participants lifted an object four times in a row successively in 1, 1.5, 2, 2.5, 2, 1.5, and 1 g. We continuously measured grip force, load force and the gravitoinertial acceleration that was aligned with body axis (perceived gravity). Participants adopted stereotyped grasping movements immediately upon entry in a new environment and needed only one trial to adapt grip forces to a stable performance in each new gravity environment. This result was underlined by good correlations between grip and load forces in the first trial. Participants predictively applied larger grip forces when they expected increasing gravity steps. They also decreased grip force when they expected decreasing gravity steps, but not as much as they could, indicating imperfect anticipation in that condition. The participants' performance could rather be explained by a combination of successful scaling of grip force according to gravity changes and a separate safety factor. The data suggest that in highly unfamiliar dynamic environments, grip force regulation is characterized by a combination of a successful anticipation of the experienced environmental condition, a safety factor reflecting strategic response to uncertainties about the environment and rapid feedback mechanisms to optimize performance under constant conditions. PMID- 29527177 TI - Key Inflammatory Processes in Human NASH Are Reflected in Ldlr-/-.Leiden Mice: A Translational Gene Profiling Study. AB - Introduction: It is generally accepted that metabolic inflammation in the liver is an important driver of disease progression in NASH and associated matrix remodeling/fibrosis. However, the exact molecular inflammatory mechanisms are poorly defined in human studies. Investigation of key pathogenic mechanisms requires the use of pre-clinical models, for instance for time-resolved studies. Such models must reflect molecular disease processes of importance in patients. Herein we characterized inflammation in NASH patients on the molecular level by transcriptomics and investigated whether key human disease pathways can be recapitulated experimentally in Ldlr-/-.Leiden mice, an established pre-clinical model of NASH. Methods: Human molecular inflammatory processes were defined using a publicly available NASH gene expression profiling dataset (GSE48452) allowing the comparison of biopsy-confirmed NASH patients with normal controls. Gene profiling data from high-fat diet (HFD)-fed Ldlr-/-.Leiden mice (GSE109345) were used for assessment of the translational value of these mice. Results: In human NASH livers, we observed regulation of 65 canonical pathways of which the majority was involved in inflammation (32%), lipid metabolism (16%), and extracellular matrix/remodeling (12%). A similar distribution of pathways across these categories, inflammation (36%), lipid metabolism (24%) and extracellular matrix/remodeling (8%) was observed in HFD-fed Ldlr-/-.Leiden mice. Detailed evaluation of these pathways revealed that a substantial proportion (11 out of 13) of human NASH inflammatory pathways was recapitulated in Ldlr-/-.Leiden mice. Furthermore, the activation state of identified master regulators of inflammation (i.e., specific transcription factors, cytokines, and growth factors) in human NASH was largely reflected in Ldlr-/-.Leiden mice, further substantiating its translational value. Conclusion: Human NASH is characterized by upregulation of specific inflammatory processes (e.g., "Fcgamma Receptor-mediated Phagocytosis in Macrophages and Monocytes," "PI3K signaling in B Lymphocytes") and master regulators (e.g., TNF, CSF2, TGFB1). The majority of these processes and regulators are modulated in the same direction in Ldlr-/-.Leiden mice fed HFD with a human-like macronutrient composition, thus demonstrating that specific experimental conditions recapitulate human disease on the molecular level of disease pathways and upstream/master regulators. PMID- 29527178 TI - The Zero Suicide Model: Applying Evidence-Based Suicide Prevention Practices to Clinical Care. AB - Suicide is reaching epidemic proportions, with over 44,000 deaths by suicide in the US, and 800,000 worldwide in 2015. This, despite research and development of evidence-based interventions that target suicidal behavior directly. Suicide prevention efforts need a comprehensive approach, and research must lead to effective implementation across public and mental health systems. A 10-year systematic review of evidence-based findings in suicide prevention summarized the areas necessary for translating research into practice. These include risk assessment, means restriction, evidence-based treatments, population screening combined with chain of care, monitoring, and follow-up. In this article, we review how suicide prevention research informs implementation in clinical settings where those most at risk present for care. Evidence-based and best practices address the fluctuating nature of suicide risk, which requires ongoing risk assessment, direct intervention and monitoring. In the US, the National Action Alliance for Suicide Prevention has put forth the Zero Suicide (ZS) Model, a framework to coordinate a multilevel approach to implementing evidence-based practices. We present the Assess, Intervene and Monitor for Suicide Prevention model (AIM-SP) as a guide for implementation of ZS evidence-based and best practices in clinical settings. Ten basic steps for clinical management model will be described and illustrated through case vignette. These steps are designed to be easily incorporated into standard clinical practice to enhance suicide risk assessment, brief interventions to increase safety and teach coping strategies and to improve ongoing contact and monitoring of high-risk individuals during transitions in care and high risk periods. PMID- 29527173 TI - Obesity, Metabolic Syndrome, and Musculoskeletal Disease: Common Inflammatory Pathways Suggest a Central Role for Loss of Muscle Integrity. AB - Inflammation can arise in response to a variety of stimuli, including infectious agents, tissue injury, autoimmune diseases, and obesity. Some of these responses are acute and resolve, while others become chronic and exert a sustained impact on the host, systemically, or locally. Obesity is now recognized as a chronic low grade, systemic inflammatory state that predisposes to other chronic conditions including metabolic syndrome (MetS). Although obesity has received considerable attention regarding its pathophysiological link to chronic cardiovascular conditions and type 2 diabetes, the musculoskeletal (MSK) complications (i.e., muscle, bone, tendon, and joints) that result from obesity-associated metabolic disturbances are less frequently interrogated. As musculoskeletal diseases can lead to the worsening of MetS, this underscores the imminent need to understand the cause and effect relations between the two, and the convergence between inflammatory pathways that contribute to MSK damage. Muscle mass is a key predictor of longevity in older adults, and obesity-induced sarcopenia is a significant risk factor for adverse health outcomes. Muscle is highly plastic, undergoes regular remodeling, and is responsible for the majority of total body glucose utilization, which when impaired leads to insulin resistance. Furthermore, impaired muscle integrity, defined as persistent muscle loss, intramuscular lipid accumulation, or connective tissue deposition, is a hallmark of metabolic dysfunction. In fact, many common inflammatory pathways have been implicated in the pathogenesis of the interrelated tissues of the musculoskeletal system (e.g., tendinopathy, osteoporosis, and osteoarthritis). Despite these similarities, these diseases are rarely evaluated in a comprehensive manner. The aim of this review is to summarize the common pathways that lead to musculoskeletal damage and disease that result from and contribute to MetS. We propose the overarching hypothesis that there is a central role for muscle damage with chronic exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle dysregulation can result in dysregulated tissue repair and an imbalance toward negative adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The commonalities support the conclusion that musculoskeletal pathology with MetS should be evaluated in a comprehensive and integrated manner to understand risk for other MSK-related conditions. Implications for conservative management strategies to regulate MetS are discussed, as are future research opportunities. PMID- 29527180 TI - A Cross-Sectional Analysis of Students' Intuitions When Interpreting CIs. AB - We explored how students interpret the relative likelihood of capturing a population parameter at various points of a CI in two studies. First, an online survey of 101 students found that students' beliefs about the probability curve within a CI take a variety of shapes, and that in fixed choice tasks, 39% CI [30, 48] of students' responses deviated from true distributions. For open ended tasks, this proportion rose to 85%, 95% CI [76, 90]. We interpret this as evidence that, for many students, intuitions about CIs distributions are ill formed, and their responses are highly susceptible to question format. Many students also falsely believed that there is substantial change in likelihood at the upper and lower limits of the CI, resembling a cliff effect (Rosenthal and Gaito, 1963; Nelson et al., 1986). In a follow-up study, a subset of 24 post graduate students participated in a 45-min semi-structured interview discussing the students' responses to the survey. Analysis of interview transcripts identified several competing intuitions about CIs, and several new CI misconceptions. During the interview, we also introduced an interactive teaching program displaying a cat's eye CI, that is, a CI that uses normal distributions to depict the correct likelihood distribution. Cat's eye CIs were designed to help students understand likelihood distributions and the relationship between interval length, C% level and sample size. Observed changes in students' intuitions following this teaching program suggest that a brief intervention using cat's eyes can reduce CI misconceptions and increase accurate CI intuitions. PMID- 29527179 TI - Schizophrenia and Category-Selectivity in the Brain: Normal for Faces but Abnormal for Houses. AB - Face processing is regularly found to be impaired in schizophrenia (SZ), thus suggesting that social malfunctioning might be caused by dysfunctional face processing. Most studies focused on emotional face processes, whereas non emotional face processing received less attention. While current reports on abnormal face processing in SZ are mixed, examinations of non-emotional face processing compared to adequate control stimuli may clarify whether SZ is characterized by a face-processing deficit. Patients with SZ (n = 28) and healthy controls (n = 30) engaged in an fMRI scan where images of non-emotional faces and houses were presented. A simple inverted-picture detection task warranted the participants' attention. Region of interest (ROI) analyses were conducted on face sensitive regions including the fusiform face area, the occipital face area, and the superior temporal sulcus. Scene-sensitivity was assessed in the parahippocampal place area (PPA) and served as control condition. Patients did not show aberrant face-related neural processes in face-sensitive regions. This finding was also evident when analyses were done on individually defined ROIs or on in-house-localizer ROIs. Patients revealed a decreased specificity toward house stimuli as reflected in decreased neural response toward houses in the PPA. Again, this result was supported by supplementary analyses. Neural activation toward neutral faces was not found to be impaired in SZ, therefore speaking against an overall face-processing deficit. Aberrant activation in scene sensitive PPA is also found in assessments of memory processes in SZ. It is up to future studies to show how impairments in PPA relate to functional outcome in SZ. PMID- 29527181 TI - Tonal Symmetry Induces Fluency and Sense of Well-Formedness. AB - Fluency influences grammaticality judgments of visually presented strings in artificial grammar learning (AGL). Of many potential sources that engender fluency, symmetry is considered to be an important factor. However, symmetry may function differently for visual and auditory stimuli, which present computationally different problems. Thus, the current study aimed to examine whether objectively manipulating fluency by speeding up perception (i.e., manipulating the inter-stimulus interval, ISI, between each syllable of a string) influenced judgments of tonal strings; and thus how symmetry-based fluency might influence judgments. In Experiment 1, with only a test phase, participants were required to give their preference ratings of tonal strings as a measurement of fluency. In experiment 2, participants were instructed to make grammaticality judgments after being incidentally trained on tonal symmetry. Results of Experiment 1 showed that tonal strings with shorter ISI were liked more than those with longer ISI while such difference was not found between symmetric and asymmetric strings without training. Additionally, Experiment 2 found both main effects of symmetry and ISI as well as an interaction. In particular, only asymmetric strings were more likely to be judged as grammatical when they were presented at a shorter ISI. Taken together, participants were sensitive to the fluency induced by the manipulation of ISI and sensitive to symmetry only after training. In sum, we conclude that objective speed influenced grammaticality judgments, implicit learning of tonal symmetry resulted in enhanced fluency, and that fluency may serve as a basis for grammaticality judgments. PMID- 29527182 TI - Improving Emotional Intelligence through Personality Development: The Effect of the Smart Phone Application based Dharma Life Program on Emotional Intelligence. AB - Emotional intelligence is established to predict success in leadership effectiveness in various contexts and has been linked to personality factors. This paper introduces Dharma Life Program, a novel approach to improving emotional intelligence by targeting maladaptive personality traits and triggering neuroplasticity through the use of a smart-phone application and mentoring. The program uses neuroplasticity to enable users to create a more adaptive application of their maladaptive traits, thus improving their emotional intelligence. In this study 26 participants underwent the Dharma Life Program in a leadership development setting. We assessed their emotional and social intelligence before and after the Dharma Life Program intervention using the Emotional and Social Competency Inventory (ESCI). The study found a significant improvement in the lowest three competencies and a significant improvement in almost all domains for the entire sample. Our findings suggest that the completion of the Dharma Life Program has a significant positive effect on Emotional and Social Competency scores and offers a new avenue for improving emotional intelligence competencies. PMID- 29527183 TI - Moral Judgments of In-Group and Out-Group Harm in Post-conflict Urban and Rural Croatian Communities. AB - Our research brings to light features of the social world that impact moral judgments and how they do so. The moral vignette data presented were collected in rural and urban Croatian communities that were involved to varying degrees in the Croatian Homeland War. We argue that rapid shifts in moral accommodations during periods of violent social strife can be explained by considering the role that coordination and social agents' ability to reconfigure their social network (i.e., relational mobility) play in moral reasoning. Social agents coordinate on (moral) norms, a general attitude which broadly facilitates cooperation, and makes possible the collective enforcement of compliance. During social strife interested parties recalibrate their determination of others' moral standing and recast their established moral circle, in accordance with their new or prevailing social investments. To that extent, social coordination-and its particular promoters, inhibitors, and determinants-effects significant changes in individuals' ranking of moral priorities. Results indicate that rural participants evaluate the harmful actions of third parties more harshly than urban participants. Coordination mediates that relationship between social environment and moral judgment. Coordination also matters more for the moral evaluation of the harmful actions of moral scenarios involving characters belonging to different social units than for scenarios involving characters belonging to the same group. Participants high in relational mobility-that ability to recompose one's social network-moralize similarly wrongdoings perpetrated by both in- and out-group members. Those low in relational mobility differentiate when an out-group member causes the harm. Additionally, perceptions of third-party guilt are also affected by specifics of the social environment. Overall, we find that social coordination and relational mobility affect moral reasoning more so than ethnic commitment. PMID- 29527184 TI - How Many Types of Dystonia? Pathophysiological Considerations. AB - Dystonia can be seen in a number of different phenotypes that may arise from different etiologies. The pathophysiological substrate of dystonia is related to three lines of research. The first postulate a loss of inhibition which may account for the excess of movement and for the overflow phenomena. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Finally, there are strong pieces of evidence from animal and human studies suggesting that alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation may play a pivotal role in primary dystonia. These working hypotheses have been generalized in all form of dystonia. On the other hand, several pieces of evidence now suggest that the pathophysiology may be slightly different in the different types of dystonia. Therefore, in the present review, we would like to discuss the neural mechanisms underlying the different forms of dystonia to disentangle the different weight and role of environmental and predisposing factors. PMID- 29527185 TI - Intra-Arterial Thrombolysis for Acute Central Retinal Artery Occlusion: A Systematic Review and Meta-Analysis. AB - Background and purpose: Acute central retinal artery occlusion (CRAO) is a serious ophthalmologic emergency that may result in monocular blindness. To date, studies evaluating intra-arterial thrombolysis (IAT) have not shown a definitive clinical benefit. We have conducted a systematic review with a meta-analysis to effectively evaluate this treatment option. Methods: A systematic literature search was focused on studies containing five or more patients undergoing IAT that included a control group treated with standard therapy. Pooled meta-analysis was performed. Results: Five retrospective controlled studies and one randomized clinical trial were identified satisfying all inclusion criteria resulting in the analysis of 236 patients treated with IAT and 255 patients treated with ST. A pooled fixed effects analysis resulted in an estimated odds ratio of 2.52, 95% CI (1.69, 3.77) (P < 0.0001) favoring IAT. Conclusion: IAT is a promising therapeutic option for CRAO with great potential. Further randomized trials are needed to establish a significant benefit and ensure the safety of the intervention. PMID- 29527186 TI - Basilar Artery Lateral Displacement May Be Associated with Migraine with Aura. AB - Objective: The objective of this study is to determine whether structural features of the vertebrobasilar arterial system are related to migraine. Background: Alterations in cerebral vascular structure and function have been associated with migraine, possibly mediated by hypoperfusion and/or endothelial dysfunction triggering cortical spreading depression. Vessel tortuosity, in particular, has been associated with both altered hemodynamics and endothelial function. Symptoms of migraine with aura (MWA) often localize to the occipital cortex, and evidence supports the localization of a migraine generator to the brain stem, suggesting that the vertebrobasilar system may be of particular relevance. Methods: We performed a post hoc exploratory analysis of data collected in a prospective, observational, case-control study enrolling MWA, migraine without aura (MwoA), and control subjects in a 1:1:1 ratio. 3 T high resolution MR angiography was used to assess vascular structure, and arterial spin-labeled perfusion MRI to measure interictal cerebral blood flow (CBF). White matter lesions were assessed using T2/FLAIR. Vertebral and basilar artery (BA) diameters and BA total lateral displacement were measured. Results: 162 subjects were included (52 control/52 MWA/58 MwoA). Mean age was 33 +/- 6 years, and 78% were female. BA diameter was similar across groups (3.6 +/- 0.6 mm in all 3 groups). BA displacement was similar in MwoA (5.1 +/- 3.0 mm) and controls (4.9 +/- 3.1 mm), but tended to be greater in MWA (6.3 +/- 3.8 mm, p = 0.055 vs. controls). BA displacement increased with age (p < 0.001) was greater in men vs. women (6.6 +/- 4.2 vs. 5.1 +/- 3.0, p = 0.02) and with increased migraine frequency (p = 0.03). In multivariate analysis, BA displacement was significantly greater in MWA subjects (p = 0.02), with older age (p = 0.003), and in men (p = 0.046). In regression analysis adjusted for age and sex, BA displacement remained significantly greater with increasing migraine frequency (p = 0.02). There was no association between BA displacement and interictal posterior cerebral artery territory CBF or overall white matter lesions. Conclusion: BA lateral displacement may be associated with MWA as well as headache frequency. This association does not appear to be mediated by cerebral hypoperfusion. PMID- 29527187 TI - Emerging Viral Infections in Sub-Saharan Africa and the Developing Nervous System: A Mini Review. AB - The global public health concern is heightened over the increasing number of emerging viruses, i.e., newly discovered or previously known that have expanded into new geographical zones. These viruses challenge the health-care systems in sub-Saharan Africa (SSA) countries from which several of them have originated and been transmitted by insects worldwide. Some of these viruses are neuroinvasive, but have been relatively neglected by neuroscientists. They may provide experiments by nature to give a time window for exposure to a new virus within sizeable, previously non-infected human populations, which, for instance, enables studies on potential long-term or late-onset effects on the developing nervous system. Here, we briefly summarize studies on the developing brain by West Nile, Zika, and Chikungunya viruses, which are mosquito-borne and have spread worldwide out of SSA. They can all be neuroinvasive, but their effects vary from malformations caused by prenatal infections to cognitive disturbances following perinatal or later infections. We also highlight Ebola virus, which can leave surviving children with psychiatric disturbances and cause persistent infections in the non-human primate brain. Greater awareness within the neuroscience community is needed to emphasize the menace evoked by these emerging viruses to the developing brain. In particular, frontline neuroscience research should include neuropediatric follow-up studies in the field on long-term or late-onset cognitive and behavior disturbances or neuropsychiatric disorders. Studies on pathogenetic mechanisms for viral-induced perturbations of brain maturation should be extended to the vulnerable periods when neurocircuit formations are at peaks during infancy and early childhood. PMID- 29527188 TI - Polysaccharide IV from Lycium barbarum L. Improves Lipid Profiles of Gestational Diabetes Mellitus of Pregnancy by Upregulating ABCA1 and Downregulating Sterol Regulatory Element-Binding Transcription 1 via miR-33. AB - Lycium barbarum L. (LBL) has beneficial effects on gestational diabetes mellitus (GDM) but the related mechanism remains unclear. Polysaccharides of LBL (LBLP) are the main bioactive components of LBL. miR-33, ATP-binding cassette transporter A1 (ABCA1) and sterol regulatory element-binding transcription 1 (SREBF1) affect lipid profiles, which are associated with GDM risk. LBLP may exert protective against GDM by affecting these molecules. Four LBLP fractions: LBLP-I, LBLP-II, LBLP-III, and LBLP-IV were isolated from LBL and further purified by using DEAE-Sephadex column. The effects of purified each fraction on pancreatic beta cells were comparatively evaluated. A total of 158 GDM patients were recruited and randomly divided into LBL group (LG) and placebo group (CG). miR-33 levels, lipid profiles, insulin resistance and secretory functions were measured. The association between serum miR-33 levels and lipid profiles were evaluated by using Spearman's rank-order correlation test. After 4-week therapy, LBL reduced miR-33 level, insulin resistance and increased insulin secretion of GDM patients. LBL increased the levels of ABCA1, high-density lipoprotein cholesterol (HDL-C) and reduced miR-33, SREBF1, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and malondialdehyde. Homeostatic model assessment of beta-cell function and insulin resistance was lower in LG than in CG, whereas homeostatic model assessment of beta-cell function and insulin secretory function was higher in LG than in CG. There was a strong positive association between miR-33 level and TG, or TC and or LDL-C, and a strong negative association between miR-33 level and HDL-C. The levels of miR-33 had negative relation with ABCA1 and positive relation with SREBF1. ABCA1 has negative relation with TG, TC, and LDL-C and positive relation with HDL-C. Inversely, SREBF1 had positive relation with TG, TC, and LDL-C and negative relation with HDL-C. The main bioactive compound LBLP-IV of LBL increased insulin secretion of beta cells and the levels of ABCA1, and reduced miR-33 levels and SREBF1 in beta cells. However, LBLP-IV could not change the levels of these molecules anymore when miR-33 was overexpressed or silenced. LBLP IV had the similar effects with LBL on beta cells while other components had no such effects. Thus, LBLP-IV from LBL improves lipid profiles by upregulating ABCA1 and downregulating SREBF1 via miR-33. PMID- 29527190 TI - Effects of Growth Hormone Replacement on Peripheral Muscle and Exercise Capacity in Severe Growth Hormone Deficiency. AB - Objective: The aim of this study is to evaluate the effect of growth hormone therapy (rGH) on mitochondrial function on peripheral muscle and to correlate with exercise capacity in subjects with severe adult growth hormone deficiency (GHD). Design: Six months, double-blind, randomized, crossover, placebo controlled trial of subcutaneous rGH in 17 patients with GHD. Measurements: Quadriceps muscle biopsies were obtained at baseline, 3 months, and 6 months to measure succinate dehydrogenase (SDH) to assess mitochondrial activity. Exercise capacity was measured with cardiopulmonary exercise testing. Lipids, glycemic parameters, and body fat levels were also measured. Results: Serum insulin-like growth factor 1 (IGF1) levels reduced fat mass by 3.2% (p < 0.05) and normalized with rGH in the active phase (p < 0.005). Patients showed an increase in SDH (p < 0.01) from base line that differed between placebo and rGH therapy treatment groups (p < 0.05): those treated by rGH followed by placebo showed a significant increase in SDH (p < 0.001) followed by a decrease, with a significant between group difference at the end of 6 months (p < 0.05). No significant improvements or correlation with exercise capacity was found. Conclusion: Short-term rGH for 3 months normalized IGF1 levels, reduced fat mass, and had a significant effect on mitochondrial function, but exercise capacity was unchanged. Clinical Trial Registration: Number ISRCTN94165486. PMID- 29527189 TI - The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. AB - For more than 35 years, the NOD mouse has been the primary animal model for studying autoimmune diabetes. During this time, striking similarities to the human disease have been uncovered. In both species, unusual polymorphisms in a major histocompatibility complex (MHC) class II molecule confer the most disease risk, disease is caused by perturbations by the same genes or different genes in the same biological pathways and that diabetes onset is preceded by the presence of circulating autoreactive T cells and autoantibodies that recognize many of the same islet antigens. However, the relevance of the NOD model is frequently challenged due to past failures translating therapies from NOD mice to humans and because the appearance of insulitis in mice and some patients is different. Nevertheless, the NOD mouse remains a pillar of autoimmune diabetes research for its usefulness as a preclinical model and because it provides access to invasive procedures as well as tissues that are rarely procured from patients or controls. The current article is focused on approaches to improve the NOD mouse by addressing reasons why immune therapies have failed to translate from mice to humans. We also propose new strategies for mixing and editing the NOD genome to improve the model in ways that will better advance our understanding of human diabetes. As proof of concept, we report that diabetes is completely suppressed in a knock-in NOD strain with a serine to aspartic acid substitution at position 57 in the MHC class II Abeta. This supports that similar non-aspartic acid substitutions at residue 57 of variants of the human class II HLA-DQbeta homolog confer diabetes risk. PMID- 29527191 TI - Pseudomonas rhizophila S211, a New Plant Growth-Promoting Rhizobacterium with Potential in Pesticide-Bioremediation. AB - A number of Pseudomonas strains function as inoculants for biocontrol, biofertilization, and phytostimulation, avoiding the use of pesticides and chemical fertilizers. Here, we present a new metabolically versatile plant growth promoting rhizobacterium, Pseudomonas rhizophila S211, isolated from a pesticide contaminated artichoke field that shows biofertilization, biocontrol and bioremediation potentialities. The S211 genome was sequenced, annotated and key genomic elements related to plant growth promotion and biosurfactant (BS) synthesis were elucidated. S211 genome comprises 5,948,515 bp with 60.4% G+C content, 5306 coding genes and 215 RNA genes. The genome sequence analysis confirmed the presence of genes involved in plant-growth promoting and remediation activities such as the synthesis of ACC deaminase, putative dioxygenases, auxin, pyroverdin, exopolysaccharide levan and rhamnolipid BS. BS production by P. rhizophila S211 grown on olive mill wastewater based media was effectively optimized using a central-composite experimental design and response surface methodology (RSM). The optimum conditions for maximum BS production yield (720.80 +/- 55.90 mg/L) were: 0.5% (v/v) inoculum size, 15% (v/v) olive oil mill wastewater (OMWW) and 40 degrees C incubation temperature at pH 6.0 for 8 days incubation period. Biochemical and structural characterization of S211 BS by chromatography and spectroscopy studies suggested the glycolipid nature of the BS. P. rhizophila rhamnolipid was stable over a wide range of temperature (40-90 degrees C), pH (6-10), and salt concentration (up to 300 mM NaCl). Due to its low cost production, emulsification activities and high performance in solubilization enhancement of chemical pesticides, the indigenous BS-producing PGPR S211 could be used as a promising agent for environmental bioremediation of pesticide contaminated agricultural soils. PMID- 29527192 TI - Bacterial Preferences for Specific Soil Particle Size Fractions Revealed by Community Analyses. AB - Genetic fingerprinting demonstrated in previous studies that differently sized soil particle fractions (PSFs; clay, silt, and sand with particulate organic matter (POM)) harbor microbial communities that differ in structure, functional potentials and sensitivity to environmental conditions. To elucidate whether specific bacterial or archaeal taxa exhibit preference for specific PSFs, we examined the diversity of PCR-amplified 16S rRNA genes by high-throughput sequencing using total DNA extracted from three long-term fertilization variants (unfertilized, fertilized with minerals, and fertilized with animal manure) of an agricultural loamy sand soil and their PSFs. The PSFs were obtained by gentle ultrasonic dispersion, wet sieving, and centrifugation. The abundance of bacterial taxa assigned to operational taxonomic units (OTUs) differed less than 2.7% between unfractionated soil and soil based on combined PSFs. Across the three soil variants, no archaeal OTUs, but many bacterial OTUs, the latter representing 34-56% of all amplicon sequences, showed significant preferences for specific PSFs. The sand-sized fraction with POM was the preferred site for members of Bacteroidetes and Alphaproteobacteria, while Gemmatimonadales preferred coarse silt, Actinobacteria and Nitrosospira fine silt, and Planctomycetales clay. Firmicutes were depleted in the sand-sized fraction. In contrast, archaea, which represented 0.8% of all 16S rRNA gene sequences, showed only little preference for specific PSFs. We conclude that differently sized soil particles represent distinct microenvironments that support specific bacterial taxa and that these preferences could strongly contribute to the spatial heterogeneity and bacterial diversity found in soils. PMID- 29527193 TI - Streptococcus agalactiae Inhibits Candida albicans Hyphal Development and Diminishes Host Vaginal Mucosal TH17 Response. AB - Streptococcus agalactiae and Candida albicans often co-colonize the female genital tract, and under certain conditions induce mucosal inflammation. The role of the interaction between the two organisms in candidal vaginitis is not known. In this study, we found that co-infection with S. agalactiae significantly attenuated the hyphal development of C. albicans, and that EFG1-Hwp1 signal pathway of C. albicans was involved in this process. In a mouse model of vulvovaginal candidiasis (VVC), the fungal burden and the levels of pro inflammatory cytokines, IL-1beta, IL-6 and TNF-alpha showed a increase on co infection with S. agalactiae, while the level of TH17 T cells and IL-17 in the cervicovaginal lavage fluid were significantly decreased. Our results indicate that S. agalactiae inhibits C. albicans hyphal development by downregulating the expression of EFG1-Hwp1. The interaction between S. agalactiae and C. albicans may attenuate host vaginal mucosal TH17 immunity and contribute to mucosal colonization by C. albicans. PMID- 29527194 TI - A Glycine Riboswitch in Streptococcus pyogenes Controls Expression of a Sodium:Alanine Symporter Family Protein Gene. AB - Regulatory RNAs play important roles in the control of bacterial gene expression. In this study, we investigated gene expression regulation by a putative glycine riboswitch located in the 5'-untranslated region of a sodium:alanine symporter family (SAF) protein gene in the group A Streptococcus pyogenes serotype M49 strain 591. Glycine-dependent gene expression mediated by riboswitch activity was studied using a luciferase reporter gene system. Maximal reporter gene expression was observed in the absence of glycine and in the presence of low glycine concentrations. Differences in glycine-dependent gene expression were not based on differential promoter activity. Expression of the SAF protein gene and the downstream putative cation efflux protein gene was investigated in wild-type bacteria by RT-qPCR transcript analyses. During growth in the presence of glycine (>=1 mM), expression of the genes were downregulated. Northern blot analyses revealed premature transcription termination in the presence of high glycine concentrations. Growth in the presence of 0.1 mM glycine led to the production of a full-length transcript. Furthermore, stability of the SAF protein gene transcript was drastically reduced in the presence of glycine. We conclude that the putative glycine riboswitch in S. pyogenes serotype M49 strain 591 represses expression of the SAF protein gene and the downstream putative cation efflux protein gene in the presence of high glycine concentrations. Sequence and secondary structure comparisons indicated that the streptococcal riboswitch belongs to the class of tandem aptamer glycine riboswitches. PMID- 29527195 TI - Indigenous Pseudomonas spp. Strains from the Olive (Olea europaea L.) Rhizosphere as Effective Biocontrol Agents against Verticillium dahliae: From the Host Roots to the Bacterial Genomes. AB - The use of biological control agents (BCA), alone or in combination with other management measures, has gained attention over the past decades, driven by the need to seek for sustainable and eco-friendly alternatives to confront plant pathogens. The rhizosphere of olive (Olea europaea L.) plants is a source of bacteria with potential as biocontrol tools against Verticillium wilt of olive (VWO) caused by Verticillium dahliae Kleb. A collection of bacterial isolates from healthy nursery-produced olive (cultivar Picual, susceptible to VWO) plants was generated based on morphological, biochemical and metabolic characteristics, chemical sensitivities, and on their in vitro antagonistic activity against several olive pathogens. Three strains (PIC25, PIC105, and PICF141) showing high in vitro inhibition ability of pathogens' growth, particularly against V. dahliae, were eventually selected. Their effectiveness against VWO caused by the defoliating pathotype of V. dahliae was also demonstrated, strain PICF141 being the rhizobacteria showing the best performance as BCA. Genotypic and phenotypic traits traditionally associated with plant growth promotion and/or biocontrol abilities were evaluated as well (e.g., phytase, xylanase, catalase, cellulase, chitinase, glucanase activities, and siderophore and HCN production). Multi-locus sequence analyses of conserved genes enabled the identification of these strains as Pseudomonas spp. Strain PICF141 was affiliated to the "Pseudomonas mandelii subgroup," within the "Pseudomonas fluorescens group," Pseudomonas lini being the closest species. Strains PIC25 and PIC105 were affiliated to the "Pseudomonas aeruginosa group," Pseudomonas indica being the closest relative. Moreover, we identified P. indica (PIC105) for the first time as a BCA. Genome sequencing and in silico analyses allowed the identification of traits commonly associated with plant-bacteria interactions. Finally, the root colonization ability of these olive rhizobacteria was assessed, providing valuable information for the future development of formulations based on these strains. A set of actions, from rhizosphere isolation to genome analysis, is proposed and discussed for selecting indigenous rhizobacteria as effective BCAs. PMID- 29527196 TI - Cultivation-Independent and Cultivation-Dependent Analysis of Microbes in the Shallow-Sea Hydrothermal System Off Kueishantao Island, Taiwan: Unmasking Heterotrophic Bacterial Diversity and Functional Capacity. AB - Shallow-sea hydrothermal systems experience continuous fluctuations of physicochemical conditions due to seawater influx which generates variable habitats, affecting the phylogenetic composition and metabolic potential of microbial communities. Until recently, studies of submarine hydrothermal communities have focused primarily on chemolithoautotrophic organisms, however, there have been limited studies on heterotrophic bacteria. Here, fluorescence in situ hybridization, high throughput 16S rRNA gene amplicon sequencing, and functional metagenomes were used to assess microbial communities from the shallow sea hydrothermal system off Kueishantao Island, Taiwan. The results showed that the shallow-sea hydrothermal system harbored not only autotrophic bacteria but abundant heterotrophic bacteria. The potential for marker genes sulfur oxidation and carbon fixation were detected in the metagenome datasets, suggesting a role for sulfur and carbon cycling in the shallow-sea hydrothermal system. Furthermore, the presence of diverse genes that encode transporters, glycoside hydrolases, and peptidase indicates the genetic potential for heterotrophic utilization of organic substrates. A total of 408 cultivable heterotrophic bacteria were isolated, in which the taxonomic families typically associated with oligotrophy, copiotrophy, and phototrophy were frequently found. The cultivation independent and -dependent analyses performed herein show that Alphaproteobacteria and Gammaproteobacteria represent the dominant heterotrophs in the investigated shallow-sea hydrothermal system. Genomic and physiological characterization of a novel strain P5 obtained in this study, belonging to the genus Rhodovulum within Alphaproteobacteria, provides an example of heterotrophic bacteria with major functional capacity presented in the metagenome datasets. Collectively, in addition to autotrophic bacteria, the shallow-sea hydrothermal system also harbors many heterotrophic bacteria with versatile genetic potential to adapt to the unique environmental conditions. PMID- 29527197 TI - Multiple, Distinct Intercontinental Lineages but Isolation of Australian Populations in a Cosmopolitan Lichen-Forming Fungal Taxon, Psora decipiens (Psoraceae, Ascomycota). AB - Multiple drivers shape the spatial distribution of species, including dispersal capacity, niche incumbency, climate variability, orographic barriers, and plate tectonics. However, biogeographic patterns of fungi commonly do not fit conventional expectations based on studies of animals and plants. Fungi, in general, are known to occur across exceedingly broad, intercontinental distributions, including some important components of biological soil crust communities (BSCs). However, molecular data often reveal unexpected biogeographic patterns in lichenized fungal species that are assumed to have cosmopolitan distributions. The lichen-forming fungal species Psora decipiens is found on all continents, except Antarctica and occurs in BSCs across diverse habitats, ranging from hot, arid deserts to alpine habitats. In order to better understand factors that shape population structure in cosmopolitan lichen-forming fungal species, we investigated biogeographic patterns in the cosmopolitan taxon P. decipiens, along with the closely related taxa P. crenata and P. saviczii. We generated a multi locus sequence dataset based on a worldwide sampling of these taxa in order to reconstruct evolutionary relationships and explore phylogeographic patterns. Both P. crenata and P. decipiens were not recovered as monophyletic; and P. saviczii specimens were recovered as a monophyletic clade closely related to a number of lineages comprised of specimens representing P. decipiens. Striking phylogeographic patterns were observed for P. crenata, with populations from distinct geographic regions belonging to well-separated, monophyletic lineages. South African populations of P. crenata were further divided into well-supported sub-clades. While well-supported phylogenetic substructure was also observed for the nominal taxon P. decipiens, nearly all lineages were comprised of specimens collected from intercontinental populations. However, all Australian specimens representing P. decipiens were recovered within a single well-supported monophyletic clade consisting solely of Australian samples. Our study supports up to 10 candidate species-level lineages in P. decipiens, based on genealogical concordance and coalescent-based species delimitation analyses. Our results support the general pattern of the biogeographic isolation of lichen-forming fungal populations in Australia, even in cases where closely related congeners have documented intercontinental distributions. Our study has important implications for understanding factors influencing diversification and distributions of lichens associated with BSC. PMID- 29527199 TI - Selective Grazing by a Tropical Copepod (Notodiaptomus iheringi) Facilitates Microcystis Dominance. AB - Top-down grazer control of cyanobacteria is a controversial topic due to conflicting reports of success and failure as well as a bias toward studies in temperate climates with large generalist grazers like Daphnia. In the tropical lowland lakes of Brazil, calanoid copepods of the Notodiaptomus complex dominate zooplankton and co-exist in high abundance with permanent blooms of toxic cyanobacteria, raising questions for grazer effects on bloom dynamics (i.e., top down control vs. facilitation of cyanobacterial dominance). Accordingly, the effect of copepod grazing on the relative abundance of Microcystis co-cultured with a eukaryotic phytoplankton (Cryptomonas) was evaluated in a series of 6-day laboratory experiments. Grazer effects were tested in incubations where the growth of each phytoplankton in the presence or absence of the copepod Notodiaptomus iheringi was monitored in 1 L co-cultures, starting with a 6-fold initial dominance of Cryptomonas by biomass. Compared to the no grazer controls, N. iheringi reduced the growth of both phytoplankton, but Cryptomonas growth was reduced to negative values while Microcystis growth continued positively despite grazers. Hence, in a matter of 6 days selective grazing by N. iheringi increased the biomass of Microcystis relative to Cryptomonas by an order of magnitude compared to controls, and thus, facilitated the dominance of this cyanobacterium. To account for the potential effect of allelopathy, we performed a secondary experiment comparing the abundance and growth rate of Microcystis and Cryptomonas in single and mixed co-cultures in the absence of grazers. The growth rate of Microcystis was unaffected by the presence or relative abundance of Cryptomonas, and vice versa, indicating no allelopathic effects. Our results suggest that selectively grazing zooplankton may facilitate cyanobacteria blooms by grazing on their eukaryotic phytoplankton competitors in nature. Given that selective grazers predominate zooplankton biomass in warmer waters, grazer facilitation of blooms may be a common but poorly understood regulator of plankton dynamics in a warmer and more eutrophic world. PMID- 29527198 TI - The Genome-Scale Integrated Networks in Microorganisms. AB - The genome-scale cellular network has become a necessary tool in the systematic analysis of microbes. In a cell, there are several layers (i.e., types) of the molecular networks, for example, genome-scale metabolic network (GMN), transcriptional regulatory network (TRN), and signal transduction network (STN). It has been realized that the limitation and inaccuracy of the prediction exist just using only a single-layer network. Therefore, the integrated network constructed based on the networks of the three types attracts more interests. The function of a biological process in living cells is usually performed by the interaction of biological components. Therefore, it is necessary to integrate and analyze all the related components at the systems level for the comprehensively and correctly realizing the physiological function in living organisms. In this review, we discussed three representative genome-scale cellular networks: GMN, TRN, and STN, representing different levels (i.e., metabolism, gene regulation, and cellular signaling) of a cell's activities. Furthermore, we discussed the integration of the networks of the three types. With more understanding on the complexity of microbial cells, the development of integrated network has become an inevitable trend in analyzing genome-scale cellular networks of microorganisms. PMID- 29527200 TI - Whole Genome Sequence Analysis of CTX-M-15 Producing Klebsiella Isolates Allowed Dissecting a Polyclonal Outbreak Scenario. AB - Extended-spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae pose an important threat of infection with increased morbidity and mortality, especially for immunocompromised patients. Here, we use the rise of multidrug-resistant K. pneumoniae in a German neurorehabilitation center from April 2015 to April 2016 to dissect the benefit of whole genome sequencing (WGS) for outbreak analyses. In total, 53 isolates were obtained from 52 patients and examined using WGS. Two independent analysis strategies (reference-based and -free) revealed the same distinct clusters of two CTX-M-15 producing K. pneumoniae clones (ST15, n = 31; ST405, n = 7) and one CTX-M-15 producing Klebsiella quasipneumoniae strain (ST414, n = 8). Additionally, we determined sequence variations associated with antimicrobial resistance phenotypes in single isolates expressing carbapenem and colistin resistance, respectively. For rapid detection of the major K. pneumoniae outbreak clone (ST15), a selective triplex PCR was deduced from WGS data of the major outbreak strain and K. pneumoniae genome data deposited in central databases. Moreover, we introduce two novel open-source applications supporting reference genome selection (refRank; https://gitlab.com/s.fuchs/refRank) and alignment-based SNP-filtering (SNPfilter; https://gitlab.com/s.fuchs/snpfilter) in NGS analyses. PMID- 29527201 TI - Designing Antibacterial Peptides with Enhanced Killing Kinetics. AB - Antimicrobial peptides (AMPs) are gaining attention as substitutes for antibiotics in order to combat the risk posed by multi-drug resistant pathogens. Several research groups are engaged in design of potent anti-infective agents using natural AMPs as templates. In this study, a library of peptides with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family were screened using popular online prediction algorithms. These peptide variants were designed in a manner to retain the conserved residues within the MAP family. The prediction algorithms were found to effectively classify peptides based on their antimicrobial nature. In order to improve the activity of the identified peptides, molecular dynamics (MD) simulations, using bilayer and micellar systems could be used to design and predict effect of residue substitution on membranes of microbial and mammalian cells. The inference from MD simulation studies well corroborated with the wet-lab observations indicating that MD-guided rational design could lead to discovery of potent AMPs. The effect of the residue substitution on membrane activity was studied in greater detail using killing kinetic analysis. Killing kinetics studies on Gram-positive, negative and human erythrocytes indicated that a single residue change has a drastic effect on the potency of AMPs. An interesting outcome was a switch from monophasic to biphasic death rate constant of Staphylococcus aureus due to a single residue mutation in the peptide. PMID- 29527202 TI - Comprehensive Evaluation of the MBT STAR-BL Module for Simultaneous Bacterial Identification and beta-Lactamase-Mediated Resistance Detection in Gram-Negative Rods from Cultured Isolates and Positive Blood Cultures. AB - Objective: This study evaluated the capability of a MALDI Biotyper system equipped with the newly introduced MBT STAR-BL module to simultaneously perform species identification and beta-lactamase-mediated resistance detection in bacteremia -causing bacteria isolated from cultured isolates and patient-derived blood cultures (BCs). Methods: Two hundred retrospective cultured isolates and 153 prospective BCs containing Gram-negative rods (GNR) were collected and subjected to direct bacterial identification, followed by the measurement of beta lactamase activities against ampicillin, piperacillin, cefotaxime, ceftazidime, and meropenem using the MBT STAR-BL module. The results and turnaround times were compared with those of routine microbiological processing. All strains were also characterized by beta-lactamase PCR and sequencing. Results: Using the saponin based extraction method, MALDI-TOF MS correctly identified bacteria in 116/134 (86.6%) monomicrobial BCs. The detection sensitivities for beta-lactamase activities against ampicillin, piperacillin, third-generation cephalosporin and meropenem were 91.3, 100, 97.9, and 100% for cultured isolates, and 80.4, 100, 68.8, and 40% for monomicrobial BCs (n = 134) respectively. The overall specificities ranged from 91.5 to 100%. Furthermore, the MBT STAR-BL and conventional drug susceptibility test results were concordant in 14/19 (73.7%) polymicrobial cultures. Reducing the logRQ cut-off value from 0.4 to 0.2 increased the direct detection sensitivities for beta-lactamase activities against ampicillin, cefotaxime and meropenem in BCs to 85.7, 87.5, and 100% respectively. The MBT STAR-BL test enabled the reporting of beta-lactamase producing GNR at 14.16 and 47.64 h before the interim and final reports of routine BCs processing, respectively, were available. Conclusion: The MALDI Biotyper system equipped with the MBT STAR-BL module enables the simultaneous rapid identification of bacterial species and beta-lactamase-mediated resistance from BCs and cultured isolates. Adjustment of the logRQ cut-off value to 0.2 significantly increased the detection sensitivities for clinically important drug resistant pathogens. PMID- 29527203 TI - Fungal Deoxynivalenol-Induced Enterocyte Distress Is Attenuated by Adulterated Adlay: In Vitro Evidences for Mucoactive Counteraction. AB - Adlay is a cereal crop that has long been used as traditional herbal medicine and as a highly nourishing food. However, deoxynivalenol (DON), the most prevalent trichothecene mycotoxin worldwide, frequently spoils grains, including adlay, via fungal infection. On the basis of an assumption that the actions of DON in the gut could be modified by adlay consumption, we simulated the impacts of co exposure in enterocytes and investigated the effectiveness of treatment with adlay for reducing the risk of DON-induced inflammation and epithelia barrier injury. In particular, adlay suppressed DON-induced pro-inflammatory signals such as mitogen-activated kinase transduction and the epidermal growth factor receptor linked pathway. In addition to regulation of pro-inflammatory responses, adlay treatment interfered with DON-induced disruption of the epithelial barrier. Mechanistically, adlay could boost the activation of protein kinase C (PKC) and cytosolic translocation of human antigen R (HuR) protein, which played critical roles in the epithelial restitution, resulting in protection against disruption of enterocyte barrier integrity. Notably, DON abrogated the Ras homolog gene family member A GTPase-mediated actin cytoskeletal network, which was diminished by adlay treatment in PKC and HuR-dependent ways. Taken together, this study provides evidences for adlay-based attenuation of trichothecene-induced gut distress, implicating potential use of a new gut protector against enteropathogenic insults in diets. PMID- 29527204 TI - Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India. AB - Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive form of primary immunodeficiency disorder (PID) characterized by the deficiency of MHC class II molecules. This deficiency affects the cellular and humoral immune response by impairing the development of CD4+ T helper (Th) cells and Th cell-dependent antibody production by B cells. Affected children typically present with severe respiratory and gastrointestinal tract infections. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy available for treating these patients. This is the first report from India wherein we describe the clinical, immunological, and molecular findings in five patients with MHC class II deficiency. Our patients presented with recurrent lower respiratory tract infection as the most common clinical presentation within their first year of life and had a complete absence of human leukocyte antigen antigen D-related (HLA-DR) expression on B cells and monocytes. Molecular characterization revealed novel mutations in RFAXP, RFX5, and CIITA genes. Despite genetic heterogeneity, these patients were clinically indistinguishable. Two patients underwent HSCT but had a poor survival outcome. Detectable level of T cell receptor excision circles (TRECs) were measured in our patients, highlighting that this form of PID may be missed by TREC-based newborn screening program for severe combined immunodeficiency. PMID- 29527205 TI - Proximity of Cytomegalovirus-Specific CD8+ T Cells to Replicative Senescence in Human Immunodeficiency Virus-Infected Individuals. AB - Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, age-related morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other age-related morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIV-infected individuals seropositive for anti-CMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under long-term ART. Median levels of IL-6, TNF-alpha, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8+ T cells' shorter than the general lymphocyte population, CD57+CD8+ T cells' shorter than CD8+ T cells' and CMV-specific CD57+CD8+ T cells' the shortest of all. Telomeres of HIV-specific CD8+ T cells were longer than those of CMV-specific CD8+ T cells in all cases tested and over 10 years, CMV specific CD8+ T cell telomeres of two HIV-infected individuals eroded faster than those of HIV-specific CD8+ T cells. These data indicate that CMV-specific CD8+ T cells of HIV-infected individuals are the lymphocytes closest to telomere-imposed replicative senescence. Exhaustive proliferation of CMV-specific CD8+ T cells in HIV-infected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation. PMID- 29527206 TI - The Armadillo (Dasypus novemcinctus): A Witness but Not a Functional Example for the Emergence of the Butyrophilin 3/Vgamma9Vdelta2 System in Placental Mammals. AB - 1-5% of human blood T cells are Vgamma9Vdelta2 T cells whose T cell receptor (TCR) contain a TRGV9/TRGJP rearrangement and a TRDV2 comprising Vdelta2-chain. They respond to phosphoantigens (PAgs) like isopentenyl pyrophosphate or (E)-4 hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) in a butyrophilin 3 (BTN3) dependent manner and may contribute to the control of mycobacterial infections. These cells were thought to be restricted to primates, but we demonstrated by analysis of genomic databases that TRGV9, TRDV2, and BTN3 genes coevolved and emerged together with placental mammals. Furthermore, we identified alpaca (Vicugna pacos) as species with typical Vgamma9Vdelta2 TCR rearrangements and currently aim to directly identify Vgamma9Vdelta2 T cells and BTN3. Other candidates to study this coevolution are the bottlenose dolphin (Tursiops truncatus) and the nine-banded armadillo (Dasypus novemcinctus) with genomic sequences encoding open reading frames for TRGV9, TRDV2, and the extracellular part of BTN3. Dolphins have been shown to express Vgamma9- and Vdelta2-like TCR chains and possess a predicted BTN3-like gene homologous to human BTN3A3. The other candidate, the armadillo, is of medical interest since it serves as a natural reservoir for Mycobacterium leprae. In this study, we analyzed the armadillo genome and found evidence for multiple non-functional BTN3 genes including genomic context which closely resembles the organization of the human, alpaca, and dolphin BTN3A3 loci. However, no BTN3 transcript could be detected in armadillo cDNA. Additionally, attempts to identify a functional TRGV9/TRGJP rearrangement via PCR failed. In contrast, complete TRDV2 gene segments preferentially rearranged with a TRDJ4 homolog were cloned and co-expressed with a human Vgamma9-chain in murine hybridoma cells. These cells could be stimulated by immobilized anti-mouse CD3 antibody but not with human RAJI-RT1Bl cells and HMBPP. So far, the lack of expression of TRGV9 rearrangements and BTN3 renders the armadillo an unlikely candidate species for PAg-reactive Vgamma9Vdelta2 T cells. This is in line with the postulated coevolution of the three genes, where occurrence of Vgamma9Vdelta2 TCRs coincides with a functional BTN3 molecule. PMID- 29527207 TI - HLA-G Haplotypes Are Differentially Associated with Asthmatic Features. AB - Human leukocyte antigen (HLA)-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC). Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G) expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA G dosage is challenging because of its many levels of polymorphism (dimerization, association with beta2-microglobulin, and alternative splicing), thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF) binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a multicenter cohort, thus support the pertinence of HLA-G haplotypes as predictive genetic markers for asthma. PMID- 29527208 TI - Integrative Approaches to Understand the Mastery in Manipulation of Host Cytokine Networks by Protozoan Parasites with Emphasis on Plasmodium and Leishmania Species. AB - Diseases by protozoan pathogens pose a significant public health concern, particularly in tropical and subtropical countries, where these are responsible for significant morbidity and mortality. Protozoan pathogens tend to establish chronic infections underscoring their competence at subversion of host immune processes, an important component of disease pathogenesis and of their virulence. Modulation of cytokine and chemokine levels, their crosstalks and downstream signaling pathways, and thereby influencing recruitment and activation of immune cells is crucial to immune evasion and subversion. Many protozoans are now known to secrete effector molecules that actively modulate host immune transcriptome and bring about alterations in host epigenome to alter cytokine levels and signaling. The complexity of multi-dimensional events during interaction of hosts and protozoan parasites ranges from microscopic molecular levels to macroscopic ecological and epidemiological levels that includes disrupting metabolic pathways, cell cycle (Toxoplasma and Theileria sp.), respiratory burst, and antigen presentation (Leishmania spp.) to manipulation of signaling hubs. This requires an integrative systems biology approach to combine the knowledge from all these levels to identify the complex mechanisms of protozoan evolution via immune escape during host-parasite coevolution. Considering the diversity of protozoan parasites, in this review, we have focused on Leishmania and Plasmodium infections. Along with the biological understanding, we further elucidate the current efforts in generating, integrating, and modeling of multi-dimensional data to explain the modulation of cytokine networks by these two protozoan parasites to achieve their persistence in host via immune escape during host parasite coevolution. PMID- 29527209 TI - Receptor-Interacting Protein Kinases 1 and 3, and Mixed Lineage Kinase Domain Like Protein Are Activated by Sublytic Complement and Participate in Complement Dependent Cytotoxicity. AB - The complement system participates in the pathogenesis of many diseases. Complement activation produces several active protein complexes and peptides, including the terminal C5b-9 complexes. It was reported that C5b-9 complexes insert into the plasma membrane and cause membrane perturbation, intracellular calcium surge, metabolic depletion, and osmotic lysis. Previously, we showed that complement-dependent cytotoxicity (CDC) is regulated by JNK and Bid. Here, we demonstrate that three mediators in TNFalpha-induced necroptosis (regulated necrosis), the receptor-interacting protein kinases, receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL), are activated by complement and contribute to CDC. Cell treatment with necrostatin-1 (Nec-1), a RIPK1 inhibitor, GSK'872, a RIPK3 inhibitor, or necrosulfonamide and GW806742X, MLKL inhibitors, restrain CDC. These findings were confirmed by using specific siRNAs targeting the synthesis of these proteins. Mouse fibroblasts lacking RIPK3 or MLKL were found to be less sensitive to C5b-9 than were wild-type (WT) fibroblasts. Enhanced CDC was achieved by RIPK1 or RIPK3 overexpression but not by the overexpression of a RHIM-RIPK1 mutant nor by a kinase-dead RIPK3 mutant. Nec-1 reduces the CDC of WT but not of RIPK3-knockout fibroblasts. Cells treated with a sublytic dose of complement exhibit co-localization of RIPK3 with RIPK1 in the cytoplasm and co-localization of RIPK3 and MLKL with C5b-9 at the plasma membrane. Data supporting cooperation among the RIP kinases, MLKL, JNK, and Bid in CDC are presented. These results provide a deeper insight into the cell death process activated by complement and identify potential points of cross talk between complement and other inducers of inflammation and regulated necrosis. PMID- 29527210 TI - Polymorphisms in Toll-Like Receptor 10 and Tuberculosis Susceptibility: Evidence from Three Independent Series. AB - Background: The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis. There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB). Methods: Using a self-validating case-control design, we tested for an association between seven TLR10 polymorphisms and susceptibility to TB in three independent series with two distinct populations. Single-nucleotide polymorphism (SNP) genotypes were determined by the SNPscanTM method. Three genetic models (additive, dominant, and recessive) as well as multiple-SNP score analyses were used to evaluate the risk of TB associated with the TLR10 SNPs. Results: By comparing TB patients with healthy controls, we observed two SNPs (rs11466617 and rs4129009) that were associated with decreased risk of TB in the Tibetan population, but did not in the Chinese Han population. Further analysis demonstrated that the rs11466617 Chengdu cohort genotype served as a protective factor against the progression of latent TB infection (LTBI) to active TB under the recessive model. None of the SNPs were significantly different in comparisons of TB-uninfected people with LTBI individuals. Additionally, when the underlying four TB-associated loci were considered together in a multiple-SNP score analysis, we observed an allele dose-dependent decrease in TB risk in Tibetans. Conclusion: Variants of TLR10 may show an ethnic specificity on susceptibility to TB in Tibetan individuals. rs11466617 affected the susceptibility to progress from LTBI to active TB disease, but was not associated with the establishment of LTBI after M. tuberculosis exposure. More studies are needed to verify this genetic epidemiological result and unravel the role of TLR10 SNPs in the pathogenesis of TB. PMID- 29527211 TI - The Footprints of Poly-Autoimmunity: Evidence for Common Biological Factors Involved in Multiple Sclerosis and Hashimoto's Thyroiditis. AB - Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS) have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto's thyroiditis (HT), suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date. In the present study, we sought to investigate mechanisms which may lead to the frequent coexistence of MS and HT by analyzing several factors related to the pathogenesis of MS and HT in patients affected by one or both diseases, as well as in healthy donors. In particular, we analyzed peripheral blood mononuclear cell gene-expression levels of common candidate genes such as TNFAIP3, NR4A family, BACH2, FOXP3, and PDCD5, in addition to the regulatory T cell (Treg) percentage and the 25-hydroxy vitamin D serum levels. Our findings support the plausibility of the existence of common deregulated mechanisms shared by MS and HT, such as BACH2/PDCD5-FOXP3 pathways and Tregs. Although the biological implications of these data need to be further investigated, we have highlighted the relevance of studies comparing different autoimmune pathologies for the understanding of the core concepts of autoimmunity. PMID- 29527213 TI - Reciprocal Hosts' Responses to Powdery Mildew Isolates Originating from Domesticated Wheats and Their Wild Progenitor. AB - The biotroph wheat powdery mildew, Blumeria graminis (DC.) E.O. Speer, f. sp. tritici Em. Marchal (Bgt), has undergone long and dynamic co-evolution with its hosts. In the last 10,000 years, processes involved in plant evolution under domestication, altered host-population structure. Recently both virulence and genomic profiling separated Bgt into two groups based on their origin from domestic host and from wild emmer wheat. While most studies focused on the Bgt pathogen, there is significant knowledge gaps in the role of wheat host diversity in this specification. This study aimed to fill this gap by exploring qualitatively and also quantitatively the disease response of diverse host panel to powdery mildew [105 domesticated wheat genotypes (Triticum turgidum ssp. dicoccum, T. turgidum ssp. durum, and T. aestivum) and 241 accessions of its direct progenitor, wild emmer wheat (T. turgidum ssp. dicoccoides)]. A set of eight Bgt isolates, originally collected from domesticated and wild wheat was used for screening this wheat collection. The isolates from domesticated wheat elicited susceptible to moderate plant responses on domesticated wheat lines and high resistance on wild genotypes (51.7% of the tested lines were resistant). Isolates from wild emmer elicited reciprocal disease responses: high resistance of domesticated germplasm and high susceptibility of the wild material (their original host). Analysis of variance of the quantitative phenotypic responses showed a significant Isolates * Host species interaction [P(F) < 0.0001] and further supported these findings. Furthermore, analysis of the range of disease severity values showed that when the group of host genotypes was inoculated with Bgt isolate from the reciprocal host, coefficient of variation was significantly higher than when inoculated with its own isolates. This trend was attributed to the role of major resistance genes in the latter scenario (high proportion of complete resistance). By testing the association between disease severity and geographical distance from the source of inoculum, we have found higher susceptibility in wild emmer close to the source. Both qualitative and quantitative assays showed a reciprocal resistance pattern in the wheat host and are well aligned with the recent findings of significant differentiation into wild-emmer and domesticated-wheat populations in the pathogen. PMID- 29527212 TI - Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy. AB - Currently, a marked number of clinical trials on cancer treatment have revealed the success of immunomodulatory therapies based on immune checkpoint inhibitors that activate tumor-specific T cells. However, the therapeutic efficacy of cancer immunotherapies is only restricted to a small fraction of patients. A deeper understanding of key mechanisms generating an immunosuppressive tumor microenvironment (TME) remains a major challenge for more effective antitumor immunity. There is a growing evidence that the TME supports inappropriate metabolic reprogramming that dampens T cell function, and therefore impacts the antitumor immune response and tumor progression. Notably, the immunosuppressive TME is characterized by a lack of crucial carbon sources critical for T cell function and increased inhibitory signals. Here, we summarize the basics of intrinsic and extrinsic metabolic remodeling and metabolic checkpoints underlying the competition between cancer and infiltrating immune cells for nutrients and metabolites. Intriguingly, the upregulation of tumor programmed death-L1 and cytotoxic T lymphocyte-associated antigen 4 alters the metabolic programme of T cells and drives their exhaustion. In this context, targeting both tumor and T cell metabolism can beneficially enhance or temper immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies. PMID- 29527214 TI - Stereoisomers of the Bacterial Volatile Compound 2,3-Butanediol Differently Elicit Systemic Defense Responses of Pepper against Multiple Viruses in the Field. AB - The volatile compound 2,3-butanediol, which is produced by certain strains of root-associated bacteria, consists of three stereoisomers, namely, two enantiomers (2R,3R- and 2S,3S-butanediol) and one meso compound (2R,3S butanediol). The ability of 2,3-butanediol to induce plant resistance against pathogenic fungi and bacteria has been investigated; however, little is known about its effects on induced resistance against viruses in plants. To investigate the effects of 2,3-butanediol on plant systemic defense against viruses, we evaluated the disease control capacity of each of its three stereoisomers in pepper. Specifically, we investigated the optimal concentration of 2,3-butanediol to use for disease control against Cucumber mosaic virus and Tobacco mosaic virus in the greenhouse and examined the effects of drench application of these compounds in the field. In the field trial, treatment with 2R,3R-butanediol and 2R,3S-butanediol significantly reduced the incidence of naturally occurring viruses compared with 2S,3S-butanediol and control treatments. In addition, 2R,3R butanediol treatment induced the expression of plant defense marker genes in the salicylic acid, jasmonic acid, and ethylene signaling pathways to levels similar to those of the benzothiadiazole-treated positive control. This study reports the first field trial showing that specific stereoisomers of 2,3-butanediol trigger plant immunity against multiple viruses. PMID- 29527215 TI - TaMAPK4 Acts as a Positive Regulator in Defense of Wheat Stripe-Rust Infection. AB - Highly conserved mitogen-activated protein kinase (MAPK) cascades regulate numerous plant processes, including hormonal responses, stress, and innate immunity. In this research, TaMAPK4 was predicted to be a target of tae-miR164. We verified the binding and suppression of TaMAPK4 by co-expression in Nicotiana benthamiana. Moreover, we found TaMAPK4 was localized in the cytoplasm and nucleus using transient expression analyses. TaMAPK4 transcripts increased following salicylic acid (SA) treatment and when host plants were infected with an avirulent race of the stripe-rust pathogen. Silencing of TaMAPK4 by virus induced gene silencing permitted increased colonization by the avirulent pathogen race. Detailed histological results showed increased Puccinia striiformis (Pst) hyphal length, hyphal branches, and infection uredinial size compared to the non silenced control. SA accumulation and the transcript levels of TaPR1, TaPR2, and TaPR5 were significantly down-regulated in TaMAPK4 knockdown plants. Overall, these results suggest that TaMAPK4 plays an important role in signaling during the wheat-Pst interaction. These results present new insights into MAPK signaling in wheat defense to rust pathogen. PMID- 29527217 TI - Leaf Movements of Indoor Plants Monitored by Terrestrial LiDAR. AB - Plant leaf movement is induced by some combination of different external and internal stimuli. Detailed geometric characterization of such movement is expected to improve understanding of these mechanisms. A metric high-quality, non invasive and innovative sensor system to analyze plant movement is Terrestrial LiDAR (TLiDAR). This technique has an active sensor and is, therefore, independent of light conditions, able to obtain accurate high spatial and temporal resolution point clouds. In this study, a movement parameterization approach of leaf plants based on TLiDAR is introduced. For this purpose, two Calathea roseopicta plants were scanned in an indoor environment during 2 full days, 1 day in natural light conditions and the other in darkness. The methodology to estimate leaf movement is based on segmenting individual leaves using an octree-based 3D-grid and monitoring the changes in their orientation by Principal Component Analysis. Additionally, canopy variations of the plant as a whole were characterized by a convex-hull approach. As a result, 9 leaves in plant 1 and 11 leaves in plant 2 were automatically detected with a global accuracy of 93.57 and 87.34%, respectively, compared to a manual detection. Regarding plant 1, in natural light conditions, the displacement average of the leaves between 7.00 a.m. and 12.30 p.m. was 3.67 cm as estimated using so-called deviation maps. The maximum displacement was 7.92 cm. In addition, the orientation changes of each leaf within a day were analyzed. The maximum variation in the vertical angle was 69.6 degrees from 12.30 to 6.00 p.m. In darkness, the displacements were smaller and showed a different orientation pattern. The canopy volume of plant 1 changed more in the morning (4.42 dm3) than in the afternoon (2.57 dm3). The results of plant 2 largely confirmed the results of the first plant and were added to check the robustness of the methodology. The results show how to quantify leaf orientation variation and leaf movements along a day at mm accuracy in different light conditions. This confirms the feasibility of the proposed methodology to robustly analyse leaf movements. PMID- 29527216 TI - Trichoderma asperellum T42 Reprograms Tobacco for Enhanced Nitrogen Utilization Efficiency and Plant Growth When Fed with N Nutrients. AB - Trichoderma spp., are saprophytic fungi that can improve plant growth through increased nutrient acquisition and change in the root architecture. In the present study, we demonstrate that Trichoderma asperellum T42 mediate enhancement in host biomass, total nitrogen content, nitric oxide (NO) production and cytosolic Ca2+ accumulation in tobacco. T42 inoculation enhanced lateral root, root hair length, root hair density and root/shoot dry mass in tobacco under deprived nutrients condition. Interestingly, these growth attributes were further elevated in presence of T42 and supplementation of NO3- and NH4+ nutrients to tobacco at 40 and 70 days, particularly in NO3- supplementation, whereas no significant increment was observed in nia30 mutant. In addition, NO production was more in tobacco roots in T42 inoculated plants fed with NO3- nutrient confirming NO generation was dependent on NR pathway. NO3- dependent NO production contributed to increase in lateral root initiation, Ca2+ accumulation and activities of nitrate transporters (NRTs) in tobacco. Higher activities of several NRT genes in response to T42 and N nutrients and suppression of ammonium transporter (AMT1) suggested that induction of high affinity NRTs help NO3- acquisition through roots of tobacco. Among the NRTs NRT2.1 and NRT2.2 were more up-regulated compared to the other NRTs. Addition of sodium nitroprusside (SNP), relative to those supplied with NO3-/NH4+ nutrition and T42 treated plants singly, and with application of NO inhibitor, cPTIO, confirmed the altered NO fluorescence intensity in tobacco roots. Our findings suggest that T42 promoted plant growth significantly ant N content in the tobacco plants grown under N nutrients, notably higher in NO3-, providing insight of the strategy for not only tobacco but probably for other crops as well to adapt to fluctuating nitrate availability in soil. PMID- 29527218 TI - Benefits from Below: Silicon Supplementation Maintains Legume Productivity under Predicted Climate Change Scenarios. AB - Many studies demonstrate that elevated atmospheric carbon dioxide concentrations (eCO2) can promote root nodulation and biological nitrogen fixation (BNF) in legumes such as lucerne (Medicago sativa). But when elevated temperature (eT) conditions are applied in tandem with eCO2, a more realistic scenario for future climate change, the positive effects of eCO2 on nodulation and BNF in M. sativa are often much reduced. Silicon (Si) supplementation of M. sativa has also been reported to promote root nodulation and BNF, so could potentially restore the positive effects of eCO2 under eT. Increased nitrogen availability, however, could also increase host suitability for aphid pests, potentially negating any benefit. We applied eCO2 (+240 ppm) and eT (+4 degrees C), separately and in combination, to M. sativa growing in Si supplemented (Si+) and un-supplemented soil (Si-) to determine whether Si moderated the effects of eCO2 and eT. Plants were either inoculated with the aphid Acyrthosiphon pisum or insect-free. In Si- soils, eCO2 stimulated plant growth by 67% and nodulation by 42%, respectively, whereas eT reduced these parameters by 26 and 48%, respectively. Aphids broadly mirrored these effects on Si- plants, increasing colonization rates under eCO2 and performing much worse (reduced abundance and colonization) under eT when compared to ambient conditions, confirming our hypothesized link between root nodulation, plant growth, and pest performance. Examined across all CO2 and temperature regimes, Si supplementation promoted plant growth (+93%), and root nodulation (+50%). A. pisum abundance declined sharply under eT conditions and was largely unaffected by Si supplementation. In conclusion, supplementing M. sativa with Si had consistent positive effects on plant growth and nodulation under different CO2 and temperature scenarios. These findings offer potential for using Si supplementation to maintain legume productivity under predicted climate change scenarios without making legumes more susceptible to insect pests. PMID- 29527219 TI - Anther Morphological Development and Stage Determination in Triticum aestivum. AB - Anther development progresses through 15 distinct developmental stages in wheat, and accurate determination of anther developmental stages is essential in anther and pollen studies. A detailed outline of the development of the wheat anther through its entire developmental program, including the 15 distinct morphological stages, is presented. In bread wheat (Triticum aestivum), anther developmental stages were correlated with five measurements, namely auricle distance, spike length, spikelet length, anther length and anther width. Spike length and auricle distance were shown to be suitable for rapid anther staging within cultivars. Anther length is an accurate measurement in determining anther stages and may be applicable for use between cultivars. Tapetal Programmed Cell Death (PCD) in wheat begins between late tetrad stage (stage 8) and the early young microspore stage (stage 9) of anther development. Tapetal PCD continues until the vacuolate pollen stage (stage 11), at which point the tapetum fully degrades. The timing of tapetal PCD initiation is slightly delayed compared to that in rice, but is two stages earlier than in the model dicot Arabidopsis. The MYB80 gene, which encodes a transcription factor regulating the timing of tapetal PCD, reaches its peak expression at the onset of tapetal PCD in wheat. PMID- 29527220 TI - QTL-By-Environment Interaction in the Response of Maize Root and Shoot Traits to Different Water Regimes. AB - Drought is a major abiotic stress factor limiting maize production, and elucidating the genetic control of root system architecture and plasticity to water-deficit stress is a crucial problem to improve drought adaptability. In this study, 13 root and shoot traits and genetic plasticity were evaluated in a recombinant inbred line (RIL) population under well-watered (WW) and water stress (WS) conditions. Significant phenotypic variation was observed for all observed traits both under WW and WS conditions. Most of the measured traits showed significant genotype-environment interaction (GEI) in both environments. Strong correlations were observed among traits in the same class. Multi-environment (ME) and multi-trait (MT) QTL analyses were conducted for all observed traits. A total of 48 QTLs were identified by ME, including 15 QTLs associated with 9 traits showing significant QTL-by-Environment interactions (QEI). QTLs associated with crown root angle (CRA2) and crown root length (CRL1) were identified as having antagonistic pleiotropic effects, while 13 other QTLs showed signs of conditional neutrality (CN), including 9 and 4 QTLs detected under WW and WS conditions, respectively. MT analysis identified 14 pleiotropic QTLs for 13 traits, SNP20 (1@79.2 cM) was associated with the length of crown root (CR), primary root (PR), and seminal root (SR) and might contribute to increases in root length under WS condition. Taken together, these findings contribute to our understanding of the phenotypic and genotypic patterns of root plasticity in response to water deficiency, which will be useful to improve drought tolerance in maize. PMID- 29527221 TI - Convergent Evolution of Slick Coat in Cattle through Truncation Mutations in the Prolactin Receptor. AB - Evolutionary adaptations are occasionally convergent solutions to the same problem. A mutation contributing to a heat tolerance adaptation in Senepol cattle, a New World breed of mostly European descent, results in the distinct phenotype known as slick, where an animal has shorter hair and lower follicle density across its coat than wild type animals. The causal variant, located in the 11th exon of prolactin receptor, produces a frameshift that results in a truncated protein. However, this mutation does not explain all cases of slick coats found in criollo breeds. Here, we obtained genome sequences from slick cattle of a geographically distinct criollo breed, namely Limonero, whose ancestors were originally brought to the Americas by the Spanish. These data were used to identify new causal alleles in the 11th exon of the prolactin receptor, two of which also encode shortened proteins that remove a highly conserved tyrosine residue. These new mutations explained almost 90% of investigated cases of animals that had slick coats, but which also did not carry the Senepol slick allele. These results demonstrate convergent evolution at the molecular level in a trait important to the adaptation of an animal to its environment. PMID- 29527222 TI - Age- and Tissue-Specific Expression of Senescence Biomarkers in Mice. AB - Cellular senescence is a state of irreversible cellular growth arrest accompanied by distinct changes in gene expression and the acquisition of a complex proinflammatory secretory profile termed the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in aged tissues and contribute to age-related disease in mice. Increasing evidence that selective removal of senescent cells can ameliorate diseases of late life and extend lifespan in mice has given rise to the development of senolytics that target senescent cells as anti-aging therapeutics. To realize the full potential of senolytic medicine, robust biomarkers of senescence must be in place to monitor the in vivo appearance of senescent cells with age, as well as their removal by senolytic treatments. Here we investigate the dynamic changes in expression of the molecular hallmarks of senescence, including p16Ink4a , p21Cip1 , and SASP factors in multiple tissues in mice during aging. We show that expression of these markers is highly variable in age- and tissue-specific manners. Nevertheless, Mmp12 represents a robust SASP factor that shows consistent age dependent increases in expression across all tissues analyzed in this study and p16Ink4a expression is consistently increased with age in most tissues. Likewise, in humans CDKN2A (p16Ink4a ) is one of the top genes exhibiting elevated expression in multiple tissues with age as revealed by data analysis of the Genotype-Tissue Expression (GTEx) project. These results support the targeting of p16Ink4a expressing-cells in senolytic treatments, while emphasizing the need to establish a panel of robust biomarkers of senescence in vivo in both mice and humans. PMID- 29527224 TI - Association between Helicobacter pylori Infection and Nonalcoholic Fatty Liver Disease: A Single-Center Clinical Study. AB - Objective: To investigate the association between Helicobacter pylori (H. pylori) infection and nonalcoholic fatty liver disease (NAFLD). Methods: Data from 2051 participants who underwent 13C urea breath test and abdominal ultrasound examinations was collected. Participants were allocated to NAFLD risk group and NAFLD nonrisk group based on definite risk factors for NAFLD. The relationship between H. pylori infection and NAFLD was analyzed. Results: No significant difference was found between rates of H. pylori infection and NAFLD using the chi square test (P = 0.30) or regression analysis (P = 0.70). There was no significant difference between rates of H. pylori infection with and without NAFLD (P = 0.47) in the NAFLD risk group or in the NAFLD nonrisk group (P = 0.59). There was no significant difference between rates of H. pylori infection in men (P = 0.69) and in women (P = 0.27) or in participants aged 18-40 years (P = 0.43), 41-65 years (P = 0.14), and >=66 years (P = 0.66) with and without NAFLD in the NAFLD risk group or between the same sex or age groups (P = 0.82, P = 0.66, P = 0.24, P = 0.53, and P = 1.00, resp.) in the NAFLD nonrisk group. Conclusions: H. pylori infection does not appear to increase the NAFLD prevalence rate or to be associated with, or a risk factor for, NAFLD. PMID- 29527223 TI - PTEN at the interface of immune tolerance and tumor suppression. AB - BACKGROUND: PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. The PTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models of Pten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality. OBJECTIVE: To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator. METHODS: This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted. RESULTS: Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape. CONCLUSION: Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells. PMID- 29527225 TI - Spermatozoal Fractalkine Signaling Pathway Is Upregulated in Subclinical Varicocele Patients with Normal Seminogram and Low-Level Leucospermia. AB - Background: Fractalkine is produced in seminal plasma in small amounts and correlates with sperm motility. Purpose: To investigate the possible effect of low-level leucospermia on spermatozoa oxidative stress and sDNA fragmentation in patients with subclinical varicocele and apparently normal seminogram, and also to study the role of spermatozoal fractalkine and its receptor (CX3CR1) gene expression as a marker of spermatozoa inflammatory response. Methods: This study included 80 patients with subclinical varicocele (45 fertile and 35 infertile) and 45 age-matched fertile volunteers. In semen samples, fractalkine and CX3CR1 gene expression were investigated by qRT-PCR. Moreover, seminal plasma malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Results: There are significant decrease in semen quality and significant increase in seminal leucocytes count in subclinical varicocele. Our results show a significant increase in MDA and TAC levels, DNA fragmentation, and expression levels of fractalkine and its receptor (CX3CR1) in subclinical varicocele groups. Conclusion: Subclinical varicocele induces seminal and spermatozoal subclinical inflammatory response in the form of low-level leucospermia and increased mRNA expression of the fractalkine signaling pathway, leading to increased spermatozoal ROS production, oxidative stress, and DNA fragmentation. These could cooperate in the pathogenesis of delayed fertility in males with subclinical varicocele. PMID- 29527226 TI - Osseointegration of a 3D Printed Stemmed Titanium Dental Implant: A Pilot Study. AB - In this pilot study, a 3D printed Grade V titanium dental implant with a novel dual-stemmed design was investigated for its biocompatibility in vivo. Both dual stemmed (n = 12) and conventional stainless steel conical (n = 4) implants were inserted into the tibial metaphysis of New Zealand white rabbits for 3 and 12 weeks and then retrieved with the surrounding bone, fixed, dehydrated, and embedded into epoxy resin. The implants were analyzed using correlative histology, microcomputed tomography, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The histological presence of multinucleated osteoclasts and cuboidal osteoblasts revealed active bone remodeling in the stemmed implant starting at 3 weeks and by 12 weeks in the conventional implant. Bone-implant contact values indicated that the stemmed implants supported bone growth along the implant from the coronal crest at both 3 and 12-week time periods and showed bone growth into microporosities of the 3D printed surface after 12 weeks. In some cases, new bone formation was noted in between the stems of the device. Conventional implants showed mechanical interlocking but did have indications of stress cracking and bone debris. This study demonstrates the comparable biocompatibility of these 3D printed stemmed implants in rabbits up to 12 weeks. PMID- 29527228 TI - Obesity Enhances the Conversion of Adipose-Derived Stromal/Stem Cells into Carcinoma-Associated Fibroblast Leading to Cancer Cell Proliferation and Progression to an Invasive Phenotype. AB - Obesity is associated with enhanced tumor growth and progression. Within the adipose tissue are adipose-derived stromal/stem cells (ASCs) that have been shown to convert into carcinoma-associated fibroblast (CAFs) in the presence of tumor derived factors. However, the impact of obesity on the ASCs and on the conversion of ASCs into CAFs has not been demonstrated. In the current study, ASCs isolated from lean donors (BMI < 25; lnASCs) were compared with ASCs isolated from obese donors (BMI > 30, obASCs). The contribution of tumor-derived factors on the conversion of ASCs to CAFs was investigated. Following exposure to cancer cells, obASCs expressed higher levels of CAF markers, including NG2, alpha-SMA, VEGF, FAP, and FSP, compared to lnASCs. To investigate the crosstalk between ASCs and breast cancer cells, MCF7 cells were serially cocultured with lnASCs or obASCs. After coculture with lnASCs and obASCs, MCF7 cells demonstrated enhanced proliferation and expressed an invasive phenotype morphologically, with more pronounced effects following exposure to obASCs. Long-term exposure to obASCs also enhanced the expression of protumorgenic factors. Together, these results suggest that obesity alters ASCs to favor their rapid conversion into CAFs, which in turn enhances the proliferative rate, the phenotype, and gene expression profile of breast cancer cells. PMID- 29527227 TI - Successful Low-Cost Scaffold-Free Cartilage Tissue Engineering Using Human Cartilage Progenitor Cell Spheroids Formed by Micromolded Nonadhesive Hydrogel. AB - The scaffold-free tissue engineering using spheroids is pointed out as an approach for optimizing the delivery system of cartilage construct. In this study, we aimed to evaluate the micromolded nonadhesive hydrogel (MicroTissues(r)) for spheroid compaction (2-day culture) and spontaneous chondrogenesis (21-day culture) using cartilage progenitors cells (CPCs) from human nasal septum without chondrogenic stimulus. CPC spheroids showed diameter stability (486 MUm +/- 65), high percentage of viable cells (88.1 +/- 2.1), and low percentage of apoptotic cells (2.3%). After spheroid compaction, the synthesis of TGF-beta1, TGF-beta2, and TGF-beta3 was significantly higher compared to monolayer (p < 0.005). Biomechanical assay revealed that the maximum forces applied to spheroids after chondrogenesis were 2.6 times higher than for those cultured for 2 days. After spontaneous chondrogenesis, CPC spheroids were entirely positive for N-cadherin, collagen type II and type VI, and aggrecan and chondroitin sulfate. Comparing to monolayer, the expression of SOX5 and SOX6 genes analyzed by qPCR was significantly upregulated (p < 0.01). Finally, we observed the capacity of CPC spheroids starting to fuse. To the best of our knowledge, this is the first time in the scientific literature that human CPC spheroids were formed by micromolded nonadhesive hydrogel, achieving a successful scaffold-free cartilage engineering without chondrogenic stimulus (low cost). PMID- 29527229 TI - In Vitro Activity of Iclaprim against Methicillin-Resistant Staphylococcus aureus Nonsusceptible to Daptomycin, Linezolid, or Vancomycin: A Pilot Study. AB - Iclaprim is a bacterial dihydrofolate reductase inhibitor in Phase 3 clinical development for the treatment of acute bacterial skin and skin structure infections and hospital-acquired bacterial pneumonia caused by Gram-positive bacteria. Daptomycin, linezolid, and vancomycin are commonly used antibiotics for these indications. With increased selective pressure to these antibiotics, outbreaks of bacterial resistance to these antibiotics have been reported. This in vitro pilot study evaluated the activity of iclaprim against methicillin resistant Staphylococcus aureus (MRSA) isolates, which were also not susceptible to daptomycin, linezolid, or vancomycin. Iclaprim had an MIC <= 1 ug/ml to the majority of MRSA isolates that were nonsusceptible to daptomycin (5 of 7 (71.4%)), linezolid (26 of 26 (100%)), or vancomycin (19 of 28 (66.7%)). In the analysis of time-kill curves, iclaprim demonstrated >= 3 log10 reduction in CFU/mL at 4-8 hours for tested strains and isolates nonsusceptible to daptomycin, linezolid, or vancomycin. Together, these data support the use of iclaprim in serious infections caused by MRSA nonsusceptible to daptomycin, linezolid, or vancomycin. PMID- 29527230 TI - Pathogenicity and Whole Genome Sequence Analysis of a Pseudorabies Virus Strain FJ-2012 Isolated from Fujian, Southern China. AB - The outbreaks of pseudorabies have been frequently reported in Bartha-K61 vaccinated farms in China since 2011. To study the pathogenicity and evolution of the circulating pseudorabies viruses in Fujian Province, mainland China, we isolated and sequenced the whole genome of a wild-type pseudorabies virus strain named "FJ-2012." We then conducted a few downstream bioinformatics analyses including phylogenetic analysis and pathogenic analysis and used the virus to infect 6 pseudorabies virus-free piglets. FJ-2012-infected piglets developed symptoms like high body temperature and central nervous system disorders and had high mortality rate. In addition, we identified typical micropathological changes such as multiple gross lesions in infected piglets through pathological analysis and conclude that the FJ-2012 genome is significantly different from known pseudorabies viruses, in which insertions, deletions, and substitutions are observed in multiple immune and virulence genes. In summary, this study shed lights on the molecular basis of the prevalence and pathology of the pseudorabies virus strain FJ-2012. The genome of FJ-2012 could be used as a reference to study the evolution of pseudorabies viruses, which is critical to the vaccine development of new emerging pseudorabies viruses. PMID- 29527231 TI - Role of survey response rates on valid inference: an application to HIV prevalence estimates. AB - Background: Nationally-representative surveys suggest that females have a higher prevalence of HIV than males in most African countries. Unfortunately, these results are made on the basis of surveys with non-ignorable missing data. This study evaluates the impact that differential survey nonresponse rates between males and females can have on the point estimate of the HIV prevalence ratio of these two classifiers. Methods: We study 29 Demographic and Health Surveys (DHS) from 2001 to 2010. Instead of employing often used multiple imputation models with a Missing at Random assumption that may not hold in this setting, we assess the effect of ignoring the information contained in the missing HIV information for males and females through three proposed statistical measures. These measures can be used in settings where the interest is comparing the prevalence of a disease between two groups. The proposed measures do not utilize parametric models and can be implemented by researchers of any level. They are: (1) an upper bound on the potential bias of the usual practise of using reported HIV prevalence estimates that ignore subjects who have missing HIV outcomes. (2) Plausible range intervals to account for nonresponses, without any additional parametric modeling assumptions. (3) Prevalence ratio inflation factors to correct the point estimate of the HIV prevalence ratio, if estimates of nonresponders' HIV prevalences were known. Results: In 86% of countries, males have higher upper bounds of HIV prevalence than females, this is consonant with males possibly having higher infection rates than females. Additionally, 74% of surveys have a plausible range that crosses 1.0, suggesting a plausible equivalence between male and female HIV prevalences. Conclusions: It is quite reasonable to conclude that there is so much DHS nonresponse in evaluating the HIV status question, that existing data is plausibly generated by the situation where the virus is equally distributed between the sexes. PMID- 29527232 TI - Simian adenoviruses as vaccine vectors. AB - Replication incompetent human adenovirus serotype 5 (HAdV-C5) has been extensively used as a delivery vehicle for gene therapy proteins and infectious disease antigens. These vectors infect replicating and nonreplicating cells, have a broad tissue tropism, elicit high immune responses and are easily purified to high titers. However, the utility of HAdV-C5 vectors as potential vaccines is limited due to pre-existing immunity within the human population that significantly reduces the immunogenicity of HAdV-C5 vaccines. In recent years, adenovirus vaccine development has focused on simian-derived adenoviral vectors, which have the desirable vector characteristics of HAdV-C5 but with negligible seroprevalence in the human population. Here, we discuss recent advances in simian adenovirus vaccine vector development and evaluate current research specifically focusing on clinical trial data. PMID- 29527233 TI - Improved apple latent spherical virus-induced gene silencing in multiple soybean genotypes through direct inoculation of agro-infiltrated Nicotiana benthamiana extract. AB - Background: Virus induced gene silencing (VIGS) is a powerful genomics tool for interrogating the function of plant genes. Unfortunately, VIGS vectors often produce disease symptoms that interfere with the silencing phenotypes of target genes, or are frequently ineffective in certain plant genotypes or tissue types. This is especially true in crop plants like soybean [Glycine max (L.) Merr]. To address these shortcomings, we modified the inoculation procedure of a VIGS vector based on Apple latent spherical virus (ALSV). The efficacy of this new procedure was assessed in 19 soybean genotypes using a soybean Phytoene desaturase (GmPDS1) gene as the VIGS target. Silencing of GmPDS1 was easily scored as photo-bleached leaves and/or stems. Results: In this report, the ALSV VIGS vector was modified by mobilizing ALSV cDNAs into a binary vector compatible with Agrobacterium tumefaciens-mediated delivery, so that VIGS-triggering ALSV variants could be propagated in agro-infiltrated Nicotiana benthamiana leaves. Homogenate of these N. benthamiana leaves was then applied directly onto the unifoliate of young soybean seedlings to initiate systemic gene silencing. This rapid inoculation method bypassed the need for a particle bombardment apparatus. Among the 19 soybean genotypes evaluated with this new method, photo-bleaching indicative of GmPDS1 silencing was observed in nine, with two exhibiting photo bleaching in 100% of the inoculated individuals. ALSV RNA was detected in pods, embryos, stems, leaves, and roots in symptomatic plants of four genotypes. Conclusions: This modified protocol allowed for inoculation of soybean plants via simple mechanical rubbing with the homogenate of N. benthamiana leaves agro infiltrated with ALSV VIGS constructs. More importantly, inoculated plants showed no apparent virus disease symptoms which could otherwise interfere with VIGS phenotypes. This streamlined procedure expanded this functional genomics tool to nine soybean genotypes. PMID- 29527234 TI - Wavefront shaping with disorder-engineered metasurfaces. AB - Recently, wavefront shaping with disordered media has demonstrated optical manipulation capabilities beyond those of conventional optics, including extended volume, aberration-free focusing and subwavelength focusing. However, translating these capabilities to useful applications has remained challenging as the input output characteristics of the disordered media (P variables) need to be exhaustively determined via O(P) measurements. Here, we propose a paradigm shift where the disorder is specifically designed so its exact input-output characteristics are known a priori and can be used with only a few alignment steps. We implement this concept with a disorder-engineered metasurface, which exhibits additional unique features for wavefront shaping such as a large optical memory effect range in combination with a wide angular scattering range, excellent stability, and a tailorable angular scattering profile. Using this designed metasurface with wavefront shaping, we demonstrate high numerical aperture (NA > 0.5) focusing and fluorescence imaging with an estimated ~2.2*108 addressable points in an ~8 mm field of view. PMID- 29527235 TI - New Directions and Challenges in Preventing Conduct Problems in Early Childhood. AB - In this article, we review advances in developing and preventing conduct problems in early childhood and identify challenges. Among the topics we address are expanding the targets of prevention programs beyond improving parenting skills, implementing family-based interventions during early childhood for families living in impoverished communities, making greater use of community platforms that serve young children at risk for early conduct problems, and incorporating techniques such as motivational interviewing to improve families' engagement in nontraditional mental health settings. PMID- 29527237 TI - Fracture-pattern-related therapy concepts in distal humeral fractures. AB - Around one third of humeral fractures and 2-6% of all fractures occur to the distal part of the humerus. There is a bimodal distribution differentiating between young male patients with high-energy and elderly female patients with low energy trauma related to osteoporosis. The AO classification and Dubberley subclassification are used in daily routine. Most fractures are diagnosed on radiographs. For further evaluation, three-dimensional computed tomography is recommended, especially for comminuted or complex fractures. Owing to the long immobilization and resultant poor functional outcome, conservative treatment is followed for inoperable patients. The operative approach and osteosynthesis depend on the fracture pattern. In A1 avulsion fractures, open reduction and screw fixation are recommended. In A2/A3 fractures, a triceps-sparing approach following a 90 degrees double-plate construction (radial dorsal/ulnar lateral) with locking plates is favored. Partial articular B1/B2 fractures are exposed via a medial or lateral approach using unilateral locking plates to stabilize the medial/lateral column. Coronal shear fractures (B3) are classified after Dubberley and are treated via an extended Kocher approach and headless compression screws in anteroposterior direction. If there is a further posterior comminution or a lateral column fragment, stabilization is needed for the lateral/medial column with a precontoured locking plate. In solely articular fracture patterns, a dorsal approach with either a 90 degrees or 180 degrees double-plate construction is advised. If a reconstruction is not possible owing to fracture complexity or bone quality, total elbow arthroplasty is a viable option. However, lifelong limitation in weight-bearing up to 5 kg, limited longevity, and the potential for complicated revision surgery should be considered. PMID- 29527236 TI - Uncovering the molecular mechanisms of lignocellulose digestion in shipworms. AB - Lignocellulose forms the structural framework of woody plant biomass and represents the most abundant carbon source in the biosphere. Turnover of woody biomass is a critical component of the global carbon cycle, and the enzymes involved are of increasing industrial importance as industry moves away from fossil fuels to renewable carbon resources. Shipworms are marine bivalve molluscs that digest wood and play a key role in global carbon cycling by processing plant biomass in the oceans. Previous studies suggest that wood digestion in shipworms is dominated by enzymes produced by endosymbiotic bacteria found in the animal's gills, while little is known about the identity and function of endogenous enzymes produced by shipworms. Using a combination of meta-transcriptomic, proteomic, imaging and biochemical analyses, we reveal a complex digestive system dominated by uncharacterized enzymes that are secreted by a specialized digestive gland and that accumulate in the cecum, where wood digestion occurs. Using a combination of transcriptomics, proteomics, and microscopy, we show that the digestive proteome of the shipworm Lyrodus pedicellatus is mostly composed of enzymes produced by the animal itself, with a small but significant contribution from symbiotic bacteria. The digestive proteome is dominated by a novel 300 kDa multi-domain glycoside hydrolase that functions in the hydrolysis of beta-1,4 glucans, the most abundant polymers in wood. These studies allow an unprecedented level of insight into an unusual and ecologically important process for wood recycling in the marine environment, and open up new biotechnological opportunities in the mobilization of sugars from lignocellulosic biomass. PMID- 29527238 TI - Fractures of the capitellum humeri and their associated injuries. AB - Objective: Fractures of the capitellum are rare injuries but are often more complex and of a greater extent than assumed from conventional radiographs. Classification is usually based on their extension in relation to the trochlea the trochlea and on the number of fragments. Information on associated injuries is limited and only reported in small case series. The aim of this retrospective study was to report on our experience with capitellar fractures and their associated injuries. Methods: We retrospectively reviewed all patients treated for fractures of the capitellum humeri at our institute between 2005 and 2017. Fractures were classified according to the Bryan-Morrey and the Dubberley classification and analyzed for their associated injuries depending on the fracture type using the chi-squared test. Results: A total of 27 capitellar fractures were treated at our institute between 2005 and 2017. The median age of the patients was 57 years (range, 4-78) and they were all treated operatively. Associated injuries of the elbow were found in 12 cases (ten radial head fractures, two elbow dislocations, two tears of the radial collateral ligament). The injury mechanism was known for 26 patients (four fell on their outstretched arm, 19 suffered a direct blow to their elbow, two had a traffic accident). Conclusion: The incidence of radial head fractures is high in patients with capitellar fractures. Patients suffering a fracture of the capitellum humeri should be thoroughly examined for such associated injuries since a missed diagnosis can lead to poor outcomes. PMID- 29527239 TI - Rehabilitation following rotator cuff repair: A work of the Commission Rehabilitation of the German Society of Shoulder and Elbow Surgery e. V. (DVSE) in collaboration with the German Association for Physiotherapy (ZVK) e. V., the Association Physical Therapy, Association for Physical Professions (VPT) e. V. and the Section Rehabilitation-Physical Therapy of the German Society for Orthopaedics and Trauma e. V. (DGOU). AB - Background: Tears and lesions of the rotator cuff are a frequent cause of shoulder pain and disability. Surgical repair of the rotator cuff is a valuable procedure to improve shoulder function and decrease pain. However, there is no consensus concerning the rehabilitation protocol following surgery. Objectives: To review and evaluate current rehabilitation contents and protocols after rotator cuff repair by reviewing the existing scientific literature and providing an overview of the clinical practice of selected German Society of Shoulder and Elbow Surgery e. V. (DVSE) shoulder experts. Materials and methods: A literature search for the years 2004-2014 was conducted in relevant databases and bibliographies including the Guidelines International Network, National Guidelines, PubMed, Cochrane CentralRegister of Controlled Trials, Cochrane Database of Systematic Reviews, and the Physiotherapy Evidence Database. In addition, 63 DVSE experts were contacted via online questionnaire. Results: A total of 17 studies, four reviews and one guideline fulfilled the inclusion criteria. Based on these results and the obtained expert opinions, a four-phase rehabilitation protocol could be developed. PMID- 29527240 TI - Altered DNA methylation is associated with aberrant gene expression in parenchymal but not airway fibroblasts isolated from individuals with COPD. AB - Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease of the lungs that is currently the fourth leading cause of death worldwide. Genetic factors account for only a small amount of COPD risk, but epigenetic mechanisms, including DNA methylation, have the potential to mediate the interactions between an individual's genetics and environmental exposure. DNA methylation is highly cell type-specific, and individual cell type studies of DNA methylation in COPD are sparse. Fibroblasts are present within the airway and parenchyma of the lung and contribute to the aberrant deposition of extracellular matrix in COPD. No assessment or comparison of genome-wide DNA methylation profiles in the airway and parenchymal fibroblasts from individuals with and without COPD has been undertaken. These data provide valuable insight into the molecular mechanisms contributing to COPD and the differing pathologies of small airways disease and emphysema in COPD. Methods: Genome-wide DNA methylation was evaluated at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip array in the airway (non-COPD n = 8, COPD n = 7) and parenchymal fibroblasts (non-COPD n = 17, COPD n = 29) isolated from individuals with and without COPD. Targeted gene expression was assessed by qPCR in matched RNA samples. Results: Differentially methylated DNA regions were identified between cells isolated from individuals with and without COPD in both airway and parenchymal fibroblasts. Only in parenchymal fibroblasts was differential DNA methylation associated with differential gene expression. A second analysis of differential DNA methylation variability identified 359 individual differentially variable CpG sites in parenchymal fibroblasts. No differentially variable CpG sites were identified in the airway fibroblasts. Five differentially variable methylated CpG sites, associated with three genes, were subsequently assessed for gene expression differences. Two genes (OAT and GRIK2) displayed significantly increased gene expression in cells isolated from individuals with COPD. Conclusions: Differential and variable DNA methylation was associated with COPD status in the parenchymal fibroblasts but not airway fibroblasts. Aberrant DNA methylation was associated with altered gene expression imparting biological function to DNA methylation changes. Changes in DNA methylation are therefore implicated in the molecular mechanisms underlying COPD pathogenesis and may represent novel therapeutic targets. PMID- 29527241 TI - Barriers to Gender-Affirming Care for Transgender and Gender Nonconforming Individuals. AB - Gender-affirming care, including hormone therapy, "top" (e.g., chest reconstruction surgery) and "bottom" (e.g., vaginoplasty, phalloplasty, metoidioplasty, etc.) surgeries, and puberty blockers, is an efficacious treatment of gender dysphoria for transgender and gender nonconforming (TGNC) individuals. However, many TGNC people encounter significant barriers in accessing gender-affirming care, which we detail via results from on online study. Participants included 256 TGNC individuals (78.9% White, ages 16-73, Mage =28.4). Among participants, 61.3% were receiving hormone therapy, 22.7% had undergone top surgery, and 5.5% had undergone bottom surgery. Open-ended responses (n=201) were thematically analyzed and common barriers included finances and insurance issues, a lack of service availability, and fears or worries. Participants reported various systemic issues and incidents of bias within medical and mental health fields, as well as a lack of medical provider awareness and education. Other themes were interpersonal barriers (e.g., fears of rejection); age and need of parental consent for minors; other medical issues; and a lack of information about how to acquire care. These findings can be utilized to educate professionals in medical and mental health fields about barriers their TGNC patients may encounter in receiving affirming care, and suggest a number of ways to improve access to these services. PMID- 29527242 TI - The Importance of Contextual Factors in Carrying Out Childhood Violence Surveys: a Case Study from Indonesia. AB - Nationally representative research into violence against children is necessary to understand the scale and complexity of such violence and to evaluate prevention efforts. To date, however, most countries do not have adequate data. In 2013, the government of Indonesia conducted a national Violence Against Children Survey (VACS). This was a cross-sectional household survey of male and female 13-to-24- year-olds designed to estimate physical, emotional, and sexual violence prevalence. The target was to interview at least 2580 individuals; but response rates were much lower than anticipated (females = 66.6%; males = 56.1%). Insufficient data was available across several variables and there were unexpected anomalies in obtained data. We conducted a retrospective analysis of the survey to understand impediments and to advise future national efforts in Indonesia and other low-to-middle-income contexts. Survey managers and implementers (n = 22) were interviewed online and in person. We also carried out secondary analysis of the child survey data to identify factors possibly associated with (non-)response and assessed field notes from interviewers. Culturally inappropriate timing of data-collection (during Ramadan) may have had a negative impact on household responsiveness and the availability of children at home. Face-toface interviews in households were considered to impede participation and disclosure. Survey field staff and managers expressed the need for deeper training and a more comprehensive pilot. Recommendations to improve privacy and anonymity include the use of self-administered questionnaires and school-based rather than at-home surveys. These and other findings from this case study may be useful in planning future surveys in Indonesia and similar social and cultural contexts. PMID- 29527243 TI - Unpacking the Relationship between Parental Migration and Child well-Being: Evidence from Moldova and Georgia. AB - Using household survey data collected between September 2011 and December 2012 from Moldova and Georgia, this paper measures and compares the multidimensional well-being of children with and without parents abroad. While a growing body of literature has addressed the effects of migration for children 'left behind', relatively few studies have empirically analysed if and to what extent migration implies different well-being outcomes for children, and fewer still have conducted comparisons across countries. To compare the outcomes of children in current- and non-migrant households, this paper defines a multidimensional well being index comprised of six dimensions of wellness: education, physical health, housing conditions, protection, communication access, and emotional health. This paper challenges conventional wisdom that parental migration is harmful for child well-being: while in Moldova migration does not appear to correspond to any positive or negative well-being outcomes, in Georgia migration was linked to higher probabilities of children attaining well-being in the domains of communication access, housing, and combined well-being index. The different relationship between migration and child well-being in Moldova and Georgia likely reflects different migration trajectories, mobility patterns, and levels of maturity of each migration stream. PMID- 29527244 TI - Factor Structure and Factorial Invariance of the Strengths and Difficulties Questionnaire among Children of Prisoners and their Parents. AB - Parental imprisonment has been linked to a variety of adverse psychological outcomes for children and adolescents. The Strengths and Difficulties Questionnaire (SDQ) has been widely used to assess behavioural and emotional difficulties among 7-17 year olds in the general population and more recently has been utilised among samples of children of prisoners. Previous research has variously tested traditional one-, three- and five- factor solutions to the SDQ, and more recently one bifactor solution has been examined. Based on a sample of children of prisoners (N = 724) and their non-imprisoned parent or caregiver (N = 658), the aim of the present study was to simultaneously compare nine alternative factor structures, including previously tested models and alternative bifactor solutions. Tests of factorial invariance and composite reliability were also performed. The five-factor model was found to provide the best fit for the data. Tests of factorial invariance revealed that the five-factor model provided an equally acceptable, but not identical fit, among boys and girls. Composite reliability scores were low for the Conduct Problems and Peer Problems subscales. The utility of the SDQ in measuring psychological functioning in response to parental imprisonment is discussed. PMID- 29527245 TI - Self-efficacy and self-care-related outcomes following Alexander Technique lessons for people with chronic neck pain in the ATLAS randomised, controlled trial. AB - Introduction: ATLAS was a pragmatic randomised (1:1:1 ratio), controlled trial recruiting patients with chronic neck pain (N = 517) and evaluating one-to-one Alexander Technique lessons, or acupuncture, each plus usual care, compared with usual care alone. The primary outcome (12-month Northwick Park Neck Pain Questionnaire [NPQ]) demonstrated significant and clinically meaningful reductions in neck pain and associated disability for both interventions compared with usual care alone. Here we describe pre-specified, self-efficacy and other self-care-related outcomes for the Alexander group compared with usual care. Methods: Participants reported on 11 self-efficacy/self-care-related outcome measures at 6 and 12 months. Linear or logistic regression models evaluated changes in parameters and impact on NPQ. Alexander teachers reported on lesson content. Results: Lesson content reflected standard UK practice. The Alexander group (n = 172) reported significantly greater improvements, compared with usual care alone (n = 172), in most of the self-efficacy/self-care measures (9/11 measures at 6 months, and 8/11 at 12 months), including the ability to reduce pain in daily life. At 6 months, 81% (106/131) of Alexander participants reported significant improvement in the way they lived and cared for themselves (versus 23% for usual care), increasing to 87% (117/135) at 12 months (usual care: 25%). NPQ scores at both 6 and 12 months were related to improvement in self-efficacy and ability to reduce pain during daily life. Conclusions: Alexander Technique lessons led to long-term improvements in the way participants lived their daily lives and managed their neck pain. Alexander lessons promote self-efficacy and self-care, with consequent reductions in chronic neck pain. PMID- 29527246 TI - Food in My Neighborhood: Exploring the Food Environment through Photovoice with Urban, African American Youth. AB - This study adapted Photovoice methodology for younger participants to better understand the perceptions of urban African American youth on their food environments and diets. Youth (n = 17, ages 10-13 years) photographed and described, using novel narrative-based activities, the myriad places they regularly acquired "junk food" from environments saturated with such but differed in their assessments of the availability and desirability of more nutritious alternative foods. Youth often discussed specific foods as well as peers and adults in their lives as either entirely "healthy" or "unhealthy." This concrete thinking should be considered when designing messaging strategies to improve diets in similar populations. Overall, Photovoice is an engaging and effective method to engage youth in efforts to improve food environments and diets. PMID- 29527247 TI - Motivators of and Barriers to Engaging in Physical Activity: Perspectives of Low Income Culturally Diverse Adolescents and Adults. AB - Background: Obesity rates are rising in the United States, especially among low income and racial/ethnic minority individuals. Exploring motivators and barriers relative to engaging in physical activity is imperative. Purpose: The purpose of this study was to identify motivators and barriers relative to engagement in physical activity as reported by culturally diverse low-income adolescents and adults. Methods: A total of 91 adolescent (11 to 15 years of age) and adult (18 years of age or older) participants who self-identified as African American, Hispanic, or non-Hispanic White engaged in age group-, race/ethnicity-, and gender-concordant focus groups. Results: Qualitative data analysis indicated that the motivators and barriers most commonly identified among the adolescent and adult focus groups were: social influence; time and priorities; physical environment; fun and enjoyment; inherently physical activities; weight concerns; fatigue, physical discomfort and current fitness level; and immediate positive feelings. Discussion: Findings were generally similar across age group, gender and race/ethnicity. Age group-specific, gender-specific and race/ethnicity specific motivators and barriers were related to how commonly the motivators and barriers were identified among each group. Translation to Health Education Practice: Implications for increasing physical activity among low-income culturally diverse adolescents and adults are discussed. PMID- 29527248 TI - Use of Hyaluronic Acid-Based Biological Bilaminar Matrix in Wound Bed Preparation: A Case Series. AB - Objectives: To analyze the efficacy of a hyaluronic acid--based matrix in the treatment of lesions where the extracellular matrix was lost. Methods: Prospective, noncomparative clinical case series. Results: Twelve patients with 12 serious surgical wounds of different etiologies participated in this project. Many defects showed exposed muscle, tendons, and/or bone. After thorough debridement, a hyaluronic acid--based matrix, with a removable, semipermeable silicone top layer, was applied for the purpose of generating a neodermis. In a number of cases, the matrix was combined with negative pressure wound therapy. All wounds developed granulation tissue. Nine wounds were subsequently closed with a split-skin autograft. There was no graft failure. Three wounds healed by secondary intention. All wounds showed complete reepithelialization. Discussion: Lesions with exposed tendon and bone are difficult to heal. Providing a granulation tissue through the use of an extracellular matrix in which cellular repopulation leads to the development of granulation tissue has been shown to be beneficial with regard to the speed and quality of healing. In this case series, the use of a hyaluronic acid--based matrix was shown to provide a granulation tissue and all lesions healed completely. Conclusion: This case series shows a strong trend for Hyalomatrix to play an important role in supporting wound healing in complex, surgical wounds. PMID- 29527249 TI - Functional Reconstruction of Severely Burned Hand With Osseous Blood Flow Deficiency With Immediate Surgery Using an Abdominal Bipediceled Flap: A Case Report. AB - Objective: When hands suffer burns, the tendons and digital bones are rarely injured because of the quick withdrawal reflex away from the heat source. Hence, a consensus of opinion regarding the treatment of severe hand burns with osseous blood flow deficiency has not been reached among clinicians. Methods: The patient was a 28-year-old woman whose fingers were accidentally soaked in heated cooking oil (160 degrees C-170 degrees C) for approximately 1 minute. The result was fourth-degree (extending to the tendon) digital burns of the distal end of the proximal interphalangeal joint with blood flow deficiency to the skin, tendon, and bone. Results: We performed immediate reconstructive surgery using an abdominal bipediceled flap. Two weeks later, after the flap was separated, all fingers showed complete range of motion, restoration of the metacarpophalangeal joint, and a high range (0 degrees -75 degrees ) of proximal interphalangeal joint mobility with an acceptable digital length. Conclusions: Our experience shows that immediate surgery is highly preferable for deep burns of the hand to avoid delayed intractable complications and to achieve better and faster results. PMID- 29527250 TI - Temporary Abdominal Closure Combined With an Irrigating System Utilizing Hypochlorous Acid Solution to Decrease Abdominal Mucopurulence. AB - Introduction: Leaving the abdominal cavity open is a well-described and frequently utilized technique in the treatment of severe intra-abdominal sepsis. Irrigation through a negative pressure wound therapy device is a technique employed to assist in the closure of wounds as well as the reduction of bacterial contamination. Furthermore, hypochlorous acid has been found to be safe and effective in microorganismal elimination from extremity wounds. There is no literature regarding the infusion of hypochlorous solution into the abdominal cavity for intra-abdominal sepsis or mucopurulent abscesses or biofilm. Objectives: A 47-year-old man with granulomatosis polyangiitis was started on weekly rituximab. After 4 infusions, skin sloughing, ultimately diagnosed as toxic epidermal necrolysis, developed. During the hospital course, he developed sepsis and bowel perforation necessitating an exploratory laparotomy. The abdomen was left open with a temporary abdominal closure using the Abthera open abdomen negative wound therapy device; however, the abdomen remained infected with visually diffuse, thickening mucopurulence despite multiple washouts. Therefore, a VAC Vera-Flo irrigation device was combined with the Abthera open abdomen negative wound therapy device and cyclical irrigation of hypochlorous acid. After 72 hours, the purulence visually was improved and no adverse events were recorded with the placement of intra-abdominal hypochlorous acid. Conclusions: The combination of two medical devices for the intra-abdominal instillation of irrigation is considered "off-label use" from the manufacturer's recommendations. In addition, the repeated instillation of hypochlorous acid solution has not been described but was noted to have visually decreased the contaminated effluent within the intra-abdominal fluid. PMID- 29527251 TI - Mediated Leader Effects: The Impact of Newspapers' Portrayal of Party Leadership on Electoral Support. AB - Conventional wisdom holds that party leaders matter in democratic elections. As very few voters have direct contact with party leaders, media are voters' primary source of information about these leaders and, thus, the likely origin of leader effects on party support. Our study focuses on these supposed electoral effects of the media coverage of party leaders. We examine the positive and negative effects of specific leadership images in Dutch newspapers on vote intentions. To this end, we combine an extensive automated content analysis of leadership images in the media with a panel data set, the Dutch 1Vandaag Opinion Panel (1VOP), consisting of more than fifty thousand unique respondents and 110 waves of interviews conducted between September 2006 and September 2012. The results confirm that media coverage of party leaders' character traits affects voters: Positive mediated leadership images increase support for the leader's party, while negative images decrease this support. However, this influence is not unconditional: During campaign periods, positive leadership images have a stronger effect, while negative images no longer have an impact on subsequent vote intentions. PMID- 29527252 TI - The Effect of On-Pump and Off-Pump Bypass Operations on Oxidative Damage and Antioxidant Parameters. AB - Objective: The aim of the study is to determine the oxidative status in on-pump and off-pump coronary artery surgery and contribute to possible surgical choices in clinical practices in accordance with the information obtained as a result of this study. Methods: 52 patients undergoing open heart surgery (26 patients in on pump group and 26 patients in off-pump group) were included in the study. MDA, GPx, GSH, CAT, and SOD were investigated in blood samples. Results: In the on pump group, it was determined that there were a significant increase in MDA level in the peroperative period compared to the preoperative and postoperative periods and a significant increase in GSH level in the postoperative period than in the preoperative period. Additionally, while there was a significant decrease in CAT activity in the postoperative period than in the peroperative period, there was a statistically significant increase in SOD enzyme activity in the postoperative period compared to the preoperative and peroperative periods. A statistically significant increase was observed in SOD enzyme activity in the postoperative period in on-pump compared to off-pump group. Conclusion: It is thought that this oxidative damage can be suppressed by administering a suitable antioxidant supplement in the preoperative and peroperative periods among patients undergoing the on-pump operation. PMID- 29527253 TI - Health Insurance Mandates, Mammography, and Breast Cancer Diagnoses. AB - We examine the effects of state health insurance mandates requiring coverage of screening mammograms. We find evidence that mammography mandates significantly increased mammography screenings by 4.5-25 percent. Effects are larger for women with less than a high school degree in states that ban deductibles, a policy similar to a provision of federal health reform that eliminates cost-sharing for preventive care. We also find that mandates increased detection of early stage in situ pre-cancers. Finally, we find a substantial proportion of the increased screenings were attributable to mandates that are not consistent with current recommendations of the American Cancer Society. PMID- 29527254 TI - Cross-Sectional HIV Incidence Surveillance: A Benchmarking of Approaches for Estimating the 'Mean Duration of Recent Infection'. AB - The application of biomarkers for 'recent' infection in cross-sectional HIV incidence surveillance requires the estimation of critical biomarker characteristics. Various approaches have been employed for using longitudinal data to estimate the Mean Duration of Recent Infection (MDRI) - the average time in the 'recent' state. In this systematic benchmarking of MDRI estimation approaches, a simulation platform was used to measure accuracy and precision of over twenty approaches, in thirty scenarios capturing various study designs, subject behaviors and test dynamics that may be encountered in practice. Results highlight that assuming a single continuous sojourn in the 'recent' state can produce substantial bias. Simple interpolation provides useful MDRI estimates provided subjects are tested at regular intervals. Regression performs the best - while 'random effects' describe the subject-clustering in the data, regression models without random effects proved easy to implement, stable, and of similar accuracy in scenarios considered; robustness to parametric assumptions was improved by regressing 'recent'/'non-recent' classifications rather than continuous biomarker readings. All approaches were vulnerable to incorrect assumptions about subjects' (unobserved) infection times. Results provided show the relationships between MDRI estimation performance and the number of subjects, inter-visit intervals, missed visits, loss to follow-up, and aspects of biomarker signal and noise. PMID- 29527255 TI - Glycogenic hepatopathy: A narrative review. AB - Glycogenic hepatopathy (GH) is a rare complication of the poorly controlled diabetes mellitus characterized by the transient liver dysfunction with elevated liver enzymes and associated hepatomegaly caused by the reversible accumulation of excess glycogen in the hepatocytes. It is predominantly seen in patients with longstanding type 1 diabetes mellitus and rarely reported in association with type 2 diabetes mellitus. Although it was first observed in the pediatric population, since then, it has been reported in adolescents and adults with or without ketoacidosis. The association of GH with hyperglycemia in diabetes has not been well established. One of the essential elements in the pathophysiology of development of GH is the wide fluctuation in both glucose and insulin levels. GH and non-alcoholic fatty liver disease (NAFLD) are clinically indistinguishable, and latter is more prevalent in diabetic patients and can progress to advanced liver disease and cirrhosis. Gradient dual-echo MRI can distinguish GH from NAFLD; however, GH can reliably be diagnosed only by liver biopsy. Adequate glycemic control can result in complete remission of clinical, laboratory and histological abnormalities. There has been a recent report of varying degree of liver fibrosis identified in patients with GH. Future studies are required to understand the biochemical defects underlying GH, noninvasive, rapid diagnostic tests for GH, and to assess the consequence of the fibrosis identified as severe fibrosis may progress to cirrhosis. Awareness of this entity in the medical community including specialists is low. Here we briefly reviewed the English literature on pathogenesis involved, recent progress in the evaluation, differential diagnosis, and management. PMID- 29527257 TI - Cell fusion in the liver, revisited. AB - There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century were initially interpreted to show "transdifferentiation", but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear. PMID- 29527258 TI - Management of bacterial infection in the liver transplant candidate. AB - Bacterial infection (BI) is a common cause of impairment of liver function in patients with cirrhosis, especially in the liver transplant candidates. These patients share an immunocompromised state and increased susceptibility to develop community and hospital-acquired infections. The changing epidemiology of BI, with an increase of multidrug resistant strains, especially in healthcare-associated settings, represents a critical issue both in the waiting list and in the post operative management. This review focused on the role played by BI in patients awaiting liver transplantation, evaluating the risk of drop-out from the waiting list, the possibility to undergo liver transplantation after recovery from infection or during a controlled infection. PMID- 29527259 TI - Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research. AB - The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver. PMID- 29527256 TI - Hepatitis C virus: Morphogenesis, infection and therapy. AB - Hepatitis C virus (HCV) is a major cause of liver diseases including liver cirrhosis and hepatocellular carcinoma. Approximately 3% of the world population is infected with HCV. Thus, HCV infection is considered a public healthy challenge. It is worth mentioning, that the HCV prevalence is dependent on the countries with infection rates around 20% in high endemic countries. The review summarizes recent data on HCV molecular biology, the physiopathology of infection (immune-mediated liver damage, liver fibrosis and lipid metabolism), virus diagnostic and treatment. In addition, currently available in vitro, ex vivo and animal models to study the virus life cycle, virus pathogenesis and therapy are described. Understanding of both host and viral factors may in the future lead to creation of new approaches in generation of an efficient therapeutic vaccine. PMID- 29527260 TI - Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied. AB - Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet activating factor, lysophosphatidylcholine, and less effectively phosphatidylcholine. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases. PMID- 29527261 TI - Spontaneous bacterial and fungal peritonitis in patients with liver cirrhosis: A literature review. AB - Spontaneous bacterial (SBP) and spontaneous fungal peritonitis (SFP) can be a life-threatening infection in patients with liver cirrhosis (LC) and ascites. One of the possible mechanisms of developing SBP is bacterial translocation. Although the number of polymorphonuclear cells in the culture of ascitic fluid is diagnostic for SBP, secondary bacterial peritonitis is necessary to exclude. The severity of underlying liver dysfunction is predictive of developing SBP; moreover, renal impairment and infections caused by multidrug-resistant (MDR) organism are associated with a fatal prognosis of SBP. SBP is treated by antimicrobials, but initial empirical treatment may not succeed because of the presence of MDR organisms, particularly in nosocomial infections. Antibiotic prophylaxis is recommended for patients with LC at a high risk of developing SBP, gastrointestinal bleeding, or a previous episode of SBP, but the increase in the risk of developing an infection caused by MDR organisms is a serious concern globally. Less is known about SFP in patients with LC, but the severity of underlying liver dysfunction may increase the hospital mortality. SFP mortality has been reported to be higher than that of SBP partially because the difficulty of early differentiation between SFP and SBP induces delayed antifungal therapy for SFP. PMID- 29527262 TI - Impact of direct acting antivirals on occurrence and recurrence of hepatocellular carcinoma: Biologically plausible or an epiphenomenon? AB - Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Chronic hepatitis C virus infection (HCV) is the most common cause of HCC in many European countries, Japan and Pakistan. Introduction of the new direct acting antivirals (DAAs) has revolutionized the management of HCV worldwide, with high rates of sustained virologic response in patients who could not have tolerated the previous interferon based treatments. However, recently there have been reports raising caution about the long term effects of DAAs, particularly a possible increased risk of HCC. Therefore this review explores the current molecular studies as well as clinical data that investigate the impact of DAAs on occurrence and recurrence of HCC. PMID- 29527263 TI - Homologous recombination mediates stable Fah gene integration and phenotypic correction in tyrosinaemia mouse-model. AB - AIM: To stably correct tyrosinaemia in proliferating livers of fumarylacetoacetate-hydrolase knockout (Fah-/-) mice by homologous-recombination mediated targeted addition of the Fah gene. METHODS: C57BL/6 Fah?exon5 mice served as an animal model for human tyrosinaemia type 1 in our study. The vector was created by amplifying human Fah cDNA including the TTR promoter from a lentivirus plasmid as described. The Fah expression cassette was flanked by homologous arms (620 bp and 749 bp long) of the Rosa26 gene locus. Mice were injected with 2.1 * 108 VP of this vector (rAAV8-ROSA26.HAL-TTR.Fah-ROSA26.HAR) via the tail vein. Mice in the control group were injected with 2.1 * 108 VP of a similar vector but missing the homologous arms (rAAV8-TTR.Fah). Primary hepatocytes from Fah-/- recipient mice, treated with our vectors, were isolated and 1 * 106 hepatocytes were transplanted into secondary Fah-/- recipient mice by injection into the spleen. Upon either vector application or hepatocyte transplantation NTBC treatment was stopped in recipient mice. RESULTS: Here, we report successful HR-mediated genome editing by integration of a Fah gene expression cassette into the "safe harbour locus" Rosa26 by recombinant AAV8. Both groups of mice showed long-term survival, weight gain and FAH positive clusters as determined by immunohistochemistry analysis of liver sections in the absence of NTBC treatment. In the group of C57BL/6 Fah?exon5 mice, which have been transplanted with hepatocytes from a mouse injected with rAAV8-ROSA26.HAL TTR.Fah-ROSA26.HAR 156 d before, 6 out of 6 mice showed long-term survival, weight gain and FAH positive clusters without need for NTBC treatment. In contrast only 1 out 5 mice, who received hepatocytes from rAAV8-TTR.Fah treated mice, survived and showed few and smaller FAH positive clusters. These results demonstrate that homologous recombination-mediated Fah gene transfer corrects the phenotype in a mouse model of human tyrosinaemia type 1 (Fah-/- mice) and is long lasting in a proliferating state of the liver as shown by withdrawal of NTBC treatment and serial transplantation of isolated hepatocytes from primary Fah-/- recipient mice into secondary Fah-/- recipient mice. This long term therapeutic efficacy is clearly superior to our control mice treated with episomal rAAV8 gene therapy approach. CONCLUSION: HR-mediated rAAV8 gene therapy provides targeted transgene integration and phenotypic correction in Fah-/- mice with superior long term efficacy compared to episomal rAAV8 therapy in proliferating livers. PMID- 29527264 TI - Multipotent stromal cells stimulate liver regeneration by influencing the macrophage polarization in rat. AB - AIM: To investigate the influence of the umbilical cord-derived multipotent stromal cells (MSCs) on recovery of the liver after the subtotal resection, that is, removal of 80% of the organ mass, a renowned model of the small-for-size liver remnant syndrome. METHODS: The MSCs were obtained from the intervascular tissue of umbilical cords, dissected from rat fetuses, by the explant culture technique. The vital labeling of MSCs with RKN26 was carried out on the 3rd passage. The subtotal resection was performed on male Sprague-Dawley rats. The experimental group animals received a transplant 106 MSCs infused into the spleen. Hepatocyte proliferation was assessed by counting of either mitotic figures or Ki67-positive cells in microscopic images. MSC differentiation was assessed with antibodies to hepatocyte-specific marker cytokeratin 18 (CK18), cholangiocyte-specific protein CK19, smooth muscle cell-specific protein alpha SMA, the endothelial cell marker CD31, or the active fibroblast marker FAPalpha. Total macrophages of the liver were selectively stained in cryosections incubated with anti-CD68 antibodies (1:100, Abcam), while the M2a and M2c macrophage populations were selectively stained with anti-CD206 antibodies. Expression of interleukin and growth factor genes was evaluated with PCR-RT. RESULTS: Intrasplenic allogeneic transplantation of the umbilical cord-derived multipotent stromal cells stimulates reparative processes within the residual liver tissue after subtotal resection (removal of 80% of the organ mass), as indicated by increased rates of hepatocyte proliferation and accelerated organ mass recovery. These effects may result from paracrine influence of the transplanted cells on the resident macrophage population of the liver. The transplantation favors polarization of macrophages to M2 phenotype (the M2-polarized macrophages specifically express CD206; they are known to suppress inflammation and support tissue repair). No differentiation of the transplanted cells into any of the liver cell types have been observed in the study. CONCLUSION: We found no direct evidence for the paracrine effect of MSCs on liver regeneration after the subtotal liver resection in rats. However, the paracrine mechanism of the therapeutic activity of transplanted MSC is indirectly indicated by a decrease in the total number of CD68 + macrophages and an increase in the proportion of M2 pro-repair macrophages in the regenerating liver as compared to animals in which the transplantation was only mimicked. PMID- 29527265 TI - Morphological and biochemical effects of weekend alcohol consumption in rats: Role of concentration and gender. AB - AIM: To examine the association between weekend alcohol consumption and the biochemical and histological alterations at two different concentrations of alcohol in both genders in rats. METHODS: Wistar rats weighing 170-200 g were divided into groups as follows: (1) Control groups; and (2) weekend alcohol consumption group: 2 d/weekly per 12 wk, at two different concentrations: (1) Group of males or females with a consumption of a solution of alcohol at 40%; and (2) group of males or females with a consumption of a solution of alcohol at 5%. At the end of the experiment, serum and liver samples were obtained. The following enzymes and metabolites were determined in serum: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase, and Gamma-Glutamyltransferase, and glucose, triglycerides, cholesterol, bilirubin, and albumin. Liver samples from each group were employed to analyze morphological abnormalities by light microscopy. RESULTS: In all of the weekend alcohol-consumption groups, AST activity presented a significant, 10-fold rise. Regarding ALT activity, the groups with weekend alcohol consumption presented a significant increase that was six times greater. Bilirubin levels increased significantly in both groups of females. We observed a significant increase in the parameters of fatty change and inflammation due to weekend alcohol consumption. Only the group of females that consumed alcohol at 40% presented slight hepatocellular disorganization. CONCLUSION: The results obtained herein provide solid evidence that weekend alcohol consumption gives rise to liver damage, demonstrated by biochemical and histological alterations, first manifested acutely, and prolonged weekend alcohol consumption can cause greater, irreversible damage. PMID- 29527266 TI - Survival outcomes of liver transplantation for hepatocellular carcinoma in patients with normal, high and very high preoperative alpha-fetoprotein levels. AB - AIM: To investigate the impact of alpha-fetoprotein (AFP) on long-term recurrence rate and overall survival and we also aimed to define the level of AFP leading to a higher risk of disease recurrence and affecting patient survival. METHODS: Data of adult patients who received liver transplant (LT) for hepatocellular carcinoma (HCC) at our hospital from January 2000 to December 2013 were reviewed. Reviewed data included demographic characteristics, preoperative AFP level, operative details, follow-up details, and survival outcomes. Patients were mostly listed for LT based on Milan or UCSF criteria. For the purpose of this study, normal AFP level was defined as AFP value < 10 ng/mL, high AFP level was defined as AFP value >= 10 to < 400 ng/mL, and very high AFP level was defined as AFP >= 400 ng/mL. The patients were divided into these 3 groups accordingly. Survival rates were plotted as Kaplan-Meier curves and compared by log-rank analysis. Continuous variables were expressed as median (interquartile range). Categorical variables were compared by Spearman's test. Discriminative analysis was used to define the lowest value of AFP that could affect the overall survival in study population. Statistical significance was defined by a P value of < 0.05. RESULTS: Totally 250 adult patients underwent LT for HCC in the study period. Eight-four of them received deceased-donor LT and 166 had living-donor LT. The patients were divided into 3 groups: Group A, AFP < 10 ng/mL (n = 83); Group B, AFP >= 10 to < 400 ng/mL (n = 131); Group C, AFP >= 400 ng/mL (n = 36). The commonest etiology was hepatitis-B-related cirrhosis. The Model for End-stage Liver Disease scores in these groups were similar (median, 13 vs 13 vs 12; P = 0.745). The time to operation in Group A was longer (median, 94 vs 31 vs 35 d; P = 0.001). The groups were similar in hospital mortality (P = 0.626) and postoperative complication (P = 0.702). Pathology of explants showed that the 3 groups had similar numbers of tumor nodules, but the tumors in Group C were larger (A: 2.5 cm, B: 3.0 cm, C: 4.0 cm; P = 0.003). Group C had a bigger proportion of patients who were beyond Milan criteria (P = 0.010). Poor differentiation and vascular permeation were also more common in this group (P = 0.017 and P = 0.003 respectively). It also had poorer 5-year survival (A: 85.5%, B: 82.4%, C: 66%; P = 0.029). The 5-year disease-free survival was 84.3% in Group A, 80.1% in Group B, and 61.1% in Group C. Receiver operating characteristic area under the curve for AFP in predicting tumor recurrence was 0.685. The selected cut-off value was 54 ng/mL for AFP (C index 0.685; 95%CI: 0.592-0.779; sensitivity 0.595; specificity 0.687). On discriminative analysis, AFP value of 105 ng/mL was shown to affect the overall survival of the patients. CONCLUSION: HCC patients with a high preoperative AFP level had inferior survival after LT. AFP level of 54 ng/mL was associated with disease recurrence, and AFP level of 105 ng/mL was found to be the cut-off value for overall survival difference. PMID- 29527267 TI - Hepatitis C virus knowledge improves hepatitis C virus screening practices among primary care physicians. AB - AIM: To understand the role of knowledge as a promoter of hepatitis C virus (HCV) screening among primary care physicians (PCP). METHODS: A 45-item online questionnaire assessing knowledge of HCV natural history, risk factors, and treatment was distributed to 163 PCP. Logistic regression, adjusted for survey responses, assessed associations between PCP knowledge of HCV natural history and treatment and birth cohort (i.e., birth between 1945 and 1965) screening. Response stratification and weighting were used to account for nonresponse and to permit extension of responses to the entire survey population. Associations between various predictors including demographic characteristics, level of training, and HCV treatment experience and HCV knowledge were assessed. RESULTS: Ninety-one individuals (55.8%) responded. Abnormal liver enzymes (49.4%), assessment of HCV-related risk factors (30.6%), and birth cohort membership (20%) were the leading HCV screening indications. Most PCP (64.7%) felt that the combination of risk-factor and birth cohort screening utilizing a self administered survey while awaiting the physician (55.3%) were the most efficient screening practices. Implementation of birth cohort screening was associated with awareness of the recommendations (P-value = 0.01), knowledge of HCV natural history (P-value < 0.01), and prior management of HCV patients (P-value < 0.01). PCP with knowledge of HCV treatment was also knowledgeable about HCV natural history (P-value < 0.01). Similarly, awareness of age-based screening recommendations was associated with HCV treatment knowledge (P-value = 0.03). CONCLUSION: Comprehensive knowledge of HCV is critical to motivate HCV screening. PCP-targeted educational interventions are required to expand the HCV workforce and linkage-to-care opportunities as we seek global HCV eradication. PMID- 29527268 TI - Outcomes assessment of hepatitis C virus-positive psoriatic patients treated using pegylated interferon in combination with ribavirin compared to new Direct Acting Antiviral agents. AB - AIM: To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C (CHC) treated with new Direct-Acting Antiviral agents (DAAs) compared to pegylated interferon-2alpha plus ribavirin (P/R) therapy. METHODS: This is a retrospective study involving psoriatic patients in biological therapy who underwent anti-hepatitis C virus (HCV) treatment at the Department of Dermatology Galeazzi Orthopaedic Institute Milan, Italy from January 2010 to November 2017. The patients were divided into two groups: patients that underwent therapy with DAAs and patients that underwent HCV treatment with P/R. Patients were assessed by a dermatologist for psoriasis symptoms, collecting Psoriasis Area Severity Index (PASI) scores and the Dermatology Quality of Life Index (DLQI). PASI and DLQI scores were evaluated 24 wk after the end of HCV treatment and were assumed as an outcome of the progression of psoriasis. Switching to a different bDMARD was considered as an inadequate response to biological therapy. The dropout of HCV therapy and sustained virological response (SVR) were considered as outcomes of HCV therapy. RESULTS: Fifty-nine psoriatic patients in biological therapy underwent antiviral therapy for CHC. Of this, 27 patients were treated with DAAs and 32 with P/R. After 24 wk post treatment, the DLQI and the PASI scores were significantly lower (P < 0.001 and P < 0.005, respectively) in the DAAs group compared with P/R group. None of the patients in the DAAs group (0/27) compared to 8 patients of the P/R group (8/32) needed a shift in biological treatment. CONCLUSION: DAAs seem to be more effective and safe than P/R in HCV-positive psoriatic patients on biological treatment. Fewer dermatological adverse events may be due to interferon-free therapy. PMID- 29527270 TI - Primary hepatic peripheral T-cell lymphoma associated with Epstein-Barr viral infection. AB - Primary hepatic peripheral T-cell lymphoma (H-PTCL) is one of the rarest forms of non-Hodgkin lymphoma. We report a patient who presented with worsening jaundice, abdominal pain, and vomiting. Laboratory values were significant for elevated total bilirubin, alkaline phosphatase, and liver aminotransferases. Following a liver biopsy, histopathology revealed several large dense clusters of atypical T lymphocytes which were CD2+, CD3+, CD5+, CD7-, CD4+, CD8-, CD56-, CD57-, CD30+ by immunohistochemistry. The proliferation index was approximately 70% by labeling for ki67/mib1. The above histological profile was consistent with peripheral T cell lymphoma of the liver. Epstein-Barr viral serology indicated a remote infection, a likely risk factor for PTCL. Bone marrow biopsy was negative for malignancy, further supporting hepatic origin. PMID- 29527269 TI - Outcomes of kidney transplantation in patients with hepatitis B virus infection: A systematic review and meta-analysis. AB - AIM: To assess outcomes of kidney transplantation including patient and allograft outcomes in recipients with hepatitis B virus (HBV) infection, and the trends of patient's outcomes overtime. METHODS: A literature search was conducted using MEDLINE, EMBASE and Cochrane Database from inception through October 2017. Studies that reported odds ratios (OR) of mortality or renal allograft failure after kidney transplantation in patients with HBV [defined as hepatitis B surface antigen (HBsAg) positive] were included. The comparison group consisted of HBsAg negative kidney transplant recipients. Effect estimates from the individual study were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017080657). RESULTS: Ten observational studies with a total of 87623 kidney transplant patients were enrolled. Compared to HBsAg-negative recipients, HBsAg positive status was significantly associated with increased risk of mortality after kidney transplantation (pooled OR = 2.48; 95%CI: 1.61-3.83). Meta regression showed significant negative correlations between mortality risk after kidney transplantation in HBsAg-positive recipients and year of study (slopes = 0.062, P = 0.001). HBsAg-positive status was also associated with increased risk of renal allograft failure with pooled OR of 1.46 (95%CI: 1.08-1.96). There was also a significant negative correlation between year of study and risk of allograft failure (slopes = -0.018, P = 0.002). These associations existed in overall analysis as well as in limited cohort of hepatitis C virus-negative patients. We found no publication bias as assessed by the funnel plots and Egger's regression asymmetry test with P = 0.18 and 0.13 for the risks of mortality and allograft failure after kidney transplantation in HBsAg-positive recipients, respectively. CONCLUSION: Among kidney transplant patients, there are significant associations between HBsAg-positive status and poor outcomes including mortality and allograft failure. However, there are potential improvements in patient and graft survivals in HBsAg-positive recipients overtime. PMID- 29527271 TI - INVENTION IS NOT AN OPTION. AB - Inventors help solve all kinds of problems. The AAAS-Lemelson Invention Ambassador program celebrates inventors who have an impact on global challenges, making our communities and the globe better, one invention at a time. In this paper, we introduce two of these invention ambassadors: Dr. Suzie Pun and Dr. Juan Gilbert. Dr. Suzie Pun is the Robert F. Rushmer Professor of Bioengineering, an adjunct professor of chemical engineering, and a member of the Molecular Engineering and Sciences Institute at the University of Washington. Dr. Juan Gilbert is the Andrew Banks Family Preeminence Endowed Professor and chair of the Computer & Information Science & Engineering Department at the University of Florida. Both have a passion for solving problems and are dedicated to teaching their students to change the world. PMID- 29527272 TI - Something old, something new. PMID- 29527273 TI - Incidence and demographical characteristics of patients with post-traumatic stress disorder due to motor vehicle accidents. AB - Introduction: Motor vehicle accidents (MVAs) are daily occurrences in Malaysia but the extent to which victims are psychologically affected is not well known. The objective of this study is to determine the incidence and demographic characteristics of patients with post-traumatic stress disorder (PTSD) due to MVAs at a university hospital in Malaysia. Methods: Patients presenting to the emergency department from August to October 2014 due to MVA-related injuries were recruited. After a period of at least one month, they were followed-up and screened using the validated Malay Post Traumatic Stress Disorder Checklist Civilian version. A score of 30 was chosen as the cut-off point for PTSD. Results: In total, 112 patients presented to the emergency department following MVAs during the study period. Of these, 60.7% agreed for the follow-up. Among the respondents, the mean age was 26 years, 91.2% were males, 66.2% were married, 85.3% were Malays and 88.3% were Muslims. The calculated incidence of PTSD was 7.4%. There was no significant difference noted between the PTSD and non-PTSD groups. Conclusion: A considerable number of MVA victims in Malaysia may develop PTSD after the accident. Further research is needed to explore the factors that contribute or protect to develop the condition. PMID- 29527274 TI - Self-management approaches among hypertensive residents in nursing homes in Malaysia. AB - Introduction: The prevalence of hypertension in Malaysia is increasing and an effective management of hypertension is important to reduce cardiovascular morbidity and mortality. Objective: To determine the knowledge, awareness and perception towards hypertension among residents in nursing homes as well as the roles of caregivers in hypertension management. Methods: A face-to-face survey with 200 hypertensive residents and 30 caregivers from 24 nursing homes in Kuala Lumpur and Selangor, Malaysia was conducted. Results: Of all the hypertensive residents, 90.5% (n = 181) knew that lowering their blood pressure could improve their health. Most residents strongly believed that taking antihypertensive drugs is important for keeping their high blood pressure under control (n = 162, 81%). Taking medication was perceived as the most important factor in controlling the high blood pressure (58%, n = 116) compared to lifestyle or diet modification. The majority of the caregivers reported that they played a major role in managing hypertension, especially with regards to medication-taking. task (66.7%, n = 20). Conclusion: The knowledge, attitude and perceptions of hypertension play a relatively major role in the self-management of hypertension. The role of caregivers also needed to be recognised in managing hypertension in nursing homes. PMID- 29527275 TI - Post-treatment impact and needs of prostate cancer survivors in Malaysia; a qualitative study. AB - Introduction: There are limited studies conducted on the needs of cancer survivors in developing countries like Malaysia. This qualitative study aimed at exploring the post-treatment impact and needs of prostate cancer survivors. Methods: A qualitative study design was used. One in-depth interview and four focus group discussions were conducted with 24 prostate cancer survivors (age range: 58-79 years) from government and private hospitals in Malaysia in 2013. Trained researchers used a topic guide to guide the interviews, which were audio recorded, transcribed verbatim, checked and managed with Nvivo 10 software. A thematic approach was used to analyse the data. Results: Three main themes emerged from the analysis: (a) impact of prostate cancer on the survivors, (b) support needed for coping and (c) information needs. Prostate cancer has an important impact on the survivors' lifestyle after treatment. Some of them have to live with the post-treatment side effects. They were anxious about the possibility of relapse. In addition to family and peer support, there were participants who felt that spiritual support was important in helping them cope with the possibility of relapse. The survivors felt that they did not receive enough information about post-treatment care, dietary measures and supplements for relapse prevention, treatment and prognosis. Conclusion: Prostate cancer has a significant impact on the survivor's lifestyle, emotional and physical health. They need information and emotional support from the healthcare professionals, family and peers. Therefore, it is important for healthcare providers to explore the needs of prostate cancer survivors and provide the necessary support. PMID- 29527276 TI - Intra-aural tick resulting in facial nerve paresis. AB - The presence of a tick in the ear is an uncommon problem encountered by the department of otorhinolaryngology. A tick infestation in the ear can be a traumatising experience for the patient. Here, we report a case of a woman who presented with left facial weakness due to the presence of a tick in the external auditory canal. PMID- 29527277 TI - Black tongue. PMID- 29527278 TI - Facial nerve palsy in a child: Bell's palsy? Think again! AB - Introduction: Half of facial paralysis in children is idiopathic at origin. However, dismissing facial paralysis as being idiopathic without a thorough history and meticulous examination could be disastrous as illustrated by this case. Case report: We report a case of sphenoid wing meningioma in a 4-year-old girl. She first presented with only facial asymmetry that was noticed by her mother. Examination suggested a left upper motor neuron facial nerve palsy. A sphenoid wing meningioma was found on magnetic resonance imaging (MRI) of her brain. She underwent craniotomy and total tumour excision. Histopathological examination of the tumour showed a grade 1 transitional type meningioma. Meningiomas in children are rare compared to the adult population. Presentations in children may be delayed due to their inability to recognise or communicate abnormalities. Distinguishing between upper and lower motor neuron facial palsy is crucial in decision making for facial paralysis in children. PMID- 29527279 TI - Xanthogranulomatous pyelonephritis with reno-colic fistula: A rare complication of urinary tract infection. AB - Urinary tract infection (UTI) is one of the most common presentations in general practice and, in most instances, occurs in a single episode and is easily treated with a course of anti-microbial therapy. In the case of recurrent urinary tract infections, it is important to consider evaluation for any underlying causes. We report the case of a 32 year old female who had recurrent UTIs; this was a case of recurrent UTI secondary to xanthogranulomatous pyelonephritis from renal stones with resultant reno-colic fistula formation. PMID- 29527280 TI - Varicella zoster causing preseptal cellulitis - uncommon but possible. AB - Background: Varicella has been known to be a harmless childhood disease. However, it has been reported that severe complications have taken place following Varicella infection, in both immunocompetent, as well as immunocompromised, individuals. Cutaneous complications of Varicella may manifest as preseptal cellulitis, albeit rarely. Report: We present a case of a 4-year-old boy who presented with symptoms and signs of preseptal cellulitis following Varicella infection. He was referred to the otorhinolaryngology team for a nasoendoscopy to rule out sinusitis, in view of the fear that a child presenting with a swollen red eye may be a case of true orbital cellulitis. He was treated successfully with intravenous antibiotics and surgical drainage of the preseptal collection. Conclusion: It is imperative for clinicians to be aware that a simple Varicella infection may lead to cutaneous complications in the pediatric age group, especially in children who are 4 years and younger. They may develop preseptal cellulitis, whose presentation might mimic that of orbital cellulitis. Empirical treatment with antibiotics would be advantageous for the patient. A nasoendoscopic examination may also be warranted in these cases to rule out sinusitis as a cause of orbital cellulitis. PMID- 29527281 TI - Simple Question Towards Diagnosis: Did You Eat Fish? PMID- 29527282 TI - Recurrent transient visual loss in a middle aged woman. AB - Visual loss is a common presenting complaint in primary care. We present a case of recurrent transient visual loss in a middle aged woman. Her funduscopy showed bilateral optic disc swelling. We have highlighted the differentiation of bilateral optic disc swelling at the primary care level as the management differs according to the diagnosis. PMID- 29527283 TI - Inventory Control System for a Healthcare Apparel Service Centre with Stockout Risk: A Case Analysis. AB - Based on the real-world inventory control problem of a capacitated healthcare apparel service centre in Hong Kong which provides tailor-made apparel-making services for the elderly and disabled people, this paper studies a partial backordered continuous review inventory control problem in which the product demand follows a Poisson process with a constant lead time. The system is controlled by an (Q,r) inventory policy which incorporate the stockout risk, storage capacity, and partial backlog. The healthcare apparel service centre, under the capacity constraint, aims to minimize the inventory cost and achieving a low stockout risk. To address this challenge, an optimization problem is constructed. A real case-based data analysis is conducted, and the result shows that the expected total cost on an order cycle is reduced substantially at around 20% with our proposed optimal inventory control policy. An extensive sensitivity analysis is conducted to generate additional insights. PMID- 29527284 TI - A mini-library system to investigate non-essential residues of lipid phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1. AB - We recently identified a peptide-peptoid hybrid, PPS1, which specifically recognized lipid-phosphatidylserine (PS). PPS1 consists of distinct positively charged and hydrophobic residue-containing regions. PPS1 monomer was inactive, but the dimeric form, PPS1D1, displayed strong cytotoxicity for lung cancer cells compared to normal cells in vitro, and reduced the tumor growth in vivo. The minimum pharmacophore of PPS1D1 showed that the first (methionine) and fourth (N lysine) residues were not important for PPS1D1 cytotoxic activity. In this study, we further investigated these two residues, in particular the fourth residue that lies between the most important four residue hydrophobic region and two positively charged residues, to determine whether replacements of these moieties could gain activity improvements, or render PPS1D1 totally insensitive for binding recognition. The positively charged fourth residue N-lysine was replaced with the substituents having varied physiochemical properties, such as aromatic hydrophobic, aliphatic-alicyclic, heterocyclic, and negatively charged residues, developing a mini-library of 39 derivatives. The standard 3-(4,5-dimethylthiazol 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) colorimetric and/or the calcein AM cell viability assays performed on HCC4017 lung cancer cells indicated that the fourth position of PPS1D1 was insensitive to most changes, except reversal to the negative charge significantly affected the activity. This observation may be due to the neutralization of the nearby positively charged residue that is essential for binding. In addition, shortening each monomeric sequence by eliminating the methionine at the first position did not affect the activity. PMID- 29527285 TI - Narrow-Spectrum Antibacterial Agents. AB - While broad spectrum antibiotics play an invaluable role in the treatment of bacterial infections, there are some drawbacks to their use, namely selection for and spread of resistance across multiple bacterial species, and the detrimental effect they can have upon the host microbiome. If the causitive agent of the infection is known, the use of narrow-spectrum antibacterial agents has the potential to mitigate some of these issues. This review outlines the advantages and challenges of narrow-spectrum antibacterial agents, discusses the progress that has been made toward developing diagnostics to enable their use, and describes some of the narrow-spectrum antibacterial agents currently being investigated against some of the most clinically important bacteria including Clostridium difficile, Mycobacterium tuberculosis and several ESKAPE pathogens. PMID- 29527286 TI - Phenylethynyl-substituted Heterocycles Inhibit Cyclin D1 and Induce the Expression of Cyclin-dependent Kinase Inhibitor p21Wif1/Cip1 in Colorectal Cancer Cells. AB - Fluorinated, phenylethynyl-substituted heterocycles that possessed either an N methylamino or N,N-dimethylamino group attached to heterocycles including pyridines, indoles, 1H-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21Wif1/Cip1) served as a readout for antineoplastic activity at a cellular level. On a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)-N methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-N,N dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A). PMID- 29527287 TI - Genotoxicity of ortho-quinones: reactive oxygen species versus covalent modification. AB - o-Quinones are formed metabolically from natural and synthetic estrogens as well as upon exposure to polycyclic aromatic hydrocarbons (PAH) and contribute to estrogen and PAH carcinogenesis by genotoxic mechanisms. These mechanisms include the production of reactive oxygen species to produce DNA strand breaks and oxidatively damaged nucleobases; and the formation of covalent depurinating and stable DNA adducts. Unrepaired DNA-lesions can lead to mutation in critical growth control genes and cellular transformation. The genotoxicity of the o quinones is exacerbated by nuclear translocation of estrogen o-quinones by the estrogen receptor and by the nuclear translocation of PAH o-quinones by the aryl hydrocarbon receptor. The properties of o-quinones, their formation and detoxication mechanisms, quinone-mediated DNA lesions and their mutagenic properties support an important role in hormonal and chemical carcinogenesis. PMID- 29527288 TI - A collection of annotated and harmonized human breast cancer transcriptome datasets, including immunologic classification. AB - The increased application of high-throughput approaches in translational research has expanded the number of publicly available data repositories. Gathering additional valuable information contained in the datasets represents a crucial opportunity in the biomedical field. To facilitate and stimulate utilization of these datasets, we have recently developed an interactive data browsing and visualization web application, the Gene Expression Browser (GXB). In this note, we describe a curated compendium of 13 public datasets on human breast cancer, representing a total of 2142 transcriptome profiles. We classified the samples according to different immune based classification systems and integrated this information into the datasets. Annotated and harmonized datasets were uploaded to GXB. Study samples were categorized in different groups based on their immunologic tumor response profiles, intrinsic molecular subtypes and multiple clinical parameters. Ranked gene lists were generated based on relevant group comparisons. In this data note, we demonstrate the utility of GXB to evaluate the expression of a gene of interest, find differential gene expression between groups and investigate potential associations between variables with a specific focus on immunologic classification in breast cancer. This interactive resource is publicly available online at: http://breastcancer.gxbsidra.org/dm3/geneBrowser/list. PMID- 29527289 TI - Factors determining access to oral health services among children aged less than 12 years in Peru. AB - Background: Understanding problems of access to oral health services requires knowledge of factors that determine access. This study aimed to evaluate factors that determine access to oral health services among children aged <12 years in Peru between 2014 and 2015. Methods: We performed a secondary data analysis of 71,614 Peruvian children aged <12 years and their caregivers. Data were obtained from the Survey on Demography and Family Health 2014-2015 (Encuesta Demografica y de Salud Familiar - ENDES). Children's access to oral health services within the previous 6 months was used as the dependent variable (i.e. Yes/No), and the Andersen and col model was used to select independent variables. Predisposing (e.g., language spoken by tutor or guardian, wealth level, caregivers' educational level, area of residence, natural region of residence, age, and sex) and enabling factors (e.g. type of health insurance) were considered. Descriptive statistics were calculated, and multivariate analysis was performed using generalized linear models (Poisson family). Results: Of all the children, 51% were males, 56% were aged <5 years, and 62.6% lived in urban areas. The most common type of health insurance was Integral Health Insurance (57.8%), and most respondents were in the first quintile of wealth (31.6%). Regarding caregivers, the most common educational level was high school (43.02%) and the most frequently spoken language was Spanish (88.4%). Univariate analysis revealed that all variables, except sex and primary educational level, were statistically significant. After adjustment, sex, area of residence, and language were insignificant, whereas the remaining variables were statistically significant. Conclusions: Wealth index, caregivers' education level, natural region of residence, age, and type of health insurance are factors that determine access to oral health services among children aged <12 years in Peru. These factors should be considered when devising strategies to mitigate against inequities in access to oral health services. PMID- 29527290 TI - Dermal fibroblasts from patients with Parkinson's disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations. AB - Background: Recently, the development of Parkinson's disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression. PMID- 29527291 TI - Immunoexpression of P63 and SOX2 in triple-negative breast cancers, Indonesia. AB - BACKGROUND: Using immunohistochemical stains to target specific breast cancer markers has become indispensable for evaluation of small diagnostic tissue specimens, and therefore novel marker cocktails for specific breast cancers are required. This study was conducted to assess the immunoexpression of P63 and SOX2 in triple negative breast cancer (TNBC), and to evaluate the predictive diagnostic value of these markers for specific types of TNBC. METHODS: Histological slides and paraffin blocks of TNBC cases were collected from Dr. Hasan Sadikin Hospital, Bandung, Indonesia from 5-years period (2011-2015). Each histological slide was subjected to immunohistochemical staining for P63 (nucleus and cytoplasm) and SOX2 (nucleus), with specific primer antibodies. Immunoexpression of P63 and SOX2 was evaluated using immunoreactivity scoring. Associations between P63 and SOX2 immunoexpression and TNBC types were assessed using Mann Whitney tests. In addition, the predictive diagnostic values of these markers were assessed. RESULTS: Forty TNBC histological slides were included, and 23 (57.5%) were Basal-like type TNBC and 17 (42.5%) were Non basal-like type TNBC. Immunoexpression of P63 nucleus and SOX2 was not different between types of TNBC. However, immunoexpression of P63 in the cytoplasm in Basal-like type TNBC was significantly higher than in Non basal-like type TNBC ( p=0.021). Predictor diagnostic value analysis suggested that immunoexpression of P63 in cytoplasm had 56.5% sensitivity and 70.6% specificity for diagnosing Basal-like type TNBC, with area under curve of 0.64. Conclusions: Immunoexpression of P63 in the cytoplasm has a relatively weak diagnostic value to discriminate Basal-like and Non basal-like types of TNBC. PMID- 29527292 TI - Identification of diverse defense mechanisms in trout red blood cells in response to VHSV halted viral replication. AB - Background: It has been described that fish nucleated red blood cells (RBCs) generate a wide variety of immune-related gene transcripts when viruses highly replicate inside them and are their main target cell. The immune response and mechanisms of fish RBCs against viruses targeting other cells or tissues has not yet been explored and is the objective of our study. Methods: Trout RBCs were obtained from peripheral blood, ficoll purified and exposed to Viral Haemorrhagic Septicaemia virus (VHSV). Immune response was evaluated by means of RT-qPCR, flow cytometry, immunofluorescence and isobaric tag for relative and absolute quantification (iTRAQ) protein profiling Results: VHSV N gene transcripts incremented early postexposure and were drastically decreased after 6 hours postexposure (hpe). The expression of the type I interferon ( ifn1) gene was significantly downregulated at early postexposure (3 hpe), together with a gradual downregulation of interferon-inducible mx and pkr genes until 72 hpe. Type I IFN protein was downregulated and interferon-inducible Mx protein was maintained at basal levels. Co-culture assays of RBCs with TSS (stromal cell line from spleen) revealed the IFN crosstalk between both cell types. On the other hand, anti-microbial peptide beta-defensin 1 and neutrophil chemotactic factor interleukin 8 were slightly upregulated in VHSV-exposed RBCs Isobaric tag for relative and absolute quantification (iTRAQ) revealed that VHSV exposure can induce a global protein downregulation in trout RBCs, mainly related to RNA stability and proteasome pathways. The antioxidant/antiviral response is also suggested to be involved in the response of trout RBCs to VHSV. Conclusions: A variety of mechanisms are proposed to be implicated in the antiviral response of trout RBCs against VHSV halted infection. Ongoing research is focused on understanding the mechanisms in detail. To our knowledge, this is the first report that implicates fish RBCs in the antiviral response against viruses not targeting RBCs. PMID- 29527293 TI - Portable respiratory polygraphy monitoring of obese mothers the first night after caesarean section with bupivacaine/morphine/fentanyl spinal anaesthesia. AB - Background: Obesity, abdominal surgery, and intrathecal opioids are all factors associated with a risk for respiratory compromise. The aim of this observational study was to explore the use of portable respiratory polygraphy for monitoring of obese mothers for respiratory depression the first night after caesarean section (CS) with bupivacaine/morphine/fentanyl spinal anaesthesia. Methods: Consecutive obese (BMI >30 kg/m 2) mothers, >=18 years, scheduled for CS with bupivacaine/morphine/fentanyl spinal anaesthesia were monitored with a portable polygraphy device Embletta /NOX on the first postoperative night. The apnoea hypopnea index (AHI) was identified by clinical algorithm and assessed in accordance to general guidelines. Results: Forty mothers were invited to participate: 27 consented, 23 were included, but polysomnography registration failed in 3. Among the 20 mothers: 11 had an AHI <5; 7, AHI 5-15; and 2, AHI >15. The oxygen desaturation index (ODI) was on average 4.4, and eight patients had an ODI >5. Those mothers with a high AHI (15.3 and 18.2) did not show high ODI or signs of hypercapnia on transcutaneous CO 2 registration. Mean saturation was 94% (91-96), and four mothers had mean saturation between 90-94%, but none had a mean SpO 2 <90%. Mean nadir saturation was 71% (range, 49-81%). None of the mothers showed clinical signs or symptoms of severe respiratory depression, shown by routine clinical monitoring. Conclusion: We found portable polygraphy registration during early post-CS in moderately obese mothers having had intrathecal morphine/fentanyl cumbersome and although episodes of oxygen saturation decrease were noticed, obstructive events and episodes of desaturation were commonly not synchronised. Upper airway obstructions seem not be of major importance in this clinical setting. Monitoring of respiratory rate, SpO 2 and possibly transcutaneous CO 2 in mothers at high risk of respiratory distress warrants further studies. Preoperative screening in obese patients, at risk for sleep breathing disorder, is of course of value. PMID- 29527294 TI - Case Report: Propranolol increases the therapeutic response to temozolomide in a patient with metastatic paraganglioma. AB - This case report presents the clinical evolution and management of a patient with a hereditary paraganglioma syndrome. This disease is characterized by rare tumors of neural crest origin that are symmetrically distributed along the paravertebral axis from the base of the skull and neck to the pelvis. In addition, these patients may develop renal cancer, gastrointestinal stromal tumors, pituitary adenomas, and bone metastasis in some cases. To date no successful therapeutic treatment has been reported. Total resection with postoperative radiotherapy and chemotherapy have been advocated, especially for the multiple metastasis. Here we show how the combination of high doses of the beta blocker propranolol (3 mg/Kg/day) and the DNA intercalating agent, temozolomide, has been successful in the treatment of a SDHA metastatic paraganglioma. PMID- 29527295 TI - Evaluation of antibiotic susceptibility in wound infections: A pilot study from Bangladesh. AB - Introduction: Infections due to antibiotic resistant bacteria have increased alarmingly in both developed and developing countries. Unrestrained and rapidly spreading bacterial growth has turned the management of wound infections into a serious challenge. This study aimed to determine the prevalence of different bacterial pathogens and their antibiotic susceptibility in various types of wound infections. Methods: A cross-sectional study was conducted to collect 105 wound swabs. All isolated bacteria were identified based on colony characteristics, gram stain and standard biochemical tests, and antibiotic susceptibility testing (AST) with the disc diffusion method. Descriptive statistics were used to present the study findings, and all analyses were performed using Stata Version 13. Results: The rate of isolation of bacteria was 92.3%. Staphylococcus aureus was found to be the most frequent isolate (55.7%), followed by Escherichia coli (23.7%), Pseudomonas spp. (8.2%), and Streptococcus pyogenes (7.2%). Gram positive bacteria were mostly (60%) found sensitive to vancomycin, azithromycin, gentamicin, imipenem, cefixime, and ceftriaxone in this study. Among the Gram negative bacteria, Escherichia coli (>60%) showed sensitivity to cefixime, azithromycin, cefuroxime, ceftriaxone, cefotaxime, gentamycin, and ceftazidime. Conclusions: The diversity of isolated bacteria and their susceptibility patterns signify a need to implement a proper infection control strategy, which can be achieved by carrying out antibiotic sensitivity tests of the isolates. PMID- 29527296 TI - Management of eight labor and delivery patients dependent on buprenorphine (SubutexTM): A retrospective chart review. AB - Background: Opioid use during pregnancy is a growing concern in the United States. Buprenorphine has been recommended by "The American College of Obstetrics and Gynecology" as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy. The partial MU-opioid agonists' unique pharmacology, including its long half time and high affinity to the MU opioid receptor, complicates patient management in a highly kinetic, and often urgent field like obstetric anesthesia. We reviewed our management and outcomes in this medically complex population. Methods: An Institutional Review Board (IRB) approved retrospective chart review was conducted of women admitted to the University of Washington Medical Center Labor and Delivery unit from July 2012 to November 2013 using buprenorphine. All deliveries, including intrauterine fetal demise, were included. Results: Eight women were admitted during this period to our L&D floor on buprenorphine. All required peri-partum anesthetic management either for labor and/or cesarean delivery management. Analgesic management included dilaudid or fentanyl PCA and/or continued epidural infusion, and in one instance ketamine infusion, while the pre-admission buprenorphine regimen was continued. Five babies were viable, two women experienced intrauterine fetal death at 22 and 36 weeks gestational age (GSA), respectively, and one neonate died shortly after delivery due to a congenital diaphragmatic hernia. Conclusions: This case series illuminates the medical complexity of parturients using buprenorphine. Different treatment modalities in the absence of evidence based guidelines included additional opioid administration and continued epidural analgesia. The management of post-cesarean pain in patients on partial MU-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care. PMID- 29527297 TI - Incorporating health workers' perspectives into a WHO guideline on personal protective equipment developed during an Ebola virus disease outbreak. AB - Background: Ebola virus disease (EVD) health facility transmission can result in infection and death of health workers. The World Health Organization (WHO) supports countries in preparing for and responding to public health emergencies, which often require developing new guidance in short timelines with scarce evidence. The objective of this study was to understand frontline physicians' and nurses' perspectives about personal protective equipment (PPE) use during the 2014-2016 EVD outbreak in West Africa and to incorporate these findings into the development process of a WHO rapid advice guideline. Methods : We surveyed frontline physicians and nurses deployed to West Africa between March and September of 2014. Results: We developed the protocol, obtained ethics approval, delivered the survey, analysed the data and presented the findings as part of the evidence-to-decision tables at the expert panel meeting where the recommendations were formulated within eight weeks. Forty-four physicians and nurses responded to the survey. They generally felt at low or extremely low risk of virus transmission with all types of PPE used. Eye protection reduced the ability to provide care, mainly due to impaired visibility because of fogging. Heat and dehydration were a major issue for 76% of the participants using goggles and for 64% using a hood. Both gowns and coveralls were associated with significant heat stress and dehydration. Most participants (59%) were very confident that they were using PPE correctly. Conclusion : Our study demonstrated that it was possible to incorporate primary data on end-users' preferences into a rapid advice guideline for a public health emergency in difficult field conditions. Health workers perceived a balance between transmission protection and ability to care for patients effectively while wearing PPE. These findings were used by the guideline development expert panel to formulate WHO recommendations on PPE for frontline providers caring for EVD patients in outbreak conditions. PMID- 29527298 TI - Response heterogeneity: Challenges for personalised medicine and big data approaches in psychiatry and chronic pain. AB - Response rates to available treatments for psychological and chronic pain disorders are poor, and there is a considerable burden of suffering and disability for patients, who often cycle through several rounds of ineffective treatment. As individuals presenting to the clinic with symptoms of these disorders are likely to be heterogeneous, there is considerable interest in the possibility that different constellations of signs could be used to identify subgroups of patients that might preferentially benefit from particular kinds of treatment. To this end, there has been a recent focus on the application of machine learning methods to attempt to identify sets of predictor variables (demographic, genetic, etc.) that could be used to target individuals towards treatments that are more likely to work for them in the first instance. Importantly, the training of such models generally relies on datasets where groups of individual predictor variables are labelled with a binary outcome category - usually 'responder' or 'non-responder' (to a particular treatment). However, as previously highlighted in other areas of medicine, there is a basic statistical problem in classifying individuals as 'responding' to a particular treatment on the basis of data from conventional randomized controlled trials. Specifically, insufficient information on the partition of variance components in individual symptom changes mean that it is inappropriate to consider data from the active treatment arm alone in this way. This may be particularly problematic in the case of psychiatric and chronic pain symptom data, where both within subject variability and measurement error are likely to be high. Here, we outline some possible solutions to this problem in terms of dataset design and machine learning methodology, and conclude that it is important to carefully consider the kind of inferences that particular training data are able to afford, especially in arenas where the potential clinical benefit is so large. PMID- 29497495 TI - Improving the biomedical research literature: insights from authors' editors can help journal editors define and refine their core competencies. AB - A team of stakeholders in biomedical publishing recently proposed a set of core competencies for journal editors, as a resource that can inform training programs for editors and ultimately improve the quality of the biomedical research literature. This initiative, still in its early stages, would benefit from additional sources of expert information. Based on our experiences as authors' editors, we offer two suggestions on how to strengthen these competencies so that they better respond to the needs of readers and authors - the main users of and contributors to research journals. First, journal editors should be able to ensure that authors are given useful feedback on the language and writing in submitted manuscripts, beyond a (possibly incorrect) blanket judgement of whether the English is "acceptable" or not. Second, journal editors should be able to deal effectively with inappropriate text re-use and plagiarism. These additional competencies would, we believe, be valued by other stakeholders in biomedical research publication as markers of editorial quality. PMID- 29527300 TI - The immunology of Zika Virus. AB - Zika virus (ZIKV) was initially thought to cause only mild, self-limiting symptoms. However, recent outbreaks have been associated with the autoimmune disease Guillain-Barre syndrome and causally linked to a congenital malformation known as microcephaly. This has led to an urgent need for a safe and effective vaccine. A comprehensive understanding of the immunology of ZIKV infection is required to aid in the design of such a vaccine. Whilst details of both innate and adaptive immune responses to ZIKV are emerging, further research is needed. As immunopathogenesis has been implicated in poor outcomes following infection with the related dengue virus, identification of cross-reactive immune responses between flaviviruses and the impact they may have on disease progression is also of high importance. PMID- 29527301 TI - Update on regulation and effector functions of Th17 cells. AB - T-helper cells that produce IL-17 are recognized as a significant subset within cell-mediated adaptive immunity. These cells are implicated in both the pathology of inflammatory disorders as well as the clearance of extracellular infections and the maintenance of the microbiota. However, the dynamic nature of this cell type has created controversy in understanding Th17 induction as well as Th17 phenotyping, since these cells may switch from Th17 to Treg or Th17 to Th1 cytokine profiles under certain conditions. This review highlights recent advances in Th17 cells in understanding their role in commensal regulation, sex difference in immune outcomes and the immunology of pregnancy, as well as inventive experimental models that have allowed for an increased understanding of Th17 regulation and induction. PMID- 29527302 TI - World TB Day 2018: The Challenge of Drug Resistant Tuberculosis. AB - On 24th March, the world commemorates the day in 1882 when Dr Robert Koch announced his discovery of Mycobacterium tuberculosis (MTB). Over 130 years later, tuberculosis (TB) continues to affect individuals, communities, and entire health systems and economies. Koch unsuccessfully tried to 'cure' TB, and despite major advances in other areas of medicine, control of TB remains elusive- in 2016 TB was the leading infectious cause of death. The STOP TB partnership and World Health Organization (WHO) have announced their theme for World TB Day 2018 "Wanted: Leaders for a TB-Free World. You can make history. End TB." This theme recognizes that TB is much larger than any one person, institute or discipline of research, and provides an opportunity for us to reflect on the major challenges and consider how we, as a scientific community, can work together and take the lead to address the global crisis of drug-resistant TB (DR-TB). PMID- 29527303 TI - Colonization of long-term care facility residents in three Italian Provinces by multidrug-resistant bacteria. AB - Background: Rationale and aims of the study were to compare colonization frequencies with MDR bacteria isolated from LTCF residents in three different Northern Italian regions, to investigate risk factors for colonization and the genotypic characteristics of isolates. The screening included Enterobacteriaceae expressing extended-spectrum beta-lactamases (ESbetaLs) and high-level AmpC cephalosporinases, carbapenemase-producing Enterobacteriaceae, Pseudomonas aeruginosa or Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Methods: Urine samples and rectal, inguinal, oropharyngeal and nasal swabs were plated on selective agar; resistance genes were sought by PCR and sequencing. Demographic and clinical data were collected. Results: Among the LTCF residents, 75.0% (78/104), 69.4% (84/121) and 66.1% (76/115) were colonized with at least one of the target organisms in LTCFs located in Milan, Piacenza and Bolzano, respectively. ESbetaL producers (60.5, 66.1 and 53.0%) were highly predominant, mainly belonging to Escherichia coli expressing CTX-M group-1 enzymes. Carbapenemase-producing enterobacteria were found in 7.6, 0.0 and 1.6% of residents; carbapemenase producing P. aeruginosa and A. baumannii were also detected. Colonization by MRSA (24.0, 5.7 and 14.8%) and VRE (20.2, 0.8 and 0.8%) was highly variable. Several risk factors for colonization by ESbetaL-producing Enterobacteriaceae and MRSA were found and compared among LTCFs in the three Provinces. Colonization differences among the enrolled LTCFs can be partially explained by variation in risk factors, resident populations and staff/resident ratios, applied hygiene measures and especially the local antibiotic resistance epidemiology. Conclusions: The widespread diffusion of MDR bacteria in LTCFs within three Italian Provinces confirms that LTCFs are an important reservoir of MDR organisms in Italy and suggests that future efforts should focus on MDR screening, improved implementation of infection control strategies and antibiotic stewardship programs targeting the complex aspects of LTCFs. PMID- 29527304 TI - Metabolomics characterization of colostrum in three sow breeds and its influences on piglets' survival and litter growth rates. AB - Background: Colostrum is the first secretion produced by mammary glands during the hours immediately preceding and succeeding parturition. This secretion differs from milk and represents an essential vehicle of passive immunity, prebiotic compounds and growth factors involved in intestinal development. Most of the literature concerning colostrum composition refers mainly to human and cow; and little is known about pig colostrum metabolome and how it varies between pig breeds and different farrowing parity. Thus, the aim of the present research is to provide new information about pig colostrum composition and the associations between metabolites, the sows' breed and the survival and growth rates of their litters. Results: Colostrum samples were gathered from 58 parturitions of sows belonging to three different breeds chosen for their importance in Italian heavy pig production: 31 Large White, 15 Landrace and 12 Duroc respectively. The defatted and ultrafiltered colostrum samples were analysed using 1H-NMR spectroscopy. Principal Components Analysis (PCA) was assessed on the obtained spectra. In addition, using a Stepwise Regression and a Linear Regression analyses the metabolites named after the signals assignment were tested for their associations with piglets' performances. Twenty-five metabolites were identified, comprehending monosaccharides, disaccharides (such as lactose), organic acids (lactate, citrate, acetate and formate), nitrogenous organic acids (such as creatine) and other compounds, including nucleotides. PCA results evidence a clustering due to breed and season effects. Lactose was the main compound determining the assignment of the samples into different clusters according to the sow breed. Furthermore, some metabolites showed to be associated with piglets' performance and survival traits: acetate and taurine were positively related to litter weight gain and piglets' survival rate, respectively, while dimethylamine and cis-aconitate were linked to new-borns' impaired ability to survive. Conclusions: The results obtained suggest that colostrum composition is affected by breed, which, together with environmental conditions, may cause changes in colostrum metabolites content with possible consequences on piglets' performances. Among the identified metabolites, acetate, taurine, dimethylamine and cis-aconitate showed consistent associations with piglets' survival rate and litter weight gain, implying that these compounds may affect new-borns' ability to survive. PMID- 29527305 TI - Influenza and influenza-like syndromes: the subjects' beliefs, the attitude to prevention and treatment, and the impact in Italian general population. AB - Background: Influenza and influenza-like syndromes (I-LSs) are infectious diseases occurring on a seasonal basis which can lead to upper (URTI) and lower respiratory tract illness (LRTI) of different severity. The approach to these disorders is unfortunately not uniform. Aim of the study was to investigate real life people beliefs, the attitude to their prevention and treatment, and their impact in general population. Methods: A cross-sectional survey via Computer Assisted Telephone Interview (CATI) was carried out using a specific questionnaire investigating influenza episode rates, subjects behavior in case of influenza and I-LSs, and prescribed therapy. Results: 1,202 subjects completed the questionnaire: median age was 46, 49% male, 20% active smokers. 57% of respondents experienced at least one episode of influenza or I-LS in the previous 12 months; episodes were usually home-managed, shorter than 2 weeks and more frequent in fall and winter (73% of the total). GP resulted the first health-care option (56%); almost 3% of respondents referred to the emergency room, and hospitalization occurred in 1%. Mucolytics resulted the most prescribed drugs (55%) followed by antibiotics and aerosol therapy (37-38%). Even if more than 70% of subjects considered vaccination essential, only 14% received influenza vaccination yearly and almost 60% had never received vaccination. Approximately 36% of respondents regarded homeopathy (namely Oscillococcinum) as an helpful alternative because of perceived as safer. Conclusions: Seasonal prevalence of I LSs and influenza partially overlap. As virus identification is not a common procedure in daily practice, only a clinical discrimination is possible. Antibiotic prescription is still too high and largely inappropriate. Influenza vaccination is strongly encouraged, but different strategies are also used. Other approaches are receiving increasing attention in general population, and subjects' willingness to spend out-of-pocket for effective remedies is also increasing. The discrepancy between subjects' beliefs and health care actions likely reflects the insufficiency of institutional preventive strategies. In general, the approach to influenza and I-LSs appear variable and highly dependent of subjects' and their GPs' cultural beliefs. PMID- 29527307 TI - Compliance with guidelines for disease management in diabetes: results from the SwissDiab Registry. AB - Objective: Tight glycemic control and aggressive treatment of additional cardiovascular risk factors can substantially reduce risk of diabetes-related complications. In 2013, the Swiss Society of Endocrinology and Diabetology (SSED) established national criteria on good disease management in diabetes, but little is known about compliance in clinical care. Here we assessed to what extent patients from two tertiary care centers in the German-speaking part of Switzerland enrolled in the Swiss Diabetes (SwissDiab) Registry adhere to the SSED criteria. Research design and methods: SwissDiab is a prospective observational cohort study of patients regularly treated at Swiss tertiary diabetes centers. Data were collected through standardized annual health examinations. Baseline participant descriptive statistics, stratified by diabetes mellitus type 1 (DM1) and type 2 (DM2), were compared with SSED targets for glycemic control, blood pressure, blood lipids, weight maintenance, and ophthalmic examination. Results: By the end of 2016, 604 participants with DM1 (40%) and DM2 (60%) had data available for analyses, 36% and 29% women, respectively. At baseline, all the SSED targets were met with two exceptions: a glycated hemoglobin A1c value <7% was measured in 32% of participants with DM1 (SSED target: >=40%) and 47% and 56% of overweight or obese participants with DM1 and DM2, respectively, received nutritional counseling in the previous year (SSED target: >=80%). Conclusions: The SSED targets for good disease management in diabetes were achieved in the majority of participants at the time of enrollment, but results also highlight areas where disease management can be improved, particularly the role of nutrition counseling. PMID- 29527308 TI - Variables associated with HbA1c and weight reductions when adding liraglutide to multiple daily insulin injections in persons with type 2 diabetes (MDI Liraglutide trial 3). AB - Objective: To evaluate variables associated with hemoglobin A1c (HbA1c) and weight reduction when adding liraglutide to persons with type 2 diabetes treated with multiple daily insulin injections (MDI). Research design and methods: This was a reanalysis of a previous trial where 124 patients were enrolled in a double blind, placebo-controlled, multicenter randomized trial carried out over 24 weeks. Predictors for effect on change in HbA1c and weight were analyzed within the treatment group and with concurrent interaction analyses. Correlation analyses for change in HbA1c and weight from baseline to week 24 were made. Results: The mean age at baseline was 63.7 years, 64.8% were men, the mean number of insulin injections was 4.4 per day, the mean daily insulin dose was 105 units and the mean HbA1c was 74.5 mmol/mol (9.0%). The mean HbA1c and weight reductions were 12.3 mmol/mol (1.13%; P<0.001) and 3.8 kg (P<0.001) greater in liraglutide than placebo-treated persons. There was no significant predictor for greater effect on HbA1c that existed in all analyses (univariate, multivariate and interaction analyses against controls). For a greater weight reduction when adding liraglutide, a lower HbA1c level at baseline was a predictor (liraglutide group P=0.002, P=0.020 for liraglutide group vs placebo). During follow-up in the liraglutide group, no significant correlation was found between change in weight and change in HbA1c (r=0.09, P=0.46), whereas a correlation existed between weight and insulin dose reduction (r=0.44, P<0.001). Conclusion: Weight reduction becomes greater when adding liraglutide in patients with type 2 diabetes treated with MDI who had a lower HbA1c level compared with those with a higher HbA1c level. There was no correlation between reductions in HbA1c and weight when liraglutide was added, that is, different patient groups responded with HbA1c and weight reductions. Trial registration number: EudraCT nr: 2012-001941-42. PMID- 29527309 TI - Association of type 1 diabetes and concentrations of drinking water components in Newfoundland and Labrador, Canada. AB - Objective: To determine the association between drinking water quality and rates of type 1 diabetes in the Newfoundland and Labrador (NL) population, which has one of the highest incidences of type 1 diabetes reported globally. Research design and methods: The study used a community-based, case-control design. We first calculated incidence rates of type 1 diabetes at the provincial, regional and community levels. The connection between incidence rates and components in public water supplies were then analyzed in three ways: to evaluate differences in water quality between communities with and without incident cases of type 1 diabetes, and to analyze the relationship between water quality and incidence rates of type 1 diabetes at both the community and regional levels. Results: The provincial incidence of type 1 diabetes was 51.7/100 000 (0-14 year age group) for the period studied. In the community-based analysis, there were significant associations found between higher concentrations of arsenic (beta=0.268, P=0.013) and fluoride (beta=0.202, P=0.005) in drinking water and higher incidence of type 1 diabetes. In the regional analysis, barium (beta=-0.478, P=0.009) and nickel (beta=-0.354, P=0.050) concentrations were negatively associated with incidence of type 1 diabetes. Conclusions: We confirmed the high incidence of type 1 diabetes in NL. We also found that concentrations of some components in drinking water were associated with higher incidence of type 1 diabetes, but no component was found to have a significant association across the three different levels of analysis performed. PMID- 29527310 TI - Appendicular muscle mass and fasting triglycerides predict serum liver aminotransferases in young female collegiate athletes. AB - Objective: We test the hypothesis that aspartate aminotransferase (AST) may be associated inversely with serum triglycerides (TG) and positively with high density lipoprotein (HDL) cholesterol in young athletes because athletes have larger amounts of muscle mass. Research design and methods: Pearson's correlation coefficients were calculated between serum AST and alanine aminotransferase (ALT) and body composition identified by dual-energy X-ray absorptiometry, markers of insulin resistance, serum lipids, lipoproteins, apolipoproteins, adiponectin and leptin in 174 female collegiate athletes (18-22 years). Multivariate linear regression analyses were used to identify independent determinants of the aminotransferases. Results: AST and ALT showed positive correlation with appendicular skeletal muscle mass (ASM) and height-adjusted ASM. In addition, ALT as well as AST showed inverse, not positive, association with fasting TG. Further, both AST and ALT showed positive associations with HDL cholesterol and apolipoprotein AI, a major apolipoprotein of HDL particles. Multivariate analysis revealed that height-adjusted ASM and TG (inverse) were independent determinants for AST and ALT. Further, fat mass index (inverse) and resting heart rate (inverse) predicted AST and apolipoprotein AI predicted ALT. Conclusions: In young female collegiate athletes, both serum AST and ALT showed inverse association with fasting TG and positive association with apoAI, both of which may be mediated through positive association between the aminotransferases and ASM. The association between ALT and TG is opposite in direction in young athletes (inverse) and in the general population (positive). PMID- 29527311 TI - Development and validation of a prediction model for insulin-associated hypoglycemia in non-critically ill hospitalized adults. AB - Objective: To develop and validate a multivariable prediction model for insulin associated hypoglycemia in non-critically ill hospitalized adults. Research design and methods: We collected pharmacologic, demographic, laboratory, and diagnostic data from 128 657 inpatient days in which at least 1 unit of subcutaneous insulin was administered in the absence of intravenous insulin, total parenteral nutrition, or insulin pump use (index days). These data were used to develop multivariable prediction models for biochemical and clinically significant hypoglycemia (blood glucose (BG) of <=70 mg/dL and <54 mg/dL, respectively) occurring within 24 hours of the index day. Split-sample internal validation was performed, with 70% and 30% of index days used for model development and validation, respectively. Results: Using predictors of age, weight, admitting service, insulin doses, mean BG, nadir BG, BG coefficient of variation (CVBG), diet status, type 1 diabetes, type 2 diabetes, acute kidney injury, chronic kidney disease (CKD), liver disease, and digestive disease, our model achieved a c-statistic of 0.77 (95% CI 0.75 to 0.78), positive likelihood ratio (+LR) of 3.5 (95% CI 3.4 to 3.6) and negative likelihood ratio (-LR) of 0.32 (95% CI 0.30 to 0.35) for prediction of biochemical hypoglycemia. Using predictors of sex, weight, insulin doses, mean BG, nadir BG, CVBG, diet status, type 1 diabetes, type 2 diabetes, CKD stage, and steroid use, our model achieved a c-statistic of 0.80 (95% CI 0.78 to 0.82), +LR of 3.8 (95% CI 3.7 to 4.0) and LR of 0.2 (95% CI 0.2 to 0.3) for prediction of clinically significant hypoglycemia. Conclusions: Hospitalized patients at risk of insulin-associated hypoglycemia can be identified using validated prediction models, which may support the development of real-time preventive interventions. PMID- 29527312 TI - Maintenance of renal function in a patient with a history of acute paroxysmal nocturnal hemoglobinuria-associated kidney injury. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by intravascular hemolysis, thrombosis and bone marrow failure. Acute kidney injury, including acute renal failure, have been reported in patients with PNH. We report the case of a 36-year-old male patient with PNH who developed acute kidney injury following an infection of undetermined diagnosis. Although hemolysis was initially controlled and renal function stabilized following packed red blood cell transfusion and empirical levofloxacin and prednisone, he later experienced recurrent episodes of hemolysis and hematuria requiring monthly red blood cell support. Given the high risk of thromboembolic events, treatment with standard-dose eculizumab was started. The patient's hematologic values improved, renal function was maintained, and no thromboembolic events occurred. PMID- 29527313 TI - A randomised controlled trial of gemcitabine hydrochloride plus S-1 combination therapy versus gemcitabine hydrochloride therapy alone in pancreatic cancer patients aged >=75 years: a study protocol for an open-label randomised feasibility study. AB - Introduction: In Japan, the age of patients with pancreatic cancer has increased. Combination chemotherapies such as 5-fluorouracil/leucovorin, oxaliplatin and irinotecan therapy and gemcitabine hydrochloride (GEM) +nab paclitaxel therapy have been developed as the standard treatments for young patients with advanced recurrent pancreatic cancer. However, both therapies produce toxicity and their administration is limited by the patients' age or performance status. The efficacy and safety data obtained in the GEST study-a large-scale randomised controlled study conducted in patients with pancreatic cancer in Japan-suggested that GEM +S-1 (GS) combination therapy is a promising candidate for those aged between 75 and 80 years. However, for patients aged >=80 years, no efficacy or safety data on GS therapy are currently available. Methods and analysis: This open-label, randomised phase II study will involve patients with advanced recurrent pancreatic cancer, aged >=75 years, with favourable general conditions. Using the electronic data capture system, participants will be randomly allocated to groups with standard treatment (GEM therapy alone) and study treatment (GS therapy). The treatments will be administered until the conditions meet the discontinuation criteria. The primary endpoint is overall survival. Ethics and dissemination: This trial has been approved by the National Hospital Organisation's Central Review Board (H28-NHOD-01). Discussion: This study will reveal if GS therapy could be a standard treatment option for elderly patients with pancreatic cancer, by clarifying its efficacy and safety. Trial registration number: UMIN000025747; Pre-results. PMID- 29527314 TI - Clinical impact of physical exercise on sleep disorder as assessed by actigram in patients with chronic pancreatitis: a study protocol for a randomised controlled trial. AB - Introduction: In most chronic pancreatitis (CP) cases, malabsorption, pain, and weight loss are the leading clinical symptoms, which significantly worsen the quality of life (QOL) and decreased QOL in patients with CP can cause sleep disorder. There is a growing body of evidence that recognises the favourable effects of physical exercise (PE), however, there are limited data currently available concerning patients with CP undergoing PE. Actigram is a device for gathering objective sleep/awake data in the natural sleeping surroundings over an extended time period. In this study, we will aim to prospectively investigate the effect of PE on sleep disorder as assessed by actigram in patients with CP. Methods and analysis: This study is a non-double-blind randomised controlled trial. Study participants will be randomised into the PE group and the control group. When registering patients, precise assessment for nutritional status and daily physical activities will be undertaken in each study patient. In the PE group, physical activities equal to or higher than walking for 60 min/day should be strongly recommended. Sleep quality using actigram will be prospectively compared in the two groups. The primary endpoint is the activity index in actigram at 12 weeks. Ethics and dissemination: Ethical approval for the study was granted by the Institutional Review Board at Hyogo College of Medicine (approval number 2767). Results will be presented at relevant conferences and submitted to an appropriate journal following trial closure and analysis. Trial registration number: UMIN000029265 (https://upload.umin.ac.jp/); Pre-results. PMID- 29527315 TI - Effect of exercise therapy on sarcopenia in pancreatic cancer: a study protocol for a randomised controlled trial. AB - Introduction and purpose: Sarcopenia is defined as a decrease in muscle mass and muscle strength, and it has been demonstrated to be an adverse predictor in numerous types of cancers. Exercise therapy (ET) carries multiple health benefits in several diseases. Despite these clinical benefits, there are limited data available regarding patients with pancreatic cancer (PC) undergoing ET. We aim to prospectively examine the effect of ET on sarcopenia in patients with PC. Methods and analysis: All clinical stages of PC can be included. When registering study subjects, a precise evaluation of the nutritional status and the daily physical activities performed will be undertaken individually, for each participant. Study participants will be randomly allocated into two groups: (1) the ET and standard therapy group and (2) the standard therapy group. Amelioration of sarcopenia at 3 months postrandomisation will be the primary endpoint. Muscle mass will be calculated using bioimpedance analysis. Sarcopenia will be defined based on the current Asian guidelines. Participants will be instructed to perform exercises with > 3 metabolic equivalents (mets; energy consumption in physical activities/resting metabolic rate) for 60 min/day and to perform exercises with > 23 mets/week. In the ET group, physical activities equal to or greater than walking for 60 min/day will be strongly recommended. Ethics and dissemination: The Institutional Review Board at Hyogo College of Medicine has approved this study protocol (approval no. 2772). The final data will be publicly announced. A report releasing the study results will be submitted for publication. Trial registration number: UMIN000029271; Pre-results. PMID- 29527316 TI - Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis. AB - Background: Severe colitis flare from ulcerative colitis (UC) or Crohn's disease (CD) may be refractory to corticosteroids and antitumour necrosis factor (TNF) agents resulting in high colectomy rates. We aimed to describe the utility of tacrolimus to prevent colectomy during second-line vedolizumab initiation after corticosteroid and anti-TNF treatment failure in paediatric severe colitis. Methods: A retrospective cohort analysis was performed between 1 October 2014 and 31 October 2016 at a single tertiary care centre. Inclusion criteria were patients with severe colitis who received tacrolimus before or during vedolizumab induction and previous exposure to anti-TNF therapy with or without corticosteroids. The initiation of tacrolimus was clinician dependent based on an institutional protocol. Results: Twelve patients (10 UC, two CD; median age 16 years; three female) received at least one dose of vedolizumab 10 mg/kg (max of 300 mg) due to anti-TNF therapy failure and persistent flare not responsive to corticosteroids. Of the 12 patients, eight (67%) and four (33%) had failed one or two anti-TNF agents, respectively. Tacrolimus was initiated for acute disease severity during hospitalisation (58%) or ongoing flare during outpatient care (42%). 9 (75%) of 12 patients avoided colectomy or inflammatory bowel disease related surgery at 24 weeks and eight (68%) continued on vedolizumab maintenance with no adverse events out to 80 weeks. Conclusion: We report real-world data on the outcome of tacrolimus around vedolizumab initiation in paediatric UC or CD after corticosteroid and anti-TNF therapy treatment failure. Our pilot experience indicates a potential benefit of concomitant tacrolimus when initiating vedolizumab therapy. PMID- 29527317 TI - Implication of exercise interventions on sleep disturbance in patients with pancreatic cancer: a study protocol for a randomised controlled trial. AB - Introduction and purpose: Patients with pancreatic cancer (PC) have long been known to have high rates of depression. Depression in patients with PC can be linked to sleep disturbance. The American College of Sports Medicine notes that physical exercise is safe for most patients with cancer and physical inactivity should be avoided. However, clinical impacts of exercise interventions (EIs) on patients with PC have been poorly investigated. We aim to prospectively examine the effect of EIs on sleep disturbance in patients with PC using actigraphy, which is an objective measurement of motor activity and sleep. Methods and analysis: This trial is a non-double blind randomised controlled trial. Standard therapy for each patient with PC will be allowed. When registering study subjects, a thorough assessment of the nutritional status and the daily physical activities performed will be undertaken individually for each participant. Study subjects will be randomly assigned into two groups: (1) the EI and standard therapy group or (2) the standard therapy group. In the EI and standard therapy group, physical activities equal to or higher than walking for 60 min/day will be strongly recommended. The primary outcome measure is the sleep-related variable using actigraphy (activity index) at 12 weeks. Ethics and dissemination: The trial received approval from the Institutional Review Board at Hyogo College of Medicine (approval no. 2769). Final data will be publicly announced. A report releasing the study findings will be submitted for publication to an appropriate peer-reviewed journal. Trial registration number: UMIN000029272; Pre-results. PMID- 29527318 TI - Study for every other day administration of vonoprazan in maintenance treatment of erosive GERD: study protocol for a multicentre randomised cross-over study. AB - Introduction: The first drug selected for treatment of gastro-oesophageal reflux disease (GERD) and prevention of the recurrence is a proton pump inhibitor (PPI), but recently, a potassium-competitive acid blocker (P-CAB) was put on the market in Japan. Its onset of effect is faster than PPI, and it takes more than 2 days to recover acid secretion after the withdrawal period. Therefore, unlike PPI, the usefulness of every other day administration or discontinuous administration is expected. Methods and analysis: This study is a prospective, multicentre, open label, two-period randomised cross-over study to compare the efficacy and safety of PPI every other day administration and P-CAB every other day administration in 120 patients who receive erosive GERD maintenance therapy with PPI. Patients will be randomly allocated to receive 4 weeks P-CAB or PPI followed by 4 weeks cross over, where those on P-CAB will receive PPI and vice versa. The primary endpoint is proportion of asymptomatic patients. Secondary endpoints are suppressive effect of GERD symptoms, proportion of asymptomatic patients at each time point, safety and cost-saving effect of P-CAB every other day administration, compliance with every other day administration, and proportion of asymptomatic patients at the first month of study drug administration. Ethics and dissemination: This study was approved by the National Hospital Organization Central Review Board for Clinical Trials (5 December 2017). Discussion: If P-CAB every other day administration is established as one of GERD maintenance therapies, there is merit in both medical cost reduction and the safety to alleviate elevation in serum gastrin. Trial registration number: UMIN000034701. PMID- 29527319 TI - Inferior heel pain in soccer players: a retrospective study with a proposal for guidelines of treatment. AB - Background: The cause of heel pain among soccer players is multifactorial and is related to repetitive microtrauma due to impact forces involving technical moves, but also the playground, the exercise mode, the recovery time, the climatic conditions and the footwear used. Aim: To investigate the aetiology of plantar heel pain of soccer players with the objective of proposing an example of guidelines for treatment. Methods: We investigated the prevalence and characteristics of inferior heel pain of 1473 professional, semiprofessional and amateur players. All evaluated subjects were submitted to a specific rehabilitation protocol that involved advanced physical therapies and viscoelastic insoles depending on the aetiology of pain. Results: Clinical and instrumental examinations revealed that 960 of 1473 athletes had inferior heel pain. These patients were divided into seven groups based on aetiology: sural nerve compression, abductor digiti minimi compression, atrophy and inflammation of the fat pad, plantar fasciitis, stress injury of the heel spur, stress fracture of the heel bone and heel spur. The proposed rehabilitation treatment aims for a reduction of pain and an early return to sports, with excellent results. Conclusions: According to what was observed in the present study, related also to the specific treatment of inferior heel pain, and considering the technological progress achieved in recent years, we can now propose an integrated therapeutic approach to treatment of heel pain, properly differentiated according to specific aetiology. PMID- 29527320 TI - Postmatch recovery of physical performance and biochemical markers in team ball sports: a systematic review. AB - Background: Insufficient postmatch recovery in elite players may cause an increased risk of injuries, illnesses and non-functional over-reaching. Objective: To evaluate postmatch recovery time courses of physical performance and biochemical markers in team ball sport players. Study design: Systematic review. Data sources: PubMed and Web of Science. Eligibility criteria for selecting studies: This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Critical Review Form for Quantitative Studies was used to evaluate quality. Studies were included if they met the following criteria: (1) original research evaluated players' physical recovery postmatch; (2) team/intermittent sports; and (3) at least two postmeasurements were compared with baseline values. Results: Twenty eight studies were eligible. Mean methodological quality was 11.2+/-1.11. Most used performance tests and biochemical markers were the countermovement jump test, sprint tests and creatine kinase (CK), cortisol (C) and testosterone (T), respectively. Summary/conclusions: The current evidence demonstrates that underlying mechanisms of muscle recovery are still in progress while performance recovery is already reached. CK recovery time courses are up to >=72 hours. Soccer and rugby players need more time to recover for sprint performance, CK and C in comparison to other team ball sports. There are more high-quality studies needed regarding recovery in various team sports and recovery strategies on an individual level should be evaluated. Clinical relevance: Ongoing insufficient recovery can be prevented by the use of the presented recovery time courses as specific practical recovery guidelines. PMID- 29527321 TI - Sport and exercise medicine consultants are reliable in assessing tendon neovascularity using ultrasound Doppler. AB - Objective: Several lower limb tendinopathy treatment modalities involve identification of pathological paratendinous or intratendinous neovascularisation to target proposed co-location of painful neoneuralisation. The ability to reliably locate and assess the degree of neovascularity is therefore clinically important. The Modified Ohberg Score (MOS) is frequently used to determine degree of neovascularity, but reliability has yet to be established among Sport and Exercise Medicine (SEM) consultants. This study aims to determine inter-rater and intra-rater reliability of an SEM consultant cohort when assessing neovascularity using the 5-point MOS. Method: Eleven participants (7 male and 4 female) provided 16 symptomatic Achilles and patella tendons. These were sequentially examined using power Doppler (PD) enabled ultrasound (US) imaging by 6 SEM consultants who rated neovascular changes seen using the MOS. Representative digital scan images were saved for rescoring 3 weeks later. Inter-rater and intra-rater reliability of the MOS was examined using intraclass correlation coefficient (ICC) and Kappa Agreement scores. Results: Neovascular changes were reported in 65.6% of 96 scans undertaken. ICC for inter-rater reliability was 0.86 and Fleiss Kappa 0.52. ICC for intra-rater reliability was 0.95 and Weighted Kappa 0.91. Conclusions: Neovascular changes were present in two-thirds of symptomatic tendons. Excellent SEM consultant inter-rater and intra-rater reliability was demonstrated. These findings support the use of PD-enabled US to assess neovascularity by appropriately experienced SEM consultants. Furthermore, future interventional research using a similarly experienced SEM consultant cohort can be undertaken with assurance that assessment of neovascularity will be reliable. PMID- 29527322 TI - Run Clever - No difference in risk of injury when comparing progression in running volume and running intensity in recreational runners: A randomised trial. AB - Background/aim: The Run Clever trial investigated if there was a difference in injury occurrence across two running schedules, focusing on progression in volume of running intensity (Sch-I) or in total running volume (Sch-V). It was hypothesised that 15% more runners with a focus on progression in volume of running intensity would sustain an injury compared with runners with a focus on progression in total running volume. Methods: Healthy recreational runners were included and randomly allocated to Sch-I or Sch-V. In the first eight weeks of the 24-week follow-up, all participants (n=839) followed the same running schedule (preconditioning). Participants (n=447) not censored during the first eight weeks entered the 16-week training period with a focus on either progression in intensity (Sch-I) or volume (Sch-V). A global positioning system collected all data on running. During running, all participants received real time, individualised feedback on running intensity and running volume. The primary outcome was running-related injury (RRI). Results: After preconditioning a total of 80 runners sustained an RRI (Sch-I n=36/Sch-V n=44). The cumulative incidence proportion (CIP) in Sch-V (reference group) were CIP2 weeks 4.6%; CIP4 weeks 8.2%; CIP8 weeks 13.2%; CIP16 weeks 28.0%. The risk differences (RD) and 95% CI between the two schedules were RD2 weeks=2.9%(-5.7% to 11.6%); RD4 weeks=1.8%(-9.1% to 12.8%); RD8 weeks=-4.7%(-17.5% to 8.1%); RD16 weeks=-14.0% ( 36.9% to 8.9%). Conclusion: A similar proportion of runners sustained injuries in the two running schedules. PMID- 29527323 TI - Visualisation of facet joint recesses of the cadaveric spine: a micro-CT and sheet plastination study. AB - Objectives: The size and shape of a joint cavity are the key determinates for the mobility of the joint. The anatomy and configuration of the facet joint (FJ) recesses at different levels of the spine remain unclear and controversial. The aim of this study was to identify the configuration of the FJ recesses in the cervical, thoracic and lumbar spine using a combination of micro-CT and sheet plastination techniques. Methods: Of 19 cadavers (9 males, 10 females, age range of 54-89 years), the FJ cavities of 3 spines were injected with contrast filling and scanned with micro-CT, and 16 plastinated spines were prepared as the series of sagittal (9 sets), transverse (5 sets) or coronal (2 sets) sections with a thickness of 2.5 mm and examined under a stereoscopic microscope. Results: This study characterised the FJ spaces and recesses of the spine and found that (1) the configuration and extent of the FJ recesses varied along the spine. The optimal needle approach to the FJ cavity was via an anterolateral or posterolateral recess at the cervical level, along the tip of the inferior articular process at the thoracic level and via the posteromedial recess at the lumbar level. (2) The FJ cavity did not communicate with the retrodural space. Conclusion: The anatomical features of the FJ recesses at different levels of the spine confirm no direct communication between the FJ cavity and retrodural space. PMID- 29527324 TI - Epithelial and mesenchymal prostate cancer cell population dynamics on a complex drug landscape. AB - We have improved our microfluidic cell culture device that generates an in vitro landscape of stress heterogeneity. We now can do continuous observations of different cancer cell lines and carry out downstream analysis of cell phenotype as a function of position on the stress landscape. We use this technology to probe adaption and evolution dynamics in prostate cancer cell metapopulations under a stress landscape of a chemotherapeutic drug (docetaxel). The utility of this approach is highlighted by analysis of heterogenous prostate cancer cell motility changes as a function of position in the stress landscape. Because the technology presented here is easily adapted to a standard epifluorescence microscope it has the potential for broad application in preclinical drug development and assays of likely drug efficacy. PMID- 29527325 TI - Injectable Polyethylene Glycol Hydrogel for Islet Encapsulation: an in vitro and in vivo Characterization. AB - An injection of hydrogel-encapsulated islets that controls blood glucose levels over long term would provide a much needed alternative treatment for type 1 diabetes mellitus (T1DM). To this end, we tested the feasibility of using an injectable polyethylene glycol (PEG) hydrogel as a scaffold for islet encapsulation. Encapsulated islets cultured in vitro for 6 days showed excellent cell viability and released insulin with higher basal and stimulated insulin secretion than control islets. Host responses to PEG hydrogels were studied by injecting PEG hydrogels (no treatment and vehicle controls used) into the peritoneal cavities of B6D2F1 mice and monitoring alterations in body weight, food and water intake, and blood glucose levels. After 2 weeks, peritoneal cavity cells were harvested, followed by hydrogel retrieval, and extraction of spleens. Body weights, food and water intake, and blood glucose levels were unaltered in mice injected with hydrogels compared to no treatment and vehicle-injected control mice. Frozen sections of a hydrogel showed the presence of tissues and small number of immune cells surrounding the hydrogel but no cell infiltration into the hydrogel bulk. Spleen sizes were not significantly different under the experimental conditions. Peritoneal cavity cells were slightly higher in mice injected with hydrogels compared to control mice but no statistical difference between vehicle- and hydrogel-injected mice was noted. As an in vivo feasibility study, streptozotocin-induced diabetic mice were injected with vehicle or hydrogels containing 50 islets each into two sites, the peritoneal cavity and a subcutaneous site on the back. Transient control of blood glucose levels were observed in mice injected with hydrogels containing islets. In summary, we developed an injectable PEG hydrogel that supported islet function and survival in vitro and in vivo and elicited only a mild host response. Our work illustrates the feasibility of using injectable PEG hydrogels for islet encapsulation. PMID- 29527326 TI - A Phantom Study of Terahertz Spectroscopy and Imaging of Micro- and Nano-diamonds and Nano-onions as Contrast Agents for Breast Cancer. AB - THz imaging is effective in distinguishing between cancerous, healthy, and fatty tissues in breast tumors, but a challenge remains in the contrast between cancerous and fibroglandular (healthy) tissues. This work investigates carbon based nanoparticles as potential contrast agents for terahertz imaging of breast cancer. Microdiamonds, nanodiamonds, and nanometer-scale onion-like carbon are characterized with terahertz transmission spectroscopy in low-absorption backgrounds of polydimethylsiloxane or polyethylene. The refractive index and absorption coefficients are calculated based on the measured electric fields. Nanodiamonds show little effect on the terahertz signal, microdiamonds express resonance-like, size-dependent absorption peaks, and onion-like carbon provides a uniform increase in the optical properties even at low concentration. Due to its strong interaction with terahertz frequencies and ability to be activated for selective binding to cancer cells, onion-like carbon is implemented into engineered three-dimensional breast tumor models composed of phantom tissue mimicking infiltrating ductal carcinoma surrounded by a phantom mimicking healthy fibroglandular tissue. This model is imaged using the terahertz reflection mode to examine the effectiveness of contrast agents for differentiation between the two tissue types. In both spectroscopy and imaging, a 10% concentration of onion like carbon shows the strongest impact on the terahertz signal and holds promise as a terahertz contrast agent. PMID- 29527327 TI - DNA methylation profile is associated with the osteogenic potential of three distinct human odontogenic stem cells. AB - Among the various sources of human autologous stem cells, stem cells isolated from dental tissues exhibit excellent properties in tissue engineering and regenerative medicine. However, the distinct potential of these odontogenic cell lines remains unclear. In this study, we analyzed DNA methylation patterns to determine whether specific differences existed among three different odontogenic cell types. Using the HumanMethylation450 Beadchip, the whole genomes of human dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), and dental follicle progenitor cells (DFPCs) were compared. Then, the osteogenic potential of these cells was evaluated both in vitro and in vivo, and the methylation levels of certain genes related to bone formation differed among the three cell lines. P values less than 0.05 were considered to indicate statistical significance. The three cell types showed highly similar DNA methylation patterns, although specific differences were identified. Gene ontology analysis revealed that one of the most significantly different gene categories was related to bone formation. Thus, expression of cell surface epitopes and osteogenic related transcription factors as well as the bone formation capacity were compared. The results showed that compared with DFPCs and DPSCs, PDLSCs had higher transcription levels of osteogenic-related factors, a higher in vitro osteogenic potential, and an increased new bone formation capacity in vivo. In conclusion, the results of this study suggested that the differential DNA methylation profiles could be related to the osteogenic potential of these human odontogenic cell populations. Additionally, the increased osteogenic potential of PDLSCs might aid researchers or clinicians in making better choices regarding tissue regeneration and clinical therapies. PMID- 29527328 TI - Targeting IL-2: an unexpected effect in treating immunological diseases. AB - Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis since Treg dysfunction in both animals and humans is associated with multi-organ autoimmune and inflammatory disease. While IL-2 is generally considered to promote T-cell proliferation and enhance effector T-cell function, recent studies have demonstrated that treatments that utilize low-dose IL-2 unexpectedly induce immune tolerance and promote Treg development resulting in the suppression of unwanted immune responses and eventually leading to treatment of some autoimmune disorders. In the present review, we discuss the biology of IL-2 and its signaling to help define the key role played by IL-2 in the development and function of Treg cells. We also summarize proof-of-concept clinical trials which have shown that low-dose IL-2 can control autoimmune diseases safely and effectively by specifically expanding and activating Treg. However, future studies will be needed to validate a better and safer dosing strategy for low dose IL-2 treatments utilizing well-controlled clinical trials. More studies will also be needed to validate the appropriate dose of IL-2/anti-cytokine or IL 2/anti-IL-2 complex in the experimental animal models before moving to the clinic. PMID- 29527329 TI - The dual-inhibitory effect of miR-338-5p on the multidrug resistance and cell growth of hepatocellular carcinoma. AB - Chemotherapeutic treatments against hepatocellular carcinoma (HCC) are necessary for both inoperable patients to improve prospects for survival and surgery patients to improve the outcome after surgical resection. However, multidrug resistance (MDR) is a major obstacle to obtaining desirable results. Currently, increasing the chemotherapy sensitivity of tumor cells or discovering novel tumor inhibitors is an effective therapeutic strategy to solve this issue. In the present study, we uncovered the dual-inhibitory effect of miR-338-5p: on the one hand, it could downregulate ABCB1 expression and sensitize HCC cells to doxorubicin and vinblastine by directly targeting the 3'-untranslated region (3' UTR) of ABCB1, while, on the other hand, it could suppress the proliferation of HCC cells by directly targeting the 3'-UTR of EGFR and reducing EGFR expression. Since EGFR regulates ABCB1 levels, the indirect action of miR-338-5p in ABCB1 modulation was revealed, in which miR-338-5p inhibits ABCB1 expression by targeting the EGFR/ERK1/2 signaling pathway. These data indicate that the miR-338 5p/EGFR/ABCB1 regulatory loop plays a critical role in HCC, and a negative correlation between miR-338-5p and EGFR or ABCB1 was also detected in HCC clinical samples. In conclusion, these findings reveal a critical role for miR 338-5p in the regulation of MDR and proliferation of HCC, suggesting the potential therapeutic implications of miR-338-5p in HCC treatment. PMID- 29527330 TI - ETV2 mediates endothelial transdifferentiation of glioblastoma. AB - Glioblastoma multiforme (GBM) is characterized by extensive endothelial hyperplasia. Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor cells into endothelial cells (endo-transdifferentiation). The molecular mechanism underlying this process remains poorly defined. Here, we show that the expression of ETS variant 2 (ETV2), a master regulator of endothelial cell development, is highly correlated with malignancy. Functional studies demonstrate that ETV2 is sufficient and necessary for the transdifferentiation of a subpopulation of CD133+/Nestin+ GBM/neural stem cells to an endothelial lineage. Combinational studies of ChIP-Seq with gain-of-function RNA-Seq data sets suggest that ETV2, in addition to activating vascular genes, represses proneural genes to direct endo transdifferentiation. Since endo-transdifferentiation by ETV2 is VEGF-A independent, it likely accounts for the observed resistance of GBM tumor cells to anti-angiogenesis therapy. Further characterization of the regulatory networks mediated by ETV2 in endo-transdifferentiation of GBM tumor cells should lead to the identification of more effective therapeutic targets for GBM. PMID- 29527332 TI - Outcomes for patients with head and neck squamous cell carcinoma presenting with N3 nodal disease. AB - Background: The present study evaluated clinical outcomes for patients with head and neck squamous cell carcinoma presenting with N3 nodal disease. Methods: A retrospective analysis of N3 head and neck squamous cell carcinoma patients was performed. Pearson chi-square and Wilcoxon signed-rank tests were used to analyze patient demographics, disease characteristics, and treatment variables. Survival was evaluated using Kaplan-Meier curves with the log-rank test. Univariate analysis using Cox proportional hazards models was used to define factors associated with overall survival. Patient and tumor characteristics associated with treatment assignments were analyzed by univariate multinomial logistic regression. Results: We identified 36 patients with radiographically-defined N3 disease. For the entire cohort, median follow-up was 23.6 (range 2.8-135.0) months, and overall survival was 60% at 2 years and 30% at 5 years. Overall survival was similar between patients receiving primary surgery, radiotherapy, or chemoradiotherapy (p = 0.10). Primary, regional, and distant control at 5 years was 71%, 66%, and 53%, respectively. There was a trend towards improved regional control with primary surgery (p = 0.07). Planned neck dissection following primary chemoradiotherapy did not improve regional control (p = 0.55). Patients with p16-positive tumors exhibited improved overall (p = 0.05) and metastatic recurrence-free survival (p < 0.05). There were no factors predictive of treatment assignment nor factors associated with overall survival, local and regional control, or distant metastases free-survival on univariate analysis. Conclusions: Patients with N3 head and neck squamous cell carcinoma exhibit 5 year overall survival rates of approximately 30% regardless of treatment modality. Planned neck dissection does not improve regional control in patients undergoing definitive chemoradiotherapy. p16-positive patients represent a favorable cohort. Distant failure comprises the major failure pattern and should be the focus of future studies in improving the outcome of this patient cohort. PMID- 29527331 TI - Targeting oncogenic Myc as a strategy for cancer treatment. AB - The MYC family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. Although Myc inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of Myc has been a challenge for decades owing to its "undruggable" protein structure. Hence, alternatives to Myc blockade have been widely explored to achieve desirable anti-tumor effects, including Myc/Max complex disruption, MYC transcription and/or translation inhibition, and Myc destabilization as well as the synthetic lethality associated with Myc overexpression. In this review, we summarize the latest advances in targeting oncogenic Myc, particularly for cancer therapeutic purposes. PMID- 29527333 TI - 'Nobody is after you; it is your initiative to start work': a qualitative study of health workforce absenteeism in rural Uganda. AB - Background: Published evidence on the drivers of absenteeism among the health workforce is mainly limited to high-income countries. Uganda suffers the highest rate of health workforce absenteeism in Africa, attracting attention but lacking a definitive ameliorative strategy. This study aimed to explore the underlying reasons for absenteeism in the public and private 'not-for-profit' health sector in rural Uganda. Methods: We undertook an empirical qualitative study, located within the critical realist paradigm. We used case study methodology as a sampling strategy, and principles of grounded theory for data collection and analysis. Ninety-five healthcare workers were recruited through focus groups and in-depth interviews. The NVivo V.10 software package was used for data management. Results: Healthcare workers' absenteeism was explained by complex interrelated influences that could be seen to be both external to, and within, an individual's motivation. External influences dominated in the public sector, especially health system factors, such as delayed or omitted salaries, weak workforce leadership and low financial allocation for workers' accommodation. On the other hand, low staffing-particularly in the private sector-created work overload and stress. Also, socially constructed influences existed, such as the gendered nature of child and elderly care responsibilities, social class expectations and reported feigned sickness. Individually motivated absenteeism arose from perceptions of an inadequate salary, entitlement to absence, financial pressures heightening a desire to seek supplemental income, and educational opportunities, often without study leave. Conclusion: Health workforce managers and policy makers need to improve governance efficiencies and to seek learning opportunities across different health providers. PMID- 29527334 TI - Preparedness for delivering non-communicable disease services in primary care: access to medicines for diabetes and hypertension in a district in south India. AB - Introduction: Non-communicable diseases (NCDs) have become a major public health challenge worldwide; they account for 28 million deaths per year in low-and middle-income countries (LMICs). Like many other LMICs, India is struggling to organise quality care for a large NCD-affected population especially at the primary healthcare level. The aim of this study was to assess local health system preparedness in a south Indian primary healthcare setting for addressing diabetes and hypertension. Methods: This paper draws on a mixed-methods research study on access to medicines conducted in Tumkur, Karnataka, India. We used quantitative data from household and health facility surveys, and qualitative data from focus group discussions and in-depth interviews with health workers and patients. We identified systemic drivers that influence utilisation of services at government primary health centres (PHCs) using thematic analysis of qualitative data and a systems framework on access to medicines to assess supply and demand side factors. Results: Majority of households depend on private facilities for diabetes and hypertension care because of the lack of laboratory facilities and frequent medicine stockouts at PHCs. Financial and managerial resource allocation for NCDs and prioritisation of care and processes related to NCDs was suboptimal compared to the prominence of this agenda at global and national levels. Primary healthcare has a limited role even in the activities under the national programme that addresses diabetes and hypertension. Discussion: The study finds critical gaps in the preparedness of PHCs and district health systems in organising and managing care for diabetes and hypertension. Due to the lack of continuous care organised through PHCs, patients depend on expensive and often episodic care in the private sector. There is a need to improve managerial and financial resource allocation towards diabetes and hypertension (and other NCDs) at the district level. Trial registration number: CTRI/2015/03/005640; Pre-results. PMID- 29527336 TI - Queen bee in a beehive: WHO as meta-governor in global health governance. PMID- 29527335 TI - Applying a health system perspective to the evolving Farmacia Popular medicines access programme in Brazil. AB - The Farmacia Popular Program (FPP) launched a subsidy system in Brazil, but in coexistence with the ongoing regular governmental access to medicines (Unified Health System (SUS) dispensings) mechanisms, causing overlaps in terms of financing and target population. This characteristic is quite different from most countries with medicines cost-sharing schemes. This paper aims to analyse the FPP under a health systems perspective considering the different health system levels. We analysed the findings from the study 'Impact of consecutive subsidies policies on access to and use of medicines in Brazil - ISAUM-Br', designed with the objective of describing and evaluating the impact of the government medicines subsidy policies implemented between 2004 and 2011. Patient share of copayment increased with the implementation of the intervention, which decreased the reference price and decreased with SNP (Saude Nao Tem Preco; zero copayment for patients). There was an increased number of FPP dispensations over time, but SUS dispensings remained the most important source for medicines, especially for hypertension and diabetes. FPP allowed the establishment of a well-designed pharmaceutical information system in the country. Despite the improvement on control mechanism, fraud remained a problem. There were important effects on the pharmaceutical market and sales of generic medicines. FPP has proven to be a very important policy for promoting access to medicines for hypertension and diabetes in Brazil. Examining this policy with a health system perspective has allowed us to highlight many of its important consequences, including for the first time a broad and consistent information system on access to medicines in the country. PMID- 29527337 TI - Defining quality indicators for emergency care delivery: findings of an expert consensus process by emergency care practitioners in Africa. AB - Facility-based emergency care delivery in low-income and middle- income countries is expanding rapidly, particularly in Africa. Unfortunately, these efforts rarely include measurement of the quality or the impact of care provided, which is essential for improvement of care provision. Our aim was to determine context appropriate quality indicators that will allow uniform and objective data collection to enhance emergency care delivery throughout Africa. We undertook a multiphase expert consensus process to identify, rank and refine quality indicators. A comprehensive review of the literature identified existing indicators; those associated with a substantial burden of disease in Africa were categorised and presented to consensus conference delegates. Participants selected indicators based on inclusion criteria and priority clinical conditions. The indicators were then presented to a group of expert clinicians via on-line survey; all meeting agreements were refined in-person by a separate panel and ranked according to validity, feasibility and value. The consensus working group selected seven conditions addressing nearly 75% of mortality in the African region to prioritise during indicator development, and the final product at the end of the multiphase study was a list of 76 indicators. This comprehensive process produced a robust set of quality indicators for emergency care that are appropriate for use in the African setting. The adaptation of a standardised set of indicators will enhance the quality of care provided and allow for comparison of system strengthening efforts and resource distribution. PMID- 29527338 TI - What drives political commitment for nutrition? A review and framework synthesis to inform the United Nations Decade of Action on Nutrition. AB - Introduction: Generating country-level political commitment will be critical to driving forward action throughout the United Nations Decade of Action on Nutrition (2016-2025). In this review of the empirical nutrition policy literature, we ask: what factors generate, sustain and constrain political commitment for nutrition, how and under what circumstances? Our aim is to inform strategic 'commitment-building' actions. Method: We adopted a framework synthesis method and realist review protocol. An initial framework was derived from relevant theory and then populated with empirical evidence to test and modify it. Five steps were undertaken: initial theoretical framework development; search for relevant empirical literature; study selection and quality appraisal; data extraction, analysis and synthesis and framework modification. Results: 75 studies were included. We identified 18 factors that drive commitment, organised into five categories: actors; institutions; political and societal contexts; knowledge, evidence and framing; and, capacities and resources. Irrespective of country-context, effective nutrition actor networks, strong leadership, civil society mobilisation, supportive political administrations, societal change and focusing events, cohesive and resonant framing, and robust data systems and available evidence were commitment drivers. Low-income and middle-income country studies also frequently reported international actors, empowered institutions, vertical coordination and capacities and resources. In upper-middle-income and high-income country studies, private sector interference frequently undermined commitment. Conclusion: Political commitment is not something that simply exists or emerges accidentally; it can be created and strengthened over time through strategic action. Successfully generating commitment will likely require a core set of actions with some context-dependent adaptations. Ultimately, it will necessitate strategic actions by cohesive, resourced and strongly led nutrition actor networks that are responsive to the multifactorial, multilevel and dynamic political systems in which they operate and attempt to influence. Accelerating the formation and effectiveness of such networks over the Nutrition Decade should be a core task for all actors involved. PMID- 29527339 TI - Sociocultural and health system factors associated with mortality among febrile inpatients in Tanzania: a prospective social biopsy cohort study. AB - Introduction: Communicable diseases are the leading causes of death in Tanzania despite the existence of effective treatment tools. We aimed to assess the sociocultural and health system factors associated with mortality from febrile illness in northern Tanzania. Methods: We interviewed febrile inpatients to determine prevalence of barriers in seeking or receiving care and grouped these barriers using the Three Delays model (delays at home, in transport and at healthcare facilities). We assessed 6-week mortality and, after matching on age, gender and severity of illness, measured the association between delays and mortality using conditional logistic regression. Results: We enrolled 475 children, of whom 18 (3.8%) died, and 260 adults, of whom 34 (13.0%) died. For children, home delays were not associated with mortality. Among adults, a delay in care-seeking due to not recognising severe symptoms was associated with mortality (OR: 3.01; 95% CI 1.24 to 7.32). For transport delays, taking >1 hour to reach a facility increased odds of death in children (OR: 3.27; 95% CI 1.11 to 9.66) and adults (OR: 3.03; 95% CI 1.32 to 6.99). For health system delays, each additional facility visited was associated with mortality for children (OR: 1.59; 95% CI 1.06 to 2.38) and adults (OR: 2.00; 95% CI 1.17 to 3.41), as was spending >4 days between the first facility visit and reaching tertiary care (OR: 4.39; 95% CI 1.49 to 12.93). Conclusion: Our findings suggest that delays at home, in transport and in accessing tertiary care are risk factors for mortality from febrile illness in northern Tanzania. Interventions that may reduce mortality include community education regarding severe symptoms, expanding transportation infrastructure and streamlining referrals to tertiary care for the sickest patients. PMID- 29527340 TI - Determinants of neonatal, infant and under-five mortality in a war-affected country: analysis of the 2010 Household Health Survey in South Sudan. AB - Background: Under-five children born in a fragile and war-affected setting of South Sudan are faced with a high risk of death as reflecting in high under-five mortality. In South Sudan health inequities and inequitable condition of daily living play a significant role in childhood mortality. This study examines factors associated with under-five mortality in South Sudan. Methods: The study population includes 8125 singleton, live birth, under-five children born in South Sudan within 5 years prior to the 2010 South Sudan Household Survey. Factors associated with neonatal, infant and under-five deaths were examined using generalised linear latent and mixed models with the logit link and binomial family that adjusted for cluster and survey weights. Results: The multivariate analysis showed that mothers who reported a previous death of a child reported significantly higher risk of neonatal (adjusted OR (AOR)=3.74, 95% confidence interval (CI 2.88 to 4.87), P<0.001), infant (AOR=3.19, 95% CI (2.62 to 3.88), P<0.001) and under-five deaths (AOR=3.07, 95% CI (2.58 to 3.64), P<0.001). Other associated factors included urban dwellers (AOR=1.37, 95% CI (1.01 to 1.87), P=0.045) for neonatal, (AOR=1.35, 95% CI (1.08 to 1.69), P=0.009) for infants and (AOR=1.39, 95% CI (1.13 to 1.71), P=0.002) for under-five death. Unimproved sources of drinking water were significantly associated with neonatal mortality (AOR=1.91, 95% CI (1.11 to 3.31), P=0.02). Conclusions: This study suggested that the condition and circumstances in which the child is born into, and lives with, play a role in under-five mortality, such as higher mortality among children born to teenage mothers. Ensuring equitable healthcare service delivery to all disadvantaged populations of children in both urban and rural areas is essential but remains a challenge, while violence continues in South Sudan. PMID- 29527341 TI - Does antenatal micronutrient supplementation improve children's cognitive function? Evidence from the follow-up of a double-blind randomised controlled trial in Nepal. AB - Introduction: Multiple Micronutrient (MMN) supplementation during pregnancy can decrease the proportion of infants born low birth weight and small for gestational age. Supplementation could also enhance children's cognitive function by improving access to key nutrients during fetal brain development and increasing birth weight, especially in areas where undernutrition is common. We tested the hypothesis that children whose mothers received MMN supplementation during pregnancy would have higher intelligence in early adolescence compared with those receiving Iron and Folic Acid (IFA) only. Methods: We followed up children in Nepal, whose mothers took part in a double-blind Randomised Controlled Trial (RCT) that compared the effects on birth weight and gestational duration of antenatal MMN versus IFA supplementation. We assessed children's Full Scale Intelligence Quotient (FSIQ) using the Universal Non-verbal Intelligence Test (UNIT), and their executive function using the counting Stroop test. The parent trial was registered as ISRCTN88625934. Results: We identified 813 (76%) of the 1069 children whose mothers took part in the parent trial. We found no differences in FSIQ at 12 years between MMN and IFA groups (absolute difference in means (diff): 1.25, 95% CI -0.57 to 3.06). Similarly, there were no differences in mean UNIT memory (diff: 1.41, 95% CI -0.48 to 3.30), reasoning (diff: 1.17, 95% CI -0.72 to 3.06), symbolic (diff: 0.97, 95% CI -0.67 to 2.60) or non-symbolic quotients (diff: 1.39, 95% CI -0.60 to 3.38). Conclusion: Our follow-up of a double-blind RCT in Nepal found no evidence of benefit from antenatal MMN compared with IFA for children's overall intelligence and executive function at 12 years. PMID- 29527342 TI - Evaluation of research on interventions aligned to WHO 'Best Buys' for NCDs in low-income and lower-middle-income countries: a systematic review from 1990 to 2015. AB - Background: Non-communicable diseases (NCDs) are the leading cause of death and disability worldwide, with low-income and middle-income countries experiencing a disproportionately high burden. Since 2010 WHO has promoted 24 highly cost effective interventions for NCDs, dubbed 'best buys'. It is unclear whether these interventions have been evaluated in low-income and lower-middle-income countries (LLMICs). Aim: To systematically review research on interventions aligned to WHO 'best buys' for NCDs in LLMICs. Methods: We searched 13 major databases and included papers conducted in the 83 World Bank-defined LLMICs, published between 1 January 1990 and 5 February 2015. Two reviewers independently screened papers and assessed risk of bias. We adopted a narrative approach to data synthesis. The primary outcomes were NCD-related mortality and morbidity, and risk factor prevalence. Results: We identified 2672 records, of which 36 were included (608 940 participants). No studies on 'best buys' were found in 89% of LLMICs. Nineteen of the 36 studies reported on the effectiveness of tobacco-related 'best buys', presenting good evidence for group interventions in reducing tobacco use but weaker evidence for interventions targeting individuals. There were fewer studies on smoking bans, warning labels and mass media campaigns, and no studies on taxes or marketing restrictions. There was supportive evidence that cervical screening and hepatitis B immunisation prevent cancer in LLMICs. A single randomised controlled trial supported polypharmacy for cardiovascular disease. Fourteen of the 'best buy' interventions did not have any good evidence for effectiveness in LLMICs. Conclusions: We found studies on only 11 of the 24 interventions aligned with the WHO 'best buys' from LLMIC settings. Most LLMICs have not conducted research on these interventions in their populations. LLMICs should take action to implement and evaluate 'best buys' in their national context, based on national priorities, and starting with interventions with the strongest evidence base. PMID- 29527343 TI - Productive disruption: opportunities and challenges for innovation in infectious disease surveillance. PMID- 29527344 TI - Community health workers improve disease control and medication adherence among patients with diabetes and/or hypertension in Chiapas, Mexico: an observational stepped-wedge study. AB - Background: Non-communicable diseases (NCDs) contribute greatly to morbidity and mortality in low-income and middle-income countries (LMICs). Community health workers (CHWs) may improve disease control and medication adherence among patients with NCDs in LMICs, but data are lacking. We assessed the impact of a CHW-led intervention on disease control and adherence among patients with diabetes and/or hypertension in Chiapas, Mexico. Methods: We conducted a prospective observational study among adult patients with diabetes and/or hypertension, in the context of a stepped-wedge roll-out of a CHW-led intervention. We measured self-reported adherence to medications, blood pressure and haemoglobin A1c at baseline and every 3 months, timed just prior to expansion of the intervention to a new community. We conducted individual-level mixed effects analyses of study data, adjusting for time and clustering by patient and community. Findings: We analysed 108 patients. The CHW-led intervention was associated with a twofold increase in the odds of disease control (OR 2.04, 95% CI 1.15 to 3.62). It was also associated with optimal adherence assessed by 30 day recall (OR 1.86; 95% CI 1.15 to 3.02) and a positive self-assessment of adherence behaviour (OR 2.29; 95% CI 1.26 to 4.15), but not by 5-day recall. Interpretation: A CHW-led adherence intervention was associated with disease control and adherence among adults with diabetes and/or hypertension. This study supports a role of CHWs in supplementing comprehensive primary care for patients with NCDs in LMICs. Trial registration number: NCT02549495. PMID- 29527345 TI - Can lay health workers support the management of hypertension? Findings of a cluster randomised trial in South Africa. AB - Introduction: In low/middle-income countries with substantial HIV and tuberculosis epidemics, health services often neglect other highly prevalent chronic conditions, such as hypertension, which as a result are poorly managed. This paper reports on a study to assess the effect on hypertension management of lay health workers (LHW) working in South African rural primary healthcare clinics to support the provision of integrated chronic care. Methods: A pragmatic cluster randomised trial with a process evaluation in eight rural clinics assessed the effect of adding two LHWs supporting nurses in providing chronic disease care in each intervention clinic over 18 months. Control clinics continued with usual care. The main outcome measure was the change in the difference of percentage of clinic users who had elevated cardiovascular risk associated with high blood pressure (BP) before and after the intervention, as measured by two cross-sectional population surveys. Results: There was no improvement in BP control among users of intervention clinics as compared with control clinics. However, the LHWs improved clinic functioning, including overall attendance, and attendance on the correct day. All clinics faced numerous challenges, including rapidly increasing number of users of chronic care, unreliable BP machines and cuffs, intermittent drug shortages and insufficient space. Conclusion: LHWs improved the process of providing care but improved BP control required improved clinical care by nurses which was compromised by large and increasing numbers of patients, the dominance of the vertically funded HIV programme and the poor standards of equipment in clinics. Trial registration number: ISRCTN12128227. PMID- 29527346 TI - Social health insurance for the poor: lessons from a health insurance programme in Karnataka, India. AB - Life-saving technology used to treat catastrophic illnesses such as heart disease and cancer is often out of reach for the poor. As life expectancy increases in poor countries and the burden from chronic illnesses continues to rise, so will the unmet need for expensive tertiary care. Understanding how best to increase access to and reduce the financial burden of expensive tertiary care is a crucial task for the global health community in the coming decades. In 2010, Karnataka, a state in India, rolled out the Vajpayee Arogyashree scheme (VAS), a social health insurance scheme focused on increasing access to tertiary care for households below the poverty line. VAS was rolled out in a way that allowed for robust evaluation of its causal effects and several studies have examined various impacts of the scheme on poor households. In this analysis article, we summarise the key findings and assess how these findings can be used to inform other social health insurance schemes. First, the evidence suggests that VAS led to a substantial reduction in mortality driven by increased tertiary care utilisation as well as use of better quality facilities and earlier diagnosis. Second, VAS significantly reduced the financial burden of receiving tertiary care. Third, these benefits of social health insurance were achieved at a reasonable cost to society and taxpayers. Several unique features of VAS led to its success at improving health and financial well-being including effective outreach via health camps, targeting expensive conditions with high disease burden, easy enrolment process, cashless treatment, bundled payment for hospital services, participation of both public and private hospitals and prior authorisation to improve appropriateness of care. PMID- 29527347 TI - Staged implementation of a two-tiered hospital-based neonatal care package in a resource-limited setting in Eastern Uganda. AB - Neonatal mortality remains a major global challenge. Most neonatal deaths occur in low-income countries, but it is estimated that over two-thirds of these deaths could be prevented if achievable interventions are scaled up. To date, initiatives have focused on community and obstetric interventions, and there has been limited simultaneous drive to improve neonatal care in the health facilities where the sick neonates are being referred. Few data exist on the process of implementing of neonatal care packages and their impact. Evidence-based guidelines for neonatal care in health facilities in low-resource settings and direction on how to achieve these standards of neonatal care are therefore urgently needed. We used the WHO-Recommended Quality of Care Framework to build a strategy for quality improvement of neonatal care in a busy government hospital in Eastern Uganda. Twelve key interventions were designed to improve infrastructure, equipment, protocols and training to provide two levels of neonatal care. We implemented this low-cost, hospital-based neonatal care package over an 18-month period. This data-driven analysis paper illustrates how simple changes in practice, provision of basic equipment and protocols, ongoing training and dedicated neonatal staff can reduce neonatal mortality substantially even without specialist equipment. Neonatal mortality decreased from 48% to 40% (P=0.25) after level 1 care was implemented and dropped further to 21% (P<0.01) with level 2 care. In our experience, a dramatic impact on neonatal mortality can be made through modest and cost-effective interventions. We recommend that stakeholders seeking to improve neonatal care in low-resource settings adopt a similar approach. PMID- 29527348 TI - Does insurance enrolment increase healthcare utilisation among rural-dwelling older adults? Evidence from the National Health Insurance Scheme in Ghana. AB - Introduction: This paper examines the relationship between national health insurance enrolment and the utilisation of inpatient and outpatient healthcare for older adults in rural areas in Ghana. The Ghanaian National Health Insurance Scheme (NHIS) aims to improve affordability and increase the utilisation of healthcare. However, the system has been criticised for not being responsive to the needs of older adults. The majority of older adults in Ghana live in rural areas with poor accessibility to healthcare. With an ageing population, a specific assessment of whether the scheme has benefitted older adults, and also if the benefit is equitable, is needed. Methods: Using the Ghanaian Living Standards Survey from 2012 to 2013, this paper uses propensity score matching to estimate the effect of enrolment within the NHIS on the utilisation of inpatient and outpatient care among older people aged 50 and over. Results: The raw results show higher utilisation of healthcare among NHIS members, which persists after matching. NHIS members were 6% and 9% more likely to use inpatient and outpatient care, respectively, than non-members. When these increases were disaggregated for outpatient care, the non-poor and females were seen to benefit more than their poor and male counterparts. For inpatient care, the benefits of enrolment were equal by poverty status and sex. However, overall, poor older adults use health services much less than the non-poor older adults even when enrolled. Conclusion: The results indicate that NHIS coverage does increase healthcare utilisation among rural older adults but that inequalities remain. The poor are still at a great disadvantage in their use of health services overall and benefit less from enrolment for outpatient care. The receipt of healthcare is significantly influenced by a set of auxiliary barriers to access to healthcare even where insurance should remove the financial burden of ad hoc out of pocket payments. PMID- 29527349 TI - Achieving universal health coverage in small island states: could importing health services provide a solution? AB - Background: Universal health coverage (UHC) is difficult to achieve in settings short of medicines, health workers and health facilities. These characteristics define the majority of the small island developing states (SIDS), where population size negates the benefits of economies of scale. One option to alleviate this constraint is to import health services, rather than focus on domestic production. This paper provides empirical analysis of the potential impact of this option. Methods: Analysis was based on publicly accessible data for 14 SIDS, covering health-related travel and health indicators for the period 2003-2013, together with in-depth review of medical travel schemes for the two highest importing SIDS-the Maldives and Tuvalu. Findings: Medical travel from SIDS is accelerating. The SIDS studied generally lacked health infrastructure and technologies, and the majority of them had lower than the recommended number of physicians in a country, which limits their capacity for achieving UHC. Tuvalu and the Maldives were the highest importers of healthcare and notably have public schemes that facilitate medical travel and help lower the out-of-pocket expenditure on medical travel. Although different in approach, design and performance, the medical travel schemes in Tuvalu and the Maldives are both examples of measures used to increase access to health services that cannot feasibly be provided in SIDS. Interpretation: Our findings suggest that importing health services (through schemes to facilitate medical travel) is a potential mechanism to help achieve universal healthcare for SIDS but requires due diligence over cost, equity and quality control. PMID- 29527351 TI - Why we are still failing to measure the nutrition transition. PMID- 29527350 TI - mCME project V.2.0: randomised controlled trial of a revised SMS-based continuing medical education intervention among HIV clinicians in Vietnam. AB - Background: Continuing medical education (CME) is indispensable, but costs are a barrier. We tested the effectiveness of a novel mHealth intervention (mCME V.2.0) promoting CME among Vietnamese HIV clinicians. Methods: We enrolled HIV clinicians from three provinces near Hanoi. The 6-month intervention consisted of (1) daily short message service multiple-choice quiz questions, (2) daily linked readings, (3) links to online CME courses and (4) feedback messages describing the performance of the participant relative to the group. Control participants had equal access to the online CME courses. Our primary endpoint was utilisation of the online CME courses; secondary endpoints were self-study behaviour, performance on a standardised medical exam and job satisfaction. Results: From 121 total HIV clinicians in the three provinces, 106 (87.6%) enrolled, and 48/53 intervention (90%) and 47/53 control (89%) participants completed the endline evaluations. Compared with controls, intervention participants were more likely to use the CME courses (risk ratio (RR) 2.3, 95% CI 1.4 to 3.8, accounting for 83% of course use (P<0.001)). Intervention participants increased self-study behaviours over controls in terms of use of medical textbooks (P<0.01), consulting with colleagues (P<0.01), searching on the internet (P<0.001), using specialist websites (P=0.02), consulting the Vietnam HIV/AIDS treatment guidelines (P=0.02) and searching the scientific literature (P=0.09). Intervention participants outperformed controls on the exam (+23% vs +12% score gains, P=0.05) and had higher job satisfaction. Conclusion: The mCME V.2.0 intervention improved self-study behaviour, medical knowledge and job satisfaction. This approach has potential for expansion in Vietnam and similar settings. Trial registration number: NCT02381743. PMID- 29527352 TI - Quagmire of epidemic disease outbreaks reporting in Nigeria. PMID- 29527353 TI - Going beyond killer apps: building a better mHealth evidence base. PMID- 29527354 TI - Adaptation with robustness: the case for clarity on the use of 'resilience' in health systems and global health. PMID- 29527355 TI - Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India. AB - There is growing national and international concern about the drug regulatory system in India. Parliamentary reports have highlighted the presence of high numbers of unapproved medicines and irrational combinations of both approved and unapproved drugs in the Indian market-place. Fixed-dose combinations (FDCs) are a peculiar feature of the Indian pharmaceutical landscape. Although metformin is a first-line treatment, FDCs for diabetes in India account for two-thirds of all diabetes medicine sales, and some have not been approved by the Central Drugs Standard Control Organization (CDSCO). This study examines the basis of efficacy and safety of top-selling metformin FDCs in India against four WHO criteria from clinical trials guidelines for the approval of FDCs. Data from a commercial drug sales database (PharmaTrac) were combined with searches through published literature, clinical trial registries, and published and unpublished trial websites of metformin FDCs in adults with type 2 diabetes mellitus. Five metformin FDCs in India from November 2011 to October 2012 accounted for 80% of all metformin FDC sales by value and volume. Although all five had obtained CDSCO approval, three had been sold and marketed prior to receiving this approval. Evaluation of published and unpublished clinical trials of these five FDCs found none provided robust evidence of safety and efficacy for the treatment of type 2 diabetes. Recommendations are made for publishing evidence that underpins drug approvals, marketing bans, greater transparency through updated clinical trials databases and legislative reform in order to prevent irrational FDCs from entering the market. PMID- 29527356 TI - mHealth text and voice communication for monitoring people with chronic diseases in low-resource settings: a realist review. AB - Background: Routine monitoring by patients and healthcare providers to manage chronic disease is vital, though this can be challenging in low-resourced health systems. Mobile health (mHealth) has been proposed as one way to improve management of chronic diseases. Past mHealth reviews have proposed the need for a greater understanding around how the theoretical constructs in mHealth interventions actually work. In response, we synthesised evidence from primary studies on monitoring of chronic diseases using two-way digital text or voice communication between a patient and health worker. We did this in order to understand the important considerations for the design of mHealth interventions. Method: Articles retrieved were systematically screened and analysed to elicit explanations of mHealth monitoring interventions. These explanations were consolidated into programme theory and compared with existing theory and frameworks. We identified variation in outcomes to understand how context moderates the outcome. Results: Four articles were identified-monitoring of hypertension and HIV/AIDS from: Kenya, Pakistan, Honduras and Mexico and South Africa. Six components were found in all four interventions: reminders, patient observation of health state, motivational education/advice, provision of support communication, targeted actions and praise and encouragement. Intervention components were mapped to existing frameworks and theory. Variation in outcome identified in subgroup analysis suggests greater impact is achieved with certain patient groups, such as those with low literacy, those with stressful life events or those early in the disease trajectory. There was no other evidence in the included studies of the effect of context on the intervention and outcome. Conclusion: mHealth interventions for monitoring chronic disease in low-resource settings, based on existing frameworks and theory, can be effective. A match between what the intervention provides and the needs or social factors relevant to specific patient group increases the effect. It was not possible to understand the impact of context on intervention and outcome beyond these patient-level measures as no evidence was provided in the study reports. PMID- 29527357 TI - Human rights versus societal norms: a mixed methods study among healthcare providers on social stigma related to adolescent abortion and contraceptive use in Kisumu, Kenya. AB - Introduction: Adolescent pregnancy represents a serious public health issue in sub-Saharan Africa, and stigmatising attitudes are contributing factors. This study investigates stigmatising attitudes related to adolescent pregnancy, abortion and contraceptive use among healthcare providers working with postabortion care (PAC) in a low-resource setting in Kenya. Methods: A mixed methods approach in a convergent design was utilised to capture attitudes related to abortion and contraceptive use among 86 (f=62; m=19) PAC providers in Kisumu, Kenya. Two Likert-scale questionnaires were used: the 18-item Stigmatising Attitudes, Beliefs and Actions Scale (SABAS) and the 7-item Contraceptive Use Stigma Scale (CUSS). 74 PAC providers responded to the SABAS, 44 to the CUSS and 12 participated in two focus group discussions. Descriptive statistics, psychometric tests of instruments and qualitative content analysis were conducted and reported in accordance with Consolidated Criteria for Reporting Qualitative Research. Results: Cronbach's alpha coefficients for the total instrument was 0.88 (SABAS) and 0.84 (CUSS). The majority, 92% (68/74) agreed that a woman who has had an abortion should be treated equally to everyone else, 27% (20/74) considered abortion a sin and 30% (22/74) believed she will make abortion a habit. Contraceptive use among adolescent women was associated with promiscuity (39%; 17/44), hence contraceptives should only be available to married women (36%; 16/44), and 20% (9/44) believed that contraceptive use causes infertility. The providers encouraged women's autonomy and their rights to sexual and reproductive health; however, unclear regulations reinforce religious and cultural beliefs, which hampers implementation of evidence-based contraceptive counselling. Conclusion: Stigmatising attitudes towards young women in need of abortion and contraception is common among PAC providers. Their work is characterised by a conflict between human rights and societal norms, thus highlighting the need for interventions targeting PAC providers to reduce stigma and misconceptions related to abortion and contraception among adolescent women. PMID- 29527358 TI - Costing of three feeding regimens for home-based management of children with uncomplicated severe acute malnutrition from a randomised trial in India. AB - Trial design: Three feeding regimens-centrally produced ready-to-use therapeutic food, locally produced ready-to-use therapeutic food, and augmented, energy dense, home-prepared food-were provided in a community setting for children with severe acute malnutrition (SAM) in the age group of 6-59 months in an individually randomised multicentre trial that enrolled 906 children. Foods, counselling, feeding support and treatment for mild illnesses were provided until recovery or 16 weeks. Methods: Costs were estimated for 371 children enrolled in Delhi in a semiurban location after active survey and identification, enrolment, diagnosis and treatment for mild illnesses, and finally treatment with one of the three regimens, both under the research and government setting. Direct costs were estimated for human resources using a price times quantity approach, based on their salaries and average time taken for each activity. The cost per week per child for food, medicines and other consumables was estimated based on the total expenditure over the period and children covered. Indirect costs for programme management including training, transport, non-consumables, infrastructure and equipment were estimated per week per child based on total expenditures for research study and making suitable adjustments for estimations under government setting. Results: No significant difference in costs was found across the three regimens per covered or per treated child. The average cost per treated child in the government setting was estimated at US$56 (<3500 rupees). Conclusion: Home based management of SAM with a locally produced ready-to-use therapeutic food is feasible, acceptable, affordable and very cost-effective in terms of the disability-adjusted life years saved and gross national income per capita of the country. The treatment of SAM at home needs serious attention and integration into the existing health system, along with actions to prevent SAM. Trial registration number: NCT01705769; Pre-results. PMID- 29527359 TI - Phospholipid Vesicles in Media for Tribological Studies against Live Cartilage. AB - Introduction: Pre-clinical testing of hemiarthroplasty devices requires that the tribological conditions present in vivo with live cartilage be closely duplicated. A current limitation in the tribological testing of live cartilage involves the use of cell-culture media as lubricant. Study Aim: to develop and test a new hyaluronan-phospholipid based medium (HA-phospholipid medium) that combines the rheological and frictional properties of synovial fluid with the nourishing properties of culture media to keep cells alive. Materials and Methods: The HA-phospholipid medium consisted of culture medium with added phospholipid dipalmitoylphosphatidylcholine (0.3 mg/mL), and hyaluronic acid (2.42 mg/mL). A standard cell culture medium was used as the control. The rheology of each medium was determined using a flat plate configuration. Bovine calf cartilage was used to assess cell viability and friction in each medium. For friction measurements, a cobalt-chrome alloy ball was articulated against cartilage disks immersed in medium. Results: Lipid vesicles 0.1 to 50 MUm in diameter were identified in the HA-phospholipid medium. Cartilage cell viability was significantly higher in the HA-phospholipid medium (62% +/- 8%, 95% CI) than in control medium (49.5% +/- 5%) (p = 0.009). The HA-phospholipid medium exhibited strong shear-thinning behavior, similar to synovial fluid, with viscosities ~100-fold higher at 10 s-1 and 5-fold higher at 20,000 s-1 than the approximately Newtonian control medium. The HA-phospholipid medium also yielded 20% lower friction values than the control medium after one hour of testing. Conclusions: The rheological and friction results indicate that the HA phospholipid medium is superior to the control cell culture medium in emulating the shear thinning and lubricative properties of natural synovial fluid, making it more clinically relevant for in vitro wear and friction testing with live cartilage. PMID- 29527360 TI - Science Possible Selves and the Desire to be a Scientist: Mindsets, Gender Bias, and Confidence during Early Adolescence. AB - In the United States, gender gaps in science interest widen during the middle school years. Recent research on adults shows that gender gaps in some academic fields are associated with mindsets about ability and gender-science biases. In a sample of 529 students in a U.S. middle school, we assess how explicit boy science bias, science confidence, science possible self (belief in being able to become a scientist), and desire to be a scientist vary by gender. Guided by theories and prior research, we use a series of multivariate logistic regression models to examine the relationships between mindsets about ability and these variables. We control for self-reported science grades, social capital, and race/ethnic minority status. Results show that seeing academic ability as innate ("fixed mindsets") is associated with boy-science bias, and that younger girls have less boy-science bias than older girls. Fixed mindsets and boy-science bias are both negatively associated with a science possible self; science confidence is positively associated with a science possible self. In the final model, high science confident and having a science possible self are positively associated with a desire to be a scientist. Facilitating growth mindsets and countering boy science bias in middle school may be fruitful interventions for widening participation in science careers. PMID- 29527361 TI - Detection of the "Crossed Aorta Sign" during Echocardiography before Angiography. AB - We report the case of an anomalous circumflex (Cx) origin from the right sinus of Valsalva with retroaortic course observed in a modified apical four-chamber view during transthoracic study (TTE). This finding is known as the "crossed aorta sign." Usually, the diagnosis of this congenital anomaly of coronary circulation is established during coronary angiography. In this case, the diagnosis was performed by echocardiography before angiography. We believe that recent improvements in echocardiography increase the potential of this imaging technology also in the diagnosis of coronary artery anomalies. PMID- 29527362 TI - Sarcomatoid Carcinoma of the Oral Cavity: A Diagnostic Dilemma. AB - Sarcomatoid carcinoma (SC) is a rare variant of squamous cell carcinoma which is characterized by a dysplastic epithelial component and a stromal element with invasive fusiform or spindle-shaped cells. The clinical and histopathologic characteristics make it very difficult to distinguish SC from epithelioid sarcoma (ES). We present a case of a 51-year-old man with a soft tissue mass in the oral cavity diagnosed as proximal variant of epithelioid sarcoma on incisional biopsy. A thorough radiologic examination was conducted to rule out the possibility of a primary elsewhere in the body. Supraomohyoid neck dissection, mandibular resection, and reconstruction with recon plates were carried out. Histopathologic examination was suggestive of epithelioid variant of SC which was contrary to the incisional biopsy report. The dilemma in diagnosis was resolved by observing the presence of invading atypical epithelial cells into the stroma confirming the epithelial origin of the tumor. PMID- 29527363 TI - Methicillin-Sensitive Staphylococcus aureus Suppurative Thyroiditis with Thyrotoxicosis. AB - Intravenous drug use (IVDU) can lead to numerous complications from skin abscesses to bacteremia to endocarditis. Here, we present a rare case of acute suppurative thyroiditis as a complication of IVDU, in which a 26-year-old female with a past medical history of IVDU presented to the emergency department for evaluation of a large right sided neck mass. On exam, she had signs of sepsis and thyrotoxicosis. Fine needle aspiration confirmed suppurative thyroiditis. Blood cultures and culture from fine needle aspiration grew Staphylococcus aureus. Patient was treated with 2 weeks of intravenous antibiotics with good resolution of her symptoms. PMID- 29527364 TI - Community-Acquired Cavitary Pseudomonas Pneumonia Linked to Use of a Home Humidifier. AB - Pseudomonas aeruginosa is an opportunistic pathogen that rarely causes pneumonia in otherwise healthy patients. We describe a case of community-acquired P. aeruginosa pneumonia in a previously healthy individual who likely acquired the infection from a home humidifier. PMID- 29527365 TI - Surgical Management of Pilocytic Astrocytoma of the Optic Nerve: A Case Report and Review of the Literature. AB - Optic nerve astrocytomas (ONAs) are frequent types of optic nerve gliomas (ONGs), which can affect the visual pathway. An 18-year-old male patient was admitted to our department with right-sided intraorbital/retrobulbar swelling, which progressively grew over several months. Clinical examination showed right-sided diplopia, mydriasis, low visual acuity (0.4), exophthalmus (3 cm), epiphora, and severe retrobulbar pain. There was a family history of high-grade (IV) astrocytomas in which two of the family members died due to the disease. Preoperative MRI scan revealed a soft tissue mass around the retrobulbar area of the right eye with intact orbital bony walls. Surgery was performed whereby it was dissected freely from the muscles and was separated from the optic nerve and the globe. Histopathologic analysis confirmed a benign astrocytoma. The follow-up examination revealed no recurrent or residual tumor. A systemic review of the literature indicates that early diagnosis and experienced multidisciplinary management are required in case of unilateral, resectable forms of ONAs with no distant metastasis, in order to provide a long-time survival of patients. Surgical intervention of unilateral ONAs is a relatively safe procedure, allowing complete or partial tumor removal with minimal morbidity and low recurrence rate. PMID- 29527366 TI - An Aggressive Form of Langerhan Cell Histiocytosis in an Adult: Therapeutic Challenges. AB - Langerhans cell histiocytosis (LCH) is rare in adults. Regular follow-up is mandatory due to reoccurrence. A 35-year-old male with an incidental left iliac bone lesion was diagnosed with LCH. He later became symptomatic with hip pain and spread of the disease. Despite excision of the symptomatic iliac lesion, he had progression while on cytarabine and nivolumab, evidenced by increased bone pain and involvement of other bones on imaging. He underwent excision of the jaw lesion followed by vinblastine; he was pain free and had stable disease on PET imaging after 3 months. LCH is an uncommon neoplasia. Treatment is reserved for symptomatic patients while asymptomatic patients are observed. Follow-up is imperative due to the risk of reoccurrence. Despite surgical treatment together with one of the front-line agents for refractory disease, in this case cytarabine, he still had progression of the disease. Furthermore, the trial of nivolumab was of no benefit. This case highlights good response to vinblastine which is previously reported to have good success. No trials are published, and the optimal strategy has yet to be defined. LCH with multiple bony involvement can be aggressive and therapeutically challenging. PMID- 29527367 TI - Fusion Surgery Required for Recurrent Pediatric Atlantoaxial Rotatory Fixation after Failure of Temporary Fixation with Instrumentation. AB - In cases of chronic irreducible and recurrent unstable atlantoaxial rotatory fixation (AARF), closed reduction and its maintenance are often unsuccessful, requiring surgical treatment. The purpose of the present report is to describe a rare case of pediatric AARF that required multiple treatments. A 6-year-old boy was diagnosed as having type 2 AARF. After conservative treatment, the patient was treated with temporary fixation surgery (C1-C2 Magerl) without a bone graft in consideration of motion preservation after screw removal. AARF recurred after the screw removal and required fusion surgery (Magerl-Brooks) with an iliac bone graft. Ultimately, bone union was achieved and the screws were removed 11 months after the surgery. We recommend surgeons be cautious when choosing temporary fixation surgery for AARF in small children. Further investigation is needed to determine the optimal time before screw removal. PMID- 29527368 TI - Bipolar Dislocation of the Clavicle: A Report of Two Cases with Different Injury Patterns and a Literature Review. AB - Bipolar dislocation of the clavicle is a rare injury that is defined as a concomitant dislocation of the ipsilateral acromioclavicular joint and sternoclavicular joint. This injury is also described as a floating clavicle. Although this injury has been known for nearly two centuries, knowledge about it is limited and the treatment strategy remains controversial. Bipolar dislocation includes several combinations of both joints' injury types. We reported two patients with bipolar dislocation of the clavicle: one with an anterior dislocation and the other with a posterior dislocation of the sternoclavicular joint. After reviewing the currently available literature, we discussed these cases to highlight the necessity of a specific treatment approach that is modified based on the pattern of each joint's lesion. PMID- 29527369 TI - Sacral Osteoneogenesis after Complete Sacrectomy in a Patient with Ewing Sarcoma. AB - Ewing sarcomas are the second most common primary malignant bone tumors in childhood and adolescence which rapidly metastasize. Due to improvement of treatment options in recent years, the survival rate has significantly increased. Nevertheless, lethality is still high, and neurologic symptoms are frequent. To the best of our knowledge, this is the first reported case of a sacral osteoneogenesis after complete sacrectomy in a patient with Ewing sarcoma. PMID- 29527370 TI - Medial Condyle Fracture (Kilfoyle Type III) of the Distal Humerus with Transient Fishtail Deformity after Surgery. AB - A "Fishtail deformity" is one of the well-known complications following pediatric lateral condyle or supracondylar fractures of the humerus. We herein report a case of medial condyle fracture (Kilfoyle type III) in an 11-year-old boy. He had a transient "fishtail deformity" of the trochlear groove after open reduction and internal fixation. As occurred in the current case, the bone remodeling and the improvement of ischemia of the trochlea after medial condyle fracture may be associated with the likelihood of recovery from transient "fishtail deformity." PMID- 29527371 TI - ANCA-Negative Granulomatosis with Polyangiitis Presenting with Hypertrophic Cranial Pachymeningitis, Abducens Nerve Palsy, and Stenosis of the Internal Carotid Artery. AB - We report a rare case of granulomatosis with polyangiitis (GPA) presenting with hypertrophic cranial pachymeningitis (HCP), abducens nerve palsy, and stenosis of the internal carotid artery (ICA). A 59-year-old Japanese man presented with a year history of nasal obstruction and a 2-month history of slight headache. Histopathological examination of the granulomatous mucosa in the ethmoid sinuses resected by endoscopic sinus surgery revealed necrotizing vasculitis with multinucleated giant cells. The patient was diagnosed with the limited form of GPA as a result of the systemic examination. He declined immunosuppressive treatment. Eighteen months after the diagnosis of GPA, he presented with diplopia and severe headache. Though nasal findings indicating GPA were not observed in the nasal cavity, CT scan revealed a lesion of the right sphenoid sinus eroding the bone of the clivus. Gadolinium-enhanced MRI of the brain showed thickening of the dura mater around the right cavernous sinus and clivus. Magnetic resonance angiography and cerebral angiography revealed narrowing at the C5 portion of the ICA. Intravenous methylprednisolone pulse therapy followed by oral prednisolone and cyclophosphamide resolved headache and dramatically improved HCP and stenosis of the ICA. PMID- 29527372 TI - Urethral Caruncle Presented as Premature Menarche in a 4-Year-Old Girl. AB - Urethral caruncle (UC) is a benign fleshy outgrowth at the urethral meatus. It was first described by Samuel Sharp in 1750 and occurs mainly at the posterior lip of the urethra, and the exact aetiology is still uncertain. More often it was seen in the postmenopausal women, and only few cases are reported in young girls. Patients may be asymptomatic and could find this as an incidental finding or they may present with symptoms such as dysuria, bleeding per vagina, haematuria, a mass protruding through vagina, and acute retention of urine. Here, we report the case history of a 4-year-old girl presented with vaginal bleeding which was taken as she has attended menarche and found to have urethral caruncle which was the cause for bleeding. Histology confirmed the diagnosis, and girl was completely cured following surgical excision. PMID- 29527373 TI - Pantoea agglomerans Infections in Children: Report of Two Cases. AB - Introduction: Pantoea agglomerans, primarily an environmental and agricultural organism has been reported as both commensal and pathogen of humans. We present two case reports of P. agglomerans infections in children that involved the meninges and bloodstream. Case Presentations: A 6-month-old female baby, diagnosed as congenital hydrocephalus secondary to aqueduct stenosis with ventriculoperitoneal shunt in situ, operated 14 days back was brought to the pediatric emergency with a two-day history of high fever associated with vomiting, irritability, excessive crying, and decreased feeding. Postoperative meningitis was confirmed as cerebrospinal fluid culture revealed P. agglomerans. She responded well with a 14-day intravenous (IV) course of ceftriaxone. Also, we report a case of a 3-year-old male child referred to our center with a provisional diagnosis of UTI with chickenpox for further evaluation. During his 24-hour stay at the local hospital, he had received oral antibiotics and urinary catherization. Urine culture of catheter clamp urine was sterile. P. agglomerans was grown in blood culture. He was treated successfully with IV ceftriaxone and amikacin. Conclusion: P. agglomerans can cause postsurgical meningitis and bloodstream infection in children. The clinical course of infection was mild and timely administration of proper antibiotic resulted in a favorable outcome. PMID- 29527374 TI - Lysosomal Acid Lipase Deficiency: Report of Five Cases across the Age Spectrum. AB - Lysosomal acid lipase (LAL) deficiency is an autosomal recessive lysosomal storage disorder caused by mutations in the LIPA gene that leads to premature organ damage and mortality. We present retrospective data from medical records of 5 Brazilian patients, showing the broad clinical spectrum of the disease. PMID- 29527375 TI - Long-Term Consequences of Fetal Angiotensin II Receptor Antagonist Exposure. AB - Fetal angiotensin II receptor antagonist exposure is associated with major complications and even death when administered during pregnancy. Neonates frequently require intensive care treatment, and mortality is high. Despite this well-known risk potential, a considerable number of women still receive angiotensin II receptor antagonists during pregnancy to treat arterial hypertension. Although clinical symptoms in the neonatal period are well described, few reports address long-term follow-up after fetal exposure to angiotensin II receptor antagonists. We here report on a patient who was unwittingly exposed to olmesartan medoxomil during pregnancy. After birth, the neonate presented with mild clinical symptoms, mainly affecting the kidneys. However, neurodevelopmental follow-up revealed a delay in motor development with muscular hypotonia and failure to thrive at age 2 years. This case highlights the fact that, despite not causing neurological symptoms in the neonatal period, fetal angiotensin II receptor antagonist exposure during pregnancy might lead to neurodevelopmental impairment in later life. PMID- 29527376 TI - Corrigendum to "A Rare Cause of Childhood Cerebellitis-Influenza Infection: A Case Report and Systematic Review of Literature". AB - [This corrects the article DOI: 10.1155/2017/4039358.]. PMID- 29527377 TI - Lymphatic Drainage of Legs Reduces Edema of the Arms in Children with Lymphedema. AB - Objective: The aim of the present study is to report on the reduction of edema of lymphedematous arms just by treating the lower limbs. Methods: A 16-year-old girl reported that she has started having right lower limb edema at the age of three. At age 13, she performed a lymphoscintigraphy that confirmed the diagnosis of primary lymphedema of the four limbs. Recently she sought treatment at the Clinica Godoy in Sao Jose do Rio Preto where she was submitted to intensive treatment for eight hours per day for five days using manual (Godoy & Godoy technique) and mechanical lymphatic therapy (RA Godoy(r)) of the lower limbs, cervical lymphatic therapy (cervical stimulation), and the continuous use of a grosgrain stocking. Results: At the end of treatment, reductions in the sizes of both arms and legs were noted even without the use of any specific therapy for the arms. After four years, the size of the arms was normal. Conclusion: Treatment of lymphedema of the legs has systemic repercussions that may lead to the reduction in swelling of other untreated regions of the body. PMID- 29527378 TI - It Is Not Always Sepsis: Fatal Tachypnea in a Newborn. AB - Coarctation of the aorta (CoA) is a congenital cardiac malformation that is well understood. Despite being well characterized, CoA is a commonly missed congenital heart disease (CHD) during the newborn period. We report a full-term nine-day-old male who presented to the pediatric emergency department (ED) with isolated tachypnea. After an initial sepsis workup, subsequent investigations revealed critical CoA. Because the primary workup focused on sepsis, there was a significant delay in prostaglandin E1 (PGE1) initiation. This case illustrates the importance of early CoA recognition and timely initiation of PGE1 in newborns who present with suspected sepsis along with tachypnea. PMID- 29527379 TI - Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V. AB - Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation. PMID- 29527380 TI - Bartter Syndrome Type 1 Presenting as Nephrogenic Diabetes Insipidus. AB - Bartter syndrome (BS) type 1 (OMIM #601678) is a hereditary salt-losing renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, polyuria, recurrent vomiting, and growth retardation. It is caused by loss-of-function mutations of the SLC12A1 gene, encoding the furosemide-sensitive Na-K-Cl cotransporter. Recently, a phenotypic variability has been observed in patients with genetically determined BS, including absence of nephrocalcinosis, hypokalemia, and/or metabolic alkalosis in the first year of life as well as persistent metabolic acidosis mimicking distal renal tubular acidosis. We report the case of a child with a genetically determined diagnosis of Bartter syndrome type 1 who presented with a phenotype of nephrogenic diabetes insipidus, with severe hypernatremia and urinary concentrating defect. In these atypical cases, molecular analysis is mandatory to define the diagnosis, in order to establish the correct clinical and therapeutic management. PMID- 29527381 TI - An 8-Year-Old Child with Delayed Diagnosis of Netherton Syndrome. AB - We report an 8-year-old boy with Netherton syndrome who was misdiagnosed and treated as severe atopic dermatitis. The diagnosis of Netherton syndrome was not made until the child was 8 years of age. We discuss the pitfalls in the diagnosis and alert physicians to the proper and early diagnosis of this syndrome. The child was treated with a low dose (0.25 mg/kg) of oral acitretin and a topical moisturizer with marked improvement of his skin and pruritus in 2 months. At 6 month follow-up, the skin was almost clear of erythema and scaling, and the hair was longer and stronger. The dose of acitretin was reduced to 0.12 mg/kg for another 6 months and then discontinued. PMID- 29527382 TI - Bronchogenic Cyst as an Unusual Cause of a Persistent Cough and Wheeze in Children: A Case Report and Literature Review. AB - Wheezing and cough are common case scenarios that pediatricians encountered in their office practices. Although a bronchogenic cyst is an uncommon condition, it is essential to be considered in the differential diagnosis of a chronic cough and wheezing among young children who fail to respond to appropriate medical treatment. A 28-month-old girl was referred to our pediatric pulmonology clinic with persistent symptoms of a cough and wheeze unresponsive to standard asthma therapy. This presentation prompted us to undertake a detailed diagnostic evaluation. The evaluation exposed a cystic mass in the middle mediastinum compressing the trachea and left main bronchus. The cyst was excised and confirmed pathologically to be a benign bronchogenic cyst. Subsequently, the patient recovered well and had been free of respiratory symptoms during follow-up visits. This report highlights one of the rare causes of wheezing and cough in young children and emphasizes the importance of considering it in the differential diagnosis of a child presenting with refractory asthma-like symptoms. This is important for early diagnosis and management and to avoid unpredictable complications of this treatable condition. PMID- 29527383 TI - Virtual Surgical Planning and Piezoelectric Surgery in Tumor Extirpative Surgery Aimed at Inferior Alveolar Nerve Preservation. AB - A myriad of extirpative surgical protocols for the management of benign tumors of the jaws have been presented in the literature. Through significant advancements in computer-aided design and computer-aided manufacturing (CAD/CAM) technology and surgical instrumentation, today surgeons have at their disposal robust technology-driven techniques that are aimed at improving surgical outcomes. Our goal is to investigate the benefits of implementing virtual surgical planning (VSP) in conjunction with piezoelectric surgery (PES) to ensure success while minimizing the risk of complications during extirpation of tumors of the mandible. This case report describes the successful extirpation of an ossifying fibroma of the mandible in an adult patient using both VSP and PES. PMID- 29527384 TI - Spleen-Preserving Surgery in Splenic Artery Aneurysm. AB - Endovascular interventions are increasingly used in the treatment of a splenic artery aneurysm (SAA), which is a rare and life-threatening clinical disorder. However, in cases of SAA rupture, minimally invasive interventions are unsuitable, and open surgery remains the gold standard method. In open surgery, care should be taken to preserve the spleen and its immune function in cases where an arterial segment of sufficient length allows for reconstruction. An SAA was detected in a 51-year-old woman who presented to our polyclinic with left upper quadrant pain. An endovascular intervention was unsuccessful, and open surgery was performed. Approximately 5 cm of aneurysm in the middle segment of the splenic artery was treated by arterial anastomosis, and the spleen was preserved. The patient experienced no postoperative complications and remained asymptomatic at the seventh month of follow-up. The aim of this case report is to emphasize the importance of splenic sparing surgery in cases of SAAs. PMID- 29527385 TI - Removal of Lead from Water Using Calcium Alginate Beads Doped with Hydrazine Sulphate-Activated Red Mud as Adsorbent. AB - Calcium alginate beads doped with hydrazine sulphate-treated red mud are investigated as adsorbent for extracting lead ions from water using batch methods of extraction. Different extraction conditions are optimised for maximum lead extraction. Substantial amount of lead is removed, and the adsorption ability is found to be 138.6 mg/g. Surface characterization using FTIR, EDX, and FESEM confirms that lead is "onto" the surface of the adsorbent. Thermodynamic parameters, adsorption isotherms, and kinetics of adsorption are analysed. Adsorption is "physisorption" in nature and spontaneous. The adsorbent developed can be regenerated using 0.1 M HCl. Thus regenerated adsorbent can be used as the adsorbent for further removal of lead at least 10 times, and this enables the complete removal of lead from water by repetitive use of the regenerated adsorbent. The beads facilitate the easy filtration. The methodology developed is successfully applied for removing lead from industrial waste waters. PMID- 29527386 TI - A Compliant Four-bar Linkage Mechanism that Makes the Fingers of a Prosthetic Hand More Impact Resistant. AB - Repeated mechanical failure due to accidental impact is one of the main reasons why people with upper-limb amputations abandon commercially-available prosthetic hands. To address this problem, we present the design and evaluation of a compliant four-bar linkage mechanism that makes the fingers of a prosthetic hand more impact resistant. Our design replaces both the rigid input and coupler links with a monolithic compliant bone, and replaces the follower link with three layers of pre-stressed spring steel. This design behaves like a conventional four bar linkage but adds lateral compliance and eliminates a pin joint, which is a main site of failure on impact. Results from free-end and fixed-end impact tests show that, compared to those made with a conventional four-bar linkage, fingers made with our design absorb up to 11% more energy on impact with no mechanical failure. We also show the integration of these fingers in a prosthetic hand that is low-cost, light-weight, and easy to assemble, and that has grasping performance comparable to commercially-available hands. PMID- 29527387 TI - IDH1, ATRX, and BRAFV600E mutation in astrocytic tumors and their significance in patient outcome in north Indian population. AB - Background: According to the current World Health Organization (WHO) classification of central nervous system (CNS) tumors (2016), histological diagnosis of gliomas should be supplemented by molecular information. This study was carried out to determine the frequency of isocitrate dehydrogenase 1 (IDH1), ATRX, and BRAF V600E mutations in different grade astrocytomas and their prognostic value. Methods: Eighty cases of astrocytoma (15 pilocytic astrocytoma, 25 diffuse astrocytoma, 15 anaplastic astrocytoma, and 25 glioblastoma) with follow-up information were analyzed using immunohistochemistry for IDH1 mutant protein, ATRX, p53, and BRAF. Sanger sequencing was carried out for IDH1 exon 4 and BRAF exon 15. Results: All pilocytic astrocytoma and primary glioblastoma cases were negative for IDH1 mutation. IDH1 mutation was detected in 80% (20/25) DA and 87% (13/15) AA cases. IDH1 R132H was the commonest IDH1 mutation (94.1%) and immunohistochemistry showed 100% sensitivity and specificity to detect this mutation. Loss of nuclear ATRX expression was found in 87% (20/23) and 100% (14/14) DA and AA cases, respectively. IDH1 mutant DA patients had longer overall survival than IDH1 wild cases, although this difference was not significant (79.5 months vs. 42.5 months, P value 0.417). BRAF V600E mutation was not detected in any astrocytic tumor. Conclusions: IDH1 and ATRX mutations are very common in diffuse astrocytoma and anaplastic astrocytoma, while they are rare in pilocytic astrocytoma and glioblastoma. Immunohistochemistry for IDH1 and ATRX can successfully characterize the diffuse gliomas into molecularly defined groups in majority of the cases. BRAF V600E mutation is rare in astrocytic tumors in Indian population. PMID- 29527388 TI - Enlargement of an incidental internal carotid artery aneurysm embedded in pituitary adenoma associated with medical shrinkage of the tumor: Case report. AB - Background: Currently, transsphenoidal surgery (TSS) is the preferred method for surgical treatment of intrasellar pituitary adenomas. However, it carries some risk of intraoperative arterial injuries, which is mainly attributed to direct iatrogenic rupture of the internal carotid artery (ICA). There is anecdotal evidence suggesting that intracranial aneurysms are coincidentally found significantly more frequently in the setting of pituitary adenomas than when the incidence is compared to other intracranial neoplasms. The exact cause of this discrepancy remains unclear, but it certainly raises concerns about the potential existence of an ICA aneurysm, which might be encountered during TSS and in some cases may cause hemorrhagic complications. Case Description: We present a case of a patient who was found to have a growth hormone (GH)-secreting pituitary adenoma and a coexisting cavernous ICA aneurysm which was embedded within the tumor. The patient underwent medical treatment of the adenoma. However, shrinkage of the tumor was associated with enlargement of the observed aneurysm, warranting endovascular intervention. Conclusions: This case report is an illustration for physicians to be conscientious about the potential danger posed by the coexistence of an intratumoral aneurysm in the setting of a pituitary adenoma. Special attention should be given to recognition of an intrinsic flow void signal on the presurgical imaging of the tumor, and if observed, magnetic resonance angiography (MRA) should be performed for preoperative planning. If MRA is not performed routinely, detailed review of high-resolution magnetic resonance imaging is recommended to detect any flow artifacts suggestive of an aneurysm. PMID- 29527389 TI - A case of adult anaplastic cerebellar ganglioglioma. AB - Background: Anaplastic posterior fossa ganglioglioma in adults is exceedingly rare. To date, only one case of adult anaplastic posterior fossa ganglioglioma has been reported in the English literature and none has been described at the cerebellum. To our knowledge, this report is the third case of malignant posterior fossa ganglioglioma in adults and the first at the cerebellum. In general, this entity can be misdiagnosed preoperatively as a primary posterior fossa neoplasm, and by reporting our clinical and radiographic observations we want to add to the existing literature on this rare entity. Case Description: A 40-year-old man presented with a history of headaches and dizziness and progressive gait disturbance and was diagnosed with anaplastic ganglioglioma in the posterior fossa. Conclusions: Although rare, our case demonstrates that anaplastic ganglioglioma should be considered in the differential diagnosis of infratentorial tumors in adult patients. PMID- 29527391 TI - Neurenteric cyst of the conus medullaris. AB - Background: Neurenteric cysts (NECs) are rare developmental malformations of the central nervous system (CNS) which originate as benign congenital lesions. They originate from developmental foregut precursors, and are presumed to be the result of abnormal partitioning of the embryonic notochord plate. Such NECs predominantly arise in the cervical region in patients around 6 years of age or in their twenties or thirties. Notably, NECs of the conus medullaris are exceedingly rare, especially in patients of advanced age. Case Description: A 70 year-old male presented with bilateral upper thigh and leg pain of over 20 years duration. His pain worsened over the past 3 years, and he sought surgical management. Although his neurological exam was normal, the lumbar magnetic resonance imaging revealed an intradural, nonenhancing, thin-walled, cystic lesion at L1/conus medullaris. The lesion was successfully resected without any adverse sequelae. Conclusions: NECs are rare congenital legions that involve the spine. Here, an L1 intradural extramedullay neuroenteric cyst of the conus medullaris was resected without complications. PMID- 29527390 TI - The posterior nasoseptal flap: A novel technique for closure after endoscopic transsphenoidal resection of pituitary adenomas. AB - Background: While effective for the repair of large skull base defects, the Hadad Bassagasteguy nasoseptal flap increases operative time and can result in a several-week period of postoperative crusting during re-mucosalization of the denuded nasal septum. Endoscopic transsphenoidal surgery for pituitary adenoma resection is generally not associated with large dural defects and high-flow cerebrospinal fluid (CSF) leaks requiring extensive reconstruction. Here, we present the posterior nasoseptal flap as a novel technique for closure of skull defects following endoscopic resection of pituitary adenomas. This flap is raised in all surgeries during the transnasal exposure using septal mucoperiosteum that would otherwise be discarded during the posterior septectomy performed in binostril approaches. Methods: We present a retrospective, consecutive case series of 43 patients undergoing endoscopic transsphenoidal resection of a pituitary adenoma followed by posterior nasoseptal flap placement and closure. Main outcome measures were extent of resection and postoperative CSF leak. Results: The mean extent of resection was 97.16 +/- 1.03%. Radiographic measurement showed flap length to be adequate. While a defect in the diaphragma sellae and CSF leak were identified in 21 patients during surgery, postoperative CSF leak occurred in only one patient. Conclusions: The posterior nasoseptal flap provides adequate coverage of the surgical defect and is nearly always successful in preventing postoperative CSF leak following endoscopic transsphenoidal resection of pituitary adenomas. The flap is raised from mucoperiosteum lining the posterior nasal septum, which is otherwise resected during posterior septectomy. Because the anterior septal cartilage is not denuded, raising such flaps avoids the postoperative morbidity associated with the larger Hadad Bassagasteguy nasoseptal flap. PMID- 29527392 TI - Adult hemispheric cerebellar medulloblastoma. AB - Background: Medulloblastoma is an embryonal neoplasm and accounts for 1% of all adult intracranial tumors. It is associated with many familiar cancer syndromes, but there is no known cause for medulloblastoma. Many studies have documented differences between childhood and adult medulloblastomas in terms of location, proliferation, and apoptotic indices. There are four histological groups - classic and the variant forms (desmoplastic/nodular, anaplasic, and large cell). There are four major subgroups according to molecular configuration: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 with differences between them according to prognostic outcomes. Case Description: We present the case of a 19 year-old female who complained of headache and vomiting. On neurological exam, she was awake, conscious, and had mild truncal ataxia, dysmetria, and intentional tremor. Brain magnetic resonance imaging (MRI) showed an intra-axial left hemisphere cerebellar lesion causing midline shift tonsilar herniation. She was submitted for posterior fossa craniotomy and microsurgical resection of cerebellar tumor and then to 18 Gy adjuvant radiotherapy to the tumor bed and 23 Gy to the neuroaxis. Conclusion: This article briefly discusses the newest points in classification, diagnosis, and treatment of medulloblastoma. This case illustrates the diagnostic workup and treatment of a rare tumor in adults showing the importance of molecular and histological studies for the treatment and counseling of the patient. Medulloblastoma has different prognosis depending on the histological and molecular feature. Accessing these different features is essential to better plan the treatment as well as inform the patient regarding the disease and its prognosis. PMID- 29527393 TI - Treatment of cervical radiculopathy: A review of the evolution and economics. AB - Background: The surgical treatment of cervical radiculopathy has centered around anterior cervical discectomy and fusion (ACDF). Alternatively, the posterior cervical laminoforaminotomy/microdiscectomy (PCF/PCM), which results in comparable outcomes and is more cost-effective, has been underutilized. Methods: Here, we compared the direct/indirect costs, reoperation rates, and outcome for ACDF and PCF vs. PCM using PubMed, Medline, and Embase databases. Results: There were no significant differences between the re-operative rates of PCF/PCM (2% to 9.8%) versus ACDF (2% to 8%). Direct costs of ACDF were also significantly higher; the 1-year cost-utility analysis demonstrated that ACDF had $131,951/QALY while PCM had $79,856/QALY. Conclusion: PCF/PCM for radiculopathy are safe and more cost-effective vs. ACDF, and have similar clinical outcomes. PMID- 29527394 TI - Combined microsurgical and endoscopic technique for removal of extensive intracranial epidermoids. AB - Background: Intracranial epidermoid tumors are challenging lesions because they grow along the subarachnoid spaces around delicate neurovascular structures and often extend from one compartment to another. The purpose of this study was to determine the usefulness of endoscopic assistance in the microsurgical resection of these lesions, in which total resection is therapy of choice. Methods: A total of 48 cases of intracranial epidermoids were treated by combined microscopic and endoscopic techniques. Initially, the tumor was removed under the microscope and after ensuring maximum excision, the endoscope was used to find out and excise any residual tumor. Results: Out of these 48 cases complete excision was achieved in 44 cases and subtotal excision in four patients. Postoperative complications were seen in 17 patients, but none of the complications was attributed to the use of endoscope. Overall use of endoscope benefited 79% of cases. Conclusion: We recommend combined microsurgical and endoscopic approach to achieve complete/maximum resection of extensive intracranial epidermoid tumors. PMID- 29527395 TI - Falcine meningioma in Von Hippel-Lindau disease: An unusual association. AB - Background: Von Hippel-Lindau (VHL) disease is an autosomal dominant condition characterized by formation of multiple benign and malignant tumors. In this disease supratentorial lesions are rare and no falcine meningioma has been previously reported. Differential diagnosis is very difficult and the histopathological examination is the definitive method for diagnosis. Case Description: A patient with VHL underwent a suboccipital craniotomy for removal of cerebellar hemangioblastoma and after 2 years magnetic resonance imaging (MRI) showed an iperintense solid mass located at posterior part of the falx. Histological diagnosis revealed meningioma. Conclusion: The only case in the literature of falcine meningioma in a patient with Von Hippel-Lindau disease, discovered during radiological follow-up, is described and a surgical management is proposed. PMID- 29527396 TI - How to perform the Wiltse posterolateral spinal approach: Technical note. AB - Background: The paraspinal, posterolateral, or Wiltse approach is an old technique that observes the principles of an MIS procedure. The aim of this study was to provide a step-by-step description from the literature of the Wiltse paraspinal approach and analyze its main advantages and limitations. Methods: Here, we provide a step-by-step description of the Wiltse approach. Utilizing PubMed and Lilacs and the Mesh terms "Wiltse approach," "paraspinal approach," "muscle sparing approach," and "lumbar spine," we identified 10 papers. We then put together, based on these publications, a step-by-step analysis of the preparation, patient positioning, skin incision, fascial opening, dissection, bone identification, retractors, deperiostization, decompression, discectomy, instrumentation, arthrodesis, and closure for the Wiltse technique. Results: Most papers underscored the minimally invasive aspects of the typical Wiltse approach. Advantages included minimal intraoperative bleeding, a shorter hospital length of stay, and a low infection rate. Conclusion: The classical approach described by Wiltse is essentially minimally invasive, sparing both the muscle planes and soft tissues, allowing for ample far lateral lumbar decompression, including discectomy and fusion, with a low complication rate. PMID- 29527397 TI - Wolf in Sheep's clothing: Intracranial actinomycosis masquerading as en-plaque meningioma. AB - Background: Actinomycosis israeli is a gram-positive non-acid-fast bacterium and is the most common causative agent of actinomycosis. It usually presents as a brain abscess via a secondary spread from the cervicofacial region or lungs. However, presentation as an en-plaque lesion with bone involvement out of proportion to brain parenchyma is rare and needs to be acknowledged. Case Description: We report a case of intracranial en-plaque lesion in a 47-year-old female with restriction of mouth opening and right third nerve palsy for 1 year. Imaging showed hyperostosis of the maxilla, temporal base, sphenoid, and zygoma with dural thickening suggestive of a meningioma. Surgical decompression yielded a granulomatous lesion along with empirical antitubercular therapy. However, patient succumbed to the infection and final histopathology revealed actinomycosis infection. Conclusion: Adequate knowledge along with clinical suspicion are the pillars to treating this unfortunate disease. Cheek swelling with bone involvement should be actively sought as risk factors. This case presents a unique opportunity to identify the fox among the sheep by elucidating the characteristic imaging findings and intraoperative view of this rare entity. PMID- 29527398 TI - Axial and oblique C2 pedicle diameters and feasibility of C2 pedicle screw placement: Technical note. AB - Background: For C2 pedicle screw placement/instrumentation, it is critical to adequately measure the axial and oblique C2 pedicle diameters utilizing the intraoperative O-arm. Methods: Thirty-three patients who underwent C2 pedicle screw placement (2013-2016) utilizing the O-arm with tri-planar reconstruction. As O-arm software does not allow calibrated measurements with the application's measurement tool, we directly measured axial and oblique widths of the C2 pedicles on the screen with a regular ruler (e.g., "screen width of C2 pedicle"). Results: The axial width of the C2 pedicles ranged from 6 to 15 mm on the right (mean 10.44 +/- 2.15 mm) to 7 to 14 mm (10.29 +/- 1.72 mm) on the left. The oblique width of C2 pedicles ranged from 10 to 19 mm on the right (mean, 14.73 +/ 1.85 mm) and from 12 to 19 mm on the left (mean, of 15.33 +/- 1.67 mm). These measurements indicated that oblique screen widths of the C2 pedicles were 1.4 and 1.5 times higher than their axial screen widths on the right and left sides, respectively. Conclusions: The oblique screen widths of the C2 pedicles better predict the feasibility of C2 pedicle screw placement vs. their axial screen width as measured with a regular ruler. PMID- 29527399 TI - Nursing review of spinal meningiomas. AB - Background: Spinal meningiomas are found in patients typically between the ages of 75 and 84: some report the average age to be 50. They occur with an incidence of approximately 1000 patients per year in the US, are mostly single (90%) rather than multiple (10%), and arise from the spinal meninges (arachnoid/dura). Tumors are typically posterior/posterolateral (70%) in location, leaving the remaining 30% in the anterior/anterolateral spinal canal. They produce symptoms and signs of radiculopathy (nerve root) and/or myelopathy (cord compression) depending on their site of origin. Methods: Meningiomas may be single/sporadic (90%) or multifocal. They may arise primarily/spontaneously, can be radiation-induced, or associated with neurofibromatosis. They are found most frequently in females vs. males in up to a 3.4:1 ratio, occur predominantly in the thoracic spine. They are found in decreasing order in the cervical and lumbar spinal canals. The diagnosis of a meningioma is based on magnetic resonance (MR) studies, where tumors are isointense on T1 weighted MR, and hyperintense onf T2-weighted MR images; they also typically uniformly enhance with Gd-DTPA. On computed tomography (CT) examinations, they are usually characterized as calcified/hyperdense. Results: The neurological deficits resulting from meningiomas and the rapidity of symptom/sign progression dictate whether they are treated surgically or nonsurgically. Management choices include; stereotactic radiation therapy only, and/or in combination with varied surgical resection techniques. Conclusions: The majority of benign spinal cord tumors are meningiomas (40%) that are predominantly found in the thoracic spine in middle-aged females. Tumor levels (e.g. in descending order cervical, thoracic, lumbar), and their location (e.g. anterior/anterolateral 30%; dorsal/dorsolateral 70%) best determine whether nonoperative, operative, and/or operative intervention combined with routine vs. stereotactic radiosurgery are warranted. PMID- 29527400 TI - Intramolecular Hydrogen Bond Activation: Thiourea-Organocatalyzed Enantioselective 1,3-Dipolar Cycloaddition of Salicylaldehyde-Derived Azomethine Ylides with Nitroalkenes. AB - An organocatalytic strategy for the synthesis of tetrasubstituted pyrrolidines with monoactivated azomethine ylides in high enantiomeric excess and excellent exo/endo selectivity is presented. The key to success is the intramolecular activation via hydrogen bonding through an o-hydroxy group, which allows the dipolar cycloaddition to take place in the presence of azomethine ylides bearing only one activating group. The intramolecular hydrogen bond in the azomethine ylide and the intermolecular hydrogen bond with the catalyst have been demonstrated by DFT calculations and mechanistic proofs to be crucial for the reaction to proceed. PMID- 29527401 TI - Revealing Lattice Expansion of Small-Pore Zeolite Catalysts during the Methanol to-Olefins Process Using Combined Operando X-ray Diffraction and UV-vis Spectroscopy. AB - In small-pore zeolite catalysts, where the size of the pores is limited by eight ring windows, aromatic hydrocarbon pool molecules that are formed inside the zeolite during the Methanol-to-Olefins (MTO) process cannot exit the pores and are retained inside the catalyst. Hydrocarbon species whose size is comparable to the size of the zeolite cage can cause the zeolite lattice to expand during the MTO process. In this work, the formation of retained hydrocarbon pool species during MTO at a reaction temperature of 400 degrees C was followed using operando UV-vis spectroscopy. During the same experiment, using operando X-ray Diffraction (XRD), the expansion of the zeolite framework was assessed, and the activity of the catalyst was measured using online gas chromatography (GC). Three different small-pore zeolite frameworks, i.e., CHA, DDR, and LEV, were compared. It was shown using operando XRD that the formation of retained aromatic species causes the zeolite lattice of all three frameworks to expand. Because of the differences in the zeolite framework dimensions, the nature of the retained hydrocarbons as measured by operando UV-vis spectroscopy is different for each of the three zeolite frameworks. Consequently, the magnitude and direction of the zeolite lattice expansion as measured by operando XRD also depends on the specific combination of the hydrocarbon species and the zeolite framework. The catalyst with the CHA framework, i.e., H-SSZ-13, showed the biggest expansion: 0.9% in the direction along the c-axis of the zeolite lattice. For all three zeolite frameworks, based on the combination of operando XRD and operando UV-vis spectroscopy, the hydrocarbon species that are likely to cause the expansion of the zeolite cages are presented; methylated naphthalene and pyrene in CHA, 1 methylnaphthalene and phenalene in DDR, and methylated benzene and naphthalene in LEV. Filling of the zeolite cages and, as a consequence, the zeolite lattice expansion causes the deactivation of these small-pore zeolite catalysts during the MTO process. PMID- 29527402 TI - Broad-Scope Rh-Catalyzed Inverse-Sonogashira Reaction Directed by Weakly Coordinating Groups. AB - We report the alkynylation of C(sp2)-H bonds with bromoalkynes (inverse Sonogashira reaction) directed by synthetically useful ester, ketone, and ether groups under rhodium catalysis. Other less common directing groups such as amine, thioether, sulfoxide, sulfone, phenol ester, and carbamate are also suitable directing groups. Mechanistic studies indicate that the reaction proceeds by a turnover-limiting C-H activation step via an electrophilic-type substitution. PMID- 29527403 TI - Highly Selective Oxidation of Ethyl Lactate to Ethyl Pyruvate Catalyzed by Mesoporous Vanadia-Titania. AB - The direct oxidative dehydrogenation of lactates with molecular oxygen is a "greener" alternative for producing pyruvates. Here we report a one-pot synthesis of mesoporous vanadia-titania (VTN), acting as highly efficient and recyclable catalysts for the conversion of ethyl lactate to ethyl pyruvate. These VTN materials feature high surface areas, large pore volumes, and high densities of isolated vanadium species, which can expose the active sites and facilitate the mass transport. In comparison to homogeneous vanadium complexes and VO x /TiO2 prepared by impregnation, the meso-VTN catalysts showed superior activity, selectivity, and stability in the aerobic oxidation of ethyl lactate to ethyl pyruvate. We also studied the effect of various vanadium precursors, which revealed that the vanadium-induced phase transition of meso-VTN from anatase to rutile depends strongly on the vanadium precursor. NH4VO3 was found to be the optimal vanadium precursor, forming more monomeric vanadium species. V4+ as the major valence state was incorporated into the lattice of the NH4VO3-derived VTN material, yielding more V4+-O-Ti bonds in the anatase-dominant structure. In situ DRIFT spectroscopy and density functional theory calculations show that V4+-O-Ti bonds are responsible for the dissociation of ethyl lactate over VTN catalysts and for further activation of the deprotonation of beta-hydrogen. Molecular oxygen can replenish the surface oxygen to regenerate the V4+-O-Ti bonds. PMID- 29527404 TI - In Situ Luminescence Thermometry To Locally Measure Temperature Gradients during Catalytic Reactions. AB - Bandshape luminescence thermometry during in situ temperature measurements has been reported by preparing three catalytically relevant systems, which show temperature-dependent luminescence. One of these systems was further investigated as a showcase for application. Microcrystalline NaYF4 doped with Er3+ and Yb3+ was mixed with a commercial zeolite H-ZSM-5 to investigate the Methanol-to Hydrocarbons (MTH) reaction, while monitoring the reaction products with online gas chromatography. Due to the exothermic nature of the MTH reaction, a front of increased temperature migrating down the fixed reactor bed was visualized, showing the potential for various applications of luminescence thermometry for in situ measurements in catalytic systems. PMID- 29527405 TI - A Rational Active-Site Redesign Converts a Decarboxylase into a C=C Hydratase: "Tethered Acetate" Supports Enantioselective Hydration of 4-Hydroxystyrenes. AB - The promiscuous regio- and stereoselective hydration of 4-hydroxystyrenes catalyzed by ferulic acid decarboxylase from Enterobacter sp. (FDC_Es) depends on bicarbonate bound in the active site, which serves as a proton relay activating a water molecule for nucleophilic attack on a quinone methide electrophile. This "cofactor" is crucial for achieving improved conversions and high stereoselectivities for (S)-configured benzylic alcohol products. Similar effects were observed with simple aliphatic carboxylic acids as additives. A rational redesign of the active site by replacing the bicarbonate or acetate "cofactor" with a newly introduced side-chain carboxylate from an adjacent amino acid yielded mutants that efficiently acted as C=C hydratases. A single-point mutation of valine 46 to glutamate or aspartate improved the hydration activity by 40% and boosted the stereoselectivity 39-fold in the absence of bicarbonate or acetate. PMID- 29527406 TI - A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials. AB - Objective To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother-neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at >=24 weeks' GA. Results Among 17,912 mother-neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at <31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately. PMID- 29527407 TI - Transient Neonatal Diabetes Mellitus in a Very Preterm Infant due to ABCC8 Mutation. AB - Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes occurring within 6 months from birth. NDM can be permanent or transient (TNDM). We report the case of a preterm infant with TNDM due to an ABCC8 mutation identified by next generation sequencing. The pancreatic adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel is a key regulator of insulin secretion. Gain-of-function mutations in the genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the channel cause neonatal diabetes. The patient was successfully managed with insulin lispro at a 1:100 dilution, drawn up in an insulin pen injector with a 4 mm needle. The insulin lispro dilution allowed administration of the exact insulin doses, obtaining a good glycemic control and minimizing the burden of injections. At 2 months, corrected age insulin doses were progressively decreased until discontinuation. PMID- 29527408 TI - Clinicians' Personal Theories of Developmental Disorders Explain Their Judgments of Effectiveness of Interventions. AB - Evidence-based psychotherapy requires clinicians to consider theories of psychopathology and evidence about effectiveness, and their experience when choosing interventions. Research on clinical decision making indicates that clinicians' theories of disorders might be personal and inform judgments and choices beyond current scientific theory and evidence. We asked 20 child therapists to draw models of how they believed that biological, psychological, environmental, and behavioral factors interact to cause and maintain four common developmental disorders. They were also asked to judge the effectiveness of interventions recommended in the literature. Therapists showed only fair agreement about the factors and a slight to fair agreement about the causal relations between these, and just fair agreement about interventions' effectiveness. Despite these disagreements, we could predict effectiveness judgments from therapists' personal theories, which indicates that clinicians use personal theories in decision making. We discuss the implications of these findings for evidence-based practice. PMID- 29527409 TI - The little shrimp that could: phylogeography of the circumtropical Stenopus hispidus (Crustacea: Decapoda), reveals divergent Atlantic and Pacific lineages. AB - The banded coral shrimp, Stenopus hispidus (Crustacea: Decapoda: Stenopodidea) is a popular marine ornamental species with a circumtropical distribution. The planktonic larval stage lasts ~120-253 days, indicating considerable dispersal potential, but few studies have investigated genetic connectivity on a global scale in marine invertebrates. To resolve patterns of divergence and phylogeography of S. hispidus, we surveyed 525 bp of mitochondrial cytochrome c oxidase subunit I (COI) from 198 individuals sampled at 10 locations across ~27,000 km of the species range. Phylogenetic analyses reveal that S. hispidus has a Western Atlantic lineage and a widely distributed Indo-Pacific lineage, separated by sequence divergence of 2.1%. Genetic diversity is much higher in the Western Atlantic (h = 0.929; pi = 0.004) relative to the Indo-Pacific (h = 0.105; pi < 0.001), and coalescent analyses indicate that the Indo-Pacific population expanded more recently (95% HPD (highest posterior density) = 60,000-400,000 yr) than the Western Atlantic population (95% HPD = 300,000-760,000 yr). Divergence of the Western Atlantic and Pacific lineages is estimated at 710,000-1.8 million years ago, which does not readily align with commonly implicated colonization events between the ocean basins. The estimated age of populations contradicts the prevailing dispersal route for tropical marine biodiversity (Indo-Pacific to Atlantic) with the oldest and most diverse population in the Atlantic, and a recent population expansion with a single common haplotype shared throughout the vast Indian and Pacific oceans. In contrast to the circumtropical fishes, this diminutive reef shrimp challenges our understanding of conventional dispersal capabilities of marine species. PMID- 29527410 TI - The enhancement by arbuscular mycorrhizal fungi of the Cd remediation ability and bioenergy quality-related factors of five switchgrass cultivars in Cd contaminated soil. AB - A greenhouse experiment was carried out to investigate the effects of arbuscular mycorrhizal fungi (AMF) on the growth, P and Cd concentrations and bioenergy quality-related factors of five cultivars of switchgrass, including three lowland cultivars (Alamo (Ala), Kanlow (Kan), Performer (Per)) and two highland cultivars (Blackwell (Bw), Summer (Sum)), with 0, 1 and 10 mg/kg Cd addition levels. The results showed that AMF inoculation notably increased the biomass and P concentrations of all the cultivars. The Cd concentrations in the roots were higher than those in the shoots of all cultivars irrespective of inoculation, but the AMF had different effects on Cd accumulation in highland and lowland cultivars. AMF inoculation decreased the shoot and root concentrations in Ala and Kan, increased the shoot and root concentrations of Cd in Bw and Sum, and increased shoot Cd concentrations and decreased root Cd concentrations in Per. The highest Cd concentrations were detected in the roots of Bw and in the shoots of Sum with AMF symbiosis. Bw contained the highest total extracted Cd which was primarily in the roots. Ala had the second highest extracted Cd in the shoots, reaching 32% with 1 mg/kg of added Cd, whereas Sum had the lowest extracted Cd. AMF symbiosis had varied effects on bioenergy quality-related factors: for example, AMF decreased the ash lignin content in Ala and the C/N in Sum, increased the nitrogen, gross calorie values, and maintained the hemicellulose and cellulose contents in all cultivars with all tested concentrations of Cd. A principal component analysis (PCA) showed that AMF inoculation could enhance, weaken or transform (positive-negative, PC1-PC2) the correlations of these factors with the principle components under Cd stress. Therefore, AMF symbiosis enhanced the growth of different cultivars of switchgrass, increased/decreased Cd accumulation, promoted Cd extraction, and regulated the bioenergy quality-related factors in Cd-polluted areas. Bw is a suitable cultivar for phytostabilization due to high root Cd stabilization, whereas Ala is an appropriate cultivar for phytoremediation of less polluted areas because of its high Cd extraction and excellent bioenergy quality. PMID- 29527411 TI - Genetic diversity and connectivity of the megamouth shark (Megachasma pelagios). AB - The megamouth shark (Megachasma pelagios) was described as a new species in 1983. Since then, only ca. 100 individuals have been observed or caught. Its horizontal migration, dispersal, and connectivity patterns are still unknown due to its rarity. Two genetic markers were used in this study to reveal its genetic diversity and connectivity pattern. This approach provides a proxy to indirectly measure gene flow between populations. Tissues from 27 megamouth sharks caught by drift nets off the Hualien coast (eastern Taiwan) were collected from 2013 to 2015. With two additional tissue samples from megamouths caught in Baja California, Mexico, and sequences obtained from GenBank, we were able to perform the first population genetic analyses of the megamouth shark. The mtDNA cox1 gene and a microsatellite (Loc 6) were sequenced and analyzed. Our results showed that there is no genetic structure in the megamouth shark, suggesting a possible panmictic population. Based on occurrence data, we also suggest that the Kuroshio region, including the Philippines, Taiwan, and Japan, may act as a passageway for megamouth sharks to reach their feeding grounds from April to August. Our results provide insights into the dispersal and connectivity of megamouth sharks. Future studies should focus on collecting more samples and conducting satellite tagging to better understand the global migration and connectivity pattern of the megamouth shark. PMID- 29527412 TI - Effects of xylo-oligosaccharide and flavomycin on the immune function of broiler chickens. AB - This study investigated the effects of xylo-oligosaccharide (XOS) and flavomycin (FLA) on the performance and immune function of broiler chickens. A total of 150 ArborAcres broilers were randomly divided into three groups and fed for six weeks from one day of age in cascade cages. The diets of each test group were (1) a basal diet, (2) the basal diet supplemented with 2 mg/kg FLA, and (3) the basal diet supplemented with 2 mg/kg XOS. At 21 and 42 days, the growth performance index values and short-chain fatty acid (SCFA) concentrations in the cecum were quantified. Furthermore, immunoglobulin G (IgG) and plasma interleukin 2 (IL-2) as well as mRNA expression of LPS-Induced TNF-alpha Factor (LITAF), Toll-like receptor-5 (TLR5) and interferon gamma (IFNgamma ) in the jejunum were quantified. The results showed that administration of XOS or FLA to chickens significantly improved the average daily gain. Supplementation with XOS increased acetate and butyrate in the cecum, while FLA supplementation increased propionate in the cecum. An increase in plasma IgG was observed in XOS-fed 21-day-old broilers, but FLA supplementation decreased IgG in the plasma of 42-day-old broilers and increased plasma IL-2. Furthermore, FLA or XOS supplementation downregulated mRNA expression of IFNgamma , LITAF and TLR5. The above data suggest that addition of XOS and FLA to the diet could improve the growth performance of broilers and reduce the expression of cytokine genes by stimulating SCFA. PMID- 29527413 TI - Changes in nutrients and decay rate of Ginkgo biloba leaf litter exposed to elevated O3 concentration in urban area. AB - Ground-level ozone (O3) pollution has been widely concerned in the world, particularly in the cities of Asia, including China. Elevated O3 concentrations have potentially influenced growth and nutrient cycling of trees in urban forest. The decomposition characteristics of urban tree litters under O3 exposure are still poorly known. Ginkgo biloba is commonly planted in the cities of northern China and is one of the main tree species in the urban forest of Shenyang, where concentrations of ground-level O3 are very high in summer. Here, we hypothesized that O3 exposure at high concentrations would alter the decomposition rate of urban tree litter. In open-top chambers (OTCs), 5-year-old G. biloba saplings were planted to investigate the impact of elevated O3 concentration (120 ppb) on changes in nutrient contents and decomposition rate of leaf litters. The results showed that elevated O3 concentration significantly increased K content (6.31 +/- 0.29 vs 17.93 +/- 0.40, P < 0.01) in leaves of G. biloba, significantly decreased the contents of total phenols (2.82 +/- 0.93 vs 1.60 +/- 0.44, P < 0.05) and soluble sugars (86.51 +/- 19.57 vs 53.76 +/- 2.40, P < 0.05), but did not significantly alter the contents of C, N, P, lignin and condensed tannins, compared with that in ambient air. Furthermore, percent mass remaining in litterbags after 150 days under ambient air and elevated O3 concentration was 56.0% and 52.8%, respectively. No significant difference between treatments was observed in mass remaining at any sampling date during decomposition. The losses of the nutrients in leaf litters of G. biloba showed significant seasonal differences regardless of O3 treatment. However, we found that elevated O3 concentration slowed down the leaf litter decomposition only at the early decomposition stage, but slightly accelerated the litter decomposition at the late stage (after 120 days). This study provides our understanding of the ecological processes regulating biogeochemical cycles from deciduous tree species in high-O3 urban area. PMID- 29527414 TI - Use of seaweed Ulva lactuca for water bioremediation and as feed additive for white shrimp Litopenaeus vannamei. AB - Two experimental feeding trials were conducted during four weeks to evaluate the use of Ulva lactuca in shrimp culture: (1) for wastewater bioremediation, and (2) using different inclusion levels of U. lactuca meal in shrimp feed. In feeding trial 1, shrimp reared under seaweed U. lactuca water exchange in a re circulation system (SWE) resulted in similar growth and feed utilization as shrimp reared with clean water exchange (CWE). Shrimp under no water exchange (NWE) resulted in significant lower growth and higher feed conversion rate (FCR) compared to the other treatments (p < 0.05). Nitrogen compounds and phosphate in water from SWE and CWE treatments did not present significant differences during the experimental trial (p > 0.05). In feeding trial 2, U. lactuca biomass produced by wastewater bioremediation in SWE treatment were dried and ground to formulate diets containing 0, 1, 2, and 3% U. lactuca meal (0UL, 1UL, 2UL, and 3UL). Shrimp fed the 3 UL diet resulted in a significant (p < 0.05) improvement of growth and FCR, and enhanced whole shrimp lipid and carotenoid content by 30 and 60%, respectively, compared to control diet. Seaweed U. lactuca is suggested as a desirable species for wastewater bioremediation in integrated aquaculture systems, and its meal as a good feed additive for farmed shrimp. PMID- 29527415 TI - Identification and characterization of the cytosine-5 DNA methyltransferase gene family in Salvia miltiorrhiza. AB - Cytosine DNA methylation is highly conserved epigenetic modification involved in a wide range of biological processes in eukaryotes. It was established and maintained by cytosine-5 DNA methyltransferases (C5-MTases) in plants. Through genome-wide identification, eight putative SmC5-MTase genes were identified from the genome of Salvia miltiorrhiza, a well-known traditional Chinese medicine material and an emerging model medicinal plant. Based on conserved domains and phylogenetic analysis, eight SmC5-MTase genes were divided into four subfamilies, including MET, CMT, DRM and DNMT2. Genome-wide comparative analysis of the C5 MTase gene family in S. miltiorrhiza and Arabidopsis thaliana, including gene structure, sequence features, sequence alignment and conserved motifs, was carried out. The results showed conservation and divergence of the members of each subfamily in plants. The length of SmC5-MTase open reading frames ranges widely from 1,152 (SmDNMT2) to 5,034 bp (SmMET1). The intron number of SmC5 MTases varies between 7 (SmDRM1) and 20 (SmCMT1 and SmCMT2b). These features were similar to their counterparts from Arabidopsis. Sequence alignment and conserved motif analysis showed the existence of highly conserved and subfamily-specific motifs in the C5-MTases analyzed. Differential transcript abundance was detected for SmC5-MTases, implying genome-wide variance of DNA methylation in different organs and tissues. Transcriptome-wide analysis showed that the transcript levels of all SmC5-MTase genes was slightly changed under yeast extract and methyl jasmonate treatments. Six SmC5-MTases, including SmMET1, SmCMT1, SmCMT2a, SmCMT2b, SmCMT3 and SmDRM1, were salicylic acid-responsive, suggesting the involvement of SmC5-MTases in salicylic acid-dependent immunity. These results provide useful information for demonstrating the role of DNA methylation in bioactive compound biosynthesis and Dao-di herb formation in medicinal plants. PMID- 29527416 TI - Immobilized TiO2 on glass spheres applied to heterogeneous photocatalysis: photoactivity, leaching and regeneration process. AB - Heterogeneous photocatalysis using titanium dioxide as catalyst is an attractive advanced oxidation process due to its high chemical stability, good performance and low cost. When immobilized in a supporting material, additional benefits are achieved in the treatment. The purpose of this study was to develop a simple protocol for impregnation of TiO2-P25 on borosilicate glass spheres and evaluate its efficiency in the photocatalytic degradation using an oxidizable substrate (methylene blue), in a Compound Parabolic Concentrator (CPC) reactor. The assays were conducted at lab-scale using radiation, which simulated the solar spectrum. TiO2 leaching from the glass and the catalyst regeneration were both demonstrated. A very low leaching ratio (0.03%) was observed after 24 h of treatment, suggesting that deposition of TiO2 resulted in good adhesion and stability of the photocatalyst on the surface of borosilicate. This deposition was successfully achieved after calcination of the photocatalyst at 400 degrees C (TiO2-400 degrees C). The TiO2 film was immobilized on glass spheres and the powder was characterized by scanning electron microscopy (SEM), X-ray diffraction and BET. This characterization suggested that thermal treatment did not introduce substantial changes in the measured microstructural characteristics of the photocatalyst. The immobilized photocatalyst degraded more than 96% of the MB in up to 90 min of reaction. The photocatalytic activity decreased after four photocatalytic cycles, but it was recovered by the removal of contaminants adsorbed on the active sites after washing in water under UV-Vis irradiation. Based on these results, the TiO2-400 degrees C coated on glass spheres is potentially a very attractive option for removal of persistent contaminants present in the environment. PMID- 29527417 TI - Global analysis of A-to-I RNA editing reveals association with common disease variants. AB - RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process. PMID- 29527418 TI - The adipokine C1q TNF related protein 3 (CTRP3) is elevated in the breast milk of obese mothers. AB - Background: C1q TNF related protein 3 (CTRP3) is a relatively novel hormonal factor primarily derived from adipose tissue and has anti-diabetic properties. To determine if CTRP3 could play a role in early childhood development, the purpose of this study was to establish the presence of CTRP3 in breast milk (BM) and to determine whether CTRP3 levels were correlated with pregravid obesity status of the mother. Methods: Breast milk was collected from breast-feeding mothers who had a pregravid body mass index (BMI) classification of normal weight (BMI 18-25 kg/m2, n = 23) or obese (BMI > 30 kg/m2, n = 14). Immunoprecipitation followed by immunoblot analysis confirmed the presence of CTRP3 in BM. The concentration of CTRP3 in BM samples was determined by ELISA. Additional bioactive components were also measured by commercially available assays: ghrelin, insulin, leptin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and glucose. Bioactive components in normal weight and obese mothers were compared using unpaired t-test (parametric) and Mann-Whitney U-test (non-parametric), as appropriate. Results: The primary findings of this study are that the adipokine CTRP3 is present in BM and CTRP3 levels are increased with pregravid obesity. Additionally, this study independently confirmed previous work that BM from obese mothers has a higher concentration of insulin and leptin. Further, no differences were observed in BM between obese and normal weight mothers in ghrelin, adiponectin, IL-6, TNF-alpha, or glucose levels. Conclusion: This study identified a novel factor in BM, CTRP3, and showed that BM CTRP3 levels higher in obese mothers. Because of the purported insulin sensitizing effect of CTRP3, it is possible that the elevated levels of CTRP3 in the BM of obese mothers may offset negative effects of elevated leptin and insulin levels in the BM of obese mothers. Future studies will need to be conducted to determine the relevance of CTRP3 in BM and to examine the presence of other adipose tissue-derived hormonal factors. PMID- 29527419 TI - Genetic analysis of 'Candidatus Phytoplasma aurantifolia' associated with witches' broom on acid lime trees. AB - "Candidatus Phytoplasma aurantifolia" is associated with witches' broom disease of lime in Oman and the UAE. A previous study showed that an infection by phytoplasma may not necessarily result in the physical appearance of witches' broom symptoms in some locations in Oman and the UAE. This study investigated whether phytoplasma strains belonging to "Ca. P. aurantifolia" (based on the 16S rRNA gene analysis) in locations where disease symptoms are expressed are different from phytoplasma in locations where disease symptoms are not expressed. About 21 phytoplasma strains (15 from areas and trees with disease symptoms and six from areas and trees without disease symptoms) were included in the analysis. The study utilized sequences of the imp and SAP11 genes to characterize the 21 strains. Phylogenetic analysis of both genes showed that the 21 strains are similar to each other and to reference strains in GenBank. The study shows that there is a low level of diversity among all phytoplasma strains. In addition, it shows that phytoplasma in places where witches' broom symptoms are not expressed are similar to phytoplasma in places where disease symptoms are expressed. This may suggest that disease expression is not linked to the presence of different phytoplasma strains, but may be due to other factors such as weather conditions. PMID- 29527420 TI - Genome-wide identification and characterization of Dof transcription factors in eggplant (Solanum melongena L.). AB - Eggplant (Solanum melongena L.) is an important vegetable cultivated in Asia, Africa and southern Europe and, following tomato and pepper, ranks as the third most important solanaceous vegetable crop. The Dof (DNA-binding with one finger) family is a group of plant-specific transcription factors that play important roles in plant growth, development, and response to biotic and abiotic stresses. The genes in the Dof family have been identified and analysed in many plant species, but the information remains lacking for eggplant. In the present study, we identified 29 SmeDof members from the eggplant genome database, which were classifed into nine subgroups. The phylogeny, gene structure, conserved motifs and homologous genes of SmeDof genes were comprehensively investigated. Subsequently, we analysed the expression patterns of SmeDof genes in six different eggplant subspecies. The results provide novel insights into the family of SmeDof genes and will promote the understanding of the structure and function of Dof genes in eggplant, and the role of Dof expression during stress. PMID- 29527421 TI - Environmental DNA for freshwater fish monitoring: insights for conservation within a protected area. AB - Background: Many fish species have been introduced in wild ecosystems around the world to provide food or leisure, deliberately or from farm escapes. Some of those introductions have had large ecological effects. The north American native rainbow trout (Oncorhynchus mykiss Walbaum, 1792) is one of the most widely farmed fish species in the world. It was first introduced in Spain in the late 19th century for sport fishing (Elvira 1995) and nowadays is used there for both fishing and aquaculture. On the other hand, the European native brown trout (Salmo trutta L.) is catalogued as vulnerable in Spain. Detecting native and invasive fish populations in ecosystem monitoring is crucial, but it may be difficult from conventional sampling methods such as electrofishing. These techniques encompass some mortality, thus are not adequate for some ecosystems as the case of protected areas. Environmental DNA (eDNA) analysis is a sensitive and non-invasive method that can be especially useful for rare and low-density species detection and inventory in water bodies. Methods: In this study we employed two eDNA based methods (qPCR and nested PCR-RFLP) to detect salmonid species from mountain streams within a protected area, The Biosphere Reserve and Natural Park of Redes (Upper Nalon Basin, Asturias, Northern Spain), where brown trout is the only native salmonid. We also measured some habitat variables to see how appropriate for salmonids the area is. The sampling area is located upstream impassable dams and contains one rainbow trout fish farm. Results: Employing qPCR methodology, brown trout eDNA was detected in all the nine sampling sites surveyed, while nested PCR-RFLP method failed to detect it in two sampling points. Rainbow trout eDNA was detected with both techniques at all sites in the Nalon River' (n1, n2 and n3). Salmonid habitat units and water quality were high from the area studied. Discussion: In this study, a high quantity of rainbow trout eDNA was found upstream and downstream of a fish farm located inside a Biosphere Reserve. Unreported escapes from the fish farm are a likely explanation of these results. Since salmonid habitat is abundant and the water quality high, the establishment of rainbow trout populations would be favored should escapes occur. Environmental DNA has here proved to be a valuable tool for species detection in freshwater environments, and the probe-based qPCR highly sensitive technique for detection of scarce species. We would recommend this method for routine monitoring and early detection of introduced species within natural reserves. PMID- 29527422 TI - Cellular prion protein and gamma-synuclein overexpression in LS 174T colorectal cancer cell drives endothelial proliferation-to-differentiation switch. AB - Background: Tumor-induced angiogenesis is an imperative event in pledging new vasculature for tumor metastasis. Since overexpression of neuronal proteins gamma synuclein (gamma-Syn) and cellular prion protein (PrPC) is always detected in advanced stages of cancer diseases which involve metastasis, this study aimed to investigate whether gamma-Syn or PrPC overexpression in colorectal adenocarcinoma, LS 174T cells affects angiogenesis of endothelial cells, EA.hy 926 (EA). Methods: EA cells were treated with conditioned media (CM) of LS 174T gamma-Syn or LS 174T-PrP, and their proliferation, invasion, migration, adhesion and ability to form angiogenic tubes were assessed using a range of biological assays. To investigate plausible background mechanisms in conferring the properties of EA cells above, nitrite oxide (NO) levels were measured and the expression of angiogenesis-related factors was assessed using a human angiogenesis antibody array. Results: EA proliferation was significantly inhibited by LS 174T-PrP CM whereas its telomerase activity was reduced by CM of LS 174T-gamma-Syn or LS 174T-PrP, as compared to EA incubated with LS 174T CM. Besides, LS 174T-gamma-Syn CM or LS 174T-PrP CM inhibited EA invasion and migration in Boyden chamber assay. Furthermore, LS 174T-gamma-Syn CM significantly inhibited EA migration in scratch wound assay. Gelatin zymography revealed reduced secretion of MMP-2 and MMP-9 by EA treated with LS 174T-gamma Syn CM or LS 174T-PrP CM. In addition, cell adhesion assay showed lesser LS 174T gamma-Syn or LS 174T-PrP cells adhered onto EA, as compared to LS 174T. In tube formation assay, LS 174T-gamma-Syn CM or LS 174T-PrP CM induced EA tube formation. Increased NO secretion by EA treated with LS 174T-gamma-Syn CM or LS 174T-PrP CM was also detected. Lastly, decreased expression of pro-angiogenic factors like CXCL16, IGFBP-2 and amphiregulin in LS 174T-gamma-Syn CM or LS 174T PrP CM was detected using the angiogenesis antibody array. Discussion: These results suggest that overexpression of gamma-Syn or PrPC could possibly be involved in colorectal cancer-induced angiogenesis by inducing an endothelial proliferation-differentiation switch. NO could be the main factor in governing this switch, and modulation on the secretion patterns of angiogenesis-related proteins could be the strategy of colorectal cancer cells overexpressing gamma Syn or PrPC in ensuring this transition. PMID- 29527423 TI - Tailored Explanation: A Strategy to Minimize Nonresponse in Demographic Items Among Low-income Racial and Ethnic Minorities. AB - There is a high rate of nonresponse for demographic items in survey research, particularly for racial and ethnic minority respondents. This present study examined whether providing an explanation to racial and ethnic minority respondents prior to asking a set of demographic questions would increase respondents' motivation to reduce nonresponse to gender, income, age, and race items. Using a cross-sectional, randomized comparison design, 99 respondents were randomly assigned to two groups. Group 1 did not receive an explanation for asking the demographic questions. Group 2 received an explanation designed to be relevant and meaningful to them concerning the significance and potential use of demographic information for racial and ethnic minority populations. A proportional difference test was used to calculate the differences in the proportion of respondents' motivation to complete demographic survey items between the groups. A proportional difference effect size (Cohen's h effect size) was used to determine the magnitude of difference between the two groups. Over 50% of respondents were African Americans. While none of the item non-responses for both groups is statistically significant in terms of proportional differences, there is small (Cohen's h= 0.184) to moderate (Cohen's h=0.342) effect in reducing demographic item non-response when an explanation was provided to respondents. Specifically, adding an explanation made the biggest improvement in reporting income. The study findings support the importance of providing participants with an explanation that is relevant and meaningful to increase motivation and thereby minimize item nonresponse. PMID- 29527425 TI - The Evolution and Structure of Extreme Optical Lightning Flashes. AB - This study documents the composition, morphology, and motion of extreme optical lightning flashes observed by the Lightning Imaging Sensor (LIS). The furthest separation of LIS events (groups) in any flash is 135 km (89 km), the flash with the largest footprint had an illuminated area of 10,604 km2, and the most dendritic flash has 234 visible branches. The longest-duration convective LIS flash lasted 28 s and is overgrouped and not physical. The longest-duration convective-to-stratiform propagating flash lasted 7.4 s, while the longest duration entirely stratiform flash lasted 4.3 s. The longest series of nearly consecutive groups in time lasted 242 ms. The most radiant recorded LIS group (i.e., "superbolt") is 735 times more radiant than the average group. Factors that impact these optical measures of flash morphology and evolution are discussed. While it is apparent that LIS can record the horizontal development of the lightning channel in some cases, radiative transfer within the cloud limits the flash extent and level of detail measured from orbit. These analyses nonetheless suggest that lightning imagers such as LIS and Geostationary Lightning Mapper can complement ground-based lightning locating systems for studying physical lightning phenomena across large geospatial domains. PMID- 29527424 TI - Formaldehyde in the Tropical Western Pacific: Chemical sources and sinks, convective transport, and representation in CAM-Chem and the CCMI models. AB - Formaldehyde (HCHO) directly affects the atmospheric oxidative capacity through its effects on HOx. In remote marine environments, such as the Tropical Western Pacific (TWP), it is particularly important to understand the processes controlling the abundance of HCHO because model output from these regions is used to correct satellite retrievals of HCHO. Here, we have used observations from the CONTRAST field campaign, conducted during January and February 2014, to evaluate our understanding of the processes controlling the distribution of HCHO in the TWP as well as its representation in chemical transport/climate models. Observed HCHO mixing ratios varied from ~500 pptv near the surface to ~75 pptv in the upper troposphere. Recent convective transport of near surface HCHO and its precursors, acetaldehyde and possibly methyl hydroperoxide, increased upper tropospheric HCHO mixing ratios by ~33% (22 pptv); this air contained roughly 60% less NO than more aged air. Output from the CAM-Chem chemistry transport model (2014 meteorology) as well as nine chemistry climate models from the Chemistry Climate Model Initiative (free-running meteorology) are found to uniformly underestimate HCHO columns derived from in situ observations by between 4 and 50%. This underestimate of HCHO likely results from a near factor of two underestimate of NO in most models, which strongly suggests errors in NOx emissions inventories and/or in the model chemical mechanisms. Likewise, the lack of oceanic acetaldehyde emissions and potential errors in the model acetaldehyde chemistry lead to additional underestimates in modeled HCHO of up to 75 pptv (~15%) in the lower troposphere. PMID- 29527426 TI - Spectral Characteristics of VLF Sferics Associated With RHESSI TGFs. AB - We compared the modeled energy spectral density of very low frequency (VLF) radio emissions from terrestrial gamma ray flashes (TGFs) with the energy spectral density of VLF radio sferics recorded by Duke VLF receiver simultaneously with those TGFs. In total, six events with world wide lightning location network (WWLLN) defined locations were analyzed to exhibit a good fit between the modeled and observed energy spectral densities. In VLF range the energy spectral density of the TGF source current moment is found to be dominated by the contribution of secondary low-energy electrons and independent of the relativistic electrons which play their role in low-frequency (LF) range. Additional spectral modulation by the multiplicity of TGF peaks was found and demonstrated a good fit for two TGFs whose VLF sferics consist of two overlapping pulses each. The number of seeding pulses in TGF defines the spectral shape in VLF range, which allows to retrieve this number from VLF sferics, assuming they were radiated by TGFs. For two events it was found that the number of seeding pulses is small, of the order of 10. For the rest of the events the lower boundary of the number of seeding pulses was found to be between 10 to 103. PMID- 29527427 TI - Using Long-Term Satellite Observations to Identify Sensitive Regimes and Active Regions of Aerosol Indirect Effects for Liquid Clouds Over Global Oceans. AB - Long-term (1981-2011) satellite climate data records of clouds and aerosols are used to investigate the aerosol-cloud interaction of marine water cloud from a climatology perspective. Our focus is on identifying the regimes and regions where the aerosol indirect effects (AIEs) are evident in long-term averages over the global oceans through analyzing the correlation features between aerosol loading and the key cloud variables including cloud droplet effective radius (CDER), cloud optical depth (COD), cloud water path (CWP), cloud top height (CTH), and cloud top temperature (CTT). An aerosol optical thickness (AOT) range of 0.13 < AOT < 0.3 is identified as the sensitive regime of the conventional first AIE where CDER is more susceptible to AOT than the other cloud variables. The first AIE that manifests as the change of long-term averaged CDER appears only in limited oceanic regions. The signature of aerosol invigoration of water clouds as revealed by the increase of cloud cover fraction (CCF) and CTH with increasing AOT at the middle/high latitudes of both hemispheres is identified for a pristine atmosphere (AOT < 0.08). Aerosol invigoration signature is also revealed by the concurrent increase of CDER, COD, and CWP with increasing AOT for a polluted marine atmosphere (AOT > 0.3) in the tropical convergence zones. The regions where the second AIE is likely to manifest in the CCF change are limited to several oceanic areas with high CCF of the warm water clouds near the western coasts of continents. The second AIE signature as represented by the reduction of the precipitation efficiency with increasing AOT is more likely to be observed in the AOT regime of 0.08 < AOT < 0.4. The corresponding AIE active regions manifested themselves as the decline of the precipitation efficiency are mainly limited to the oceanic areas downwind of continental aerosols. The sensitive regime of the conventional AIE identified in this observational study is likely associated with the transitional regime from the aerosol-limited regime to the updraft-limited regime identified for aerosol-cloud interaction in cloud model simulations. PMID- 29527428 TI - Ultralight super-hydrophobic carbon aerogels based on cellulose nanofibers/poly(vinyl alcohol)/graphene oxide (CNFs/PVA/GO) for highly effective oil-water separation. AB - With the worsening of the oil-product pollution problem, oil-water separation has attracted increased attention in recent years. In this study, a porous three dimensional (3D) carbon aerogel based on cellulose nanofibers (CNFs), poly(vinyl alcohol) (PVA) and graphene oxide (GO) was synthesized by a facile and green approach. The resulting CNF/PVA/GO aerogels were synthesized through an environmentally friendly freeze-drying process and then carbonized to yield CNF/PVA/GO carbon aerogels with low density (18.41 mg cm-3), high porosity (98.98%), a water contact angle of 156 degrees (super-hydrophobic) and high oil absorption capacity (97 times its own weight). The carbonization treatment of the CNF/PVA/GO aerogel not only improved the hydrophobic properties but also enhanced the adsorption capacity and specific surface area. Given the many good performance characteristics and the facile preparation process of carbon aerogels, these materials are viable candidates for use in oil-water separation and environmental protection. PMID- 29527429 TI - Revealing the interference effect of Majorana fermions in a topological Josephson junction. AB - We study theoretically the local density of states (DOS) in a topological Josephson junction. We show that the well-known 4pi Josephson effect originates from the interference effect between two Majorana fermions (MFs) that are localized at the Josephson junction. In addition, the DOS for electrons (holes) shows the 4pi interference information along each parity conserved energy spectrum. The DOS displays a 2pi period oscillation when two trivial states interfere with each other. This means that the DOS information may be used to distinguish the MFs from trivial localized states. We suggest that the interference effect and the DOS can be detected by using two STM leads or two normal leads. A single side lead can only detect the Andreev reflection tunneling process in the junction, which cannot reveal information about the interference effect in general. However, using two side leads, we can reveal information about the interference effect of the MFs as well as the DOS by combining Andreev reflection with the electron transmission process. PMID- 29527430 TI - Green synthesis of fluorescent carbon dots from spices for in vitro imaging and tumour cell growth inhibition. AB - Carbon dots have demonstrated great potential as luminescent nanoparticles in bioapplications. Although such nanoparticles appear to exhibit low toxicity compared to other metal luminescent nanomaterials, today we know that the toxicity of carbon dots (C-dots) strongly depends on the protocol of fabrication. In this work, aqueous fluorescent C-dots have been synthesized from cinnamon, red chilli, turmeric and black pepper, by a one-pot green hydrothermal method. The synthesized C-dots were firstly characterized by means of UV-vis, fluorescence, Fourier transform infrared and Raman spectroscopy, dynamic light scattering and transmission electron microscopy. The optical performance showed an outstanding ability for imaging purposes, with quantum yields up to 43.6%. Thus, the cytotoxicity of the above mentioned spice-derived C-dots was evaluated in vitro in human glioblastoma cells (LN-229 cancer cell line) and in human kidney cells (HK-2 non-cancerous cell line). Bioimaging and viability studies were performed with different C-dot concentrations from 0.1 to 2 mg.mL-1, exhibiting a higher uptake of C-dots in the cancer cultures compared to the non-cancerous cells. Results showed that the spice-derived C-dots inhibited cell viability dose dependently after a 24 h incubation period, displaying a higher toxicity in LN 229, than in HK-2 cells. As a control, C-dots synthesized from citric acid did not show any significant toxicity in either cancerous or non-cancerous cells, implying that the tumour cell growth inhibition properties observed in the spice derived C-dots can be attributed to the starting material employed for their fabrication. These results evidence that functional groups in the surface of the C-dots might be responsible for the selective cytotoxicity, as suggested by the presence of piperine in the surface of black pepper C-dots analysed by ESI-QTOF MS. PMID- 29527431 TI - Single-step process to improve the mechanical properties of carbon nanotube yarn. AB - Carbon nanotube (CNT) yarns exhibit low tensile strength compared to conventional high-performance carbon fibers due to the facile sliding of CNTs past one another. Electron beam (e-beam) irradiation was employed for in a single-step surface modification of CNTs to improve the mechanical properties of this material. To this end, CNT yarns were simultaneously functionalized and crosslinked using acrylic acid (AA) and acrylonitrile (AN) in an e-beam irradiation process. The chemical modification of CNT yarns was confirmed by X ray photoelectron spectroscopy (XPS), Raman spectroscopy and scanning electron microscopy (SEM). The best improvement in mechanical properties was achieved on a sample treated with an aqueous solution of AA and subsequent irradiation. CNT yarn treatment with AA enhanced the strength (444.5 +/- 68.4 MPa) by more than 75% and the modulus (21.5 +/- 0.6 GPa) by more than 144% as compared to untreated CNT yarn (strength 251 +/- 26.5 MPa and modulus 8.8 +/- 1.2 GPa). PMID- 29527432 TI - Electron interactions with the heteronuclear carbonyl precursor H2FeRu3(CO)13 and comparison with HFeCo3(CO)12: from fundamental gas phase and surface science studies to focused electron beam induced deposition. AB - In the current contribution we present a comprehensive study on the heteronuclear carbonyl complex H2FeRu3(CO)13 covering its low energy electron induced fragmentation in the gas phase through dissociative electron attachment (DEA) and dissociative ionization (DI), its decomposition when adsorbed on a surface under controlled ultrahigh vacuum (UHV) conditions and exposed to irradiation with 500 eV electrons, and its performance in focused electron beam induced deposition (FEBID) at room temperature under HV conditions. The performance of this precursor in FEBID is poor, resulting in maximum metal content of 26 atom % under optimized conditions. Furthermore, the Ru/Fe ratio in the FEBID deposit (~3.5) is higher than the 3:1 ratio predicted. This is somewhat surprising as in recent FEBID studies on a structurally similar bimetallic precursor, HFeCo3(CO)12, metal contents of about 80 atom % is achievable on a routine basis and the deposits are found to maintain the initial Co/Fe ratio. Low temperature (~213 K) surface science studies on thin films of H2FeRu3(CO)13 demonstrate that electron stimulated decomposition leads to significant CO desorption (average of 8-9 CO groups per molecule) to form partially decarbonylated intermediates. However, once formed these intermediates are largely unaffected by either further electron irradiation or annealing to room temperature, with a predicted metal content similar to what is observed in FEBID. Furthermore, gas phase experiments indicate formation of Fe(CO)4 from H2FeRu3(CO)13 upon low energy electron interaction. This fragment could desorb at room temperature under high vacuum conditions, which may explain the slight increase in the Ru/Fe ratio of deposits in FEBID. With the combination of gas phase experiments, surface science studies and actual FEBID experiments, we can offer new insights into the low energy electron induced decomposition of this precursor and how this is reflected in the relatively poor performance of H2FeRu3(CO)13 as compared to the structurally similar HFeCo3(CO)12. PMID- 29527433 TI - Fabrication and photoactivity of ionic liquid-TiO2 structures for efficient visible-light-induced photocatalytic decomposition of organic pollutants in aqueous phase. AB - To investigate the effect of the ionic liquid (IL) chain length on the surface properties and photoactivity of TiO2, a series of TiO2 microspheres have been synthesized via a solvothermal method assisted by 1-methyl-3-octadecylimidazolium chloride ([ODMIM][Cl]) and 1-methyl-3-tetradecylimidazolium chloride ([TDMIM][Cl]). All as-prepared samples were characterized by X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), diffuse reflectance spectroscopy (DRS), scanning transmission microscopy (STEM) and the Brunauer Emmett-Teller (BET) surface area method, whereas the photocatalytic activity was evaluated by the degradation of phenol in aqueous solution under visible light irradiation (lambda > 420 nm). The highest photoefficiency (four times higher than pristine TiO2) was observed for the TiO2 sample obtained in the presence of [TDMIM][Cl] for a IL to TiO2 precursor molar ratio of 1:3. It was revealed that interactions between the ions of the ionic liquid and the surface of the growing titanium dioxide spheres results in a red-shift of absorption edge for the IL TiO2 semiconductors. In this regard, the direct increase of the photoactivity of IL-TiO2 in comparison to pristine TiO2 was observed. The active species trapping experiments indicated that O2*- is the main active species, created at the surface of the IL-TiO2 material under visible-light illumination, and is responsible for the effective phenol degradation. PMID- 29527434 TI - Anchoring Fe3O4 nanoparticles in a reduced graphene oxide aerogel matrix via polydopamine coating. AB - Reduced graphene oxide-magnetite hybrid aerogels attract great interest thanks to their potential applications, e.g., as magnetic actuators. However, the tendency of magnetite particles to migrate within the matrix and, ultimately, escape from the aerogel structure, remains a technological challenge. In this article we show that coating magnetite particles with polydopamine anchors them on graphene oxide defects, immobilizing the particles in the matrix and, at the same time, improving the aerogel structure. Polydopamine coating does not affect the magnetic properties of magnetite particles, making the fabricated materials promising for industrial applications. PMID- 29527435 TI - Towards 3D crystal orientation reconstruction using automated crystal orientation mapping transmission electron microscopy (ACOM-TEM). AB - To relate the internal structure of a volume (crystallite and phase boundaries) to properties (electrical, magnetic, mechanical, thermal), a full 3D reconstruction in combination with in situ testing is desirable. In situ testing allows the crystallographic changes in a material to be followed by tracking and comparing the individual crystals and phases. Standard transmission electron microscopy (TEM) delivers a projection image through the 3D volume of an electron transparent TEM sample lamella. Only with the help of a dedicated TEM tomography sample holder is an accurate 3D reconstruction of the TEM lamella currently possible. 2D crystal orientation mapping has become a standard method for crystal orientation and phase determination while 3D crystal orientation mapping have been reported only a few times. The combination of in situ testing with 3D crystal orientation mapping remains a challenge in terms of stability and accuracy. Here, we outline a method to 3D reconstruct the crystal orientation from a superimposed diffraction pattern of overlapping crystals without sample tilt. Avoiding the typically required tilt series for 3D reconstruction enables not only faster in situ tests but also opens the possibility for more stable and more accurate in situ mechanical testing. The approach laid out here should serve as an inspiration for further research and does not make a claim to be complete. PMID- 29527436 TI - Sensing behavior of flower-shaped MoS2 nanoflakes: case study with methanol and xylene. AB - Recent research interest in two-dimensional (2D) materials has led to an emerging new group of materials known as transition metal dichalcogenides (TMDs), which have significant electrical, optical, and transport properties. MoS2 is one of the well-known 2D materials in this group, which is a semiconductor with controllable band gap based on its structure. The hydrothermal process is known as one of the scalable methods to synthesize MoS2 nanostructures. In this study, the gas sensing properties of flower-shaped MoS2 nanoflakes, which were prepared from molybdenum trioxide (MoO3) by a facile hydrothermal method, have been studied. Material characterization was performed using X-ray diffraction, Brunauer-Emmett-Teller surface area measurements, elemental analysis using energy dispersive X-ray spectroscopy, and field-emission scanning electron microscopy. The gas sensing characteristics were evaluated under exposure to various concentrations of xylene and methanol vapors. The results reveal higher sensitivity and shorter response times for methanol at temperatures below 200 degrees C toward 200 to 400 ppm gas concentrations. The sensing mechanisms for both gases are discussed based on simulation results using density functional theory and charge transfer. PMID- 29527437 TI - Facile phase transfer of gold nanorods and nanospheres stabilized with block copolymers. AB - A fast route to transfer Au nanoparticles from aqueous to organic media is proposed based on the use of a high molecular mass diblock copolymer of styrene and 2-vinylpyridine for ligand exchange at the nanoparticle surface. The method enables the preparation of stable sols of Au nanorods with sizes of up to tens of nanometers or Au nanospheres in various organic solvents. By comparing the optical absorbance spectra of Au hydro- and organosols with the data of numerical simulations of the surface plasmon resonance, we find that nanoparticles do not aggregate and confirm the transmission electron microscopy data regarding their shape and size. The proposed approach can be effective in preparing hybrid composites without the use of strong thiol and amine surfactants. PMID- 29527439 TI - Optimisation of purification techniques for the preparation of large-volume aqueous solar nanoparticle inks for organic photovoltaics. AB - In this study we have optimised the preparation conditions for large-volume nanoparticle inks, based on poly(3-hexylthiophene) (P3HT):indene-C60 multiadducts (ICxA), through two purification processes: centrifugal and crossflow ultrafiltration. The impact of purification is twofold: firstly, removal of excess sodium dodecyl sulfate (SDS) surfactant from the ink and, secondly, concentration of the photoactive components in the ink. The removal of SDS was studied in detail both by a UV-vis spectroscopy-based method and by surface tension measurements of the nanoparticle ink filtrate; revealing that centrifugal ultrafiltration removed SDS at a higher rate than crossflow ultrafiltration even though a similar filter was applied in both cases (10,000 Da Mw cut-off). The influence of SDS concentration on the aqueous solar nanoparticle (ASNP) inks was investigated by monitoring the surface morphology/topography of the ASNP films using atomic force microscopy (AFM) and scanning electron microscopy (SEM) and photovoltaic device performance as a function of ultrafiltration (decreasing SDS content). The surface morphology/topography showed, as expected, a decreased number of SDS crystallites on the surface of the ASNP film with increased ultrafiltration steps. The device performance revealed distinct peaks in efficiency with ultrafiltration: centrifuge purified inks reached a maximum efficiency at a dilution factor of 7.8 * 104, while crossflow purified inks did not reach a maximum efficiency until a dilution factor of 6.1 * 109. This difference was ascribed to the different wetting properties of the prepared inks and was further corroborated by surface tension measurements of the ASNP inks which revealed that the peak efficiencies for both methods occurred for similar surface tension values of 48.1 and 48.8 mN m-1. This work demonstrates that addressing the surface tension of large-volume ASNP inks is key to the reproducible fabrication of nanoparticle photovoltaic devices. PMID- 29527438 TI - Mechanistic insights into plasmonic photocatalysts in utilizing visible light. AB - The utilisation of sunlight as an abundant and renewable resource has motivated the development of sustainable photocatalysts that can collectively harvest visible light. However, the bottleneck in utilising the low energy photons has led to the discovery of plasmonic photocatalysts. The presence of noble metal on the plasmonic photocatalyst enables the harvesting of visible light through the unique characteristic features of the noble metal nanomaterials. Moreover, the formation of interfaces between noble metal particles and semiconductor materials further results in the formation of a Schottky junction. Thereby, the plasmonic characteristics have opened up a new direction in promoting an alternative path that can be of value to the society through sustainable development derived through energy available for all for diverse applications. We have comprehensively prepared this review to specifically focus on fundamental insights into plasmonic photocatalysts, various synthesis routes, together with their strengths and weaknesses, and the interaction of the plasmonic photocatalyst with pollutants as well as the role of active radical generation and identification. The review ends with a pinnacle insight into future perspectives regarding realistic applications of plasmonic photocatalysts. PMID- 29527440 TI - Tuning adhesion forces between functionalized gold colloidal nanoparticles and silicon AFM tips: role of ligands and capillary forces. AB - Adhesion forces between functionalized gold colloidal nanoparticles (Au NPs) and scanning probe microscope silicon tips were experimentally investigated by atomic force microscopy (AFM) equipped with PeakForce QNM (Quantitative Nanoscale Mechanics) module. Au NPs were synthesized by a seed-mediated process and then functionalized with thiols containing different functional groups: amino, hydroxy, methoxy, carboxy, methyl, and thiol. Adhesion measurements showed strong differences between NPs and silicon tip depending on the nature of the tail functional group. The dependence of the adhesion on ligand density for different thiols with identical functional tail-group was also demonstrated. The calculated contribution of the van der Waals (vdW) forces between particles was in good agreement with experimentally measured adhesive values. In addition, the adhesion forces were evaluated between flat Au films functionalized with the same molecular components and silicon tips to exclude the effect of particle shape on the adhesion values. Although adhesion values on flat substrates were higher than on their nanoparticle counterparts, the dependance on functional groups remained the same. PMID- 29527441 TI - Perovskite-structured CaTiO3 coupled with g-C3N4 as a heterojunction photocatalyst for organic pollutant degradation. AB - A novel graphitic carbon nitride (g-C3N4)-CaTiO3 (CTCN) organic-inorganic heterojunction photocatalyst was synthesized by a facile mixing method, resulting in the deposition of CaTiO3 (CT) nanoflakes onto the surface of g-C3N4 nanosheets. The photocatalytic activity of the as-synthesized heterojunction (along with the controls) was evaluated by studying the degradation of an aqueous solution of rhodamine B (RhB) under UV, visible and natural sunlight irradiation. The CTCN heterojunction with 1:1 ratio of g-C3N4/CT showed the highest photocatalytic activity under sunlight irradiation and was also demonstrated to be effective for the degradation of a colorless, non-photosensitizing pollutant, bisphenol A (BPA). The superior photocatalytic performance of the CTCN heterojunction could be attributed to the appropriate band positions, close interfacial contact between the constituents and extended light absorption (both UV and visible region), all of which greatly facilitate the transfer of photogenerated charges across the heterojunction and inhibit their fast recombination. In addition, the two-dimensional (2D) morphology of g C3N4nanosheets and CT nanoflakes provides enough reaction sites due to their larger surface area and enhances the overall photocatalytic activity. Furthermore, the active species trapping experiments validate the major role played by superoxide radicals (O2-*) in the degradation of pollutants. Based on scavenger studies and theoretically calculated band positions, a plausible mechanism for the photocatalytic degradation of pollutants has been proposed and discussed. PMID- 29527442 TI - Combined pulsed laser deposition and non-contact atomic force microscopy system for studies of insulator metal oxide thin films. AB - We have designed and developed a combined system of pulsed laser deposition (PLD) and non-contact atomic force microscopy (NC-AFM) for observations of insulator metal oxide surfaces. With this system, the long-period iterations of sputtering and annealing used in conventional methods for preparing a metal oxide film surface are not required. The performance of the combined system is demonstrated for the preparation and high-resolution NC-AFM imaging of atomically flat thin films of anatase TiO2(001) and LaAlO3(100). PMID- 29527443 TI - Cyclodextrin-assisted synthesis of tailored mesoporous silica nanoparticles. AB - Mesoporous silica nanoparticles (MSNs) have sparked considerable interest in drug/gene delivery, catalysis, adsorption, separation, sensing, antireflection coatings and bioimaging because of their tunable structural properties. The shape, size and pore structure of MSNs are greatly influenced by the type of additives used, e.g., solvent and pore-templating agent. Here, we studied the influence of cyclodextrin (CD) molecules on the formation of MSNs. The nanoparticles over 100 nm in diameter were synthesized by surfactant-templated, hydrolysis-polycondensation reactions in the presence of pristine CD (beta-CD) or hydroxypropyl-functionalized CDs (HP-gamma-CD and HP-beta-CD). Depending on the formulation conditions, differently shaped MSNs, such as bean-like, spherical, ellipsoid, aggregate and faceted were generated. The morphology and size of MSNs varied with the CD-type used. Generally, spherical particles were obtained with beta-CD, while a faceted morphology was observed for the particles synthesized using HP-CDs. The particle size could be tuned by adjusting the amount of CD used; increasing the CD concentration led to larger particles. MSNs synthesized in the presence of beta-CD displayed a smaller particle size than those produced with HP-functional CDs. FTIR, TGA and solid-state 13C NMR demonstrated the adsorption of CDs on the particle surfaces. The proposed concept allows for the synthesis of silica nanoparticles with control over particle shape and size by adjusting the concentration of additives in a simple, one-pot reaction system for a wide range of applications. PMID- 29527444 TI - The effect of atmospheric doping on pressure-dependent Raman scattering in supported graphene. AB - Atmospheric doping of supported graphene was investigated by Raman scattering under different pressures. Various Raman spectra parameters were found to depend on the pressure and the substrate material. The results are interpreted in terms of atmospheric adsorption leading to a change in graphene charge carrier density and the effect of the substrate on the electronic and phonon properties of graphene. It was found that adsorption of molecules from the atmosphere onto graphene doped with nitrogen (electron doping) compensates for the electron charge. Furthermore, the atmosphere-induced doping drastically decreases the spatial heterogeneity of charge carriers in graphene doped with nitrogen, while the opposite effect was observed for undoped samples. The results of this study should be taken into account for the development of sensors and nanoelectronic devices based on graphene. PMID- 29527445 TI - Dynamics and fragmentation mechanism of (C5H4CH3)Pt(CH3)3 on SiO2 surfaces. AB - The interaction of trimethyl(methylcyclopentadienyl)platinum(IV) ((C5H4CH3)Pt(CH3)3) molecules on fully and partially hydroxylated SiO2 surfaces, as well as the dynamics of this interaction were investigated using density functional theory (DFT) and finite temperature DFT-based molecular dynamics simulations. Fully and partially hydroxylated surfaces represent substrates before and after electron beam treatment and this study examines the role of electron beam pretreatment on the substrates in the initial stages of precursor dissociation and formation of Pt deposits. Our simulations show that on fully hydroxylated surfaces or untreated surfaces, the precursor molecules remain inactivated while we observe fragmentation of (C5H4CH3)Pt(CH3)3 on partially hydroxylated surfaces. The behavior of precursor molecules on the partially hydroxylated surfaces has been found to depend on the initial orientation of the molecule and the distribution of surface active sites. Based on the observations from the simulations and available experiments, we discuss possible dissociation channels of the precursor. PMID- 29527446 TI - Short-chain perfluoroalkyl acids: environmental concerns and a regulatory strategy under REACH. AB - Background: Short-chain PFASs (per- and polyfluoroalkyl substances) are widely used as alternatives to long-chain PFASs. Long-chain PFASs become gradually regulated under REACH (EC No. 1907/2006) and other international regulations, due to having persistent, bioaccumulative and toxic properties and/or being toxic for reproduction. The increasingly used short-chain PFASs are assumed to have a lower bioaccumulation potential. Nonetheless, they have other properties of concern and are already widely distributed in the environment, also in remote regions. The REACH Regulation does not directly address these emerging properties of concern, complicating the implementation of regulatory measures. Therefore, this study illustrates these environmental concerns and provides a strategy for a regulation of short-chain PFASs within REACH. Results: Short-chain PFASs have a high mobility in soil and water, and final degradation products are extremely persistent. This results in a fast distribution to water resources, and consequently, also to a contamination of drinking water resources. Once emitted, short-chain PFASs remain in the environment. A lack of appropriate water treatment technologies results in everlasting background concentrations in the environment, and thus, organisms are permanently and poorly reversibly exposed. Considering such permanent exposure, it is very difficult to estimate long-term adverse effects in organisms. Short-chain PFASs enrich in edible parts of plants and the accumulation in food chains is unknown. Regarding these concerns and uncertainties, especially with respect to the precautionary principle, short chain PFASs are of equivalent concern to PBT substances. Therefore, they should be identified as substances of very high concern (SVHC) under REACH. The SVHC identification should be followed by a restriction under REACH, which is the most efficient way to minimize the environmental and human exposure of short-chain PFASs in the European Union. Conclusion: Due to an increasing use of short-chain PFASs, an effective regulation is urgently needed. The concerns of short-chain PFASs do not match the "classical" concerns as defined under REACH, but are not of minor concern. Therefore, it is of advantage to clearly define the concerns of short-chain PFASs. This might facilitate the following restriction process under REACH. PMID- 29527447 TI - A new regulator of cellulase and xylanase in the thermophilic fungus Myceliophthora thermophila strain ATCC 42464. AB - Myceliophthora thermophila (ATCC 42464) is a thermophilic fungus that produces cellulolytic enzymes with high thermal stability. Unlike its mesophile counterparts, study on gene expression regulation of cellulolytic enzymes in M. thermophila is inadequate. This work identified the function of MHR1, a putative transcription regulator of cellulolytic enzymes in M. thermophila that was found through RNA-Seq based gene expression profile analysis. RNA interference was used to study the role of MHR1. A recombinant plasmid, pUC19-Ppdc-mhr1-Tpdc, which contained the RNAi sequence for mhr1 was constructed and transformed into M. thermophila. One of the transformants, MtR5, in which the RNA interference efficiency was the highest, was used for the following studies. In the mhr1 silenced strain MtR5, the filter paper hydrolyzing activity was 1.33-fold; beta 1, 4-endoglucanase activity was 1.65-fold; and xylanase activity was 1.48-fold higher than those of the parental strain after induction, respectively, by wheat straw powder. qRT-PCR showed that gene expression of cbh1, cbh2, egl3 and xyr1 were 9.56-, 37.36-, 56.14- and 28.30-fold higher in MtR5 than in wild type, respectively. Our findings suggest that the transcription factor MHR1 of M. thermophila can repress cellulase and xylanase activities. Silenced mhr1 results in increased expression not only of the main cellulase genes, but also of the positive regulatory gene xyr1. This work is relevant to the development of M. thermophila as an industrial production host for cellulolytic and hemicellulolytic enzymes, which could be used to degrade a wide range of different biomass, converting lignocellulosic feedstock into sugar precursors for biofuels. PMID- 29527448 TI - Molecular identification of Saraca asoca from its substituents and adulterants. AB - Abstract: Saraca asoca (Roxb.) De Wilde is an important medicinal plant from the Western Ghats of India, traditionally used in treatment of various gynecological disorders. Increasing commercial demand and decreasing numbers has resulted in this plant becoming endangered with crude drug materials being extensively substituted/adulterated with other plant species. The present study was undertaken with the objective of development and evaluation of multivariate cluster analysis of ISSR fingerprints against rbcL-based DNA barcodes as tool to understand the relationships and to differentiate common adulterants and substituents from S. asoca. ISSR-based Hierarchical Cluster Analysis was carried out on 41 samples of S. asoca and 5 each of the 5 common substituent/adulterant plants and the clustering patterns were evaluated against DNA-sequence-based barcoding of rbcL region of their plastids. Factorial analysis and Principal Coordinate Analysis revealed distinct groups of genetic pools of respective taxa thereby confirming the utility of ISSR fingerprinting as a useful tool for differentiation between the genuine and the adulterants/substituents. NCBI-BLAST search on DNA barcode rbcL region confirmed the results of ISSR assays. Therefore, our study demonstrated the utility of simple, cost-effective method of ISSR fingerprinting coupled with rbcL barcoding in differentiating this important medicinal plant from its common adulterants/substituents. Graphical Abstract: PMID- 29527449 TI - Mathematical modeling of fed-batch fermentation of Schizochytrium sp. FJU-512 growth and DHA production using a shift control strategy. AB - To obtain high-cell-density cultures of Schizochytrium sp. FJU-512 for DHA production, two stages of fermentation strategy were used and carbon/nitrogen ratio, DO and temperature were controlled at different levels. The final dry cell weight, total lipid production and DHA yield in 15 l bioreactor reached 103.9, 37.2 and 16.0 g/l, respectively. For the further study of microbial growth and DHA production dynamics, we established a set of kinetic models for the fed-batch production of DHA by Schizochytrium sp. FJU-512 in 15 and 100 l fermenters and a compensatory parameter n was integrated into the model in order to find the optimal mathematical equations. A modified Logistic model was proposed to fit the cell growth data and the following kinetic parameters were obtained: um = 0.0525/h, Xm = 100 g/l and n = 4.1717 for the 15 l bioreactor, as well as um = 0.0382/h, Xm = 107.4371 g/l and n = 10 for the 100 l bioreactor. The Luedeking Piret equations were utilized to model DHA production, yielding values of alpha = 0.0648 g/g and beta = 0.0014 g/g/h for the 15 l bioreactor, while the values of alpha and beta obtained for the 100 l fermentation were 0.0209 g/g and 0.0030 g/g/h. The predicted results compared with experimental data showed that the established models had a good fitting precision and were able to exactly depict the dynamic features of the DHA production process. PMID- 29527450 TI - Identification and characterization of finger millet OPAQUE2 transcription factor gene under different nitrogen inputs for understanding their role during accumulation of prolamin seed storage protein. AB - In this study, we report the isolation and characterization of the mRNA encoding OPAQUE2 (O2) like TF of finger millet (FM) (Eleusine coracana) (EcO2). Full length EcO2 mRNA was isolated using conserved primers designed by aligning O2 mRNAs of different cereals followed by 3' and 5' RACE (Rapid Amplification of cDNA Ends). The assembled full-length EcO2 mRNA was found to contain an ORF of 1248-nt coding the 416 amino acids O2 protein. Domain analysis revealed the presence of the BLZ and bZIP-C domains which is a characteristic feature of O2 proteins. Phylogenetic analysis of EcO2 protein with other bZIP proteins identified using finger millet transcriptome data and O2 proteins of other cereals showed that EcO2 shared high sequence similarity with barley BLZ1 protein. Transcripts of EcO2 were detected in root, stem, leaves, and seed development stages. Furthermore, to investigate nitrogen responsiveness and the role of EcO2 in regulating seed storage protein gene expression, the expression profiles of EcO2 along with an alpha-prolamin gene were studied during the seed development stages of two FM genotypes (GE-3885 and GE-1437) differing in grain protein content (13.8 and 6.2%, respectively) grown under increasing nitrogen inputs. Compared to GE-1437, the EcO2 was relatively highly expressed during the S2 stage of seed development which further increased as nitrogen input was increased. The Ecalpha-prolamin gene was strongly induced in the high protein genotype (GE-3885) at all nitrogen inputs. These results indicate the presence of nitrogen responsiveness regulatory elements which might play an important role in accumulating protein in FM genotypes through modulating EcO2 expression by sensing plant nitrogen status. PMID- 29527451 TI - Prospecting Ammoniphilus sp. JF isolated from agricultural fields for butachlor degradation. AB - Butachlor is a chloroacetamide herbicide used worldwide for controlling weeds in plants of rice, corn, soybean and other crops. In this study, indigenous bacterial species Ammoniphilus sp. JF was isolated from the agricultural fields of Punjab and identified using 16S ribosomal RNA analysis. The bacteria utilized butachlor as the sole carbon source and showed complete degradation (100 mg/L) within 24 h of incubation. Two intermediate products, namely 1,2 benzenedicarboxylic acid, bis(2-methylpropyl) ester and 2,4-bis(1,1 dimethylethyl)-phenol were observed at the end of butachlor degradation. To the best of author's knowledge, biodegradation of butachlor by indigenous Ammoniphilus sp. JF from the agricultural fields of Punjab has not been reported so far. PMID- 29527452 TI - Optimization of the fermentation conditions for the mutant strain of beta cyclodextrin glycosyltransferase H167C to produce cyclodextrins. AB - The cyclodextrin glycosyltransferase (CGTase) was used to catalyze the conversion of starch into cyclodextrins (CD) in industry. Improving the activity of CGTase to produce more CD with relative low cost is intensely interesting and has drawn wide attention. Amino acid mutation of His167 into Cys significantly enhanced beta-CGTase activity; however, optimization of culture conditions for beta-CGTase H167C remains unclear. To determine this, the medium and culture conditions for beta-CGTase-H167C were optimized with response surface methodology. Maximum activity of beta-CGTase-H167C was obtained with the medium containing 1.1% corn starch, 4.4% corn steep liquor, 1.1% peptone, 0.02% MgSO4.7H2O and 0.1% K2HPO4.3H2O that were cultured with the initial pH 8.4, incubation temperature at 37.4 degrees C, with 5% inoculation size and shaking speed at 202 r/min. Under the optimal conditions, the activity of beta-CGTase-H167C was up to 4355 U/mL, which is 1.93-fold in comparison with the initial activity. Our results established the promising culture strategy for the production of cyclodextrins by beta-CGTase-H167C. PMID- 29527453 TI - Enhanced enzymatic hydrolysis of corncob by ultrasound-assisted soaking in aqueous ammonia pretreatment. AB - Ultrasound-assisted soaking in aqueous ammonia (USAA) pretreatment with 15 wt% aqueous ammonia under low temperature (~ 60 degrees C) and short-time (< 12 min) low-frequency (20 kHz, 60-650 W) ultrasound has been investigated for enhancement of enzymatic hydrolysis of corncob. Operational parameters of energy density (2.93-17.07 W/mL) and sonication time (0.34-11.66 min) that affect cellulose recovery, delignification, and sugar recovery yield were studied and optimized. The maximum cellulose recovery, delignification and sugar recovery yield determined at the optimum conditions (energy density 10 W/mL, sonication time 11.66 min) were 83.8, 84.7, and 77.6%, respectively. The corncob pretreated using USAA has a lower hemicellulose content (28.9% vs 31.8%), a slightly lower crystallinity index value (42.7% vs 43.7%), and a larger surface cavity diameter (> 36 MUm vs < 20 MUm) than that pretreated using soaking in aqueous ammonia (SAA) pretreatment. The USAA pretreatment was proved to be a reliable and effective method for corncob pretreatment. PMID- 29527454 TI - In vitro and in silico characterization of a novel dextranase from Pochonia chlamydosporia. AB - The objective of this study was to purify, characterize, and phylogenetically and structurally analyze the dextranase produced by the fungus Pochonia chlamydosporia. Dextranase produced by the fungus P. chlamydosporia was purified to homogeneity in two steps, with a yield of 152%, purification factor of 6.84 and specific activity of 358.63 U/mg. Its molecular weight was estimated by SDS PAGE at 64 kDa. The enzyme presented higher activity at 50 degrees C and pH 5.0, using 100 mM citrate-phosphate buffer, was inhibited by Ag1+, Hg2+, Cu2+, Mg2+, and presented KM of 23.60 uM. Mature dextranase is composed of 585 amino acids residues, with a predicted molecular weight of 64.38 kDa and pI 5.96. This dextranase showed a strong phylogenetic similarity when compared to Trichoderma harzianum dextranase. Its structure consists of two domains: the first composed by 15 beta strands, and the second composed by a right-handed parallel beta helix. PMID- 29527455 TI - Full-length genome sequence of Cyrtanthus elatus virus-A isolated from Narcissus tazetta in India. AB - Narcissus tazetta L. is a bulbous ornamental plant popular for its notable fragrant flowers which make it the plant of high importance. In spite of its economic value, narcissus is found to be susceptible for a number of diseases borne by fungi, bacteria, nematodes, and viruses. A potyvirus, Cyrtanthus elatus virus-A isolate NBRI16 (CEVA-NBRI16), associated with leaf chlorotic stripe disease of N. tazetta cv. Paperwhite was reported for first time in India from our laboratory based on the partial coat protein gene sequence. In present study, the full-length genomic sequence of CEVA-NBRI16 is determined which consists of 9942 nucleotides, excluding the polyA tail, and encodes a single large polyprotein of 3102 amino acids with the genomic features typical of a potyvirus. It shares highest 93% nucleotide sequence identity and closest phylogenetic relationship with sequences of CEVA-Marijiniup7-1 and CEVA-Marijiniup7-2, both reported from Australia on Cyrtanthus elatus host. The full-length genomic sequence of CEVA from narcissus plant is being reported for the first time from India. PMID- 29527456 TI - Optimization of hydrolysis conditions for the mannooligosaccharides copra meal hydrolysate production. AB - Copra meal is a good source of galactomannan and its mannooligosaccharides have prebiotic properties. However, limited data are available concerning the ideal requirements for mannan hydrolysis. Thus, optimum hydrolysis conditions for the production of oligosaccharides from copra meal hydrolysate were investigated using response surface methodology. Model validation provided good agreement between experimental results and predicted responses. Maximum oligosaccharide of 14.41 +/- 0.09 mg/ml (20 ml) was obtained at an enzyme concentration of 16.52 U/ml, substrate concentration 15% and reaction time 12 h. On a larger scale, this increased to 15.76 +/- 0.04 mg/ml (200 ml) and 16.89 mg/ml (2000 ml). Defatted copra meal hydrolysate promoted the growth of beneficial bacteria as lactobacilli and bifidobacteria, while inhibiting pathogens Salmonella serovar Enteritidis S003, Escherichia coli E010, Staphylococcus aureus TISTR 029 and Shigella dysenteriae DMST 1511. Higher yield of oligosaccharides under optimum conditions indicated the potential of this method for production of mannooligosaccharides from copra meal hydrolysate on an industrial scale. PMID- 29527457 TI - The Use of New Communications Technologies to Evaluate and Intervene in Substance Use Disorders. AB - The widespread availability of high speed, mobile cellular telephones and other advances in communication technology have the potential to change the way that interventions for substance use disorders (SUD) are delivered and how progress is monitored. This article reviews recent research on the use of new technology to monitor progress and deliver interventions for SUD. Several studies of telephone based interventions show positive effects, but sometimes only in certain subgroups. However, other studies produced negative results. Studies support the use of interactive voice response (IVR) and personal digital assistants (PDAs) to conduct assessments, but there is little data on whether IVR- or PDA-based interventions improve outcomes. Text messaging has received comparatively little research, but appears promising as a means to conduct assessments and deliver automated interventions. Finally, smartphone technology provides the widest range of features and interventions and the greatest flexibility, but few intervention studies that use them have been conducted. PMID- 29527459 TI - Integrating mindfulness training in school health education to promote healthy behaviors in adolescents: Feasibility and preliminary effects on exercise and dietary habits. AB - Whether mindfulness training (MT) could improve healthy behaviors is unknown. This study sought to determine feasibility and acceptability of integrating MT into school-based health education (primary outcomes) and to explore its possible effects on healthy behaviors (exploratory outcomes). Two high schools in Massachusetts (2014-2015) were randomized to health education plus MT (HE-MT) (one session/week for 8 weeks) or to health education plus attention control (HE AC). Dietary habits (24-h dietary recalls) and moderate-to-vigorous physical activity (MVPA/7-day recalls) were assessed at baseline, end of treatment (EOT), and 6 months thereafter. Quantile regression and linear mixed models were used, respectively, to estimate effects on MVPA and dietary outcomes adjusting for confounders. We recruited 53 9th graders (30 HEM, 23 HEAC; average age 14.5, 60% white, 59% female). Retention was 100% (EOT) and 96% (6 months); attendance was 96% (both conditions), with moderate-to-high satisfaction ratings. Among students with higher MVPA at baseline, MVPA was higher in HE-MT vs. HE-AC at both EOT (median difference = 81 min/week, p = 0.005) and at 6 months (p = 0.004). Among males, median MVPA was higher (median difference = 99 min/week) in HE-MT vs. HEAC at both EOT (p = 0.056) and at 6 months (p = 0.04). No differences were noted in dietary habits. In sum, integrating school-based MT into health education was feasible and acceptable and had promising effects on MVPA among male and more active adolescents. These findings suggest that MT may improve healthy behaviors in adolescents and deserve to be reproduced in larger, rigorous studies. PMID- 29527460 TI - Prevalence of food insecurity among food bank users in Germany and its association with population characteristics. AB - The prevalence of food insecurity (FI) among food bank users in many European countries is unknown. The study aims to examine FI prevalence and associated population characteristics among this particular group of disadvantaged people in Germany. Food insecurity status was assessed among 1033 adult food bank users with a mean age of 53 years (57% female, 43% male) in Germany in 2015 using the food insecurity experience scale (FIES). About half of the participants (55.8%) were single with no children and born in Germany. Over 37% had a self-reported BMI of 30 kg/m2 or above and 37.4% indicated to smoke. Over 70% of the food bank users can be described as food insecure. Of those, about 35% were considered mildly food insecure. Almost 30% were categorized as moderately food insecure while over 7% were categorized as severely food insecure. Significant associations with food insecurity were found for gender, age, subjective health status, smoking, duration of food bank use, school education and family type. Among this socially disadvantaged population, food insecurity is highly prevalent and public health efforts should be focusing on this vulnerable population taken into account the identified population and behavioral characteristics associated with food insecurity. PMID- 29527461 TI - Arguments for amending smoke-free legislation in U.S. states to restrict use of electronic nicotine delivery systems. AB - The uneven diffusion of local and state laws restricting the use of electronic nicotine delivery systems (ENDS) in the United States may be a function of inconclusive scientific evidence and lack of guidance from the federal government. The objective of this study was to assess whether the rationale for amending clean indoor air acts (CIAAs) is being conflated by issues that are not directly relevant to protecting the health of ENDS non-users. Online sources were used in identifying bills (n = 25) that were presented in U.S. state legislatures from January 2009 to December 2015. The bills were categorized into one of three groups: 1) bills amending comprehensive CIAAs (n = 11), 2) bills prohibiting use of ENDS in places frequented by youth (n = 5), and 3) remaining bills that varied between the two categories (n = 9). Arguments presented in committee hearings were coded as scientific, public health, economic, enforcement, freedom, or regulatory. Arguments pertaining to amendment of clean indoor air acts spanned several categories, many of which were not directly relevant to the aims of the legislation. This finding could assist lawmakers and expert witnesses in making arguments that yield greater success in amending legislation. Alternatively, inconclusive scientific data on the hazards of ENDS aerosols might encourage lawmakers to propose legislation that prohibits ENDS use in places frequented by youths. PMID- 29527462 TI - Vascular robustness: The missing parameter in cardiovascular risk prediction. AB - Undetected high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor scores is an acknowledged obstacle to CVD prevention. The vasculature's functional robustness against risk factor derailment may serve as a novel discriminator of mortality risk under similar risk factor loads. To test this assumption, we hypothesized that the expected inverse robustness-mortality association is verifiable as a significant trend along the age spectrum of risk factor-challenged cohorts. This is a retrospective cohort study of 372 adults (mean age 56.1 years, range 21-92; 45% female) with a variety of CV risk factors. An arterial model (VascAssist 2, iSYMED GmbH, Germany) was used to derive global parameters of arterial function from non invasively acquired pulse pressure waves. Participants were stratified by health status: apparently healthy (AH; n = 221); with hypertension and/or hypercholesterolemia (CC; n = 61); with history of CV event(s) (CVE; n = 90). Multivariate linear regression was used to derive a robustness score which was calibrated against the CVD mortality hazard rate of a sub-cohort of the LURIC study (n = 1369; mean age 59.1 years, range 20-75; 37% female). Robustness correlated linearly with calendar age in CC (F(1, 59) = 10.42; p < 0.01) and CVE (F(1, 88) = 40.34; p < 0.0001) but not in the AH strata, supporting the hypothesis of preferential elimination of less robust individuals along the aging trajectory under risk factor challenges. Vascular robustness may serve as a biomarker of vulnerability to CVD risk factor challenges, prognosticating otherwise undetectable elevated risk for premature CVD mortality. PMID- 29527458 TI - TRAF molecules in inflammation and inflammatory diseases. AB - Purpose of Review: This review presents an overview of the current knowledge of TRAF molecules in inflammation with an emphasis on available human evidence and direct in vivo evidence of mouse models that demonstrate the contribution of TRAF molecules in the pathogenesis of inflammatory diseases. Recent Findings: The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic proteins was initially identified as signaling adaptors that bind directly to the intracellular domains of receptors of the TNF-R superfamily. It is now appreciated that TRAF molecules are widely employed in signaling by a variety of adaptive and innate immune receptors as well as cytokine receptors. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-kappaBs (NF-kappaBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). Most of these signaling pathways have been linked to inflammation, and therefore TRAF molecules were expected to regulate inflammation and inflammatory responses since their discovery in 1990s. However, direct in vivo evidence of TRAFs in inflammation and especially in inflammatory diseases had been lacking for many years, partly due to the difficulty imposed by early lethality of TRAF2-/-, TRAF3-/-, and TRAF6-/- mice. With the creation of conditional knockout and lineage-specific transgenic mice of different TRAF molecules, our understanding about TRAFs in inflammation and inflammatory responses has rapidly advanced during the past decade. Summary: Increasing evidence indicates that TRAF molecules are versatile and indispensable regulators of inflammation and inflammatory responses and that aberrant expression or function of TRAFs contributes to the pathogenesis of inflammatory diseases. PMID- 29527463 TI - Validity of Walk Score(r) as a measure of neighborhood walkability in Japan. AB - Objective measures of environmental attributes have been used to understand how neighborhood environments relate to physical activity. However, this method relies on detailed spatial data, which are often not easily available. Walk Score(r) is a free, publicly available web-based tool that shows how walkable a given location is based on objectively-derived proximity to several types of local destinations and street connectivity. To date, several studies have tested the concurrent validity of Walk Score as a measure of neighborhood walkability in the USA and Canada. However, it is unknown whether Walk Score is a valid measure in other regions. The current study examined how Walk Score is correlated with objectively-derived attributes of neighborhood walkability, for residential addresses in Japan. Walk Scores were obtained for 1072 residential addresses in urban and rural areas in Japan. Five environmental attributes (residential density, intersection density, number of local destinations, sidewalk availability, and access to public transportation) were calculated using geographic information systems for each address. Pearson's correlation coefficients between Walk Score and these environmental attributes were calculated (conducted in May 2017). Significant positive correlations were observed between Walk Score and environmental attributes relevant to walking. Walk Score was most closely associated with intersection density (r = 0.82) and with the number of local destinations (r = 0.77). Walk Score appears to be a valid measure of neighborhood walkability in Japan. Walk Score will allow urban designers and public health practitioners to identify walkability of local areas without relying on detailed geographic data. PMID- 29527464 TI - Physical activity and annual medical outlay in U.S. colorectal, breast and prostate cancer survivors. AB - Multiple chronic conditions in cancer survivors are highly prevalent and may increase health care costs for both patients and the health care system. Studies of cancer survivors reveal positive effects of physical activity (PA) on reducing risk of cancer recurrence, other chronic conditions, and secondary cancer. Few nationally representative studies have examined how physical activity levels have affected survivors' annual economic burden in the United States. Leisure-time physical activity data from the National Health Interview Survey was linked to health care expenditure data from the Medical Expenditure Panel Survey data (2008 2012). We calculated per-person annual total medical expenditures for identified colorectal, breast, and prostate cancer survivors. We conducted multivariable analyses controlled for survival years and other sociodemographic variables. Generalized linear models were performed to measure correlation between medical expenditure and PA level using STATA 14. All analyses considered the complex survey design and were conducted in 2017. Of 1015 cancer survivors sampled, 30% (n = 305) adhered to physical activity recommendation, while the other 70% (n = 710) did not. Multivariable-adjusted expenditure in adherence group was $9108.8 (95% CI 7410.9-10,806.7) versus 12,899.1 (95% CI 11,450.2-14,348) in non adherence group. Stratified analyses revealed cancer survivors who adhered to their PA recommendation saved $4686.1 (1-5 years' survival time) and $2874.5 (11 or more years' survival time) on average for total health care expenditure, respectively. Analyses of the national representative sample revealed that the economic burden of survivors from the three most prevalent cancers is substantial. Increasing survivor's PA to guidelines may reduce U.S. health care expenditure. PMID- 29527465 TI - Assessment of trends in cervical cancer screening rates using healthcare claims data: United States, 2003-2014. AB - Improved understanding of the natural history of cervical cancer has led to changes in screening recommendations, including the addition of the human papillomavirus (HPV) testing as an option in routine screening. Most studies of screening trends have used national self-reported survey data. To better understand recent trends in cervical cancer screening, including cytology (Papanicolaou, or Pap, tests) and human papillomavirus co-tests (HPV + Pap test), we used healthcare claims data to examine screening practices and trends. We analyzed screening among commercially-insured females ages 18-65 during 2005-2014 who were continuously enrolled during three or more contiguous calendar years, to identify those who received cervical cancer screening with a Pap test or co-test. We examined screening prevalence by age group and year. During the latter years of our study period, screening prevalence (regardless of screening method) declined significantly for women in all age groups examined. Despite declines in overall screening, the prevalence of co-testing increased in all age groups except those aged 18-20. In 2014, women aged 30-39 had the highest overall screening uptake (77.5%) and the highest use of co-testing (44.4%); this group also had the lowest overall declines in screening over the time period (-4.5%). These screening measures from healthcare claims were lower than self-reported screening from national surveys of the general population. More research to explore the reasons for these differences is needed to ensure that women are receiving appropriate screening, and to better understand why screening prevalence is declining among this population of commercially insured women. PMID- 29527466 TI - Identifying quality improvement targets to facilitate colorectal cancer screening completion. AB - The colorectal cancer (CRC) screening process involves multiple interfaces (communication exchanges and transfers of responsibility for specific actions) among primary care and gastroenterology providers, laboratory, and administrative staff. After a retrospective electronic health record (EHR) analysis discovered substantial clinic variation and low CRC screening prevalence overall in an urban, integrated safety-net system, we launched a qualitative analysis to identify potential quality improvement targets to enhance fecal immunochemical test (FIT) completion, the system's preferred screening modality. Here, we report examination of organization-, clinic-, and provider-level interfaces over a three year period (December 2011-October 2014). We deployed in parallel 3 qualitative data collection methods: (1) structured observation (90+ hours, 10 sites); (2) document analysis (n > 100); and (3) semi-structured interviews (n = 41) and conducted iterative thematic analysis in which findings from each method cross informed subsequent data collection. Thematic analysis was guided by a conceptual model and applied deductive and inductive codes. There was substantial variation in protocols for distributing and returning FIT kits both within and across clinics. Providers, clinic and laboratory staff had differing access to important data about FIT results based on clinical information system used and this affected results reporting. Communication and coordination during electronic referrals for diagnostic colonoscopy was suboptimal particularly for co-morbid patients needing anesthesia clearance. Our multi-level approach elucidated organizational deficiencies not evident by quantitative analysis alone. Findings indicate potential quality improvement intervention targets including: (1) best practices implementation across clinics; (2) detailed communication to providers about FIT results; and (3) creation of EHR alerts to resolve pending colonoscopy referrals before they expire. PMID- 29527467 TI - Social integration and healthy aging among U.S. women. AB - Background: Social integration has been related to risk of chronic diseases and mental health conditions. Purpose: We investigated the association between social integration in midlife with subsequent health and well-being in aging. Methods: We included women from the Nurses' Health Study in the United States, who had no major chronic diseases in 1996 when we assessed social integration, using the Berkman-Syme Social Network Index. We defined healthy aging after 16 years of follow-up, when women ranged from 66 to 91 years, on the basis of survival along with 4 health criteria, assessed in 2012: no history of major chronic disease diagnosis, no self-reported impairment in memory, and no major impairments in physical function or mental health. Results: Of the 41,013 surviving participants in 2012 with information on social integration and health criteria, 6206 (15.1%) were healthy agers (i.e., met all four criteria) and the remaining 34,807 (84.9%) were usual agers. After multivariable adjustment, women who were socially integrated at midlife had modestly better odds (odds ratio = 1.38, 95% confidence interval: 1.23, 1.55) of healthy aging compared to women who were socially isolated. Conclusions: In this study, we found that women who were more socially integrated were more likely to be healthy agers. The results provide evidence for a longitudinal association between social integration and healthy aging. PMID- 29527468 TI - Primary care providers' discussion of fall prevention approaches with their older adult patients-DocStyles, 2014. AB - Falls are the leading cause of fatal and non-fatal injuries among older adults. The American and British Geriatric Societies recommend a fall risk assessment to identify risk factors and guide interventions to prevent these falls. This study describes the self-reported discussion of fall prevention approaches used by primary care providers (PCPs)-family practitioners, internists and nurse practitioners-who treat older adults. Results are described overall and by PCP type. We analyzed a sample of 1210 U.S. PCPs who participated in the 2014 DocStyles survey. PCPs reported on their recommendation of fall prevention approaches including general exercise, Tai Chi, medication adjustments, home safety modifications, vitamin D supplements, assistive devices, alarm systems, and referral to physical therapy, foot specialist, or vision specialist. Frequencies and adjusted odds ratios for fall prevention approaches were assessed by provider and practice characteristics. Self-reported discussion of any fall prevention approaches was 89.3%. Controlling for provider and practice characteristics, there were significant differences for some approaches by provider type. Family practitioners were more likely to suggest home modification [adjusted Odds Ratio: 1.8 (1.3-2.4)], exercise [aOR: 2.0 (1.5-2.5)], and Tai Chi [aOR: 1.5 (1.0-2.2)] than internists. Nurse practitioners were more likely to suggest home modification [aOR: 2.1 (1.3-3.4)] and less likely to suggest vitamin D [aOR: 0.6 (0.4-1.0)] than internists. Fall prevention suggestions vary by type of PCP. Dissemination of geriatric guidelines should include all PCPs who routinely see older adults. PMID- 29527469 TI - Neighborhood crime and access to health-enabling resources in Chicago. AB - Neighborhood crime may be an important social determinant of health in many high poverty, urban communities, yet little is known about its relationship with access to health-enabling resources. We recruited an address-based probability sample of 267 participants (ages >=35 years) on Chicago's South Side between 2012 and 2013. Participants were queried about their perceptions of neighborhood safety and prior experiences of neighborhood crime. Survey data were paired to a comprehensive, directly-observed census of the built environment on the South Side of Chicago. Multivariable logistic regression models were used to examine access to health-enabling resources (potential and realized access) as a function of neighborhood crime (self-reported neighborhood safety and prior experience of theft or property crime), adjusting for sociodemographic characteristics and self reported health status. Low potential access was defined as a resident having nearest resources >1 mile from home; poor realized access was defined as bypassing nearby potential resources to use resources >1 mile from home. Poor neighborhood safety was associated with low potential access to large grocery stores (AOR = 1.73, 95% CI = 1.04, 2.87), pharmacies (AOR = 2.24, 95% CI = 1.33, 3.77), and fitness resources (AOR = 1.93, 95% CI = 1.15, 3.24), but not small grocery stores. Any prior experience of neighborhood crime was associated with higher adjusted odds of bypassing nearby pharmacies (AOR = 3.78, 95% CI = 1.11, 12.87). Neighborhood crime may be associated with important barriers to accessing health-enabling resources in urban communities with high rates of crime. PMID- 29527470 TI - Automated diagnosis of temporal lobe epilepsy in the absence of interictal spikes. AB - Objective: To diagnose and lateralise temporal lobe epilepsy (TLE) by building a classification system that uses directed functional connectivity patterns estimated during EEG periods without visible pathological activity. Methods: Resting-state high-density EEG recording data from 20 left TLE patients, 20 right TLE patients and 35 healthy controls was used. Epochs without interictal spikes were selected. The cortical source activity was obtained for 82 regions of interest and whole-brain directed functional connectivity was estimated in the theta, alpha and beta frequency bands. These connectivity values were then used to build a classification system based on two two-class Random Forests classifiers: TLE vs healthy controls and left vs right TLE. Feature selection and classifier training were done in a leave-one-out procedure to compute the mean classification accuracy. Results: The diagnosis and lateralization classifiers achieved a high accuracy (90.7% and 90.0% respectively), sensitivity (95.0% and 90.0% respectively) and specificity (85.7% and 90.0% respectively). The most important features for diagnosis were the outflows from left and right medial temporal lobe, and for lateralization the right anterior cingulate cortex. The interaction between features was important to achieve correct classification. Significance: This is the first study to automatically diagnose and lateralise TLE based on EEG. The high accuracy achieved demonstrates the potential of directed functional connectivity estimated from EEG periods without visible pathological activity for helping in the diagnosis and lateralization of TLE. PMID- 29527471 TI - Task-free spectral EEG dynamics track and predict patient recovery from severe acquired brain injury. AB - For some patients, coma is followed by a state of unresponsiveness, while other patients develop signs of awareness. In practice, detecting signs of awareness may be hindered by possible impairments in the patient's motoric, sensory, or cognitive abilities, resulting in a substantial proportion of misdiagnosed disorders of consciousness. Task-free paradigms that are independent of the patient's sensorimotor and neurocognitive abilities may offer a solution to this challenge. A limitation of previous research is that the large majority of studies on the pathophysiological processes underlying disorders of consciousness have been conducted using cross-sectional designs. Here, we present a study in which we acquired a total of 74 longitudinal task-free EEG measurements from 16 patients (aged 6-22 years, 12 male) suffering from severe acquired brain injury, and an additional 16 age- and education-matched control participants. We examined changes in amplitude and connectivity metrics of oscillatory brain activity within patients across their recovery. Moreover, we applied multi-class linear discriminant analysis to assess the potential diagnostic and prognostic utility of amplitude and connectivity metrics at the individual-patient level. We found that over the course of their recovery, patients exhibited nonlinear frequency band-specific changes in spectral amplitude and connectivity metrics, changes that aligned well with the metrics' frequency band-specific diagnostic value. Strikingly, connectivity during a single task-free EEG measurement predicted the level of patient recovery approximately 3 months later with 75% accuracy. Our findings show that spectral amplitude and connectivity track patient recovery in a longitudinal fashion, and these metrics are robust pathophysiological markers that can be used for the automated diagnosis and prognosis of disorders of consciousness. These metrics can be acquired inexpensively at bedside, and are fully independent of the patient's neurocognitive abilities. Lastly, our findings tentatively suggest that the relative preservation of thalamo-cortico-thalamic interactions may predict the later reemergence of awareness, and could thus shed new light on the pathophysiological processes that underlie disorders of consciousness. PMID- 29527472 TI - ADHD and maturation of brain white matter: A DTI study in medication naive children and adults. AB - Several diffusion tensor imaging (DTI) studies in attention deficit hyperactivity disorder (ADHD) have shown a delay in brain white matter (WM) development. Because these studies were mainly conducted in children and adolescents, these WM abnormalities have been assumed, but not proven to progress into adulthood. To provide further insight in the natural history of WM maturation delay in ADHD, we here investigated the modulating effect of age on WM in children and adults. 120 stimulant-treatment naive male ADHD children (10-12 years of age) and adults (23 40 years of age) with ADHD (according to DSM-IV; all subtypes) were included, along with 23 age and gender matched controls. Fractional anisotropy (FA) values were compared throughout the WM by means of tract-based spatial statistics (TBSS) and in specific regions of interest (ROIs). On both TBSS and ROI analyses, we found that stimulant-treatment naive ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Significant age * group interactions for whole brain FA (p = 0.015), as well as the anterior thalamic radiation (p = 0.015) suggest that ADHD affects the brain WM age-dependently. In contrast to prior studies conducted in medicated ADHD children, we did not find WM alterations in stimulant treatment naive children, only treatment-naive adults. Thus, our findings suggest that the reported developmental delay in WM might appear after childhood, and that previously reported differences between ADHD children and normal developing peers could have been attributed to prior ADHD medications, and/or other factors that affect WM development, such as age and gender. PMID- 29527473 TI - Fibre-specific white matter changes in multiple sclerosis patients with optic neuritis. AB - Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross section, that can be estimated for each fibre direction in each voxel (termed a "fixel"). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 +/- 10.2 years, 11 females) and 14 healthy controls (32.7 +/- 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS. PMID- 29527474 TI - Linked functional network abnormalities during intrinsic and extrinsic activity in schizophrenia as revealed by a data-fusion approach. AB - Abnormalities in functional brain networks in schizophrenia have been studied by examining intrinsic and extrinsic brain activity under various experimental paradigms. However, the identified patterns of abnormal functional connectivity (FC) vary depending on the adopted paradigms. Thus, it is unclear whether and how these patterns are inter-related. In order to assess relationships between abnormal patterns of FC during intrinsic activity and those during extrinsic activity, we adopted a data-fusion approach and applied partial least square (PLS) analyses to FC datasets from 25 patients with chronic schizophrenia and 25 age- and sex-matched normal controls. For the input to the PLS analyses, we generated a pair of FC maps during the resting state (REST) and the auditory deviance response (ADR) from each participant using the common seed region in the left middle temporal gyrus, which is a focus of activity associated with auditory verbal hallucinations (AVHs). PLS correlation (PLS-C) analysis revealed that patients with schizophrenia have significantly lower loadings of a component containing positive FCs in default-mode network regions during REST and a component containing positive FCs in the auditory and attention-related networks during ADR. Specifically, loadings of the REST component were significantly correlated with the severities of positive symptoms and AVH in patients with schizophrenia. The co-occurrence of such altered FC patterns during REST and ADR was replicated using PLS regression, wherein FC patterns during REST are modeled to predict patterns during ADR. These findings provide an integrative understanding of altered FCs during intrinsic and extrinsic activity underlying core schizophrenia symptoms. PMID- 29527475 TI - An acute bout of aerobic or strength exercise specifically modifies circulating exerkine levels and neurocognitive functions in elderly individuals with mild cognitive impairment. AB - Although exercise is an effective way to decrease the risk of developing Alzheimer's disease, the biological basis for such benefits from the different exercise modes remains elusive. The present study thus aimed (i) to investigate the effects of acute aerobic or resistance exercise on neurocognitive performances and molecular markers when performing a cognitive task involving executive functioning in older adults with amnestic mild cognitive impairment (aMCI), and (ii) to explore relationships of acute exercise-induced neurocognitive changes with changes in circulating levels of neuroprotective growth factors (e.g., BDNF, IGF-1, VEGF, and FGF-2, collectively termed 'exerkines'), elicited by different acute exercise modes. Sixty-six older adults with aMCI were recruited and randomly assigned to an aerobic exercise (AE) group, a resistance exercise (RE) group, or a non-exercise-intervention (control) group. The behavioral [i.e., accuracy rate (AR) and reaction time (RT)] and electrophysiological [i.e., event-related potential (ERP) P3 latency and amplitude collected from the Fz, Cz, and Pz electrodes] indices were simultaneously measured when participants performed a Flanker task at baseline and after either an acute bout of 30 min of moderate-intensity AE, RE or a control period. Blood samples were taken at three time points, one at baseline (T1) and two after an acute exercise intervention (T2 and T3: before and after cognitive task test, respectively). The results showed that the acute AE and RE not only improved behavioral (i.e., RTs) performance but also increased the ERP P3 amplitudes in the older adults with aMCI. Serum FGF-2 levels did not change with acute aerobic or resistance exercise. However, an acute bout of aerobic exercise significantly increased serum levels of BDNF and IGF-1 and tended to increase serum levels of VEGF in elderly aMCI individuals. Acute resistance exercise increased only serum IGF-1 levels. However, the exercise-induced elevated levels of these molecular markers returned almost to baseline levels in T3 (about 20 min after acute exercise). In addition, changes in the levels of neurotrophic and angiogenic factors were not correlated with changes in RTs and P3 amplitudes. The present findings of changes in neuroprotective growth factors and neurocognitive performances through acute AE or RE suggest that molecular and neural prerequisites for exercise-dependent plasticity are preserved in elderly aMCI individuals. However, the distinct pattern of changes in circulating molecular biomarkers induced by two different exercise modes in aMCI elderly individuals and the potentially interactive mechanisms of the effects of BDNF, IGF-1, and VEGF on amyloid-beta provide a basis for future long-term exercise intervention to investigate whether AE relative to RE might be more effective in prevention/treatment of an early stage neurodegenerative disease. PMID- 29527476 TI - Connectome-wide investigation of altered resting-state functional connectivity in war veterans with and without posttraumatic stress disorder. AB - Altered resting-state functional connectivity in posttraumatic stress disorder (PTSD) suggests neuropathology of the disorder. While seed-based fMRI connectivity analysis is often used for the studies, such analysis requires defining a seed location a priori, which restricts search scope and could bias findings toward presupposed areas. Recently, a comprehensive exploratory voxel wise connectivity analysis, the connectome-wide association approach, has been introduced using multivariate distance matrix regression (MDMR) for resting-state functional connectivity analysis. The current study performed a connectome-wide investigation of resting-state functional connectivity for war veterans with and without PTSD compared to non-trauma-exposed healthy controls using MDMR. Thirty five male combat veterans with PTSD (unmedicated), 18 male combat veterans without PTSD (veterans control, VC), and 28 age-matched non-trauma-exposed healthy males (NC) participated in a resting-state fMRI scan. MDMR analysis was used to identify between-groups differences in regions with altered connectivity. The identified regions were used as a seed for post-hoc functional connectivity analysis. The analysis revealed that PTSD patients had hypoconnectivity between the left lateral prefrontal regions and the salience network regions as well as hypoconnectivity between the parahippocampal gyrus and the visual cortex areas. Connectivity between the ventromedial prefrontal cortex and the middle frontal gyrus and between the parahippocampal gyrus and the anterior insula were negatively correlated with PTSD symptom severity. VC subjects also had altered functional connectivity compared to NC, including increased connectivity between the posterior insula and several brain regions and decreased connectivity between the precuneus region and several other brain areas. The decreased connectivity between the lateral prefrontal regions and the salience network regions in PTSD was consistent with previous reports that indicated lowered emotion-regulation function in these regions. The decreased connectivity between the parahippocampal gyrus and visual cortex supported the dual representation theory of PTSD, which suggests dissociation between sensory and contextual memory representations in PTSD. The theory also supposes that the precuneus is a region that triggers retrieval of sensory memory of traumatic events. The decreased connectivity at the precuneus for VC might be associated with suppressing such a process. PMID- 29527477 TI - Removal of artifacts from resting-state fMRI data in stroke. AB - We examined the effect of lesion on the resting-state functional connectivity in chronic post-stroke patients. We found many instances of strong correlations in BOLD signal measured at different locations within the lesion, making it hard to distinguish from the connectivity between intact and strongly connected regions. Regression of the mean cerebro-spinal fluid signal did not alleviate this problem. The connectomes computed by exclusion of lesioned voxels were not good predictors of the behavioral measures. We came up with a novel method that utilizes Independent Component Analysis (as implemented in FSL MELODIC) to identify the sources of variance in the resting-state fMRI data that are driven by the lesion, and to remove this variance. The resulting functional connectomes show better correlations with the behavioral measures of speech and language, and improve the out-of-sample prediction accuracy of multivariate analysis. We therefore advocate this preprocessing method for studies of post-stroke functional connectivity, particularly in samples with large lesions. PMID- 29527478 TI - MRI features predict p53 status in lower-grade gliomas via a machine-learning approach. AB - Background: P53 mutation status is a pivotal biomarker for gliomas. Here, we developed a machine-learning model to predict p53 status in lower-grade gliomas based on radiomic features extracted from conventional magnetic resonance (MR) images. Methods: Preoperative MR images were retrospectively obtained from 272 patients with primary grade II/III gliomas. The patients were randomly allocated in a 2:1 ratio to a training (n = 180) or validation (n = 92) set. A total of 431 radiomic features were extracted from each patient. The lest absolute shrinkage and selection operator (LASSO) method was used for feature selection and radiomic signature construction. Subsequently, a machine-learning model to predict p53 status was established using the selected features and a Support Vector Machine classifier. The predictive performance of all individual features and the model was calculated using receiver operating characteristic curves in both the training and validation sets. Results: The p53-related radiomic signature was built using the LASSO algorithm; this procedure consisted of four first-order statistics or related wavelet features (including Maximum, Median, Minimum, and Uniformity), a shape and size-based feature (Spherical Disproportion), and ten textural features or related wavelet features (including Correlation, Run Percentage, and Sum Entropy). The prediction accuracies based on the area under the curve were 89.6% in the training set and 76.3% in the validation set, which were better than individual features. Conclusions: These results demonstrate that MR image texture features are predictive of p53 mutation status in lower-grade gliomas. Thus, our procedure can be conveniently used to facilitate presurgical molecular pathological diagnosis. PMID- 29527479 TI - Cross-sectional and longitudinal voxel-based grey matter asymmetries in Huntington's disease. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder that can be genetically confirmed with certainty decades before clinical onset. This allows the investigation of functional and structural changes in HD many years prior to disease onset, which may reveal important mechanistic insights into brain function, structure and organization in general. While regional atrophy is present at early stages of HD, it is still unclear if both hemispheres are equally affected by neurodegeneration and how the extent of asymmetry affects domain-specific functional decline. Here, we used whole-brain voxel-based analysis to investigate cross-sectional and longitudinal hemispheric asymmetries in grey matter (GM) volume in 56 manifest HD (mHD), 83 pre-manifest HD (preHD), and 80 healthy controls (HC). Furthermore, a regression analysis was used to assess the relationship between neuroanatomical asymmetries and decline in motor and cognitive measures across the disease spectrum. The cross-sectional analysis showed striatal leftward-biased GM atrophy in mHD, but not in preHD, relative to HC. Longitudinally, no net 36-month change in GM asymmetries was found in any of the groups. In the regression analysis, HD-related decline in quantitative-motor (Q-Motor) performance was linked to lower GM volume in the left superior parietal cortex. These findings suggest a stronger disease effect targeting the left hemisphere, especially in those with declining motor performance. This effect did not change over a period of three years and may indicate a compensatory role of the right hemisphere in line with recent functional imaging studies. PMID- 29527480 TI - Delineation of the visual pathway in paediatric optic pathway glioma patients using probabilistic tractography, and correlations with visual acuity. AB - Background: Radiological biomarkers which correlate with visual function are needed to improve the clinical management of optic pathway glioma (OPG) patients. Currently, these are not available using conventional magnetic resonance imaging (MRI) sequences. The aim of this study was to determine whether diffusion MRI could be used to delineate the entire optic pathway in OPG patients, and provide imaging biomarkers within this pathway which correlate with a patient's visual acuity (VA). Methods: Multi-shell diffusion MRI data were acquired in a cohort of paediatric OPG patients, along with VA measurements in each eye. Diffusion MRI data were processed using constrained spherical deconvolution and probabilistic fibre tractography, to delineate the white matter bundles forming the optic pathway in each patient. Median fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured in the optic nerves, tracts, and radiations, and correlated against each patient's VA. Results: In the optic nerves, median FA significantly correlated with VA (R2adj = 0.31, p = 0.0082), with lower FA associated with poorer vision. In the optic radiations, both lower FA and higher ADC were significantly associated with poorer vision (R2adj = 0.52, p = 0.00075 and R2adj = 0.50, p = 0.0012 respectively). No significant correlations between VA and either FA or ADC were found in the optic tracts. Conclusions: Multi-shell diffusion MRI provides in vivo delineation of the optic pathway in OPG patients, despite the presence of tumour invasion. This technique provides imaging biomarkers which are sensitive to microstructural damage to the underlying white matter in this pathway, which is not always visible on conventional MRI. PMID- 29527481 TI - Behavioral and EEG responses to social evaluation: A two-generation family study on social anxiety. AB - Social anxiety disorder is an invalidating psychiatric disorder characterized by extreme fear and avoidance of one or more social situations in which patients might experience scrutiny by others. The goal of this two-generation family study was to delineate behavioral and electrocortical endophenotypes of social anxiety disorder related to social evaluation. Nine families of patients with social anxiety disorder (their spouse and children, and siblings of these patients with spouse and children) performed a social judgment paradigm in which they believed to be evaluated by peers. For each peer, participants indicated their expectation about the evaluative outcome, after which they received social acceptance or rejection feedback. Task behavior, as well as the feedback-related EEG brain potentials (N1, FRN, P3) and theta power were tested as candidate endophenotypes based on two criteria: co-segregation with social anxiety disorder within families and heritability. Results indicated that reaction time for indicating acceptance-expectations might be a candidate behavioral endophenotype of social anxiety disorder, possibly reflecting increased uncertainty or self-focused attention and vigilance during the social judgment paradigm. N1 in response to expected rejection feedback and P3 in response to acceptance feedback might be candidate electrocortical endophenotypes of social anxiety disorder, although the heritability analyses did not remain significant after correcting for multiple tests. Increased N1 possibly reflects hypervigilance to socially threatening stimuli, and increased P3 might reflect that positive feedback is more important for, and/or less expected by, participants with social anxiety disorder. Finally, increased feedback-related negativity and theta power in response to unexpected rejection feedback compared to the other conditions co-segregated with social anxiety disorder, but these EEG measures were not heritable. The candidate endophenotypes might play a new and promising role in future research on genetic mechanisms, early detection and/or prevention of social anxiety disorder. PMID- 29527482 TI - Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease. AB - Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 +/- 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo perfusion and hypo-metabolism were associated with amyloid deposition. Cross sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD. PMID- 29527483 TI - Age-related functional brain changes in FMR1 premutation carriers. AB - The FMR1 premutation confers a 40-60% risk for males of developing a neurodegenerative disease called the Fragile X-associated Tremor Ataxia Syndrome (FXTAS). FXTAS is a late-onset disease that primarily involves progressive symptoms of tremor and ataxia, as well as cognitive decline that can develop into dementia in some patients. At present, it is not clear whether changes to brain function are detectable in motor regions prior to the onset of frank symptomatology. The present study therefore aimed to utilize an fMRI motor task for the first time in an asymptomatic premutation population. Premutation carriers without a diagnosis of FXTAS (n = 17) and a group of healthy male controls (n = 17), with an age range of 24-68 years old, were recruited for this cross-sectional study. This study utilized neuroimaging, molecular and clinical measurements, employing an fMRI finger-tapping task with a block design consisting of sequential finger-tapping, random finger-tapping and rest conditions. The imaging analysis contrasted the sequential and random conditions to investigate activation changes in response to a change in task demand. Additionally, measurements were obtained of participant tremor, co-ordination and balance using the CATSYS-2000 system and measures of FMR1 mRNA were quantified from peripheral blood samples using quantitative real-time PCR methodology. Premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001). Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability. PMID- 29527484 TI - Alteration of brain network topology in HIV-associated neurocognitive disorder: A novel functional connectivity perspective. AB - HIV is capable of invading the brain soon after seroconversion. This ultimately can lead to deficits in multiple cognitive domains commonly referred to as HIV associated neurocognitive disorders (HAND). Clinical diagnosis of such deficits requires detailed neuropsychological assessment but clinical signs may be difficult to detect during asymptomatic injury of the central nervous system (CNS). Therefore neuroimaging biomarkers are of particular interest in HAND. In this study, we constructed brain connectivity profiles of 40 subjects (20 HIV positive subjects and 20 age-matched seronegative controls) using two different methods: a non-linear mutual connectivity analysis approach and a conventional method based on Pearson's correlation. These profiles were then summarized using graph-theoretic methods characterizing their topological network properties. Standard clinical and laboratory assessments were performed and a battery of neuropsychological (NP) tests was administered for all participating subjects. Based on NP testing, 14 of the seropositive subjects exhibited mild neurologic impairment. Subsequently, we analyzed associations between the network derived measures and neuropsychological assessment scores as well as common clinical laboratory plasma markers (CD4 cell count, HIV RNA) after adjusting for age and gender. Mutual connectivity analysis derived graph-theoretic measures, Modularity and Small Worldness, were significantly (p < 0.05, FDR adjusted) associated with the Executive as well as Overall z-score of NP performance. In contrast, network measures derived from conventional correlation-based connectivity did not yield any significant results. Thus, changes in connectivity can be captured using advanced time-series analysis techniques. The demonstrated associations between imaging-derived graph-theoretic properties of brain networks with neuropsychological performance, provides opportunities to further investigate the evolution of HAND in larger, longitudinal studies. Our analysis approach, involving non-linear time-series analysis in conjunction with graph theory, is promising and it may prove to be useful not only in HAND but also in other neurodegenerative disorders. PMID- 29527485 TI - Large-scale brain organization during facial emotion processing as a function of early life trauma among adolescent girls. AB - Background: A wealth of research has investigated the impact of early life trauma exposure on functional brain activation during facial emotion processing and has often demonstrated amygdala hyperactivity and weakened connectivity between amygdala and medial PFC (mPFC). There have been notably limited investigations linking these previous node-specific findings into larger-scale network models of brain organization. Method: To address these gaps, we applied graph theoretical analyses to fMRI data collected during a facial emotion processing task among 88 adolescent girls (n = 59 exposed to direct physical or sexual assault; n = 29 healthy controls), aged 11-17, during fMRI. Large-scale organization indices of modularity, assortativity, and global efficiency were calculated for stimulus specific functional connectivity using an 883 region-of-interest parcellation. Results: Among the entire sample, more severe early life trauma was associated with more modular and assortative, but less globally efficient, network organization across all stimulus categories. Among the assaulted girls, severity of early life trauma and PTSD diagnoses were both simultaneously related to increased modular brain organization. We also found that more modularized network organization was related both to amygdala hyperactivation and weakened connectivity between amygdala and medial PFC. Conclusions: These results demonstrate that early life trauma is associated with enhanced brain organization during facial emotion processing and that this pattern of brain organization might explain the commonly observed association between childhood trauma and amygdala hyperactivity and weakened connectivity with mPFC. Implications of these results for neurocircuitry models are discussed. PMID- 29527486 TI - Risk for affective disorders is associated with greater prefrontal gray matter volumes: A prospective longitudinal study. AB - Background: Major depression and bipolar disorders aggregates in families and are linked with a wide range of neurobiological abnormalities including cortical gray matter (GM) alterations. Prospective studies of individuals at familial risk may expose the neural mechanisms underlying risk transmission. Methods: We used voxel based morphometry to investigate changes in regional GM brain volume, over a seven-year period, in 37 initially healthy individuals having a mono- or di zygotic twin diagnosed with major depression or bipolar disorder (high-risk group; mean age 41.6 yrs.) as compared to 36 individuals with no history of affective disorders in the index twin and first-degree relatives (low-risk group; mean age 38.5 yrs.). Results: Groups did not differ in regional GM volume changes over time. However, independent of time, high-risk twins had significantly greater GM volumes in bilateral dorsal anterior cingulate, inferior frontal gyrus and temporoparietal regions as compared to low-risk twins. Further, individuals who developed an affective disorder at follow-up (n = 12), had relatively the largest GM volumes, both at baseline and follow-up, in the right dorsal anterior cingulate cortex and right inferior frontal cortex compared to high- and low-risk twins who remained well at follow-up. Conclusion: This pattern of apparently stable grater regional GM volume may constitute a neural marker of an increased risk for developing an affective disorder in individuals at familial risk. PMID- 29527487 TI - Hypersynchrony in MEG spectral amplitude in prospectively-identified 6-month-old infants prenatally exposed to alcohol. AB - Early identification of children who experience developmental delays due to prenatal alcohol exposure (PAE) remains a challenge for individuals who do not exhibit facial dysmorphia. It is well-established that children with PAE may still exhibit the cognitive and behavioral difficulties, and individuals without facial dysmorphia make up the majority of individuals affected by PAE. This study employed a prospective cohort design to capture alcohol consumption patterns during pregnancy and then followed the infants to 6 months of age. Infants were assessed using magnetoencephalography to capture neurophysiological indicators of brain development and the Bayley Scales of Infant Development-III to measure behavioral development. To account for socioeconomic and family environmental factors, we employed a two-by-two design with pregnant women who were or were not using opioid maintenance therapy (OMT) and did or did not consume alcohol during pregnancy. Based on prior studies, we hypothesized that infants with PAE would exhibit broad increased spectral amplitude relative to non-PAE infants. We also hypothesized that the developmental shift from low to high frequency spectral amplitude would be delayed in infants with PAE relative to controls. Our results demonstrated broadband increased spectral amplitude, interpreted as hypersynchrony, in PAE infants with no significant interaction with OMT. Unlike prior EEG studies in neonates, our results indicate that this hypersynchrony was highly lateralized to left hemisphere and primarily focused in temporal/lateral frontal regions. Furthermore, there was a significant positive correlation between estimated number of drinks consumed during pregnancy and spectral amplitude revealing a dose-response effect of increased hypersynchrony corresponding to greater alcohol consumption. Contrary to our second hypothesis, we did not see a significant group difference in the contribution of low frequency to high frequency amplitude at 6 months of age. These results provide new evidence that hypersynchrony, previously observed in neonates prenatally exposed to high levels of alcohol, persists until 6 months of age and this measure is detectable with low to moderate exposure of alcohol with a dose response effect. These results indicate that hypersynchrony may provide a sensitive early marker of prenatal alcohol exposure in infants up to 6 months of age. PMID- 29527489 TI - Dynamic functional connectivity in Parkinson's disease patients with mild cognitive impairment and normal cognition. AB - The objective was to assess dynamic functional connectivity (FC) and local/global connectivity in Parkinson's disease (PD) patients with mild cognitive impairment (PD-MCI) and with normal cognition (PD-NC). The sample included 35 PD patients and 26 healthy controls (HC). Cognitive assessment followed an extensive neuropsychological battery. For resting-state functional MRI (rs-fMRI) analysis, independent component analysis (ICA) was performed and components were located in 7 networks: Subcortical (SC), Auditory (AUD), Somatomotor (SM), visual (VI), cognitive-control (CC), default-mode (DMN), and cerebellar (CB). Dynamic FC analysis was performed using the GIFT toolbox. FC differences between groups in each FC state were analysed with the network-based statistic (NBS) approach. Finally, a graph-theoretical analysis for local/global parameters was performed. The whole sample showed 2 dynamic FC states during the rs-fMRI. PD-MCI patients showed decreased mean dwell time in the hypo-connectivity state (p = 0.030) and showed increased number of state transitions (p = 0.007) compared with the HC. In addition, in the hypo-connectivity state, PD-MCI patients showed reduced inter network FC between the SM-CC, SM-VI, SM-AUD, CC-VI and SC-DMN compared with the HC (p < 0.05-FDR). These FC alterations in PD-MCI were accompanied by graph topological alterations in nodes located in the SM network (p < 0.001). In contrast, no differences were found between the PD-NC and HC. Findings suggest the presence of dynamic functional brain deteriorations in PD-MCI that are not present in PD-NC, showing the PD-MCI group dynamic FC dysfunctions, reduced FC mostly between SM-CC networks and graph-topological deteriorations in the SM network. A dynamic FC approach could be helpful to understand cognitive deterioration in PD. PMID- 29527488 TI - Increased insula-putamen connectivity in X-linked dystonia-parkinsonism. AB - Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP) suggests tissue loss may occur first and/or most severely in the striatal striosome compartment, followed later by cell loss in the matrix compartment. However, little is known about how this relates to pathogenesis and pathophysiology. While MRI cannot visualize these striatal compartments directly in humans, differences in relative gradients of afferent cortical connectivity across compartments (weighted toward paralimbic versus sensorimotor cortex, respectively) can be used to infer potential selective loss in vivo. In the current study we evaluated relative connectivity of paralimbic versus sensorimotor cortex with the caudate and putamen in 17 individuals with XDP and 17 matched controls. Although caudate and putamen volumes were reduced in XDP, there were no significant reductions in either "matrix-weighted", or "striosome weighted" connectivity. In fact, paralimbic connectivity with the putamen was elevated, rather than reduced, in XDP. This was driven most strongly by elevated putamen connectivity with the anterior insula. There was no relationship of these findings to disease duration or striatal volume, suggesting insula and/or paralimbic connectivity in XDP may develop abnormally and/or increase in the years before symptom onset. PMID- 29527490 TI - Callous-unemotional traits and brain structure: Sex-specific effects in anterior insula of typically-developing youths. AB - : Callous-unemotional traits are characterized by a lack of empathy, a disregard for others' feelings and shallow or deficient affect, such as a lack of remorse or guilt. Neuroanatomical correlates of callous-unemotional traits have been demonstrated in clinical samples (i.e., adolescents with disruptive behavior disorders). However, it is unknown whether callous-unemotional traits are associated with neuroanatomical correlates within normative populations without clinical levels of aggression or antisocial behavior. Here we investigated the relationship between callous-unemotional traits and gray matter volume using voxel-based morphometry in a large sample of typically-developing boys and girls (N = 189). Whole-brain multiple regression analyses controlling for site, total intracranial volume, and age were conducted in the whole sample and in boys and girls individually. Results revealed that sex and callous-unemotional traits interacted to predict gray matter volume when considering the whole sample. This interaction was driven by a significant positive correlation between callous unemotional traits and bilateral anterior insula volume in boys, but not girls. Insula gray matter volume explained 19% of the variance in callous-unemotional traits for boys. Our results demonstrate that callous-unemotional traits are related to variations in brain structure beyond psychiatric samples. This association was observed for boys only, underlining the importance of considering sex as a factor in future research designs. Future longitudinal studies should determine whether these findings hold over childhood and adolescence, and whether the neuroanatomical correlates of callous-unemotional traits are predictive of future psychiatric vulnerability. General scientific summary: This study suggests that callous-unemotional traits have a neuroanatomical correlate within typically developing boys, but not girls. Bilateral anterior insula volume explains up to 19% of the variance in callous-unemotional traits in boys. PMID- 29527491 TI - Spectral bandwidth of interictal fast epileptic activity characterizes the seizure onset zone. AB - The foremost aim of presurgical epilepsy evaluation is the delineation of the seizure onset zone (SOZ). There is increasing evidence that fast epileptic activity (FEA, 14-250 Hz) occurring interictally, i.e. between seizures, is predominantly localized within the SOZ. Currently it is unknown, which frequency band of FEA performs best in identifying the SOZ, although prior studies suggest highest concordance of spectral changes with the SOZ for high frequency changes. We suspected that FEA reflects dampened oscillations in local cortical excitatory inhibitory neural networks, and that interictal FEA in the SOZ is a consequence of reduced oscillatory damping. We therefore predict a narrowing of the spectral bandwidth alongside increased amplitudes of spectral peaks during interictal FEA events. To test this hypothesis, we evaluated spectral changes during interictal FEA in invasive EEG (iEEG) recordings of 13 patients with focal epilepsy. In relative spectra of beta and gamma band changes (14-250 Hz) during FEA, we found that spectral peaks within the SOZ indeed were significantly more narrow-banded and their power changes were significantly higher than outside the SOZ. In contrast, the peak frequency did not differ within and outside the SOZ. Our results show that bandwidth and power changes of spectral modulations during FEA both help localizing the SOZ. We propose the spectral bandwidth as new source of information for the evaluation of EEG data. PMID- 29527492 TI - Brain functional connectivity in sleep-related hypermotor epilepsy. AB - Objectives: To evaluate functional connectivity (FC) in patients with sleep related hypermotor epilepsy (SHE) compared to healthy controls. Methods: Resting state fMRI was performed in 13 patients with a clinical diagnosis of SHE (age = 38.3 +/- 11.8 years, 6 M) and 13 matched healthy controls (age = 38.5 +/- 10.8 years, 6 M).Data were first analysed using probabilistic independent component analysis (ICA), then a graph theoretical approach was applied to assess topological and organizational properties at the whole brain level. We evaluated node degree (ND), betweenness centrality (BC), clustering coefficient (CC), local efficiency (LE) and global efficiency (GE). The differences between the two groups were evaluated non-parametrically. Results: At the group level, we distinguished 16 RSNs (Resting State Networks). Patients showed a significantly higher FC in sensorimotor and thalamic regions (p < 0.05 corrected). Compared to controls, SHE patients showed no significant differences in network global efficiency, while ND and BC were higher in regions of the limbic system and lower in the occipital cortex, while CC and LE were higher in regions of basal ganglia and lower in limbic areas (p < 0.05 uncorrected). Discussion and conclusions: The higher FC of the sensorimotor cortex and thalamus might be in agreement with the hypothesis of a peculiar excitability of the motor cortex during thalamic K complexes. This sensorimotor-thalamic hyperconnection might be regarded as a consequence of an alteration of the arousal regulatory system in SHE. An altered topology has been found in structures like basal ganglia and limbic system, hypothesized to be involved in the pathophysiology of the disease as suggested by the dystonic-dyskinetic features and primitive behaviours observed during the seizures. PMID- 29527493 TI - The verbal nature of worry in generalized anxiety: Insights from the brain. AB - Background: The Cognitive Avoidance Theory of Worry argues that worry is a cognitive strategy adopted to control the physiological arousal associated with anxiety. According to this theory, pathological worry, as in Generalized Anxiety Disorder (GAD), is verbal in nature, negative and abstract, rather than concrete. Neuroimaging studies link the expression of worry to characteristic modes of brain functional connectivity, especially in relation to the amygdala. However, the distinctive features of worry (verbal, abstract, negative), and their relationship to physiological arousal, have not so far been mapped to brain function. Methods: We addressed this omission by undertaking a resting-state functional magnetic resonance neuroimaging study of 19 patients with GAD and 21 controls, before and after induction of perseverative cognitions, while measuring emotional bodily arousal from heart rate (HR). Seed-based analyses quantified brain changes in whole brain functional connectivity from the amygdala. Results: In GAD, the induction increased negative thoughts and their verbal content. In line with predictions, the verbal expression of worry in GAD was associated with higher HR at baseline and attenuated HR increases after induction of perseverative cognitions. Within brain, the increased use of words during worry, and the associated dampening of HR after induction were mediated by the strength of functional connectivity between the amygdala and default mode network 'hubs' and the opercular cortex. The negative content of worry was further related to functional communication between amygdala and cingulo-opercular and temporal cortices. Conclusions: Findings provide a neurobiological basis for the impact of verbal worry on HR in GAD. PMID- 29527494 TI - Grey matter volume and cortical structure in Prader-Willi syndrome compared to typically developing young adults. AB - Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a characteristic overeating disorder, mild to moderate intellectual disability, and a variable range of social and behavioral difficulties. Consequently, widespread alterations in neural structure and developmental and maturational trajectory would be expected. To date, there have been few quantitative and systematic studies of brain morphology in PWS, although alterations of volume and of cortical organisation have been reported. This study aimed to investigate, in detail, the structure of grey matter and cortex in the brain in a sample of young adults with PWS in a well-matched case-controlled analysis. 20 young adults with PWS, aged 19-27 years, underwent multiparameter mapping magnetic resonance imaging sequences, from which measures of grey matter volume, cortical thickness and magnetisation transfer saturation, as a proxy measure of myelination, were examined. These variables were investigated in comparison to a control group of 40 typically developing young adults, matched for age and sex. A voxel-based morphometry analysis identified large and widespread bilateral clusters of both increased and decreased grey matter volume in the brain in PWS. In particular, widespread areas of increased volume encompassed parts of the prefrontal cortex, especially medially, the majority of the cingulate cortices, from anterior to posterior aspects, insula cortices, and areas of the parietal and temporal cortices. Increased volume was also reported in the caudate, putamen and thalamus. The most ventromedial prefrontal areas, in contrast, showed reduced volume, as did the parts of the medial temporal lobe, bilateral temporal poles, and a small cluster in the right lateral prefrontal cortex. Analysis of cortical structure revealed that areas of increased volume in the PWS group were largely driven by greater cortical thickness. Conversely, analysis of myelin content using magnetisation transfer saturation indicated that myelination of the cortex was broadly similar in the PWS and control groups, with the exception of highly localised areas, including the insula. The bilateral nature of these abnormalities suggests a systemic biological cause, with possible developmental and maturational mechanisms discussed, and may offer insight into the contribution of imprinted genes to neural development. PMID- 29527495 TI - Orbitofrontal sulcogyral morphology is a transdiagnostic indicator of brain dysfunction. AB - Atypical sulcogyral patterns in the orbitofrontal cortex (OFC) are associated with increased risk for schizophrenia, as well as with quantitative traits associated with schizophrenia, such as anhedonia. Here we conduct a cross diagnostic comparison to assess whether atypical OFC sulcogyral patterns confer risk for multiple brain disorders. We examined structural images from 4 groups of adult participants (N = 189), including those diagnosed with schizophrenia (SZ; N = 49), bipolar disorder (BP; N = 46), attention deficit hyperactivity disorder (ADHD; N = 41), and controls (N = 53). OFC sulcogyral pattern types were determined based on the continuity of the medial and lateral orbitofrontal sulcus. Chi-square analysis was performed to compare the sulcogyral pattern frequency distributions between patient groups and controls. We find that both SZ and BP groups had atypical pattern distributions, with increased atypical pattern frequencies relative to controls in the left hemisphere, consistent with the overlapping clinical features and genetic etiology of these disorders (SZ: chi2 = 17.6; p < 0.001; BP: chi2 = 19.2, p < 0.001). The ADHD group distribution did not significantly differ from controls (chi2 = 5.5; p = 0.06, NS.). Similar sulcogyral pattern frequencies across BP and SZ suggest that the sulcogyral phenotype may map more directly to a trait that is transdiagnostic. These results suggest that sulcogyral patterns present a novel morphological indicator for increased susceptibility to multiple psychiatric diagnoses. PMID- 29527496 TI - White matter hyperintensity and stroke lesion segmentation and differentiation using convolutional neural networks. AB - White matter hyperintensities (WMH) are a feature of sporadic small vessel disease also frequently observed in magnetic resonance images (MRI) of healthy elderly subjects. The accurate assessment of WMH burden is of crucial importance for epidemiological studies to determine association between WMHs, cognitive and clinical data; their causes, and the effects of new treatments in randomized trials. The manual delineation of WMHs is a very tedious, costly and time consuming process, that needs to be carried out by an expert annotator (e.g. a trained image analyst or radiologist). The problem of WMH delineation is further complicated by the fact that other pathological features (i.e. stroke lesions) often also appear as hyperintense regions. Recently, several automated methods aiming to tackle the challenges of WMH segmentation have been proposed. Most of these methods have been specifically developed to segment WMH in MRI but cannot differentiate between WMHs and strokes. Other methods, capable of distinguishing between different pathologies in brain MRI, are not designed with simultaneous WMH and stroke segmentation in mind. Therefore, a task specific, reliable, fully automated method that can segment and differentiate between these two pathological manifestations on MRI has not yet been fully identified. In this work we propose to use a convolutional neural network (CNN) that is able to segment hyperintensities and differentiate between WMHs and stroke lesions. Specifically, we aim to distinguish between WMH pathologies from those caused by stroke lesions due to either cortical, large or small subcortical infarcts. The proposed fully convolutional CNN architecture, called uResNet, that comprised an analysis path, that gradually learns low and high level features, followed by a synthesis path, that gradually combines and up-samples the low and high level features into a class likelihood semantic segmentation. Quantitatively, the proposed CNN architecture is shown to outperform other well established and state of-the-art algorithms in terms of overlap with manual expert annotations. Clinically, the extracted WMH volumes were found to correlate better with the Fazekas visual rating score than competing methods or the expert-annotated volumes. Additionally, a comparison of the associations found between clinical risk-factors and the WMH volumes generated by the proposed method, was found to be in line with the associations found with the expert-annotated volumes. PMID- 29527497 TI - Dysfunctional frontal lobe activity during inhibitory tasks in individuals with childhood trauma: An event-related potential study. AB - Background: Individuals who experience childhood trauma are vulnerable to various psychological and behavioral problems throughout their lifetime. This study aimed to investigate whether individuals with childhood trauma show altered frontal lobe activity during response inhibition tasks. Methods: In total, 157 healthy individuals were recruited and instructed to perform a Go/Nogo task during electroencephalography recording. Source activities of N2 and P3 of Nogo event related potentials (ERP) were analyzed. The Childhood Trauma Questionnaire (CTQ) and Barratt Impulsivity Scale (BIS) were applied. Individuals were divided into three groups based on their total CTQ score: low CTQ, middle CTQ, and high CTQ groups. Results: The high CTQ group exhibited significantly higher BIS scores than the low CTQ group. P3 amplitudes of the differences between Nogo and Go ERP waves exhibited higher mean values in the low CTQ than the high CTQ group, with trending effects. In Nogo-P3, the source activities of the right anterior cingulate cortex, bilateral medial frontal cortex (MFC), bilateral superior frontal gyrus (SFG), and right precentral gyrus were significantly lower in the high CTQ than the low CTQ group. Motor impulsivity showed a significant negative correlation with activities of the bilateral MFC and SFG in Nogo-P3 conditions. Conclusions: Our study revealed that individuals with childhood trauma have inhibitory failure and frontal lobe dysfunction in regions related to Nogo-P3. PMID- 29527498 TI - Structural and effective connectivity in focal epilepsy. AB - Patients with medically-refractory focal epilepsy may be candidates for neurosurgery and some may require placement of intracranial EEG electrodes to localise seizure onset. Assessing cerebral responses to single pulse electrical stimulation (SPES) may give diagnostically useful data. SPES produces cortico cortical evoked potentials (CCEPs), which infer effective brain connectivity. Diffusion-weighted images and tractography may be used to estimate structural brain connectivity. This combination provides the opportunity to observe seizure onset and its propagation throughout the brain, spreading contiguously along the cortex explored with electrodes, or non-contiguously. We analysed CCEPs and diffusion tractography in seven focal epilepsy patients and reconstructed the effective and structural brain networks. We aimed to assess the inter-modal similarity of the networks at a large scale across the cortex, the effective and structural connectivity of the ictal-onset zone, and investigate potential mechanisms of non-contiguous seizure spread. We found a significant overlap between structural and effective networks. Effective network CCEP amplitude, baseline variation, and outward connectivity was higher at ictal-onset zones, while structural connection strength within the ictal-onset zone tended to be higher. These findings support the concept of hyperexcitable cortex being associated with seizure generation. The high prevalence of structural and effective connections from the ictal-onset zone to sites of non-contiguous spread suggests that macroscopic structural and effective connections are plausible routes for non-contiguous seizure spread. PMID- 29527499 TI - Visual processing deficits in 22q11.2 Deletion Syndrome. AB - Carriers of the rare 22q11.2 microdeletion present with a high percentage of positive and negative symptoms and a high genetic risk for schizophrenia. Visual processing impairments have been characterized in schizophrenia, but less so in 22q11.2 Deletion Syndrome (DS). Here, we focus on visual processing using high density EEG and source imaging in 22q11.2DS participants (N = 25) and healthy controls (N = 26) with an illusory contour discrimination task. Significant differences between groups emerged at early and late stages of visual processing. In 22q11.2DS, we first observed reduced amplitudes over occipital channels and reduced source activations within dorsal and ventral visual stream areas during the P1 (100-125 ms) and within ventral visual cortex during the N1 (150-170 ms) visual evoked components. During a later window implicated in visual completion (240-285 ms), we observed an increase in global amplitudes in 22q11.2DS. The increased surface amplitudes for illusory contours at this window were inversely correlated with positive subscales of prodromal symptoms in 22q11.2DS. The reduced activity of ventral and dorsal visual areas during early stages points to an impairment in visual processing seen both in schizophrenia and 22q11.2DS. During intervals related to perceptual closure, the inverse correlation of high amplitudes with positive symptoms suggests that participants with 22q11.2DS who show an increased brain response to illusory contours during the relevant window for contour processing have less psychotic symptoms and might thus be at a reduced prodromal risk for schizophrenia. PMID- 29527500 TI - Metabolic brain networks in aging and preclinical Alzheimer's disease. AB - Metabolic brain networks can provide insight into the network processes underlying progression from healthy aging to Alzheimer's disease. We explore the effect of two Alzheimer's disease risk factors, amyloid-beta and ApoE epsilon4 genotype, on metabolic brain networks in cognitively normal older adults (N = 64, ages 69-89) compared to young adults (N = 17, ages 20-30) and patients with Alzheimer's disease (N = 22, ages 69-89). Subjects underwent MRI and PET imaging of metabolism (FDG) and amyloid-beta (PIB). Normal older adults were divided into four subgroups based on amyloid-beta and ApoE genotype. Metabolic brain networks were constructed cross-sectionally by computing pairwise correlations of metabolism across subjects within each group for 80 regions of interest. We found widespread elevated metabolic correlations and desegregation of metabolic brain networks in normal aging compared to youth and Alzheimer's disease, suggesting that normal aging leads to widespread loss of independent metabolic function across the brain. Amyloid-beta and the combination of ApoE epsilon4 led to less extensive elevated metabolic correlations compared to other normal older adults, as well as a metabolic brain network more similar to youth and Alzheimer's disease. This could reflect early progression towards Alzheimer's disease in these individuals. Altered metabolic brain networks of older adults and those at the highest risk for progression to Alzheimer's disease open up novel lines of inquiry into the metabolic and network processes that underlie normal aging and Alzheimer's disease. PMID- 29527501 TI - Effect of rs1344706 in the ZNF804A gene on the brain network. AB - ZNF804A rs1344706 (A/C) was the first SNP that reached genome-wide significance for schizophrenia. Recent studies have linked rs1344706 to functional connectivity among specific brain regions. However, no study thus far has examined the role of this SNP in the entire functional connectome. In this study, we used degree centrality to test the role of rs1344706 in the whole-brain voxel wise functional connectome during the resting state. 52 schizophrenia patients and 128 healthy controls were included in the final analysis. In our whole-brain analysis, we found a significant interaction effect of genotype * diagnosis at the precuneus (PCU) (cluster size = 52 voxels, peak voxel MNI coordinates: x = 9, y = - 69, z = 63, F = 32.57, FWE corrected P < 0.001). When we subdivided the degree centrality network according to anatomical distance, the whole-brain analysis also found a significant interaction effect of genotype * diagnosis at the PCU with the same peak in the short-range degree centrality network (cluster size = 72 voxels, F = 37.29, FWE corrected P < 0.001). No significant result was found in the long-range degree centrality network. Our results elucidated the contribution of rs1344706 to functional connectivity within the brain network, and may have important implications for our understanding of this risk gene's role in functional dysconnectivity in schizophrenia. PMID- 29527502 TI - Systematic comparison of different techniques to measure hippocampal subfield volumes in ADNI2. AB - Objective: Subfield-specific measurements provide superior information in the early stages of neurodegenerative diseases compared to global hippocampal measurements. The overall goal was to systematically compare the performance of five representative manual and automated T1 and T2 based subfield labeling techniques in a sub-set of the ADNI2 population. Methods: The high resolution T2 weighted hippocampal images (T2-HighRes) and the corresponding T1 images from 106 ADNI2 subjects (41 controls, 57 MCI, 8 AD) were processed as follows. A. T1 based: 1. Freesurfer + Large-Diffeomorphic-Metric-Mapping in combination with shape analysis. 2. FreeSurfer 5.1 subfields using in-vivo atlas. B. T2-HighRes: 1. Model-based subfield segmentation using ex-vivo atlas (FreeSurfer 6.0). 2. T2 based automated multi-atlas segmentation combined with similarity-weighted voting (ASHS). 3. Manual subfield parcellation. Multiple regression analyses were used to calculate effect sizes (ES) for group, amyloid positivity in controls, and associations with cognitive/memory performance for each approach. Results: Subfield volumetry was better than whole hippocampal volumetry for the detection of the mild atrophy differences between controls and MCI (ES: 0.27 vs 0.11). T2 HighRes approaches outperformed T1 approaches for the detection of early stage atrophy (ES: 0.27 vs.0.10), amyloid positivity (ES: 0.11 vs 0.04), and cognitive associations (ES: 0.22 vs 0.19). Conclusions: T2-HighRes subfield approaches outperformed whole hippocampus and T1 subfield approaches. None of the different T2-HghRes methods tested had a clear advantage over the other methods. Each has strengths and weaknesses that need to be taken into account when deciding which one to use to get the best results from subfield volumetry. PMID- 29527503 TI - The potential value of probabilistic tractography-based for MR-guided focused ultrasound thalamotomy for essential tremor. AB - Magnetic Resonance-guided Focused UltraSound (MRgFUS) offers an incisionless approach to treat essential tremor (ET). Due to lack of evident internal anatomy on traditional structural imaging, indirect targeting must still be used to localize the lesion. Here, we investigate the potential predictive value of probabilistic tractography guided thalamic targeting by defining how tractography defined targets, lesion size and location, and clinical outcomes interrelate. MR imaging and clinical outcomes from 12 ET patients that underwent MRgFUS thalamotomy in a pilot study at the University of Virginia were evaluated in this analysis. FSL was used to evaluate each patient's voxel-wise thalamic connectivity with FreeSurfer generated pre- and post-central gyrus targets, to generate thalamic target maps. Using Receiver Operating Characteristic curves, the overlap between these thalamic target maps and the MRgFUS lesion was systematically evaluated relative to clinical outcome. To further define the connectivity characteristics of effective MRgFUS thalamotomy lesions, we evaluated whole brain probabilistic tractography of lesions (using post-treatment imaging to define the lesion pre-treatment diffusion tensor MRI). The structural connectivity difference was explored between subjects with the best clinical outcome relative to all others. Ten of twelve patients presented high percentage of overlapping between connectivity-based thalamic segmentation maps and lesion area. The improvement of clinical score was predicted (AUC: 0.80) using the volume of intersection between the thalamic target (precentral gyrus) map and MRgFUS induced lesion as feature. The main structural differences between those with different magnitudes of response were observed in connectivity to the pre- and post-central gyri and brainstem/cerebellum. MRgFUS thalamotomy lesions characterized by strong structural connectivity to precentral gyrus demonstrated better responses in a cohort of patients treated with MRgFUS for ET. The intersection between lesion and thalamic-connectivity maps to motor - sensory targets proved to be effective in predicting the response to the therapy. These imaging techniques can be used to increase the efficacy and consistency of outcomes with MRgFUS and potentially shorten treatment times by identifying optimal targets in advance of treatment. PMID- 29527504 TI - Combining viscoelasticity, diffusivity and volume of the hippocampus for the diagnosis of Alzheimer's disease based on magnetic resonance imaging. AB - Dementia due to Alzheimer's Disease (AD) is a neurodegenerative disease for which treatment strategies at an early stage are of great clinical importance. So far, there is still a lack of non-invasive diagnostic tools to sensitively detect AD in early stages and to predict individual disease progression. Magnetic resonance elastography (MRE) of the brain may be a promising novel tool. In this proof-of concept study, we investigated whether multifrequency-MRE (MMRE) can detect differences in hippocampal stiffness between patients with clinical diagnosis of dementia due to AD and healthy controls (HC). Further, we analyzed if the combination of three MRI-derived parameters, i.e., hippocampal stiffness, hippocampal volume and mean diffusivity (MD), improves diagnostic accuracy. Diagnostic criteria for probable dementia due to AD were in line with the NINCDS ADRDA criteria and were verified through history-taking (patient and informant), neuropsychological testing, routine blood results and routine MRI to exclude other medical causes of a cognitive decline. 21 AD patients and 21 HC (median age 75 years) underwent MMRE and structural MRI, from which hippocampal volume and MD were calculated. From the MMRE-images maps of the magnitude |G*| and phase angle phi of the complex shear modulus were reconstructed using multifrequency inversion. Median values of |G*| and phi were extracted within three regions of interest (hippocampus, thalamus and whole brain white matter). To test the predictive value of the main outcome parameters, we performed receiver operating characteristic (ROC) curve analyses. Hippocampal stiffness (|G*|) and viscosity (phi) were significantly lower in the patient group (both p < 0.001). ROC curve analyses showed an area under the curve (AUC) for | G*| of 0.81 [95%CI 0.68 0.94]; with sensitivity 86%, specificity 67% for cutoff at |G*| = 980 Pa) and for phi an AUC of 0.79 [95%CI 0.66-0.93]. In comparison, the AUC of MD and hippocampal volume were 0.83 [95%CI 0.71-0.95] and 0.86 [95%CI 0.74-0.97], respectively. A combined ROC curve of |G*|, MD and hippocampal volume yielded a significantly improved AUC of 0.90 [95%CI 0.81-0.99]. In conclusion, we demonstrated reduced hippocampal stiffness and reduced hippocampal viscosity, as determined by MMRE, in patients with clinical diagnosis of dementia of the AD type. Diagnostic sensitivity was further improved by the combination with two other MRI-based hippocampal parameters. These findings motivate further investigation whether MMRE can detect decreased brain stiffness already in pre dementia stages, and whether these changes predict cognitive decline. PMID- 29527505 TI - Establishing pathological cut-offs for lateral ventricular volume expansion rates. AB - Background: A percent brain volume change (PBVC) cut-off of -0.4% per year has been proposed to distinguish between pathological and physiological changes in multiple sclerosis (MS). Unfortunately, standardized PBVC measurement is not always feasible on scans acquired outside research studies or academic centers. Percent lateral ventricular volume change (PLVVC) is a strong surrogate measure of PBVC, and may be more feasible for atrophy assessment on real-world scans. However, the PLVVC rate corresponding to the established PBVC cut-off of -0.4% is unknown. Objective: To establish a pathological PLVVC expansion rate cut-off analogous to -0.4% PBVC. Methods: We used three complementary approaches. First, the original follow-up-length-weighted receiver operating characteristic (ROC) analysis method establishing whole brain atrophy rates was adapted to a longitudinal ventricular atrophy dataset of 177 relapsing-remitting MS (RRMS) patients and 48 healthy controls. Second, in the same dataset, SIENA PBVCs were used with non-linear regression to directly predict the PLVVC value corresponding to -0.4% PBVC. Third, in an unstandardized, real world dataset of 590 RRMS patients from 33 centers, the cut-off maximizing correspondence to PBVC was found. Finally, correspondences to clinical outcomes were evaluated in both datasets. Results: ROC analysis suggested a cut-off of 3.09% (AUC = 0.83, p < 0.001). Non-linear regression R2 was 0.71 (p < 0.001) and a - 0.4% PBVC corresponded to a PLVVC of 3.51%. A peak in accuracy in the real-world dataset was found at a 3.51% PLVVC cut-off. Accuracy of a 3.5% cut-off in predicting clinical progression was 0.62 (compared to 0.68 for PBVC). Conclusions: Ventricular expansion of between 3.09% and 3.51% on T2-FLAIR corresponds to the pathological whole brain atrophy rate of 0.4% for RRMS. A conservative cut-off of 3.5% performs comparably to PBVC for clinical outcomes. PMID- 29527506 TI - Marked improvement of thyroid function and autoimmunity by Aloe barbadensis miller juice in patients with subclinical hypothyroidism. AB - Some natural compounds decrease serum levels of thyroid autoantibodies, but results are inconsistent and thyroid function has been evaluated infrequently; moreover, the effects of Aloe on thyroid autoimmunity and function have been examined in very few studies. This study stems from the observation of one co author, who has Hashimoto's thyroiditis (HT)-related subclinical hypothyroidism (SCH). Upon checking her biochemical thyroid panel when taking daily Aloe barbardensis Miller juice (ABMJ) for thyroid-unrelated reasons, she noticed a decrease in serum thyroperoxidase autoantibodies (TPOAb) and thyrotropin (TSH) and an increase in serum free thyroxine (FT4). Based on this observation, we enrolled 30 consecutive HT women with levothyroxine-untreated SCH and high TPOAb levels. All of them took ABMJ (50 ml daily) for nine months and were tested for serum TSH, FT4, free triiodothyronine (FT3) and TPOAb. Measurements were performed at baseline and at months 3 and 9. TSH, FT4 and TPOAb improved significantly already at month 3 and further (-61%, +23% and -56%) at month 9. However, FT3 decreased significantly at month 3 (-16%) with no further decrease at month 9, so that the FT4:FT3 ratio increased significantly (+33% and + 49%). At baseline, 100% of women had TSH > 4.0 mU/L and TPOAb > 400 U/ml, but frequencies fell to 0% and 37%, respectively, at month 9. In contrast, a control group (namely, 15 untreated SCH women of comparable age and baseline levels of TSH, FT4, FT3 and TPOAb) had no significant changes in any index. We conclude that the daily intake of 100 ml ABMJ for 9 months in women with HT-related SCH decreases the burden of thyroid autoimmune inflammation. In addition, ABMJ rescues thyrocyte function, with decreased need for conversion of the prohormone T4 into the more active T3 through ABMJ-induced inhibition of T4 deiodination. PMID- 29527507 TI - Cognitive and psychopathology correlates of brain white/grey matter structure in severely psychotic schizophrenic inpatients. AB - The brain structural correlates of cognitive and psychopathological symptoms within the active phase in severely psychotic schizophrenic inpatients have been rarely investigated. Twenty-eight inpatients with a DSM-5 diagnosis of Schizophrenia (SZ), admitted for acute psychotic decompensation, were assessed through a comprehensive neuropsychological and psychopathological battery. All patients underwent a high-resolution T1-weighted magnetic resonance imaging investigation. Increased psychotic severity was related to reduced grey matter volumes in the medial portion of the right superior frontal cortex, the superior orbitofrontal cortex bilaterally and to white matter volume reduction in the medial portion of the left superior frontal area. Immediate verbal memory performance was related to left insula and inferior parietal cortex volume, while long-term visuo-spatial memory was related to grey matter volume of the right middle temporal cortex, and the right (lobule VII, CRUS1) and left (lobule VI) cerebellum. Moreover, psychotic severity correlated with cognitive inflexibility and negative symptom severity was related to visuo-spatial processing and reasoning disturbances. These findings indicate that a disruption of the cortical subcortical-cerebellar circuit, and distorted memory function contribute to the development and maintenance of psychotic exacerbation. PMID- 29527508 TI - Is serum copeptin a modifiable biomarker in autosomal dominant polycystic kidney disease? AB - The availability of disease-modifying drugs for the management of autosomal dominant polycystic kidney disease (ADPKD) has accelerated the need to accurately predict renal prognosis and/or treatment response in this condition. Arginine vasopressin (AVP) is a critical determinant of postnatal kidney cyst growth in ADPKD. Copeptin (the C-terminal glycoprotein of the precursor AVP peptide) is an accurate surrogate marker of AVP release that is stable and easily measured by immunoassay. Cohort studies show that serum copeptin is correlated with disease severity in ADPKD, and predicts future renal events [decline in renal function and increase in total kidney volume (TKV)]. However, serum copeptin is strongly correlated with creatinine, and its additional value as a prognostic biomarker over estimated glomerular filtration rate and TKV is not certain. It has also been suggested that copeptin could be a predictive biomarker to select ADPKD patients who are most likely to benefit from AVP-modifying therapies, but prospective data to validate this assumption are required. In this regard, long term randomised clinical trials evaluating the effect of prescribed water intake on renal cyst growth may contribute to addressing this hypothesis. In conclusion, although serum copeptin is aligned with the basic pathogenesis of ADPKD, further rigorous studies are needed to define if it will contribute to enabling the delivery of personalised care in ADPKD. PMID- 29527509 TI - Diabetic muscle infarction in end-stage renal disease: A scoping review on epidemiology, diagnosis and treatment. AB - Diabetic muscle infarction (DMI) refers to spontaneous ischemic necrosis of skeletal muscle among people with diabetes mellitus, unrelated to arterial occlusion. People with DMI may have coexisting end-stage renal disease (ESRD) but little is known about its epidemiology and clinical outcomes in this setting. This scoping review seeks to investigate the characteristics, clinical features, diagnostic evaluation, management and outcomes of DMI among people with ESRD. Electronic database (PubMed/MEDLINE, CINAHL, SCOPUS and EMBASE) searches were conducted for ("diabetic muscle infarction" or "diabetic myonecrosis") and ("chronic kidney disease" or "renal impairment" or "dialysis" or "renal replacement therapy" or "kidney transplant") from January 1980 to June 2017. Relevant cases from reviewed bibliographies in reports retrieved were also included. Data were extracted in a standardized form. A total of 24 publications with 41 patients who have ESRD were included. The mean age at the time of presentation with DMI was 44.2 years. Type 2 diabetes was present in 53.7% of patients while type 1 in 41.5%. In this cohort, 60.1% were receiving hemodialysis, 21% on peritoneal dialysis and 12.2% had kidney transplantation. The proximal lower limb musculature was the most commonly affected site. Muscle pain and swelling were the most frequent manifestation on presentation. Magnetic resonance imaging (MRI) provided the most specific findings for DMI. Laboratory investigation findings are usually non-specific. Non-surgical therapy is usually used in the management of DMI. Short-term prognosis of DMI is good but recurrence occurred in 43.9%. DMI is an uncommon complication in patients with diabetes mellitus, including those affected by ESRD. In comparison with unselected patients with DMI, the characteristics and outcomes of those with ESRD are generally similar. DMI may also occur in kidney transplant recipients, including pancreas-kidney transplantation. MRI is the most useful diagnostic investigation. Non-surgical treatment involving analgesia, optimization of glycemic control and initial bed rest can help to improve recovery rate. However, recurrence of DMI is relatively frequent. PMID- 29527510 TI - Genetic defects in ciliary genes in autosomal dominant polycystic kidney disease. AB - AIM: To evaluate the genetic defects of ciliary genes causing the loss of primary cilium in autosomal dominant polycystic kidney disease (ADPKD). METHODS: We analyzed 191 structural and functional genes of the primary cilium using next generation sequencing analysis. We analyzed the kidney samples, which were obtained from 7 patients with ADPKD who underwent nephrectomy. Each sample contained polycystic kidney tissue and matched normal kidney tissue. RESULTS: In our study, we identified genetic defects in the 5 to 15 genes in each ADPKD sample. The most frequently identified defects were found in genes encoding centrosomal proteins (PCM1, ODF2, HTT and CEP89) and kinesin family member 19 (KIF19), which are important for ciliogenesis. In addition, pathogenic mutations in the PCM1 and KIF19 genes were found in all ADPKD samples. Interestingly, mutations in the genes encoding the intraflagellar transport proteins, which are the basis of animal models of ADPKD, were only rarely detected. CONCLUSION: The results of our study revealed the actual state of structural ciliary genes in human ADPKD tissues and provided valuable indications for further research. PMID- 29527511 TI - Treatment-Related Predictive and Prognostic Factors in Trimodality Approach in Stage IIIA/N2 Non-Small Cell Lung Cancer. AB - While there are no established pretreatment predictive and prognostic factors in patients with stage IIIA/pN2 non-small cell lung cancer (NSCLC) indicating a benefit to surgery as a part of trimodality approach, little is known about treatment-related predictive and prognostic factors in this setting. A literature search was conducted to identify possible treatment-related predictive and prognostic factors for patients for whom trimodality approach was reported on. Overall survival was the primary endpoint of this study. Of 30 identified studies, there were two phase II studies, 5 "prospective" studies, and 23 retrospective studies. No study was found which specifically looked at treatment related predictive factors of improved outcomes in trimodality treatment. Of potential treatment-related prognostic factors, the least frequently analyzed factors among 30 available studies were overall pathologic stage after preoperative treatment and UICC downstaging. Evaluation of treatment response before surgery and by pathologic tumor stage after induction therapy were analyzed in slightly more than 40% of studies and found not to influence survival. More frequently studied factors-resection status, degree of tumor regression, and pathologic nodal stage after induction therapy as well as the most frequently studied factor, the treatment (in almost 75% studies)-showed no discernible impact on survival, due to conflicting results. Currently, it is impossible to identify any treatment-related predictive or prognostic factors for selecting surgery in the treatment of patients with stage IIIA/pN2 NSCLC. PMID- 29527512 TI - Editorial: Data Based Radiation Oncology-Design of Clinical Trials. PMID- 29527513 TI - Growth and Immune Evasion of Lymph Node Metastasis. AB - Cancer patients with lymph node (LN) metastases have a worse prognosis than those without nodal disease. However, why LN metastases correlate with reduced patient survival is poorly understood. Recent findings provide insight into mechanisms underlying tumor growth in LNs. Tumor cells and their secreted molecules engage stromal, myeloid, and lymphoid cells within primary tumors and in the lymphatic system, decreasing antitumor immunity and promoting tumor growth. Understanding the mechanisms of cancer survival and growth in LNs is key to designing effective therapy for the eradication of LN metastases. In addition, uncovering the implications of LN metastasis for systemic tumor burden will inform treatment decisions. In this review, we discuss the current knowledge of the seeding, growth, and further dissemination of LN metastases. PMID- 29527515 TI - Live-Cell Mesothelioma Biobank to Explore Mechanisms of Tumor Progression. AB - Experimental models closely representing in vivo conditions allow investigating mechanisms of resistance. Our aims were to establish a live-cell biobank of malignant pleural mesothelioma (MPM) samples and to obtain proof of principle that primary culture chemoresistant models, mimicking tumor progression observed in patients, can be obtained in vitro, providing a useful tool to investigate underlying mechanisms. Primary mesothelioma cultures were established from 235 samples between 2007 and 2014. Of two MPM patients, primary cultures obtained at different time points: at initial diagnosis, after neoadjuvant treatment at surgery and/or after tumor recurrence, were deeply investigated. Cells and corresponding tumor tissue were characterized by mesothelial protein and gene expression analysis. In addition, primary cultures from chemo naive patients were exposed to increasing doses of cisplatin/pemetrexed during three months and compared with non-treated cells in a cytotoxicity assay, and by selected profiling of senescence markers. In vitro chemoresistance in the primary mesothelioma cell cultures was associated with increased Thy1 (CD90) expression. Thy1 expression in MPM samples was significantly associated with poor overall survival in the TCGA MPM cohort. Our results illustrate that the establishment of a large live-cell MPM biobank contributes to a better understanding of therapy resistance observed in vivo, which eventually may lead to a more logical approach for developing new treatment strategies. PMID- 29527514 TI - Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy. AB - Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewisa, Lewisb, and sialyl Lewisa) and type II (H2, Lewisx, Lewisy, and sialyl Lewisx) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated expression of pertinent fucosyltransferases (FUTs). Nevertheless, the impact of fucose-containing moieties on tumor cell biology is not fully elucidated yet. Here, we review the relevance of tumor overexpressed FUTs and their respective synthesized Lewis determinants in critical aspects associated with cancer progression, such as increased cell survival and proliferation, tissue invasion and metastasis, endothelial to mesenchymal transition, endothelial and immune cell interaction, angiogenesis, multidrug resistance, and cancer stemness. Furthermore, we discuss the potential use of enhanced levels of fucosylation as glycan biomarkers for early prognosis, diagnosis, and disease monitoring in cancer patients. PMID- 29527517 TI - Biofilm Formation in Klebsiella pneumoniae Bacteremia Strains Was Found to be Associated with CC23 and the Presence of wcaG. AB - Klebsiella pneumoniae bacteremia biofilm traits and distribution characteristics have not been clarified. This study aimed to determine the prevalence and characteristics of K. pneumoniae bacteremia biofilm formation (BF) and to explore the virulence factors associated with K. pneumoniae BF. A total of 250 K. pneumoniae bacteremia isolates were collected from patients in Shenzhen and Shanghai, China. Virulence genes in their genomes were detected by PCR. The isolates were subjected to multilocus sequence typing (MLST) and clonal complex (CC) classification based on housekeeping genes. Biofilms were detected by crystal violet staining. Greater BF was observed in isolates from young adults (<40 years old) than in those from seniors (>=65 years old; P = 0.002). MLST yielded 65 different sequence types (STs), with the most represented STs being ST11, ST23, and ST65, and the main CCs were CC23 and CC65; CC23 isolates exhibited greater BF than CC65 or ST11 isolates (both P < 0.001). BF was more pronounced among magA(K1), aero+, rmpA+, rmpA2+, allS+, wcaG+, and iutA+ isolates than in isolates that were negative for these virulence factors. Multivariate regression analysis revealed only wcaG as an independent risk factor for BF (odds ratio 11.426, P < 0.001), and BF was decreased when wcaG was silenced by antisense RNA. In conclusion, BF in K. pneumoniae bacteremia isolates was found to be associated with CC23 classification and the presence of the wcaG virulence factor gene. PMID- 29527518 TI - Management of Diarrhoeal Dehydration in Childhood: A Review for Clinicians in Developing Countries. AB - The survival of a child with severe volume depletion at the emergency department depends on the competency of the first responder to recognize and promptly treat hypovolemic shock. Although the basic principles on fluid and electrolytes therapy have been investigated for decades, the topic remains a challenge, as consensus on clinical management protocol is difficult to reach, and more adverse events are reported from fluid administration than for any other drug. While the old principles proposed by Holliday and Segar, and Finberg have stood the test of time, recent systematic reviews and meta-analyses have highlighted the risk of hyponatraemia, and hyponatraemic encephalopathy in some children treated with hypotonic fluids. In the midst of conflicting literature on fluid and electrolytes therapy, it would appear that isotonic fluids are best suitable for the correction of hypotonic, isonatraemic, and hypernatraemic dehydration. Although oral rehydration therapy is adequate to correct mild to moderate isonatraemic dehydration, parenteral fluid therapy is safer for the child with severe dehydration and those with changes in serum sodium. The article reviews the pathophysiology of water and sodium metabolism and, it uses the clinical case examples to illustrate the bed-side approach to the management of three different types of dehydration using a pre-mixed isotonic fluid solution (with 20 or 40 mmol/L of potassium chloride added depending on the absence or presence of hypokalemia, respectively). When 3% sodium chloride is unavailable to treat hyponatraemic encephalopathy, 0.9% sodium chloride becomes inevitable, albeit, a closer monitoring of serum sodium is required. The importance of a keen and regular clinical and laboratory monitoring of a child being rehydrated is emphasized. The article would be valuable to clinicians in less-developed countries, who must use pre-mixed fluids, and who often cannot get some suitable rehydrating solutions. PMID- 29527516 TI - Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia. AB - The importance of epigenetic dysregulation to acute myeloid leukemia (AML) pathophysiology has become increasingly apparent in recent years. Epigenetic regulators, including readers, writers, and erasers, are recurrently dysregulated by way of chromosomal translocations, somatic mutations, or genomic amplification in AML and many of these alterations are directly implicated in AML pathogenesis. Mutations in epigenetic regulators are often discovered in founder clones and persist after therapy, indicating that they may contribute to a premalignant state poised for the acquisition of cooperating mutations and frank malignancy. Apart from the proto-oncogenic impact of these mutations, the AML epigenome is also shaped by other epigenetic factors that are not mutated but co-opted by AML oncogenes, presenting with actionable vulnerabilities in this disease. Targeting the AML epigenome might also be important for eradicating AML leukemia stem cells, which can be critical for disease maintenance and resistance to therapy. In this review, we describe the importance of epigenetic regulators in AML. We also summarize evidence implicating specific epigenetic regulators in AML pathobiology and discuss emerging epigenome-based therapies for the treatment of AML in the clinic. PMID- 29527519 TI - Radiological Correlates of Raised Intracranial Pressure in Children: A Review. AB - Radiological assessment of the head is a routine part of the management of traumatic brain injury. This assessment can help to determine the requirement for invasive intracranial pressure (ICP) monitoring. The radiological correlates of elevated ICP have been widely studied in adults but far fewer specific pediatric studies have been conducted. There is, however, growing evidence that there are important differences in the radiological presentations of elevated ICP between children and adults; a reflection of the anatomical and physiological differences, as well as a difference in the pathophysiology of brain injury in children. Here in, we review the radiological parameters that correspond with increased ICP in children that have been described in the literature. We then describe the future directions of this work and our recommendations in order to develop non-invasive and radiological markers of raised ICP in children. PMID- 29527522 TI - Low Prevalence of Human Pathogens on Fresh Produce on Farms and in Packing Facilities: A Systematic Review. AB - Foodborne illness burdens individuals around the world and may be caused by consuming fresh produce contaminated with bacterial, parasite, and viral pathogens. Pathogen contamination on produce may originate at the farm and packing facility. This research aimed to determine the prevalence of human pathogens (bacteria, parasites, and viruses) on fresh produce (fruits, herbs, and vegetables) on farms and in packing facilities worldwide through a systematic review of 38 peer-reviewed articles. The median and range of the prevalence was calculated, and Kruskal-Wallis tests and logistic regression were performed to compare prevalence among pooled samples of produce groups, pathogen types, and sampling locations. Results indicated a low median percentage of fresh produce contaminated with pathogens (0%). Both viruses (p-value = 0.017) and parasites (p value = 0.033), on fresh produce, exhibited higher prevalence than bacteria. No significant differences between fresh produce types or between farm and packing facility were observed. These results may help to better quantify produce contamination in the production environment and inform strategies to prevent future foodborne illness. PMID- 29527521 TI - Developing a Return to Work Intervention for Breast Cancer Survivors with the Intervention Mapping Protocol: Challenges and Opportunities of the Needs Assessment. AB - Return to work (RTW) is an important step for breast cancer survivors (BCSs). However, they face many barriers that affect particularly women with low socioeconomic status (SES). Health care, workplace, and insurance actors lack knowledge and collaborate poorly. No intervention to date has proven effective to reduce social disparities in employment after breast cancer. The intervention mapping (IM) protocol is being used in France to develop, implement, and evaluate an intervention to facilitate and sustain RTW after breast cancer [FAciliter et Soutenir le retour au TRAvail apres un Cancer du Sein (FASTRACS) project]. The research question of this study was to elicit the needs for RTW after breast cancer from various stakeholders' point of view. The aim of this study was to describe the process and the preliminary results of the needs assessment of the FASTRACS project. Different methods were followed to (a) establish and work with a planning group and (b) conduct a needs assessment to create a logic model of the problem. A planning group was organized to gather the stakeholders with the research team. A review of the literature and indicators was conducted to identify the magnitude of the problem and the factors influencing RTW. A qualitative inquiry was conducted with 12 focus groups and 48 individual semi structured interviews to explore the needs and experience of the stakeholders. The results of these tasks were the proposition of a charter of partnership to structure the participative process, a review of the scientific evidence and indicators, and the description by the stakeholders of their needs and experience. Many stakeholders disagreed with the concept of "early intervention." They advocated for a better support of BCSs during their RTW, emphasized as a process. Anticipation, intersectoral collaboration, and workplace accommodation were mentioned to fit the needs of the BCS and their environment. A logic model of the problem was elaborated from these data. The ability of the model to consider specific characteristics of women with low SES is discussed, with a view to developing the FASTRACS intervention through the next steps of the IM protocol. PMID- 29527520 TI - Extremely Low-Frequency Magnetic Fields and Redox-Responsive Pathways Linked to Cancer Drug Resistance: Insights from Co-Exposure-Based In Vitro Studies. AB - Electrical devices currently used in clinical practice and common household equipments generate extremely low-frequency magnetic fields (ELF-MF) that were classified by the International Agency for Research on Cancer as "possible carcinogenic." Assuming that ELF-MF plays a role in the carcinogenic process without inducing direct genomic alterations, ELF-MF may be involved in the promotion or progression of cancers. In particular, ELF-MF-induced responses are suspected to activate redox-responsive intracellular signaling or detoxification scavenging systems. In fact, improved protection against oxidative stress and redox-active xenobiotics is thought to provide critical proliferative and survival advantage in tumors. On this basis, an ever-growing research activity worldwide is attempting to establish whether tumor cells may develop multidrug resistance through the activation of essential cytoprotective networks in the presence of ELF fields, and how this might trigger relevant changes in tumor phenotype. This review builds a framework around how the activity of redox responsive mediators may be controlled by co-exposure to ELF-MF and reactive oxygen species-generating agents in tumor and cancer cells, in order to clarify whether and how such potential molecular targets could help to minimize or neutralize the functional interaction between ELF-MF and malignancies. PMID- 29527523 TI - Exposure to Mobile Phone-Emitted Electromagnetic Fields and Human Attention: No Evidence of a Causal Relationship. AB - In the past 20 years of research regarding effects of mobile phone-derived electromagnetic fields (EMFs) on human cognition, attention has been one of the first and most extensively investigated functions. Different domains investigated covered selective, sustained, and divided attention. Here, the most relevant studies on this topic have been reviewed and discussed. A total of 43 studies are reported and summarized: of these, 31 indicated a total absence of statistically significant difference between real and sham signal, 9 showed a partial improvement of attentional performance (mainly increase in speed of performance and/or improvement of accuracy) as a function of real exposure, while the remaining 3 showed inconsistent results (i.e., increased speed in some tasks and slowing in others) or even a worsening in performance (reduced speed and/or deteriorated accuracy). These results are independent of the specific attentional domain investigated. This scenario allows to conclude that there is a substantial lack of evidence about a negative influence of non-ionizing radiations on attention functioning. Nonetheless, published literature is very heterogeneous under the point of view of methodology (type of signal, exposure time, blinding), dosimetry (accurate evaluation of specific absorption rate-SAR or emitted power), and statistical analyses, making arduous a conclusive generalization to everyday life. Some remarks and suggestions regarding future research are proposed. PMID- 29527525 TI - Neuronal Mechanism for Compensation of Longitudinal Chromatic Aberration-Derived Algorithm. AB - The human visual system faces many challenges, among them the need to overcome the imperfections of its optics, which degrade the retinal image. One of the most dominant limitations is longitudinal chromatic aberration (LCA), which causes short wavelengths (blue light) to be focused in front of the retina with consequent blurring of the retinal chromatic image. The perceived visual appearance, however, does not display such chromatic distortions. The intriguing question, therefore, is how the perceived visual appearance of a sharp and clear chromatic image is achieved despite the imperfections of the ocular optics. To address this issue, we propose a neural mechanism and computational model, based on the unique properties of the S-cone pathway. The model suggests that the visual system overcomes LCA through two known properties of the S channel: (1) omitting the contribution of the S channel from the high-spatial resolution pathway (utilizing only the L and M channels). (b) Having large and coextensive receptive fields that correspond to the small bistratified cells. Here, we use computational simulations of our model on real images to show how integrating these two basic principles can provide a significant compensation for LCA. Further support for the proposed neuronal mechanism is given by the ability of the model to predict an enigmatic visual phenomenon of large color shifts as part of the assimilation effect. PMID- 29527526 TI - A Model for Phylogenetic Chemosystematics: Evolutionary History of Quinones in the Scent Gland Secretions of Harvestmen. AB - By the possession of unique exocrine scent glands, Opiliones (harvestmen) arise as a perfect model for studies on the evolutionary history of secretion chemistry. Among gland compounds of harvestmen, it is the quinones that represent recurring elements across the secretions of all suborders. Reliable data on quinone-distribution, however, is only known for Laniatores (benzoquinones) and Cyphophthalmi (naphthoquinones). We here unraveled the quinone-distribution across scent gland secretions of the third large harvestman suborder, the Palpatores (= Eu- and Dyspnoi): Naphthoquinones were found in phalangiid Eupnoi across all subfamilies as well as in nemastomatid (and at least one ischyropsalid) Dyspnoi. Benzoquinones (1,4-benzoquinone) were restricted to a small entity within Eupnoi, namely platybunine Phalangiidae, probably misplaced Gyantinae (currently Sclerosomatidae) and Amilenus (incertae sedis). Our findings, combined with data from Laniatores and Cyphophthalmi, allow evaluation of a comprehensive chemosystematic model for Opiliones for the first time. Evolutionary scenarios imply naphthoquinones as scent gland compounds of common ancestry, having evolved in an early harvestman ancestor and present in cyphophthalmids and palpatoreans, but lost in laniatoreans. Benzoquinones evolved later and independently at least twice: once in the secretions of gonyleptoid Laniatores (alkylated benzoquinones), and a second time in a lineage of phalangiid Eupnoi (1,4-benzoquinone). PMID- 29527524 TI - Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases. AB - Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chemical probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) whilst exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomography (PET)] have reached the clinical research stage. Many chemical compounds, whilst presenting promising in vitro results as oxygen sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, especially in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compounds under oxygen concentration gradients in living cells allows an expansion of the scope of compounds toward in vivo applications which, in turn, would help translate these into clinical applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing molecules having a metal ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of molecular imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclinical and clinical setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers. PMID- 29527527 TI - Lenvatinib-Associated Cervical Artery Dissections in a Patient with Radioiodine Refractory Metastatic Papillary Thyroid Carcinoma. AB - Lenvatinib is a tyrosine kinase inhibitor (TKI) approved by the FDA for the treatment of radioiodine-refractory (RAIR) thyroid cancers. Side effects can be severe, however, and include headaches, hypertension, arterial and venous thromboembolic events, and fatalities. Cervical artery dissections (CADs) are leading contributors of cerebral ischemia in young adults, yet the pathophysiology is poorly understood. Here, we describe a case of a 34-year-old female with recurrent, metastatic, RAIR papillary thyroid cancer who, following her second week of lenvatinib treatment, developed significant CAD which resolved following the termination of the TKI therapy. Given the lack of risk factors for the disorder in the patient's history, the known cardiovascular events associated with the drug, previously described cases of arterial dissections linked to VEGF inhibitors, and the temporal relationship between the onset of symptoms and the treatment start date, a causal relationship between the CAD and lenvatinib is suggested. PMID- 29527528 TI - Reflections on Dry Eye Syndrome Treatment: Therapeutic Role of Blood Products. AB - Dry eye syndrome (DES) is a multifactorial, frequent, pathology characterized by deficient tear production or increased evaporation of tears and associated with ocular surface alteration and inflammation. It mostly affects, but not exclusively, older individuals and leads to varying degrees of discomfort and decreased quality of life. Although the typical treatments of DES rely on using artificial tears, polyunsaturated fatty acids, integrin antagonists, anti inflammatory agents, or on performing punctal occlusion, recently, standardized blood-derived serum eye drops (SED) are generating much interest as a new physiological treatment option. The scientific rationale in using SED for treating or releasing the symptoms of DES is thought to lie in its composition in multiple factors that resembles that of tears and contributes to the healing and protection of the ocular surface. This manuscript seeks to provide relevant background information on the management of DES, and on the increasing role that various types of SED or platelet lysates, from autologous or allogeneic origins, are playing in the improved therapeutic management of this pathology. The increasing role played by blood establishments in producing better-standardized SED is also addressed. PMID- 29527529 TI - Sodium and Potassium Intake from Food Diaries and 24-h Urine Collections from 7 Days in a Sample of Healthy Greek Adults. AB - Objective: The main objective of the present study was to evaluate sodium and potassium intake, employing 24 h and spot urine samples and food diaries for seven consecutive days. Methods: For seven consecutive days subjects recorded their food and drink intakes, and recorded and collected all urinations. Food sodium and potassium intake were analyzed in 24- and 6-h intervals from wake-up time. Urine indices were analyzed in first morning, 24- and 6-h intervals samples over the day from wake-up time. The study took place in Agricultural University of Athens, Greece. In total, 163 healthy subjects (age 39 +/- 12 years; 74 females) were enrolled in the study. Results: Mean urine sodium excretion was 2,803.3 +/- 1,249.0 mg/day (121.9 +/- 54.3 mmol/day) and mean urine potassium excretion was 2,152.2 +/- 913.3 mg/day (55.2 +/- 23.4 mmol/day). The highest potassium concentration was measured in the afternoon, while the lowest sodium concentration was measured in the overnight 6-h interval. Food sodium intake was 1,983.2 +/- 814.1 mg/day and food potassium was 2,264.5 +/- 653.3 mg/day. The sources that contribute most in food sodium intake are dairy products 24%, breads 22%, and savory snacks 17%. Conclusion: Strategies should encourage the Greek population to moderate sodium intake and promote potassium intake, thus adopting a healthier dietary and lifestyle pattern. PMID- 29527531 TI - Functionality and Interfaces of a Herd Health Decision Support System for Practising Dairy Cattle Veterinarians in New Zealand. AB - Decision-making processes to assess and improve the health of dairy herds are often unstructured due to the complexity of interactions that exist between the health and productivity of the herd, for which there are no ready to hand solutions. Decisions made in the face of these complex herd health problems are often based on the experience and perceptions of what might be a quick or the easiest solution. To shift from this unstructured process to semistructured decision-making requires a more holistic understanding of potential health problems and access to herd productivity information and to analytical methods suitable for examining and evaluating such data. Technological advances in agriculture have made the development of such information technology systems both possible and relatively accessible to decision makers working with dairy herds (e.g., veterinarians). The timely access and appropriate analysis of herd productivity data provides the herd health advisor with the opportunity to track and benchmark the performance of dairy herds. Thus, a decision support system (DSS) will use best available evidence to guide the allocation of resources to specific, most promising herd health interventions. This article presents an example of a DSS-based on collection of data and algorithm of analysis. PMID- 29527530 TI - Structural and Mechanistic Basis for Extended-Spectrum Drug-Resistance Mutations in Altering the Specificity of TEM, CTX-M, and KPC beta-lactamases. AB - The most common mechanism of resistance to beta-lactam antibiotics in Gram negative bacteria is the production of beta-lactamases that hydrolyze the drugs. Class A beta-lactamases are serine active-site hydrolases that include the common TEM, CTX-M, and KPC enzymes. The TEM enzymes readily hydrolyze penicillins and older cephalosporins. Oxyimino-cephalosporins, such as cefotaxime and ceftazidime, however, are poor substrates for TEM-1 and were introduced, in part, to circumvent beta-lactamase-mediated resistance. Nevertheless, the use of these antibiotics has lead to evolution of numerous variants of TEM with mutations that significantly increase the hydrolysis of the newer cephalosporins. The CTX-M enzymes emerged in the late 1980s and hydrolyze penicillins and older cephalosporins and derive their name from the ability to also hydrolyze cefotaxime. The CTX-M enzymes, however, do not efficiently hydrolyze ceftazidime. Variants of CTX-M enzymes, however, have evolved that exhibit increased hydrolysis of ceftazidime. Finally, the KPC enzyme emerged in the 1990s and is characterized by its broad specificity that includes penicillins, most cephalosporins, and carbapenems. The KPC enzyme, however, does not efficiently hydrolyze ceftazidime. As with the TEM and CTX-M enzymes, variants have recently evolved that extend the spectrum of KPC beta-lactamase to include ceftazidime. This review discusses the structural and mechanistic basis for the expanded substrate specificity of each of these enzymes that result from natural mutations that confer oxyimino-cephalosporin resistance. For the TEM enzyme, extended spectrum mutations act by establishing new interactions with the cephalosporin. These mutations increase the conformational heterogeneity of the active site to create sub-states that better accommodate the larger drugs. The mutations expanding the spectrum of CTX-M enzymes also affect the flexibility and conformation of the active site to accommodate ceftazidime. Although structural data are limited, extended-spectrum mutations in KPC may act by mediating new, direct interactions with substrate and/or altering conformations of the active site. In many cases, mutations that expand the substrate profile of these enzymes simultaneously decrease the thermodynamic stability. This leads to the emergence of additional global suppressor mutations that help correct the stability defects leading to increased protein expression and increased antibiotic resistance. PMID- 29527532 TI - MYC is not detected in highly proliferating normal spermatogonia but is coupled with CIP2A in testicular cancers. AB - High MYC expression is linked to proliferative activity in most normal tissues and in cancer. MYC also supports self-renewal and proliferation of many types of tissue progenitor cells. Cancerous inhibitor of PP2A (CIP2A) promotes MYC phosphorylation and activity during intestinal crypt regeneration in vivo and in various cancers. CIP2A also supports male germ cell proliferation in vivo. However, the role of MYC in normal germ cell proliferation and spermatogonial progenitor self-renewal is currently unclear. Here, we demonstrate that male germ cells are CIP2A-positive but lack detectable levels of MYC protein; whereas MYC is highly expressed in Leydig cells and peritubular myoid cells contributing thereby to the testicular stem cell niche. On the other hand, MYC was co expressed with CIP2A in testicular cancers. These results demonstrate that CIP2A and MYC are spatially uncoupled in the regulation of spermatogenesis, but functional relationship between these two human oncoproteins is established during testicular cancer transformation. We propose that further analysis of mechanisms of MYC silencing in spermatogonial progenitors may reveal novel fundamental information relevant to understanding of MYC expression in cancer. PMID- 29527533 TI - Differentiation of the Follicular Neoplasm on the Gray-Scale US by Image Selection Subsampling along with the Marginal Outline Using Convolutional Neural Network. AB - We conducted differentiations between thyroid follicular adenoma and carcinoma for 8-bit bitmap ultrasonography (US) images utilizing a deep-learning approach. For the data sets, we gathered small-boxed selected images adjacent to the marginal outline of nodules and applied a convolutional neural network (CNN) to have differentiation, based on a statistical aggregation, that is, a decision by majority. From the implementation of the method, introducing a newly devised, scalable, parameterized normalization treatment, we observed meaningful aspects in various experiments, collecting evidence regarding the existence of features retained on the margin of thyroid nodules, such as 89.51% of the overall differentiation accuracy for the test data, with 93.19% of accuracy for benign adenoma and 71.05% for carcinoma, from 230 benign adenoma and 77 carcinoma US images, where we used only 39 benign adenomas and 39 carcinomas to train the CNN model, and, with these extremely small training data sets and their model, we tested 191 benign adenomas and 38 carcinomas. We present numerical results including area under receiver operating characteristic (AUROC). PMID- 29527534 TI - Upregulations of Clcn3 and P-Gp Provoked by Lens Osmotic Expansion in Rat Galactosemic Cataract. AB - Objective: Lens osmotic expansion, provoked by overactivated aldose reductase (AR), is the most essential event of sugar cataract. Chloride channel 3 (Clcn3) is a volume-sensitive channel, mainly participating in the regulation of cell fundamental volume, and P-glycoprotein (P-gp) acts as its modulator. We aim to study whether P-gp and Clcn3 are involved in lens osmotic expansion of galactosemic cataract. Methods and Results: In vitro, lens epithelial cells (LECs) were primarily cultured in gradient galactose medium (10-60 mM), more and more vacuoles appeared in LEC cytoplasm, and mRNA and protein levels of AR, P-gp, and Clcn3 were synchronously upregulated along with the increase of galactose concentration. In vivo, we focused on the early stage of rat galactosemic cataract, amount of vacuoles arose from equatorial area and scattered to the whole anterior capsule of lenses from the 3rd day to the 9th day, and mRNA and protein levels of P-gp and Clcn3 reached the peak around the 9th or 12th day. Conclusion: Galactosemia caused the osmotic stress in lenses; it also markedly leads to the upregulations of AR, P-gp, and Clcn3 in LECs, together resulting in obvious osmotic expansion in vitro and in vivo. PMID- 29527535 TI - Assessing the Performance of a Noninvasive Glucose Monitor in People with Type 2 Diabetes with Different Demographic Profiles. AB - Background: Noninvasive glucose-monitoring devices represent an exciting frontier in diabetes research. GlucoTrack(r) is a noninvasive device that indirectly measures glucose fluctuation in the earlobe tissue. However, GlucoTrack measurements may be susceptible to effects of quasi-stable factors that may be affected by demographic profiles. The current study, thus, examined device performances in people with type 2 diabetes with different demographic profiles, focusing on age, gender, body mass, and whether the earlobe is pierced. Materials and Methods: Clinical trials were conducted on 172 type 2 adult diabetic subjects. Device performance was clinically evaluated using the Clarke error grid (CEG) analysis and statistically assessed using absolute relative difference (ARD). Results: CEG analysis revealed that 97.6% of glucose readings were within the clinically acceptable CEG A + B zones. Mean and median ARD were 22.3% and 18.8%, respectively. Likelihood ratio and parametric bootstrap tests revealed that there were no significant differences in ARD values across age, gender, body mass, and whether the earlobe was pierced, indicating that the accuracy of GlucoTrack remains consistent across the tested demographic profiles. Conclusions: Our results suggest that GlucoTrack performance does not depend on demographic profiles of its users and it is thus suitable for various people with type 2 diabetes. PMID- 29527536 TI - Adherence to Mediterranean Diet Pattern among Spanish Adults Attending a Medical Centre: Nondiabetic Subjects and Type 1 and 2 Diabetic Patients. AB - Objective: To identify adherence to Mediterranean diet among two groups of Spanish adults: diabetic patients and nondiabetic subjects. Methods: Adherence to Mediterranean diet was measured by a 14-item screener (scale: 0-14; <=5: low, 6 9: moderate, and >=10: high) in 351 volunteers. Results: Mean age was 50.97 +/- 12.58 in nondiabetics (n = 154) and 59.50 +/- 13.34 in diabetics (n = 197). The whole sample scored 8.77 +/- 1.82. Score was 9.19 +/- 1.84 in nondiabetic females (n = 58) and 8.15 +/- 1.79 in diabetic females (n = 85) (p = 0.003), due to lower consumption of olive oil (p = 0.005) and nuts (p = 0.000). Type 2 diabetic males (n = 79; 8.76 +/- 1.88) consumed less olive oil than healthy males (n = 28; 9.36 +/- 1.59) (p = 0.046). Up to 30-year-old nondiabetics scored lower than more than 60-year-old nondiabetics (8.40 +/- 1.5 versus 9.74 +/- 2.03; p = 0.047). The youngest ate less olive oil (p = 0.002) and more pastries (p = 0.007). Conclusions: The sample presented moderate adherence to Mediterranean diet in all subgroups. Scientific evidence about the benefits of Mediterranean diet, olive oil, and nuts supports the recommendation to increase consumption of olive oil and nuts in diabetic women and of daily olive oil in type 2 diabetic men, reducing consumption of red meat, butter, and pastries, and to promote Mediterranean diet among the youngest of the sample studied. PMID- 29527537 TI - Robot-assisted vitreoretinal surgery: current perspectives. AB - Vitreoretinal microsurgery is among the most technically challenging of the minimally invasive surgical techniques. Exceptional precision is required to operate on micron scale targets presented by the retina while also maneuvering in a tightly constrained and fragile workspace. These challenges are compounded by inherent limitations of the unassisted human hand with regard to dexterity, tremor and precision in positioning instruments. The limited human ability to visually resolve targets on the single-digit micron scale is a further limitation. The inherent attributes of robotic approaches therefore, provide logical, strategic and promising solutions to the numerous challenges associated with retinal microsurgery. Robotic retinal surgery is a rapidly emerging technology that has witnessed an exponential growth in capabilities and applications over the last decade. There is now a worldwide movement toward evaluating robotic systems in an expanding number of clinical applications. Coincident with this expanding application is growth in the number of laboratories committed to "robotic medicine". Recent technological advances in conventional retina surgery have also led to tremendous progress in the surgeon's capabilities, enhanced outcomes, a reduction of patient discomfort, limited hospitalization and improved safety. The emergence of robotic technology into this rapidly advancing domain is expected to further enhance important aspects of the retinal surgery experience for the patients, surgeons and society. PMID- 29527538 TI - Therapeutic Applications of BCI Technologies. AB - Brain-computer interface (BCI) technology can restore communication and control to people who are severely paralyzed. There has been speculation that this technology might also be useful for a variety of diverse therapeutic applications. This survey considers possible ways that BCI technology can be applied to motor rehabilitation following stroke, Parkinson's disease, and psychiatric disorders. We consider potential neural signals as well as the design and goals of BCI-based therapeutic applications. These diverse applications all share a reliance on neuroimaging and signal processing technologies. At the same time, each of these potential applications presents a series of unique challenges. PMID- 29527539 TI - Durability of Efavirenz Compared With Boosted Protease Inhibitor-Based Regimens in Antiretroviral-Naive Patients in the Caribbean and Central and South America. AB - Background: Efavirenz (EFV) and boosted protease inhibitors (bPIs) are still the preferred options for firstline antiretroviral regimens (firstline ART) in Latin America and have comparable short-term efficacy. We assessed the long-term durability and outcomes of patients receiving EFV or bPIs as firstline ART in the Caribbean, Central and South America network for HIV epidemiology (CCASAnet). Methods: We included ART-naive, HIV-positive adults on EFV or bPIs as firstline ART in CCASAnet between 2000 and 2016. We investigated the time from starting until ending firstline ART according to changes of third component for any reason, including toxicity and treatment failure, death, and/or loss to follow up. Use of a third-line regimen was a secondary outcome. Kaplan-Meier estimators of composite end points were generated. Crude cumulative incidence of events and adjusted hazard ratios (aHRs) were estimated accounting for competing risk events. Results: We included 14 519 patients: 12 898 (89%) started EFV and 1621 (11%) bPIs. The adjusted median years on firstline ART were 4.6 (95% confidence interval [CI], 4.4-4.7) on EFV and 3.8 (95% CI, 3.8-4.0) on bPI (P < .001). Cumulative incidence of firstline ART ending at 10 years of follow-up was 32% (95% CI, 31-33) on EFV and 44% (95% CI, 39-48) on bPI (aHR, 0.88; 95% CI, 0.78 0.97). The cumulative incidence rates of third-line initiation in the bPI-based group were 6% (95% CI, 2.4-9.6) and 2% (95% CI, 1.4-2.2) among the EFV-based group (P < .01). Conclusions: Durability of firstline ART was longer with EFV than with bPIs. EFV-based regimens may continue to be the preferred firstline regimen for our region in the near future due to their high efficacy, relatively low toxicity (especially at lower doses), existence of generic formulations, and affordability for national programs. PMID- 29527540 TI - Trauma exposure, discrimination, and romantic relationship functioning: A longitudinal investigation among LGB young adults. AB - Sexual orientation-related discrimination is common among sexual minority individuals, but its influence on romantic relationship functioning remains unclear. Further, exposure to potentially traumatic events may influence the association between discrimination and relationship functioning, but this has not been tested among sexual minority couples to date. The current study examines breadth of lifetime trauma exposure as a moderator of the associations between recent discrimination and changes in relationship functioning (satisfaction, commitment, and trust) over twelve months among 86 racially/ethnically diverse sexual minority young adults in relationships. For those with low trauma exposure, discrimination was associated with increases in satisfaction and commitment, but not trust. In contrast, for those with high trauma exposure, discrimination was not associated with changes in relationship functioning. Thus, some partnered sexual minority young adults may experience resilience in the face of discrimination, such that discrimination may promote positive relationship functioning. However, this does not appear to extend to those with more extensive trauma exposure histories. With an eye toward informing interventions, these findings call for additional research on individual differences in responses to discrimination, such as support seeking and dyadic coping. PMID- 29527541 TI - Evaluation of aerodynamic characteristics of a coupled fluid-structure system using generalized Bernoulli's principle: An application to vocal folds vibration. AB - In this work we explore the aerodynamics flow characteristics of a coupled fluid structure interaction system using a generalized Bernoulli equation derived directly from the Cauchy momentum equations. Unlike the conventional Bernoulli equation where incompressible, inviscid, and steady flow conditions are assumed, this generalized Bernoulli equation includes the contributions from compressibility, viscous, and unsteadiness, which could be essential in defining aerodynamic characteristics. The application of the derived Bernoulli's principle is on a fully-coupled fluid-structure interaction simulation of the vocal folds vibration. The coupled system is simulated using the immersed finite element method where compressible Navier-Stokes equations are used to describe the air and an elastic pliable structure to describe the vocal fold. The vibration of the vocal fold works to open and close the glottal flow. The aerodynamics flow characteristics are evaluated using the derived Bernoulli's principles for a vibration cycle in a carefully partitioned control volume based on the moving structure. The results agree very well to experimental observations, which validate the strategy and its use in other types of flow characteristics that involve coupled fluid-structure interactions. PMID- 29527542 TI - Immunoprecipitation of Tri-methylated Capped RNA. AB - Cellular quiescence (also known as G0 arrest) is characterized by reduced DNA replication, increased autophagy, and increased expression of cyclin-dependent kinase p27Kip1. Quiescence is essential for wound healing, organ regeneration, and preventing neoplasia. Previous findings indicate that microRNAs (miRNAs) play an important role in regulating cellular quiescence. Our recent publication demonstrated the existence of an alternative miRNA biogenesis pathway in primary human foreskin fibroblast (HFF) cells during quiescence. Indeed, we have identified a group of pri-miRNAs (whose mature miRNAs were found induced during quiescence) modified with a 2,2,7-trimethylguanosine (TMG)-cap by the trimethylguanosine synthase 1 (TGS1) protein and transported to the cytoplasm by the Exportin-1 (XPO1) protein. We used an antibody against (TMG)-caps (which does not cross-react with the (m7G)-caps that most pri-miRNAs or mRNAs contain [Luhrmann et al., 1982]) to perform RNA immunoprecipitations from total RNA extracts of proliferating or quiescent HFFs. The novelty of this assay is the specific isolation of pri-miRNAs as well as other non-coding RNAs containing a TMG-cap modification. PMID- 29527543 TI - Data on the effect of improved TiO2/FTO interface and Ni(OH)2 cocatalyst on the photoelectrochemical performances and stability of CdS cased ZnIn2S4/TiO2 heterojunction. AB - This data article presents the experimental evidences of the effect of TiO2 fluorine doped tin oxide interface annealing and Ni(OH)2 cocatalysts on the photoelectrochemical, structural, morphological and optical properties of Ni(OH)2/CdS/ZnIn2S4/TiO2 heterojunction. The Raman spectroscopy exhibits the sharp features of the rutile phase of TiO2 and in agreement with the X-ray diffraction data. The band gap energy of the 500 degrees C sample was found to be 3.12 eV, further it was increased to 3.20, 3.22 eV for samples annealed at 600 and 700 degrees C respectively. The decrease in the band gap energy at 500 degrees C related to the oxygen vacancies and was analysed by photoluminescence spectroscopy analysis. The synthesis, characterization methods and other experimental details of TiO2 based heterostructure are also provided. The presence of CdS and ZnIn2S4 coating on surface of TiO2 electrodes providing a high surface area, extended visible absorption and helps to improve the change separation. This data article contains data related to the research article entitled "Highly efficient and stable 3D Ni(OH)2/CdS/ZnIn2S4/TiO2 heterojunction under solar light: Effect of an improved TiO2/FTO interface and cocatalyst" (Mahadik et al., 2017) [1]. PMID- 29527544 TI - Data on genetic associations of carotid atherosclerosis markers in Mexican American and European American rheumatoid arthritis subjects. AB - Carotid Intima-media thickness (CIMT) and plaque are well established markers of subclinical atherosclerosis and are widely used for identifying subclinical atherosclerotic disease. We performed association analyses using Metabochip array to identify genetic variants that influence variation in CIMT and plaque, measured using B-mode ultrasonography, in rheumatoid arthritis (RA) patients. Data on genetic associations of common variants associated with both CIMT and plaque in RA subjects involving Mexican Americans (MA) and European Americans (EA) populations are presented in this article. Strong associations were observed after adjusting for covariate effects including baseline clinical characteristics and statin use. Susceptibility loci and genes and/or nearest genes associated with CIMT in MAs and EAs with RA are presented. In addition, common susceptibility loci influencing CIMT and plaque in both MAs and EAs have been presented. Polygenic Risk Score (PRS) plots showing complementary evidence for the observed CIMT and plaque association signals are also shown in this article. For further interpretation and details, please see the research article titled "A Genetic Association Study of Carotid Intima-Media Thickness (CIMT) and Plaque in Mexican Americans and European Americans with Rheumatoid Arthritis" which is being published in Atherosclerosis (Arya et al., 2018) [1].(Arya et al., in press) Thus, common variants in several genes exhibited significant associations with CIMT and plaque in both MAs and EAs as presented in this article. These findings may help understand the genetic architecture of subclinical atherosclerosis in RA populations. PMID- 29527545 TI - Data on incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants. AB - This article contains the data showing the different characteristics of atrial fibrillation (AF) patients treated with vitamin K (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) screened for the presence of liver fibrosis (LF) and followed to record the occurrence of bleeding and cardiovascular events (CVEs). A detailed description of major and minor bleedings is provided according to anticoagulant treatment (VKAs vs. NOACs) and to the presence of LF. Data here reported also show a higher incidence rate of CVEs in VKA-treated patients, but not in those on NOACs. The data are supplemental to our original research article titled "Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non vitamin K antagonists oral anticoagulants" (Pastori et al., 2018) [1]. PMID- 29527546 TI - Data and videos for ultrafast synchrotron X-ray imaging studies of metal solidification under ultrasound. AB - The data presented in this article are related to the paper entitled 'Ultrafast synchrotron X-ray imaging studies of microstructure fragmentation in solidification under ultrasound' [Wang et al., Acta Mater. 144 (2018) 505-515]. This data article provides further supporting information and analytical methods, including the data from both experimental and numerical simulation, as well as the Matlab code for processing the X-ray images. Six videos constructed from the processed synchrotron X-ray images are also provided. PMID- 29527547 TI - An enlarging, ulcerated scalp nodule. PMID- 29527548 TI - Lip ulceration in an immunocompromised patient. PMID- 29527549 TI - Asymptomatic progressive symmetric telangiectatic patches of the extremities. PMID- 29527550 TI - The value of visual inspection with acetic acid and Pap smear in cervical cancer screening program in low resource settings - A population-based study. AB - This study aims to determine the diagnostic values of visual inspection with acetic acid (VIA) and Pap smear in a cervical cancer screening program at a community level in Vietnam. A cross-sectional analysis was obtained, including 1034 women of reproductive age from Thua Thien Hue Province, Vietnam from 09/2012 to 09/2013. Samples were taken from cervixes for Pap smear testing, followed by visual inspection with acetic acid. Subjects with abnormal VIA and/or positive cytology results were invited for colposcopy and biopsy. Histologic confirmed cervical intraepithelial neoplasia (CIN2+) served as gold standards for diagnostic values analysis. Abnormal VIA results were recorded in 87 cases (7.7%). The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of VIA for CIN2+ were 88.8%, 43.8%, 63.4%, 51.2% and 83.3%, respectively. Diagnostic values of Pap smear were 58.0%, 85.2%, 69.9%, 83.3% and 61.3% for its sensitivity, specificity, accuracy, PPV and NPV, respectively. VIA yielded high sensitivity but its accuracy is still limited in pre-cancerous lesions during cervical cancer screening. The Pap smear has acceptable sensitivity and specificity, but its false-negative rate is still high. We recommend a combination of different tests to increase the efficiency of screening in our community. PMID- 29527552 TI - Perioperative airway management for aortic valve replacement in an adult with mucopolysaccharidosis type II (Hunter syndrome). AB - We herein report anesthetic management during aortic valve replacement for aortic valve regurgitation in a patient with adult mucopolysaccharidosis type II (MPS type 2) (Hunter syndrome). This disorder is rare and related to the accumulation of a mucopolysaccharide in lysosomes. It affects various organs, including the airways, heart, and central nerves. In children with MPS type 2, the risk of airway obstruction during anesthesia/sedation is high, and the degree of difficulty increases with aging. The patient described herein was a 33-year-old male without mental retardation. Before surgery, trismus, megaloglossia, and the disturbance of cervical vertebral excursion were noted, suggesting difficulties with ventilation/intubation. Anesthesia was induced under sedation/spontaneous respiration. A laryngeal deployment was conducted using a video laryngoscope; however, the Cormack grade was III. Nasotracheal fiber intubation was performed, and airway obstruction occurred. A muscle relaxant was administered, facilitating ventilation. However, subglottic stenosis, which was not detected before the surgery, made the tracheal tube insertion difficult. Aortic valve replacement was performed without complications. A detailed postoperative examination of the airways revealed oropharyngeal soft tissue outgrowth, narrowing of the upper airway, subglottic stenosis, and displacement/circumflex of the airway axis. Either awake intubation or rapid induction can be selected for this patient; however, either way have risks of airway obstruction. It is important that strategies under light anesthesia or incomplete neuromuscular blockade should be avoided for such our patient as suggested in the JSA airway management guidelines. A preoperative multidisciplinary airway assessment and simulation are important. PMID- 29527551 TI - Moderate intensity physical activity associates with CSF biomarkers in a cohort at risk for Alzheimer's disease. AB - Introduction: Alzheimer's disease (AD) is characterized by the presence of amyloid beta (Abeta) plaques, neurofibrillary tangles, and neurodegeneration, evidence of which may be detected in vivo via cerebrospinal fluid (CSF) sampling. Physical activity (PA) has emerged as a possible modifier of these AD-related pathological changes. Consequently, the aim of this study was to cross sectionally examine the relationship between objectively measured PA and CSF levels of Abeta42 and tau in asymptomatic late-middle-aged adults at risk for AD. Methods: Eighty-five cognitively healthy late-middle-aged adults (age = 64.31 years, 61.2% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They wore an accelerometer (ActiGraph GT3X+) for one week to record free-living PA, yielding measures of sedentariness and various intensities of PA (i.e., light, moderate, and vigorous). They also underwent lumbar puncture to collect CSF, from which Abeta42, total tau, and phosphorylated tau were immunoassayed. Regression analyses were used to examine the association between accelerometer measures and CSF biomarkers, adjusting for age, sex, and other relevant covariates. Results: Engagement in moderate PA was associated with higher Abeta42 (P = .008), lower total tau/Abeta42 (P = .006), and lower phosphorylated tau/Abeta42 (P = .030). In contrast, neither light nor vigorous PA was associated with any of the biomarkers. Increased sedentariness was associated with reduced Abeta42 (P = .014). Discussions: In this cohort, moderate PA, but not light or vigorous, was associated with a favorable AD biomarker profile, while sedentariness was associated with greater Abeta burden. These findings suggest that a physically active lifestyle may play a protective role against the development of AD. PMID- 29527553 TI - White light-emitting contrast image capsule endoscopy for visualization of small intestine lesions: a pilot study. AB - Background and study aims: Capsule endoscopy (CE) has become a routine means of diagnosing obscure gastrointestinal bleeding (OGIB) in the small intestine. Capsules using novel blue-enhanced white light-emitting diodes are expected to acquire clearer contrast images (CIs) of the small bowel vasculature. We conducted a pilot study to examine whether CIs facilitate visualization of small bowel erosions, ulcers, and areas of angioectasia compared with standard white light images (WLIs). Patients and methods: A total of 24 patients with OGIB were recruited in this study. The main outcome measure was visibility of lesions on CIs compared with WLIs. We also examined the color difference between lesions and normal mucosa (DeltaE) with each imaging modality. Results: Three experienced physicians retrospectively evaluated 138 images of small bowel lesions (107 erosions, or ulcers, and 31 areas of angioectasia) obtained from 24 CE examinations. The endoscopists judged that compared with WLIs, CIs afforded easier identification of erosions or ulcers in 29 of 107 cases (27.1 %), were non inferior in 68 of 107 cases (63.6 %), and were inferior in 10 of 107 cases (9.3 %). Identification of angioectasia was judged to be easier with CIs in 15 of 31 cases (48.4 %), non-inferior in 13 of 31 cases (41.9 %), and inferior in 3 of 31 cases (9.7 %). DeltaE was significantly higher for CIs than WLIs, especially for angioectasia, potentially explaining why lesions were easier to visualize. Conclusions: CIs obtained by CE appear to facilitate identification of small bowel erosions, ulcers, and areas of angioectasia compared with WLIs. PMID- 29527554 TI - Linked color imaging enhances endoscopic detection of sessile serrated adenoma/polyps. AB - Background and study aims: Although new image-enhanced endoscopy (IEE) technologies such as blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI) have been developed, their utility for the detection of sessile serrated adenoma/polyps (SSA/Ps) is still unclear. This study aimed to evaluate the utility of BLI, BLI-bright, and LCI for SSA/P detection in still image examinations and in a prospective randomized controlled trial (RCT). Patients and methods: A group of 6 expert and non-expert endoscopists read 200 endoscopic still images containing SSA/P lesions using white light image (WLI), BLI, BLI bright, and LCI. Color differences were calculated using the color space method. A prospective RCT of tandem colonoscopy with WLI and LCI was performed. Patients with SSA/P and those with a history of SSA/P that had been endoscopically removed were enrolled and randomly allocated to WLI-LCI or LCI-WLI groups. Additional endoscopic detection rates for SSA/P were compared between the 2 groups. Results: LCI showed the highest SSA/P detection rate among the 4 modes for both expert and non-expert endoscopists. The detection rate with LCI for the 6 expert endoscopists (mean 98.3 +/- standard deviation 2.0 %) was significantly higher than that with WLI (86.7 +/- 6.0 %, P < 0.01). Likewise, the detection rate with LCI for the 6 non-expert endoscopists (92.3 +/- 2.9 %) was significantly higher than that with WLI (72.7 +/- 11.5 %, P < 0.01). The color difference of SSA/P with LCI was the highest among the 4 modes, and was significantly higher than with WLI (median 15.9, (interquartile range 13.7 - 20.6) vs. 10.2, (7.6 - 14.2); P < 0.0001). In the RCT, a total of 44 patients (WLI-LCI 22 vs. LCI-WLI 22) underwent colonoscopy. The additional detection rate for SSA/P in the second inspection in the WLI-LCI group (21.6 %, 8/37) was significantly higher than in the LCI-WLI group (3.2 %, 1/31; P = 0.02). The small, flat, non-mucus and isochromatic SSA/Ps in the transverse colon were detected more frequently in the second inspection with LCI. Conclusions: LCI was the most sensitive mode for SSA/P detection among WLI, BLI, BLI-bright, and LCI in the still image examinations. Our RCT strongly suggests that LCI is superior to conventional WLI for SSA/P detection during colonoscopy. UMIN000017599. PMID- 29527555 TI - Effectiveness and safety of endoscopic radial incision and cutting for severe benign anastomotic stenosis after surgery for colorectal carcinoma: a three-case series. AB - Benign colonic anastomotic stenosis sometimes occurs after surgical resection and usually requires surgical or endoscopic dilation. Limited data are available on the effectiveness and safety of the endoscopic radial incision and cutting (RIC) method at sites other than the esophagus. The aim of this retrospective study was to investigate the effectiveness and safety of RIC dilation for severe benign anastomotic colonic stenosis. Subjects were 3 men (median age 72 years, range 65 76 years) who developed severe benign anastomotic stenosis after surgical resection for colorectal carcinoma and were subsequently treated by RIC dilation at Hiroshima City Asa Citizens Hospital between May 2014 and December 2016. Severe anastomotic stenosis was defined as a narrowed anastomosis through which a standard colonoscope could not be passed. The median interval from surgery to RIC was 21 months (range 9 - 29 months). RIC was successful in all 3 patients and reduced the severity of dyschezia postoperatively; 2 patients experienced improvement after a single RIC session and the other after 6 RIC sessions. No treatment-related adverse events or re-stenosis requiring repeat dilation was noted during a median follow-up of 27 months (range 8 - 37 months). Our findings indicate that the RIC technique can be applied safely and effectively to various sites in the colon, avoiding the need for reoperation. PMID- 29527556 TI - Risk factors for post-colorectal endoscopic submucosal dissection (ESD) coagulation syndrome: a multicenter, prospective, observational study. AB - Background and study aims: Colorectal cancer (CRC) is one of the most common neoplasms and endoscopic submucosal dissection (ESD) is an effective treatment for early-stage CRC. However, it has been observed that patients undergoing ESD often complain of pain, even if ESD has been successfully performed. Risk factors for such pain still remain unknown. The aim of this study was to explore the risk factors for post-colorectal ESD coagulation syndrome (PECS). Patients and methods : This was a prospective multicenter observational trial (UMIN000016781) conducted in 106 of 223 patients who underwent ESD between March 2015 and April 2016. We investigated age, sex, tumor location, ESD operation time, lesion size, duration of hospitalization, and frequency of PECS. We defined PECS as local abdominal pain (evaluated on a visual analogue scale) in the region corresponding to the site of the ESD that occurred within 4 days of the procedure. Results : PECS occurred in 15/106 (14.2 %), and 10 were women ( P = 0.01, OR: 7.74 [1.6 - 36.4]), 7 had lesions in the cecum ( P < 0.001, OR: 20.6 [3.7 - 115.2]), and 9 in whom ESD operation time was > 90 min ( P = 0.002, OR: 10.3 [2.4 - 44.6]). Frequency of deviation from the prescribed clinical path was significantly higher (47 % [7/15] vs. 2 % [2/91], P < 0.001, OR: 38.9 [6.9 - 219.6]), and hospital stay was significantly longer in the PECS group. . Conclusions : Female gender, location of lesion in the cecum, and ESD operation time > 90 minutes were significant risk factors independent of PECS. These findings are important to management of PECS. . PMID- 29527557 TI - Endoscopic submucosal dissection to relieve a flexure of the gastric conduit after esophagectomy. AB - Background and study aims A 70-year-old-man underwent an esophagectomy and posterior mediastinal reconstruction for esophageal cancer that was curatively resected. Although the patient was allowed to eat after surgery, he repeatedly vomited after drinking water or eating meals and required continuous hospitalization. An upper gastrointestinal series and endoscopic examination revealed an obstruction due to the flexure of the gastric conduit, which was repeatedly treated with endoscopic balloon dilation. Endoscopic balloon dilation was completely ineffective, however, because the obstruction was not due to a small lumen diameter, but rather to severe flexure. We hypothesized that the power of contraction provided by ulcer scar formation after mucosal resection could straighten the flexure, and thus removed a piece of the mucosa 8 cm in diameter on the oral side of the flexure by endoscopic submucosal dissection (ESD) 4 months after the esophagectomy. Endoscopic examination on post-ESD Day 10 revealed that the gastric conduit flexure was straightened due to ulcer scarring, and obstruction at the flexure opened over time. Meals were restarted and the patient could eat without vomiting. He was discharged from the hospital 5 weeks after ESD. This is the first case report of obstruction due to flexure of the gastric conduit after esophagectomy that was successfully treated with mucosectomy using ESD. Mucosectomy using ESD may be an effective treatment option for obstruction due to flexure of the gastric conduit after esophagectomy. PMID- 29527558 TI - Heparin priming of EUS-FNA needles does not adversely affect tissue cytology or immunohistochemical staining. AB - Background and study aims: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) or biopsy (FNB) is an indispensable diagnostic tool. Improvements in needling technique have led to increasing tissue yields. Blood clogging of the needle can cause difficulties with specimen handling and stylet passage, which improves when the needle is primed with heparin before use. However, the effect of heparin on cytology, histology or immunochemistry (IHC) of FNA and FNB specimens is unknown. The goal of the study was to evaluate heparin priming on cytologic/histologic appearance, IHC staining, ease of stylet passage, and specimen bloodiness. Patients and methods: This was a retrospective study of patients undergoing EUS-FNA/FNB. Needle sizes were 25 gauge (g), 22 g, and 19 g. Heparin priming of the needle was done and the stylet replaced ("dry heparin") or suction attached without replacing the stylet ("wet heparin"). Smears and cellblocks were examined by pathologists, and IHC staining were done as needed. Specimen bloodiness was compared with matched controls. Results: Adequate tissue yields were obtained in all samples (37 heparin, 36 no heparin). Heparin priming did not exhibit negative effects on cytologic or histologic interpretation of the specimens, nor IHC. There was no difference in cellblock bloodiness between the heparin primed needle specimens and the non-heparin control group. . Conclusions: Heparin priming of EUS-FNA or FNB needles does not negatively affect cytologic or histologic interpretation, nor interfere with IHC. In addition, heparin priming does not increase specimen bloodiness. When the "wet suction" technique is used for EUS-FNA, heparin priming can be used instead of saline priming of the EUS needle. PMID- 29527559 TI - EUS-guided gastroenterostomy in management of benign gastric outlet obstruction. AB - Background and study aims: Endoscopic ultrasound-guided gastroenterostomy (EUS GE) in malignant gastric outlet obstruction (GOO) appears to be promising; however, its role in benign GOO is unclear. The aim of this study was to ascertain the clinical efficacy and safety of EUS-GE in benign GOO. Patients and methods: This was an international retrospective series involving 5 tertiary centers. Consecutive patients who underwent EUS-GE between 1/2013 - 10/2016 for benign GOO were included. The primary endpoint was the rate of clinical success defined as ability to tolerate oral intake without vomiting. Secondary endpoints included technical success and rate of adverse events (AE). Results: Overall, 26 patients (46.2 % female; mean age 57.7 +/- 13.9 years) underwent EUS-GE for benign GOO due to strictures from chronic pancreatitis (n = 11), surgical anastomosis (n = 6), peptic ulcer disease (n = 5), acute pancreatitis (n = 1), superior mesentery artery syndrome (n = 1), caustic injury (n = 1), and hematoma (n = 1). Technical success was achieved in 96.2 %. Dilation of the lumen apposing metal stent was performed in 13/25 (52 %) with a mean maximum diameter of 14.6 +/ 1.0 mm. Mean procedure time was 44.6 +/- 26.1 min. Clinical success was observed in 84.0 % with a mean time to oral intake of 1.4 +/- 1.9 days and a median follow up of 176.5 (IQR: 47 - 445.75) days. Rate of unplanned re-intervention was 4.8 %. 3 AE were noted including 2 misdeployed stents and 1 gastric leak needing surgical intervention following elective GE stent removal. Conclusions: EUS-GE is a promising treatment for benign GOO. Larger and prospective data are needed to further validate this novel endoscopic technique in treating benign GOO of various etiologies. PMID- 29527560 TI - Magnifying endoscopy with narrow-band imaging for gastric heterotopic pancreas. AB - Background and study aims: Heterotopic pancreas is a common subepithelial lesion in the stomach. However, its histological diagnosis is difficult when tissue samples are obtained with a conventional biopsy forceps. This study aimed to describe the magnifying endoscopy with narrow-band imaging (ME-NBI) features of gastric heterotopic pancreas. Patients and methods: We retrospectively analyzed a database of all patients who underwent endoscopic ultrasonography (EUS) at Pusan National University Hospital from January 2010 to December 2010. Thirty-six patients with endosonographically diagnosed heterotopic pancreas who underwent ME NBI and endoscopic ultrasonography (EUS) simultaneously were studied. The ME-NBI features of their lesions were analyzed. Results: Thirty lesions were located in the antrum and six in the body. Six lesions (17 %) showed umbilication or central dimpling on the surface, and nine (25 %) had a macroscopic opening on the surface. On ME-NBI, a microscopic opening was identified in 22 (81 %) of 27 lesions wherein a macroscopic opening was not observed during conventional endoscopy. Macroscopic or microscopic opening was observed in 31 lesions (86 %). The frequency of macroscopic or microscopic opening was higher in lesions with anechoic duct-like structures than in lesions without such structures on EUS (91 % [29/32] vs 50 % [2/4], P = 0.027). Focal loss of microsurface structure and presence of a thickened submucosal vessel were observed in 6 (17 %) and 5 lesions (14 %), respectively. Conclusions : The characteristic ME-NBI feature of heterotopic pancreas is presence of a microscopic opening on its surface. This ME NBI feature is potentially useful for differentiating heterotopic pancreas from other gastric subepithelial tumors. PMID- 29527562 TI - Nomenclature for radiopharmaceuticals, consultation of your opinion! PMID- 29527561 TI - Impact of electrosurgical unit mode on post esophageal endoscopic submucosal dissection stricture in an in vivo porcine model. AB - Background and aim: Strictures are a major complication of esophageal endoscopic submucosal dissection (ESD) for superficial esophageal carcinoma. Post ESD, stricture develops during the process of scar formation, which is related to inflammation caused by ESD. We planned a study to evaluate whether certain electrosurgical unit modes could attenuate strictures after esophageal ESD. Methods: A total of 16 ESD, three-quarters of the esophageal circumference, were performed in four live pigs. A ball-tip Flush knife was used for mucosal incision. Submucosal dissection was performed using a Hook knife in monopolar mode and a ball-tip Jet B-knife in bipolar mode. Applied electrosurgical unit modes were FORCED COAG, SWIFT COAG, SPRAY COAG, ENDO CUT in monopolar mode, and FORCED COAG in bipolar mode. One month after ESD, the pigs were killed humanely and the severity of strictures and fibrosis was assessed. Results: The resected site in the esophagus showed complete mucosal regrowth and scar formation in all pigs. The quotients of stricture following ENDO CUT, SWIFT COAG, FORCED COAG effect2, FORCED COAG effect3, FORCED COAG effect4, SPRAY COAG, and Bipolar FORCED COAG mode were 16 %, 28 %, 38 %, 33 %, 51 %, 39 %, and 47 %, respectively. The equivalent quotients of fibrosis were 7 %, 28 %, 31 %, 30 %, 35 %, 63 %, and 100 %, respectively. ENDO CUT mode was associated with the lowest mean quotients of stricture and fibrosis. Conclusion: ENDO CUT mode showed promising results to attenuate fibrosis and strictures after esophageal ESD. PMID- 29527563 TI - [64Cu]NOTA-pentixather enables high resolution PET imaging of CXCR4 expression in a preclinical lymphoma model. AB - Background: The chemokine receptor 4 (CXCR4) is an important molecular target for both visualization and therapy of tumors. The aim of the present study was the synthesis and preclinical evaluation of a 64Cu-labeled, CXCR4-targeting peptide for positron emission tomography (PET) imaging of CXCR4 expression in vivo. Methods: For this purpose, 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), or 1,4,7-triazacyclononane-triacetic acid (NOTA) was conjugated to the highly affine CXCR4-targeting pentixather scaffold. Affinities were determined using Jurkat T-lymphocytes in competitive binding assays employing [125I]FC131 as the radioligand. Internalization and efflux studies of [64Cu]NOTA pentixather were performed in chem-1 cells, stably transfected with hCXCR4. The stability of the tracer was evaluated in vitro and in vivo. Small-animal PET and biodistribution studies at different time points were performed in Daudi lymphoma bearing severe combined immunodeficiency (SCID) mice. Results: [64Cu]NOTA pentixather was rapidly radiolabeled at 60 degrees C with high radiochemical yields >=90% and purities >99%. [64Cu]NOTA-pentixather offered the highest affinity of the evaluated peptides in this study (IC50 = 14.9 +/- 2.1 nM), showed efficient CXCR4-targeting in vitro and was stable in blood and urine with high resistance to transchelation in ethylenediaminetetraacetic acid (EDTA) challenge studies. Due to the enhanced lipophilicity of [64Cu]NOTA-pentixather (logP = 1.2), biodistribution studies showed some nonspecific accumulation in the liver and intestines. However, tumor accumulation (13.1 +/- 1.5% ID/g, 1.5 h p.i.) was CXCR4-specific and higher than in all other organs and resulted in high resolution delineation of Daudi tumors in PET/CT images in vivo. Conclusions: [64Cu]NOTA-pentixather was fast and efficiently radiolabeled, showed effective CXCR4-targeting, high stability in vitro and in vivo and resulted in high resolution PET/CT images accompanied with a suitable biodistribution profile, making [64Cu]NOTA-pentixather a promising tracer for future application in humans. PMID- 29527564 TI - Synthesis, gallium labelling and characterization of P04087, a functionalized phosphatidylserine-binding peptide. AB - Background: Radiolabeled phosphatidylserine (PS)-binding peptides represent an innovative strategy for molecular imaging of apoptosis and thrombus. The hexapeptide PGDLSR was described as a selective and high affinity ligand for PS. In this work, we synthesized and evaluated a gallium labelled-PGDLSR peptide as a potential and selective radiopharmaceutical for nuclear imaging. PGDLSR-beta alanine-NODAGA (P04087) was prepared using Fmoc-based synthesis and then chelated with cold gallium, 68Ga and 67Ga. The affinity of Ga-P04087 for PS was evaluated by a competitive binding assay using biotinylated AnnexinV. The in vitro stability of the radiotracer was checked at room temperature and after incubation in human serum at 37 degrees C with and without a metalloprotease inhibitor. The in vivo binding of 67Ga-P04087 to phosphatidylserine was evaluated in a rat model of infective endocarditis. Results: PGDLSR was successfully prepared with a yield of 31%. P04087 was obtained with a yield of 28% and in high chemical purity (>95%). The radiochemical purities of 67Ga-P04087 and 68Ga-P04087 exceeded 98% in all cases. IC50 of P04087 and Ga-P04087 were in the same order of magnitude (10 7M). The radiolabelled product was stable for 24 h at room temperature, but was very rapidly degraded in human serum in the absence of a protease inhibitor, which had a stabilizing effect. No focal uptake could be detected visually in the cardiac area on SPECT images. On autoradiography however, a focal uptake of 67Ga P04087 in the valve area was present and histological slices demonstrated localization of peptide binding at the peripheral layer of vegetations. Conclusion: In spite of the preservation of the peptide affinity to the PS after its conjugation to the NODAGA chelator, and of the presence of 67Ga-P04087 uptake on autoradiography, the absence of detectable foci in vivo in the valve area may be attributed to both the low intensity of the signal and the presence of background activity originating from blood pool and surrounding tissues in the living animals. Further modifications are necessary to design a radiolabeled peptide with higher binding potencies to PS while possessing enhanced metabolic stability in vivo. PMID- 29527565 TI - Sulcal Polymorphisms of the IFC and ACC Contribute to Inhibitory Control Variability in Children and Adults. AB - Inhibitory control (IC) is a core executive function that enables humans to resist habits, temptations, or distractions. IC efficiency in childhood is a strong predictor of academic and professional success later in life. Based on analysis of the sulcal pattern, a qualitative feature of cortex anatomy determined during fetal life and stable during development, we searched for evidence that interindividual differences in IC partly trace back to prenatal processes. Using anatomical magnetic resonance imaging (MRI), we analyzed the sulcal pattern of two key regions of the IC neural network, the dorsal anterior cingulate cortex (ACC) and the inferior frontal cortex (IFC), which limits the inferior frontal gyrus. We found that the sulcal pattern asymmetry of both the ACC and IFC contributes to IC (Stroop score) in children and adults: participants with asymmetrical ACC or IFC sulcal patterns had better IC efficiency than participants with symmetrical ACC or IFC sulcal patterns. Such additive effects of IFC and ACC sulcal patterns on IC efficiency suggest that distinct early neurodevelopmental mechanisms targeting different brain regions likely contribute to IC efficiency. This view shares some analogies with the "common variant-small effect" model in genetics, which states that frequent genetic polymorphisms have small effects but collectively account for a large portion of the variance. Similarly, each sulcal polymorphism has a small but additive effect: IFC and ACC sulcal patterns, respectively, explained 3% and 14% of the variance of the Stroop interference scores. PMID- 29527566 TI - Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice. AB - Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21). These mice were tested for locomotor response to cocaine, and spatial reversal learning was assessed in operant conditioning chambers. As predicted, compared to control mice, autoDrd2 KO animals demonstrated heightened sensitivity to the locomotor stimulating effect of cocaine (10 mg/kg, i.p.), confirming previous research using a similar genetic model. In the spatial reversal learning task, autoDrd2-KO mice were slower to reach a learning criterion and had difficulty sustaining a prolonged nose poke response, measurements conceptually related to impaired response inhibition. Rate of learning of the initial discrimination and latencies to collect rewards, to initiate trials and to produce a response were unaffected by genetic deletion of D2 autoreceptors, discarding possible motor and motivational factors. Together, these findings confirm the role of D2 autoreceptors in reversal learning and suggest a broader involvement in behavioral inhibition mechanisms. PMID- 29527567 TI - Reliability-Weighted Integration of Audiovisual Signals Can Be Modulated by Top down Attention. AB - Behaviorally, it is well established that human observers integrate signals near optimally weighted in proportion to their reliabilities as predicted by maximum likelihood estimation. Yet, despite abundant behavioral evidence, it is unclear how the human brain accomplishes this feat. In a spatial ventriloquist paradigm, participants were presented with auditory, visual, and audiovisual signals and reported the location of the auditory or the visual signal. Combining psychophysics, multivariate functional MRI (fMRI) decoding, and models of maximum likelihood estimation (MLE), we characterized the computational operations underlying audiovisual integration at distinct cortical levels. We estimated observers' behavioral weights by fitting psychometric functions to participants' localization responses. Likewise, we estimated the neural weights by fitting neurometric functions to spatial locations decoded from regional fMRI activation patterns. Our results demonstrate that low-level auditory and visual areas encode predominantly the spatial location of the signal component of a region's preferred auditory (or visual) modality. By contrast, intraparietal sulcus forms spatial representations by integrating auditory and visual signals weighted by their reliabilities. Critically, the neural and behavioral weights and the variance of the spatial representations depended not only on the sensory reliabilities as predicted by the MLE model but also on participants' modality specific attention and report (i.e., visual vs. auditory). These results suggest that audiovisual integration is not exclusively determined by bottom-up sensory reliabilities. Instead, modality-specific attention and report can flexibly modulate how intraparietal sulcus integrates sensory signals into spatial representations to guide behavioral responses (e.g., localization and orienting). PMID- 29527568 TI - Losing Control in Social Situations: How the Presence of Others Affects Neural Processes Related to Sense of Agency. AB - Social contexts substantially influence individual behavior, but little is known about how they affect cognitive processes related to voluntary action. Previously, it has been shown that social context reduces participants' sense of agency over the outcomes of their actions and outcome monitoring. In this fMRI study on human volunteers, we investigated the neural mechanisms by which social context alters sense of agency. Participants made costly actions to stop inflating a balloon before it burst. On "social" trials, another player could act in their stead, but we analyzed only trials in which the other player remained passive. We hypothesized that mentalizing processes during social trials would affect decision-making fluency and lead to a decreased sense of agency. In line with this hypothesis, we found increased activity in the bilateral temporo parietal junction (TPJ), precuneus, and middle frontal gyrus during social trials compared with nonsocial trials. Activity in the precuneus was, in turn, negatively related to sense of agency at a single-trial level. We further found a double dissociation between TPJ and angular gyrus (AG): activity in the left AG was not sensitive to social context but was negatively related to sense of agency. In contrast, activity in the TPJ was modulated by social context but was not sensitive to sense of agency. PMID- 29527570 TI - Synthesis of microgel sensors for spatial and temporal monitoring of protease activity. AB - Proteases are involved in almost every important cellular activity, from embryonic morphogenesis to apoptosis. To study protease activity in situ, hydrogels provide a synthetic mimic of the extracellular matrix (ECM) and have utility as a platform to study activity, such as those related to cell migration, in three-dimensions. While 3-dimensional visualization of protease activity could prove quite useful to elucidate the proteolytic interaction at the interface between cells and their surrounding environment, there has been no versatile tool to visualize local proteolytic activity in real time. Here, micron-sized gels were synthesized by inverse suspension polymerization using thiolene photo-click chemistry. The size distribution was selected to avoid cellular uptake and to lower cytotoxicity, while simultaneously allowing the integration of peptide based FRET sensors of local cell activity. Proteolytic activity of collagenase was detected within an hour via changes in fluorescence of embedded microgels; incubation of microgel sensors with A375 melanoma cells showed upregulated MMP activity in the presence of soluble fibronectins in media. The microgel sensors were readily incorporated into both gelatin and poly(ethylene glycol) (PEG) hydrogels and used to successfully detect spatiotemporal proteolytic activity of A375 melanoma cells. Finally, a tumor model was constructed from a hydrogel microwell array that was used to aggregate A375 melanoma cells, and local variations in proteolytic activity were monitored as a function of distance from the cell aggregate center. PMID- 29527569 TI - Collateral Projections Innervate the Mammillary Bodies and Retrosplenial Cortex: A New Category of Hippocampal Cells. AB - To understand the hippocampus, it is necessary to understand the subiculum. Unlike other hippocampal subfields, the subiculum projects to almost all distal hippocampal targets, highlighting its critical importance for external networks. The present studies, in male rats and mice, reveal a new category of dorsal subiculum neurons that innervate both the mammillary bodies (MBs) and the retrosplenial cortex (RSP). These bifurcating neurons comprise almost half of the hippocampal cells that project to RSP. The termination of these numerous collateral projections was visualized within the medial mammillary nucleus and the granular RSP (area 29). These collateral projections included subiculum efferents that cross to the contralateral MBs. Within the granular RSP, the collateral projections form a particularly dense plexus in deep Layer II and Layer III. This retrosplenial termination site colocalized with markers for VGluT2 and neurotensin. While efferents from the hippocampal CA fields standardly collateralize, subiculum projections often have only one target site. Consequently, the many collateral projections involving the RSP and the MBs present a relatively unusual pattern for the subiculum, which presumably relates to how both targets have complementary roles in spatial processing. Furthermore, along with the anterior thalamic nuclei, the MBs and RSP are key members of a memory circuit, which is usually described as both starting and finishing in the hippocampus. The present findings reveal how the hippocampus simultaneously engages different parts of this circuit, so forcing an important revision of this network. PMID- 29527571 TI - Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening. AB - Improved in vitro models are needed to better understand cancer progression and bridge the gap between in vitro proof-of-concept studies, in vivo validation, and clinical application. Multicellular tumor spheroids (MCTS) are a popular method for three-dimensional (3D) cell culture, because they capture some aspects of the dimensionality, cell-cell contact, and cell-matrix interactions seen in vivo. Many approaches exist to create MCTS from cell lines, and they have been used to study tumor cell invasion, growth, and how cells respond to drugs in physiologically relevant 3D microenvironments. However, there are several discrepancies in the observations made of cell behaviors when comparing between MCTS formation methods. To resolve these inconsistencies, we created and compared the behavior of breast, prostate, and ovarian cancer cells across three MCTS formation methods: in polyNIPAAM gels, in microwells, or in suspension culture. These methods formed MCTS via proliferation from single cells or passive aggregation, and therefore showed differential reliance on genes important for cell-cell or cell-matrix interactions. We also found that the MCTS formation method dictated drug sensitivity, where MCTS formed over longer periods of time via clonal growth were more resistant to treatment. Toward clinical application, we compared an ovarian cancer cell line MCTS formed in polyNIPAAM with cells from patient-derived malignant ascites. The method that relied on clonal growth (PolyNIPAAM gel) was more time and cost intensive, but yielded MCTS that were uniformly spherical, and exhibited the most reproducible drug responses. Conversely, MCTS methods that relied on aggregation were faster, but yielded MCTS with grapelike, lobular structures. These three MCTS formation methods differed in culture time requirements and complexity, and had distinct drug response profiles, suggesting the choice of MCTS formation method should be carefully chosen based on the application required. PMID- 29527572 TI - Variability in Quantitative DCE-MRI: Sources and Solutions. AB - DCE-MRI has been extensively used for diagnosis, prognosis and therapy monitoring of various diseases including cancer. However, it has been reported that the perfusion parameters measured by DCE-MRI largely vary across different research sites, preventing data comparison in multi-institutional clinical trials. Recently, novel perfusion phantoms have been developed to correct scanner-driven errors, enabling quality assurance of quantitative DCE-MRI measurement. However, the sources for the variability in quantitating perfusion parameters are not only MRI scanners but also software packages and imaging protocols set by the operators. In this manuscript, the various sources influencing the variability in quantitative DCE-MRI measurement are reviewed, and the proper solutions to minimize those are discussed. PMID- 29527573 TI - Continuous Electronic Fetal Monitoring during Labor: A Critique and a Reply to Contemporary Proponents. AB - A half century after continuous electronic fetal monitoring (EFM) became the omnipresent standard of care for the vast majority of labors in the developed countries, and the cornerstone for cerebral palsy litigation, EFM advocates still do not have any scientific evidence justifying EFM use in most labors or courtrooms. Yet, these EFM proponents continue rationalizing the procedure with a rhetorical fog of meaningless words, misleading statistics, archaic concepts, and a complete disregard for medical ethics. This article illustrates the current state of affairs by providing an evidence-based review penetrating the rhetorical fog of a prototypical EFM advocate. PMID- 29527574 TI - Diffusion Tensor Imaging for Assessment of Response to Neoadjuvant Chemotherapy in Patients With Breast Cancer. AB - In this study, the prognostic significance of tumor metrics derived from diffusion tensor imaging (DTI) was evaluated in patients with locally advanced breast cancer undergoing neoadjuvant therapy. DTI and contrast-enhanced magnetic resonance imaging were acquired at 1.5 T in 34 patients before treatment and after 3 cycles of taxane-based therapy (early treatment). Tumor fractional anisotropy (FA), principal eigenvalues (lambda1, lambda2, and lambda3), and apparent diffusion coefficient (ADC) were estimated for tumor regions of interest drawn on DTI data. The association between DTI metrics and final tumor volume change was evaluated with Spearman rank correlation. DTI metrics were investigated as predictors of pathological complete response (pCR) by calculating the area under the receiver operating characteristic curve (AUC). Early changes in tumor FA and ADC significantly correlated with final tumor volume change post therapy (rho = -0.38, P = .03 and rho = -0.71, P < .001, respectively). Pretreatment tumor ADC was significantly lower in the pCR than in the non-pCR group (P = .04). At early treatment, patients with pCR had significantly higher percent changes of tumor lambda1, lambda2, lambda3, and ADC than those without pCR. The AUCs for early percent changes in tumor FA and ADC were 0.60 and 0.83, respectively. The early percent changes in tumor eigenvalues and ADC were the strongest DTI-derived predictors of pCR. Although early percent change in tumor FA had a weak association with pCR, the significant correlation with final tumor volume change suggests that this metric changes with therapy and may merit further evaluation. PMID- 29527575 TI - 'Take Ten' improving the surgical post-take ward round: a quality improvement project. AB - Background: The surgical post-take ward round is a complex multidisciplinary interaction in which new surgical patients are reviewed and management plans formulated. Its fast-paced nature can lead to poor communication and inaccurate or incomplete documentation with potential detriment to patient safety. Junior team members often do not fully understand the diagnosis and management plan. Aims: The aims of this project were to improve both communication and documentation on the surgical post-take ward round, influencing patient safety. Methods: The ward round was deconstructed to identify individual roles and determine where intervention would have the most impact. Ten important points were identified that should be documented in the management of an acute surgical patient; observations, examination, impression, investigations, antibiotics, intravenous fluids, VTE assessment, nutrition status, estimated length of stay and ceiling of treatment. A 'Take Ten' checklist was devised with these items to be used as a 'time out' after each patient with the whole team for discussion, clarification and clear documentation. Four plan do study act cycles were completed over a period of a year. A retrospective review of post-take documentation preintervention and postintervention was performed, and the percentage of points that were accurately documented was calculated. For further clarification, 2 weekends were compared-one where the checklist was used and one where it was not. Results: Results showed documentation postintervention varied between categories but there was improvement in documentation of VTE assessment, fluids, observations and investigations. On direct comparison of weekends the checklist showed improved documentation in all categories except length of stay. Junior team members found the checklist improved understanding of diagnosis and management plan, and encouraged a more effective ward round. Conclusion: The 'Take Ten' checklist has been well received. Three years on from its inception, the checklist has become an integral part of the post-take ward round, thanks to the multidisciplinary engagement in the project. PMID- 29527576 TI - Multidisciplinary analysis of invasive meningococcal disease as a framework for continuous quality and safety improvement in regional Australia. AB - Background: System factors in a regional Australian health district contributed to avoidable care deviations from invasive meningococcal disease (IMD) management guidelines. Traditional root cause analysis (RCA) is not well-suited to IMD, focusing on individual cases rather than system improvements. As IMD requires complex care across healthcare silos, it presents an opportunity to explore and address system-based patient safety issues. Context: Baseline assessment of IMD cases (2005-2006) identified inadequate triage, lack of senior clinician review, inconsistent vital sign recording and laboratory delays as common issues, resulting in antibiotic administration delays and inappropriate or premature discharge. Methods: Clinical governance, in partnership with clinical and public health services, established a multidisciplinary Meningococcal Reference Group (MRG) to routinely review management of all IMD cases. The MRG comprised representatives from primary care, acute care, public health, laboratory medicine and clinical governance. Baseline data were compared with two subsequent evaluation points (2011-2012 and 2013-2015). Interventions: Phase I involved multidisciplinary process mapping and development of a standardised audit tool from national IMD management guidelines. Phase II involved formalisation of group processes and advocacy for operational change. Phase III focused on dissemination of findings to clinicians and managers. Results: Greatest care improvements were observed in the final evaluation. Median antibiotic delay decreased from 72 to 42 min and proportion of cases triaged appropriately improved from 38% to 75% between 2013 and 2015. Increasing fatal outcomes were attributed to the emergence of more virulent meningococcal serotypes. Conclusions: The MRG was a key mechanism for identifying system gaps, advocating for change and enhancing communication and coordination across services. Employing IMD case review as a focus for district-level process reflection presents an innovative patient safety approach, combining the strengths of prospective hazard analysis with more traditional RCA methodologies. PMID- 29527577 TI - Detection of Fetal Arrhythmia Using Optically-Pumped Magnetometers. PMID- 29527578 TI - The sound of migration: exploring data sonification as a means of interpreting multivariate salmon movement datasets. AB - The migration of Pacific salmon is an important part of functioning freshwater ecosystems, but as populations have decreased and ecological conditions have changed, so have migration patterns. Understanding how the environment, and human impacts, change salmon migration behavior requires observing migration at small temporal and spatial scales across large geographic areas. Studying these detailed fish movements is particularly important for one threatened population of Chinook salmon in the Snake River of Idaho whose juvenile behavior may be rapidly evolving in response to dams and anthropogenic impacts. However, exploring movement data sets of large numbers of salmon can present challenges due to the difficulty of visualizing the multivariate, time-series datasets. Previous research indicates that sonification, representing data using sound, has the potential to enhance exploration of multivariate, time-series datasets. We developed sonifications of individual fish movements using a large dataset of salmon otolith microchemistry from Snake River Fall Chinook salmon. Otoliths, a balance and hearing organ in fish, provide a detailed chemical record of fish movements recorded in the tree-like rings they deposit each day the fish is alive. This data represents a scalable, multivariate dataset of salmon movement ideal for sonification. We tested independent listener responses to validate the effectiveness of the sonification tool and mapping methods. The sonifications were presented in a survey to untrained listeners to identify salmon movements with increasingly more fish, with and without visualizations. Our results showed that untrained listeners were most sensitive to transitions mapped to pitch and timbre. Accuracy results were non-intuitive; in aggregate, respondents clearly identified important transitions, but individual accuracy was low. This aggregate effect has potential implications for the use of sonification in the context of crowd-sourced data exploration. The addition of more fish, and visuals, to the sonification increased response time in identifying transitions. PMID- 29527579 TI - Foliar secretory structures in Ekebergia capensis (Meliaceae). AB - Ekebergia capensis is a medium-sized to large evergreen to deciduous tree ranging from southern Africa to Ethiopia. Two morphologically-distinct variants of E. capensis, southern and northern, may be recognized in southern Africa. Despite its wide distribution range there appear to be no published reports on the secretory structures occurring on the leaves. In very young leaves, colleters on the petiolules, adjacent portions of the rachis and the midrib of the adaxial leaflet surfaces, secrete fluid which at least partly covers these developing areas. This is the first record of colleters in Meliaceae. In addition, several extrafloral nectaries (EFNs) are found in variable positions on the abaxial side of the leaflets. No stomata are associated with the EFNs. The glandular tissue of active EFNs is surrounded by druse crystals of calcium oxalate and consists of secretory cells some of whose walls are separated by "strands" of amorphous lipophilic material, especially in a radial orientation. EFNs on developing leaves are inconspicuous but with time, frequently become more easily visible due to the accumulation of pinkish/reddish anthocyanins. Even on senescent leaves, shed in autumn, large droplets of nectar are frequently visible on the EFNs. The secretory tissue originates from protoderm and ground tissues. Slight differences in abundance, size, shape, position and structure exist between the EFNs of the southern and northern forms. Varying proportions of glucose, fructose and sucrose were detected in the rather viscous nectar with the most abundant sugar usually being fructose. Ants were only rarely observed feeding on the nectar. This finding is in conflict with the generally accepted idea that EFNs provide food for ants which in turn protect the plant from herbivores. More detailed studies of the chemistry of the nectar, which is relatively copious, may provide clues as to the function. PMID- 29527580 TI - Gene array analysis of PD-1H overexpressing monocytes reveals a pro-inflammatory profile. AB - We have previously reported that overexpression of Programmed Death -1 Homolog (PD-1H) in human monocytes leads to activation and spontaneous secretion of multiple pro inflammatory cytokines. Here we evaluate changes in monocytes gene expression after enforced PD-1H expression by gene array. The results show that there are significant alterations in 51 potential candidate genes that relate to immune response, cell adhesion and metabolism. Genes corresponding to pro inflammatory cytokines showed the highest upregulation, 7, 3.2, 3.0, 5.8, 4.4 and 3.1 fold upregulation of TNF-alpha, IL-1 beta, IFN-alpha, gamma, lambda and IL-27 relative to vector control. The data are in agreement with cytometric bead array analysis showing induction of proinflammatory cytokines, IL-6, IL-1beta and TNF alpha by PD-1H. Other genes related to inflammation, include transglutaminase 2 (TG2), NF-kappaB (p65 and p50) and toll like receptors (TLR) 3 and 4 were upregulated 5, 4.5 and 2.5 fold, respectively. Gene set enrichment analysis (GSEA) also revealed that signaling pathways related to inflammatory response, such as NFkappaB, AT1R, PYK2, MAPK, RELA, TNFR1, MTOR and proteasomal degradation, were significantly upregulated in response to PD-1H overexpression. We validated the results utilizing a standard inflammatory sepsis model in humanized BLT mice, finding that PD-1H expression was highly correlated with proinflammatory cytokine production. We therefore conclude that PD-1H functions to enhance monocyte activation and the induction of a pro-inflammatory gene expression profile. PMID- 29527581 TI - Highly photostable nanogels for fluorescence-based theranostics. AB - A novel photo-crosslinkable nanogel is prepared from a biodegradable polymer template with intrinsic photoluminescence and high photostability. The fluorescent nanogels display excellent biodegradability and cytocompatibility owed to the facile synthesis scheme involving a solvent-and surfactant-free one pot reaction, derived entirely from biocompatible monomers citric acid, maleic acid, L-cysteine, and poly(ethylene glycol). The resultant nanogels are less than 200 nm in diameter with a narrow size distribution and monodispersity, and demonstrate long-term structural stability in biological buffer for two weeks. To gauge potential in theranostic applications, the fluorescent nanogels were surface functionalized with biologically active RGD peptides and encapsulated with active anti-cancer drug Doxorubicin, resulting in a pH-responsive controlled drug release in acidic pH resembling tumor environments. The strong fluorescence of the nanogels enabled tracking of targeted drug delivery, showing that drug loaded nanogels homed into the cytoplasmic regions of prostate cancer cells to significantly induce cell death. These photo-crosslinkable and biodegradable nanogels pose as a strong candidate for theranostic medicine, demonstrating versatile functionalization, high stability in biological buffers, and capacity for real-time fluorescence-based monitoring of targeted drug delivery. PMID- 29527582 TI - The aryl hydrocarbon receptor as a moderator of host-microbiota communication. AB - The aryl hydrocarbon receptor (AHR) is an important component of the host microbiota communication network. Comparisons of wild-type and Ahr-null mice as well as from exposure studies with potent AHR ligands (e.g., 2,3,7,8 tetrachlorodibenzo-p-dioxin) have provided compelling evidence that the AHR may be a master regulator of the host-microbiota interaction thus helping to shape the immune system and impact host metabolism. Metabolomics and sequenced-based microbial community profiling, two recent technological advances, have helped to solidify this host-microbiota signaling concept and identified not only how specific ligands generated by the host and by the microbiota can activate the AHR, but also how activation/disruption of the AHR can influence and shape the microbiota. We are just beginning to understand how the temporal nature and tissue- and microbiota-specific generation of AHR ligands contribute to many AHR dependent processes. In this review, we focus on several recent advances where metabolomics and characterization of the microbiota structure and function have generated new perspectives by which to evaluate AHR activity. PMID- 29527583 TI - ROLE OF CYTOCHROME P450S IN THE GENERATION AND METABOLISM OF REACTIVE OXYGEN SPECIES. AB - The cytochrome P450 (CYP) enzymes are a diverse group of heme monooxygenases that, through the course of their reaction cycle, contribute to cellular reactive oxygen species (ROS). CYP enzymes play a crucial role in human physiology and are involved in drug and xenobiotic metabolism as well as biosynthesis of endogenous molecules and are expressed throughout the human body. However, during the course of the CYP catalytic cycle, ROS can be generated through uncoupling of the enzymatic cycle. ROS is known to modify endogenous molecules, included lipids, proteins, and nucleic acids, which can lead to cell damage and death and contribute to disease development. ROS has been implicated in a wide range of diseases and conditions, including cancer and ageing, but ROS also play a role in the normal physiological functions in the cell. Here, we discuss specific examples whereby ROS generated by CYPs contribute to or protect against various phenomena, such as hyperoxic lung injury, oxidative hepatic toxicity, formation of DNA adducts from lipid peroxidation products. We have also discussed the mechanistic roles of CYP enzymes belonging to various families, and their effect on cellular ROS production, in relation to normal cellular function as well as disease pathophysiology. PMID- 29527584 TI - EEG-Based Brain-Computer Interfaces. AB - Brain-Computer Interfaces (BCIs) are real-time computer-based systems that translate brain signals into useful commands. To date most applications have been demonstrations of proof-of-principle; widespread use by people who could benefit from this technology requires further development. Improvements in current EEG recording technology are needed. Better sensors would be easier to apply, more confortable for the user, and produce higher quality and more stable signals. Although considerable effort has been devoted to evaluating classifiers using public datasets, more attention to real-time signal processing issues and to optimizing the mutually adaptive interaction between the brain and the BCI are essential for improving BCI performance. Further development of applications is also needed, particularly applications of BCI technology to rehabilitation. The design of rehabilitation applications hinges on the nature of BCI control and how it might be used to induce and guide beneficial plasticity in the brain. PMID- 29527585 TI - A Prospective Randomized Comparative Dosing Trial of Ranibizumab In Bevacizumab Resistant Diabetic Macular Edema: The REACT Study. AB - Purpose: To assess the efficacy of ranibizumab for persistent diabetic macular edema (DME) previously treated with bevacizumab and compare monthly vs treat-and extend (TAE) dosing. Design: 12-month, open-label, prospective randomized comparative dosing study. Participants: 27 participants with persistent foveal involving DME recently treated with bevacizumab. Methods: All subjects were to receive three initial monthly 0.3 mg ranibizumab injections before randomization to monthly (n=15) or TAE (n=12) injection protocols over 12 months. Treatment interval was extended by two weeks up to a maximum interval of 12 weeks in the TAE group if central subfield thickness (CST) was <= 300 MUm or complete absence of intraretinal or subretinal fluid on the macular cube was observed. Follow-up interval was decreased by 2 weeks if CST increased above 300 MUm with associated intraretinal and/or subretinal fluid. Main Outcome Measures: Change in Early Treatment of Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA), CST, adverse events. Results: Prior to study enrollment, subjects received an average of 8.6 bevacizumab injections. At month 12, mean ETDRS BCVA improved by + 5.3 letters (p<0.05) and mean CST decreased by -99.6 MUm (p<0.01) in all patients. At study exit, 18.5 % of subjects gained >= 3 lines of vision and 3.7% of subjects lost >= 3 lines. Patients treated via the TAE protocol gained +8.4 letters and decreased CST by -120.2 MUm whereas those treated by monthly injection gained +2.7 letters and decreased CST by -83.1 MUm at month 12. Conclusions: Following conversion to ranibizumab in eyes with persistent DME refractory to bevacizumab, significant functional and anatomic improvements were noted. Visual and anatomical outcomes were similar in TAE and monthly treatment protocols. PMID- 29527587 TI - Cardiac fibroblasts: from origin to injury. AB - The cardiac fibroblast has essential roles in production and maintenance of extracellular matrix. While its role in maladaptive myocardial remodeling has been a focus of many studies, the cardiac fibroblast has become a topic of great interest as a contributor to heart physiology and as a therapeutic target. Recent reports are changing how we view and study the cardiac fibroblast by providing greater insights into fibroblast biology using refined techniques for fibroblast identification and manipulation. Here, we briefly summarize some of these fundamental recent findings. PMID- 29527586 TI - Rho kinase signaling and cardiac physiology. AB - Rho kinases (ROCKs) are the first discovered RhoA effectors that are now widely known for their effects on actin organization. Recent studies have shown that ROCKs play important roles in cardiac physiology. Abnormal activation of ROCKs participate in multiple cardiovascular pathological processes, including cardiac hypertrophy, apoptosis, fibrosis, systemic hypertension, and pulmonary hypertension. ROCK inhibitors, fasudil and statins, have shown beneficial cardiovascular effects in many animal studies, clinical trials, and applications. Here, we mainly discuss the current understanding of the physiological roles of Rho kinase signaling in the heart, and briefly summarize the roles of ROCKs in cardiac-related vascular dysfunctions. We will also discuss the clinical application of ROCK inhibitors. PMID- 29527588 TI - Numerical algorithms for scatter-to-attenuation reconstruction in PET: empirical comparison of convergence, acceleration, and the effect of subsets. AB - : The use of scattered coincidences for attenuation correction of positron emission tomography (PET) data has recently been proposed. For practical applications, convergence speeds require further improvement, yet there exists a trade-off between convergence speed and the risk of non-convergence. In this respect, a maximum-likelihood gradient-ascent (MLGA) algorithm and a two-branch back-projection (2BP), which was previously proposed, were evaluated. Methods: MLGA was combined with the Armijo step size rule; and accelerated using conjugate gradients, Nesterov's momentum method, and data subsets of different sizes. In 2BP, we varied the subset size, an important determinant of convergence speed and computational burden. We used three sets of simulation data to evaluate the impact of a spatial scale factor. Results and discussion: The Armijo step size allowed 10-fold increased step sizes compared to native MLGA. Conjugate gradients and Nesterov momentum lead to slightly faster, yet non-uniform convergence; improvements were mostly confined to later iterations, possibly due to the non linearity of the problem. MLGA with data subsets achieved faster, uniform, and predictable convergence, with a speed-up factor equivalent to the number of subsets and no increase in computational burden. By contrast, 2BP computational burden increased linearly with the number of subsets due to repeated evaluation of the objective function, and convergence was limited to the case of many (and therefore small) subsets, which resulted in high computational burden. Conclusion: Possibilities of improving 2BP appear limited. While general-purpose acceleration methods appear insufficient for MLGA, results suggest that data subsets are a promising way of improving MLGA performance. PMID- 29527589 TI - Synchrotron X-Ray Diffraction Dynamic Sampling for Protein Crystal Centering. AB - A supervised learning approach for dynamic sampling (SLADS) was developed to reduce X-ray exposure prior to data collection in protein structure determination. Implementation of this algorithm allowed reduction of the X-ray dose to the central core of the crystal by up to 20-fold compared to current raster scanning approaches. This dose reduction corresponds directly to a reduction on X-ray damage to the protein crystals prior to data collection for structure determination. Implementation at a beamline at Argonne National Laboratory suggests promise for the use of the SLADS approach to aid in the analysis of X-ray labile crystals. The potential benefits match a growing need for improvements in automated approaches for microcrystal positioning. PMID- 29527591 TI - Intersection of stress and gender in association with transitions in past year DSM-5 substance use disorder diagnoses in the United States. AB - Background: Stress contributes to the development and maintenance of substance use disorders (SUD), with some research suggesting that the impact of stress on SUD is greater in women. However, this has yet to be evaluated in a national dataset, across major substances of abuse. Methods: Using data from the newly available U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Wave 3; n=36,309) we evaluated relationships among past year stressful life events (0 or 1 vs. 2+ events, range 0-16) and gender, and their association with transitions (new vs. absent cases; ongoing vs. remitted cases) in Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) alcohol use disorder (AUD), tobacco use disorder (TUD), cannabis use disorder (CUD), and nonmedical prescription opioid use disorder (OUD) diagnoses. Results: Having 2 or more stressful life events in the past year increased the odds of having a new AUD, TUD, CUD, and OUD (OR=3.14, 2.15, 5.52, and 3.06, respectively) or ongoing AUD, TUD, and CUD (OR=2.39, 2.62, and 2.95, respectively) compared to 0 or 1 stressful life event. A stress by gender interaction for new vs. absent AUD demonstrated that having 2 or more stressful life events was associated with increased odds of new AUD in men (OR=2.51) and even greater odds of new AUD in women (OR=3.94). Conclusions: Results highlight that stress is a robust factor in both men and women with new or ongoing substance use disorders, and that effective treatments for substance use should consider the role of stress in addiction etiology and maintenance. There was little evidence for gender differences in the role of stress on transitions in substance use disorders, except for the onset of alcohol use disorders. Given that rates of alcohol use disorders are increasing in women; the impact of stress needs to be considered. PMID- 29527592 TI - Data Science in the Research Domain Criteria Era: Relevance of Machine Learning to the Study of Stress Pathology, Recovery, and Resilience. AB - Diverse environmental and biological systems interact to influence individual differences in response to environmental stress. Understanding the nature of these complex relationships can enhance the development of methods to: (1) identify risk, (2) classify individuals as healthy or ill, (3) understand mechanisms of change, and (4) develop effective treatments. The Research Domain Criteria (RDoC) initiative provides a theoretical framework to understand health and illness as the product of multiple inter-related systems but does not provide a framework to characterize or statistically evaluate such complex relationships. Characterizing and statistically evaluating models that integrate multiple levels (e.g. synapses, genes, environmental factors) as they relate to outcomes that a free from prior diagnostic benchmarks represents a challenge requiring new computational tools that are capable to capture complex relationships and identify clinically relevant populations. In the current review, we will summarize machine learning methods that can achieve these goals. PMID- 29527590 TI - Chronic Stress in Adolescents and Its Neurobiological and Psychopathological Consequences: An RDoC Perspective. AB - The Research Domain Criteria (RDoC) initiative provides a strategy for classifying psychopathology based on behavioral dimensions and neurobiological measures. Neurodevelopment is an orthogonal dimension in the current RDoC framework; however, it has not yet been fully incorporated into the RDoC approach. A combination of both a neurodevelopmental and RDoC approach offers a multidimensional perspective for understanding the emergence of psychopathology during development. Environmental influence (e.g., stress) has a profound impact on the risk for development of psychiatric illnesses. It has been shown that chronic stress interacts with the developing brain, producing significant changes in neural circuits that eventually increase the susceptibility for development of psychiatric disorders. This review highlights effects of chronic stress on the adolescent brain, as adolescence is a period characterized by a combination of significant brain alterations, high levels of stress, and emergence of psychopathology. The literature synthesized in this review suggests that chronic stress-induced changes in neurobiology and behavioral constructs underlie the shared vulnerability across a number of disorders in adolescence. The review particularly focuses on depression and substance use disorders; however, a similar argument can also be made for other psychopathologies, including anxiety disorders. The summarized findings underscore the need for a framework to integrate neurobiological findings from disparate psychiatric disorders and to target transdiagnostic mechanisms across disorders. PMID- 29527594 TI - A Novel Distal Enhancer Mediates Inflammation-, PTH-, and Early Onset Murine Kidney Disease-Induced Expression of the Mouse Fgf23 Gene. AB - Fibroblast growth factor 23 (FGF23) production is regulated by both calciotropic hormones and inflammation. Consistent with this, elevated FGF23 levels are associated with inflammatory markers as well as parathyroid hormone (PTH) in various disease states, including chronic kidney disease (CKD). However, the molecular mechanisms underpinning Fgf23 transcription in response to these regulators are largely unknown. We therefore utilized chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) data from an osteocyte cell line to identify potential regulatory regions of the Fgf23 gene. Based on ChIP-seq analysis of enhancer-associated histone modifications, including H3K4 methylation and H3K9 acetylation, we discovered several potential enhancers for Fgf23, one of which was located 16kb upstream of the gene's transcriptional start site. Deletion of this putative enhancer from the mouse genome using CRISPR-Cas9 technology led to lower bone, thymus, and spleen expression of Fgf23 mRNA without altering circulating levels of the intact hormone, although as previously reported, only bone displayed significant basal expression. Nevertheless, lack of the -16kb enhancer blunted FGF23 upregulation in a tissue-specific manner by the acute inflammatory inducers lipopolysaccharide (LPS), interleukin-1-beta (IL 1beta), and tumor necrosis factor-alpha (TNFalpha) in bone, non-osseous tissues, and in circulation. Lack of the -16kb enhancer also inhibited PTH-induced bone Fgf23 mRNA. Moreover, the absence of this Fgf23 enhancer in an oxalate diet induced murine CKD model prevented the early onset induction of osseous, renal, and thymic Fgf23 mRNA levels and led to a significant blunting of elevated circulating intact FGF23 levels. These results suggest that -16kb enhancer mediates the induction of Fgf23 by inflammation and PTH and facilitates the increase in FGF23 expression in a murine model of CKD. As exemplified herein, these Fgf23 enhancer-deleted mice will provide a unique model in which to study the role of FGF23 expression in inflammatory diseases. PMID- 29527595 TI - Dramatic Response to Crizotinib in a Patient with Lung Cancer Positive for an HLA DRB1-MET Gene Fusion. PMID- 29527593 TI - The role of stress in the pathogenesis and maintenance of obsessive-compulsive disorder. AB - Individuals with OCD often identify psychosocial stress as a factor that exacerbates their symptoms, and many trace the onset of symptoms to a stressful period of life or a discrete traumatic incident. However, the pathophysiological relationship between stress and OCD remains poorly characterized: it is unclear whether trauma or stress is an independent cause of OCD symptoms, a triggering factor that interacts with a preexisting diathesis, or simply a nonspecific factor that can exacerbate OCD along with other aspects of psychiatric symptomatology. Nonetheless, preclinical research has demonstrated that stress has conspicuous effects on corticostriatal and limbic circuitry. Specifically, stress can lead to neuronal atrophy in frontal cortices (particularly the medial prefrontal cortex), the dorsomedial striatum (caudate), and the hippocampus. Stress can also result in neuronal hypertrophy in the dorsolateral striatum (putamen) and amygdala. These neurobiological effects mirror reported neural abnormalities in OCD and may contribute to an imbalance between goal-directed and habitual behavior, an imbalance that is implicated in the pathogenesis and expression of OCD symptomatology. The modulation of corticostriatal and limbic circuits by stress and the resultant imbalance between habit and goal-directed learning and behavior offers a framework for investigating how stress may exacerbate or trigger OCD symptomatology. PMID- 29527596 TI - Association of air particulate pollution with bone loss over time and bone fracture risk: analysis of data from two independent studies. AB - Background: Air particulate matter (PM) is a ubiquitous environmental exposure associated with oxidation, inflammation, and age-related chronic disease. Whether PM is associated with loss of bone mineral density (BMD) and risk of bone fractures is undetermined. Methods: We conducted two complementary studies of: (i) long-term PM <2.5 MUm (PM2.5) levels and osteoporosis-related fracture hospital admissions among 9.2 million Medicare enrollees of the Northeast/Mid Atlantic United States between 2003-2010; (ii) long-term black carbon [BC] and PM2.5 levels, serum calcium homeostasis biomarkers (parathyroid hormone, calcium, and 25-hydroxyvitamin D), and annualized BMD reduction over a 8-year follow-up of 692 middle-aged (46.7+/-12.3 yrs), low-income BACH/Bone cohort participants. Findings: In the Medicare analysis, risk of bone fracture admissions at osteoporosis-related sites was greater in areas with higher PM2.5 levels (Risk ratio [RR] 1.041, 95% Confidence Interval [CI], 1.030, 1.051). This risk was particularly high among low-income communities (RR 1.076; 95% CI, 1.052, 1.100). In the longitudinal BACH/Bone study, baseline BC and PM2.5 levels were associated with lower serum PTH (Estimate for baseline one interquartile increase in 1-year average BC= -1.16, 95% CI -1.93, -0.38; Estimate for baseline one interquartile increase in 1-year average PM2.5= -7.39; 95%CI -14.17, -0.61). BC level was associated with higher BMD loss over time at multiple anatomical sites, including femoral neck (-0.08%/year per one interquartile increase; 95% CI -0.14, 0.02%/year) and ultradistal radius (-0.06%/year per one interquartile increase; 95% CI -0.12, -0.01%/year). Interpretation: Our results suggest that poor air quality is a modifiable risk factor for bone fractures and osteoporosis, especially in low-income communities. PMID- 29527597 TI - Progression towards smoking cessation: Qualitative analysis of successful, unsuccessful, and never quitters. AB - BACKGROUND: Understanding how people transition between phases of not making a quit attempt to stopping smoking successfully is important in order to optimize interventions. This study aimed to explore differences in attitudes towards smoking and quitting among smokers and ex-smokers. METHODS: Adult (age 18 and over) successful (n = 8), unsuccessful (n = 8) and never quitters (n = 7) were recruited through stop-smoking services in England. Semi-structured interviews were conducted and data were analysed using framework analysis. RESULTS: Seven themes (starting to smoke, positive appraisal of smoking, responsibility for past/current smoking, negative effects of smoking, reasons to quit, process of quitting, and identity) were identified in all groups. Sub-group differences were explored and used to derive six typologies with descriptive characteristics: committed smokers, aware smokers, forced attempters, struggling attempters, pragmatic ex-smokers, and committed non-smokers. Using these typologies and the smallest number of differentiating factors between them (awareness of negative effects, motivation to stop and acceptance of responsibility), a parsimonious model of progression towards smoking cessation was developed. CONCLUSIONS: Awareness of negative effects, motivation and, crucially, a sense of commitment for taking responsibility to take actions towards behavior change may be important for whether smokers attempt to quit and progress to a successful quit attempt. PMID- 29527598 TI - Locally affine diffeomorphic surface registration for planning of metopic craniosynostosis surgery. AB - The outcome of cranial vault reconstruction for the surgical treatment of craniosynostosis heavily depends on the surgeon's expertise because of the lack of an objective target shape. We introduce a surface-based diffeomorphic registration framework to create the optimal post-surgical cranial shape during craniosynostosis treatment. Our framework estimates and labels where each bone piece needs to be cut using a reference template. Then, it calculates how much each bone piece needs to be translated and in which direction, using the closest normal shape from a multi-atlas as a reference. With our locally affine approach, the method also allows for bone bending, modeling independently the transformation of each bone piece while ensuring the consistency of the global transformation. We evaluated the optimal plan for 15 patients with metopic craniosynostosis. Our results showed that the automated surgical planning creates cranial shapes with a reduction in cranial malformations of 51.43% and curvature discrepancies of 35.09%, which are the two indices proposed in the literature to quantify cranial deformities objectively. In addition, the cranial shapes created were within healthy ranges. PMID- 29527599 TI - Mining Public Datasets for Modeling Intra-City PM2.5 Concentrations at a Fine Spatial Resolution. AB - Air quality models are important for studying the impact of air pollutant on health conditions at a fine spatiotemporal scale. Existing work typically relies on area-specific, expert-selected attributes of pollution emissions (e,g., transportation) and dispersion (e.g., meteorology) for building the model for each combination of study areas, pollutant types, and spatiotemporal scales. In this paper, we present a data mining approach that utilizes publicly available OpenStreetMap (OSM) data to automatically generate an air quality model for the concentrations of fine particulate matter less than 2.5 MUm in aerodynamic diameter at various temporal scales. Our experiment shows that our (domain-) expert-free model could generate accurate PM2.5 concentration predictions, which can be used to improve air quality models that traditionally rely on expert selected input. Our approach also quantifies the impact on air quality from a variety of geographic features (i.e., how various types of geographic features such as parking lots and commercial buildings affect air quality and from what distance) representing mobile, stationary and area natural and anthropogenic air pollution sources. This approach is particularly important for enabling the construction of context-specific spatiotemporal models of air pollution, allowing investigations of the impact of air pollution exposures on sensitive populations such as children with asthma at scale. PMID- 29527600 TI - Microfluidic approaches for probing amyloid assembly and behaviour. AB - The self-assembly of proteins into supramolecular structures and machinery underpins biological activity in living systems. Misassembled, misfolded and aggregated protein structures can, by contrast, have deleterious activity and such species are at the origin of a number of disease states ranging from cancer to neurodegenerative disorders. In particular, the formation of highly ordered protein aggregates, amyloid fibrils, from normally soluble peptides and proteins, is the common pathological hallmark of a range a group of over fifty protein misfolding disorders. Because of the critical role of the process in the aetiology of such disorders, as well as the quest to understand the basic principles of protein folding and misfolding, the amyloid phenomenon has become a central area of modern biomedical research. Advances in our knowledge of the physical properties of amyloid systems have, however, also highlighted the potential of amyloid structures in the context of materials science. In this review, we explore how microfluidic approaches can be used to study aspects of amyloid assembly and behaviour that are challenging to probe under bulk solution conditions. We discuss the use of volume confinement to probe very early events in the amyloid formation process. In addition, the well-defined fluid flow properties within channels with dimensions on the micron scale can be exploited to measure the physical properties of protein aggregates, such as their sizes and charges, to shed light on the physical and chemical parameters defining amyloid species. Moreover, the molecular species formed during aggregation reactions have physical dimensions spanning at least three orders of magnitude, and microfluidic techniques are well suited to work with analytes of such disparate dimensions. Furthermore, the flexibility of the design of microfluidic devices lends itself to adaptable experimental setups, including the study of protein self-assembly within living cells. Finally, we highlight the salient features of microfluidic experiments that facilitate probing complex biological systems, and discuss their use in the exploration of amyloids as a class of functional material. PMID- 29527601 TI - Lower ammoniation activation energy of CoN nanosheets by Mn doping with superior energy storage performance for secondary ion batteries. AB - Cationic doping has been regarded as an effective strategy to improve the electrochemical performance of transition metal composites for lithium ion batteries (LIBs). Herein, we report manganese doped cobalt nitrides (Mn0.33Co0.67N) as a novel anode material for LIBs with a high reversible capacity close to 900 mA h g-1 after 150 cycles at a current density of 0.5 A g 1, which is superior to 749 mA h g-1 of undoped CoN. The most fascinating performance of Mn0.33Co0.67N is the rate capability, in which 91% of capacity is maintained when the current density increases ten-fold from 0.2 A g-1 to 2.0 A g 1. This enhanced electrochemical performance is attributed to the fact that Mn doping makes it faster to regenerate Co-N bonds, as evidenced by a calculated apparent ammoniation activation energy (Ea) decrease from 113 kJ mol-1 to 96 kJ mol-1. This fast regeneration of Co-N bonds upon conversion reactions is believed to prevent the nitride electrode from a partial loss of charge capacity upon high rate cycling, in turn facilitating the extrinsic pseudocapacitive contribution. PMID- 29527602 TI - Current progress in the controlled synthesis and biomedical applications of ultrasmall (<10 nm) NaREF4 nanoparticles. AB - The design and fabrication of rare earth upconversion nanoparticle (UCNP)-based nanomedical platforms have evoked increasing interest. However, their bio-safety is always the most worrisome problem. Most nanoparticles can accumulate in the internal organs, leading to acute toxicity, a long-term inflammatory response, or even fibrosis and cancer. In contrast, ultrasmall (sub-10 nm) nanoparticles have minimal safety risk because they can escape from macrophages, pass biological barriers, and be easily degraded or excreted from the body. In this review, we mainly introduce new progress in preparation strategies, imaging and drug delivery with regards to ultrasmall UCNPs, with an emphasis on rare earth fluorides, NaREF4. Finally, we discuss the future outlook and challenges relating to ultrasmall UCNPs. PMID- 29527603 TI - A black phosphorus nanosheet-based siRNA delivery system for synergistic photothermal and gene therapy. AB - Gene therapy with small interfering RNA (siRNA) has been proved to be a promising technology to treat various diseases by hampering the production of target proteins. However, developing a delivery system that has high efficiency in transporting siRNA without obvious side effects remains a challenge. Herein, we designed a new survivin siRNA delivery system based on polyethyleneimine functionalized black phosphorus (BP) nanosheets which could suppress tumor growth by silencing survivin expression. Combined with the photothermal properties of the BP nanosheets, the presented delivery system shows excellent therapy efficiency for tumors. Therefore, the BP-based delivery system would be a promising tool for future clinical applications. PMID- 29527604 TI - Fe3C nanoparticles encapsulated in highly crystalline porous graphite: salt template synthesis and enhanced electrocatalytic oxygen evolution activity and stability. AB - Fe3C nanoparticles encapsulated in 3D porous graphite frameworks are fabricated via a cost-effective and scalable in situ salt template method. Thanks to the highly graphitic protecting layer on Fe3C nanoparticles and the 3D porous frameworks, the obtained materials exhibit excellent long-term durability and comparable electrocatalytic oxygen evolution activity with the state-of-the-art RuO2 catalyst. PMID- 29527605 TI - An umpolung of Lewis acidity/basicity at nitrogen by deprotonation of a cyclic (amino)(aryl)nitrenium cation. AB - A cyclic (amino)(aryl)nitrenium cation 2 has been achieved by treatment of spiro[fluorene-9,3'-indazole] (1) with Ph2CHCl and AgBF4. This cation 2 is Lewis acidic at nitrenium N1, reacting with PMe3 affording a Lewis acid/base adduct 3. In contrast, deprotonation of 2 with other bases provides a neutral compound 4 which is Lewis basic at N1, reacting with electrophiles including GaCl3, MeOTf and PhNCO. PMID- 29527606 TI - Temperature-dependent self-assembly of a purely organic cage in water. AB - Using a novel dynamic covalent approach relying on reversible hydrazone formation, a purely organic 3-dimensional prismatic cage was developed in water at elevated temperatures. By lowering the temperature, the hydrazone bond becomes kinetically inert. This self-assembled cage acts as an effective receptor for donor-acceptor pairs, whose interactions are weak in the absence of the cage. PMID- 29527607 TI - An optimal trapdoor zeolite for exclusive admission of CO2 at industrial carbon capture operating temperatures. AB - High purity molecular trapdoor chabazite with an optimal Si/Al ratio (1:9) was prepared from fly ash. Gas adsorption isotherms and binary breakthrough experiments show dramatically large selectivities for CO2 over N2 and CH4, which are the highest among physisorbents at operating temperatures suitable for postcombustion carbon capture and natural gas separations. PMID- 29527608 TI - Convergent synthesis of trifunctional molecules by three sequential azido-type selective cycloadditions. AB - A facile strategy for the synthesis of trifunctional molecules involving three sequential selective triazole-forming reactions is proposed. This method exploits three kinds of mechanistically different azido-type-selective cycloadditions. Three different azidophiles could be efficiently connected to a triazido platform molecule with three types of azido groups in a consecutive manner, which rendered a practical trifunctional molecule readily available. PMID- 29527609 TI - Engineering iridium-based metal organic frameworks towards electrocatalytic water oxidation. AB - Intensive efforts have been made towards designing water oxidation catalysts using homogeneous metal complexes. However, poor stability, caused by structure collapse and strong oxidants, prohibits further application of these catalysts. Therefore, the fabrication of stable and efficient water oxidation catalysts with robust structures and mild driving forces is in high demand. In this paper, we demonstrate the heterogeneous, porous and stable structure of Ir-doped metal organic frameworks (MOFs) by functionalizing bipyridine-incorporated MOFs with [IrCp*Cl(MU-Cl)]2 complexes. The resultant Ir-doped MOFs were immobilized on the surface of a glassy carbon electrode to drive the water oxidation process directly by electricity. Through the condition optimization, the enhanced electrocatalytic activity with an onset potential of 0.87 V versus the normal hydrogen electrode (NHE) towards oxygen evolution reaction with the highest Faradaic efficiency of 99% could be obtained. Moreover, it maintains high activity with no apparent loss for at least 3600 s. The excellent electrochemical performance may be ascribed to the unique MOFs structure, which not only protects the molecular catalyst from collapse, but also facilitates uniform distribution of active sites and efficient electron transfer through the channel. PMID- 29527610 TI - On the prediction of core level binding energies in molecules, surfaces and solids. AB - Core level binding energies, directly measured by X-ray photoelectron spectroscopy (XPS), provide unique information regarding the chemical environment of atoms in a given system. However, interpretation of XPS in extended systems may not be straightforward and requires assistance from theory. The different state-of-the-art theoretical methods commonly used to approach core level binding energies and their shifts with respect to a given reference are reviewed and critically assessed with special emphasis on recently developed theoretical methods and with a focus on future applications in materials and surface sciences. PMID- 29527611 TI - Increasing the selectivity to ethylene in the MTO reaction by enhancing diffusion limitation in the shell layer of SAPO-34 catalyst. AB - The zinc cation accommodation in the cavities of the shell layer and the facilitated aromatic formation over the zinc cation modified SAPO-34 with a core shell like structure introduce extra diffusion limitation for bulky hydrocarbons, which increases the selectivity to ethylene and the ethylene to propylene ratio at the initial stage of the MTO reaction. PMID- 29527612 TI - Copper-catalyzed decarboxylative cyclization via tandem C-P and C-N bond formation: access to 2-phosphorylmethyl indoles. AB - A novel copper-catalyzed decarboxylative cyclization of ethynyl benzoxazinanones with P(O)H compounds has been developed. This protocol leads to a series of 2 phosphorylmethyl indoles with high efficiency and selectivity (up to 99% yield) through tandem C-P/C-N bond formation under mild conditions. PMID- 29527613 TI - Formal synthesis of chelamidine alkaloids and their derivatives. AB - A concise two-step operation of alpha-amination of aldehydes and subsequent Friedel-Crafts/Prins-type cyclization towards accessing tetrahydrobenzo[c]phenanthridine and related structures was developed. The reaction displayed a broad substrate scope and good tolerance to a variety of substituents such as different aromatic heterocyclic rings. In addition, the effectiveness of this protocol was also demonstrated in the formal synthesis of homochelidonine and chelamidine. PMID- 29527614 TI - Small molecule activation of nitriles coordinated to the [Re6Se8]2+ core: formation of oxazine, oxazoline and carboxamide complexes. AB - Novel oxazine, oxazoline and carboxamide cluster complexes were prepared when different nucleophilic oxygen species reacted with nitriles coordinated to the Lewis acidic [Re6Se8]2+ cluster core. Reaction of ICH2CH2O- (generated in situ) with [Re6Se8(PEt3)5(NCR)]A2 (1A2 (R = Me) and 2A2 (R = Ph) where A = BF4-), leads to the formation of [Re6Se8(PEt3)5(2-methyloxazoline)]2+ (32+) and [Re6Se8(PEt3)5(2-phenyloxazoline)]2+ (42+). Similarly, reaction of BrCH2CH2CH2O- with the same nitrile complexes, 1A2 and 2A2 (where A = BF4- or SbF6-) leads to the corresponding oxazine complexes, [Re6Se8(PEt3)5(2-methyloxazine)]2+ (52+) and [Re6Se8(PEt3)5(2-phenyloxazine)]2+ (62+). In addition, reaction of 2(BF4)2 with KOH leads to the formation of the carboxamide complex, [Re6Se8(PEt3)5(phenylcarboxamide)](BF4) (7(BF4)). The neutral oxazine and oxazoline ligands can be removed using either heat or UV irradiation; UV irradiation was found to be more efficient at ligand removal as indicated by the shorter reaction times. The relative coordination strength of the neutral N-donor ligands was determined by these reaction times. X-ray structure determinations of 5(BF4)2 and 7(BF4) are also reported. PMID- 29527616 TI - EUROPEAN SPINE JOURNAL MAX AEBI AWARD FOR CLINICAL SCIENCE 2016/2017. PMID- 29527615 TI - Intracellular Ca2+ release decelerates mitochondrial cristae dynamics within the junctions to the endoplasmic reticulum. AB - Mitochondria are multifunctional organelles that essentially contribute to cell signaling by sophisticated mechanisms of communications. Live cell imaging studies showed that mitochondria are dynamic and complex structures that form ramified networks by directed movements, fission, and fusion events. There is emerging evidence that the morphology of mitochondria determines cellular functions and vice versa. Several intracellular signaling pathways and messengers including Ca2+ dynamically influence the architecture of mitochondria. Because electron microscopy cannot be utilized for an assessment of dynamics of mitochondrial morphology in intact cells, most studies were performed using wide field or laser confocal fluorescence microscopies that, due to limitations of their spatial resolution, do not allow investigating sub-mitochondrial structures. Accordingly, our understanding of the dynamics of substructures of mitochondria is quite limited. Here, we present a robust super-resolution method to quantify the dynamics of mitochondrial cristae, the main substructures of the inner mitochondrial membrane, exploiting structured illumination microscopy (SIM). We observed that knockdown of the dynamin-like 120-kDa protein, which is encoded by the OPA1 gene, specifically reduces the dynamics of the mitochondrial cristae membranes (CM), while the inner boundary membrane (IBM) remained flexible. We further used dual color SIM to quantify the dynamics of CM in the junction between mitochondria and the endoplasmic reticulum (ER; mitochondrial associated membranes, MAMs). Intracellular Ca2+ release spatially reduced CM dynamics in MAMs. Moreover, CM-dynamics was independent from matrix Ca2+ signal. Our data suggest that local Ca2+ signals specifically control CM-dynamics and structure to facilitate a well-balanced functional (Ca2+) interplay between mitochondria and the ER. PMID- 29527617 TI - GRAMMER EUROPEAN SPINE JOURNAL AWARD FOR BASIC SCIENCE AND APPLIED RESEARCH 2016/2017. PMID- 29527618 TI - Long-Term Impact of a Tailored Seclusion Reduction Program: Evidence for Change? AB - International comparative studies show that Dutch seclusion rates are relatively high. Therefore, several programs to change this practice were developed and implemented. The purpose of this study was to examine the impact of a seclusion reduction program over a long time frame, from 2004 until 2013. Three phases could be identified; the phase of development and implementation of the program (2004-2007), the project phase (2008-2010) and the consolidation phase (2011 2013). Five inpatient wards of a mental health institute were monitored. Each ward had one or more seclusion rooms. Primary outcome were the number and the duration of seclusion incidents. Involuntary medication was monitored as well to rule out substitution of one coercive measure by another. Case mix correction for patient characteristics was done by a multi-level logistic regression analysis with patient characteristics as predictors and hours seclusion per admission hours as outcome. Seclusion use reduced significantly during the project phase, both in number (-73%) and duration (-80%) and was not substituted by the use of enforced medication. Patient compilation as analyzed by the multi- level regression seemed not to confound the findings. Findings show a slight increase in number and seclusion days over the last year of monitoring. Whether this should be interpreted as a continuous or temporary trend remains unclear and is subject for further investigation. PMID- 29527620 TI - Endoscopic management of third ventricular colloid cysts in mildly dilated lateral ventricles. AB - Colloid cysts of the third ventricle are considered as benign lesions. The clinical manifestations are not clear in most of cases. Many treatment options are available and endoscopic removal of the cysts proves to be a very successful method especially if the lateral ventricles are moderately or severely dilated. Sometimes, we faced cases with non- or mildly dilated ventricles which may add more risks to the operation, limit the radicality of removal, or abort the procedure entirely. Sixteen cases of colloid cyst with mildly dilated ventricles were operated upon between 2008 and 2016 using the rigid endoscopic system. Twelve were female and four were male. Their ages were between 17 and 40 years old. Headaches and epileptic fits were the presenting symptoms in 13 cases and 2 cases respectively. One case was asymptomatic. The patients were followed up from 1 to 4 years. Total removal in 12 cases and evacuation of the contents and partial removal in 4 cases. Mild transient complications occurred in the form of fever in seven cases, vomiting in four cases or short-term recent memory loss in three cases. No deaths occurred due to the procedures. Working endoscopically in enlarged ventricles is very effective and easy; however, small sized ventricles do not prevent safe and effective complete removal of colloid cysts. Cases with residual cyst wall do not suffer from recurrence. PMID- 29527619 TI - How should incidental NEN of the pancreas and gastrointestinal tract be followed? AB - Neuroendocrine gastro-entero-pancreatic neoplasms (GEP-NENs) constitute a heterogeneous group of tumors, whose incidence has increased over the years. The most frequent site for primary disease is the stomach followed by small and large intestine, and pancreas. In the last decade, a dramatic growing in the incidence of small, incidental GEP-NENs has been recorded. In parallel, an increasing attitude toward more conservative approaches instead of surgical management has being widely spreading. This is particularly true for small, asymptomatic, pancreatic NEN as for these tumor forms an active surveillance has proven to be safe and feasible. Primary site and biological features of the neoplasms lead to different strategies and indications for surveillance and follow-up. This review focuses on the current evidence on modality and timing of surveillance and conservative treatment of incidentally discovered lesions. PMID- 29527622 TI - Teaching TransAnal Irrigation (TAI): why it is mandatory. PMID- 29527623 TI - SGSM2, a putative Rab2a GAP, regulates lysozyme sorting in Paneth cells. PMID- 29527621 TI - Predictors of treatment response to liraglutide in type 2 diabetes in a real world setting. AB - AIMS: There is an unmet need among healthcare providers to identify subgroups of patients with type 2 diabetes who are most likely to respond to treatment. METHODS: Data were taken from electronic medical records of participants of an observational, retrospective study in Italy. We used logistic regression models to assess the odds of achieving glycated haemoglobin (HbA1c) reduction >= 1.0% point after 12-month treatment with liraglutide (primary endpoint), according to various patient-related factors. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify distinct homogeneous patient subgroups with different odds of achieving the primary endpoint. RESULTS: Data from 1325 patients were included, of which 577 (43.5%) achieved HbA1c reduction >= 1.0% point (10.9 mmol/mol) after 12 months. Logistic regression showed that for each additional 1% HbA1c at baseline, the odds of reaching this endpoint were increased 3.5 times (95% CI: 2.90-4.32). By use of RECPAM analysis, five distinct responder subgroups were identified, with baseline HbA1c and diabetes duration as the two splitting variables. Patients in the most poorly controlled subgroup (RECPAM Class 1, mean baseline HbA1c > 9.1% [76 mmol/mol]) had a 28-fold higher odds of reaching the endpoint versus patients in the best-controlled group (mean baseline HbA1c <= 7.5% [58 mmol/mol]). Mean HbA1c reduction from baseline was as large as - 2.2% (24 mol/mol) in the former versus - 0.1% (1.1 mmol/mol) in the latter. Mean weight reduction ranged from 2.5 to 4.3 kg across RECPAM subgroups. CONCLUSIONS: Glycaemic response to liraglutide is largely driven by baseline HbA1c levels and, to a lesser extent, by diabetes duration. PMID- 29527624 TI - Deficit schizophrenia is a discrete diagnostic category defined by neuro-immune and neurocognitive features: results of supervised machine learning. AB - Deficit schizophrenia is characterized by neurocognitive impairments and changes in the patterning of IgA/IgM responses to plasma tryptophan catabolites (TRYCATs). In the current study, supervised pattern recognition methods, including logistic regression analysis (LRA), Support Vector Machine (SVM), and Soft Independent Modeling of Class Analogy (SIMCA), were used to examine whether deficit schizophrenia is a discrete diagnostic class with respect to Consortium To Establish a Registry for Alzheimer's disease (CERAD) and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests and IgA/IgM responses to noxious (NOX) and generally more protective (PRO) TRYCATs. We recruited patients with (n = 40) and without (n = 40) deficit schizophrenia and healthy volunteers (n = 40). The combined use of TRYCAT and CERAD features strongly segregates deficit from nondeficit schizophrenia and healthy controls. Three out of the top five most important features in LRA, SVM and SIMCA agreed, namely two different NOX/PRO TRYCAT ratios and false memory recall. SIMCA shows that deficit schizophrenia is significantly separated from nondeficit schizophrenia and controls with as top 6 features IgA responses to picolinic acid, IgM responses to 3-OH-kynurenine and kynurenic acid, and impairments in Word List Memory and Verbal Fluency Tests and Mini-Mental State Examination. Nevertheless, nondeficit schizophrenia was not significantly separated from controls. The results show that schizophrenia is not a unitary disease with mere continuous differences in severity of illness between apparent subtypes. Deficit schizophrenia is a qualitatively distinct class defined by neuroimmune (autoimmune responses to TRYCATs) and neurocognitive (episodic and semantic memory) features coupled or not with clinical (negative) symptoms. PMID- 29527625 TI - Reduced Alternating Gaze During Social Interaction in Infancy is Associated with Elevated Symptoms of Autism in Toddlerhood. AB - In typical development, infants often alternate their gaze between their interaction partners and interesting stimuli, increasing the probability of joint attention toward surrounding objects and creating opportunities for communication and learning. Children with Autism Spectrum Disorder (ASD) have been found to engage less in behaviors that can initiate joint attention compared to typically developing children, but the role of such atypicalities in the development of ASD during infancy is not fully understood. Here, using eye tracking technology in a live setting, we show that 10-month-olds at high familial risk for ASD engage less in alternating gaze during interaction with an adult compared to low risk infants. These differences could not be explained by low general social preference or slow visual disengagement, as the groups performed similarly in these respects. We also found that less alternating gaze at 10 months was associated with more social ASD symptoms and less showing and pointing at 18 months. These relations were similar in both the high risk and the low risk groups, and remained when controlling for general social preference and disengagement latencies. This study shows that atypicalities in alternating gaze in infants at high risk for ASD emerge already during the first 10 months of life - a finding with theoretical as well as potential practical implications. PMID- 29527626 TI - Early Identification of ASD Through Telemedicine: Potential Value for Underserved Populations. AB - Increasing access to diagnostic services is crucial for identifying ASD in young children. We therefore evaluated a telemedicine assessment procedure. First, we compared telediagnostic accuracy to blinded gold-standard evaluations (n = 20). ASD cases identified via telemedicine were confirmed by in-person evaluation. However, 20% of children diagnosed with ASD in-person were not diagnosed via telemedicine. Second, we evaluated telediagnostic feasibility and acceptability in a rural catchment. Children (n = 45) and caregivers completed the telemedicine procedure and provided feedback. Families indicated high levels of satisfaction. Remote diagnostic clinicians diagnosed 62% of children with ASD, but did not feel capable of ruling-in or out ASD in 13% of cases. Findings support preliminary feasibility, accuracy, and clinical utility of telemedicine-based assessment of ASD for young children. PMID- 29527627 TI - Synthetic Dibenzoxanthene Derivatives Induce Apoptosis Through Mitochondrial Pathway in Human Hepatocellular Cancer Cells. AB - A new series of dibenzoxanthenes 4a-4f were synthesized through the nucleophilic substitution and characterized by NMR and MS spectra. Their antitumor activity was screened by MTT assay. Compounds (except 4b and 4c) displayed strong growth inhibitory effects against chosen five tumor cells under light irradiation. The molecular mechanism of compound-induced cell apoptosis was investigated by AO/EB staining, comet assay, DCFH-DA, JC-1 fluorescent probe, and western blotting. Compounds induced the apoptosis of HepG2 cells and DNA damage. Location assay showed that compounds entered the nucleus of tumor cells. Furthermore, it was found that compounds induced loss of mitochondrial membrane potential, acceleration of ROS production, and activation of caspse-3, caspase-7, and caspase-9 proteins. Compounds upregulated the expression of pro-apoptotic Bim and Bax and downregulated the expression of anti-apoptotic Bcl-xl and Bcl-2. These results indicated that compounds induced the apoptosis of HepG2 cells through ROS mediated mitochondrial pathway. The induction of apoptosis by dibenzoxanthenes may provide an important mechanism for their cancer chemopreventive function. PMID- 29527629 TI - What Is Narrative Therapy and How Can It Help Health Humanities? PMID- 29527628 TI - Efficiencies of Low-Level Laser Therapy (LLLT) and Gabapentin in the Management of Peripheral Neuropathy: Diabetic Neuropathy. AB - Diabetic neuropathy (DN) is the highly occurred complication of diabetes mellitus; it has been defined as an event of peripheral nerve dysfunction characterized by pain, allodynia, hyperalgesia, and paraesthesia. The current study was conducted to evaluate the efficacy of low-level laser therapy (LLLT) in the management of neuropathy in diabetic rats. The used animals were divided into the following groups: negative control, streptozotocin-induced diabetic rats, and diabetic rats with peripheral neuropathy (DNP) and DNP treated with gabapentin or with LLLT. Behavioral tests were carried out through hotplate test for the determination of pain sensations and the Morris water maze test for spatial reference memory evaluation. Blood samples were collected at the end of treatment for biochemical determinations. In the current study, the latency of hind-paw lick decreased significantly when DNP are treated with gabapentin or LLLT. The Morris water maze test showed that LLLT treatment improved memory that deteriorated in DNP more than gabapentin do. The results of the biochemical study revealed that LLLT could not affect the level of beta-endorphin that decreased in DNP but significantly decreased S100B that rose in DNP. PGE2 and cytokines IL 1beta, IL-10, and TNF-alpha showed significant increase in DNP compared with control group. The gabapentin administration or LLLT application significantly reversed the levels of the mentioned markers towards the normal values of the controls. Levels of serum MDA and nitric oxide increased significantly in the DNP but rGSH showed significant decrease. These markers were improved significantly when the DNP were treated with gabapentin or LLLT. The treatment with gabapentin or LLLT significantly decreased the raised level in total cholesterol in DNP but could not decrease the elevated level of triglycerides, while LDL cholesterol decreased significantly in DNP treated with gabapentin but not affected by LLLT. Values of serum alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), urea, and creatinine increased significantly in the DPN and diabetic rats without peripheral neuropathy (PN) compared with control group. The treatment of DNP with gabapentin induced significant increases in ALAT and ASAT activities but LLLT treatment induced significant decreases in ALAT and ASAT activities as compared with DNP group. Neither gabapentin nor LLLT could improve the elevated levels of serum urea and creatinine in the DNP. It could be concluded that LLLT is more safe and effective than gabapentin in the management of neuropathy in diabetic rats. PMID- 29527630 TI - Anatomical characterization of hoof growth pattern in six Iranian sheep breeds and its possible implication for trimming recommendations. AB - The objective of this study was to compare hoof anatomy, hoof growth pattern, and hoof weight-bearing surface of six different Iranian sheep breeds to identify possible differences in the hoof anatomical features that could help to minimize adverse effects of hoof trimming methods. Front and hind hooves of 2-year-old, previously untrimmed, pastured dairy ewes of six Iranian breeds (Afshari, Moghani, Kurdi, Makoui, Chaleshtori, and Lori-Bakhtiari; n = 180 ewes; 30 ewes per breed) were collected after slaughter. Medial and lateral claws were incised sagittally and anatomical measurements such as toe length, heel height, toe height, sole thickness, sole length, and toe angle were recorded in each claw. Data were analyzed using mixed model equations including breed, claw (lateral or medial), hoof (front or hind) and their interactions as fixed effects, and ewe as random effect. Breed differences were observed for all hoof measurements (P < 0.05). Chaleshtori sheep had higher measurements for most of the traits studied while Afshari and Makoui sheep had lower measurements. All measurements, except for toe length and toe height to solar surface to heel height ratio, were significantly greater in the front hooves than in the hind hooves (P < 0.05). Soles were longer in the medial claws compared to the lateral claws of the front hooves (P < 0.05). Results suggest the observed breed differences could interfere with establishing a standard, uniform hoof trimming method for sheep. For instance, it might be possible that while Afshari and Makoui sheep could require more conservative trimming, Chaleshtori sheep could require to be trimmed more. In consequence, hoof trimming methods might need to be adjusted to specific breed characteristics to avoid possible tissue damage. PMID- 29527631 TI - Phase II trial of ifosfamide in combination with the VEGFR inhibitor sorafenib in advanced soft tissue sarcoma: a Spanish group for research on sarcomas (GEIS) study. AB - Background Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48-81) and 37% (95% CI 22-55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94-6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials. PMID- 29527632 TI - The Role of Phonetic Similarity and Orthographic Information in Asymmetrical Lexical Encoding in Second Language. AB - This study examined two possible sources of asymmetrical lexical access: phonetic proximity to the nearest L1 category and orthographic information. Three groups of native Korean speakers learned Arabic non-words with sound pairs with/without an L1-dominant category (/l-r/ vs. /chi-h/), and then their phonetic categorization and lexical encoding abilities were evaluated. One group was presented with the same letters for the target pair (e.g., for both /l/ and /r/), the second group, different letters (e.g., for /l/, for /r/), and the third group, auditory input only. The results of discrimination did not show any effect of these two sources, whereas in lexical encoding, (1) a pair with an L1-dominant category was more accurately encoded; and (2) orthographic information hindered the lexical encoding. In the following spelling recall task, the scores from the learners with different letters for the target pair were similar to a ceiling. Thus, orthographic information might help them to have target-like representation, despite difficulties in online processing. PMID- 29527633 TI - A robust and accurate surrogate method for monitoring the frequency and duration of combined sewer overflows. AB - Discharges of untreated wastewater from combined sewer overflows (CSOs) can affect hydraulic stress and have significant environmental impacts on receiving water bodies. Common flow rate and water level sensors for monitoring of CSO events are expensive in terms of investment costs, installation, operation and maintenance. This paper presents a novel surrogate method to detect CSO events by using two low-cost temperature sensors. The novelty is the experimental setup for installation of temperature sensors in CSO structures and an algorithm developed to automatically calculate the duration of CSO events considering the response time of the system. The occurrence and duration of CSO events is computed based on the convergence of the two temperature signals. The method was tested under field conditions in a CSO structure, and the results were compared to the information gathered from a parallel installed flow sensor. The application of two temperature sensors installed inside a CSO structure was proven to be robust and accurate for the automatic detection of the occurrence and duration of CSO events. Within the 7-month test phase, 100% of the 20 CSO events could be detected without false detections. The accuracy of detecting the start and end of the CSO events was 2 min in comparison to the flow sensor. PMID- 29527634 TI - Novel alanines bearing a heteroaromatic side chain: synthesis and studies on fluorescent chemosensing of metal cations with biological relevance. AB - A family of novel thienylbenzoxazol-5-yl-L-alanines, consisting of an alanine core bearing a benzoxazole at the side chain with a thiophene ring at position 2, substituted with different (hetero)aryl substituents, was synthesised to study the tuning of the photophysical and chemosensory properties of the resulting compounds. These novel heterocyclic alanines 3a-f and a series of structurally related bis-thienylbenzoxazolyl-alanines 3g-j were evaluated for the first time in the recognition of selected metal cations with environmental, medicinal and analytical interest such as Co2+, Cu2+, Zn2+ and Ni2+, in acetonitrile solution, with the heterocycles at the side chain acting simultaneously as the coordinating and reporting units, via fluorescence changes. This behaviour can be explained by the involvement of the electron donor heteroatoms in the recognition event, through complexation of the metal cations. The spectrofluorimetric titrations showed that thienylbenzoxazolyl-alanines 3a-j and 4a,b were non-selective fluorimetric chemosensors for the above-mentioned cations, with the best results being obtained for the interaction of Cu2+ with bis-alanine 3j and deprotected alanines 4a,b. The encouraging photophysical and metal ion sensing properties of these thienylbenzoxazolyl-alanines suggest that they can be used to obtain bioinspired fluorescent reporters for metal ion such as peptides/proteins with chemosensory/probing ability. PMID- 29527635 TI - Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer. AB - OPINION STATEMENT: Bone health and breast cancer are two connected subjects, because breast cancer patients have a higher prevalence of osteopenia/osteoporosis and reduced bone health parameters than healthy woman of the same age. Therefore, the positive effect of adjuvant bisphosphonate therapy plays an important role in breast cancer treatment. Several randomized trials have studied bisphosphonates in the adjuvant setting in postmenopausal woman and demonstrated their potential to prevent treatment-induced bone loss. The prevention of fractures and the subsequent preservation of patients' quality of life are important arguments for the use of adjuvant bisphosphonates in postmenopausal breast cancer patients. In addition, trials of adjuvant bone targeted agents showed a reduction of recurrences in and outside bone and an improved outcome in patients treated with bisphosphonates. PMID- 29527636 TI - Possible Pharmacodynamic and Pharmacokinetic Drug-Drug Interactions That Are Likely to Be Clinically Relevant and/or Frequent in Bipolar Disorder. AB - PURPOSE OF REVIEW: Patients with bipolar disorder are frequently treated with polypharmacy. This article should provide clinicians with an understanding of how polypharmacy can contribute to pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). RECENT FINDINGS: The pharmacokinetics and pharmacodynamics of lithium and other mood stabilizers (valproate, lamotrigine, carbamazepine, oxcarbazepine, and eslicarbazepine), antipsychotics, and selective serotonin reuptake inhibitors (SSRIs) were reviewed and summarized in the first four tables describing their pharmacokinetic and pharmacodynamic mechanisms. Four tables summarized the DDIs which are likely to be clinically relevant in adults with bipolar disorder: two for mania treatments (with and without carbamazepine), one for maintenance treatments, and one for depression treatments. The purpose is to be practical, helping clinicians pay attention to and manage polypharmacy, avoiding adverse drug reactions (ADRs) in patients with bipolar disorder, including both the frequent ADRs and those rare but potentially lethal ADRs. Future articles should improve these tables. PMID- 29527637 TI - Lifelong Learning for Clinical Practice: How to Leverage Technology for Telebehavioral Health Care and Digital Continuing Medical Education. AB - PURPOSE OF REVIEW: Psychiatric practice continues to evolve and play an important role in patients' lives, the field of medicine, and health care delivery. Clinicians must learn a variety of clinical care systems and lifelong learning (LLL) is crucial to apply knowledge, develop skills, and adjust attitudes. Technology is rapidly becoming a key player-in delivery, lifelong learning, and education/training. RECENT FINDINGS: The evidence base for telepsychiatry/telemental health via videoconferencing has been growing for three decades, but a greater array of technologies have emerged in the last decade (e.g., social media/networking, text, apps). Clinicians are combining telepsychiatry and these technologies frequently and they need to reflect on, learn more about, and develop skills for these technologies. The digital age has solidified the role of technology in continuing medical education and day-to-day practice. Other fields of medicine are also adapting to the digital age, as are graduate and undergraduate medical education and many allied mental health organizations. In the future, there will be more online training, simulation, and/or interactive electronic examinations, perhaps on a monthly cycle rather than a quasi-annual or 10-year cycle of recertification. PMID- 29527638 TI - Testing the Timing: Time Factor in Radiation Treatment for Head and Neck Cancers. AB - OPINION STATEMENT: Overall radiation treatment time has long been recognized as an important factor in head and neck tumor control. The concern of tumor growth in waiting time either before starting radiotherapy or during treatment is substantial given its negative impact on clinical outcome. There is an overwhelming evidence that increasing the time to initiate treatment increases the tumor burden and worsens the prognosis. This effect is more pronounced especially in patients with an early stage cancer disease. Delay in treatment initiation is contributed by both health care- and patient-related factors. Health care-related factors include advancement in diagnostic modalities and transfer of patient to academic health care centers accompanied by delayed referrals and long-awaited appointments. Patient-related factors include delayed reporting time and socioeconomic factors. An efficient transition of care along with access of cancer care modalities to community health care centers will not only improve the quality of care in secondary health care centers but also help decrease the patient burden in tertiary centers. A quick and well-structured multidisciplinary appointment program is fundamental in shortening the time required for patient referrals, thus increasing the optimal survival time for Head and Neck cancer patients with early initiation of treatment. PMID- 29527639 TI - Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19. AB - Spinocerebellar ataxia type 19 (SCA19), allelic with spinocerebellar ataxia type 22 (SCA22), is a rare syndrome caused by mutations in the KCND3 gene which encodes the potassium channel Kv4.3. Only 18 SCA19/22 families and sporadic cases of different ethnic backgrounds have been previously reported. As in other SCAs, the SCA19/22 phenotype is variable and usually consists of adult-onset slowly progressive ataxia and cognitive impairment; myoclonus and seizures; mild Parkinsonism occurs in some cases. Here we describe a Swedish SCA19/22 family spanning five generations and harboring the T377M mutation in KCND3. For the first time for this disease, 18F-fluorodeoxyglucose PET was assessed revealing widespread brain hypometabolism. In addition, we identified white matter abnormalities and found unusual features for SCA19/22 including early age of onset and fast rate of progression in the late course of disease in the oldest patient of this family. PMID- 29527640 TI - Is there a blood pressure lowering effect of MRAs in heart failure? An overview and meta-analysis. AB - Although mineralocorticoid antagonists (MRAs) have been proposed as effective fourth-line blood pressure (BP) lowering agents in resistant hypertension, this effect in heart failure is undetermined. In this synthesis of heart failure randomized controlled trials (RCTs), we evaluated the extent of BP lowering following MRA treatment against placebo. We searched Medline and the Cochrane Collaboration Library databases from 1991 to September 2016 for RCTs, in which MRAs were compared with placebo. The quality of RCTs was assessed with Cochrane risk of bias tool. Outcomes were the extent of systolic and diastolic BP lowering. We included seven studies (13,354 patients, 65.8% males, mean age of 66.3 years, mean follow-up period of 9.4 months, mean baseline BP of 123.5/75.0 mmHg) of MRAs compared with placebo. MRAs were not significantly associated with systolic - 1.8 (95% CI: - 8.0, 4.4) mmHg or diastolic - 0.3 (95% CI: - 3.4, 2.7) mmHg, BP reduction. Although systolic BP was not lowered by spironolactone, diastolic BP was lowered by - 3.0 (95% CI: - 3.4, - 2.6) mmHg. Eplerenone treatment did not significantly lowered systolic [- 0.04 (95% CI: - 4.4, 4.3) mmHg], but it was associated with minimal diastolic BP increase [1.0 (95% CI: 0.5, 1.53) mmHg]. MRAs were not associated with systolic and diastolic BP reduction in heart failure patients. This finding suggests that MRAs should be used according to their indications in heart failure independently of initial BP levels. PMID- 29527641 TI - Morphological and molecular characterisation of Isospora butcherae n. sp. in a silvereye (Zosterops lateralis) (Latham, 1801). AB - A new Isospora (Apicomplexa:Eimeriidae) species is described from a silvereye (Zosterops lateralis) in Western Australia. Sporulated oocysts of this species are spherical, 24.2 (23.1-25.2) * 23.3 (22.8-23.9) MUm, with a shape index (length/width) of 1.02, and with a smooth bi-layered oocyst wall, 1.2 MUm thick (outer layer 0.9 MUm, inner 0.3 MUm). A polar granule is present, but the oocyst residuum and a micropyle are absent. The ovoid-shaped sporocysts are 16.1 (15.7 17.3) * 10.5 (15.7-17.3) MUm and have a shape index of 1.53. A hemidome-shaped Stieda and a rectangular-shaped substieda body are present. A sporocyst residuum is present and composed of numerous granules of different sizes scattered among the sporozoites. The oocysts from this isolate are morphologically different from those of all known Isospora spp. This coccidian parasite was molecularly characterised at the 18S, 28S ribosomal RNA and the mitochondrial cytochrome oxidase (COI) gene. At the 18S locus, based on 1210 bp of sequence, this new isolate exhibited 99.9, 99.8, 99.7 and 99.5% similarity to I. sp. MAH-2013a (KF648870) from a superb starling (Lamprotornis superbus) in Canada, I. sp. MS 2003 (AY33157) from a Southern cape sparrow (Plocepasser mahali) in America, I. sp. Tokyo (AB75786) from Japan and I. sp. respectively. Further analysis of a subgroup of 300 bp long 18S sequences (n = 11), including I. anthochaerae and the other three Isospora characterised from birds in Western Australia, revealed that I. butcherae n. sp. exhibited 98.3% similarity to both I. sp. MAH-2013a (KF648870) and I. MS-2003 (AY33171). At the 28S locus, this new isolate exhibited 97.3% similarity with I. sp. MS-2003 from a California towhee (Melozone crissalis). At the COI locus, this new isolate exhibited 99.8% similarity to I. neochmiae from a red-browed finch. Based on morphological and molecular data, this isolate is a new species of Isospora, which is named Isospora butcherae n. sp. after Mrs. June Butcher for her lifelong dedication as a wildlife rehabilitator. Graphical abstract ?. PMID- 29527642 TI - Correction to: Green drugs in the fight against Anisakis simplex-larvicidal activity and acetylcholinesterase inhibition of Origanum compactum essential oil. AB - The article Green drugs in the fight against Anisakis simplex-larvicidal activity and acetylcholinesterase inhibition of Origanum compactum essential oil, written by Victor Lopez, Maria Cascella, Giovanni Benelli, Filippo Maggi, Carlota Gomez Rincon. PMID- 29527643 TI - An International Approach to Enhancing a National Guideline on Driving and Dementia. AB - PURPOSE OF REVIEW: The purpose of this study was to update a national guideline on assessing drivers with dementia, addressing limitations of previous versions which included a lack of developmental rigor and stakeholder involvement. METHODS: An international multidisciplinary team reviewed 104 different recommendations from 12 previous guidelines on assessing drivers with dementia in light of a recent review of the literature. Revised guideline recommendations were drafted by consensus. A preliminary draft was sent to specialist physician and occupational therapy groups for feedback, using an a priori definition of 90% agreement as consensus. RECENT FINDINGS: The research team drafted 23 guideline recommendations, and responses were received from 145 stakeholders. No recommendation was endorsed by less than 80% of respondents, and 14 (61%) of the recommendations were endorsed by more than 90%.The recommendations are presented in the manuscript. The revised guideline incorporates the perspectives of consensus of an expert group as well as front-line clinicians who regularly assess drivers with dementia. The majority of the recommendations were based on evidence at the level of expert opinion, revealing gaps in the evidence and future directions for research. PMID- 29527644 TI - A randomized controlled trial to evaluate the Make Safe Happen(r) app-a mobile technology-based safety behavior change intervention for increasing parents' safety knowledge and actions. AB - BACKGROUND: Many unintentional injuries that occur in and around the home can be prevented through the use of safety equipment and by consistently following existing safety recommendations. Unfortunately, uptake of these safety behaviors is unacceptably low. This paper describes the design of the Make Safe Happen(r) smartphone application evaluation study, which aims to evaluate a mobile technology-based safety behavior change intervention on parents' safety knowledge and actions. METHODS: Make Safe Happen(r) app evaluation study is a randomized controlled trial. Participants will be parents of children aged 0-12 years who are recruited from national consumer online survey panels. Parents will complete a pretest survey, and will be randomized to receive the Make Safe Happen(r) app or a non-injury-related app, and then complete a posttest follow-up survey after 1 week. Primary outcomes are: (1) safety knowledge; (2) safety behaviors; (3) safety device acquisition and use, and (4) behavioral intention to take safety actions. RESULTS: Anticipated study results are presented. CONCLUSIONS: Wide reaching interventions, to reach substantial parent and caregiver audiences, to effectively reduce childhood injuries are needed. This study will contribute to the evidence-base about how to increase safety knowledge and actions to prevent home-related injuries in children. TRIAL REGISTRATION NUMBER: NCT02751203 ; Pre results. PMID- 29527645 TI - Ion homeostasis, osmoregulation, and physiological changes in the roots and leaves of pistachio rootstocks in response to salinity. AB - Pistachio, one of the important tree nuts, is cultivated in arid and semi-arid regions where salinity is the most common abiotic stress encountered by this tree. However, the mechanisms underlying salinity tolerance in this plant are not well understood. In the present study, five 1-year-old pistachio rootstocks (namely Akbari, Badami, Ghazvini, Kale-Ghouchi, and UCB-1) were treated with four saline water regimes (control, 8, 12, and 16 dS m-1) for 100 days. At high salinity level, all rootstocks showed decreased relative water content (RWC), total chlorophyll content (TCHC), and carotenoids in the leaf, while ascorbic acid (AsA) and total soluble proteins (TSP) were reduced in both leaf and root organs. In addition, the total phenolic compounds (TPC), proline, glycine betaine, total soluble carbohydrate (TSC), and H2O2 content increased under salinity stress in all studied rootstocks. Three different ion exclusion strategies were observed in the studied rootstocks: (i) Na+ exclusion in UCB-1, because most of its Na+ is retained in the roots; (ii) Cl- exclusion in Badami, in which most of its Cl- remained in the roots; and (iii) similar concentrations of Na+ and Cl- were observed in the leaves and roots of Ghazvini, Akbari, and Kale-Ghouchi. Transport capacity (ST value) of K+ over Na+ from the roots to the leaves was more observable in UCB-1 and Ghazvini. Overall, the root system cooperated more effectively in UCB-1 and Badami for retaining and detoxifying an excessive amount of Na+ and Cl-. The results presented here provide important inputs to better understand the salt tolerance mechanism in a tree species for developing more salt-tolerant genotypes. Based on the results obtained here, the studied rootstocks from tolerant to susceptible are arranged as follows: UCB-1 > Badami > Ghazvini > Kale-Ghouchi > Akbari. PMID- 29527646 TI - Modes of selenium occurrence and LCD modeling of selenite desorption/adsorption in soils around the selenium-rich core, Ziyang County, China. AB - Studying the modes of selenium occurrence in high-Se soils and its behaviors can improve understanding and evaluating its cycling, flux, and balance in geo ecosystems and its influence on health. In this paper, using a modified sequential chemical extraction technique, seven operationally defined selenium fractions and Se valence distribution were determined about five soils in which paddy was planted (W1, W2, W3, W4, W5) and five soils in which maize was planted (H1, H2, H3, H4, H5) around the selenium-rich core, Ziyang County, Shaanxi Province, China. The results show that selenium fractions in the soils mainly include sulfide/selenide and base-soluble Se, and ligand-exchangeable Se is also high for five soils in which paddy was planted. For water-soluble Se, Se (IV) is main Se valence and almost no Se (VI) was determined about five soils in which paddy was planted, while almost 1:1 of Se (IV) and Se (VI) coexist about five soils in which maize was planted. For exchangeable Se, similar results were found. For the first time, two typical high-Se soils (W1 soil and H1 soil) were chosen to measure the pH-dependent solid-solution distribution of selenite in the pH range 3-9, and the results were explained using LCD (ligand and charge distribution) adsorption modeling. The desorbed selenite concentrations from the two soils are in general underestimated by the model due to a comparable binding affinity of phosphate and selenite on goethite and much lower amount of total selenite than total reactively adsorbed phosphate. The pH dependency of adsorption of selenite added to the soil can be successfully described with the LCD model for W1 soil. Whereas considering the influence of Al-oxides, by lowering selenite adsorption affinity constant K of Se adsorption on goethite by 16 times, the LCD model can describe the adsorption much better. The results can help to understand selenium cycling, flux, and balance in typical high-Se soils. PMID- 29527647 TI - Sorption of selected pharmaceuticals by a river sediment: role and mechanisms of sediment or Aldrich humic substances. AB - Sorption of pharmaceuticals onto sediments is frequently related to organic matter content. Thus, the present work aimed to compare the effect of humic substances (HS) extracted from a river sediment versus Aldrich (HS) on the sorption of selected pharmaceuticals onto this river sediment. The results exhibited no "unique" effect of the presence of HS from the same origin. Thus, the sediment HS increased the sorption of sulfamethoxazole (SMX), diclofenac (DCF), and trimethoprim (TMP), but reduced the sorption of atenolol (ATN). The presence of Aldrich HS increased the sorption of TMP and ATN and decreased the sorption of SMX and DCF. Fluorescence quenching measurements revealed that these effects cannot be explained only by the presence of pharmaceutical HS associations. The use of several sorption models suggested that the sorption of SMX, DCF, and ATN involves multilayer mechanisms. Furthermore, it was pointed out that the presence of HS does not change the sorption mechanisms although it was observed interaction between HS and the sediment. Indeed, the sediment HS sorbs onto the sediment whereas the Aldrich HS tends to mobilize organic compounds from the sediment to the solution. PMID- 29527648 TI - The toxicity of cadmium ion (Cd2+) to phycocyanin: an in vitro spectroscopic study. AB - The pollution of heavy metals is a severer problem for the ecosystems in waters. The toxicity of Cd2+ on phycocyanin (PC) is studied in molecular level in this work. The fluorescence quenching of PC is observed by the adding Cd2+ from 0 to 500 * 10-7 mol L-1. From the theoretical calculation and the time-resolved fluorescence decay profiles, the fluorescence quenching of PC by Cd2+ is found to be static. The synchronous fluorescence spectra are used to study the change in amino acid residues of PC molecules, indicating that the effect of Cd2+ on the Trp of PC is more significant than the Tyr. The UV-Vis absorbance of tetrapyrrole decreases from 0.26 to 0.23 cps with increasing Cd2+ concentration, suggesting that Cd2+ affects the light adsorption and the photosynthesis function of PC. The circular dichroism spectra reveal that adding Cd2+ also changes the secondary structure (alpha-helix) of PC. PMID- 29527649 TI - Heavy metals transfer in the olive tree and assessment of food contamination risk. AB - Due to constraints of fresh water for agricultural irrigation, wastewater was used for irrigation of agricultural land as alternative water resources in arid and semi-arid Tunisian regions. However, long-term irrigation may cause contamination by heavy metals in the soil as well as for crops, thus becoming a threat to humans. To understand the effect of irrigation with wastewater on the concentrations of heavy metals Cr, Cu, Mn, Zn, and Pb, in soil and plants, soil samples and plants were collected and analyzed. Results have shown that all soil samples do not exhibit extreme values. The content of heavy metals in the surface layer (0-30 cm) is much higher than that in depth. Overall, the concentrations of Mn, Pb, Cu, Cr, and Zn in soil were found to be lower than the authorized national safety limits. Moreover, the content in both parts of forage crops have not exceeded the WHO standard. For olive trees, no negative values were found in the different organs, which was also true for the extracted oil. An exception happened for the oils produced from fallen olives in direct contact with the wastewater and the soil. Therefore, to ensure food security and wastewater use for irrigation, monitoring and control of pollution is required. Graphical abstract Biomass production from treated wastewater without risk. PMID- 29527651 TI - Distillers' grains anaerobic digestion residue biochar used for ammonium sorption and its effect on ammonium leaching from an Ultisol. AB - The aim of this work was to explore the potential application of biochar from distillers' grains anaerobic digestion residue pyrolyzed at 700 degrees C (ADR DG700) to ammonium (NH4+) adsorption from aqueous solution, as well as its effect on NH4+ leaching from an Ultisol. The adsorption kinetic of NH4+ on the ADR-DG700 could be described by an Elovich model (R2 = 0.995), and the combined Langmuir Freundlich model (R2 = 0.997) fitted the isotherm data better than the Langmuir, Freundlich, Redlich-Peterson, and Temkin models with a maximum adsorption of 11.41 mg N g-1. The NH4+ adsorption on ADR-DG700 was mainly controlled by the cation exchange, the surface complexation with oxygen-containing functional groups of carboxyl C?O (C?O) and carbohydrate C?OH, as well as the electrostatic interactions with Si?O?Si functional group. In addition, the ADR-DG700 soil application reduced 2.48-20.67% of NH4+-N leaching loss after nitrogen fertilizer application in an Ultisol. These results suggested that the ADR-DG700 could be a sorbent for NH4+-contaminated water as well as an inhibitor for soil NH4+ leaching. PMID- 29527652 TI - Diagnostic use of lung ultrasound compared to chest radiograph for suspected pneumonia in a resource-limited setting. AB - BACKGROUND: Lung ultrasound is an effective tool for diagnosing pneumonia in developed countries. Diagnostic accuracy in resource-limited countries where pneumonia is the leading cause of death is unknown. The objective of this study was to evaluate the sensitivity of bedside lung ultrasound compared to chest X ray for pneumonia in adults presenting for emergency care in a low-income country. METHODS: Patients presenting to the emergency department with suspected pneumonia were evaluated with bedside lung ultrasound, single posterioranterior chest radiograph, and computed tomography (CT). Using CT as the gold standard, the sensitivity of lung ultrasound was compared to chest X-ray for the diagnosis of pneumonia using McNemar's test for paired samples. Diagnostic characteristics for each test were calculated. RESULTS: Of 62 patients included in the study, 44 (71%) were diagnosed with pneumonia by CT. Lung ultrasound demonstrated a sensitivity of 91% compared to chest X-ray which had a sensitivity of 73% (p = 0.01). Specificity of lung ultrasound and chest X-ray were 61 and 50% respectively. CONCLUSIONS: Bedside lung ultrasound demonstrated better sensitivity than chest X-ray for the diagnosis of pneumonia in Nepal. TRIAL REGISTRATION: ClinicalTrials.gov, registration number NCT02949141 . Registered 31 October 2016. PMID- 29527650 TI - Quantification of polychlorinated biphenyl contamination using human placenta as biomarker from Punjab Province, Pakistan. AB - The present study biomonitored the placental polychlorinated biphenyl (PCB) concentrations in women from Punjab Province, Pakistan, that provides the pioneer data for occurrence and body burden of PCBs in placental tissues from South Asian women. The ?34PCB concentrations in placental tissues were ranged from 20.2 to 115.98 ng/g lipid weight (lip. wt.), with predominance of tetra-PCB (54.67%). The levels of ?8DL-PCBs and ?6-indicator PCBs were ranged from 2.03 to 27.64 ng/g (lip. wt.) and 1.71 to 30.8 ng/g (lip. wt.), respectively. The WHO-TEQ2005 values for DL-PCBs were ranged from 1.18 * 10-5 to 0.067 ng/g (lip. wt.), with highest value evaluated for CB-126. The estimated daily intake (EDI) for DL-PCBs was ranged from 9.27 * 10-8 to 5.25 * 10-4 pg WHO-TEQ/kg body weight (bw), which was within the tolerable daily intake (TDI) values established by international organizations. The spatial distribution patterns of Sigma34PCB concentrations from study area have shown relative higher concentrations in samples from urban and industrial cities than rural areas, and industrial and urban releases along with e-waste handling were recognized as vital PCB sources in the environment. In order to ascertain the transplacental transfer of PCBs, the fetal growth parameters were correlated with the ?34PCB concentrations in placental tissues. The relationship between ?34PCB concentrations in placental tissues and infant's anthropometric measures through multiple linear regression showed a negative correlation of infant's body weight (R2 = 0.0728), crown to heel length (R2 = 0.068), head circumference (R2 = 0.0342), chest circumference (R2 = 0.0001), and mid arm circumference (R2 = 0.0096) that noticeably highlights the inhibited fetal anthropometric development associated with maternal PCB bioaccumulation. Hence, an immediate elimination of ongoing PCB addition in the studied area has been emphasized and further investigations are suggested to appropriately manage the public and neonatal health risks in the region. PMID- 29527654 TI - British Society of Haematology Guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding. PMID- 29527653 TI - Secretome of Differentiated PC12 Cells Enhances Neuronal Differentiation in Human Mesenchymal Stem Cells Via NGF-Like Mechanism. AB - The secretome-mediated responses over cellular physiology are well documented. Stem cells have been ruling the field of secretomics and its role in regenerative medicine since the past few years. However, the mechanistic aspects of secretome mediated responses and the role of other cells in this area remain somewhat elusive. Here, we investigate the effects of secretome-enriched conditioned medium (CM) of neuronally differentiated PC12 cells on the neuronal differentiation of human mesenchymal stem cells (hMSCs). The exposure to CM at a ratio of 1:1 (CM: conditioned medium of PC12 cells) led to neuronal induction in hMSCs. This neuronal induction was compared with a parallel group of cells exposed to nerve growth factor (NGF). There was a marked increase in neurite length and expression of neuronal markers (beta-III tubulin, neurofilament-M (NF M), synaptophysin, NeuN in exposed hMSCs). Experimental group co-exposed to NGF and CM showed an additive response via MAPK signaling and directed the cells particularly towards cholinergic lineage. The ability of CM to enhance the neuronal properties of stem cells could aid in their rapid differentiation into neuronal subtypes in case of stem cell transplantation for neuronal injuries, thus broadening the scope of non-stem cell-based applications in the area of secretomics. PMID- 29527655 TI - Development of Enriched Core Competencies for Health Services and Policy Research. AB - OBJECTIVE: To develop an enriched set of core competencies for health services and policy research (HSPR) doctoral training that will help graduates maximize their impact across a range of academic and nonacademic work environments and roles. DATA SOURCES/STUDY SETTING: Data were obtained from multiple sources, including literature reviews, key informant interviews, stakeholder consultations, and Expert Working Group (EWG) meetings between January 2015 and March 2016. The study setting is Canada. STUDY DESIGN: The study used qualitative methods and an iterative development process with significant stakeholder engagement throughout. DATA COLLECTION/EXTRACTION METHODS: The literature reviews, key informant interviews, existing data on graduate career trajectories, and EWG deliberations informed the identification of career profiles for HSPR graduates and the competencies required to succeed in these roles. Stakeholder consultations were held to vet, refine, and validate the competencies. PRINCIPAL FINDINGS: The EWG reached consensus on six sectors and eight primary roles in which HSPR doctoral graduates can bring value to employers and the health system. Additionally, 10 core competencies were identified that should be included or further emphasized in the training of HSPR doctoral students to increase their preparedness and potential for impact in a variety of roles within and outside of traditional academic workplaces. CONCLUSION: The results offer an expanded view of potential career paths for HSPR doctoral graduates and provide recommendations for an expanded set of core competencies that will better equip graduates to maximize their impact on the health system. PMID- 29527656 TI - Pain and opioid use after reversal of sickle cell disease following HLA-matched sibling haematopoietic stem cell transplant. PMID- 29527657 TI - Rituximab-induced acute and delayed serum sickness in thrombotic thrombocytopenic purpura: the role of anti-rituximab antibodies. PMID- 29527658 TI - Clinical features and therapeutic challenges of cytopenias belonging to alps and alps-related (ARS) phenotype. PMID- 29527659 TI - Robust Machine Learning Variable Importance Analyses of Medical Conditions for Health Care Spending. AB - OBJECTIVE: To propose nonparametric double robust machine learning in variable importance analyses of medical conditions for health spending. DATA SOURCES: 2011 2012 Truven MarketScan database. STUDY DESIGN: I evaluate how much more, on average, commercially insured enrollees with each of 26 of the most prevalent medical conditions cost per year after controlling for demographics and other medical conditions. This is accomplished within the nonparametric targeted learning framework, which incorporates ensemble machine learning. Previous literature studying the impact of medical conditions on health care spending has almost exclusively focused on parametric risk adjustment; thus, I compare my approach to parametric regression. PRINCIPAL FINDINGS: My results demonstrate that multiple sclerosis, congestive heart failure, severe cancers, major depression and bipolar disorders, and chronic hepatitis are the most costly medical conditions on average per individual. These findings differed from those obtained using parametric regression. CONCLUSIONS: The literature may be underestimating the spending contributions of several medical conditions, which is a potentially critical oversight. If current methods are not capturing the true incremental effect of medical conditions, undesirable incentives related to care may remain. Further work is needed to directly study these issues in the context of federal formulas. PMID- 29527660 TI - Impact of socioeconomic status on survival for patients with anal cancer. AB - BACKGROUND: Although outcomes for patients with squamous cell carcinoma of the anus (SCCA) have improved, the gains in benefit may not be shared uniformly among patients of disparate socioeconomic status. In the current study, the authors investigated whether area-based median household income (MHI) is predictive of survival among patients with SCCA. METHODS: Patients diagnosed with SCCA from 2004 through 2013 in the Surveillance, Epidemiology, and End Results registry were included. Socioeconomic status was defined by census-tract MHI level and divided into quintiles. Multivariable Cox proportional hazards models and logistic regression were used to study predictors of survival and radiotherapy receipt. RESULTS: A total of 9550 cases of SCCA were included. The median age of the patients was 58 years, 63% were female, 85% were white, and 38% were married. In multivariable analyses, patients living in areas with lower MHI were found to have worse overall survival and cancer-specific survival (CSS) compared with those in the highest income areas. Mortality hazard ratios for lowest to highest income were 1.32 (95% confidence interval [95% CI], 1.18-1.49), 1.31 (95% CI, 1.16-1.48), 1.19 (95% CI, 1.06-1.34), and 1.16 (95% CI, 1.03-1.30). The hazard ratios for CSS similarly ranged from 1.34 to 1.22 for lowest to highest income. Older age, black race, male sex, unmarried marital status, an earlier year of diagnosis, higher tumor grade, and later American Joint Committee on Cancer stage of disease also were associated with worse CSS. Income was not found to be associated with the odds of initiating radiotherapy in multivariable analysis (odds ratio of 0.87 for lowest to highest income level; 95% CI, 0.63-1.20). CONCLUSIONS: MHI appears to independently predict CSS and overall survival in patients with SCCA. Black race was found to remain a predictor of SCCA survival despite controlling for income. Further study is needed to understand the mechanisms by which socioeconomic inequalities affect cancer care and outcomes. Cancer 2018;124:1791-7. (c) 2018 American Cancer Society. PMID- 29527661 TI - Cutaneous seeding of neoplastic plasma cells to a site of bruising in a patient with relapsed myeloma. PMID- 29527663 TI - Rapid Advances in Immunotherapy to Treat Cancer. AB - Immunotherapy is now the fourth pillar of cancer therapy, with surgery, radiation, and traditional chemotherapy being the remaining pillars. Over the past decade, enthusiasm for immunotherapy has increased because of, in part, data showing that it consistently improves overall survival in select patients with historically refractory cancers. This issue covers various aspects of immunotherapy ranging from use of 1) chimeric antigen receptor (CAR) T cells to treat patients with B-cell acute lymphoblastic leukemia; 2) population pharmacokinetic/dynamic modeling to develop new immune checkpoint inhibitors; and 3) simulations of existing population pharmacokinetic models of immunotherapy to minimize waste without compromising exposure and efficacy. PMID- 29527665 TI - Patient-Centered Reverse Translation. PMID- 29527667 TI - Bortezomib plus EPOCH is effective as frontline treatment in patients with plasmablastic lymphoma. PMID- 29527668 TI - Successful therapy of ocular rosacea with topical ivermectin. PMID- 29527669 TI - Neurothekeoma, a hard to diagnose neoplasm among red nodules. PMID- 29527670 TI - Adjustable versus non-adjustable sutures for strabismus. AB - BACKGROUND: Strabismus, or squint, can be defined as a deviation from perfect ocular alignment and can be classified in many ways according to its aetiology and presentation. Treatment can be broadly divided into medical and surgical options, with a variety of surgical techniques being available, including the use of adjustable or non-adjustable sutures for the extraocular muscles. There exists an uncertainty as to which of these techniques produces a better surgical outcome, and an opinion that the adjustable suture technique may be of greater benefit in certain situations. OBJECTIVES: To determine if either an adjustable suture or non-adjustable suture technique is associated with a more accurate long term ocular alignment and to identify specific situations in which it would be of benefit to use a particular method. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 13 June 2017. We contacted experts in the field for further information. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) comparing adjustable to non-adjustable sutures for strabismus surgery. DATA COLLECTION AND ANALYSIS: We used standard procedures recommended by Cochrane. Two review authors independently screened search results and extracted data. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We identified one RCT comparing adjustable and non-adjustable sutures in primary horizontal strabismus surgeries in 60 children aged less than 12 years in Egypt. The study was not masked and we judged it at high risk of detection bias. Ocular alignment was defined as orthophoria or a horizontal tropia of 8 prism dioptres (PD) or less at near and far distances. At six months, there may be a small increased chance of ocular alignment with adjustable sutures compared with non adjustable sutures clinically, however, the confidence intervals (CIs) were wide and were compatible with an increased chance of ocular alignment in the non adjustable sutures group, so there was no statistical difference (risk ratio (RR) 1.18, 95% CI 0.91 to 1.53). We judged this to be low-certainty evidence, downgrading for imprecision and risk of bias. At six months, 730 per 1000 children in the non-adjustable sutures group had ocular alignment. The study authors reported that there were no complications during surgery. The trials did not assess patient satisfaction and resource use and costs. AUTHORS' CONCLUSIONS: We could reach no reliable conclusions regarding which technique (adjustable or non-adjustable sutures) produced a more accurate long-term ocular alignment following strabismus surgery or in which specific situations one technique is of greater benefit than the other, given the low-certainty and chance with just the one study. More high-quality RCTs are needed to obtain clinically valid results and to clarify these issues. Such trials should ideally 1. recruit participants with any type of strabismus or specify the subgroup of participants to be studied, for example, thyroid, paralytic, non-paralytic, paediatric; 2. randomise all consenting participants to have either adjustable or non-adjustable surgery prospectively; 3. have at least six months of follow-up data; and 4. include reoperation rates as an outcome measure. PMID- 29527671 TI - Knowledge, attitudes, and first-aid measures about epilepsy among primary school teachers in northern Iran. AB - OBJECTIVE: To assess knowledge, attitudes, and first-aid measures about epilepsy among primary school teachers. METHOD: This cross-sectional study was conducted with participation of 342 primary school teachers during September 2016 to January 2017 in cities of Babol and Qaem-Shahr in Mazandaran Province in northern Iran. Primary schools were selected using simple random sampling. Data were collected through interviews using a structured questionnaire. The knowledge section included general knowledge, causes, symptoms, seizure triggers, first-aid measures, and recommended treatments. The Likert scale was used for the attitudes section. Answers about first-aid measures were categorized as helpful or harmful. RESULTS: The level of total knowledge score of 25 (7.7%) teachers was very high, 140 (43.3%) high, 141 (43.8%) moderate, and 17 (5.2%) low. The mean score about general knowledge was as follows: 6.1 (1.9), range = 0-9; causes 6.3 (1.9), range = 0-10; symptoms of seizures 8.5 (2.5), range = 0-12; and first-aid measures 6.8 (2.0), range = 0-11. Some 83% knew not taking anticonvulsants regularly could trigger seizures, and all teachers said a person with epilepsy should go see a physician. Attitudes were generally positive except for marriage and having children. The level of first-aid measures score of 8 (7.2) teachers was very high, 79 (70.5) high, 25 (22.3) low. Teachers with teaching experience at special schools took more helpful measures CONCLUSIONS: The knowledge of teachers about epilepsy was insufficient, attitudes toward people with epilepsy were generally positive, and first-aid measures at the last witnessed seizure were fairly helpful. Having teaching experience in special schools had a positive influence over knowledge and taking appropriate first-aid measure at time of the last witnessed seizure. PMID- 29527673 TI - Adjunctive perampanel for partial-onset seizures. PMID- 29527672 TI - Pseudobulbar affect as a negative prognostic indicator in amyotrophic lateral sclerosis. AB - OBJECTIVE: To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population-based incident cohort of amyotrophic lateral sclerosis (ALS). METHODS: Incident ALS cases, diagnosed according to El Escorial criteria, were enrolled from a prospective population-based registry in Puglia, Southern Italy. The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate PBA. Total scores range from 7 to 35. A score >=13 was used to identify PBA. Cox proportional hazard models were used for survival analysis. The modified C-statistic for censored survival data was used for models' discrimination. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify subgroups of patients with different patterns of risk, depending on baseline characteristics. RESULTS: We enrolled 94 sporadic ALS, median age of 64 years (range: 26-80). At the censoring date, 65 of 94 (69.2%), 39 of 60 (65.0%), and 26 of 34 (76.5%) patients reached the outcome (tracheotomy/death), in the whole, non PBA and in the PBA groups, respectively. Kaplan-Meier survival curves for the two subgroups were not significantly different (log-rank test: 1.3, P = .25). The discrimination ability of a multivariable model with demographic and clinical variables of interest was not improved by adding PBA. In the RECPAM analysis, ALSFRSr and the total score of CNS-LS scale (=10) were the most important variables for differentiating all risk categories. CONCLUSIONS: These preliminary results underlie that the presence of PBA at entry negatively influences survival in a specific subgroup of patients with ALS characterized by less functional impairment. PMID- 29527674 TI - New heterozygous variant in GP1BB gene is responsible for an inherited form of macrothrombocytopenia. PMID- 29527675 TI - Overrepresentation of patients from HTLV-1 endemic countries among T cell Non Hodgkin lymphomas in the Netherlands: an indication of under-diagnosis of Adult T cell leukaemia/lymphoma. PMID- 29527676 TI - A phase II study of carfilzomib in the treatment of relapsed/refractory mantle cell lymphoma. PMID- 29527677 TI - The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. AB - BACKGROUND AND OBJECTIVES: In this targeted systematic review, we aimed to identify up-to-date prevalence estimates of migraine and severe headache in adults from population-based US government surveys. Our goal was to assess the stability of prevalence estimates over time, and to identify additional information pertinent to the burden and treatment of migraine and other severe headache conditions. METHODS: We searched for the most current publicly available summary statistics from the National Health Interview Survey (NHIS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), and the National Ambulatory Medical Care Survey (NAMCS). We extracted and summarized data from each study over time and as a function of demographic variables. RESULTS: The prevalence and burden of self-reported migraine and severe headache in the US adult population is high, affecting roughly 1 out of every 6 American and 1 in 5 women over a 3 month period (15.3% overall [95% CI 14.75-15.85], 9.7% of males [95% CI 9.05 10.35] and 20.7% of females [95% CI 19.84-21.56]). The prevalence has been remarkably stable over a period of 19 years. The prevalence of migraine or severe headache in 2015 was highest in American Indian or Alaska Natives (18.4%) compared with whites, blacks, or Hispanics, with the lowest prevalence in Asians (11.3%). There is a higher burden of migraine in those aged 18-44 (17.9%), people who are unemployed (21.4%), those with family income less than $35,000 per year (19.9%), and the elderly and disabled (16.4%). Headache is consistently the fourth or fifth most common reason for visits to the emergency department, accounting for roughly 3% of all emergency department visits annually. In reproductive aged women, headache is the third leading cause of emergency department visits. CONCLUSIONS: Severe headache and migraine remain important public health problems that are more common and burdensome for women, particularly women of childbearing age, and other historically disadvantaged segments of the population. These inequities could be exacerbated if new high cost treatments are inaccessible to those who need them most. PMID- 29527678 TI - Interoperability: What Is It, How Can We Make It Work for Clinicians, and How Should We Measure It in the Future? PMID- 29527679 TI - Renal protection by atorvastatin in a murine model of sickle cell nephropathy. AB - Recent studies have demonstrated pleiotropic effects of statins in various mouse models of kidney disease. In this study, Townes humanized sickle cell mice were treated for 8 weeks with atorvastatin at a dose of 10 mg/kg/day starting at 10 weeks of age. Treatment with atorvastatin significantly reduced albuminuria, and improved both urine concentrating ability and glomerular filtration rate. Atorvastatin also decreased markers of kidney injury and endothelial activation, and ameliorated oxidant stress in renal tissues and peripheral macrophages. Atorvastatin downregulated the expression of mRNA levels of the NADPH oxidases, Cybb (also termed Nox2) and Nox4, which are major sources of oxidant stress in the kidney. These findings highlight the pleiotropic effects of atorvastatin and suggest that it may provide beneficial effects in sickle cell nephropathy. PMID- 29527680 TI - An apple NAC transcription factor enhances salt stress tolerance by modulating the ethylene response. AB - It is known that ethylene signaling is involved in the regulation of the salt stress response. However, the molecular mechanism of ethylene-regulated salt stress tolerance remains largely unclear. In this study, an apple NAM ATAF CUC transcription factor, MdNAC047, was isolated and functionally characterized to be involved in ethylene-modulated salt tolerance. MdNAC047 gene was significantly induced by salt treatment and its overexpression conferred increased tolerance to salt stress and facilitated the release of ethylene. Quantitative real-time-PCR analysis demonstrated that overexpression of MdNAC047 increased the expression of ethylene-responsive genes. Electrophoretic mobility shift assay, yeast one-hybrid and dual-luciferase assays suggested that MdNAC047 directly binds to the MdERF3 (ETHYLENE RESPONSE FACTOR) promoter and activates its transcription. In addition, genetic analysis assays indicated that MdNAC047 regulates ethylene production at least partially in an MdERF3-dependent pathway. Overall, we found a novel 'MdNAC047-MdERF3-ethylene-salt tolerance' regulatory pathway, which provide new insight into the link between ethylene and salt stress. PMID- 29527681 TI - Hormone-sensitive lipase preferentially redistributes to lipid droplets associated with perilipin-5 in human skeletal muscle during moderate-intensity exercise. AB - KEY POINTS: Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) are the key enzymes involved in intramuscular triglyceride (IMTG) lipolysis. In isolated rat skeletal muscle, HSL translocates to IMTG-containing lipid droplets (LDs) following electrical stimulation, but whether HSL translocation occurs in human skeletal muscle during moderate-intensity exercise is currently unknown. Perilipin-2 (PLIN2) and perilipin-5 (PLIN5) proteins have been implicated in regulating IMTG lipolysis by interacting with HSL and ATGL in cell culture and rat skeletal muscle studies. This study investigated the hypothesis that HSL (but not ATGL) redistributes to LDs during moderate-intensity exercise in human skeletal muscle, and whether the localisation of these lipases with LDs was affected by the presence of PLIN proteins on the LDs. HSL preferentially redistributed to PLIN5-associated LDs whereas ATGL distribution was not altered with exercise; this is the first study to illustrate the pivotal step of HSL redistribution to PLIN5-associated LDs following moderate-intensity exercise in human skeletal muscle. ABSTRACT: Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) control skeletal muscle lipolysis. ATGL is present on the surface of lipid droplets (LDs) containing intramuscular triglyceride (IMTG) in both the basal state and during exercise. HSL translocates to LD in ex vivo electrically stimulated rat skeletal muscle. Perilipin-2- and perilipin-5 associated lipid droplets (PLIN2+ and PLIN5+ LDs) are preferentially depleted during exercise in humans, indicating that these PLINs may control muscle lipolysis. We aimed to test the hypothesis that in human skeletal muscle in vivo HSL (but not ATGL) is redistributed to PLIN2+ and PLIN5+ LDs during moderate intensity exercise. Muscle biopsies from 8 lean trained males (age 21 +/- 1 years, BMI 22.6 +/- 1.2 kg m-2 and VO2 peak 48.2 +/- 5.0 ml min-1 kg-1 ) were obtained before and immediately following 60 min of cycling exercise at ~59% VO2 peak . Cryosections were stained using antibodies targeting ATGL, HSL, PLIN2 and PLIN5. LDs were stained using BODIPY 493/503. Images were obtained using confocal immunofluorescence microscopy and object-based colocalisation analyses were performed. Following exercise, HSL colocalisation to LDs increased (P < 0.05), and was significantly greater to PLIN5+ LDs (+53%) than to PLIN5- LDs (+34%) (P < 0.05), while the increases in HSL colocalisation to PLIN2+ LDs (+16%) and PLIN2- LDs (+28%) were not significantly different. Following exercise, the fraction of LDs colocalised with ATGL (0.53 +/- 0.04) did not significantly change (P < 0.05) and was not affected by PLIN association to the LDs. This study presents the first evidence of exercise-induced HSL redistribution to LDs in human skeletal muscle and identifies PLIN5 as a facilitator of this mechanism. PMID- 29527682 TI - Peer-mediated intervention to improve play skills in children with autism spectrum disorder: A feasibility study. AB - BACKGROUND/AIM: Children with autism spectrum disorder (ASD) frequently demonstrate impaired play skills and poor quality social interactions compared to typically developing peers. Complex interventions to improve play skills should be investigated with randomised control trials (RCT) where possible to support evidence-based practice for occupational therapists. Prior to a RCT, multiple feasibility studies are recommended to identify barriers to the trial. The aim of this study is to adapt a complex intervention to improve play skills in children with ASD and investigate the feasibility of conducting a RCT. METHODS: Participants were 10 children with ASD paired with typically developing playmates chosen by their families. Pairs attended 10 intervention sessions involving video modelling, therapist- and peer-mediation and free play. Participant numbers needed for future investigation of effectiveness were calculated and time and cost considerations were reviewed. The Test of Playfulness (ToP) was the primary outcome measure; both parent- and child-report outcome measures were evaluated for appropriateness. RESULTS: To determine effectiveness of the intervention 34 pairs in both control and intervention groups will be needed to conduct a RCT over an 18-month timeframe. ToP scores showed a positive, but not statistically significant trend from pre- to post-intervention. These improvements were maintained at follow-up in both clinic and home environments. The Piers-Harris 2 and the Parent Relationship Questionnaire were identified as appropriate secondary outcome measures; additional parent- and teacher-report outcome measures are recommended for the RCT. CONCLUSION: A RCT to investigate effectiveness of this intervention for improving play skills of children with ASD and their playmates are feasible. PMID- 29527683 TI - Effectiveness of interventions for co-residing family caregivers of people with dementia: Systematic review and meta-analysis. AB - BACKGROUND/AIM: Occupational therapists and health practitioners commonly provide interventions to family caregivers of people with dementia with the aim of relieving burden, depression, and disruptions in health and social support. To date, the effects of multicomponent interventions specifically targeting these four important outcomes has not been established. The aim of this study was to evaluate the effectiveness of multicomponent interventions on four outcomes for co-residing family caregivers of people with dementia. METHODS: A comprehensive database search of the literature was performed using CINAHL, MEDLINE, PubMed, PsycINFO, OTseeker, EMBASE and the Cochrane library. Randomised control trials (RCTs) that included multicomponent interventions for co-residing family caregivers addressing burden, depression, health and social support were selected. Relevant articles were critically reviewed and study results were synthesised. Meta-analysis was conducted separately. RESULTS: Twenty-two of 358 retrieved studies were selected, with 15 studies being included in the meta analyses. The multicomponent interventions identified were comprised of a range of different individual strategies. Significant effective results were found for all four specified outcomes. CONCLUSIONS: Many types of multicomponent interventions appear beneficial on all of the four specified outcomes. The literature presents a trend that multicomponent interventions consisting of a combination of counselling, support groups, education, stress and mood management or telephone support are important strategies within an effective multicomponent intervention. PMID- 29527684 TI - Effects of freezing conditions on quality changes in blueberries. AB - BACKGROUND: Freezing preservation is one of the most effective methods used to maintain the flavour and nutritional value of fruit. This research studied the effects of different freezing conditions, -20 degrees C, -40 degrees C, -80 degrees C, and immersion in liquid nitrogen, on quality changes of freeze-thawed blueberries. The water distribution estimates of blueberries were measured based on low-field nuclear magnetic resonance (LF-NMR) analysis. The pectin content, drip loss, and fruit texture were also detected to evaluate quality changes in samples. RESULTS: The freezing curves of blueberry showed super-cooling points at -20 degrees C and - 40 degrees C, whereas super-cooling points were not observed at -80 degrees C or in liquid nitrogen. After freeze-thaw treatment, the relaxation time of the cell wall water (T21 ), cytoplasm water and extracellular space (T22 ), and vacuole water (T23 ) were significantly shortened compared to fresh samples, which suggested a lower liquidity. Although the freezing speed for samples immersed in liquid nitrogen was faster than other treatments, samples treated at -80 degrees C showed better quality regarding vacuole water holding, drip loss, and original pectin content retention. CONCLUSION: This study contributed to understanding how freezing temperature affects the qualities of blueberries. The super-fast freezing rate might injure fruit, and an appropriate freezing rate could better preserve blueberries. (c) 2018 Society of Chemical Industry. PMID- 29527685 TI - Sonographic diagnosis of four water beads causing small-bowel obstruction in an 18-month-old boy. AB - We report a rare case of sonographic (US) diagnosis of four water beads causing small-bowel obstruction in an 18-month-old boy. The boy presented with a 3-day history of repeated bouts of abdominal pain and vomiting, which became bilious on the last day. Abdominal US examination showed four rounded anechoic masses in the small bowel. Urgent exploratory laparotomy revealed that the obstruction was caused by three large water beads with a diameter of 2.8 cm and fragments of a fourth one. Foreign bodies should be considered in cases of small-bowel obstruction; US can be very helpful in the diagnosis of water beads in the bowel. PMID- 29527686 TI - Home exercise programs supported by video and automated reminders for patients with stroke: A qualitative analysis. AB - BACKGROUND: Allied health professionals working in rehabilitation often prescribe home exercise programs. Smart technology offers an alternative format for presentation of home exercise programs with potential advantages over traditional paper-based programs, but how do patients feel about this? DESIGN: This qualitative analysis was part of a convergent mixed methods design, using in depth, semi-structured interviews to explore the lived experience of patients utilising touch screen tablets to support an upper limb home exercise program post stroke. METHODS: Ten male participants with stroke and upper limb impairment who received home exercise programs using video and reminders on tablet computers participated. Interviews were transcribed and analysed thematically. RESULTS: There were three main themes: (1) exercises on the tablet helped patients' recovery in a variety of ways; (2) everyone could use the tablet for their home exercise program; but (3) not everyone liked using the tablet. CONCLUSIONS AND SIGNIFICANCE OF THE STUDY: Smart technology is increasingly accessible and provides a novel, convenient way to provide home exercise programs post stroke with a number of benefits. This technology is not for everyone, but may be well suited to patients who already own and use these devices in daily life. Automated reminders were not viewed as a useful reminder tool. PMID- 29527687 TI - Mathematical model of CO2 release during milk fermentation using natural kefir grains. AB - BACKGROUND: Milk fermentation takes place in the presence of various micro organisms, producing a variety of dairy products. The oldest of them is kefir, which is usually produced by the fermentation of milk with kefir grains. Carbon dioxide (CO2 ), as one of the process products, also contributes to the characteristic flavor of kefir. The amount of CO2 generated during fermentation depends on bioprocessing conditions and may change, which is not desirable at the industrial level. RESULTS: In this study we developed a simplified mathematical model of CO2 release in the milk-fermentation process. An intuitive approach based on superposition and experimental analysis was used for the modeling. The chemical system studied was considered as a two-input (temperature, rotational frequency of the stirrer) one-output (CO2 concentration) dynamic system. CONCLUSION: Based on an analysis of CO2 release transients in the case of non simultaneous stepwise changed input quantities, two differential equations were defined that describe the influence of the two input quantities on the output quantity. The simulation results were verified by experiments. The proposed model can be used for a comprehensive analysis of the process that is being studied and for the design and synthesis of advanced control systems, which will ensure a controlled CO2 release at the industrial level. (c) 2018 Society of Chemical Industry. PMID- 29527689 TI - Commentary on McGillis Hall, L., Lalonde, M., Kashin, J., Yoo, C., & Moran, J. (2017) Changing nurse licensing examinations: media analysis and implication of the Canadian experience. PMID- 29527688 TI - Delivery of an anti-transthyretin Nanobody to the brain through intranasal administration reveals transthyretin expression and secretion by motor neurons. AB - Transthyretin (TTR) is a transport protein of retinol and thyroxine in serum and CSF, which is mainly secreted by liver and choroid plexus, and in smaller amounts in other cells throughout the body. The exact role of TTR and its specific expression in Central Nervous System (CNS) remains understudied. We investigated TTR expression and metabolism in CNS, through the intranasal and intracerebroventricular delivery of a specific anti-TTR Nanobody to the brain, unveiling Nanobody pharmacokinetics to the CNS. In TTR deficient mice, we observed that anti-TTR Nanobody was successfully distributed throughout all brain areas, and also reaching the spinal cord. In wild-type mice, a similar distribution pattern was observed. However, in areas known to be rich in TTR, reduced levels of Nanobody were found, suggesting potential target-mediated effects. Indeed, in wild-type mice, the anti-TTR Nanobody was specifically internalized in a receptor-mediated process, by neuronal-like cells, which were identified as motor neurons. Whereas in KO TTR mice Nanobody was internalized by all cells, for late lysosomal degradation. Moreover, we demonstrate that in vivo motor neurons also actively synthesize TTR. Finally, in vitro cultured primary motor neurons were also found to synthesize and secrete TTR into culture media. Thus, through a novel intranasal CNS distribution study with an anti-TTR Nanobody, we disclose a new cell type capable of synthesizing TTR, which might be important for the understanding of the physiological role of TTR, as well as in pathological conditions where TTR levels are altered in CSF, such as amyotrophic lateral sclerosis. PMID- 29527690 TI - On the use of the term 'frequency' in applied behavior analysis. AB - There exists a terminological problem in applied behavior analysis: the term frequency has been used as a synonym for both rate (the number of responses per time) and count (the number of responses). To guide decisions about the use and meaning of frequency, we surveyed the usage of frequency in contemporary behavior analytic journals and textbooks and found that the predominant usage of frequency was as count, not rate. Thus, we encourage behavior analysts to use frequency as a synonym for count. PMID- 29527691 TI - EXTENDing fetal life: postnatal placentae for preterm babies. PMID- 29527692 TI - The impact of a Role Emerging Placement while a student occupational therapist, on subsequent qualified employability, practice and career path. AB - BACKGROUND: Although Role Emerging Placements (REP) are now a common feature in pre-registration occupational therapy curricula, there is a need to expand the understanding of the impact of this experience on employability, practice and career path of qualified occupational therapists. METHOD: A case finding online survey was used to create a purposive sample for Thematic Analysis of semi structured interviews with practising occupational therapists from one UK Masters' level pre-registration occupational therapy program. RESULTS: The case finding survey (n = 19) led to recruitment of six participants to be interviewed. The qualitative findings reflected the impact of a REP experience on occupational therapists' employability, practice and career path. The complementary features of the more traditional placement and the role emergent type of placement were considered as being useful and beneficial to qualified practice regardless of setting. However, the REP additionally, had an internal and outward impact. Internally, the therapist gains a passion for occupation-focussed practice and builds confidence to promote both self and the profession. Outwardly, the therapist can offer extra skills in qualified practice, particularly in innovative service development and delivery, thereby offering added value for employability. CONCLUSION: A REP experience as an occupational therapy student, can develop additional skills for qualified professional practice than traditional practice placements alone. The impact of such a placement matches with the 'Generation Y' traits of young adults who are now starting to emerge into training and the work place, translates well into a variety of working environments and lasts into career development. The placement model of occupation focussed project development and the less apprentice style learning of a REP may be influential, and could be a suitable model within traditional placements. PMID- 29527693 TI - Relationship between inferior vena cava diameter ratio and central venous pressure. AB - PURPOSE: To explore the relationship between the shape of the inferior vena cava (IVC) lumen and central venous pressure (CVP). METHODS: In 60 patients undergoing mechanical ventilation and CVP monitoring in the Intensive Care Unit of Peking Union Medical College Hospital from July to October 2016, we measured with B-mode ultrasonography the transverse maximum (MXD) and minimum diameter (MID) of the IVC at end expiration, and calculated the diameter ratio (DR) as MXD/MID. Patients were divided into three groups according to CVP: low (CVP < 8 mm Hg), intermediate (8 mm Hg <= CVP <= 10 mm Hg), and high (CVP > 10 mm Hg). RESULTS: MXD was 2.32 +/- 0.41 cm, MID was 1.41 +/- 0.40 cm, and DR was 1.76 +/- 0.49. CVP was 9.27 +/- 2.99 mm Hg. DR correlated with CVP (r = -0.527, P < .001). The low CVP group had greater dispersion of DR values, with a large variety in IVC shape (elliptical, irregular, teardrop-shaped, partially collapsed...). The area under the ROC curve for predicting CVP with DR, with a CVP threshold of 8 mm Hg was 0.835 (95% CI, 0.726-0.945; P < .05). With a DR cutoff value of 1.76, sensitivity was 0.765 and specificity was 0.781. CONCLUSIONS: DR above 1.7 is predictive of CVP < 8 mm Hg. PMID- 29527694 TI - Failure to expand the motor unit size to compensate for declining motor unit numbers distinguishes sarcopenic from non-sarcopenic older men. AB - KEY POINTS: The age-related loss of muscle mass is related to the loss of innervating motor neurons and denervation of muscle fibres. Not all denervated muscle fibres are degraded; some may be reinnervated by an adjacent surviving neuron, which expands the innervating motor unit proportional to the numbers of fibres rescued. Enlarged motor units have larger motor unit potentials when measured using electrophysiological techniques. We recorded much larger motor unit potentials in relatively healthy older men compared to young men, but the older men with the smallest muscles (sarcopenia) had smaller motor unit potentials than healthy older men. These findings suggest that healthy older men reinnervate large numbers of muscle fibres to compensate for declining motor neuron numbers, but a failure to do so contributes to muscle loss in sarcopenic men. ABSTRACT: Sarcopenia results from the progressive loss of skeletal muscle mass and reduced function in older age. It is likely to be associated with the well-documented reduction of motor unit numbers innervating limb muscles and the increase in size of surviving motor units via reinnervation of denervated fibres. However, no evidence exists to confirm the extent of motor unit remodelling in sarcopenic individuals. The aim of the present study was to compare motor unit size and number between young (n = 48), non-sarcopenic old (n = 13), pre sarcopenic (n = 53) and sarcopenic (n = 29) men. Motor unit potentials (MUPs) were isolated from intramuscular and surface EMG recordings. The motor unit numbers were reduced in all groups of old compared with young men (all P < 0.001). MUPs were higher in non-sarcopenic and pre-sarcopenic men compared with young men (P = 0.039 and 0.001 respectively), but not in the vastus lateralis of sarcopenic old (P = 0.485). The results suggest that extensive motor unit remodelling occurs relatively early during ageing, exceeds the loss of muscle mass and precedes sarcopenia. Reinnervation of denervated muscle fibres probably expands the motor unit size in the non-sarcopenic and pre-sarcopenic old, but not in the sarcopenic old. These findings suggest that a failure to expand the motor unit size distinguishes sarcopenic from pre-sarcopenic muscles. PMID- 29527695 TI - Oxytocin regulates reunion affiliation with a pairmate following social separation in marmosets. AB - While separation from significant social partners produces a host of neurobiological and behavioral perturbations, including behavioral distress and increased glucocorticoid production, positive social interactions upon reunion are critical for the reestablishment of normative relationship dynamics and the attenuation of the biobehavioral stress response. The hormone oxytocin has critical and pervasive roles in reproductive and behavioral processes across the lifespan, and plays a particularly prominent role in social bonding. In this study, we examined the extent that oxytocin modulates interactions with a pairmate following separation challenges that varied in both social context (isolation; separation) and duration (long; short), in marmosets. We demonstrated that the impact of pharmacological manipulations of the oxytocin system on the expression of affiliation upon reunion depended on both the context and duration of the separation challenge. Specifically, marmosets treated with an oxytocin antagonist spent less time in proximity with their pairmate upon reunion following a long-separation challenge. During the short-separation challenge, marmosets engaged in more social gaze when separated with an opposite-sex stranger, but not when separated with their mate. Furthermore, marmosets that received the most social gaze from opposite-sex strangers spent the most time in proximity with their long-term mate upon reunion. We also showed that marmosets treated with an OT agonist received increased levels of gaze from opposite-sex strangers, but not from their mate. Overall, these results suggest that marmosets are sensitive to the nature of the social interactions during separation, and subsequently alter their expression of affiliation upon reunion with their long term mate. These findings further implicate oxytocin as a bond-enhancing molecule that regulates the reestablishment of normative levels of affiliation with a mate following separation, and add to the emerging literature that suggests the OT system underlies critical behavioral processes that contribute to the preservation of long-lasting social bonds. PMID- 29527696 TI - Protective potential of royal jelly against cadmium-induced infertility in male rats. AB - This study aimed to investigate the protective potential of Royal jelly (RJ) against cadmium (Cd)-induced testicular dysfunction in rats. Thirty-five adult male Wistar rats were assigned into five groups. G I; (control) injected intraperitoneally with saline, G II injected intraperitoneally with a single dose of CdCl2 (1 mg/kg BW), G III received RJ (100 mg/kg BW/day) orally, G IV was pre treated with RJ for 1 week then, treated with CdCl2 , and G V was co-treated with RJ and CdCl2 . After day 56, serum and tissue samples were collected and analysed. The results showed decreased serum testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), superoxide dismutase, glutathione reductase, sperm motility and count while increased malondialdehyde, nitric oxide, tumour necrosis factor-alpha (TNF-alpha) and sperm abnormalities, along with a severely damaged seminiferous tubules epithelium with cytoplasmic and nuclear disruptions following Cd toxicity. Additionally, Cd stimulated testicular mRNA expression of TNF-alpha while inhibited those of steroidogenic acute regulatory protein, cytochrome P450 cholesterol side chain cleavage enzyme androgen binding protein, FSH-receptor, LH-receptor, androgen receptor, 3beta hydroxysteroid dehydrogenase (HSD), 17beta-HSD, and cytochrome P450 17A1. These negative alterations of cadmium were greatly reduced by RJ treatment. This study concluded that RJ protects against Cd-induced testicular toxicity. PMID- 29527697 TI - Erratum: "Analysis of the track- and dose-averaged LET and LET spectra in proton therapy using the geant4 Monte Carlo code" [Med. Phys. 42 (11), page range 6234 6247(2015)]. PMID- 29527698 TI - Initial experience with AAPM's new publisher. PMID- 29527699 TI - Erratum: "Monte Carlo simulations of 3 He ion physical characteristics in a water phantom and evaluation of radiobiological effectiveness" [Med. Phys. 43 (2), page range 761-776(2016)]. PMID- 29527700 TI - Grape seed extract attenuates dexamethasone-induced testicular and thyroid dysfunction in male albino rats. AB - This study scrutinised the ameliorative properties of grape seed extract (GSE) in dexamethasone (DEX)-induced testicular and thyroid dysfunction associated with oxidative stress in male albino rats. Thirty-two healthy adult male albino rats were divided into four groups of eight animals each: normal, DEX control, DEX + GSE (200 mg/kg body weight) group and DEX + GSE (400 mg/kg body weight) group. The body weight gain and testes weight were assessed. Plasma testosterone and thyroid profile were determined. Testicular glucose-6-phosphate dehydrogenase (G 6-PDH), acid phosphatase (ACP), total protein and glutathione (GSH) levels, as well as catalase (CAT) activity also histopathological changes of the testis were evaluated. DEX treatment caused a significant decrease in body weight gain and weight of testes. Significant alterations in enzymatic and nonenzymatic antioxidants were observed. Moreover, a marked reduction in plasma testosterone levels and thyroid profile was observed. The administration of GSE significantly attenuated the deleterious effects of oxidative stress induced by DEX, as well as attenuated DEX-induced testicular and thyroid damage. Furthermore, DEX induced histological alterations in the testis. GSE ameliorated the injurious effects of DEX and improved the histological alterations in the testis. PMID- 29527702 TI - Efficacy and safety of daily use of tadalafil in treatment of patients with premature ejaculation: A randomised placebo-controlled clinical trial. AB - The study aimed to evaluate the efficacy and safety of the once-daily use of 5 mg tadalafil in the treatment of patients with premature ejaculation (PE). In a single-blind placebo-controlled clinical study, it was carried out on 100 patients with PE. All patients were randomised equally divided into two groups (50 patients each). Group 1 was given placebo in the form of oral multivitamin tablet once a day for 6 weeks. Group 2 was given 5 mg tadalafil once a day for 6 weeks. All patients were asked to complete Arabic Index of Premature Ejaculation (AIPE) before and after the treatment. This study showed that there were no statistically significant differences between patients in the placebo and tadalafil groups regarding the mean values of the seven questions and total scores of the AIPE questionnaire before treatment (p value >.05). The mean values of the seven questions and total scores of AIPE questionnaire in the tadalafil group were significantly higher than the placebo group after treatment (p value = .001). This study concluded that once-daily use of 5 mg tadalafil for 6 weeks was effective and well tolerated in the treatment of patients with PE. PMID- 29527701 TI - Identification of an IL-1-induced gene expression pattern in AR+ PCa cells that mimics the molecular phenotype of AR- PCa cells. AB - BACKGROUND: In immunosurveillance, bone-derived immune cells infiltrate the tumor and secrete inflammatory cytokines to destroy cancer cells. However, cancer cells have evolved mechanisms to usurp inflammatory cytokines to promote tumor progression. In particular, the inflammatory cytokine, interleukin-1 (IL-1), is elevated in prostate cancer (PCa) patient tissue and serum, and promotes PCa bone metastasis. IL-1 also represses androgen receptor (AR) accumulation and activity in PCa cells, yet the cells remain viable and tumorigenic; suggesting that IL-1 may also contribute to AR-targeted therapy resistance. Furthermore, IL-1 and AR protein levels negatively correlate in PCa tumor cells. Taken together, we hypothesize that IL-1 reprograms AR positive (AR+ ) PCa cells into AR negative (AR- ) PCa cells that co-opt IL-1 signaling to ensure AR-independent survival and tumor progression in the inflammatory tumor microenvironment. METHODS: LNCaP and PC3 PCa cells were treated with IL-1beta or HS-5 bone marrow stromal cell (BMSC) conditioned medium and analyzed by RNA sequencing and RT-QPCR. To verify genes identified by RNA sequencing, LNCaP, MDA-PCa-2b, PC3, and DU145 PCa cell lines were treated with the IL-1 family members, IL-1alpha or IL-1beta, or exposed to HS-5 BMSC in the presence or absence of Interleukin-1 Receptor Antagonist (IL 1RA). Treated cells were analyzed by western blot and/or RT-QPCR. RESULTS: Comparative analysis of sequencing data from the AR+ LNCaP PCa cell line versus the AR- PC3 PCa cell line reveals an IL-1-conferred gene suite in LNCaP cells that is constitutive in PC3 cells. Bioinformatics analysis of the IL-1 regulated gene suite revealed that inflammatory and immune response pathways are primarily elicited; likely facilitating PCa cell survival and tumorigenicity in an inflammatory tumor microenvironment. CONCLUSIONS: Our data supports that IL-1 reprograms AR+ PCa cells to mimic AR- PCa gene expression patterns that favor AR targeted treatment resistance and cell survival. PMID- 29527703 TI - Is there any correlation between sperm parameters and chromatin quality with embryo morphokinetics in patients with male infertility? AB - The main goal was to evaluate the correlation between sperm parameters and chromatin quality with embryo kinetics via time-lapse monitoring system (TLM). A total of 40 couples involved in the ICSI program as a result of male infertility. For assessment of sperm chromatin and DNA quality, we used aniline blue, toluidine blue, chromomycin A3, acridine orange and terminal transferase-mediated deoxyuridine triphosphate biotin end labelling assays. All mature oocytes were injected, and the generated zygotes (2PNs) were cultured in TLM. In day 3 after injection, single embryo transfer (SET) was carried out according to the morphology and morphokinetics. The patients were followed up until delivery. There were positive significant correlations between sperm count with CC2 (r = .330, p = .049), T4 (r = .329, p = .038), T6 (r = .342, p = .035) and T7 (r = .374, p = .025). Also, there were positive significant correlations between nonprogressive motility and T2 (r = 0.323, p = .042), T3 (r = .411, p = .013) and T4 (r = .418, p = .007). Regarding the sperm chromatin quality assays, there were negative significant correlations between CMA3 and CC2 (r = -.272, p = .049) and between acridine orange and T5 (r = -.221, p = .040). It seems that the abnormal sperm parameters and chromatin alteration affect the normal embryo kinetics in ICSI program. PMID- 29527704 TI - Activity of Antarctic fungi extracts against phytopathogenic bacteria. AB - : This study aims to obtain secondary metabolites extracts from filamentous fungi isolated from soil and marine sediments from Antarctic ecosystems and to assess its potential antibacterial activity on Xanthomonas euvesicatoria and Xanthomonas axonopodis pv. passiflorae (phytopathogenic bacteria causing diseases in pepper and tomato and passionfruit, respectively). Among the 66 crude intracellular and extracellular extracts obtained from fungi recovered from soil and 79 obtained from marine sediment samples, 25 showed the ability to prevent the growth of X. euvesicatoria in vitro and 28 showed the ability to prevent the growth of X. axonopodis pv. passiflorae in vitro. Intracellular and extracellular extracts from soil fungi inhibited around 97% of X. euvesicatoria and 98% of X. axonopodis pv. passiflorae at 2.1 mg ml-1 . The average inhibition rates against X. euvesicatoria and X. axonopodis pv. passiflorae for intracellular and extracellular extracts from marine sediments fungi were around 96 and 97%, respectively, at 3.0 mg ml-1 . Extracts containing secondary metabolites with antimicrobial activity against X. euvesicatoria and X. axonopodis pv. passiflorae were obtained, containing possible substitutes for the products currently used to control these phytopathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: Micro organisms from extreme ecosystems, such as the Antarctic ecosystem, need to survive in harsh conditions with low temperatures, low nutrients and high UV radiation. Micro-organisms adapt to these conditions evolving diverse biochemical and physiological adaptations essential for survival. All this makes these micro organisms a rich source of novel natural products based on unique chemical scaffolds. Discovering novel bioactive compounds is essential because of the rise in antibiotic-resistant micro-organisms and the emergence of new infections. Fungi from Antarctic environments have been proven to produce bioactive secondary metabolites against various micro-organisms, but few studies have shown activity against Xanthomonas phytopathogens. PMID- 29527705 TI - Identification of small droplets of photosynthetic squalene in engineered Synechococcus elongatus PCC 7942 using TEM and selective fluorescent Nile red analysis. AB - : To identify microbial squalene that has been widely used in various industrial applications, intracellular formation of photosynthetic squalene was investigated using the previously engineered Synechococcus elongatusPCC 7942 strain. Unlike the proposed localization of squalene in the membrane bilayer, small droplets were identified in the cytoplasm of S. elongatusPCC 7942 as squalene using transmission electron microscopy analysis. Determination of the diameters of the squalene droplets with manual examination of 1016 droplets in different squalene producing strains indicated larger squalene droplets in larger cells. Based on the observation of a sole droplet of squalene in a cyanobacterium, fluorescent Nile red was used for the selective staining of squalene. The fluorescent intensities were correlated with squalene contents determined using gas chromatography-mass spectrometry. Photosynthetic squalene was identified as a small droplet in S. elongatusPCC 7942, and this noninvasive quantitative method could be useful to promote high-throughput strain development for squalene production. SIGNIFICANCE AND IMPACT OF THE STUDY: Engineering of Cyanobacteria has focused on sustainable production of squalene by converting CO2 . Before improving the photosynthetic squalene production, we characterized formation of squalene, showing small droplets in the cytoplasm instead of single granule. Based on the finding and the analysis, this study has provided valuable evidences how further metabolic engineering strategies should apply to enhance the production yield. PMID- 29527706 TI - Employer knowledge of federal requirements for recording work-related injuries and illnesses: Implications for occupational injury surveillance data. AB - BACKGROUND: Accuracy of the Bureau of Labor Statistics Survey of Occupational Injuries and Illnesses (SOII) data is dependent on employer compliance with workplace injury and illness recordkeeping requirements. Characterization of employer recordkeeping can inform efforts to improve the data. METHODS: We interviewed representative samples of SOII respondents from four states to identify common recordkeeping errors and to assess employer characteristics associated with limited knowledge of the recordkeeping requirements and non compliant practices. RESULTS: Less than half of the establishments required to maintain OSHA injury and illness records reported doing so. Few establishments knew to omit cases limited to diagnostic services (22%) and to count unscheduled weekend days as missed work (27%). No single state or establishment characteristic was consistently associated with better or worse record-keeping. CONCLUSION: Many employers possess a limited understanding of workplace injury recordkeeping requirements, potentially leading them to over-report minor incidents, and under-report missed work cases. PMID- 29527707 TI - Neither fish nor fowl: A perceived mismatch in norms and values between oneself, other students, and people back home undermines adaptation to university. AB - Students from low social-class background often struggle to adapt to university. Previous research shows that perceived incompatibility between social-class background identity and student identity is one reason, but little is known about the underlying causes of identity incompatibility. In three studies, we expected and found that students with low subjective social-class background perceived their values differently from other students, but also differently from people back home, and both increased identity incompatibility. Identity incompatibility negatively affected the student identity. Additionally, the current research also identifies specific patterns of norm and value differences that are prone to perceived identity incompatibility. The findings demonstrate that perceived differences in values from both groups are important mechanisms for identity incompatibility induced by the transition to university that may affect student identities and potentially their university trajectories. PMID- 29527708 TI - Reactive aggression tracks within-participant changes in women's salivary testosterone. AB - The relation between testosterone and aggression has been relatively well documented in men, but it is less well understood in women. Here we assessed the relationship between salivary testosterone and reactive aggression (i.e., rejection rate for unfair offers) in the Ultimatum Game. Forty naturally cycling women were tested twice, once in the late follicular phase (around ovulation) and once during the luteal phase. Ovulation was determined using urine test strips measuring luteinizing hormone levels. Salivary samples were assayed for testosterone, estradiol, progesterone, and cortisol at both test sessions. There was no association with the cycle, but multilevel modeling revealed a significant within-participant association between testosterone and rejection rate for extremely unfair offers (i.e., high reactive aggression), indicating that women showed greater reactive aggression when their testosterone levels were higher. Additionally, we found that women with relatively high individual concentrations of testosterone were more likely to reject extremely unfair offers than women with relatively low concentrations of testosterone. This study is the first to demonstrate that women react more aggressively in response to provocation when their testosterone level is high than when their testosterone is low, suggesting that testosterone plays an important role in the regulation of women's aggressive behavior following social provocation. PMID- 29527710 TI - Photodynamic therapy: Promoting in vitro efficacy of photodynamic therapy by liposomal formulations of a photosensitizing agent. AB - OBJECTIVE: A relatively low level of lysosomal photodamage has been shown capable of promoting the efficacy of photodamage simultaneously or subsequently directed to mitochondrial/ER sites. The procedure has hitherto involved the use of two photosensitizing agents that require irradiation at two different wavelengths and different formulation techniques. This, together with different pharmacokinetic profiles of the photosensitizers, adds a layer of complexity to a protocol that we have sought to circumvent. In this study, liposomal formulations were used to direct photodamage created by benzoporphyrin derivative (BPD, Verteporfin) to lysosomes, mitochondria and the ER. This resulted in the development of an optimal targeting profile using a single agent and a single wavelength of activating irradiation. MATERIALS/METHODS: These studies were carried out in monolayer cultures of OVCAR5 tumor cells. BPD localization was modified by lipid anchoring and formulation in liposomes, and was assessed by fluorescence microscopy. Irradiation was carried out at 690 +/- 10 nm with photodamage assessed also using fluorescent probes and microscopy. RESULTS: BPD normally localizes in a wide variety of sub-cellular loci that include both mitochondria and the ER, but lysosomes are spared from photodamage. Using a liposomal formulation containing BPD anchored to a lipid resulted in the targeting of lysosomes. A mixture of liposomes containing "free" and "anchored" BPD was shown to significantly promote photokilling. Eliminating cholesterol from the formulation of the anchored product enhanced lysosomal photodamage; prior studies had revealed that excess cholesterol can have a cytoprotective effect when lysosomes are the PDT target. DISCUSSION: The ability of a liposomal formulation to change localization patterns permits directing photodynamic therapy toward specific sub-cellular loci, thereby promoting photokilling. Incorporating chemotherapeutic agents into such formulations could represent a logical next step in assessing the ability of directed photodamage to enhance tumor eradication. Lasers Surg. Med. 50:499-505, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29527709 TI - Drug-coated balloons for de novo lesions in small coronary arteries: rationale and design of BASKET-SMALL 2. AB - The treatment of coronary small vessel disease (SVD) remains an unresolved issue. Drug-eluting stents (DES) have limited efficacy due to increased rates of instent restenosis, mainly caused by late lumen loss. Drug-coated balloons (DCB) are a promising technique because native vessels remain structurally unchanged. Basel Stent Kosten-Effektivitats Trial: Drug-Coated Balloons vs. Drug-Eluting Stents in Small Vessel Interventions (BASKET-SMALL 2) is a multicenter, randomized, controlled, noninferiority trial of DCB vs DES in native SVD for clinical endpoints. Seven hundred fifty-eight patients with de novo lesions in vessels <3 mm in diameter and an indication for percutaneous coronary intervention such as stable angina pectoris, silent ischemia, or acute coronary syndromes are randomized 1:1 to angioplasty with DCB vs implantation of a DES after successful initial balloon angioplasty. The primary endpoint is the combination of cardiac death, nonfatal myocardial infarction, and target-vessel revascularization up to 1 year. Secondary endpoints include stent thrombosis, Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding, and long-term outcome up to 3 years. Based on clinical endpoints after 1 year, we plan to assess the noninferiority of DCB compared to DES in patients undergoing primary percutaneous coronary intervention for SVD. Results will be available in the second half of 2018. This study will compare DCB and DES regarding long-term safety and efficacy for the treatment of SVD in a large all-comer population. PMID- 29527711 TI - Relationship between nuclear DNA fragmentation, mitochondrial DNA damage and standard sperm parameters in spermatozoa of fertile and sub-fertile men before and after freeze-thawing procedure. AB - The aim of this study was to assess the stability of nuclear and mitochondrial DNA (n-DNA and mt-DNA) of spermatozoa under freeze-thawing and to find out the correlation between them and their association with standard sperm parameters. Forty-three semen samples were collected from fertile (G.1; n = 29) and sub fertile (G.2; n = 14). N-DNA fragmentation was determined by TUNEL assay and mt DNA using caspase 3 staining. Each semen sample was frozen at -196 degrees C by the programmed freezer. Freeze-thawing decrease vitality, total motility and membrane integrity from (43.02 +/- 22.74%; 31.63 +/- 18.15%; 51.5 +/- 24.82%) to (22.71 +/- 17.3%; 9.21 +/- 6.61%; 34.64 +/- 19.92% respectively [p < .001]). G.1 native spermatozoa stained positive with TUNEL and caspase 3 were (14.85 +/- 17.6% and 5.8 +/- 11.59%) and increased after freeze-thawing to 27.54 +/- 19.74% (p = .004) and 7.3 +/- 6.13% (p = .01) respectively. In G.2, TUNEL and caspase 3 were (19.84 +/- 17.52% and 7.53 +/- 8.56%) and increased to (29.48 +/- 16.97% [p = .03] and 10.21 +/- 11.73%). In conclusion, freeze-thawing process affects not only semen parameters but also n-DNA and mt-DNA. Therefore, n-DNA and mt-DNA could be used as sensitive parameters for assessment of the cryodamage of human spermatozoa. PMID- 29527712 TI - Intra- and interobserver variability in nodule size of rectosigmoid endometriosis measured by two- and three-dimensional transvaginal sonography. AB - INTRODUCTION: The aim of the study was to assess the intra- and interobserver variability of two- and three-dimensional rectosigmoid nodule size measurements by transvaginal sonography in patients with rectosigmoid endometriosis. MATERIAL AND METHODS: Intra- and interobserver variability was assessed in 10 and 30 patients, respectively. Measurements in two dimensions were performed in real time during the scan, and three-dimensional measurements of volume were done on a computer. Differences within and between observers were expressed in absolute units (mm) and percentage (%) of average nodule size. Coefficient of repeatability and Bland-Altman plots with limits of agreement were used to evaluate the intra- and interobserver variability. RESULTS: Intra- and interobserver variability in two-dimensional sonography ranged from 11 to 14 mm (46-51%) for length, 3 to 6 mm (32-57%) for depth and 5 to 9 mm (33-58%) for width of the nodule. Results of three-dimensional sonography, with assessment of nodule volume, showed intra- and interobserver variability 0.4 to 2.5 times the average nodule size. CONCLUSIONS: Measurements of rectosigmoid endometriosis nodule size with two- and three- dimensional transvaginal sonography were associated with large intra- and interobserver variability. These techniques should therefore be used with caution in clinical control and research of nodule growth. PMID- 29527713 TI - Evaluation of serum miR-191-5p, miR-24-3p, miR-128-3p, and miR-376c-3 in multiple sclerosis patients. AB - BACKGROUND: Biomarkers that could be used in early diagnosis of multiple sclerosis (MS), segregation of disease subtypes, and discrimination of the aggressive disease course from the benign one are urgently needed. OBJECTIVE: The aim of this study was to investigate the specificity of circulating microRNAs: miR-191-5p, miR-128-3p, miR-24-3p, and miR-376c-3p in MS and evaluate their association with disease activity and disability progression. METHODS: The expressions of circulating miRNAs were studied in serum of 100 subjects (53 relapsing-remitting (RRMS), 20 primary progressive (PPMS), and 27 controls), using miScript serum miRNA RT-PCR assay techniques. RESULTS: In comparison with controls, miR-191-5p and miR-24-3p were overexpressed in RRMS and PPMS, with no differences between the subtypes. miR-24-3p correlated positively with the disability progression index in the combined group of all patients with MS. miR 128-3p showed tendency toward the predominant expression in PPMS and correlated positively with the annual relapse rate in RRMS. miR-376c-3p expression levels did not differ between the groups, and no associations were found to clinical parameters. CONCLUSION: This study highlighted the connection of circulating miRNAs to MS. miR-24-3p and miR-128-3p showed a tendency of association with disability accumulation and disease activity, respectively. Further studies should evaluate their suitability for clinical use. PMID- 29527714 TI - Clinical aspects of 49 infertile males with 45,X/46,XY mosaicism karyotype: A case series. AB - Disorders of sex development (DSD) are congenital abnormalities as an atypical development process in either gonadal or chromosomal structure. It is the cause of the abnormality in phenotype and characteristics. Chromosomal analysis plays an important role in the DSD determination. 45,X/46,XY mosaicism is a rare karyotype, and its prevalence is about 1.5 in 10,000 newborns. It affects the growth, hormonal balance, gonad development and histology. All data such as height, male general appearance, testis size and volume, external genitalia, spermogram and hormonal levels, testis pathology, Y chromosome microdeletion and karyotype, and assisted reproductive technology (ART) outcome were recorded based on patients profile and history. We investigated 64 infertile males with 45,X/46,XY mosaicism. Fifteen cases who had structural abnormalities in Y chromosome were excluded. From 49 available spermogram, 21 cases reported as azoospermic men, while 28 of them classified as nonazoospermic patients in which four of them displayed normal spermogram. According to hormonal evaluation, there were no significant differences between azoospermic and nonazoospermic groups. In azoospermia, only three couples underwent an ART cycle in which all of them failed. From 14 nonazoospermic cases who entered into the ART cycle, three cases experienced a successful pregnancy that one of the prosperous outcomes was twins. In 45,X/46,XY cases, both 45,X and 46,XY cell lines are seen. Various distributions of both cell lines can reflect a wide range of phenotypes that may be the most comprehensive evaluation in infertile males with 45,X/46,XY karyotype. It assumes that karyotyping as a main diagnostic test can enable us to find these rare cases. PMID- 29527715 TI - Does pelvic floor muscle maximum voluntary contraction improve after vaginal pelvic organ prolapse surgery? A prospective study. AB - AIMS: to assess pelvic floor muscle maximum voluntary contraction (MVC) before and after surgical treatment for pelvic organ prolapse (POP). METHODS: This was a prospective observational study with women scheduled for surgical correction of POP. Assessments occurred 15 days before and 40 days after surgery. The primary outcome was pelvic floor muscle (PFM) MVC measured using the manometer PeritronTM. The average strength of PFM contraction was also measured. Secondary outcomes were assessed using the Pelvic Organ Prolapse Quantification (POP-Q) score. The Student paired t-test was used for quantitative data. For the pre and postsurgery comparisons of PFM strength in relation to POP-Q value we used the nonparametric Kruskal-Wallis test for dependent variables. The level of significance adopted was P < 0.05. RESULTS: Sixty-seven women were recruited, 65 (97%) completed the study. The mean age of participants was 62 +/- 10.2. There was no difference (1.9 cm H2 O +/- 12.9; P = 0.22) between MVC before (27.1 cm H2 O +/- 17.0) and after surgery (29 cm H2 O +/- 17.8). The average contraction was higher after surgery (2.3 cmH2 O +/- 8.6; P = 0.03). The higher the severity of pre and postsurgery POP, the worse the MVC. CONCLUSION: There was no difference in MVC pre and postsurgery, however we found an improvement in PFM average contraction strength postsurgery. PMID- 29527716 TI - Can you score with balloons to enhance outcomes after drug coated balloon angioplasty? Insights from the Paris DCB Registry for in-stent restenosis. AB - OBJECTIVES: The objective of this study was to assess the 12-month clinical outcomes in patients with drug-eluting stent in-stent restenosis (DES-ISR) who were either pre-dilated with non-compliant balloons (NCBA) and with additional scoring balloons (NCBA + SBA) prior to drug coated balloon (DCB) angioplasty. METHODS: This monocentric, retrospective study included patients with DES-ISR who were routinely treated over a 2-year time span. Patients with stable angina and documented ischemia or selected forms of unstable angina due to a culprit DES-ISR lesion were analyzed. The primary endpoint was the clinically driven target lesion revascularization (TLR) rate at 12 months. Secondary endpoints included post-interventional lumen gain and late lumen loss (LLL) at 6 months. RESULTS: The 12-month TLR rates in 124 patients who underwent either NCBA + SBA or NCBA only group were not different (17.3%, 9/52 vs 11.6%, 8/69, P = 0.371) and low as compared to other comparable studies. The use of SBA led to equally high post minimal lumen diameters (MLD) in both treatment arms (NCBA 2.21 +/- 0.33 vs NCBA + SBA 2.18 +/- 0.41, P = 0.868). We did not find a significant difference in late lumen loss (LLL) between both groups (0.50 +/- 0.62 mm vs 0.40 +/- 0.46 mm, P = 0.468). CONCLUSIONS: Scoring Balloon Angioplasty can safely and effectively prepare DES-ISR lesions to render them suitable for DCB angioplasty with acceptable TLR and MACE rates. PMID- 29527717 TI - Outcomes following balloon mitral valvuloplasty in pregnant females with mitral stenosis and significant sub valve disease with severe decompensated heart failure. AB - BACKGROUND: Mitral stenosis may present with decompensated heart failure during pregnancy. Many patients do have advanced sub valve disease and present late with decompensated state. The outcomes of balloon mitral valvuloplasty (BMV) in such advanced sub valve disease with severe heart failure in pregnancy has not been specifically studied till now. METHODS: A descriptive study looking at the immediate and long-term outcomes of pregnant patients with MS who presented with severe heart failure and sub valve disease who had undergone BMV. RESULTS: Ninety six patients were studied. The mean gestational age was 23.4 +/- 10.9 weeks .Mean SpO2 was 89% at admission,17% were in cardiogenic shock and 33.33 were on mechanical ventilation. The mean Wilkin's score was 9.71 +/- 2.1 and sub valve score was 3.3 +/- 0.12. BMV was successful in 77 (80.2%) patients and failed in 19. In 5.2% cases, acute severe MR occurred. There were 11 maternal deaths (six in failed and five in success group). A successful obstetric outcome was seen in 71 patients in success (92%) and 11/19 (57%) in failed (P < 0.001). The obstetric outcomes were better in success versus failure group. Anova post hoc analysis showed sustained gradient reductions at 1 and 5 year follow-up (P = 0.03) in success group. CONCLUSIONS: BMV offers substantial improvement in clinical outcomes among pregnant patients with MS and heart failure even with severe sub valve disease. The morality rate among failed was high at 31%. The obstetric outcomes were poor after a failed BMV. Outcomes following balloon mitral valvuloplasty in pregnant females with mitral stenosis and significant sub valve disease with severe decompensated heart failure. PMID- 29527718 TI - Stress and social behaviors of maternally deprived captive giraffes (Giraffa camelopardalis). AB - Maternal deprivation can cause long-term behavioral changes in captive mammals. Studies regarding captive ungulates have also indicated behavioral shifts in the presence of the animal keeping staff; however, little is known about these effects in captive giraffes (Giraffa camelopardalis). To examine this, we observed a population of reticulated giraffes composed of maternally raised and maternally deprived individuals by direct and camera observations at Binder Park Zoo, Battle Creek, Michigan. We conducted observations using a unique ethogram with special regard for behaviors that might indicate stress or anti-social tendencies. Several variables can interact to create behavioral changes; to account for this, our study design examined the interactive effects of observation technique, raising style, and temperature on giraffe behavior. The results of these observations showed a significant increase in the rate of stereotypic and antisocial behaviors resulting from the interaction of observation technique and raising style. Stereotypic behaviors in particular showed a marked increased during cooler temperatures among giraffes of all raising style. Likewise, raising style, observation technique, and their interaction significantly impacted the time spent rubbing the enclosure. The findings of this study suggest that captive giraffe behavior can be a complex response to multiple factors and studies only examining single factors might oversimplify behavioral shifts. PMID- 29527720 TI - Distribution trends of Indonesia's health care resources in the decentralization era. AB - Indonesia has been decentralized since 2001, and we evaluated the distribution trends of physicians, puskesmas (community health centers), hospitals, and hospital beds in 34 provinces in Indonesia for 2000 to 2014. Inequality index of Gini showed improvement of the distribution of physicians and decreased from 0.38 to 0.29. The indices in distributions of hospitals and hospital beds also decreased from 0.26 to 0.17 and from 0.25 to 0.18, respectively. However, the index in the distribution of puskesmas increased from 0.19 to 0.28. We also investigated the legislative transitions of the laws concerning health resources and found the strong affects of compulsory work laws for physicians and the increment of health budget. In the decentralization era, the local governments have some political autonomy for the development of health resources; however, the national government should monitor the nationwide distribution of health resources and advice necessary recommendations to the local governments. PMID- 29527719 TI - Association between PLA2G12A polymorphism and patients with schizophrenia in a southern Chinese Han population. AB - BACKGROUND: Elevated phospholipase A2 (PLA2) activity is reported to be involved in the development of schizophrenia. Further study revealed an association between PLA2 groups XIIA (PLA2G12A) polymorphism and patients with schizophrenia in a northeast Chinese Han population. OBJECTIVE: This study will further examine whether PLA2G12A rs3087494 polymorphism is associated with patients with schizophrenia in a southern Chinese Han population. METHODS: This polymorphism was genotyped in 438 patients with schizophrenia (diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-IV) and 876 healthy controls using a case-control design. Demographic and clinical data were collected in all subjects. RESULTS: The allele and genotype frequencies of PLA2G12A rs3087494 polymorphism significantly differed between groups (both, p < .001). These differences still were significant by adjusting for sex and age. However, there was no difference in age at onset among 3 genotype groups in patients with schizophrenia by adjusting for the variables (F = 0.22, p = .80). Stepwise multivariate regression analysis showed that this polymorphism was not associated with age at onset in patients with schizophrenia (beta = .008, t = .07, p = .94). CONCLUSIONS: Our results indicated that even though PLA2G12A rs3087494 polymorphism did not influence age at onset in patients with schizophrenia, it may play an important role in the susceptibility to schizophrenia in a southern Chinese Han population. PMID- 29527721 TI - Proteases and nucleases involved in the biphasic digestion process of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae). AB - Management of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), an invasive, agricultural pest in the United States, has presented significant challenges. This polyphagous insect uses both extra-oral and gut based digestion thwarting protein- or nucleotide-based control strategies. The objective of this study was to biochemically characterize the digestive enzymes (proteases and nucleases) from the saliva, salivary gland and the gut of H. halys. Enzyme profiles for the two tissues and saliva radically differ: The pH optimum for proteases in the gut was six, with cysteine proteases predominant. In contrast, the alkaline pH optima for protease activity in the salivary gland (8 10) and saliva (7) reflected abundant serine protease and cathepsin activities. RNase enzymes were most abundant in saliva, while dsRNase and DNase activities were higher in the salivary gland and saliva compared to those in the gut. These very different enzyme profiles highlight the biphasic digestive system used by this invasive species for efficient processing of plant nutrients. Knowledge of H. halys digestive physiology will allow for counteractive measures targeting digestive enzymes or for appropriate protection of protein- or nucleotide-based management options targeting this pest. PMID- 29527722 TI - Using the Severity of Dependence Scale to screen for DSM-5 khat use disorder. AB - OBJECTIVE: This study aimed to determine the efficacy of the Severity of Dependence Scale (SDS) as a screening tool for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-defined khat use disorder. METHODS: Cross sectional, purposive sample of past-year khat consumers aged 16 and above were recruited from khat markets and cafes from university and general community in Adama, Ethiopia. Participants self-completed a survey comprising current substance use disorder. RESULTS: The SDS formed a unifactorial structure, consistent with the dependence construct. Almost three quarters (73%) of the sample were identified as experiencing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition khat use disorder. The SDS demonstrated excellent discrimination (area under the curve = 0.92) and an optimal cut-off as a score of 3 or greater, with sensitivity of 81% and specificity of 96%. This classification validly identified a group with more frequent and higher dose khat use than participants that did not screen positive. CONCLUSION: Although khat is a mild stimulant, there is clear evidence that some consumers are both concerned with their use and experience problems associated with their use. Consistent with its application for other drugs, the SDS is a brief and simple screening tool that appears to validly identify individuals experiencing a khat use disorder syndrome and experiencing high rates of adverse consequences in association with use. PMID- 29527723 TI - Contact allergy caused by stannous fluoride in toothpaste. PMID- 29527724 TI - Contact hypersensitivity in patients with psoriasis. PMID- 29527725 TI - Occupational contact allergy to sodium cocoamphopropionate in a skin protection cream. PMID- 29527726 TI - Widespread eczema in an elderly patient. PMID- 29527727 TI - Occupational immediate contact allergy to hydrolysed wheat protein after cosmetic exposure. PMID- 29527728 TI - An Italian multicentre study on methylchloroisothiazolinone/methylisothiazolinone contact sensitivity: understanding the structure-activity relationship. PMID- 29527729 TI - Gentamicin allergy as an unexpected 'hidden' cause of complications in knee arthroplasty. PMID- 29527730 TI - Contact allergy to moisturizers in Finland: the tale of the lurking tube in the medicine cupboard. PMID- 29527731 TI - Eucalyptus species as a cause of airborne allergic contact dermatitis. PMID- 29527732 TI - Nigerian sleep study found that children slept less and had more problems than children in other countries. AB - AIM: We studied sleep patterns, sleep problems and associated socio-demographic factors among children aged one year to 12 years in Lagos, Nigeria. METHODS: This prospective hospital-based study involved 432 children (55% males) who came for routine paediatric care at the Lagos State University Teaching Hospital. Information on socio-demographics, sleeping patterns and specific sleep disorders was obtained. RESULTS: The mean age of the subjects was 5.4 +/- 3.3 years. Night sleep duration decreased significantly with age from 9.6 +/- 1.3 hours at one to four years to 8.7 +/- 1.0 hours at nine years to 12 years (p < 0.001). There was no significant gender difference in bedtimes (p = 0.057), rise times (p = 0.095) and night sleep duration (p = 0.191). Most (70%) napped during the day, and 26% of these did so on a regular basis. The most common sleep problems were enuresis (42%), afraid of sleeping alone (38%), snoring (28%) and sleep talking (24%). There was no significant association between sleep duration (p > 0.05), sleep problems (p > 0.05) and socio-demographic characteristics. Comparisons with other studies showed that the children had shorter sleep duration than peers in other countries and regions and a higher prevalence of sleep disorders. CONCLUSION: Children in Nigeria had shorter sleep duration and more sleep problems than children in other international studies. PMID- 29527733 TI - Synthesis, biological evaluation, and docking studies of some 5-chloro-2(3H) benzoxazolone Mannich bases derivatives as cholinesterase inhibitors. AB - A series of N-substituted-5-chloro-2(3H)-benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC50 = 7.53 +/- 0.17 MUM), while compound 11 was found to be the most active compound against BuChE (IC50 = 17.50 +/- 0.29 MUM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC50 = 1.04 +/- 0.04 mM) than Trolox (IC50 = 1.50 +/- 0.05 mM). PMID- 29527734 TI - FOSB immunoreactivity in endothelia of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia). AB - BACKGROUND: Accurate distinction of epithelioid hemangioma (EH) from its malignant mimics is paramount but remains challenging due to its wide morphological spectrum and lack of objective molecular markers. FOSB oncogenic activation was recently identified as a key event in endothelial proliferation. We sought to investigate the FOSB staining pattern in EH with angiolymphoid hyperplasia with eosinophilia (EH-AHLE) morphology and to evaluate its value in differential diagnosis of epithelioid vascular tumors. METHODS: From the authors' files, 15 representative cases of EH-ALHE were selected and evaluated for their FOSB immunostaining pattern. Other vascular proliferations which can be morphological mimics were also tested: epithelioid hemangioendothelioma (EHE) (5 cases) and epithelioid angiosarcoma (EAS) (5 cases). RESULTS: All 15 cases of EH ALHE showed strong and homogeneous FOSB nuclear expression in endothelial cells with ample cytoplasm and intracytoplasmic vacuoles. All cases of EHE and EAS lacked FOSB immunoreactivity or showed only incidental weak FOSB immunoreactivity in less than 5 nuclei per lesion. CONCLUSIONS: FOSB immunohistochemistry is sensitive in the diagnosis of EH-ALHE, and allows differentiation from its histological mimics. An immunohistochemical panel including not only pan cytokeratin AE1/AE3 and endothelial markers, but also FOSB, helps in the diagnosis of epithelioid vascular tumors. PMID- 29527735 TI - The Uganda version of the Pediatric Evaluation of Disability Inventory (PEDI). Part I: Cross-cultural adaptation. AB - BACKGROUND: The Pediatric Evaluation of Disability Inventory (PEDI) was developed and standardized to measure functional performance in American children. So far, no published study has examined the use of the PEDI in sub-Saharan Africa. This study describes the adaptation, translation, and validation process undertaken to develop a culturally relevant PEDI for Uganda (PEDI-UG). METHOD: The cross cultural adaptation and translation of the PEDI was performed in a series of steps. A project manager and a technical advisory group were involved in all steps of adaptation, translation, cognitive debriefing, and revision. Translation and back-translation between English and Luganda were performed by professional translators. Cognitive debriefing of two subsequent adapted revisions was performed by a field-testing team on a total of 75 caregivers of children aged 6 months to 7.5 years. RESULTS: The PEDI-UG was established in both English (the official language) and Luganda (a local language) and comprises 185 items. Revisions entailed deleting irrelevant items, modifying wording, inserting new items, and incorporating local examples while retaining the meaning of the original PEDI. Item statements were rephrased as questions. Seven new items were inserted and 19 items deleted. To accommodate major differences in living conditions between rural and urban areas, 10 alternative items were provided. CONCLUSIONS: The PEDI-UG is to be used to measure functional limitations in both clinical practice and research, in order to assess and evaluate rehabilitative procedures in children with developmental delay and disability in Uganda. In this study, we take the first step by translating and adapting the original PEDI version to the culture and life conditions in both rural and urban Uganda. In subsequent studies, the tool's psychometric properties will be examined, and the tool will be tested in children with developmental delay and disability. PMID- 29527736 TI - Time-of-flight MR-angiography with a helical trajectory and slice-super resolution reconstruction. AB - PURPOSE: To improve 2D noncontrast-enhanced MRA by using a helical time-of-flight (TOF) acquisition technique and a slice-super-resolution reconstruction. METHODS: The TOF technique is combined with a helical trajectory with golden-angle-based radial projection reordering. A continuous spatial shift in slice direction is realized by adjusting the frequency of the excitation pulse between the individual projections. The limited resolution along the shift direction is improved by a deconvolution with simulated slice profile. The helical TOF (hTOF) was compared in vivo with a conventional 2D and 3D TOF. RESULTS: Results from in vivo experiments on the carotid show that the visual resolution in slice direction can be improved by using hTOF and the slice-super-resolution reconstruction. The vessels appear up to 1.5 times sharper and can be better separated from each other. Compared to 2D TOF images, the stair step artifacts are strongly reduced in reformatted hTOF images, whereas measurement time is decreased by at least 35%. Compared to 3D TOF, the hTOF offers a higher blood-to background contrast, better visualization of smaller vessels, and reduced measurement time. CONCLUSION: The hTOF benefits from a 2D acquisition and a 3D reconstruction, which makes it a promising technique for the noncontrast-enhanced imaging of the carotid. PMID- 29527737 TI - Risk factors for surgical site infection after transvaginal mesh placement in a nationwide Japanese cohort. AB - AIMS: We conducted a nationwide survey on perioperative management and antimicrobial prophylaxis of transvaginal mesh surgeries for pelvic organ prolapse in Japan to understand the practice and risk factors for surgical site infection (SSI). METHODS: Health records of women undergoing tension-free vaginal mesh (TVM) surgeries from 2010 to 2012 were obtained from 135 medical centers belonging to the Japanese Society of Pelvic Organ Prolapse Surgery. The questionnaire addressed hospital volume, perioperative management, and SSI. Risk factors for SSI were investigated by comparing cases with and without SSI. RESULTS: The hospital volume among institutions varied from 0 to 248 per year (median 16.7). Preoperative hair removal, bowel preparation, and urine culture were routinely performed at 74 (55%), 66 (49%), and 24 (18%) hospitals, respectively. Prophylactic antimicrobials used were mostly first-generation (43%) or second-generation (42%) cephalosporin. SSI was reported in 86 of 9323 patients (0.92%). A multivariate analysis indicated lower hospital volume (odds ratio [OR], 0.995 [by 1-point increase]; P < 0.001), preoperative bowel preparation (OR, 2.08; P = 0.013), non-routine urine culture (OR, 3.00; P = 0.0006), and the use of antibiotics other than first-generation cephalosporin (OR, 5.29; P = 0.0011) as significant risk factors for SSI. In contrast, the cut-off points of hospital volume for preventing SSI was 116.7 cases (area under curve: 0.61). CONCLUSION: The prevalence of SSI in TVM surgeries was 0.92% in Japan. Lower hospital volume, bowel preparation, non-routine preoperative urine culture, and prophylactic antibiotics other than first-generation cephalosporin significantly elevated the incidence of SSI. PMID- 29527738 TI - Retracted: Novel spiro-thiazolidin-4-one and thioether derivatives of benzylidene flavanones: New leads in cancer and microbial chemotherapy. AB - : The above article from Archiv der Pharmazie, published online on 12 March 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Prof. Holger Stark, and Wiley VCH Verlag GmbH & Co. KGaA, Weinheim. The retraction has been agreed due to errors in the spectroscopic data of the investigated new compounds. REFERENCE TO RETRACTION: S. Mukhtar, M. A. Alsharif, M. I. Alahmdi, H. Parveen, A. U. Khan, Arch. Pharm. Chem. Life Sci. 2018;1-12. DOI: 10.1002/ardp.201700397. PMID- 29527739 TI - Task sharing in the eye care workforce: Screening, detection, and management of diabetic retinopathy in Pakistan. A case study. AB - PURPOSE: Diabetic retinopathy (DR) is a preventable cause of vision loss. Reducing vision loss due to DR and providing access to eye care services for people with diabetes have been severely constrained by a shortage in the number of ophthalmologists. This study aimed to explore the potential for task sharing in the eye care workforce for screening, detection, and management of DR. METHODS: Using purposive sampling, 24 participants were recruited from four selected hospitals in 2 provinces in Pakistan. Face-to-face interviews were conducted to explore the potential for task sharing in DR management. RESULTS: Amongst 24 participants recruited, 22 (91.7%) including administrators (n = 3), ophthalmologists (n = 10), optometrists (n = 3), mid-level eye care workers (n = 4), and endocrinologist (2) participated in the study. All participants indicated the need for an organised screening program for DR detection through task sharing. Participants suggested that people with diabetes can be sent directly to an optometrist for initial eye exams, rather than making them wait to be examined by an ophthalmologist. Factors favouring task sharing included the name task sharing rather than task shifting and a high demand for eye care services. Major barriers to implementation of task sharing included the lack of a trained eye care workforce in the healthcare system and the lack of coordination amongst health professionals and policy makers. CONCLUSION: Participants were accepting task sharing approach and believed that task sharing could improve access to eye care services for people with diabetes and better utilise the services of eye and healthcare providers. PMID- 29527740 TI - Fracture strength of zirconia implant abutments on narrow diameter implants with internal and external implant abutment connections: A study on the titanium resin base concept. AB - BACKGROUND: There is limited knowledge regarding the strength of zirconia abutments with internal and external implant abutment connections and zirconia abutments supported by a titanium resin base (Variobase, Straumann) for narrow diameter implants. OBJECTIVES: To compare the fracture strength of narrow diameter abutments with different types of implant abutment connections after chewing simulation. MATERIAL AND METHODS: Hundred and twenty identical customized abutments with different materials and implant abutment connections were fabricated for five groups: 1-piece zirconia abutment with internal connection (T1, Cares-abutment-Straumann BL-NC implant, Straumann Switzerland), 1-piece zirconia abutment with external hex connection (T2, Procera abutment-Branemark NP implant, Nobel Biocare, Sweden), 2-piece zirconia abutments with metallic insert for internal connection (T3, Procera abutment-Replace NP implant, Nobel Biocare), 2-piece zirconia abutment on titanium resin base (T4, LavaPlus abutment-VarioBase Straumann BL-NC implant, 3M ESPE, Germany) and 1-piece titanium abutment with internal connection (C, Cares-abutment-Straumann BL-NC implant, Straumann, Switzerland). All implants had a narrow diameter ranging from 3.3 to 3.5 mm. Sixty un-restored abutments and 60 abutments restored with glass-ceramic crowns were tested. Mean bending moments were compared using ANOVA with p-values adjusted for multiple comparisons using Tukey's procedure. RESULTS: The mean bending moments were 521 +/- 33 Ncm (T4), 404 +/- 36 Ncm (C), 311 +/- 106 Ncm (T1) 265 +/- 22 Ncm (T3) and 225 +/- 29 (T2) for un-restored abutments and 278 +/ 84 Ncm (T4), 302 +/- 170 Ncm (C), 190 +/- 55 Ncm (T1) 80 +/- 102 Ncm (T3) and 125 +/- 57 (T2) for restored abutments. For un-restored abutments, C and T4 had similar mean bending moments, significantly higher than those of the three other groups (p < .05). Titanium abutments (C) had significantly higher bending moments than identical zirconia abutments (T1) (p < .05). Zirconia abutments (T1) with internal connection had higher bending moments than zirconia abutments with external connection (T2) (p < .05). For all test groups, the bending moments were significantly reduced when restored with all-ceramic crowns. CONCLUSIONS: For narrow diameter abutments, the fracture strength of 2-piece internal connected zirconia abutments fixed on titanium resin bases was similar to those obtained for 1-piece titanium abutments. Narrow diameter zirconia abutments with internal connection exhibited higher fracture strength than zirconia abutments with an external connection. Titanium abutments with an internal connection were significantly stronger than identical zirconia abutments. PMID- 29527741 TI - Predictive validity and efficiency of ongoing visual-inspection criteria for interpreting functional analyses. AB - Prior research has evaluated the reliability and validity of structured criteria for visually inspecting functional-analysis (FA) results on a post-hoc basis, after completion of the FA (i.e., post-hoc visual inspection [PHVI]; e.g., Hagopian et al., 1997). However, most behavior analysts inspect FAs using ongoing visual inspection (OVI) as the FA is implemented, and the validity of applying structured criteria during OVI remains unknown. In this investigation, we evaluated the predictive validity and efficiency of applying structured criteria on an ongoing basis by comparing the interim interpretations produced through OVI with (a) the final interpretations produced by PHVI, (b) the authors' post-hoc interpretations (PHAI) reported in the research studies, and (c) the consensus interpretations of these two post-hoc analyses. Ongoing visual inspection predicted the results of PHVI and the consensus interpretations with a very high degree of accuracy, and PHAI with a reasonably high degree of accuracy. Furthermore, the PHVI and PHAI results involved 32 FA sessions, on average, whereas the OVI required only 19 FA sessions to accurately identify the function(s) of destructive behavior (i.e., a 41% increase in efficiency). We discuss these findings relative to other methods designed to increase the accuracy and efficiency of FAs. PMID- 29527742 TI - Use of autobilevel ventilation in patients with obstructive sleep apnea: An observational study. AB - Continuous positive airway pressure (CPAP) is the first-choice treatment for obstructive sleep-disordered breathing. Automatic bilevel ventilation can be used to treat obstructive sleep-disordered breathing when CPAP is ineffective, but clinical experience is still limited. To assess the outcome of titration with CPAP and automatic bilevel ventilation, the charts of 356 outpatients (obstructive sleep apnea, n = 242; chronic obstructive pulmonary disease + obstructive sleep apnea overlap, n = 80; obesity hypoventilation syndrome [OHS], n = 34; 103 females) treated for obstructive sleep-disordered breathing from January 2014 to April 2017 were reviewed. Positive airway pressure titration was considered successful in the case of sleep-disordered breathing resolution (apnea hypopnea index <10/hr) with cumulative time at SaO2 < 90% (CT90%) <10% and/or improved daytime arterial blood gases at the end of titration. CPAP was effective in 268 patients (75.0%). CPAP treatment failure (n = 88) occurred in 13.6% of obstructive sleep apnea, 32.5% of overlap, and 85.3% of OHS patients. Compared with successful CPAP cases, patients undergoing the automatic bilevel ventilation trial showed higher body mass index (39.3 +/- 10.5 kg/m2 versus 34.8 +/- 6.9 kg/m2 , p < 0.0001), worse mean nocturnal SaO2 (89.2 +/- 4.0% versus 91.3 +/- 4.0%, p < 0.003) and CT90% (40.6 +/- 28.6% versus 24.0 +/- 23.3%), but similar age (62.8 +/- 11.9 years versus 60.5 +/- 12.0 years, p = 0.11), apnea-hypopnea index (39.4 +/- 23.2/hr versus 41.0 +/- 21.2/hr, p = 0.55) and oxygen desaturation index (37.8 +/- 23.5/hr versus 39.2 +/- 21.1/hr, p = 0.61) at diagnosis. Automatic bilevel ventilation was successful in 79.5% of CPAP treatment failures (n = 70). Automatic bilevel ventilation failure was independently associated with baseline body mass index >40 kg/m2 (odds ratio 6.16, confidence interval 1.50-25.17, p = 0.011) and CT90% >42% (odds ratio 5.87, confidence interval 1.39-24.83, p = 0.016). During follow-up, automatic bilevel ventilation treatment failed in seven patients (10%), and compliance was similar in CPAP (4.5 +/- 2.2 hr) and automatic bilevel ventilation (5.2 +/- 2.3 hr, p = 0.09) groups. Automatic bilevel ventilation was useful to treat sleep-disordered breathing, but failed in patients with severe OHS. PMID- 29527743 TI - "Anatomy is the great ocean of intelligence upon which the true physician must sail". PMID- 29527744 TI - Associations between self-reported sleep measures and dietary behaviours in a large sample of Australian school students (n = 28,010). AB - This study examined the associations between self-reported sleep timing and quality, and the frequency of breakfast and junk food consumption in 28,010 Australian school students (mean +/- SD age = 13.3 +/- 1.2 years, 51% male). After controlling for age, sex and socioeconomic status, regression analyses revealed that the odds of missing breakfast were significantly higher in children who reported poor sleep or later bedtimes, while the odds of junk food consumption were significantly higher in children reporting later weeknight bedtimes (p < 0.001). These findings suggest that sleep timing and quality influence the dietary choices of adolescents. PMID- 29527746 TI - Chiral Binaphthylbis(4,4'-Bipyridin-1-Ium)/Cucurbit[8]Uril Supramolecular System and Its Induced Circularly Polarized Luminescence. AB - Circularly polarized luminescence (CPL) induced by host-guest complexation remains a challenge in supramolecular chemistry. Herein, a couple of CPL-silent enantiomeric guest binaphthylbis(4,4'-bipyridinium) salts can emit obvious CPL in the presence of cucurbit[8]uril in aqueous media, due to the restriction of molecular rotation limitation effect. Such CPL can be reversibly adjusted by the addition of acid and base. Furthermore, the resultant supramolecular systems can interact with DNA, accompanied by the morphological conversion from branched supramolecular nanowires to exfoliated nanowires, which can enable to the exploration of such supramolecular systems as DNA markers by CPL signals. PMID- 29527745 TI - GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels. AB - BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine. The first 2 XLTx procedures were performed under a non-survival protocol that allowed a 72-hour follow-up of the recipients with general anesthesia, while the remaining 9 underwent a survival protocol with the intention of weaning from ventilation. RESULTS: Lung graft survivals in the 2 non-survival animals were 48 and >72 hours, while survivals in the other 9 were 25 and 28 hours, at 5, 5, 6, 7, >7, 9, and 10 days. One baboon with graft survival >7 days, whose entire lung graft remained well aerated, was euthanized on POD 7 due to malfunction of femoral catheters. hCD47 expression of donor lungs was detected in both alveoli and vessels only in the 3 grafts surviving >7, 9, and 10 days. All other grafts lacked hCD47 expression in endothelial cells and were completely rejected with diffuse hemorrhagic changes and antibody/complement deposition detected in association with early graft loss. CONCLUSIONS: To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7 days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47. PMID- 29527747 TI - A cautionary note on Bayesian estimation of population size by removal sampling with diffuse priors. AB - We consider the problem of estimating a population size by removal sampling when the sampling rate is unknown. Bayesian methods are now widespread and allow to include prior knowledge in the analysis. However, we show that Bayes estimates based on default improper priors lead to improper posteriors or infinite estimates. Similarly, weakly informative priors give unstable estimators that are sensitive to the choice of hyperparameters. By examining the likelihood, we show that population size estimates can be stabilized by penalizing small values of the sampling rate or large value of the population size. Based on theoretical results and simulation studies, we propose some recommendations on the choice of the prior. Then, we applied our results to real datasets. PMID- 29527748 TI - Synthesis and HNO Donating Properties of the Piloty's Acid Analogue Trifluoromethanesulphonylhydroxamic Acid: Evidence for Quantitative Release of HNO at Neutral pH Conditions. AB - Trifluoromethanesulphonylhydroxamic acid, CF3 SO2 NHOH, is shown to release HNO under physiological pH conditions. A two-step synthesis is presented with the first complete characterization of CF3 SO2 NHOH. This molecule rapidly decomposes in neutral aqueous solution to cleanly release HNO and CF3 SO2- , which was demonstrated using the HNO traps TXPTS and HOCbl, and by 19 F NMR spectroscopy. PMID- 29527749 TI - Stability of High-Performance Pt-Based Catalysts for Oxygen Reduction Reactions. AB - Due to their environmental sustainability and high efficiency, proton-exchange membrane fuel cells (PEMFCs) are expected to be an essential type of energy source for electric vehicles, energy generation, and the space industry in the coming decades. Here, the recent developments regarding shape-controlled nanostructure catalysts are reviewed, with a focus on the stability of high performance Pt-based catalysts and related mechanisms. The catalysts, which possess great activity, are still far from meeting the requirements of their applications, due to stability issues, especially in membrane electrode assemblies (MEAs). Thus, solutions toward the comprehensive performance of Pt based catalysts are discussed here. The research trends and related theories that can promote the application of Pt-based catalysts are also provided. PMID- 29527750 TI - Stable High-Performance Perovskite Solar Cells via Grain Boundary Passivation. AB - The trap states at grain boundaries (GBs) within polycrystalline perovskite films deteriorate their optoelectronic properties, making GB engineering particularly important for stable high-performance optoelectronic devices. It is demonstrated that trap states within bulk films can be effectively passivated by semiconducting molecules with Lewis acid or base functional groups. The perovskite crystallization kinetics are studied using in situ synchrotron-based grazing-incidence X-ray scattering to explore the film formation mechanism. A model of the passivation mechanism is proposed to understand how the molecules simultaneously passivate the Pb-I antisite defects and vacancies created by under coordinated Pb atoms. In addition, it also explains how the energy offset between the semiconducting molecules and the perovskite influences trap states and intergrain carrier transport. The superior optoelectronic properties are attained by optimizing the molecular passivation treatments. These benefits are translated into significant enhancements of the power conversion efficiencies to 19.3%, as well as improved environmental and thermal stability of solar cells. The passivated devices without encapsulation degrade only by ~13% after 40 d of exposure in 50% relative humidity at room temperature, and only ~10% after 24 h at 80 degrees C in controlled environment. PMID- 29527751 TI - Electrode Materials, Electrolytes, and Challenges in Nonaqueous Lithium-Ion Capacitors. AB - Among the various energy-storage systems, lithium-ion capacitors (LICs) are receiving intensive attention due to their high energy density, high power density, long lifetime, and good stability. As a hybrid of lithium-ion batteries and supercapacitors, LICs are composed of a battery-type electrode and a capacitor-type electrode and can potentially combine the advantages of the high energy density of batteries and the large power density of capacitors. Here, the working principle of LICs is discussed, and the recent advances in LIC electrode materials, particularly activated carbon and lithium titanate, as well as in electrolyte development are reviewed. The charge-storage mechanisms for intercalative pseudocapacitive behavior, battery behavior, and conventional pseudocapacitive behavior are classified and compared. Finally, the prospects and challenges associated with LICs are discussed. The overall aim is to provide deep insights into the LIC field for continuing research and development of second generation energy-storage technologies. PMID- 29527752 TI - Central chemosensitivity is augmented during 2 h of thermoneutral head-out water immersion in healthy men and women. AB - NEW FINDINGS: What is the central question of the study? Is central chemosensitivity blunted during thermoneutral head-out water immersion in healthy humans? What is the main finding and its importance? Central chemosensitivity is augmented during thermoneutral head-out water immersion in healthy men and women. Thus, we suggest that the central chemoreceptors do not contribute to CO2 retention during head-out water immersion. ABSTRACT: Carbon dioxide retention occurs during water immersion. Therefore, we tested the hypothesis that central chemosensitivity to hypercapnia is blunted during 2 h of thermoneutral head-out water immersion (HOWI) in healthy young adults. Twenty-six participants (age 22 +/- 2 years; body mass index 24 +/- 3 kg m-2 ; 14 women) participated in two experimental visits: a HOWI visit (HOWI) and a dry time-control visit (Control). Central chemosensitivity was assessed via a rebreathing test at baseline, 10, 60, 90 and 120 min and after HOWI and Control. End-tidal CO2 tension (P ET ,CO2), minute ventilation, blood pressure and heart rate were recorded continuously. The P ET ,CO2 increased from baseline throughout HOWI (peak increase at 120 min 2 +/- 2 mmHg; P < 0.001), and the change in P ET ,CO2 was greater throughout HOWI than Control (P < 0.001). The change in minute and alveolar ventilation was not different throughout time (P >= 0.173) or between conditions (P >= 0.052). Central chemosensitivity was greater than at baseline throughout HOWI (peak increase 0.74 +/- 1.01 l min-1 mmHg-1 at 120 min; P < 0.001), and the change in central chemosensitivity was greater throughout HOWI than Control (P <= 0.006). We also divided the cohort into tertiles based on baseline central chemosensitivity (i.e. Low, Intermediate and High) and compared Low versus High during HOWI. Low demonstrated an increase in P ET ,CO2 starting at 10 min (2 +/- 3 mmHg; P < 0.001), whereas High did not exhibit an increase in P ET ,CO2 until 60 min (2 +/- 2 mmHg; P = 0.018). These data indicate that CO2 retention occurs throughout HOWI despite augmented central chemosensitivity and that having a high baseline central chemosensitivity might delay the onset of CO2 retention. PMID- 29527753 TI - Relationship between ethical leadership and organisational commitment of nurses with perception of patient safety culture. AB - AIM: To determine the relationship between ethical leadership, organisational commitment of nurses and their perception of patient safety culture. BACKGROUND: Patient safety, organisational commitment and ethical leadership styles are very important for improving the quality of nursing care. METHODS: In this descriptive correlational study, 340 nurses were selected using random sampling from the hospitals in Tehran in 2016. Data were analysed using descriptive and inferential statistics in SPSS v.20. RESULTS: There was a significant positive relationship between the ethical leadership of nursing managers, perception of patient safety culture and organisational commitment. The regression analysis showed that nursing managers' ethical leadership and nurses' organisational commitment is a predictor of patient safety culture and confirms the relationship between the variables. CONCLUSION: Regarding the relationship between the nurses' safety performance, ethical leadership and organisational commitment, it seems that the optimisation of the organisational commitment and adherence to ethical leadership by administrators and managers in hospitals could improve the nurses' performance in terms of patient safety. IMPLICATIONS FOR NURSING MANAGEMENT: Implementing ethical leadership seems to be one feasible strategy to improve nurses' organisational commitment and perception of patient safety culture. Efforts by nurse managers to develop ethical leadership reinforce organisational commitment to improve patient outcomes. Nurse managers' engagement and performance in this process is vital for a successful result. PMID- 29527754 TI - The Coping with Unusual Experiences for Children Study (CUES): A pilot randomized controlled evaluation of the acceptability and potential clinical utility of a cognitive behavioural intervention package for young people aged 8-14 years with unusual experiences and emotional symptoms. AB - OBJECTIVES: Health care guidelines recommend psychological interventions for childhood unusual experiences that are associated with distress or adverse functional impact (UEDs), based on adult, rather than child-specific, evidence. We report the first randomized controlled evaluation of the acceptability and potential clinical utility of cognitive behavioural therapy for childhood UEDs (CBT-UED). DESIGN: Pilot randomized controlled trial. METHODS: Participants aged 8-14 years were recruited from referrals to community services for children with emotional/behavioural problems and screened for self-reported UEDs. RESULTS: Of around 1,000 referrals over 36 months, 304 (30%) were identified to the research team, 174 (57%) were successfully contacted, 110 (63%) consented to screening, 96 (87%) attended a screening assessment, and 51 (53%) reported UEDs. Forty-nine (96%) consented to randomization to either CBT-UED (9-12 weekly sessions of 40-50 min, adjunctive to usual care, n = 24) or treatment-as-usual/waitlist control (TAU/WL, n = 25). Childhood internalizing emotional symptoms (e.g., feeling 'nervous'/'scared'/'tearful'/'worried'/'sick'; proposed primary outcome), UEDs, depression, anxiety, and childhood psychopathology (secondary outcomes) were measured at baseline, at 12 weeks, and, where therapy was ongoing but incomplete (<12 sessions) at 12 weeks, at end-of-treatment (EOT). Twenty-two CBT-UED participants (92%) attended >=5 sessions. Forty-four participants (90%) completed 12-week assessments (CBT-UED, n = 21/24, 88%; TAU/WL, n = 23/25, 92%). Preliminary findings were encouraging for emotional symptoms and UEDs, but otherwise mixed. CONCLUSIONS: Retention, screening, and consent rates were as anticipated; recruitment took longer than planned. Trial procedures were acceptable to young people, their families, and clinicians. Therapy exceeded 12 weeks, but was well-received, with no serious adverse events attributed to participation. Further evaluation is needed. PRACTITIONER POINTS: Around half of 8- to 14-year-olds in Child and Adolescent Mental Health Services reported distressing unusual experiences. An age-adapted cognitive behavioural intervention appears feasible, and safe to deliver, with the potential to augment standard care. This is a pilot study, and further evaluation is needed. Longer term outcomes should be a focus of future evaluation. PMID- 29527755 TI - Superconductivity in the 2-Dimensional Homologous Series AMm Bi3 Q5+m (m=1, 2) (A=Rb, Cs; M=Pb, Sn; Q=Se, Te). AB - Superconductivity in the two-dimensional AMm Bi3 Q5+m family of semimetals is reported. The AMBi3 Te6 (m=1) and AM2 Bi3 Te7 (m=2) members of the homologous series with A=Rb, Cs and M=Pb, Sn undergo a bulk superconducting transition ranging from 2.7 to 1.4 K depending on the composition. The estimated superconducting volume fraction is about 90 %. Superconducting phase diagrams as a function of chemical pressure are constructed for the solid solution products of each member of the homologous series, AMBi3-x Sbx Te6-y Sey and AM2 Bi3-x Sbx Te7-y Sey (0<=x<=3 or 0<=y<=2). The structural flexibility of the ternary AMm M'3 Te5+m semiconducting homology to form isostructural analogues with a variety of metals, M=Pb, Sn; M'=Bi, Sb, gives access to a large number of electronic configurations and superconductivity due to chemical pressure effects. PMID- 29527756 TI - Corticosteroids in acute exacerbations of idiopathic interstitial pneumonias: Time to debate - Reply. PMID- 29527757 TI - Disturbed sleep and activity in toddlers with early signs of attention deficit hyperactivity disorder (ADHD). AB - This study investigated whether early signs of attention deficit hyperactivity disorder (ADHD) in toddlers aged 2-3 years are associated with disturbed sleep and activity levels. Participants were recruited from the Odense Child Cohort, and children scoring above the 93rd percentile on the ADHD scale of the Child Behaviour Checklist 11/2-5 were categorised as cases and compared with age- and gender-matched normal-scoring controls. Daytime and nocturnal activity for 24 children with ADHD traits (cases) and 25 healthy controls was assessed through 7 days of actigraphy, and parents completed the Children's Sleep Habits Questionnaire (CSHQ) and the ADHD Rating Scale IV Preschool Version (ADHD-RS). Cases differed significantly on actigraphic parameters by having fewer minutes of moderate-to-vigorous physical activity (MVPA), prolonged total sleep time, fewer sleep interruptions, and increased night-to-night variability. A significant association was found between fewer minutes of MVPA and higher parent-reported motor activity on the ADHD-RS. Furthermore, increased night-to-night variability was significantly associated with higher total scores on both CSHQ and ADHD-RS. The findings show that early signs of ADHD are associated with an irregular sleep pattern and lower daytime activity, as illustrated by actigraphy. Studies investigating early ADHD risk factors could lead to a preschool ADHD risk index to help guide future early intervention. PMID- 29527759 TI - The influence of food order on postprandial glucose levels in children with type 1 diabetes. AB - OBJECTIVE: To evaluate the effect of the order of intake of carbohydrates, protein, and fat on postprandial glucose levels in children with type 1 diabetes (T1D). Our hypothesis was that postprandial glucose levels would be lower when fat and protein are consumed prior to carbohydrates, compared to a meal where all macronutrients are combined. METHODS: A randomized, open-label, within-subject crossover study was conducted. Twenty patients aged 7 to 17 years diagnosed with T1D for >1 year consumed 2 isocaloric meals (with similar composition) in random order. In 1 meal, the protein and fat part was consumed 15 minutes prior to the carbohydrates (test meal). In the other meal, all macronutrients were consumed together (standard meal). Capillary blood glucose measurements and continuous glucose monitoring system were used to assess multiple glucose levels during a 3 hour postprandial period. RESULTS: Overall, mean glucose levels were 1 mmol/L lower following the test meal compared to the standard meal (9.30 +/- 3.20 vs 10.24 +/- 3.35 mmol/L; P < .001). No significant difference in peak glucose was found. Glucose excursions were 1.5 and 1 mmol/L lower at 30 and 120 minutes following the test meal. A reduction in the total time period in which glucose levels exceeded 10 and 12 mmol/L of 28.7 (P = .001) and 22.3 minutes (P = .004), respectively, after the test meal was found. CONCLUSIONS: This study shows that consumption of protein and fat prior to carbohydrates results in lower postprandial glucose levels and reduced glycemic variability in children with T1D. PMID- 29527758 TI - Toolbox: Creating a systematic database of secretory pathway proteins uncovers new cargo for COPI. AB - A third of yeast genes encode for proteins that function in the endomembrane system. However, the precise localization for many of these proteins is still uncertain. Here, we visualized a collection of ~500 N-terminally, green fluorescent protein (GFP), tagged proteins of the yeast Saccharomyces cerevisiae. By co-localizing them with 7 known markers of endomembrane compartments we determined the localization for over 200 of them. Using this approach, we create a systematic database of the various secretory compartments and identify several new residents. Focusing in, we now suggest that Lam5 resides in contact sites between the endoplasmic reticulum and the late Golgi. Additionally, analysis of interactions between the COPI coat and co-localizing proteins from our screen identifies a subset of proteins that are COPI-cargo. In summary, our approach defines the protein roster within each compartment enabling characterization of the physical and functional organization of the endomembrane system and its components. PMID- 29527760 TI - Challenges in clinical teaching investigated: Towards sustainable staff recruitment and retention in dentistry. AB - PURPOSE: The study was conducted to identify possible factors and potential barriers that affect the retention and recruitment of clinical teaching staff at the Faculty of Dentistry, University of Otago, New Zealand. METHODOLOGY: A short questionnaire survey was distributed to 47 clinical teaching staff to understand the retention strategies and barriers. The collected quantitative and qualitative data were analysed and presented. FINDINGS: The response rate was 96%, with an equal distribution of female and male clinicians. The majority of participants were European New Zealanders. Themes influencing retention strategies were the necessity of formal teaching skills, clinical teaching as a career pathway, pay progression, lack of support and heavy workload. PRACTICAL IMPLICATIONS: Results suggested that generally the respondents to this survey were motivated to give back to their profession through engaging in dental clinical teaching. This study identified that lack of a career development and minimal pay progression are major factors impacting on the retention of clinical teaching staff. PMID- 29527761 TI - Temperature-Correlated Afterglow of a Semiconducting Polymer Nanococktail for Imaging-Guided Photothermal Therapy. AB - Nanoparticles for photothermal therapy: Real-time temperature monitoring is critical to reduce the nonspecific damage during photothermal therapy (PTT); however, PTT agents that can emit temperature-related signals are rare and limited to few inorganic nanoparticles. We herein synthesize a semiconducting polymer nanococktail (SPNCT ) that can not only convert photo-energy to heat but also emit temperature-correlated luminescence after cessation of light excitation. Such an afterglow luminescence of the SPNCT detects tumors more sensitively than fluorescence as a result of the elimination of tissue autofluorescence, while its temperature-dependent nature allows tumor temperature to be optically monitored under near-infrared (NIR) laser irradiation. Thus, SPNCT represents the first organic optical nanosystem that enables optical imaging guided PTT without real-time light excitation. PMID- 29527763 TI - Corticosteroids in acute exacerbations of idiopathic interstitial pneumonias: Time to debate. PMID- 29527764 TI - Cross-talk between ovarian cancer cells and macrophages through periostin promotes macrophage recruitment. AB - Tumor-associated macrophages (TAMs) contribute to tumor progression, but it is not clear how they are recruited to tumor sites. Here we showed that periostin (POSTN) was present at high levels in ovarian cancer ascetic fluids and was correlated with CD163+ TAMs. The high POSTN level and macrophage infiltration were inversely associated with relapse-free survival for ovarian cancer patients. In vitro studies showed that coculture with macrophages significantly increased POSTN production in ovarian cancer cells. Further investigation found that POSTN production in ovarian cancer cells was promoted by transforming growth factor beta generated by macrophages. Moreover, siRNA of POSTN and POSTN neutralizing antibody treatment showed that ovarian cancer cell-derived POSTN promoted the recruitment of macrophages and modulated their cytokine secretion profile. Collectively, these data indicated that POSTN was an important factor for macrophage recruitment in the tumor microenvironment and is involved in the interactions between macrophages and ovarian cancer cells. PMID- 29527765 TI - Characterization of a red pigment from Fusarium chlamydosporum exhibiting selective cytotoxicity against human breast cancer MCF-7 cell lines. AB - AIM: This research aims to characterize the pigment produced by isolated fungi and to evaluate its anticancer activities. METHODS AND RESULTS: Pigment-producing fungi was isolated and identified as Fusarium chlamydosporum. The pigment was extracted with chloroform, purified by preparative TLC and characterized by Fourier transmittance infrared, electron spray ionization mass spectroscopy, liquid chromatography mass spectroscopy and nuclear magnetic resonance (NMR) (1 HNMR, 13 C NMR) spectral analysis, which revealed the pigment to be 'long chain hydrocarbons with poly unsaturated groups' (m/z 702). Pigment stability varied with different pH, temperature and sunlight conditions. The pigment-induced cell death in human breast adenocarcinoma cells MCF-7 and showed no significant toxicity in CHOK 1 cells. Lipid peroxidation assay revealed that treatment with pigment was able to reduce the lipid peroxidation caused by H2 O2 in MCF-7 cells. CONCLUSIONS: The F. chlamydosporum pigment is a compound of long-chain hydrocarbons with poly unsaturated groups, possessing selective cytotoxicity in MCF-7 cancer cell lines. SIGNIFICANCE AND IMPACT OF THE STUDY: The pigment can be used as a colouring agent in cosmetics. Its anticancer potential can be used in production of therapeutics in increasing demand cancer research. PMID- 29527767 TI - Recent Changes to the Editorial Board. PMID- 29527768 TI - Commentary on Egerton-Warburton et al. (2018): Alcohol-related injury in the emergency department and the alcohol attributable fraction. PMID- 29527770 TI - Commentary on Chang et al. (2018): Assessing prescribing volume and patient risk implementation considerations. PMID- 29527766 TI - Racial disparities in bipolar disorder treatment and research: a call to action. AB - OBJECTIVES: Health disparities between individuals of African and European ancestry are well documented. The disparities in bipolar disorder may be driven by racial bias superimposed on established factors contributing to misdiagnosis, including: evolving empirically based diagnostic criteria (International Classification of Diseases [ICD], Research Diagnostic Criteria [RDC] and Diagnostic and Statistical Manual [DSM]), multiple symptom domains (i.e. mania, depression and psychosis), and multimodal medical and additional psychiatric comorbidity. METHODS: For this paper, we reviewed the phenomenological differences between bipolar individuals of African and European ancestry in the context of diagnostic criteria and clinical factors that may contribute to a potential racial bias. RESULTS: Published data show that bipolar persons of African ancestry, compared with bipolar persons of non-African ancestry, are more often misdiagnosed with a disease other than bipolar disorder (i.e. schizophrenia). Additionally, studies show that there are disparities in recruiting patients of African ancestry to participate in important genomic studies. This gap in biological research in this underrepresented minority may represent a missed opportunity to address potential racial differences in the risk and course of bipolar illness. CONCLUSION: A concerted effort by the research community to increase inclusion of diverse persons in studies of bipolar disorder through community engagement may facilitate fully addressing these diagnostic and treatment disparities in bipolar individuals of African ancestry. PMID- 29527772 TI - Dithieno[3,2-b:2',3'-d]pyrrol Fused Nonfullerene Acceptors Enabling Over 13% Efficiency for Organic Solar Cells. AB - A new electron-rich central building block, 5,5,12,12-tetrakis(4-hexylphenyl) indacenobis-(dithieno[3,2-b:2',3'-d]pyrrol) (INP), and two derivative nonfullerene acceptors (INPIC and INPIC-4F) are designed and synthesized. The two molecules reveal broad (600-900 nm) and strong absorption due to the satisfactory electron-donating ability of INP. Compared with its counterpart INPIC, fluorinated nonfullerene acceptor INPIC-4F exhibits a stronger near-infrared absorption with a narrower optical bandgap of 1.39 eV, an improved crystallinity with higher electron mobility, and down-shifted highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels. Organic solar cells (OSCs) based on INPIC-4F exhibit a high power conversion efficiency (PCE) of 13.13% and a relatively low energy loss of 0.54 eV, which is among the highest efficiencies reported for binary OSCs in the literature. The results demonstrate the great potential of the new INP as an electron-donating building block for constructing high-performance nonfullerene acceptors for OSCs. PMID- 29527773 TI - Histomorphometry of pancreas development in hybrid chicken (Galus galus) embryo and fetus. AB - The pancreas comprises an important metabolic organ of endocrine and exocrine character that has embryonic origin of rudimentary buds that fuse to form the organ. The present work aims to describe the pancreatic histogenesis of hybrid chick embryos (Gallus gallus). The research was performed in the UFPI, previously approved by the CEUA with protocol no. 040/15. We used 120 fertilized eggs of hybrid chickens kept in an incubator with controlled temperature and humidity. Daily collections of embryos and fetuses were performed from 4 to 21 days of incubation through the anatomical dissection consecutive the euthanasia. The tissues, previously fixed in 10% buffered formaldehyde, were submitted to histological processing and stained with hematoxylin-eosin. Finally, the mounted slides were analyzed in image software to obtain histomorphometric data, which were submitted to statistical analysis. The pancreas of hybrid chicken embryos originates around the fourth day of incubation with the dorsal and ventral pancreatic bud formation, which are composed by epithelial and mesenchymal cells. These cells differ in exocrine and endocrine cells. Around twelve embryonic days occurs the buds fusion and the immature organ formation that will give continue with the ductal system development, vascularization and compartmentalization of the endocrine and exocrine parts. Until 21st day of incubation it is possible to identify undifferentiated tissue forms which suggesting postnatal histogenesis. The description of pancreas histogenesis using histometric data on hybrid chicken embryos contributes to the clarification of embryonic development and reaffirms the premise that chickens serve as an experimental model for embryonic study of mammals. PMID- 29527775 TI - Multiple compliant processes: A reply to Haslam and Reicher on the engaged followership explanation of 'obedience' in Milgram's experiments. AB - Haslam and Reicher (2018, Br. J. Soc. Psychol., 57, 292-300) offer a thoughtful rejoinder to our critique (Hollander & Turowetz, 2017, Br. J. Soc. Psychol, 56, 655-674) of their theory of engaged followership, currently the most important explanation of 'obedient' behaviour in the Milgram paradigm. Our immersion in Milgram's archived audio recordings has led us to new findings about participants' perspectives, as well as to dissatisfaction with the theory in its present version. Following a brief discussion of our findings, which cast the theory in doubt, we respond to Haslam and Reicher's argument that these data may in fact be consistent with it. Our response identifies three limitations of engaged followership emerging from this debate. Despite the strengths of the theory and these authors' impressive re-analysis of our findings, important reasons remain for scepticism that engaged followership operated in Milgram's experiments in the way, and to the extent, that they claim. Rather, 'obedience' appears amenable to multiple empirically grounded explanations, only one of which is engaged followership. PMID- 29527774 TI - A novel pooled-sample multiplex luminex assay for high-throughput measurement of relative telomere length. AB - OBJECTIVES: Relative telomere length (RTL) is a potential biomarker of aging and risk for chronic disease. Previously, we developed a probe-based RTL assay on Luminex platform, where probes for Telomere (T) and reference gene (R) for a given DNA sample were tested in a single well. Here, we describe a method of pooling multiple samples in one well to increase the throughput and cost effectiveness. METHODS: We used four different microbeads for the same T-probe and four different microbeads for the same R-probe. Each pair of probe sets were hybridized to DNA in separate plates and then pooled in a single plate for all the subsequent steps. We used DNA samples from 60 independent individuals and repeated in multiple batches to test the precision. RESULTS: The precision was good to excellent with Intraclass correlation coefficient (ICC) of 0.908 (95% CI 0.856-0.942). More than 67% of the variation in the RTL could be explained by sample-to-sample variation; less than 0.1% variation was due to batch-to-batch variation and 0.3% variation was explained by bead-to-bead variation. We increased the throughput of RTL Luminex assay from 60 to 240 samples per run. The new assay was validated against the original Luminex assay without pooling (r = 0.79, P = 1.44 * 10-15 ). In an independent set of samples (n = 550), the new assay showed a negative correlation of RTL with age (r = -0.41), a result providing external validation for the method. CONCLUSION: We describe a novel high throughput pooled-sample multiplex Luminex assay for RTL with good to excellent precision suitable for large-scale studies. PMID- 29527776 TI - Sublingual microcirculatory alterations in cirrhotic patients. AB - OBJECTIVE: To assess sublingual microcirculation in cirrhotic patients and its relationship to spider angiomas, complications, and outcome. METHODS: Thirty-one cirrhotic patients were prospectively compared to 31 matched controls. Sublingual microcirculation was evaluated by videomicroscopy. We specifically looked for capillaries with increased RBCV, which was defined as a velocity higher than the percentile 100th of controls. RESULTS: Compared to controls, cirrhotic patients showed decreased total and PVD (14.4 +/- 2.2 vs 16.0 +/- 1.3 and 14.1 +/- 2.3 vs 15.9 +/- 1.6 mm/mm2 , respectively, P < .001 for both) and increased HFI (0.64 +/ 0.39 vs 0.36 +/- 0.21, P = .001). They also exhibited high RBCV in 2% of the microvessels (P < .0001). Patients with MELD score >=10 had higher RBCV than patients with score <10 (1414 +/- 290 vs 1206 +/- 239 MUm/s, P < .05). Patients with spider angiomas showed lower vascular densities. Microcirculation did not differ between survivors and nonsurvivors. CONCLUSIONS: Cirrhosis is associated with microcirculatory alterations that can be easily monitored in the sublingual mucosa. Alterations included decreased density and PPV and hyperdynamic microvessels. The most striking finding, however, was the microvascular heterogeneity. Patients with spider angiomas had more severe alterations. Larger studies should clarify the relationship between microcirculatory abnormalities and outcome. PMID- 29527777 TI - Three-dimensional facial phenotyping in obstructive sleep apnoea. PMID- 29527778 TI - Translucency of Zirconia Ceramics before and after Artificial Aging. AB - PURPOSE: The aging of zirconia ceramics (Y-TZP) is associated with tetragonal to monoclinic phase transformation. This change in microstructure may affect the optical properties of the ceramic. This study examines the effect of aging on the translucency of different zirconia materials. MATERIALS AND METHODS: 120 disc shaped specimens were fabricated from four zirconia materials: Cercon ht white, BruxZir Solid Zirconia, Zenostar T0, Lava Plus (n = 30 per group). Accelerated aging was performed in a steam autoclave (134 degrees C, 0.2 MPa, 5 hours). CIELab coordinates (L*, a*, b*) and luminous reflectance (Y) were measured with a spectrophotometer before and after aging. Contrast ratio (CR) and translucency parameter (TP) were calculated from the L*, a*, b*, and Y tristimulus values. The general linear model (Bonferroni adjusted) was used to compare both parameters before and after aging, as well as between the different zirconia materials (p <= 0.05). RESULTS: CR and TP differed significantly before and after aging in all groups tested. Before aging, Zenostar T showed the highest and Lava Plus showed the lowest translucency. After aging, Cercon ht and Zenostar T showed the highest and BruxZir and Lava Plus the lowest translucency. CONCLUSIONS: Aging reduced the translucency in all specimens tested. Furthermore, translucency differed between the zirconia brands tested. Nevertheless, the differences were below the detectability threshold of the human eye. The aging process can influence the translucency and thus the esthetic outcome of zirconia restorations; however, the changes in translucency were minimal and probably undetectable by the human eye. PMID- 29527779 TI - Atomic force microscopy analysis of SasA-KaiC complex formation involved in information transfer from the KaiABC clock machinery to the output pathway in cyanobacteria. AB - The cyanobacterial clock oscillator is composed of three clock proteins: KaiA, KaiB and KaiC. SasA, a KaiC-binding EnvZ-like orthodox histidine kinase involved in the main clock output pathway, exists mainly as a trimer (SasA3mer ) and occasionally as a hexamer (SasA6mer ) in vitro. Previously, the molecular mass of the SasA-KaiCDD complex, where KaiCDD is a mutant KaiC with two Asp substitutions at the two phosphorylation sites, has been estimated by gel-filtration chromatography to be larger than 670 kDa. This value disagrees with the theoretical estimation of 480 kDa for a SasA3mer -KaiC hexamer (KaiC6mer ) complex with a 1:1 molecular ratio. To clarify the structure of the SasA-KaiC complex, we analyzed KaiCDD with 0.1 mmol/L ATP and 5 mmol/L MgCl2 (Mg-ATP), SasA and a mixture containing SasA and KaiCDD6mer with Mg-ATP by atomic force microscopy (AFM). KaiCDD images were classified into two types with height distribution corresponding to KaiCDD monomer (KaiCDD1mer ) and KaiCDD6mer , respectively. SasA images were classified into two types with height corresponding to SasA3mer and SasA6mer , respectively. The AFM images of the SasA KaiCDD mixture indicated not only KaiCDD1mer , KaiCDD6mer , SasA3mer and SasA6mer , but also wider area "islands," suggesting the presence of a polymerized form of the SasA-KaiCDD complex. PMID- 29527780 TI - Pulmonary hypertension in combined pulmonary fibrosis and emphysema: A tale of two cities. PMID- 29527781 TI - Automated assessment of absolute nailfold capillary number on videocapillaroscopic images: Proof of principle and validation in systemic sclerosis. AB - BACKGROUND: Absolute nailfold capillary number should be a putative biomarker in selected rheumatic diseases but could be time-consuming and not highly repeatable. OBJECTIVE: To validate an automated software for absolute nailfold capillary number and density evaluation, on NVC images in SSc. METHODS: An automated software to count nailfold capillary number (AUTOCAPI) had been constructed, through an exploratory image set. Subsequently, application rules have been created to define the ROI in NVC images, through a training images set. The software reliability was assessed through calculation of the ICC between automatic and manual counting, by four independent observers, on the same NVC images. RESULTS: The following ICC's were obtained per observer, for the patients with SSc (40 images), the healthy (20 images), and the PRP subgroups (20 images), respectively: 0.94, 0.81, and 0.62 (observer 1); 0.94, 0.91, and 0.67 (observer 2); 0.88, 0.56, and 0.64 (observer 3); and 0.88, 0.85, and 0.85 (observer 4). CONCLUSIONS: The validation of an automated software for measuring absolute nailfold capillary number and density in SSc was achieved. The integration into the pre-existing imaging software should make the assessment of the capillary number in NVC easier, quicker, and standardized. PMID- 29527782 TI - Sex-related association of serum uric acid with inflammation, kidney function and blood pressure in type 1 diabetic patients. AB - BACKGROUND/OBJECTIVE: Recent studies suggest that uric acid (UA) is a mediator of diabetic nephropathy. We hypothesized that serum UA would associate with the prevalence of diabetic nephropathy in youth with type 1 diabetes (T1D), and that this relationship would differ by sex. METHODS: We examined 120 young boys and the same number of girls with T1D. C-reactive protein (CRP), interleukin-6 (IL 6), interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha), UA, cystatin C serum concentrations, albumin excretion rate and blood pressure were also analyzed. RESULTS: T1D boys had higher serum UA and creatinine concentration, as well as albumin excretion rate and estimated glomerular filtration rate than T1D girls. Moreover, newly diagnosed nephropathy was more common in male subjects in comparison to female patients. Only in T1D boys serum UA was positively correlated with concentrations of subclinical inflammatory markers (CRP, IL-6, TNF-alpha), the indicators of renal function (albumin excretion rate, serum cystatin C level), blood pressure and negatively correlated with anti inflammatory IL-10. In addition, only in T1D girls serum UA concentration was negatively correlated with hemoglobin A1c. CONCLUSIONS: Serum UA is associated with nephropathy prevalence, albeit only in boys with T1D and may be an important risk factor for predicting diabetes-related cardiorenal complications in these patients. PMID- 29527783 TI - Comprehensive review and annotation of susceptibility SNPs associated with obesity-related traits. AB - We aimed to summarize the results of genetic association studies for obesity and provide a comprehensive annotation of all susceptibility single nucleotide polymorphisms (SNPs). A total of 72 studies were summarized, resulting in 90,361 susceptibility SNPs (738 index SNPs and 89,623 linkage disequilibrium SNPs). Over 90% of the susceptibility SNPs are located in non-coding regions, and it is challenging to understand their functional significance. Therefore, we annotated these SNPs by using various functional databases. We identified 24,623 functional SNPs, including 4 nonsense SNPs, 479 missense SNPs, 399 untranslated region SNPs which might affect microRNA binding, 262 promoter and 5,492 enhancer SNPs which might affect transcription factor binding, 7 splicing sites, 76 SNPs which might affect gene methylation levels, 1,839 SNPs under natural selection and 17,351 SNPs which might modify histone binding. Expression quantitative trait loci analyses for functional SNPs identified 98 target genes, including 69 protein coding genes, 27 long non-coding RNAs and 3 processed transcripts. The percentage of protein coding genes that could be correlated with obesity-related pathways directly or through gene-gene interaction is 75.36 (52/69). Our results may serve as an encyclopaedia of obesity susceptibility SNPs and offer guide for functional experiments. PMID- 29527784 TI - Distribution and ultrastructure of the antennal sensilla of the grape weevil Naupactus xanthographus (Coleoptera: Curculionidae). AB - The grape weevil, Naupactus xanthographus Germar (Coleoptera: Curculionidae), is a polyphagous insect native to southern South America that causes considerable damage in grape and other fruit species. In this study, the morphology and ultrastructure of the antennae and the antennal sensilla of N. xanthographus were investigated using scanning electron microscopy and transmission electron microscopy. The antennae consist of a scape, a pedicel, a funicle, and a zone called the "club," which are all formed by a total of 12 antennomers. Different types of sensilla were observed: sensilla trichoidea, sensilla chaetica type 1 and 2, sensilla basiconica, and sensilla rod-like. No sexual dimorphism was observed. The possible functions of the sensilla are discussed in relation to their morphology and ultrastructure. PMID- 29527785 TI - SOCS1 is associated with clinical progression and acts as an oncogenic role in triple-negative breast cancer. AB - Suppressors of cytokine signaling 1 (SOCS1) is a member of SOCS family and acts as negative regulators of cytokine signaling by direct inhibition of receptor associated janus kinases. The clinical significance and biological function of SOCS1 in variant tumor tissues and at variant tumor stages is still controversial. The aim of our study is to confirm the expression status of SOCS1 in triple-negative breast cancer (TNBC) tissues and cell lines, and explore the clinical value and biological function of SOCS1 in TNBC. In microarray data sets (GDS2250 and GDS817), we observed SOCS1 was overexpressed in TNBC tissues and cell line compared with normal mammary tissues and mammary epithelial cell line, or non-TNBC tissues and cell line. Furthermore, SOCS1 mRNA and protein overexpression were confirmed in TNBC tissues and cell lines compared with normal mammary tissues and mammary epithelial cell lines or non-TNBC tissues and cell lines. SOCS1 protein overexpression was obviously associated with advanced clinical stage, large tumor size, more lymph node metastasis, present distant metastasis, and malign histological grade. Downregulation of SOCS1 expression suppressed TNBC cells proliferation and promoted cell apoptosis. In conclusion, SOCS1 is associated with clinical progression in TNBC patients and acts as an oncogenic role in regulating TNBC cells proliferation and apoptosis. (c) 2018 IUBMB Life, 70(4):320-327, 2018. PMID- 29527786 TI - How did I not see that? Perspectives of nonconsumer mental health researchers on the benefits of collaborative research with consumers. AB - Coproduction of research between consumers of mental health services and nonconsumer mental health researchers is increasing. There is some research available describing consumer perspectives of this experience. However, there is a notable lack of research on other (nonconsumer) researcher experiences of and views about consumer involvement in coproduced research. A qualitative exploratory study was undertaken to examine perspectives of mental health researchers about consumer involvement in research. In-depth individual interviews were undertaken with 11 nonconsumer mental health researchers in Australia and New Zealand. Interview transcripts were analysed to identify major themes. There were three interacting themes: the salience of experiential difference, expanded learning, and enhanced research. The dynamic between different perspectives and learning had the effect of enhancing research across the spectrum of study phases and in ensuring research was of value to different groups. The findings emphasize the important contribution consumer researchers can make to mental health research by bringing their unique perspective and enhancing an environment of mutual learning. Findings also point to the need for foregrounding the numerous benefits of joint research between consumer and other researchers to enhance and improve clinical practice and the development of policy. PMID- 29527787 TI - Bioenergetic theory predicts infection dynamics of human schistosomes in intermediate host snails across ecological gradients. AB - Epidemiological dynamics depend on the traits of hosts and parasites, but hosts and parasites are heterogeneous entities that exist in dynamic environments. Resource availability is a particularly dynamic and potent environmental driver of within-host infection dynamics (temporal patterns of growth, reproduction, parasite production and survival). We developed, parameterised and validated a model for resource-explicit infection dynamics by incorporating a parasitism module into dynamic energy budget theory. The model mechanistically explained the dynamic multivariate responses of the human parasite Schistosoma mansoni and its intermediate host snail to variation in resources and host density. At the population level, feedbacks mediated by resource competition could create a unimodal relationship between snail density and human risk of exposure to schistosomes. Consequently, weak snail control could backfire if reductions in snail density release remaining hosts from resource competition. If resource competition is strong and relevant to schistosome production in nature, it could inform control strategies. PMID- 29527788 TI - Activity-Based Probes Developed by Applying a Sequential Dehydroalanine Formation Strategy to Expressed Proteins Reveal a Potential alpha-Globin-Modulating Deubiquitinase. AB - We report a general and novel semisynthetic strategy for the preparation of ubiquitinated protein-activity-based probes on the basis of sequential dehydroalanine formation on expressed proteins. We applied this approach to construct a physiologically and therapeutically relevant ubiquitinated alpha globin probe, which was used for the enrichment and proteomic identification of alpha-globin-modulating deubiquitinases. We found USP15 as a potential deubiquitinase for the modulation of alpha-globin, an excess of which aggravates beta-thalassemia symptoms. This development opens new opportunities for activity based-probe design to shed light on the important aspects underlying ubiquitination and deubiquitination in health and disease. PMID- 29527789 TI - Use of a metabolomic approach to non-invasively diagnose non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. AB - AIMS: To assess the utility of existing metabolomics scores to classify liver disease in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A total of 220 patients with T2DM were recruited. Patients underwent routine laboratory tests, liver proton magnetic resonance spectroscopy (1 H-MRS), a 75-g oral glucose tolerance test, and liver biopsy if 1 H-MRS findings indicated non alcoholic fatty liver disease. A serum sample was blindly provided to OWL Metabolomics on which to run the OWLiver Care and OWLiver tests. RESULTS: When compared with liver biopsy, the OWLiver Care and OWLiver tests had a suboptimal performance in patients with T2DM (areas under the receiver-operating characteristic [AUROC] curve both <0.70). Given the discordance of these results in this heterogeneous, multiethnic cohort compared with those of a previous report in predominantly white patients without diabetes, we examined the influence of age, ethnicity and other variables on test performance. A specific subset of patients was selected to mirror the characteristics of the population used for the development of this model (ie, white patients without T2DM). Among white patients with good glycaemic control (glycated haemoglobin <53mmol/mol [or <7%]) and without cirrhosis, the AUROC curve was significantly improved (0.79 [CI 95%: 0.68-0.90]). Among white patients with lower insulin resistance (homeostatic model assessment of insulin resistance <3) and without cirrhosis, the AUROC was even higher: 0.87 (CI 95%: 0.76-0.97). CONCLUSIONS: There is a great need to develop non-invasive approaches to diagnose non-alcoholic steatohepatitis in patients with T2DM; models originally developed for patients without diabetes cannot be directly applied to patients with T2DM. PMID- 29527790 TI - Immune cell and cytokine patterns in children with type 1 diabetes mellitus undergoing a remission phase: A longitudinal study. AB - OBJECTIVE: Type 1 diabetes (T1D) develops in distinct stages, before and after disease onset. Whether the natural course translates into different immunologic patterns is still uncertain. This study aimed at identifying peripheral immune patterns at key time-points, in T1D children undergoing remission phase. METHODS: Children with new-onset T1D and healthy age and gender-matched controls were recruited at a pediatric hospital. Peripheral blood samples were evaluated by flow cytometry at 3 longitudinal time-points: onset (T1), remission phase (T2) and established disease (T3). Cytokine levels were quantified by multiplex assay. Fasting C-peptide, HbA1c, and 25OHD were also measured. RESULTS: T1D children (n = 28; 10.0 +/- 2.6 years) showed significant differences from controls in circulating neutrophils, T helper (Th)17 and natural killer (NK) cells, with relevant variations during disease progression. At onset, neutrophils, NK, Th17 and T cytotoxic (Tc)17 cells were decreased. As disease progressed, neutrophil counts recovered whereas NK counts remained low. Th17 and Tc17 cells behavior followed the neutrophil variation pattern. B-cells were lowest in the remission phase and regulatory T-cells significantly declined after remission. Two cytokine response profiles were identified. Low cytokine-responders showed higher circulating fasting C-peptide levels at onset and longer remission periods. C peptide inversely correlated with pro-inflammatory and cytotoxic cells. CONCLUSIONS: Our data suggest an association between immune cells, cytokine patterns and metabolic counterparts. The dynamic changes of circulating immune cells during disease progression involve key innate and acquired immune cell types. This longitudinal picture of T1D progression may enable disease staging and patient stratification, essential for individualized treatment. PMID- 29527791 TI - Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects. AB - Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in mammals nor of the pathophysiology of the disease. Since the identification of the genes, we have set up the molecular diagnostic of THES in routine, gathering a large cohort with clinical and molecular data. Here, we report the phenotype and genotype analysis of this cohort together with an extensive literature review of THES cases worldwide, that is, 96 individuals harboring mutations in one gene or the other. We set up locus specific databases for both genes and reviewed the type of mutation as well as their localization in the proteins. No hot spot is evidenced for any type of mutation. The phenotypic analysis was first made on the whole cohort but is limited due to heterogeneity in clinical descriptions. We then examined the lab diagnostic cohort in detail for clinical manifestations. For the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment. PMID- 29527792 TI - Avoiding Thiol Compound Interference: A Nanoplatform Based on High-Fidelity Au-Se Bonds for Biological Applications. AB - Gold nanoparticles (Au NPs) assembled through Au-S covalent bonds have been widely used in biomolecule-sensing technologies. However, during the process, detection distortions caused by high levels of thiol compounds can still significantly influence the result and this problem has not really been solved. Based on the higher stability of Au-Se bonds compared to Au-S bonds, we prepared selenol-modified Au NPs as an Au-Se nanoplatform (NPF). Compared with the Au-S NPF, the Au-Se NPF exhibits excellent anti-interference properties in the presence of millimolar levels of glutathione (GSH). Such an Au-Se NPF that can effectively avoid detection distortions caused by high levels of thiols thus offers a new perspective in future nanomaterial design, as well as a novel platform with higher stability and selectivity for the in vivo application of chemical sensing and clinical therapies. PMID- 29527794 TI - Corrigendum. PMID- 29527793 TI - Identification of immunohistochemical localization of irisin in the dwarf hamster (Phodopus roborovskii) tissues. AB - Irisin is mainly secreted by heart and skeletal muscle cells. It is an exercise induced protein that converts white adipose tissue to brown. Increased irisin expression was lead to weight loss and improved glucose tolerance. We investigated irisin immunoreactivity in various tissues of the dwarf hamsters (Phodopus roborovskii). Tissues were processed, embedded in paraffin, sectioned at 5 MUm and stained immunohistochemically for irisin. In the retina, irisin was found almost all layers, except outer nuclear layer. Also, irisin immunoreactivity was observed in the skin, cornea, striated muscle, parotid gland, tongue, oesophagus, stomach and small intestine. The findings from this study support the notion that skeletal muscle is not the primary source of irisin. PMID- 29527795 TI - Distribution of CD68-, CD8-, MHCI- and MHCII-positive cells in the bull and ram testis and epididymis. AB - The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. The testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. Thus, this study aimed to immunohistochemically demonstrate the distribution and localization of CD68-, CD8-, MHCI- and MHCII-positive immune cells in the testes and epididymes. Negative immunoreactivity was detected in the seminiferous tubule epithelium and peritubular myoid cells of the testes upon staining in CD68, CD8 and MHC Class I. Positive CD68 immunoreaction was determined in the Sertoli cells and some Leydig cells. The detection of positive cells for CD8 clearly indicated the presence of lymphocytes. Furthermore, the staining with MHCI intensity was ascertained to vary from weak to moderate in the Sertoli and Leydig cells and connective tissue cells. MHCII-positive immunoreactivity was determined in myoid cells and Leydig cells in the interstitial area. The epithelium of the epididymis showed positive staining for CD68 and CD8, but the stroma displayed a rather weak staining. In the ram epididymis, neither intraepithelial nor interstitial positive reaction was observed for MHCI. In the epididymis, the basal cells displayed a stronger staining for MHCII. In conclusion, these cells not only contribute to local immunity through their direct effects on the quality of fertility in males, but also contribute either directly or indirectly to immune privilege by minimizing the development of both autoimmune reactions and potentially harmful risks. PMID- 29527796 TI - In praise of open-mindedness. PMID- 29527797 TI - The predictability of a lake phytoplankton community, over time-scales of hours to years. AB - Forecasting changes to ecological communities is one of the central challenges in ecology. However, nonlinear dependencies, biotic interactions and data limitations have limited our ability to assess how predictable communities are. Here, we used a machine learning approach and environmental monitoring data (biological, physical and chemical) to assess the predictability of phytoplankton cell density in one lake across an unprecedented range of time-scales. Communities were highly predictable over hours to months: model R2 decreased from 0.89 at 4 hours to 0.74 at 1 month, and in a long-term dataset lacking fine spatial resolution, from 0.46 at 1 month to 0.32 at 10 years. When cyanobacterial and eukaryotic algal cell densities were examined separately, model-inferred environmental growth dependencies matched laboratory studies, and suggested novel trade-offs governing their competition. High-frequency monitoring and machine learning can set prediction targets for process-based models and help elucidate the mechanisms underlying ecological dynamics. PMID- 29527798 TI - A Monoaryllead Trichloride That Resists Reductive Elimination. AB - Transmetallation of Pb(OAc)4 with R2 Hg (1), followed by treatment with HCl in Et2 O, provided RPbCl3 (2), the first kinetically stabilized monoorganolead trihalide that resists reductive elimination under ambient conditions. The kinetic stabilisation relies on an intramolecularly coordinating O-donor substituent (R=6-Ph2 P(O)-Ace-5-). The gram-scale preparation of 2 was key for the synthesis of unsymmetrically substituted diaryllead dichlorides RR'PbCl2 (3 a, R'=Ph; 3 b, R'=4-MeOC6 H4 ; 3 c, R'=4-Me2 NC6 H4 ). PMID- 29527799 TI - Early limb patterning in the direct-developing salamander Plethodon cinereus revealed by sox9 and col2a1. AB - Direct-developing amphibians form limbs during early embryonic stages, as opposed to the later, often postembryonic limb formation of metamorphosing species. Limb patterning is dramatically altered in direct-developing frogs, but little attention has been given to direct-developing salamanders. We use expression patterns of two genes, sox9 and col2a1, to assess skeletal patterning during embryonic limb development in the direct-developing salamander Plethodon cinereus. Limb patterning in P. cinereus partially resembles that described in other urodele species, with early formation of digit II and a generally anterior to-posterior formation of preaxial digits. Unlike other salamanders described to date, differentiation of preaxial zeugopodial cartilages (radius/tibia) is not accelerated in relation to the postaxial cartilages, and there is no early differentiation of autopodial elements in relation to more proximal cartilages. Instead, digit II forms in continuity with the ulnar/fibular arch. This amniote like connectivity to the first digit that forms may be a consequence of the embryonic formation of limbs in this direct-developing species. Additionally, and contrary to recent models of amphibian digit identity, there is no evidence of vestigial digits. This is the first account of gene expression in a plethodontid salamander and only the second published account of embryonic limb patterning in a direct-developing salamander species. PMID- 29527800 TI - Walk, swim or fly? Locomotor mode predicts genetic differentiation in vertebrates. AB - Limited dispersal is commonly used to explain differences in diversification rates. An obvious but unexplored factor affecting dispersal is the mode of locomotion used by animals. Whether individuals walk, swim or fly can dictate the type and severity of geographical barriers to dispersal, and determine the general range over which genetic differentiation might occur. We collated information on locomotion mode and genetic differentiation (FST ) among vertebrate populations from over 400 published articles. Our results showed that vertebrate species that walk tend to have higher genetic differentiation among populations than species that swim or fly. Within species that swim, vertebrates in freshwater systems have higher genetic differentiation than those in marine systems, which is consistent with the higher number of species in freshwater environments. These results show that locomotion mode can impact gene flow among populations, supporting at a broad-scale what has previously been proposed at smaller taxonomical scales. PMID- 29527801 TI - Piezoresistive Pressure Sensor Based on Synergistical Innerconnect Polyvinyl Alcohol Nanowires/Wrinkled Graphene Film. AB - Piezoresistive sensor is a promising pressure sensor due to its attractive advantages including uncomplicated signal collection, simple manufacture, economical and practical characteristics. Here, a flexible and highly sensitive pressure sensor based on wrinkled graphene film (WGF)/innerconnected polyvinyl alcohol (PVA) nanowires/interdigital electrodes is fabricated. Due to the synergistic effect between WGF and innerconnected PVA nanowires, the as-prepared pressure sensor realizes a high sensitivity of 28.34 kPa-1 . In addition, the device is able to discern lightweight rice about 22.4 mg (~2.24 Pa) and shows excellent durability and reliability after 6000 repeated loading and unloading cycles. What is more, the device can detect subtle pulse beat and monitor various human movement behaviors in real-time. PMID- 29527802 TI - The "Dirty Ice" of the McMurdo Ice Shelf: Analogues for biological oases during the Cryogenian. AB - The Cryogenian (~717-636 Ma) is characterized by widespread glaciation and dramatic fluctuations in biogeochemical cycling during the Sturtian and Marinoan glaciations. The Snowball Earth hypothesis posits that during this period, ice covered oceans of more or less global extent shut down or greatly diminished photosynthesis in the marine realm. However, rather than suffering a catastrophic loss of biodiversity, fossil evidence suggests that major eukaryotic lineages survived and, indeed, the end of the Cryogenian marks the onset of a rapid diversification of eukaryotic life. Persistence of diverse life forms through glaciations is thought to have occurred in supraglacial refugia although the exact nature and full extent of such habitats remain uncertain. We present further evidence for the diversity and characteristics of supraglacial ecosystems on the McMurdo Ice Shelf in Antarctica and suggest that refugia analogous to "dirty ice," that is debris-covered ice shelf ecosystems, potentially provided nutrient-rich and long-lasting biological Cryogenian oases. We also discuss how features of the McMurdo Ice Shelf indicate that mechanisms exist whereby material can be exchanged between the shallow sea floor and the surfaces of ice shelves along continental margins, providing vectors whereby ice shelf ecosystems can nourish underlying seafloor communities and vice versa. PMID- 29527803 TI - Electrospun N-Doped Porous Carbon Nanofibers Incorporated with NiO Nanoparticles as Free-Standing Film Electrodes for High-Performance Supercapacitors and CO2 Capture. AB - Carbon nanofibers (CNF) with a 1D porous structure offer promising support to encapsulate transition-metal oxides in energy storage/conversion relying on their high specific surface area and pore volume. Here, the preparation of NiO nanoparticle-dispersed electrospun N-doped porous CNF (NiO/PCNF) and as free standing film electrode for high-performance electrochemical supercapacitors is reported. Polyacrylonitrile and nickel acetylacetone are selected as precursors of CNF and Ni sources, respectively. Dicyandiamide not only improves the specific surface area and pore volume, but also increases the N-doping level of PCNF. Benefiting from the synergistic effect between NiO nanoparticles (NPs) and PCNF, the prepared free-standing NiO/PCNF electrodes show a high specific capacitance of 850 F g-1 at a current density of 1 A g-1 in 6 m KOH aqueous solution, good rate capability, as well as excellent long-term cycling stability. Moreover, NiO NPs dispersed in PCNF and large specific surface area provide many electroactive sites, leading to high CO2 uptake, and high-efficiency CO2 electroreduction. The synthesis strategy in this study provides a new insight into the design and fabrication of promising multifunctional materials for high-performance supercapacitors and CO2 electroreduction. PMID- 29527804 TI - Amplification-Free Multi-RNA-Type Profiling for Cancer Risk Stratification via Alternating Current Electrohydrodynamic Nanomixing. AB - Simultaneous analysis of messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA)-multi-RNA-type profiling-is increasingly crucial in cancer diagnostics. Yet, rapid multi-RNA-type profiling is challenging due to enzymatic amplification reliance and RNA-type-dependent characteristics. Here, a nanodevice is reported to uniquely use alterable alternating current electrohydrodynamic (ac EHD) forces to enhance probe-target hybridization prior to direct native RNA target detection, without target amplification or surface functionalization. To exemplify clinical applicability, noninvasive screening of next-generation prostate cancer (PCa) RNA biomarkers (of different types) in patient urine samples is performed. A strong correlation between multi-RNA-type expression and aggressive PCa is found, and the nanodevice performance is statistically evaluated. It is believed that this miniaturized system exhibits great potential for cancer risk stratification via multi-RNA-type profiling. PMID- 29527805 TI - Prognostic significance of hypermethylation of death-associated protein kinase (DAPK) gene CpG island in dogs with high-grade B-cell lymphoma. AB - Death-associated protein kinase (DAPK) is a serine/threonine kinase and a tumour suppressor gene. Diffuse large B-cell lymphomas with inactivated DAPK through hypermethylation of a CpG island is known to result in a biologically aggressive phenotype in humans. This retrospective study was carried out to analyse the prognostic significance of DAPK CpG island hypermethylation in canine lymphoma. We hypothesized that DAPK CpG island hypermethylation can be a negative prognostic indicator in dogs with nodal high-grade B-cell lymphoma. Forty-seven dogs with high-grade B-cell lymphoma, according to the updated Kiel classification, were evaluated after being treated with a CHOP (vincristine, cyclophosphamide, doxorubicin and prednisolone)-based chemotherapy protocol. The methylation status of the DAPK CpG island was examined by methylation-specific PCR. Progression-free survival (PFS) and overall survival (OS) were compared using the Kaplan-Meier analysis and log-rank test. The cox proportional hazard regression model was used to evaluate the effect of multiple variables. Hypermethylation of the DAPK CpG island was detected in 21 of the 47 dogs. The PFS and OS in dogs with the hypermethylation (median: 220 and 266 days, respectively) were significantly shorter than those of dogs without hypermethylation (median: 301 and 412 days, respectively) (PFS, P = .036; OS, P = .007). In the multivariate analysis, hypermethylation of the DAPK CpG island remained an independent prognostic factor in predicting shortened PFS (P = .047) and OS (P = .021) as well as clinical substage b. Overall, hypermethylation of the DAPK CpG island was a negative prognostic factor in canine high-grade B-cell lymphoma. PMID- 29527806 TI - Evaluation of allyl isothiocyanate as a soil fumigant against soil-borne diseases in commercial tomato (Lycopersicon esculentum Mill.) production in China. AB - BACKGROUND: Root-knot nematodes (Meloidogyne spp.), soil-borne diseases and weeds seriously reduce the commercial yield of tomatoes grown under protected cultivation in China. Allyl isothiocyanate (AITC), a natural product obtained from damaged Brassica tissues, was evaluated as a potential replacement for the fumigant methyl bromide (MB) for use in the greenhouse production of tomatoes in China. RESULTS: The dose-response assay indicates that AITC has high biological activity against major bacterial and fungal pathogens (EC50 of 0.225-4.199 mg L-1 ). The bioassay results indicate that AITC has good efficacy against root-knot nematodes (LC50 of 18.046 mg kg-1 ), and moderate efficacy against fungal pathogens (LC50 of 27.999-29.497 mg kg-1 ) and weeds (LC50 of 17.300-47.660 mg kg 1 ). The potting test indicates that AITC significantly improved plant vigor. Field trials indicate that AITC showed good efficacy against Meloidogyne spp. and Fusarium spp. (both ~ 80%) as well as Phytophthora spp. and Pythium spp. (both ~ 70%), and improved plant vigor and marketable yield. CONCLUSION: AITC used as a soil fumigant (30-50 g m-2 ) effectively controlled major bacterial and fungal pathogens, root-knot nematode, weeds and increased plant vigor, yield and farmers' income in tomato cultivated under protected agriculture in China. (c) 2018 Society of Chemical Industry. PMID- 29527807 TI - Cytochrome P450 Induction and Xeno-Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator-Activated Receptor alpha at the Crossroads of Toxicokinetics and Toxicodynamics. AB - Pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AHR) and peroxisome proliferator-activated receptor alpha (PPARalpha) are ligand-activated transcription factors that regulate expression of many xenobiotic-metabolizing enzymes including several cytochrome P450 (CYP) enzymes. Many xenobiotics induce CYP enzymes through these intracellular receptors and consequently affect toxicokinetics and possible metabolic activation of the receptor ligands and other xenobiotics utilizing similar metabolic pathways. However, it is now apparent that the xenobiotic receptors regulate also many endogenous functions and signalling pathways, and xenobiotic exposure thus may dysregulate an array of fundamental cell functions. This MiniReview surveys and discusses the multifaceted roles of xenobiotic receptors, for which CYP induction may serve as the first alert and possibly a biomarker for exposure to xenobiotics. With the current emergence of the adverse outcome pathway (AOP) concept, these receptors are being and will be assigned as molecular initiating events or key events in numerous discrete toxicity pathways. PMID- 29527808 TI - Tetragonal Single-Crystalline Boron Nanowires with Strong Anisotropic Light Scattering Behaviors and Photocurrent Response in Visible-Light Regime. AB - Boron is a narrow-bandgap (1.56 eV) semiconductor with high melting-point, low density, large Young's modulus and very high refractive index (3.03) close to silicon. Therefore, boron nanostructures is expected to possess strong visible light scattering properties. However, photonic and optoelectronic properties of the boron nanostructures are seldom studied until now. In this paper, we have successfully prepared single-crystalline boron nanowire (BNW) arrays with high density on Si substrate. All the BNWs are found to possess strong light scattering behaviors in the visible regime. Most of all, the scattered light is found to polarize along the longitudinal direction of the nanowire. They also have excellent second-harmonic generation (SHG) properties under ultrafast laser irradiation. Further optoelectronic measurements show that an individual BNW device exhibits notable photocurrent responses in the visible-light range at ambient conditions, which can be attributed to the strong coupling effect between individual BNW and the visible light. The maximum photoresponsivity of an individual BNW can reach up to 12.12 A W-1 at a voltage of 10 V, and the response time is only 18 ms. Therefore, it unveils that the BNWs have a promising future in visible-light communications and detections. PMID- 29527810 TI - CORRIGENDUM. PMID- 29527809 TI - Microfluidic Model Porous Media: Fabrication and Applications. AB - Complex fluid flow in porous media is ubiquitous in many natural and industrial processes. Direct visualization of the fluid structure and flow dynamics is critical for understanding and eventually manipulating these processes. However, the opacity of realistic porous media makes such visualization very challenging. Micromodels, microfluidic model porous media systems, have been developed to address this challenge. They provide a transparent interconnected porous network that enables the optical visualization of the complex fluid flow occurring inside at the pore scale. In this Review, the materials and fabrication methods to make micromodels, the main research activities that are conducted with micromodels and their applications in petroleum, geologic, and environmental engineering, as well as in the food and wood industries, are discussed. The potential applications of micromodels in other areas are also discussed and the key issues that should be addressed in the near future are proposed. PMID- 29527811 TI - Constructing Multifunctional Heterostructure of Fe2 O3 @Ni3 Se4 Nanotubes. AB - Heterostructures have attracted increasing attention due to their amazing synergetic effects, which may improve the electrochemical properties, such as good electrical/ionic conductivity, electrochemical activity, and mechanical stability. Herein, novel hierarchical Fe2 O3 @Ni3 Se4 nanotubes are successfully fabricated by a multistep strategy. The nanotubes show length sizes of ~250-500 nm, diameter sizes of ~100-150 nm, and wall thicknesses of ~10 nm. The as prepared Fe2 O3 @Ni3 Se4 nanotubes with INi:Fe = 1:10 show excellent Li storage properties (897 mAh g-1 high reversible charge capacity at 0.1 A g-1 ), good rate performance (440 mAh g-1 at 5 A g-1 ), and outstanding long-term cycling performance (440 mAh g-1 at 5 A g-1 during the 300th cycle) as an anode material for lithium ion batteries. In addition, the Fe2 O3 @Ni3 Se4 nanotubes with INi:Fe = 1:10 (the atomic ratio between Ni and Fe) show superior electrocatalytic performance toward the oxygen evolution reaction with an overpotential of only 246 mV at 10 mA cm-2 and a low Tafel slope of 51 mV dec-1 in 1 m KOH solution. PMID- 29527812 TI - Closed-incision negative pressure therapy to reduce groin wound infections in vascular surgery: a randomised controlled trial. AB - Groin wound infections pose a major problem in vascular surgery. Closed-incision negative pressure therapy (ciNPT) was especially designed for the management of incisions at risk of surgical site infections. The aim of this study was to investigate whether ciNPT is able to reduce the incidence of wound infections after vascular surgery. Data on 132 consecutive patients, scheduled for vascular surgery with a longitudinal femoral cutdown, were collected prospectively. All patients were randomised either to the ciNPT group (n = 64) or the control group (n = 68) with conventional dressing. In the ciNPT group, the foam dressing was applied intraoperatively and removed after 5 days. The control group received an absorbent dressing. All wounds were evaluated after 5 and 42 days. Infections were graded according the Szilagyi classification (I-III degrees ). There were no significant differences between both groups considering patient characteristics. Indications for surgery were peripheral arterial disease in 95% (125/132) and aneurysm in 5% (7/132). The overall infection rates were 14% (9/64) in the ciNPT group and 28% (19/68) in the control group (P = 0.055). Early infections were observed in 6% (4/64) of the ciNPT group and 15% (10/68) of the control group (P = 0.125). ciNPT did not reduce infection rates associated with different risk factors for infection. While the experiences with the ciNPT device were encouraging, the study fails to provide evidence of the efficacy of the device to reduce groin wound infections after vascular surgery. It illustrates far more that larger multicentre studies are required and appear promising to provide further evidence for the use of ciNPT. PMID- 29527813 TI - Effect of lower urinary tract symptoms on the quality of life and sexual function of males in China, Taiwan, and South Korea: Subgroup analysis of a cross sectional, population-based study. AB - OBJECTIVE: Lower urinary tract symptoms (LUTS) in males can reduce patients' quality of life (QoL) and affect sexual function and satisfaction. Although this has been documented in the US, Canada, Germany, Italy, UK, and Sweden, data are limited on the effects of LUTS on QoL and sexual function in Asian men. The present subgroup analysis of an Internet-based survey correlated the incidence of male LUTS by severity and category with self-assessed QoL and sexual function and satisfaction measures. METHODS: Males aged >=40 years were randomly selected from consumer survey panels in China, Taiwan, and South Korea. LUTS were defined using the International Continence Society (ICS) 2002 symptom definitions; symptom severity was assessed by the International Prostate Symptom Score (IPSS). The effect of LUTS on QoL was assessed using Patient Perception of Bladder Condition (PPBC) and IPSS QoL scores. Sexual function and satisfaction were assessed using the International Index of Erectile Function (IIEF). RESULTS: Men with moderate to-severe LUTS and overlap of voiding, storage, and post-micturition symptom categories reported dissatisfaction with their QoL and sexual function. LUTS severity was negatively correlated with IIEF scores. Overlap of LUTS categories had a greater effect on QoL and sexual satisfaction than the incidence of just 1 LUTS. CONCLUSION: The findings of the present study suggest that LUTS is prevalent in >60% of Asian males aged >=40 years and is associated with reduced QoL and sexual function, particularly in those with overlap of LUTS categories and greater symptom severity. PMID- 29527814 TI - Frequent infection of wild boar with atypical porcine pestivirus (APPV). AB - The recently identified atypical porcine pestivirus (APPV) was demonstrated to be the causative agent of the neurological disorder "congenital tremor" in newborn piglets. Despite its relevance and wide distribution in domestic pigs, so far nothing is known about the situation in wild boar, representing an important wild animal reservoir for the related classical swine fever virus. In this study, 456 wild boar serum samples obtained from northern Germany were investigated for the presence of APPV genomes and virus-specific antibodies. Results of real-time RT PCR analyses revealed a genome detection rate of 19%. Subsequent genetic characterization of APPV (n = 12) from different hunting areas demonstrated close genetic relationship and, with exception of APPV from one location, displayed less than 3.3% differences in the analysed partial NS3 encoding region. Furthermore, indirect Erns ELISA revealed an antibody detection rate of approx. 52%, being in line with the high number of viremic wild boar. Analysis of fifteen wild boar samples from the Republic of Serbia by Erns antibody ELISA provided evidence that APPV is also abundant in wild boar populations outside Germany. High number of genome and seropositive animals suggest that wild boar may serve as an important virus reservoir for APPV. PMID- 29527815 TI - Diversity of microbial communities potentially involved in mercury methylation in rice paddies surrounding typical mercury mining areas in China. AB - Mercury can be a serious hazard to human health, especially in paddy soils surrounding mining areas. In this study, mercury (Hg)-methylating microbes with the potential biomarker gene hgcA were obtained from 45 paddy soil samples in mercury mining areas in Fenghuang, Wanshan, and Xunyang. In different areas, the abundance of the hgcA gene was affected by different environmental factors, including organic matter, pH, total carbon content, total nitrogen content, and total mercury content. Phylogenetic analysis showed that hgcA microbes in paddy soils were potentially members of the phyla Proteobacteria, Euryarchaeota, Chloroflexi, and two unnamed groups. Canonical correspondence analysis showed that pH and organic matter impacted the hgcA gene diversity and the microbial community structures in paddy soils. The identification of Hg-methylating microbes may be crucial for understanding mercury methylation/demethylation processes, which would be helpful in assessing the risk of methylmercury contamination in the food chain. PMID- 29527816 TI - Commissioning of a dedicated commercial Co-60 total body irradiation unit. AB - We describe the commissioning of the first dedicated commercial total body irradiation (TBI) unit in clinical operation. The Best Theratronics GammaBeam 500 is a Co-60 teletherapy unit with extended field size and imaging capabilities. Radiation safety, mechanical and imaging systems, and radiation output are characterized. Beam data collection, calibration, and external dosimetric validation are described. All radiation safety and mechanical tests satisfied relevant requirements and measured dose distributions meet recommendations of American Association of Physicists in Medicine (AAPM) Report #17. At a typical treatment distance, the dose rate in free space per unit source activity using the thick flattening filter is 1.53 * 10-3 cGy*min-1 *Ci-1 . With a 14,000 Ci source, the resulting dose rate at the midplane of a typical patient is approximately 17 and 30 cGy/min using the thick and thin flattening filters, respectively, using the maximum source to couch distance. The maximum useful field size, defined by the 90% isodose line, at this location is 225 * 78 cm with field flatness within 5% over the central 178 * 73 cm. Measured output agreed with external validation within 0.5%. End-to-end testing was performed in a modified Rando phantom. In-house MATLAB software was developed to calculate patient-specific dose distributions using DOSXYZnrc, and fabricate custom 3D printed forms for creating patient-specific lung blocks. End-to-end OSLD and diode measurements both with and without lung blocks agreed with Monte Carlo calculated doses to within 5% and in-phantom film measurements validated dose distribution uniformity. Custom lung block transmission measurements agree well with design criteria and provide clinically favorable dose distributions within the lungs. Block placement is easily facilitated using the flat panel imaging system with an exposure time of 0.01 min. In conclusion, a novel dedicated TBI unit has been commissioned and clinically implemented. Its mechanical, dosimetric, and imaging capabilities are suitable to provide state-of-the-art TBI for patients as large as 220 cm in height and 78 cm in width. PMID- 29527818 TI - Vascular fibrinoid necrosis in the urinary bladder of ketamine abusers: A new finding that may provide a clue to the pathogenesis of ketamine-induced vesicopathy. AB - Two 31-year-old women who had abused ketamine, 1 for 8 years and 1 for 5 years, presented with ketamine-induced vesicopathy with urinary frequency, decreased bladder capacity, and detrusor overactivity. An enterocystoplasty was performed in both cases. The pathology of the urinary bladders in both women showed ulcerative cystitis and fibrinoid necrosis of vessels; the latter was confirmed by Masson trichrome staining. Fibrinoid necrosis of vessels is a kind of immune complex-mediated vasculitis that induces the release of inflammatory mediators, with subsequent thrombosis, ischemic injury, and eventual tissue necrosis in localized areas, the so-called Arthus reaction. The new finding of fibrinoid necrosis in the urinary bladders of ketamine abusers may provide a new clue to the pathogenesis of ketamine-induced vesicopathy. PMID- 29527817 TI - Trends in Use of Paracetamol in the Nordic Countries. AB - Paracetamol (acetaminophen) is one of the most commonly used analgesics in Europe; however, both the safety and efficacy of paracetamol have recently been questioned. Little is known about cross-national differences in the sales of paracetamol. Using national wholesale statistics and nationwide prescription drug registers, we investigated trends in total and prescribed use of paracetamol in the Nordic countries. The total sales of paracetamol (Anatomical Therapeutic Chemical (ATC) classification system code: N02BE01) measured as defined daily doses (DDD) per 1000 inhabitants/day, and the sales by prescription (users per 1000 inhabitants/year), increased in the Nordic countries from 2000 to 2015. The total sales were highest in Denmark throughout the period, with 65 DDD per 1000 inhabitants/day and lowest in Iceland with 30 DDD per 1000 inhabitants/day in 2015. The cross-national difference in total sales of paracetamol was smaller in 2015 than in 2000. The proportion of paracetamol (DDD per 1000 inhabitants/day) sold by prescription was also highest in Denmark (78%), compared with 75% in Finland, 69% in Sweden, 61% in Norway and 38% in Iceland. Paracetamol by prescription was more common at older ages and among women. Total and prescribed sales of paracetamol have increased in all five Nordic countries over time. Cross national differences exist, with highest sales per capita in Denmark throughout the period. PMID- 29527819 TI - Cathodic Electrodeposition of Ni-Mo on Semiconducting NiFe2 O4 for Photoelectrochemical Hydrogen Evolution in Alkaline Media. AB - Photocathodes for hydrogen evolution from water were made by electrodeposition of Ni-Mo layers on NiFe2 O4 substrates, deposited by spin coating on F:SnO2 -glass. Analysis confirmed the formation of two separate layers, without significant reduction of NiFe2 O4 . Bare NiFe2 O4 was found to be unstable under alkaline conditions during (photo)electrochemistry. To improve the stability significantly, the deposition of a bifunctional Ni-Mo layer through a facile electrodeposition process was performed and the composite electrodes showed stable operation for at least 1 h. Moreover, photocurrents up to -2.1 mA cm-2 at 0.3 V vs. RHE were obtained for Ni-Mo/NiFe2 O4 under ambient conditions, showing that the new combination functions as both a stabilizing and catalytic layer for the photoelectrochemical evolution of hydrogen. The photoelectrochemical response of these composite electrodes decreased with increasing NiFe2 O4 layer thickness. Transient absorption spectroscopy showed that the lifetime of excited states is short and on the ns timescale. An increase in lifetime was observed for NiFe2 O4 of large layer thickness, likely explained by decreasing the defect density in the primary layer(s), as a result of repetitive annealing at elevated temperature. The photoelectrochemical and transient absorption spectroscopy results indicated that a short charge carrier lifetime limits the performance of Ni-Mo/NiFe2 O4 photocathodes. PMID- 29527821 TI - On the relationship status for Arf and NPM1 - it's complicated. AB - Arf levels are tightly regulated in cells and correlate with the level of ribosome biogenesis and proliferative status of cells. Through multivalent interactions with NPM1 - a regulator of ribosome biogenesis, and Mdm2 - a regulator of cellular fate, Arf integrates within the nucleolar matrix, altering its structure, dynamics and function and therefore modulates the cell cycle. PMID- 29527823 TI - Prognostic Factors in Acute Aluminium Phosphide Poisoning: A Risk-Prediction Nomogram Approach. AB - Aluminium phosphide (AlP) is a toxic agent associated with a high mortality rate following acute exposure from various routes. The aim of this study was to determine the clinical and laboratory findings useful for predicting the medical outcome of AlP-poisoned patients using established scoring systems. This is a prospective study of AlP-poisoned patients from 2010 to 2015 in Ardabil, Iran. All patients that presented with a confirmed diagnosis of acute AlP poisoning in the study interval were included in the study. Clinical and laboratory data, using Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score II (SAPS II) scoring systems, were compared for their predictive value in determining differences between survived and non-survived patients. Univariate analysis (Mann Whitney or t-test), multiple logistic regression analysis, receiver operating characteristic (ROC) curve analysis and the Pearson correlation test were performed using STATA/SE 13.0 and the Nomolog Software. A total of 68 AlP poisoned patients with confirmed acute AlP poisoning were included for evaluation. Of these, 36 were non-survived. Multiple logistic regression analysis was performed using parameters and values derived from patient clinical and laboratory data, and revealed that four factors were significant for predicting mortality: Glasgow coma score (GCS); systolic blood pressure (SBP); urinary output (UOP); and serum HCO3 . A four-variable, risk-prediction nomogram was developed for identifying high-risk patients and predicting the risk of mortality. Study results showed that SBP of <92.5 mmHg (p = 0.006); HCO3- < 12.9 mEq/L (p = 0.01), UOP < 1725 mL/day (p = 0.04); and GCS < 14.5 (p = 0.003) were significant predictors of AlP mortality. Scoring systems analysis showed SAPS II score >24.5, APACHE II score >8.5 and SOFA score >7.5 were predictive of non survival patients. The results of our study showed that SBP, GCS, UOP and serum HCO3 levels are the best prognostic factors for predicting mortality in AlP poisoned patients. According to the area under the ROC curve of the APACHE II score, when compared with SOFA and SAPS II scores, the APACHE II score can more effectively discriminate between non-survivors and survived patients. PMID- 29527824 TI - Robust identification of deletions in exome and genome sequence data based on clustering of Mendelian errors. AB - Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared with XHMM, and a significant enrichment of 15q11.2 deletions compared with controls. In addition, MEM identified eight cases of uniparental disomy, sample switches, and DNA contamination. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools. PMID- 29527825 TI - Microwave ablation for lung cancer patients with a single lung: Clinical evaluation of 11 cases. AB - BACKGROUND: The study was conducted to retrospectively evaluate the safety and effectiveness of computed tomography (CT)-guided percutaneous microwave ablation (MWA) for peripheral non-small cell lung cancer (NSCLC) in 11 patients with a single lung after pneumonectomy. METHODS: From May 2011 to March 2015, 11 single lung patients (8 men and 3 women; mean age 60.3 years, range 46-71) with peripheral NSCLC underwent 12 sessions of MWA. Eleven tumors measuring 13-52 mm (mean 30.2 mm) were treated. Follow-up was performed via CT scan at 1, 3, 6, 12, 18, and 24 months after the procedure and annually thereafter. Clinical outcomes were evaluated and complications after MWA were summarized. RESULTS: At a median follow-up period of 20 months (range 6-38), four patients showed evidence of local recurrence at a rate of 36.4% (4/11). Median overall survival was 20 months. The overall survival rates at one, two, and three years after MWA were 88.7%, 63.6%, and 42.3%, respectively. Complications after MWA included pneumothorax (33.3%), hemoptysis (33.3%), intrapulmonary bleeding (25%), pleural effusion (16.7%), and pulmonary infection (8.3%). None of the patients died during the procedure or in the 30 days after MWA. CONCLUSION: CT-guided percutaneous MWA is safe and effective for the treatment of peripheral NSCLC in patients with a single lung after prior pneumonectomy. PMID- 29527826 TI - CT-guided nephrostomy: Re-inventing the wheel for the occasional interventionalist. AB - Percutaneous nephrostomy insertion has, in recent times, become a subspecialised skill performed by an interventional trained Radiologist. However, this creates access issues, particularly in remote and regional medical centres. In this article, we describe a simple and effective method for computed tomography (CT) guided percutaneous nephrostomy insertion, utilising the CT interventional skills of the general radiologist. PMID- 29527827 TI - Oil type and cross-linking influence growth of Aureobasidium melanogenum on vegetable oils as a single carbon source. AB - Aureobasidium melanogenum is the main fungus found in a spontaneously formed biofilm on a oil-treated wood. This dark colored biofilm functions as a protective coating. To better understand biofilm formation, in this study A. melanogenum was cultured on olive oil and raw linseed oil. Metabolic activity and oil conversion were measured. The results show that A. melanogenum is able to grow on linseed oil and olive oil as a single carbon source. The fungus produces the enzyme lipase to convert the oil into fatty acids and glycerol. Metabolic activity and oil conversion were equal on linseed oil and olive oil. The fungus was not able to grow on severe cross-linked linseed oil, meaning that the degree of cross-linking of the oil is important for growth of A. melanogenum. Dark coloring of the colony was seen on linseed oil, which might be a stress response on the presence of autoxidation products in linseed oil. The colony on olive oil showed delayed melanin production indicating an inhibitory effect of olive oil on melanin production. PMID- 29527828 TI - The role of advanced geriatric nurses in Norway: A descriptive exploratory study. AB - BACKGROUND: Care of older adults in the community is becoming increasingly complex. However, nursing staff often has insufficient knowledge and skills to adequately address the needs of frail older adults. There is therefore a need for nurses with advanced qualifications. To meet this need, advanced geriatric nursing has been introduced in Norway. AIMS AND OBJECTIVES: This study aimed to describe the experiences of nurses with their new role as advanced geriatric nurses in care of older adults and to determine what strategies the nurses considered important in the development of their new role. DESIGN: This study applied a descriptive, exploratory design. METHODS: In-depth interviews were conducted with 21 nurses who had undergone an educational programme to become advanced geriatric nurses in Norway in 2016. Content analysis was used to analyse the data. FINDINGS: The participants described a complex and extensive nursing role, which they related to a new understanding of the patients, relatives and the system in which they worked. This new gaze had developed based on a combination of their new knowledge, their skills, experiences and professional interests. The opportunities to use their role depended on their workplace conditions. They related to contextual challenges at their workplace in different ways to optimise the use of their new gaze. CONCLUSIONS: Common for all participants was a broader and deeper understanding of the patient's health and life situation, which guided participants' actions. The key issue in developing the new role was developing effective strategies to foster role integration. IMPLICATIONS FOR PRACTICE: Advanced geriatric nurses should collaborate with their managers to create a role that takes advantage of their knowledge and skills, as well as collaborate with colleagues to enhance understanding of utilisation of their role. PMID- 29527829 TI - Determination of nursing students' attitudes towards the use of technology. AB - AIM: The use of technology is increasingly important in nursing education and practice. For this reason, it is necessary to determine the attitudes of nursing students towards technology. METHODS: This study was conducted with 508 nursing students. A personal information form that was prepared by the researchers and the Attitudes Toward Technology Scale were used as the data collection tools. RESULTS: The mean score that was obtained by the nursing students from the Attitudes Toward Technology Scale was 61.53 +/- 1.13. The Cronbach's alpha coefficient was found to be 0.90. There was a statistically significant difference between the sexes, using a computer, tablet, or laptop, using technology to reach health-related information, and for professional development, using mobile applications related to drug information. There was also a statistical difference between using the Periscope and Scorpio accounts from social media and using Excel and PowerPoint from Microsoft programs. CONCLUSION: Nursing students are capable of technology-based teaching, which can be expanded as a result. PMID- 29527830 TI - Muscle phenotype is related to motor unit behavior of the vastus lateralis during maximal isometric contractions. AB - Previous investigations have reported a relationship between skeletal muscle phenotype and motor unit (MU) firing parameters during submaximal contractions. The purpose of the current investigation, however, was to examine the relationships between motor unit firing behavior during a maximal voluntary contraction, Myosin Heavy Chain (MHC) isoform content, and various molecular neuromuscular targets of the vastus lateralis (VL) muscle in resistance-trained men. Ten resistance-trained males completed a trapezoidal ramp contraction up to 100% of their maximal voluntary isometric strength (MVIC). Surface electromyography was recorded from the VL using a multichannel electrode array and decomposed to examine the firing characteristics of individual MUs. A skeletal muscle biopsy of the VL was also collected from each subject. Regression analyses were performed to identify relationships between type II fiber area and the slopes and/or intercepts of the mean firing rate (FRMEAN ) versus recruitment threshold (RT), max firing rate (FRMAX ) versus RT, and RT versus MU action potential amplitude (MUAPPP ) relationships. There were significant inverse relationships between type II fiber area and the y-intercept of the FR versus RT relationship (P < 0.05). Additionally, strong relationships (r > 0.5) were found between type II fiber area and FRMEAN versus RT slope and RT versus MUAPPP slope and intercept. These data further support the hypothesis that skeletal muscle phenotype is related to MU behavior during isometric contraction. However, our data, in concert with previous investigations, may suggest that these relationships are influenced by the intensity of the contraction. PMID- 29527831 TI - Development of a selective androgen receptor modulator for transdermal use in hypogonadal patients. AB - We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose-dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4-week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men. PMID- 29527832 TI - Programme fidelity of specialized early intervention in Denmark. AB - AIM: Specialized early intervention (SEI) treatment in meta-analysis has proven to be effective, compared to usual treatment, in treating first-episode psychosis, and the dissemination of SEI services is increasing. A prerequisite for upholding positive effects is to ensure fidelity to the treatment concept once tested. The aim of this study was to map programme fidelity of SEI teams in Denmark by testing a newly developed fidelity scale. METHODS: The 18-item SEI fidelity scale was assessed by visiting SEI teams in person. The scale is divided into 2 dimensions: one concerning the structure and the other concerning the character and content of the treatment. Interviews were conducted with team leaders, patients and members of the staff, and team conferences were observed. Satisfactory fidelity can be obtained at 2 levels: an elite level and an adequate level. RESULTS: In total, 96% (n = 22) of the Danish SEI teams participated in the fidelity study. An elite fidelity score was achieved by 32% of the teams, scoring 15 or 16 on the 18-point scale; 27% reached adequate level. With regard to the structural domain of the scale, we found variation among the teams. CONCLUSIONS: The multimodal approach was found to be very efficient in evaluating elements critical to SEI teams in Denmark. A low score on the structural domain could, in the long term, lead to an inability to maintain a well-functioning team and provide high-quality treatment. PMID- 29527833 TI - Reduced innate immunity of Cuban Treefrogs at leading edge of range expansion. AB - During geographic range expansion, populations of non-indigenous species at the invasion front may benefit from directing resources away from immune defense. To test this hypothesis, we investigated the strength of two innate immune components in populations of invasive Cuban Treefrogs (Osteopilus septentrionalis) in a long-colonized area (core region) and at the invasion front (leading-edge region). First, we compared the region-specific metabolic response of frogs injected with an endotoxin that induces systemic inflammation (lipopolysaccharide, LPS) to sham-injected control frogs pooled from both regions. Males and females were analyzed independently because we detected a sex related difference in mass-independent metabolism of control frogs, with males exhibiting a significantly higher metabolic rate (F1, 21 = 29.02, P < 0.001) than females. We observed a significantly higher metabolic rate in LPS-injected core frogs compared with control frogs for both males (P = 0.041) and females (P = 0.007). Conversely, in leading-edge populations, there was no significant difference in the metabolic rate of LPS-injected and control frogs (males, P = 0.195; females, P = 0.132). Second, we directly compared bacterial killing ability of frog blood plasma between regions. Bactericidal ability of plasma was significantly greater in frogs from the core region in comparison with those at the leading edge (F1, 26 = 28.67, P < 0.001). For both immune components that we examined, populations from the core exhibited stronger immune responses. Our findings support hypotheses predicting an inverse relationship between immunity and range expansion. PMID- 29527834 TI - Sonochemistry-Assembled Stimuli-Responsive Polymer Microcapsules for Drug Delivery. AB - Stimuli-responsive polymer microcapsules (PMs) fabricated by the sonochemical method have emerged for developing useful drug delivery systems, and the latest developments are mainly focusing on the synthetic strategies and properties such as structure, size, stability, loading capacity, drug delivery, and release. There, the primary attribution of sonochemistry is to offer a simple and practical approach for the preparation of PMs. Structure, size, stability, and properties of PMs are designed mainly according to synthetic materials, implementation schemes, or specific demands. Numerous functionalities of PMs based on different stimuli are demonstrated: targeting motion in a magnetic field or adhering to the living cells with sensitive sites through molecular recognition, and stimuli-triggered release including enzymatic catalysis, chemical reaction as well as physical or mechanical process. The current review discusses the basic principles and mechanisms of stimuli effects, and describes the progress in the application such as targeted drug systems and controlled drug systems, and also gives an outlook on the future challenges and opportunities for drug delivery and theranostics. PMID- 29527835 TI - Carbon-Dot-Decorated TiO2 Nanotubes toward Photodynamic Therapy Based on Water Splitting Mechanism. AB - The use of visible light to produce reactive oxygen species (ROS) from renewable water splitting is a highly promising means in photodynamic therapy (PDT). Up to date, diverse inorganic-organic hybrid materials developed as photosensitizers still undergo low therapeutic efficiency and/or poor stability. Herein, a kind of carbon-nanodot-decorated TiO2 nanotubes (CDots/TiO2 NTs) composite is developed and applied for photodynamic therapy. Upon 650 nm laser light excitation, the emissions with short wavelengths (325-425 nm) from the CDots as a result of upconversion process excite TiO2 NTs to form electron/hole (e- /h+ ) pairs, triggering the reaction with the adsorbed oxidants to produce ROS. Moreover, the CDots deposited on the surface of TiO2 NTs markedly enhance the light absorption response and narrow the band gap compared with anatase TiO2 nanoparticles, thereby increasing the photosensitizing efficiency. Besides, the CDots show high chemical catalytic activity for H2 O2 decomposition even if no light is needed, which is essential for PDT. The excellent therapeutic performance actuated by 650 nm light is demonstrated by in vitro and in vivo assays. This photosensitizer comprises low-cost, earth-abundant, environment-friendly merits, and especially excellent stability, implying its feasible application in biomedical field. PMID- 29527836 TI - NanoTRAIL-Oncology: A Strategic Approach in Cancer Research and Therapy. AB - TRAIL is a member of the tumor necrosis factor superfamily that can largely trigger apoptosis in a wide variety of cancer cells, but not in normal cells. However, insufficient exposure to cancer tissues or cells and drug resistance has severely impeded the clinical application of TRAIL. Recently, nanobiotechnology has brought about a revolution in advanced drug delivery for enhanced anticancer therapy using TRAIL. With the help of materials science, immunology, genetic engineering, and protein engineering, substantial progress is made by expressing fusion proteins with TRAIL, engineering TRAIL on biological membranes, and loading TRAIL into functional nanocarriers or conjugating it onto their surfaces. Thus, the nanoparticle-based TRAIL (nanoTRAIL) opens up intriguing opportunities for efficient and safe bioapplications. In this review, the mechanisms of action and biological function of TRAIL, as well as the current status of TRAIL treatment, are comprehensively discussed. The application of functional nanotechnology combined with TRAIL in cancer therapy is also discussed. PMID- 29527837 TI - Patterns of rpoC Mutations in Drug-Resistant Mycobacterium tuberculosis Isolated from Patients in South Korea. AB - BACKGROUND: Rifampicin (RFP) is one of the principal first-line drugs used in combination chemotherapies against Mycobacterium tuberculosis, and its use has greatly shortened the duration of chemotherapy for the successful treatment of drug-susceptible tuberculosis. Compensatory mutations have been identified in rpoC that restore the fitness of RFP-resistant M. tuberculosis strains with mutations in rpoB. To investigate rpoC mutation patterns, we analyzed 93 clinical M. tuberculosis isolates from patients in South Korea. METHODS: Drug-resistant mycobacterial isolates were cultured to determine their susceptibility to anti tubercular agents. Mutations in rpoC were identified by sequencing and compared with the relevant wild-type DNA sequence. RESULTS: In total, 93 M. tuberculosis clinical isolates were successfully cultured and tested for drug susceptibilities. They included 75 drug-resistant tuberculosis species, of which 66 were RFP-resistant strains. rpoC mutations were found in 24 of the 66 RFP resistant isolates (36.4%). Fifteen different types of mutations, including single mutations (22/24, 91.7%) and multiple mutations (2/24, 8.3%), were identified, and 12 of these mutations are reported for the first time in this study. The most frequent mutation involved a substitution at codon 452 (nt 1356) resulting in amino acid change F452L. CONCLUSION: Fifteen different types of mutations were identified and were predominantly single-nucleotide substitutions (91.7%). Mutations were found only in dual isoniazid- and RFP-resistant isolates of M. tuberculosis. No mutations were identified in any of the drug-susceptible strains. PMID- 29527838 TI - Tuberculosis Relief Belt Supporting Project (Tuberculosis Patient Management Project for Poverty Group). AB - BACKGROUND: The "Tuberculosis Relief Belt Supporting Project (Tuberculosis Patient Management Project for Poverty Groups)" is a national program for socioeconomically vulnerable tuberculosis (TB) patients. We sought to evaluate the clinical and socioeconomic characteristics of poverty-stricken TB patients, and determined the need for relief. METHODS: We examined in-patients with TB, who were supported by this project at the National Medical Center from 2014 to 2015. We retrospectively investigated the patients' socioeconomic status, clinical characteristics, and project expenditures. RESULTS: Fifty-eight patients were enrolled. Among 55 patients with known income status, 24 (43.6%) had no income. Most patients (80%) lived alone. A total of 48 patients (82.8%) had more than one underlying disease. More than half of the enrolled patients (30 patients, 51.7%) had smear-positive TB. Cavitary disease was found in 38 patients (65.5%). Among the 38 patients with known resistance status, 19 (50%) had drug-resistant TB. In terms of disease severity, 96.6% of the cases had moderate-to-severe disease. A total of 14 patients (26.4%) died during treatment. Nursing expenses were supported for 12 patients (20.7%), with patient transportation costs reimbursed for 35 patients (60%). In terms of treatment expenses for 31 people (53.4%), 93.5% of them were supported by uninsured benefits. CONCLUSION: Underlying disease, infectivity, drug resistance, severity, and death occurred frequently in socioeconomically vulnerable patients with TB. Many uninsured treatment costs were not supported by the current government TB programs, and the "Tuberculosis Relief Belt Supporting Project" compensated for these limitations. PMID- 29527839 TI - Serial Changes in Mannose-Binding Lectin in Patients with Sepsis. AB - BACKGROUND: Mannose-binding lectin (MBL) deficiency leads to increased susceptibility to infection. We investigated whether serial changes in MBL levels are associated with the prognosis of patients diagnosed with septic shock, and correlated with cytokine levels. METHODS: We enrolled 131 patients with septic shock in the study. We analyzed the serum samples for MBL and cytokine levels at baseline and 7 days later. Samples on day 7 were available in 73 patients. RESULTS: We divided the patients with septic shock into four groups according to serum MBL levels (<1.3 MUg/mL or >=1.3 MUg/mL) on days 1 and 7. Patients with low MBL levels on day 1 and high MBL levels on day 7 showed a favorable prognosis for 28-day survival (odds ratio, 1.96, 95% confidence interval, 1.10-2.87; p=0.087). The high MBL group on day 7 showed a significant decrease in monocyte chemoattractant protein 1, interleukin (IL)-1beta, IL-6, IL-8, interferon-gamma, and granulocyte macrophage colony-stimulating factor levels compared with the low MBL group on day 7. CONCLUSION: The increase in MBL levels of patients with septic shock may suggest a favorable prognosis and attenuate pro-inflammatory and anti-inflammatory responses. PMID- 29527840 TI - Increased Risk of Exacerbation in Asthma Predominant Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome. AB - BACKGROUND: Obstructive airway disease patients with increased variability of airflow and incompletely reversible airflow obstruction are often categorized as having asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS). ACOS is heterogeneous with two sub-phenotypes: asthma-ACOS and COPD-ACOS. The objective of this study was to determine the difference in risk of exacerbation between the two sub-phenotypes of ACOS. METHODS: A total of 223 patients exhibiting incompletely reversible airflow obstruction with increased variability (spirometrically defined ACOS) were enrolled. These patients were divided into asthma-ACOS and COPD-ACOS according to their physician's diagnosis and smoking history of 10 pack-years. Within-group comparisons were made for asthma-ACOS versus COPD-ACOS and light smokers versus heavy smokers. RESULTS: Compared to patients with COPD-ACOS, patients with asthma-ACOS experienced exacerbation more often despite their younger age, history of light smoking, and better lung function. While the light-smoking group showed better lung function, they made unscheduled outpatient clinic visits more frequently. On multivariate analysis, asthma-ACOS and poor inhaler compliance were significantly associated with more than two unscheduled clinic visits during the previous year. CONCLUSION: Spirometrically defined ACOS includes heterogeneous subgroups with different clinical features. Phenotyping of ACOS by physician's diagnosis could be significant in predicting future risk of exacerbation. PMID- 29527841 TI - Comparison of Multiple Chronic Obstructive Pulmonary Disease (COPD) Indices in Chinese COPD Patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a serious chronic condition with a global impact. Symptoms of COPD include progressive dyspnea, breathlessness, cough, and sputum production, which have a considerable impact on the lives of patients. In addition to the human cost of living with COPD and the resulting death, COPD entails a huge economic burden on the Chinese population, with patients spending up to one-third of the average family income on COPD management in some regions is clinically beneficial to adopt preventable measures via prudent COPD care utilization, monetary costs, and hospitalizations. METHODS: Toward this end, this study compared the relative effectiveness of six indices in predicting patient healthcare utilization, cost of care, and patient health outcome. The six assessment systems evaluated included the three multidimensional Body mass index, Obstruction, Dyspnea, Exercise capacity index, Dyspnea, Obstruction, Smoking, Exacerbation (DOSE) index, and COPD Assessment Test index, or the unidimensional measures that best predict the future of patient healthcare utilization, cost of care, and patient health outcome among Chinese COPD patients. RESULTS: Multiple linear regression models were created for each healthcare utilization, cost, and outcome including a single COPD index and the same group of demographic variables for each of the outcomes. CONCLUSION: We conclude that the DOSE index facilitates the prediction of patient healthcare utilization, disease expenditure, and negative clinical outcomes. Our study indicates that the DOSE index has a potential role beyond clinical predictions. PMID- 29527842 TI - Different Pattern of Chronic Obstructive Pulmonary Disease Assessment Test Score between Chronic Bronchitis and Non-chronic Bronchitis Patients. AB - BACKGROUND: Chronic bronchitis (CB) is an important phenotype in chronic obstructive pulmonary disease (COPD). The purpose of this study is to evaluate different pattern of COPD assessment test (CAT) score between CB and non-CB patients. METHODS: Patients were recruited from 45 centers in Korea, as part of the Korean COPD Subgroup Study cohort. CB was defined when sputum continued for at least 3 months. RESULTS: Total 958 patients with COPD were eligible for analysis. Among enrolled patients, 328 (34.2%) were compatible with CB. The CAT score was significantly higher in patients with CB than non-CB, and each component of CAT score showed a similar result. CB was significantly associated with CAT score when adjusted with age, sex, modified Medical Research Council, and post-bronchodilator forced expiratory volume in 1 second. Each component of CAT score between patients with CB and non-CB showed different pattern according to Global Initiative for Chronic Obstructive Lung Disease grade. CONCLUSION: CAT score is significantly higher in patients with CB than non-CB. Each component of CAT score was significantly different between two groups. PMID- 29527843 TI - Pemetrexed Continuation Maintenance versus Conventional Platinum-Based Doublet Chemotherapy in EGFR-Negative Lung Adenocarcinoma: Retrospective Analysis. AB - BACKGROUND: Although targeted therapy and immuno-oncology have shifted the treatment paradigm for lung cancer, platinum-based combination is still the standard of care for advanced non-small cell lung cancer (NSCLC). Pemetrexed continuation maintenance therapy has been approved and increasingly used for patients with nonsquamous NSCLC. However, the efficacy of this strategy has not been proven in patients without driving mutations. The objective of this study was to compare the clinical benefit of pemetrexed continuation maintenance to conventional platinum-based doublet in epidermal growth factor receptor (EGFR) negative lung adenocarcinoma. METHODS: A total of 114 patients with EGFR-negative lung adenocarcinoma who were treated with platinum doublet were retrospectively enrolled. We compared the survival rates between patients received pemetrexed maintenance after four-cycled pemetrexed/cisplatin and those received at least four-cycled platinum doublet without maintenance chemotherapy as a first-line treatment. RESULTS: Forty-one patients received pemetrexed maintenance and 73 received conventional platinum doublet. Median progression-free survival (PFS), which was defined as the time from the day of response evaluation after four cycles of chemotherapy to disease progression or death, was significantly higher in the pemetrexed maintenance group compared to conventional group (5.8 months vs. 2.2 months, p<0.001). Median overall survival showed an increasing trend in the pemetrexed maintenance group (22.3 months vs. 16.1 months, p=0.098). Multivariate analyses showed that pemetrexed maintenance chemotherapy was associated with better PFS (hazard ratio, 0.73; 95% confidence interval, 0.15 0.87). CONCLUSION: Compared to conventional platinum-based chemotherapy, premetrexed continuation maintenance treatment is associated with better clinical outcome for the patients with EGFR wild-type lung adenocarcinoma. PMID- 29527844 TI - Altered Thoracic Cage Dimensions in Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) may cause changes in the shape of the thoracic cage by increasing lung volume and hyperinflation. This study investigated changes in thoracic cage dimensions and related factors in patients with COPD. METHODS: We enrolled 85 patients with COPD (76 males, 9 females; mean age, 70.6+/-7.1 years) and 30 normal controls. Thoracic cage dimensions were measured using chest computed tomography at levels 3, 6, and 9 of the thoracic spine. We measured the maximal transverse diameter, mid-sagittal anteroposterior (AP) diameter, and maximal AP diameter of the right and left hemithorax. RESULTS: The average AP diameter was significantly greater in patients with COPD compared with normal controls (13.1+/-2.8 cm vs. 12.2+/-1.13 cm, respectively; p=0.001). The ratio of AP/transverse diameter of the thoracic cage was also significantly greater in patients with COPD compared with normal controls (0.66+/-0.061 vs. 0.61+/-0.86; p=0.002). In COPD patients, the AP diameter of the thoracic cage was positively correlated with body mass index (BMI) and 6-minute walk test distance (r=0.395, p<0.001 and r=0.238, p=0.028) and negatively correlated with increasing age (r=-0.231, p=0.034). Multiple regression analysis revealed independent correlation only between BMI and increased ratio of AP/transverse diameter of the thoracic cage (p<0.001). CONCLUSION: Patients with COPD exhibited an increased AP diameter of the thoracic cage compared with normal controls. BMI was associated with increased AP diameter in these patients. PMID- 29527845 TI - The Comparison of Clinical Variables in Two Classifications: GOLD 2017 Combined Assessment and Spirometric Stage of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: There are limited number of studies that investigate clinical variables instead of chronic obstructive lung disease (COPD) management according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 classification. The aim of the study was to investigate whether there was a difference between GOLD 2017 classification and spirometric stage in clinical variables in patients with COPD. The data of 427 male patients with stable COPD were investigated retrospectively. METHODS: Patients were allocated into combined assessment of GOLD 2017 and spirometric stage. Age, amount of smoking, pulmonary function, modified Medical Research Council (mMRC), incremental shuttle walk test (ISWT), Hospital Anxiety-Depression Scale (HADS), St. George's Respiratory Questionnaire (SGRQ), body mass index (BMI), and fat free mass index (FFMI) were recorded. RESULTS: Seventy-three (17%) patients were in group A, 103 (24%) constituted group B, 38 (9%) were included in group C, and 213 (50%) comprised group D according to the combined assessment of GOLD 2017. Twenty-three patients (5%) were in stage 1, 95 (22%) were in stage 2, 149 (35%) were in stage 3, and 160 (38%) were in stage 4 according to spirometric stage. According to GOLD 2017, age, amount of smoking, mMRC, BMI, FFMI, SGRQ, HADS, forced vital capacity, forced expiratory volume in 1 second (FEV1), and ISWT were significantly different between groups. Ages, amount of smoking, FFMI, BMI, HADS of group A were different from B and D. Smiliar values of FEV1 were found in A-C and B-D. A and C had smiliar ISWT. According to spirometric stage, BMI, FFMI of stage 4 were statistically different. mMRC, ISWT, and SGRQ of stages 3 and 4 were different from other stages, amongst themselves. FEV1 was correlated with mMRC, SGRQ, anxiety scores, BMI, FFMI, and ISWT. CONCLUSION: This study showed that the GOLD ABCD classification might not represent the severity of COPD sufficiently well in terms of lung function or exercise capacity. The combination of both spirometric stage and combined assessment of GOLD 2017 is important, especially for estimating clinical variables. PMID- 29527846 TI - Smoking Cessation Strategies Targeting Specific Populations. AB - Quitting smoking helps smokers maintain their health and extend their lifespan by 10 or more years. Treatment strategies for smoking cessation should be tailored to individual smokers with special needs based on their specific circumstances. It is recommended that pregnant women adopt smoking cessation through counseling and behavioral interventions because the safety of medications has yet to be established. Counseling is the main strategy for smoking cessation in adolescents and nicotine replacement therapy can be used with caution in individuals with serious nicotine dependence. It is important for smokers with psychiatric diseases to quit smoking following accurate assessment of their depression status. Nicotine replacement therapy, varenicline, and bupropion can be used for smoking cessation in smokers with psychiatric disorders. The incidence of cardiovascular disease decreased according to the smoking status and the duration of smoking cessation. In smokers with chronic obstructive pulmonary disease (COPD) who used a combination of counseling and pharmacotherapy the quitting rate was more than twice as high as subjects who used behavioral interventions alone. Varenicline can be used as the most effective anti-smoking drug by most smokers including those with psychiatric disorders, cardiovascular disease, and COPD. PMID- 29527847 TI - Bibliometric Analysis of Research Productivity in Latent Tuberculosis: Are We Focusing Our Research Efforts on the Right Areas? PMID- 29527848 TI - Corticosteroid Therapy in Combination with Antibiotics for Erysipelas. AB - BACKGROUND: Erysipelas, an acute infection of the dermal and subcutaneous tissue, is normally treated with antibiotics. Previous data indicated that treatment with prednisone in combination with antibiotics results in significant acceleration of the healing phase. OBJECTIVES: To investigate the effectiveness of corticosteroids combined with antibiotics for the treatment of erysipelas. METHODS: A retrospective study was conducted on hospitalized patients diagnosed with erysipelas between 2004 and 2011 at the Department of Dermatology at Sheba Medical Center, Israel. Data included epidemiology, medical background, and course of the disease as documented at admission and during hospitalization. RESULTS: Data were collected on 173 patients (66% males) who were divided into two groups: a control group treated with antibiotics only (97 patients) and a study group treated with antibiotics and prednisone (76 patients). The study group presented with a more severe form of erysipelas (bullous) and those patients were hospitalized for a longer period (8.5 vs. 7 days). Nevertheless, the study group exhibited a 71% clinical improvement shortly after being treated with prednisone, without significant side effects. Short-term follow-up revealed more edema in the study group; however, long-term follow-up revealed a higher incidence of erythema and recurrence of erysipelas in the control group. The return to full function was faster in the study group than in the control group. CONCLUSIONS: Combining prednisone with antibiotics for the treatment of erysipelas should be considered, especially in severe cases. In addition, a prospective double-blind study should be conducted to verify these conclusions. PMID- 29527849 TI - How Prevalent is Hydronephrosis Secondary to Acute Appendicitis: A Cross Sectional Study. AB - BACKGROUND: Right hydronephrosis secondary to acute appendicitis is an under reported phenomenon with only several case reports published. OBJECTIVES: To assess the incidence of this phenomenon in our database of patients diagnosed with acute appendicitis. METHODS: Data were collected on 1092 patients who underwent surgery due to acute appendicitis between 2003 and 2007 in our tertiary medical center. The data entailed demographic, surgical, and hospitalization parameters including ultrasound or computed tomography examinations and presence of right hydronephrosis prior to surgery. RESULTS: Out of 1092 patients, appendicitis was eventually diagnosed in 87.4% of the patients. Only 594 (54%) had preoperative imaging performed prior to surgery (ultrasound or computed tomography). Out of these 594 patients, 21 (3.5%) had a new right hydronephrosis diagnosed and all had appendicitis with 15/21 (71%) having a retrocecal appendix. Of those with retrocecal appendix, 10 were pregnant women (48%). Erythrocyturia was present in 15/21 patients (71%) and in 10/11 of patients (91%) after excluding those who were pregnant. No significant differences were seen in patients with hydronephrosis regarding age, hospitalization, and surgery time. In all patients, an ultrasound was performed 2 weeks after surgery demonstrating the disappearance of hydronephrosis. Median follow-up time was 41.7 months (range 14.8-118.4 months). CONCLUSIONS: Our study shows that 3.5% of our cohort had right hydronephrosis secondary to acute appendicitis. Although this presentation is very rare, physicians should be aware of this phenomenon and the risk for delayed diagnosis and treatment of acute appendicitis. PMID- 29527850 TI - Use of Aromatase Inhibitors in IVF for Fertility Preservation of Non-Breast Cancer Patients: A Case Series. AB - BACKGROUND: Controlled ovarian hyperstimulation (COH) followed by oocyte retrieval is a leading option for fertility preservation before chemotherapy, yet this procedure causes excessive serum levels of estradiol (E2), which are often detrimental for cancer patients. Aromatase inhibitors are often used in breast cancer patients during COH to prevent elevated levels of E2. OBJECTIVES: To describe our experience with COH for oocyte cryopreservation in non-breast cancer patients using aromatase inhibitors. METHODS: Of the five patients treated, two had an aggressive abdominal desmoid tumor, one had endometrial carcinoma, one had uterine sarcoma, and one patient had a brain oligodendroglioma. In all cases the treating oncologist suggested an association between estrogen and possible tumor progression. All patients were treated with a standard in vitro fertilization antagonist protocol combined with aromatase inhibitors, similar to the protocol used for breast cancer patients. RESULTS: The average duration of treatment was 10.5 days, mean peak E2 was 2348 pmol/L, mean number of oocytes aspirated was 17.3, and a mean of 14.6 embryos/oocytes were cryopreserved. CONCLUSIONS: COH with aromatase inhibitors is apparently effective in non-breast cancer patients and spares exposure to high E2 levels. PMID- 29527851 TI - Structured, Protocol-Based Pulse-Oximetry Measurement Improves the Evaluation of Hypoxemic Patients at Hospital Admission. AB - BACKGROUND: Accurate pulse oximetry reading at hospital admission is of utmost importance, mainly for patients presenting with hypoxemia. Nevertheless, there is no accepted or evidence-based protocol for such structured measuring. OBJECTIVES: To devise and assess a structured protocol intended to increase the accuracy of pulse oximetry measurement at hospital admission. METHODS: The authors performed a prospective comparison of protocol-based pulse-oximetry measurement with non protocol based readings in consecutive patients at hospital admission. They also calculated the relative percentage of improvement for each patient (before and after protocol implementation) as a fraction of the change in peripheral capillary oxygen saturation (SpO2) from 100%. RESULTS: A total of 460 patients were recruited during a 6 month period. Implementation of a structured measurement protocol significantly changed saturation values. The SpO2 values of 24.7% of all study participants increased after protocol implementation (ranging from 1% to 21% increase in SpO2 values). Among hypoxemic patients (initial SpO2 < 90%), protocol implementation had a greater impact on final SpO2 measurements, increasing their median SpO2 readings by 4% (3-8% interquartile range; P < 0.05). Among this study population, 50% of the cohort improved by 17% of their overall potential and 25% improved by 50% of their overall improvement potential. As for patients presenting with hypoxemia, the median improvement was 31% of their overall SpO2 potential. CONCLUSIONS: Structured, protocol based pulse-oximetry may improve measurement accuracy and reliability. The authors suggest that implementation of such protocols may improve the management of hypoxemic patients. PMID- 29527852 TI - Fetal Renal to Abdominal Ratio: A Constant Measurement Throughout Gestation. AB - BACKGROUND: Sonographic assessment of the fetal kidneys is an integral part of the prenatal anatomical survey. OBJECTIVES: To evaluate the fetal renal to abdominal (RTA) ratio throughout pregnancy and to investigate whether this ratio can be a potential diagnostic landmark for congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Measurements of the anterior-posterior diameters of the fetal kidney and fetal abdomen (APAD) were obtained prospectively. The RTA was calculated as the ratio between them in in two groups: normal population vs. CAKUT cases. RTA in CAKUT cases was compared to RTA in a normal population. RESULTS: The study group was comprised of 210 women. The mean gestational age for the fetuses was 31 +/- 5.6 weeks (range 14-40 weeks). Fetal RTA ratio was found to be 0.28 +/- 0.03 throughout pregnancy from early second trimester to term, with high reproducibility of measurements. During the study period the RTA was evaluated in nine cases referred for suspected CAKUT. All cases demonstrated a different ratio according to the renal anomaly. High ratio was observed in one case of overgrowth syndrome (Beckwith Wiedenmann syndrome; 0.47), three cases of infantile polycystic kidney (0.45-0.47), and three cases of a solitary kidney (0.31-0.35), while cases of dysplastic kidneys revealed a low ratio (0.14-0.18). CONCLUSIONS: Prenatal RTA ratio is constant throughout gestation. An abnormal ratio should lead to meticulous renal investigation to rule out kidney disease. PMID- 29527853 TI - The Possible Role of Human Papillomavirus Infection in the prognosis of Oral Squamous Cell Carcinoma in a Northern Israel Population. AB - BACKGROUND: Several types of human papillomavirus (HPV) have been found to be associated with oral squamous cell carcinoma (OSCC). Still, the significance of HPV infection and its relationship to patient prognosis remains an important matter of debate. OBJECTIVES: To investigate the incidence of HPV infection in OSCC patients in northern Israel populations to determine its role in the etiology and prognosis of OSCC. METHODS: OSCC tissues were gathered from the pathology departments at Rambam and Padeh medical centers in northern Israel. HPV DNA typing and immunohistochemistry for p16INK4A antibodies were conducted to evaluate their incidence in OSCC tissues. Statistical analysis regarding its expression in the different sub-populations (Jews, Arabs, Druze) was conducted using chi-square and Fisher's exact tests. RESULTS: The study included 82 patients: 53 men and 29 woman; median age 62.1 years; 54 Jews, 25 Arabs, and 3 Druze. The overall incidence of HPV expression was 45% (n=37). The median age of HPV-positive patients was 53 years vs. 65.8 in the negative group (P < 0.001). The 5 year overall survival of HPV-positive patients was not significantly higher than HPV-negative patients. A significant association was found between P16 expression and overall survival (log-rank P = 0.001). CONCLUSIONS: HPV infection in OSCC was not found to be significant in this study; however, P16 expression in the tumor tissue was found to be a positive prognostic factor for better survival. PMID- 29527854 TI - Infants Born with Esophageal Atresia with or without Tracheo-Esophageal Fistula: Short- and Long-Term Outcomes. AB - BACKGROUND: The estimated incidence of esophageal atresia (EA) with or without tracheo-esophageal fistula (TEF) is 1:3500 live births. During childhood these patients have various co-morbidities, but the overall quality of life among adults is similar to that of the general population. OBJECTIVES: To evaluate short- and long-term co-morbidities and quality of life among infants born with EA +/- TEF at a large single medical center. METHODS: Medical records of 65 children born over a 21 year period were reviewed for short- and long-term medical data. Telephone interviews were conducted with 46 of their parents regarding medical problems and quality of life after home discharge. RESULTS: The main long-term co-morbidities during the first 2 years of life, 4-6 years of age, and during adolescence (12-16 years) included gastro-esophageal reflux disease (GERD) in 56.5%, 35.8%, and 18.7%, respectively; stridor in 84.8%, 45.2%, and 12.5%, respectively; hyper-reactive airway disease (HRAD) in 43.5%, 35.5%, and 36.5%, respectively; recurrent pneumonia in 43.5%, 32.3%, and 18.8%, respectively; and overall recurrent hospitalizations in 87%, 41.9%, and 25%, respectively. The quality of life was reportedly affected among 100%, 75%, and 33.3% respectively. CONCLUSIONS: Long-term follow-up of patients with EA +/- TEF indicates a high burden of co-morbidities during the first 6 years of life, with a gradual decrease in symptoms thereafter. Nevertheless, HRAD continued to impact the daily life of about one-third of the older adolescents, and GERD one-fifth. A long-term multidisciplinary follow-up should be conducted to prevent late onset complications that may affect the quality of life. PMID- 29527855 TI - Thyroid Disease in Pregnancy: A Clinical Survey among Endocrinologists, Gynecologists, and Obstetricians in Israel. AB - OBJECTIVES: To study the current practices in the management of subclinical hypothyroidism (SCH) and thyroid nodules during pregnancy of obstetricians/gynecologists (OB/GYNs) and endocrinologists in Israel. METHODS: An electronic questionnaire was sent by email to all members of the Israeli Endocrine Society and the Israel Society of Obstetrics and Gynecology. Questionnaires included demographic data and clinical scenarios with questions regarding the screening and management of pregnant women with SCH, hypothyroxinemia, and a palpable thyroid nodule. The questionnaire for OB/GYNs was slightly modified. RESULTS: We received 90 responses from endocrinologists and 42 responses from OB/GYNs. Among endocrinologists, 39% would repeat a thyroid stimulating hormone (TSH) test of 2.9 mU/L with normal free thyroxine and treat with thyroxine if the second result was above 2.5 mU/L. Among OB/GYNs, 73% would manage a woman with SCH at the beginning of her pregnancy by themselves and only 22% would start thyroxine after a first TSH result above 2.5 mU/L. Concerning screening, 57% endocrinologists and 71% OB/GYNs recommended screening for thyroid dysfunction in every woman at the beginning of her pregnancy. Among endocrinologists, 54% would order an ultrasound for a palpable thyroid nodule and perform a fine needle aspiration only for suspicious lesions. CONCLUSIONS: The medical approach to thyroid disease in pregnant women remains a matter of controversy. Our results support the need for larger and prospective clinical studies. PMID- 29527856 TI - The Clinical Significance of HPV Type in Women with Recurrent Cytological Atypia. AB - BACKGROUND: The human papillomavirus (HPV) test has proven to be efficient in triaging women with abnormal Pap findings in women with low cytological atypia, but there is no data about the accuracy for large loop excision of transformation zone in cases of recurrent atypia. OBJECTIVES: To assess the clinical correlation between results of HPV typing and conization histology in women who had recurrent abnormal Pap test results with no colposcopy findings. METHODS: Our retrospective cohort study included 138 women enrolled in the Maccabi Healthcare Services who had consecutive atypical Pap test results for 2 years in which no abnormal colposcopic findings were detected. These women had an HPV typing and then conization. RESULTS: Among the total study population (n=138), 71.7% had negative histology, 19.6% had <= cervical intraepithelial neoplasia grade 1 (<= CIN1), and 8.7% had CIN2+. With regard to HPV typing, 34.8% were negative and 65.2% were positive. Of those testing positive, 34.4% were positive for HPV 16 or 18. Sensitivity, specificity, positive predictive value, and negative predictive values of HPV typing for women were 89.7%, 44.4%, 38.9%, and 91.7%, respectively, and for HPV 16 or 18: 71.4%, 67.7%, 32.3%, and 100.0%, respectively. After stratification by cytological grades, for women with high-grade cervical cytology, the sensitivity and negative predictive values of the HPV typing were higher than among low-grade cervical cytology, while specificity and positive predictive values were lower. CONCLUSIONS: HPV typing is a useful tool for the management of patients with persistently abnormal Pap test results. PMID- 29527857 TI - Diagnostic Value of Serum Bilirubin and Liver Enzyme Levels in Acute Appendicitis. AB - BACKGROUND: Acute appendicitis (AA) is one of the most common indications for emergency abdominal surgery. OBJECTIVES: To assess the diagnostic and prognostic value of serum bilirubin and liver enzyme levels in the management of acute appendicitis. METHODS: Consecutive emergency department patients referred for a surgical consult for suspected AA were prospectively enrolled in the study. Data regarding demographic, clinical and laboratory results were recorded. Receiver operating characteristic (ROC) curve was performed for all evaluated parameters. Clinical and laboratory markers were evaluated for diagnostic accuracy and correlation to the clinical severity, histology reports, and length of hospital stay. RESULTS: The study was comprised of 100 consecutive patients. ROC curve analysis revealed white blood cell count, absolute neutrophils count (ANC), C reactive protein, total-bilirubin and direct-bilirubin levels as significant factors for diagnosis of AA. The combination of serum bilirubin levels, alanine transaminase levels, and ANC yielded the highest area under the curve (0.898, 95% confidence interval 0.835-0.962, P<0.001) with a diagnostic accuracy of 86%. In addition, total and direct bilirubin levels significantly correlated with the severity of appendicitis as described in the operative and pathology reports (P < 0.01). Total and direct bilirubin also significantly correlated with the length of hospital stay (P < 0.01). CONCLUSIONS: Serum bilirubin levels, alone or combined with other markers, may be considered as a clinical marker for AA correlating with disease existence, severity, and length of hospital stay. These findings support the routine use of serum bilirubin levels in the workup of patients with suspected AA. PMID- 29527858 TI - Ethnicity of Symptomatic Coronary Artery Disease Referred for Coronary Angiography in the Galilee: Prevalence, Risk Factors, and a Case for Screening and Modification. AB - BACKGROUND: Coronary artery disease (CAD) has known risk factors. Individual risks related to specific ethnicities are complex and depend on genetic predisposition and lifestyle. OBJECTIVES: To compare the nature and prevalence of risk factors in Arab and non-Arab ethnic patients with symptomatic obstructive CAD referred for coronary angiography. METHODS: CAD, defined as coronary angiography with a >= 50% narrowing in >= 1 vessel, was diagnosed in 1029 patients admitted to a medical center between April 2014 and October 2015. Patients were divided into two groups according to ethnic origin: Arab vs. non Arab. Demographics, clinical presentation, and coronary risk profiles were compared. RESULTS: The diagnosis of CAD was made during ST-elevation myocardial infarction (STEMI) in 198 patients (19%) who arrived at the clinic, 620 (60%) with unstable angina/non-STEMI, and 211 (21%) with stable angina. Patients with symptomatic CAD and Arab ethnicity were 47% more prevalent than non-Arab patients presenting with CAD. The Arab patients were appoximately 5 years younger, 50% more likely to be active smokers, 25% more likely to be obese, and more likely to have a family history of CAD. Other coronary risk factors were similar between the two groups. CONCLUSIONS: Smoking and obesity, which are potentially modifiable CAD risk factors, stood out as major risk factors, in addition to genetic disposition, among Arab and non-Arab patients with symptomatic CAD. Screening and educational interventions for smoking cessation, obesity control, and compliance to treatment of co-morbidities should be attempted in order to decrease CAD in the Arab population. PMID- 29527859 TI - Outcome of Idiopathic Membranous Nephropathy: A Retrospective Study. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common causes of nephrotic syndrome (NS) in Caucasian adults. Most patients have good renal prognosis, but 30-40% may progress to end stage renal disease (ESRD). OBJECTIVES: To evaluate the efficacy and safety of immunosuppressive treatment (IST) in high-risk patients. METHODS: All IMN patients diagnosed by kidney biopsy from 2004-2010 were included. Clinical and laboratory data were collected at each follow-up visit. Risk assessment for renal progression classified patients as high risk if: 24 hour protein excretion > 6 g/day, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, and severe disabling or life threatening clinical symptoms of NS were present. RESULTS: Among 290 biopsies, 37 patients (12.7%) were IMN. They were allocated to the high-risk IST group (n=16) or low-risk supportive treatment (ST) group (n=21) according to the likelihood of developing renal failure. Mean follow-up was 47 +/- 17.3 months. Complete and partial remission rate was 68.7% for high-risk IST vs. 90.4% for low-risk ST. In the high-risk IST group, eGFR was significantly lower at 30 months (65.5 +/- 28.6 vs. 85.3 +/- 21.6 at baseline, P < 0.05). Four high-risk patients reached ESRD. In the low-risk ST group, eGFR remained stable at 30 and 60 months. CONCLUSIONS: This study showed a high remission rate for IMN. IST with prednisolone and cyclophosphamide provided favorable renal outcomes in most high-risk patients. The very high remission rate obtained in the low-risk patients confirms the adequacy of supportive treatment in this group. PMID- 29527860 TI - Recurrent Pericarditis: Is Immunotherapy the Answer? PMID- 29527861 TI - Possible Autoimmune Primary Ovarian Insufficiency in Patients with Selective IgA Deficiency. PMID- 29527862 TI - Challenges in the Diagnosis of Cytomegalovirus Colitis in a Presumed Immunocompetent Patient: Interpretation of Clinical Condition, Tissue, and Serum Cytomegalovirus Polymerase Chain Reaction Findings. PMID- 29527863 TI - Primary Marginal Zone Lymphoma of the Lung and Organizing Pneumonia: A Diagnostic Challenge. PMID- 29527864 TI - Left ventricular support during complex transradial percutaneous coronary intervention for complete revascularization. AB - Although there is not uniform definition of high-risk percutaneous coronary intervention (PCI), patients with severe three-vessel disease, left main disease, single remaining patent vessel and/or depressed left ventricular ejection fraction are considered a high-risk population. In this setting, periprocedural hemodynamic instability represents a serious issue. Percutaneous mechanical circulatory support (MCS) devices may improve both safety and efficacy of high risk PCI. Indeed, MCS help to maintain coronary perfusion pressure and reduce myocardial workload, providing the operator sufficient time to reach the target of complete revascularization. The most used MCS are intra-aortic balloon pump and Impella. There are a plenty of data in literature about the efficacy and safety of the use of MCS in high risk PCI performed through the femoral access. However there is a paucity of data about the use of MCS in transradial high risk PCI. Radial over femoral access has been showed to reduce bleeding complications and therefore may further improve the outcome of high risk PCI. Herein we report a case of transradial high risk PCI supported by the Impella 2.5 L and review the available data on this topic. PMID- 29527865 TI - Delivering ultimate bifurcation treatment. AB - Coronary bifurcation lesions are accounted in about 20% of all percutaneous coronary interventions and despite all-round improvements in their treatment are still perceived as complex lesion subset in interventional cardiology. Treatment of bifurcations, being technically demanding primarily due to the unique bifurcation anatomy, is related to lower procedural success rate and increased rates of long-term adverse cardiac events. According to published data, provisional approach remains a default strategy for majority of bifurcation PCI, but when perfected, two-stent bifurcation techniques can also yield good clinical outcomes. In this paper, we summarize in stepwise fashion technical aspects of optimal, evidence-based bifurcation treatment aiming to accomplish best procedural results and favorable long-term prognosis. PMID- 29527866 TI - Percutaneous coronary intervention in patients refused from surgery: a different entity? AB - Patients with left main or multivessel coronary artery disease (CAD) and depressed left ventricular function undergoing coronary artery by-pass grafting (CABG) have a markedly worse prognosis compared with general population. As a consequence, these patients are often refused for surgical revascularization. At the same time, surgical ineligibility is associated with poor clinical outcome when these patients are referred for percutaneous coronary intervention (PCI). However, recent studies suggest that a revascularization strategy with a protected percutaneous coronary intervention (PCI) using a mechanical assistance device may be a viable alternative. In particular, the development of percutaneous left ventricular assist devices such as Impella has been an important step to facilitate the care of these high-risk patients. In this review we discuss about conditions for surgical ineligibility and the clinical outcome of PCI in high-risk patients ineligible for surgery. Moreover, we discuss about the evidences supporting the use of Impella in high-risk patients ineligible for surgery. PMID- 29527867 TI - Orthodontics and Moebius syndrome: an observational study. AB - BACKGROUND: Moebius syndrome is a rare condition characterized by bilateral facial and abducens nerve paralysis. The aim of this study is to evaluate the main orthodontic features and the frequency of associated clinical characteristics in patients with Moebius syndrome (MS). METHODS: According to Terzis classifications, 58 patients with MS aged 8 months to 46 years old underwent orthodontics and clinical examination. RESULTS: Strabismus, upper and lower limb malformations, lip and palatal cleft were frequently associated with MS. Reduced TM movements were noted (48%). Cephalometric analysis did not allow identifying a typical facies and a characteristic cephalometric pattern; we have noticed a higher prevalence of Class II (56%) with micrognathia and excessive maxillary development probably due to the lack of lip seal. Early treatment is recommended, with a multidisciplinary approach to reduce the impact of sequelae on the lives of MS patients or their families. CONCLUSIONS: Early treatment is recommended, with a multidisciplinary approach to diminish the impact of sequelae on the lives of MS patients or their families. PMID- 29527868 TI - Cryobiology of ovarian tissues: known knowns and known unknowns. AB - To model the cryobiological responses of cells and tissues, the cellular membrane permeability characteristics are often measured at suprazero temperatures as well as at subzero temperatures with and without the presence of extra-cellular ice. These measured membrane permeability characteristics are then used to predict the responses of cells and tissues for a given thermal insult with the ultimate aim of mitigating the damage caused during the freeze-thaw process. This brief review articles summarizes efforts from my research group over the past 15 years as related to cryobiology of mammalian ovarian tissue sections, i.e., the known knowns as well as the critical cryobiological knowledge that is still lacking to rationally design optimal cryopreservation protocols for ovarian tissues, i.e., the known unknowns. PMID- 29527869 TI - Vitrification of human oocytes. AB - In recent years, growing evidence for the safety and efficiency of oocyte vitrification has made this technique be increasingly proposed for fertility preservation (FP). The populations who could benefit from FP include oncological patients who need the option to preserve their gametes before undergoing potential sterilizing treatment, patients with non-oncologic conditions requiring gonadotoxic chemotherapy and women who wish to delay their motherhood for a variety of reasons. By vitrifying oocytes, women have the chance to conceive in the future, have their own genetic offspring and maintain their reproductive autonomy. This review focuses on describing current knowledge on oocyte vitrification as a means to preserve female fertility. We present the general experience of our group and others in FP for both oncological and non-oncological reasons. PMID- 29527887 TI - Immunological, vascular, metabolic, and autonomic changes seen with aging possible implications for poor outcomes in the elderly following decompressive hemicraniectomy for malignant MCA stroke: a critical review. AB - Stroke is one of the leading causes of mortality and morbidity worldwide and requires rapid and intensive treatment to prevent adverse outcomes. Decompressive hemicraniectomy stands as the gold standard for surgical resolution of the intracranial swelling which accompanies cerebral infarction; however, the benefits of this procedure are not as well achieved in the elderly (age >65 yoa) compared to the younger population. This is a critical review performed on all available literature relating to middle cerebral artery (MCA) stroke in the elderly with emphasis on articles examining causality of adverse outcomes in this group over younger populations. Utilizing PRISMA guidelines, we initially identified 1462 articles. After screening, four clear areas of physiological change associated with aging were identified and expounded upon as they relate to MCA stroke. These four areas include: immunological, autonomic, mitochondrial, and vascular changes. Elderly patients have a decreased and declining capacity to regulate the inflammation that develops post infarction and this contributes to adverse outcomes from a neurological stand point. Additionally, aging decreases the ability of elderly patients to regulate their autonomic system resulting in aberrant blood pressures systemically post infarction. With age, the mitochondrial response to ischemia is exaggerated and causes greater local damage in elderly patients compared to younger populations. Finally, there are numerous vascular changes that occur with age including accumulation of homocysteine and atherosclerosis which together contributed to decreased structural integrity of the vasculature in the elderly and render decreased support to the recovery process post infarction. We conclude that physiological changes inherent in the aging process serve to intensify adverse outcomes that are commonly associated with strokes in the elderly. Identification and subsequent minimization of these risk factors could allow for more effective management of elderly patients, post stroke, and promote better clinical outcomes. PMID- 29527888 TI - Reanalyzing the "far medial" (transcondylar-transtubercular) approach based on three anatomical vectors: the ventral posterolateral corridor. AB - Endoscopic endonasal access to the jugular foramen and occipital condyle - the transcondylar-transtubercular approach - is anatomically complex and requires detailed knowledge of the relative position of critical neurovascular structures, in order to avoid inadvertent injury and resultant complications. However, access to this region can be confusing as the orientation and relationships of osseous, vascular, and neural structures are very much different from traditional dorsal approaches. This review aims at providing an organizational construct for a more understandable framework in accessing the transcondylar-transtubercular window. The region can be conceptualized using a three-vector coordinate system: vector 1 represents a dorsal or ventral corridor, vector 2 represents the outer and inner circumferential anatomical limits; in an "onion-skin" fashion, key osseous, vascular, and neural landmarks are organized based on a 360-degree skull base model, and vector 3 represents the final core or target of the surgical corridor. The creation of an organized "global-positioning system" may better guide the surgeon in accessing the far-medial transcondylar-transtubercular region, and related pathologies, and help understand the surgical limits to the occipital condyle and jugular foramen - the ventral posterolateral corridor - via the endoscopic endonasal approach. PMID- 29527889 TI - The limits of the endoscopic endonasal transclival approach for posterior fossa tumors. AB - Endoscopic endonasal approaches (EEA) have gained popularity and acceptance in skull base surgery over the last two decades. So-called expanded EEA allow access in the sagittal plane from the frontal sinus to the odontoid process. The endoscopic endonasal transclival approach allows a unique trajectory into the midline clivus and skull base that is unachievable from traditional craniotomy approaches to lesions such as chondrosarcomas, chordomas, and posterior fossa meningiomas. In this review, we will assess the benefits and drawbacks to using an endoscopic endonasal approach versus transcranial approach to these challenging lesions, assess the anatomical limits of endoscopic endonasal transclival surgery, and discuss the published literature on the topic. PMID- 29527890 TI - Squaraine Dye for a Visibly Transparent All-Organic Optical Upconversion Device with Sensitivity at 1000 nm. AB - Efficient light detection in the near-infrared (NIR) wavelength region is central to emerging applications such as medical imaging and machine vision. An organic upconverter (OUC) consists of a NIR-sensitive organic photodetector (OPD) and an visible organic light-emitting diode (OLED), connected in series. The device converts NIR light directly to visible light, allowing imaging of a NIR scene in the visible. Here, we present an OUC composed of a NIR-selective squaraine dye based OPD and a fluorescent OLED. The OPD has a peak sensitivity at 980 nm and an internal photon-to-current conversion efficiency of ~100%. The OUC conversion efficiency (0.27%) of NIR to visible light is close to the expected maximum. The materials of the OUC multilayer stack absorb very little light in the visible wavelength range. In combination with an optimized semitransparent metal top electrode, this enabled the fabrication of transparent OUCs with an average visible transmittance of 65% and a peak transmittance of 80% at 620 nm. Visibly transparent OUCs are interesting for window-integrated electronic circuits or imaging systems that allow for the simultaneous detection of directly transmitted visible and NIR upconverted light. PMID- 29527891 TI - Geochemical Effects of Millimolar Hydrogen Concentrations in Groundwater: An Experimental Study in the Context of Subsurface Hydrogen Storage. AB - Hydrogen storage in geological formations is one of the most promising technologies for balancing major fluctuations between energy supply from renewable energy plants and energy demand of customers. If hydrogen gas is stored in a porous medium or if it leaks into a shallow aquifer, redox reactions can oxidize hydrogen and reduce electron acceptors such as nitrate, FeIII and MnIV (hydro)oxides, sulfate, and carbonate. These reactions are of key significance, because they can cause unintentional losses in hydrogen stored in porous media and they also can cause unwanted changes in the composition of protected potable groundwater. To represent an aquifer environment enclosing a hydrogen plume, laboratory experiments using sediment-filled columns were constructed and percolated by groundwater in equilibrium with high (2-15 bar) hydrogen partial pressures. Here, we show that hydrogen is consumed rapidly in these experiments via sulfate reduction (18 +/- 5 MUM h-1) and acetate production (0.030 +/- 0.006 h-1), while no methanogenesis took place. The observed reaction rates were independent from the partial pressure of hydrogen and hydrogen consumption only stopped in supplemental microcosm experiments where salinity was increased above 35 g L-1. The outcomes presented here are implemented for planning the sustainable use of the subsurface space within the ANGUS+ project. PMID- 29527892 TI - Asymmetric Total Synthesis of Dragonbloodins A1 and A2. AB - The first asymmetric total synthesis of dragonbloodins A1 and A2, a pair of unprecedented chalcone-flavan heterotrimmers, has been achieved through a series of rationally designed or bioinspired transformations. Key elements of the synthesis include a highly efficient heterotrimerization reaction to assemble the two chalcone units and one flavan unit in one pot and a tandem oxidative dearomatization/cyclization/oxygenation reaction to forge the polycyclic core of dragonbloodins A1 and A2. The present synthesis unambiguously confirms the biogenetic relationship and absolute stereochemistry of dragonbloodins A1 and A2. PMID- 29527893 TI - Synthesis and Properties of the p-Sulfonamide Analogue of the Green Fluorescent Protein (GFP) Chromophore: The Mimic of GFP Chromophore with Very Strong N-H Photoacid Strength. AB - The para-sulfonamide analogue ( p-TsABDI) of a green fluorescent protein (GFP) chromophore was synthesized to mimic the GFP chromophore. Its S1 excited-state p Ka* value in dimethylsulfoxide (DMSO) is -1.5, which is strong enough to partially protonate dipolar aprotic solvents and causes excited-state proton transfer (ESPT), so it can partially mimic the GFP chromophore to further study the ESPT-related photophysics and the blinking phenomenon of GFP. In comparison with 8-hydroxypyrene-1,3,6-trisulfonate (HPTS) (p Ka = 7.4, p Ka* = 1.3 in water), p-TsABDI (p Ka = 6.7, p Ka* = -1.5 in DMSO) is a better photoacid for pH jump studies. PMID- 29527894 TI - Per- and Polyfluoroalkyl Substances in Swedish Groundwater and Surface Water: Implications for Environmental Quality Standards and Drinking Water Guidelines. AB - The aim of this study was to assess per- and polyfluoroalkyl substances (PFASs) in the Swedish aquatic environment, identify emission sources, and compare measured concentrations with environmental quality standards (EQS) and (drinking) water guideline values. In total, 493 samples were analyzed in 2015 for 26 PFASs (?26PFASs) in surface water, groundwater, landfill leachate, sewage treatment plant effluents and reference lakes, focusing on hot spots and drinking water sources. Highest ?26PFAS concentrations were detected in surface water (13 000 ng L-1) and groundwater (6400 ng L-1). The dominating fraction of PFASs in surface water were perfluoroalkyl carboxylates (PFCAs; 64% of ?26PFASs), with high contributions from C4-C8 PFCAs (94% of ?PFCAs), indicating high mobility of shorter chain PFCAs. In inland surface water, the annual average (AA)-EQS of the EU Water Framework Directive of 0.65 ng L-1 for ?PFOS (linear and branched isomers) was exceeded in 46% of the samples. The drinking water guideline value of 90 ng L-1 for ?11PFASs recommended by the Swedish EPA was exceeded in 3% of the water samples from drinking water sources ( n = 169). The branched isomers had a noticeable fraction in surface- and groundwater for perfluorooctanesulfonamide, perfluorohexanesulfonate, and perfluorooctanesulfonate, highlighting the need to include branched isomers in future guidelines. PMID- 29527895 TI - Electrophilic Borylation of Terminal Alkenes with BBr3/2,6-Disubstituted Pyridines. AB - A variety of terminal alkenes, as well as heteroaromatic compounds, are borylated by the combined use of BBr3/2,6-dichloropyridine (B3) or BBr3/2,6-lutidine (B5). alpha,alpha-Diarylalkenes prefer the former reagent combination, while other alkenes prefer the latter. Mechanistic considerations strongly suggest that the former and latter reactions proceed through electrophilic substitution reactions with BBr3 and [BBr2.B5]+BBr4-, respectively. PMID- 29527896 TI - Picosecond Solvation Dynamics in Nanoconfinement: Role of Water and Host-Guest Complexation. AB - The dynamics of solvation of an excited chromophore, 5-(4"-dimethylaminophenyl)-2 (4'-sulfophenyl)oxazole, sodium salt (DMO), has been explored in confined nanoscopic environments of beta-cyclodextrin (betaCD) and heptakis(2,6-di- O methyl)-beta-cyclodextrin (DIMEB). Solvation occurs on a distinctly slower time scale (tauS3 ~ 47 ps, tauS4 ~ 517 ps) in the host cavity of DIMEB than in that of betaCD (tauS3 ~ 20 ps, tauS4 ~ 174 ps). The calculated equilibrium solvation response of DMO was characterized by four relaxation components (tauS1 ~ 0.46 0.48 ps, tauS2 ~ 3.2-3.4 ps, tauS3 ~ 32.3-37.7 ps, and tauS4 ~ 232-485 ps), of which the longer ones (tauS3, tauS4) are well-consistent with experiments, whereas the ultrafast components (tauS1, tauS2) are unresolved. The observed time constant (tauS3) within the ~20-47 ps range arises from slow water molecules in the primary hydration layers of the host CDs and is slower for DIMEB than for betaCD presumably due to longer-lived and stronger hydrogen bonds that water forms with the former host relative to the latter. Decomposition of the calculated solvation response of DMO has revealed that conformational fluctuations of the macrocyclic hosts give rise to the observed long-time relaxation component (tauS4), which is much slower for the inclusion complexes with DIMEB than for those with betaCD because of slower conformational dynamics of the former host than that of the latter. PMID- 29527897 TI - Biodegradable Polymer with Hydrolysis-Induced Zwitterions for Antibiofouling. AB - Persistent protein resistance is critical for marine antibiofouling. We have prepared copolymer of 2-methylene-1,3-dioxepane (MDO), tertiary carboxybetaine ester (TCB), and 7-methacryloyloxy-4-methylcoumarin (MAMC) via radical ring opening polymerization, where MDO, TCB, and MAMC make the polymer degradable, protein resistible, and photo-cross-linkable, respectively. Our study shows that the polymer can well adhere to the substrate with controlled degradation and water adsorption rate in artificial seawater (ASW). Particularly, the polymer film can generate zwitterions via surface hydrolysis in ASW. Quartz crystal microbalance with dissipation measurements reveal that such hydrolysis-induced zwitterionic surface can effectively resist nonspecific protein adsorption. Moreover, the surface can inhibit the adhesion of marine bacteria Pseudomonas sp. and Vibrio alginolyticus as well as clinical bacterium Escherichia coli. PMID- 29527898 TI - Gas-Phase Ion Spectroscopy of Congo Red Dianions and Their Complexes with Betaine. AB - Congo Red (CR) is an azo dye that is negatively charged in aqueous solutions. Here we report on the intrinsic electronic properties of CR dianions from mass spectroscopy experiments on bare dianions and their complexes with betaine (B). As betaine is a zwitterion, it possesses a large dipole moment and is a good reporter on the sensitivity of CR to microenvironmental changes. Photoexcitation of CR2- in the visible region resulted in several fragment ions after absorption of at least three photons, with major fragmentation routes due to breakage of one or both C-NN bonds, one azo linkage, and/or the bonds to sulfite. Their yields as a function of excitation wavelength reveal a broad absorption in the visible region with the lowest-energy band located at ~500 nm. Features are observed with a spacing of ~1500 cm-1. One photon was sufficient to dissociate CR2-.B, and its action spectrum was almost identical to those of CR2- in accordance with previous findings that a symmetric ion is essentially unaffected by changes in its microenvironment. Electron detachment occurs in the UV with threshold energy of 3.6 +/- 0.1 eV for CR2- and 3.81 +/- 0.06 eV for CR2-.B. Attempts to measure fluorescence from photoexcited CR2- were unsuccessful. PMID- 29527899 TI - Photo-Driven Synthesis of C6-Polyfunctionalized Phenanthridines from Three Component Reactions of Isocyanides, Alkynes, and Sulfinic Acids by Electron Donor Acceptor Complex. AB - A novel and efficient photoinduced synthesis of C6-polyfunctionalized phenanthridines from three-component reactions of isocyanides, alkynes and sulfinic acids was developed. The reactions generated the corresponding products with high selectivity through the photochemical activity of the formed electron donor-acceptor (EDA) complex during the reaction via a radical tandem process under mild conditions. PMID- 29527900 TI - Synthesis of Alkyl Indium Reagents by Using Unactivated Alkyl Chlorides and Their Applications in Palladium-Catalyzed Cross-Coupling Reactions with Aryl Halides. AB - An efficient method for the preparation of alkyl indium reagents by using unactivated and cheap alkyl chlorides as substrates in the presence of indium and LiI was developed. The thus-formed alkyl indium species effectively underwent palladium-catalyzed cross-coupling reactions with aryl halides with wide functional group tolerance. PMID- 29527901 TI - Pancreatic panniculitis as a presentation symptom of acinar cell carcinoma. AB - Pancreatic panniculitis is a rare skin manifestation associated with pancreatic conditions. This condition has similar characteristics to those of other panniculitis types and its course parallels the triggering condition and may occasionally precede it. We report the case of a female patient with asymptomatic pancreatic panniculitis; the etiologic study identified a pancreatic acinar cell carcinoma with liver metastases. PMID- 29527902 TI - Tender red subcutaneous nodules in an adult female: a challenging diagnosis. AB - Pancreatic panniculitis is an uncommon and rare skin complication of systemic fat necrosis associated with pancreatitis post-ampullectomy. Besides the rarity of the condition, the clinical history and physical examination for diagnosis is also important. PMID- 29527903 TI - Update of the SEPD position statement on the use of biosimilars for inflammatory bowel disease. AB - In 2013, the European Medicines Agency (EMA) approved the biosimilar infliximab (CT-P13) for the full range of indications of the originator product, based on data from two trials conducted in rheumatoid arthritis and ankylosing spondylitis. The same year, our Society published a position statement that was later reviewed. PMID- 29527904 TI - Using the internet to evaluate the opinion of patients with inflammatory bowel disease with regard to the available information. AB - BACKGROUND AND AIMS: patients need information for shared decision making. The aims of the study were to ascertain how patients with inflammatory bowel disease (IBD) felt about the information available and the way that their doctors informed them. In addition, how patients used the internet and factors that predicted a positive information evaluation were also assessed. METHOD: a 39-item survey was designed that was distributed via the internet, principally using a Spanish Facebook site. RESULTS: four hundred and twenty completed surveys were received. Patients rated the information available with a mean of 8 points (maximum of 10) and 71% felt that their doctor informed them well or very well. Various deficiencies were found such as little information available at the time of diagnosis (58%); doubts after seeing the specialist (70%); insufficient information about IBD complications, disease course and dietary aspects; and a lack of appropriate internet webpage recommendations from specialists or pharmacists. Patients ranked the internet fourth as an information source, followed by their specialist, patient associations and other patients. Independent predictive factors of feeling well informed (>= 8) included age, OR 1.539 (CI 1.047-2.261), p = 0.028; education, OR 1.544 (CI 1.110-2.147), p = 0,010; IBD evolution time, OR 1.267 (CI 1.003-1,601), p = 0.047; and good or very good information from the specialist, OR 3.262 (CI 2.425-4.388), p < 0.001. CONCLUSIONS: patients generally felt that they were well informed. However, there were aspects that needed improvement, such as information for younger patients or a lower education level, the information provided at diagnosis, information about specific or insufficiently covered IBD aspects and suggestions from doctors about high quality websites. PMID- 29527905 TI - Outbreak of acute hepatitis A in the health area served by the Hospital Universitario Virgen de la Victoria (HUVV): a change in epidemiology. AB - In 2016, an outbreak of hepatitis A was identified in the Malaga province among patients with specific epidemiological characteristics, which were predominantly males. This is a report of 51 subjects with acute hepatitis A and a mean age of 35.7 years, 90% were male and 55% of cases were men who had had sex with other men within the last two months. Half of them required hospitalization for significant coagulopathy at diagnosis and no cases progressed to fulminant failure or encephalopathy. Four patients had ascites at the time of diagnosis. This outbreak adds to those reported in the United Kingdom and the Netherlands with a similar number of cases and epidemiology. These studies highlight the importance of epidemiological surveillance, the need for vaccination in this particular at risk population and the need for informative campaigns in order to prevent this disease. PMID- 29527906 TI - Consequences of a Dieulafoy's lesion in gastric surgery. AB - In relation to the articles published in this journal by Valdivielso-Cortazar and Relea-Perez, we have recently operated a patient who presented a digestive hemorrhage in immediate postoperative period due to Dieulafoy's lesion at the mechanical gastrojejunal anastomosis. PMID- 29527907 TI - Transcription regulators and hormones involved in the development of brown fat and white fat browning: transcriptional and hormonal control of brown/beige fat development. AB - The high prevalence of obesity and related metabolic complications has inspired research on adipose tissues. Three kinds of adipose tissues are identified in mammals: brown adipose tissue (BAT), beige or brite adipose tissue and white adipose tissue (WAT). Beige adipocytes share some characteristics with brown adipocytes such as the expression of UCP1. Beige adipocytes can be activated by environmental stimuli or pharmacological treatment, and this change is accompanied by an increase in energy consumption. This process is called white browning, and it facilitates the maintenance of a lean and healthy phenotype. Thus, promoting beige adipocyte development in WAT shows promise as a new strategy in treating obesity and related metabolic consequences. In this review, we summarized the current understanding of the regulators and hormones that participate in the development of brown fat and white fat browning. PMID- 29527908 TI - Novel patterns of left ventricular mechanical activity during experimental cardiac arrest in pigs. AB - We conducted an experimental study to evaluate the presence of coordinated left ventricular mechanical myocardial activity (LVMA) in two types of experimentally induced cardiac arrest: ventricular fibrillation (VF) and pulseless electrical activity (PEA). Twenty anesthetized domestic pigs were randomized 1:1 either to induction of VF or PEA. They were left in nonresuscitated cardiac arrest until the cessation of LVMA and microcirculation. Surface ECG, presence of LVMA by transthoracic echocardiography and sublingual microcirculation were recorded. One minute after induction of cardiac arrest, LVMA was identified in all experimental animals. In the PEA group, rate of LVMA was of 106+/-12/min. In the VF group, we identified two patterns of LVMA. Six animals exhibited contractions of high frequency (VFhigh group), four of low frequency (VFlow group) (334+/-12 vs. 125+/ 32/min, p<0.001). A time from cardiac arrest induction to asystole (19.2+/-7.2 vs. 7.3+/-2.2 vs. 8.3+/-5.5 min, p=0.003), cessation of LVMA (11.3+/-5.6 vs. 4.4+/-0.4 vs. 7.4+/-2.9 min, p=0.027) and cessation of microcirculation (25.3+/ 12.6 vs. 13.4+/-2.4 vs. 23.2+/-8.7 min, p=0.050) was significantly longer in VFlow group than in VFhigh and PEA group, respectively. Thus, LVMA is present in both VF and PEA type of induced cardiac arrest and moreover, VF may exhibit various patterns of LVMA. PMID- 29527909 TI - The metabolism of 5-methylcytosine residues in DNA. AB - The fundamental biochemical processes of 5-methylcytosine (5-mC) synthesis, maintenance, conversion and removal determine the time and spatial pattern of DNA methylation. This has a strong effect on a plethora of physiological aspects of cellular metabolism. While the presence of 5-mC within the promoter region can silence gene expression, its derivative - 5-hydroxymethylcytosine exerts an opposite effect. Dysregulations in the metabolism of 5-mC lead to an altered DNA methylation pattern which is linked with a disrupted epigenome, and are considered to play a significant part in the etiology of several human diseases. A summary of recent knowledge about the molecular processes participating in DNA methylation pattern shaping is provided here. PMID- 29527910 TI - Differences in muscle metabolism in patients with type I diabetes - influence of gender and nephropathy studied by (31)P MR spectroscopy. AB - Type I diabetes mellitus (DM1) is a complex disease with adverse effects on organs and tissues despite compensation by insulin treatment. The goal of our study was to study how kidney diseases change (31)P MR parameters of muscle metabolism in DM1 patients with respect to gender. 51 DM1 patients (19 m/14 f without and 13 m/5 f with nephropathy) and 26 (14 m/12 f) healthy volunteers were examined using (31)P magnetic resonance spectroscopy at 3T tomograph at rest, and during and after a calf muscle exercise. The exercise consisted of a six-minute plantar flexion using a pedal ergometer followed by a six-minute recovery. It is reflected by reduced relative beta-ATP and increased Pi and phosphodiester signals to phosphocreatine (PCr) at rest and prolongation of the PCr recovery time after the exercise. Measurement on healthy volunteers indicated differences between males and females in pH at the rest and after the exercise only. These differences between patients groups were not significant. We have proven that nephropathy affects the metabolism in diabetic patients and our results confirm significant difference between patients with and without nephropathy. Gender differences in pH were observed only between male and female healthy volunteers. PMID- 29527911 TI - Alcohol and fetoplacental vasoconstrictor reactivity. AB - Alcohol abuse during pregnancy is a well-known factor in fetal morbidity, including smaller fetal size. We have shown that chronic hypoxia, considered the main pathogenetic factor in intrauterine growth restriction, elevates fetoplacental vascular resistance (and vasoconstrictor reactivity) and thus, presumably, reduces placental blood flow. We thus hypothesized that alcohol may affect the fetus - in addition to other mechanisms - by altering fetoplacental vascular resistance and/or reactivity. Using isolated, double-perfused rat placenta model, we found that maternal alcohol intake in the last third of gestation doubled the vasoconstrictor responses to angiotensin II but did not affect resting vascular resistance. Reactivity to acute hypoxic challenges was unchanged. Chronic maternal alcohol intake in a rat model alters fetoplacental vasculature reactivity; nevertheless, these changes do not appear as serious as other detrimental effects of alcohol on the fetus. PMID- 29527912 TI - Brain-derived neurotrophic factor modulates intestinal barrier by inhibiting intestinal epithelial cells apoptosis in mice. AB - We aimed to investigate the effects of brain-derived neurotrophic factor (BDNF) on apoptosis of intestinal epithelial cells (IECs) and alterations of intestinal barrier integrity using BDNF knock-out mice model. Colonic tissues from BDNF(+/+) mice and BDNF(+/-) mice were prepared for this study. The integrity of colonic mucosa was evaluated by measuring trans-mucosa electrical resistance and tissue conductance in Ussing chamber. The colonic epithelial structure was analyzed by transmission electron microscopy. Apoptosis involvement was determined with TUNEL staining, active caspase-3 immunostaining and Western blotting for the protein expression of active caspase-3, Bax and Bcl-2. The expression levels and distribution of tight junction proteins were evaluated by immunohistochemistry or Western blots. Compared with BDNF(+/+) mice, BDNF(+/-) mice displayed impaired integrity and ultrastructure alterations in their colonic mucosa, which was characterized by diminished microvilli, mitochondrial swelling and epithelial cells apoptosis. Altered intestinal barrier function was linked to excessive apoptosis of IECs demonstrated by the higher proportion of TUNEL-positive apoptotic cells and enhanced caspase activities in BDNF(+/-) mice. Increased expression of Bax and claudin-2 proteins and reduced Bcl-2 and tight junction proteins (occludin, ZO-1 and claudin-1) expression were also detected in the colonic mucosa of BDNF(+/-) mice. BDNF may play a role in the maintenance of intestinal barrier integrity via its anti-apoptotic properties. PMID- 29527913 TI - Diabetic macular edema-like ocular lesions in male spontaneously diabetic torii fatty rats. AB - Diabetic macular edema (DME) is a major factor contributing to visual disabilities in diabetic patients, and the number of patients is increasing. Animal models play a key role in the development of novel therapies. In this study, pathophysiological analyses of ocular lesions in Spontaneously Diabetic Torii (SDT) fatty rats were performed. First, vascular endothelial growth factor (VEGF) concentrations in vitreous humor, retinal vascular permeability and retinal thickness were measured in SDT fatty rats (Experiment 1). Furthermore, the pharmacological effects of two anti-diabetic drugs, phlorizin and pioglitazone, on retinal lesions were evaluated (Experiment 2). As results, the SDT fatty rats exhibited VEGF increase in vitreous humor at 8 and 16 weeks of age, and both retinal vascular hyperpermeability and retinal thickening at 16 weeks of age. In particular, the layers between the retinal internal limiting membrane and the outer nuclear layer were thickened. Phlorizin treatment from 4 to 16 weeks of age improved hyperglycemia and normalized retinal thickness; however, the effect of pioglitazone on retinal thickness was not strong despite the normalization of hyperglycemia. These data demonstrate that the male SDT fatty rat is a useful model for developing new therapeutic approaches in DME. PMID- 29527915 TI - Age-dependent effect of long-term microwave radiation on postnatal neurogenesis in rats: morphological and behavioral study. AB - Processes of adult neurogenesis can be influenced by environmental factors. Here, we investigated the effect of microwave radiation (MWR) on proliferation and cell dying in the rat rostral migratory stream (RMS) - a migration route for the neuroblasts of the subventricular zone. Adult and juvenile (two weeks old) rats were exposed to a pulsed-wave MWR at the frequency of 2.45 GHz for 1 or 3 h daily during 3 weeks. Adult rats were divided into two groups: without survival and with two weeks survival after irradiation. Juvenile rats survived till adulthood, when were tested in the light/dark test. Proliferating cells in the RMS were labeled by Ki-67; dying cells were visualized by Fluoro-Jade C histochemistry. In both groups of rats irradiated as adults we have observed significant decrease of the number of dividing cells within the RMS. Exposure of juvenile rats to MWR induced only slight decrease in proliferation, however, it strikingly affected cell death even two months following irradiation. In addition, these rats displayed locomotor hyperactivity and decreased risk assessment in adulthood. Our results suggest that the long-lasting influence of radiation is manifested by affected cell survival and changes in animals' behavior. PMID- 29527914 TI - Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto caval fistula. AB - We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF. PMID- 29527916 TI - The influence of testosterone on the expression and function of vitamin D(3) receptor (VDR) protein in the porcine ovarian follicle. AB - Recently it has been shown that vitamin D(3) acting via its cognate receptor (VDR) regulates the growth, differentiation and function of female reproductive tissues including ovary. The aim of the study was to examine the effect of testosterone (T) and its antagonist 2-hydroxyflutamide (HF) on VDR protein expression and function in porcine ovarian follicles. Medium size antral follicles expressing great amount of androgen receptors and represent high steroidogenic activity were used in this research. After 6 h incubation of whole follicles with T, HF or T+HF, immunohistochemical analysis of VDR revealed its nuclear localization in granulosa and theca interna cells in control and experimental groups. The expression of VDR protein was shown as a band of 48 kDa. There were no significant differences between either experimental group and the control. T influenced the function of VDR through decreased formation of VDR/RXR (retinoid X receptor) complexes (P<0.05) in both granulosa and theca interna cells, but HF abolished this effect only in granulosa cells (P<0.05). These results suggest that androgens regulate the response of follicular cells to vitamin D3 in pigs ovary via regulation of VDR transcriptional activity. PMID- 29527917 TI - Circadian leptin concentration changes in critically ill heart failure patients. AB - Physiologically, leptin concentration is controlled by circadian rhythm. However, in critically ill patients, circadian rhythm is disrupted. Thus we hypothesized that circadian leptin concentration changes are not preserved in critically ill patients. Ten consecutive critically ill heart failure patients with the clinical indication for mechanical ventilation and sedation were included into our study. Plasma leptin concentration was measured every 4 h during the first day (0-24 h) and during the third day (48-72 h) after admission. During the first day, there were significant leptin concentration changes (ANOVA, p<0.05), characterized by an increase in concentration by 44 % (16-58 %); p=0.02 around noon (10 am-2 pm) and then a decrease in concentration by 7 % (1-27 %); p=0.04 in the morning (2 am 6 am). In contrast, there was no significant change in leptin concentration during the third day after admission (ANOVA, p=0.79). Based on our preliminary results, we concluded that in critically ill heart failure patients, the circadian rhythm of plasma leptin concentration seems to be preserved during the first but not during the third day after admission. PMID- 29527918 TI - Modulation of iris sphincter and ciliary muscles by urocortin 2. AB - Urocortin 2 (UCN2) is a peptide related to corticotropin-releasing factor, capable of activating CRF-R2. Among its multisystemic effects, it has actions in all 3 muscle subtypes. This study's aim was to determine its potential role in two of the intrinsic eye muscle kinetics. Strips of iris sphincter (rabbit) and ciliary (bovine) muscles were dissected and mounted in isometric force-transducer systems filled with aerated-solutions. Contraction was elicited using carbachol (10(-6) M for iris sphincter, 10(-5) M for ciliary muscle), prior adding to all testing substances. UCN2 induced relaxation in iris sphincter muscle, being the effect maximal at 10(-7) M concentrations (-12.2 % variation vs. control). This effect was abolished with incubation of indomethacin, antisauvagine-30, chelerytrine and SQ22536, but preserved with L-nitro-L-arginine. In carbachol pre stimulated ciliary muscle, UCN2 (10(-5) M) enhanced contraction (maximal effect of 18.2 % increase vs. control). UCN2 is a new modulator of iris sphincter relaxation, dependent of CRF-R2 activation, synthesis of prostaglandins (COX pathway) and both adenylate cyclase and PKC signaling pathways, but independent of nitric oxide production. Regarding ciliary muscle, UCN2 enhances carbachol induced contraction, in higher doses. PMID- 29527919 TI - Dehydroepiandrosterone reduced lipid droplet accumulation via inhibiting cell proliferation and improving mitochondrial function in primary chicken hepatocytes. AB - Dehydroepiandrosterone (DHEA) possesses fat-reducing effect, while little information is available on whether DHEA regulates cell proliferation and mitochondrial function, which would, in turn, affect lipid droplet accumulation in the broiler. In the present study, the lipid droplet accumulation, cell proliferation, cell cycle and mitochondrial membrane potential were analysis in primary chicken hepatocytes after DHEA treated. The results showed that total area and counts of lipid droplets were significantly decreased in hepatocytes treated with DHEA. The cell viability was significantly increased, while cell proliferation was significantly inhibited in a dose dependent manner in primary chicken hepatocytes after DHEA treated. DHEA treatment significantly increased the cell population in S phase and decreased the population in G2/M in primary chicken hepatocytes. Meanwhile, the cyclin A and cyclin-dependent kinases 2 (CDK2) mRNA abundance were significantly decreased in hepatocytes after DHEA treated. No significant differences were observed in the number of mitochondria, while the mitochondrial membrane permeability and succinate dehydrogenase (SDH) activity were significantly increased in hepatocytes after DHEA treated. In conclusion, our results demonstrated that DHEA reduced lipid droplet accumulation by inhibiting hepatocytes proliferation and enhancing mitochondrial function in primary chicken hepatocytes. PMID- 29527920 TI - Effects of an antioxidant protective topical formulation on eye exposed to ultraviolet-irradiation: a study in rabbit animal model. AB - Ultraviolet-radiation exerts a well-known role in the development of various ocular diseases and may contribute to the progress of age-related macular degeneration. Therefore, the use of compounds able to protect the eyes from UV induced cellular damage is challenging. The aim of this study has been to test the protective effects of an antioxidant topical formulation against UV-induced damage in rabbit eyes. Twelve male rabbits were used. Animals were divided into 4 groups of 3 animals each. Control group (CG) did not receive any irradiation and/or eye drop. The other three experimental groups were treated as follows: the first group received only UVR irradiation for 30 min, without eye drop supplementation (Irradiation group, IG), the second (G30) and the third (G60) groups received UV irradiation for 30' and 60', respectively, and eye drop supplementation (riboflavin, d-alpha-tocopheryl polyethylene glycol, proline, glycine, lysine and leucine solution) every 15 min for three hours. In the IG group a significant increase of oxidized glutathione (GSSG) and hydrogen peroxide (H(2)O(2)) was recorded in the aqueous humor, whereas ascorbic acid levels were significantly lower when compared to control eyes. In the groups exposed to UVR rays for 30 min, and treated with the topical antioxidant formulation, the GSSG, H(2)O(2) and ascorbic acid levels were similar to those recorded in controls, whereas in the G60 group the three markers significantly differ from control group. In the lens, a significant decrease of alpha tocopherol and total antioxidant capacity (TAC) was recorded in IG-animals as compared to control group, whereas malondialdehyde (MDA) levels were significantly higher in UV induced eye than in control eyes. In the G30 groups the alpha tocopherol, MDA and TAC levels do not significantly differ from those recorded in controls, whereas in the G60 group these three markers significantly differ from control group. Present findings demonstrate that topical treatment with the antioxidant formulation used herein protects ocular structures from oxidative stress induced by UV exposure in in vivo animal model. PMID- 29527921 TI - A blood pact: the significance and implications of eIF4E on lymphocytic leukemia. AB - Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of hematological diseases. As a node of convergence for several oncogenic signaling pathways, eIF4E has attracted a great deal of interest from biologists and clinicians whose efforts have been targeting this translation factor and its biological circuits in the battle against leukemia. The role of eIF4E in myeloid leukemia has been ascertained and drugs targeting its functions have found their place in clinical trials. Little is known, however, about the pertinence of eIF4E to the biology of lymphocytic leukemia and a paucity of literature is available in this regard that prospectively evaluates the topic to guide practice in hematological cancer. A comprehensive analysis on the significance of eIF4E translation factor in the clinical picture of leukemia arises, therefore, as a compelling need. This review presents aspects of eIF4E involvement in the realm of the lymphoblastic leukemia status; translational control of immunological function via eIF4E and the state-of-the-art in drugs will also be outlined. PMID- 29527922 TI - IDH2-deficient mice develop spinal deformities with aging. AB - Spinal deformities such as scoliosis and kyphosis are incurable, and can lead to decreased physical function, pain, and reduced quality of life. Despite much effort, no clear therapies for the treatment of these conditions have been found. Therefore, the development of an animal model for spinal deformity would be extremely valuable to our understanding of vertebral diseases. In this study, we demonstrate that mice deficient in the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2) develop spinal deformities with aging. We use morphological analysis as well as radiographic and micro-CT imaging of IDH2 deficient mice to characterize these deformities. Histological analysis showed increased abnormalities in IDH2-deficient mice compared to wild type mice. Taken together, the results suggest that IDH2 plays a critical role in maintaining the spinal structure by affecting the homeostatic balance between osteoclasts and osteoblasts. This indicates that IDH2 might be a potent target for the development of therapies for spinal deformities. Our findings also provide a novel animal model for vertebral disease research. PMID- 29527923 TI - HIV testing prevalence in selected Chicago community areas: the importance of local-level data. AB - While data on HIV testing prevalence is readily available at the national, state, and more rarely at the city level, few data are available on HIV testing at the community level, where public health initiatives may be most effectively implemented. Community-level data are necessary given that city, state, and national estimates mask variation occurring at the community level in large urban areas. This type of data is crucial for informing education efforts both within the community and among providers. The current study uses the Sinai Community Health Survey 2.0, a cross-sectional, population-based probability survey of adults in selected Chicago communities to determine the prevalence of ever tested for HIV by community area, sex, race/ethnicity, and age (n = 1496). Across the surveyed community areas, ever tested prevalence ranged from a low of 35% in Norwood Park (predominantly White) to a high of 85% in North Lawndale (predominantly Black). Ever tested differences by community area were statistically significant (Rao Scott chi-square p = 0.003). Across the sampled communities, 65% of females, 55% of males, 80% of Blacks, 62% of Puerto Ricans, 53% of Mexicans, and 44% of Whites had ever been tested for HIV (Rao Scott chi square p < 0.01). Ever tested prevalence was highest in the 35-44 age group (72%) and lowest in the 65+ age group (33%) (Rao Scott chi-square p = 0.001). Local level HIV screening data are integral to understanding where (geographically and among which sub-populations) additional services are needed and may also help in directing and securing funding for such services. The evidence suggests that success in identifying and linking HIV positive individuals to care is most likely to be found through a combination of healthcare- and non-healthcare-based initiatives. Ideally, efforts will be coordinated to encompass both of these settings. PMID- 29527924 TI - Enhanced anti-bacterial activities of ZnO nanoparticles and ZnO/CuO nanocomposites synthesized using Vaccinium arctostaphylos L. fruit extract. AB - A green synthesis route was developed for preparation of the ZnO nanoparticles and ZnO/CuO nanocomposites by using Vaccinium arctostaphylos L. fruit extract, and their anti-bacterial activities against two pathogenic bacteria, Escherichia coli (Gram negative) and Staphylococcus aureus (Gram positive), were investigated. The fabricated nanomaterials were characterized by XRD, EDX, FESEM, TEM, TGA, FT-IR, UV-vis DRS and BET instruments. The results showed that the sizes of ZnO and CuO nanoparticles in the ZnO/CuO (10%) nanocomposite were 12 and 8 nm, respectively. In addition, specific surface areas of the ZnO (W), ZnO (ext) and ZnO/CuO samples were 29.3, 27.5 and 18.0 m2/g-1, respectively. The results obtained from EDX, TGA, FT-IR and UV-Vis DRS analyses displayed that some of the organic compounds from the fruit extract have bonded to the surface of the samples fabricated in the presence of the fruit extract. The results revealed that the anti-bacterial activity of the fabricated samples is as ZnO/CuO (10%) > ZnO/CuO (5%) > ZnO (ext) > ZnO (W). Viability percentages for E. coli and S. aureus bacteria were 12.1 +/- 0.39 and 14.9 +/- 0.65 in the presence of the ZnO/CuO (10%) nanocomposite, respectively. The SEM images clearly demonstrated the disruption of the bacterial membranes during the inactivation process. PMID- 29527925 TI - Synthesis of nanomedicines by nanohybrids conjugating ginsenosides with auto targeting and enhanced MRI contrast for liver cancer therapy. AB - A new methodology has been developed with conjugating nanoparticles (NPs) with an active ingredient of Chinese herbs for nanomedicines with auto-targeting and enhanced magnetic resonance imaging (MRI) for liver cancer therapy. Fe@Fe3O4 NPs are first synthesized via the programed microfluidic process, whose surfaces are first modified with -NH2 groups using a silane coupling technique that uses (3 aminopropyl)trimethoxysilane (APTMS) as the coupling reagent and are subsequently activated by the bifunctional amine-active cross-linker [e.g. disuccinimidyl suberate (DSS)]. The model medicines of ginsenosides pre-activated by APTMS are further cross-linked with activated NPs, forming the desired nanomedicines (Nano Fe-GSS). Sizes and structures of Fe@Fe3O4 NPs were characterized by transmission electron microscopy and X-ray diffraction, revealing that their core-shell structures consist of amorphous boron doped Fe cores and partial crystalline Fe3O4 shells. The accomplishment of coupling reactions in the final nanomedicines is confirmed by the characterization of the composition of NPs and Nano-Fe-GSS via X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FT-IR) spectroscopy. The nanoparticles' effects as MRI contrast agents are further investigated by comparing the T2 weighted spin echo imaging (T2WI) in livers before and after intravenous injection and intragastric administration of nanomedicines. The results indicate that these nanomedicines possess enhanced MRI effects. Investigation of the toxicity and metabolism of Nano-Fe-GSS suggests that they are safe to related vital organs. The results provide an efficient alternative route to synthesize desired multi-functional nanomedicines based on NPs and the active ingredients of Chinese herbs, which can promote their potential synergistic effects in anti-tumor therapy. PMID- 29527926 TI - Near-infrared light-activatable siRNA delivery by microcapsules for combined tumour therapy. AB - A polyelectrolyte microcapsule-based layer-by-layer (LbL) technique has been widely used as a multifunctional vehicle for combined tumor therapy. Meanwhile, with the rapid development of combined tumour therapy, the challenge for designing multifunctional drug delivery system has attracted much more attention. Herein, we developed a new type of microcapsule (MC) system called MPA@siRNA@DOX@MC, which conjugated with siRNA and DOX as well as ICG-Der-02 (MPA) by electrostatic absorption. MPA as indocyanine green (ICG) fluorescence dye, exhibiting high fluorescence emission and photothermal conversion ability under NIR laser irradiation, was uploaded onto this drug system for realizing the controllable drug release and cancer theranostics. In addition, the results revealed that MPA@siRNA@DOX@MC possessed several ideal properties including high drug-loading capacity, excellent siRNA transfection efficiency, siRNA sequence protection and remarkably improved tumour-targeting capacity. Moreover, the combined therapy based on this drug system displayed improved therapeutic efficacy and negligible side effects both in vivo and in vitro experiment. Ultimately, MPA@siRNA@DOX@MC drug delivery system successfully combined the photothermal therapy and chemotherapy with controlled siRNA sequence silencing may have a promising potential in combined tumor therapy. PMID- 29527927 TI - Acute beetroot juice administration improves peak isometric force production in adolescent males. AB - The purpose of this study was to examine the effects of acute beetroot juice (BR) administration on repeated sprint performance and isometric force production in adolescent males. Twelve male adolescents (age, 16.8 +/- 1.0 years; height, 178.8 +/- 9.2 cm; mass, 74.8 +/- 12.5 kg; peak height velocity, 2.53 +/- 1.2 years) participated in this double-blind, placebo-controlled, crossover designed study. Participants consumed 2 * 70 mL of BR (~12.9 mmol NO3-; Beet It Sport) or a nitrate-depleted placebo (PL) at 2.5 h prior to performing isometric mid-thigh pulls (IMTP) and 4 repeated 20-s Wingate sprints interspersed with 4 min of rest. Sprint data were analyzed by a 2 * 4 (group * time) repeated-measures ANOVA while a dependent t test was used to compare conditions for IMTP peak force. A significant main effect for time (p < 0.05) was observed for peak power (PP), average power (Pavg), and fatigue index (FI) across sprints. Compared with sprint 1, sprint 4 resulted in significant decreases in PP (p < 0.000; -16.6%) and Pavg (p = 0.000; -21.8%) and FI was significantly elevated (p < 0.000; 15.2%). No significant group * time interactions were observed between conditions for PP (p = 0.402), Pavg (p = 0.479), or FI (p = 0.37). IMTP peak force was significantly higher (p = 0.004; 13.9%) following BR consumption compared with PL. The repeated sprint protocol resulted in significant fatigue while BR did not influence sprint performance. However, it appears BR administration may improve peak force production in adolescent males. PMID- 29527928 TI - MiR-21 regulates the apoptosis of keloid fibroblasts by caspase-8 and the mitochondria-mediated apoptotic signaling pathway via targeting FasL. AB - MicroRNA-21 (miR-21) has been found to be upregulated in keloid tissue and to affect the proliferation and apoptosis of keloid fibroblasts; however, the possible mechanisms remain unclear. In this study, we aimed to evaluate the role of miR-21 in FasL-induced caspase-8 activation and the mitochondria-mediated apoptotic signaling pathway in keloid fibroblasts. Our study found that the protein level of FasL was decreased by miR-21 over-expression, while being enhanced by miR-21 inhibition in keloid fibroblasts. Subsequently, the mitochondria-mediated apoptosis of keloid fibroblasts was restrained by miR-21 over-expression, as evidenced by enhanced mitochondrial membrane potential and decreased production of mitochondrial ROS. Moreover, over-expression of miR-21 inhibited the activation of the caspase-8 and the mitochondria-mediated apoptotic signaling pathway. As expected, inhibition of miR-21 had the opposite effects. Finally, silencing of FasL suppressed miR-21 inhibition-induced apoptosis by inactivation of caspase-8 and the mitochondria-mediated apoptotic signaling pathway, which was comparable to Z-IETD-FMK, a caspase-8 inhibitor. Taken together, these results suggest that miR-21 regulates the apoptosis of keloid fibroblasts via targeting FasL, and caspase-8 and the mitochondria-mediated apoptotic signaling pathway is involved in this process. Our findings provide evidence that miR-21 may be considered to be a therapeutic target for keloids. PMID- 29527929 TI - Notch signaling as a therapeutic target for acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease. Therapeutic alternatives with effective anti-leukemic potential and low toxicity are needed. Areas covered: This review provides an overview of the currently available drugs directly or indirectly targeting Notch signaling in ALL. Besides considering the known Notch targeting approaches, such as gamma secretase inhibitors (GSIs) and Notch inhibiting antibodies (mAbs), currently in clinical trials, we focus on the recent insights into the molecular mechanisms underlying the Notch signaling regulation in ALL. Expert opinion: Novel drugs targeting specific steps of Notch signaling or intersecting pathways could improve the efficiency of the conventional hematological cancers therapies. Further studies are required to translate the new findings into future clinical applications. PMID- 29527930 TI - HPLC profiling of phenolics and flavonoids of Adonidia merrillii fruits and their antioxidant and cytotoxic properties. AB - In this study the antioxidant and cytotoxicity activity of the Adonidia merrillii fruits were investigated using different solvent polarities (methanol, ethyl acetate and water). The results showed that the total phenolic and flavonoid contents of the methanolic extract was higher compare with other extract with respective values of 17.80 +/- 0.45 mg gallic acid equivalents/g dry weight (DW) and 5.43 +/- 0.33 mg rutin equivalents/g DW. Beside that The RP-HPLC analyses indicated the presence of gallic acid, pyrogallol, caffeic acid, vanillic acid, syringic acid, naringin and rutin. In the DPPH, NO2 and ABTS scavenging assays, the methanolic extract exhibited higher antioxidant activity as compared to the ethyl acetate and water extracts. The extracts exhibited moderate to weak cytotoxic activity in the assays using human hepatocytes (Chang liver cells) and NIH/3T3 (fibroblasts cell) cell lines. The findings showed the Adonidia merrillii fruit extracts to possess considerable antioxidant and cytotoxicity properties. The fruit, therefore, is a potential candidate for further work to discover antioxidant and cytotoxic drugs from natural sources. PMID- 29527933 TI - Potential role of liver enzyme levels as predictive markers of glucose metabolism disorders in a Tunisian population. AB - The relationship between liver enzymes and T2D risk is inconclusive. We aimed to evaluate the association between liver markers and risk of carbohydrate metabolism disorders, as well as their discriminatory power, for T2D prediction. This cross-sectional study enrolled 216 participants classified as normoglycemic, prediabetic, newly diagnosed diabetics, and diagnosed diabetics. All participants underwent anthropometric and biochemical measurements. The relationship between hepatic enzymes and glucose metabolism markers was evaluated by analyses of covariance. The associations between liver enzymes and incident carbohydrate metabolism disorders were analyzed through logistic regression and their discriminatory capacity to predict T2D by ROC analysis. High AP, ALT, gammaGT, and AST levels were independently related to decreased insulin sensitivity. Interestingly, a higher AP level was significantly associated with an increased risk of prediabetes (p = 0.017), newly diagnosed diabetes (p = 0.004), and T2D (p = 0.007). An elevated gammaGT level was an independent risk factor for T2D (p = 0.032) and undiagnosed T2D (p = 0.010) in prediabetic and normoglycemic subjects, respectively. In ROC analysis, AP was a powerful predictor of incident diabetes and significantly improved T2D prediction. Liver enzymes within the normal range, specifically AP levels, are associated with increased risk of carbohydrate metabolism disorders and significantly improved T2D prediction. PMID- 29527934 TI - HIV Risk perception and eligibility for pre-exposure prophylaxis in women involved in the criminal justice system. AB - Women involved in the criminal justice system (WICJ) are at high risk of acquiring HIV and would benefit from HIV pre-exposure prophylaxis (PrEP) but there are no studies in this population to inform PrEP implementation programs. We conducted a cross-sectional survey of HIV-uninfected, cis-gender women on probation, parole and/or recently released from prison/jail to assess PrEP awareness, eligibility, potential barriers to uptake, and the PrEP care continuum. The 125 WICJ surveyed reported high rates of HIV risk behaviors including recent transactional sex (22.4%) and unsafe injection practices (14.4%). Despite 33% (n = 42) meeting eligibility criteria for PrEP, only 25% were aware of PrEP and one person was currently using it. Just 16.7% of those who were PrEP eligible perceived they were at risk for HIV. Following a brief explanation of PrEP, 90% said they would try it if recommended by their physician. Compared to those not PrEP eligible (n = 83), PrEP eligible women were less likely to be stably housed or have a primary care provider, and were more likely to be violence-exposed, charged with drug possession, have lifetime substance use, or living with Hepatitis C infection. WICJ frequently engage in HIV risk behaviors that make them eligible for PrEP. Uptake may be limited by lack of PrEP awareness or underestimation of personal HIV risk. WICJ report receptiveness to PrEP and represent an important population for targeted PrEP implementation programs. PMID- 29527938 TI - Utilization of radiotherapy and stereotactic body radiation therapy for renal cell cancer in the USA. AB - AIM: This study evaluated national practice patterns of cT1N0M0 renal cell cancer, with a focus on stereotactic body radiation therapy (SBRT) utilization. METHODS: The National Cancer Database was queried (2004-2013) for patients with newly-diagnosed cT1a/bN0M0 renal cell cancer that received definitive treatment. Temporal trends in utilization were tabulated. RESULTS: Altogether, 138,495 patients met inclusion criteria; 13,725 (9.9%) patients received ablative therapy, 57,924 (41.8%) partial nephrectomy, 67,168 (48.5%) radical nephrectomy and 308 (0.2%) external beam radiation therapy (EBRT). The proportion of EBRT that was SBRT increased substantially from 25% in 2004 to 95.4% in 2013, with a sharp inflection point from 2005 to 2006. CONCLUSION: SBRT utilization has sharply risen over time; in most recent years, the vast majority of EBRT is delivered in the form of SBRT. PMID- 29527939 TI - Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference? AB - AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication. CONCLUSION: In the absence of direct comparative evidence, the results of this network meta-analysis represent the best available evidence for decision making in the first-line treatment of metastatic luminal breast cancer. PMID- 29527942 TI - A new glycoprotein SPG-8700 isolated from sweet potato with potential anti-cancer activity against colon cancer. AB - A new small molecule glycoprotein SPG-8700 with potential anti-colorectal cancer activity was firstly separated by tracking of bioactivity from a new sweet potato variety Zhongshu-1. Matrix-assisted laser desorption ionization mass spectrometry, high-performance liquid chromatography and amino acid analyzer were applied separately to determine the molecular weight and compositions of this glycoprotein. Flow cytometry analysis and western blotting analysis were employed to explore it's mechanism of the anti-colorectal cancer. The molecular weight of glycoprotein was 8703.8D (SPG-8700). Relative sugar and protein contents in SPG 8700 were 73.4 and 26.6%, comprising more than 6 types of sugars (mannose, rhamnose, glucuronic acid, glucose, galactose and arabinose with a proportion of 1:6.9:7.3:1.5:46:21). Further results indicated that SPG-8700 promoted apoptosis in HCT-116 cells through regulating the expression of Bcl-2 and Bax and had no effect on the growth of normal cells. PMID- 29527943 TI - Focal adhesions are involved in simulated-microgravity-induced basilar and femoral arterial remodelling in rats. AB - Recent studies have suggested that microgravity-induced arterial remodelling contributes to post-flight orthostatic intolerance and that multiple mechanisms are involved in arterial remodelling. However, the initial mechanism by which haemodynamic changes induce arterial remodelling is unknown. Focal adhesions (FAs) are dynamic protein complexes that have mechanotransduction properties. This study aimed to investigate the role of FAs in simulated-microgravity-induced basilar and femoral arterial remodelling. A 4-week hindlimb-unweighted (HU) rat model was used to simulate the effects of microgravity, and daily 1-hour intermittent artificial gravity (IAG) was used to prevent arterial remodelling. After 4-week HU, wall thickness, volume of smooth muscle cells (SMCs) and collagen content were increased in basilar artery but decreased in femoral artery (P < 0.05). Additionally, the expression of p-FAK Y397 and p-Src Y418 was increased and reduced in SMCs of basilar and femoral arteries, respectively, by HU (P < 0.05). The number of FAs was increased in basilar artery and reduced in femoral artery by HU (P < 0.05). Furthermore, daily 1-hour IAG prevented HU induced differential structural adaptations and changes in FAs of basilar and femoral arteries. These results suggest that FAs may act as mechanosensors in arterial remodelling by initiating intracellular signal transduction in response to altered mechanical stress induced by microgravity. PMID- 29527949 TI - Triple negative breast cancer: are we scoring a home run? PMID- 29527950 TI - Incorporation of Baccharis dracunculifolia DC (Asteraceae) leaf extract into phosphatidylcholine-cholesterol liposomes improves its anti-inflammatory effect in vivo. AB - The aerial parts of Baccharis dracunculifolia (BdE) is used in the Brazilian folk medicine to treat inflammatory conditions. Here we examined the ability of free and liposomal BdE to modulate reactive oxygen species generation in human neutrophils in vitro and zymosan-induced acute joint inflammation in Wistar rats. We prepared biocompatible liposomes of soya phosphatidylcholine and cholesterol with low diameter, homogeneous size distribution, and neutral surface charge. Free BdE decreased joint swelling, total leucocyte and neutrophil infiltration, and the synovial levels of tumour necrosis factor-alpha and interleukins 6 and 1beta. Incorporation of BdE into liposomes preserved its capacity to inhibit the neutrophil superoxide anion and total reactive oxygen species generation, and improved its anti-inflammatory effect in vivo by decreasing the effective BdE dose by nearly sixfold. The same liposome type lowered the effective dose of caffeic acid by nearly sixteenfold. Therefore, incorporation of BdE into phosphatidylcholine-cholesterol liposomes improves its anti-inflammatory effect. PMID- 29527951 TI - Triterpenoids and lignans from the stems of Schisandra glaucescens. AB - Two new triterpenoids, 24(E)-3alpha,12alpha-dihydroxyl-lanost-9(11),24-dien-26 oid acid (1) and 3,4-seco-24(Z)-6alpha,7beta-dihydroxyl-cycloart-4(28),24-dien 3,26-dioic-3-methyl ester (2), and ten known ones (3-12), together with eight lignans (13-20), were isolated from the stems of Schisandra glaucescens. Their structures were established on the basis of extensive spectroscopic analyses. Compounds 1-3, 5-7, 9, 11-13 and 15-18 were isolated from this species for the first time. 1 and 2 were evaluated for their in vitro cytotoxicities against the mouse cancer B16 cell line, human cancer HepG2 and MCF7 cell lines by MTT assay. PMID- 29527952 TI - Study of the pharmacokinetics of polymerized porcine hemoglobin (pPolyHb). AB - Polymerized porcine hemoglobin (pPolyHb), a kind of glutaraldehyde-polymerized haemoglobin-based oxygen carrier, was developed as a potential red blood substitute for clinical applications. Assessment of its absorption, distribution, and metabolism is a major determinant of its safety and efficacy. In this study, a series of pharmacokinetic parameters of pPolyHb were measured and calculated in different animal models, such as the top-load model, the 50% exchange transfusion model and the haemorrhagic shock model. The results showed that the kinetic process of pPolyHb in rats conforms to the laws of linear pharmacokinetics in vivo. The half-life of pPolyHb was superior and more stable under non pathological conditions, but in clinical situations such as trauma and anaemia, the half-life of pPolyHb may decline. The study of clearance (CL) and the apparent volume of distribution (Vd) of pPolyHb in these three different animal models demonstrated longer residence and a predominant, targeted role of pPolyHb with little accumulation in tissues. Through this study, the superior pharmacokinetic characteristics of pPolyHb have been proved and will aid in the determination of a reasonable dosing regimen and administration interval in clinical situations. PMID- 29527953 TI - High glucose causes vascular dysfunction through Akt/eNOS pathway: reciprocal modulation by juglone and resveratrol. AB - Transient elevations in blood glucose level may lead to changes in vascular function. Herein, we investigated the effects of high-glucose or high-fructose challenge, as well as potential influence of juglone or resveratrol on vascular reactivity, Akt/eNOS, and insulin signaling effectors in rat aorta. Aortic segments of rats were incubated with high glucose (30 mmol/L) or high fructose (2 mmol/L) in the absence and presence of juglone (5 MUmol/L) or resveratrol (10 MUmol/L). Acute high-glucose incubation markedly decreased acetylcholine-induced relaxation, which is further inhibited by juglone, but ameliorated by resveratrol. Incubation with high glucose caused significant reduction in pAkt/total Akt and peNOS/total eNOS ratios, as well as in the expression of some genes involved in insulin signaling. Juglone produced a further impairment, whereas resveratrol resulted in an improvement on the expression profiles of these proteins and genes. Acute exposure of aortic segments to high glucose causes a reduction in acetylcholine-induced relaxation in association with suppression of Akt/eNOS pathway, as well as several genes in insulin signaling pathway. Juglone and resveratrol have opposite actions on vascular relaxation and the above signaling targets. These findings could be relevant for the treatment of hyperglycemia-induced vascular complications. PMID- 29527955 TI - Antidepressant-like effect of Casimiroa pubescens root extracts. AB - In this study, we investigated the antidepressant-like effects of the hexane (HCP), ethyl acetate (ECP) and methanol (MCP) extracts of the roots of Casimiroa pubescens Ramirez (Rutaceae) using the forced swim test (FST). In an initial experiment, each extract was orally administered to mice only once 60 min before to the FST. In a second experiment, doses were administered 24, 7 and 1 h before testing. Our results showed that the triple administration of the extracts provided a stronger effect than single administration. However, the combination of HCP at 7.5 mg/kg and imipramine (IMI) at 12.5 mg/kg showed the greatest effect. The coumarins 3-(1',1', dimethyl allyl)-herniarin, auraptene, 8-geranyl oxy psoralen, isopimpinellin and the flavonoid zapotin were isolated from the extracts. The hexane extract of C. pubescens showed an antidepressant-like activity, which may inspire further studies on developing new antidepressant agents. PMID- 29527956 TI - Evolution of medical education in the Department of Medicine of the Complutense University of Madrid in the last decade. AB - OBJECTIVES: This paper aims to show changes in Medical Education in the Department of Medicine at the Complutense University of Madrid in the last 10-15 years. RESULTS: Medical education in the Department of Medicine at the Complutense University of Madrid has undergone significant changes in the last 10 15 years. An attempt to summarize these shows that radical change in the teaching of medicine for both teachers and students has taken place in three areas: 1. Progressive development of Patient-centered medical education. 2. Development of a competency-based training concerned with the mastering of knowledge and skills and their evaluation through objective and structured clinical assessment tests. 3. Introducing simulation techniques and virtual reality in the teaching of clinical practice aimed at improving our students' training and enhancing patient safety. CONCLUSIONS: We believe that the changes applied have pleased students as well as teachers and even patients and are helping to improve the training of our students. PMID- 29527958 TI - Molecular dynamics simulations reveal structural insights into inhibitor binding modes and mechanism of casein kinase II inhibitors. AB - Casein kinase-II, a member of protein kinase family, plays significant role in different cellular processes such as cell growth, differentiation, proliferation, gene expression, and embryogenesis. Being a potent suppressor of apoptosis, it serves as a significant link for its association with various types of malignancies such as colorectal and breast cancer. To overcome its pathological role in various cancerous diseases, CK-II procures great consideration as a therapeutic target. This study aimed at understanding the binding mechanism and structural properties of benzimidazole derivatives by utilizing various computational tools including docking simulation, three-dimensional quantitative structure activity relationships and molecular dynamic simulation. Structure based 3D-QSAR techniques such as CoMFA and CoMSIA models, were established from the conformations gained by protein-ligand docking approach. The attained models have showed a good extrapolative power for internal as well as external validation. Moreover, MD simulation was carried out to explain the detailed binding mechanism and the comparison of inhibitor's binding mode with diverse biological activities. A good correlation was observed among docking studies, MD results, and contour map analysis. Interestingly new molecules were designed using detail structural information from MD simulation, showed higher potency of inhibition (pIC50 7.6-7.7) compare to the most active compound of the series. PMID- 29527957 TI - Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy. AB - AIM: Discordance between primary tumor and paired metastases biology has been widely detected in metastatic breast cancer. The aim of this study was to evaluate the prognostic impact of Ki67, estrogen receptor (ER), progesterone receptor (PR) and HER2 discordance. METHODS: We retrospectively analyzed a cohort of 544 patients affected by metastatic breast cancer. Variation in ER, PR, Ki67 and HER2 expression between primary site and recurrence was tested through the McNemar test. RESULTS: A significant variation was observed in respect to ER, PR and Ki67 status (12.65%, p = 0.0072; 49.71%, p < 0.0001; 35%, p < 0.0001, respectively). Among patients with ER or PR discordance, the driver of therapeutic decisions was the ER status. Moreover, we observed a therapy-related reduction of ER in taxanes or aromatase inhibitors-exposed patients (odds ratio: 3.59; 95% CI: 1.66-7.77; p = 0.001 and odds ratio: 2.07; 95% CI: 0.96-4.44; p = 0.06, respectively). CONCLUSION: Biopsy of metastatic lesions may influence the decision-making process translating into better outcome. PMID- 29527959 TI - Dynamics of populations with individual variation in dispersal on bounded domains. AB - Most classical models for the movement of organisms assume that all individuals have the same patterns and rates of movement (for example, diffusion with a fixed diffusion coefficient) but there is empirical evidence that movement rates and patterns may vary among different individuals. A simple way to capture variation in dispersal that has been suggested in the ecological literature is to allow individuals to switch between two distinct dispersal modes. We study models for populations whose members can switch between two different nonzero rates of diffusion and whose local population dynamics are subject to density dependence of logistic type. The resulting models are reaction-diffusion systems that can be cooperative at some population densities and competitive at others. We assume that the focal population inhabits a bounded region and study how its overall dynamics depend on the parameters describing switching rates and local population dynamics. (Traveling waves and spread rates have been studied for similar models in the context of biological invasions.) The analytic methods include ideas and results from reaction-diffusion theory, semi-dynamical systems, and bifurcation/continuation theory. PMID- 29527960 TI - Caffeine and energy drink use by combat arms soldiers in Afghanistan as a countermeasure for sleep loss and high operational demands. AB - OBJECTIVES: Combat deployments are characterized by high operational demands with limited opportunities for sleep leading to fatigue and degraded cognitive and operational performance. Caffeine in moderate doses is recognized as an effective intervention for physical and cognitive decrements associated with sleep loss. METHODS: This report is based on data collected by two separate, independently conducted surveys administered in Afghanistan in 2011-2012. It assessed caffeine use and sleep disruption among U.S. Army combat soldiers (J-MHAT 8; n = 518) and among deployed soldiers with different military assignments (USARIEM Deployment Survey; n = 260). RESULTS: Daily caffeine intake assessed in the J-MHAT 8 survey averaged 404 +/- 18 mg. In the USARIEM Deployment Survey, intake was 303 +/- 29 mg and was significantly higher among combat arms soldiers (483 +/- 100 mg) compared to combat service support personnel (235 +/- 23 mg). In both surveys, over 55% of total caffeine intake was from energy drinks. Additional sources of caffeine included coffee, tea, sodas, gum, candy, and over-the-counter medications. Higher caffeine intake was not associated with ability to fall asleep at night or wake-up in the morning (J-MHAT 8 survey). Higher caffeine consumption was associated with disrupted sleep from high operational tempo and nighttime duties of combat operations. DISCUSSION: Overall caffeine consumption and energy drink use in Afghanistan was greater than among non-deployed soldiers and civilians. Caffeine was frequently used as a countermeasure during night operations to offset adverse effects of sleep loss on physical and cognitive function, consistent with current Department of the Army recommendations. PMID- 29527961 TI - Spectroscopic and molecular docking studies on the albumin-binding properties of metal(II) complexes of Mannich base derived from lawsone. PMID- 29527962 TI - Neonatal hypoxia of the second twin after vaginal delivery of the first twin: what matters? AB - OBJECTIVE: Optimal management of twin deliveries is controversial. We aimed to assess potential risk factors correlated to the development of hypoxia in the second twin after vaginal delivery of the first twin. STUDY DESIGN: This is a retrospective observational study including diamniotic twin pregnancies delivering at our Institution at 35 weeks of gestational age or more, weighing >=1800 g. Hypoxia was defined as at least one of the following: Apgar score <5 at 10 minute, neonatal resuscitation for >10 minutes, neonatal acidosis (pH <=7 and/or BE >=12 mmol/L). RESULTS: A number of 275 diamniotic twin pregnancies met the inclusion criteria and were divided within the following groups: (1) second twin not developing neonatal hypoxia (n = 265); and (2) second twin developing neonatal hypoxia (n = 10). The rate of second twins with neonatal hypoxia during the study period was 3.6% (10/275). Abnormal cardiotocography during the intertwin delivery interval, defined as ACOG category III, was significantly correlated to second twin hypoxia. Of interest, there was no significant difference in the intertwin delivery interval between the study groups. In addition, breech presentation of the second twin did not show to be a risk factor for neonatal hypoxia. None of the second twins developing neonatal hypoxia was reported to have encephalopathy (follow up of at least 24 months). At multivariate analysis, only abnormal cardiotocography was an independent risk factor for second twin hypoxia (OR 17.8, 95% CI 4.1-77.2). CONCLUSIONS: In our study, neonatal hypoxia was significantly correlated to abnormal cardiotocography, while intertwin delivery interval was not correlated to the development of this adverse neonatal outcome. PMID- 29527963 TI - A feature extraction method for adaptive DBS using an improved EMD. AB - OBJECTIVE: Local field potential (LFP) of a patient with Parkinson's disease often shows abnormal oscillation phenomenon. Extracting and studying this phenomenon and designing adaptive deep brain stimulation (DBS) control library have great significance in the treatment of disease. MATERIALS AND METHODS: This paper has designed a feature extraction method based on modified empirical mode decomposition (EMD) which extracts the abnormal oscillation signal in the time domain to increase the overall performance. The intrinsic mode function (IMF) component which contains abnormal oscillation is extracted by using EMD before an intrinsic characteristic of the oscillation signal is obtained. Abnormal oscillation signal is acquired using signal normalization, peak counting, and envelope method with a threshold which in turn keeps the integrity and accuracy as well as the efficiency. RESULTS: Comparative study of eight patients (six patients with DBS closed and drugs stopped; two patients with stimulation) has verified the feasibility of using modified EMD in extracting abnormal oscillation signal. The results showed that patients who take DBS suffer less abnormal oscillation than those who take no treatment. These results match the energy rise in the band of 3-30 Hz on local field potential spectrum of the patient with Parkinson's disease. CONCLUSIONS: Unlike previous oscillation extraction algorithm, improved EMD feature extraction method directly isolates abnormal oscillation signal from LFP. Significant improvement has been made in feature extraction algorithm in adaptability, real-time performance, and accuracy. PMID- 29527964 TI - Comparative study on ATG-thymoglobulin versus ATG-fresenius for the graft-versus host disease (GVHD) prophylaxis in allogeneic stem cell transplantation from matched unrelated donor: a single-centre experience over the contemporary years. PMID- 29527965 TI - Comparative analysis of the mitochondrial genomes of six newly sequenced diatoms reveals group II introns in the barcoding region of cox1. AB - Diatoms are the most diverse lineage of algae and at the base of most aquatic food webs, but only 11 of their mitochondrial genomes have been described. Herein, we present the mitochondrial genomes of six diatom species, including: Melosira undulata, Nitzschia alba, Surirella sp., Entomoneis sp., Halamphora coffeaeformis, and Halamphora calidilacuna. Comparison of these six genomes to the 11 currently published diatom mitochondrial genomes revealed a novel ubiquitous feature block consisting of tatC-orf157-rps11. The presence of intronic retrotransposable elements in the barcoding region of cox1 in the Halamphora genomes may explain historic difficulty (especially PCR) with cox1 as a universal barcode for diatoms. Our analysis suggests that high rates of variability in number and position of introns, in many commonly used coding sequences, prevent these from being universally viable as barcodes for diatoms. Therefore, we suggest researchers examine the chloroplast and/or nuclear genomes for universal barcoding markers. PMID- 29527966 TI - Transforming medical education in Kazakhstan: Successful case of internationalization from Karaganda State Medical University. AB - BACKGROUND: Medical education in Kazakhstan has been literally transformed in the past 10 years. Kazakhstan inherited the Soviet-time discipline-based teacher centered system of education when no decisions could be made independently. The curriculum was mostly governed in a traditional way, with lectures being the core, little use of e-learning tools, and assessment through oral exams and multiple-choice questions. Most of the universities still preserve the subject based curriculum with elements of integrated learning. METHODS: Being the most active member of International Space Education, Karaganda State Medical University (KSMU) took the initiative to adapt the full integrated curriculum mostly based on problem-based, team-based learning, and use of virtual patient cases. The given approach was chosen because of active involvement of our University in nine Tempus and Erasmus+projects including reforming of Public Health and Nursing curriculum, human resources development, active learning, credit mobility, and move towards autonomy of medical schools. RESULTS: KSMU became the coordinator of two of these projects, taking its active position in internationalization of medical education. We actively use technology-based medical education, pro-actively adapting deliberate practice in acquiring essential practical skills, for which KSMU was recognized by an ASPIRE-to Excellence Award in simulation. CONCLUSIONS: Kazakhstan hopes to become the leader in medical education in Central Asia and suggests other Universities in the area to adopt its approach to internationalization of medical education. PMID- 29527967 TI - Curriculum reform and evolution: Innovative content and processes at one US medical school. AB - AIM: Curriculum reform in medical schools continues to be an ever-present and challenging activity in medical education. This paper describes one school's experiences with specific curricular innovations that were developed or adapted and targeted to meet a clear set of curricular goals during the curriculum reform process. Those goals included: (a) promoting active learning and learner engagement; (b) establishing early professional identity; and (c) developing physician competencies in an integrated and contextual manner while allowing for individualized learning experiences for the millennial student. METHODS: Six specific innovations championed by the school are described in detail. These included Themes in Medical Education, Translational Pillars, Stony Brook Teaching Families, Transition Courses, Educational Continuous Quality Improvement Processes, and our Career Advising Program. Development of the ideas and design of the innovations were done by faculty and student teams. RESULTS: We discuss successes and ongoing challenges with these innovations which are currently in the fourth year of implementation. CONCLUSIONS: Our curriculum reform has emphasized the iterative process of curriculum building. Based on our experience, we discuss general and practical guidelines for curriculum innovation in its three phases: setting the stage, implementation, and monitoring for the achievement of intended goals. PMID- 29527968 TI - LINP1 facilitates DNA damage repair through non-homologous end joining (NHEJ) pathway and subsequently decreases the sensitivity of cervical cancer cells to ionizing radiation. AB - LncRNA in non-homologous end joining (NHEJ) pathway 1 (LINP1) is an lncRNA which promotes therapeutic resistance in triple-negative breast cancer (TNBC). However, the expression and function of LINP1 in cervical cancer is not yet well understood. In this study, we evaluated the expression levels of LINP1 in tumor tissues and cell lines of cervical cancer. We found that LINP1 associates with NHEJ proteins (Ku80 and DNA-PKcs). LINP1 translocates from cytosol to nucleus in response to irradiation. In addition, LINP1 knockdown significantly increases the levels of cleaved caspase3 and PARP, leading to enhanced cell apoptosis after ionizing radiation (IR). LINP1-knockdown cells showed delayed repairs of DNA double-strand breaks (DSBs) after IR. Finally, LINP1 knockdown increases radiosensitivity of Hela S3 cells. These results suggest that LINP1 facilitates DSBs repair through NHEJ pathway and may thus serve as a prognostic marker and a potential target for the therapy of cervical cancer. PMID- 29527969 TI - Doxorubicin and paclitaxel carried by methoxy poly(ethylene glycol)-poly(lactide co-glycolide) is superior than traditional drug-delivery methods. AB - AIM: To evaluate the advantages of nanomaterial methoxy poly(ethylene glycol) poly(lactide-co-glycolide) (mPEG-PLGA) encapsulated doxorubicin (D/DOX) and paclitaxel (T/TAX; mPEG-PLGA-DT) over free form of DOX and TAX (DOX/TAX). MATERIALS & METHODS: Metabonomics was conducted to characterize the systemic metabolic response of allograft breast cancer model mice to mPEG-PLGA-DT and DOX/TAX treatments. RESULTS: Breast tumor growth induced metabolic reprogram in serum and multiple organs. DOX/TAX treatment could ameliorate the elevated energy and nucleotides demands in some organs while mPEG-PLGA-DT treatment showed outstanding therapeutic outcomes in restoring the metabolic phenotypes of serum and kidney from tumor-bearing mice to the healthy state. CONCLUSION: This investigation proved the biological advantages of mPEG-PLGA-DT over DOX/TAX in molecular level through the comparison between their metabolic responses in vivo. PMID- 29527970 TI - Development and Utilization of VHH Antibodies Derived from Camelus Dromedarius Against Foot-and-Mouth Disease Virus. AB - Foot-and-mouth disease (FMD) is an acute, highly contagious, and economically devastating viral disease of domestic and wildlife species. For effective implementation of FMD control program, there is an imperative need for developing a rapid, sensitive, and specific diagnostics which help in the identification of serotypes involved in the outbreaks. The humoral immune response of the Camelidae is unique since in these animals 75% of circulating antibodies are constituted by heavy-chain antibodies and 25% are conventional immunoglobulin with two identical heavy chains. In the present study, we developed and characterized FMD virus specific single-domain heavy-chain antibodies (VHHs) against inactivated whole virus antigens of FMDV serotypes O (INDR2/1975), A (IND40/2000), and Asia 1 (IND63/1972) vaccine strains. After six rounds of panning and enrichment, these VHHs were stably expressed in Escherichia coli cells. The VHHs directed against outer capsid proteins of FMD virus were successfully utilized as the capture antibody in liquid-phase blocking ELISA (LPBE) thus replacing rabbit coating antibodies. Our study demonstrated the utility of FMD virus-specific VHHs as potential candidates in FMD research and diagnostic application. PMID- 29527971 TI - From the workshop to the workplace: Relocating faculty development in postgraduate medical education. AB - INTRODUCTION: Postgraduate medical education takes place almost entirely in the clinical workplace, supported by healthcare professionals who strive to combine service and educational roles. Over the past decade, we have witnessed the emergence and growth of new forms of educational activity within postgraduate medical education. Under the umbrella term of "faculty development", these activities move beyond a narrow emphasis on "teaching the teachers to teach" to a wide range of interventions focused on enhancing educational climate, educational infrastructure and educational practices within and across healthcare organizations. METHOD: Drawing on key developments in the UK over the last 10 years, we trace how faculty development in postgraduate medical education has evolved, illustrate the plurality of purposes, and practices currently being adopted and signal emerging trends. DISCUSSION: We highlight that due to the location of UK medical training programs outside "the academy", innovations and developments in faculty development are largely silent in the formal medical education literature. Changing demographics, service pressures, and evolving healthcare systems continue to present serious challenges to both work-based training and learning. PMID- 29527972 TI - Students as partners: Our experience of setting up and working in a student engagement friendly framework. AB - BACKGROUND: Student engagement (SE) in the curriculum is a positive indicator in the development of students deeply involved in their learning. It also has several benefits for the schools' level of educational innovation and quality assurance. METHOD: In order to identify the most important pearls from the last decade of educational developments within the field of SE at the Faculty of Medicine University of Maribor, we searched through our school's archives, publications and research in the field of medical education. RESULTS: Three areas were identified as the most important SE complements: (i) peer teaching, (ii) school governance, and (iii) extracurricular activities. The paper highlights how many student-driven initiatives move from informal frameworks toward a formal structure, elective courses, and, in the end, compulsory components of the curriculum. DISCUSSION: As demonstrated by the three educational achievements at our school, fostering a high level of SE can lead to innovative curricular changes, benefit the whole school and enable students to deliver highly impactful extracurricular projects. PMID- 29527973 TI - A Cluster-Randomized Trial of Blood-Pressure Reduction in Black Barbershops. AB - BACKGROUND: Uncontrolled hypertension is a major problem among non-Hispanic black men, who are underrepresented in pharmacist intervention trials in traditional health care settings. METHODS: We enrolled a cohort of 319 black male patrons with systolic blood pressure of 140 mm Hg or more from 52 black-owned barbershops (nontraditional health care setting) in a cluster-randomized trial in which barbershops were assigned to a pharmacist-led intervention (in which barbers encouraged meetings in barbershops with specialty-trained pharmacists who prescribed drug therapy under a collaborative practice agreement with the participants' doctors) or to an active control approach (in which barbers encouraged lifestyle modification and doctor appointments). The primary outcome was reduction in systolic blood pressure at 6 months. RESULTS: At baseline, the mean systolic blood pressure was 152.8 mm Hg in the intervention group and 154.6 mm Hg in the control group. At 6 months, the mean systolic blood pressure fell by 27.0 mm Hg (to 125.8 mm Hg) in the intervention group and by 9.3 mm Hg (to 145.4 mm Hg) in the control group; the mean reduction was 21.6 mm Hg greater with the intervention (95% confidence interval, 14.7 to 28.4; P<0.001). A blood-pressure level of less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% of the participants in the control group (P<0.001). In the intervention group, the rate of cohort retention was 95%, and there were few adverse events (three cases of acute kidney injury). CONCLUSIONS: Among black male barbershop patrons with uncontrolled hypertension, health promotion by barbers resulted in larger blood-pressure reduction when coupled with medication management in barbershops by specialty-trained pharmacists. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT02321618 .). PMID- 29527975 TI - Lower extremity osteoarthritis is associated with lower health-related quality of life among retired professional footballers. AB - OBJECTIVE: The objective of the current study was to explore whether retired professional footballers suffering from lower extremity OA have a lower health related quality of life than those without OA or current professional footballers. METHODS: An observational study based on a cross-sectional design by means of questionnaires was conducted. Participants were retired and current professional footballers recruited by the World Players' Union (FIFPro). Information about lower extremity OA (clinically diagnosed by a medical professional) was gathered, while health-related quality of life (Global Physical Health and Global Mental Health scores) was assessed through a validated scale. RESULTS: A total of 396 retired and 361 current professional footballers were included in the analyses (response rate of 54%). The group of retired professional footballers was on average 36 years old, and they had competed in professional football for 11 years (retired for 5 years). The group of current professional footballers was on average 25 years old, and they had been active in professional football for 7 years. Within the group of retired professional footballers, prevalence of lower extremity OA was 33%. Both Global Physical Health and Global Mental Health scores among retired professional footballers with lower extremity OA were significantly lower than among retired players without OA and current players, but these scores were nearly similar to the norm for the general population (regardless the presence of OA or not). CONCLUSIONS: Health-related quality of life among retired professional footballers with lower extremity OA was significantly lower than among retired players without OA and current players but nearly similar to the norm for the general population (regardless the presence of OA or not). A rational recommendation is that a support measure such as the After Career Consultation should be introduced among retired professional footballers in order to empower their sustainable health and quality of life, focussing especially on the prevention of the occurrence or worsening of lower extremity OA. PMID- 29527976 TI - Psychosexual outcomes in women of reproductive age at more than two-years from excisional cervical treatment - a cross-sectional study. AB - PURPOSE: To investigate the long-term psychosexual outcomes in women following excisional cervical treatment. MATERIALS AND METHODS: Women with cold-knife conization (CKC) or large loop excision of the transformation zone (LLETZ) treatment were interviewed after a follow-up colposcopy visit. Their demographics, treatment and psychosexual characteristics were recorded. RESULTS: One hundred and forty six women with a mean age of 35.2 +/- 5.4 years underwent either LLETZ (68.5%) or CKC (31.5%) treatment within 4.7 +/- 2.7 years (range: 2 15) before the interview. 27.4% of women were less interested in sexual intercourse following treatment in comparison with their interest before. Those women with less interest in sexual intercourse after treatment had higher anxiety and depression scores and were more worried about disease progression. Women with post-treatment complications were at risk of less interest in sexual intercourse and of greater anxiety and depression. Women with abnormal smears at follow-up were at risk of greater anxiety. The type of treatment and grade of dysplasia did not affect their interest in sexual intercourse or the anxiety and depression scores. CONCLUSIONS: Approximately, one-third of women at more than two years post-treatment may suffer from less interest in sexual intercourse, have relatively greater anxiety and depression, and might still be concerned about the possibility of disease progression. PMID- 29527977 TI - Droplet digital PCR is an accurate method to assess methylation status on FFPE samples. AB - Most tissue samples available for cancer research are archived as formalin-fixed paraffin-embedded (FFPE) samples. However, the fixation process and the long storage duration lead to DNA fragmentation and hinder epigenome analysis. The use of droplet digital PCR (ddPCR) to detect DNA methylation has recently emerged. In this study, we compare an optimized ddPCR assay with a conventional qPCR assay by targeting a dilution series of control DNA. In addition, we compare the ddPCR technology with results from Infinium arrays targeting two separate CpG sites on a set of colon adenoma FFPE samples. Our data demonstrate that qPCR and ddPCR assess methylation status equally well on dilution controls with a high DNA input. However, the methylation detection on low-input samples is more accurate using ddPCR. The proposed primer design (methylation-independent primers with amplification of solely the converted DNA target) will allow for methylation detection, independent of bisulfite conversion efficiency. Those data show that ddPCR can be used for methylation analysis on FFPE samples with a wide range of DNA input and that the precision of the assay depends largely on the total amount of amplifiable DNA fragments. Due to accessibility of the ddPCR technology and its accuracy on high- as well as low-DNA input samples, we propose the use of this approach for studies involving degraded FFPE samples. PMID- 29527978 TI - Parental insightfulness: retrospect and prospect. AB - We open this introductory paper to the special issue with the theoretical and clinical roots of the insightfulness concept. Next, the Insightfulness Assessment (IA) is presented, followed by a review of key empirical findings supporting the IA. The central points in the papers in this special issue are reviewed next. These include the use of the IA with parents of children ranging in age from infancy to adolescence, its applicability outside the parent-child relationship (e.g. insightfulness toward a close friend), its use with high-risk mothers, and the usefulness of insightfulness both as a continuous and a categorical measure. The clinical applications of the IA are discussed, and we close with future directions for IA research. PMID- 29527979 TI - Phenolic compounds from the aerial parts of Clematis viticella L. and their in vitro anti-inflammatory activities. AB - Phytochemical investigations on the EtOH extract of Clematis viticella led to the isolation of six flavonoid glycosides, isoorientin (1), isoorientin 3'-O-methyl ether (2), quercetin 7-O-alpha-L-rhamnopyranoside (3), quercetin 3,7-di-O-alpha-L rhamnopyranoside (4), manghaslin (5) and chrysoeriol 7-O-beta-D-glucopyranoside (6), one phenylethanol derivative, hydroxytyrosol (7), along with three phenolic acids, caffeic acid (8), (E)-p-coumaric acid (9) and p-hydroxybenzoic acid (10). The structures of the isolates were elucidated on the basis of NMR and HR-MS data. All compounds were isolated from C. viticella for the first time. Compounds 7 and 8 showed significant anti-inflammatory activity at 100 MUM by reducing the release of NO in LPS-stimulated macrophages comparable to positive control indomethacin. Compounds 3 and 7 exhibited anti-inflammatory activity through lowering the levels of TNF-alpha while 1, 3 and 5 decreased the levels of neopterin better than the positive controls. PMID- 29527980 TI - Genetic Variants in ADD1 Gene and their Associations with Growth Traits in Cattle. AB - The alpha-adducin (ADD1) is a subunit of adducin which is a cytoskeleton heterodimeric protein. Adducin participates in oocytes chromosome meiosis of mice, prompting adducin has an effect on embryonic development. Adducin gene mutation has significantly functional change. So the present study was to identify and characterize polymorphisms within the coding region of the bovine ADD1 gene among different cattle breeds. Here, 11 novel single nucleotide polymorphisms (SNPs 1-11) were identified by DNA sequencing and polymerase chain reaction-single stranded conformational polymorphism, there were one synonymous mutation in exon 1 (SNP1); four missense mutations in exons 4, 7, and 8 (SNPs 3 6); and six mutations in introns 4, 12, 13, and 14 (SNPs 2, 7-10). The statistical analyses indicated that the some SNPs are associated with the growth traits (body length, body height, chest circumference, and hucklebone width) in Chinese Jiaxian cattle population. Our results provide evidence that polymorphisms in the ADD1 gene are associated with growth traits, and may be used for marker-assisted selection in beef cattle breeding program. PMID- 29527981 TI - Diabetes Mellitus and Renal Transplantation: A Short Update. PMID- 29527982 TI - Transplant Patients With Failing Renal Allografts. AB - Progress in patient care and immunosuppressive medications has resulted in improved allograft survival in the early posttransplant period; however, substantial graft loss continues in the long term. Therefore, the number of dialysis patients with failed allografts is increasing progressively. These patients have a worse prognosis than naive dialysis patients. Cardiovascular causes are the leading cause of death, followed by infections and malignancies. Delay in return to dialysis, a chronic inflammatory state, infections, and cancer are contributing factors to mortality, whereas type of dialysis modality does not have a significant effect on outcomes. Graft nephrectomy is a risky operation; therefore, it should not be a routine procedure and rather should be performed only when indicated. Overall, most grafts are left in place, whereas graft nephrectomy is performed in atients with graft intolerance syndrome. Management of immunosuppressive drugs after graft failure is controversial. In the case of maintaining immunosuppression, there is increased risk of infections, cardiovascular diseases, and malignancies and also steroid-related adverse effects. On the other hand, discontinuation of immunosuppressants may result in loss of residual allograft function and also acute graft inflammation. Together, immunosuppressive drugs are almost always discontinued in these patients because of their inherent adverse effects. Considering the sequence of cessation, first antiproliferative drugs are stopped, followed by calcineurin inhibitors, and finally steroids. Because many studies show a clear survival benefit, every attempt should be made for a retransplant in patients with failed renal allografts. PMID- 29527983 TI - Preoperative Echocardiographic Differences and Transplant Outcomes Among Patients Receiving Simultaneous Liver-Kidney Versus Liver Transplant Alone. AB - OBJECTIVES: Liver transplant and simultaneous liver-kidney transplant are major surgeries performed on high-risk individuals with end-stage liver disease and end stage renal disease. We sought to examine the relationship between pretransplant echocardiographic parameters and outcomes in our simultaneous liver-kidney transplant and liver transplant-alone populations. MATERIALS AND METHODS: In our retrospective analysis, we included adult patients who underwent index transplant from January 1, 2010 to December 31, 2015 at Johns Hopkins Comprehensive Transplant Center. RESULTS: Our study included 312 patients, 266 who underwent liver transplant alone and 46 who underwent simultaneous liver-kidney transplant. Baseline population demographics were similar in both groups of patients. Primary diagnosis at transplant was similar in both groups except that patients undergoing liver transplant were more likely to have a diagnosis of hepatocellular carcinoma, whereas those undergoing simultaneous liver-kidney transplant were more likely to have polycystic kidney disease. Within the liver transplant-alone group, the strongest demographic predictor of poor outcome was age at transplant. The strongest echocar diographic predictors were related to elevated left ventricular ejection fraction and right ventricular systolic pressure. CONCLUSIONS: In our investigation regarding whether the pretransplant cardiovascular evaluation predicted outcomes for patients undergoing liver transplant alone and patients undergoing simultaneous liver-kidney transplant, we found that elevations in right ventricular systolic pressure and left ventricular ejection fraction may be associated with poor outcomes in the posttransplant period. PMID- 29527984 TI - Surgical Challenge in Pediatric Kidney Transplant Vascular Anastomosis. AB - During pediatric kidney transplant, surgical challenges occasionally occur. In particular, vascular anastomosis should be considered for children with small body weight < 12 kg, multiple renal arteries, vascular anomaly, and inferior vena cava occlusion. In pediatric patients, a living-donor renal graft is usually donated from a parent. Therefore, the renal artery and vein are too large to be anastomosed with the recipient's internal iliac artery and external iliac vein. In children who are > 12 kg, the renal artery and vein could be anastomosed with the external iliac artery and the external iliac vein. In children who are < 10 kg, the renal artery and vein should be anastomosed directly with the aorta and inferior vena cava. A pediatric transplant surgeon should consider arterial and venous anastomosis sites before transplant surgery. In small children with partial or total inferior vena cava occlusion, the venous anastomosis site should be evaluated. If the graft is placed on the left side, a venous graft must be used as a bridge between the renal vein and inferior vena cava. In 13 kidney transplants in children with inferior vena cava occlusion, 7 were on the left and 6 were on the right side. A patent segment of the inferior vena cava, the left original renal vein, an ascending lumbar vein, an azygos vein, the first graft renal vein, and a portal vein were used for venous anastomosis in 6, 2, 2, 1, 1 and 1 recipient, respectively. One child had graft loss due to renal vein thrombosis and one died of hemorrhage immediately posttransplant. Three had grafts with relatively long-term function, but these were lost due to chronic allograft nephropathy 100, 122, and 137 months posttransplant. However, the other 8 recipients have so far maintained graft function from 6 to 138 months since transplant. PMID- 29527974 TI - Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. AB - BACKGROUND: Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. METHODS: We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). RESULTS: In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention to-treat analysis. CONCLUSIONS: In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .). PMID- 29527985 TI - Surgical Challenge in Pediatric Kidney Transplant: Lower Urinary Tract Abnormality. AB - Lower urinary tract abnormalities are difficult to resolve in pediatric kidney transplant patients. Measure of residual urine, voiding cystourethrography, retrograde urethrography, cystometry, electromyography of urethral external sphincter muscle, urethrometry, and uroflowmetry are the primary methods for evaluation of lower urinary tract abnormalities. Endoscopic resection or ablation of urethral valves is required in children with posterior urethral valve to treat obstruction, but bladder function does not always recover and may deteriorate to end-stage renal failure even after the obstruction is released. This bladder dysfunction in posterior urethral valve defines valve bladder syndrome. Vesicoureteral reflux caused by high vesical pressure can cause even worse renal graft function posttransplant. In our patient group, urinary diversion occurred with Mitrofanoff conduit using an appendix in 6 children, a Yang-Monti channel conduit using ileum in 1 patient, with cystostomy in 3 children, and with augmented cystoplasty in 9 children before or simultaneously with kidney transplant. These procedures should be selected based on the type of lower urinary tract abnormality including bladder function. Recently, we have preferred a continent diversion for self-catheterization in children with lower urinary tract abnormalities. We have conducted 9 augmented cystoplasty procedures using a portion of the sigmoid colon or ileum. Seventeen children retained their own bladders when the transplant ureter was implanted. Most patients needed clean intermittent catheterization, depending on the residual urine volume and a bladder function. Ten-year graft survival rate in kidney transplant in our department is 98% in 36 children with lower urinary tract abnormalities. Lower urinary tract abnormality is not always a risk factor for pediatric kidney transplant; however, a preoperative evaluation is important to choose the best option for urinary diversion. PMID- 29527986 TI - Kaposi Sarcoma in the Era of Rapamycin Remains a Therapeutic Challenge in Organ Transplant Recipients. AB - Solid-organ transplant recipients are at higher risk of developing Kaposi sarcoma, which is a multicentric vascular neoplasm of lymphatic endothelium derived cells. Reducing doses of immunosuppressive drugs and switching from calcineurin inhibitors to the mammalian target of rapamycin inhibitor rapamycin have been suggested as an effective first-line treatment modality in most patients. Herein, we report a 64-year-old renal transplant recipient who developed multiple cutaneous and visceral Kaposi sarcoma lesions 2 months after transplant. The patient showed no improvement, with progression of the disease until month 15 of the suggested therapy of rapamycin. PMID- 29527987 TI - Quality of Life Through Gender Role Perspective in Candidate Renal Transplant Recipients: A Report From Baskent University Using the Short Form 36 Health Survey. AB - OBJECTIVES: The aim of the study was to evaluate the quality of life of patients with end-stage renal disease through a "gender role perspective." Patients were on hemodialysis treatment and on a wait list for transplant. MATERIALS AND METHODS: This study was conducted at the Baskent University Adana, Ankara, and Istanbul hemodialysis centers. Patients completed Short Form 36 Health Survey questionnaires voluntarily to evaluate quality of life. The questions were answered independently by patients while they were undergoing hemodialysis treatment. RESULTS: The mean age of participants was 54 +/- 16.5 years. Quality of life was found to be higher in men (44.7 +/- 19.2), and there was a negative correlation between quality of life and age in both sexes, as well as marriage age, number of pregnancies, and age of patient at the first live birth in women (P < .05). We found statistically significant differences between men and women regarding physical health and mental health dimensions. Quality of life scores increased with level of education (P < .001). In addition, patients in Ankara had the highest quality of life compared with Istanbul and Adana (P < .01). Average time on hemodialysis treatment, the number of weekly hemodialysis sessions, mean time of the disease, and mean duration of abandoning hemodialysis sessions were negatively associated with all components of quality of life (P < .05). CONCLUSIONS: We found that sex, education level, social status, and home city of patients had a high impact on quality of life. Thus, it is essential to educate both male and female patients regarding sex/gender and health issues before transplant to increase the recipient's physical and mental health dimensions. PMID- 29527988 TI - Liver Biopsy Results in Potential Donor Evaluation in Living Related Liver Transplant. AB - OBJECTIVES: The number of living-donor liver transplants has been increasing due to the growing discrepancy between the number of patients on wait lists for liver transplant and the availability of deceased donations. Evaluations of potential liver donors should ensure the safety of the surgical procedure for both the donor and recipient. Liver biopsy is the criterion standard for selecting optimal donors. In this study, we evaluated the importance of preoperative liver biopsy in selecting donor candidates. MATERIALS AND METHODS: We evaluated the data of 612 living-related liver donor candidates who received liver biopsies between January 2001 and June 2017 at our center. RESULTS: In the 612 liver donor candidates (328 male, 284 female; age range, 18-69 years), 416 liver biopsies (68%) were reported as normal and 196 liver biopsies (32%) had pathologic findings. Of 196 donors with pathologic findings, 86 (44%) had fatty changes and 24 (12%) had portal inflammation. CONCLUSIONS: The high rate of pathologic findings in liver biopsy of healthy-appearing donor candidates indicated the importance of liver biopsy in the preoperative evaluation of donors. PMID- 29527989 TI - Complications of Liver Transplant in Adult Patients With the Hepatic Form of Wilson Disease. AB - OBJECTIVES: Wilson disease is an autosomal, recessive, inherited disorder of copper metabolism that results in the accumulation of copper in many organs and tissues. This disease is mainly characterized by dysfunction due to copper accumulation in the liver, kidney, brain, cornea, bone, heart, and blood cells. The clinical spectrum is broad in Wilson disease. Asymptomatic Wilson disease may be present, but findings related to the involvement of an individual organ or multiple organ failure can be seen. These findings can include neurologic and neuropsychiatric complications. Our aim here was to examine the neurologic complications and our clinical experience in patients who underwent liver transplant for Wilson disease in our clinic. MATERIALS AND METHODS: We retrospectively reviewed the medical records of transplant patients with Wilson disease who were seen at Baskent University Faculty of Medicine Transplantation Science between 2005 and 2017. Patient demographics, neurologic complaints, findings from neurologic examinations, and imaging findings were recorded. We also recorded the presence of the Kayser-Fleischer ring, serum ceruloplasmin, 24 hour copper urine levels, and levels of dry copper in liver in each patient. RESULTS: Our study included 19 patients who ranged in age range from 18 to 44 years (mean age of 26 years). Seven of 19 patients (36.8%) had neurologic symptoms, including epileptic seizures in 2 patients (10.5%), encephalopathy in 1 patient (5.2%), tremor in 3 patients (15.7%), and headache in 1 patient (5.2%). The cause of these long-term neurologic complications was the immunosuppressive drugs. Patients with epileptic seizures were provided with seizure control medication (levetiracetam). Tremor did not need treatment. CONCLUSIONS: In Wilson disease, neurologic complications can be severe. The most common complication seen in our patients was tremor. Early diagnosis and treatment may slow down neurologic disability. PMID- 29527990 TI - Pretransplant Renal Arterial Vasculopathy of Donor Predicts Poor Renal Allograft Survival. AB - OBJECTIVES: Transplant vasculopathy is a significant predictor of poor outcome. We investigated whether age or pretransplant renal arterial vasculopathy of grafted kidneys affected allograft survival. MATERIALS AND METHODS: This study included 148 recipients and their donors. All donors underwent pretransplant renal arterial biopsy, with renal artery vascular score determined for each artery. Chronic rejection and graft loss were noted for all patients. RESULTS: Variable grades of pretransplant renal arterial lesions were noted in 103 donors (69.6%). A positive correlation was found between donor age and renal artery score (r = 0.650, P < .001), and chronic rejection and graft loss were found to increase with increasing score (P < .001). Recipient and donor age was significantly associated with graft loss and chronic rejection. With either younger or older donors, recipients had similar and best results regarding chronic rejection and graft loss if donors had renal artery scores of 0 or 1, but worse effects if donors had scores of 2 or 3. Five-year allograft survival rates for scores of 0, 1, 2, and 3 were 91%, 68%, 46%, and 33%. Univariate analyses showed that acute rejection episode (relative risk: 2.729, 95% confidence interval, 1.496-4.977; P = .001), older (? 50 y) donor age (relative risk: 1.970, 95% confidence interval, 1.038-3.736; P = .04), and donor renal artery score (relative risk: 2.466, 95% confidence interval, 1.382-4.401; P = .002) were associated with decreased allograft survival. Multivariate Cox analysis showed that only acute rejection episode (relative risk: 3.585, 95% confidence interval, 1.781-7.217; P < .001) and renal artery score (relative risk: 2.642; 95% confidence interval, 1.355-5.150; P = .004) were independent predictors of allograft survival. CONCLUSIONS: Pretransplant vasculopathy in donor renal artery implies a poor prognosis for renal allograft survival and is independent of other risk factors. Pretransplant renal artery biopsy is recommended for both deceased and living donors, and therapeutic interventions to modify transplant vasculopathy progression should start early posttransplant in recipients with affected renal arteries. PMID- 29527991 TI - Frequency of Finding Family Donors: A Single Center Experience. AB - OBJECTIVES: Allogeneic hematopoietic stem cell transplant is a curative treatment option for many hematologic diseases. The existence of a fully compatible donor for recipients is the first condition for minimized transplant-related mortality and morbidity. The best donor for hematopoietic stem cell transplant is an HLA matched sibling donor. The possibility of finding an HLA-matched sibling is less than 30% worldwide. Hematopoietic stem cell transplant is needed for an increasing number of patients every year, but the ability to find a fully compatible donor has limited its use. MATERIALS AND METHODS: From August 2012 to May 2017, we screened 412 adult patients who required AHSCT and their families for HLA tissue groups who were seen at our center (Baskent University Adana Dr. Turgut Noyan Research and Medical Center Hematology Unit). To screen tissue groups at our center, we perform lowresolution typing for HLA-A, -B, -C, -DRB1, and -DQB. If an HLA genotype cannot be identified, verification typing is done using highresolution testing. RESULTS: We found matched family donors in 227 (55%) of 412 patients screened at our center. The ratio of HLAmatched related donors was 83% for 279 patients who received allogeneic stem cell transplant. CONCLUSIONS: The likelihood of finding eligible unrelated donors has been gradually increasing, in part due to the development of the National Bone Marrow Bank. However, a careful screening for related donors is still important. Our findings indicate the importance of careful examination of family genealogy and of careful family screening in our region. PMID- 29527992 TI - The Effect of Standardized Interviews on Organ Donation. AB - OBJECTIVES: Organ donation is the most important stage for organ transplant. Studies reveal that attitudes of families of brain-dead patients toward donation play a significant role in their decision. We hypothesized that supporting family awareness about the meaning of organ donation, including saving lives while losing a loved one, combined with being informed about brain death and the donation process must be maintained by intensive care unit physicians through standardized interviews and questionnaires to increase the donation rate. MATERIALS AND METHODS: We retrospectively evaluated the final decisions of families of 52 brain-dead donors treated at our institution between 2014 and 2017. Data underwent descriptive analyses. The standard interview content was generated after literature search results were reviewed by the authors. Previously, we examined the impact of standardized interviews done by intensive care unit physicians with relatives of potential brain-dead donors regarding decisions to donate or reasons for refusing organ donation. After termination of that study, interviews were done according to the intensivist's orientation, resulting in significantly decreased donation rates. Standardized interviews were then started again, resulting in increased donation rates. RESULTS: Of 17 families who participated in standardized interviews, 5 families (29.4%) agreed to donate organs of their brain-dead relatives. In the other group of families, intensivists governed informing the families of donation without standardized interviews. In this group of 35 families, 5 families (14.3%) approved organ donation. The decision regarding whether to agree to organ donation was statistically different between the 2 family groups (P < .05). CONCLUSIONS: Conducting a standard interview between relatives of brain-dead donors and the intensivists, facilitating visits between relatives and the brain-dead patients, and informing relatives about the donation process resulted in an increased rate of organ donation compared with routine protocols. PMID- 29527993 TI - Nursing Care After Kidney Transplant: Case Report. AB - Kidney transplant is the leading treatment method for patients with recent renal failure in terms of quality of life, cost, and survival. After transplant, rejection, infection, cardiovascular diseases, malignancies, immunosuppressive therapy failure, and psychologic problems may occur. Posttransplant nursing care is as important as pretransplant nursing care in terms of enhancing quality of life, preventing complications, and providing necessary changes to treatment. In this report, we presented ways to increase quality of care after transplant and outlined standardized nursing care to reduce work and time loads by ensuring integrative and systematic approaches of nurses. PMID- 29527994 TI - Obesity in the Kidney Transplant Process. AB - Obesity, which has become an increasing problem worldwide, poses a risk for kidney transplant recipients both before and after surgery. In this literature review, we studied the effects of obesity before and after kidney transplant. There are numerous studies and different opinions on the effects of obesity on graft function before and after transplant. Obesity prolongs surgery time and the ischemic process. A large cohort study of 11 836 recipients noted a close association between body mass index and delayed renal transplant and delayed graft function. However, another study found that being overweight or obese before transplant did not have any effects over the medium and long term. A 20 year follow-up study indicated that the firstyear body mass index in recipients after renal transplant had a greater effect on graft function and survival than body mass index before transplant. Still, another study found that body mass index had no effects on graft function and survival. In the study, 3-year graft function and mortality rates of morbidly obese people without diabetes, the functional status without dialysis, and living-donor transplant were reported to be much lower than in those with normal weight. In conclusion, there is no consensus on the effects of obesity before and after transplant, and it has been pointed out that more research should be done on this subject. PMID- 29527995 TI - Factors Predisposing to the Use of Complementary Therapies in Patients With Chronic Renal Failure. AB - OBJECTIVES: Our aim was to gather information about complementary medicine applications used by chronic renal failure patients and their relation to demographic factors. MATERIALS AND METHODS: Of 1750 chronic renal disease patients who were undergoing hemodialysis, only 450 patients attended in the study. Among 450 patients, 388 gave consent and were interviewed using a previously tested questionnaire. Questions about complementary and alternative medicine use, a list of commonly used methods, and the sources of knowledge about these were asked of all patients. RESULTS: We observed a significant difference in the patients who were using complementary and alternative medicines before and after diagnosis of chronic renal disease (P < .001). We noted that 87% of the patients used complementary and alternative medicines before diagnosis and 49.8% used these after diagnosis. Among the patients who used complementary and alternative medicines, 76% had faith in these therapies. Of patients who used complementary and alternative medicines, 95% believed that the remedies or processes used were beneficial to their health. Furthermore, 71% of users had great confidence in these therapies and had no belief that these could be harmful. Of those who used complementary and alternative therapies, 51% had no idea whether these therapies were harmful. The source of knowledge was mass media tools (47%), social life (friends, relatives, neighbors, colleagues; 45%), and other patients with chronic renal disease (8%). CONCLUSIONS: Complementary and alternative medicine therapies have a significant impact on patients with chronic renal disease. Doctors can warn patients about possible dangers of complementary and alternative medicine remedies and treatments. PMID- 29527996 TI - Causes of Hemoptysis in Renal Transplant Patients. AB - OBJECTIVES: Hemoptysis is a symptom that can be caused by airway disease, pulmonary parenchymal disease, or pulmonary vascular disease, or it can be idiopathic. Infection is the most common cause of hemoptysis, accounting for 60% to 70% of cases. Hemoptysis is also an initial symptom of diffuse alveolar hemorrhage syndrome, although it may be absent at presentation in one-third of patients. Diffuse alveolar hemorrhage is characterized by disruption of the alveolar-capillary basement membranes because of either injury or inflammation of the arterioles, venules, or capillaries, resulting in bleeding in alveolar spaces. To date, no study in the literature has investigated the cause of hemoptysis in renal transplant patients. In this retrospective study, we aimed to investigate the causes of hemoptysis in renal recipients. MATERIALS AND METHODS: The data included in this study were obtained from 352 renal transplant patients who were consulted by the pulmonology department regarding hemoptysis between 2011 and 2017 at Baskent University. Patient medical records were reviewed for demographic, clinical, radiographic, bronchoscopic features, and microbiology data. Immunosuppressive drugs and clinical outcome data were also noted. RESULTS: This study included 352 renal transplant patients (139 male patients with mean age of 34.9 +/- 7 years and 113 female patients with mean age of 31.1 +/- 5 years). Hemoptysis was detected in 17 patients (4.8%),with 3 (0.85%) having massive hemoptysis as a result of diffuse alveolar hemorrhage syndrome. Fourteen of our patient group (4%) had pneumonia, and Aspergillus species was detected in 5 patients (1.4%). The only reason for diffuse alveolar hemorrhage was immunosuppressive agents, including sirolimus and mycophenolate mofetil. CONCLUSIONS: Hemoptysis is an important respiratory symptom in renal transplant patients. Although community- or hospital-acquired pneumonia may result in hemoptysis, drug-induced diffuse alveolar hemorrhage and Aspergillus infection should be considered for causes in renal transplant patients. PMID- 29527997 TI - Hand-Grip Strength Is Associated With Serum Testosterone and Albumin Levels in Male Kidney Transplant Recipients. AB - OBJECTIVES: In kidney transplant recipients, reduced muscle mass and hand-grip strength are associated with impaired nutritional status. Serum testosterone is highly associated with muscle strength in the general population. Here, we aimed to determine the associations among serum testosterone, hand-grip strength, and nutritional and inflammatory parameters, as well as graft function. MATERIALS AND METHODS: Our study included 144 stable male kidney transplant recipients from our renal transplant outpatient clinic. All patients were evaluated for clinical parameters (age, duration of hemodialysis, and posttransplant time), biochemical parameters (calcium, phosphorus, parathyroid hormone, C-reactive protein, albumin, creatinine), and serum testosterone levels. Body composition was analyzed with the bioimpedance spectroscopy analysis technique using a body composition monitor that estimates body mass index and percent fat. Hand-grip strength was analyzed by using a dynamometer (ProHealthcareProducts.com, Park City, UT, USA). We calculated estimated glomerular filtration rate using the Modification of Diet in Renal Disease-4 equation. RESULTS: Demographic characteristics, duration of dialysis before transplant, biochemical parameters, and estimated glomerular filtration rates were similar among study patients. Mean (standard deviation) serum testosterone was 588.0 (55.5) ng/dL, mean body mass index was 26.8 (0.6) kg/m2, and mean hand-grip strength was 42.2 (1.7) mm2. Serum testosterone levels were positively correlated with hand-grip strength (r = 0.445; P = .033) and serum albumin (r = 0.399; P = .05) and negatively correlated with serum C-reactive protein (r = -0.454; P = .05) and age. In linear multiple regression analysis, serum albumin (P = .033) and testosterone levels (P = .038) were shown to be predictors of hand-grip strength. However, we could not show a significant correlation between graft function and testosterone. CONCLUSIONS: Serum testosterone level is correlated with hand-grip strength and C-reactive protein and albumin levels, which may indicate that testosterone affects nutritional status and inflammation in male renal transplant recipients. PMID- 29527998 TI - Posttransplant Pulmonary Hypertension Is Correlated With Acute Rejection and Death Among Cardiac Transplant Recipients: A Single Center Study. AB - OBJECTIVES: Endomyocardial biopsy sampling is used to check acute rejection after cardiac transplant. However, it may lead to tricuspid valve injury and cardiac perforation; therefore, less invasive tools may be useful. Right heart catheterization provides valuable information about cardiac hemodynamics. Herein, we aimed to determine the correlation of right heart catheterization parameters with acute rejection and death during cardiac transplant follow-up. MATERIALS AND METHODS: We retrospectively evaluated follow-up right heart catheterization and endomyocardial biopsy results from 47 adult patients who underwent cardiac transplant at Baskent University Faculty of Medicine between 2004 and 2016. Right heart catheterization parameters were compared between deceased and surviving patients and were correlated with acute cellular and humoral rejection. Averaged right heart catheterization parameters were correlated with death. We used Cox regression analysis to determine risk of death and acute cellular rejection and Kaplan-Meier survival analysis to determine any survival differences associated with pulmonary hypertension. RESULTS: There were 47 patients (38 males, 9 females) with a mean age of 44 +/- 10 years at transplant. In our patient group, 18 patients (38.3%) died at a median time of 11.2 months. Ninety endomyocardial biopsy samples (22.1%) showed cellular rejection, and 61 samples (4.5%) showed humoral rejection. The deceased patients had significantly greater mean and systolic pulmonary artery pressures, which were significantly correlated with acute cellular rejection. Death was significantly correlated with averaged values of mean and systolic pulmonary artery pressures. Our Cox regression analysis revealed that pulmonary hypertension was significantly associated with risk of death and acute cellular rejection. A Kaplan-Meier survival analysis revealed that pulmonary hypertension was associated with a significantly lower median survival. CONCLUSIONS: Pulmonary artery pressures are significantly correlated with acute cellular rejection and death after cardiac transplant. Pulmonary hypertension significantly increases the risk of death and shortens survival after cardiac transplant. PMID- 29527999 TI - Prevalence and Angiographic Characteristics of Coronary Vasospasm Detected at Surveillance Coronary Angiograms Among Patients With Heart Transplants. AB - OBJECTIVES: Coronary vasospasm in heart transplant recipients occurs through various mechanisms. It has been linked to allograft rejection and coronary vasculopathy, which can result in mortality during follow-up. Here, we investigated the prevalence of coronary vasospasm among heart transplant recipients undergoing surveillance coronary angiography procedures. MATERIALS AND METHODS: This study was prospectively performed at Baskent University Faculty of Medicine by retrospectively analyzing medical information of patients who underwent bicaval heart transplant between 2003 and 2016 and subsequently had coronary angiography to rule out allograft vasculopathy. We analyzed prevalence of coronary vasospasm, affected vessels, underlying vessel properties, and treatment modalities. Coronary vasospasm was defined as transient diffuse or localized luminal narrowing, either spontaneously or catheter-induced, relieved spontaneously or with nitroglycerine. RESULTS: Forty-one coronary angiography procedures were performed using the standard Judkins technique. Among these, 5 patients showed coronary vasospasm a mean of 2 years after cardiac transplant. All vasospasm episodes involved the left anterior descending artery, with 2 also involving the circumflex artery and 1 involving the right coronary artery. The degree of luminal narrowing ranged from mild to severe. Episodes that involved the left anterior descending artery more often diffusely involved most of the vessel. In 3 patients, vasospasms were recurrent. Three patients had underlying coronary artery disease, which was relieved in 2 patients who progressed by stent implant. Neither ischemic events nor reduction of ejection fraction was observed during follow-up. There were also no occurrences of cellular or humoral rejection or death in any of the patients with vasospasm. CONCLUSIONS: Coronary vasospasm is common in heart transplant recipients. It may be diffuse or localized and occur spontaneously or because of underlying coronary artery disease. Factors, including allograft vasculopathy, associated with coronary vasospasm remain to be determined, and further related research is needed. PMID- 29528000 TI - Clinical and Morphologic Diagnostic Assessments of Liver Diseases After Liver Transplant. AB - OBJECTIVES: At the National Scientific Center of Surgery named A. Syzganova, more than 100 liver transplants have been conducted from 2012 to November 2017. Survival and quality of life of patients in the posttransplant period largely depend on the compliance of patients, monitoring of complications, cause of liver disease, the severity of the condition of patients in the pretransplant period, and the technical features of the operation. The aims of the study were to analyze the results of liver biopsy in patients after liver transplant and to evaluate the value of morphologic studies of the liver for the diagnosis of complications in the posttransplant period. MATERIALS AND METHODS: Liver transplant recipients undergoing liver biopsy between 2012 and 2017 were analyzed. Our study included 40 liver biopsies in 29 patients after orthotopic liver transplant who fulfilled the inclusion criteria. RESULTS: In 51.7% of cases in patients (that is, in 15 of 29 patients), biopsy data revealed changes characteristic of rejection. Biliary complications were found in 10.34% of patients, recurrent liver diseases were confirmed in 17.24% of patients, 3.45% of patients had confirmed cholangitis, and 6.90% of patients were diagnosed with liver steatosis. CONCLUSIONS: Histopathology assessment of allograft liver biopsies plays an important role in the differential diagnosis of posttransplant complications and in identifying the cause of graft damage; having this information can lead to the appropriate therapeutic intervention. PMID- 29528001 TI - Nonmelanoma Skin Cancers in Solid-Organ Transplant Recipients: A Single Center Experience. AB - OBJECTIVES: Skin cancers are one of the most common malignancies in solid-organ transplant recipients. Increased age and immunosuppressive drug use are risk factors for posttransplant skin malignancies. We evaluated nonmelanocytic skin cancer incidence and development time in transplant patients. MATERIALS AND METHODS: We reviewed 1833 patients who received kidney, liver, and heart grafts between 1996 and 2016 at Baskent University. We excluded melanocytic skin cancers, premalignant lesions, and benign skin tumors. RESULTS: Of 1833 patients, 1253 were male (68.4%) and 580 were female (31.6%), composed of 1133 kidney (61.8%), 512 liver (27.9%), and 120 heart recipients (6.5%). Of these, 22 patients (18 kidney/3 liver/1 heart) developed 23 different types of skin cancer. Prevalence of skin cancer was 1.20%. Mean age at presentation was 55.8 years (range, 37-71 y). Average time from transplant to skin malignancy was 6.1 years (range, 1-13 y), with the most common being basal cell carcinoma (43%, 10 cases), followed by squamous cell carcinoma (39%, 9 cases) and Kaposi sarcoma (13%, 3 cases). Tumor sites included head and neck (15 case), trunk (2 cases), lower extremity (2 cases), and upper extremity (2 cases). Neither local recurrence nor distant metastasis was shown. CONCLUSIONS: Skin cancer risk is increased in solid organ transplant recipients versus the general population. Although squamous cell carcinoma is the most common tumor in this patient population, followed by basal cell carcinoma, we found this reversed in our patients. The low prevalence of skin malignancy (1.20%) may be associated with close clinical follow-up to detect premalignant skin lesions and the lowdose immunosuppressive drug regimen. We believe that local recurrence and distant metastasis were absent because we use a wide surgical margin of excision and provide strict follow-up. Routine dermatologic follow-up visits of transplant recipients are recommended to detect and treat early skin cancer and premalignant lesions and thus lower morbidity and mortality. PMID- 29528002 TI - Descemet Membrane Endothelial Keratoplasty: Outcomes in the First Year of Experience. AB - OBJECTIVES: We aimed to report the clinical outcomes of Descemet membrane endothelial keratoplasty in our first year of experience. MATERIALS AND METHODS: Patients who underwent Descemet membrane endothelial keratoplasty at the Baskent University Faculty of Medicine, Department of Ophthalmology, between 2015 and 2016 were included in the study. Patient demographics, cause of endothelial dysfunction, best-corrected visual acuity, central corneal thickness, graft survival, follow-up duration, and intraoperative and postoperative complications were recorded. RESULTS: Five eyes of 5 patients (4 female, 1 male) with a mean age of 53.4 +/- 12.7 years were included. Cause of endothelial dysfunction included corneal endothelial dystrophy in 3 patients, pseudophakic bullous keratopathy in 1 patient, and endothelial graft failure after previous penetrating keratoplasty in 1 patient. Pre-stripped Descemet membranes obtained from the Ankara State Hospital Eye Bank were used. Mean duration of postoperative follow-up was 7.4 +/- 3.7 months. Mean preoperative Snellen best-corrected visual acuity and central corneal thickness were 0.24 +/- 0.15 and 625.5 +/- 97.4 MUm. Mean best-corrected visual acuity increased to 0.67 +/- 0.26 (P = .02) in the first month and to 0.84 +/- 0.11 (P < .01) at the end of follow-up. Mean central corneal thickness decreased to 546.6 +/- 28.4 MUm (P = .03). Graft detachment was observed in 1 patient on the first postoperative day, and it was reattached successfully by injection of air into the anterior chamber. There were no intraoperative complications. All corneas were clear at the end of follow-up. CONCLUSIONS: Descemet membrane endothelial keratoplasty provides a new and exciting option for endothelial transplant and has the potential to become the primary procedure for surgical management of Fuchs endothelial dystrophy and corneal endothelial disease. Rapid visual rehabilitation with few and manageable complications and good visual outcomes are the major advantages of this procedure. PMID- 29528003 TI - Experience With Cardiac Implantable Electrical Device Explantation After Cardiac Transplantation: A Report of 16 Cases From a Single Center in a Period of 5 Years. AB - OBJECTIVES: Cardiac implantable electrical devices are widely used for patients with advanced heart failure and are usually explanted during orthotopic heart transplant. However, lead fragments and the pulse generator are sometimes left after the procedure. Given the concerns of infectious and thromboembolic complications, their removal is recommended. Herein, we report our experience with cardiac implantable electrical device explantation after orthotopic heart transplant. MATERIALS AND METHODS: We included recipients of heart transplants performed at Baskent University Faculty of Medicine, Department of Cardiovascular Surgery, who underwent lead and pulse generator explantation by manual traction between January 2012 and June 2017. We analyzed patient demographic, clinical, biochemical, and treatment properties. RESULTS: Sixteen patients (11 males, 5 females) with a median age of 45 years (range, 18-52 y) were included. Two patients (12.5%) died during follow-up but not secondary to device explantation. All patients were using immunosuppressives and 50% were receiving antiplatelet/anticoagulant agents. All pulse generators were located at the left prepectoral area, with tips of lead fragments in the superior vena cava or left subclavian vein. No procedural complications were observed. Aspirin was continued uninterrupted perioperatively, warfarin was stopped 2 days before the procedure, and low-molecular-weight heparins were skipped on the morning and evening of the procedure. One patient (6.3%) complained of postoperative pain, and another (6.3%) developed a pocket hematoma, which was treated conservatively. No patient developed fever, clinical infection, or major bleeding. Preoperative and postoperative levels of hemoglobin, white blood cells, and C-reactive protein were similar. No demographic, procedural, or biochemical variable was significantly correlated with postprocedural complications. CONCLUSIONS: In our cohort, explantation of lead fragments and pulse generators of cardiac implantable electrical devices was safe after heart transplant. It appears that neither antiplatelet/anticoagulant agents nor immunosuppressives seem to put patients at increased risk of postoperative complications. PMID- 29528004 TI - The Economics of Organ Transplantation. AB - To determine the cost effectiveness of transplantation, we analyzed the financial economics of the organ and tissue transplant process. We compared the cost of this process with traditional modalities for treating endstage liver and kidney disease. Medical, surgical, legal, social, ethical, and religious issues are important in organ transplant procedures. Government, health insurance companies, and uninsured individuals are affected by the financial economics of organ transplantation. The distribution of financial burden differs among countries and is dependent on the unique circumstances of each country. PMID- 29528005 TI - Influence of Social, Economic, Familial, Marital Status, and Disease Adaptation on the Physical and Mental Health Dimensions of Patients Who Are Candidates for Renal Transplant. AB - OBJECTIVES: End-stage renal disease is a disease with a long duration, requiring patients to live with the limitations imposed by their condition. Stressors associated with this disease are demanding, with patients dependent on support from their social environment. Here, we aimed to show the influences of familial, social, economic, and marital status on quality of life in patients with end stage renal disease. MATERIALS AND METHODS: Patients (190 women/188 men) who were under hemodialysis treatment and on transplant wait lists were included in the study. To evaluate the quality of life, patients completed the Short Form 36 health survey questionnaire voluntarily while undergoing hemodialysis treatment. All Short Form 36 questionnaire components were analyzed separately, and all social, economic, and business life dimensions were examined with another questionnaire. RESULTS: Significant differences were observed between single and married patients regarding physical and mental health dimensions (P < .001), with quality of life higher in single patients than in married. Patients who lived in villages had lower health quality than patients who resided in cities or towns (P < .01). Patients who were home owners and who had a job had higher degrees of health quality than those who did not (P < .01). The lowest Short Form 36 scores were in housewives and farmers (P < .001). Comparisons between patients who went home after hemodialysis versus those who went to work showed better Short Form 36 scores in working patients (P < .001). Patients with private insurance and family support had better Short Form 36 scores (P < .001). Patients who did not comply with their doctor and dietician showed the lowest health quality (P < .05). Regular or irregular drug use did not affect scores. CONCLUSIONS: Familial, social, economic, and marital statuses, in addition to the influence of disease adaptation, independently affected the well-being of patients with end-stage renal disease. PMID- 29528006 TI - Effects of Web-Based Educational Intervention on Self-Management in Kidney Recipients. AB - Information technology and the Internet are rapidly becoming effective tools for teaching. Selfmanagement skills are important for adaptation and long-term survival in kidney recipients. Web-based training may help patients develop self management skills through information access. This literature review aimed to determine the effects of Web-based educational intervention on self-management in kidney recipients. The Internet supports effective health education intervention strategies by providing a learning environment that is always available. Medicine management, routine follow-up, awareness of the signs and symptoms of rejection, infection prevention, self-monitoring, physical activity, and nutrition are important during the posttransplant period. Another important component of achievement in related matters is the competence of individuals with their own self-management. Webbased training is beneficial for appointment follow-up, nutritional adaptation, and treatment of anxiety and depression. Web-based training allows kidney recipients to access information at any time and place; this information promotes proper self-management. PMID- 29528007 TI - Ultrasonography Findings of Urinary Tract Infection After Kidney Transplant: A Case Report. AB - Urinary tract infection is the most common complication after kidney transplant and often is associated with graft loss and mortality. Ultrasonography is the most widely applied imaging modality for diagnosis of complications after kidney transplant. Here, we report a case of a 52-year-old male patient who underwent renal transplant 1 month earlier and who presented with fever, leukocytosis, and leukocyturia. Klebsiella pneumoniae was found in the urine and blood cultures. Ultrasonography revealed multiple, ill-defined margined, hypoechoic areas and cysts within the cortex. Both clinical findings and ultrasonography findings were resolved after antimicrobial therapy. One month later, the patient presented again with fatigue, leukocytosis, and leukocyturia. Blood and urine culture results were consistent with Klebsiella pneumoniae. Ultrasonography revealed large hypoechoic mass, including multiple cysts in the upper pole of the transplanted kidney. Doppler ultrasonography showed increased vascularity within the hypoechoic mass and surrounding parenchyma. Renal parenchymal echogenicity was also increased in the upper pole. Ultrasonography-guided percutaneous drainage was performed. Clinical, laboratory, and ultrasonography findings were resolved after antimicrobial therapy. Ultrasonography plays an important role in the diagnosis and evaluation of the treatment response of urinary tract infections after kidney transplant. PMID- 29528008 TI - Pneumonia in Renal Transplant Recipients: A Single-Center Study. AB - OBJECTIVES: Pulmonary infections are a significant cause of morbidity and mortality in solid-organ transplant recipients despite enhanced facilities for perioperative care. The aim of this study was to evaluate the demographic characteristics, clinical course, and outcomes of renal transplant recipients with pneumonia. MATERIALS AND METHODS: The medical records of all renal transplant recipients from January 2010 to December 2014 were retrospectively reviewed, and patients diagnosed with pneumonia according to Centers for Disease Control and Prevention criteria were evaluated. Pneumonia was classified as community acquired or nosocomial. Patient demographics, microbiologic findings, need for intensive care/mechanical ventilation over the course of treatment, and information about clinical follow-up and mortality were all recorded. RESULTS: Eighteen (13.4%) of 134 renal transplant recipients had 25 pneumonia episodes within the study period. More than half (56%) of the pneumonia episodes developed within the first 6 months of transplant, whereas 44% developed after 6 months (all > 1 year). Eight cases (32%) were considered nosocomial pneumonia, and 17 (68%) were considered community-acquired pneumonia. Bacteria were the most common cause of pneumonia (28%), and fungi ranked second (8%). No viral or mycobacterial agents were detected. No patients required prolonged mechanical ventilation. No statistically significant difference was found in the need for intensive care or regarding mortality between patients with nosocomial and community-acquired pneumonia. Two patients (11%) died, and all remaining patients recovered. CONCLUSIONS: The present study confirmed that pneumonia after renal transplant is not a rare complication but a significant cause of morbidity. Long-term and close follow-up for pneumonia is necessary after renal transplant. PMID- 29528009 TI - Renal Allograft With Calcium Oxalate Deposition: Association with Urinary Tract Infection and Development of Interstitial Fibrosis. AB - OBJECTIVES: The interaction between calcium oxalate deposition and urinary tract infection is not well established. We aimed to identify the association between these and to determine the role of calcium oxalate deposition on interstitial fibrosis development. MATERIALS AND METHODS: Renal allograft biopsies of 967 patients were reviewed to identify those with calcium oxalate deposition in the renal allograft, with 27 (2.8%) identified. Follow-up biopsies were conducted to reevaluate for calcium oxalate presence and interstitial fibrosis development. At time of biopsy, presence of urinary tract infection and oxaluria was also examined from medical records. RESULTS: Mean time for development of calcium oxalate deposition in renal allografts was 1.7 +/- 0.4 and 32.7 +/- 21.6 months in patients with primary and secondary oxalosis, respectively (P < .001). Of 27 patients with calcium oxalate deposition, 7 (25.9%) showed tubulointerstitial nephritis, with 2 also having urinary tract infection. Four patients (14.8%) had only urinary tract infection. Causes of tubulointerstitial nephritis were secondary to bacterial infection in 2 and secondary to viral infection in 5 patients (2 polyomaviruses, 2 cytomegaloviruses, 1 adenovirus). Time until development of interstitial fibrosis after calcium oxalate deposition was 3.5 +/- 2.1 and 10.3 +/- 4.1 months in patients with primary and secondary oxalosis, respectively (P = .01). Time until graft loss after calcium oxalate deposition was 9.3 +/- 7.8 and 21.8 +/- 12 months in those with primary and secondary oxalosis (P < .001), with 1-, 3-, and 5-year kidney graft survival of 43%, 28%, and 0% and 100%, 100%, and 67% in those with primary and secondary oxalosis, respectively. CONCLUSIONS: Calcium oxalate deposits increased the risk of urinary tract infection and tubulointerstitial nephritis, with bacteria inducing increased presence of calcium oxalate deposition in a renal allograft. Calcium oxalate deposition had a significant influence on interstitial fibrosis development, therefore negatively affecting graft survival. PMID- 29528010 TI - De Novo Thrombotic Microangiopathy in Renal Transplant Patients. AB - OBJECTIVES: Thrombotic microangiopathy is a form of renal capillary injury possibly associated with calcineurin inhibitor toxicity, acute humoral rejection, infections, and recurrent diseases. Here, we examined its incidence in patients diagnosed with acute and chronic active humoral rejection, polyomavirus nephropathy, acute cellular rejection, and immunoglobulin A recurrence. MATERIALS AND METHODS: In total, 272 renal allograft recipients who met the inclusion criteria were reevaluated for presence of renal thrombotic microangiopathy. Thrombotic microangiopathy diagnosis was established by clinical, laboratory, and histologic features. C4d expression in peritubular capillaries was determined. Clinical data were collected from medical records. RESULTS: Of 272 patients (mean age of 42.8 +/- 12.7 years), only 74 patients (27.2%) had de novo thrombotic microangiopathy, which was found in 30/90 patients (33.3%) with acute humoral rejection, 9/51 (17.6%) with acute cellular rejection, 22/53 (41.5%) with chronic active humoral rejection, 10/55 (18.2%) with polyomavirus nephropathy, and 3/23 (13%) with immunoglobulin A nephropathy. Significant differences were shown between therapy type and thrombotic microangiopathy development (P = .02). Patients who received cyclosporine (38.5%) tended to show higher incidence of thrombotic microangiopathy than patients who received tacrolimus (20.7%) or sirolimus (7.7%). Patients with C4d-positive acute humoral (97.6% vs 2.4%) and chronic active humoral rejection (68.2% vs 31.8%) had greater incidence of thrombotic microangiopathy versus those who were C4d-negative. Graft loss was significantly higher in C4d-positive than in C4d-negative thrombotic microangiopathy groups (P < .001). Overall 1-, 3-, and 5-year graft survival was 94%, 85%, and 85% versus 83%, 51%, and 51% in thrombotic microangiopathy-negative versus thrombotic microangiopathy-positive patients (P < .001). CONCLUSIONS: Acute humoral rejection and chronic active humoral rejection were the most common and therefore most important causes of de novo thrombotic microangiopathy in renal transplant patients. Its presence in the renal allograft biopsy should arouse suspicion for underlying acute or chronic active humoral rejection. PMID- 29528011 TI - FGF23, NGAL, and Endostatin: the Predictors of Allograft Function in Renal Transplant Recipients. AB - OBJECTIVES: Increased circulating levels of fibroblast growth factor 23, neutrophil gelatinase-associated lipocalin, and endostatin are independent risk factors for cardiovascular disease. Here, we evaluated correlations among these parameters and graft dysfunction and their relation with arterial stiffness. MATERIALS AND METHODS: This prospective study included 73 maintenance kidney transplant patients with stable allograft function who had received the transplant at least 36 months previously. We calculated the estimated glomerular filtration rate (eGFR). Pulsewave velocity was determined. Serum levels of fibroblast growth factor 23, neutrophil gelatinaseassociated lipocalin, and endostatin were measured by enzyme-linked immunosorbent assay. RESULTS: Demographic characteristics and pulse-wave velocity values were similar in groups 1 and 2 (GFR < 60 and > 60 mL/min, respectively). Mean levels of fibroblast growth factor 23 (P = .036), neutrophil gelatinaseassociated lipocalin (P = .018), and endostatin were significantly higher in group 1. Fibroblast growth factor 23 was negatively correlated with eGFR (r = -0.267, P = .023) and positively correlated with neutrophil gelatinase-associated lipocalin (r = 0.258, P = .036) and endostatin (r = 0.321, P = .006). Serum endostatin levels were positively correlated with pulse-wave velocity (r = 0.276, P = .019). In linear regression analysis, eGFR was detected as the unique predictor of neutrophil gelatinase-associated lipocalin (P = .001). In addition, each 1 mL/min decrease in eGFR resulted in a 0.281 pg/mL increase in fibroblast growth factor 23 (P = .023) and a 0.04 ng/mL increase in neutrophil gelatinase-associated lipocalin (P = .007); each 1 cm/s increase in pulse-wave velocity resulted in a 3648.7 U/L increase of endostatin (P = .019). CONCLUSIONS: All 3 parameters were associated with loss of graft function in kidney transplant recipients. Moreover, endostatin can be used as an independent predictor for cardiovascular morbidity in this population. PMID- 29528012 TI - Morphologic and Immunologic Characteristics of Hepatocellular Carcinoma for Prognosis of Surgical Intervention. AB - OBJECTIVES: Hepatocellular carcinoma is the predominant malignancy in patients with cirrhosis and chronic liver disease. Our aim was to assess the morphologic, radiologic, and immunologic charac teristics of hepatocellular carcinoma and liver cirrhosis concerning surgical treatment tactics. MATERIALS AND METHODS: We performed a cross-sectional analysis of a prospective study performed at the JSC National Scientific Center of Surgery (named after A. Syzganov). The study included 58 patients: 31 with hepatocellular carcinoma (53.4%) and 27 with chronic liver disease (46.6%). The average age of patients was 55.6 +/- 1.7 years. RESULTS: Patients were tested for hepatitis B virus and hepatitis C virus infection. Patients with elevated levels of alfa-fetoprotein, alanine aminotransferase, and total bilirubin were detected. Morphologic signs of hepatocellular carcinoma with a predominance of a trabecular type rather than a solid type of tumor were found. Patients with hepatocellular carcinoma underwent surgical liver resection and transarterial chemoembolization before living-donor liver transplant. One-year survival rate of patients with hepatocellular carcinoma was 93.5%. CONCLUSIONS: The diagnosis and surgical options for hepatocellular carcinoma should be studied, taking into account the expanded laboratory characteristics of cancer. PMID- 29528013 TI - Early Postoperative Infections After Liver Transplant. AB - OBJECTIVES: Despite surgical advances and effective prophylactic strategies in liver transplant, infection is still a major cause of morbidity and mortality. Up to 80% of liver recipients will develop at least 1 infection during the first year after liver transplant. The spectrum and manifestations of these infections are broad and variable. Their diagnosis and treatment are often delayed because immunosuppressive therapy diminishes inflammatory responses. However, if an infection is not identified early enough and treated properly, it can have devastating consequences. In addition, prophylactic approaches remain controversial. Our aim was to review our early postoperative infection management after liver transplant. MATERIALS AND METHODS: We retrospectively evaluated infections that occurred during the first hospital stay of transplant patients. Infections were grouped as surgical site and nonsurgical site infections. Consequences and treatment protocols of infections were stratified according to the Clavien scale. RESULTS: Between December 1988 and January 2017, we performed 561 liver transplants at our center (patient age range, 6 months to 64 years), which included 401 living-donor (72%) and 160 deceaseddonor (28%) liver transplants. Early postoperative infections were detected in 131 patients (23.3%), comprising 67 surgical site (51%), 56 nonsurgical site (43%), and 8 combined surgical and nonsurgical site infections (6%). Although no mortalities occurred in patients with single nonsurgical or surgical site infections, there were 4 mortalities in patients with combined surgical and nonsurgical site infections. In the 4 other patients with combined infections, 3 patients required endoscopic or radiologic intervention and 1 recovered from single-organ dysfunction. CONCLUSIONS: Initiation of appropriate prophylactic and therapeutic protocols at the right time decreases morbidity and mortality due to infection in liver transplant recipients. Increased understanding and effective approaches to prevent infection are essential to improving both graft and recipient survival. PMID- 29528014 TI - Liver Peliosis: A Life-Threatening Condition With No Clear Indication for Liver Transplant. AB - We present a 21-year-old patient, remarkable for huge hepatomegaly with the liver, occupying almost the entire abdominal cavity, and mild portal hypertension due to splenic vein compression. After ultrasonography-guided liver biopsy, performed to establish the diagnosis, the patient had bleeding from the liver. Fortunately, emergency laparotomy was started immediately, and the patient was saved. Macroscopically, the liver appeared to be of purple-red color, flabby to the touch, and able to be easily wrinkled with fingers. When all available clinical data were considered, a diagnosis of liver peliosis was made. The patient was recommended close follow-up at the specialized liver surgery clinic with access to emergency surgical procedures, including liver transplant. PMID- 29528015 TI - Prognosis of Patients Following Liver Transplant From Deceased and Living Donors. AB - OBJECTIVES: Liver transplant is the only treatment option for patients with end stage liver disease. MATERIALS AND METHODS: Liver transplant procedures performed from June 2013 to March 2017 were evaluated. We evaluated the postoperative period in recipients of livers from deceased and living donors. RESULTS: Of 31 liver transplant procedures in 30 recipients, 12 were from deceased and 19 from living donors. The final analysis included 24 liver transplants (11 males, 13 females), with 10 from deceased and 14 from living donors. No deaths or life threatening and debilitating complications were shown in liver donors. All living donor liver transplants were performed utilizing the right lobe, the volume of which was calculated using contrast-enhanced computed tomography. Most living donor liver recipients had viral hepatitis, whereas most deceased-donor liver recipients had autoimmune liver disease. Median age of recipients of deceased donations was 39.3 years (median admission duration of 28.1 days), and median age of recipients of donations from living donors was 45.4 years (median admission duration of 36.4 days). All patients were started on an immunosuppression protocol, which included basiliximab on days 0 and 4, tacrolimus, mycophenolate, and prednisolone. Of 24 recipients, 5 were taking prednisolone 10 mg/day or less at discharge. CONCLUSIONS: Most of our liver transplant procedures were living donor liver transplants (61.3%). Most patients who received living donations had viral hepatitis, with all cases related to autoimmune liver disease receiving deceased donations. This may be related to the possibility of antiviral therapy controlling all stages of liver disease versus no chance of controlling autoimmune liver disease. Living-donor liver transplant recipients required more time to recover to reach initial liver volume; 20.8% of recipients were discharged with prednisolone of 10 mg/day or less. Our results suggest a need for further development of nonsteroidal immunosuppression strategies to minimize infections and steroid-related adverse effects. PMID- 29528016 TI - Liver Transplant and Reexpansion Pulmonary Edema: A Case Report. AB - Hydrothorax occurs frequently in patients with endstage liver disease and usually requires drainage of pulmonary effusion during the hepatectomy phase of liver transplant. Reexpansion pulmonary edema is a rare but potentially fatal complication seen after rapid reexpansion of the collapsed lung following thoracentesis of pleural fluid or tube drainage of pneumothorax. This condition, which manifests with various degrees of clinical severity, is rarely reported following liver transplantation. Herein, we present a 62-year-old male patient who developed reexpansion pulmonary edema after drainage of massive pleural effusion, which caused a total collapse in the right hemithorax during liver transplant. Six hours after pleural fluid drainage, the patient developed a nonproductive cough, mild tachypnea, shortness of breath, and low oxygen saturation (88%). His chest radiograph showed diffuse heterogeneous opacities in the right hemithorax. Computed tomography of the thorax revealed consolidations containing air bronchograms and ground glass opacities in the parenchyma of the right lung; these findings did not extend to the periphery and were observed less frequently in the inferoposterior left lung. These symptoms and radiologic findings were diagnosed as reexpansion pulmonary edema. Complete clinical and radiologic improvements were achieved within 72 hours of mechanical ventilatory support. PMID- 29528017 TI - Budd-Chiari Syndrome Diagnosed in a Patient Listed for Liver Transplant and Considered to be Contraindicated for the Operation. AB - We report the clinical case of 23-year-old patient with liver cirrhosis of unknown genesis, significant resistant ascites, and 2 episodes of bleeding from esophageal varices. Evaluation did not find any cause of liver disease, and the patient was placed on the transplant wait list due to subcompensated liver function (Model for End-Stage Liver Disease score of 16, Child-Pugh class B) and poorly controlled severe portal hypertension. After treatment with diuretics, largevolume paracentesis, antibiotics, and vasoconstrictors, hepatorenal syndrome and spontaneous bacterial peritonitis resolved and liver function improved significantly. Because the patient showed consistently good liver function and resistant portal hypertension, liver transplant was delayed with decision to perform transjugular intrahepatic portosystemic shunting instead. During the attempt of shunting, occlusive thrombosis of the iliac veins, inferior vena cavae, and hepatic veins were diagnosed and the procedure was stopped. Therefore, considering preserved liver function and severe portal hypertension, diagnosis of Budd-Chiari syndrome with subsequent development of liver cirrhosis was made. The patient was recommended to undergo evaluation to exclude thrombophilia as a cause of thrombosis. PMID- 29528018 TI - Smoking Behavior of Heart Transplant Patients: A Retrospective Study. AB - OBJECTIVES: Smoking is an important risk factor for development of complications in heart transplant patients and plays an important role in the mortality of these patients. The aim of this study was to compare the survival of heart transplant patients after transplant versus their smoking status before transplant. MATERIALS AND METHODS: Patients who had heart transplant procedures at the Baskent University Hospital Cardiovascular Surgery Department between 2005 and 2016 were analyzed retrospectively with regard to their smoking status and survival after transplant. We divided the 51 included adult patients into 2 groups: nonsmokers and ex-smokers. Data were analyzed with SPSS software (Statistical Package for Social Sciences for Windows, version 23.0, SPSS Inc., Chicago, IL, USA). Descriptive statistics are shown as means +/- standard deviation, and differences between means were determined with t tests. Survival statistics were evaluated with Kaplan-Meier analyses using log-rank test. RESULTS: Of 51 heart transplant patients, 40 were male (78.4%) and 11 were female (21.6%) patients. Mean age was 42.5 +/- 14.2 years in male patients and 30.4 +/- 13.2 years in female patients (95% confidence interval, 2.4-21.8). Although 36 patients(70.6%) were still living at follow-up, 15 patients had died (29.4%). According to smoking status, 30 patients (58.8%) were nonsmokers and 21 patients (41.2%) were ex-smokers, who showed smoking rate of 23.7 +/- 26.0 packs/year. We found that patients who were nonsmokers survived longer; however, at time of analysis (September 30, 2017), survival was not mature yet for the nonsmoking group. Median survival time for patients who were ex-smokers was 93.0 months(log rank test = .099) CONCLUSIONS: Our study showed that patients in the nonsmoking group survived longer after heart transplant. Early smoking cessation can prolong survival of heart transplant patients. PMID- 29528019 TI - Treatment of Left Ventricular Assist Device Thrombosis: Single-Center Experience. AB - Heart failure is the one of the biggest health problem in the world. Because of limited donors for heart transplant procedures, the ventricular assist device has become a solution for heart failure therapy. With the increase in number of ventricular assist devices, the incidence of complications has also increased. One of the most important life-threatening complications is ventricular assist device thrombosis. Medical therapy and changes in the ventricular assist device are the main therapy methods for ventricular assist device thrombosis. In this study, we showed our clinical experience with treatment of ventricular assist device thrombosis. PMID- 29528020 TI - Transforming Growth Factor beta1 in Patients with Type 2 Diabetes Mellitus After Fetal Pancreatic Stem Cell Transplant. AB - OBJECTIVES: Our objective was to determine transforming growth factor beta1 levels in patients with type 2 diabetes mellitus after fetal pancreatic stem cell transplant. MATERIALS AND METHODS: We examined 10 patients (age range, 41-65 y) with type 2 diabetes mellitus, which we subsequently divided into 2 groups. Group 1 comprised 5 patients who received fetal pancreatic stem cell transplant (cells were 16-18 wk gestation) performed by intravenous infusion. Group 2 comprised 5 patients (control group) who were on hypoglycemic tablet therapy or insulin therapy. The quantity of fetal stem cells infused was 5 to 6 * 106. We analyzed transforming growth factor beta1, C-peptide, and glycated hemoglobin levels in patients before and 3 months after fetal pancreatic stem cell transplant. RESULTS: In patients with type 2 diabetes mellitus, fetal pancreatic stem cell transplant led to a significant increase in transforming growth factor beta1 levels, from 16 364.8 to 35 730.4 ng/mL (P = .008), with trend in decreased glycated hemoglobin levels, from 7.96% to 6.98% (P = .088) after 3 months. CONCLUSIONS: Transforming growth factor beta1 levels increased significantly within 3 months after fetal pancreatic stem cell transplant in patients with type 2 diabetes mellitus. PMID- 29528021 TI - Clinical Characteristics of Acinetobacter baumannii Infection in Solid-Organ Transplant Recipients. AB - OBJECTIVES: Acinetobacter baumannii, depending on the immune status of the host, may result in one of the most serious hospital infections. Infections involving A. baumannii infection have been recently rising. However, little is known about the clinical features of A. baumannii infection in solid-organ transplant recipients. We aimed to share our clinical experiences with A. baumannii infection in our transplant recipients. MATERIALS AND METHODS: Between 2011 and 2017, 41 solid-organ transplant patients developed A. baumannii infection at Baskent University Hospital. Medical records were reviewed, and patient demographics, microbiology results, and overall outcome data were noted. RESULTS: Of 41 solid-organ transplant patients with A. baumannii infection, 29 were male and 12 were female patients with mean age of 47.15 +/- 13.24 years. Our infection rate with A. baumannii infection was 6.1%. The most common sites of infection were deep tracheal aspirate (48.8%)and bloodstream (36.6%). Onset of infection 1 year posttransplant was identified in 58.5% of recipients. Risk factors included presence of invasive procedures (56.1%) and administration of high-dose corticosteroids for rejection 1 year before infection (68.3%). Thirty-day mortality rate was 41.5% (17/41 patients) and was not associated with the infection site, microbiological cure, clinical cure, and drug resistance in our study group. CONCLUSIONS: Acinetobacter baumannii is an important cause of hospital-acquired infection and mortality worldwide. A major problem with A. baumannii infection is delayed initiation of appropriate antibiotic treatment and the rising numbers of extensively drug-resistant organisms. Predicting the potential risk factors, especially in the already at-risk solid-organ transplant population, has an important role in patient outcomes. PMID- 29528022 TI - Radiologically Occult Invasive Pulmonary Aspergillosis in a Patient With Liver Transplant. AB - Invasive pulmonary aspergillosis is an infection seen in patients receiving intensive immunosuppressive regimens, such as transplant recipients. Some risk factors that increase the incidence of infection have been determined, and patients defined as having high risk are recommended to take antifungal prophylaxis and be monitored closely. Here, we present a liver transplant patient with mild respiratory symptoms and a normal chest radiography on day 26 posttransplant. However, he had acute renal failure and underwent hemodialysis, which are both defined to increase significantly the risk of aspergillosis. Although the radiographic scan was initially normal, thorax tomography and later bronchoscopy showed findings compatible with pulmonary aspergillosis, and the patient was started on antifungal treatment. The nonspecific mild symptoms and an initial normal radiology can make diagnosis of invasive fungal infections difficult; thus caution and close follow-up of high-risk patients should be performed. PMID- 29528023 TI - Intracranial Fungal Infection After Solid-Organ Transplant. AB - Neurologic complications after solid-organ transplant reveal a great spectrum of pathologies. Intracranial hemorrhages, cerebral ischemic lesions, infarctions, lymphoproliferative disorders, and infections, including aspergillosis, have been observed after liver transplant. Fungi constitute nearly 5% of all central nervous system infections, mainly occurring in immunocompromised patients. The most common causative agent is Aspergillus species. It presents either as maxillary sinusitis or pulmonary infection. Brain involvement of Aspergillus carries a high rate of mortality. Aspergillosis presents in the forms of meningitis, mycotic aneurysms, infarctions, and mass lesions. Aspergillosis does not have a specific radiologic appearance. Parenchymal aspergillosis has heterogenous signal intensity (hypointense on T1-weighted and hyperintense on T2 weighted images). Here, we present 3 patients who underwent solid-organ transplant and developed central nervous system aspergillosis. Different modalities of neurosurgical intervention were performed in combination with chemotherapy as part of their fungal therapy. PMID- 29528024 TI - Utility of Mean Platelet Volume to Diagnose Pneumonia in Patients With Solid Organ Transplant. AB - OBJECTIVES: Despite improved success with solid-organ transplant procedures, recipients remain at risk for infections, including pneumonia, due to their immunosuppressive regimens. In solid-organ transplant patients, clinical findings of pneumonia can be nonspecific, and diagnosis of pneumonia may be difficult as several conditions (drug lung, hypervolemia, infections, hemorrhage) can led to pulmonary infiltrates, mimicking pneumonia in these patients. The role of mean platelet volume, a predictor of inflammatory disease, with elevated values inversely correlated with inflammatory problems, in the diagnosis of pneumonia has not yet been investigated in solid-organ transplant patients. Here, we retrospectively investigated mean platelet volume in diagnosis of pneumonia in transplant patients. MATERIALS AND METHODS: Medical records of solid-organ transplant patients from 2011 to 2016 were reviewed for demographic, clinical, radiographic, laboratory, and microbiology data. Transplant type, immunosuppressive drugs, and clinical outcomes were noted. Pneumonia diagnosis was based on clinical respiratory symptoms and signs, imaging findings, positive microbiological tests, pathologic findings, laboratory findings, or effective clinical treatment trials. RESULTS: Our study included 70 patients (47 male/23 female; mean age of 46 +/- 14 years), comprising 26 liver and 44 renal transplant recipients. Pneumonia was diagnosed radiologically in 30 patients (42.9%), with procalcitonin positive in 11 patients (36.7%), C-reactive protein elevated in 29 patients (96.7%), and leukocytes increased in 6 patients (20%). When laboratory measurements were compared with mean platelet volume, mean platelet volume values were significantly lower in patients with pneumonia who had elevated procalcitonin levels (P = .038). CONCLUSIONS: We found that mean platelet volume for diagnosis of pneumonia in solid-organ transplant patients was not a promising tool. Considering the difficulties in caring for transplant patients with pulmonary infiltrates, clinical decisions should be based on clinical, laboratory, microbiological, and radiologic findings. PMID- 29528025 TI - Natural Thermal Spa Water Versus Hyperthermic Tap Water for Treatment of Recalcitrant Hand Warts in Organ Transplant Recipients: A Patient-Blinded, Comparative Preliminary Study. AB - OBJECTIVES: Cutaneous warts represent a major problem in organ transplant recipients because of their extensive involvement and persistent course. Current therapeutic modalities often fail to achieve a successful response in patients with warts. We experienced a case involving an organ transplant recipient with recalcitrant mosaic warts who presented with complete clearance of lesions in 3 days after thermal spa bathing. Here, we evaluated the efficacy of natural thermal water versus hyperthermic tap water for treatment of recalcitrant hand warts in organ transplant recipients. MATERIALS AND METHODS: In this preliminary study, the right hands of 5 organ transplant recipients with hand warts were immersed in thermal water, while the left hands were soaked in tap water at 44 degrees C to 47 degrees C. Treatment involved three 45-minute sessions per week for 1 month. The total number and size of the warts and the hyperkeratosis severity grade were noted. RESULTS: After 12 sessions, none of the patients exhibited any marked improvement in the size or number of warts, although 3 patients had a slight decrease in their hyperkeratosis severity grade. CONCLUSIONS: Our preliminary data indicate that neither thermal spa water nor hyperthermic tap water is effective for treatment of recalcitrant hand warts in organ transplant recipients. However, new trials using thermal water supplied from different geographical locations should be performed before this observation can be generalized. PMID- 29528026 TI - Aesthetic Surgery in Transplant Patients: A Single Center Experience. AB - OBJECTIVES: Transplant patients, like the nontransplant population, can have surgical interventions for body shape disorders. Studies on aesthetic surgeries in transplant patients are scarce. Our aim was to share our experiences with various aesthetic procedures in solid-organ transplant recipients. MATERIALS AND METHODS: Six (5 female, 1 male) transplant patients who received surgical corrections of the aging face, ptosis and lipodystrophy of the breast, and abdomen at the Baskent University Plastic Reconstructive and Aesthetic Surgery Department between 2010 and 2017 were included. Five patients had renal transplants, and 1 patient had liver transplant. Minimal aesthetic procedures, including botulinum toxin, dermal filler injections, and scar revisions, were excluded. All patients were consulted to transplant team preoperatively and hospitalized in the transplant inpatient clinic. RESULTS: Mean age was 46 years. Aesthetic surgeries included breast reduction (2 patients), high suprasuperficial musculoaponeurotic system face lift (1 patient), blepharoplasty (2 patients), and dermofat grafting (1 patient). Mean hospitalization duration was 2.5 days. Four patients had no minor or major complications. One patient had skin flap necrosis, which healed with secondary intention. Another patient had ectropion after lower lid blepharoplasty, which was corrected with another procedure. CONCLUSIONS: Transplant patients are a special group of patients who receive long-term immunosuppressive treatment and medications like high-dose steroids. These treatments can lead to dermal atrophy and cause pseudo-skin laxity. Removal of excess skin and fat tissue should be considered. Efforts should be made to avoid complications such as skin necrosis and unpredictable wound healing problems when resecting the excess tissue. Preoperative consultation with transplant surgeons and keeping operative times short are other important factors. Body dysmorphologies that interfere with normal life activities and demand for younger appearance are the main reasons of aesthetic procedures. Transplant patients can be operated safely with preoperative planning, consultation with transplant surgeons, and close follow-up. PMID- 29528027 TI - A Multicenter Survey: How Do Transplant Dermatologists Monitor Organ Transplant Recipients With Nevi? AB - OBJECTIVES: The incidence and mortality of melanoma are increased in organ transplant recipients. Multiple acquired common and dysplastic nevi are risk factors for melanoma. A new or changing nevus may suggest melanoma. Strategies used by transplant dermatologists to monitor nevi are unknown. Herein, we aimed to assess the methods used by transplant dermatologists for monitoring multiple acquired common nevi, dysplastic nevi, and new or changing nevi. MATERIALS AND METHODS: A questionnaire was e-mailed to 63 members of the Skin Care in Organ Transplant Patients, Europe. RESULTS: Thirty-eight (92.7%) of 41 responders reported that they instruct their patients to perform regular self-skin examinations. Of 41 responders, 41.5% prescribed screening every 6 months, 36.6% prescribed it every 12 months, 12.2% prescribed it every 3 months, and 9.7% performed screening without regular intervals. Regarding type of examination, 80.5% performed full-body skin examinations with the naked eye, 70.7% performed dermoscopy of clinically suspicious nevi, 53.6% offered dermoscopic photography of dermoscopically suspicious nevi, 36.6% provided close-up photography of clinically suspicious nevi, 34.1% performed baseline total body photography, and 24.4% conducted dermoscopy of all nevi. We also found that 7.3%, 4.9%, and 4.9% performed only full-body skin examination with the naked eye, only dermoscopy of clinically suspicious nevi, and only dermoscopy of all nevi, respectively. CONCLUSIONS: Dedicated transplant dermatologists perform a wide variety of nevi screening procedures in organ transplant recipients. Transplant dermatologists should include sequential digital dermoscopic imaging in their armamentarium to follow organ transplant recipients with melanocytic lesions. A combination of techniques is advisable for detecting early posttransplant melanomas. PMID- 29528028 TI - Skin Cancer Risk Awareness and Sun-Protective Behavior Among Solid-Organ Transplant Recipients. AB - OBJECTIVES: Solid-organ transplant recipients are at an increased risk of developing skin cancer; this risk is due to long-term graft-preserving immunosuppressive therapy, and excessive sun exposure is a major contributing factor to this process. The aim of this study was to evaluate the skin cancer awareness and sun-protective behavior of solid-organ transplant recipients. MATERIALS AND METHODS: In all, 70 consecutive solid-organ transplant recipients were evaluated regarding knowledge of their increased skin cancer risk and regarding the influence of this knowledge on their sun-protective practices, by applying a questionnaire during their routine check-up visits. RESULTS: Of 70 solid-organ transplant recipients, 38 (54.3%) stated knowledge of hazardous consequences of sun exposure; however, only 28 (40%) had the knowledge of causal relationship between sun and skin cancer development. There were 31 patients (44.3%) who were unable to recall anybody giving any information to them about sun protection, and 40 patients (57.1%) had never visited a dermatology clinic. The 10 solid-organ transplant recipients (14.3%) who used sunscreen creams daily had been undergoing regular dermatologic examination. Regarding sun-protective clothing, only 8 patients (11.4%) had been wearing a suitable hat, long sleeves, and sunglasses when outdoors. There was a statistically significant difference between the groups who had visited a dermatology clinic versus those who had not regarding knowledge of sun protection, the causal relationship between sun exposure and skin cancer, the use of sunscreens, and use of sun-protective clothing (P < .05). CONCLUSIONS: Our data showed that dermatologic examination and education of patients about skin cancer development and sunscreen measures improved the sun-protective habits of solid-organ transplant recipients. Therefore, orderly visits once or twice a year should be strongly advised for this patient population by their medical care providers. PMID- 29528029 TI - Development of first- and second-language vocabulary knowledge among language minority children: evidence from single language and conceptual scores. AB - This study evaluated the development of vocabulary knowledge over the course of two academic years, beginning in preschool, in a large sample (N = 944) of language-minority children using scores from single-language vocabulary assessments and conceptual scores. Results indicated that although children began the study with higher raw scores for Spanish vocabulary knowledge than for English vocabulary knowledge, this was reversed by the end of the first year of the study. Similarly, at the beginning of the study unique Spanish vocabulary scores were larger than unique English or shared Spanish-English vocabulary scores; however, by the end of the first year of the study children's shared Spanish-English vocabulary scores were larger than unique English vocabulary scores, which were larger than unique Spanish vocabulary scores. These trends continued through the second year of the study. These results suggest that conceptual scoring is a useful assessment technique for children with limited exposure to their second language. Implications for assessment and instruction are discussed. PMID- 29528030 TI - Effects of dietary concentrate composition and linseed oil supplementation on the milk fatty acid profile of goats. AB - Milk fat composition can be modulated by the inclusion of lipid supplements in ruminant diets. An interaction between the lipid supplement and the forage to concentrate ratio or the type of forage in the rations may affect milk fat composition. However, little is known about the effects of the starch-to-non forage NDF ratio in the concentrate and lipid supplementation of goat diets. The aim of this work was to determine the role of dietary carbohydrates in goats rations supplemented with linseed oil on animal performance and milk fatty acid (FA) profile. A total of 16 dairy goats were allocated to two simultaneous experiments (two treatments each), in a crossover design with four animals per treatment and two experimental periods of 25 days. In both experiments alfalfa hay was the sole forage and the forage to concentrate ratio (33:67) remained constant. The concentrate in experiment 1 consisted of barley, maize and soybean meal (concentrate rich in starch), whereas it included soybean hulls replacing 25% of barley and 25% maize in experiment 2 (concentrate rich in NDF). As a result, the starch-to-non-forage NDF ratio was 3.1 in experiment 1 and it decreased to 0.8 in experiment 2. Both concentrates were administered either alone or in combination with 30 g/day of linseed oil. Animal performance parameters were not affected by experimental treatments. In contrast, major changes were observed in milk FA profile due to lipid supplementation and the type of concentrate. Linseed oil significantly raised vaccenic and rumenic acids as well as alpha-linolenic acid and its biohydrogenation intermediates while decreased medium-chain saturated FA (12:0 to 16:0) in milk fat. Milk fat contents of odd and branched-chain FA and trans-10 18:1 responded differently to linseed oil supplementation according to the concentrate fed. PMID- 29528031 TI - How do doctors deliver a diagnosis of dementia in memory clinics? AB - BACKGROUND: Dementia diagnosis rates are increasing. Guidelines recommend that people with dementia should be told their diagnosis clearly and honestly to facilitate future planning. Aims To analyse how doctors deliver a dementia diagnosis in practice. METHOD: Conversation analysis was conducted on 81 video recorded diagnosis feedback meetings with 20 doctors from nine UK memory clinics. RESULTS: All doctors named dementia; 59% (n = 48) approached the diagnosis indirectly but delicately ('this is dementia') and 41% (n = 33) approached this directly but bluntly ('you have Alzheimer's disease'). Direct approaches were used more often with people with lower cognitive test scores. Doctors emphasised that the dementia was mild and tended to downplay its progression, with some avoiding discussing prognosis altogether. CONCLUSIONS: Doctors are naming dementia to patients. Direct approaches reflect attempts to ensure clear diagnosis. Downplaying and avoiding prognosis demonstrates concerns about preserving hope but may compromise understanding about and planning for the future. Declaration of interest None. PMID- 29528032 TI - Can a digital medicine system improve adherence to antipsychotic treatment? AB - A substantial proportion of people with mental health conditions do not adhere to prescribed pharmacological treatments. Poor adherence is probably one of the most critical elements contributing to relapse in people with schizophrenia and other severe mental disorders. In order to tackle this global issue, in November 2017 the Food and Drug Administration approved a tablet formulation of the atypical antipsychotic aripiprazole embedded with a novel digital adherence-assessment device. In this commentary, we critically appraised the potential beneficial and harmful consequences of this new digital formulation of aripiprazole, and we highlighted expected implications for clinical practice. PMID- 29528033 TI - Incidence of Childhood Eosinophilic Esophagitis in Central Brazil: How Many Are We Missing? AB - BACKGROUND: Few studies have assessed the incidence of eosinophilic esophagitis (EoE) in childhood. Our study aimed to determine the incidence of EoE in pediatric patients undergoing upper gastrointestinal endoscopy (UGE), with analysis of epidemiological data including sex, age, symptoms, frequency of atopy, and endoscopic and histological findings. METHODS: We performed a retrospective, observational, analytical study of the medical records of patients aged 0 to 14 years who underwent UGE in a tertiary hospital from January 2004 to January 2014. RESULTS: A total of 4071 upper digestive endoscopies were performed in 2651 patients. Esophageal eosinophilia was found in 405 biopsy reports, and 127 patients had >=15/HPF. The clinical histories of 70 patients were analyzed. Sixty-three fulfilled the diagnostic criteria for EoE, 3 fulfilled the criteria for eosinophilic gastroenteritis, and 4 cases were secondary to caustic ingestion. The mean annual incidence was 2.48/100 000 individuals/year and the cumulative incidence over 10 years was 24.8/100 000. No statistical differences were found between responders to proton pump inhibitors and nonresponders for age, gender, atopic diseases, symptoms, and endoscopy findings. CONCLUSIONS: The incidence of EoE in the present study was similar to that reported in the literature. However, these data may be underestimated owing to difficulties accessing UGE. Increased knowledge of esophageal eosinophilic diseases in childhood requires associated improvements in health infrastructure. PMID- 29528034 TI - Corrigendum to "Stability analysis of a deterministic dose calculation for MRI guided radiotherapy". AB - Modern effort in radiotherapy to address the challenges of tumor localization and motion has led to the development of MRI guided radiotherapy technologies. Accurate dose calculations must properly account for the effects of the MRI magnetic fields. Previous work has investigated the accuracy of a deterministic linear Boltzmann transport equation (LBTE) solver that includes magnetic field, but not the stability of the iterative solution method. In this work, we perform a stability analysis of this deterministic algorithm including an investigation of the convergence rate dependencies on the magnetic field, material density, energy, and anisotropy expansion. The iterative convergence rate of the continuous and discretized LBTE including magnetic fields is determined by analyzing the spectral radius using Fourier analysis for the stationary source iteration (SI) scheme. The spectral radius is calculated when the magnetic field is included (1) as a part of the iteration source, and (2) inside the streaming collision operator. The non-stationary Krylov subspace solver GMRES is also investigated as a potential method to accelerate the iterative convergence, and an angular parallel computing methodology is investigated as a method to enhance the efficiency of the calculation. SI is found to be unstable when the magnetic field is part of the iteration source, but unconditionally stable when the magnetic field is included in the streaming-collision operator. The discretized LBTE with magnetic fields using a space-angle upwind stabilized discontinuous finite element method (DFEM) was also found to be unconditionally stable, but the spectral radius rapidly reaches unity for very low density media and increasing magnetic field strengths indicating arbitrarily slow convergence rates. However, GMRES is shown to significantly accelerate the DFEM convergence rate showing only a weak dependence on the magnetic field. In addition, the use of an angular parallel computing strategy is shown to potentially increase the efficiency of the dose calculation. PMID- 29528035 TI - The impact of the oxygen scavenger on the dose-rate dependence and dose sensitivity of MAGIC type polymer gels. AB - Recent developments in radiation therapy aimed at more precise dose delivery along with higher dose gradients (dose painting) and more efficient dose delivery with higher dose rates e.g. flattening filter free (FFF) irradiation. Magnetic resonance-imaging based polymer gel dosimetry offers 3D information for precise dose delivery techniques. Many of the proposed polymer gels have been reported to exhibit a dose response, measured as relaxation rate DeltaR2(D), which is dose rate dependent. A lack of or a reduced dose-rate sensitivity is very important for dosimetric accuracy, especially with regard to the increasing clinical use of FFF irradiation protocols with LINACs at high dose rates. Some commonly used polymer gels are based on Methacrylic-Acid-Gel-Initiated-by-Copper (MAGIC). Here, we report on the dose sensitivity (DeltaR2/DeltaD) of MAGIC-type gels with different oxygen scavenger concentration for their specific dependence on the applied dose rate in order to improve the dosimetric performance, especially for high dose rates. A preclinical x-ray machine ('Yxlon', E = 200 kV) was used for irradiation to cover a range of dose rates from low [Formula: see text] min = 0.6 Gy min-1 to high [Formula: see text] max = 18 Gy min-1. The dose response was evaluated using R2-imaging of the gel on a human high-field (7T) MR-scanner. The results indicate that all of the investigated dose rates had an impact on the dose response in polymer gel dosimeters, being strongest in the high dose region and less effective for low dose levels. The absolute dose rate dependence [Formula: see text] of the dose response in MAGIC-type gel is significantly reduced using higher concentrations of oxygen scavenger at the expense of reduced dose sensitivity. For quantitative dose evaluations the relative dose rate dependence of a polymer gel, normalized to its sensitivity is important. Based on this normalized sensitivity the dose rate sensitivity was reduced distinctly using an increased oxygen scavenger concentration with reference to standard MAGIC-type gel formulation at high dose rate levels. The proposed gel composition with high oxygen scavenger concentration exhibits a larger linear active dose response and might be used especially in FFF-radiation applications and preclinical dosimetry at high dose rates. We propose in general to use high dose rates for calibration and evaluation as the change in relative dose sensitivity is reduced at higher dose rates in all of the investigated gel types. PMID- 29528036 TI - Potential of non-invasive breath tests for preselecting individuals for invasive gastric cancer screening endoscopy. AB - BACKGROUND: Regular screening for gastric cancer (GC) is based on invasive upper gastrointestinal endoscopy and is limited to few high-incidence countries. As GC is a major cause of cancer death worldwide, a non-invasive, simple screening test is of value. We assessed the prevalence of preclinical GC and the corresponding numbers needed to screen (NNS) to detect GC cases both without and with preselection using breath tests from the literature in various populations. METHODS: Using age- and sex-specific GC incidence data and rates of transition from preclinical to clinical GC, we estimated the prevalences of preclinical GC worldwide in populations aged 50-74 years, and we evaluated the accuracy of breath testing for GC detection based on published studies. We then derived the expected positive predictive values for breath testing in populations with different preclinical GC prevalences. RESULTS: Four studies reporting the sensitivity and specificity of breath tests were identified, and summary estimates of 83% sensitivity and 91% specificity were derived by meta-analysis. The estimates of the overall prevalence of preclinical GC were <0.5% in men and <0.2% in women aged 50-74 years across different regions of the world. The positive predictive values, the prevalence among breath test positive people, were approximately nine-fold higher in all populations, resulting in an approximately nine-fold lower NNS to detect one GC case when breath tests were used for preselection for screening. CONCLUSION: Given the low prevalence of preclinical GC, non-invasive breath tests show promise for making screening more efficient. Further validation of breath tests and evidence on the rates of transition from preclinical to clinical GC are needed to validate the breath test approach. PMID- 29528037 TI - A methodology to investigate the impact of image distortions on the radiation dose when using magnetic resonance images for planning. AB - We developed a novel technique to study the impact of geometric distortion of magnetic resonance imaging (MRI) on intensity-modulated radiation therapy treatment planning. The measured 3D datasets of residual geometric distortion (a 1.5 T MRI component of an MRI linear accelerator system) was fitted with a second order polynomial model to map the spatial dependence of geometric distortions. Then the geometric distortion model was applied to computed tomography (CT) image and structure data to simulate the distortion of MRI data and structures. Fourteen CT-based treatment plans were selected from patients treated for gastrointestinal, genitourinary, thoracic, head and neck, or spinal tumors. Plans based on the distorted CT and structure data were generated (as the distorted plans). Dose deviations of the distorted plans were calculated and compared with the original plans to study the dosimetric impact of MRI distortion. The MRI geometric distortion led to notable dose deviations in five of the 14 patients, causing loss of target coverage of up to 3.68% and dose deviations to organs at risk in three patients, increasing the mean dose to the chest wall by up to 6.19 Gy in a gastrointestinal patient, and increases the maximum dose to the lung by 5.17 Gy in a thoracic patient. PMID- 29528038 TI - Erratum: A delayed acute complication of bariatric surgery: Gastric remnant haemorrhagic ulcer after Roux-en-Y gastric bypass. AB - [This corrects the article DOI: 10.4103/jmas.JMAS_148_16]. PMID- 29528040 TI - Author Correction: Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. AB - This corrects the article DOI: 10.1038/ncomms15732. PMID- 29528039 TI - Berberine Protects Against Palmitate-Induced Apoptosis in Tubular Epithelial Cells by Promoting Fatty Acid Oxidation. AB - BACKGROUND Increased lipid accumulation in renal tubular epithelial cells (TECs) contributes to their injury and dysfunction and progression of tubulointerstitial fibrosis. Berberine (BBR), a natural plant alkaloid isolated from traditional medicine herbs, is effective in lowing serum lipid, and has a protective effect on chronic kidney disease (CKD) with dyslipidemia, including diabetic nephropathy. The aim of this study was to investigate the effect of BBR on palmitate (PA)-induced lipid accumulation and apoptosis in TECs. MATERIAL AND METHODS Human kidney proximal tubular epithelial cell line (HK-2) cells were treated with PA, BBR, and/or palmitoyltransferase 1A (CPT1A) inhibitor Etomoxir. Intracellular lipid content was assessed by Oil Red O and Nile Red staining. Cell apoptosis rate was evaluated by flow cytometry assay. The expression of apoptosis related protein cleaved-caspase3 and fatty acid oxidation (FAO)-regulating proteins, including CPT1A, peroxisome proliferator-activated receptor alpha (PPARalpha), and PPARgamma co-activator-1alpha (PGC1alpha), was measured by Western blot analysis and immunofluorescence. RESULTS In the present study, PA treatment increased intracellular lipid deposition accompanied by elevated apoptosis in TECs compared with control group, whereas the protein expression of CPT1A, PPARalpha, and PGC1alpha, did not correspondingly increase in TECs. BBR significantly up-regulated the protein expression of CPT1A, PPARalpha, and PGC1alpha in TECs treated with or without PA, and reversed PA-induced intracellular lipid accumulation and apoptosis. Moreover, the CPT1A inhibitor Etomoxir counteracted the protective effect of BBR in TECs. CONCLUSIONS These in vitro findings suggest that PA can induce intracellular lipid accumulation and apoptosis in TECs, and the mechanism may be associated with inducing defective FAO, whereas BBR can protect TECs against PA-induced intracellular lipid accumulation and apoptosis by promoting FAO. PMID- 29528041 TI - Reducing missed opportunities for vaccination in selected provinces of Mozambique: A study protocol. AB - Background: A missed opportunity for vaccination (MOV) refers to any contact with health services by an individual who is eligible for vaccination, which does not result in the person receiving the vaccine doses for which he or she is eligible. A consortium of partners, including VillageReach, the Ministry of Health in Mozambique and the World Health Organization, will implement a strategy to reduce MOV in Mozambique. The strategy involves demonstrating the magnitude of missed opportunities and their causes, and exploring tailored health system interventions to reduce them, with the aim of increasing vaccination coverage and timeliness of vaccinations. Methods: A mixed-methods approach will incorporate both quantitative and qualitative tools. The assessment will target caregivers of children between the ages of 0-23 months who attend a health facility in the selected districts on the day of the assessment. Caregivers who are at least 18 years old will be eligible for inclusion. Another component of the assessment will target all health workers in the selected health facilities on the day of the assessment. A sample of 30 health facilities in different regions of the country will be assessed, with a target sample size of 600 caregiver exit interviews, 300 health worker interviews and focus group discussions with both caregivers and health workers. Data collection will commence late 2017, and the data will be electronically captured, managed and analyzed. Thematic analysis of data from the qualitative aspects of the assessment will be conducted, presenting the scope of interviews, representative verbatim quotes and key conclusions. Conclusions: A concerted effort to reduce or eliminate MOV could increase vaccine coverage by up to 30% and may contribute to wider improvements in efficiencies of service delivery beyond the immunization program. In addition, the findings could contribute to a better understanding of MOV in similar settings. PMID- 29528042 TI - Does Late Gadolinium Enhancement still have Value? Right Ventricular Internal Mechanical Work, Ea/Emax and Late Gadolinium Enhancement as Prognostic Markers in Patients with Advanced Pulmonary Hypertension via Cardiac MRI. AB - Objectives: Investigate the impact of Right Ventricular (RV) Internal Work (IW), ratio of arterial to ventricular end-systolic elastance (Ea/Emax), and RV Insertion Point (IP) Late Gadolinium Enhancement (LGE) on outcome in Pulmonary Hypertension (PH) patients. Background: LGE is well known to be present within the RVIPs and Inter Ventricular Septum (IVS) in PH patients, but its prognostic role remains complex and potentially overestimated via 2D qualitative relative to the 3D quantitative measures now available. However, Ea/Emax, a measure of ventricular-arterial coupling and IW, when added to external cardiac work i.e. the P-V loop area as correlates to the heart's energy demands, might fundamentally improve measures of prognosis as they interrogate physiology beyond just the RV. Methods: Cardiac Magnetic Resonance Imaging (CMR) of 124 PH patients (age = 60+/-13, 85F) referred to a large tertiary PH center, was retrospectively examined for RV volumetric and functional indices and RVIP LGE%. Right Heart Catheterizations (RHC) performed within 1+/-2 months of the CMR were reviewed. Ea/Emax was derived as RV End-Systolic Volume (ESV/RVSV). IW was estimated as RVESV *(RV end-systolic pressure-RV diastolic pressure). Patients were followed from date of CMR for up to 5 years for MACE (death, hospitalized RV failure, initiation of parenteral prostacyclin, sustained ventricular arrhythmia or referral for lung transplantation). Results: MACE was high; 48/124 (39%) patients had MACE by 1.6+/-1.3 years. Neither RVIP nor IVS LGE using visual assessment or even 3D quantization predicted MACE. The strongest predictor of MACE was RVIW (OR=1.00013, p<0.002), vs. mPAP, RV mass, RV EF and IP LGE. Conclusions: Surprisingly, neither a single time-point RVIP nor whole IVS LGE% can predict outcome in the largest cohort of PH patients studied to date when compared with conventional or contemporary metrics of disease progression. CMR-LGE appears to lose its' prognostic value in PH patients in stark contradistinction to all other left and right-sided human myocardial pathologies. PMID- 29528043 TI - Methylene Blue and Hydrogen Peroxide for Photodynamic Inactivation in Root Canal A New Protocol for Use in Endodontics. AB - Objective: Antimicrobial photodynamic therapy (aPDT) is a controversial approach for endodontic disinfection. The objective of this study was to test the photosensitiser (PS) concentration and assess the optical shielding phenomenon, the use of hydrogen peroxide (H2O2) and minimal energy irradiation to optimise endodontic aPDT for suggesting a protocol for clinical use. Methods: Different parameters for aPDT were tested. Aqueous solutions of methylene blue (MB) at 50, 100, 150 and 300 MUM were tested in vitro for optical shield and reactive oxygen species (ROS) production by the reduction of N,N-dimethyl-4-notrosoaniline (RNO) at 440 nm absorbance when irradiated using a diode laser (660 nm). Ten single rooted teeth were inoculated with bioluminescent bacteria Pseudomonas aeruginosa for 72 hours to form biofilms. Bioluminescence imaging was used to serially evaluate the minimum energy necessary during endodontic aPDT using MB and a diode laser coupled to an optical fibre for intracanal microbial reduction. In addition, teeth (n=21) infected with Enterococcus faecalis were treated with sequential combinations of endodontic aPDT and H2O2 and the colony-forming unit (CFU) was determined. Results: ROS production was inversely proportional to the MB concentration in the solution due to quenching of MB. Optical shielding limited light penetration at high MB concentrations. The use of H2O2 before aPDT achieved higher disinfection compared to conventional aPDT or when MB was irradiated in an H2O2 solution. Energy irradiation of 9.6 J achieved a significant reduction and further light delivery did not produce further reduction. Conclusion: PS concentration of about 50 MUM, biofilm pre-treatment with H2O2 for 1 min and energy irradiation around 10 J appear to be an effective protocol for endodontic aPDT. PMID- 29528044 TI - Implementation and process analysis of pilot scale multi-phase anaerobic fermentation and digestion of faecal sludge in Ghana. AB - Background. In Ghana, faecal sludge (FS) from on-site sanitation facilities is often discharged untreated into the environment, leading to significant insults to environmental and human health. Anaerobic digestion offers an attractive pathway for FS treatment with the concomitant production of energy in the form of methane. Another innovative option includes separating digestion into acidogenesis (production of volatile fatty acids (VFA)) and methanogenesis (production of methane), which could ultimately facilitate the production of an array of biofuels and biochemicals from the VFA. This work describes the development, implementation and modeling based analysis of a novel multiphase anaerobic fermentation-digestion process aimed at FS treatment in Kumasi, Ghana. Methods. A pilot-scale anaerobic fermentation process was implemented at the Kumasi Metropolitan Assembly's Oti Sanitary Landfill Site at Adanse Dompoase. The process consisted of six 10 m reactors in series, which were inoculated with bovine rumen and fed with fecal sludge obtained from public toilets. The performance of the fermentation process was characterized in terms of both aqueous and gaseous variables representing the conversion of influent organic carbon to VFA as well as CH 4. Using the operating data, the first-ever process model for FS fermentation and digestion was developed and calibrated, based on the activated sludge model framework. Results and Conclusions. This work represents one of the first systematic efforts at integrated FS characterization and process modeling to enable anaerobic fermentation and digestion of FS. It is shown that owing to pre-fermentation of FS in public septage holding tanks, one could employ significantly smaller digesters (lower capital costs) or increased loading capabilities for FS conversion to biogas or VFA. Further, using the first ever calibrated process model for FS fermentation and digestion presented herein, we expect improved and more mechanistically informed development and application of different process designs and configurations for global FS management practice. PMID- 29528045 TI - The Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA): Data on mortality, by HIV status and stage on the HIV care continuum, among the general population in seven longitudinal studies between 1989 and 2014. AB - Timely progression of people living with HIV (PLHIV) from the point of infection through the pathway from diagnosis to treatment is important in ensuring effective care and treatment of HIV and preventing HIV-related deaths and onwards transmission of infection. Reliable, population-based estimates of new infections are difficult to obtain for the generalised epidemics in sub-Saharan Africa. Mortality data indicate disease burden and, if disaggregated along the continuum from diagnosis to treatment, can also reflect the coverage and quality of different HIV services. Neither routine statistics nor observational clinical studies can estimate mortality prior to linkage to care nor following disengagement from care. For this, population-based data are required. The Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa brings together studies in Kenya, Malawi, South Africa, Tanzania, Uganda, and Zimbabwe. Eight studies have the necessary data to estimate mortality by HIV status, and seven can estimate mortality at different stages of the HIV care continuum. This data note describes a harmonised dataset containing anonymised individual-level information on survival by HIV status for adults aged 15 and above. Among PLHIV, the dataset provides information on survival during different periods: prior to diagnosis of infection; following diagnosis but before linkage to care; in pre-antiretroviral treatment (ART) care; in the first six months after ART initiation; among people continuously on ART for 6+ months; and among people who have ever interrupted ART. PMID- 29528046 TI - Assembled genomic and tissue-specific transcriptomic data resources for two genetically distinct lines of Cowpea ( Vigna unguiculata (L.) Walp). AB - Cowpea ( Vigna unguiculata (L.) Walp) is an important legume crop for food security in areas of low-input and smallholder farming throughout Africa and Asia. Genetic improvements are required to increase yield and resilience to biotic and abiotic stress and to enhance cowpea crop performance. An integrated cowpea genomic and gene expression data resource has the potential to greatly accelerate breeding and the delivery of novel genetic traits for cowpea. Extensive genomic resources for cowpea have been absent from the public domain; however, a recent early release reference genome for IT97K-499-35 ( Vigna unguiculata v1.0, NSF, UCR, USAID, DOE-JGI, http://phytozome.jgi.doe.gov/) has now been established in a collaboration between the Joint Genome Institute (JGI) and University California (UC) Riverside. Here we release supporting genomic and transcriptomic data for IT97K-499-35 and a second transformable cowpea variety, IT86D-1010. The transcriptome resource includes six tissue-specific datasets for each variety, with particular emphasis on reproductive tissues that extend and support the V. unguiculata v1.0 reference. Annotations have been included in our resource to allow direct mapping to the v1.0 cowpea reference. Access to this resource provided here is supported by raw and assembled data downloads. PMID- 29528047 TI - Correction to: PML: Regulation and multifaceted function beyond tumor suppression. AB - [This corrects the article DOI: 10.1186/s13578-018-0204-8.]. PMID- 29528049 TI - The Nervous Flyer: Nerves, Flying and the First World War. AB - This is not an article about 'shell-shock'. It explores the military medical response to nervous disorders in the Royal Flying Corps. The First World War exposed the propensity of pilots to the nervous and psychological rigours of aerial warfare, but their unique experiences have been overlooked in favour of 'trauma' in infantrymen. This represents a critical lacuna in the historiography of military medicine, for flying personnel were studied apart from 'shell shocked' soldiers. This article will show that flyers were believed to be medically different, and what set them apart from men in the trenches was their unique employment. The war necessitated, and provided the conditions for, the study of the medical problems of flying, including the significant nervous strains. Medical officers quickly established that flying not only affected bodily functions, but also 'wore down' the nerves that regulated psychological responses. This article will therefore present the medical view. It will study the research of air-minded medical officers and the conclusions reached on the nervous disorders of flying personnel. PMID- 29528050 TI - Point-of-contact Interactive Record Linkage (PIRL): A software tool to prospectively link demographic surveillance and health facility data. AB - Linking a health and demographic surveillance system (HDSS) to data from a health facility that serves the HDSS population generates a research infrastructure for directly observed data on access to and utilization of health facility services. Many HDSS sites, however, are in areas that lack unique national identifiers or suffer from data quality issues, such as incomplete records, spelling errors, and name and residence changes, all of which complicate record linkage approaches when applied retrospectively. We developed Point-of-contact Interactive Record Linkage (PIRL) software that is used to prospectively link health records from a local health facility to an HDSS in rural Tanzania. This prospective approach to record linkage is carried out in the presence of the individual whose records are being linked, which has the advantage that any uncertainty surrounding their identity can be resolved during a brief interaction, whereby extraneous information (e.g., household membership) can be referred to as an additional criterion to adjudicate between multiple potential matches. Our software uses a probabilistic record linkage algorithm based on the Fellegi-Sunter model to search and rank potential matches in the HDSS data source. Key advantages of this software are its ability to perform multiple searches for the same individual and save patient-specific notes that are retrieved during subsequent clinic visits. A search on the HDSS database (n=110,000) takes less than 15 seconds to complete. Excluding time spent obtaining written consent, the median duration of time we spend with each patient is six minutes. In this setting, a purely automated retrospective approach to record linkage would have only correctly identified about half of the true matches and resulted in high linkage errors; therefore highlighting immediate benefit of conducting interactive record linkage using the PIRL software. PMID- 29528048 TI - Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial. AB - : Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15 20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6 month arm (1.6%, P<0.01). We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832. PMID- 29528051 TI - Nuclear quantum effects on the liquid-liquid phase transition of a water-like monatomic liquid. AB - Polyamorphic substances have the ability to exist in more than one liquid and/or glass states. Examples include water, silicon, and hydrogen. In many of these substances, nuclear quantum effects may become important in the proximity of the liquid-liquid and glass-glass transformation. Here, we study the nuclear quantum effects on a monatomic liquid that exhibits water-like anomalous properties and a liquid-liquid phase transition (LLPT) ending at a liquid-liquid critical point (LLCP). By performing path integral Monte Carlo simulations with different values of the Planck's constant h, we are able to explore how the location of the LLCP/LLPT in the P-T plane shifts as the system evolves from classical, h = 0, to quantum, h > 0. We find that, as the quantum nature of the liquid (as quantified by h) increases, and the atoms in the liquid become more delocalized, the LLCP pressure increases, the LLCP temperature decreases, and the LLCP volume remains constant. In addition, the crystallization temperature decreases with increasing h. For large values of h, the LLCP is not accessible due to rapid crystallization. The structure of the liquids studied at different values of h are also investigated. PMID- 29528052 TI - High-resolution synchrotron terahertz investigation of the large-amplitude hydrogen bond librational band of (HCN)2. AB - The high-resolution terahertz absorption spectrum of the large-amplitude intermolecular donor librational band nu of the homodimer (HCN)2 has been recorded by means of long-path static gas-phase Fourier transform spectroscopy at 207 K employing a highly brilliant electron storage ring source. The rovibrational structure of the nu band has the typical appearance of a perpendicular type band of a Sigma-Pi transition for a linear polyatomic molecule. The generated terahertz spectrum is analyzed employing a standard semi rigid linear molecule Hamiltonian, yielding a band origin nu0 of 119.11526(60) cm 1 together with values for the excited state rotational constant B', the excited state quartic centrifugal distortion constant DJ' and the l-type doubling constant q for the degenerate state associated with the nu mode. The until now missing donor librational band origin enables the determination of an accurate experimental value for the vibrational zero-point energy of 2.50 +/- 0.05 kJ mol 1 arising from the entire class of large-amplitude intermolecular modes. The spectroscopic findings are complemented by CCSD(T)-F12b/aug-cc-pV5Z (electronic energies) and CCSD(T)-F12b/aug-cc-pVQZ (force fields) electronic structure calculations, providing a (semi)-experimental value of 17.20 +/- 0.20 kJ mol-1 for the dissociation energy D0 of this strictly linear weak intermolecular CHN hydrogen bond. PMID- 29528053 TI - Halocarbons as hydrogen bond acceptors: a spectroscopic study of haloethylbenzenes (PhCH2CH2X, X = F, Cl, Br) and their hydrate clusters. AB - The electronic spectra of 2-bromoethylbenzene and its chloro and fluoro analogues have been recorded by resonant two-photon ionisation (R2PI) spectroscopy. Anti and gauche conformers have been assigned by rotational band contour analysis and IR-UV ion depletion spectroscopy in the CH region. Hydrate clusters of the anti conformers have also been observed, allowing the role of halocarbons as hydrogen bond acceptors to be examined in this context. The donor OH stretch of water bound to chlorine is red-shifted by 36 cm-1, or 39 cm-1 in the case of bromine. Although classed as weak H-bond acceptors, halocarbons are favourable acceptor sites compared to pi systems. Fluorine stands out as the weakest H-bond acceptor amongst the halogens. Chlorine and bromine are also weak H-bond acceptors, but allow for more geometric lability, facilitating complimentary secondary interactions within the host molecule. Ab initio and DFT quantum chemical calculations, both harmonic and anharmonic, aid the structural assignments and analysis. PMID- 29528054 TI - Molecular dynamics simulation on the mechanical properties of natural-rubber graft-rigid-polymer/rigid-polymer systems. AB - A coarse-grained model-based molecular dynamics simulation was employed to investigate the mechanical properties of NR-graft-rigid-polymer/rigid-polymer systems (N30-g-(R3)6/R10). An external factor (the strain rate) as well as internal factors such as the nonbonding interaction strength, the proportion of rigid polymers, and architecture parameters (the length and number of graft chains in a molecule) were examined for their effect on the tensional behavior of N30-g-(R3)6/R10 systems. Simulation results show that a higher strain rate can promote the enhancement of mechanical performance, such as a higher modulus or yield stress. Moreover, the stress and modulus increase with an increase of the nonbonding interaction strength within rigid polymers or of the rigid polymer proportion in the systems. However, the increasing stress was found to reach a limit with a continuously increasing rigid polymer proportion. On increasing the number of graft chains in a molecule, the stress increases at small strains. However, at large strains, the evident increase in stress was found in systems in which a graft molecule has longer graft chains. In addition, our research shows that N30-g-(R3)6/R10 blends exhibit improved mechanical properties and better compatibilities relative to N30/R10, which is consistent with the experimental results. Lastly, comparisons with experimental observations were also made to ensure the rationality of the simulation results. Overall, bond stretching, bond orientation, and nonbonding interactions were found to be crucial in governing the mechanical properties of the N30-g-(R3)6/R10 systems. These findings may provide important information for further experimental and simulation studies of NR hybrid materials. PMID- 29528055 TI - Cadmium sulfide as an efficient electron transport material for inverted planar perovskite solar cells. AB - Dispersible cadmium sulfide (CdS) nanoparticles are synthesized by a facile solvothermal reaction and are used for the first time as an electron transport layer (ETL) in inverted planar perovskite solar cells. The CdS ETL has superb electron extraction and transport properties, leading to a solar cell with light hysteresis and a high efficiency of 13.36%. PMID- 29528056 TI - Carbon dioxide as a green carbon source for the synthesis of carbon cages encapsulating porous silicon as high performance lithium-ion battery anodes. AB - Si/C composite is one of the most promising candidate materials for next generation lithium-ion battery anodes. Herein, we demonstrate the novel structure of carbon cages encapsulating porous Si synthesized by the reaction between magnesium silicide (Mg2Si) and carbon dioxide (CO2) and subsequent acid washing. Benefitting from the in situ deposition through magnesiothermic reduction of CO2, the carbon cage seals the inner Si completely and shows higher graphitization than that obtained from the decomposition of acetylene. After removing MgO, pores are created, which can accommodate the volume change of the Si anode during the charge/discharge process. As the anode material for lithium-ion batteries, the porous Si/C electrode shows a charge capacity of ~1124 mA h g-1 after 100 cycles with 86.4% capacity retention at the current density of 0.4 A g-1. When the current density increases to 1.6 and 3.2 A g-1, the capacity can still be maintained at ~860 and ~460 mA h g-1, respectively. The prominent cycling and rate performance is contributed by the built-in space for Si expansion, static carbon cages that prevent penetration of electrolyte and stabilize the solid electrolyte interface (SEI) outside, and fast charge transport by the novel structure. PMID- 29528057 TI - Azobenzene-based polymers: emerging applications as cell culture platforms. AB - The fabrication of biomaterials whose properties are activated or inhibited on demand via light is appealing for fundamental biological studies as well as for the development of new applications in tissue engineering and regenerative medicine. One of the most widely used molecules in light-controlled systems is azobenzene for its ability to isomerise in response to light. In this minireview, the fundamental landmarks towards the application of azobenzene-containing materials as cell culture substrates will be highlighted, foreseeing their massive use as next-generation cell-instructive materials. PMID- 29528058 TI - Fabrication and assessment of an electrospun polymeric microfiber-based platform under bulk flow conditions with rapid and efficient antigen capture. AB - Correction for 'Fabrication and assessment of an electrospun polymeric microfiber based platform under bulk flow conditions with rapid and efficient antigen capture' by Carlton F. O. Hoy et al., Analyst, 2018, 143, 865-873. PMID- 29528059 TI - Cationic peroxidase from proso millet induces human colon cancer cell necroptosis by regulating autocrine TNF-alpha and RIPK3 demethylation. AB - A cationic peroxidase (POD) was purified from proso millet seeds (PmPOD) using ammonium sulfate fractionation, cation exchange, and size exclusion chromatography. The purified PmPOD showed toxicity to normal cells and tumor cells, but was more sensitive in HT29 cells. Furthermore, the mechanism driving HCT116 and HT29 cell death by PmPOD was the induction of receptor interacting protein kinase 1 (RIPK1)- and RIPK3-dependent necroptosis, independent of apoptosis. More importantly, PmPOD could induce tumor necrosis factor-alpha (TNF alpha) production through transcriptional upregulation. In addition, PmPOD could restore RIPK3 expression in HCT116 cells via the demethylation of the RIPK3 genomic sequence. Taken together, these results suggest that two distinct mechanisms are involved in PmPOD-induced necroptosis: the autocrine production of TNF-alpha and the restoration of RIPK3 expression. PMID- 29528060 TI - Insights into the interfacial strengthening mechanisms of calcium-silicate hydrate/polymer nanocomposites. AB - The mechanical properties of organic/inorganic composites can be highly dependent on the interfacial interactions. In this work, with organic polymers intercalated into the interlayer of inorganic calcium silicate hydrate (C-S-H), the primary binding phase of Portland cement, great ductility improvement is obtained for the nanocomposites. Employing reactive molecular dynamics, the simulation results indicate that strong interfacial interactions between the polymers and the substrate contribute greatly to strengthening the materials, when C-S-H/poly ethylene glycol (PEG), C-S-H/poly acrylic acid (PAA), and C-S-H/poly vinyl alcohol (PVA) were subject to uniaxial tension along different lattice directions. In the x and z direction tensile processes, the Si-OCa bonds of the C S-H gel, which were elongated and broken to form Si-OH and Ca-OH, play a critical role in loading resistance, while the incorporation of polymers bridged the neighboring silicate sheets, and activated more the hydrolytic reactions at the interfaces to avoid strain localization, thus increasing the tensile strength and postponing the fracture. On the other hand, Si-O-Si bonds of C-S-H mainly take the load when tension was applied along the y direction. During the post-yield stage, rearrangements of silicate tetrahedra occurred to prevent rapid damage. The polymer intercalation further elongates this post-yield period by forming interfacial Si-O-C bonds, which promote rearrangements and improve the connectivity of the defective silicate morphology, significantly improving the ductility. Among the polymers, PEG exhibits the strongest interaction with C-S-H, and thus C-S-H/PEG possesses the highest ductility. We expect that the molecular scale mechanisms interpreted here will shed new light on the stress-activated chemical interactions at the organic/inorganic interfaces, and help eliminate the brittleness of cement-based materials on a genetic level. PMID- 29528061 TI - Catalytic, metal-free sulfonylcyanation of alkenes via visible light organophotoredox catalysis. AB - The group transfer radical addition of olefins with tosyl cyanide has been accomplished via visible light-induced organophotoredox catalysis. A diverse array of olefins is amenable to this protocol, furnishing beta-sulfonyl nitriles with excellent efficiency under metal-free and redox-neutral conditions. A closed catalytic cycle is operative in this transformation, providing complementary reactivity to the classic radical chain process. PMID- 29528062 TI - Methanol-to-olefin conversion in ABC-6 zeolite cavities: unravelling the role of cavity shape and size from density functional theory calculations. AB - We report a density functional theory (DFT) study to investigate methanol-to olefin (MTO) conversion in four types of ABC-6 zeolite cavities (cha, avl, aft and h1) by varying their shape and size. Based on a side-chain alkylation mechanism, the reaction energies and barriers of methylations, deprotonations and eliminations for hydrocarbon pool (HP) intermediates are calculated. In the cha cavity, methylations and eliminations are found to possess low barriers as attributed to the strong confinement effect of the elliptical and small cha cavity. The avl and aft cavities also exhibit low barriers of the first and second methylations, and similar barriers of eliminations for producing olefins as in cha. Due to the narrow shape and large size of the h1 cavity, most of the reaction barriers in h1 are the highest. The stabilities of HP species and transition states in the four cavities are quantified by the Gibbs energy profiles. It is found that aft with a wide dimension is favorable for the stability, especially for the charged HP species. The DFT calculation results reveal that the activity and selectivity of MTO conversion in zeolite cavities are strongly governed by the confinement effect, which depends on cavity shape and size. We also predict that zeolites with aft cavities might have good performance for MTO conversion. PMID- 29528063 TI - Carbon dioxide-based facile synthesis of cyclic carbamates from amino alcohols. AB - We report herein a straightforward general method for the synthesis of cyclic carbamates from amino alcohols and carbon dioxide in the presence of an external base and a hydroxyl group activating reagent. Utilizing p-toluenesulfonyl chloride (TsCl), the reaction proceeds under mild conditions, and the approach is fully applicable to the preparation of various high value-added 5- and 6-membered rings as well as bicyclic fused ring carbamates. DFT calculations and experimental results indicate a SN2-type reaction mechanism with high regio-, chemo-, and stereoselectivity. PMID- 29528064 TI - Holey nickel hydroxide nanosheets for wearable solid-state fiber-supercapacitors. AB - Holey nickel hydroxide (Ni(OH)2) nanosheets with a mean thickness of 2 nm are facilely synthesized, and then embedded in carbon nanotube (CNT) scaffolds to construct a hybrid fiber electrode, which shows a high volumetric capacitance of 335.9 F cm-3 at 0.8 A cm-3 and superior rate performance. The hybrid supercapacitor made from the Ni(OH)2/CNT fiber can deliver a high specific capacitance of 24.8 F cm-3 and an energy density of 5.8 mW h cm-3 with outstanding mechanical stability under repeated bending conditions. PMID- 29528065 TI - Optical emission of GaN/AlN quantum-wires - the role of charge transfer from a nanowire template. AB - We show that one-dimensional (1d) GaN quantum-wires (QWRs) exhibit intense and spectrally sharp emission lines. These QWRs are realized in an entirely self assembled growth process by molecular beam epitaxy (MBE) on the side facets of GaN/AlN nanowire (NW) heterostructures. Time-integrated and time-resolved photoluminescence (PL) data in combination with numerical calculations allow the identification and assignment of the manifold emission features to three different spatial recombination centers within the NWs. The recombination processes in the QWRs are driven by efficient charge carrier transfer effects between the different optically active regions, providing high intense QWR luminescence despite their small volume. This is deduced by a fast rise time of the QWR PL, which is similar to the fast decay-time of adjacent carrier reservoirs. Such processes, feeding the ultra-narrow QWRs with carriers from the relatively large NWs, can be the key feature towards the realization of future QWR-based devices. While processing of single quantum structures with diameters in the nm range presents a serious obstacle with respect to their integration into electronic or photonic devices, the QWRs presented here can be analyzed and processed using existing techniques developed for single NWs. PMID- 29528066 TI - Clarifying the role of cryo- and lyo-protectants in the biopreservation of proteins. AB - Biopharmaceuticals are frequently stored in the frozen state to avoid rapid degradation. Moreover, therapeutic proteins are frequently made into a dried form to provide long-term storage. However, both freezing and drying stresses can result in protein unfolding and aggregation. Thus, a proper formulation, containing suitable excipients, must be used to avoid loss of activity. Here, the conformational stability of a model protein, human growth hormone, is studied during freezing, and in the dried state as well, using molecular dynamics. The impact of the ice-water interface and of water removal is deeply investigated, and the role of protectants in preventing denaturation phenomena is addressed. We found that good cryo-protectants not always are equally effective as lyo protectants, and experimental data confirmed simulation results. From this analysis, we also discovered that the interaction of stabilizers with specific amino acid sequences of the protein, rather than with the molecule as a whole, seems to be a crucial issue in the preservation of protein structure. This finding was confirmed for another protein, i.e., lactate dehydrogenase, thus suggesting that it is a generally applicable result. Remarkably, those sequences which unfolded during freezing and drying, generally coincided with the aggregation prone regions of the protein. PMID- 29528067 TI - Zeolites with isolated-framework and oligomeric-extraframework hafnium species characterized with pair distribution function analysis. AB - Zeolites containing framework heteroatoms (e.g., Ti, Sn, and Hf) with open coordination sites behave as solid-state Lewis acids and exhibit remarkable catalytic properties unachievable with bulk oxides. However, direct evidence confirming the incorporation of such heteroatom species into the zeolite framework is difficult to obtain because of the limited number of analytical methods capable of discerning framework incorporation from extraframework species. In this work, the structural environments of hafnium (Hf) framework and extraframework species added post-synthetically into *BEA zeolites were analyzed using coupled pair distribution function (PDF) and diffuse reflectance (DR) UV vis measurements. PDF analysis enabled the visualization and identification of framework and extraframework HfOx species, both of which were undetectable by traditional X-ray and neutron diffraction methods. Reactivity data from the aldol condensation of benzaldehyde and acetone confirmed that framework Hf species are responsible for catalytic activity. PMID- 29528068 TI - Efficient and ultraviolet durable planar perovskite solar cells via a ferrocenecarboxylic acid modified nickel oxide hole transport layer. AB - Planar perovskite solar cells (PSCs) that use nickel oxide (NiOx) as a hole transport layer have recently attracted tremendous attention because of their excellent photovoltaic efficiencies and simple fabrication. However, the electrical conductivity of NiOx and the interface contact properties of the NiOx/perovskite layer are always limited for the NiOx layer fabricated at a relatively low annealing temperature. Ferrocenedicarboxylic acid (FDA) was firstly introduced to modify a p-type NiOx hole transport layer in PSCs, which obviously improves the crystallization of the perovskite layer and hole transport and collection abilities and reduces carrier recombination. PSCs with a FDA modified NiOx layer reached a PCE of 18.20%, which is much higher than the PCE (15.13%) of reference PSCs. Furthermore, PSCs with a FDA interfacial modification layer show better UV durability and a hysteresis-free effect and still maintain the original PCE value of 49.8%after being exposed to UV for 24 h. The enhanced performance of the PSCs is attributed to better crystallization of the perovskite layer, the passivation effect of FDA, superior interface contact at the NiOx/perovskite layers and enhancement of the electrical conductivity of the FDA modified NiOx layer. In addition, PSCs with FDA inserted at the interface of the perovskite/PCBM layers can also improve the PCE to 16.62%, indicating that FDA have dual functions to modify p-type and n-type carrier transporting layers. PMID- 29528069 TI - 1,1'-Binaphthyl-substituted diphosphene: synthesis, structures, and chiral optical properties. AB - 1,1'-Binaphthyl-substituted diphosphene 1 possessing a P[double bond, length as m dash]P double bond and an axially chiral 1,1'-binaphthyl group was synthesized and fully characterized. Diphosphene 1 was prepared as an optically active form and thus is the first example of a chiral diphosphene. The CD spectra of 1 showed apparent circular dichroism in the longer wavelength region, caused by the P[double bond, length as m-dash]P moiety. PMID- 29528070 TI - Efficient entrapment and catalytic conversion of lithium polysulfides on hollow metal oxide submicro-spheres as lithium-sulfur battery cathodes. AB - Li-S battery technology, with high theoretical capacity and energy density, has drawn much attention in recent years as a possible replacement for current Li-ion battery technologies. A major drawback of Li-S batteries is a severe capacity fading effect which, to a large extent, stems from the dissolution and diffusion of lithium polysulfides (LiPS) that are formed during both charge and discharge cycles. The self-discharge caused by the LiPS migration during the charge process (the so-called "shuttle effect") often leads to the capacity decay of Li-S batteries. Herein, hollow structured metal oxide (Co3O4, Mn2O3, and NiO) submicro spheres are prepared by a novel method and employed as efficient LiPS immobilizers. These Li-S batteries, based on the developed metal oxide spheres, possess outstanding rate capability and cycling stability. The best performing S/C/Co3O4 electrode delivers excellent cycling stability with only a 0.066% capacity decay per cycle during 550 cycles. Moreover, its discharge capacity is as high as 428 mA h g-1 at a 3C rate which is far superior to that of bare S/C (115 mA h g-1) at 3C. The fast kinetics of the electrocatalytic conversion of LiPS on the developed Co3O4 electrode and its unique hollow structure are the key factors that lead to its outstanding performance as a Li-S battery cathode material. PMID- 29528071 TI - Graphene-based aptasensors: from molecule-interface interactions to sensor design and biomedical diagnostics. AB - Graphene-based nanomaterials have been widely utilized to fabricate various biosensors for environmental monitoring, food safety, and biomedical diagnostics. The combination of aptamers with graphene for creating biofunctional nanocomposites improved the sensitivity and selectivity of fabricated biosensors due to the unique molecular recognition and biocompatibility of aptamers. In this review, we highlight recent advances in the design, fabrication, and biomedical sensing application of graphene-based aptasensors within the last five years (2013-current). The typical studies on the biomedical fluorescence, colorimetric, electrochemical, electrochemiluminescence, photoelectrochemical, electronic, and force-based sensing of DNA, proteins, enzymes, small molecules, ions, and others are demonstrated and discussed in detail. More attention is paid to a few key points such as the conjugation of aptamers with graphene materials, the fabrication strategies of sensor architectures, and the importance of aptamers on improving the sensing performances. It is expected that this work will provide preliminary and useful guidance for readers to understand the fabrication of graphene-based biosensors and the corresponding sensing mechanisms in one way, and in another way will be helpful to develop novel high performance aptasensors for biological analysis and detection. PMID- 29528072 TI - N-Heterotricyclic cationic carbene ligands. Synthesis, reactivity and coordination chemistry. AB - The direct dialkylation of triazolo[4,3-b]isoquinolin-3-ylidene structures readily affords dicationic N-heterotricyclic azolium salts. These are suitable starting materials for the synthesis of transition metal complexes containing N heterotricyclic, cationic ligands characterized by extended charge delocalization. Silver and gold complexes as well as mono- and dicationic rhodium(i) complexes have been prepared and characterized, and the electronic properties of the ligand have been evaluated by using the TEP parameter and by comparison with a non-cationic analogue. X-Ray diffraction analysis of several carbene-metal complexes shows a negligible effect of the charge on the structures of the complexes. The catalytic activity of a tricationic gold complex has been evaluated in the intramolecular hydroarylation of a terminal alkyne. PMID- 29528073 TI - Modulation of the carboxamidine redox potential through photoinduced spiropyran or fulgimide isomerisation. AB - Carboxamidines functionalized with either a spiropyran or fulgimide photoswitch were prepared on multigram scales. The thermal, electrochemical, and photochemical ring isomerizations of these compounds were studied and the results compared with related systems. The photochemical isomerisations were found to be reversible and could be followed by 1H NMR and UV-vis spectroscopy. The spiropyran/merocyanine couple was thermally active and an activation enthalpy of 116 kJ mol-1 was measured for ring-opening. These measurements yielded an enthalpy difference of 25 kJ mol-1 between the open and closed states which is consistent with DFT calculations. DFT calculations predicted a charge transfer to the carboxamidine group upon ring closure in the fulgimide and a charge transfer from the carboxamidine group upon switching the spiropyran to the merocyanine form. This was confirmed experimentally by monitoring the change in the oxidation potential assigned to the carboxamidine group. The potential of these molecules to therefore act as a new class of photoresponsive ligands that can modulate the ligand field of a complex is discussed. PMID- 29528074 TI - Arsenite increases Cyclin D1 expression through coordinated regulation of the Ca2+/NFAT2 and NF-kappaB pathways via ERK/MAPK in a human uroepithelial cell line. AB - To understand the direct link between Cyclin D1, and nuclear factor of activated T cells 2 (NFAT2) and nuclear factor (NF)-kappaB in arsenic-treated bladder cells, as well as the association between MAPK and NFAT signaling, we determined whether or not the Ca2+/NFAT pathway is activated in an arsenic-treated normal urothelial cell line and determined the roles of NFAT and NF-kappaB signals in the regulation of Cyclin D1 expression. The SV-40 immortalized human uroepithelial cell line, SV-HUC-1, was treated with NaAsO2 for 24 h (0, 1, 2, 4, 8, and 10 MUM) and 10, 20, 30, and 40 weeks (0 and 0.5 MUM). We found that arsenite increased the intracellular Ca2+ levels and induced NFAT2 nuclear translocation after treatment for 24 h. The level of NFAT2 mRNA and expression of total protein and nuclear protein were increased after long-term treatment with 0.5 MUM arsenite for 30 and 40 weeks compared to the cells treated for 24 h. In addition, NF-kappaB p50 and p65 nuclear protein expression increased significantly in cells treated with 2-8 MUM arsenite for 24 h, which was consistent with NFAT2 nuclear expression. Furthermore, an ERK inhibitor (U0126) significantly reduced the expression of NFAT2 nuclear protein, and an ERK and JNK inhibitor decreased the levels of p65 and p50 nuclear protein. Cyclin D1 is known as a proto-oncogene and the level of this protein was increased in SV-HUC-1 cells treated with arsenite for 24 h and long-term. An NFAT inhibitor (CsA) and NF kappaB inhibitor (PDTC) all markedly reduced Cyclin D1 protein expression. Treatment with U0126 also significantly decreased Cyclin D1 protein expression while JNK and p38 inhibitors did not attenuate the arsenite-associated increase in Cyclin D1 protein expression. The results suggest that regulation of Cyclin D1 protein expression by arsenite in SV-HUC-1 cells is dependent on ERK/NFAT2 and ERK/NF-kappaB, but is not dependent on JNK or p38. PMID- 29528075 TI - Recent advances in anti-angiogenic nanomedicines for cancer therapy. AB - Angiogenesis is a normal physiological remodeling process initiated at the time of embryonic development and lessened with the progress of time. Nevertheless, continuous activation of stringent signaling pathways and proangiogenic factors during tumorigenesis (a pathological condition) instigates serious vessel abnormalities eliciting severe therapeutic inefficiency. In principle, systemic delivery of robust antiangiogenic drugs often fails to reach these abnormal tumor vessels depicting poor pharmacokinetics, biodistribution profiles and adverse side effects in vivo. Recently, the advent of nanotechnology has offered numerous advantages encompassing high drug payloads, increased blood half-life and reduced toxicity; likewise, such nanomedicines can also target the key components of the tumor microenvironment and tumor cells effectively. Synergistic targeting of malignant cells and vessel abnormalities via integration of antiangiogenic and other potent combinational regimens in a single nanoplatform can revitalize therapeutic success. In this review, we will discuss the most promising nanotechnological advancements rehabilitating angiogenesis, and emerging nanocarriers comprehending gene delivery, stem cell therapies and dynamic combinational strategies for effective anticancer therapy. PMID- 29528076 TI - Diverse copper(iii) trifluoromethyl complexes with mono-, bi- and tridentate ligands and their versatile reactivity. AB - Cu(iii) trifluoromethyl complexes are proposed as essential intermediates for many copper-promoted trifluoromethylation reactions, but remain elusive and scarcely explored. We report herein the isolation and spectroscopic and X-ray crystallographic characterization of diverse CuIII-CF3 complexes (6-10) with varied coordinating motifs (mono-, bi- or tridentate) and formal charges (neutral or monoanionic) for the ligand L (L is pyridine, 2,4,6-trimethylpyridine, quinol 8-yloxide or 2,6-bis(2'-pyridyl)pyridine). Square planar complexes 6, 7 and 9 show rapid dynamic behavior in solution possibly due to the weak Cu-CF3 bonds that can quickly dissociate and recombine with the CF3 radical. In contrast, 10, with octahedral geometry, is more rigid. Reactivity studies show that except for ion-pair complex 8, they are highly reactive for the trifluoromethylation of arylboronic acids and the C-H bond of terminal alkynes. Furthermore, syn-fluoro- and -oxy-trifluoromethylation across the triple bond of alkynes can be achieved using 6 and CsF or NaOPh. These results greatly expand the scope of isolated and well-characterized Cu(iii)-CF3 complexes, and establish their versatile reactivity that may be widely involved in copper-mediated trifluoromethylation reactions, thus substantiating the essential yet undeveloped aspects of trifluoromethylation chemistry. PMID- 29528077 TI - Advanced emulsions via noncovalent interaction-mediated interfacial self assembly. AB - We demonstrate that the traditional emulsification theory can be enriched by a self-assembly approach, in which hydrophilic copolymers with one block exhibiting noncovalent forces with the oil phase self-assemble at the oil-water interface, thereby reducing interfacial tension and forming emulsions. This approach was established using affinity diblock copolymers that can interact with oil molecules through electrostatic interactions or hydrogen-bonding. Nanoemulsions with excellent stability were successfully obtained simply via vortexing. The self-assembled emulsions showed unexpected catastrophic phase inversion, further extending the phase structures to bicontinuous and reverse emulsions. Complex emulsions could also be fabricated by this strategy. In addition, the thus prepared nanoemulsions can be used to engineer different nanomaterials. PMID- 29528078 TI - Synthesis and radiometric evaluation of diglycolamide functionalized mesoporous silica for the chromatographic separation of actinides Th, Pa and U. AB - The separation of Th, Pa, and U is of high importance in many applications including nuclear power, nuclear waste, environmental and geochemistry, nuclear forensics and nuclear medicine. Diglycolamide (DGA)-based resins have shown the ability to separate many elements, however, these resins consist of non-covalent impregnation of the DGA molecules on the resin backbone resulting in co-elution of the extraction molecule during separation cycles, therefore limiting their long-term and repeated use. Covalently binding the DGA molecules onto silica is one way to overcome this issue. Herein, measured equilibrium distribution coefficients of normal extraction chromatographic DGA resin and a covalently bound form (KIT-6-N-DGA sorbent) are reported. Several differences are observed between the two systems, the most significant being observed for uranium, which demonstrated significantly lower sorption behavior on KIT-6-N-DGA. These results indicate that U can effectively be separated from Th and Pa using KIT-6-N-DGA, a task that could not be completed with the use of normal DGA alone. PMID- 29528079 TI - Taxol-modified collagen scaffold implantation promotes functional recovery after long-distance spinal cord complete transection in canines. AB - Treatment of spinal cord injury (SCI) remains a clinical challenge worldwide because of the complicated inhibitory microenvironment formed post-injury, reduced axonal regenerative ability of spinal cord neurons, and scarcity of endogenous neurogenesis within the lesion center. Taxol, in addition to stabilizing microtubules, has shown potential for decreasing axonal degeneration and reducing scar formation after SCI in rodents. In this study, we further verified the therapeutic effects and clinical potential of Taxol on restriction of scar formation and promotion of neuronal regeneration and functional recovery after severe spinal cord transection in a large animal (canine) model. A linear ordered collagen scaffold (LOCS) combined with Taxol was implanted into the injury site after the complete removal of 1 cm of spinal tissue. Afterwards, diligent nursing and multi-system rehabilitation were carried out during a half year period of observation. The results showed that LOCS + Taxol implantation markedly promoted motor-evoked potentials and locomotion recovery. Moreover, histological analysis demonstrated that LOCS + Taxol implantation significantly increased neurogenesis and axon regeneration to reconnect the spinal cord stumps. Additionally, reduced glial scar formation was observed within the lesion site. Thus, LOCS + Taxol implantation treatment is a promising combinatorial therapy for the treatment of acute long-distance spinal cord defects. PMID- 29528080 TI - Synthesis and properties of N-methylimidazole solvates of vanadium(ii), chromium(ii) and iron(ii) phthalocyanines. Strong NIR absorption in VII(MeIm)2(Pc2-). AB - N-Methylimidazole (MeIm) solvates of vanadium(ii), chromium(ii) and iron(ii) phthalocyanines: [VII(MeIm)2(Pc2-)]0.MeIm (1) and [MII(MeIm)2(Pc2-)]0.2C6H4Cl2 (M = V (2), Cr (3), and Fe (4)) have been obtained and studied in a crystalline form. It has been shown that central metal atoms have the +2 oxidation state in 1 4 and dianionic Pc2- macrocycles are formed. Optical spectra of 1-3 (VII, CrII) are different from that of 4 (FeII) due to the appearance of intense absorption bands in the NIR range at 1187 nm for 1 and 2 and 1178 nm for 3 and manifestation of multiple bands in the visible range. Absorption in the NIR range is explained by unusually small gaps between the molecular orbitals at around HOMO and LUMO for MeIm solvated CrIIPc and VIIPc. The essential diradicaloid character of the Pc macrocycles in [CrII(MeIm)2(Pc2-)]0, in which alpha- and beta-orbitals are distributed in different regions of the macrocycle, has also been shown. In this case, the diradicaloid character is comparable to that of aromatic hydrocarbon heptacene. Magnetic properties of 1-3 are defined by metal atoms with a S = 3/2 spin state for VII and S = 1 for CrII. Compounds 1-3 manifest broad isotropic EPR signals at 4.2 K with g = 2.0188 and a linewidth (DeltaH) of 81.8 mT for 1 (VII), g = 1.8300 and a linewidth DeltaH = 161.0 mT for 2 (VII), and g = 2.0534 and DeltaH = 60.27 mT for 3 (CrII). These signals shifted to smaller g-factors with the temperature increase. Integral intensity of narrow EPR signals from Pc3- does not exceed 0.1% from those of broad signals in 1-3. Complex 4 is EPR silent due to the presence of diamagnetic FeII and Pc2-. PMID- 29528081 TI - DNA damage photo-induced by chloroharmine isomers: hydrolysis versus oxidation of nucleobases. AB - Photodynamic therapy (PDT) is an emerging clinical treatment currently being used against a wide range of both cancerous and noncancerous diseases. The search for new active photosensitizers as well as the development of novel selective delivery systems are the major challenges faced in the application of PDT. We investigated herein three chloroharmine derivatives (6-, 8- and 6,8 dichloroharmines) with quite promising intrinsic photochemical tunable properties and their ability to photoinduce DNA damage in order to elucidate the underlying photochemical mechanisms. Data revealed that the three compounds are quite efficient photosensitizers. The overall extent of photo-oxidative DNA damage induced by both 8-chloro-substituted beta-carbolines is higher than that induced by 6-chloro-harmine. The predominant type of lesion generated also depends on the position of the chlorine atom in the beta-carboline ring. Both 8-chloro substituted beta-carbolines mostly oxidize purines via type I mechanism, whereas 6-chloro-harmine mainly behaves as a "clean" artificial photonuclease inducing single-strand breaks and site of base loss via proton transfer and concerted (HO- mediated) hydrolytic attack. The latter finding represents an exception to the general photosensitizing reactions and, to the best of our knowledge, this is the first time that this process is well documented. The controlled and selective production of different oxygen-independent lesions could be fine-tuned by simply changing the substituent groups in the beta-carboline ring. This could be a promising tool for the design and development of novel photo-therapeutic agents aimed to tackle hypoxic conditions shown in certain types of tumours. PMID- 29528082 TI - Iron-catalyzed ortho trifluoromethylation of anilines via picolinamide assisted photoinduced C-H functionalization. AB - A convenient, oxidant-free protocol was developed for the ortho trifluoromethylation of aniline via picolinamide assisted Fe-promoted C-H functionalization under ultraviolet irradiation. In this transformation acetone essentially acted as both a solvent to dissolve reactants and a low-cost radical initiator to efficiently generate a CF3 radical from Langlois' reagent. A broad substrate scope was tolerated and picolinamide bearing strong electron withdrawing groups also could be transformed into the corresponding products with acceptable yields. Furthermore, the value of this method has been highlighted via the efficient synthesis of the nonsteroidal anti-inflammatory drug floctafenine. PMID- 29528083 TI - Tuning the catalytic activity of colloidal noble metal nanocrystals by using differently charged surfactants. AB - The catalytic activity of metal nanocrystals is mainly tuned through the control of their shapes and sizes. However, the shapes and sizes of many metal nanocrystals are difficult to control and therefore their catalytic activity is hard to tune. Here, we demonstrate another approach, using differently charged surfactants, for tuning the catalytic activity of metal nanocrystals. Au and Pd nanocrystals capped with cationic cetyltrimethylammonium bromide (CTAB) and anionic citrate are chosen to study the effect of surfactant charges on the catalytic activity. The oxidation of o-phenylenediamine to 2,3-diaminophenazine by H2O2 is selected as a model reaction. The prepared Au and Pd nanocrystals are initially capped with CTAB, which is changed to citrate through surfactant exchange. Owing to the relatively weak electrostatic interaction of CTAB with the nanocrystals, the surfactant exchange does not induce observable changes in nanocrystal shapes and sizes. In contrast, the catalytic activity is greatly improved by the surfactant exchange. XPS analysis and theoretical calculations indicate that the adsorption of anionic citrate enriches the electrons of the nanocrystal surfaces, while the adsorption of CTAB depletes the electrons of the nanocrystal surfaces. The different catalytic activities of CTAB and citrate capped nanocrystals arise from the different behaviors of electron transfer between the surfactants and the nanocrystal surface. Since the surfacants that electrostatically bind to the metal nanocrystals are facile to exchange into other surfactants, our findings provide an effective way to tuning the catalytic activity of metal nanocrystals. PMID- 29528084 TI - Bidirectional light-induced conductance switching in molecular wires containing a dimethyldihydropyrene unit. AB - Photochromic coordination polymers, based on zinc(ii) bis-terpyridine-appended dimethyldihydropyrene building blocks, have been synthesized following stepwise synthesis on a surface yielding photo-switchable molecular junctions. Under irradiation, reversible structural changes occur by the isomerization of the photosensitive units, thus inducing conductance switching of the molecular junctions with a good reproducibility. PMID- 29528085 TI - Soy isoflavone effects on the adrenal glands of orchidectomized adult male rats: a comprehensive histological and hormonal study. AB - Genistein (G) and related soy phytoestrogens have been studied for potential usefulness in different chronic diseases, and may ameliorate signs of aging. They have a profound influence on the hypothalamo-pituitary-adrenal (HPA) axis. The present study utilized the rat model of mild andropause to thoroughly evaluate the effects of G and soy extract on the adrenal gland and related blood hormones. Adult male rats were orchidectomized (Orx) or sham operated (SO). Orx rats received daily subcutaneous injections for 3 weeks of solvent, or G (Orx+G, 30 mg/kg), or commercial soy extract (Orx+Soy, 30 mg/kg). Adrenal glands and blood were harvested at the end of the treatment for hormone analyses, histology and design-based stereology. Compared to SO rats Orx evoked significant (P<0.05) changes including: the replicating cell number in the 3 adrenocortical zones; vascularity and cortical volume and blood levels of adrenocorticotropic hormone (ACTH), aldosterone and dehydroepiandrosterone (DHEA). When comparing Orx vs. Orx+G groups the following significant (P<0.05) changes were observed: a further increase in number of replicating cells in zonas glomerulosa and reticularis, vasculature network presence, cortical and zona reticularis volumes, ACTH and corticosterone concentrations, and lower DHEA levels. Comparing Orx vs. Orx+Soy resulted in elevated (P<0.05) ACTH and corticosterone levels. Structural integrity of the adrenal gland was unchanged vs. SO rats. Overall, G and soy extract treatments resulted in proliferative activity and/or vasculature support in the adrenal cortex. The data and current literature support the impression of a beneficial effect of soy components on the homeostatic response to stress. PMID- 29528086 TI - Epac1 is involved in cell cycle progression in lung cancer through PKC and Cx43 regulation. AB - INTRODUCTION: The exchange protein directly activated by cAMP (Epac1), a downstream target of the second messenger cAMP, modulates multiple biological effects of cAMP, alone or in cooperation with protein kinase A (PKC). Epac1 is necessary for promoting protein kinase C (PKC) translocation and activation. The aim of the study was to assess the intensity of Epac1 and protein kinase C (PKC) immunoreactivity in lung cancer and para-carcinoma tissues, and their associations with clinical-pathological indexes. Correlations between the immunoreactivity of Epac1, PKC, A-kinase anchor protein 95 (AKAP95) and connexin43 (Cx43) were also examined. MATERIAL AND METHODS: Epac1, Cx43 (46 cases) and PKC, AKAP95 (45 cases) immunoexpression levels were determined in tissue samples of lung cancer and in 12 samples of neighboring para-carcinoma specimens by the PV-9000 Two-step immunohistochemical technique. RESULTS: The percentage of Epac1 positive samples was significantly lower in lung cancer tissue than in neighboring para-carcinoma specimens (37% vs. 83.3%, p < 0.05); the difference in PKC immunoreactivity was not significant (64.4% vs. 91.7%). Epac1 expression was associated with the degree of malignancy and lymph node metastasis (P < 0.05), but not with histological type (P > 0.05), whereas PKC expression was not related to these parameters. Interestingly, Epac1 expression was correlated with PKC and Cx43 expression. Moreover, PKC expression was correlated with AKAP95 expression. CONCLUSION: Normal Epac1 expression may suppress lung cancer occurrence and metastasis, and its downregulation is involved in cell cycle progression in lung cancer through PKC and Cx43 regulation. PMID- 29528087 TI - Improving evidence informed policy-making for health in the Eastern Mediterranean Region. PMID- 29528088 TI - Independent prescription of medicines and diagnostic test advice by final year medical students in Punjab. AB - Sale of medicines is not rigorously controlled in Pakistan. Therefore, medical students start prescribing drugs and advising diagnostic tests before they graduate. This cross-sectional study investigated the frequency of independent medical prescription by 180 stratified, randomly selected final year medical students from 3 public medical colleges in Punjab, Pakistan. Data were obtained by self-administered questionnaire. One hundred and twelve students had prescribed medicines independently without any supervision; 38 had performed a physical examination before prescribing; and 74 had advised and 49 interpreted diagnostic tests independently. Forty-four students had administered injectable drugs and one third of these were administered without seeing expiry dates. The most frequently prescribed drugs were nonsteroidal antiinflammatory drugs (92%) and antibiotics (73%). The most frequently advised tests were complete blood cell count, chest X-ray and urine detailed reports. One hundred and twenty-seven participants thought that medical students should not prescribe drugs. There was a significant relationship between gender and household income and prescription practices. Many final year medical students had prescribed drugs and advised diagnostic tests before graduation. PMID- 29528089 TI - Challenges impeding integration of oral health into primary health care. AB - The primary healthcare (PHC) services in the Islamic Republic of Iran have succeeded in addressing high levels of communicable diseases; however, they seem less able to deal with maternal and paediatric oral diseases. The aim of this study was to examine problems in integrating oral health services into PHC. This was a qualitative research study comprising focus group discussions and interviews. Five focus-group discussions were held with midwives, family healthcare practitioners, rural PHC workers, duty-service dentists, and public health dentists. Also, individual interviews were organized with experts of faculty members in related fields, informant managers and policy makers, and in depth interviews were done with pregnant women in four PHC centres. Audiotapes were transcribed following each session, and then a qualitative thematic analysis was carried out on gathered data. Data analysis resulted in 4 main themes relating to the challenges: environmental, educational, organizational and school based programme factors. This study provides a clearer understanding of the challenges of integrating oral health services into PHC. PMID- 29528090 TI - Genetic characterization of the Anopheles maculipennis complex (Diptera: Culicidae) in Morocco: a fundamental tool for malaria control. AB - The Anopheles maculipennis complex has been implicated in the transmission of malaria, which was endemic in Morocco until 2010. Climate change, intensification of international travel and the permanent presence of the vector increase the risk of malaria re-emergence. Using polymerase chain reaction assay (PCR), this study attempts to identify the possible presence of the Maculipennis complex in several areas of Morocco, based on the concept of risk. Eighty-six mosquito specimens were analyzed using PCR amplification of the ITS2 (Internal Transcribed Spacer 2) sequence of ribosomal DNA. The ITS2 sequences of the mosquitoes were compared to those of the 7 species of the Maculipennis complex available in GenBank. The results obtained confirm the presence of Anopheles labranchiae. In order to enable technology transfer, DNA extraction and amplification steps are presented for the first time in detail, given the fact that the technique is still unknown to several Moroccan peripheral laboratories. PMID- 29528091 TI - Assessment of the quality of life in patients on haemodialysis in Iraq. AB - Chronic kidney disease requires life-long renal replacement therapy, which can greatly impair the quality of life (QOL) of patients. This cross-sectional study aimed to assess the QOL of patients on haemodialysis, and the factors affecting it, at the dialysis unit of Basra General Hospital. A total of 104 patients with end-stage renal disease on haemodialysis were included. Data were collected using the World Health Organization QOL questionnaire. Sociodemographic and clinical data were also collected. Of the 104 patients, 57% were male, 73% were older than 45 years, 87% were of middle and low socioeconomic status, 70% had been on dialysis for more than 1 year, 74% had arteriovenous fistula vascular access, 34% had diabetes and 48% were positive for hepatitis virus. All domains of QOL (physical health, psychological, social relationships and environment) were affected; the physical domain was the most severely affected. Older age, lower socioeconomic status, longer duration of dialysis, central line vascular access, having diabetes and positive hepatitis serology were significantly associated with lower QOL (P < 0.05). PMID- 29528092 TI - Trend and seroprevalence of Epstein-Barr virus in Bahrain: 2001-2015. AB - In Bahrain, adequate epidemiological information is lacking concerning the rate of EBV infection, which could be helpful in order to develop measures to protect against EBV infections. The aim of this study, was to investigate the trend of EBV infection in Bahrain over a 15-year period, 2001-2015. The EBV serological results of 10 560 patients with possible EBV infection were evaluated. Samples taken at the Salmaniya Medical Complex during 2001-2015 were included. The presence or absence of EBV viral capsid antigen (VCA) IgG, VCA IgM and EBV nuclear antigen (EBNA) IgG antibodies was recorded. Of the 10 560 samples, 10 333 were usable; of these, 86.1% were seropositive with an increasing trend of EBV infection over the study period. Primary EBV infection was found in 7.4% of the seropositive samples; of these, 47.3% were between 5 and 19 years. EBV reactivation was found in 11% of the seropositive samples; of these, 50% were > 25 years of age. The youngest seropositive patient was 11 months old. EBV is a common viral infection in Bahrain. Most primary infections occur between 1 and 5 years while most reactivation infections occur after the age of 25 years. Serial surveillance of EBV infection is needed in Bahrain. Measures to protect against EBV infections should be implemented. PMID- 29528093 TI - Investigation of breastfeeding training based on BASNEF model on the intensity of postpartum blues. AB - Postpartum blues is a major risk factor for the incidence of postpartum depression and disruption of breastfeeding. This semi-experimental study investigated the effect of breastfeeding training based on the BASNEF model on severity of postpartum blues in 2012. Four educational sessions based on the BASNEF model were held separately for pregnant women and their mothers, mothers in-law and spouses. The control group received routine care at the clinic. After delivery, women's knowledge of and attitude towards postpartum blues were evaluated using the Zung Self- Rating Depression Scale. There were significant differences between the groups regarding mean scores of knowledge, mothers' evaluation of behaviour outcomes, attitude, and enabling factors. Also, the mean score for postpartum blues was significantly lower in the intervention group compared to the control group. In conclusion, training based on the BASNEF model had a positive effect on maternal knowledge and attitude and, consequently, the intensity of postpartum blues. Further studies are required to determine the reliability and effectiveness of this method. PMID- 29528094 TI - Changes in dietary habits, physical activity and status of metabolic syndrome among expatriates in Saudi Arabia. AB - The aim of this paper is to assess the impact of living in Saudi Arabia on expatriate employees and their families' behavioural cardiovascular risk factors (BCVRFs), and to examine the association between changes in BCVRFs and metabolic syndrome (MetS). A cross-sectional study was conducted on 1437 individuals, aged >= 18 years, from King Saud University in Riyadh, Saudi Arabia. We used the World Health Organization STEPS questionnaire to ask every participant questions about BCVRFs twice: (1) to reflect their period of living in Saudi Arabia and (2) to shed light upon life in their country of origin. Their mean age was 40.9 (11.7) years. The prevalence of BCVRFs was as follows: tobacco use in 156 (11%), physical inactivity in 1049 (73%) low intake of fruit and vegetables in 1264 (88%) and MetS in 378 (26%). Residing in Saudi Arabia had reduced physical activity and intake of fruit and vegetables. There was also a significant increase in the fast food consumption. In conclusion, living in Saudi Arabia had a significant negative effect on BCVRFs. However, there was no statistically significant association between changes in fruit and vegetable intake and physical activity and MetS status, except that intake of fast food was lower among participants with MetS. PMID- 29528095 TI - Ethical reflections on the principle of patient autonomy. AB - In a world open to the movement of people, medical ethics is today associated with the area of loyal behavior of the practitioner and oriented in the patient's interest and accountability of each. The universal vision of respect for the dignity of the sick person progresses. Yet, many behaviours are sometimes illegitimate, but not in principle legally reprehensible. One of the main principles marking the observance of patient consent is based on the autonomy given to the patient to decide for himself what appears to be adapted to his or her care. The patient must be the one who makes the final decision on issues concerning them and doctors must act to respect it. Therefore, they must accept that the patient has a different value system. PMID- 29528096 TI - Evaluation of vaccination efficiency against HBV among Syrian multitransfused patients. AB - This cross-sectional study estimates HBV prevalence and evaluates vaccination efficiency among multitransfused patients. 159 patients with various hemoglobinopathies were tested for HBsAg, anti-HBs, and anti-HBc, using enzyme linked immunosorbent assay (ELISA). The serological results were then compared with the relevant documentation in medical records. Seropositivity of HBV was detected in 1/8 of recruited patients. Serological immunity was found in only half of patients, while the other half were either infected or non-immune. The vaccination against HBV appeared inefficient in almost half of vaccinated patients and was not documented in the medical records of 1/6 of patients. Thus, multitransfused patients are at risk of acquiring hepatitis B infection. Applying prophylactic vaccination, documenting vaccine doses, and monitoring immune response are highly recommended. PMID- 29528098 TI - WHO events addressing public health priorities. PMID- 29528097 TI - The forgotten history of pre-modern epidemiology: contribution of Ibn An-Nafis in the Islamic golden era. PMID- 29528099 TI - What is the standard of care for primary mediastinal B cell lymphoma; R-CHOP or DA-EPOCH-R? - Response to Melani et al. PMID- 29528100 TI - Activated prothrombin complex concentrate (FEIBA(r) ) in acquired haemophilia A: a large multicentre Italian study - the FAIR Registry. PMID- 29528101 TI - From candidate to president: Donald Trump's effect on an executive coaching client. AB - Political events leading up to, and following the results of, the November, 2016 election have affected patients in psychotherapy as well as clients working with executive coaches. This article follows developments in coaching work with one male, middle-aged, highly successful but "interpersonally challenged" client that are traceable to the client's reactions to the election and to the president himself. PMID- 29528102 TI - Moral injury process and its psychological consequences among Israeli combat veterans. AB - OBJECTIVES: We aim to examine the link between exposure to potentially morally injurious events (PMIEs) and posttraumatic stress disorder symptoms (PTSS). We also aim to explore the mediating roles of depressive attributions, trauma related guilt and shame, and self-disgust in the relationship between PMIEs and PTSS among combat veterans. METHOD: A volunteers' sample of 191 Israeli combat veterans responded to self-report questionnaires in a cross-sectional design study. RESULTS: More than one-fifth of the sample reported experiencing PMIEs but only betrayal based experience was related to PTSS. Importantly, betrayal based experience was associated with depressive attributions which increased the level of trauma-related distressing guilt, intrinsic shame and self-disgust, which in turn were associated with high levels of PTSS. CONCLUSIONS: PMIEs, and especially betrayal based experiences, are related to PTSS among Israeli veterans. Depressive attributions, trauma-related distressing guilt, intrinsic shame, and self-disgust might serve as possible mechanisms for the links between PMIEs and PTSS. PMID- 29528104 TI - Altered lipid metabolism could drive the bone marrow failure in fanconi anaemia. PMID- 29528103 TI - Initial evaluation of the effects of an environmental-focused problem-solving intervention for transition-age young people with developmental disabilities: Project TEAM. AB - AIM: Project TEAM (Teens making Environment and Activity Modifications) teaches transition-age young people with developmental disabilities, including those with co-occurring intellectual or cognitive disabilities, to identify and resolve environmental barriers to participation. We examined its effects on young people's attainment of participation goals, knowledge, problem-solving, self determination, and self-efficacy. METHOD: We used a quasi-experimental, repeated measures design (initial, outcome, 6-week follow-up) with two groups: (1) Project TEAM (28 males, 19 females; mean age 17y 6mo); and (2) goal-setting comparison (21 males, 14 females; mean age 17y 6mo). A matched convenience sample was recruited in two US states. Attainment of participation goals and goal attainment scaling (GAS) T scores were compared at outcome. Differences between groups for all other outcomes were analyzed using linear mixed effects models. RESULTS: At outcome, Project TEAM participants demonstrated greater knowledge (estimated mean difference: 1.82; confidence interval [CI]: 0.90, 2.74) and ability to apply knowledge during participation (GAS: t[75]=4.21; CI: 5.21, 14.57) compared to goal-setting. While both groups achieved significant improvements in knowledge, problem-solving, and self-determination, increases in parent reported self determination remained at 6-week follow-up only for Project TEAM (estimated mean difference: 4.65; CI: 1.32, 7.98). Significantly more Project TEAM participants attained their participation goals by follow-up (Project TEAM=97.6%, goal setting=77.1%, p=0.009). INTERPRETATION: Both approaches support attainment of participation goals. Although inconclusive, Project TEAM may uniquely support young people with developmental disabilities to act in a self-determined manner and apply an environmental problem-solving approach over time. WHAT THIS PAPER ADDS: Individualized goal-setting, alone or during Project TEAM (Teens making Environment and Activity Modifications) appears to support attainment of participation goals. Project TEAM appears to support young people with developmental disabilities to apply an environmental problem-solving approach to participation barriers. Parents of young people with developmental disabilities report sustained changes in self-determination 6 weeks after Project TEAM. PMID- 29528105 TI - Manual dexterity in young and healthy older adults. 1. Age- and gender-related differences in unimanual and bimanual performance. AB - This study aimed to better characterize age-related differences in dexterity by using an integrative approach where movement times and kinematics were measured for both hands. Forty-five young (age 19-31) and 55 healthy older adults (age 60 88) were evaluated during unimanual and bimanual performance of the Purdue Pegboard Test. Gender effects were also assessed. From video-recorded data, movement times and kinematics were obtained for reaching, grasping, transport, and inserting. Results showed that older adults had longer movement times for grasping and inserting with the right hand, and across all movements with the left hand. Kinematic differences were found in path length, linear, and angular velocity. The patterns of slowing were similar in unimanual and bimanual tasks. Gender effects showed more slowing in older males than older females. Age differences in dexterity not only comprise slowing of movements but also kinematic alterations. The importance of gender in hand function was demonstrated. PMID- 29528106 TI - Local variation in embryo development rate in annual fish. AB - Extreme asynchrony in embryo development, a typical feature of annual killifish living in temporary pools, represents a bet-hedging strategy to cope with unpredictable rainfall. African annual killifish are distributed across a large precipitation gradient, raising the potential for local adaptation in the degree of developmental asynchrony (e.g. higher in arid areas, lower in humid areas). Eight populations of two sister species, Nothobranchius furzeri and Nothobranchius kadleci, from sites along the rainfall gradient were tested and compared for asynchrony and duration of embryo development. Degree of asynchrony and mean duration of embryo development did not differ across the examined range. Despite generally high developmental variability, fish from more arid regions (where rain is more erratic) produced a significantly higher proportion of short developing embryos. Comparable developmental asynchrony, regardless of precipitation level, suggests that all populations tested need to cope with some level of rainfall stochasticity. By producing more short-developing embryos, however, fish in more arid areas with relatively more erratic rains are better adapted to very short pool durations and are more likely to produce multiple offspring generations within a single rainy season. PMID- 29528107 TI - Assessing the capacity for compensatory growth in growth-hormone transgenic coho salmon Oncorhynchus kisutch. AB - The effect of feed cycling (consisting of periods of starvation followed by periods of refeeding to satiation) on compensatory growth was evaluated in growth hormone transgenic and non-transgenic wild-type coho salmon Oncorhynchus kisutch. The specific growth rate (GSR ) of feed-restricted non-transgenic O. kisutch was not significantly different from the GSR of fully-fed non-transgenic O. kisutch during two refeeding periods, whereas the GSR of feed-restricted transgenic O. kisutch was significantly higher in relation to the GSR of fully-fed transgenic O. kisutch during the second refeeding period, but not during the first, indicating that growth compensation mechanisms are different between non transgenic and growth-hormone (GH)-transgenic O. kisutch and may depend on life history (i.e. previous starvation). Despite the non-significant growth rate compensation in non-transgenic O. kisutch, these fish showed a level of body mass catch-up growth not displayed by transgenic O. kisutch. PMID- 29528108 TI - Novel insights into the role of mitochondrial fusion and fission in cardiomyocyte apoptosis induced by ischemia/reperfusion. AB - As the main source of energy in the body, mitochondria are highly dynamic organelles, which are constantly going through fusion and fission. The fine balance of mitochondrial fusion and fission plays an important role in maintaining the stability of cardiomyocyte homeostasis. The processes of mitochondrial fusion and fission are very complex, which is mediated by fusion and fission proteins. Disruptions in these processes through controlling fusion and fission proteins affect mitochondrial functions and cardiomyocyte survival. Ischemia/reperfusion (I/R) can regulate the expression and post-translational modifications of fusion and fission proteins thereby inducing the abnormality of mitochondrial fusion and fission and cardiomyocyte apoptosis. Furthermore, intervention with the expression and function of fusion and fission proteins influences on cardiomyocyte apoptosis under I/R conditions. In this review, we focus on the current developments in the effects of mitochondrial fusion and fission on cardiomyocyte functions, the implications for cardiomyocyte apoptosis in response to I/R, and possible mechanisms. And we review their roles as a potential therapeutic target for treating I/R-induced cardiomyocyte injury. PMID- 29528109 TI - Outcomes of early parent-child adrenocortical attunement in the high-risk offspring of depressed parents. AB - This study examined the impact of parent-child attunement of morning cortisol on parenting and child outcomes in dyads with and without parental depression. Participants included 142 parent-child dyads (3-5 years-old) who provided morning cortisol samples at Wave 1, and 98 dyads returned for the 3-year follow-up at Wave 2. Results indicated that for parents with a history of depression and for female children, stronger attunement predicted increases in parental hostility from Wave 1 to Wave 2. For females only, stronger attunement was related to children's depressive symptoms at Wave 1 and Wave 2. Stronger attunement was also associated with increases in children's depressive symptoms from Wave 1 to Wave 2, poorer psychosocial functioning at Wave 1, and ADHD symptoms at Wave 2. Findings highlight attunement as an important biological process related to parenting and child outcomes and suggest it may play a role in the intergenerational transmission of depression risk. PMID- 29528111 TI - In Memoriam: Fran Katz. PMID- 29528110 TI - Gold nanoparticles crosslinking by peptides and amino acids: A tool for the colorimetric identification of amino acids. AB - Gold nanoparticles are known to aggregate in the presence of proper multifunctional compounds. For those larger than 3 nm, the process can be followed with the naked eye because the surface plasmon absorption band of the particles shifts to longer wavelengths and the solution color changes from red to blue. To exploit this property, we have used amino acids and peptides as crosslinking agents in ethanol at low uM concentrations. In the case of amino acids, we report a straightforward protocol for their colorimetric identification. We also report that the presence of precise secondary structure and conformational constraints in oligopeptides, directly influence their crosslinking ability. A discussion on the nature of the interactions that induce these phenomena is also reported. PMID- 29528112 TI - N-methylation in amino acids and peptides: Scope and limitations. AB - Active pharmaceutical ingredients (APIs) can be divided into two types, namely chemical and biological entities. Traditionally, the former has been associated with the so-called small molecules. The revival of peptides in pharmaceutical industry results from their importance in many biological roles. However, low metabolic stability and the lack of oral availability of most peptides is the main drawback for peptide to fulfill that paradigmatic situation. In this regard, efforts are being channeled into addressing this issue by introducing restrictions into the flexible peptide backbone, mainly through N-methyl amino acids (NMAAs) or development of small cyclic peptides. In many cases, both the above restrictions are combined with the aim to enhance oral availability. The synthesis of NMAAs is complex and their introduction into the peptide chain brings additional synthetic challenges and also sometimes leads to side reactions. Here we discuss the most efficient methods for the synthesis of NMAAs (either in solution or in solid phase) and also their introduction into peptide sequences. Special attention is also given to the detection of side reactions and the most efficient way to prevent them. PMID- 29528113 TI - Bromotryptophans and their incorporation in cyclic and bicyclic privileged peptides. AB - While revisiting biologically active natural peptides, the importance of the tryptophan residue became clear. In this article, the incorporation of this amino acid, brominated at different positions of the indole ring, into cyclic peptides was successfully achieved. These products demonstrated improved properties in terms of passive diffusion, permeability across membranes, biostability in human serum and cytotoxicity. Moreover, these brominated tryptophans at positions 5, 6, or 7 proved to be compatible as building blocks to prepare bicyclic stapled peptides by performing on-resin Suzuki-Miyaura cross-coupling reactions. PMID- 29528115 TI - A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles. AB - KEY POINTS: Activation of focal adhesion kinase (FAK) by integrin signalling facilitates smooth muscle contraction by transmitting the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue. Here we report that electrical field stimulation (EFS) of cholinergic motor neurons activates FAK in gastric fundus smooth muscles, and that FAK activation by EFS is atropine-sensitive but nicardipine-insensitive. PDBu and calyculin A contracted gastric fundus muscles Ca2+ -independently and also activated FAK. Inhibition of FAK activation inhibits the contractile responses evoked by EFS, and inhibits CPI-17 phosphorylation at T38. This study indicates that mechanical force or tension is sufficient to activate FAK, and that FAK appears to be involved in the activation of the protein kinase C-CPI-17 Ca2+ sensitization pathway in gastric fundus smooth muscles. These results reveal a novel role for FAK in gastric fundus smooth muscle contraction by facilitating CPI-17 phosphorylation. ABSTRACT: Smooth muscle contraction involves regulating myosin light chain phosphorylation and dephosphorylation by myosin light chain kinase and myosin light chain phosphatase. C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) and myosin phosphatase targeting subunit of myosin light-chain phosphatase (MYPT1) are crucial for regulating gastrointestinal smooth muscle contraction by inhibiting myosin light chain phosphatase. Integrin signalling involves the dynamic recruitment of several proteins, including focal adhesion kinase (FAK), to focal adhesions. FAK tyrosine kinase activation is involved in cell adhesion to the extracellular matrix via integrin signalling. FAK participates in linking the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue. Here, we show that cholinergic stimulation activates FAK in gastric fundus smooth muscles. Electrical field stimulation in the presence of Nomega -nitro-l-arginine methyl ester and MRS2500 contracted gastric fundus smooth muscle strips and increased FAK Y397 phosphorylation (pY397). Atropine blocked the contractions and prevented the increase in pY397. The FAK inhibitor PF-431396 inhibited the contractions and the increase in pY397. PF-431396 also inhibited the electrical field stimulation-induced increase in CPI-17 T38 phosphorylation, and reduced MYPT1 T696 and T853, and myosin light chain S19 phosphorylation. Ca2+ influx was unaffected by PF-431396. Nicardipine inhibited the contractions but had no effect on the increase in pY397. Phorbol 12,13 dibutyrate or calyculin A contracted gastric fundus smooth muscle strips Ca2+ independently and increased pY397. Our findings suggest that FAK is activated by mechanical forces during contraction and reveal a novel role of FAK in the regulation of CPI-17 phosphorylation. PMID- 29528116 TI - Pharmacokinetics studies of 4'-cyano-2'-deoxyguanosine, a potent inhibitor of the hepatitis B virus, in rats. AB - OBJECTIVES: 4'-cyano-2'-deoxyguanosine (CdG), a novel nucleoside analogue, has a high degree of antiviral activity against the chronic hepatitis B virus (HBV). The objective of this study was to develop an analytical method for quantitatively determining CdG levels in biological samples by liquid chromatography-mass spectrometry (LC/MS) and to investigate the pharmacokinetic properties of CdG in rats after intravenous and oral administration. METHODS: An analytical method using a UPLC system interfaced with a TOF-MS system was developed and validated. The pharmacokinetic properties after the intravenous and oral administration of CdG to rats were evaluated. In vivo pharmacokinetic interactions between CdG and entecavir were also investigated. KEY FINDINGS: A rapid, simple and selective method for the quantification of CdG in biological samples was established using LC/MS with solid-phase extraction. In vivo pharmacokinetic studies of CdG in rats demonstrated that CdG is highly bioavailable, is rapidly absorbed from the intestinal tract, is then distributed to the liver rather than kidney and is ultimately excreted via the urine in an unchanged form. The co-administration of CdG and entecavir led to pharmacokinetic interactions with each other. CONCLUSIONS: The data generated in this study provide support for the clinical development of CdG for use in the treatment of HBV. PMID- 29528114 TI - Understanding and designing head-to-tail cyclic peptides. AB - Cyclic peptides (CPs) are an exciting class of molecules with a variety of applications. However, design strategies for CP therapeutics, for example, are generally limited by a poor understanding of their sequence-structure relationships. This knowledge gap often leads to a trial-and-error approach for designing CPs for a specific purpose, which is both costly and time-consuming. Herein, we describe the current experimental and computational efforts in understanding and designing head-to-tail CPs along with their respective challenges. In addition, we provide several future directions in the field of computational CP design to improve its accuracy, efficiency and applicability. These advances, combined with experimental techniques, shall ultimately provide a better understanding of these interesting molecules and a reliable working platform to rationally design CPs with desired characteristics. PMID- 29528117 TI - The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease. AB - KEY POINTS: The reason(s) for the increased central arterial stiffness in chronic obstructive pulmonary disease (COPD) are not well understood. In this study, we inhibited the carotid chemoreceptor with both low-dose dopamine and hyperoxia, and observed a decrease in central arterial stiffness and muscle sympathetic nervous activity in COPD patients, while no change was observed in age- and risk matched controls. Carotid chemoreceptor inhibition increased vascular conductance, secondary to reduced arterial blood pressure in COPD patients. Findings from the current study suggest that elevated carotid chemoreceptor activity may contribute to the increased arterial stiffness typically observed in COPD patients. ABSTRACT: Chronic obstructive pulmonary disease (COPD) patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (forced expired volume in 1 s (FEV1 ) predicted +/- SD: 83 +/- 18%) and 13 age- and risk-matched controls completed resting CV function measurements with either i.v. saline or i.v. dopamine (2 MUg kg-1 min-1 ) while breathing normoxic or hyperoxic air (100% O2 ). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxic or hyperoxic air. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P < 0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (P < 0.05) in COPD, while no change was observed in controls. CC inhibition decreased PWV and MSNA, and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in COPD. PMID- 29528118 TI - Effects of group size on school structure and behaviour in yellow-eyed mullet Aldrichetta forsteri. AB - Schooling behaviour in yellow-eyed mullet Aldrichetta forsteri, a common fish species in New Zealand estuarine habitats, was investigated to identify interaction rules associated with group formation. Tank-based three-dimensional studies of three group sizes (15, 75 and 150 individuals) were carried out to measure the effects of these different group sizes on school structure during control, predation risk and foraging behavioural states. Increased group size positively correlated with nearest-neighbour distance in control and foraging states. Swimming speed was the lowest in all three behavioural states in groups of 15 fish compared with 75 or 150. Immediate behavioural response following visual exposure to a simulated avian predator differed between groups resulting in loss of structure in larger groups. School shape was an oblong-oblate spheroid with a length, breadth and height ratio of 5:2:1 and the area of free space surrounding individual fish was spherical in shape with a high degree of spatial isotropy present in all size groups. These findings challenge traditional theories based on either local or global properties as key drivers of group structure. Instead, our results suggest that a more collaborative approach involving both group size and rules pertaining to nearest-neighbour interactions affects collective behaviours in this species. PMID- 29528119 TI - Sibling experience modulates perceptual narrowing toward adult faces in the first year of life. AB - During the first year of life face discrimination abilities narrow toward adult human faces of the most frequently encountered ethnic group/s. Earlier studies showed that perceptual learning under laboratory-training protocols can modulate this narrowing process. Here we investigated whether natural experience acquired in everyday settings with an older sibling's face can shape the trajectory of perceptual narrowing towards adult faces. Using an infant-controlled habituation procedure we measured discrimination of adult (Experiment 1) and child faces (Experiment 2) in 3- and 9- month-old infants with and without a child sibling. Discrimination of adult faces was observed for infants at both ages, although accompanied by posthabituation preferences in opposite directions, whereas at both ages the discrimination of child faces critically depended on sibling experience. These results provide the first evidence that natural experience acquired with siblings affects the tuning properties of infant face representation. PMID- 29528120 TI - Contractile heterogeneity in ventricular myocardium. AB - The transmural heterogeneity of the contractility in ventricular muscle has not been well-studied. Here, we investigated the calcium transient and sarcomere contraction/relaxation in the endocardial (Endo) and epicardial (Epi) myocytes. Endo and Epi myocytes were isolated from C57/BL6 mice by Langendorff perfusion. Ca2+ transient and sarcomere contraction/relaxation were recorded simultaneously at different stimulation frequencies using a dual excitation fluorescence photomultiplier system. We found that the Endo myocytes have higher baseline diastolic calcium, significantly larger calcium transient and stronger sarcomere shortening than Epi myocytes. However, both the rising and decline phases for calcium transient and sarcomere shortening were slower in Endo than in Epi myocytes. When simulation frequency was increased from 1 to 3 Hz, a greater percent increase in the diastole calcium level, Ca2+ transient and sarcomere shortening amplitude has been observed in the Endo myocytes. Accordingly, the frequency-dependent acceleration in the decay rate of calcium transient and sarcomere relaxation was more profound in the Endo than in Epi myocytes. Western blot analysis showed that CaMKII activity was significantly higher in Epi than in Endo myocardium before stimulation. However, this transmural heterogeneity was reversed by rapid pacing. CaMKII inhibition by KN93 diminished the frequency dependent alterations of Ca2+ transient and sarcomere contraction. Our results suggest that the contractility of ventricular myocytes is heterogeneous. The Endo myocardium is the major force generating layer in the heart, both at slow and fast heart rate, and the transmural heterogeneity of CaMKII activation plays an important role in the frequency-dependent alterations. PMID- 29528121 TI - Teaching & Learning Tips 6: The flipped classroom. AB - Challenge: The "flipped classroom" is a pedagogical model in which instructional materials are delivered to learners outside of class, reserving class time for application of new principles with peers and instructors. Active learning has forever been an elusive ideal in medical education, but the flipped class model is relatively new to medical education. What is the evidence for the "flipped classroom," and how can these techniques be applied to the teaching of dermatology to trainees at all stages of their medical careers? PMID- 29528122 TI - Anti-CD20 immunotherapy as a bridge to tolerance, after allogeneic stem cell transplantation for patients with chronic lymphocytic leukaemia: results of the CLLX4 trial. PMID- 29528123 TI - Finding a needle in a haystack: Bacteroides fragilis polysaccharide A as the archetypical symbiosis factor. AB - Starting from birth, all animals develop a symbiotic relationship with their resident microorganisms that benefits both the microbe and the host. Recent advances in technology have substantially improved our ability to direct research toward the identification of important microbial species that affect host physiology. The identification of specific commensal molecules from these microbes and their mechanisms of action is still in its early stages. Polysaccharide A (PSA) of Bacteroides fragilis is the archetypical example of a commensal molecule that can modulate the host immune system in health and disease. This zwitterionic polysaccharide has a critical impact on the development of the mammalian immune system and also on the stimulation of interleukin 10-producing CD4+ T cells; consequently, PSA confers benefits to the host with regard to experimental autoimmune, inflammatory, and infectious diseases. In this review, we summarize the current understanding of the immunomodulatory effects of B. fragilis PSA and discuss these effects as a novel immunological paradigm. In particular, we discuss recent advances in our understanding of the unique functional mechanisms of this molecule and its therapeutic potential, and we review the recent literature in the field of microbiome research aimed at discovering new commensal products and their immunomodulatory potential. PMID- 29528124 TI - From the basic science of biological effects of ultrashort electrical pulses to medical therapies. AB - This article is based on my presentation at the D'Arsonval Ceremony at the Joint Annual Meeting of the Bioelectromagnetics Society and the European BioElectromagnetics Association in Hangzhou, China, in June of 2017. It describes the pathway from the first studies on the effects of intense, nanosecond pulses on biological cells to the development of medical therapies based on these effects. The motivation for the initial studies of the effects of high voltage, nanosecond pulses on mammalian cells was based on a simple electrical circuit model, which predicted that such pulses allow us to affect not just the plasma membrane but also the subcellular structures. The first experimental study that confirmed this hypothesis was published in 2001 in the Bioelectromagnetics journal. It was followed by a large number of publications that showed that such ultrashort pulses affect cell functions, such as programmed cell death, and, at lower intensity, calcium mobilization from intracellular structures. These basic studies were leading to novel cancer treatments, treatments of cardiac arrhythmia, and advanced wound healing. Further, by reducing the pulse duration into the picosecond range, antenna-based neural stimulation seems to be possible. This manuscript gives an overview of the progress in this field of research in the decade after the initial bioelectric studies with high-voltage, nanosecond pulses, particularly the research performed at the Frank Reidy Research Center for Bioelectrics. It also tells you about my journey and that of my colleagues at the Center for Bioelectrics into and through this fascinating bioelectromagnetics research area. Bioelectromagnetics. 39:257-276, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29528125 TI - Development of an orange juice beverage formulated with oat beta-glucan and whey protein isolate. AB - BACKGROUND: A beverage was developed using beta-glucan and whey protein isolate (WPI). The sensory attributes and changes of the physiochemical properties (pH value, total acidity, total soluble solids, sugar-acid ratio, color, viscosity, turbidity, and browning index) of the beverage during 48-h storage were evaluated by comparison with the commercial product and a blank sample. RESULTS: The sweetness, smoothness, and overall acceptance of the developed beverage were similar to the commercial and blank samples. The suspension stability of the developed beverage was significantly better than that of the commercial products. The total acidity of the beverage decreased considerably after 36-h storage. Regarding color changes, the three samples showed a significant increase in L and b values after 6 h of storage. The viscosity of the developed beverage rose significantly after 24 h of storage. The increase in the concentration of beta glucan in the mixed hydrocolloid caused a significant elevation in the levels of viscosity. CONCLUSION: The sensory and physicochemical analysis results obtained by the panelists revealed that the developed beverage was acceptable and possessed stable physicochemical attributes. Our present findings indicate that the developed beverage has excellent potential for commercialization. (c) 2018 Society of Chemical Industry. PMID- 29528126 TI - HDlive Flow Silhouette Mode for Diagnosis of Ectopia Cordis With a Left Ventricular Diverticulum at 15 Weeks' Gestation. PMID- 29528127 TI - "A disease of our time": The Catholic Church's condemnation and absolution of psychoanalysis (1924-1975). AB - The present paper is focused on the evolution of the position of the Catholic Church toward psychoanalysis. Even before Freud's The Future of an Illusion (1927), psychoanalysis was criticized by Catholic theologians. Psychoanalysis was viewed with either contempt or with indifference, but nonpsychoanalytic psychotherapy was accepted, especially for pastoral use. Freudian theory remained for most Catholics a delicate and dangerous subject for a long time. From the center to the periphery of the Vatican, Catholic positions against psychoanalysis have varied in the way that theological stances have varied. In the middle decades of the twentieth century, some Catholics changed their attitudes and even practiced psychoanalysis, challenging the interdict of the Holy Office, which prohibited psychoanalytic practice until 1961. During the Cold War, psychoanalysis progressively became more and more relevant within Catholic culture for two main reasons: changes in psychoanalytic doctrine (which began to stress sexuality to a lesser degree) and the increasing number of Catholic psychoanalysts, even among priests. Between the 1960s and the 1970s, psychoanalysis was eventually accepted and became the main topic of a famous speech by Pope Paul VI. This paper illustrates how this acceptance was a sort of unofficial endorsement of a movement that had already won acceptance within the Church. The situation was fostered by people like Maryse Choisy or Leonardo Ancona, who had advocated within the Church for a sui generis use of psychoanalysis (e.g., proposing a desexualized version of Freudian theories), despite warnings and prohibitions from the hierarchies of the Church. PMID- 29528129 TI - Evaluating Z Scores to Quantify Levator Hiatal Distensibility by 3-Dimensional Ultrasonography in Nulliparas and Women With Pelvic Organ Prolapse. AB - OBJECTIVES: To use Z scores to quantify hiatal distensibility and to test the performance of Z scores for levator hiatal areas in predicting substantial pelvic organ prolapse (POP). METHODS: We undertook a retrospective study of the data from 145 nulliparas and 166 patients with POP who had a clinical POP examination with 3-dimensional translabial ultrasonography. Z scores were used to normalize levator hiatal areas of nulliparas. The Z score model for the hiatal area was built by the formula Z score = (measured value - predicted mean value)/predicted standard deviation and was used to evaluate hiatal ballooning in women with POP. RESULTS: Valid data were gathered from 134 nulliparas and 159 patients with POP. POP stage 1 was found in 46 women, stage 2 in 62, stage 3 in 43, and stage 4 in 8. We built the Z score model as follows: Z-Av = (measured value - 17.15)/3.11, where Av represented the minimal levator hiatal area on the maximum Valsalva maneuver. The levator hiatal area was strongly related to the POP stage (P < .001). On a receiver operating characteristic curve analysis, the cutoff of Z-Av was 1 for POP stage 2 or higher (sensitivity, 77%; specificity, 60%) and substantial POP on ultrasonography (sensitivity, 84%; specificity, 75%). CONCLUSIONS: Hiatal distensibility can be exactly evaluated by Z-Av. A Z-Av value of less than 1.0 was defined as a "normal hiatal expansion," 1 to 3 as "mild ballooning," 3 to 5 as "moderate ballooning," 5 to 7 as "marked ballooning," and 7 or greater as "severe ballooning." PMID- 29528128 TI - Validation of the oesophageal hypervigilance and anxiety scale for chronic oesophageal disease. AB - BACKGROUND: Oesophageal hypervigilance and anxiety can drive symptom experience in chronic oesophageal conditions, including gastro-oesophageal reflux disease, achalasia and functional oesophageal disorders. To date, no validated self-report measure exists to evaluate oesophageal hypervigilance and anxiety. AIMS: This study aims to develop a brief and reliable questionnaire assessing these constructs, the oesophageal hypervigilance and anxiety scale (EHAS). METHODS: Questions for the EHAS were drawn from 4 existing validated measures that assessed hypervigilance and anxiety adapted for the oesophagus. Patients who previously underwent high-resolution manometry testing at a university-based oesophageal motility clinic were retrospectively identified. Patients were included in the analysis if they completed the EHAS as well as questionnaires assessing symptom severity and health-related quality of life at the time of the high-resolution manometry. RESULTS: Nine hundred and eighty-two patients aged 18 85 completed the study. The EHAS demonstrates excellent internal consistency (alpha = 0.93) and split-half reliability (Guttman = 0.87). Inter-item correlations indicated multicollinearity was not achieved; thus, no items were removed from the original 15-item scale. Principal components factor analysis revealed two subscales measuring symptom-specific anxiety and symptom-specific hypervigilance. Construct validity for total and subscale scores was supported by positive correlations with symptom severity and negative correlations with health related quality of life. CONCLUSIONS: The EHAS is a 15-item scale assessing oesophageal hypervigilance and symptom-specfic anxiety. The EHAS could be useful in evaluating the role of these constructs in several oesophageal conditions in which hypersensitivity, hypervigilance and anxiety may contribute to symptoms and impact treatment outcomes. PMID- 29528130 TI - Comparison of the Diagnostic Performance of Power Doppler Ultrasound and a New Microvascular Doppler Ultrasound Technique (AngioPLUS) for Differentiating Benign and Malignant Breast Masses. AB - This study was performed to compare the diagnostic performance of power Doppler ultrasound (US) and a new microvascular Doppler US technique (AngioPLUS; SuperSonic Imagine, Aix-en-Provence, France) for differentiating benign and malignant breast masses. Power Doppler US and AngioPLUS findings were available in 124 breast masses with confirmed pathologic results (benign, 80 [64.5%]; malignant, 44 [35.5%]). The diagnostic performance of each tool was calculated to distinguish benign from malignant masses using a receiver operating characteristic curve analysis and compared. The area under the curve showed that AngioPLUS was superior to power Doppler US in differentiating benign from malignant breast masses, but the difference was not statistically significant. PMID- 29528131 TI - Characterization of Thoracic Pathophysiologic Conditions in Patients Receiving High-Frequency Oscillatory Ventilation: Pediatric Experience. AB - High-frequency oscillatory ventilation (HFOV) is a mode of mechanical ventilation used in severe pediatric respiratory failure. Thoracic ultrasound (US) is a powerful tool for diagnosing acute pathophysiologic conditions during spontaneous respiration and conventional noninvasive and invasive mechanical ventilation. High-frequency oscillatory ventilation differs from conventional modes of ventilation in that it does not primarily use bulk flow delivery for gas exchange but, rather, a number of alternative mechanisms as the result of pressure variations oscillating around a constant distending pressure. Thoracic US has not been well described in patients receiving HFOV, and it is unclear whether the US findings for assessing thoracic pathophysiologic conditions during conventional ventilation are applicable to patients receiving HFOV. We discuss the similarities and differences of thoracic US findings in patients who are spontaneously breathing or receiving conventional ventilation compared to those in patients receiving HFOV. PMID- 29528132 TI - Platelet-leucocyte aggregation is augmented in cirrhosis and further increased by platelet transfusion. AB - BACKGROUND: Thrombocytopenia and circulating dysfunctional immune cells are commonly observed in patients with cirrhosis. Platelets may form complexes with neutrophils, monocytes and T cells modulating their function. We recently reported increased frequencies of platelet-complexed neutrophils in cirrhosis with evidence of neutrophil activation upon contact with healthy platelets in vitro. Whether this occurs in vivo following platelet transfusion and contributes to systemic inflammation and endothelial activation is unknown. AIMS: To characterise platelet-leucocyte aggregation in cirrhosis and to determine whether elective platelet transfusion results in perturbations associated with changes in markers of haemostasis, inflammation or endothelial activation. METHODS: We collected blood from cirrhotics (n = 19) before and following elective platelet transfusion. We measured platelet-leucocyte aggregation, activation and function, and markers of platelet activation, systemic inflammation and endothelial activation by flow cytometry. Haemostasis was assessed by thromboelastometry and plasma haemostatic proteins. RESULTS: We observed a 2.5-fold increase in platelet complexed neutrophils in patients with cirrhosis compared with healthy subjects and twofold more platelets attached per monocyte and T cell. All platelet complexed leucocytes expressed higher levels of activation markers and platelet complexed neutrophils had higher resting oxidative burst and phagocytic capacity than their nonplatelet-complexed counterparts (P < 0.001); most pronounced in patients with cirrhosis. Paradoxically, platelet-complexed leucocyte frequency decreased with increasing MELD score. Platelet transfusion increased soluble CD40 ligand (platelet activation marker), the frequency of platelet-complexed monocytes (P < 0.05) and improved haemostatic status. CONCLUSION: Cirrhotic patients have activated circulating platelet-complexed leucocytes with increased platelet-monocyte aggregation following elective platelet transfusion. Elective platelet transfusion might therefore exacerbate immune dysfunction in cirrhosis. PMID- 29528133 TI - Triple-mixture of Zn, Mn, and Fe increases bioaccumulation and causes oxidative stress in freshwater neotropical fish. AB - Metal bioaccumulation and oxidative stress biomarkers were determined in Prochilodus lineatus to understand the effects of short-term exposure to a triple mixture of Zn, Mn, and Fe. Three independent tests were carried out, in which fish were exposed to 3 concentrations of Zn (0.18, 1.0, and 5.0 mg L-1 ), Mn (0.1, 0.5, and 5.0 mg L-1 ), and in the mix test to Fe (5.0 mg L-1 ) and a mixture of Zn (1.0 mg L-1 ) + Mn (0.5 mg L-1 ), with and without Fe. After exposure for 96 h, tissues were removed for metal bioaccumulation analysis and oxidative stress biomarkers were determined in liver, along with DNA damage in blood cells. Our results revealed that Zn and Mn were bioaccumulated in fish tissues after exposure to 5.0 mg L-1 , whereas Fe only bioaccumulated in muscle and gills after mixture exposure. Results indicated that 1 metal interfered with the other's bioaccumulation. In P. lineatus, 5 mg L-1 of both Mn and Fe were toxic, because damage was observed (lipid peroxidation [LPO] in liver and DNA damage in blood cells), whereas Zn induced liver responses (metallothionein [MT] and reduced glutathione [GSH] increases) to prevent damage. In terms of bioaccumulation and alterations of oxidative stress biomarkers, we showed that Zn, Mn, and Fe triple-mixture enhances individual metal toxicity in Neotropical fish P. lineatus. Environ Toxicol Chem 2018;37:1749-1756. (c) 2018 SETAC. PMID- 29528134 TI - Mental Transformation Skill in Young Children: The Role of Concrete and Abstract Motor Training. AB - We examined the effects of three different training conditions, all of which involve the motor system, on kindergarteners' mental transformation skill. We focused on three main questions. First, we asked whether training that involves making a motor movement that is relevant to the mental transformation-either concretely through action (action training) or more abstractly through gestural movements that represent the action (move-gesture training)-resulted in greater gains than training using motor movements irrelevant to the mental transformation (point-gesture training). We tested children prior to training, immediately after training (posttest), and 1 week after training (retest), and we found greater improvement in mental transformation skill in both the action and move-gesture training conditions than in the point-gesture condition, at both posttest and retest. Second, we asked whether the total gain made by retest differed depending on the abstractness of the movement-relevant training (action vs. move-gesture), and we found that it did not. Finally, we asked whether the time course of improvement differed for the two movement-relevant conditions, and we found that it did-gains in the action condition were realized immediately at posttest, with no further gains at retest; gains in the move-gesture condition were realized throughout, with comparable gains from pretest-to-posttest and from posttest-to retest. Training that involves movement, whether concrete or abstract, can thus benefit children's mental transformation skill. However, the benefits unfold differently over time-the benefits of concrete training unfold immediately after training (online learning); the benefits of more abstract training unfold in equal steps immediately after training (online learning) and during the intervening week with no additional training (offline learning). These findings have implications for the kinds of instruction that can best support spatial learning. PMID- 29528135 TI - Effect of calibration methods on the accuracy of angiographic measurements during transcatheter procedures in dogs. AB - BACKGROUND: Different methods to perform reference calibration of an angiographic image exist; however, a prospective comparison of calibration methods has yet to be investigated in veterinary medicine. OBJECTIVE: To compare angiographic measurements using two commonly employed reference calibration methods, an esophageal pigtail marker catheter (EC) versus a radiopaque table ruler (TR). ANIMALS: Thirty-five client-owned dogs undergoing transcatheter intervention. METHODS: Prospective comparison study. Two reference calibration methods, EC and TR, were recorded in dogs undergoing transcatheter procedures from May 2016 to July 2017. Relevant measurements were performed in triplicate and averaged after image calibration to either EC or TR. Comparisons between methods were made by correlation, paired t-test, the method of Bland and Altman, and Passing-Bablok regression. RESULTS: A total of 39 angiographic structures were measured. Interventions included balloon pulmonary valvuloplasty (n = 21), patent ductus arteriosus occlusion (n = 11), subaortic or sub-pulmonary balloon dilatation (n = 4), and cor triatriatum membranostomy (n = 3). Angiographic measurements were larger when calibrated to EC versus TR (P < .0001). The mean bias was 0.86 mm, with greater bias for larger measurements. The EC measurements were ~10% greater than TR based on regression analysis. Weight was correlated to the difference between methods (rho = 0.55, P = .0003). CONCLUSIONS AND CLINICAL IMPORTANCE: Angiographic image calibration using a ruler placed on the fluoroscopy table underestimates the size of a structure by ~10% as compared with a marker catheter placed within the esophagus. This effect is greatest when measuring larger structures such as the pulmonary valve annulus and in larger dogs. PMID- 29528136 TI - A framework for investigating illegal wildlife trade on social media with machine learning. AB - Article impact statement: Machine learning can be used to automatically monitor and assess illegal wildlife trade on social media platforms. PMID- 29528138 TI - When is more frequent hemodialysis beneficial? AB - The use of frequent hemodialysis (HD) is growing, with the hope of improving outcomes in end-stage renal disease. We narratively review the three randomized trials, 15 comparative cohort studies, and several case series of frequent HD that empirically demonstrate the potential efficacy and adverse effects of these regimens. Taken together, the randomized studies suggest frequent HD may result in left ventricular mass regression. This effect is most pronounced when left ventricular mass is abnormal, but attenuated by significant residual urine output. Both frequent short and long HD consistently improved blood pressure control and reduced antihypertensive use, despite greater weekly interdialytic weight gains. Serum phosphate was lowered. Frequent short daytime HD improved health-related quality of life, while frequent long overnight HD did not. Regarding adverse effects, frequent HD patients underwent significantly more procedures to salvage arteriovenous vascular accesses. An absolute increase in hypotensive episodes was observed with frequent short HD, while frequent long HD accelerated residual renal function loss and increased perceived caregiver burden. The effect of frequent HD on mortality is controversial, due to conflicting results and limitations of published studies. Finally, pregnancy outcomes may be substantially better with frequent long HD. On the basis of these data, we suggest frequent HD is most likely to benefit patients with left ventricular hypertrophy particularly if there is minimal urine output, those unable to attain dry weight on a thrice weekly schedule, and pregnant women. All patients receiving frequent HD should be advised of and monitored for potential risks. PMID- 29528137 TI - Evaluation of seminal plasma proteomics and relevance of FSH in identification of nonobstructive azoospermia: A preliminary study. AB - Nonobstructive azoospermia (NOA) patients present with high levels of serum FSH. At the protein level, the aetiology and pathways underlying different subtypes of NOA are unclear. The aim was to evaluate quantitatively differences in proteomic profiles of NOA patients presenting with normal serum FSH and normal testicular volume and high serum FSH and small testicular volume. The study comprised of 14 nonobstructive azoospermic men (N = 4; normal FSH and normal testicular volume and N = 10; high FSH and small testicular volume) and seven normozoospermic men. Proteomic analysis was done using LC-MS. GSTM3 and PGK2 were less abundant in the normal and high FSH group compared to controls. HSPA4L and HSPA4 were exclusively present in control group whereas HSP90AB1, HSPA1B, HSP90AA1 and HSPA2 were less abundant and exclusive to the normal and high FSH group. We have identified six heat-shock proteins that may have a role in the pathology of NOA. FSH and testicular volume by itself are not good markers of NOA. The inverse association of GSTM3 and PGK2 regulation with FSH levels along with 12 proteins exclusively in NOA groups suggests further evaluation of their predictive potential in a larger cohort of patients. PMID- 29528140 TI - Axial complex and associated structures of the sea urchin Strongylocentrotus pallidus (Sars, G.O. 1871) (Echinodermata: Echinoidea). AB - Studies of echinoid microscopic anatomy over the last two centuries have created a number of inaccuracies and mistakes that have accumulated in the descriptions of the intricate organization of the coelomic system of Echinoidea. To clarify the situation, we reconstructed the axial complex and radial complex of the echinoid Strongylocentrotus pallidus. The water ring is located between the perivisceral coelom and the perioral coelom. The oral haemal ring lies between the coelothelia of the water-vascular, perivisceral, and perioral rings. The axial part of the axial organ communicates with the oral haemal ring in interradius CD, but the axial coelom does not form the axocoelomic perihaemal ring. The ventral intestinal haemal vessel originates from the oral haemal ring in radius A, and then branches into a network of capillaries, from which the dorsal intestinal vessel starts. The pericardial coelom envelopes the pericardial part of the axial organ, the lacunae of which communicate with the haemocoel of the body wall and with the axial part of the axial organ. The genital haemal ring and the dorsal intestinal vessel communicate with the axial organ. The genital coelom passes in the CD interradius on the side opposite to the hindgut. There is a somatocoelomic perihaemal ring, which sends a pair of coelomic outgrowths into each radius, accompanied by a radial haemal vessel in the oral part. The mistakes and inaccuracies of early descriptions of the echinoid axial complex are listed. The axial complex and associated structures of sea urchins are compared with other eleutherozoans. PMID- 29528139 TI - Associations between expression levels of nucleotide excision repair proteins in lymphoblastoid cells and risk of squamous cell carcinoma of the head and neck. AB - Squamous cell carcinoma of head and neck (SCCHN) is one of the most common malignancies worldwide, and nucleotide excision repair (NER) is involved in SCCHN susceptibility. In this analysis of 349 newly diagnosed SCCHN patients and 295 cancer-free controls, we investigated whether expression levels of eight core NER proteins were associated with risk of SCCHN. We quantified NER protein expression levels in cultured peripheral lymphocytes using a reverse-phase protein microarray. Compared with the controls, SCCHN patients had statistically significantly lower expression levels of ERCC3 and XPA (P = 0.001 and 0.001, respectively). After dividing the subjects by controls' median values of expression levels, we found a dose-dependent association between an increased risk of SCCHN and low expression levels of ERCC3 (adjusted OR, 1.75, and 95% CI: 1.26-2.42; Ptrend = 0.008) and XPA (adjusted OR, 1.88; 95% CI, 1.35-2.60; Ptrend = 0.001). We also identified a significant multiplicative interaction between smoking status and ERCC3 expression levels (P = 0.014). Finally, after integrating demographic and clinical variables, we found that the addition of ERCC3 and XPA expression levels to the model significantly improved the sensitivity of the expanded model on SCCHN risk. In conclusion, reduced protein expression levels of ERCC3 and XPA were associated with an increased risk of SCCHN. However, these results need to be confirmed in additional large studies. PMID- 29528141 TI - Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice. AB - The molecular mechanisms underlying the pathogenesis of diffuse-type gastric cancer (DGC) have not been adequately explored due to a scarcity of appropriate animal models. A recently developed tool well suited for this line of investigation is the Pdx-1-Cre;Cdh1F/+ ;Trp53F/F ;Smad4F/F (pChe PS) mouse model that spontaneously develops metastatic DGC showing nearly complete E-cadherin loss. Here, we performed a proteogenomic analysis to uncover the molecular changes induced by the concurrent targeting of E-cadherin, p53, and Smad4 loss. The gene expression profiles of mouse DGCs and in vivo gastric phenotypes from various combinations of gene knockout demonstrated that these mutations collaborate to activate cancer-associated pathways to generate aggressive DGC. Of note, WNT-mediated epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM)-cytokine receptor interactions were prominently featured. In particular, the WNT target gene osteopontin (OPN) that functions as an ECM cytokine is highly upregulated. In validation experiments, OPN contributed to DGC stemness by promoting cancer stem cell (CSC) survival and chemoresistance. It was further found that Bcl-xL acts as a targetable downstream effector of OPN in DGC CSC survival. In addition, Zeb2 and thymosin-beta4 (Tbeta4) were identified as prime candidates as suppressors of E-cadherin expression from the remaining Cdh1 allele during DGC development. Specifically, Tbeta4 suppressed E-cadherin expression and anoikis while promoting cancer cell growth and migration. Collectively, these proteogenomic analyses broaden and deepen our understanding of the contribution of key driver mutations in the stepwise carcinogenesis of DGC through novel effectors, namely OPN and Tbeta4. PMID- 29528142 TI - In vivo imaging of Alpha7 nicotinic receptors as a novel method to monitor neuroinflammation after cerebral ischemia. AB - In vivo positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChRs) is a promising tool for the imaging evaluation of neurologic and neurodegenerative diseases. However, the role of alpha7 nAChRs after brain diseases such as cerebral ischemia and its involvement in inflammatory reaction is still largely unknown. In vivo and ex vivo evaluation of alpha7 nAChRs expression after transient middle cerebral artery occlusion (MCAO) was carried out using PET imaging with [11 C]NS14492 and immunohistochemistry (IHC). Pharmacological activation of alpha7 receptors was evaluated with magnetic resonance imaging (MRI), [18 F]DPA-714 PET, IHC, real time polymerase chain reaction (qPCR) and neurofunctional studies. In the ischemic territory, [11 C]NS14492 signal and IHC showed an expression increase of alpha7 receptors in microglia and astrocytes after cerebral ischemia. The role played by alpha7 receptors on neuroinflammation was supported by the decrease of [18 F]DPA-714 binding in ischemic rats treated with the alpha7 agonist PHA 568487 at day 7 after MCAO. Moreover, compared with non-treated MCAO rats, PHA-treated ischemic rats showed a significant reduction of the cerebral infarct volumes and an improvement of the neurologic outcome. PHA treatment significantly reduced the expression of leukocyte infiltration molecules in MCAO rats and in endothelial cells after in vitro ischemia. Despite that, the activation of alpha7 nAChR had no influence to the blood brain barrier (BBB) permeability measured by MRI. Taken together, these results suggest that the nicotinic alpha7 nAChRs play a key role in the inflammatory reaction and the leukocyte recruitment following cerebral ischemia in rats. PMID- 29528143 TI - Nickel exposure induces persistent mesenchymal phenotype in human lung epithelial cells through epigenetic activation of ZEB1. AB - Nickel (Ni) is an environmental and occupational carcinogen, and exposure to Ni is associated with lung and nasal cancers in humans. Furthermore, Ni exposure is implicated in several lung diseases including chronic inflammatory airway diseases, asthma, and fibrosis. However, the mutagenic potential of Ni is low and does not correlate with its potent toxicity and carcinogenicity. Therefore, mechanisms underlying Ni exposure-associated diseases remain poorly understood. Since the health risks of environmental exposures often continue post exposure, understanding the exposure effects that persist after the termination of exposure could provide mechanistic insights into diseases. By examining the persistent effects of Ni exposure, we report that Ni induces epithelial-mesenchymal transition (EMT) and that the mesenchymal phenotype remains irreversible even after the termination of exposure. Ni-induced EMT was dependent on the irreversible upregulation of ZEB1, an EMT master regulator, via resolution of its promoter bivalency. ZEB1, upon activation, downregulated its repressors as well as the cell-cell adhesion molecule, E-cadherin, resulting in the cells undergoing EMT and switching to persistent mesenchymal status. ZEB1 depletion in cells exposed to Ni attenuated Ni-induced EMT. Moreover, Ni exposure did not induce EMT in ZEB1-depleted cells. Activation of EMT, during which the epithelial cells lose cell-cell adhesion and become migratory and invasive, plays a major role in asthma, fibrosis, and cancer and metastasis, lung diseases associated with Ni exposure. Therefore, our finding of irreversible epigenetic activation of ZEB1 by Ni exposure and the acquisition of persistent mesenchymal phenotype would have important implications in understanding Ni-induced diseases. PMID- 29528144 TI - Seasonality of dipteran-mediated methylmercury flux from ponds. AB - Methylmercury (MeHg) is an aquatic contaminant that can be transferred to terrestrial predators by emergent aquatic insects. We assessed the effects of month and pond permanence on dipteran-mediated MeHg flux (calculated as emergent dipteran biomass * dipteran MeHg concentration) in 10 experimental ponds. Emergent dipterans were collected weekly from permanent ponds with bluegill (Lepomis macrochirus; n = 5) and semipermanent ponds without fish (n = 5) over a 7-mo period (February-August, 2015). We detected a significant effect of month on MeHg flux from 6 dipteran taxa and aggregate MeHg flux, with the highest MeHg flux from herbivorous/detritivorous chironomid midges and predatory midges in March; biting midges, phantom midges and herbivorous/detritivorous orthoclad midges in April; and mosquitoes in August. Aggregate dipteran-mediated MeHg flux peaked in April and then declined throughout the remainder of the summer. We did not detect a significant main effect of pond permanence or a significant month * pond permanence interaction effect on MeHg flux for any of the taxa examined in the present study or for aggregate MeHg flux. Given their ubiquity in aquatic systems and their importance in food webs at the land-water interface, dipterans are important taxa that should not be overlooked as a part of the Hg cycle. Environ Toxicol Chem 2018;37:1846-1851. (c) 2018 SETAC. PMID- 29528146 TI - Biochemical and pharmacological characterization of Trimersurus malabaricus snake venom. AB - Trimeresurus malabaricus is a venomous pit viper species endemic to southwestern part of India. In earlier reports, we have shown that envenomation by T. malabaricus venom leading to strong local tissue damage but the mechanism of action is not clearly revealed. Local tissue damage affected by T. malabaricus venom is of great importance since the poison has serious systemic effects including death in the case of multiple attacks. The present study details the major manifestations of T. malabaricus venom and the induction of local tissue damage, which suggests that most toxins are present in the form of hydrolytic enzymes. Hydrolytic activity of the enzymes was measured and the data indicated that protease and phospholipase A2 activity was high which is responsible for local tissue damage. Furthermore, the role of hydrolytic enzymes in the induction of pathological events such as hemorrhage, edema, myotoxicity, and blood coagulation examination were assessed through animal models. PMID- 29528145 TI - Timosaponin A-III inhibits oncogenic phenotype via regulation of PcG protein BMI1 in breast cancer cells. AB - Polycomb group (PcG) protein BMI1 is an important regulator of oncogenic phenotype and is often overexpressed in several human malignancies including breast cancer. Aberrant expression of BMI1 is associated with metastasis and poor prognosis in cancer patients. At present, therapy reagents that can efficiently inhibit the expression of BMI1 are not very well known. Here, we report that Timosaponin A-III (TA-III), a steroidal saponin obtained from the rhizomes of an herb, Anemarrhena asphodeloides, strongly inhibits expression of BMI1 in breast cancer cells. Treatment of breast cancer cells with TA-III resulted in inhibition of oncogenic phenotypes such as proliferation, migration and invasion, and induction of cellular senescence. Inhibition of these oncogenic phenotypes was accompanied by downregulation of BMI1 expression and histone posttranslational modification activity of PRC1. The mechanistic analysis of TA-III-induced inhibition of oncogenic activity and BMI1 expression suggests that downregulation of c-Myc mediates TA-III effect on BMI1. We further show that exogenous BMI1 overexpression can overcome TA-III-induced inhibition of oncogenic phenotypes. We also show that TA-III induces expression of tumor suppressive miR-200c and miR 141, which are negatively regulated by BMI1. In summary, our data suggest that TA III is a potent inhibitor of BMI1 and that it can be successfully used to inhibit the growth of tumors where PcG protein BMI1 and PcG activities are upregulated. PMID- 29528147 TI - Computational Characterization of the Mechanism for the Oxidative Coupling of Benzoic Acid and Alkynes by Rhodium/Copper and Rhodium/Silver Systems. AB - DFT calculations were applied to study the oxidative coupling between benzoic acid and 1-phenyl-1-propyne catalyzed by [CpRhCl2 ]2 (Cp=cyclopentadienyl) by using either Cu(OAc)2 (H2 O) or Ag(OAc) as the terminal oxidant, a process that has been experimentally shown to have subtleties related to regioselectivity (placement of the phenyl substituent of the alkyne in the isocoumarin product) and chemoselectivity (isocoumarin or naphthalene derivatives). Calculations reproduced the experimental results and showed the involvement of the oxidant throughout the catalytic cycle. The regioselectivity was found to be decided in the alkyne insertion step, in particular by the relative arrangement of the two phenyl groups. The high chemoselectivity towards isocoumarin associated to Cu(OAc)2 (H2 O) could be explained by the fact that the copper moiety blocks the CO2 extrusion pathway, which would lead to naphthalene derivatives, something that does not happen if Ag(OAc) is used. PMID- 29528148 TI - SusE facilitates starch uptake independent of starch binding in B. thetaiotaomicron. AB - The Bacteroides thetaiotaomicron starch utilization system (Sus) is a model system for nutrient acquisition by gut Bacteroidetes, a dominant phylum of gut bacteria. The Sus includes SusCDEFG, which assemble on the cell surface to capture, degrade and import starch. While SusD is an essential starch-binding protein, the precise role(s) of the partially homologous starch-binding proteins SusE and SusF has remained elusive. We previously reported that a non-binding version of SusD (SusD*) supports growth on starch when other members of the multi protein complex are present. Here we demonstrate that SusE supports SusD* growth on maltooligosaccharides, and determine the domains of SusE essential for this function. Furthermore, we demonstrate that SusE does not need to bind starch to support growth in the presence of SusD*, suggesting that the assembly of SusCDE is most important for maltooligosaccharide uptake in this context. However, starch binding by proteins SusDEF directs the uptake of maltooligosaccharides of specific lengths, suggesting that these proteins equip the cell to scavenge a range of starch fragments. These data demonstrate that the assembly of core Sus proteins SusCDE is secondary to their glycan binding roles, but glycan binding by Sus proteins may fine tune the selection of glycans from the environment. PMID- 29528149 TI - Avoidance tests as a tool to detect sublethal effects of oil-impacted sediments. AB - Currently, risk assessment for oil contamination does not consider behavioral responses of benthos to oil toxicity. Avoidance of oil-contaminated sediment by benthic amphipods, however, may be a highly sensitive endpoint for sublethal effects of commonly used distillate fuels. In the present study, the avoidance behavior of temperate freshwater (Gammarus pulex) and marine (Gammarus locusta) amphipods was tested by allowing them to choose between a reference sediment and a distillate marine grade A (DMA) oil-spiked sediment. Avoidance of DMA-spiked sediment at 1000 mg/kg dry weight was significant within the total exposure time (96 h) in G. pulex and within the first 72 h in G. locusta in 1 of 2 tests. Absence of DMA avoidance at lower concentrations (<=250 mg/kg dry wt) indicates that test species can only detect DMA above these concentrations. However, sensitivity to oil may vary according to the phenology and physiological conditions of the populations involved, such as the species temperature tolerance and reproductive stage. The results suggest that avoidance tests may be used as an alternative to traditional chronic toxicity tests provided that a causal link between avoidance and long-term effects can be established. Environ Toxicol Chem 2018;37:1757-1766. (c) 2018 SETAC. PMID- 29528150 TI - Oral health self-perception, dental caries, and pain: the role of dental fear underlying this association. AB - BACKGROUND: Oral health perception has multidimensional nature and can be influenced not only by clinical conditions but also by psychosocial characteristics. HYPOTHESIS: Dental fear could modify the association between dental caries and dental pain and the perception of negative impact. DESIGN: A cross-sectional study was conducted with (n = 1,196) children aged 8-12 years attending public and private schools in Pelotas/Brazil. Children were interviewed and examined. Oral health perception was assessed using a global oral health impact item. Crude and adjusted multivariable regression models were built and effect modification of dental fear in the association between clinical indicators and perception of impact was tested. RESULTS: Compared with children without fear and caries, children with fear and dental caries presented a 1.45 higher prevalence of negative impact (95% CI: 1.18-1.79) while those without fear and with dental caries had a 1.31 higher prevalence (95% CI: 1.11-1.54) after adjustments. Also, the prevalence of negative perception was higher for children with fear and dental pain (PR: 2.95; 95% CI: 1.59-2.39) and for children without fear and with pain (PR: 1.53; 95% CI: 1.29-1.80), compared to children without fear and pain. CONCLUSION: The presence of fear increased the effect of pain and caries on children's oral health perception. PMID- 29528151 TI - Community-acquired and transfusion-transmitted babesiosis are increasing: why and what to do? PMID- 29528152 TI - The precautionary principle and use of Group A plasma in recipients of unknown ABO blood group. PMID- 29528153 TI - Horton sees a speck: automated testing undone by a fragment. PMID- 29528155 TI - More data needed to establish maternal breast milk IgG as cause for anti-D hemolytic disease of fetus and newborn. PMID- 29528156 TI - Ignorance is not bliss. PMID- 29528157 TI - A Green-LED Driven Source of Hydrated Electrons Characterized from Microseconds to Hours and Applied to Cross-Couplings. AB - We present a novel photoredox catalytic system that delivers synthetically usable concentrations of hydrated electrons when illuminated with a green light-emitting diode (LED). The catalyst is a ruthenium complex protected by an anionic micelle, and the urate dianion serves as a sacrificial donor confined to the aqueous bulk. By virtue of its chemical properties, this donor not only suppresses charge recombination that would limit the electron yield, but also enables this system to perform cross-couplings through the action of hydrated electrons, the first examples of which are reported here. We have investigated the kinetics of all the steps involving the electron and its direct precursor in a comparative study by means of laser flash photolysis and by monitoring product formation during LED photolysis. Despite the differences in timescales, each approach on its own already gives a complete picture of the reaction over a temporal range spanning ten orders of magnitude. Discrepancies between the kinetic parameters obtained with the two complementary techniques can be rationalized with the slow secondary chemistry of the system; they reveal that the product-based method provides a more accurate description because it also responds to the changes of the system composition during a synthesis; hence, they demonstrate that in complex systems the timescale of the experimental observation should be matched to that of the actual application. PMID- 29528158 TI - Impaired rich club and increased local connectivity in children with traumatic brain injury: Local support for the rich? AB - Recent evidence has shown the presence of a "rich club" in the brain, which constitutes a core network of highly interconnected and spatially distributed brain regions, important for high-order cognitive processes. This study aimed to map the rich club organization in 17 young patients with moderate to severe TBI (15.71 +/- 1.75 years) in the chronic stage of recovery and 17 age- and gender matched controls. Probabilistic tractography was performed on diffusion weighted imaging data to construct the edges of the structural connectomes using number of streamlines as edge weight. In addition, the whole-brain network was divided into a rich club network, a local network and a feeder network connecting the latter two. Functional outcome was measured with a parent questionnaire for executive functioning. Our results revealed a significantly decreased rich club organization (p values < .05) and impaired executive functioning (p < .001) in young patients with TBI compared with controls. Specifically, we observed reduced density values in all three subnetworks (p values < .005) and a reduced mean strength in the rich club network (p = .013) together with an increased mean strength in the local network (p = .002) in patients with TBI. This study provides new insights into the nature of TBI-induced brain network alterations and supports the hypothesis that the local subnetwork tries to compensate for the biologically costly subnetwork of rich club nodes after TBI. PMID- 29528159 TI - Scanning electron microscopy as a tool for authentication of oil yielding seed. AB - Now-a-days, plant species are consumed globally for various purposes and this increasing demand leads to adulteration due to gradually exploitation in natural resources. The major causes of adulteration may be confusion in nomenclature, unawareness of authentic sources, unavailability of authentic sources, color resemblances, deficiencies in collection procedures, and misidentification. This study aims to use the microscopic techniques such as scanning electron microscopy for the authentication of the oil yielding seeds of four important and traditionally used species Prunus persica, Prunus domestica, and Eruca sativa and Argemone Mexicana from their adulterants. All of these are versatile in usage. Locally, these four plants are adulterated badly and there is need to provide a criteria and a complete monograph for correct identification. This research may prove to be helpful for quality control and as well for future studies to explore other novel aspects of these plants. PMID- 29528160 TI - Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning. AB - The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance. PMID- 29528162 TI - Antibiotics resistance of Helicobacter pylori in children with upper gastrointestinal symptoms in Hangzhou, China. AB - BACKGROUND: The decreasing eradication rate of Helicobacter pylori is mainly because of the progressive increase in its resistance to antibiotics. Studies on antimicrobial susceptibility of H. pylori in children are limited. This study aimed to investigate the resistance rates and patterns of H. pylori strains isolated from children. MATERIALS AND METHODS: Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori, and susceptibility to six antibiotics (clarithromycin, amoxicillin, gentamicin, furazolidone, metronidazole, and levofloxacin) was tested from 2012-2014. RESULTS: A total of 545 H. pylori strains were isolated from 1390 children recruited. The total resistance rates of H. pylori to clarithromycin, metronidazole, and levofloxacin were 20.6%, 68.8%, and 9.0%, respectively. No resistance to amoxicillin, gentamicin, and furazolidone was detected. 56.1% strains were single resistance, 19.6% were resistant to more than one antibiotic, 16.7% for double resistance, and 2.9% for triple resistance in 413 strains against any antibiotic. And the H. pylori resistance rate increased significantly from 2012-2014. There was no significant difference in the resistance rates to clarithromycin, metronidazole, and levofloxacin between different gender, age groups, and patients with peptic ulcer diseases or nonulcer diseases. CONCLUSIONS: Antibiotic resistance was indicated in H. pylori strains isolated from children in Hangzhou, and it increased significantly during the 3 years. Our data strongly support current guidelines, which recommend antibiotic susceptibility tests prior to eradication therapy. PMID- 29528161 TI - Heritability of aggression following social evaluation in middle childhood: An fMRI study. AB - Middle childhood marks an important phase for developing and maintaining social relations. At the same time, this phase is marked by a gap in our knowledge of the genetic and environmental influences on brain responses to social feedback and their relation to behavioral aggression. In a large developmental twin sample (509 7- to 9-year-olds), the heritability and neural underpinnings of behavioral aggression following social evaluation were investigated, using the Social Network Aggression Task (SNAT). Participants viewed pictures of peers that gave positive, neutral, or negative feedback to the participant's profile. Next, participants could blast a loud noise toward the peer as an index of aggression. Genetic modeling revealed that aggression following negative feedback was influenced by both genetics and environmental (shared as well as unique environment). On a neural level (n = 385), the anterior insula and anterior cingulate cortex gyrus (ACCg) responded to both positive and negative feedback, suggesting they signal for social salience cues. The medial prefrontal cortex (mPFC) and inferior frontal gyrus (IFG) were specifically activated during negative feedback, whereas positive feedback resulted in increased activation in caudate, supplementary motor cortex (SMA), and dorsolateral prefrontal cortex (DLPFC). Decreased SMA and DLPFC activation during negative feedback was associated with more aggressive behavior after negative feedback. Moreover, genetic modeling showed that 13%-14% of the variance in dorsolateral PFC activity was explained by genetics. Our results suggest that the processing of social feedback is partly explained by genetic factors, whereas shared environmental influences play a role in behavioral aggression following feedback. PMID- 29528163 TI - Internationally educated nurses' descriptions of their access to structural empowerment while working in another country's health care context. AB - AIM: To examine internationally educated nurses' experiences of empowerment structures using Kanter's theory of structural empowerment. BACKGROUND: There has been an increase in the number of nurses working in other countries worldwide and concerns have been raised regarding their working conditions. METHOD: Semi structured interviews were conducted with a purposive sample of 11 internationally educated nurses. Directed content analysis was used to analyse the data and Kanter's theory of empowerment was used as a framework. RESULTS: Access to information was generally good. Access to support for their relationship with their managers varied. Regarding access to resources, nurses unfamiliar with clinical leadership found team leadership challenging. Access to in-house learning opportunities were reported as good. Access to informal power was more common than access to formal power. CONCLUSIONS: The findings support Kanter's theory and demonstrate that internationally experienced nurses encountered varying degrees of access to empowering structures. Access to information and formal power was more general and related to the unit. Access to resources, support, opportunities and informal power were related to both the unit and the informants' specific situation as IENs. IMPLICATIONS FOR NURSING MANAGEMENT: Managers need to support IENs when having a team leadership role, facilitate encounters between IENs and ordinary staff, and establishing mentorship for IENs. PMID- 29528165 TI - Dibenzo[a,e]pentalenophanes: Bending a Non-Alternant Hydrocarbon. AB - In cyclophanes, an aromatic moiety is incorporated into a (strained) cyclic structure. Of particular interest as model systems for bent carbon nanostructures are those containing polycyclic aromatic hydrocarbons. Dibenzo[a,e]pentalene (DBP) is a non-alternant polycyclic hydrocarbon with small band gap and tunable optoelectronic properties. However, changing these properties by bending of the DBP structure has yet to be investigated. Herein, we report the synthesis, optoelectronic, and structural properties of (2,7)dibenzo[a,e]pentalenophanes with four different bridge sizes and bending angles of the DBP unit, accompanied by (TD)DFT calculations. The last, strain-inducing dehydration reaction was accomplished by using Burgess' reagent. The HOMO and LUMO levels and the magnetic shielding of protons pointing inside the cyclophane cavity grew stepwise with increasing ring strain. Single-crystal X-ray structures of the smallest three derivatives revealed a near semi-circle and a bend angle of the DBP unit of almost 88 degrees for the smallest derivative. We demonstrated the synthetic versatility of our approach by varying the substituents at the DBP unit, allowing for further tuning of optoelectronic properties. The synthetic strategy presented herein may pave the way for the synthesis of conjugated DBP nanorings. PMID- 29528164 TI - Thioester-containing proteins in the tsetse fly (Glossina) and their response to trypanosome infection. AB - Thioester-containing proteins (TEPs) are conserved proteins with a role in innate immune immunity. In the current study, we characterized the TEP family in the genome of six tsetse fly species (Glossina spp.). Tsetse flies are the biological vectors of several African trypanosomes, which cause sleeping sickness in humans or nagana in livestock. The analysis of the tsetse TEP sequences revealed information about their structure, evolutionary relationships and expression profiles under both normal and trypanosome infection conditions. Phylogenetic analysis of the family showed that tsetse flies harbour a genomic expansion of specific TEPs that are not found in other dipterans. We found a general expression of all TEP genes in the alimentary tract, mouthparts and salivary glands. Glossina morsitans and Glossina palpalis TEP genes display a tissue specific expression pattern with some that are markedly up-regulated when the fly is infected with the trypanosome parasite. A different TEP response was observed to infection with Trypanosoma brucei compared to Trypanosoma congolense, indicating that the tsetse TEP response is trypanosome-specific. These findings are suggestive for the involvement of the TEP family in tsetse innate immunity, with a possible role in the control of the trypanosome parasite. PMID- 29528166 TI - Two-year-olds use adults' but not peers' points. AB - In the current study, 24- to 27-month-old children (N = 37) used pointing gestures in a cooperative object choice task with either peer or adult partners. When indicating the location of a hidden toy, children pointed equally accurately for adult and peer partners but more often for adult partners. When choosing from one of three hiding places, children used adults' pointing to find a hidden toy significantly more often than they used peers'. In interaction with peers, children's choice behavior was at chance level. These results suggest that toddlers ascribe informative value to adults' but not peers' pointing gestures, and highlight the role of children's social expectations in their communicative development. PMID- 29528167 TI - Silver oxysalts promote cutaneous wound healing independent of infection. AB - Chronic wounds often exist in a heightened state of inflammation whereby excessive inflammatory cells release high levels of proteases and reactive oxygen species (ROS). While low levels of ROS play a fundamental role in the regulation of normal wound healing, their levels need to be tightly regulated to prevent a hostile wound environment resulting from excessive levels of ROS. Infection amplifies the inflammatory response, augmenting levels of ROS which creates additional tissue damage that supports microbial growth. Antimicrobial dressings are used to combat infection; however, the effects of these dressing on the wound environment and healing independent of infection are rarely assessed. Cytotoxic or adverse effects on healing may exacerbate the hostile wound environment and prolong healing. Here we assessed the effect on healing independent of infection of silver oxysalts which produce higher oxidative states of silver (Ag2+ /Ag3+ ). Silver oxysalts had no adverse effect on fibroblast scratch wound closure whilst significantly promoting closure of keratinocyte scratch wounds (34% increase compared with control). Furthermore, dressings containing silver oxysalts accelerated healing of full-thickness incisional wounds in wild-type mice, reducing wound area, promoting reepithelialization, and dampening inflammation. We explored the mechanisms by which silver oxysalts promote healing and found that unlike other silver dressings tested, silver oxysalt dressings catalyze the breakdown of hydrogen peroxide to water and oxygen. In addition, we found that silver oxysalts directly released oxygen when exposed to water. Collectively, these data provide the first indication that silver oxysalts promote healing independent of infection and may regulate oxidative stress within a wound through catalysis of hydrogen peroxide. PMID- 29528168 TI - Body checking and body avoidance in eating disorders: Systematic review and meta analysis. AB - This review sought to systematically review and quantify the evidence related to body checking and body avoidance in eating disorders (EDs) to gauge the size of effects, as well as examine potential differences between clinical and nonclinical populations, and between different ED subtypes. PsycINFO, PsycARTICLES, PsycEXTRA, Cochrane Library, and MEDLINE databases were searched for academic literature published until October 2017. A grey literature search was also conducted. Fifty-two studies were identified for the systematic review, of which 34 were eligible for meta-analysis. Only female samples were included in the meta-analysis. ED cases experienced significantly higher body checking (d = 1.26, p < .001) and body avoidance (d = 1.88, p < .001) overall relative to healthy controls, but neither behaviour varied by ED subtype. In nonclinical samples, body checking (r = .60) and body avoidance (r = .56) were significantly correlated with ED pathology (p < .001). These findings support transdiagnostic theoretical models and approaches to ED treatment and early intervention programmes. PMID- 29528170 TI - Structure and substrate specificity of beta-ketoacyl-acyl carrier protein synthase III from Acinetobacter baumannii. AB - Originally annotated as the initiator of fatty acid synthesis (FAS), beta ketoacyl-acyl carrier protein synthase III (KAS III) is a unique component of the bacterial FAS system. Novel variants of KAS III have been identified that promote the de novo use of additional extracellular fatty acids by FAS. These KAS III variants prefer longer acyl-groups, notably octanoyl-CoA. Acinetobacter baumannii, a clinically important nosocomial pathogen, contains such a multifunctional KAS III (AbKAS III). To characterize the structural basis of its substrate specificity, we determined the crystal structures of AbKAS III in the presence of different substrates. The acyl-group binding cavity of AbKAS III and co-crystal structure of AbKAS III and octanoyl-CoA confirmed that the cavity can accommodate acyl groups with longer alkyl chains. Interestingly, Cys264 formed a disulfide bond with residual CoA used in the crystallization, which distorted helices at the putative interface with acyl-carrier proteins. The crystal structure of KAS III in the alternate conformation can also be utilized for designing novel antibiotics. PMID- 29528169 TI - Vestibular brain changes within 70 days of head down bed rest. AB - Head-down-tilt bed rest (HDBR) is frequently utilized as a spaceflight analog research environment to study the effects of axial body unloading and fluid shifts that are associated with spaceflight in the absence of gravitational modifications. HDBR has been shown to result in balance changes, presumably due to sensory reweighting and adaptation processes. Here, we examined whether HDBR results in changes in the neural correlates of vestibular processing. Thirteen men participated in a 70-day HDBR intervention; we measured balance, functional mobility, and functional brain activity in response to vestibular stimulation at 7 time points before, during, and after HDBR. Vestibular stimulation was administered by means of skull taps, resulting in activation of the vestibular cortex and deactivation of the cerebellar, motor, and somatosensory cortices. Activation in the bilateral insular cortex, part of the vestibular network, gradually increased across the course of HDBR, suggesting an upregulation of vestibular inputs in response to the reduced somatosensory inputs experienced during bed rest. Furthermore, greater increase of activation in multiple frontal, parietal, and occipital regions in response to vestibular stimulation during HDBR was associated with greater decrements in balance and mobility from before to after HDBR, suggesting reduced neural efficiency. These findings shed light on neuroplastic changes occurring with conditions of altered sensory inputs, and reveal the potential for central vestibular-somatosensory convergence and reweighting with bed rest. PMID- 29528171 TI - Glycidyl Triazolyl Polymers: Poly(ethylene glycol) Derivatives Functionalized by Azide-Alkyne Cycloaddition Reaction. AB - Glycidyl triazolyl polymer (GTP), which is the product of the Huisgen dipolar cycloaddition reaction between glycidyl azide polymer and alkyne derivatives, is featured here. GTP is the multifunctionalized poly(ethylene glycol) (PEG). The drawback of PEG is that linear PEG has the functional group only at both ends. The low loading capability of the functional groups limits the possibilities of PEG applications. GTP facilitates the synthesis of multifunctionalized PEG derivatives. In this article, 74 examples of GTP homopolymers and copolymers are introduced. The synthetic protocols and work-up processes of GTP are summarized. In addition, application studies are reviewed: for example, stimuli-responsive and self-healing materials, materials for electrical memory devices, ion conductive materials, and biomedical materials. Finally, some issues on GTP synthesis and future directions for GTP-based polymer materials are proposed. PMID- 29528172 TI - Survey of the prevalence and methodology of quality assurance for B-mode ultrasound image quality among veterinary sonographers. AB - Image quality in B-mode ultrasound is important as it reflects the diagnostic accuracy and diagnostic information provided during clinical scanning. Quality assurance programs for B-mode ultrasound systems/components are comprised of initial quality acceptance testing and subsequent regularly scheduled quality control testing. The importance of quality assurance programs for B-mode ultrasound image quality using ultrasound phantoms is well documented in the human medical and medical physics literature. The purpose of this prospective, cross-sectional, survey study was to determine the prevalence and methodology of quality acceptance testing and quality control testing of image quality for ultrasound system/components among veterinary sonographers. An online electronic survey was sent to 1497 members of veterinary imaging organizations: the American College of Veterinary Radiology, the Veterinary Ultrasound Society, and the European Association of Veterinary Diagnostic Imaging, and a total of 167 responses were received. The results showed that the percentages of veterinary sonographers performing quality acceptance testing and quality control testing are 42% (64/151; 95% confidence interval 34-52%) and 26% (40/156: 95% confidence interval 19-33%) respectively. Of the respondents who claimed to have quality acceptance testing or quality control testing of image quality in place for their ultrasound system/components, 0% have performed quality acceptance testing or quality control testing correctly (quality acceptance testing 95% confidence interval: 0-6%, quality control testing 95% confidence interval: 0-11%). Further education and guidelines are recommended for veterinary sonographers in the area of quality acceptance testing and quality control testing for B-mode ultrasound equipment/components. PMID- 29528173 TI - A Readily Accessible Class of Chiral Cp Ligands and their Application in RuII Catalyzed Enantioselective Syntheses of Dihydrobenzoindoles. AB - Chiral cyclopentadienyl (Cpx ) ligands have a large application potential in enantioselective transition-metal catalysis. However, the development of concise and practical routes to such ligands remains in its infancy. We present a convenient and efficient two-step synthesis of a novel class of chiral Cpx ligands with tunable steric properties that can be readily used for complexation, giving Cpx RhI , Cpx IrI , and Cpx RuII complexes. The potential of this ligand class is demonstrated with the latter in the enantioselective cyclization of azabenzonorbornadienes with alkynes, affording dihydrobenzoindoles in up to 98:2 e.r., significantly outperforming existing binaphthyl-derived Cpx ligands. PMID- 29528174 TI - Stress, anxiety, and depression of both partners in infertile couples are associated with cytokine levels and adverse IVF outcome. AB - PROBLEM: Psychiatric disorders and stress in women have been associated with poor IVF outcome. We hypothesized that both partners in the infertile couples are emotionally affected, and cytokines in both may link psychological to reproductive outcome. METHOD OF STUDY: Forty-five IVF couples completed questionnaires and visual analog scales for stress and psychiatric disorders and had cytokines measured in serum, semen, cervicovaginal, and follicular fluids. Multivariable analyses, t tests, maximum likelihood estimates, Spearman correlation, and data mining were applied. RESULTS: Psychopathology was found in 72% of the couples. Female and male stress were associated with stress, anxiety, and depression in the respective partner, and with a lower likelihood of clinical pregnancy and live birth. Lower serum TGF-beta and higher cervicovaginal IL-6 and IL-1beta were associated with stress. In data decision trees, cytokines in relation to stress and depression in both partners were found indicative of IVF failure. CONCLUSION: Infertile couples may benefit from psychiatric evaluation and treatment of both partners. PMID- 29528175 TI - Randomized Controlled Clinical Trial to Compare Posterior Implant-Supported Modified Monolithic Zirconia and Metal-Ceramic Single Crowns: One-Year Results. AB - PURPOSE: The purpose of this randomized controlled clinical trial was to investigate the prosthetic outcomes of posterior implant-supported single crowns (SCs) with a modified monolithic zirconia or metal-ceramic design at 1 year of loading. MATERIALS AND METHODS: Forty participants with 73 dental implants in need of at least 1 maxillary or mandibular posterior implant-supported SC were consecutively selected for this study. The included participants were randomly divided into modified monolithic zirconia (MMZ) and metal-ceramic (MC) groups. The implant-supported SCs were examined after 1 year for survival and technical complications. Descriptive statistics were used to illustrate the data, and the association associated risks of complications were estimated using the logistic regression model with Firth's approach for rare outcome (alpha = 0.05). RESULTS: During the observation period, 2 participants in the MC group were lost to follow up. A total of 38 participants with 70 posterior implant-supported SCs (36 and 34 SCs in the MMZ and MC groups respectively) completed the 1-year follow-up examination. One implant failed in the MMZ group. The 1-year survival rates for implants and crowns were both 97.2% in the MMZ group. The survival rates for implants and crowns were both 100% in the MC group. One screw loosening event was observed in one screw-retained SC in the MMZ group; however, 8 complication events occurred in 7 SCs in the MC group. Therefore, the complication-free rates were 97.1% and 79.4% in the MMZ and MC SCs respectively. The most common complication in the MC group was screw loosening (14.7%), followed by loss of retention (5.9%), and ceramic fracture (2.9%). Significantly more technical complications were observed in the MC SCs than MMZ SCs (p = 0.0432). CONCLUSION: The modified monolithic zirconia design applied to the posterior implant supported SCs had a significantly lower technical complication rate than did the metal-ceramic one. PMID- 29528176 TI - Quality of life in children with retinoblastoma after enucleation in China. AB - OBJECTIVE: To study the quality of life of Chinese pediatric patients with retinoblastoma (RB) after enucleation and the influencing factors. METHODS: A questionnaire survey was performed on 71 cases of pediatric patients with RB after enucleation and 80 cases of healthy children, using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQLTM 4.0). RESULTS: The social dimension scores, school dimension scores, and total scores for the PedsQLTM 4.0 among the pediatric patients with RB were statistically significantly lower than those of healthy children. The influencing factors were unilateral/bilateral affected eyes, diagnosis age, and ocular prosthesis satisfaction. CONCLUSION: Early discovery, timely treatment, increased eye salvage rate, and cosmetic effects of ocular prosthesis were key factors for increasing the quality of life of pediatric patients with RB. Attention should be paid to the health, social, and school development of pediatric patients with RB. PMID- 29528177 TI - Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3] Sigmatropic/1,2-Migration Cascade of Benzothiophene S-Oxides. AB - Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]-sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2-migration to access C2 functionalized benzothiophenes. PMID- 29528178 TI - Iliopsoas hematoma in a patient with sickle cell disease. AB - Although musculoskeletal pain in patients with sickle cell disease (SCD) is most frequently the result of vaso-occlusive episodes, clinicians often consider other etiologies including osteomyelitis, avascular necrosis, and trauma. In this study, we report the case of a young female with SCD with hip and back pain secondary to a nontraumatic iliopsoas periosteal hematoma with evidence of adjacent bone infarction. The pathophysiology, diagnostic considerations, and management of periosteal hematomas in SCD are reviewed. This case highlights the need for recognition of unusual causes of musculoskeletal pain in SCD. PMID- 29528179 TI - Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation. AB - BACKGROUND: Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo-SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context. MATERIALS AND METHODS: A retrospective study was carried out on children hospitalized between 2007 and 2015 for allo-SCT with TBI-based myeloablative conditioning associated with cyclophosphamide (CY, 60 mg/kg/day * 2 days) or EP. The primary endpoint of the study was the occurrence of acute kidney injury (AKI). Additional endpoints were time to recovery for children with AKI, survival, and treatment-related mortality. RESULTS: Thirty-five patients were analyzed (CY: 22 vs. EP: 13). AKI occurred more frequently in the EP group than in the CY one (69% vs. 27%, adjusted odds ratio 6.0, 95% confidence interval [CI] [1.145; 31.445], P = 0.03). The median time to recovery was estimated at 3 days, 95% CI (2; 17), with CY and 11 days 95% CI (5; 18) with EP (adjusted hazard ratio of recovery for EP vs. CY 0.262, 95% CI [0.071; 0.969], P = 0.04). No significant difference was highlighted between the two treatments for survival or for treatment-related mortality. DISCUSSION: This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect. PMID- 29528180 TI - Randomized trial comparing caregiver-only family-focused treatment to standard health education on the 6-month outcome of bipolar disorder. AB - OBJECTIVES: Caregivers of people with bipolar disorder often have depression and health problems. This study aimed to evaluate the sustained effects of a 12-15 week psychoeducational intervention on the health and mental health of caregivers of persons with bipolar disorder. We also evaluated the effects of the intervention on patients' mood symptoms over 6 months post-treatment. METHODS: Caregivers of 46 persons with bipolar disorder were randomized to 12-15 weeks of a caregiver-only adaptation of family-focused treatment (FFT), in which caregivers were instructed on self-care strategies and ways to assist the patient in managing the illness, or to 8-12 sessions of standard health education. Independent evaluators assessed caregivers' depression and physical health and patients' mood symptoms before treatment, immediately after the treatment, and at 6 months post-treatment. RESULTS: Randomization to FFT was associated with greater decreases in depression for both caregivers and patients over a 6-month follow-up period post-treatment. Reductions in patients' depression scores over 6 months post-treatment were mediated by reductions in caregivers' depression scores (z = -2.74, P < .01). CONCLUSIONS: Interventions that are effective in reducing mood symptoms and improving health behavior in caregivers may have important health and mental health benefits for patients with bipolar disorder. Specifically, a treatment focused on caregiver education about bipolar disorder and the need for the caregiver to attend to his/her own health and mental health can benefit patients, even without their direct participation. PMID- 29528182 TI - Erratum. PMID- 29528183 TI - Positive emotion in distress as a potentially effective emotion regulation strategy for depression: A preliminary investigation. AB - OBJECTIVES: Emotion regulation utilizing positive emotion during negative emotional states might be one of the effective ways to alleviate depression and anxiety problems among people with emotional disorders. This study examined the psychometric properties and incremental validity of the Positive Emotion In Distress Scale (PEIDS), a newly developed self-report scale, in a sample of university students in Japan. DESIGN AND METHODS: To examine the psychometric properties of the PEIDS, the scale was completed by Japanese university students (396 men and 363 women; mean age of 19.92). Participants additionally answered the Emotion Regulation Questionnaire, Rumination and Reflection Questionnaire - Shorter Version, Affective Style Questionnaire, Positive and Negative Affective Schedule, and Hospital Anxiety and Depression Scale. The survey was conducted at two time points separated by 1 month to assess test-retest reliability and validity of the PEIDS. RESULTS: Exploratory and confirmatory factor analyses confirmed a one-factor structure. Reliability was confirmed by high internal consistency and test-retest stability; the convergent and discriminant validity was confirmed by correlations with related and unrelated variables. The results of hierarchical regression analyses demonstrated that positive emotion in distress might predict depression above and beyond the effect of baseline depression and other common emotion regulation strategies. CONCLUSIONS: The PEIDS showed acceptable reliability and validity within young adults and a non-clinical population in Japan. Further research will be needed to examine the effect of positive emotion among clinical populations. PRACTITIONER POINTS: Previous research suggests that positive emotions play a key role in recovery from depression and anxiety problems through some forms of psychotherapy. The Positive Emotion In Distress Scale (PEIDS) measures individual differences regarding the extent to which people can experience positive emotions in negative emotional states. Results suggested that the subjective rating of the ability to experience positive emotions in distress might alleviate depression prospectively but not anxiety problems. The effect of positive emotion in distress demonstrated to have beyond the effects of other emotion regulation strategies. PMID- 29528181 TI - Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. AB - BACKGROUND: Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. PROCEDURE: Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. RESULTS: Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27 97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. CONCLUSIONS: The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management. PMID- 29528184 TI - Obesity, sedentary lifestyle, and video games: The new thrombophilia cocktail in adolescents. AB - Rates of venous thromboembolism have increased in the adolescent population over the last two decades, likely due to advanced diagnostics, increased use of central venous catheters, chronic medical conditions, obesity, and oral contraceptive use. Of these factors, a modifiable risk factor for adolescents is obesity. Sedentary lifestyle and prolonged immobilization are additional prothrombotic risk factors that are often associated with obesity. With ever increasing screen time, sedentary behavior has risen accordingly, especially among gamers. We present four cases of adolescents who developed life-threatening venous thromboembolic events in the setting of obesity, sedentary lifestyle and/or immobilization, and prolonged video game use. PMID- 29528185 TI - Oxidative Coupling of Anionic Abnormal N-Heterocyclic Carbenes: Efficient Access to Janus-Type 4,4'-Bis(2H-imidazol-2-ylidene)s. AB - The oxidative coupling of anionic imidazol-4-ylidenes protected at the C2 position with [MnCp(CO)2 ] or BH3 led to the corresponding 4,4'-bis(2H-imidazol-2 ylidene) complexes or adducts, in which the two carbene moieties are connected through a single C-C bond. Subsequent acidic treatment of the later species led to the corresponding 4,4'-bis(imidazolium) salts in good yields. The overall procedure offers practical access to a novel class of Janus-type bis(NHC)s. Strikingly, the coplanarity of the two NHC rings within the mesityl derivative 4,4'-bis(IMes), favored by steric hindrance along with stabilizing intramolecular C-H???pi aryl interactions, allows the alignment of the pi-systems and, as a direct consequence, significant electron communication through the bis(carbene) scaffold. PMID- 29528186 TI - Should we replace etoposide phosphate by etoposide for allogeneic hematopoetic stem-cell transplantation in children? PMID- 29528187 TI - Down-regulation of dishevelled-2 inhibits cell proliferation and invasion in hepatoblastoma. AB - BACKGROUND: Hepatoblastoma (HB) is the most common liver cancer found in early childhood. These patients suffer poor outcomes and need novel therapies. An abnormal activation of Wnt signaling is the hallmark of HB tumorigenesis, and its pathway is a potential candidate for a pharmacological intervention. PROCEDURE: Tissue samples of patients with HB were collected for RNA-seq, quantitative real time PCR, and immunohistochemistry to identify if disheveled-2 (Dvl-2) was a target gene. The correlation between Dvl-2 expression and different clinicopathological features was analyzed using statistical methods. Proliferation and invasion assays were applied after knocking down Dvl-2 by shRNA in HepG2 and Huh6 HB cell lines. The antitumor effect of niclosamide on HB was ascertained in vitro and in vivo. RESULTS: Dvl-2 was overexpressed in 90% of patients with HB, and Dvl-2 expression was positively correlated with the age of patients with HB. Knockdown of Dvl-2 could inhibit proliferation and invasion of HB cell lines. Also, niclosamide, a Food and Drug Administration approved antihelminth compound, could effectively inhibit HB cell growth in vitro and in vivo via downregulation of Dvl-2 and beta-catenin expression. CONCLUSIONS: Our results implicate that Dvl-2 is a potential therapeutic target in HB, and niclosamide could have clinical potential to treat patients with HB. PMID- 29528188 TI - Challenges in fertility preservation among male adolescent and young adult cancer survivors. PMID- 29528189 TI - Petting away pre-exam stress: The effect of therapy dog sessions on student well being. AB - Recently, many universities have implemented programmes in which therapy dogs and their handlers visit college campuses. Despite the immense popularity of therapy dog sessions, few randomized studies have empirically tested the efficacy of such programmes. The present study evaluates the efficacy of such a therapy dog programme in improving the well-being of university students. This research incorporates two components: (a) a pre/post within-subjects design, in which 246 participants completed a brief questionnaire immediately before and after a therapy dog session and (b) an experimental design with a delayed-treatment control group, in which all participants completed baseline measures and follow up measures approximately 10 hr later. Only participants in the experimental condition experienced the therapy dog session in between the baseline and follow up measures. Analyses of pre/post data revealed that the therapy dog sessions had strong immediate benefits, significantly reducing stress and increasing happiness and energy levels. In addition, participants in the experimental group reported a greater improvement in negative affect, perceived social support, and perceived stress compared with those in the delayed-treatment control group. Our results suggest that single, drop-in, therapy dog sessions have large and immediate effects on students' well-being, but also that the effects after several hours are small. PMID- 29528190 TI - Low Protease Content in Medicago truncatula Cell Cultures Facilitates Recombinant Protein Production. AB - Medicago truncatula is an established model for studying legume biology. More recently, it has also been exploited as a Molecular Farming platform for the production of recombinant proteins, with the successful expression of fungal and human proteins in plants and cell suspension cultures of this species. One of the challenges that now must be overcome is the degradation of final products during production and downstream processing stages. In the M. truncatula genome, there are more than 400 putative protease-encoding genes, but to date, the proteolytic content of Medicago cell cultures has not been studied. In this report, the proteolytic activities that can potentially hamper the successful production of recombinant proteins in this system are evaluated. The potential proteases responsible for the degradation of target proteins are identified. Interestingly, the number of proteases found in Medicago spent medium is considerably lower than that of the well-established tobacco bright yellow 2 (BY-2) system. Papain-like cysteine proteases are found to be the major contributors to recombinant protein degradation in Medicago. This knowledge is used to engineer a cell line with reduced endogenous protease activity by expressing a selective protease inhibitor, further improving this expression platform. PMID- 29528191 TI - Thyroid cancer in adolescents and young adults. AB - In adolescents and young adults, thyroid cancer accounts for 13% of all invasive neoplasms, being three times more frequent in females, but overdiagnosis and overtreatment are common. There are two therapeutic approaches, one radical and no longer preferred in all instances, and the other conservative. Permanent complications of surgery and metabolic irradiation can affect quality of life and carry an economic burden. The overall survival rate approaches 100% for patients with differentiated thyroid cancer regardless of the extent of treatment. Medullary thyroid carcinoma is a very different entity, occurring most frequently in the context of hereditary tumor susceptibility syndromes. PMID- 29528192 TI - Deriving a water quality guideline for protection of aquatic communities exposed to triclosan in the Canadian environment. AB - Triclosan is an antibacterial and antifungal chemical used in a variety of consumer products, including soaps, detergents, moisturizers, and cosmetics. Aquatic ecosystems may be exposed to triclosan following the release of remaining residues in wastewater effluents and biosolids. In December 2017, Environment and Climate Change Canada (ECCC) released a federal environmental quality guideline (FEQG) report that contained a federal water quality guideline (FWQG) for triclosan. This guideline will be used as an adjunct to the risk assessment and risk management of priority chemicals identified under the Government of Canada's Chemicals Management Plan (CMP). The FWQG value for triclosan (0.47 MUg/L) was derived by ECCC using a hazardous concentration for 5% of species (HC5) from a species sensitivity distribution (SSD). We recalculated the FWQG after performing an independent analysis and evaluation of the available aquatic toxicity data for triclosan and compared our results with the ECCC FWQG value. Our independent analysis of the available aquatic toxicity data entailed conducting a literature search of all available and relevant studies, evaluating the quality and reliability of all studies considered using thorough and consistent study evaluation criteria, and thereby generating a data set of high-quality toxicity values. The selected data set includes 22 species spanning 5 taxonomic groups. An SSD was developed using this data set following the ECCC approaches. The HC5 from the SSD derived based on our validated data set is 0.76 MUg/L. This HC5 value is slightly greater (i.e., less sensitive) than the value presented in ECCC's final FWQG. Integr Environ Assess Manag 2018;14:437-441. (c) 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). PMID- 29528193 TI - Dimerization of the Benzyl Radical in a High-Temperature Pyrolysis Reactor Investigated by IR/UV Ion Dip Spectroscopy. AB - We investigate the self-reaction of benzyl, C7 H7 , in a high-temperature pyrolysis reactor. The work is motivated by the observation that resonance stabilized benzyl radicals can accumulate in reactive environments and contribute to the formation of polycyclic aromatic hydrocarbons (PAHs) and soot. Reaction products are detected by IR/UV ion dip spectroscopy, using infrared radiation from the free electron laser FELIX, and are identified by comparison with computed spectra. Among the reaction products identified by their IR absorption are several PAHs linked to toluene combustion such as bibenzyl, phenanthrene, diphenylmethane, and fluorene. The identification of 9,10-dihydrophenanthrene provides evidence for a mechanism of phenanthrene formation from bibenzyl that proceeds by initial cyclization rather than an initial hydrogen loss to stilbene. PMID- 29528194 TI - Multisite Studies Demonstrate Positive Relationship Between Practice Environments and Smoking Cessation Counseling Evidence-Based Practices. AB - PROBLEM: High-quality smoking cessation counseling guidelines for people who use tobacco are not fully integrated in acute-care services presenting missed opportunities to improve health outcomes. The role of the practice environment on enhancing or inhibiting guideline use is unknown. OBJECTIVE: To examine the relationship between the nurse practice environment and nurses' use of smoking cessation counseling practices, and to evaluate the effect of the individual nurse and organization characteristics on nurse smoking cessation counseling practices. DESIGN: Cross-sectional secondary analysis of survey data from two multisite studies. SAMPLE: The sample included responses from registered nurses (N = 844) in 45 hospitals (22 rural hospitals from the Eastern United States and 23 Magnet hospitals across the United States). METHODS: Linear mixed model was used to adjust intradependency among the responses of individual nurses nested within hospitals. Data were abstracted from survey responses including nurse characteristics, the Smoking Cessation Counseling Scale (SCCS), and the Practice Environment Scale-Nursing Work Index (PES). RESULTS: Increasing positive relationships exist between PES and SCCS total and subscales scores. Also, SCCS total scores were significantly related with favorable PES total scores (SCCS score difference of 0.26 between favorable and unfavorable PES scores, SE = .08, p = .002) controlling for other covariates. Non-White respondents (vs. White) demonstrated a positive association with SCCS total scores (difference of .18, SE = .07, p = .010), but not in advanced counseling. LINKING EVIDENCE TO ACTION: Nurse practice environments are positively associated with the use of evidence based smoking cessation practices by nurses. As practice environments become more favorable, higher level counseling practices occur more often. Healthcare leaders should focus on enhancing the practice environment using a quality improvement approach and framework for evidence translation. Quality improvement initiatives should be prioritized in which high-quality evidence is available to support nursing processes. PMID- 29528195 TI - Langerhans cell histiocytosis mimicking molluscum contagiosum: A case series. AB - Langerhans cell histiocytosis (LCH) is a disorder characterized by accumulation of Langerhans-like cells in one or various organs. A correct staging work-up is essential since there are multiorgan presentations with a poor prognosis. We report three patients with LCH skin lesions mimicking molluscum contagiosum in association with both high and low risk organ involvement. This peculiar cutaneous presentation can be a clue for the diagnosis of LCH, a disease with potentially severe systemic involvement. PMID- 29528196 TI - Pediatric choroid plexus carcinoma: Biologically and clinically in need of new perspectives. AB - Choroid plexus (CP) carcinoma is a rare pediatric brain neoplasm. Recent studies have highlighted the potential of genome-wide methylation and gene expression profiling to provide additional layers of information to improve tumor risk stratification. There is a lack of data regarding the best therapy, and approaches have been heterogeneous. Despite multidisciplinary treatment approaches, the outcome remains guarded and treatments have been based on case series and expert opinions. In this study, we discuss the recent wealth of data regarding CP carcinoma molecular biology and current management. We also briefly highlight the remaining barriers to formulate the best treatment strategies, and future therapeutic potentials. PMID- 29528198 TI - Application of nanotechnology in biosensors for enhancing pathogen detection. AB - Rapid detection and identification of pathogenic microorganisms is fundamental to minimizing the spread of infectious disease, and informing clinicians on patient treatment strategies. This need has led to the development of enhanced biosensors that utilize state of the art nanomaterials and nanotechnology, and represent the next generation of diagnostics. A primer on nanoscale biorecognition elements such as, nucleic acids, antibodies, and their synthetic analogs (molecular imprinted polymers), will be presented first. Next the application of various nanotechnologies for biosensor transduction will be discussed, along with the inherent nanoscale phenomenon that leads to their improved performance and capabilities in biosensor systems. A future outlook on characterization and quality assurance, nanotoxicity, and nanomaterial integration into lab-on-a-chip systems will provide the closing thoughts. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > Biosensing. PMID- 29528197 TI - Divergent transcriptional profiles in pediatric asthma patients of low and high socioeconomic status. AB - AIM: There are marked socioeconomic disparities in pediatric asthma control, but the molecular origins of these disparities are not well understood. To fill this gap, we performed genome-wide expression profiling of monocytes and T-helper cells from pediatric asthma patients of lower and higher socioeconomic status (SES). METHOD: Ninety-nine children with asthma participated in a cross-sectional assessment. Out of which 87% were atopic, and most had disease of mild (54%) or moderate (29%) severity. Children were from lower-SES (n = 49; household income <$50 000) or higher-SES (n = 50; household income >$140 000) families. Peripheral blood monocytes and T-helper cells were isolated for genome-wide expression profiling of mRNA. RESULTS: Lower-SES children had worse asthma quality of life relative to higher-SES children, by both their own and their parents' reports. Although the groups had similar disease severity and potential confounds were controlled, their transcriptional profiles differed notably. The monocytes of lower-SES children showed transcriptional indications of up-regulated anti microbial and pro-inflammatory activity. The T-helper cells of lower-SES children also had comparatively reduced expression of genes encoding gamma-interferon and tumor necrosis factor-alpha, cytokines that orchestrate Type 1 responses. They also showed up-regulated activity of transcription factors that polarize cells towards Type 2 responses and promote Th17 cell maturation. CONCLUSION: Collectively, these patterns implicate pro-inflammatory monocytes and Type 2 cytokine activity as mechanisms contributing to worse asthma control among lower SES children. PMID- 29528199 TI - An assessment of set up position for MRI scanning for the purposes of rectal cancer radiotherapy treatment planning. AB - INTRODUCTION: A magnetic resonance (MR) scanner for radiotherapy treatment simulation was commissioned in our department in June 2013. Practical set up and MR image quality trade-offs using a variety of patient positions and immobilisation devices routinely used in the treatment planning of rectal cancer patients were considered. The study also aimed to investigate the MR compatibility of the device materials with a focus on temperature changes during routine clinical examinations. METHODS: Ten volunteers were scanned: (1) Prone on a Civco Contoura Bellyboard (BBB), (2) Prone on a Civco MR Series Bellyboard (WBB), (3) Prone with no bellyboard and (4) Supine. All scans were performed with a T2 weighted (T2 -w) turbo spin echo (TSE) sequence. Images were scored by five assessors for: (1) ease of identifying specific organs, (2) overall image quality and (3) signal to noise ratio (SNR). Temperature changes were measured for each volunteer in each position. RESULTS: Both expert scores and SNR analysis demonstrated that images obtained in the supine position allowed for easier and clearer delineation of the organs. Image factors such as artefacts and noise, along with the overall image quality, also performed better in the supine position. The carbon fibre bellyboard did not demonstrate significant heating during scanning with the T2 -w TSE transverse sequence. CONCLUSIONS: A supine position was determined to be superior to the other positions in a majority of comparisons. The volunteers did not experience any increased temperature changes during scanning on the bellyboard in comparison to the other positions. PMID- 29528200 TI - Improving the delivery of health care to patients: radiographers and frontline image interpretation. AB - Australia led the world in raising the level of entry-level education to practice as a radiographer. It now lags behind in formalising radiographer input into the process of image interpretation. The time has come to rectify this situation. PMID- 29528201 TI - Clavibacter michiganensis ssp. michiganensis: bacterial canker of tomato, molecular interactions and disease management. AB - Bacterial canker disease is considered to be one of the most destructive diseases of tomato (Solanum lycopersicum), and is caused by the seed-borne Gram-positive bacterium Clavibacter michiganensis ssp. michiganensis (Cmm). This vascular pathogen generally invades and proliferates in the xylem through natural openings or wounds, causing wilt and canker symptoms. The incidence of symptomless latent infections and the invasion of tomato seeds by Cmm are widespread. Pathogenicity is mediated by virulence factors and transcriptional regulators encoded by the chromosome and two natural plasmids. The virulence factors include serine proteases, cell wall-degrading enzymes (cellulases, xylanases, pectinases) and others. Mutational analyses of these genes and gene expression profiling (via quantitative reverse transcription-polymerase chain reaction, transcriptomics and proteomics) have begun to shed light on their roles in colonization and virulence, whereas the expression of tomato genes in response to Cmm infection suggests plant factors involved in the defence response. These findings may aid in the generation of target-specific bactericides or new resistant varieties of tomato. Meanwhile, various chemical and biological controls have been researched to control Cmm. This review presents a detailed investigation regarding the pathogen Cmm, bacterial canker infection, molecular interactions between Cmm and tomato, and current perspectives on improved disease management. PMID- 29528202 TI - Early predictors of unresponsiveness to high-flow nasal cannula therapy in a pediatric emergency department. AB - AIM: High-flow nasal cannula (HFNC) is a new treatment option for pediatric respiratory distress and we aimed to assess early predictive factors of unresponsiveness to HFNC therapy in a pediatric emergency department (ED). METHOD: Patients who presented with respiratory distress and were treated by HFNC, were included. The age, gender, weight, medical history, diagnosis, vital signs, oxygen saturation/fraction of inspired oxygen (SpO2 /FiO2 ) ratio, modified Respiratory Distress Assessment Instrument (mRDAI) scores, medical interventions, duration of HFNC therapy, time to escalation, adverse effects, and laboratory test results were obtained from medical and nursing records. The requirement of a higher level of respiratory support due to unchanged or increased RR compared to initial RR, incipient, or progressive respiratory acidosis, incipient hemodynamic instability was defined as unresponsiveness to HFNC. RESULTS: The study enrolled 154 children with a median age of 10 months (interquartile range [IQR], 5.7-22.5 months). The diagnosis was acute bronchiolitis in 59 patients (38.3%), bacterial pneumonia in 64 patients (41.6%), and atypical or viral pneumonia in 31 patients (20.1%). Twenty-five patients (16.2%) were in the unresponsive group, and the median time for escalating respiratory support was 7 h (IQR: 4-20 h). The unresponsive group had lower SpO2 and SpO2 /FiO2 (SF) ratio on admission, lower venous pH, and higher partial pressure of carbon dioxide (pCO2 ) (P = 0.002, P = 0.012, and P = 0.001, respectively). Also the alteration of RR, mRDAI score, and SF ratio at the first hour was greater in the responsive group. The cut-off value of SF ratio at the first hour of HFNC was 195 for unresponsiveness. CONCLUSION: The low initial SpO2 and SF ratio, respiratory acidosis, and SF ratio less than 195 at the first hours of treatment were related to unresponsiveness to HFNC therapy in our pediatric emergency department. PMID- 29528203 TI - Functional Gastrointestinal Disorders: Foreword. PMID- 29528204 TI - Functional Gastrointestinal Disorders: Approach to Patients With Functional Gastrointestinal Disorders. AB - Functional gastrointestinal disorders (FGIDs) are among the most challenging conditions to diagnose and manage. FGIDs are a heterogeneous group of conditions with varying and sometimes vague symptomatology. The Rome IV classification is the most comprehensive resource on FGIDs. FGIDs are common and are associated with significant social and economic burdens. The patient perspective includes anxiety, emotional distress, and mistrust of health care. Psychological stressors and concomitant psychiatric illness are common but not always present. Clinician understanding of these disorders is limited, and there are many barriers to adequate care. A strong clinician-patient relationship is essential. Management includes education, reassurance, dietary modification, pharmacotherapy, and psychological interventions. PMID- 29528205 TI - Functional Gastrointestinal Disorders: Functional Upper Gastrointestinal Disorders in Adults. AB - Functional upper gastrointestinal disorders are common and cause significant patient distress and health care cost. These disorders typically are classified as either esophageal or gastroduodenal. Functional esophageal disorders include functional heartburn, reflux hypersensitivity, and functional dysphagia. Functional gastroduodenal disorders include functional dyspepsia and cyclic vomiting syndrome. Cyclic vomiting syndrome should be suspected in any patient with multiple episodes of vomiting with no apparent cause that completely resolve between episodes. Evaluation often is dependent on clinical findings. Therefore, a thorough history and physical examination are required to rule out any structural organic etiologies of red flag signs and symptoms. Diagnosis is ultimately based on Rome IV criteria. Education about the condition and lifestyle modifications is an ideal initial management for all functional upper gastrointestinal disorders. When this strategy alone is ineffective, behavioral therapy and pharmacotherapy can be useful. For patients with functional dyspepsia, acid suppression therapy and Helicobacter pylori eradication may be effective for improving long-term symptomatology. For patients who do not benefit from initial medical treatment, antidepressants and bismuth may be useful. PMID- 29528206 TI - Functional Gastrointestinal Disorders: Functional Lower Gastrointestinal Disorders in Adults. AB - Functional lower gastrointestinal disorders include irritable bowel syndrome (IBS), functional constipation, functional fecal incontinence, and functional anorectal pain. These disorders are common and have significant medical and social effects. They also can be challenging to manage. Patients with mild symptoms may benefit from lifestyle modification. IBS is classified into two subtypes: diarrhea-predominant and constipation-predominant. Depending on the IBS subtype and its likely etiology, patients may benefit from treatment with antispasmodics, antidepressants, guanylate cyclase-C agonists, chloride channel activators, antidiarrheal agents, probiotics, and/or antibiotics. Functional constipation responds to many of the same treatments as constipation-predominant IBS, which include guanylate cyclase-C agonists and chloride channel activators. The management of functional fecal incontinence includes behavioral therapy, relief of constipation (disimpaction, bulking agents), and antidiarrheal drugs. Functional anorectal pain management has not been well studied, but patient symptoms may improve with physical therapy, antispasmodics, nerve block, or onabotulinumtoxinA injection. PMID- 29528207 TI - Functional Gastrointestinal Disorders: Functional Gastrointestinal Disorders in Children. AB - Functional gastrointestinal disorders (FGIDs) are common among children and cause tremendous distress for patients and families. Family physicians should know how to diagnose and manage some of the more common childhood FGIDs. These include infant regurgitation, infant colic, infant dyschezia, cyclic vomiting syndrome, functional nausea and vomiting, functional diarrhea and constipation, abdominal migraine, and nonspecific functional abdominal pain. Diagnosis requires a thorough history and physical examination to rule out red flag signs and symptoms for structural or organic etiologies. Rome IV criteria can help establish a specific diagnosis so that clinicians can select a therapeutic approach and share prognosis with the patient and family. In general, FGID management requires a biopsychosocial approach. This includes symptom management with drugs, where applicable, and establishing a therapeutic relationship with the child and family to relieve distress and dysfunction that may be caused by or cause the FGID. Behavioral therapies such as direct behavioral therapy for younger children and cognitive behavioral therapy for older children are helpful for most FGIDs. More recent approaches include use of probiotics and drugs. Probiotics, for example, can help alleviate symptoms of infant colic in exclusively breastfed infants. PMID- 29528208 TI - Polymorphous Supercapacitors Constructed from Flexible Three-Dimensional Carbon Network/Polyaniline/MnO2 Composite Textiles. AB - Polymorphous supercapacitors were constructed from flexible three-dimensional carbon network/polyaniline (PANI)/MnO2 composite textile electrodes. The flexible textile electrodes were fabricated through a layer-by-layer construction strategy: PANI, carbon nanotubes (CNTs), and MnO2 were deposited on activated carbon fiber cloth (ACFC) in turn through an electropolymerization process, "dipping and drying" method, and in situ chemical reaction, respectively. In the fabricated ACFC/PANI/CNTs/MnO2 textile electrodes, the ACFC/CNT hybrid framework serves as a porous and electrically conductive 3D network for the rapid transmission of electrons and electrolyte ions, where ACFC, PANI, and MnO2 are high-performance supercapacitor electrode materials. In the electrolyte of H2SO4 solution, the textile electrode-based symmetric supercapacitor delivers superior areal capacitance, energy density, and power density of 4615 mF cm-2 (for single electrode), 157 MUW h cm-2, and 10372 MUW cm-2, respectively, whereas asymmetric supercapacitor assembled with the prepared composite textile as the positive electrode and ACFC as the negative electrode exhibits an improved energy density of 413 MUW h cm-2 and a power density of 16120 MUW cm-2. On the basis of the ACFC/PANI/CNTs/MnO2 textile electrodes, symmetric and asymmetric solid-state textile supercapacitors with a PVA/H2SO4 gel electrolyte were also produced. These solid-state textile supercapacitors exhibit good electrochemical performance and high flexibility. Furthermore, flexible solid-state fiber-like supercapacitors were prepared with fiber bundle electrodes dismantled from the above composite textiles. Overall, this work makes a meaningful exploration of the versatile applications of textile electrodes to produce polymorphous supercapacitors. PMID- 29528209 TI - Three-Dimensional Honeycomb-Structural LiAlO2-Modified LiMnPO4 Composite with Superior High Rate Capability as Li-Ion Battery Cathodes. AB - In the efforts toward the rapidly increasing demands for high-power application, cathode materials with three-dimensional (3D) architectures have been proposed. Here, we report the construction of the 3D LiAlO2-LiMnPO4/C cathode materials for lithium-ion batteries in an innovation way. The as-prepared 3D active materials LiMnPO4/C and the honeycomb-like Li-ion conductor LiAlO2 framework are used as working electrode directly without additional usage of polymeric binder. The electrochemical performance has been improved significantly due to the special designed core-shell architectures of LiMnPO4/C@LiAlO2. The 3D binder-free electrode exhibits high rate capability as well as superior cycling stability with a capability of ~105 mAh g-1 and 98.4% capacity retention after 100 cycles at a high discharge rate of 10 C. Such synthesis method adopted in our work can be further extended to other promising candidates and would also inspire new avenues of development of 3D materials for lithium-ion batteries. PMID- 29528210 TI - Inorganic Self-Assembled Bioactive Artificial Proto-Osteocells Inducing Bone Regeneration. AB - Since the discovery of osteoinduction in the early 20th century, innovative biomaterials with osteoinductive potential have emerged as candidates for bone repair. Recently, artificial protocell models have demonstrated great potential for tissue regeneration. Herein, we developed artificial bioactive proto osteocells by self-assembly of biodegradable biphasic-phosphate particles in the form of aqueous bone morphogenetic protein 2 (BMP2)-containing Pickering emulsions in corn oil to fulfill the release of BMP2 with controlled and local efficacy. These artificial proto-osteocells have the advantage of (1) being directly injected into the target location to avert reported side effects of BMP2, minimizing surgical complications, (2) exhibiting the capability of osteoinduction as shown in both in vitro and in vivo models, and (3) demonstrating calcific deposition locally by utilizing the biodegradable calcium phosphate shell. The efficiency of BMP2 within the artificial proto-osteocells showed 25 times greater bone-inducing potential when compared to the control. This study demonstrates for the first time a new strategy toward utilizing material-based artificial proto-osteocells to tackle medical issues in bone tissue repair and regeneration. PMID- 29528211 TI - Large Reduction of Hot Spot Temperature in Graphene Electronic Devices with Heat Spreading Hexagonal Boron Nitride. AB - Scanning thermal microscopy measurements reveal a significant thermal benefit of including a high thermal conductivity hexagonal boron nitride (h-BN) heat spreading layer between graphene and either a SiO2/Si substrate or a 100 MUm thick Corning flexible Willow glass (WG) substrate. At the same power density, an 80 nm thick h-BN layer on the silicon substrate can yield a factor of 2.2 reduction of the hot spot temperature, whereas a 35 nm thick h-BN layer on the WG substrate is sufficient to obtain a factor of 4.1 reduction. The larger effect of the h-BN heat spreader on WG than on SiO2/Si is attributed to a smaller effective heat transfer coefficient per unit area for three-dimensional heat conduction into the thick, low-thermal conductivity WG substrate than for one-dimensional heat conduction through the thin oxide layer on silicon. Consequently, the h-BN lateral heat-spreading length is much larger on WG than on SiO2/Si, resulting in a larger degree of temperature reduction. PMID- 29528212 TI - Local Electronic Structure Changes in Polycrystalline CdTe with CdCl2 Treatment and Air Exposure. AB - Postdeposition CdCl2 treatment of polycrystalline CdTe is known to increase the photovoltaic device efficiency. However, the precise chemical, structural, and electronic changes that underpin this improvement are still debated. In this study, spectroscopic photoemission electron microscopy was used to spatially map the vacuum level and ionization energy of CdTe films, enabling the identification of electronic structure variations between grains and grain boundaries (GBs). In vacuo preparation and inert transfer of oxide-free CdTe surfaces isolated the separate effects of CdCl2 treatment and ambient oxygen exposure. Qualitatively, grain boundaries displayed lower work function and downward band bending relative to grain interiors, but only after air exposure of CdCl2-treated CdTe. Analysis of numerous space charge regions at grain boundaries showed an average depletion width of 290 nm and an average band bending magnitude of 70 meV, corresponding to a GB trap density of 1011 cm-2 and a net carrier density of 1015 cm-3. These results suggest that both CdCl2 treatment and oxygen exposure may be independently tuned to enhance the CdTe photovoltaic performance by engineering the interface and bulk electronic structure. PMID- 29528213 TI - Uncovering the Cellular and Molecular Mechanisms of Synapse Formation and Functional Specificity Using Central Neurons of Lymnaea stagnalis. AB - All functions of the nervous system are contingent upon the precise organization of neuronal connections that are initially patterned during development, and then continually modified throughout life. Determining the mechanisms that specify the formation and functional modulation of synaptic circuitry are critical to advancing both our fundamental understanding of the nervous system as well as the various neurodevelopmental, neurological, neuropsychiatric, and neurodegenerative disorders that are met in clinical practice when these processes go awry. Defining the cellular and molecular mechanisms underlying nervous system development, function, and pathology has proven challenging, due mainly to the complexity of the vertebrate brain. Simple model system approaches with invertebrate preparations, on the other hand, have played pivotal roles in elucidating the fundamental mechanisms underlying the formation and plasticity of individual synapses, and the contributions of individual neurons and their synaptic connections that underlie a variety of behaviors, and learning and memory. In this Review, we discuss the experimental utility of the invertebrate mollusc Lymnaea stagnalis, with a particular emphasis on in vitro cell culture, semi-intact and in vivo preparations, which enable molecular and electrophysiological identification of the cellular and molecular mechanisms governing the formation, plasticity, and specificity of individual synapses at a single-neuron or single-synapse resolution. PMID- 29528214 TI - Achieving 14.4% Alcohol-Based Solution-Processed Cu(In,Ga)(S,Se)2 Thin Film Solar Cell through Interface Engineering. AB - An optimization of band alignment at the p-n junction interface is realized on alcohol-based solution-processed Cu(In,Ga)(S,Se)2 (CIGS) thin film solar cells, achieving a power-conversion-efficiency (PCE) of 14.4%. To obtain a CIGS thin film suitable for interface engineering, we designed a novel "3-step chalcogenization process" for Cu2- xSe-derived grain growth and a double band gap grading structure. Considering S-rich surface of the CIGS thin film, an alternative ternary (Cd,Zn)S buffer layer is adopted to build favorable "spike" type conduction band alignment instead of "cliff" type. Suppression of interface recombination is elucidated by comparing recombination activation energies using a dark J- V- T analysis. PMID- 29528215 TI - Vacuum-Assisted Low-Temperature Synthesis of Reduced Graphene Oxide Thin-Film Electrodes for High-Performance Transparent and Flexible All-Solid-State Supercapacitors. AB - Simple and easily integrated design of flexible and transparent electrode materials affixed to polymer-based substrates hold great promise to have a revolutionary impact on the functionality and performance of energy storage devices for many future consumer electronics. Among these applications are touch sensors, roll-up displays, photovoltaic cells, health monitors, wireless sensors, and wearable communication devices. Here, we report an environmentally friendly, simple, and versatile approach to produce optically transparent and mechanically flexible all-solid-state supercapacitor devices. These supercapacitors were constructed on tin-doped indium oxide coated polyethylene terephthalate substrates by intercalation of a polymer-based gel electrolyte between two reduced graphene oxide (rGO) thin-film electrodes. The rGO electrodes were fabricated simply by drop-casting of graphene oxide (GO) films, followed by a novel low-temperature (<=250 degrees C) vacuum-assisted annealing approach for the in situ reduction of GO to rGO. A trade-off between the optical transparency and electrochemical performance is determined by the concentration of the GO in the initial dispersion, whereby the highest capacitance (~650 MUF cm-2) occurs at a relatively lower optical transmittance (24%). Notably, the all-solid-state supercapacitors demonstrated excellent mechanical flexibility with a capacity retention rate above 90% under various bending angles and cycles. These attributes underscore the potential of the present approach to provide a path toward the realization of thin-film-based supercapacitors as flexible and transparent energy storage devices for a variety of practical applications. PMID- 29528216 TI - Efficient Encapsulation of Small S2-4 Molecules in MOF-Derived Flowerlike Nitrogen-Doped Microporous Carbon Nanosheets for High-Performance Li-S Batteries. AB - Lithium-sulfur (Li-S) battery is regarded as one of the most promising next generation efficient energy storage systems because of its ultrahigh theoretical capacity of 1675 mAh/g and energy density of 2600 Wh/kg accompanied by the environmental benignity and abundance from natural sulfur. However, the insulating nature of sulfur and the dissolution of the polysulfides Li2S n (4 <= n <= 8) seriously restrict its practical application. The metastable small sulfur molecules (S2-4) stored in microporous carbon (pore size of <0.6 nm) as the active materials can avoid the production of the soluble polysulfide and solve the shuttle effect thoroughly. In addition, the conductivity of sulfur can be also improved. However, the preparation of microporous carbon materials with reasonable pore size and unique morphology for efficiently encapsulating S2-4 is still challenging. Herein, three flowerlike microporous nitrogen-doped carbon nanosheets with the pore size of <0.6 nm (namely, FMNCN-800, -900, and -1000) as the cathode materials in Li-S batteries were obtained from temperature-dependent carbonization of the metal-organic framework (MOF), Zn-TDPAT, which was from the simply reflux reaction of N-rich ligand H6TDPAT with Zn(II) salt. Our study showed that the FMNCN-900 from carbonization of Zn-TDPAT at 900 degrees C has suitable pore volume and nitrogen content, accommodating small S2-4 molecules in its micropores with the mass uptake of about 45%. Meanwhile, the appropriate amount of the nitrogen doping and the unique nanostructure of the flowerlike carbon nanosheet in the FMNCN-900 can effectively support its fast electronic transmission and lithium-ion conduction. The resulting S@FMNCN-900 composite cathode material presents the excellent electrochemical property in the Li-S battery (here the carbonate as electrolytes) with a reversible capacity of about 1220 mAh/g at 0.1C after 200 cycles and even 727 mAh/g at 2C after the long-term cycle of 1000 with only around 0.02% capacity loss per cycle. Obviously, the results indicate that the delicate construction of MOF-derived nitrogen-doped microporous carbon nanosheet is a promising strategy to develop novel electrode material for high-performing Li-S batteries. PMID- 29528217 TI - Oligothiophene-Indandione-Linked Narrow-Band Gap Molecules: Impact of pi Conjugated Chain Length on Photovoltaic Performance. AB - Solution-processed organic solar cells (OSCs) based on narrow-band gap small molecules hold great promise as next-generation energy-converting devices. In this paper, we focus on a family of A-pi-D-pi-A-type small molecules, namely, BDT nT-ID ( n = 1-4) oligomers, consisting of benzo[1,2- b:4,5- b']dithiophene (BDT) as the central electron-donating (D) core, 1,3-indandione (ID) as the terminal electron-accepting (A) units, and two regioregular oligo(3-hexylthiophene)s ( nT) with different numbers of thiophene rings as the pi-bridging units, and elucidate their structure-property-function relationships. The effects of the length of the pi-bridging nT units on the optical absorption, thermal behavior, morphology, hole mobility, and OSC performance were systematically investigated. All oligomers exhibited broad and intense visible photoabsorption in the 400-700 nm range. The photovoltaic performances of bulk heterojunction OSCs based on BDT- nT IDs as donors and a fullerene derivative as an acceptor were studied. Among these oligomers, BDT-2T-ID, incorporating bithiophene as the pi-bridging units, showed better photovoltaic performance with a maximum power conversion efficiency as high as 6.9% under AM 1.5G illumination without using solvent additives or postdeposition treatments. These favorable properties originated from the well developed interpenetrating network morphology of BDT-2T-ID, with larger domain sizes in the photoactive layer. Even though all oligomers have the same A-D-A main backbone, structural modulation of the pi-bridging nT length was found to impact their self-organization and nanostructure formation in the solid state, as well as the corresponding OSC device performance. PMID- 29528218 TI - Potential of Near-Infrared Chemical Imaging as Process Analytical Technology Tool for Continuous Freeze-Drying. AB - Near-infrared chemical imaging (NIR-CI) is an emerging tool for process monitoring because it combines the chemical selectivity of vibrational spectroscopy with spatial information. Whereas traditional near-infrared spectroscopy is an attractive technique for water content determination and solid state investigation of lyophilized products, chemical imaging opens up possibilities for assessing the homogeneity of these critical quality attributes (CQAs) throughout the entire product. In this contribution, we aim to evaluate NIR-CI as a process analytical technology (PAT) tool for at-line inspection of continuously freeze-dried pharmaceutical unit doses based on spin freezing. The chemical images of freeze-dried mannitol samples were resolved via multivariate curve resolution, allowing us to visualize the distribution of mannitol solid forms throughout the entire cake. Second, a mannitol-sucrose formulation was lyophilized with variable drying times for inducing changes in water content. Analyzing the corresponding chemical images via principal component analysis, vial-to-vial variations as well as within-vial inhomogeneity in water content could be detected. Furthermore, a partial least-squares regression model was constructed for quantifying the water content in each pixel of the chemical images. It was hence concluded that NIR-CI is inherently a most promising PAT tool for continuously monitoring freeze-dried samples. Although some practicalities are still to be solved, this analytical technique could be applied in-line for CQA evaluation and for detecting the drying end point. PMID- 29528219 TI - Peptide Retention in Hydrophilic Strong Anion Exchange Chromatography Is Driven by Charged and Aromatic Residues. AB - Hydrophilic strong anion exchange chromatography (hSAX) is becoming a popular method for the prefractionation of proteomic samples. However, the use and further development of this approach is affected by the limited understanding of its retention mechanism and the absence of elution time prediction. Using a set of 59 297 confidentially identified peptides, we performed an explorative analysis and built a predictive deep learning model. As expected, charged residues are the major contributors to the retention time through electrostatic interactions. Aspartic acid and glutamic acid have a strong retaining effect and lysine and arginine have a strong repulsion effect. In addition, we also find the involvement of aromatic amino acids. This suggests a substantial contribution of cation-pi interactions to the retention mechanism. The deep learning approach was validated using 5-fold cross-validation (CV) yielding a mean prediction accuracy of 70% during CV and 68% on a hold-out validation set. The results of this study emphasize that not only electrostatic interactions but rather diverse types of interactions must be integrated to build a reliable hSAX retention time predictor. PMID- 29528220 TI - Simple Approach to Reducing Particle Trapping Voltage in Insulator-Based Dielectrophoretic Systems. AB - Insulator-based dielectrophoresis (iDEP) is a microfluidic technique used for particle analysis in a wide array of applications. Significant efforts are dedicated to improve iDEP systems by reducing voltage requirements. This study assesses how the performance of an iDEP system, in terms of particle trapping, depends on the number of insulating obstacles longitudinally present in the microchannel. In analogy with Kirchhoff's loop rule, iDEP systems were analyzed as a series combination of electrical resistances, where the equivalent resistance of the post array is composed by a number of individual resistors (columns of insulating posts). It was predicted by the COMSOL model, and later confirmed by experimental results, that reducing the number of columns of insulating posts significantly affects the electric field distribution, decreasing the required voltage to dielectrophoretically trap particles within the post array. As an application, it was demonstrated that decreasing the number of columns in the post array allows for the dielectrophoretic trapping of nanometer-scale particles at voltages well below those reported in previous similar iDEP systems. These findings illustrate how the iDEP channel configuration can be customized for specific applications. PMID- 29528221 TI - Fabrication of a Co(OH)2/ZnCr LDH "p-n" Heterojunction Photocatalyst with Enhanced Separation of Charge Carriers for Efficient Visible-Light-Driven H2 and O2 Evolution. AB - Photocatalytic generation of H2 and O2 by water splitting remains a great challenge for clean and sustainable energy. Taking into the consideration promising heterojunction photocatalysts, analogous energy issues have been mitigated to a meaningful extent. Herein, we have architectured a highly efficient bifunctional heterojunction material, i.e., p-type Co(OH)2 platelets with an n-type ZnCr layered double hydroxide (LDH) by an ultrasonication method. Primarily, the Mott-Schottky measurements confirmed the n- and p-type semiconductive properties of LDH and CH material, respectively, with the construction of a p-n heterojunction. The high resolution transmission electron microscopy results suggest that surface modification of ZnCr LDH by Co(OH)2 hexagonal platelets could form a fabulous p-n interfacial region that significantly decreases the energy barrier for O2 and H2 production by effectively separating and transporting photoinduced charge carriers, leading to enhanced photoreactivity. A deep investigation into the mechanism shows that a 30 wt % Co(OH)2-modified ZnCr LDH sample liberates maximum H2 and O2 production in 2 h, i.e., 1115 and 560 MUmol, with apparent conversion efficiencies of H2 and O2 evolution of 13.12% and 6.25%, respectively. Remarkable photocatalytic activity with energetic charge pair transfer capability was illustrated by electrochemical impedance spectroscopy, linear sweep voltammetry, and photoluminescence spectra. The present study clearly suggests that low-cost Co(OH)2 platelets are the most crucial semiconductors to provide a new p-n heterojunction photocatalyst for photocatalytic H2 and O2 production on the platform of ZnCr LDH. PMID- 29528222 TI - Theoretical Studies on DNA-Cleavage Mechanism of Copper(II) Complexes: Probing Generation of Reactive Oxygen Species. AB - Theoretical studies on DNA-cleavage properties of [Cu(bba)(diimine)] 1-4 have been carried out using density functional theory (DFT) and docking methods. The optimized structures of Cu(II) complexes were docked into DNA, glutathiones (GSH), and ascorbic acids (VC) so that the corresponding docking models were obtained. To explore DNA-cleavage properties of Cu(II) complexes, the docking models of complexes with GSH and VC were further optimized using DFT method, while the docking models of complexes with DNA were optimized using QM/MM method because DNA is a supramolecular system. The rate constants ket between complexes and DNA, GSH, and VC, oxidation-reduction potentials of complexes, and binding energies of complexes with GSH and VC were computed. The DNA-cleavage abilities of Cu(II) complexes in the presence VC, GSH, and H2O2 were explored and the experimental results could be reasonably explained. Finally, the DNA-cleavage mechanism of Cu(II) complexes was described in detail, which would contribute to future design of novel anticancer Cu(II) complexes. PMID- 29528223 TI - Synthesis of Antimicrobial Poly(guanylurea)s. AB - Bacterial infections are serious health threats. Emerging drug resistance in bacteria further poses serious challenges to the treatment options involving traditional antibiotics. Antimicrobial polymers disrupt the physical cell membrane integrity of bacteria to address the drug resistance problems. Here, we introduce a conceptually new class of antimicrobial polymers containing positively charged guanylurea backbones for enhanced antimicrobial effects. The initial structure-activity relationship studies demonstrate that poly(guanylurea piperazine)s (PGU-Ps) exhibit excellent antimicrobial activity against different types of bacteria with high selectivity. The new design concept of using a positively charged guanylurea backbone will contribute to the development of future biocompatible, specific, and selective antimicrobial polymers. PMID- 29528224 TI - In Silico Design and in Vitro Characterization of Universal Tyrosine Kinase Peptide Substrates. AB - A majority of the 90 human protein tyrosine kinases (PTKs) are understudied "orphan" enzymes with few or no known substrates. Designing experiments aimed at assaying the catalytic activity of these PTKs has been a long-running problem. In the past, researchers have used polypeptides with a randomized 4:1 molar ratio of glutamic acid to tyrosine as general PTK substrates. However, these substrates are inefficient and perform poorly for many applications. In this work, we apply the KINATEST-ID pipeline for artificial kinase substrate discovery to design a set of candidate "universal" PTK peptide substrate sequences. We identified two unique peptide sequences from this set that had robust activity with a panel of 15 PTKs tested in an initial screen. Kinetic characterization with seven receptor and nonreceptor PTKs confirmed these peptides to be efficient and general PTK substrates. The broad scope of these artificial substrates demonstrates that they should be useful as tools for probing understudied PTK activity. PMID- 29528225 TI - Base-Free Iron Hydrosilylene Complexes via an alpha-Hydride Migration that Induces Spin Pairing. AB - Two new base-free hydrosilylene complexes of iron were synthesized using the novel starting material Cp*( iPr2MeP)FeMes. These Cp*( iPr2MeP)Fe(H)SiHR (R = DMP, Trip) complexes are in equilibrium with the corresponding iron silyl complexes, Cp*( iPr2MeP)FeSiH2R, which can be trapped and characterized for R = Trip. Unlike the Ru analogues, the Fe silylene complex with R = DMP is observed to undergo an intramolecular C-H activation involving formal addition of a benzylic C-H bond across the Fe-Si bond. This increased activity for bond activations is also observed for reactions with hydrogen, where Fe reacts faster than a Ru analog to form the hydrogenation product, Cp*( iPr2MeP)H2FeSiH2DMP. PMID- 29528226 TI - SlMYC2 Involved in Methyl Jasmonate-Induced Tomato Fruit Chilling Tolerance. AB - MYC2, a basic helix-loop-helix transcription factor, is a master regulator in Jasmonic acid (JA) signaling pathway. However, the functions of SlMYC2 in methyl jasmonate (MeJA)-mediated fruit chilling tolerance are far from being clearly understood. Thus, in the present work, we constructed SlMYC2-silenced tomato fruit by virus-induced gene silencing (VIGS) and investigated the function of SlMYC2 in MeJA-induced tomato fruit chilling tolerance. The results showed that MeJA treatment markedly induced the SlMYC2 expression; increased proline content, lycopene content, and antioxidant enzyme activities, including superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase; inhibited the increase of electrical conductivity and malondialdehyde content; and effectively reduced the chilling injury (CI) incidence and CI index. However, these effects of MeJA treatment were partially counteracted in SlMYC2-silenced tomato fruit, and the CI incidence and CI index in ( SlMYC2-silenced + MeJA)-treated fruit were higher than those in MeJA-treated fruit. Our results indicated that SlMYC2 might be involved in MeJA-induced chilling tolerance, possibly by ameliorating the antioxidant enzyme system of fruit and increasing proline and lycopene levels. PMID- 29528227 TI - Trichodermides A-E: New Peptaibols Isolated from the Australian Termite Nest Derived Fungus Trichoderma virens CMB-TN16. AB - Chemical analysis of a fermentation of the Australian termite nest-derived fungus Trichoderma virens CMB-TN16 yielded five new acyclic nonapeptides, trichodermides A-E (1-5). Amino acid residues, configurations, and sequences were determined by a combination of spectroscopic (NMR and MS-MS) and chemical (C3 Marfey's) methods. The trichodermides adhere to the sequence homology pattern common to Trichoderma 11 amino acid residue peptaibols; however, unlike other peptaibols the trichodermides do not exhibit antibacterial or antifungal activity and exhibit low to no cytotoxicity against mammalian cells. This variability in biological activity highlights the importance of knowing both planar structures and absolute configurations when interpreting structure-activity relationships. PMID- 29528228 TI - High-Resolution 2D NMR of Disordered Proteins Enhanced by Hyperpolarized Water. AB - This study demonstrates the usefulness derived from relying on hyperpolarized water obtained by dissolution DNP, for site-resolved biophysical NMR studies of intrinsically disordered proteins. Thanks to the facile amide-solvent exchange experienced by protons in these proteins, 2D NMR experiments that like HMQC rely on the polarization of the amide protons, can be enhanced using hyperpolarized water by several orders of magnitude over their conventional counterparts. Optimizations of the DNP procedure and of the subsequent injection into the protein sample are necessary to achieve these gains while preserving state-of-the art resolution; procedures enabling this transfer of the hyperpolarized water and the achievement of foamless hyperpolarized protein solutions are demonstrated. These protocols are employed to collect 2D 15N-1H HMQC NMR spectra of alpha synuclein, showing residue-specific enhancements >=100* over their thermal counterparts. These enhancements, however, vary considerably throughout the residues. The biophysics underlying this residue-specific behavior upon injection of hyperpolarized water is theoretically examined, the information that it carries is compared with results arising from alternative methods, and its overall potential is discussed. PMID- 29528229 TI - Mesoscopic Oxide Double Layer as Electron Specific Contact for Highly Efficient and UV Stable Perovskite Photovoltaics. AB - The solar to electric power conversion efficiency (PCE) of perovskite solar cells (PSCs) has recently reached 22.7%, exceeding that of competing thin film photovoltaics and the market leader polycrystalline silicon. Further augmentation of the PCE toward the Shockley-Queisser limit of 33.5% warrants suppression of radiationless carrier recombination by judicious engineering of the interface between the light harvesting perovskite and the charge carrier extraction layers. Here, we introduce a mesoscopic oxide double layer as electron selective contact consisting of a scaffold of TiO2 nanoparticles covered by a thin film of SnO2, either in amorphous (a-SnO2), crystalline (c-SnO2), or nanocrystalline (quantum dot) form (SnO2-NC). We find that the band gap of a-SnO2 is larger than that of the crystalline (tetragonal) polymorph leading to a corresponding lift in its conduction band edge energy which aligns it perfectly with the conduction band edge of both the triple cation perovskite and the TiO2 scaffold. This enables very fast electron extraction from the light perovskite, suppressing the notorious hysteresis in the current-voltage ( J-V) curves and retarding nonradiative charge carrier recombination. As a result, we gain a remarkable 170 mV in open circuit photovoltage ( V oc) by replacing the crystalline SnO2 by an amorphous phase. Because of the quantum size effect, the band gap of our SnO2-NC particles is larger than that of bulk SnO2 causing their conduction band edge to shift also to a higher energy thereby increasing the V oc. However, for SnO2-NC there remains a barrier for electron injection into the TiO2 scaffold decreasing the fill factor of the device and lowering the PCE. Introducing the a-SnO2 coated mp-TiO2 scaffold as electron extraction layer not only increases the V oc and PEC of the solar cells but also render them resistant to UV light which forebodes well for outdoor deployment of these new PSC architectures. PMID- 29528230 TI - Thermal Properties and Segmental Dynamics of Polymer Melt Chains Adsorbed on Solid Surfaces. AB - The glass transition of supported polystyrene (PS) and poly(2-vinylpyridine) (P2VP) thin films in the vicinity of the substrate interface was studied by using a nanoplasmonic sensing (NPS) method. This "nanocalorimetric" approach utilizes localized surface plasmon resonance from two-dimensional arrangements of sensor nanoparticles deposited on SiO2-coated glass substrates. The NPS results demonstrated the existence of a high glass transition temperature ( Tg,high) along with the bulk glass transition temperature ( Tg,bulk ~ 100 degrees C for PS and P2VP) within the thin films: Tg,high ~ 160 degrees C for PS and Tg,high ~ 200 degrees C for P2VP. To understand the origin of the Tg,high, we also studied the thermal transitions of lone polymer chains strongly adsorbed onto the substrate surface using solvent rinsing. Interestingly, the NPS data indicated that the Tg,high is attributed to the adsorbed polymer chains. To provide a better understanding of the mechanism of the Tg,high, molecular dynamics simulations were performed on a PS film adsorbed on hydrophobic and hydrophilic substrates. The simulation results illuminated the presence of a higher density region closest to the substrate surface regardless of the magnitude of the polymer-solid interactions. We postulate that the highly packed chain conformation reduces the free volume at the substrate interface, resulting in the Tg,high. Moreover, the simulation results revealed that the deviation of the Tg,high from the bulk Tg,bulk becomes larger as the polymer-substrate interaction increases, which is in line with the experimental findings. PMID- 29528231 TI - Dearomative Diallylation of N-Acylindoles Mediated by FeCl3. AB - Three-dimensional indolines possessing two contiguous-stereogenic centers were obtained stereoselectively via the FeCl3-mediated dearomative introduction of two allyl groups to N-acylindoles with allyltrimethylsilane. Synthetic transformations allowed obtention of trans-tetrahydrocarbazoles and an aza[4.4.3]propellane scaffold by RCM. Selective hydration of one of the allyl groups was also achieved. PMID- 29528232 TI - MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3. AB - Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. MicroRNAs have been increasingly implicated in NSCLC and may serve as novel therapeutic targets to combat cancer. Here we investigated the functional implication of miR-188 in NSCLC. We first analyzed miR-188 expression in both NSCLC clinical samples and cancer cell lines. Next we investigated its role in A549 and H2126 cells with cell proliferation, migration, and apoptosis assays. To extend the in vitro study, we employed both xenograft model and LSL- K-ras G12D lung cancer model to examine the role of miR-188 in tumorigenesis. Last we tested MAP3K3 as miR-188 target in NSCLC model. MiR-188 expression was significantly downregulated at the NSCLC tumor sites and lung cancer cells. In vitro transfection of miR-188 reduced cell proliferation and migration potential and promoted cell apoptosis. In xenograft model, miR-188 inhibited tumor growth derived from cancer cells. Intranasal miR-188 administration reduced tumor formation in NSCLC animal model. MAP3K3 was validated as direct target of miR 188. Knocking down MAP3K3 in mice also inhibited tumorigenesis in LSL- K-ras G12D model. Our results demonstrate that miR-188 and its downstream target MAP3K3 could be a potential therapeutic target for NSCLC. PMID- 29528233 TI - Multifunctional Surface Modification of Nanodiamonds Based on Dopamine Polymerization. AB - Surface functionalization of nanodiamonds (NDs), which is of great interest in advanced material and therapeutic applications, requires the immobilization of functional species, such as nucleic acids, bioprobes, drugs, and metal nanoparticles, onto NDs' surfaces to form stable nanoconjugates. However, it is still challenging to modify the surface of NDs due to the complexity of their surface chemistry and the low density of each functional group on the surfaces of NDs. In this work, we demonstrate a general applicable surface functionalization approach for the preparation of ND-based core-shell nanoconjugates using dopamine polymerization. By taking advantage of the universal adhesion and versatile reactivity of polydopamine, we have effectively conjugated DNA and silver nanoparticles onto NDs. Moreover, the catalytic activity of ND-supported silver nanoparticle was characterized by the reduction of 4-nitrophenol, and the addressability of NDs was tested through DNA hybridization that formed satellite ND-gold nanorod conjugation. This simple and robust method we have presented may significantly improve the capability for attaching various functionalities onto NDs and open up new platforms for applications of NDs. PMID- 29528234 TI - Parallel and Perpendicular Alignment of Anisotropic Particles in Free Liquid Microjets and Emerging Microdroplets. AB - Liquid microjets play a key role in fiber spinning, inkjet printing, and coating processes. In all of these applications, the liquid jets carry dispersed particles whose spatial and orientational distributions within the jet critically influence the properties of the fabricated structures. Despite its importance, there is currently no knowledge about the orientational distribution of particles within microjets and droplets. Here, we demonstrate a microfluidic device that allows to determine the local particle distribution and orientation by X-ray scattering. Using this methodology, we discovered unexpected changes in the particle orientation upon exiting the nozzle to form a free jet, and upon jet break-up into droplets, causing an unusual biaxial particle orientation. We show how flow and aspect ratio determine the flow orientation of anisotropic particles. Furthermore, we demonstrate that the observed phenomena are a general characteristic of anisotropic particles. Our findings greatly enhance our understanding of particle orientation in free jets and droplets and provide a rationale for controlling particle alignment in liquid jet-based fabrication methodologies. PMID- 29528235 TI - Copper-Catalyzed Diastereo- and Enantioselective Borylative Cyclization: Synthesis of Enantioenriched 2,3-Disubstituted Indolines. AB - The development of an efficient, straightforward approach for access to a wide range of enantioenriched boron-containing 2,3-disubstituted indolines via highly chemo-, diastereo-, and enantioselective copper-catalyzed intramolecular boraylative cyclization of readily available 2-styrylimines is reported. This reaction proceeds under very mild conditions and displays a high degree of functional group compatibility. The practicability of this approach is demonstrated by a gram-scale reaction and further transformations of the chiral borylated indolines. PMID- 29528236 TI - Glycosyl Cross-Coupling with Diaryliodonium Salts: Access to Aryl C-Glycosides of Biomedical Relevance. AB - A stereospecific cross-coupling reaction of anomeric nucleophiles with diaryliodonium triflates resulting in the synthesis of aryl C-glycosides is reported. This process capitalizes on a stereoretentive reaction of configurationally stable C1 stannanes and is promoted by a palladium catalyst in the presence of a bulky phosphine ligand that suppresses the undesired beta elimination. The utility of this reaction has been demonstrated in the preparation of a series of C-glycosides derived from common saccharides resulting in exclusive transfer of anomeric configuration from the anomeric nucleophile to the product, and in the synthesis of empagliflozin, a commercial antidiabetic drug. PMID- 29528237 TI - Catalytic Method for the Synthesis of C-N-Linked Bi(heteroaryl)s Using Heteroaryl Ethers and N-Benzoyl Heteroarenes. AB - C-N-linked bi(heteroaryl)s are synthesized by a rhodium-catalyzed N heteroarylation reaction of N-benzoyl heteroarenes including azoles/azolones, pyridones, cyclic ureas, and cyclic imides using heteroaryl aryl ethers. The reaction involves the covalent bond-exchange reaction of N-CO and HetAr-O bonds without using metal bases and exhibits a broad applicability, giving diverse C-N linked bi(heteroaryl)s containing five- and six-membered heteroarenes. The N heteroarylation of N-H azoles/azolones and pyridone proceeds at higher reaction temperatures. PMID- 29528238 TI - Polymerization of Isoprene Promoted by Aminophosphine(ory)-Fused Bipyridine Cobalt Complexes: Precise Control of Molecular Weight and cis-1,4- alt-3,4 Sequence. AB - Ligands N-(dialkyl or arylphosphino)-(2,2'-bipyridin)-6-amine (L1, aryl = Ph; L2, alkyl = tBu; L3, alkyl = adamantyl (Ad)) as well as the corresponding oxidized N (2,2'-bipyridin-6-yl)- P, P-dialkyl or aryl phosphinic amide (L4, aryl = Ph; L5, alkyl = tBu; L6, alkyl = Ad) congeners were designed and coordinated to cobalt dichloride. The structures of formed complexes were characterized by IR and elemental analyses, as well as characterizations of the X-ray diffractions for complexes Co4 and Co6, which revealed the cobalt center is expectedly pentacoordinated in a distorted trigonal bipyramidal configuration with a prolonged Co-O(?P) bond . In combination with MMAO, complex Co2 was highly active in cis-1,4- alt-3,4 enchained polymerization. The hemilabile nature of O?P is possible for the alternating eta4- cis-1,4 and eta2-3,4 coordination, and insertion at the metal-carbon bond ensued. In combination with AlEt2Cl, each of complexes Co4, Co5, and Co6 was capable of converting isoprene to polyisoprene in a control mode with observed polymerization rate constants ( kobs = 0.1531 L mol 1 min-1 (Co4), 0.1382 L mol-1 min-1 (Co5), and 0.0902 L mol-1 min-1 (Co6)). The activation energy of the polymerization by Co4 falls in the range of 27-31 kJ/mol by determining kobs values at 0, 30, and 50 degrees C. The 13C NMR analyses of the obtained polyisoprene revealed that complexes Co4, Co5, and Co6 have a cis 1,4 selectivity of 86.6-93.4% with a 3,4 selectivity of 6.6-13.4%. This catalyst system can also be applied to block copolymerization of isoprene and myrcene in a living cis-1,4 fashion; therefore, a new biosourced monomer-based elastomer has been achieved. PMID- 29528239 TI - Nanoscale Water Contact Angle on Polytetrafluoroethylene Surfaces Characterized by Molecular Dynamics-Atomic Force Microscopy Imaging. AB - The aim of this study is to link polytetrafluoroethylene (PTFE) surface characteristics with its wetting properties in the nanoscale. To do this using molecular dynamics (MD) simulation, three series of rough PTFE surfaces were generated by annealing and compressing and next characterized by the application of the MD version of the atomic force microscopy (AFM) method. The values of specific surface areas were additionally calculated. The TIP4P/2005 water model was used to study the wetting properties of obtained PTFE samples. The simulated water contact angle (WCA) value for the most flat (but slightly rough) sample having PTFE density is equal to 106.94 degrees , and it is close to the value suggested for a perfect PTFE surface on the basis of experimental results. Also, the changes in the WCA with PTFE compression are in the same range as experimentally reported. The obtained MD simulation results make it possible to link, for the first time, the WCA values with the surface MD-AFM root-mean-square roughness and with the PTFE density. Finally, we show that for PTFE wetting in the nanoscale, the line tension is negligible and the Bormashenko's equation reduces to the Cassie-Baxter (CB) model. In fact, our simulation results are close to the CB mechanism. PMID- 29528240 TI - Synthetic Method for 2'-Amino-LNA Bearing Any of the Four Nucleobases via a Transglycosylation Reaction. AB - A transglycosylation reaction of 2'-amino-locked nucleic acid (LNA) from thymine (T) to other nucleobases adenine (A), guanine (G), and 5-methylcytosine (mC) has been developed. This reaction proceeds in high yield and with high beta selectivity. The mild reaction conditions enable the coexistence of acid-labile protecting groups, including a 4,4'-dimethoxytrytyl (DMTr) group. 2'-Amino-LNAs bearing any nucleobase can now be easily synthesized. PMID- 29528241 TI - Performance of U-net based pyramidal lucas-kanade registration on free-breathing multi-b-value diffusion MRI of the kidney. AB - OBJECTIVE: In free-breathing multi-b-value diffusion-weighted imaging (DWI), a series of images typically requires several minutes to collect. During respiration the kidney is routinely displaced and may also undergo deformation. These respiratory motion effects generate artifacts and these are the main sources of error in the quantification of intravoxel incoherent motion (IVIM) derived parameters. This work proposes a fully automated framework that combines a kidney segmentation to improve the registration accuracy. METHODS: 10 healthy subjects were recruited to participate in this experiment. For the segmentation, U-net was adopted to acquire the kidney's contour. The segmented kidney then served as a region of interest (ROI) for the registration method, known as pyramidal Lucas-Kanade. Our proposed framework confines the kidney's solution range, thus increasing the pyramidal Lucas-Kanade's accuracy. To demonstrate the feasibility of our presented framework, eight regions of interest were selected in the cortex and medulla, and data stability was estimated by comparing the normalized root-mean-square error (NRMSE) values of the fitted data from the bi exponential intravoxel incoherent motion model pre- and post- registration. RESULTS: The results show that the NRMSE was significantly lower after registration both in the cortex (p < 0.05) and medulla (p < 0.01) during free breathing measurements. In addition, expert visual scoring of the derived apparent diffusion coefficient (ADC), f, D and D* maps indicated there were significant improvements in the alignment of the kidney in the post-registered image. CONCLUSION: The proposed framework can effectively reduce the motion artifacts of misaligned multi-b-value DWIs and the inaccuracies of the ADC, f, D and D* estimations. Advances in knowledge: This study demonstrates the feasibility of our proposed fully automated framework combining U-net based segmentation and pyramidal Lucas-Kanade registration method for improving the alignment of multi-b-value diffusion-weighted MRIs and reducing the inaccuracy of parameter estimation during free-breathing. PMID- 29528242 TI - IFN-alpha in advanced well-differentiated neuroendocrine tumors: the neglected drug? PMID- 29528243 TI - Untargeted metabolomics reveals multiple metabolites influencing smoking-related DNA methylation. AB - AIM: We conducted a joint metabolomic-epigenomic study to identify patterns of epigenetic associations with smoking-related metabolites. PATIENTS & METHODS: We performed an untargeted metabolome-wide association study of smoking and epigenome-wide association studies of smoking-related metabolites among 180 male twins. We examined the patterns of epigenetic association linked to smoking related metabolites using hierarchical clustering. RESULTS: Among 12 annotated smoking-related metabolites identified from a metabolome-wide association study, we observed significant hypomethylation associated with increased level of N acetylpyrrolidine, cotinine, 5-hydroxycotinine and nicotine and hypermethylation associated with increased level of 8-oxoguanine. Hierarchical clustering revealed common and unique epigenetic-metabolic associations related to smoking. CONCLUSION: Our study suggested that a joint metabolome-epigenome approach can reveal additional details in molecular responses to the environmental exposure to understand disease risk. PMID- 29528245 TI - Invited Brief Commentary on IUVS -2017-0216. PMID- 29528244 TI - Cell penetrating peptides functionalized gambogic acid-nanostructured lipid carrier for cancer treatment. AB - Tumor-targeted delivery is considered a crucial component of current anticancer drug development and is the best approach to increase the efficacy and reduce the toxicity. Nanomedicine, particularly ligand-based nanoparticles have shown a great potential for active targeting of tumor. Cell penetrating peptide is one of the promising ligands in a targeted cancer therapy. In this study, the gambogic acid-loaded nanostructured lipid carrier (GA-NLC) was modified with two kinds of cell penetrating peptides (cRGD and RGERPPR). The GA-NLC was prepared by emulsification and solvent evaporation method and coupled with cRGD, RGERPPR, and combination cRGD and RGERPPR to form GA-NLC-cRGD, GA-NLC-RGE, and GA-NLC cRGD/RGE, respectively. The formulations were characterized by their particle size and morphology, zeta potential, encapsulation efficiency, and differential scanning calorimetry. In vitro cytotoxicity and cellular uptake study of the formulations were performed against breast cancer cell (MDA-MB-231). Furthermore, in vivo biodistribution and antitumor activity of the formulations were determined by in vivo imaging and in tumor-bearing nude mice, respectively. The result of in vitro cytotoxicity study showed that GA-NLC-RGE exhibited a significantly higher cytotoxicity on MDA-MB-231 as compared with GA-NLC and GA Sol. Similarly, RGE-Cou-6-NLC showed remarkably higher uptake by the cells than other NLCs over the incubation period. The in vivo imaging study has demonstrated that among the formulations, the RGE-decorated DiR-NLC were more accumulated in the tumor site. The in vivo antitumor activity revealed that RGE-GA-NLC inhibits the tumor growth more efficiently than other formulations. In conclusion, RGERPPR has a potential as an effective carrier in targeting drug delivery of anticancer agents. PMID- 29528246 TI - Statin use in Brazil: findings and implications. AB - INTRODUCTION AND OBJECTIVES: Statins have become an integral part of treatment to reduce cardiac events in patients with cardiovascular disease. However, their use within the public healthcare system in Brazil is unknown. Consequently, we sought to determine and characterize statin use in primary healthcare delivered by the public health system (SUS) in Brazil and evaluate associated patient factors to improve future use. METHODS: Cross-sectional study with a national representative sample from five Brazilian regions, derived from the National Survey on Access, Use and Promotion of Rational Use of Medicines using a multi-stage complex sampling plan. Patients over 18 years old were interviewed from July 2014 to May 2015. The prevalences of statin use and self-reported statin adherence were determined amongst medicine users. The associations between statin use and sociodemographic/health condition variables were assessed using logistic regression. RESULTS: A total of 8803 patients were interviewed, of whom 6511 were medicine users. The prevalence of statin use was 9.4% with simvastatin (90.3%), atorvastatin (4.7%) and rosuvastatin (1.9%) being the most used statins. Poor adherence was described by 6.5% of patients. Statin use was significantly associated with age >=65 years old, higher educational level, residence in the South, metabolic and heart diseases, alcohol consumption and polypharmacy. CONCLUSIONS: This is the first population based study in Brazil to assess statin use in SUS primary healthcare patients. Addressing inequalities in access and use of medicines including statins is an important step in achieving the full benefit of statins in Brazil, with the findings guiding future research and policies. PMID- 29528247 TI - Managing the side effects of multiple sclerosis therapy: pharmacotherapy options for patients. AB - INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disease with an unpredictable outcome. Immune-modulatory treatment aims at decreasing long-term disability. With the increasing number of treatment options, it is essential to fully digest the possible side effects of the available therapeutics and to monitor patients is essential. Areas covered: All approved disease-modifying drugs (DMD) for MS are discussed in this review. Mode of action, adverse effects, reported risks for infections and malignancies, and pregnancy related issues are discussed in the review. The authors also provide suggestions for monitoring therapy. For all approved DMDs the pivotal studies have been included for possible side effects, as well as reports by health authorities. For this manuscript, PubMed was checked for reports on side effects for various drugs. Expert opinion: Treatment options in MS are manifold, each carrying different risks. The safety-risk profile for approved agents is favorable. Knowing and monitoring these possible side effects is essential to minimize risks associated with treatment. Presently, the long-term experience for some of these therapies is missing and this must be addressed. PMID- 29528248 TI - Calcium phosphate-based nanosystems for advanced targeted nanomedicine. AB - Synthetic calcium phosphates (CaPs) are the most widely accepted bioceramics for the repair and reconstruction of bone tissue defects. The recent advancements in materials science have prompted a rapid progress in the preparation of CaPs with nanometric dimensions, tailored surface characteristics, and colloidal stability opening new perspectives in their use for applications not strictly related to bone. In particular, the employment of CaPs nanoparticles as carriers of therapeutic and imaging agents has recently raised great interest in nanomedicine. CaPs nanoparticles, as well as other kinds of nanoparticles, can be engineered to specifically target the site of the disease (cells or organs), thus minimizing their dispersion in the body and undesired organism-nanoparticles interactions. The most promising and efficient approach to improve their specificity is the 'active targeting', where nanoparticles are conjugated with a targeting moiety able to recognize and bind with high efficacy and selectivity to receptors that are highly expressed only in the therapeutic site. The aim of this review is to give an overview on advanced targeted nanomedicine with a focus on the most recent reports on CaP nanoparticles-based systems, specifically designed for the active targeting. The distinctive characteristics of CaP nanoparticles with respect to the other kinds of nanomaterials used in nanomedicine are also discussed. PMID- 29528249 TI - How does race/ethnicity influence pharmacological response to asthma therapies? AB - INTRODUCTION: Our understanding of whether and/or how ethnicity influences pharmacological response to asthma therapies is still very scarce. A possible explanation for the increased asthma treatment failures observed in ethnic and racial minorities receiving asthma therapies is that some of these groups may have a pharmacogenomic predisposition to either nonresponse or to adverse response with a specific class of drugs. However, the effects of ethnicity on pharmacological response to asthma therapies are also, and mainly, determined by socioeconomic and environmental factors to a varying extent, depending on the ethnic groups. Areas covered: Genetic, socioeconomic and environmental factors that can affect the pharmacotherapeutic responses to asthma medications and their link(s) to race/ethnicity have been examined and critically discussed. Expert opinion: Differences in genetic ancestry are definitely non-modifiable factors, but socioeconomic and environmental disadvantages are all factors that can be modified. It is likely that improved outcomes may be achieved when tailored and multifaceted approaches that include home, school, and clinician-based interventions are implemented. Consequently, it is critical to determine if a clinical intervention programme combined with implementation strategies that attempt to reduce inequalities can reduce asthma disparities, including the influence of ethnicity and race on pharmacological response to asthma therapies. PMID- 29528250 TI - Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma. AB - AIM: SLC7A11 is a gene that encodes a cystine-glutamate antiporter, which has been detected to be overexpressed in various cancers. Thus, we aimed to validate its expression and clinical significance in liver cancer. METHODS: Bioinformatic analysis was conducted and a tissue microarray was utilized for detecting SLC7A11 expression in liver cancer tissues by immunohistochemistry assay. RESULTS: High expressions of SLC7A11 have no association with clinical parameters such as age, sex and clinical stages, except for advanced pathological stages. Cox regression analysis revealed that SLC7A11 might be an independent prognostic factor for liver cancer patients. CONCLUSION: SLC7A11 overexpression might be a novel biomarker and a potential unfavorable prognostic factor as well as a potential therapeutic target for liver carcinoma. PMID- 29528251 TI - Clinical safety and tolerability of tedizolid phosphate in the treatment of acute bacterial skin and skin structure infections. AB - BACKGROUND: We evaluated safety and tolerability of tedizolid phosphate at the 200-mg once-daily dose approved for 6-day treatment of skin and skin-structure infections. RESEARCH DESIGN AND METHODS: Clinical adverse event (AE) and laboratory data were pooled across completed clinical studies (13 phase 1, two phase 2, and two phase 3), for all participants who received >=1 dose of tedizolid 200 mg, linezolid 600 mg (phase 3 only), or placebo (phase 1 only). RESULTS: 1280 participants received tedizolid (phase 1: n = 355; phase 2/3: n = 925). In total, 13% received >6 doses of tedizolid (range: 7-21); in phase 2/3, 94% of participants received >=5 doses (range: 5-10). Drug-related AEs occurred in 27% of participants (most commonly gastrointestinal reactions in 13% of participants and headache in 4%). Most AEs were mild-moderate in severity; <1% of participants discontinued treatment due to AEs. Tedizolid and linezolid had similar frequency, severity, and types of drug-related AEs. Tolerability in clinically important subpopulations (obese, n = 346; elderly, n = 99; renal impairment, n = 40; hepatic disease/impairment, n = 294) appeared comparable to the overall population. CONCLUSIONS: Tedizolid, given orally or intravenously at 200 mg, has a favorable safety profile. Clinical trial and postmarketing experience with treatment >=7 days is limited. PMID- 29528253 TI - Morphing the feature-based multi-blocks of normative/healthy vertebral geometries to scoliosis vertebral geometries: development of personalized finite element models. AB - Personalized Finite Element (FE) models and hexahedral elements are preferred for biomechanical investigations. Feature-based multi-block methods are used to develop anatomically accurate personalized FE models with hexahedral mesh. It is tedious to manually construct multi-blocks for large number of geometries on an individual basis to develop personalized FE models. Mesh-morphing method mitigates the aforementioned tediousness in meshing personalized geometries every time, but leads to element warping and loss of geometrical data. Such issues increase in magnitude when normative spine FE model is morphed to scoliosis affected spinal geometry. The only way to bypass the issue of hex-mesh distortion or loss of geometry as a result of morphing is to rely on manually constructing the multi-blocks for scoliosis-affected spine geometry of each individual, which is time intensive. A method to semi-automate the construction of multi-blocks on the geometry of scoliosis vertebrae from the existing multi-blocks of normative vertebrae is demonstrated in this paper. High-quality hexahedral elements were generated on the scoliosis vertebrae from the morphed multi-blocks of normative vertebrae. Time taken was 3 months to construct the multi-blocks for normative spine and less than a day for scoliosis. Efforts taken to construct multi-blocks on personalized scoliosis spinal geometries are significantly reduced by morphing existing multi-blocks. PMID- 29528252 TI - Candidate gene DNA methylation associations with breast cancer characteristics and tumor progression. AB - AIM: We examined methylation patterns with aggressive tumor phenotypes and investigated demographic, socioeconomic and reproductive predictors of gene methylation. MATERIALS & METHODS: Pyrosequencing quantified methylation of BRCA1, EGFR, GSTM2, RASSF1, TFF1 and Sat 2. We used quantile regression models to calculate adjusted median methylation values by estrogen and progesterone receptor (ER/PR) status. Bivariate associations between participant characteristics and methylation were examined. RESULTS: Higher percent methylation of GSTM2 was observed in ER/PR-negative compared with ER/PR-positive tumors in ductal carcinoma in situ (14 vs 2%) and invasive (35 vs 3%) tissue components. Trends in aberrant GSTM2 methylation across tissue components were stronger among ER/PR-negative tumors (p-interaction <0.001). Black women were more likely to have ER/PR-negative tumors (p = 0.01) and show hypermethylation of GSTM2 compared with other women (p = 0.05). CONCLUSION: GSTM2 promoter hypermethylation may serve as a potential biomarker of aggressive tumor development and a mechanism for ER/PR-negative tumor progression. PMID- 29528254 TI - Effects of Laparascopic Hernia Repair by PIRS (Percutaneous Internal Ring Suturing) Technique on Testicular Artery Blood Supply. PMID- 29528255 TI - Does sarcopenia affect outcome in patients with non-small-cell lung cancer harboring EGFR mutations? AB - AIM: To evaluate gefitinib outcomes in EGFR-mutated non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, according to their sarcopenia status. PATIENTS & METHODS: We retrospectively evaluated 33 patients with advanced NSCLC and EGFR mutations (exon 19 or 21), dividing them into sarcopenic patients, with low skeletal muscle index <=39 cm2/m2 for women and <=55 cm2/m2 for men, and nonsarcopenic patients. RESULTS: Sarcopenia does not affect response to gefitinib treatment in EGFR mutated NSCLC patients, even if it is a bad prognostic indicator for overall survival (p = 0.035). CONCLUSION: Early recognition of sarcopenia is beneficial for prevention of cancer cachexia and detection of patients at potential risk of serious adverse events. Gefitinib dosage should be reduced and modulated in sarcopenic patients. PMID- 29528256 TI - Emerging growth factor receptor antagonists for ovarian cancer treatment. AB - INTRODUCTION: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy. EOC outcomes remain unsatisfactory despite aggressive surgical approach, disease chemo-sensitivity and recent introduction of agents targeting angiogenesis and tumour genome instability. Advances in EOC research have allowed for a tailored treatment approach and accelerated development of novel treatments strategies from bench to bed side, anticipated to improve patient outcomes. Areas covered: Comprehensive review of growth factor receptor antagonists for EOC treatment currently in different stages of development was performed. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase and major conferences. We focused on agents that antagonize growth factors promoting sustained proliferative signaling, angiogenesis and evasion of immune destruction blocking the receptor or its stimulating factors. Expert opinion: Receptor signaling has been well characterized for most cancer generating pathways. Growth receptor antagonists are represented by both high receptor affinity monoclonal antibodies as well as tyrosine kinase inhibitors; both are especially effective when a related predictive biomarker of response is identified. Therefore, along with the promising development of novel receptor antagonists or modulators in EOC treatment, targeting essential growth pathways in the tumour and associated microenvironment, is fundamental for biomarker discovery and towards achieving significant improvements in response. PMID- 29528258 TI - Treatment of basal cell carcinoma: is intralesional methotrexate an option? PMID- 29528257 TI - Perceived patient burden and acceptability of whole body MRI for staging lung and colorectal cancer; comparison with standard staging investigations. AB - OBJECTIVE: To evaluate perceived patient burden and acceptability of whole body MRI (WB-MRI) compared to standard staging investigations, and identify predictors of reduced tolerance. METHODS: Patients recruited to multicentre trials comparing WB-MRI with standard staging scans for lung and colorectal cancer were invited to complete two questionnaires: a baseline questionnaire at recruitment, measuring demographics, comorbidities, and distress; and a follow-up questionnaire after staging, measuring recovery time, comparative acceptability/satisfaction between WB-MRI and CT (colorectal cancer) and PET-CT (lung cancer), and perceived scan burden (scored 1, low; 7, high). Results: 115 patients (median age 66.3 years; 67 males) completed follow up and 103 baseline questionnaires. 69 (63.9%) reported "immediate" recovery from WB-MRI and 73 (65.2%) judged it "very acceptable". Perceived WB-MRI burden was greater than for CT (p < 0.001) and PET CT (p < 0.001). High distress and comorbidities were associated with greater WB MRI burden in adjusted analyses, with deprivation only approaching significance (adjusted regression beta = 0.223, p = 0.025; beta = 0.191, p = 0.048; beta = 0.186, p = 0.059 respectively). Age (p = 0.535), gender (p = 0.389), ethnicity (p = 0.081) and cancer type (p = 0.201) were not predictive of WB-MRI burden. CONCLUSION: WB-MRI is marginally less acceptable and more burdensome than standard scans, particularly for patients with pre-existing distress and comorbidities. Advances in knowledge: This research shows that WB-MRI scan burden, although low, is higher than for current staging modalities among patients with suspected colorectal or lung cancer. Psychological and physical comorbidities adversely impact on patient experience of WB-MRI. Patients with high distress or comorbid illness may need additional support to undergo a WB MRI. PMID- 29528259 TI - Nitrogen metabolism in cyanobacteria: metabolic and molecular control, growth consequences and biotechnological applications. AB - Cyanobacteria are one of the earliest branching groups of organisms on the planet, and during their evolutionary history were submitted to varying selective pressures. Nowadays, cyanobacteria can grow in a variety of conditions, using a large number of nitrogen sources. The control of the nitrogen metabolism in cyanobacteria depends on a fine-tuning regulatory network involving 2 oxoglutarate (2-OG), PII, PipX, and NtcA. This network answers to the cellular 2 OG levels, which reflects the cellular carbon/nitrogen balance, and as an output regulates gene expression, translation, protein activities and thus metabolic pathways. Hence, the diurnal regulation of growth may be directly dependent of this network, as it coordinates the use of photoassimilates towards either growth or the accumulation of reserves, based on the environmental conditions. Therefore, analysis of the nitrogen control network is not only important to comprehend the metabolic control of growth in cyanobacteria, but is also a target to improve cyanobacterial biotechnological potential. In this review, we discuss the mechanisms involved in the control of nitrogen metabolism and its potential role in the diurnal regulation of growth. Then, we highlight why a better understanding of the mechanisms involved in the partitioning of carbon and nitrogen towards growth or storage would increase the biotechnological potential of these organisms. PMID- 29528260 TI - Prevalence of hypertension determined by ambulatory blood pressure monitoring (ABPM) and body composition in long-term survivors of childhood cancer. AB - AIM: In recent years, survival rates of childhood cancers have significantly increased, and occurrence of long-term adverse late effects (eg, insulin resistance, diabetes mellitus, metabolic syndrome, hypertension) has become increasingly important. Early diagnosis of obesity/hypertension in childhood is essential to avoid morbidity in the adulthood. Therefore, this study was aimed to determine the blood pressure (BP) profile by ambulatory BP monitoring (ABPM) method, and prevalence of hypertension, obesity, abdominal obesity among childhood cancer survivors. MATERIAL AND METHOD: The study was carried out with 52 cancer survivors. The ABPM measurement was performed during 24 hours. The anthropometric measurements of patients were performed using standardized protocols. The body composition analysis was performed with bioelectrical impedance analysis (BIA) method. Statistical significance was considered at p < 0.05. RESULTS: The mean age of patients was 12.84 +/- 3.88 years. Time off therapy ranged 24-125 month. The prevalence of prehypertension and hypertension were 57.7% and 9.6%, respectively. There was no statistically significant relationship between diagnosis and BP status (p = 0.59). The prevalence of obesity, and abdominal obesity were 1.9% and 30.4%, respectively. There was a positive correlation between waist circumference (WC) and time off therapy (p = 0.046). The WC was found to be higher in patients who received cranial irradiation (p = 0.048). Weight/WC were higher in patients who used corticosteroids in the treatment (p = 0.019). CONCLUSION: Careful follow up of BP, weight and WC is necessary for long-term cancer survivors to prevent complications. Especially patients who receive cranial radiotherapy and use corticosteroid are at increased risk of abdominal obesity. PMID- 29528261 TI - Influence of IL15 gene variations on the clinical features, treatment response and risk of developing childhood acute lymphoblastic leukemia in Latvian population. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Modern treatment protocols allow achievement of long-term event-free survival rates in up to 85% of cases, although the treatment response varies among different patient groups. It is hypothesized that treatment response is influenced by the IL15 gene variations, although research results are conflicting. To analyze IL15 gene variations influence treatment response, clinical course and the risk of developing ALL we performed a case-control and family-based study. The study included 81 patients with childhood ALL. DNA samples of both or one biological parent were available for 62 of ALL patients and 130 age and gender adjusted healthy samples were used as a control group. Analyzed IL15 gene variations: rs10519612, rs10519613 and rs17007695 were genotyped using PCR-RFLP assay. Our results shows that IL15 gene variations haplotypes are associated with the risk of developing childhood ALL (p < 0.05), although there is no such association for the variations separately. The variations rs10519612 and rs1059613 in a recessive pattern of inheritance were associated with hyperdiploidy (p = 0.048). Analyzed genetic variations had no impact on other clinical features and treatment response (assessed by the minimal residual disease) in our study. PMID- 29528262 TI - Definitive chemoradiation or surgery in elderly patients with potentially curable esophageal cancer in the Netherlands: a nationwide population-based study on patterns of care and survival. AB - BACKGROUND: The aim of our study was to describe treatment patterns and the impact on overall survival among elderly patients (75 years and older) with potentially curable esophageal cancer. MATERIAL AND METHODS: Between 2003 and 2013, 13,244 patients from the nationwide population-based Netherlands Cancer Registry (NCR) were diagnosed with potentially curable esophageal cancer (cT2-3, X, any cN, cM0, X) of which 34% were elderly patients (n = 4501). RESULTS: Surgical treatment with or without neoadjuvant treatment remained stable among elderly patients (around the 16% between 2003 and 2013). However, among younger patients, surgical treatment increased from 60.2 to 67.0%. The use of definitive chemoradiation (dCRT) increased in elderly patients from 1.9 to 19.5% and in younger patients from 5.2 to 17.2%. Due to the increase in dCRT, treatment with curative intent doubled in the elderly from 17 to 37.1%. Multivariable Cox regression revealed that elderly patients with an adenocarcinoma receiving surgery alone or dCRT had a significantly worse overall survival compared to those receiving surgery with neoadjuvant chemo (radio) therapy (nCRT/CT) (HR: 1.7 95% CI 1.4-2.0 and HR: 1.9 95% CI 1.5-2.3). However, among elderly with squamous cell carcinoma overall survival was comparable between dCRT, surgery alone and surgery with nCRT/CT. CONCLUSIONS: Survival was comparable among elderly patients with squamous cell carcinoma who underwent surgery with nCRT/CT, surgery alone or received dCRT, while elderly patients with an adenocarcinoma who underwent surgery with nCRT/CT had a better overall survival when compared with surgery alone or dCRT. Therefore, dCRT can be considered as a reasonable alternative for surgery among potentially curable elderly patients with esophageal squamous cell carcinoma. However, in elderly patients with esophageal adenocarcinoma surgery with nCRT/CT is still preferable regarding overall survival. PMID- 29528263 TI - Correction to: Luemsamran, Rootman, White, Nassiri, and Heran, The role of biopsy in lacrimal gland inflammation: A clinicopathologic study. PMID- 29528264 TI - Chondrocyte affinity peptide modified PAMAM conjugate as a nanoplatform for targeting and retention in cartilage. AB - AIM: To develop a nanocarrier for targeted delivery of agents to the cartilage. MATERIALS & METHODS: Chondrocyte affinity peptide modified PEGylated polyamidoamine conjugates (CAP-PEG-PAMAM) were prepared and rhodamine B isothiocyanate (RB) fluorophore was linked on them for comparative biological tracing and profiling. RESULTS: CAP4-PP-RB exhibited much more efficient cellular uptake in vitro than that of PEG-PAMAM-RB. Both the conjugates were likely internalized by chondrocytes via clathrin and caveolin co-mediated endocytosis, and delivered to lysosomes. In vivo imaging demonstrated the fluorescein-labeled nanocarrier was capable to persist in the joint cavity of rats for a prolonged time. Furthermore, the CAP4-PEG-PAMAM showed a good biocompatibility and enhanced penetration effects in vivo. CONCLUSION: CAP-PEG-PAMAM could be an effective nanocarrier for intra-articular delivery of agents to cartilage. PMID- 29528265 TI - Current progress of immunoinformatics approach harnessed for cellular- and antibody-dependent vaccine design. AB - Immunoinformatics plays a pivotal role in vaccine design, immunodiagnostic development, and antibody production. In the past, antibody design and vaccine development depended exclusively on immunological experiments which are relatively expensive and time-consuming. However, recent advances in the field of immunological bioinformatics have provided feasible tools which can be used to lessen the time and cost required for vaccine and antibody development. This approach allows the selection of immunogenic regions from the pathogen genomes. The ideal regions could be developed as potential vaccine candidates to trigger protective immune responses in the hosts. At present, epitope-based vaccines are attractive concepts which have been successfully trailed to develop vaccines which target rapidly mutating pathogens. In this article, we provide an overview of the current progress of immunoinformatics and their applications in the vaccine design, immune system modeling and therapeutics. PMID- 29528266 TI - Bee genera, diversity and abundance in genetically modified canola fields. AB - Intensive agricultural practices resulting in large scale habitat loss ranks as the top contributing factors in the global bee decline. Growing Genetically Modified Herbicide Tolerant (GMHT) crops as large monocultures has resulted extensive applications of herbicides leading to the degradation of natural habitats surrounding farmlands. Herbicide tolerance trait is beneficial for crops such as Canola (Brassica napus) that are extremely vulnerable to weed competition. While the trait in itself does not harm pollinators, growing genetically modified herbicide tolerant cultivars indirectly contributes towards pollinator declines through habitat loss. Canola, a mass-flowering crop is highly attractive to bee pollinators and the extensive adoption of the herbicide tolerant trait has led to depletion of non-crop floral resources. Extensive use of herbicide in and near fields with herbicide tolerant cultivars systematically eliminates semi-natural habitats around agricultural fields which consist of non crop flowering plants. Planting pollinator strips provides floral resources for bees after crop flowering. We document the bee genera in canola and the adjoining pollinator strip. The overlap in bee genera reinforces the importance of pollinator habitats in agricultural landscape. PMID- 29528267 TI - Optimization of sodium percarbonate pretreatment for improving 2,3-butanediol production from corncob. AB - Sodium percarbonate (SP), a kind of alkaline strong oxidant, was applied to corncob pretreatment. The optimized pretreatment conditions were at 4% (w/v) SP concentration with solid-to-liquid (SLR) ratio of 1:10 treating for 4 hr at 60 degrees C. This pretreatment resulted in 91.06% of cellulose and 84.08% of hemicellulose recoveries with 34.09% of lignin removal in corncob. The reducing sugar yield from SP-pretreated corncob was 0.56 g/g after 72 hr of enzymatic hydrolysis, 1.75-folds higher than that from raw corncob. 2,3-butanediol production by Enterobacer cloacae in simultaneous saccharification fermentation was 29.18 g/L using SP-pretreated corncob as a substrate, which was 11.12 times of that using raw corncob. Scanning electron microscope, X-ray diffraction, and Fourier transform infrared spectra analysis indicated that physical characteristics, crystallinity, and structure of corncob had changed obviously after SP pretreatment. This simple and novel pretreatment method was effective for delignification and carbohydrate retention in microbial production of 2,3 butanediol from lignocellulose biomass. PMID- 29528268 TI - Platelet Toll-like receptor expression and activation induced by lipopolysaccharide and sepsis. AB - Platelets and Toll-like receptor (TLR) signalling play a role in the immune response during sepsis. Although preclinical knowledge about the role of platelet TLR signalling is increasing, data during human sepsis are less abundant. Moreover, controversy remains about the effect of the TLR4 agonist lipopolysaccharide (LPS) on platelet activation. We therefore assessed platelet TLR expression during human and murine sepsis. Moreover, we investigated the effect of TLR4 signalling on platelet activation and TLR expression. Platelets from healthy controls stimulated with LPS did not show classical platelet activation (P-selectin, CD63 and phosphatidylserine expression), potentiation of subthreshold agonist stimulation nor platelet-leukocyte complex formation. LPS stimulation however did increase maximal mitochondrial respiration in a TLR4 dependent manner. Platelet stimulation with LPS did not alter TLR expression. Platelet stimulation with thrombin receptor activating peptide increased TLR5 and TLR9, but not TLR2 or TLR4 expression. Platelets from patients with sepsis and mice with experimental sepsis showed platelet activation, but unaltered TLR expression. These results indicate that sepsis-induced platelet activation is not associated with altered platelet TLR expression and, although platelets are responsive to LPS, stimulation of platelet TLR4 does not result in classical platelet activation. PMID- 29528269 TI - Fusarium algeriense, sp. nov., a novel toxigenic crown rot pathogen of durum wheat from Algeria is nested in the Fusarium burgessii species complex. AB - A novel crown rot pathogen of wheat discovered during pathogen surveys in Algeria in 2014 and 2015 is formally described as Fusarium algeriense. Multilocus molecular phylogenetic data resolved the eight isolates of this pathogen as a genealogically exclusive species lineage in the F. burgessii species complex. The previously described species of this complex, F. burgessii and F. beomiforme, produce abundant chlamydospores in culture, and their optimal temperature for growth is 30 C. In comparison, F. algeriense did not produce chlamydospores under the conditions tested and its optimal temperature for growth is 25 C. Furthermore, F. algeriense differs from F. burgessii because it does not produce polyphialides and F. beomiforme, because it does not produce globose-to-napiform conidia in the aerial mycelium. Isolates of F. algeriense induced moderate crown rot on the susceptible spring wheat cultivar Norm in a temperature-controlled incubator. Fusarium burgessii and F. beomiforme, in contrast, only induced mild symptoms of this disease. BLASTn searches of the whole-genome sequence of F. algeriense strains NRRL 66647 and 66648, using homologs of genes that are responsible for synthesis of toxic secondary metabolites, indicated that they have the potential to produce several polyketide and non-ribosomal peptide derived mycotoxins. However, moniliformin and 2-AOD-ol (2-amino-14,16 dimethyloctadecan-3-ol) were the only mycotoxins detected by liquid chromatography-mass spectrometry (LC-MS) analyses of strains cultivated in vitro on a solid medium. A polymerase chain reaction (PCR) assay for MAT idiomorph revealed that MAT1-1 and MAT1-2 strains of F. algeriense were present in Algeria, which suggests this pathogen might possess a heterothallic sexual reproductive mode. PMID- 29528270 TI - Toxin-producing Epichloe bromicola strains symbiotic with the forage grass Elymus dahuricus in China. AB - Cool-season grasses (Poaceae subfamily Pooideae) are an important forage component for livestock in western China, and many have seed-transmitted symbionts of the genus Epichloe, fungal endophytes that are broadly distributed geographically and in many tribes of the Pooideae. Epichloe strains can produce any of several classes of alkaloids, of which ergot alkaloids and indole diterpenes can be toxic to mammalian and invertebrate herbivores, whereas lolines and peramine are more selective against invertebrates. The authors characterized genotypes and alkaloid profiles of Epichloe bromicola isolates symbiotic with Elymus dahuricus, an important forage grass in rangelands of China. The endophyte was seed-transmitted and occasionally produced fruiting bodies (stromata), but its sexual state was not observed on this host. The genome sequence of E. bromicola isolate E7626 from El. dahuricus in Xinjiang Province revealed gene sets for peramine, ergot alkaloids, and indole-diterpenes. In multiplex polymerase chain reaction (PCR) screens of El. dahuricus-endophyte isolates from Beijing and two locations in Shanxi Province, most were also positive for these genes. Ergovaline and other ergot alkaloids, terpendoles and other indole diterpenes, and peramine were confirmed in El. dahuricus plants with E. bromicola. The presence of ergot alkaloids and indole-diterpenes in this grass is a potential concern for managers of grazing livestock. PMID- 29528271 TI - Genetic polymorphisms of vitamin D3 metabolizing CYP24A1 and CYP2R1 enzymes in Turkish patients with ischemic stroke. AB - Objective Vitamin D deficiency is known as an important risk factor in pathogenesis of atherosclerosis, which contributes to stroke development. Genetic variations including single nucleotide polymorphisms (SNPs) in enzymes involved in vitamin D metabolism can affect susceptibility to the development of stroke. Therefore, the objective of this study was to investigate the association between polymorphisms of vitamin D metabolizing enzymes (rs927650 SNP in CYP24A1, and rs10741657 SNP in CYP2R1 genes,) and ischemic stroke risk in Turkish population. Materials and methods To test this hypothesis, we designed a case-control study which consisted of 256 ischemic stroke patients and 132 controls. Genotypes were determined by PCR-RFLP technique. Results No significant differences were found between patients and controls in terms of CYP24A1 rs927650 and CYP2R1 rs10741657 genotype frequencies. Polymorphic allele frequencies of CYP24A1 rs927650 and CYP2R1 rs10741657 were 0.414 and 0.660 in stroke patients, respectively. Conclusion This is the first study conducted regarding the association of CYP24A1 rs927650 and CYP2R1 rs10741657 genetic polymorphisms and ischemic stroke risk. The polymorphic genotypes of these polymorphisms, together with hypertension, diabetes, smoking, and obesity, were found as significant risk factors for ischemic stroke. PMID- 29528273 TI - Interactions of 4,4'-diaminoazobenzene derivatives with telomeric G-quadruplex DNA. AB - The development of small molecules to stabilize the G-quadruplex structure has garnered significant attention for anticancer drug discovery. Herein, we report the synthesis of several 4,4'-diaminoazobenzene derivatives containing different substituent groups and their ability to bind and stabilize telomeric G-quadruplex DNA. Circular dichroism (CD) spectroscopy was performed to characterize the quadruplex topologies, measure stabilization effects, and evaluate their capabilities for conformational photoregulation. 4,4'-Diaminoazobenzene derivatives were found to moderately stabilize quadruplex structures but not affect conformational photoregulation. This work further develops the design and general understanding of the stabilization effects of small molecules with telomeric G-quadruplex DNA. PMID- 29528272 TI - Angiogenic and inflammatory biomarkers for screening and follow-up in patients with pulmonary arterial hypertension. AB - OBJECTIVE: To identify circulating angiogenic and inflammatory biomarkers with potential in screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc), and in early diagnosis and determination of treatment response in PAH. METHOD: Plasma samples were taken at the time of PAH diagnosis and at treatment follow-up after a median (interquartile range) of 4 months (3-9.8 months) in idiopathic (n = 9) and SSc-associated PAH (n = 11). In patients with SSc-associated PAH, plasma samples had also been gathered a median of 2 years (0.8-3 years) before PAH diagnosis (n = 10). Additional plasma samples were retrieved at two time-points separated by a median of 12 years (10-13 years) from SSc patients who did not develop PAH (n = 10) and from controls (n = 8). Angiogenic and inflammatory biomarkers were analysed by multiplex immunoassays. RESULTS: Plasma levels of placenta growth factor (PlGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), and tumour necrosis factor-alpha (TNF-alpha) were higher (p < 0.05) in SSc patients who later developed PAH than in those who did not. Plasma vascular endothelial growth factor (VEGF)-D increased (p < 0.05) in SSc patients as PAH developed. Plasma levels of PlGF, VEGF-A, VEGF-D, sVEGFR-1, interleukin-6, and TNF-alpha were higher (p < 0.05) in PAH than controls. There were no significant differences in circulating biomarkers between idiopathic and SSc-associated PAH. Plasma sVEGFR-1 decreased (p < 0.05) after initiating PAH-targeted treatments. CONCLUSIONS: Plasma levels of PlGF, sVEGFR-1, TNF-alpha, and VEGF-D have potential in screening for SSc associated PAH. Plasma sVEGFR-1 may be a biomarker of treatment response. PMID- 29528274 TI - Spine-shortening osteotomy for patients with tethered cord syndrome: a systematic review and meta-analysis. AB - Purpose Tethered cord syndrome (TCS) is the clinical manifestation of an abnormal stretch on the spinal cord, caused by several pathological conditions. Tethered cord release is the gold standard treatment for TCS. However, direct untethering carries potential risks of spinal cord injury, post-operative retethering, and CSF-related complications. Spine-shortening osteotomy (SSO) has recently been performed as an alternative technique to avoid these risks. We aimed to systematically review the literature on indications and outcome of SSO in TCS patients. Methods We searched PubMed, Embase, Google Scholar, and the Cochrane Library to identify all studies on SSO in TCS patients. We used random or fixed effects models to calculate rates and 95% confidence intervals to establish the rates of clinical improvement in TCS patients performed with SSO. Sensitive analysis and metaregression were made to explore potential sources of heterogeneit. Results We identified six eligible surveys with a total population of 57. Rates ranged from 62 to 88% for neurological deficits improvement, 80-100% for motor function improvement, 60-96% for pain or numbness scores improvement, 13-67% for sensory function improvement, and 79-100% for urinary and bowel dysfunction improvement. We noted substantial heterogeneity in rate estimates for motor function and urinary and bowel dysfunction improvement (all Cochran's chi2 significant at P < 0.001; I2 = 78.11%, 95%CI 61-94%; 84.28%, 18-100%; respectively). Conclusion SSO is a safe and effective technique for TCS patients, especially in more challenging cases, such as complex malformations or revision surgery. However, future cohort studies and randomized studies with large numbers and the power to provide illumination for the surgical decision-making of TCS are warranted. PMID- 29528275 TI - Re: Luemsamran et al.: The role of biopsy in lacrimal gland inflammation: a clinicopathologic study. PMID- 29528276 TI - Toxic metals in ayurvedic preparations from a public health lead poisoning cluster investigation. AB - Background Herbal formulations, traditional medicine, and complementary and alternative medicine are used by the majority of the world's population. Toxicity associated with use of Ayurvedic products due to metal content is an increasingly recognized potential public health problem. Objectives Report on toxic metals content of Ayurvedic products obtained during an investigation of lead poisoning among users of Ayurvedic medicine. Methods Samples of Ayurvedic formulations were analyzed for metals and metalloids following established US. Environmental Protection Agency methods. Results Lead was found in 65% of 252 Ayurvedic medicine samples with mercury and arsenic found in 38 and 32% of samples, respectively. Almost half of samples containing mercury, 36% of samples containing lead and 39% of samples containing arsenic had concentrations of those metals per pill that exceeded, up to several thousand times, the recommended daily intake values for pharmaceutical impurities. Conclusions Lack of regulations regarding manufacturing and content or purity of Ayurvedic and other herbal formulations poses a significant global public health problem. PMID- 29528277 TI - Fistulinella ruschii, sp. nov., and a new record of Fistulinella campinaranae var. scrobiculata for the Atlantic Forest, Brazil. AB - Fistulinella is a small genus of boletoid fungi in the subfamily Austroboletoideae in the order Boletales. In this paper, F. ruschii from the Atlantic Forest is proposed as new to science and F. campinaranae var. scrobiculata, known from the Brazilian Amazon forest, is recorded for the first time in the Atlantic Forest. Macro- and microscopic descriptions, molecular data (nuc rDNA ITS1-5.8S-ITS2 and nuc 28S rDNA), photographs of the basidiomata, and scanning electron microscopy images of basidiospores are provided for both species. Based on sampling of six taxa, New World Fistulinella is found to be a strongly supported monophyletic group, but the genus at large is nonmonophyletic. PMID- 29528278 TI - Cationic-bilayered nanoemulsion of fusidic acid: an investigation on eradication of methicillin-resistant Staphylococcus aureus 33591 infection in burn wound. AB - AIM: The aim of the current study was to investigate the therapeutic efficacy of cationic-charged bilayered nanoemulsion for topical delivery of fusidic acid in eradicating methicillin-resistant Staphylococcus aureus (MRSA) bacterial burn wound infection. MATERIALS & METHODS: The developed carriers were characterized for particle size, antibacterial activity, cell viability assay in HaCat cell lines, rheological profile, ex vivo and in vivo studies, namely, full thickness MRSA 33591 murine burn wound infection via topical route. RESULTS: The developed cationic bilayered nanogel offered enhanced drug permeation, reduction in bacterial load and enhanced wound contraction along with faster re epithelialization in burn wounds. CONCLUSION: The results encourage the exploration of the potential of cationic nanogel in treating resistant microorganisms such as MRSA, especially for application in burn wound infection. PMID- 29528279 TI - Reliability of intensity-based physical activity measurement using an activity monitor in people with subacute stroke in the hospital setting: a cross-sectional study. AB - Background Activity monitors are known to provide quantitative evaluation of physical activity in people with stroke. However, little evidence is available on the test-retest reliability and suitable measuring conditions for evaluating physical activity with an activity monitor in people with subacute stroke at a hospital setting. Objectives To evaluate reliability of physical activity measurement using an activity monitor in different measuring conditions in hospitalized people with subacute stroke according to gait ability. Methods Sixty nine participants with subacute stroke were categorized based on their gait ability: group 1 (n = 22), could walk independently at sufficient gait speed (>=0.9 m/s); group 2 (n = 11), could walk independently with insufficient gait speed (<0.9 m/s); group 3 (n = 36), required assistance in walking. Physical activity (sedentary behavior, light-intensity physical activity, moderate-to vigorous physical activity) was measured using an activity monitor (OMRON, HJA350 IT) for seven consecutive days. All physical activity variables were calculated in five conditions defined according to measurement periods (3, 5, or 7 days with or without weekends). Results In groups 1 and 2, intraclass correlation coefficients were high across all measuring conditions in all physical activity variables (>0.7). In group 3, intraclass correlation coefficients were high in all measuring conditions (>0.7) except for three weekdays measuring condition (0.563-0.922). Conclusions In hospitalized people with subacute stroke, the central tendency of intensity-based physical activity could be assessed with good reliability using an activity monitor. For reliable measurement, more measurement days are needed in those with dependent walking compared to those with independent walking. PMID- 29528280 TI - A whole new world: a qualitative investigation of parents' experiences in transitioning their preterm child with cerebral palsy to developmental/rehabilitation services. AB - BACKGROUND: Parents' experiences transitioning their children from neonatal to developmental/rehabilitation services (DRS) are unknown. METHODS: A qualitative descriptive approach was used, including interviews with 18 parents (13 mothers and 5 fathers) of children born preterm and diagnosed with cerebral palsy (CP), located in a large urban center in Canada. Interview data underwent thematic analysis. RESULTS: Parents' experiences with transition to DRS were a whole new world with three key themes: Wanting to know what to expect, feeling supported in their transition, and getting there emotionally and physically. Transition broke an emotional bond with neonatal services while parents were simultaneously entering DRS, experiencing their child's CP diagnosis, and reliving prior emotional trauma. CONCLUSIONS: The findings reveal a cumulative emotional burden for parents in the first 3 years of life; a known critical period for parenting and early childhood development. Early transition interventions should consider including enhanced supports and services for parents. PMID- 29528281 TI - Editorial: Signaling Molecules as Biomarkers and Therapeutic Targets for Alzheimer's Disease: A New Perspective. PMID- 29528282 TI - Cigarette Smoking During Pregnancy: United States, 2016. AB - Maternal tobacco use during pregnancy has been linked to a host of negative infant and child outcomes, including low birthweight, preterm birth, and various birth defects (1-5). The 2003 revision of the U.S. Standard Certificate of Live Birth included new and modified items on maternal cigarette smoking before and during pregnancy. The 2016 natality data file is the first for which this information is available for all states and the District of Columbia (D.C.). This report presents the prevalence of cigarette smoking at any time during pregnancy among women who gave birth in 2016 in the United States by state of residence as well as maternal race and Hispanic origin, age, and educational attainment. PMID- 29528283 TI - Correction: MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. PMID- 29528284 TI - POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels. AB - Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin's actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin's effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels. PMID- 29528285 TI - Movement maintains forebrain neurogenesis via peripheral neural feedback in larval zebrafish. AB - The postembryonic brain exhibits experience-dependent development, in which sensory experience guides normal brain growth. This neuroplasticity is thought to occur primarily through structural and functional changes in pre-existing neurons. Whether neurogenesis also mediates the effects of experience on brain growth is unclear. Here, we characterized the importance of motor experience on postembryonic neurogenesis in larval zebrafish. We found that movement maintains an expanded pool of forebrain neural precursors by promoting progenitor self renewal over the production of neurons. Physical cues associated with swimming (bodily movement) increase neurogenesis and these cues appear to be conveyed by dorsal root ganglia (DRG) in the zebrafish body: DRG-deficient larvae exhibit attenuated neurogenic responses to movement and targeted photoactivation of DRG in immobilized larvae expands the pallial pool of proliferative cells. Our results demonstrate the importance of movement in neurogenic brain growth and reveal a fundamental sensorimotor association that may couple early motor and brain development. PMID- 29528286 TI - Nociceptive interneurons control modular motor pathways to promote escape behavior in Drosophila. AB - Rapid and efficient escape behaviors in response to noxious sensory stimuli are essential for protection and survival. Yet, how noxious stimuli are transformed to coordinated escape behaviors remains poorly understood. In Drosophila larvae, noxious stimuli trigger sequential body bending and corkscrew-like rolling behavior. We identified a population of interneurons in the nerve cord of Drosophila, termed Down-and-Back (DnB) neurons, that are activated by noxious heat, promote nociceptive behavior, and are required for robust escape responses to noxious stimuli. Electron microscopic circuit reconstruction shows that DnBs are targets of nociceptive and mechanosensory neurons, are directly presynaptic to pre-motor circuits, and link indirectly to Goro rolling command-like neurons. DnB activation promotes activity in Goro neurons, and coincident inactivation of Goro neurons prevents the rolling sequence but leaves intact body bending motor responses. Thus, activity from nociceptors to DnB interneurons coordinates modular elements of nociceptive escape behavior. PMID- 29528289 TI - Magnetoencephalography as a Tool for Neuropsychiatric Research. PMID- 29528287 TI - ICE1 promotes the link between splicing and nonsense-mediated mRNA decay. AB - The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5-10% of non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens in model organisms; however, the increased complexity of gene expression regulation in human cells suggests that additional proteins may participate in the human NMD pathway. To identify proteins required for NMD, we performed a genome-wide RNAi screen against >21,000 genes. Canonical members of the NMD pathway were highly enriched as top hits in the siRNA screen, along with numerous candidate NMD factors, including the conserved ICE1/KIAA0947 protein. RNAseq studies reveal that depletion of ICE1 globally enhances accumulation and stability of NMD-target mRNAs. Further, our data suggest that ICE1 uses a putative MIF4G domain to interact with exon junction complex (EJC) proteins and promotes the association of the NMD protein UPF3B with the EJC. PMID- 29528290 TI - Opposing Effects of Cannabis Use on Electroencephalographic Measures of Auditory Repetition Suppression in Schizophrenia and Healthy Controls. PMID- 29528291 TI - Understanding Working Memory and Attentional Control Impairments in Schizophrenia. PMID- 29528292 TI - Stochastic Dynamic Models for Computational Psychiatry and Computational Neurology. PMID- 29528293 TI - Clinical Applications of Stochastic Dynamic Models of the Brain, Part I: A Primer. AB - Biological phenomena arise through interactions between an organism's intrinsic dynamics and stochastic forces-random fluctuations due to external inputs, thermal energy, or other exogenous influences. Dynamic processes in the brain derive from neurophysiology and anatomical connectivity; stochastic effects arise through sensory fluctuations, brainstem discharges, and random microscopic states such as thermal noise. The dynamic evolution of systems composed of both dynamic and random effects can be studied with stochastic dynamic models (SDMs). This article, Part I of a two-part series, offers a primer of SDMs and their application to large-scale neural systems in health and disease. The companion article, Part II, reviews the application of SDMs to brain disorders. SDMs generate a distribution of dynamic states, which (we argue) represent ideal candidates for modeling how the brain represents states of the world. When augmented with variational methods for model inversion, SDMs represent a powerful means of inferring neuronal dynamics from functional neuroimaging data in health and disease. Together with deeper theoretical considerations, this work suggests that SDMs will play a unique and influential role in computational psychiatry, unifying empirical observations with models of perception and behavior. PMID- 29528294 TI - Clinical Applications of Stochastic Dynamic Models of the Brain, Part II: A Review. AB - Brain activity derives from intrinsic dynamics (due to neurophysiology and anatomical connectivity) in concert with stochastic effects that arise from sensory fluctuations, brainstem discharges, and random microscopic states such as thermal noise. The dynamic evolution of systems composed of both dynamic and random fluctuations can be studied with stochastic dynamic models (SDMs). This article, Part II of a two-part series, reviews applications of SDMs to large scale neural systems in health and disease. Stochastic models have already elucidated a number of pathophysiological phenomena, such as epilepsy and hypoxic ischemic encephalopathy, although their use in biological psychiatry remains rather nascent. Emerging research in this field includes phenomenological models of mood fluctuations in bipolar disorder and biophysical models of functional imaging data in psychotic and affective disorders. Together with deeper theoretical considerations, this work suggests that SDMs will play a unique and influential role in computational psychiatry, unifying empirical observations with models of perception and behavior. PMID- 29528296 TI - Effects of Acute Ketamine Infusion on Visual Working Memory: Event-Related Potentials. AB - BACKGROUND: Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia. METHODS: Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task. RESULTS: Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group. CONCLUSIONS: We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade. PMID- 29528295 TI - Aberrant Oscillatory Synchrony Is Biased Toward Specific Frequencies and Processing Domains in the Autistic Brain. AB - BACKGROUND: Prevailing theories suggest that autism spectrum disorder (ASD) results from impaired brain communication, causing aberrant synchrony among neuronal populations. However, it remains debated whether synchrony abnormalities are among local or long-range circuits, are circuit specific or are generalized, reflect hypersynchrony or reflect hyposynchrony, and are frequency band-specific or are distributed across the frequency spectrum. METHODS: To help clarify these unresolved questions, we recorded spontaneous magnetoencephalography data and used a data-driven, whole-brain analysis of frequency-specific interregional synchrony in higher-functioning adolescents and adults, with 17 ASD and 18 control subjects matched on age, IQ, and sex, and equal for motion. RESULTS: Individuals with ASD showed local hypersynchrony in the theta band (4-7 Hz) in the lateral occipitotemporal cortex. Long-range hyposynchrony was seen in the alpha band (10-13 Hz), which was most prominent in neural circuitry underpinning social processing. The magnitude of this alpha band hyposynchrony was correlated with social symptom severity. CONCLUSIONS: These results suggest that although ASD is associated with both decreased long-range synchrony and increased posterior local synchrony, with each effect limited to a specific frequency band, impairments in social functioning may be most related to decreased alpha band synchronization between critical nodes of the social processing network. PMID- 29528297 TI - Opposing Effects of Cannabis Use on Late Auditory Repetition Suppression in Schizophrenia Patients and Healthy Control Subjects. AB - BACKGROUND: Chronic cannabis use may cause neurocognitive deficits and increase the risk of psychosis. Nevertheless, the effects of cannabis use on neurocognitive functioning in schizophrenia have remained largely unspecified. METHODS: Here, we studied repetition suppression of auditory event-related responses in a paired-stimulus design in a mixed sample of schizophrenia patients (n = 34) and healthy control subjects (n = 45) with chronic heavy cannabis use and schizophrenia patients (n = 33) and healthy control subjects (n = 61) without cannabis use. RESULTS: Repeated measures analysis yielded an overall significant reduction of P50 amplitude between first and second stimulus (p < .02), which was not different between the groups, a reduction of N100 amplitude, which was different for schizophrenia patients compared with healthy control subjects independent of cannabis use (p < .02), and a significant interaction between diagnosis and chronic cannabis use on the reduction of the P200 amplitude (p < .001). While chronic cannabis use was related with increased P200 suppression ratios in control subjects (with chronic cannabis use: 0.55 +/- 0.04; without chronic cannabis use: 0.40 +/- 0.03; p < .02), the reverse effect was found in schizophrenia (with chronic cannabis use: 0.36 +/- 0.05; without chronic cannabis use: 0.54 +/- 0.05; p < .02). This result remained significant after inclusion of potential confounders. Total lifetime cannabis use showed a significant correlation with the P200 suppression ratio in otherwise healthy control subjects (r = .28, p < .007). By contrast, the duration of time since last cannabis use was significantly correlated with the P200 suppression ratio in schizophrenia patients (r = .42, p < .002). CONCLUSIONS: In aggregate, these diverging effects of chronic cannabis use on P200 repetition suppression may suggest underlying alterations in the endocannabinoid system in schizophrenia. PMID- 29528298 TI - Tapeworm chromosomes: their value in systematics with instructions for cytogenetic study. AB - The history and value of cytogenetic features for addressing questions of the evolution and systematics of tapeworms (Cestoda) are briefly reviewed along with instructions for collecting karyological data. As a supplement to worm morphology, chromosome number and morphology have been helpful in determining the systematic status of some genera in the Diphyllobothriidae and species in the Bothriocephallidea. In addition, many new techniques for chromosome analysis have been recently applied in morphological and molecular studies of invertebrates, including tapeworms. Methods of molecular karyology, fluorescence in situ hybridisation, and chromosomal location of satellite DNA, microsatellites or histone genes may also provide useful data to inference of taxonomic relationships and for revealing trends or general lines of chromosome evolution. However, as karyological data are available only for few tapeworms, they are seldom an integral part of evolutionary and taxonomic studies of cestodes. A primary reason for this lack of karyological data may lie in general difficulties in working with tapeworm chromosomes. To address these problems, herein we present a well-tested, step-by-step illustrated guide on the fixation of tapeworm material and preparation of their chromosomes for cytogenetic studies. The technique requires standard glassware, few reagents and simple equipment such as needles; it can also be used on other neodermatan flatworms. PMID- 29528299 TI - High density of fox and cat faeces in kitchen gardens and resulting rodent exposure to Echinococcus multilocularis and Toxoplasma gondii. AB - The faeces of the red fox, Vulpes vulpes (Linnaeus), and the domestic cat, Felis catus (Linnaeus), can be responsible for spreading eggs of Echinococcus multilocularis Leuckart, 1863 and oocysts of Toxoplasma gondii (Nicolle et Manceaux, 1908) into the environment. The accidental ingestion of these eggs or oocysts, through consumption of raw fruits or vegetables grown in or in contact with contaminated soil, can lead to alveolar echinococcosis (AE) or toxoplasmosis in humans. The present study provides a quantitative assessment of the faecal deposition by foxes and cats in kitchen gardens where fruits and vegetables are grown and its consequences for zoonosis transmission. The density of definitive host faeces is considered as one of the main factors in infection risk for intermediate hosts. The density of fox and cat faeces, as well as the prevalence of both AE and toxoplasmosis in rodent populations (contaminated by ingestion of eggs or oocysts), were compared within and outside kitchen gardens. Our results showed that the mean density of fox faeces did not significantly differ between kitchen gardens and habitat edges (0.29 +/- 0.04 faeces/m2 vs 0.22 +/- 0.02 faeces/m2), the latter being known as an area of high fox faeceal densities. The density of cat faeces was significantly higher within the kitchen garden than outside (0.86 +/- 0.22 faeces/m2 vs 0.04 +/- 0.02 faeces/m2). The sampled kitchen gardens might therefore be considered as possible hotspots for both fox and cat defecation. Of the 130 rodents trapped, 14% were infected by at least one species of fox or cat intestinal parasite. These rodents were significantly more often infected when they were exposed to a kitchen garden. These results suggest that the deposit of fox and cat faeces in kitchen gardens would significantly impact the risk of human exposure to E. multilocularis and T. gondii. and should be prevented using effective means. PMID- 29528300 TI - Pressure-induced Lifshitz and structural transitions in NbAs and TaAs: experiments and theory. AB - High pressure Raman, resistivity and synchrotron x-ray diffraction studies on Weyl semimetals NbAs and TaAs have been carried out along with density functional theoretical (DFT) analysis to explain pressure induced structural and electronic topological phase transitions. The frequencies of first order Raman modes harden with increasing pressure, exhibiting a slope change at [Formula: see text] GPa for NbAs and [Formula: see text] GPa for TaAs. The resistivities of NbAs and TaAs exhibit a minimum at pressures close to these transition pressures and also a change in the bulk modulus is observed. Our first-principles calculations reveal that the transition is associated with an electronic Lifshitz transition at [Formula: see text] for NbAs while it is a structural phase transition from body centered tetragonal to hexagonal phase at [Formula: see text] for TaAs. Further, our DFT calculations show a structural phase transition at 24 GPa from body centered tetragonal phase to hexagonal phase. PMID- 29528301 TI - Spectroscopic evidence for two-gap superconductivity in the quasi-1D chalcogenide Nb2Pd0.81S5. AB - Low-dimensional electronic systems with confined electronic wave functions have attracted interest due to their propensity toward novel quantum phases and their use in wide range of nanotechnologies. The newly discovered chalcogenide Nb2PdS5 possesses a quasi-one-dimensional electronic structure and becomes superconducting. Here, we report spectroscopic evidence for two-band superconductivity, where soft point-contact spectroscopic measurements in the superconducting (SC) state reveal Andreev reflection in the differential conductance G. Multiple peaks in G are observed at 1.8 K and explained by the two band Blonder-Tinkham-Klapwijk model with two gaps Delta1 = 0.61 meV and Delta2 = 1.20 meV. The progressive evolution of G with temperature and magnetic field corroborates the multiple nature of the SC gaps. PMID- 29528302 TI - Magnetic field mediated conductance oscillation in graphene p-n junctions. AB - The electronic transport of graphene p-n junctions under perpendicular magnetic field is investigated in theory. Under low magnetic field, the transport is determined by the resonant tunneling of Landau levels and conductance versus magnetic field shows a Shubnikov-de Haas oscillation. At higher magnetic field, the p-n junction subjected to the quasi-classical regime and the formation of snake states results in periodical backscattering and transmission as magnetic field varies. The conductance oscillation pattern is mediated both by magnetic field and the carrier concentration on bipolar regions. For medium magnetic field between above two regimes, the combined contributions of resonant tunneling, snake states oscillation and Aharanov-Bohm interference induce irregular oscillation of conductance. At very high magnetic field, the system is subjected to quantum Hall regime. Under disorder, the quantum tunneling at low magnetic field is slightly affected and the oscillation of snake states at higher magnetic field is suppressed. In the quantum Hall regime, the conductance is a constant as predicted by the mixture rule. PMID- 29528303 TI - A framework for good biofilm reactor modeling practice (GBRMP). AB - A researcher or practitioner can employ a biofilm model to gain insight into what controls the performance of a biofilm process and for optimizing its performance. While a wide range of biofilm-modeling platforms is available, a good strategy is to choose the simplest model that includes sufficient components and processes to address the modeling goal. In most cases, a one-dimensional biofilm model provides the best balance, and good choices can range from hand-calculation analytical solutions, simple spreadsheets, and numerical-method platforms. What is missing today is clear guidance on how to apply a biofilm model to obtain accurate and meaningful results. Here, we present a five-step framework for good biofilm reactor modeling practice (GBRMP). The first four steps are (1) obtain information on the biofilm reactor system, (2) characterize the influent, (3) choose the plant and biofilm model, and (4) define the conversion processes. Each step demands that the model user understands the important components and processes in the system, one of the main benefits of doing biofilm modeling. The fifth step is to calibrate and validate the model: System-specific model parameters are adjusted within reasonable ranges so that model outputs match actual system performance. Calibration is not a simple 'by the numbers' process, and it requires that the modeler follows a logical hierarchy of steps. Calibration requires that the adjusted parameters remain within realistic ranges and that the calibration process be carried out in an iterative manner. Once each of steps 1 through 5 is completed satisfactorily, the calibrated model can be used for its intended purpose, such as optimizing performance, trouble-shooting poor performance, or gaining deeper understanding of what controls process performance. PMID- 29528304 TI - Estimation and evaluation of auto-flocculated algae harvesting efficiency using the population balance in turbulence model in flotation process. AB - Algae are considered water pollutants because they form algal blooms in stagnant water. Algae harvesting technology, however, can help convert them into a useful industrial material like biomass. The core technique (flocculation) separates microalgae from other flocculants, allowing for the harvest of clean and pure algal biomass. This study aims to estimate and evaluate algal separation (removal or harvesting) efficiency (X) to concurrently obtain the objectives of algal bloom management and algal particle collection. To simulate algal separation by auto-flocculation (no flocculants) related flotation, the population balance in turbulence (PBT) model is used. Model simulations are conducted under optimal conditions provided by previous studies about the biological impact factors of algae, operating parameters of the flotation process, and so on. This modeling study determines the efficiency (X) of separating algae from the water body in the separation zone after forming auto-flocculated bubble-floc agglomerates by making them collide and attach to each other in the contact zone of the flotation tank. The X is examined as a function of size distribution of agglomerates and bubbles and of the number of initially injected bubbles. Optimal conditions for forming and harvesting the agglomerates may be found through further modeling studies. PMID- 29528305 TI - Anti-fouling graphene oxide based nanocomposites membrane for oil-water emulsion separation. AB - Anti-fouling copper hydroxide nanowires (CHNs)-graphene oxide (GO) nanocomposites membrane was fabricated by a vacuum-assisted filtration self-assembly process. CHNs were covered on the surface and inserted into the interlayers of the GO nanosheets to form the rough surface and nanostructure channels. The membrane with water contact angles (CAs) of 53 degrees and oil CAs of 155 degrees exhibited superior stability, hydrophilicity, underwater superoleophobicity and ultralow oil adhesion, and hence it could separate the oil-water emulsion with a high efficiency of >99%. This membrane showed the combined advantages of high oil rejection rate and ultralow membrane fouling, making it promising for practical oil-water emulsion separation applications. PMID- 29528306 TI - The use of vertical flow constructed wetlands for the treatment of hyper eutrophic water bodies with dense cyanobacterial blooms. AB - Eutrophication often leads to the periodic proliferation of harmful cyanobacterial blooms (HCBs), which threaten the sustainability of freshwater ecosystems and lead to serious environmental, health and economic damage. Hence, it is vitally important to take effective measures to manage HCBs and associated problems. In this study, vertical flow constructed wetlands (CWs) were operated under different hydraulic loading rates (HLRs) to treat a hyper-eutrophic water body with HCBs. Six sampling ports (representing different layers) were evenly distributed along the water flow direction to study the purification processes of CWs. With HLRs ranging from 0.2 m/d to 0.8 m/d, total nitrogen (TN), total phosphorus (TP), COD, total suspended solid (TSS) and Chlorophyll a (Chl.a) were efficiently treated by CWs, and they were mainly removed at the second layer of CWs. The concentrations of two cyanobacterial metabolites (geosmin and beta cyclocitral) in the effluent were mostly below their odorous threshold concentrations. As the HLRs increased, the treatment efficiencies of the CWs decreased gradually. There was no removal of TP, Chl.a, geosmin, or beta cyclocitral at an HLR of 1.0 m/d. Under suitable HLRs, this type of CW could provide a promising way to control HCBs and associated odorous problems in hyper eutrophic water bodies. PMID- 29528307 TI - Characterization of domestic graywater and graywater solids. AB - The knowledge of loads and concentrations is fundamental for the design of graywater treatment units, but the data on the characteristics of graywater and in particular graywater solids are weak. As general design values regarding graywater treatment facilities are not available for Germany, the objective of this article is to elaborate the characteristics of graywater and graywater solids. This paper describes the results of six sampling campaigns carried out on graywater systems in the German cities Berlin, Lubeck and Kiel. All graywater samples were collected proportional to the flow and the graywater solids were gathered separately. The collected data include graywater volumes and characteristics regarding the organic pollution (chemical oxygen demand (COD), 5 day biochemical oxygen demand (BOD5)) and nutrients (total nitrogen (TN), total phosphorus (TP)). The graywater volume fluctuated depending on the location. The specific average flow was 68 litre per inhabitant per day (L/inh.d). Inhabitant specific loads of 49.3 gCODt/inh.d, 28 gBOD5/inh.d, 1 gTNt/inh.d and 0.38 gTPt/inh.d (subscript 't' = total) were found. Information about the composition of graywater solids in terms of quantity and quality is seriously lacking. Therefore, graywater solids were examined with respect to organic matter (COD) and nutrients (TN, TP). The contribution of graywater solids with particle sizes over 200 microns in relation to the total inhabitant-specific load was approximately 3-8% depending on the parameter. The qualitative and quantitative characteristics of the investigated graywater fractions may serve as a base for the estimation of design values. PMID- 29528308 TI - Synthesis of ZnWO4/Ag3PO4 p-n heterojunction photocatalyst and enhanced visible light photocatalytic applications. AB - The ZnWO4/Ag3PO4 nanocomposites synthesized by simple precipitation processes were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM) and UV-vis diffuse reflectance spectra. The results indicated that the ZnWO4 nanorods dispersed well on the surface of Ag3PO4 particles and ball-and-rod structure p-n heterojunctions were successfully fabricated. In subsequent degradation experiments of methyl orange (MO), ZnWO4/Ag3PO4 composites showed the highest photocatalytic activity compared to pure Ag3PO4 and ZnWO4, due to the presence of ZnWO4/Ag3PO4 heterojunctions, which could separate and transfer the electron-hole pairs generated by visible light and enhance the photocatalytic performance of the catalysts. The band gap structure and degradation mechanism of the enhanced photocatalytic materials are also discussed in this article. In conclusion, the ZnWO4/Ag3PO4 composite is a promising and excellent photocatalyst for the degradation of dye wastewater under visible light irradiation. PMID- 29528309 TI - Removal of Fast Green FCF dye from aqueous solutions using Flower Gel as a low cost adsorbent. AB - The purpose of this study was to investigate the removal of Fast Green FCF dye from aqueous solutions using Flower Gel in a batch adsorption process. The effect of different parameters such as pH, contact time, adsorbent dosage, stirrer speed and temperature were studied, and various isotherms including Langmuir, Freundlich and Tempkin were applied. The adsorbent characteristics were determined by microscopic analysis, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction and ultraviolet-visible (UV-vis) spectrophotometry. The results showed that the equilibrium experimental data fitted well to the Langmuir isotherm and the maximum adsorption capacity for this adsorbent was 58.82 mg/g. The adsorption kinetic data followed the pseudo-second-order kinetic model and the thermodynamic parameters of the adsorption, such as Gibbs free energy (DeltaG degrees ), enthalpy (DeltaH degrees ) and entropy (DeltaS degrees ), showed that the Fast Green FCF adsorption process by Flower Gel was spontaneous and exothermic in nature. PMID- 29528310 TI - Chemical stress from Fe salts dosing on biological phosphorus and potassium behavior. AB - In simultaneous precipitation, interaction between chemical and biological P removal could not be ignored. This work investigated effects of ferrous sulfate and Fe precipitates on metabolic behavior of bio-P and its counter cation of potassium. After dosing, mixed liquid suspended solids (MLSS) increased 9%, pH decreased from 7.35 to 7.00, sludge volume index (SVI) decreased, electrical conductivity increased. Chemical oxygen demand (COD) and NH3 removal was not affected. Fe dosing initially showed synergistic effect, and then inhibition appeared at accumulative dose above 10 mgFe/gMLSS. Both precipitate FePO4 and Fe(OH)3 deteriorated effluent P. FePO4 dissolved 35% in anaerobic phase which failed to be totally reprecipitated in oxic phase, resulting in increased effluent P. FePO4 inhibited K uptake rather than bio-P uptake. Fe(OH)3 caused reduction of bio-P release, meanwhile, its inhibition on K and bio-P uptake was greater than FePO4. Phosphorus metabolism was inhibited when sludge contained 0.15 mM FePO4 or 0.10 mM Fe(OH)3. Increased K/P molar ratio and coefficient b could be indicators for Fe residual in sludge. Intermittent dosing was suggested for wastewater treatment plant (WWTP) operation. PMID- 29528311 TI - A research on shape-controllable synthesis of Ag3PO4/AgBr and its degradation of ciprofloxacin. AB - Antibiotic ciprofloxacin is one of the commonly used broad spectrum fluoroquinolone human and veterinary drugs. Because of the overuse of human beings, the presence of ciprofloxacin has been detected in a variety of environmental matrices. To solve this problem, a facile, environmentally-friendly Ag3PO4/AgBr composite photocatalyst was synthesized by a simple precipitation method at room temperature in the presence of cetyltrimethyl ammonium bromide (CTAB). CTAB was served as surfactant and the source of bromide ions. The as prepared Ag3PO4/AgBr microspheres were characterized by means of powder X-ray diffraction (XRD), scanning electron microscope (SEM) and UV-visible diffuse reflectance spectroscopy (UV-vis DRS). The results revealed that the Ag3PO4/AgBr sample (synthesized with CTAB, 0.8 g) exhibited the highest photocatalytic activity to the photodegradation rate of 96.36%. Moreover, mechanism detection experiment indicated that h+ was the major active species in the degradation process. So the enhanced photocatalytic activity of Ag3PO4/AgBr composites is attributed to its excellent separation of photogenerated electron-hole pairs through Ag3PO4/AgBr heterojunction. Also, Ag3PO4/AgBr heterojunction has a lower band gap compared to pure Ag3PO4 and pure AgBr, so higher efficiency of light harvesting is equipped. PMID- 29528312 TI - Antimicrobial activity of ZnO-TiO2 nanomaterials synthesized from three different precursors of ZnO: influence of ZnO/TiO2 weight ratio. AB - In this study, ZnO-TiO2 nanoparticles were synthesized from three different precursors for ZnO (zinc acetate di-hydrate, zinc nitrate hexahydrate and zinc sulfate heptahydrate) and titanium (IV) isopropoxide for TiO2. The prepared nanomaterials were calcined at 500 degrees C for 3 h and characterized by various physicochemical techniques such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and transmission electron microscopy, combined with energy dispersive X-ray spectroscopy (TEM-EDS). The obtained results showed that the crystalline structure, size and morphology of the ZnO TiO2 nanoparticles are strongly influenced by the nature of the precursor of ZnO, as well as the ZnO/TiO2 weight ratio. The antibacterial and antifungal activities of the synthesized nanomaterials were evaluated, in the dark, against five multi resistant of Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella Paratyphi A) bacteria and a fungus (Candida albicans), which are pathogenic for humans. The obtained results showed that pure TiO2 anatase is inactive against the tested strains, while the addition of ZnO to TiO2 improves noticeably the effectiveness of TiO2 nanoparticles, depending on the nature of the precursor of ZnO and the ZnO/TiO2 weight ratio. PMID- 29528313 TI - Biodepuration of domestic sewage, textile effluents and acid mine drainage using starch-based xerogel from recycled potato peels. AB - Water is a finite resource. Its safety and cleanliness are highly important to meet current and future human needs. Compared to other resources, water represents a main factor to achieve development in several areas and leads to economic progress of a nation. However, in recent years, the excessive demographic and industrial growth has exacerbated water contamination. In this study, the biodepuration process of domestic sewage (DS), textile effluents (TE) and acid mine drainage (AMD) is conducted using starch-based xerogel from potato (Solanum tuberosum) peels. Results showed that the treatment is effective to achieve the reduction of 5-day biochemical oxygen demand. The most important result was the achievement of heavy metals removal for the three components. Firstly, there was a reduction of barium, zinc, and cadmium (91, 60 and 46%, respectively) for raw AMD. Secondly, there was a reduction in the levels of zinc, aluminum, and barium (89, 86 and 64%, respectively) for TE biodepuration. Finally, results showed a reduction in zinc, iron and cadmium levels (81, 78 and 57%, respectively) for DS biodepuration. PMID- 29528314 TI - Plant-endophyte synergism in constructed wetlands enhances the remediation of tannery effluent. AB - Liquid effluent produced from tanning industries is loaded with organic and inorganic contaminants, particularly heavy metals, which may cause severe damage to the ecosystem. Constructed wetland (CW) is a promising product of the research in the field of ecological engineering which helps to overcome aquatic pollution. This investigation aims to develop a plant-endophyte synergism in CW for the efficient remediation of tannery effluent. In a vertical flow CW, Brachiaria mutica was vegetated and augmented with three endophytic bacterial strains. Results showed a reduction of 82% in COD, 94% in BOD5, and 95% in Cr by plant endophyte synergism in CWs and it was significantly higher than the use of plants alone. Similarly, nutrients (N and P), lipids, ion content, SO42-, and Cl- showed similar reduction by the combined action of endophytes and B. mutica in CWs. The endophytes inoculation enhanced bacterial population in different compartments of the plants vegetated in CWs and the maximum was observed in the roots. This study revealed that plant-endophyte synergism in CWs can enhance the remediation of industrial wastewater. PMID- 29528315 TI - Improved UV/O3 method for measuring the chemical oxygen demand. AB - We improved the ultraviolet (UV)/O3-based method for measuring chemical oxygen demand (COD) in water. An on-line COD monitoring device was developed and the UV/O3 method was used to oxidize sample solutions. A model was established by using support vector machines (SVM) algorithm to estimate dissolved oxygen and CO2 in solutions. Based on the measured data by each sensor during the oxidation process and the estimated dissolved oxygen and CO2, the UV/O3-based COD test accuracy was improved. This approach overcomes many problems associated with the conventional COD determination techniques such as long analysis time, consumption of expensive and toxic reagents, and production of secondary toxic waste. The effect of important parameters on the measurement of COD was systematically investigated. The improved method was successfully applied to determine the COD of real samples from environmental water. Compared with the standard dichromate method, our UV/O3-based COD test method is more effective. The assay time of 10 15 min/sample can be readily achieved. A practical detection limit of 0.89 mg/L COD with a linear range of 1-300 mg/L was achieved under the normal conditions. PMID- 29528316 TI - Research on CFD numerical simulation and flow field characteristics of countercurrent-cocurrent dissolved air flotation. AB - Countercurrent-cocurrent dissolved air flotation (CCDAF), the popular water purification device, which consists of collision and adhesion contact zones, showed favorable flotation conditions for micro-bubble adhesion and stability. In this study, computational fluid dynamics (CFD) numerical simulation was employed to confirm that the unique CCDAF configuration create reasonable and that the flow field characteristics were good no matter for single phase or gas-liquid two phase conditions. In addition, the turbulence of the flow field was enhanced with the increasing influent load; the swirling was remarkably reduced with the increase of gas holdup. Meanwhile, a thick micro-bubble filter layer was formed in the separation zone, which favored bubble-flocs agglomerating and rising. The force analysis also showed that the cross section within the tank contribute to the uniformity of the bottom water collection as well as enlargement of the bottom outflow area, therefore improving the overall flotation performance. The simulation results revealed for the CCDAF process can provide technical guidance for engineering design and application. PMID- 29528317 TI - Increasing methane content in biogas and simultaneous value added product recovery using microbial electrosynthesis. AB - Electrosynthesis of multi-carbon compounds from the carbon dioxide present in biogas is a nascent approach towards purification of biogas. Microbial electrosynthesis (MES) cells, fabricated using different electrode materials, were operated using different electrolytes and mixed anaerobic culture as biocatalysts in the cathodic chamber under an applied cathode potential of -0.7 V vs standard hydrogen electrode (SHE). The rate of production of acetate, isobutyrate, propionate and 2-piperidinone from reduction of CO2 in the cathodic chamber of the MES was 0.81 mM/day, 0.63 mM/day, 0.44 mM/day and 0.53 mM/day, respectively. As methane was also present in the biogas, methyl derivatives of these acids were also found in traces in catholyte. It was observed that the use of nickel foam as an anode, 1 M NiSO4 solution as anolyte, graphite felt as a cathode, phosphate buffer solution as catholyte at a pH of 5.2 proved to be the best possible combination for MES for this study to get enhanced product yield at higher energy efficiency. PMID- 29528318 TI - Adsorption of methyl orange dye onto biochar adsorbent prepared from chicken manure. AB - In this work, the biochar adsorbent carboxymethyl cellulose (CMC), was prepared from the pyrolysis (600 degrees C, 120 min) of chicken manure for the removal of methyl orange (MO) from aqueous solution, and its physicochemical properties were characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectra (FTIR). The experimental parameters including agitation speed, initial solution pH, biochar dosage and contact time on the adsorption properties of MO from aqueous solution onto CMC were investigated in batch experiments. The kinetic adsorption of different initial concentration could be accurately described by the pseudo-second-order model and the overall rate process was apparently influenced by external mass transfer and intra-particle diffusion. Furthermore, the Langmuir isotherm model showed a better fit with equilibrium data (R2 > 0.99), with the maximum adsorption capacity of 39.47 mg.g-1 at 25 degrees C. Moreover, the thermodynamic parameters indicated that the adsorption of MO onto CMC was a spontaneous and endothermic process. The results of this study indicated that CMC could be used as a promising biomass adsorbent material for aqueous solutions containing MO. PMID- 29528319 TI - Preparation of bio-based magnetic adsorbent and application for efficient removal of Cd(II) from water. AB - A novel magnetic bio-adsorbent (MCIA) was developed, characterized and tested for its Cd(II) removal from aqueous solution. MCIA could be easily separated from the solution after equilibrium adsorption due to its super-paramagnetic property. The functional and magnetic bio-material was an attractive adsorbent for the removal of Cd(II) from aqueous solution owing to the abundant adsorption sites, amino group and oxygen-containing groups on the surface of Cyclosorus interruptus. The experimental results indicated that the MCIA exhibited excellent adsorption ability and the adsorption process was spontaneous and endothermic. The adsorption isotherm was consistent with the Langmuir model. The adsorption kinetic fitted the pseudo-second-order model very well. The maximum adsorption capacity of Cd(II) onto MCIA was 40.8, 49.4, 54.6 and 56.6 mg/g at 293, 303, 313 and 323 K, respectively. And the MCIA exhibited an excellent reusability and impressive regeneration. Therefore, MCIA could serve as a sustainable, efficient and low-cost magnetic adsorbent for Cd(II) removal from aqueous solution. PMID- 29528320 TI - Adsorption of tetracycline from water using glutaraldehyde-crosslinked electrospun nanofibers of chitosan/poly(vinyl alcohol). AB - In this work, the preparation and characterization of glutaraldehyde-crosslinked electrospun nanofibers of chitosan/poly(vinyl alcohol) (GCCPN) as a new adsorbent for tetracycline (TC) is reported. Electrospun nanofibers of chitosan/poly(vinyl alcohol) (PVA) were prepared by employing a 75:25 volumetric ratio of chitosan:PVA, voltage of 30 kV, collection distance of 10 cm, and injection flow rate of 2 mL/h. Then, the nanofibers were crosslinked via applying the glutaraldehyde on them for 3 h at 40 degrees C. The nanofibers were characterized using scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction. Uniform beadless nanofibers with minimum diameters of 3-11 and 6-18 nm were obtained before and after crosslinking, respectively. Then the applicability of the synthesized GCCPN for removal of TC from aqueous solutions was investigated. The response surface method was applied to evaluate the influence of pH (6-12), TC concentration (50 250 mg/L) and the adsorbent dose (0.05-0.25 g in 20 mL solution) on the adsorption characteristics of GCCPN. The maximum adsorption capacity was 102 mg/g. The adsorption kinetics was explained most effectively by the pseudo-second order model. The adsorption data of TC on the GCCPN surface was explained well by the Langmuir isotherm model. PMID- 29528321 TI - Removal of sulfate from wet FGD wastewater by co-precipitation with calcium hydroxide and sodium aluminate. AB - Chemical precipitation method was adopted to remove sulfate from wet flue gas desulfurization (FGD) wastewater and mixtures of Ca(OH)2 (CH) and NaAlO2 (SA) were used as precipitants. The mechanisms of sulfate removal were explored according to the experimental and simulated results. These showed that three kinds of precipitations, which were gypsum, ettringite and co-precipitation onto aluminum hydroxides, were formed when sulfate in water reacted with CH and SA. The optimum operation condition for removing sulfate was that the molar ratio of CH/SA was 2, the initial pH value 5, the precipitant dosage 15 g/L, the reaction time 20 min, and the reaction temperature 55 degrees C. The sulfate was reduced from 4,881 mg/L to 784 mg/L under the optimized condition. In addition, the heavy metals and fluoride were also mostly removed. The post treatments of the supernatant illustrated that removal of sulfate from wet FGD wastewater by co precipitation with CH and SA was a better choice. PMID- 29528322 TI - Numerical modeling on sediment capture in catch basins. AB - Catch basins are designed to convey surface runoff into sewer systems. They are also found to be effective in retaining sediments. A number of factors can influence catch basin sediment capture efficiency, such as sediment size distribution, flow hydraulics and catch basin design. To better understand the influence of these factors, numerical simulations using the Eulerian-Lagrangian method were conducted to provide insights into flow fields and to predict sediment capture rates. The numerical model was validated using previous experimental measurements of flow field and sediment capture rates for sediment sizes larger than 0.25 mm. The influence of catch basin designs, including the bottom sump and inflow arrangements, was also studied, and an equation was developed for predicting the capture rate. PMID- 29528323 TI - The effect of mixing on fermentation of primary solids, glycerol, and biodiesel waste. AB - In this study, the effect of mixing on volatile fatty acid (VFA) production and composition was investigated through running five identical bench-scale reactors that were filled with primary solid and dosed with either pure glycerol or biodiesel waste. Experimental results revealed that there was an inverse correlation between the mixing intensity and the VFA production. The total VFA production in the un-mixed reactor was 9,787 +/- 3,601 mg COD/L, whereas in the reactor mixed at 100 rpm this dropped to 3,927 +/- 1,175 mg COD/L, while both types of reactor were dosed with pure glycerol at the beginning of each cycle to reach the initial concentration of 1,000 mg/L (1,217 mg COD/L). Propionic acid was the dominant VFA in all the reactors except the reactor mixed at 30 rpm. It is hypothesized that low mixing facilitated hydrogen transfer between obligate hydrogen producing acetogens (OHPA) and hydrogen consuming acidogens in these non methanogenic reactors. Also, in a narrower range of mixing (0 or 7 rpm), the total VFA production in biodiesel waste-fed reactors was considerably higher than that of pure glycerol-fed reactors. PMID- 29528324 TI - Preparation of chitosan/amine modified diatomite composites and adsorption properties of Hg(II) ions. AB - A green functional adsorbent (CAD) was prepared by Schiff base reaction of chitosan and amino-modified diatomite. The morphology, structure and adsorption properties of the CAD were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy and Brunauer Emmett Teller measurements. The effect of pH value, contact time and temperature on the adsorption of Hg(II) ions for the CAD is discussed in detail. The experimental results showed that the CAD had a large specific surface area and multifunctional groups such as amino, hydroxyl and Schiff base. The optimum adsorption effect was obtained when the pH value, temperature and contact time were 4, 25 degrees C and 120 min, respectively, and the corresponding maximum adsorption capacity of Hg(II) ions reached 102 mg/g. Moreover, the adsorption behavior of Hg(II) ions for the CAD followed the pseudo-second-order kinetic model and Langmuir model. The negative DeltaG0 and DeltaH0 suggested that the adsorption was a spontaneous exothermic process. PMID- 29528325 TI - Significance of buoyancy in turbulence closure for computational fluid dynamics modelling of ultraviolet disinfection in maturation ponds. AB - Buoyancy-driven turbulent dispersion in a maturation pond is studied using a combination of field measurements and computational fluid dynamics. Modelling flow in maturation ponds requires turbulent closure models because of the large physical size and the need to model on diurnal timescales. Simulation results are shown to be more sensitive to the inclusion of a buoyancy production term appearing in the turbulent transport equations than to the model choice. Comparisons with experimental thermal profiles show that without this term, thermal mixing is over-predicted. When including the term, stratification occurs but thermal mixing is under-predicted in the lower water column. In terms of pond performance, the effect of this term is to cause increased surface die-off of Escherichia coli during sunlight hours due to the generation of stratification. It is recommended that future modelling consider and implement this term. PMID- 29528326 TI - Scale-up of a packed bed column for wastewater treatment. AB - After checking the success of the biosorption process to remove heavy metals from wastewater using olive tree pruning as a cheap biosorbent in the laboratory scale, the scale-up is necessary to progress towards industrial applications chance. The aim of this work was the study of the effect of scale-up in the process of biosorption of Pb(II) with olive tree pruning in a packed bed column. Experiments were performed using two different scale-up criteria and results obtained in both scales were compared. Similar parameters were obtained for each pair of equivalent tests, with a slightly advanced of the obtained breakthrough curves in the pilot plant. The experimental results were fitted by the Thomas model and the obtained mean values were KTh = 0.187 mL/min.mg and q0 = 20.59 mg/g for criterion 1 and KTh = 0.217 mL/min.mg and q0 = 20.27 mg/g for criterion 2. Finally, the mathematical model was applied to simulate industrial applications and it was obtained that under optimal operative conditions, a column according to the criterion 1 was able to operate 2.3 h, and a column according to the criterion 2 was able to operate for 3.6 h. PMID- 29528327 TI - ADM1 modelling of large-scale covered in-ground anaerobic reactor treating sugarcane vinasse. AB - In this paper, we demonstrate in a clear procedure the application of the Anaerobic Digestion Model No. 1 (ADM1) to model a large-scale covered in-ground anaerobic reactor (Cigar), processing sugarcane vinasse from a biorefinery in Brazil. The biochemical make-up (carbohydrates, proteins, and lipids) of the substrate was analysed based on the food industry standards. Two distinct subsets of data, based on the sugarcane harvest season for bioethanol and sugar production in 2012 and 2014, were used to direct and cross validate the model, respectively. We fitted measured data by estimating two key parameters against biogas flow rate: the degradation extent (fd) and the first order hydrolysis rate coefficient (khyd). By cross validation we show that the fitted model can be generalised to represent the behaviour of the reactor under study. Therefore, motivated by practical and industrial application of ADM1, for both different reactors types and substrates, we show aspects on the implementation of ADM1 to a specific large-scale reactor for anaerobic digestion of sugarcane vinasse. PMID- 29528328 TI - Heterogeneous catalytic ozonation of hydroquinone using sewage sludge-derived carbonaceous catalysts. AB - This study converted sewage sludge into a carbonaceous catalyst via pyrolysis and employed it in the ozonation of hydroquinone. The catalyst was characterized by Mossbauer spectroscopy, X-ray photoelectron spectroscopy, temperature programmed desorption, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. Intermediate products were detected by gas chromatography-mass spectrometry, and a pathway for hydroquinone degradation was proposed. The results showed that sludge pyrolyzed at 700 degrees C promoted hydroquinone degradation, compared with commercial activated carbon derived from coal. When the catalyst dose was 0.5 g/L, the hydroquinone (200 mg/L) removal rate reached 97.86% after exposure to ozone (the ozone concentration was 17 mg/L and the flow rate was 50 mL/min) for 60 min. The results indicated that basic groups contributed to the catalysis. PMID- 29528329 TI - Assessment of toxic metals in water and sediment of Pasur River in Bangladesh. AB - This study was conducted to assess the levels of toxic metals like arsenic (As), chromium (Cr), cadmium (Cd), and lead (Pb) in water and sediments of the Pasur River in Bangladesh. The ranges of Cr, As, Cd, Pb in water were 25.76-77.39, 2.76 16.73, 0.42-2.98 and 12.69-42.67 MUg/L and in sediments were 20.67-83.70, 3.15 19.97, 0.39-3.17 and 7.34-55.32 mg/kg. The level of studied metals in water samples exceeded the safe limits of drinking water, indicating that water from this river is not safe for drinking and cooking. Certain indices, including pollution load index (PLI) and contamination factor (Cif) were used to assess the ecological risk. The PLI indicated progressive deterioration of sediments by the studied metals. Potential ecological risks of metals in sediment indicated low to considerable risk. However, the Cif values of Cd ranged from 0.86 to 8.37 revealed that the examined sediments were strongly impacted by Cd. Considering the severity of potential ecological risk (PER) for single metal (Eir), the descending order of contaminants was Cd > Pb > As > Cr. According the results, some treatment scheme must formulate and implement by the researchers and related management organizations to save the Pasur River from metals contamination. PMID- 29528330 TI - Hydraulic simulation of perforated pipe systems feeding vertical flow constructed wetlands. AB - For successfully operating a vertical flow constructed wetland, the uniform distribution of wastewater on the surface of the soil filter is essential. In research, however, this aspect is often overlooked. This study presents a methodology for assessing discharge uniformity from perforated pipe systems via hydraulic modeling. First, the requirements and conditions for the simulation of perforated pipe systems are investigated and the model basics are explained. Then the whole process of model build-up, calibration, application and analysis is presented and discussed. The modeling is done by the software EPANET and supported by pressure measurements in the pipe system of a small wetland treating domestic sewage. A crucial factor in the modeling process is the choice of loss coefficients in dividing junctions. Different approaches for calculating such coefficients are compared. Model calibration is undertaken via the multicriterion optimization algorithm NSGA-II. By calibrating two parameters, a reasonable goodness of fit with the measured pressure values was achieved. Model results show that distribution uniformity of the pipe system in question is poor. An outlook on potential applications of hydraulic modeling of perforated pipe systems in vertical flow constructed wetlands is given. PMID- 29528331 TI - Novel p-n junction UiO-66/BiOI photocatalysts with efficient visible-light induced photocatalytic activity. AB - Novel visible-light-induced UiO-66/BiOI photocatalysts with a p-n junction structure have been prepared for the first time through a facile hydrothermal method. The prepared photocatalysts were characterized using the powder X-ray diffraction, high resolution transmission electron microscopy, scanning electron microscopy, UV-visible diffuse reflectance spectra, and N2 adsorption-desorption (Brunauer-Emmett-Teller) techniques respectively. The photodegradation performances of UiO-66/BiOI photocatalysts were evaluated by photodegrading salicylic acid under visible-light irradiation. The UiO-66/BiOI composites displayed much higher photocatalytic efficiencies than pure BiOI under visible light. When the content of UiO-66 was 5.2 wt%, the composite (UiO-66/BiOI-2) has the best photocatalytic activity. Most of the salicylic acid molecules can be degraded in 100 min. The degradation rate of UiO-66/BiOI-2 samples is higher than single BiOI and UiO-66. The enhanced photocatalytic performance of UiO-66/BiOI may be ascribed to the formation of p-n heterojunctions between BiOI and UiO-66, which facilitates the transfer and separation of the photogenerated charge carriers. After recycling of the photocatalyst for five times for the photodegradation of salicylic acid, more than 85% of salicylic acid could still be degraded in the fifth cycle, implying that the as-prepared photocatalysts are highly stable. PMID- 29528332 TI - Evaluation of Ficus benjamina wood chip-based fungal biofiltration for the treatment of Tequila vinasses. AB - This study was focused on the application of an aerobic biofiltration (BF) with Ficus benjamina wood chips as support medium, inoculated with two basidiomycete fungi, Phanerochaete chrysosporium (BF 1) and Trametes versicolor (BF 2), to treat Tequila vinasses from a Tequila industry. The biofiltration system was compared with a biofilter system without basidiomycete fungi (BF W), in order to determine the influence of fungi on the treatment of vinasses. Three different vinasses/water ratios (30/70, 40/60, and 50/50) were evaluated. The maximum removals of chemical oxygen demand (COD) obtained during each operation step were 72% (BF 1), 72% (BF 2), and 8% (BF W) for 30 vinasses/70 water; 72% (BF 1), 73% (BF 2), and 66% (BF W) for 40 vinasses/60 water; and 22% (BF 1), 20% (BF 2), and 18% (BF W) for 50 vinasses/50 water. The total organic carbon (TOC) removal was significantly increased using a volumetric organic load of 5.5 kg COD m-3d-1. During the operation of the biofilters, the enzymatic activity of laccase was present, even at the step of highest concentration of vinasses. PMID- 29528333 TI - Effect of source water/wastewater quality on bacterial removal during electrocoagulation. AB - Bacterial removal during electrocoagulation (EC) was investigated employing samples from four different water/wastewater sources, namely, greywater, river water, secondary treated sewage and tap water spiked with Escherichia coli. Effects of current density and electrolysis time on the bacterial removal with aluminium electrodes were evaluated. For greywater, river water and secondary treated sewage, total coliform and E. coli removal efficiencies were not significantly different for the tested samples and varied in the range of 2.22 2.53 log10 units at a current density of 1 mA/cm2 and electrolysis time of 30 min. Higher removals up to 3.80 log10 units could be obtained at higher current density of 5 mA/cm2. Heterotrophic bacterial removals were higher compared with coliforms for the tested samples. Further, higher removal was obtained with spiked E. coli in tap water compared with naturally occurring coliforms in other samples. A comparison of bacterial removal by chemical coagulation (CC) employing alum at optimum dose with that by EC with 1 mA/cm2 current density and 30 min electrolysis time showed significantly higher removal by EC (2.22-2.53 log10 removal) compared with CC (1.40-1.80 log10 removal) for the three tested samples. Upon storage up to 48 h, no significant regrowth/decay of organisms was observed in the EC-treated samples. PMID- 29528334 TI - A novel image processing-based system for turbidity measurement in domestic and industrial wastewater. AB - Wastewater treatment facilities are continually challenged to meet both environmental regulations and reduce running costs (particularly energy and staffing costs). Improving the efficiency of operational monitoring at wastewater treatment plants (WWTPs) requires the development and implementation of appropriate performance metrics; particularly those that are easily measured, strongly correlate to WWTP performance, and can be easily automated, with a minimal amount of maintenance or intervention by human operators. Turbidity is the measure of the relative clarity of a fluid. It is an expression of the optical property that causes light to be scattered and absorbed by fine particles in suspension (rather than transmitted with no change in direction or flux level through a fluid sample). In wastewater treatment, turbidity is often used as an indicator of effluent quality, rather than an absolute performance metric, although correlations have been found between turbidity and suspended solids. Existing laboratory-based methods to measure turbidity for WWTPs, while relatively simple, require human intervention and are labour intensive. Automated systems for on-site measuring of wastewater effluent turbidity are not commonly used, while those present are largely based on submerged sensors that require regular cleaning and calibration due to fouling from particulate matter in fluids. This paper presents a novel, automated system for estimating fluid turbidity. Effluent samples are imaged such that the light absorption characteristic is highlighted as a function of fluid depth, and computer vision processing techniques are used to quantify this characteristic. Results from the proposed system were compared with results from established laboratory-based methods and were found to be comparable. Tests were conducted using both synthetic dairy wastewater and effluent from multiple WWTPs, both municipal and industrial. This system has an advantage over current methods as it provides a multipoint analysis that can be easily repeated for large volumes of wastewater effluent. Although the system was specifically designed and tested for wastewater treatment applications, it could have applications such as in drinking water treatment, and in other areas where fluid turbidity is an important measurement. PMID- 29528336 TI - What goes around comes around: modeling malaria transmission from humans back to mosquitos. AB - Malaria, caused by mosquito-transmitted Plasmodium parasites, continues to take a major toll on global health. The development of drugs and vaccines that reduce malaria transmission from humans back to mosquitos could contribute to the control and eventual eradication of malaria, but research models for the early clinical evaluation of candidate interventions are lacking. In this issue of the JCI, Collins and colleagues report the successful transmission of Plasmodium falciparum parasites from humans to mosquitoes during controlled human malaria infection, thus providing a potential tool to accelerate the development of much needed transmission-blocking drugs and vaccines. PMID- 29528335 TI - Insulin resistance causes inflammation in adipose tissue. AB - Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa. PMID- 29528337 TI - Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry. AB - Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic "mimics" using subunits that do not exist in the natural world. We developed a platform based on D-amino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus. This nonnatural peptide was highly stable in human serum and gastric acid, reflecting an intrinsic resistance to physical and enzymatic degradation. In vitro, the synthetic agonist stimulated and expanded an archetypal repertoire of polyfunctional human influenza virus specific CD8+ T cells. In vivo, specific responses were elicited in naive humanized mice by subcutaneous vaccination, conferring protection from subsequent lethal influenza challenge. Moreover, the synthetic agonist was immunogenic after oral administration. This proof-of-concept study highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery. PMID- 29528339 TI - Cell-based molecularly targeted therapy: targeting oncoproteins with T cell receptor gene therapy. AB - As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be "druggable," tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation. T cells genetically engineered to express an anti-BRAFV600E T cell receptor (TCR) from the patient demonstrated recognition of an epitope that spanned the BRAFV600E mutation. These findings suggest that BRAFV600E might be targeted therapeutically with adoptive transfer of anti-BRAFV600E T cells. This research supports the emerging therapeutic paradigm of targeting oncogenic drivers with T cell immunotherapy. PMID- 29528340 TI - On the distinct binding modes of expansin and carbohydrate-binding module proteins on crystalline and nanofibrous cellulose: implications for cellulose degradation by designer cellulosomes. AB - Transformation of cellulose into monosaccharides can be achieved by hydrolysis of the cellulose chains, carried out by a special group of enzymes known as cellulases. The enzymatic mechanism of cellulases is well described, but the role of non-enzymatic components of the cellulose-degradation machinery is still poorly understood, and difficult to measure using experiments alone. In this study, we use a comprehensive set of atomistic molecular dynamics simulations to probe the molecular details of binding of the family-3a carbohydrate-binding module (CBM3a) and the bacterial expansin protein (EXLX1) to a range of cellulose substrates. Our results suggest that CBM3a behaves in a similar way on both crystalline and amorphous cellulose, whereas binding of the dual-domain expansin protein depends on the substrate crystallinity, and we relate our computed binding modes to the experimentally measured features of CBM and expansin action on cellulose. PMID- 29528338 TI - LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions. AB - UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1)+ NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance. PMID- 29528342 TI - Chemical synthesis of two-dimensional atomic crystals, heterostructures and superlattices. AB - Two-dimensional atomic crystals (2DACs) have attracted intense recent interest. With a nearly perfect crystalline structure and dangling-bond free surface, these atomically thin materials have emerged as a new material platform for fundamental materials science and diverse technology opportunities at the limit of single atom thickness. Over the past decade, a wide range of 2DACs has been prepared by mechanically exfoliating bulk layered crystals, which has fueled the rapid progress of the entire field in terms of fundamental physics and basic device demonstrations. However, studies to date are largely limited to mechanically exfoliated flakes, which are clearly not scalable for practical applications. The chemical synthesis of these materials has been lagging far behind fundamental property investigations or novel device demonstrations, which limits further progress of the field. To explore the full potential of 2DACs requires a robust synthesis of these atomically thin materials and scalable construction of complex heterostructures with designed spatial modulation of chemical compositions and electronic structures. The extreme aspect ratio and highly delicate nature of the atomically thin crystals pose a significant synthetic challenge beyond traditional bulk crystals and have motivated considerable efforts worldwide. Here we will review the recent advances, challenges and future perspective of the chemical synthesis of 2DACs, heterostructures and superlattices. PMID- 29528341 TI - Cell density overrides the effect of substrate stiffness on human mesenchymal stem cells' morphology and proliferation. AB - The effect of substrate stiffness on the cellular morphology, proliferation, and differentiation of human mesenchymal stem cells (hMSCs) has been extensively researched and well established. However, the majority of these studies are done with a low seeding density where cell to cell interactions do not play a significant role. While these conditions permit an analysis of cell-substratum interactions at the single cell level, such a model system fails to capture a critical aspect of the cellular micro-environment in vivo, i.e. the cell-cell interaction via matrix deformation (i.e., strain). To address this question, we seeded hMSCs on soft poly-acrylamide (PAA) gels, at a seeding density that permits cells to be mechanically interacting via the underlying substrate. We found that as the intercellular distance decreases with the increasing seeding density, cellular sensitivity towards the substrate rigidity becomes significantly diminished. With the increasing seeding density, the cell spread area increased on a soft substrate (500 Pa) but reduced on an even slightly stiffer substrate (2 kPa) as well as on glass making them indistinguishable at a high seeding density. Not only in terms of cell spread area but also at a high seeding density, cells formed mature focal adhesions and prominent stress fibres on a soft substrate similar to that of the cells being cultured on a stiff substrate. The decreased intercellular distance also influenced the proliferation rate of the cells: higher seeding density on the soft substrate showed cell cycle progression similar to that of the cells on glass substrates. In summary, this paper demonstrates how the effect of substrate rigidity on the cell morphology and fate is a function of inter-cellular distance when seeded on a soft substrate. Our AFM data suggest that such changes happen due to local strain stiffening of the soft PAA gel, an effect that has been rarely reported in the literature so far. PMID- 29528343 TI - High-efficiency, deep blue ZnCdS/CdxZn1-xS/ZnS quantum-dot-light-emitting devices with an EQE exceeding 18. AB - We report a facile and robust synthesis of ZnCdS core/shell quantum dots (QDs) with thick CdxZn1-xS (x = constant) uniform alloys as an intermediate shell which can provide effective confinement of excitons within the ZnCdS cores and ultrathin ZnS outermost shell to improve the stability by epitaxial growth at a relatively high temperature. The resulting nearly monodisperse ZnCdS/CdxZn1 xS/ZnS core/shell QDs have high photoluminescence quantum yield (near to 100%) and high color purity (full width at half maximum (FWHM) < 18 nm). More importantly, the ZnCdS/CdxZn1-xS/ZnS core/shell QDs have good chemical/photochemical stability and more efficient carrier transport performance compared with ZnCdS/ZnS core/shell QDs. Two types of QDs of ZnCdS/ZnS and ZnCdS/CdxZn1-xS/ZnS were incorporated into the solution-processed hybrid QD-based light-emitting device structure as the emissive layer. We find that the presence of the CdxZn1-xS shell makes a profound impact on device performances such as the external quantum efficiency and current efficiency. The corresponding light emitting diodes exhibited a high EQE exceeding 18%, a peak current efficiency of 3.4 cd A-1 and low efficiency roll-off. Such excellent results of ZnCdS/CdxZn1 xS/ZnS-based QLEDs are likely attributable to the QD's high PL QY and very thin ZnS outermost shell which did not sacrifice the charge injection efficiency in QLEDs. PMID- 29528344 TI - Two-photon graphene quantum dot modified Gd2O3 nanocomposites as a dual-mode MRI contrast agent and cell labelling agent. AB - For obtaining high-resolution macroscopical anatomical information and high sensitivity microscopical optical signals, it is highly desirable to develop dual modality magnetic resonance imaging (MRI) and fluorescent probes in medical imaging simultaneously. In this study, Gd2O3 nanoparticles were modified with two photon graphene quantum dots (GQD), integrating a magnetic resonance imaging (MRI) contrast agent with two-photon imaging functionality into one nanoprobe. A photoluminescence study indicated that the GQD modification process integrated MRI properties with both one-photon and two-photon imaging properties. Gd2O3/GQD nanocomposites showed a significantly improved longitudinal relaxivity (r1 = 15.995 mM-1 s-1) in comparison with commercial Magnevist (Gd-DTPA, r1 = 4.5 mM-1 s-1) and some reported papers. Excellent water solubility and good biocompatibility make Gd2O3/GQD nanocomposites an ideal dual-modal imaging agent, suggesting their potential and significant biological and clinical applications in the future. PMID- 29528345 TI - From a ureidopyrimidinone containing organic precursor to excavated iron-nitrogen codoped hierarchical mesoporous carbon (Ex-FeN-MC) as an efficient bifunctional electrocatalyst. AB - A hierarchical excavated iron-nitrogen codoped mesoporous carbon (Ex-FeN-MC) electrocatalyst has been successfully synthesized by pyrolysis of the unique ureidopyrimidinone containing organic precursor MAMIS by using silica as the mesoporous template and iron nitrate as the source of iron. The selected organic precursor has multifunctionalities with diverse distribution of nitrogen and oxygen species which constitute interesting features to prepare the Ex-FeN-MC electrocatalyst. The as-prepared Ex-FeN-MC material shows unexpectedly higher catalytic activities towards ORR/OER performances with an overpotential of 250 mV for OER in alkaline solution at a current density of 10 mA cm-2, while the ORR activity is almost similar to that of commercial Pt/C. It is believed that the excellent electrochemical performance results from the synergic contribution of the hierarchical uniform mesoporous structure, evenly distributed iron nanoparticles and high density of Ex-FeN-MC catalytically active sites. The presence of the hierarchical uniform mesoporous structure considerably accelerates the mass transfer and efficiently promotes the full utilization of active sites. Furthermore, it also possesses amorphous carbon in coexistence with lattice graphitic carbon which also enhanced the ORR/OER performances. Our research findings can surely provide a new insight to design highly active ORR/OER electrocatalysts by utilizing more novel organic precursors to provide interesting characteristics to electrocatalysts, as well as open up a route for constructing unique multifunctional materials with mesoporous architectures for electrocatalysis and supercapacitor applications. PMID- 29528346 TI - Influence of anchoring in the phase behaviour of discotic liquid crystals. AB - Molecular dynamics simulations were performed for a Gay-Berne discotic fluid confined in a slab geometry for two different anchorings: homeotropic (face-on) and planar (edge-on), and for two different confinement lengths. Our results show that the behaviour of the more confined system in the temperature region of the isotropic-nematic transition is critically influenced by the presence of the walls: the growth of the solid-liquid crystal interface spans over the entire width of the cell, and the character of the transition is changed from first order to continuous. For all the confined systems studied, we observe a higher nematic-columnar transition temperature and a smaller nematic phase region in the phase diagram, as compared with the behaviour of the infinite system. PMID- 29528347 TI - Molecular shape as a means to control the incidence of the nanostructured twist bend phase. AB - Liquid crystalline phases with a spontaneous twist-bend modulation are most commonly observed for dimers and bimesogens with nonamethylene spacers. In order to redress this balance we devised a simple chemical intermediate that can be used to prepare unsymmetrical bimesogens; as a proof of concept we prepared and studied eleven novel materials with all found to exhibit the twist-bend phase and exhibit a linear relationship between TN-I and TTB-N. A computational study of the conformational landscape reveals the octamethyleneoxy spacer to have a broader distribution of bend-angles than the nonamethylene equivalent, leading to reductions in the thermal stability of the TB phase. This result indicates that a tight distribution of bend-angles should stabilise the TB phase and lead to direct TB-Iso phase transitions, and conversely a broader distribution should destabilise the TB phase which may allow new states of matter that are occluded by the incidence of this phase to be revealed. PMID- 29528348 TI - Discovery of a self-assembling and self-adjuvant lipopeptide as a saccharide-free peptide vaccine targeting EGFRvIII positive cutaneous melanoma. AB - Recently, tumor immunotherapy has achieved great progress in the treatment of hematological and solid neoplasms. The DC vaccines, KLH-conjugated vaccines or glycosylated peptide vaccines can efficiently induce immune responses against tumors. In the current study, we have discovered cholesteryl PADRE-EGFRvIII epitope-conjugated lipopeptide self-assembled micelles as a potential self adjuvant vaccine against cutaneous melanoma. The lipopeptide vaccines were synthesized using a standard solid phase peptide synthesis method, and these vaccines could elicit both a humoral and a cellular immune response to EGFRvIII positive melanoma cells. Their high humoral immunoreaction stimulation properties in combination with their cytotoxic T-cell eliciting properties provide them with potent tumor inhibitory capacity. In therapeutic and preventive xenograft models of B16-EGFRvIII melanoma cells, the self-adjuvant lipopeptide vaccine micelles efficiently prevented tumor growth as well as tumorigenesis. Our results provide a novel platform for eliciting immune responses to non-antigenic cancer-related epitopes in peptide cancer vaccine discovery and development. PMID- 29528352 TI - A single-phase all-solid-state lithium battery based on Li1.5Cr0.5Ti1.5(PO4)3 for high rate capability and low temperature operation. AB - We report a battery made from a single material using Li1.5Cr0.5Ti1.5(PO4)3 as the anode, cathode and electrolyte. A high rate capability at room temperature and very low-temperature operation (233 K) were possible as a result of the superior ionic conductivity and low interfacial resistance obtained from the single-phase cell design. PMID- 29528353 TI - Synthesis of thioureido peptidomimetics employing alkyl azides and dithiocarbamates. AB - An unprecedented approach for the assembly of thioureido peptidomimetics is developed employing alkyl azides and dithiocarbamates. Dithiocarbamates react with alkyl azides with the liberation of N2 and elemental sulfur thereby leading to thiourea in a traceless manner. Thioureido peptidomimetics are thus furnished in good yields with no epimerization. This process is mild, free from the use of a base, scalable and step economic. The practicability of this methodology has been highlighted by the synthesis of N,N'-orthogonally protected thioureido peptidomimetics. PMID- 29528355 TI - A 18F radiolabelled Zn(ii) sensing fluorescent probe. AB - A selective fluorescent probe for Zn(ii), AQA-F, has been synthesized. AQA-F exhibits a ratiometric shift in emission of up to 80 nm upon binding Zn(ii) ([AQA F] = 0.1 mM, [Zn(ii)Cl2] = 0-300 MUM). An enhancement of quantum yield from Phi = 4.2% to Phi = 35% is also observed. AQA-F has a binding constant, Kd = 15.2 MUM with Zn(ii). This probe has been shown to respond to endogenous Zn(ii) levels in vitro in prostate and prostate cancer cell lines. [18F]AQA-F has been synthesized with a radiochemical yield of 8.6% and a radiochemical purity of 97% in 88 minutes. AQA-F shows the potential for a dual modal PET/fluorescence imaging probe for Zn(ii). PMID- 29528356 TI - Synthesis and application of a new hexamethyl-1,1'-spirobiindane-based chiral bisphosphine (HMSI-PHOS) ligand in asymmetric allylic alkylation. AB - The emerging and versatile application of chiral bisphosphine ligands in diverse asymmetric reactions has resulted in great demand for novel bisphosphine ligands containing different innovative backbones. Herein, a new type of chiral spiro bisphosphine ligand (HMSI-PHOS) has been developed on the basis of a hexamethyl 1,1'-spirobiindane motif. A series of new HMSI-PHOS ligands were synthesized and used in Pd-catalyzed asymmetric allylic alkylation reactions, and moderate to good yields and enantioselectivities were obtained with phenyl substituted ligands. PMID- 29528357 TI - 2-Deoxyglycosyl 3-benzoylpropionates as novel donors for the direct and stereoselective synthesis of 2-deoxy-glycosides. AB - Lewis acid mediated stereoselective synthesis of 2-deoxy-O-glycosides has been demonstrated using 2-deoxyglycosyl 3-benzoylpropionates as novel glycosyl donors. These newly developed donors are easily synthesized from simple glycals, are stable at room temperature and react with ease to provide products with high stereoselectivity. These donors can be successfully utilized with all types of acceptors (primary, secondary and tertiary alcohols) for the synthesis of 2-deoxy glycosides. Additionally, these newly developed glycosyl donors are also efficient for the synthesis of trisaccharides. PMID- 29528358 TI - Charging nanoparticles: increased binding of Gd@C82(OH)22 derivatives to human MMP-9. AB - Unlike most matrix metalloproteinase (MMP) inhibitors, which target the conserved catalytic zinc site, Gd@C82(OH)22 indirectly inhibits MMP-9 activity by binding at the ligand specificity S1' loop. The allosteric binding makes Gd@C82(OH)22 a promising inhibitor selective for MMP-9. However, the hydrophobic nature of the aromatic carbon cage may cause Gd@C82(OH)22 to self-aggregate in aqueous solutions, hence weakening the binding. In this study, we designed Gd@C82(OH)22 derivatives aiming at improving the binding affinity for MMP-9. Upon a mutation that substitutes a new functional group (-PO42-, -CH2CO2-, -CO2-, -NH3+, or CONH2) for a hydroxyl group on the fullerenol surface, we calculated the changes in the binding free energy to the catalytic domain of human MMP-9 using the free energy perturbation (FEP) method. We found that the higher the net charge of the functional group, the stronger the binding. Compared with Gd@C82(OH)22, Gd@C82(OH)21(PO4)2- binds at least 1.5 to 2.5 kcal mol-1 more strongly to MMP-9. The binding is specifically controlled by electrostatic interactions between the phosphate group and the charged residues at the binding site. In addition to the net charge, the binding free energy can be delicately adjusted by other factors, such as the functionalization site on Gd@C82(OH)22, the local environment of the putative binding site of MMP-9, and the presence of ions near the charged functional group. The results of our study shed light on the potential of developing Gd@C82(OH)22 derivatives as nanodrugs for treating the pathological diseases associated with unregulated MMP-9 activity. PMID- 29528359 TI - Combining cooperativity with sequestration: a novel strategy for discrimination of single nucleotide variants. AB - We present a novel strategy for the discrimination of single nucleotide variants (SNVs) by combining cooperativity with sequestration, which displays remarkably high specificity (discrimination factors ranging from 67 to 618 with a median of 194) against 12 model SNVs and can be easily integrated with PCR amplification to detect KRAS G12D mutation. PMID- 29528360 TI - Organic molecule-based photothermal agents: an expanding photothermal therapy universe. AB - Over the last decade, organic photothermal therapy (PTT) agents have attracted increasing attention as a potential complement for, or alternative to, classical drugs and sensitizers involving inorganic nanomaterials. In this tutorial review, we provide a structured description of the main classes of organic photothermal agents and their characteristics. Representative agents that have been studied in the context of photothermal therapy since 2000 are summarized and recent advances in using PTT agents to address various cancers indications are highlighted. PMID- 29528361 TI - The effects of treatment with atorvastatin versus rosuvastatin on endothelial dysfunction in patients with hyperlipidaemia. AB - INTRODUCTION: Statins can reduce cardiovascular events and improve endothelial function. However, differences in the effect of statins on endothelial dysfunction have not been researched sufficiently. Here, we aimed to compare the effects of atorvastatin versus rosuvastatin on endothelial function via flow mediated and endothelial-independent dilation. METHODS: Hyperlipidaemic subjects on treatment with statins for one year (either 20 mg/day atorvastatin or 10 mg/day rosuvastatin) were enrolled in the study. In accordance with the literature, flow-mediated dilation (FMD) and nitrate-mediated endothelium independent dilation (EID) were measured by ultrasonography on the right brachial artery of each subject. Baseline and final measurements were compared in each group and between the groups. RESULTS: One hundred and four subjects (50 atorvastatin and 54 rosuvastatin users) were enrolled in the study. Fifty-eight subjects were female. The groups were statistically similar in terms of age and body mass index, and haemoglobin, creatinine, total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein cholesterol levels. In each group, the mean final FMD and EID values were higher compared to their respective baseline values, but the mean changes in FMD and EID were statistically similar in both groups (p = 0.958 for FMD and 0.827 for EID). There was no statistically significant difference between the atorvastatin and rosuvastatin groups in terms of final FMD and EID values (p = 0.122 and 0.115, respectively). CONCLUSIONS: This study demonstrated that both one-year atorvastatin and rosuvastatin treatments significantly improved endothelial function, when assessed with FMD and EID and measured by ultrasonography. However, the amount of improvement in endothelial dysfunction was similar in the two treatments. PMID- 29528362 TI - Histone 3 lysine 4, 9, and 27 demethylases expression profile in fertilized and cloned bovine and porcine embryos. AB - Epigenetic modifications in the C-terminal domain of histones coordinate important events during early development including embryo genome activation (EGA) and cell differentiation. In this study, the mRNA expression profile of the main lysine demethylases (KDMs) acting on the lysine 4 (H3K4), 9 (H3K9), and 27 (H3K27) of the histone H3 was determined at pre-, during and post-EGA stages of bovine and porcine embryos produced by in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). In IVF embryos, mRNA abundance of most KDMs revealed a bell-shaped profile with peak expression around the EGA period, i.e. Day 3 for porcine (KDM2B, KDM5B, KDM5C, KDM4B, KDM4C, KDM6A, KDM6B, and KDM7A), and Day 4 for bovine (KDM1A, KDM5A, KDM5B, KDM5C, KDM3A, KDM4A, KDM4C, and KDM7A). The mRNA profile of KDM1A, KDM2B, KDM3A, KDM3B, KDM6A, and KDM6B differed between porcine and bovine IVF embryos. Several differences were also observed between SCNT and IVF, which includes a precocious peak in the mRNA expression of KDM1A, KDM3A, KDM4C, KDM5A, KDM5B, KDM5C, KDM6A, and KDM7A in bovine SCNT embryos; absence of mRNA peak for KDM4B, KDM4C, and KDM6A in porcine SCNT embryos; and early decreasing in KDM5B and KDM5C mRNA in porcine SCNT embryos. Based on the mRNA profile, this study has identified several KDMs that are likely involved in the regulation of the EGA transition, KDMs that may have a species specific role in bovine and porcine embryos, and KDMs that are improperly expressed during cell reprogramming in SCNT embryos. PMID- 29528363 TI - West African Ancestry and Nocturnal Blood Pressure in African Americans: The Jackson Heart Study. AB - BACKGROUND: African Americans have a higher prevalence of nocturnal hypertension and nondipping blood pressure than European Americans, but the genetic contribution to these racial differences remains unclear. We assessed the association of the percentage West African genetic ancestry with nocturnal hypertension and nondipping blood pressure in 932 African Americans from the Jackson Heart Study. METHODS: Using percentage West African ancestry determined from 389 ancestry informative markers, participants were categorized into tertiles (tertile 1 [low]: <79.3%, tertile 2: >=79.3-86.3%, and tertile 3 [high]: >86.3%). Nocturnal hypertension was defined as mean nighttime (midnight-6 am) systolic (SBP)/diastolic blood pressure >=120/70 mm Hg. Nondipping blood pressure was defined as mean nighttime-to-daytime (10 am-8 pm) SBP ratio >0.90. RESULTS: Nocturnal hypertension was present in 57.9% of participants; 66.6% had nondipping blood pressure. The mean age was 59.4 years, 32.8% were male, and 56.0% were taking antihypertensive medication. The prevalence ratios (95% confidence interval) adjusted for age, sex, cardiovascular disease risk factors, and socioeconomic and psychosocial factors comparing participants with moderate and high to those with low percentage West African ancestry for nocturnal hypertension were 0.98 (0.87-1.10) and 0.95 (0.84-1.08), respectively, and for nondipping blood pressure was 0.96 (0.86-1.07) and 0.98 (0.88-1.09), respectively. CONCLUSIONS: West African ancestry was not associated with nocturnal hypertension and nondipping blood pressure among African Americans. While rare genetic variants cannot be ruled out, these data highlight the need to better understand how environmental and behavioral factors contribute to differences in nocturnal blood pressure among African Americans compared with European Americans. PMID- 29528364 TI - iFeature: a Python package and web server for features extraction and selection from protein and peptide sequences. AB - Summary: Structural and physiochemical descriptors extracted from sequence data have been widely used to represent sequences and predict structural, functional, expression and interaction profiles of proteins and peptides as well as DNAs/RNAs. Here, we present iFeature, a versatile Python-based toolkit for generating various numerical feature representation schemes for both protein and peptide sequences. iFeature is capable of calculating and extracting a comprehensive spectrum of 18 major sequence encoding schemes that encompass 53 different types of feature descriptors. It also allows users to extract specific amino acid properties from the AAindex database. Furthermore, iFeature integrates 12 different types of commonly used feature clustering, selection and dimensionality reduction algorithms, greatly facilitating training, analysis and benchmarking of machine-learning models. The functionality of iFeature is made freely available via an online web server and a stand-alone toolkit. Availability and implementation: http://iFeature.erc.monash.edu/; https://github.com/Superzchen/iFeature/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29528365 TI - Why are the seed cones of conifers so diverse at pollination? AB - Background and Aims: Form and function relationships in plant reproductive structures have long fascinated biologists. Although the intricate associations between specific pollinators and reproductive morphology have been widely explored among animal-pollinated plants, the evolutionary processes underlying the diverse morphologies of wind-pollinated plants remain less well understood. Here we study how this diversity may have arisen by focusing on two conifer species in the pine family that have divergent reproductive cone morphologies at pollination. Methods: Standard histology methods, artificial wind pollination assays and phylogenetic analyses were used in this study. Key Results: A detailed study of cone ontogeny in these species reveals that variation in the rate at which their cone scales mature means that pollination occurs at different stages in their development, and thus in association with different specific morphologies. Pollination experiments nevertheless indicate that both species effectively capture pollen. Conclusions: In wind-pollinated plants, morphological diversity may result from simple variation in development among lineages rather than selective pressures for any major differences in function or performance. This work also illustrates the broader importance of developmental context in understanding plant form and function relationships; because plant reproductive structures perform many different functions over their lifetime, subtle differences in development may dramatically alter the specific morphologies that they use to meet these demands. PMID- 29528366 TI - Review of Diagnostic Test Accuracy (DTA) studies in older people. AB - Diagnostic Test Accuracy (DTA) describes a field of research that aims to assess how well a test is able to detect or exclude a condition of interest. Although geriatric medicine is not as reliant on investigations as other medical disciplines, almost all patient encounters with older adults will involve some form of diagnostic assessment. Thus, understanding the terminology and methods of DTA is essential for any clinician. In this review we use examples based around the diagnosis of dementia to highlight issues in DTA research. Some of these are generic to any DTA research and some are particularly pertinent to older adults. One can apply a test accuracy framework to a clinical question by defining four key components: the condition of interest; the index test(s) (i.e. the assessment(s) of interest); the reference standard (the best available method for assessing the condition of interest) and the population or healthcare setting in which testing takes place. Test accuracy is often described using complementary measures of sensitivity and specificity. However, many other metrics to describe test accuracy are available; in clinical practice predictive values may have greater utility. These and other descriptive statistics can be derived from a two by two table that cross-classifies the index test results with the reference standard results. Test performance and utility is not only determined by accuracy, other measures such as feasibility and acceptability should be considered and may be of particular importance when describing test performance in older adults with physical and cognitive impairments. PMID- 29528367 TI - Past, present, and future of nitrous oxide. AB - Introduction: For a drug that has been omnipresent for nearly 200 years, nitrous oxide's (N2O) future seems less certain than its illustrious past. Environmental concerns are coming to the fore and may yet outweigh important clinical benefits. Sources of data: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. Areas of agreement: The analgesic and anaesthetic advantages of N2O remain despite a plethora of newer agents. Areas of controversy: N2O greenhouse gas effect and its inhibition of key enzymes involved in protein and DNA synthesis have provided further fuel for those intent on eliminating its further clinical use. Growing points: The use of N2O for treatment-resistant depression has gained traction. Areas timely for developing research: Comparative studies for N2O role in combatting the prescription opioid analgesic epidemic may well provide further clinical impetus. PMID- 29528368 TI - Associations between aging-related changes in grip strength and cognitive function in older adults: A systematic review. AB - Objectives: Grip strength and cognitive function reflect upper body muscle strength and mental capacities. Cross-sectional research has suggested that in old age these two processes are moderately to highly associated, and that an underlying common cause drives this association. Our aim was to synthesize and evaluate longitudinal research addressing whether changes in grip strength are associated with changes in cognitive function in healthy older adults. Methods: We systematically reviewed English-language research investigating the longitudinal association between repeated measures of grip strength and of cognitive function in community-dwelling older adults to evaluate the extent to which the two indices decline concurrently. We used four search engines: Embase, PsychINFO, PubMed, and Web of Science. Results: Of 459 unique citations, 6 met our full criteria: 4 studies reported a longitudinal association between rates of change in grip strength and cognitive function in older adults, 2 of which reported the magnitudes of these associations as ranging from low to moderate; 2 studies reported significant cross-sectional but not longitudinal associations among rates of change. All studies concluded that cognitive function and grip strength declined, on average, with increasing age, although with little to no evidence for longitudinal associations among rates of change. Conclusions: Future research is urged to expand the study of physical and cognitive associations in old age using a within-person and multi-study integrative approach to evaluate the reliability of longitudinal results with greater emphasis on the magnitude of this association. PMID- 29528369 TI - Implications of a National Health Insurance Marketplace. PMID- 29528370 TI - METHCOMP: a special purpose compression platform for DNA methylation data. AB - Motivation: DNA methylation is one of the most important epigenetic mechanisms in cells that exhibits a significant role in controlling gene expressions. Abnormal methylation patterns have been associated with cancer, imprinting disorders and repeat-instability diseases. As inexpensive bisulfite sequencing approaches have led to significant efforts in acquiring methylation data, problems of data storage and management have become increasingly important. The de facto compression method for methylation data is gzip, which is a general purpose compression algorithm that does not cater to the special format of methylation files. We propose METHCOMP, a new compression scheme tailor-made for bedMethyl files, which supports random access. Results: We tested the METHCOMP algorithm on 24 bedMethyl files retrieved from four randomly selected ENCODE assays. Our findings reveal that METHCOMP offers an average compression ratio improvement over gzip of up to 7.5x. As an example, METHCOMP compresses a 48 GB file to only 0.9 GB, which corresponds to a 98% reduction in size. Availability and implementation: METHCOMP is freely available at https://github.com/jianhao2016/METHCOMP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29528371 TI - Sensitive and robust assessment of ChIP-seq read distribution using a strand shift profile. AB - Motivation: Chromatin immunoprecipitation followed by sequencing (ChIP-seq) can detect read-enriched DNA loci for point-source (e.g. transcription factor binding) and broad-source factors (e.g. various histone modifications). Although numerous quality metrics for ChIP-seq data have been developed, the 'peaks' thus obtained are still difficult to assess with respect to signal-to-noise ratio (S/N) and the percentage of false positives. Results: We developed a quality assessment tool for ChIP-seq data, strand-shift profile (SSP), which quantifies S/N and peak reliability without peak calling. We validated SSP in-depth using >= 1000 publicly available ChIP-seq datasets along with virtual data to demonstrate that SSP provides a quantifiable and sensitive score to different S/Ns for both point- and broad-source factors, which can be standardized across diverse cell types and read depths. SSP also provides an effective criterion to judge whether a specific normalization or a rejection is required for each sample, which cannot be estimated by quality metrics currently available. Finally, we show that 'hidden-duplicate reads' cause aberrantly high S/Ns, and SSP provides an additional metric to avoid them, which can also contribute to estimation of peak mode (point- or broad-source) of samples. Availability and implementation: SSP is open source software written in C++ and can be downloaded at https://github.com/rnakato/SSP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29528372 TI - THE AUTHORS REPLY. PMID- 29528374 TI - Corrigendum. PMID- 29528373 TI - RE: "A MULTINOMIAL REGRESSION APPROACH TO MODEL OUTCOME HETEROGENEITY". PMID- 29528375 TI - Diagnostic accuracy of Instrumental Activities of Daily Living for dementia in community-dwelling older adults. AB - Background: many people living with dementia remain underdiagnosed and unrecognised. Screening strategies are important for early detection. Objective: to examine whether the Lawton's Instrumental Activities of Daily Living (IADL) scale, compared with other cognitive screening tools-the Mini-Mental State Examination (MMSE), and the Ascertain Dementia 8-item Informant Questionnaire (AD8)-can identify older (>= 65 years) adults with dementia. Design: population based cross-sectional observational study. Setting: all 19 counties in Taiwan. Participants: community-dwelling older adults (n = 10,340; mean age 74.87 +/- 6.03). Methods: all participants underwent a structured in-person interview. Dementia was identified using National Institute on Aging-Alzheimer's Association core clinical criteria for all-cause dementia. Receiver operator characteristic curves were used to determine the discriminant abilities of the IADL scale, MMSE and AD8 to differentiate participants with and without dementia. Results: we identified 917 (8.9%) participants with dementia, and 9,423 (91.1%) participants without. The discriminant abilities of the MMSE, AD8 and IADL scale (cutoff score: 6/7; area under curve = 0.925; sensitivity = 89%; specificity = 81%; positive likelihood ratio = 4.75; accuracy = 0.82) were comparable. Combining IADL with AD8 scores significantly improved overall accuracy: specificity = 93%; positive likelihood ratio = 11.74; accuracy = 0.92. Conclusions: our findings support using IADL scale to screen older community-dwelling residents for dementia: it has discriminant power comparable to that of the AD8 and MMSE. Combining the IADL and the AD8 improves specificity. PMID- 29528376 TI - Kernelized rank learning for personalized drug recommendation. AB - Motivation: Large-scale screenings of cancer cell lines with detailed molecular profiles against libraries of pharmacological compounds are currently being performed in order to gain a better understanding of the genetic component of drug response and to enhance our ability to recommend therapies given a patient's molecular profile. These comprehensive screens differ from the clinical setting in which (i) medical records only contain the response of a patient to very few drugs, (ii) drugs are recommended by doctors based on their expert judgment and (iii) selecting the most promising therapy is often more important than accurately predicting the sensitivity to all potential drugs. Current regression models for drug sensitivity prediction fail to account for these three properties. Results: We present a machine learning approach, named Kernelized Rank Learning (KRL), that ranks drugs based on their predicted effect per cell line (patient), circumventing the difficult problem of precisely predicting the sensitivity to the given drug. Our approach outperforms several state-of-the-art predictors in drug recommendation, particularly if the training dataset is sparse, and generalizes to patient data. Our work phrases personalized drug recommendation as a new type of machine learning problem with translational potential to the clinic. Availability and implementation: The Python implementation of KRL and scripts for running our experiments are available at https://github.com/BorgwardtLab/Kernelized-Rank-Learning. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29528377 TI - Identification of a novel host protein interacting with Toxoplasma gondii toxofilin via a yeast two-hybrid system. PMID- 29528379 TI - Obesity and esophagectomy for esophageal cancer: is it only the high BMI that defines prognosis? PMID- 29528380 TI - Visual-Olfactory Interactions: Bimodal Facilitation and Impact on the Subjective Experience. AB - Odors are inherently ambiguous and therefore susceptible to redundant sensory as well as context information. The identification of an odor object relies largely on visual input. Thus far, it is unclear whether visual and olfactory stimuli are indeed integrated at an early perceptual stage and which role the congruence between the visual and olfactory inputs plays. Previous studies on visual olfactory interaction used either congruent or incongruent information, leaving it open whether nuances of visual-olfactory congruence shape perception differently. We aimed to answer 1) whether visual-olfactory information is integrated at early stages of processing, 2) whether visual-olfactory congruence is a gradual or dichotomous phenomenon, and 3) whether visual information influences bimodal stimulus evaluation and odor identity. We found a bimodal response time speedup that is consistent with parallel processing according to race models. Subjectively, pleasantness of bimodal stimuli increased with increasing congruence, and orange images biased odor composition toward orange. Visual-olfactory congruence was perceived in gradual and distinct categories, consistent with the notion that congruence is a gradual phenomenon. Together, the data provide evidence for bimodal facilitation consistent with parallel processing of the visual and olfactory stimuli, and that visual-olfactory interactions influence various levels of the subjective experience. PMID- 29528378 TI - Association of sporadic and familial Barrett's esophagus with breast cancer. AB - Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC). Based on striking aggregation of breast cancer and BE/EAC within families as well as shared risk factors and molecular mechanisms of carcinogenesis, we hypothesized that BE may be associated with breast cancer. Pedigree analysis of families identified prospectively at multiple academic centers as part of the Familial Barrett's Esophagus Consortium (FBEC) was reviewed and families with aggregation of BE/EAC and breast cancer are reported. Additionally, using a matched case-control study design, we compared newly diagnosed BE cases in Caucasian females with breast cancer (cases) to Caucasian females without breast cancer (controls) who had undergone upper endoscopy (EGD). Two familial pedigrees, meeting a stringent inclusion criterion, manifested familial aggregation of BE/EAC and breast cancer in an autosomal dominant inheritance pattern with incomplete penetrance. From January 2008 to October 2016, 2812 breast cancer patient charts were identified, of which 213 were Caucasian females who underwent EGD. Six of 213 (2.82%) patients with breast cancer had pathology confirmed BE, compared to 1 of 241 (0.41%) controls (P-value < 0.05). Selected families with BE/EAC show segregation of breast cancer. A breast cancer diagnosis is marginally associated with BE. We postulate a common susceptibility between BE/EAC and breast cancer. PMID- 29528381 TI - Impact of truncal valve surgery on the outcomes of the truncus arteriosus repair. AB - OBJECTIVES: Preoperative moderate or greater truncal valve (TV) insufficiency is one of the most important factors influencing mortality in children with truncus arteriosus. We therefore sought to determine the impact of TV insufficiency and concomitant TV surgery on children who underwent truncus arteriosus repair at a single institution. METHODS: We reviewed 180 patients who underwent truncus arteriosus repair between 1979 and 2016. Preoperative echocardiography demonstrated TV insufficiency in 80 patients (mild: 33.9%, 61/180; moderate: 9.4%, 17/180 and severe: 1.1%, 2/180). RESULTS: Twenty-one patients had concomitant TV surgery with an early mortality of 19% (4/21) and overall survival of 70.8 +/- 10.1% at 25 years. There were 60 neonates, 11 of whom had concomitant TV surgery with an early mortality of 27% (3/11) and overall survival of 62.3 +/- 15.0% at 20 years. Concomitant TV repair (P = 0.5) was not a risk factor for death. TV reoperation was common in those who had concomitant TV surgery, with freedom from reoperation of 19.2 +/- 14.9% at 20 years. In the remaining 159 patients, 14 required subsequent TV surgery, and the freedom from TV surgery was 84.0 +/- 4.6% at 20 years. At a median follow-up of 18.5 years, TV insufficiency was none or trivial in 79.6% (109/137) and mild or less in 98.5% (135/137) of patients. CONCLUSIONS: Most patients with mild TV insufficiency are free from TV surgery up to 25 years. The durability of TV repair is poor. Most patients with moderate or greater TV insufficiency and a quadricuspid TV will require TV surgery. PMID- 29528382 TI - Combined Endoscopic/Sonographic-based Risk Matrix Model for Predicting One-year Risk of Surgery: A Prospective Observational Study of a Tertiary Centre Severe/Refractory Crohn's Disease Cohort. AB - Background: In the management of Crohn's disease [CD] patients, having a simple score combining clinical, endoscopic, and imaging features to predict the risk of surgery could help to tailor treatment more effectively. Aims: We aimed to prospectively evaluate the 1-year risk factors for surgery in refractory/severe CD and to generate a risk matrix for predicting the probability of surgery at 1 year. Methods: CD patients needing a disease re-assessment at our tertiary inflammatory bowel disease [IBD] centre underwent clinical, laboratory, endoscopic, and bowel sonography [BS] examinations within 1 week. The optimal cut off values in predicting surgery were identified using receiver operating characteristic [ROC] curves for the Simple Endoscopic Score for CD [SES-CD], bowel wall thickness [BWT] at BS, and small bowel CD extension at BS. Binary logistic regression and Cox regression were then carried out. Finally, the probabilities of surgery were calculated for selected baseline levels of covariates and results were arranged in a prediction matrix. Results: Of 100 CD patients, 30 underwent surgery within 1 year. SES-CD >=9 (odds ratio [OR] 15.3; p <0.001], BWT >=7 mm [OR 15.8; p <0.001], small bowel CD extension at BS >=33 cm [OR 8.23; p <0.001], and stricturing/penetrating behaviour [OR 4.3; p <0.001] were the only independent factors predictive of surgery at 1 year, based on binary logistic and Cox regressions. Our matrix model combined these risk factors, and the probability of surgery ranged from 0.48% to 87.5% [16 combinations]. Conclusions: Our risk matrix combining clinical, endoscopic, and ultrasonographic findings can accurately predict the 1-year risk of surgery in patients with severe/refractory CD requiring a disease re-evaluation. This tool could be of value in clinical practice, serving as the basis for a tailored management of CD patients. PMID- 29528383 TI - Neuregulin-1 attenuates stress-induced vascular senescence. AB - Aims: Cardiovascular ageing is a key determinant of life expectancy. Cellular senescence, a state of irreversible cell cycle arrest, is an important contributor to ageing due to the accumulation of damaged cells. Targeting cellular senescence could prevent age-related cardiovascular diseases. In this study, we investigated the effects of neuregulin-1 (NRG-1), an epidermal growth factor with cardioprotective and anti-atherosclerotic effects, on cellular senescence. Methods and results: Senescence was induced in cultured rat aortic endothelial cells (ECs) and aortic smooth muscle cells (SMCs) by 2 h exposure to 30 uM hydrogen peroxide (H2O2). Cellular senescence was confirmed after 72 h using senescence-associated-beta-galactosidase staining (SA-beta-gal), cell surface area, and western blot analyses of SA pathways (acetyl-p53, p21). Recombinant human NRG-1 (rhNRG-1, 20 ng/mL) significantly reduced H2O2-induced senescence, as shown by a lower number of SA-beta-gal positive cells, smaller surface area and lower expression of acetyl-p53. In C57BL/6 male mice rendered diabetic with streptozotocin (STZ), rhNRG-1 attenuated cellular senescence in aortic ECs and SMCs. Next, we created mice with SMC-specific knockdown of the NRG 1 receptor ErbB4. Aortic SMCs isolated from SMC-specific ErbB4 deficient mice (ErbB4f/+ SM22alpha-Cre+) showed earlier cellular senescence in vitro compared with wild-type (ErbB4+/+ SM22alpha-Cre+) SMCs. Furthermore, when rendered diabetic with STZ, ErbB4f/+ SM22alpha-Cre+ male mice showed significantly more vascular senescence than their diabetic wild-type littermates and had increased mortality. Conclusions: This study is the first to explore the role of NRG-1 in vascular senescence. Our data demonstrate that NRG-1 markedly inhibits stress induced premature senescence in vascular cells in vitro and in the aorta of diabetic mice in vivo. Consistently, deficiency in the NRG-1 receptor ErbB4 provokes cellular senescence in vitro as well as in vivo. PMID- 29528384 TI - Central versus peripheral cannulation of extracorporeal membrane oxygenation support during double lung transplant for pulmonary hypertension. AB - OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has become the standard of cardiopulmonary support during a sequential double lung transplant for pulmonary hypertension. Whether central or peripheral cannulation is the best strategy for these patients remains unknown. Our goal was to determine which is the best strategy by comparing 2 populations of patients. METHODS: We performed a single centre retrospective study based on an institutional prospective lung transplant database. RESULTS: Between January 2011 and November 2016, 103 patients underwent double lung transplant for pulmonary hypertension. We compared 54 patients who had central ECMO (cECMO group) to 49 patients who had peripheral ECMO (pECMO group). The pECMO group had significantly more bridged patients who received emergency transplants (31% vs 6%, P = 0.001). The incidence of Grade 3 primary graft dysfunction requiring ECMO (14% vs 11%, P = not significant) and of in hospital mortality (11% vs 14%, P = not significant) was similar between the groups. Groin infections (16% vs 4%, P = 0.031), deep vein thrombosis (27% vs 11%, P = 0.044) and lower limb ischaemia (12% vs 2%, P = 0.031) occurred significantly more often in the pECMO group. The number of chest reopenings for bleeding or infection was similar between the groups. The 3-month, 1-year and 5 year survival rates did not differ between the groups (P = 0.94). CONCLUSIONS: Central or peripheral ECMO produced similar results during double lung transplant for pulmonary hypertension in terms of in-hospital deaths and long-term survival rates. Central ECMO provided satisfactory results without major bleeding provided the patient was weaned from ECMO at the end of the procedure. Despite the rate of groin and lower limb complications, peripheral cannulation remained the preferred solution to bridge the patient to transplant or for postoperative support. PMID- 29528385 TI - Effect of Faecal Microbiota Transplantation for Treatment of Clostridium difficile Infection in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Cohort Studies. AB - Background: Evidence concerning the effect of faecal microbiota transplantation [FMT] in Clostridium difficile infection [CDI] patients with inflammatory bowel disease [IBD] has not been firmly established. Therefore, we performed a systematic review and meta-analysis to evaluate FMT treatment outcomes in patients with IBD treated for CDI. Methods: An electronic search of four databases was conducted until November 1, 2017. Cohort studies of FMT efficacy and safety in CDI patients with IBD were included. Pooled effect sizes were calculated with 95% confidence intervals [CI] using a random-effects model. Results: Nine cohort studies comprising a total of 346 CDI patients with IBD were included. The initial cure rate was 81% [95% CI = 76%-85%] and the overall cure rate was up to 89% [95% CI = 83%-93%], both with no significant heterogeneity. The recurrence rate was 19% [95% CI = 13%-27%] with moderate heterogeneity [Cochran's Q, p = 0.19; I2 = 33%]. There was no significant difference in the CDI cure rate after FMT in patients with and without IBD (risk ratio [RR] = 0.92; 95% CI = 0.81-1.05; Cochran's Q, p = 0.06; I2 = 53%). Subgroup analysis revealed a similar CDI treatment effects after FMT in patients with Crohn's disease and in those with ulcerative colitis [p = 0.1804]. Four studies reported adverse events of IBD flares. Conclusions: FMT is an effective therapy for CDI in patients with IBD. Well-designed randomised controlled trials and well-conducted microbiological studies are needed to validate its efficacy and safety. PMID- 29528386 TI - Pre-admission use of platelet inhibitors and short-term stroke mortality: a population-based cohort study. AB - Aims: The impact of pre-admission antiplatelet treatment on prognosis after stroke is poorly understood. We, therefore, investigated whether pre-admission use of aspirin and clopidogrel was associated with mortality in patients hospitalized with ischaemic stroke, intracerebral haemorrhage (ICH), or subarachnoid haemorrhage (SAH). Methods and results: We used nationwide population-based registries to identify all first-time hospitalizations for stroke and subsequent mortality in patients treated with aspirin and clopidogrel in Denmark during 2004-2012. Based on redeemed prescriptions, we computed absolute 30-day mortality rates and mortality rate ratios (MRRs) for current platelet inhibitor users and non-users. We used Cox regression to control for potentially confounding factors. Among platelet inhibitor non-users, 30-day stroke mortality was 12.0% (8.8% for ischaemic stroke, 29.6% for ICH, and 21.2% for SAH). Compared with non-users, the adjusted 30-day MRR (aMRR) was increased among ICH patients using aspirin [1.19, 95% confidence interval (CI) 1.09-1.31]. Although wider CIs, similar increased point estimates were observed in users of both aspirin and clopidogrel (aMRR = 1.26, 95% CI 0.84-1.91). In contrast, current use of both aspirin and clopidogrel was associated with reduced mortality from ischaemic stroke (aMRR = 0.67, 95% CI 0.48-0.94), while use of aspirin alone was not. Conclusion: Among patients hospitalized for first-time ICH, pre admission platelet inhibitor use was associated with increased 30-day mortality compared with non-use. In patients hospitalized for ischaemic stroke, 30-day mortality was reduced in users of both aspirin and clopidogrel, but not in users of aspirin alone. PMID- 29528387 TI - Antioxidant Effects of Four Heartwood Extractives on Midgut Enzyme Activity in Heterotermes indicola (Blattodea: Rhinotermitidae). AB - Heterotermes indicola (Wasmann) (Blattodea: Rhinotermitidae) is a species of subterranean termite that is a destructive pest of wood and wood products in Pakistan. This study evaluated the antioxidant and antienzyme potential of heartwood extractives against H. indicola. Heartwood extractives of four durable wood species, Tectona grandis (L.f), Dalbergia sissoo (Roxb.), Cedrus deodara (Roxb.), and Pinus roxburghii (Sarg.) were removed from wood shavings via soxhlet extraction with an ethanol:toluene solvent system. The antioxidant potential of the extractive compounds was determined using the DPPH (2,2-diphenyl-1 picrylhydrazyl) radical scavenging test. Results showed maximum antioxidant activity for extractives of D. sissoo. D. sissoo had the lowest IC50 (the concentration where 50% inhibition of the DPPH radical is obtained) at 28.83 ug/ml among the heartwood extractives evaluated. This antioxidant activity, however, was not concentration dependent as was observed in the other heartwood extractives tested. At the maximum test concentration, T. grandis showed the highest percent inhibition at 89.7%, but this inhibition was lower compared to the positive control antioxidant compounds butylated hydroxytoluene and quercetin. When termites were fed filter paper treated with IC50s of the extractives and control compounds, glutathione S-transferase activity in the guts of H. indicola workers was significantly reduced by T. grandis and D. sissoo extractives. Similarly, esterase activity was reduced more by P. roxburghii extractives compared to control antioxidant treatments and other tested extractives. However, none of the extractives examined significantly reduced the activity of catalase enzymes in H. indicola compared to treatments with the antioxidant control compounds. PMID- 29528388 TI - How to Increase the Butyrate-producing Capacity of the Gut Microbiome: Do IBD Patients Really Need Butyrate Replacement and Butyrogenic Therapy? PMID- 29528389 TI - Dose-Dependent Negative Effects of Prior Multiple Vaccinations Against Influenza A and Influenza B Among Schoolchildren: A Study of Kamigoto Island in Japan During the 2011-2012, 2012-2013, and 2013-2014 Influenza Seasons. AB - Background: We investigated the negative effects of prior multiple vaccinations on influenza vaccine effectiveness (VE) and analyzed the association of VE with prior vaccine doses. Methods: Patients aged 9-18 years presenting with influenza like illness at a community hospital on a remote Japanese island during the 2011 2012, 2012-2013, and 2013-2014 influenza seasons were tested for influenza using a rapid diagnostic test (RDT). A test-negative, case-control study design was used to estimate the VEs of trivalent inactivated influenza vaccine. Histories of vaccination and medically attended influenza (MA-flu) A and B during 3 previous seasons were collected from registry systems. VE was calculated using multilevel mixed-effects logistic regression models adjusted for the history of RDT confirmed MA-flu. Results: During 3 influenza seasons, 1668 influenza-like illness episodes were analyzed, including 421 and 358 episodes of MA-fluA and MA fluB, respectively. The adjusted VE (95% confidence interval) yielded significant dose-dependent attenuations by prior vaccinations against both MA-fluA (0 doses during previous 3 seasons: 96% [69%-100%], 1 dose: 48% [-7% to 74%], 2 doses: 52% [11%-74%], 3 doses: 21% [-25% to 51%]; P for trend < .05) and MA-fluB (0 doses: 66% [-5% to 89%], 1 dose: 48% [-14% to 76%], 2 doses: 34% [-33% to 67%], 3 doses: -7% [-83% to 37%]; P for trend < .05). After excluding episodes of MA-flu during prior 3 seasons, similar trends were observed. Conclusions: Repeated previous vaccinations over multiple seasons had significant dose-dependent negative impacts on VE against both MA-fluA and MA-fluB. Further studies to confirm this finding are necessary. PMID- 29528390 TI - Expression of C9orf72-related dipeptides impairs motor function in a vertebrate model. AB - Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Different hypotheses exist about the underlying disease mechanism including loss of function by haploinsufficiency, toxicity arising as a result of RNA or dipeptide repeats (DPRs). Five different DPRs are produced by repeat-associated non-ATG-initiated translation of the G4C2 repeats. Though earlier studies have indicated toxicity of the DPRs in worms, flies, primary cultured cells and cell lines, the effect of expressing DPRs of amyotrophic lateral sclerosis-relevant length has not been tested on motor behaviour in vertebrate models. In this study, by expressing constructs with alternate codons encoding different lengths of each DPR (40, 200 and 1000) in the vertebrate zebrafish model, the GR DPR was found to lead to the greatest developmental lethality and morphological defects, and GA, the least. However, expressing 1000 repeats of any DPR, including the 'non-toxic' GA DPR led to locomotor defects. Based on these observations, a transgenic line stably expressing 100 GR repeats was generated to allow specific regional and temporal expression of GR repeats in vivo. Expression of GR DPRs ubiquitously resulted in severe morphological defects and reduced swimming. However, when expressed specifically in motor neurons, the developmental defects were significantly reduced, but the swimming phenotype persisted, suggesting that GR DPRs have a toxic effect on motor neuron function. This was validated by the reduction in motor neuron length even in already formed motor neurons when GR was expressed in these. Hence, the expression of C9orf72-associated DPRs can cause significant motor deficits in vertebrates. PMID- 29528391 TI - Proof of concept study of a novel pacemapping algorithm as a basis to guide ablation of ventricular arrhythmias. AB - Aims: To determine if a software algorithm can use an individualized distance morphology difference model, built from three initial pacemaps, to prospectively locate the exit site (ES) of ventricular arrhythmias (VA). Methods and results: Consecutive patients undergoing ablation of VA from a single centre were recruited. During mapping, three initial pacing points were collected in the chamber of interest and the navigation algorithm applied to predict the ES, which was corroborated by conventional mapping techniques. Thirty-two patients underwent ES prediction over 35 procedures. Structural heart disease was present in 16 (7 ischaemic cardiomyopathy, 9 non-ischaemic cardiomyopathy), median ejection fraction 45% [Interquartile range (IQR) 26]. The remainder had normal hearts. The navigation algorithm was applied to 46 VA (24 left ventricle, 11 right ventricular outflow tract, 5 left ventricular outflow tract, 4 right ventricle, 2 epicardial) and successfully located the site of best pacemap match in 45 within a median area of 196.5 mm2 (IQR 161.3, range 46.6-1288.2 mm2). Conclusions: In a diverse population of patients with and without structural heart disease, the ES of VA can be accurately and reliably identified to within a clinically useful target area using a simple software navigation algorithm based on pacemapping. PMID- 29528392 TI - Yeast screen for modifiers of C9orf72 poly(glycine-arginine) dipeptide repeat toxicity. AB - A hexanucleotide repeat expansion in the C9orf72 gene has been identified as the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. The expanded hexanucleotide repeat is translated by an unconventional mechanism to produce five species of dipeptide repeat (DPR) proteins, glycine-proline (GP), glycine-alanine (GA), glycine-arginine (GR), proline-alanine (PA) and proline arginine (PR). Of these, the arginine-rich ones, PR and GR, are highly toxic in a variety of model systems, ranging from human cells, to Drosophila, to even the budding yeast, Saccharomyces cerevisiae. We recently performed a genetic screen in yeast for modifiers of PR toxicity and identified suppressors and enhancers, many of which function in nucleocytoplasmic transport. Whether or not GR toxicity involves similar mechanisms to PR is unresolved. Therefore, we performed a genetic screen in yeast to identify modifiers of GR toxicity and compared the results of the GR screen to results from our previous PR screen. Surprisingly, there was only a small degree of overlap between the two screens, suggesting potential for distinct toxicity mechanisms between PR and GR. PMID- 29528393 TI - Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development. AB - Bicaudal D2 (BICD2) encodes a highly conserved motor adaptor protein that regulates the dynein-dynactin complex in different cellular processes. Heterozygous mutations in BICD2 cause autosomal dominant lower extremity predominant spinal muscular atrophy-2 (SMALED2). Although, various BICD2 mutations have been shown to alter interactions with different binding partners or the integrity of the Golgi apparatus, the specific pathological effects of BICD2 mutations underlying SMALED2 remain elusive. Here, we show that the fibroblasts derived from individuals with SMALED2 exhibit stable microtubules. Importantly, this effect was observed regardless of where the BICD2 mutation is located, which unifies the most likely cellular mechanism affecting microtubules. Significantly, overexpression of SMALED2-causing BICD2 mutations in the disease relevant cell type, motor neurons, also results in an increased microtubule stability which is accompanied by axonal aberrations such as collateral branching and overgrowth. To study the pathological consequences of BICD2 mutations in vivo, and to address the controversial debate whether two of these mutations are neuron or muscle specific, we generated the first Drosophila model of SMALED2. Strikingly, neuron-specific expression of BICD2 mutants resulted in reduced neuromuscular junction size in larvae and impaired locomotion of adult flies. In contrast, expressing BICD2 mutations in muscles had no obvious effect on motor function, supporting a primarily neurological etiology of the disease. Thus, our findings contribute to the better understanding of SMALED2 pathology by providing evidence for a common pathomechanism of BICD2 mutations that increase microtubule stability in motor neurons leading to increased axonal branching and to impaired neuromuscular junction development. PMID- 29528395 TI - CXCL1-CXCR2 lead monocytes to the heart of the matter. PMID- 29528394 TI - Calpain 3 and CaMKIIbeta signaling are required to induce HSP70 necessary for adaptive muscle growth after atrophy. AB - Mutations in CAPN3 cause autosomal recessive limb girdle muscular dystrophy 2A. Calpain 3 (CAPN3) is a calcium dependent protease residing in the myofibrillar, cytosolic and triad fractions of skeletal muscle. At the triad, it colocalizes with calcium calmodulin kinase IIbeta (CaMKIIbeta). CAPN3 knock out mice (C3KO) show reduced triad integrity and blunted CaMKIIbeta signaling, which correlates with impaired transcriptional activation of myofibrillar and oxidative metabolism genes in response to running exercise. These data suggest a role for CAPN3 and CaMKIIbeta in gene regulation that takes place during adaptation to endurance exercise. To assess whether CAPN3- CaMKIIbeta signaling influences skeletal muscle remodeling in other contexts, we subjected C3KO and wild type mice to hindlimb unloading and reloading and assessed CaMKIIbeta signaling and gene expression by RNA-sequencing. After induced atrophy followed by 4 days of reloading, both CaMKIIbeta activation and expression of inflammatory and cellular stress genes were increased. C3KO muscles failed to activate CaMKIIbeta signaling, did not activate the same pattern of gene expression and demonstrated impaired growth at 4 days of reloading. Moreover, C3KO muscles failed to activate inducible HSP70, which was previously shown to be indispensible for the inflammatory response needed to promote muscle recovery. Likewise, C3KO showed diminished immune cell infiltration and decreased expression of pro-myogenic genes. These data support a role for CaMKIIbeta signaling in induction of HSP70 and promotion of the inflammatory response during muscle growth and remodeling that occurs after atrophy, suggesting that CaMKIIbeta regulates remodeling in multiple contexts: endurance exercise and growth after atrophy. PMID- 29528396 TI - Increased expression of microRNA-15a and microRNA-15b in skeletal muscle from adult offspring of women with diabetes in pregnancy. AB - Offspring of women with diabetes in pregnancy exhibit skeletal muscle insulin resistance and are at increased risk of developing type 2 diabetes, potentially mediated by epigenetic mechanisms or changes in the expression of small non coding microRNAs. Members of the miR-15 family can alter the expression or function of important proteins in the insulin signalling pathway, affecting insulin sensitivity and secretion. We hypothesized that exposure to maternal diabetes may cause altered expression of these microRNAs in offspring skeletal muscle, representing a potential underlying mechanism by which exposure to maternal diabetes leads to increased risk of cardiometabolic disease in offspring. We measured microRNA expression in skeletal muscle biopsies of 26- to 35-year-old offspring of women with either gestational diabetes (O-GDM, n = 82) or type 1 diabetes (O-T1DM, n = 67) in pregnancy, compared with a control group of offspring from the background population (O-BP, n = 57) from an observational follow-up study. Expression of both miR-15a and miR-15b was increased in skeletal muscle obtained from O-GDM (both P < 0.001) and O-T1DM (P = 0.024, P = 0.005, respectively) compared with O-BP. Maternal 2 h post OGTT glucose levels were positively associated with miR-15a expression (P = 0.041) in O-GDM after adjustment for confounders and mediators. In all groups collectively, miRNA expression was significantly positively associated with fasting plasma glucose, 2 h plasma glucose and HbA1c. We conclude that fetal exposure to maternal diabetes is associated with increased skeletal muscle expression of miR-15a and miR-15b and that this may contribute to development of metabolic disease in these subjects. PMID- 29528397 TI - A genome-wide association study of growth and fatness traits in two pig populations with different genetic backgrounds. AB - Improvement in growth and fatness traits are the main objectives in pig all breeding programs. Tenth rib backfat thickness (10RIBBFT) and days to 100 kg (D100), which are good predictors of carcass lean content and growth rate, respectively, are economically important traits and also main breeding target traits in pigs. To investigate the genetic mechanisms of 10RIBBFT and D100 of pigs, we sampled 1,137 and 888 pigs from 2 Yorkshire populations of American and British origin, respectively, and conducted genome-wide association study (GWAS) through combined analysis and meta-analysis, to identify SNPs associated with 10RIBBFT and D100. A total of 11 and 7 significant SNPs were identified by combined analysis for 10RIBBFT and D100, respectively. And in meta-analysis, 8 and 7 significant SNPs were identified for 10RIBBFT and D100, respectively. Among them, 6 and 5 common significant SNPs in two analysis results were, respectively, identified associated with 10RIBBFT and D100, and correspondingly explained 2.09% and 0.52% of the additive genetic variance of 10RIBBFT and D100. Further bioinformatics analysis revealed 10 genes harboring or close to these common significant SNPs, 5 for 10RIBBFT and 5 for D100. In particular, Gene Ontology analysis highlighted 6 genes, PCK1, ANGPTL3, EEF1A2, TNFAIP8L3, PITX2, and PLA2G12, as promising candidate genes relevant with backfat thickness and growth. PCK1, ANGPTL3, EEF1A2, and TNFAIP8L3 could influence backfat thickness through phospholipid transport, regulation of lipid metabolic process through the glycerophospholipid biosynthesis and metabolism pathway, the metabolism of lipids and lipoproteins pathway. PITX2 has a crucial role in skeletal muscle tissue development and animal organ morphogenesis, and PLA2G12A plays a role in the lipid catabolic and phospholipid catabolic processes, which both are involved in the body weight pathway. All these candidate genes could directly or indirectly influence fat production and growth in Yorkshire pigs. Our findings provide novel insights into the genetic basis of growth and fatness traits in pigs. The candidate genes for D100 and 10RIBBFT are worthy of further investigation. PMID- 29528399 TI - Lethal and Sublethal Effects of Mineral Oil on Potato Pests. AB - Mineral oil is a product used to reduce Potato Virus Y transmission in potato fields. However, there is little information available about other effects that oil may have on insect pests of potato. To better understand how mineral oil affects potato pests, we performed a series of experiments testing the effects of oil on mortality, behavior, and development of potato aphids, Macrosiphum euphorbiae (Thomas) (Hemiptera: Aphididae), green peach aphids, Myzus persicae (Sulzer) (Hemiptera: Aphididae), and Colorado potato beetles, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae). All three species showed negative behavioral responses to oil-treated potato foliage. Oil treatment also increased aphid mortality. Colorado potato beetle mortality was not affected, but developing on oil-treated potato plants resulted in prolonged development and smaller adults. Additionally, oil acted synergistically with the entomopathogenic fungus Beauveria bassiana (Balsamo) Vuillemin (Hypocreales: Clavicipitaceae); Colorado potato beetle larvae were killed more rapidly when sprayed with both products compared with when sprayed with B. bassiana alone. Based on these results, mineral oil has the potential for expanded use in potato IPM programs. PMID- 29528398 TI - Developmental Origins of Health and Disease: the relevance to developing nations. AB - Low- and middle-income countries (LMICs), particularly those in sub-Saharan Africa, are experiencing rapid increases in the prevalence of non-communicable diseases (NCDs), which may not be fully explained by urbanization and associated traditional risk factors such as tobacco smoking, excessive alcohol consumption, poor diet or physical inactivity. In this commentary, we draw attention to the concept of Developmental Origins of Health and Disease (DOHaD), where environmental insults in early life can contribute to long-term risk of NCDs, the impact of which would be particularly important in LMICs where poverty, malnutrition, poor sanitation and infections are still prevalent. PMID- 29528400 TI - The Management of Intestinal Penetrating Crohn's Disease. AB - Crohn's disease (CD) leads to the development of complications through progressive uncontrolled inflammation and the transmural involvement of the bowel wall. Most of the available literature on penetrating CD focuses on the perianal phenotype. The management of nonperianal penetrating complications poses its own set of challenges and can result in significant morbidity and an increased risk of mortality. Few controlled trials have been published evaluating this subgroup of patients for clinicians to use for guidance. Utilizing the available evidence, we review the epidemiology, presentation, and modalities used to diagnosis and assess intestinal fistulas, phlegmons, and abscesses. The literature regarding the medical, endoscopic, and surgical management options are reviewed providing physicians with a therapeutic framework to comprehensively treat these nonperianal penetrating complications. Through a multidisciplinary evidence-based approach to the complex sequela of CD outcomes can be improved and patient's quality of life enhanced.10.1093/ibd/izx108_video1izx108_Video5754037501001. PMID- 29528401 TI - Assessment of knowledge, attitudes and practices towards newborn screening for congenital hypothyroidism before and after a health education intervention in pregnant women in a hospital setting in Pakistan. AB - Background: Most congenital hypothyroidism (CH) is not avertable; however, the adverse effects of CH are preventable with early detection and treatment. It is a common congenital endocrine disorder that affects 1 in 2000-4000 newborns globally. The true incidence in Pakistan is unknown. Data from hospital studies quote an incidence of 1 in 1600-2000. The aim of this study was to uncover existing knowledge of CH and screening for the condition and to assess the impact of health education on mothers' knowledge and attitudes towards having their newborns screened. Methods: The study was conducted from January 2012 to August 2013 at a local hospital in Karachi, Pakistan. This was a prospective, interventional cohort study implemented through a pre- and post-cross-sectional knowledge, attitudes and practices (KAP) survey. Interviews were conducted using structured questionnaires on CH. Results: At baseline (pre-intervention survey), 400 participants consented and 355 (88.9%) completed the study. There was a significant increase in awareness among participating women following the intervention (20% to approximately 98%). Similarly, 78.9% agreed to opt for a screening test for their newborns following delivery as compared with 57.7% in the pre-intervention KAP survey (relative risk 1.38, p-value <0.0001). Conclusion: Unfortunately, the majority of mothers were unaware of CH and its implications, leading to less screening and fewer diagnoses. This study underlines the importance of education in screening programmes to create awareness and maximize uptake. PMID- 29528402 TI - On the meaning of global health and the role of global health journals. PMID- 29528403 TI - Physical activity and bone health: understanding mechanical strain-related stimuli. PMID- 29528404 TI - Spatio-temporal dynamics of sulfur bacteria during oxic--anoxic regime shifts in a seasonally stratified lake. AB - Sulfate-reducing bacteria (SRB) and sulfur-oxidizing bacteria drive major transformations in the sulfur cycle, and play vital roles in oxic--anoxic transitions in lakes and coastal waters. However, information on the succession of these sulfur bacteria in seasonally stratified lakes using molecular biological techniques is scarce. Here, we used 16S rRNA gene amplicon sequencing to study the spatio-temporal dynamics of sulfur bacteria during oxic--anoxic regime shifts in Lake Vechten. Oxygen and sulfate were mixed throughout the water column in winter and early spring. Meanwhile, SRB, green sulfur bacteria (GSB), purple sulfur bacteria (PSB), and colorless sulfur bacteria (CSB) exclusively inhabited the sediment. After the water column stratified, oxygen and nitrate concentrations decreased in the hypolimnion and various SRB species expanded into the anoxic hypolimnion. Consequently, sulfate was reduced to sulfide, stimulating the growth of PSB and GSB in the metalimnion and hypolimnion during summer stratification. When hypoxia spread throughout the water column during fall turnover, SRB and GSB vanished from the water column, whereas CSB (mainly Arcobacter) and PSB (Lamprocystis) became dominant and oxidized the accumulated sulfide under micro-aerobic conditions. Our results support the view that, once ecosystems have become anoxic and sulfidic, a large oxygen influx is needed to overcome the anaerobic sulfur cycle and bring the ecosystems back into their oxic state. PMID- 29528405 TI - Stent grafting simulation using a three-dimensional printed model for extensive aortic arch repair combined with coarctation. AB - Stent grafting for complex aortic anatomy remains a challenge. In particular, stent graft collapse (i.e. infolding) is possible when an excessive oversized device is needed. We describe a case of preoperative stent grafting simulation using a three-dimensional (3D) printed model for extensive aortic arch repair in a 69-year-old woman with multiple aneurysms combined with coarctation. The patient was scheduled to undergo staged hybrid repair. A stent graft larger than 28 mm in diameter was needed to deploy into a coarctation of 15 mm in diameter during the 2nd stage of the operation. Preoperative, experimental stent grafting using a 3D printed model indicated that infolding would likely not occur. Therefore, we proceeded with surgery, which was successful. This technology could be a useful application for planning complicated stent grafting. PMID- 29528407 TI - Diabetes mellitus is an independent prognostic factor for mid-term and long-term survival following transcatheter aortic valve implantation: a systematic review and meta-analysis. AB - Prior studies have proposed the unfavourable roles of diabetes mellitus (DM) in surgical populations. For patients who underwent transcatheter aortic valve implantation, the prognostic value of DM remains controversial. This review summarizes the effects of DM on short-term, mid-term and long-term prognosis in patients who undergo transcatheter aortic valve implantation. We searched the PubMed database to identify eligible articles. The odds ratio and hazard ratio with the corresponding 95% confidence interval were adopted for synthesizing short-term and medium- to long-term survival outcomes, respectively. The heterogeneity level and publication bias between studies were also estimated. Finally, 20 observational studies enrolling 19 260 patients met the eligibility criteria and, thus, were included in this review. An overall analysis identified that DM was significantly associated with the poor medium- to long-term overall survival (hazard ratio 1.21, 95% confidence interval 1.03-1.41; P = 0.019). However, no significant impact of DM on 30-day mortality was observed (odds ratio 1.10, 95% confidence interval 0.86-1.41; P = 0.46) in patients undergoing transcatheter aortic valve implantation. Further subgroup analyses indicated that the prognostic value of DM for medium- to long-term overall survival remained significant in the subgroups of multivariable origins of incorporated data, duration of follow-ups (1-year/>=2-year follow-up), Western populations and insulin-dependent diabetes mellitus. This meta-analysis demonstrates that DM is a strongly independent predictor for poor medium- to long-term overall survival but shows no significant effect of DM on 30-day mortality. Our findings need to be further verified and modified by more worldwide studies. PMID- 29528406 TI - Supplementation of Bacillus subtilis-based probiotic reduces heat stress-related behaviors and inflammatory response in broiler chickens. AB - Probiotics reduce stress-related inflammation and abnormal behaviors in humans and rodents via regulation of the microbiota-gut-brain axis. The objective of this study was to determine if probiotic, Bacillus subtilis, has similar functions in broiler chickens under heat stress (HS). Two hundred forty 1-d-old broiler chicks were assigned to 48 pens with 4 treatments: Thermoneutral (TN)-RD (regular diet), TN-PD (the regular diet mixed with 1 * 106 CFU/g feed probiotic), HS-RD and HS-PD. Probiotic (Sporulin) was fed from day 1; and HS at 32 degrees C for 10 h daily was initiated at day 15. The data showed that final BW, average daily gain , and feed conversion efficiency were improved in PD groups as compared to RD groups regardless of the ambient temperature (P < 0.01). Heterophil to lymphocyte ratio was affected by treatment and its value was in the order of HS-RD > HS-PD > TN-RD > TN-PD birds (P < 0.01). Compared to TN birds, HS birds spent more time in wing spreading, panting, squatting close to the ground, drinking, sleeping, dozing, and sitting but spent less time in eating, standing, and walking (P < 0.05 or 0.01). In addition, HS birds had greater levels of hepatic IL-6, IL-10, heat shock protein (HSP)70, and HSP70 mRNA expression (P < 0.01) and greater levels of cecal IgA and IgY (P < 0.01) compared to TN birds. Within TN groups, TN-PD birds had greater concentrations of hepatic IL-10 (P < 0.05) and cecal IgA (P < 0.01) than TN-RD birds. Within HS groups, HS-PD birds spent less time in wing spreading, panting, squatting close to the ground, drinking, sleeping, dozing, and sitting but spent more time in eating, foraging, standing, and walking than HS-RD birds (P < 0.05 or 0.01). The HS-PD birds also had lower concentrations of hepatic IL-6 and HSP70 (P < 0.01), whereas greater levels of IL-10 (P < 0.05) and lower concentrations of cecal IgA and IgY (P < 0.01). These results indicate that broilers fed the probiotic, B. subtilis, are able to cope with HS more effectively by ameliorating heat-induced behavioral and inflammatory reactions through regulation of microbiota-modulated immunity. PMID- 29528409 TI - Solid to ground-glass opacity ratio in lung adenocarcinomas: is it a new criterion for limited pulmonary resection? PMID- 29528408 TI - Broad-spectrum inhibition of Phytophthora infestans by fungal endophytes. AB - Phytophthora infestans is a devastating pathogen of tomato and potato. It readily overcomes resistance genes and applied agrochemicals and hence even today causes large yield losses. Fungal endophytes provide a largely unexplored avenue of control of Phy. infestans. Not only do endophytes produce a wide array of bioactive metabolites, they may also directly compete with and defeat pathogens in planta. Here, we tested 12 fungal endophytes isolated from different plant species in vitro for their production of metabolites with anti- Phytophthora activity. Four well-performing isolates were evaluated for their ability to suppress nine isolates of Phy. infestans on agar medium and in planta. Two endophytes reliably inhibited all Phy. infestans isolates on agar medium, of which Phoma eupatorii isolate 8082 was the most promising. It nearly abolished infection by Phy. infestans in planta. Our data indicate a role for the production of anti-Phytophthora compounds by the fungus and/or an enhanced plant defense response, as evident by an enhanced anthocyanin production. Here, we present a potential biocontrol agent, which can inhibit a broad-spectrum of Phy. infestans isolates. Such broadly acting inhibition is ideal, because it allows for effective control of genetically diverse isolates and may slow the adaptation of Phy. infestans. PMID- 29528410 TI - Meta-analysis of endophyte-infected tall fescue effects on cattle growth rates. AB - The objective of this study was to quantitatively summarize literature reporting endophyte-infected (Neotyphodium coenophialum) tall fescue (Festuca arundinacea) effects on cattle ADG. This meta-analysis evaluated endophyte infection level, climate, and forage yield using a literature dataset of 138 treatments from 20 articles. Three infection level measurements were tested: endophyte infection as a percentage of infected tillers (E%); ergovaline concentration in ppb ([E]); and total ergot alkaloid concentration ([TEA]). Three types of climate variables were used: base values (temperature, humidity, and relative humidity), climate indices (heat index and temperature-heat index [THI]), and novel climate variables accounting for duration of climate effects. Mixed effect models, weighted by 1/SEM, including a random effect of study were built for each factorial combination of measurement method and climate variable group. Because many studies were missing SEM, two datasets were used: one containing only data with SEM reported and one that also included missing-SEM data. For the complete-SEM dataset (CSD), models were weighted by 1/SEM. In the missing-SEM dataset (MSD) the mean reported 1/SEM was assigned as the weight for all missing SEM treatments. Although 18 initial models were created (2 * 3 * 3 factorial approach), the backward stepwise derivation resulted in models that included only endophyte infection level, suggesting a negative relationship between infection level and ADG. The CSD models predicted ADG to decrease 39 and 33 g/d with each increase of 100 ppb of [TEA] and [E], and by 39 g/d for each increase of 10% E%. In the MSD dataset, predicted ADG decreased by 39 and 33 g/d with each increase of 100 ppb of [TEA] and [E], and by 47 g/d for each increase of 10% E%. All relationships reported had P < 0.05. After visual inspection of the data, piecewise regression was used to identify an infection threshold (IT) of 60 ppb [E] and 11 E%, where the effect of infection level was constant on either side of the IT. The ADG was 40% and 49% greater for infection levels below the IT for [E] and E%, respectively. Across THI values in the analysis, ADG decreases ranged from 11.2% to 45.0% for cattle grazing endophyte-infected tall fescue compared to non-ergot alkaloid endophyte infected tall fescue. Pasture E%, [E], and [TEA] have a negative relationship with ADG in growing cattle, and increasing temperature decreases ADG when infection level is greater than the IT. PMID- 29528411 TI - Conserved genomic and amino acid traits of cold adaptation in subzero-growing Arctic permafrost bacteria. AB - Permafrost accounts for 27% of all soil ecosystems and harbors diverse microbial communities. Our understanding of microorganisms in permafrost, their activities and adaptations, remains limited. Using five subzero-growing (cryophilic) permafrost bacteria, we examined features of cold adaptation through comparative genomic analyses with mesophilic relatives. The cryophiles possess genes associated with cold adaptation, including cold shock proteins, RNA helicases, and oxidative stress and carotenoid synthesis enzymes. Higher abundances of genes associated with compatible solutes were observed, important for osmoregulation in permafrost brine veins. Most cryophiles in our study have higher transposase copy numbers than mesophiles. We investigated amino acid (AA) modifications in the cryophiles favoring increased protein flexibility at cold temperatures. Although overall there were few differences with the mesophiles, we found evidence of cold adaptation, with significant differences in proline, serine, glycine and aromaticity, in several cryophiles. The use of cold/hot AA ratios of >1, used in previous studies to indicate cold adaptation, was found to be inadequate on its own. Comparing the average of all cryophiles to all mesophiles, we found that overall cryophiles had a higher ratio of cold adapted proteins for serine (more serine), and to a lesser extent, proline and acidic residues (fewer prolines/acidic residues). PMID- 29528412 TI - High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort. AB - Objectives: To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to a dolutegravir-based regimen, regardless of the genotypic susceptibility score (GSS). Patients and methods: This was an observational single-centre study assessing ART-treated patients with plasma viral load (pVL) <50 copies/mL who were switched to a dolutegravir-based regimen with 1 year of follow-up. PCR negative was defined as an undetected PCR signal. Trough plasma concentration (C24) was determined using UPLC-MS/MS. Results: Two hundred and thirty-nine patients initiated a dolutegravir-based regimen: 12%, 29% and 59% had a total GSS of 1 or 1.5 (group 1), 2 or 2.5 (group 2) and 3 (group 3), respectively. At switch initiation, the median time since first ART and the median duration with pVL <50 copies/mL were 13 years (IQR = 6 19) and 3 years (IQR = 1-6), respectively. Median times since last genotype were 9, 10 and 5 years for groups 1, 2 and 3, respectively. Twenty patients (8.4%) discontinued the dolutegravir-based regimen due to adverse events. During the study, 96.4% (n = 661/686) of all pVL were <50 copies/mL. Four patients (1.7%) experienced virological failure (two pVL >50 copies/mL) without emergence of resistance; these patients' GSSs were 2, 2.5, 3 and 3. The median dolutegravir C24 was 1545 ng/mL (IQR = 1150-2097). Of the patients with pVL <20 copies/mL, 72% were PCR negative during the follow-up, with no difference between the three groups of patients. Conclusions: This observational cohort study showed a high level of virological suppression maintenance in the first year following the switch to a dolutegravir-based regimen, even in patients with GSS <=2. PMID- 29528413 TI - 'Happy the man, who, studying nature's laws, Thro' known effects can trace the secret cause.' Do we have enough pieces to solve the pyrazinamide puzzle? AB - A low pH was assumed to be required for the activity of pyrazinoic acid (the active form of pyrazinamide) against Mycobacterium tuberculosis, but recently activity has been demonstrated at neutral pH. Renewed interest in pyrazinamide has led to an increasing number of potential targets and the suspicion that pyrazinamide is a 'dirty drug'. However, it is our opinion that the recent demonstration that pyrazinoic acid is active against PanD provides an alternative explanation for the secret of pyrazinamide's unusual activity. In this article we propose that PanD is the primary target of pyrazinoic acid but expression of pyrazinoic acid susceptibility requires an intact stress response. As the mycobacterial stress response requires the interaction of a number of genes, disruption of any could result in an inability to enter the susceptible phenotype. We believe this model can explain most of the recent observations of the seemingly diverse spectrum of activity of pyrazinamide. PMID- 29528414 TI - Carbon-ion radiotherapy for inoperable endometrial carcinoma. AB - This is a pooled analysis to evaluate the toxicity and efficacy of carbon-ion radiotherapy (C-ion RT) for inoperable endometrial carcinoma. Eligible patients had previously untreated Stage I-III endometrial carcinoma without para-aortic lymph node metastasis. Total dose to the tumor was 62.4-74.4 Gy [relative biological effectiveness (RBE)] in 20 fractions, and the dose to the gastrointestinal tract was limited to <60 Gy (RBE). Intracavitary brachytherapy was not combined in the present study. Fourteen patients with endometrial carcinoma were analyzed. Ten of the 14 patients were judged medically inoperable, and the others refused surgery. The numbers of patients with Stage I, II and III disease were 1, 9 and 4, respectively. Tumor size was 3.8-13.8 cm in maximum diameter. Median follow-up periods for all patients and surviving patients were 50 months (range, 12-218 months) and 78 months (range, 23-218 months), respectively. Two of three patients receiving 62.4-64.8 Gy (RBE) had local recurrence whereas none of 11 patients receiving 68.0 Gy (RBE) or more had local recurrence. Three patients developed distant metastases and one of them also had local recurrence. The 5-year local control, progression-free survival, overall survival, and cause-specific survival rates were 86%, 64%, 68% and 73%, respectively. No patient developed Grade 3 or higher acute or late toxicity. The present study showed that C-ion RT alone could be a safe and curative treatment modality for inoperable endometrial carcinoma. PMID- 29528416 TI - Musical Tasks and Energetic Arousal. AB - Background: Music is widely recognized as a motivating stimulus. Investigators have examined the use of music to improve a variety of motivation-related outcomes; however, these studies have focused primarily on passive music listening rather than active participation in musical activities. Objective: To examine the influence of participation in musical tasks and unique participant characteristics on energetic arousal. Methods: We used a one-way Welch's ANOVA to examine the influence of musical participation (i.e., a non-musical control and four different musical task conditions) upon energetic arousal. In addition, ancillary analyses of participant characteristics including personality, age, gender, sleep, musical training, caffeine, nicotine, and alcohol revealed their possible influence upon pretest and posttest energetic arousal scores. Results: Musical participation yielded a significant relationship with energetic arousal, F(4, 55.62) = 44.38, p = .000, estimated omega2 = 0.60. Games-Howell post hoc pairwise comparisons revealed statistically significant differences between five conditions. Descriptive statistics revealed expected differences between introverts' and extraverts' energetic arousal scores at the pretest, F(1, 115) = 6.80, p = .010, partial eta2= .06; however, mean differences failed to reach significance at the posttest following musical task participation. No other measured participant characteristics yielded meaningful results. Conclusions: Passive tasks (i.e., listening to a story or song) were related to decreased energetic arousal, while active musical tasks (i.e., singing, rhythm tapping, and keyboard playing) were related to increased energetic arousal. Musical task participation appeared to have a differential effect for individuals with certain personality traits (i.e., extroverts and introverts). PMID- 29528415 TI - Epitope-Specific Humoral Responses to Human Cytomegalovirus Glycoprotein-B Vaccine With MF59: Anti-AD2 Levels Correlate With Protection From Viremia. AB - The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase 2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB enzyme-linked immunosorbent assay (ELISA) antibody levels whose titer correlated directly with protection against posttransplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focused on 4 key antigenic domains (AD) of gB (AD1, AD2, AD4, and AD5), measuring antibody levels in patient sera and correlating these with posttransplant HCMV viremia. Vaccination of seropositive patients significantly boosted preexisting antibody levels against the immunodominant region AD1 as well as against AD2, AD4, and AD5. A decreased incidence of viremia correlated with higher antibody levels against AD2 but not with antibody levels against the other 3 ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients. PMID- 29528417 TI - No Effect of Pegylated Interferon-alpha on Total HIV-1 DNA Load in HIV-1/HCV Coinfected Patients. AB - Pegylated interferon-alpha (pIFN-alpha) is suggested to lower human immunodeficiency virus type-1 (HIV-1) DNA load in antiretroviral therapy (ART) treated patients. We studied kinetics of HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV) coinfected patients, treated with pIFN-alpha for HCV and categorized into 3 groups according to start of ART: chronic HIV-1 infection (n = 22), acute HIV-1 infection (n = 8), no-ART (n = 10). Total HIV-1 DNA levels in 247 peripheral blood mononuclear cell samples were stable before, during, and after pIFN-alpha treatment in all groups. Our results question the benefit of pIFN alpha as an immunotherapeutic agent for reducing the HIV-1 reservoir. PMID- 29528419 TI - Evaluation of Stereotactic Radiotherapy of the Resection Cavity After Surgery of Brain Metastases Compared to Postoperative Whole-Brain Radiotherapy (ESTRON)-A Single-Center Prospective Randomized Trial. AB - BACKGROUND: Neurosurgical resection is recommended for symptomatic brain metastases, in oligometastatic patients or for histology acquisition. Without adjuvant radiotherapy, roughly two-thirds of the patients relapse at the resection site within 24 mo, while the risk of new metastases in the untreated brain is around 50%. Adjuvant whole-brain radiotherapy (WBRT) can reduce the risk of both scenarios of recurrence significantly, although the associated neurocognitive toxicity is substantial, while stereotactic radiotherapy (SRT) improves local control at comparably low toxicity. OBJECTIVE: To compare locoregional control and treatment-associated toxicity for postoperative SRT and WBRT after the resection of 1 brain metastasis in a single-center prospective randomized study. METHODS: Fifty patients will be randomized to receive either hypofractionated SRT of the resection cavity and single- or multisession SRT of all unresected brain metastases (up to 10 lesions) or WBRT. Patients will be followed-up regularly and the primary endpoint of neurological progression-free survival will be assessed by magnetic resonance imaging (MRI). Quality of life and neurocognition will be assessed in 3-mo intervals using standardized tests and EORTC questionnaires. EXPECTED OUTCOMES: We expect to show that postoperative SRT of the resection cavity and further unresected brain metastases is a valid means of improving locoregional control over observation at less neurocognitive toxicity than caused by WBRT. DISCUSSION: The present study is the first to compare locoregional control as well as neurocognitive toxicity for postoperative SRT and WBRT in patients with up to 10 metastases, while utilizing a highly sensitive and standardized MRI protocol for treatment planning and follow-up. PMID- 29528420 TI - Annual changes in the Fukushima residents' views on the safety of water and air environments and their associations with the perception of radiation risks. AB - Fukushima residents' negative views on the safety of water and air environments have been a concern since the Fukushima Dai-ichi Nuclear power plant (FDNPP) accident. The objective of this study was to clarify the factors determining these negative views and their association with radiation risk perception using the opinion poll conducted by Fukushima Prefecture from 2010 to 2015. In a model, in which the objective variables were the views on the safety of water and air environments, and the explanatory variables were the regions constituting Fukushima and the age and sex of the residents, the odds ratio (OR) of the views on the safety of the water and air environments (reference region: the least affected region) was significantly low at 0.11 [95% confidence interval (CI): 0.04-0.28] to 0.18 (0.07-0.46) in the Hamadori region including the evacuation order area, from the accident in 2011 to 2015, with the exception of 2014. In another model, in which the region was excluded from the explanatory variables and radiation risk perception, the distance from the FDNPP and the air dose rate were added to the previous model as an explanatory variable, the views on the safety of the water and air environments were strongly associated with low radiation risk perception (low anxiety) in 2012-2015 [OR: 7.73 (5.25-11.4) to 10.3 (6.71-15.8)], distance from FDNPP, and age, but not with air dose rate. This result suggests that the radiation risk perception, distance from FDNPP, and age were factors determining people's views on the safety of the water and air environment. PMID- 29528421 TI - The outcome of mitral regurgitation after the repair of anomalous left coronary artery from the pulmonary artery in infants and older children. AB - OBJECTIVES: Mitral regurgitation (MR) in the majority of infants with an anomalous left coronary artery from the pulmonary artery (ALCAPA) has been shown to improve without concomitant mitral valve repair. However, the outcome of MR in older children with ALCAPA is unclear. The purpose of this study was to compare the outcome of MR following the ALCAPA repair in infants and older children. METHODS: Forty-six patients (34 were younger than 1 year and 12 were aged 1-12 years) underwent the repair for ALCAPA in our institution from June 2006 to June 2016. Baseline and follow-up data were collected from records, and the latest echocardiogram was performed for all surviving patients from June 2017 to August 2017. RESULTS: Of the 34 infants, 82% had moderate-to-severe ventricular dysfunction, and 47% had significant MR at presentation. Fifty-seven percent of the older age group had MR, though none of them had ventricular dysfunction. Two infants and 3 older children underwent concomitant mitral valve repair. There were 2 early deaths in the infantile group. On follow-up, ventricular function normalized in 88% of infants; 12.5% of the infants had moderate-to-severe MR on follow-up, and 50% of the older children had moderate-to-severe MR on follow-up. CONCLUSIONS: The ALCAPA repair has excellent survival outcomes in all age groups. MR improves in the majority of infants with revascularization alone. MR worsens or persists in a significant number of older children following the ALCAPA repair, and they are more likely to require reinterventions for the mitral valve on follow-up. PMID- 29528422 TI - Exploration of genetic basis underlying individual differences in radiosensitivity within human populations using genome editing technology. AB - DNA double-strand breaks (DSBs) induced by ionizing radiation (IR) are the initial and critical step in major alteration of genetic information and cell death. To prevent deleterious effects, DNA repair systems recognize and re-join DNA DSBs in human cells. It has been suggested that there are individual differences in radiosensitivity within human populations, and that variations in DNA repair genes might contribute to this heterogeneity. Because confounding factors, including age, gender, smoking, and diverse genetic backgrounds within human populations, also influence the cellular radiosensitivity, to accurately measure the effect of candidate genetic variations on radiosensitivity, it is necessary to use human cultured cells with a uniform genetic background. However, a reverse genetics approach in human cultured cells is difficult because of their low level of homologous recombination. Engineered endonucleases used in genome editing technology, however, can enable the local activation of DNA repair pathways at the human genome target site to efficiently introduce genetic variations of interest into human cultured cells. Recently, we used this technology to demonstrate that heterozygous mutations of the ATM gene, which is responsible for a hyper-radiosensitive genetic disorder, ataxia-telangiectasia, increased the number of chromosomal aberrations after IR. Thus, understanding the heterozygous mutations of radiosensitive disorders should shed light on the genetic basis underlying individual differences in radiosensitivity within human populations. PMID- 29528423 TI - A Role for Salivary Peptides in the Innate Defense Against Enterotoxigenic Escherichia coli. AB - Background: Diarrheal disease from enterotoxigenic Escherichia coli (ETEC) causes significant worldwide morbidity and mortality in young children residing in endemic countries and is the leading cause of traveler's diarrhea. As ETEC enters the body through the oral cavity and cotransits the digestive tract with salivary components, we hypothesized that the antimicrobial activity of salivary proteins might extend beyond the oropharynx into the proximal digestive tract. Results: Here, we show that the salivary peptide histatin-5 binds colonization factor antigen I pili, thereby blocking adhesion of ETEC to intestinal epithelial cells. Mechanistically, we demonstrate that histatin-5 stiffens the typically dynamic pili, abolishing their ability to function as spring-like shock absorbers, thereby inhibiting colonization within the turbulent vortices of chyme in the gastrointestinal tract. Conclusions: Our data represent the first report of a salivary component exerting specific antimicrobial activity against an enteric pathogen and suggest that histatin-5 and related peptides might be exploited for prophylactic and/or therapeutic uses. Numerous viruses, bacteria, and fungi traverse the oropharynx to cause disease, so there is considerable opportunity for various salivary components to neutralize these pathogens prior to arrival at their target organ. Identification of additional salivary components with unexpectedly broad antimicrobial spectra should be a priority. PMID- 29528424 TI - Do the public think medical regulation keep them safe? AB - Objective: To assess public knowledge and expectations of the ways to assess doctors' competence to ensure patient safety. Design setting and participants: Telephone survey of a random sample of 1000 non-institutionalized Hong Kong residents. Measures and results: Only 5% of public were correct that doctors are not required to periodically be assessed, and 9% were correct that the doctors are not required to update knowledge and skills for renewing their license. These results echo international studies showing a low public knowledge of medical regulation. The public overwhelmingly felt a periodic assessment (92%) and requirements for continuous medical education (91%) were important processes for assuring doctors' competence. A high proportion of the public felt that lay representation in the Medical Council was insufficient. Conclusion: There is a significant gap between public expectations and understanding of the existing medical regulation and the actual policies and practices. Despite a lack of public knowledge, the public thought it important to have an ongoing structured monitoring and assessment mechanism to assure doctors' competence. The public also expects a greater involvement in the regulatory processes as members of the Medical Council. There is a need to review and enhance the current regulatory system to meet public expectation and ensure accountability for the privilege and trust granted by the State in professional self-regulation. In the context of our complex health system, a thorough understanding on the dynamic interactions between different institutions and their complementary roles in a meta-regulatory framework is required in assuring patient safety. PMID- 29528425 TI - Selection of carbon beam therapy: biophysical models of carbon beam therapy. AB - Variation in the relative biological effectiveness (RBE) within the irradiation field of a carbon beam makes carbon-ion radiotherapy unique and advantageous in delivering the therapeutic dose to a deep-seated tumor, while sparing surrounding normal tissues. However, it is crucial to consider the RBE, not only in designing the dose distribution during treatment planning, but also in analyzing the clinical response retrospectively. At the National Institute of Radiological Sciences, the RBE model was established based on the response of human salivary gland cells. The response was originally handled with a linear-quadratic model, and later with a microdosimetric kinetic model. Retrospective analysis with a tumor-control probability model of non-small cell cancer treatment revealed a steep dose response in the tumor, and that the RBE of the tumor was adequately estimated using the model. A commonly used normal tissue complication probability model has not yet fully been accountable for the variable RBE of carbon ions; however, analysis of rectum injury after prostate cancer treatment suggested a highly serial-organ structure for the rectum, and a steep dose response similar to that observed for tumors. PMID- 29528426 TI - Vertical Distribution and Daily Flight Periodicity of Ambrosia Beetles (Coleoptera: Curculionidae) in Florida Avocado Orchards Affected by Laurel Wilt. AB - Ambrosia beetles have emerged as significant pests of avocado ((Persea americana Mill. [Laurales: Lauraceae])) due to their association with pathogenic fungal symbionts, most notably Raffaelea lauricola T.C. Harr., Fraedrich & Aghayeva (Ophiostomatales: Ophiostomataceae), the causal agent of the laurel wilt (LW) disease. We evaluated the interaction of ambrosia beetles with host avocado trees by documenting their flight height and daily flight periodicity in Florida orchards with LW. Flight height was assessed passively in three avocado orchards by using ladder-like arrays of unbaited sticky traps arranged at three levels (low: 0-2 m; middle: 2-4 m; high: 4-6 m). In total, 1,306 individuals of 12 Scolytinae species were intercepted, but six accounted for ~95% of the captures: Xyleborus volvulus (Fabricius) (Coleoptera: Curculionidae), Xyleborinus saxesenii Ratzeburg (Coleoptera: Curculionidae), Euplatypus parallelus (Fabricius) (Coleoptera: Curculionidae), Xyleborus bispinatus Eichhoff (Coleoptera: Curculionidae), Xyleborus affinis Eichhoff (Coleoptera: Curculionidae), and Hypothenemus sp. (Coleoptera: Curculionidae). The primary vector of R. lauricola, Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae), was not detected. Females of X. volvulus showed a preference for flight at low levels and X. bispinatus for the low and middle levels; however, captures of all other species were comparable at all heights. At a fourth orchard, a baiting method was used to document flight periodicity. Females of X. saxesenii and Hypothenemus sp. were observed in flight 2-2.5 h prior to sunset; X. bispinatus, X. volvulus, and X. affinis initiated flight at ~1 h before sunset and Xylosandrus crassiusculus (Motschulsky) (Coleoptera: Curculionidae) at 30 min prior to sunset. Results suggest that ambrosia beetles in South Florida fly near sunset (when light intensity and wind speed decrease) at much greater heights than previously assumed and have species-specific patterns in host-seeking flight. PMID- 29528427 TI - Addressing the challenge of proper delineation of lymph node stations in modern radiotherapy for lung cancer. AB - We greatly appreciate the recent publication of a Japan Lung Cancer Society and Japanese Society for Radiation Oncology consensus-based computed tomographic atlas for defining regional lymph node stations (LNSs) for radiotherapy for lung cancer. This atlas is based on the International Association for the Study of Lung Cancer (IASLC) consensus lymph node map, which resolved differences between the Japanese and American classification and was incorporated into the seventh edition of the TNM staging system. The authors must be commended for providing a very clear, comprehensive presentation of the borders of the mediastinal and hilar LNSs, using a multidisciplinary approach. The Atlas created by Itazawa et al. is the second published consensus-based atlas for defining the LNSs for lung cancer radiotherapy according to the IASLC-endorsed LNS map. The differences between the two published atlases of LNS delineation in radiation oncology are discussed. PMID- 29528428 TI - Extended and Continuous Decline in Effective Population Size Results in Low Genomic Diversity in the World's Rarest Hyena Species, the Brown Hyena. AB - Hyenas (family Hyaenidae), as the sister group to cats (family Felidae), represent a deeply diverging branch within the cat-like carnivores (Feliformia). With an estimated population size of <10,000 individuals worldwide, the brown hyena (Parahyaena brunnea) represents the rarest of the four extant hyena species and has been listed as Near Threatened by the IUCN. Here, we report a high coverage genome from a captive bred brown hyena and both mitochondrial and low coverage nuclear genomes of 14 wild-caught brown hyena individuals from across southern Africa. We find that brown hyena harbor extremely low genetic diversity on both the mitochondrial and nuclear level, most likely resulting from a continuous and ongoing decline in effective population size that started ~1 Ma and dramatically accelerated towards the end of the Pleistocene. Despite the strikingly low genetic diversity, we find no evidence of inbreeding within the captive bred individual and reveal phylogeographic structure, suggesting the existence of several potential subpopulations within the species. PMID- 29528429 TI - Comparison of Enzymatic Assay for HBA1C Measurement (Abbott Architect) With Capillary Electrophoresis (Sebia Minicap Flex Piercing Analyser). AB - Objective: To compare the analytical performances of the enzymatic method (EM) and capillary electrophoresis (CE) for hemoglobin A1c (HbA1c) measurement. Methods: Imprecision, carryover, stability, linearity, method comparison, and interferences were evaluated for HbA1c via EM (Abbott Laboratories, Inc) and CE (Sebia). Results: Both methods have shown overall within-laboratory imprecision of less than 3% for International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) units (<2% National Glycohemoglobin Standardization Program [NGSP] units). Carryover effects were within acceptable criteria. The linearity of both methods has proven to be excellent (R2 = 0.999). Significant proportional and constant difference were found for EM, compared with CE, but were not clinically relevant (<5 mmol/mol; NGSP <0.5%). At the clinically relevant HbA1c concentration, stability observed with both methods was acceptable (bias, <3%). Triglyceride levels of 8.11 mmol per L or greater showed to interfere with EM and fetal hemoglobin (HbF) of 10.6% or greater with CE. Conclusion: The enzymatic method proved to be comparable to the CE method in analytical performances; however, certain interferences can influence the measurements of each method. PMID- 29528430 TI - Mental Health Stigma and Its Effects on Treatment-Related Outcomes: A Narrative Review. AB - Introduction: Many service members experiencing symptoms of mental health conditions do not receive mental health care for these symptoms. The stigma associated with having a mental health condition or seeking treatment is often cited as a specific barrier to mental health care. However, study results bearing on the question of whether and how stigma may reduce treatment-seeking have been inconsistent. Methods: We searched 10 databases for sources published between 2004 and 2014 that prospectively linked stigma to treatment-related outcomes (such as treatment seeking, retention, and reports of symptoms) using longitudinal data and predictive models. The searches yielded 2,409 sources. After reviewing titles and abstracts for relevance, we retained 15 sources to undergo full-text review. Results: Overall, this review illustrates that evidence exploring the direct effect of stigma on treatment-related outcomes is still scant. We identified two studies whose outcomes conflict when it comes to stigma and treatment-initiation and utilization, and three studies found no relationship between stigma and treatment-initiation and utilization. One study suggested that the relationship between stigma and experience of symptoms is nuanced and may depend on the type of stigma and types of symptoms considered. Meager evidence was available to inform the relationship between stigma and treatment duration, attrition, and quality of life/functioning. The evidence was not sufficient to draw conclusions about the state of these relationships. No conclusions could be made about the direct impact of stigma on treatment-related outcomes among military service members given that only two studies explored this relationship among military service members. Conclusion: Current research does not provide a true understanding of the degree to which mental illness stigma affects treatment related outcomes for service members experiencing mental health challenges. This understanding could only be developed through a longitudinal study assessing prospectively whether stigma affects treatment-utilization in the military. Should such a study show that stigma reduces treatment-utilization, the military would need to consider whether changes to their current approaches to stigma reduction are warranted. PMID- 29528431 TI - Pollination Requirements of Almond (Prunus dulcis): Combining Laboratory and Field Experiments. AB - Almond (Prunus dulcis (Mill.) D. A. Webb; Rosales: Rosaceae) is a cash crop with an estimated global value of over seven billion U.S. dollars annually and commercial varieties are highly dependent on insect pollination. Therefore, the understanding of basic pollination requirements of the main varieties including pollination efficiency of honey bees (Apis mellifera, Linnaeus, Hymenoptera: Apidae) and wild pollinators is essential for almond production. We first conducted two lab experiments to examine the threshold number of pollen grains needed for successful pollination and to determine if varietal identity or diversity promotes fruit set and weight. Further, we examined stigma and ovules of flowers visited by Apis and non-Apis pollinators in the field to study the proportion of almond to non-almond pollen grains deposited, visitation time per flower visit, and tube set. Results indicate that the threshold for successful fertilization is around 60 pollen grains, but pollen can be from any compatible variety as neither pollen varietal identity nor diversity enhanced fruit set or weight. Andrena cerasifolii Cockerell (Hymenoptera: Andrenidae) was a more effective pollinator on a per single visit basis than Apis and syrphid flies. Nevertheless, Apis was more efficient than A. cerasifolii and syrphid flies as they spent less time on a flower during a single visit. Hence, planting with two compatible varieties and managing for both Apis and non-Apis pollinators is likely to be an optimal strategy for farmers to secure high and stable pollination success. PMID- 29528432 TI - Intracranial Dural Arteriovenous Fistulas with Pial Arterial Supply. AB - BACKGROUND: Pial arterial supplies are sometimes found in patients with dural arteriovenous fistulas (DAVFs), though their characteristics have rarely been clarified. OBJECTIVE: To investigate the characteristics of pial arterial supplies in DAVFs and to discuss their pathophysiology and treatment. METHODS: Two hundred four consecutive patients with intracranial DAVFs over 11 yr were retrospectively reviewed. Clinical factors and radiological findings, including the presence of pial arterial supplies, were evaluated. Supply from a pial artery was classified into 2 categories: dilated pre-existing dural branches of pial arteries, and a "pure" pial supply. RESULTS: Twenty-three of 204 patients (11.3%) showed an additional pial arterial supply. Multivariate analysis identified 3 independent predictors of a pial arterial supply: younger age (P < .0005), DAVF within the tentorium (P = .0162), and presence of venous dilatation (P = .0001). A dilated pre-existing dural branch of a pial artery was identified in 17 patients, while 8 had a pure pial supply. Of these 23 patients, 17 underwent interventional therapy. No postoperative intracranial hemorrhage or infarction occurred in patients with pial arterial supplies. CONCLUSION: An additional pial supply is not uncommon in DAVFs and may be explained by a rich physiological pial arterial supply to the dura mater from the posterior circulation, while potential angiogenesis due to venous hypertension remains speculative. Prior to interventional treatment for DAVFs, recognition of a pial arterial supply to the DAVF might influence the treatment strategy and could help avoid inadvertent retrograde embolization of brain supplying vessels through the pial network. PMID- 29528433 TI - Schlafen-8 is essential for lymphatic endothelial cell activation in experimental autoimmune encephalomyelitis. AB - Schlafen-8 (Slfn8) is a member of the Schlafen family of proteins, which harbor helicase domains and are induced by LPS and interferons. It has been reported that the Schlafen family are involved in various cellular functions, including proliferation, differentiation and regulation of virus replication. Slfn8 has been implicated in T-cell differentiation in the thymus. However, the roles of Slfn8 in the immune system remains unclear. In this study, we generated Slfn8 knockout mice (Slfn8-/-) and investigated the immunological role of Slfn8 using the T-cell-mediated autoimmune model experimental autoimmune encephalomyelitis (EAE). We found that the clinical score was reduced in Slfn8-/- mice. IL-6 and IL 17A cytokine production, which are associated with EAE onset and progression, were decreased in the lymph nodes of Slfn8-/- mice. Immune cell populations in Slfn8-/- mice, including macrophages, neutrophils, T cells and B cells, did not reveal significant differences compared with wild-type mice. In vitro activation of Slfn8-/- T cells in response to TCR stimulation also did not reveal significant differences. To confirm the involvement of non-hematopoietic cells, we isolated CD45- CD31+ endothelial cells and CD45-CD31- gp38+ fibroblastic reticular cells by FACS sorting. We showed that the levels of IL-6 and Slfn8 mRNA in CD45- CD31+ endothelial cells were increased after EAE induction. In contrast, the level of IL-6 mRNA after EAE induction was markedly decreased in CD31+ endothelial cells from Slfn8-/- mice. These results indicate that Slfn8 may play a role in EAE by regulating inflammation in endothelial cells. PMID- 29528434 TI - A bHLH Transcription Factor Regulates Bisbibenzyl Biosynthesis in the Liverwort Plagiochasma appendiculatum. AB - Liverworts, a section of the bryophyte plants which pioneered the colonization of terrestrial habitats, produce cyclic bisbibenzyls as secondary metabolites. These compounds are generated via the phenylpropanoid pathway, similar to flavonoid biosynthesis, for which basic helix-loop-helix (bHLH) transcription factors have been identified as one of the important regulators in higher plants. Here, a bHLH gene homolog (PabHLH) was isolated from the liverwort species Plagiochasma appendiculatum and its contribution to bisbibenzyl biosynthesis was explored. Variation in the abundance of PabHLH transcript mirrored that of tissue bisbibenzyl content in three different liverwort tissues. A phylogenetic analysis based on the bHLH domain sequence suggested that the gene encodes a member of bHLH subgroup IIIf, which clusters proteins involved in flavonoid synthesis. The gene's transient expression in onion epidermal cells implied that its product localized to the nucleus, and a transactivation assays in yeast showed that it was able to activate transcription. In both callus and thallus, the overexpression of PabHLH boosted bisbibenzyl accumulation, while also up regulating PaPAL, Pa4CL1, PaSTCS1 and two genes encoding P450 cytochromes, and its RNA interference (RNAi)-induced suppression down-regulated the same set of genes and reduced the accumulation of bisbibenzyls. The abundance of PaCHS and PaFNSI transcript was related to flavonoid accumulation in transgenic thallus. PabHLH represents a candidate for the metabolic engineering of bisbibenzyl content. PMID- 29528435 TI - Bilayered Medium for Rapid Isolation of Mycobacterium tuberculosis. AB - Background: A bilayered medium (BLM) seemed to indicate a rapid recovery time from Mycobacterium tuberculosis (M. tuberculosis) for the patients in question, namely, 48 hours. Method: Sputum specimens collected from 112 patients with clinically suspected pulmonary tuberculosis were subjected to Ziehl-Neelsen staining and inoculation on Lowenstein-Jensen medium (LJM) and BLM. Results: BLM grew all the 36 (100%) smear positive samples, while LJM grew only 20 (55.5%). On the first 2 days of incubation, BLM grew M. tuberculosis colonies in 14 specimens and in 36 specimens after 3 to 6 days. From the seventh day until the end of the incubation period, BLM grew M. tuberculosis in only 9 specimens. The mean (SD) time for detection on BLM was 6 (5) days, whereas on LJM, it was 22 (12) days. Conclusions: BLM is more sensitive than LJM in positive and negative smears. It was also much faster than other methods in detecting the presence of M. tuberculosis. PMID- 29528436 TI - Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients. AB - Background: Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal. Methods: We analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells. Results: We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients. Conclusion: Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients. PMID- 29528437 TI - Searching for a Serological Correlate of Protection for a CMV Vaccine. PMID- 29528438 TI - Assessing the Risk of Establishment of Rhagoletis cerasi (Diptera: Tephritidae) in the United States and Globally. AB - The European cherry fruit fly, Rhagoletis cerasi (L.) (Diptera: Tephritidae), is a highly destructive pest of cherries (Prunus spp.) (Rosaceae) in Europe and Asia. In 2016, R. cerasi was detected in Ontario, Canada, and in 2017 in New York State, USA, the first records of this pest in North America. The initial detections in Canada caused concern for the major cherry-growing states of Michigan, Washington, Oregon, and California in the United States. Establishment of R. cerasi in the United States could restrict cherry exports to other markets and increase costs needed for fly control, but it is unknown if R. cerasi can establish in U.S. commercial cherry regions. Here, we used the CLIMEX ecological niche model to determine the risk of establishment of R. cerasi in the United States and globally. Within the United States under a no-irrigation scenario, R. cerasi would establish in the East and West Coasts; however, under an irrigation scenario, its distribution would expand to the major cherry-growing regions in the interior of central and eastern Washington and in California. Results also showed that if introduced, R. cerasi would likely establish in eastern China, Japan, the Koreas, Australia, New Zealand, South America, South Africa, Mexico, and Canada. Host plant (Prunus spp. and Lonicera spp. [Caprifoliaceae]) presence, although not included in models, would affect fly establishment. Our results stress the importance of surveying for R. cerasi to prevent its spread and establishment within the United States and other countries. PMID- 29528439 TI - Glycated albumin versus hemoglobin A1c and mortality in diabetic hemodialysis patients: a cohort study. AB - Background: For glycemic control in diabetic patients on dialysis it was unclear what level of glycated albumin (GA) was associated with the lowest mortality and GA's utility. Accordingly, we examined the difference in association between GA and hemoglobin A1c (HbA1c) with 1-year mortality in a cohort of the Japanese Society for Dialysis Therapy. Methods: We examined 84 282 patients with prevalent diabetes who were on maintenance hemodialysis (HD) (female 30.3%; mean age 67.3 +/- 11.2 years; mean dialysis vintage 6.4 +/- 4.5 years). Of them, 22 441 had both GA and HbA1c. We followed these for a year, 2013-14, using Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence limits for 1-year mortality after adjusting for potential confounders such as baseline age, sex, smoking and diabetes type. Results: One-year mortality was lowest in diabetic HD patients who had GA levels of 15.6-18.2% and HbA1c levels of 5.8-6.3%. The associations were linear or J-shaped for GA and U-shaped for HbA1c. Adjusted HRs were significantly higher in patients with GA <12.5% and GA >=22.9%. This trend flattened in elderly patients, those with higher hemoglobin or those with prior cardiovascular disease. In addition, the C-statistics, Harrell's C and category free net reclassification improvement to predict 1-year mortality were better when GA was added to the model than when HbA1c was added. Conclusions: There was a linear or J-shaped association between GA and 1-year mortality, with the lowest mortality at GA 15.6-18.2%. Furthermore, our analyses suggest the potential superiority of GA over HbA1c in predicting mortality. PMID- 29528440 TI - Corrigendum to "Challenges Associated With Applying Physiologically Based Pharmacokinetic Modeling for Public Health Decision-Making". PMID- 29528441 TI - Endovascular Treatment of Posterior Cerebral Artery Aneurysms With Flow Diversion: Case Series and Systematic Review. AB - BACKGROUND: Flow diversion of posterior cerebral artery (PCA) aneurysms has not been widely reported, possibly owing to concerns regarding parent vessel size and branch vessel coverage. OBJECTIVE: To examine the safety and effectiveness of PCA aneurysm flow diverter treatment. METHODS: Retrospective review of PCA aneurysms treated with the Pipeline Embolization Device (PED; Medtronic Inc, Dublin, Ireland) at 3 neurovascular centers, including periprocedural complications and clinical and angiographic outcomes. Systematic review of the literature identified published reports of PCA aneurysms treated with flow diversion. Rates of aneurysm occlusion and complications were calculated, and outcomes of saccular and fusiform aneurysm treatments were compared. RESULTS: Ten PCA aneurysms in 9 patients were treated with the PED. There were 2 intraprocedural thromboembolic events (20%), including 1 symptomatic infarction and 1 delayed PED thrombosis. Eight of 10 patients returned to or improved from their baseline functional status. Complete aneurysm occlusion with parent vessel preservation was achieved in 75% (6/8) of cases at mean follow-up of 16.7 mo. Eleven of 12 (92%) major branch vessels covered by a PED remained patent. Including the present study, systematic review of 15 studies found a complete aneurysm occlusion rate of 88% (30/34) and complication rate of 26% (10/38), including 5 symptomatic ischemic strokes (13%; 5/38). Fusiform aneurysms more frequently completely occluded compared with saccular aneurysms (100% vs 70%; P = .03) but were associated with a higher complication rate (43% vs 9%; P = .06). CONCLUSION: The safety and effectiveness profile of flow diverter treatment of PCA aneurysms may be acceptable in select cases. PMID- 29528442 TI - Preoperative prognostic nutritional index as a predictor of outcomes in elderly patients after surgery for lung cancer. AB - Background and objective: The prognostic nutritional index (PNI) is based on the serum albumin level and lymphocyte count, and is a useful predictor of survival in various cancers. However, the utility of PNI in lung cancer has not been examined. The aim of this study is to assess PNI as a prognostic factor in elderly patients after surgery for primary lung cancer. Methods: A retrospective review was performed in 131 elderly patients (>=75 years old) with lung cancer who underwent curative operations at our hospital from July 2008 to December 2014. Survival was calculated by the Kaplan-Meier method. The effects of PNI and clinicopathological factors on survival were evaluated in univariate and multivariate Cox regression analyses. Results: The 5-year cancer-specific survival (CSS) rates of patients with PNI >= 45 and <45 were 76.2% and 47.8%, respectively (P = 0.0166), and the 5-year overall survival (OS) rates were 61.9% and 39.8%, respectively (P = 0.0275). Among patients who died within 5 years, mortality due to other diseases was 31%. Univariate analysis identified gender (P = 0.003), serum carcinoembryonic antigen (CEA) (P = 0.009), PNI (P = 0.027), c stage (P = 0.005), histological type (P = 0.001) and p-stage (P < 0.001) as prognostic factors. In multivariate analysis, CEA (HR 2.487, P = 0.0169), PNI (HR 2.737, P = 0.0289) and p-stage (HR 3.294, P = 0.007) were independent prognostic factors in elderly patients after curative surgery for lung cancer. Conclusions: CEA, PNI and p-stage are independent prognostic factors in elderly patients after surgery for primary lung cancer. Therefore, determination of preoperative PNI may be useful for treatment planning in elderly patients with lung cancer. PMID- 29528443 TI - Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open Label, Dose-Escalation Phase I/II Trial. AB - BACKGROUND: The median time to recurrence of glioblastoma (GB) following multimodal treatment is ~7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes. OBJECTIVE: To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective. METHODS: INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin. RESULTS: Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval [CI]: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT. CONCLUSION: These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted. PMID- 29528444 TI - Adaptation of Bordetella pertussis to the Respiratory Tract. AB - There is a lack of insight into the basic mechanisms by which Bordetella pertussis adapts to the local host environment during infection. We analyzed B. pertussis gene expression in the upper and lower airways of mice and compared this to SO4-induced in vitro Bvg-regulated gene transcription. Approximately 30% of all genes were differentially expressed between in vitro and in vivo conditions. This included several novel potential vaccine antigens that were exclusively expressed in vivo. Significant differences in expression profile and metabolic pathways were identified between the upper versus the lower airways, suggesting distinct antigenic profiles. We found high-level expression of several Bvg-repressed genes during infection, and mouse vaccination experiments using purified protein fractions from both Bvg- and Bvg+ cultures demonstrated protection against intranasal B. pertussis challenge. This study provides novel insights into the in vivo adaptation of B. pertussis and may facilitate the improvement of pertussis vaccines. PMID- 29528445 TI - Preface. PMID- 29528447 TI - Clinical Use of Cerebrovascular Compliance Imaging to Evaluate Revascularization in Patients With Moyamoya. AB - BACKGROUND: Surgical revascularization is often performed in patients with moyamoya, however routine tools for efficacy evaluation are underdeveloped. The gold standard is digital subtraction angiography (DSA); however, DSA requires ionizing radiation and procedural risk, and therefore is suboptimal for routine surveillance of parenchymal health. OBJECTIVE: To determine whether parenchymal vascular compliance measures, obtained noninvasively using magnetic resonance imaging (MRI), provide surrogates to revascularization success by comparing measures with DSA before and after surgical revascularization. METHODS: Twenty surgical hemispheres with DSA and MRI performed before and after revascularization were evaluated. Cerebrovascular reactivity (CVR)-weighted images were acquired using hypercapnic 3-Tesla gradient echo blood oxygenation level-dependent MRI. Standard and novel analysis algorithms were applied (i) to quantify relative CVR (rCVRRAW), and decompose this response into (ii) relative maximum CVR (rCVRMAX) and (iii) a surrogate measure of the time for parenchyma to respond maximally to the stimulus, CVRDELAY. Measures between time points in patients with good and poor surgical outcomes based on DSA-visualized neoangiogenesis were contrasted (signed-rank test; significance: 2-sided P < .050). RESULTS: rCVRRAW increases (P = .010) and CVRDELAY decreases (P = .001) were observed pre- vs post-revascularization in hemispheres with DSA-confirmed collateral formation; no difference was found pre- vs post-revascularization in hemispheres with poor revascularization. No significant change in rCVRMAX post revascularization was observed in either group, or between any of the MRI measures, in the nonsurgical hemisphere. CONCLUSION: Improvement in parenchymal compliance measures post-revascularization, primarily attributed to reductions in microvascular response time, is concurrent with collateral formation visualized on DSA, and may be useful for longitudinal monitoring of surgical outcomes. PMID- 29528446 TI - Characterization of migratory primordial germ cells in the aorta-gonad mesonephros of a 4.5-week-old human embryo: a toolbox to evaluate in vitro early gametogenesis. AB - STUDY QUESTION: Which set of antibodies can be used to identify migratory and early post-migratory human primordial germ cells (hPGCs)? STUDY FINDING: We validated the specificity of 33 antibodies for 31 markers, including POU5F1, NANOG, PRDM1 and TFAP2C as specific markers of hPGCs at 4.5 weeks of development of Carnegie stage (CS12-13), whereas KIT and SOX17 also marked the intra-aortic hematopoietic stem cell cluster in the aorta-gonad-mesonephros (AGM). WHAT IS KNOWN ALREADY: The dynamics of gene expression during germ cell development in mice is well characterized and this knowledge has proved crucial to allow the development of protocols for the in vitro derivation of functional gametes. Although there is a great interest in generating human gametes in vitro, it is still unclear which markers are expressed during the early stages of hPGC development and many studies use markers described in mouse to benchmark differentiation of human PGC-like cells (hPGCLCs). Early post-implantation development differs significantly between mice and humans, and so some germ cells markers, including SOX2, SOX17, IFITM3 and ITGA6 may not identify mPGCs and hPGCs equally well. STUDY DESIGN, SIZE, DURATION: This immunofluorescence study investigated the expression of putative hPGC markers in the caudal part of a single human embryo at 4.5 weeks of development. PARTICIPANTS/MATERIALS, SETTING, METHODS: We have investigated by immunofluorescence the expression of a set of 33 antibodies for 31 markers, including pluripotency, germ cell, adhesion, migration, surface, mesenchymal and epigenetic markers on paraffin sections of the caudal part, including the AGM region, of a single human embryo (CS12-13). The human material used was anonymously donated with informed consent from elective abortions without medical indication. MAIN RESULTS AND THE ROLE OF CHANCE: We observed germ cell specific expression of NANOG, TFAP2C and PRDM1 in POU5F1+ hPGCs in the AGM. The epigenetic markers H3K27me3 and 5mC were sufficient to distinguish hPGCs from the surrounding somatic cells. Some mPGC-markers were not detected in hPGCs, but marked other tissues; whereas other markers, such as ALPL, SOX17, KIT, TUBB3, ITGA6 marked both POU5F1+ hPGCs and other cells in the AGM. We used a combination of multiple markers, immunostaining different cellular compartments when feasible, to decrease the chance of misidentifying hPGCs. LARGE SCALE DATA: Non-applicable. LIMITATIONS REASONS FOR CAUTION: Material to study early human development is unique and very rare thus restricting the sample size. We have used a combination of antibodies limited by the number of paraffin sections available. WIDER IMPLICATIONS OF THE FINDINGS: Most of our knowledge on early gametogenesis has been obtained from model organisms such as mice and is extrapolated to humans. However, since there is a dedicated effort to produce human artificial gametes in vitro, it is of great importance to determine the expression and specificity of human-specific germ cell markers. We provide a systematic analysis of the expression of 31 different markers in paraffin sections of a CS12-13 embryo. Our results will help to set up a toolbox of markers to evaluate protocols to induce hPGCLCs in vitro. STUDY FUNDING AND COMPETING INTEREST(S): M.G.F. was funded by Fundacao para a Ciencia e Tecnologia (FCT) [SFRH/BD/78689/2011] and S.M.C.S.L. was funded by the Interuniversity Attraction Poles (IAP, P7/07) and the European Research Council Consolidator (ERC CoG-725722-OVOGROWTH). The authors declare no conflict of interest. PMID- 29528448 TI - White Blood Cell Count Improves Prediction of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Immune dysregulation has long been implicated in the development of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To determine the relationship of inflammatory cell biomarkers with DCI. METHODS: We evaluated 849 aSAH patients who were enrolled into a prospective observational cohort study and had a white blood cell (WBC) differential obtained within 72 h of bleed onset. RESULTS: WBC count > 12.1 * 109/L (odds ratio 4.6; 95% confidence interval [CI]: 1.9-11, P < 0.001) was the strongest Complete Blood Count (CBC) predictor of DCI after controlling for clinical grade (P < .001), thickness of SAH blood on admission computed tomography (P = .002), and clipping aneurysm repair (P < .001). A significant interaction between clinical grade and WBC count (odds ratio 0.8, 95% CI: 0.6 1.0, P = .02) revealed that good-grade patients with elevated WBC counts (49%: 273/558) had increased odds for DCI indistinguishable from poor-grade patients. Multivariable Cox regression also showed that elevated WBC counts in good-grade patients increased the hazard for DCI to that of poor-grade patients (hazard ratio 2.1, 95% CI 1.3-3.2, P < .001). Receiver operating characteristic curve analysis of good-grade patients revealed that WBC count (area under the curve [AUC]: 0.63) is a stronger DCI predictor than the modified Fisher score (AUC: 0.57) and significantly improves multivariable DCI prediction models (Z = 2.0, P = .02, AUC: 0.73; PPV: 34%; NPV: 92%). CONCLUSION: Good-grade patients with early elevations in WBC count have a similar risk and hazard for DCI as poor-grade patients. Good-grade patients without elevated WBC may be candidates to be safely downgraded from the intensive care unit, leading to cost savings for both patient families and hospitals. PMID- 29528449 TI - Neck Remnants and the Risk of Aneurysm Rupture After Endovascular Treatment With Coiling or Stent-Assisted Coiling: Much Ado About Nothing? AB - BACKGROUND: Neck remnants are not uncommon after endovascular treatment of cerebral aneurysms. Critics of endovascular treatments for cerebral aneurysms cite neck remnants as evidence in favor of microsurgical clipping. However, studies have failed to evaluate the true clinical significance of aneurysm neck remnants following endovascular therapies. OBJECTIVE: To assess the clinical significance of residual aneurysm necks and to determine the rate of subsequent rupture following coiling or stent-assisted coiling of cerebral aneurysms. METHODS: We retrospectively reviewed the records of 1292 aneurysm cases that underwent endovascular treatment at 4 institutions. Aneurysms treated by primary coiling or stent-assisted coiling were included in the study; those treated by flow diversion were excluded Aneurysms with residual filling (i.e., Raymond-Roy Occlusion Classification II, neck remnant; or III, residual aneurysm filling) were assessed for their risk of subsequent rupture. RESULTS: A total of 626 aneurysms were identified as having residual filling immediately posttreatment. Of these, 13 aneurysms (2.1%) ruptured during the follow-up period (mean 7.3 mo; range 1-84 mo). Eleven of the 13 (84.6%) were ruptured at presentation. Rupture at presentation, the size of the aneurysm, and the increasing age of the patient were predictive of posttreatment rupture. CONCLUSION: We found that unruptured aneurysms with residual necks following endovascular treatment posed a very low risk of rupture (0.6%). However, patients presenting with ruptured aneurysms had a higher risk of rerupture from a neck remnant (3.4%). These results highlight the importance of achieving complete angiographic occlusion of ruptured aneurysms. PMID- 29528450 TI - Sterilized talc pleurodesis for malignant pleural effusions: a Phase II study for investigational new drug application in Japan. AB - Background: Malignant pleural effusion is a commonly seen complication of malignancies such as lung and breast cancers. In Western countries, talc is frequently used as a standard therapeutic agent (pleurodesis agent) with the aim of alleviating symptoms including dyspnea and chest pain. Talc is not recognized as a pleurodesis agent in Japan. The aim of this study was to verify the efficacy and safety of sterilized talc (NPC-05) for the introduction of talc in Japan. Methods: The study was a single-arm, open-label, investigator-initiated trial conducted jointly at six institutions. The subjects were 30 patients with malignant pleural effusions. A solution of 4 g NPC-05 suspended in 50 ml physiological saline was instilled into the pleural space to perform pleurodesis. Results: The efficacy of NPC-05 for pleural adhesion 30 days after pleurodesis was 83.3% (25/30 cases). Amelioration of dyspnea and pain (chest pain) was seen. Commonly seen adverse effects were increased C-reactive protein (CRP) and fever. Nearly all adverse events were phenomena previously reported as adverse effects of talc. No acute respiratory distress syndrome (ARDS) or other serious side effects occurred. Conclusion: The efficacy and safety of NPC-05 for malignant pleural effusion in Japanese patients was verified, and the clinical outcomes with talc were confirmed to be the same as previously reported in other countries. There is thought to be a high level of need for this agent in the treatment of malignant pleural effusion in Japan. PMID- 29528451 TI - Raman micro-spectroscopy analysis of different sperm regions: a species comparison. AB - STUDY QUESTION: Is Raman micro-spectroscopy a valid approach to assess the biochemical hallmarks of sperm regions (head, midpiece and tail) in four different species? SUMMARY ANSWER: Non-invasive Raman micro-spectroscopy provides spectral patterns enabling the biochemical characterization of the three sperm regions in the four species, revealing however high similarities for each region among species. WHAT IS KNOWN ALREADY: Raman micro-spectroscopy has been described as an innovative method to assess sperm features having the potential to be used as a non-invasive selection tool. However, except for nuclear DNA, the identification and assignment of spectral bands in Raman-profiles to the different sperm regions is scarce and controversial. STUDY DESIGN SIZE, DURATION: Raman spectra from head, midpiece and tail of four different species were obtained. Sperm samples were collected and smeared on microscope slides. Air dried samples were subjected to Raman analysis using previously standardized procedures. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm samples from (i) two donors attending the infertility clinic at the Centre of Reproductive Medicine and Andrology; (ii) two C57BL/6 -TgN (ACTbEGFP) 1Osb adult mice; (iii) two adult Cynomolgus monkeys (Macaca fascicularis) and (iv) two sea urchins (Arbacia punctulata) were used to characterize and compare their spectral profiles. Differences and similarities were confirmed by principal component analysis (PCA). MAIN RESULTS AND THE ROLE OF CHANCE: Several novel region-specific peaks were identified. The three regions could be differentiated by distinctive Raman patterns irrespective of the species. However, regardless of the specie, their main spectral pattern remains mostly unchanged. These results were corroborated by the PCA analysis and suggest that the basic constituents of spermatozoa are biochemically similar among species. LIMITATIONS REASONS FOR CAUTION: Further research should be performed in live sperm to validate the detected spectral bands and their use as markers of distinctive regions. WIDER IMPLICATIONS OF THE FINDINGS: Raman peaks that have never been described in the sperm cell were detected. Particularly important are those that are unique to the midpiece as they might be a reference to the identification of sperm mitochondria, whose function is highly correlated with that of sperm. In the future, Raman micro spectroscopy has the potential to be applied in assessment of male fertility. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by BMBF project 'Sperm Ident' (FKZ:13N13024) and the DAAD-CRUP bilateral exchange program (AI A06/16-57213087). S.A. is a recipient of a fellowship from the Portuguese foundation for science and technology (FCT SFRH/BPD/110160/2015) and R.DC. is a recipient of a DAAD PhD stipend (91590556). There is no competing interest. PMID- 29528452 TI - Forsythia suspensa extract attenuates breast muscle oxidative injury induced by transport stress in broilers. AB - This experiment was conducted with 144 male Arbor Acre broilers (one d old, weighing 45.6 +/- 1.3 g) to determine protective effects of Forsythia suspensa extract (FSE) against breast muscle oxidative injury induced by transport stress (TS). The birds were randomly allotted to one of 4 treatments in a 2 * 2 factorial arrangement. The treatments consisted of broilers fed diets supplemented without or with FSE (100 mg/kg) and challenged without or with TS for 3 h before slaughter. Transport stress increased live BW loss of broilers (P < 0.05), and the adverse effect was attenuated by FSE (P < 0.05). Serum levels of corticoserone and lactate were increased for broilers after transportation (P < 0.05), whereas these parameters were not affected by FSE. After slaughter, neither breast muscle pH value at 45 min and 24 h postmortem nor 24 h drip loss value was influenced by TS or FSE, whereas TS increased the value of pH decline within 24 h postmortem (P < 0.05). Transportation decreased redness and increased yellowness value of breast muscle in broilers (P < 0.05), and FSE tended to have (P = 0.06) or had the converse changes (P < 0.05). Comparing with non-transported birds, the birds subjected to transportation had greater malondialdehyde (MDA) content and avUCP mRNA expression (P < 0.05) and lower 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity (P < 0.05) in breast muscle, whereas the birds supplemented with FSE had lower MDA content (P < 0.05) and greater DPPH radical scavenging activity (P < 0.05). Transport caused decreases (P < 0.05) in total antioxidant capacity and glutathione peroxidase activity, and the decreases were improved by FSE (P < 0.05). Collectively, live BW loss and breast muscle oxidative injury were increased by TS in broilers and could be attenuated by FSE via directly scavenging free radicals and increased antioxidant capacity. Therefore, FSE could protect broilers against breast muscle oxidative injury induced by TS. PMID- 29528453 TI - SlLAX1 is Required for Normal Leaf Development Mediated by Balanced Adaxial and Abaxial Pavement Cell Growth in Tomato. AB - Leaves are the major plant organs with a primary function for photosynthesis. Auxin controls various aspects of plant growth and development, including leaf initiation, expansion and differentiation. Unique and intriguing auxin features include its polar transport, which is mainly controlled by the AUX1/LAX and PIN gene families as influx and efflux carriers, respectively. The role of AUX1/LAX genes in root development is well documented, but the role of these genes in leaf morphogenesis remains unclear. Moreover, most studies have been conducted in the plant model Arabidopsis thaliana, while studies in tomato are still scarce. In this study, we isolated six lines of the allelic curly leaf phenotype 'curl' mutants from a gamma-ray and EMS (ethyl methanesulfonate) mutagenized population. Using a map-based cloning strategy combined with exome sequencing, we observed that a mutation occurred in the SlLAX1 gene (Solyc09g014380), which is homologous to an Arabidopsis auxin influx carrier gene, AUX1 (AtAUX1). Characterization of six alleles of single curl mutants revealed the pivotal role of SlLAX1 in controlling tomato leaf flatness by balancing adaxial and abaxial pavement cell growth, which has not been reported in tomato. Using TILLING (Targeting Induced Local Lesions IN Genome) technology, we isolated an additional mutant allele of the SlLAX1 gene and this mutant showed a curled leaf phenotype similar to other curl mutants, suggesting that Solyc09g014380 is responsible for the curl phenotype. These results showed that SlLAX1 is required for normal leaf development mediated by balanced adaxial and abaxial pavement cell growth in tomato. PMID- 29528454 TI - Consumers' acceptability of indigenous cockerel. AB - Commercial poultry production, although fairly well developed, continues to develop rapidly in Africa and other areas of the world. The local chickens, which may perhaps be harnessed and exploited for poverty alleviation, form part of the many local assets of underprivileged people living in the rural areas. In view of this, the study aims to investigate consumer acceptability of indigenous chicken meats using survey and sensory evaluation. The survey is comprised mainly of interviewing market women and supplying birds to them for sale in order to find answers to questions related to marketability or otherwise of the naked-neck, frizzled naked-neck, and normal-feathered cockerels. An experiment was carried out to evaluate consumers' preference of the 3 genotypes, namely NanaFf, Nanaff, and nanaff. The birds used were of the fourth generation (F4) offspring of crosses between local heterozygous naked neck (Nana) and heterozygous frizzled (Ff) males and hybrid commercial Lohmann females. Three hundred (300) cockerels that were 11 wk old crossbreds (100 of each of the 3 genotypic groups) were randomly housed in 15 open-sided, deep-litter pens with 20 cockerels in each pen in a completely randomized design for 9 wk. Burgers were prepared from the breast muscle of the carcass for sensory evaluation. The results from the survey indicated that a majority (91.7%) of the respondents admitted that they would readily accept to sell the naked-neck cockerels. Also, at almost all the sales points, the Nanaff was first to be sold out, followed by the nanaff feathered with the NanaFf being the last both before and during the major season's sales. The results from the sensory evaluation indicated that the burgers from nanaff and NanaFf birds had significantly (P < 0.05) lower acceptability levels than those from the Nanaff birds. The naked-neck gene cockerel had a positive effect on cockerel meat and marketability. PMID- 29528455 TI - Lumbar Sympathetic Plexus Block as a Treatment for Postamputation Pain: Methodology for a Randomized Controlled Trial. AB - Objective: We present a technical protocol for rigorous assessment of patient reported outcomes and psychophysical testing relevant to lumbar sympathetic blocks for the treatment of postamputation pain (PAP). This description is intended to inform future prospective investigation. Design: Series of four participants from a blinded randomized sham-controlled trial. Setting: Tertiary, urban, academic pain medicine center. Subjects: Four participants with a single lower limb amputation and associated chronic PAP. Methods: Participants were randomized to receive a lumbar sympathetic block with 0.25% bupivacaine or sham needle placement. Patient-rated outcome measures included the numerical rating scale (NRS) for pain, the McGill Pain Questionnaire-Short Form, Center for Epidemiological Studies Depression Scale, Pain and Anxiety Symptoms Scale-short version, and Pain Disability Index (PDI). Psychophysical and biometric testing was also performed, which included vibration sensation testing, pinprick sensation testing, brush sensation testing, Von Frey repeated weighted pinprick sensation, and thermal quantitative sensory testing. Results: In the four described cases, treatment of PAP with a single lumbar sympathetic block but not sham intervention resulted in reduction of both residual limb pain and phantom limb pain as well as perceived disability on the PDI at three-month follow-up. Conclusions: An appropriately powered randomized controlled study using this methodology may not only aid in determining the possible clinical efficacy of lumbar sympathetic block in PAP, but could also improve our understanding of underlying pathophysiologic mechanisms of PAP. PMID- 29528456 TI - Effects of Spinosad, Imidacloprid, and Lambda-cyhalothrin on Survival, Parasitism, and Reproduction of the Aphid Parasitoid Aphidius colemani. AB - Insecticides can affect biological control by parasitoids. Here, we examined the lethal and sublethal effects of two conventional insecticides, imidacloprid and lambda-cyhalothrin, and a reduced-risk bioinsecticide, spinosad, on the aphid parasitoid Aphidius colemani Viereck (Hymenoptera: Braconidae). Concentration mortality curves generated from insecticide residue bioassays found that wasps were nearly 20-fold more susceptible to spinosad than imidacloprid and lambda cyhalothrin. Imidacloprid and lambda-cyhalothrin compromised adult parasitoid longevity, but not as dramatically as spinosad: concentrations >200 ng spinosad/cm2 reduced wasp longevity by half. Imidacloprid and lambda-cyhalothrin also compromised aphid parasitism by wasps. Although increasing imidacloprid concentrations led to increased host viability and reduced progeny production, lambda-cyhalothrin did not affect viability of parasitized hosts or parasitoid progeny production in a dose-dependent manner. Our results demonstrate that reduced risk bioinsecticide products like spinosad can be more toxic to biological control agents than certain conventional insecticides. PMID- 29528457 TI - Tobacco treatment implementation within 28 commission on cancer accredited programs in the Northeast region of the USA: A pilot study. AB - Cancer survivors are a rapidly growing population and an important target for tobacco treatment interventions. Continued smoking after the diagnosis of cancer is associated with a higher risk of cancer recurrence and mortality. Systematic tobacco cessation programs are effective. This study surveyed American College of Surgeons Commission on Cancer (CoC) programs in the Northeast region of the USA regarding their tobacco control programs. Seventy percent of cancer survivors are treated within CoC programs. The purpose of this study was to describe the extent of implementation of tobacco treatment and determine the organizational delivery of tobacco treatment as measured by the presence of goals to address smoking, leadership support, and integration of tobacco treatment guidelines into care delivery. Data were collected by a survey. The Assessment of Chronic Illness Care questionnaire was used to collect data on implementation of tobacco treatment services. Descriptive statistics were used to analyze the data. Most programs (78.6%) had an electronic health record and of these 68% captured smoking status. Implementation of tobacco treatment was not optimal for identifying smokers, providing patients with community linkages or self-care cessation support. Implementation of decision aides for pharmacotherapy and reassessment of smoking status were the least developed areas. Moreover, the organizational delivery for tobacco treatment was less than optimal. Many cancer programs have not implemented systems to deliver optimal tobacco treatment. Efforts should be made to help cancer programs develop sustainable system-wide programs that address the urgent need to deliver tobacco treatment to all cancer survivors. PMID- 29528458 TI - Effects of low oxygen during chorioallantoic membrane development on post-hatch growing performance of broiler chickens. AB - The prenatal circulatory system is adaptive and capable of plasticity designed for the needs of the growing tissue. When a broiler embryo is faced with hypoxic stress, the process of angiogenesis in tissues begins. Exposure to hypoxic conditions of 17% oxygen during the chorioallantoic membrane (CAM) development (E5 to E12) affected the circulatory system and contributed to an increase in the blood oxygen carrying capacity. The present study aimed to evaluate the effects of hypoxic exposure during CAM development on post-hatch performance of broilers and to examine whether hypoxic exposure improved sustainability of birds exposed to acute heat stress.Two consecutive trials, with male broilers from each of the incubation treatments-optimal conditions and exposure to hypoxia of 15 or 17% oxygen, for 12 h/day, during CAM development-were conducted. In experiment 1, 60 male chicks from each group were raised in individual cages. In experiment 2, 160 male chicks from each group were raised in 40-chick pens until marketing. On d 35, 20 birds from each group were transferred to individual cages kept at a temperature of 23 degrees C for 72 h, and then birds were exposed to 35 degrees C for 5 hours. Body temperatures were measured at 0, 2, and 5 h of the heat exposure. In both experiments BW, feed intake, and FCR were recorded. At marketing, chicks were slaughtered, and relative weights of breast muscle, abdominal fat pad, heart, and liver were calculated.Hypoxia treatment resulted in a FCR advantage. Food intake was similar in all treatments, but groups exposed to hypoxia grew better than controls until the age of 35 days. Hypoxia-treated groups had higher relative breast, heart, and liver weights than controls. Body temperatures of hypoxia-treated chickens remained lower during heat stress exposure, and their mortality rate was lower as well. Intermittent exposure to moderate hypoxia during CAM development confers advantages to broilers in feed utilization efficiency and in coping with heat stress. It may be considered as a mitigating step in incubation to facilitate broilers in achieving their full growth potential. PMID- 29528459 TI - Molecular Phylogeny and Dating Reveal a Terrestrial Origin in the Early Carboniferous for Ascaridoid Nematodes. AB - Ascaridoids are among the commonest groups of zooparasitic nematodes (roundworms) and occur in the alimentary canal of all major vertebrate groups, including humans. They have an extremely high diversity and are of major socio-economic importance. However, their evolutionary history remains poorly known. Herein, we performed a comprehensive phylogenetic analysis of the Ascaridoidea. Our results divided the Ascaridoidea into six monophyletic major clades, i.e., the Heterocheilidae, Acanthocheilidae, Anisakidae, Ascarididae, Toxocaridae, and Raphidascarididae, among which the Heterocheilidae, rather than the Acanthocheilidae, represents the sister clade to the remaining ascaridoids. The phylogeny was calibrated using an approach that involves time priors from fossils of the co-evolving hosts, and dates the common ancestor of the Ascaridoidea back to the Early Carboniferous (approximately 360.47-325.27 Ma). The divergence dates and ancestral host types indicated by our study suggest that members of the Ascaridoidea first parasitized terrestrial tetrapods, and subsequently, extended their host range to elasmobranchs and teleosts. We also propose that the fundamental terrestrial-aquatic switches of these nematodes were affected by changes in sea-level during the Triassic to the Early Cretaceous. PMID- 29528460 TI - Systematic review: chronic obstructive pulmonary disease and work-related outcomes. AB - Background: Several studies have assessed the impact of chronic obstructive pulmonary disease (COPD) on work ability and work productivity; however, this relationship is poorly understood. Aims: To undertake a systematic review to assess the effects of COPD on employment, absenteeism and presenteeism. Methods: A comprehensive search using CINAHL, Embase, MEDLINE and the Cochrane Library was conducted to include epidemiological studies from 1937 to August 2017. One reviewer screened all citations. Shortlisted full-text articles were independently assessed by a second reviewer. Data were extracted by one reviewer with a random sample of papers (45%) checked by a second reviewer. Results: Forty four studies were included; the majority of evidence was from cross-sectional studies, and some cohort studies. COPD patients had lower employment rates than those without COPD. Among those in work, most studies showed patients with COPD took more time off work than those without and reported poorer work performance (presenteeism), although evidence for this association was weaker. The influence of disease severity on these outcomes was unclear; however, it appeared that increasing severity of airflow obstruction was associated with reduced likelihood of being employed. A number of methodological limitations were found among the evidence, including the lack of adjustment for important confounders. Conclusions: Future studies are required which assess the impact of COPD on presenteeism using validated presenteeism instruments and consistent reporting methods. Robust studies are now needed to identify modifiable factors associated with these poorer working outcomes to inform future interventions aimed at improving work productivity among those with COPD. PMID- 29528461 TI - Targeting cell cycle dependencies represent a novel therapeutic approach for selected sarcoma subgroups. PMID- 29528462 TI - The complete mitochondrial DNA sequence from Kazachstania sinensis reveals a general +1C frameshift mechanism in CTGY codons. AB - The complete mitochondrial DNA (mtDNA) sequence from Kazachstania sinensis was analysed and compared to mtDNA from related yeasts. It contained the same set of genes; however, it only contained 23 tRNAs, as the trnR2 gene was absent. Most of the 12 introns within cox1, cob and rnl genes were inserted in the same sites as in other yeasts; however, two introns in rnl were in unusual positions. Traits such as gene order and GC cluster number were more related to Saccharomyces than to the other Kazachstania or linked clades. The most exceptional feature was the +1 frameshift in cox3, atp6 and cob open reading frames that was also found in other Kazachstania, Nakaseomyces delphensis and Candida glabrata. Comparison of DNA and protein sequences revealed the universal sites of +1C frameshifts were either CTGT or CTGC sequences. Moreover, an A->G substitution was found at position 37 in the anticodon stem loop tRNA gene for cysteine in all species with frameshifts but not in other sibling yeasts. This substitution allowed strong Watson-Crick base-pairing between an unmodified G (ACG) and the skipped C in the CTGY, leading to this quadruplet being read as cysteine. PMID- 29528463 TI - Erratum. PMID- 29528464 TI - Ranging behavior relates to welfare indicators pre- and post-range access in commercial free-range broilers. AB - Little is known about the effect of accessing an outdoor range on chicken welfare. We tracked individual ranging behavior of 538 mixed-sex Ross 308 chickens on a commercial farm across 4 flocks in winter and summer. Before range access, at 17 to 19 d of age, and post-range access, at 30 to 33 and 42 to 46 d of age in winter and summer flocks respectively, welfare indicators were measured on chickens (pre-range: winter N = 292; summer N = 280; post-range: winter N = 131; summer N = 140), including weight, gait score, dermatitis and plumage condition. Post-ranging autopsies were performed (winter: N = 170; summer: N = 60) to assess breast burn, leg health, and ascites. Fewer chickens accessed the range in winter flocks (32.5%) than summer flocks (82.1%). Few relationships between welfare and ranging were identified in winter, likely due to minimal ranging and the earlier age of post-ranging data collection compared to summer flocks. In summer flocks prior to range access, chickens that accessed the range weighed 4.9% less (P = 0.03) than chickens that did not access the range. Pre ranging weight, gait score, and overall plumage cover predicted the amount of range use by ranging chickens in summer flocks (P < 0.01), but it explained less than 5% of the variation, suggesting other factors are associated with ranging behavior. In summer flocks post-range access, ranging chickens weighed 12.8% less than non-ranging chickens (P < 0.001). More range visits were associated with lower weight (P < 0.01), improved gait scores (P = 0.02), greater breast plumage cover (P = 0.02), lower ascites index (P = 0.01), and less pericardial fluid (P = 0.04). More time spent on the range was associated with lower weight (P < 0.01) and better gait scores (P < 0.01). These results suggest that accessing an outdoor range in summer is partly related to changes in broiler chicken welfare. Further investigations are required to determine causation. PMID- 29528465 TI - [Correction: Amyloidosis of the Small Intestine Following Whipple Operation is a Rare Cause of Chronic Ileus and has to be Considered as Differential Diagnosis]. PMID- 29528466 TI - Pregnancy Outcomes after Endometrial Ablation in a Multi-institutional Cohort. AB - OBJECTIVE: The objective of this study was to determine the incidence of morbidly adherent placenta in pregnancies after endometrial ablation. STUDY DESIGN: We performed a retrospective cohort analysis using a large, multiinstitutional deidentified clinical database, IBM EPM: Explore (IBM Corporation, Somers, NY). We identified women who underwent endometrial ablation and had a subsequent delivery between 1999 and 2016. Patients with a delivery and no prior ablation were used as controls. The association between morbidly adherent placenta, ablation, and other known risk factors for morbidly adherent placenta was analyzed using multivariable logistic regression. RESULTS: Of 162,100 reproductive-aged women who underwent endometrial ablation, 2,770 women (1.71%) subsequently had a delivery. The rate of morbidly adherent placenta was 1 in 13.9 pregnancies after ablation compared with 1 in 838.7 pregnancies in the control group (adjusted odds ratio [aOR], 20.22, p < 0.0001). CONCLUSION: Pregnancies that occurred after endometrial ablation were associated with increased rates of morbidly adherent placenta. PMID- 29528467 TI - Association of Resident Duty Hour Restrictions, Level of Trainee, and Number of Available Residents with Mortality in the Neonatal Intensive Care Unit. AB - OBJECTIVE: This article assesses the effect of reducing consecutive hours worked by residents from 24 to 16 hours on yearly total hours worked per resident in the neonatal intensive care unit (NICU) and evaluates the association of resident duty hour reform, level of trainee, and the number of residents present at admission with mortality in the NICU. STUDY DESIGN: This is a 6-year retrospective cohort study including all pediatric residents working in a Level 3 NICU (N = 185) and infants admitted to the NICU (N = 8,159). Adjusted odds ratios (aOR) were estimated for mortality with respect to Epoch (2008-2011 [24-hour shifts] versus 2011-2014 [16-hour shifts]), level of trainee, and the number of residents present at admission. RESULTS: The reduction in maximum consecutive hours worked was associated with a significant reduction of the median yearly total hours worked per resident in the NICU (381 hour vs. 276 hour, p < 0.01). Early mortality rate was 1.2% (50/4,107) before the resident duty hour reform and 0.8% (33/4,052) after the reform (aOR, 0.57; 95% confidence interval [CI], 0.33 0.98). Neither level of trainee (aOR, 1.22; 95% CI, 0.71-2.10; junior vs. senior) nor the number of residents present at admission (aOR, 2.08; 95% CI, 0.43-10.02, 5-8 residents vs. 0-2 residents) were associated with early mortality. Resident duty hour reform was not associated with hospital mortality (aOR, 0.73; 95% CI, 0.50-1.07; after vs. before resident duty hour reform). CONCLUSION: Resident duty hour restrictions were associated with a reduction in the number of yearly hours worked by residents in the NICU as well as a significant decrease in adjusted odds of early mortality but not of hospital mortality in admitted neonates. PMID- 29528468 TI - A Prediction Model for Severe Maternal Morbidity in Laboring Patients at Term. AB - OBJECTIVE: To determine the factors associated with severe maternal morbidity in a modern cohort of women laboring at term and to create a prediction model. STUDY DESIGN: This is a retrospective cohort study of all term, laboring patients with live births at a single tertiary care center from 2004 to 2014. The primary outcome was composite maternal morbidity including organ failure, amniotic fluid embolism, anesthesia complications, sepsis, shock, thrombotic events, transfusion, or hysterectomy. Multivariable logistic regression was used to identify independent risk factors. Antepartum, intrapartum, and combined risk scores were created and test characteristics were analyzed. RESULTS: Among 19,249 women delivering during the study period, 323 (1.68%) patients experienced severe morbidity, with blood transfusion the most common complication (286, 1.49%). Factors in the antepartum model included advanced maternal age, race, hypertension, nulliparity, history of cesarean delivery, smoking, and unfavorable Bishop score. Intrapartum factors included mode of delivery, use of cervical ripening agents or oxytocin, prolonged second stage, and macrosomia. The combined model had an area under the curve of 0.76 (95% confidence interval [CI], 0.73, 0.79). CONCLUSION: This three-part risk scoring system can help clinicians counsel patients and guide clinical decision making for anticipating severe maternal morbidity and necessary resources. PMID- 29528469 TI - Stage I Twin-Twin Transfusion Syndrome: Outcomes of Expectant Management and Prognostic Features. AB - OBJECTIVE: This article describes the natural history of stage I twin-twin transfusion syndrome (TTTS) including risk of progression to higher stage TTTS and pregnancy outcomes, and to identify risk factors for progression. STUDY DESIGN: Retrospective cohort study of monochorionic diamniotic (MCDA) twin pregnancies from 2006 to 2016 with expectantly managed Quintero stage I TTTS. RESULTS: A total of 30 MCDA twin pregnancies with expectantly managed stage I TTTS were identified. Of these, eight (26.7%) progressed to higher stage TTTS. Median gestational age (GA) at diagnosis for those that progressed was 18.9 +/- 2.9 weeks versus 21.4 +/- 3.4 weeks in those that remained stable (p = 0.06). Presence of an arterioarterial (A-A) anastomosis was assessed for 20/30 patients, and eight A-A were identified. Of those, 7/8 (87.5%) remained stable. In the complete cohort, a tiny or transiently visible bladder was noted in seven donor twins. Of these, 4/7 (57.1%) progressed. Excluding one termination, 47/58 (81.0%) fetuses survived. CONCLUSION: With expectant management of stage I TTTS, nearly three-fourths of pregnancies remain stable and most have survival of >= 1 twin. A A anastomoses were not associated with progression to higher stage TTTS, whereas earlier GA at diagnosis or a small or intermittently visible donor bladder may herald greater risk of progression. PMID- 29528470 TI - The Utility of Repeat Midtrimester Anatomy Ultrasound for Anomaly Detection. AB - INTRODUCTION: Although guidelines recommend repeat ultrasound in the setting of an incomplete fetal anatomic survey, the clinical utility of this practice has not been established. As such, we aimed to assess the yield of repeat ultrasound for anomaly detection following an incomplete survey. MATERIALS AND METHODS: This is a retrospective cohort study of all singletons who underwent a midtrimester anatomic ultrasound at University of Alabama at Birmingham (UAB) from 2006 to 2014. Patients with an incomplete ultrasound underwent repeat examinations until completion. The population was divided into cohorts FIRST, SECOND, and THIRD, corresponding to the ultrasound at which the exam was deemed complete. Each detected anomaly was tallied. The number of ultrasounds needed to detect an anomaly was then assessed per group. RESULTS: Of 15,768 ultrasounds performed on 13,740 patients, 11,828 exams were completed on first attempt; 1,796 patients required a second, while 116 patients required a third scan or more. We detected 324 anomalies; 93.8% in FIRST, 5.9% in SECOND, and 0.3% in THIRD. The number of scans needed to detect an anomaly was 39, 189, and 348 for FIRST, SECOND, and THIRD, respectively. CONCLUSION: Over 90% of anomalies are detected on the initial fetal anatomic survey. The incremental diagnostic yield then decreases, requiring appreciably more repeat scans to detect one anomaly. PMID- 29528471 TI - Contributing Reviewers in 2017. PMID- 29528472 TI - HRI Malta 2017: Homeopathy Research-Past, Present and Future. PMID- 29528473 TI - Homeopathy Use in the United States and Implications for Public Health: A Review. AB - Homeopathy is used by just over 2% of the U.S. population, predominantly for respiratory, otorhinolaryngology, and musculoskeletal complaints. Individual users who see a homeopathic provider for care are more likely to perceive the therapy as helpful than those who do not; however, only 19% of users in the United States see a provider. The rest presumably rely upon over-the-counter products. Recent clinical trials highlight several areas in which homeopathy may play a role in improving public health, including infectious diseases, pain management, mental health, and cancer care. This review examines recent studies in these fields, studies assessing costs associated with homeopathic care, safety, and regulations in the United States. Data suggest the potential for public health benefit from homeopathy, especially for conditions such as upper respiratory infections and fibromyalgia. PMID- 29528475 TI - Degree of Response to Homeopathic Potencies Correlates with Dipole Moment Size in Molecular Detectors: Implications for Understanding the Fundamental Nature of Serially Diluted and Succussed Solutions. AB - BACKGROUND: The use of solvatochromic dyes to investigate homeopathic potencies holds out the promise of understanding the nature of serially succussed and diluted solutions at a fundamental physicochemical level. Recent studies have shown that a range of different dyes interact with potencies and, moreover, the nature of the interaction is beginning to allow certain specific characteristics of potencies to be delineated. AIMS AND METHODS: The study reported in this article takes previous investigations further and aims to understand more about the nature of the interaction between potencies and solvatochromic dyes. To this end, the UV-visible spectra of a wide range of potential detectors of potencies have been examined using methodologies previously described. RESULTS: Results presented demonstrate that solvatochromic dyes are a sub-group of a larger class of compounds capable of demonstrating interactions with potencies. In particular, amino acids containing an aromatic bridge also show marked optical changes in the presence of potencies. Several specific features of molecular detectors can now be shown to be necessary for significant interactions with homeopathic potencies. These include systems with a large dipole moment, electron delocalisation, polarizability and molecular rigidity. CONCLUSIONS: Analysis of the optical changes occurring on interaction with potencies suggests that in all cases potencies increase the polarity of molecular detectors to a degree that correlates with the size of the compound's permanent or ground dipole moment. These results can be explained by inferring that potencies themselves have polarity. Possible candidates for the identity of potencies, based on these and previously reported results, are discussed. PMID- 29528474 TI - The N-of-1 Clinical Trial: A Timely Research Opportunity in Homeopathy. AB - BACKGROUND: The randomised controlled trial (RCT) is considered the 'gold standard' for establishing treatment efficacy or effectiveness of an intervention, but its data do not infer response in an individual patient. Individualised clinical care, a fundamental principle in complementary and alternative medicine (CAM), including homeopathy, seems well disposed in principle to being researched by single-patient (N-of-1) study design. Guidelines for reporting N-of-1 trials have recently been developed. OBJECTIVE: To overview the current status in the literature of the N-of-1 method and its application in medicine, including CAM. To consider whether the N-of-1 trial design offers an opportunity for novel research in homeopathy. N-OF-1 TRIAL DESIGN: The N-of-1 trial applies the principles of the conventional crossover, blinded, RCT design. The treatment under study and the comparator are repeated in a randomised order, and with suitable washout time, over a defined period. N-of-1 design is constrained for use in chronic stable conditions, and for interventions that have quick onset and cessation of effect, with modest or negligible carryover. Outcome data can be aggregated and interpreted for the individual subject; they can also be pooled with data from several similar N-of-1 trials, enabling more generalisable conclusions. THE N-OF-1 TRIAL IN CAM: The typical individualisation of patient care can be accommodated in N-of-1 study design if the patient and the specific therapeutic intervention are selected within the constraints of the method. Application of the N-of-1 method in CAM has been advocated but has been mainly limited, in practice, to a small number of studies in herbal and traditional Chinese medicine. THE N-OF-1 TRIAL IN HOMEOPATHY: Individualised homeopathy can be accommodated for investigation within the same methodological constraints; less in-depth homeopathic approaches to prescribing are also amendable to investigation using the N-of-1 method. No such studies have been published. We identify three main targets in its ready applicability to homeopathy: (1) to optimise clinical care in an individual patient; (2) to investigate whether the outcomes of treatment using homeopathy differ from those of placebo; (3) to aggregate data from a series of N-of-1 trials to enable broader conclusions about a group of patients or intervention. CONCLUSION: The N of-1 trial design offers important new investigative possibilities in homeopathy and should be explored as a means to optimise individualised health care or investigate effectiveness of the homeopathic intervention compared with placebo in individual subjects. PMID- 29528476 TI - Evidence that Extreme Dilutions of Paclitaxel and Docetaxel Alter Gene Expression of In Vitro Breast Cancer Cells. AB - BACKGROUND: Gene expression analysis of cells treated with extreme dilutions or micro amounts of drugs has been used to provide useful suggestions about biological responses. However, most of the previous studies were performed on medicines being prepared from a variety of herbal and metal sources. This study investigated the effects of ultramolecular dilution of the taxane anti-cancer drugs, which are not commonly used in homeopathic medicines, on mRNA expression profiles of five key genes (p53, p21, COX-2, TUBB2A and TUBB3) in the breast cancer cell line MCF-7. METHOD: MCF-7 cells were exposed to paclitaxel (Taxol) or docetaxel (Taxotere) preparations (6X, 5C and 15C dilutions prepared from pharmacological concentration of 25 nmol/L) for 72 hours. The cell culture groups were evaluated with the trypan blue dye exclusion method for the proliferation/cytotoxicity rates, immuno-staining beta-tubulin for microtubule organization, and reverse transcription polymerase chain reaction for gene expression levels.Fold-change in gene expression was determined by the DeltaDeltaCt method. RESULTS: The administration of diluted preparations had little or no cytotoxic effect on MCF-7 cells, but altered the expression of genes analyzed with a complex effect. According to the DeltaDeltaCt method with a five fold expression difference (p < 0.05) as a cut-off level, ultra-high dilutions of paclitaxel and docetaxel showed differential effects on the studied genes with a concentration-independent activity. Furthermore, the dilutions disrupted the microtubule structure of MCF-7 cells, suggesting that they retain their biological activity. CONCLUSION: Despite some limitations, our findings demonstrate that gene expression alterations also occur with ultra-high dilutions of taxane drugs. PMID- 29528477 TI - Homeopathic Dilutions, Hahnemann Principles, and the Solvent Issue: Must We Address Ethanol as a "Homeopathic" or a "Chemical" Issue? AB - INTRODUCTION: Homeopathic remedies usually contain a significant amount of ethanol as a co-solvent with water, a pharmaceutical formulation that may raise some concern when remedies are tested in vitro or in laboratory animals, due to the assessed toxicity of ethanol on cell cultures and organisms. The amount of alcohol in a homeopathic remedy is adjusted following the different homeopathic pharmacopoeias but it is rarely below 30% v/v, which is a molar mass established to meet both Hahnemann's traditional heritage and the hypothetical role of ethanol in "imprinting" water, through the formation of nanobubbles, with the homeopathic activity of the remedy. AIMS: This article aims at discussing the role of ethanol in homeopathic dilutions and how its chemical nature should affect the experimental approach in homeopathy. ISSUES UNDER DEBATE: While the content of ethanol in a homeopathic remedy should be as low as 20% v/v, which is a molar fraction able to catalyze the formation of nanobubbles in a dynamized alcohol-water dilution, this amount raises concern about ethanol toxicology in the experimental research with laboratory animals or in vitro. Several authors diluted 1:100 ethanol 30% v/v from their tested homeopathic dilutions with distilled water to prevent the cytotoxic effect of the alcohol, but in doing so, they probably reduced the ability of ethanol (now 0.3% v/v) to induce the formation of nanobubbles, thus probably affecting the homeopathic property of the same dilution. This may generate concerns about how to manage an experimental setting, to meet both the "chemical" nature of ethanol and its role in "homeopathy," an issue that is discussed in the article. CONCLUSION: Any author working with homeopathic dilutions containing a molar fraction of ethanol higher than 20% should take into account the fact that ethanol is cytotoxic and may be a catalyst to the formation of nanobubbles, and so should adjust the experimental approach accordingly. PMID- 29528478 TI - Proofs that Homeopathic Medicine Works: Dossier "Scientific Evidence for Homeopathy" (Revista de Homeopatia, Sao Paulo Homeopathic Medical Association). PMID- 29528479 TI - The Materialist View of Homeopathy: An Alternative Hypothesis and the Connection with Hormesis. PMID- 29528480 TI - HRI Malta 2017-Cutting Edge Research in Homeopathy: HRI's Third International Research Conference in Malta. AB - The third international conference on "Cutting Edge Research in Homeopathy" organised by the Homeopathy Research Institute (HRI) was held on the inspiring and historic island of Malta from 9th to 11th of June, 2017. One hundred and two abstracts underwent peer review by the HRI Scientific Advisory Committee and external experts to produce the programme of 36 oral presentations and 37 posters, presented by researchers from 19 countries. The 2.5-day programme covered a diverse range of topics, including quantitative and qualitative clinical research, basic research, veterinary research, and provings. These intensive plenary and parallel sessions were interspersed with multiple opportunities for delegates to discuss and exchange ideas, in particular through interactive panel discussions and a pre-conference workshop. The continuing commitment of the homeopathy research community to generate high-quality studies in this rapidly evolving field was clear. In this conference report, we present highlights from this memorable event. PMID- 29528481 TI - All-Inside Anterior Cruciate Ligament Reconstruction-A Systematic Review of Techniques, Outcomes, and Complications. AB - The all-inside technique (AIT) for anterior cruciate ligament reconstruction (ACLR) is gaining popularity as a more anatomic, less invasive, technique with the potential for more rapid recovery. This systematic review aims to critically assess components of the technique, its safety profile, outcomes, and complications. PUBMED, EMBASE, and MEDLINE were searched for studies discussing primary ACLR using the AIT. Article screening, quality assessment, and data abstraction were completed in duplicate, and a minimal clinically important difference (MCID) was used to frame the descriptive results in a clinically significant context. A total of 13 studies satisfied the inclusion criteria. Five hundred twenty six patients (mean age 31.9 +/- 5.9 years) underwent ACLR using the AIT. The mean follow-up was 18.2 +/- 7.7 months. Graft choice included autograft (73.8%) and allograft (26.2%). Drilling techniques for femoral sockets were outside-in (53.4%) and through the anteromedial portal (35.4%), whereas tibial sockets were drilled outside-in (35.0%) and through the superomedial portal (3.8%). The rehabilitation protocol had an immediate focus on obtaining full knee extension, jogging permitted 2 to 4 months postoperatively in 61.5% of studies, and return to cutting and pivoting sports 6 to 9 months postoperatively in 69.2% of studies. A MCID was reached for subjective International Knee Documentation Committee scores at 6, 12, and 24 months follow-up and Lysholm knee score at 24 months follow-up. An improvement in outcomes was most notably between 6 and 12 months postoperatively. There was a total of 31 complications (5.89%) and included graft rerupture (2.47%), loss of extension of 1 degrees to 10 degrees (1.14%), and cartilage or meniscus injuries on the operated knee (0.760%). Complications related to the surgical technique were not reported. The AIT for ACLR shows potential as a minimally invasive approach given the low graft failure rates and short-term improvements in knee function and stability, pain and patient important outcomes from this approach. Comparative studies with large sample sizes and a long-term follow-up are required to assess the proposed advantages of this technique. This is a Level IV study. PMID- 29528482 TI - Cryoballoon ablation of atrial fibrillation in patients with advanced systolic heart failure and cardiac implantable electronic devices. AB - BACKGROUND: Pulmonary vein isolation with cryoballoon catheter ablation (CCB) is an effective method of treatment in patients with atrial fibrillation (AF), but in patients with heart failure (HF) the role of CCB remains unknown. AIM: The aim of the study was to assess the feasibility, effectiveness, and safety of CCB in patients with HF and cardiac im-plantable electronic devices (CIEDs), the impact of the procedure on symptoms, and echocardiographic parameters. METHODS: Thirty consecutive HF patients with left ventricular ejection fraction (LVEF) <= 40% and CIED, referred for CCB of AF, were included. Procedural parameters were compared to a group of 59 consecutive patients without cardiac diseases referred for CCB (control group). RESULTS: The number of veins ablated per patient was smaller and application was performed less frequently in the right inferior pulmonary vein in the HF group compared with the control group (66.7% vs. 88.1%; p = 0.01, respectively). In two (6.7%) patients from the HF group and in five (8.5%) from the control group procedure-related complications occurred (p = 0.76). After six months 21 HF patients (70%), after one year 13 (43%), and after 625 days only three (10%) were free from arrhythmia. AF burden was significantly reduced after six months compared to the pre-ablation period (18.5% vs. 52.9%; p = 0.001). New York Heart Association and European Heart Rhythm Association classes were both significantly (p < 0.001) reduced and LVEF was higher after six months in the HF patients. CONCLUSIONS: Safety and feasibility of CCB for AF in HF patients with CIED are comparable to subjects with structurally nor-mal heart; however, stable positioning of the balloon in the right inferior pulmonary vein may be more challenging. Although late recurrences are common, ablation reduces arrhythmia burden and leads to a long-term improvement of symptoms and echocardiographic indices. PMID- 29528483 TI - Differences in knowledge among patients with atrial fibrillation receiving non vitamin K antagonist oral anticoagulants and vitamin K antagonists. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for stroke prevention in patients with atrial fibrillation (AF) worldwide. Few articles have compared current understanding of AF patients about the disease and anticoagulant therapy in relation to the medications used. AIM: We sought to compare the knowledge of AF and anticoagulation between AF patients treated with NOACs and those on vitamin K antagonists (VKAs). METHODS: We used the Jessa AF Knowledge Questionnaire (JAKQ), developed and validated in Belgium. Patients were re-cruited at a tertiary centre in Krakow, Poland. RESULTS: A total of 479 AF patients completed the JAKQ. Patients on NOACs (n = 276, 57.6%) compared with those on VKAs (n = 175, 36.5%) did not differ regarding demographic and clinical variables. The mean score of the JAKQ was very similar in the NOAC and VKA group (60.7 +/- 17.0% vs. 61.6 +/- 17.1%; p = 0.4, respectively). The differences in the proportion of correct responses referred to three questions. Consequences of AF, such as blood clots and cerebral infarction, were more obvious for patients on NOACs compared with those on VKAs (81.5% vs. 70.9%; p = 0.01). The patients on NOACs (78.7% vs. 67.6%; p = 0.009) more frequently considered consulting a physician for advice concerning anticoagulant treatment before surgery, while fewer patients on NOACs were aware of the need to take their medication even if they did not feel AF (76.1% vs. 89.7%; p = 0.0004). Only 25.9% of the VKA patients and 49.3% of the NOAC users knew what to do if they missed a dose of the anticoagulant. CONCLUSIONS: The knowledge of arrhythmia and anticoagulation is better regarding the safety issues among subjects on NOACs compared with those on VKAs. Irrespective of the type of oral anticoagulation therapy, education of AF patients should be improved. PMID- 29528484 TI - Effects of Caps on Cost Sharing for Skilled Nursing Facility Services in Medicare Advantage Plans. AB - OBJECTIVES: To evaluate a federal regulation effective in 2011 that limited how much that Medicare Advantage (MA) plans could charge for the first 20 days of care in a skilled nursing facility (SNF). DESIGN: Difference-in-differences retrospective analysis comparing SNF utilization trends from 2008-2012. SETTING: Select MA plans. PARTICIPANTS: Members of 27 plans with mandatory cost sharing reductions (n=132,000) and members of 21 plans without such reductions (n=138,846). MEASUREMENTS: Mean monthly number of SNF admissions and days per 1,000 members; annual proportion of MA enrollees exiting the plan. RESULTS: In plans with mandated cost sharing reductions, cost sharing for the first 20 days of SNF care decreased from an average of $2,039 in 2010 to $992 in 2011. In adjusted analyses, plans with mandated cost-sharing reductions averaged 158.1 SNF days (95% confidence interval (CI)=153.2-163.1 days) per 1,000 members per month before the cost sharing cap. This measure increased by 14.3 days (95% CI=3.8-24.8 days, p=0.009) in the 2 years after cap implementation. However, increases in SNF utilization did not significantly differ between plans with and without mandated cost-sharing reductions (adjusted between-group difference: 7.1 days per 1,000 members, 95% CI=-6.5-20.8, p=.30). Disenrollment patterns did not change after the cap took effect. CONCLUSIONS: When a federal regulation designed to protect MA members from high out-of-pocket costs for postacute care took effect, the use of SNF services did not change. PMID- 29528485 TI - Transcranial Magnetic Stimulation for Migraine Prevention in Adolescents: A Pilot Open-Label Study. AB - OBJECTIVE: To assess the feasibility, tolerability, and patient acceptability of single-pulse transcranial magnetic stimulation (sTMS) for migraine prevention in adolescents in an open-label pilot study. BACKGROUND: Migraine is common in adolescents and can be disabling. Well tolerated preventative therapies that are safe and effective are needed. METHODS: This was an open-label prospective pilot feasibility study of sTMS for migraine prevention in adolescents aged 12-17 years. Participants used sTMS twice daily in a preventative fashion, as well as additional pulses as needed acutely. A 4-week baseline run-in period (weeks 1-4) was followed by a 12-week treatment period. Feasibility was the primary outcome. Secondary outcomes included tolerability and acceptability, as well as the change in headache days, number of moderate/severe headache days, days of acute medication use, and PedMIDAS (headache disability) scores between the run-in period (weeks 1-4) and the third month of treatment (weeks 13-16). RESULTS: Twenty-one participants enrolled. Nineteen completed the baseline run-in, and 12 completed the study. Using sTMS proved feasible and acceptable with overall high compliance once treatment administration was streamlined. Initially, for preventive treatment, participants were asked to give 2 pulses, wait 15 minutes, then give 2 additional pulses twice daily. This 15-minute delay proved challenging for adolescents, particularly on school days, and therefore was dropped. Study completion rate went from 4/13 (31%) to 7/8 (88%) once this change was made, P = .024. On average, participants used the device preventively between 22 and 24 days over a 28-day block. There were no serious adverse events. Two participants reported mild discomfort with device use. CONCLUSION: sTMS appears to be a feasible, well-tolerated, and acceptable nonpharmacologic preventive treatment for migraine in adolescents. In designing future trials of sTMS for migraine prevention in adolescents, streamlined treatment administration will be essential to minimize drop-out. Efficacy needs to be assessed in a larger trial. PMID- 29528486 TI - High-power, red-light-emitting diode irradiation enhances proliferation, osteogenic differentiation, and mineralization of human periodontal ligament stem cells via ERK signaling pathway. AB - BACKGROUND: Light-emitting diode (LED) is attracting attention as a new light source for phototherapy. However, its effects on periodontal tissue regeneration remain unknown. The aim of this study was to examine the effects of high-power, red LED irradiation on human periodontal ligament stem cells (PDLSCs), which play an important role in periodontal tissue regeneration. METHODS: PDLSCs were derived from adult human third molars. The light source was red LED (peak wavelength: 650 nm). Energy densities ranging from 0 to 10 J/cm2 were tested to determine the optimal dose. PDLSC proliferation was measured using two parameters: live cell protease and ATP levels. After the cells were induced to differentiate, the effect of LED irradiation on osteogenic differentiation and mineralization was examined, with particular focus on the extracellular signal regulated kinase (ERK)1/2 signaling pathway using an ERK inhibitor (PD98059). RESULTS: LED irradiation at 8 J/cm2 led to a significant increase in PDLSC proliferation and enhanced Runx2 and Osterix mRNA expression, Alkaline phosphatase activity, procollagen type I C-peptide and osteocalcin production, calcium deposition, and alizarin red S staining. In addition, LED induced the activation of ERK1/2, and the effects of LED on PDLSC proliferation, differentiation, and mineralization could be suppressed by treatment with PD98059. CONCLUSIONS: The results of this study show that 650-nm high-power, red, LED irradiation increases PDLSCs proliferation, and osteogenic differentiation and mineralization, mediated by ERK1/2 activation. These findings suggest that LED may be a useful tool for periodontal tissue regeneration. PMID- 29528487 TI - Patterns of psychological health problems and family maltreatment among United States Air Force members. AB - OBJECTIVES: We sought to identify subgroups of individuals based on patterns of psychological health problems (PH; e.g., depressive symptoms, hazardous drinking) and family maltreatment (FM; e.g., child and partner abuse). METHOD: We analyzed data from very large surveys of United States Air Force active duty members with romantic partners and children. RESULTS: Latent class analyses indicated six replicable patterns of PH problems and FM. Five of these classes, representing ~98% of survey participants, were arrayed ordinally, with increasing risk of multiple PH problems and FM. A sixth group defied this ordinal pattern, with pronounced rates of FM and externalizing PH problems, but without correspondingly high rates/levels of internalizing PH problems. CONCLUSIONS: Ramifications of these results for intervention are discussed. PMID- 29528489 TI - Personality correlates of intimate partner violence subtypes: A latent class analysis. AB - Perpetrators of intimate partner violence (IPV) represent a heterogeneous group who engage in a variety of aggressive acts which often co-occur. However, few studies take this co-occurrence into consideration. Failure to consider overlapping forms of IPV confounds understanding of risk factors for physical IPV, which in turn undermines identification, prevention, and intervention efforts. Though rarely studied in emerging adults, personality variables have recently been identified as important correlates of IPV. The primary aims of the current studies are to identify distinct subgroups of moderate and severe psychological and physical IPV and personality covariates of class membership. Two studies were conducted at different public regional universities in the northeast (n = 500; n = 497). Both samples were about two-thirds female, approximately one-half White, one-fifth Black, and one-quarter Latino, of any race. Latent Class Analysis identified three subgroups in both studies: low, moderate, and severe IPV. The severe and moderate IPV groups included those who reported threats and moderate physical IPV while the severe IPV group also included those who engaged in severe and injurious forms of physical IPV. Multinomial regression analysis showed that impulsive aggression discriminated moderate and severe from low IPV (Study 1), and more frequent emotionally abusive and controlling behavior, a hostile-dominant interpersonal style and trait aggression discriminated among all three groups, with severe IPV having the greatest likelihood of controlling behavior and aggression (Study 2). IPV is represented by distinct subgroups that vary by severity of IPV with different personality covariates. General aggressive and domineering tendencies in relationships characterize those engaging in severe IPV. PMID- 29528488 TI - Automated trajectory planning for laser interstitial thermal therapy in mesial temporal lobe epilepsy. AB - OBJECTIVE: Surgical resection of the mesial temporal structures brings seizure remission in 65% of individuals with drug-resistant mesial temporal lobe epilepsy (MTLE). Laser interstitial thermal therapy (LiTT) is a novel therapy that may provide a minimally invasive means of ablating the mesial temporal structures with similar outcomes, while minimizing damage to the neocortex. Systematic trajectory planning helps ensure safety and optimal seizure freedom through adequate ablation of the amygdalohippocampal complex (AHC). Previous studies have highlighted the relationship between the residual unablated mesial hippocampal head and failure to achieve seizure freedom. We aim to implement computer assisted planning (CAP) to improve the ablation volume and safety of LiTT trajectories. METHODS: Twenty-five patients who had previously undergone LiTT for MTLE were studied retrospectively. The EpiNav platform was used to automatically generate an optimal ablation trajectory, which was compared with the previous manually planned and implemented trajectory. Expected ablation volumes and safety profiles of each trajectory were modeled. The implemented laser trajectory and achieved ablation of mesial temporal lobe structures were quantified and correlated with seizure outcome. RESULTS: CAP automatically generated feasible trajectories with reduced overall risk metrics (P < .001) and intracerebral length (P = .007). There was a significant correlation between the actual and retrospective CAP-anticipated ablation volumes, supporting a 15 mm diameter ablation zone model (P < .001). CAP trajectories would have provided significantly greater ablation of the amygdala (P = .0004) and AHC (P = .008), resulting in less residual unablated mesial hippocampal head (P = .001), and reduced ablation of the parahippocampal gyrus (P = .02). SIGNIFICANCE: Compared to manually planned trajectories CAP provides a better safety profile, with potentially improved seizure-free outcome and reduced neuropsychological deficits, following LiTT for MTLE. PMID- 29528490 TI - Identification of key amino acid residues determining product specificity of 2,3 oxidosqualene cyclase in Oryza species. AB - Triterpene synthases, also known as 2,3-oxidosqualene cyclases (OSCs), synthesize diverse triterpene skeletons that form the basis of an array of functionally divergent steroids and triterpenoids. Tetracyclic and pentacyclic triterpene skeletons are synthesized via protosteryl and dammarenyl cations, respectively. The mechanism of conversion between two scaffolds is not well understood. Here, we report a promiscuous OSC from rice (Oryza sativa) (OsOS) that synthesizes a novel pentacyclic triterpene orysatinol as its main product. The OsOS gene is widely distributed in indica subspecies of cultivated rice and in wild rice accessions. Previously, we have characterized a different OSC, OsPS, a tetracyclic parkeol synthase found in japonica subspecies. Phylogenetic and protein structural analyses identified three key amino acid residues (#732, #365, #124) amongst 46 polymorphic sites that determine functional conversion between OsPS and OsOS, specifically, the chair-semi(chair)-chair and chair-boat-chair interconversions. The different orientation of a fourth amino acid residue Y257 was shown to be important for functional conversion The discovery of orysatinol unlocks a new path to triterpene diversity in nature. Our findings also reveal mechanistic insights into the cyclization of oxidosqualene into tetra- and pentacyclic skeletons, and provide a new strategy to identify key residues determining OSC specificity. PMID- 29528491 TI - Direct detection of male quality can facilitate the evolution of female choosiness and indicators of good genes: Evolution across a continuum of indicator mechanisms. AB - The evolution of mating displays as indicators of male quality has been the subject of extensive theoretical and empirical research for over four decades. Research has also addressed the evolution of female mate choice favoring such indicators. Yet, much debate still exists about whether displays can evolve through the indirect benefits of female mate choice. Here, we use a population genetic model to investigate how the extent to which females can directly detect male quality influences the evolution of female choosiness and male displays. We use a continuum framework that incorporates indicator mechanisms that are traditionally modeled separately. Counter to intuition, we find that intermediate levels of direct detection of male quality can facilitate, rather than impede, the evolution of female choosiness and male displays in broad regions of this continuum. We examine how this evolution is driven by selective forces on genetic quality and on the display, and find that direct detection of male quality results in stronger indirect selection favoring female choosiness. Our results imply that displays maybe more likely to evolve when female choosiness has already evolved to discriminate perceptible forms of male quality. They also highlight the importance of considering general female choosiness, as well as preference, in studies of "good genes." PMID- 29528493 TI - Divergent in shape and convergent in function: Adaptive evolution of the mandible in Sub-Antarctic mice. AB - Convergent evolution in similar environments constitutes strong evidence of adaptive evolution. Transported with people around the world, house mice colonized even remote areas, such as Sub-Antarctic islands. There, they returned to a feral way of life, shifting towards a diet enriched in terrestrial macroinvertebrates. Here, we test the hypothesis that this triggered convergent evolution of the mandible, a morphological character involved in food consumption. Mandible shape from four Sub-Antarctic islands was compared to phylogeny, tracing the history of colonization, and climatic conditions. Mandible shape was primarily influenced by phylogenetic history, thus discarding the hypothesis of convergent evolution. The biomechanical properties of the jaw were then investigated. Incisor in-lever and temporalis out-lever suggested an increase in the velocity of incisor biting, in agreement with observations on various carnivorous and insectivorous rodents. The mechanical advantage related to incisor biting also revealed an increased functional performance in Sub Antarctic populations, and appears to be an adaptation to catch prey more efficiently. The amount of change involved was larger than expected for a plastic response, suggesting microevolutionary processes were evolved. This study thus denotes some degree of adaptive convergent evolution related to changes in habitat-related changes in dietary items in Sub-Antarctic mice, but only regarding simple, functionally relevant aspects of mandible morphology. PMID- 29528492 TI - Targeted resequencing reveals genomic signatures of barley domestication. AB - Barley (Hordeum vulgare) is an established model to study domestication of the Fertile Crescent cereals. Recent molecular data suggested that domesticated barley genomes consist of the ancestral blocks descending from multiple wild barley populations. However, the relationship between the mosaic ancestry patterns and the process of domestication itself remained unclear. To address this knowledge gap, we identified candidate domestication genes using selection scans based on targeted resequencing of 433 wild and domesticated barley accessions. We conducted phylogenetic, population structure, and ancestry analyses to investigate the origin of the domesticated barley haplotypes separately at the neutral and candidate domestication loci. We discovered multiple selective sweeps that occurred on all barley chromosomes during domestication in the background of several ancestral wild populations. The ancestry analyses demonstrated that, although the ancestral blocks of the domesticated barley genomes were descended from all over the Fertile Crescent, the candidate domestication loci originated specifically in its eastern and western parts. These findings provided the first molecular evidence implicating multiple wild or protodomesticated lineages in the process of barley domestication initiated in the Levantine and Zagros clusters of the origin of agriculture. PMID- 29528494 TI - The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation. AB - BACKGROUND: Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL-4 and IL-13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL-4 or IL-13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL-13 signal. METHODS: We systematically identified periostin-dependent expression profile using DNA microarrays. We then investigated whether IL-24 downregulates filaggrin expression downstream of the IL-13 signals and whether IL-13-induced IL-24 expression and IL-24-induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL-24 and activation of STAT3 in mite-treated mice and in AD patients. RESULTS: We identified IL-24 as an IL-13-induced molecule in a periostin-dependent manner. Keratinocytes are the main IL-24-producing tissue resident cells stimulated by IL-13 in a periostin-dependent manner via STAT6. IL 24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL-13/periostin pathway. Wild-type mite treated mice showed significantly enhanced expression of IL-24 and activation of STAT3 in the epidermis, which disappeared in both STAT6-deficient and periostin deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL-24 expression was enhanced in the epidermis of skin tissues taken from AD patients. CONCLUSIONS: The IL-13/periostin pathway induces IL-24 production in keratinocytes, playing an important role in barrier dysfunction in AD. PMID- 29528495 TI - Policies Regarding Sexual Expression in Spanish Long-Term Care Facilities for Older People. PMID- 29528496 TI - Impact of the 2016 US presidential election on OCD symptom presentation: A case illustration. AB - A recent survey of Americans found that the majority experienced stress during and after the 2016 United States presidential election. Psychosocial, environmental stressors can have a unique impact on symptom presentation in mental health disorders. This manuscript details a case illustration of an individual whose symptoms of obsessive-compulsive disorder were directly linked to the election, as well as how these symptoms were addressed via treatment with intensive exposure and response prevention. PMID- 29528497 TI - "She's woke": The paradoxical effects of the 2016 election on an individual client. AB - The purpose of this article is to present a case history of an individual client deeply affected by the 2016 election of Donald Trump: an unexpected key to her self-empowerment. Raised in poverty and with a history of being sexually abused, the client's anger and frustration at Hillary Clinton's loss in the election led to an examination in therapy of the role of gender in her life and enabled her to strengthen her sense of agency in her world. PMID- 29528498 TI - Mapping xylem failure in disparate organs of whole plants reveals extreme resistance in olive roots. AB - The capacity of plant species to resist xylem cavitation is an important determinant of resistance to drought, mortality thresholds, geographic distribution and productivity. Unravelling the role of xylem cavitation vulnerability in plant evolution and adaptation requires a clear understanding of how this key trait varies between the tissues of individuals and between individuals of species. Here, we examine questions of variation within individuals by measuring how cavitation moves between organs of individual plants. Using multiple cameras placed simultaneously on roots, stems and leaves, we were able to record systemic xylem cavitation during drying of individual olive plants. Unlike previous studies, we found a consistent pattern of root > stem > leaf in terms of xylem resistance to cavitation. The substantial variation in vulnerability to cavitation, evident among individuals, within individuals and within tissues of olive seedlings, was coordinated such that plants with more resistant roots also had more resistant leaves. Preservation of root integrity means that roots can continue to supply water for the regeneration of drought damaged aerial tissues after post-drought rain. Furthermore, coordinated variation in vulnerability between leaf, stem and root in olive plants suggests a strong selective pressure to maintain a fixed order of cavitation during drought. PMID- 29528499 TI - Population Pharmacokinetics and Exposure-Response Analyses of Eslicarbazepine Acetate Efficacy and Safety in Monotherapy of Partial-Onset Seizures. AB - Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). ESL pharmacokinetics (PK) and exposure-response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1-2 studies (ESL 600-1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure-response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1 compartment model with first-order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin ) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported. PMID- 29528500 TI - Comparison of the longitudinal effects of persistent periodic breathing and apnoea on cerebral oxygenation in term- and preterm-born infants. AB - KEY POINTS: Periodic breathing and apnoea were more common in preterm compared to age-matched term-born infants across the first 6 months after term-corrected age. Periodic breathing decreased with age in both term and preterm infants. Apnoea duration was not different between groups; however, the decline in apnoea index with postnatal age observed in the term infants was not seen in the preterm infants. Falls in tissue oxygenation index (brain TOI) associated with apnoeas were greater in the preterm infants at all three ages studied. The clinical significance of falls in brain TOI during periodic breathing and apnoea on neurodevelopmental outcome is unknown and warrants further investigations. ABSTRACT: Periodic breathing and short apnoeas are common in infants, particularly those born preterm, but are thought to be benign. The aim of our study was to assess the incidence and impact of periodic breathing and apnoea on heart rate, oxygen saturation and brain tissue oxygenation index (TOI) in infants born at term and preterm over the first 6 months after term equivalent age. Nineteen term-born infants (38-42 weeks gestational age) and 24 preterm infants (born at 27-36 weeks gestational age) were studied at 2-4 weeks, 2-3 months and 5 6 months post-term-corrected age during sleep. Periodic breathing episodes were defined as three or more sequential apnoeas each lasting >=3 s and apnoeas as >=3 s in duration. The mean duration of periodic breathing episodes was longer in term infants than in preterm infants at 2-4 weeks (P < 0.05) and at 5-6 months (P < 0.05); however, the nadir in TOI was significantly less in the term infants at 2-3 months (P < 0.001). Apnoea duration was not different between groups; however, the decline in apnoea index with postnatal age observed in the term infants was not seen in the preterm infants. Falls in TOI associated with apnoeas were greater in the preterm infants at all three ages studied. In conclusion, periodic breathing and short apnoeas were more common in infants born preterm and falls in cerebral oxygenation were greater than in the term group. The clinical significance of this on neurodevelopmental outcome is unknown and warrants further investigations. PMID- 29528502 TI - Long-term evaluation (20 years) of the outcomes of coronally advanced flap in the treatment of single recession-type defects. AB - BACKGROUND: Coronally advanced flap (CAF) has been considered as one of the most predictable and versatile root coverage procedures. Thus, the aims of this study are two-fold: 1) to evaluate the long-term outcomes following CAF in the treatment of gingival recession (GR); and 2) to explore the influence of several tooth/patient-related factors on the stability of gingival margin at 5, 10, and 20 years after surgery. METHODS: Ninety-four patients with 97 GR (73 Miller's Class I and 24 Miller's Class III) were treated with CAF in a private practice between 1984 and 1996. Recession depth (RD), probing depth (PD), keratinized tissue (KT) width and patient/tooth-associated variables were recorded for each GR at baseline, 1 year, 5 years, 10 years, 15 years and 20 years after surgery. Parametric, non-parametric, and logistic regression statistics were used throughout the study RESULTS: A total of 72 patients with 72 GR were available for analysis at the 20-year follow-up examination (final patients' dropout rate = 23.4%). Statistically significant improvements were found for RD in all evaluations (P < 0.05). Little more than a half (56%) of the sites treated with CAF did not display RD changes between the short-term (i.e., 1 year) and long term (i.e., 20 years) examinations. Overall, mean root coverage (MRC) decreased from 68.59% to 56.11%. The achievement of complete root coverage (CRC) 1 year after treatment was associated to GR not presenting interdental tissue loss (P = 0.001), the root condition (i.e., lack of non-carious cervical lesion [step] - P < 0.001), an attached KT band >= 2 mm (P = 0.019), and baseline RD (P = 0.020). GR recurrence seemed to be influenced by age, RD at 1-year follow-up, sites displaying an attached KT < 2 mm and interdental tissue loss. CONCLUSIONS: The aging process, the condition of the interdental periodontal tissue, and the presence of an attached KT band < 2 mm seem to be negative factors influencing the stability of the gingival margin during the 20-year observation period. PMID- 29528501 TI - The myth of the immature barrier systems in the developing brain: role in perinatal brain injury. AB - Central nervous system homeostasis is maintained by cellular barriers that protect the brain from external environmental changes and protect the CNS from harmful molecules and pathogens in the blood. Historically, for many years these barriers were thought of as immature, with limited functions, during brain development. In this review, we will present advances in the understanding of the barrier systems during development and evidence to show that in fact the barriers serve many important neurodevelopmental functions and that fetal and newborn brains are well protected. We will also discuss how ischaemic injury or systemic inflammation may breach the integrity of the barriers in the developing brain. PMID- 29528503 TI - Ethylene signaling induces gelatinous layers with typical features of tension wood in hybrid aspen. AB - The phytohormone ethylene impacts secondary stem growth in plants by stimulating cambial activity, xylem development and fiber over vessel formation. We report the effect of ethylene on secondary cell wall formation and the molecular connection between ethylene signaling and wood formation. We applied exogenous ethylene or its precursor 1-aminocyclopropane-1-carboxylic acid (ACC) to wild type and ethylene-insensitive hybrid aspen trees (Populus tremula * tremuloides) and studied secondary cell wall anatomy, chemistry and ultrastructure. We furthermore analyzed the transcriptome (RNA Seq) after ACC application to wild type and ethylene-insensitive trees. We demonstrate that ACC and ethylene induce gelatinous layers (G-layers) and alter the fiber cell wall cellulose microfibril angle. G-layers are tertiary wall layers rich in cellulose, typically found in tension wood of aspen trees. A vast majority of transcripts affected by ACC are downstream of ethylene perception and include a large number of transcription factors (TFs). Motif-analyses reveal potential connections between ethylene TFs (Ethylene Response Factors (ERFs), ETHYLENE INSENSITIVE 3/ETHYLENE INSENSITIVE3 LIKE1 (EIN3/EIL1)) and wood formation. G-layer formation upon ethylene application suggests that the increase in ethylene biosynthesis observed during tension wood formation is important for its formation. Ethylene-regulated TFs of the ERF and EIN3/EIL1 type could transmit the ethylene signal. PMID- 29528504 TI - Appraising reappraisal: Exploring its role in the context of behavioral exposure for contamination fears. AB - OBJECTIVES: A large body of work suggests that cognitive reappraisal is an effective strategy for modifying emotional intensity. In addition, its habitual use has been linked to adaptive psychological functioning, operationalized as low levels of symptoms of psychopathology. However, little is known about the impact of cognitive reappraisal on behavioral aspects of mental disorders. For example, the experience of fear is often accompanied by the behavioral urge to avoid the feared stimuli. Although there is evidence to suggest that cognitive reappraisal reduces fear in the moment, there is less information about the impact on behavioral correlates. METHOD: To that end, we recruited 90 participants who experienced substantial contamination concerns (i.e., obsessive-compulsive disorder symptoms) and asked them to participate in exposure tasks that consisted of gradually coming into contact with contaminated objects (i.e., approach behavior). We randomly assigned participants to one of three conditions: (1) reappraise the emotion-eliciting stimulus, (2) reappraise their emotional response, or (3) no specific emotion regulation instructions. RESULTS: Reappraising the stimulus, but not reappraising the emotional response, led to significantly greater behavioral approach (p = .02) than the no-instruction condition during exposure. There were no significant differences in subjective state anxiety between any of the conditions. CONCLUSION: These findings suggest that certain types of reappraisal may lead to greater approach behavior during exposure even in the absence of subjective emotional changes. More broadly, they underscore the importance of examining the role of emotion regulation strategies (including different types of reappraisal) on the behavioral aspects of mental disorders. PMID- 29528505 TI - Effect of hepatitis C infection on the quality of life. AB - PURPOSE: To assess the quality of life (QoL) of patients with hepatitis C infection (HCI) and its correlations with demographic and clinical variables. DESIGN AND METHODS: QoL and depressive symptoms were evaluated with the validated rating instruments of the 36-item short form (SF-36) generic health survey and the second version of the self-rated Beck depression inventory (BDI-II) in a cross-sectional design and correlated with basic demographic and clinical variables, including the Fibroscan score, which indicates the severity of liver impairment. FINDINGS: A cohort of 60 HCI patients who participated in the study scored lower than the general population on all domains of the SF-36. In the multivariate correlation analysis, only the physical functioning domain of the SF 36 showed a significant correlation with age, gender, and BD-II and Fibroscan scores. IMPLICATIONS FOR CLINICAL PRACTICE: QoL is lower for patients who are older, female, and have depressive symptoms. Progression of hepatic cirrhosis is associated with lower QoL in the physical domain. PMID- 29528506 TI - Influence of iron redox state on black ripe olive processing. AB - BACKGROUND: The oxidation and polymerization of the phenolic compounds present in black ripe olives give rise to their black shiny colour, which is fixed by the addition of ferrous salts such as ferrous gluconate. Among the many variables that can affect the success of this fixation step, the influence of pH on this process was assessed on fruits of the Hojiblanca cultivar processed at pilot plant scale. Hence the aim of this work was to gain knowledge on the development of this fixation step, in particular on olives that were oxidized with a single alkaline treatment. RESULTS: It was found that the penetration of the ferric cation into the olive flesh was an extremely slow process and it led to less-dark olives. Besides, at a pH higher than 6 the oxidation of the ferrous to the ferric cation was a very rapid reaction, and olives that were processed with initial pH adjusted to 4 units had a darker colour than those without pH correction. Ultrafiltration/nanofiltration of oxidized olive solutions spiked with ferric ions or even pure oxidized ferric solutions through membranes of 10, 3 and 1 kDa revealed that ferric ions formed high-molecular structures that inhibited the penetration of the ion into the olive flesh and therefore the fixation of the black colour. CONCLUSION: The results presented in this study suggest that the formation of ferric ions during the colour fixation step of black ripe olives must be avoided to obtain darker olives. Consequently, the initial pH of the ferrous gluconate solution must be corrected to avoid oxidation of the ferrous to ferric cations during the fixation step. This study will contribute to the improvement of the colour fixation step of black ripe olive processing. (c) 2018 Society of Chemical Industry. PMID- 29528508 TI - Melatonin biosynthesis enzymes recruit WRKY transcription factors to regulate melatonin accumulation and transcriptional activity on W-box in cassava. AB - Melatonin is widely involved in growth, development, and stress responses in plants. Although the melatonin synthesis enzymes have been identified in various plants, their interacting proteins remain unknown. Herein, overexpression of tryptophan decarboxylase 2 (MeTDC2)-interacting proteins, N-acetylserotonin O methyltransferase 2 (MeASMT2) interacting proteins, and N-acetylserotonin O methyltransferase 3 (MeASMT3) in cassava leaf protoplasts resulted in more melatonin than when other enzymes were overexpressed. Through yeast two-hybrid, 14 MeTDC2-interacting proteins, 24 MeASMT2 interacting proteins, and 9 MeASMT3 interacting proteins were identified. Notably, we highlighted MeWRKY20 and MeWRKY75 as common interacting proteins of the 3 enzymes, as evidenced by yeast two-hybrid, and in vivo bimolecular fluorescence complementation (BiFC). Moreover, co-overexpression of MeTDC2/MeASMT2/3 with MeWRKY20/75 in cassava leaf protoplasts did not only activated the transcriptional activities of MeWRKY20 and MeWRKY75 on W-box, but also induced the effects of MeTDC2, MeASMT2/3 on endogenous melatonin levels. Taken together, 3 melatonin synthesis enzymes (MeTDC2, MeASMT2/3) interact with MeWRKY20/75 to form a protein complex in cassava. This information significantly extends the knowledge of the complex modulation of plant melatonin signaling. PMID- 29528509 TI - Effects of water viscosity and tongue ingestion site on tongue pressure during food bolus propulsion. AB - The purpose of this study was to help provide data to help to implement effective rehabilitation following surgery for oral cancer by comparing tongue pressure production for water and thickened water from the anterior and posterior parts of the tongue during swallowing. Ten healthy volunteers (7 men, 3 women; age 27.6 +/ 1.5 years) participated in the experiments. Tongue pressure during 3 mL water and 3 mL thickened water at the anterior and posterior tongue during swallowing was measured using a sensor sheet system with five measuring points on the hard palate. The sequential order of the points, maximal magnitude and duration of tongue pressure at each point were compared based on water viscosity and tongue ingestion site. There was a common pattern in the sequential order of tongue pressure generation among the two swallowing conditions. The maximal magnitude of tongue pressure was significantly higher when swallowing thickened water than when swallowing water at all points except for the anterior-median and mid-median part. Moreover, the pressure at all sites during posterior ingestions was significantly lower than that during anterior ingestion. The present results provide mean values of tongue pressure during voluntarily triggered swallowing in anterior ingestion and posterior ingestion in young, healthy dentate individuals; these values can be clinically referenced for tongue pressure measurement in the evaluation of patients with dysphagia. The use of reference values may help streamline the diagnosis, treatment and rehabilitation of dysphagia. PMID- 29528510 TI - 2-(Hydroxyimino)aldehydes: Photo- and Physicochemical Properties of a Versatile Functional Group for Monomer Design. AB - In the context of our research on stimuli-responsive polymers bearing the 2 (hydroxyimino)aldehyde (HIA) group, we have explored the photochemical behavior and physicochemical properties of a number of HIAs. Interpretation of the experimental data is supported by quantum mechanical calculations. HIAs are expected to undergo photoisomerization, chelate metal ions, yield hydrogen-bonded dimers or oligomers, exhibit relatively low pKa s, and form >C=NO. radicals through OH hydrogen abstraction or oxidation of the oximate ion. Besides the well established E/Z oxime photoisomerism, we observed a Norrish-Yang cyclization resulting in cyclobutanol oximes, to our knowledge not previously described in the literature. The acidity, bond dissociation enthalpies, and electrochemical properties of the HIAs are compared with literature data of simple oximes. The results are discussed in relation to the many potential applications for HIAs, with emphasis on the synthesis of novel HIA-containing responsive polymers. PMID- 29528511 TI - Structural analysis of lysine-4 methylated histone H3 proteins using synchrotron radiation circular dichroism spectroscopy. AB - We report structural alterations of histone H3 proteins induced by lysine-4 (K4) monomethylation, dimethylation, and trimethylation identified by using synchrotron radiation circular dichroism spectroscopy. Compared with unmethylated H3, monomethylation and dimethylation induced increases in alpha-helix structures and decreases in beta-strand structures. In contrast, trimethylation decreased alpha-helix content but increased beta-strand content. The structural differences among K4-unmethylated/methylated H3 may allow epigenetic enzymes to discriminate the substrates both chemically and sterically. PMID- 29528507 TI - Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review. AB - In recent years, lymphangiogenesis, the process of lymphatic vessel formation from existing lymph vessels, has been demonstrated to have a significant role in diverse pathologies, including cancer metastasis, organ graft rejection, and lymphedema. Our understanding of the mechanisms of lymphangiogenesis has advanced on the heels of studies demonstrating vascular endothelial growth factor C as a central pro-lymphangiogenic regulator and others identifying multiple lymphatic endothelial biomarkers. Despite these breakthroughs and a growing appreciation of the signaling events that govern the lymphangiogenic process, there are no FDA approved drugs that target lymphangiogenesis. In this review, we reflect on the lessons available from the development of antiangiogenic therapies (26 FDA approved drugs to date), review current lymphangiogenesis research including nanotechnology in therapeutic drug delivery and imaging, and discuss molecules in the lymphangiogenic pathway that are promising therapeutic targets. PMID- 29528512 TI - Computational studies on the water-catalyzed stereoinversion mechanism of glutamic acid residues in peptides and proteins. AB - In contrast with the common belief that all the amino acid residues in higher organisms are l-forms, d-amino acid residues have been recently detected in various aging tissues. Aspartic acid (Asp) residues are known to be the most prone to stereoinvert via cyclic imide intermediate. Although the glutamic acid (Glu) is similar in chemical structure to Asp, little has been reported to detect d-Glu residues in human proteins. In this study, we investigated the mechanism of the Glu-residue stereoinversion catalyzed by water molecules using B3LYP/6 31+G(d,p) density functional theory calculations. We propose that the Glu-residue stereoinversion proceeds via a cyclic imide intermediate, i.e., glutarimide (GI). All calculations were performed by using a model compound in which a Glu residue was capped with acetyl and methylamino groups on the N- and C-termini, respectively. We found that two water molecules catalyze the three steps involved in the GI formation: iminolization, cyclization, and dehydration. The activation energy required for the Glu residue to form a GI intermediate was estimated to be 32.3 kcal mol-1 , which was higher than that of the experimental Asp-residue stereoinversion. This calculation result suggests that the Glu-residue stereoinversion is not favored under the physiological condition. PMID- 29528514 TI - Prenatal and postnatal evolution of isolated fetal splenic cysts. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence, the prenatal, and postnatal evolution of isolated fetal splenic cysts. METHODS: All cases of suspected fetal splenic cyst or abdominal unidentified cyst discovered during routine ultrasound scan, from 2007 to 2017, and referred to a French tertiary care center, were retrospectively collected. For each case, several prenatal parameters and postnatal evolution were reported. RESULTS: Among 5450 cases of fetal anomalies, 14 patients (0.3%) had a prenatal diagnosis of fetal splenic cysts. Median gestational age at diagnosis was 30.1 weeks. A unique cyst was present in 78.6%, whereas 2 cysts were observed in 14.3% and 3 cysts in 7.1%. During the pregnancy, cysts remained the same (78.6%) or disappeared (21.4%). Ultrasound scans at 6 months of age found total disappearance of the cysts (36.4%), spontaneous reduction from 2 to 1 cyst (18.2%) or persistence of the cysts (45.4%). CONCLUSION: Fetal splenic cysts are rare images, always isolated, usually unique and mainly found during third trimester of pregnancy. Their evolution is to disappear spontaneously during pregnancy or at 6 months of age leaving only half of them to remain beyond that age but without any symptoms. PMID- 29528515 TI - Synthesis and Immunological Studies of Oligosaccharides that Consist of the Repeating Unit of Streptococcus pneumoniae Serotype 3 Capsular Polysaccharide. AB - A highly convergent and efficient strategy was developed for the chemical synthesis of complex oligosaccharides of Streptococcus pneumoniae type 3 capsular polysaccharides that contain multiple glucuronic acid units. Once the oligoglucosides were efficiently and stereoselectively assembled, the designated glucose units were regioselectively oxidized to glucuronic acid in one step at the final synthetic stage, which helped avoid difficult glycosylations that involved glucuronic acid. The target oligosaccharides had a free amino group at the reducing terminus and varied caps at the non-reducing terminus to enable further modification and structure-activity relationship studies. Immunological evaluations of the oligosaccharide-tetanus toxoid conjugates showed that they elicited robust T-cell-dependent immunoglobulin G antibody responses and that the sugar chain length had a major impact on their immunological properties. In particular, the penta- and hexasaccharides were identified as promising antigens for vaccine development. PMID- 29528516 TI - The environmental neurotoxin beta-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model. AB - The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10-day-old male rats revealed a high and selective uptake in the pineal gland at 30 minutes to 24 hours after 14 C-L-BMAA administration (0.68 mg/kg). Primary pinealocyte cultures exposed to 0.05-3 mmol/L BMAA showed a 57% 93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2 weeks after BMAA administration (460 mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress. PMID- 29528517 TI - Enantioselective behaviour of tetraconazole during strawberry wine-making process. AB - The fate of tetraconazole enantiomers in strawberries during wine-making process was studied. The residues were determined by ultra-performance convergence chromatography tandem triple quadrupole mass spectrometry after each process steps. Results indicated that there was significant enantioselective dissipation of tetraconazole enantiomers during the fermentation process. And (-) tetraconazole degraded faster than (+)-tetraconazole. The half-lives of (-) tetraconazole and (+)-tetraconazole were 3.12, 3.76 days with washing procedure and 3.18, 4.05 days without washing procedure. The processing factors of strawberry wine samples after each step were generally less than 1. In particular, the processing factors of the fermentation process were the lowest. The results could help facilitate more accurate risk assessments of tetraconazole during wine-making process. PMID- 29528518 TI - Prevalence and correlates of low physical activity in the Iranian population: National survey on non-communicable diseases in 2011. AB - To assess the prevalence and correlates of low physical activity among Iranian population aged 15-64 years. We used the data collected in National Surveillance of Risk Factors of Non-Communicable Diseases in Iran, 2011. Physical activity was categorized in 3 levels of low, moderate, and high based on a Persian version of Global Physical Activity Questionnaire. The multistage cluster sampling design was accounted for using complex survey analysis method. The sample included 10016 individuals; 41.7% (n = 4178) were men and 58.3% (n = 5837) were women. The mean (SD) age of participants was 38.8 (14.9) years also, and 69.8% (n = 6991) of the participants were from urban areas. The prevalence of low physical activity in the whole population was estimated to be 44.8% (95% CI: 41.7, 48.1). The odds of lower physical activity in the women were 3 times greater than men (OR = 3.14; 95% CI: 2.64, 3.57); in the wealthiest people was 25% lower than the poorest people (OR = 0.75; 95% CI: 0.60, 0.94). The odds of lower physical activity in the age groups 55-64 years were 44% greater than the youngest age groups 15-24 years (OR = 1.44; 95% CI: 1.23, 1.68). The odds of lower physical activity in the obese participants were 18% greater than normal-weight people (OR = 1.18; 95% CI: 1.01, 1.38).). The odds of lower physical activity in diabetic patients were 30% greater than healthy people (OR: 1.30; 95% CI: 1.07, 1.57). The prevalence of low physical activity in Iran, 2011 was high. The correlates of low physical activity in Iran are different to those of Western populations. The main associated factors with low physical activity were female gender, urban area, low socioeconomic status, obesity, diabetes, and older age. Public health policies should target the groups at highest risk of low physical activity. PMID- 29528519 TI - Serum DHEA and Its Sulfate Are Associated With Incident Fall Risk in Older Men: The MrOS Sweden Study. AB - The adrenal-derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. Many of the actions of DHEAS are considered to be mediated through metabolism into androgens and estrogens in peripheral target tissues. The predictive value of serum DHEA and DHEAS for the likelihood of falling is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEA and DHEAS levels and incident fall risk in a large cohort of older men. Serum DHEA and DHEAS levels were analyzed with mass spectrometry in the population-based Osteoporotic Fractures in Men study in Sweden (n = 2516, age 69 to 81 years). Falls were ascertained every 4 months by mailed questionnaires. Associations between steroid hormones and falls were estimated by generalized estimating equations. During a mean follow-up of 2.7 years, 968 (38.5%) participants experienced a fall. High serum levels of both DHEA (odds ratio [OR] per SD increase 0.85; 95% CI, 0.78 to 0.92) and DHEAS (OR 0.88, 95% CI, 0.81 to 0.95) were associated with a lower incident fall risk in models adjusted for age, BMI, and prevalent falls. Further adjustment for serum sex steroids or age-related comorbidities only marginally attenuated the associations between DHEA or DHEAS and the likelihood of falling. Moreover, the point estimates for DHEA and DHEAS were only slightly reduced after adjustment for lean mass and/or grip strength. Also, the addition of the narrow walk test did not substantially alter the associations between serum DHEA or DHEAS and fall risk. Finally, the association with incident fall risk remained significant for DHEA but not for DHEAS after simultaneous adjustment for lean mass, grip strength, and the narrow walk test. This suggests that the associations between DHEA and DHEAS and falls are only partially mediated via muscle mass, muscle strength, and/or balance. In conclusion, older men with high DHEA or DHEAS levels have a lesser likelihood of a fall. (c) 2018 American Society for Bone and Mineral Research. PMID- 29528520 TI - Isothermal titration calorimetry for chiral chemistry. AB - One of the most powerful techniques that are currently available to measure thermodynamic parameters such as enthalpy (DeltaH), Gibbs free energy (DeltaG), entropy changes (DeltaS), and binding affinity in chemical reactions is isothermal titration calorimetry (ITC). Recent advances in instrumentation have facilitated the development of ITC as a very essential analytical tool in biology and chemistry. In this article, we will focus on a review of the literature on the application of ITC for the study of chiral systems and chiral interactions. We present studies in which the ITC technique is used to study chiral interactions, for instance in chiral solutions, chiral organometallic complexes, guest-host chiral binding interactions, and biological macromolecules. Finally, we put strong emphasis on the most recent application of ITC for the study of chirality in nanosystems and at the nanoscale. PMID- 29528521 TI - Striatal cholinergic receptor activation causes a rapid, selective and state dependent rise in cortico-striatal beta activity. AB - Cortico-basal ganglia-thalamic (CBT) beta oscillations (15-30 Hz) are elevated in Parkinson's disease and correlated with movement disability. To date, no experimental paradigm outside of loss of dopamine has been able to specifically elevate beta oscillations in the CBT loop. Here, we show that activation of striatal cholinergic receptors selectively increased beta oscillations in mouse striatum and motor cortex. In individuals showing simultaneous beta increases in both striatum and M1, beta partial directed coherence (PDC) increased from striatum to M1 (but not in the reverse direction). In individuals that did not show simultaneous beta increases, beta PDC increased from M1 to striatum (but not in the reverse direction), and M1 was characterized by persistent beta-high frequency oscillation phase-amplitude coupling. Finally, the direction of beta PDC distinguished between beta sub-bands. This suggests that (1) striatal cholinergic tone exerts state-dependent and frequency-selective control over CBT beta power and coordination; (2) ongoing rhythmic dynamics can determine whether elevated beta oscillations are expressed in striatum and M1; and (3) altered striatal cholinergic tone differentially modulates distinct beta sub-bands. PMID- 29528522 TI - Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia dolosa (genomovar VI). AB - Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n = 11) at various medical centers across the US between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1, 3, and 5 years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased one-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa-infected patients was 43% in patients that survived the first year post-transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post-transplant. PMID- 29528513 TI - Avenues to molecular imaging of dying cells: Focus on cancer. AB - Successful treatment of cancer patients requires balancing of the dose, timing, and type of therapeutic regimen. Detection of increased cell death may serve as a predictor of the eventual therapeutic success. Imaging of cell death may thus lead to early identification of treatment responders and nonresponders, and to "patient-tailored therapy." Cell death in organs and tissues of the human body can be visualized, using positron emission tomography or single-photon emission computed tomography, although unsolved problems remain concerning target selection, tracer pharmacokinetics, target-to-nontarget ratio, and spatial and temporal resolution of the scans. Phosphatidylserine exposure by dying cells has been the most extensively studied imaging target. However, visualization of this process with radiolabeled Annexin A5 has not become routine in the clinical setting. Classification of death modes is no longer based only on cell morphology but also on biochemistry, and apoptosis is no longer found to be the preponderant mechanism of cell death after antitumor therapy, as was earlier believed. These conceptual changes have affected radiochemical efforts. Novel probes targeting changes in membrane permeability, cytoplasmic pH, mitochondrial membrane potential, or caspase activation have recently been explored. In this review, we discuss molecular changes in tumors which can be targeted to visualize cell death and we propose promising biomarkers for future exploration. PMID- 29528523 TI - Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer. AB - RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genomewide association studies (GWASs) have identified multiple intergenic single-nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (high-throughput chromosome conformation capture [Hi-C]), epigenetic annotation, and a series of functional assays. The eQTL analysis identified six potential functional SNPs (rs9533090, rs9594738, r8001611, rs9533094, rs9533095, and rs9594759) exclusively correlated with RANKL gene expression (p < 0.001) at 13q14.11. Co-localization analyses suggested that eQTL signal for RANKL and BMD GWAS signal shared the same causal variants. Hi-C analysis and functional annotation further validated that the first five osteoporosis SNPs are located in a super-enhancer region to regulate the expression of RANKL via long-range chromosomal interaction. Particularly, dual-luciferase assay showed that the region harboring rs9533090 in the super-enhancer has the strongest enhancer activity, and rs9533090 is an allele-specific regulatory SNP. Furthermore, deletion of the region harboring rs9533090 using CRISPR/Cas9 genome editing significantly reduced RANKL expression in both mRNA level and protein level. Finally, we found that the rs9533090-C robustly recruits transcription factor NFIC, which efficiently elevates the enhancer activity and increases the RANKL expression. In summary, we provided a feasible method to identify regulatory noncoding SNPs to distally regulate their target gene underlying the pathogenesis of osteoporosis by using bioinformatics data analyses and experimental validation. Our findings would be a potential and promising therapeutic target for precision medicine in osteoporosis. (c) 2018 American Society for Bone and Mineral Research. PMID- 29528524 TI - Age-associated impairments in contraction-induced rapid-onset vasodilatation within the forearm are independent of mechanical factors. AB - NEW FINDINGS: What is the central question of this study? We examined whether the mechanical contribution to contraction-induced rapid-onset vasodilatation (ROV) differed with age and whether ROV is associated with peripheral artery stiffness. Furthermore, we examined how manipulation of perfusion pressure modulates ROV in young and older adults. What is the main finding and its importance? The mechanical contribution to ROV is similar in young and older adults. Conversely, peripheral arterial stiffness is not associated with ROV. Enhancing perfusion pressure augments ROV to a similar extent in young and older adults. These results suggest that age-related attenuations in ROV are not attributable to a mechanical component and that ROV responses are independent of peripheral artery stiffness. ABSTRACT: Contraction-induced rapid-onset vasodilatation (ROV) is modulated by perfusion and transmural pressure in young adults; however, this effect remains unknown in older adults. The present study examined the mechanical contribution to ROV in young versus older adults, the influence of perfusion pressure and whether these responses are associated with arterial stiffness. Forearm vascular conductance (in millilitres per minute per 100 mmHg) was measured in 12 healthy young (24 +/- 4 years old) and 12 older (67 +/- 3 years old) adults during: (i) single dynamic contractions at 20% of maximal voluntary contraction; and (ii) single external mechanical compression of the forearm (200 mmHg) positioned above, at and below heart level. Carotid-radial pulse-wave velocity characterized upper limb arterial stiffness. Total ROV responses to single muscle contractions and single external mechanical compressions were attenuated in older adults at heart level (P < 0.05); however, the relative mechanical contribution to contraction-induced peak (46 +/- 14 versus 40 +/- 18%; P = 0.21) and total (37 +/- 21 versus 32 +/- 18%; P = 0.27) responses were not different between young and older adults. Reducing or enhancing perfusion pressure altered ROV responses to a similar extent between young and older adults (P < 0.05). Upper limb arterial stiffness was not associated with peak (r = 0.02; P = 0.93) or total vascular conductance (r = -0.01; P = 0.96) in the group as a whole. Our data suggest that: (i) age-associated attenuations in ROV are not attributable to a mechanical component; (ii) enhancing perfusion pressure augments ROV to a similar extent between young and older adults; and (iii) basal upper limb arterial stiffness is not associated with the vasodilator responses after a single skeletal muscle contraction in young and older adults. PMID- 29528525 TI - Selecting and applying indicators of ecosystem collapse for risk assessments. AB - Ongoing ecosystem degradation and transformation are major threats to biodiversity. Measuring ecosystem change toward collapse relies on monitoring indicators that quantify key ecological processes. Yet little guidance is available on selection and use of indicators for ecosystem risk assessment. We reviewed indicator use in ecological studies of ecosystem collapse in marine pelagic and temperate forest ecosystems. We examined indicator-selection methods, indicator types (geographic distribution, abiotic, biotic), methods of assessing multiple indicators, and temporal quality of time series. We compared how these factors were applied in the ecological studies with how they were applied in risk assessments by using the International Union for Conservation of Nature's Red List of Ecosystems (RLE), for which indicators are used to estimate risk of ecosystem collapse. Ecological studies and RLE assessments rarely reported how indicators were selected, particularly in terrestrial ecosystems. Few ecological studies and RLE assessments quantified ecosystem change based on all 3 indicator types, and indicators types used differed between marine and terrestrial ecosystems. Several studies used indices or multivariate analyses to assess multiple indicators simultaneously, but RLE assessments did not because as RLE guidelines advise against them. Most studies and RLE assessments used time-series data that spanned at least 30 years, which increases the probability of reliably detecting change. Limited use of indicator-selection protocols and infrequent use of all 3 indicator types may hamper accurate detection of change. To improve the value of risk assessments for informing policy and management, we recommend using explicit protocols, including conceptual models, to identify and select indicators; a range of indicators spanning distributional, abiotic, and biotic features; indices and multivariate analyses with extreme care until guidelines are developed; time series with sufficient data to increase ability to accurately diagnose directional change; data from multiple sources to support assessments; and explicitly reporting steps in the assessment process. PMID- 29528526 TI - Minocycline alters expression of inflammatory markers in autonomic brain areas and ventilatory responses induced by acute hypoxia. AB - NEW FINDINGS: What is the central question of this study? Microglia are presumed to be the source of inflammatory mediators that contribute to hypoxia-induced neuroinflammation. However, the relationship between microglial activity during hypoxia and inflammatory responses in specific autonomic brain regions is not well understood. Therefore, we hypothesized that acute hypoxia initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. What is the main finding and its importance? Acute hypoxia initiated neuroinflammatory mechanisms specifically in brain autonomic nuclei responsible for cardiorespiratory control, i.e. the rostral ventrolateral medulla and paraventricular nucleus of the hypothalamus. Our findings emphasize the importance of microglia for the maintenance of autonomic adjustments during physiological challenges, such as hypoxia, or during cardiorespiratory reflex activation elicited by the arterial chemoreceptors. ABSTRACT: Prolonged and continuous exposure of mammals to a low oxygen environment (chronic hypoxia) elicits remarkable morphological and physiological adjustments. These include altered gene expression, increased peripheral chemosensitivity, enhanced respiratory drive and sympathoexcitation. The current study examines the hypothesis that acute hypoxia (AH) initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. Male Wistar rats pretreated with vehicle or minocycline (30 mg kg-1 day-1 for 5 days) were subjected to AH (8% O2 , balance N2 ) or normoxia (21% O2 ) for 3 h. AH increased interleukin (IL)-6, IL-1beta and matrix metalloprotease 9 (MMP9) mRNA expression in the paraventricular nucleus of the hypothalamus (PVH) and rostral ventrolateral medulla (RVLM) and tumour necrosis factor alpha (TNFalpha) in the RVLM. Treatment with minocycline, an inhibitor of microglial activation, decreased IL-1beta, TNFalpha and MMP9 mRNA expression in the RVLM, and increased IL-6 mRNA expression in the RVLM and PVH of rats exposed to AH. Minocycline treatment also elicited a decrease in the number of activated neurons in the RVLM/C1 neurons (expressed as Fos+ /tyrosine hydroxylase+ ), the number of Fos-activated neurons in the PVH and the increase in ventilation elicited by AH. When viewed together, these results suggest that AH modulates the expression of inflammatory mediators in autonomic brain nuclei that may be involved in the responses to chemoreceptor activation. PMID- 29528527 TI - Prevalence of electronic nicotine delivery systems (ENDS) use among youth globally: a systematic review and meta-analysis of country level data. AB - OBJECTIVE: To describe the prevalence and change in prevalence of electronic nicotine delivery systems (ENDS) use in youth by country and combustible smoking status. METHODS: Databases and the grey literature were systematically searched to December 2015. Studies describing the prevalence of ENDS use in the general population aged <=20 years in a defined geographical region were included. Where multiple estimates were available within countries, prevalence estimates of ENDS use were pooled for each country separately. RESULTS: Data from 27 publications (36 surveys) from 13 countries were included. The prevalence of ENDS ever use in 2013-2015 among youth were highest in Poland (62.1%; 95%CI: 59.9-64.2%), and lowest in Italy (5.9%; 95%CI: 3.3-9.2%). Among non-smoking youth, the prevalence of ENDS ever use in 2013-2015 varied, ranging from 4.2% (95%CI: 3.8-4.6%) in the US to 14.0% in New Zealand (95%CI: 12.7-15.4%). The prevalence of ENDS ever use among current tobacco smoking youth was the highest in Canada (71.9%, 95%CI: 70.9 72.8%) and lowest in Italy (29.9%, 95%CI: 18.5-42.5%). Between 2008 and 2015, ENDS ever use among youth increased in Poland, Korea, New Zealand and the US; decreased in Italy and Canada; and remained stable in the UK. CONCLUSIONS: There is considerable heterogeneity in ENDS use among youth globally across countries and also between current smokers and non-smokers. Implications for public health: Population-level survey data on ENDS use is needed to inform public health policy and messaging globally. PMID- 29528528 TI - Mapping floral resources for honey bees in New Zealand at the catchment scale. AB - Honey bees require nectar and pollen from flowers: nectar for energy and pollen for growth. The demand for nectar and pollen varies during the year, with more pollen needed in spring for colony population growth and more nectar needed in summer to sustain the maximum colony size and collect surplus nectar stores for winter. Sufficient bee forage is therefore necessary to ensure a healthy bee colony. Land-use changes can reduce the availability of floral resources suitable for bees, thereby increasing the susceptibility of bees to other stressors such as disease and pesticides. In contrast, land-based management decisions to protect or plant bee forage can enhance pollen and nectar supply to bees while meeting other goals such as riparian planting for water-quality improvement. Commercial demand for honey can also put pressure on floral resources through over-crowding of hives. To help understand and manage floral resources for bees, we developed a spatial model for mapping monthly nectar and pollen production from maps of land cover. Based on monthly estimated production data we mapped potential monthly supply of nectar and pollen to a given apiary location in the landscape. This is done by summing the total production within the foraging range of the apiary while subtracting the estimated nectar converted to energy for collection. Ratios of estimated supply over theoretical hive demand may then be used to infer a potential landscape carrying capacity to sustain hives. This model framework is quantitative and spatial, utilizing estimated flight energy costs for nectar foraging. It can contribute to management decisions such as where apiaries could be placed in the landscape depending on floral resources and where nectar limited areas may be located. It can contribute to planning areas for bee protection or planting such as in riparian vegetation. This would aid managed bee health, wild pollinator protection, and honey production. We demonstrate the methods in a case study in New Zealand where there is a growing demand for manuka (Leptospermum scoparium) honey production. PMID- 29528529 TI - Sense of coherence is a predictor of survival: A prospective study in women treated for breast cancer. AB - OBJECTIVE: Sense of coherence (SOC) reflects a person's overall orientation to life. Sense of coherence guides the person in finding and utilizing resources to maintain health and manage stress. Previously, we demonstrated SOC's stability over time among breast cancer (BC) patients, and in the present article, SOC's predictive value for survival is tested. METHODS: A cohort of 487 women underwent surgery for invasive BC and completed preoperatively the SOC-13 within a multicenter trial. Hazard ratios (HRs) were performed to identify significant independent predictors and their association with increase in SOC. RESULTS: Over a median follow-up time of 10 years, patients with a higher SOC had 63% lower risk of BC progression (HR 0.63; 95% CI, 0.11 to 0.85, P .03), 80% lower risk of BC mortality (HR 0.80; 95% CI, 0.38 to 0.96, P .00), and 80% lower risk of all cause mortality (HR 0.80; 95% CI, 0.47 to 0.93, P .00) than patients with a lower SOC. The mortality risk declined by 2.3% for every 1-unit increase in SOC, both for BC mortality (HR 0.98; 95% CI, 0.96 to 0.99, P .01) and for all-cause mortality (HR 0.98; 95% CI, 0.96 to 0.99, P .00). The risk of progression declined by 1.4% for every 1-unit increase in SOC (HR 0.99; 95% CI, 0.97 to 1.00, P .03). CONCLUSIONS: This study provides evidence of SOC's predictive value for disease progression and BC-caused and all-cause mortality. Sense of coherence provides a complement when designing individual plans that aims to support patients during their treatment. PMID- 29528530 TI - Charge Neutralization Drives the Shape Reconfiguration of DNA Nanotubes. AB - Reconfiguration of membrane protein channels for gated transport is highly regulated under physiological conditions. However, a mechanistic understanding of such channels remains challenging owing to the difficulty in probing subtle gating-associated structural changes. Herein, we show that charge neutralization can drive the shape reconfiguration of a biomimetic 6-helix bundle DNA nanotube (6HB). Specifically, 6HB adopts a compact state when its charge is neutralized by Mg2+ ; whereas Na+ switches it to the expanded state, as revealed by MD simulations, small-angle X-ray scattering (SAXS), and FRET characterization. Furthermore, partial neutralization of the DNA backbone charges by chemical modification renders 6HB compact and insensitive to ions, suggesting an interplay between electrostatic and hydrophobic forces in the channels. This system provides a platform for understanding the structure-function relationship of biological channels and designing rules for the shape control of DNA nanostructures in biomedical applications. PMID- 29528531 TI - A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia. AB - BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP. PMID- 29528532 TI - Impact of left atrial volume, sphericity, and fibrosis on the outcome of catheter ablation for atrial fibrillation. AB - INTRODUCTION: To investigate the relation between left atrial (LA) volume, sphericity, and fibrotic content derived from contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) and their impact on the outcome of catheter ablation for atrial fibrillation (AF). METHODS AND RESULTS: In 83 patients undergoing catheter ablation for AF, CE-CMR was used to assess LA volume, sphericity, and fibrosis. There was a significant correlation between LA volume and sphericity (R = 0.535, P < 0.001) and between LA volume and fibrosis (R = 0.241, P = 0.029). Multivariate analyses demonstrated that LA volume was the strongest independent predictor of AF recurrence after catheter ablation (1.019, P = 0.018). CONCLUSION: LA volume, sphericity, and fibrosis were closely related; however, LA volume was the strongest predictor of AF recurrence after catheter ablation. PMID- 29528533 TI - Sexual and romantic challenges among young Danes diagnosed with cancer: Results from a cross-sectional nationwide questionnaire study. AB - OBJECTIVE: The negative impact of malignant disease on sexual and relational functioning is well documented among adults but scarcely investigated among adolescents and young adults. This study explored the body image, self-perceived attractiveness, and sexual/romantic experiences of Danes diagnosed with cancer at the age of 15 to 29 years. It also aimed to clarify whether self-perceived needs for counseling were in fact met by health care providers. METHODS: All Danes who had been diagnosed with cancer at the age of 15 to 29 years during the period 2009 to 2013 were included in a cross-sectional nationwide questionnaire study. Eight hundred twenty-two questionnaires were returned, yielding a response rate of 45%. RESULTS: More than half of the respondents (53.8%) reported that cancer had altered their body image negatively, while 44.6% felt that disease had lowered their feeling of being attractive. Nearly one-third (31.3%) and one fourth (23.6%), respectively, had experienced a negative impact on their desire to have sex or to flirt/date/have a partner. Female responders were more affected than males on most variables, and breast cancer patients were approximately 4 times more at risk for sexual and romantic adversities than patients with melanoma of the skin. Although more than 80% indicated a need to discuss issues of sexuality and intimacy with a health professional, 49.5% and 61.7%, respectively, had talked little or not at all with professionals during hospitalization and follow-up consultations. CONCLUSIONS: Young cancer patients experience sexual and romantic challenges along with a lack of self-perceived attractiveness. Their substantial need for dialogue and counselling should be met in health care settings. PMID- 29528534 TI - Genomics-driven discovery of a novel self-resistance mechanism in the echinocandin-producing fungus Pezicula radicicola. AB - The echinocandins are antifungal lipopeptides targeting fungi via noncompetitive inhibition of the beta-1,3-d-glucan synthase FKS1 subunit. A novel echinocandin resistance mechanism involving an auxiliary copy of FKS1 in echinocandin producing fungus Pezicula radicicola NRRL 12192 was discovered. We sequenced the genome of NRRL 12192 and predicted two FKS1-encoding genes (prfks1n and prfks1a), rather than a single FKS1 gene typical of filamentous ascomycetes. The prfks1a gene sits immediately adjacent to an echinocandin (sporiofungin) gene cluster, which was confirmed by disruption of prnrps4 and abolishment of sporiofungin production. Disruption of prfks1a dramatically increased the strain's sensitivity to exogenous echinocandins. In the absence of echinocandins, transcription levels of prfks1a relative to beta-tubulin in the wild type and in Deltaprnrps4 stains were similar. Moreover, prfks1a is consistently transcribed at low levels and is upregulated in the presence of exogenous echinocandin, but not during growth conditions promoting endogenous production of sporiofungin. Therefore, we conclude that prfks1a is primarily responsible for protecting the fungus against extracellular echinocandin toxicity. The presence of unclustered auxiliary copies of FKS1 with high similarity to prfks1a in two other echinocandin-producing strains suggests that this previously unrecognized resistance mechanism may be common in echinocandin-producing fungi of the family Dermataceae of the class Leotiomycetes. PMID- 29528535 TI - Author's response to Letter to the Editor: "Environmental determinants of high population rates of sexually transmitted diseases". PMID- 29528536 TI - An exploratory study of social problems experienced by ambulatory cancer patients in Japan: Frequency and association with perceived need for help. AB - OBJECTIVE: Little is known about the social problems experienced by cancer patients in non-Western countries. The aims of this study were (1) to explore the characteristics and frequencies of social problems in cancer outpatients, as well as their associations with the need for help, and (2) to take the initial steps to develop an instrument for the assessment of cancer-related social problems in Japan. METHODS: A cross-sectional group of 109 patients completed the Social Problem Checklist and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. Participants rated the levels of the problem severity and the need for help on each item. Factor structure, internal consistency, and construct validity were also assessed. RESULTS: In total, 72.5% of the participants encountered >=1 problem, and 33% experienced >=1 serious problem. The amount of help needed tended to be lower than problem severity, especially for family and social life issues. The most common reason for not needing help, as reported by approximately 40% of patients who experienced problems, was the preference for self-management. A 3-factor model was extracted that included financial matters, medical information, and family and social life. Excellent internal consistencies for each factor and convergent correlations between the relevant subscales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Social Problem Checklist were confirmed. CONCLUSIONS: A substantial proportion of participants had cancer-related social problems, but they had ambivalent help-related needs. Interventions that enhance the patient's abilities for self-care could be essential to help cancer outpatients manage social problems in Japan. PMID- 29528537 TI - The association between adolescent condom use and individual and environmental resilience protective factors. AB - OBJECTIVE: Individual and environmental resilience protective factors are suggested to be associated with adolescent condom use; however, previous studies have not comprehensively examined such associations. This study aimed to determine the associations between condom use, and numerous individual and environmental resilience protective factors in sexually active Australian adolescents. METHODS: Participants were Grade 10 students attending 28 Australian government high schools (n=1,688). An online survey (2011) collected data regarding: sexual intercourse (past year), condom use and 14 individual and environmental resilience protective factors. Multivariable backward stepwise logistic regression models examined associations between student condom use and protective factors (total, subscale). RESULTS: Only total environmental protective factors remained in the final total score model; students with higher total environmental protective factors scores were 2.59 times more likely to always use a condom(95%CI:1.80-3.74). Only three of 14 protective factor subscales were associated with a higher likelihood of always using a condom in the final subscale model (individual: goals/aspirations; environmental: community participation, pro-social peers). CONCLUSIONS: Total environmental and three protective factor subscales demonstrated prominent associations with consistent use of condoms in sexually active adolescents. Implications for public health: Consideration of particular resilience protective factors in adolescent sexual risk behaviour prevention, such as condom use, is warranted. PMID- 29528538 TI - The timing and extent of acute physiotherapy involvement following lung transplantation: An observational study. AB - BACKGROUND AND PURPOSE: Physiotherapy "standard care" for the acute post lung transplant recipient has not yet been documented. We aimed to analyse how soon patients commence exercise and how much time is dedicated to this during physiotherapy sessions acutely post lung transplantation. METHODS: Prospective observational study of bilateral sequential and single lung transplant recipients for any indication, >=18 years. Participants were observed during 6 physiotherapy sessions: 3 initial and 3 prior to acute inpatient discharge. Duration and content of each session was recorded, consisting of physical exercise and non exercise tasks. RESULTS: Thirty participants, 20 male, median age 58.5 (interquartile range 54.5-65.0) were observed over 173 sessions. Chronic obstructive pulmonary disease was the most common transplant indication (n = 12, 40%). Bilateral lung transplant was performed in 90% (n = 27) of participants. First time to mobilise was 2 (2-3) days. Participants received 14 (12.8-23.8) sessions over 18 (17-31) days. The mean duration of physiotherapy in the initial phase was 107.8 (standard deviation 21.8) min, with 22.9 (7.5) min spent exercising. In the final phase, exercise time increased to 28.1 (11.4) min out of 84.1 (24.6) min. Assessment was the most common non-exercise component, at 26.6 (7.9) and 22.1 (12.5) min across the three initial and final sessions. IMPLICATIONS FOR PHYSIOTHERAPY PRACTICE: Lung transplant recipients spent 21-34% of observed sessions performing physical exercise beginning 48 hr following surgery. Remaining physiotherapist time was spent on assessment, respiratory interventions, education, and patient-specific duties. The use of physiotherapy assistants, structured, progressive exercise programs, and continued workplace innovation may enable a higher percentage of physiotherapist supervised physical exercise in the future. PMID- 29528539 TI - Uneven progress in reducing exposure to violence at home for New Zealand adolescents 2001-2012: a nationally representative cross-sectional survey series. AB - OBJECTIVE: To explore trends, and identify risk factors, that may explain changes in adolescent exposure to family violence over time. METHODS: Data for this study was drawn from the Youth 2000 series of cross-sectional surveys, carried out with New Zealand high school students in 2001, 2007 and 2012. Latent class analysis was used to understand different patterns of exposure to multiple risks for witnessing violence at home among adolescents. RESULTS: Across all time periods, there was no change in witnessing emotional violence and a slight decline in witnessing physical violence at home. However, significant differences were noted between 2001 and 2007, and 2007 and 2012, in the proportion of adolescents who reported witnessing emotional and physical violence. Four latent classes were identified in the study sample; these were characterised by respondents' ethnicity, concerns about family relationships, food security and alcohol consumption. For two groups (characterised by food security, positive relationships and lower exposure to physical violence), there was a reduction in the proportion of respondents who witnessed physical violence but an increase in the proportion who witnessed emotional violence between 2001 and 2012. For the two groups characterised by poorer food security and higher exposure to physical violence, there were no changes in witnessing of physical violence in the home. Implications for public health: In addition to strategies directly aimed at violence, policies are needed to address key predictors of violence exposure such as social disparities, financial stress and alcohol use. These social determinants of health cannot be ignored. PMID- 29528540 TI - Intentional self-harm and assault hospitalisations and treatment cost of children in Australia over a 10-year period. AB - OBJECTIVE: To examine the magnitude, 10-year temporal trends and treatment cost of intentional injury hospitalisations of children aged <=16 years in Australia. METHOD: A retrospective examination of linked hospitalisation and mortality data for children aged <=16 years during 1 July 2001 to 30 June 2012 with self-harm or assault injuries. Negative binomial regression examined temporal trends. RESULTS: There were 18,223 self-harm and 13,877 assault hospitalisations, with a treatment cost of $64 million and $60.6 million, respectively. The self-harm hospitalisation rate was 59.8 per 100,000 population (95%CI 58.96-60.71) with no annual decrease. The assault hospitalisation rate was 29.9 per 100,000 population (95%CI 29.39-30.39) with a 4.2% annual decrease (95%CI -6.14- -2.31, p<0.0001). Poisoning was the most common method of self-harm. Other maltreatment syndromes were common for children <=5 years of age. Assault by bodily force was common for children aged 6-16 years. CONCLUSIONS: Health professionals can play a key role in identifying and preventing the recurrence of intentional injury. Psychosocial care and access to support services are essential for self-harmers. Parental education interventions to reduce assaults of children and training in conflict de-escalation to reduce child peer-assaults are recommended. Implications for public health: Australia needs a whole-of-government and community approach to prevent intentional injury. PMID- 29528541 TI - Take care to identify apathy in idiopathic rapid eye movement sleep behavior disorder. PMID- 29528542 TI - Two novel decarboxylase genes play a key role in the stereospecific catabolism of dehydrodiconiferyl alcohol in Sphingobium sp. strain SYK-6. AB - Sphingobium sp. strain SYK-6 is able to use a phenylcoumaran-type biaryl, dehydrodiconiferyl alcohol (DCA), as a sole source of carbon and energy. In SYK-6 cells, the alcohol group of the B-ring side chain of DCA was first oxidized to the carboxyl group, and then the alcohol group of the A-ring side chain was oxidized to generate 5-(2-carboxyvinyl)-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy 2,3-dihydrobenzofuran-3-carboxylate (DCA-CC). We identified phcF, phcG and phcH, which conferred the ability to convert DCA-CC into 3-(4-hydroxy-3-(4-hydroxy-3 methoxystyryl)-5-methoxyphenyl)acrylate (DCA-S) in a host strain. These genes exhibited no significant sequence similarity with known enzyme genes, whereas phcF and phcG, which contain a DUF3237 domain of unknown function, showed 32% amino acid sequence identity with each other. The DCA-CC conversion activities were markedly decreased by disruption of phcF and phcG, indicating that phcF and phcG play dominant roles in the conversion of DCA-CC. Purified PhcF and PhcG catalysed the decarboxylation of the A-ring side chain of DCA-CC, producing DCA S, and showed enantiospecificity towards (+)- and (-)-DCA-CC respectively. PhcF and PhcG formed homotrimers, and their Km for DCA-CC were determined to be 84 MUM and 103 MUM, and Vmax were 307 MUmol?min-1 ?mg-1 and 137 MUmol?min-1 ?mg-1 respectively. In conclusion, PhcF and PhcG are enantiospecific decarboxylases involved in phenylcoumaran catabolism. PMID- 29528543 TI - Samarium Polystibides Derived from Highly Activated Nanoscale Antimony. AB - Zintl ions in molecular compounds are of fundamental interest for basic research and application. Two reactive antimony sources are presented that allow direct access to molecular polystibide compounds. These are Sb amalgam (Sb/Hg) and ultrasmall Sb0 nanoparticles (d=6.6+/-0.8 nm), which were used independently as precursors for the synthesis of the largest f-element polystibide, [(Cp*2 Sm)4 Sb8 ]. Whereas the reaction of the nanoparticles with [Cp*2 Sm] directly led to [(Cp*2 Sm)4 Sb8 ], Sm/Sb/Hg intermediates were isolated when using Sb/Hg as the precursor. These Sm/Sb/Hg intermediates [{(Cp*2 Sm)2 Sb}2 (MU-Hg)] and [{(Cp*2 Sm)3 (MU4 ,eta1:2:2:2 -Sb4 )}2 Hg] were synthetically trapped and structurally characterized, giving insight in the formation mechanism of polystibide compounds. PMID- 29528544 TI - Single cell observations show persister cells wake based on ribosome content. AB - Since persister cells survive antibiotic treatments through dormancy and resuscitate to reconstitute infections, it is imperative to determine the rate at which these cells revive. Using two sets of Escherichia coli persister cells, those arising after antibiotic treatment at low levels and those generated at high levels by ceasing transcription via rifampicin pretreatment (shown to be bona fide persisters through eight sets of experiments), we used microscopy of single cells to determine that the resuscitation of dormant persisters is heterogeneous and includes cells that grow immediately. In all, five phenotypes were found during the observation of persister cells when fresh nutrients were added: (i) immediate division, (ii) immediate elongation followed by division, (iii) immediate elongation but no division, (iv) delayed elongation/division and (v) no growth. In addition, once cell division begins, the growth rate is that of exponential cells. Critically, the greater the ribosome content, the faster the persister cells resuscitate. PMID- 29528545 TI - Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'? AB - BACKGROUND AND PURPOSE: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. METHODS: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration <=5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. RESULTS: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. CONCLUSIONS: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease. PMID- 29528546 TI - Environmental determinants of high population rates of sexually transmitted diseases. PMID- 29528547 TI - Microbial pathways for nitrogen loss in an upland soil. AB - The distribution and importance of anaerobic ammonium oxidation (anammox) and nitrite-dependent anaerobic methane oxidation (n-damo) have been identified in aquatic ecosystems; their role in agricultural upland soils however has not yet been well investigated. In this study, we examined spatio-temporal distributions of anammox and n-damo bacteria in soil profiles (300 cm depth) from an agricultural upland. Monitoring nitrogen (N) conversion activity using isotope tracing techniques over the course of one year showed denitrification (99.0% N loss in the winter and 85.0% N-loss in the summer) predominated over anammox (1.0% N-loss in the winter and 14.4% N-loss in the summer) and n-damo (0.6% N loss in the winter) in surface soils (0-20 cm). While below 20 cm depth, N-loss was dominated by anammox (79.4 +/- 14.3% in the winter and 65.4 +/- 12.5% in the summer) and n-damo was not detected. Phylogenetic analysis showed that Candidatus Brocadia anammoxidans dominated the anammox community in the surface soil and Candidatus Brocadia fulgida dominated below 20 cm depth. Dissimilatory nitrate reduction to ammonium (DNRA), another nitrite reduction process, was found to play a limited role (4.9 +/- 3.5%) in the surface soil compared with denitrification; below 80 cm DNRA rates were much higher than rates of anammox and denitrification. Ammonium oxidation was the main source of NO2- above 80 cm (70.9 +/- 23.3%), the key influencing factor on anammox rates, and nitrate reduction (100%) was the main NO2- source below 80 cm. Considering the anammox, n damo and denitrification rates as a whole in the sampled soil profile, denitrification is still the main N-loss process in upland soils. PMID- 29528548 TI - Adaptive evolution to a high purine and fat diet of carnivorans revealed by gut microbiomes and host genomes. AB - Carnivorous members of the Carnivora reside at the apex of food chains and consume meat-only diets, rich in purine, fats and protein. Here, we aimed to identify potential adaptive evolutionary signatures compatible with high purine and fat metabolism based on analysis of host genomes and symbiotic gut microbial metagenomes. We found that the gut microbiomes of carnivorous Carnivora (e.g., Felidae, Canidae) clustered in the same clade, and other clades comprised omnivorous and herbivorous Carnivora (e.g., badgers, bears and pandas). The relative proportions of genes encoding enzymes involved in uric acid degradation were higher in the gut microbiomes of meat-eating carnivorans than plant-eating species. Adaptive amino acid substitutions in two enzymes, carnitine O palmitoyltransferase 1 (CPT1A) and lipase F (LIPF), which play a role in fat digestion, were identified in Felidae-Candidae species. Carnivorous carnivorans appear to endure diets high in purines and fats via gut microbiomic and genomic adaptations. PMID- 29528549 TI - Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Nabiximols (Sativex(r) ) is a cannabinoid-based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks. METHODS: Whole-genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non-responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro-inflammatory agents to support the immunomodulatory properties of the drug. RESULTS: Individual effect size was modest; however, we observed a downregulation of several immune-related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS. CONCLUSIONS: Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results. PMID- 29528550 TI - Microbial biodegradation of biuret: defining biuret hydrolases within the isochorismatase superfamily. AB - Biuret is a minor component of urea fertilizer and an intermediate in s-triazine herbicide biodegradation. The microbial metabolism of biuret has never been comprehensively studied. Here, we enriched and isolated bacteria from a potato field that grew on biuret as a sole nitrogen source. We sequenced the genome of the fastest-growing isolate, Herbaspirillum sp. BH-1 and identified genes encoding putative biuret hydrolases (BHs). We purified and characterized a functional BH enzyme from Herbaspirillum sp. BH-1 and two other bacteria from divergent phyla. The BH enzymes reacted exclusively with biuret in the range of 2 11 umol min-1 mg-1 protein. We then constructed a global protein superfamily network to map structure-function relationships in the BH subfamily and used this to mine > 7000 genomes. High-confidence BH sequences were detected in Actinobacteria, Alpha- and Beta-proteobacteria, and some fungi, archaea and green algae, but not animals or land plants. Unexpectedly, no cyanuric acid hydrolase homologs were detected in > 90% of genomes with BH homologs, suggesting BHs may have arisen independently of s-triazine ring metabolism. This work links genotype to phenotype by enabling accurate genome-mining to predict microbial utilization of biuret. Importantly, it advances understanding of the microbial capacity for biuret biodegradation in agricultural systems. PMID- 29528551 TI - Prevalence of appropriate colorectal cancer screening and preferences for receiving screening advice among people attending outpatient clinics. AB - OBJECTIVE: To examine among people attending outpatient clinics aged 50-74 at average risk of colorectal cancer (CRC): 1) The proportion who report: a) faecal occult blood test (FOBT) within the past two years; and b) colonoscopy within the past five years, including the reasons for undergoing colonoscopy; 2) characteristics associated with under-screening; 3) For those who are under screened, the proportion who are: a) willing to receive help and the acceptability of different methods of receiving help, and; b) unwilling to receive help and reasons for this. METHODS: Cross-sectional survey of 197 participants attending a major regional hospital in New South Wales, Australia. Multivariable logistic regression was used to determine correlates of under screening. RESULTS: A total of 59% reported either FOBT in the past two years or colonoscopy in the past five years. Of those reporting colonoscopy in the past five years, 21% were potentially over-screened. Males were more likely than females to be under-screened. Of those under-screened (41%), fewer than half were willing to receive screening advice. Conclusions and implications for public health: A significant proportion of people attending outpatient clinics are under screened for CRC, with some people also over-screened. There is a need to explore strategies to overcome both under- and over-screening. PMID- 29528553 TI - Design of a drug discovery course for non-science majors. AB - "Drug Discovery" is a 13-week lecture and laboratory-based course that was developed to introduce non-science majors to foundational chemistry and biochemistry concepts as they relate to the unifying theme of drug discovery. The first part of this course strives to build students' understanding of molecules, their properties, the differences that enable them to be separated from one another, and their abilities to bind to biological receptors and elicit physiological effects. After building students' molecular worldview, the course then focuses on four classes of drugs: antimicrobials, drugs that affect the mind, steroid-based drugs, and anti-cancer drugs. During each of these modules, an emphasis is placed on how understanding the basis of disease and molecular level interactions empowers us to identify novel medicinal compounds. Periodic in class discussions based on articles pertinent to class topics ranging from the spread of antibiotic resistance, to the molecular basis of addiction, to rational drug design, are held to enable students to relate course material to pressing problems of national and daily concern. In addition to class time, weekly inquiry based laboratories allow students to critically analyze data related to course concepts, and later in the semester give students an opportunity to design and implement their own experiments to screen for antimicrobial activity. This course provides students with an understanding of the importance of chemistry and biochemistry to human health while emphasizing the process, strategies, and challenges related to drug discovery. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:327-335, 2018. PMID- 29528554 TI - Identifying the Mechanism of Continued Growth of the Solid-Electrolyte Interphase. AB - Continued growth of the solid-electrolyte interphase (SEI) is the major reason for capacity fade in modern lithium-ion batteries. This growth is made possible by a yet unidentified transport mechanism that limits the passivating ability of the SEI towards electrolyte reduction. We, for the first time, differentiate the proposed mechanisms by analyzing their dependence on the electrode potential. Our calculations are compared to recent experimental capacity-fade data. We show that the potential dependence of SEI growth facilitated by solvent diffusion, electron conduction, or electron tunneling qualitatively disagrees with the experimental observations. Only diffusion of Li interstitials results in a potential dependence matching the experiments. Therefore, we identify the diffusion of neutral radicals, such as Li interstitials, as the cause of long-term SEI growth. PMID- 29528555 TI - Integrating GWAS and gene expression data for functional characterization of resistance to white mould in soya bean. AB - White mould of soya bean, caused by Sclerotinia sclerotiorum (Lib.) de Bary, is a necrotrophic fungus capable of infecting a wide range of plants. To dissect the genetic architecture of resistance to white mould, a high-density customized single nucleotide polymorphism (SNP) array (52 041 SNPs) was used to genotype two soya bean diversity panels. Combined with resistance variation data observed in the field and greenhouse environments, genome-wide association studies (GWASs) were conducted to identify quantitative trait loci (QTL) controlling resistance against white mould. Results showed that 16 and 11 loci were found significantly associated with resistance in field and greenhouse, respectively. Of these, eight loci localized to previously mapped QTL intervals and one locus had significant associations with resistance across both environments. The expression level changes in genes located in GWAS-identified loci were assessed between partially resistant and susceptible genotypes through a RNA-seq analysis of the stem tissue collected at various time points after inoculation. A set of genes with diverse biological functionalities were identified as strong candidates underlying white mould resistance. Moreover, we found that genomic prediction models outperformed predictions based on significant SNPs. Prediction accuracies ranged from 0.48 to 0.64 for disease index measured in field experiments. The integrative methods, including GWAS, RNA-seq and genomic selection (GS), applied in this study facilitated the identification of causal variants, enhanced our understanding of mechanisms of white mould resistance and provided valuable information regarding breeding for disease resistance through genomic selection in soya bean. PMID- 29528556 TI - Role of circulating tumor DNA in the management of early-stage lung cancer. AB - Lung cancer is one of the most common cancers and the predominant cause of cancer related death in the world. The low accuracy of early detection techniques and high risk of relapse greatly contribute to poor prognosis. An accurate clinical tool that can assist in diagnosis and surveillance is urgently needed. Circulating tumor DNA (ctDNA) is free DNA shed from tumor cells and isolated from peripheral blood. The genomic profiles of ctDNA have been shown to closely match those of the corresponding tumors. With the development of approaches with high sensitivity and specificity, ctDNA plays a vital role in the management of lung cancer as a result of its reproducible, non-invasive, and easy-to-obtain characteristics. However, most previous studies have focused on advanced lung cancer. Few studies have investigated ctDNA in the early stages of the disease. In this review, we focus on ctDNA obtained from patients in the early stage of lung cancer, provide a summary of the related literature to date, and describe the main approaches to ctDNA and the clinical applications. PMID- 29528557 TI - Physiological and iTRAQ-Based Quantitative Proteomics Analysis of Methyl Jasmonate-Induced Tolerance in Brassica napus Under Arsenic Stress. AB - Brassica napus plants exposed to 200 MUM arsenic (As) exhibited high-level of stress condition, which led to inhibited growth, enhanced lipid peroxidation, and disrupted cellular ultrastructures. Exogenous application of methyl jasmonate (MeJA) alleviated the As-induced oxidative stress and improved the plant growth and photosynthesis. In this study, changes in the B. napus leaf proteome are investigated in order to identify molecular mechanisms involved in MeJA-induced As tolerance. The study identifies 177 proteins that are differentially expressed in cultivar ZS 758; while 200 differentially expressed proteins are accumulated in Zheda 622, when exposed to As alone and MeJA+As treatments, respectively. The main objective was to identify the MeJA-regulated protein under As stress. Consistent with this, iTRAQ detected 61 proteins which are significantly accumulated in ZS 758 leaves treated with MeJA under As stress. While in Zheda 622, iTRAQ detected 49 MeJA-induced proteins under As stress. These significantly expressed proteins are further divided into five groups on the base of their function, that is, stress and defense, photosynthesis, carbohydrates and energy production, protein metabolism, and secondary metabolites. Taken together, this study sheds light on the molecular mechanisms involved in MeJA-induced As tolerance in B. napus leaves and suggests a more active involvement of MeJA in plant physiological processes. PMID- 29528558 TI - Preparing graduate student teaching assistants in the sciences: An intensive workshop focused on active learning. AB - In the past ten years, increasing evidence has demonstrated that scientific teaching and active learning improve student retention and learning gains in the sciences. Graduate teaching assistants (GTAs), who play an important role in undergraduate education at many universities, require training in these methods to encourage implementation, long-term adoption, and advocacy. Here, we describe the design and evaluation of a two-day training workshop for first-year GTAs in the life sciences. This workshop combines instruction in current research and theory supporting teaching science through active learning as well as opportunities for participants to practice teaching and receive feedback from peers and mentors. Postworkshop assessments indicated that GTA participants' knowledge of key topics increased during the workshop. In follow-up evaluations, participants reported that the workshop helped them prepare for teaching. This workshop design can easily be adapted to a wide range of science disciplines. Overall, the workshop prepares graduate students to engage, include, and support undergraduates from a variety of backgrounds when teaching in the sciences. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:318 326, 2018. PMID- 29528559 TI - Improving large class performance and engagement through student-generated question banks. AB - Disciplines such as Biochemistry and Molecular Biology, which involve concepts not included in the high-school curriculum, are very challenging for many first year university students. These subjects are particularly difficult for students accustomed to surface learning strategies involving memorization and recall of facts, as a deeper understanding of the relationship between concepts is needed for successful transfer to related areas and subsequent study. In this article, we explore an activity in a very large first year Molecular Biology course, in which students create multiple-choice questions related to targeted learning outcomes, and then answer and evaluate one another's questions. This activity encompasses elements of both self- and peer-assessment and the generative tasks of creating questions and producing written feedback may contribute to a deeper understanding of the material. We make use of a free online platform to facilitate all aspects of the process and analyze the effect of student engagement with the task on overall course performance. When compared to previous semester's cohorts, we observe a pronounced improvement in class performance on exam questions targeting similar concepts to the student-generated questions. In addition, those students that engage to a greater extent with the activity perform significantly better on the targeted exam questions than those who are less active, yet all students perform similarly on a set of isolated control questions appearing on the same exam. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:306-317, 2018. PMID- 29528560 TI - A Stable Plasmonic Cu@Cu2 O/ZnO Heterojunction for Enhanced Photocatalytic Hydrogen Generation. AB - The localized surface plasmon resonance (LSPR) effect has been widely utilized in photocatalysis, but most reported LSPR materials are based on noble metals of gold or silver with high chemical stability. Plasmonic copper nanoparticles that exhibit an LSPR absorbance at 600 nm are promising for many applications, such as photocatalysis. Unfortunately, plasmonic copper nanoparticles are affected by serious surface oxidation in air. Herein, a novel lollipop-shaped Cu@Cu2 O/ZnO heterojunction nanostructure was designed, for the first time, to stabilize the plasmonic Cu core by decorating Cu@Cu2 O core-shell structures with ZnO nanorods. This Cu@Cu2 O/ZnO nanostructure exhibited significantly enhanced stability than that of regular Cu@Cu2 O, which accounted for the remarkably enhanced photocatalytic H2 evolution rate through water splitting, relative to pristine ZnO nanorods, over an extended wavelength range due to the plasmonic Cu core. PMID- 29528561 TI - Comparison of demographic fitness and biocontrol effectiveness of two parasitoids, Encarsia sophia and Eretmocerus hayati (Hymenoptera: Aphelinidae), against Bemisia tabaci (Hemiptera: Aleyrodidae). AB - BACKGROUND: The autoparasitoid Encarsia sophia and the primary parasitoid Eretmocerus hayati are two important parasitoids used against the whitefly Bemisia tabaci, with different reproductive strategies. To incorporate these two parasitoids into a sustainable whitefly control program, it is necessary to evaluate and compare their fitness and biocontrol effectiveness under identical experimental conditions. The demographic characteristics, parasitism rate and host-feeding rate of En. sophia and Er. hayati were analyzed using an age-stage, two-sex life table and the CONSUME-MSChart computer program. RESULTS: The mean fecundity of Er. hayati (211.4 offspring per female) was significantly higher than that of En. sophia (101.6 offspring per female), although the oviposition days of En. sophia was longer than that of Er. hayati. No significant difference was found in the intrinsic rate of increase (r), finite rate of increase (lambda) or net reproduction rate (R0 ) between the two parasitoid species, but the mean generation time (T) of En. sophia (18.8 days) was significantly shorter than that of Er. hayati (20.5 days). The net host feeding rate (C0 ) of En. sophia was 84.1 whiteflies per individual, significantly higher than the 17.6 whiteflies per individual consumed by Er. hayati. The finite killing rate (nu) of En. sophia (0.6713) for whitefly was significantly greater than that produced by Er. hayati (0.3652). CONCLUSION: The En. sophia population can increase faster and have a higher killing potential than the Er. hayati population. Taking both the demographic fitness and killing potential of the two parasitoids into consideration, En. sophia would be the preferred choice to release in a biological control program. (c) 2018 Society of Chemical Industry. PMID- 29528562 TI - Two enzymes of the acetone degradation pathway of Desulfococcus biacutus: coenzyme B12 -dependent 2-hydroxyisobutyryl-CoA mutase and 3-hydroxybutyryl-CoA dehydrogenase. AB - Degradation of acetone by the sulfate-reducing bacterium Desulfococcus biacutus involves an acetone-activation reaction different from that used by aerobic or nitrate-reducing bacteria, because the small energy budget of sulfate-reducing bacteria does not allow for major expenditures into ATP-consuming carboxylation reactions. In the present study, an inducible coenzyme B12 -dependent conversion of 2-hydroxyisobutyryl-CoA to 3-hydroxybutyryl-CoA was demonstrated in cell-free extracts of acetone-grown D. biacutus cells, together with a NAD+ -dependent oxidation of 3-hydroxybutyryl-CoA to acetoacetyl-CoA. Genes encoding two mutase subunits and a dehydrogenase, which were found previously to be strongly induced during growth with acetone, were heterologously expressed in E. coli. The activities of the purified recombinant proteins matched with the inducible activities observed in cell-free extracts of acetone-grown D. biacutus: proteins (IMG locus tags) DebiaDRAFT_04573 and 04574 constituted a B12 -dependent 2 hydroxyisobutyryl-CoA/3-hydroxybutyryl-CoA mutase, and DebiaDRAFT_04571 was a 3 hydroxybutyryl-CoA dehydrogenase. Hence, these enzymes play key roles in the degradation of acetone and define an involvement of CoA esters in the pathway. Further, the involvement of 2-hydroxyisobutyryl-CoA strongly indicates that the carbonyl-C2 of acetone is added, most likely, to formyl-CoA through a TDP dependent enzyme that is co-induced in acetone-grown cells and is encoded in the same gene cluster as the identified mutase and dehydrogenase. PMID- 29528563 TI - Effect of cDMEM media containing Ectoine on human periodontal ligament mesenchymal stem cell survival and differentiation. AB - BACKGROUND/AIM: Ectoine is an amino acid that can preserve osmotic balance and has more preservative activity than other osmoregulators. There are no published reports on the osmoregulators' effects on viability or differentiation of dental stem cells. The aim of this study was to investigate the effect of Ectoine as a storage media on the viability and differentiation potential of human periodontal ligament mesenchymal stem cells (hPDLMSCs). MATERIALS AND METHODS: hPDLMSCs were obtained from impacted third molar teeth. The cells were isolated, submitted to trilineage differentiation, and characterized by flow cytometer (FC). hPDLMSCs were incubated with different media containing Ectoine, complete DMEM (cDMEM), Ectoine+cDMEM, milk, and tap water for 2, 6, 12, and 24 h. The cells were analyzed by FC for viability, early-apoptosis, late apoptosis, and necrosis rates. Osteogenic and fibroblastic differentiation in hPDLMSCs were investigated by Alizarin red stain and vimentin expression. RESULTS: All treated groups showed significant decreases in cell viability after 2 h. Significant increases were detected in the number of dead cells between 2 and 12 h in all groups except the Ectoine+cDMEM group. The deposition of mineral matrix nodules was significantly higher in cells cultured with Ectoine+cDMEM compared with the other media. Higher vimentin expressions were detected in cells cultured with cDMEM and Ectoine+cDMEM media, respectively. CONCLUSIONS: Ectoine added to cDMEM media, promoted cell survival plus osteogenic and fibroblastic differentiation of hPDLMSCs. PMID- 29528564 TI - Controlled Assembly of Porphyrin-MoS2 Composite Nanosheets for Enhanced Photoelectrochemical Performance. AB - As a promising non-precious metal photoelectrochemical (PEC) catalyst, MoS2 exhibits high electrocatalytic activity and stability, while the weak light absorption efficiency and low photoresponse current limit its practical application. Herein, a facile co-assembly approach is proposed to construct porphyrin-MoS2 composite photoelectrocatalysts. The as-prepared photoelectrocatalysts show a significantly enhanced photocurrent response as high as 16 MUA cm-2 , which is about 2 times higher than that of bare MoS2 . Furthermore, the obtained porphyrin-MoS2 catalysts exhibit excellent durability when tested for 23000 s, thus providing a useful strategy for the design of highly efficient dye-sensitized PEC catalysts. PMID- 29528565 TI - Ruthenium Tris-bipyridine Single-Molecule Junctions with Multiple Joint Configurations. AB - Single-molecule junctions are of particular interest in molecular electronics. To realize molecular electronic devices, it is crucial that functional single molecule junctions are connected to each other by using joint units on the atomic scale. However, good joint units have not been reported because controlling the charge transport directions through the junctions is not trivial. Here, we report a joint unit that controls and changes the charge transport directions through the junctions, by using a ruthenium-tris-bipyridine (RuBpy) complex. The RuBpy single-molecule junction was fabricated with scanning tunnelling microscopy-based break junction techniques. The RuBpy single-molecule junction showed two distinct high and low conductance states. The two states were characterized by the conductance measurement, the correlation analysis, and the comparative experiment of bipyridine (Bpy), which is the ligand unit of RuBpy. We demonstrate that the Ru complex has multiple charge transport paths, where the charge is carried vertically and horizontally through the complex depending on the path. PMID- 29528566 TI - Difficult conversations: Discussing prognosis with children with cystic fibrosis. AB - : Background Despite the chronic, progressive, and life-threatening nature of cystic fibrosis (CF), there are no guidelines for when and how to communicate prognosis to children with CF. METHODS: Semi-structured interviews with young adults with CF, parents of young adults with CF, and multidisciplinary CF health care providers assessed recall of and practices for communicating about prognosis. Recommendations for improvements were also solicited. RESULTS: Young adults with CF recalled learning that life expectancy is limited by CF between the ages of 8 and 16 years, and that CF is a progressive disease between the ages of 7 and 19 years. They reported that the information often came from CF physicians or from online resources. Patients and parents reported earlier knowledge of prognosis than providers assumed. While learning about prognosis caused sadness and stress for some patients and families, others denied negative feelings. Interestingly, most patients reported that disclosure of prognosis had minimal impact on their adherence and treatment goals. Patients and parents reported wanting physicians to be involved in conversations about prognosis. However, providers noted several barriers to discussing prognosis, including their own reluctance, time limitations, and uncertainty about appropriate timing and content of communication. CONCLUSIONS: Communication about prognosis is important but also difficult for providers, patients, and families. Appropriately timed conversations, using tools to facilitate communication, could ensure patients receive timely, accurate information. PMID- 29528567 TI - TNF receptor-associated factor 1 as a biomarker for assessment of non-small cell lung cancer metastasis and overall survival. AB - BACKGROUND AND AIM: Non-small cell lung cancer (NSCLC), which comprises 80%-85% of all lung cancer cases, is one of the most common human malignancies. Despite great improvements in diagnostic technology and the introduction of new therapeutic agents in recent years, the 5-year survival rate of NSCLC is still low. Tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) plays an important role in the TNF-related apoptosis-inducing ligand (TRAIL) associated signal pathway. METHODS: In this study, we aim to illuminate the function of TRAF1 in NSCLC. Toward that end, TRAF1 expression was detected using immunohistochemistry (IHC) in specimens from 200 NSCLC patients. The function of TRAF1 in the A549 and H1299 cell lines was evaluated by colony formation and MTT assays. RESULTS: Our data showed that TRAF1 was significantly upregulated in NSCLC tissues. TRAF1 expression was positively associated with NSCLC lymphatic metastasis and clinical stage and was negatively associated with overall patient survival. TRAF1 promoted NSCLC cell proliferation CONCLUSION: TRAF1 expression was positively associated with NSCLC lymphatic metastasis and histological grade and was negatively associated with overall patient survival. TRAF1 may be an important therapeutic target for NSCLC. PMID- 29528569 TI - A Deep Proteomics Perspective Into Grape Berry Quality Traits During Ripening. AB - Discovery-based proteomics studies have an important role in the understanding of the biochemical processes that occur during grape berry ripening. The ripening process is relevant in determining grape berry quality. For a proteome analysis of grape berry ripening, Kambiranda et al. (2018) applied a label-free mass spectrometry-based quantitative approach. The authors reported the identification of proteins associated with the production flavor, aroma and ethylene production. Despite the valuable contribution of discovery-based proteomics studies, the picture is still incomplete. Future efforts in gaining proteome coverage would benefit the identification of proteins associated with grape berry quality traits. PMID- 29528568 TI - Estimation of transversely isotropic material properties from magnetic resonance elastography using the optimised virtual fields method. AB - Magnetic resonance elastography (MRE) has been used to estimate isotropic myocardial stiffness. However, anisotropic stiffness estimates may give insight into structural changes that occur in the myocardium as a result of pathologies such as diastolic heart failure. The virtual fields method (VFM) has been proposed for estimating material stiffness from image data. This study applied the optimised VFM to identify transversely isotropic material properties from both simulated harmonic displacements in a left ventricular (LV) model with a fibre field measured from histology as well as isotropic phantom MRE data. Two material model formulations were implemented, estimating either 3 or 5 material properties. The 3-parameter formulation writes the transversely isotropic constitutive relation in a way that dissociates the bulk modulus from other parameters. Accurate identification of transversely isotropic material properties in the LV model was shown to be dependent on the loading condition applied, amount of Gaussian noise in the signal, and frequency of excitation. Parameter sensitivity values showed that shear moduli are less sensitive to noise than the other parameters. This preliminary investigation showed the feasibility and limitations of using the VFM to identify transversely isotropic material properties from MRE images of a phantom as well as simulated harmonic displacements in an LV geometry. PMID- 29528570 TI - Quantitative Proteomic Analysis of Staphylococcus aureus Treated With Punicalagin, a Natural Antibiotic From Pomegranate That Disrupts Iron Homeostasis and Induces SOS. AB - Staphylococcus aureus, a bacterial, food-borne pathogen of humans, can contaminate raw fruits and vegetables. While physical and chemical methods are available to control S. aureus, scientists are searching for inhibitory phytochemicals from plants. One promising compound from pomegranate is punicalagin, a natural antibiotic. To get a broader understanding of the inhibitory effect of punicalagin on S. aureus growth, high-throughput mass spectrometry and quantitative isobaric labeling was used to investigate the proteome of S. aureus after exposure to a sublethal dose of punicalagin. Nearly half of the proteins encoded by the small genome were interrogated, and nearly half of those exhibited significant changes in accumulation. Punicalagin treatment altered the accumulation of proteins and enzymes needed for iron acquisition, and it altered amounts of enzymes for glycolysis, citric acid cycling, protein biosynthesis, and purine and pyrimidine biosynthesis. Punicalagin treatment also induced an SOS cellular response to damaged DNA. Transcriptional comparison of marker genes shows that the punicalagin-induced iron starvation and SOS responses resembles those produced by EDTA and ciprofloxacin. These results show that punicalagin adversely alters bacterial growth by disrupting iron homeostasis and that it induces SOS, possibly through DNA biosynthesis inhibition. PMID- 29528571 TI - Hypertonic saline: Not useful in infant bronchiolitis? PMID- 29528572 TI - Respiratory function in healthy Emirati children using forced oscillations. AB - BACKGROUND: The forced oscillation technique (FOT) allows the quantification of respiratory function, does not require active cooperation and as such is ideally suited for use in young children. The application of the FOT in non-Caucasian populations is limited and it remains unclear if current reference ranges for the FOT in Caucasian children are appropriate for children in the Arabian Peninsula. This study explored the use of the FOT in healthy school-aged children in the United Arab Emirates (UAE). METHODS: Lung function using FOT was assessed in healthy Emirati children aged 4-12 years. Using a validated questionnaires general medical and respiratory histories were obtained. Prediction equations for resistance (Rrs), reactance (Xrs), and area under reactance curve (AX) were calculated and compared to previous studies. RESULTS: FOT was successfully obtained in 291 healthy Emirati children. Linear regression modelling including weight, height, age, and gender in transformed FOT outcomes demonstrated that height was the strongest predictor of FOT outcomes (P < 0.001). Using the equated prediction equation Z-scores were calculated. FOT outcomes in Emirati children did not match previously published reference equations in Caucasians children (P < 0.001). CONCLUSION: FOT measurements were feasible in Emirati school-children. New FOT reference equation in Emirati children were derived. FOT reference equation in Emirati children was different from published equations in Caucasians. PMID- 29528573 TI - The impact of reclassifying suicides in pregnancy and in the postnatal period on maternal mortality ratios. PMID- 29528574 TI - Prevalence of Vitamin D Deficiency in Adult Patients with Systemic Lupus Erythematosus in Kingdom of Bahrain. AB - Vitamin D deficiency (VDD) has been implicated as an important factor in the development or aggravation of systemic lupus erythematous (SLE). Patients with SLE are especially prone to the development of VDD due to the nature of their illness and avoidance of sun exposure. The prevalence of VD status in Bahraini patients with SLE has not been studied. Our aim is to study the prevalence of VDD in Bahraini cohort with SLE. Fifty-eight Bahraini patients with SLE were included retrospectively in this study. Most of the patients were females 50/58. The patients were followed at the rheumatology department at "Salmanyia medical complex". Controls were fifty-eight age-matched healthy Bahraini subjects. Serum levels of 25 (OH) vitamin D were estimated using chemilumenescence immunoassay. Chi Square and T-Test were used for analysis a p value of <= 0.05 was considered significant. There was statistically significant difference (P <= 0.05) in the mean serum levels of vitamin D between patients (30.67 nmol/l) and controls (39.95 nmom/L). In the SLE patients there were 49.1% deficient, 47.1% insufficient and 3.8% were Optimal. In the controls; 27% was deficient, 52% insufficient and 21% optimal. In conclusion, There was high prevalence of VDD in Bahraini patients with SLE. Both patients and controls had low vitamin D serum levels, however the patients had statistically significant lower levels. Our study also highlights the need for studying the effects of correcting hypovitaminosis on the disease activity in SLE patients. PMID- 29528575 TI - Serum Thymus and Activation Regulated Chemokine (TARC), IL- 18 and IL-18 Gene Polymorphism as Associative Factors with Atopic Dermatitis. AB - Atopic dermatitis (AD) is a worldwide chronic inflammation of skin.Many factors and chemokines play role in pathogenesis of AD. Identifying the reliable biomarkers to diagnose and assess severity of AD is important. In this study we aimed to find a reliable biomarker to determine the severity of AD and monitor treatment as well as, examining the possible association between IL-18 gene [rs 187238] promoter polymorphism and AD disease. The study included 30 Egyptian patients with AD and 30 healthy controls. Patients were clinically evaluated according to SCORAD scoring system. For each subject levels of Thymus and activation regulated chemokine (TARC), IL-18, total IgE and Lactate dehydrogenase enzyme (LDH) in serum were measured and Polymorphism in IL-18 gene was analyzed using restriction fragment length polymorphism (RFLP). Patients were reevaluated after treatment. Serum levels of TARC, IL-18, IgE and LDH were significantly higher in patients than controls, and were associated with high SCORAD score. G allele was risk factor with OR 2.31 (1.10- 4.85) and significant p-value < 0.05 for AD. GG genotype was significantly associated with elevated serum levels of TARC, IL-18 and IgE. After treatment serum level of TARC showed significant decrease and was associated with low SCORAD score. We concluded that TARC, IL-18, total IgE and LDH are potential markers of severity in AD. G allele in IL-18 gene [rs 187238] is risk factor for AD while C allele is considered protective. TARC is also a reliable marker formonitoring treatment. PMID- 29528576 TI - The Role of Bcl-2 and Bax as Markers of Disease Progression in Hepatitis C Virus Infected Patients. AB - Many apoptotic markers have been linked to hepatic cell injury in HCV-related liver diseases, and hence could be used as potential markers for early detection of the disease. The present study aimed to assess the role of apoptotic markers Bcl-2 and Bax in the pathogenesis of chronic HCV-related liver diseases. A total of 85 participants were enrolled into the study; 70 chronic HCV patients (35 non cirrhotic and 35 cirrhotic), and 15 healthy controls. The serum levels of Bcl-2 and Bax were assayed in all participants by ELISA. Bcl-2 and Bcl-2/Bax ratio were significantly higher in non-cirrhotic patients than the cirrhotic and controls (P < 0.001). Bax was significantly higher in cirrhotic patients compared to the other groups (P < 0.001). Positive and negative correlations were found between serum Bcl-2, Bax, Bcl-2/Bax ratio and HCV viral load in non-cirrhotic and cirrhotic patients respectively. These findings provide an evidence that apoptosis is dysregulated in patients with chronic HCV. PMID- 29528577 TI - Serum MicroRNA-122 and MicroRNA-155: Markers of Disease Progression in Hepatitis C viral infection. AB - Chronic HCV with its longstanding complications of cirrhosis and HCC is a highly prevalent and challenging problem in Egypt. Recently, microRNAs are ranked as potential biomarkers for early diagnosis of HCV related complications. The aim of the present study was to evaluate the role of miRNA-122 and miRNA-155 for prediction of progression of HCV infection and for diagnosis of HCC. A total of 92 chronic HCV patients [chronic HCV (group 1, n =32); chronic HCV with cirrhosis (group 2, n=31); chronic HCV with HCC (group 3, n=29)] were enrolled into the study. Expression of serum miRNA-122 and miRNA-155 was assayed by real-time PCR in all participants. The serum level of miR-122 was significantly higher in chronic HCV patients than in healthy controls and both of cirrhotic and HCC patients (P < 0.001). Serum miR-155 was significantly elevated in HCC than in controls and non-HCC patients (P < 0.001). MiR-155 at the cut-off value of >6.11 for HCC diagnosis, had sensitivity and specificity of 72.4% and 95.2%, respectively. In conclusion; microRNA-122 is a potential marker of progression of hepatocytes injury in patients infected with HCV but not a reliable marker for diagnosis of HCC. MicroRNA-155 is a relatively reliable marker for HCC detection. PMID- 29528578 TI - Adsorption Technique in Pre-Transfusion Testing For Patients with Warm Type Autoimmune Hemolytic Anemia. AB - Warm auto-antibodies are directed against patients' own red blood cell antigens and can interfere with and complicate investigations for the detection and identification of RBC allo-antibodies. Most patients with autoimmune hemolytic anemia (AIHA) have already been transfused and the patients' phenotype can be difficult to determine. In warm type AIHA; the auto- antibodies in the patient's serum react with all normal red blood cells and make it impossible to find compatible blood. Special appropriate compatibility test procedures in a reference laboratory allow the detection and identification of clinically significant allo- Abs that may be masked by the auto- Abs. Adsorption is an available technique to remove serum auto-antibodies and subsequently detect the underlying allo-antibodies against red blood cell antigens that can significantly complicate transfusion therapy in previously transfused patients with autoimmune hemolytic anemia. This centre establish a suitable adsorption technique in their transfusion service which can remove all auto-antibodies and detect underlying allo-antibodies to provide safety and effectiveness of blood transfusion for patients. Continue without subheading. These patients subjected to allo adsorption on different phases; in this procedure adsorption of auto-antibodies from the patient's serum is carried out using three to four different samples of allogenic red cells of varying phenotypes. Of the 300 patients; 69 (23%) revealed co-existing allo-antibodies with auto-antibodies and 231 (77%) revealed only auto antibodies. It is concluded that the adsorption technique is an effective way to get rid of auto-antibodies and make it easy to detect the underlying allo antibodies. PMID- 29528579 TI - Relevance of 25 (OH) Vitamin D deficiency on Hashimoto's Thyroiditis. AB - An association between low levels of vitamin D and Hashimoto's thyroiditis was suggested. This study aimed to determine the status of 25 (OH) vitamin D in Hashimoto's thyroiditis. A case-control study was designed, a Hashimoto's thyroiditis patient group (n=30) and two control groups including Graves' disease (30) and a healthy control group (20). TSH, Free T3, Free T4, antithyroid antibodies (antithyroglobulin and antithyroid peroxidase), calcium and serum 25 (OH) vitamin D were assessed. Vitamin D and calcium levels were significantly lower in Hashimoto thyroiditis and Graves' disease versus healthy controls. Vitamin D was deficient in 76.7% of Hashimoto thyroiditis and 70% of Graves' disease compared to 20.0% of healthy control, and negatively correlated with antithyroglobulin and antithyroid peroxidase in Hashimoto's thyroiditis group. Vitamin D is recommended for patients with vitamin D deficiency. Further investigations are needed to evaluate the preventive and therapeutic effects of vitamin D in autoimmune thyroid disease. PMID- 29528580 TI - Association of CTLA-4 +49 A/G and CT60 Gene Polymorphism with Graves' Disease. AB - Graves' disease (GD) is an organ specific autoimmune disease of thyroid gland with genetic and environmental causes. One of genetic factors that have been implicated in the development of this disease is CTLA-4 gene polymorphism. This study aimed to investigate the association of CTLA-4 polymorphisms at position +49A/G, and CT60 with susceptibility to Graves' disease in Saudi patients. 40 adult Saudi patients with GD and 30 healthy controls were genotyped for the +49 A/G and CT60 of the CTLA4 gene using restriction fragment length polymorphism analysis (RFLP). There was a significant difference between GG genotype and AA genotype in GD patient in comparison to control group (P = 0.007), GG genotype was the most prevalent and the AA genotype was less frequent in the GD patients. The G allele at position +49 was more frequent in patients with GD than in the control group. Statistically significant differences between A and G alleles of GD patient and control groups were found (p= 0.003; OR =2.85 and 95% CI =1.4 5.7). The G allele in CT60 was higher in GD patients than those in controls (OR=2.8, 95% CI =1.4-5.7 and P = 0.004). In conclusion, CTLA-4 polymorphism at position 49 and CT60 may be potentially associated with the risk of GD among Saudi patients. PMID- 29528581 TI - MicroRNA 26a Expression in Peripheral Blood Mononuclear Cells and Correlation with Serum Interleukin-17 in Relapsing-Remitting Multiple Sclerosis Patients. AB - Multiple sclerosis (MS) is a chronic multifocal inflammatory demyelinating disease. One of the main cells that play a crucial role in pathogenesis of MS is T helper 17 (Th 17). There are growing interests in nominating microRNAs in Th17 cell differentiation and suggesting new therapeutic modalities. The aim of the study was to assess microRNA 26a (miR26a) expression in peripheral blood mononuclear cells of relapsing - remitting MS patients as compared to healthy control subjects and examine association of these levels with serum IL17. Forty (40) relapsing - remitting MS patients were enrolled based on the MacDonald criteria (20 in relapsing phase and 20 in remitting phase). In addition, twenty (20) healthy control subjects were included. Blood samples were subjected to quantitative polymerase chain reaction (qPCR) for miR26a and ELISA for serum IL 17 levels. A significant upregulation of miR26a relative expression level (?? Ct) and serum IL17 level (pg/ml) was found in total MS patients and remitting MS patients when compared with controls (P < 0.001). Among the relapsing group, a significant increase in miR26a expression levels (P= 0.004) but not serum IL17 level was demonstrated. Insignificant correlation between miR26a expression and serum IL17 in MS patients was detected (r= 0.08, P= 0.62). In conclusion, a significant increase of these two biomarkers (miR26a & IL17) occurs in relapsing remitting MS patients, and this reflects their important role in pathogenesis and disease development. PMID- 29528582 TI - Interleukin-22 and Chemokine Interferon gamma -Inducible-10 (IP-10) Levels in Chronic Hepatitis C Patients and Treatment Response to Pegylated Interferon and Ribavirin Therapy. AB - IL-22 plays a vital role in improving hepatic damage by targeting hepatocytes that express high levels of IL-22 receptor1. IP-10 is a chemokine that recruit mononuclear cells to liver parenchyma and improves the host immune response against hepatitis C virus. The study targeted 27 patients with chronic HCV who received pegylated Interferon and Ribavirin. IL-22 and IP-10 serum levels were measured by Elisa. The level of the serum IL-22 is higher in HCV patients groups receiving the antiviral treatment compared to control group and its levels significantly increased with response to treatment. The level of the serum IP-10 is higher in HCV patients groups compared to control group and its level significantly decreased with effective antiviral treatment. In conclusion, IL-22 and IP-10 levels could be used with a high sensitivity and specificity during antiviral treatment of HCV infected patients as predictive markers for treatment response. PMID- 29528583 TI - Circulating Fibroblast Growth Factors 21 and 23 as Biomarkers of Progression in Diabetic Nephropathy in Type 2 Diabetes with Normoalbuminuria. AB - Diabetic nephropathy (DN) is a progressive kidney disease. Previous studies reported that microalbuminuria might not be a sufficient marker to identify diabetic patients at risk of kidney disease progression. Fibroblast growth factors 21 (FGF21) and 23 (FGF23) may play an important role in the DN development and progression. We aimed to assess levels of FGF21 and FGF23 in patients with type 2 diabetes (T2D) with normoalbuminurea, to determine their association with other biochemical parameters and to verify their role as contributing factors to development of DN. The present study included 30 T2D patients with normoalbuminurea (urinary albumin excretion, UAE; less than 30 mg/ 24 hours), and 30 sex and age matched healthy individuals as a control group. Levels of FGF21 and FGF 23 were measured by ELISA. We observed significant increase in FGF21 (P=0.019) and in FGF23 (P=0.000) levels in patients compared with controls. There was a positive correlation between FGF21 and FGF23 and between each of them and other biochemical parameters: cholesterol, triglycerides, LDL cholesterol, FBS, creatinine, HA1C and UAE. Negative correlation was found between both of FGF21 and FGF23 and GFR. We concluded that elevated serum FGF21 and FGF23 levels may be useful biomarkers for predicting kidney disease progression, especially in the early stages of DN. PMID- 29528584 TI - Effect of Allergen Specific Immunotherapy on Serum levels of IL-17 and IL-35 in Allergic Rhinitis Patients. AB - Allergic rhinitis (AR) is mediated by many proinflammatory and anti-inflammatory cytokines as interleuhin-17 (IL-17) and interleukin-35 (IL-35) respectively. We assessed the effect of allergen specific immunotherapy (IT) on the serum levels of IL-17 and IL-35 in patients with AR sensitive to house dust mites (HDMs). Twenty patients with AR sensitive to HDMs and ten healthy control subjects were included in the study. Sensitivity to HDMs was diagnosed by positive skin prick test. Patients were treated by cluster IT. They were assessed by medical history, skin prick test, nasal symptoms scores, and measurement of serum IL-17 and IL-35 levels by ELISA technique before and after IT. All patients showed significant improvement in the skin test reactions and nasal symptoms scores after IT except for the postnasal drip which showed non-significant improvement. Serum IL-17 levels were higher in patients before IT than in control subjects and showed a significant decrease after IT. Serum IL-35 levels were lower in patients before IT than in control subjects and showed a significant increase after IT. No significant difference in the serum levels of IL-17 and IL-35 was observed between the patients and control subjects after IT. It was concluded that allergen specific IT decreases IL-17 and increases IL-35 in patients with AR sensitive to HDMs. PMID- 29528585 TI - Food Specific IgE as A Biomarker of Oral Immunotherapy Efficacy in Comparison to Double Blind Food Challenge Test. AB - Specific immunotherapy (SIT) is one of the important lines for the treatment of food allergy. Efficacy tests for clinical response to SIT are limited and subjective. In this study, we aimed to evaluate the validity of food specific Ig E levels as a biomarker of clinical improvement in children with food allergy treated with oral immunotherapy (OIT). We analysed 184 children with food allergy, 143 had undergone 2 years of food OIT and 41 were on allergen restricted diet and considered as control. All patients were subjected to Double-Blind Placebo-Controlled Food Challenge test (DBPCFC), allergic symptom score calculation, and serum food specific Ig E level before and after oral immunotherapy for treated patients and after 2 year of allergen restricted diet for the control group. Receiver Ooperating Ccharacteristic Ccurves (ROCs) analysis was done to determine the cut off, areas under the curve, sensitivity, and specificity were calculated for the specific Ig E test. According to the result of DBPCFC and result of food specific Ig E test, milk Milk allergy was the most frequently food allergy as it was encountered in 76 children out of 184 children (41.3%) , followed by egg and fish allergy in 64(34.7%), and 44 (23.7%) cases, respectively. Oral desensitization was successful in 91 %, 82%, and 67% of patients with milk, Egg, and fish allergy, respectively. The OIT group showed a statistically significant greater reduction in symptom scores compared to the control group (P < 0.001). Also, there was a significant decrease in food specific Ig E level in responders for all types of food allergy tested (P ?0.001), and . In responders group, there was significant correlation between the specific IgE level and symptom scores (r = 0.5, P = 0.03). Food specific Ig E levels cut off levels were < 0.8, < 2.05, and < 23 IU/ml allowed detection of effective OIT for milk, egg, and fish allergy, respectively. It is concluded that serum specific Ig E is correlated correlates with the clinical response to OIT and offers an advantage over double blind challenge test which is a risky and time consuming process. PMID- 29528586 TI - Validity of Specific Immunoglobulin E Assay in Tear Film for Detection of Allergens Inducing Different Types of Allergic Conjunctivitis. AB - This is a prospective interventional comparative study which aimed to investigate correlation between tear film allergen specific IgE levels and the skin prick test in diagnosing different types of allergic conjunctivitis. One hundred twenty patients with allergic conjunctivitis were included in this study and were classified into 4 groups based on the type of allergic conjunctivitis. Patients were subjected to skin prick test (SPT). Micro capillary method was used to collect tear samples for the quantitative assessment of specific IgE by Immune blot assay. The most common allergens were mixed mould, mixed pollen, and mixed mite. The results of tear film specific IgE in detection of allergens were evaluated against the SPT. The Receiving Operating Characteristic Curve (ROCs) revealed that tear film allergen-specific IgE specificity was 100% and sensitivity was 75%-100% to the three common allergens in the 4 studied groups. The correlation between tear's specific IgE and skin prick test was statistically significant for pollen, mite, and mould allergens in patient with SAK (r = 0.821, P ? 0.001 for pollen, r = 0.964, P ? 0.001 for mite, and r= 0.811, P ? 0.02 for mould ), PAC (r = 0.851, P ? 0.001 for pollen, r = 0.826, P ? 0.001 for mite, and r= 0.861, P ? 0.001 for mould) and VKC (r = 0.802, P ? 0.001 for pollen, r = 0.894, P ? 0.001 for mite, and r= 0.861, P ? 0.061 for mould). In patient with AKC, the correlation was statistically significant for only mite allergen (r = 1, P ? 0.001). We concluded that Tear film specific IgE test can be considered as a good alternative to skin prick test in diagnosis of the causative allergens in allergic conjunctivitis. PMID- 29528587 TI - CD81 and CD19 as Marker of Activity in Systemic Lupus Erythematosus Disease. AB - Systemic Lupus Erythematosus is systematic auto-immune disease characterized by abnormal activation of B cell with production of autoantibodies. Due to its heterogeneous course, there is a need for new markers to help in diagnosing and monitoring disease activity. The aim of this study was to identify the immunopathological role of CD19 and CD81 expression in patients with SLE and their correlation with the disease activity. Peripheral blood (PB) was collected from 40 SLE patients (20 active and 20 inactive) and 20 controls. All were subjected to CBC, Anti-ds DNA, Redial immunodiffusion (RID) for C3 and C4 as activity markers, and detection of CD19 and CD81 surface expression using flow cytometry. CD19 and CD81 were significantly reduced and correlated with disease activity. It is concluded that CD 19 and CD 81 are potential markers for diagnosing and monitoring SLE patients. PMID- 29528588 TI - Vitamin D receptor Fok1 & Bsm 1 Gene Polymorphisms in Systemic Lupus Erythematosus and Osteoarthritis: Autoimmune Inflammatory versus Degenerative Model. AB - Vitamin D deficiency has been described in SLE and OA. Low vitamin D level is prevalent in Egyptian SLE patients while controversial studies are present regarding its level in OA patients in Egypt. We investigated whether vitamin D receptor (VDR) genes Bsm1 and Fok1 polymorphisms could be used as genetic markers for the susceptibility to SLE and /or OA in a sample of Egyptian population. The study was carried out on 100 SLE patients, 100 osteoarthritic patients and 100 normal controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Our results showed a statistically significant difference in Fok1 genotype distribution between SLE and OA patients (p=0.001). In SLE group, the "f" allele was significantly over-represented where 30% had "f" allele compared to 0% in OA (P = 0.03). Fok1 ff genotypes showed a significant association with disease activity in SLE patients. In addition, the fb haplotype frequency was significantly higher in SLE patients than controls (P=0.01). In conclusion Fok1 genotype and f allelic frequencies may be susceptible risk factors for SLE rather than OA in Egyptian patients. PMID- 29528589 TI - The Effect of Autologous Serum Therapy in Chronic Spontaneous Urticaria Depends on Autologous Serum Skin Test Positivity. AB - Chronic spontaneous urticaria (CSU) is a common distressing disease caused mainly by autoreactive mechanisms. Autologous serum therapy (AST) has been tried for treatment of many autoimmune diseases including chronic urticaria. We assessed the effect of AST in autologous serum skin test (ASST)-positive and ASST-negative CSU patients. The study included 40 patients clinically diagnosed as CSU. Twenty ASST-positive patients and 20 ASST-negative patients received AST for 8 weeks. Urticarial activity was assessed at baseline, 4th week, 9th week, and at the 12th week by the weekly urticarial activity score (UAS-7) according to the EAACI/GA2LEN/EDF/WAO guidelines. Antihistamine pill burden was assessed at every visit. The mean UAS-7 was significantly decreased in ASST-positive patients after AST at the 4th and 9th weeks (P < 0.05) but the decrease was non-significant at the 12th week. In ASST-negative patients, the decrease in the mean UAS-7 was significant only at the 4th week. Ten percent of the ASST-positive patients showed complete remission after AST and no patients in either group showed relapse after treatment. There was no difference in the mean UAS-7 between the two groups at baseline but significant difference was observed at 4th, 9th and 12th week. The difference in antihistamine pill burden was also significant at the 12th week (P < 0.001). We concluded that AST is more efficient in decreasing disease severity and antihistamine use in ASST-positive CSU patients than in ASST negative patients. PMID- 29528590 TI - Toll Like Receptor 3 Polymorphisms in Hepatitis B Virus Infection. AB - Hepatitis B virus (HBV) is the one of the major causes of chronic liver disease. Individuals exposed to HBV show wide spectrum outcomes including immunized persons, asymptomatic carrier, chronic active hepatitis, cirrhosis and HCC. The outcome of HBV infection and the severity of associated liver diseases are determined by the nature and strength of host immune responses against the virus. There is accumulating evidence that the innate branch of the host immune system plays an important role in the control of HBV infection. Various components including toll-like receptor (TLR) contribute to this nonspecific innate immune response .TLR3 play an important role in innate immune response against viral pathogens. Single nucleotide polymorphisms (SNPs) in the TLR3 could be considered as factors for the susceptibility to viral pathogens including HBV. This study aimed to investigate the distribution of six SNPs of the TLR3 gene in patients infected with HBV and to determine the relation between these SNPs and the clearance of hepatitis B virus. These SNPs were tested by direct sequencing. Three groups were investigated: chronic HBV carrier (25 patients), chronic active HBV carrier (16 patients) and 13 persons who were previously exposed to HBV and became immunized. These 3 groups were examined for six SNPs (rs5743311, rs5743312, rs5743313, rs5743314, rs5743315, and rs78726532). The analysis showed high frequencies of GCTCCA haplotype and CCA haplotype in the immunized group when compared to chronic hepatitis B groups (P < 0.05). These findings indicate that genetic variations in the TLR3 gene could affect the outcome of HBV infection. PMID- 29528591 TI - ? PMID- 29528592 TI - ? PMID- 29528593 TI - [Suffering at work among medical students: qualitative study using semi structured interviews]. AB - INTRODUCTION: Suffering at work among health professionals is a hot topic. Medical students, doctors of tomorrow, are far from being spared. Prevalence of anxiety and mood disorders range from 20.3 to 69 % for the former and from 12 to 30 % for the latter. The purpose of this article is to determine these factors by qualitative research, according to medical students' points of view. METHODS: It is a qualitative study using semistructured interviews. The analysis is done according to the Grounded Theory. RESULTS: 12 medical students are interviewed. They expressed difficulties at work and positive factors. Three major themes are identified in selective coding: occupational factors, " study " factors and individual factors. All themes are both a source of well-being and ill-being according to the situations specified in the results. CONCLUSION: Studying medicine includes positive and negative aspects. Abandonment issues, lack of recognition and insufficient coaching emerge from our study. Screening of suffering at work should be systematic for medical students. PMID- 29528594 TI - [Elderly's suicide attempt]. AB - Suicide attempts among the elderly (more than 65 years old) is a topic that is scarcely studied despite its prevalence. In recent years, researchers from all over the world started to study and publishing about this phenomenon. Several research studies tried to single out elderly people's suicide risk factors, focusing particularly on neurobiological alterations linked to the aging process. Some prevention techniques have already been developed and produced convincing results. Through this literature review, we set out to give both a general and summarized view on suicide and suicide attempts among the elderly. PMID- 29528595 TI - [Perspectives on resilience : trait or aptitude ?] AB - In this paper, we discuss various issues related to the concept of resilience, which is conventionally defined as a dynamic process allowing for a positive adaptation in a context of significant adversity. First, we try to draw the reader's attention to the importance of the concept of resilience in terms of public health. Second, we address the difficulty of measuring resilience in a relevant and operational manner. Third, we then address the question of whether resilience can be conceived only in the context of a confrontation with trauma, or whether its application can be relevant to the everyday nontraumatic adversity. In this regard, we introduce and define another coping strategy which is the Sense of Coherence (SOC). Fourth, we discuss the nature of resilience, that is to say, whether it should be considered as a personality trait or as an aptitude. We try to show that this problem arises from the difficulty to specify the emotional processes involved in resilience. Finally, we propose future research perspectives that should allow us to better understand the concept of resilience. PMID- 29528596 TI - [Treatment of sensory information in neurodevelopmental disorders]. AB - INTRODUCTION: The processing of information coming from the elementary sensory systems conditions the development and fulfilment of a child's abilities. A dysfunction in the sensory stimuli processing may generate behavioural patterns that might affect a child's learning capacities as well as his relational sphere. The DSM-5 recognizes the sensory abnormalities as part of the symptomatology of Autism Spectrum Disorders. However, similar features are observed in other neurodevelopmental disorders. Over the years, these conditions have been the subject of numerous controversies. Nowadays, they are all grouped together under the term of Neurodevelopmental Disorders in DSM-5. The semiology of these disorders is rich and complex due to the frequent presence of comorbidities and their impact on cognitive, behavioural, and sensorimotor organization but also on a child's personality, as well as his family, his school, or his social relationships. MATERIAL AND METHODS: We carried out a review of the literature on the alterations in the treatment of sensory information in ASD but also on the different neurodevelopmental clinical panels in order to show their impact on child development. FINDINGS: Atypical sensory profiles have been demonstrated in several neurodevelopmental clinical populations such as Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorders, Dysphasia and Intellectual Disability. CONCLUSION: Abnomalies in the processing of sensory information should be systematically evaluated in child developmental disorders. PMID- 29528597 TI - [Transition from child and adolescent to adult mental health care]. AB - Adolescents and young adults are at particularly at-risk population in mental health. For a large majority of patients suffering from chronic psychiatric condition, the age of onset of psychiatric symptoms is less than 24 years, while the coverage in psychiatric care is the lowest between 16 and 24. Presenting a psychiatric pathology during childhood and adolescence constitutes an independent risk factor for the occurrence of adverse life events in adulthood. Furthermore, that population is at the edge between child and adolescent mental health services (CAMHS) and adult mental health services (AMHS). Transition is the deliberate and planned movement from CAMHS to AMHS. CAMHS and AMHS struggle to achieve optimal transitions between them. Many barriers exist at the interface of the two types of structure and some young people who require continuous care during this period do not have access to it. There are also too few specific psychiatric services for the population of adolescents and young adults. Some recommendations emerge to intend to guide practices, but the literature lacks data to better define this population and build guidelines about the transition between CAMHS and AMHS and about specific services for adolescents and young adults in psychiatry. PMID- 29528598 TI - [Depression in adolescents and multiculturality : a multifactorial analysis of psychological suffering inside a family in crisis]. AB - The complexity of depressive diagnosis and other forms of expression of psychological suffering during adolescence explain why particular caution is required. The medico-psycho-social determinants of teenager's mental health enjoin us to support a holistic analysis of these situations. Different analysis spectra - symptomatic, environnemental, anthropological, cultural - allow us to understand a situation at different levels of interpretation. As we will see through a clinical case examination, the difficulty of depressive diagnosis in a multicultural background is increased by the ethnocentrical aspect of this category. PMID- 29528599 TI - [Transcranial Direct Current Stimulation (tDCS) : psychiatric use]. AB - Transcranial Direct Current Stimulation (tDCS) is a cheap, easy to use, and relatively safe noninvasive brain stimulation technique. It is increasingly used in several indications in psychiatry and neurology, mainly for depression, chronic pain and cognitive decline due to degenerative brain diseases. Its efficacy is probable in depression and must still be confirmed in numerous other indications. Lowcost devices for the general public are easy to find on the internet and are frequently used for non-therapeutic indications, like the improvement of video gamers' performances. A non-medical use could represent a public health hazard, due to lack of control on stimulation parameters i.e. localization, duration and intensity. PMID- 29528600 TI - [74-year-old man with a complex acromio-clavicular disjunction]. AB - Acromioclavicular dislocation is a frequent pathology commonly encountered in traumatology. Therefore, its management is generally standardized, guided by clinical and radiological evaluation. This can range from conservative treatment by limb immobilization and functional rehabilitation, to surgical treatment by using minimally invasive techniques. We present the particular case of a 74-year old patient with an acromioclavicular dislocation associated with a non-displaced fracture of the coracoid process as well as of the spine of the scapula. This article aims to describe the diagnostic traps as well as discuss the treatment options for this complex presentation. PMID- 29528601 TI - ? AB - Trained in the ULB, pupil of Albert Brachet, Ernest Van Campenhout frequented successively the Universite Libre de Bruxelles (ULB), the Yale University and the Montreal University, to settle definitively in the Universite Catholique de Louvain (UCL), where he becomes professor of anatomy, histology and embryology. Despite the fact that his most interest was the autonomic innervation of the digestive tract, he examined a lot of problems, and his severe and rigorous teaching impressed a number of student's generations. PMID- 29528602 TI - ESTIMATING THE COST OF AGRICULTURAL MORBIDITY IN MAINE AND NEW HAMPSHIRE. AB - This article provides an estimate for the economic costs of agricultural injuries sustained in the states of Maine and New Hampshire between the years 2008 and 2010. The authors used a novel dataset of 562 agriculturally related occupational injuries, and cost estimates were generated using the CDC's Web-based Injury Statistics Query and Reporting System (WISQARS). Individual cases from the dataset that did not match the query options for WISQARS were excluded. Of the 562 agricultural injuries identified in the dataset, 361 met the WISQARS criteria. The remaining 201 cases were judged to be incompatible with the WISQARS query criteria. Significant differences (p 0.0001) were found between the median costs of eight types of injury. Amputations (median = $70,077) and fractures (median = $13,365) were found to be the most expensive types of injury. The total cost of the 361 injuries for which estimates were available was $6,342,270. Injuries that reportedly involved machinery were found to be more expensive than injuries caused by animals. This article highlights the difference in the total cost of injury between types of injuries and demonstrates that agricultural injuries were a significant economic burden for Maine and New Hampshire for the years 2008-2010. These data can be used to direct future preventive efforts. Finally, this article suggests that WISQARS is a powerful tool for estimating injury costs without requiring access to treatment or billing records. PMID- 29528603 TI - EVALUATION OF AGRICULTURAL TRACTOR SEAT COMFORT WITH A NEW PROTOCOL BASED ON PRESSURE DISTRIBUTION ASSESSMENT. AB - Professional drivers have been found to be at a high risk of developing low back pain due to prolonged sitting and vehicle vibration. In a previous survey carried out on 1,155 tractor drivers, tractor vibration and/or incorrect posture while driving were found to cause low back disorders in more than 80% of the interviewed drivers. In this context, the present research introduces a new evaluation protocol to assess the ergonomic characteristics of agricultural tractor seats through the use of pressure sensors, taking into account both static and dynamic conditions. The degree of comfort was defined by analyzing the pressure distribution exerted by a sample of 12 drivers sitting on two seats in five different operating conditions. The pressure distribution values thus obtained were compared with the corresponding pressures recorded with the 12 drivers sitting on a reference seat (rigid seat, backrest, and suspension) designed for the purpose. From the comparison, it was possible to define a comfort index (CI) that allowed an objective assessment of the two seats. Statistical analysis showed that the CIs of the two seats were significantly different in all five operating conditions. Moreover, the two seats showed different CIs as a function of the operating condition. Although less comfortable, one seat showed almost constant CI values in all five operating conditions. Conversely, the other seat showed a progressively decreasing CI from the static condition to the uneven ground condition. PMID- 29528604 TI - DESIGN AND EVALUATION OF INDIVIDUAL ELEMENTS OF THE INTERFACE FOR AN AGRICULTURAL MACHINE. AB - If a user-centered approach is not used to design information displays, the quantity and quality of information presented to the user may not match the needs of the user, or it may exceed the capability of the human operator for processing and using that information. The result may be an excessive mental workload and reduced situation awareness of the operator, which can negatively affect the machine performance and operational outcomes. The increasing use of technology in agricultural machines may expose the human operator to excessive and undesirable information if the operator's information needs and information processing capabilities are ignored. In this study, a user-centered approach was used to design specific interface elements for an agricultural air seeder. Designs of the interface elements were evaluated in a laboratory environment by developing high fidelity prototypes. Evaluations of the user interface elements yielded significant improvement in situation awareness (up to 11%; overall mean difference = 5.0 (4.8%), 95% CI (6.4728, 3.5939), p 0.0001). Mental workload was reduced by up to 19.7% (overall mean difference = -5.2 (-7.9%), n = 30, a = 0.05). Study participants rated the overall performance of the newly designed user-centered interface elements higher in comparison to the previous designs (overall mean difference = 27.3 (189.8%), 99% CI (35.150, 19.384), p 0.0001. PMID- 29528605 TI - MODIFIED PATH METHODOLOGY FOR OBTAINING INTERVAL-SCALED POSTURAL ASSESSMENTS OF FARMWORKERS. AB - Agricultural workers perform tasks that frequently require awkward and extreme postures that are associated with musculoskeletal disorders (MSDs). The PATH (Posture, Activity, Tools, Handling) system currently provides a sound methodology for quantifying workers' exposure to these awkward postures on an ordinal scale of measurement, which places restrictions on the choice of analytic methods. This study reports a modification of the PATH methodology that instead captures these postures as degrees of flexion, an interval-scaled measurement. Rather than making live observations in the field, as in PATH, the postural assessments were performed on photographs using ImageJ photo analysis software. Capturing the postures in photographs permitted more careful measurement of the degrees of flexion. The current PATH methodology requires that the observer in the field be trained in the use of PATH, whereas the single photographer used in this modification requires only sufficient training to maintain the proper camera angle. Ultimately, these interval-scale measurements could be combined with other quantitative measures, such as those produced by electromyograms (EMGs), to provide more sophisticated estimates of future risk for MSDs. Further, these data can provide a baseline from which the effects of interventions designed to reduce hazardous postures can be calculated with greater precision. PMID- 29528612 TI - Application Analysts Help Bridge the Revenue Cycle, IT Gap. AB - Having application analysts in the patient business services department helps Community Hospital of the Monterey Peninsula get the most from its health information system software. PMID- 29528613 TI - Patient Advocacy Program Proves to be a Worthy Investment. AB - A key to Baptist Hospitals of Southeast Texas's successful advocacy program is staff with strong customer service skills and knowledge of coverage and payment options. PMID- 29528614 TI - U.S. Regions Vary by Payer Mix and Deductions. PMID- 29528615 TI - Position paper on olfactory dysfunction. AB - Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and majorhealth outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following:* Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopywith small diameter endoscopes.* Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability.* Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odourthreshold, and/or one of odour identification or discrimination.* Comprehensive chemosensory assessment should include gustatory screening.* Smell training can be helpful in patients with olfactory loss of several aetiologies. Conclusions: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field. PMID- 29528616 TI - Photocatalytic Hydrogen Production with Conjugated Polymers as Photosensitizers. AB - Artificial photosynthesis is a chemical process that aims to capture energy from sunlight to produce solar fuels. Light absorption by a robust and efficient photosensitizer is one of the key steps in solar energy conversion. However, common photosensitizers, including [Ru(bpy)3]2+ (RuP), remain far from the ideal. In this work, we exploited the performance of conjugated polymers (CPs) as photosensitizers in photodriven hydrogen evolution in aqueous solution (pH 6). Interestingly, CPs, such as poly(fluorene- co-phenylene) derivative (429 mmolH2.gCP-1.h-1), exhibit steady and high reactivity toward hydrogen evolution; this performance can rival that of a phosphonated RuP under the same conditions, indicating that CPs are promising metal-free photosensitizers for future applications in photocatalysis. PMID- 29528617 TI - Energy Transfer between Semiconducting Polymer Dots and Gold Nanoparticles in a Photoelectrochemical System: A Case Application for Cathodic Bioanalysis. AB - We report herein the energy transfer (ET) between semiconducting polymer dots (Pdots) and gold nanoparticles (Au NPs) in a photoelectrochemical (PEC) system and its feasibility for cathodic bioanalysis application. Specifically, COOH capped Pdots were first fabricated and then assembled onto the indium-tin oxide (ITO) surface, followed by the modification of single-strand (ss) DNA probe (pDNA). After the DNA hybridization with the Au NP-tethered complementary ssDNA (Au NP-tDNA), the Au NPs were brought into the close proximity of Pdots. Upon light stimulation, photoluminescence (PL) was annihilated, fluorescence was attenuated, and the photocurrent intensity was evidently decreased. This ET-based PEC DNA sensor exhibited a linear range from 1 fM to 10 pM with a detection limit of 0.97 fM at a signal-to-noise ratio of 3. The present work first exploited the ET between Pdots and Au NPs, and we believe this phenomenon will spark new interest in the study of various Pdots-based ET-influenced PEC systems and thus catalyze increasing studies for specific bioanalytical purposes. PMID- 29528618 TI - High-Pressure CO2 Sorption in Polymers of Intrinsic Microporosity under Ultrathin Film Confinement. AB - Ultrathin microporous polymer films are pertinent to the development and further spread of nanotechnology with very promising potential applications in molecular separations, sensors, catalysis, or batteries. Here, we report high-pressure CO2 sorption in ultrathin films of several chemically different polymers of intrinsic microporosity (PIMs), including the prototypical PIM-1. Films with thicknesses down to 7 nm were studied using interference-enhanced in situ spectroscopic ellipsometry. It was found that all PIMs swell much more than non-microporous polystyrene and other high-performance glassy polymers reported previously. Furthermore, chemical modifications of the parent PIM-1 strongly affected the swelling magnitude. By investigating the behavior of relative refractive index, nrel, it was possible to study the interplay between micropores filling and matrix expansion. Remarkably, all studied PIMs showed a maximum in nrel at swelling of 2-2.5% indicating a threshold point above which the dissolution in the dense matrix started to dominate over sorption in the micropores. At pressures above 25 bar, all PIMs significantly plasticized in compressed CO2 and for the ones with the highest affinity to the penetrant, a liquidlike mixing typical for rubbery polymers was observed. Reduction of film thickness below 100 nm revealed pronounced nanoconfinement effects and resulted in a large swelling enhancement and a quick loss of the ultrarigid character. On the basis of the partial molar volumes of the dissolved CO2, the effective reduction of the Tg was estimated to be ~200 degrees C going from 128 to 7 nm films. PMID- 29528619 TI - Correction to Synergistic Effect of Double-Shelled and Sandwiched TiO2@Au@C Hollow Spheres with Enhanced Visible-Light-Driven Photocatalytic Activity. PMID- 29528620 TI - New Insights into the Interphase between the Na Metal Anode and Sulfide Solid State Electrolytes: A Joint Experimental and Computational Study. AB - In this work, we investigated the interface between the sodium anode and the sulfide-based solid electrolytes Na3SbS4 (NAS), Na3PS4 (NPS), and Cl-doped NPS (NPSC) in all-solid-state-batteries (ASSBs). Even though these electrolytes have demonstrated high ionic conductivities in the range of 1 mS cm-1 at ambient temperatures, sulfide sold-state electrolytes (SSEs) are known to be unstable with Na metal, though the exact reaction mechanism and kinetics of the reaction remain unclear. We demonstrate that the primary cause of capacity fade and cell failure is a chemical reaction spurred on by electrochemical cycling that takes place at the interface between the Na anode and the SSEs. To investigate the properties of the Na-solid electrolyte interphase (SSEI) and its effect on cell performance, the SSEI was predicted computationally to be composed of Na2S and Na3Sb for NAS and identified experimentally via X-ray photoelectron spectroscopy (XPS). These two compounds give the SSEI mixed ionic- and electronic-conducting properties, which promotes continued SSEI growth, which increases the cell impedance at the expense of cell performance and cycle life. The SSEI for NPS was similarly found to be comprised of Na2S and Na3P, but XPS analysis of Cl-doped NPS (NPSC) showed the presence of an additional compound at the SSEI, NaCl, which was found to mitigate the decomposition of NPS. The methodologies presented in this work can be used to predict and optimize the electrochemical behavior of an all-solid-state cell. Such joint computational and experimental efforts can inform strategies for engineering a stable electrolyte and SSEI to avoid such reactions. Through this work, we call for more emphasis on SSE compatibility with both anodes and cathodes, essential for improving the electrochemical properties, longevity, and practicality of Na-based ASSBs. PMID- 29528621 TI - Electrochemical Determination of Ca2+ Based On Recycling Formation of Highly Selective DNAzyme and Gold Nanoparticle-Mediated Amplification. AB - Calcium ion (Ca2+) plays a critical and indispensable role in many physiological and biochemical processes in the human body. In this report, we demonstrate a novel electrochemical method for the determination of the Ca2+ level aided by three functional DNA probes and gold nanoparticles (AuNPs). It affords high selectivity in sensing Ca2+ over other metal cations, which is due to the adoption of the DNAzyme at the electrode interface with exceptionally high binding ability. This method also integrates recycling formation of DNAzyme and AuNPs-mediated amplification; thus, high sensitivity is promised. Therefore, this work provides a favorable way to probe Ca2+ for biomedical applications. PMID- 29528622 TI - Supercritical Angle Fluorescence Characterization Using Spatially Resolved Fourier Plane Spectroscopy. AB - Most fluorescent immunoassays require a wash step prior to read-out due to the otherwise overwhelming signal of the large number of unbound (bulk) fluorescent molecules that dominate over the signal from the molecules of interest, usually bound to a substrate. Supercritical angle fluorescence (SAF) sensing is one of the most promising alternatives to total internal reflection fluorescence for fluorescence imaging and sensing. However, detailed experimental investigation of the influence of collection angle on the SAF surface sensitivity, i.e., signal to background ratio (SBR), is still lacking. In this Letter, we present a novel technique that allows to discriminate the emission patterns of free and bound fluorophores simultaneously by collecting both angular and spectral information. The spectrum was probed at multiple positions in the back focal plane using a multimode fiber connected to a spectrometer and the difference in intensity between two fluorophores was used to calculate the SBR. Our study clearly reveals that increasing the angle of SAF collection enhances the surface sensitivity, albeit at the cost of decreased signal intensity. Furthermore, our findings are fully supported by full-field 3D simulations. PMID- 29528624 TI - Quantitation and Stability of Protein Conjugation on Liposomes for Controlled Density of Surface Epitopes. AB - The number and spacing of B-cell epitopes on antigens have a profound impact on the activation of B cells and elicitation of antibody responses, the quantitative aspects of which may be utilized for rational design of vaccines. Ni-chelating liposomes have been widely used as protein carriers in experimental studies of vaccine delivery, owing to the convenience and versatility of this conjugation chemistry. However, the epitope number per particle as well as the stability of protein conjugation on liposomes remain far less characterized. Here we have developed quantitative methods to measure the average spatial density of proteins on liposomes using both ensemble and single-molecule techniques and demonstrated their utility using liposomes conjugated with native proteins of two different sizes. These studies revealed that the initial density of protein conjugation on Ni-chelating liposomes can be finely controlled, but the density can decrease over time upon dilution due to the noncovalent nature of Ni-chelation chemistry. These results indicate that an alternative method other than the Ni-chelation chemistry is needed for stable conjugation of epitopes onto liposomes and also suggest a general strategy that can be used to precisely regulate the epitope density on liposomes for B-cell antigen delivery. PMID- 29528623 TI - Squaramide-Based Supramolecular Materials for Three-Dimensional Cell Culture of Human Induced Pluripotent Stem Cells and Their Derivatives. AB - Synthetic hydrogel materials can recapitulate the natural cell microenvironment; however, it is equally necessary that the gels maintain cell viability and phenotype while permitting reisolation without stress, especially for use in the stem cell field. Here, we describe a family of synthetically accessible, squaramide-based tripodal supramolecular monomers consisting of a flexible tris(2 aminoethyl)amine (TREN) core that self-assemble into supramolecular polymers and eventually into self-recovering hydrogels. Spectroscopic measurements revealed that monomer aggregation is mainly driven by a combination of hydrogen bonding and hydrophobicity. The self-recovering hydrogels were used to encapsulate NIH 3T3 fibroblasts as well as human-induced pluripotent stem cells (hiPSCs) and their derivatives in 3D. The materials reported here proved cytocompatible for these cell types with maintenance of hiPSCs in their undifferentiated state essential for their subsequent expansion or differentiation into a given cell type and potential for facile release by dilution due to their supramolecular nature. PMID- 29528625 TI - Chemical Cleavage of an Asp-Cys Sequence Allows Efficient Production of Recombinant Peptides with an N-Terminal Cysteine Residue. AB - Peptides with an N-terminal cysteine residue allow site-specific modification of proteins and peptides and chemical synthesis of proteins. They have been widely used to develop new strategies for imaging, drug discovery, diagnostics, and chip technologies. Here we present a method to produce recombinant peptides with an N terminal cysteine residue as a convenient alternative to chemical synthesis. The method is based on the release of the desired peptide from a recombinant fusion protein by mild acid hydrolysis of an Asp-Cys sequence. To test the general validity of the method we prepared four fusion proteins bearing three different peptides (20-37 amino acid long) at the C-terminus of a ketosteroid isomerase derived and two Onconase-derived carriers for the production of toxic peptides in E. coli. The chosen peptides were (C)GKY20, an antimicrobial peptide from the C terminus of human thrombin, (C)ApoBL, an antimicrobial peptide from an inner region of human Apolipoprotein B, and (C)p53pAnt, an anticancer peptide containing the C-terminal region of the p53 protein fused to the cell penetrating peptide Penetratin. Cleavage efficiency of Asp-Cys bonds in the four fusion proteins was studied as a function of pH, temperature, and incubation time. In spite of the differences in the amino acid sequence (GTGDCGKY, GTGDCHVA, GSGTDCGSR, SQGSDCGSR) we obtained for all the proteins a cleavage efficiency of about 70-80% after 24 h incubation at 60 degrees C and pH 2. All the peptides were produced with very good yield (5-16 mg/L of LB cultures), high purity (>96%), and the expected content of free thiol groups (1 mol per mole of peptide). Furthermore, (C)GKY20 was modified with PyMPO-maleimide, a commercially available fluorophore bearing a thiol reactive group, and with 6-hydroxy-2 cyanobenzothiazole, a reagent specific for N-terminal cysteines, with yields of 100% thus demonstrating that our method is very well suited for the production of fully reactive peptides with an N-terminal cysteine residue. PMID- 29528626 TI - Collision Cross Section (CCS) Database: An Additional Measure to Characterize Steroids. AB - Ion mobility spectrometry enhances the performance characteristics of liquid chromatography-mass spectrometry workflows intended to steroid profiling by providing a new separation dimension and a novel characterization parameter, the so-called collision cross section (CCS). This work proposes the first CCS database for 300 steroids (i.e., endogenous, including phase I and phase II metabolites, and exogenous synthetic compounds), which involves 1080 ions and covers the CCS of 127 androgens, 84 estrogens, 50 corticosteroids, and 39 progestagens. This large database provides information related to all the ionized species identified for each steroid in positive electrospray ionization mode as well as for estrogens in negative ionization mode. CCS values have been measured using nitrogen as drift gas in the ion mobility cell. Generally, direct correlation exists between mass-to-charge ratio ( m/ z) and CCS because both are related parameters. However, several steroids mainly steroid glucuronides and steroid esters have been characterized as more compact or elongated molecules than expected. In such cases, CCS results in additional relevant information to retention time and mass spectral data for the identification of steroids. Moreover, several isomeric steroid pairs (e.g., 5beta-androstane-3,17-dione and 5alpha-androstane-3,17-dione) have been separated based on their CCS differences. These results indicate that adding the CCS to databases in analytical workflows increases selectivity, thus improving the confidence in steroids analysis. Consequences in terms of identification and quantification are discussed. Quality criteria and a construction of an interlaboratory reproducibility approach are also reported for the obtained CCS values. The CCS database described here is made publicly available. PMID- 29528627 TI - Magnetic Anisotropy from Trigonal Prismatic to Trigonal Antiprismatic Co(II) Complexes: Experimental Observation and Theoretical Prediction. AB - A family of trigonal antiprismatic Co(II) complexes was synthesized, which exhibited field-induced Raman process dominated single-molecule magnet behavior. Despite the coordination environment of Co(II) being of similar symmetry, the four complexes exhibit distinct dynamic magnetic properties owing to their packing arrangements and dipole-dipole interactions. On the basis of computational results we have demonstrated that the g z and giso values follow a cosine relation with respect to the rotated angle phi (twist angle phi defined as the rotation angle of one coordination square away from the eclipse conformation to the other). PMID- 29528628 TI - Computational Investigation of Carbene-Phosphinidenes: Correlation between 31P Chemical Shifts and Bonding Features to Estimate the pi-Backdonation of Carbenes. AB - Detailed investigations of the electronic structure and bonding scenario in different carbene-phosphinidenes have been presented using state-of-the-art computational methods (BP86/def2-TZVPP//BP86/def2-SVP). We have endeavored to find the correlation of the calculated 31P chemical shifts with different bonding parameters of compounds to access the relative pi-acceptor strengths of the carbenes. 31P chemical shifts exhibit a weak correlation with sigma-polarizations of Ccarb-P bonds toward phosphorus; however excellent correlations are obtained in the case of pi-polarizations of Ccarb-P bonds toward the carbene carbon (Ccarb) and NPA charges on phosphorus atoms. 31P chemical shifts also show excellent correlations with the electron densities and energy densities of Ccarb P bonds at BCPs, as suggested by QTAIM calculations. Moreover, EDA-NOCV analysis is implemented to gain brief insight into the bonding scenario in this class of compounds. Good correlation exists between the interaction energies between the carbene and PPh fragments and 31P chemical shifts. Additionally, we have investigated the correlations of calculated 31P chemical shifts with different bonding parameters of the corresponding free carbenes. The bonding scenario in different carbene-substituted phosphinidenes is also explored to see how the bonding situation depends on various substituents on phosphinidenes. The other substituted carbene-phosphinidenes show correlations similar to those of carbene phenylphosphinidenes. PMID- 29528629 TI - Comment on "Investigation of the Iron-Peroxo Complex in the Fenton Reaction: Kinetic Indication, Decay Kinetics, and Hydroxyl Radical Yields". PMID- 29528630 TI - At the Borderline between Metal-Metal Mixed Valency and a Radical Bridge Situation: Four Charge States of a Diruthenium Complex with a Redox-Active Bis( mer-tridentate) Ligand. AB - The complex ions [L3Ru(MU,eta3:eta3-BL)RuL3] n+ (1 n+, L3 = 4,4',4"-tri- tert butyl-2,6,2',6"-terpyridine and H2BL2- = 1,2-bis(salicyloyl)hydrazide(2-)) were isolated with PF6- or ClO4- counterions ( n = 1) and as bis(hexafluorophosphate) ( n = 2). Structural, electrochemical, and spectroscopic characterization reveals the monocation as intermediate ( Kc = 108.2) in the three-step reversible redox system 10/+/2+/3+. The 1+ ion has the molecule-bridged (Ru- - -Ru 4.727 A) ruthenium centers involved in five- and six-membered chelate rings, and it exhibits long-wavelength absorptions at lambdamax 2240, 1660, and 1530 nm (epsilonmax = 1000, 3000, and 8000 M-1 cm-1, respectively), which would be compatible with a RuIIIRuII mixed-valent situation or with a coordinated radical ion bridge. In fact, EPR and DFT analysis of 1+ reveals that the spin is equally distributed over the ligand bridge and over both metals. The oxidized paramagnetic ions 12+ and 13+ have been studied by 1H NMR and EPR and by TD-DFT supported UV-vis-NIR and MIR (mid-IR) spectroelectrochemistry. The capacity of various kinds of bis( mer-tridentate) bridging ligands (pi donors or pi acceptors, cyclometalated or noncyclometalated) for mediating metal-metal interactions is discussed. PMID- 29528631 TI - Regio- and Stereoselective Hydroamination of Alkynes Using an Ammonia Surrogate: Synthesis of N-Silylenamines as Reactive Synthons. AB - An anti-Markovnikov selective hydroamination of alkynes with N-silylamines to afford N-silylenamines is reported. The reaction is catalyzed by a bis(amidate)bis(amido)Ti(IV) catalyst and is compatible with a variety of terminal and internal alkynes. Stoichiometric mechanistic studies were also performed. This method easily affords interesting N-silylenamine synthons in good to excellent yields and the easily removable silyl protecting group enables the catalytic synthesis of primary amines. PMID- 29528633 TI - [2+2]-Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-Azabicyclo[3.2.0]heptanes. AB - A one-step synthesis of functionalized 3-azabicyclo[3.2.0]heptanes by [2+2] photochemical intermolecular cycloaddition of N-benzylmaleimide to alkenes was elaborated. The obtained compounds were easily transformed into the bi- and tricyclic analogues of piperidine, morpholine, piperazine, and GABA, which are advanced building blocks for drug discovery. PMID- 29528632 TI - Folding-Degradation Relationship of a Membrane Protein Mediated by the Universally Conserved ATP-Dependent Protease FtsH. AB - ATP-dependent protein degradation mediated by AAA+ proteases is one of the major cellular pathways for protein quality control and regulation of functional networks. While a majority of studies of protein degradation have focused on water-soluble proteins, it is not well understood how membrane proteins with abnormal conformation are selectively degraded. The knowledge gap stems from the lack of an in vitro system in which detailed molecular mechanisms can be studied as well as difficulties in studying membrane protein folding in lipid bilayers. To quantitatively define the folding-degradation relationship of membrane proteins, we reconstituted the degradation using the conserved membrane integrated AAA+ protease FtsH as a model degradation machine and the stable helical-bundle membrane protein GlpG as a model substrate in the lipid bilayer environment. We demonstrate that FtsH possesses a substantial ability to actively unfold GlpG, and the degradation significantly depends on the stability and hydrophobicity near the degradation marker. We find that FtsH hydrolyzes 380-550 ATP molecules to degrade one copy of GlpG. Remarkably, FtsH overcomes the dual energetic burden of substrate unfolding and membrane dislocation with the ATP cost comparable to that for water-soluble substrates by robust ClpAP/XP proteases. The physical principles elucidated in this study provide general insights into membrane protein degradation mediated by ATP-dependent proteolytic systems. PMID- 29528634 TI - Stapled, Long-Acting Glucagon-like Peptide 2 Analog with Efficacy in Dextran Sodium Sulfate Induced Mouse Colitis Models. AB - Glucagon-like peptide 2 (GLP-2) is a hormone that has been shown to stimulate intestinal growth and attenuate intestinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is hampered by the short half-life in vivo. We now describe a highly potent, stapled long-acting GLP-2 analog, peptide 10, that has a more than 10-fold longer half-life than teduglutide and improved intestinotrophic and anti-inflammatory effects in mouse models of DSS-induced colitis. PMID- 29528635 TI - Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding. AB - Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94. PMID- 29528636 TI - Integration of Environmental and Developmental (or Metabolic) Control of Seed Mass by Sugar and Ethylene Metabolisms in Arabidopsis. AB - In higher plants, seed mass is an important to evolutionary fitness. In this context, seedling establishment positively correlates with seed mass under conditions of environmental stress. Thus, seed mass constitutes an important agricultural trait. Here, we show loss-of-function of YODA (YDA), a MAPKK Kinase, and decreased seed mass, which leads to susceptibility to drought. Furthermore, we demonstrate that yda disrupts sugar metabolisms but not the gaseous plant hormone, ethylene. Our data suggest that the transcription factor EIN3 (ETHYLENE INSENSITIVE3), integral to both sugar and ethylene metabolisms, physically interacts with YDA. Further, ein3-1 mutants exhibited increased seed mass. Genetic analysis indicated that YDA and EIN3 were integral to a sugar-mediated metabolism cascade which regulates seed mass by maternally controlling embryo size. It is well established that ethylene metabolism leads to the suppression of drought tolerance by the EIN3 mediated inhibition of CBF1, a transcription factor required for the expression genes of abiotic stress. Our findings help guide the synthesis of a model predicting how sugar/ethylene metabolisms and environmental stress are integrated at EIN3 to control both the establishment of drought tolerance and the production of seed mass. Collectively, these insights into the molecular mechanism underpinning the regulation of plant seed size may aid prospective breeding or design strategies to increase crop yield. PMID- 29528637 TI - Palladium-Catalyzed Selective Generation of CO from Formic Acid for Carbonylation of Alkenes. AB - A general and selective palladium-catalyzed alkoxycarbonylation of all kinds of alkenes with formic acid (HCOOH, FA) is described. Terminal, di-, tri-, and tetra substituted including functionalized olefins are converted into linear esters with high yields and regioselectivity. Key-to-success is the use of specific palladium catalysts containing ligands with built-in base, e.g., L5. Comparison experiments demonstrate that the active catalyst system not only facilitates isomerization and carbonylation of alkenes but also promotes the selective decomposition of HCOOH to CO under mild conditions. PMID- 29528638 TI - Alkylamine-Templated Niccolite Frameworks of [GaIIIMII(HCOO)6]- (M = Fe, Ni): Structure, Magnetism, and Dielectricity. AB - The five heterometallic formate frameworks [EtA][GaIIIFeII(HCOO)6] (1; EtA = CH3CH2NH3+), [DMA][GaIIIFeII(HCOO)6] (2; DMA = (CH3)2NH2+), [DEtA][GaIIIFeII(HCOO)6] (3; DEtA = (CH3CH2)2NH2+), [MA][GaIIINiII(HCOO)6] (4; MA = CH3NH3+), and [DMA][GaIIINiII(HCOO)6] (5) were synthesized through solvothermal methods. Complexes 1-5 are isotructural, and all crystallize in the trigonal P31 c space group. Each metal center is 6-connected, with each HCOO- bridging ligand in an anti-anti mode to build a three-dimensional niccolite-like architecture. All of the complexes exhibit weak ferromagnetism at low temperature. A variable temperature (VT) dielectric study indicates that the dielectric anomaly is induced by the freezing of motions from the protonated amines during the freezing process. PMID- 29528639 TI - Rapid and Large-Scale Synthesis of IRMOF-3 by Electrochemistry Method with Enhanced Fluorescence Detection Performance for TNP. AB - Rapid and large-scale synthesis of metal-organic frameworks (MOFs) materials is of great significance for their practical applications. For the first time, we have electrochemically synthesized IRMOF-3 at room temperature by applying a voltage to a zinc electrode immersed in electrolyte containing 2 aminoterephthalic acid (NH2-H2BDC). The reaction conditions, including the ratio of solvent (electrolyte), the applied voltage, and different reaction times, were investigated and optimized. The degree of crystallinity and nanomorphology of the synthesized IRMOF-3 can be controlled by changing the reaction conditions. More importantly, we demonstrated that the electrochemical synthesis strategy can rapidly obtain nanoscale IRMOF-3 with high crystallinity on a gram scale. In addition, in comparison with the product of solvothermal synthesis, the electrochemically synthesized nanoscale IRMOF-3 exhibits improved fluorescent detection ability to 2,4,6-trinitrophenol (TNP) with a detection limit of about 0.1 ppm. PMID- 29528640 TI - Pest Management Strategies Against the Coffee Berry Borer (Coleoptera: Curculionidae: Scolytinae). AB - Coffee ( Coffea arabica and C. canephora) is one of the most widely traded agricultural commodities and the main cash crop in ~80 tropical countries. Among the factors that limit coffee production, the coffee berry borer, Hypothenemus hampei (Ferrari) has been considered the main insect pest, causing losses of over U.S. $500 million dollars annually. Control of this pest has been hindered by two main factors: the cryptic nature of the insect (i.e., protected inside the coffee berry) and the availability of coffee berries in the field allowing the survival of the pest from one generation to the next. Coffee berry borer control has primarily been based on the use of synthetic insecticides. Management strategies have focused on the use of African parasitoids ( Cephalonomia stephanoderis, Prorops nasuta, and Phymastichus coffea), fungal entomopathogens ( Beauveria bassiana), and insect traps. These approaches have had mixed results. Recent work on the basic biology of the insect has provided novel insights that might be useful in developing novel pest management strategies. For example, the discovery of symbiotic bacteria responsible for caffeine breakdown as part of the coffee berry borer microbiome opens new possibilities for pest management via the disruption of these bacteria. Some chemicals with repellent propieties have been identified, and these have a high potential for field implementation. Finally, the publication of the CBB genome has provided insights on the biology of the insect that will help us to understand why it has been so successful at exploiting the coffee plant. Here I discuss the tools we now have against the CBB and likely control strategies that may be useful in the near future. PMID- 29528641 TI - Membrane Capacitive Deionization with Constant Current vs Constant Voltage Charging: Which Is Better? AB - Membrane capacitive deionization (MCDI) can be typically operated with constant voltage (CV) or constant current (CC) mode in the charging stage. While a series of previous studies have compared both charging modes to identify the better operating mode, neither their performance evaluation protocols were consistent, nor did their conclusions unanimously converge. This study presents a new framework to evaluate and compare MCDI performance, considering the kinetic efficiency, the energetic efficiency, and the intrinsic trade-off between the two. A key prerequisite for making rational comparison of performance between MCDI operations is that the operations being compared should all result in the same target adsorption. With this key prerequisite and the new evaluation framework based on the trade-off curve between kinetic and energetic efficiencies, our experimental assessment and theoretical analysis suggest that whether CC or CV charging is more efficient is strongly dependent on the target adsorption and, to a less extent, on the kinetic rate of charging. However, the advantage in energy or kinetic efficiency of one charging mode over that of the other is relatively small in all cases. Our study also reveals that, for a given MCDI system, there exist regimes of target adsorptions and kinetic rates that can only be achieved by either CC or CV charging, or even regimes that can be achieved by neither charging mode. In summary, this study revises our current understanding regarding the comparison of the two typical charging modes in MCDI, and introduces a new framework for comparing the performance of different MCDI and CDI operations. PMID- 29528642 TI - Response to Comment on "Investigation of the Iron-Peroxo Complex in the Fenton Reaction: Kinetic Indication, Decay Kinetics, and Hydroxyl Radical Yields". PMID- 29528643 TI - Internal Rotation of OH Group in 4-Hydroxy-2-butynenitrile Studied by Millimeter Wave Spectroscopy. AB - Cyanoacetylene, HCC-CN is a ubiquitous molecule in the Universe. However, its interstellar chemistry is not well understood and its understanding requires laboratory data including rotational spectroscopy of possible products coming from a reaction with another compounds. In this study we present the first spectroscopic characterization of gauche conformation of 4-hydroxy-2 butynenitrile (HOCH2CCCN), a formal adduct of cyanoacetylene on formaldehyde, in the frequency range up to 500 GHz. The analysis of the rotational spectrum was complicated by internal rotation of the OH group that connects two equivalent gauche configurations. The spectral assignment was aided by high-level quantum chemical calculations that were particularly useful in the interpretation of torsional-rotational part of the problem. The applied reduced-axis-system (RAS) formalism allowed fitting within experimental accuracy the lines with K a < 18. We also present the method of search for initial global solution of torsional rotational problem within RAS formalism. Accurate spectroscopic parameters obtained in this study provide a reliable basis for the detection of 4-hydroxy-2 butynenitrile in the interstellar medium. PMID- 29528645 TI - Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads. AB - Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure-activity relationship (SAR) and the structure-reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple negative breast cancer with enhanced antitumor effects in vitro and in vivo while displaying lower toxicity to normal human mammary epithelial cells in comparison to oridonin. PMID- 29528646 TI - Ab Initio Molecular Dynamics and Lattice Dynamics-Based Force Field for Modeling Hexagonal Boron Nitride in Mechanical and Interfacial Applications. AB - Hexagonal boron nitride (hBN) is an up-and-coming two-dimensional material, with applications in electronic devices, tribology, and separation membranes. Herein, we utilize density-functional-theory-based ab initio molecular dynamics (MD) simulations and lattice dynamics calculations to develop a classical force field (FF) for modeling hBN. The FF predicts the crystal structure, elastic constants, and phonon dispersion relation of hBN with good accuracy and exhibits remarkable agreement with the interlayer binding energy predicted by random phase approximation calculations. We demonstrate the importance of including Coulombic interactions but excluding 1-4 intrasheet interactions to obtain the correct phonon dispersion relation. We find that improper dihedrals do not modify the bulk mechanical properties and the extent of thermal vibrations in hBN, although they impact its flexural rigidity. Combining the FF with the accurate TIP4P/Ice water model yields excellent agreement with interaction energies predicted by quantum Monte Carlo calculations. Our FF should enable an accurate description of hBN interfaces in classical MD simulations. PMID- 29528644 TI - Capillary Electrophoresis Separations of Glycans. AB - Capillary electrophoresis has emerged as a powerful approach for carbohydrate analyses since 2014. The method provides high resolution capable of separating carbohydrates by charge-to-size ratio. Principle applications are heavily focused on N-glycans, which are highly relevant to biological therapeutics and biomarker research. Advances in techniques used for N-glycan structural identification include migration time indexing and exoglycosidase and lectin profiling, as well as mass spectrometry. Capillary electrophoresis methods have been developed that are capable of separating glycans with the same monosaccharide sequence but different positional isomers, as well as determining whether monosaccharides composing a glycan are alpha or beta linked. Significant applications of capillary electrophoresis to the analyses of N-glycans in biomarker discovery and biological therapeutics are emphasized with a brief discussion included on carbohydrate analyses of glycosaminoglycans and mono-, di-, and oligosaccharides relevant to food and plant products. Innovative, emerging techniques in the field are highlighted and the future direction of the technology is projected based on the significant contributions of capillary electrophoresis to glycoscience from 2014 to the present as discussed in this review. PMID- 29528647 TI - Identification and Quantitation of Aerosol Products of the Reaction of beta Pinene with NO3 Radicals and Implications for Gas- and Particle-Phase Reaction Mechanisms. AB - Substantial amounts of gas- and particle-phase organic nitrates have been reported in field studies of atmospheric chemistry conducted around the world, and it has been proposed that a significant fraction of these may be formed from the nighttime reaction of monoterpenes with NO3 radicals. In the study presented here, beta-pinene (a major global monoterpene emission) was reacted with NO3 radicals in an environmental chamber and the molecular and functional group composition of the resulting secondary organic aerosol (SOA) was determined using a variety of methods. Eight products, which comprised ~95% of the SOA mass, were identified and quantified. More than 90% (by mass) of these consisted of acetal heterodimers and heterotrimers that were apparently formed through acid-catalyzed reactions in phase-separated particles. The molar yield of the major oligomer was 16.7%, and the yields of the other six and the single monomer ranged from 1.1% to 2.9%, for a total yield of 30.7%. From these analyses it was determined that the yields of the two major monomer building blocks were 25.9% and 23.6%, and that those of the other four ranged from 2.0% to 4.8%, for a total monomer yield of 62.4%. The measured SOA mass yield was 88.9% and the O/C, N/C, and H/C ratios, molecular weight, and density of the SOA calculated from the results of functional group analysis of the bulk SOA were 0.40, 0.11, 1.79, 217 g mol-1, and 1.21 g cm-3, respectively, similar to values estimated from results of molecular analysis. The results demonstrate the combined importance of RO2* + RO2* reactions, alkoxy radical decomposition and isomerization, and acid-catalyzed particle-phase reactions in the NO3 radical-initiated oxidation of beta-pinene and subsequent formation of SOA and should be useful for understanding reactions of other monoterpenes and for developing models for the laboratory and atmosphere. PMID- 29528648 TI - Testing Electronic Friction Models: Vibrational De-excitation in Scattering of H2 and D2 from Cu(111). AB - At present, molecular dynamics with electronic friction (MDEF) is the workhorse model to go beyond the Born-Oppenheimer approximation in modeling dynamics of molecules at metal surfaces. Concomitant friction coefficients can be calculated with either the local density friction approximation (LDFA) or orbital-dependent friction (ODF), which, unlike LDFA, accounts for anisotropy while relying on other approximations. Due to the computational cost of ODF, extensive high dimensional MDEF trajectory calculations of experimentally measurable observables have hitherto only been performed based on LDFA. We overcome this limitation with a continuous neural-network-based representation. In our first application to the scattering of vibrationally excited H2 and D2 from Cu(111), we predict up to three times higher vibrational de-excitation probabilities with ODF than with LDFA. These results indicate that anisotropic electronic friction can be important for specific molecular observables. Future experiments can test for this "fingerprint" of different approximations underlying state-of-the-art MDEF. PMID- 29528649 TI - Synthesis of Emulsion-Templated Magnetic Porous Hydrogel Beads and Their Application for Catalyst of Fenton Reaction. AB - The pristine Fe3O4 nanoparticle (FeNP) is supposed to be a good catalyst of Fenton processes which have shown significant potential for water purification. Herein the magnetic macroporous hydrogel beads, having an open-cell structure, were synthesized by sedimentation polymerization of pristine FeNP stabilized oil in-water high internal phase emulsions. The effects of the FeNP amount, internal phase fraction, and the costabilizer Tween85 concentration on the structure, such as interconnecting degree, void size, and its distribution of both the surface and inner of the beads, were investigated. With a methyl orange (MO) aqueous solution passing through a chromatography column that was filled with the FeNPs loaded hydrogel beads, the efficiency of these hydrogel beads as catalyst for Fenton reaction to decompose MO in water was tested. The MO was decomposed quickly at the first hour, followed by decomposed gradually in a further 5 h, and the decomposition rate of MO could be up to 99.6% at the end of the test. Moreover, MO decomposition rate remained over 98.2% in six batches which were run in the same beads filled column. The results showed that these FeNPs loaded porous hydrogel beads were reusable and highly efficient supporter for catalysis of Fenton reaction for decomposing organic pollutants in water. PMID- 29528650 TI - Reproducing Quantum Probability Distributions at the Speed of Classical Dynamics: A New Approach for Developing Force-Field Functors. AB - Modeling nuclear quantum effects is required for accurate molecular dynamics (MD) simulations of molecules. The community has paid special attention to water and other biomolecules that show hydrogen bonding. Standard methods of modeling nuclear quantum effects like Ring Polymer Molecular Dynamics (RPMD) are computationally costlier than running classical trajectories. A force-field functor (FFF) is an alternative method that computes an effective force field that replicates quantum properties of the original force field. In this work, we propose an efficient method of computing FFF using the Wigner-Kirkwood expansion. As a test case, we calculate a range of thermodynamic properties of Neon, obtaining the same level of accuracy as RPMD, but with the shorter runtime of classical simulations. By modifying existing MD programs, the proposed method could be used in the future to increase the efficiency and accuracy of MD simulations involving water and proteins. PMID- 29528651 TI - Correction to "Direct Measurements of Quantum Kinetic Energy Tensor in Stable and Metastable Water near the Triple Point: An Experimental Benchmark". PMID- 29528652 TI - Ringlike Migration of a Droplet Propelled by an Omnidirectional Thermal Gradient. AB - The interfacial phenomenon associated with the ringlike motion of a liquid droplet subjected to an omnidirectional thermal gradient is investigated. An experimentally verified model is proposed for estimating the droplet migration velocity. It is shown that the unbalanced interfacial tension acting on the liquid in the radial direction provides the necessary propulsion for the migration, whereas the internal force acting on the adjoining liquid contributes to the equilibrium condition in the circumferential direction. This study puts forward the understanding of the interfacial spreading phenomenon, the knowledge of which is important in applications where liquid lubricants are encountered with directionally unstable thermal gradients. PMID- 29528653 TI - Chemical Dynamics Simulations of Thermal Desorption of Protonated Dialanine from a Perfluorinated Self-Assembled Monolayer Surface. AB - Classical chemical dynamics simulation results are presented for the thermal desorption kinetics and energetics of protonated dialanine ions (ala2-H+) physisorbed on/in a perfluorinated self-assembled monolayer (F-SAM) surface. Previously developed analytic potentials were used for the F-SAM and the ala2 H+/F-SAM intermolecular interaction, and the AMBER valence force field was used for ala2-H+. The activation energy, Ea = 13.2 kcal/mol, determined from the simulations is consistent with previous simulations of the ala2-H+/F-SAM binding energy. The A-factor, 7.8 * 1011 s-1, is about an order of magnitude lower than those representative of small molecule desorption from metal and semiconductor surfaces. This finding is consistent with the decreased entropies of ala2-H+ and the F-SAM upon desorption. Using the Arrhenius parameters for ala2-H+ desorption from the F-SAM, the lifetime of ala2-H+ adsorbed on the F-SAM at 300 K is 5 * 10 3 s. Larger peptide ions are expected to have longer adsorption lifetimes. PMID- 29528654 TI - Three-Body Hydrogen Bond Defects Contribute Significantly to the Dielectric Properties of the Liquid Water-Vapor Interface. AB - We present a simple model of aqueous interfacial molecular structure, and we use this model to isolate the effects of hydrogen bonding on the dielectric properties of the liquid water-vapor interface. We show that water's interfacial molecular structure can be understood by considering the orientational preferences of a single molecule immersed in the environment of the average interfacial density field. We illustrate that depth-dependent orientational anisotropy is determined by the geometric constraints of hydrogen bonding, and we show that the primary features of atomistic simulation data can be reproduced by assuming an idealized, perfectly tetrahedral hydrogen bonding geometry. We demonstrate that nonideal hydrogen bond geometries are required to account for variations in the orientational polarization and polarizability of the interface. Finally, we highlight that these properties contain significant contributions from a specific type of geometrically distorted three-body hydrogen bond defect that is preferentially stabilized at the interface. PMID- 29528656 TI - Physical Stability and Dissolution Behavior of Ketoconazole-Organic Acid Coamorphous Systems. AB - In an earlier investigation, coamorphous systems of ketoconazole (KTZ) prepared with each oxalic (OXA), tartaric (TAR), citric (CIT), and succinic (SUC) acid, revealed drug-acid ionic or hydrogen bonding interactions in the solid-state (Fung et al, Mol. Pharmaceutics, 2018, 15 (3), 1052-1061). We showed that the drug-acid interactions in KTZ-TAR were the strongest, followed by KTZ-OXA, KTZ CIT, and KTZ-SUC. In this study, we investigated the crystallization propensity and dissolution behavior of the KTZ-acid coamorphous systems. When in contact with water (either as water vapor or as aqueous phosphate buffer), while KTZ-CIT and KTZ-TAR were physically stable and resisted crystallization, KTZ-SUC and KTZ OXA crystallized more readily than KTZ alone. The dissolution performances of the coamorphous systems were compared using the area under the curve (AUC) obtained from the concentration-time profiles. KTZ-OXA exhibited the highest AUC, while it was about the same for KTZ-TAR and KTZ-CIT and the lowest for KTZ-SUC. The enhancement in dissolution appeared to become more pronounced as the strength of the acid (OXA > TAR > CIT > SUC) increased. Coamorphization with acid caused at least a two-fold increase in AUC when compared with amorphous KTZ. The decrease in pH of the diffusion layer of the dissolving solid, brought about by the acid, is at least partially responsible for the dissolution enhancement. In addition, the particles of KTZ-OXA, KTZ-TAR, and KTZ-CIT were much smaller than those of KTZ-SUC. The consequent effect on surface area could be another contributing factor to the initial dissolution behavior. PMID- 29528655 TI - Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery. AB - We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long acting nitric oxide donor, both loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC), in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified and CAR-modified liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia induced PAH rats. We also conducted morphometric studies (degree of muscularization, arterial medial wall thickness, and collagen deposition) after treating the PAH rats with test and control formulations. When the rats were treated acutely and chronically, the reduction in mPAP was more pronounced in the liposomal formulation-treated rats than in plain drug-treated rats. CAR-modified liposomes were more selective in reducing mPAP than unmodified liposomes of the drugs. Both drugs, formulated in CAR-modified liposomes, reduced the degree of muscularization, medial arterial wall thickness, and collagen deposition more than the combination of plain drugs did. As seen with the in vivo data, CAR modified liposomes of fasudil or DN increased the levels of the vasodilatory signaling molecule, cGMP, in the smooth muscle cells of PAH-afflicted human pulmonary arteries. Overall, fasudil and DN, formulated in liposomes, could be used as a combination therapy for a better management of PAH. PMID- 29528657 TI - Exploring Redox Properties of Aromatic Amino Acids in Water: Contrasting Single Photon vs Resonant Multiphoton Ionization in Aqueous Solutions. AB - Direct measurements of the valence ionization energies and the reorganization energies of the three aromatic amino acids, l-tyrosine, l-tryptophan, and l phenylalanine, in aqueous solution using the liquid microjet technique and two different photoemission methods-X-ray photoelectron spectroscopy (XPS) at 175 eV photon energy and resonant two-photon ionization (R2PI) using 2 * 267 nm (2 * 4.64 eV) UV laser light-are reported. l-Tryptophan has the lowest vertical ionization energy, 7.3 eV, followed by tyrosine (7.8 eV) and phenylalanine (~8.7 eV). Essentially, no variation in recovered orbital energies is observed comparing near threshold ionization to X-ray ionization. Superior sensitivity of the (background-free) R2PI scheme for solutions with very low solute concentration (<2 mM) is demonstrated in contrast to the single-photon XPS measurements, which often requires solute concentrations of 0.1-1 molar. This higher sensitivity along with chemical selectivity of the R2PI technique can be exploited for both spectroscopic assignment and as an analytical tool. The nature of the adiabatic ionization energy for the three aromatic amino acids has been explored by the R2PI approach and by empirically formulating the correlation between the estimated ionization onset with electronic and nuclear relaxation on the excited state surface. Our results have implications for understanding one electron transfer within enzymes and in redox situations where (ir)reversible deprotonation occurs such as those manifest in the biochemistry of oxidation damage. PMID- 29528658 TI - Effects of Gas-Particle Partitioning on Refractive Index and Chemical Composition of m-Xylene Secondary Organic Aerosol. AB - The formation of secondary organic aerosols (SOAs) contains partitioning processes of the oxidation products between the gas and particle phases, which could change the particle-phase composition when particles grow. However, the effects of these processes on the optical properties of SOA remain poorly understood. In this study, we performed smog chamber experiments to investigate the effects of gas-particle partitioning (GPP) on the refractive index (RI) and chemical composition of the m-xylene SOA. Here, we show that the GPP processes, as organic mass increases, can increase the proportions of semivolatile and intermediate-volatility organic compounds (SVOCs and IVOCs) in the particle phase and result in the decrease of SOA RI real part for 0.09 +/- 0.02 (without seeds) and 0.15 +/- 0.02 (with seeds). This indicates that the SOA optical properties are closely related to the total organic mass and molecular-level composition. In addition, the presence of inorganic seeds promotes the GPP to the particle phase and hence further decreases the RI real part for 0.05 +/- 0.02. As pre-existing aerosols are ubiquitous in the ambient atmosphere, it is suggested that there should be a certain correction when the SOA RI of previous laboratory studies is applied to air quality and climate models. PMID- 29528659 TI - Electrophoretically Deposited Y2O3:Bi3+,Eu3+ Nanosheet Films with High Transparency for Near-Ultraviolet to Red Light Conversion. AB - Fluorescent films were fabricated by depositing Y2O3:Bi3+,Eu3+ nanosheets, which emit red light under near-UV irradiation. The Y2O3:Bi3+,Eu3+ nanosheets were obtained by calcining hydroxide precursor nanosheets synthesized through a hydrothermal method. An aqueous dispersion of positively charged Y2O3:Bi3+,Eu3+ nanosheets with polyethyleneimine adsorbed to the surface was prepared for their deposition. Fluorescent nanosheets were electrophoretically deposited on a transparent conductive substrate under a constant voltage. The obtained nanosheet films were dense and uniform and showed excellent photostability against the excitation light. Growth of the nanosheet film caused a decrease in transmittance and an increase in the photoluminescence intensity. The former effect was attributed to light scattering from inner voids and the rough surface of the film. A polyvinylpyrrolidone (PVP) coating on the film improved the transmittance to be greater than 70% over the visible region. These effects were attributed to antireflection effects at the film surface owing to the low refractive index of PVP. Furthermore, suppression of light scattering by coating the rough surface with a smooth PVP film and filling of voids in the nanosheet film with PVP also improved the transmittance. PMID- 29528660 TI - Palladium-Catalyzed Seven-Membered Silacycle Construction: 1,7-Enyne Hydroxycyclization To Give a Benzosilepine Skeleton. AB - A palladium-catalyzed hydroxycyclization reaction of 1,7-enynes to afford seven membered silacycles (1 H-benzo[ b]silepine skeletons) is developed. This is the first example of both seven-membered ring construction from enynes using a palladium catalyst and hydroxycyclization of enynes to give seven-membered silacycles. PMID- 29528661 TI - Ultrathin Polypyrrole Nanosheets via Space-Confined Synthesis for Efficient Photothermal Therapy in the Second Near-Infrared Window. AB - Extensive efforts have been devoted to synthesizing photothermal agents (PTAs) that are active in the first near-infrared (NIR) region (650-950 nm). However, PTAs for photothermal therapy in the second NIR window (1000-1350 nm) are still rare. Here, it is shown that two-dimensional ultrathin polypyrrole (PPy) nanosheets prepared via a novel space-confined synthesis method could exhibit unique broadband absorption with a large extinction coefficient of 27.8 L g-1 cm 1 at 1064 nm and can be used as an efficient PTA in the second NIR window. This unique optical property is attributed to the formation of bipolaron bands in highly doped PPy nanosheets. The measured prominent photothermal conversion efficiency could achieve 64.6%, surpassing previous PTAs that are active in the second NIR window. Both in vitro and in vivo studies reveal that these ultrathin PPy nanosheets possess good biocompatibility and notable tumor ablation ability in the second NIR window. Our study highlights the potential of ultrathin two dimensional polymers with unique optical properties in biomedical applications. PMID- 29528662 TI - Polyols-Infused Slippery Surfaces Based on Magnetic Fe3O4-Functionalized Polymer Hybrids for Enhanced Multifunctional Anti-Icing and Deicing Properties. AB - High durability, low cost, and superior anti-icing and active deicing multifunctional surface coatings, especially in the extreme environment, are highly desired to inhibit and/or eliminate the detriment of icing in many fields, such as automobile, aerospace, and power transmission. Herein, we first report a facile and versatile strategy to prepare novel slippery polyols-infused porous surfaces (SPIPS's) with the inexpensive polyols as the lubricant liquids. These SPIPS's are fabricated by a spray-coating approach based on amino-modified magnetic Fe3O4 nanoparticles (MNP@NH2) and amphiphilic P(poly(ethylene glycol) methyl ether methacrylate- co-glycidyl methacrylate) copolymer covalent cross linked hybrids, followed by infusion with various polyols. The as-prepared surface exhibits excellent antifrosting property, that is, it can greatly postpone frost formation as long as 2700 s at -18 degrees C. Meanwhile, differential scanning calorimetry results clearly demonstrate that SPIPS's show a remarkable freezing point depression capacity and the crystallization point of water can be decreased as low as -36.8 degrees C. The SPIPS also displays an extremely low ice adhesion strength (0.1 kPa) due to its unique surface characteristics. Moreover, outstanding active thermal deicing property is achieved for these slippery surfaces because of intrinsically photothermal effect of magnetic Fe3O4 nanoparticle. Hence, these results indicate that this kind of multifunctional bioinspired slippery surface, with superb stability, good cost effectiveness, and easy fabrication, can be used as a promising candidate for anti-icing and deicing applications. PMID- 29528663 TI - Naltrexone maintenance fails to alter amphetamine effects on intracranial self stimulation in rats. AB - Pharmacotherapy to treat stimulant use disorders continues to be an unmet medical need. Some evidence supports both the role of opioids in mediating abuse-related amphetamine effects and the potential utility of opioid antagonists as therapeutic candidates for treating amphetamine abuse. This study used intracranial self-stimulation (ICSS) to evaluate effects of exposure to and termination of naltrexone maintenance on rewarding amphetamine effects in an ICSS procedure in rats. Morphine and cocaine were included as positive and negative controls, respectively. Male Sprague-Dawley rats (N = 40) were trained to lever press for electrical brain stimulation to the medial forebrain bundle via an implanted electrode. Rats were then implanted with osmotic pumps delivering naltrexone (0.001 mg/kg/h, SC, 0.01 mg/kg/h, SC, or 0.1 mg/kg/h, SC) or saline for 14 days. Cumulative dose-effect curves were determined for amphetamine (0.032 mg/kg to 0.32 mg/kg), cocaine (1 mg/kg to 10 mg/kg), and morphine (1 mg/kg to 10 mg/kg) during the 2nd week of naltrexone maintenance. Additionally, dose-effect curves for morphine and amphetamine were determined again 24 hr after pump removal. Our results suggest that (a) exposure to and termination of naltrexone maintenance do not affect baseline ICSS responding, (b) naltrexone doses sufficient to antagonize morphine did not alter amphetamine or cocaine effects, and (c) termination of naltrexone treatment produced weak evidence for increased morphine sensitivity but no change in amphetamine effects. Our results do not support naltrexone as a pharmacotherapy for amphetamine and cocaine abuse and also suggest that termination from chronic naltrexone does not increase sensitivity to abuse-related morphine or amphetamine effects in ICSS. (PsycINFO Database Record PMID- 29528664 TI - Relax while you rehabilitate: A pilot study integrating a novel, yoga-based mindfulness group intervention into a residential military brain injury rehabilitation program. AB - OBJECTIVE: This preliminary, pilot study assessed the effectiveness of a group based, mindfulness intervention in a residential, rehabilitation setting with specific focus on assessing participants' self-report of perceived benefit of the intervention on overall health, pain, sleep, mood/anxiety, attention, and self awareness, as well as implementing modifications needed for successful intervention application among a diverse, clinical military population. METHOD/DESIGN: Participants were 19 veterans and active duty service members with a history of traumatic brain injury (TBI; 63% severe) who completed a mindfulness based group intervention during inpatient admission at a Veterans Affairs Polytrauma Transitional Rehabilitation Program (PTRP). Mindfulness and yoga skills were taught in a required, weekly group incorporated into participants' rehabilitation schedule. Opinions and attitudes about mindfulness, as well as pertinent self-report outcome measures, were obtained pre- and postgroup participation. RESULTS: Results suggested that participation in the group was positively associated with individuals' self-reported belief about the benefit of mindfulness in the areas of overall health, physical health, mood, focus, and self-awareness. The more groups attended, the more positive the participants' beliefs about potential impact on overall health and mood became, even while controlling for length of rehabilitation stay. Additionally, several specific group modifications relevant to this population (e.g., physical/environmental modifications, repetition, ignoring/reorienting) were implemented to support successful participation. CONCLUSIONS/IMPLICATIONS: These preliminary and exploratory findings suggest that it may be worthwhile for psychologists, clinicians, and other health care providers working with a mixed TBI population, and more specifically a military population with TBI, to consider introducing mindfulness skills as part of multidisciplinary rehabilitation. (PsycINFO Database Record PMID- 29528665 TI - Norway rats (Rattus norvegicus) communicate need, which elicits donation of food. AB - Reciprocal cooperation has been observed in a wide range of taxa, but the proximate mechanisms underlying the exchange of help are yet unclear. Norway rats reciprocate help received from partners in an iterated Prisoner's Dilemma game. For donors, this involves accepting own costs to the benefit of a partner, without obtaining immediate benefits in return. We studied whether such altruistic acts are conditional on the communication of the recipient's need. Our results show that in a 2-player mutual food-provisioning task, prospective recipients show a behavioral cascade reflecting increasing intensity. First, prospective receivers reach out for the food themselves, then they emit ultrasonic calls toward their partner, before finally showing noisy attention grabbing behaviors. Food-deprived individuals communicate need more intensively than satiated ones. In return, donors provide help corresponding to the intensity of the recipients' communication. This indicates that rats communicate their need, which changes the helping propensity of potential donors. Communication of need and corresponding adjustment of cooperation may be a widespread proximate mechanism explaining the mutual exchange of services between animals. (PsycINFO Database Record PMID- 29528666 TI - Social basis of vocal interactions in western lowland gorillas (Gorilla g. gorilla). AB - Authors have raised the possibility of identifying primitive forms of conversational rules in monkeys: temporally ruled vocal interactions, call overlap avoidance, and socially based calling partner preferences. The question as to how these abilities have evolved in the primate lineage remains open to debate, particularly because studies based on apes are scarce and controversial. We studied a captive group of western lowland gorillas and tested the influence of caller characteristics and the type of bond between calling partners on vocal behavior based on the following: age, dominance, spatial proximity, sociopositive contact, and gaze. Four calling patterns that are call type dependent were identified: vocal interaction with and (more frequently) without call overlap, isolated calling, and repeated calling. Adult calls and grunts (contact calls) were predominant during vocal interactions, and the "response" delay was most often around half a second. The frequency of grunt dyadic exchanges was found to be linked to spatial proximity, gaze exchanges, and age proximity between calling partners. The dominance rank of callers determined the rate of contribution to these exchanges. These results show that some apes use rule-governed call exchanges and that these socially guided vocal interactions are more widespread than previously believed. (PsycINFO Database Record PMID- 29528667 TI - Initial evidence for probabilistic reasoning in a grey parrot (Psittacus erithacus). AB - Research has shown that some forms of inferential reasoning are likely widespread throughout the animal kingdom (e.g., exclusion, in which a subject infers the placement of a reward by eliminating potential alternative sites), but other types of inferential tasks have not been extensively tested. We examined whether a nonhuman might succeed in an experiment based on probabilistic reasoning, specifically, the ability to make inferences about a sample based on information about a population. A Grey parrot (Psittacus erithacus), previously trained to use English labels referentially to identify objects, observed a human researcher deposit 2 different types of items in a 3:1 ratio (e.g., 3 corks and 1 piece of paper) into an opaque bucket. One item was then randomly withdrawn while hidden from the parrot's view. When asked to identify the still-hidden object, the parrot's vocal responses tracked this 3:1 ratio over a large number of trials. Some levels of probabilistic reasoning therefore are not limited to humans, nonhuman primates, or even mammals. (PsycINFO Database Record PMID- 29528668 TI - Risk factors for the transition from suicide ideation to suicide attempt: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). AB - Prior research has shown that most known risk factors for suicide attempts in the general population actually predict suicide ideation rather than attempts among ideators. Yet clinical interest in predicting suicide attempts often involves the evaluation of risk among patients with ideation. We examined a number of characteristics of suicidal thoughts hypothesized to predict incident attempts in a retrospective analysis of lifetime ideators (N = 3,916) drawn from a large (N = 29,982), representative sample of United States Army soldiers. The most powerful predictors of first nonfatal lifetime suicide attempt in a multivariate model controlling for previously known predictors (e.g., demographics, mental disorders) were: recent onset of ideation, presence and recent onset of a suicide plan, low controllability of suicidal thoughts, extreme risk-taking or "tempting fate," and failure to answer questions about the characteristics of one's suicidal thoughts. A predictive model using these risk factors had strong accuracy (area under the curve [AUC] = .93), with 66.2% of all incident suicide attempts occurring among the 5% of soldiers with highest composite predicted risk. This high concentration of risk in this retrospective study suggests that a useful clinical decision support model could be constructed from prospective data to identify those with highest risk of subsequent suicide attempt. (PsycINFO Database Record PMID- 29528669 TI - Neighborhood racial discrimination and the development of major depression. AB - This study examined the impact of neighborhood racial discrimination on the development of major depressive disorder (MDD) in a sample of African American women. Participants were 499 women from Georgia and Iowa with no history of MDD who were followed for 9 to 11 years. Several neighborhood characteristics (community social disorder, community cohesion, and community racism) and individual characteristics (negative life events, financial strain, personal outlook, religious involvement, relationship quality, negative affectivity, and individual experiences of racism) were employed as predictors of whether or not the women met criteria for MDD during this period of time. In a multilevel logistic regression analysis, neighborhood-level discrimination as well as individual-level variables including the number of negative life events, financial strain, and negative affectivity were found to be significant predictors of developing MDD. Analyses of cross-level interactions indicated that the effects of neighborhood-level discrimination were moderated by the quality of individuals' relationships, such that better relationships with others served to lessen the effect of neighborhood discrimination on depression. Implications of these findings for understanding the negative effects of racial discrimination are discussed. (PsycINFO Database Record PMID- 29528671 TI - Network analysis of psychopathy in forensic patients. AB - The question of which features represent the most central components of psychopathy remains unresolved and is the subject of considerable debate. Network analysis, which is a relatively new way to conceptualize mental disorders that emphasizes complex causal systems, provides a means to graphically and quantitatively describe the centrality of the various symptoms of a disorder. We applied association and adaptive LASSO networks on two samples of forensic patients. The first sample included forensic inpatients (N = 277) who were administered the Psychopathy Checklist-Revised (Hare, 2003), and the second sample included patients who previously had been civilly committed (N = 1136), who were administered the Psychopathy Checklist: Screening Version (Hart, Cox, & Hare, 1995). The models indicated the items on the affective facet are highly central across both samples and methods, and the item "lack of remorse" was especially central to the networks. Conversely, interpersonal, lifestyle, and antisocial facets generally resulted in low centrality in the models of both samples. Thus, the models lend support to the importance of affective deficits as the primary feature of psychopathy when psychopathy is assessed using the Hare Psychopathy Checklist measures. (PsycINFO Database Record PMID- 29528670 TI - Dimensions of deprivation and threat, psychopathology, and potential mediators: A multi-year longitudinal analysis. AB - Prior research demonstrates a link between exposure to childhood adversity and psychopathology later in development. However, work on mechanisms linking adversity to psychopathology fails to account for specificity in these pathways across different types of adversity. Here, we test a conceptual model that distinguishes deprivation and threat as distinct forms of childhood adversity with different pathways to psychopathology. Deprivation involves an absence of inputs from the environment, such as cognitive and social stimulation, that influence psychopathology by altering cognitive development, such as verbal abilities. Threat includes experiences involving harm or threat of harm that increase risk for psychopathology through disruptions in social-emotional processing. We test the prediction that deprivation, but not threat, increases risk for psychopathology through altered verbal abilities. Data were drawn from the Child Development Project (N = 585), which followed children for over a decade. We analyze data from assessment points at age 5, 6, 14, and 17 years. Mothers completed interviews at age 5 and 6 on exposure to threat and deprivation experiences. Youth verbal abilities were assessed at age 14. At age 17, mothers reported on child psychopathology. A path analysis model tested longitudinal paths to internalizing and externalizing problems from experiences of deprivation and threat. Consistent with predictions, deprivation was associated with risk for externalizing problems via effects on verbal abilities at age 14. Threat was associated longitudinally with both internalizing and externalizing problems, but these effects were not mediated by verbal abilities. Results suggest that unique developmental mechanisms link different forms of adversity with psychopathology. (PsycINFO Database Record PMID- 29528672 TI - Interpersonal stressors and negative affect in individuals with borderline personality disorder and community adults in daily life: A replication and extension. AB - Affective instability and interpersonal stress are key features of borderline personality disorder (BPD). They were shown to covary in the daily lives of patients in a recent ambulatory assessment study (Hepp et al., 2017) that observed comparatively larger positive associations between interpersonal stressors and negative affect in individuals with BPD than those with depressive disorders. The present study sought to replicate these findings, collecting data on hostility, sadness, fear, and rejection or disagreement events from 56 BPD and 60 community control participants for 21 days, 6 times a day. Using identical statistical procedures, the positive associations between momentary rejection/disagreement and hostility, sadness, and fear were replicated. Again replicating the original study, the rejection-hostility, rejection-sadness, and disagreement-hostility associations were significantly stronger in the BPD group. Time-lagged analyses extended the original study, revealing that rejection was associated with subsequent hostility and sadness more strongly in the BPD group, as was disagreement with subsequent hostility and fear. Though small, we argue that the observed group differences reflect meaningful pervasive responses in a daily life context. Future research should consider these when implementing affect regulation strategies that are applicable in interpersonal contexts for all individuals, but particularly those with BPD. (PsycINFO Database Record PMID- 29528674 TI - Investigating the social costs of schizophrenia: Facial expressions in dyadic interactions of people with and without schizophrenia. AB - People with schizophrenia show marked reductions in their emotional expressiveness, generally known as blunted affect. In this study, we tested whether interaction partners would evaluate community-dwelling participants with schizophrenia less favorably than healthy controls and whether this difference would be explained by reduced smiling behavior related to schizophrenia. We also tested whether deficient affect recognition would predict reduced smiling. We created 3 study groups, consisting of 28 participants each, participants with schizophrenia (SZ), healthy controls (HC), and naive healthy interaction partners (IP). IP engaged in 2 separate same-sex dyadic interactions with matched members of each of the other 2 groups, SZ and HC, in a repeated-measures study design. During the interactions, we assessed the amount of smiling and mimicry of smiling via electromyography. After the interactions, IP rated their willingness for future interactions with SZ and HC, respectively. IP indicated less willingness for future interactions with SZ than with HC participants (d = -0.72) but SZ and HC did not differ with respect to smiling or affect recognition. Better affect recognition predicted more smiling; more smiling predicted more favorable social evaluations. Within SZ participants, disorganization symptoms but no other symptom dimensions were associated with the social evaluations. In conclusion, community-dwelling people with schizophrenia face social challenges that go beyond the adverse effects of stigmatization. Future work needs to clarify the role of different symptom dimensions and behavioral aspects contributing to the interpersonal costs of schizophrenia to derive interventions targeted at social reintegration. (PsycINFO Database Record PMID- 29528673 TI - GABRA2, alcohol, and illicit drug use: An event-level model of genetic risk for polysubstance use. AB - GABRA2, the gene encoding the alpha2 subunit of the GABAA receptor, potentially plays a role in the etiology of problematic drinking, as GABRA2 genotype has been associated with subjective response to alcohol and other alcohol-related reward processes. The GABRA2 gene has also been associated with illicit drug use, but the extent to which associations with drug use are independent of associations with alcohol use remains unclear, partly because most previous research has used a cross-sectional design that cannot discriminate comorbidity at the between person level and co-occurrence within-persons. The present study used a daily monitoring method that assessed the effects of GABRA2 variation on substance use as it occurred in the natural environment during emerging adulthood. Non-Hispanic European participants provided DNA samples and completed daily reports of alcohol and drug use for 1 month per year across 4 years (N = 28,263 unique observations of N = 318 participants). GABRA2 variants were associated with illicit drug use in both sober and intoxicated conditions. Moreover, the effect of GABRA2 variation on drug use was moderated by an individual's degree of intoxication. These findings are consistent with recent genetic and neuroscience research, and they suggest GABRA2 variation influences drug-seeking behavior through both alcohol-related and alcohol-independent pathways. (PsycINFO Database Record PMID- 29528676 TI - Children with autism spectrum disorder show pronoun reversals in interpretation. AB - Pronoun reversals, saying you when meaning I, in children with autism spectrum disorder (ASD) are generally viewed as manifesting in early development and speech production only. This study investigates pronoun reversals in later development (age 6-12) in interpretation in 48 Dutch-speaking children with ASD and 43 typically developing (TD) peers. We contrasted children's interpretation of I and you in indirect and direct speech reports, with the latter type requiring an additional perspective shift. To examine which cognitive processes are involved in pronoun interpretation, additional tasks were administered to measure Theory of Mind (ToM) understanding, cognitive inhibition, cognitive flexibility, and working memory. We found that children with ASD showed more problems than TD children interpreting pronouns in direct speech, resulting in pronoun reversals in interpretation. Children with ASD hardly improved with age. Older children with ASD thus showed more pronoun reversals than did their TD peers. ToM understanding, working memory, IQ, and verbal ability, but not inhibition and flexibility, were associated with pronoun interpretation. ToM understanding in particular was associated with correct pronoun interpretation in older TD children relative to younger TD children, but this improvement was not found in children with ASD. These findings indicate that pronoun reversals most likely result from perspective-shifting difficulties. We conclude that pronoun reversals are more pronounced in individuals with ASD, occur beyond early development, and require sufficient cognitive resources. The relation with ToM understanding, but not inhibition and flexibility, suggests that pronoun reversals are best classified as a social communication problem in the diagnosis of ASD. (PsycINFO Database Record PMID- 29528675 TI - Cognition and community functioning in schizophrenia: The nature of the relationship. AB - Although cognition is one of the most important predictors of community functioning in schizophrenia, little is known about the causes of this correlation. To our knowledge, this study is the first to examine the extent to which this correlation is genetically mediated and whether the genetic correlation is specific to schizophrenia. Six hundred thirty-six participants from 43 multigenerational families with at least two relatives with schizophrenia and 135 unrelated controls underwent diagnostic interview and cognition and functioning assessment. Quantitative genetic analyses were conducted using maximum-likelihood variance decomposition methods implemented in SOLAR (Almasy & Blangero, 1998). Among patients with schizophrenia, cognition and community functioning were positively correlated and genetic effects shared between them were significant contributors to this relationship whereas environmental effects shared between them were not. In contrast, genetic effects were not shared significantly between cognition in depressed or nondiagnosed relatives and community functioning in schizophrenia. In all analyses, the contributions of social cognition to community functioning were accounted for by general cognition. These findings support heritable factors that contribute to the correlation between cognition and community functioning that are relatively specific to schizophrenia and are not significantly shared with depression or a lack of psychopathology. This suggests the possibility of identifying specific genetic variants that contribute to this correlation and to these important individual differences among schizophrenia patients. (PsycINFO Database Record PMID- 29528677 TI - Perinatal testosterone contributes to mid-to-post pubertal sex differences in risk for binge eating in male and female rats. AB - Exposure to testosterone early in life may contribute to sex differences and pubertal changes in risk for eating pathology (i.e., females > males, after pubertal onset). Specifically, perinatal testosterone permanently alters brain structure/function and drives the masculinization of several sex-differentiated behaviors. However, the effects of perinatal testosterone are often not evident until puberty when increases in gonadal hormones activate the expression of sex typical behavior, including eating behaviors (e.g., chow intake; saccharin preference) in rodents. Despite perinatal testosterone's masculinizing effects on general feeding behavior, it remains unknown if perinatal testosterone exposure contributes to sex differences in pathological eating. The current study addressed this gap by examining whether perinatal testosterone exposure decreases risk for binge eating proneness after pubertal onset in male and female rats. Sprague-Dawley rats (n = 40 oil-treated control females; n = 39 testosterone treated females; n = 40 oil-treated control males) were followed longitudinally across pre-to-early puberty, mid-to-late puberty, and adulthood. The binge eating prone (BEP)/binge eating resistant (BER) rodent model was used to identify individual differences in binge eating proneness across the dimensional spectrum. As expected, testosterone-treated females and control males showed masculinized (i.e., lower) risk for binge eating as compared to control females, but only after midpuberty. These animal data are significant in suggesting that perinatal testosterone exposure may protect against binge eating and underlie sex differences in binge eating prevalence during and after puberty. (PsycINFO Database Record PMID- 29528679 TI - Mapping self-face recognition strategies in congenital prosopagnosia. AB - OBJECTIVE: Recent evidence showed that individuals with congenital face processing impairment (congenital prosopagnosia [CP]) are highly accurate when they have to recognize their own face (self-face advantage) in an implicit matching task, with a preference for the right-half of the self-face (right perceptual bias). Yet the perceptual strategies underlying this advantage are unclear. Here, we aimed to verify whether both the self-face advantage and the right perceptual bias emerge in an explicit task, and whether those effects are linked to a different scanning strategy between the self-face and unfamiliar faces. METHOD: Eye movements were recorded from 7 CPs and 13 controls, during a self/other discrimination task of stimuli depicting the self-face and another unfamiliar face, presented upright and inverted. RESULTS: Individuals with CP and controls differed significantly in how they explored faces. In particular, compared with controls, CPs used a distinct eye movement sampling strategy for processing inverted faces, by deploying significantly more fixations toward the nose and mouth areas, which resulted in more efficient recognition. Moreover, the results confirmed the presence of a self-face advantage in both groups, but the eye movement analyses failed to reveal any differences in the exploration of the self-face compared with the unfamiliar face. Finally, no bias toward the right half of the self-face was found. CONCLUSIONS: Our data suggest that the self-face advantage emerges both in implicit and explicit recognition tasks in CPs as much as in good recognizers, and it is not linked to any specific visual exploration strategies. (PsycINFO Database Record PMID- 29528678 TI - Network analysis of pediatric eating disorder symptoms in a treatment-seeking, transdiagnostic sample. AB - Classifying eating disorders in youth is challenging in light of developmental considerations and high rates of diagnostic migration. Understanding the transactional relationships among eating disorder symptoms, both across the transdiagnostic spectrum and within specific diagnostic categories, may clarify which core eating disorder symptoms contribute to, and maintain, eating-related psychopathology in youth. We utilized network analysis to investigate interrelationships among eating disorder symptoms in 636 treatment-seeking children and adolescents (90.3% female) ages 6-18 years (M age = 15.4 +/- 2.2). An undirected, weighted network of eating disorder symptoms was created using behavioral and attitudinal items from the Eating Disorder Examination. Across diagnostic groups, symptoms reflecting appearance-related concerns (e.g., dissatisfaction with shape and weight) and dietary restraint (e.g., a desire to have an empty stomach) were most strongly associated with other eating disorder symptoms in the network. Binge eating and compensatory behaviors (e.g., self induced vomiting) were strongly connected to one another but not to other symptoms in the network. Network connectivity was similar across anorexia nervosa, bulimia nervosa, and otherwise specified feeding or eating disorder subgroups. Among treatment-seeking children and adolescents, dietary restraint and shape- and weight-related concerns appear to play key roles in the psychopathology of eating disorders, supporting cognitive-behavioral theories of onset and maintenance. Similarities across diagnostic categories provide support for a transdiagnostic classification scheme. Clinical interventions should seek to disrupt these symptoms early in treatment to achieve maximal outcomes. (PsycINFO Database Record PMID- 29528680 TI - Reading in developmental prosopagnosia: Evidence for a dissociation between word and face recognition. AB - OBJECTIVE: Recent models suggest that face and word recognition may rely on overlapping cognitive processes and neural regions. In support of this notion, face recognition deficits have been demonstrated in developmental dyslexia. Here we test whether the opposite association can also be found, that is, impaired reading in developmental prosopagnosia. METHOD: We tested 10 adults with developmental prosopagnosia and 20 matched controls. All participants completed the Cambridge Face Memory Test, the Cambridge Face Perception test and a Face recognition questionnaire used to quantify everyday face recognition experience. Reading was measured in four experimental tasks, testing different levels of letter, word, and text reading: (a) single word reading with words of varying length,(b) vocal response times in single letter and short word naming, (c) recognition of single letters and short words at brief exposure durations (targeting the word superiority effect), and d) text reading. RESULTS: Participants with developmental prosopagnosia performed strikingly similar to controls across the four reading tasks. Formal analysis revealed a significant dissociation between word and face recognition, as the difference in performance with faces and words was significantly greater for participants with developmental prosopagnosia than for controls. CONCLUSIONS: Adult developmental prosopagnosics read as quickly and fluently as controls, while they are seemingly unable to learn efficient strategies for recognizing faces. We suggest that this is due to the differing demands that face and word recognition put on the perceptual system. (PsycINFO Database Record PMID- 29528681 TI - Sleep disturbances and internalizing behavior problems following pediatric traumatic injury. AB - OBJECTIVE: This prospective longitudinal study investigated sleep disturbance (SD) and internalizing problems after traumatic injury, including traumatic brain injury (TBI) or extracranial/bodily injury (EI) in children and adolescents, relative to typically developing (TD) children. We also examined longitudinal relations between SD and internalizing problems postinjury. METHOD: Participants (N = 87) ages 8-15 included youth with TBI, EI, and TD children. Injury groups were recruited from a Level 1 trauma center after sustaining vehicle-related injuries. Parent-reported SD and internalizing problems were assessed at preinjury/baseline, and 6 and 12 months postinjury. Linear mixed models evaluated the relation of group and time of assessment on outcomes. RESULTS: Controlling for age, the combined traumatic injury group experienced significantly higher postinjury levels of SD (p = .042) and internalizing problems (p = .024) than TD children; however, TBI and EI injury groups did not differ from each other. Injury severity was positively associated with SD in the EI group only, but in both groups SD was associated with additional postinjury sequelae, including fatigue and externalizing behavior problems. Internalizing problems predicted subsequent development of SD but not vice versa. The relation between injury and SD 1 year later was consistent with mediation by internalizing problems at 6 months postinjury. CONCLUSIONS: Children with both types of traumatic injury demonstrated higher SD and internalizing problems than healthy children. Internalizing problems occurring either prior to or following pediatric injury may be a risk factor for posttraumatic SD. Consequently, internalizing problems may be a promising target of intervention to improve both SD and related adjustment concerns. (PsycINFO Database Record PMID- 29528683 TI - Conceptual size in developmental dyscalculia and dyslexia. AB - OBJECTIVE: People suffering from developmental dyscalculia (DD) are known to have impairment in numerical abilities and have been found to have weaker processing of countable magnitudes. However, not much research was done on their abilities to process noncountable magnitudes. An example of noncountable magnitude is conceptual size (e.g., mouse is small and elephant is big). Recently, we found that adults process conceptual size automatically. The current study examined automatic processing of conceptual size in students with DD and developmental dyslexia. METHOD: Conceptual and physical sizes were manipulated orthogonally to create congruent (e.g., a physically small apple compared to a physically large violin) and incongruent (e.g., a physically large apple compared to a physically small violin) conditions. Participants were presented with 2 objects and had to choose the larger one. Each trial began with an instruction to respond to the physical or to the conceptual dimension. RESULTS: Control and the dyslexic groups presented automatic processing of both conceptual and physical sizes. The dyscalculic group presented automatic processing of physical size but not automaticity of processing conceptual size. CONCLUSION: Our results fit with previous findings of weaker magnitude representation in those with DD, specifically regarding noncountable magnitudes, and support theories of a shared neurocognitive substrate for different types of magnitudes. (PsycINFO Database Record PMID- 29528682 TI - A framework for executive function in the late elementary years. AB - OBJECTIVE: Executive function (EF) is a commonly used but difficult to operationalize construct. In this study, we considered EF and related components as they are commonly presented in the neuropsychological literature, as well as the literatures of developmental, educational, and cognitive psychology. These components have not previously been examined simultaneously, particularly with this level of comprehensiveness, and/or at this age range or with this sample size. We expected that the EF components would be separate but related, and that a bifactor model would best represent the data relative to alternative models. METHOD: We assessed EF with 27 measures in a large sample (N = 846) of late elementary school-age children, many of whom were struggling in reading, and who were demographically diverse. We tested structural models of EF, from unitary models to methodological models, utilizing model-comparison factor analytic techniques. We examined both a common factor as well as a bifactor structure. RESULTS: Initial models showed strong overlap among several latent EF variables. The final model was a bifactor model with a common EF, and five specific EF factors (working memory-span/manipulation and planning; working memory-updating; generative fluency, self-regulated learning; metacognition). CONCLUSIONS: Results speak to the commonality and potential separability of EF. These results are discussed in light of prevailing models of EF and how EF might be used for structure/description, prediction, and for identifying its mechanism for relevant outcomes. (PsycINFO Database Record PMID- 29528685 TI - Intergenerational contacts and depressive symptoms among older parents in Eastern Europe. AB - OBJECTIVE: We investigate the association between parent-child contact frequency and changes in older parents' depressive symptoms in Bulgaria, Georgia and Russia. These are countries in which societal transformations may mean that psychological feelings of security engendered by having children in close contact may have particularly important implications for the mental health of older parents. METHODS: We analysed data from two waves of the Generation and Gender Surveys conducted three years apart and took account of relationships with more than one child. Analyses were performed using OLS regression models, adjusted for depressive symptoms at baseline. RESULTS: Among mothers increases in depressive symptoms were greater for those who lacked at least weekly contact with any child than for those with frequent contact with at least one child (b = 0.64; p<0.01). Increases in depressive symptoms were associated with infrequent contacts with children, even after controlling for relationship quality (b = 0.55; p<0.05). Among unpartnered fathers, less than weekly meetings with children were associated with increases in depressive symptoms. CONCLUSIONS: Among mothers and unpartnered fathers changes in depressive symptoms varied by parent-child contact. The adverse effect of not having a partner on fathers' mental health was reduced, but not eliminated, by having frequent contacts with adult children. PMID- 29528684 TI - Word-list intrusion errors predict progression to mild cognitive impairment. AB - OBJECTIVE: Preclinical Alzheimer's disease (AD) defined by a positive AD biomarker in the presence of normal cognition is presumed to precede mild cognitive impairment (MCI). Subtle cognitive deficits and cognitive inefficiencies in preclinical AD may be detected through process and error scores on neuropsychological tests in those at risk for progression to MCI. METHOD: Cognitively normal participants (n = 525) from the Alzheimer's Disease Neuroimaging Initiative were followed for up to 5 years and classified as either stable normal (n = 305) or progressed to MCI (n = 220). Cox regressions were used to determine whether baseline process scores on the Rey Auditory Verbal Learning Test (AVLT; intrusion errors, learning slope, proactive interference, retroactive interference) predicted progression to MCI and a Clinical Dementia Rating (CDR) score of 1 after considering demographic characteristics, apolipoprotein E epsilon4 status, cerebrospinal fluid AD biomarkers, ischemia risk, mood, functional difficulty, and standard neuropsychological total test scores for the model. RESULTS: Baseline AVLT intrusion errors predicted progression to MCI (hazard ratio = 1.04, 95% confidence interval 1.01-1.07, p = .008) and improved model fit after the other valuable predictors were already in the model, chi2(df = 1) = 6.330, p = .012. AVLT intrusion errors also predicted progression to CDR = 1 (hazard ratio = 1.10, 95% confidence interval 1.02-1.18, p = .016) and again improved model fit, chi2(df = 1) = 4.682, p = .030. CONCLUSIONS: Intrusion errors on the AVLT contribute unique value for predicting progression from normal cognition to MCI and normal cognition to mild dementia (CDR = 1). Intrusion errors appear to reflect subtle change and inefficiencies in cognition that precede impairment detected by neuropsychological total scores. (PsycINFO Database Record PMID- 29528687 TI - Peak Lower Extremity Landing Kinematics in Dancers and Nondancers. AB - CONTEXT: Anterior cruciate ligament (ACL) injuries often occur during jump landings and can have detrimental short-term and long-term functional effects on quality of life. Despite frequently performing jump landings, dancers have lower incidence rates of ACL injury than other jump-landing athletes. Planned versus unplanned activities and footwear may explain differing ACL-injury rates among dancers and nondancers. Still, few researchers have compared landing biomechanics between dancers and nondancers. OBJECTIVE: To compare the landing biomechanics of dancers and nondancers during single-legged (SL) drop-vertical jumps. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 39 healthy participants, 12 female dancers (age = 20.9 +/- 1.8 years, height = 166.4 +/- 6.7 cm, mass = 63.2 +/- 16.4 kg), 14 female nondancers (age = 20.2 +/- 0.9 years, height = 168.9 +/- 5.0 cm, mass = 61.6 +/- 7.7 kg), and 13 male nondancers (age = 22.2 +/- 2.7 years, height = 180.6 +/- 9.7 cm, mass = 80.8 +/- 13.2 kg). INTERVENTION(S): Participants performed SL-drop-vertical jumps from a 30-cm-high box in a randomized order in 2 activity (planned, unplanned) and 2 footwear (shod, barefoot) conditions while a 3-dimensional system recorded landing biomechanics. MAIN OUTCOME MEASURE(S): Overall peak sagittal-plane and frontal-plane ankle-, knee-, and hip-joint kinematics (joint angles) were compared across groups using separate multivariate analyses of variance followed by main-effects testing and pairwise-adjusted Bonferroni comparisons as appropriate ( P < .05). RESULTS: No 3-way interactions existed for sagittal plane or frontal-plane ankle (Wilks lambda = 0.85, P = .11 and Wilks lambda = 0.96, P = .55, respectively), knee (Wilks lambda = 1.00, P = .93 and Wilks lambda = 0.94, P = .36, respectively), or hip (Wilks lambda = 0.99, P = .88 and Wilks lambda = 0.97, P = .62, respectively) kinematics. We observed no group * footwear interactions for sagittal-plane or frontal-plane ankle (Wilks lambda = 0.94, P = .43 and Wilks lambda = 0.96, P = .55, respectively), knee (Wilks lambda = 0.97, P = .60 and Wilks lambda = 0.97, P = .66, respectively), or hip (Wilks lambda = 0.99, P = .91 and Wilks lambda = 1.00, P = .93, respectively) kinematics, and no group * activity interactions were noted for ankle frontal-plane (Wilks lambda = 0.92, P = .29) and sagittal- and frontal-plane knee (Wilks lambda = 0.99, P = .81 and Wilks lambda = 0.98, P = .77, respectively) and hip (Wilks lambda = 0.88, P = .13 and Wilks lambda = 0.85, P = .08, respectively) kinematics. A group * activity interaction (Wilks lambda = 0.76, P = .02) was present for ankle sagittal-plane kinematics. Main-effects testing revealed different ankle frontal plane angles across groups ( F2,28 = 3.78, P = .04), with male nondancers having greater ankle inversion than female nondancers ( P = .05). CONCLUSIONS: Irrespective of activity type or footwear, female nondancers landed with similar hip and knee kinematics but greater peak ankle eversion and less peak ankle dorsiflexion (ie, positions associated with greater ACL injury risk). Ankle kinematics may differ between groups due to different landing strategies and training used by dancers. Dancers' training should be examined to determine if it results in a reduced occurrence of biomechanics related to ACL injury during SL landing. PMID- 29528688 TI - Second malignancy versus recurrence after complete resection of thymoma. AB - Background Patients undergoing complete resection of thymoma occasionally develop a recurrence of thymoma; they are also at risk of developing a second malignancy. The objective of our study was to compare the incidence and mortality of a second malignancy versus a recurrence of thymoma during the postoperative follow-up period after complete resection of thymoma. Methods A retrospective chart review was performed on our prospectively maintained database to identify patients undergoing complete resection of thymoma at our institution between 1991 and 2016. The incidence and related mortality of a second malignancy or recurrence of thymoma were recorded. Results One hundred and sixty-four patients were identified. Follow-up ranged from 1 to 239 months (median 54 months). During follow-up, 12 patients had a recurrence of thymoma and 14 developed a second malignancy. The mean risk ratio of recurrence to second malignancy was 0.58 (95% confidence interval: 0.48-0.69) at 5 years, 0.58 (95% confidence interval: 0.49 0.68) at 10 years, and 0.51 (95% confidence interval: 0.43-0.60) at 15 years. The mean risk ratio of recurrence versus second malignancy for related death was 0.59 (95% confidence interval: 0.50-0.70) at 5 years and 0.61 (95% confidence interval: 0.52-0.72) at 10 years. Conclusion It appears that patients undergoing complete resection of thymoma have a higher incidence of a second malignancy and a greater related mortality rate than a recurrence of thymoma. A multiinstitutional database is required to more rigorously evaluate both risks and to confirm our results. PMID- 29528686 TI - Synthetic Biology Approaches to Engineer Probiotics and Members of the Human Microbiota for Biomedical Applications. AB - An increasing number of studies have strongly correlated the composition of the human microbiota with many human health conditions and, in several cases, have shown that manipulating the microbiota directly affects health. These insights have generated significant interest in engineering indigenous microbiota community members and nonresident probiotic bacteria as biotic diagnostics and therapeutics that can probe and improve human health. In this review, we discuss recent advances in synthetic biology to engineer commensal and probiotic lactic acid bacteria, bifidobacteria, and Bacteroides for these purposes, and we provide our perspective on the future potential of these technologies. PMID- 29528689 TI - A cost effectiveness analysis of maintenance cognitive stimulation therapy (MCST) for people with dementia: examining the influence of cognitive ability and living arrangements. AB - OBJECTIVES: Identify if cost-effectiveness of Maintenance Cognitive Simulation Therapy (MCST) differs by type of living arrangement and cognitive ability of the person with dementia. Next, a value of information analysis is performed to inform decisions about future research. METHODS: Incremental cost-effectiveness analysis applying seemingly unrelated regressions using data from a multicentre RCT of MCST versus treatment as usual in a population which had already received 7 weeks of CST for dementia (ISRCTN: 26286067). The findings from the cost effectiveness analysis are used to inform a value of information analysis. RESULTS: The results are dependent upon how quality adjusted life years (QALYs) are measured. MCST might be cost-effective compared to standard treatment for those who live alone and those with higher levels of cognitive functioning. If a further RCT was to be conducted for this sub-group of the population, value of information analysis suggests a total sample of 48 complete cases for both sub groups would be required for a two-arm trial. The expected net gain of conducting this future research is L920 million. CONCLUSION: Preliminary results suggest that MCST may be most cost-efficient for people with dementia who live alone and/or who have higher cognition. Future research in this area is needed. PMID- 29528690 TI - White matter hyperintensities and headache: A population-based imaging study (HUNT MRI). AB - OBJECTIVE: To examine the relationship between white matter hyperintensities and headache. METHODS: White matter hyperintensities burden was assessed semi quantitatively using Fazekas and Scheltens scales, and by manual and automated volumetry of MRI in a sub-study of the general population-based Nord-Trondelag Health Study (HUNT MRI). Using validated questionnaires, participants were categorized into four cross-sectional headache groups: Headache-free (n = 551), tension-type headache (n = 94), migraine (n = 91), and unclassified headache (n = 126). Prospective questionnaire data was used to further categorize participants into groups according to the evolution of headache during the last 12 years: Stable headache-free, past headache, new onset headache, and persistent headache. White matter hyperintensities burden was compared across headache groups using adjusted multivariate regression models. RESULTS: Individuals with tension-type headache were more likely to have extensive white matter hyperintensities than headache-free subjects, with this being the case across all methods of white matter hyperintensities assessment (Scheltens scale: Odds ratio, 2.46; 95% CI, 1.44-4.20). Migraine or unclassified headache did not influence the odds of having extensive white matter hyperintensities. Those with new onset headache were more likely to have extensive white matter hyperintensities than those who were stable headache-free (Scheltens scale: Odds ratio, 2.24; 95% CI, 1.13-4.44). CONCLUSIONS: Having tension-type headache or developing headache in middle age was linked to extensive white matter hyperintensities. These results were similar across all methods of assessing white matter hyperintensities. If white matter hyperintensities treatment strategies emerge in the future, this association should be taken into consideration. PMID- 29528691 TI - Testing the diagnostic criteria of tension-type headache. PMID- 29528692 TI - Effects of nerve growth factor experimentally-induced craniofacial muscle sensitization on referred pain frequency and number of headache days: A double blind, randomized placebo-controlled study. AB - OBJECTIVE: To assess if repeated intramuscular injections of nerve growth factor into the temporalis and masseter muscles increase mechanical sensitivity and entropy scores. Furthermore, to investigate if increased mechanical sensitivity would lead to increased prevalence of referred pain in the studied individuals. Finally, if increased muscle sensitization would lead to an increase in number of headache days during the experimental period. METHODS: The present double-blind, randomized placebo-controlled study recruited 16 healthy participants who were injected with nerve growth-factor, on 2 days, into the masseter and temporalis muscles and isotonic saline on the contralateral side. Mechanical sensitivity was assessed at seven different time-points (total of 21 days) by application of three different forces to 15 different sites of both muscles. Participants were asked after each force application if they experienced referred pain and were asked to keep a headache diary during the experimental period. RESULTS: In summary, a) repeated intramuscular injections of nerve-growth-factor caused an increase in mechanical sensitivity for the masseter but not the temporalis muscle, and an increase in entropy scores when compared to the isotonic saline side. b) Both referred pain frequency and number of headache days were not increased following nerve-growth-factor injections. CONCLUSIONS: These findings support the idea that mechanical sensitization in the masseter and temporalis muscles differs following injections of nerve growth factor. Furthermore, referred pain and headache frequency do not seem to be related to nerve growth factor sensitization in this model. These findings support the idea that in healthy individuals referred pain may be an epiphenomenon of the muscle in response to noxious input. PMID- 29528693 TI - Interaction between memory impairment and depressive symptoms can exacerbate anosognosia: a comparison of Alzheimer's disease with mild cognitive impairment. AB - OBJECTIVE: To investigate the effects of interactions between memory impairment, depressive symptoms, and anosognosia. METHODS: Anosognosia for memory impairment was assessed in 118 patients with Alzheimer's disease (AD), 47 patients with mild cognitive impairment (MCI), and 17 non-diagnosed controls (NC) using a questionnaire and evaluation of the anosognosia score as the discrepancy between ratings of the patient and a relative. Demographic characteristics, such as the relationship of the patient with the relative and the activities of daily living (ADL) were evaluated. Memory impairment was evaluated with the Rivermead Behavioral Memory Test (RBMT), depressive symptoms were evaluated using the Geriatric Depression Scale (GDS) 15 items version. RESULTS: In the MCI group, a stepwise multiple regression analysis showed an interaction between RBMT and GDS scores, and simple slope analysis indicated that scores for RBMT at low GDS (-1 standard deviation) were positively correlated with self-rated memory impairment. In the AD group, the relationship of the patient with the relative, ADL, and GDS and RBMT scores were associated with the anosognosia score. CONCLUSION: Patients with MCI who have no depressive symptoms may be able to more accurately evaluate their memory impairment than those who have depressive symptoms and patients with AD. The evaluation by relatives, depressive symptoms or ADL of patients may distort evaluation of anosognosia for memory impairment in patients with AD or MCI. It seems necessary to include not only depression scale scores but also results of objective memory tests in the patients' medical information for the correct assessment of anosognosia. PMID- 29528694 TI - Outcomes of Surgical Treatment for Anterior Tibial Stress Fractures in Athletes: A Systematic Review. AB - BACKGROUND: Although most anterior tibial stress fractures heal with nonoperative treatment, some may require surgical management. To our knowledge, no systematic review has been conducted regarding surgical treatment strategies for the management of chronic anterior tibial stress fractures from which general conclusions can be drawn regarding optimal treatment in high-performance athletes. PURPOSE: This systematic review was conducted to evaluate the surgical outcomes of anterior tibial stress fractures in high-performance athletes. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: In February 2017, a systematic review of the PubMed, MEDLINE, Cochrane, SPORTDiscus, and CINAHL databases was performed to identify studies that reported surgical outcomes for anterior tibial stress fractures. Articles meeting the inclusion criteria were screened, and reported outcome measures were documented. RESULTS: A total of 12 studies, published between 1984 and 2015, reporting outcomes for the surgical treatment of anterior tibial stress fractures were included in this review. All studies were retrospective case series. Collectively, surgical outcomes for 115 patients (74 males; 41 females) with 123 fractures were evaluated in this review. The overall mean follow-up was 23.3 months. The most common surgical treatment method reported in the literature was compression plating (n = 52) followed by drilling (n = 33). Symptom resolution was achieved in 108 of 123 surgically treated fractures (87.8%). There were 32 reports of complications, resulting in an overall complication rate of 27.8%. Subsequent tibial fractures were reported in 8 patients (7.0%). Moreover, a total of 17 patients (14.8%) underwent a subsequent procedure after their initial surgery. Following surgical treatment for anterior tibial stress fracture, 94.7% of patients were able to return to sports. CONCLUSION: The available literature indicates that surgical treatment of anterior tibial stress fractures is associated with a high rate of symptom resolution and return to play in athletes, although the high complication rate and potential need for subsequent procedures are important considerations for surgeons and patients. PMID- 29528695 TI - Evaluating Tau-U With Oral Reading Fluency Data and the Impact of Measurement Error. AB - Recently, researchers have argued that using quantitative effect sizes in single case design (SCD) research may facilitate the identification evidence-based practices. Indices to quantify nonoverlap are among the most common methods for quantifying treatment effects in SCD research. Tau-U represents a family of effect size indices that were developed to address criticisms of previously developed measures of nonoverlap. However, more research is necessary to determine the extent to which Tau-U successfully addresses proposed limitations of other nonoverlap methods. This study evaluated Tau-U effect sizes, derived from multiple-baseline designs, where researchers used curriculum-based measures of reading (CBM-R) to measure reading fluency. Specifically, we evaluated the distribution of the summary Tau-U statistic when applied to a large set of CBM-R data and assessed how the variability inherent in CBM-R data may influence the obtained Tau-U values. Findings suggest that the summary Tau-U statistic may be susceptible to ceiling effects. Moreover, the results provide initial evidence that error inherent in CBM-R scores may have a small but meaningful influence on the obtained effect sizes. Implications and recommendations for research and practice are discussed. PMID- 29528697 TI - Energy Expenditure May Explain Why Coffee Drinkers Have Lower Mortality. PMID- 29528696 TI - The Responsible Inclusion of Students Receiving Special Education Services for Emotional Disturbance: Unraveling the Practice to Research Gap. AB - The majority of students receiving special education services for emotional disturbance (ED) receive a significant amount of instruction in general education classrooms, which emphasizes curriculums based on college and career readiness standards. In turn, those teachers who provide instruction to students with ED in inclusive settings are responsible for using evidence-based practices (EBPs) for those teaching situations in which they exist to meet free appropriate public education (FAPE) mandates. However, the identification of EBPs is a necessary pre condition to eventual school adoption and teacher use of such practices. In this investigation, we completed a synthesis of syntheses to (a) determine the degree to which academic intervention research has focused on students with ED in general education classrooms and (b) identify practices that are effective at improving the academic performance of students with ED in these settings. Overall, few studies were identified. Of those studies identified, half did not disaggregate outcomes for students with ED. A quality indicator coding based on the What Works Clearinghouse (WWC) design standards revealed that no studies with disaggregated outcomes permitted causal inferences. Implications for school practice and areas for future research are discussed. PMID- 29528698 TI - Opioids in Cardiovascular Disease: Therapeutic Options. AB - The World Health Organization suggests that the cardiovascular diseases (CVDs) are the major cause of mortality and account for two-thirds of the deaths all over the world. These diseases kill about 17 million people every year and 3 in every 10 deaths are due to these diseases. The past decade has seen considerable improvements in diagnosis as well as treatment of various heart diseases. Various new therapeutic targets are being identified through in-depth knowledge of the disease mechanisms which has favored the testing of new strategies leading to newer treatment options. Opioid peptides and G-protein-coupled opioid receptors (ORs) have been previously studied widely in terms of central nervous system actions in mitigating the pain and drug abuse. The OR agonism or antagonism induces cytoprotective states in the myocardium, rendering these receptors as an attractive target for protection of heart from the fatal heart diseases. The opioids can provide an extended window of protection of the heart from various diseases. Although the mechanisms may not be fully understood, they seem to play a crucial role in various CVDs such as hypertension, hyperlipidemia, ischemic heart disease myocardial ischemia, and congestive heart failure. Since these compounds are already being used in acute and chronic pain, soon these compounds might be approved for use as cardioprotective agents. The following review focuses on the new information acquired on the role of the ORs in various CVDs. PMID- 29528699 TI - Idaho's Actions Continue Challenges For ACA. AB - The Trump administration proposed liberalizing rules governing non-ACA-compliant, short-term coverage; responding to state guidance, Blue Cross of Idaho filed health plans not meeting ACA requirements. PMID- 29528700 TI - Going back to school - An opportunity for lifelong learning for people with dementia in Denmark (Innovative practice). AB - The provision of lifelong learning for older people is often promoted as a way of engaging socially and maintaining cognitive function. The concept is also used with people with dementia, but is often limited to short-term programmes. Innovative practice from Denmark takes this concept further, offering people with early stage dementia the opportunity to return to school to attend classes in cognitive training, music, art and woodcraft. A pilot study conducted by the school of teaching and communication (Voksenskolen For Undervisning og Kommunikation) offers evidence for the benefits of prolonged educational programmes for people with dementia in maintaining decision-making, cognitive function and social interactions, with limited evidence of the impact on memory. Further evidence is required to understand the impact of a person with dementia attending school as a student and to understand if this concept is transferrable to a different cultural setting. PMID- 29528701 TI - Deep brain stimulation for people with Alzheimer's disease: Anticipating potential effects on the tripartite self. AB - Memory dysfunction and cognitive impairments due to Alzheimer's disease can affect the selfhood and identity of afflicted individuals, causing distress to both people with Alzheimer's disease and their caregivers. Recently, a number of case studies and clinical trials have been conducted to determine the potential of deep brain stimulation as a therapeutic modality for people with Alzheimer's disease. Some of these studies have shown that deep brain stimulation could induce flashbacks and stabilize or even improve memory. However, deep brain stimulation itself has also been attributed as a potential threat to identity and selfhood, especially when procedure-related adverse events arise. We anticipate potential effects of deep brain stimulation for people with Alzheimer's disease on selfhood, reconciling information from medical reports, psychological, and sociological investigations on the impacts of deep brain stimulation or Alzheimer's disease on selfhood. A tripartite model of the self that extends the scope of Rom Harre's and Steve Sabat's social constructionist framework was used. In this model, potential effects of deep brain stimulation for Alzheimer's disease on Self 1 or singularity through use of first-person indexicals, and gestures of self-reference, attribution, and recognition; Self 2 or past and present attributes, knowledge of these characteristics, and continuity of narrative identity; and Self 3 or the relational and social self are explored. The ethical implications of potential effects of deep brain stimulation for Alzheimer's disease on the tripartite self are then highlighted, focusing on adapting informed consent procedures and care provided throughout the trial to account for both positive and negative plausible effects on Self 1, Self 2, and Self 3. PMID- 29528702 TI - Moderating Effect of Motor Proficiency on the Relationship Between ADHD Symptoms and Sleep Problems in Children With Attention Deficit Hyperactivity Disorder Combined Type. AB - OBJECTIVES/BACKGROUND: A high proportion of children with Attention Deficit Hyperactivity Disorder- Combined type (ADHD-CT) experience sleep and motor problems. This study investigated (a) whether motor proficiency moderated the relationship between ADHD symptoms and sleep problems in children with and without ADHD-CT and (b) whether this moderation differed as a function of ADHD diagnosis. PARTICIPANTS: A sample of 70 primary school male children between 8-15 years were recruited; children with ADHD-CT (n = 38; mean age 10 years, 2 months [SD = 1 year, 6 months]) and a typically developing (TD) (n = 32; mean age 9 years, 6 months [SD = 1 year, 5 months]) group. METHODS: Motor proficiency was measured using the Movement Assessment Battery for Children-2nd Edition (MABC-2), ADHD symptoms were measured using the Conners' Parent Rating Scale (CPRS) and parent reported sleep problems were measured using the Children's Sleep Habits Questionnaire (CSHQ). RESULTS: Children who reported higher ADHD symptoms and lower motor proficiency scores reported more sleep problems. The moderation effect only held in children with a diagnosis of ADHD-CT and not in the typically developing group. CONCLUSIONS: These findings indicate that children who experience greater severity of ADHD symptoms who also have lower motor proficiency may be at increased risk of experiencing sleep problems. These findings also illustrate the importance of considering motor proficiency when exploring risk factors for sleep problems in children with ADHD-CT as well as sleep interventions. PMID- 29528703 TI - Prognostic Significance of the Prognostic Nutritional Index in Patients with Recurrent Esophageal Squamous Cell Carcinoma. AB - The aim of this study was to evaluate the prognostic impact of the prognostic nutritional index (PNI) in patients with recurrent esophageal squamous cell carcinoma (ESCC). We retrospectively reviewed 76 ESCC patients who developed recurrence after curative subtotal esophagectomy at Nara Medical University Hospital between January 2001 and October 2016. The PNI at ESCC recurrence was calculated as 10 * serum albumin (g/dl) + 0.005 * total lymphocyte count (/mm3). The cutoff value of the PNI was set at 45. Multivariate analysis was performed to identify the prognostic factors. The mean PNI was 44.0 +/- 5.8, and 42 (55.3%) patients had a PNI <45 at recurrence. The multivariate analysis identified a low PNI (P = 0.047), multiple recurrence sites (P = 0.002), and no treatment for recurrence (P = 0.034) as independent factors for a short survival time after recurrence. A low PNI was significantly associated with a high performance status score, high C-reactive protein level, and short duration of treatment for recurrence. In conclusion, the PNI at recurrence can predict the survival time in patients with recurrent ESCC. PMID- 29528704 TI - The Effect of Vitamin D Supplementation on Breast Density Changes: A Clinical Trial Study. AB - : The aim of this study was to determine the effect of supplementation with 50,000 IU/monthly vitamin D for 1 yr on breast density in Iranian women. METHODS: This double-blind, placebo-controlled, single center clinical trial was conducted among 400 women aged 40 yr and older. Participants were allocated to 2 groups. Group 1 received vitamin D (Cholecalciferol) 50,000 IU in tablet form, monthly, for 1 yr. Group 2 received vitamin E 400 IU in tablet form, monthly, for the same period of time. Participants had follow-up clinic visits every 6 mo and received an annual mammogram. RESULTS: Final data were evaluated based on 216 and 194 women in the vitamin D and control groups. The mean decrease in mammographic density was -5.01%(95% CI, -9.9% to -0.01%) and -2.34 %(95% CI, -6.84% to -2.15%) in the vitamin D and control groups, respectively. There was no significant association between vitamin D consumption and breast density after 1 yr (OR = 0.7, 95% CI, 0.46 to 1.06; P = 0.1).Similar results were observed when multivariate model of logistic regression analysis was performed. CONCLUSIONS: This study showed that monthly consumption of 50,000 IU of vitamin D supplementation for 1 yr did not affect breast density. PMID- 29528705 TI - Inoculation Protocols Influence the Thermal Resistance of Salmonella Enteritidis PT 30 in Fabricated Almond, Wheat, and Date Products. AB - Inoculation methods in pathogen inactivation studies ideally represent conditions that might occur in real-world scenarios. Surface contamination in or on low moisture foods affects Salmonella thermal resistance, which is critically important for process validation applications. The objective of this study was to quantify the effect of inoculation protocol on the thermal resistance of Salmonella Enteritidis PT 30 in fabricated low-moisture foods. Almond meal, almond butter, wheat meal, wheat flour, and date paste were inoculated via prefabrication and postfabrication protocols. In the prefabrication protocol, kernels and fruits were surface inoculated and equilibrated to a target water activity (aw) (0.40 for almond and wheat products, 0.45 for date products) before fabricating meal, butter, flour, or paste and then reequilibrating the samples to the target aw. In the postfabrication protocol, meal, butter, flour, and paste were fabricated before inoculation and equilibration. All inoculated and equilibrated samples were subjected to isothermal treatment (80 degrees C), pulled sequentially during processing, cooled, serially diluted, and plated to enumerate survivors. Log-linear and Weibull-type models were fit to the Salmonella survivor data and were compared via the corrected Akaike information criterion. Pre- and postfabrication protocols resulted in significant differences ( P < 0.05) in Salmonella thermal resistance in all products. Overall, the thermal resistance of Salmonella Enteritidis PT 30 in almond products was greater ( P < 0.05) than in wheat products, which was also greater ( P < 0.05) than in date paste. Additionally, Salmonella was more thermally resistant in almond products and date paste when inoculated pre- rather than postfabrication; however, the opposite was true for wheat products. These results indicate that the means of inoculation can significantly affect thermal resistance of Salmonella in low-moisture foods. PMID- 29528706 TI - Morphological and Dose-Dependent Study on the Effect of Methyl, Hexyl, and Dodecyl Rosmarinate on Staphylococcus carnosus LTH1502: Use of the Weibull Model. AB - The mechanisms of three antimicrobial rosmarinates (methyl-RE1, hexyl-RE6, and dodecyl-RE12) were investigated against Staphylococcus carnosus LTH1502. Scanning electron microscopy was used to determine the morphology of treated cells to gain information on potential changes in the site of action of compounds. The survival data obtained from antimicrobial activity assays were fitted to a nonlinear Weibull model to assess changes in inactivation behavior. Generally, esters became more effective with increasing length of the alkyl chain, resulting in a lower concentration for inhibition and inactivation. Weibull distribution parameters showed a downward concave inactivation pattern for RE1 above a critical concentration, indicative of a delayed log phase of the antimicrobial activity, with few cells being inactivated immediately after treatment and more cells being affected at later times. In contrast, esters having longer alkyl chains (RE6 and RE12) had an upward concave inactivation behavior, with more cells being inactivated immediately after addition of compounds. Cellular morphologies suggest that the antimicrobial mode of action of esters transitions from one that acts intracellularly (RE1) to one that predominately affects bacterial membrane (RE6 and RE12) due to changes in physicochemical properties of esters. Assessment that is based on the parameters of the Weibull model could, thus, be used to evaluate antimicrobial efficiency, in addition to MIC. PMID- 29528707 TI - The association between students taking elective courses in chiropractic technique and their anticipated chiropractic technique choices in future practice. AB - OBJECTIVE:: To assess students' opinions of the potential influence of taking elective courses in chiropractic techniques and their future practice preferences. METHODS:: An anonymous, voluntary survey was conducted among graduating students from a doctor of chiropractic program. The survey included questions regarding the chiropractic technique elective courses they had completed and the potential influence of these courses on their chiropractic technique choices in future practice. Surveys were pretested for face validity, and data were analyzed using descriptive and inferential statistics. RESULTS:: Of the 56 surveys distributed, 46 were completed, for a response rate of 82%. More than half of the students reported having taken at least 1 elective course in diversified technique (80%), Cox technique (76%), Activator Methods (70%), or sacro-occipital technique (63%). Less than half of the respondents reported taking technique elective courses in Gonstead or Thompson techniques. More than half of the students stated they were more likely to use Activator (72%), Thompson (68%), diversified (57%), or Cox (54%) techniques in their future practice after taking an elective course in that technique. Females stated that they were more likely to use Activator Methods ( p = .006) in future practice. CONCLUSION:: Chiropractic technique elective courses in the doctor of chiropractic curriculum may influence students' choices of future practice chiropractic technique. PMID- 29528708 TI - Parity of access to memory services in London for the BAME population: a cross sectional study. AB - OBJECTIVE: To investigate whether referrals to memory services in London reflect the ethnic diversity of the population. METHODS: Memory service data including referral rates of BAME was collected from London Clinical Commissioning Groups (CCGs). RESULTS: The expected percentage of BAME referrals using census data was compared against White British population percentages using the chi squared test. We found that within 13,166 referrals to memory services across London, the percentage of people from BAME groups was higher than would be expected (20.3 versus 19.4%; chi2 = 39.203, d.f. = 1, p < 0.0001) indicating that generally people from BAME groups are accessing memory services. Seventy-nine percent of memory services had more referrals than expected or no significant difference for all BAME groups. When there were fewer referrals then expected, the largest difference in percentage for an individual ethnic group was 3.3%. CONCLUSIONS: Results are encouraging and may indicate a significant improvement in awareness of dementia and help seeking behaviour among BAME populations. Prevalence of dementia in some ethnic groups may be higher so these numbers could still indicate under-referral. Due to the data available we were unable to compare disease severity or diagnosis type. PMID- 29528709 TI - INTERDEM Academy: a training and career development initiative vital to capacity building of early stage psychosocial dementia researchers in Europe. PMID- 29528710 TI - What Is New in Prenatal Skeletal Dysplasias? AB - OBJECTIVE: The purpose of this article is to discuss advances in imaging and diagnosis of skeletal dysplasias. CONCLUSION: Skeletal dysplasias are a heterogeneous group of disorders affecting bone and cartilage and characterized by abnormal shape, growth, and integrity of the skeleton. These disorders may be inherited in a multitude of genetic patterns-autosomal dominant, autosomal recessive, somatic mosaic, imprinting errors of metabolism, X-linked, and teratogenic exposure. Most are monogenic diseases. The prenatal diagnosis is challenging; the findings are first seen during routine ultrasound. PMID- 29528711 TI - Abdominal Attenuation Values on Virtual and True Unenhanced Images Obtained With Third-Generation Dual-Source Dual-Energy CT. AB - OBJECTIVE: The purpose of this study is to investigate the magnitude of differences between attenuation values measured on virtual unenhanced images and true unenhanced images obtained using third-generation dual-source dual-energy CT (DECT). SUBJECTS AND METHODS: A total of 83 patients requiring thoracoabdominal CT for cancer workup were included in this prospective study. CT examinations included true unenhanced acquisitions (tube potential, 120 kVp) and arterial and portal phase dual-energy CT (DECT) acquisitions (tube potential, 100 kVp and Sn 150 kVp [where Sn denotes the interposition of a tin filter in the high-energy beam]; tube current-exposure time product, 190 and 95 mAs). Virtual unenhanced images were created using two commercially available DECT postprocessing algorithms, one of which was designed to create liver images (hereafter referred to as VNC1 images) and the other of which was designed to create images of organs containing minor amounts of fat (hereafter referred to as VNC2 images). Attenuation values on the liver, spleen, paraspinal muscles, retroperitoneal fat, renal cortex and medulla, and gallbladder and bladder lumens were measured. RESULTS: The attenuation values of all tissues were significantly different between virtual unenhanced and true unenhanced images (p = < 0.001-0.042), except for the liver and spleen in the portal phase and muscles in both phases. When statistically significant, correlations between these differences and body mass index (weight in kilograms divided by the square of height in meters) depended on the tissue imaged and algorithm used. The percentage of cases in which these differences were 10 HU or greater was 1% for the liver and approximately 5% for the spleen and muscles, regardless of the algorithm and phase, but on VNC1 images it reached approximately 30% for the kidney, 70% for the gallbladder and bladder, and depending on the phase, 40-70% for fat. On VNC2 images, the percentage of cases in which these differences were 20 HU or greater was approximately 90% for fat. CONCLUSION: Abdominal virtual unenhanced images obtained with third generation dual-source DECT still should not replace true unenhanced images because of substantial differences in attenuation measurements for fluid, fat, and renal tissues. PMID- 29528712 TI - Comprehensive Multimodality Imaging Review of Complications of Penile Prostheses. AB - OBJECTIVE: The objective of our article is to review the role of imaging in the diagnosis of various complications of a penile prosthesis (PP). CONCLUSION: Complications of a PP can be categorized into three groups: first, malpositioning, which includes buckling, floppy glans, erosion, migration, and crossover; second, mechanical failure, which includes fracture, aneurysm, and leakage; and, third, infection. Radiography, sonography, CT, and MRI are useful in the detection of these complications and complement each other, with MRI being the most useful imaging modality among them. PMID- 29528713 TI - Effect of Combined 68Ga-PSMAHBED-CC Uptake Pattern and Multiparametric MRI Derived With Simultaneous PET/MRI in the Diagnosis of Primary Prostate Cancer: Initial Experience. AB - OBJECTIVE: The purpose of this study is to assess whether temporal changes in 68Ga-prostate-specific membrane antigen (PSMA)-HBED-CC uptake and multiparametric MRI parameters derived using PET/MRI can aid in characterization of benign and malignant prostate lesions. MATERIALS AND METHODS: Thirty-five men with 29 malignant and six benign prostate lesions undergoing complete clinical workup including histologic analysis were enrolled for this retrospective study. All had undergone simultaneous whole-body 68Ga-PSMAHBED-CC PET/MRI. Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) assessment was made using a 5 point scale showing the likelihood of cancer with the combination of multiparametric MRI findings. Gallium-68-PSMA uptake was recorded at two time points: early (7 minutes) and delayed (54 minutes), adopting a copy-and-paste function of the ROI defined on MR images. ROC curve analysis was performed to test the diagnostic accuracy of early versus delayed PSMA uptake (measured as maximum standardized uptake value [SUV]). A multiple-ROI analysis was done to obtain ROCs for combined PET SUV and multiparametric MRI datasets. Spearman analysis was performed to assess the correlations. RESULTS: There was a significant difference between early and delayed PSMA uptake in malignant prostatic lesions (p < 0.01), which was able to characterize prostate lesions with an AUC of 0.83 and 0.94. Combined ROC analysis of PI-RADSv2 category derived from multiparametric MRI and differential PSMA uptake in characterizing prostatic lesions improved the AUC to 0.99. CONCLUSION: Dual-phase PSMA uptake improves accuracy of classifying malignant versus benign prostate lesions and complements multiparametric MRI in the diagnosis of prostate cancer. PMID- 29528714 TI - Neonatal Bowel Disorders: Practical Imaging Algorithm for Trainees and General Radiologists. AB - OBJECTIVE: Neonatal bowel disorders require prompt and accurate diagnosis to avoid potential morbidity and mortality. Symptoms such as feeding intolerance, emesis, or failure to pass meconium may prompt a radiologic evaluation. CONCLUSION: We discuss the most common neonatal bowel disorders and present a practical imaging algorithm for trainees and general radiologists. PMID- 29528715 TI - Value of Fetal MRI in the Era of Fetal Therapy for Management of Abnormalities Involving the Chest, Abdomen, or Pelvis. AB - OBJECTIVE: The purpose of this article is to present illustrative cases highlighting the value of fetal MRI as a problem-solving tool in evaluating anomalies of the fetal chest, abdomen, and pelvis that are being evaluated for fetal therapy. CONCLUSION: Fetal MRI is an increasingly valuable noninvasive tool for evaluating fetal anomalies in the age of fetal therapy. Although ultrasound remains the primary diagnostic imaging modality, MRI can provide additional information to assist parental counseling and patient care. PMID- 29528716 TI - Heuristics and Cognitive Error in Medical Imaging. AB - OBJECTIVE: The field of cognitive science has provided important insights into mental processes underlying the interpretation of imaging examinations. Despite these insights, diagnostic error remains a major obstacle in the goal to improve quality in radiology. In this article, we describe several types of cognitive bias that lead to diagnostic errors in imaging and discuss approaches to mitigate cognitive biases and diagnostic error. CONCLUSION: Radiologists rely on heuristic principles to reduce complex tasks of assessing probabilities and predicting values into simpler judgmental operations. These mental shortcuts allow rapid problem solving based on assumptions and past experiences. Heuristics used in the interpretation of imaging studies are generally helpful but can sometimes result in cognitive biases that lead to significant errors. An understanding of the causes of cognitive biases can lead to the development of educational content and systematic improvements that mitigate errors and improve the quality of care provided by radiologists. PMID- 29528717 TI - Malignant Mesothelioma in Individuals With Nonmesothelial Neoplasms. AB - CONTEXT: - Malignant mesothelioma (MM) is a component of the BAP1 tumor predisposition syndrome. Other than in BAP1 familial studies, nonmesothelial neoplasms in individuals with MM has not been comprehensively assessed. OBJECTIVE: - To assess the spectrum and prevalence of nonmesothelial neoplasms in individuals with MM. DESIGN: - Individuals with MM and second neoplasms were identified from a database of 3900 MM cases. The expected prevalence of each type of neoplasm was calculated and compared with the actual prevalence in the study population using available Surveillance, Epidemiology, and End Results data and other published data. RESULTS: - Two hundred seventy nonmesothelial neoplasms were identified in 241 individuals (6% of the study population) with MM. Prostate adenocarcinoma was most common. Non-Hodgkin lymphoma, Hodgkin lymphoma, lung carcinoma, urothelial carcinoma, breast carcinoma, chronic lymphocytic leukemia, clear cell renal cell carcinoma, head and neck squamous cell carcinoma, papillary renal cell carcinoma, multiple myeloma/plasmacytoma, meningioma, pleomorphic undifferentiated sarcoma, chronic myelogenous leukemia, ocular melanoma, hepatocellular carcinoma, liposarcoma, and Wilms tumor all were more prevalent than expected. CONCLUSIONS: - Nonmesothelial neoplasms are uncommon in individuals with MM, but certain tumor types are increased in prevalence. In an unselected study population with respect to BAP1 status, the prevalence of several tumor types described in BAP1 mutation carriers, including lung carcinoma, clear cell renal cell carcinoma, breast carcinoma, meningioma, pleomorphic undifferentiated sarcoma, and ocular melanoma, was increased. PMID- 29528718 TI - Distribution of 21-Gene Recurrence Scores Among Breast Cancer Histologic Subtypes. AB - CONTEXT: - The 21-gene recurrence score (RS) provides a probability of distant recurrence for estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. The utility of RS for rarer histologic subtypes of breast cancer is uncertain. OBJECTIVE: - To determine the distribution of RS among various histologic subtypes using a population database. DESIGN: - Women between the ages of 18 and 75 with estrogen receptor-positive, HER2-negative breast cancer and known RS results were identified using the Surveillance, Epidemiology, and End Results database. Recurrence scores were categorized into risk groups using both traditional and Trial Assigning Individualized Options for Treatment cutoffs. Multivariable logistic regression was used to determine factors associated with high-risk RS. RESULTS: - We identified 45 618 patients with stage I to III, estrogen receptor-positive, HER2-negative breast cancer who had RS available. Overall, 3087 (7%) and 6337 (14%) of cancers were classified as high risk based on traditional and Trial Assigning Individualized Options for Treatment RS cutoffs, respectively. The proportion of high-risk RS ranged from 1% (tubular, 2 of 225) to 68% (medullary, 13 of 19) and 4% (tubular, 10 of 225) to 79% (medullary, 15 of 19) for traditional and Trial Assigning Individualized Options for Treatment cutoffs, respectively. Based on multivariable logistic regression (excluding medullary), subtypes other than invasive ductal carcinoma and papillary carcinoma were significantly associated with lower RS. The strongest predictors of a high-risk RS were higher tumor grade and negative progesterone receptor status. CONCLUSIONS: - We identified distinct distributions of RS among different histologic subtypes of breast cancer. Excluding medullary carcinoma, histologic subtypes other than invasive ductal carcinoma and papillary carcinoma all predict lower RS. PMID- 29528719 TI - Youth Mental Health Should Be a Top Priority for Health Care in Canada. AB - In this article we have provided a perspective on the importance and value of youth mental health services for society and argued that advancing youth mental health services should be the number one priority of health services in Canada. Using the age period of 12-25 years for defining youth, we have provided justification for our position based on scientific evidence derived from clinical, epidemiological and neurodevelopmental studies. We have highlighted the early onset of most mental disorders and substance abuse as well as their persistence into later adulthood, the long delays experienced by most help seekers and the consequence of such delays for young people and for society in general. We have also provided a brief review of the current gross inadequacies in access and quality of care available in Canada. We have argued for the need for a different conceptual framework of youth mental disorders as well as for a transformation of the way services are provided in order not only to reduce the unmet needs but also to allow a more meaningful exploration of the nature of such problems presenting in youth and the best way to treat them. We have offered some ideas based on previous work completed in this field as well as current initiatives in Canada and elsewhere. Any transformation of youth mental health services in Canada must take into consideration the significant geographic, cultural and political diversity across the provinces, territories and indigenous peoples across this country. PMID- 29528721 TI - University-Based Residency Training. PMID- 29528720 TI - Patient, Treatment, and Health Care Utilization Variables Associated with Adherence to Metabolic Monitoring Practices in Children and Adolescents Taking Second-Generation Antipsychotics. AB - OBJECTIVE: Children and adolescents with a range of psychiatric disorders are increasingly being prescribed atypical or second-generation antipsychotics (SGAs). While SGAs are effective at treating conduct and behavioural symptoms, they infer significant cardiometabolic risk. This study aims to explore what patient, treatment, and health care utilization variables are associated with adherence to Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) metabolic monitoring guidelines. METHOD: A retrospective chart review of 294 children and adolescents accessing a large outpatient psychiatry setting within a 2-year study period (2014-2016) was conducted. Baseline and follow-up metabolic monitoring, demographic, treatment, and health care utilization variables were then assessed over a 1-year period of interest. RESULTS: Metabolic monitoring practices did not adhere to CAMESA guidelines and were very poor over the 1-year observation period. There were significant differences between children (ages 4-12 years, n = 99) and adolescents (ages 13-18 years, n = 195). In adolescents, factors associated with any baseline metabolic monitoring were a higher number of psychiatry visits (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.10 to 1.41), longer duration of contact (OR, 14; 95% CI, 2.31 to 82.4), and use of other non-SGA medications (OR, 3.2; 95% CI, 1.17 to 8.94). Among children, having an emergency room visit (OR, 3.4; 95% CI, 1.01 to 11.71) and taking aripiprazole (OR, 7.4; 95% CI, 2.02 to 27.45) increased the odds of receiving baseline metabolic monitoring. CONCLUSION: Findings from this study highlight the need for better metabolic monitoring for children and adolescents taking SGAs. Enhanced focus on opportunities for multidisciplinary collaboration is needed to improve the quality of care offered to this population. PMID- 29528722 TI - Biomechanical Evaluation of Circumtibial and Transmembranous Routes for Posterior Tibial Tendon Transfer for Dropfoot. AB - BACKGROUND: Tibialis posterior tendon transfer is performed when loss of dorsiflexion has to be compensated. We evaluated the circumtibial (CT), above retinaculum transmembranous (TMAR), and under-retinaculum transmembranous (TMUR) transfer gliding resistance and foot kinematics in a cadaveric foot model during ankle range of motion (ROM). METHODS: Eight cadaveric foot-ankle distal tibia specimens were dissected free of soft tissues on the proximal end, applying an equivalent force to 50% of the stance phase to every tendon, except for the Achilles tendon. Dorsiflexion was tested with all of the tibialis posterior tendon transfer methods (CT, TMAR, and TMUR) using a tension tensile machine. A 10-repetition cycle of dorsiflexion and plantarflexion was performed for each transfer. Foot motion and the force needed to achieve dorsiflexion were recorded. RESULTS: The CT transfer showed the highest gliding resistance ( P < .01). Regarding kinematics, all transfers decreased ankle ROM, with the CT transfer being the condition with less dorsiflexion compared with the control group (6.8 vs 15 degrees, P < .05). TMUR transfer did perform better than TMAR with regard to ankle dorsiflexion, but no difference was shown in gliding resistance. The CT produced a supination moment on the forefoot. CONCLUSION: The CT transfer had the highest tendon gliding resistance, achieved less dorsiflexion and had a supination moment. Clinical Relevance We suggest that the transmembranous tibialis posterior tendon transfer should be the transfer of choice. The potential bowstringing effect when performing a tibialis posterior tendon transfer subcutaneously (TMAR) could be avoided if the transfer is routed under the retinaculum, without significant compromise of the final function and even with a possible better ankle range of motion. PMID- 29528723 TI - Intraoperative Findings of Lateral Ligament Avulsion Fractures and Outcome After Refixation to the Fibula. AB - BACKGROUND: An acute ankle sprain can result in a bony avulsion of the lateral ankle ligaments. The extent of concomitant lesions and subsequent instability patterns are not clearly understood. The high incidence of old avulsion fractures found in symptomatic chronic ankle instability may indicate the need for primary fixation. METHODS: Ten patients (5 male, 5 female; mean age, 34 years; range, 15 64 years) with bony avulsion fractures of the fibula after acute ankle sprains were included. All patients were treated after a mean of 7.7 days (range, 2-17 days) with screw fixation of the fragment to the fibula. Clinical and radiographic assessments were performed, and the extent of ligament injury was documented. RESULTS: The anterior talofibular ligament and calcaneofibular ligament were found to be attached to the avulsion fragment. The average size was 6.3 mm (range, 4-9 mm) in width from anterior to posterior and 5.2 mm (range, 4-7 mm) in length from superior to inferior. The displacement of the fragment increased under varus stress. Two patients had cartilage lesions in the lateral talus. After a mean follow-up period of 2.4 years (range, 2-4 years), all were clinically and radiographically stable, and patients were satisfied. CONCLUSIONS: It was observed arthroscopically that the anterior talofibular ligament and calcaneofibular ligament were attached to the fragment. This is critical because motion between the fragment and the fibula may prevent spontaneous healing. Primary fixation of the fragment prevented rotational instability and was efficient to restore function and stability. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29528724 TI - Outcome of Percutaneous Fixation of Acute Achilles Tendon Ruptures. AB - BACKGROUND: Conservative treatment of an acute Achilles rupture remains a viable and acceptable option as does surgical fixation, with open and percutaneous repair consisting the main operative techniques. The purpose of this study was to compare the outcomes and complication rates of open versus percutaneous surgical procedures. METHODS: From 2009 to 2016, 131 patients were admitted to our department with clinically and radiologically confirmed acute Achilles tendon ruptures. Of those, 82 patients met our inclusion criteria and were randomized into 2 groups, group A (open repair) and group B (percutaneous suturing). Suture equipment was the same for both groups. All patients followed the same rehabilitation protocol. Functional evaluation was made using American Orthopaedic Ankle & Foot Society (AOFAS) hindfoot and Achilles tendon Total Rupture Score (ATRS) questionnaires at the 12-month follow-up. Ankle range of motion (ROM), return-to-work time, and complication rates were additionally measured. RESULTS: Both techniques had similar results regarding complication rates and return-to-work time. The major complication in group A was superficial infection (7%) and skin necrosis (3%), whereas 3 patients in group B developed paresthesias due to sural nerve entrapment. Patients in group B had better AOFAS hindfoot (96/100) and ATRS (95/100) scores, but the difference was not significant. ROM was similar in both groups at the 12-month follow-up. CONCLUSION: Percutaneous suturing seems to be a safe and effective technique that offers good functional outcomes and low complication rates in patients with acute Achilles tendon ruptures who elect to have surgery. LEVEL OF EVIDENCE: Level II, prospective case series. PMID- 29528725 TI - Towards Automation and Augmentation of the Design of Schedulers for Cellular Communications Networks. AB - Evolutionary computation is used to automatically evolve small cell schedulers on a realistic simulation of a 4G-LTE heterogeneous cellular network. Evolved schedulers are then further augmented by human design to improve robustness. Extensive analysis of evolved solutions and their performance across a wide range of metrics reveals evolution has uncovered a new human-competitive scheduling technique which generalises well across cells of varying sizes. Furthermore, evolved methods are shown to conform to accepted scheduling frameworks without the evolutionary process being explicitly told the form of the desired solution. Evolved solutions are shown to out-perform a human-engineered state-of-the-art benchmark by up to 50%. Finally, the approach is shown to be flexible in that tailored algorithms can be evolved for specific scenarios and corner cases, allowing network operators to create unique algorithms for different deployments, and to postpone the need for costly hardware upgrades. PMID- 29528726 TI - Constraint Handling Guided by Landscape Analysis in Combinatorial and Continuous Search Spaces. AB - The notion and characterisation of fitness landscapes has helped us understand the performance of heuristic algorithms on complex optimisation problems. Many practical problems, however, are constrained, and when significant areas of the search space are infeasible, researchers have intuitively resorted to a variety of constraint-handling techniques intended to help the algorithm manoeuvre through infeasible areas and toward feasible regions of better fitness. It is clear that providing constraint-related feedback to the algorithm to influence its choice of solutions overlays the violation landscape with the fitness landscape in unpredictable ways whose effects on the algorithm cannot be directly measured. In this work, we apply metrics of violation landscapes to continuous and combinatorial problems to characterise them. We relate this information to the relative performance of six well-known constraint-handling techniques to demonstrate how some properties of constrained landscapes favour particular constraint-handling approaches. For the problems with sampled feasible solutions, a bi-objective approach was the best performing approach overall, but other techniques performed better on problems with the most disjoint feasible areas. For the problems with no measurable feasibility, a feasibility ranking approach was the best performing approach overall, but other techniques performed better when the correlation between fitness values and the level of constraint violation was high. PMID- 29528727 TI - Suboptimal Vitamin B Intakes of Zambian Preschool Children: Evaluation of 24-Hour Dietary Recalls. AB - BACKGROUND: Hidden hunger affects individuals who chronically consume an inadequate intake of at least 1 micronutrient and is associated with low dietary diversity. Little data are available on dietary intake or status assessment of B vitamins among preschool children in Zambia. OBJECTIVES: The aim of this study was to assess 24-hour dietary recall records obtained from Zambian children aged 3 to 7 years for B vitamin intake in relation to adequacy and change over time in the same community. METHODS: Twenty-four-hour dietary recalls were collected from 2 studies that were 2 years apart in the same district of Zambia. Data were retrospectively analyzed for B vitamin intake, that is, biotin, vitamin B12, folate, niacin, pantothenic acid, vitamin B6, riboflavin, and thiamin. The estimated average requirement (EAR) cut point method was used to assess inadequacy prevalence for EARs established by the Institute of Medicine in the United States. RESULTS: For all B vitamins, mean values were below the EARs established for children 4 to 8 years old. Relative to the EAR, children had the highest intakes of vitamin B6 with inadequacies of 77.9% and 60.1% in 2010 and 2012, respectively. The highest prevalence of inadequate intake was associated with folate, where >=95% of the children had intakes below the EAR in both studies. CONCLUSIONS: All median vitamin B intakes were inadequate among these young children in rural Zambia. Future researchers and policy makers may need to consider B vitamin status in resource-poor areas of the country. PMID- 29528728 TI - Tuberculosis on the intensive care unit. AB - Patients with tuberculosis admitted to the intensive care unit represent a small (1-3%) yet significant subset of the global tuberculosis burden. This article reviews current evidence supporting the diagnosis and management of patients with tuberculosis admitted to an intensive care unit from a combination of cohort studies and national and international tuberculosis guidelines. This review considers admission, diagnosis, mechanical ventilation, infection control, treatment and prognosis of patients with tuberculosis admitted to an intensive care unit. It highlights both diagnostic and management challenges and areas where ambiguity remains and further evidence is required. PMID- 29528729 TI - Erratum. PMID- 29528730 TI - Sir Frederic Still: first professor of paediatrics in the UK. PMID- 29528732 TI - Current and future perspectives in autoimmune hepatitis. AB - Autoimmune hepatitis occurs in genetically susceptible individuals as a result of loss of immunological tolerance to hepatic autoantigens that can be precipitated by environmental triggers. The clinical manifestation is usually insidious but can be also acute with liver failure. The diagnosis is made on the basis of antibody positivity, elevated immunoglobulin G levels and interface hepatitis on liver histology. Induction of remission is achieved with high-dose steroids in the majority of cases, and maintenance of remission with azathioprine. Treatment withdrawal is achievable only in a small proportion of patients. Patients with acute liver failure unresponsive to steroids or those with end-stage liver failure or hepatocellular carcinoma may require liver transplantation. Variant forms of overlapping autoimmune hepatitis with either primary biliary cholangitis or sclerosing cholangitis are associated with worse outcomes. New insights into the pathophysiology of the disease may provide novel therapeutic targets and a more individualized approach to treatment of autoimmune hepatitis. PMID- 29528731 TI - Delivering the 48-hour antimicrobial review on inpatient drug charts. AB - BACKGROUND: Prolonged or inappropriate antibiotic therapy increases the risk of health-care-associated infections and the development of resistance to antibiotics, and lengthens hospital admissions. There are clear guidelines on antimicrobial stewardship which state that antibiotics should be reviewed between 48 and 72 hours from commencement ( National Institute of Health and Care Excellence, 2015 ). Despite these guidelines this review was often not documented as having been carried out on the authors' inpatient wards. METHODS: A quality improvement project was undertaken with the aim of improving the percentage completion of the 48-hour antimicrobial review box section of the inpatient drug charts to over 90% across two 30-bed acute respiratory wards within 7 weeks. The primary outcome measures were percentage completion of 48-hour antibiotic review and number of days on intravenous antibiotics. The quality improvement programme took place over 7 weeks and included seven interventions designed to improve completion of the 48-hour review. RESULTS: During the study, the percentage completion of 48-hour review rose from a baseline median of 68% to 100% and was accompanied by a reduction in the number of days on intravenous antibiotics from a baseline median of 2.25 days to 1.5 days. CONCLUSIONS: This simple quality improvement project led to a greatly improved review of antimicrobial therapy which was associated with significantly reduced time on intravenous antibiotics. The quality improvement methodology could easily be adapted for other inpatient medical wards. PMID- 29528734 TI - The chief registrar: a new Royal College of Physicians leadership initiative for trainees. PMID- 29528733 TI - Learning lessons in medicine: reflecting on the case of Dr Bawa-Garba. PMID- 29528735 TI - Thrombus detachment causing lower limb embolism in acute myocardial infarction. PMID- 29528736 TI - Femoral nerve block vs adductor canal block for total knee arthroplasty. PMID- 29528738 TI - Tackling delirium: a crucial target for improving clinical outcomes. AB - Delirium is a common and debilitating syndrome in hospitalized patients, and its impact on mortality, morbidity and duration of hospital admission is increasingly apparent. Delirium is a complex phenomenon, for which there is no specific treatment, but research over the last decade has revealed contributing factors, many of which are modifiable, and preventative strategies have demonstrated benefit. This review highlights the importance of reducing the impact of delirium on hospitalized patients, and summarizes the current evidence for strategies to achieve this. Current recommendations focus on the pre-emptive implementation of multi-modal non-pharmacological interventions to reduce the occurrence of delirium in the first place, and routine monitoring using validated tools to identify delirious patients early. Potential therapies for established delirium remain controversial. PMID- 29528739 TI - Medical schools must prepare students for leadership. PMID- 29528740 TI - How to run a large group teaching session. PMID- 29528741 TI - Addisonian crisis: assessment and management. PMID- 29528742 TI - The SNOOZE project: the impact of night shifts on junior doctors' reaction times. PMID- 29528743 TI - Acute respiratory distress syndrome associated with femoral osteomyelitis. PMID- 29528744 TI - So you want a career in forensic and legal medicine? PMID- 29528746 TI - Clinical News. PMID- 29528745 TI - Trial without catheter. PMID- 29528747 TI - E-portfolios, reflections and the case of Dr Bawa-Garba. PMID- 29528748 TI - Fragility fractures in the upper limb: proximal and distal humerus. AB - The incidence of fragility fractures of the humerus is increasing worldwide. Although clinicians are aware of fractures of hips and wrists, fractures of the shoulder and elbow do not receive much attention. A considerable proportion of the elderly population (estimated at 10-24%) is dependent on walking aids. A well functioning and pain-free shoulder and elbow is essential for use of these aids. The impact of loss of mobility in the elderly is well known, hence the overall impact of these fractures on the individual can be considerable. This article increases the awareness of these fractures among non-orthopaedic colleagues and provides a brief outline of their management. In the elderly population using walking aids, the shoulder and elbow are effectively weight-bearing joints. Fractures of the shoulder or elbow in the elderly require extra attention to maintain their mobility during this period by physiotherapy to the lower limbs and chest. In patients who mobilize using a frame, the use of a stick on the opposite side of the injury may have to be considered while recovery is in progress. PMID- 29528749 TI - Biomarker-guided antibiotic cessation in sepsis: evidence and future challenges. AB - Sepsis is a medical emergency, which requires the initiation of broad-spectrum antimicrobial agents as early as possible. In the absence of positive microbiological cultures providing targeted antimicrobial advice, broad-spectrum antibiotics are commonly continued until there is clinical evidence of infection resolution. With an absence of robust evidence to inform when it is safe to stop antimicrobial agents in sepsis, the duration of antimicrobial courses may be longer than is required. Prolonged courses of potent broad-spectrum antimicrobials increase the risk of adverse drug events and contribute to the growing emergence of multidrug resistant pathogens, which is a global public health emergency. The protocolised use of protein biomarkers to guide clinical decision making can be used to help combat excessive durations of antimicrobials in patients with sepsis. This article reviews the current evidence for biomarker guided antimicrobial discontinuation protocols in sepsis, identifies related evidence gaps and examines future innovation challenges in this field. PMID- 29528750 TI - Clinical Efficacy of Diphenylcyclopropenone Immunotherapy as Monotherapy for Multiple Viral Warts. AB - BACKGROUND: Diphenylcyclopropenone (DPCP) immunotherapy for viral warts has been used for many years, but no studies have analyzed the treatment effects of DPCP alone, without the use of conventional therapy before immunotherapy. OBJECTIVES: We evaluated clinical efficacy of DPCP monotherapy compared to cryotherapy and pulsed dye laser (PDL) therapy. We also assessed the impact of initial sensitization on clinical response. METHODS: We retrospectively analyzed the medical records of 250 patients with multiple viral warts between January 2008 and December 2015. RESULTS: The DPCP-only group (n = 43) showed a lower clinical response (75.6%) than the cryotherapy-only group (n = 171, 89.8%, P < .01) and PDL-only group (n = 36, 90.3%, P < .01). The positive clinical response was 76.3% (119/156) in the successful sensitization group (n = 21) and 74.4% in the failed sensitization group ( P = .870). CONCLUSIONS: DPCP monotherapy has a lower clinical response than conventional therapy. Initial sensitization to DPCP does not predict a failed response with continued immunotherapy for viral warts. PMID- 29528751 TI - Exaggerated Arthropod Bite Reaction During Pregnancy: A Case Report. AB - INTRODUCTION: The diagnosis of exaggerated bite reactions is based on the clinical and pathological characteristics of the lesions. These reactions can be an indicator of impending immune suppression. METHODS: The authors report the case of a 35-year-old pregnant woman who presented with a pruriginous vesicular and pustular eruption over her thighs and buttocks. The clinical and pathological findings were compatible with an exaggerated bite reaction. The patient did not report any severe or exaggerated reaction to insect bites in the past. It was her first episode. CONCLUSION: Exaggerated bite reactions have been described with hematological malignancies, mostly chronic lymphocytic leukemia. In our literature review, we did not find any reports of severe local bite reactions occurring during pregnancy. We hypothesize that the changes in the immune system during pregnancy might explain the development of exaggerated bite reactions in our patient. PMID- 29528752 TI - Corrigendum. PMID- 29528753 TI - A Canadian Population-Based Cohort to the Study Cost and Burden of Surgically Resected Hidradenitis Suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating disease with long-lasting comorbidities that impose direct and indirect costs on the health care system. However, limited studies have estimated the burden of this disease in Canada, and no population-based studies have previously addressed this condition. OBJECTIVES: This work describes the characteristics of a population based HS cohort to address the existing knowledge gap on the burden of HS for the Canadian health care system. This cohort will provide a foundation for further studies about clinical outcomes and risk factors of HS by providing opportunities for merging additional databases. METHODS: Data on demographic information, morbidities, relative resource use, and the cost of sectorial services were obtained from the Institute for Clinical Evaluative Sciences (ICES). All residents of Ontario covered by the Ontario Health Insurance Plan (OHIP) between April 1, 2002, and March 31, 2013, who underwent surgery for HS, defined by OHIP billing codes, were included. RESULTS: A total of 6244 cases were included in the analysis, following quality control procedures. Twice as many females were treated surgically relative to males. The majority of individuals treated were under the age of 64, with more than half having a moderate level of morbidity (according to Resource Utilization Bands defined by the Johns Hopkins Adjusted Clinical Group Classification System). CONCLUSIONS: This cohort study is the first population-based resource about HS in Canada. Administrative population based databases provide essential information to assess the burden of chronic diseases and identify factors associated with higher cost. PMID- 29528754 TI - The effect of surgeon's preference for hybrid or cemented fixation on the long term survivorship of total knee replacement. AB - Background and purpose - Recent direct comparative reports suggest that hybrid fixation may have a similar or superior outcome to cemented fixation in total knee replacement (TKR); however, a paucity of long-term data exists. To minimize the confounders of a direct comparison, we performed an instrumental variable analysis examining the revision rate of 2 cohorts of patients based on their surgeon's preference for cemented or hybrid fixation. Methods - Registry data were obtained from 1999 until 2015 for 2 cohorts of patients who received minimally stabilized TKR, defined as those treated by high-volume hybrid fixation preferring surgeons, designated routinely hybrid (RH), and those treated by high volume cemented fixation preferring surgeons, designated routinely cemented (RC). Results - At 13 years, the cumulative percentage revision of the RC cohort was 4.8% (CI 4.1-5.7) compared with 5.5% (CI 3.5-8.7) for the RH cohort. The revision risk for each cohort was the same for all causes (HR =1.0 (CI (0.84-1.20)), non infective causes, and for infection. This finding was irrespective of patient age or sex, patella resurfacing, and with non-cross-linked polyethylene (NXLPE). The RH cohort who received cross-linked polyethylene (XLPE) had a lower revision risk than the RC cohort with XLPE (HR =0.57 (0.37-0.88), p = 0.01). Interpretation - The risk of revision for the patients of surgeons who prefer cemented fixation in minimally stabilized TKR is the same as for the patients of surgeons who prefer hybrid fixation, except when used with XLPE, where hybrid fixation has a lower revision risk. PMID- 29528755 TI - Emerging therapeutic targets for the treatment of malignant rhabdoid tumors. AB - INTRODUCTION: Malignant Rhabdoid Tumor (MRT) is a rare and highly aggressive malignancy primarily affecting infants and young children. The most common anatomic locations are the central nervous system (AT/RT), the kidneys (RTK) and other soft tissues (eMRT). The genetic origin of this disease is linked to mutations in SMARCB1, a gene encoding a core subunit of the SWI/SNF chromatin remodeling complex. Areas covered: Conventional multimodal treatment may offer a significant survival benefit to certain patients. It remains to be determined, however, which patients will prove resistant to chemotherapy and need novel therapeutic approaches. Herein we discuss key signal transduction pathways involved in the pathogenesis of rhabdoid tumors for potential targeted therapy (EZH2, DNMT, HDAC, CDK4/6/Cyclin D1/Rb, AURKA, SHH/GLI1, Wnt/beta-Catenin, immunotherapy). Additional agents currently evaluated in preclinical settings and experimental clinical trials are discussed. Expert opinion: MRTs are genetically homogeneous, but epigenetically distinct malignancies. While there is an abundance of experimental in vitro studies evaluating potential therapeutic avenues, a dearth of clinical trials specifically for this entity persists. In order to improve outcome patients need to be carefully stratified and treated by targeted therapies combined with conventional chemotherapy or with new, less selective experimental agents in phase I/II clinical trials. PMID- 29528756 TI - Vasoactive androgens: Vasorelaxing effects and their potential regulation of blood pressure. AB - BACKGROUND: Testosterone, 5alpha- and 5beta-dihydrotestosterone (-DHT) induce an acute in vitro vasorelaxation and in vivo vasodepressor, hypotensive and antihypertensive responses. Our aim was to study whether androgen-induced blood pressure (BP) reduction is involved with a blockade of Ca2+ influx through L-type voltage-operated calcium channels (L-VOCCs) and/or the signaling pathways of alpha1-adrenoceptors to induce vasoconstriction, which are one of the major mechanisms of BP maintenance. MATERIALS AND METHODS: The relaxing potency and efficacy of each androgen in large conduit (thoracic aorta) and resistance (mesenteric) arteries from male hypertensive (SHR) and normotensive (WKY) rats were established. Blood vessels were isometrically recorded and precontracted with KCl or phenylephrine (Phe). RESULTS: Androgens induced concentration dependent vasorelaxation in precontracted arteries from SHR and WKY rats. 5beta DHT was always the most potent vasorelaxant in arteries from SHR. The KCl-induced contraction resulted significantly more sensitive to androgen-induced vasorelaxation than the Phe-induced contraction. On Phe-induced contraction, 5beta-DHT was more potent in the mesenteric artery than in the thoracic aorta. CONCLUSIONS: The vasorelaxation induced by androgens is mainly mediated by blocking L-VOCCs and in lesser extent by the blockade of multiple signaling pathways operative during alpha-adrenoceptor-induced vasoconstriction. 5beta-DHT regulates vascular resistance and BP by mainly acting in the mesenteric arterial bed, which may explain its outstanding antihypertensive response previously reported. PMID- 29528757 TI - Polyautoimmunity in Patients with LPS-Responsive Beige-Like Anchor (LRBA) Deficiency. AB - BACKGROUND: Polyautoimmunity is defined as the presence of more than one autoimmune disorder in a single patient. Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency is one of the monogenic causes of polyautoimmunity. The aim of this study was to report the characteristics of polyautoimmunity in patients with LRBA deficiency. METHODS: A total of 14 LRBA deficiency patients with confirmed autoimmunity were enrolled in this study. For those patients with polyautoimmunity, demographic information, clinical records, laboratory, and molecular data were collected. We also compared our results with the currently reported patients with LRBA deficiency associated with polyautoimmunity. RESULTS: In 64.2% (9 out of 14) of patients, autoimmunity presented as polyautoimmunity. In these patients, autoimmune cytopenias were the most frequent complication, observed in seven patients. Three patients presented with four different types of autoimmune conditions. The review of the literature showed that 41 of 72 reported LRBA deficient patients (74.5%) had also polyautoimmunity, with a wide spectrum of autoimmune diseases described. Hematopoietic stem cell transplantation is increasingly used as the treatment for patients with severe polyautoimmunity associated to LRBA deficiency. CONCLUSIONS: Mutation in LRBA gene is one of the causes of monogenic polyautoimmunity. Awareness of this association is important in order to make an early diagnosis and prompt treatment. PMID- 29528758 TI - Update on early instillation of chemotherapy after transurethral resection of non muscle-invasive bladder cancer. AB - INTRODUCTION: Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent disease. Early bladder chemotherapy instillation (EBCI) after transurethral resection (TURB) is an efficient way to diminish recurrence. However, this method is often challenged. Areas covered: There was a recent publication of a large meta-analysis with the original patient data and the largest study ever on EBCI. Both brought new evidence on EBCI. Also the results of the 2 trials of EBCI with apaziquone appeared. EBCI is discussed among other methods to decrease recurrence. Expert commentary: EBCI obtains a 35% relative reduction of recurrence with the best results in low risk tumors. However, tumors with an EORTC recurrence score of 5 or more do not respond. It should be given within a few hours after TURB. Mitomycin C and epirubicin have been most widely used with no difference in response. Intensive rinsing of the bladder is also able to reduce recurrence rates by about 21%. A rare, but major problem and reason for not using EBCI is the possible extravasation of the drug after TURB. Apaziquone is rapidly inactivated in tissue and blood and is therefore ideal for local use. Two phase III trials however obtained only a modest result. PMID- 29528759 TI - Hemoadsorption of high-mobility-group box 1 using a porous polymethylmethacrylate fiber in a swine acute liver failure model. AB - BACKGROUND: High-mobility-group box chromosomal protein 1 has been identified as an important mediator of various kinds of acute and chronic inflammation. In this study, we aimed to develop a column that effectively adsorbs high-mobility-group box chromosomal protein 1 by altering the pore size of the fiber. MATERIALS AND METHODS: First, we produced three types of porous polymethylmethacrylate fiber by altering the concentration of polymethylmethacrylate dissolved in dimethylsulfoxide. We then selected a fiber based on the results of an in vitro incubation test of high-mobility-group box chromosomal protein 1 adsorption. Using the selected fiber, we constructed a new column and tested its high mobility-group box chromosomal protein 1 adsorption capacity during 4-h extracorporeal hemoperfusion in a swine acute liver failure model. RESULTS: Electron microscope observation showed that the three types of fibers had different pore sizes on the surface and in cross section, which were dependent on the concentration of polymethylmethacrylate. In the in vitro incubation test, fiber with moderate-sized pores demonstrated the highest adsorption capacity. In the in vivo hemoperfusion study, the ratio of the high-mobility-group box chromosomal protein 1 concentration at the outlet versus the inlet of the column was significantly lower with the new column than with the control column during 4 h extracorporeal hemoperfusion. The normalized plasma level of high-mobility group box chromosomal protein 1 at 12 h after the completion of hemoperfusion was significantly lower with the new column than with the control column. CONCLUSION: The newly developed polymethylmethacrylate column adsorbs high-mobility-group box chromosomal protein 1 during hemoperfusion in swine ALF model. PMID- 29528760 TI - The Effect of Antiamoebic Agents on Viability, Proliferation and Migration of Human Epithelial Cells, Keratocytes and Endothelial Cells, In Vitro. AB - PURPOSE: To analyze the effect of diamidines (hexamidine-diisethionat (HD), propamidin-isethionate (PD), dibromopropamidine-diisethionat (DD)), and biguanides (polyhexamethylen biguanid (PHMB), chlorhexidine (CH)) on human corneal epithelial cell, keratocyte and endothelial cell viability, proliferation, and migration, in vitro. METHODS: For epithelial and endothelial cells a human cell line and for keratocytes primary cultures were used (n = 6 each). We used 3.9x10-4-0.1% HD, PD or DD, 3.9x10-4-0.0125% PD, 7.8x10-5-0.02% PHMB or CH concentration for 24 h to determine viability (Cell Proliferation Kit XTT), proliferation (Cell Proliferation ELISA BrdU kit), and migration using wound healing assay. Viability/proliferation/migration values of each drug were summarized as "area under curve" (AUC) together with a Mann-Whitney test. RESULTS: HCEC, keratocyte, and HCEC-12 viability AUC, comparing PD and PHMB (p <= 0.014 for all; PD better) or PD and HD (p <= 0.011 for all; PD better) differed significantly. Keratocyte and HCEC-12 viability AUC comparing CH and HD (p <= 0.027; CH better), HCEC-12 viability AUC comparing PD and HD (p = 0.005; PD better) and HCEC viability AUC comparing CH and PHMB (p = 0.014; CH better) differed significantly. HCEC proliferation AUC, comparing PD with PHMB, CH, DD, HD (p <= 0.016; PD worse for all) and keratocyte proliferation AUC, comparing PHMB with HD, PD (p = 0.004; p = 0.002; PHMB better for both), CH with HD, PD (p <= 0.001; CH better for both) and DD with PD (p = 0.043; DD better) differed significantly. Keratocyte migration AUC comparing PD with control, PHMB, CH, DD and HD differed significantly (p <= 0.012; PD worse for all). CONCLUSIONS: Propamidin-isethionate as diamidine and chlorhexidin as biguanide may be used clinically to reduce cytotoxicity of antiamoebic treatment on human corneal cells. Diamidines reduce proliferation of human epithelial cells and keratocytes more than biguanides and propamidin-isethionate reduces migration of keratocytes. Therefore, in spite of lower cytotoxicity, the inhibitory effect on proliferation and migration indicates that extended use of propamidin-isethionate should be avoided in patients. PMID- 29528761 TI - Prediction of DNA damage and G2 chromosomal radio-sensitivity ex vivo in peripheral blood mononuclear cells with label-free Raman micro-spectroscopy. AB - PURPOSE: Liquid biopsies are a potentially rich store of biochemical information that can be linked to an individual's response to therapeutic treatments, including radiotherapy, and which may ultimately play a role in the individualization of treatment regimens. Peripheral blood mononuclear cells (PBMCs) can be used not only for the biochemical profiling of the individual, but also, being living cells, can provide insights into the individuals response to ionizing radiation exposure. MATERIALS AND METHODS: The present study attempts to link the biochemical profile of lymphocytes within PBMCs obtained through Raman spectroscopy to in vitro measures of low-dose (<0.5Gy) DNA damage response and cytogenetic metrics of radiosensitivity in a cohort of healthy controls and prostate cancer patients (from CTRIAL-IE(ICORG) 08-17, NCT00951535). All parallel metrics to the Raman spectra of the cells were obtained ex vivo in cycling peripheral blood lymphocytes, with radiosensitivity estimated using the G2 chromosomal assay and DNA damage assessed using gammaH2AX fluorescence. Spectra from a total of 26 healthy volunteers and 22 prostate cancer patients were obtained. RESULTS: The links between both measures of cellular response to ionizing radiation and the Raman spectra were modeled using partial least squares regression (PLSR) and support-vector regression (SVR). It was found that neither regression approach could predict radiation-induced G2 score well, but could predict gammaH2AX MFI with the SVR outperforming PLSR, implying a non-linear relationship between spectral measurements and measures of DNA damage. CONCLUSIONS: Raman spectroscopy of PBMCs represents a label-free approach for prediction of DNA damage levels for either prospective or retrospective analysis. PMID- 29528762 TI - Modifications in the spectrum of bone mass predictive factors with menopausal status. AB - PURPOSE: Fat mass (FM) is a source of adipocytokines, with both positive and negative bone consequences. We aimed to investigate the role of body composition and adipokines as predictive factors for bone mass in women. METHODOLOGY: This cross-sectional study included 93 women (38 premenopausal and 55 postmenopausal). Bone mineral density (BMD) and body composition were assessed by dual-energy X ray absorptiometry. Serum levels of leptin, adiponectin, resistin, and also of the phosphocalcic markers parathormone and vitamin D were measured. RESULTS: Only lean mass (LM) was an independent predictor of BMD in premenopausal women (r2 = 0.381, p < 0.001 for femoral neck BMD, r2 = 0.2, p < 0.01 for whole-body BMD) in both unadjusted and age-adjusted models. The effect of total FM upon BMD became nonsignificant when LM was added to the models assessed. In postmenopausal women, although LM, trunk-to-leg fat ratio, and resistin were initially associated with BMD in unadjusted models, only the trunk-to-leg fat ratio independently predicted BMD at various sites (r2 = 0.171, p < 0.01 for lumbar BMD, r2 = 0.078, p < 0.05 for radius BMD, r2 = 0.094, p < 0.05 for whole-body BMD) after adjusting for age. CONCLUSIONS: While in premenopausal women the effect of LM upon bone is prevalent, after menopause, the fat distribution reflected by trunk-to-leg fat ratio is a major determinant of bone mass at different sites. Our study also stresses that the relationship between total FM and BMD is not mediated by adipokines in women irrespective of menopausal status and body composition, but it is largely mediated by LM only in young premenopausal women. PMID- 29528764 TI - Drugs With Anticholinergic Potential and Risk of Falls With Hip Fracture in the Elderly Patients: A Case-Control Study. AB - BACKGROUND/OBJECTIVE: To determine the association between the use of anticholinergic drugs and the risk of falls with hip fracture in a population older than 60 years. METHODS: A case-control study in patients older than 60 years with a diagnosis of hip fracture. All drugs dispensed during the previous 30 days were identified. Sociodemographic, clinical, pharmacological (drugs according to the Anticholinergic Risk Scale [ARS]), and polypharmacy variables were analyzed. MEASUREMENTS: Falls with hip fracture and type of drug according to the ARS. RESULTS: A total of 300 patients with hip fracture and 600 controls were included. The mean age was 81.6 +/- 8.9 years, with female predominance (71.3%). The use of drugs with moderate (odds ratio [OR]: 1.97, 95% confidence interval [CI]: 1.19-3.27) or high ARS scores (OR: 1.83, 95% CI: 1.13-2.96) increased the probability of fracture. CONCLUSIONS: There was an association between the use of drugs with anticholinergic properties and the probability of hip fracture in elderly patients and it was possible to establish the level of risk. PMID- 29528763 TI - Clinical Markers of Anxiety Subtypes in Parkinson Disease. AB - OBJECTIVE: The aim of this work was to investigate marker profiles for proposed anxiety subtypes in Parkinson disease (PD). METHODS: We used the persistent anxiety, episodic anxiety, and avoidance behavior subscales of the Parkinson Anxiety Scale as dependent variables in multivariable linear regression analyses using a cross-sectional data set of 311 patients with PD. Independent variables consisted of a range of demographic, psychiatric, and disease-specific markers. RESULTS: In the most parsimonious model of persistent anxiety, higher Hamilton Depression Rating Scale scores, a history of anxiety, fewer years of education, lower Mini-Mental State Examination scores, lower Lawton Instrumental Activities of Daily Living scores, female sex, and complications of therapy (higher Unified Parkinson Disease Rating Scale part IV scores) were all associated with more severe persistent anxiety. Markers associated with more severe episodic anxiety included PD-specific disturbances of activities of daily living, complications of therapy, higher Hamilton Depression Rating Scale scores, female sex, and a history of anxiety. Finally, higher Hamilton Depression Rating Scale scores, a history of anxiety, complications of therapy, and longer disease duration were associated with avoidance behavior. After excluding clinically depressed patients with PD, disease severity and longer disease duration were significantly associated with episodic anxiety, but not with persistent anxiety. CONCLUSION: Persistent anxiety is mainly influenced by nonspecific markers, while episodic anxiety seems to be more PD-specific compared to persistent anxiety and may be more situational or contextual. These results provide support for possible distinct underlying constructs for anxiety subtypes in PD. PMID- 29528765 TI - Gender as a Moderator of Descriptive Norms and Substance Use among Latino College Students. AB - This study addresses gaps in the literature by testing gender differences in the associations between substance use norms and substance use among Latino college students. Secondary data analysis was conducted using data from the 2009 National College Health Assessment. Participants selected for this study were 4,336 Latino undergraduates. Linear mixed modeling was used to test gender as a moderator of the relationship between alcohol use norms and alcohol use as well as marijuana use norms and marijuana use. Results indicated that the strength of the relationships between norms and substance use was stronger for males than for females. Substance use rates and gender roles differ for Latinos and Latinas and may partially account for the stronger relationship between these constructs for males. Implications for future research and prevention are discussed. PMID- 29528767 TI - RETRACTED: Online Education Improves Dementia Knowledge: Evidence From an International Intervention. PMID- 29528766 TI - Assessment of genotoxicity and genomic instability in rat primary astrocytes exposed to 872 MHz radiofrequency radiation and chemicals. AB - PURPOSE: We examined genotoxicity, co-genotoxicity and induced genomic instability (IGI) in primary astrocytes exposed to radiofrequency (RF) radiation. MATERIALS AND METHODS: Rat primary astrocytes were exposed to 872 MHz GSM modulated or continuous wave (CW) RF radiation at specific absorption rates of 0.6 or 6.0 W/kg for 24 h. Menadione (MQ) and methyl methanesulfonate (MMS; only in genotoxicity experiments) were used as co-exposures. Alkaline Comet assay and flow cytometric micronucleus scoring were used to detect genetic damage. RESULTS: No IGI was observed from RF radiation alone or combined treatment with MQ. RF radiation alone was not genotoxic. RF radiation combined with chemical exposure showed some statistically significant differences: increased DNA damage at 6.0 W/kg but decreased DNA damage at 0.6 W/kg in cells exposed to GSM-modulated RF radiation and MQ, and increased micronucleus frequency in cells exposed to CW RF radiation at 0.6 W/kg and MMS. CONCLUSIONS: Exposure to GSM modulated RF radiation at levels up to 6.0 W/kg did not induce or enhance genomic instability in rat primary astrocytes. Lack of genotoxicity from RF radiation alone was convincingly shown in multiple experiments. Co-genotoxicity of RF radiation and genotoxic chemicals was not consistently supported by the results. PMID- 29528768 TI - Effect of Low-Energy-Dense Diet Rich in Multiple Functional Foods on Weight-Loss Maintenance, Inflammation, and Cardiovascular Risk Factors: A Randomized Controlled Trial. AB - BACKGROUND: There are no investigations regarding the effects of consuming low energy-dense diets rich in multiple functional foods on weight-loss maintenance, inflammatory markers, and cardiovascular disease (CVD) risk factors simultaneously. METHOD: This randomized controlled trial design was conducted on 90 men and women who were under a previous weight loss diet. Three months of intervention with recruitment at Allzahra Hospital, Isfahan, Iran, was done. Intervention was conducted following achieving 7-11 kg weight loss. Participants were encouraged to consumed these three: an isocaloric control diet (50% of energy from carbohydrate, 35% from fat, 15% from protein), a low-glycemic-index diet (LE) (60% from carbohydrate, 25% from fat, and 15% from protein), and a low glycemic-index diet rich in multiple functional foods (LE + FF) (60% from carbohydrate, 25% from fat, and 15% from protein). Fasting blood glucose, serum insulin level, lipid profiles, inflammatory markers, adiponectin, systolic and diastolic blood pressure, and anthropometric measurements were assessed using standard guidelines. RESULTS: The percent changes of weight, waist, and body mass index (BMI), systolic and diastolic blood pressure, malondialdehyde (MDA), high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF) alpha, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and fasting blood glucose (FBS) were substantially more decreased in the LE + FF group compared to the LE and control groups (p <= 0.03). Percent change of adiponectin among the LE + FF group was significantly more enhanced (7.29 +/- 0.10) compared with the LE group (1.28 +/- 0.20) (p = 0.001). Significantly more increment in the percent change of total antioxidant capacity (TAC) (6.91 +/- 0.10) was obtained among the LE + FF group compared to the LE group (1.79 +/- 0.04). CONCLUSIONS: This study provides established evidence supporting the beneficial effects of a low-energy-dense diet rich in multiple functional foods diet on improving weight-loss maintenance, inflammation, and cardiovascular risk factors. PMID- 29528769 TI - Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine. AB - Amifostine is a potent antioxidant that protects against ionizing radiation effects. In this study, we evaluated the effect of Amifostine administered before total-body irradiation (TBI), at a drug dose that protects against TBI lethality, for potential protection against radiation-induced late effects such as a shortened lifespan and cancer. Three groups of mice were studied: 0 Gy control; 10.8 Gy TBI with Amifostine pretreatment; and 5.4 Gy TBI alone. Animals were monitored for their entire lifespan. The median survival times for mice receiving 0, 5.4 or 10.8 Gy TBI were 706, 460 and 491 days, respectively. Median survival of both irradiated groups was significantly shorter compared to nonirradiated mice ( P < 0.0001). Cancer incidence (hematopoietic and solid tumors) was similar between the irradiated groups and was significantly greater than for the 0 Gy controls. The ratio of hematopoietic-to-solid tumors differed among the groups, with the 5.4 Gy group having a higher incidence of hematopoietic neoplasms compared to the 10.8 Gy/Amifostine group (1.8-fold). Solid tumor incidence was greater in the 10.8 Gy/Amifostine group (1.6-fold). There are few mouse lifespan studies for agents that protect against radiation-induced lethality. Mice treated with 10.8 Gy/Amifostine yielded a lower incidence of hematopoietic neoplasms and higher incidence of solid neoplasms. In conclusion, mice protected from lethal TBI have a shortened lifespan, due in large part to cancer induction after exposure compared to nonexposed controls. Amifostine treatment did protect against radiation-induced hematopoietic tumors, while protection against solid neoplasms was significant but incomplete. PMID- 29528770 TI - Delivery of DTPA through Liposomes as a Good Strategy for Enhancing Plutonium Decorporation Regardless of Treatment Regimen. AB - In this study, we assessed the efficacy of unilamellar 110-nm liposomes encapsulating the chelating agent diethylenetriaminepentaacetic acid (DTPA) in plutonium-exposed rats. Rats were contaminated by intravenous administration of the soluble citrate form of plutonium. The comparative effects of liposomal and free DTPA at similar doses were examined in terms of limitation of alpha activity burden in rats receiving various treatment regimens. Liposomal DTPA given at 1 h after contamination more significantly prevented the accumulation of plutonium in tissues than did free DTPA. Also, when compared to free DTPA, liposome-entrapped DTPA was more efficient when given at late times for mobilization of deposited plutonium. In addition, repeated injections of liposomal DTPA further improved the removal of plutonium compared to single injection. Various possible mechanisms of action for DTPA delivered through liposomes are discussed. The advantage of liposomal DTPA over free DTPA was undoubtedly directly and indirectly due to the better cell penetration of DTPA when loaded within liposomes, mainly in the tissues of the mononuclear phagocytic system. The decorporation induced by liposomal DTPA may result first from intracellular chelation of plutonium deposited in soft tissues, predominantly in the liver. Afterwards, the slow release of free DTPA molecules from these same tissues may enable a sustained action of DTPA, probably mainly by extracellular chelation of plutonium available on bone surfaces. In conclusion, decorporation of plutonium can be significantly improved by liposomal encapsulation of DTPA regardless of the treatment regimen applied. PMID- 29528771 TI - Lethal fat embolism complicating Sotos syndrome. AB - Sotos syndrome is a rare congenital syndrome caused by deletions or mutations in the NSD1 gene (chromosome 5q35) which results in overgrowth. A wide range of manifestations may result in unexpected and/or early death, including congenital cardiac malformations and tumours, epilepsy, intra-tumoural haemorrhage or embolism and bleeding diatheses. A case of lethal pulmonary fat embolism complicating revision of a left total hip replacement following spontaneous fracture is reported in a 39-year-old man with Sotos syndrome. This case demonstrates that orthopaedic problems later in life may be added to potential causes of premature death in this syndrome. PMID- 29528772 TI - Functional Food and Cardiovascular Disease Prevention and Treatment: A Review. AB - Cardiovascular disease (CVD) is now the leading cause of death globally and is a growing health concern. Lifestyle factors, including nutrition, play an important role in the etiology and treatment of CVD. Functional foods based on their basic nutritional functions can decrease the risk of many chronic diseases and have some physiological benefits. They contain physiologically active components either from plant or animal sources, marketed with the claim of their ability to reduce heart disease risk, focusing primarily on established risk factors, which are hyperlipidemia, diabetes, metabolic syndrome, obesity/overweight, elevated lipoprotein A level, small dense low-density lipoprotein cholesterol (LDL-C), and elevated inflammatory marker levels. Functional foods are suspected to exert their cardioprotective effects mainly through blood lipid profile level and improve hypertension control, endothelial function, platelet aggregation, and antioxidant actions. Clinical and epidemiological observations indicate that vegetable and fruit fiber, nuts and seeds, sea foods, coffee, tea, and dark chocolate have cardioprotective potential in humans, as well whole-grain products containing intact grain kernels rich in fiber and trace nutrients. They are nutritionally more important because they contain phytoprotective substances that might work synergistically to reduce cardiovascular risk. This review will focus on the reciprocal interaction between functional foods and the potential link to cardiovascular health and the possible mechanisms of action. PMID- 29528773 TI - A comparison of measured versus self-reported anthropometrics for assessing obesity in adults: a literature review. AB - AIMS: Up-to-date information on the accuracy between different anthropometric data collection methods is vital for the reliability of anthropometric data. A previous review on this matter was conducted a decade ago. Our aim was to conduct a literature review on the accuracy of self-reported height, weight, and body mass index (BMI) against measured values for assessing obesity in adults. To obtain an overview of the present situation, we included studies published after the previous review. Differences according to sex, BMI groups, and continents were also assessed. METHODS: Studies published between January 2006 and April 2017 were identified from a literature search on PubMed. RESULTS: Our search retrieved 62 publications on adult populations that showed a tendency for self reported height to be overestimated and weight to be underestimated when compared with measured values. The findings were similar for both sexes. BMI derived from self-reported height and weight was underestimated; there was a clear tendency for underestimation of overweight (from 1.8%-points to 9.8%-points) and obesity (from 0.7%-points to 13.4%-points) prevalence by self-report. The bias was greater in overweight and obese participants than those of normal weight. Studies conducted in North America showed a greater bias, whereas the bias in Asian studies seemed to be lower than those from other continents. CONCLUSIONS: With globally rising obesity rates, accurate estimation of obesity is essential for effective public health policies to support obesity prevention. As self-report bias tends to be higher among overweight and obese individuals, measured anthropometrics provide a more reliable tool for assessing the prevalence of obesity. PMID- 29528774 TI - Explaining excess morbidity amongst homeless shelter users: A multivariate analysis for the Danish adult population. AB - AIMS: This article analyses excess morbidity amongst homeless shelter users compared to the general Danish population. The study provides an extensive control for confounding and investigates to what extent excess morbidity is explained by homelessness or other risk factors. METHODS: Data set includes administrative micro-data for 4,068,926 Danes who were 23 years or older on 1 January 2007. Nationwide data on shelter use identified 14,730 individuals as shelter users from 2002 to 2006. Somatic diseases were measured from 2007 to 2011 through diagnosis data from hospital discharges. The risk of somatic diseases amongst shelter users was analysed through a multivariate model that decomposed the total effect into a direct effect and indirect effects mediated by other risk factors. RESULTS: The excess morbidity associated with shelter use is substantially lower than in studies that did not include an extensive control. Approximately 80% of excess morbidity amongst shelter users is attributed to other risk factors. A large part of the excess morbidity is explained by substance abuse problems and lack of employment, whilst mental illness, low income, low education, civil status and ethnic minority background explain only a limited part. However, when conducting an extensive control for confounding, a significantly higher morbidity was identified amongst shelter users for infectious diseases, lung, skin, blood and digestive diseases, injuries, and poisoning. CONCLUSIONS: Ill health amongst homeless shelter users is widely explained by substance abuse problems and other risk factors. Nonetheless, for many diseases homelessness poses an additional risk to the health. PMID- 29528775 TI - Number of hospital contacts with alcohol problems predicts later risk of alcoholic liver cirrhosis. AB - AIMS: Alcoholic liver cirrhosis is usually preceded by years of heavy drinking. We investigated whether the risk of alcoholic liver cirrhosis increases as the number of hospital contacts with alcohol problems goes up. METHODS: This was a supplementary analysis on a nationwide register-based cohort study. All patients in Denmark with an initial hospital contact with alcohol problems (alcohol intoxication, harmful alcohol use or alcohol dependence) 1998-2002, free of liver disease, were followed for diagnosis of alcoholic liver cirrhosis. The number of subsequent hospital contacts with alcohol problems was estimated as a time dependent variable for each patient. RESULTS: In all, 36,044 hospital patients with an initial hospital contact with alcohol problems were included. These patients had 301,525 subsequent hospital contacts with alcohol problems. Risk of alcoholic liver cirrhosis increased ( p < 0.0001) with number of alcohol hospital contacts in both men and women for up to nine contacts. CONCLUSIONS: The number of prior hospital contacts with alcohol problems might provide clinicians with a helpful metric in deciding whether to offer preventive interventions for alcoholic liver cirrhosis. PMID- 29528776 TI - Venovenous extracorporeal life support in patients with HIV infection and Pneumocystis jirovecii pneumonia. AB - AIM: As experience with extracorporeal life support (ECLS) increases, indications for its use have expanded to diverse patient populations, including those with HIV infection. Pneumocystis jirovecii pneumonia (PJP) is a particularly devastating complication of HIV infections. The objective of this study was to review ECLS use in HIV-positive patients, with particular emphasis on those with concomitant PJP infection. METHODS: All patients were treated by the same ECLS team, consisting of an ECLS specialist intensivist, cardiothoracic surgeon and allied medical professionals at three healthcare institutions. The same ECLS protocol was utilized for all patients during the study period. A retrospective review was performed for all HIV-positive patients placed on ECLS from May 2011 to October 2014. Demographic, clinical, ECLS and complication data were reviewed to identify risk factors for death. RESULTS: A total of 22 HIV-positive patients received ECLS therapy during the study period. All patients were supported with venovenous ECLS and overall survival to hospital discharge was 68%. Survival amongst the PJP positive cohort was 60%. Non-survivors were more likely to require inotropic medications on ECLS (100% non-survivors vs. 46.7% survivors, p=0.022) and had a longer total duration of ECLS (13 days non-survivors vs. 7 days survivors, p=0.011). No difference was observed between PJP-positive and PJP negative patients with regard to demographic data, complication rates or survival. CONCLUSION: ECLS is a viable treatment option in carefully selected HIV positive patients, including those with severe disease as manifested by PJP infection. PMID- 29528777 TI - ING5 is a Potential Target for Osteosarcoma Therapy. AB - Osteosarcoma is one of the most common primary malignant bone tumors. The inhibitor of growth family of protein 5 has been identified as a tumor suppressor in many cancers. In this study, we confirmed the downregulation of the both inhibitor of growth family of protein 5 and messenger RNA levels in cancer tissues using Western blot and real-time polymerase chain reaction. In order to find the antitumor roles of inhibitor of growth family of protein 5, osteosarcoma cells, HOS, and MG63 were transfected with the plasmid pCDNA-3.1-inhibitor of growth family of protein 5. Overexpression of Inhibitor of growth family of protein 5 could induce apoptosis and inhibit cell proliferation in osteosarcoma cells. Furthermore, Western blot analysis showed that p-Smad2, p-Smad3, and Smad4 were increased in inhibitor of growth family of protein 5-expressing osteosarcoma cells. Our results indicated that overexpression of inhibitor of growth family of protein 5 in osteosarcoma cells induces apoptosis by activating the Smad pathway, thus proposing a promising role for inhibitor of growth family of protein 5 in treatment of patients with osteosarcoma. PMID- 29528778 TI - Physician decision making in anticoagulating atrial fibrillation: a prospective survey of a physician notification system for atrial fibrillation detected on cardiac implantable electronic devices of patients at increased risk of stroke. AB - OBJECTIVES: The objectives of this study were to evaluate the effectiveness of a physician notification system for atrial fibrillation (AF) detected on cardiac devices, and to assess predictors of anticoagulation in patients with device detected AF. METHODS: In 2013, a physician notification system for AF detected on a patient's CIED [including pacemakers, implantable cardioverter defibrillators (ICD) or cardiac resynchronization therapy (CRT) devices] was implemented, with a recommendation to consider oral anticoagulation in high-risk patients. We prospectively investigated the effectiveness of this system, and evaluated both patient and physician predictors of anticoagulation, as well as factors influencing physician decision making in prescribing anticoagulation. Both uni- and multivariable analysis as well as descriptive statistics were used in the analysis. RESULTS: We identified 177 patients with device-detected AF, 126 with a CHADS2 ?2. Only 41% were prescribed anticoagulation at any point within 12 months. On multivariable analysis, stroke risk as predicted by CHADS2 was not a predictor of anticoagulation. ASA use predicted a lower rate of anticoagulation (OR 0.39, 95% CI 0.16-0.97, p = 0.04); physicians in practice for <20 years were more likely to prescribe anticoagulation (OR 3.39, 95% CI 1.28-8.93, p = 0.01); and physicians who believed both cardiologist and family doctor should be involved in managing anticoagulation were more likely to prescribe anticoagulation (OR 3.28, 95% CI 1.02-10.5, p = 0.05). CONCLUSIONS: Patients on aspirin were less likely to be anticoagulated. Physicians in practice for <20 years and who believed that both the general practitioner and cardiologist should be involved in managing anticoagulants were more likely to prescribe anticoagulation. PMID- 29528780 TI - Perpetrating Violence Increases Identification With Violent Groups: Survey Evidence From Former Combatants. AB - Heightened group identification motivates individuals to perpetrate violence, but can perpetrating violence-in and of itself-increase identification with violent groups? I test this idea using archival surveys of ex-combatants. In Liberia, where many combatants joined their violent group willingly, the data show a positive association between perpetrating violence and identification with one's violent group (Study 1). These results hold even when controlling for potentially confounding variables such as being abducted into the group versus joining willingly, length of time in the group, and personally experiencing violence. Study 2 replicates and extends this finding with data from ex-combatants in Uganda who were abducted into their group, using a natural experiment in which some abductees were forced to perpetrate violence whereas other abductees were not. These findings support a cycle of violence in which perpetrating violence increases identification with violent groups and heightened identification increases future violent behavior. PMID- 29528779 TI - Differential mRNA expression of inflammasome genes NLRP1 and NLRP3 in abdominal aneurysmal and occlusive aortic disease. AB - NLRP1 and NLRP3 inflammasomes might differentially mediate the chronic inflammatory response in abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD). We measure differential relative gene expression of NLRP1 and NLRP3 inflammasomes in aortic tissues from 30 patients undergoing AAA open repair compared to aortic biopsies from 30 patients undergoing surgery to treat AOD. Aortic wall samples from autopsy without aortic disease were used as controls. NLRP3 was overexpressed in patients with AAA and AOD (RQ 1.185 +/- 0.15, and 1.098 +/- 0.05, respectively) compared to donors (RQ 1.001 +/- 0.08) (OR 2.8, 95% CI 1.2-4.3, p < 0.05 for AAA and OR 2.1, 95% CI 1.1-3.8, p < 0.05 for AOD). NLRP1 gene expression was significantly upregulated in patients with AOD (RQ 1.197 +/- 0.09). Meanwhile, NLRP1 was normal expressed in AAA (RQ 1.003 +/- 0.07) as well as in autopsy aortic specimens (RQ 1.005 +/- 0.11). Enhanced NLRP1 expression in AOD was even significant when compared to AAA (OR 2.3, 95% CI 1.2-3.3, p < 0.05) or controls (OR 2.2, 95% CI 1.1-3.1, p < 0.05). According to our findings, NLRP3 could be involved in the common etiology of AAA and AOD, whereas NLRP1 appears to have a specific role in AOD development. PMID- 29528781 TI - Intergroup Leadership Across Distinct Subgroups and Identities. AB - Resolving intergroup conflict is a significant and often arduous leadership challenge, yet existing theory and research rarely, if ever, discuss or examine this situation. Leaders confront a significant challenge when they provide leadership across deep divisions between distinct subgroups defined by self contained identities-The challenge is to avoid provoking subgroup identity distinctiveness threat. Drawing on intergroup leadership theory, three studies were conducted to test the core hypothesis that, where identity threat exists, leaders promoting an intergroup relational identity will be better evaluated and are more effective than leaders promoting a collective identity; in the absence of threat, leaders promoting a collective identity will prevail. Studies 1 and 2 ( N = 170; N = 120) supported this general proposition. Study 3 ( N = 136) extended these findings, showing that leaders promoting an intergroup relational identity, but not a collective identity, improved intergroup attitudes when participants experienced an identity distinctiveness threat. PMID- 29528782 TI - The Emergence of Contextual Social Psychology. AB - Social psychology experiences recurring so-called "crises." This article maintains that these episodes actually mark advances in the discipline; these "crises" have enhanced relevance and led to greater methodological and statistical sophistication. New statistical tools have allowed social psychologists to begin to achieve a major goal: placing psychological phenomena in their larger social contexts. This growing trend is illustrated with numerous recent studies; they demonstrate how cultures and social norms moderate basic psychological processes. Contextual social psychology is finally emerging. PMID- 29528784 TI - Wilson disease and lupus nephritis: is it coincidence or a true association? AB - A 12-year-old girl born to third-degree consanguineous parents presented with recurrent episodes of haematuria for 8 months in association with peri-orbital and lower limb oedema for 20 days. There was no jaundice, hepatomegaly or neurological abnormality at presentation. An older brother had died following jaundice at 10 years of age. Urinalysis showed multiple dysmorphic erythrocytes without proteinuria and there was leucopenia, thrombocytopenia and hypo albuminaemia (23 g/L). C3 component of complementaemia was low and anti-nuclear antibodies and anti-double-stranded DNA antibodies were strongly positive by immunofluorescence. Systemic lupus erythematosus (SLE) was considered but the severe hypo-albuminaemia was unexplained. During the pre-renal biopsy work-up, a deranged coagulation profile with raised transaminases prompted evaluation for chronic liver disease which culminated in the diagnosis of Wilson disease. Treatment with penicillamine and immunosuppressants was initiated, but there was neurological deterioration on Day 30 of admission and she died owing to worsening liver failure on the Day 41. Post-mortem liver biopsy demonstrated cirrhosis and post-mortem renal biopsy showed features of class-II lupus nephritis. Auto-immune antibodies and autoimmune disorders have been reported in Wilson disease and there are anecdotal reports of an association of SLE with Wilson disease. However, this case is unique in that lupus nephritis was the presenting manifestation before Wilson disease was diagnosed. The underlying pathophysiological mechanisms of this association requires further research. PMID- 29528783 TI - Sociodemographic Characteristics, Patterns of Crack Use, Concomitant Substance Use Disorders, and Psychiatric Symptomatology in Treatment-Seeking Crack Dependent Individuals in Brazil. AB - Crack cocaine (crack) dependence is a severe disorder associated with considerable morbidity and mortality, constituting a major public health problem in Brazil. The aim of this study was to improve understanding of the profile of treatment-seeking crack-dependent individuals. We recruited 65 crack-dependent individuals from among those seeking treatment at an outpatient clinic for alcohol and drug treatment in the city of Sao Paulo, Brazil. Assessments, conducted between August 2012 and July 2014, focused on sociodemographic characteristics, the pattern/history of crack use, treatment history, concomitant substance use disorders, psychiatric symptomatology, and impulsivity. In the study sample, males predominated, as did unemployment, homelessness, and low levels of education. On average, the participants had smoked crack for 10 years. Most had previously been treated for crack dependence. Concomitant DSM-IV diagnoses of dependence on other substances were common, dependence on tobacco and alcohol being the most prevalent. Participants presented significant psychiatric symptomatology and impulsivity, with nearly half of the sample presenting psychotic symptoms, 90% presenting depressive symptoms, and 80% presenting anxiety symptoms. Most treatment-seeking crack-dependent individuals in Brazil are living in extremely poor social conditions and are struggling with the severe, chronic, and comorbid features of this disorder. PMID- 29528785 TI - Implementing reverse mentoring to address social isolation among older adults. AB - Reverse mentoring is a means to address the social work Grand Challenge of social isolation. Among older adults, reverse mentoring can improve social connection by increasing the digital competence of older adults so they can use technology for social benefit, and by facilitating intergenerational connections with young adult mentors. In this paper, reverse mentoring is examined within an intergenerational program that serves older adults and utilizes the native technological knowledge and skills of young adults who mentor older adult participants. Qualitative data were collected through young adult mentor logs of each session, and through open-ended questions on the post-surveys collected from older adults and young adult mentors. Qualitative analysis revealed three themes related to social connection: (1) an increased sense of self-efficacy for older adults as they build confidence in technological use, and for young adults as they develop leadership skills through mentoring, (2) the breaking down of age related stereotypes, and (3) intergenerational engagement and connection. The findings demonstrate that reverse mentoring can be used in various settings to decrease the social isolation of older adults by developing intergenerational connections and increasing older adult usage of technology. PMID- 29528786 TI - Housing versus treatment first for supportive housing participants with substance use disorders: A comparison of housing and public service use outcomes. AB - BACKGROUND: Homeless persons with substance use disorders (SUD) have high disease risk, poor access to health care, and are frequent users of Medicaid and other social services. Low-demand supportive housing with no prerequisites for treatment or sobriety has been shown to improve housing stability and decrease public service use for chronically homeless persons with serious mental illness (SMI) and chronic medical conditions. The impact of low-demand housing on individuals with SUD but without co-occurring SMI has been little studied. This evaluation compares housing retention and use of crisis public services (jail, emergency department visits, hospitalization, and substance detoxification) between individuals treated and untreated for SUD before move-in to a low-demand supportive housing program in New York City. METHODS: The authors used matched administrative records for individuals with SUD but no SMI placed in supportive housing during 2007-2012. Participants received SUD treatment (n = 1425; treated participants) or were not treated (n = 512; active users) at housing application. Propensity score-weighted regression analyses were used to best estimate the effect of SUD treatment on incarceration, public service utilization, and housing retention. RESULTS: Persons not treated for SUD had a significantly longer tenure in supportive housing than treated participants. However, not treated tenants were more likely to be incarcerated. Opioid agonist therapy and older age decreased the risk of housing discharge, whereas detoxification and inpatient SUD treatment increased the risk of discharge. CONCLUSIONS: Persons with SUD can achieve residential stability in supportive housing that does not require SUD treatment before admission. PMID- 29528787 TI - Begin with the End in Mind: A three-part workshop series to facilitate end-of life discussions with members of the community. AB - Death is among the most avoided topics of conversation. Although end-of-life planning may greatly benefit individuals and their survivors, research and practice indicate that family, friends, and even health care providers resist discussing end-of-life plans. Consequences of not planning ahead have created a public health issue. This article describes a community-level intervention that facilitates those necessary conversations among elders who have at least begun to talk with others about their wishes. A free, three-part educational workshop series on end-of-life planning titled "Begin with the End in Mind" was developed at a midwestern university. A survey was distributed to all attendees to learn about their beliefs regarding end-of-life planning. Inductive content analysis was used to understand participants' thoughts about discussing end-of-life planning. Findings from 33 participants suggest a concern about making plans and ensuring others would follow their wishes. In conclusion, this article offers a roadmap for gerontologists and others to use in engaging the community to think about and act on end-of-life public health issues. PMID- 29528788 TI - Coffee intake, health-related quality of life, and associated factors of overactive bladder in older Korean women living in rural South Korea. AB - Overactive bladder (OAB) is a common health problem in older women. The aim of the study was to investigate coffee consumption, health-related quality of life (HRQOL), and associated factors of OAB in older Korean women living in rural South Korea. A total of 248 women aged 65 years and older participated in this study. Chi-square tests, t-tests, and multivariable logistic regressions were performed. The means of coffee consumption between OAB and non-OAB groups were not significantly different. Women with OAB showed significantly lower HRQOL than women with stress urinary incontinence only. OAB was associated with high body mass index and poor health status. PMID- 29528789 TI - How does paid sick leave relate to health care affordability and poverty among US workers? AB - Secondary data analysis on the 2015 National Health Interview Survey was conducted to determine if having paid sick leave increases the odds of being able to afford specific health care goods and services, and not having access to paid sick leave increases the odds of being in poverty, being food insecure and having elevated medical costs among a representative sample of US workers age 18-64. We found a statistically significant association between paid sick leave and ability to afford dental care, eyeglasses and prescription medication. Workers who lack paid sick leave are more likely than those with paid sick leave to be in poverty and have high medical costs. In conclusion, we found a relationship between paid sick leave benefits and being able to afford needed healthcare services and goods and being more vulnerable to economic hardship. PMID- 29528791 TI - Estimation of lifetime attributable risks (LARs) of cancer associated with abdominopelvic radiotherapy treatment planning computed tomography (CT) simulations. AB - PURPOSE: The present study attempts to calculate organ-absorbed and effective doses for cancer patients to estimate the possible cancer induction and cancer mortality risks resulting from 64-slice abdominopelvic computed tomography (CT) simulations for radiotherapy treatment planning (RTTP). MATERIAL AND METHODS: A group of 70 patients, who underwent 64-slice abdominopelvic CT scan for RTTP, voluntarily participated in the present study. To calculate organ and effective doses in a standard phantom of 70 kg, the collected dosimetric parameters were used with the ImPACT CT Patient Dosimetry Calculator. Patient-specific organ dose and effective dose were calculated by applying related correction factors. For the estimation of lifetime attributable risks (LARs) of cancer incidence and cancer-related mortality, doses in radiosensitive organs were converted to risks based on the data published in Biological Effects of Ionizing Radiation VII (BEIR VII). RESULTS: The mean +/- standard deviation (SD) of the effective dose for males and females were 13.87 +/- 2.37 mSv (range: 9.25-18.82 mSv) and 13.04 +/- 3.42 mSv (range: 6.99-18.37 mSv), respectively. The mean +/- SD of LAR of cancer incidence was 35.34 +/- 13.82 cases in males and 34.49 +/- 9.63 cases in females per 100,000 persons. The LAR of cancer mortality had the mean +/- SD value of 15.38 +/- 4.25 and 16.72 +/- 3.87 cases per 100,000 persons in males and females respectively. CONCLUSION: Increase in the LAR of cancer occurrence and mortality due to abdominopelvic treatment planning CT simulation is noticeable and should be considered. PMID- 29528792 TI - Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). AB - Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine. PMID- 29528793 TI - Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Fruquintinib After Two Prior Chemotherapy Regimens in Chinese Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. AB - Purpose Patients with advanced non-small-cell lung cancer (NSCLC) who fail two lines of chemotherapy have unmet medical needs. The kinase inhibitor fruquintinib selectively targets vascular endothelial growth factor receptors and, hence, tumor angiogenesis and lymphogenesis. This randomized, double-blind, placebo controlled, multicenter phase II trial evaluated the efficacy and safety of fruquintinib in patients with advanced nonsquamous NSCLC who experienced disease progression after second-line chemotherapy. Patients and Methods Eligible patients were randomly assigned (two to one; stratified by epidermal growth factor receptor status) to receive fruquintinib or placebo, both in combination with best supportive care. Oral fruquintinib (5 mg once daily) was given in 4 week cycles of 3 weeks of treatment followed by 1 week off. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was progression-free survival (PFS) evaluated by a blinded image central review (BICR) committee. Secondary end points included investigator evaluated PFS, objective response rate, disease control rate, overall survival, and safety. Results Ninety-one patients from 12 hospitals received treatment with fruquintinib (n = 61) or placebo (n = 30). Median PFS was 3.8 months with fruquintinib by both BICR and investigators' evaluations (hazard ratio by BICR, 0.34; 95% CI, 0.20 to 0.57; P < .001). Three- and 6-month survival rates were 90.2% and 67.2% in the fruquintinib group and 73.3% and 58.8% in the placebo group, respectively. The objective response rate and disease control rate were 13.1% and 60.7% with fruquintinib, compared with 0% and 13.3% with placebo ( P = .041 and < .001), respectively. The most common treatment-emergent adverse events with fruquintinib (>= grade 3) were hypertension (8.2%), hand-foot syndrome (4.9%), and proteinuria (4.9%). Conclusion Third- and fourth-line fruquintinib for advanced NSCLC was superior to placebo and had an acceptable safety profile. PMID- 29528794 TI - Gaps in Receipt of Clinically Indicated Genetic Counseling After Diagnosis of Breast Cancer. AB - Purpose Little is known about the extent to which genetic counseling is integrated into community practices for patients newly diagnosed with breast cancer. We examined the receipt of clinically indicated genetic counseling in these patients. Patients and Methods We surveyed 5,080 patients between the ages of 20 and 79 years, diagnosed from July 2013 to August 2015 with early-stage breast cancer and reported to the SEER registries of Georgia and Los Angeles County. Surveys were linked to SEER clinical data and genetic test results. The study sample (N = 1,711) comprised patients with indications for formal genetic risk evaluation. Results Overall, 47.4% did not get tested, 40.7% tested negative, 7.4% had a variant of uncertain significance only, and 4.5% had a pathogenic mutation. Three quarters (74.6%) received some form of genetic counseling (43.5%, formal counseling and 31.1%, physician-directed discussion). Virtually all tested patients (96.1%) reported some form of genetic discussion (62.2%, formal counseling and 33.9%, physician-directed discussion). However, only one half (50.6%) of those not tested received any discussion about genetics. Younger women were more likely to report some type of counseling, controlling for other factors: odds ratio, 4.5 (95% CI, 2.6 to 8.0); 1.9 (95% CI, 1.1 to 3.3); and 1.5 (95% CI, 1.0 to 2.3) for women younger than 50 years of age, 50 to 59 years of age, and 60 to 69 years of age versus those 70 years of age and older. Patients' assessments of the amount of information they received about whether to get tested were similarly high whether they were counseled by a genetics expert or by a physician only (80.8% v 79.4% stated information was just right, P = .59). Conclusion Less than one half (43.5%) of patients with clinical indications received formal genetic counseling. There is a large gap between mandates for timely pretest formal genetic counseling in higher-risk patients and the reality of practice today. PMID- 29528795 TI - Cross-linking multilayers of poly-l-lysine and hyaluronic acid: Effect on mesenchymal stem cell behavior. AB - BACKGROUND: Cells possess a specialized machinery through which they can sense physical as well as chemical alterations in their surrounding microenvironment that affect their cellular behavior. AIM: In this study, we aim to establish a polyelectrolyte multilayer system of 24 layers of poly-l-lysine and hyaluronic acid to control stem cell response after chemical cross-linking. METHODS AND RESULTS: The multilayer build-up process is monitored using different methods, which show that the studied polyelectrolyte multilayer system grows exponentially following the islands and islets theory. Successful chemical cross-linking is monitored by an increased zeta potential toward negative magnitude and an extraordinary growth in thickness. Human adipose-derived stem cells are used here and a relationship between cross-linking degree and cell spreading is shown as cells seeded on higher cross-linked polyelectrolyte multilayer show enhanced spreading. Furthermore, cells that fail to establish focal adhesions on native and low cross-linked polyelectrolyte multilayer films do not proliferate to a high extent in comparison to cells seeded on highly cross-linked polyelectrolyte multilayer, which also show an increased metabolic activity. Moreover, this study shows the relation between cross-linking degree and human adipose-derived stem cell lineage commitment. Histological staining reveals that highly cross-linked polyelectrolyte multilayers support osteogenic differentiation, whereas less cross-linked and native polyelectrolyte multilayers support adipogenic differentiation in the absence of any specific inducers. CONCLUSION: Owing to the precise control of polyelectrolyte multilayer properties such as potential, wettability, and viscoelasticity, the system presented here offers great potential for guided stem cell differentiation in regenerative medicine, especially in combination with materials exhibiting a defined surface topography. PMID- 29528796 TI - Effect of dry needling on cubital tunnel syndrome: Three case reports. AB - This case series describes three patients who presented with right medial elbow pain managed unsuccessfully with conservative treatment that included medication, massage, exercise therapy, ultrasound therapy, neurodynamic mobilization, and taping. Diagnosis of cubital tunnel syndrome was based on palpatory findings, a positive elbow flexion test, and a positive Tinel's sign. Conventionally, the intervention for this entrapment has been surgical decompression, with successful outcomes. This is potentially a first-time description of the successful management of cubital tunnel syndrome with dry needling (DN) using a recently published DN grading system. The patients were seen twice a week for 2 weeks with immediate improvements noted in all the outcome measures after the first treatment session. At discharge, they were pain-free and fully functional, which was maintained up to a 6-month follow-up. PMID- 29528797 TI - Peer Victimization and Dating Violence Victimization: The Mediating Role of Loneliness, Depressed Mood, and Life Satisfaction. AB - Peer victimization and dating violence victimization have serious negative effects on adolescents' health, and they seem to be related. However, the mediating processes in this relationship have not been sufficiently analyzed. The purpose of this study was to analyze the direct and indirect relationships between peer victimization and dating violence victimization, considering the possible mediator role of loneliness, depressed mood, and life satisfaction. These relationships are analyzed in boys and girls, and in early and middle adolescence. From an initial sample of 1,038 Spanish adolescents, those who had or had had in the past 12 months a dating relationship (647 adolescents; 49.1% boys, M = 14.38, SD = 1.43) were included in this study. Multigroup structural equation modeling was used to test a double mediation model simultaneously for boys and girls, testing the invariance of the relationships among variables across genders. The same technique was used to test the model simultaneously for early and middle adolescence, testing the invariance of the relationships among variables across age groups. Results revealed a positive direct relationship between peer victimization and dating violence victimization, as well as the partial mediating role of loneliness and life satisfaction in this relationship. The mediator role of depressed mood was not supported. The same mediational model was confirmed in boys and girls, and in early and middle adolescence. These results highlight the important role of loneliness and life satisfaction to explain the link between peer victimization and dating violence victimization in adolescence. These findings may be useful for developing intervention programs aimed at preventing situations of multiple victimization during adolescence. PMID- 29528798 TI - The Secondary Traumatic Stress Scale: Confirmatory Factor Analyses With a National Sample of Victim Advocates. AB - Secondary traumatic stress (STS) is a pattern of psychological symptoms that approximates the symptoms of posttraumatic stress disorder (PTSD) and occurs in professionals who are exposed to individuals who have experienced trauma. While victim advocates are frontline health professionals who are trained to support victims of crime and interpersonal violence and are at risk for developing STS, they have been largely neglected in the extant literature on STS. The STS Scale (STSS) is a 17-item self-report questionnaire utilized to assess frequency of symptoms of intrusion, avoidance, and arousal, specifically related to providing services to victims of trauma. The purpose of this study was to investigate the psychometric properties of the STSS with a sample of victim advocates ( N = 135) using confirmatory factor analysis (CFA). Results indicated that both a single factor model and three-factor model were equivalent. This study represents a first attempt to validate a measure of STS among victim advocates, a unique and understudied population who are at risk for developing STS given their work with individuals who have experienced interpersonal violence. Establishing effective, easy to administer, and efficient measures of STS is important given that this population encounters secondary trauma on a regular basis in the context of their job. While additional theoretical work regarding the construct of STS is needed, the STSS did demonstrate high reliability with this population and thus can be used as part of the assessment of STS among victim advocates. PMID- 29528799 TI - Identity Abuse as a Tactic of Violence in LGBTQ Communities: Initial Validation of the Identity Abuse Measure. AB - Intimate partner violence (IPV; i.e., physical, sexual, or psychological abuse by a current or former partner) remains a public health concern with devastating personal and societal costs. Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals are also vulnerable to a dimension of IPV called identity abuse (IA); that is, abuse tactics that leverage systemic oppression to harm an individual. Yet, we know little about its relative prevalence in subgroups of the LGBTQ community. This study developed and evaluated a measure of IA, and explored its prevalence in a sample of 734 sexual minority adults. The sample included women (53.1%), men (27.4%), and transgender or gender nonconforming "TGNC" (19.3%) participants. The majority of participants identified as queer or pansexual (38.7%), then gay (23.6%), lesbian (22.8%), and bisexual (13.6%). Participants completed an online survey that included measures of IA and physical, sexual, and psychological abuse. The IA items formed a unidimensional factor structure with strong internal consistency and construct validity. Nearly one fifth of the sample (16.8%) experienced past year IA and 40.1% reported adult IA. Women experienced greater exposure to IA in adulthood than men, and TGNC participants reported higher rates of IA in adulthood and in the last year compared to their cisgender counterparts. The odds of queer or bisexual participants reporting IA in adulthood were almost three times higher than gay participants, and two times higher than lesbian participants. Findings have implications for advancing assessment of partner abuse in the LGBTQ community, LGBTQ-competent clinical care, and training of practitioners. PMID- 29528800 TI - Do Multiple Forms of Social Capital Mediate the Relationship Between Parental Violence and Children's Maladaptive Behaviors? AB - Many things can harm children's well-being. Among them, exposure to parental violence makes children vulnerable and often leads to aggression and/or depression. However, not all children who have suffered parental violence show aggressive behavior or depressive mood. Social capital, defined as resources accruing from interpersonal relationships, was proposed to significantly mediate the relationships among adverse experiences and their negative impacts. In previous studies, social capital accrued from parents played a positive role for children in violent situations, but children exposed to parental violence need alternative sources of social capital. This study targeted fourth-grade Korean children and aimed to identify and test the role of various forms of social capital to help children overcome negative consequences from parental violence. Siblings, friends, teachers, neighbors, and online acquaintances were sources of social capital, and the results showed that social capital from siblings, teachers, neighbors, or online acquaintances mediated in the relationships between parental violence and aggressive behavior. In addition, social capital from siblings and online acquaintances mediated in the relationships between parental violence and depressive mood. The findings have implications in terms of intervention. It is suggested that multiple forms of social capital from children's immediate environments are helpful in their adaptation from exposure to parental violence, and thus, relationship-based interventions are recommended. PMID- 29528801 TI - Transphobia-Based Violence, Depression, and Anxiety in Transgender Women: The Role of Body Satisfaction. AB - Psychological processes may mediate the relationship between minority stress and mental health though limited data exist showing this pathway among trans women. Trans women's degree of satisfaction with their body is associated with mental health outcomes. This study used a model of minority stress to explore for indirect effects on the association between transphobia-based victimization and anxiety and depression through one's degree of body satisfaction. Analysis also explored for racial differences. Transgender women ( N = 233) were recruited in 2013 using respondent-driven sampling. Sociodemographics, transphobia-based victimization experiences such as having been physically abused, body satisfaction, and mental health were measured. Analyses assessed for direct and indirect associations while controlling for gender confirmation therapies (i.e., cross-sex hormone therapy and gender confirmation surgeries) and racial identity; 57% reported depression and 42.1% reported anxiety diagnoses. Participants averaged nearly three of six assessed violence experiences. More than 20% reported low body satisfaction. Contrary to authors' expectations, those reporting African American and Other racial identity experienced less transphobia based violence than whites. Transphobia-based violence was significantly associated with anxiety, depression, and body satisfaction. Body satisfaction was associated with mental health diagnoses. Bootstrapping revealed significant indirect and total effects. Body satisfaction mediated the relationship between transphobia-based violence and mental health. Clinical intervention that promotes body satisfaction including access to gender confirmation therapies, especially hormone therapy, may prevent negative mental health outcomes among trans women. Individual intervention, however, is not a panacea for structural discrimination. Attention to structural interventions that reduce gender minority stressors including transphobia-based violence is necessary. PMID- 29528802 TI - School Victimization, Immigration, Dropping Out, and Gender Disparities. AB - The children of immigrants face a number of educational hurdles, such as disparate rates of victimization and increased risk of dropping out of high school. Few studies have explored how school victimization can explain the relationship between immigrant generation status and the likelihood of dropping out. The current study explores if, and how, the associations between school victimization, feeling unsafe at school, and dropping out vary across immigration generations andgender. Data are drawn from the Educational Longitudinal Study of 2002. The sample for this study consists of 9,870 first ( N = 1,170, 12%), second ( N = 1,540, 16%), and third-plus ( N = 7,160, 73%) generation, female ( N = 5,050; 51%), and male (4,820; 49%) students in 580 public schools. Results indicate partial support for segmented assimilation and highlight important nuances related to immigrant generation status.in relation to key variables. For both males and females, generational status, victimization, and feeling unsafe at school significantly influence the likelihood (positively and negatively) of dropping out. In regard to school victimization, first generation females are less likely to drop out than third-plus generation females. For males, victimization at school generally decreases their likelihood of dropping out, except for second generation males who have an increased likelihood of dropping out. Females who feel unsafe are generally more likely to drop out, with no significant differences across generations. For males, feeling unsafe at school generally increases the likelihood of dropping out, except for second generation males who have a decreased likelihood of dropping out. PMID- 29528803 TI - Maltreatment and Affective and Behavioral Problems in Emerging Adults With and Without Oppositional Defiant Disorder Symptoms: Mediation by Parent-Child Relationship Quality. AB - The current study examined the indirect effect of maternal and paternal emotional and physical maltreatment on affective and behavioral symptoms of oppositional defiant disorder (ODD) through parent-child relationship quality; gender and overall ODD symptoms were examined as moderators. Participants included 2,362 emerging adults who completed questionnaires about parental emotional and physical maltreatment, parent-child relationship quality, and affective and behavioral ODD symptoms. These characteristics were compared across parent and child gender (i.e., maternal and paternal effects as well as male and female differences) as well as participants reporting high and low ODD symptoms. In the low ODD group, indirect effects of emotional maltreatment occurred in all parent child dyads except the mother-son dyad, whereas in the high ODD group, indirect effects occurred only in the father-son dyad. Indirect effects of physical maltreatment occurred only in the father-son dyad in the low ODD group, and only in the mother-daughter dyad on behavioral ODD symptoms in the high ODD group. The results suggest that specific parent-child gender dyads respond differently, warranting further investigation of gender effects. Moreover, emerging adults in the low ODD symptoms group demonstrated a positive association between parental maltreatment and ODD symptoms and a negative association between parent-child relationship quality and ODD symptoms, whereas those high in the high ODD symptoms group did not demonstrate these associations. That is, emerging adults reporting high ODD symptoms demonstrated no relationship between their ODD symptoms and harsh parenting, suggesting an ineffective coercive process. PMID- 29528804 TI - Complexity and gaps: The high-hanging fruit of dementia and palliative care research. PMID- 29528805 TI - Molecular insights into substrate binding mechanism of undecaprenyl pyrophosphate with membrane integrated phosphatidyl glycerophosphate phosphatase B (PgpB) using molecular dynamics simulation approach. AB - Undecaprenyl phosphate (C55-P) acts as carrier lipid in the synthesis of peptidoglycan, which is de novo synthesized from dephosphorylation of undecaprenyl pyrophosphate (C55-PP). The phosphatidylglycerol phosphate phosphatase B (PgpB) catalyzes the dephosphorylation of C55-PP and forms C55-P. As no structural study has been made regarding the binding of C55-PP to PgpB, in the current study, in silico molecular docking, followed by 150 ns molecular dynamics simulation of the putative binding complex in membrane/solvent environment has been performed to understand conformational dynamics. Results are compared with simulated apo form and PE inhibitor-bound form. Analysis of correlated residual fluctuation network in apo form, C55-PP bound and PE inhibitor-bound form suggests that difference in dynamic coupling between TM domain and alpha2 and alpha3 helix of periplasmic domain provides ligand binding to facilitate catalysis or to show inhibitory activity. Distance distribution in catalytic residual pair, H207-R104; H207-R201 and H207-D211 which stabilizes phosphate-enzyme intermediate shows a narrow peak in 2.4-3.6 A in substrate-bound compared to apo form. Binding interactions and binding free energy analyses complement the partial inhibition of PE where PE has less binding free energy compared to the C55-PP substrate as well as the difference in binding interaction with catalytic pocket. Thus, the present study provides how substrate binding couples the movement in TM domain and periplasmic domain which might help in the understanding of active site communication in PgpB. C55-PP phosphatase interactions with a catalytic pocket of PgpB provide new insight for designing drugs against bacterial infection. PMID- 29528806 TI - Neostigmine Hyperinflation. PMID- 29528807 TI - The Effectiveness of Dialectical Behavior Therapy Skills Training Group vs. Cognitive Therapy Group on Reducing Depression and Suicide Attempts for Borderline Personality Disorder in Taiwan. AB - In this study the effectiveness of the condensed Dialectical Behavior Therapy Skills Training Group (DBTSTG) was compared to the Cognitive Therapy Group (CTG) in reducing depression and suicide reattempt and modifying emotion regulation strategies among those with borderline personality disorder (BPD). A total of 82 depressed BPD college students with a suicidal history within the past 6-months were randomly allocated to DBTSTG or CTG. Both groups had similar reductions in suicide reattempts and depression after the intervention and 6-month follow-ups. However, the CTG showed improvements in cognitive errors, but the DBTSTG revealed increases in acceptance and decreases in suppression scores. Both groups were effective in decreasing depression and suicide reattempt in BPD college students, probably through increasing adaptive antecedent-focused or response-focused strategies of emotion regulation, respectively. PMID- 29528808 TI - Phenotypic and genotypic characteristics of Trueperella pyogenes isolated from ruminants. AB - Trueperella pyogenes is an opportunistic pathogen that causes suppurative infections in animals including humans. Data on phenotypic and genotypic properties of T. pyogenes isolated from ruminants, particularly goats and sheep, are lacking. We characterized, by phenotypic and genotypic means, T. pyogenes of caprine and ovine origin, and established their phylogenetic relationship with isolates from other ruminants. T. pyogenes isolates ( n = 50) from diagnostic specimens of bovine ( n = 25), caprine ( n = 19), and ovine ( n = 6) origin were analyzed. Overall, variable biochemical activities were observed among the T. pyogenes isolates. The fimbriae-encoding gene, fimE, and neuraminidase-encoding gene, nanH, were, respectively, more frequently detected in the large ( p = 0.0006) and small ( p = 0.0001) ruminant isolates. Moreover, genotype V ( plo/ nanH/ nanP/ fimA/ fimC) was only detected in the caprine and ovine isolates, whereas genotype IX ( plo/ nanP/ fimA/ fimC/ fimE) was solely present in the isolates of bovine origin ( p = 0.0223). The 16S rRNA gene sequences of all T. pyogenes isolates were clustered with the reference T. pyogenes strain ATCC 19411 and displayed a high degree of identity to each other. Our results highlight phenotypic and genotypic diversity among ruminant isolates of T. pyogenes and reinforce the importance of characterization of more clinical isolates to better understand the pathogenesis of this bacterium in different animal species. PMID- 29528809 TI - Histologic characterization of eosinophilic encephalitis in horses in Florida. AB - Eosinophils within the central nervous system are abnormal and are usually associated with fungal or parasitic infections in horses. Causative agents include Halicephalobus gingivalis, Sarcocystis neurona, and Neospora hughesi. Confirmation of these organisms via specific testing is typically not performed, and final diagnoses are often presumptive. With molecular technology, many of these organisms can now be confirmed. This is important for emerging and zoonotic pathogens, including Angiostrongylus cantonensis, an emerging parasite of interest in the southeastern United States. We retrospectively analyzed eosinophilic encephalitides in Floridian horses for H. gingivalis, S. neurona, and A. cantonensis, applied descriptors to equine eosinophilic encephalitides, and determined if a relationship existed between these descriptions and specific etiologic agents. In a database search for horses with eosinophilic and other encephalitides submitted to the University of Florida, College of Veterinary Medicine, Anatomic Pathology Service, we identified 27 horses with encephalitis, and performed DNA isolation and rtPCR on formalin-fixed, paraffin-embedded blocks from these cases. Real-time PCR identified 6 horses positive for S. neurona and 4 horses positive for H. gingivalis; all horses were negative for A. cantonensis. All 25 control horses were negative for H. gingivalis, S. neurona, and A. cantonensis. Pattern analysis and eosinophil enumeration were not useful in differentiating among causes of eosinophilic encephalitides in horses in our study. PMID- 29528810 TI - A blastema-predominant canine renal nephroblastoma with gingival metastasis: case report and literature review. AB - Nephroblastomas are uncommon embryonal tumors in dogs. We report herein a blastema-predominant nephroblastoma with gingival metastasis in an 8-y-old Miniature Pinscher dog. Histologically, the mass was composed mainly of blastemal elements with minor epithelial and mesenchymal differentiation. Metastatic masses in the gingiva had histologic and immunohistochemical features similar to those of the primary renal nephroblastoma. Neoplastic cells were extensively positive for both vimentin and PAX8, and scattered positive for cytokeratin. Using the clinical staging of human Wilms tumor, we staged our case as stage IV with <4 mo of survival time. We summarized previous studies of canine renal and spinal nephroblastomas, and analyzed the correlations among clinical staging, histologic classification, and mean survival time of dogs with renal nephroblastomas. Clinical staging was significantly correlated with survival time, as shown in humans. In dogs, however, additional factors can potentially influence the outcome of treatment and disease development. PMID- 29528811 TI - Excess EDTA interferes with cortisol measurement using a solid-phase, chemiluminescent enzyme immunoassay. AB - Hormone assays that use a solid-phase, automated, chemiluminescent enzyme immunoassay (CEIA) with an alkaline phosphatase-tagged hormone or antibody as a reporter are performed on serum or EDTA plasma in our laboratory. CEIA cortisol results appeared to increase in the presence of excess EDTA. We investigated the effect of the addition of different amounts of EDTA on cortisol concentrations in pooled canine serum samples. The recommended EDTA plasma concentration of 4.1 mmol/L (1.8 mg/mL) did not alter cortisol concentrations when added to serum pools; however, the addition of >=5.1 mmol/L (2.25 mg/mL) of EDTA increased apparent concentrations of cortisol. Supplementation of serum samples with MgCl2 to 5 mmol/L reversed the effect of EDTA up to a concentration of ~8.1 mmol/L (3.6 mg/mL). Our findings show that CEIA cortisol results on EDTA plasma can be artificially increased if the EDTA concentration exceeds 5.1 mmol/L. PMID- 29528812 TI - Comparative analysis of Campylobacter isolates from wild birds and chickens using MALDI-TOF MS, biochemical testing, and DNA sequencing. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was compared to conventional biochemical testing methods and nucleic acid analyses (16S rDNA sequencing, hippurate hydrolysis gene testing, whole genome sequencing [WGS]) for species identification of Campylobacter isolates obtained from chickens ( Gallus gallus domesticus, n = 8), American crows ( Corvus brachyrhynchos, n = 17), a mallard duck ( Anas platyrhynchos, n = 1), and a western scrub-jay ( Aphelocoma californica, n = 1). The test results for all 27 isolates were in 100% agreement between MALDI-TOF MS, the combined results of 16S rDNA sequencing, and the hippurate hydrolysis gene PCR ( p = 0.0027, kappa = 1). Likewise, the identifications derived from WGS from a subset of 14 isolates were in 100% agreement with the MALDI-TOF MS identification. In contrast, biochemical testing misclassified 5 isolates of C. jejuni as C. coli, and 16S rDNA sequencing alone was not able to differentiate between C. coli and C. jejuni for 11 sequences ( p = 0.1573, kappa = 0.0857) when compared to MALDI TOF MS and WGS. No agreement was observed between MALDI-TOF MS dendrograms and the phylogenetic relationships revealed by rDNA sequencing or WGS. Our results confirm that MALDI-TOF MS is a fast and reliable method for identifying Campylobacter isolates to the species level from wild birds and chickens, but not for elucidating phylogenetic relationships among Campylobacter isolates. PMID- 29528813 TI - Non-toxigenic Corynebacterium ulcerans sequence types 325 and 339 isolated from two dogs with ulcerative lesions in Italy. AB - Corynebacterium ulcerans, an emerging pathogen related to C. diphtheriae and C. pseudotuberculosis, is able to cause disease in both human and animal hosts. C. ulcerans may harbor acquired virulence factors such as dermonecrotic exotoxin phospholipase D (PLD) and the prophage-encoded diphtheria toxin (DT). Infections typically occur in persons reporting close contact with animals. In pets, C. ulcerans has been isolated from both asymptomatic carriers and clinically affected dogs and cats. We describe the isolation and characterization of C. ulcerans strains from 2 pet dogs with ulcerative lesions in Italy. The 2 isolates tested negative for both DT genes, but were PLD-producers and belonged to sequence types (STs) 325 and 339. These 2 cases highlight that C. ulcerans cutaneous infections might be underestimated in pets, given that many veterinary laboratories do not routinely consider and/or identify Corynebacterium species from cutaneous samples. Early detection and molecular typing of C. ulcerans is essential in order to implement effective treatment and to prevent diffusion and possible zoonotic transmission of certain STs. PMID- 29528814 TI - Imaging of Juvenile Hip Conditions Predisposing to Premature Osteoarthritis Erratum. PMID- 29528815 TI - Updates in Diagnosis, Management, and Treatment of Neuroblastoma. AB - Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system. It is the most common extracranial solid tumor of childhood and accounts for up to 15% of all pediatric cancer fatalities. The manifestation of neuroblastoma is variable depending on the location of the tumor and on the presence or absence of paraneoplastic syndromes. The prognosis of neuroblastoma is also highly variable, ranging from spontaneous regression to widespread metastatic disease that is unresponsive to treatment. The age of the patient, stage of disease, histopathologic results, and multiple biologic factors contribute to the presurgical and pretreatment risk stratification of a patient with neuroblastoma. Multimodality anatomic imaging with ultrasonography, computed tomography, and magnetic resonance imaging, as well as functional or metabolic nuclear imaging, are essential to determining the risk status of a patient with neuroblastoma. Patients at low risk of metastasis or death receive minimal intervention and those at high risk receive multimodality treatment. New immunotherapeutic techniques and nuclear medicine-targeted therapies have emerged and are demonstrating promising response rates for patients at high risk. This article reviews updates in the diagnosis, management, and treatment of neuroblastoma that have evolved over the past 2 decades, including emphasis on presurgical risk stratification, genetic evaluation of tumors, and the use of modern, high quality, advanced imaging modalities. (c)RSNA, 2018. PMID- 29528816 TI - Dual-Energy CT for Abdominal and Pelvic Trauma. AB - Computed tomography (CT) is key to the assessment of hemodynamically stable patients with blunt or penetrating trauma to the abdomen and pelvis. Dual-energy (DE) CT is a technology that allows acquisition of data at both high and low kilovolt peaks, allowing materials that have different x-ray absorption behaviors as a function of kilovolt peak (such as iodine) to be differentiated and quantified. DE CT has a variety of postprocessing applications that may be helpful in abdominal and pelvic trauma, including iodine-selective imaging, virtual monenergetic imaging, and virtual noncalcium imaging. Both iodine selective imaging and virtual monoenergetic imaging can increase the conspicuity of traumatic solid-organ and hollow visceral injuries, making injuries easier to detect and categorize. Iodine-selective imaging, through the use of iodine maps and virtual noncontrast images, can assist in the evaluation of active contrast extravasation. Virtual noncalcium images can unmask bone marrow edema, improving detection of subtle fractures. The purpose of this review article is to familiarize radiologists with the basic physics and technical principles of DE CT, common postprocessing techniques, and the potential added value of DE CT in patients with abdominal and pelvic trauma. The technical limitations of DE CT are also reviewed, as are diagnostic pitfalls and common challenges in interpretation. (c)RSNA, 2018. PMID- 29528817 TI - Endometrial Thickness in Symptomatic Postmenopausal Patients Receiving Hormone Replacement Therapy or Tamoxifen. PMID- 29528818 TI - Liver Iron Quantification with MR Imaging: A Primer for Radiologists. AB - Iron overload is a systemic disorder and is either primary (genetic) or secondary (exogenous iron administration). Primary iron overload is most commonly associated with hereditary hemochromatosis and secondary iron overload with ineffective erythropoiesis (predominantly caused by beta-thalassemia major and sickle cell disease) that requires long-term transfusion therapy, leading to transfusional hemosiderosis. Iron overload may lead to liver cirrhosis and hepatocellular carcinoma, in addition to cardiac and endocrine complications. The liver is one of the main iron storage organs and the first to show iron overload. Therefore, detection and quantification of liver iron overload are critical to initiate treatment and prevent complications. Liver biopsy was the historical reference standard for detection and quantification of liver iron content. Magnetic resonance (MR) imaging is now commonly used for liver iron quantification, including assessment of distribution, detection, grading, and monitoring of treatment response in iron overload. Several MR imaging techniques have been developed for iron quantification, each with advantages and limitations. The liver-to-muscle signal intensity ratio technique is simple and widely available; however, it assumes that the reference tissue is normal. Transverse magnetization (also known as R2) relaxometry is validated but is prone to respiratory motion artifacts due to a long acquisition time, is presently available only for 1.5-T imaging, and requires additional cost and delay for off line analysis. The R2* technique has fast acquisition time, demonstrates a wide range of liver iron content, and is available for 1.5-T and 3.0-T imaging but requires additional postprocessing software. Quantitative susceptibility mapping has the highest sensitivity for detecting iron deposition; however, it is still investigational, and the correlation with liver iron content is not yet established. (c)RSNA, 2018. PMID- 29528819 TI - Idiopathic Granulomatous Mastitis: Manifestations at Multimodality Imaging and Pitfalls. AB - Idiopathic granulomatous mastitis (IGM) is a rare benign inflammatory breast entity characterized by lobulocentric granulomas. IGM has a persistent or recurrent disease course and affects parous premenopausal women with a history of lactation. It has also been associated with hyperprolactinemia. The most common clinical sign is a palpable tender mass. However, the nonspecific manifestations and varied demographic features of this condition, as well as the other similar appearing and superimposed breast entities, pose substantial diagnostic challenges. Entities with similar manifestations include inflammatory breast cancer (IBC), infective mastitis, foreign body injection granulomas, mammary duct ectasia, diabetic fibrous mastopathy, and systemic granulomatous processes. The strategy for imaging IGM depends on patient age, clinical manifestations, and risk factors. Targeted ultrasonography, mammography, and less commonly, magnetic resonance imaging have proven to be useful for imaging evaluation. Core-needle biopsy, with or without fine-needle aspiration for cytopathologic examination, and culture analysis are usually required to exclude IBC and other benign inflammatory breast processes. Patients with IGM have an excellent prognosis when they are appropriately treated with oral steroids or second-line immunosuppressive and prolactin-lowering medications. However, surgical excision may be an option for patients in whom medication therapy is unsuccessful. Imaging surveillance can be offered to patients with incidentally encountered IGM or mild symptoms. Clinical suspicion for this rare disease and the breast imager's prompt diagnosis can lead to an improved patient outcome. The purpose of this article is to review the imaging manifestations of IGM in a multimodality case-based format and to describe relevant clinical and imaging-based differential diagnoses. The associated pitfalls, epidemiologic and histopathologic factors, clinical manifestations, natural course, and management of IGM also are discussed. (c)RSNA, 2018. PMID- 29528820 TI - Predictive Modeling and Feature Selection: The Way Forward in Texture Analysis. PMID- 29528821 TI - Lynch Syndrome: Genomics Update and Imaging Review. AB - Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites. Over time, the accumulation of mutations in microsatellites and elsewhere in the genome can affect the production of important cellular proteins, spurring tumorigenesis. Universal testing of colorectal tumors for microsatellite instability (MSI) is now recommended to (a) prevent cases of Lynch syndrome being missed owing to the use of clinical criteria alone, (b) reduce morbidity and mortality among the relatives of affected individuals, and (c) guide management decisions. Organ specific cancer risks and associated screening paradigms vary according to the sex of the affected individual and the type of germline DNA alteration causing the MSI. Furthermore, Lynch syndrome-associated cancers have different pathologic, radiologic, and clinical features compared with their sporadic counterparts. Most notably, Lynch syndrome-associated tumors tend to be more indolent than non-Lynch syndrome-associated neoplasms and thus may respond differently to traditional chemotherapy regimens. The high MSI in cases of colorectal cancer reflects a difference in the biologic features of the tumor, possibly with a unique susceptibility to immunotherapy. (c)RSNA, 2018. PMID- 29528822 TI - Multimedia-enhanced Radiology Reports: Concept, Components, and Challenges. AB - Multimedia-enhanced radiology report (MERR) development is defined and described from an informatics perspective, in which the MERR is seen as a superior information-communicating entity. Recent technical advances, such as the hyperlinking of report text directly to annotated images, improve MERR information content and accessibility compared with text-only reports. The MERR is analyzed by its components, which include hypertext, tables, graphs, embedded images, and their interconnections. The authors highlight the advantages of each component for improving the radiologist's communication of report content information and the user's ability to extract information. Requirements for MERR implementation (eg, integration of picture archiving and communication systems, radiology information systems, and electronic medical record systems) and the authors' initial experiences and challenges in MERR implementation at the National Institutes of Health are reviewed. The transition to MERRs has provided advantages over use of traditional text-only radiology reports because of the capacity to include hyperlinked report text that directs clinicians to image annotations, images, tables, and graphs. A framework is provided for thinking about the MERR from the user's perspective. Additional applications of emerging technologies (eg, artificial intelligence and machine learning) are described in the crafting of what the authors believe is the radiology report of the future. (c)RSNA, 2018. PMID- 29528823 TI - Cross-sectional Imaging of Splenic Lesions: RadioGraphics Fundamentals | Online Presentation. PMID- 29528824 TI - An Interventionalist's Guide to Hemoptysis in Cystic Fibrosis. AB - Massive hemoptysis occurs in a minority of patients with cystic fibrosis, with an annual incidence of 1%. Although rare, massive hemoptysis can be a severe and potentially fatal complication of this disease. Beyond the acute life-threatening event, hemoptysis in patients with cystic fibrosis has been associated with faster decline in lung function, accelerated need for lung transplant, and increased mortality. The bronchial arteries are the culprit vessels in over 90% of cases of hemoptysis. This normally quiescent vascular system undergoes remarkable hypertrophy, collateralization, and angiogenesis before the onset of hemoptysis, introducing numerous pitfalls for the interventionalist. However, in experienced hands, bronchial artery embolization is a safe and potentially lifesaving therapy. Preprocedural noninvasive imaging, specifically computed tomographic angiography, has been repeatedly validated for helping to localize the likely site of bleeding, characterizing pertinent arterial anatomy, and promoting efficient and effective intervention; it has been recommended for all stable patients with hemoptysis. Success in the angiographic suite requires a thorough understanding of normal and variant bronchial arterial anatomy, appropriate patient selection, and a meticulous embolization technique. A meticulous approach to imaging and intervention, conscientious of both visualized and nonvisualized collateral pathways and nontarget vessels, can minimize potentially devastating complications. This review summarizes the current literature, modern procedural techniques, and emerging controversies, serving to guide an evolving approach to management of patients with cystic fibrosis and hemoptysis. (c)RSNA, 2018. PMID- 29528825 TI - PET/CT in Oncologic Imaging of Nodal Disease: Pearls and Pitfalls: RadioGraphics Fundamentals | Online Presentation. PMID- 29528826 TI - Current and Novel Techniques for Metal Artifact Reduction at CT: Practical Guide for Radiologists. AB - Artifacts caused by metallic implants appear as dark and bright streaks at computed tomography (CT), which severely degrade the image quality and decrease the diagnostic value of the examination. When x-rays pass through a metal object, depending on its size and composition, different physical effects negatively affect the measurements in the detector, most notably the effects of photon starvation and beam hardening. To improve image quality and recover information about underlying structures, several artifact reduction methods have been introduced in modern CT systems. Projection-based metal artifact reduction (MAR) algorithms act in projection space and replace corrupted projections caused by metal with interpolation from neighboring uncorrupted projections. MAR algorithms primarily suppress artifacts that are due to photon starvation. The dual-energy CT technique is characterized by data acquisition at two different energy spectra. Dual-energy CT provides synthesized virtual monochromatic images at different photon energy (kiloelectron volt) levels, and virtual monochromatic images obtained at high kiloelectron volt levels are known to reduce the effects of beam hardening. In clinical practice, although MAR algorithms can be applied after image acquisition, the decision whether to apply dual-energy CT for the patient usually needs to be made before image acquisition. Radiologists should be more familiar with the clinical and technical features of each method and should be able to choose the optimal method according to the clinical situation. (c)RSNA, 2018. PMID- 29528827 TI - Endobronchial Paraganglioma: AIRP Best Cases in Radiologic-Pathologic Correlation. AB - Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP). PMID- 29528829 TI - Intrauterine Linear Echogenicities in the Gravid Uterus: What Radiologists Should Know. AB - Intrauterine linear echogenicity (ILE) is a common ultrasonographic finding in the gravid uterus and has variable causes and variable maternal and fetal outcomes. Correctly categorizing ILE during pregnancy is crucial for guiding surveillance and advanced imaging strategies. Common causes of ILE include membranes in multiple gestations, uterine synechiae with amniotic sheets, and uterine duplication anomalies. Less common causes include circumvallate placenta, chorioamniotic separation, and hemorrhage between membranes. Amniotic band syndrome is a rare but important diagnosis to consider, as it causes severe fetal defects. Imaging findings enable body stalk anomaly, a lethal defect, to be distinguished from amniotic bands, which although destructive are not necessarily lethal. This review describes the key imaging findings used to differentiate the various types of ILE in pregnancy, thus enabling accurate diagnosis and appropriate patient counseling. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29528828 TI - Imaging and Management of Blunt Cerebrovascular Injury. AB - Blunt cerebrovascular injury (BCVI) is a relatively rare but potentially devastating finding in patients with high-energy blunt force trauma or direct cervical and/or craniofacial injury. The radiologist plays an essential role in identifying and grading the various types of vascular injury, including minimal intimal injury, dissection with raised intimal flap or intraluminal thrombus, intramural hematoma, pseudoaneurysm, occlusion, transection, and arteriovenous fistula. Early identification of BCVI is important, as treatment with antithrombotic therapy has been shown to reduce the incidence of postinjury ischemic stroke. Patients with specific mechanisms of injury, particular imaging findings, or certain clinical signs and symptoms have been identified as appropriate and cost-effective for BCVI screening. Although digital subtraction angiography was previously considered the standard examination for screening, technologic improvements have led to its replacement with computed tomographic angiography. Of note, although not appropriate for screening, improvements in magnetic resonance angiography with vessel wall imaging hold promise as supplemental imaging studies that may improve diagnostic specificity for vessel wall injuries. Understanding the screening criteria, imaging modalities of choice, imaging appearances, and grading of BCVI is essential for the radiologist to ensure fast and appropriate diagnosis and treatment. This article details the imaging evaluation of BCVI and discusses the clinical and follow-up imaging implications of specific injury findings. (c)RSNA, 2018. PMID- 29528830 TI - Imaging of Intestinal and Multivisceral Transplantation. AB - Intestinal transplantation has evolved from its experimental origins in the mid 20th century to its status today as an established treatment option for patients with end-stage intestinal failure who cannot be sustained with total parenteral nutrition. The most common source of intestinal failure in both adults and children is short-bowel syndrome, but a host of other disease processes can lead to this common end-point. The development of intestinal transplantation has presented multiple hurdles for the transplant community, including technical challenges, immunologic pitfalls, and infectious complications. Despite these hurdles, the success rate has climbed over the past decades owing to achievements that include improved surgical techniques, new immunosuppressive regimens, and more effective strategies for posttransplant surveillance and management. Nearly 2800 intestinal transplants have been performed worldwide, and current patient and graft survival rates are now comparable to those of other types of solid organ transplantations. As their population continues to increase, it will be increasingly likely that intestinal-transplant patients will seek imaging at sites other than transplant centers. Therefore, it is important that diagnostic and interventional radiologists be familiar with the procedure, its common variations, and the spectrum of postoperative complications. In this article, the authors provide an overview of intestinal transplantation, including the indications, variations, expected postoperative anatomy, and range of potential complications. (c)RSNA, 2018. PMID- 29528831 TI - Revisions to the TNM Staging of Lung Cancer: Rationale, Significance, and Clinical Application. AB - Lung cancer remains the leading cause of cancer-related mortality worldwide. To formulate effective treatment strategies and optimize patient outcomes, accurate staging is essential. Lung cancer staging has traditionally relied on a TNM staging system, for which the International Association for the Study of Lung Cancer (IASLC) has recently proposed changes. The revised classification for this eighth edition of the TNM staging system (TNM-8) is based on detailed analysis of a new large international database of lung cancer cases assembled by the IASLC for the purposes of this project. Fundamental changes incorporated into TNM-8 include (a) modifications to the T classification on the basis of 1-cm increments in tumor size; (b) grouping of lung cancers that result in partial or complete lung atelectasis or pneumonitis; (c) grouping of tumors with involvement of a main bronchus irrespective of distance from the carina; (d) reassignment of diaphragmatic invasion in terms of T classification; (e) elimination of mediastinal pleural invasion from the T classification; and (f) subdivision of the M classification into different descriptors on the basis of the number and site of extrathoracic metastases. In response to these revisions, established stage groups have been modified, and others have been created. In addition, recommendations for classifying patterns of disease that result in multiple sites of pulmonary involvement, including multiple primary lung cancers, lung cancers with separate tumor nodules, multiple ground-glass/lepidic lesions, and consolidation, as well as recommendations for lesion measurement, are addressed. Understanding the key revisions introduced in TNM-8 allows radiologists to accurately stage patients with lung cancer and optimize therapy. (c)RSNA, 2018. PMID- 29528832 TI - Embryonal Tumors of the Central Nervous System: From the Radiologic Pathology Archives. AB - Embryonal tumors of the central nervous system (CNS) are highly malignant undifferentiated or poorly differentiated tumors of neuroepithelial origin and have been defined as a category in the World Health Organization (WHO) classification since the first edition of the "Blue Book" in 1979. This category has evolved over time to reflect our ever-improving understanding of tumor biology and behavior. With the most recent update in 2016, many previous histologic diagnoses incorporate molecular parameters for the first time (genetically defined entities). While medulloblastoma and atypical teratoid/rhabdoid tumor are familiar carryovers from the 2007 CNS WHO classification, there are major changes to the embryonal tumor category: for example, elimination of the term CNS primitive neuroectodermal tumor and addition of a new genetically defined entity, embryonal tumor with multilayered rosettes, C19MC-altered. The purpose of this article is to discuss both the radiologic pathologic features of CNS embryonal tumors and the new molecularly defined types/subtypes that will become the standard classification/terminology for future diagnoses and tumor research. PMID- 29528833 TI - Four Levels of Diagnosis in the Rare Pediatric Embryonal Tumor of the CNS Called Embryonal Tumor with Multilayered Rosettes. PMID- 29528834 TI - Invited Commentary on "Imaging of Intestinal and Multivisceral Transplantation". PMID- 29528835 TI - Neuromyelitis Optica Spectrum Disorders: Spectrum of MR Imaging Findings and Their Differential Diagnosis-Erratum. PMID- 29528836 TI - Editor's Recognition Awards. PMID- 29528837 TI - Corrigendum. PMID- 29528838 TI - A Rare Case of Axillary Artery Pseudoaneurysm Due to Shoulder Dislocation Treated With Percutaneous Thrombin Injection. AB - The incidence of combined neurovascular injuries among patients with high-energy shoulder trauma ranges from 27% to 44%. However, the presentation of an axillary artery pseudoaneurysm (PSA) due to shoulder dislocation without an associated osseous fracture is a very rare condition. Moreover, treatment of combined neurologic and vascular injuries of the shoulder remains controversial. Additionally, minimally invasive treatments such as thrombin injection have been mainly evaluated in patients with iatrogenic femoral artery PSAs. Therefore, we aim to report a rare case of axillary artery PSA associated with brachial plexus injury after shoulder dislocation treated with percutaneous thrombin injection. PMID- 29528839 TI - Deep Brachial Artery Pseudoaneurysm Following Arthroscopic Shoulder Debridement. AB - Vascular injuries resulting from arthroscopic surgeries are rare with a reported incidence of 0.005% of elective orthopedic procedures. We report a case of a 49 year-old male who developed a deep brachial artery pseudoaneurysm following an arthroscopic shoulder debridement and lysis of adhesions. He was successfully embolized with resolution of the pseudoaneurysm within 6 weeks of treatment. A review of the literature demonstrates that pseudoaneurysm formation after arthroscopic procedures is rare and pseudoaneurysms of the deep brachial artery have yet to be reported. PMID- 29528840 TI - Endovascular Repair of Incidentally Found Subclavian Artery Aneurysm: A Case Report From an Urban Level 1 Trauma Center. AB - Subclavian artery aneurysms (SAAs) are historically rare peripheral aneurysm. However, it can be associated with serious life-threatening complications including rupture, thrombosis, and embolism. The majority of such aneurysms are found incidentally. Historically, SAA have been repaired via an open approach. Increasing case reports demonstrate successful management of SAAs with endovascular repair. The present report describes a case of incidentally discovered large proximal saccular subclavian aneurysm with suspected remote traumatic etiology with a successful endovascular repair. PMID- 29528841 TI - Endovascular Treatment of Symptomatic Thoracic Aneurysm Due to Periaortic Lymphoma. AB - An aggressive periaortic lymphoma could very rarely invade the aortic wall. We present a unique case of a patient with symptomatic thoracic aneurysm and imminent rupture due to the periaortic lymphoma, in which endovascular treatment using stent graft was applied. After stabilization of the aorta and histological confirmation of aggressive B-cell lymphoma by computed tomography-guided biopsy, the antilymphoma therapy was initiated. Despite the full treatment, the patient died 12 months later. PMID- 29528843 TI - Observation of Wigner crystal phase and ripplon-limited mobility behavior in monolayer CVD MoS2 with grain boundary. AB - Two-dimensional electron gas (2DEG) is crucial in condensed matter physics and is present on the surface of liquid helium and at the interface of semiconductors. Monolayer MoS2 of 2D materials also contains 2DEG in an atomic layer as a field effect transistor (FET) ultrathin channel. In this study, we synthesized double triangular MoS2 through a chemical vapor deposition method to obtain grain boundaries for forming a ripple structure in the FET channel. When the temperature was higher than approximately 175 K, the temperature dependence of the electron mobility MU was consistent with those in previous experiments and theoretical predictions. When the temperature was lower than approximately 175 K, the mobility behavior decreased with the temperature; this finding was also consistent with that of the previous experiments. We are the first research group to explain the decreasing mobility behavior by using the Wigner crystal phase and to discover the temperature independence of ripplon-limited mobility behavior at lower temperatures. Although these mobility behaviors have been studied on the surface of liquid helium through theories and experiments, they have not been previously analyzed in 2D materials and semiconductors. We are the first research group to report the similar temperature-dependent mobility behavior of the surface of liquid helium and the monolayer MoS2. PMID- 29528844 TI - Multifunctionality in coating films including Nb-doped TiO2 and Cs x WO3: near infrared shielding and photocatalytic properties. AB - Various types of coating films were obtained from hydrothermally synthesized Nb doped TiO2 (NTO) and Cs x WO3 (CWO) nanoparticles. The coating films possessed multifunctionality including near infrared (NIR) absorption and photocatalysis abilities. The NTO and CWO nanoparticles were synthesized by a unique solvothermal reaction in which water induced by an esterification reaction between alcohol and carboxylic acid can act as a hydrolyzing agent for metal precursors. NTO was synthesized by the unique solvothermal reaction for the first time. The reaction accompanied by the reduction of Ti4+ to Ti3+ led to the formation of nanoparticles with both NIR absorption and photocatalytic properties. The effect of the ethanol-acetic acid ratio on the morphology of the obtained NTO was investigated, and the larger amount of acetic acid led to a larger nanoparticle size, indicating the size controllability. The two types of coating film, including CWO and NTO nanoparticles, were obtained for comparison: (1) coexistent coating film: one side of the quartz glass was coated with a dispersion, including both CWO and NTO nanoparticles, and (2) double-sided coating film: a quartz glass coated with a CWO dispersion on one side and an NTO dispersion on the other side. The double-sided coating led to higher multifunctionality. Furthermore, the optimized condition for the double-sided coating was investigated by using various NTO particles obtained using different ethanol-acetic acid ratios. PMID- 29528845 TI - Preclinical evaluation of severely defective manganese-based nanocrystal as a liver-specific contrast media for MR imaging: comparison with Gd-EOB-DTPA and MnDPDP. AB - Manganese-based (chemically formulated of KMnF3) nanocrystal was evaluated as a liver-specific contrast agent for MR imaging and its imaging performance was also compared with those of two commercial hepatobiliary contrast media (Gd-EOB-DTPA and MnDPDP). KMnF3 nanocrystal was post-treated using a plasma technique to cause severe defects, leading to appropriate water dispersibility and high relaxivity. Severely defective KMnF3 nanocrystal (SD-KMnF3) has characteristic high tolerance, as evidenced by cytotoxicity on the macrophage cell, and acute and subchronic toxicity on the healthy mouse. SD-KMnF3 showed better hepatic MR imaging as the T 1 relaxation time of the liver decreased to only 17% of the control group, compared to 22% of the control group for Gd-EOB-DTPA (P < 0.01) and 42% of the control group for MnDPDP (P < 0.001). As applied to MR imaging of the allograft orthotopic model of liver cancer, statistical studies demonstrated that SD-KMnF3 significantly improved the tumor's contrast-to-noise ratio, compared with Gd-EOB-DTPA (P < 0.01) and MnDPDP (P < 0.01) by spin-echo pulse sequence, and even better performance (P < 0.001) by gradient-echo sequence. Our findings indicate that SD-KMnF3 could serve as a hepatic contrast agent for imaging liver cancer such as hepatocarcinoma or metastatic lesions. PMID- 29528842 TI - Antiparasitic activity in Asteraceae with special attention to ethnobotanical use by the tribes of Odisha, India. AB - The purpose of this review is to survey the antiparasitic plants of the Asteraceae family and their applicability in the treatment of parasites. This review is divided into three major parts: (a) literature on traditional uses of Asteraceae plants for the treatment of parasites; (b) description of the major classes of chemical compounds from Asteraceae and their antiparasitic effects; and (c) antiparasitic activity with special reference to flavonoids and terpenoids. This review provides detailed information on the reported Asteraceae plant extracts found throughout the world and on isolated secondary metabolites that can inhibit protozoan parasites such as Plasmodium, Trypanosoma, Leishmania, and intestinal worms. Additionally, special attention is given to the Asteraceae plants of Odisha, used by the tribes of the area as antiparasitics. These plants are compared to the same plants used traditionally in other regions. Finally, we provide information on which plants identified in Odisha, India and related compounds show promise for the development of new drugs against parasitic diseases. For most of the plants discussed in this review, the active compounds still need to be isolated and tested further. PMID- 29528846 TI - Ultrathin nanoporous membranes for insulator-based dielectrophoresis. AB - Insulator-based dielectrophoresis (iDEP) is a simple, scalable mechanism that can be used for directly manipulating particle trajectories in pore-based filtration and separation processes. However, iDEP manipulation of nanoparticles presents unique challenges as the dielectrophoretic force [Formula: see text] exerted on the nanoparticles can easily be overshadowed by opposing kinetic forces. In this study, a molecularly thin, SiN-based nanoporous membrane (NPN) is explored as a breakthrough technology that enhances [Formula: see text] By numerically assessing the gradient of the electric field square [Formula: see text]-a common measure for [Formula: see text] magnitude-it was found that the unique geometrical features of NPN (pore tapering, sharp pore corner and ultrathin thickness) act in favor of intensifying the overall [Formula: see text] A comparative study indicated that [Formula: see text] generated in NPN are four orders of magnitude larger than track-etched polycarbonate membranes with comparable pore size. The stronger [Formula: see text] suggests that iDEP can be conducted under lower voltage bias with NPN: reducing joule heating concerns and enabling solutions to have higher ionic strength. Enabling higher ionic strength solutions may also extend the opportunities of iDEP applications under physiologically relevant conditions. This study also highlights the effects of [Formula: see text] induced by the ion accumulation along charged surfaces (electric-double layer (EDL)). EDL-based [Formula: see text] exists along the entire charged surface, including locations where geometry-based iDEP is negligible. The high surface-to-volume ratio of NPN offers a unique platform for exploiting such EDL-based DEP systems. The EDL-based [Formula: see text] was also found to offset the geometry-based [Formula: see text] but this effect was easily circumvented by reducing the EDL thickness (e.g. increasing the ionic strength from 0.1 to 100 mM). The results from this study imply the potential application of iDEP as a direct, in-operando antifouling mechanism for ultrafiltration technology, and also as an active tuning mechanism to control the cut-off size limit for continuous selectivity of nanomembrane-based separations. PMID- 29528847 TI - Forces and electronic transport in a contact formed by a graphene tip and a defective MoS2 monolayer: a theoretical study. AB - A theoretical study of a graphene-like tip used in atomic force microscopy (AFM) is presented. Based on first principles simulations, we proved the low reactivity of this kind of tip, using a MoS2 monolayer as the testing sample. Our simulations show that the tip-MoS2 interaction is mediated through weak van der Waals forces. Even on the defective monolayer, the interaction is reduced by one order of magnitude with respect to the values obtained using a highly reactive metallic tip. On the pristine monolayer, the S atoms were imaged for large distances together with the substitutional defects which should be observed as brighter spots in non-contact AFM measurements. This result is in contradiction with previous simulations performed with Cu or Si tips where the metallic defects were imaged for much larger distances than the S atoms. For shorter distances, the Mo sites will be brighter even though a vacancy is formed. On the other hand, the largest conductance value is obtained over the defect formed by two Mo atoms occupying a S divacancy when the half-occupied p y -states of the graphene-like tip find a better coupling with d-orbitals of the highest substitutional atom. Due to the weak interaction, no conductance plateau is formed in any of the sites. A great advantage of this tip lies in the absence of atomic transfer between the tip and the sample leading to a more stable AFM measurement. Finally, and as previously shown, we confirm the atomic resolution in a scanning tunneling microscopy simulation using this graphene-based tip. PMID- 29528848 TI - Mo0.5W0.5S2 for Q-switched pulse generation in ytterbium-doped fiber laser. AB - In this work, we fabricate the Mo0.5W0.5S2 by microwave-assisted solvothermal method, and report the Q-switched Yb-doped fiber lasers (YDFL) using Mo0.5W0.5S2 polymer film and tapered fiber as the saturable absorbers (SAs). The modulation depth and saturable intensity of the film SA are 5.63% and 6.82 MW cm-2. The shortest pulse duration and the maximum single pulse energy are 1.22 MUs and 148.8 nJ for the film SA, 1.46 MUs and 339 nJ for the fiber-taper SA. To the best of our knowledge, this is the first report on the Q-switched YDFL using Mo0.5W0.5S2 SAs. PMID- 29528849 TI - In-plane electric field controlled ferromagnetism and anisotropic magnetoresistance in an LSMO/PMN-PT heterostructure. AB - We report the in-plane electric field controlled ferromagnetism of La2/3Sr1/3MnO3 (LSMO) films epitaxially deposited on [Pb(Mg1/3Nb2/3)O3]0.7-(PbTiO3)0.3 (PMN-PT) (001), (011) and (111) single crystal substrates. The in-plane coercivities (H c?) and remanences of the LSMO films greatly depend on the in-plane electric field applied on the PMN-PT (001) and (011) substrates. The experimental change of H c? is consistent with the Stoner-Wohlfarth model and first principle calculation with the electric field varying from -10 to 10 kV cm-1. Moreover, the Curie temperature and anisotropic magnetoresistance of the LSMO films can also be manipulated by an in-plane electric field. Finally, the LSMO/PMN-PT (001) heterostructure is designed to be a new kind of magnetic signal generator with the source of electric field. PMID- 29528851 TI - Adolescent transition among young people with perinatal HIV in high-income and low-income settings. AB - PURPOSE OF REVIEW: To summarize evidence for health outcomes among adolescents and young people living with HIV (AYLHIV) who have transitioned to adult care/adulthood, views of AYLHIV and providers on the transition process, and the effect of adolescent and youth friendly services (AYFS) on outcomes. RECENT FINDINGS: A total of 43 studies were identified [n = 13 high-income countries (HICs), n = 30 low-/middle-income countries (LMICs)]. In HICs, around 75% of patients were retained in care at approximately 4 years posttransition. In LMICs, retention worsened from older adolescence into young adulthood. Across both contexts, comparisons of mortality, immunological, and virological outcomes were hampered by a limited number of studies and/or different definitions and study durations. AYLHIV and providers reported several factors that could aid transition and AYFS had generally positive outcomes. SUMMARY: Overall, outcomes varied by study and context; direct comparison was severely hampered by the inclusion of different populations of AYLHIV (sometimes with small numbers and a lack of comparison groups), the use of different outcome definitions, varying follow-up duration, and the lack of a specific transition process in LMICs. Future studies need to consider harmonizing definitions and implementing unique patient identifiers, and data linkage techniques to improve the evidence base on long-term outcomes. PMID- 29528850 TI - Adolescent lives matter: preventing HIV in adolescents. AB - PURPOSE OF REVIEW: Many of the almost 2 million HIV infections that occurred globally in the last year occurred among adolescents and young people, particularly those from East and Southern Africa and within key populations. Global HIV epidemic control will require that new infections among these youth populations be curtailed. This review examines the most effective prevention approaches to reach these adolescent populations in the next 5 years. RECENT FINDINGS: Adolescents are in transition and are developmentally unique. They have specific needs and challenges, which if not addressed will result in less than successful interventions. Tailored, layered, combination prevention packages that take into account specific adolescent needs and involve biomedical, behavioural and structural components are recommended. These packages should be designed for and with the meaningful input of adolescents, and involve their peers in their implementation and execution. Where possible, age-appropriate health and social interventions that go beyond HIV should be bundled and offered in a variety of community-based venues that are already acceptable to and frequented by adolescents. SUMMARY: It is urgent that we reach adolescents globally with the most effective HIV prevention approaches. HIV prevention investment in this population has immediate and longer-term benefits. PMID- 29528852 TI - Fixed dose darunavir boosted with cobicistat combined with emtricitabine and tenofovir alafenamide fumarate. AB - PURPOSE OF REVIEW: In an era when virological efficacy approaches 100%, novel antiretroviral (ARV) therapies must deliver better tolerability, safety, and convenient coformulated regimens. We review the phase II and III clinical data on the fixed dose combination (FDC) darunavir (DRV) 800mg / cobicistat (COBI/C) 150 mg / emtricitabine (F/FTC) 200 mg / tenofovir alafenamide fumarate (TAF) 10mg (D/C/F/TAF) for the treatment of HIV-1 infection. RECENT FINDINGS: In an exploratory phase II study, D/C/F/TAF FDC demonstrated similar virological efficacy to darunavir/cobicistat FDC + F /tenofovir disoproxil fumarate (TDF) FDC in treatment-naive HIV-1-infected individuals with favorable bone and renal outcomes. These findings led to two subsequent international phase III double blind randomized controlled trials; AMBER and EMERALD. In the (treatment naive) AMBER study, D/C/F/TAF FDC was noninferior to component regimen F/TDF + darunavir/cobicistat with favorable bone and renal outcomes at week 48. In the EMERALD study (switch study for virologically suppressed patients), D/C/F/TAF showed noninferior efficacy to F/TDF and boosted protease inhibitor (bPI) regimen at week 48 also with favorable renal and bone outcomes. No virological failure was observed, and no resistance to TDF or darunavir emerged in either study. SUMMARY: In clinical trials, D/C/F/TAF FDC demonstrated excellent, noninferior virological efficacy, maintained a high genetic barrier and conferred the additional safety benefits of TAF. As the first one pill, once daily, protease inhibitor-based regimen, D/C/F/TAF FDC offers a new option for the treatment of HIV infection. PMID- 29528853 TI - Drug resistance in patients with tuberculous pleural effusions. AB - PURPOSE OF REVIEW: To summarize data regarding categories, detection methods, prevalence and patterns of drug resistance among patients with tuberculous pleural effusion (TPE) and to comment on the management of suspected drug resistant TPE. RECENT FINDINGS: Pleural and pulmonary tuberculosis (TB) present similar patterns of drug resistance. Approximately 10% and 6-10% of pleural Mycobacterium tuberculosis isolates are resistant to at least one first-line anti TB drug or at least isoniazid, respectively. The prevalence of multidrug resistant-pleural and extensively drug-resistant-pleural TB is 1-3% and 0-1%, respectively. SUMMARY: Although guidelines suggest the empirical standard anti-TB regimen (i.e. 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampicin) for TPE treatment, the data regarding drug resistance among TPE patients are limited. The few studies examining the issue report a notable drug resistance. In suspected drug-resistant TPE, every effort is warranted to isolate M. tuberculosis to perform drug susceptibility testing and provide guided therapy. For this purpose, the use of cultures or molecular methods with pleural biopsies is superior to their use in pleural fluid. If still M. tuberculosis cannot be detected, prolonged administration of ethambutol with isoniazid and rifampicin during the continuation phase of treatment might be considered. PMID- 29528854 TI - The role of procalcitonin in the management of pleural infection. AB - PURPOSE OF REVIEW: Pleural infection is a common problem associated with significant morbidity and mortality. Systemic or pleural fluid markers for reliably identifying pleural infection are limited. Procalcitonin (PCT) is known to be elevated in bacterial infection and is currently used for diagnosis and decision-making regarding antibiotic duration in respiratory infections. This review investigates if there is a role for serum and pleural fluid PCT (pf-PCT) in diagnosis and management of pleural infection. RECENT FINDINGS: Studies investigating the role of PCT have been limited by small patient numbers and heterogenous control populations. Overall, serum PCT (s-PCT) does not have a role superior to that of C-reactive protein (CRP) or leucocyte count (LCC) in diagnosing pleural infection or monitoring response to treatment. Similarly, pf PCT demonstrated low sensitivity and specificity for diagnosing pleural infection. There was no role for PCT in determining which patients would require surgery as opposed to tube drainage alone. SUMMARY: There is currently insufficient evidence to recommend routine use of PCT for diagnosis and monitoring of pleural infection. PMID- 29528855 TI - Dementia Prevalence in Greece: The Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). AB - INTRODUCTION: Study of the epidemiology of dementia to gain insight into putative predisposing and prophylactic factors is the first step toward establishing effective preventive and therapeutic strategies for this ever-growing public health problem. Relevant data in Greece are scattered and outdated. METHODS: We investigated dementia prevalence as part of a population-representative epidemiological study [Hellenic Longitudinal Investigation of Aging and Diet (HELIAD)] in 2 Greek regions. RESULTS: Our sample comprised 1792 adults 65 years of age or older, who received a full neurological and neuropsychological evaluation that led to a consensus diagnosis. The overall prevalence of dementia was 5.0%, with 75.3% of the cases attributed to Alzheimer disease. Dementia odds were 15.8% higher for every year of advancing age and 9.4% lower for every additional year of education. Carrying at least 1 APOE-epsilon4 allele doubled the risk of dementia, whereas sex did not exert a statistically significant effect. CONCLUSIONS: Our results are consistent with previous research in Southern European countries; dementia prevalence in Greece is in the lower range of what has been reported globally. PMID- 29528856 TI - When Decrease Abeta1-42 in CSF May Not Mean Alzheimer's Disease: Insights From Two Case Reports With Early Onset Dementia. PMID- 29528857 TI - Hand of FATe: lipid metabolism in hematopoietic stem cells. AB - PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) reside in the bone marrow and are important in replenishing all cells in the blood through a process termed hematopoiesis. One of the defining characteristics of HSCs is that they must be able to balance their self-renewal capacity with their differentiation into committed blood cells in various blood lineages. For these events to occur, HSCs must be tightly regulated in the bone marrow by intrinsic and extrinsic factors to maintain steady hematopoiesis. RECENT FINDINGS: Recently, the effect on how metabolism regulates HSC function has received a great amount of attention. In particular, lipids have been found to participate in mitochondrial activity to maintain HSCs, a role previously overlooked due to HSCs being thought of as mostly glycolytic. Moreover, there has been a re-emergence of how adipocytes in the bone marrow can regulate HSCs. SUMMARY: As these areas evolve, more studies are required to determine the exact contribution of lipids toward HSC maintenance. These studies will allow newer therapeutic targets to help reduce abnormal hematopoiesis such as myelopoiesis, which contributes to many metabolic diseases. PMID- 29528858 TI - The journey towards understanding lipoprotein(a) and cardiovascular disease risk: are we there yet? AB - PURPOSE OF REVIEW: Evidence continues to mount for an important role for elevated plasma concentrations of lipoprotein(a) [Lp(a)] in mediating risk of atherothrombotic and calcific aortic valve diseases. However, there continues to be great uncertainty regarding some basic aspects of Lp(a) biology including its biosynthesis and catabolism, its mechanisms of action in health and disease, and the significance of its isoform size heterogeneity. Moreover, the precise utility of Lp(a) in the clinic remains undefined. RECENT FINDINGS: The contribution of elevated Lp(a) to cardiovascular risk continues to be more precisely defined by larger studies. In particular, the emerging role of Lp(a) as a potent risk factor for calcific aortic valve disease has received much scrutiny. Mechanistic studies have identified commonalities underlying the impact of Lp(a) on atherosclerosis and aortic valve disease, most notably related to Lp(a)-associated oxidized phospholipids. The mechanisms governing Lp(a) concentrations remain a source of considerable dispute. SUMMARY: This article highlights some key remaining challenges in understanding Lp(a) actions and clinical significance. Most important in this regard is demonstration of a beneficial effect of lowering Lp(a), a development that is on the horizon as effective Lp(a)-lowering therapies are being tested in the clinic. PMID- 29528859 TI - Emerging Implications of Genetic Testing in Inherited Primary Arrhythmia Syndromes. AB - Inherited primary arrhythmia syndromes are genetically determined disorders of cardiac ion channels or ion channel macromolecular complexes usually associated with a higher risk of sudden cardiac death. These conditions have a very broad spectrum of clinical manifestations, ranging from an asymptomatic course to syncope, atrial and ventricular arrhythmias, and conduction disturbances, but may produce sudden infant death syndrome and unexplained sudden cardiac death in apparently healthy individuals. During the last 20 years, the evolving knowledge on the genetic basis of inherited arrhythmia syndromes has dramatically reshaped our understanding of these conditions and, consequently, had a great impact on patient care. Based on the knowledge of the genetic substrates, specific risk factors for individual genotypes have been identified, and various investigations have been launched with the intention of developing a gene- and even mutation specific therapy. Preliminary results from animal studies suggest that gene therapy rescues the normal ion channel function and thereby prevents cardiac events in some primary arrhythmia syndromes, which suggests that upon appropriate validation in a clinical setting, it may become available for affected patients. The purpose of this review is to provide clinicians with a contemporary insight into the role of genetic testing in the diagnosis, therapy, and prognosis of patients with primary arrhythmia syndromes, and the clinical implications of screening family members who are at risk of sudden cardiac death. PMID- 29528860 TI - Deep learning applications in ophthalmology. AB - PURPOSE OF REVIEW: To describe the emerging applications of deep learning in ophthalmology. RECENT FINDINGS: Recent studies have shown that various deep learning models are capable of detecting and diagnosing various diseases afflicting the posterior segment of the eye with high accuracy. Most of the initial studies have centered around detection of referable diabetic retinopathy, age-related macular degeneration, and glaucoma. SUMMARY: Deep learning has shown promising results in automated image analysis of fundus photographs and optical coherence tomography images. Additional testing and research is required to clinically validate this technology. PMID- 29528861 TI - Recent clinically relevant highlights from the Diabetic Retinopathy Clinical Research Network. AB - PURPOSE OF REVIEW: To present some recent clinically relevant results from Diabetic Retinopathy Clinical Research (DRCR) Network trials that may guide management of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR). RECENT FINDINGS: Among eyes with DME and visual acuity 20/50 or worse, aflibercept, on average, had greater improvement in visual acuity over 2 years compared with bevacizumab or ranibizumab. Aflibercept is associated with higher rates of improvements in diabetic retinopathy severity among eyes with PDR and vision-impairing DME at baseline compared with bevacizumab or ranibizumab. Among eyes with persistent central-involved DME after at least six antivascular endothelial growth factor (anti-VEGF) injections, no difference in mean visual acuity improvement was observed between eyes that received continued ranibizumab and sham injections versus ranibizumab and intravitreous sustained dexamethasone drug-delivery system, especially for phakic eyes. For eyes with PDR, ranibizumab was associated with lower rates of developing PDR-worsening events compared with panretinal photocoagulation, especially among eyes that did not receive ranibizumab for central-involved DME at baseline. Ranibizumab is cost-effective for PDR for eyes with, not without, vision-impairing central-involved DME, highlighting challenges when safety and efficacy results are at odds with cost effectiveness results. SUMMARY: Aflibercept for DME, in certain circumstances, is more likely to have superior visual acuity and anatomical outcomes compared with bevacizumab or ranibizumab. No vision benefits are apparent, especially for phakic eyes, by adding intravitreous corticosteroids for persistent DME following anti-VEGF injections. PMID- 29528862 TI - Implantation, removal and replacement of subretinal electronic implants for restoration of vision in patients with retinitis pigmentosa. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on the efforts to restore vision through subretinal implants in patients with degenerative retinal diseases. In addition to the current technique and its latest improvements, it will focus on the surgical technique of implantation as well as explantation and reimplantation. RECENT FINDINGS: The durability of the current subretinal implant RETINA IMPLANT Alpha AMS has increased substantially compared with the predecessor model RETINA IMPLANT Alpha IMS. According to validated examinations in the laboratory, a median lifetime of 4.7 years will be reached in clinical use; in similar examinations, the previous model has reached only 8 months. Visual function has slightly increased. The surgical technique for subretinal implants is complex and demanding for ophthalmic surgeons, as it is multifaceted and combines novel surgical steps in areas, which are not commonly entered such as the suprachoroidal and the subretinal space. The surgical approach for implantation has matured considerably and has led to successful implantation in 64 patient cases. Surgical challenges are now mainly encountered with the exact subfoveal positioning of the device. The explantation procedure is relatively straight-forward because the implant can be withdrawn in a reverse direction along the already existent subretinal path. Reimplantations, however, are more challenging because some degree of scar tissue may exist along the path of the chip and around the scleral trapdoor. Nevertheless, reimplantations have now been carried out successfully in four patients. SUMMARY: The new RETINA IMPLANT Alpha AMS shows significantly improved durability compared with the predecessor model RETINA IMPLANT Alpha IMS. The subretinal implant offers excellent visual results but requires experienced surgeons. Explantation of devices is straight-forward, and reimplantations are challenging but have been successful in four patients. PMID- 29528863 TI - Intraoperative Sedation With Dexmedetomidine is Superior to Propofol for Elderly Patients Undergoing Hip Arthroplasty: A Prospective Randomized Controlled Study. AB - BACKGROUND: Peripheral nerve block is a preferable method for elderly patients receiving hip arthroplasty. Sedation with dexmedetomidine may reduce postoperative delirium (POD). The aim of this study was to investigate whether intraoperative sedation with dexmedetomidine, as a supplementary to peripheral nerve block for elderly patients receiving total hip arthroplasty, can decrease the prevalence of POD. METHODS: A prospective, randomized controlled study was conducted with patients 65 years of age or older who underwent total hip arthroplasty between June 2016 and June 2017. The patients were randomly assigned to receive a lumbosacral plexus plus T12 paravertebral block supplemented with propofol or dexmedetomidine for sedation. Incidence of POD was the primary endpoint and was determined with the confusion assessment method, and incidence of postoperative cognitive dysfunction (POCD) was assessed with the mini-mental state examination. The time of ambulation, discharge time, and complications over a 30-day postsurgery period were also recorded. RESULTS: A total of 296 patients were randomly assigned to 2 groups. The patients sedated with dexmedetomidine had lower incidences of POD and POCD and were out of bed and discharged sooner than the patients sedated with propofol. There was no difference in complications between the 2 groups. CONCLUSIONS: As a supplementary to peripheral nerve block, intraoperative sedation with dexmedetomidine could be associated with a lower incidence of POD, which may have benefits on reducing the incidence of early POCD and offering a better short-term recovery for elderly patients receiving hip arthroplasty. PMID- 29528864 TI - Fear-avoidance and Pelvic Floor Muscle Function are Associated With Pain Intensity in Women With Vulvodynia. AB - OBJECTIVE: To investigate the association between fear-avoidance variables, pelvic floor muscle (PFM) function, pain intensity in women with provoked vestibulodynia (PVD), as well as the moderator effect of partner support. MATERIALS AND METHODS: A sample of 173 women diagnosed with PVD participated in the study. Fear-avoidance variables were assessed with validated self administered questionnaires: pain catastrophizing (Pain Catastrophizing Scale), pain-related fear (Pain Anxiety Symptoms Scale), and partner support (Partner Support Questionnaire). Pain intensity was evaluated using a numerical rating scale. PFM function, including maximal strength, speed of contraction, flexibility, and muscle tone, was evaluated with a dynamometric speculum. RESULTS: Pain catastrophizing was significantly associated with pain intensity (beta=0.310, P<0.001), partner support (beta=0.194, P=0.004), and PFM flexibility (beta=-0.255, P<0.001). Fear-avoidance, PFM variables, and partner support explained 28.3% of the variance in pain during intercourse (P<0.001). The addition of PFM was of particular interest as it explained a significant addition of 9% of the variance in pain intensity. Partner support was found to moderate the association between pain intensity and catastrophizing. Among women with high partner support, catastrophizing was not significantly related to pain (b=0.150, P=0.142). When partner support was low, catastrophizing was significantly related to pain (b=0.068, P<0.001). DISCUSSION: Findings of this study support that the symptomatology of PVD can be explained partly by fear-avoidance variables and PFM function. This study supports the significant role of PFM function and its importance in the pathophysiology of PVD. It also sheds light on the role of partner support and its moderating effect on pain catastrophizing. PMID- 29528865 TI - Autoimmune manifestations of infections. AB - PURPOSE OF REVIEW: To provide an update about the interactions between infections and autoimmune diseases (AIDs), from the molecular perspective to the clinical spectrum and the differentiation between infection and disease activity. RECENT FINDINGS: Any kind of infection may modify the innate and adaptive immune response through the following mechanisms: molecular mimicry, superantigens, epitope spreading and B-cell activation. The consequence is the overproduction of antibodies shared with those found in AIDs. Viral infections, especially HIV and hepatitis C virus, can stimulate the production of antiphospholipid antibodies and confer an increased risk to develop antiphospholipid syndrome. SUMMARY: The identification of risk factors to develop infections in patients with AIDs is remarkable to prevent them. These factors are the use of steroids and immunosuppressants, the involvement of a major organ (lungs, brain and kidney) and severe activity. Biomarkers to differentiate infection from disease activity are scarce, but the combination of procalcitonine and C-reactive protein seems to have higher specificity and sensibility to identify infections in patients with AIDs. Finally, the clinical judgment is the hallmark to differentiate between infections and disease activity. PMID- 29528866 TI - The utility and limitations of using trabecular bone score with FRAX. AB - PURPOSE OF REVIEW: Trabecular bone score (TBS) is a texture index derived from the lumbar spine dual-energy X-ray absorptiometry which can assess skeletal quality and provide information about fracture risk independent of bone mineral density (BMD). TBS is useful in assessing osteoporotic fracture risk, with lower TBS values associated with increased fracture risk. In this article, we review the current state of TBS, including its utility and limitations in the assessment and management of osteoporosis, with particular emphasis on the recent literature. RECENT FINDINGS: Ten-year fracture risk assessment using the FRAX tool can be improved through the use of a TBS adjustment. The use of TBS-adjusted FRAX can change management in a modest but significant number of patients, particularly in those close to an intervention threshold. Change in lumbar spine TBS for patients undergoing antiresorptive treatment is not a useful indicator of antifracture effect. SUMMARY: Lumbar spine TBS provides information complementary to conventional BMD, and has been shown to be clinically useful for enhancing fracture risk prediction. PMID- 29528867 TI - Literature Review of Spinal Cord Glioblastoma. AB - OBJECTIVES: This systematic review aims to investigate spinal cord glioblastoma (scGBM) and correlations between patient traits and survival outcome, as well as differences in cohorts administered temozolomide or total resections, through an analysis of published cases reported up to October 2016. METHODS: We obtained patient data by querying PubMed and Google Scholar with predetermined search terms and inclusion criteria that enabled the identification of relevant case reports. Survival was compared using Kaplan-Meier curves and log-rank analyses. RESULTS: Of 153 patients with scGBM identified through a literature search, 135 met the predetermined search and inclusion criteria. Median overall survival (OS) for the resulting cohort was 12 (95% CI, 10-14) months. The female sex was found to significantly predict worse outcomes, and a sizable number of patients with long-term disease were found to have afflictions of the thoracic spinal cord. Neither the pediatric, temozolomide nor total resection subgroups had significantly improved survival characteristics, by log-rank analysis, relative to counterparts. CONCLUSIONS: These data elucidate the characteristics of patients with scGBM. For more sophisticated and in-depth analyses in the future, it is imperative that time-of-treatment information is recorded in future case reports. In addition, all case reports should be made available to prevent publication bias. PMID- 29528868 TI - Pretreatment with P2Y12 inhibitors and outcome in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention. AB - AIMS: Preload with clopidogrel, ticagrelor, or prasugrel in the setting of ST segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) is frequently applied. Limited data are available regarding the outcome impact of pretreatment with these drugs in the real world. METHODS AND RESULTS: The outcome of 760 STEMI patients treated by primary PCI receiving clopidogrel, prasugrel, or ticagrelor (n = 269, 327, 164, respectively) was evaluated. Patients in the clopidogrel group were older, whereas those in the ticagrelor group had less hypertension but were more active smokers. Angiographic characteristics were comparable among the three groups. At 1 month, more events were observed in the clopidogrel group (11.1%) than in the ticagrelor and prasugrel groups (7.1 vs. 5.1%, P = 0.025), whereas the number of events in the ticagrelor and prasugrel groups did not differ. At 1 year, similar differences existed, mainly driven by a higher rate of death (19.5%, P = 0.008) or stent thrombosis (2 vs. 1.3% for ticagrelor, P = 0.132; vs. 0.3% for prasugrel, P = 0.07) in the clopidogrel group. In-hospital and 1-year bleeding rates were similar between groups. CONCLUSION: In real-world practice, pretreatment with prasugrel or ticagrelor in ongoing STEMI treated by primary PCI seems to be a well tolerated alternative strategy compared with clopidogrel but provides superior benefit in terms of outcomes. PMID- 29528869 TI - Cardio-oncology organization patterns in Italy: one size does not fit all. AB - AIMS: Cardio-oncology is imposing as the specialty deputed to the management of a large and rapidly increasing population of cancer patients receiving anticancer treatments with cardiovascular side effects or presenting with cardiac and oncological comorbidities. Organization patterns dramatically vary across Italy. METHODS: On the behalf of ANMCO, we have analyzed the characteristics of cardio oncology services across different hospital types in Italy. A questionnaire was sent out to all ANMCO divisions inquiring about inner organization, workload, multidisciplinary team and inter-hospital connections. RESULTS: Ninety-eight centers sent back the questionnaire. We summarize different paths into four reference assistance models (sizes XL, L, M and S) according to hospital characteristics, cardio-oncology population size, specialists availability, local facilities and the hospital-surrounding network. We define sizes of the proposed pathways highlighting the need to tailor the model in each single situation. CONCLUSION: No single cardio-oncology organization model can be applied to all hospitals. Each center could select the size/model that best fits its organization. Multidisciplinarity and networking play a crucial role. PMID- 29528870 TI - Periprosthetic Tibial Fractures. AB - Periprosthetic fractures around total knee arthroplasty have become an increasingly common and challenging orthopaedic problem. Appropriate management of these fractures depends on careful scrutiny of radiographs and a thorough clinical history to exclude the diagnosis of a periprosthetic infection. In a periprosthetic tibial fracture with a stable, well-aligned tibial component and well-aligned mechanical tibial axis, the fracture can be successfully managed with closed reduction and cast immobilization; meticulous follow-up is essential to ensure that the alignment is maintained. Major fracture displacement, tibial component instability, and tibial component malalignment are all indications for surgical intervention. The ideal surgical intervention depends on the fracture characteristics and the stability and alignment of the tibial component. PMID- 29528871 TI - Echocardiographic assessment of left ventricular morphology and function in patients with fibromuscular dysplasia: the ARCADIA-POL study. AB - OBJECTIVE: To provide a comprehensive assessment of left ventricle (LV) structure, and function and to detect alterations in cardiac properties in relationship to presence, subtypes and extent of fibromuscular dysplasia (FMD). METHODS: We studied 144 patients with FMD. The control group consisted of 50 matched individuals. Office and ambulatory blood pressure levels were evaluated. Echocardiography was employed to assess: left ventricular mass index (LVMI), systolic function including speckle tracking echocardiography and diastolic function assessed by mitral flow and tissue Doppler imaging. RESULTS: There were no differences in LV morphology and function between patients with FMD and the control group. Among 128 patients with renal FMD, there were no differences in LVMI and LV systolic function between patients with unifocal and multifocal FMD. The patients with multifocal FMD were characterized by lower early diastolic velocity (e') as compared with unifocal FMD and control groups. However, in a multivariate regression model, e' was not independently correlated with FMD. There were no associations between echocardiographic indexes and vascular involvement of FMD. Also, there were no differences in LV morphology and function in patients with significant renal artery stenosis (RAS) compared with patients with history of significant RAS and patients with nonsignificant RAS. CONCLUSION: Our study in contrast to those with atherosclerotic RAS, did not show differences in LV morphology and function between FMD patients and matched controls. Although FMD can result in hypertension and serious vascular complications, there is no proof that it can alter LV regardless of FMD type and its extent. PMID- 29528872 TI - Case detection in primary aldosteronism: high-diagnostic value of the aldosterone to-renin ratio when performed under standardized conditions. AB - OBJECTIVE: The aldosterone-to-renin ratio is widely used and is the recommended screening modality for primary aldosteronism by the Endocrine Society Guideline. However, studies on its diagnostic accuracy have been inconsistent, which is mainly because of methodological limitations. We set out to evaluate this diagnostic value by using a highly standardized study protocol, which is in line with the Endocrine Society Guideline recommendations regarding indications for screening, testing conditions and reference standards in daily clinical practice. METHODS: In this prospective study, 233 consecutive patients referred to the University Medical Center Utrecht with difficult-to-control hypertension were enrolled. In addition to aldosterone-to-renin ratio measurements, all patients underwent a saline infusion test as a reference standard. A plasma aldosterone concentration greater than 280 pmol/l after saline infusion was considered diagnostic for aldosteronism and the plasma renin activity was assessed to exclude patients with secondary aldosteronism from the final primary aldosteronism diagnosis. RESULTS: Correlation of the aldosterone-to-renin ratio (cut-off >5) with primary aldosteronism diagnosis showed 16 true positive, 29 false positive, 188 true negative and 0 false negative aldosterone-to-renin ratios, resulting in a sensitivity of 100% (CI 75.9-100), specificity of 86.7% (CI 81.2-90.7), positive-predictive value of 35.6% (CI 22.3-51.3) and negative predictive value of 100% (CI 97.5-100.0). The corresponding area under the curve was 0.933 (CI 0.900-0.966). CONCLUSION: These findings show that the aldosterone to-renin ratio is a good screening modality for primary aldosteronism and is without a high risk of missing a primary aldosteronism diagnosis whenever performed under well standardized conditions. PMID- 29528873 TI - Relationship of Anticoagulant Therapy With Cognitive Impairment Among Patients With Atrial Fibrillation: A Meta-Analysis and Systematic Review. AB - BACKGROUND: At present, it is considered that atrial fibrillation (AF) is a risk factor for cognitive impairment and dementia. It is independent of stroke, but the relationship between anticoagulant drugs and cognitive function in patients with AF is unknown. OBJECTIVE: The purpose of this study was to complete a meta analysis of studies and investigate the association between anticoagulant therapy and cognitive impairment in patients with AF. METHODS AND RESULTS: Two investigators systematically searched the Cochrane Library, PubMed, EMBASE databases, and Web of Science for all studies that present associations. Hazard ratios (HRs) were extracted and pooled. Finally, the 8 studies included 471,057 participants; time in therapeutic range (TTR) <25% versus TTR >75%; (HR 3.02, 95% CI 1.12-8.91; P = 0.03); TTR 25%-50% versus TTR >75% (HR 2.44, 95% CI 0.95-6.22; P = 0.06); TTR 50%-75% versus TTR >75% (HR 1.75, 95% CI 0.90-3.99; P = 0.1); oral anticoagulants (OAC) versus No OAC (HR 0.71, 95% CI 69-0.74; P < 0.00001); and new oral anticoagulants versus warfarin (HR 0.51, 95% CI 0.37-0.71; P < 0.00001). CONCLUSIONS: OACs significantly reduce the occurrence of cognitive impairment in patients with AF. Compared with warfarin, new oral anticoagulants have an efficiently protective effect on cognition. In the range of INR 2-3, with the increase of TTR, the incidence of cognitive impairment is lower. PMID- 29528874 TI - High-Density Lipoprotein Functionality as a New Pharmacological Target on Cardiovascular Disease: Unifying Mechanism That Explains High-Density Lipoprotein Protection Toward the Progression of Atherosclerosis. AB - The formation of the atherosclerotic plaque that is characterized by the accumulation of abnormal amounts of cholesterol-loaded macrophages in the artery wall is mediated by both inflammatory events and alterations of lipid/lipoprotein metabolism. Reverse transport of cholesterol opposes the formation and development of atherosclerotic plaque by promoting high density lipoprotein (HDL) mediated removal of cholesterol from peripheral macrophages and its delivery back to the liver for excretion into the bile. Although an inverse association between HDL plasma levels and the risk of cardiovascular disease (CVD) has been demonstrated over the years, several studies have recently shown that the antiatherogenic functions of HDL seem to be mediated by their functionality, not always associated with their plasma concentrations. Therefore, assessment of HDL function, evaluated as the capacity to promote cell cholesterol efflux, may offer a better prediction of CVD than HDL levels alone. In agreement with this idea, it has recently been shown that the assessment of serum cholesterol efflux capacity (CEC), as a metric of HDL functionality, may represent a predictor of atherosclerosis extent in humans. The purpose of this narrative review is to summarize the current evidence concerning the role of cholesterol efflux capacity that is important for evaluating CVD risk, focusing on pharmacological evidences and its relationship with inflammation. We conclude that HDL therapeutics are a promising area of investigation but strategies for identifying efficacy must move beyond the idea of simply raising static HDL-cholesterol levels and toward methods of measuring the dynamics of HDL particle remodeling and the generation of lipid-free apolipoprotein A-I (apoA-I). In this way, apoA-I, unlike mature HDL, can promote the greatest extent of cholesterol efflux relieving cellular cholesterol toxicity and the inflammation it causes. PMID- 29528875 TI - Cost-effectiveness of CI in developing countries. AB - PURPOSE OF REVIEW: Cost-effectiveness of cochlear implants is a major concern for expanding these services to low-income and middle-income developing countries. RECENT FINDINGS: Recent studies have applied appropriate methodology to make determination of cost-effectiveness for cochlear implants in developing countries. In addition, important parameters that effect cost-effectiveness have been reviewed in a systematic way. The combination of these new studies along with existing reports of cochlear implant programmes in developing countries allows for a discussion of cost and outcomes determinants that drive cost effectiveness in these environments. SUMMARY: Cochlear implants are a very cost effective treatment for profound hearing loss in all high-resource countries and in many low-income and middle-income developing countries. A number of cost considerations affect cost-effectiveness of cochlear implants in developing countries including device cost and device-related expenses such as power consumption and reliability, but also including rehabilitation and access-related expenses. Large-scale programmes confer an advantage for cost-effectiveness, primarily through device-related savings. PMID- 29528876 TI - Descriptive Analysis of Patient Misidentification From Incident Report System Data in a Large Academic Hospital Federation. AB - INTRODUCTION: Patient misidentification continues to be an issue in everyday clinical practice and may be particularly harmful. Incident reporting systems (IRS) are thought to be cornerstones to enhance patient safety by promoting learning from failures and finding common root causes that can be corrected. The aim of this study was to describe common patient misidentification incidents and contributory factors related to perioperative care. DESIGN AND SETTINGS: We retrospectively analyzed IRS data reported by healthcare workers from a large academic hospital federation from 2011 to 2014. All patient misidentification incidents that occurred during perioperative care were reviewed and classified using the international classification for patient safety taxonomy. Incident type, contributory factor, error type, and consequences for the patient and for the organization were extracted for each incident report. RESULTS: Among the 293 reported incidents, the most frequent errors were missing wristbands (34%), wrong charts or notes in files (20%), administrative issues (19%), and wrong labeling (14%). The main contributory factors included the absence of patient identity control (30%), patient transfer (30%), and emergency context (8%). Data on patient and institutional consequences were scarce. Events of missing and wrong identities on wristbands were rarely detected when patients were transferred from the admission ward to the operating room or the radiology department. CONCLUSION: These results illustrate that misidentification errors are still common in France. This work contributes to enhancing interest in IRS data analysis to define or refine patient safety improvement strategies related to misidentification errors in healthcare institutions. PMID- 29528877 TI - Genetic Variant of SOCS3 Gene is Functionally Associated With Lumbar Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: This is a genetic association study. OBJECTIVE: To investigate association between suppressor of cytokine signaling-3 (SOCS3) gene polymorphisms and the onset and progression of lumbar adolescent idiopathic scoliosis (AIS) and to further clarify its role in the regulation of SOCS3 expression in AIS patients. SUMMARY OF BACKGROUND DATA: Some studies showed that muscle development imbalance may be responsible for onset and progression of lumbar AIS. SOCS3 is one of the significant regulators of skeletal muscle development, and in vitro study showed that SOCS3 influences myoblast differentiation. MATERIALS AND METHODS: Rs4969198 was genotyped in 476 lumbar AIS patients and 672 controls. The differences of genotype and allele distributions between patients and controls were calculated using the chi test. Paravertebral muscles were collected from 53 AIS, 23 congenital scoliosis, and 18 lumbar disk herniation patients. AIS patients were classified into 3 groups according to the genotypes of each single nucleotide polymorphisms, and 1-way analysis of variance test was used to compare SOCS3 expression among different groups and genotypes. RESULTS: Patients were found to have a significantly higher frequency of GG than the controls (40.8% vs. 29.9%, odds ratio=1.36; P=0.000), and the frequency of allele G was found to be remarkably higher in the patients than the controls (65.3% vs. 56.7%, odds ratio=1.15; P=0.000). AIS patients had significantly less muscle expression of the SOCS3 than the congenital scoliosis patients (2.73+/-2.17 vs. 4.62+/-2.41; P=0.006) and the lumbar disk herniation patients (2.73+/-2.17 vs. 4.12+/-2.93; P=0.009). The SOCS3 expression was significantly correlated with the curve severity (r=0.472; P=0.014). CONCLUSIONS: The SOCS3 gene is significantly associated with the development of lumbar AIS in Chinese population. Decreased expression of SOCS3 is associated with larger severity of lumbar AIS. LEVEL OF EVIDENCE: Level III. PMID- 29528878 TI - Hidden Blood Loss in Posterior Lumbar Fusion Surgery: An Analysis of Risk Factors. AB - STUDY DESIGN: Descriptive study. OBJECTIVES: This study aimed to evaluate the hidden blood loss (HBL) of patients who underwent lumbar fusion surgery for degenerative spine and to analyze its risk factors. SUMMARY OF BACKGROUND DATA: When planning transfusion strategies, blood loss calculation is important. However, in clinical practice, spine surgeons usually ignore the possibility that a large amount of HBL may occur after lumbar fusion surgery. MATERIALS AND METHODS: We studied the patients who underwent posterior lumbar fusion (PLF) surgery for degenerative spine from 2014 to 2015 in one institution. The patient's demographics, comorbid conditions, coagulation panel value, surgical time, number of levels fused, American Society of Anesthesiologists (ASA) classification, cell saver, preoperative hematocrit level, preoperative hemoglobin level, and postoperative complications were collected retrospectively. Pearson correlation analyses were used to find an association between patient characteristics and HBL. Multivariate linear analysis was used to determine independent risk factors of HBL. RESULTS: We reviewed 169 consecutive patients who underwent PLF surgery for degenerative spine in one institution. The mean amount of HBL was 588 mL, which was 39% of the total blood loss. On the basis of the model of multiple linear regression analysis, the multilevel fusion (P=0.001), surgical time (P=0.034), and fibrinogen level (P=0.027) were independent risk factors that contributed to HBL, but age of 60 years or above (P=0.110), postoperative complications (P=0.278), and cell saver were not (P=0.739). CONCLUSIONS: We conclude that a large amount of HBL may occur in patients who underwent PLF surgery for degenerative spine. In addition, significant hidden loss may have a correlation with postoperative mortality. Multilevel fused, surgical time, and fibrinogen level should be paid close attention when considering strategies of fluid infusion and blood transfusion. PMID- 29528879 TI - Associations Between Risk Factors and Overactive Bladder: A Meta-analysis. AB - OBJECTIVE: The purpose of this study was to investigate the risk factors of overactive bladder (OAB). METHODS: The PubMed, Embase, and Cochrane Library databases were retrieved through May 2016. Odds ratios (OR) or standard mean differences (SMDs) with 95% confidence intervals (CIs) were used to evaluate the associations between risk factors and OAB. Heterogeneity among studies was examined using chi test based on the Q and I tests. RESULTS: A total of 28 articles were analyzed in our study. The results suggested that age and body mass index were significantly higher in OAB patients than in non-OAB controls (SMDs [95% CIs], 0.30 [0.19-0.41] and 0.39 [0.24-0.53]). A significant negative association was found between employment status and OAB (OR [95% CIs], 0.64 [0.46 0.90]). However, sex, educational level, parity, vaginal delivery, race, menopause, marital status, smoking, and alcohol consumption were not significantly different in OAB and non-OAB control patients (ORs [95% CIs], 0.95 [0.59-1.55], 1.04 [0.82, 1.33], 0.98 [0.56-1.70], 1.66 [0.90-3.07], 0.98 [0.75 1.28], 1.84 [0.23-14.70], 0.97 [0.78-1.19], 0.91 [0.77-1.08], and 0.88 [0.71 1.09], respectively). In addition, the number of parities and vaginal deliveries in OAB patients also showed no significant differences compared with non-OAB control patients (SMDs [95% CI], 0.05 [-0.27 to 0.38] and -0.16 [0.40 to 0.09]). CONCLUSIONS: This meta-analysis suggests that age and body mass index are associated with increased risks of OAB, whereas employment status is associated with a decreased risk of OAB. Further prospective studies with large sample sizes are needed to confirm this conclusion.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29528880 TI - Noninfectious causes of fever in adults. AB - Fever is a common clinical sign encountered in hospitalized patients and often represents the cardinal sign of infectious processes. However, a number of noninfectious etiologies causing fever should be considered prior to initiating broad-spectrum antibiotic therapy. Reducing unnecessary antibiotic use is crucial in an era of increasing resistance. PMID- 29528881 TI - Understanding health policy to improve primary care management of obesity. AB - NPs are ideal candidates for implementing positive health changes for obese patients. Providers have medical expertise and can promote obesity reduction strategies to their patients. Increased awareness of the influence of health policy and clinical implications for obesity management are needed. PMID- 29528882 TI - The "Double Whammy": Women's Experiences of Weight Gain After Diagnosis and Treatment for Schizophrenia Spectrum Disorders. AB - High levels of lifestyle risk factors compound medication side effects, resulting in high rates of obesity among people with schizophrenia spectrum disorders (SSDs). Obesity and related comorbidities increase the levels of disability and disadvantage in this population. Little research has explored the lived experiences in relation to this issue, and less has considered the experiences of women. Our aim in this study was to understand the experiences of women who gained weight after their diagnosis and treatment for SSDs. We carried out up to three in-depth qualitative interviews with 11 women over 2 years. Data were analyzed using constructivist grounded theory procedures. The women described a "double whammy"-like experience whereby weight gain and obesity came with their diagnosis and treatment of an SSD and brought with it additional challenges. The double whammy parallels the co-occurrence of mental illness and substance misuse. Implications of these parallels for service provision are discussed. PMID- 29528883 TI - Paliperidone-Associated Atrioventricular Block. PMID- 29528884 TI - Does the Use of Clean or Sterile Dressing Technique Affect the Incidence of Wound Infection? AB - PURPOSE: The purpose of this article is to examine the evidence and provide recommendations for the use of clean or sterile dressing technique with dressing application to prevent wound infection. QUESTION: In all persons with acute or chronic wounds, does the use of clean or sterile dressing technique affect incidence of wound infection? SEARCH STRATEGY: A search of the literature was performed by a trained university librarian, which resulted in 473 articles that examined any age group that dealt with application of a wound dressing using either sterile or nonsterile technique. A systematic approach was used to review titles, abstracts, and text, yielding 4 studies that met inclusion criteria. Strength of the evidence was rated using rating methodology from Essential Evidence Plus: Levels of Evidence and Oxford Center for Evidence-Based Medicine, adapted by Gray and colleagues. Johns Hopkins Nursing Evidence-Based Practice Nursing Research Appraisal Tool was used to rate the quality of the evidence. FINDINGS: All 4 studies reported no significant difference in the rate of wound infection when using either clean or sterile technique with dressing application. The strength of the evidence for the identified studies was identified as level 2 (1 level A, 3 level B). The study sizes were variable, and the wounds included do not represent the continuum of wounds clinically encountered across the board. CONCLUSION/RECOMMENDATION: Evidence indicates that the use of clean technique for acute wound care is a clinically effective intervention that does not affect the incidence of infection. There is no recommendation that can be made regarding type of dressing technique for a chronic wound due to the lack of evidence in the literature. PMID- 29528885 TI - ACUTE RETINAL NECROSIS AND CONTRALATERAL CUTANEOUS ERUPTION AFTER THE SHINGLES VACCINE. AB - PURPOSE: To the best of our knowledge, we present a rare case report describing an occurrence of acute retinal necrosis in an otherwise healthy individual who received the shingles vaccine. METHODS: Observational case report. PATIENT: A 63 year-old healthy and immunocompetent white man presented with change of vision in the left eye after blunt trauma. A diagnosis of corneal abrasion was made. During follow-up, a detailed history discovered a progressive deterioration in vision over the past few weeks. Three months before presentation, he had received the shingles vaccine (Zostavax); 1 month before presentation, he reported an episode of varicella skin eruption on the face. RESULTS: On examination, the patient was found to have acute retinal necrosis with white satellite lesions in the fundus of the left eye. An anterior chamber paracentesis and polymerase chain reaction confirmed the diagnosis of varicella-zoster virus. CONCLUSION: Varicella-zoster virus reactivation after shingles vaccination may predispose both immunocompetent and immunocompromised individuals to herpes-zoster ophthalmicus, leading to acute retinal necrosis. PMID- 29528886 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY AFTER PREWORKOUT HAVOK INGESTION. AB - PURPOSE: To describe a case of transient, partial, central retinal artery occlusion with paracentral acute middle maculopathy optical coherence tomography presentation in a young healthy patient after ingestion of the synephrine containing supplement, Havok. METHODS: Retrospective case report with fundus photography, fluorescein angiography, and optical coherence tomography. RESULTS: A 20-year-old man presented with severe acute vision loss in the right eye. Dilated examination demonstrated cherry red spot with surrounding edema in the macula. Optical coherence tomography showed hyperreflectivity in the middle retinal layer of the macula consistent with paracentral acute middle maculopathy. Fluorescein angiography showed delayed arteriovenous transit time consistent with a central retinal artery occlusion. Bloodwork to investigate a hypercoagulable state and vasculitis were negative. At 1-week follow-up, dilated examination demonstrated resolution of the cherry red spot. At 3 months, the patient's visual acuity was back to normal. Fluorescein angiography showed complete resolution of the retinal artery occlusion, but optical coherence tomography of the macula demonstrated mild, residual middle retina thinning consistent with chronic presentation of paracentral acute middle maculopathy. CONCLUSION: Because of synephrine's physiological and structural similarity to the vasoconstrictive compound ephedra, it is reasonable to suggest that there is potential health hazard in this performance-enhancing compound.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29528887 TI - LOCALIZATION OF MACULAR CRYSTALS ASSOCIATED WITH CHRONIC RETINAL DETACHMENT TO THE POSTERIOR HYALOID USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To present a case of crystalline retinopathy associated with chronic retinal detachment and localize the macular crystals using spectral domain optical coherence tomography. METHODS: Case Report. RESULTS: A 37-year-old man with previously treated chronic retinal detachment presented with normal vision and crystalline maculopathy. Spectral domain optical coherence tomography localized the macular crystals to the posterior hyaloid membrane and on the internal limiting membrane, but not within the retina. CONCLUSION: The macular crystals in crystalline retinopathy associated with chronic retinal detachment most likely originate in the subretinal space beneath the detached retina, migrate through the retinal break into the vitreous cavity, and lodge on the surface of the internal limiting membrane. When the posterior hyaloid membrane separates, the crystals, which are attached to the posterior hyaloid membrane, elevate from the retina. PMID- 29528888 TI - Cognitive Impairment in Fibromyalgia: A Meta-Analysis of Case-Control Studies. AB - OBJECTIVE: Cognitive dysfunction has been reported in individuals with fibromyalgia. However, findings regarding cognitive function examined using neuropsychological tests have been inconsistent. The aim of the study was to determine domain-specific cognitive impairment in patients with fibromyalgia compared with healthy controls. METHODS: We conducted a meta-analysis that systematically searched six databases (PubMed, Ovid MEDLINE, Embase, CINAHL, PsycINFO, and Web of Science) for articles published before September 2017. RESULTS: Twenty-three case-control studies with a total of 2096 participants were included in the meta-analysis. Cognitive function was significantly lower (g = 0.87, 95% confidence interval [CI] = 0.60-1.15) in individuals with fibromyalgia than in healthy controls. Large effect sizes were found in learning/memory and attention/psychomotor speed (g = 0.94, p = .013; g = 1.22, p < .001, respectively); medium effect sizes were reported in executive function and working memory (g = 0.72, p < .001; g = 0.75, p < .001, respectively). Depression and anxiety scores were associated with the effect size of group differences in cognitive function (B = 0.11, p < .001, 95% CI = 0.09-0.13; B = 0.02, p < .001, 95% CI = 0.01-0.02, respectively). CONCLUSIONS: Cognitive impairment across different cognitive domains was found in individuals with fibromyalgia compared with healthy controls. Mood states (depression and anxiety) may explain the heterogeneity across studies. PMID- 29528889 TI - New directions in point-of-care ultrasound at the crossroads of paediatric emergency and critical care. AB - PURPOSE OF REVIEW: The diagnostic capability, efficiency and versatility of point of-care ultrasound (POCUS) have enabled its use in paediatric emergency medicine (PEM) and paediatric critical care (PICU). This review highlights the current applications of POCUS for the critically ill child across PEM and PICU to identify areas of progress and standardized practice and to elucidate areas for future research. RECENT FINDINGS: POCUS technology continues to evolve and advance bedside clinical care for critically ill children, with ongoing research extending its use for an array of clinical scenarios, including respiratory distress, trauma and dehydration. Rapidly evolving and upcoming applications include diagnosis of pneumonia and acute chest syndrome, identification of intra abdominal injury via contrast-enhancement, guidance of resuscitation, monitoring of increased intracranial pressure and procedural guidance. SUMMARY: POCUS is an effective and burgeoning method for both rapid diagnostics and guidance for interventions and procedures. It has clinical application for a variety of conditions that span PEM and PICU settings. Formal POCUS training is needed to standardize and expand use of this valuable technology by PICU and PEM providers alike. PMID- 29528890 TI - Approach to pulmonary vascular disease in the ICU. AB - PURPOSE OF REVIEW: Pulmonary vascular disease (PVD) complicates the course of many cardiovascular, pulmonary and other systemic diseases in children. The physiological sequelae (pulmonary hypertension and elevated pulmonary vascular resistance) can overwhelm the right ventricle and lead to circulatory collapse. Despite the common end-point, the preceding pathophysiology is complex and variable and requires a tailored approach to diagnosis and management. In this article, we will review the most recent evidence and explore an approach to current controversies in the diagnosis and management of common or challenging patient subgroups. RECENT FINDINGS: New methods of interpreting data derived from echocardiography and cardiac magnetic resonance imaging may assist in risk stratification and response to therapy. In specific patient subgroups, standard pharmacological therapies to reduce right ventricle afterload may be overutilized, ineffective and in some cases harmful. In the patient failing pharmacological therapy, new and novel techniques are being explored including temporary extracorporeal mechanical circulatory support, pumpless lung assist devices and novel surgical and catheterization procedures. SUMMARY: PVD is a diverse entity, and attention to the underlying pathophysiology is essential for appropriate management. Despite significant advances in our understanding, the majority of data comes from small uncontrolled studies and must be interpreted with caution. PMID- 29528891 TI - Complicated pneumonia: current concepts and state of the art. AB - PURPOSE OF REVIEW: This review aims to provide clinicians engaged in the care of infants and children an update on the current understanding of the epidemiology, etiology, diagnostic evaluation, and clinical management of complicated pneumonia. The review provides timely information surrounding areas of consensus and ongoing research. RECENT FINDINGS: The epidemiology and etiologies of complicated pneumonia continue to evolve over the past several decades in context of the introduction of new vaccines. We review uncommon and emerging pathogens. Immunocompromised patients are particularly at risk for complications. The 2011 clinical practice guidelines for pediatric community-acquired pneumonia from The Pediatric Infectious Diseases Society/Infectious Diseases Society of America and the British Thoracic Society are changing approaches to evaluation and management. The efficacy of new diagnostic laboratory studies, and imaging techniques, continues to be studied. Antibiotics are the mainstay of treatment, with several new options to consider. Techniques for the drainage of parapneumonic effusions continue to optimize. SUMMARY: Although much is known about complicated pneumonia, it remains a significant burden. New diagnostic and therapeutic interventions hold much promise. This review seeks to provide clinicians with evidence that motivates a reasoned approach to the evaluation and management of complicated pneumonia. PMID- 29528892 TI - Initial presentation and management of pediatric heart failure. AB - PURPOSE OF REVIEW: Heart failure is a rare but morbid diagnosis in the pediatric patient presenting to the emergency department (ED). Familiarity of the ED physician with the presentation, work-up, and management of pediatric heart failure is essential as accurate diagnosis is reliant on a high degree of suspicion. RECENT FINDINGS: Studies evaluating pediatric heart failure are limited by its rarity and the heterogeneity of underlying conditions. However, recent reports have provided new data on the epidemiology, presentation, and outcomes of children with heart failure. SUMMARY: The recent studies reviewed here highlight the significant diagnostic and management challenges that pediatric heart failure presents given the variety and lack of specificity of its presenting signs, symptoms, and diagnostic work-up. This review provides the ED physician with a framework for understanding of pediatric heart failure to allow for efficient diagnosis and management of these patients. The primary focus of this review is heart failure in structurally normal hearts. PMID- 29528893 TI - ED overload, the flu, and you. PMID- 29528894 TI - Strategies for overcoming language barriers in healthcare. PMID- 29528895 TI - Use of psychotropic medication in women with psychotic disorders at menopause and beyond. AB - PURPOSE OF REVIEW: Drugs have been extensively prescribed for the treatment of psychotic symptoms in schizophrenia and related disorders, as well as for the management of psychotic features in delirium, dementia and affective disorders. The aim of this narrative review is to focus on the recent literature on drug treatment in women with psychosis at the transition to menopause and subsequently. RECENT FINDINGS: The recent literature emphasizes the following points: the efficacy of antipsychotic medication in psychosis is largely confined to the alleviation of delusions and hallucinations; menopause and ageing alter the kinetics and dynamics of drug action; drugs other than antipsychotics are currently being tested to address the cognitive, affective and negative symptoms of psychotic illnesses; menopausal symptoms add to comorbidities and require simultaneous treatment, raising the probability of deleterious drug interactions; antipsychotic drugs have many side effects and contribute to high mortality rates in the older psychosis population. SUMMARY: A major implication for research is that antipsychotic drugs with a wider range of action and with fewer side effects are urgently needed. The clinical implications of the pharmacotherapy of psychotic illness are: older women's needs must be assessed through a comprehensive history and review of systems and physical and mental examination. To avoid adverse effects, drug dosages are best kept low and polypharmacy avoided wherever possible. It is important to frequently reassess older patients, as their pharmacotherapy requirements change with age and with comorbidity. PMID- 29528896 TI - Toward personalized treatment of hallucinations. AB - PURPOSE OF REVIEW: Hallucinations are common and often stressful experiences, occurring in all sensory modalities. They frequently complicate many disorders or situations, such as Parkinson's disease, schizophrenia, hearing or vision loss, intoxications and delirium. Although psychoeducation, coping techniques and psychotherapy may be broadly applicable, they do not address a specific underlying brain mechanism. Pharmacotherapy may effectively alleviate hallucinations if the corresponding mechanism is present, whereas in its absence, may only cause harmful side effects. Therefore, pharmacotherapy needs input about underlying brain mechanisms. RECENT FINDINGS: Recent findings suggest new underlying neurobiological mechanisms as possible therapeutic targets in selected patients, for example increased glutamate levels. In addition, neuronavigation can guide repetitive transcranial magnetic stimulation treatment of auditory verbal hallucinations to target-specific cortical regions. SUMMARY: We propose the use of neuroimaging methods to better understand the interaction of different mechanisms underlying hallucinations and to use this knowledge to guide pharmacotherapy or focal brain stimulation in a personalized manner. In addition, we suggest evidence from various imaging modalities should converge to answer a research question. We believe this 'convergence of evidence' avoids the problem of overreliance on single and isolated findings. PMID- 29528897 TI - Urban mental health: challenges and perspectives. AB - PURPOSE OF REVIEW: To provide an update on urban mental health and highlight the challenges that require urgent attention. RECENT FINDINGS: The majority of the world's population live in towns and urbanization is expected to increase in all areas of the world. Challenges to mental health in urban areas include loneliness, violence, high crime rates, homelessness, noise and other pollutants, traffic accidents, drug abuse, and insufficiency of mental health services. SUMMARY: Urbanization is a global and growing phenomenon that pose significant challenges to mental health and mental health services. Fast and unstructured urbanization, such as that seen in many developing countries, further exacerbates these challenges. There are promising initiatives emerging including initiatives to end homelessness, to improve access to green areas in urban environments, to provide emergency psychiatric services, and to develop new forms of mental health services adjusted to urban settings. Regrettably there are no universally accepted guidelines that would help governments in structuring health services for people with mental illness in towns and help to prevent mental health problems related to rapid urbanization. PMID- 29528898 TI - New findings in pharmacogenetics of schizophrenia. AB - PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects. RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications. SUMMARY: The findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings. PMID- 29528899 TI - Mental health and urbanization: a Russian perspective. AB - PURPOSE OF REVIEW: Despite being a pressing problem, the influence of urbanization on mental health is still underestimated in Russia. Although few studies on the topic in recent years were available, viewpoints of the expert community in Russia will be presented. Intensive urbanization impacts on the living conditions of the majority of the country's population being associated with mass migration of the population, a change in the structure of employment, the restructuring of family relations, and the need to adapt to unaccustomed living conditions. RECENT FINDING: Modern urbanization can adversely affect mental health due to stressful factors related to overpopulation, environmental contamination, poverty, violence, and lack of social support. SUMMARY: The main factors that directly affect mental health in Russia are consequences of urbanization such as:The society and the Government are taking a number of measures to prevent the consequences of urbanization (restrictions in the consumption of alcohol and tobacco, mass green plantations, a ban on noise in the evening, closure of landfills, etc.). PMID- 29528900 TI - The impact of urbanization on mental health in India. AB - PURPOSE OF REVIEW: India has experienced rapid urbanization in the last few decades. This review focuses on recent research related to the effects of urbanization on mental health with a specific focus on various population groups in urban India. RECENT FINDINGS: With a specific focus on recent research undertaken amongst special populations such as youth, women and the elderly, the findings demonstrate increasing rates of substance use and technology addiction among youth; high self-harm rates in various groups such as adolescents and women; the effects of violence and abuse on the mental health of women; psychological distress among the elderly in modern urban India. SUMMARY: The article highlights the direct and indirect effects of urbanization on mental health of various populations and emphasizes the need to develop individual-level and policy-level strategies to manage problems arising out of the same. PMID- 29528901 TI - Ten-year evolution of suicide rates and economic indicators in large Brazilian urban centers. AB - PURPOSE OF REVIEW: This was a retrospective ecological study to examine the relationship between suicide rates and economic indicators in large Brazilian urban centers. Data on macroeconomic indicators (GDP and unemployment rates) and suicide rates of the largest Brazilian cities were collected from January 2006 to December 2015. RECENT FINDINGS: Six cities were included in the study: Porto Alegre in the South, Recife and Salvador in the Northeast, and Belo Horizonte, Sao Paulo and Rio de Janeiro in the Southeast region. We observed a 4% increase in the age-adjusted suicide rate in these large Brazilian urban centers from 2006 to 2015, which is less pronounced than the 9% increase in the national rates of suicide observed in the same period. SUMMARY: The effect of economic indicators was heterogeneous among the centers, but, overall, the variation in suicide rates was inversely related to unemployment and did not show a significant relationship with GDP. These findings indicate a more complex link between economics and suicide whenever looking at local regional indicators. Further research should focus on possible intervening factors, what may inform better preventive interventions. PMID- 29528903 TI - Urbanization and mental health: a developing world perspective. PMID- 29528902 TI - Electroconvulsive therapy (ECT) in schizophrenia: a review of recent literature. AB - PURPOSE OF REVIEW: ECT remains an important, yet underutilized, treatment for schizophrenia. Recent research shows that medication-resistant patients with schizophrenia, including those resistant to clozapine, respond well to ECT augmentation. The purpose of this article is to review recent studies of the use of ECT in the treatment of schizophrenia. RECENT FINDINGS: We performed an electronic database search for articles on ECT and schizophrenia, published in 2017. The main themes of these articles are: epidemiological data on ECT use from various countries; retrospective studies, prospective studies and meta-analyses focusing on efficacy and cognitive side-effects of ECT in schizophrenia; ECT technical parameters and potential biomarkers. SUMMARY: There is growing evidence to support the use of ECT for augmentation of antipsychotic response in the treatment of schizophrenia. Cognitive side-effects are generally mild and transient. In fact, many studies show improvement in cognition, possibly related to the improvement in symptoms. There is wide variation among countries in the use of ECT for the treatment of schizophrenia. There are also variations in the choice of ECT electrode placement, parameters and schedules. These technical differences are likely minor and should not interfere with the treatment being offered to patients. Further, long-term studies are needed to optimize ECT treatment parameters, to examine the effect of maintenance ECT and to investigate neuroimaging/biomarkers to understand the mechanism of action and identify potential response predictors to ECT. PMID- 29528904 TI - The Association Between the Neutrophil-to-Lymphocyte Ratio and Mortality in Patients with Acute Respiratory Distress Syndrome: A Retrospective Cohort Study. AB - PURPOSE: Systemic inflammation relates to the initiation and progression of acute respiratory distress syndrome (ARDS). As neutrophil-to-lymphocyte ratio (NLR) has been shown to be a prognostic inflammatory biomarker in various diseases, in this study, we sought to explore whether NLR is a prognostic factor in patients with ARDS. METHODS: A retrospective study was performed on patients diagnosed as ARDS admitted to the intensive care unit (ICU). We calculated the NLR by dividing the neutrophil count by the lymphocyte count and categorized patients into four groups based on quartile of NLR values. The association of NLR quartiles and 28 day mortality was assessed using multivariable Cox regression. Secondary outcomes included ICU mortality and hospital mortality. RESULTS: A total of 224 patients were included in the final analysis. The median (interquartile range) NLR from first quartile to fourth quartile were as follow: 6.88 (4.61-7.94), 13.06 (11.35 14.89), 20.99 (19.09-23.19), 39.39 (32.63-50.15), respectively. The 28-day mortality for the same groups were as follows: 10.7%, 19.6%, 41.4%, 53.6% (p < 0.001). Cox regression analysis showed NLR was a significant risk factor predicting 28-day mortality (first quartile, reference group; second quartile, adjusted hazard ratio (HR)= 1.674, 95% confidence interval (CI), 0.462 to 6.063, p = 0.432; third quartile, HR = 5.075, 95%CI, 1.554 to 16.576, p = 0.007; fourth quartile, HR = 5.815, 95% CI, 1.824 to 18.533, p = 0.003). Similar trends were observed for ICU mortality and hospital mortality. CONCLUSIONS: High NLR was associated with poor outcome in critically ill patients with ARDS. The PLR therefore appears to be a prognostic biomarker of outcomes in critically ill patients with ARDS. Further investigation is required to validate this relationship with data collected prospectively. PMID- 29528905 TI - Myocarditis and cardiomyopathy. AB - PURPOSE OF REVIEW: The aim of this study is to summarize the literature describing the pathogenesis, diagnosis and management of cardiomyopathy related to myocarditis. RECENT FINDINGS: Myocarditis has a variety of causes and a heterogeneous clinical presentation with potentially life-threatening complications. About one-third of patients will develop a dilated cardiomyopathy and the pathogenesis is a multiphase, mutlicompartment process that involves immune activation, including innate immune system triggered proinflammatory cytokines and autoantibodies. In recent years, diagnosis has been aided by advancements in cardiac MRI, and in particular T1 and T2 mapping sequences. In certain clinical situations, endomyocardial biopsy (EMB) should be performed, with consideration of left ventricular sampling, for an accurate diagnosis that may aid treatment and prognostication. SUMMARY: Although overall myocarditis accounts for a minority of cardiomyopathy and heart failure presentations, the clinical presentation is variable and the pathophysiology of myocardial damage is unique. Cardiac MRI has significantly improved diagnostic abilities, but endomyocardial biopsy remains the gold standard. However, current treatment strategies are still focused on routine heart failure pharmacotherapies and supportive care or cardiac transplantation/mechanical support for those with end stage heart failure. PMID- 29528906 TI - Viral myocarditis: a prime example for endomyocardial biopsy-guided diagnosis and therapy. AB - PURPOSE OF REVIEW: Myocarditis is an inflammatory disease of the cardiac muscle mainly caused by viral infection. Due to the diverse clinical presentation of myocarditis, accurate diagnosis demands simultaneous histologic, immunohistochemical and molecular biological workup of endomyocardial biopsies (EMBs) as defined by the position statement of the Working Group on Myocardial and Pericardial Diseases of the European Society of Cardiology on myocarditis. RECENT FINDINGS: Endomyocardial biopsy-based analysis of viral transcriptional activity, mRNA expression, epigenetics and region-specific protein expression analysis via imaging mass spectrometry have led to the identification of novel potential diagnostic criteria, markers with prognostic value and therapeutic targets for the treatment of viral myocarditis, opening new avenues for novel therapies, including cell therapies, as well as the use of established treatment options, be it from other indications. SUMMARY: Under certain clinical scenarios EMB-based analysis is required to come to a tailored individualized therapy that improves symptoms and prognosis of patients with acute and chronic viral-driven cardiac inflammation. PMID- 29528907 TI - Recurrence of Rectal Prolapse After Surgical Repair in Women With Pelvic Organ Prolapse. AB - BACKGROUND: Pelvic organ prolapse is prevalent among women with rectal prolapse. OBJECTIVE: This study aimed to determine whether clinically significant pelvic organ prolapse impacts rectal prolapse recurrence after surgical repair. DESIGN: A retrospective cohort. SETTING: This study was performed at a single managed care institution. PATIENTS: Consecutive women undergoing rectal prolapse repair between 2008 and 2016 were included. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Full-thickness rectal prolapse recurrence was compared between 4 groups: abdominal repair without pelvic organ prolapse (AR-POP); abdominal repair with pelvic organ prolapse (AR+POP); perineal repair without pelvic organ prolapse PR-POP; and perineal repair with pelvic organ prolapse (PR+POP). Recurrence-free period and hazard of recurrence were compared using Kaplan-Meier and Cox proportional hazards methods. To identify potential confounding risk factors for rectal prolapse recurrence, the characteristics of subjects with/without recurrence were compared with univariable and multivariable analyses. RESULTS: Overall, pelvic organ prolapse was present in 33% of 112 women and was more prevalent among subjects with rectal prolapse recurrence (52.4% vs 28.6%, p = 0.04). Median follow-up was 42.5 months; rectal prolapse recurrence occurred in 18.8% at a median of 9 months. The rate of recurrence and the recurrence-free period differed significantly between groups: AR-POP 3.8%, 95.7 months; AR+POP 13.0%, 86.9 months; PR-POP 34.8%, 42.1 months; PR+POP 57.1%, 23.7 months (p < 0.001). Compared with AR-POP the HR (95% CI) of rectal prolapse recurrence was 3.1 (0.5-18.5) for AR+POP; 14.7 (3.0-72.9) for PR-POP and 31.1 (6.2-154.5) for PR+POP. Compared with AR+POP, PR+POP had a shorter recurrence free period (p < 0.001) and a higher hazard of recurrence (HR, 10.2; 95% CI, 2.1 49.3). LIMITATIONS: The retrospective design was a limitation of this study. CONCLUSIONS: Pelvic organ prolapse was associated with a higher rectal prolapse recurrence rate and earlier recurrence in women undergoing perineal, but not abdominal, repairs. Multidisciplinary evaluation can facilitate individualized management of women with rectal prolapse. Abdominal repair should be considered in women with concomitant rectal and pelvic organ prolapse. See Video Abstract at http://links.lww.com/DCR/A513. PMID- 29528908 TI - Closing Perianal Fistulas Using a Laser: Long-Term Results in 103 Patients. AB - BACKGROUND: Primary closure of the fistula tract using energy emitted by a radial fiber connected to a diode laser is a novel procedure for treating perianal fistulas. OBJECTIVE: The aim of this study was to determine the long-term effectiveness of this new technique. DESIGN: The surgical objective was to seal the fistula tract using laser energy. SETTINGS: The study was conducted at a single day-case surgery center. PATIENTS: Between April 2012 and June 2016, 103 consecutive patients with primary or recurrent perianal fistula underwent a laser closure procedure using a 12-watt laser emitting at a wavelength of 1470 nm. MAIN OUTCOME MEASURES: Patients were classified according to the Park classification, and healing was evaluated based on the perianal fistula disease severity score. RESULTS: Among the 103 patients treated using the laser closure procedure, 82 (80%) were men and 21 (20%) were women. The median age of the patients was 43 years (range, 18-78 y). Fifty-three patients (52%) had previous perianal fistula repair surgery. Based on the Park classification, 56 patients (54%) had intersphincteric fistula, 29 (28%) had transsphincteric fistula, 11 (11%) had suprasphincteric or extrasphincteric fistula, and 7 (7%) had superficial perianal fistula. Based on the perianal disease severity score, 41 patients (40%) obtained overall complete healing, 38 (37%) had persistent symptomatic drainage, 20 (19%) had slight drainage with minimal symptoms, and 4 (4%) had painful symptomatic drainage. LIMITATIONS: This was a retrospective analysis of noncomparative data with a lack of formal prospective continence assessment. CONCLUSIONS: Closure of perianal fistulas using a laser should be considered as a treatment option but with modest expectations. Although our complete healing rate was not as high as in earlier studies, this technique is a reasonable option with nearly no risk of sphincter damage when treating perianal fistulas. See Video Abstract at http://links.lww.com/DCR/A545. PMID- 29528909 TI - Increased Postoperative Morbidity Associated With Prolonged Laparoscopic Colorectal Resections Is Not Increased by Resident Involvement. AB - BACKGROUND: Although longer operative times are associated with increased postoperative morbidity, the influence of surgical residents on this association is unclear. OBJECTIVE: The purpose of this study was to evaluate whether morbidity associated with operative times in laparoscopic colorectal surgery is increased by resident training. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted using a national database. PATIENTS: Laparoscopic ileocolectomies, partial colectomies, and low anterior resections were identified in the National Surgical Quality Improvement Project (2005-2012). This cohort was stratified by the presence of resident involvement (postgraduate clinical year <=5) and then divided into tertiles of operative time (low, medium, and high), allowing comparisons of cases by duration with resident involvement with cases of similar length without resident involvement. MAIN OUTCOME MEASURES: Postoperative morbidity (infectious and noninfectious), length of hospital stay, and unplanned reoperations were the primary study outcomes. RESULTS: A total of 20,785 procedures were identified. In aggregate, prolonged operative time was associated with both infectious (OR = 1.49, p < 0.001 with residents; OR = 1.38, p < 0.001 without residents) and noninfectious complications (OR = 1.51, p < 0.001 with residents; OR = 1.48, p < 0.001 without residents) when compared with short cases without residents. Longer hospital stay was observed both within the highest (additional 1.2 days (p < 0.001) with residents; 1.1 days (p < 0.001) without residents) and middle (additional 0.4 days (p < 0.001) with residents; 0.4 days (p = 0.001) without residents) tertiles of operative time. Within the highest tertile of operative length, there was no statistically significant difference in complication rates between cases with and without resident participation. LIMITATIONS: The study was limited by its retrospective design and inability to define the complexity of case and extent of resident involvement. CONCLUSIONS: Although longer operative times confer increased postoperative morbidity, there was no significant difference in complication rates within the highest tertile between cases with and without resident participation. Resident involvement does not appear to add to the risk of morbidity associated with longer and more complicated surgeries. See Video Abstract at http://links.lww.com/DCR/A440. PMID- 29528910 TI - A Preliminary Study of Computed Tomography Coronary Angiography Within a Single Cardiac Cycle in Patients With Atrial Fibrillation Using 256-Row Detector Computed Tomography. AB - OBJECTIVE: The purpose of this study was to evaluate the image quality and radiation dose of computed tomography (CT) coronary angiography using a 256-row detector CT scanner in a single cardiac cycle in patients with atrial fibrillation (AF). METHODS: Seventy consecutive patients (41 men and 29 women; age range was from 37 to 84 years, mean age was 61.7 +/- 10.2 years; body mass index range was from 15.08 to 36.45 kg/m, mean body mass index was 25.9 +/- 3.5 kg/m) with persistent or paroxysmal AF during acquisition, who were not receiving any medications for heart rate (HR) regulation, were imaged with a 256-row detector CT scanner (Revolution CT, GE healthcare). According to the HR or HR variability (HRV) the patients were divided into 4 groups: group A (HR, >=75 bpm; n = 36), group B (HR, <75 bpm; n = 34), group C (HRV, >=50 bpm; n = 26), and group D (HRV, <50 bpm; n = 44). The snapshot freeze algorithm reconstruction was used to reduce motion artifacts whenever necessary. Two experienced radiologists, who were blinded to the electrocardiograph and reconstruction information, independently graded the CT images in terms of visibility and artifacts with a 4 grade rating scale (1, excellent; 2, good; 3, poor; 4, insufficient) using the 18 segment model. Subjective image quality scores and effective dose (ED) were calculated and compared between these groups. RESULTS: The HR during acquisition ranged from 47 to 222 bpm (88.24 +/- 36.80 bpm). A total of 917 in 936 coronary artery segments were rated as diagnostically evaluable (98.2 +/- 0.04%). There was no significant linear correlation between mean image quality and HR or HRV (P > 0.05). Snapshot freeze reconstruction technique was applied in 28 patients to reduce motion artifacts and thus showed image quality was improved from 93.2% to 98.4%. The ED was 3.05 +/- 2.23 mSv (0.49-11.86 mSv) for all patients, and 3.76 +/- 2.22 mSv (0.92-11.17 mSv), 2.30 +/- 2.02 mSv (0.49-11.86 mSv), 3.89 +/- 2.35 mSv (1.18-11.86 mSv), and 2.56 +/- 2.03 mSv (0.49-11.17 mSv) for groups A, B, C, and D, respectively. There were significant differences in mean ED between groups A and B, as well as C and D (P <0.05). CONCLUSIONS: This study shows that CT coronary angiography with use of a new 256-row detector CT in single cardiac cycle achieves diagnostic image quality but with lower radiation dose in patients with AF. Heart rate or HRV has no significant effect on image quality. PMID- 29528911 TI - The effect of kidney volume estimation on dosimetry in lutetium-177 DOTATATE therapy. AB - BACKGROUND: The kidneys are the dose-limiting organ in lutetium-177 DOTATATE therapy. Therefore, it is advisable to perform critical organ dosimetry focussed on renal dose in treated patients. A key uncertainty in such dose estimates is the use of standard phantoms to represent the individual patient. The primary aim of this study was to investigate the accuracy of methods for estimating kidney size, and hence absorbed kidney dose, by comparison with individual measurements from computed tomography (CT) imaging. MATERIALS AND METHODS: Kidney volume was measured using diagnostic CT images for 57 patients who underwent lutetium-177 DOTATATE therapy. Kidney mass was also estimated in two ways: using the standard adult phantoms, as well as through the application of a weight scaling factor to these phantoms and their organs. Dose calculations were performed for each of the three methods using OLINDA/EXM software. RESULTS: Scaling of the phantom by patient weight gave a more accurate result when compared with the CT gold standard than the standard phantom. The dose difference from the CT method had mean values of 1.4% (SD=22.6%) and 8.4% (SD=21.5%) for scaled and unscaled, respectively. Patient weight was not found to be a good predictor of kidney mass in these patients (r of 0.12 from linear regression analysis). CONCLUSION: The most accurate method of organ volume estimation would be individual measurements from CT imaging; however, where this is not possible, scaling of organ masses by weight ratio is more accurate than the use of the standard phantom. PMID- 29528913 TI - Community-acquired Pneumonia With Pleural Effusion in Children and Municipal Human Development Index in Rio de Janeiro, Brazil. AB - BACKGROUND: This study evaluated admissions with severe community-acquired pneumonia (CAP) with pleural effusion (PE) in a pediatric university hospital and the impact of the increased average municipal human development index (M-HDI) in the local incidence of the disease in the last decade. METHODS: This is a retrospective longitudinal study of patients (0-13 years old) with CAP. The municipal human development index (M-DHI) of the place of residence of patients was obtained. We calculate the crude odds ratios (ORs) of variables related to risk of developing PE. The variables that reached a significance level of 80% (P < 0.20) were selected for multivariate analysis. The logistic regression model was used for the selection of the parsimonious model, according to the likelihood ratio. RESULTS: The 465 patients' ages ranged from 1 to 174 months. The median of age (months) in children with PE was 36.00; in children without the PE was 29.00 (P < 0.011); media of variation in M-HDI in the period in patients with PE was 0.767 +/- 0.002 and in patients without PE was 0.778 +/- 0.002 (P < 0.001). In the logistic regression model, the absence of comorbidity (OR = 2.909) and the HDI < 0.770 (OR = 3.015) were predictive factors associated with PE. CONCLUSION: The progressive increase of the M-DHI during the study period, although to a slightly higher level, was correlated with the reduction in the number of admissions with CAP with PE. PMID- 29528914 TI - A Randomized, Double-blind, Active-controlled Clinical Trial of a Cell Culture derived Inactivated Trivalent Influenza Vaccine (NBP607) in Healthy Children 6 Months Through 18 Years of Age. AB - BACKGROUND: Although a number of cell culture-derived influenza vaccines have been approved for use in adults, there have been few clinical trials of cell culture-derived seasonal influenza vaccines for young children. METHODS: We conducted a randomized, double-blind phase III clinical trial to evaluate the safety and immunogenicity of a cell culture-derived subunit trivalent inactivated influenza vaccine (NBP607, SK Chemicals Co., Ltd., Seongnam, Korea) in healthy children 6 months of age through 18 years. Subjects were randomized to receive either a study vaccine or an egg-based control vaccine. Antibody levels were measured by the hemagglutination inhibition assay, using cell-derived antigens. Solicited adverse events were assessed for 7 days after each injection. Serious adverse events were collected for 6 months after vaccination. RESULTS: A total of 374 participants completed the study. No deaths, vaccine-related serious adverse events or withdrawals resulting from adverse events were reported. Rates of solicited and unsolicited adverse events were similar in 2 groups. Overall, NBP607 met the immunogenicity criteria of the Committee for Proprietary Medicinal Products for the 3 influenza strains. Between the NBP607 group and the control group, immunogenicity endpoints were comparable. Participants younger than 3 years of age had lower immunologic responses against the influenza B virus in both the NBP607 group and the control group. CONCLUSIONS: The immunogenicity and safety were comparable between the NBP607 group and the control group. NBP607 is well tolerated and immunogenic in children 6 months of age through 18 years. PMID- 29528915 TI - Regarding Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort, Gavin Bart et al. PMID- 29528916 TI - Author Response to Stoklosa and Haber. PMID- 29528917 TI - Dos and Don'ts in Pregnancy: Truths and Myths. AB - Pregnancy is a time of excitement and anxiety. The reality for pregnant women is that their actions could affect their pregnancies and their fetuses. As such, they need to know what they should and should not do to minimize risk and optimize outcomes. Whereas this advice used to come from doctors, a few books, and some family and friends, in the age of the internet, women are now bombarded with information and recommendations, which are often confusing at best and conflicting at worst. The objective of this review is to present current, evidence-based recommendations for some of the things that pregnant women should and should not routinely do during pregnancy. PMID- 29528918 TI - Statewide Quality Improvement Initiative to Reduce Early Elective Deliveries and Improve Birth Registry Accuracy. AB - OBJECTIVE: To evaluate the success of a quality improvement initiative to reduce early elective deliveries at less than 39 weeks of gestation and improve birth registry data accuracy rapidly and at scale in Ohio. METHODS: Between February 2013 and March 2014, participating hospitals were involved in a quality improvement initiative to reduce early elective deliveries at less than 39 weeks of gestation and improve birth registry data. This initiative was designed as a learning collaborative model (group webinars and a single face-to-face meeting) and included individual quality improvement coaching. It was implemented using a stepped wedge design with hospitals divided into three balanced groups (waves) participating in the initiative sequentially. Birth registry data were used to assess hospital rates of nonmedically indicated inductions at less than 39 weeks of gestation. Comparisons were made between groups participating and those not participating in the initiative at two time points. To measure birth registry accuracy, hospitals conducted monthly audits comparing birth registry data with the medical record. Associations were assessed using generalized linear repeated measures models accounting for time effects. RESULTS: Seventy of 72 (97%) eligible hospitals participated. Based on birth registry data, nonmedically indicated inductions at less than 39 weeks of gestation declined in all groups with implementation (wave 1: 6.2-3.2%, P<.001; wave 2: 4.2-2.5%, P=.04; wave 3: 6.8-3.7%, P=.002). When waves 1 and 2 were participating in the initiative, they saw significant decreases in rates of early elective deliveries as compared with wave 3 (control; P=.018). All waves had significant improvement in birth registry accuracy (wave 1: 80-90%, P=.017; wave 2: 80-100%, P=.002; wave 3: 75-100%, P<.001). CONCLUSIONS: A quality improvement initiative enabled statewide spread of change strategies to decrease early elective deliveries and improve birth registry accuracy over 14 months and could be used for rapid dissemination of other evidence-based obstetric care practices across states or hospital systems. PMID- 29528919 TI - Health Care Disparity and Pregnancy-Related Mortality in the United States, 2005 2014. AB - OBJECTIVE: To quantitate the contribution of various demographic factors to the U.S. maternal mortality ratio. METHODS: This was a retrospective observational study. We analyzed data from the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics database and the Detailed Mortality Underlying Cause of Death database (CDC WONDER) from 2005 to 2014 that contains mortality and population counts for all U.S. counties. Bivariate correlations between the maternal mortality ratio and all maternal demographic, lifestyle, health, and medical service utilization characteristics were calculated. We performed a maximum likelihood factor analysis with varimax rotation retaining variables that were significant (P<.05) in the univariate analysis to deal with multicollinearity among the existing variables. RESULTS: The United States has experienced an increase in maternal mortality ratio since 2005 with rates increasing from 15 per 100,00 live births in 2005 to 21-22 per 100,000 live births in 2013 and 2014. (P<.001) This increase in mortality was most pronounced in non-Hispanic black women, with ratios rising from 39 to 49 per 100,000 live births. A significant correlation between state mortality ranking and the percentage of non-Hispanic black women in the delivery population was demonstrated. Cesarean deliveries, unintended births, unmarried status, percentage of deliveries to non-Hispanic black women, and four or fewer prenatal visits were significantly (P<.05) associated with the increased maternal mortality ratio. CONCLUSION: The current U.S. maternal mortality ratio is heavily influenced by a higher rate of death among non-Hispanic black or unmarried patients with unplanned pregnancies. Racial disparities in health care availability and access or utilization by underserved populations are important issues faced by states seeking to decrease maternal mortality. PMID- 29528920 TI - Occult Gynecologic Cancer in Women Undergoing Hysterectomy or Myomectomy for Benign Indications. AB - OBJECTIVE: To estimate the prevalence of corpus uteri, cervix uteri, and ovarian malignancy in women undergoing hysterectomy or myomectomy for presumed benign indications. METHODS: We conducted a secondary analysis of data from the 2014 2015 American College of Surgeons National Surgical Quality Improvement Program. Adult women undergoing hysterectomies and myomectomies without evidence for known or suspected cancer at the beginning of surgery were identified from the database. Our primary outcome measure was pathology-confirmed malignancy in the corpus uteri, cervix uteri, and ovary. We performed adjusted logistic regression analysis to examine the association of patient characteristics with the risk for malignancy. RESULTS: Our sample included 24,076 women undergoing hysterectomy and 2,368 women undergoing myomectomy. Malignancy of the corpus uteri was found in 1.44% (95% CI 1.29-1.59%) of the women undergoing hysterectomy. The prevalence varied considerably across surgical routes with the rate being 0.23% (95% CI 0.06 0.58%) in laparoscopic supracervical hysterectomy and 1.89% (95% CI 1.65-2.14%) in total laparoscopic or laparoscopic-assisted vaginal hysterectomy. Older women were significantly more likely to have preoperatively undetected malignancy of the corpus uteri (adjusted odds ratio 6.46, 95% CI 4.96-8.41 for age 55 years or older vs age 40-54 years). Additionally, 0.60% (95% CI 0.50-0.70%) and 0.19% (95% CI 0.14-0.25%) of the women undergoing hysterectomy were found to have malignancy of the cervix uteri and the ovary, respectively. Among patients undergoing myomectomy, 0.21% (95% CI 0.03-0.40%) were found to have malignancy of the corpus uteri with no occult cervical or ovarian cancer identified. CONCLUSION: Prevalence of occult corpus uteri, cervical, and ovarian malignancy was 1.44%, 0.60%, and 0.19%, respectively, among women undergoing hysterectomy and it varied by patient age and surgical route. PMID- 29528921 TI - Clitoral Reconstruction Using a Vaginal Graft After Female Genital Mutilation. AB - BACKGROUND: Clitoral reconstruction after genital mutilation is a feasible and effective strategy to reduce clitoral pain, improve sexual pleasure, and restore vulvar appearance. TECHNIQUE: We describe a novel surgical technique for clitorolabial reconstruction using a vaginal graft. EXPERIENCE: We present a series of 32 consecutive women who underwent this procedure at Ivan Manero Clinic, Barcelona, Spain, and were prospectively followed. The total Female Sexual Function Index changed favorably from 16 before surgery to 29 after surgery (P<.05). Likewise, the Female Self-Image Genital Scale changed favorably from 11 to 23 (P<.05). CONCLUSION: Clitoral reconstruction after genital mutilation was associated with improved sexual function and genital aesthetic perception. PMID- 29528923 TI - Autoimmune Progesterone Dermatitis Presenting as Stevens-Johnson Syndrome. PMID- 29528922 TI - Quality Improvement to Demonstrate the Lack of Reliability of the Human Papillomavirus mRNA Assay to Identify Women With Latent Human Papillomavirus Infections. AB - OBJECTIVE: To assess the consistency between human papillomavirus (HPV) mRNA testing in women with a history of previous HPV infections diagnosed by HPV DNA assay and the potential effects on follow-up HPV screening. METHODS: This was a quality improvement study that used data from a pathology laboratory software database reviewed from November 2014 to June 2016 to identify female patients aged 30 years or older with greater than one HPV-positive result, including one or more HPV mRNA assay results and one or more documented HPV DNA assay results for comparison. Previous correlative cytology and colposcopic histopathology were also documented. American College of Obstetricians and Gynecologists' cervical cancer screening guidelines were used to compare potential differences in follow up recommendations. RESULTS: Four hundred twenty-five charts for female patients 30 years of age or older were identified with one or more prior high-risk HPV infections by DNA assay. There was a 69.3% difference in HPV mRNA results compared with previous HPV DNA-positive results. There was a potential change in follow-up for 71.7% of patients with one prior high-risk-HPV-positive result and 60.0% of patients with two or more prior high-risk HPV-positive results. There were 231 colposcopy reports evaluated in this study. Of these, 62 (26.8%) were abnormal colposcopy reports, including 45 low-grade squamous intraepithelial lesions, 15 high-grade squamous intraepithelial lesions, and two cancers. Twenty five (40.3%) abnormal colposcopy findings were in patients with a history of at least than two prior HPV DNA-positive results and a report of currently being HPV negative with the mRNA assay. CONCLUSION: The HPV mRNA assays are less sensitive for detection of latent HPV infections compared with HPV DNA assays. Based on these data and the potential change in follow-up care, the HPV mRNA assay should not be used for a primary screening tool for cervical cancer. Many pathology laboratories have shifted to using the HPV mRNA assay without clear discussion with gynecologists about the effects on patient follow-up. The type of HPV assay being used should be documented and any HPV mRNA result confirmed by HPV DNA assay. PMID- 29528924 TI - Harm Reduction for Abortion in the United States. AB - : Access to abortion in the United States has eroded significantly. Accordingly, there is a growing movement to empower women to self-induce abortion. To date, physicians' roles and responsibilities in this changing environment have not been defined. Here, we consider a harm reduction approach to first-trimester abortion as a way for physicians to honor clinical and moral obligations to care for women, negotiate ever-increasing abortion restrictions, and support women who consider abortion self-induction. Harm reduction approaches to abortion have been successfully implemented in a range of countries around the world and typically take the form of teaching women how to use misoprostol. When women self administer misoprostol, rather than resort to other means such as self instrumentation or abdominal trauma, to end a pregnancy, maternal mortality falls. There are clinical and ethical benefits as well as limitations to a harm reduction approach to abortion in U.S. SETTINGS: Its legal implications for patients and physicians are unclear. Ultimately, we suggest that despite its limitations, a harm reduction approach may help both physicians and patients. PMID- 29528925 TI - Family Planning and Counseling Desires of Women Who Have Experienced Miscarriage. AB - OBJECTIVE: To explore initial pregnancy intentions and postmiscarriage family planning needs and counseling preferences of women experiencing spontaneous abortion. METHODS: We conducted semistructured qualitative interviews with women who recently experienced spontaneous abortion to explore their feelings about conception, pregnancy, and miscarriage; their future family planning goals; and contraceptive counseling preferences. Two trained coders utilized an inductive, iterative approach to code transcripts and identify themes using Atlas.ti software to organize the analysis. RESULTS: We interviewed 26 women reporting varied intentions in their recent pregnancies: 54% were trying to conceive, 27% were not trying but not preventing, and 19% were attempting to avoid pregnancy. Participants reported a range of feelings about the pregnancy diagnoses and eventual miscarriages with some relatively unemotional ("a little disappointed...suffering for two months for nothing") and others feeling devastated by their pregnancy losses ("in shock," "for it to be taken away was crushing"). Varying character and intensity of emotional reactions were seen across the range of initial pregnancy intentions. Some participants had consistent childbearing plans before and after miscarriage, whereas others experienced their pregnancies and losses as clarifying events leading to changed goals moving forward ("it was a wake-up call"). Although family planning needs were inconsistently addressed after spontaneous abortion, women were generally receptive to the idea of contraceptive counseling, though they had different preferences regarding timing, ranging from immediately to weeks later. CONCLUSION: Women's reproductive goals after spontaneous abortion cannot be inferred based on initial pregnancy intention or emotional reactions to pregnancy loss. Health care providers should offer family planning counseling to all women after spontaneous abortion, remaining responsive to individual patient needs. PMID- 29528927 TI - Abnormal Vaginal Bleeding in Women Desiring Contraception Who Are Taking Anticoagulation Therapy. AB - A 30-year-old nulligravid woman is referred to you for heavy menstrual cycles. Although her menstrual cycles were previously light, she was recently diagnosed with an unprovoked lower extremity venous thromboembolism and is taking anticoagulation therapy after a negative thrombophilia workup. She wants help with her vaginal bleeding and desires contraception. PMID- 29528926 TI - Prevalence of Depression Among Women of Reproductive Age in the United States. AB - OBJECTIVE: To describe the prevalence, use of antidepressants, and predictors of major and minor depression among nonpregnant women of childbearing age. METHODS: Using data from the National Health and Nutrition Examination Surveys 2007-2014, we performed a cross-sectional study of 3,705 nonpregnant women of childbearing age. The primary outcome is the prevalence of major depression, and secondary outcomes are the prevalence of minor depression, rates of antidepressant use, and predictors of major and minor depression. Major and minor depression were classified using the Patient Health Questionnaire 9. Univariate and multivariate associations between major depression and minor depression with potential predictors were estimated using multinomial logistic regression. RESULTS: The overall prevalences of major and minor depression were 4.8% (95% CI 4.0-5.7%) and 4.3% (95% CI 3.5-5.2%), respectively. The prevalences of antidepressant use among women with major depression and minor depression were 32.4% (95% CI 25.3-40.4%) and 20.0% (95% CI 12.9-29.7%), respectively. Factors most strongly associated with major depression were government insurance (adjusted relative risk [RR] ratio 2.49, 95% CI 1.56-3.96) and hypertension (adjusted RR 2.09, 95% CI 1.25 3.50); for minor depression, these were education less than high school (adjusted RR 4.34, 95% CI 2.09-9.01) or high school education (adjusted RR 2.92, 95% CI 1.35-6.31). CONCLUSION: Our analysis indicates that 1 in 20 nonpregnant women of childbearing age experience major depression. Antidepressants are used by one third of those with major depression and one fifth of those with minor depression. PMID- 29528928 TI - Gottesfeld-Hohler Memorial Foundation Zika Virus Think Tank Summary. AB - At a think tank bringing together experts on fetal neuroimaging, obstetric infectious diseases, and public health, we discussed trends in all of these areas for Zika virus. There is a wide variety of imaging findings in affected fetuses, influenced by timing of infection and probably host factors. The resources for diagnosis and interventions also vary by location with the hardest hit areas often having the fewest resources. We identified potential areas for both research and clinical collaboration as the Zika virus epidemic continues to evolve. PMID- 29528929 TI - A Unique Institutional Response to the Zika Virus Epidemic. AB - In 2015, Zika virus rapidly emerged as a concern for obstetric patients and health care providers as the disease spread geographically and it was discovered that Zika virus infection had the potential to cause devastating birth defects. Essentially overnight, obstetric care providers were faced with an influx of rapidly evolving information and an increased workload. New systems, workflows, and personnel were needed to effectively address the new patient care needs fueled by the burgeoning Zika virus epidemic. The University of California, San Francisco responded by filling a Zika Response Nurse Coordinator position to take on tasks necessary to design a systematic approach for Zika virus management. The Zika Response Coordinator at the University of California, San Francisco serves as a subject matter expert who counsels patients and health care providers, arranges testing and follow-up care after potential Zika virus exposure, and helps design the screening tools, protocols, and educational material needed to manage the evolving Zika virus response. The position has enabled a Zika virus response that has been tightly coordinated, consistent, and thorough without overburdening health care providers. The Zika Response Nurse Coordinator Role serves as a template for how institutions can model coordinated Zika virus care and prepare for future threats that will necessitate a focused and rapid response. Timely institutional financial support is critical for an appropriate response to emerging diseases for not only Zika virus but future epidemics as well. PMID- 29528931 TI - In Another Room on Another Floor. PMID- 29528930 TI - Anaphylactic Shock After Intravenous Fluorescein Administration for Intraoperative Cystoscopy. AB - BACKGROUND: Rates of administration of intravenous sodium fluorescein during cystoscopy have increased since indigotindisulfonate sodium was removed from the market in 2014. Although sodium fluorescein has been extensively evaluated and found to be safe, side effects including anaphylaxis have been observed, with an incidence between 0.05% and 1.0%. CASE: We present a case of anaphylactic shock after administration of intravenous sodium fluorescein for the assessment of ureteral efflux in a patient with a history of frequent severe allergic reactions undergoing urethral lysis and cystoscopy for urinary retention. Cardiopulmonary structure and function were evaluated and found to be normal. An elevated serum tryptase level was identified, indicating an anaphylactoid reaction. Timely recognition of symptoms associated with a severe allergic reaction in the setting of hemodynamic instability with prompt supportive and pharmacologic therapy was vital in the patient's recovery. CONCLUSION: Health care providers must be aware of this potential complication, especially in patients with a history of severe allergic reactions. PMID- 29528932 TI - Manual Compared With Electric Vacuum Aspiration for Treatment of Molar Pregnancy. AB - OBJECTIVE: To evaluate uterine evacuation of patients with molar pregnancy, comparing manual with electric vacuum aspiration. METHODS: This is a retrospective cohort study of patients with molar pregnancy followed at the Rio de Janeiro Trophoblastic Disease Center from January 2007 to December 2016. The individual primary study outcomes were incomplete uterine evacuation, uterine perforation, development of uterine synechia, and development of postmolar gestational trophoblastic neoplasia. Secondary endpoints were other features of the perioperative outcomes (operative time, rate of transfusion, hemoglobin change, length of stay) and the clinical course of neoplasia (Prognostic Risk Score, presence of metastases, time to remission, and need for multiagent chemotherapy). RESULTS: Among 1,727 patients with molar pregnancy, 1,206 underwent electric vacuum aspiration and 521 underwent manual vacuum aspiration. After human chorionic gonadotropin normalization, patients with benign molar pregnancy were followed for 6 months and patients treated for gestational trophoblastic neoplasia were followed for 12 months. Baseline risk factors for gestational trophoblastic neoplasia and demographic features were similar between the treatment groups. Uterine synechia developed less frequently after manual vacuum aspiration than after electric vacuum aspiration, 6 of 521 vs 63 of 1,206 (adjusted odds ratio [OR] 0.21, 95% CI 0.09-0.49), despite no differences in the occurrence of incomplete uterine evacuation, 65 of 521 vs 161 of 1,206 (adjusted OR 0.93, 95% CI 0.69-1.27), development of postmolar gestational trophoblastic neoplasia, 90 of 521 vs 171 of 1,206 (adjusted OR 1.26, 95% CI 0.96-1.67), or the need for multiagent chemotherapy, 22 of 521 vs 41 of 1,206 (adjusted OR 0.81, 95% CI 0.73-1.28). CONCLUSION: Manual vacuum aspiration appears to be similar to electric vacuum aspiration for treatment of molar pregnancy and may be associated with less development of uterine synechia. PMID- 29528933 TI - Simultaneous Compared With Interval Medical Abortion Regimens Where Home Use Is Restricted. AB - OBJECTIVE: To evaluate outcomes with simultaneous administration of mifepristone and misoprostol for medical abortion at 63 days of gestation or less in the year after its implementation in a British clinic system. METHODS: We conducted a retrospective cohort study using deidentified data from the electronic booking and complications databases and medical records of women who underwent medical abortion at British Pregnancy Advisory Service. Our primary outcome was treatment success with simultaneous dosing compared with a regimen with a 24- to 48-hour interval between medications. We defined success as complete abortion without surgical evacuation and without continuing pregnancy. To assess relative regimen effectiveness while accounting for self-assignment to simultaneous or interval dosing, we modeled the probability of treatment success using logistic regression with propensity score adjustment for demographic and clinical characteristics. Secondary outcomes were reasons for abortion failure and clinically significant adverse events (hospital admission, blood transfusion, intravenous antibiotic administration). RESULTS: Of 28,901 women treated between May 2015 and April 2016, 85% chose simultaneous dosing. Overall success rates were high with both regimens but lower with simultaneous than with interval dosing (94.5% vs 97.1%, respectively, adjusted relative risk 0.973, 95% CI 0.967-0.979). For both regimens, success rates were lower at higher gestational ages, but the relative effectiveness of simultaneous dosing did not vary significantly with gestational age (P=.268). Surgical intervention rates for continuing pregnancy were lowest at 49 days of gestation or less (1.4% simultaneous vs 0.2% interval, P<.001) and highest at 57-63 days of gestation (5.0% and 2.2%, P<.001). The rate of clinically significant adverse events was 0.2% and did not differ by regimen (P=.972). CONCLUSION: Simultaneous administration of mifepristone and misoprostol is 97% as effective as a 24- to 48-hour interval at all gestational ages 63 days or less with no increase in the risk of clinically significant adverse events. Pragmatic use of simultaneous dosing is reasonable given the small difference in effectiveness. PMID- 29528934 TI - A 15-Year Study of Trends in Authorship by Gender in Two U.S. Obstetrics and Gynecology Journals. AB - OBJECTIVE: To assess whether there was a significant trend in the number of women as first, last, and coauthors in two U.S. journals of obstetrics and gynecology over the past 15 years and to assess whether this publication rate was commensurate with the percentage of women in the academic specialty. METHODS: This retrospective study identified the gender of first and last authors of original research articles for the years 2000, 2005, 2010, and 2015. We determined trends in publication rates of authorship and coauthorship by pairing the gender of the first and last authors. We selected a subset of the data to compare the percentages of women authors with MDs at U.S. academic institutions with the nationally reported percentages of women faculty in the specialty. RESULTS: The journals yielded 2,699 articles for analysis. The percentage of articles written by women as first authors increased from 37% in 2000 to 71% in 2015 and, as last authors, increased from 26% in 2000 to 49% in 2015. Paired as coauthors, women published at a rate of 11% in 2000 to 38% in 2015. The analysis of a subset of 1,621 articles showed that as first authors, women published at a rate equal to or above the percentage of women in academics, but as last authors published fewer articles than expected. CONCLUSION: Women published more articles over time, kept pace or exceeded their faculty percentages as first authors, lagged behind these percentages as last authors, and as coauthors eventually surpassed the publication rate of male coauthors. PMID- 29528935 TI - Autoimmune Progesterone Dermatitis Mistaken for Stevens-Johnson Syndrome. AB - BACKGROUND: Autoimmune progesterone dermatitis is an uncommon disease presenting with cyclical skin eruptions corresponding with the menstrual cycle luteal phase. Because symptoms are precipitated by rising progesterone levels, treatment relies on hormone suppression. CASE: A 22-year-old nulligravid woman presented with symptoms mistaken for Stevens-Johnson syndrome. A cyclic recurrence of symptoms occurred, and the diagnosis of autoimmune progesterone dermatitis was made by an intradermal progesterone challenge. After 48 months, her disease remained refractory to medical management, and definitive surgical treatment with bilateral oophorectomy was performed. CONCLUSIONS: Autoimmune progesterone dermatitis is a challenging diagnosis as a result of its rarity and variety of clinical presentations. Treatment centers on suppression of endogenous progesterone and avoidance of exogenous triggers. When these modalities fail, surgical management must be undertaken. PMID- 29528936 TI - What Is New in Health Disparities?: Best Articles From the Past Year. AB - This month we focus on current research in health disparities. Dr. Resnik discusses six recent publications, which are concluded with a "bottom line" that is a take-home message. A complete reference for each can be found in on this page along with direct links to abstracts. PMID- 29528937 TI - Harm Reduction Protocols for Early Abortion: A Middle Way? PMID- 29528938 TI - Connect the Dots-April 2018. PMID- 29528939 TI - An Ode to Ultrasonography: The Window to the Pelvis. PMID- 29528940 TI - Notice of Retraction and Replacement: "Health Care Disparity and State-Specific Pregnancy-Related Mortality in the United States, 2005-2014" (Moaddab A, Dildy GA, Brown HL, Bateni ZH, Belfort MA, Sangi-Haghpeykar H, Clark SL). PMID- 29528941 TI - Stigma Reduction Among African American Women With HIV: UNITY Health Study. AB - INTRODUCTION: African American women encounter disproportionately high rates of HIV-related morbidity and mortality, which is partially mediated through stigma and its effect on HIV treatment adherence. OBJECTIVE: To assess the effect of the UNITY peer support workshop on HIV-related stigma among African American women living with HIV, compared with a time and attention control group. METHODS: African American women living with HIV were randomized to the UNITY workshop or a breast cancer education control group. Interventions took place in HIV clinics in Chicago, IL and Birmingham, AL. Participants self-reported HIV-related stigma and social support at baseline, after workshop, and at 4 follow-up visits over 12 months. RESULTS: Two hundred thirty-nine participants (UNITY n = 124; breast cancer education n = 115) were assessed over 1 year. Both arms experienced decreases in mean stigma scores over time. Our model estimated that allocation to UNITY was not associated with a significant difference in stigma points over time. Post hoc analysis suggested that preceding increases in perceived social support are associated with decreased HIV-related stigma in this population. CONCLUSIONS: Although UNITY did not significantly reduce HIV-related stigma in this population, our findings suggest that social support may be key to HIV related stigma reduction. PMID- 29528943 TI - Impact of HLA Allele-KIR Pairs on Disease Outcome in HIV-Infected Thai Population. AB - BACKGROUND: Class I human leukocyte antigen (HLA) molecules contribute to HIV control through antigen presentation to both cytotoxic T lymphocytes and natural killer cells. Contribution of cytotoxic T lymphocytes to HIV clinical outcome by HLA alleles has been well studied. However, reports about the role of natural killer cells in HIV clinical outcome, particularly, about the effect of HLA killer immunoglobulin-like receptor (KIR) pairs, remain incomplete. METHODS: The effects of HLA allele-KIR pairs on HIV clinical outcome were statistically analyzed in a Thai cohort of treatment-naive chronically infected population (n = 209). RESULTS: Five HLA allele-KIR pairs scored significantly in viral load (VL) differences. Among them, opposing effects on VL were identified among subjects expressing KIR2DL2 ligands within the HLA-C1 group: higher VL in individuals expressing HLA-B*46:01+KIR2DL2+ compared with individuals without KIR (HLA B*46:01+KIR2DL2-) (5.0 vs 4.6 log10 copies/mL, P = 0.02), in HLA-C*01:02+KIR2DL2+ (5.0 vs 4.6 log10 copies/mL; P = 0.02), and lower VL in HLA-C*12:03+KIR2DL2+ (4.3 vs 5.6 log10 copies/mL; P = 0.01). In the longitudinal analysis of a ten-year follow-up, HLA-B*46:01+KIR2DL2+ve subjects also had a higher mortality rate compared with the subjects without that pair, independent of variables including antiretroviral treatment, as well as CD4 T-cell count, sex, and age (adjusted hazard ratio 5.9, P = 0.02). CONCLUSION: We identified several HLA allele-KIR pairs associated with clinical outcome differences including opposing effects on VL within 1 HLA group with the same KIR. Among them, HLA-B*46:01 emerged in Southeast Asia about 50,000 years ago and is now the most prevalent HLA-B allele in that area. These findings highlight that each endemic area has unique features of anti-HIV innate immunity that impact clinical outcome. PMID- 29528942 TI - Neutralization Sensitivity of a Novel HIV-1 CRF01_AE Panel of Infectious Molecular Clones. AB - BACKGROUND: HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE derived reagents are essential. Here, we present a panel of 14 HIV-1 infectious molecular clones (IMCs) identified from different stages of infection and characterization of their neutralization sensitivity using 2 standard assays. METHODS: One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1. A panel of IMCs was generated, expressing envs of viruses from acute (Fiebig stages I/II and I-IV) and chronic (>Fiebig VI) infection. Neutralization assays were performed using TZM-bl or A3R5 cell lines, and sera or monoclonal antibodies (mAbs). Wilcoxon matched-paired test was used to assess neutralization differences between assays and reagents; correlation coefficients were evaluated by linear regression. RESULTS: Neutralization potency observed was significantly higher in the A3R5 assay when testing mAbs and serum pools (P < 0.0001); the stage of infection from which env was derived did not associate with IMC neutralization sensitivity. Neutralization values from A3R5 and TZM-bl assays were strongly correlated when mAbs were tested (R = 0.7, P < 0.0001), but a weaker association was seen with serum pools (R = 0.17, P = 0.03). CONCLUSIONS: This novel panel of CRF01_AE reporter IMC is useful for assessing vaccine-induced neutralizing antibodies in multiple assays, including those using primary cell targets. The significant differences in TZM-bl and A3R5 neutralization sensitivity, as well as the poor association when using polyclonal sera indicates the need for caution in choosing one specific platform. PMID- 29528945 TI - Impact of Preadmission Opioid Treatment on 1-Year Mortality Following Nonsurgical Intensive Care. AB - OBJECTIVES: Compare all-cause mortality following nonsurgical ICU admission for opioid users with nonusers. DESIGN: Nationwide register-based cohort study. SETTING: All 43 ICUs in Denmark (7,028,668 citizens cumulatively during the study period). The Danish National Health Service provides universal healthcare, guaranteeing equal access to healthcare along with partial reimbursement for prescribed drugs. PATIENTS: All 118,388 nonsurgical patients admitted to an ICU from 2005 to 2014. INTERVENTION: Patients were categorized according to timing of last redeemed opioid prescription before admission: current user (prior 0-30 d), recent user (prior 31-365 d), former user (prior 365+ d), or nonuser (no prescription since 1994). MEASUREMENTS: All-cause mortality 0-30 days and 31-365 days following ICU admission was calculated using the Kaplan-Meier method. Crude and adjusted hazard ratios with 95% CIs were computed using Cox regression, comparing users with nonusers. Adjusted models included age, gender, socioeconomic factors, comedications, and comorbidity. MAIN RESULTS: Fifteen percent of the patients were current opioid users, 15% recent users, 30% former users, and 40% nonusers. Zero- to 30-day mortality was 35% for current users, 29% for recent users, 24% for former users, and 21% for nonusers. After confounder adjustment, current users remained at elevated risk during the first 30 days following ICU admission (hazard ratio, 1.20; 95% CI, 1.15-1.24). No association remained for recent or former users. A similar pattern was evident for 31-365-day all-cause mortality: 24% for current users, 19% for recent users, 13% for former users, and 10% for nonusers. During 31-365 days of follow-up, both current users and recent users remained at elevated risk of mortality after adjustment (hazard ratio, 1.47; 95% CI, 1.39-1.55 and hazard ratio, 1.20; 95% CI, 1.13-1.27, respectively). CONCLUSIONS: Current opioid users experience increased mortality during the first year following ICU admission. PMID- 29528944 TI - Rilpivirine Plasma and Cervicovaginal Concentrations in Women During Pregnancy and Postpartum. AB - BACKGROUND: Concentrations of antiretrovirals in the genital tract play a key role in preexposure prophylaxis. This study aims to describe rilpivirine (Edurant) concentrations in the genital tract in pregnant and postpartum women. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1026s is an ongoing, prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women that include a cohort receiving rilpivirine combination regimen. Intensive pharmacokinetics evaluations were performed at steady state during the second and third trimester, and postpartum. Plasma and directly aspirated cervicovaginal fluid (CVF) samples were collected at 4 time points around an observed dose and measured using high-performance liquid chromatography with ultraviolet detection, [plasma; lower limit of quantification (LLQ) = 10 ng/mL] or liquid chromatography-tandem mass spectrometry (CVF; LLQ = 1 ng/mL). RESULTS: A total of 24 women were included in the analysis. For all time points combined, median (interquartile range) rilpivirine concentrations were 70 ng/mL (23-121) in CVF and 92 ng/mL (49-147) in plasma. The CVF to plasma AUC(0-4) ratios were significantly higher in the second (0.90, 90% CI: 0.61 to 1.46) and third trimesters of pregnancy compared with postpartum (0.40, 90% CI: 0.19 to 0.87). Three of 189 (1.6%) plasma samples in 2 women were below the LLQ and the corresponding CVF concentrations. Seventeen additional CVF concentrations (10.6%) were below LLQ in 13 participants. No major safety concerns were noted. CONCLUSIONS: Rilpivirine concentrations were higher in the CVF during pregnancy compared with postpartum. CVF Rilpivirine is likely to achieve inhibitory concentrations effective for preventing peripartum HIV transmission. PMID- 29528946 TI - Does Regional Lung Strain Correlate With Regional Inflammation in Acute Respiratory Distress Syndrome During Nonprotective Ventilation? An Experimental Porcine Study. AB - OBJECTIVE: It is known that ventilator-induced lung injury causes increased pulmonary inflammation. It has been suggested that one of the underlying mechanisms may be strain. The aim of this study was to investigate whether lung regional strain correlates with regional inflammation in a porcine model of acute respiratory distress syndrome. DESIGN: Retrospective analysis of CT images and positron emission tomography images using [F]fluoro-2-deoxy-D-glucose. SETTING: University animal research laboratory. SUBJECTS: Seven piglets subjected to experimental acute respiratory distress syndrome and five ventilated controls. INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages, followed by 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressures (mean, 4 cm H2O) and high inspiratory pressures (mean plateau pressure, 45 cm H2O). All animals were subsequently studied with CT scans acquired at end-expiration and end-inspiration, to obtain maps of volumetric strain (inspiratory volume - expiratory volume)/expiratory volume, and dynamic positron emission tomography imaging. Strain maps and positron emission tomography images were divided into 10 isogravitational horizontal regions-of interest, from which spatial correlation was calculated for each animal. MEASUREMENTS AND MAIN RESULTS: The acute respiratory distress syndrome model resulted in a decrease in respiratory system compliance (20.3 +/- 3.4 to 14.0 +/- 4.9 mL/cm H2O; p < 0.05) and oxygenation (PaO2/FIO2, 489 +/- 80 to 92 +/- 59; p < 0.05), whereas the control animals did not exhibit changes. In the acute respiratory distress syndrome group, strain maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions, which was similar to the distribution of [F]fluoro-2-deoxy-D-glucose uptake observed in the positron emission tomography images, resulting in a positive spatial correlation between both variables (median R = 0.71 [0.02-0.84]; p < 0.05 in five of seven animals), which was not observed in the control animals. CONCLUSION: In this porcine acute respiratory distress syndrome model, regional lung strain was spatially correlated with regional inflammation, supporting that strain is a relevant and prominent determinant of ventilator induced lung injury. PMID- 29528947 TI - Risk Factors for Pulmonary Complications After Laparoscopic Pylorus-preserving Pancreaticoduodenectomy: A Retrospective Observational Analysis. AB - Laparoscopic pylorus-preserving pancreaticoduodenectomy (LPPPD) is less invasive than open pylorus-preserving pancreaticoduodenectomy. However, LPPPD has a long operation time with pneumoperitoneum, which may affect the postoperative pulmonary complications (PPCs). We retrospectively evaluated the incidence of PPCs and their risk factors in LPPPD. In 191 patients who underwent LPPPD, the incidence of PPCs was 28.8% (n=55). Multivariate logistic regression analysis revealed that the risk factors for PPCs were male sex [odds ratio (OR), 2.518; P=0.008], high body mass index (OR, 1.172; P=0.024), and low preoperative serum albumin level (OR, 0.390; P=0.032). Length of hospital stay was significantly longer in the PPC group than in the no-PPC group [17 (14 to 26) vs. 14 (13 to 18) d, P<0.001]. There was no difference in the incidence of surgical complications between the PPC group and the no-PPC group (14.5% vs. 6.6%, P=0.096). These results provide useful information for perioperative pulmonary management in patients undergoing LPPPD. PMID- 29528948 TI - Comparison of the Recurrence Rates of Nonparasitic Hepatic Cysts Treated With Laparoscopy or With Open Fenestration: A Meta-Analysis. AB - OBJECTIVE: This study aimed to compare the recurrence rates of nonparasitic hepatic cysts that were treated with laparoscopy or open fenestration. MATERIALS AND METHODS: PubMed, Embase, Cochrane Library, Web of Science, Wan-fang data, CNKI, CqVip, and CBM were searched for randomized controlled trials, cohort, and case-control studies that reported on the treatment of nonparasitic hepatic cysts with laparoscopy or with open fenestration. Studies that were published from the establishment of the databases to October 1, 2016 were retrieved. STATA software (version 13) was utilized for statistical analysis. RESULTS: A total of 31 studies were included. Meta-analysis showed that the recurrence rates of hepatic cysts between the laparoscopy-deroofing and open-deroofing groups had no difference (odds ratio, 0.72; 95% confidence interval, 0.50-1.02; P=0.061). This result was in agreement with the result of subgroup analysis for solitary and multiple hepatic cyst. CONCLUSIONS: These findings underscore the distinct role of laparoscopy deroofing in the treatment of hepatic cysts because of the certainty of its long-term curative effect. PMID- 29528949 TI - Pelvic Drain After Laparoscopic Low Anterior Resection for Rectal Cancer in Patients With Diverting Stoma. AB - BACKGROUND: This study is intended to assess whether the use of pelvic drain reduces incidence of pelvic sepsis in the era of laparoscopic low anterior resection (LAR). PATIENTS AND METHODS: In total, 200 of consecutive patients who underwent laparoscopic LAR for rectal cancer with diverting stoma were analyzed. RESULTS: Pelvic sepsis occurred in 14 of 110 patients (12.7%) in the drain group and in 9 of 90 patients (10.0%) in the no drain group (P=0.548). Furthermore, there were no differences in the incidence of anastomotic leakage, time to diagnosis of pelvic sepsis, and type of treatments for pelvic sepsis. CONCLUSIONS: Prophylactic pelvic drain use after laparoscopic LAR in patients with diverting stoma does not reduce incidence of pelvic sepsis. Routine use of pelvic drain is not recommended. This study was registered at UMIN (Registration Number: UMIN000026076). PMID- 29528951 TI - What's New in Shock, April 2018? PMID- 29528950 TI - Laparoscopic Total Pancreatectomy for Chronic Pancreatitis. AB - Although minimally invasive pancreatectomy has been performed increasingly for pancreatic malignancies, many authors feel that a history of pancreatitis is a contraindication to either laparoscopic or robotic-assisted pancreatectomy. Shown here is a video (Supplemental Digital Content 1, http://links.lww.com/SLE/A172) of a laparoscopic total pancreatectomy with splenectomy for chronic pancreatitis. This patient was denied auto-islet cell transplantation because of insurance restraints. In total, 4 laparoscopic total pancreatectomies have been attempted and completed. Indications for laparoscopic total pancreatectomy have been 2 for diffuse intraductal papillary mucinous neoplasm, 1 for pancreatic adenocarcinoma, and the above-mentioned patient. No patient suffered a biliary leak, and the average length of stay was 5 days (range, 4 to 8 d). History of pancreatitis is a relative contraindication to minimally invasive pancreatectomy. It should be performed by surgeons with expertise in both open and minimally invasive pancreatic surgery. PMID- 29528954 TI - Comparison Between Bench Press Throw and Ballistic Push-up Tests to Assess Upper Body Power in Trained Individuals. AB - Bartolomei, S, Nigro, F, Ruggeri, S, Malagoli Lanzoni, I, Ciacci, S, Merni, F, Sadres, E, Hoffman, JR, and Semprini, G. Comparison between bench press throw and ballistic push-up tests to assess upper-body power in trained individuals. J Strength Cond Res 32(6): 1503-1510, 2018-The purpose of this study was to validate the ballistic push-up (BPU) test performed with hands on a force plate as a method to measure upper-body power. Twenty-eight experienced resistance trained men (age = 25.4 +/- 5.2 years; body mass = 78.5 +/- 9.0 kg; body height = 179.6 +/- 7.8 cm) performed, 2 days apart, a bench press 1 repetition maximum (1RM) test and upper-body power tests. Mean power (MP) and peak power (PP) were assessed using the bench press throw (BT) test and the BPU test performed in randomized order. The area under the force/power curve (AUC) obtained at BT was also calculated. Power expressed at BPU was estimated using a time-based prediction equation. Mean force and the participant's body weight were used to predict the bench press 1RM. Pearson product-moment correlations were used to examine relationships between the power assessment methods and between the predicted 1RM bench and the actual value. Large correlations (0.79; p < 0.001) were found between AUC and MP expressed at BPU. Large correlations were also detected between MP and PP expressed at BT and BPU (0.75; p < 0.001 and 0.74; p < 0.001, respectively). Very large correlations (0.87; p < 0.001) were found between the 1RM bench and the 1RM predicted by the BPU. Results of this study indicate that BPU represents a valid and reliable method to estimate the upper body power in resistance-trained individuals. PMID- 29528955 TI - Effects of Small-Sided Games and High-Intensity Interval Training on Aerobic and Repeated Sprint Performance and Peripheral Muscle Oxygenation Changes in Elite Junior Basketball Players. AB - Delextrat, A, Gruet, M, and Bieuzen, F. Effects of small-sided games and high intensity interval training on aerobic and repeated sprint performance and peripheral muscle oxygenation changes in elite junior basketball players. J Strength Cond Res 32(7): 1882-1891, 2018-The aim of the current study was to compare the effects of 6 weeks of small-sided game (SSG) and high-intensity interval training (HIIT) on aerobic fitness and muscle oxygenation during a repeated sprint (RS) sequence in elite male junior basketball players. Twenty participants (14.3 +/- 0.5 years; 176.8 +/- 12.5 cm; 74.5 +/- 9.8 kg) performed pre- and post-tests interspersed by 6 weeks of SSG or HIIT training. Testing sessions consisted of the 30-15 intermittent fitness test and an RS sequence (2 bouts of 15 seconds). During RS, muscle oxygenation parameters (tissue saturation index [TSI, %], postsprint muscle reoxygenation rate) were measured using near infrared spectroscopy. The results showed that both training interventions similarly improved maximal aerobic speed (VIFT, 3.4 and 4.1%, respectively, for HIIT and SSG, P < 0.05) as well as RS ability (smaller percentage decrement by 62.5 and 21.6%, respectively, for HIIT and SSG, P < 0.05). Both training interventions also resulted in a greater DeltaTSI during the second sprint (47.8 114%, P < 0.05) and significant improvements in postsprint reoxygenation after both sprints (+23.0 to +107.7%). Finally, the variation in muscle reoxygenation after sprint 1 was significantly associated with improvements in aerobic (DeltaVIFT, r = 0.61, P = 0.008) and anaerobic (Delta% Dec during RS, r = -0.487, P = 0.028) performances. The current study has observed that SSG and HIIT resulted in similar improvements in aerobic and anaerobic variables and a better muscle oxygenation capacity during RS. Coaches should be aware that both trainings are applicable methodologies to improve in-season aerobic and anaerobic fitness capacities in junior basketball players. PMID- 29528956 TI - Effects of Heavy Squat Training on a Vibration Platform on Maximal Strength and Jump Performance in Resistance-Trained Men. AB - Hammer, RL, Linton, JT, and Hammer, AM. Effects of heavy squat training on a vibration platform on maximal strength and jump performance in resistance-trained men. J Strength Cond Res 32(7): 1809-1815, 2018-The purpose of this investigation was to determine maximal strength and jump performance outcomes of heavy squat training on a low-amplitude (<1.0 mm peak-to-peak) vibration platform (VP). Nineteen recreationally resistance-trained college-aged men (22.3 +/- 1.66 years) completed the 6-week study. Participants were randomly assigned to 1 of 2 training groups: SQT (n = 10) performed conventional back squats on the floor and SQTV (n = 9) performed back squats on the VP. Supervised training took place over 12 sessions (2 d.wk), which used an aggressive strength development protocol (85 95% 1 repetition maximum [1RM]), which was identically followed by both groups. After the intervention, both groups showed (via t-test) a marked increase (p < 0.001) in 1RM squat strength (SQT = 34.5 kg vs. SQTV = 36.2 kg), but there was no significant difference (via mixed analysis of variance) between groups (p = 0.875). Standing broad jump performance increased by an average of 5-6 cm, but was not significantly changed in either group (SQT; p = 0.199, SQTV; p = 0.087). In conclusion, squats performed with whole body vibration (WBV) were not superior to conventional squats with respect to maximal strength and jump performance outcomes. It seems that there was no additive effect of superimposed WBV training on strength beyond that caused by strength training alone. This study can help strength conditioning professionals and athletes make an informed decision on whether to invest in a VP and use WBV as an alternative or a complementary mode of training. PMID- 29528957 TI - Association of Hip and Trunk Strength With Three-Dimensional Trunk, Hip, and Knee Kinematics During a Single-Leg Drop Vertical Jump. AB - Martinez, AF, Lessi, GC, Carvalho, C, and Serrao, FV. Association of hip and trunk strength with three-dimensional trunk, hip, and knee kinematics during a single-leg drop vertical jump. J Strength Cond Res 32(7): 1902-1908, 2018 Kinematic changes have been correlated with different lower-limb injuries. Movement is influenced by multiple factors and strength is one of the contributors that can influence it. Thus, the aim of this study was to evaluate the correlation among trunk and hip isometric strength with trunk and lower-limb kinematics during a single-leg drop vertical jump. Twenty-three healthy recreational female athletes aged between 18 and 35 years underwent isometric evaluation of hip abductor, hip extensor, and lateral trunk muscle strength and 3 dimensional trunk and lower-limb kinematics during a single-leg drop vertical jump. Pearson's correlation coefficients (r) were calculated to establish the association among hip and trunk strength and trunk, hip, and knee kinematics. As result, no significant correlations were found between the peak and movement excursion values of kinematic and hip and trunk isometric strength data. The lack of correlation between isometric strength and kinematics in healthy female athletes indicates that intervention programs should not be focused solely on strength exercises to influence the movement pattern during single-landing activities. PMID- 29528958 TI - Elite Junior Australian Football Players Experience Significantly Different Loads Across Levels of Competition and Training Modes. AB - Lathlean, TJH, Gastin, PB, Newstead, S, and Finch, CF. Elite junior Australian football players experience significantly different loads across levels of competition and training modes. J Strength Cond Res 32(7): 2031-2038, 2018-Well developed physical qualities such as high jumping ability, running endurance, acceleration, and speed can help aspiring junior elite Australian football (AF) players transition to the Australian Football League competition. To do so, players need to experience sufficient load to enhance their physical resilience without increasing their risk of negative outcomes in terms of impaired wellness or injury. The aim of this study was to investigate the differences in load for different levels of competition and training modes across one competitive season. Elite junior AF players (n = 562, aged 17.7 +/- 0.3, range: 16-18 years) were recruited from 9 teams across the under-18 state league competition in Victoria. All players recorded their training and match intensities according to the session rating of perceived exertion method. Training sessions were categorized according to skills, strength, conditioning, and other activities, whereas matches were identified according to level of competition. The loads in U18 state league matches (656.7 +/- 210.9 au) were significantly higher (p = 0.027) than those in school matches (643.3 +/- 260.9 au) and those in U18 representative matches (617.2 +/- 175.4). Players, who undertook more than one match per week, experienced significantly less load in subsequent matches (p < 0.001). Furthermore, U18 state league training sessions carried the most load when compared with other training modes. This article highlights that different combinations of training and match involvement affect overall player load, which may predispose players to negative outcomes such as impaired wellness or increased injury risk. PMID- 29528959 TI - Seasonal changes in anthropometric, physiological, nutritional, and performance factors in collegiate rowers. AB - Well-controlled seasonal distribution of training intensity appears to be an important variable for endurance athletes' success as competitors and/or for avoidance of overtraining. The aim of this study was to examine the interrelationships of training distribution, body composition, energy intake/expenditure, and rowing ergometer performance throughout the 2012-2013 season. In the present study of 15 collegiate male rowers, most of whom started rowing during their time at the university, we divided the 2012-2013 season (total 37 weeks) into 3 phases (off-season, December to mid-March, 16 weeks; pre season, late March to April, 5 weeks; and in-season, May to August, 16 weeks) and analyzed the transition of 2000-m rowing ergometer time, training intensity/volume, body composition (body weight and body fat) and energy intake/expenditure in each phase. There were significant main effects of the training time by the intensities; 2000-m rowing ergometer time; energy expenditure; and protein, fat, and carbohydrate intake across the seasons (p < 0.05). Two findings were particularly important. First, on-water high-intensity training, especially for inexperienced rowers, may contribute to improvement of 2000-m rowing ergometer performance. Second, higher intake of carbohydrate, and to a lesser degree, protein, is necessary for optimal training adaptation (e.g., increase of muscle glycogen content), and results in better 2000-m performance on the rowing ergometer. Also, those findings may be beneficial to the coaches who are interested in designing the well-controlled seasonal training program, which is especially intended to improve the 2000-m rowing ergometer performance as well as avoidance of overtraining. PMID- 29528960 TI - Knee Kinetics during Squats of Varying Loads and Depths in Recreationally Trained Females. AB - The back squat exercise is typically practiced with varying squat depths and barbell loads. However, depth has been inconsistently defined, resulting in unclear safety precautions when squatting with loads. Additionally, females exhibit anatomical and kinematic differences to males which may predispose them to knee joint injuries. The purpose of this study was to characterize peak knee extensor moments (pKEMs) at three commonly practiced squat depths of above parallel, parallel, and full depth, and with three loads of 0% (unloaded), 50%, and 85% depth-specific one repetition maximum (1RM) in recreationally active females. Nineteen females (age, 25.1 +/- 5.8 years; body mass, 62.5 +/- 10.2 kg; height, 1.6 +/- 0.10 m; mean +/- SD) performed squats of randomized depth and load. Inverse dynamics were used to obtain pKEMs from three-dimensional knee kinematics. Depth and load had significant interaction effects on pKEMs (p = 0.014). Significantly greater pKEMs were observed at full depth compared to parallel depth with 50% 1RM load (p = 0.001, d = 0.615), and 85% 1RM load (p = 0.010, d = 0.714). Greater pKEMs were also observed at full depth compared to above parallel depth with 50% 1RM load (p = 0.003, d = 0.504). Results indicate effect of load on female pKEMs do not follow a progressively increasing pattern with either increasing depth or load. Therefore, when high knee loading is a concern, individuals are must carefully consider both the depth of squat being performed and the relative load they are using. PMID- 29528961 TI - The Short-Term Training and Detraining Effects of Supervised Versus Unsupervised Resistance Exercise in Aging Adults. AB - This study compared the effects of a 4-week supervised (SUP) and unsupervised (UNSUP) resistance training programme followed by 12 weeks of detraining (DET). Thirty-six healthy aging adults (age: 53.6 +/- 3.6 years; body mass index: 28.3 +/- 5.1 kg/m) were randomly allocated to a SUP group (n = 17) or an UNSUP group (n = 19). Participants completed three training sessions per week using resistance bands and body weight movements. Measures of physical performance were administered at baseline, at the end of the training programme, and after the DET period. Function was assessed with the six minute walk test (6MWT), timed up-and go (TUG), 30 s chair sit-to-stand (STS), stair-climb test (SCT), 40 m fast-paced walk test (FPWT) and sit-and-reach test (SRT), whereas the isometric mid-thigh pull (IMTP) and hand grip test were used to measure muscle strength. Following training, improvements in performance were found in the 6MWT, TUG, 30 s chair STS, SCT, FPWT, SRT, and IMTP (p < 0.05), with no significant differences between groups (p > 0.05). In addition, the majority of training-induced improvements remained significantly above baseline values after the DET period (p < 0.05). No significant between-group differences were observed following training or DET (p > 0.05). Four weeks of either SUP or UNSUP resistance training is sufficient to substantially improve muscle strength and function in aging adults, and these gains are largely preserved following prescribed exercise cessation. Home-based resistance training appears to be a practical and effective alternative to traditional SUP programmes that may help circumvent many barriers to physical activity in aging adults. PMID- 29528962 TI - Effect of Resistance Training Frequency on Neuromuscular Performance and Muscle Morphology after Eight Weeks in Trained Men. AB - The purpose of this study was to investigate the chronic effects of training muscle groups 1 day per week vs. 2 days per week on neuromuscular performance and morphological adaptations in trained men with the number of sets per muscle group equated between conditions. Participants were randomly assigned in 2 experimental groups: 1 session.wk per muscle group (G1, n = 10), where every muscle group was trained once a week with 16 sets or 2 sessions.wk per muscle group (G2, n = 10), where every muscle group was trained twice a week with 8 sets per session. All other variables were held constant over the 8-week study period. No significant difference between conditions for maximal strength in the back squat or bench press, muscle thickness in the elbow extensors, elbow flexors, or quadriceps femoris, and muscle endurance in the back squat and bench press performed at 60% 1RM was detected. Effect size favored G2 for some outcome measurements, suggesting the potential of a slight benefit to the higher training frequency. In conclusion, both G1 and G2 significantly enhance neuromuscular adaptations, with a similar change noted between experimental conditions. PMID- 29528963 TI - Effectiveness of a healthy lifestyle intervention for chronic low back pain: a randomised controlled trial. AB - We assessed the effectiveness of a 6-month healthy lifestyle intervention, on pain intensity in patients with chronic low back pain who were overweight or obese. We conducted a pragmatic randomised controlled trial, embedded within a cohort multiple randomised controlled trial of patients on a waiting list for outpatient orthopaedic consultation at a tertiary hospital in NSW, Australia. Eligible patients with chronic low back pain (>3 months in duration) and body mass index >=27 kg/m and <40 kg/m were randomly allocated, using a central concealed random allocation process, to receive advice and education and referral to a 6-month telephone-based healthy lifestyle coaching service, or usual care. The primary outcome was pain intensity measured using an 11-point numerical rating scale, at baseline, 2 weeks, and monthly for 6 months. Data analysis was by intention-to-treat according to a prepublished analysis plan. Between May 13, 2015, and October 27, 2015, 160 patients were randomly assigned in a 1:1 ratio to the intervention or usual care. We found no difference between groups for pain intensity over 6 months (area under the curve, mean difference = 6.5, 95% confidence interval -8.0 to 21.0; P = 0.38) or any secondary outcome. In the intervention group, 41% (n = 32) of participants reported an adverse event compared with 56% (n = 45) in the control group. Our findings show that providing education and advice and telephone-based healthy lifestyle coaching did not benefit patients with low back pain who were overweight or obese, compared with usual care. The intervention did not influence the targeted healthy lifestyle behaviours proposed to improve pain in this patient group. PMID- 29528964 TI - Repeated touch and needle-prick stimulation in the neonatal period increases the baseline mechanical sensitivity and postinjury hypersensitivity of adult spinal sensory neurons. AB - Noxious stimulation at critical stages of development has long-term consequences on somatosensory processing in later life, but it is not known whether this developmental plasticity is restricted to nociceptive pathways. Here, we investigate the effect of repeated neonatal noxious or innocuous hind paw stimulation on adult spinal dorsal horn cutaneous mechanical sensitivity. Neonatal Sprague-Dawley rats of both sexes received 4 unilateral left hind paw needle pricks (NPs, n = 13) or 4 tactile (cotton swab touch) stimuli, per day (TC, n = 11) for the first 7 days of life. Control pups were left undisturbed (n = 17). When adult (6-8 weeks), lumbar wide-dynamic-range neuron activity in laminae III-V was recorded using in vivo extracellular single-unit electrophysiology. Spike activity evoked by cutaneous dynamic tactile (brush), pinch and punctate (von Frey hair) stimulation, and plantar receptive field areas were recorded, at baseline and 2 and 5 days after left plantar hind paw incision. Baseline brush receptive fields, von Frey hair, and pinch sensitivity were significantly enhanced in adult NP and TC animals compared with undisturbed controls, although effects were greatest in NP rats. After incision, injury sensitivity of adult wide-dynamic-range neurons to both noxious and dynamic tactile hypersensitivity was significantly greater in NP animals compared with TC and undisturbed controls. We conclude that both repeated touch and needle-prick stimulation in the neonatal period can alter adult spinal sensory neuron sensitivity to both innocuous and noxious mechanical stimulation. Thus, spinal sensory circuits underlying touch and pain processing are shaped by a range of early-life somatosensory experiences. PMID- 29528966 TI - In Case you Missed It-Basic Science Advances in Transplantation 2017. AB - Developments in organ preservation techniques, novel immunosuppressants and improved diagnostics have made organ transplantation the success it is today. That does not mean that we are not still striving to perfect techniques, or that there are no more problems to solve. New strategies to address the donor organ shortage, prevent and manage antibody-mediated rejection, lower long-term allograft failure rates and reduce the toxicity of lifelong immunosuppressive medication are urgently needed, and are being widely researched. Both fundamental research and preclinical studies aim to solve these problems, and ultimately, benefit organ transplant recipients. This article highlights the latest technical developments and trends in xenotransplantation, tissue injury and regeneration, immunosuppression, and transplantation immunology described in the most viewed and cited articles published in the Basic Sciences section of the Transplantation journal during the year 2017. PMID- 29528965 TI - Evaluation of different drug classes on transient sciatic nerve injury-depressed marble burying in mice. AB - A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (ie, pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury (CCI) of the sciatic nerve elicits common pain-stimulated responses (ie, mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within 1 week. Although drugs representing distinct classes of analgesics (ie, morphine, valdecoxib, and gabapentin) reversed both CCI-induced and CCI-depressed nociceptive measures, diazepam lacked antinociceptive effects in all assays and the kappa-opioid receptor agonist U69593 reversed pain-stimulated, but not pain depressed behaviors. In addition, we tested drugs targeting distinct components of the endocannabinoid system, including agonists at cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as inhibitors of the endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase. Each of these drugs reversed all CCI-induced nociceptive measures, with the exception of the fatty acid amide hydrolase inhibitor that reversed pain-stimulated behaviors, only. These findings support the use of the mouse marble-burying assay as a model of pain-depressed behavior within the first week of sciatic nerve injury to examine candidate analgesics. These data also support existing preclinical research that cannabinoid receptor agonists and inhibitors of endocannabinoid regulating enzymes merit consideration for the treatment of pain. PMID- 29528968 TI - The Effect of Pregnancy on the Long-term Risk of Graft Loss, Cardiovascular Disease, and Death in Kidney Transplanted Women in Norway: A Retrospective Cohort Study. AB - BACKGROUND: Kidney transplant recipients have now conceived for almost 50 years. Nevertheless, few studies have evaluated long-term health outcomes for kidney transplanted women after pregnancies. METHODS: We conducted a retrospective cohort study of all Norwegian women receiving a kidney transplant before the age of 50 years between 1969 and 2013, with graft loss, cardiovascular disease, and death as outcomes. Baseline characteristics for all women were ascertained at first transplantation, with information about exposure, outcomes, and potential confounders collected from medical records. To account for changes in pregnancy status, data were analyzed using proportional hazard Cox regression with pregnancy status as a time-dependent covariate changing at the time of pregnancy. RESULTS: Of 650 women studied, 124 had a pregnancy after kidney transplantation. During the study period, graft loss, cardiovascular disease, and death occurred in 237, 73, and 274 women, respectively. Pregnancy was associated with 54% lower risk of graft loss (95% confidence interval [CI]: 25% to 71%) and 72% lower risk of death (95% CI, 53%-84%). Adjusting for possible confounders had a minimal impact on estimated values. There were considerable uncertainties and no statistically significant results regarding the estimated risk of cardiovascular disease after pregnancy (univariate hazard ratio, 0.91; 95% CI, 0.43-1.92; multivariate hazard ratio, 0.71; 95% CI, 0.32-1.60). CONCLUSIONS: Kidney transplanted women with pregnancies have a low risk of subsequent graft loss or death. These results are reassuring for the current clinical practice. PMID- 29528967 TI - Defining Outcomes for beta-cell Replacement Therapy in the Treatment of Diabetes: A Consensus Report on the Igls Criteria From the IPITA/EPITA Opinion Leaders Workshop. AB - beta-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of beta-cell replacement therapy. There was consensus that beta-cell replacement therapy could be considered as a treatment for beta-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal beta-cell graft function is defined by near-normal glycemic control (HbA1c <=6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good beta-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal beta-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed beta-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes. PMID- 29528969 TI - GreenLight Laser for benign prostatic hyperplasia. AB - PURPOSE OF REVIEW: GreenLight photoselective vaporization (GL-PV) is now established in the treatment of benign prostatic enlargement. The present review outlines the available technical armamentarium and summarizes the current best evidence on functional and safety outcomes. Moreover, future technical developments and refinements are presented. RECENT FINDINGS: GL-PV has evolved to be the most commonly performed procedure, second to conventional transurethral resection of the prostate (TURP) for surgical management of benign prostatic obstruction (BPO). On the basis of the data published in the randomized controlled Goliath study, GL-PV with 180-W technology is noninferior in terms of functional outcomes compared with TURP considering short and intermediate follow up with a complication-free rate of around 80% after 24 months.The ongoing push towards high-power lasers can be explained by their more effective tissue ablative effect, leading to shorter operating times. Comparative analysis between high-power and low-power laser systems demonstrated similar retreatment rates and most institutions are, therefore, now performing 180-W GL-PV.Performed as an outpatient procedure, GL-PV is cost-effective with a low hospital re-admission rate. Plasma kinetic vaporization of the prostate (PKVP) has recently emerged as a potential contender in the field; also GreenLight enucleation of the prostate (GreenLEP) might be even more effective than GL-PV. SUMMARY: GL-PV appears to be a well tolerated surgical alternative for patients suffering from BPO. Long-term follow-up data from 120-W and 180-W laser systems are still pending. Potential competitors have recently been brought to the market and further trials and long term data will show, whether GL-PV will stand the test of time. Regardless of technical specifications, surgeon's experience remains essential to achieve good functional and safety outcomes. PMID- 29528970 TI - Robotic assisted simple prostatectomy: recent advances. AB - PURPOSE OF REVIEW: Robotic assisted simple prostatectomy (RASP) represents a minimally invasive evolution of traditional open simple prostatectomy for the surgical treatment of severe lower urinary tract symptoms (LUTS) because of benign prostatic enlargement (BPE). Aim of the present review is to summarize the most recent evidence on this novel procedure, and to better define its current role in the surgical armamentarium for the treatment of BPE. RECENT FINDINGS: Several studies demonstrated that RASP can be safely and effectively performed in centers with sufficient expertise. The procedure can duplicate its open counterpart with the advantage of lower perioperative morbidity, and ultimately faster patient recovery. Overall, the status of RASP seems to be well beyond that of an 'investigational' procedure, and guidelines should be amended accordingly.Nevertheless, it remains to be determined what the place of the RASP procedure in the surgical armamentarium for the treatment of symptomatic BPE will be. Over the most recent years, few comparative studies have been reported, allowing in part to draw some conclusions. RASP seems to be attractive when compared with open simple prostatectomy as it can offer less blood loss, and shorter hospital stay. However, its advantages over transurethral enucleation techniques - such as HoLEP - remain unclear. There are some specific indications, such as the presence of concomitant bladder diverticula or stones, for example, where a robotic approach could represent an appealing solution. Ultimately, further research should look at a cost analysis to determine which technique can be more cost effective. Last, the issue of the learning curve for the different procedures for symptomatic BPE remain to be further scrutinized. SUMMARY: RASP offers potential advantages over other available techniques for the treatment of large prostate glands. In centers, wherever a solid robotic program is already in place, this procedure is likely to be increasingly implemented. PMID- 29528971 TI - Effects of 5-alpha reductase inhibitors: new insights on benefits and harms. AB - PURPOSE OF REVIEW: The use of 5-alpha reductase inhibitors (5ARIs) for the treatment of benign prostatic hyperplasia (BPH) and other diseases has been proposed and studied. However, the controversy about its benefits and harms for other diseases has persisted. In this review, we will discuss the newly identified effects of 5ARIs based on recently published studies. RECENT FINDINGS: These drugs are currently recommended in clinical guidelines for BPH. However, the reporting of adverse effects, including sexual dysfunction as well as neurologic, endocrine, and cardiovascular effects, have been controversial. There are reports of additional effects of 5ARI in prostate cancer and bladder cancer. Although 5ARIs have been prescribed for the treatment of androgenic alopecia (AGA), postfinasteride syndrome can result, with symptoms that range from sexual dysfunction to muscle atrophy. SUMMARY: Clinical applications of 5ARIs have been established for the treatment of BPH and AGA from a series of randomized controlled trials. The adverse effects of 5ARIs affect only a small proportion of treated patients and can be resolved with discontinued treatment. It will be necessary to establish the mechanism by which 5ARIs elicit these effects through better designed studies. PMID- 29528972 TI - The role of urodynamics in the surgical management of benign prostatic obstruction. AB - PURPOSE OF REVIEW: Benign prostatic obstruction (BPO) is a common cause of lower urinary tract symptoms (LUTS) in elderly men. However, such symptoms are often caused by primary detrusor overactivity or underactivity. Surgical management where BPO is absent or merely incidental has a lower chance of success, and exposes the patient to the potential complications of surgery. This review discusses the diagnostic challenges facing this common presentation. RECENT FINDINGS: Most evidence comes from small, historical prospective cohort studies. A Cochrane review found only two studies that met the prespecified inclusion criteria. It concluded that urodynamics changed decision-making regarding surgery for LUTS but it was not possible to determine whether this impacted upon outcome. A systematic review of several noninvasive alternatives to urodynamics could not recommend any of them over urodynamic pressure-flow study assessment. Further research is currently in progress, the 'UPSTREAM' study, which is a randomized, multicentre trial. Men are randomized to undergo investigation with clinical evaluation and uroflowmetry, or to additionally receive urodynamics. The primary aim is to determine the impact of urodynamics on the assessment pathway. SUMMARY: Assessment of BPO involves determining whether it has a contributory role in individual patients. This is a crucial factor in outcome, as surgery can give poor results if the symptoms are principally caused by detrusor dysfunction (overactivity or underactivity). Urodynamics can help determine this if undertaken to a suitable standard. Further research will identify the precise role of this test modality. PMID- 29528973 TI - Investigational procedures in benign prostatic hypertrophy. AB - PURPOSE OF REVIEW: As benign prostatic hypertrophy (BPH) becomes a more common disease, there has been a dramatic rise in the number of investigational procedures being developed to manage it. We seek to present an overview of the most recently developed treatments and present clinical data related to application wherever available. RECENT FINDINGS: As a greater number of treatments become available for BPH, improved diagnostic testing could prove beneficial in helping guide patient selection. Efforts are underway to identify serum biomarkers associated with BPH as well as new classifications strategies, specifically with MRI, to determine both the anatomy of BPH as well as its histologic distribution. Outpatient-based procedures for BPH currently being developed include the temporary implantable nitinol device as well as intraprostatic injections such as Botox and PRX302. Aquablation is a novel technique that uses robotically guided high-pressured saline to ablate prostate tissue. Early data suggests noninferiority compared with TURP. Finally, efforts are underway to apply robotics to BPH with the advent of a robotic transurethral platform being designed for prostate enucleation. SUMMARY: Many new techniques are poised to be introduced to the BPH market over the coming years. The unique risk/benefit profiles as well as associated clinical outcomes of each will need to be studied in detail in order to help identify proper roles in the management of patients with symptomatic disease. PMID- 29528974 TI - Changes in morning salivary melatonin correlate with prefrontal responses during working memory performance. AB - Humans demonstrate a circadian rhythm of melatonin production that closely tracks the daily light/dark cycle, with profound increases in circulating levels during the night-time and nearly nonexistent levels during daylight hours. Although melatonin is known to play a role in preparing the brain and body for sleep, its effects on cognition and brain function are not well understood. We hypothesized that declines in morning melatonin would be associated with increased functional activation within cortical regions involved in alertness, attention, and executive function. We measured the change in salivary melatonin from mid-morning to late-morning in 26 healthy young adults who were also exposed to a 30-min period of blue or amber light followed by functional MRI during a working memory task (N-back). Brain activation was regressed on the change in melatonin scores from the mid-morning to late-morning saliva samples and the role of light exposure was also assessed. Although overall melatonin levels did not change significantly over the morning at the group level, individual declines in salivary melatonin were associated with significant increases in activation within the left dorsomedial and right inferior lateral prefrontal cortex during the 2-back condition (P<0.05, cluster corrected). Medial prefrontal activation also correlated modestly with better vigilance performance during the 0-back (P<0.05), but not the 1-back or 2-back conditions. The light condition did not affect the outcomes. These findings suggest declining melatonin levels in the morning are associated with increased prefrontal cortex functioning and may play a role in the increased frontal activation that occurs following awakening. PMID- 29528975 TI - Reduction in Mortality Following Pediatric Rapid Response Team Implementation. AB - OBJECTIVE: To evaluate the effectiveness of a physician-led rapid response team program on morbidity and mortality following unplanned admission to the PICU. DESIGN: Before-after study. SETTING: Single-center quaternary-referral PICU. PATIENTS: All unplanned PICU admissions from the ward from 2005 to 2011. INTERVENTIONS: The dataset was divided into pre- and post-rapid response team groups for comparison. MEASUREMENTS AND MAIN RESULTS: A Cox proportional hazards model was used to identify the patient characteristics associated with mortality following unplanned PICU admission. Following rapid response team implementation, Pediatric Risk of Mortality, version 3, illness severity was reduced (28.7%), PICU length of stay was less (19.0%), and mortality declined (22%). Relative risk of death following unplanned admission to the PICU after rapid response team implementation was 0.685. CONCLUSIONS: For children requiring unplanned admission to the PICU, rapid response team implementation is associated with reduced mortality, admission severity of illness, and length of stay. Rapid response team implementation led to more proximal capture and aggressive intervention in the trajectory of a decompensating pediatric ward patient. PMID- 29528976 TI - Survival and Long-Term Functional Outcomes for Children With Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation. AB - OBJECTIVES: To identify patient- and disease-related factors related to survival and favorable outcomes for children who underwent extracorporeal cardiopulmonary resuscitation after a refractory cardiac arrest. DESIGN: Retrospective observational study with prospective assessment of long-term functional outcome. PATIENTS: Fifty-six consecutive children undergoing extracorporeal cardiopulmonary resuscitation at our institution from 2007 to 2015. Median age at arrest was 3.5 months (interquartile range, 1-53). SETTING: Tertiary pediatric university hospital with a referral heart center. INTERVENTIONS: Health-related quality of life and family functioning assessment with the Pediatric Quality of Life Inventory and the McMaster Family Assessment Device. MEASUREMENTS AND MAIN RESULTS: Fifty-eight consecutive extracorporeal cardiopulmonary resuscitation episodes were included, with 46 (79.3%) related to primary cardiac conditions. Initial cannulation site was central in 19 (32.8%) and peripheral in 39 (67.2%). Survival to decannulation was 77.6% with survival at hospital discharge and at the end of the follow-up period being 65.5% and 62.1%, respectively. Time to follow-up was 38 months (interquartile range, 19-52). Patients who survived tended to be younger (3.5 mo [1 mo to 2 yr] vs 7 mo [1.25 mo to 17 yr]; p = 0.3) with decreased extracorporeal cardiopulmonary resuscitation times (28 min [15-47 min] vs 37.5 min [28.5-55 min]; p = 0.04). Those who received therapeutic hypothermia tended to have higher hospital survival (21/28 [75%] vs 16/29 [55%]; p = 0.08). Follow-up assessments of survivors demonstrated good quality of life and family functioning (Pediatric Quality of Life Inventory, 84 [76-89.5]; McMaster Family Assessment Device, 1.62 [1.33-1.83]). CONCLUSIONS: In this series, extracorporeal cardiopulmonary resuscitation was associated with relatively high survival rates and a good health-related quality of life and family functioning. Larger series are needed to assess whether this technique should be more broadly available in the pediatric critical care community. PMID- 29528977 TI - Hospital Variation in Intensive Care Resource Utilization and Mortality in Newly Diagnosed Pediatric Leukemia. AB - OBJECTIVES: To evaluate hospital-level variability in resource utilization and mortality in children with new leukemia who require ICU support, and identify factors associated with variation. DESIGN: Retrospective cohort study. SETTING: Children's hospitals contributing to the Pediatric Health Information Systems administrative database from 1999 to 2011. PATIENTS: Inpatients less than 25 years old with newly diagnosed acute lymphocytic leukemia or acute myeloid leukemia requiring ICU support (n = 1,754). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Evaluated exposures included leukemia type, year of diagnosis, and hospital-wide proportion of patients with public insurance. The main outcome was hospital mortality. Wide variability existed in the ICU resources used across hospitals. Combined acute lymphocytic leukemia and acute myeloid leukemia mortality varied by hospital from 0% (95% CI, 0-14.8%) to 42.9% (95% CI, 17.7 71.1%). A mixed-effects model with a hospital-level random effect suggests significant variation across hospitals in mortality (p = 0.007). When including patient and hospital factors as fixed effects into the model, younger age, acute myeloid leukemia versus acute lymphocytic leukemia diagnosis, leukemia diagnosis prior to 2005, hospital-wide proportion of public insurance patients, and hospital-level proportion of leukemia patients receiving ICU care are significantly associated with mortality. The variation across hospitals remains significant with all patient factors included (p = 0.021) but is no longer significant after adjusting for the hospital-level factors proportion of public insurance and proportion receiving ICU care (p = 0.48). CONCLUSIONS: Wide hospital-level variability in ICU resource utilization and mortality exists in the care of children with leukemia requiring ICU support. Hospital payer mix is associated with some mortality variability. Additional study into how ICU support could be standardized through clinical practice guidelines, impact of payer mix on hospital resources allocation to the ICU, and subsequent impact on patient outcomes is warranted. PMID- 29528978 TI - CLINICAL AND GENETIC CHARACTERISTICS OF MALE PATIENTS WITH RPGR-ASSOCIATED RETINAL DYSTROPHIES: A Long-Term Follow-up Study. AB - PURPOSE: To describe the phenotype and clinical course of patients with RPGR associated retinal dystrophies, and to identify genotype-phenotype correlations. METHODS: A multicenter medical records review of 74 male patients with RPGR associated retinal dystrophies. RESULTS: Patients had retinitis pigmentosa (RP; n = 52; 70%), cone dystrophy (COD; n = 5; 7%), or cone-rod dystrophy (CORD; n = 17; 23%). The median follow-up time was 11.6 years (range 0-57.1). The median age at symptom onset was 5.0 years (range 0-14 years) for patients with RP and 23.0 years (range 0-60 years) for patients with COD/CORD. The probability of being blind (best-corrected visual acuity <0.05) at the age of 40 was 20% and 55% in patients with RP and COD/CORD, respectively. RPGR-ORF15 mutations were associated with high myopia (P = 0.01), which led to a faster best-corrected visual acuity decline in patients with RP (P < 0.001) and COD/CORD (P = 0.03). Patients with RP with RPGR-ORF15 mutations had a faster visual field decline (P = 0.01) and thinner central retina (P = 0.03) than patients with mutations in exon 1 to 14. CONCLUSION: Based on best-corrected visual acuity survival probabilities, the intervention window for gene therapy for RPGR-associated retinal dystrophies is relatively broad in patients with RP. RPGR-ORF15 mutations were associated with COD/CORD and with a more severe phenotype in RP. High myopia is a risk factor for faster best-corrected visual acuity decline. PMID- 29528979 TI - SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN COATS DISEASE. AB - PURPOSE: To evaluate microstructural retinal abnormalities on spectral domain optical coherence tomography (SD-OCT) imaging of eyes with Coats disease. METHODS: This is a multicenter, retrospective study in which SD-OCT images of patients with treatment-naive Coats disease were correlated with clinical examination and visual acuity and, when available, followed longitudinally over time. RESULTS: Macular SD-OCT of 27 eyes with Coats disease revealed intraretinal edema (59%), intraretinal exudates (67%), subretinal fluid (37%), subretinal exudate (48%), ellipsoid zone disruption (52%), external limiting membrane disruption (41%), and subfoveal nodule (26%). All these microstructural abnormalities correlated with worse baseline and final visual acuities (P < 0.05) on univariate analysis, except for intraretinal edema which exhibited a nonstatistically significant trend toward worse baseline visual acuity (P = 0.16). Within stage 2b eyes, external limiting membrane disruption and subretinal nodule on SD-OCT were associated with worse baseline visual acuity (P = 0.02 for both), and there was a trend toward worse final visual acuity with external limiting membrane disruption and subretinal nodule (P = 0.17 for both) and worse baseline (P = 0.08) and final (P = 0.13) visual acuities with ellipsoid zone disruption. No microstructural abnormalities were noted on OCT of fellow eyes. CONCLUSION: Spectral domain OCT can identify microstructural abnormalities in Coats disease that are associated on univariate analysis with worse baseline visual acuity and visual prognosis. Further larger studies are necessary. PMID- 29528980 TI - LARGE UVEAL MELANOMA (>=10 MM THICKNESS): Clinical Features and Millimeter-by Millimeter Risk of Metastasis in 1311 Cases. The 2018 Albert E. Finley Lecture. AB - PURPOSE: To analyze the clinical features and rate of metastatic disease in eyes with large (>=10 mm thickness) uveal melanoma. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: There were 1,311 consecutive patients. METHODS: Retrospective medical chart review. MAIN OUTCOME MEASURES: Clinical features and rate of metastatic melanoma. RESULTS: Of 1,311 patients with large melanoma, the mean age was 59 years (median 60, range 6-98 years) and 95% were white. Mean tumor basal dimension was 17 mm (median 17, range 7-25 mm), and mean tumor thickness was 12 mm (median 12, range 10-24 mm). Mean distance to the foveola was 6 mm (median 6, range 0-19 mm) and to optic nerve was 6 mm (median 5, range 0-19 mm). Of all eyes, using Kaplan-Meier analysis, metastasis occurred in 11, 30, 45, and 52% at 1, 3, 5, and 7 years, respectively. According to tumor thickness (10.0-11.0, 11.1-12.0, 12.1-13.0, 13.1-14.0, 14.1-15.0, 15.1-16.0, and >16.0 mm), metastasis at 1 year was found in 7, 12, 13, 15, 18, 22, and 20%; metastasis at 3 years was 24, 27, 37, 35, 51, 69, and 57%; metastasis at 5 years was 38%, 42%, 56%, 48%, 61%, not available, and 66%; and metastasis at 7 years was 47%, 47%, 61%, 57%, 61%, not available, and 66%. Clinical features associated with fewer metastatic events included Bruch membrane rupture (7-year metastasis at 48%, P = 0.018) and macular location (7-year metastasis at 32%, P = 0.014), whereas those with worse outcome included extraocular extension (7-year metastasis at 79%, P < 0.001). There was no significant difference in rate of melanoma-related metastasis for patients treated with plaque radiotherapy versus enucleation. CONCLUSION: Large uveal melanoma demonstrates 7-year rate of metastasis at 52%, with generalized increasing risk per 1-mm or 2-mm thickness increments. Extraocular extension was associated with greater metastatic rate, whereas Bruch membrane rupture and macular location demonstrated lower rate. PMID- 29528981 TI - THE THICKNESSES OF CHOROID, MACULAR SEGMENTS, PERIPAPILLARY RETINAL NERVE FIBER LAYER, AND RETINAL VASCULAR CALIBER IN HIV-1-INFECTED PATIENTS WITHOUT INFECTIOUS RETINITIS. AB - PURPOSE: To evaluate choroidal, macular, peripapillary retinal nerve fiber layer (RNFL) thicknesses and retinal vascular caliber alterations in HIV-1-infected patients without opportunistic infections. METHODS: This cross-sectional study included 45 HIV-1-infected patients and 47 healthy subjects. Spectral domain optical coherence tomography was used for assessment of choroidal, macular, peripapillary RNFL thicknesses and retinal vascular caliber alterations. RESULTS: The mean CD4 count was 426 +/- 226 cells per milliliter and the mean HIV-1 RNA level was 1.8 * 10 +/- 3.6 * 10 copies/mL in HIV-infected group. Central inner plexiform, superior photoreceptor, superior and nasal retinal pigment epithelium layers were thinner in HIV-infected patients compared with control subjects (P < 0.05). The differences in sectoral retinal thicknesses lost their significance after Bonferroni correction (P < 0.01). The average thickness of pericentral retina within 3 mm was thinner in the photoreceptor layer in HIV-infected patients compared with control subjects (P = 0.033). The differences in peripapillary RNFL thickness, choroidal thickness, and retinal vascular caliber were not significant between the groups. Choroidal thickness and pericentral outer plexiform were thinner, whereas peripapillary RNFL was thicker in newly diagnosed cases (16 patients) compared with patients having treatment for at least 4 months or longer (27 patients, P < 0.05, Mann-Whitney U test). HIV-1 RNA showed negative correlation with choroidal thickness (r = -0.435, P = 0.003) and positive correlation with peripapillary RNFL in central (r = 0.323, P = 0.032) and superonasal (r = 0.369, P = 0.014) sectors. CONCLUSION: Choroidal thickness was thinner in newly diagnosed patients compared with patients on treatment. Viral load showed negative correlation with choroidal thickness. Retinal segmental alterations occurred in HIV-infected patients compared with control subjects. PMID- 29528982 TI - NOVEL ENDOSCOPE-ASSISTED VITREOUS SURGERY COMBINED WITH ATMOSPHERIC ENDOSCOPIC TECHNIQUE AND/OR SUBRETINAL ENDOSCOPIC TECHNIQUE FOR RHEGMATOGENOUS RETINAL DETACHMENT WITH GRADE C PROLIFERATIVE VITREORETINOPATHY. AB - PURPOSE: The purpose of this study was to investigate the clinical outcomes of novel endoscope-assisted vitreous surgery techniques in patients with rhegmatogenous retinal detachment complicated by Grade C proliferative vitreoretinopathy. METHODS: Eight consecutive patients who had undergone endoscope-assisted vitreous surgery for rhegmatogenous retinal detachment complicated by Grade C proliferative vitreoretinopathy were investigated. The peripheral vitreous was cut under air with the aid of endoscopic view (atmospheric endoscopic technique), and the subretinal proliferation was removed under subretinal endoscopic observation (subretinal endoscopic technique). RESULTS: Retinal reattachment was achieved after the primary surgery without a large retinotomy and scleral buckling in each case. The mean follow-up was 16.8 months (range, 8-28 months). Atmospheric endoscopic technique was performed in all cases, and subretinal endoscopic technique was performed in three cases. After surgery, the mean best-corrected visual acuity significantly improved from 20/778 to 20/111 (P = 0.014). Although microretinal breaks occurred during the removal of vitreous using atmospheric endoscopic technique in all cases, there were no severe postoperative complications, such as retinal detachment or proliferative vitreoretinopathy. CONCLUSION: Endoscope-assisted vitreous surgery with atmospheric endoscopic technique and/or subretinal endoscopic technique is safe and effective in the treatment of rhegmatogenous retinal detachment with Grade C proliferative vitreoretinopathy. PMID- 29528983 TI - Reply. PMID- 29528984 TI - Internal Limiting Membrane Flap Technique for Macular Holes: Is it Ready for Prime Time? PMID- 29528985 TI - Minimally Invasive Ab Interno Four-Point Scleral Fixation of Intraocular Lens. PMID- 29528986 TI - High Baseline Anal Human Papillomavirus and Abnormal Anal Cytology in a Phase 3 Trial of the Quadrivalent Human Papillomavirus Vaccine in Human Immunodeficiency Virus-Infected Individuals Older Than 26 Years: ACTG 5298. AB - BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine (qHPV; types 6, 11, 16, 18) is indicated for men and women aged 9 to 26 years to prevent HPV associated anogenital high-grade squamous intraepithelial lesions (HSIL) and cancer. ACTG 5298 was a randomized placebo controlled Phase 3 study in human immunodeficiency virus (HIV)-infected men who have sex with men, and women of qHPV to prevent persistent anal HPV infection. Baseline data are presented here. METHODS: Human immunodeficiency virus-infected men who have sex with men, and women 27 years or older without previous anogenital or oral cancer were enrolled. Baseline anal cytology, high-resolution anoscopy and collection of anal, oral, and vaginal specimens for HPV genotyping were performed and acceptability assessed. RESULTS: Five hundred seventy-five (575) participants were enrolled (82% men and 18% women). Median age was 47 years. Race/ethnicity was 46% white, 31% black, and 20% Hispanic. Plasma HIV-1 RNA was less than 50 copies/mL in 83% and median CD4 T count was 602 cells/MUL. Abnormal anal cytology was detected in 62%, with corresponding HSIL on biopsy (bHSIL) in 33%. Anal HPV 6, 11, 16, and 18 were detected in 25%, 13%, 32%, and 18% of the participants, respectively. Prevalence of 0, 1, 2, 3, and 4 qHPV types was 40%, 38%, 17%, 4%, and 1%, respectively. Oral infection with 1 or more qHPV type was detected in 10% of the participants. Study procedures were generally acceptable. CONCLUSIONS: At study baseline, there was a high prevalence of abnormal anal cytology, bHSIL, and HPV infection. Sixty percent of the participants had anal infection with preventable qHPV types. PMID- 29528987 TI - Creating Innovative Sexually Transmitted Infection Testing Options for University Students: The Impact of an STI Self-testing Program. AB - BACKGROUND: National-level data suggest that sexually transmitted infection (STI) testing rates among young adults are low. The purpose of this study was to evaluate the acceptability of an STI self-testing program at a university health center. Few evaluations on the acceptability of collegiate self-testing programs and their effect on testing uptake have been conducted. METHODS: To assess acceptability and uptake of self-testing (urine and self-collected vaginal swab), we conducted a brief self-administered survey of students accessing a large US based university health center from January to December 2015. RESULTS: In 2015, University Health Services experienced a 28.5% increase in chlamydia (CT)/gonorrhea (GC) testing for male individuals and 13.7% increase in testing for female students compared to 2013 (baseline). In 2015, 12.4% of male students and 4.8% of female students tested positive for CT/GC via clinician testing, whereas 12.9% of male students and 12.4% of female students tested positive via self-testing. Female students were more likely to test positive for CT/GC when electing to test via self-test versus a clinician test (chi(1, N = 3068) = 36.54, P < 0.01); no significant difference in testing type was observed for male students. Overall, 22.5% of students who opted for the self-test option completed the acceptability survey; 63% reported that their main reason for testing was unprotected sex. In the past year, 42% reported 4 or more partners. The majority were very satisfied and likely to use the service again (82%). CONCLUSIONS: Self testing may be an efficient and effective way to provide STI testing for students and increase testing uptake. Self-reports of multiple partners, unprotected sex, and detected infections suggest that at-risk students are using the service. PMID- 29528988 TI - Let's Take A "Selfie": Self-Collected Samples for Sexually Transmitted Infections. PMID- 29528989 TI - Sexually Transmitted Infection Prevention With Long-Acting Reversible Contraception: Factors Associated With Dual Use. PMID- 29528990 TI - NKG2D Immunoligand rG7S-MICA Enhances NK Cell-mediated Immunosurveillance in Colorectal Carcinoma. AB - Colorectal carcinoma (CRC) is one of the most common malignant cancers worldwide. The poor response of CRC to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies for its potential efficiency. However, cetuximab, as one of the first-line targeted drugs in the treatment of CRC, has drug resistance and poor prognosis in clinic. To address this, a novel bispecific protein with CRC targeting and natural killer (NK) cell triggering was used for treatment. NK cell-mediated immunosurveillance is normally activated by the activating receptor natural killer cell receptor NK group 2, member D (NKG2D), which binds its key ligand major histocompatibility complex (MHC) class I-related chain A (MICA) expressed on the tumor cells. To trigger NK cell-mediated cytotoxicity, we fused MICA portion to a single-chain antibody fragment rG7S targeting the tumor-associated antigen CD24. In vitro, flow cytometry, cytotoxicity assay, degranulation, and cytokines release assay revealed that the fusion protein rG7S-MICA could both binds to CD24 and NKG2D which enhances NK cell sensitivity and NKG2D-mediated immunosurveillance against CD24 CRC cells. Furthermore, in a CD24 CRC-bearing nude mice model, rG7S-MICA effectively recruits NK cell to the tumor site and increase the release of cytokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), and shows potential antitumor effects. In conclusion, rG7S-MICA provides a novel immunotherapeutic strategy for CRC, which could be further developed against other CD24 malignancies. PMID- 29528991 TI - Whole Recombinant Saccharomyces cerevisiae Yeast Expressing Ras Mutations as Treatment for Patients With Solid Tumors Bearing Ras Mutations: Results From a Phase 1 Trial. AB - We are developing whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, engineered to encode target proteins, which stimulate immune responses against malignant cells expressing those targets. This phase 1 trial, enrolling patients with advanced colorectal or pancreas cancer, was designed to evaluate safety, immunogenicity, response, and overall survival of ascending doses of the GI-4000 series of products, which express 3 different forms of mutated Ras proteins. The study enrolled 33 heavily pretreated subjects (14 with pancreas and 19 with colorectal cancer), whose tumors were genotyped before enrollment to identify the specific ras mutation and thereby to identify which GI-4000 product to administer. No dose limiting toxicities were observed and no subject discontinued treatment due to a GI-4000 related adverse event (AE). The majority of AEs and all fatal events were due to underlying disease progression and AE frequencies were not significantly different among dose groups. GI-4000 was immunogenic, as Ras mutation-specific immune responses were detected on treatment in ~60% of subjects. No objective tumor responses were observed but based on imaging, clinical status and/or biochemical markers, stable disease was observed in 6 subjects (18%) on day 29, while 1 subject had stable disease at days 57 and 85 follow-up visits. The median overall survival was 3.3 months (95% confidence interval, 2.3-5.3 mo), and 5 subjects survived past the 48-week follow-up period. No significant dose-dependent trends for survival were observed. This first clinical trial in humans with GI-4000 demonstrated a favorable safety profile and immunogenicity in the majority of subjects. PMID- 29528992 TI - Syphilis Vaccine Development: Requirements, Challenges, and Opportunities. AB - Syphilis, caused by the spirochete Treponema pallidum subspecies pallidum, continues to be a prevalent disease in low- and middle-income countries, and has reemerged in key populations, including men who have sex with men, in high-income nations. The rising number of cases shows that syphilis elimination will require augmentation of public health screening and treatment campaigns with syphilis vaccine development and implementation initiatives. Optimal vaccine candidates, deciphered from careful consideration of the pathogenic mechanisms used by T. pallidum, will need to be paired with appropriate human-track adjuvants designed to elicit the correlates of protection needed to prevent infection/disease. This article provides an overview of the development pipeline customized for a syphilis vaccine, including the preferred product characteristics, the investment case, and a proposed vaccinogen selection strategy outlining the essential qualities that need to be targeted by a syphilis vaccine. PMID- 29528994 TI - Time to Develop Standardized Molecular Diagnostics for the Simultaneous Detection of Neisseria gonorrhoeae and Its Antimicrobial Resistance. PMID- 29528993 TI - Biomedical Research Priorities for Modern Syphilis Clinical Management, Diagnosis, and Vaccines: Overview and Commentary for Unit 1. AB - The first session at the 2016 Syphilis Summit provided an opportunity for laboratory researchers and clinicians to comment on gaps in biomedical knowledge and technologies. Predominant themes in the presentations and discussion included the need for optimization of existing diagnostic tests, commercial availability, and Food and Drug Administration approval of nucleic acid amplification tests for primary and secondary syphilis, development of sensitive and specific new blood tests for diagnosis of active (vs treated) syphilis infection, clarification of the best measures for adequacy of response to treatment, continued study of complications of syphilis, including neurosyphilis and ocular syphilis, and development of a safe and effective vaccine that will protect against transmission and complications of disseminated infection (including congenital and neurosyphilis). Renewed and sustained support of biomedical syphilis research and an influx of talent could move the needle in the fight against this reemerging ancient disease. PMID- 29528995 TI - Reactor Grids for Prioritizing Syphilis Investigations: Are Primary Syphilis Cases Being Missed? AB - BACKGROUND: Health departments prioritize investigations of reported reactive serologic tests based on age, gender, and titer using reactor grids. We wondered how reactor grids are used in different programs, and if administratively closing investigations of low-titer tests could lead to missed primary syphilis cases. METHODS: We obtained a convenience sample of reactor grids from 13 health departments. Interviews with staff from several jurisdictions described the role of grids in surveillance and intervention. From 5 jurisdictions, trends in reactive nontreponemal tests and syphilis cases over time (2006-2015) were assessed by gender, age, and titer. In addition, nationally-reported primary syphilis cases (2013-2015) were analyzed to determine what proportion had low titers (<=1:4) that might be administratively closed by grids without further investigation. RESULTS: Grids and follow-up approaches varied widely. Health departments in the study received a total of 48,573 to 496,503 reactive serologies over a 10-year period (3044-57,242 per year). In 2006 to 2015, the number of reactive serologies increased 37% to 169%. Increases were largely driven by tests for men although the ratios of tests per reported case remained stable over time. Almost one quarter of reported primary syphilis had low titers that would be excluded by most grids. The number of potentially missed primary syphilis cases varied by gender and age with 41- to 54-year-old men accounting for most. CONCLUSIONS: Reactor grids that close tests with low titers or from older individuals may miss some primary syphilis cases. Automatic, computerized record searches of all reactive serologic tests could help improve prioritization. PMID- 29528996 TI - Acceptability and Feasibility of Rapid Chlamydial, Gonococcal, and Trichomonal Screening and Treatment in Pregnant Women in 6 Low- to Middle-Income Countries. AB - BACKGROUND: Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) infections during pregnancy are linked with adverse birth outcomes. However, few countries have prenatal CT, NG, or TV screening programs. In this study, we aimed to evaluate the acceptability and feasibility of CT, NG, and TV screening and treatment among pregnant women across 6 low- to middle-income countries. METHODS: A total of 1817 pregnant women were screened for CT, NG, and TV in Botswana, the Democratic Republic of Congo, Haiti, South Africa, and Vietnam. An additional 640 pregnant women were screened for CT in Peru. Screening occurred between December 2012 and October 2017. Acceptability of screening was evaluated at each site as the proportion of eligible women who agreed to participate in screening. Feasibility of treatment was calculated as the proportion of women who tested positive that received treatment. RESULTS: Acceptability of screening and feasibility of treatment was high across all 6 sites. Acceptability of screening ranged from 85% to 99%, and feasibility of treatment ranged from 91% to 100%. DISCUSSION: The high acceptability and feasibility of screening and treatment of CT, NG, and TV among pregnant women supports further research to evaluate the cost-effectiveness of prenatal CT, NG, and TV screening programs. PMID- 29528997 TI - Lack of Consensus in Physician Recommendations Regarding Return to Driving After Cervical Spine Surgery. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: The goal of this study is to investigate how surgeons differ in collar and narcotic use, as well as return to driving recommendations following cervical spine surgeries and the associated medico-legal ramifications of these conditions. SUMMARY OF BACKGROUND DATA: Restoration of quality of life is one of the main goals of cervical spine surgery. Patients frequently inquire when they may safely resume driving after cervical spine surgery. There is no consensus regarding postoperative driving restrictions. This study addresses how surgeons differ in their recommendations concerning cervical immobilization, narcotic analgesia, and suggested timeline of return to driving following cervical spine surgery. METHODS: Surgeons at the Cervical Spine Research Society annual meeting completed anonymous surveys assessing postoperative patient management following fusion and nonfusion cervical spine surgeries. RESULTS: Seventy percent of surgeons returned completed surveys (n = 71). About 80.3% were orthopedic surgeons and 94.2% completed a spine fellowship. Experienced surgeons (>15 years in practice) were more likely to let patients return to driving within 2 weeks than less experienced surgeons (47.1% vs. 24.3%, P = 0.013) for multilevel anterior discectomy and fusion (ACDF) and laminectomy with fusion procedures. There were no differences between surgeons practicing inside and outside the USA for prescribing collars or return to driving time. Cervical collars were used more for fusions than nonfusions (57.7% vs. 31.0%, P = 0.001). Surgeons reported 75.3% of patients ask when they may resume driving. For cervical fusions, 31.4% of surgeons allowed their patients to resume driving while restricting them with collars for longer durations. Furthermore, 27.5% of surgeons allowed their patients to resume driving while taking narcotics postoperatively. CONCLUSION: This survey-based study highlights the lack of consensus regarding patient "fitness to drive" following cervical spine surgery. The importance of establishing evidence-based guidelines is critical, as recommendations for driving in the postoperative period may have significant medical, legal, and financial implications. LEVEL OF EVIDENCE: 5. PMID- 29528998 TI - Differing Age Represents Differing Underlying diagnoses in Adult Spinal Deformity: Why Include Them in the Same Cohort? PMID- 29528999 TI - Impact of Multilevel Facetectomy and Rod Curvature on Anatomical Spinal Reconstruction in Thoracic Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A prospective, nonrandomized study. OBJECTIVE: The aim of this study was to assess surgical outcomes of multilevel facetectomy and rod curvature with simultaneous double-rod rotation technique for anatomical spinal reconstruction in thoracic adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Although some surgical techniques maintain or restore thoracic kyphosis (TK), next-generation strategies for thoracic AIS should include corrections in three anatomical planes. METHODS: The study included 39 consecutive patients with Lenke 1 or Lenke 2 thoracic AIS treated at our institution. After all-level facetectomy at instrumentation level, except for the lowest intervertebral segment, two rods were identically bent to guide postoperative anatomical TK without reference to the intraoperative coronal alignment of the AIS deformity. Outcome measures included patient demographics, radiographic measurements, and Scoliosis Research Society (SRS) questionnaire scores. RESULTS: After 2 years of follow-up, the average main thoracic Cobb angle correction rate was 83.5%, and the final correction loss was 2.2 degrees . The average preoperative TK (T5-T12) significantly increased from 13.2 degrees to 24.6 degrees (P < 0.001) at final follow-up. The percentage of patients with a T6-T8 location of the TK apex significantly increased from 51.3% preoperatively to 87.2% at final follow-up. The average preoperative vertebral rotation angle significantly decreased from 18.7 degrees to 12.8 degrees postoperatively (P < 0.001). The average preoperative total SRS questionnaire score significantly increased from 3.5 to 4.5 (P < 0.001) at final follow-up. There was no implant breakage and vascular and neurologic complications, with all patients demonstrating solid fusion at final follow-up. CONCLUSION: Multilevel facetectomy and rod curvature play an important role in anatomical spinal reconstruction in patients with thoracic AIS. From the spatiotemporal point of view, four dimensional correction could be actively performed by rod curvature under multilevel facetectomy and is expected to obtain an anatomical thoracic spine postoperatively, indicating that an anatomically designed rod could be supplied as a pre-bent rod. LEVEL OF EVIDENCE: 3. PMID- 29529000 TI - Patient's Subjective Impression of Cervical Range of Motion: A Mixed-methods Approach. AB - STUDY DESIGN: Mixed-method. OBJECTIVE: To evaluate the association between objective and subjective cervical range of motion (ROM) among patients with neck pain, and to assess the awareness of impairments. SUMMARY OF BACKGROUND DATA: Cervical ROM is frequently used to evaluate neck pain, but it is also important to know what a patient expects from treatment, because this can profoundly affect treatment outcomes and patient satisfaction. METHODS: We used a cervical ROM instrument, the Neck Disability Index (NDI), and a self-administered ROM questionnaire for the neck (S-ROM-Neck). Ten patients took part in semi structured interviews. Correlations were analyzed using Spearman rank order correlations (rs). Differences between patient and assessor were evaluated by the Mann-Whitney U test. Qualitative data were analyzed by content analysis. RESULTS: Thirty participants (mean age 43.80 years; 21 females) were included. The correlation (rs) for the S-ROM-Neck between patient and assessor was 0.679 [95% confidence interval (95% CI) 0.404-0.884; P = 0.000]. The correlation between the NDI and S-ROM-Neck was 0.178 (95% CI -0.233 to -0.533; P = 346) for the assessor and -0.116 (95% CI -0.475 to -0.219, P = 0.541) for the patient (U = 448, z = 0.030, P = 0.976). Qualitative analysis revealed that patients had general restrictions in daily life and with specific movements, but that they adjusted their behavior to avoid impairment. CONCLUSION: There was a significant correlation between patient and therapist ratings of cervical spine mobility. Although patients experience restriction while moving and are impaired in specific activities, they adjust their lifestyle to accommodate their limitations. LEVEL OF EVIDENCE: 4. PMID- 29529001 TI - Synchrotron Radiation Imaging Reveals the Role of Estrogen in Promoting Angiogenesis After Acute Spinal Cord Injury in Rats. AB - STUDY DESIGN: The efficacy of estrogen on vessel angiogenesis in acute spinal cord injury (SCI) in a rat model was evaluated by synchrotron radiation. OBJECTIVE: Here, we investigate the change in injured spinal cord vessels and used the synchrotron radiation to investigate the effect of estrogen on vessel angiogenesis and functional recovery in a rat model of SCI. SUMMARY OF BACKGROUND DATA: The promotion of angiogenesis after SCI may be a therapeutic target in the treatment of SCI. Estrogen has been reported to improve locomotor recovery after SCI. However, how estrogen regulates angiogenesis in acute SCI and enhances neurological functional recovery has not been fully characterized. METHODS: Synchrotron radiation imaging combined with histological methods was used to image angiogenesis in acute spinal cord treatment with estrogen in rats. RESULTS: Synchrotron radiation imaging vividly demonstrated three-dimensional vessel changes in the spinal cord after injury. The imaging showed that vessel number, vessel volume fraction, and vessel connectivity value in the groups treated with estrogen after SCI were significantly increased compared to control groups (P < 0.05). Vessel angiogenesis increased in groups treated with estrogen compared with control rats, which was confirmed with histological staining. Estrogen treatment also attenuated the injury-induced lesion area compared with control groups and improved locomotor functional recovery after SCI. CONCLUSION: The results indicated that synchrotron radiation is a powerful imaging tool for visualizing angiogenesis after acute SCI. Estrogen treatment exerted a neuroprotective effect on acute SCI treatment by promoting angiogenesis and reducing the injury-induced lesion area could be recommended as a potential preclinical treatment approach for acute SCI. LEVEL OF EVIDENCE: N/A. PMID- 29529002 TI - NRS20: Combined Back and Leg Pain Score: A Simple and Effective Assessment of Adult Spinal Deformity. AB - STUDY DESIGN: Multicenter, prospective study of consecutive adult spinal deformity (ASD) patients. OBJECTIVE: To evaluate back and leg pain as a combined score in ASD and compare their relative and cumulative correlations with health related quality of life (HRQOL) and sagittal parameters. SUMMARY OF BACKGROUND DATA: Pain and disability are commonly reported in patients with ASD. This can affect their back, their legs or both. ASD-associated pain has been correlated with numerous HRQOL scores and radiological parameters. METHODS: Preoperative pain intensity was assessed with a Numerical Rating Scale (NRS) for individual back and leg pain as well as a combined score, NRS20 (0-20, back plus leg pain).This yielded a range of static measures in all patients with ASD with differing burdens of disease. Linear regression analysis was performed to calculate the correlation between pain and HRQOL scores (Scoliosis Research Society 22, 36-Item Short Form Health Survey Physical Component Summary, 36-Item Short Form Health Survey Mental Component Summary, Core Outcome Measures Index, and Oswestry Disability Index), and radiological spinopelvic parameters (sagittal and coronal planes). RESULTS: A total of 1309 patients were included in this study. A combined score (NRS20) was better correlated with HRQOL (P < 0.01 for all) and sagittal parameters (P < 0.01 for all) than individual back or leg pain scores. Evaluation of the relative contributions of back and leg pain demonstrate a higher correlation with HRQOL scores for back pain and a higher correlation with sagittal parameters for leg pain. The distribution of NRS20 pain scores demonstrated three clear patterns of pain: back pain only, moderate back pain with varying mild-moderate leg pain, and severe equivalent back and leg pain. Similar values were noted for nonoperative and operative patients. CONCLUSION: The distribution and intensity of pain and its correlations with clinical and radiological parameters provide insight into the pathogenesis of ASD. A combined score has a simple yet valuable contribution to the assessment of symptoms in ASD. LEVEL OF EVIDENCE: 3. PMID- 29529003 TI - Selective Anterior Lumbar Interbody Fusion for Low Back Pain Associated With Degenerative Disc Disease Versus Nonsurgical Management. AB - STUDY DESIGN: This is a retrospective cohort study. OBJECTIVE: To evaluate the long-term outcomes of selective one- to two-level anterior lumbar interbody fusions (ALIFs) in the lower lumbar spine versus continued nonsurgical management. SUMMARY OF BACKGROUND DATA: Low back pain associated with lumbar intervertebral disc degeneration is common with substantial economic impact, yet treatment remains controversial. Surgical fusion has previously provided mixed results with limited durable improvement of pain and function. METHODS: Seventy five patients with one or two levels of symptomatic Pfirrmann grades 3 to 5 disc degeneration from L3-S1 were identified. All patients had failed at least 6 months of nonsurgical treatment. Forty-two patients underwent one- or two-level ALIFs; 33 continued multimodal nonsurgical care. Patients were evaluated radiographically and the visual analog pain scale (VAS), Oswestry Disability Index (ODI), EuroQol five dimensions (EQ-5D), and Patient-Reported Outcomes Measurement Information System scores for pain interference, pain intensity, and anxiety. As-treated analysis was performed to evaluate outcomes at a mean follow up of 7.4 years (range: 2.5-12). RESULTS: There were no differences in pretreatment demographics or nonsurgical therapy utilization between study arms. At final follow-up, the surgical arm demonstrated lower VAS, ODI, EQ-5D, and Patient-Reported Outcomes Measurement Information System pain intensity scores versus the nonsurgical arm. VAS and ODI scores improved 52.3% and 51.1% in the surgical arm, respectively, versus 15.8% and -0.8% in the nonsurgical arm. Single level fusions demonstrated improved outcomes versus two-level fusions. The pseudarthrosis rate was 6.5%, with one patient undergoing reoperation. Asymptomatic adjacent segment degeneration was identified in 11.9% of patients. CONCLUSION: Selective ALIF limited to one or two levels in the lower lumbar spine provided improved pain and function when compared with continued nonsurgical care. ALIF may be a safe and effective treatment for low back pain associated with disc degeneration in select patients who fail nonsurgical management. LEVEL OF EVIDENCE: 3. PMID- 29529004 TI - One Brace: One Visit: Treatment of Pediatric Distal Radius Buckle Fractures With a Removable Wrist Brace and No Follow-up Visit. AB - BACKGROUND: Previous studies have showed the efficacy of removable brace treatment for distal radius buckle fractures in children, whereas others have independently suggested that these injuries do not require additional radiographic imaging. However, no study has sought to collectively determine whether treating pediatric distal radius buckle fractures with a removable brace and no follow-up visit or imaging after the initial visit is a safe and satisfactory protocol. METHODS: In total, 42 consecutive patients with a distal forearm buckle fracture seen by a single fellowship trained pediatric orthopaedic surgeon were eligible to participate. Two patients refused participation, yielding 40 patients treated with a standard protocol of immobilization with a removable wrist brace for a prescribed period of time with no additional imaging or clinical follow-up. Two staggered telephone surveys were then conducted. The first survey was conducted within 1 week of the designated brace-removal date to determine the exact date the brace was discontinued. The second survey was conducted 5 to10 months postinjury to determine patient outcomes and parent satisfaction. RESULTS: In total, 100% of patients were reached for the initial survey and 90% (36/40) of patients were reached for the secondary survey. There were no complications, including refracture or residual pain, following treatment. In total, 100% of parents felt their child had returned to full and normal function and all said they would choose to have the same treatment again. In total, 67% of parents would have had to take time off from work and 77% of children would have missed school if they had hypothetically been required to attend a follow-up appointment. CONCLUSION: Treatment of pediatric distal forearm buckle fractures with a removable wrist brace and no follow-up visit or radiographs results in both excellent patient outcomes and parental satisfaction. LEVEL OF EVIDENCE: Level IV-case series. PMID- 29529005 TI - Who Gets Compartment Syndrome?: A Retrospective Analysis of the National and Local Incidence of Compartment Syndrome in Patients With Supracondylar Humerus Fractures. AB - PURPOSE: Although acute compartment syndrome (ACS) is associated with pediatric supracondylar humerus (SCH) fractures, there are limited data describing its incidence and risk factors. The purpose of our study was to report the local and national incidence of ACS with SCH and floating elbow (concomitant SCH and forearm) fracture patterns and the associated risk factors. METHODS: We retrospectively queried data for SCH fracture patients over a 4-year period from our institution (a level I pediatric trauma center) and the National Trauma Data Bank (NTDB). Data on demographics, mechanism of injury, open versus closed fracture, length of stay, presence or absence of forearm fractures, and incidence of traumatic compartment syndrome were analyzed. The student t and chi tests were utilized for group comparisons of continuous and categorical variables, respectively. Logistic regression was used to identify risk factors for compartment syndrome. Results are summarized as means with SD or odds ratios (OR) with 95% confidence intervals (CI). Statistical significance was set at P<0.05. RESULTS: At our institution, 839 patients with SCH fractures met inclusion criteria. In total, 814 (97.02%) patients (average age, 5.96+/-2.58 y) sustained isolated SCH fractures during the indicated timeframe. SCH fractures with an associated forearm fracture were identified in 25 (2.98%) patients (average age, 7.00+/-3.03 y). Three patients (0.36%) with isolated SCH fractures were observed to have compartment syndrome. No compartment syndromes were identified in the patients with floating elbows.Within the same time period, the NTDB identified 31,234 SCH fractures met inclusion criteria. Of those, 31,167 patients had isolated SCH fractures (average age, 5.5+/-2.7 y). In total, 67 of the SCH patients (0.2%, P<0.0001) had documented ACS (average age, 7.3+/-3.5 y). The NTDB identified 1565 patients with floating elbows, including 13 (0.8%, P<=0.0001) who developed compartment syndrome (average age, 6.47+/-2.71 y). The NTDB query also identified 530 patients with neurovascular injury (NVI), with 4.5% (n=24) that developed compartment syndrome. In the regression analysis, older age (OR, 1.1; 95% CI, 1.0-1.2; P<0.0092), male sex (OR, 2.7; 95% CI, 1.5-4.8; P=0.0005), floating elbow fracture pattern (OR, 3.2; 95% CI, 1.7-6.1; P=0.0003) and NVI (OR, 25.0; 95% CI, 14.6-42.8; P<=0.0001) were identified as risk factors for developing compartment syndrome. CONCLUSIONS: Data from our institution and NTDB reveal that acute traumatic compartment syndrome is rare, occurring in ~2 to 3 fractures of 1000. However, there is a significantly increased risk with NVI, floating elbow fractures, males, and older patients. SIGNIFICANCE: Characterizing the incidence and associated risk factors of ACS with concomitant SCH and forearm fracture patterns can improve clinical understanding and management of pediatric patients. PMID- 29529006 TI - A Dynamically Focusing Cochlear Implant Strategy Can Improve Vowel Identification in Noise. AB - OBJECTIVES: The standard, monopolar (MP) electrode configuration used in commercially available cochlear implants (CI) creates a broad electrical field, which can lead to unwanted channel interactions. Use of more focused configurations, such as tripolar and phased array, has led to mixed results for improving speech understanding. The purpose of the present study was to assess the efficacy of a physiologically inspired configuration called dynamic focusing, using focused tripolar stimulation at low levels and less focused stimulation at high levels. Dynamic focusing may better mimic cochlear excitation patterns in normal acoustic hearing, while reducing the current levels necessary to achieve sufficient loudness at high levels. DESIGN: Twenty postlingually deafened adult CI users participated in the study. Speech perception was assessed in quiet and in a four-talker babble background noise. Speech stimuli were closed-set spondees in noise, and medial vowels at 50 and 60 dB SPL in quiet and in noise. The signal to noise ratio was adjusted individually such that performance was between 40 and 60% correct with the MP strategy. Subjects were fitted with three experimental strategies matched for pulse duration, pulse rate, filter settings, and loudness on a channel-by-channel basis. The strategies included 14 channels programmed in MP, fixed partial tripolar (sigma = 0.8), and dynamic partial tripolar (sigma at 0.8 at threshold and 0.5 at the most comfortable level). Fifteen minutes of listening experience was provided with each strategy before testing. Sound quality ratings were also obtained. RESULTS: Speech perception performance for vowel identification in quiet at 50 and 60 dB SPL and for spondees in noise was similar for the three tested strategies. However, performance on vowel identification in noise was significantly better for listeners using the dynamic focusing strategy. Sound quality ratings were similar for the three strategies. Some subjects obtained more benefit than others, with some individual differences explained by the relation between loudness growth and the rate of change from focused to broader stimulation. CONCLUSIONS: These initial results suggest that further exploration of dynamic focusing is warranted. Specifically, optimizing such strategies on an individual basis may lead to improvements in speech perception for more adult listeners and improve how CIs are tailored. Some listeners may also need a longer period of time to acclimate to a new program. PMID- 29529008 TI - Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients With Crohn's Disease. AB - BACKGROUND: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. Understanding pharmacokinetics (PK) of ADL is essential to optimize individual dosing in daily practice. The aim of this study was to evaluate PK of ADL in patients with CD and to identify factors that influence PK of ADL. METHODS: In a retrospective cohort study, the authors reviewed the charts of 96 patients with CD receiving ADL induction and maintenance treatment. This patient cohort was used for external validation of population pharmacokinetic models of ADL available from literature. In addition, a novel population PK model was developed using nonlinear mixed-effects modeling. RESULTS: None of the literature models properly described the PK of ADL in our cohort. Therefore, a novel population pharmacokinetic model was developed. Clearance of ADL increased 4-fold in the presence of anti-ADL antibodies. Patients who received ADL every week had a 40% higher clearance compared with patients receiving ADL every other week. CONCLUSIONS: Clearance of ADL increased in the presence of anti-ADL antibodies and was associated with weekly ADL administrations. In clinical practice, the decision to intensify ADL treatment to weekly administrations is primarily based on disease activity. Increased disease activity may be the result of lower drug concentrations due to higher clearance. However, increased disease activity may also increase clearance due to increased target engagement. The causal relationship between these factors remains to be elucidated. PMID- 29529007 TI - Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants After Cardiac Surgery. AB - BACKGROUND: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. METHODS: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. RESULTS: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2*IGFBP-7) >=0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) >=529.57 at 24 hours (OR 2.76; 95% CI, 1.06 7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. CONCLUSIONS: In this pilot study, urine TIMP-2*IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice. PMID- 29529009 TI - Quantification of Idelalisib in Human Plasma by Ultra-Performance Liquid Chromatography Coupled to Mass Spectrometry in Negative Ionization Mode. AB - BACKGROUND: Idelalisib is the first orally active selective phosphatidylinositol 3-kinase delta inhibitor approved by Food and Drug Administration and European Medicines Agency in 2014 for the treatment of several types of blood cancer. Idelalisib is widely used as a monotherapy or in combination with rituximab, bendamustine, or ofatumumab with a significant efficacy. However, idelalisib has shown increased risk of infection and a higher frequency of serious adverse events. It may be useful to determine idelalisib concentration in human plasma to adjust dose and to manage adverse effects in clinical practice. METHODS: After a single-step protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-high performance liquid chromatography system coupled with mass tandem spectrometry in a negative ionization mode using isotope-labeled internal standard. This method was validated by studies of its linearity, accuracy, imprecision, limit of quantification, recovery, matrix effect, selectivity, and stability. RESULTS: The quantification method was linear from 10 to 2500 ng/mL with a 5 ng/mL lower limit of quantification that encompasses the clinical range of drug concentration. The intraday and interday imprecisions were below 8.1% and 11.4%, respectively. The recoveries and matrix effect of idelalisib were 85.6% +/- 1.2% and 95.7% +/- 3.0%, respectively, which are consistent, precise, and reproducible (coefficient of variation % < 15%). Peak plasma concentration and trough plasma concentration ranges of idelalisib reached 1591-1937 ng/mL and 256.3-303.3 ng/mL, respectively, in 3 follicular lymphoma patients treated with idelalisib 150 mg twice a day. CONCLUSIONS: A robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated to quantify idelalisib concentration in human plasma. This method was effectively applied to 3 follicular lymphoma patients. PMID- 29529010 TI - Potential of Oral Fluid as a Clinical Specimen for Compliance Monitoring of Psychopharmacotherapy. AB - BACKGROUND: Oral fluid (OF) is being developed as a specimen for the determination of drug intake as an alternative to serum and plasma. It is generally considered as an attractive specimen due to the noninvasive nature of the sampling procedure and the relation to the free fraction of drug in the blood. These features are of particular value in drug treatment of psychiatric disorders. To establish OF for the purpose of monitoring drug therapy, the relationship between concentrations in OF and serum/plasma must be documented. This study explored one promising sampling device and comprised the following 10 drugs: aripiprazole, citalopram, duloxetine, escitalopram, mirtazapine, pipamperone, pregabalin, promethazine, quetiapine, and venlafaxine. METHODS: For this purpose, 100 paired serum and OF samples were collected from patients undergoing pharmacotherapy and analyzed using a liquid chromatography-tandem mass spectrometry method. A commercial method from Chromsystems for the determination of these drugs in plasma was used and was adapted for OF and ultrafiltrated (Centrifree device) serum. RESULTS: The ratio of each individual pair of samples was used to calculate a mean and SD value between OF and serum free and total concentrations. The OF concentration ratios to serum total fraction differed markedly between substances and differed from 10-fold lower to 8-fold higher. The ratios to serum free fractions were always higher. The relation between the OF and serum concentrations was also evaluated by regression analysis and determination of slopes and correlation coefficients. For all measured relations, there was a statistically significant relation between the OF and serum concentrations. The degree of drug protein binding was in agreement with literature. The aripiprazole, duloxetine, pipamperone, pregabalin, and promethazine concentrations in ultrafiltrated serum were not possible to measure because of low concentrations and nonspecific binding. CONCLUSIONS: Despite a strong statistical correlation between OF and serum concentrations observed for most of the studied substances, it is still evident that OF concentrations cannot simply substitute serum/plasma as therapeutic drug monitoring specimen, but rather be considered as a unique specimen. We believe that OF is a promising matrix especially for compliance testing in psychiatry settings. The Greiner Bio One device used in this study provides a sampling procedure that offers advantages over the available alternatives. PMID- 29529011 TI - Comparison of Biological Screening and Diagnostic Indicators to Detect In Utero Opiate and Cocaine Exposure Among Mother-Infant Dyads: Erratum. PMID- 29529012 TI - Enhancement and Suppression of Ionization in Drug Analysis Using HPLC-MS/MS in Support of Therapeutic Drug Monitoring: A Review of Current Knowledge of Its Minimization and Assessment: Erratum. PMID- 29529013 TI - Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance: Erratum. PMID- 29529014 TI - Retracted: Minimally Invasive Cardiac Surgery in China: Multi-Center Experience. AB - On Authors request: "Wrong total number of cases selected in the article, wrong number of cases in the minimally invasive surgery, and there are errors in the hospital complications" Reference: Minimally Invasive Cardiac Surgery in China: Multi-Center Experience Kun Hua, Yang Zhao, Ran Dong, Taoshuai Liu Med Sci Monit 2018;24: 421-426 10.12659/MSM.905408. PMID- 29529015 TI - Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. AB - Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal like subtype is under microenvironmental control and is therapeutically actionable. PMID- 29529016 TI - Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization. AB - Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17 month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals. PMID- 29529017 TI - Improved Ribo-seq enables identification of cryptic translation events. AB - Ribosome profiling has been used to predict thousands of short open reading frames (sORFs) in eukaryotic cells, but it suffers from substantial levels of noise. PRICE (https://github.com/erhard-lab/price) is a computational method that models experimental noise to enable researchers to accurately resolve overlapping sORFs and noncanonical translation initiation. We experimentally validated translation using major histocompatibility complex class I (MHC I) peptidomics and observed that sORF-derived peptides efficiently enter the MHC I presentation pathway and thus constitute a substantial fraction of the antigen repertoire. PMID- 29529018 TI - Alignment of single-cell trajectories to compare cellular expression dynamics. AB - Single-cell RNA sequencing and high-dimensional cytometry can be used to generate detailed trajectories of dynamic biological processes such as differentiation or development. Here we present cellAlign, a quantitative framework for comparing expression dynamics within and between single-cell trajectories. By applying cellAlign to mouse and human embryonic developmental trajectories, we systematically delineate differences in the temporal regulation of gene expression programs that would otherwise be masked. PMID- 29529019 TI - Perceptually relevant speech tracking in auditory and motor cortex reflects distinct linguistic features. AB - During online speech processing, our brain tracks the acoustic fluctuations in speech at different timescales. Previous research has focused on generic timescales (for example, delta or theta bands) that are assumed to map onto linguistic features such as prosody or syllables. However, given the high intersubject variability in speaking patterns, such a generic association between the timescales of brain activity and speech properties can be ambiguous. Here, we analyse speech tracking in source-localised magnetoencephalographic data by directly focusing on timescales extracted from statistical regularities in our speech material. This revealed widespread significant tracking at the timescales of phrases (0.6-1.3 Hz), words (1.8-3 Hz), syllables (2.8-4.8 Hz), and phonemes (8-12.4 Hz). Importantly, when examining its perceptual relevance, we found stronger tracking for correctly comprehended trials in the left premotor (PM) cortex at the phrasal scale as well as in left middle temporal cortex at the word scale. Control analyses using generic bands confirmed that these effects were specific to the speech regularities in our stimuli. Furthermore, we found that the phase at the phrasal timescale coupled to power at beta frequency (13-30 Hz) in motor areas. This cross-frequency coupling presumably reflects top-down temporal prediction in ongoing speech perception. Together, our results reveal specific functional and perceptually relevant roles of distinct tracking and cross-frequency processes along the auditory-motor pathway. PMID- 29529020 TI - The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen encoding var genes. AB - Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to-or is selected by-this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to-or are selected by the host environment in severe malaria. PMID- 29529021 TI - Particle-based simulations of polarity establishment reveal stochastic promotion of Turing pattern formation. AB - Polarity establishment, the spontaneous generation of asymmetric molecular distributions, is a crucial component of many cellular functions. Saccharomyces cerevisiae (yeast) undergoes directed growth during budding and mating, and is an ideal model organism for studying polarization. In yeast and many other cell types, the Rho GTPase Cdc42 is the key molecular player in polarity establishment. During yeast polarization, multiple patches of Cdc42 initially form, then resolve into a single front. Because polarization relies on strong positive feedback, it is likely that the amplification of molecular-level fluctuations underlies the generation of multiple nascent patches. In the absence of spatial cues, these fluctuations may be key to driving polarization. Here we used particle-based simulations to investigate the role of stochastic effects in a Turing-type model of yeast polarity establishment. In the model, reactions take place either between two molecules on the membrane, or between a cytosolic and a membrane-bound molecule. Thus, we developed a computational platform that explicitly simulates molecules at and near the cell membrane, and implicitly handles molecules away from the membrane. To evaluate stochastic effects, we compared particle simulations to deterministic reaction-diffusion equation simulations. Defining macroscopic rate constants that are consistent with the microscopic parameters for this system is challenging, because diffusion occurs in two dimensions and particles exchange between the membrane and cytoplasm. We address this problem by empirically estimating macroscopic rate constants from appropriately designed particle-based simulations. Ultimately, we find that stochastic fluctuations speed polarity establishment and permit polarization in parameter regions predicted to be Turing stable. These effects can operate at Cdc42 abundances expected of yeast cells, and promote polarization on timescales consistent with experimental results. To our knowledge, our work represents the first particle-based simulations of a model for yeast polarization that is based on a Turing mechanism. PMID- 29529022 TI - Proteomic analysis of corneal endothelial cell-descemet membrane tissues reveals influence of insulin dependence and disease severity in type 2 diabetes mellitus. AB - The objective of this study was to characterize the proteome of the corneal endothelial cell layer and its basement membrane (Descemet membrane) in humans with various severities of type II diabetes mellitus compared to controls, and identify differentially expressed proteins across a range of diabetic disease severities that may influence corneal endothelial cell health. Endothelium Descemet membrane complex tissues were peeled from transplant suitable donor corneas. Protein fractions were isolated from each sample and subjected to multidimensional liquid chromatography and tandem mass spectrometry. Peptide spectra were matched to the human proteome, assigned gene ontology, and grouped into protein signaling pathways unique to each of the disease states. We identified an average of 12,472 unique proteins in each of the endothelium Descemet membrane complex tissue samples. There were 2,409 differentially expressed protein isoforms that included previously known risk factors for type II diabetes mellitus related to metabolic processes, oxidative stress, and inflammation. Gene ontology analysis demonstrated that diabetes progression has many protein footprints related to metabolic processes, binding, and catalysis. The most represented pathways involved in diabetes progression included mitochondrial dysfunction, cell-cell junction structure, and protein synthesis regulation. This proteomic dataset identifies novel corneal endothelial cell and Descemet membrane protein expression in various stages of diabetic disease. These findings give insight into the mechanisms involved in diabetes progression relevant to the corneal endothelium and its basement membrane, prioritize new pathways for therapeutic targeting, and provide insight into potential biomarkers for determining the health of this tissue. PMID- 29529023 TI - In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy. AB - The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies. PMID- 29529024 TI - LAILAPS-QSM: A RESTful API and JAVA library for semantic query suggestions. AB - In order to access and filter content of life-science databases, full text search is a widely applied query interface. But its high flexibility and intuitiveness is paid for with potentially imprecise and incomplete query results. To reduce this drawback, query assistance systems suggest those combinations of keywords with the highest potential to match most of the relevant data records. Widespread approaches are syntactic query corrections that avoid misspelling and support expansion of words by suffixes and prefixes. Synonym expansion approaches apply thesauri, ontologies, and query logs. All need laborious curation and maintenance. Furthermore, access to query logs is in general restricted. Approaches that infer related queries by their query profile like research field, geographic location, co-authorship, affiliation etc. require user's registration and its public accessibility that contradict privacy concerns. To overcome these drawbacks, we implemented LAILAPS-QSM, a machine learning approach that reconstruct possible linguistic contexts of a given keyword query. The context is referred from the text records that are stored in the databases that are going to be queried or extracted for a general purpose query suggestion from PubMed abstracts and UniProt data. The supplied tool suite enables the pre-processing of these text records and the further computation of customized distributed word vectors. The latter are used to suggest alternative keyword queries. An evaluated of the query suggestion quality was done for plant science use cases. Locally present experts enable a cost-efficient quality assessment in the categories trait, biological entity, taxonomy, affiliation, and metabolic function which has been performed using ontology term similarities. LAILAPS-QSM mean information content similarity for 15 representative queries is 0.70, whereas 34% have a score above 0.80. In comparison, the information content similarity for human expert made query suggestions is 0.90. The software is either available as tool set to build and train dedicated query suggestion services or as already trained general purpose RESTful web service. The service uses open interfaces to be seamless embeddable into database frontends. The JAVA implementation uses highly optimized data structures and streamlined code to provide fast and scalable response for web service calls. The source code of LAILAPS-QSM is available under GNU General Public License version 2 in Bitbucket GIT repository: https://bitbucket.org/ipk_bit_team/bioescorte-suggestion. PMID- 29529025 TI - Parallel roles of transcription factors dFOXO and FER2 in the development and maintenance of dopaminergic neurons. AB - Forkhead box (FOXO) proteins are evolutionarily conserved, stress-responsive transcription factors (TFs) that can promote or counteract cell death. Mutations in FOXO genes are implicated in numerous pathologies, including age-dependent neurodegenerative disorders, such as Parkinson's disease (PD). However, the complex regulation and downstream mechanisms of FOXOs present a challenge in understanding their roles in the pathogenesis of PD. Here, we investigate the involvement of FOXO in the death of dopaminergic (DA) neurons, the key pathological feature of PD, in Drosophila. We show that dFOXO null mutants exhibit a selective loss of DA neurons in the subgroup crucial for locomotion, the protocerebral anterior medial (PAM) cluster, during development as well as in adulthood. PAM neuron-targeted adult-restricted knockdown demonstrates that dFOXO in adult PAM neurons tissue-autonomously promotes neuronal survival during aging. We further show that dFOXO and the bHLH-TF 48-related-2 (FER2) act in parallel to protect PAM neurons from different forms of cellular stress. Remarkably, however, dFOXO and FER2 share common downstream processes leading to the regulation of autophagy and mitochondrial morphology. Thus, overexpression of one can rescue the loss of function of the other. These results indicate a role of dFOXO in neuroprotection and highlight the notion that multiple genetic and environmental factors interact to increase the risk of DA neuron degeneration and the development of PD. PMID- 29529027 TI - Correction: Extracellular Vesicle-Mediated Transfer of Genetic Information between the Hematopoietic System and the Brain in Response to Inflammation. AB - [This corrects the article DOI: 10.1371/journal.pbio.1001874.]. PMID- 29529026 TI - Argonaute2 and LaminB modulate gene expression by controlling chromatin topology. AB - Drosophila Argonaute2 (AGO2) has been shown to regulate expression of certain loci in an RNA interference (RNAi)-independent manner, but its genome-wide function on chromatin remains unknown. Here, we identified the nuclear scaffolding protein LaminB as a novel interactor of AGO2. When either AGO2 or LaminB are depleted in Kc cells, similar transcription changes are observed genome-wide. In particular, changes in expression occur mainly in active or potentially active chromatin, both inside and outside LaminB-associated domains (LADs). Furthermore, we identified a somatic target of AGO2 transcriptional repression, no hitter (nht), which is immersed in a LAD located within a repressive topologically-associated domain (TAD). Null mutation but not catalytic inactivation of AGO2 leads to ectopic expression of nht and downstream spermatogenesis genes. Depletion of either AGO2 or LaminB results in reduced looping interactions within the nht TAD as well as ectopic inter-TAD interactions, as detected by 4C-seq analysis. Overall, our findings reveal coordination of AGO2 and LaminB function to dictate genome architecture and thereby regulate gene expression. PMID- 29529028 TI - Closely related, yet unique: Distinct homo- and heterodimerization patterns of G protein coupled chemokine receptors and their fine-tuning by cholesterol. AB - Chemokine receptors, a subclass of G protein coupled receptors (GPCRs), play essential roles in the human immune system, they are involved in cancer metastasis as well as in HIV-infection. A plethora of studies show that homo- and heterodimers or even higher order oligomers of the chemokine receptors CXCR4, CCR5, and CCR2 modulate receptor function. In addition, membrane cholesterol affects chemokine receptor activity. However, structural information about homo- and heterodimers formed by chemokine receptors and their interplay with cholesterol is limited. Here, we report homo- and heterodimer configurations of the chemokine receptors CXCR4, CCR5, and CCR2 at atomistic detail, as obtained from thousands of molecular dynamics simulations. The observed homodimerization patterns were similar for the closely related CC chemokine receptors, yet they differed significantly between the CC receptors and CXCR4. Despite their high sequence identity, cholesterol modulated the CC homodimer interfaces in a subtype specific manner. Chemokine receptor heterodimers display distinct dimerization patterns for CXCR4/CCR5 and CXCR4/CCR2. Furthermore, associations between CXCR4 and CCR5 reveal an increased cholesterol-sensitivity as compared to CXCR4/CCR2 heterodimerization patterns. This work provides a first comprehensive structural overview over the complex interaction network between chemokine receptors and indicates how heterodimerization and the interaction with the membrane environment diversifies the function of closely related GPCRs. PMID- 29529029 TI - Muller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error. AB - A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic mouse models to demonstrate that Prss56 mutations leading to reduced ocular size and hyperopia act via a loss of function mechanism. Using a conditional gene targeting strategy, we show that PRSS56 derived from Muller glia contributes to ocular growth, implicating a new retinal cell type in ocular size determination. Importantly, we demonstrate that persistent activity of PRSS56 is required during distinct developmental stages spanning the pre- and post-eye opening periods to ensure optimal ocular growth. Thus, our mouse data provide evidence for the existence of a molecule contributing to both the prenatal and postnatal stages of human ocular growth. Finally, we demonstrate that genetic inactivation of Prss56 rescues axial elongation in a mouse model of myopia caused by a null mutation in Egr1. Overall, our findings identify PRSS56 as a potential therapeutic target for modulating ocular growth aimed at preventing or slowing down myopia, which is reaching epidemic proportions. PMID- 29529030 TI - The C-terminal of CASY-1/Calsyntenin regulates GABAergic synaptic transmission at the Caenorhabditis elegans neuromuscular junction. AB - The C. elegans ortholog of mammalian calsyntenins, CASY-1, is an evolutionarily conserved type-I transmembrane protein that is highly enriched in the nervous system. Mammalian calsyntenins are strongly expressed at inhibitory synapses, but their role in synapse development and function is still elusive. Here, we report a crucial role for CASY-1 in regulating GABAergic synaptic transmission at the C. elegans neuromuscular junction (NMJ). The shorter isoforms of CASY-1; CASY-1B and CASY-1C, express and function in GABA motor neurons where they regulate GABA neurotransmission. Using pharmacological, behavioral, electrophysiological, optogenetic and imaging approaches we establish that GABA release is compromised at the NMJ in casy-1 mutants. Further, we demonstrate that CASY-1 is required to modulate the transport of GABAergic synaptic vesicle (SV) precursors through a possible interaction with the SV motor protein, UNC-104/KIF1A. This study proposes a possible evolutionarily conserved model for the regulation of GABA synaptic functioning by calsyntenins. PMID- 29529031 TI - Large-scale profiling of noncoding RNA function in yeast. AB - Noncoding RNAs (ncRNAs) are emerging as key regulators of cellular function. We have exploited the recently developed barcoded ncRNA gene deletion strain collections in the yeast Saccharomyces cerevisiae to investigate the numerous ncRNAs in yeast with no known function. The ncRNA deletion collection contains deletions of tRNAs, snoRNAs, snRNAs, stable unannotated transcripts (SUTs), cryptic unstable transcripts (CUTs) and other annotated ncRNAs encompassing 532 different individual ncRNA deletions. We have profiled the fitness of the diploid heterozygous ncRNA deletion strain collection in six conditions using batch and continuous liquid culture, as well as the haploid ncRNA deletion strain collections arrayed individually onto solid rich media. These analyses revealed many novel environmental-specific haplo-insufficient and haplo-proficient phenotypes providing key information on the importance of each specific ncRNA in every condition. Co-fitness analysis using fitness data from the heterozygous ncRNA deletion strain collection identified two ncRNA groups required for growth during heat stress and nutrient deprivation. The extensive fitness data for each ncRNA deletion strain has been compiled into an easy to navigate database called Yeast ncRNA Analysis (YNCA). By expanding the original ncRNA deletion strain collection we identified four novel essential ncRNAs; SUT527, SUT075, SUT367 and SUT259/691. We defined the effects of each new essential ncRNA on adjacent gene expression in the heterozygote background identifying both repression and induction of nearby genes. Additionally, we discovered a function for SUT527 in the expression, 3' end formation and localization of SEC4, an essential protein coding mRNA. Finally, using plasmid complementation we rescued the SUT075 lethal phenotype revealing that this ncRNA acts in trans. Overall, our findings provide important new insights into the function of ncRNAs. PMID- 29529032 TI - Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians. AB - BACKGROUND: The Human T-Lymphotropic Virus type 1c subtype (HTLV-1c) is highly endemic to central Australia where the most frequent complication of HTLV-1 infection in Indigenous Australians is bronchiectasis. We carried out a prospective study to quantify the prognosis of HTLV-1c infection and chronic lung disease and the risk of death according to the HTLV-1c proviral load (pVL). METHODOLOGY/PRINCIPAL FINDINGS: 840 Indigenous adults (discharge diagnosis of bronchiectasis, 154) were recruited to a hospital-based prospective cohort. Baseline HTLV-1c pVL were determined and the results of chest computed tomography and clinical details reviewed. The odds of an association between HTLV-1 infection and bronchiectasis or bronchitis/bronchiolitis were calculated, and the impact of HTLV-1c pVL on the risk of death was measured. Radiologically defined bronchiectasis and bronchitis/bronchiolitis were significantly more common among HTLV-1-infected subjects (adjusted odds ratio = 2.9; 95% CI, 2.0, 4.3). Median HTLV-1c pVL for subjects with airways inflammation was 16-fold higher than that of asymptomatic subjects. There were 151 deaths during 2,140 person-years of follow-up (maximum follow-up 8.13 years). Mortality rates were higher among subjects with HTLV-1c pVL >=1000 copies per 105 peripheral blood leukocytes (log rank chi2 (2df) = 6.63, p = 0.036) compared to those with lower HTLV-1c pVL or uninfected subjects. Excess mortality was largely due to bronchiectasis-related deaths (adjusted HR 4.31; 95% CI, 1.78, 10.42 versus uninfected). CONCLUSION/SIGNIFICANCE: Higher HTLV-1c pVL was strongly associated with radiologically defined airways inflammation and with death due to complications of bronchiectasis. An increased risk of death due to an HTLV-1 associated inflammatory disease has not been demonstrated previously. Our findings indicate that mortality associated with HTLV-1c infection may be higher than has been previously appreciated. Further prospective studies are needed to determine whether these results can be generalized to other HTLV-1 endemic areas. PMID- 29529033 TI - Characterization of the Mel1c melatoninergic receptor in platypus (Ornithorhynchus anatinus). AB - Melatonin is a neurohormone produced in both animals and plants. It binds at least three G-protein-coupled receptors: MT1 and MT2, and Mel1cGPR. Mammalian GPR50 evolved from the reptilian/avian Mel1c and lost its capacity to bind melatonin in all the therian mammal species that have been tested. In order to determine if binding is lost in the oldest surviving mammalian lineage of monotremes we investigated whether the melatonin receptor has the ability to bind melatonin in the platypus (Ornithorhynchus anatinus), and evaluated its pharmacological profile. Sequence and phylogenetic analysis showed that platypus has in fact retained the ancestral Mel1c and has the capacity to bind melatonin similar to other mammalian melatonin receptors (MT1 and MT2), with an affinity in the 1 nM range. We also investigated the binding of a set of melatoninergic ligands used previously to characterize the molecular pharmacology of the melatonin receptors from sheep, rats, mice, and humans and found that the general profiles of these compounds make Mel1c resemble human MT1 more than MT2. This work shows that the loss of GPR50 binding evolved after the divergence of monotremes less than 190MYA in therian mammals. PMID- 29529034 TI - Gap junction plasticity as a mechanism to regulate network-wide oscillations. AB - Cortical oscillations are thought to be involved in many cognitive functions and processes. Several mechanisms have been proposed to regulate oscillations. One prominent but understudied mechanism is gap junction coupling. Gap junctions are ubiquitous in cortex between GABAergic interneurons. Moreover, recent experiments indicate their strength can be modified in an activity-dependent manner, similar to chemical synapses. We hypothesized that activity-dependent gap junction plasticity acts as a mechanism to regulate oscillations in the cortex. We developed a computational model of gap junction plasticity in a recurrent cortical network based on recent experimental findings. We showed that gap junction plasticity can serve as a homeostatic mechanism for oscillations by maintaining a tight balance between two network states: asynchronous irregular activity and synchronized oscillations. This homeostatic mechanism allows for robust communication between neuronal assemblies through two different mechanisms: transient oscillations and frequency modulation. This implies a direct functional role for gap junction plasticity in information transmission in cortex. PMID- 29529035 TI - Localization of RNA and translation in the mammalian oocyte and embryo. AB - The tight correlation between mRNA distribution and subsequent protein localization and function indicate a major role for mRNA localization within the cell. RNA localization, followed by local translation, presents a mechanism for spatial and temporal gene expression regulation utilized by various cell types. However, little is known about mRNA localization and translation in the mammalian oocyte and early embryo. Importantly, fully-grown oocyte becomes transcriptionally inactive and only utilizes transcripts previously synthesized and stored during earlier development. We discovered an abundant RNA population in the oocyte and early embryo nucleus together with RNA binding proteins. We also characterized specific ribosomal proteins, which contribute to translation in the oocyte and embryo. By applying selected markers to mouse and human oocytes, we found that there might be a similar mechanism of RNA metabolism in both species. In conclusion, we visualized the localization of RNAs and translation machinery in the oocyte, that could shed light on this terra incognita of these unique cell types in mouse and human. PMID- 29529036 TI - Long-term outcome of smear-positive tuberculosis patients after initiation and completion of treatment: A ten-year retrospective cohort study. AB - BACKGROUND: The status of tuberculosis (TB) patients since initiation of treatment is unknown in South Ethiopia. The objective of this study was to assess the long-term outcomes of smear-positive TB patients since initiation and completion of treatment, which includes TB recurrence and mortality of TB patients. METHODS: We did a retrospective cohort study on 2,272 smear-positive TB patients who initiated treatment for TB from September 1, 2002-October 10, 2012 in health facilities in Dale district and Yirgalem town administration. We followed them from the date of start of treatment to either the date of interview or date of death. RESULTS: Recurrence rate of TB was 15.2 per 1000 person-years. Recurrence was higher for re-treatment cases (adjusted hazard ratio (aHR), 2.7; 95% CI, 1.4-5.3). Mortality rate of TB patients was 27.1 per 1,000 person-years. The risk was high for patients above 34 years of age (aHR, 2.1; 95% CI, 1.2-3.9), poor patients (aHR, 1.3; 95% CI, 1.0-1.8), patients with poor treatment outcomes (aHR, 6.7; 95% CI, 5.1-8.9) and for patients treated at least 3 times (aHR 4.8; 95% CI, 2.1-11.1). The excess mortality occurred among patients aged above 34 years was high (41.2/1000 person years). CONCLUSION: High TB recurrence and death of TB patients was observed among our study participants. Follow-up of TB patients with the risk factors and managing them could reduce the TB burden. PMID- 29529037 TI - Relatively slow stochastic gene-state switching in the presence of positive feedback significantly broadens the region of bimodality through stabilizing the uninduced phenotypic state. AB - Within an isogenic population, even in the same extracellular environment, individual cells can exhibit various phenotypic states. The exact role of stochastic gene-state switching regulating the transition among these phenotypic states in a single cell is not fully understood, especially in the presence of positive feedback. Recent high-precision single-cell measurements showed that, at least in bacteria, switching in gene states is slow relative to the typical rates of active transcription and translation. Hence using the lac operon as an archetype, in such a region of operon-state switching, we present a fluctuating rate model for this classical gene regulation module, incorporating the more realistic operon-state switching mechanism that was recently elucidated. We found that the positive feedback mechanism induces bistability (referred to as deterministic bistability), and that the parameter range for its occurrence is significantly broadened by stochastic operon-state switching. We further show that in the absence of positive feedback, operon-state switching must be extremely slow to trigger bistability by itself. However, in the presence of positive feedback, which stabilizes the induced state, the relatively slow operon state switching kinetics within the physiological region are sufficient to stabilize the uninduced state, together generating a broadened parameter region of bistability (referred to as stochastic bistability). We illustrate the opposite phenotype-transition rate dependence upon the operon-state switching rates in the two types of bistability, with the aid of a recently proposed rate formula for fluctuating-rate models. The rate formula also predicts a maximal transition rate in the intermediate region of operon-state switching, which is validated by numerical simulations in our model. Overall, our findings suggest a biological function of transcriptional "variations" among genetically identical cells, for the emergence of bistability and transition between phenotypic states. PMID- 29529039 TI - Technology, attributions, and emotions in post-secondary education: An application of Weiner's attribution theory to academic computing problems. AB - As technology becomes increasingly integrated with education, research on the relationships between students' computing-related emotions and motivation following technological difficulties is critical to improving learning experiences. Following from Weiner's (2010) attribution theory of achievement motivation, the present research examined relationships between causal attributions and emotions concerning academic computing difficulties in two studies. Study samples consisted of North American university students enrolled in both traditional and online universities (total N = 559) who responded to either hypothetical scenarios or experimental manipulations involving technological challenges experienced in academic settings. Findings from Study 1 showed stable and external attributions to be emotionally maladaptive (more helplessness, boredom, guilt), particularly in response to unexpected computing problems. Additionally, Study 2 found stable attributions for unexpected problems to predict more anxiety for traditional students, with both external and personally controllable attributions for minor problems proving emotionally beneficial for students in online degree programs (more hope, less anxiety). Overall, hypothesized negative effects of stable attributions were observed across both studies, with mixed results for personally controllable attributions and unanticipated emotional benefits of external attributions for academic computing problems warranting further study. PMID- 29529038 TI - The complete chloroplast genome sequence of Epipremnum aureum and its comparative analysis among eight Araceae species. AB - Epipremnum aureum is an important foliage plant in the Araceae family. In this study, we have sequenced the complete chloroplast genome of E. aureum by using Illumina Hiseq sequencing platforms. This genome is a double-stranded circular DNA sequence of 164,831 bp that contains 35.8% GC. The two inverted repeats (IRa and IRb; 26,606 bp) are spaced by a small single-copy region (22,868 bp) and a large single-copy region (88,751 bp). The chloroplast genome has 131 (113 unique) functional genes, including 86 (79 unique) protein-coding genes, 37 (30 unique) tRNA genes, and eight (four unique) rRNA genes. Tandem repeats comprise the majority of the 43 long repetitive sequences. In addition, 111 simple sequence repeats are present, with mononucleotides being the most common type and di- and tetranucleotides being infrequent events. Positive selection pressure on rps12 in the E. aureum chloroplast has been demonstrated via synonymous and nonsynonymous substitution rates and selection pressure sites analyses. Ycf15 and infA are pseudogenes in this species. We constructed a Maximum Likelihood phylogenetic tree based on the complete chloroplast genomes of 38 species from 13 families. Those results strongly indicated that E. aureum is positioned as the sister of Colocasia esculenta within the Araceae family. This work may provide information for further study of the molecular phylogenetic relationships within Araceae, as well as molecular markers and breeding novel varieties by chloroplast genetic transformation of E. aureum in particular. PMID- 29529040 TI - Sharing-based social capital associated with harvest production and wealth in the Canadian Arctic. AB - Social institutions that facilitate sharing and redistribution may help mitigate the impact of resource shocks. In the North American Arctic, traditional food sharing may direct food to those who need it and provide a form of natural insurance against temporal variability in hunting returns within households. Here, network properties that facilitate resource flow (network size, quality, and density) are examined in a country food sharing network comprising 109 Inuit households from a village in Nunavik (Canada), using regressions to investigate the relationships between these network measures and household socioeconomic attributes. The results show that although single women and elders have larger networks, the sharing network is not structured to prioritize sharing towards households with low food availability. Rather, much food sharing appears to be driven by reciprocity between high-harvest households, meaning that poor, low harvest households tend to have less sharing-based social capital than more affluent, high-harvest households. This suggests that poor, low-harvest households may be more vulnerable to disruptions in the availability of country food. PMID- 29529041 TI - Metabolomic and inflammatory mediator based biomarker profiling as a potential novel method to aid pediatric appendicitis identification. AB - Various limitations hinder the timely and accurate diagnosis of appendicitis in pediatric patients. The present study aims to investigate the potential of metabolomics and cytokine profiling for improving the diagnosis of pediatric appendicitis. Serum and plasma samples were collected from pediatric patients for metabolic and inflammatory mediator analyses respectively. Targeted metabolic profiling was performed using Proton Nuclear Magnetic Resonance Spectroscopy and Flow Injection Analysis Mass Spectrometry/Mass Spectrometry and targeted cytokine/chemokine profiling was completed using a multiplex platform to compare children with and without appendicitis. Twenty-three children with appendicitis and 35 control children without appendicitis from the Alberta Sepsis Network pediatric cohorts were included. Metabolomic profiling revealed clear separation between the two groups with very good sensitivity (80%), specificity (97%), and AUROC (0.93 +/- 0.05) values. Inflammatory mediator analysis also distinguished the two groups with high sensitivity (82%), specificity (100%), and AUROC (0.97 +/- 0.02) values. A biopattern comprised of 9 metabolites and 7 inflammatory compounds was detected to be significant for the separation between appendicitis and control groups. Integration of these 16 significant compounds resulted in a combined metabolic and cytokine profile that also demonstrated strong separation between the two groups with 81% sensitivity, 100% specificity and AUROC value of 0.96 +/- 0.03. The study demonstrated that metabolomics and cytokine mediator profiling is capable of distinguishing children with appendicitis from those without. These results suggest a potential new approach for improving the identification of appendicitis in children. PMID- 29529042 TI - Protease signaling through protease activated receptor 1 mediate nerve activation by mucosal supernatants from irritable bowel syndrome but not from ulcerative colitis patients. AB - BACKGROUND & AIMS: The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC). METHOD: Effects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques. We identify differentially expressed proteins with proteome analysis. RESULTS: Nerve activation by IBS supernatants was prevented by the protease activated receptor 1 (PAR1) antagonist SCHE79797. UC supernatants also activated enteric neurons through protease dependent mechanisms but without PAR1 involvement. Proteome analysis of the supernatants identified 204 proteins, among them 17 proteases as differentially expressed between IBS, UC and HC. Of those the four proteases elastase 3a, chymotrypsin C, proteasome subunit type beta-2 and an unspecified isoform of complement C3 were significantly more abundant in IBS compared to HC and UC supernatants. Of eight proteases, which were upregulated in IBS, the combination of elastase 3a, cathepsin L and proteasome alpha subunit-4 showed the highest prediction accuracy of 98% to discriminate between IBS and HC groups. Elastase synergistically potentiated the effects of histamine and serotonin-the two other main neuroactive substances in the IBS supernatants. A serine protease inhibitor isolated from the probiotic Bifidobacterium longum NCC2705 (SERPINBL), known to inhibit elastase like proteases, prevented nerve activation by IBS supernatants. CONCLUSION: Proteases in IBS and UC supernatants were responsible for nerve activation. Our data demonstrate that proteases, particularly those signalling through neuronal PAR1, are biomarker candidates for IBS, and protease profiling may be used to characterise IBS. PMID- 29529043 TI - Controlled branched-chain amino acids auxotrophy in Listeria monocytogenes allows isoleucine to serve as a host signal and virulence effector. AB - Listeria monocytogenes (Lm) is a saprophyte and intracellular pathogen. Transition to the pathogenic state relies on sensing of host-derived metabolites, yet it remains unclear how these are recognized and how they mediate virulence gene regulation. We previously found that low availability of isoleucine signals Lm to activate the virulent state. This response is dependent on CodY, a global regulator and isoleucine sensor. Isoleucine-bound CodY represses metabolic pathways including branched-chain amino acids (BCAA) biosynthesis, however under BCAA depletion, as occurs during infection, BCAA biosynthesis is upregulated and isoleucine-unbound CodY activates virulence genes. While isoleucine was revealed as an important input signal, it was not identified how internal levels are controlled during infection. Here we show that Lm regulates BCAA biosynthesis via CodY and via a riboregulator located upstream to the BCAA biosynthesis genes, named Rli60. rli60 is transcribed when BCAA levels drop, forming a ribosome mediated attenuator that cis-regulates the downstream genes according to BCAA supply. Notably, we found that Rli60 restricts BCAA production, essentially starving Lm, a mechanism that is directly linked to virulence, as it controls the internal isoleucine pool and thereby CodY activity. This controlled BCAA auxotrophy likely evolved to enable isoleucine to serve as a host signal and virulence effector. PMID- 29529044 TI - WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis. AB - A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations. Variants were detected in 15 probands (2.5%) in 602 families with presumably autosomal dominant or mitochondrial HL, and in four probands (0.7%) in 559 sporadic cases; however, no variants were detected in the other 1,388 probands with autosomal recessive or unknown family history. Among the 30 individuals possessing variants, marked variations were observed in the onset of HL as well as in the presence of progressive HL and tinnitus. Vestibular symptoms, which had been rarely reported, were present in 7 out of 30 (23%) of the affected individuals. The most prevalent audiometric configuration was low-frequency type; however, some individuals had high frequency HL. Haplotype analysis in three mutations (p.A716T, p.K836T, and p.E864K) suggested that the mutations occurred at these mutation hot spots. The present study provided new insights into the audiovestibular phenotypes in patients with WFS1 mutations. PMID- 29529045 TI - Psychometric properties of the Sexual Excitation/Sexual Inhibition Inventory for Women and Men (SESII-W/M) and the Sexual Excitation Scales/Sexual Inhibition Scales short form (SIS/SES-SF) in a population-based sample in Germany. AB - The Sexual Excitation Sexual/Inhibition Inventory for Women and Men (SESII-W/M) and the Sexual Excitation Scales/Sexual Inhibition Scales short form (SIS/SES-SF) are two self-report questionnaires for assessing sexual excitation (SE) and sexual inhibition (SI). According to the dual control model of sexual response, SE and SI differ between individuals and influence the occurrence of sexual arousal in given situations. Extreme levels of SE and SI are postulated to be associated with sexual difficulties or risky sexual behaviors. The present study was designed to assess the psychometric properties of the German versions of both questionnaires utilizing a large population-based sample of 2,708 participants (Mage = 51.19, SD = 14.03). Overall, psychometric evaluation of the two instruments yielded good convergent and discriminant validity and mediocre to good internal consistency. The original 30-item version of the SESII-W/M did not show a sufficient model fit. For a 24-item version of the SESII-W/M partial strong measurement invariance across gender, and strong measurement invariance across relationship status, age, and educational levels were established. The original structure (14 items, 3 factors) of the SIS/SES-SF was not replicated. However, a 4-factor model including 13 items showed a good model fit and strong measurement invariance across the before-mentioned participant groups. For both questionnaires, partial strong measurement invariance with the original American versions of the scales was found. As some factors showed unsatisfactory internal consistency and the factor structure of the original scales could not be replicated, scores on several SE- and SI-factors should be interpreted with caution. However, most analyses indicated sufficient psychometric quality of the German SESII-W/M and SIS/SES-SF and their use can be recommended in German speaking samples. More research with diverse samples (i.e., different sexual orientations, individuals with sexual difficulties) is needed to ensure the replicability of the factor solutions presented in this study. PMID- 29529046 TI - Zinc transporters belonging to the Cation Diffusion Facilitator (CDF) family have complementary roles in transporting zinc out of the cytosol. AB - Zinc is an essential trace element that is required for the function of a large number of proteins. As these zinc-binding proteins are found within the cytosol and organelles, all eukaryotes require mechanisms to ensure that zinc is delivered to organelles, even under conditions of zinc deficiency. Although many zinc transporters belonging to the Cation Diffusion Facilitator (CDF) families have well characterized roles in transporting zinc into the lumens of intracellular compartments, relatively little is known about the mechanisms that maintain organelle zinc homeostasis. The fission yeast Schizosaccharomyces pombe is a useful model system to study organelle zinc homeostasis as it expresses three CDF family members that transport zinc out of the cytosol into intracellular compartments: Zhf1, Cis4, and Zrg17. Zhf1 transports zinc into the endoplasmic reticulum, and Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. Here we have used the high and low affinity ZapCY zinc-responsive FRET sensors to examine cytosolic zinc levels in yeast mutants that lack each of these CDF proteins. We find that deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency, whereas deletion of zhf1 results in zinc accumulating in the cytosol when zinc is not limiting. We also show that the expression of cis4, zrg17, and zhf1 is independent of cellular zinc status. Taken together our results suggest that the Cis4/Zrg17 complex is necessary for zinc transport out of the cytosol under conditions of zinc-deficiency, while Zhf1 plays the dominant role in removing zinc from the cytosol when labile zinc is present. We propose that the properties and/or activities of individual CDF family members are fine tuned to enable cells to control the flux of zinc out of the cytosol over a broad range of environmental zinc stress. PMID- 29529047 TI - High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing. AB - The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements. PMID- 29529049 TI - Population well-being and electoral shifts. AB - Population wellbeing, an aggregate measure of positive mental, physical, and emotional health, has previously been used as a marker of community thriving. We examined whether several community measures of wellbeing, and their change since 2012, could be used to understand electoral changes that led to the outcome of the 2016 United States presidential election. We found that areas of the US which had the largest shifts away from the incumbent party had both lower wellbeing and greater drops in wellbeing when compared with areas that did not shift. In comparison, changes in income were not related to voting shifts. Well-being may be more useful in predicting and understanding electoral outcomes than some more conventional voting determinants. PMID- 29529048 TI - Swimming pool exposure is associated with autonomic changes and increased airway reactivity to a beta-2 agonist in school aged children: A cross-sectional survey. AB - BACKGROUND: Endurance swimming exercises coupled to disinfection by-products exposure has been associated with increased airways dysfunction and neurogenic inflammation in elite swimmers. However, the impact of swimming pool exposure at a recreational level on autonomic activity has never been explored. Therefore, this study aimed to investigate how swimming pool attendance is influencing lung and autonomic function in school-aged children. METHODS: A total of 858 children enrolled a cross sectional survey. Spirometry and airway reversibility to beta-2 agonist, skin-prick-tests and exhaled nitric oxide measurements were performed. Pupillometry was used to evaluate autonomic nervous function. Children were classified as current swimmers (CS), past swimmers (PS) and non-swimmers (NS), according to the amount of swimming practice. RESULTS: Current swimmers group had significantly lower maximum and average pupil constriction velocities when compared to both PS and NS groups (3.8 and 5.1 vs 3.9 and 5.3 vs 4.0 and 5.4 mm/s, p = 0.03 and p = 0.01, respectively). Moreover, affinity to the beta-2 agonist and levels of exhaled nitric oxide were significantly higher in CS when compared to NS (70 vs 60 mL and 12 vs 10 ppb, p<0.01 and p = 0.03, respectively). A non-significant trend for a higher risk of asthma, atopic eczema and allergic rhinitis was found with more years of swimming practice, particularly in atopic individuals (beta = 1.12, 1.40 and 1.31, respectively). After case-case analysis, it was possible to observe that results were not influenced by the inclusion of individuals with asthma. CONCLUSIONS: Concluding, swimming pool attendance appears to be associated with autonomic changes and increased baseline airway smooth muscle constriction even in children without asthma. PMID- 29529050 TI - Transmembrane protease, serine 4 (TMPRSS4) is upregulated in IPF lungs and increases the fibrotic response in bleomycin-induced lung injury. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by epithelial cell activation, expansion of the fibroblast population and excessive extracellular matrix accumulation. The mechanisms are incompletely understood but evidence indicates that the deregulation of several proteases contributes to its pathogenesis. Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that may promote migration and facilitate epithelial to mesenchymal transition (EMT), two critical processes in the pathogenesis of IPF. Thus, we hypothesized that over-expression of TMPRSS4 in the lung could promote the initiation and/or progression of IPF. In this study we first evaluated the expression and localization of TMPRSS4 in IPF lungs by real time PCR, western blot and immunohistochemistry. Then we examined the lung fibrotic response in wild-type and TMPRSS4 deficient mice using the bleomycin-induced lung injury model. We found that this protease is upregulated in IPF lungs, where was primarily expressed by epithelial and mast cells. Paralleling the findings in vivo, TMPRSS4 was expressed by alveolar and bronchial epithelial cells in vitro and unexpectedly, provoked an increase of E-cadherin. No expression was observed in normal human or IPF lung fibroblasts. The lung fibrotic response evaluated at 28 days after bleomycin injury was markedly attenuated in the haplodeficient and deficient TMPRSS4 mice. By morphology, a significant reduction of the fibrotic index was observed in KO and heterozygous mice which was confirmed by measurement of collagen content (hydroxyproline: WT: 164+/-21.1 MUg/lung versus TMPRSS4 haploinsufficient: 110.2+/-14.3 MUg/lung and TMPRSS4 deficient mice: 114.1+/-24.2 MUg/lung (p<0.01). As in IPF, TMPRSS4 was also expressed in epithelial and mast cells. These findings indicate that TMPRSS4 is upregulated in IPF lungs and that may have a profibrotic role. PMID- 29529051 TI - Comprehensive analysis of small RNAs expressed in developing male strobili of Cryptomeria japonica. AB - Deep sequencing of small RNAs (sRNAs) in developing male strobili of second generation offspring originating from a nuclear genic male sterile tree of Cryptomeria japonica were performed to characterize sRNA populations in the male strobili at early pollen developmental stages. Comparing to sequences of microRNA (miRNA) families of plant species and sRNAs expressed in the reproductive organs of representative vascular plants, 37 conserved miRNA families were detected, of which eight were ubiquitously expressed in the reproductive organs of land plant species. In contrast, miR1083 was common in male reproductive organs of gymnosperm species but absent in angiosperm species. In addition to conserved miRNAs, 199 novel miRNAs candidates were predicted. The expression patterns of the obtained sRNAs were further investigated to detect the differentially expressed (DE) sRNAs between genic male sterile and fertile individuals. A total of 969 DE sRNAs were obtained and only three known miRNA families were included among them. These results suggest that both conserved and species-specific sRNAs contribute to the development of male strobili in C. japonica. PMID- 29529052 TI - Jointly learning word embeddings using a corpus and a knowledge base. AB - Methods for representing the meaning of words in vector spaces purely using the information distributed in text corpora have proved to be very valuable in various text mining and natural language processing (NLP) tasks. However, these methods still disregard the valuable semantic relational structure between words in co-occurring contexts. These beneficial semantic relational structures are contained in manually-created knowledge bases (KBs) such as ontologies and semantic lexicons, where the meanings of words are represented by defining the various relationships that exist among those words. We combine the knowledge in both a corpus and a KB to learn better word embeddings. Specifically, we propose a joint word representation learning method that uses the knowledge in the KBs, and simultaneously predicts the co-occurrences of two words in a corpus context. In particular, we use the corpus to define our objective function subject to the relational constrains derived from the KB. We further utilise the corpus co occurrence statistics to propose two novel approaches, Nearest Neighbour Expansion (NNE) and Hedged Nearest Neighbour Expansion (HNE), that dynamically expand the KB and therefore derive more constraints that guide the optimisation process. Our experimental results over a wide-range of benchmark tasks demonstrate that the proposed method statistically significantly improves the accuracy of the word embeddings learnt. It outperforms a corpus-only baseline and reports an improvement of a number of previously proposed methods that incorporate corpora and KBs in both semantic similarity prediction and word analogy detection tasks. PMID- 29529053 TI - The impact of cognateness of word bases and suffixes on morpho-orthographic processing: A masked priming study with intermediate and high-proficiency Portuguese-English bilinguals. AB - Recent studies have suggested that proficient bilinguals show morphological decomposition in the L2, but the question remains as to whether this process is modulated by the cognateness of the morphemic constituents of L2 words and by L2 proficiency. To answer this question was the main goal of the present research. For that purpose, a masked priming lexical decision task was conducted manipulating for the first time the degree of orthographic overlap of the L2 word as a whole, as well as of their morphemic constituents (bases and suffixes). Thirty-four European Portuguese-English bilinguals (16 intermediate and 18 high proficient) and 16 English native-speaking controls performed the task in English. Results revealed that both groups of bilinguals decomposed words as the native control group. Importantly, results also showed that morphological priming effects were sensitive not only to cross-language similarities of words as a whole, but also to their morphemic constituents (especially, suffixes). PMID- 29529054 TI - Selection and validation of reference genes for quantitative gene expression analyses in black locust (Robinia pseudoacacia L.) using real-time quantitative PCR. AB - Black locust (Robinia pseudoacacia L.) is an easy to raise, fast growing, medium sized deciduous tree species highly tolerant to harsh eco-conditions, i.e., drought and harsh winters, and it is widely adaptable to sandy, loamy, and marshy soils. The basis for this adaptability remains to be investigated at the transcriptomic level using real-time quantitative PCR (qPCR). Selection of a reliable gene for the normalization of qPCR data is important for obtaining accurate results in gene expression. The goal of this study was to identify an appropriate reference gene from 12 candidate genes for gene expression analysis in black locust exposed to various stressors such as abscisic acid (ABA), NaCl, polyethylene glycol (PEG) and varying temperatures. In GeNorm and NormFinder analyses, ACT (actin) and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) gene expression were the most stable in all conditions except heat stress, but in BestKeeper analysis, GAPDH and helicase gene expression were the most stable under NaCl and heat stress. In contrast, ACT and GAPDH were highest under abscisic acid (ABA), GAPDH and betaTUB (beta tubulin) under cold stress, and helicase and EF1alpha (elongation factor 1 alpha) under PEG stress. We found that the most stable reference gene combination for all conditions was ACT and GAPDH. Additionally, the expression pattern of NAC2 (a transcription factor) and BGL2 in different tissues and under different stress conditions was analyzed relative to ACT and GAPDH and UBQ (ubiquitin) the least stably expressed gene. NAC2 and BGL2 both had highest expression in flowers and pods under ABA stress at 48h. This study provides useful reference genes for future gene expression studies in black locust. PMID- 29529055 TI - Influence of dialysis membrane composition on plasma bisphenol A levels during online hemodiafiltration. AB - INTRODUCTION: Bisphenol A (BPA) is an ubiquitous environmental toxin that is also found in dialyzers. Online hemodiafiltration (OL-HDF) more efficiently clears high molecular weight molecules, and this may improve BPA clearance. However, the BPA contents of dialysis membranes may be a source of BPA loading during OL-HDF. METHODS: A prospective study assessed plasma BPA levels in OL-HDF patients using BPA-free (polynephron) or BPA-containing (polysulfone) dialyzers in a crossover design with two arms, after a run-in OL-HDF period of at least 6 months with the same membrane: 31 patients on polynephron at baseline were switched to polysulfone membranes for 3 months (polynephron-to-polysulfone) and 29 patients on polysulfone were switched to polynephron for 3 months (polysulfone-to polynephron). RESULTS: After a run-in OL-HDF period of at least 6 months with the same membrane, baseline pre-dialysis BPA was lower in patients on polynephron (8.79+/-7.97 ng/ml) than in those on polysulfone (23.42+/-20.38 ng/mL, p<0.01), but still higher than in healthy controls (<2 ng/mL). After 3 months of polynephron-to-polysulfone switch, BPA was unchanged (8.98+/-7.88 to 11.14+/ 15.98 ng/mL, ns) while it decreased on the polysulfone-to-polynephron group (23.42+/-20.38 to 11.41+/-12.38 ng/mL, p<0.01). CONCLUSION: OL-HDF for 3 months with BPA-free dialyzer membranes was associated to a significant decrease in predialysis BPA levels when compared to baseline BPA levels while on a BPA containing membrane. PMID- 29529056 TI - Epidemiological and histological findings implicate matrix Gla protein in diastolic left ventricular dysfunction. AB - OBJECTIVES: A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure-a measure of diastolic LV dysfunction increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp ucMGP). We also studied the distribution of active and inactive MGP in human myocardium. METHODS: We measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss. RESULTS: Among Flemish and Swiss, E/e' (6.78 vs. 6.73) and dp-ucMGP (3.94 MUg/L vs. 4.20 MUg/L) were similarly distributed. In multivariable-adjusted models, for each doubling of dp-ucMGP, E/e' increased by 0.26, 0.33 and 0.31 in Flemish, Swiss and both cohorts combined (P<=0.026); the odds ratios for having E/e' >= 8.5 were 1.99, 3.29 and 2.36, respectively (P<=0.017). Cardiac biopsies from patients with ischemic or dilated cardiomyopathy and healthy hearts (n = 4 for each) were stained with conformation-specific MGP antibodies. In diseased compared with normal hearts, uncarboxylated inactive MGP was more prevalent (P<=0.004) in the perivascular matrix and interstitium (204.4 vs. 8.6 MUm2 per field) and phosphorylated active MGP in and around capillaries and interstitial cells (31.3 vs. 6.6 number of positive capillaries and cells per field). CONCLUSIONS: Our study supports a role of activated MGP in maintaining myocardial integrity and diastolic LV performance and can potentially be translated into new strategies for managing diastolic LV dysfunction and preventing its progression to heart failure. PMID- 29529057 TI - Changes in stroke risk by freedom-from-stroke time in simulated populations with atrial fibrillation: Freedom-from-event effect when event itself is a risk factor. AB - The risk of atrial fibrillation (AF)-related stroke is usually assessed by calculating the CHA2DS2-VASc score, the components of which are various risk factors, including prior stroke. Although prior stroke is considered the strongest risk factor, the associated risk is actually inferred. Nevertheless, it implies a "freedom-from-event effect" (FEE)-the longer a patient is stroke-free, the lower the stroke risk. Although dynamic prognostication has been applied to cancer, the FEE has been ignored in AF, probably because of methodological difficulties. We conducted a simulation study to evaluate the FEE in the risk of AF-related stroke. We modeled various populations of AF patients and simulated the development of stroke assuming a nonhomogeneous Poisson process, where the hazard depends on age, comorbidities, and individual variability. Parameters were set so that the model respects the CHA2DS2-VASc scoring scheme and reproduces the 1-year CHA2DS2-VASc score-wise stroke risk and relative risk conferred by real world risk factors. We tracked stroke risk over 0 to 15 years of freedom-from stroke time (FST), both prospective FST (pFST), which begins at the time of diagnosis and continues to the future, and retrospective FST (rFST), which begins at the present and looks backward to the time of diagnosis. The pFST counterbalanced the increase in stroke risk conferred by aging; in patients with a CHA2DS2-VASc score of 1, the pFST offset 62% of the age-conferred risk increase. The rFST reduced the stroke risk; in patients with a CHA2DS2-VASc score of 2 and without prior stroke, an rFST of 6.8 years reduced the stroke risk to the midpoint between CHA2DS2-VASc scores 1 and 2. The study results suggest that the FEE should be considered in evaluating stroke risk in patients with AF. The FEE may be important in other recurrent diseases for which a prior event is a risk factor for a future event. PMID- 29529058 TI - Correction: Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006753.]. PMID- 29529060 TI - Retraction: Angiopoietin-Like 4 Confers Resistance to Hypoxia/Serum Deprivation Induced Apoptosis through PI3K/Akt and ERK1/2 Signaling Pathways in Mesenchymal Stem Cells. PMID- 29529059 TI - Investigating the modulation of genetic effects on late AMD by age and sex: Lessons learned and two additional loci. AB - Late-stage age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly with a complex etiology. The most important non modifiable risk factors for onset and progression of late AMD are age and genetic risk factors, however, little is known about the interplay between genetics and age or sex. Here, we conducted a large-scale age- and sex-stratified genome-wide association study (GWAS) using 1000 Genomes imputed genome-wide and ExomeChip data (>12 million variants). The data were established by the International Age related Macular Degeneration Genomics Consortium (IAMDGC) from 16,144 late AMD cases and 17,832 controls. Our systematic search for interaction effects yielded significantly stronger effects among younger individuals at two known AMD loci (near CFH and ARMS2/HTRA1). Accounting for age and gene-age interaction using a joint test identified two additional AMD loci compared to the previous main effect scan. One of these two is a novel AMD GWAS locus, near the retinal clusterin-like protein (CLUL1) gene, and the other, near the retinaldehyde binding protein 1 (RLBP1), was recently identified in a joint analysis of nuclear and mitochondrial variants. Despite considerable power in our data, neither sex dependent effects nor effects with opposite directions between younger and older individuals were observed. This is the first genome-wide interaction study to incorporate age, sex and their interaction with genetic effects for late AMD. Results diminish the potential for a role of sex in the etiology of late AMD yet highlight the importance and existence of age-dependent genetic effects. PMID- 29529061 TI - Profiling DNA methylation differences between inbred mouse strains on the Illumina Human Infinium MethylationEPIC microarray. AB - The Illumina Infinium MethylationEPIC provides an efficient platform for profiling DNA methylation in humans at over 850,000 CpGs. Model organisms such as mice do not currently benefit from an equivalent array. Here we used this array to measure DNA methylation in mice. We defined probes targeting conserved regions and performed differential methylation analysis and compared between the array based assay and affinity-based DNA sequencing of methyl-CpGs (MBD-seq) and reduced representation bisulfite sequencing. Mouse samples consisted of 11 liver DNA from two strains, C57BL/6J (B6) and DBA/2J (D2), that varied widely in age. Linear regression was applied to detect differential methylation. In total, 13,665 probes (1.6% of total probes) aligned to conserved CpGs. Beta-values (beta value) for these probes showed a distribution similar to that in humans. Overall, there was high concordance in methylation signal between the EPIC array and MBD seq (Pearson correlation r = 0.70, p-value < 0.0001). However, the EPIC probes had higher quantitative sensitivity at CpGs that are hypo- (beta-value < 0.3) or hypermethylated (beta-value > 0.7). In terms of differential methylation, no EPIC probe detected a significant difference between age groups at a Benjamini Hochberg threshold of 10%, and the MBD-seq performed better at detecting age dependent change in methylation. However, the top most significant probe for age (cg13269407; uncorrected p-value = 1.8 x 10-5) is part of the clock CpGs used to estimate the human epigenetic age. For strain, 219 EPIC probes detected significant differential methylation (FDR cutoff 10%) with ~80% CpGs associated with higher methylation in D2. This higher methylation profile in D2 compared to B6 was also replicated by the MBD-seq data. To summarize, we found only a small subset of EPIC probes that target conserved sites. However, for this small subset the array provides a reliable assay of DNA methylation and can be effectively used to measure differential methylation in mice. PMID- 29529062 TI - Across-subjects classification of stimulus modality from human MEG high frequency activity. AB - Single-trial analyses have the potential to uncover meaningful brain dynamics that are obscured when averaging across trials. However, low signal-to-noise ratio (SNR) can impede the use of single-trial analyses and decoding methods. In this study, we investigate the applicability of a single-trial approach to decode stimulus modality from magnetoencephalographic (MEG) high frequency activity. In order to classify the auditory versus visual presentation of words, we combine beamformer source reconstruction with the random forest classification method. To enable group level inference, the classification is embedded in an across subjects framework. We show that single-trial gamma SNR allows for good classification performance (accuracy across subjects: 66.44%). This implies that the characteristics of high frequency activity have a high consistency across trials and subjects. The random forest classifier assigned informational value to activity in both auditory and visual cortex with high spatial specificity. Across time, gamma power was most informative during stimulus presentation. Among all frequency bands, the 75 Hz to 95 Hz band was the most informative frequency band in visual as well as in auditory areas. Especially in visual areas, a broad range of gamma frequencies (55 Hz to 125 Hz) contributed to the successful classification. Thus, we demonstrate the feasibility of single-trial approaches for decoding the stimulus modality across subjects from high frequency activity and describe the discriminative gamma activity in time, frequency, and space. PMID- 29529063 TI - Type 1 diabetes care: Improvement by standardization in a diabetes rehabilitation clinic. An observational report. AB - BACKGROUND: T1D treatment requires informed self-responsible patients, who, however, frequently miss their therapeutic goals, providing considerable potential for improvement. METHODS: This observational report evaluates T1D patients [N = 109], aged >=18 years (range 22-82), poorly controlled at home, at and 3 weeks after their admission to our diabetes rehabilitation clinic [DRC], where they were offered standardized, but unmonitored life-style modification. RESULTS: At admission, patients displayed elevated HbA1c values (66 mmol/mol [57; 81]), a high prevalence of co-morbidities (88%), lipodystrophies due to monolocal insulin injections (42%), a low rate of influenza (16%) and pneumococcal (7%) immunization, and underuse of lipid-lowering drugs (-38%). Standardization of life-style improved glucose (p<0.0001) and lipid metabolism (LDL/HDL ratio p<0.01) permitting reduction of insulin dose and reduction of add-on glucose lowering drugs (GLDs) other than metformin. Outcome was independent of the mode of insulin treatment strategy and more marked at initially high HbA1c, with DRC costs/d less than 25% of those encountered at standard hospitals. CONCLUSION: Type 1 diabetes care requires i) insulin treatment, food intake and life style to be handled in concert, ii) this need cannot be replaced by arbitrary addition of add-on GLDs, and iii) training to this end is 75% cheaper at a DRC than in standard hospitals. PMID- 29529064 TI - Evaluation of the Leap Motion Controller during the performance of visually guided upper limb movements. AB - Kinematic analysis of upper limb reaching provides insight into the central nervous system control of movements. Until recently, kinematic examination of motor control has been limited to studies conducted in traditional research laboratories because motion capture equipment used for data collection is not easily portable and expensive. A recently developed markerless system, the Leap Motion Controller (LMC), is a portable and inexpensive tracking device that allows recording of 3D hand and finger position. The main goal of this study was to assess the concurrent reliability and validity of the LMC as compared to the Optotrak, a criterion-standard motion capture system, for measures of temporal accuracy and peak velocity during the performance of upper limb, visually-guided movements. In experiment 1, 14 participants executed aiming movements to visual targets presented on a computer monitor. Bland-Altman analysis was conducted to assess the validity and limits of agreement for measures of temporal accuracy (movement time, duration of deceleration interval), peak velocity, and spatial accuracy (endpoint accuracy). In addition, a one-sample t-test was used to test the hypothesis that the error difference between measures obtained from Optotrak and LMC is zero. In experiment 2, 15 participants performed a Fitts' type aiming task in order to assess whether the LMC is capable of assessing a well-known speed-accuracy trade-off relationship. Experiment 3 assessed the temporal coordination pattern during the performance of a sequence consisting of a reaching, grasping, and placement task in 15 participants. Results from the t test showed that the error difference in temporal measures was significantly different from zero. Based on the results from the 3 experiments, the average temporal error in movement time was 40+/-44 ms, and the error in peak velocity was 0.024+/-0.103 m/s. The limits of agreement between the LMC and Optotrak for spatial accuracy measures ranged between 2-5 cm. Although the LMC system is a low cost, highly portable system, which could facilitate collection of kinematic data outside of the traditional laboratory settings, the temporal and spatial errors may limit the use of the device in some settings. PMID- 29529065 TI - "Letting myself go forward past wrongs": How regulatory modes affect self forgiveness. AB - The present research addresses the question of whether regulatory-mode orientations affect self-forgiveness. We expected that people with a strong locomotion orientation would be more inclined to self-forgiveness because of their tendencies toward movement and change, which focus them on the future, whereas people with a strong assessment orientation would refrain from self forgiveness due to their evaluative tendencies which focus them on the past. These hypotheses were supported by the results in four studies that tested the relation between regulatory modes and self-forgiveness by measuring (Studies 1, 3 and 4) and manipulating (Study 2) regulatory-mode-orientations. Finally, in Study 4 we examined more closely our hypothesis that the relation between self forgiveness and regulatory modes is mediated by past and future temporal foci. The implications of the results for regulatory mode theory are also discussed. PMID- 29529066 TI - Type 2 diabetes prevalence and its risk factors in HIV: A cross-sectional study. AB - BACKGROUND: Type 2 diabetes (T2D) has a reported greater prevalence and poorer treatment outcomes in people living with HIV (PLWH) than comparable HIV uninfected cohorts. We conducted a cross-sectional study to delineate the factors driving T2D in PLWH in an ethnically diverse cohort, and additionally observed how these have changed over time. SETTING: We studied a diverse HIV cohort in London to determine the prevalence and risk factors for T2D, and compared them to a cohort studied 10 years previously. METHODS: Patients were classified as normoglycaemic (fasting glucose <6.0 mmol/l) or dysglycaemic (>=6.0 mmol/l). The relative contribution to dysglycaemia of modifiable and fixed factors, including demographics, anthropometrics, comorbidities, immune status, and HIV therapy, were analysed using univariate and logistic regression analyses. RESULTS: T2D prevalence was 15.1% in 2015 with a relative risk of 2.4 compared to the general population. The prevalence compared to 6.8% ten years earlier. The 2015 versus the 2005 cohort was significantly older (median age 49 (42-57) years versus 41 (IQR 35-47), p<0.001), had a higher BMI (27.4 (23.3-29.9) versus 24.9 (22.4-28.0) kg/m2 respectively, p = 0.019) and hypertensive (37.9% versus 19.6 respectively, p<0.001). The strongest predictors of dysglycaemia in the 2015 cohort were hepatic steatosis and hypertension, odds ratios (OR) and 95% confidence intervals (CI) 6.74 (3.48-13.03) and 2.92 (1.66-5.16) respectively, and also HIV-related factors of weight gain following antiretroviral initiation and longer known duration of HIV infection (OR 1.07 (1.04-1.11) and 1.06 (1.02-1.10) respectively). CONCLUSIONS: The alarmingly high prevalence of T2D in HIV requires improved screening, targeted to older patients and those with a longer duration of exposure to antiretrovirals. Effective diabetes prevention and management strategies are needed urgently to reduce this risk; such interventions should target both conventional risk factors, such as abdominal obesity, and HIV specific risk factors such as weight gain following initiation of antiretrovirals. PMID- 29529068 TI - Correction: Gaussian decomposition of high-resolution melt curve derivatives for measuring genome-editing efficiency. AB - [This corrects the article DOI: 10.1371/journal.pone.0190192.]. PMID- 29529067 TI - Targeted release of stromal cell-derived factor-1alpha by reactive oxygen species sensitive nanoparticles results in bone marrow stromal cell chemotaxis and homing, and repair of vascular injury caused by electrical burns. AB - Rapid repair of vascular injury is an important prognostic factor for electrical burns. This repair is achieved mainly via stromal cell-derived factor (SDF) 1alpha promoting the mobilization, chemotaxis, homing, and targeted differentiation of bone marrow mesenchymal stem cells (BMSCs) into endothelial cells. Forming a concentration gradient from the site of local damage in the circulation is essential to the role of SDF-1alpha. In a previous study, we developed reactive oxygen species (ROS)-sensitive PPADT nanoparticles containing SDF-1alpha that could degrade in response to high concentration of ROS in tissue lesions, achieving the goal of targeted SDF-1alpha release. In the current study, a rat vascular injury model of electrical burns was used to evaluate the effects of targeted release of SDF-1alpha using PPADT nanoparticles on the chemotaxis of BMSCs and the repair of vascular injury. Continuous exposure to 220 V for 6 s could damage rat vascular endothelial cells, strip off the inner layer, significantly elevate the local level of ROS, and decrease the level of SDF 1alpha. After injection of Cy5-labeled SDF-1alpha-PPADT nanoparticles, the distribution of Cy5 fluorescence suggested that SDF-1alpha was distributed primarily at the injury site, and the local SDF-1alpha levels increased significantly. Seven days after injury with nanoparticles injection, aggregation of exogenous green fluorescent protein-labeled BMSCs at the injury site was observed. Ten days after injury, the endothelial cell arrangement was better organized and continuous, with relatively intact vascular morphology and more blood vessels. These results showed that SDF-1alpha-PPADT nanoparticles targeted the SDF-1alpha release at the site of injury, directing BMSC chemotaxis and homing, thereby promoting vascular repair in response to electrical burns. PMID- 29529069 TI - Correction: The bacterial community associated with the sheep gastrointestinal nematode parasite Haemonchus contortus. AB - [This corrects the article DOI: 10.1371/journal.pone.0192164.]. PMID- 29529070 TI - Effects of 14 days of bed rest and following physical training on metabolic cost, mechanical work, and efficiency during walking in older and young healthy males. AB - In this study, we investigated: i) the effects of bed rest and a subsequent physical training program on metabolic cost (Cw), mechanical work and efficiency during walking in older and young men; ii) the mechanisms underlying the higher Cw observed in older than young men.Twenty-three healthy male subjects (N = 16 older adults, age 59.6+/-3.4 years; N = 7 young, age: 23.1+/-2.9 years) participated in this study. The subjects underwent 14 days of bed rest followed by two weeks of physical training (6 sessions). Cw, mechanical work, efficiency, and co-contraction time of proximal muscles (vastus lateralis and biceps femoris) and distal muscles (gastrocnemius medialis and tibialis anterior) were measured during walking at 0.83, 1.11, 1.39, 1.67 m.s-1 before bed rest (pre-BR), after bed rest (post-BR) and after physical training (post-PT).No effects of bed rest and physical training were observed on the analysed parameters in either group. Older men showed higher Cw and lower efficiency at each speed (average +25.1 and 20.5%, P<0.001, respectively) compared to young. Co-contraction time of proximal and distal muscles were higher in older than in young men across the different walking speeds (average +30.0 and +110.3%, P<0.05, respectively).The lack of bed rest and physical training effects on the parameters analyzed in this study may be explained by the healthy status of both young and older men, which could have mitigated the effects of these interventions on walking motor function. On the other hand, the fact that older adults showed greater Cw, overall higher co contraction time of antagonist lower limb muscles, and lower efficiency compared to the young cohort throughout a wide range of walking speed may suggest that older adults sacrificed economy of walking to improve stability. PMID- 29529071 TI - Robot-assisted voluntary initiation reduces control-related difficulties of initiating joint movement: A phenomenal questionnaire study on shaping and compensation of forward gait. AB - Humans employ various control strategies to initiate and maintain bodily movement. In case that the normal gait function is impaired, exoskeleton robots provide motor assistance during therapy. While the robotic control system builds on kinematic gait functions, the patient's voluntary efforts to initiate motion also contribute to the effectiveness of the therapy process. However, it is currently not well understood how voluntary initiation as a subjective capacity affects the physiological level of motor control. In order to understand the functional nexus between voluntary initiation and motor control, we interviewed patients undergoing robotic gait rehabilitation with the HAL exoskeleton robot about their experience and command of voluntarily initiating forward gait while using the HAL system. Their reports provide phenomenal evidence for voluntary initiation as a distinct cognitive act that comes as phenomenal performance. Furthermore, phenomenal evidence about the functional relation of intention and initiation correlates with FIM-M gait scores. Based on the assumption that HAL reduces control-related difficulties of voluntarily initiating joint movement, we identified two cognitive control strategies, shaping and compensation of gait, that imply a heterarchic organization of the human system of action control. PMID- 29529072 TI - Growth differentiation factor-15 levels and the risk of contrast induced acute kidney injury in acute myocardial infarction patients treated invasively: A propensity-score match analysis. AB - BACKGROUND: Growth differentiation factor-15 (GDF-15) is an emerging biomarker for risk stratification in cardiovascular disease. Contrast-induced acute kidney injury (AKI) is an important complication in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI). In this retrospectively observational study, we aimed to determine the role of GDF-15 and the risk of AKI in acute myocardial infarction (AMI) patients. METHODS: The medical records of 1195 patients with AMI were reviewed. After exclusion criteria, a total of 751 eligible patients who underwent CAG or PCI were studied. Preoperative clinical parameters including GDF-15 levels were recorded. Multivariate logistic regression analysis was used to identify the risk factors of AKI. Subsequently, to reduce a potential selection bias and to balance differences between the two groups, a propensity score-matched analysis was performed. We recorded the 30-day all-cause mortality of the total study population. Kaplan-Meier analysis was performed to identify the association between short term survival in AMI patients and GDF-15 level. RESULTS: Among 751 enrolled patients, 106 patients (14.1%) developed AKI. Patients were divided into two groups: AKI group (n = 106) and non-AKI group (n = 645). GDF-15 levels were significantly higher in AKI group compared to non-AKI group (1328.2 +/- 349.7 ng/L vs. 1113.0 +/- 371.3 ng/L, P <0.001). Multivariate logistic regression analyses showed GDF-15 was an independent risk factor of AKI (per 1000 ng/L increase of GDF-15, OR: 3.740, 95% CI: 1.940-7.207, P < 0.001). According to GDF 15 tertiles, patients were divided into three groups. Patients in middle (OR 2.93, 95% CI: 1.46-5.89, P = 0.003) and highest GDF-15 tertile (OR 3.72, 95% CI: 1.87-7.39, P <0.001) had higher risk of AKI compared to patients in the lowest GDF-15 tertile. The propensity score-matched group set comprised of 212 patients. Multivariate logistic regression revealed that GDF-15 is still an independent risk factor for AKI after matching (per 1000 ng/L increase of GDF-15, OR: 2.395, 95% CI: 1.020-5.626, P = 0.045). Based on the Kaplan-Meier analysis, the risk of 30-day all-cause mortality increased in higher GDF-15 tertiles log rank chi square: 29.895, P <0.001). CONCLUSION: This suggests that preoperative plasma GDF 15 is an independent risk factor of AKI in AMI patients underwent CAG or PCI. GDF 15 and AKI are associated with poor short term survival of AMI patients. PMID- 29529073 TI - Non-alcoholic fatty liver disease, liver biomarkers and stroke risk: The Reasons for Geographic and Racial Differences in Stroke cohort. AB - BACKGROUND AND PURPOSE: Liver disease, particularly non-alcoholic fatty liver disease (NAFLD), is a risk factor for cardiovascular disease, but little is known about its relationship with ischemic stroke. METHODS: In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort of 30,239 American black and white adults, we assessed baseline NAFLD as fatty liver index (FLI) >60, and assessed liver biomarkers aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and the AST/ALT ratio and risk of incident ischemic stroke over 5.8 years using a case-cohort study design. RESULTS: Considering 572 strokes and a 1,017-person cohort sample, NAFLD was inversely associated with stroke risk in men (HR: 0.50; 95% CI: 0.26, 0.96), as was being in the highest ALT quintile versus the lowest (HR: 0.39; 95% CI: 0.19, 0.78) and the highest versus lowest GGT quintile (HR: 0.45, 95% CI: 0.24, 0.85), but not in women. Conversely, FLI score above the 90th percentile was associated with increased stroke risk among women (HR: 2.26; 95% CI: 1.14 4.47), but not men. AST was not associated with stroke risk in either sex. AST/ALT ratio >2 was strongly associated with increased stroke risk in whites, but not blacks (HRs: 3.64; 95% CI: 1.42-9.35 and 0.97; 95% CI: 0.45-1.99, respectively; p for interaction = 0.03). CONCLUSIONS: The relationships between NAFLD, liver biomarkers, and ischemic stroke are complex, and sex and race differences we observed require further study and confirmation. PMID- 29529074 TI - Integrated analysis of transcriptome and proteome changes related to the Ogura cytoplasmic male sterility in cabbage. AB - Cabbage (Brassica oleracea L. var. capitata), an important vegetable crop in the Brassicaceae family, is economically important worldwide. In the process of hybrid seed production, Ogura cytoplasmic male sterility (OguCMS), controlled by the mitochondrial gene orf138, has been extensively used for cabbage hybrid production with complete and stable male sterility. To identify the critical genes and pathways involved in the sterility and to better understand the underlying molecular mechanisms, the anther of OguCMS line R2P2CMS and the fertile line R2P2 were used for RNA-seq and iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) proteome analysis. RNA-seq analysis generated 13,037,109 to 13,066,594 SE50-clean reads, from the sterile and fertile lines, which were assembled into 36,890 unigenes. Among them, 1,323 differentially expressed genes (DEGs) were identified, consisting of 307 up- and 1016 down-regulated genes. For ITRAQ analysis, a total of 7,147 unique proteins were identified, and 833 were differentially expressed including 538 up- and 295 down-regulated proteins. These were mainly annotated to the ribosome, spliceosome and mRNA surveillance pathways. Combined transcriptomic and proteomic analyses identified 22 and 70 genes with the same and opposite expression profiles, respectively. Using KEGG analysis of DEGs, gibberellin mediated signaling pathways regulating tapetum programmed cell death and four different pathways involved in sporopollenin synthesis were identified. Secretion and translocation of the sporopollenin precursors were identified, and the key genes participating in these pathways were all significantly down-regulated in R2P2CMS. Light and transmission electron (TE) microscopy revealed fat abnormal tapetum rather than vacuolization and degradation at the tetrad and microspore stages of the OguCMS line. This resulted in the failed deposition of sporopollenin on the pollen resulting in sterility. This study provides a comprehensive understanding of the mechanism underlying OguCMS in cabbage. PMID- 29529075 TI - Characteristics and risk factors for inconsistency between the risk of exacerbations and the severity of airflow limitation in COPD based on GOLD 2017: A retrospective, cross-sectional study. AB - BACKGROUND AND OBJECTIVES: The clinical implications of the discordance between the risk of exacerbations and the level of airflow limitation in patients with chronic obstructive pulmonary disease (COPD) are still unknown. This study aimed to clarify the clinical significance of such discordance in the management of COPD by exploring its characteristics and risk factors. METHODS: In this retrospective, cross-sectional study, participating physicians completed a detailed patient record form for each participating outpatient with COPD. The data, collected by the Taiwan Obstructive Lung Disease consortium, were managed and analyzed. RESULTS: Of the enrolled participants, 316 (41.7%) had an inconsistency between the risk of exacerbations and the severity of airflow limitation. Univariate analysis showed that more severe airflow limitation (p = 0.000), higher COPD assessment test (CAT) scores (p = 0.003) and modified Medical Research Council (mMRC) scales (p = 0.008), and the presence of at least one (p = 0.000) or two (p = 0.003) co-morbidities were significantly associated with such inconsistency. More severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 3 and 4 classification; odds ratio (OR) = 27.09, p = 0.000 and OR = 25.15, p = 0.000, respectively) and the presence of at least one co-morbidity (OR = 2.01, p = 0.001) were still associated with the inconsistency in multivariate logistic regression analysis. Furthermore, the presence of wheezing (OR = 3.90, p = 0.000) and at least two co-morbidities (OR = 5.43, p = 0.005) were independent risk factors for an inconsistency of a high risk of exacerbations / GOLD 1 or 2 and the CAT score?10 (OR = 1.58, p = 0.007), mMRC scale 2-4 (OR = 1.53, p = 0.017), and the presence of at least one co morbidity (OR = 2.55, p = 0.000) for an inconsistency of a low risk of exacerbations / GOLD 3 or 4. CONCLUSIONS: The patients with COPD and an inconsistency between the risk of exacerbations and level of airflow limitation had unique clinical characteristics and risk factors for this inconsistency. Management of these patients should include more detailed evaluations. PMID- 29529076 TI - Correction: Serum selenium levels and the risk of progression of laryngeal cancer. AB - [This corrects the article DOI: 10.1371/journal.pone.0184873.]. PMID- 29529077 TI - Brain region-specific expression of genes mapped within quantitative trait loci for behavioral responsiveness to acute stress in Fisher 344 and Wistar Kyoto male rats. AB - Acute stress responsiveness is a quantitative trait that varies in severity from one individual to another; however, the genetic component underlying the individual variation is largely unknown. Fischer 344 (F344) and Wistar Kyoto (WKY) rat strains show large differences in behavioral responsiveness to acute stress, such as freezing behavior in response to footshock during the conditioning phase of contextual fear conditioning (CFC). Quantitative trait loci (QTL) have been identified for behavioral responsiveness to acute stress in the defensive burying (DB) and open field test (OFT) from a reciprocal F2 cross of F344 and WKY rat strains. These included a significant QTL on chromosome 6 (Stresp10). Here, we hypothesized that the Stresp10 region harbors genes with sequence variation(s) that contribute to differences in multiple behavioral response phenotypes between the F344 and WKY rat strains. To test this hypothesis, first we identified differentially expressed genes within the Stresp10 QTL in the hippocampus, amygdala, and frontal cortex of F344 and WKY male rats using genome-wide microarray analyses. Genes with both expression differences and non-synonymous sequence variations in their coding regions were considered candidate quantitative trait genes (QTGs). As a proof-of-concept, the F344.WKY-Stresp10 congenic strain was generated with the Stresp10 WKY donor region into the F344 recipient strain. This congenic strain showed behavioral phenotypes similar to those of WKYs. Expression patterns of Gpatch11 (G-patch domain containing 11), Cdkl4 (Cyclin dependent kinase like 4), and Drc1 (Dynein regulatory complex subunit 1) paralleled that of WKY in the F344.WKY-Stresp10 strain matching the behavioral profiles of WKY as opposed to F344 parental strains. We propose that these genes are candidate QTGs for behavioral responsiveness to acute stress. PMID- 29529078 TI - Mannitol oxidase and polyol dehydrogenases in the digestive gland of gastropods: Correlations with phylogeny and diet. AB - Mannitol oxidase and polyol dehydrogenases are enzymes that convert polyalcohols into sugars. Mannitol oxidase was previously investigated in terrestrial snails and slugs, being also present in a few aquatic gastropods. However, the overall distribution of this enzyme in the Gastropoda was not known. Polyol dehydrogenases are also poorly studied in gastropods and other mollusks. In this study, polyalcohol oxidase and dehydrogenase activities were assayed in the digestive gland of 26 species of gastropods, representing the clades Patellogastropoda, Neritimorpha, Vetigastropoda, Caenogastropoda and Heterobranchia. Marine, freshwater and terrestrial species, including herbivores and carnivores were analyzed. Ultrastructural observations were undertake in species possessing mannitol oxidase, in order to investigate the correlation between this enzyme and the presence of tubular structures known to be associated with it. Mannitol oxidase activity was detected in the digestive gland of herbivores from the clades Caenogastropoda and Heterobranchia, but not in any carnivores or in herbivores from the clades Patellogastropoda, Neritimorpha and Vetigastropoda. In most of the species used in this study, dehydrogenase activities were detected using both D-mannitol and D-sorbitol as substrates. Nevertheless, in some carnivores these activities were not detected with both polyalcohols. Ultrastructural observations revealed tubular structures in digestive gland cells of some species having mannitol oxidase activity, but they were not observed in others. Based on our results, we suggest that mannitol oxidase first occurred in a herbivorous or omnivorous ancestor of Apogastropoda, the clade formed by caenogastropods and heterobranchs, being subsequently lost in those species that shifted towards a carnivorous diet. PMID- 29529079 TI - Discovery of circa 115,000-year-old bone retouchers at Lingjing, Henan, China. AB - Most Chinese lithic industries dated between 300,000 and 40,000 are characterized by the absence of Levallois debitage, the persistence of core-and-flake knapping, the rarity of prepared cores, their reduction with direct hard hammer percussion, and the rarity of retouched flakes. Here we report the discovery of seven bone soft hammers at the early hominin Lingjing site (Xuchang County, Henan) dated to 125,000-105,000. These artefacts represent the first instance of the use of bone as raw material to modify stone tools found at an East Asian early Late Pleistocene site. Three types of soft hammers are identified. The first consists of large bone flakes resulting from butchery of large herbivores that were utilized as such for expedient stone tools retouching or resharpening. The second involved the fracture of weathered bone from medium size herbivores to obtain elongated splinters shaped by percussion into sub-rectangular artefacts. Traces observed on these objects indicate intensive and possibly recurrent utilization, which implies their curation over time. The last consists of antler, occasionally used. Lingjing bone tools complement what we know about archaic hominin cultural adaptations in East Asia and highlight behavioural consistencies that could not be inferred from other cultural proxies. This discovery provides a new dimension to the debate surrounding the existence of the Middle Palaeolithic in the region. The attribution of East Asian sites to the Middle Palaeolithic assumes that cultural traits such as the Levallois method represent evolutionary hallmarks applicable to regions of the world different from those in which they were originally found. Here, we promote an approach that consists in identifying, possibly from different categories of material culture, the original features of each regional cultural trajectory and understanding the behavioural and cognitive implications they may have had for past hominin populations. PMID- 29529080 TI - Correction: Trends of racial and ethnic disparities in virologic suppression among women in the HIV Outpatient Study, USA, 2010-2015. AB - [This corrects the article DOI: 10.1371/journal.pone.0189973.]. PMID- 29529081 TI - Correction: Predicted Shifts in Small Mammal Distributions and Biodiversity in the Altered Future Environment of Alaska: An Open Access Data and Machine Learning Perspective. AB - [This corrects the article DOI: 10.1371/journal.pone.0132054.]. PMID- 29529082 TI - Responses of ecosystem water use efficiency to spring snow and summer water addition with or without nitrogen addition in a temperate steppe. AB - Water use efficiency (WUE) is an important indicator of ecosystem functioning but how ecosystem WUE responds to climate change including precipitation and nitrogen (N) deposition increases is still unknown. To investigate such responses, an experiment with a randomized block design with water (spring snowfall or summer water addition) and nitrogen addition was conducted in a temperate steppe of northern China. We investigated net ecosystem CO2 production (NEP), gross ecosystem production (GEP) and evapotranspiration (ET) to calculate ecosystem WUE (WUEnep = NEP/ET or WUEgep = GEP/ET) under spring snow and summer water addition with or without N addition from 2011 to 2013. The results showed that spring snow addition only had significant effect on ecosystem WUE in 2013 and summer water addition showed positive effect on ecosystem WUE in 2011 and 2013, as their effects on NEP and GEP is stronger than ET. N addition increased ecosystem WUE in 2012 and 2013 both in spring snow addition and summer water addition for its increasing effects on NEP and GEP but no effect on ET. Summer water addition had less but N addition had greater increasing effects on ecosystem WUE as natural precipitation increase indicating that natural precipitation regulates ecosystem WUE responses to water and N addition. Moreover, WUE was tightly related with atmospheric vapor-pressure deficit (VPD), photosynthetic active radiation (PAR), precipitation and soil moisture indicating the regulation of climate drivers on ecosystem WUE. In addition, it also was affected by aboveground net primary production (ANPP). The study suggests that ecosystem WUE responses to water and N addition is determined by the change in carbon process rather than that in water process, which are regulated by climate change in the temperate steppe of northern China. PMID- 29529083 TI - Pleiotropic roles of Clostridium difficile sin locus. AB - Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR', coding for SinR (112 aa) and SinR' (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus's role in C. difficile physiology. Transcriptome analysis of the sinRR' mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR' acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis. PMID- 29529084 TI - Experimental Chagas disease-induced perturbations of the fecal microbiome and metabolome. AB - Trypanosoma cruzi parasites are the causative agents of Chagas disease. These parasites infect cardiac and gastrointestinal tissues, leading to local inflammation and tissue damage. Digestive Chagas disease is associated with perturbations in food absorption, intestinal traffic and defecation. However, the impact of T. cruzi infection on the gut microbiota and metabolome have yet to be characterized. In this study, we applied mass spectrometry-based metabolomics and 16S rRNA sequencing to profile infection-associated alterations in fecal bacterial composition and fecal metabolome through the acute-stage and into the chronic stage of infection, in a murine model of Chagas disease. We observed joint microbial and chemical perturbations associated with T. cruzi infection. These included alterations in conjugated linoleic acid (CLA) derivatives and in specific members of families Ruminococcaceae and Lachnospiraceae, as well as alterations in secondary bile acids and members of order Clostridiales. These results highlight the importance of multi-'omics' and poly-microbial studies in understanding parasitic diseases in general, and Chagas disease in particular. PMID- 29529085 TI - A non-invasive, quantitative study of broadband spectral responses in human visual cortex. AB - Currently, non-invasive methods for studying the human brain do not routinely and reliably measure spike-rate-dependent signals, independent of responses such as hemodynamic coupling (fMRI) and subthreshold neuronal synchrony (oscillations and event-related potentials). In contrast, invasive methods-microelectrode recordings and electrocorticography (ECoG)-have recently measured broadband power elevation in field potentials (~50-200 Hz) as a proxy for locally averaged spike rates. Here, we sought to detect and quantify stimulus-related broadband responses using magnetoencephalography (MEG). Extracranial measurements like MEG and EEG have multiple global noise sources and relatively low signal-to-noise ratios; moreover high frequency artifacts from eye movements can be confounded with stimulus design and mistaken for signals originating from brain activity. For these reasons, we developed an automated denoising technique that helps reveal the broadband signal of interest. Subjects viewed 12-Hz contrast-reversing patterns in the left, right, or bilateral visual field. Sensor time series were separated into evoked (12-Hz amplitude) and broadband components (60-150 Hz). In all subjects, denoised broadband responses were reliably measured in sensors over occipital cortex, even in trials without microsaccades. The broadband pattern was stimulus-dependent, with greater power contralateral to the stimulus. Because we obtain reliable broadband estimates with short experiments (~20 minutes), and with sufficient signal-to-noise to distinguish responses to different stimuli, we conclude that MEG broadband signals, denoised with our method, offer a practical, non-invasive means for characterizing spike-rate-dependent neural activity for addressing scientific questions about human brain function. PMID- 29529086 TI - Genetic diversity of Avena ventricosa populations along an ecogeographical transect in Cyprus is correlated to environmental variables. AB - Avena ventricosa Balansa ex Coss. is considered the C-genome donor of the cultivated hexaploid oat and is a 'priority' species for conservation, since it has limited geographic distribution and the only recorded populations in Europe are present in Cyprus. The current study attempts to characterize the genetic structure and fragmentation of the species via the application of genotypic markers. It was revealed that the genetic variety was mainly allocated among the populations collected, since clustering obtained was according to the geographic origin of the samples and the habitat. Species distribution modeling showed that the most important climatic variable defining A. ventricosa distribution is the mean diurnal temperature. Furthermore, significant association of the genetic structure to environmental variables was detected; overall, a negative association to precipitation was confirmed, while significant correlations of genetic structure and the temperature at the time of anthesis and germination were established. The safeguarding of this valuable genetic resource is discussed. PMID- 29529087 TI - Implementation of a decentralized community-based treatment program to improve the management of Buruli ulcer in the Ouinhi district of Benin, West Africa. AB - BACKGROUND: Mycobacterium ulcerans infection, commonly known as Buruli ulcer (BU), is a debilitating neglected tropical disease. Its management remains complex and has three main components: antibiotic treatment combining rifampicin and streptomycin for 56 days, wound dressings and skin grafts for large ulcerations, and physical therapy to prevent functional limitations after care. In Benin, BU patient care is being integrated into the government health system. In this paper, we report on an innovative pilot program designed to introduce BU decentralization in Ouinhi district, one of Benin's most endemic districts previously served by centralized hospital-based care. METHODOLOGY/PRINCIPAL FINDINGS: We conducted intervention-oriented research implemented in four steps: baseline study, training of health district clinical staff, outreach education, outcome and impact assessments. Study results demonstrated that early BU lesions (71% of all detected cases) could be treated in the community following outreach education, and that most of the afflicted were willing to accept decentralized treatment. Ninety-three percent were successfully treated with antibiotics alone. The impact evaluation found that community confidence in decentralized BU care was greatly enhanced by clinic staff who came to be seen as having expertise in the care of most chronic wounds. CONCLUSIONS/SIGNIFICANCE: This study documents a successful BU outreach and decentralized care program reaching early BU cases not previously treated by a proactive centralized BU program. The pilot program further demonstrates the added value of integrated wound management for NTD control. PMID- 29529088 TI - Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy. AB - Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved in Duchenne muscular dystrophy that are decipherable from serum proteome. PMID- 29529089 TI - RAGE-specific single chain Fv for PET imaging of pancreatic cancer. AB - Noninvasive detection of both early pancreatic neoplasia and metastases could enhance strategies to improve patient survival in this disease that is notorious for an extremely poor prognosis. There are almost no identifiable targets for non invasive diagnosis by positron emission tomography (PET) for patients with pancreatic ductal adenocarcinoma (PDAC). Over-expression of the receptor for advanced glycation end products (RAGE) is found on the cell surface of both pre neoplastic lesions and invasive PDAC. Here, a RAGE-specific single chain (scFv) was developed, specific for PET imaging in syngeneic mouse models of PDAC. An anti-RAGE scFv conjugated with a sulfo-Cy5 fluorescence molecule showed high affinity and selectivity for RAGE expressing pancreatic tumor cells and genetically engineered KRASG12D mouse models of PDAC. An in vivo biodistribution study was performed with the 64Cu-radiolabled scFv in a syngeneic murine pancreatic cancer model, demonstrating both the feasibility and potential of an anti-RAGE scFv for detection of PDAC. These studies hold great promise for translation into the clinic. PMID- 29529090 TI - 'More than a feeling': An empirical investigation of hedonistic accounts of animal welfare. AB - Many scientists studying animal welfare appear to hold a hedonistic concept of welfare -whereby welfare is ultimately reducible to an animal's subjective experience. The substantial advances in assessing animal's subjective experience have enabled us to take a step back to consider whether such indicators are all one needs to know if one is interested in the welfare of an individual. To investigate this claim, we randomly assigned participants (n = 502) to read one of four vignettes describing a hypothetical chimpanzee and asked them to make judgments about the animal's welfare. Vignettes were designed to systematically manipulate the descriptive mental states the chimpanzee was described as experiencing: feels good (FG) vs. feels bad (FB); as well as non-subjective features of the animal's life: natural living and physical healthy (NH) vs. unnatural life and physically unhealthy (UU); creating a fully-crossed 2 (subjective experience) X 2 (objective life value) experimental design. Multiple regression analysis showed welfare judgments depended on the objective features of the animal's life more than they did on how the animal was feeling: a chimpanzee living a natural life with negative emotions was rated as having better welfare than a chimpanzee living an unnatural life with positive emotions. We also found that the supposedly more purely psychological concept of happiness was also influenced by normative judgments about the animal's life. For chimpanzees with positive emotions, those living a more natural life were rated as happier than those living an unnatural life. Insofar as analyses of animal welfare are assumed to be reflective of folk intuitions, these findings raise questions about a strict hedonistic account of animal welfare. More generally, this research demonstrates the potential utility of using empirical methods to address conceptual problems in animal welfare and ethics. PMID- 29529092 TI - A dynamic analysis of S&P 500, FTSE 100 and EURO STOXX 50 indices under different exchange rates. AB - In this study, we assess the dynamic evolution of short-term correlation, long term cointegration and Error Correction Model (hereafter referred to as ECM) based long-term Granger causality between each pair of US, UK, and Eurozone stock markets from 1980 to 2015 using the rolling-window technique. A comparative analysis of pairwise dynamic integration and causality of stock markets, measured in common and domestic currency terms, is conducted to evaluate comprehensively how exchange rate fluctuations affect the time-varying integration among the S&P 500, FTSE 100 and EURO STOXX 50 indices. The results obtained show that the dynamic correlation, cointegration and ECM-based long-run Granger causality vary significantly over the whole sample period. The degree of dynamic correlation and cointegration between pairs of stock markets rises in periods of high volatility and uncertainty, especially under the influence of economic, financial and political shocks. Meanwhile, we observe the weaker and decreasing correlation and cointegration among the three developed stock markets during the recovery periods. Interestingly, the most persistent and significant cointegration among the three developed stock markets exists during the 2007-09 global financial crisis. Finally, the exchange rate fluctuations, also influence the dynamic integration and causality between all pairs of stock indices, with that influence increasing under the local currency terms. Our results suggest that the potential for diversifying risk by investing in the US, UK and Eurozone stock markets is limited during the periods of economic, financial and political shocks. PMID- 29529091 TI - Effects of Ramadan fasting on aspirin resistance in type 2 diabetic patients. AB - AIMS: Ramadan fasting (RF) may affect aspirin resistance. We conducted this study in patients with cardiovascular risk (CVR) factors to assess the effect of RF on aspirin resistance and explore whether type 2 diabetes mellitus (DM) would influence this effect. METHODS: A total of 177 stable patients with >=2 CVR factors were recruited. All patients observed RF and were taking aspirin. Physical exam and standard biological tests including glycaemia and serum lipids data were performed before Ramadan (Pre-R), at the last week of Ramadan (R) and four weeks after the end of Ramadan (Post-R). In the same visits caloric intake was calculated and platelet reactivity to aspirin was assessed using Verify Now point-of-care assay. RESULTS: In the overall population, there was no significant change in absolute aspirin reaction unit (ARU) values and in metabolic parameters. In DM patients (n = 127), ARU change from Pre-R values was+19.7 (p = 0.01) and +14.4 (p = 0.02) respectively at R and Post-R. During Ramadan, glycaemia, triglycerides, and cholesterol levels increased significantly and returned to Pre-R values thereafter. These changes were not observed in non-DM patients. CONCLUSIONS: During RF aspirin resistance increased only in DM patients. This effect persisted one month after Ramadan. Simultaneous alteration of glycemic control and increase of serum lipids levels could potentially be a favorable factor. STUDY REGISTRATION: The protocol was registered at clinicaltrials.gov under: NCT02720133. PMID- 29529093 TI - Correction: EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006123.]. PMID- 29529095 TI - Distinguishing cell shoving mechanisms. AB - Motivated by in vitro time-lapse images of ovarian cancer spheroids inducing mesothelial cell clearance, the traditional agent-based model of cell migration, based on simple volume exclusion, was extended to include the possibility that a cell seeking to move into an occupied location may push the resident cell, and any cells neighbouring it, out of the way to occupy that location. In traditional discrete models of motile cells with volume exclusion such a move would be aborted. We introduce a new shoving mechanism which allows cells to choose the direction to shove cells that expends the least amount of shoving effort (to account for the likely resistance of cells to being pushed). We call this motility rule 'smart shoving'. We examine whether agent-based simulations of different shoving mechanisms can be distinguished on the basis of single realisations and averages over many realisations. We emphasise the difficulty in distinguishing cell mechanisms from cellular automata simulations based on snap shots of cell distributions, site-occupancy averages and the evolution of the number of cells of each species averaged over many realisations. This difficulty suggests the need for higher resolution cell tracking. PMID- 29529094 TI - Multiple origins of downy mildews and mito-nuclear discordance within the paraphyletic genus Phytophthora. AB - Phylogenetic relationships between thirteen species of downy mildew and 103 species of Phytophthora (plant-pathogenic oomycetes) were investigated with two nuclear and four mitochondrial loci, using several likelihood-based approaches. Three Phytophthora taxa and all downy mildew taxa were excluded from the previously recognized subgeneric clades of Phytophthora, though all were strongly supported within the paraphyletic genus. Downy mildews appear to be polyphyletic, with graminicolous downy mildews (GDM), brassicolous downy mildews (BDM) and downy mildews with colored conidia (DMCC) forming a clade with the previously unplaced Phytophthora taxon totara; downy mildews with pyriform haustoria (DMPH) were placed in their own clade with affinities to the obligate biotrophic P. cyperi. Results suggest the recognition of four additional clades within Phytophthora, but few relationships between clades could be resolved. Trees containing all twenty extant downy mildew genera were produced by adding partial coverage of seventeen additional downy mildew taxa; these trees supported the monophyly of the BDMs, DMCCs and DMPHs but suggested that the GDMs are paraphyletic in respect to the BDMs or polyphyletic. Incongruence between nuclear only and mitochondrial-only trees suggests introgression may have occurred between several clades, particularly those containing biotrophs, questioning whether obligate biotrophic parasitism and other traits with polyphyletic distributions arose independently or were horizontally transferred. Phylogenetic approaches may be limited in their ability to resolve some of the complex relationships between the "subgeneric" clades of Phytophthora, which include twenty downy mildew genera and hundreds of species. PMID- 29529096 TI - Grass pollen production and group V allergen content of agriculturally relevant species and cultivars. AB - Grass pollen is the main cause of hay fever and allergic asthma in warm temperate climates during summer. The aim of this study was to determine the content of group 5 major allergens in pollen grains of agriculturally important grass species/cultivars. For each cultivar flowering dates and pollen production of cut anthers were observed in the field and in a climate chamber, respectively. An ELISA was used to quantify the group 5 allergens (Phl p5) in pollen extracts which were gained from the grass species Kentucky bluegrass, perennial rye grass, timothy, cocksfoot, annual / Italian rye grass, hybrid rye grass and festulolium. The group 5 allergen content of species varied between 0.01 ng (Kentucky bluegrass) and 0.06 ng (timothy) per pollen grain. On cultivar level the pollen allergenic content differed up to 74-times within the selected grass species. Results from this study might be helpful for the reduction of allergen exposure coming from agriculture grass production e.g. by an adapted grass selection or by the cultivation of grasses with low allergenic content in plant breeding. PMID- 29529097 TI - How many sightings to model rare marine species distributions. AB - Despite large efforts, datasets with few sightings are often available for rare species of marine megafauna that typically live at low densities. This paucity of data makes modelling the habitat of these taxa particularly challenging. We tested the predictive performance of different types of species distribution models fitted to decreasing numbers of sightings. Generalised additive models (GAMs) with three different residual distributions and the presence only model MaxEnt were tested on two megafauna case studies differing in both the number of sightings and ecological niches. From a dolphin (277 sightings) and an auk (1,455 sightings) datasets, we simulated rarity with a sighting thinning protocol by random sampling (without replacement) of a decreasing fraction of sightings. Better prediction of the distribution of a rarely sighted species occupying a narrow habitat (auk dataset) was expected compared to the distribution of a rarely sighted species occupying a broad habitat (dolphin dataset). We used the original datasets to set up a baseline model and fitted additional models on fewer sightings but keeping effort constant. Model predictive performance was assessed with mean squared error and area under the curve. Predictions provided by the models fitted to the thinned-out datasets were better than a homogeneous spatial distribution down to a threshold of approximately 30 sightings for a GAM with a Tweedie distribution and approximately 130 sightings for the other models. Thinning the sighting data for the taxon with narrower habitats seemed to be less detrimental to model predictive performance than for the broader habitat taxon. To generate reliable habitat modelling predictions for rarely sighted marine predators, our results suggest (1) using GAMs with a Tweedie distribution with presence-absence data and (2) implementing, as a conservative empirical measure, at least 50 sightings in the models. PMID- 29529098 TI - Validation of a microRNA target site polymorphism in H3F3B that is potentially associated with a broad schizophrenia phenotype. AB - Despite much progress, few genetic findings for schizophrenia have been assessed by functional validation experiments at the molecular level. We previously reported evidence for genetic linkage of broadly defined schizophrenia to chromosome 17q25 in a sample of 24 multiplex families. 2,002 SNPs under this linkage peak were analyzed for evidence of linkage disequilibrium using the posterior probability of linkage (PPL) framework. SNP rs1060120 produced the strongest evidence for association, with a PPLD|L score of 0.21. This SNP is located within the 3'UTR of the histone gene H3F3B and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to H3F3B transcripts would be altered by the allelic variants of rs1060120. We used dual luciferase assays to experimentally validate this interaction. The rs1060120 A allele significantly reduced luciferase expression, indicating a stronger interaction with miR-616 than the G allele (p = 0.000412). These results provide functional validation that this SNP could alter schizophrenia epigenetic mechanisms thereby contributing to schizophrenia-related disease risk. PMID- 29529099 TI - Gene expression profiling in a mouse model of retinal vein occlusion induced by laser treatment reveals a predominant inflammatory and tissue damage response. AB - PURPOSE: Retinal vein occlusion (RVO) has been investigated in several laser induced animal models using pigs, rabbits and rats. However, laser-induced RVO has been rarely reported in mice, despite the impressive number of available mutants, ease of handling and cost effectiveness. The aim of this study was to further assess the feasibility of a RVO mouse model for gene expression analysis and its possible use to investigate effects of hypoxia. METHODS: C57Bl/6J mice were injected with eosin Y for photo-sensitization. Subsequently, large retinal veins were laser-treated in one eye to induce vascular occlusion. Contralateral control eyes received non-occlusive retinal laser treatment sparing large vessels. The animals were followed for up to eight days and assessed by funduscopy, angiography, hypoxyprobe staining, histopathology and gene expression analysis by qPCR and RNA sequencing (RNAseq). Another group of mice was left untreated and studied at a single time point to determine baseline characteristics. RESULTS: Laser-induced RVO persisted in half of the treated veins for three days, and in a third of the veins for the whole observation period of 8 days. Funduscopy revealed large areas of retinal swelling in all laser-treated eyes, irrespective of vascular targeting or occlusion status. Damage of the outer retina, retinal pigment epithelium (RPE), and even choroid and sclera at the laser site was observed in histological sections. Genes associated with inflammation or cell damage were highly up-regulated in all laser treated eyes as detected by RNAseq and qPCR. Retinal hypoxia was observed by hypoxyprobe staining in all RVO eyes for up to 5 days with a maximal extension at days 2 and 3, but no significant RVO-dependent changes in gene expression were detected for angiogenesis- or hypoxia-related genes. CONCLUSION: The laser induced RVO mouse model is characterized by a predominant general inflammatory and tissue damage response, which may obscure distinct hypoxia- and angiogenesis related effects. A non-occlusive laser treatment control is essential to allow for proper data interpretation and should be mandatory in animal studies of laser induced RVO to dissect laser-induced tissue damage from vascular occlusion effects. PMID- 29529100 TI - Heart rate variability among women undergoing in vitro fertilization treatment: Its predictive ability for pregnancy. AB - OBJECTIVE: This study aimed to assess predictive ability of heart rate variability (HRV) for pregnancy outcomes with in vitro fertilization (IVF) treatment. RESEARCH DESIGN AND METHOD: A total of 180 women with 261 cycles of IVF and 211 embryo transfers (ETs) were analyzed. HRV was measured at four times during IVF treatment: the first date of menstruation, r-HCG (Ovidrel) administration, and before and after ET. Pregnancy indicators included chemical pregnancy, ongoing pregnancy (> 10 weeks), and live birth (pregnancy > 24 weeks). Mixed effect models were applied to identify predictors for IVF pregnancy. The area under the receiver operating characteristic curve (AUC) was used to assess prediction models for pregnancy. RESULTS: The HRV values increased during IVF treatment and then decreased after ET. The trend of changes in HRV values during IVF treatment was significant among patients with chemical pregnancy (p < 0.01) and those with live birth (p = 0.02). Women without pregnancy had lower HRV compared to those with IVF pregnancy (p < 0.05). With a one unit increase in HRV difference before and after ET, the odds of chemical pregnancy decreased by 18% (odds ratio; OR: 0.82, 95% CI: 0.70-0.97, p < 0.02). With a one year increase in maternal age, the odds decreased by 16% (OR: 0.84, 95% CI: 0.76-0.93, p < 0.01), 25% (OR: 0.75, 95% CI: 0.58-0.93, p = 0.02), and 28% (OR: 0.72, 95% CI: 0.54 0.91, p = 0.01) for chemical pregnancy, ongoing pregnancy, and live birth, respectively. The AUCs were 0.77 (95% CI: 0.70, 0.84), 0.89 (0.79, 0.98), and 0.91(0.83, 0.99) for the prediction models for chemical pregnancy, ongoing pregnancy, and live birth, respectively. CONCLUSIONS: Reduced HRV may be an indicator for low chance of IVF pregnancy. The changes in HRV before and after ET and maternal age might be prognostic predictors of IVF pregnancy. PMID- 29529101 TI - A search for the in trans role of GraL, an Escherichia coli small RNA. AB - Small RNA are very important post-transcriptional regulators in both, bacteria and eukaryotes. One of such sRNA is GraL, encoded in the greA leader region and conserved among enteric bacteria. Here, we conducted a bioinformatics search for GraL's targets in trans and validated our findings in vivo by constructing fusions of probable targets with lacZ and measuring their activity when GraL was overexpressed. Only one target's activity (nudE) decreased under those conditions and was thus selected for further analysis. In the absence of GraL and greA, the nudE::lacZ fusion's beta-galactosidase activity was increased. However, a similar effect was also visible in the strain deleted only for greA. Furthermore, overproduction of GreA alone increased the nudE::lacZ fusion's activity as well. This suggests existence of complex regulatory loop-like interactions between GreA, GraL and nudE mRNA. To further dissect this relationship, we performed in vitro EMSA experiments employing GraL and nudE mRNA. However, stable GraL-nudE complexes were not detected, even though the detectable amount of unbound GraL decreased as increasing amounts of nudE mRNA were added. Interestingly, GraL is being bound by Hfq, but nudE easily displaces it. We also conducted a search for genes that are synthetic lethal when deleted along with GraL. This revealed 40 genes that are rendered essential by GraL deletion, however, they are involved in many different cellular processes and no clear correlation was found. The obtained data suggest that GraL's mechanism of action is non-canonical, unique and requires further research. PMID- 29529102 TI - Regional resting state perfusion variability and delayed cerebrovascular uniform reactivity in subjects with chronic carotid artery stenosis. AB - The aim of this study was to assess regional perfusion at baseline and regional cerebrovascular resistance (CVR) to delayed acetazolamide challenge in subjects with chronic carotid artery stenosis. Sixteen patients (ten males) aged 70.94+/ 7.71 with carotid artery stenosis >= 90% on the ipsilateral side and <= 50% on the contralateral side were enrolled into the study. In all patients, two computed tomography perfusion examinations were carried out; the first was performed before acetazolamide administration and the second 60 minutes after injection. The differences between mean values were examined by paired two-sample t-test and alternative nonparametric Wilcoxon's test. Normality assumption was examined using W Shapiro-Wilk test. The lowest resting-state cerebral blood flow (CBF) was observed in white matter (ipsilateral side: 18.4+/-6.2; contralateral side: 19.3+/-6.6) and brainstem (ipsilateral side: 27.8+/-8.5; contralateral side: 29.1+/-10.8). Grey matter (cerebral cortex) resting state CBF was below the normal value for subjects of this age: frontal lobe - ipsilateral side: 30.4+/ 7.0, contralateral side: 33.7+/-7.1; parietal lobe - ipsilateral side: 36.4+/ 11.3, contralateral side: 42.7+/-9.9; temporal lobe - ipsilateral side: 32.5+/ 8.6, contralateral side: 39.4+/-10.8; occipital lobe - ipsilateral side: 24.0+/ 6.0, contralateral side: 26.4+/-6.6). The highest resting state CBF was observed in the insula (ipsilateral side: 49.2+/-17.4; contralateral side: 55.3+/-18.4). A relatively high resting state CBF was also recorded in the thalamus (ipsilateral side: 39.7+/-16.9; contralateral side: 41.7+/-14.1) and cerebellum (ipsilateral side: 41.4+/-12.2; contralateral side: 38.1+/-11.3). The highest CVR was observed in temporal lobe cortex (ipsilateral side: +27.1%; contralateral side: +26.1%) and cerebellum (ipsilateral side: +27.0%; contralateral side: +34.6%). The lowest CVR was recorded in brain stem (ipsilateral side: +20.2%; contralateral side: +22.2%) and white matter (ipsilateral side: +18.1%; contralateral side: +18.3%). All CBF values were provided in milliliters of blood per minute per 100 g of brain tissue (ml/100g/min). Resting state circulation in subjects with carotid artery stenosis is low in all analysed structures with the exception of insula and cerebellum. Acetazolamide challenge yields relatively uniform response in both hemispheres in the investigated population. Grey matter is more reactive to acetazolamide challenge than white matter or brainstem. PMID- 29529103 TI - Scaly pink patches: differentiating psoriasis from basal cell carcinoma. AB - Dermoscopy, commonly used to analyze skin tumors, has more recently been used to evaluate inflammatory dermatoses. We performed a systematic review of the literature to assess the role of dermoscopy in evaluating psoriasis, and briefly reviewed the findings with an emphasis on the specificity or sensitivity of the dermoscopic findings of psoriasis. We also describe the case of a 63-year-old man with a history of psoriasis and basal cell carcinoma (BCC) who presented with a new scaly pink patch on the back. This case highlights the importance of dermoscopy in differentiating patches and plaques of psoriasis from BCC. PMID- 29529104 TI - Psoriasis treatment in HIV-positive patients: a systematic review of systemic immunosuppressive therapies. AB - The management of psoriatic disease in the human immunodeficiency virus (HIV) positive population is challenging. The clinical course often is progressive and refractory; therefore, first- and second-line therapies including topical agents, phototherapy, and oral retinoids often are inadequate. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge. A comprehensive systematic review of the literature via a PubMed search of articles indexed for MEDLINE using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with several systemic immunosuppressive agents yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, infliximab, and ustekinumab. The limited data suggest that biologic therapies may be effective for cases of psoriasis recalcitrant to other systemic agents and may have a positive effect on CD4 and viral counts when used in combination with highly active antiretroviral therapy (HAART); however, further studies are needed. PMID- 29529105 TI - A review of neurologic complications of biologic therapy in plaque psoriasis. AB - The use of biologic medications has represented a great advancement in the treatment of moderate to severe plaque psoriasis and has improved patients' quality of life. Despite the increasing popularity of biologics, their neurological side effects have been a constant concern. Reports of demyelinating diseases associated with tumor necrosis factor alpha (TNF-alpha) inhibitors continue to accumulate. Additionally, efalizumab was withdrawn from the market in 2009 for causing progressive multifocal leukoencephalopathy (PML). These reports highlight the need for dermatologists to inform patients of the risks and promote informed decision-making with patients prior to starting a biologic agent. Dermatologists also need to recognize early manifestations of neurologic side effects. This review provides an overview of the literature on neurologic diseases that have been found to be associated with biologic agents used for plaque psoriasis. Clinical presentations and diagnostic workups of such diseases are given to aid dermatologists in their early diagnosis and referral. PMID- 29529106 TI - Perceptions of tanning risk among melanoma patients with a history of indoor tanning. AB - A new US Food and Drug Administration (FDA) regulation classified tanning beds as class II, requiring indoor tanning facilities to inform users of the risk of skin cancer in efforts to reverse the growing trend in indoor tanning. However, little is known from the patient's perspective on whether knowledge of the risk of skin cancer development is a deterrent to indoor tanning. There also is conflicting literature regarding the relationship among frequency of indoor tanning, age at onset of melanoma diagnosis, and characteristics of diagnosis in melanoma patients with a history of indoor tanning. An international survey was conducted in patients 18 years and older who self-reported being diagnosed with melanoma after indoor tanning. The purpose of this study was to investigate the patients' perspective on indoor-tanning behaviors as associated with the severity of their melanomas and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors. PMID- 29529107 TI - The clock is ticking. PMID- 29529108 TI - Irregular yellow-brown plaques on the trunk and thighs. PMID- 29529109 TI - Purpuric macule of the right axilla. PMID- 29529110 TI - What's eating you? clinical manifestations of Dermacentor tick bites. AB - Dermacentor ticks are hard ticks found throughout most of North America and are easily identified by their large size, ornate scutum, and prominent dorsal pits. They are important disease vectors and are implicated in transmission of Rocky Mountain spotted fever (RMSF), Colorado tick fever, tularemia, and erlichiosis. They also are an important cause of fatal tick paralysis. PMID- 29529111 TI - No sulfates, no parabens, and the "no-poo" method: a new patient perspective on common shampoo ingredients. AB - The ingredients in shampoos and other cosmetic products have become scrutinized by the general public and the Internet has contributed to misinformation about certain shampoos. Dermatologists must be prepared to acknowledge the concerns that their patients have about common shampoo ingredients to dispel the myths that may misinform patient decision-making. This article reviews the controversy surrounding the use of sulfates and parabens in shampoos, as well as commonly used shampoo alternatives, often called the "no-poo" method. PMID- 29529112 TI - Regenerative medicine in cosmetic dermatology. AB - Stem cell therapies are at the forefront of regenerative aesthetic medicine. Multipotent stem cells and induced pluripotent stem cells (iPSCs), progenitor cells that result from the dedifferentiation of specialized adult cells, have demonstrated promise in tissue regeneration for a wide range of dermatologic conditions and aesthetic applications. Herein, we review the potential of stem cells as a new frontier in aesthetic dermatology. PMID- 29529113 TI - Local depigmentation of a tattoo. PMID- 29529114 TI - Yellow-orange hairless plaque on the scalp. PMID- 29529115 TI - Graft-versus-host disease presenting along Blaschko lines: cutaneous mosaicism. PMID- 29529116 TI - Periorbital lupuslike presentation of graft-versus-host disease. PMID- 29529117 TI - Differentiating trigeminal motor neuropathy and progressive hemifacial atrophy. PMID- 29529118 TI - Complete remission of metastatic Merkel cell carcinoma in a patient with severe psoriasis. PMID- 29529119 TI - Primary cutaneous follicle center lymphoma mimicking folliculitis. AB - Primary cutaneous follicle center lymphoma (PCFCL) is the most common type of cutaneous B-cell lymphoma. The cutaneous manifestations of PCFCL typically include solitary erythematous or violaceous plaques, nodules, or tumors of varying sizes. Grouped lesions also may be observed, but multifocal disease is rare. We report the case of a 54-year-old woman diagnosed with PCFCL with an unusual clinical presentation resembling folliculitis or Grover disease. Histologic studies demonstrated extensive lymphoma cells in a nodular and diffuse pattern. Immunohistochemical studies demonstrated that the neoplastic cells were positive for CD20, CD79a, BCL-2, and BCL-6; CD3, CD5, and cyclin D1 were negative. These findings were consistent with PCFCL. Further evaluation for systemic disease via positron emission tomography-computed tomography and bone marrow biopsy was unremarkable. Increased awareness of this presentation of PCFCL can facilitate earlier diagnosis and intervention, which may result in improved patient outcomes. PMID- 29529120 TI - Nonmalignant cutaneous findings associated with vemurafenib. PMID- 29529121 TI - Panniculitis, pancreatitis, and polyarthritis: a rare clinical syndrome. AB - A rare triad composed of lobular panniculitis in the setting of pancreatitis and polyarthritis is termed panniculitis, pancreatitis, and polyarthritis (PPP) syndrome. Pancreatic panniculitis is a rare form of subcutaneous fat necrosis associated with underlying pancreatic disease. We describe a case of PPP syndrome and review the relevant literature associated with this rare clinical syndrome. Despite numerous adjuvant therapies, definitive treatment of PPP syndrome requires correction of the underlying pancreatic disease. PMID- 29529122 TI - What do you want to be when you grow up? pearls for postresidency planning. AB - Dermatology is an exciting and rewarding specialty. Looking for jobs after training can be a daunting task. From deciding to pursue a fellowship or a job in private practice, the opportunities are extensive. I have collected advice from recent dermatology graduates to help jump-start the planning process. PMID- 29529123 TI - Tumor necrosis factor alpha inhibitors in the treatment of toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) is a rare, life-threatening adverse drug reaction for which there is no standardized or consistently effective treatment. Due to a greater understanding of disease pathogenesis and the identification of tumor necrosis factor (TNF) alpha as a mediator of keratinocyte death, TNF-alpha antagonists have been used in the treatment of TEN. Specifically, infliximab and etanercept have been shown to be effective at halting disease progression. The objective of this study is to review published case reports and case series using anti-TNF-alpha medications in the treatment of TEN. Results of many of the articles reviewed support the use of TNF-alpha inhibitors in TEN in both adult and pediatric populations; however, the risks caused by these potent immunosuppressants must be weighed, and if administered, patients must be closely monitored for infections. Additional studies are needed to further characterize the role of TNF-alpha inhibition in the treatment of TEN. PMID- 29529124 TI - Protective effect of estrogen against intervertebral disc degeneration is attenuated by miR-221 through targeting estrogen receptor alpha. AB - Dysfunction of cartilaginous endplates (CEP) is an important etiologic aspect of intervertebral disc degeneration (IDD) because the endplate has nutritional and biomechanical functions in maintaining proper disc health. In this study, we investigated the regulatory effects of estrogen on degenerated human CEP cells and the involvement of miR-221 in these effects. Normal and degenerated human CEP tissues were collected from patients with idiopathic scoliosis and IDD, respectively. CEP cells were isolated from these tissues. Polymerase chain reaction (PCR) and western blot analysis were performed to detect the expression of specific genes and proteins, respectively. Apoptosis and cell cycle were analyzed by flow cytometry. The results showed that the levels of aggrecan, collagen II, TGF-beta and estrogen receptor alpha (ERalpha) were decreased in degenerated CEP tissues, while the levels of MMP-3, adamts-5, IL-1beta, TNF alpha, IL-6, and miR-221 were increased. Treatment of degenerated CEP cells with 17beta-estradiol (E2) increased the expressions of aggrecan and collagen II, as well as the secretion of TGF-beta, but decreased IL-6 secretion. Moreover, E2 inhibited the apoptosis, resumed cell-cycle progression in G0/G1 phase, and improved the cell viability. These data indicate that estrogen has protective effect against degeneration of CEP cells. Furthermore, ERalpha was confirmed to be a target of miR-221 by the luciferase assay. The synthetic miR-221 mimics or knockdown of ERalpha attenuated the protective effects of E2, but miR-221 inhibitors promoted the protective effects of E2. These results suggest that miR 221 may impair the protective effect of estrogen in degenerated CEP cells through targeting ERalpha. This study reveals an important mechanism underlying the degeneration of CEP cells. PMID- 29529125 TI - Response to Letter From Fuller-Thomson "Might Lifetime Exposure to Lead Confound the Association between Hearing Impairment and Incident Dementia?" PMID- 29529126 TI - A concise review of opioid-induced esophageal dysfunction: is this a new clinical entity? AB - Opioids have become the most widely prescribed analgesics in Western countries. Opioid-induced bowel dysfunction is a widely known adverse effect, with constipation the most common manifestation. Most of the opioid-related effects occur in the stomach, small intestine, and colon and have been widely studied. However, the effects related to esophageal motility are less known. Recently published retrospective studies have suggested that long-term use of opioids can cause esophageal motility dysfunction, reflecting symptoms similar to motility disorders, such as achalasia and functional esophagogastric junction outflow obstruction. The most common manometric findings, as reported in the literature, for patients with opioid-induced dysphagia undergoing long-term therapy with these drugs are impaired lower esophageal sphincter relaxation, high amplitude/velocity, and simultaneous esophageal waves, higher integrated relaxation pressure, lower distal latency, and the esophageal contractility can be normal, hypercontractile, or premature. Based on these studies, a new clinical entity known as opioid-induced esophageal dysfunction has been postulated. For these patients, the diagnostic method of choice is high-resolution manometry, although other causes should be ruled out through endoscopy or Computed Tomography (CT). The best therapeutic option for these patients is withdrawal of the opioid; however, this is not always possible, and other options need to be investigated, such as pneumatic dilation and botulinum toxin injection, considering the risks versus the benefits. PMID- 29529127 TI - Reply to Zhang et al. PMID- 29529128 TI - Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy. PMID- 29529129 TI - Might Lifetime Exposure to Lead Confound the Association Between Hearing Impairment and Incident Dementia? PMID- 29529130 TI - Reply: The expanding neurological phenotype of DNM1L-related disorders. PMID- 29529132 TI - The Contributions of Fiber Atrophy, Fiber Loss, In Situ Specific Force, and Voluntary Activation to Weakness in Sarcopenia. AB - The contributions of fiber atrophy, fiber loss, in situ specific force, and voluntary activation to weakness in sarcopenia remain unclear. To investigate, 40 older (20 women; age 72 +/- 4 years) and 31 younger adults (15 women, age 22 +/- 3 years) completed measurements. The knee extensor maximal voluntary torque (MVC) was measured as well as voluntary activation, patella tendon moment arm length, muscle volume, and fascicle architecture to estimate in situ specific force. Fiber cross-sectional area (FCSA), fiber numbers, and connective tissue contents were also estimated from vastus lateralis biopsies. The MVC, quadriceps volume, and specific force were 39%, 28%, and 17% lower, respectively, in old compared with young, but voluntary activation was not different. The difference in muscle size was due in almost equal proportions to lower type II FCSA and fewer fibers. Five years later (n = 23) the MVC, muscle volume and voluntary activation in old decreased an additional 12%, 6%, and 4%, respectively, but there was no further change in specific force. In situ specific force declines relatively early in older age and reduced voluntary activation occurs later, but the overall weakness in sarcopenia is mainly related to loss of both type I and II fibers and type II fiber atrophy. PMID- 29529133 TI - Human T-Cell Leukemia Virus-1 Infection Is Associated With Atherosclerosis as Measured by Carotid Intima-Media Thickness in Japanese Community-Dwelling Older People. AB - The association between human T-cell leukemia virus-1 (HTLV-1) and atherosclerosis remains to be determined. This case-control study aimed to investigate this association as measured by carotid intima-media thickness (CIMT). HTLV-1 infection was positively associated with CIMT, independent of atherosclerotic risks. PMID- 29529134 TI - The expanding neurological phenotype of DNM1L-related disorders. PMID- 29529131 TI - ChIP-ping the branches of the tree: functional genomics and the evolution of eukaryotic gene regulation. AB - Advances in the methods for detecting protein-DNA interactions have played a key role in determining the directions of research into the mechanisms of transcriptional regulation. The most recent major technological transformation happened a decade ago, with the move from using tiling arrays [chromatin immunoprecipitation (ChIP)-on-Chip] to high-throughput sequencing (ChIP-seq) as a readout for ChIP assays. In addition to the numerous other ways in which it is superior to arrays, by eliminating the need to design and manufacture them, sequencing also opened the door to carrying out comparative analyses of genome wide transcription factor occupancy across species and studying chromatin biology in previously less accessible model and nonmodel organisms, thus allowing us to understand the evolution and diversity of regulatory mechanisms in unprecedented detail. Here, we review the biological insights obtained from such studies in recent years and discuss anticipated future developments in the field. PMID- 29529136 TI - Increase Access to Timely and Periodic Viral Load Testing to Achieve the 90-90-90 Targets for Human Immunodeficiency Virus in China. PMID- 29529135 TI - Estimating the Hospital Burden of Norovirus-Associated Gastroenteritis in England and Its Opportunity Costs for Nonadmitted Patients. AB - Background: Norovirus places a substantial burden on healthcare systems, arising from infected patients, disease outbreaks, beds kept unoccupied for infection control, and staff absences due to infection. In settings with high rates of bed occupancy, opportunity costs arise from patients who cannot be admitted due to beds being unavailable. With several treatments and vaccines against norovirus in development, quantifying the expected economic burden is timely. Methods: The number of inpatients with norovirus-associated gastroenteritis in England was modeled using infectious and noninfectious gastrointestinal Hospital Episode Statistics codes and laboratory reports of gastrointestinal pathogens collected at Public Health England. The excess length of stay from norovirus was estimated with a multistate model and local outbreak data. Unoccupied bed-days and staff absences were estimated from national outbreak surveillance. The burden was valued conventionally using accounting expenditures and wages, which we contrasted to the opportunity costs from forgone patients using a novel methodology. Results: Between July 2013 and June 2016, 17.7% (95% confidence interval [CI], 15.6%-21.6%) of primary and 23.8% (95% CI, 20.6%-29.9%) of secondary gastrointestinal diagnoses were norovirus attributable. Annually, the estimated median 290000 (interquartile range, 282000-297000) occupied and unoccupied bed-days used for norovirus displaced 57800 patients. Conventional costs for the National Health Service reached L107.6 million; the economic burden approximated to L297.7 million and a loss of 6300 quality-adjusted life-years annually. Conclusions: In England, norovirus is now the second-largest contributor of the gastrointestinal hospital burden. With the projected impact being greater than previously estimated, improved capture of relevant opportunity costs seems imperative for diseases such as norovirus. PMID- 29529137 TI - HDAC4 regulates vascular inflammation via activation of autophagy. AB - Aims: Angiotensin II (Ang II) causes vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of cardiovascular diseases. Therefore, interventions in inflammation may contribute to the reduction of cardiovascular diseases. Here, we aim to demonstrate that HDAC4, one of class IIa family histone de-acetylases (HDACs) members, promotes autophagy-dependent vascular inflammation. Methods and results: By loss-of function approaches, our study provides the first evidence that HDAC4 mediates Ang II-induced vascular inflammation in vitro and in vivo. In response to the Ang II, HDAC4 expression is up-regulated rapidly, with increased autophagic flux and inflammatory mediators in vascular endothelial cells (VECs). In turn, HDAC4 deficiency suppresses activation of autophagy, leading to reduced inflammation in Ang II-induced VECs. Consistently, using autophagy inhibitor or silencing LC3-II also alleviates vascular inflammation. Furthermore, HDAC4 regulates autophagy via facilitating transcription factor forkhead box O3a (FoxO3a) de-acetylation, thereby to increase its transcriptional activity. Loss of HDAC4 in VECs results in inhibition of FoxO3a de-acetylation to block its transcriptional activity, leading to downregulation of the downstream FoxO3a target, and hence reduces autophagy and vascular inflammation. FoxO3a silencing using siRNA approach significantly inhibits activation of autophagy. Finally, knockdown of HDAC4 in Ang II-infused mouse models ameliorates vascular inflammation, suggesting that inhibitor of HDAC4 may be potential therapeutics for vascular diseases associated with inflammation. Conclusion: These results suggest that HDAC4-mediated FoxO3a acetylation regulates Ang II-induced autophagy activation, which in turn plays an essential role in causing vascular inflammation. PMID- 29529138 TI - Control Banding Tools for Engineered Nanoparticles: What the Practitioner Needs to Know. AB - Control banding (CB) has been widely recommended for the selection of exposure controls for engineered nanomaterials (ENMs) in the absence of ENM-specific occupational exposure limits (OELs). Several ENM-specific CB strategies have been developed but have not been systematically evaluated. In this article, we identify the data inputs and compare the guidance provided by eight CB tools, evaluated on six ENMs, and assuming a constant handling/use scenario. The ENMs evaluated include nanoscale silica, titanium dioxide, silver, carbon nanotubes, graphene, and cellulose. Several of the tools recommended the highest level of exposure control for each of the ENMs in the evaluation, which was driven largely by the hazard banding. Dustiness was a factor in determining the exposure band in many tools, although most tools did not provide explicit guidance on how to classify the dustiness (high, medium, low), and published data are limited on this topic. The CB tools that recommended more diverse control options based on ENM hazard and dustiness data appear to be better equipped to utilize the available information, although further validation is needed by comparison to exposure measurements and OELs for a variety of ENMs. In all CB tools, local exhaust ventilation was recommended at a minimum to control exposures to ENMs in the workplace. Generally, the same or more stringent control levels were recommended by these tools compared with the OELs proposed for these ENMs, suggesting that these CB tools would generally provide prudent exposure control guidance, including when data are limited. PMID- 29529139 TI - Protein use and weight-gain quality in very-low-birth-weight preterm infants fed human milk or formula. AB - Background: Nutritional management of preterm infants aims to approximate the tissue growth and body composition of a fetus of the same postmenstrual age. The adequacy of the quality of protein supply can influence the rate and the relative quality of weight gain. Objective: We investigated the protein balance according to feeding regimen and the association between human milk feeding and fat-free mass content at the term-corrected age in very-low-birth-weight preterm infants. Design: A prospective observational study was conducted. Inclusion criteria were as follows: healthy infants, gestational age <=32 wk, birth weight <1500 g, stable clinical conditions, and feeding by mouth with human milk or formula at discharge. Infants were enrolled at hospital discharge. At enrollment, macronutrient intakes and protein balance were determined. Anthropometric measurements and body composition were also assessed. The nutritional composition of human milk was calculated by infrared spectroscopy. The protein balance was determined according to the nitrogen balance standard method. Body composition was assessed by an air-displacement plethysmography system. At the term-corrected age, anthropometry and body composition assessments were repeated. Results: Seventeen preterm infants fed fortified human milk and 15 preterm infants fed formula were enrolled. At discharge, despite similar macronutrient intakes, infants fed fortified human milk showed a higher nitrogen balance (expressed as mg . kg-1 . d-1) compared with preterm formula-fed infants (mean +/- SD: 488.3 +/ 75 compared with 409.8 +/- 85 mg . kg-1 . d-1, P = 0.009). At term-corrected age, growth was similar in the 2 groups, whereas fortified human milk-fed infants showed a higher percentage of fat-free mass (85.1% +/- 2.8% compared with 80.8% +/- 3.2%, P = 0.002). Moreover, at multiple linear regression, fat-free mass content was independently associated with being fed human milk (R2 = 0.93, P < 0.0001). Conclusion: Our findings suggest that human milk feeding is associated with early fat-free mass deposition in healthy and stable preterm infants. This trial was registered at www.clinicaltrials.gov as NCT03013374. PMID- 29529140 TI - Comment on "Sarcopenic obesity, weight loss, and mortality: the English Longitudinal Study of Aging". PMID- 29529141 TI - Reply to R Wang and P Chen. PMID- 29529143 TI - US restaurant sector can promote healthy food environments to reduce obesity risk. PMID- 29529144 TI - Reply to VI Kraak. PMID- 29529142 TI - Prospective associations of poor diet quality with long-term incidence of protein energy malnutrition in community-dwelling older adults: the Health, Aging, and Body Composition (Health ABC) Study. AB - Background: Protein-energy malnutrition (PEM) is a major problem in older adults. Whether poor diet quality is an indicator for the long-term development of PEM is unknown. Objective: The aim was to determine whether poor diet quality is associated with the incidence of PEM in community-dwelling older adults. Design: We used data on 2234 US community-dwelling older adults aged 70-79 y of the Health, Aging, and Body Composition (Health ABC) Study. In 1998-1999, dietary intake over the preceding year was measured by using a Block food-frequency questionnaire. Indicators of diet quality include the Healthy Eating Index (HEI), energy intake, and protein intake. Outcomes were determined annually by using measured weight and height and included the following: 1) incident PEM [body mass index (in kg/m2) <20, involuntary weight loss of >=5% in the preceding year at any follow-up examination, or both] and 2) incident persistent PEM (having PEM at 2 consecutive follow-up examinations). Associations of indicators of diet quality with 4-y and 3-y incidence of PEM and persistent PEM, respectively, were examined by multivariable Cox regression analyses. Results: The quality of the diet, as assessed with the HEI, was rated as "poor" for 6.4% and as "needs improvement" for 73.0% of the participants. During follow-up, 24.9% of the participants developed PEM and 8.5% developed persistent PEM. A poor HEI score was not associated with incident PEM or persistent PEM. Lower baseline energy intake was associated with a lower incidence of PEM (HR per 100-kcal/d lower intake: 0.98; 95% CI: 0.97, 0.99) and persistent PEM (HR: 0.97; 95% CI: 0.95, 0.99), although lower baseline protein intake was observed to be associated with a higher incidence of persistent PEM (HR per 10-g/d lower intake: 1.15; 95% CI: 1.03, 1.29). Conclusions: These findings do not indicate that a poor diet quality is a risk factor for the long-term development of PEM in community-dwelling older adults, although there is an indication that lower protein intake is associated with higher PEM risk. PMID- 29529145 TI - Contribution to the understanding of how principal component analysis-derived dietary patterns emerge from habitual data on food consumption. AB - Background: Principal component analysis (PCA) is a widely used exploratory method in epidemiology to derive dietary patterns from habitual diet. Such dietary patterns seem to originate from intakes on multiple days and eating occasions. Therefore, analyzing food intake of study populations with different levels of food consumption can provide additional insights as to how habitual dietary patterns are formed. Objective: We analyzed the food intake data of German adults in terms of the relations among food groups from three 24-h dietary recalls (24hDRs) on the habitual, single-day, and main-meal levels, and investigated the contribution of each level to the formation of PCA-derived habitual dietary patterns. Design: Three 24hDRs were collected in 2010-2012 from 816 adults for an European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam subcohort study. We identified PCA-derived habitual dietary patterns and compared cross-sectional food consumption data in terms of correlation (Spearman), consistency (intraclass correlation coefficient), and frequency of consumption across all days and main meals. Contribution to the formation of the dietary patterns was obtained through Spearman correlation of the dietary pattern scores. Results: Among the meals, breakfast appeared to be the most consistent eating occasion within individuals. Dinner showed the strongest correlations with "Prudent" (Spearman correlation = 0.60), "Western" (Spearman correlation = 0.59), and "Traditional" (Spearman correlation = 0.60) dietary patterns identified on the habitual level, and lunch showed the strongest correlations with the "Cereals and legumes" (Spearman correlation = 0.60) habitual dietary pattern. Conclusions: Higher meal consistency was related to lower contributions to the formation of PCA-derived habitual dietary patterns. Absolute amounts of food consumption did not strongly conform to the habitual dietary patterns by meals, suggesting that these patterns are formed by complex combinations of variable food consumption across meals. Dinner showed the highest contribution to the formation of habitual dietary patterns. This study provided information about how PCA-derived dietary patterns are formed and how they could be influenced. PMID- 29529146 TI - Protein leucine content is a determinant of shorter- and longer-term muscle protein synthetic responses at rest and following resistance exercise in healthy older women: a randomized, controlled trial. AB - Background: Older women may not be consuming enough protein to maintain muscle mass. Augmentation of protein intake with leucine may enhance the muscle protein synthetic response in older women to aid in maintaining muscle mass. Objective: We measured the acute (hourly) and integrated (daily) myofibrillar protein synthesis (myoPS) response to consumption of a high-quality mixed protein beverage compared with an isonitrogenous protein beverage with added leucine. Design: In a parallel design, free-living, healthy older women (aged 65-75 y, n = 11/group) consumed a fixed, weight-maintaining diet with protein at 1.0 g . kg-1 . d-1 and were randomly assigned to twice-daily consumption of either 15 g milk protein beverage containing 4.2 g leucine (LEU) or 15 g mixed protein (milk and soy) beverage containing 1.3 g leucine (CON). Unilateral leg resistance exercise allowed a determination of acute ([13C6]-phenylalanine infusion, hourly rate) and integrated (deuterated water ingestion, daily rate) exercised and rested myoPS responses. Results: Acute myoPS increased in response to feeding in the rested (CON: 13% +/- 4%; LEU: 53% +/- 5%) and exercised (CON: 30% +/- 4%; LEU: 87% +/- 7%) leg in both groups, but the increase was greater in LEU (P < 0.001). Integrated myoPS increased during the supplementation period in both legs (rested: 9% +/-1%; exercised: 17% +/- 2%; P < 0.001) in LEU, but in the exercised leg only (7% +/- 2%; P < 0.001) in CON. Conclusions: A 15-g protein-containing beverage with ~4 g leucine induced greater increases in acute and integrated myoPS than did an isonitrogenous, isoenergetic mixed-protein beverage. Declines in muscle mass in older women may be attenuated with habitual twice-daily consumption of a protein beverage providing 15 g protein and higher (4.2 g/serving) amounts of leucine. This trial was registered at clinicaltrials.gov as NCT02282566. PMID- 29529148 TI - The effect of magnesium supplementation on blood pressure: multivariate meta regression scenario. PMID- 29529147 TI - FTO genotype impacts food intake and corticolimbic activation. AB - Background: Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with "high-risk" FTO genotypes exhibit preference for high-fat foods, reduced satiety responsiveness, and greater food intake consistent with impaired satiety. Objective: We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype. Design: We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal. Results: Higher-risk participants reported less subjective fullness (chi2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (chi2 = 3.92, P < 0.05), and consumed ~350 more kilocalories than lower-risk participants (beta = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by "fattening" food images (compared with objects) in the medial orbital frontal cortex (beta = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (beta = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (beta = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (beta = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01). Conclusion: The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663. PMID- 29529149 TI - Dietary fat intake may be associated with the risk of non-Hodgkin lymphoma. PMID- 29529150 TI - Reply to P-L Peng and P-F Chen. PMID- 29529151 TI - Reply to F Teymoori et al. PMID- 29529152 TI - Comments regarding the article "Maternal protein intake in pregnancy and offspring metabolic health at age 9-16 y: results from a Danish cohort of gestational diabetes mellitus pregnancies and controls." PMID- 29529153 TI - Reply to SA Lederman. PMID- 29529154 TI - Letter in response to "Low-fat dietary pattern and cardiovascular disease: results from the Women's Health Initiative randomized controlled trial", July 2017. PMID- 29529155 TI - Reply to DR Merkle. PMID- 29529156 TI - Early pregnancy folate-cobalamin interactions and their effects on cobalamin status and hematologic variables throughout pregnancy. AB - Background: Periconception folic acid supplementation is widespread, but how it interacts with cobalamin status is rarely considered. Objective: The aim of this study was to investigate whether first-trimester folate-cobalamin interactions affect pregnancy cobalamin status, hematologic variables, and pregnancy outcomes. Design: In the longitudinal Reus-Tarragona Birth Cohort study from <12 gestational weeks throughout pregnancy, fasting plasma and red blood cell (RBC) folate, plasma cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), hemoglobin, mean cell volume (MCV), postglucose-load serum glucose, gestational hypertension, gestational age at birth, and birth weight were recorded in 563 participants. Results: The highest plasma folate concentrations occurred in the first trimester when folic acid supplement use was extensive. Supplementation beyond the first trimester interacted with time of pregnancy on plasma folate, RBC folate, and tHcy throughout pregnancy (P interaction <0.001). Plasma folate and RBC folate were higher and tHcy was lower in continued supplement users than in nonusers. Elevated plasma folate (>=30 nmol/L) occurred in 78.9% of women who exceeded the recommended 400 ug folic acid/d. First-trimester folate-cobalamin status interactions were associated with MMA (P-interaction <0.001) throughout pregnancy. When plasma cobalamin was suboptimal (<=221 pmol/L; n = 36), participants with elevated plasma folate (n = 11) had higher MMA concentrations than did those with nonelevated plasma folate (n = 23). First-trimester folate-MMA status interactions were associated with MCV throughout pregnancy (P-interaction <0.01) and with cord plasma holoTC (P interaction <0.05). The mean difference (95% CI) in MCV (fL) between women with elevated and nonelevated plasma folate status was -2.12 (-3.71, -0.52) for top quartile plasma MMA (>=0.139 umol/L) and 0.60 (-0.39, 1.60) for plasma MMA <0.139 umol/L. Cord plasma holoTC was higher in women with elevated compared with nonelevated plasma folate status only for MMA <0.139 umol/L. Folate-cobalamin interactions were not associated with the other investigated outcomes. Conclusion: First-trimester folate-cobalamin status interactions were associated with plasma MMA and MCV throughout pregnancy. This trial was registered at www.clinicaltrials.gov as NCT01778205. PMID- 29529157 TI - Randomized controlled clinical trial of behavioral lifestyle intervention with partial meal replacement to reduce excessive gestational weight gain. AB - Background: Behavioral lifestyle interventions during pregnancy can prevent excessive gestational weight gain (GWG) in women with normal weight; however, effective interventions to reduce GWG in ethnically diverse women with obesity are lacking. Objective: A randomized controlled trial was conducted to test whether a behavioral lifestyle intervention with partial meal replacement reduces GWG rate in Hispanic and non-Hispanic women with overweight or obesity relative to enhanced usual care. Design: Participants (n = 257) were recruited in San Luis Obispo, California, and Providence, Rhode Island, between November 2012 and May 2016. Participants were pregnant (mean +/- SD: 13.6 +/- 1.8 wk of gestation) with overweight or obesity and had a mean age of 30.3 y; 41.6% of participants were Hispanic. Women were randomly assigned within site and by ethnicity to enhanced usual care (n = 128) or to a behavioral lifestyle intervention with partial meal replacement (n = 129). The primary outcome was GWG per week of observation. Secondary outcomes were proportions exceeding Institute of Medicine (IOM) guidelines for total GWG, changes in weight-control behaviors and cardiovascular disease risk factors, and incidence of pregnancy complications. Study retention was 99.6% (256 of 257). Results: The intervention compared with usual care resulted in less mean +/- SD weekly GWG (0.33 +/- 0.25 compared with 0.39 +/- 0.23 kg/wk; P = 0.02) and total GWG (9.4 +/- 6.9 compared with 11.2 +/- 7.0 kg; P = 0.03) and reduced the proportion of women who exceeded IOM guidelines for total GWG (41.1% compared with 53.9%; P = 0.03). No significant group * time * demographic subgroup (ethnicity, BMI, age, parity, and income) interactions were observed. Among intervention participants, greater meal replacement intake was related to reduced GWG rate (beta = -0.07; 95% CI:-0.12, -0.03; P = 0.002). The intervention compared with usual care increased weight-control strategies (P < 0.0001) and cognitive restraint (P < 0.0001) and reduced triglycerides (P = 0.03). Conclusion: Prenatal behavioral intervention with partial meal replacement significantly reduced GWG in Hispanic and non-Hispanic women with overweight or obesity. This trial was registered at www.clinicaltrials.gov as NCT01545934. PMID- 29529158 TI - Systematic review and meta-analysis of remotely delivered interventions using self-monitoring or tailored feedback to change dietary behavior. AB - Background: Self-monitoring (SM) of diet and tailored feedback (TF) have been suggested as tools for changing dietary behavior. New technologies allow users to monitor behavior remotely, potentially improving reach, adherence, and outcomes. Objective: We conducted a systematic literature review and meta-analysis to address the following question: are remotely delivered standalone (i.e., no human contact) interventions that use SM or TF effective in changing eating behaviors? Design: Five databases were searched in October 2016 (updated in September 2017). Only randomized controlled trials published after 1990 were included. Trials could include any adult population with no history of disordered eating which delivered an SM or TF intervention without direct contact and recorded actual dietary consumption as an outcome. Three assessors independently screened the search results. Two reviewers extracted the study characteristics, intervention details, and outcomes, and assessed risk of bias using the Cochrane tool. Results were converted to standardized mean differences and incorporated into a 3-level (individuals and outcomes nested in studies) random effects meta-analysis. Results: Twenty-six studies containing 21,262 participants were identified. The majority of the studies were judged to be unclear or at high risk of bias. The meta-analysis showed dietary improvement in the intervention group compared to the control group with a standardized mean difference of 0.17 (95% CI: 0.10, 0.24; P < 0.0001). The I2 statistic for the meta-analysis was 0.77, indicating substantial heterogeneity in results. A "one study removed" sensitivity analysis showed that no single study excessively influenced the results. Conclusions: Standalone interventions containing self-regulatory methods have a small but significant effect on dietary behavior, and integrating these elements could be important in future interventions. However, there was substantial variation in study results that could not be explained by the characteristics we explored, and there were risk-of-bias concerns with the majority of studies. PMID- 29529159 TI - Determination of gluten consumption in celiac disease patients on a gluten-free diet. AB - Background: Celiac disease (CD) patients adhering to a gluten-free diet (GFD) are exposed frequently to low levels of gluten that contribute to symptoms and persistent intestinal histologic damage. Objective: We analyzed prior clinical data to determine how much gluten is accidentally consumed while on a GFD. The aim was to understand the range of gluten consumption for a wide distribution of CD patients. Design: A meta-analysis was conducted on data from 2 different clinical programs: 1) measurements of gluten in stool and urine in CD and non-CD populations; and 2) analysis of data from trials for the investigational therapeutic latiglutenase. The stool and urine studies included controlled gluten challenges. A calibration factor was applied that allowed normal ingestion of gluten to be computed from the urine and stool measurements. From the latiglutenase trial data, a determination of gluten consumption was made by estimating how much gluten was eliminated from patients' diets due to a trial effect that led to improved histology even in the placebo group. Results: The average inadvertent exposure to gluten by CD individuals on a GFD was estimated to be ~150-400 (mean) and ~100-150 (median) mg/d using the stool test and ~300 400 (mean) and ~150 (median) mg/d using the urine test. The analyses of the latiglutenase data for CD individuals with moderate to severe symptoms indicate that patients ingested significantly >200 mg/d of gluten. Conclusions: These surrogate biomarkers of gluten ingestion indicate that many individuals following a GFD regularly consume sufficient gluten to trigger symptoms and perpetuate intestinal histologic damage. PMID- 29529160 TI - Impact of food supplements on hemoglobin, iron status, and inflammation in children with moderate acute malnutrition: a 2 * 2 * 3 factorial randomized trial in Burkina Faso. AB - Background: Children with moderate acute malnutrition (MAM) are treated with lipid-based nutrient supplements (LNSs) or corn-soy blends (CSBs) but little is known about the impact of these supplements on hemoglobin, iron status, and inflammation. Objective: The objective of this study was to investigate the impact of supplementary foods for treatment of MAM on hemoglobin, iron status, inflammation, and malaria. Design: A randomized 2 * 2 * 3 factorial trial was conducted in Burkina Faso. Children aged 6-23 mo with MAM received 500 kcal/d as LNS or CSB, containing either dehulled soy (DS) or soy isolate (SI) and different quantities of dry skimmed milk (0%, 20% or 50% of total protein) for 12 wk. The trial was double-blind with regard to quality of soy and quantity of milk, but not matrix (CSB compared to LNS). Hemoglobin, serum ferritin (SF), serum soluble transferrin receptor (sTfR), serum C-reactive protein (CRP), serum alpha1-acid glycoprotein (AGP), and malaria antigens were measured at inclusion and after supplementation. Results: Between September 2013 and August 2014, 1609 children were enrolled. Among these, 61 (3.8%) were lost to follow-up. During the 12-wk supplementation period, prevalence of anemia, low SF adjusted for inflammation (SFAI), elevated sTfR, and iron-deficiency anemia decreased by 16.9, 8.7, 12.6 and 10.5 percentage points. Children who received LNS compared to CSB had higher hemoglobin (2 g/L; 95% CI: 1, 4 g/L), SFAI (4.2 ug/L; 95% CI: 2.9, 5.5 ug/L), and CRP (0.8 mg/L; 95% CI: 0.4, 1.2 mg/L) and lower sTfR (-0.9 mg/L, 95% CI: -1.3, 0.6 mg/L) after the intervention. Replacing DS with SI or increasing milk content did not affect hemoglobin, SFAI, sTfR, or CRP. Conclusion: Supplementation with LNS compared to CSB led to better hemoglobin and iron status, but overall prevalence of anemia remained high. The higher concentrations of acute-phase proteins in children who received LNSs requires further investigation. This trial was registered at www.controlled-trials.com as ISRCTN42569496. PMID- 29529161 TI - The effects of apples and apple juice on acute plasma uric acid concentration: a randomized controlled trial. AB - Background: The consumption of large amounts of fructose from added sugars results in the hepatic production and export of uric acid into the circulation. Objective: Our aim was to test whether fructose present in fruit is of sufficient quantity or in a form that will increase uric acid concentration. Design: Seventy three participants were randomly assigned to 1 of 3 groups to ingest small (205 g) and large (410 g) servings of apple segments, small (170 mL) and large (340 mL) servings of apple juice, or a glucose and a fructose control beverage. Within each group, participants ingested both treatments in a crossover design. The fructose control and the large servings of apple and juice contained 26.7 g fructose. Test foods were ingested within 10 min. Blood samples were taken at baseline and at 30 and 60 min after intake. Results: Plasma uric acid concentrations increased after the intake of all fructose-containing treatments and decreased after the glucose beverage. The mean (95% CI) increase in uric acid at 30 min was 15 umol/L (10, 21 umol/L) for the fructose control and 19 umol/L (8, 30 umol/L) and 17 umol/L (9, 24 umol/L) for the large servings of apple and apple juice, respectively. There was no difference in change in uric acid between baseline and 30 min when comparing the apple (3 umol/L; 95% CI: -8, 14 umol/L) and apple juice (-7 umol/L; 95% CI: -18, 5 umol/L) with the fructose control. Blood pressure taken 70 min after ingestion was unaffected by any treatment (P > 0.05). There was no difference in change in satiety scores between the fructose and glucose control beverages (P > 0.05). Participants felt more satiated 30 min after ingesting whole apple than after apple juice. The glycemic response reflected the amount of glucose in each treatment. Conclusions: The body acutely responds to fructose regardless of source. Longer-term studies are required to assess how small and transient increases in plasma uric acid contribute to health. This trial was registered with the Australian New Zealand Clinical Trials Registry at https://www.anzctr.org.au/trial/registration/trialreview.aspx?id=367974 as ACTRN12615000215527. PMID- 29529163 TI - Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde? PMID- 29529162 TI - Carbohydrate quality and quantity and risk of coronary heart disease among US women and men. AB - Background: The carbohydrate-to-fiber ratio is a recommended measure of carbohydrate quality; however, its relation to incident coronary heart disease (CHD) is not currently known. Objective: We aimed to assess the relation between various measures of carbohydrate quality and incident CHD. Design: Data on diet and lifestyle behaviors were prospectively collected on 75,020 women and 42,865 men participating in the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) starting in 1984 and 1986, respectively, and every 2-4 y thereafter until 2012. All participants were free of known diabetes mellitus, cancer, or cardiovascular disease at baseline. Cox proportional hazards regression models were used to assess the relation between dietary measures of carbohydrate quality and incident CHD. Results: After 1,905,047 (NHS) and 921,975 (HPFS) person-years of follow-up, we identified 7,320 cases of incident CHD. In models adjusted for age, lifestyle behaviors, and dietary variables, the highest quintile of carbohydrate intake was not associated with incident CHD (pooled-RR = 1.04; 95% CI: 0.96, 1.14; P-trend = 0.31). Total fiber intake was not associated with risk of CHD (pooled-RR = 0.94; 95% CI: 0.85, 1.03; P-trend = 0.72), while cereal fiber was associated with a lower risk for incident CHD (pooled-RR = 0.80; 95% CI: 0.74, 0.87; P-trend < 0.0001). In fully adjusted models, the carbohydrate to-total fiber ratio was not associated with incident CHD (pooled-RR = 1.04; 95% CI: 0.96, 1.13; P-trend = 0.46). However, the carbohydrate-to-cereal fiber ratio and the starch-to-cereal fiber ratio were associated with an increased risk for incident CHD (pooled-RR = 1.20; 95% CI: 1.11, 1.29; P-trend < 0.0001, and pooled RR = 1.17; 95%CI: 1.09, 1.27; P-trend < 0.0001, respectively). Conclusion: Dietary cereal fiber appears to be an important component of carbohydrate quality. The carbohydrate-to-cereal fiber ratio and the starch-to-cereal fiber ratio, but not the carbohydrate-to-fiber ratio, was associated with an increased risk for incident CHD. Future research should focus on how various measures of carbohydrate quality are associated with CHD prevention. This trial was registered at clinicaltrials.gov as NCT03214861. PMID- 29529164 TI - Is leucine content in dietary protein the key to muscle preservation in older women? PMID- 29529165 TI - Is folic acid safe for non-muscle-invasive bladder cancer patients? An evidence based cohort study. AB - Background: Patients with cancer are highly concerned about food choices and dietary supplements that may affect their treatment outcomes. Excess folic acid (synthetic folate) from supplements or fortification can lead to accumulation of unmetabolized folic acid in the systemic circulation and urine and may promote cancer growth, especially among those with neoplastic alterations. Objective: We investigated the prospective association between synthetic compared with natural folate intake and clinical outcomes in non-muscle-invasive bladder cancer (NMIBC), which is a highly recurrent disease. Design: In a cohort of 619 NMIBC patients, folate intake at diagnosis was assessed with a previously validated food-frequency questionnaire and categorized according to tertiles. After a median follow-up of 5.2 y, 303 tumor recurrence and 108 progression events were documented from medical record review. Multivariable Cox proportional hazards and logistic models were used to estimate adjusted HRs and ORs with 95% CIs. Results: Synthetic folic acid intake was positively associated with a risk of recurrence among NMIBC patients (medium compared with low intake-HR: 1.72; 95% CI: 1.20, 2.48; P = 0.003; high compared with low intake-HR: 1.80; 95% CI: 1.14, 2.84; P = 0.01). Patients with a higher folic acid intake were more likely to have multifocal tumors at diagnosis (medium or high compared with low-OR: 2.08; 95% CI: 1.08, 4.02; P = 0.03). In contrast, natural folate intake tended to be inversely associated with the risk of progression (medium or high compared with low-HR: 0.68; 95% CI: 0.44, 1.04; P = 0.08). Conclusions: A high intake of synthetic folic acid, in contrast to the natural forms, is associated with an increased risk of recurrence in NMIBC and multifocal tumors at diagnosis, which suggests that folic acid may be unsafe for NMIBC patients. These findings provide some evidence for nutritional consultation with regard to folate intake among NMIBC patients. PMID- 29529167 TI - Role of Vitamin D in the Natural History of Inflammatory Bowel Disease. AB - Inflammatory bowel disease [IBD], including ulcerative colitis and Crohn's disease, is a chronic and unpredictable condition characterised by alternating periods of remission interspersed with relapses. In recent years, accumulating support for an immunomodulating effect of vitamin D on both the innate and the adaptive immune systems has been presented. Through the vitamin D receptor, the active form of vitamin D, 1,25[OH]2D, induces antimicrobial peptide secretion, decreases dendritic cell activity, and promotes Th2 and regulatory T cell development and activity. In addition, vitamin D promotes an increased ratio of anti-inflammatory cytokines to pro-inflammatory cytokines. Studies in IBD point to a role for vitamin D in ameliorating disease outcome. Suboptimal circulating levels of 25-hydroxyvitamin D are common in IBD and appear to be associated with an increased risk of flares, IBD-related hospitalisations and surgeries, an inadequate response to tumour necrosis factor [TNF] inhibitors, a deterioration in quality of life, and low bone mineral density. With only few available randomised double-blind, placebo-controlled studies investigating therapeutic effects of vitamin D related to IBD, further research is necessary to determine the true therapeutic potential of vitamin D, as well as to define its optimal range in serum to achieve and maintain quiescence of disease. This review aims to summarise the latest knowledge on the extraskeletal effects of vitamin D in IBD, and outlines the potential deleterious consequences of vitamin D deficiency in this patient cohort. PMID- 29529166 TI - Development of a Dynamic Multi-Protein Signature of Postoperative Delirium. AB - Background: Delirium is common, morbid, and costly, yet its biology is poorly understood. We aimed to develop a multi-protein signature of delirium by identifying proteins associated with delirium from unbiased proteomics and combining them with delirium biomarkers identified in our prior work (interleukin [IL]-6 and IL-2). Methods: We used the Successful Aging after Elective Surgery (SAGES) Study of adults age >=70 undergoing major non-cardiac surgery (N=560; 24% delirium). Plasma was collected preoperatively (PREOP) and on postoperative day 2 (POD2). In a nested matched case-control study involving 12 pairs of delirium cases and no-delirium controls, isobaric tags for relative and absolute quantitation-based (iTRAQ) mass spectrometry proteomics was applied to identify the top set of delirium-related proteins. With these proteins, we then conducted enzyme-linked immunosorbent assay (ELISA) confirmation, and if confirmed, ELISA validation in 75 matched pairs. Multi-marker conditional logistic regression was used to select the 'best' PREOP and POD2 models for delirium. Results: We identified three proteins from iTRAQ: C-reactive protein (CRP), zinc alpha-2 glycoprotein (AZGP1) and alpha-1 antichymotrypsin (SERPINA3). The 'best' multi protein models of delirium included: PREOP: CRP and AZGP1 (Bayesian Information Criteria [BIC] 93.82, c-statistic 0.77); and POD2: IL-6, IL-2, and CRP (BIC 87.11, c-statistic 0.84). Conclusion: The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers) and others at the time of delirium (disease markers). Our dynamic, multi-protein signature for delirium improves our understanding of delirium pathophysiology and may identify patients at-risk of this devastating disorder that threatens independence of older adults. PMID- 29529168 TI - Elevated Total Homocysteine in All Participants and Plasma Vitamin B12 Concentrations in Women Are Associated With All-Cause and Cardiovascular Mortality in the Very Old: The Newcastle 85+ Study. AB - Background: Folate and vitamin B12 are keys to the correct functioning of one carbon (1-C) metabolism. The current evidence on associations between 1-C metabolism biomarkers and mortality is inconclusive and generally based on younger or institutionalized populations. This study aimed to determine the associations between biomarkers of 1-C metabolism and all-cause and cardiovascular (CVD) mortality in the very old. Methods: The Newcastle 85+ Study is a prospective longitudinal study of participants aged 85 at recruitment living in Northeast England. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were available for 752-766 participants. Associations between biomarkers of 1-C metabolism and all-cause and CVD mortality for up to 9 years were assessed by Cox proportional hazard models and confirmed by restricted cubic splines. Results: Participants with higher tHcy concentrations had higher risk of death from any cause (hazard ratio [HR] [*10 MUmol/L]: 1.24, 95% confidence interval [CI]: 1.10-1.41) and cardiovascular diseases (HR [*10 MUmol/L]: 1.23, 95% CI: 1.04-1.45) than those with lower concentrations; and women with higher plasma vitamin B12 concentrations had increased risk of all-cause and cardiovascular mortality (HR [*100 pmol/L]: 1.10, 95% CI: 1.04-1.16) after adjustment for key sociodemographic, lifestyle, and health confounders. Conclusion: Higher concentrations of tHcy in all participants and plasma vitamin B12 in women were associated with increased risk of all-cause and CVD mortality in the very old. This confirms findings for tHcy in younger populations but the adverse relationships between elevated plasma vitamin B12 concentrations and mortality in this setting are novel and require further investigation. PMID- 29529170 TI - Focus cardiac ultrasound core curriculum and core syllabus of the European Association of Cardiovascular Imaging. AB - There is a growing trend of using ultrasound examination of the heart as a first line diagnostic tool for initial patient evaluation in acute settings. Focus cardiac ultrasound (FoCUS) is a standardized but restricted cardiac ultrasound examination that may be undertaken by a range of medical professionals with diverse backgrounds. The intention of this core curriculum and syllabus is to define a unifying framework for educational and training processes/programmes that should result in competence in FoCUS for various medical professionals dealing with diagnostics and treatment of cardiovascular emergencies. The European Association of Cardiovascular Imaging prepared this document in close cooperation with representatives of the European Society of Anaesthesiology, the European Association of Cardiothoracic Anaesthesiology, the Acute Cardiovascular Care Association of the European Society of Cardiology and the World Interactive Network Focused On Critical Ultrasound. It aims to provide the key principles and represents a guide for teaching and training of FoCUS. We offer this document to the emergency and critical care community as a reference outline for teaching materials and courses related to FoCUS, for promoting teamwork and encouraging the development of the field. PMID- 29529171 TI - Reversible aortic valve stenosis with Loffler endocarditis. PMID- 29529169 TI - Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. AB - Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long term ADT or, for most non-metastatic cases, ADT for >=2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly*6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting >=1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naive prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476. PMID- 29529172 TI - Prescription of high-risk medications among patients with chronic kidney disease: a cross-sectional study from the Washington, Wyoming, Alaska, Montana and Idaho region Practice and Research Network. AB - Background: Patients with chronic kidney disease (CKD) are at high risk for adverse drug events related to medication dosing errors and prescriptions for relatively contraindicated medications, such as non-steroidal anti-inflammatory drugs (NSAIDs). Objectives: To examine the scope of and variation in prescribing relatively contraindicated medications and medications above the recommended dose levels among patients with stage III/IV CKD in primary care practice. Methods: This is a cross-sectional descriptive study that used structured electronic health record data. The study participants were patients aged 18 years and older from three primary care clinics in a practice-based research network. Number/proportion of adult patients with stage III/IV CKD; proportion of these patients with at least one NSAID or other relatively contraindicated medication prescribed over 2 years. Results: Of the 7586 eligible adult patients, 4.9% had stage III/IV CKD; 46.6% of these 373 patients with stage III/IV CKD were prescribed at least one relatively contraindicated drug (acarbose, chlorpropamide, glyburide, nitrofurantoin or any NSAID) during the 2-year study period; and 34.0% of patients with stage III/IV CKD were prescribed NSAIDs. Conclusions: Primary care patients with stage III/IV CKD were frequently prescribed or had documented use of relatively contraindicated drugs and thus were at risk of adverse drug events. Given the significant number of individuals with CKD in the USA, research that examines rates of adverse events related to these prescriptions and that tests primary care-based interventions to decrease inappropriate prescribing of relatively contraindicated medications to these patients is needed. PMID- 29529173 TI - The danger lurks dastardly in the coronary vessel wall: spotlight on patients' vulnerability. PMID- 29529174 TI - Mitral plasticity: possible target for intervention in patients with ischaemic mitral regurgitation? PMID- 29529175 TI - An unusual cause of ventricular flutter. PMID- 29529176 TI - Optimization of physicochemical parameters of tannase post-purification and its versatile bioactivity. AB - The present study investigates the optimization of tannase production from Aspergillus nidulans for various physicochemical parameters and harvests tannase for its chemical characterization. The maximum tannase activity was observed on the third day of incubation at 35 degrees C and the stability was observed at pH 5.5-6.0 by holding its 100% activity. The tannase was partially purified from A. nidulans [FT10] by ammonium sulfate precipitation at different concentrations, and it was found that at 80% of ammonium sulfate concentration, the precipitate exhibited the maximum activity for tannase of 96 U/ml. LCMS showed its M/Z value as 162.3 which was reconfirmed by SDS-PAGE. The UV spectrum and FTIR confirmed the presence of two oxy- and three hydroxyl groups in the benzene ring structure. The antibacterial activity of tannase was enhanced with antibiotics such as streptomycin and ceftazidime whereas the biofilm formation was significantly inhibited by the purified tannase. The scavenging activity was greatly increased with purified component and when the concentration of the purified tannase, FT10 was increased. To the best of our knowledge, this is one of the few reports where microbial species was used as the source for producing tannase enzyme and its role in various bioactivities such as antibacterial, anti-biofilm and antioxidant activity was evaluated. PMID- 29529177 TI - Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry. AB - Aims: The optimal fractional flow reserve (FFR) cut-off value for revascularization is debated. We evaluated the prognosis for deferred and performed revascularization in coronary stenosis with FFR values in the grey zone (0.75-0.80). Methods and results: This study included 1334 native coronary stenosis with grey-zone FFR values in 1334 patients from the prospective multicentre Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve registry. Revascularization was deferred for 683 patients (deferred group) and performed for 651 (performed group). The primary outcome, a composite of death, target-vessel myocardial infarction (MI), and target vessel revascularization (TVR) occurred in 55 (8.1%) patients in the deferred group and 55 (8.4%) in the performed group [adjusted hazard ratio (aHR) 1.05, 95% confidence interval (CI) 0.67-1.66; P = 0.79] during a median follow-up of 2.9 years (interquartile range 1.5-4.1 years). Overall mortality and spontaneous MI did not differ between the groups (mortality 2.5% vs. 2.0%; aHR 0.82, 95% CI 0.34 2.00; P = 0.66; spontaneous MI 0.7% vs. 0.5%; aHR 1.85, 95% CI 0.35-9.75; P = 0.47). Myocardial infarction was significantly higher in the performed group (0.7% vs. 3.2%; aHR 0.27, 95% CI 0.09-0.80; P = 0.02) mainly because of a higher risk of periprocedural MI. Target vessel revascularization was significantly higher in the deferred group (5.7% vs. 3.7%; aHR 2.17, 95% CI 1.17-4.02; P = 0.01). Conclusion: For coronary stenosis with grey-zone FFR, revascularization was not associated with better clinical outcomes. The higher likelihood of periprocedural MI with revascularization was offset by the higher likelihood of TVR with deferral. Trial registration: Clinicaltrials.gov identifier: NCT01366404. PMID- 29529178 TI - Yield improvement of epothilones in Burkholderia strain DSM7029 via transporter engineering. AB - Transporter engineering has been shown to be a positive approach for enhancing natural product titers in microbial cell factories by expelling target compounds out of feasible hosts. In this work, two multidrug efflux pumps, Orf14 and Orf3, were modulated in the epothilone production strain Burkholderia DSM7029::Tn5-km epo (named G32) via Red/ET engineering to increase heterologous polyketide epothilone yields. Compared with the prior G32 strain, the total production of several epothilones in the G32::orf14-orf3 mutant was meaningfully doubled according to high-performance liquid chromatography-mass spectrometer analysis. Typically for epothilone B, in simple and clear liquid medium CYMG, the overall productivity in the engineered high-yield producer G32::orf14-orf3 was improved for almost 3-fold, from 2.7 to about 8.1 MUg/l. Additionally, the ratio of extracellular to intracellular accumulation of epothilone B was raised from 9.3:1 to 13.7:1 in response to expression of two putative transport genes orf14 and orf3. Hence, we strongly recommend that the Orf14 and Orf3 transporters export epothilone, thus promotes the forward reaction of biosynthesis on epothilone manufacture inside the cells. Our results afford a practical stage for yield improvement of other heterologous natural products in broad chassis cells. PMID- 29529179 TI - Physical Functioning Decline and Mortality in Older Adults with Multimorbidity: Joint Modeling of Longitudinal and Survival Data. AB - Background: Multimorbidity is common among older adults and strongly associated with physical functioning decline and increased mortality. However, the full spectrum of direct and indirect effects of multimorbidity on physical functioning and survival has not been quantified. We aimed to determine the longitudinal relationship of multimorbidity on physical functioning and quantify the impact of multimorbidity and multimorbidity-attributed changes in physical functioning on mortality risk. Methods: The Health and Retirement Study is a nationally representative population-based prospective cohort of adults aged 51 or older. In 2000, participants were interviewed about physician-diagnosed chronic conditions, from which their multimorbidity-weighted index (MWI) was computed. Between 2000 2011, participants reported their current physical functioning using a modified Short Form-36. With MWI as a time-varying exposure, we jointly modeled its associations with physical functioning and survival. Results: The final sample included 74,037 observations from 18,174 participants. At baseline, participants had a weighted mean MWI of 4.64.2 (range 0-36.8). During follow-up, physical functioning declined -1.72 (95% CI: -1.77, -1.67, p<0.001) HRS physical functioning units per point MWI in adjusted models. Over follow-up, 6,362 (34%) participants died. Mortality risk increased 8% (HR 1.08, 95% CI 1.07-1.08, p<0.001) per point MWI in adjusted models. Across all population subgroups, MWI was associated with greater physical functioning decline and mortality risk. Conclusions: Multimorbidity and its associated decline in physical functioning were significantly associated with increased mortality. These associations can be predicted with an easily interpreted and applied multimorbidity index that can better identify and target adults at increased risk for disability and death. PMID- 29529182 TI - The prognostic impact of periprocedural myocardial infarction and injury. PMID- 29529181 TI - Estimation of myocardial work from pressure-strain loops analysis: an experimental evaluation. AB - Purpose: The area of left ventricular (LV) pressure-strain loop (PSL) is used as an index of regional myocardial work. The purpose of the present work is to compare the main segmental PSL markers and the derived global work indices, when they are calculated using an estimated pressure signal or an observed pressure signal. Methods and results: In nine patients implanted with a bi-ventricular pace-maker (CRT), LV pressure was invasively measured in five conditions: CRT off, LV-pacing, right ventricular-pacing and two different CRT-pacing. For each condition, systolic blood pressure was measured by brachial artery cuff-pressure and transthoracic echocardiography loops were recorded simultaneously. The error and relative root mean square error (rRMSE) between measured and estimated pressure were calculated for each patient and each configuration. Correlation coefficient (R2) and Bland-Altman (BA) analysis were performed for PSL area and work indices. A total of 43 different haemodynamic conditions were compared (774 segmental PSL). The global rRMSE between estimated and measured LV-pressure was 12.3 mmHg. The estimated and measured segmental LV-PSL were strongly correlated, with an R2 of 0.98. BA analysis shows that the mean bias for the estimation of segmental LV-PSL area is 86.0 mmHg.%. A significant bias effect with linearly increasing error with pressure values is observed. R2 >= 0.88 and a mean bias in BA analysis <=41.4 mmHg.% was observed for the estimation of global myocardial work indices. Conclusion: The non-invasive estimation for LV pressure-strain loop area and the global myocardial work indices obtained from LV-PSL strongly correlates with invasive measurements. PMID- 29529183 TI - Identification of influencing factors and strategies to improve communication between general practitioners and community nurses: a qualitative focus group study. AB - Background: As the number of patients with complex healthcare needs grows, inter professional collaboration between primary care professionals must be constantly optimized. General practitioners (GPs) and community nurses (CNs) are key professions in primary care; however, poor GP-CN communication is common, and research into the factors influencing its quality is limited. Objective: To explore patient-related GP-CN communication and facilitating and hindering factors, and to identify strategies to enhance this communication. Method: A qualitative focus group design was used to identify the facilitating and hindering factors and strategies for improvement. In a Dutch primary care setting, 6 mono-professional focus group interviews (3 meetings of 13 GPs; 3 meetings of 18 CNs) were organized between June 2015 and April 2016, recorded and transcribed verbatim. Two independent researchers performed the coding of these interviews, identifying their categories and themes. Results: Results show that, despite the regular contact between GPs and CNs, communication was generally perceived as poor in effectiveness and efficiency by both professions. Mutual trust was considered the most important facilitating factor for effective communication. Profession-specific factors (e.g. differences in responsibility and profession-specific language) and organizational factors (e.g. lack of shared care plans, no in-person communication, lack of time) may be of influence on communication. Participants' suggestions for improvement included organizing well structured and reimbursed team meetings and facilitating face-to-face contact. Conclusion: GP-CN patient-related communication benefits most from trusting inter personal relationships. Inter-professional training programmes should address both professional and organizational factors and should be evaluated for their effect on quality of care. PMID- 29529184 TI - Contained right atrial rupture: an unusual presentation of a rare primary cardiac tumour. PMID- 29529180 TI - Echocardiographic reference ranges for normal left atrial function parameters: results from the EACVI NORRE study. AB - Aims: To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. Methods and results: A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and -0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. Conclusion: The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions. PMID- 29529185 TI - Validation of reference genes for reverse transcription real-time quantitative PCR analysis in the deep-sea bacterium Shewanella psychrophila WP2. AB - Reference genes are critical to obtain reliable results of reverse transcription real-time quantitative PCR (RT-qPCR), which is widely used for relative quantification of gene expression. In this study, we evaluated the validity of seven candidate reference genes for normalization in RT-qPCR analysis in the deep sea bacterium Shewanella psychrophila WP2 under different environmental conditions. Among the set of genes investigated, gyrA, 16S rRNA and rho were identified as the most suitable reference genes for WP2 at different temperatures, hydrostatic pressures and salinities, respectively. Notably, the rho gene is conserved in Shewanella genus and other deep-sea bacteria, thus, could be used as a versatile reference gene for RT-qPCR analysis of these microorganisms under extreme environmental conditions. PMID- 29529186 TI - To meet the unmet needs. PMID- 29529187 TI - Multiple embolization in infective endocarditis. PMID- 29529188 TI - Erratum. PMID- 29529189 TI - CORRIGENDUM FOR "Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development". PMID- 29529190 TI - Should de-escalation of bone-targeting agents be standard of care? PMID- 29529192 TI - Bone marrow PDGFRalpha+Sca-1+-enriched mesenchymal stem cells support survival of and antibody production by plasma cells in vitro through IL-6. AB - Plasma cells (PCs) acquiring long lifespans in the bone marrow (BM) play a pivotal role in the humoral arm of immunological memory. The PCs reside in a special BM niche and produce antibodies against past-encountered pathogens or vaccine components for a long time. In BM, cysteine-X-cysteine (CXC) chemokine receptor type 4 (CXCR4)-expressing PCs and myeloid cells such as dendritic cells are attracted to and held by CXC chemokine ligand 12 (CXCR12)-secreting stromal cells, where survival of the PCs is supported by soluble factors such as IL-6 and APRIL (a proliferation-inducing ligand) produced by neighboring myeloid cells. Although these stromal cells are also supposed to be involved in the support of the survival and antibody production, the full molecular mechanism has not been clarified yet. Here, we show that BM PDGFRalpha+Sca-1+-enriched mesenchymal stem cells (MSCs), which can contribute as stromal cells for hematopoietic stem cells, also support in vitro survival of and antibody production by BM PCs. IL-6 produced by MSCs was found to be involved in the support. Immunohistochemistry of BM sections suggested a co-localization of a minor population of PCs with PDGFRalpha+Sca-1+ MSCs in the BM. We also found that the sort-purified MSC preparation was composed of multiple cell groups with different gene expression profiles, as found on single-cell RNA sequencing, to which multiple roles in the in vitro PC support could be attributed. PMID- 29529191 TI - Overview of mitral regurgitation in Europe: results from the European Registry of mitral regurgitation (EuMiClip). AB - Aims: To determine the prevalence of mitral regurgitation (MR) in a large cohort of consecutive patients undergoing clinically indicated echocardiography and to examine the distribution of primary and secondary MR. Methods and results: All patients undergoing an echocardiographic study in 19 European centres within a 3 month period were prospectively included. MR assessment was performed as recommended by the European Association of Cardiovascular Imaging (EACVI). MR was classified according to mechanism as primary or secondary and aetiologies were reported. A total of 63 463 consecutive echocardiographic studies were reviewed. Any degree of MR was described in 15 501 patients. Concomitant valve disease of at least moderate grade was present in 28.5% of patients, being tricuspid regurgitation the most prevalent. In the subgroup of moderate and severe MR (n = 3309), 55% of patients had primary MR and 30% secondary MR. Both mechanisms were described in 14% of the studies. According to Carpentier's classification, 26.7% of MR were classified as I, 19.9% of MR as II, 22.4% of MR as IIIa, and 31.1% of MR as IIIb. Conclusion: To date, this is the largest echocardiography-based study to analyse the prevalence and aetiology distribution of MR in Europe. The burden of secondary MR was higher than previously described, representing 30% of patients with significant MR. In our environment, degenerative disease is the most common aetiology of primary MR (60%), whereas ischaemic is the most common aetiology of secondary MR (51%). Up to 70% of patients with severe primary MR may have a Class I indication for surgery. However, the optimal therapeutic approach for secondary MR remains uncertain. PMID- 29529193 TI - Multifocal bilateral palmar and digital varices. PMID- 29529194 TI - Dyssynergic Defecation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. AB - Background: Inflammatory bowel disease (IBD) patients often continue to experience nonspecific gastrointestinal symptoms despite quiescent disease. Unlike non-IBD patients, IBD patients with dyssynergic defecation (DD) may present with various symptoms such as diarrhea, fecal incontinence, constipation, and rectal discomfort. Despite its importance and treatability, DD in IBD patients is not well recognized in practice. We conducted a systematic review and meta-analysis on the prevalence, diagnosis, and management of DD in IBD patients with ongoing defecatory symptoms. Methods: We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews (from 1966 through February 2017) to identify relevant studies on the prevalence, diagnostic methods, or management of DD in IBD patients with and without ileal pouch-anal anastomoses (IPAAs). A random effects model was used to calculate the pooled estimates with 95% confidence intervals (CIs). Heterogeneity was assessed with I2 statistics, Cochran Q statistic, and sensitivity analyses. Results: Seven studies (n = 442) were included. In patients with ongoing defecatory symptoms, the prevalence of DD without IPAA ranged from 45% to 97%, and in patients with IPAA, it ranged from 25% to 75%. The prevalence of DD in IPAA patients with and without pouchitis ranged from 17% to 67% and 29% to 50%, respectively. The pooled response rate to biofeedback therapy in patients without IPAA was 70% (95% CI, 55%-84%; I2 = 95%; P < 0.01), and it was 86% (95% CI, 67%-98%; I2 = 61%; P = 0.05) in those with IPAA. Conclusions: Despite limited data, the current literature suggests that DD is highly prevalent in active or quiescent IBD patients with ongoing defecatory symptoms and is responsive to biofeedback therapy. Although more studies are needed, DD should be considered in IBD patients with persistent defecatory symptoms. PMID- 29529196 TI - Catheter intervention to treat migrated temporary epicardial pacing wire into the left side of the heart. AB - Temporary epicardial pacing wires (TEPWs) have been used routinely in cardiovascular surgery. Most TEPWs are associated with low morbidity, and serious complications rarely occur. Migration of TEPWs is rare and typically involves the right side of the heart. Migration into the left side of the heart is extremely rare, and most patients with this complication have been treated with open surgery. We describe 2 patients with migration of TEPWs into the left side of the heart who were treated using a catheter intervention technique. PMID- 29529195 TI - Effects of prenatal exposure to ambient air pollutant PM10 on ultrasound-measured fetal growth. AB - Background: Limited epidemiological studies have investigated the relationship between prenatal exposure to ambient particulate matter and risk of abnormal fetal growth, and have reached inconclusive results. No study has been conducted in areas with very high air pollution levels. We investigated the hypothesis that exposure to high levels of particulate matter with aerodynamic diameter no larger than 10 um (PM10) during pregnancy increases the risk of abnormal fetal growth. Methods: A birth cohort study was performed in Lanzhou, China, 2010-12, including 8877 pregnant women with 18 583 ultrasound measurements of four fetal growth parameters during pregnancy, including biparietal diameter (BPD), femur length (FL), head circumference (HC) and abdominal circumference (AC). Mixed-effects modelling was used to examine the associations between PM10 exposure and risk of abnormal fetal growth. Results: When average PM10 exposure from conception until the ultrasound examination exceeded 150 ug/m3, there were significant increases in standardized FL (beta = 0.095, P = 0.0012) and HC (beta = 0.090, P = 0.0078) measures. When average PM10 exposure was treated as continuous variable, we found a significant decrease in standardized BPD (beta = -0.018, P = 0.0016) as per 10 ug/m3 increase in PM10. After examining the associations by various exposure windows, positive associations between higher levels of PM10 and fetal overgrowth were consistently seen for HC measures. Conclusions: Our study suggested that prenatal exposure to high levels of ambient PM10 increased the risk of abnormal fetal growth. The findings from our study have important public health implications and also call for future studies to explore the underlying mechanisms and post-natal consequences of these findings. PMID- 29529197 TI - A New Multidimensional Questionnaire to Assess Awareness of Age-Related Change (AARC). AB - Background and Objectives: This two-study article describes the development and evaluation of a multidimensional questionnaire based on the subjective aging construct Awareness of Age-Related Change (AARC). AARC captures the inherent multidimensionality and complexity of aging attitudes, which are strongly linked to indicators of successful aging, including health and well-being. Research Design and Methods: In Study 1, we generated a large item pool related to subjective aging experiences and then evaluated the psychometric properties of a 189-item version of the AARC questionnaire in a sample of 396 adults aged 40-95 years. Based on findings from Study 1, we retained the best-performing items and arrived at a more parsimonious 50-item version (AARC-50). In Study 2, the psychometric properties of the 50-item version were examined in an expanded sample of 424 adults ages 40-98. Results: Factor analyses in Study 1 indicated a two-factor structure of the questionnaire, representing the awareness of positive (AARC-Gains) and negative (AARC-Losses) age-related changes across five behavioral domains. Confirmatory factor analysis in Study 2 further supported this two-factor structure. In both studies, the AARC questionnaire demonstrated strong psychometric properties, including scale and item reliability, convergent and divergent validity, and predictive validity. Discussion and Implications: The availability of a reliable and valid assessment tool for measuring AARC-Gains and AARC-Losses allows researchers to capture detailed information about adults' positive and negative self-perceptions of aging across multiple behavioral domains, which are instrumental for promoting successful aging. PMID- 29529198 TI - A Novel Topical PPARgamma Agonist Induces PPARgamma Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models. AB - Background: Peroxisome proliferator-activated receptor-gamma (PPARgamma) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARgamma agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARgamma-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPARgamma agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis. Results: AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-alpha, IL-1beta, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-alpha, IL-1beta, and IL-13 levels. Conclusions: AS002 triggers anti-inflammatory PPARgamma activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients. PMID- 29529200 TI - Development of the 'Sigue la Huella' physical activity intervention for adolescents in Huesca, Spain. AB - Engaging in physical activity (PA) on a regular and adequate basis generates considerable benefits for health. In developed countries, the time spent doing PA is decreasing, whilst sedentary time (ST) is increasing. A multicomponent school based intervention programme, called 'Sigue la Huella' (Follow the Footprint), was developed to reduce sedentary lifestyles and increase PA levels. This programme has proven to be effective in increasing the daily levels of moderate to vigorous PA, in decreasing ST and in improving motivational outcomes in secondary education students, in the city of Huesca (Spain). The study design was quasi-experimental, longitudinal and by cohorts, and it was carried out in four schools, two as an experimental group (n = 368) and two as a control group (n = 314). During the 25 months' intervention, this programme adopted a holistic approach aiming to create favourable environments to engage in PA, and the empowerment of students to get actively involved in the design and execution of the activities, assuming responsibility for managing and optimizing their own PA. The programme is theoretically based on the social-ecological model and self determination theory, and it provided evidence for four actions or components that can be used in school-based PA promotion: tutorial action, Physical Education at school, dissemination of information and participation in institutional programmes and events. The aim of this article is to describe the main characteristics of the intervention programme that have proved to be effective with respect to the objectives proposed. PMID- 29529199 TI - Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss. AB - Reactive oxygen species exert important functions in regulating several cellular signalling pathways. However, an excessive accumulation of reactive oxygen species can perturb the redox homeostasis leading to oxidative stress, a condition which has been associated to many neurodegenerative disorders. Accordingly, alterations in the redox state of cells and mitochondrial homeostasis are established hallmarks in both familial and sporadic Parkinson's disease cases. PINK1 and Parkin are two genes which account for a large fraction of autosomal recessive early-onset forms of Parkinson's disease and are now firmly associated to both mitochondria and redox homeostasis. In this study we explored the hypothesis that superoxide anions participate in the generation of the Parkin and PINK1 associated phenotypic effect by testing the capacity of endogenous and exogenous superoxide dismutating molecules to rescue the toxic effects induced by loss of PINK1 or Parkin, in both cellular and fly models. Our results demonstrate the positive effect of an increased level of superoxide dismutase proteins on the pathological phenotypes, both in vitro and in vivo. A more pronounced effectiveness for mitochondrial SOD2 activity points to the superoxide radicals generated in the mitochondrial matrix as the prime suspect in the definition of the observed phenotypes. Moreover, we also demonstrate the efficacy of a SOD-mimetic compound, M40403, to partially ameliorate PINK1/Parkin phenotypes in vitro and in vivo. These results support the further exploration of SOD-mimetic compounds as a therapeutic strategy against Parkinson's disease. PMID- 29529201 TI - Is it safe to go back into the water? A systematic review and meta-analysis of the risk of acquiring infections from recreational exposure to seawater. AB - Background: Numerous illnesses are associated with bathing in natural waters, although it is assumed that the risk of illness among bathers exposed to relatively clean waters found in high-income countries is negligible. A systematic review was carried out to quantify the increased risk of experiencing a range of adverse health outcomes among bathers exposed to coastal water compared with non-bathers. Methods: In all 6919 potentially relevant titles and abstracts were screened, and from these 40 studies were eligible for inclusion in the review. Odds ratios (OR) were extracted from 19 of these reports and combined in random-effect meta-analyses for the following adverse health outcomes: incident cases of any illness, ear infections, gastrointestinal illness and infections caused by specific microorganisms. Results: There is an increased risk of experiencing symptoms of any illness [OR = 1.86, 95% confidence interval (CI): 1.31 to 2.64, P = 0.001] and ear ailments (OR = 2.05, 95% CI: 1.49 to 2.82, P < 0.001) in bathers compared with non-bathers. There is also an increased risk of experiencing gastrointestinal ailments (OR = 1.29, 95% CI: 1.12 to 1.49, P < 0.001). Conclusions: This is the first systematic review to evaluate evidence on the increased risk of acquiring illnesses from bathing in seawater compared with non-bathers. Our results support the notion that infections are acquired from bathing in coastal waters, and that bathers have a greater risk of experiencing a variety of illnesses compared with non-bathers. PMID- 29529202 TI - Prolonged estrogen (E2) treatment prior to frozen-blastocyst transfer decreases the live birth rate. AB - STUDY QUESTION: How does the duration of estrogen (E2) treatment prior to frozen blastocyst transfers affect the live birth rate (LBR)? SUMMARY ANSWER: Prolonged E2 exposure as part of artificial endometrial preparation (AEP) significantly decreases the LBR after autologous frozen-thawed blastocyst transfer. WHAT IS KNOWN ALREADY: One effective method for endometrial preparation prior to frozen embryo transfer is AEP, a sequential regimen with E2 and progesterone, which aims to mimic the endocrine exposure of the endometrium in a normal cycle. Nevertheless, the optimal duration of E2 administration prior to transfer remains unknown. STUDY DESIGN, SIZE, DURATION: An observational cohort study was conducted in a tertiary care university hospital between 01/07/2012 and 31/12/2015. The main inclusion criteria was having a single frozen-thawed blastocyst transfer with an AEP using exogenous E2. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1377 frozen-thawed blastocyst transfers were assigned to four groups according to the duration of the E2 administration prior to the embryo transfers. These comprised a '<=21 days' group (n = 330), a '22-28 days' group (n = 665), a '29-35 days' group (n = 289) and a '36-48 days' group (n = 93). The '<=21 days' group' was taken as the reference group. The main measured outcome was the LBR following frozen-thawed blastocyst transfers. Statistical analysis was conducted using univariate and multivariate logistic regression models. MAIN RESULTS AND THE ROLE OF CHANCE: LBR significantly decreased when the E2 exposure prior to the frozen-thawed blastocyst transfer exceeded 28 days: OR = 0.66; 95% CI [0.46-0.95]; P = 0.026 and OR = 0.49 [0.27-0.89]; P = 0.018, respectively, for the '29 to 35 days' group and for the '36 to 48 days' group compared to the reference group. Early pregnancy loss rates significantly increased when the E2 exposure lasted more than 35 days prior to the frozen thawed blastocyst transfer (OR = 2.37 [1.12-5.05]; P = 0.025 vs. the reference group). After multivariate logistic regression, E2 exposure lasting more than 28 days prior to the frozen-thawed blastocyst transfer was associated with a decrease in the LBR, for the '29-35 days' group (OR = 0.65; [0.45-0.95]; P = 0.044) as for the '36-48 days' group (OR = 0.49; [0.26-0.92]; P = 0.035), vs. the reference group. LIMITATIONS, REASONS FOR CAUTION: One limitation is linked to the observational design of this study. WIDER IMPLICATIONS OF THE FINDINGS: In order to give patients the best chance to obtain a live birth after frozen-thawed blastocyst transfer, the length of E2 exposure prior to the frozen-blastocyst transfer should not exceed 28 days. This study provides new insight in regard to endometrial preparation using AEP prior to frozen-blastocyst transfer. STUDY FUNDING/COMPETING INTEREST(S): No funding and no competing interest. PMID- 29529203 TI - Clinical pathways for primary care: current use, interest and perceived usability. AB - Objective: Translating clinical evidence to daily practice remains a challenge and may improve with clinical pathways. We assessed interest in and usability of clinical pathways by primary care professionals. Methods: An online survey was created. Interest in pathways for patient care and learning was assessed at start and finish. Participants completed baseline questions then pathway-associated question sets related to management of 2 chronic diseases. Perceived pathway usability was assessed using the system usability scale. Accuracy and confidence of answers was compared for baseline and pathway-assisted questions. Results: Of 115 participants, 17.4% had used clinical pathways, the lowest of decision support tool types surveyed. Accuracy and confidence in answers significantly improved for all pathways. Interest in using pathways daily or weekly was above 75% for the respondents. Conclusion: There is low utilization of, but high interest in, clinical pathways by primary care clinicians. Pathways improve accuracy and confidence in answering written clinical questions. PMID- 29529204 TI - Strategies of adaptation of microorganisms of the three domains of life to high salt concentrations. AB - Hypersaline environments with salt concentrations up to NaCl saturation are inhabited by a great diversity of microorganisms belonging to the three domains of life. They all must cope with the low water activity of their environment, but different strategies exist to provide osmotic balance of the cells' cytoplasm with the salinity of the medium. One option used by many halophilic Archaea and a few representatives of the Bacteria is to accumulate salts, mainly KCl and to adapt the entire intracellular machinery to function in the presence of molar concentrations of salts. A more widespread option is the synthesis or accumulation of organic osmotic, so-called compatible solutes. Here, we review the mechanisms of osmotic adaptation in a number of model organisms, including the KCl accumulating Halobacterium salinarum (Archaea) and Salinibacter ruber (Bacteria), Halomonas elongata as a representative of the Bacteria that synthesize organic osmotic solutes, eukaryotic microorganisms including the unicellular green alga Dunaliella salina and the black yeasts Hortaea werneckii and the basidiomycetous Wallemia ichthyophaga, which use glycerol and other compatible solutes. The strategies used by these model organisms and by additional halophilic microorganisms presented are then compared to obtain an integrative picture of the adaptations to life at high salt concentrations in the microbial world. PMID- 29529205 TI - Carotid stenosis with impaired brain flow reserve is associated with an increased risk of stroke in on-pump cardiovascular surgery. AB - OBJECTIVES: To prevent haemodynamic stroke during cardiovascular surgery in patients with carotid stenosis, we routinely evaluated magnetic resonance angiography and selectively evaluated brain perfusion single-photon emission computed tomography with acetazolamide challenge. Off-pump surgery was preferred when cerebral blood flow reserve was impaired. This strategy's usefulness was investigated. METHODS: Among the 1059 consecutive patients who underwent preoperative carotid screening by magnetic resonance angiography, 84 (7.9%) patients had >50% stenosis; 45 of them underwent brain single-photon emission computed tomography. The severity of cerebral blood flow compromise was estimated by the proportion of Stage 2 area in the affected territory, in which both resting blood flow (<32 ml/min) and flow reserve (<10%) were reduced. RESULTS: Perioperative stroke occurred in 1.7% overall (18/1059), in 6% (5/84) of those with carotid stenosis and in 1.3% (13/975) of those without stenosis (P = 0.010). On subgroup analysis, carotid stenosis was associated with an increased risk of stroke in the on-pump surgery group [n = 949, 5/59 (9%) with stenosis vs 11/890 (1.1%) without stenosis, P = 0.002], while it was not in the off-pump group [n = 110, 0/25 (0%) with stenosis vs 2/85 (2%) without stenosis, P = 0.59]. With respect to the role of acetazolamide single-photon emission computed tomography, 2 of the 4 patients with Stage 2 area >10% undergoing on-pump surgery without preceding carotid revascularization developed stroke, while none of the 21 patients with Stage 2 area <10% undergoing on-pump surgery developed stroke (P = 0.020). CONCLUSIONS: Carotid stenosis is a risk factor for perioperative stroke in on-pump surgery. Patients with large Stage 2 area (>10%) are at increased risk of perioperative stroke when on-pump surgery is performed. PMID- 29529206 TI - Mechanical Bowel Preparation (MBP) Prior to Elective Colorectal Resections in Crohn's Disease Patients. AB - Background: Studies addressing the role of mechanical bowel preparation (MBP) in Crohn's disease (CD) patients are lacking. Methods: Consecutive elective colorectal resections for CD have been included in the present analysis. Exclusion criteria were small bowel resections not including colon, urgent surgeries, surgeries for cancer, and abdominoperineal resections for perianal disease. MBP was performed routinely between 1992 and 2004, omitted between 2005 and 2015, and reintroduced in 2016.Intraabdominal septic complications (IASC) were anastomotic leakage, intraabdominal abscess, intestinal fistula, and peritonitis. Results: Overall, 680 bowel resections for CD have been performed between 1992 and 2017. After exclusion of the abovementioned patients, 549 patients were included in the present analysis. The IASC rate was 12% in patients undergoing surgery after MPB as opposed to 24% when MBP was omitted (P < 0.001). By the multivariate analysis, preoperative MBP significantly reduced the risk of IASC (Hazard ratio 0.45; 95% CI, 0.23 - 0.86; P = 0.016). Preoperative weight loss (HR 2.0; 95% CI, 1.1 - 3.6; P = 0.024), penetrating disease (HR 2.6; 95% CI, 1.3 - 5.4; P = 0.01), and stapled as opposed to hand-sewn ileocolic anastomosis (HR 3.3; 95% CI, 1.4 - 7.7; P = 0.006) were associated with an increased risk of IASC. The positive impact of MBP was strongest on anastomotic complication rate in patients undergoing ileocolic resections for penetrating disease (11% vs 36%, P < 0.001). Conclusion: Preoperative MPB should be strongly considered before colorectal surgery in patients with CD, especially in patients undergoing ileocolic resections for penetrating disease. PMID- 29529207 TI - Host cell cytosolic immune response during Plasmodium liver stage development. AB - Recent years have witnessed a great gain in knowledge regarding parasite-host cell interactions during Plasmodium liver stage development. It is now an accepted fact that a large percentage of sporozoites invading hepatocytes fail to form infectious merozoites. There appears to be a delicate balance between parasite survival and elimination and we now start to understand why this is so. Plasmodium liver stage parasites replicate within the parasitophorous vacuole (PV), formed during invasion by invagination of the host cell plasma membrane. The main interface between the parasite and hepatocyte is the parasitophorous vacuole membrane (PVM) that surrounds the PV. Recently, it was shown that autophagy marker proteins decorate the PVM of Plasmodium liver stage parasites and eliminate a proportion of them by an autophagy-like mechanism. Successfully developing Plasmodium berghei parasites are initially also labeled but in the course of development, they are able to control this host defense mechanism by shedding PVM material into the tubovesicular network (TVN), an extension of the PVM that releases vesicles into the host cell cytoplasm. Better understanding of the molecular events at the PVM/TVN during parasite elimination could be the basis of new antimalarial measures. PMID- 29529210 TI - Longitudinal Associations of Autonomy, Relatedness, and Competence with the Well being of Nursing Home Residents. AB - Background and Objectives: As proposed by the self-determination theory, satisfying nursing home residents' needs for autonomy, relatedness, and competence may improve their well-being. This is the first study to test the longitudinal relations of the satisfaction of these three basic psychological needs to the subjective well-being of nursing home residents and to determine whether a balance among the satisfaction of the three needs is important for well being. Research Design and Methods: Participants in this longitudinal survey study included 128 physically frail residents (mean age 85 years) at four Dutch nursing homes. Satisfaction of the three basic psychological needs was measured at baseline, and depressive feelings and life satisfaction 5-8 months later. Absolute differences between the three basic need satisfaction scores were summed to create a score of need satisfaction balance. Results: All three needs were related to both well-being measures over time, although autonomy had the strongest relationships. Only autonomy and competence were uniquely associated with depressive feelings, and only autonomy was uniquely associated with life satisfaction. The need satisfaction balance score was related to well-being independent of the autonomy and relatedness scores. Discussion and Implications: These results confirm that all three basic psychological needs are important for nursing home residents' well-being, with autonomy having the strongest and most consistent relationship to their well-being. Additionally, high satisfaction of one need does not compensate for low satisfaction of another. Supporting residents' needs for autonomy, relatedness, and competence should, therefore, have a central role in nursing home culture-change interventions. PMID- 29529209 TI - Handgrip Strength and Blood Pressure in Children and Adolescents: Evidence From NHANES 2011 to 2014. AB - BACKGROUND: Previous studies have reported that handgrip strength, a measure of muscular fitness, is associated with cardiovascular risk factors. However, the association of handgrip strength with blood pressure (BP) in children has been inconsistent. We tested the association of handgrip strength with systolic and diastolic BP in children and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. METHODS: The study included 3,929 participants aged 8-19 years who underwent a handgrip test. The sum of the maximum handgrip strength from both hands was used. General linear models were used to examine the associations between handgrip strength and the outcome variables. RESULTS: After adjustment for age, race, sex, body mass index, and physical activities, handgrip strength was significantly and positively associated with systolic (P < 0.0001) and diastolic (P = 0.01) BP. There was an increasing trend in systolic BP as handgrip strength increased from the bottom quartile to the top quartile, with 2.1 mm Hg difference between the top and the bottom quartiles (P for trend <0.0001). Similar results were observed for diastolic BP. CONCLUSIONS: Muscular fitness is positively associated with BP in children and adolescents. The implications and underlying mechanisms for these results need further examinations. PMID- 29529208 TI - Comparisons of bacterial and archaeal communities in the rumen and a dual-flow continuous culture fermentation system using amplicon sequencing. AB - Dual-flow continuous culture (CC) fermenters are commonly used to study rumen fermentation in vitro. Research using culture-based and oligonucleotide techniques has shown that certain microbial populations within fermenters may be maintained at abundances similar to those observed in vivo. In this study, bacterial and archaeal communities in the rumen of dairy cattle and in a dual flow CC fermentation system were compared using high-throughput amplicon sequencing targeting the V4 hypervariable region of 16S rRNA. We hypothesized that the in vitro system harbored a comparable bacterial and archaeal community to that observed in the rumen. Members of the Bacteroidetes and Firmicutes made up the 2 most abundant phyla in the rumen, inoculum, and fermenters and did not differ among sample types (P > 0.10). Similarly, Prevotellaceae, the most abundant family in all 3 sample types, did not differ based on source (P = 0.80). However, beta diversity analyses revealed that bacterial and archaeal communities differed between fermenters and rumen samples (P <= 0.001), but fermenter bacterial and archaeal communities stabilized by day 4 of each period. While the overall bacterial and archaeal community differs between natural rumens and those detected in in vitro fermenter systems, several prominent taxa were maintained at similar relative abundances suggesting that fermenters may provide a suitable environment in which to study shifts among the predominant members of the microbial community. PMID- 29529213 TI - Bone cement in the right heart. PMID- 29529212 TI - Inverse Association Between Circulating Monocyte-Platelet Complexes and Inflammation in Ulcerative Colitis Patients. AB - Background: Circulating monocytes from active ulcerative colitis (UC) patients produced high levels of tumor necrosis factor-alpha(TNFalpha) and interleukin(IL) 6 after Toll-like receptors (TLR) stimulation. Since platelets (PLT) can bind to leukocytes, thereby decreasing inflammatory cytokine production, UC patients may exhibit different levels of monocyte-platelet complexes depending on disease activity. Methods: We compared among healthy donors, active (onset flare and relapse), and inactive UC patients the presence of circulating monocyte-platelet complexes (CD14+PLT+) and membrane CD162 expression by flow cytometry. Lipopolysaccharide- binding protein, TNFalpha, and IL-10 were compared by ELISA. Binding of CD14+PLT+ to human umbilical vein endothelial cells (HUVECs) were analyzed by immunofluorescence. Results: Onset flare UC patients had the lowest levels of CD14+PLT+. Membrane CD162, crucial for the PLT binding, was downregulated only on monocytes from onset flare UC patients. Membrane CD162 expression on CD14+ cells inversely correlated with lipopolysaccharide binding protein levels. As an expected consequence, more CD14+PLT+ than CD14+PLT- from onset flare UC patients bound to activated HUVECs. TNFalpha tended to negatively correlate with CD14+PLT+ in relapse and inactive UC patients, whereas IL-10 positively correlated with CD14+PLT+ in all UC patients (r = -0.43, P = 0.1 and r = 0.61, P = 0.01, respectively). The anti-inflammatory role of PLT binding to monocytes was confirmed in cocultures of PLT and monocytes. These cocultures increased the percentage of CD14+PLT+ and IL-10 production, and decreased TNFalpha production. These anti-inflammatory effects were abolished when we blocked the binding of PLT with neutralizing anti-CD62P antibody. Conclusions: Decreased CD162 expression associated with endotoxemia reduced the binding of PLT to monocytes through membrane CD162-CD62P, favoring the inflammatory response of onset flare UC patients. PMID- 29529211 TI - Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation. AB - Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation. The striking efficacy of HSP90i plus chemotherapy vs chemotherapy alone was reproduced in a patient-derived xenograft (PDX) model from a breast cancer patient with a BRCA1 mutation (mean tumor volume [SD], No. of tumors: vehicle 8.38 [7.07] mm3, n = 3; HSP90i 4.18 [1.93] mm3, n = 5; cisplatin plus gemcitabine 3.31 [1.95] mm3, n = 5; cisplatin plus gemcitabine plus HSP90i 0.065 [0.076] mm3, n = 6). This case and the PDX demonstrate the efficacy for therapeutic inhibition of HSP90 in a BRCA-mutated patient, opening a new potential avenue for better identifying patients who might benefit most from HSP90i. PMID- 29529214 TI - Response. PMID- 29529215 TI - The Role of Heparan Sulfate Proteoglycans as an Attachment Factor for Rabies Virus Entry and Infection. AB - Rabies virus (RABV) is the causative agent of fatal neurological disease. Cellular attachment is the initial and essential step for viral infections. Although extensive studies have demonstrated that RABV uses various target cell molecules to mediate infection, no specific molecule has been identified as an attachment factor for RABV infection. Here we demonstrate that cellular heparan sulfate (HS) supports RABV adhesion and subsequent entry into target cells. Enzymatic removal of HS reduced cellular susceptibility to RABV infection, and heparin, a highly sulfated form of HS, blocked viral adhesion and infection. The direct binding between RABV glycoprotein and heparin was demonstrated, and this interaction was shown to require HS N- and 6-O-sulfation. We also revealed that basic amino acids in the ectodomain of RABV glycoprotein serve as major determinants for the RABV-HS interaction. Collectively, our study highlights a previously undescribed role of HS as an attachment factor for RABV infection. PMID- 29529216 TI - Effects of Storage and Granary Weevil Infestation on Gel Electrophoresis and Protein Solubility Properties of Hard and Soft Wheat Flours. AB - The objective of this study was to investigate the effects of storage and granary weevil, Sitophilus granarius (L.; Coleoptera: Curculionidae), infestation on pH, protein solubility (PS) and gel electrophoresis properties of meal and roller milled flours of hard (Ceyhan-99 cv.) and soft (Eser cv.) wheat cultivars, respectively, after 6 mo of storage. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) technique was applied for studying the electrophoretic properties. Hard and soft wheats were infested with non-sexed S. granarius at a rate of two adults/ kg, and stored for 6 mo at 30 +/- 1 degrees C and 70 +/- 5% RH. The pest-free wheat samples were used as control. The infested and its control samples were collected monthly, and after cleaning the granary weevils, they were hammer-milled or roller-milled in order to get meal flours and roller milled flours, respectively. The effect of infestation on the storage proteins was more obvious in meal flours than that of the roller-milled flours. Granary weevil feeding resulted secreting of hydrolyzing enzymes and increased the acidity of flours; subsequently the breaking and releasing of some storage proteins generally caused a decrease in pH and an increase in PS values of the meal flours of wheat cultivars. SDS-PAGE results generally indicated that towards the end of storage, the insect population, that greatly increased, caused minor protein depletions resulting decreasing protein band intensities between 113 and 58 kDa of hard wheat meal flour and 101 and 40 kDa of soft wheat roller-milled flour. Consequently, the potential effect of changes probably occurred in high molecular weight glutenin subunits of both wheat cultivars. PMID- 29529217 TI - Beyond Expert Opinion: Progress in the Development of Evidence-Based Screening Guidelines for Survivors of Childhood Cancer. PMID- 29529218 TI - Technical note: an R package for fitting sparse neural networks with application in animal breeding. AB - Neural networks (NNs) have emerged as a new tool for genomic selection (GS) in animal breeding. However, the properties of NN used in GS for the prediction of phenotypic outcomes are not well characterized due to the problem of over parameterization of NN and difficulties in using whole-genome marker sets as high dimensional NN input. In this note, we have developed an R package called snnR that finds an optimal sparse structure of a NN by minimizing the square error subject to a penalty on the L1-norm of the parameters (weights and biases), therefore solving the problem of over-parameterization in NN. We have also tested some models fitted in the snnR package to demonstrate their feasibility and effectiveness to be used in several cases as examples. In comparison of snnR to the R package brnn (the Bayesian regularized single layer NNs), with both using the entries of a genotype matrix or a genomic relationship matrix as inputs, snnR has greatly improved the computational efficiency and the prediction ability for the GS in animal breeding because snnR implements a sparse NN with many hidden layers. PMID- 29529219 TI - Effect of the Procalcitonin Assay on Antibiotic Use in Critically Ill Children. AB - We retrospectively studied the effect of introducing procalcitonin into clinical practice on antibiotic use within a large academic pediatric intensive care unit. In the absence of a standardized algorithm, availability of the procalcitonin assay did not reduce the frequency of antibiotic initiations or the continuation of antibiotics for greater than 72 hours. PMID- 29529220 TI - MicroRNA-192-5p is a predictive biomarker of survival for Stage IIIB colon cancer patients. AB - Background: The poor clinical prognosis of Stage IIIB colon cancer patients is due in part to the current lack of an effective diagnostic method being available and highlights a need for the identification of novel biomarkers like microRNA (miRNA). Patients and methods: We used microarray analysis to compare the miRNA expression profiles of eight Stage IIIB colon cancer patients with worse clinical outcome (those who developed liver metastases between 8 and 18 months after surgery) against eight 'cured' Stage IIIB colon cancer patients (those who remained disease free following surgery during the same monitoring period). In addition, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed examining miRNAs in tumor tissue of 98 patients with Stage IIIB colon cancer. Results: We found, miRNA-192-3p and miRNA-192-5p were down regulated in the patients with worsening disease compared to the control 'cured' Stage IIIB colon cancer patients (P = 0.026 and P = 0.042, respectively). Patients with higher expression of miRNA-192-5p had higher 5-year disease-free survival (DFS) (84.21%) and overall survival (OS) (89.47%) than those with lower targeted miRNA expression DFS (38.8%; hazard ratio (HR): 3.74, 95% confidence interval (CI): 1.52-9.23, P = 0.042) and OS (48.57%; HR: 5.01, 95% CI: 1.75-14.38, P = 0.033). In contrast, patients with higher expression of miRNA-192-3p did not appear to statistically impact the survival of patients in this setting (DFS 73.33% vs 64.7%, HR: 0.68, 95% CI: 0.31-1.52, P = 0.35; OS 76.67% vs 66.17%, HR: 0.62, 95% CI: 0.27-1.45, P = 0.27). Conclusions: The decreased expression of miRNA-192-5p found for patients with relapsing disease might represent a highly predictive marker to use for the prognosis of Stage IIIB colon cancer patients. PMID- 29529221 TI - Opportunities to Understand Unique Cancer Risks in Global HIV-Infected Populations. PMID- 29529223 TI - Risk of Breast, Prostate, and Colorectal Cancer Diagnoses Among HIV-Infected Individuals in the United States. AB - Background: Although people living with HIV or AIDS (PLWHA) are at higher risk for many cancers, breast, prostate, and colorectal cancer rates are lower in this patient population. Because these tumors are often screen-detected, these inverse associations could be driven by HIV-related differences in utilization of cancer screening. Methods: We ascertained incident breast, prostate, and colorectal cancer in PLWHA using data from the HIV/AIDS Cancer Match Study (1996-2012). Comparisons with general population cancer rates were made using standardized incidence ratios (SIRs), overall and stratified by tumor stage/size, breast cancer estrogen receptor status, and colorectal site. We also examined the potential effect of study design and unmeasured confounding on inverse standardized incidence ratios. Results: Compared with the general population, PLWHA had lower rates of invasive breast (SIR = 0.63, 95% confidence interval [CI] = 0.58 to 0.68), prostate (SIR = 0.48, 95% CI = 0.46 to 0.51), proximal colon (SIR = 0.67, 95% CI = 0.59 to 0.75), distal colon (SIR = 0.51, 95% CI = 0.43 to 0.59), and rectal cancers (SIR = 0.69, 95% CI = 0.61 to 0.77). Reduced risk persisted across tumor stage/size for prostate and colorectal cancers. Although distant-stage breast cancer rates were not reduced (SIR = 0.94, 95% CI = 0.73 to 1.20), HIV-infected women had lower rates of large (>5 cm) breast tumors (SIR = 0.65, 95% CI = 0.50 to 0.83). The magnitude of these inverse standardized incidence ratios could not plausibly be attributed to case underascertainment, out-migration, or unmeasured confounding. Conclusions: Breast, prostate, and colorectal cancer rates are markedly lower among PLWHA, including rates of distant-stage/large tumors that are not generally screen-detected. This set of inverse HIV-cancer associations is therefore unlikely to be due primarily to differential screening and may instead represent biological relationships requiring future investigation. PMID- 29529224 TI - System-Wide Analysis Unravels the Differential Regulation and In Vivo Essentiality of Virulence-Associated Proteins B and C Toxin-Antitoxin Systems of Mycobacterium tuberculosis. AB - Toxin-antitoxin (TA) systems are bicistronic genetic modules that are ubiquitously present in bacterial genomes. The Mycobacterium tuberculosis genome encodes 90 putative TA systems, and these are considered to be associated with maintenance of bacterial genomic stability or bacterial survival under unfavorable environmental conditions. The majority of these in M. tuberculosis have been annotated as belonging to the virulence-associated protein B and C (VapBC) family. However, their precise role in bacterial physiology has not been elucidated. Here, we functionally characterized VapC toxins from M. tuberculosis and show that overexpression of some homologs inhibits growth of Mycobacterium bovis bacillus Calmette-Guerin in a bacteriostatic manner. Expression profiling of messenger RNA revealed that these VapC toxins were differentially induced upon exposure of M. tuberculosis to stress conditions. We also unraveled that transcriptional cross-activation exists between TA systems in M. tuberculosis. This study provides the first evidence for the essentiality of VapBC3 and VapBC4 systems in M. tuberculosis virulence. PMID- 29529222 TI - Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older. AB - Background: The herpes zoster subunit vaccine (HZ/su), consisting of varicella zoster virus glycoprotein E (gE) and AS01B Adjuvant System, was highly efficacious in preventing herpes zoster in the ZOE-50 and ZOE-70 trials. We present immunogenicity results from those trials. Methods: Participants (ZOE-50: >=50; ZOE-70: >=70 years of age) received 2 doses of HZ/su or placebo, 2 months apart. Serum anti-gE antibodies and CD4 T cells expressing >=2 of 4 activation markers assessed (CD42+) after stimulation with gE-peptides were measured in subcohorts for humoral (n = 3293) and cell-mediated (n = 466) immunogenicity. Results: After vaccination, 97.8% of HZ/su and 2.0% of placebo recipients showed a humoral response. Geometric mean anti-gE antibody concentrations increased 39.1 fold and 8.3-fold over baseline in HZ/su recipients at 1 and 36 months post-dose 2, respectively. A gE-specific CD42+ T-cell response was shown in 93.3% of HZ/su and 0% of placebo recipients. Median CD42+ T-cell frequencies increased 24.6-fold (1 month) and 7.9-fold (36 months) over baseline in HZ/su recipients and remained >=5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups. Conclusions: Most HZ/su recipients developed robust immune responses persisting for 3 years following vaccination. Clinical Trials Registration: NCT01165177; NCT01165229. PMID- 29529225 TI - Left ventricular global longitudinal strain and long-term prognosis in patients with chronic obstructive pulmonary disease after acute myocardial infarction. AB - Aims: Left ventricular (LV) systolic function is a known prognostic factor after ST-segment elevation myocardial infarction (STEMI). We evaluated the prognostic value of LV global longitudinal strain (GLS) in patients with chronic obstructive pulmonary disease (COPD) after STEMI. Methods and results: One hundred and forty three STEMI patients with COPD (mean age 70 +/- 11 years, 71% male), were retrospectively analysed. Left ventricular ejection fraction (LVEF) and LV GLS were measured on transthoracic echocardiography within 48 h of admission. Patients were followed for the occurrence of all-cause mortality and the combined endpoint of all-cause mortality and heart failure hospitalization. After a median follow-up of 68 (interquartile range 38.5-99) months, 66 (46%) patients died and 70 (49%) patients reached the combined endpoint. The median LV GLS was -14.4%. Patients with LV GLS >-14.4% (more impaired) showed higher cumulative event rates of all-cause mortality (19%, 26%, and 44% vs. 7%, 8%, and 18% at 1, 2, and 5 years follow-up; log-rank P = 0.004) and the combined endpoint (26%, 34%, and 50% vs. 8%, 10%, and 20% at 1, 2, and 5 years follow-up; log-rank P = 0.001) as compared to patients with LV GLS <=-14.4%. In multivariate analysis, LV GLS > 14.4% was independently associated with increased all-cause mortality and the combined endpoint [hazard ratio (HR) 2.07; P = 0.02 and HR 2.20; P = 0.01, respectively] and had incremental prognostic value over LVEF demonstrated by a significant increase in chi2 (P = 0.023 and P = 0.011, respectively). Conclusion: Impaired LV GLS is independently associated with worse long-term survival in STEMI patients with COPD and has incremental prognostic value over LVEF. PMID- 29529226 TI - Net energy content of canola meal fed to growing pigs and effect of experimental methodology on energy values. AB - An experiment was conducted to determine the digestible energy (DE), metabolizable energy (ME), and net energy (NE) contents of canola meal (CM) and to investigate the effects of basal diet [corn diet vs. corn-soybean meal (SBM) diet] and methodology (difference method vs. regression method) on energy values of CM. Thirty-six growing barrows (20.8 +/- 1.0 kg initial body weight [BW]) were individually housed in metabolism crates and randomly allotted to one of six dietary treatments to give six replicates per treatment. The six experimental diets included a corn diet, a corn-SBM diet, a corn diet with 15 or 30% of CM, and a corn-SBM diet with 15 or 30% of CM. The DE, ME, and NE of CM were determined using the corn diet or the corn-SBM diet as a basal diet. In each basal diet, two additional diets containing 15 or 30% of CM were formulated to compare the determined energy values by the difference method and estimated energy values from the regression method. Feeding level was set at 550 kcal ME/kg BW0.6 per day. Pigs were fed experimental diets for 16 d including 10 d for adaptation and 6 d for total collection of feces and urine. Pigs were then moved into indirect calorimetry chambers to determine 24 h heat production (HP) and 12 h fasting HP. The DE, ME, and NE of CM determined by the difference method were within the 95% confidence intervals estimated for the DE, ME, and NE of CM by the regression method regardless of the basal diets used, which indicates that the difference and regression methods give equivalent DE, ME, and NE of CM. However, when the goodness of fit for the linear model was compared, the r2 of the regression analysis from the corn-SBM diet (0.78) was relatively greater than that from corn diet (0.40). The estimated NE of CM by the prediction equations generated by either the corn diet or corn-SBM diets were 2,096 kcal/kg and 1,960 kcal/kg (as-fed basis), respectively, whereas those values determined by the difference method were 2,233 kcal/kg and 2,106 kcal/kg (as-fed basis), respectively. In conclusion, the NE of CM determined in the current study was, on average, 2,099 kcal/kg (as-fed basis). The difference and regression methods do not give different NE value of CM fed to growing pigs. Although the NE values of CM determined using either the corn diet or the corn-SBM diet were not different, the greater r2 of the regression analysis from the corn-SBM diet than that from the corn diet suggests that the corn-SBM diet is a more appropriate basal diet for NE determination of ingredients. PMID- 29529227 TI - Methods and consequences of including feed intake and efficiency in genetic selection for multiple-trait merit. AB - Methods are presented for including feed intake and efficiency in genetic selection for multiple-trait merit when commercial production is from any combination of pasture or concentrates. Consequences for the production system and for individual animals are illustrated with a beef cattle example. Residual feed intake at pasture (RFI-p), residual feed intake in the feedlot (RFI-f), and cow condition score are additional traits of the breeding objective. Feed requirement change is costed in the economic values of other objective traits. Selection responses are examined when feed costs are ignored, partially or fully included in the breeding objective, and when net feed intake (NFI) EBVs are added to the index. When all feed cost was included and NFI EBVs were in the index, selection (with selection intensity, i = 1) increased production system $ net return by 6.0%, $ per unit of product by 5.2%, $ per unit of feed by 6.6%, total product by 0.7% and product per unit of feed by 1.3%. There was little change in production system total feed. When feed cost was ignored, selection decreased production system $ net return, $ per unit of product, and $ per unit of feed. At the individual trait level, when feed was fully included there were increases in weaning weight-direct (0.8 kg), feedlot entry weight (1.4 kg), dressing % (0.04%), carcass meat % (0.36%), carcase fat depth (0.12 mm), carcass marbling score (0.02 score), cow condition score (0.01 score), calving ease-direct (0.97%), calving ease-maternal (0.22%) and cow weaning rate (1.3%), and decreases in weaning weight-maternal (-0.9 kg), RFI-p (-0.09 kg DM/d), RFI-f (-0.11 kg DM/d), sale weight (-1.6 kg) and cow weight (-8.7 kg). Gains were evident over a range of feed price. Selection for $ net return also increased $ net return per unit of feed, suggesting that $ net return per unit area would increase in grazing industries. Feed cost for trait change was the source of a major genotype * environment interaction affecting animal rankings. Where industry production environments vary, and feed cost for trait change varies with the environment, we recommend that industry indexes be derived for more than one level of feed cost. Cow condition score did not decline while biological and economic efficiency of the production system and individual animal were improving, suggesting that efficiency can be improved under multiple-trait selection without compromising breeding cow welfare. PMID- 29529228 TI - Live Longer Better: The Historical Roots of Human Growth Hormone as Anti-Aging Medicine. AB - In recent years, historians have turned their attention to the emergence of anti aging medicine, suggesting that this interest group coalesced in the wake of widespread availability of recombinant human growth hormone (HGH) after 1985. We take a longer view of modern anti-aging medicine, unearthing a nexus of scientific, medical, and cultural factors that developed over several decades in the twentieth century to produce circumstances conducive to the emergence of this medical sub-specialty established on the premise of the anti-aging effects of HGH. Specifically, we locate these roots in earlier hormone replacement therapies and in the so-called life extension movement. We reveal the continual tension between, on the one hand, champions of a mainstream medical specialty and a field of biomedical research that aimed to improve health for the aged and, on the other hand, advocates who campaigned for medical endeavors to preserve midlife health in perpetuity, and even to extend the human lifespan. We also demonstrate that the two groups shared a belief in science to solve - or at least to ameliorate - the problems of aging. This commitment to science has been the hallmark of twentieth and twenty-first century prescriptions for living life longer and better. PMID- 29529229 TI - Present developments in reaching an international consensus for a model-based approach to particle beam therapy. AB - Particle beam therapy (PBT), including proton and carbon ion therapy, is an emerging innovative treatment for cancer patients. Due to the high cost of and limited access to treatment, meticulous selection of patients who would benefit most from PBT, when compared with standard X-ray therapy (XRT), is necessary. Due to the cost and labor involved in randomized controlled trials, the model-based approach (MBA) is used as an alternative means of establishing scientific evidence in medicine, and it can be improved continuously. Good databases and reasonable models are crucial for the reliability of this approach. The tumor control probability and normal tissue complication probability models are good illustrations of the advantages of PBT, but pre-existing NTCP models have been derived from historical patient treatments from the XRT era. This highlights the necessity of prospectively analyzing specific treatment-related toxicities in order to develop PBT-compatible models. An international consensus has been reached at the Global Institution for Collaborative Research and Education (GI CoRE) joint symposium, concluding that a systematically developed model is required for model accuracy and performance. Six important steps that need to be observed in these considerations include patient selection, treatment planning, beam delivery, dose verification, response assessment, and data analysis. Advanced technologies in radiotherapy and computer science can be integrated to improve the efficacy of a treatment. Model validation and appropriately defined thresholds in a cost-effectiveness centered manner, together with quality assurance in the treatment planning, have to be achieved prior to clinical implementation. PMID- 29529230 TI - Cumulative Antiretroviral Exposure Measured in Hair Is Not Associated With Measures of HIV Persistence or Inflammation Among Individuals on Suppressive ART. AB - Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir (TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV 1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation. PMID- 29529231 TI - Early progressive feeding in extremely preterm infants: a randomized trial. AB - Background: Due to insufficient evidence, extremely preterm infants (<=28 wk of gestation) rarely receive early progressive feeding (small increments of feeding volumes between 1 and 4 d after birth). We hypothesized that early progressive feeding increases the number of full enteral feeding days in the first month after birth. Objective: The aim of this study was to determine the feasibility and efficacy of early progressive feeding in extremely preterm infants. Design: In this single-center randomized trial, extremely preterm infants born between September 2016 and June 2017 were randomly assigned to receive either early progressive feeding without trophic feeding (early feeding group) or delayed progressive feeding after a 4-d course of trophic feeding (delayed feeding group). Treatment allocation occurred before or on feeding day 1. The primary outcome was the number of full enteral feeding days in the first month after birth. Secondary outcomes were death, necrotizing enterocolitis (NEC), culture proven sepsis, growth percentiles at 36 wk postmenstrual age, use of parenteral nutrition, and need for central venous access. Results: Sixty infants were included (median gestational age: 26 wk; mean +/- SD birth weight: 832 +/- 253 g). The primary outcome differed between groups (median difference favoring the early feeding group: +2 d; 95% CI: 0, 3 d; P = 0.02). Early progressive feeding reduced the use of parenteral nutrition (4 compared with 8 d; P <= 0.01) and the need for central venous access (9 compared with 13 d; P <= 0.01). The outcome of culture-proven sepsis (10% compared with 27%; P = 0.18), restricted growth (weight, length, and head circumference <10th percentile) at 36 wk postmenstrual age (25% compared with 50%; P = 0.07), and the composite outcome of NEC or death (27% compared with 20%; P = 0.74) did not differ between groups. Conclusion: Early progressive feeding increases the number of full enteral feeding days in extremely preterm infants. This trial was registered at www.clinicaltrials.gov as NCT02915549. PMID- 29529232 TI - Expression Levels of Odorant Receptor Genes in the Savanna Tsetse Fly, Glossina morsitans morsitans. AB - Tsetse flies (Glossina) are vectors of African trypanosomiasis. Olfaction plays a critical role in Glossina behavior, including larviposition, feeding, and reproduction. Odorant receptors (ORs) are important in insect chemoreception as they bind volatile odorants and transport them to olfactory receptor neurons to elicit behavioral response. To better understand Glossina chemoreception, we used quantitative polymerase chain reaction to examine the expression levels of ORs in female and male Glossina morsitans morsitans Wiedemann, 1850 (Diptera: Glossinidae) antennae and legs. Results showed that G. m. morsitans ORs code for a transmembrane domain and are involved in odorant binding. The ORs had homologs in Drosophila, mosquitoes, other Glossina species, and the reduced number of tsetse ORs could be linked to its restricted blood-feeding diet. The OR genes were more highly expressed in antennae than the legs with GmmOR33 and GmmOR45 transcript levels being high in the female and male antennae, respectively, whereas GmmOR26 and GmmOR34 levels were high in female and male G. m. morsitans legs, respectively. These findings identified sex- and tissue-specific G. m. morsitans ORs. The expression levels of OR genes in female and male G. m. morsitans could be conserved in function with the antenna being the main olfactory organ. Thus, this study provides a blueprint to explore the functional roles of tsetse ORs with the potential to identify molecular targets that can be used to control the vector based on disruption of its chemosensory system. PMID- 29529233 TI - Flow Diversion for the Treatment of Basilar Apex Aneurysms. AB - BACKGROUND: Flow diversion for basilar apex aneurysms has rarely been reported. OBJECTIVE: To assess flow diversion for basilar apex aneurysms in a multicenter cohort. METHODS: Retrospective review of prospectively maintained databases at 8 academic institutions was performed from 2009 to 2016 to identify patients with basilar apex aneurysms treated with flow diversion. Clinical and radiographic data were analyzed. RESULTS: Sixteen consecutive patients (median age 54.5 yr) underwent 18 procedures to treat 16 basilar apex aneurysms with either the Pipeline Embolization Device (Medtronic Inc, Dublin, Ireland) or Flow Redirection Endoluminal Device (Microvention, Tustin, California). Five aneurysms (31.3%) were treated in the setting of subarachnoid hemorrhage. Seven aneurysms (43.8%) were treated with flow diversion alone, while 9 (56.2%) underwent flow diversion and adjunctive coiling. At a median follow-up of 6 mo, complete (100%) and near complete (90%-99%) occlusion was noted in 11 (68.8%) aneurysms. Incomplete occlusion occurred more commonly in patients treated with flow diversion alone compared to those with adjunctive coiling. Patients with partial occlusion were significantly younger. Retreatment with an additional flow diverter and adjunctive coiling occurred in 2 aneurysms with wide necks. There was 1 mortality in a patient (6.3%) who experienced posterior cerebral artery and cerebellar strokes as well as subarachnoid hemorrhage after the placement of a flow diverter. Minor complications occurred in 2 patients (12.5%). CONCLUSION: Flow diversion for the treatment of basilar apex aneurysms results in acceptable occlusion rates in highly selected cases. Both primary flow diversion and rescue after failed clipping or coiling resulted in a modified Rankin Scale score that was either equal or better than at presentation and the technology represents a viable alternative or adjunctive option. PMID- 29529234 TI - Performance and welfare of steers housed on concrete slatted floors at fixed and dynamic (allometric based) space allowances. AB - The objectives of the study were to determine whether allometric equations are suitable for estimating the space requirements of finishing beef cattle housed on concrete slatted floors (CSF) and to examine the effect of fixed and dynamic space allowances on the performance and welfare of these cattle. Continental crossbred steers [n = 120: mean initial live weight, 590 (SD 29.8) kg] were blocked by breed, weight, and age and assigned to 1 of 5 space allowance treatments (3 fixed and 2 dynamic) on CSF: 1) 2.0 m2 per animal, 2) 2.5 m2 per animal, 3) 3.0 m2 per animal, 4) Equation 1 (E1); y = 0.033w0.667, where y = m2 per animal and w = body weight, and 5) Equation 2 (E2); y = 0.048w0.667. The length of the feed face was 3.0 m for all treatments. Steers were offered grass silage and concentrates ad libitum. DMI was recorded weekly on a pen basis. Steers were weighed and dirt scored every 14 d. Blood samples were collected every 28 d, and analyzed for complete cell counts. Behavior was recorded using closed-circuit infrared cameras. Steers' hooves were inspected for lesions at the beginning of the study and post-slaughter. Slaughter weight and ADG were lowest, and feed conversion ratio (FCR) was poorest, for steers accommodated at 2.0 m2, and slaughter weight and ADG were greatest, and FCR was the best, for steers accommodated at E2 (P < 0.05); steers accommodated at 2.5 m2 were intermediate (P > 0.05) to those accommodated at 2.0 m2 and both 3.0 m2 and E1, whereas steers accommodated at 3.0 m2 and E1 were intermediate (P > 0.05) to 2.5 m2 and E2. Carcass weight of steers housed at 2.0 m2 was lower (P < 0.05) than all other treatments. Steers housed at 2.5 m2 had lower carcass weights (P < 0.05) than those with accommodated at E1 and E2, whereas the carcass weight of steers accommodated at 3.0 m2 was intermediate. Carcass fat scores and hide weights were lower (P < 0.05) in steers accommodated at 2.0 m2 than those housed at E2 with other treatments being intermediate. The number of steers lying at any one time and the number of steers observed grooming themselves was lower (P < 0.05) at 2.0 m2 than any other treatment. Dirt scores, hoof lesion number, and hematological measurements were not affected by treatment. It was concluded that 2.0 m2 per animal was an insufficient space allowance for housing finishing beef steers and that the equation y = 0.033w0.667 is sufficient for estimating the space required by finishing beef cattle housed on CSF. PMID- 29529235 TI - Cyber-Seniors. PMID- 29529236 TI - GAA*TTC repeat expansion in human cells is mediated by mismatch repair complex MutLgamma and depends upon the endonuclease domain in MLH3 isoform one. AB - DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSbeta (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA*TTC, CAG*CTG and CGG*CCG repeat expansion, suggesting a shared mechanism. MutSbeta has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear. Here we show that MutLgamma (MLH1-MLH3) is the MutL complex responsible for GAA*TTC repeat expansion. Lentiviral expression of shRNA targeting MutL nuclease components MLH1, PMS2, and MLH3 revealed that reduced expression of MLH1 or MLH3 reduced the repeat expansion rate in a human Friedreich ataxia cell model, while targeting PMS2 did not. Using splice-switching oligonucleotides we show that MLH3 isoform 1 is active in GAA*TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not. MLH3 isoform switching slowed repeat expansion in both model cells and FRDA patient fibroblasts. Our work indicates a specific and active role for MutLgamma in the expansion process and reveals plausible targets for disease modifying therapies. PMID- 29529237 TI - Phosphatidylserine on microparticles and associated cells contributes to the hypercoagulable state in diabetic kidney disease. AB - Background: Relatively little is known about the role of phosphatidylserine (PS) in procoagulant activity (PCA) in patients with diabetic kidney disease (DKD). This study was designed to evaluate whether exposed PS on microparticles (MPs) and MP-origin cells were involved in the hypercoagulability in DKD patients. Methods: DKD patients (n = 90) were divided into three groups based on urinary albumin excretion rate, defined as normoalbuminuria (No-A) (<30 mg/24 h), microalbuminuria (Mi-A) (30-299 mg/24 h) or macroalbuminuria (Ma-A) (>300 mg/24 h), and compared with healthy controls (n = 30). Lactadherin was used to quantify PS exposure on MPs and their original cells. Healthy blood cells (BCs) and human umbilical vein endothelial cells (HUVECs) were treated with 25, 5 or 2.5 mmol/L glucose as well as 3-12 mg/dL uric acid and cells were evaluated by clotting time and purified coagulation complex assays. Fibrin production was determined by turbidity. PS exposure and fibrin strands were observed using confocal microscopy. Results: Using flow cytometry, we found that PS+ MPs (derived from platelets, erythrocytes, HUVECs, neutrophils, monocytes and lymphocytes) and BCs were significantly higher in patients than in controls. Furthermore, the number of PS+ MPs and BCs in patients with Ma-A was significantly higher than in patients with No-A. Similarly, we observed markedly elevated PS exposure on HUVECs cultured with serum from patients with Ma-A versus serum from patients with Mi-A or normoalbuminuria. In addition, circulating PS+ MPs cooperated with PS+ cells, contributing to markedly shortened coagulation time and dramatically increased FXa/thrombin generation and fibrin formation in each DKD group. Confocal microscopy images demonstrated colocalization of fibrin with PS on HUVECs. Moreover, blockade of exposed PS on MPs and cells with lactadherin inhibited PCA by ~80%. In vitro, BCs and endothelial cells exposed more PS in hypoglycemia or hyperglycemia. Interestingly, reconstitution experiments showed that hypoglycemia-treated cells could be further activated or injured when recovery is obtained reaching hyperglycemia. Moreover, uric acid induced PS exposure on cells (excluding platelets) at concentrations >6 mg/dL. Linear regression analysis showed that levels of PS+ BCs and microparticles were positively correlated with uric acid and proteinuria, but negatively correlated with glomerular filtration rate. Conclusions: Our results suggest that PS+ MPs and MP-origin cells play procoagulant roles in patients with DKD. Blockade of PS could become a novel therapeutic modality for the prevention of thrombosis in these patients. PMID- 29529238 TI - Prerupture Intracranial Aneurysm Morphology in Predicting Risk of Rupture: A Matched Case-Control Study. AB - BACKGROUND: Maximal size and other morphological parameters of intracranial aneurysms (IAs) are used when deciding if an IA should be treated prophylactically. These parameters are derived from postrupture morphology. As time and rupture may alter the aneurysm geometry, possible morphological predictors of a rupture should be established in prerupture aneurysms. OBJECTIVE: To identify morphological parameters of unruptured IAs associated with later rupture. METHODS: Nationwide matched case-control study. Twelve IAs that later ruptured were matched 1:2 with 24 control IAs that remained unruptured during a median follow-up time of 4.5 (interquartile range, 3.7-8.2) yr. Morphological parameters were automatically measured on 3-dimensional models constructed from angiograms obtained at time of diagnosis. Cases and controls were matched by aneurysm location and size, patient age and sex, and the PHASES (population, hypertension, age, size of aneurysm, earlier subarachnoid hemorrhage from another aneurysm, and site of aneurysm) score did not differ between the 2 groups. RESULTS: Only inflow angle was significantly different in cases vs controls in univariate analysis (P = .045), and remained significant in multivariable analysis. Maximal size correlated with size ratio in both cases and controls (P = .015 and <.001, respectively). However, maximal size and inflow angle were correlated in cases but not in controls (P = .004. and .87, respectively). CONCLUSION: A straighter inflow angle may predispose an aneurysm to changes that further increase risk of rupture. Traditional parameters of aneurysm morphology may be of limited value in predicting IA rupture. PMID- 29529239 TI - Hydrotropism: how roots search for water. AB - Fresh water is an increasingly scarce resource for agriculture. Plant roots mediate water uptake from the soil and have developed a number of adaptive traits such as hydrotropism to aid water foraging. Hydrotropism modifies root growth to respond to a water potential gradient in soil and grow towards areas with a higher moisture content. Abscisic acid (ABA) and a small number of genes, including those encoding ABA signal transducers, MIZ2/GNOM, and the hydrotropism specific MIZ1, are known to be necessary for the response in Arabidopsis thaliana, whereas the role of auxin in hydrotropism appears to vary depending on the plant species. This review will describe recent progress characterizing the hormonal regulation of hydrotropism. Recent advances in identifying the sites of hydrotropic perception and response, together with its interaction with gravitropism, will also be discussed. Finally, I will describe putative mechanisms for perception of the water potential gradient and a potential role for hydrotropism in acclimatizing plants to drought conditions. PMID- 29529240 TI - Reproducibility of TEG Parameters in Stable Cirrhotics. AB - Background: Thromboelastography (TEG) has become the standard of care in liver transplant surgery to identify real-time abnormalities in the coagulation cascade. To our knowledge, no studies have been performed to measure the intrasubject reproducibility of TEG parameters in cirrhotic patients. Objective: To perform a validation study to determine the reproducibility of TEG in cirrhosis. Methods: We recruited 30 patients with stable cirrhosis and tested 25 of them. Two blood specimens were drawn 1 hour apart; we measured the TEG parameters R time, K time, angle, maximum amplitude (MA), and functional fibrinogen (FF), along with conventional coagulation parameters. Reproducibility was assessed using the intraclass coefficient test. The TEG parameters were then compared with conventional coagulation test results. Results: The K time, angle, MA, and FF results showed excellent reproducibility (r > 0.7; P <.001). Platelets and fibrinogen correlated with MA and K time; prothrombin time (PT) and activated partial thromboplastin time (aPTT) were inversely correlated with MA. Conclusion: All parameters were reproducible when measured 1 hour apart. TEG may be suitable to investigate coagulation characteristics in patients with clinically stable cirrhosis; however, further studies are needed in patients with more advanced cirrhosis, in whomblood product use may be more prevalent. PMID- 29529241 TI - The Future of Memories. PMID- 29529242 TI - Rif1 acts through Protein Phosphatase 1 but independent of replication timing to suppress telomere extension in budding yeast. AB - The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Delta cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1-PP1 interaction is known to cause precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if late replication is forced through deletion of nearby replication origins, indicating that Rif1 can control telomere length independent of replication timing. Moreover we find that, even at a de novo telomere created after DNA synthesis during a mitotic block, Rif1-PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening. PMID- 29529245 TI - Seroprevalences of Antibodies to 11 Human Papillomavirus (HPV) Types Mark Cumulative HPV Exposure. AB - Background: The antibody responses against human papillomavirus type 16 (HPV-16) and HPV-18 are well known, but many genital HPV types are oncogenic. We assessed the correlation between detection of type-specific HPV DNA and antibodies for 11 HPV types. Methods: A total of 2024 women attending the organized national cervical cancer screening program in Slovenia were tested for cervical high-risk HPV DNA (HPV-16, -18, -31, -33, -35, -39, -45, -52, -56, -58, -59, and -68) and serum anti-HPV antibodies. Of these, 1848 women were tested with the same methods 3 years earlier. Results: Type-specific antibodies against 10 of 11 HPV types (HPV-16, -18, -31, -33, -35, -39, -45, -52, -56, and -58) were associated with concomitant presence of type-specific DNA (median odds ratio [OR], 7.5; 95% confidence interval [CI], 2.2-26.1). When the concomitant presence of type specific HPV DNA at the 3-year visit was combined with the presence of the same HPV DNA type 3 years earlier, the statistical precision was greatly improved, and antibodies against all 11 types (HPV-16, -18, -31, -33, -35, -39, -45, -52, -56, 58, and -59) were associated with the presence of DNA of the same HPV type (median OR, 7.4; 95% CI, 4.2-12.8). Sensitivity had a slight tendency to increase (from 47% to 52%) when DNA positivity at the earlier time point was included, whereas specificity was the same (88%). Seroconversion was associated with previous HPV DNA positivity. Seropositivity mostly remained stable during the observation period. Conclusions: For 11 HPV types, type-specific seropositivity was associated with the presence of DNA of the same HPV type (either concomitantly or previously). Antibodies to these HPV types mark cumulative HPV exposure. PMID- 29529243 TI - Single-target regulators form a minor group of transcription factors in Escherichia coli K-12. AB - The identification of regulatory targets of all TFs is critical for understanding the entire network of the genome regulation. The lac regulon of Escherichia coli K-12 W3110 is composed of the lacZYA operon and its repressor lacI gene, and has long been recognized as the seminal model of transcription regulation in bacteria with only one highly preferred target. After the Genomic SELEX screening in vitro of more than 200 transcription factors (TFs) from E. coli K-12, however, we found that most TFs regulate multiple target genes. With respect to the number of regulatory targets, a total of these 200 E. coli TFs form a hierarchy ranging from a single target to as many as 1000 targets. Here we focus a total of 13 single-target TFs, 9 known TFs (BetI, KdpE, LacI, MarR, NanR, RpiR, TorR, UlaR and UxuR) and 4 uncharacterized TFs (YagI, YbaO, YbiH and YeaM), altogether forming only a minor group of TFs in E. coli. These single-target TFs were classified into three groups based on their functional regulation. PMID- 29529244 TI - High-resolution 3D models of Caulobacter crescentus chromosome reveal genome structural variability and organization. AB - High-resolution three-dimensional models of Caulobacter crescentus nucleoid structures were generated via a multi-scale modeling protocol. Models were built as a plectonemically supercoiled circular DNA and by incorporating chromosome conformation capture based data to generate an ensemble of base pair resolution models consistent with the experimental data. Significant structural variability was found with different degrees of bending and twisting but with overall similar topologies and shapes that are consistent with C. crescentus cell dimensions. The models allowed a direct mapping of the genomic sequence onto the three dimensional nucleoid structures. Distinct spatial distributions were found for several genomic elements such as AT-rich sequence elements where nucleoid associated proteins (NAPs) are likely to bind, promoter sites, and some genes with common cellular functions. These findings shed light on the correlation between the spatial organization of the genome and biological functions. PMID- 29529246 TI - Reactive oxygen species and redox regulation in mesophyll and bundle sheath cells of C4 plants. AB - Redox regulation, antioxidant defence, and reactive oxygen species (ROS) signalling are critical in performing and tuning metabolic activities. However, our concepts have mostly been developed for C3 plants since Arabidopsis thaliana has been the major model for research. Efforts to convert C3 plants to C4 to increase yield (such as IRRI's C4 Rice Project) entail a better understanding of these processes in C4 plants. Various photosynthetic enzymes that take part in light reactions and carbon reactions are regulated via redox components, such as thioredoxins as redox transmitters and peroxiredoxins. Hence, understanding redox regulation in the mesophyll and bundle sheath chloroplasts of C4 plants is of paramount importance: it appears impossible to utilize efficient C4 photosynthesis without understanding its exact redox needs and the regulation mechanisms used during light reactions. In this review, we discuss current knowledge on redox regulation in C3 and C4 plants, with special emphasis on the mesophyll and bundle sheath differences that are found in C4. In these two cell types in C4 plants, linear and cyclic electron transport in the chloroplasts operate differentially when compared to C3 chloroplasts, changing the redox needs of the cell. Therefore, our focus is on photosynthetic light reactions, ROS production dynamics, antioxidant defence, and thiol-based redox regulation, with the aim of providing an overview of our current knowledge. PMID- 29529247 TI - High-throughput construction of multiple cas9 gene variants via assembly of high depth tiled and sequence-verified oligonucleotides. AB - Selective retrieval of sequence-verified oligonucleotides (oligos) from next generation sequencing (NGS) flow cells, termed megacloning, promises accurate and reliable gene synthesis. However, gene assembly requires a complete collection of overlapping sense and nonsense oligos, and megacloning does not typically guarantee the complete production of sequence-verified oligos. Therefore, missing oligos must be provided via repetitive rounds of megacloning, which introduces a bottleneck for scaled-up efforts at gene assembly. Here, we introduce the concept of high-depth tiled oligo design to successfully utilize megacloned oligos for gene synthesis. Using acquired oligos from a single round of the megacloning process, we assembled 72 of 81 target Cas9-coding gene variants. We further validated 62 of these cas9 constructs, and deposited the plasmids to Addgene for subsequent functional characterization by the scientific community. This study demonstrates the utility of using sequence-verified oligos for DNA assembly and provides a practical and reliable optimized method for high-throughput gene synthesis. PMID- 29529248 TI - Protein composition of catalytically active U7-dependent processing complexes assembled on histone pre-mRNA containing biotin and a photo-cleavable linker. AB - 3' end cleavage of metazoan replication-dependent histone pre-mRNAs requires the multi-subunit holo-U7 snRNP and the stem-loop binding protein (SLBP). The exact composition of the U7 snRNP and details of SLBP function in processing remain unclear. To identify components of the U7 snRNP in an unbiased manner, we developed a novel approach for purifying processing complexes from Drosophila and mouse nuclear extracts. In this method, catalytically active processing complexes are assembled in vitro on a cleavage-resistant histone pre-mRNA containing biotin and a photo-sensitive linker, and eluted from streptavidin beads by UV irradiation for direct analysis by mass spectrometry. In the purified processing complexes, Drosophila and mouse U7 snRNP have a remarkably similar composition, always being associated with CPSF73, CPSF100, symplekin and CstF64. Many other proteins previously implicated in the U7-dependent processing are not present. Drosophila U7 snRNP bound to histone pre-mRNA in the absence of SLBP contains the same subset of polyadenylation factors but is catalytically inactive and addition of recombinant SLBP is sufficient to trigger cleavage. This result suggests that Drosophila SLBP promotes a structural rearrangement of the processing complex, resulting in juxtaposition of the CPSF73 endonuclease with the cleavage site in the pre-mRNA substrate. PMID- 29529249 TI - PERK/eIF2alpha signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1alpha translation. AB - HIF1alpha (hypoxia inducible factor 1alpha) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1alpha activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1alpha by preventing efficient HIF1alpha translation. Activation of PERK inhibits de novo HIF1alpha protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1alpha mRNA 5'UTR. Our data indicate that activation of the UPR can sensitise tumor cells to hypoxic stress, indicating that chemical activation of the UPR could be a strategy to target hypoxic malignant cancer cells. PMID- 29529250 TI - An interspecific barberry hybrid enables genetic dissection of non-host resistance to the stem rust pathogen Puccinia graminis. AB - Stem rust, caused by Puccinia graminis (Pg), remains a devastating disease of wheat, and the emergence of new Pg races virulent on deployed resistance genes fuels the ongoing search for sources of durable resistance. Despite its intrinsic durability, non-host resistance (NHR) is largely unexplored as a protection strategy against Pg, partly due to the inherent challenge of developing a genetically tractable system within which NHR segregates. Here, we demonstrate that Pg's far less studied ancestral host, barberry (Berberis spp.), provides such a unique pathosystem. Characterization of a natural population of B. *ottawensis, an interspecific hybrid of Pg-susceptible B. vulgaris and Pg resistant B. thunbergii (Bt), reveals that this uncommon nothospecies can be used to dissect the genetic mechanism(s) of Pg-NHR exhibited by Bt. Artificial inoculation of a natural population of B. *ottawensis accessions, verified via genotyping by sequencing to be first-generation hybrids, revealed 51% susceptible, 33% resistant, and 16% intermediate phenotypes. Characterization of a B. *ottawensis full sib family excluded the possibility of maternal inheritance of the resistance. By demonstrating segregation of Pg-NHR in a hybrid population, this study challenges the assumed irrelevance of Bt to Pg epidemiology and lays a novel foundation for the genetic dissection of NHR to one of agriculture's most studied pathogens. PMID- 29529251 TI - Genetic Differentiation and Structure of Sitobion avenae (Hemiptera: Aphididae) Populations From Moist, Semiarid and Arid Areas in Northwestern China. AB - Drought is predicted to be more frequent, prolonged, and intensive in many areas around the globe under future warming scenarios, which can have significant impacts on aphids in different agricultural systems. However, studies on the genetic structuring process underlying changing aphid biology and ecology under drought are rare. To address the issue, we collected the wheat aphid, Sitobion avenae (Fabricius) (Hemiptera: Aphididae), clones from moist, semiarid, and arid areas of northwestern China and genotyped them with microsatellite markers. We found 59 multilocus genotypes from 235 collected individuals. Populations of S. avenae in different areas showed a moderately high level of genetic diversity. FIS values across all loci in all S. avenae populations were found to be negative, indicating heterozygote excess and prevalent parthenogenesis in our sampling areas. The appearance of a relatively large number of unique genotypes in Yulin provided evidence for the existence of sexual reproduction there. Based on Bayesian clustering analyses, the majority of individuals from moist and semiarid areas belonged to one cluster, whereas most individuals from arid areas fell into another cluster. We found little population structure of S. avenae in moist or semiarid areas, but a significant population structure for arid areas. Significant amounts of migration of S. avenae were found between our sampling areas although the migration was asymmetric between areas. This study provides insights into the genetic diversity, divergence, and structure of aphid populations under drought, as well as valuable information for improving aphid management strategies in drought-inflicted areas under future warming scenarios. PMID- 29529253 TI - The critical role of Bach2 in regulating type 2 chronic airway inflammation. AB - Although Bach2 (broad complex-tramtrack-bric a brac and Cap'n'collar homology 2) plays an important role in regulating Th2 cell differentiation and type 2 immune responses, the underlying molecular mechanisms remain unclear. Our current studies demonstrate that Bach2 associates with Batf (basic leucine zipper transcription factor ATF-like) family transcription factors and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the interferon regulatory factor 4 (Irf4) containing Batf complex to activator protein 1 (AP-1) motifs in the Th2 cytokine gene locus and suppresses Th2 cytokine production and/or Th2 cell differentiation. The deletion of Batf ameliorated the spontaneous development of type 2 airway inflammation that is found in mice with Bach2 deficiency specifically in T cells. Interestingly, Bach2 regulates Batf and Batf3 expression via two distinct pathways. First, the Bach2-Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf Irf4 complex. Second, Bach2 suppresses interleukin 4 (IL-4)-induced augmentation of Batf and Batf3 expression through the regulation of IL-4 production. These findings suggest that IL-4 and Batf family transcription factors form a positive feedback amplification loop to induce Th2 cell differentiation and that Bach2 Batf interactions block the formation of this amplification loop. Furthermore, we found that reductions in Bach2 confer an innate immunological function on CD4 T cells to induce antigen-independent cytokine production. Some Bach2-deficient lung CD4 T cells showed characteristic features similar to pathogenic Th2 cells, including IL-33 receptor expression and IL-33-dependent Th2 cytokine production. These results suggest a critical role for Bach2 in regulating Th2 cell differentiation and the subsequent onset of chronic type 2 inflammation. PMID- 29529252 TI - A regulatory RNA is involved in RNA duplex formation and biofilm regulation in Sulfolobus acidocaldarius. AB - Non-coding RNAs (ncRNA) are involved in essential biological processes in all three domains of life. The regulatory potential of ncRNAs in Archaea is, however, not fully explored. In this study, RNA-seq analyses identified a set of 29 ncRNA transcripts in the hyperthermophilic archaeon Sulfolobus acidocaldarius that were differentially expressed in response to biofilm formation. The most abundant ncRNA of this set was found to be resistant to RNase R treatment (RNase R resistant RNA, RrrR(+)) due to duplex formation with a reverse complementary RNA (RrrR(-)). The deletion of the RrrR(+) gene resulted in significantly impaired biofilm formation, while its overproduction increased biofilm yield. RrrR(+) was found to act as an antisense RNA against the mRNA of a hypothetical membrane protein. The RrrR(+) transcript was shown to be stabilized by the presence of the RrrR(-) strand in S. acidocaldarius cell extracts. The accumulation of these RrrR duplexes correlates with an apparent absence of dsRNA degrading RNase III domains in archaeal proteins. PMID- 29529254 TI - A new scope for orlistat: Effect of approved anti-obesity drug against experimental microsporidiosis. AB - As the current therapies for intestinal microsporidiosis are either inconsistent in their efficacies or hampered by several adverse effects, alternative antimicrosporidial agents are being sought. The present study is the first that was designed to evaluate the potency of orlistat, an approved anti-obesity drug, against intestinal microsporidiosis caused by both Enterocytozoon bieneusi and Encephalitozoon intestinalis. Results were assessed through studying fecal and intestinal spore load, intestinal histopathological changes, viability, and infectivity of spores from treated animals. Results showed that orlistat has promising antimicrosporidia potential, with better results in E. intestinalis than E. bieneusi. The animals that received orlistat showed statistically significant decrease in the fecal and intestinal spore load, when compared to the corresponding control infected nontreated mice. The results were insignificant compared to fumagillin and albendazole. Light microscopic examination of stained intestinal sections revealed amelioration of the pathological changes and decreased inflammatory cells detected in the control infected nontreated mice. Spores encountered from stool of orlistat-treated E. bieneusi and E. intestinalis mice showed low viability and significant reduction of infectivity versus their control. Thus, considering the results of the present work, orlistat proved its effectiveness against the intestinal microsporidial infection. PMID- 29529256 TI - Clinical and echocardiographic factors associated with mitral plasticity in patients with chronic inferior myocardial infarction. AB - Aims: Ischaemic mitral regurgitation (IMR) is consequence of left ventricular (LV) remodelling after myocardial infarction. In some cases, the mitral valve enlarges to compensate for LV remodelling and tenting, improving its coaptation; a process termed 'plasticity'. We sought to identify clinical and echocardiographic factors associated with plasticity in patients with chronic inferior myocardial infarction (CII). Methods and results: This study included 91 revascularized CII patients and 46 controls. Plasticity and IMR severity were evaluated by 2D transthoracic echocardiography. Compared with controls, CII patients were older (59 vs. 25 years) and mostly men (80% vs. 46%), both P < 0.001. Chronic inferior myocardial infarction patients also had significant LV remodelling: larger LV volumes, larger mitral tenting areas, larger coaptation depths, longer mitral leaflets and chords, and worse mitral regurgitation (all P <= 0.03). Of 91 CII patients, 60 had mitral plasticity (longer anterior and posterior leaflets and longer posterior chords, all P < 0.001), despite not exhibiting significantly larger LV volumes, tenting area or coaptation depth, when compared with patients with no plasticity. Contralateral (anterior) papillary muscle-to-annulus length tended to be increased in CII plasticity patients (P = 0.05). Also they had less moderate and severe IMR (both P < 0.04) compared with non-plasticity CII patients. Multivariate analysis demonstrated independent associations between plasticity and smoking [odds ratio (OR) 0.03, 0.002-0.57; P = 0.019], duration of type-2 diabetes (OR 1.19, 1.007-1.42; P = 0.04) and haemoglobin (OR 2.17, 1.25-3.76; P = 0.005). Conclusion: Mitral plasticity results in less moderate and severe IMR. Longer time-duration of diabetes mellitus and higher haemoglobin level are independently associated with mitral plasticity, while smoking independently associates with no plasticity. Increased anterior papillary muscle-to-annulus length in CII patients with plasticity suggests complex LV remodelling mechanisms are involved in plasticity. PMID- 29529255 TI - N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. AB - Previous studies have revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in embryonic stem cells (ESCs), but the biological function of m6A in large intergenic noncoding RNA (lincRNA) is unknown. Here, we showed that the internal m6A modification of linc1281 mediates a competing endogenous RNA (ceRNA) model to regulate mouse ESC (mESC) differentiation. We demonstrated that loss of linc1281 compromises mESC differentiation and that m6A is highly enriched within linc1281 transcripts. Linc1281 with RRACU m6A sequence motifs, but not an m6A-deficient mutant, restored the phenotype in linc1281-depleted mESCs. Mechanistic analyses revealed that linc1281 ensures mESC identity by sequestering pluripotency-related let-7 family microRNAs (miRNAs), and this RNA RNA interaction is m6A dependent. Collectively, these findings elucidated the functional roles of linc1281 and its m6A modification in mESCs and identified a novel RNA regulatory mechanism, providing a basis for further exploration of broad RNA epigenetic regulatory patterns. PMID- 29529257 TI - Genetic variants in CYP7A1 and risk of myocardial infarction and symptomatic gallstone disease. AB - Aims: Myocardial infarction (MI) and gallstone disease (GSD) are intrinsically linked via cholesterol metabolism. We tested the hypothesis that genetic variants in the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, are associated with risk of MI and GSD in the general population. Methods and results: We performed tests of association between lipid levels and eight rare non-synonymous mutations and two common variants, rs2081687 and rs3808607, in CYP7A1 in 100 149 individuals from the general population. We further tested whether weighted allele scores for rs2081687 and rs3808607, which were associated with increased plasma levels of low-density lipoprotein (LDL) cholesterol, were associated with an increased risk of both MI and symptomatic GSD. During a mean follow-up of 7 years (0-23 years), MI developed in 2326 individuals and GSD in 2007. For rare mutations, CYP7A1 allele count was associated with an increase in LDL cholesterol of 12% (0.4 mmol/L) for individuals with the highest vs. the lowest allele count (P for trend = 3 * 10-4). For common variants, CYP7A1 weighted allele scores in individuals with a score >0.04 vs. <=0 were associated with stepwise increases in LDL cholesterol of up to 2.4% (0.08 mmol/L), and with corresponding multifactorially adjusted hazard ratios of 1.25 [95% confidence interval (CI) 1.10-1.41] for MI and 1.39 (95% CI 1.22-1.59) for GSD (P for trend = 5 * 10-4 and 2 * 10-7, respectively). Results were similar in meta-analyses including publicly available data from large consortia. Conclusion: Genetic variants in CYP7A1 which are associated with increased levels of LDL cholesterol, are associated with an increased risk of both MI and GSD. PMID- 29529258 TI - Implications of CpG islands on chromosomal architectures and modes of global gene regulation. AB - CpG islands (CGIs) have long been implicated in the regulation of vertebrate gene expression. However, the involvement of CGIs in chromosomal architectures and associated gene expression regulations has not yet been thoroughly explored. By combining large-scale integrative data analyses and experimental validations, we show that CGIs clearly reconcile two competing models explaining nuclear gene localizations. We first identify CGI-containing (CGI+) and CGI-less (CGI-) genes are non-randomly clustered within the genome, which reflects CGI-dependent spatial gene segregation in the nucleus and corresponding gene regulatory modes. Regardless of their transcriptional activities, CGI+ genes are mainly located at the nuclear center and encounter frequent long-range chromosomal interactions. Meanwhile, nuclear peripheral CGI- genes forming heterochromatin are activated and internalized into the nuclear center by local enhancer-promoter interactions. Our findings demonstrate the crucial implications of CGIs on chromosomal architectures and gene positioning, linking the critical importance of CGIs in determining distinct mechanisms of global gene regulation in three-dimensional space in the nucleus. PMID- 29529260 TI - Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development. AB - The U.S. Environmental Protection Agency's ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential apical effects relevant to risk assessors. Thus, efforts are underway to develop AOPs relevant to pathway-specific perturbations detected in ToxCast assays. Previous work identified a "cytotoxic burst" (CTB) phenomenon wherein large numbers of the ToxCast assays begin to respond at or near test chemical concentrations that elicit cytotoxicity, and a statistical approach to defining the bounds of the CTB was developed. To focus AOP development on the molecular targets corresponding to ToxCast assays indicating pathway-specific effects, we conducted a meta-analysis to identify which assays most frequently respond at concentrations below the CTB. A preliminary list of potentially important, target-specific assays was determined by ranking assays by the fraction of chemical hits below the CTB compared with the number of chemicals tested. Additional priority assays were identified using a diagnostic-odds-ratio approach which gives greater ranking to assays with high specificity but low responsivity. Combined, the two prioritization methods identified several novel targets (e.g., peripheral benzodiazepine and progesterone receptors) to prioritize for AOP development, and affirmed the importance of a number of existing AOPs aligned with ToxCast targets (e.g., thyroperoxidase, estrogen receptor, aromatase). The prioritization approaches did not appear to be influenced by inter-assay differences in chemical bioavailability. Furthermore, the outcomes were robust based on a variety of different parameters used to define the CTB. PMID- 29529261 TI - Does locally relevant, real-time infection epidemiological data improve clinician management and antimicrobial prescribing in primary care? A systematic review. AB - Purpose: Antimicrobial resistance is a significant threat to public health. Diagnostic uncertainty is a key driver of antimicrobial prescribing. We sought to determine whether locally relevant, real-time syndromic or microbiological infection epidemiology can improve prescribing by reducing diagnostic uncertainty. Methods: Eligible studies investigated effects on primary care prescribing for common infections in Organisation For Economic Co-Operation And Development countries. We searched Medline, Embase, Cumulative index to nursing and allied health literature, Web of Science, grey literature sources, thesis databases and trial registries. Results: We identified 9548 reports, of which 17 were eligible, reporting 12 studies, of which 3 reported relevant outcomes. The first (observational) showed antibacterial prescribing for upper respiratory infections reduced from 26.4% to 8.6% (P = 0.01). The second (observational) showed antibacterial prescribing reduced during influenza pandemic compared with seasonal influenza periods [odds ratio (OR) 0.72 (95% CI, 0.68 to 0.77), P < 0.001], while antiviral prescribing increased [OR 6.43 (95% CI, 5.02 to 8.25), P < 0.001]. The likelihood of prescribing also decreased as the number of infection cases a physician saw increased in the previous week [OR 0.57 (95% CI, 0.51 to 0.63), P < 0.001 for >=12 versus <=1 patient). The third (randomized-controlled trial) showed an absolute reduction in antibacterial prescribing of 5.1% during a period of moderate influenza activity (P < 0.05). We did not find measures of diagnostic certainty, harms or costs. Conclusion: There is promising evidence that epidemiological syndromic and microbiological data can reduce primary care antimicrobial prescribing. Future research should use randomized designs of behaviourally informed interventions, investigate costs and harms, and establish mechanisms of behaviour change. PROSPERO registration: CRD42016038871. PMID- 29529259 TI - Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves. AB - Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03). Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk. PMID- 29529263 TI - Social Networks, Role-Relationships, and Personality in Older Adulthood. AB - Objectives: This article examines the implications of personality traits for social network connectedness in older adulthood, across different social relationships. Methods: This article uses data from the National Social Life Health and Aging Project (NSHAP), a nationally-representative, longitudinal survey of community-dwelling older Americans (N = 2,261). Network characteristics were predicted using Poisson and negative binomial regression (for network size) as well as multilevel identity-linked and ordinal-logit-linked regressions (for tie strength). Results: Extraversion and agreeableness were associated with tie strength, and extraversion was weakly associated with friend network size. Few trait-by-role-relationship interactions emerged, although more-neurotic persons were more likely to talk about their health with friends. Discussion: Personality traits impact the strength of social network ties in older adulthood. However, traits may have minimal impact on network size. The consequences of personality also appear to be largely consistent across different social relationships. PMID- 29529262 TI - Hierarchical interactions between Fnr orthologs allows fine-tuning of transcription in response to oxygen in Herbaspirillum seropedicae. AB - Bacteria adjust the composition of their electron transport chain (ETC) to efficiently adapt to oxygen gradients. This involves differential expression of various ETC components to optimize energy generation. In Herbaspirillum seropedicae, reprogramming of gene expression in response to oxygen availability is controlled at the transcriptional level by three Fnr orthologs. Here, we characterised Fnr regulons using a combination of RNA-Seq and ChIP-Seq analysis. We found that Fnr1 and Fnr3 directly regulate discrete groups of promoters (Groups I and II, respectively), and that a third group (Group III) is co regulated by both transcription factors. Comparison of DNA binding motifs between the three promoter groups suggests Group III promoters are potentially co activated by Fnr3-Fnr1 heterodimers. Specific interaction between Fnr1 and Fnr3, detected in two-hybrid assays, was dependent on conserved residues in their dimerization interfaces, indicative of heterodimer formation in vivo. The requirements for co-activation of the fnr1 promoter, belonging to Group III, suggest either sequential activation by Fnr3 and Fnr1 homodimers or the involvement of Fnr3-Fnr1 heterodimers. Analysis of Fnr proteins with swapped activation domains provides evidence that co-activation by Fnr1 and Fnr3 at Group III promoters optimises interactions with RNA polymerase to fine-tune transcription in response to prevailing oxygen concentrations. PMID- 29529264 TI - Rapamycin for inclusion body myositis: targeting non-inflammatory mechanisms. PMID- 29529265 TI - Role of the food matrix and digestion on calculation of the actual energy content of food. AB - The energy content of food is calculated on the basis of general factors for fat, protein, and carbohydrates. These general factors were derived by W.O. Atwater in the late 19th century, while additional factors for dietary fiber, polyols, and organic acids were introduced more recently. These factors are applied indiscriminately to all types of foods, yet the same nutrient may be digested to different extents to generate energy, depending on the characteristics of the food matrix, the processing methods applied to foods, and the meal composition. As a consequence, the actual energy content of food may differ from what is theoretically calculated with the Atwater factors. In this review, the relationship of macronutrient digestibility with food structure, macronutrient structure, and food composition is examined, and the implications for the amount of energy achievable through diet are highlighted. Estimates of the discrepancy between calculated energy content and actual energy content are provided for different diets. The findings may have implications for consumer purchasing decisions as well as for the design of dietary interventions. PMID- 29529266 TI - Varieties of Self Disorder: A Bio-Pheno-Social Model of Schizophrenia. AB - The self-disorder model offers a unifying way of conceptualizing schizophrenia's highly diverse symptoms (positive, negative, disorganized), of capturing their distinctive bizarreness, and of conceiving their longitudinal development. These symptoms are viewed as differing manifestations of an underlying disorder of ipseity or core-self: hyper-reflexivity/diminished-self-presence with accompanying disturbances of "grip" or "hold" on reality. Recent revision to this phenomenological theory, in particular distinguishing primary-vs-secondary factors, offers a bio-pheno-social model that is consistent with recent empirical findings and offers several advantages: (1) It helps account for the temporal variations of the symptoms or syndrome, including longitudinal progression, but also the shorter-term, situationally reactive, and sometimes defensive or quasi intentional variability of symptom-expression that can occur in schizophrenia (consistent with understanding some aspects of ipseity-disturbance as dynamic and mutable, involving shifting attitudes or experiential orientations). (2) It accommodates the overlapping of some key schizophrenic symptoms with certain nonschizophrenic conditions involving dissociation (depersonalization, derealization), including depersonalization disorder and panic disorder, thereby acknowledging both shared and distinguishing symptoms. (3) It integrates recent neurocognitive and neurobiological as well as psychosocial (eg, influence of trauma and culture) findings into a coherent but multi-factorial neuropsychological account. An adequate model of schizophrenia will postulate shared disturbances of core-self experiences that nevertheless can follow several distinct pathways and occur in various forms. Such a model is preferable to uni dimensional alternatives-whether of schizophrenia or ipseity-disturbance-given its ability to account for distinctive yet varying experiential and neurocognitive abnormalities found in research on schizophrenia, and to integrate these with recent psychosocial and neurobiological findings. PMID- 29529267 TI - A crucial role for maternal dietary methyl donor intake in epigenetic programming and fetal growth outcomes. AB - The fetal origins of health and disease framework has identified extremes in fetal growth and birth weight as factors associated with the lifelong generation of chronic diseases such as obesity, diabetes, cardiovascular disease, and hypertension. Maternal nutrition plays a critical role in fetal and placental development, in part by providing the methyl groups required to establish the fetus's genome structure and function, notably through DNA methylation. The goal of this narrative review is to describe the role of maternal dietary methyl donor (methionine, folate, and choline) and cofactor (zinc and vitamins B2, B6, and B12) intake in one-carbon metabolism and DNA methylation in the fetus and placenta, as well as their impacts on fetal growth and lifelong health outcomes, with specific examples in animals and humans. Based on the available evidence, it is concluded that intake of different amounts of dietary methyl donors and cofactors during pregnancy may alter fetal growth and development, thus establishing a major link between early environmental exposure and disease development in the offspring later in life. PMID- 29529268 TI - Metaviz: interactive statistical and visual analysis of metagenomic data. AB - Large studies profiling microbial communities and their association with healthy or disease phenotypes are now commonplace. Processed data from many of these studies are publicly available but significant effort is required for users to effectively organize, explore and integrate it, limiting the utility of these rich data resources. Effective integrative and interactive visual and statistical tools to analyze many metagenomic samples can greatly increase the value of these data for researchers. We present Metaviz, a tool for interactive exploratory data analysis of annotated microbiome taxonomic community profiles derived from marker gene or whole metagenome shotgun sequencing. Metaviz is uniquely designed to address the challenge of browsing the hierarchical structure of metagenomic data features while rendering visualizations of data values that are dynamically updated in response to user navigation. We use Metaviz to provide the UMD Metagenome Browser web service, allowing users to browse and explore data for more than 7000 microbiomes from published studies. Users can also deploy Metaviz as a web service, or use it to analyze data through the metavizr package to interoperate with state-of-the-art analysis tools available through Bioconductor. Metaviz is free and open source with the code, documentation and tutorials publicly accessible. PMID- 29529269 TI - Lethal and Sublethal Effects on Tamarixia triozae (Hymenoptera: Eulophidae), an Ectoparasitoid of Bactericera cockerelli (Hemiptera: Triozidae), of Three Insecticides Used on Solanaceous Crops. AB - Lethal and sublethal effects of refined soybean oil, imidacloprid, and abamectin on Tamarixia triozae (Burks; Hymenoptera: Eulophidae) were assessed after exposure of the eggs, larvae, and pupae of this parasitoid to three concentrations of these active substances: the LC50 for fourth-instar Bactericera cockerelli (Sulc.; Hemiptera: Triozidae) and 50% and 100% of the minimum field registered concentration (MiFRC). Soybean oil caused 26-61% mortality in T. triozae eggs and 6-19% in larvae; mortality in both eggs and larvae was <=19% for imidacloprid and 4-100% for abamectin. All three compounds caused <18% mortality of T. triozae pupae, with the exception of the abamectin 50% (47%) and 100% (72%) MiFRC. The mortality of larvae and pupae derived from treated eggs was <=39% for all three insecticides, and that of pupae derived from treated larvae was <=10%. In general, emergence of adults developed from treated eggs, larvae, and pupae was affected more by abamectin than by the other treatments. The proportion of females derived from all three development stages was not affected by treatment with the compounds, except when the parasitoid was treated as larvae with the soybean oil 100 and 50% MiFRC (66 and 68%, respectively) or when treated as pupae with the imidacloprid LC50 and 100% MiFRC (~60%). Female longevity was generally higher than that of males. The use of imidacloprid, soybean oil, and abamectin in combination with T. triozae for pest control may be effective when the parasitoid is in the pupal stage because this stage is less susceptible than other immature stages. PMID- 29529271 TI - Does interest in smoking affect youth selection of pro-smoking videos? A selective exposure experiment. AB - Introduction: Many pro-smoking videos on YouTube reach view counts in the hundreds of thousands and more. Yet, there is limited information on who is viewing these potentially misleading videos. This study attempts to understand the viewership of online pro-smoking videos to examine if youth at high risk for smoking are more likely to watch these videos. Method: We conducted a selective exposure experiment with a national sample of youths (ages 15-21 years; N = 614), to identify characteristics that make individuals more likely to select pro smoking videos. During a 10-minute browsing session, participants were given a set of 16 videos (8 smoking and 8 non-smoking) and were asked to view video(s) of their choice. Exposure to videos was unobtrusively logged. View count was manipulated such that smoking videos had either high or low views. Results: Behavioral data revealed that youth with higher interest in smoking were more likely to select and spend more time watching pro-smoking videos than were youth with lower interest in smoking. The view count manipulation did not affect selection patterns. However, exposure to high view count smoking videos was associated with more positive attitudes toward smoking. Conclusions: The findings of this study call into question the existence and prominence of pro-smoking videos on YouTube and brings to attention the need for regulatory or monitoring efforts of such content. PMID- 29529270 TI - Brain Subtyping Enhances The Neuroanatomical Discrimination of Schizophrenia. AB - Identifying distinctive subtypes of schizophrenia could ultimately enhance diagnostic and prognostic accuracy. We aimed to uncover neuroanatomical subtypes of chronic schizophrenia patients to test whether stratification can enhance computer-aided discrimination of patients from control subjects. Unsupervised, data-driven clustering of structural MRI (sMRI) data was used to identify 2 subtypes of schizophrenia patients drawn from a US-based open science repository (n = 71) and we quantified classification improvements compared to controls (n = 74) using supervised machine learning. We externally validated the unsupervised and supervised learning models in a heterogeneous German validation sample (n = 316), and characterized symptom, cognition, and longitudinal symptom change signatures. Stratification improved classification accuracies from 68.5% to 73% (subgroup 1) and 78.8% (subgroup 2), respectively. Increased accuracy was also found when models were externally validated, and an average gain of 9% was found in supplementary analyses. The first subgroup was associated with cortical and subcortical volume reductions coupled with substantially longer illness duration, whereas the second subgroup was mainly characterized by cortical reductions, reduced illness duration, and comparatively less negative symptoms. Individuals within each subgroup could be identified using just 10 clinical questions at an accuracy of 81.2%, and differential cognitive and symptom course signatures were suggested in multivariate analyses. Our findings suggest that sMRI-based subtyping enhances the neuroanatomical discrimination of schizophrenia by identifying generalizable brain patterns that align with a clinical staging model of the disorder. These findings could be used to improve illness stratification for biomarker-based computer-aided diagnoses. PMID- 29529272 TI - DOSIMETRIC CHARACTERIZATION OF COLLIMATORS FOR SPATIALLY FRACTIONATED PROTON THERAPY OF THE EYE. AB - The aim of these studies was to investigate depth dose distribution of a 60 MeV proton beam formed by a set of dedicated mesh-formed collimators. The set of mini beams formed by the mesh is scattered in the tissue and lead to uniform energy deposition in the target volume. The rationale is to protect the eyelid skin from complications after hypofractionated radiation therapy. The experimental verification of the depth dose distribution for collimators of 1-3 mm mesh size was performed in solid state and water phantoms on 60 MeV proton beam from the AIC-144 cyclotron. The measurements were accompanied by Monte Carlo calculations of proton transport using the FLUKA code. The result demonstrate that the smallest mesh diameter of 1 mm leads to fast broadening of the resulting mini beams due to multiple proton scattering in the collimator. The effect is diminishing with growing collimator diameter. PMID- 29529274 TI - A Shortened Version of the Reasons for Living-Older Adults Scale for Clinical and Research Utility. AB - Background and Objectives: Older adults have elevated suicide rates, and identification of protective factors, such as reasons for living, is important in preventing suicide. The Reasons for Living-Older Adults scale (RFL-OA) is a 69 item measure of these protective factors in late life, which yields good psychometric properties. However, its length limits its utility in some clinical and research contexts where a shorter measure is ideal. The objective of this study was to create a shortened version of the RFL-OA. Research Design and Methods: First, data collected previously during validation of the original RFL OA (n = 199, age 65 and older, 65% female) were used to select 30 items, spanning all content areas, that were highly endorsed. Second, new data were collected (n = 219, age 60 and older, 52% female) with the 30-item RFL-OA and measures of depression, hopelessness, suicidal ideation, religiosity, health, and social desirability to examine the measure's internal consistency and convergent and discriminant validity. Results: Scores on the 30-item RFL-OA exhibited strong internal consistency. The short RFL-OA demonstrated good convergent validity via significant, moderate correlations with suicidal ideation, hopelessness, depression, and religiosity. It demonstrated adequate discriminant validity via only small correlations with disability, subjective health, and social desirability. Discussion and Implications: The shorter RFL-OA has good psychometric properties among community-dwelling older adults. It may have greater utility, compared to the original 69-item measure, for clinicians and researchers with limited time but who want to assess protective factors against suicidal behavior in late life. PMID- 29529273 TI - The Association Between Trajectories of Physical Activity and All-Cause and Cause Specific Mortality. AB - Background: The benefits of physical activity (PA) for health have primarily been evaluated during midlife. Whether patterns of change in late-life PA associate with overall and cause-specific mortality remains unclear. Methods: We examined the association between PA trajectories and subsequent mortality among 3,767 men aged >=65 years. Men self-reported PA using the Physical Activity Scale for the Elderly (PASE) at up to four time points from 2000 through 2009 (Year 7); mortality was assessed over an average of 7.1 years after the Year 7 contact. Group-based trajectory modeling identified patterns of PA change. Cox proportional hazards models described associations between patterns of change in PA, Year 7 PA, and subsequent mortality risk. Results: Three discrete PA patterns were identified, all with declining PA. Compared to low-activity declining men, moderate (hazard ratio [HR] = 0.78; 95% confidence interval [CI]: 0.70, 0.88) and high-activity (HR = 0.69, 95% CI: 0.57, 0.83) declining groups were associated with lower risk of all-cause mortality. Among models with a single time point, the last time point (Year 7 PA score) was a strong predictor of mortality with HR = 0.85 (95% CI: 0.78, 0.93) per SD increase in PASE score. PA patterns were not a risk factor for mortality after adjustment for the Year 7 PA score. Conclusions: Recent PA levels are a stronger indicator of subsequent mortality risk than PA patterns reported over the prior 7 years or prior PA level, suggesting that current PA rather than history of PA is the most relevant parameter in clinical settings. PMID- 29529275 TI - Combinatorial Regulation of Stilbene Synthase Genes by WRKY and MYB Transcription Factors in Grapevine (Vitis vinifera L.). AB - Stilbene synthase (STS) is the key enzyme leading to the biosynthesis of resveratrol. Recently we reported two R2R3-MYB transcription factor (TF) genes that regulate the stilbene biosynthetic pathway in grapevine: VviMYB14 and VviMYB15. These genes are strongly co-expressed with STS genes under a range of stress and developmental conditions, in agreement with the specific activation of STS promoters by these TFs. Genome-wide gene co-expression analysis using two separate transcriptome compendia based on microarray and RNA sequencing data revealed that WRKY TFs were the top TF family correlated with STS genes. On the basis of correlation frequency, four WRKY genes, namely VviWRKY03, VviWRKY24, VviWRKY43 and VviWRKY53, were further shortlisted and functionally validated. Expression analyses under both unstressed and stressed conditions, together with promoter-luciferase reporter assays, suggested different hierarchies for these TFs in the regulation of the stilbene biosynthetic pathway. In particular, VviWRKY24 seems to act as a singular effector in the activation of the VviSTS29 promoter, while VviWRKY03 acts through a combinatorial effect with VviMYB14, suggesting that these two regulators may interact at the protein level as previously reported in other species. PMID- 29529276 TI - Multimodality imaging in endomyocardial fibrosis associated with Hodgkin lymphoma. PMID- 29529277 TI - "Organic," "natural," and "additive-free" cigarettes: Comparing the effects of advertising claims and disclaimers on perceptions of harm. AB - Introduction: The U.S. Tobacco Control Act restricts advertising or labeling that suggests one tobacco product is less harmful than another. We sought to examine how "organic," "natural," and "additive-free" advertising claims and corresponding disclaimers affect perceptions of cigarettes' harm. Methods: Participants were a national probability sample of adults in the U.S. (n = 1,114, including 344 smokers). We conducted a 5 (claim) * 2 (disclaimer) between subjects factorial experiment. Participants viewed a Natural American Spirit cigarettes ad claiming they were "organic," "natural," "additive-free," "light," or "regular;" and with or without a corresponding disclaimer. The outcome was perceived harm of the advertised cigarettes. Among smokers, we also assessed interest in switching within their current brand to cigarettes with this characteristic (e.g., "additive-free"). Results: Claims in the ad had a large effect on perceived harm (Cohen's d = 0.87, 95% CI: 0.47-1.29). Claims of cigarettes being "organic," "natural," or "additive-free" reduced perceived harm from the advertised cigarettes, as compared to "regular" and "light" claims. Disclaimers had a small effect, increasing perceived harm (d = 0.25, 95% CI: 0.08 0.41). The problematic claims also increased smokers' interest in switching. Disclaimers had no effect on smokers' interest in switching. Conclusions: "Organic," "natural," and "additive-free" claims may mislead people into thinking that the advertised cigarettes are less harmful than other cigarettes. Disclaimers did not offset misperceptions of harm created by false claims. The U.S. Food and Drug Administration should restrict the use of these misleading claims in tobacco advertising. PMID- 29529278 TI - Testing Positive on a Multigene Panel Does Not Suffice to Determine Disease Risks. PMID- 29529279 TI - Nonclinical Safety Assessment of the gamma-Secretase Inhibitor Avagacestat. AB - The toxicity of avagacestat, a sulfonamide-based gamma (gamma)-secretase inhibitor that was in development as a treatment for Alzheimer's disease, was evaluated in a comprehensive nonclinical toxicology program that included 6-month and 1-year repeat-dose toxicity studies in rats and dogs, respectively. There was a spectrum of mechanism-based changes attributed to inhibition of Notch signaling that regulates the differentiation and proliferation of cells throughout development and in adult tissues. In both rats and dogs, ovarian follicular degeneration and atrophy and a low incidence of granulosa cell hyperplasia and benign granulosa-thecal cell tumors were observed. Gastrointestinal (GI) findings, including goblet cell metaplasia, dilatation of intestinal crypts/glands, mucosal epithelial necrosis and regeneration, and villous atrophy, were limited to dogs that had clinical evidence of GI toxicity. Other avagacestat related findings attributed to interference with Notch signaling included decreases in peripheral lymphocytes (T and/or B cells) and lymphoid depletion in lymph nodes and the spleen in both species, as well as epiphyseal cartilage and trabecular bone changes in rats. Pharmacologically mediated decreases in brain and cerebrospinal fluid levels of beta-amyloid (Abeta) peptides Abeta40 and Abeta42 and decreased expression of white blood cell mRNA levels of the Notch regulated gene hairy and enhancer of split-1 confirmed target engagement at all doses. Reductions in brain Abeta peptide levels (22 to 34%) in dogs after 1 year at exposures up to the no-observed-effect level for GI toxicity of 1.1* the human plasma exposure, and reversible GI changes at a 3.2* multiple, indicated that a sustained pharmacodynamic effect was attained at exposures without dose-limiting toxicity. PMID- 29529280 TI - Magnetic resonance angiography in giant cell arteritis: results of a randomized controlled trial of tocilizumab in giant cell arteritis. AB - Objective: To analyse magnetic resonance angiographic (MRA) vessel wall signals from a randomized controlled trial of tocilizumab (TCZ) to treat GCA. Methods: Participants were assigned in a 2:1 ratio to receive either TCZ + glucocorticoids (GCs) or placebo + GC infusions at 4-week intervals for 52 weeks. GCs were started at 1 mg/kg/day, then tapered to 0.1 mg/kg/day at week 12 and thereafter down to zero. Patients with initial positive MRA findings underwent control MRA at weeks 12 and 52. Vessel wall signals were scored from 0 (normal) to 3 (intense late enhancement). Outcomes were the number of patients with complete MRA remission at weeks 12 and 52, and changes in vasculitis score, vessel anatomy and atherosclerosis. Results: Of the 30 randomized participants, nine TCZ and two placebo patients had no vessel wall enhancement on initial MRA. At week 12, MRAs were performed in nine TCZ and four placebo patients (nine and three in clinical remission, respectively). Three (33%) TCZ patients showed normalization of vessel wall signals compared with one (25%) placebo patient. At week 52, there was additional MRA improvement in some TCZ patients, but one-third showed persistent or increased late vessel wall enhancement. There was no formation of aneurysms or stenosis and no increase in atherosclerosis. Conclusions: Although TCZ resulted in complete clinical and laboratory remission of GCA over 52 weeks, MRA signals in vessel walls normalized in only one-third of patients. Whether these signals are of prognostic importance remains to be determined. PMID- 29529281 TI - Novel insights into the aetiology of granulomatosis with polyangiitis-a case control study using the Clinical Practice Research Datalink. AB - Objectives: We aimed to provide insights into the aetiology of granulomatosis with polyangiitis (GPA), by conducting a large case-control study using a general population-based, prospectively collected database of healthcare records. Methods: We compared all incident cases of GPA in the Clinical Practice Research Datalink 1990-2014, with up to 10 age-, sex- and general practice-matched controls. We identified potential risk factors, recorded numbers of cases and controls exposed to each, and calculated odds ratios (ORs) using conditional logistic regression. Our main analysis excluded data recorded during 1 year before diagnosis, to prevent early symptoms being mistaken for risk factors. Results: We identified 757 people with GPA and matched 7546 controls. People with GPA were five times more likely to have a previous diagnosis of bronchiectasis (OR = 5.1, 95% CI: 2.7, 9.4; P < 0.0001), and these effects remained stable in diagnoses recorded >5 years prior to diagnosis. People with GPA were two to three times more likely than controls to have previous diagnoses of autoimmune diseases or chronic renal impairment, and these effects also remained stable >5 years prior to diagnosis. People with GPA were more likely to have a diagnosis of pulmonary fibrosis (OR = 5.7, 95% CI: 1.7, 19.5; P = 0.01) and sinus infections (OR = 2.7, 95% CI: 1.8, 4.2; P < 0.0001) recorded in the 3 years before diagnosis, but not before this. We also found former smoking, some medications and higher socio-economic status significantly, but less strongly, associated. Conclusion: We found novel long-term associations between GPA and pre-existing bronchiectasis and autoimmune diseases. PMID- 29529282 TI - The investment case for hepatitis B and C in South Africa: adaptation and innovation in policy analysis for disease program scale-up. AB - Even though WHO has approved global goals for hepatitis elimination, most countries have yet to establish programs for hepatitis B and C, which account for 320 million infections and over a million deaths annually. One reason for this slow response is the paucity of robust, compelling analyses showing that national HBV/HCV programs could have a significant impact on these epidemics and save lives in a cost-effective, affordable manner. In this context, our team used an investment case approach to develop a national hepatitis action plan for South Africa, grounded in a process of intensive engagement of local stakeholders. Costs were estimated for each activity using an ingredients-based, bottom-up costing tool designed by the authors. The health impact and cost-effectiveness of the Action Plan were assessed by simulating its four priority interventions (HBV birth dose vaccination, PMTCT, HBV treatment and HCV treatment) using previously developed models calibrated to South Africa's demographic and epidemic profile. The Action Plan is estimated to require ZAR3.8 billion (US$294 million) over 2017 2021, about 0.5% of projected government health spending. Treatment scale-up over the initial 5-year period would avert 13 000 HBV-related and 7000 HCV-related deaths. If scale up continues beyond 2021 in line with WHO goals, more than 670 000 new infections, 200 000 HBV-related deaths, and 30 000 HCV-related deaths could be averted. The incremental cost-effectiveness of the Action Plan is estimated at $3310 per DALY averted, less than the benchmark of half of per capita GDP. Our analysis suggests that the proposed scale-up can be accommodated within South Africa's fiscal space and represents good use of scarce resources. Discussions are ongoing in South Africa on the allocation of budget to hepatitis. Our work illustrates the value and feasibility of using an investment case approach to assess the costs and relative priority of scaling up HBV/HCV services. PMID- 29529284 TI - Evaluating implementation of the Ebola response in Margibi County, Liberia. AB - Implementation of the Ebola response was credited with reducing incidence of Ebola virus disease (EVD) in West Africa; however little is known about the amount and kind of Ebola response activities that were ultimately successful in addressing the 2014 outbreak. We collaboratively monitored Ebola response activities and associated effects in Margibi County, Liberia, a rural county in Liberia deeply affected by the outbreak. We used a participatory monitoring and evaluation system, including key informant interviews and document review, to systematically document activities, code them, characterize their contextual features, and discover and communicate patterns in Ebola response activities to essential stakeholders. We also measured incidence of EVD over time. Results showed a distinct pattern in Ebola response activities and key events, which corresponded with subsequent decreased EVD incidence. These data are suggestive of the role of Ebola response activities played in reducing the incidence of EVD within Margibi County, which included implementing safe burials, social mobilization and community engagement and case management. Systematic monitoring and evaluation of response activities to control disease outbreaks holds lessons for implementing and evaluating similar comprehensive and multi-sectoral community health efforts. PMID- 29529283 TI - Investigation of sliding DNA clamp dynamics by single-molecule fluorescence, mass spectrometry and structure-based modeling. AB - Proliferating cell nuclear antigen (PCNA) is a trimeric ring-shaped clamp protein that encircles DNA and interacts with many proteins involved in DNA replication and repair. Despite extensive structural work to characterize the monomeric, dimeric, and trimeric forms of PCNA alone and in complex with interacting proteins, no structure of PCNA in a ring-open conformation has been published. Here, we use a multidisciplinary approach, including single-molecule Forster resonance energy transfer (smFRET), native ion mobility-mass spectrometry (IM MS), and structure-based computational modeling, to explore the conformational dynamics of a model PCNA from Sulfolobus solfataricus (Sso), an archaeon. We found that Sso PCNA samples ring-open and ring-closed conformations even in the absence of its clamp loader complex, replication factor C, and transition to the ring-open conformation is modulated by the ionic strength of the solution. The IM MS results corroborate the smFRET findings suggesting that PCNA dynamics are maintained in the gas phase and further establishing IM-MS as a reliable strategy to investigate macromolecular motions. Our molecular dynamic simulations agree with the experimental data and reveal that ring-open PCNA often adopts an out-of plane left-hand geometry. Collectively, these results implore future studies to define the roles of PCNA dynamics in DNA loading and other PCNA-mediated interactions. PMID- 29529285 TI - Disruption of Nuclear Receptor Signaling Alters Triphenyl Phosphate-Induced Cardiotoxicity in Zebrafish Embryos. AB - Triphenyl phosphate (TPHP) is an unsubstituted aryl phosphate ester used as a flame retardant and plasticizer within the United States. Using zebrafish as a model, the objectives of this study were to rely on (1) mRNA-sequencing to uncover pathways disrupted following embryonic TPHP exposure and (2) high-content screening to identify nuclear receptor ligands that enhance or mitigate TPHP induced cardiotoxicity. Based on mRNA-sequencing, TPHP exposure from 24 to 72-h postfertilization (hpf) resulted in a concentration-dependent increase in the number of transcripts significantly affected at 72 hpf, and pathway analysis revealed that 5 out of 9 nuclear receptor pathways were associated with the retinoid X receptor (RXR). Based on a screen of 74 unique nuclear receptor ligands as well as follow-up experiments, 2 compounds-ciglitazone (a peroxisome proliferator-activated receptor gamma, or PPARgamma, agonist) and fenretinide (a pan-retinoic acid receptor, or RAR, agonist)-reliably mitigated TPHP-induced cardiotoxicity in the absence of effects on TPHP uptake or metabolism. As these data suggested that TPHP may be activating RXR (a heterodimer for both RARs and PPARgamma), we coexposed embryos to HX 531-a pan-RXR antagonist-from 24 to 72 hpf and, contrary to our hypothesis, found that coexposure to HX 531 significantly enhanced TPHP-induced cardiotoxicity. Using a luciferase reporter assay, we also found that TPHP did not activate nor inhibit chimeric human RXRalpha, RXRbeta, or RXRgamma, suggesting that TPHP does not directly bind nor interact with RXRs. Overall, our data suggest that TPHP may interfere with RXR-dependent pathways involved in cardiac development. PMID- 29529287 TI - Between Food and Medicine: Artificial Digestion, Sickness, and the Case of Benger's Food. AB - In the nineteenth century, food and diet became central to a public health increasingly focused on individual behavior and on the cost of sickness. Because of its potential to impact the economic uptake of food inside individual bodies, digestion became a crucial site of physiological investigation in this context. Out of physiological research on digestion emerged a group of medicinal food products based on digestive enzymes (then referred to as digestive ferments), so called artificially digested foods. The paper examines the creation and significance of these products, focusing on the case of Benger's Food. It places Benger's Food in the context of shifting professional boundaries between physicians, pharmacists, and nurses and changing approaches to the pathophysiology of sickness. Contrary to previous enzyme-based products, Benger's Food was not imagined as a specific therapeutic targeted at a particular digestive disease, but as a universal solution to illness. To function as a public health tool, Benger's Food had to be broadly applicable and palatable, and be understood as a food rather than as a medicine. The paper uncovers the conceptual and material work involved in achieving this. By doing so, it shows the intersection between food and medicine as the result of a historically specific process of creation and management. PMID- 29529288 TI - Resistance to Diamide Insecticides in Plutella xylostella (Lepidoptera: Plutellidae): Comparison Between Lab-Selected Strains and Field-Collected Populations. AB - Diamondback moth, Plutella xylostella (L.; Lepidoptera: Plutellidae), is an important pest of crucifers worldwide. The extensive use of diamide insecticides has led to P. xylostella resistance and this presents a serious threat to vegetable production. We selected chlorantraniliprole (Rf) and flubendiamide (Rh) resistance strains of P. xylostella with resistance ratios of 684.54-fold and 677.25-fold, respectively. The Rf and Rh strains underwent 46 and 36 generations of lab-selection for resistance, respectively. Low cross resistance of Rh to cyantraniliprole was found. Cross resistance to chlorfenapyr, tebufenozid, and indoxacarb was not found in Rf and Rh strains. The P. xylostella ryanodine receptor gene (PxRyR) transcripts level in the Rf and Rh strains was up regulated. Except for Rf34 and Rh36, PxRyR expression in all generations of Rf and Rh selection gradually increased with increasing resistance. Two resistant populations were field-collected from Guangzhou Baiyun (Rb) and Zengcheng (Rz) and propagated for several generations without exposure to any pesticide had higher PxRyR expression than the susceptible strain (S). In the S strain, PxRyR expression was not related to the resistance ratio. Gene sequencing found that the RyR 4946 gene site was glycine (G) in the S, Rf, and Rh strains, and was glutamate (E) with 70% and 80% frequency in the Rb and Rz populations, respectively. The 4946 gene site was substituted by valine (V) with the frequency of 30% and 20% in Rb and Rz populations, respectively. These results increase the understanding of the mechanisms of diamide insecticide resistance in P. xylostella. PMID- 29529286 TI - Discovery of new type I toxin-antitoxin systems adjacent to CRISPR arrays in Clostridium difficile. AB - Clostridium difficile, a major human enteropathogen, must cope with foreign DNA invaders and multiple stress factors inside the host. We have recently provided an experimental evidence of defensive function of the C. difficile CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR associated) system important for its survival within phage-rich gut communities. Here, we describe the identification of type I toxin-antitoxin (TA) systems with the first functional antisense RNAs in this pathogen. Through the analysis of deep-sequencing data, we demonstrate the general co-localization with CRISPR arrays for the majority of sequenced C. difficile strains. We provide a detailed characterization of the overlapping convergent transcripts for three selected TA pairs. The toxic nature of small membrane proteins is demonstrated by the growth arrest induced by their overexpression. The co-expression of antisense RNA acting as an antitoxin prevented this growth defect. Co-regulation of CRISPR-Cas and type I TA genes by the general stress response Sigma B and biofilm-related factors further suggests a possible link between these systems with a role in recurrent C. difficile infections. Our results provide the first description of genomic links between CRISPR and type I TA systems within defense islands in line with recently emerged concept of functional coupling of immunity and cell dormancy systems in prokaryotes. PMID- 29529290 TI - Cognitive Behavioral Therapy for Depression, Anxiety, and Stress in Caregivers of Dementia Patients: A Systematic Review and Meta-Analysis. AB - Background and Objectives: There is limited evidence for the efficacy of cognitive behavioral therapy (CBT) in managing psychological morbidities in caregivers of dementia patients. To evaluate changes in dementia caregivers' depression, anxiety, and stress following CBT. Also to assess quality of life, intervention adherence/satisfaction and therapy effectiveness using different formats, frequencies, and delivery methods. Research Design and Methods: Studies were identified through electronic bibliographic searches (MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Library) and from gray literature (Conference Proceedings Citation Index and clinicaltrials.gov). Data were pooled for meta analysis. Results: Twenty-five studies were included. Depression (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI] -0.47 to -0.21; p < .001) and stress (SMD = -0.36; 95% CI: -0.52 to -0.20; p < .001) were significantly reduced after CBT, relative to comparator groups, while anxiety was not (SMD = 0.10; 95% CI: -0.18 to 0.39; p = .47). A subgroup analysis demonstrated that statistically significant reductions in depression and stress were limited to group, but not individual, formats. An additional subgroup analysis revealed that eight CBT sessions or fewer were equally effective as more than eight sessions at significantly reducing depression and stress, relative to comparator groups. Furthermore, analysis with independent samples t-tests demonstrated no statistically significant differences between mean changes in depression (MD = 0.79; 95% CI: -0.45 to 2.03; p = .21) and stress (MD = 0.21; 95% CI: -1.43 to 1.85; p = .80) when directly comparing CBT groups of <=8 and >8 sessions. Discussion and Implications: Group CBT provides small but significant benefits to caregivers' depression and stress. Therapy cost-effectiveness may be improved by limiting therapy to group formats and eight sessions. PMID- 29529289 TI - Plasma Levels of Soluble Tumor Necrosis Factor Receptor 2 (sTNFR2) Are Associated with Hippocampal Volume and Cognitive Performance in Patients with Schizophrenia. AB - Background: An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. Methods: We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. Results: We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment. PMID- 29529291 TI - Dosage of Single Low-Dose Primaquine to Stop Malaria Transmission. PMID- 29529292 TI - Weight gain after smoking cessation: more data to refute concerns. AB - Take home figure. PMID- 29529293 TI - Corrigendum. PMID- 29529294 TI - Any sleep is a dream far away: a nominal group study assessing how gout affects sleep. AB - Objective: There are no qualitative studies of sleep in gout; the aim of this study was to examine the impact of gout on sleep. Methods: Nine nominal groups were conducted, oversampling for African-Americans and women with gout. Patients discussed and rank-ordered their concerns. Results: Nine nominal groups with 46 gout patients were conducted with mean age, 61 years (s.d. 10.6) and gout duration, 14.9 years (s.d. 12); 63% were men, 46% African-American, 52% married, 46% retired and 63% were allopurinol users. The most frequently cited highly ranked concerns could be divided into three categories. The first category, character of sleep interruption, included the concerns: severe and complete sleep interruption by gout flare pain (nine groups); and inability to get rapid eye movement sleep (one group). The second category, causes of sleep interruption, included: inability to get into a comfortable position during sleep (six groups); anxiety and depression associated with severe gout pain (seven groups); sleep interruption by moderate chronic joint pain (three groups); frequent trips to the bathroom interfering with sleep (two groups); gout medication side effects (four groups); frequent trips to the emergency room (one group); joint swelling with physical/functional deficit interfering with sleep (two groups); and flare pain interfering with sleep apnoea management (two groups). The final category, consequences of sleep interruption, included: effect on daily functioning (two groups); worsens other health conditions, which then affect sleep (four groups); and cumulative effect on sleep (one group). Conclusion: Gout has significant impact on sleep quantity, quality and architecture. Sleep disruption due to gout has several pathways and significant consequences. PMID- 29529295 TI - Services for spondyloarthritis: a survey of patients and rheumatologists. AB - Objectives: There have been significant advances in axial spondyloarthritis (axSpA), with implications for service delivery. We evaluated the state of axSpA rheumatology services and how people with axSpA perceive their care. Methods: An online patient survey was emailed to all members of the National Ankylosing Spondylitis Society and advertised widely via social media. Separately, a Web based questionnaire about axSpA services was sent to rheumatologists at all 172 acute hospital trusts in the UK. Results: From the National Ankylosing Spondylitis Society survey, data for 1979 surveys (56% males) were available for analysis. The majority of respondents had longstanding disease and identified their diagnosis as AS, with only 44% aware of the term axSpA. Eighty-two per cent of respondents were currently attending a rheumatologist, with 43% on biologic agents. Satisfaction scores for rheumatology care were high. Respondents' concerns included access during disease flares and adverse effects of analgesics. From the rheumatology survey, the concept and terminology of axSpA was widely accepted by respondents (88%). The majority of centres had at least one rheumatologist with a specialist interest in axSpA (62%), dedicated axSpA clinics (58%) or a multidisciplinary team for axSpA (64%). BASDAI (99%), BASFI (74%) and BASMI (65%) were routinely performed. All centres had access to MRI scans, but scanning protocols varied and were often sub-optimal. Conclusion: Although overall satisfaction with rheumatology care was high, the results indicate significant unmet patient needs and discrepancies in service provision. This information will inform the development of quality standards for axSpA in order to improve quality and deliver equitable care for all patients. PMID- 29529296 TI - Timing of Operative Intervention in Traumatic Spine Injuries Without Neurological Deficit. AB - BACKGROUND: Numerous studies have demonstrated the benefits of early decompression and stabilization in unstable spine injuries with incomplete neurological deficits. However, a clear consensus on timing to operative intervention still does not exist in those with a normal neurological exam and unstable spine. OBJECTIVE: To determine the optimal timing of operative intervention in traumatic spine injuries without neurological deficit. METHODS: Retrospective chart review at a single institution was performed including patients with traumatic spine injuries without neurological deficit admitted from December 2001 to August 2012. Estimated intraoperative blood loss (EBL), in hospital complications, postoperative hospital length of stay (HLOS), intensive care unit length of stay (ICULOS), and ventilator days were recorded. Delayed surgery was defined as surgery 72 h after admission. RESULTS: A total of 456 patients were included for analysis. There was a trend towards statistical significance between the time to operative intervention and EBL in bivariate analysis (P = .07). In the risk-adjusted multivariable analysis delayed vs early surgery was not associated with increased EBL or complications. Delayed surgery was associated with increased ICULOS (odds ratio [OR] = 2.19; 95% confidence interval [CI]: 1.38-3.51; P = .001), ventilator days (OR = 2.09; 95% CI: 1.28 3.43; P = .004), and increased postoperative HLOS (OR = 1.84; 95% CI: 1.22-2.76; P = .004). CONCLUSION: Earlier operative intervention was associated with decreased ICULOS, ventilator days, and postoperative HLOS and did not show a statistically significant increase in EBL or complications. Earlier operative intervention for traumatic spine injuries without neurological deficit provides better outcomes compared to delayed surgery. PMID- 29529297 TI - Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing. AB - Background: Li-Fraumeni syndrome (LFS) has traditionally been identified by single-gene testing (SGT) of TP53 triggered by clinical criteria, but the widespread use of multigene panel tests (MGPTs) has upended this paradigm. We sought to compare the personal and family cancer histories of TP53-positive result (TP53+) carriers who were identified by either MGPT or SGT. Methods: Of 44 310 individuals who underwent testing of TP53 in a single clinical diagnostic laboratory between 2010 and 2014, 44 086 (40 885 MGPT and 3201 SGT) met study eligibility criteria. Personal cancer histories were available for 38 938 subjects. The frequency of germline TP53 results and various phenotypic manifestations were compared according to test type. All statistical tests were two-sided. Results: MGPT TP53+ individuals (n = 126) had an older median age at first cancer than SGT TP53+ carriers (n = 96; women: median = 36 vs 28 years, P < .001; and men: median = 40 vs 15 years, P = .004). The median age of breast cancer diagnosis was 40 years in MGPT TP53+ women vs 33 years in SGT TP53+ women (P < .001). In both cohorts, childhood and LFS core cancers, and for women, multiple primary cancers (not multiple breast tumors), were associated with TP53+ results. Established LFS testing criteria were less often met by MGPT TP53+ individuals. Conclusions: MGPT TP53+ individuals differ in phenotype from those ascertained through SGT and are notably older at cancer diagnosis and less likely to meet LFS clinical criteria. These findings suggest that LFS may have a greater phenotypic spectrum than previously appreciated. This has implications for the counseling of MGPT TP53+ individuals. Prospective follow-up of these individuals and families is needed to re-evaluate cancer risks. PMID- 29529298 TI - Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus. AB - CHD1 is a conserved chromatin remodeling enzyme required for development and linked to prostate cancer in adults, yet its role in human cells is poorly understood. Here, we show that targeted disruption of the CHD1 gene in human cells leads to a defect in early double-strand break (DSB) repair via homologous recombination (HR), resulting in hypersensitivity to ionizing radiation as well as PARP and PTEN inhibition. CHD1 knockout cells show reduced H2AX phosphorylation (gammaH2AX) and foci formation as well as impairments in CtIP recruitment to the damaged sites. Chromatin immunoprecipitation following a single DSB shows that the reduced levels of gammaH2AX accumulation at DSBs in CHD1-KO cells are due to both a global reduction in H2AX incorporation and poor retention of H2AX at the DSBs. We also identified a unique N-terminal region of CHD1 that inhibits the DNA binding, ATPase, and chromatin assembly and remodeling activities of CHD1. CHD1 lacking the N terminus was more active in rescuing the defects in gammaH2AX formation and CtIP recruitment in CHD1-KO cells than full length CHD1, suggesting the N terminus is a negative regulator in cells. Our data point to a role for CHD1 in the DSB repair process and identify a novel regulatory region of the protein. PMID- 29529299 TI - The association between copy number aberration, DNA methylation and gene expression in tumor samples. AB - We systematically studied the association between somatic copy number aberration (SCNA), DNA methylation and gene expression using -omic data from The Cancer Genome Atlas (TCGA) on six cancer types: breast cancer, colon cancer, glioblastoma, leukemia, lower-grade glioma and prostate cancer. A major challenge for such integrated study is that the association between DNA methylation and gene expression is severely confounded by tumor purity and cell type composition, which are often unobserved and difficult to estimate. To overcome this challenge, we developed a method to remove confounding effects by calculating the principal components that span the space of the latent factors. Another intriguing findings of our study is that there could be both positive and negative associations between SCNA and DNA methylation, while the CpGs with negative/positive associations with SCNA are often located around CpG islands/ocean, respectively. A joint study of SCNA, DNA methylation, and gene expression suggest that SCNA often affect DNA methylation and gene expression independently. PMID- 29529300 TI - Tail-end dehulling of canola meal improves apparent and standardized total tract digestibility of phosphorus when fed to growing pigs. AB - Tail-end dehulling of canola meal (CM) has been shown to reduce dietary fiber and increase crude protein content in the dehulled meal. The application of this procedure also increased the total and non-phytate P content in the dehulled meal. However, it is unclear if dehulling affects P digestibility in the different fractions (i.e., the dehulled meal and the coarse fraction) and if it differs when fed to growing pigs at two different BW. Therefore, two experiments were conducted to determine the apparent (ATTD) and standardized (STTD) total tract digestibility of P in dehulled CM fed to growing pigs. Diets containing non dehulled regular canola meal (RCM), and two fractions produced using sieve size of 355 um: a low-fiber high-protein fraction (dehulled canola meal [DCM]) and a high-fiber low-protein fraction (coarse canola meal [CCM]) as the only source of P were fed to growing pigs at two different BW. A total of 48 pigs were used for the two experiments. In experiment 1, 24 barrows [(Yorkshire * Landrace) * Duroc] with initial BW of 24.5 +/- 1.68 kg were individually housed in metabolism crates and fed the experimental diets for 10 d for total fecal collection. In experiment 2, 24 barrows with an average initial BW of 73.8 +/- 4.93 kg were used; experimental diets and fecal collection procedures were the same as in experiment 1. Each experiment used six replicates per treatment. A P-free diet was used to determine basal endogenous losses of P (139.6 +/- 10.7 and 150.89 +/- 20.1 mg/kg of DMI for experiments 1 and 2, respectively). Data were analyzed as a completely randomized design. In experiment 1, the ATTD and STTD of P were greater (P < 0.05) for DCM (42.4% and 46.1%) than for the RCM (32.0% and 35.7%) and CCM (24.5% and 28.4%) diets. In experiment 2, the ATTD and STTD of P were greater (P < 0.05) for DCM (38.7% and 42.8%) than for the CCM diet (22.6% and 26.8%); whereas the values for RCM diet were intermediate (31.0% and 35.0%) and not different from the DCM and CCM. In conclusion, dehulling canola meal increased ATTD and STTD of P in growing pigs of different BW; however, there was no effect of BW. PMID- 29529301 TI - Corrigendum: Induced abortion. PMID- 29529303 TI - "Isolated" Suprascapular Neuropathy: Compression, Traction, or Inflammation? AB - BACKGROUND: Several hypotheses have been proposed for the pathophysiology of suprascapular nerve (SSN) palsy, including compression, traction, and nerve inflammation. OBJECTIVE: To provide insight into the pathophysiology of isolated nontraumatic SSN palsy by performing critical reinterpretations of electrodiagnostic (EDX) studies and magnetic resonance (MR) images of patients with such diagnosis. METHODS: We retrospectively reviewed all patients referred to our institution for the past 20 yr with a diagnosis of nontraumatic isolated suprascapular neuropathy who had an upper extremity EDX study and a shoulder or brachial plexus MR scan. Patient charts were reviewed to analyze their initial clinical examination, and their original EDX study and MR images were reinterpreted by an experienced neurologist and a musculoskeletal radiologist, respectively, both blinded from the authors' hypothesis and from each other's findings. RESULTS: Fifty-nine patients were included. Fifty of them (85%) presented with at least 1 finding that was inconsistent with an isolated SSN palsy. Forty patients (68%) had signs on physical examination beyond the SSN distribution. Thirty-one patients (53%) had abnormalities on their EDX studies not related to the SSN. Twenty-two patients (37%) had denervation atrophy in other muscles than the spinati, or neural hyperintensity in other nerves than the SSN on their MR scans, without any evidence of SSN extrinsic compression. CONCLUSION: The great majority of patients with presumed isolated SSN palsy had clinical, electrophysiological, and/or imaging evidence of a more diffuse pattern of neuromuscular involvement. These data strongly support an inflammatory pathophysiology in many cases of "isolated" SSN palsy. PMID- 29529302 TI - Translational profiling of B cells infected with the Epstein-Barr virus reveals 5' leader ribosome recruitment through upstream open reading frames. AB - The Epstein-Barr virus (EBV) genome encodes several hundred transcripts. We have used ribosome profiling to characterize viral translation in infected cells and map new translation initiation sites. We show here that EBV transcripts are translated with highly variable efficiency, owing to variable transcription and translation rates, variable ribosome recruitment to the leader region and coverage by monosomes versus polysomes. Some transcripts were hardly translated, others mainly carried monosomes, showed ribosome accumulation in leader regions and most likely represent non-coding RNAs. A similar process was visible for a subset of lytic genes including the key transactivators BZLF1 and BRLF1 in cells infected with weakly replicating EBV strains. This suggests that ribosome trapping, particularly in the leader region, represents a new checkpoint for the repression of lytic replication. We could identify 25 upstream open reading frames (uORFs) located upstream of coding transcripts that displayed 5' leader ribosome trapping, six of which were located in the leader region shared by many latent transcripts. These uORFs repressed viral translation and are likely to play an important role in the regulation of EBV translation. PMID- 29529304 TI - Diffusion Tensor Imaging in a Large Longitudinal Series of Patients With Cervical Spondylotic Myelopathy Correlated With Long-Term Functional Outcome. AB - BACKGROUND: Fractional anisotropy (FA) of the high cervical cord correlates with upper limb function in acute cervical cord injury. We investigated the correlation between preoperative FA at the level of maximal compression and functional recovery in a group of patients after decompressive surgery for cervical spondylotic myelopathy (CSM). OBJECTIVE: To determine the usefulness of FA as a biomarker for severity of CSM and as a prognostic biomarker for improvement after surgery. METHODS: Patients received diffusion tensor imaging (DTI) scans preoperatively. FA values of the whole cord cross-section at the level of maximal compression and upper cervical cord (C1-2) were calculated. Functional status was measured using the modified Japanese Orthopedic Association (mJOA) scale preoperatively and at follow-up up to 2 yr. Regression analysis between FA and mJOA was performed. DTI at C4-7 was obtained in controls. RESULTS: Forty-four CSM patients enrolled prior to decompression were compared with 24 controls. FA at the level of maximal compression correlated positively with preoperative mJOA score. Preoperative FA correlated inversely with recovery throughout the postoperative period. This was statistically significant at 12 mo postoperation and nearly so at 6 and 24 mo. Patients with preoperative FA <0.55 had a statistically significant difference in outcome compared to FA >0.55. CONCLUSION: In the largest longitudinal study of this kind, FA promises a valid biomarker for severity of CSM and postoperative improvement. FA is an objective measure of function and could provide a basis for prognosis. FA is particularly useful if preoperative values are less than 0.55. PMID- 29529305 TI - Building a rheumatology team for Africa: enhancing the roles of patients and non specialists. PMID- 29529306 TI - Monitoring for retinal toxicity in patients taking hydroxychloroquine and chloroquine. PMID- 29529307 TI - Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. AB - Objectives: This analysis set out to estimate the risk of opportunistic infection (OI) among patients with RA by biologic class. Methods: The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis is a prospective observational cohort study established to evaluate safety of biologic therapies. The population included adults commencing biologic therapy for RA. The primary outcome was any serious OI excluding tuberculosis (TB). Event rates were compared across biologic classes using Cox proportional hazards with adjustment for potential confounders identified a priori. Analysis of the incidence of TB was performed separately. Results: In total, 19 282 patients with 106 347 years of follow-up were studied; 142 non-TB OI were identified at a rate of 134 cases/100 000 patient years (pyrs). The overall incidence of OI was not significantly different between the different drug classes; however, the rate of Pneumocystis infection was significantly higher with rituximab than with anti-TNF therapy (adjusted hazard ratio = 3.2, 95% CI: 1.4, 7.5). The rate of TB fell dramatically over the study period (783 cases/100 000 pyrs in 2002 to 38 cases/100 000 pyrs in 2015). The incidence of TB was significantly lower among rituximab users than anti-TNF users, with 12 cases/100 000 pyrs compared with 65 cases/100 000 pyrs. Conclusions: The overall rate of OI was not significantly different between drug classes; however, a subtle difference in the pattern of OI was seen between the cohorts. Patient factors such as age, gender and comorbidity were the most important predictors of OI. PMID- 29529308 TI - Cryptococcosis in the koala (Phascolarctos cinereus): pathogenesis and treatment in the context of two atypical cases. AB - Disseminated cryptococcosis caused by Cryptococcus gattii (molecular type VGI) was diagnosed in an adult free-ranging female koala (Phascolarctos cinereus). Subclinical cryptococcosis was later diagnosed in this koala's joey. In the adult koala, a pathological fracture of the tibia was associated with the bone lysis of marked focal cryptococcal osteomyelitis. Limb-sparing orthopedic intervention, in the setting of disseminated cryptococcosis, was judged to have a poor prognosis, and the adult koala was euthanized. The joey was removed and hand-reared. Serological testing revealed persistent and increasing cryptococcal capsular antigenemia in the absence of clinical signs of disease and it was subsequently treated with oral fluconazole for approximately 16 months, rehabilitated and released into the wild. It was sighted 3 months post-release in a good state of health and again at 18 months post-release but was not recaptured on either occasion. This is the first published report of cryptococcal appendicular osteomyelitis in a koala. It is also the first report of concurrent disease in a dependent juvenile and the successful treatment of subclinical cryptococcosis to full resolution of the cryptococcal antigenemia in a free-ranging koala. This paper provides a discussion of cryptococcal osteomyelitis in animals, host pathogen-environment interactions and treatment and monitoring protocols for cryptococcosis in koalas. Published reports describing the treatment of cryptococcosis in koalas are also collated and summarised. PMID- 29529309 TI - Relationship Between T-Cell Responses to CMV, Markers of Inflammation, and Frailty in HIV-uninfected and HIV-infected Men in the Multicenter AIDS Cohort Study. AB - Background: Both aging and treated human immunodeficiency virus (HIV)-infected populations exhibit low-level chronic immune activation of unknown etiology, which correlates with morbidity and mortality. Cytomegalovirus (CMV) infection is common in both populations, but its relation to immune activation is unknown. Methods: T cells from men who have sex with men (22 virologically suppressed HIV+, 20 HIV-) were stimulated with peptides spanning 19 CMV open reading frames, and intracellular cytokine responses were assessed. Soluble and cellular inflammatory markers were assessed by multiplex electrochemiluminescence and flow cytometry, respectively. Frailty was assessed by the Fried criteria. Results: All men had responses to CMV. Proportions of CMV-responsive T cells correlated strongly (r >= 0.6 or <= -0.6; P < .05) with immunologic markers, depending on donor HIV and frailty status. Markers significantly correlated in some groups after adjustment for multiple comparisons included interferon-gamma, tumor necrosis factor-alpha, interleukin-6, and several chemokines in serum, and the proportion of activated T cells. The magnitude of the CD4 IL-2 response significantly predicted onset of frailty in HIV- nonfrail men, but not in HIV+ nonfrail men. Conclusions: T-cell responses to CMV may strongly influence chronic immune activation in HIV-uninfected and virologically suppressed HIV-infected men, and may predict frailty in HIV-uninfected men. PMID- 29529311 TI - Middle Cerebral Artery Aneurysm "Neck Overhang": Decreased Postclipping Residual Using the Intersecting Clipping Technique. AB - BACKGROUND: Middle cerebral artery (MCA) aneurysms continue to be viewed by many as primarily surgical entities. OBJECTIVE: To introduce a new, easily measurable dimension termed "neck overhang," defined as the amount of the aneurysm that extends proximal to the 2 dimensionally defined "neck" and to evaluate the utility of the intersecting clipping technique (use of straight clip and intersecting fenestrated clip) to adapt to this overhanging segment's specific dimensions and achieve better obliteration of the MCA aneurysms. METHODS: We reviewed retrospectively 100 MCA aneurysms treated surgically over the last 10 yr at our institution. We identified the clipping technique that was performed (intersecting vs "standard" technique) and we evaluated the presence of a postoperative remnant. We then correlated these with the aneurysm's overhanging neck length. RESULTS: Forty-three aneurysms were treated with the intersecting clipping technique. The overall rate of remnant was 16%. In the standard group, the rate of remnant was 23%, whereas with intersecting clipping that was 7% (P = .029). Within the standard clipping group, we found that the optimum threshold for length of the neck overhang was >=1.9 mm in order to predict the occurrence of residual. Applying this threshold to the intersecting clipping technique group resulted in a reduction in remnant from 35% in the standard group to 9%. CONCLUSION: Neck overhang >1.9 mm is associated with a higher chance of postclipping residual aneurysm in MCA aneurysms. The intersecting clipping technique is a versatile technique that can conform to various aneurysms' geometry and can reduce the rate of post clipping residual for aneurysms with high neck overhang. PMID- 29529310 TI - Global brain dynamics during social exclusion predict subsequent behavioral conformity. AB - Individuals react differently to social experiences; for example, people who are more sensitive to negative social experiences, such as being excluded, may be more likely to adapt their behavior to fit in with others. We examined whether functional brain connectivity during social exclusion in the fMRI scanner can be used to predict subsequent conformity to peer norms. Adolescent males (n = 57) completed a two-part study on teen driving risk: a social exclusion task (Cyberball) during an fMRI session and a subsequent driving simulator session in which they drove alone and in the presence of a peer who expressed risk-averse or risk-accepting driving norms. We computed the difference in functional connectivity between social exclusion and social inclusion from each node in the brain to nodes in two brain networks, one previously associated with mentalizing (medial prefrontal cortex, temporoparietal junction, precuneus, temporal poles) and another with social pain (dorsal anterior cingulate cortex, anterior insula). Using predictive modeling, this measure of global connectivity during exclusion predicted the extent of conformity to peer pressure during driving in the subsequent experimental session. These findings extend our understanding of how global neural dynamics guide social behavior, revealing functional network activity that captures individual differences. PMID- 29529312 TI - DNA lesions proximity modulates damage tolerance pathways in Escherichia coli. AB - The genome of all organisms is constantly threatened by numerous agents that cause DNA damage. When the replication fork encounters an unrepaired DNA lesion, two DNA damage tolerance pathways are possible: error-prone translesion synthesis (TLS) that requires specialized DNA polymerases, and error-free damage avoidance that relies on homologous recombination (HR). The balance between these two mechanisms is essential since it defines the level of mutagenesis during lesion bypass, allowing genetic variability and adaptation to the environment, but also introduces the risk of generating genome instability. Here we report that the mere proximity of replication-blocking lesions that arise in Escherichia coli's genome during a genotoxic stress leads to a strong increase in the use of the error-prone TLS. We show that this increase is caused by the local inhibition of HR due to the overlapping of single-stranded DNA regions generated downstream of the lesions. This increase in TLS is independent of SOS activation, but its mutagenic effect is additive with the one of SOS. Hence, the combination of SOS induction and lesions proximity leads to a strong increase in TLS that becomes the main lesion tolerance pathway used by the cell during a genotoxic stress. PMID- 29529313 TI - Size-dependent genotoxicity of silver, gold and platinum nanoparticles studied using the mini-gel comet assay and micronucleus scoring with flow cytometry. AB - Metallic nanoparticles (NPs) are promising nanomaterials used in different technological solutions as well as in consumer products. Silver (Ag), gold (Au) and platinum (Pt) represent three metallic NPs with current or suggested use in different applications. Pt is also used as vehicle exhaust catalyst leading to a possible exposure via inhalation. Despite their use, there is limited data on their genotoxic potential and possible size-dependent effects, particularly for Pt NPs. The aim of this study was to explore size-dependent genotoxicity of these NPs (5 and 50 nm) following exposure of human bronchial epithelial cells. We characterised the NPs and assessed the viability (Alamar blue assay), formation of DNA strand breaks (mini-gel comet assay) and induction of micronucleus (MN) analysed using flow cytometry (in vitro microflow kit). The results confirmed the primary size (5 and 50 nm) but showed agglomeration of all NPs in the serum free medium used. Slight reduced cell viability (tested up to 50 ug/ml) was observed following exposure to the Ag NPs of both particle sizes as well as to the smallest (5 nm) Au NPs. Similarly, at non-cytotoxic concentrations, both 5 and 50 nm-sized Ag NPs, as well as 5 nm-sized Au NPs, increased DNA strand breaks whereas for Pt NPs only the 50 nm size caused a slight increase in DNA damage. No clear induction of MN was observed in any of the doses tested (up to 20 ug/ml). Taken together, by using the comet assay our study shows DNA strand breaks induced by Ag NPs, without any obvious differences in size, whereas effects from Au and Pt NPs were size-dependent in the sense that the 5 nm-sized Au NPs and 50 nm-sized Pt NPs particles were active. No clear induction of MN was observed for the NPs. PMID- 29529315 TI - Historical Perspective of Mitochondria in the Toxicological Sciences. PMID- 29529316 TI - The Life and Times of John Doull, PhD, MD (1922-2017). PMID- 29529317 TI - Toxicology and Tributaries in Texas. PMID- 29529318 TI - Moderate social sensitivity in a risky context supports adaptive decision making in adolescence: evidence from brain and behavior. AB - Adolescence is a time of increased social-affective sensitivity, which is often related to heightened health-risk behaviors. However, moderate levels of social sensitivity, relative to either low (social vacuum) or high levels (exceptionally attuned), may confer benefits as it facilitates effective navigation of the social world. The present fMRI study tested a curvilinear relationship between social sensitivity and adaptive decision-making. Participants (ages 12-16; N = 35) played the Social Analogue Risk Task, which measures participants' willingness to knock on doors in order to earn points. With each knock, the facial expression of the house's resident shifted from happy to somewhat angrier. If the resident became too angry, the door slammed and participants lost points. Social sensitivity was defined as the extent to which adolescents adjusted their risky choices based on shifting facial expressions. Results confirmed a curvilinear relationship between social sensitivity and self-reported adaptive decision-making at the behavioral and neural level. Moderate adolescent social sensitivity was modulated via heightened tracking of social cues in the temporoparietal junction, insula and dorsolateral prefrontal cortex and related to adaptive decision-making. These findings suggest that social-affective sensitivity may positively impact outcomes in adolescence and have implications for interventions to help adolescents reach mature social goals into adulthood. PMID- 29529319 TI - Relationships among mortality, performance, and disorder traits in broiler chickens: a genetic and genomic approach. AB - Four performance-related traits [growth trait (GROW), feed efficiency trait 1 (FE1) and trait 2 (FE2), and dissection trait (DT)] and 4 categorical traits [mortality (MORT) and 3 disorder traits (DIS1, DIS2, and DIS3)] were analyzed using linear and threshold single- and multi-trait models. Field data included 186,596 records of commercial broilers from Cobb-Vantress, Inc. Average information restricted maximum likelihood and Gibbs sampling-based methods were used to obtain estimates of the (co)variance components, heritabilities, and genetic correlations in a traditional approach using best linear unbiased prediction (BLUP). The ability to predict future breeding values (measured as realized accuracy) was checked in the last generation when traditional BLUP and single-step genomic BLUP were used. Heritability estimates for GROW, FE1, and FE2 in single- and multi-trait models were similar and moderate (0.22 to 0.26) but high for DT (0.48 to 0.50). For MORT, DIS1, and DIS2, heritabilities were 0.13, 0.24, and 0.34, respectively. Estimates from single- and multi-trait models were also very similar. However, heritability for DIS3 was higher from the single trait threshold model than for the multi-trait linear-threshold model (0.29 vs. 0.19). Genetic correlations between growth traits and MORT were weak, except for maternal GROW, which had a moderate negative correlation (-0.50) with MORT. The genetic correlation between MORT and DIS1 was strong and positive (0.77). Feed efficiency 1, which was moderately heritable (0.25) and is highly selected for, was not genetically related to MORT of broilers and other disorders. Broiler MORT also had moderate heritability (0.13), which suggests that MORT and FE1 can be improved through selection without negatively impacting other important traits. Selection of heavier maternal GROW also may decrease offspring MORT. PMID- 29529320 TI - Longitudinal strain by speckle tracking echocardiography in constrictive pericarditis. PMID- 29529321 TI - Supplementing goat kids with coconut medium chain fatty acids in early life influences growth and rumen papillae development until 4 months after supplementation but effects on in vitro methane emissions and the rumen microbiota are transient. AB - : The aim of this study was to investigate the methane (CH4) reducing potential of a combination of prenatal and/or postnatal treatment with coconut oil medium chain fatty acids (CO MCFA) in goat kids. The hypothesis is that influencing rumen function during early life has more chances for success than in the adult life, related to the resilience of the mature rumen microbiota. Forty-eight pregnant does were split into two experimental groups: treated does (D+) received 40 g/d of CO MCFA in a test compound feed, while control does (D-) received a control compound feed, during the last 3 wk of gestation. Twin kids from 10 does of each group were split up into a treated (K+) and nontreated (K-) group, resulting in four experimental groups: D+K+, D+K-, D-K+, and D-K-. The K+ kids received 1.8 mL/d of CO MCFA from birth until 2-wk postweaning (11 wk). Irrespective of treatment, the experimental rearing conditions resulted in absence of rumen protozoa at all sampling times, assessed by quantitative PCR (qPCR). In vitro incubations with rumen fluid at 4 wk old showed 82% lower CH4 production of inoculum from D+K+ kids compared to D-K- kids (P = 0.01). However, this was accompanied by lower total volatile fatty acids (tVFA) production (P = 0.006) and higher hydrogen accumulation (P = 0.008). QPCR targeting the mcrA and rrs genes confirmed a lower abundance of total methanogens (P < 0.02) and total eubacteria (P = 0.02) in D+K+ kids at 4 wk old. Methanogenic activity, as assessed by mcrA expression by RT-qPCR, was also lower in these kids. However, activity did not always reflect methanogen abundance. At 11 and 28 wk old, prenatal and postnatal effects on in vitro fermentation and rumen microbiota disappeared. Nevertheless, lower milk replacer intake in the first 4 wk resulted in reduced BW in K+ kids, persisting until 28 wk of age. Additionally, differences assigned to postnatal treatment were found in papillae density, width, and length in different areas of the rumen, recorded at 28 wk old. CONCLUSION: prenatal and postnatal supplementation with CO MCFA reduced in vitro CH4 emissions until 4 wk old by depressing methanogen abundance and activity but at the expense of rumen fermentation and eubacterial abundance. Unfortunately, daily gain of K+ kids was suppressed. Some rumen papillae characteristics differed at 28 wk old due to postnatal treatment which ended at 11 wk old, indicating rumen papillary development can be affected by the early-life nutritional circumstances. PMID- 29529323 TI - Rapid M1 Hemoclips Arteriotomy Repair After Emergency Coil Embolectomy. AB - BACKGROUND: The vascular closure staple clips have been studied in animal models and shown to have comparable results with sutured repair when it comes to the healing process, degree of vessel narrowing, and risk of thrombosis. However, they are clearly superior when the speed of application is taken into account, and they were clinically used in many vascular repair processes. Nevertheless, their usefulness in intracranial vascular surgery has not been described. OBJECTIVE: To describe the usefulness of hemoclips in fast and efficient repair of medium-sized and large intracranial vessels. METHODS: Two female patients diagnosed with giant symptomatic cavernous sinus aneurysms were undergoing elective endovascular procedures that were complicated by the dislodgement of coils into the M1 segment of the middle cerebral artery. Both patients were treated performing M1 arteriotomies and coil embolectomy. To avoid prolonged temporary occlusion in the M1 perforator's territory, the arteriotomies were repaired using microhemoclips in less than 10 min with re-establishment of flow. RESULTS: In both patients, flow was re-established in the M1 segments. In 1 patient, the coils extended to the temporal M2 causing intimal injury and leading to diminished flow. M1 segments in both patients were patent on later angiographic studies. CONCLUSION: We describe the advantage of emergent cerebrovascular arteriotomy and embolectomy in a rapid repair process that helped avoid massive ischemic injury. We believe this technique should be added to the armamentarium of neurosurgical cerebrovascular options. PMID- 29529322 TI - Revising the Structural Diversity of Ribosomal Proteins Across the Three Domains of Life. AB - Ribosomal proteins are indispensable components of a living cell, and yet their structures are remarkably diverse in different species. Here we use manually curated structural alignments to provide a comprehensive catalog of structural variations in homologous ribosomal proteins from bacteria, archaea, eukaryotes, and eukaryotic organelles. By resolving numerous ambiguities and errors of automated structural and sequence alignments, we uncover a whole new class of structural variations that reside within seemingly conserved segments of ribosomal proteins. We then illustrate that these variations reflect an apparent adaptation of ribosomal proteins to the specific environments and lifestyles of living species. Finally, we show that most of these structural variations reside within nonglobular extensions of ribosomal proteins-protein segments that are thought to promote ribosome biogenesis by stabilizing the proper folding of ribosomal RNA. We show that although the extensions are thought to be the most ancient peptides on our planet, they are in fact the most rapidly evolving and most structurally and functionally diverse segments of ribosomal proteins. Overall, our work illustrates that, despite being long considered as slowly evolving and highly conserved, ribosomal proteins are more complex and more specialized than is generally recognized. PMID- 29529324 TI - The US Federal Tox21 Program: A strategic and operational plan for continued leadership. AB - The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be tested, time and resource intensive nature of traditional toxicity tests, and unexpected adverse effects that occur in pharmaceutical clinical trials despite the extensive toxicological testing.Over a decade ago, the U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), National Center for Advancing Translational Sciences (NCATS), and the Food and Drug Administration (FDA) formed a federal consortium for "Toxicology in the 21st Century" (Tox21) with a focus on developing and evaluating in vitro high-throughput screening (HTS) methods for hazard identification and providing mechanistic insights.The Tox21 consortium generated data on thousands of pharmaceuticals and datapoor chemicals, developed better understanding of the limits and applications of in vitro methods, and enabled incorporation of HTS data into regulatory decisions. To more broadly address the challenges in toxicology, Tox21 has developed a new strategic and operational plan that expands the focus of its research activities. The new focus areas include developing an expanded portfolio of alternative test systems, addressing technical limitations of in vitrotest systems, curating legacy in vivo toxicity testing data, establishing scientific confidence in the in vitrotest systems, and refining alternative methods for characterizing pharmacokinetics and in vitro assay disposition.The new Tox21 strategic and operational plan addresses key challenges to advance toxicology testing and will benefit both the organizations involved and the toxicology community. PMID- 29529325 TI - Julio R. Villanueva, microbiologist, researcher, and mentor of generations of scientists. AB - On November 21, 2017, Professor Julio R. Villanueva died in Salamanca. Born on April 27, 1928 in Villamayor, council of Pilona (Asturias), he lived almost to the age of 90. His was an accomplished life, full of endeavors and exciting works in the world of research and teaching, which earned him very broad recognition both in Spain and the international arena. Villanueva was undoubtedly the driving force of Fundamental Microbiology in Spain. His early steps came at a time when experimental biology was arriving at an important new age, using microbial systems for experimentation that lead to general conclusions about all living beings. The unveiling of the majority of biological phenomena came from the study of microbial systems. From this context Villanueva derived his motivation - he was always known for the energy he put into all his endeavors - to promote his research and create a scientific and academic school of thought. He tried to project his passion for research at the University at all costs, in a manner that was often timely, and other times not so much, and always proclaimed that only universities that research actively deserve their titles. To this purpose, he sought out the most highly qualified and motivated graduates to invite to join his group and pursue academic careers. We, his disciples, always felt the encouragement - and also the demand - to continually train in research, as an essential requirement of being a university professor. Few mentors have encouraged the lives of so many researchers, valuing above all else their virtues and motivation, with no interest other than for them to be the best. Committed to Spain reaching the highest scientific and academic levels, he also served in important positions, such as the Rector of the University of Salamanca. In his laboratory, a critical resource for microbial studies was initiated, creating the Spanish Type Culture Collection (CECT), which continues today at the University of Valencia. His efforts in favor of promoting research were also developed in collaboration with outstanding organizations, especially the Ramon Areces Foundation. He was tireless when participating on the selection committees for diverse educational and scientific awards, highlighted by the "Premio Principe (Princesa) de Asturias" for scientific and technical research, which he chaired for several years. And finally, it is also necessary to remember his performance as "full academician" and President of the Royal National Academy of Pharmacy (Spain). Prof. Villanueva always showed special appreciation for the living world as a whole, with its immense diversity despite the unity of essential processes that occur in all living things. In taxonomy, his name was given to a biological species, not microbial but of insects: A few years ago, the INBio (an important center in global biodiversity in Costa Rica) described a new species of fly, assigning the name of Mesorhaga villanuevi. Given the name by the Australian researcher Bickel, it is a small insect collected in the foothills of the Guanacaste mountain range. Without a doubt, Prof. Villanueva appreciated this designation of the exotic species. To better understand the key aspects of his life and work, we put the different phases in context with the circumstances in which they happened. PMID- 29529326 TI - Genetic diversity reflects geographical origin of Ralstonia solanacearum strains isolated from plant and water sources in Spain. AB - The characterization and intraspecific diversity of a collection of 45 Ralstonia solanacearum strains isolated in Spain from different sources and geographical origins is reported. To test the influence of the site and the host on strain diversity, phenotypic and genotypic analysis were performed by a polyphasic approach. Biochemical and metabolic profiles were compared. Serological relationship was evaluated by Indirect-ELISA using polyclonal and monoclonal antibodies. For genotypic analysis, hrpB and egl DNA sequence analysis, repetitive sequences (rep-PCR), amplified fragment length polymorphism (AFLP) profiles and macrorestriction with XbaI followed by pulsed field gel electrophoresis (PFGE) were performed. The biochemical and metabolic characterization, serological tests, rep-PCR typing and phylogenetic analysis showed that all analysed strains belonged to phylotype II sequevar 1 and shared homogeneous profiles. However, interesting differences among strains were found by AFLP and macrorestriction with XbaI followed by PFGE techniques, some profiles being related to the geographical origin of the strains. Diversity results obtained offer new insights into the biogeography of this quarantine organism and its possible sources and reservoirs in Spain and Mediterranean countries. PMID- 29529327 TI - Transmission and survival of carbapenem-resistant Acinetobacter baumannii outside hospital setting. AB - Acinetobacter baumannii origin and its epidemiology is under a great concern worldwide since this microorganism has become a leading nosocomial pathogen of the 21th century among the "ESKAPE" group of microorganisms. The aim of the study was to monitor and explore the epidemiology of this important hospital pathogen in the second largest clinical university hospital in Croatia. The presence of A. baumannii in hospital wastewater, as a route for possible transmission outside of the hospital setting, as well as its survival in environmental conditions including seawater, was investigated. During the examination period, ten both carbapenem and multidrug-resistant isolates of A. baumannii were recovered from hospital wastewater and compared to the clinical isolates originating from the same monitoring period. Multiplex PCR confirmed that four wastewater isolates harboured blaOXA-23-like, while five wastewater isolates harboured blaOXA-40-like genes sharing 100% sequence identity with blaOXA-72 sequence described in the same hospital in 2009, confirming the presence of an endemic cluster. Survival of A. baumannii in natural seawater was examined during 50 days of monitoring and to the best of our knowledge, was performed for the first time. PMID- 29529328 TI - Fate of Bacillus cereus within phagocytic cells. AB - In this study we assessed the interaction of different strains of Bacillus cereus with murine peritoneal macrophages and cultured phagocytic cells (Raw 264.7 cells). Association, internalization, intracellular survival, routing of bacteria to different compartments and expression of MHCII were assessed in cells infected with different strains of B. cereus in vegetative form. Association values (adhering + internalized bacteria) and phagocytosis were higher for strain B10502 than those for strains 2 and M2. However, after 90 min interaction, intracellular survival was higher for strain 2 than for strains M2 and B10502. Acquisition of lysosomal markers by B. cereus containing vacuoles (BcCV), assessed by LAMP1 and Lysotracker labelling occurred shortly after internalization. The highest ratio of LAMP1(+)-BcCV was found for strain M2. This strain was able to survive longer than strain B10502 which routes to LAMP1 containing vacuoles to a lesser extent. In addition, strain M2 stimulated expression of MHCII by infected cells. Confocal analyses 60 or 90 min post-infection showed different percentages of co localization of bacteria with Lysotracker. Results suggest strain-dependent interaction and intracellular killing of B. cereus by phagocytic cells. These findings could be relevant for the pathogenic potential of Bacillus cereus strains. PMID- 29529329 TI - Developmental stages identified in the trophozoite of the free-living Alveolate flagellate Colpodella sp. (Apicomplexa). AB - In this study we performed light, immunofluorescent and transmission electron microscopy of Colpodella trophozoites to characterize trophozoite morphology and protein distribution. The use of Giemsa staining and antibodies to distinguish Colpodella life cycle stages has not been performed previously. Rhoptry and beta tubulin antibodies were used in immunofluorescent assays (IFA) to identify protein localization and distribution in the trophozoite stage of Colpodella (ATCC 50594). We report novel data identifying "doughnut-shaped" vesicles in the cytoplasm and apical end of Colpodella trophozoites reactive with antibodies specific to Plasmodium merozoite rhoptry proteins. Giemsa staining and immunofluorescent microscopy identified different developmental stages of Colpodella trophozoites, with the presence or absence of vesicles corresponding to maturity of the trophozoite. These data demonstrate for the first time evidence of rhoptry protein conservation between Plasmodium and Colpodella and provide further evidence that Colpodella trophozoites can be used as a heterologous model to investigate rhoptry biogenesis and function. Staining and antibody reactivity will facilitate phylogenetic, biochemical and molecular investigations of Colpodella sp. Developmental stages can be distinguished by Giemsa staining and antibody reactivity. PMID- 29529330 TI - Overview of laboratory methods to diagnose Leptospirosis and to identify and to type leptospires. AB - Leptospirosis is a virulent zoonosis with a global distribution. Pathogenic spirochetes of the genus Leptospira are responsible for this disease, and the primary animal reservoirs are rodentvvvs. Direct and indirect contact with infected urine constitutes the main route of transmission. Renal failure and advanced abortions are frequently observed in animals affected by leptospirosis, causing serious problems for farms. In humans, there is a high rate of mortality (10 percent), and farmers and persons in contact with water are frequently exposed. However, vaccines and strict prevention measures confer protection against leptospirosis. Serological tests facilitate the detection and identification of leptospire strains. Such tests are based on specific surface antigen recognition and are used for clinical analyses. To determine which serovars circulate in the environment, leptospires must be typed. Molecular methods, such as restriction enzyme-based techniques and the sequencing of specific regions, permit serovar identification. Unfortunately, although there are numerous techniques, they are not very efficient, and thus, new methods must be developed. With the advent of genomic sequencing, a substantial amount of information regarding leptospire genomes is now available, facilitating the selection of regions to discriminate between strains. Typing is important for both epidemiologic purposes and clinical analyses. PMID- 29529331 TI - The relationship between pre-operative hypertension and intra-operative haemodynamic changes known to be associated with postoperative morbidity. AB - Hypertension is not consistently associated with postoperative cardiovascular morbidity and is therefore not considered a major peri-operative risk factor. However, hypertension may predispose to peri-operative haemodynamic changes known to be associated with peri-operative morbidity and mortality, such as intra operative hypotension and tachycardia. The objective of this study was to determine whether pre-operative hypertension was independently associated with haemodynamic changes known to be associated with adverse peri-operative outcomes. We performed a five-day multicentre, prospective, observational cohort study which included all adult inpatients undergoing elective, non-cardiac, non obstetric surgery. We recruited 343 patients of whom 164 (47.8%) were hypertensive. An intra-operative mean arterial pressure of < 55 mmHg occurred in 59 (18.2%) patients, of which 25 (42.4%) were hypertensive. Intra-operative tachycardia (heart rate> 100 beats.min-1 ) occurred in 126 (38.9%) patients, of whom 61 (48.4%) were hypertensive. Multivariable logistic regression did not show an independent association between the stage of hypertension and either clinically significant hypotension or tachycardia, when controlled for ASA physical status, functional status, major surgery, duration of surgery or blood transfusion. There was no association between pre-operative hypertension and peri operative haemodynamic changes known to be associated with major morbidity and mortality. These data, therefore, support the recommendation of the Joint Guidelines of the Association of Anaesthetists of Great Britain and Ireland (AAGBI) and the British Hypertension Society to proceed with elective surgery if a patient's blood pressure is < 180/110 mmHg. PMID- 29529332 TI - Lung ultrasound compared with chest X-ray in diagnosing postoperative pulmonary complications following cardiothoracic surgery: a prospective observational study. AB - Postoperative pulmonary complications are common after cardiothoracic surgery and are associated with adverse outcomes. The ability to detect postoperative pulmonary complications using chest X-rays is limited, and this technique requires radiation exposure. Little is known about the diagnostic accuracy of lung ultrasound for the detection of postoperative pulmonary complications after cardiothoracic surgery, and we therefore aimed to compare lung ultrasound with chest X-ray to detect postoperative pulmonary complications in this group of patients. We performed this prospective, observational, single-centre study in a tertiary intensive care unit treating adult patients who had undergone cardiothoracic surgery. We recorded chest X-ray findings upon admission and on postoperative days 2 and 3, as well as rates of postoperative pulmonary complications and clinically-relevant postoperative pulmonary complications that required therapy according to the treating physician as part of their standard clinical practice. Lung ultrasound was performed by an independent researcher at the time of chest X-ray. We compared lung ultrasound with chest X-ray for the detection of postoperative pulmonary complications and clinically-relevant postoperative pulmonary complications. We also assessed inter-observer agreement for lung ultrasound, and the time to perform both imaging techniques. Subgroup analyses were performed to compare the time to detection of clinically-relevant postoperative pulmonary complications by both modalities. We recruited a total of 177 patients in whom both lung ultrasound and chest X-ray imaging were performed. Lung ultrasound identified 159 (90%) postoperative pulmonary complications on the day of admission compared with 107 (61%) identified with chest X-ray (p < 0.001). Lung ultrasound identified 11 out of 17 patients (65%) and chest X-ray 7 out of 17 patients (41%) with clinically-relevant postoperative pulmonary complications (p < 0.001). The clinically-relevant postoperative pulmonary complications were detected earlier using lung ultrasound compared with chest X-ray (p = 0.024). Overall inter-observer agreement for lung ultrasound was excellent (kappa = 0.907, p < 0.001). Following cardiothoracic surgery, lung ultrasound detected more postoperative pulmonary complications and clinically-relevant postoperative pulmonary complications than chest X-ray, and at an earlier time-point. Our results suggest lung ultrasound may be used as the primary imaging technique to search for postoperative pulmonary complications after cardiothoracic surgery, and will enhance bedside decision making. PMID- 29529333 TI - A Review and Conceptual Model of Factors Correlated with Postmortem Root Band Formation. AB - It is generally accepted within the forensic trace evidence community that a postmortem root band (PMRB) can appear in the root of hairs attached to remains during decomposition. Presently, the specific sequences of events and/or exact molecular signals that lead to the formation of a PMRB are not well understood. The published literature addressing the abiotic and biotic factors that correlate with the formation of PMRBs is reviewed and a conceptual model for the formation of PMRBs is proposed. PMID- 29529334 TI - Bisphosphonate Drug Holiday and Fracture Risk: A Population-Based Cohort Study. AB - Holidays from bisphosphonates (BPs) may help to prevent rare adverse events such as atypical femoral fractures, but may be appropriate only if risk of osteoporosis-related fractures does not increase. Our objective was to compare the incidence of osteoporosis-related fractures among women who had a BP holiday to those who continued to use BPs. This retrospective cohort study, conducted within four Kaiser Permanente integrated health system regions, included 39,502 women aged >=45 years with >=3 years exposure to BP. Participants with a BP holiday (>=12 months with no use) were compared to persistent (use with >=50% adherence) and nonpersistent (use with <50% adherence) users for incident osteoporosis-related fractures. The BP holiday (n = 11,497), nonpersistent user (n = 10,882), and persistent user groups (n = 17,123) were observed for 156,657 person-years. A total of 5199 osteoporosis-related fractures (including 1515 hip fractures and 2147 vertebral fractures) were observed. Compared to the persistent use group, there was a slight difference in overall osteoporosis-related fracture risk (HR 0.92; 95% CI, 0.84 to 0.99)and no difference in hip fracture risk (HR 0.95; 95% CI, 0.83 to 1.10) for the BP holiday group. A slight reduction in risk of vertebral fracture was observed (HR 0.83; 95% CI, 0.74 to 0.95). Compared to the nonpersistent user group, the BP holiday group was at decreased risk for osteoporosis-related fractures (HR 0.71; 95% CI, 0.65 to 0.79), vertebral fractures (HR 0.68; 95% CI, 0.59 to 0.78), and hip fractures (HR 0.59; 95% CI, 0.50 to 0.70). Women who undertake a BP holiday from BP of >=12 months duration for any reason after >=3 years of BP use do not appear to be at greater risk of osteoporosis-related fragility fracture, hip, or vertebral fractures compared to ongoing BP users. In our cohort, BP holiday remains a viable strategy for balancing the benefits and potential harms associated with long-term BP use. (c) 2018 American Society for Bone and Mineral Research. PMID- 29529335 TI - Improved Safety and Efficacy of Small-Bore Feeding Tube Confirmation Using an Electromagnetic Placement Device. AB - BACKGROUND: Early enteral nutrition has been shown to decrease complications and improve patient outcomes. Post pyloric feeding is recommended for patients with gastric intolerance or at high risk for aspiration. Feeding tube placement can be challenging and pose risk of pulmonary complications. Reliance on radiographic confirmation for feeding tube placement exposes the patient to radiation. Electromagnetic placement device (EMPD) may offer a method to minimize pulmonary complications, increase successful placement, and decrease radiation exposure to the patient. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of using EMPD verification, instead of routine abdominal radiographic confirmation, for small-bore feeding tube placement. RESULTS: Variables evaluated were adverse events, utilization of radiographs for confirmation, and success rate of feeding tube placement in the ordered location. Two time frames were reviewed. In a 1-year period, 3754 small-bore feeding tubes were placed using EMPD, with zero adverse events noted. Radiographic confirmation was utilized in 0%-29.2% of the EMPD placed tubes. Successful placement of feeding tubes using EMPD ranged from 94%-99.6%. During a 5-year period, 7081 EMPD feeding tubes were evaluated. One adverse event, pneumothorax, occurred during the placement of these 7081 tubes, for a rate of 0.014%. CONCLUSION: Feeding tube placement confirmation is safe and efficacious via EMPD providing an effective method of feeding tube placement with a success rate >94% into the desired location. EMPD is an accurate verification method of distal tip location, eliminating the need for routine abdominal radiographic confirmation. PMID- 29529337 TI - Copper Supplementation in Premature Infants With Parenteral Nutrition-Associated Cholestasis. AB - The aim of this study was to evaluate the effect of intermittent parenteral copper supplementation (IPC) on serum copper status and biochemical and hematological measures of copper toxicity and deficiency in premature infants with parenteral nutrition (PN)-associated cholestasis (PNAC). We performed a prospective nested observational study in premature infants with PNAC who received IPC after the development of PNAC. Infants with chromosomal disorders, TORCH (toxoplasmosis, parvovirus, syphilis, rubella, cytomegalovirus, herpes, human immunodeficiency virus) infection, metabolic disorder, and/or surgical abnormality of the hepatobiliary system were excluded. Serum copper concentrations were measured once every 2-4 weeks while receiving PN; 24 premature infants were studied. The mean gestational age (GA) of infants was 28.6 +/- 4.7 weeks. On regression analysis, there was no significant association between IPC and serum copper concentration (coefficient 2.72, 95% CI: -27 to 32; P = .84) after controlling for GA, gender, and baseline copper intake before PNAC. There was no significant association of IPC with alanine and aspartate transaminases levels (hepatotoxicity) and platelet count, hematocrit, white blood cell count, and neutrophil count (measures of copper deficiency) after controlling for confounders. GA and postmenstrual age were independently and positively associated with serum copper concentration after controlling for confounders on regression analyses. Thus, IPC in premature infants with PNAC does not influence copper status and is not associated with biochemical and hematological measures of copper deficiency and/or toxicity. Serum copper concentration in premature infants with PNAC receiving IPC is determined by the degree of prematurity and postmenstrual age. PMID- 29529336 TI - Factors affecting outcomes following pelvic exenteration for locally recurrent rectal cancer. AB - BACKGROUND: Pelvic exenteration for locally recurrent rectal cancer (LRRC) is associated with variable outcomes, with the majority of data from single-centre series. This study analysed data from an international collaboration to determine robust parameters that could inform clinical decision-making. METHODS: Anonymized data on patients who had pelvic exenteration for LRRC between 2004 and 2014 were accrued from 27 specialist centres. The primary endpoint was survival. The impact of resection margin, bone resection, node status and use of neoadjuvant therapy (before exenteration) was assessed. RESULTS: Of 1184 patients, 614 (51.9 per cent) had neoadjuvant therapy. A clear resection margin (R0 resection) was achieved in 55.4 per cent of operations. Twenty-one patients (1.8 per cent) died within 30 days and 380 (32.1 per cent) experienced a major complication. Median overall survival was 36 months following R0 resection, 27 months after R1 resection and 16 months following R2 resection (P < 0.001). Patients who received neoadjuvant therapy had more postoperative complications (unadjusted odds ratio (OR) 1.53), readmissions (unadjusted OR 2.33) and radiological reinterventions (unadjusted OR 2.12). Three-year survival rates were 48.1 per cent, 33.9 per cent and 15 per cent respectively. Bone resection (when required) was associated with a longer median survival (36 versus 29 months; P < 0.001). Node-positive patients had a shorter median overall survival than those with node-negative disease (22 versus 29 months respectively). Multivariable analysis identified margin status and bone resection as significant determinants of long-term survival. CONCLUSION: Negative margins and bone resection (where needed) were identified as the most important factors influencing overall survival. Neoadjuvant therapy before pelvic exenteration did not affect survival, but was associated with higher rates of readmission, complications and radiological reintervention. PMID- 29529338 TI - Pre-operative anaemia, intra-operative hepcidin concentration and acute kidney injury after cardiac surgery: a retrospective observational study. AB - Acute kidney after cardiac surgery is more common in anaemic patients, whereas haemolysis during cardiopulmonary bypass may lead to iron-induced renal injury. Hepcidin promotes iron sequestration by macrophages: hepcidin concentration is reduced by anaemia and increased by inflammation. We analysed the associations in 525 patients between pre-operative anaemia (haemoglobin < 130 g.l-1 in men and < 120 g.l-1 in women), intra-operative hepcidin concentration and acute kidney injury (dialysis or > 26.4 MUmol.l-1 or > 50% creatinine increase during the first two days after cardiac surgery. Rates of pre-operative anaemia and postoperative kidney injury were 109/525 (21%) and 36/525 (7%), respectively. The median (IQR [range]) intra-operative hepcidin concentration was 20 (10-33 [0 125]) MUg.l-1 and was lower in anaemic patients than those who were not: 15 (4-28 [0-125]) MUg.l-1 vs. 21 (12-33 [0-125]) MUg.l-1 , respectively, p = 0.002. Four variables were independently associated with postoperative kidney injury, for which the beta-coefficients (SE) were: minutes on cardiopulmonary bypass, 0.016 (0.004), p < 0.001; intra-operative hepcidin concentration, 0.032 (0.008), p < 0.001; pre-operative anaemia, 1.97 (0.56), p < 0.001; and Cleveland clinic risk score, 0.88 (0.35), p = 0.005. Contrary to generally increased rates of kidney injury in patients with higher hepcidin concentrations, rates of kidney injury in anaemic patients were lower in patients with higher hepcidin concentrations, beta coefficient (SE) -0.037 (0.01), p = 0.007. In cardiac surgical patients the rate of postoperative acute kidney injury predicted by the Cleveland risk score might be adjusted for pre-operative anaemia and intra-operative cardiopulmonary bypass time and hepcidin concentration. Pre-operative correction of anaemia, reduction in intra-operative bypass time and modification of iron homeostasis and hepcidin concentration might reduce acute kidney injury. PMID- 29529339 TI - Could OX40 agonist antibody promote activation of the anti-tumor immune response in gastric cancer? AB - BACKGROUND AND OBJECTIVES: OX40, a membrane-bound molecule of the tumor-necrosis factor-receptor superfamily, is a critical costimulatory receptor during the immune response, especially to T cells, but studies described their presence of OX-40 on neutrophils and monocytes, suggesting a potential role in the activation of immune response. Our aim was to characterize costimulatory receptors OX40 expression on circulating leukocytes in gastric cancer to identify novel targets for immunotherapy. METHODS: Peripheral blood mononuclear cells were isolated from 24 gastric cancer patients and 34 healthy controls and the expression of costimulatory (OX40) receptors were analyzed on T cells, neutrophil and monocyte using monoclonal antibodies by flow cytometry. RESULTS: We found that the higher levels of OX40 + T cells, monocytes/OX40+ and neutrophils/OX40+ from gastric cancer patients when compared to controls (P < 0.0001), and also higher levels of OX40+ T cells when compared to stages III and IV (P = 0.02). Percentage levels of total T cells were similar between patients and controls. CONCLUSIONS: OX40 as a therapeutic agent has been investigated in many preclinical tumor models. Our findings suggest that of levels of costimulatory in T cells in GC will direct future studies on the role that costimulatory receptors play in the failure of T cell-mediated immunity. PMID- 29529340 TI - Recent Progress in the Study of Molecularly Doped Metals. AB - A unique materials' methodology enables the doping of metals with functional molecules, polymers, enzymes, and nanoparticles. The resulting materials have either the combined properties of the metal and the dopants, or new, sometimes synergetic properties that are not found in the separate components, emerge. Metals that have been doped so far include gold, silver, copper, iron, gallium, palladium, platinum, and several alloys. Numerous applications have been demonstrated including catalysis, biocatalysis, bioactivity, electrochemistry (including new type of batteries), corrosion resistance, induction of chirality, tailoring unconventional properties to metals, and more. Doping of metals and adsorption on them are completely different processes, doping being a 3D event, while adsorption is a 2D process. Thus, practically all special properties and functionalities that have been demonstrated are apparent only in the doped case. Here, progress made in this field in the past four years is reviewed, including methodologies for obtaining metallic doped thin films, enhancing corrosion resistance, biomedical applications, and the use of doped metals for complex catalytic network of reactions. PMID- 29529341 TI - Expanding Home-Based Primary Care to American Indian Reservations and Other Rural Communities: An Observational Study. AB - BACKGROUND/OBJECTIVES: Home-based primary care (HBPC) is a comprehensive, interdisciplinary program to meet the medical needs of community-dwelling populations needing long-term care (LTC). The U.S. Department of Veterans Affairs (VA) expanded its HBPC program to underserved rural communities, including American Indian reservations, providing a "natural laboratory" to study change in access to VA LTC benefits and utilization outcomes for rural populations that typically face challenges in accessing LTC medical support. DESIGN: Pretest Posttest quasi-experimental approach with interrupted time-series design using linked VA, Medicare, and Indian Health Service (IHS) records. SETTING: American Indian reservations and non-Indian communities in rural HBPC catchment areas. PARTICIPANTS: 376 veterans (88 IHS beneficiaries, 288 non-IHS beneficiaries) with a HBPC length of stay of 12 months or longer. MEASUREMENTS: Baseline demographic and health characteristics, activities of daily living (ADL), previous VA enrollment, and hospital admissions and emergency department (ED) visits as a function of time, accounting for IHS beneficiary and functional statuses. RESULTS: For HBPC users, VA enrollment increased by 22%. At baseline, 30% of IHS and non-IHS beneficiaries had 2 or more ADLs impairments; IHS populations were younger (P < .001) and had more diagnosed chronic diseases (P = .007). Overall, hospital admissions decreased by 0.10 (95% confidence interval (CI) = -0.14 to 0.05) and ED visits decreased by 0.13 (95% CI = -0.19 to -0.07) in the 90 days after HBPC admission (Ps < .001) and these decreases were maintained over 1 year follow-up. Before HBPC, probability of hospital admission was 12% lower for IHS than non-IHS beneficiaries (P = .02). CONCLUSION: Introducing HBPC to rural areas increased access to LTC and enrollment for healthcare benefits, with equitable outcomes in IHS and non-IHS populations. PMID- 29529342 TI - DNA hydroxymethylation of colorectal primary carcinoma and its association with survival. AB - METHODS: A total of 71 cases of colorectal carcinoma with hepatic metastasis were enrolled from the Department of Pathology of SIR RUN RUN SHAW Hospital. Paired primary tumors, hepatic metastases, and normal mucosa samples were collected from formalin-fixed paraffin-embedded tissues by manual macrodissection. And global levels of DNA methylation and hydroxymethylation in these tissues, measured by an ELISA-like microplate-based colorimetric methods. The immunohistochemical expression of 5-methylcytosine and 5-hydroxymethylcytosine were analyzed also. RESULTS: The levels of DNA methylation in both primary and metastatic tumors were elevated when compared with normal mucosa, while DNA hydroxymethylation decreased slightly in those tissues. Similar results were observed in immunohistochemical staining. DNA methylation in hepatic metastases differed significantly in lymph node metastases (P = 0.037). And DNA hydroxymethylation in colorectal primary carcinoma was significantly different between tumor grade group (P = 0.018) and gender group (P = 0.048) respectively. And survival analyzes revealed that higher levels DNA hydroxymethylation were associated with better prognosis in colorectal primary carcinoma (P < 0.05). CONCLUSION: DNA hydroxymethylation correlated with less aggressive tumor behavior in colorectal cancer and were identified as an independent prognostic factor in patients' overall survival, and downregulation of DNA hydroxymethylation may serve as a useful biomarker for colorectal cancer prognosis evaluation. PMID- 29529343 TI - Intralesional PV-10 for the treatment of in-transit melanoma metastases-Results of a prospective, non-randomized, single center study. AB - BACKGROUND: Patients with in-transit melanoma metastases frequently experience high rates of recurrence, limited overall survival and reduced quality of life. After promising results within a Phase II, multi-center study, PV-10 treatment was continued at our institution for patients with in-transit disease. METHODOLOGY: An open-label, non-randomized, prospective study was performed at the Princess Alexandra Hospital, Queensland, Australia. Patients were treated with PV-10 in accordance with the treatment protocol established during a previous Phase II study. The primary outcome was the complete response of treated lesions. RESULTS: Forty-five patients were enrolled over a total of 82 treatment episodes from July 2008 to December 2015. With sequential PV-10 treatments the complete response rate was 42% and overall response rate 87% on an intention to treat analysis. The median follow-up duration was 22 months and the median overall survival was 25 months from first PV-10 treatment. Having fewer than 15 metastases at the time of treatment was associated with a complete response (P = 0.03). CONCLUSIONS: Intralesional PV-10 provided rapid lesion-specific ablation of melanoma metastases with well-tolerated local effects and minimal systemic adverse events. This therapy should be considered for patients with multiple accessible deposits within the spectrum of low to moderate disease volume. PMID- 29529344 TI - Applications of liquid-based separation in conjunction with mass spectrometry to the analysis of forensic evidence. AB - In the past few years, there has been a significant effort by the forensic science community to develop new scientific techniques for the analysis of forensic evidence. Forensic chemists have been spearheaded to develop information rich confirmatory technologies and techniques and apply them to a broad array of forensic challenges. The purpose of these confirmatory techniques is to provide alternatives to presumptive techniques that rely on data such as color changes, pattern matching, or retention time alone, which are prone to more false positives. To this end, the application of separation techniques in conjunction with mass spectrometry has played an important role in the analysis of forensic evidence. Moreover, in the past few years the role of liquid separation techniques, such as liquid chromatography and capillary electrophoresis in conjunction with mass spectrometry, has gained significant tractions and have been applied to a wide range of chemicals, from small molecules such as drugs and explosives, to large molecules such as proteins. For example, proteomics and peptidomics have been used for identification of humans, organs, and bodily fluids. A wide range of HPLC techniques including reversed phase, hydrophilic interaction, mixed-mode, supercritical fluid, multidimensional chromatography, and nanoLC, as well as several modes of capillary electrophoresis mass spectrometry, including capillary zone electrophoresis, partial filling, full filling, and micellar electrokenetic chromatography have been applied to the analysis drugs, explosives, and questioned documents. In this article, we review recent (2015-2017) applications of liquid separation in conjunction with mass spectrometry to the analysis of forensic evidence. PMID- 29529345 TI - Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations. AB - Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of oral hypoglycaemic agents with therapeutic benefits beyond better glycaemic control. A major concern of the sodium-glucose co-transporter 2 inhibitors is their propensity to cause euglycaemic ketoacidosis in the peri-operative period and the potential for this critical diagnosis to be delayed or missed entirely. This review attempts to collate the case reports of sodium-glucose co-transporter 2 inhibitor ketoacidosis associated with surgery to highlight and put a perspective on this peri-operative issue. Preventive strategies and the management of the ketoacidosis are discussed. PMID- 29529346 TI - Mitigating Sports Injury Risks Using Internet of Things and Analytics Approaches. AB - Sport injuries restrict participation, impose a substantial economic burden, and can have persisting adverse effects on health-related quality of life. The effective use of Internet of Things (IoT), when combined with analytics approaches, can improve player safety through identification of injury risk factors that can be addressed by targeted risk reduction training activities. Use of IoT devices can facilitate highly efficient quantification of relevant functional capabilities prior to sport participation, which could substantially advance the prevailing sport injury management paradigm. This study introduces a framework for using sensor-derived IoT data to supplement other data for objective estimation of each individual college football player's level of injury risk, which is an approach to injury prevention that has not been previously reported. A cohort of 45 NCAA Division I-FCS college players provided data in the form of self-ratings of persisting effects of previous injuries and single-leg postural stability test. Instantaneous change in body mass acceleration (jerk) during the test was quantified by a smartphone accelerometer, with data wirelessly transmitted to a secure cloud server. Injuries sustained from the beginning of practice sessions until the end of the 13-game season were documented, along with the number of games played by each athlete over the course of a 13-game season. Results demonstrate a strong prediction model. Our approach may have strong relevance to the estimation of injury risk for other physically demanding activities. Clearly, there is great potential for improvement of injury prevention initiatives through identification of individual athletes who possess elevated injury risk and targeted interventions. PMID- 29529347 TI - Oral health education for the masses. PMID- 29529348 TI - A Framework to Understand Extreme Space Weather Event Probability. AB - An extreme space weather event has the potential to disrupt or damage infrastructure systems and technologies that many societies rely on for economic and social well-being. Space weather events occur regularly, but extreme events are less frequent, with a small number of historical examples over the last 160 years. During the past decade, published works have (1) examined the physical characteristics of the extreme historical events and (2) discussed the probability or return rate of select extreme geomagnetic disturbances, including the 1859 Carrington event. Here we present initial findings on a unified framework approach to visualize space weather event probability, using a Bayesian model average, in the context of historical extreme events. We present disturbance storm time (Dst) probability (a proxy for geomagnetic disturbance intensity) across multiple return periods and discuss parameters of interest to policymakers and planners in the context of past extreme space weather events. We discuss the current state of these analyses, their utility to policymakers and planners, the current limitations when compared to other hazards, and several gaps that need to be filled to enhance space weather risk assessments. PMID- 29529349 TI - Tuning the Size of Nanoassembles: A Hierarchical Transfer of Information from Dendrimers to Polyion Complexes. AB - The generation of dendrimers is a powerful tool in the control of the size and biodistribution of polyion complexes (PIC). Using a combinatorial screening of six dendrimers (18-243 terminal groups) and five oppositely charged PEGylated copolymers, a dendrimer-to-PIC hierarchical transfer of structural information was revealed with PIC diameters that increased from 80 to 500 nm on decreasing the dendrimer generation. This rise in size, which was also accompanied by a micelle-to-vesicle transition, is interpreted according to a cone- to rod-shaped progression in the architecture of the unit PIC (uPIC). This precise size tuning enabled dendritic PICs to act as nanorulers for controlled biodistribution. Overall, a domino-like control of the size and biological properties of PIC that is not attainable with linear polymers is feasible through dendrimer generation. PMID- 29529350 TI - The Changing Role of Patient Education in Osteoporosis. PMID- 29529351 TI - Towards the Next Generation of Lochmann-Schlosser Superbases: A Potassium Neopentyl/Alkoxy Aggregate used in the Tetra-Functionalization of Ferrocene. AB - Lochmann-Schlosser superbases are formed by mixing alkyllithium with potassium alkoxides. These reagents could prove their synthetic usefulness and reliability in many reactions over five decades. However, despite many efforts, the real source of the exceptional reactivity remained a secret. The seemingly manageable system of four components (lithium, potassium atoms, alkyl groups, and alkoxy groups) and their interaction is obscured by poor solubility and fierce reactivity. Recent progress was achieved by using neopentyllithium, leading to alkane-soluble aggregates with varying lithium/potassium content and a flexible alkyl/alkoxy ratio. Herein, we isolated two new alkane-soluble alkyl/alkoxy mixed aggregates, [Li4 KNp2 (OtBu)3 ] and [K4 Np(OtAm)3 ]. The latter compound is a thermally stable three-component potassium alkyl/alkoxy base with well-defined stoichiometry, in contrast to lithium-containing Lochmann-Schlosser bases with variable metal and alkyl/alkoxy content. In a simple protocol, this potassium base gave tetrametalated ferrocene, which was converted into 1,1',3,3' ferrocenetetracarboxylic acid by reaction with CO2 . A subsequent conversion into the methyl ester allowed its separation from accompanying di- and tri-substituted ferrocenes. PMID- 29529352 TI - Polyphenol Phase-II Metabolites are Detectable in Human Plasma after Ingestion of 13 C Labeled Spinach-a Pilot Intervention Trial in Young Healthy Adults. AB - SCOPE: After intrinsic labeling of spinach (Spinacia oleracea L., Chenopodiaceae) with 13 CO2 , we investigated if labeled polyphenol metabolites were detectable in human plasma. METHODS AND RESULT: In a pilot intervention trial, five healthy men consumed 5 g freeze-dried 13 C labeled spinach, including a total amount of 160 MUmol methoxyflavonols, including 70 MUmol 5,3',4'-trihydroxy-3-methoxy-6,7 methylendioxyflavone-4'-glucuronide. Plasma samples of all subjects were analyzed with regard to their 13 C/12 C ratio. Additionally, 13 C labeled metabolites of patuletin, spinacetin, and 5,3',4'-trihydroxy-3-methoxy-6,7-methylendioxyflavone (TMM) were analyzed in plasma samples in a subgroup of three subjects. TMM glucuronide, TMM-sulfate, and spinacetin-glucuronide-sulfate, the latter as 12 C113 C16 and 13 C17 isotopologs, were tentatively identified. Plasma concentration of TMM-glucuronide and TMM-sulfate reached cmax from 19.1-54.3 and 22.5-125.5 nmol L-1 , respectively, 7-9 h post-ingestion. CONCLUSION: It seems likely that 13 C labeled TMM-glucuronide and TMM-sulfate are phase-II metabolites which were converted after colonic transformation. Variations in plasma kinetics were observed for these two metabolites and may be attributed to the individual composition of the microbiota. We conclude that 13 C labeled polyphenol metabolites are detectable and quantifiable in human plasma. PMID- 29529353 TI - The max-intracerebral hemorrhage score predicts long-term outcome of intracerebral hemorrhage. AB - AIMS: Little is known about the performance of the maximally treated intracerebral hemorrhage (max-ICH) score in predicting unfavorable long-term functional outcome and death in patients with intracerebral hemorrhage (ICH) in China. We aimed to validate the performance of the max-ICH score and compared it with other recognized scores. METHODS: We derived data from the China National Stroke Registry (CNSR). Receiver-operating characteristic (ROC) analysis and Hosmer-Lemeshow test were used to measure the score performance. We compared the performance of max-ICH score with six recognized models, including the ICH score, ICH functional outcome score (ICH-FOS), Essen-ICH score, modified intracerebral hemorrhage (MICH) score, intracerebral hemorrhage grading scale (ICH-GS), and functional outcome (FUNC) score. RESULTS: A total of 2581 patients with spontaneous ICH were enrolled in the study. The max-ICH score was similar or superior to the six existing scores in predicting long-term unfavorable functional outcome after ICH with good discrimination (AUC 0.83, 95% confidence interval [CI] 0.81-0.84) and calibration (Hosmer-Lemeshow P = 0.19). For predicting death, the AUC of max-ICH was 0.81 (95% CI 0.79-0.83). CONCLUSIONS: The easy-to-use max-ICH score is a reliable tool to predict unfavorable long-term (12-month) functional outcome and death after intracerebral hemorrhage in the Chinese population. PMID- 29529354 TI - Nanofibered Gelatin-Based Nonwoven Elasticity Promotes Epithelial Histogenesis. AB - Regarding tissue regeneration, mechanics of biomaterials gains progressive importance. Therefore, this study reports on in situ crosslinked electrospun gelatin nonwoven mats (NWMs) whose distinct modulus of elasticity (ME) promotes epithelial tissue formation in a graded manner. NWMs, comprising fiber diameters in various distributions, yield an ME of about 2.1, 3.2, and 10.9 kPa. A two-step approach of preclinical in vitro validation identifies the elasticity of 3.2 kPa as superior to the other, regarding the histogenetic epithelial outcome. Hence, this 3.2 kPa candidate NWM is colonized with oral mucosal epithelial keratinocytes in the absence or presence of mesenchymal fibroblasts and/or endothelial cells. Evaluation of epithelial histogenesis at days 1 to 10 occurs by colorimetric and fluorescence-based immunohistochemistry (IHCH) of specific biomarkers. These include cytokeratins (CK) 14, CK1, and involucrin that indicate different stages of epithelial differentiation, as well as the basement membrane constituent collagen type IV and Ki-67 as a proliferation marker. Intriguingly, histogenesis and IHCH reveal the best resemblance of the native epithelium by the NWM alone, irrespective of other cell counterparts. These findings prove the gelatin NWM a convenient cell matrix, and evidence that NWM mechanics is important to promote epithelial histogenesis in view of prospective clinical applications. PMID- 29529356 TI - Novel options in the nonsurgical management of chronic rhinosinusitis. PMID- 29529357 TI - Dysregulation of miRNA and its potential therapeutic application in schizophrenia. AB - Although it is generally believed that genetic and developmental factors play critical roles in pathogenesis of schizophrenia, however, the precise etiological mechanism of schizophrenia remains largely unknown. Over past decades, miRNAs have emerged as an essential post-transcriptional regulator in gene expression regulation. The importance of miRNA in brain development and neuroplasticity has been well-established. Abnormal expression and dysfunction of miRNAs are known to involve in the pathophysiology of many neuropsychiatric diseases including schizophrenia. In this review, we summarized the recent findings in the schizophrenia-associated dysregulation of miRNA and functional roles in the development and pathogenesis of schizophrenia. We also discussed the potential therapeutic implications of miRNA regulation in the illness. PMID- 29529355 TI - Low-dose curcumin stimulates proliferation of rat embryonic neural stem cells through glucocorticoid receptor and STAT3. AB - AIMS: This study was to determine whether curcumin had any effect on the proliferation of neural stem cell (NSC), analyze the expression of glucocorticoid receptor (GR), signal transducer and activator of transcription 3 (STAT3), and Notch1 at transcription and protein level, and discuss the related mechanisms. METHODS AND RESULTS: NSCs were harvested from E15 SD rat brain and cultured. All experiments were performed at the second passage. Cell cytotoxicity, cell viability, and proliferation assays were used to figure out the optimal concentration of curcumin, which can be used for the protein and mRNA studies. The results showed that by downregulation of GR and STAT3 expression, 0.5 MUmol L 1 curcumin exhibited the most pronounced effect in promoting the proliferation of NSCs, which were also induced by antagonists of GR and STAT3, but was inhibited by GR agonist. CONCLUSION: This study shows that low-dose curcumin stimulates the proliferation of NSCs, which is probably by inhibiting the mRNA and protein expressions of GR and directly or indirectly regulating the STAT3 via the synergistic effect of GR and STAT3 pathways and its related signal pathways. PMID- 29529358 TI - A Path Analysis of Nutrition, Stimulation, and Child Development Among Young Children in Bihar, India. AB - Nutrition plays an important role in the development of a child, particularly in low- and middle-income countries where malnutrition is often widespread. The relation between diet, hemoglobin, nutritional status, motor development, stimulation and mental development was examined in a cross-sectional sample of 1,079 children 12-18 months of age living in rural Bihar, India. Path analysis revealed associations between (a) length-for-age z-scores and motor development, standardized beta (beta) = .285, p < .001, and (b) motor and all mental development outcomes (language: beta = .422; personal-social: beta = .490; memory: beta = .139; and executive function: beta = .072, all p < .001). Additionally, stimulation was significantly associated with language scores and hemoglobin concentration with memory. These findings inform interventions aimed at improving child development in Northern India. PMID- 29529360 TI - Dual-Level Approach to Instanton Theory. AB - Instanton theory is an established method to calculate rate constants of chemical reactions including atom tunneling. Technical and methodological improvements increased its applicability. Still, a large number of energy and gradient calculations is necessary to optimize the instanton tunneling path, and second derivatives of the potential energy along the tunneling path have to be evaluated, restricting the range of suitable electronic structure methods. To enhance the applicability of instanton theory, we present a dual-level approach in which instanton optimizations and Hessian calculations are performed using an efficient but approximate electronic structure method, and the potential energy along the tunneling path is recalculated using a more accurate method. This procedure extends the applicability of instanton theory to high-level electronic structure methods for which analytic gradients may not be available, like local linear-scaling approaches. We demonstrate for the analytical Eckart barrier and three molecular systems how the dual-level instanton approach corrects for the largest part of the error caused by the inaccuracy of the efficient electronic structure method. This reduces the error of the calculated rate constants significantly. PMID- 29529359 TI - Tissue-like Neural Probes for Understanding and Modulating the Brain. AB - Electrophysiology tools have contributed substantially to understanding brain function, yet the capabilities of conventional electrophysiology probes have remained limited in key ways because of large structural and mechanical mismatches with respect to neural tissue. In this Perspective, we discuss how the general goal of probe design in biochemistry, that the probe or label have a minimal impact on the properties and function of the system being studied, can be realized by minimizing structural, mechanical, and topological differences between neural probes and brain tissue, thus leading to a new paradigm of tissue like mesh electronics. The unique properties and capabilities of the tissue-like mesh electronics as well as future opportunities are summarized. First, we discuss the design of an ultraflexible and open mesh structure of electronics that is tissue-like and can be delivered in the brain via minimally invasive syringe injection like molecular and macromolecular pharmaceuticals. Second, we describe the unprecedented tissue healing without chronic immune response that leads to seamless three-dimensional integration with a natural distribution of neurons and other key cells through these tissue-like probes. These unique characteristics lead to unmatched stable long-term, multiplexed mapping and modulation of neural circuits at the single-neuron level on a year time scale. Last, we offer insights on several exciting future directions for the tissue-like electronics paradigm that capitalize on their unique properties to explore biochemical interactions and signaling in a "natural" brain environment. PMID- 29529361 TI - Combined Experimental and Computational Investigation of the Elementary Reaction of Ground State Atomic Carbon (C; 3P j) with Pyridine (C5H5N; X1A1) via Ring Expansion and Ring Degradation Pathways. AB - We explored the elementary reaction of atomic carbon (C; 3P j) with pyridine (C5H5N; X1A1) at a collision energy of 34 +/- 4 kJ mol-1 utilizing the crossed molecular beams technique. Forward-convolution fitting of the data was combined with high-level electronic structure calculations and statistical (RRKM) calculations on the triplet C6H5N potential energy surface (PES). These investigations reveal that the reaction dynamics are indirect and dominated by large range reactive impact parameters leading via barrier-less addition to the nitrogen atom and to two chemically nonequivalent "aromatic" carbon-carbon bonds forming three distinct collision complexes. At least two reaction pathways through atomic hydrogen loss were identified on the triplet surface. These channels involve multiple isomerization steps of the initial collision complexes via ring-opening and ring expansion forming an acyclic 1-ethynyl-3-isocyanoallyl radical (P1; 2A") and a hitherto unreported seven-membered 1-aza-2 dehydrocyclohepta-2,4,6-trien-4-yl radical isomer (P3; 2A), respectively. For RRKM calculations at zero collision energy, representing conditions in cold molecular clouds, the ring expansion product P3 is formed nearly exclusively for the atomic hydrogen loss channel, but based on these computations, the molecular fragmentation channel forming acetylene (C2H2) plus 3-cyano-2-propen-1-ylidene (P6; 3A") accounts for nearly all of the degradation products of the reaction of atomic carbon with pyridine, proposing a destruction pathway of interstellar pyridine, which may account for the absence in the detection of pyridine in the interstellar medium. These results are also discussed in light of the isoelectronic carbon-benzene (C6H6; X1A1) system with important implications to the rapid degradation of nitrogen-bearing polycyclic aromatic hydrocarbons (NPAHs) in the interstellar medium compared to mass growth processes of PAH counterparts through ring expansion. PMID- 29529362 TI - Morphology- and Porosity-Tunable Synthesis of 3D Nanoporous SiGe Alloy as a High Performance Lithium-Ion Battery Anode. AB - The lithium storage performance of silicon (Si) can be enhanced by being alloyed with germanium (Ge) because of its good electronic and ionic conductivity. Here, we synthesized a three-dimensional nanoporous (3D-NP) SiGe alloy as a high performance lithium-ion battery (LIB) anode using a dealloying method with a ternary AlSiGe ribbon serving as the precursor. The morphology and porosity of the as-synthesized SiGe alloy can be controlled effectively by adjusting the sacrificial Al content of the precursor. With an Al content of 80%, the 3D-NP SiGe presents uniformly coral-like structure with continuous ligaments and hierarchical micropores and mesopores, which leads to a high reversible capacity of 1158 mA h g-1 after 150 cycles at a current density of 1000 mA g-1 with excellent rate capacity. The strategy might provide guidelines for nanostructure optimization and mass production of energy storage materials. PMID- 29529363 TI - Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling. AB - Due to the low intrinsic acidity of amines, palladium-catalyzed C-N cross coupling has been plagued continuously by the necessity to employ strong, inorganic, or insoluble bases. To surmount the many practical obstacles associated with these reagents, we utilized a commercially available dialkyl triarylmonophosphine-supported palladium catalyst that facilitates a broad range of C-N coupling reactions in the presence of weak, soluble bases. The mild and general reaction conditions show extraordinary tolerance for even highly base sensitive functional groups. Additionally, insightful heteronuclear NMR studies using 15N-labeled amine complexes provide evidence for the key acidifying effect of the cationic palladium center. PMID- 29529364 TI - A Universal Method to Engineer Metal Oxide-Metal-Carbon Interface for Highly Efficient Oxygen Reduction. AB - Oxygen is the most abundant element in the Earth's crust. The oxygen reduction reaction (ORR) is also the most important reaction in life processes and energy converting/storage systems. Developing techniques toward high-efficiency ORR remains highly desired and a challenge. Here, we report a N-doped carbon (NC) encapsulated CeO2/Co interfacial hollow structure (CeO2-Co-NC) via a generalized strategy for largely increased oxygen species adsorption and improved ORR activities. First, the metallic Co nanoparticles not only provide high conductivity but also serve as electron donors to largely create oxygen vacancies in CeO2. Second, the outer carbon layer can effectively protect cobalt from oxidation and dissociation in alkaline media and as well imparts its higher ORR activity. In the meanwhile, the electronic interactions between CeO2 and Co in the CeO2/Co interface are unveiled theoretically by density functional theory calculations to justify the increased oxygen absorption for ORR activity improvement. The reported CeO2-Co-NC hollow nanospheres not only exhibit decent ORR performance with a high onset potential (922 mV vs RHE), half-wave potential (797 mV vs RHE), and small Tafel slope (60 mV dec-1) comparable to those of the state-of-the-art Pt/C catalysts but also possess long-term stability with a negative shift of only 7 mV of the half-wave potential after 2000 cycles and strong tolerance against methanol. This work represents a solid step toward high efficient oxygen reduction. PMID- 29529365 TI - Doubly and Triply Charged Species Formed from Chlorobenzene Reveal Unusual C-Cl Multiple Bonding. AB - In free-radical halogenation of aromatics, singly charged ions are usually formed as intermediates. These stable species can be easily observed by time-of-flight mass spectrometry (TOF-MS). Here we used electron and proton beams to ionize chlorobenzene (C6H5Cl) and investigate the ions stability by TOF-MS. Additionally to the singly charged parent ion and its fragments, we find a significant yield of doubly and triply charged parent ions not previously reported. In order to characterize these species, we used high-level theoretical methods based on density functional theory (DFT), coupled-cluster (CC), and generalized valence bond (GVB) to calculate the structure, relative stabilities, and bonding of these dications and trications. The most stable isomers exhibit unusual carbon-chlorine multiple bonding: a terminal C?Cl double bond in a formyl-like CHCl moiety (1, rC Cl = 1.621 A) and a ketene-like C?C?Cl cumulated species (2, rC-Cl = 1.542 A). The calculations suggest that an excited state of 2 has a nitrile-like C=Cl triple bond structure. PMID- 29529366 TI - Glucose Sensing with Phenylboronic Acid Functionalized Hydrogel-Based Optical Diffusers. AB - Phenylboronic acids have emerged as synthetic receptors that can reversibly bind to cis-diols of glucose molecules. The incorporation of phenylboronic acids in hydrogels offers exclusive attributes; for example, the binding process with glucose induces Donnan osmotic pressure resulting in volumetric changes in the matrix. However, their practical applications are hindered because of complex readout approaches and their time-consuming fabrication processes. Here, we demonstrate a microimprinting method to fabricate densely packed concavities in phenylboronic acid functionalized hydrogel films. A microengineered optical diffuser structure was imprinted on a phenylboronic acid based cis-diol recognizing motif prepositioned in a hydrogel film. The diffuser structure engineered on the hydrogel was based on laser-inscribed arrays of imperfect microlenses that focused the incoming light at different focal lengths and direction resulting in a diffused profile of light in transmission and reflection readout modes. The signature of the dimensional modulation was detected in terms of changing focal lengths of the microlenses due to the volumetric expansion of the hydrogel that altered the diffusion spectra and transmitted beam profile. The transmitted optical light spread and intensity through the sensor was measured to determine variation in glucose concentrations at physiological conditions. The sensor was integrated in a contact lens and placed over an artificial eye. Artificial stimulation of variation in glucose concentration allowed quantitative measurements using a smartphone's photodiode. A smartphone app was utilized to convert the received light intensity to quantitative glucose concentration values. The developed sensing platform offers low cost, rapid fabrication, and easy detection scheme as compared to other optical sensing counterparts. The presented detection scheme may have applications in wearable real-time biomarker monitoring devices at point-of-care settings. PMID- 29529367 TI - Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand-Receptor Complexes. AB - We previously combined molecular dynamics (classical or simulated annealing) with ligand-receptor contacts analysis as a means to extract valid pharmacophore model(s) from single ligand-receptor complexes. However, molecular dynamics methods are computationally expensive and time-consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within a reasonable time scale. The new method is based on ligand-receptor contacts analysis following energy relaxation of a predetermined set of randomly deformed complexes generated from the targeted crystallographic structure. Ligand-receptor contacts maintained across many deformed/relaxed structures are assumed to be critical and used to guide pharmacophore development. This methodology was implemented to develop valid pharmacophore models for PI3K-gamma, RENIN, and JAK1. The resulting pharmacophore models were validated by receiver operating characteristic (ROC) analysis against inhibitors extracted from the CHEMBL database. Additionally, we implemented pharmacophores extracted from PI3K-gamma to search for new inhibitors from the National Cancer Institute list of compounds. The process culminated in new PI3K gamma/mTOR inhibitory leads of low micromolar IC50s. PMID- 29529368 TI - Antenna-Enhanced Fluorescence Correlation Spectroscopy Resolves Calcium-Mediated Lipid-Lipid Interactions. AB - Fluorescence correlation spectroscopy (FCS) has provided a wealth of information on the composition, structure, and dynamics of cell membranes. However, it has proved challenging to reach the spatial resolution required to resolve biophysical interactions at the nanometer scale relevant to many crucial membrane processes. In this work, we form artificial cell membranes on dimeric, nanoplasmonic antennas, which shrink the FCS probe volume down to the ~20 nm length scale. By analyzing the autocorrelation functions associated with the fluorescence bursts from individual fluorescently tagged lipids moving through the antenna "hotspots", we show that the confinement of the optical readout volume below the diffraction limit allows the temporal resolution of FCS to be increased by up to 3 orders of magnitude. Employing this high spatial and temporal resolution to probe diffusion dynamics of individual dye-conjugated lipids, we further show that lipid molecules diffuse either as single entities or as pairs in the presence of calcium ions. Removal of calcium ions by addition of the chelator EDTA almost completely removes the complex contribution, in agreement with previous theoretical predications on the role of calcium ions in mediating transient interactions between zwitterionic lipids. We envision that antenna-enhanced FCS with single-molecule burst analysis will enable resolving a broad range of challenging membrane biophysics questions, such as stimuli-induced lipid clustering and membrane protein dynamics. PMID- 29529369 TI - Transferable Neural Networks for Enhanced Sampling of Protein Dynamics. AB - Variational autoencoder frameworks have demonstrated success in reducing complex nonlinear dynamics in molecular simulation to a single nonlinear embedding. In this work, we illustrate how this nonlinear latent embedding can be used as a collective variable for enhanced sampling and present a simple modification that allows us to rapidly perform sampling in multiple related systems. We first demonstrate our method is able to describe the effects of force field changes in capped alanine dipeptide after learning about a model using AMBER99. We further provide a simple extension to variational dynamics encoders that allows the model to be trained in a more efficient manner on larger systems by encoding the outputs of a linear transformation using time-structure based independent component analysis (tICA). Using this technique, we show how such a model trained for one protein, the WW domain, can efficiently be transferred to perform enhanced sampling on a related mutant protein, the GTT mutation. This method shows promise for its ability to rapidly sample related systems using a single transferable collective variable, enabling us to probe the effects of variation in increasingly large systems of biophysical interest. PMID- 29529370 TI - Red/Green Currant and Sea Buckthorn Berry Press Residues as Potential Sources of Antioxidants for Food Use. AB - The potential for using extracts of press residues from black, green, red, and white currants and from sea buckthorn berries as sources of antioxidants for foods use was investigated. Press residues were extracted with ethanol in four consecutive extractions, and total Folin-Ciocalteu (F-C) reactive material and authentic phenolic compounds were determined. Radical quenching capability and mechanisms were determined from total peroxyl radical-trapping antioxidant capacity (TRAP) and oxygen radical absorbance capacity (ORAC) assays and from diphenylpicrylhydrazyl (DPPH) kinetics, respectively; specific activities were normalized to F-C reactive concentrations. Levels of total F-C reactive materials in press residue extracts were higher than in many fruits and showed significant radical quenching activity. Black currant had the highest authentic phenol content and ORAC, TRAP, and DPPH reactivity. Sea buckthorn grown in northern Finland showed extremely high total specific DPPH reactivity. These results suggest that berry press residues offer attractive value-added products that can provide antioxidants for use in stabilizing and fortifying foods. PMID- 29529371 TI - Imaging Bulk and Edge Transport near the Dirac Point in Graphene Moire Superlattices. AB - Van der Waals structures formed by aligning monolayer graphene with insulating layers of hexagonal boron nitride exhibit a moire superlattice that is expected to break sublattice symmetry. Despite an energy gap of several tens of millielectronvolts opening in the Dirac spectrum, electrical resistivity remains lower than expected at low temperature and varies between devices. While subgap states are likely to play a role in this behavior, their precise nature is unclear. We present a scanning gate microscopy study of moire superlattice devices with comparable activation energy but with different charge disorder levels. In the device with higher charge impurity (~1010 cm-2) and lower resistivity (~10 kOmega) at the Dirac point we observe current flow along the graphene edges. Combined with simulations, our measurements suggest that enhanced edge doping is responsible for this effect. In addition, a device with low charge impurity (~109 cm-2) and higher resistivity (~100 kOmega) shows subgap states in the bulk, consistent with the absence of shunting by edge currents. PMID- 29529372 TI - Organocatalytic Transannular Approach to Stereodefined Bicyclo[3.1.0]hexanes. AB - A diastereodivergent approach to highly substituted bicyclo[3.1.0]hexanes has been developed through a transannular alkylation reaction that builds up the bicyclic core employing asymmetric organocatalysis as the tool for the installation of all stereocenters. On one hand, a Michael/Michael cascade process between enals and 4-alkenyl sulfamidate imines under the iminium/enamine activation manifold provides an oxathiazole-2,2-dioxide-fused cyclohexane adduct that, after isolation, is subsequently engaged in a transannular alkylation/hydrolysis through enamine activation by the use of a primary amine. On the other hand, the corresponding C-2 epimers are directly obtained from the same starting materials in a single operation through a cascade Michael/Michael/transannular alkylation/hydrolysis sequence through sequential iminium/enamine/enamine combination of aminocatalytic activation manifolds. PMID- 29529373 TI - Collagen Fibrils: Nature's Highly Tunable Nonlinear Springs. AB - Tissue hydration is well known to influence tissue mechanics and can be tuned via osmotic pressure. Collagen fibrils are nature's nanoscale building blocks to achieve biomechanical function in a broad range of biological tissues and across many species. Intrafibrillar covalent cross-links have long been thought to play a pivotal role in collagen fibril elasticity, but predominantly at large, far from physiological, strains. Performing nanotensile experiments of collagen fibrils at varying hydration levels by adjusting osmotic pressure in situ during atomic force microscopy experiments, we show the power the intrafibrillar noncovalent interactions have for defining collagen fibril tensile elasticity at low fibril strains. Nanomechanical tensile tests reveal that osmotic pressure increases collagen fibril stiffness up to 24-fold in transverse (nanoindentation) and up to 6-fold in the longitudinal direction (tension), compared to physiological saline in a reversible fashion. We attribute the stiffening to the density and strength of weak intermolecular forces tuned by hydration and hence collagen packing density. This reversible mechanism may be employed by cells to alter their mechanical microenvironment in a reversible manner. The mechanism could also be translated to tissue engineering approaches for customizing scaffold mechanics in spatially resolved fashion, and it may help explain local mechanical changes during development of diseases and inflammation. PMID- 29529374 TI - Active Radiative Thermal Switching with Graphene Plasmon Resonators. AB - We theoretically demonstrate a near-field radiative thermal switch based on thermally excited surface plasmons in graphene resonators. The high tunability of graphene enables substantial modulation of near-field radiative heat transfer, which, when combined with the use of resonant structures, overcomes the intrinsically broadband nature of thermal radiation. In canonical geometries, we use nonlinear optimization to show that stacked graphene sheets offer improved heat conductance contrast between "ON" and "OFF" switching states and that a >10* higher modulation is achieved between isolated graphene resonators than for parallel graphene sheets. In all cases, we find that carrier mobility is a crucial parameter for the performance of a radiative thermal switch. Furthermore, we derive shape-agnostic analytical approximations for the resonant heat transfer that provide general scaling laws and allow for direct comparison between different resonator geometries dominated by a single mode. The presented scheme is relevant for active thermal management and energy harvesting as well as probing excited-state dynamics at the nanoscale. PMID- 29529375 TI - Persistence Length, End-to-End Distance, and Structure of Coarse-Grained Polymers. AB - Coarse-grained (CG) polymer simulations can access longer times and larger lengths than all-atom (AA) molecular dynamics simulations; however, not all CG models correctly reproduce polymer properties on all length scales. Here we coarse-grain atomistic position data from polyethylene (PE) and polytetrafluoroethylene (PTFE) melt simulations by combining lambda backbone carbon atoms in a single CG bead. Resulting CG variables have correlations along the chain backbone that depend on the coarse-graining scale lambda and are generally not reproduced by independent bond-length, bond-angle and torsion-angle distributions. By constructing distributions of CG variables equivalent to those from simulated CG potentials we are able to evaluate the bond-orientation correlation for different CG models at reduced computational cost. CG models and potentials that include only nonbonded, bond-length, and bond-angle interactions computed by Boltzmann inversion correctly reproduce the CG variable distributions but do not necessarily reproduce the chain stiffness, overestimating the persistence length Lp and end-to-end distance ? R2?1/2 with increasing lambda. While CG models that include an independent torsion angle match the bond orientation correlation and ? R2?1/2 better, only approximate models that include correlations between bond and torsion angles match the true bond-orientation correlation. PMID- 29529376 TI - Asymmetric Nanopore Electrode-Based Amplification for Electron Transfer Imaging in Live Cells. AB - Capturing real-time electron transfer, enzyme activity, molecular dynamics, and biochemical messengers in living cells is essential for understanding the signaling pathways and cellular communications. However, there is no generalizable method for characterizing a broad range of redox-active species in a single living cell at the resolution of cellular compartments. Although nanoelectrodes have been applied in the intracellular detection of redox-active species, the fabrication of nanoelectrodes to maximize the signal-to-noise ratio of the probe remains challenging because of the stringent requirements of 3D fabrication. Here, we report an asymmetric nanopore electrode-based amplification mechanism for the real-time monitoring of NADH in a living cell. We used a two step 3D fabrication process to develop a modified asymmetric nanopore electrode with a diameter down to 90 nm, which allowed for the detection of redox metabolism in living cells. Taking advantage of the asymmetric geometry, the above 90% potential drop at the two terminals of the nanopore electrode converts the faradaic current response into an easily distinguishable bubble-induced transient ionic current pattern. Therefore, the current signal was amplified by at least 3 orders of magnitude, which was dynamically linked to the presence of trace redox-active species. Compared to traditional wire electrodes, this wireless asymmetric nanopore electrode exhibits a high signal-to-noise ratio by increasing the current resolution from nanoamperes to picoamperes. The asymmetric nanopore electrode achieves the highly sensitive and selective probing of NADH concentrations as low as 1 pM. Moreover, it enables the real-time nanopore monitoring of the respiration chain (i.e., NADH) in a living cell and the evaluation of the effects of anticancer drugs in an MCF-7 cell. We believe that this integrated wireless asymmetric nanopore electrode provides promising building blocks for the future imaging of electron transfer dynamics in live cells. PMID- 29529377 TI - Unusual Suppression of the Superconducting Energy Gap and Critical Temperature in Atomically Thin NbSe2. AB - It is well-known that superconductivity in thin films is generally suppressed with decreasing thickness. This suppression is normally governed by either disorder-induced localization of Cooper pairs, weakening of Coulomb screening, or generation and unbinding of vortex-antivortex pairs as described by the Berezinskii-Kosterlitz-Thouless (BKT) theory. Defying general expectations, few layer NbSe2, an archetypal example of ultrathin superconductors, has been found to remain superconducting down to monolayer thickness. Here, we report measurements of both the superconducting energy gap Delta and critical temperature TC in high-quality monocrystals of few-layer NbSe2, using planar junction tunneling spectroscopy and lateral transport. We observe a fully developed gap that rapidly reduces for devices with the number of layers N <= 5, as does their TC. We show that the observed reduction cannot be explained by disorder, and the BKT mechanism is also excluded by measuring its transition temperature that for all N remains very close to TC. We attribute the observed behavior to changes in the electronic band structure predicted for mono- and bi- layer NbSe2 combined with inevitable suppression of the Cooper pair density at the superconductor-vacuum interface. Our experimental results for N > 2 are in good agreement with the dependences of Delta and TC expected in the latter case while the effect of band-structure reconstruction is evidenced by a stronger suppression of Delta and the disappearance of its anisotropy for N = 2. The spatial scale involved in the surface suppression of the density of states is only a few angstroms but cannot be ignored for atomically thin superconductors. PMID- 29529378 TI - New Insights into the Regulation of Endothelial Lung Permeability in Pneumonia. The Interplay between Angiopoietins 1 and 2. PMID- 29529380 TI - Exploring below the Tip of the Iceberg: The Prognostic Impact of Acute Exacerbations of Chronic Obstructive Pulmonary Disease in Primary Care. PMID- 29529379 TI - The Microbiome Regulates Pulmonary Responses to Ozone in Mice. AB - Previous reports demonstrate that the microbiome impacts allergic airway responses, including airway hyperresponsiveness, a characteristic feature of asthma. Here we examined the role of the microbiome in pulmonary responses to a nonallergic asthma trigger, ozone. We depleted the microbiota of conventional mice with either a single antibiotic (ampicillin, metronidazole, neomycin, or vancomycin) or a cocktail of all four antibiotics given via the drinking water. Mice were then exposed to room air or ozone. In air-exposed mice, airway responsiveness did not differ between antibiotic- and control water-treated mice. Ozone caused airway hyperresponsiveness, the magnitude of which was decreased in antibiotic cocktail-treated mice versus water-treated mice. Except for neomycin, single antibiotics had effects similar to those observed with the cocktail. Compared with conventional mice, germ-free mice also had attenuated airway responsiveness after ozone. 16S ribosomal RNA gene sequencing of fecal DNA to characterize the gut microbiome indicated that bacterial genera that were decreased in mice with reduced ozone-induced airway hyperresponsiveness after antibiotic treatment were short-chain fatty acid producers. Serum analysis indicated reduced concentrations of the short-chain fatty acid propionate in cocktail-treated mice but not in neomycin-treated mice. Dietary enrichment with pectin, which increased serum short-chain fatty acids, also augmented ozone induced airway hyperresponsiveness. Furthermore, propionate supplementation of the drinking water augmented ozone-induced airway hyperresponsiveness in conventional mice. Our data indicate that the microbiome contributes to ozone induced airway hyperresponsiveness, likely via its ability to produce short-chain fatty acids. PMID- 29529381 TI - The Effects of Timed Light Exposure in Critically Ill Patients: A Randomized Controlled Pilot Clinical Trial. PMID- 29529383 TI - Physical characteristics cannot be used to predict cooling time using cold-water immersion as a treatment for exertional hyperthermia. AB - We examined if physical characteristics could be used to predict cooling time during cold water immersion (CWI, 2 degrees C) following exertional hyperthermia (rectal temperature >=39.5 degrees C) in a physically heterogeneous group of men and women (n = 62). Lean body mass was the only significant predictor of cooling time following CWI (R2 = 0.137; P < 0.001); however, that prediction did not provide the precision (mean residual square error: 3.18 +/- 2.28 min) required to act as a safe alternative to rectal temperature measurements. PMID- 29529382 TI - Prognostic Significance of Large Airway Dimensions on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. AB - RATIONALE: Large airway dimensions on computed tomography (CT) have been associated with lung function, symptoms, and exacerbations in chronic obstructive pulmonary disease (COPD), as well as with symptoms in smokers with preserved spirometry. Their prognostic significance in persons without lung disease remains undefined. OBJECTIVES: To examine associations between large airway dimensions on CT and respiratory outcomes in a population-based cohort of adults without prevalent lung disease. METHODS: The Multi-Ethnic Study of Atherosclerosis recruited participants ages 45-84 years without cardiovascular disease in 2000 2002; we excluded participants with prevalent chronic lower respiratory disease (CLRD). Spirometry was measured in 2004-2006 and 2010-2012. CLRD hospitalizations and deaths were classified by validated criteria through 2014. The average wall thickness for a hypothetical airway of 10-mm lumen perimeter on CT (Pi10) was calculated using measures of airway wall thickness and lumen diameter. Models were adjusted for age, sex, principal components of ancestry, body mass index, smoking, pack-years, scanner, percent emphysema, genetic risk score, and initial forced expiratory volume in 1 second (FEV1) percent predicted. RESULTS: Greater Pi10 was associated with 9% faster FEV1 decline (95% confidence interval [CI], 2 to 15%; P = 0.012) and increased incident COPD (odds ratio, 2.22; 95% CI, 1.43 3.45; P = 0.0004) per standard deviation among 1,830 participants. Over 78,147 person-years, higher Pi10 was associated with a 57% higher risk of first CLRD hospitalization or mortality (P = 0.0496) per standard deviation. Of Pi10's component measures, both greater airway wall thickness and narrower lumen predicted incident COPD and CLRD clinical events. CONCLUSIONS: In adults without CLRD, large airway dimensions on CT were prospectively associated with accelerated lung function decline and increased risks of COPD and CLRD hospitalization and mortality. PMID- 29529384 TI - The Sandman in the ICU: A Novel Use of Dexmedetomidine? PMID- 29529385 TI - Corrigendum: Constructing Rich False Memories of Committing Crime. PMID- 29529386 TI - Cell Type-Specific Quantification of Telomere Length and DNA Double-strand Breaks in Individual Lung Cells by Fluorescence In Situ Hybridization and Fluorescent Immunohistochemistry. AB - Telomeres are small repetitive DNA sequences at the ends of chromosomes which act as a buffer in age-dependent DNA shortening. Insufficient telomere repeats will be recognized as double-strand breaks. Presently, it is becoming more evident that telomere attrition, whether or not caused by mutations in telomere maintenance genes, plays an important role in many inflammatory and age associated diseases. In this report, a method to (semi)quantitatively assess telomere length and DNA double-strand breaks in formalin-fixed paraffin-embedded (FFPE) tissue is described. Therefore, a novel combination of quantitative fluorescence in situ hybridization, tissue elution, and immunofluorescence staining techniques was developed. Caveolin-1 (type 1 pneumocytes), pro surfactant protein C (type 2 pneumocytes), club cell-10 (club cells), and alpha smooth muscle actin (smooth muscle cells) markers were used to identify cell types. To visualize all the different probes, restaining the tissue by heat mediated slide elution is essential. Fluorescent signals of telomeres and DNA double-strand breaks were quantified using the Telometer plugin of ImageJ. As example, we analyzed lung tissue from a familial pulmonary fibrosis patient with a mutation in the telomere-associated gene poly(A)-specific ribonuclease ( PARN). The protocol displays a novel opportunity to directly quantitatively link DNA double-strand breaks to telomere length in specific FFPE cells. PMID- 29529388 TI - Quality of Life Matters: It Is Time to Integrate Scalp Cooling in Routine Clinical Practice. PMID- 29529387 TI - The effects of different passive static stretching intensities on recovery from unaccustomed eccentric exercise - a randomized controlled trial. AB - Effects of passive static stretching intensity on recovery from unaccustomed eccentric exercise of right knee extensors was investigated in 30 recreationally active males randomly allocated into 3 groups: high-intensity (70%-80% maximum perceived stretch), low-intensity (30%-40% maximum perceived stretch), and control. Both stretching groups performed 3 sets of passive static stretching exercises of 60 s each for hamstrings, hip flexors, and quadriceps, over 3 consecutive days, post-unaccustomed eccentric exercise. Muscle function (eccentric and isometric peak torque) and blood biomarkers (creatine kinase and C reactive protein) were measured before (baseline) and after (24, 48, and 72 h) unaccustomed eccentric exercise. Perceived muscle soreness scores were collected immediately (time 0), and after 24, 48, and 72 h postexercise. Statistical time * condition interactions observed only for eccentric peak torque (p = 0.008). Magnitude-based inference analyses revealed low-intensity stretching had most likely, very likely, or likely beneficial effects on perceived muscle soreness (48-72 h and 0-72 h) and eccentric peak torque (baseline-24 h and baseline-72 h), compared with high-intensity stretching. Compared with control, low-intensity stretching had very likely or likely beneficial effects on perceived muscle soreness (0-24 h and 0-72 h), eccentric peak torque (baseline-48 h and baseline 72 h), and isometric peak torque (baseline-72 h). High-intensity stretching had likely beneficial effects on eccentric peak torque (baseline-48 h), but likely had harmful effects on eccentric peak torque (baseline-24 h) and creatine kinase (baseline-48 h and baseline-72 h), compared with control. Therefore, low intensity stretching is likely to result in small-to-moderate beneficial effects on perceived muscle soreness and recovery of muscle function post-unaccustomed eccentric exercise, but not markers of muscle damage and inflammation, compared with high-intensity or no stretching. PMID- 29529389 TI - Management of Chemotherapy-Induced Alopecia With Scalp Cooling. AB - Chemotherapy-induced alopecia is a common and distressing adverse effect of many types of chemotherapy. Scalp cooling has been used since the 1970s for prevention of chemotherapy-induced alopecia; however, most data regarding this treatment modality are retrospective in nature, and use in the United States has been limited by safety concerns, specifically the potential for scalp metastases. Two prospective studies of scalp-cooling systems performed in the United States were published within the last year and add evidence supporting the efficacy and safety of scalp cooling in preventing chemotherapy-induced alopecia in patients receiving chemotherapy for solid tumor malignancies. Available data suggest that this technology is most effective for taxane-based chemotherapy regimens compared with anthracycline-based chemotherapy regimens. Two scalp-cooling devices have been cleared by the US Food and Drug Administration, and multiple cold caps are available for patient rental. The adverse effect profile of scalp cooling includes scalp pain, headache, and chills but is tolerable for most patients included in recent clinical trials. Retrospective data suggest that the incidence of scalp metastases related to scalp cooling is low and should not limit use of this technology. Logistic issues related to use of scalp cooling include availability of devices, inconsistent insurance coverage, and incorporation of use into typical infusion center workflow. PMID- 29529390 TI - Inhibition of GSK-3beta induces AP-1-mediated osteopontin expression to promote cholestatic liver fibrosis. AB - The contribution of glycogen synthase kinase-3beta (GSK-3beta) to cholestatic liver disease (CLD) remains unknown. We investigated the role and mechanism of GSK-3beta in vivo in liver tissues of patients with CLD and the bile duct ligation (BDL) mouse model and in vitro using a hepatic progenitor cell (HPC) and hepatic stellate cell (HSC) coculture system. In liver tissues of patients with CLD, expression of the inactive form of GSK-3beta, phospho-GSK-3beta(Ser9), was increased in HPCs. GSK-3beta inhibition by SB216763 treatment aggravated liver fibrosis and elevated the expression of osteopontin (OPN) in the BDL mouse model. OPN was significantly overexpressed in liver tissues and serum from patients with CLD. In an HPC and HSC coculture system, inhibition of GSK-3beta induced OPN production, which activated HSCs in a cholestatic environment. The expression of activator protein 1 (AP-1), an important downstream transcription factor of GSK 3beta, was significantly increased in liver tissues of patients with CLD and SB216763-treated BDL mice. Finally, OPN expression was directly modulated by AP 1. These observations indicate that GSK-3beta inhibition up-regulates OPN expression via AP-1 activation, which accelerates the progression of cholestatic liver fibrosis in patients with CLD and in BDL mice.-Zhuang, S., Hua, X., He, K., Zhou, T., Zhang, J., Wu, H., Ma, X., Xia, Q., Zhang, J. Inhibition of GSK-3beta induces AP-1-mediated osteopontin expression to promote cholestatic liver fibrosis. PMID- 29529391 TI - Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway. AB - Polarity complexes, including the PAR (Partitioning-defective), CRB (Crumbs) and SCRIB (Scribble) complexes, are required for the physiologic establishment, stabilization, and maintenance of a functional apical-basolateral polarity. Inactivation of some of the polarity complexes results in cystic kidneys, and apical-basolateral polarity defects are commonly observed in autosomal-dominant polycystic kidney disease (ADPKD); however, little is known about the role that polarity complexes play in ADPKD. Here, we demonstrate that Scribble, a core protein of the SCRIB complex, is down-regulated in ADPKD cell lines and the zebrafish model of this disease ( pkd2 morphants). Overexpression of Scribble could reduce cyst formation in pkd2 morphants, and loss of scrib led to a dilated pronephric duct in zebrafish. Furthermore, the Hippo signaling pathway was inactivated in scrib mutants and pkd2 morphants in which Yes-associated protein (YAP), which is physiologically located in the cytoplasm, was translocated to the nucleus. Of note, overexpression of cytoplasmic YAP, instead of nuclear YAP, could reduce cyst formation in pkd2 morphants. Consistently, knockout of yap resulted in cystic kidneys in zebrafish, which was rescued by the overexpression of cytoplasmic YAP, but not nuclear YAP. Finally, scrib and yap had a genetic interaction with pkd2 in cyst formation, and the overexpression of Scribble attenuated the down-regulation of cytoplasmic YAP in ADPKD. Altogether, our data indicate that Scribble induces the phosphorylation of YAP and, consequently, influences cyst formation in ADPKD by mediating YAP nucleocytoplasmic shuttling. Xu, D., Lv, J., He, L., Fu, L., Hu, R., Cao, Y., Mei, C. Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway. PMID- 29529392 TI - Short-term effect of FSH on gene expression in bovine granulosa cells in vitro. AB - In reproduction, FSH is one of the most important hormones, especially in females, because it controls the number of follicles and the rate of follicular growth. Although several studies have examined the follicular response at the transcriptome level, it is difficult to obtain a clear and complete picture of the genes responding to an increase in FSH in an in vivo context because follicles undergo rapid morphological and physical changes during their growth. To help define the transcriptome downstream response to FSH, an in vitro model was used in the present study to observe the short-term (4h) cellular response. Gene expression analysis highlighted a set of novel transcripts that had not been reported previously as being part of the FSH response. Moreover, the results of the present study indicate that the epithelial to mesenchymal transition pathway is inhibited by short-term FSH stimuli, maintaining follicles in a growth phase and preventing differentiation. Modulating gene expression in vitro has physiological limitations, but it can help assess the potential downstream response and begin the mapping of the granulosa cell transcriptome in relation to FSH. This information is a key feature to help discriminate between the effects of FSH and LH, or to elucidate the overlapping of insulin-like growth factor 1 and FSH in the granulosa mitogenic response. PMID- 29529393 TI - Asthma and rhinitis among Chinese children - Indoor and outdoor air pollution and indicators of socioeconomic status (SES). AB - BACKGROUND: Few data exist on asthma and rhinitis across China in relation to indoor and outdoor air pollution, climate and socioeconomic factors. The main aim was to study associations between asthma, rhinitis and current respiratory symptoms among pre-school children across China and selected indoor and outdoor exposure and indicators of socio-economic status (SES) in mutually adjusted models. METHODS: Chinese children (3-6 yr.) (n = 39,782) were recruited from randomly selected day care centres in seven cities in China. Data on asthma, respiratory symptoms, rhinitis, indoor and outdoor exposure at home and SES were assessed by a parentally administered questionnaire. Lifetime mean ambient temperature, PM10, NO2, and GDP per capita on city level were calculated. RESULTS: Totally 7.4% had ever doctors' diagnosed (DD) asthma and 8.7% DD rhinitis, 19.7% had current wheeze, 45.0% rhinitis and 16.9% cough. DD-asthma was associated with ambient temperature (OR = 1.15, 95% CI 1.11-1.20 per degrees C), NO2 (OR = 1.16, 95% CI 1.02-1.33 per 10 MUg/m3), indoor mould/dampness (OR = 1.25, 95% CI 1.13-1.39) and living near major roads (OR = 1.13, 95% CI 1.02 1.25). DD-rhinitis was associated with ambient temperature (OR = 1.07, 95% CI 1.05-1.10 per degrees C), NO2 (OR = 1.20, 95% CI 1.09-1.32 per 10 MUg/m3), GDP (OR = 1.03, 95% CI 1.01-1.06 per 10,000 RenMinBi/year), indoor mould/dampness (OR = 1.23, 95% CI 1.11-1.35), passive smoking (OR = 1.11, 95% CI 1.01-1.21), and living near major roads (OR = 1.14, 95% CI 1.03-1.25). Children in suburban or rural areas, in larger families (>=5 persons) and with prenatal farm exposure had less DD-asthma and DD-rhinitis. CONCLUSIONS: Economic development level of the city, higher SES, ambient temperature, NO2, PM10, traffic air pollution and mould/dampness can be risk factors for asthma and rhinitis and respiratory symptoms among pre-school children in China. Breastfeeding, large family size and early-life farm exposure could be protective factors. PMID- 29529394 TI - The association between plasma big endothelin-1 levels at admission and long-term outcomes in patients with atrial fibrillation. AB - BACKGROUND AND AIMS: The prognostic role of big endothelin-1 (ET-1) in atrial fibrillation (AF) is unclear. We aimed to assess its predictive value in patients with AF. METHODS: A total of 716 AF patients were enrolled and divided into two groups based on the optimal cut-off value of big ET-1 in predicting all-cause mortality. The primary outcomes were all-cause mortality and major adverse events (MAEs). Cox regression analysis and net reclassification improvement (NRI) analysis were performed to assess the predictive value of big ET-1 on outcomes. RESULTS: With the optimal cut-off value of 0.55 pmol/L, 326 patients were classified into the high big ET-1 levels group. Cardiac dysfunction and left atrial dilation were factors related to high big ET-1 levels. During a median follow-up of 3 years, patients with big ET-1 >= 0.55 pmol/L had notably higher risk of all-cause death (44.8% vs. 11.5%, p < 0.001), MAEs (51.8% vs. 17.4%, p < 0.001), cardiovascular death, major bleeding, and tended to have higher thromboembolic risk. After adjusting for confounding factors, high big ET-1 level was an independent predictor of all-cause mortality (hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.46-3.05; p < 0.001), MAEs (HR 2.05, 95% CI 1.50-2.80; p = 0.001), and cardiovascular death (HR 2.44, 95% CI 1.52-3.93; p < 0.001). NRI analysis showed that big ET-1 allowed a significant improvement of 0.32 in the accuracy of predicting the risk of both all-cause mortality and MAEs. CONCLUSIONS: Elevated big ET-1 levels is an independent predictor of long-term all-cause mortality, MAEs, and cardiovascular death in patients with AF. PMID- 29529395 TI - Spectrum effect and spectrum bias in the oscillometric ankle brachial index to diagnose peripheral arterial disease: Clinical implications. AB - BACKGROUND AND AIMS: The diagnostic performance of the oscillometric ankle brachial index (ABI) to detect peripheral arterial disease (PAD) varies among populations, suggesting a spectrum effect. When this heterogeneity modifies post test probabilities, a spectrum bias arises. This study evaluates the presence and influence of spectrum effect and spectrum bias on test performance and clinical decisions. METHODS: Oscillometric and Doppler ABI were compared in two settings: Primary-Care (333 legs) and Vascular-Service (41 legs). Spectrum effect was assessed using stratification and logistic regression, while spectrum bias was assessed through graphical and statistical tests based on predictive values and likelihood ratios, respectively. RESULTS: Across subgroups, sensitivity ranged from 61.5% to 90.9%, and specificity from 81.8% to 99.1%. Logistic regression confirmed a spectrum effect in setting, diabetes, smoking status and age (univariate), and setting and diabetes (multivariate model). The positive likelihood ratio ranged from 5.0 to 89.1 in subgroups, leading to a spectrum bias in diabetic, smoking (both subgroups) and age (both subgroups). Therefore, a positive test ruled in differently the disease across subgroups, with a high rate of false positives in diabetic, smoking and >75-year-old patients. The negative likelihood ratio ranged from 0.09 to 0.39 in subgroups, with significant spectrum bias in Primary-Care patients, non-diabetics and smokers. Thus, in these subgroups, a negative test ruled out the disease with less certainty. CONCLUSIONS: Spectrum effect and spectrum bias were found in oscillometric ABI to detect PAD, potentially affecting clinical decisions, especially for positive tests. Information about spectrum variables and the application of specific subgroups indicators are necessary. PMID- 29529396 TI - The role of alternative salience in the derivation of scalar implicatures. AB - Comprehension can be enriched by considering what a speaker could have said but did not; namely, the alternative. For example, "Betty passed some of her exams" can be interpreted as "Betty passed some but not all of her exams". This enriched interpretation is an example of a scalar implicature. We consider whether the salience and use of the alternative are independent processes in the derivation of scalar implicatures or whether use is dependent on salience. Participants completed three sentence interpretation experiments in which the sentences invited scalar implicatures. The experiments used a structural priming paradigm with alternatives and implicatures as primes. We found that (1) adults could be primed to derive scalar implicatures when the alternative was the prime (2) they did so at a rate equal to if the scalar implicature itself were the prime. In the absence of evidence that the use of the alternative can be primed independently of its salience, we conclude that salience and use are not independent processes. Instead, we suggest that when the alternative is sufficiently salient, the implicature will automatically be derived. PMID- 29529397 TI - What are the factors that contribute to road accidents? An assessment of law enforcement views, ordinary drivers' opinions, and road accident records. AB - What are the main contributing factors to road accidents? Factors such as inexperience, lack of skill, and risk-taking behaviors have been associated with the collisions of young drivers. In contrast, visual, cognitive, and mobility impairment have been associated with the collisions of older drivers. We investigated the main causes of road accidents by drawing on multiple sources: expert views of police officers, lay views of the driving public, and official road accident records. In Studies 1 and 2, police officers and the public were asked about the typical causes of road traffic collisions using hypothetical accident scenarios. In Study 3, we investigated whether the views of police officers and the public about accident causation influence their recall accuracy for factors reported to contribute to hypothetical road accidents. The results show that both expert views of police officers and lay views of the driving public closely approximated the typical factors associated with the collisions of young and older drivers, as determined from official accident records. The results also reveal potential underreporting of factors in existing accident records, identifying possible inadequacies in law enforcement practices for investigating driver distraction, drug and alcohol impairment, and uncorrected or defective eyesight. Our investigation also highlights a need for accident report forms to be continuously reviewed and updated to ensure that contributing factor lists reflect the full range of factors that contribute to road accidents. Finally, the views held by police officers and the public on accident causation influenced their memory recall of factors involved in hypothetical scenarios. These findings indicate that delay in completing accident report forms should be minimised, possibly by use of mobile reporting devices at the accident scene. PMID- 29529398 TI - Design and screening of syringic acid analogues as BAX activators-An in silico approach to discover "BH3 mimetics". AB - Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach. Results from the docking studies revealed that, SA1, SA9, SA10, SA14 and SA21 analogues have shown good interaction with BAX trigger site, of which SA10 and SA14 bound specifically with Lys21 at alpha1 helix of BAX, a critical residue involved in BAX activation. All docking calculations of SA analogues were compared with clinically tested BH3 mimetics. In this entire in silico study, SA analogous have performed an ideal binding interactions with BAX compared to BH3 mimetics. Further, in silico point mutation of BAX-Lys21 to Glu21 resulted in structural change in BAX and showed reduced binding energy and hydrogen bond interactions of the selected ligands. Based on these findings, we propose that virtual screening and mutation analysis of BAX is found to be the critical advance method towards the discovery of novel anticancer therapeutics. PMID- 29529399 TI - Angiogenesis in peripheral arterial disease. AB - Peripheral arterial disease (PAD) refers to narrowing of the peripheral arteries and atherosclerosis is the most important cause. In patients with PAD, revascularization is the preferred therapeutic strategy; nonetheless several patients are not deemed candidates for it due to advanced disease or several comorbidities. The main target of therapeutic angiogenesis is to promote development of new arterial vessels and improve perfusion of ischemic tissue. Angiogenic growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), administered intramuscularly or intra-arterially, have been shown to promote angiogenesis and development of collateral vasculature in preclinical studies. However, clinical studies failed to confirm their efficacy in ulcer healing and prevention of amputation, among patients with claudication or critical limb ischemia (CLI). Autologous progenitor cell therapy with bone marrow or adipose-derived progenitor cells administered intra-arterially or intra-muscularly, was shown to improve claudication symptoms and ankle-brachial index in small studies. However, subsequent randomized controlled studies did not demonstrate any beneficial effects of stem cell therapy on amputation rates and survival. Although, therapeutic angiogenesis remains an area of interest in PAD with several ongoing studies of investigational therapies, so far the use of these strategies in clinical practice has not been successful. PMID- 29529400 TI - Employment and weight status: The extreme case of body concern in South Korea. AB - For an industrialized nation, obesity rates in South Korea are extremely low. Yet, reflecting an extremely fat-averse, thin-positive society, efforts to lose weight are now reportedly very common. Since the 1980s, South Korea has experienced an increasingly flexible and insecure labor market which was exacerbated by the 1997 economic recession. In this social and economic setting, body shape and weight status, as human capital, may have gained significant bargaining power in the labor market. Consequently, we propose that Koreans, particularly those who are employed in "stable" jobs (i.e., non-manual and regular jobs), would increasingly engage in intense weight management and reduction activities even when not technically overweight or obese as a means to job security and upward mobility. Using nationally-representative data from the Korean Nutrition and Health Examination Survey (KNHANES), we identify the changing role of weight concerns versus actual body weight in predicting South Korean efforts to lose weight between 2001 (KNHANES-phase 1) and 2007-2009 (phase 4). The patterns were examined by occupation type (manual and non-manual jobs) and status (regular and non-regular jobs). Oaxaca decomposition analysis supported that people's perception of being "fat," rather than actual weight status, was crucial to explaining accelerated weight management efforts in South Korea over the decade (coef. = 0.062 and p-value < .0001 for male with regular work; coef. = 0.031 and p-value = .002 for female with regular work). Occupation status, rather than employment in itself, mattered. Job stability predicted increased effort; the pattern of change through time suggests efforts to invest high levels of effort in appearance positively impacts both employment opportunity and stability. PMID- 29529401 TI - Can we increase organ donation by reducing the disincentives? An experimental analysis. AB - Our research utilizes the experimental economics laboratory to investigate the impact that reducing disincentives has on organ donation. The experiment consists of four treatments across different levels of donation related costs, which reflect the disincentives associated with being an organ donor. Our experimental results indicate that sizable increases in the organ donation rate are achievable if we reduce the level of disincentives present. The largest observed donation rates arise when a financial return is offered for being an organ donor, which is prohibited under the National Organ Transplant Act (NOTA), but nearly 80% of the gains observed under the positive financial incentives can be achieved if all of the disincentives are eliminated. PMID- 29529402 TI - Cognitive Training in Addiction: Does It Have Clinical Potential? PMID- 29529403 TI - Saccadic Eye Movement System and Agency Disorders: Yes, They Are Related! PMID- 29529404 TI - The Neurobiological Correlates of Psychotic-like Experiences in a Community Sample Provide Insights Into the Structure of Psychotic Disorders. PMID- 29529405 TI - Attentional Bias to Reminders of the Deceased as Compared With a Living Attachment in Grieving. AB - BACKGROUND: Grieving individuals demonstrate attentional bias toward reminders of the deceased versus neutral stimuli. We sought to assess bias toward reminders of the deceased versus a living attachment figure and to evaluate similarities and differences in the neural correlates of deceased- and living-related attention. We also sought to identify grief process variables associated with deceased related attentional bias. METHODS: Twenty-five subjects grieving the death of a first-degree relative or partner within 14 months performed an emotional Stroop task, using words related to a deceased or a living attachment figure, and a standard Stroop task, to identify general selective attention, during functional magnetic resonance imaging. Subjects rated word sadness, complicated grief symptoms, depression severity, attachment style, emotional pain, nonacceptance, yearning, and intrusions. RESULTS: We identified an attentional bias to deceased related versus living-related words, independent of age, depression severity/history, loss type, word sadness, medication use, and time since loss. Attentional bias correlated with complicated grief severity and intrusive thinking. A conjunction analysis identified joint activation in the fusiform gyrus, posterior cingulate, and temporal parietal junction across living- and deceased-related attention versus general selective attention. Insecure-avoidant attachment style correlated with decreased engagement of this network in deceased related attention. CONCLUSIONS: We have demonstrated an attentional bias to reminders of the deceased versus a living attachment in grieving. Overlapping neural circuits related to living- and deceased-related attention suggest that the bereaved employ similar processes in attending to the deceased as they do in attending to the living. Deceased-related attentional bias appears to be linked primarily to intrusive thinking about the loss. PMID- 29529406 TI - Separable Effects of Childhood Maltreatment and Adult Adaptive Functioning on Amygdala Connectivity During Emotion Processing. AB - BACKGROUND: Individuals with a history of maltreatment show altered amygdala reactivity to emotional stimuli, atypical frontal regulatory control, and differences in frontolimbic connectivity compared with nonmaltreated controls. However, despite early trauma, many individuals who experience maltreatment show resilience or adaptive functioning in adulthood including positive social, educational, and occupational outcomes. METHODS: The present study used a psychophysiological interaction model to examine the effect of adult adaptive functioning on group differences between maltreated and nonmaltreated adults in task-based amygdala functional connectivity. The task used was a facial emotion matching paradigm. Functional magnetic resonance imaging scans were collected from 41 adults with a history of substantiated childhood maltreatment and 39 nonmaltreated adults who were well matched on demographic variables, all of whom had been studied since childhood. Adaptive functioning was measured with a composite score of success on stage-salient developmental tasks. RESULTS: Consistent with previous research, we found differences in task-related amygdala functional connectivity between the maltreated and nonmaltreated groups. Effects were seen in the left hippocampus, right dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and right thalamus. However, when adult functioning was included in the model, maltreatment-related differences in amygdala connectivity were observed only in the hippocampus. Adult adaptive functioning independently predicted task-related amygdala connectivity in frontal and parietal regions across the entire sample. CONCLUSIONS: These results suggest that frontolimbic functional connectivity is predicted by positive developmental adaptation in this high-risk population, regardless of maltreatment history, whereas intralimbic connectivity (amygdala and hippocampus) is more specifically associated with maltreatment history. PMID- 29529407 TI - Neural Correlates of Emotion Regulation and Adolescent Suicidal Ideation. AB - BACKGROUND: Research on the neural correlates associated with risk for suicidal ideation (SI) has been limited, particularly in one increasingly at-risk group adolescents. Previous research with adolescents indicates that poor emotion regulation skills are linked with SI, but these studies have not previously examined neural activation in service of emotion regulation between those with and without SI histories. METHODS: Here we examine whether SI is associated with neural responses during an emotion regulation functional magnetic resonance imaging task in a group of adolescents (N = 49) 13 to 20 years of age (mean = 16.95). RESULTS: While there were no differences between youths with and without SI in self-reported emotional responses to negative pictures, youths with SI activated the dorsolateral prefrontal cortex more than youths without SI on trials in which they attempted to regulate their emotional responses compared with trials in which they passively viewed negative pictures. In contrast, during passive viewing of negative stimuli, youths with SI activated the dorsolateral prefrontal cortex, temporoparietal junction, and cerebellum less than same-age control subjects. CONCLUSIONS: These findings were robust to control subjects for depression and adversity exposure and are consistent with the idea that youths with SI have disrupted emotion regulation, potentially related to differences in recruitment of top-down control regions. In contrast, youths without SI activated regions implicated in emotion regulation even when not directed to effortfully control their emotional response. This is the first study to examine neural function during emotion regulation as a potential neural correlate of risk for SI in adolescents. PMID- 29529408 TI - Functional Activation During a Cognitive Control Task in Healthy Youth Specific to Externalizing or Internalizing Behaviors. AB - BACKGROUND: Externalizing behaviors are negative behaviors expressed outwardly, including rule breaking, aggression, and risk taking; internalizing behaviors are expressed inwardly, including depression, withdrawal, and anxiety. Such behavior can cause problems in early life and predict difficulties across the lifespan. There is evidence for a relationship between executive function and both externalizing and internalizing. However, although these behaviors occur along a spectrum, there is little neuroimaging research on this relationship in typically developing youth. METHODS: We assessed 41 youth (10-19 years of age) using the Multi-Source Interference Task during functional magnetic resonance imaging and related the findings to self-reported externalizing and internalizing scores as measured by the Youth Self-Report. We performed a general linear model using FSL software; externalizing, internalizing, age, and sex were included in the model. RESULTS: Compared to the control condition, the more difficult Multi-Source Interference Task interference condition was associated with greater engagement of the frontoparietal cognitive control system and decreased engagement of regions in the default mode network, based on a cluster threshold of Z > 3.1 (p = .01). When we examined regions uniquely associated with either internalizing or externalizing, we found that within the same group of subjects, higher externalizing behavior was associated with hyperactivity in the parietal lobe; in contrast, higher internalizing behavior was associated with increased activation in the medial prefrontal cortex. CONCLUSIONS: These findings suggest that externalizing and internalizing may be associated with altered, but different, patterns of activation during cognitive control. This has implications for our understanding of the relationship between cognitive control and behavioral problems in youth. PMID- 29529409 TI - Machine Learning of Functional Magnetic Resonance Imaging Network Connectivity Predicts Substance Abuse Treatment Completion. AB - BACKGROUND: Successfully treating illicit drug use has become paramount, yet elusive. Devising specialized treatment interventions could increase positive outcomes, but it is necessary to identify risk factors of poor long-term outcomes to develop specialized, efficacious treatments. We investigated whether functional network connectivity (FNC) measures were predictive of substance abuse treatment completion using machine learning pattern classification of functional magnetic resonance imaging data. METHODS: Treatment-seeking stimulant- or heroin dependent incarcerated participants (n = 139; 89 women) volunteered for a 12-week substance abuse treatment program. Participants performed a response inhibition Go/NoGo functional magnetic resonance imaging task prior to onset of the substance abuse treatment. We tested whether FNC related to the anterior cingulate cortex would be predictive of those who would or would not complete a 12-week substance abuse treatment program. RESULTS: Machine learning pattern classification models using FNC between networks incorporating the anterior cingulate cortex, striatum, and insula predicted which individuals would (sensitivity: 81.31%) or would not (specificity: 78.13%) complete substance abuse treatment. FNC analyses predicted treatment completion above and beyond other clinical assessment measures, including age, sex, IQ, years of substance use, psychopathy, anxiety and depressive symptomatology, and motivation for change. CONCLUSIONS: Aberrant neural network connections predicted substance abuse treatment outcomes, which could illuminate new targets for developing interventions designed to reduce or eliminate substance use while facilitating long-term outcomes. This work represents the first application of machine learning models of FNC analyses of functional magnetic resonance imaging data to predict which substance abusers would or would not complete treatment. PMID- 29529410 TI - Nicotine Abstinence Influences the Calculation of Salience in Discrete Insular Circuits. AB - BACKGROUND: Insular subdivisions show distinct patterns of resting-state functional connectivity (rsFC) with specific brain regions, each with different functional significance. Seeds in these subdivisions are employed to characterize the effects of acute nicotine abstinence on rsFC between insula subdivisions and brain networks implicated in addiction and attentional control. METHODS: In a within-subjects design, resting-state blood oxygen level-dependent data were collected from treatment-seeking smokers (N= 20) following smoking satiety and again following 48 hours of nicotine abstinence. Three right hemisphere insular regions of interest (dorsal, ventral, and posterior) served as seeds for analyses. Indices of both static and dynamic rsFC were obtained and correlated with indices of subjective withdrawal and behavioral performance. RESULTS: Abstinence-induced physiological, subjective, and cognitive differences were observed. Overall dynamic rsFC was reduced during abstinence, and circuits containing each insular seed showed changes in rsFC as a function of nicotine abstinence. Specifically, dorsal and posterior insular connections to the default mode and salience networks were enhanced, while a previously undescribed ventral insular connection to the executive control network was reduced. Further, static rsFC was significantly correlated with subjective ratings of aversive affect and withdrawal in the modified ventral and posterior insular-seeded circuits. CONCLUSIONS: As predicted, divergent connections between insula subdivisions and anticorrelated resting brain networks were observed during abstinence. These changes reflect an attentional bias toward aversive affective processing and not directly away from exogenous cognitive processing, suggesting a coordinated modulation of circuits associated with interoceptive and affective processing that instantiates an aversive state during nicotine abstinence. PMID- 29529411 TI - Working Memory Training Improves Alcohol Users' Episodic Future Thinking: A Rate Dependent Analysis. AB - BACKGROUND: Episodic thinking, whether past or future, uses similar neural machinery, and individuals with alcohol dependence have clear challenges with both. Moreover, alcohol-dependent individuals' narrowed temporal window likely gives rise to greater valuation of immediate rewards. We aimed to strengthen working memory (WM) in alcohol-dependent individuals and measure performance on near-transfer (novel WM) and far-transfer delay discounting (DD) tasks, including episodic future thinking (EFT) performance. Importantly, heterogeneous intervention responses could obscure a treatment effect due to individuals' baseline differences. Therefore, we considered WM, DD, and EFT DD scores using rate-dependent analyses. METHODS: A total of 50 alcohol-dependent individuals received either 20 active (Trained) or sham (Control) WM training sessions using the Cogmed adaptive WM training program. Participants completed a near-transfer novel WM task and far-transfer DD and EFT DD tasks before and after training. RESULTS: Active WM training improved performance on the near-transfer task. As determined by Oldham's correlation [rmean(x,y),y-x], initially low near-transfer task scores improved more than initially high scores (i.e., rate dependence) in the Trained group only. Moreover, Trained group individuals with the highest rates of EFT DD at baseline rate-dependently decreased following training, whereas WM training had no effect on DD alone. CONCLUSIONS: These data support the notion that WM training improves near-transfer task performance and may enhance the effects of EFT DD in a subset of alcohol-dependent individuals trapped within the narrowest temporal window. Rate-dependent changes highlight that we should attend to baseline performance to better identify individuals who would most benefit from an intervention. PMID- 29529412 TI - Transsaccadic Perception Deficits in Schizophrenia Reflect the Improper Internal Monitoring of Eye Movement Rather Than Abnormal Sensory Processing. AB - BACKGROUND: Symptoms of psychosis in schizophrenia reflect disturbances in sense of agency-difficulty distinguishing internally from externally generated sensory and perceptual experiences. One theory attributes these anomalies to a disruption in corollary discharge (CD), an internal copy of generated motor commands used to distinguish self-movement-generated sensations from externally generated stimulation. METHODS: We used a transsaccadic shift detection paradigm to examine possible deficits in CD and sense of agency based on the ability to perceive visual changes in 31 schizophrenia patients (SZPs) and 31 healthy control subjects. We derived perceptual measures based on manual responses indicating the transsaccadic target shift direction. We also developed a distance-from-unity line measure to quantify use of CD versus purely sensory (visual) information in evaluating visual changes in the environment after an eye movement. RESULTS: SZPs had higher perceptual thresholds in detecting shift of target location than healthy control subjects, regardless of movement direction or amplitude. Despite producing similar hypometric saccades, healthy control subjects overestimated target location, whereas SZPs relied more on the experienced visual error and consequently underestimated the target position. We show that in SZPs the postsaccadic judgment of the initial target location was largely aligned with the measure based only on visual error, suggesting a deficit in the use of CD. This CD deficit also correlated with positive schizophrenia symptoms and disturbances in sense of agency. CONCLUSIONS: These results provide a novel approach in quantifying abnormal use of CD in SZPs and provide a framework to distinguish deficits in sensory processing versus defects in the internal CD-based monitoring of movement. PMID- 29529414 TI - Effective Connectivity in Depression. AB - BACKGROUND: Resting-state functional connectivity reflects correlations in the activity between brain areas, whereas effective connectivity between different brain areas measures directed influences of brain regions on each other. Using the latter approach, we compare effective connectivity results in patients with major depressive disorder (MDD) and control subjects. METHODS: We used a new approach to the measurement of effective connectivity, in which each brain area has a simple dynamical model, and known anatomical connectivity is used to provide constraints. This helps the approach to measure the effective connectivity between the 94 brain areas parceled in the automated anatomical labeling (AAL2) atlas, using resting-state functional magnetic resonance imaging. Moreover, we show how the approach can be used to measure the differences in effective connectivity between different groups of individuals, using as an example effective connectivity in the healthy brain and in individuals with depression. The first brainwide resting-state effective-connectivity neuroimaging analysis of depression, with 350 healthy individuals and 336 patients with major depressive disorder, is described. RESULTS: Key findings are that the medial orbitofrontal cortex, implicated in reward and subjective pleasure, has reduced effective connectivity from temporal lobe input areas in depression; that the lateral orbitofrontal cortex, implicated in nonreward, has increased activity (variance) in depression, with decreased effective connectivity to and from cortical areas contralateral to language-related areas; and that the hippocampus, implicated in memory, has increased activity (variance) in depression and increased effective connectivity from the temporal pole. CONCLUSIONS: Measurements of effective connectivity made using the new method provide a new approach to causal mechanisms in the brain in depression. PMID- 29529415 TI - Neuronal autophagy and intercellular regulation of homeostasis in the brain. AB - Neurons are particularly dependent on robust quality control pathways to maintain cellular homeostasis and functionality throughout their extended lifetime. Failure to regulate protein and organelle integrity is linked to devastating neurodegenerative diseases. Autophagy is a lysosomal degradation pathway that maintains homeostasis by recycling damaged or aged cellular components. Autophagy has important functions in development of the nervous system, as well as in neuronal function and survival. In fact, defects in autophagy underlie neurodegeneration in mice and humans. Here, we review the compartment-specific dynamics and functions for autophagy in neurons. Emerging evidence suggests novel pathways for the intercellular coordination of quality control pathways between neurons and glia to maintain homeostasis in the brain. PMID- 29529413 TI - Correlation Between Levels of Delusional Beliefs and Perfusion of the Hippocampus and an Associated Network in a Non-Help-Seeking Population. AB - BACKGROUND: Delusions are a defining and common symptom of psychotic disorders. Recent evidence suggests that subclinical and clinical delusions may represent distinct stages on a phenomenological and biological continuum. However, few studies have tested whether subclinical psychotic experiences are associated with neural changes that are similar to those observed in clinical psychosis. For example, it is unclear if overactivity of the hippocampus, a replicated finding of neuroimaging studies of schizophrenia, is also present in individuals with subclinical psychotic symptoms. METHODS: To investigate this question, structural and pulsed arterial spin labeling scans were collected in 77 adult participants with no psychiatric history. An anatomical region of interest approach was used to extract resting perfusion of the hippocampus, and 15 other regions, from each individual. A self-report measure of delusional ideation was collected on the day of scanning. RESULTS: The level of delusional thinking (number of beliefs [r = .27, p = .02]), as well as the associated level of distress (r = .29, p = .02), was significantly correlated with hippocampal perfusion (averaged over right and left hemispheres). The correlations remained significant after controlling for age, hippocampal volume, symptoms of depression and anxiety, and image signal-to noise ratio, and they were confirmed in a voxelwise regression analysis. The same association was observed in the thalamus and parahippocampal, lateral temporal, and cingulate cortices. CONCLUSIONS: Similar to patients with schizophrenia, non help-seeking individuals show elevated perfusion of a network of limbic regions in association with delusional beliefs. PMID- 29529417 TI - Undergraduate psychiatry in India: A SWOT analysis. AB - Psychiatric disorders are highly prevalent and remains a huge burden on the society. In spite of that persons with mental illness are marginalized and mental health is largely being neglected. There is an acute shortage of mental health professionals in India, and also there is inadequate exposure to psychiatry during the medical undergraduate training in India. Moreover, the perception towards psychiatry and psychiatrists is not favorable among medical fraternity and policy makers. This is reflected in the fact that in spite of clearly deficient undergraduate psychiatry curriculum, no steps have been taken towards improving it and recommendations are not being implemented in true spirit. This review tries to identify the gaps in undergraduate curriculum, present a SWOT analysis of current situation and recommend the possible ways to address the deficiencies particularly in India. PMID- 29529416 TI - Axonal transport and maturation of lysosomes. AB - Lysosomes perform degradative functions that are important for all cells. However, neurons are particularly dependent on optimal lysosome function due to their extremes of longevity, size and polarity. Axons in particular exemplify the major spatial challenges faced by neurons in the maintenance of lysosome biogenesis and function. What impact does this have on the regulation and functions of lysosomes in axons? This review focuses on the mechanisms whereby axonal lysosome biogenesis, transport and function are adapted to meet neuronal demand. Important features include the dynamic relationship between endosomes, autophagosomes and lysosomes as well as the transport mechanisms that support the movement of lysosome precursors in axons. A picture is emerging wherein intermediates in the lysosome maturation processes that would only exist transiently within the crowded confines of a neuronal cell body are spatially and temporally separated over the extreme distances encountered in axons. Axons may thus offer significant opportunities for the analysis of the mechanisms that control lysosome biogenesis. Insights from the genetics and pathology of human neurodegenerative diseases furthermore emphasize the importance of efficient axonal transport of lysosomes and their precursors. PMID- 29529418 TI - High prevalence of depressive symptoms in a national sample of adults in Indonesia: Childhood adversity, sociodemographic factors and health risk behaviour. AB - BACKGROUND: The aim of this study was to investigate depressive symptoms and their association with sociodemographic factors, stressors and support, including childhood adversity, health status risk and behaviour in Indonesia. METHOD: In a cross-sectional national population survey in 2014-15 in Indonesia, 31442 adults (mean age 37.3 years, SD = 14.9, age range 15-101 years) responded to the Centers for Epidemiologic Studies Depression Scale (CES-D-10) and various other measures. RESULTS: Overall, 15.0% of participants reported moderate and 6.9% severe depressive symptoms, or 21.8% moderate or severe depressive symptoms (21.4% among men and 22.3% among women). In multivariable logistic regression among both men and women, sociodemographic factors (younger age, poor subjective economic background, being unemployed, residing in Java and main island groups), stressors (childhood hunger and poor or fair self-rated health status and having experienced disasters), lack of social trust and religiosity, having one or more chronic conditions, tobacco use and soft drink consumption were positively and obesity negatively associated with moderate or severe depressive symptoms. CONCLUSION: High rates (21.8%) of depressive symptoms were found. Several risk factors including sociodemographic factors such as younger age, stressors, lack of social support, health risk status and behaviour variables were identified which can be utilized in guiding interventions. PMID- 29529419 TI - To collapse when there are no other means to cope. PMID- 29529420 TI - Very early onset schizophrenia diagnostic challenge and cognitive remediation-A case report. PMID- 29529421 TI - Clozapine use in geriatric patients- Challenges. AB - Clozapine is the first second generation antipsychotic with different receptor profile of action. Clozapine is the most efficacious drug for the treatment of psychotic disorder and is the drug of choice in treatment resistant schizophrenia. Clozapine is used in elderly patients infrequently owing to its adverse effects profile and tolerability. There is paucity of literature with respect to clozapine use in late life. In this narrative review, we discuss clozapine use in elderly and challenges associated with its use. PMID- 29529422 TI - Testing cryopreserved European eel sperm for hybridization (A. japonica * A. anguilla). AB - The objective of this study was to assess impact of cryopreserved European eel sperm and Japanese eel native sperm on early fertilization, hatch, survival, and malformation rates of larvae, as well as develop molecular techniques to distinguish different eel species. Eggs from Japanese eel females (Anguilla japonica) were artificially fertilized with sperm of Japanese eel males and cryopreserved sperm from European eel (A. anguilla, extender was modified Tanaka solution and methanol as cryoprotectant). There were no statistical differences (p > 0.05) among the measured parameters such as fertilization, hatch and survival after 10 days post-hatch rates due to large individual differences. The malformation rate of larvae compared to the hatching rate was higher in cryopreserved groups than in the control indicating that the methodology needs further refinement. Genetic analyses (PCR-RFLP, PCR-HRM) proved a clear result in the detection of paternal contribution in hybridization between the Japanese and the European eel and applied PCR-HRM method is a quick and cost effective tool to identify illegally imported A. anguilla at the glass eel stage, which can be transported from Europe to Asia. PMID- 29529424 TI - Iodine deficiency in pregnancy: Still a health issue for the women of Cassino city, Italy. AB - OBJECTIVE: The World Health Organization, the United Nations Children's Fund, and the International Council for the Control of Iodine Deficiency Disorders recommend a median urinary iodine concentration (UIC) in pregnant women between 150 ug/L and 249 ug/L. In the present study, we evaluated whether in the urban area of Cassino (central Italy), after a national salt iodination program (30 mg/kg) was introduced in 2005, the increased demand of iodine during pregnancy was satisfied. METHODS: Between January 2016 and April 2017, 99 pregnant women were enrolled to evaluate UIC in spot urine samples, serum level of thyrotropin, free thyroxine, antithyroglobulin and antithyroperoxidase autoantibodies, and thyroid volume by ultrasonography. Eighty clinically healthy non-pregnant women were evaluated as controls. RESULTS: The median UIC was of 97.7 ug/L and 110.3 ug/L, respectively, in control and pregnant women. A significant increase (P < 0.001) of median thyroid volume was found in pregnant women, relative to control women, being, respectively, 10.4 mL (range 3.68-19.49 mL) and 7.16 mL (range 2.57 14.00 mL). A positive correlation was found between thyroid volume and anthropometric parameters, and an inverse correlation was identified between free thyroxine serum levels and anthropometric parameters. CONCLUSIONS: This observational study found that the majority of pregnant women and their fetuses appear not to be protected from the detrimental consequences of iodine deficiency. Therefore, the identification of new strategies to increase the knowledge and awareness of the general population regarding the beneficial effects of iodine supplementation during pregnancy is highly required. PMID- 29529423 TI - The genetics of adiposity. AB - Genome-wide discovery efforts have identified more than 500 genetic loci associated with adiposity traits. The vast majority of these loci were found through large-scale meta-analyses for body mass index (BMI) and waist-to-hip ratio (WHR), and in European ancestry populations. However, alternative approaches, focusing on non-European ancestry populations, more refined adiposity measures, and low-frequency (minor allele frequency (MAF)<5%) coding variants, identified additional novel loci that had not been identified before. Loci associated with overall obesity implicate pathways that act in the brain, whereas loci associated with fat distribution point to pathways involved in adipocyte biology. Pinpointing the causal gene within each locus remains challenging, but is a critical step towards translation of genome-wide association study (GWAS) loci into new biology. Ultimately, new genes may provide pharmacological targets for the development of weight loss drugs. PMID- 29529425 TI - Investigation of the bacteriophage community in induced lysates of undefined mesophilic mixed-strain DL-cultures using classical and metagenomic approaches. AB - To investigate the notion that starter cultures can be a reservoir of bacteriophages (phages) in the dairy environment, strains of three DL-starters (undefined mesophilic mixed-strain starters containing Lactococcus lactis subsp. lactis biovar. diacetylactis and Leuconostoc species) were selected and induced by mitomycin C, and the whole starters were induced spontaneously as well as by mitomycin C. Frequency of induction of 17%, 26% and 12% was estimated among the isolates of the three starters, with majority of the induced phages mostly showing morphological similarity to known P335 phages, and with a fraction of them showing atypical features. Sequences of P335 quasi-species phages were found to be the most frequent entities in almost all metaviromes derived from the induced lysates. However, sequences of Sk1virus phages (previously 936 phages) were emerged as the predominant entities following spontaneous induction of one of the starters, suggesting a phage-carrier state. Sequences of other phages such as 949, 1706, C2virus (previously c2 phages) and Leuconostoc species could also be observed but with a lower relative frequency. Taken together, the majority of the P335 quasi-species phages could represent the induced viral community of the starters and the remaining phage groups mainly represent the background ambient viral community. PMID- 29529427 TI - Identifying novel applications of dialectical behavior therapy: considering emotion regulation and parenting. AB - Dialectical behavior therapy (DBT) is an effective treatment for an increasing number of mental disorders. Its increased application to a range of disorders has been prompted by the recognition that DBT targets emotion dysregulation, which is a transdiagnostic feature underlying several forms of psychopathology. More recently, DBT has been used to target additional clinically relevant domains that are outside diagnostically bound categories, such as improving parenting quality as a means of preventing psychopathology in children of parents with psychopathology. As the ability to regulate emotions is critical to parenting, this paper uses the connection between DBT, emotion regulation, and parenting as an illustration of how focusing on mechanistic features by which DBT is effective aids in strategically identifying areas by which DBT may be a highly useful treatment option. PMID- 29529426 TI - Source identification of heavy metals in peri-urban agricultural soils of southeast China: An integrated approach. AB - Intensive human activities, in particular agricultural and industrial production have led to heavy metal accumulation in the peri-urban agricultural soils of China threatening soil environmental quality and agricultural product security. A combination of spatial analysis (SA), Pb isotope ratio analysis (IRA), input fluxes analysis (IFA), and positive matrix factorization (PMF) model was successfully used to assess the status and sources of heavy metals in typical peri-urban agricultural soils from a rapidly developing region of China. Mean concentrations of Cd, As, Hg, Pb, Cu, Zn and Cr in surface soils (0-20 cm) were 0.31, 11.2, 0.08, 35.6, 44.8, 119.0 and 97.0 mg kg-1, respectively, exceeding the local background levels except for Hg. Spatial distribution of heavy metals revealed that agricultural activities have significant influence on heavy metal accumulation in the surface soils. Isotope ratio analysis suggested that fertilization along with atmospheric deposition were the major sources of heavy metal accumulation in the soils. Based on the PMF model, the relative contribution rates of the heavy metals due to fertilizer application, atmospheric deposition, industrial emission, and soil parent materials were 30.8%, 33.0%, 25.4% and 10.8%, respectively, demonstrating that anthropogenic activities had significantly higher contribution than natural sources. This study provides a reliable and robust approach for heavy metals source apportionment in this particular peri-urban area with a clear potential for future application in other regions. PMID- 29529428 TI - Multigenerational exposure of Folsomia candida to silver: Effect of different contamination scenarios (continuous versus pulsed and recovery). AB - Effects of pollutants are mostly assessed using standard testing procedures, which cover a fraction of the animals' life cycle. Although, in nature species are exposed during multiple generations of sub-lethal doses of persistent chemicals. In the present study, we focused on the multigenerational (MG) effects of silver in Folsomia candida during 6 generations using the EC50 for reproduction as exposure concentration. We tested 9 different exposure scenarios, going from continuous 6 generations Ag exposure over pulse exposure (i.e. one generation clean, next contaminated, next clean etc.) to gradually increasing the number of exposure generations, with a final transfer to clean media. The biological endpoints assessed included survival, reproduction and size, with reproduction being the most sensitive. The biological response depended on the specific MG scenario, e.g. the 6 Ag MG caused a decreased number of juveniles from F4, whereas the pulse exposure experienced an increase in reproductive output when in clean soil. It is uncertain whether Ag causes transgenerational effects, but the reproduction levels in both pulse exposures are lower than in continuous control over the 6 generations which could be due to transference of Ag by the maternal generation. Overall, population size distribution seemed to indicate a delay in time for egg laying, with close relationship between adult survival, organisms size and reproduction output. Size monitoring allowed significant added interpretation possibilities and we strongly recommend the addition of this endpoint to the standard guideline. The smaller observed size range can have implications in terms of adaptation potential, carrying associated increased risk. PMID- 29529429 TI - Comparison of prediction methods for oxygen-18 isotope composition in shallow groundwater. AB - Groundwater is the most important source of drinking water in the world. Therefore, information on the quality and quantity is important, as is new information related to the characteristics of the aquifer and the recharge area. In the present study we focused on the isotope composition of oxygen (delta18O) in groundwater, which is a natural tracer and provides a better understanding of the water cycle, in terms of origin, dynamics and interaction. The groundwater delta18O at 83 locations over the entire Slovenian territory was studied. Each location was sampled twice during the period 2009-2011. Geostatistical tools (such us ordinary kriging, simple and multiple linear regressions, and artificial neural networks were used and compared to select the best tool. Measured values of delta18O in the groundwater were used as the dependent variable, while the spatial characteristics of the territory (elevation, distance from the sea and average annual precipitation) were used as independent variables. Based on validation data sets, the artificial neural network model proved to be the most suitable method for predicting delta18O in the groundwater, since it produced the smallest deviations from the real/measured values in groundwater. PMID- 29529430 TI - Transgenerational effects and recovery of microplastics exposure in model populations of the freshwater cladoceran Daphnia magna Straus. AB - The environmental contamination by microplastics is a global challenge to ecosystem and human health, and the knowledge on the long-term effects of such particles is limited. Thus, the effects of microplastics and post-exposure recovery were investigated over 4 generations (F0, F1, F2, F3) using Daphnia magna as model. Effect criteria were parental mortality, growth, several reproductive parameters, and population growth rate. Microplastics exposure (0.1mg/l of pristine polymer microspheres 1-5MUm diameter) caused parental mortality (10-100%), and significantly (p<=0.05) decreased growth, reproduction, and population growth rate leading to the extinction of the microplastics-exposed model population in the F1 generation. Females descending from those exposed to microplastics in F0 and exposed to clean medium presented some recovery but up to the F3 generation they still had significantly (p<=0.05) reduced growth, reproduction, and population growth rate. Overall, these results indicate that D. magna recovery from chronic exposure to microplastics may take several generations, and that the continuous exposure over generations to microplastics may cause population extinction. These findings have implications to aquatic ecosystem functioning and services, and raise concern on the long-term animal and human exposure to microplastics through diverse routes. PMID- 29529431 TI - Increased anthropogenic disturbance and aridity reduce phylogenetic and functional diversity of ant communities in Caatinga dry forest. AB - Anthropogenic disturbance and climate change are major threats to biodiversity. The Brazilian Caatinga is the world's largest and most diverse type of seasonally dry tropical forest. It is also one of the most threatened, but remains poorly studied. Here, we analyzed the individual and combined effects of anthropogenic disturbance (three types: livestock grazing, wood extraction, and miscellaneous use of forest resources) and increasing aridity on taxonomic, phylogenetic and functional ant diversity in the Caatinga. We found no aridity and disturbance effects on taxonomic diversity. In spite of this, functional diversity, and to a lesser extent phylogenetic diversity, decreased with increased levels of disturbance and aridity. These effects depended on disturbance type: livestock grazing and miscellaneous resource use, but not wood extraction, deterministically filtered both components of diversity. Interestingly, disturbance and aridity interacted to shape biodiversity responses. While aridity sometimes intensified the negative effects of disturbance, the greatest declines in biodiversity were in the wettest areas. Our results imply that anthropogenic disturbance and aridity interact in complex ways to endanger biodiversity in seasonally dry tropical forests. Given global climate change, neotropical semi arid areas are habitats of concern, and our findings suggest Caatinga conservation policies must prioritize protection of the wettest areas, where biodiversity loss stands to be the greatest. Given the major ecological relevance of ants, declines in both ant phylogenetic and functional diversity might have downstream effects on ecosystem processes, insect populations, and plant populations. PMID- 29529432 TI - Chronic exposure to low concentrations of lead induces metabolic disorder and dysbiosis of the gut microbiota in mice. AB - : Lead (Pb) is one of the most prevalent toxic, nonessential heavy metals that can contaminate food and water. In this study, effects of chronic exposure to low concentrations of Pb on metabolism and gut microbiota were evaluated in mice. It was observed that exposure of mice to 0.1mg/L Pb, supplied via drinking water, for 15weeks increased hepatic TG and TCH levels. The levels of some key genes related to lipid metabolism in the liver increased significantly in Pb-treated mice. For the gut microbiota, at the phylum level, the relative abundance of Firmicutes and Bacteroidetes changed obviously in the feces and the cecal contents of mice exposed to 0.1mg/L Pb for 15weeks. In addition, 16s rRNA gene sequencing further discovered that Pb exposure affected the structure and richness of the gut microbiota. Moreover, a 1H NMR metabolic analysis unambiguously identified 31 metabolites, and 15 metabolites were noticeably altered in 0.1mg/L Pb-treated mice. Taken together, the data indicate that chronic Pb exposure induces dysbiosis of the gut microbiota and metabolic disorder in mice. CAPSULE: Chronic Pb exposure induces metabolic disorder, dysbiosis of the gut microbiota and hepatic lipid metabolism disorder in mice. PMID- 29529433 TI - Polystyrene microplastics induce gut microbiota dysbiosis and hepatic lipid metabolism disorder in mice. AB - Microplastic (MP) has become a concerning global environmental problem. It is toxic to aquatic organisms and can spread through the food chain to ultimately pose a threat to humans. In the environment, MP can interact with microbes and act as a microbial habitat. However, effects of polystyrene MP on the gut microbiota in mammals remain unclear. Here, male mice were exposed to two different sizes of polystyrene MP for 5 weeks to explore its effect. We observed that oral exposure to 1000 MUg/L of 0.5 and 50 MUm polystyrene MP decreased the body, liver and lipid weights in mice. Mucus secretion in the gut decreased in both sizes of polystyrene MP-treated groups. Regarding the gut microbiota, at the phylum level, polystyrene MP exposure decreased the relative abundances of Firmicutes and alpha-Proteobacteria in the feces. Furthermore, high throughput sequencing of the V3-V4 region of the 16S rRNA gene revealed significant changes in the richness and diversity of the gut microbiota in the cecums of polystyrene MP-treated mice. At the genus level, a total of 6 and 8 types of bacteria changed in the 0.5 and 50 MUm polystyrene MP-treated groups, respectively. Furthermore, an operational taxonomic unit (OTU) analysis identified that 310 and 160 gut microbes were changed in the 0.5 and 50 MUm polystyrene MP-treated groups, respectively. In addition, the hepatic triglyceride (TG) and total cholesterol (TCH) levels decreased in both 1000 MUg/L 0.5 and 50 MUm polystyrene MP-treated groups. Correspondingly, the relative mRNA levels of some key genes related to lipogenesis and TG synthesis decreased in the liver and epididymal fat. These results indicated that polystyrene MP could modify the gut microbiota composition and induce hepatic lipid disorder in mice; while the mouse is a common mammal model, consequently, the health risks of MP to animals should not be ignored. PMID- 29529434 TI - Sediment composition mediated land use effects on lowland streams ecosystems. AB - Despite the widely acknowledged connection between terrestrial and aquatic ecosystems, the contribution of runoff to the sediment composition in lowland stream deposition zones and the subsequent effects on benthic invertebrates remain poorly understood. The aim of this study was therefore to investigate the mechanisms by which runoff affects sediment composition and macroinvertebrates in deposition zones of lowland stream ecosystems. To this end, sediment from runoff and adjacent instream deposition zones from streams with different land use was chemically characterized and the biological effects were assessed at the species, community and ecosystem level. Runoff and deposition zone sediment composition as well as biological responses differed clearly between forest and agricultural streams. The stream deposition zone sediment C/N ratio reflected the respective runoff sediment composition. Deposition zones in the forest stream had a higher C/N ratio in comparison to the agricultural streams. Growth of Hyalella azteca and reproduction of Asellus aquaticus were higher on forest stream sediment, whereas chironomids and worms suffered less mortality on the agricultural sediments containing only natural food. The forest stream deposition zones showed higher values for indices indicative of biological integrity and had a lower sediment oxygen demand. We concluded that agricultural land use affects lowland stream ecosystem deposition zones at the species, community and ecosystem level via altered food quality (C/N ratio) and higher oxygen demand of the sediment. PMID- 29529435 TI - Assessment of drugs and personal care products biomarkers in the influent and effluent of two wastewater treatment plants in Ho Chi Minh City, Vietnam. AB - Wastewater samples were collected at the influent and effluent of two wastewater treatment plants (WWTPs) in Ho Chi Minh City, Vietnam and then pooled to daily samples over multiple days using 6 hourly grab samples. The aim was to provide a first assessment of the occurrence, consumption, removal and release of a range of organic chemicals including pharmaceuticals and personal care products (PPCPs), illicit drugs, an artificial sweetener, tobacco and its metabolites and alcohol biomarkers (referred to here as DPCPBs). Nineteen DPCPBs were detected via direct measurement of filtered wastewater on LC-MS/MS with a concentration range of 0.05-38MUg/L. Caffeine and paracetamol were the most prominent compounds detected in the influent, while acesulfame was found at the highest concentration in the effluent of both WWTPs. Mean concentrations of metabolites of tobacco (nicotine: 7.6MUg/L, cotinine: 1.4MUg/L and hydroxycotinine: 1.7MUg/L) and alcohol (ethyl sulphate: 3.3MUg/L) were lower than those of European countries. Consumption rates based on daily mass loads and catchment population data obtained from the WWTPs were <10g/d/1000 pp for the majority of selected PPCPs, except for caffeine (300g/d/1000 pp) and paracetamol (320g/d/1000 pp). Consumption rates for codeine and methamphetamine were 0.05g/d/1000 pp and 0.17g/d/1000 pp, respectively. Consistently across the two WWTPs most of the chemicals (10) showed >80% apparent removal rate from the wastewater, three chemicals showed apparent removal efficiency of approximately 50%; and the removal efficiency could not be assessed for 5 compounds due to their low concentrations in the influent. Based on the fraction of treated and untreated wastewater (10:90) that is released into the receiving environment we estimated a total discharge of approximately 170kg per day of DPCPBs in Ho Chi Minh City. PMID- 29529436 TI - Sustainability of the use of natural capital in a city: Measuring the size and depth of urban ecological and water footprints. AB - The Sustainable Development Goals (SDGs) are limited in their ability to measure progress towards environmental sustainability especially at the city level. The aim of this paper is to provide insights into an integrated assessment of urban sustainability, with emphasis on the significance of the maintenance of natural capital stocks. The use of water and land as critical natural capital in Guiyang, a southeast city in China was investigated by bringing together the ecological footprint (EF), water footprint (WF) and corresponding capacity indicators into an improved three-dimensional (i3D) model. Results showed that Guiyang has long been operating in a state of overshoot due to shortage of annual natural capital flows and accumulated depletion of stocks. This is particularly true for land use, whose stocks maintained a relatively stable level of depletion between 2000 and 2014. As of 2014, an EF depth of 6.45 was accumulated. With respect to water use, a shift in the city's role from creditor to debtor was observed in 2004. Industrial use of natural capital has more than tripled over the past 15 years and replaced agriculture to be the main driver of water unsustainability. Overall, Guiyang's economic growth did not show signs of decoupling from the EF and WF. These findings highlight the need for effective policies that would help Guiyang reduce dependency on the use of critical natural capital. Finally, this paper provided an in-depth discussion of the methodological strengths and limitations of the i3D model and concluded that it is able to track the structural and characteristic dynamics of both flows and stocks while avoiding burden shifting across various components within single forms of natural capital from a strong sustainability perspective. Our study enhances understanding of the critical role of natural capital in ensuring urban sustainability and improving human welfare in connection with SDGs. PMID- 29529437 TI - Determination of metal-based nanoparticles in the river Dommel in the Netherlands via ultrafiltration, HR-ICP-MS and SEM. AB - We investigated the occurrence of metal-based nanoparticles in a natural system, the river Dommel in the Netherlands. The river itself is well-studied as far as hydrology and water quality is concerned, easily accessible and contains one major wastewater treatment plant discharging onto this river. We sampled water from various locations along the river and collected samples of influent, effluent and sewage sludge from the wastewater treatment plant. The sampling campaign was carried out in June 2015 and these samples were analysed for seven elements using high-resolution inductively coupled plasma mass spectrometry (HR ICP-MS), ultrafiltration with a sequence of mesh sizes and scanning electron microscopy (SEM). From the results we conclude that there are indeed nanoparticles present in the treatment plant we studied, as we found titanium and gold particles in the influent and effluent. In the river water only 10 to 20% of the mass concentration of titanium, cerium and other elements we examined is made up of free, i.e. unattached, particles with a size smaller than 20 nm or of dissolved material. The rest is attached to natural colloids or is present as individual particles or clusters of smaller particles, as it could be filtered out with 450 nm ultrafilters. We found evidence that there is no appreciable anthropogenic emission of cerium into the river, based on the geochemical relationship between cerium and lanthanum. Besides, the effluent of the treatment plant has lower concentrations of some examined elements than the surface water upstream. The treatment plant discharges much less of these elements than estimated using previous publications. However, a potential diffuse source of titanium dioxide in the form of nanoparticles or of larger particles is their use in paints and coatings, as the concentration of titanium increased considerably in the urbanised area of the river Dommel. PMID- 29529438 TI - The influence of the waterjet propulsion system on the ships' energy consumption and emissions inventories. AB - In this study we consider the problems associated with calculating ships' energy and emission inventories. Various related uncertainties are described in many similar studies published in the last decade, and applying to Europe, the USA and Canada. However, none of them have taken into account the performance of ships' propulsion systems. On the one hand, when a ship uses its propellers, there is no unanimous agreement on the equations used to calculate the main engines load factor and, on the other, the performance of waterjet propulsion systems (for which this variable depends on the speed of the ship) has not been taken into account in any previous studies. This paper proposes that the efficiency of the propulsion system should be included as a new parameter in the equation that defines the actual power delivered by a ship's main engines, as applied to calculate energy consumption and emissions in maritime transport. To highlight the influence of the propulsion system on calculated energy consumption and emissions, the bottom-up method has been applied using data from eight fast ferries operating across the Strait of Gibraltar over the course of one year. This study shows that the uncertainty about the efficiency of the propulsion system should be added as one more uncertainty in the energy and emission inventories for maritime transport as currently prepared. After comparing four methods for this calculation, the authors propose a new method for eight cases. For the calculation of the Main Engine's fuel oil consumption, differences up to 22% between some methods were obtained at low loads. PMID- 29529439 TI - Low doses of six toxicants change plant size distribution in dense populations of Lactuca sativa. AB - Toxicants are known to have negligible or stimulatory, i.e. hormetic, effects at low doses below those that decrease the mean response of a plant population. Our earlier observations indicated that at such low toxicant doses the growth of very fast- and slow-growing seedlings is selectively altered, even if the population mean remains constant. Currently, it is not known how common these selective low dose effects are, whether they are similar among fast- and slow-growing seedlings, and whether they occur concurrently with hormetic effects. We tested the response of Lactuca sativa in complete dose-response experiments to six different toxicants at doses that did not decrease population mean and beyond. The tested toxicants were IAA, parthenin, HHCB, 4-tert-octylphenol, glyphosate, and pelargonic acid. Each experiment consisted of 14,400-16,800 seedlings, 12-14 concentrations, 24 replicates per concentration and 50 germinated seeds per replicate. We analyzed the commonness of selective low-dose effects and explored if toxic effects and hormetic stimulation among fast- and slow-growing individuals occurred at the same concentrations as they occur at the population level. Irrespective of the observed response pattern and toxicant, selective low dose effects were found. Toxin effects among fast-growing individuals usually started at higher doses compared to the population mean, while the opposite was found among slow-growing individuals. Very low toxin exposures tended to homogenize plant populations due to selective effects, while higher, but still hormetic doses tended to heterogenize plant populations. Although the extent of observed size segregation varied with the specific toxin tested, we conclude that a dose-dependent alteration in size distribution of a plant population may generally apply for many toxin exposures. PMID- 29529440 TI - Spatial-temporal patterns of PM2.5 concentrations for 338 Chinese cities. AB - Air pollution has become a major concern in cities worldwide. The present study explores the spatial-temporal patterns of PM2.5 (particles with an aerodynamic diameters <=2.5MUm) and the variation in the attainment rate (the number of cities attaining the national PM2.5 standard each day) at different time-scales based on PM2.5 concentrations. One-year of monitoring was conducted in 338 cities at or above the prefectural level in China. Spatial hot spots of PM2.5 were analyzed using exploratory spatial data analysis. Meteorological factors affecting PM2.5 distributions were analyzed. The results indicate the following: (1) Diurnal variations of PM2.5 exhibited a W-shaped trend, with the lowest value observed in the afternoon. The peak concentrations occurred after the ends of the morning and evening rush hours. (2) Out of 338 cities, 235 exceeded the national annual PM2.5 standards (<=35MUg/m3), with slightly polluted (75-115MUg/m3) cities occupying the greatest proportion. (3) The attainment rate showed an inverted U shape, while there was a U-shaped pattern observed for daily and monthly mean PM2.5. (4) The spatial distribution of PM2.5 concentrations varied greatly, PM2.5 has significant spatial autocorrelation and clustering characteristics. Hot spots for pollution were mainly concentrated in the Beijing-Tianjin-Hebei area and neighboring regions, in part because of the large amount of smoke and dust emissions in this region. However, weather factors (temperature, humidity, and wind speed) also had an effect. In addition, southwest Xinjiang experienced heavy PM2.5 pollution that was mainly caused by the frequent occurrence of sandstorms, although no significant relationship was observed between PM2.5 and meteorological elements in this region. PMID- 29529441 TI - Heat waves in Portugal: Current regime, changes in future climate and impacts on extreme wildfires. AB - Heat waves (HW) can have devastating social, economic and environmental impacts. Together with long-term drought, they are the main factors contributing to wildfires. Surprisingly, the quantitative and objective analysis leading to the identification and characterization of HW in current and future climate conditions as well as its influence on the occurrence of extreme wildfires (EW) has never been performed for Portugal and are the main objectives of this study. For this reason, we assess HW in recent past and future climate based on a consistent high resolution meteorological database and have compared their occurrence with long and reliable, precise and detailed information about Portuguese fire events. Results include the characterization of HW frequency, duration, seasonality and intensity for current and different future climate conditions and their relationship with EW occurrence. We detected 130 HW between 1981 and 2010, concentrated between May and October and highest values in July and August. The highest HW number and duration is found over the Northeast corner and the south of the country while highest amplitudes are typically located in central area. HW characteristics present high inter-annual variability but are clearly associated to the temporal and spatial distribution of EW: 97% of total number of EW were active during an HW, 90% of total EW days were also HW days; 82% of the EW had duration completely contained in the duration of an HW; and, 83% of EW occurred during and in the area affected by HW. Our results also show that HW should increase in number, duration and amplitude, more significantly for RCP 8.5, and for the 30-year periods near the end of the 21st century. Findings of this study will support the definition of climate change adaptation strategies for fire danger and risk management. PMID- 29529442 TI - A meta-analysis of the effects of exposure to microplastics on fish and aquatic invertebrates. AB - Microplastics are present in aquatic ecosystems the world over and may influence the feeding, growth, reproduction, and survival of freshwater and marine biota; however, the extent and magnitude of potential effects of microplastics on aquatic organisms is poorly understood. In the current study, we conducted a meta analysis of published literature to examine impacts of exposure to microplastics on consumption (and feeding), growth, reproduction, and survival of fish and aquatic invertebrates. While we did observe within-taxa negative effects for all four categories of responses, many of the effects summarized in our study were neutral, indicating that the effects of exposure to microplastics are highly variable across taxa. The most consistent effect was a reduction in consumption of natural prey when microplastics were present. For some taxa, negative effects on growth, reproduction and even survival were also evident. Organisms that serve as prey to larger predators, e.g., zooplankton, may be particularly susceptible to negative impacts of exposure to microplastic pollution, with potential for ramifications throughout the food web. Future work should focus on whether microplastics may be affecting aquatic organisms more subtly, e.g., by influencing exposure to contaminants and pathogens, or by acting at a molecular level. PMID- 29529443 TI - Shared reality through social tuning of implicit prejudice. AB - Sharing reality with an interaction partner is a key element of social connections. One way in which shared reality can be formed in an interpersonal situation is through affiliative social tuning. Affliative social tuning occurs when individuals experience a desire to get along with their interaction partner and this affiliative motivation encourages the individual to spontaneously and genuinely align their attitudes and/or behaviors with their interaction partner to achieve a sense of shared reality. In this review, we examine when and how affiliative social tuning of implicit prejudice occurs. We also explore whether individuals garner shared reality by affiliating with ingroup members who seem to hold similar implicit beliefs. PMID- 29529444 TI - Drug Policy in Estonia. AB - The aim of this article was to present a general overview of the health care system as well as pricing and reimbursement environment in Estonia. In Estonia the main stakeholders in the pharmaceutical sector are the Ministry of Social Affairs, the State Agency of Medicine, and the Estonian Health Insurance Fund. The national health insurance scheme is public, and approximately 95% of the population is covered by it. It is a social insurance, and universal and equal access to health care based on national health insurance is granted. The Estonian Health Insurance Fund is financed from social taxes and state budget and is responsible for the reimbursement of pharmaceuticals in the hospital setting. It acts as an advisory body to the Ministry of Social Affairs on the process of reimbursement regarding cost effectiveness. Pharmaceutical products' reimbursement dossiers submission and decisions are dealt with on the state level. Health technology assessment analyses are required by the authorities and the Baltic Guidelines for Economic Evaluations of Pharmaceuticals have to be followed. The reimbursement lists are positive lists only, and the criteria upon which reimbursement decisions are based are officially defined. Revisions of reimbursement are performed depending on the need and they are based on the prices of reference countries. PMID- 29529445 TI - A "Z" shaped flexible stylet to facilitate GlideScope intubation. PMID- 29529446 TI - Frequency and distribution of primary site among gender minority cancer patients: An analysis of U.S. national surveillance data. AB - BACKGROUND: Transgender people and persons with disorders of sex development (DSD) are two separate categories of gender minorities, each characterized by unique cancer risk factors. Although cancer registry data typically include only two categories of sex, registrars have the option of indicating that a patient is transgender or has a DSD. METHODS: Data for primary cancer cases in 46 states and the District of Columbia were obtained from the North American Association of Central Cancer Registries (NAACCR) database for the period 1995-2013. The distributions of primary sites and categories of cancers with shared risk factors were examined separately for transgender and DSD patients and compared to the corresponding distributions in male and female cancer patients. Proportional incidence ratios were calculated by dividing the number of observed cases by the number of expected cases. Expected cases were calculated based on the age- and year of diagnosis-specific proportions of cases in each cancer category observed among male and female patients. RESULTS: Transgender patients have significantly elevated proportional incidence ratios (95% confidence intervals) for viral infection induced cancers compared to either males (2.3; 2.0-2.7) or females (3.3; 2.8-3.7). Adult DSD cancer patients have a similar distribution of primary sites compared to male or female patients but DSD children with cancer have ten times more cases of testicular malignancies than expected (95% confidence interval: 4.7-20). CONCLUSION: The proportions of certain primary sites and categories of malignancies among transgender and DSD cancer patients are different from the proportions observed for male or female patients. PMID- 29529447 TI - Patterns of pathologically confirmed metastasis to bone in Near East population. AB - BACKGROUND: Metastatic tumors to bone constitute the majority of bone malignancies. The site of metastasis to bone and the prognosis depend chiefly on the primary tumor. Despite all the advances in diagnostic techniques, identifying the primary tumor has not improved significantly. METHODS: A total of 576 cases (Lebanon; n = 306, Pakistan; n = 270) presenting with microscopic evidence of metastasis to bone were reviewed between 1996 and 2016. Clinical and radiologic data were recorded. RESULTS: Out of 20 types of primary tumors, unknown primary (38.2%), followed by breast (23.8%), lung (10.4%) and thyroid (4.9%) tumors were the most commonly presenting with bone metastasis. The primary source of the tumor showed significant correlation with the site of metastasis, time lag to metastasis and radiologic presentation (p < 0.001). Interestingly, a significant variation was noted between the 2 observed populations. CONCLUSION: The patterns of pathologically confirmed metastasis to skeletal sites in Near East population showed a special distribution, and variation was even observed between the 2 studied centers. Understanding the biologic variations of the primary tumors in our population may further explain the variation in patterns of metastasis. PMID- 29529448 TI - A case-control study of sleep disturbances in pediatric obsessive-compulsive disorder. AB - BACKGROUND: Sleep disturbances, including delayed sleep phase disorder (DSPD) and disorders of sleep initiation and maintenance (DIMS), have repeatedly been identified in adult obsessive-compulsive disorder (OCD). These disturbances have not been well-characterized objectively in pediatric OCD. METHODS: Thirty OCD affected youth (8-18 yrs, 40% male) and 30 age and gender-matched healthy controls (HCs) completed the Sleep Disturbances Scale for Children (SDSC), and one week of continuous actigraphy with concurrent sleep diary documentation. A subsample completed the Children's Sleep Hygiene Scale (CSHS) and Sleep Attitudes and Beliefs Scale (SABS). RESULTS: Seventy-two percent of OCD participants reported sleep disturbances versus 15% of HC participants (p < 0.001). Convergent actigraphy results suggested DIMS but not DSPD were common. DISCUSSION: The parents of OCD-affected children seem to be successfully controlling bedtimes, preventing circadian rhythm system disruptions. OCD status does adversely impact, however, the perisleep arousal system. These results have important clinical implications, suggesting sleep problems may be best managed through direct treatment of OCD symptoms. It is recommended that all pediatric OCD patients be screened for sleep disturbances to inform treatment plan development. PMID- 29529449 TI - Service providers' adherence to methadone maintenance treatment protocol in China. AB - BACKGROUND: Methadone maintenance treatment (MMT) programs have expanded rapidly in China during the last decade. However, variance in service providers' practice may have an impact on the quality of care received by the patients. This study examined Chinese service providers' adherence to the MMT protocol and its associated factors. METHODS: The study used baseline data from a randomized intervention trial implemented in MMT clinics in five provinces of China. The data were collected from January 2012 to August 2013. A total of 418 service providers from 68 MMT clinics participated in the study. Demographic and job related characteristics were collected. The providers' adherence to the MMT protocol, MMT knowledge, negative attitudes towards people who use drugs (PWUD), and perceived institutional support were assessed. RESULTS: The average adherence score was 36.7 +/- 4.3 (out of 9-45). Fewer providers adhered to the protocol items where communications with patients or families were required. After controlling for potential confounders, adherence to the MMT protocol was positively associated with perceived institutional support (standardized beta = 0.130; p = 0.0052), and negatively associated with prejudicial attitudes towards PWUD (standardized beta = -0.357; p < 0.0001). Reception of national-level MMT training was not associated with higher level of adherence to protocol. CONCLUSION: The findings suggest the potential benefits of providing institutional support to MMT providers to enhance their level of adherence to the MMT protocol. Intervention effort is needed to reduce negative attitudes towards PWUD among MMT service providers to achieve greater consistency with best practice recommendations. PMID- 29529450 TI - Effects of topical exposure to a mixture of chlorpyrifos, cypermethrin and captan on the hematological and immunological systems in male Wistar rats. AB - Most Thai orchid farmers heavily used pesticide mixtures, and were shown to have various hematologic/immunologic alterations. The present study investigated the effect of exposure of male Wistar rats to a mixture of three pesticides (chlorpyrifos, cypermethrin and captan) that are most often used by the farmers. Three groups of 10 rats were dermally exposed to three different doses (high, middle and low) for 28 consecutive days. The rats showed significant changes in body, liver, kidneys and adrenals weights. Significant changes were observed in various biological parameters including hematotoxicity (increased leukocyte and platelet counts, percent neutrophil, decreased RBC count, percent lymphocyte and eosinophil), hepatotoxicity (increased serum AST, decreased serum ALP, cholesterol, triglyceride, serum protein and albumin), and immunotoxicity (decrease in numbers of NK cells, decrease splenic proliferative response to LPS, and increase in serum IgG). These results confirm the potential health danger of exposure to these pesticide mixtures in orchid farmers. PMID- 29529451 TI - A case of positive 68Ga-DOTATOC-PET/CT pancreatic heterotopia mimicking an intestinal neuroendocrine tumor. AB - Gallium-68 DOTA-peptide positron emission tomography/computed tomography (68Ga PET/CT) has emerged as a promising tool for the diagnosis and staging of gastro entero-pancreatic neoplasms, thanks to its high sensitivity and specificity. Heterotopic pancreas, which is relatively rare, has never been reported as a possible cause of false positives of 68Ga-PET/CT. We report on the first case of a heterotopic pancreas showing pathological uptake at 68Ga-PET/CT, thus mimicking an intestinal neuroendocrine tumor. The present case suggests that heterotopic pancreas should be included among the possible causes of false positives at 68Ga PET. PMID- 29529452 TI - Effects of eliminating routine use of oral contrast for computed tomography of the abdomen and pelvis: A pilot study. AB - INTRODUCTION: Computed tomography (CT) of the abdomen and pelvis using only intravenous contrast has been shown to have a high degree of accuracy in evaluating abdominal pain. The aim of this study was to determine the effect on time to completion of study, time to radiologist read, and length of stay in the emergency department (ED) of implementing a protocol that stopped the routine use of oral contrast for CT of the abdomen and pelvis. METHODS: This was a single center, retrospective cohort study. All patients >=18 years of age who presented to the ED and required a CT of the abdomen and pelvis during the hours 0700-1500 were included. There were two one-month study periods, before and after implementing a protocol that specified oral contrast should only be used for CT scans of the abdomen and pelvis if body mass index <25 kg/m2 or age < 30 years, or if there was history of inflammatory bowel disease, gastrointestinal surgery, or suspected bowel malignancy. RESULTS: During the pre- and post-implementation periods, there were 93 and 83 patients, respectively, with mean times to CT completion of 158 min and 135 min, representing a reduction of 23 min (15%). The mean lengths of stay in the pre- and post-implementation periods were 365 min and 336 min, a decrease of 29 min (8%). CONCLUSION: A protocol without the routine use of oral contrast for CT of the abdomen and pelvis can result in improved time to completion and ED length of stay. PMID- 29529453 TI - Exploring nursing educators' use of theory and methods in search for evidence based credibility in nursing education. AB - OBJECTIVES: In this paper, a review of nursing education literature is employed to ascertain the extent to which nursing educators apply theory to their research, as well as the types of theory they employ. In addition, the use of research methodologies in the nursing education literature is explored. DESIGN: An integrative review. METHODS: A systematic search was conducted for English language, peer reviewed publications of any research design via Academic Search Complete, Science Direct, CINAHL, and Health Source: Nursing/Academic Edition databases from 2001 to 2016, of which 140 were reviewed. FINDINGS: The findings suggest that within current nursing education literature the scholarship of discovery, and the exploration of epistemologies other than nursing, in particular as they relate to teaching and learning, shows significant potential for expansion and diversification. CONCLUSIONS: The analysis highlights opportunities for nursing educators to incorporate broader theoretical, pedagogical, methodological and philosophical perspectives within teaching and the scholarship of teaching. PMID- 29529454 TI - Are we ready for the challenge of implementing risk-based breast cancer screening and primary prevention? AB - BACKGROUND: Increased knowledge of breast cancer risk factors provides opportunities to shift from a one-size-fits-all screening programme to a personalised approach, where screening and prevention is based on a woman's risk of developing breast cancer. However, potential implementation of this new paradigm could present considerable challenges which the present review aims to explore. METHODS: Bibliographic databases were searched to identify studies evaluating potential implications of the implementation of personalised risk based screening and primary prevention for breast cancer. Identified themes were evaluated using thematic analysis. RESULTS: The search strategy identified 5699 unique publications, of which 59 were selected for inclusion. Significant changes in policy and practice are warranted. The organisation of breast cancer screening spans several healthcare delivery systems and clinical settings. Feasibility of implementation depends on how healthcare is funded and arranged, and potentially varies between countries. Piloting risk assessment and prevention counselling in primary care settings has highlighted implications relating to the need for extensive additional training on risk (communication) and prevention, impact on workflow, and professionals' personal discomfort breaching the topic with women. Additionally, gaps in risk estimation, psychological, ethical and legal consequences will need to be addressed. CONCLUSION: The present review identified considerable unresolved issues and challenges. Potential implementation will require a more complex framework, in which a country's healthcare regulations, resources, and preferences related to screening and prevention services are taken into account. However, with the insights gained from the present overview, countries expecting to implement risk-based screening and prevention can start to inventory and address the issues that were identified. PMID- 29529455 TI - Marijuana use among US tobacco users: Findings from wave 1 of the population assessment of tobacco health (PATH) study. AB - BACKGROUND: With an increase in marijuana use among adults in the United States (US), understanding the potential impact of marijuana use on tobacco use and associated behavioral and health consequences, including respiratory conditions, is necessary. METHOD: Survey responses from Wave 1 of the nationally representative Population Assessment of Tobacco and Health (PATH) Study were used to assess tobacco use and marijuana use among non-current tobacco users (n = 17,952) and current established tobacco-users classified as: cigarette only users (n = 8689), e-cigarette only users (n = 437), cigar only (traditional, cigarillo, or filtered) users (n = 706), hookah only users (n = 461), smokeless tobacco only users (n = 971), cigarette + e-cigarette users (n = 709), and users of multiple tobacco products (n = 2314). RESULTS: When compared to non-current tobacco users, each tobacco user group except smokeless only users had higher odds (odds ratios ranging from 3.86-8.07) of reporting current marijuana use. Among current tobacco users, higher levels of tobacco dependence did not explain the relationship between tobacco use and marijuana use. Additionally, concurrent marijuana use was associated with lower odds of attempts to quit tobacco (OR = 0.86, 95% CI = 0.79, 0.94, p < 0.001) and a higher probability (OR = 1.35, 95CI = 1.21, 1.51, p < 0.01) of reporting a history of respiratory disease. CONCLUSIONS: The association between concurrent use of tobacco and marijuana and higher tobacco dependence and lower rates of quit attempts suggests the potential for sustained tobacco use and deleterious health effects. Further, marijuana use may represent an additive risk for respiratory harm among concurrent users of tobacco and marijuana. PMID- 29529456 TI - Rehospitalization and substance use disorder (SUD) treatment entry among patients seen by a hospital SUD consultation-liaison service. AB - BACKGROUND: Substance use disorders (SUD) are associated with non-adherence to medical care and high utilization of hospital services. This study characterized patterns and correlates of rehospitalization among patients seen by a hospital based SUD consultation-liaison (CL) team. METHODS: This study was a retrospective medical record review of patients in a large urban academic hospital who received SUD consultation and were diagnosed with opioid, cocaine, and/or alcohol use disorder (N = 267). Data were collected on patient characteristics, substance specific SUD diagnoses (opioids, cocaine, and alcohol), opioid agonist treatment (OAT) with methadone or buprenorphine (treatment status at admission; in-hospital initiation of OAT), and rehospitalization through 180 days post-discharge. Associations with rehospitalization were examined using bivariate tests of independence and multivariate logistic regression, with patient background and medical characteristics, substance-specific SUD diagnoses, and OAT status (at admission and in-hospital initiation) as predictors. RESULTS: Rehospitalization rates were higher among patients with current opioid (38% vs. 24%; p < .05) and cocaine use disorders (39% vs. 26%; p < .05) compared to patients without these diagnoses. In multivariate logistic regression analysis, the number of medical comorbidities [Adjusted Odds Ratio (AOR) = 1.2; p < .01] and opioid use disorder (AOR = 2.4, p < .05) were independently associated with rehospitalization. CONCLUSIONS: In this sample of hospital patients receiving SUD CL services, the risk of rehospitalization differed by type of SUD diagnosis. In-hospital initiation of OAT is promising for facilitating treatment linkage post-discharge, but this small study did not show differences in rehospitalization based on OAT initiation. These findings could inform services for hospital patients with comorbid SUDs. PMID- 29529458 TI - Highly efficient monodisperse Pt nanoparticles confined in the carbon black hybrid material for hydrogen liberation. AB - Dimethylamine borane (DMAB) has been considered as one of the important hydrogen sources with a simple process by the help of the efficient catalyst. For this purpose, herein, platinum nanoparticles (Pt NPs), placed inside carbon black hybrid (Pt NPs@CBH), activated carbon (Pt NPs@AC) and Vulcan carbon (Pt NPs@VC), have been prepared as highly monodisperse catalysts for dehydrogenation reactions of DMAB at room temperature. The morphological and physical structure of the monodisperse catalysts have been identified by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM) etc. The typical face-centered cubic (fcc) structure of the all prepared catalysts was verified from X-ray diffractogram. All prepared catalytic materials were measured as high-performance catalysts for dehyrocoupling of DMAB; but, Pt NPs@CBH catalyst indicated the better catalytic activity compared to the other prepared ones. Easy utilization at very small concentrations and temperature, monodisperse Pt NPs@CBH perform an eye-catching catalytic activity with providing one of the best TOF (70.28 h-1) and Ea (93.56 +/- 2 kJ/mol) for dehydrocoupling of DMAB. PMID- 29529457 TI - The combined magnetic field and iron oxide-PLGA composite particles: Effective protein antigen delivery and immune stimulation in dendritic cells. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have received much attention in drug and biomolecule delivery systems. Here, we report a delivery system using the combination of a magnetic field and the relatively biocompatible composite particles of poly(lactic-co-glycolic acid) and SPIONs (SPION-PLGA particles) for protein delivery to bone-marrow derived primary dendritic cells (BM-DCs). SPIONs with the diameter of ~10 nm were synthesized via thermal decomposition of iron(III) oleate. The SPIONs and bovine serum albumin (BSA) were encapsulated in PLGA particles of two different diameters, 300 and 500 nm. The obtained SPIONs PLGA nanocomposites exhibited superparamagnetic character, showed low cytotoxicity and were well taken up in macrophage and BM-DCs under an external magnetic field. In addition, the nanocomposites were tested for immune induction in BM-DCs. This combined SPION-PLGA carrier and an external magnetic field can significantly enhance BM-DC maturation by upregulating MHC II, CD80 and CD86 expression. Immune response induction by this strategy is verified through a significant upregulation of the IL-12 and IFN-gamma production. Moreover, no activation of BM-DCs to secrete pro-inflammatory cytokine TNF-alpha was observed for all particles. We anticipate these findings to be a starting point for vaccine researches involving the combined magnetic field and SPION-PLGA composite particles. PMID- 29529459 TI - Corrosion protection for mild steel by extract from the waste of lychee fruit in HCl solution: Experimental and theoretical studies. AB - Various experimental conditions were tested for the green extract process of corrosion inhibitor from lychee fruit waste, and the optimal extract parameters were selected using potentiodynamic polarization. The best inhibition effect of the ethanol extract of lychee's peel and seed by ultrasound for 1.5 h (EELPS) for mild steel in 0.5 M HCl was obtained at 600 mg/L using electrochemical and weight loss measurements. Theoretical calculations illustrate the adsorption sites and adsorption behavior of effective compounds. Due to the existence of hydroxyl groups and phenol rings in the main components, EELPS is considered to be a good inhibitor. PMID- 29529460 TI - Acid-functionalized carbon nanofibers for high stability, thermoelectrical and electrochemical properties of nanofluids. AB - Carbon-based nanofluids are viewed as promising thermal fluids for heat transfer applications. However, other properties, such as electrical conductivity and electrochemical behavior, are usually overlooked and rarely investigated despite their importance for the overall performance characterization of a given application. In this study, we synthesized PAN-based carbon nanofibers (CNF) by electrospinning, and characterized them using electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Raman spectroscopy, and thermogravimetric analysis. Thermoelectrical and electrochemical measurements were carried out on nanofluids. We found that, although CNF nanofluids exhibit good thermal and electrical properties with a negligible corrosive effect, the suspensions tend to sediment within a few days. However, acid treatment of CNF (F CNF), which resulted in the shortening of the fibers and the appearance of surface-oxygenated species, made F-CNF-based nanofluids exhibit superior stability in water that extended for more than 90 days, with consistent and superior thermal and electrical properties. PMID- 29529461 TI - Highly stable and flexible transparent conductive polymer electrode patterns for large-scale organic transistors. AB - The application of conductive polymer polypyrrole (PPY) towards transparent and flexible electronics has been demonstrated by a photolithography-compatible technique. The oxygen plasma pretreatment was found to be important for successful fabrication of PPY electrode patterns on flexible poly(ethylene terephthalate) (PET). By the patterning process of PPY, the transparency of PPY electrode can be improved up to >80% over the visible spectrum, which combined with the excellent chemical and physical stability of PPY shows the huge potential of PPY electrode as flexible transparent conductive electrode. In addition, PPY provides better interface connection for uniform deposition of organic semiconductor thin film. These outstanding advantages in PPY, coupled with selection of a novel anti-solvent and water-tolerant elastic dielectric, enable the photolithographic PPY patterns to be used for fabrication of large scale flexible transparent organic field-effect transistor arrays. These results open up the capability of PPY as flexible transparent electrode for flexible organic devices, and exhibit a strong potential of PPY electrode patterns for future large-scale high-precision flexible electronics. PMID- 29529462 TI - Oil-in-water emulsion impregnated electrospun poly(ethylene terephthalate) fiber mat as a novel tool for optical fiber cleaning. AB - HYPOTHESIS: The complete removal of remaining polymer debris after stripping of optical fiber cables is essential for high precision connection between two fibers. It can be anticipated that electrospun porous membranes as cleaning wipes are able to trap and retain polymer debris within their pores. Impregnation of an oil-in-water emulsion as cleaning agent lowers the interfacial tension between debris and the optical fiber thereby enabling the straightforward removal of polymer debris from the optical fiber. EXPERIMENTS: Electrospun membranes of poly(ethylene terephthalate) (PET) and cellulose acetate (CA) were obtained with fiber diameters of 0.430 MUm and 2 MUm respectively. The oil-in-water emulsion was formulated with 10 wt% medium chain triglyceride (MCT) and 10 wt% Tween 80 surfactant in an aqueous phosphate buffer solution. FINDINGS: In a scoring range from 0 to 5 for which the score 0 indicated superior cleaning and the score 5 referred to the least efficient cleaning, the electrospun fiber mats (without emulsion) scored within the range of 2-4 while emulsion impregnated electrospun fiber mats revealed the best score of 0. A drastic improvement was thus clearly evident from the obtained results when the cleaning emulsion was applied. The materials developed herein thus represent a new class of soft cleaning agents for optical fibers. PMID- 29529463 TI - Functionalized carbon dot adorned coconut shell char derived green catalysts for the rapid synthesis of amidoalkyl naphthols. AB - A one pot synthesis of carbon dot incorporated porous coconut shell char derived sulphonated catalyst is reported here for the first time and is effectively used in the multicomponent synthesis of amidoalkyl naphthol. Macroporous nature of the char is revealed from scanning electron microscopic (SEM) analysis, whereas the dispersion of carbon dots (CDs) on the porous coconut shell char is confirmed from the high resolution transmission electron microscopic (HRTEM) analysis. Fluorescence emission spectrum further confirmed the presence of CDs in the catalyst. Fourier-transform infrared (FTIR) spectral analysis of the materials indicated that sulphonation occurred both to the CD and to the porous char. X-ray photo electron spectroscopic (XPS) analysis of the most active catalyst confirmed the presence of both sulphonic acid and carboxylic acid groups in the catalyst. The coconut shell char derived materials prepared by varying the amount of H2SO4 are successfully utilized as efficient alternative green catalysts for the multicomponent reaction, where excellent activity in amidoalkyl naphthol synthesis is obtained within short periods under solvent free reaction conditions. A maximum yield of 98% is obtained in the synthesis of N-[Phenyl-(2 hydroxy-naphthalen-1-yl)-methyl]-benzamide, the representative amidoalkyl naphthol, with the best catalyst within 3 min of reaction. The catalyst is highly active for the reactions carried out with varieties of aldehydes and amides with a product yield in the range of 88-98%. The best catalyst system retained more than 90% of its initial activity even upto 6th repeated run. PMID- 29529464 TI - Extended hierarchical solvent perturbations from curved surfaces of mesoporous silica particles in a deep eutectic solvent. AB - HYPOTHESIS: Many applications of deep eutectic solvents (DES) rely on exploitation of their unique yet complex liquid structures. Due to the ionic nature of the DES components, their diffuse structures are perturbed in the presence of a charged surface. We hypothesize that it is possible to perturb the bulk DES structure far (>100 nm) from a curved, charged surface with mesoscopic dimensions. EXPERIMENTS: We performed in situ, synchrotron-based ultra-small angle X-ray scattering (USAXS) experiments to study the solvent distribution near the surface of charged mesoporous silica particles (MPS) (~0.5 um in diameter) suspended in both water and a common type of DES (1:2 choline Cl-:ethylene glycol). FINDINGS: A careful USAXS analysis reveals that the perturbation of electron density distribution within the DES extends ~1 MUm beyond the particle surface, and that this perturbation can be manipulated by the addition of salt ions (AgCl). The concentration of the pore-filling fluid is greatly reduced in the DES. Notably, we extracted the real-space structures of these fluctuations from the USAXS data using a simulated annealing approach that does not require a priori knowledge about the scattering form factor, and can be generalized to a wide range of complex small-angle scattering problems. PMID- 29529465 TI - A two-angle model of dynamic wetting in microscale capillaries under low capillary numbers with experiments. AB - OBJECTIVES: An accurate model of the dynamic contact angle thetad is critical for the calculation of capillary force in applications like enhanced oil recovery, where the capillary number Ca ranges from 10-10 to 10-5 and the Bond number Bo is less than 10-4. The rate-dependence of the dynamic contact angle under such conditions remains blurred, and is the main target of this study. EXPERIMENTS: Featuring with pressure control and interface tracking, the innovative experimental system presented in this work achieves the desired ranges of Ca and Bo, and enables the direct optical measurement of dynamic contact angles in capillaries as tiny as 40 * 20 (width * height) MUm and 80 * 20 MUm. The advancing and receding processes of wetting and nonwetting liquids were tested. FINDINGS: The dynamic contact angle was confirmed velocity-independent with 10-9 < Ca < 10-5 (contact line velocity V = 0.135-490 MUm/s) and it can be described by a two-angle model with desirable accuracy. A modified two-angle model was developed and an empirical form was obtained from experiments. For different liquids contacting the same surface, the advancing angle thetaadv approximately equals the static contact angle thetao. The receding angle thetarec was found to be a linear function of thetaadv, in good agreement with our and other experiments from the literature. PMID- 29529466 TI - The influence of natural dissolved organic matter on herbicide toxicity to marine microalgae is species-dependent. AB - Microalgae, which are the foundation of aquatic food webs, may be the indirect target of herbicides used for agricultural and urban applications. Microalgae also interact with other compounds from their environment, such as natural dissolved organic matter (DOM), which can itself interact with herbicides. This study aimed to evaluate the influence of natural DOM on the toxicity of three herbicides (diuron, irgarol and S-metolachlor), singly and in ternary mixtures, to two marine microalgae, Chaetoceros calcitrans and Tetraselmis suecica, in monospecific, non-axenic cultures. Effects on growth, photosynthetic efficiency (F'M) and relative lipid content were evaluated. The chemical environment (herbicide and nutrient concentrations, dissolved organic carbon and DOM optical properties) was also monitored to assess any changes during the experiments. The results show that, without DOM, the highest irgarol concentration (I0.5: 0.5 mg.L 1) and the strongest mixture (M2: irgarol 0.5 MUg.L-1 + diuron 0.5 MUg.L-1 + S metolachlor 5.0 MUg.L-1) significantly decreased all parameters for both species. Similar impacts were induced by I0.5 and M2 in C. calcitrans (around -56% for growth, -50% for relative lipid content and -28% for F'M), but a significantly higher toxicity of M2 was observed in T. suecica (-56% and -62% with I0.5 and M2 for growth, respectively), suggesting a possible interaction between molecules. With DOM added to the culture media, a significant inhibition of these three parameters was also observed with I0.5 and M2 for both species. Furthermore, DOM modulated herbicide toxicity, which was decreased for C. calcitrans (-51% growth at I0.5 and M2) and increased for T. suecica (-64% and -75% growth at I0.5 and M2, respectively). In addition to the direct and/or indirect (via their associated bacteria) use of molecules present in natural DOM, the characterization of the chemical environment showed that the toxic effects observed on microalgae were accompanied by modifications of DOM composition and the quantity of dissolved organic carbon excreted and/or secreted by microorganisms. This toxicity modulation in presence of DOM could be explained by (i) the modification of herbicide bioavailability, (ii) a difference in cell wall composition between the two species, and/or (iii) a higher detoxification capacity of C. calcitrans by the use of molecules contained in DOM. This study therefore demonstrated, for the first time, the major modulating role of natural DOM on the toxicity of herbicides to marine microalgae. PMID- 29529467 TI - Toxicity of sediment-bound lufenuron to benthic arthropods in laboratory bioassays. AB - This paper deals with species sensitivity distributions (SSDs) for the lipophilic insecticide lufenuron and benthic arthropods based on sediment-spiked laboratory toxicity tests. This compound that inhibits chitin synthesis and moulting of arthropods persists in sediment. Using field-collected sediment, toxicity tests were conducted with three macro-crustaceans and six insects. The Hazardous Concentration to 5% of the tested species, the HC5 (and 95% confidence limit), derived from an SSD constructed with 10d-LC50's was 2.2 (1.2-5.7) MUg/g organic carbon (OC) in dry sediment. In addition, HC5 values derived from SSDs constructed with 28d-LC10 and 28-d LC50 values were 0.13 (0.02-1.50) MUg/g OC and 2.0 (1.3-5.5) MUg/g OC, respectively. In 28d toxicity tests with Chironomus riparius and Hyalella azteca, a higher sensitivity was observed when using lufenuron-spiked field-collected sediment than in lufenuron-spiked artificial sediment. Overall, the non-biting midge C. riparius appeared to be a representative and sensitive standard test species to assess effects of lufenuron exposure in sediment. The Tier-1 (based on standard test species), Tier-2 (based on standard and additional test species) and Tier-3 (model ecosystem approach) regulatory acceptable concentrations (RACs) for sediment-spiked lufenuron did not differ substantially. The Tier-2 RAC was the lowest. Since to our knowledge this study is the first in the open literature that evaluates the tiered approach in the sediment effect assessment procedure for pesticides, we advocate that similar evaluations should be conducted for pesticides that differ in toxic mode-of action. PMID- 29529468 TI - Short-term developmental effects and potential mechanisms of azoxystrobin in larval and adult zebrafish (Danio rerio). AB - Previous study indicated that azoxystrobin had high acute toxicity to zebrafish, and larval zebrafish were more sensitive to azoxystrobin than adult zebrafish. The objective of the present study was to investigate short-term developmental effects and potential mechanisms of azoxystrobin in larval and adult zebrafish. After zebrafish embryos and adults were exposed to 0.01, 0.05 and 0.20 mg/L azoxystrobin (equal to 25, 124 and 496 nM azoxystrobin, respectively) for 8 days, the lethal effect, physiological responses, liver histology, mitochondrial ultrastructure, and expression alteration of genes related to mitochondrial respiration, oxidative stress, cell apoptosis and innate immune response were determined. The results showed that there was no significant effect on larval and adult zebrafish after exposure to 0.01 mg/L azoxystrobin. However, increased ROS, MDA concentration and il1b in larval zebrafish, as well as increased il1b, il8 and cxcl-c1c in adult zebrafish were induced after exposure to 0.05 mg/L azoxystrobin. Reduced mitochondrial complex III activity and ATP concentration, increased SOD activity, ROS and MDA concentration, decreased cytb, as well as increased sod1, sod2, cat, il1b, il8 and cxcl-c1c were observed both in larval and adult zebrafish after exposure to 0.20 mg/L azoxystrobin; meanwhile, increased p53, bax, apaf1 and casp9, alteration of liver histology and mitochondrial ultrastructure in larval zebrafish, and alteration of mitochondrial ultrastructure in adult zebrafish were also induced. The results demonstrated that azoxytrobin induced short-term developmental effects on larval zebrafish and adult zebrafish, including mitochondrial dysfunction, oxidative stress, cell apoptosis and innate immune response. Statistical analysis indicated that azoxystrobin induced more negative effects on larval zebrafish, which might be the reason for the differences of developmental toxicity between larval and adult zebrafish caused by azoxystrobin. These results provided a new insight into potential mechanisms of azoxystrobin in larval zebrafish and adult zebrafish. PMID- 29529469 TI - Transglutaminase-mediated conjugation and nitride-technetium-99m labelling of a bis(thiosemicarbazone) bifunctional chelator. AB - An assessment study involving the use of the transglutaminase (TGase) conjugation method and the nitride-technetium-99m labelling on a bis(thiosemicarbazone) (BTS) bifunctional chelating agent is presented. The previously described chelator diacetyl-2-(N4-methyl-3-thiosemicarbazone)-3-(N4-amino-3-thiosemicarbazone), H2ATSM/A, has been functionalized with 6-aminohexanoic acid (epsilon-Ahx) to generate the bifunctional chelating agent diacetyl-2-(N4-methyl-3 thiosemicarbazone)-3-[N4-(amino)-(6-aminohexanoic acid)-3-thiosemicarbazone], H2ATSM/A-epsilon-Ahx (1), suitable for conjugation to glutamine (Gln) residues of bioactive molecules via TGase. The feasibility of the TGase reaction in the synthesis of a bioconjugate derivative was investigated using Substance P (SP) as model peptide. Compounds 1 and H2ATSM/A-epsilon-Ahx-SP (2) were labelled with nitride-technetium-99m, obtaining the complexes [99mTc][Tc(N)(ATSM/A-epsilon Ahx)] (99mTc1) and [99mTc][Tc(N)(ATSM/A-epsilon-Ahx-SP)] (99mTc2). The chemical identity of 99mTc1 and 99mTc2 was confirmed by radio/UV-RP-HPLC combined with ESI MS analysis on the respective carrier-added products 99g/99mTc1 and 99g/99mTc2. The stability of the radiolabelled complexes after incubation in various environments was investigated. All the results were compared with those obtained for the corresponding 64Cu-analogues, 64Cu1 and 64Cu2. The TGase reaction allows the conjugation of 1 with the peptide, but it is not highly efficient due to instability of the chelator in the required conditions. The SP-conjugated complexes are unstable in mouse and human sera. However, indeed the BTS system can be exploited as nitride-technetium-99m chelator for highly efficient technetium labelling, thus making compound 1 worthy of further investigations for new targeted technetium and copper radiopharmaceuticals encompassing Single Photon Emission Computed Tomography and Positron Emission Tomography imaging. PMID- 29529470 TI - Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands. AB - New water soluble, enantiopure arene ruthenium compound SRuSN-(1R,4S)-[(eta6-p cymene)Ru{KNH(Bn),KNOH}Cl]Cl (Bn = benzyl, 1a') has been synthesized. The novel compound along with that previously described RRuRN-(1S,4R)-[(eta6-p cymene)Ru{KNH(Bn),KNOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a' was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A 549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a' induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a' towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells. PMID- 29529471 TI - Sterically modulated silver(I) complexes of coumarin substituted benzimidazol-2 ylidenes: Synthesis, crystal structures and evaluation of their antimicrobial and antilung cancer potentials. AB - In this contribution, a series of sterically-encumbered coumarin substituted benzimidazole-based N-heterocyclic carbene (NHC) precursors (1-12) and their silver(I)-NHC complexes (13-24) are reported. Molecular structure of NHC precursors 8 and 12 and cationic complexes 15 and 16 was established by single crystal X-ray diffraction method. The silver(I) complexes demonstrated various significant intramolecular agostic-like interactions operating between the metal center and the hydrogen atoms of the substituents alongside a variety of feeble pi-pi stacking interactions. A distorted linear coordination geometry is documented at the silver(I) center with the anti-arrangement of the ligands. Further, the complexes demonstrated promising antibacterial properties against Gram positive and Gram negative bacterial strains, especially complex 18 displayed a minimum inhibitory concentration (MIC) of 2 and 4 MUg/mL against S. aureus and E. coli, and P. aeruginosa, respectively. Furthermore, complexes 14, 15, 16 and 18 were found cytotoxic against the human lung cancer cell lines A549 and H1975 with the IC50 (concentration of the test sample required to kill 50% of the cell population) value under 10 MUM, while mono-NHC complex 20 displayed a potential drug window with the IC50 of 13.7 +/- 2.70 and 14.5 +/- 1.20 MUM against the cancer cell lines H1975 and A549, respectively. Notably, these complexes displayed relatively lesser cytotoxic behaviour against the normal skin fibroblast cell line, Hs68. All the NHC precursors displayed significantly lower biological activities compared with their respective complexes, indicating the utility of silver(I) ions in antimicrobial and antilung cancer applications. PMID- 29529472 TI - Construct validity and parent-child agreement of the six new or modified disorders included in the Spanish version of the Kiddie Schedule for Affective Disorders and Schizophrenia present and Lifetime Version DSM-5 (K-SADS-PL-5). AB - Changes to the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) incorporate the inclusion or modification of six disorders: Autism Spectrum Disorder, Social Anxiety Disorder, Intermittent Explosive Disorder, Disruptive Mood Dysregulation Disorder, Avoidant/Restrictive Food Intake Disorder and Binge Eating Disorder. The objectives of this study were to assess the construct validity and parent-child agreement of these six disorders in the Spanish language Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version (K-SADS-PL-5) in a clinical population of children and adolescents from Latin America. The Spanish version of the K-SADS-PL was modified to integrate changes made to the DSM-5. Clinicians received training in the K-SADS-PL-5 and 90% agreement between raters was obtained. A total of 80 patients were recruited in four different countries in Latin America. All items from each of the six disorders were included in a factor analysis. Parent-child agreement was calculated for every item of the six disorders, including the effect of sex and age. The factor analysis revealed 6 factors separately grouping the items defining each of the new or modified disorders, with Eigenvalues greater than 2. Very good parent-child agreements (r>0.8) were found for the large majority of the items (93%), even when considering the sex or age of the patient. This independent grouping of disorders suggests that the manner in which the disorders were included into the K-SADS-PL 5 reflects robustly the DSM-5 constructs and displayed a significant inter informant reliability. These findings support the use of K-SADS-PL-5 as a clinical and research tool to evaluate these new or modified diagnoses. PMID- 29529473 TI - In Vivo Short-Term Topical Application of BAY 11-7082 Prevents the Acidic Bile Induced mRNA and miRNA Oncogenic Phenotypes in Exposed Murine Hypopharyngeal Mucosa. AB - PURPOSE: Bile-containing gastroesophageal reflux may promote cancer at extraesophageal sites. Acidic bile can accelerate NF-kappaB activation and molecular events, linked to premalignant changes in murine hypopharyngeal mucosa (HM). We hypothesize that short-term in vivo topical application of NF-kappaB inhibitor BAY 11-7082 can prevent acidic bile-induced early preneoplastic molecular events, suggesting its potential role in disease prevention. EXPERIMENTAL DESIGN: We topically exposed HM (C57Bl/6j wild-type) to a mixture of bile acids at pH 3.0 with and without BAY 11-7082 3 times/day for 7 days. We used immunofluorescence, Western blotting, immunohistochemistry, quantitative polymerase chain reaction, and polymerase chain reaction microarrays to identify NF-kappaB activation and its associated oncogenic mRNA and miRNA phenotypes, in murine hypopharyngeal cells in vitro and in murine HM in vivo. RESULTS: Short term exposure of HM to acidic bile is a potent stimulus accelerating the expression of NF-kappaB signaling (70 out of 84 genes) and oncogenic molecules. Topical application of BAY 11-7082 sufficiently blocks the effect of acidic bile. BAY 11-7082 eliminates NF-kappaB activation in regenerating basal cells of acidic bile-treated HM and prevents overexpression of molecules central to head and neck cancer, including bcl-2, STAT3, EGFR, TNF-alpha, and WNT5A. NF-kappaB inhibitor reverses the upregulated "oncomirs" miR-155 and miR-192 and the downregulated "tumor suppressors" miR-451a and miR-375 phenotypes in HM affected by acidic bile. CONCLUSION: There is novel evidence that acidic bile-induced NF-kappaB related oncogenic mRNA and miRNA phenotypes are generated after short-term 7-day mucosal exposure and that topical mucosal application of BAY 11-7082 can prevent the acidic bile-induced molecular alterations associated with unregulated cell growth and proliferation of hypopharyngeal cells. PMID- 29529474 TI - The safety and feasibility of minimally invasive sentinel lymph node staging using indocyanine green in the management of endometrial cancer. AB - OBJECTIVES: The purpose of this study was to report on the feasibility of laparoscopic sentinel lymph node (SLN) staging using indocyanine green (ICG) in the management of endometrial cancer. STUDY DESIGN: We retrospectively evaluated the charts of presumed, clinical stage I endometrial cancer patients who underwent robotic-assisted surgery that incorporated mapping with ICG and SLN dissection from January 2016 until February 2017. Patient demographics, operative characteristics (e.g., complications, lymph node counts) and pathology data were evaluated. RESULTS: There were 87 patients who were included in the study. A total of 370 lymph nodes were removed, of which 245 were SLNs; unilateral and bilateral mapping of the SLNs was achieved in 84 (96.5%) and 71 (81.6%) of subjects, respectively. There were 10 (11.5%) patients who had metastatic disease identified within 22 (5.9%) of the total (n = 370) lymph nodes extracted, 19 (7.7%) of which were sentinel lymph nodes. We did not observe any intraoperative complications. CONCLUSION: The results from our study suggest that minimally invasive SLN staging using ICG is a feasible procedure that is potentially effective at detecting metastases, which may ultimately attenuate the incidence of surgical morbidity. PMID- 29529475 TI - Exercise during pregnancy is associated with a shorter duration of labor. A randomized clinical trial. AB - OBJECTIVE: to examine the influence of an exercise program throughout pregnancy on the duration of labor in healthy pregnant women. STUDY DESIGN: A randomized clinical trial was used (Identifier: NCT02109588). In all, 508 healthy pregnant women were randomly assigned between 9 and 11 weeks of gestation to either a Control Group (CG, N = 253) or an Exercise Group (EG, N = 255). A moderate aerobic exercise program throughout pregnancy (three weekly sessions) was used as the intervention. Mann-Whitney and Pearson chi2 tests were performed to analyze differences between groups. Survival techniques through the Kaplan-Meier method were used to estimate the median time to delivery of each group; and Gehan Breslow-Wilcoxon tests were performed to compare survival distribution between the two arms. The primary outcome studied was the length of the stages of labor. Secondary outcomes included mode of delivery, gestational age, maternal weight gain, preterm delivery, use of epidural, birthweight, Apgar scores and arterial cord pH. RESULTS: Women randomized to the EG had shorter first stage of labor (409 vs 462 min, p = 0.01), total duration of labor (450 vs 507 min, p = 0.01) as well as combined duration of first and second stages of labor (442 vs 499 min, p = 0.01). The probabilities of a woman being delivered at 250 min and 500 min (median times) were 19.1% and 62.5% in the experimental group vs 13.7% and 50.8% in the control group (Z = -2.37, p = 0.018). Results also revealed that women in the intervention group were less likely to use an epidural; and that the prevalence of neonate macrosomia was higher in the control group. CONCLUSION: A supervised physical exercise program throughout pregnancy decreased the duration of the first phase of labor as well as total time of the first two phases together, leading to a decrease in total labor time. PMID- 29529476 TI - Characterization of the population with severe iron deficiency anemia at risk of requiring intravenous iron supplementation. AB - : Iron deficiency anemia is the most frequent cause of anemia world-wide and is a very common disorder in daily medical practice. Heavy menstrual bleeding (menorrhagia) and pregnancy and delivery can cause significant iron loss leading to severe anemia The aim of the present study was to characterize the population requiring intravenous iron and identify whether gynecological and obstetric iron loss are frequent indications for treatment. MATERIAL AND METHODS: Restrospective, single center study performed in a tertiary level university hospital from January 2014 to December 2016. RESULTS: During the 3-year study period, there were 4529 treatments with intravenous iron (45.98% in men vs. 54.02% in women). The population group from 10 to 54 years of age made up 19.33% of the total treatments, with 35.93% in men and 64.01% in women (Fisher exact test, p<0.001). Intravenous iron administration for gynecological and obstetric reasons was required in 20.54% and 24.82% of the total population, respectively, representing >45% of the indications for treatment in this population. CONCLUSIONS: The need for intravenous iron is related to anemia refractory to oral treatment or the need for rapid iron recovery. Our results show that women of fertile age are a population at risk of requiring intravenous iron as compared to a male population of the same age. It is mainly due to blood los related to pregnancy, delivery and puerperium as well as heavy menstrual bleeding. PMID- 29529477 TI - Accumulation, tissue distribution, and biochemical effects of polystyrene microplastics in the freshwater fish red tilapia (Oreochromis niloticus). AB - While the presence of microplastics (MPs) in marine environments has been detected worldwide, the importance of MPs pollution in freshwater environments has also been emphasized in recent years. However, the body of knowledge regarding the biological effects of MPs on freshwater organisms is still much more limited than on marine organisms. The aim of the present study was to evaluate the accumulation and tissue distribution of MPs in the freshwater fish red tilapia (Oreochromis niloticus), as well as the biochemical effects of MPs on O. niloticus. During 14 days of exposure to 0.1 MUm polystyrene-MPs at concentrations of 1, 10, and 100 MUg L-1, the MPs concentrations in various tissues of O. niloticus generally increased over time following the order gut > gills > liver ~ brain. Moreover, the acetylcholinesterase (AChE) activity in the fish brain was inhibited by MPs exposure, with a maximum inhibition rate of 37.7%, suggesting the potential neurotoxicity of MPs to freshwater fish. The activities of cytochrome P450 (CYP) enzymes [7-ethoxyresorufin O-deethylase (EROD) and 7-benzyloxy-4-trifluoromethyl-coumarin O-dibenzyloxylase (BFCOD)] in the fish liver exhibited clear temporal variabilities, with significant decreases followed by elevations compared to the control. The alterations of the EROD and BFCOD activities indicate the potential involvement of CYP enzymes for the metabolism of MPs. The activity of antioxidative enzyme superoxide dismutase (SOD) in the liver was significantly induced throughout the exposure period, while the malondialdehyde (MDA) content did not vary with MPs exposure, suggesting that the antioxidative enzymatic system in O. niloticus could prevent oxidative damage. These results highlight the ingestion and accumulation of MPs in different tissues of freshwater fish, which lead to perturbations in fish biological systems and should be considered in environmental risk assessment. PMID- 29529478 TI - Assessment of particulate matter and ammonia emission concentrations and respective plume profiles from a commercial poultry house. AB - Poultry-emitted air pollutants, including particulate matter (PM) and ammonia, have raised concerns due to potential negative effects on human health and the environment. However, developing and optimizing remediation technologies requires a better understanding of air pollutant concentrations, the emission plumes, and the relationships between the pollutants. Therefore, we conducted ten field experiments to characterize PM (total suspended particulate [TSP], particulate matter less than 10 MUm in aerodynamic diameter [PM10], and particulate matter less than 2.5 MUm in aerodynamic diameter [PM2.5]) and ammonia emission concentration profiles from a typical commercial poultry house. The emission factors of the poultry house, which were calculated using the concentrations and fan speed, were 0.66 (0.29-0.99) g NH3-N bird-1d-1 for ammonia, 52 (44-168) g d 1AU-1 (AU = animal unit = 500 kg) for TSP, 3.48 (1.16-9.03) g d-1AU-1 for PM10, and 0.07 (0.00-0.36) g d-1AU-1 for PM2.5. PM and ammonia emission concentrations decreased as distance from the fan increased. Although emission concentrations were similar in the daytime and nighttime, diurnal and nocturnal plume shapes were different due to the increased stability of the atmosphere at night. Particle size distribution analysis revealed that, at a given height, the percentage of PM10 and PM2.5 was consistent throughout the plume, indicating that the larger particles were not settling out of the airstream faster than the smaller particles. Overall, the direction of the measured air pollutant emission plumes was dominated by the tunnel fan ventilation airflow rate and direction instead of the ambient wind speed and direction. This is important because currently-available air dispersion models use ambient or modeled wind speed and direction as input parameters. Thus, results will be useful in evaluating dispersion models for ground-level, horizontally-released, point sources and in developing effective pollutant remediation strategies for emissions. PMID- 29529479 TI - Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery. AB - The solvent-assisted active loading technology (SALT) was developed for encapsulating a water insoluble weak base into the liposomal core in the presence of 5% DMSO. In this study, we further examined the effect of various water miscible solvents in promoting active loading of other types of drugs into liposomes. To achieve complete drug loading, the amount of solvent required must result in complete drug solubilization and membrane permeability enhancement, but must be below the threshold that induces liposomal aggregation or causes bilayer disruption. We then used the SALT to load gambogic acid (GA, an insoluble model drug that shows promising anticancer effect) into liposomes, and optimized the loading gradient and lipid composition to prepare a stable formulation (Lipo-GA) that displayed >95% drug retention after incubation with serum for 3 days. Lipo GA contained a high drug-to-lipid ratio of 1/5 (w/w) with a mean particle size of ~75 nm. It also displayed a prolonged circulation half-life (1.5 h vs. 18.6 h) and enhanced antitumor activity in two syngeneic mice models compared to free GA. Particularly, complete tumor regression was observed in the EMT6 tumor model for 14 d with significant inhibition of multiple oncogenes including HIF-1alpha, VEGF A, STAT3, BCL-2, and NF-kappaB. PMID- 29529480 TI - Bridges across the intergenerational transmission of attachment gap. AB - Attachment is transmitted from one generation to the next. Adult attachment has been shown to predict the security or insecurity of children's attachment relationship with their parents. In search for the mechanism of intergenerational transmission of attachment sensitive parenting has been the main focus of research during the past four decades. Meta-analytic work confirmed the role of sensitive parenting, but a large explanatory gap remains to be explained. Parental mentalization has not yet fulfilled its promise as a bridge across the transmission gap. Here we suggest a model of intergenerational transmission that includes context and differential susceptibility, and we argue that the concept of parenting should be broadened to include autonomy support, limit-setting, protective parenting, parental warmth, and repair of mismatches. PMID- 29529481 TI - Attachment and aged care: a systematic review of current research. AB - Attachment theory is an important framework from which to examine familial aged care. Despite this, the role of attachment in later-life caregiving remains unclear. The current study presents a systematic review of papers within the last five years on attachment and various outcomes related to familial aged care. For the caregiver, attachment anxiety was associated with poorer mental health, and attachment insecurity with a more controlling manner of caregiving. The few studies conducted with care recipients found that attachment insecurity was associated with greater self-appraisals of dementia symptoms and a lower sense of security. Research continues to suffer from the use of inadequate assessments of individual differences into adult attachment. PMID- 29529482 TI - Depression: the search for separable behaviors and circuits. AB - Major depressive disorder can manifest as different combinations of symptoms, ranging from a profound and incapacitating sadness, to a loss of interest in daily life, to an inability to engage in effortful, goal-directed behavior. Recent research has focused on defining the neural circuits that mediate separable features of depression in patients and preclinical animal models, and connections between frontal cortex and brainstem neuromodulators have emerged as candidate targets. The development of methods permitting recording and manipulation of neural circuits defined by connectivity has enabled the investigation of prefrontal-neuromodulatory circuit dynamics in animal models of depression with exquisite precision, a systems-level approach that has brought new insights by integrating these fields of depression research. PMID- 29529483 TI - The role of bone morphogenetic proteins 2 and 4 in mouse dentinogenesis. AB - OBJECTIVE: The bone morphogenetic proteins (BMPs) play crucial roles in tooth development. However, several BMPs retain expression in the dentin of the fully patterned and differentiated tooth. We hypothesized that BMP signaling therefore plays a role in the function of the differentiated odontoblast, the job of which is to lay down and mineralize the dentin matrix. DESIGN: We generated mice deficient in Bmp2 and 4 using a dentin matrix protein 1 (Dmp1) promoter-driven cre recombinase that was expressed in differentiated odontoblasts. RESULTS: The first and second molars of these Bmp2 and Bmp4 double conditional knockout (DcKO) mice displayed reduced dentin and enlarged pulp chambers compared to cre-negative littermate controls. DcKO mouse dentin in first molars was characterized by small, disorganized dentinal fibers, a wider predentin layer, and reduced expression of dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1), and bone sialoprotein (BSP). DcKO mouse odontoblasts demonstrated increased type I collagen mRNA production, indicating that the loss of BMP signaling altered the rate of collagen gene expression in these cells. Bmp2 and Bmp4 single Dmp1-cre knockout mice displayed no discernable dentin phenotype. CONCLUSIONS: These data demonstrate that BMP signaling in differentiated odontoblasts is necessary for proper dentin production in mature teeth. PMID- 29529485 TI - Do asymptomatic respiratory viral infections occur? PMID- 29529484 TI - Remineralizing effect of a fluoridated gel containing sodium hexametaphosphate: An in vitro study. AB - OBJECTIVES: To evaluate in vitro the effect of neutral pH topical gels with reduced fluoride concentration (F), supplemented or not with sodium hexametaphosphate (HMP) on the remineralization of dental enamel, using a pH cycling model. Materials and methods Bovine enamel blocks with caries-like lesions were randomly treated with five gels (n = 24/group): without F/HMP (Placebo); 4500 ppm F (4500F), 4500F plus 9% HMP (4500F + HMP); 9000 ppm F (9000F); and 12,300 ppm F (Acid gel). After pH-cycling, the percentage of surface hardness recovery (%SHR), integrated loss of subsurface hardness (DeltaKHN), and concentrations of loosely- (CaF2) and firmly-bound (FA) fluoride formed and retained in/on enamel were determined. The results were analyzed by ANOVA followed by the Student-Newman-Keuls test (p < 0.001). RESULTS: The 4500F + HMP gel promoted the highest %SHR among all groups; the lowest DeltaKHN was achieved by 4500F + HMP and Acid gel, without significant differences between these. The Acid gel group presented the highest CaF2 and FA formed and retained on/in enamel (p < 0.001). CONCLUSION: Based on the present results, the addition of 9% sodium hexametaphosphate to a gel with reduced fluoride concentration (4500F) was able to significantly enhance the remineralization of artificial carious lesions in vitro when compared to 4500F, reaching protective levels similar to an acidic formulation with ~3-fold higher fluoride concentration. PMID- 29529486 TI - A systematic and quantitative evaluation of plantar stimulation: The effect of type, pattern, force of stimulation in eliciting an accurate plantar response. AB - OBJECTIVES: Systematic and quantitative evaluation of the plantar reflex has been infrequently studied in the past and can help assess the vexing variables encountered in its elicitation. The objective of this study was to determine the effect of type, pattern and force of stimulation in eliciting an accurate plantar response in patients with pyramidal dysfunction and healthy individuals. PATIENTS AND METHODS: A special instrument was designed to give a predesigned force of stimulus. The plantar surface of foot was divided into nine parts and point and stroke stimulations were studied systematically in pyramidal weakness feet (cases) and healthy control feet (controls) with predefined forces. Results were tabulated and statistically analysed. RESULTS: Stroke stimulation was superior to point stimulation in eliciting plantar response. There was no significant difference in the responses to the three predefined forces used for stroke stimulations. Sensitivity of Babinski sign was 72.9% and specificity was 100%. In pyramidal weakness feet, extensor responses were significantly elicited from lateral starting stroke patterns (67%) and on moving medially they were replaced by flexor responses (44%). Withdrawal responses increased with the stimulations reaching the distal foot and with the curvilinear component of stimulations. Sensitivity responses (related to the sensitivity of an individual) contaminate the plantar response and occasionally make its interpretation difficult. In subjects with bilateral sensitivity with unilateral disease, knowing the sensitivity pattern on the normal side improved the interpretation of plantar response on the abnormal side. CONCLUSIONS: Based on this study, the optimal method for eliciting Babinski sign accurately is to stroke the lateral aspect of the sole of the foot in a straight line up to mid foot. This should be performed in both feet three times, and if the weakness is unilateral, it should be performed in the normal leg first to aid interpretation of the affected leg. PMID- 29529487 TI - Minimally invasive resection of large dumbbell tumors of the lumbar spine: Advantages and pitfalls. AB - OBJECTIVES: The surgical management of dumbbell tumors of the lumbar spine remains controversial, because of their large volume and complex location, involving both the spinal canal and the retro peritoneum. While sporadically reported, our study aims to confirm the value of minimally invasive posterior access for the complete resection of large lumbar dumbbell tumors. PATIENTS AND METHODS: In this prospective study, we included all consecutive patients who underwent the resection of a voluminous dumbbell tumor at the lumbar spine through a minimally invasive approach, between March 2015 and August 2017. There were 4 men and 4 women, with a mean age at diagnosis of 40.6 years (range 29-58 years). The resection was performed through a trans muscular tubular retractor by the same surgical team. Operative parameters and initial postoperative course were systematically reported. Clinical and radiological monitoring was scheduled at 3 months, 1 year and 2 years. RESULTS: The mean operative time was 144 min (range 58-300 minutes) and the mean estimated blood loss was 250 ml (range 100 500 ml). Gross total resection was achieved in all patients. No major complication was reported. The mean length of hospital stay was 3.1 days (range 2 to 6 days). Histological analysis confirmed the diagnosis of grade 1 schwannoma in all patients. The mean follow up period was 14.9 months (range 6 to 26 months), and 5 patients completed at least 1-year follow-up. At 6 months the Macnab was excellent in 6 patients, good in one patient and fair in one patient because of residual neuropathic pain requiring the maintenance of a long-term treatment. No tumor recurrence was noted to date. CONCLUSION: Lumbar dumbbell tumors can be safely and completely resected using a single-stage minimally invasive procedure, in a trained team. PMID- 29529488 TI - Amelioration of collagen antibody induced arthritis in mice by an antibody directed against the fibronectin type III repeats of tenascin-C: Targeting fibronectin type III repeats of tenascin-C in rheumatoid arthritis. AB - Tenascin-C (TN-C) levels are elevated in the synovial tissue and fluid, as well as cartilage of rheumatoid arthritis (RA) patients. In addition, the presence of TN-C fragments has also been documented in arthritic cartilage. We have previously shown that a single chain variable fragment antibody (TN64), directed against the fibronectin type III repeats 1-5 (TNfnIII 1-5) of TN-C, effectively inhibits fibrotic pathology. Given that fibrosis results from chronic inflammation, and the fact that increased levels of TN-C in the synovial fluid of patients with RA contributes to synovial inflammation and joint destruction, we aimed to investigate the role of TNfnIII 1-5 region of TN-C in RA pathogenesis. Using either the wild type or variants of the two integrin-binding motifs (RGD and AEIDGIEL) present within the TNfnIII 1-5 polypeptide, we demonstrate that the adhesion and migration of synovial fibroblasts is RGD-dependent. The antibody TN64 is effective in inhibiting migration of cells in response to TnfnIII 1-5, and prevents fibroblast-mediated destruction of cartilage. The TN64 antibody was further tested in collagen antibody induced arthritic (CAIA) mice. Our data shows the efficacy of TN64 in preventing induction of arthritis, with significant downregulation of RA-associated cytokines. This suggests that components of the extracellular matrix such as the TNfnIII 1-5 region of TN-C could be exploited to develop therapies to suppress inflammation seen in RA. The TN64 antibody is one such promising candidate in the development of novel treatments for RA. PMID- 29529489 TI - Epigenetics and neurodegeneration: role of early-life nutrition. AB - Neurodegeneration represents a global problem due to the progressive increase in the aging population all over the world. The quality of life in aging and the cost for the health care system require actions to promote healthy aging. In this regard, several risk factors associated with the development of neurodegeneration can be identified, and programs to educate people on the key role of prevention could significantly ameliorate the future picture of the aging population. Here we describe the key role of the pre- and postnatal period of life during the first 1000 days of life, focusing on the importance of nutrition and a healthy lifestyle of mother and offspring for the prevention of neurodegeneration later in life. Environmental risk factors (i.e., nutrition, stress, xenobiotics, alcohol, drugs, smoking, etc.) mediate the genetic and epigenetic signature of offspring which may have long-term effects on the onset of neurodegeneration. PMID- 29529490 TI - Quantification of live Lactobacillus acidophilus in mixed populations of live and killed by application of attenuated reflection Fourier transform infrared spectroscopy combined with chemometrics. AB - Since culture-based methods are costly and time consuming, alternative methods are investigated for the quantification of probiotics in commercial products. In this work ATR- FTIR vibration spectroscopy was applied for the differentiation and quantification of live Lactobacillus (La 5) in mixed populations of live and killed La 5, in the absence and in the presence of enteric polymer Eudragit(r) L 100-55. Suspensions of live (La 5_L) and killed in acidic environment bacillus (La 5_K) were prepared and binary mixtures of different percentages were used to grow cell cultures for colony counting and spectral analysis. The increase in the number of colonies with added%La 5_L to the mixture was log-linear (r2 = 0.926). Differentiation of La 5_L from La 5_K was possible directly from the peak area at 1635 cm-1 (amides of proteins and peptides) and a linear relationship between%La 5_L and peak area in the range 0-95% was obtained. Application of partial least squares regression (PLSR) gave reasonable prediction of%La 5_L (RMSEp = 6.48) in binary mixtures of live and killed La 5 but poor prediction (RMSEp = 11.75) when polymer was added to the La 5 mixture. Application of artificial neural networks (ANNs) improved greatly the predictive ability for%La 5_L both in the absence and in the presence of polymer (RMSEp = 8.11 * 10-8 for La 5 only mixtures and RMSEp = 8.77 * 10-8 with added polymer) due to their ability to express in the calibration models more hidden spectral information than PLSR. PMID- 29529491 TI - A simple blood microdialysis in freely-moving rats for pharmacokinetic pharmacodynamic modeling study of Shengmai injection with simultaneous determination of drug concentrations and efficacy levels in dialysate. AB - Microdialysis is a powerful in vivo sampling technique for pharmacokinetic pharmacodynamic (PK-PD) modeling of drugs in pre-clinical and clinical studies. However, the noticeable limitations of previous studies using microdialysis were that animals anesthesia in the whole experiment and the combination of microdialysis and blood sampling for drug and (or) effect detection, which can obviously influence PK and PD behavior of drugs. In this study, a simple blood microdialysis sampling system in freely-moving rats was established for simultaneous study of PK and PD of Shengmai injection (SMI) effect on inducing real-time nitric oxide (NO) release on isoproterenol (ISO) induced myocardial ischemia rats. The LC-MS/MS and HPLC with fluorescence detection (HPLC-FLD) methods were developed to determine ginsenside Rg1, Rg2, Re, Rf, Rb1, Rd and Rc, the main effective components of SMI, and NOx-, the main oxidation products of NO, in dialysates respectively. Through simultaneous determination of drug concentrations and NO efficacy levels in dialysate, the developed methods were successfully applied to set up concentration-time and effect-time profiles followed by PK-PD modeling of SMI effect on inducing NO release after intravenous administration of 10.8 mL kg-1 SMI in myocardial ischemia rats. The PK-PD modeling characterized the dose-effect relationships of SMI and behaved good prediction ability. The established blood microdialysis in freely-moving rats is an appealing technology for rational PK-PD studies when selecting suitable blood endogenous micromolecule as effect marker. PMID- 29529492 TI - Simultaneous quantification of free curcuminoids and their metabolites in equine plasma by LC-ESI-MS/MS. AB - The human health benefits attributed to turmeric/curcumin spice has resulted in its wide utilization as a dietary supplement for companion pets and other animals including horses. While the quantification of free curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and their phase-2 metabolites (curcumin O-sulfate, curcumin-O-glucuronide) have been extensively investigated in human and rodent biological samples (primarily plasma and serum), there is lack of similar data for horses. Herein, we report a validated LC-ESI-MS/MS method for the simultaneous quantification of the aforementioned free curcuminoids and their metabolites in equine plasma. The linearity of the aforementioned curcuminoids and curcumin-O-sulfate was in the range of 0.5-1000 ng/mL and 1-1000 ng/mL for curcumin-O-glucuronide with 85-115% accuracy and <15% precision in equine plasma. The method was validated based on US FDA criteria and applied to characterize the pharmacokinetics of curcumin-O-sulfate in equine plasma. PMID- 29529493 TI - Does the serotonin receptor gene (rs6313 and rs6314) polymorphism have a role in suicidal attempts? AB - Suicide is an important public health problem. The aim of the present study is to determine the incidence of serotonin receptor gene polymorphisms (rs6313and rs6314) in patients with a history of suicide attempt by blood sampling and to evaluate whether a causal relation exists between gene polymorphisms and suicide. After obtaining the necessary approvals for the study, we included 178 patients with attempted suicide history admitted to the emergency room between December 14, 2016 and July 31, 2016; 174 control subjects were also included. The blood samples were tested for rs6313 and rs6314 polymorphisms. Among the 178 cases with attempted suicide history, 116 (65.2%) were females and 62 (35.8%) were males. With regard to rs6313 polymorphisms in the case group, 40 cases had AA genotype, 99 had AG genotype, and 39 had GG genotype. In the control group, 38 subjects had AA genotype, 91 had AG genotype, and 45 had GG genotype. With regard to rs6314 polymorphisms, 176 cases in the case group had AG genotype and two cases had GG genotype in the case group, whereas 171 subjects in the control group had AG genotype and three subjects had GG genotype in the control group. The present study did not find any significant association between the incidence of rs6313 and rs6314 polymorphisms and suicidal behavior. PMID- 29529494 TI - What do clinicians understand about deaths reportable to the coroner - Use of clinical scenarios to enhance learning. PMID- 29529495 TI - In silico investigation of the molecular effects caused by R123H variant in secretory phospholipase A2-IIA associated with ARDS. AB - Phospholipase A2-IIA catalyzes the hydrolysis of the sn-2 ester of glycerophospholipids. A rare c.428G > A (p.Arg143His) variant in PLA2G2A gene was found in two infants affected by acute respiratory distress syndrome (ARDS) by whole coding region and exon/intron boundaries sequencing. To obtain insights into the possible molecular effects of the rare R123H mutation in secretory PLA2 IIA (sPLA2-IIA), molecular modelling, molecular dynamics (MD) using principal component analysis (PCA) and continuum electrostatic calculations were conducted on the crystal structure of the wild type protein and on a generated model structure of the R123H mutant. Analysis of MD trajectories indicate that the overall stability of the protein is not affected by this mutation but nevertheless the catalytically crucial H-bond between Tyr51 and Asp91 as well as main electrostatic interactions in the region close to the mutation site are altered. PCA results indicate that the R123H replacement alter the internal molecular motions of the enzyme and that collective motions are increased. Electrostatic surface potential studies suggest that after mutation the interfacial binding to anionic phospholipid membranes and anionic proteins may be changed. The strengthening of electrostatic interactions may be propagated into the active site region thus potentially affecting the substrate recognition and enzymatic activity. Our findings provide the basis for further investigation and advances our understanding of the effects of mutations on sPLA2 structure and function. PMID- 29529496 TI - Identification of novel agonists and antagonists of the ecdysone receptor by virtual screening. AB - Insect growth is regulated by the steroid hormone 20-hydroxyecdysone (20E), which works via the ecdysone receptor (EcR). To identify biologically active and novel ecdysone agonists/antagonists, ligand/structure-based virtual screening combined with pharmacophore modeling and molecular docking was performed to identify novel nonsteroidal lead compounds. Nine molecules were screened and selected for an in vitro cell-based reporter bioassay. The results showed that VS-006 and VS-009 exhibited antagonistic activity in S2 cells, whereas only VS-006 exhibited antagonistic activity in Bm5 cells. Molecular dynamic simulation of VS-006 complexed with the ligand binding domain of EcR validated the binding stability of VS-006 and highlighted the key residues for further lead optimization. PMID- 29529498 TI - Metabotropic glutamate receptor involvement in the pathophysiology of amyotrophic lateral sclerosis: new potential drug targets for therapeutic applications. AB - Amyotrophic lateral sclerosis (ALS) is a complex genetic, late age-onset, progressive neurodegenerative disorder leading to the death of upper and lower motor neurons. Life expectancy after diagnosis is short due to the ongoing degeneration and to the lack of effective treatments. Axonal alterations, mitochondrial deficits, RNA changes, protein misfolding and turnover, glial dysfunction and hyperexcitability are key players in molecular mechanisms involved in the degeneration of motor neurons. In the context of hyperexcitability, metabotropic glutamate (mGlu) receptors, which are widely distributed throughout the central nervous system and act through many intracellular signaling pathways, are emerging as novel potential drug targets for the therapeutic treatment of ALS, as they are able to counteract excitotoxicity by reducing glutamate release and inducing the production of neurotrophic factors. PMID- 29529497 TI - The social neuroscience of mentalizing: challenges and recommendations. AB - Our ability to understand and think about the mental states of other people is referred to as 'mentalizing' or 'theory of mind'. It features prominently in all social behavior, is essential for maintaining relationships, and shows pronounced individual differences. Here we review new approaches to study the underlying psychological mechanisms and discuss how they could best be investigated using modern tools from social neuroscience. We list key desiderata for the field, such as validity, specificity, and reproducibility, and link them to specific recommendations for the future. We also discuss new computational modeling approaches, and the application to psychopathology. PMID- 29529499 TI - An access to a library of novel triterpene derivatives with a promising pharmacological potential by Ugi and Passerini multicomponent reactions. AB - The promising combination of natural product leads and their derivatization by isocyanide-based multicomponent reactions (IMCRs) has gained interest in accessing diversity-oriented libraries with auspicious pharmacological potential. Therefore, a set of 34 Ugi and 3 Passerini products was successfully synthesized starting from naturally occurring triterpenoids, i.e. oleanolic acid (OA) and maslinic acid (MA), followed by a biological evaluation of the novel alpha acylamino carboxamides and the alpha-acyloxy carboxamides in colorimetric SRB assays to determine their cytotoxic potential. Especially, the MA-Ugi products 6a, 6b and 7b showed a remarkable cytotoxicity for A2780 ovarian carcinoma cells in a low MUM range. Compounds 6a and 7b induced programmed cell death in part through the apoptosis pathway. PMID- 29529501 TI - Polypharmacology in HIV inhibition: can a drug with simultaneous action against two relevant targets be an alternative to combination therapy? AB - HIV infection still has a serious health and socio-economical impact and is one of the primary causes of morbidity and mortality all over the world. HIV infection and the AIDS pandemic are still matters of great concern, especially in less developed countries where the access to highly active antiretroviral therapy (HAART) is limited. Patient compliance is another serious drawback. Nowadays, HAART is the treatment of choice although it is not the panacea. Despite the fact that it suppresses viral replication at undetectable viral loads and prevents progression of HIV infection into AIDS HAART has several pitfalls, namely, long term side-effects, drug resistance development, emergence of drug-resistant viruses, low compliance and the intolerance of some patients to these drugs. Moreover, another serious health concern is the event of co-infection with more than one pathogen at the same time (e.g. HIV and HCV, HBV, herpes viruses, etc). Currently, the multi-target drug approach has become an exciting strategy to address complex diseases and overcome drug resistance development. Such multifunctional molecules combine in their structure pharmacophores that may simultaneously interfere with multiple targets and their use may eventually be more safe and efficacious than that involving a mixture of separate molecules because of avoidance or delay of drug resistance, lower incidence of unwanted drug-drug interactions and improved compliance. In this review we focus on multifunctional molecules with dual activity against different targets of the HIV life cycle or able to block replication, not only of HIV but also of other viruses that are often co-pathogens of HIV. The different approaches are documented by selected examples. PMID- 29529500 TI - Anti-inflammatory hybrids of secondary amines and amide-sulfamide derivatives. AB - The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000 fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4 positive tumor cells. Additionally, compound 7a blocked mice ear inflammation by 67% and suppressed the accumulation of inflammatory cells in an in vivo mouse ear edema evaluation. Western blot analyses revealed that 7a inhibited the CXCR4/CXCL12-mediated phosphorylation of Akt and p44 in a dose-dependent manner. Moreover, compound 7a had no observable cytotoxicity and displayed a favorable plasma stability in our preliminary pharmacokinetic study. These results confirmed that this is a feasible method to develop CXCR4 modulators for the regulation and reduction of inflammation. PMID- 29529502 TI - Molecular interaction of novel benzothiazolyl triazolium analogues with calf thymus DNA and HSA-their biological investigation as potent antimicrobial agents. AB - The binding behaviour between calf thymus DNA and synthesized benzothiazolyl triazolium derivatives as potent antimicrobial agents was explored by means of spectroscopic applications together with molecular docking study at the sub domain IIA, binding site I of human serum albumin (HSA). Most of the synthesized derivatives presented significant antimicrobial inhibition when compared with the clinical Norfloxacin, Chloromycin, and Fluconazole. In particular, compound 5q presented efficient anti-Bacillus subtilis, anti-Escherichia coli, anti Salmonella typhi, and anti-Psuedomonas aeruginosa activity with low MIC values of 2-8 MUg/mL which were relatively superior to the reference drugs. The preliminarily investigation of interaction studies with calf thymus DNA demonstrated that the most active compound 5q could effectively intercalate into DNA to form 5q-DNA complex. Further investigations revealed that human serum albumin could effectively transport compound 5q while molecular modelling studies with good docking score showed that hydrophobic interactions as well as hydrogen bonds played a significant role in the interaction of compound 5q with HSA. In addition, the cytotoxic investigation carried out on four different cancerous cell lines (3 human cell lines and 1 murine cell lines) by MTT assay presented that compound 5n is active against MDA cell lines with IC50 values less than 100 MUg/mL. PMID- 29529503 TI - Identification of small-molecule inhibitors of USP2a. AB - USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2 thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization. PMID- 29529504 TI - Synthesis and antimycobacterial activity of 1-(beta-d-Ribofuranosyl)-4 coumarinyloxymethyl- / -coumarinyl-1,2,3-triazole. AB - A series of beta-d-ribofuranosyl coumarinyl-1,2,3-triazoles have been synthesized by Cu-catalyzed cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62-70% overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in nature and some of them were found to be more active than one of the first line antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420 times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin, ethambutol and streptomycin) against multidrug resistant clinical isolate 591. Study of in silico pharmacokinetic profile indicated the drug like characters for the test molecules. Further, transmission electron microscopic experiments revealed that these compounds interfere with the constitution of bacterial cell wall possibly by targeting mycobacterial InhA and DNA gyrase enzymes. Study conducted on the activities of the test compounds on bacterial InhA and DNA gyrase revealed that the most bactericidal test compound, N1-(beta-d ribofuranosyl)-C4-(4-methylcoumarin-7-oxymethyl)-1,2,3-triazole (6b) and its corresponding directly linked conjugate N1-(beta-d-ribofuranosyl)-C4-(4 methylcoumarin-7-yl)-1,2,3-triazole (11b) significantly inhibited the activity of both the enzymes. The results were further supported by molecular docking studies of the compound 6b and 11b with bacterial InhA and DNA gyrase B enzymes. Further, the cytotoxicity study of some of the better active compounds on THP-1 macrophage cell line using MTT assay showed that the synthesized compounds were non cytotoxic. PMID- 29529505 TI - Release kinetics and cell viability of ibuprofen nanocrystals produced by melt emulsification. AB - The clinical use of poorly water-soluble drugs has become a big challenge in pharmaceutical development due to the compromised bioavailability of the drugs in vivo. Nanocrystals have been proposed as a formulation strategy to improve the dissolution properties of these drugs. The benefits of using nanocrystals in drug delivery, when compared to other nanoparticles, are related to their production facilities, simple structure, and suitability for a variety of administration routes. High pressure homogenization (HPH) is the most promising production process, which can be employed at low or high temperatures. Ibuprofen nanocrystals with a mean size below 175 nm, and polydispersity below 0.18, have been produced by melt-emulsification, followed by HPH. Two nanocrystal formulations, differing on the surfactant composition, have been produced, their in vitro ibuprofen release tested in Franz diffusion cells and adjusted to several kinetic models (zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, Baker-Lonsdale and Weibull model). Cell viability was assessed at 3, 6 and 24 h of incubation on human epithelial colorectal cells (Caco-2) by AlamarBlue(r) colorimetric assay. For both formulations, Caco-2 cells viability was dependent on the drug concentration and time of exposure. PMID- 29529506 TI - Modulation of osteogenic and haemostatic activities by tuning cationicity of genipin-crosslinked chitosan hydrogels. AB - Chitosan as a natural cationic polysaccharide has drawn wide interests as surface modification materials in orthopedic applications, with the potential to achieve combined osteogenic, antimicrobial and haemostatic functions. The cationicity of chitosan has been reported to play an important role in modifying the osteoblastic cell responses and the antibacterial activities, while its effect on the haemostatic properties has been rarely studied. To this aim, we prepared carboxymethyl chitosan hydrogels with different cationicity through crosslinking with different concentrations of genipin (1%, 2.5%, 5% and 10%). The genipin concentration strongly influenced both mesenchymal stem cell (MSC) responses and blood coagulation activity for chitosan-hydroxyapatite samples. Increasing genipin concentration overall enhanced the osteogenic and haemostatic potentials, and an optimum window of chitosan cationicity (5% genipin in our case) led to both the best MSC response and coagulant activities. In particular, the cationicity had demonstrated a profound modulation effect on the haemostatic activities of chitosan samples, through influencing three different aspects of the coagulation processes, including intrinsic coagulation pathway, aggregation and activation of platelet, and activation of erythrocyte. Tuning the crosslinking degree thus provides a simple and effective approach to achieving combined osteogenic and haemostatic functions, which has great potential in surface modification of surgical implants. PMID- 29529507 TI - Borderline personality disorder symptoms in treatment-naive actively drinking alcoholics. AB - Borderline personality disorder (BPD) is often a complicating comorbid factor in alcohol use disorders and substance use disorders. Previous work showed that abstinent alcoholics endorsed lifetime and current symptoms of most of the BPD criteria at much higher rates than controls, with much higher symptom counts for short-term abstinent alcoholic (STAA) women than men, which is consistent with such symptoms negatively affecting female alcoholics' ability to maintain abstinence. Because prior work has also shown that treatment-naive alcoholics (TNA) are not the same as treated alcoholics observed earlier in their alcohol dependence, but rather are a different population with potentially lower psychiatric comorbidity, in this study we compared BPD symptom criteria between TNA samples of comparable age to the control and STAA samples, including both men and women and individuals dependent on alcohol only or with lifetime dependence on both alcohol and drugs. BPD symptoms were obtained using the SCID-II, and endorsed symptoms were classified as current or lifetime. Logistic regression analyses were used to test for effects of group, sex, presence of a lifetime drug dependence diagnosis, and their interactions for lifetime and current symptom endorsement for each BPD criteria. Groups were compared pairwise (TNA vs. NSAC, and STAA vs. TNA). The effect of a lifetime drug dependence diagnosis was not significant for any BPD symptom variable, consistent with the alcohol groups' BPD symptoms being unaffected by the presence of a comorbid drug dependence. The primary result presented here is that TNA women have borderline symptomatology more similar to that of treated STAA than to NSAC, while TNA men have borderline symptomatology more similar to NSAC than to STAA. A visual examination of co occurring BPD symptoms showed that while more BPD symptoms are likely to be present in TNA and STAA vs. NSAC, there is no grouping of criteria (i.e., symptom cluster) that is characteristic of TNA or STAA. PMID- 29529508 TI - The unique contribution of acceptance without judgment in predicting nonsuicidal self-injury after 20-weeks of dialectical behaviour therapy group skills training. AB - The current research tested whether four dimensions of mindfulness - acceptance without judgment, observing, describing and acting with awareness - predicted frequency of nonsuicidal self-injury (NSSI) and mediate the relationship with NSSI outcomes during 20-weeks of Dialectical Behaviour Therapy (DBT) skills training for borderline personality disorder (BPD). Eighty-four self-harming individuals with BPD were randomized to either DBT skills training or to a waitlist control group. A series of regressions revealed no relationship between dimensions of mindfulness and NSSI at baseline. There was a significant effect of DBT skills training on NSSI. As well, mediation analysis indicated that acceptance without judgment, specifically, mediated the relation between DBT skills training and change in frequency of NSSI. PMID- 29529509 TI - Ce(III, IV)-MOF electrocatalyst as signal-amplifying tag for sensitive electrochemical aptasensing. AB - Metal-organic frameworks (MOFs) as a new class of porous materials have attracted increasing attention in the field of biomimetic catalysis. This study firstly reports a mixed valence state Ce-MOF possessing intrinsic catalytic activity towards thionine (Thi), and its application in constructing an amplified electrochemical aptasensor for thrombin detection. As noticed, the novel catalytic process combines the advantages of 3D infinite extension of the Ce(III, IV)-MOF skeleton containing large amounts of catalytic sites and spontaneous recycling of the Ce(III)/Ce(IV) for electrochemical reduction of Thi, thereby presenting amplified electrochemical signals. To further improve the aptasensor performance, the high selectivity of proximity binding-induced DNA strand displacement and high efficiency of exonuclease III-assisted recycling amplification were incorporated into the assay. The aptasensor was employed to detect thrombin in complex serum samples, which shows high sensitivity, specificity, stability and reproducibility. This work offers an opportunity to develop MOF-based electrocatalyst as signal-amplifying tag for versatile bioassays and catalytic applications. PMID- 29529510 TI - Novel photoluminescence enzyme immunoassay based on supramolecular host-guest recognition using L-arginine/6-aza-2-thiothymine-stabilized gold nanocluster. AB - A new photoluminescence (PL) enzyme immunoassay was designed for sensitive detection of aflatoxin B1 (AFB1) via an innovative enzyme substrate, 6-aza-2 thiothymine-stabilized gold nanocluster (AAT-AuNC) with L-arginine. The enzyme substrate with strong PL intensity was formed through supramolecular host-guest assembly between guanidine group of L-arginine and AAT capped on the surface of AuNC. Upon arginase introduction, the captured L-arginine was hydrolyzed into ornithine and urea, thus resulting in the decreasing PL intensity. Based on this principle, a novel competitive-type immunoreaction was first carried out on AFB1 bovine serum albumin (AFB1-BSA) conjugate-coated microplate, using arginase labeled anti-AFB1 antibody as the competitor. Under the optimum conditions, the PL intensity increased with the increment of target AFB1, and allowed the detection of the analyte at concentrations as low as 3.2 pg mL-1 (ppt). Moreover, L-arginine-AAT-AuNC-based PL enzyme immunoassay afforded good reproducibility and acceptable specificity. In addition, the accuracy of this methodology, referring to commercial AFB1 ELISA kit, was evaluated to analyze naturally contaminated or spiked peanut samples, giving well-matched results between two methods, thus representing a useful scheme for practical application in quantitative monitoring of mycotoxins in foodstuff. PMID- 29529511 TI - A wearable electrochemical glucose sensor based on simple and low-cost fabrication supported micro-patterned reduced graphene oxide nanocomposite electrode on flexible substrate. AB - In this study, a reduced graphene oxide (rGO)-based nanostructured composite working electrode of high quality was successfully microfabricated and micro patterned on a flexible polyimide substrate using simple low-cost fabrication processes. Gold and platinum alloy nanoparticles were electrochemically deposited onto the microfabricated rGO surface and chitosan-glucose oxidase composites were integrated onto the modified surface of the working electrode to develop a human sweat-based wearable glucose sensor application. The fabricated biosensor exhibited excellent amperometric response to glucose at a detection range of 0 2.4 mM (covers the glucose range in sweat), with a sensitivity of 48 MUA/mMcm2, a short response time (20 s), and high linearity (0.99). The detection limit for glucose was calculated as 5 um. The human sweat/mixing glucose samples initially used for testing indicated acceptable detection performance and stability for low glucose concentrations. These results confirm that the proposed nanostructured composite flexible working electrode and fabrication process are highly promising for application as human sweat-based electrochemical glucose sensors. PMID- 29529512 TI - The importance of antibody orientation in the electrochemical detection of ferritin. AB - The way of immobilization of the monoclonal antibody (type IgG) on the electrode surface has a significant effect on the amount of the immobilized protein and in consequence on current signal of protein. Herein, we demonstrate that the application of appropriately functionalized phenyl film allowed us to control the orientation of the antibody (Ab) molecules on the electrode surface. The influence of Ab orientation on the efficiency of antigen-antibody interaction was tested with an example blood plasma protein (ferritin; Ft). To control the orientation of Ab molecules the phenyl films containing -COOH or -NH2 groups were applied. Contrary to aminoethylophenyl layer, the carboxyphenyl film guaranteed the shortest distance between the redox center of the protein and the electrode surface. Additionally, the application of an external magnetic field together with magnetic nanoparticles allowed achieving the best orientation to observe well-defined ferritin current signals. The proposed method of ferritin detection can be successfully used in the concentration range of Ft between 0.1 and 30 ug dL-1. The detection limit for a carboxyphenyl film was estimated as 0.40 +/- 0.04 and 0.13 +/- 0.04 ug dL-1 for impedance and voltammetric measurements, respectively. In turn, for an aminoethylophenyl film the detection limit was 0.03 +/- 0.002 (electrochemical impedance spectroscopy; EIS) and 0.02 +/- 0.002 ug dL 1 (differential pulse voltammetry, DPV). The interday precision (reproducibility) was calculated (4.10 / 9.10% RSD) together with the intraday precision / repeatability (3.20 / 8.0% RSD) for the studied samples. The functionality of the sensor has been tested on rat blood samples. Based on the performed investigations it can be stated that the developed sensor was characterized by high selectivity and good sensitivity. PMID- 29529513 TI - Biodegradation of four selected parabens with aerobic activated sludge and their transesterification product. AB - Parabens are preservatives widely used in foodstuffs, cosmetics and pharmaceuticals, which have led to elevated paraben concentrations in wastewater and receiving waters. Laboratory-scale batch experiments were conducted to investigate the adsorption and degradation of parabens in an aerobic activated sludge system. Results show that biodegradation plays a key role in removing parabens from the aerobic system of wastewater treatment plants, while adsorption on the sludge is not significant. The effects of parent paraben concentration, concentration of mixed liquor suspended solids (MLSS), initial pH and temperature on degradation were investigated using kinetic models. The data shows that the degradation of parabens could be described by the first-order kinetic model with the rate constant ranging from 0.10 to 0.88 h-1 at 25 degrees C and pH 7.0. Paraben degradation can be enhanced by increasing the MLSS concentration and temperature, or by decreasing the parent paraben concentration. Furthermore, the pH of the incubation system should be lower than 8.0. The half-lives of the parabens were estimated to range between 0.79 and 6.9 h, with methylparaben exhibiting the slowest degradation rate. During degradation in the present system, transesterification occurred, with methylparaben being the major transformation product in the incubation systems of ethylparaben, propylparaben and butylparaben. These results were confirmed by mass spectrometry and aliphatic alcohol additive experiments. This is the first discovery of paraben transesterification in an activated sludge system, and it is associated with trace methanol in the system. PMID- 29529514 TI - Markers of oil exposure in cold-water benthic environments: Insights and challenges from a study with echinoderms. AB - In spite of increasing naval activities and petroleum exploration in cold environments, there is currently a paucity of tools available to monitor oil contamination in boreal marine life, especially in sedentary (non-fish) species that dominate benthic communities. This research aimed to identify biotic sources of variation in biomarkers using subarctic echinoderms, and to identify suitable biomarkers of their exposure to hydrocarbons. The focal species included the sea star Asterias rubens, the brittle star Ophiopholis aculeata, the sea urchin Strongylocentrotus droebachiensis, and the sea cucumber Cucumaria frondosa, which are among the most abundant echinoderms in the North Atlantic and Arctic Oceans. The latter two species are also commercially exploited. A series of 96-h acute exposures of the water-accommodating fraction (WAF) of used lubricating oil (ULO) were performed in different seasons (i.e. distinct reproductive stages). Digestive and reproductive tissues were analyzed for baseline and response levels of glutathione peroxidase (GPx) and ethoxyresorufin-O-deethylase (EROD). GPx activity was detected in the pyloric caecum, stomach, and gonad of sea stars, the intestine and gonad of sea cucumbers, and the gonad of brittle stars and sea urchins. No seasonal variation in baseline GPx activity occurred. Upon exposure to the ULO WAF, sex-based differences were elicited in the GPx activity of sea star stomachs (lower in females than males). EROD activity was present in the pyloric caeca of sea stars, and the gonads of brittle stars and sea urchins. An interaction between season and sex on baseline EROD activity was measured in the gonads of sea urchins. Ovaries exhibited significant seasonal variation in EROD activity and had greater activity than testes during the spawning and post spawning seasons. Seasonal variation in EROD activity also occurred in sea star pyloric caeca and brittle star gonads. Furthermore, testes of sea urchins exposed to the ULO WAF exhibited suppressed EROD activity compared to baseline levels. The nearly universal presence of GPx activity highlights its potential as a useful biomarker, while EROD activity was much more limited. Findings suggest a complex relationship between temporal and biotic factors on both the baseline and response levels of enzymatic activity, emphasizing the need to consider sex and sampling season in studies of biomarkers of hydrocarbon exposure in boreal indicator species that display annual reproductive cycles. PMID- 29529515 TI - Arsenic uptake and accumulation in rice (Oryza sativa L.) with selenite fertilization and water management. AB - The accumulation of arsenic (As) in rice grain is a potential threat to human health. Our study investigated the possible mediatory role of selenite fertilization on As uptake and accumulation by rice (Oryza sativa L.) under different water management regimes (aerobic or flooded) in a pot experiment. Soil solutions were also extracted during the growing season to monitor As dynamics. Results showed that As contents in the soil solutions, seedlings, and mature rice were higher under flooded than under aerobic water management. Under aerobic conditions, selenite additions slightly increased As concentrations in soil solutions (in the last two samplings), but decreased As levels in rice plants. Relative to the control, 0.5 mg kg-1 selenite decreased rice grain As by 27.5%. Under flooded conditions, however, selenite additions decreased As in soil solutions, while increased As in rice grain. Tendencies also showed that selenite additions decreased the proportion of As in rice shoots both at the seedling stage and maturity, and were more effective in aerobic soil. Our results demonstrate that the effect of selenite fertilizer on As accumulation by rice is related to water management. PMID- 29529516 TI - An assessment of the relationship between the items of the observational Wisconsin Gait Scale and the 3-dimensional spatiotemporal and kinematic parameters in post-stroke gait. AB - BACKGROUND: There are few reports in the literature investigating the relationship between observational gait scales used to assess individuals after a stroke and objective data acquired from 3-dimensional gait analysis (3DGA). RESEARCH QUESTION: The objective of this study was to compare the relationship between the specific items of the Wisconsin Gait Scale (WGS) and the matching 3 dimensional (3D) spatiotemporal and kinematic gait parameters in individuals after a stroke. In this way we evaluated whether using the simple, inexpensive, easy-to-use, observational WGS can fully substitute for the very costly and time consuming 3DGA. METHODS: The study group comprised 50 participants who had experienced a stroke and were in the chronic stage of recovery. The study participants' gait was evaluated by means of the WGS; spatiotemporal and kinematic gait parameters were examined in the Gait Laboratory with the use of the BTS Smart system. The 3D recording of gait was performed using 2 video cameras positioned in such a way that it was possible to obtain images in the frontal and the sagittal plane. RESULTS: The findings show strong (0.7 <= |R| < 0.9; p < 0.001) or very strong (0.9<= |R| < 1; p < 0.001) correlation between the specific items of the WGS and the matching 3D gait parameters. SIGNIFICANCE: The WGS is a diagnostic tool useful for conducting observational gait analysis in people with post-stroke hemiparesis and in situations when the costly objective methods of gait assessment cannot be applied for various reasons, the scale may be an effective tool enabling the assessment of gait. The WGS may be particularly useful in the subacute period of stroke as video recording of walking takes considerably less time than 3DGA. The study has been registered at the ClinicalTrials.gov, ID: ACTRN12617000436370. PMID- 29529518 TI - Potential antioxidant activity of Morita-Baylis-Hillman adducts. AB - The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity. As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1 picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives. PMID- 29529517 TI - Does local dynamic stability during unperturbed walking predict the response to balance perturbations? An examination across age and falls history. AB - BACKGROUND: Older adults are at an exceptionally high risk of falls, and most falls occur during locomotor activities such as walking. Reduced local dynamic stability in old age is often interpreted to suggest a lessened capacity to respond to more significant balance challenges encountered during walking and future falls risk. However, it remains unclear whether local dynamic stability during normal, unperturbed walking predicts the response to larger external balance disturbances. RESEARCH QUESTION: We tested the hypothesis that larger values of local dynamic instability during unperturbed walking would positively correlate with larger changes thereof due to optical flow balance perturbations. METHODS: We used trunk kinematics collected in subjects across a spectrum of walking balance integrity - young adults, older non-fallers, and older fallers - during walking with and without mediolateral optical flow perturbations of four different amplitudes. RESULTS: We first found evidence that optical flow perturbations of sufficient amplitude appear capable of revealing independent effects of aging and falls history that are not otherwise apparent during normal, unperturbed walking. We also reject our primary hypothesis; a significant negative correlation only in young adults indicated that individuals with more local dynamic instability during normal, unperturbed walking exhibited smaller responses to optical flow perturbations. In contrast, most prominently in older fallers, the response to optical flow perturbations appeared independent of their baseline level of dynamic instability. SIGNIFICANCE: We propose that predicting the response to balance perturbations in older fallers, at least that measured using local dynamic stability, likely requires measuring that response directly. PMID- 29529519 TI - Novel carbamate derivatives as selective butyrylcholinesterase inhibitors. AB - Selective butyrylcholinesterase inhibitors could be the promising drug candidates, used in treatment of Alzheimer's disease. The study describes the synthesis and biological activity of novel carbamate derivatives with N phenylpiperazine, N-benzylpiperazine and 4-benzylpiperidine moieties. Biological studies revealed that most of these compounds displayed significant activity against BuChE. Compound 16 (3-(4-phenyl-piperazin-1-ylmethyl)-phenyl phenylcarbamate) turned out to be the most active (IC50 = 2.00 MUM for BuChE). For all synthesized compounds lipophilicity and other physicochemical properties were calculated using computer programs. Relationship between these properties and activity was also checked. Binding mode with enzyme and the ensuing differences in activity were explained by the molecular modeling studies. PMID- 29529521 TI - Prenatal dexamethasone treatment in the context of at risk CAH pregnancies: Long term behavioral and cognitive outcome. AB - Dexamethasone (DEX) is used to prevent prenatal virilization in female fetuses with congenital adrenal hyperplasia (CAH). Since treatment has to be started before the genotype of the fetus is known, 7 out of 8 fetuses will be exposed to DEX without benefit. Previously, we have observed negative effects on cognition and behavior in DEX treated children. Here we evaluated neuropsychological functions, psychopathology and autistic traits in non-CAH DEX-treated adults exposed during the first trimester of fetal life (duration 6.2 +/- 2.2 weeks). Cognitive functions, psychopathology and autistic traits were compared between DEX-treated subjects (n = 23) and non-exposed controls (n = 58). Cognitive outcome was also evaluated longitudinally for DEX-treated participants. We used neuropsychological tests (Wechsler Scales and the Stroop Interference Test) and questionnaires assessing executive functions (the Barkley Deficit in Executive Functioning Scale), psychopathology (the Montgomery Asberg Depression Ratings Scale, the Hospital Anxiety and Depression Scale, the Liebowitz Social Anxiety Scale) and autistic traits (Autism Quota). We did not observe any significant differences in cognition, psychopathology or autistic traits between DEX-treated individuals and population controls. A significant improvement in verbal working memory (p = 0.038) and in impulse inhibition (p = 0.011) was seen when subjects were evaluated longitudinally. In summary, first-trimester DEX-exposed adult individuals do not show any significant neuropsychological deficits nor an increase in anxiety, depression or autistic traits, compared with a control group from the general population. The results also suggest that the observed deficits in executive functioning during childhood may improve with time. PMID- 29529520 TI - Socioeconomic status, family negative emotional climate, and anti-inflammatory gene expression among youth with asthma. AB - The glucocorticoid receptor gene NR3C1 is an important down-regulator of inflammation and is typically under-expressed in individuals with low socioeconomic status (SES). Negative emotionality has been suggested as a potential mediator of SES disparities in health outcomes. In this study, we expand this literature by naturalistically assessing negative emotionality in a key emotional environment: the family. In a sample of 104 youth with asthma (10 17 years) and their primary caregiver, we assessed SES via caregiver report, emotional expression by youth and parents in the home over four days using the electronically activated recorder (EAR), and NR3C1 expression via blood collected from youth. Although there was not a direct effect of SES on NR3C1 expression, bootstrapping mediation analyses showed a significant indirect path such that lower SES was associated with a more negative family emotional climate, which in turn predicted reduced NR3C1 expression. No mediation effects were found for family positive emotional climate. This research demonstrates the importance of examining the effects of SES on emotion expression in the family context and suggests a critical biopsychosocial pathway underlying SES-based health disparities that may extend beyond youth. PMID- 29529522 TI - Effects of intranasal oxytocin on the attentional bias to emotional stimuli in patients with bulimia nervosa. AB - BACKGROUND: Bulimia nervosa (BN) is characterized by binge eating and emotional dysregulation including increased negative affectivity (anger, anxiety). The aim of this study was to examine the effect of oxytocin on attentional processes towards anger in patients with BN. METHOD: The study design consisted of a double blind, placebo-controlled within-subject crossover, single dose experiment. Sixty four women (31 patients with BN and 33 healthy comparisons) completed self reported measures to evaluate emotional difficulties and were administered a single dose of intranasal oxytocin (40IU) or placebo followed by a visual probe detection task to examine attentional orienting to angry or happy faces. RESULTS: Patients with BN reported higher emotional dysregulation and more difficulties in controlling anger compared to the healthy comparison group. Patients with BN and the healthy women exhibited similar attentional bias to angry faces in the placebo condition. Intranasal oxytocin reduced the attentional bias towards angry faces in both the BN patients and the healthy women. CONCLUSIONS: We found that a single dose of oxytocin reduced vigilance towards angry faces in patients with BN as well as healthy women. The results showed that patients with BN are not different from healthy women in terms of vigilance towards threat. PMID- 29529523 TI - Cortisol increases the return of fear by strengthening amygdala signaling in men. AB - Relapses represent a major limitation to the long-term remission of pathological fear and anxiety. Stress modulates the acquisition and expression of fear memories and appears to promote fear recovery in patients with anxiety disorders. However, the neural correlates underlying stress hormone effects on the return of fear in humans remain unexplored. Likewise, little is known about the interactions between sex and stress hormones on return of fear phenomena. In this functional magnetic resonance imaging study, 32 men and 32 women were exposed to a fear renewal paradigm with fear acquisition in context A and extinction in context B. On the following day, participants received either cortisol or placebo 40 min before return of fear was tested in both contexts in a renewal and reinstatement test. Cortisol increased differential conditioned skin conductance responses in the extinction context B following reinstatement in men but not in women. On the neural level, this effect was characterized by enhanced fear related activation in the right amygdala in men, while an activation decrement in this region was observed after cortisol treatment in women. Our results revealed that cortisol promotes the return of fear in men by strengthening a key node of the fear network - the amygdala. We thereby provide novel insights into a sex specific mechanism mediating stress-induced fear recovery which may translate into different relapse risks and treatment strategies for men and women. PMID- 29529524 TI - Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action. AB - The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABAA agonist, GABAA antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABAA agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABAA receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them. PMID- 29529525 TI - Discrimination of different geographic varieties of Gymnema sylvestre, an anti sweet plant used for the treatment of type 2 diabetes. AB - Gymnema sylvestre (Retz.) R.Br. ex Sm. (Asclepiadaceae) is a well-known Ayurvedic anti-sweet plant for the treatment of type 2 diabetes mellitus. Although it was previously proposed that G. sylvestre exhibits chemical variation based on geography, most research on G. sylvestre has used material originating from India. Morphological and anatomical descriptions, ITS1-5.8S-ITS2 DNA sequencing, and acid hydrolysis analyses showed that G. sylvestre samples from Vietnam are distinguishable from those of Indian origin and thus suggest a dissimilarity among G. sylvestre samples with different geographic distributions. An LC-MS guided strategy targeting 3beta-glucuronide oleane-triterpenes in the Vietnamese G. sylvestre variety led to the isolation of four known compounds and nine previously undescribed compounds, named gymnemosides ND1-ND9. None of the isolated compounds were reported in the Indian sample, further supporting the geo diversity of G. sylvestre. Three compounds, gymnemosides ND7-9, exerted significant stimulatory effects on the uptake of 2-NBDG in 3T3-L1 adipocyte cells and thus have potential as lead molecules for anti-diabetes agents. PMID- 29529526 TI - An automated LS(beta)- NaI(Tl)(gamma) coincidence system as absolute standard for radioactivity measurements. AB - 4pibeta-gamma coincidence method is a powerful and widely used method to determine the absolute activity concentration of radioactive solutions. A new automated liquid scintillator based coincidence system has been designed, developed, tested and established as absolute standard for radioactivity measurements. The automation is achieved using PLC (programmable logic controller) and SCADA (supervisory control and data acquisition). Radioactive solution of 60Co was standardized to compare the performance of the automated system with proportional counter based absolute standard maintained in the laboratory. The activity concentrations determined using these two systems were in very good agreement; the new automated system can be used for absolute measurement of activity concentration of radioactive solutions. PMID- 29529527 TI - Mechano-electric finite element model of the left atrium. AB - Mechanical stretch plays a major role in modulating atrial function, being responsible for beat-by-beat responses to changes in chamber preload, enabling a prompt regulation of cardiac function. Mechano-electric coupling (MEC) operates through many mechanisms and has many targets, making it experimentally difficult to isolate causes and effects especially under sinus conditions where effects are more transient and subtle. Therefore, modelling is a powerful tool to help understand the role of MEC with respect to the atrial electromechanical interaction. We propose a cellular-based computational model of the left atrium that includes a strongly coupled MEC component and mitral flow component to account for correct pressure generation in the atrial chamber as a consequence of blood volume and contraction. The method was applied to a healthy porcine left atrium. Results of the strongly coupled simulation show that strains are higher in the areas adjacent to the mitral annulus, the rim of the appendage, around the pulmonary venous trunks and at the location of the Bachmann's bundle, approximately between the mitral annulus and the region where the venous tissue transitions into atrial. These are regions where arrhythmias are likely to originate. The role of stretch-activated channels was very small for sinus rhythm for the single cardiac beat simulation, although tension development was very sensitive to stretch. The method could be applied to investigate potential therapeutic interventions acting on the mechano-electrical properties of the left atrium. PMID- 29529528 TI - Investigating the contribution of distance-based features to automatic sleep stage classification. AB - OBJECTIVE: In this paper, the contribution of distance-based features to automatic sleep stage classification is investigated. The potency of these features is analyzed individually and in combination with 48 conventionally used features. METHODS: The distance-based set consists of 32 features extracted by calculating Itakura, Itakura-Saito and COSH distances of autoregressive and spectral coefficients of Electrocardiography (EEG) (C3-A2), Left EOG, Chin EMG and ECG signals. All the evaluations are performed on three feature sets: distance-based, conventional and total (combined distance based and conventional). Six ranking methods were used to find the top features with the highest discrimination ability in each set. The ranked feature lists were evaluated using k-Nearest Neighbor (kNN), Artificial Neural Network (ANN), and Decision-tree-based multi-SVM (DSVM) classifiers for five sleep stages including Wake, REM, N1, N2 and N3. Furthermore, the ability of distance-based and conventional features to discriminate between each pair of sleep stages was evaluated using t-test, a hypothesis testing method. RESULTS: Distance-based features occupied 25% of top-ranked features. Simulation results showed that using distance-based features together with conventional features can lead to an enhancement of accuracy. The best classification accuracy (85.5%) was achieved by DSVM classifier and 13 features selected by mRMR-MID and normalized with Min-Max method for total feature set, where two of them were from the distance-based feature set. The t-test results show that distance-based features outperform conventional features in discriminating between N1 and REM stages that is usually a challenge for classification systems. CONCLUSION: Distance-based features have a positive contribution to sleep stage classification, including enhancement of accuracy and better REM-N1 discrimination ability. SIGNIFICANCE: The main motivation for this work was to evaluate new features to characterize each sleep stage in such a way that extracted features were more powerful than conventional features, to distinguish sleep stages from each other, and to improve classifiers accuracy. PMID- 29529529 TI - The putative interplay between DJ-1/NRF2 and Dimethyl Fumarate: A potentially important pharmacological target. AB - Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade. PMID- 29529530 TI - Olfactory dysfunction in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a common chronic neurological disease that causes disability. MS can have various clinical manifestations, one of which is olfactory dysfunction. In clinical practice, olfactory disturbances are usually underdiagnosed. The aim of our study is to assess olfactory function and its relationship with MS disease duration, disability and cognition. METHOD: We assessed 31 MS patients and 24 healthy controls matched in sex and age at our MS outpatient clinic of the Istanbul Education and Research Hospital Neurology Department. Each subject was interviewed to obtain demographic data. The Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test and Montreal Cognitive Assessment (MOCA) were applied to each participant. RESULTS: The CCCRC test scores of the MS patients were lower than those in the control group (p < 0.05). Patients with a longer disease duration and more frequent attacks had lower CCCRC scores (p < 0.05). The Expanded Disability Status Scale scores had no correlation with the CCCRC test scores. The MOCA score was positively correlated with all domains of the olfactory test scores. CONCLUSION: This study supports the presence of olfactory dysfunction in early stages of MS and the correlation of cognitive impairment with olfactory dysfunction, even in the early stages of the disease in young and less physically- disabled patients. The assessment of olfaction may be helpful as a surrogate method for tracking disease progression in patients over time. PMID- 29529531 TI - Relative symbiont input and the lichen symbiotic outcome. AB - The term symbiosis was first used in biology to describe the 'living together' of fungi and algae in lichens. For much of the 20th century, the fungal partner was assumed to be invested with the ability to produce the lichen body plan in presence of a photosynthesizing partner. However, studies of fungal evolution have uncovered discordance between lichen symbiotic outcomes and genome evolution of the fungus. At the same time, evidence has emerged that the structurally important lichen cortex contains lichen-specific, single-celled microbes, suggesting it may function like a biofilm. Together, these observations suggest we may not have a complete overview of symbiotic interactions in lichens. Understanding phenotype development and evolution in lichens will require greater insight into fungal-fungal and fungal-bacterial interplay and the physical properties of the cortex. PMID- 29529532 TI - A new method measuring the interaction of radiotracers with the human P glycoprotein (P-gp) transporter. AB - In drug development, biomarkers for cerebral applications have a lower success rate compared to cardiovascular drugs or tumor therapeutics. One reason is the missing blood brain barrier penetration, caused by the tracer's interaction with efflux transporters such as the P-gp (MDR1 or ABCB1). Aim of this study was the development of a reliable model to measure the interaction of radiotracers with the human efflux transporter P-gp in parallel to the radiolabeling process. LigandTracer(r) Technology was used with the wildtype cell line MDCKII and the equivalent cell line overexpressing human P-gp (MDCKII-hMDR1). The method was evaluated based on established PET tracers with known interaction with the human P-gp transporter and in nanomolar concentration (15 nM). [11C]SNAP-7941 and [18F]FE@SNAP were used as P-gp substrates by comparing the real-time model with an uptake assay and MUPET images. [11C]DASB [11C]Harmine, [18F]FMeNER,[18F]FE@SUPPY and [11C]Me@HAPTHI were used as tracers without interactions with P-gp in vitro. However, [11C]Me@HAPTHI shows a significant increase in SUV levels after blocking with Tariquidar. The developed real-time kinetic model uses directly PET tracers in a compound concentration, which is reflecting the in vivo situation. This method may be used at an early stage of radiopharmaceutical development to measure interactions to P-gp before conducting animal experiments. PMID- 29529533 TI - Social network size relates to developmental neural sensitivity to biological motion. AB - The ability to perceive others' actions and goals from human motion (i.e., biological motion perception) is a critical component of social perception and may be linked to the development of real-world social relationships. Adult research demonstrates two key nodes of the brain's biological motion perception system-amygdala and posterior superior temporal sulcus (pSTS)-are linked to variability in social network properties. The relation between social perception and social network properties, however, has not yet been investigated in middle childhood-a time when individual differences in social experiences and social perception are growing. The aims of this study were to (1) replicate past work showing amygdala and pSTS sensitivity to biological motion in middle childhood; (2) examine age-related changes in the neural sensitivity for biological motion, and (3) determine whether neural sensitivity for biological motion relates to social network characteristics in children. Consistent with past work, we demonstrate a significant relation between social network size and neural sensitivity for biological motion in left pSTS, but do not find age-related change in biological motion perception. This finding offers evidence for the interplay between real-world social experiences and functional brain development and has important implications for understanding disorders of atypical social experience. PMID- 29529534 TI - Deregulation of E-cadherin, beta-catenin, APC and Caveolin-1 expression occurs in canine prostate cancer and metastatic processes. AB - Prostate cancer is a heterogeneous disease with high levels of clinical and gene heterogeneity, consequently offering several targets for therapy. Dogs with naturally occurring prostate cancer are useful models for molecular investigations and studying new treatment efficacy. Three genes and proteins associated with the WNT pathway (beta-catenin, APC and E-cadherin) and Caveolin-1 (CAV-1) were evaluated in canine pre-neoplastic proliferative inflammatory atrophy (PIA), prostate cancer and metastatic disease. The APC gene methylation status was also investigated. As in human prostate cancer, cytoplasmic and nuclear beta-catenin, which are fundamental for activating the canonical WNT pathway, were found in canine prostate cancer and metastasis. Membranous E cadherin was also lost in these lesions, allowing cellular migration to the stroma and nuclear localization of beta-catenin. In contrast to human prostate tumours, no APC downregulation or hypermethylation was found in canine prostate cancer. The CAV-1 gene and protein overexpression were found in canine prostate cancer, and as in humans, the highest levels were found in Gleason scores >=8. In conclusion, as with human prostate cancer, beta-catenin and E-cadherin in the WNT pathway, as well as Caveolin-1, are molecular drivers in canine prostate cancer. These findings provide additional evidence that dogs are useful models for studying new therapeutic targets in prostate cancer. PMID- 29529535 TI - Raman studies of nanocomposites catalysts: temperature and pressure effects of CeAl, CeMn and NiAl oxides. AB - High temperature and pressure effects on the physicochemical properties of binary oxides catalysts were investigated. The nanocomposites catalysts comprising of CeAl, CeMn and NiAl were characterized through various physicochemical techniques. A study of the temperature and pressure induced phenomena monitored by Raman spectroscopy was proposed and discussed. Spectral modifications of the Raman modes belonging to the CeMn suggest structural changes in the solid due to the MnO2 phase oxidation with increasing temperature. The thermal expansion and lattice anharmonicity effects were observed on CeMn due to lack of stability of the lattice vacancies. The CeAl and NiAl composites presented crystallographic stability at low temperatures however, undertake a phase transformation of NiO/Al2O3 into NiAl2O4, mostly without any deformation in its structure with increasing the temperature. It was also inferred that the binary oxides are more stables in comparison with monoxides. Detailed pressure-dependent Raman measurements of the T2g phonon mode of CeMn and NiAl revealed that the pressure contributes to modify bonds length and reduces the particles sizes of the solids. On the contrary, high pressure on CeAl sample improved the stability with addition of Al2O3 in the CeO2 lattice. The results then suggest a good stability of CeAl and NiAl composite catalysts at high pressure and low temperature and show how to prospect of tuning the catalysis for surface reactions entirely through in situ spectroscopic investigations means. PMID- 29529536 TI - Profiling and analysis of multiple constituents in Baizhu Shaoyao San before and after processing by stir-frying using UHPLC/Q-TOF-MS/MS coupled with multivariate statistical analysis. AB - Baizhu Shaoyao San (BSS) is a famous traditional Chinese medicinal formula widely used for the treatment of painful diarrhea, intestinal inflammation, and diarrhea predominant irritable bowel syndrome. According to clinical medication, three medicinal herbs (Atractylodis Macrocephalae Rhizoma, Paeoniae Radix Alba, and Citri Reticulatae Pericarpium) included in BSS must be processed using some specific methods of stir-frying. On the basis of the classical theories of traditional Chinese medicine, the therapeutic effects of BSS would be significantly enhanced after processing. Generally, the changes of curative effects mainly result from the variations of inside chemical basis caused by the processing procedure. To find out the corresponding changes of chemical compositions in BSS after processing and to elucidate the material basis of the changed curative effects, an optimized ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry in positive and negative ion modes coupled with multivariate statistical analyses were developed. As a result, a total of 186 compounds were ultimately identified in crude and processed BSS, in which 62 marker compounds with significant differences between crude and processed BSS were found by principal component analysis and t-test. Compared with crude BSS, the contents of 23 compounds were remarkably decreased and the contents of 39 compounds showed notable increase in processed BSS. The transformation mechanisms of some changed compounds were appropriately inferred from the results. Furthermore, compounds with extremely significant differences might strengthen the effects of the whole herbal formula. PMID- 29529537 TI - Intersphincteric proctectomy for rectal mucocele in a Crohn's patient with anal stenosis. A case report and review of literature. AB - In patients who have undergone a colonic resection with creation of an end colostomy, drainage of mucus secreted by the mucosa of the rectal stump may not be possible if there is an outlet obstruction. With an outlet obstruction, formation of a rectal mucocele occurs. A rectal mucocele is a rare condition which has only been reported sporadically in case reports. We present here the utility of an intersphincteric proctectomy for treatment of a rectal mucocele in a 47 year old male Crohn's patient resulting in negligible post-operative or long term morbidities. PMID- 29529538 TI - A rare case of fusiform celiac artery aneurysm after penetrating trauma. AB - INTRODUCTION: Visceral artery aneurysms are an uncommon clinical problem with aneurysms of the celiac artery only making up a small percentage of all visceral artery aneurysms. The more common splenic and hepatic aneurysms are often symptomatic with pain or rupture and associated hemorrhage. PRESENTATION OF CASE: We present a case of an otherwise healthy 30 yo male with an asymptomatic, posttraumatic arterial aneurysm of the celiac artery. He initially presented to our trauma center after sustaining multiple gunshot wounds which required multiple abdominal surgeries. He represented four weeks later with 3 days of flank pain and fever. Extensive workup yielded an incidental finding of 14 mm fusiform aneurysm of the celiac artery with associated dissection. This was not present on imaging during his initial hospitalization. The patient underwent successful endovascular management. DISCUSSION: Visceral artery aneurysms are rare and when identified often require early intervention. Posttraumatic etiologies are often due to penetrating trauma as in the case presented. Modern high resolution imaging can identify those that are not yet symptomatic. CONCLUSION: Posttraumatic visceral artery aneurysms are rare with an incidence of 0.01-0.2%, however they have a potential for high mortality if undiagnosed or untreated. An aggressive operative approach can lead to favorable outcomes. PMID- 29529539 TI - Evolution of a rare ECG pattern in an aggressive case of neonatal tuberous sclerosis complex. AB - INTRODUCTION: Rhabdomyomas are the most frequent cardiac tumors in children. Furthermore, they are often associated to tuberous sclerosis complex, an autosomal dominant neurocutaneous disorder characterized by tumor-like malformations that involve many organ systems. PRESENTATION OF THE CASE: We describe a rare ECG pattern in a severe case of neonatal tuberous sclerosis complex. DISCUSSION: In the presence of significant rhabdomyomatosis related to tuberous sclerosis, multiple clusters of rhabdomyoma-like cells can infiltrate the myocardium, with increased fibrosis areas. CONCLUSION: Considering the fact that rhabdomyomas often show spontaneous regression, close follow-up is sufficient in hemodynamically stable cases. Destruction of the conduction system, with arrhythmias as consequence, can be the presenting feature of diffuse rhabdomyomatosis. PMID- 29529540 TI - Remote acute subarachnoid hemorrhage after drainage of chronic subdural hematoma: A case report and review of the literature. AB - INTRODUCTION: Chronic subdural hematoma(CSDH) can be treated by a relatively simple burr hole surgery. Acute subarachnoid hemorrhage (SAH) occurring after surgery for CSDH has been reported as a rare but severe complication. CASE REPORT: An 88-year-old female complained of progressive headache and dizziness for one month. A right fronto-temporo-parietal CSDH with a shift in the midline structures and lateral ventricle compression was shown by computed tomography (CT) scans. Closed-system drainage of the hematoma was performed via one burr hole under general anesthesia. Two hours after we began draining the hematoma at the patient's bedside, the patient complained of headache and exhibited impaired consciousness that progressively degenerated. The drainage bag collected 200 ml of bloody liquid overa short time. A subsequent CT scan revealed SAH and an acute subdural hematoma. A CT angiogram excluded the presence of intracranial aneurysms. The patient died of hypostatic pneumonia after 15 days despite conservative medical management. DISCUSSION: Relevant literature was reviewed, and we believe that the occurrence of a hematoma in the opposite hemisphere and the hyperperfusion resulted from the rapid drainage of the hematoma, which caused the rupture of weak bridging veins during drainage. CONCLUSION: Slow decompression with closed-system drainage is recommended to avoid rapid dynamic intracranial changes during drainage of a subdural hematoma, including brain shift or restoration of normal perfusion,to prevent devastating complications. PMID- 29529541 TI - Synchronous gastric leiomyoma and intramuscular abdominal wall granular cell tumor with similar imaging features: A case report. AB - INTRODUCTION: Gastric leiomyomas are benign mesenchymal tumors, comprising about 2.5% of gastric neoplasms, which can be difficult to differentiate from gastrointestinal stromal tumors which have malignant potential. Granular cell tumors in the abdominal wall are also rare. Since mesenchymal tumors are difficult to diagnose by imaging, further studies are needed to establish the diagnosis. PRESENTATION OF CASE: A 60-year-old asymptomatic woman underwent routine upper endoscopy and was found to have a gastric submucosal lesion. Computed tomography scan also showed an abdominal wall mass. The appearance of both lesions on imaging studies were similar, but it was unclear if the two lesions had the same origin. Endoscopic ultrasound-guided fine needle aspiration biopsy of the gastric lesion was insufficient to establish the diagnosis. Laparoscopic-endoscopic cooperative resection of the gastric lesion and ultrasound-guided core-needle biopsy of the abdominal wall mass enabled pathological diagnosis of both lesions. DISCUSSION: Diagnostic imaging findings of these two lesions were similar. Histologic and immunohistochemical studies are essential to establish a definitive diagnosis. Laparoscopic-endoscopic cooperative surgery may be an effective minimally invasive approach, allowing both pathological diagnosis and complete resection of a gastric submucosal tumor, especially when endoscopic-ultrasound guided fine needle aspiration or biopsy fails to make the diagnosis. CONCLUSION: Laparoscopic-endoscopic cooperative surgery can be an effective minimally invasive approach to resect some lesions. This is first report of the patient with a synchronous gastric leiomyoma and an intramuscular granular cell tumor in the abdominal wall. PMID- 29529542 TI - Splenic torsion, a challenging diagnosis: Case report and review of literature. AB - INTRODUCTION: Wandering spleen is an unusual condition characterized by hypermobility of the spleen. This is a rare clinical entity and it's more common in childhood under 1 year of age and in third decade of life. In this second peak, it's more frequent in females. Clinical manifestations can vary from asymptomatic to abdominal emergency. Treatment is often surgical. PRESENTATION OF CASE: We presented a case report of splenic torsion from our hospital and a review of cases described in literature. This is a 40 year-old woman with complaints of upper abdominal pain associated with nausea and vomiting. A marked tenderness and a palpable abdominal mass on left hypochondrium were found as well as a slight increase in inflammatory parameters. A CT was performed and demonstrated findings compatible with splenic torsion. Surgery was performed doing laparoscopic splenectomy; Review of literature was made using the keyword combination: "wandering spleen". The research resulted in 451 articles. DISCUSSION: The physical examination and CT are fundamental for diagnosis. Surgery was performed and laparoscopic splenectomy was made because infarcted spleen; about the review of literature, the majority of patients were female and the average age at the time of diagnosis was 25.2 years. 69.5% needed splenectomy and 78.6% of surgeries were laparotomic. CONCLUSION: Splenic torsion is a rare but important differential diagnosis in patients presenting with acute abdomen. Diagnosis should be made promptly before development of life-threatening complications. Surgery is often necessary and splenopexy or splenectomy can be done. PMID- 29529543 TI - Bowel perforation by lumbar-peritoneal (LP) shunt: A rare complication of neurosurgery. AB - INTRODUCTION: Lumbar-peritoneal (LP) and ventriculo-peritoneal (VP) shunt placement is the treatment of choice for diversion of cerebrospinal fluid (CSF) from the subarachnoid space into the peritoneal cavity. This invasive procedure has been associated with several complications, most commonly infection and obstruction. Perforation of the bowel is an extremely rare complication. CASE PRESENTATION: We report a case of a 72 old female patient with LP shunt for raised intracranial pressure, who presented with LP shunt catheter protruding from anus. This was due to bowel perforation in the recto-sigmoid junction by the distal tip of lumbar-peritoneal shunt. She was surgically treated with removal of the distal part of the shunt, external drainage of the proximal part and primary closure of the perforation. DISCUSSION: The mortality after perforation is relatively high, approaching 15-18%, and it is further increased when infection is present up to 22% with central nervous system (CNS) infection such as meningitis, encephalitis, or brain abscesses (Vinchon, 2006) and 33% with intra abdominal infection. CONCLUSION: Clinical suspicion of abdominal complications by the LP should be raised when patient with hydrocephalus develops acute abdominal symptoms or infection with unusual positive CSF cultures. PMID- 29529544 TI - Continuous, emerging, and dissipating associations between prenatal maternal stress and child cognitive and motor development: The QF2011 Queensland Flood Study. PMID- 29529545 TI - Vertical ground reaction force in stationary running in water and on land: A study with a wide range of cadences. AB - PURPOSE: The aim of this study was to analyze the effect of cadence, immersion level as well as body density on the vertical component (Fymax) of ground reaction force (GRF) during stationary running (SR). METHODS: In a controlled, laboratory study, thirty-two subjects ran at a wide range of cadences (85-210 steps/min) in water, immersed to the hip and to the chest, and on dry land. Fymax. was verified by a waterproof force measurement system and predicted based on a statistical model including cadence, immersion ratio and body density. RESULTS: The effect of cadence was shown to depend on the environment: while Fymax increases linearly with increasing cadence on land; in water, Fymax reaches a plateau at both hip and chest immersions. All factors analyzed, cadence, immersion level and body density affected Fymax significantly, with immersion (aquatic * land environment) showing the greatest effect. In water, different cadences may lead to bigger changes in Fymax than the changes obtained by moving subjects from hip to chest immersion. A regression model able to predict 69% of Fymax variability in water was proposed and validated. CONCLUSION: Cadence, Immersion and body density affect Fymax in a significant and non-independent way. Besides a model of potential use in the prescription of stationary running in water, our analysis provides insights into the different responses of GRF to changes in exercise parameters between land and aquatic environment. PMID- 29529546 TI - Alterations of the serum N-glycan profile in female patients with Major Depressive Disorder. AB - BACKGROUND: Glycans are short chains of saccharides linked to glycoproteins that are known to be involved in a wide range of inflammatory processes. As depression has been consistently associated with chronic low-grade inflammation, we asked whether patients with Major Depressive Disorder show alterations in the N glycosylation pattern of serum proteins that might be linked to associated changes in inflammatory processes. METHODS: In a study cohort of 21 female patients with an acute depressive episode and 21 non-depressed female control subjects aged between 50 and 69 years, we analyzed the serum N-glycan profile by DNA Sequencer Adapted-Fluorophore Assisted Carbohydrate Electrophoresis (DSA FACE) and assessed the serum levels of interleukin (IL)- 6, tumor necrosis factor (TNF)-alpha and C-reactive protein (CRP) by chemiluminescence immunoassays and nephelometry. RESULTS: Compared to controls, MDD patients showed significant differences in the serum levels of several N-glycan structures. Alterations in the serum N-glycan profile were associated with depressive symptom severity and exploratory analyses revealed that they were most pronounced in MDD patients with a history of childhood sexual abuse. Furthermore, MDD patients showed higher levels of IL-6 and a trend for higher CRP levels, which were also associated with similar alterations in the serum N-glycan profile as those characteristic for MDD patients. LIMITATIONS: The relatively small sample size and the presence of potential confounders (e.g., BMI, smoking, medication). CONCLUSION: The results offer the first evidence that specific differences in the N-glycosylation pattern of serum proteins constitute a so far unrecognized level of biological alterations that might be involved in the immune changes associated with MDD. PMID- 29529547 TI - The use of polygenic risk scores to identify phenotypes associated with genetic risk of bipolar disorder and depression: A systematic review. AB - BACKGROUND: Identifying the phenotypic manifestations of increased genetic liability for depression (MDD) and bipolar disorder (BD) can enhance understanding of their aetiology. The polygenic risk score (PRS) derived using data from genome-wide-association-studies can be used to explore how genetic risk is manifest in different samples. AIMS: In this systematic review, we review studies that examine associations between the MDD and BD polygenic risk scores and phenotypic outcomes. METHODS: Following PRISMA guidelines, we searched EMBASE, Medline and PsycINFO (from August 2009 - 14th March 2016) and references of included studies. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate. RESULTS: Twenty-five studies were included. Overall, both polygenic risk scores were associated with other psychiatric disorders (not the discovery sample disorder) such as depression, schizophrenia and bipolar disorder, greater symptom severity of depression, membership of a creative profession and greater educational attainment. Both depression and bipolar polygenic risk scores explained small amounts of variance in most phenotypes (< 2%). LIMITATIONS: Many studies did not report standardised effect sizes. This prevented us from conducting a meta-analysis. CONCLUSIONS: Polygenic risk scores for BD and MDD are associated with a range of phenotypes and outcomes. However, they only explain a small amount of the variation in these phenotypes. Larger discovery and adequately powered target samples are required to increase power of the PRS approach. This could elucidate how genetic risk for bipolar disorder and depression is manifest and contribute meaningfully to stratified medicine. PMID- 29529548 TI - Unhealthy lifestyle factors and depressive symptoms: A Japanese general adult population survey. AB - OBJECTIVE: To investigate the relationship between unhealthy lifestyles factors and depressive symptoms among the general adult population in Japan. METHOD: Participants were randomly selected from the Japanese general adult population. Data from 2334 people aged 20 years or older were analyzed. This cross-sectional survey was conducted in August and September 2009. Participants completed a face to-face interview about unhealthy lifestyle factors, including lack of exercise, skipping breakfast, a poorly balanced diet, snacking between meals, insufficient sleep, current smoking, alcohol drinking, and obesity. Presence of depressive symptoms was defined as a score of >= 16 on the Japanese version of the Center for Epidemiologic Studies Depression Scale (CES-D). Relationships between unhealthy lifestyle factors and depressive symptoms were evaluated by multivariate logistic regression analysis adjusting for sociodemographic variables and other unhealthy lifestyle factors. RESULTS: Multivariate logistic regression analysis revealed that insufficient sleep, a poorly balanced diet, snacking between meals and lack of exercise were significantly associated with the prevalence of depressive symptoms, with odds ratios ranging from 1.56 for lack of exercise to 3.98 for insufficient sleep. LIMITATIONS: Since this study was a cross-sectional study, causal relationships could not be determined. CONCLUSION: These results suggest that promoting a healthy lifestyle focused on sleep, food intake and exercise may be important for individuals with depressive symptoms. PMID- 29529549 TI - Corrigendum to "Change in 1-year hospitalization of overall and older patients with major depressive disorder after second-generation antipsychotics augmentation treatment" [J. Affect. Disord. 230(1) (2018) 118-124]. PMID- 29529550 TI - Effects of transcranial direct current stimulation for treating depression: A modeling study. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) above the left dorsolateral prefrontal cortex (lDLPFC) has been widely used to improve symptoms of major depressive disorder (MDD). However, the effects of different stimulation protocols in the entire frontal lobe have not been investigated in a large sample including patient data. METHODS: We used 38 head models created from structural magnetic resonance imaging data of 19 healthy adults and 19 MDD patients and applied computational modeling to simulate the spatial distribution of tDCS induced electric fields (EFs) in 20 frontal regions. We evaluated effects of seven bipolar and two multi-electrode 4 * 1 tDCS protocols. RESULTS: For bipolar montages, EFs were of comparable strength in the lDLPFC and in the medial prefrontal cortex (MPFC). Depending on stimulation parameters, EF cortical maps varied to a considerable degree, but were found to be similar in controls and patients. 4 * 1 montages produced more localized, albeit weaker effects. LIMITATIONS: White matter anisotropy was not modeled. The relationship between EF strength and clinical response to tDCS could not be evaluated. CONCLUSIONS: In addition to lDLPFC stimulation, excitability changes in the MPFC should also be considered as a potential mechanism underlying clinical efficacy of bipolar montages. MDD-associated anatomical variations are not likely to substantially influence current flow. Individual modeling of tDCS protocols can substantially improve cortical targeting. We make recommendations for future research to explicitly test the contribution of lDLPFC vs. MPFC stimulation to therapeutic outcomes of tDCS in this disorder. PMID- 29529551 TI - A comparison of the PHQ-2 and MGMQ for screening for emotional health difficulties during pregnancy. AB - BACKGROUND: Routine screening for emotional health difficulties in women during pregnancy is now advocated in several countries. There is a need therefore to compare the performance of different self-report measures to accomplish this. This study reports on the comparative performance of two such measures- the well established PHQ-2, which aims to detect depression, and the more recent MGMQ, which aims to detect a wide array of negative emotions. METHOD: Women (N = 2292) attending a public hospital antenatal clinic over a 14-month period completed the two measures, either on their own (72%), verbally administered by the midwife (25%), or with an interpreter (3%). RESULTS: Similar rates of women screened positive on each instrument (PHQ-2: 11.6%; MGMQ: 12.3%), but the overlap between the two measures was low. The PHQ-2 only detected 58% of the MGMQ screen positive women, while the MGMQ detected 89.5% of the PHQ-2 screen positive women. No clinically meaningful difference in screen positive rates on either measure was evident for the administration method. LIMITATIONS: No demographic data were available apart from gestational age, and only about half the women presenting to the clinic during the time period were screened with the measures. CONCLUSION: The MGMQ detected a greater proportion of women screening positive on the PHQ-2 than vice-versa. This is part due to the MGMQ's focus on a wider range of negative emotions than just depression. Accumulating evidence for this MGMQ indicates that clinical services can consider using this simple measure if they wish to screen for a broad range of negative emotions during pregnancy and postnatally. PMID- 29529552 TI - Does ceasing exercise induce depressive symptoms? A systematic review of experimental trials including immunological and neurogenic markers. AB - BACKGROUND: Regular exercise in adults improves depressive symptoms (DS) and major depressive disorder (MDD), however the clinical effects of ceasing exercise are largely unknown. METHODS: Seven databases were searched from inception to December 2017. Eligibility criteria included English language studies investigating the effects of ceasing exercise on DS or MDD in regularly active adults with or without prior DS or MDD. Blood based markers related to exercise cessation (EC) were assessed, if recorded. Studies investigating exercise follow up periods were excluded. RESULTS: No studies investigated EC in MDD. Six studies including two RCTS and three studies investigating neurogenic and immune biological markers associated with DS met inclusion criteria (152 healthy adults, females n = 50/32.89%). Compared to baseline, EC increased DS after three days, one week, and two weeks. Female participants had significantly more DS than male participants. Following EC, no changes in brain derived neurotrophic factor (BDNF) or tumour necrosis factor alpha (TNF) were evident, however C-reactive protein (CRP) at week one and interleukin 6 (IL6) at week two were reduced. LIMITATIONS: Quality concerns including risks of attrition and reporting bias limit our confidence in these results. CONCLUSIONS: Ceasing regular exercise increases DS in healthy adults, with greater DS in females than males. Contrary to the cytokine/inflammatory hypothesis of depression, DS were associated with reduced CRP and IL6 and without increased TNF. High quality trials are needed to extend this field of research in both healthy and MDD populations. PMID- 29529553 TI - Internet-based interventions for the prevention and treatment of depression in people living in developing countries: A systematic review. AB - BACKGROUND: Internet-based interventions for depression may be a valuable resource to reduce the treatment gap for those living in developing countries. However, evidence comes mainly from developed countries. This systematic review summarized the evidence on preventive or therapeutic Internet-based interventions for depression for people who reside in developing countries. METHODS: CINAHL, EMBASE, PubMed, SciELO Citation Indexes, the Journal of Medical Internet Research, and the Telemedicine and e-Health journal, were searched up to June 2017, to identify feasibility or effectiveness studies of preventive or therapeutic Internet-based interventions for depression, with or without human support. Studies included subjects residing in developing countries, and were published in English or Spanish. Study protocols were included. Risk of bias and/or quality of the reporting of the studies included was assessed. RESULTS: Five feasibility studies, aimed at the prevention of depression, and a study protocol were included in this systematic review. Reports came mostly from the Americas (n = 4). Internet-based interventions aimed at the prevention of depression presented low levels of human support, were useful and acceptable to their users, and require further design refinements to improve their use and retention. LIMITATIONS: No gray literature was searched or included in this systematic review. Searches were limited to English and Spanish languages. DISCUSSIONS: Internet-based interventions aimed at the prevention of depression in people who reside in developing countries are in an early phase of development, limiting the generalizability of the results. Future studies must employ persuasive designs to improve user retention, incorporating larger samples and a control group to conclusively determine feasibility. PMID- 29529554 TI - Problem-gambling severity, suicidality and DSM-IV Axis II personality disorders. AB - BACKGROUND: Despite the strong associations between personality disorders and problem/pathological gambling, few studies have investigated the relationships between personality disorders, problem-gambling severity and suicidal thoughts/behaviors. OBJECTIVES: We examined the relationships between problem gambling severity and personality disorders among individuals with differing levels of suicidality (none, thoughts alone, attempts). METHODS: We analyzed data from 13,543 participants of the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC) study. First, differences in sociodemographic characteristics and prevalence of personality disorders were analyzed according to problem-gambling severity and suicidality status. Second, we performed a logistic regression to assess among the relationship between problem-gambling severity and DSM-IV Axis II psychopathology according to suicidality level. RESULTS: At-risk or problem/pathological gambling groups showed higher rates of a wide range of personality disorders compared to non-gamblers. Logistic regression showed that at-risk pathological gamblers had a higher odds ratio for any personality disorder in the group with no history of suicidality, particularly for cluster-B personality disorders. Odds ratio interaction analysis identified the relationship between problem-gambling severity and personality disorders, particularly those in cluster B, differ according to suicidality status. CONCLUSIONS: Our findings suggest a complex relationship between suicidality, problem-gambling severity and personality disorders. The stronger relationship between problem-gambling severity and personality disorders in people with no suicidality as compared to some suicidality suggests that some of the relationship between greater problem-gambling severity and Axis II psychopathology is accounted for by increased suicidality. The findings have implications for clinical interventions targeting suicidality in individuals with gambling disorders. PMID- 29529555 TI - Laser-assisted atom probe tomography of semiconductors: The impact of the focused ion beam specimen preparation. AB - This paper demonstrates the increased light absorption efficiency of semiconducting atom probe tips resulting from focused-ion-beam (FIB) preparation. We use transmission electron microscopy to show that semiconducting tips prepared with FIB are surrounded with an amorphized shell. Photomodulated optical reflectance measurements then provide evidence that FIB-induced damage leads to an increase in both sub- and supra-bandgap light absorption efficiency. Using laser-assisted atom probe tomography (La-APT) measurements, we finally show that, for a nanoscale tip geometry, the laser-induced heating of a tip during La-APT is enhanced by the FIB preparation. We conclude that, upon supra-bandgap illumination, the presence of a FIB-amorphized surface dramatically increases the light-induced heat generation inside semiconducting tips during La-APT. Furthermore, we also deduce that, in the intriguing case of sub-bandgap illumination, the amorphization plays a crucial role in the unexpected light absorption. PMID- 29529556 TI - STEMcl-A multi-GPU multislice algorithm for simulation of large structure and imaging parameter series. AB - Electron microscopy images are interference patterns and can generally not be interpreted in a straight forward manner. Typically, time consuming numerical simulations have to be employed to separate specimen features from imaging artifacts. Directly comparing numerical predictions to experimental results, realistic simulation box sizes and varying imaging parameters are needed. In this work, we introduce an accelerated multislice algorithm, named STEMcl, that is capable of simulating series of large super cells typical for defective and amorphous systems, in addition to parameter series using the massive parallelization accessible in today's commercial PC-hardware, e.g. graphics processing units (GPUs). A new numerical approach is used to overcome the memory constraint limiting the maximum computable system size. This approach creates the possibility to study systematically the contrast formation arising by structural differences. STEM simulations of structure series of a crystalline Si and an amorphous CuZr system are presented and the contrast formation of vacancies/voids are studied. The detectability of vacancies/voids in STEM experiments is discussed in terms of density changes. PMID- 29529557 TI - Vagal nerve stimulation is beneficial in postural orthostatic tachycardia syndrome and epilepsy. PMID- 29529558 TI - CHD2-epilepsy: Polygraphic documentation of self-induced seizures due to fixation off sensitivity. AB - CHD2 gene has been described in association with different types of childhood myoclonic epilepsy and is emerging as a gene involved in photosensitivity alone or combined with epilepsy. Recent studies suggest that CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity and in particular with self-induced seizures. We report the case of a child with CHD2 mutation and mild developmental impairment that since the age of 3 years started with myoclonic seizures apparently well responding to antiepileptic drugs and that subsequently developed intractable self-induced seizures. Through an accurate Video-EEG polygraphic analysis, we demonstrated that seizures are related to an abnormal increase of epileptiform activity after eye-closure or loss of fixation as observed in the Fixation-Off Sensitivity (FOS) phenomenon. In conclusion our study adds relevant features of the CHD2-epilepsy phenotype and confirms that CHD2 mutations produce a distinctive form of myoclonic epilepsy with visual-sensitive seizures. PMID- 29529559 TI - The Positive Psychology Outcome Measure (PPOM) for people with dementia: Psychometric properties and factor structure. AB - OBJECTIVES: To conduct an in-depth psychometric assessment of the PPOM; a measure of hope and resilience. METHOD: An observational study at five NHS trusts across England. Participants either completed the study using self-complete or interview led procedures, depending on their preference. Assessments were internal consistency, floor and ceiling effects, test-retest reliability, convergent validity and factor structure. RESULTS: 225 participants were recruited and completed the study, with a subsample of 48 comprising the test-retest sample. Internal consistency was excellent alpha = 0.94, and significant correlations were observed between quality of life (r = 0.627, p < .001), depression (r = 0.699, p < .001) and the Control, Autonomy, Self-realisation and Pleasure Scale (CASP-19; r = 0.73, p < .001). The PPOM remained moderately stable over a one week period (ICC: 880) and factor analyses indicated a two-factor structure solution with acceptable fit indices. DISCUSSION: The PPOM has robust psychometric properties and is now suitable for use research and practice. People who met the clinical criteria for depression were more likely to have lower scores on the PPOM, indicating criterion validity. Future work is needed to establish the PPOM as sensitive to change and to investigate the relationship between hope, resilience and depression further. PMID- 29529560 TI - Associations between copper and zinc intakes from diet and mortality from cardiovascular disease in a large population-based prospective cohort study. AB - Several studies have related cardiovascular disease (CVD) to serum concentrations of copper and zinc but not to their dietary intakes. We thought to examine the association between dietary intakes of copper and zinc with risk of mortality from CVD in a prospective study encompassing 58,646 healthy Japanese men and women aged 40-79 years. The intakes of copper and zinc were determined by a validated self-administered food frequency questionnaire, and their associations with risk of mortality from CVD were evaluated by Cox proportional hazard modelling. During 965, 970 person-years of follow-up between 1989-2009, we documented 3,388 CVD deaths [1,514 from stroke, 702 from coronary heart disease (CHD) and 1,172 from other CVD]. Copper intake was not associated with CHD mortality; however, the multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) for mortality from stroke, other CVD and total CVD in the highest versus the lowest quintiles of copper intake among men were 1.78 (1.16-2.77; P trend=0.007), 1.61 (1.01-2.81; P-trend =0.03) and 1.63 (1.21-2.33; P trend=0.001), respectively, and those among women were 1.49 (1.00-2.19; P trend=0.04), 1.59 (1.09-2.55; P-trend =0.02) and 1.36 (1.06-1.69; P-trend=0.01), respectively. Higher intakes of zinc was inversely associated with mortality from CHD in men; 0.68 (0.58-1.03; P-trend=0.05) but not women; 1.13 (0.71- 1.49; P trend=0.61). No associations were observed with other mortality endpoints. In conclusion, dietary copper intake was positively associated with mortality from CVD in both genders; whereas, higher dietary zinc intake was inversely associated with mortality from CHD in men but not women. PMID- 29529561 TI - Performance of three cardoon cultivars in an industrial heavy metal-contaminated soil: Effects on morphology, cytology and photosynthesis. AB - In the present work the cytomorphological and physiological effects on three cardoon cultivars - Sardo, Siciliano, Spagnolo - grown in a metal-polluted soil, were investigated, to assess the traits concurring to the high tolerance to metal stress observed in cv. Spagnolo compared to the other two cultivars. The plants were grown for one month on a real polluted soil collected at a dismantling battery plant, highly enriched by heavy metals, especially Cd and Pb, and their leaves were analyzed by a multidisciplinary approach. TEM observations highlighted severe ultrastructural damage in Sardo and Siciliano, and preserved cytological traits in Spagnolo. Both pigment content and photochemistry indicated a decline in photosynthesis in Sardo and Sicilano and a substantial stability of the same parameters in Spagnolo. Protein analysis indicated a decrease in D1 level in all cultivars; in Spagnolo the D1 decrease was more pronounced and associated to a significant increase in Rubisco, a pattern likely preserving photosynthetic efficiency and high biomass production. In conclusion, Spagnolo cardoon was able to face metal stress through a prompt, multiple response balancing structural and functional traits. PMID- 29529562 TI - Application of sequential extraction analysis to Pb(II) recovery by zerovalent iron-based particles. AB - Zerovalent iron (ZVI) is an environmental-friendly reactive reagent for recovering heavy metals. However, the detailed recovery mechanism remains unclear due to a lack of quantitative analysis of recovery products. Herein, microscale ZVI, nanoscale ZVI and Ni/Fe nanoparticles were used to recover Pb(II) in aqueous solution and a sequential extraction procedure (SEP) was applied to determine the formed lead species quantitatively. At high initial Pb(II) concentration (500 mg L-1), more than 99.5% of Pb(II) was immobilized by Ni/Fe and n-ZVI, whereas m-ZVI caused inferior recovery efficiency (<25%). XRD and XPS results revealed that Pb(II) was reduced to Pb0 prior to the formation of metal hydroxides as the external shell of ZVI. SEP results showed that the fraction bound to carbonates (PbO), fraction bound to iron oxides and exchangeable fraction were the main lead species conducted by Ni/Fe, n-ZVI and m-ZVI, respectively. Consequently, (co )precipitation and specific adsorption dominated Pb(II) recovery by Ni/Fe and n ZVI, whereas m-ZVI conducted Pb(II) recovery mainly via weak adsorption. The reactivity of ZVI toward Pb(II) followed the increasing order of m-ZVI << n-ZVI <= Ni/Fe. The detailed mechanisms of Pb(II) recovery conducted by different ZVI were proposed. PMID- 29529563 TI - Dynamic regulation of nucleolar architecture. AB - The nucleolus is the largest nuclear sub-compartment in which the early steps of ribosome biogenesis take place. It also plays an essential role in the assembly and function of non-ribosomal ribonucleoprotein (RNP) complexes, controls cell cycle progression and senses environmental stress. The spatial organization and dynamics of nucleolar proteins and RNA is regulated at different structural levels, which finally determine nucleolar architecture. The intimate link between nucleolar structure and function is reflected by transcription-dependent changes in nucleolus-associated chromatin, overall morphological alterations in response to external cues, and the liquid droplet-like behavior of nucleolar compartments. Here we provide a concise overview of the latest studies which integrate novel trends in nucleolar architecture research into the context of cell biology. PMID- 29529564 TI - Pretreatment of saline antibiotic wastewater using marine microalga. AB - A green microalga Chlorella sp. isolated from marine environment was investigated for its potential to pretreat saline antibiotic wastewater containing amoxicillin (AMX). Through Biolog EcoPlate assay, the Chlorella sp. showed its unique carbon source metabolic patterns under autotrophic condition. In addition, the microalga could effectively remove AMX (>99%) under initial AMX concentrations ranging from 10 to 150 mg/L through a treatability test. In the continuous AMX treatment using a lab-scale membrane photobioreactor (MPBR), a stable AMX removal efficiency of 85.6 +/- 3.8% was observed. Moreover, with the aid of a subsequent bacterial treatment, the microalgal-bacterial process (the Chlorella sp. pretreatment followed by either intertidal wetland sediment or activated sludge) can achieve simultaneous AMX removal of >99% and total organic carbon (TOC) removal of ~80%. In general, the microalgal pretreatment showed its great potential in effective removal of antibiotic residues, which could greatly enhance the overall treatment efficiency of saline antibiotic wastewater. PMID- 29529565 TI - Predictive modeling: Solubility of C60 and C70 fullerenes in diverse solvents. AB - Solubility of fullerenes imposes a major limitation to further advanced research and technological development using these novel materials. There have been continued efforts to discover better solvents and their properties that influence the solubility of fullerenes. Here, we have developed QSPR (quantitative structure-property relationship) models based on structural features of diverse solvents and large experimental data for predicting the solubility of C60 and C70 fullerenes. The developed models identified most relevant features of the solvents that encode the polarizability, polarity and lipophilicity properties which largely influence the solubilizing potential of the solvent for the fullerenes. We also established Inter-moieties solubility correlations (IMSC) based quantitative property-property relationship (QPPR) models for predicting solubility of C60 and C70 fullerenes. The QSPR and QPPR models were internally and externally validated deriving the most stringent statistical criteria and predicted C60 and C70 solubility values in different solvents were in close agreement with the experimental values. In test sets, the QSPR models yielded high correlations (R2 > 0.964) and low root mean squared error of prediction errors (RMSEP< 0.25). Results of comparison with other studies indicated that the proposed models could effectively improve the accuracy and ability for predicting solubility of C60 and C70 fullerenes in solvents with diverse structures and would be useful in development of more effective solvents. PMID- 29529566 TI - Determining the presence of chemicals with suspected endocrine activity in drinking water from the Madrid region (Spain) and assessment of their estrogenic, androgenic and thyroidal activities. AB - Endocrine disruptors (EDs) are natural or man-made chemicals that can affect the health of organisms by interfering with their normal hormonal functions. Many of these substances can cause their effects at very low doses and, considering the key role played by the endocrine system on development, organisms in early phases of growth (foetal, childhood, puberty) are especially sensitive to the action of EDs. In addition, when combined, they can show additive, antagonistic and synergistic activities. Taking all this into account it is essential to determine the presence of this kind of compounds in drinking water. Thus the main aim of the present study was to monitor the presence of substances with suspected or known endocrine activity in drinking water of the Madrid Region (MR) (Central Spain) and determine possible estrogenic, androgenic, or thyroidal activities. Water samples were collected at different times from a number of supply points that received water from reservoirs or rivers. The sampling point with the highest concentration of the analysed substances (up to 30 compounds) was DW1 (1203 ng L-1). This sampling point receives water from a drinking water treatment plant (DWTP) that serves the population from the south of the MR with treated water from the Tajuna River. DW2 was the second point with the highest concentration of the analysed substances (1021 ng L-1). DW2 receives water from one of the reservoirs in the north of the MR. The highest daily concentrations detected corresponded to the flame retardant Tris (2-chloroethyl)phosphate (TCEP) (266.55 ng L-1) and to the nonylphenol diethoxylate (188.57 ng L-1) at points DW1 and DW4, respectively, both of which are supplied with treated river water. None of the water samples exhibited androgenic, oestrogenic, or thyroidal activities in in vitro assays based on cells stably transfected with the receptors of interest and luciferase as reporter gene. These results demonstrate that water quality in the MR is high and does not present a health risk for the population, although the concentrations of some substances justify the need for local authorities to continually monitor the presence of these contaminants in order to implement any corrective measures if necessary. PMID- 29529567 TI - Current advances and trends in electro-Fenton process using heterogeneous catalysts - A review. AB - Over the last decades, advanced oxidation processes have often been used alone, or combined with other techniques, for remediation of ground and surface water pollutants. The application of heterogeneous catalysis to electrochemical advanced oxidation processes is especially useful due to its efficiency and environmental safety. Among those processes, electro-Fenton stands out as the one in which heterogeneous catalysis has been broadly applied. Thus, this review has introduced an up-to-date collation of the current knowledge of the heterogeneous electro-Fenton process, highlighting recent advances in the use of different catalysts such as iron minerals (pyrite, magnetite or goethite), prepared catalysts by the load of metals in inorganic and organic materials, nanoparticles, and the inclusion of catalysts on the cathode. The effects of physical-chemical parameters as well as the mechanisms involved are critically assessed. Finally, although the utilization of this process to remediation of wastewater overwhelmingly outnumber other utilities, several applications have been described in the context of regeneration of adsorbent or the remediation of soils as clear examples of the feasibility of the electro-Fenton process to solve different environmental problems. PMID- 29529568 TI - QSAR models for describing the toxicological effects of ILs against Candida albicans based on norm indexes. AB - The quantitative structure-activity relationship (QSAR) model is an effective alternative to traditional experimental toxicity testing, which is undoubtedly important for modern environmental risk assessment and property prediction. Based on this background, the toxicological effects of ionic liquids (ILs) against Candida albicans (C. albicans) were studied via the QSAR method. A large diverse group of 141 and 85 ILs that have a minimal inhibitory concentration (MIC) and a minimum fungicidal concentration (MBC) against C. albicans were used to obtain multiple linear regression models. These two models were developed based on matrix norm indexes and proposed based on the atomic character and position. Matrix norm indexes proposed in our research group were used to calculate the toxicity of these ILs towards C. albicans for the first time. These two models precisely estimated the toxicity of these ILs towards C. albicans with a square of correlation coefficient (R2) of = 0.930 and a standard error of estimate (SE) of = 0.254 for pMIC, and for pMBC, R2 = 0.873 and SE = 0.243. PMID- 29529569 TI - Adsorption and transformation of the anthelmintic drug niclosamide by manganese oxide. AB - The manganese oxide birnessite adsorbed and catalyzed the transformation of the anthelminthic drug niclosamide (NIS) into 2-chloro-4-nitroaniline (CNA) and 5 chlorosalicylic acid (CSA) at acidic pH. The adsorption of NIS was fitted using a linear isotherm for all conditions and reaction times. Linear adsorption constant Kd was 103 000 L kg-1 at pH 5.0. The rate of transformation was first order with respect to both MnO2 and NIS. At pH 5.0, the second order rate constant was 3.3 (+/-0.3) * 10-1 M-1 s-1. The adsorption constants and the rates of transformation decreased when pH increased from 4.0 to 5.5 because of increasing electrostatic repulsions between both negatively charged manganese oxide surface (pHzpc = 2.5) and NIS (pKa = 6.38). The presence of natural organic matter (NOM) extracted from surface water also significantly decreased the adsorption and the rates of transformation of NIS. The rate of transformation decreased by a factor of 20 in presence of 1.6 mgC L-1 even though significant amounts of NIS were adsorbed onto MnO2. The interactions between NOM and NIS were investigated by using the fluorescence quenching method and would explain that NIS adsorbed on the surface of manganese oxide was stable in presence of NOM. Thus, hydrolysis catalyzed by manganese oxide is probably not an important process compared to biodegradation and adsorption because of the presence of organic matter and pH values usually >5.5 in aquatic environment. PMID- 29529570 TI - Cytotoxicity of seven bisphenol analogues compared to bisphenol A and relationships with membrane affinity data. AB - Bisphenol A (BPA) is a chemical used in numerous industrial applications. Due to its well ascertained toxicity as endocrine disruptor, industries have started to replace it with other bisphenols whose alleged greater safety is scarcely supported by literature studies. In this study, the toxicity of seven BPA analogues was evaluated using both in silico and in vitro techniques, as compared to BPA toxicity. Furthermore, their affinity indexes for phospholipids (i.e. phospholipophilicity) were determined by immobilized artificial membrane liquid chromatography (IAM-LC) and possible relationships with in vitro toxic activity were also investigated. The results on four different cell cultures yielded similar ranking of toxicity for the bisphenols considered, with IC50 values confirming their poor acute toxicity. As compared to BPA, bisphenol AF, bisphenol B, bisphenol M, and bisphenol A diglycidyl ether resulted more toxic, while bisphenol S, bisphenol F and bisphenol E were found as the less toxic congeners. These results are partly consistent with the scale of phospholipid affinity showing that toxicity increases at increasing membrane affinity. Therefore, phospholipophilicity determination can be assumed as a useful preliminary tool to select less toxic congeners to surrogate BPA in industrial applications. PMID- 29529571 TI - Absorption of polycyclic aromatic hydrocarbons by a highly absorptive polymeric medium. AB - The efficacy of a lightly cross-linked polymeric bead to absorb polycyclic aromatic hydrocarbons (PAHs) from the surface of fresh- and salt-water in a simulated oil-spill scenario was assessed in this study. A layer of PAHs at the water surface was created by first preparing the PAHs in hexane and then carefully spiking this mixture onto the surface of water. Beads were then applied to the surface of the organic phase and the amount of hydrocarbons absorbed by the beads was examined at prescribed time intervals and at different temperatures. Absorption of PAHs into the beads was exhaustive with ~86 +/- 4% being selectively removed from the organic phase by 120 s. First order reaction rates best described the uptake kinetics and absorption rates ranged from 0.0085 (naphthalene) to 0.0325 s-1 (dibenzo[a,h]anthracene). Absorption of PAHs into the beads was driven by molecular volume (A3). Uptake rates increased markedly for PAHs with molecular volumes between 130 A3 and 190 A3. Beyond this molecular volume there was no apparent change in the rate of uptake. This study shows that these polymeric beads have a high affinity for PAHs and can be used under various environmental conditions with negligible difference in absorptive efficacy. PMID- 29529572 TI - Distributions of concentrations of bisphenol A in North American and European surface waters and sediments determined from 19 years of monitoring data. AB - Concentrations of bisphenol A (BPA) in North American and European fresh and marine surface waters and sediments were analyzed to quantify environmental levels and evaluate trends over the years 1996-2014. In North American surface water and sediment, 68% of 1030 weighted observations were below a detection limit (varied widely between studies). In Europe, 33% of 5057 weighted observations were below a detection limit. In North America and Europe, 50th percentile concentrations were 0.005 MUg L-1 and 0.029 MUg L-1 in freshwater and 0.0011 MUg L-1 and 0.007 MUg L-1 in marine water. The 95th percentile concentrations in freshwater were the same in North America and Europe at 0.30 MUg L-1 and were 0.024 MUg L-1 and 0.15 MUg L-1 in marine water, respectively. Fiftieth percentile concentrations in North American and European freshwater sediment were 0.7 ng g-1 dry weight (dw) and 7.0 ng g-1 dw and in marine sediment were 1.0 ng g-1 dw and <0.03 ng g-1 dw, respectively. The 95th percentile concentrations were 39 ng g-1 dw and 177 ng g-1 dw in freshwater sediment and 100 ng g-1 dw and 63 ng g-1 dw in marine sediment, respectively. Most concentrations were below published chronic toxicity values or regulatory limits. BPA freshwater concentrations in both regions appear to have remain relatively unchanged over the 19 year period during which BPA production and use in polycarbonate plastic production increased significantly. There is no clear correlation between BPA or polycarbonate production and BPA levels in surface waters. PMID- 29529573 TI - Impact of an atrazine-based herbicide on an agrobiont wolf spider. AB - For animals that live in association with humans, a key ecological question is how anthropogenic factors influence their life history. While major negative effects are obvious, subtle non-lethal responses to anthropogenic stimuli may provide insight into the features that lead to the success of species that thrive in habitats heavily impacted by humans. Here we explored the influence of the herbicide atrazine on various life history traits of a wolf spider that thrives in agroecosystems where it is commonly applied. We found that exposure delayed maturation and increased the probability of having molting errors. Atrazine also decreased the probability of producing an egg sac after mating, but increased the average mass of the initial egg sacs that were produced while not impacting the average number of eggs inside. The total number of eggs produced from a single mating on the other hand, was increased in the presence of atrazine through the production of multiple egg sacs. Finally, adult lifespan was shortened with exposure to atrazine. These results suggest that the atrazine based herbicides that are routinely applied to agricultural fields result in altered life history traits, potentially through endocrine disruption, that may counteract one another to allow persistence. PMID- 29529574 TI - A review of semi-volatile organic compounds (SVOCs) in the indoor environment: occurrence in consumer products, indoor air and dust. AB - As many people spend a large part of their life indoors, the quality of the indoor environment is important. Data on contaminants such as flame retardants, pesticides and plasticizers are available for indoor air and dust but are scarce for consumer products such as computers, televisions, furniture, carpets, etc. This review presents information on semi-volatile organic compounds (SVOCs) in consumer products in an attempt to link the information available for chemicals in indoor air and dust with their indoor sources. A number of 256 papers were selected and divided among SVOCs found in consumer products (n = 57), indoor dust (n = 104) and air (n = 95). Concentrations of SVOCs in consumer products, indoor dust and air are reported (e.g. PFASs max: 13.9 MUg/g in textiles, 5.8 MUg/kg in building materials, 121 ng/g in house dust and 6.4 ng/m3 in indoor air). Most of the studies show common aims, such as human exposure and risk assessment. The main micro-environments investigated (houses, offices and schools) reflect the relevance of indoor air quality. Most of the studies show a lack of data on concentrations of chemicals in consumer goods and often only the presence of chemicals is reported. At the moment this is the largest obstacle linking chemicals in products to chemicals detected in indoor air and dust. PMID- 29529575 TI - A combined effect of polybrominated diphenyl ether and aquaculture effluent on growth and antioxidative response of mangrove plants. AB - Mangrove wetland receives nutrient-rich aquaculture effluent (AE) from nearby farming activities and polybrominated diphenyl ethers (PBDEs) from the production and usage of flame retardants. The effects of BDE-209 (the most common PBDE congener), AE and their combination on two true mangrove species, namely Kandelia obovata and Avicennia marina, were compared in a 6-month microcosm study. Results showed that K. obovata was more sensitive to these contaminants than A. marina, as reflected by its enhanced production of leaf superoxide (O2-*) by BDE-209 and root malondialdehyde (MDA) by the combined BDE-209 and AE treatment. The hormesis model showed that the combined effects of BDE-209 and AE on the production of MDA, O2-* and catalase (CAT) activity in K. obovata and A. marina were antagonistic except root O2-* in A. marina, but the effects on leaf superoxide dismutase (SOD) activity in K. obovata, and root SOD and peroxidase (POD) activities in A. marina were synergistic. The defense mechanisms differed between treatment and species. The activities of SOD and POD were the main mechanisms to defend K. obovata and A. marina against BDE-209, but CAT in K. obovata and POD in A. marina were more important in defending the combined BDE-209 and AE treatment. PMID- 29529576 TI - Phytotoxicity of amoxicillin to the duckweed Spirodela polyrhiza: Growth, oxidative stress, biochemical traits and antibiotic degradation. AB - The increasing availability of antibiotics in wastewater has created a serious threat to non-target organisms in the environment. The aim of this study was to evaluate the potential toxicity of amoxicillin on duckweed Spirodela polyrhiza during a short-term exposure (7 d). The duckweed was exposed to a range of environmentally relevant (0.0001-0.01 mg L-1) and high (0.1 and 1 mg L-1) concentrations of amoxicillin. Subsequently, biomarkers of toxicity such as growth, pigments (Chl a, Chl b and carotenoids), antioxidative enzyme activity (catalase, CAT; superoxide dismutase, SOD; and ascorbate peroxidases, APX), and biochemical content (protein, lipid and starch) were analysed in their fronds. The high dose (1 mg L-1) of amoxicillin caused a significant (p < 0.05) decrease in photopigments, protein, starch and lipid content and an increase in carotenoids/total Chl and Chl a/Chl b ratios in fronds of Spirodela polyrhiza. The results showed a shift in biomarkers: a decrease in frond growth and relative growth rate (RGR) (16.2-53.8%) and an increase in the activities (mmol mg protein 1) of CAT (0.021-0.041), APX (0.84-2.49) and SOD (0.12-0.23) in fronds. The significantly (p < 0.05) greater reduction in amoxicillin content in duckweed setups (84.6-100%) than in the control (62.1-73%) suggested that phytodegradation is an important mechanism in removing antibiotics from water, apart from hydrolysis and photodegradation, which occur in control setups. Overall, the results suggested a toxic effect of amoxicillin on Spirodela polyrhiza, even at low concentrations, and nonetheless, the duckweed contributed directly to the degradation of antibiotics in the water and throughout the phytoremediation process. PMID- 29529577 TI - Inuence of major anions on the 185 nm advanced oxidation process - Sulphate, bicarbonate, and chloride. AB - The 185 nm wavelength radiation generated by the conventional low pressure mercury lamp forms the basis of an advanced oxidation process (AOP) that does not require chemical addition. The photolysis of water by 185 nm photons generates the hydroxyl radical (OH) used to degrade trace organic contaminants. While AOPs in general suffer decreased efficiency in direct proportion to the concentrations of dissolved organic matter (DOM) and alkalinity (HCO3-/CO32-), acting as OH scavengers, such solutes impose an additional parasitic effect on the 185 nm AOP as absorbers of photons. Furthermore, the major inorganic anions sulphate () and chloride (Cl-) also absorb at 185 nm to generate the highly reactive sulphate () and chlorine (Cl) radicals. Like OH, and Cl. are also scavenged by DOM and HCO3 /CO32-. Using carbamazepine as a radical probe, and t-butanol or Suwannee River isolate as model DOM, the relative reactivity of these radicals with both DOM and HCO3- was found consistent with the order . Experimental evidence suggests some interconversion between these radicals. The 185 nm AOP treatment efficiency thus depends strongly on the anionic composition of the water matrix, as well as on the relative reactivities of the target contaminant, DOM, and HCO3- with the three radicals OH, Cl., and . Changes in any of these parameters may result in substantial differences in treatment efficiency. PMID- 29529578 TI - Potential of Napier grass with cadmium-resistant bacterial inoculation on cadmium phytoremediation and its possibility to use as biomass fuel. AB - This work mainly aims to explore the potential of synergistic use of cadmium resistant bacteria and Napier grass to promote cadmium phytoremediation and the possibility of using the harvested Napier grass for biomass fuel. A pot experiment was carried out by transplanting Napier grass with and without bacterial inoculation in cadmium contaminated soil for 6 months. The results found that Micrococcus sp. significantly promoted the shoot biomass of Napier grass but not the root biomass. Micrococcus sp. and Arthrobacter sp. stimulated cadmium accumulation in the root and the shoot. Cadmium was retained more in the root than the shoot at all plantation periods. The maximum cadmium content in a whole plant was found in plants inoculated with Micrococcus sp. at six months. The values of phytoextraction coefficient and bioaccumulation factor in plants with bacterial inoculation were higher than those in the uninoculated control. Translocation factor was very low. Napier grass could be considered as a candidate plant for cadmium phytostabilization. The calorific value of Napier grass transplanted in cadmium-contaminated soil was similar to that in uncontaminated soil, but cadmium was still retained in the ash and some was emitted into the air. In conclusion, these cadmium-resistant bacteria enhanced the performance of Napier grass on cadmium phytoremediation. The harvested Napier grass can be used for biomass fuel under controlled ash and air emission from the combustion process. PMID- 29529579 TI - Midwives' perceptions of women's preferences related to midwifery care in Germany: A focus group study. AB - OBJECTIVE: To explore how midwives perceive patient preferences related to midwifery care in Germany. DESIGN: This qualitative study, which was part of a larger study, used a hermeneutic-interpretive approach and involved focus group interviews with midwives. Data collection and analysis were done in a conjoined fashion between April 2015 and September 2016. SETTING: Four focus group interviews were conducted in four different federal states of Germany. PARTICIPANTS: The sample of 20 qualified midwives was heterogeneous with regards to age, educational level, professional experience, type of midwifery care provided, and setting (employed, caseload, education) in which they provided services. FINDINGS: Three main themes were identified: Strengths and limitations of midwives' present professional profile (midwives' area of responsibility, range of services, and competency); lack of midwives and midwifery services; women's experiences of conflict in interprofessional care. Each main theme is broken down into several aspects of content. Many women are not aware of the scope of professional knowledge and expertise of midwives. Moreover, the poor delineation of midwives' and obstetricians' areas of competency in Germany's hospitals seems to be disadvantageous for the women. Midwives feel that due to context implications they cannot live up to the quality of midwifery care they aspire to. Lack of midwives results in midwives being overwhelmed, women underserved, and both disappointed. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: On the one hand, new models of midwifery/maternity care need to be developed to solve some of the existing problems; on the other hand, new forms of interprofessional cooperation and management of transition of care points are required. Overall it is important that changes are implemented in such a way that women are enabled, and welcome, to clearly state their preferences for midwifery and maternity care. Particularly in Germany, tertiary education of midwives is needed to broaden their expertise and place them on an equal footing with obstetricians. PMID- 29529580 TI - Quantification of colloidal filtration of polystyrene micro-particles on glass substrate using a microfluidic device. AB - A microfluidic device was designed to investigate filtration of particles in an electrolyte in the presence of liquid flow. Polystyrene spheres in potassium chloride solution at concentrations of 3-100 mM were allowed to settle and adhere to a glass substrate. A particle free solution at the same concentration was then flushed through the microfluidic channel at 0.03-4.0 mL/h. As the hydrodynamic drag on the adhered particles exceeded the intersurface interaction with the substrate, "pull-off" occurred and the particles detached. Filtration efficiency, alpha, was shown to a function of both ionic concentration of the liquid medium and flow speed, consistent with a phenomenological model based on the classical DLVO theory. The results elucidates the underlying physics of filtration. PMID- 29529581 TI - Comparison of radiofrequency electromagnetic field exposure levels in different everyday microenvironments in an international context. AB - BACKGROUND: The aim of this study was to quantify RF-EMF exposure applying a tested protocol of RF-EMF exposure measurements using portable devices with a high sampling rate in different microenvironments of Switzerland, Ethiopia, Nepal, South Africa, Australia and the United States of America. METHOD: We used portable measurement devices for assessing RF-EMF exposure in 94 outdoor microenvironments and 18 public transport vehicles. The measurements were taken either by walking with a backpack with the devices at the height of the head and a distance of 20-30 cm from the body, or driving a car with the devices mounted on its roof, which was 170-180 cm above the ground. The measurements were taken for about 30 min while walking and about 15-20 min while driving in each microenvironment, with a sampling rate of once every 4 s (ExpoM-RF) and 5 s (EME Spy 201). RESULTS: Mean total RF-EMF exposure in various outdoor microenvironments varied between 0.23 V/m (non-central residential area in Switzerland) and 1.85 V/m (university area in Australia), and across modes of public transport between 0.32 V/m (bus in rural area in Switzerland) and 0.86 V/m (Auto rickshaw in urban area in Nepal). For most outdoor areas the major exposure contribution was from mobile phone base stations. Otherwise broadcasting was dominant. Uplink from mobile phone handsets was generally very small, except in Swiss trains and some Swiss buses. CONCLUSIONS: This study demonstrates high RF EMF variability between the 94 selected microenvironments from all over the world. Exposure levels tended to increase with increasing urbanity. In most microenvironments downlink from mobile phone base stations is the most relevant contributor. PMID- 29529582 TI - Seasonal variations in cold climate nutrient removal: A comparison of facultative and aerated lagoons. AB - The seasonal trends in standard wastewater parameters are studied for two lagoons in the Canadian Prairies; one facultative and one aerated with the purpose of better understanding the underlying biological mechanisms in place. In particular, treatment in a cold climate is examined as treatment efficiency and function vary with geographical latitude. It was found that during the winter season, nutrients are not removed and nutrient release is observed. At the arrival of spring, biological growth occurs leading to spring awakening of the lagoons whereby nutrients start to again be removed. Phosphorus is removed by biomass assimilation and precipitation. It was found that these mechanisms were not very effective at treating this nutrient and additional treatment is required. Nitrogen is removed mainly by air stripping and its concentration is influenced by both temperature and pH, the latter of which is greatly affected by algae growth. PMID- 29529583 TI - Domestic wastewater treatment and power generation in continuous flow air-cathode stacked microbial fuel cell: Effect of series and parallel configuration. AB - In this study, a continuous flow stack consisting of 40 individual air-cathode MFC units was used to determine the performance of stacked MFC during domestic wastewater treatment operated with unconnected individual MFC and in series and parallel configuration. The voltages obtained from individual MFC units were of 0.08-1.1 V at open circuit voltage, while in series connection, the maximum power and current density were 2500 mW/m2 and 500 mA/m2 (4.9 V), respectively. In parallel connection, the maximum power and current density was 5.8 mW/m2 and 24 mA/m2, respectively. When the cells were not connected to each other MFC unit, the main bacterial species found in the anode biofilms were Bacillus and Lysinibacillus. After switching from unconnected to series and parallel connections, the most abundant species in the stacked MFC were Pseudomonas aeruginosa, followed by different Bacilli classes. This study demonstrated that when the stacked MFC was switched from unconnected to series and parallel connections, the pollutants removal, performance electricity and microbial community changed significantly. Voltages drops were observed in the stacked MFC, which was mainly limited by the cathodes. These voltages loss indicated high resistances within the stacked MFC, generating a parasitic cross current. PMID- 29529584 TI - Self-healing properties of recycled asphalt mixtures containing metal waste: An approach through microwave radiation heating. AB - The concept of self-healing asphalt mixtures by bitumen temperature increase has been used by researchers to create an asphalt mixture with crack-healing properties by microwave or induction heating. Metals, normally steel wool fibers (SWF), are added to asphalt mixtures prepared with virgin materials to absorb and conduct thermal energy. Metal shavings, a waste material from the metal industry, could be used to replace SWF. In addition, reclaimed asphalt pavement (RAP) could be added to these mixtures to make a more sustainable road material. This research aimed to evaluate the effect of adding metal shavings and RAP on the properties of asphalt mixtures with crack-healing capabilities by microwave heating. The research indicates that metal shavings have an irregular shape with widths larger than typical SWF used with asphalt self-healing purposes. The general effect of adding metal shavings was an improvement in the crack-healing of asphalt mixtures, while adding RAP to mixtures with metal shavings reduced the healing. The average surface temperature of the asphalt samples after microwave heating was higher than temperatures obtained by induction heating, indicating that shavings are more efficient when mixtures are heated by microwave radiation. CT scan analysis showed that shavings uniformly distribute in the mixture, and the addition of metal shavings increases the air voids. Overall, it is concluded that asphalt mixtures with RAP and waste metal shavings have the potential of being crack-healed by microwave heating. PMID- 29529585 TI - Three-dimensional polylactic acid@graphene oxide/chitosan sponge bionic filter: Highly efficient adsorption of crystal violet dye. AB - Owing to low bearing capacity and efficiency, traditional filters or adsorbents for removal of contaminants like crystal violet (CV) dye required frequent replacement. Besides, the combination of three-dimensional (3D) printing and bionics could break the constraints of traditional configuration. In this study, a novel depth-type hybrid polylactic acid (PLA)@graphene oxide (GO)/chitosan (CS) sponge filter with bionic fish-mouth structure was prepared and fabricated, assisted by 3D printing and double freeze-drying technology, according to the theories of vertical cross-step filtration and swirling flow. And GO/CS sponge and its filtering device were characterized by FITR, SEM, water adsorption and so on. Moreover, it was explained that the impact factors on dye removal mechanism, like GO content (or CS content), contact time, pH, temperature and bionic configuration. As a result, the bionic 3D filtering device demonstrated excellent removal efficiency (97.8+/-0.5% for CV) and GO/CS sponge exhibited higher strength (74.5+/-3.5MPa) at the condition of GO content of 9wt%, contact time of 46min, pH of 8 and 35 degrees C, respectively. Therefore, the resulting 3D PLA@GO/CS sponge bionic filter via gravity and vortex driving provided new alternatives for effectively dye-water separation, and it showed great promise for application of biological macromolecules in adsorption. PMID- 29529586 TI - Cost-Effectiveness Analysis of Diagnosis of Duchenne/Becker Muscular Dystrophy in Colombia. AB - OBJECTIVES: To determine the cost-effectiveness ratio of different courses of action for the diagnosis of Duchenne or Becker muscular dystrophy in Colombia. METHODS: The cost-effectiveness analysis was performed from the Colombian health system perspective. Decision trees were constructed, and different courses of action were compared considering the following tests: immunohistochemistry (IHC), Western blot (WB), multiplex polymerase chain reaction, multiplex ligation dependent probe amplification (MLPA), and the complete sequencing of the dystrophin gene. The time horizon matched the duration of sample extraction and analysis. Transition probabilities were obtained from a systematic review. Costs were constructed with a type-case methodology using the consensus of experts and the valuation of resources from consulting laboratories and the 2001 Social Security Institute cost manual. Deterministic sensitivity and scenario analyses were performed with one or more unavailable alternatives. Costs were converted from Colombian pesos to US dollars using the 2014 exchange rate. RESULTS: In the base case, WB was the dominant strategy, with a cost of US $419.07 and a sensitivity of 100%. This approach remains the dominant strategy down to a 98.2% sensitivity and while costs do not exceed US $837.38. If WB was not available, IHC had the best cost-effectiveness ratio, followed by MLPA and sequencing. CONCLUSIONS: WB is a cost-effective alternative for the diagnosis of patients suspected of having Duchenne or Becker muscular dystrophy in the Colombian health system. The IHC test is rated as the second-best detection method. If these tests are not available, MLPA followed by sequencing would be the most cost-effective alternative. PMID- 29529587 TI - Cost-Effective Analysis to Incorporate Non-Drug Interventions to Increase Adherence to Antiretroviral Therapy. PMID- 29529588 TI - Atypical susceptibility to the rubber hand illusion linked to sensory-localised vicarious pain perception. AB - The Rubber Hand Illusion (RHI) paradigm has been widely used to investigate the sense of body ownership. People who report experiencing the pain of others are hypothesised to have differences in computing body ownership and, hence, we predicted that they would perform atypically on the RHI. The Vicarious Pain Questionnaire (VPQ), was used to divide participants into three groups: (1) non responders (people who report no pain when seeing someone else experiencing physical pain), (2) sensory-localised responders (report sensory qualities and a localised feeling of pain) and (3) affective-general responders (report a generalised and emotional feeling of pain). The sensory-localised group, showed susceptibility to the RHI (increased proprioceptive drift) irrespective of whether stimulation was synchronous or asynchronous, whereas the other groups only showed the RHI in the synchronous condition. This is not a general bias to always incorporate the dummy hand as we did not find increased susceptibility in other conditions (seeing touch without feeling touch, or feeling touch without seeing touch), but there was a trend for this group to incorporate the dummy hand when it was stroked with a laser light. Although individual differences in the RHI have been noted previously, this particular pattern is rare. It suggests a greater malleability (i.e. insensitivity to asynchrony) in the conditions in which other bodies influence own-body judgments. PMID- 29529589 TI - Rate dependent anisotropic constitutive modeling of brain tissue undergoing large deformation. AB - This study aims constitutive modeling of rate dependent anisotropic viscoelastic brain tissue that experiences large deformation during accidental impact. Many experimental studies confirm that brain parenchyma mechanisms are strongly influenced by anisotropy, nonlinear viscoelasticity, rate dependent loading/unloading and tension-compression asymmetry of the soft brain tissues. We present a rigorous thermodynamically consistent phenomenological approach to capture these mechanisms in a single model. Model parameters are calibrated from the experiments, and mechanical responses are predicted for different loading conditions. We consider a 2-D fibrous circular tube geometry, an idealized form of a human head, to simulate shear stress distribution for a given boundary condition. Different orientations of the fibers are considered to investigate the influence of anisotropy on the shear stress. Finally, stretch rate dependency of stress responses for a particular fiber orientation is demonstrated. PMID- 29529590 TI - Reinforced chitosan membranes by microspheres for guided bone regeneration. AB - In order to improve the osteogenic activity and mechanical strength of the guided bone regeneration (GBR) membrane for repairing bone defect, nano hydroxyapatite/chitosan (nHA/CS) composite microspheres were prepared through in situ biomimetic method, then composite microspheres were incorporated into CS membrane. The morphologies and mechanical properties of the composite membranes were investigated through scanning electronic microscopy (SEM) and universal mechanical testing machine. The results show that the in situ biomimetic nHA/CS microspheres were embedded in CS membrane and were integrated tightly with CS matrix. The mechanical properties of GBR membranes containing in situ nHA/CS microspheres is significantly higher than that of membranes containing pure CS microspheres and blending nHA/CS microspheres. Its elongation rate at break reaches 5.61 +/- 0.95%. The elastic modulus and strength of the GBR membranes can reach 766.27 +/- 20.68 and 43.32 +/- 0.95 MPa, respectively. Further, The work-of fracture of the membranes with in situ microspheres approaches 2.71 +/- 0.25 J/m2, which is about 3 times of the pure CS membrane. The cell culture results display that the GBR membranes containing in situ biomimetic nHA/CS microspheres exhibit good cytocompatibility. PMID- 29529591 TI - Constitutive laws with damage effect for the human great saphenous vein. AB - Strain energy-based constitutive laws with damage effect were proposed by using existing both uniaxial tensile test and tubular biaxial inflation test data on the human great saphenous vein (GSV) segments. These laws were applied into GSV coronary artery bypass grafts (CABG) by employing a thin-walled vessel model to evaluate their passive biomechanical performance under coronary artery physiological conditions at a fixed axial pre-stretch. At a peak systolic pressure in 100-150 mmHg, a 20-33% GSV diameter dilation was predicted with the law based on tubular biaxial inflation test data and agreed well with 25% dilation in clinical observation in comparison with as small as 2-4% dilation estimated with the law based on uniaxial tensile test data. The constitutive law generated by tubular biaxial inflation test data was mostly suitable for GSV CABG under coronary artery physiological conditions than that based on uniaxial tensile test results. With these laws, the fibre ultimate stretch was extracted from uniaxial tensile test data and the structural sub-failure/damage threshold of 1.0731 was decided for the human GSV. GSV fibres could exhibit damage effect but unlikely undergo a structure failure/break, suggesting a damage factor might exist during CABG arterialization. The damage in GSV tissue might initiate or contribute to early remodelling of CABG after implantation. PMID- 29529592 TI - A life course understanding of domestic and intimate partner violence in Ghana. AB - Previous studies demonstrate the long term effects of childhood violence on future victimization and perpetration of intimate partner violence (IPV). With a few exceptions from Asia, however, this literature is largely limited to North America and Europe. To date, contributions from sub-Saharan Africa remain scant. We began to fill this gap by applying the life course theory to retrospective data collected from 2289 women in Ghana. Specifically, we examined if women's childhood experiences of family violence were associated with their later victimization and/or their perpetration of IPV. We also explored the effect of the timing and continuity of family violence over the life course. Generally, we found that women with childhood experiences of violence were more likely to be victims and perpetrators of IPV than those with no such experiences. However, the effect and significance of the violence was more pronounced if it continued from early childhood (before age 15) to adulthood (after age 15). Violence experienced after age 15 was more significant than violence experienced before age 15, and women who perpetrated IPV were significantly more likely to be victimized themselves. To improve domestic violence interventions in Ghana, it is necessary to pay attention to victims' early childhood experiences. PMID- 29529593 TI - Physical neglect in childhood as a predictor of violent behavior in adolescent males. AB - Research has established that childhood maltreatment experiences are associated with negative outcomes in adolescence, including violent and antisocial behavior (Chapple et al., 2005). Neglect is the most prevalent form of childhood maltreatment (U.S. DHHS, 2012), the consequences of which require further investigation. This study used archival data to explore whether childhood physical neglect increased the likelihood of violent behavior in a random sample of 85 males between the ages of 12-19 held at a long-term detention facility in the Northeastern United States. An anonymous survey gathered background information and data regarding childhood physical neglect and violent behavior in adolescence. A step-wise hierarchal regression model controlled for the effects of age, self-esteem, personal competency, depression, chemical drug use, family violence and a childhood history of physical abuse. Results showed that a history of childhood physical neglect was the strongest predictor of violent adolescent behavior in this sample when the data was tested for all moderator and mediator effects. PMID- 29529594 TI - Factors associated with mental health services referrals for children investigated by child welfare. AB - Although child welfare caseworkers are responsible for facilitating mental health services access for maltreated children, little is known about caseworkers' decisions to refer children to services. We aimed to identify factors associated with caseworker referral of children to mental health services after a maltreatment investigation. We analyzed data from 1956 children 2-17 years old from the Second National Survey of Child and Adolescent Well-being. We examined associations of children's predisposing, enabling, and need-related factors and caseworkers' work environment characteristics with referral to mental health services. Caseworkers referred 21.0% of children to mental health services. In multivariable analyses controlling for potential covariates, factors associated with increased odds of caseworker referral included: older child age; child sexual abuse (versus neglect); child out-of-home placement; caregiver mental health problems; prior maltreatment reports; clinically significant child behavioral problems; and child welfare agency collaborative ties with mental health providers (all p < .05). Factors associated with decreased odds of caseworker referral included child Black race (versus White race) and lack of insurance (versus Private insurance) (all p < .05). In summary, children's need for mental health services was positively associated with caseworker referral to services but certain predisposing and enabling factors and caseworker work environment characteristics also correlated with services referral. Interventions to reduce disparities in services referral by race and insurance type are critically needed. These may include child welfare agency implementation of policies for mental health screening, assessment, and services referral based on clinical need and establishment of child welfare-mental health agency collaborative ties. PMID- 29529595 TI - RANKL/OPG system regulation by endogenous PTH and PTH1R/ATF4 axis in bone: Implications for bone accrual and strength in growing rats with mild uremia. AB - Osteoprotegerin (OPG), receptor activator of NF-kappaB ligand (RANKL), and parathyroid hormone (PTH) play a central role in the regulation of bone turnover in chronic kidney disease (CKD), but their influence on bone mineral density (BMD) and strength remains unclear, particularly in children. We studied the clinical significance of OPG and RANKL in relation to PTH, femur weight, BMD, and bone biomechanical properties in growing rats after one month (CKD-1) and three months (CKD-3) of surgically-induced mild CKD. Gene expression of parathyroid hormone 1 receptor (PTH1R) and activating transcription factor 4 (ATF4), major regulators of anabolic PTH response in bone, was also determined. Serum PTH and bone PTH1R/ATF4 expression was elevated in CKD-3 compared with other groups, and it positively correlated with femur weight, BMD, and the biomechanical properties of the femoral diaphysis reflecting cortical bone strength. In contrast, bone RANKL/OPG ratios were decreased in CKD-3 rats compared with other groups, and they were inversely correlated with PTH and the other abovementioned bone parameters. However, the PTH-PTH1R-ATF4 axis exerted an unfavorable effect on the biomechanical properties of the femoral neck. In conclusion, this study showed for the first time an inverse association between serum PTH and the bone RANKL/OPG system in growing rats with mild CKD. A decrease in the RANKL/OPG ratio, associated with PTH-dependent activation of the anabolic PTH1R/ATF4 pathway, seems to be responsible for the unexpected, beneficial effect of PTH on cortical bone accrual and strength. Simultaneously, impaired biomechanical properties of the femoral neck were observed, making this bone site more susceptible to fractures. PMID- 29529596 TI - Air Pollution and Suicide in 10 Cities in Northeast Asia: A Time-Stratified Case Crossover Analysis. AB - BACKGROUND: There is growing evidence suggesting an association between air pollution and suicide. However, previous findings varied depending on the type of air pollutant and study location. OBJECTIVES: We examined the association between air pollutants and suicide in 10 large cities in South Korea, Japan, and Taiwan. METHODS: We used a two-stage meta-analysis. First, we conducted a time-stratified case-crossover analysis to estimate the short-term association between nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter [aerodynamic diameter <=10MUm (PM10), aerodynamic diameter <=2.5MUm (PM2.5), and PM10-2.5] and suicide, adjusted for weather factors, day-of-week, long-term time trends, and season. Then, we conducted a meta-analysis to combine the city-specific effect estimates for NO2, SO2, and PM10 across 10 cities and for PM2.5 and PM10-2.5 across 3 cities. We first fitted single-pollutant models, followed by two-pollutant models to examine the robustness of the associations. RESULTS: Higher risk of suicide was associated with higher levels of NO2, SO2, PM10, and PM10-2.5 over multiple days. The combined relative risks (RRs) were 1.019 for NO2 (95% confidence interval [CI]: 0.999, 1.039), 1.020 for SO2 (95% CI: 1.005, 1.036), 1.016 for PM10 (95% CI: 1.004, 1.029), and 1.019 for PM10-2.5 (95% CI: 1.005, 1.033) per interquartile range (IQR) increase in the 0-1 d average level of each pollutant. We found no evidence of an association for PM2.5. Some of the associations, particularly for SO2 and NO2, were attenuated after adjusting for a second pollutant. CONCLUSIONS: Our findings suggest that higher levels of air pollution may be associated with suicide, and further research is merited to understand the underlying mechanisms. https://doi.org/10.1289/EHP2223. PMID- 29529598 TI - Reproductive Headache? Investigating Acetaminophen as a Potential Endocrine Disruptor. PMID- 29529597 TI - Effects of Cadmium Exposure on DNA Methylation at Imprinting Control Regions and Genome-Wide in Mothers and Newborn Children. AB - BACKGROUND: Imprinted genes are defined by their preferential expression from one of the two parental alleles. This unique mode of gene expression is dependent on allele-specific DNA methylation profiles established at regulatory sequences called imprinting control regions (ICRs). These loci have been used as biosensors to study how environmental exposures affect methylation and transcription. However, a critical unanswered question is whether they are more, less, or equally sensitive to environmental stressors as the rest of the genome. OBJECTIVES: Using cadmium exposure in humans as a model, we aimed to determine the relative sensitivity of ICRs to perturbation of methylation compared to similar, nonimprinted loci in the genome. METHODS: We assayed DNA methylation genome-wide using bisulfite sequencing of 19 newborn cord blood and 20 maternal blood samples selected on the basis of maternal blood cadmium levels. Differentially methylated regions (DMRs) associated with cadmium exposure were identified. RESULTS: In newborn cord blood and maternal blood, 641 and 1,945 cadmium-associated DMRs were identified, respectively. DMRs were more common at the 15 maternally methylated ICRs than at similar nonimprinted loci in newborn cord blood (p=5.64*10-8) and maternal blood (p=6.22*10-14), suggesting a higher sensitivity for ICRs to cadmium. Genome-wide, Enrichr analysis indicated that the top three functional categories for genes that overlapped DMRs in maternal blood were body mass index (BMI) (p=2.0*10-5), blood pressure (p=3.8*10-5), and body weight (p=0.0014). In newborn cord blood, the top three functional categories were BMI, atrial fibrillation, and hypertension, although associations were not significant after correction for multiple testing (p=0.098). These findings suggest that epigenetic changes may contribute to the etiology of cadmium associated diseases. CONCLUSIONS: We analyzed cord blood and maternal blood DNA methylation profiles genome-wide at nucleotide resolution in individuals selected for high and low blood cadmium levels in the first trimester. Our findings suggest that ICRs may be hot spots for perturbation by cadmium, motivating further study of these loci to investigate potential mechanisms of cadmium action. https://doi.org/10.1289/EHP2085. PMID- 29529599 TI - LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma. AB - BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) have recently emerged as novel and potentially promising therapeutic targets in various cancers. However, the expression pattern and biological function of lncRNAs in glioma remain largely elusive. In the present study, we investigated the functional role of an lncRNA, small nucleolar RNA host gene 16 (SNHG16), in glioma. METHODS: The expression levels of SNHG16 and miR-4518 were measured using qRT-PCR. The relationship between the levels of SNHG16 and clinicopathologic features were statically analyzed. The levels of proteins were detected using western blot. Bioinformatics analysis and luciferase reporter assays were applied to the analysis of the relationship between SNHG16, miR-4518 and PRMT5. Cell viability and apoptosis were measured using MTT and apoptosis ELISA assay, respectively. RESULTS: SNHG16 was highly expressed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. Knockdown of SNHG16 inhibits the viability and induces apoptosis of glioma cells. Further investigation revealed that SNHG16 could up-regulate the expression of miR-4518 targeted gene PRMT5 via acting as an endogenous sponge of miR-4518. Moreover, SNHG16 also affects the expression of Bcl-2 family proteins and the activation of PI3K/Akt signaling pathway. CONCLUSION: Our study revealed a novel SNHG16-miR 4518-PRMT5 pathway regulatory axis in glioma pathogenesis. SNHG16 could be used as a potential therapeutic target in the treatment of glioma. PMID- 29529600 TI - Long Noncoding RNA Meg3 Regulates Mafa Expression in Mouse Beta Cells by Inactivating Rad21, Smc3 or Sin3alpha. AB - BACKGROUND/AIMS: The main pathogenic mechanism of diabetes is a decrease in the number of islet beta cells or a decline in their function. Recent studies have shown that pancreatic long noncoding RNAs (lncRNAs) have a high degree of tissue specificity and may be involved in the maintenance of islet cells function and the development of diabetes. The aim of this study was to investigate the molecular regulatory mechanism of mouse maternal expressed gene 3 (Meg3) in insulin biosynthesis in pancreatic islets. METHODS: Chromatin immunoprecipitation quantitative polymerase chain reaction (qPCR) and RNA immunoprecipitation-qPCR were used to investigate the molecular mechanism of lncRNA Meg3 in insulin biosynthesis by regulating v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker in the MIN6 beta cell line. Further, the expression levels of Meg3, Ezh2, MafA, Rad21, Smc3, and Sin3alpha were analyzed in vivo and in vitro by RT-PCR and western blotting. RESULTS: Intranuclear lncRNA Meg3 can bind EZH2, a methyltransferase belonging to the Polycomb repressive complex-2, in pancreatic islet cells. In addition, knockdown of Ezh2 can also inhibit the expression of MafA and Ins2, while expression levels of Rad21, Smc3, and Sin3alpha are upregulated, by interfering with Ezh2 or Meg3 in pancreatic beta cells. Knockdown of Meg3 resulted in the loss of EZH2 binding and H3K27 trimethylation occupancy of Rad21, Smc3, and Sin3alpha promoter regions. The inhibition of Rad21, Smc3, or Sin3alpha, which directly act on the MafA promoter, leads to upregulated expression of MafA in both MIN6 cells and mouse islets. Moreover, the synthesis and secretion of insulin were increased by inhibition of these transcription factors. CONCLUSIONS: Pancreatic lncRNA Meg3 can epigenetically regulate the expression of Rad21, Smc3, and Sin3alpha via EZH2 driven H3K27 methylation. By inhibiting the expression of Rad21, Smc3, or Sin3alpha, Meg3 promotes the expression of MafA and affects the production of insulin. PMID- 29529601 TI - Cadaver Dissection Is Obsolete in Medical Training! A Misinterpreted Notion. AB - Cadaver dissection (CD) is considered a tool for studying the structural details of the human body. Lately, conflicting opinions regarding the utility of this modality in medical training have been published in medical literature. This review of the literature examines the status of anatomy teaching with CD in traditional, modern, and postgraduate medical training across the world. Literature published in the En-glish language on topics related to CD in the past 3 decades was scrutinized using different search engines. About 200 full texts were reviewed. We describe how medical schools have continued to include CD in anatomy teaching in the traditional or modified form. Medical schools that stopped or decreased CD have learnt from their experiences, and have restarted it in modified forms by integrating it vertically with medical training. In addition, CD activities have increased in postgraduate anatomy courses, surgery training, and voluntary/optional CD programs. CD, when integrated vertically, still has a part to play in medical training in modified ways. This overview may help curriculum designers to place CD in medical curricula and training programs in a justified manner. PMID- 29529603 TI - Novel Mutations in the PKD1 and PKD2 Genes of Chinese Patients with Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND/AIMS: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. METHODS: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions. RESULTS: A total of 93 mutations in PKD1 and PKD2 were identified in 98 Chinese families with ADPKD inheritance and the detection rate was 81.7% (98/120). The mutation rates of PKD1 and PKD2 were 91.4% (85/93) and 8.6% (85/93), respectively. Among the 93 mutations, 59.1% (55/93) were reported for the first time. A total of 65 mutations (26 nonsense, 33 frameshift, 2 large deletion, and 4 typical splicing mutations) were identified as definite pathogenic mutations. The remaining 28 mutations (21 missense, 3 in-frame deletion, and 4 atypical splicing mutations) were determined as probable pathogenic mutations. In addition, 9 de novo mutations were found by pedigree analysis. Correlation analysis between genotype and phenotype revealed that patients with PKD1 mutations or truncating mutations exhibited the most severe clinical outcome. CONCLUSION: The newly identified sites for known mutations will facilitate the early diagnosis and prediction of prognosis in patients with ADPKD, and provide fundamental genetic information for clinical intervention to prevent the inheritance of this disease in affected families. PMID- 29529602 TI - Combined Inhibition of Soluble Epoxide Hydrolase and Renin-Angiotensin System Exhibits Superior Renoprotection to Renin-Angiotensin System Blockade in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats with Established Chronic Kidney Disease. AB - BACKGROUND/AIMS: We found recently that increasing renal epoxyeicosatrienoic acids (EETs) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, shows renoprotective actions and retards the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). This prompted us to examine if additional protection is provided when sEH inhibitor is added to the standard renin-angiotensin system (RAS) blockade, specifically in rats with established CKD. METHODS: For RAS blockade, an angiotensin-converting enzyme inhibitor along with an angiotensin II type receptor blocker was used. RAS blockade was compared to sEH inhibition added to the RAS blockade. Treatments were initiated 6 weeks after 5/6 NX in TGR and the follow-up period was 60 weeks. RESULTS: Combined RAS and sEH blockade exhibited additional positive impact on the rat survival rate, further reduced albuminuria, further reduced glomerular and tubulointerstitial injury, and attenuated the decline in creatinine clearance when compared to 5/6 NX TGR subjected to RAS blockade alone. These additional beneficial actions were associated with normalization of the intrarenal EETs deficient and a further reduction of urinary angiotensinogen excretion. CONCLUSION: This study provides evidence that addition of pharmacological inhibition of sEH to RAS blockade in 5/6 NX TGR enhances renoprotection and retards progression of CKD, notably, when applied at an advanced stage. PMID- 29529604 TI - Influence of SPRINT Study Type Automated Office Blood Pressure Measurements on Hypertension Diagnosis in Kidney Transplant Patients. AB - BACKGROUND/AIMS: We compare conventional office blood pressure measurements with automated SPRINT-study type readings in kidney transplant recipients in order to determine the impact of the white coat effect in a prospective observational study. METHODS: Adult patients with a functional renal transplant not dependent on dialysis were eligible. Readings were taken in the office in presence of the physician with an oscillometric method. Afterwards, readings were repeated with the patients resting alone in a quiet examination room with an automated blood pressure monitor. After 5 minutes of rest, 3 readings were taken at 1 minute intervals, with an average of these 3 readings calculated by the monitor. RESULTS: 120 patients with an average age of 58.5+/-12.2 years were included. Mean time since transplantation was 7.95+/-6.48 years. Mean eGFR (CKD-EPI) was 48.5+/-18.3 ml/min. SPRINT-study type readings were significantly lower than office readings (139.01+/-18.45 vs. 149.00+/-21.02 mmHg systolic, p<0.001; 80.88+/-11.63 mmHg vs. 84.35+/-12.41 mmHg diastolic, p <0.001). Correlation analysis for many potentially influencing factors (diabetes mellitus, transplant vintage, proteinuria, age, immunosuppression, donor type) was not significant but obese women were significantly more prone to white coat hypertension. CONCLUSION: Automated office blood pressure measurements should be considered the method of choice in kidney transplant recipients. PMID- 29529605 TI - Acetic Acid Influences BRL-3A Cell Lipid Metabolism via the AMPK Signalling Pathway. AB - BACKGROUND/AIMS: Acetic acid (AcOH), a short-chain fatty acid, is reported to have some beneficial effects on metabolism. Therefore, the aim of this study was to investigate the regulatory mechanism of acetic acid on hepatic lipid metabolism in BRL-3A cells. METHODS: We cultured and treated BRL-3A cells with different concentrations of sodium acetate (neutralized acetic acid) and BML-275 (an AMPKalpha inhibitor). The total lipid droplet area was measured by oil red O staining, and the triglyceride content was determined by a triglyceride detection kit. We detected mRNA and protein levels of lipid metabolism-related signalling molecules by RT-PCR and Western blot. RESULTS: Acetic acid treatment increased AMPKalpha phosphorylation, which subsequently increased the expression and transcriptional activity of peroxisome proliferator-activated receptor alpha and upregulated the expression of lipid oxidation genes. These changes ultimate led to increasing levels of lipid oxidation in BRL-3A cells. Furthermore, elevated AMPKalpha phosphorylation reduced the expression and transcriptional activity of the sterol regulatory element-binding protein 1c, which reduced the expression of lipogenic genes, thereby decreasing lipid biosynthesis in BRL-3A cells. Consequently, triglyceride content in acetate-treated BRL-3A cells was significantly decreased. CONCLUSIONS: These results indicate that acetic acid activates the AMPKalpha signalling pathway, leading to increased lipid oxidation and decreased lipid synthesis in BRL-3A cells, thereby reducing liver fat accumulation in vitro. PMID- 29529606 TI - Does Listening to Music during Tonsillectomy Affect Sevoflurane Consumption? AB - OBJECTIVE: The aim of this study was to investigate the effect of listening to music on the consumption of an anesthetic agent as well as postoperative recovery and pain in children undergoing elective tonsillectomy. MATERIALS AND METHODS: Fifty patients were randomized into those to whom music was played during surgery (group M) and a control group to whom music was not played (group C). The depth of anesthesia was provided by entropy levels of 50 +/- 5 in both groups. Demographic characteristics and hemodynamic parameters were recorded perioperatively. The duration of surgery, sevoflurane consumption, eye opening time, and extubation time were also recorded. p < 0.05 was considered statistically significant. RESULTS: Surgical pleth index values measured intraoperatively were statistically lower in group M than in group C. In the postanesthesia care unit children in the music group felt less pain than those in the control group according to the Wong-Baker Faces Pain Rating Scale (p = 0.035). The heart rates of the patients in the music group were statistically lower at 30 min intraoperatively and at the end of the procedure compared to the values of the control group (p = 0.015). The consumption of sevoflurane was lower in group M than in group C but the difference was not statistically significant. The need for additional fentanyl was significantly lower in group M than in group C. CONCLUSION: In this study, the children exposed to music intraoperatively needed less analgesia during surgery, and reported less pain postoperatively, but there was no difference in sevoflurane requirements. PMID- 29529607 TI - Ankle Nerve Block Adjuvant to General Anesthesia Reduces Postsurgical Pain and Improves Functional Outcomes in Hallux Valgus Surgery. AB - OBJECTIVE: Postoperative pain is a frequent problem after orthopedic procedures like hallux valgus surgery. The aim of this study was to evaluate whether ankle block improves early and mid-term functional outcomes and postoperative pain management after hallux valgus surgery in patients receiving general anesthesia. SUBJECTS AND METHODS: This randomized controlled trial investigated 60 patients who underwent hallux valgus surgery under general anesthesia. Patients were prospectively randomized into 2 groups: general anesthesia only (group A) and ankle block added to general anesthesia (group B). Age, body-mass index, tourniquet time, duration of surgery, first analgesic need time, perioperative analgesic regimen, visual analog scale (VAS), American Orthopedic Foot and Ankle Score (AOFAS), and length of hospital stay were recorded. Independent variables were analyzed by t test. Nonparametric data were analyzed by the Mann-Whitney U test. RESULTS: Patient age, demographics, and body mass indices were similar between the 2 groups. The average length of hospital stay was significantly longer in group A (p < 0.01). Group B had a longer time to first analgesic need than group A (p < 0.01). Patients in group B required less analgesic during the postoperative period. Preoperative VAS and AOFAS scores were not statistically dif ferent between the 2 groups. The postoperative day 1 VAS score was significantly lower in group B than in group A. Follow-up visits at 3, 6, and 12 months showed significantly lower VAS and higher AOFAS scores in group B than group A. CONCLUSION: Ankle block added to general anesthesia may improve early and mid-term postoperative functional outcomes and postoperative pain management in patients who undergo hallux valgus surgery. PMID- 29529608 TI - Clinicopathological Features to Predict Progression of IgA Nephropathy with Mild Proteinuria. AB - BACKGROUND/AIMS: In the past, little attention has been paid to patients with IgA nephropathy (IgAN) who had minimal proteinuria upon the onset. The aim of this study was to analyze the clinicopathological features and the prognostic factors in patients with IgA nephropathy. METHODS: Data of patients that had their first renal biopsy in our hospital and were diagnosed with primary IgAN with proteinuria <1 g/d from January 1995 to December 2014 were retrospectively examined. Clinical records of the clinicopathological features, renal function, and proteinuria were collected and investigated. The factors affecting the renal function and proteinuria were analyzed by Cox regression. The predictive efficiencies of clinical and pathological models were evaluated by Harrell concordance index (C-index). RESULTS: A total of 506 patients with IgA nephropathy were included in this study. (1) Baseline proteinuria greater than 0.5 g/d was positively associated with Oxford M, S, and T lesions. eGFR less than 90 mL/min/1.73 m2 were positively associated with Oxford T. (2) In the follow-up with a median of 50 months, 82 patients (16.2%) achieved complete clinical remission (CCR), whereas 54 patients (10.6%) showed an increase in creatinine by more than 50% (not progressing to end-stage renal disease). The cumulative proportion of creatinine increased >50%, and the values obtained by life-table analysis in 10, 15, and 20 years were 15%, 21%, and 22%, respectively. Significant differences were found in baseline age, proteinuria, and Oxford T between the group of creatinine increase >50% and the CCR group. (4) Multivariate COX regression showed that baseline age and proteinuria > 0.5 g/d were independent risk factors of adverse outcome. C-index suggested that the clinical model was more effective than the pathological models in predicting endpoint events. (5) Effect of the mean value during the follow-up on adverse endpoint events: Multivariate COX regression found that the mean proteinuria during follow up was an independent influencing factor for the increase of creatinine by more than 50%. CONCLUSION: (1) Proteinuria > 0.5g/d and eGFR < 90 mL/min/1.73 m2 may predict more severe pathological changes; (2) With the increase in age and baseline proteinuria, the risks of adverse endpoint events would increase significantly; (3) Pathology could roughly predict the adverse endpoint events but is less efficient than the clinical indicators; (4) Data during follow-up suggested that the patients should regularly test their renal function and proactively control their proteinuria. PMID- 29529609 TI - Risk Factors and Clinical Impact of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: Analysis from the China National Stroke Registry. AB - BACKGROUND: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) is a significant cause of morbidity and mortality. While it is important to detect early signs of DCI, patients with high risk of DCI are difficult to identify, and the potential risk factors are uncertain. This study aimed to identify independent risk factors of DCI and clarify their clinical impact on outcome and the disease course. METHODS: For this nationwide, multicenter, prospective clinical study involving consecutive patients with aSAH recruited from the China National Stroke Registry, demographic, clinical, radiological, and laboratorial data during hospitalisation, in-hospital complications, functional outcomes, and mortality at 3, 6, and 12 months were recorded. Using univariate and multivariate logistic regression to determine risk factors associated with the development of DCI, the contribution of DCI to short- and long-term outcomes was evaluated. RESULTS: Of all 504 patients with aSAH, 155 developed DCI. Multivariate analysis revealed that being female, a history of diabetes mellitus, a Hunt and Hess grade of 4-5, and a World Federation of Neurosurgical Societies grade of IV-V were independent risk factors of DCI. DCI was associated with high in-hospital complications, and with a high utilization rate of supporting interventions. DCI also contributed to poorer functional outcome and higher mortality at discharge and after 3, 6, and 12 months. CONCLUSIONS: Female sex, a history of diabetes mellitus, and poor clinical grade are independent early risk factors for the development of DCI and can contribute to a better identification of patients at a high risk for DCI. DCI was associated with severe clinical course, poor outcome, and mortality both in the short- and long-term in patients with aSAH in China. PMID- 29529611 TI - Editorial Comment: 2017 Knee Society Proceedings. PMID- 29529610 TI - Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients. AB - BACKGROUND/AIMS: IgA nephropathy is associated with aberrant O-glycosylation of IgA1, which is recognized by autoantibodies leading to the formation of circulating immune complexes. Some of them, after deposition into kidney mesangium, trigger glomerular injury. In patients with active disease nonresponding to angiotensin-converting enzyme inhibitors or angiotensin II blockers, corticosteroids are recommended. METHODS: The relationship between the corticosteroid therapy and serum levels of IgA, aberrantly O-glycosylated IgA1, IgA-containing immune complexes and their mesangioproliferative activity was analyzed in IgA nephropathy patients and disease and healthy controls. RESULTS: Prednisone therapy significantly reduced proteinuria and levels of serum IgA, galactose-deficient IgA1, and IgA-IgG immune complexes in IgA nephropathy patients and thus reduced differences in all of the above parameters between IgAN patients and control groups. A moderate but not significant reduction of mesangioproliferative potential of IgA-IgG immune complexes and IgA sialylation was detected. CONCLUSION: The prednisone therapy reduces overall aberrancy in IgA1 O-glycosylation in IgA nephropathy patients, but the measurement of IgA1 parameters does not allow us to predict the prednisone therapy outcome in individual patients. PMID- 29529612 TI - Saphenous Nerve Block From Within the Knee Is Feasible for TKA: MRI and Cadaveric Study. AB - BACKGROUND: Surgeon-performed periarticular injections and anesthesiologist performed femoral nerve or adductor canal blocks with local anesthetic are in common use as part of multimodal pain management regimens for patients undergoing TKA. However, femoral nerve blocks risk causing quadriceps weakness and falls, and anesthesiologist-performed adductor canal blocks are costly in time and resources and may be unreliable. We investigated the feasibility of a surgeon performed saphenous nerve ("adductor canal") block from within the knee at the time of TKA. QUESTIONS/PURPOSES: (1) Can the saphenous nerve consistently be identified distally on MRI studies, and is there a consistent relationship between the width of the femoral transepicondylar axis (TEA) and the proximal (cephalad) location where the saphenous nerve emerges from the adductor canal? With these MRI data, we asked the second question: (2) Can we utilize this anatomic relationship to simulate a surgeon-performed intraoperative block of the distal saphenous nerve from within the knee with injections of dyes after implantation of trial TKA components in cadaveric lower extremity specimens? METHODS: A retrospective analysis of 94 thigh-knee MRI studies was performed to determine the relationship between the width of the distal femur at the epicondylar axis and the proximal location of the saphenous nerve after its exit from the adductor canal and separation from the superficial femoral artery. These studies, obtained from one hospital's MRI library, had to depict the saphenous nerve in the distal thigh and the femoral epicondyles and excluded patients younger than 18 years of age or with metal implants. These studies were performed to evaluate thigh and knee trauma or unexplained pain, and 55 had some degree of osteoarthritis. After obtaining these data, TKA resections and trial component implantation were performed, using a medial parapatellar approach, in 11 fresh cadaveric lower extremity specimens. There were six male and five female limbs from cadavers with a mean age of 70 years (range, 57-80 years) and mean body mass index of 20 kg/m (range, 15-26 kg/m) without known knee arthritis. Using a blunt tipped 1.5-cm needle, we injected 10 mL each of two different colored solutions from inside the knee at two different locations and, after 30 minutes, dissected the femoral and saphenous nerves and femoral artery from the hip to the knee. Our endpoints were whether the saphenous nerve was bathed in dye and if the dye or needle was located in the femoral artery or vein. RESULTS: Based on the MRI analysis, the mean +/- SD TEA was 75 +/- 4 mm in females and 87 +/- 4 mm in males. The saphenous nerve exited the adductor canal and was located at a mean of 1.5 +/- 0.16 times the TEA width in females and a mean of 1.3 +/- 0.13 times the TEA width in males proximal to the medial epicondyle. After placement of TKA trial components and injection, the proximal injection site solution bathed the saphenous nerve in eight of 11 specimens. In two cachectic female cadaver limbs, the dye was located posteriorly to the nerve in hamstring muscle. The proximal blunt needle and colored solution were directly adjacent to but did not penetrate the femoral artery in only one specimen. CONCLUSIONS: This study indicates, based on MRI measurements, cadaveric injections, and dissections, that a surgeon performed injection of the saphenous nerve from within the knee after it exits from the adductor canal seems to be a feasible procedure. CLINICAL RELEVANCE: This technique may be a useful alternative to an ultrasound-guided block. A trial comparing surgeon- and anesthesiologist-performed nerve block should be considered to determine the clinical efficacy of this procedure. PMID- 29529613 TI - CORR Insights(r): Saphenous Nerve Block From Within the Knee Is Feasible for TKA: MRI and Cadaveric Study. PMID- 29529614 TI - Preoperative Physical Therapy Education Reduces Time to Meet Functional Milestones After Total Joint Arthroplasty. AB - BACKGROUND: As length of stay decreases for total joint arthroplasty, much of the patient preparation and teaching previously done in the hospital must be performed before surgery. However, the most effective form of preparation is unknown. This randomized trial evaluated the effect of a one-time, one-on-one preoperative physical therapy education session coupled with a web-based microsite (preopPTEd) on patients' readiness to discharge from physical therapy (PT), length of hospital stay, and patient-reported functional outcomes after total joint arthroplasty. QUESTIONS/PURPOSES: Was this one-on-one preoperative PT education session coupled with a web- based microsite associated with (1) earlier achievement of readiness to discharge from PT; (2) a reduced hospital length of stay; and (3) improved WOMAC scores 4 to 6 weeks after surgery? METHODS: Between February and June 2015, 126 typical arthroplasty patients underwent unilateral TKA or THA. As per our institution's current guidelines, all patients attended a preoperative group education class taught by a multidisciplinary team comprising a nurse educator, social worker, and physical therapist. Patients were then randomized into two groups. One group (control; n = 63) received no further education after the group education class, whereas the intervention group (experimental; n = 63) received preopPTEd. The preopPTEd consisted of a one-time, one-on-one session with a physical therapist to learn and practice postoperative precautions, exercises, bed mobility, and ambulation with and negotiation of stairs. After this session, all patients in the preopPTEd group were given access to a lateralized, joint-specific microsite that provided detailed information regarding exercises, transfers, ambulation, and activities of daily living through videos, pictures, and text. Outcome measures assessed included readiness to discharge from PT, which was calculated by adding the number of postoperative inpatient PT visits patients had to meet PT milestones. Hospital length of stay (LOS) was assessed for hospital discharge criteria and 6-week WOMAC scores were gathered by study personnel. At our institution, to meet PT milestones for hospital discharge criteria, patients have to be able to (1) independently transfer in and out of bed, a chair, and a toilet seat; (2) independently ambulate approximately 150 feet; (3) independently negotiate stairs; and (4) be independent with a home exercise program and activities of daily living. Complete followup was available on 100% of control group patients and 100% patients in the intervention group for all three outcome measures (control and intervention of 63, respectively). RESULTS: The preopPTEd group had fewer postoperative inpatient PT visits (mean, 3.3; 95% confidence interval [CI], 3.0-3.6 versus 4.4; 95% CI, 4.1-4.7; p < 0.001) and achieved readiness to discharge from PT faster (mean, 1.6 days; 95% CI, 1.2-1.9 days versus 2.7 days; 95% CI, 2.4-3.0; p < 0.001) than the control group. There was no difference in hospital LOS between the preopPTEd group and the control group (2.4 days; 95% CI, 2.1-2.6; p = 0.082 versus 2.6 days; 95% CI, 2.4-2.8; p = 0.082). There were no clinically relevant differences in 6-week WOMAC scores between the two groups. CONCLUSIONS: Although this protocol resulted in improved readiness to discharge from PT, there was no effect on LOS or WOMAC scores at 6 weeks. Preoperative PT was successful in improving one of the contributors to LOS and by itself is insufficient to make a difference in LOS. This study highlights the need for improvement in other aspects of care to improve LOS. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29529615 TI - CORR Insights(r): Preoperative Physical Therapy Education Reduces Time to Meet Functional Milestones After Total Joint Arthroplasty. PMID- 29529616 TI - Analysis of Outcomes After TKA: Do All Databases Produce Similar Findings? AB - BACKGROUND: Use of large clinical and administrative databases for orthopaedic research has increased exponentially. Each database represents unique patient populations and varies in their methodology of data acquisition, which makes it possible that similar research questions posed to different databases might result in answers that differ in important ways. QUESTIONS/PURPOSES: (1) What are the differences in reported demographics, comorbidities, and complications for patients undergoing primary TKA among four databases commonly used in orthopaedic research? (2) How does the difference in reported complication rates vary depending on whether only inpatient data or 30-day postoperative data are analyzed? METHODS: Patients who underwent primary TKA during 2010 to 2012 were identified within the National Surgical Quality Improvement Programs (NSQIP), the Nationwide Inpatient Sample (NIS), the Medicare Standard Analytic Files (MED), and the Humana Administrative Claims database (HAC). NSQIP is a clinical registry that captures both inpatient and outpatient events up to 30 days after surgery using clinical reviewers and strict definitions for each variable. The other databases are administrative claims databases with their comorbidity and adverse event data defined by diagnosis and procedure codes used for reimbursement. NIS is limited to inpatient data only, whereas HAC and MED also have outpatient data. The number of patients undergoing primary TKA from each database was 48,248 in HAC, 783,546 in MED, 393,050 in NIS, and 43,220 in NSQIP. NSQIP definitions for comorbidities and surgical complications were matched to corresponding International Classification of Diseases, 9 Revision/Current Procedural Terminology codes and these coding algorithms were used to query NIS, MED, and HAC. Age, sex, comorbidities, and inpatient versus 30-day postoperative complications were compared across the four databases. Given the large sample sizes, statistical significance was often detected for small, clinically unimportant differences; thus, the focus of comparisons was whether the difference reached an absolute difference of twofold to signify an important clinical difference. RESULTS: Although there was a higher proportion of males in NIS and NSQIP and patients in NIS were younger, the difference was slight and well below our predefined threshold for a clinically important difference. There was variation in the prevalence of comorbidities and rates of postoperative complications among databases. The prevalence of chronic obstructive pulmonary disease (COPD) and coagulopathy in HAC and MED was more than twice that in NIS and NSQIP (relative risk [RR] for COPD: MED versus NIS 3.1, MED versus NSQIP 4.5, HAC versus NIS 3.6, HAC versus NSQIP 5.3; RR for coagulopathy: MED versus NIS 3.9, MED versus NSQIP 3.1, HAC versus NIS 3.3, HAC versus NSQIP 2.7; p < 0.001 for all comparisons). NSQIP had more than twice the obesity as NIS (RR 0.35). Rates of stroke within 30 days of TKA had more than a twofold difference among all databases (p < 0.001). HAC had more than twice the rates of 30-day complications at all endpoints compared with NSQIP and more than twice the 30-day infections as MED. A comparison of inpatient and 30-day complications rates demonstrated more than twice the amount of wound infections and deep vein thromboses is captured when data are analyzed out to 30 days after TKA (p < 0.001 for all comparisons). CONCLUSIONS: When evaluating research utilizing large databases, one must pay particular attention to the type of database used (administrative claims, clinical registry, or other kinds of databases), time period included, definitions utilized for specific variables, and the population captured to ensure it is best suited for the specific research question. Furthermore, with the advent of bundled payments, policymakers must meticulously consider the data sources used to ensure the data analytics match historical sources. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529617 TI - CORR Insights(r): Analysis of Outcomes After TKA: Do All Databases Produce Similar Findings? PMID- 29529618 TI - The John N. Insall Award: Higher Tissue Concentrations of Vancomycin Achieved With Intraosseous Regional Prophylaxis in Revision TKA: A Randomized Controlled Trial. AB - BACKGROUND: In primary TKA, prophylaxis with low-dose vancomycin through intraosseous regional administration (IORA) achieves tissue concentrations six to 10 times higher than systemic administration and was shown to provide more effective prophylaxis in an animal model. However, in revision TKA, the presence of a tibial implant may compromise IORA injection, and tourniquet deflation during a prolonged procedure may lower tissue concentrations. QUESTIONS/PURPOSES: (1) Does low-dose IORA reliably provide equal or higher tissue concentrations of vancomycin compared with systemic IV administration in revision TKA? (2) Are tissue concentrations of vancomycin after IORA maintained for the duration of the revision TKA despite a period of tourniquet deflation? (3) Is there any difference in early postoperative (< 6 weeks) complications between IORA and systemic IV administration in revision TKA? METHODS: Twenty patients undergoing aseptic revision TKA were randomized to two groups. The IV group received 1 g systemic IV prophylactic vancomycin. The IORA group received 500 mg vancomycin as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet before skin incision. In all patients receiving IORA, intraosseous tibial injection was technically possible despite the presence of a tibial implant. Mean procedure length was 3.5 hours in both groups. Mean initial tourniquet inflation was 1.5 hours with a second inflation for a mean of 35 minutes during cementation. During the procedure, subcutaneous fat and bone samples were taken at regular intervals. Tissue vancomycin concentrations were measured using high-performance liquid chromatography. RESULTS: Overall geometric mean tissue concentration of vancomycin in fat samples was 3.7 MUg/g (95% confidence interval [CI], 2.6-5.2) in the IV group versus 49.3 MUg/g in the IORA group (95% CI, 33.2-73.4; ratio between means 13.5; 95% CI, 8.2-22.0; p < 0.001); mean tissue concentrations in femoral bone were 6.4 MUg/g (95% CI, 4.5-9.2) in the IV group versus 77.1 MUg/g (95% CI, 42.4-140) in the IORA group (ratio between means 12.0; 95% CI, 6.2-23.2; p < 0.001). Vancomycin concentrations in the final subcutaneous fat sample taken before closure were 5.3 times higher in the IORA group versus the IV group (mean +/- SD, 18.2 +/- 11.6 MUg/g IORA versus 3.6 +/- 2.5 MUg/g; p < 0.001). The intraarticular concentration of vancomycin on postoperative Day 1 drain samples was not different between the two groups with the numbers available (mean 4.6 MUg/L in the IV group versus 6.6 MUg/g in the IORA group; mean difference 2.0 MUg/g; 95% CI, 6.2-23.2; p = 0.08). CONCLUSIONS: IORA administration of vancomycin in patients undergoing revision TKA resulted in tissue concentrations of vancomycin five to 20 times higher than systemic IV administration despite the lower dose. High tissue concentrations were maintained throughout the procedure despite a period of tourniquet deflation. These preliminary results justify prospective cohort studies, which might focus on broader safety endpoints in more diverse patient populations. We believe that these studies should evaluate patients undergoing revision TKA in particular, because the risk of infection is greater than in patients undergoing primary TKA. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 29529619 TI - CORR Insights(r): The John N. Insall Award: Higher Tissue Concentrations of Vancomycin Achieved With Intraosseous Regional Prophylaxis in Revision TKA: A Randomized Controlled Trial. PMID- 29529620 TI - Validity and Internal Consistency of the New Knee Society Knee Scoring System. AB - BACKGROUND: In 2012, a new Knee Society Knee Scoring System (KSS) was developed and validated to address the needs for a scoring system that better encompasses the expectations, satisfaction, and physical involvement of a younger, more active population of patients undergoing TKA. Revalidating this tool in a separate population by individuals other than the developers of the scoring system seems important, because such replication would tend to confirm the generalizability of this tool. QUESTIONS/PURPOSES: The purposes of this study were (1) to validate the KSS using a separate sample of patients undergoing primary TKA; and (2) to evaluate the internal consistency of the KSS. METHODS: Intervention and control groups from a randomized controlled trial with no between-group differences were pooled. Preoperative and postoperative (6 weeks and 1 year) data were used. Patients with osteoarthritis undergoing primary TKA completed the patient-reported component of the KSS, Knee Injury and Osteoarthritis Outcome Score (KOOS), SF-12, two independent questions about expectations of surgery, and the Patient Acceptable Symptom State (PASS) single question outcome. This study included 345 patients with 221 (64%) women, an average (SD) age of 64 (8.6) years, a mean (SD) body mass index of 32.9 (7.5) kg/m, and 225 (68%) having their first primary TKA. Loss to followup in the control group was 18% and loss to followup in the intervention group was 13%. We quantified cross-sectional (preoperative scores) and longitudinal validity (pre- to postoperative change scores) by evaluating associations between the KSS and KOOS subscales using Spearman's correlation coefficient. Preoperative known-group validity of the KSS symptoms and functional activity score was evaluated with a one-way analysis of variance across three levels of physical health status using the SF-12 Physical Component Score. Known-group validity of the KSS expectation score was evaluated with an unpaired t-test by comparing means across known expectation groups. Known-group validity of the KSS satisfaction score was evaluated with an unpaired t-test by comparing means across yes/no response groupings of the PASS single-question outcome. Internal consistency for each KSS subscale was evaluated with Cronbach's alpha. RESULTS: Cross-sectional validity (ie, associations at a single point in time) was supported because correlation coefficients between KSS symptoms, functional activities, and satisfaction scores and scores on the KOOS pain subscale ranged from 0.60 to 0.73 (all correlations p < 0.01). Values were similar for associations with the KOOS function in the activities of daily living (ADL) subscale (0.66-0.69) and less (0.41-0.58) for correlations with the other three KOOS subscales. Longitudinal validity (ie, associations of change scores between two time points) was also supported because correlation coefficients between KSS symptoms, functional activities, and satisfaction change scores and the KOOS pain and ADL change scores varied from 0.63 to 0.73. Correlation coefficients were lower for the other three KOOS subscale change scores, suggesting a weaker relationship with KOOS symptoms (0.48 0.53), sports (0.47-0.51), and quality of life (0.60-0.65) (all correlations p < 0.01). Known-group validity (ie, differences between groups that are known to differ on a given characteristic) was confirmed by between-group differences for the symptoms and functional activities score comparisons as well as the comparisons with the expectations and satisfaction scores of the KSS (all p < 0.01). Cronbach's alpha (ie, association among subscale items) varied from 0.68 (discretionary activities) to 0.94 (postoperative expectations) across four KSS subscales. CONCLUSIONS: Moderate-sized correlation coefficients and consistent differences between known groups support the validity of the KSS. Internal consistency values were also acceptable. The patient-reported subscales of the KSS are a valid and internally consistent outcome assessment for TKA. PMID- 29529621 TI - CORR Insights(r): Validity and Internal Consistency of the New Knee Society Knee Scoring System. PMID- 29529622 TI - The Mark Coventry Award: Patellofemoral Arthroplasty Results in Better Range of Movement and Early Patient-reported Outcomes Than TKA. AB - BACKGROUND: Controversy exists over the surgical treatment for severe patellofemoral osteoarthritis. We therefore wished to compare the outcome of patellofemoral arthroplasty (PFA) with TKA in a blinded randomized controlled trial. QUESTIONS/PURPOSES: In the first 2 years after surgery: (1) Does the overall gain in quality of life differ between the implants based on the area under the curve of patient-reported outcomes (PROs) versus time? (2) Do patients obtain a better quality of life at specific points in time after PFA than after TKA? (3) Do patients get a better range of movement after PFA than after TKA? (4) Does PFA result in more complications than TKA? METHODS: Patients were eligible if they had debilitating symptoms and isolated patellofemoral disease. One hundred patients were included from 2007 to 2014 and were randomized to PFA or TKA (blinded for the first year; blinded to patient, therapists, primary care physicians, etc; quasiblinded to assessor). Patients were seen for four clinical followups and completed six sets of questionnaires during the first 2 postoperative years. SF-36 bodily pain was the primary outcome. Other outcomes were range of movement, PROs (SF-36, Oxford Knee Score [OKS], Knee injury and Osteoarthritis Outcome Score [KOOS]) as well as complications and revisions. Four percent (two of 50) of patients died within the first 2 years in the PFA group (none in the TKA group), and 2% (one of 50) became ill and declined further participation after 1 year in the PFA group (none in the TKA group). The mean age at inclusion was 64 years (SD 8.9), and 77% (77 of 100) were women. RESULTS: The area under the curve (AUC) up to 2 years for SF-36 bodily pain of patients undergoing PFA and those undergoing TKA was 9.2 (SD 4.3) and 6.5 (SD 4.5) months, respectively (p = 0.008). The SF-36 physical functioning, KOOS symptoms, and OKS also showed a better AUC up to 2 years for PFA compared with TKA (6.6 [SD 4.8] versus 4.2 [SD 4.3] months, p = 0.028; 5.6 [SD 4.1] versus 2.8 [SD 4.5] months, p = 0.006; 7.5 [SD 2.7] versus 5.0 [SD 3.6] months, p = 0.001; respectively). The SF-36 bodily pain improvement at 6 months for patients undergoing PFA and those undergoing TKA was 38 (SD 24) and 27 (SD 23), respectively (p = 0.041), and at 2 years, the improvement was 39 (SD 24) and 33 (SD 22), respectively (p = 0.199). The KOOS symptoms improvement at 6 months for patients undergoing PFA and those undergoing TKA was 24 (SD 20) and 7 (SD 21), respectively (p < 0.001), and at 2 years, the improvement was 27 (SD 19) and 17 (SD 21), respectively (p = 0.023). Improvements from baseline for KOOS pain, SF-36 physical functioning, and OKS also differed in favor of PFA at 6 months, whereas only KOOS symptoms showed a difference between the groups at 2 years. No PRO dimension showed a difference in favor of TKA. At 4 months, 1 year, and 2 years, the ROM change from baseline for patients undergoing PFA and those undergoing TKA was (-7 degrees [SD 13 degrees ] versus -18 degrees [SD 14 degrees ], p < 0.001; -4 degrees [SD 15 degrees ] versus -11 degrees [SD 12 degrees ], p = 0.011; and -3 degrees [SD 12 degrees ] versus -10 degrees [SD 12 degrees ], p = 0.010). There was no difference in the number of complications. During the first 2 postoperative years, there were two revisions in patients undergoing PFA (one to a new PFA and one to a TKA). CONCLUSIONS: Patients undergoing PFA obtain a better overall knee-specific quality of life than patients undergoing TKA throughout the first 2 years after operation for isolated patellofemoral osteoarthritis. At 2 years, only KOOS function differs between patients undergoing PFA and those undergoing TKA, whereas other PRO dimensions do not show a difference between groups. The observations can be explained by patients undergoing PFA recovering faster than patients undergoing TKA and the functional outcome being better for patients undergoing PFA up to 9 months. Patients undergoing PFA regain their preoperative ROM, whereas patients undergoing TKA at 2 years have lost 10 degrees of ROM. We found no differences in complications. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 29529623 TI - Can Multimodal Pain Management in TKA Eliminate Patient-controlled Analgesia and Femoral Nerve Blocks? AB - BACKGROUND: TKA pain management protocols vary widely with no current consensus on a standardized pain management regimen. Multimodal TKA pain management protocols aim to address pain control, facilitate functional recovery, and maintain patient satisfaction. QUESTIONS/PURPOSES: (1) Did changes to our pain management protocol, specifically adding liposomal bupivacaine, eliminating patient-controlled analgesia (PCA), and discontinuing femoral nerve blocks (FNBs), affect narcotic consumption after TKA? (2) Did these changes to our pain management protocols affect patient-reported pain scores? (3) Does the use of an immediate postoperative PCA affect rapid rehabilitation and functional recovery? (4) How did changes to our pain management regimen affect discharge disposition and pain-related Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores? METHODS: We retrospectively analyzed an institutional arthroplasty database between September 2013 and September 2015 containing 1808 patients who underwent primary TKA. Departmental pain management protocols were compared in 6-month periods as the protocol changed. All patients received a multimodal pain management protocol including preoperative oral medications, spinal or general anesthesia, a short-acting intraoperative pericapsular injection, and continued postoperative oral narcotics for breakthrough pain. From September 2013 to April 2014, all patients received an intraoperative FNB and a PCA for the first 24 hours postoperatively (Cohort 1). From May 2014 to October 2014, a periarticular injection of liposomal bupivacaine was added to the protocol and FNBs were discontinued (Cohort 2). After April 2015, PCA was eliminated (Cohort 3). No other major changes were made to the TKA pain management pathways. Narcotic use, pain scores on 8-hour intervals, physical therapy milestones, and discharge disposition were compared. RESULTS: Total narcotic use was the least in Cohort 3 (Cohort 3: 66 +/- 54 morphine milligram equivalents versus Cohort 2: 82 +/- 72 versus Cohort 1: 96 +/- 62; p < 0.001). There was an increase in pain score immediately after surgery in Cohort 3 (4.0 +/ 3.5 versus 1.2 +/- 2.2 versus 1.2 +/- 2.5, post hoc analysis of Cohort 2 versus 3: mean difference 2.6, 95% confidence interval [CI] 2.2-3.0; p < 0.001); however, it was not different for the remainder of the hospital stay. Patients who did not receive PCA reached functional milestones for both gait and stairs faster by postoperative day 1 (47% [328 of 698] versus 30% [158 of 527] versus 16% [93 of 583], p < 0.001; Cohort 3 versus 2: odds ratio 2.1, 95% CI 1.6-2.6; p < 0.001). Discharge to home occurred more frequently (84% [583 of 698] versus 78% [410 of 527] versus 72% [421 of 583], p = 0.010) in Cohort 3. There were no differences in pain-related HCAHPS scores across all cohorts. CONCLUSIONS: Discontinuing PCAs and FNBs from our multimodal TKA pain management protocols and adding liposomal bupivacaine resulted in fewer narcotics consumed with no difference in pain control and faster functional recovery while maintaining high HCAHPS scores relating to pain. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529624 TI - CORR Insights(r): Can Multimodal Pain Management in TKA Eliminate Patient controlled Analgesia and Femoral Nerve Blocks? PMID- 29529625 TI - Femoral Component External Rotation Affects Knee Biomechanics: A Computational Model of Posterior-stabilized TKA. AB - BACKGROUND: The correct amount of external rotation of the femoral component during TKA is controversial because the resulting changes in biomechanical knee function associated with varying degrees of femoral component rotation are not well understood. We addressed this question using a computational model, which allowed us to isolate the biomechanical impact of geometric factors including bony shapes, location of ligament insertions, and implant size across three different knees after posterior-stabilized (PS) TKA. QUESTIONS/PURPOSES: Using a computational model of the tibiofemoral joint, we asked: (1) Does external rotation unload the medial collateral ligament (MCL) and what is the effect on lateral collateral ligament tension? (2) How does external rotation alter tibiofemoral contact loads and kinematics? (3) Does 3 degrees external rotation relative to the posterior condylar axis align the component to the surgical transepicondylar axis (sTEA) and what anatomic factors of the femoral condyle explain variations in maximum MCL tension among knees? METHODS: We incorporated a PS TKA into a previously developed computational knee model applied to three neutrally aligned, nonarthritic, male cadaveric knees. The computational knee model was previously shown to corroborate coupled motions and ligament loading patterns of the native knee through a range of flexion. Implant geometries were virtually installed using hip-to-ankle CT scans through measured resection and anterior referencing surgical techniques. Collateral ligament properties were standardized across each knee model by defining stiffness and slack lengths based on the healthy population. The femoral component was externally rotated from 0 degrees to 9 degrees relative to the posterior condylar axis in 3 degrees increments. At each increment, the knee was flexed under 500 N compression from 0 degrees to 90 degrees simulating an intraoperative examination. The computational model predicted collateral ligament forces, compartmental contact forces, and tibiofemoral internal/external and varus-valgus rotation through the flexion range. RESULTS: The computational model predicted that femoral component external rotation relative to the posterior condylar axis unloads the MCL and the medial compartment; however, these effects were inconsistent from knee to knee. When the femoral component was externally rotated by 9 degrees rather than 0 degrees in knees one, two, and three, the maximum force carried by the MCL decreased a respective 55, 88, and 297 N; the medial contact forces decreased at most a respective 90, 190, and 570 N; external tibial rotation in early flexion increased by a respective 4.6 degrees , 1.1 degrees , and 3.3 degrees ; and varus angulation of the tibia relative to the femur in late flexion increased by 8.4 degrees , 8.0 degrees , and 7.9 degrees , respectively. With 3 degrees of femoral component external rotation relative to the posterior condylar axis, the femoral component was still externally rotated by up to 2.7 degrees relative to the sTEA in these three neutrally aligned knees. Variations in MCL force from knee to knee with 3 degrees of femoral component external rotation were related to the ratio of the distances from the femoral insertion of the MCL to the posterior and distal cuts of the implant; the closer this ratio was to 1, the more uniform were the MCL tensions from 0 degrees to 90 degrees flexion. CONCLUSIONS: A larger ratio of distances from the femoral insertion of the MCL to the posterior and distal cuts may cause clinically relevant increases in both MCL tension and compartmental contact forces. CLINICAL RELEVANCE: To obtain more consistent ligament tensions through flexion, it may be important to locate the posterior and distal aspects of the femoral component with respect to the proximal insertion of the MCL such that a ratio of 1 is achieved. PMID- 29529626 TI - CORR Insights(r): Femoral Component External Rotation Affects Knee Biomechanics: A Computational Model of Posterior-stabilized TKA. PMID- 29529627 TI - No Benefit of Computer-assisted TKA: 10-year Results of a Prospective Randomized Study. AB - BACKGROUND: Previously published studies reported benefits of computer-assisted surgery (CAS) in terms of radiographic implant position in TKA, but whether these improvements result in clinically important survival differences or functional differences that a patient might perceive at a minimum 10-year followup remains largely unknown. QUESTIONS/PURPOSES: We performed a prospective randomized trial and asked whether CAS (1) improved survival free from aseptic loosening; and (2) demonstrated any clear difference in patient-reported outcomes at latest followup using validated outcome measures at minimum 10-year followup. METHODS: Between January 2004 and December 2005, 80 patients scheduled for TKA were randomly assigned either to the CAS group or to the conventional technique group by the Hospital Informatics Department. The patient inclusion criteria were age 20 to 80 years old, weight < 100 kg, and consent to receive a primary knee arthroplasty performed through a medial parapatellar approach by the senior author. The exclusion criteria were a history of prior knee surgery, TKA performed for a posttraumatic indication, or revision knee surgery. The first 80 patients meeting these criteria were included in the study. There were 21 women and 19 men and in each group; mean age was 66 years (range, 58-77 years), and mean body mass index was 27 +/- 4 kg/m. An initial published study using this patient group investigated only differences regarding implant positioning in the coronal and sagittal planes. This is a secondary analysis of patients from the earlier study protocol at a minimum of 10-year followup with different endpoints. Kaplan-Meier survivorship was compared between groups, and functional patient-reported outcome measures (PROMs) were evaluated using the SF-12, Knee Injury and Osteoarthritis Outcome Score (KOOS), Forgotten Joint Score, and the new Knee Society Score. Those PROMs were not available at the time of the original randomized controlled trial and we therefore do not have baseline preoperative values demonstrating that our two groups were comparable. However, our groups were created using strict randomization and were similar in terms of demographic parameters and knee deformities. Our secondary analysis was not powered for survival analysis but had 80% power to detect a difference > 6 points on the SF-12 components and > 6 points out of 100 on the KOOS subscores (published minimal clinically important difference: 8 points) at the p < 0.05 level. RESULTS: With the numbers available, there was no difference between the CAS group and the conventional TKA group in terms of survivorship free from aseptic loosening 10 years after TKA (97%, 95% confidence interval [CI], 95%-99% versus 97%, 95% CI, 95%-99%; p = 0.98). Investigation of the latest followup PROM scores showed no difference between SF 12 scores (respectively, for CAS and control patients, physical SF-12: 72 +/- 12 versus 73 +/- 13 mean difference 0, 95% CI -3 to 3, p = 0.9; mental SF-12: 75 +/- 8 versus 73 +/- 10, mean difference 2, 95% CI 0-4, p = 0.3) as well as for all KOOS subscores (all p > 0.1). Forgotten Joint Scores were similar in both groups with 83 +/- 4 for CAS and 82 +/- 5 for control patients (mean difference 1, 95% CI 0-2, p = 0.2). Finally, the new Knee Society Scores were not statistically different between groups with a mean objective score of 82 +/- 13 for CAS patients versus 79 +/- 12 for control patients (mean difference 2, 95% CI 0-5, p = 0.5) and a mean subjective score of 83 +/- 11 versus 85 +/- 12, respectively (mean difference 2, 95% CI 0-5, p = 0.5). CONCLUSIONS: Our observations suggest that CAS used for TKA alignment with restoration of a neutral mechanical axis as the goal did not confer any substantial advantage in survivorship, function, or quality of life at 10 years after TKA. Larger studies with longitudinal collection of PROMs for functional assessment and greater numbers to assess survivorship are needed to confirm these findings. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529628 TI - CORR Insights(r): No Benefit of Computer-assisted TKA: 10-year Results of a Prospective Randomized Study. PMID- 29529629 TI - CORR Insights(r): Quantitative Primary Tumor Indocyanine Green Measurements Predict Osteosarcoma Metastatic Lung Burden in a Mouse Model. PMID- 29529630 TI - Can Aortic Balloon Occlusion Reduce Blood Loss During Resection of Sacral Tumors That Extend Into the Lower Lumber Spine? AB - BACKGROUND: Although aortic balloon occlusion has been shown to reduce blood loss during sacral tumor resections, it has not been validated in larger sacral tumors involving the lower lumbar spine. If such an approach were shown to be associated with less blood loss, it might aid the tumor surgeon in resecting these difficult tumors. QUESTIONS/PURPOSES: (1) Is the use of aortic balloon occlusion associated with reduced blood loss in sacral tumor resections when the lower lumbar spine is also involved? (2) Does the use of the aortic balloon prolong total operating time? (3) What complications are associated with the use of a balloon? METHODS: We retrospectively studied all 56 patients diagnosed with sacral tumors involving the lower lumbar spine (L4, L5) who were treated surgically between 2004 and 2015 at our institute. During that time, 30 of the patients received aortic balloon occlusion therapy, whereas 26 of the patients did not. We generally used aortic balloon occlusion during procedures for hypervascular lesions (for example, giant cell tumors or metastatic renal cancers), primary malignant lesions, and recurrent lesions. We generally avoided use of aortic balloon occlusion in patients with anatomic defects of the aorta (aortic dissection or aneurysm was strictly contraindicated), renal artery bifurcation caudal to the L2 to L3 disc, age older than 70 years or younger than 12 years, history of Stage 2 hypertension [], history of balloon use in previous surgeries, and presence of unstable plaque on abdominal CT. The demographic data, intraoperative blood loss, transfusion volume, operating time, and postoperative wound drainage between the two groups were collected and analyzed. Balloon-related complications were identified. Followup in terms of balloon-related complications was conducted in all 56 patients for at least 6 months after surgery. RESULTS: Intraoperative blood loss was determined to be less in patients treated with the balloon compared with those treated without the balloon (median volume, 2000 mL, range, 400-6000 mL versus 2650 mL, range, 550-6800 mL, respectively; median difference, 605 mL; 95% confidence interval [CI], 100-1500 mL; p = 0.035). Total operative time was not prolonged in the balloon group (including balloon insertion time) compared with those treated without it (median time, 215 minutes, range, 110-430 minutes versus 225 minutes, range, 115-340 minutes, respectively; median difference, 10 minutes; 95% CI, -40 to 30 minutes; p = 0.902). Balloon-related vascular complications included local hematoma at the puncture site in five patients, femoral artery spasm in three patients, lower limb ischemia in one patient, and femoral artery pseudoaneurysm in one patient. Acute kidney injury was found in two patients in the balloon group. CONCLUSIONS: This study demonstrated that placement of the aortic balloon at a level just caudal to the renal artery bifurcation was associated with lower intraoperative blood loss and transfusion in lumbosacral tumor resections. However, procedure-specific complications were common and there was no benefit to total operative time. We suggest that the surgical procedures still need to be further refined to minimize complications. We also recommend that prospective studies be undertaken to confirm the efficacy of aortic balloon occlusion in surgery for lumbosacral tumors. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529631 TI - Can Navigation-assisted Surgery Help Achieve Negative Margins in Resection of Pelvic and Sacral Tumors? AB - BACKGROUND: Navigation-assisted resection has been proposed as a useful adjunct to resection of malignant tumors in difficult anatomic sites such as the pelvis and sacrum where it is difficult to achieve tumor-free margins. Most of these studies are case reports or small case series, but these reports have been extremely promising. Very few reports, however, have documented benefits of navigation-assisted resection in series of pelvic and sacral primary tumors. Because this technology may add time and expense to the surgical procedure, it is important to determine whether navigation provides any such benefits or simply adds cost and time to an already complex procedure. QUESTIONS/PURPOSES: (1) What proportion of pelvic and sacral bone sarcoma resections utilizing a computer assisted resection technique achieves negative margins? (2) What are the oncologic outcomes associated with computer-assisted resection of pelvic and sacral bone sarcomas? (3) What complications are associated with navigation assisted resection? METHODS: Between 2009 and 2015 we performed 24 navigation assisted resections of primary tumors of the pelvis or sacrum. Of those, four were lost to followup after the 2-year postoperative visit. In one patient, however, there was a failure of navigation as a result of inadequate imaging, so nonnavigated resection was performed; the remaining 23 were accounted for and were studied here at a mean of 27 months after surgery (range, 12-52 months). During this period, we performed navigation-assisted resections in all patients presenting with a pelvis or sacral tumor; there was no selection process. No patients were treated for primary tumors in these locations without navigation during this time with the exception of the single patient in whom the navigation system failed. We retrospectively evaluated the records of these 23 patients and evaluated the margin status of these resections. We calculated the proportion of patients with local recurrence, development of metastases, and overall survival at an average 27-month followup (range, 12-52 months). We queried a longitudinally maintained surgical database for any complications and noted which, if any, could have been directly related to the use of the navigation assisted technique. RESULTS: In our series, 21 of 23 patients had a negative margin resection. In all patients the bone margin was negative, but two with sacral resections had positive soft tissue margins. Six of 23 patients experienced local recurrence within the study period. Three patients died during the study period. Seventeen patients demonstrated no evidence of disease at last recorded followup. We noted three intraoperative complications: one dural tear, one iliac vein laceration, and one bladder injury. Eight patients out of 23 had wound complications resulting in operative debridement. Two patients in the series developed transient postoperative femoral nerve palsy, which we believe were caused by stretch of the femoral nerve secondary to the placement of the reference array in the pubic ramus. CONCLUSIONS: Navigation-assisted resection of pelvic and sacral tumors resulted in a high likelihood of negative margin resection in this series, and we observed relatively few complications related specifically to the navigation. We have no comparison group without navigation, and future studies should indeed compare navigated with nonnavigated resection approaches in these anatomic locations. We did identify a potential navigation related complication of femoral nerve palsy in this series and suggest careful placement and observation of the reference array during the operative procedure to lessen the likelihood of this previously unreported complication. We suggest it is worthwhile to consider the use of navigation-assisted surgery in resection of tumors of the pelvis and sacrum, but further study will be needed to determine its precise impact, if any, on local recurrence and other oncologic outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29529632 TI - CORR Insights(r): Can Navigation-assisted Surgery Help Achieve Negative Margins in Resection of Pelvic and Sacral Tumors? PMID- 29529633 TI - Is Navigation-guided En Bloc Resection Advantageous Compared With Intralesional Curettage for Locally Aggressive Bone Tumors? AB - BACKGROUND: The treatment of locally aggressive bone tumors is a balance between achieving local tumor control and surgical morbidity. Wide resection decreases the likelihood of local recurrence, although wide resection may result in more complications than would happen after curettage. Navigation-assisted surgery may allow more precise resection, perhaps making it possible to expand the procedure's indications and decrease the likelihood of recurrence; however, to our knowledge, comparative studies have not been performed. QUESTIONS/PURPOSES: The purpose of this study was to compare curettage plus phenol as a local adjuvant with navigation-guided en bloc resection in terms of (1) local recurrence; (2) nononcologic complications; and (3) function as measured by revised Musculoskeletal Tumor Society (MSTS) scores. METHODS: Patients with a metaphyseal and/or epiphyseal locally aggressive primary bone tumor treated by curettage and adjuvant therapy or en bloc resection assisted by navigation between 2010 and 2014 were considered for this retrospective study. Patients with a histologic diagnosis of a primary aggressive benign bone tumor or low-grade chondrosarcoma were included. During this time period, we treated 45 patients with curettage of whom 43 (95%) were available for followup at a minimum of 24 months (mean, 37 months; range, 24-61 months), and we treated 26 patients with navigation-guided en bloc resection, of whom all (100%) were available for study. During this period, we generally performed curettage with phenol when the lesion was in contact with subchondral bone. We treated tumors that were at least 5 mm from the subchondral bone, such that en bloc resection was considered possible with computer-assisted block resection. There were no differences in terms of age, gender, tumor type, or tumor location between the groups. Outcomes, including allograft healing, nonunion, tumor recurrence, fracture, hardware failure, infection, and revised MSTS score, were recorded. Bone consolidation was defined as complete periosteal and endosteal bridging visible between the allograft-host junctions in at least two different radiographic views and the absence of pain and instability in the union site. All study data were obtained from our longitudinally maintained oncology database. RESULTS: In the curettage group, two patients developed a local recurrence, and no local recurrences were recorded in patients treated with en bloc resection. All patients who underwent navigation-guided resection achieved tumor-free margins. Intraoperative navigation was performed successfully in all patients and there were no failures in registration. Postoperative complications did not differ between the groups: in patients undergoing curettage, 7% (three of 43) and in patients undergoing navigation, 4% (one of 26) had a complication. There was no difference in functional scores: mean MSTS score for patients undergoing curettage was 28 points (range, 27-30 points) and for patients undergoing navigation, 29 (range, 27-30 points; p = 0.10). CONCLUSIONS: In this small comparative series, navigation-assisted resection techniques allowed conservative en bloc resection of locally aggressive primary bone tumors with no local recurrence. Nevertheless, with the numbers available, we saw no difference between the groups in terms of local recurrence risk, complications, or function. Until or unless studies demonstrate an advantage to navigation-guided en bloc resection, we cannot recommend wide use of this novel technique because it adds surgical time and expense. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529634 TI - CORR Insights(r): Is Navigation-guided En Bloc Resection Advantageous Compared With Intralesional Curettage for Locally Aggressive Bone Tumors? PMID- 29529635 TI - What Is the Effect of High-dose Radiation on Bone in Patients With Sacral Chordoma? A CT Study. AB - BACKGROUND: Effects of high-dose radiation using protons and photons on bone are relatively unexplored, but high rates of insufficiency fractures are reported, and the causes of this are incompletely understood. Imaging studies with pre- and postradiation scans can help one understand the effect of radiation on bone. QUESTIONS/PURPOSES: The purpose of this study was to assess the effects of high dose radiation on the trabecular density of bone in the sacrum using CT-derived Hounsfield units (HU). METHODS: Between 2009 and 2015, we treated 57 patients (older then 18 years) with sacral chordoma. Fourteen (25%) of them were treated with radiation only. The general indication for this approach is inoperability resulting from tumor size. Forty-two (74%) patients were treated with transverse sacral resections and high-dose radiotherapy (using either protons or photons or a combination) before surgery and after surgery. During this time period, our indication for this approach generally was symptomatic sacral chordoma in which resection would prevent further growth and reasonable sacrifice of nerve roots was possible. Of those patients, 21 (50%) had CT scans both before and after radiation treatment. We used HU as a surrogate for bone density. CT uses HU to derive information on tissue and bone quantity. A recent study presented reference HU values for normal (mean 133 +/- 38 HU), osteoporotic (101 +/- 25 HU), and osteopenic bone (79 +/- 32 HU). To adjust for scanning protocol-induced changes in HU, we calculated the ratio between bone inside and outside the radiation field rather than using absolute values. To assess the effect of radiation, we tested whether there was a difference in ratio (sacrum/L1) before and after radiation. A control measurement was performed (L2/L1) and also tested for a difference before and after radiation. Statistical analyses were performed using the paired t-test. RESULTS: The effects of radiation appeared confined to the intended field, because the bone density outside the treated field was not observed to decrease. The ratio of HU (a surrogate for bone density) in L2 relative to L1 did not change after radiotherapy (preradiation mean: 0.979 +/- 0.009, postradiation mean: 0.980 +/- 0.009, mean difference outside the radiation field: -0.001, 95% confidence interval [CI], -0.009 to 0.007, p = 0.799). The ratio of HU within the radiation field relative to L1 decreased after radiotherapy (preradiation mean: 0.895 +/- 0.050, postradiation mean: 0.658 +/- 0.050, mean difference inside the radiation field: 0.237, 95% CI, 0.187-0.287, p < 0.001), suggesting the bone density stayed the same outside the radiation field but decreased inside the radiation field. CONCLUSIONS: Trabecular bone density decreased after high-dose radiation therapy in a small group of patients with sacral chordoma. High-dose radiation is increasingly gaining acceptance for treating sacral malignancies; further long-term prospective studies using calibrated CT scanners and preferably bone biopsies are needed. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29529636 TI - Not All Patients Undergoing Stabilization of Impending Pathologic Fractures for Renal Cell Carcinoma Metastases to the Femur Need Preoperative Embolization. AB - BACKGROUND: Preoperative transarterial embolization has been utilized in the surgical treatment of metastatic renal cell carcinoma of the femur to decrease perioperative blood loss. However, few studies have documented its efficacy in decreasing the proportion of patients receiving transfusions in the setting of prophylactic treatment of impending pathologic femur fractures. QUESTIONS/PURPOSES: In a population of patients with metastatic renal cell carcinoma of the femur who underwent prophylactic fixation, the purpose of this study was to quantify and compare the proportion of patients who received at least one transfused unit of blood between a group treated with preoperative embolization and a group without preoperative embolization. METHODS: A retrospective study was performed using a Medicare claims-based database. International Classification of Diseases, 9 Revision and Current Procedural Terminology codes were used to identify 1285 patients with metastatic renal cell carcinoma of the femur who underwent prophylactic fixation. The proportion of patients who received one or more blood transfusions was compared between 135 patients who underwent preoperative embolization and a group of 1150 concurrent control patients who did not undergo preoperative embolization. The control group was older than the embolization group, with 44% of these patients > 75 years old and 33% of the embolization group > 75 years. There was no difference in the female:male ratio between groups. Statistical comparisons of outcomes related to transfusion percentages were performed using Pearson chi square analysis with p < 0.05 considered significant. With the numbers available, we had 80% power to detect a difference in the percentage of patients transfused of 11% between the study groups at alpha = 0.05. RESULTS: No difference in transfusion percentage was observed between preoperative transarterial embolization (41 of 135 [30%]) and the control group (359 of 1150 [31%]; relative risk, 0.973; 95% confidence interval, 0.743-1.274; p = 0.84). The percentage of all patients who received a transfusion was 31% (400 of 1285). CONCLUSIONS: Preoperative embolization may not be mandatory in the prophylactic treatment of metastatic renal cell carcinoma of the femur, as demonstrated by the 69% of patients who received zero units of blood despite not receiving embolization. However, assessment of the efficacy of embolization in decreasing blood loss in the current study is limited as a result of biases associated with the database design of the study; the decision of whether to send a patient for embolization should be made on a case-by-case basis. The current study does not identify specific risk factors that should factor into this decision and underscores the need for further research in this regard. A plausible future research design to account for the low numbers and selection bias that limited the current study as well as the existing studies might be a multicenter, retrospective case-control study. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529637 TI - Early Improvement in Pain and Functional Outcome but Not Quality of Life After Surgery for Metastatic Long Bone Disease. AB - BACKGROUND: Bone metastases represent the most frequent cause of cancer-related pain, affecting health-related quality of life and creating a substantial burden on the healthcare system. Although most bony metastatic lesions can be managed nonoperatively, surgical management can help patients reduce severe pain, avoid impending fracture, and stabilize pathologic fractures. Studies have demonstrated functional improvement postoperatively as early as 6 weeks, but little data exist on the temporal progress of these improvements or on the changes in quality of life over time as a result of surgical intervention. QUESTIONS/PURPOSES: (1) Do patients' functional outcomes, pain, and quality of life improve after surgery for long bone metastases? (2) What is the temporal progress of these changes to 1 year after surgery or death? (3) What is the overall and 30-day rate of complications after surgery for long bone metastases? (4) What are the oncologic outcomes including overall survival and local disease recurrence for this patient population? METHODS: A multicenter, prospective study from three orthopaedic oncology centers in Quebec, Canada, was conducted between 2008 and 2016 to examine the improvement in function and quality of life after surgery for patients with long bone metastases. During this time, 184 patients out of a total of 210 patients evaluated during this period were enrolled; of those, 141 (77%) had complete followup at a minimum of 2 weeks (mean, 23 weeks; range, 2-52 weeks) or until death, whereas another 35 (19%) were lost to followup but were not known to have died before the minimum followup interval was achieved. Pathologic fracture was present in 34% (48 of 141) of patients. The median Mirel's score for those who underwent prophylactic surgery was 10 (interquartile range, 10-11). Surgical procedures included intramedullary nailing (55), endoprosthetic replacement (49), plate osteosynthesis (31), extended intralesional curettage (four), and allograft reconstruction (two). Seventy-seven percent (108 of 141) of patients received radiotherapy. The Musculoskeletal Tumor Society (MSTS), Toronto Extremity Salvage Score (TESS), Brief Pain Inventory (BPI) form, and Quality Of Life During Serious Illness (QOLLTI-P) form were administered pre- and postoperatively at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. Analysis of variance followed by post hoc analysis was conducted to test for significance between pre- and postoperative scores. The Kaplan-Meier estimate was used to calculate overall survivorship and local recurrence-free survival. A p value of < 0.05 was considered statistically significant. RESULTS: MSTS and BPI pain scores improved at 2 weeks when compared with preoperative scores (MSTS: 39% +/- 24% pre versus 62% +/- 19% postoperative, mean difference [MD] 23, 95% confidence interval [CI], 16-32, p < 0.001; BPI: 52% +/- 21% pre- versus 30% +/- 21% postoperative, MD 22, 95% CI, 16-32, p < 0.001). Continuous and incremental improvement in TESS, MSTS, and BPI scores was observed temporally at 6 weeks, 3 months, 6 months, and 1 year; for example, the TESS score improved from 44% +/- 24% to 73% +/- 21% (MD 29, p < 0.001, 95% CI, 19-38) at 6 months. We did not detect a difference in quality of life as measured by the QOLLTI-P score (6 +/- 1 pre- versus 7 +/- 4 postoperative, MD 1, 95% CI, -0.4 to 3, p = 0.2). The overall and 30-day rates of systemic complications were 35% (49 of 141) and 14% (20 of 141), respectively. The Kaplan-Meier estimates for overall survival were 70% (95% CI, 62.4-78) at 6 months and 41% (95% CI, 33-49) at 1 year. Local recurrence-free survival was 17 weeks (95% CI, 11-24). CONCLUSIONS: Surgical management of metastatic long bone disease substantially improves patients' functional outcome and pain as early as 2 weeks postoperatively and should be considered for impending or pathologic fracture in patients whose survival is expected to be longer than 2 weeks provided that there are no immediate contraindications. Quality of life in this patient population did not improve, which may be a function of patient selection, concomitant chemoradiotherapy regimens, disease progression, or terminal illness, and this merits further investigation. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29529638 TI - CORR Insights(r): Early Improvement in Pain and Functional Outcome but Not Quality of Life After Surgery for Metastatic Long Bone Disease. PMID- 29529639 TI - What Are the Complications of Allograft Reconstructions for Sarcoma Resection in Children Younger Than 10 Years at Long-term Followup? AB - BACKGROUND: Preservation of limb function after resection of malignant bone tumors in skeletally immature children is challenging. Resection of bone sarcomas and reconstruction with an allograft in patients younger than 10 years old is one reconstructive alternative. However, long-term studies analyzing late complications and limb length discrepancy at skeletal maturity are scarce; this information would be important, because growth potential is altered in these patients owing to the loss of one physis during tumor resection. QUESTIONS/PURPOSES: At a minimum followup of 10 years after reconstructions in children younger than 10 years of age at the time of reconstruction, we asked what is (1) the limb length discrepancy at skeletal maturity and how was it managed; (2) the risk of amputation; (3) the risk of allograft removal; and (4) the risk of second surgery resulting from complications? METHODS: Between 1994 and 2006, we performed 22 bone allografts after bone sarcoma resections in children younger than 10 years of age. Of those, none were lost to followup before the minimum followup of 10 years was reached, and an additional six had died of disease (of whom three died since our last report on this group of patients), leaving 16 patients whom we studied here. Followup on these patients was at a mean of 13.5 years (range, 10-22 years). During the period in question, no other treatments (such as extendible prostheses, amputations, etc) were used. The mean age at the time of the original surgery was 7 years (range, 2-10 years), and the mean age of the 16 alive patients at last followup was 20 years (range, 15-28 years). This series included 10 boys and six girls with 14 osteosarcomas and two Ewing sarcomas. Ten reconstructions were performed with an intercalary allograft and six with an osteoarticular allograft. The growth plate was uninvolved in three patients, whereas in the remaining 13, the growth plate was included in the resection (seven intercalary and six osteoarticular allografts). Limb length discrepancy at skeletal maturity was measured with full-length standing radiographs, and data were collected by retrospective study of a longitudinally maintained institutional database. The risk of amputation, allograft removal, and secondary surgery resulting from a complication was calculated by a competing-risk analysis method. RESULTS: We observed no limb length discrepancy at skeletal maturity in the three patients with intercalary resections in whom we preserved the physes on both sides of the joint (two femurs and one tibia); however, one patient developed malalignment that was treated with corrective osteotomy of the tibia. The remaining 13 patients developed limb length discrepancy as a result of loss of one physis. Seven patients (four femurs, two tibias, and one humerus) developed shortening of <= 3 cm (mean, 2.4 cm; range, 1-3 cm) and no lengthening was performed. Six patients developed > 3 cm of limb discrepancy at skeletal maturity (all distal femoral reconstructions). In four patients this was treated with femoral lengthening, whereas two declined this procedure (each with 6 cm of shortening). In the four patients who had a lengthening procedure, one patient had a final discrepancy of 4 cm, whereas the other three had equal limb lengths at followup. The risk of amputation was 4% (95% confidence interval [CI], 0-15) and none occurred since our previous report. The risk of allograft removal was 15% (95% CI, 1-29) and none occurred since our previous report on this group of patients. The risk of other operations resulting from a complication was 38% (95% CI, 19-57). Eleven patients underwent a second operation resulting from a complication (three local recurrences, five fractures, one infection, one nonunion, and one tibial deformity), of which three were performed since our last report on this group of patients. CONCLUSIONS: Limb length inequalities and subsequent procedures to correct them were common in this small series of very young patients as were complications resulting in operative procedures, but overall most allografts remained in place at long-term followup. In skeletally immature children, bone allograft is one alternative among several that are available (such as rotationplasty and endoprosthesis), and future studies with long followup may be able to compare the available options with one another. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29529640 TI - CORR Insights(r): What Are the Complications of Allograft Reconstructions for Sarcoma Resection in Children Younger Than 10 Years at Long-term Followup? PMID- 29529641 TI - MRI Identification of the Osseous Extent of Pediatric Bone Sarcomas. AB - BACKGROUND: The quantitative accuracy of MRI in predicting the intraosseous extent of primary sarcoma of bone has not been definitively confirmed, although MRI is widely accepted as an accurate tool to plan limb salvage resections. Because inaccuracies in MRI determination of tumor extent could affect the ability of a tumor surgeon to achieve negative margins and avoid local recurrence, we thought it important to assess the accuracy of MR-determined tumor extent to the actual extent observed pathologically from resected specimens in pediatric patients treated for primary sarcomas of bone. QUESTIONS/PURPOSES: (1) Does the quantitative pathologic bony margin correlate with that measured on preoperative MRI? (2) Are T1- or T2-weighted MRIs most accurate in determining a margin? (3) Is there a difference in predicting tumor extent between MRI obtained before or after neoadjuvant chemotherapy and which is most accurate? METHODS: We retrospectively studied a population of 211 potentially eligible patients who were treated with limb salvage surgery between August 1999 and July 2015 by a single surgeon at a single institution for primary sarcoma of bone. Of 131 patients (62%) with disease involving the femur or tibia, 107 (51%) were classified with Ewing's sarcoma or osteosarcoma. Records were available for review in our online database for 79 eligible patients (37%). Twenty-six patients (12%) were excluded because of insufficient or unavailable clinical or pathology data and 17 patients (8%) were excluded as a result of inadequate or incomplete MR imaging, leaving 55 eligible participants (26%) in the final cohort. The length of the resected specimen was superimposed on preresection MRI sequences to compare the margin measured by MRI with the margin measured by histopathology. Arithmetic mean differences and Pearson r correlations were used to assess quantitative accuracy (size of the margin). RESULTS: All MR imaging types were positively associated with final histopathologic margin. T1-weighted MRI after neoadjuvant chemotherapy and final histopathologic margin had the strongest positive correlation of all MR imaging and time point comparisons (r = 0.846, p < 0.001). Mean differences existed between the normal marrow margin on T1-weighted MRI before neoadjuvant chemotherapy (t = 8.363; mean, 18.883 mm; 95% confidence interval [CI], 14.327-23.441; p < 0.001), T2-weighted MRI before neoadjuvant chemotherapy (t = 8.194; mean, 17.204 mm; 95% CI, 12.970-21.439; p < 0.001), T1 weighted after neoadjuvant chemotherapy (t = 10.808; mean, 22.178 mm; 95% CI, 18.042-26.313; p < 0.001), T2-weighted after neoadjuvant chemotherapy (t = 10.702; mean, 20.778 mm; 95% CI, 16.865-24.691; p < 0.001), and the final histopathologic margin. T1-weighted MRI after neoadjuvant chemotherapy compared with the final histopathologic margin had the smallest mean difference in MRI measured versus histopathologic margin size (mean, 5.9 mm; SD = 4.5 mm). CONCLUSIONS: T1 MRI after neoadjuvant chemotherapy exhibited the strongest positive correlation and smallest mean difference compared with histopathologic margin. When planning surgical resections based on MRI obtained after neoadjuvant chemotherapy, for safety, one should account for a potential difference between the apparent margin of a tumor on an MRI and the actual pathologic margin of that tumor of up to 1 cm. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 29529642 TI - CORR Insights(r): MRI Identification of the Osseous Extent of Pediatric Bone Sarcomas. PMID- 29529643 TI - Is Core Needle Biopsy Reliable in Differentiating Between Aggressive Benign and Malignant Radiolucent Bone Tumors? AB - BACKGROUND: Although there is widespread acceptance of core needle biopsy (CNB) for diagnosing solid tumors, there is reluctance by some clinicians to use CNB for aneurysmal bone cysts (ABCs) as a result of concerns of safety (bleeding, nerve injury, fracture, readmission, or infection) and reliability, particularly to rule out malignant diagnoses like telangiectatic osteosarcoma. This is especially true when CNB tissue is sent from an outside hospital, where the technique used to obtain the tissue may be spurious. QUESTIONS/PURPOSES: (1) Is CNB effective (provided adequate information to indicate appropriate surgical treatment without further open biopsy) as an initial diagnostic test for ABC? (2) Is CNB accurate (pathology consistent with the subsequent definitive surgical pathologic diagnosis) in differentiating between benign lesions such as primary or secondary ABCs and malignant radiolucent lesions such as telangiectatic osteosarcoma? (3) What are the complications of CNB? (4) Is there any difference in the effectiveness or accuracy of CNB performed at outside institutions when compared with a referral center? METHODS: A retrospective study of our musculoskeletal tumor board pathology database (1990-2016) was performed using search criteria "aneurysmal bone cyst" or "telangiectatic osteosarcoma." Only patients undergoing a CNB who proceeded to definitive surgical resection with final pathology were included. Excluding outside CNBs, CNB was performed after presentation at a musculoskeletal tumor board as a result of atypical features on imaging or history concerning for malignancy. Outside CNB tissue was reviewed by our pathologists. If there was sufficient tissue for diagnosis, the patient proceeded to definitive surgery. If not, the patient underwent open biopsy. CNB diagnosis, open biopsy results, and open surgical resection pathology were reviewed. Complications, including bleeding, infection, nerve injury, readmission, or fracture, between the CNB and definitive open surgical procedure (mean 1.6 months) were documented. CNBs were considered "effective" if they yielded pathology considered sufficient to proceed with appropriate definitive surgery without additional open biopsy. CNBs were considered "accurate" if they were effective and yielded a pathologic diagnosis that matched the subsequent definitive surgical pathology. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of obtaining a malignant diagnosis using CNB were also calculated. RESULTS: A total of 81% (59 of 73) of CNBs were effective. Ninety-three percent (55 of 59) of CNBs were classified as accurate. Diagnostic CNBs had a sensitivity and specificity of 89% (eight of nine) and 100% (51 of 51), respectively. The PPV was 1.00 and the NPV was 0.82. There were no complications. With the numbers available, there was no difference in efficacy (90% [37 of 41 versus 14 of 15]; odds ratio, 0.97 [95% confidence interval {CI}, 0.41-2.27], p = 0.94) or accuracy (92% [34 of 37 versus 13 of 14]; odds ratio, 0.87 [95% CI, 0.08-9.16], p = 0.91) between CNBs performed in house and those referred from outside. CONCLUSIONS: These data suggest that CNBs are useful as an initial diagnostic test for ABC and telangiectatic osteosarcoma. Tissue from outside CNBs can be read reliably without repeat biopsy. If confirmed by other institutions, CNB may be considered a reasonable approach to the diagnosis of aggressive, radiolucent lesions of bone. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 29529644 TI - CORR Insights(r): Is Core Needle Biopsy Reliable in Differentiating Between Aggressive Benign and Malignant Radiolucent Bone Tumors? PMID- 29529645 TI - Postoperative Day 1 Glucose May Be Associated With Wound Complications in Sarcomas Treated With Preoperative Radiation. AB - BACKGROUND: Uncontrolled blood glucose impacts key phases of the wound healing process. Various factors have been associated with postoperative wound complications in soft tissue sarcomas; however, the association of postoperative early morning blood glucose with wound complications, if any, remains to be determined. Because blood glucose levels may be modified, understanding whether glucose levels are associated with wound complications has potential therapeutic importance. QUESTIONS/PURPOSES: The purposes of this study were (1) to evaluate if postoperative early morning blood glucose is associated with the development of wound complications in soft tissue sarcomas; (2) to determine a blood glucose cutoff that may be associated with an increased risk of wound complications; and (3) to evaluate if patients with diabetes have higher postoperative blood glucose and an associated increased risk of wound complications. METHODS: From 2000 to 2015, 298 patients with Stage I to III soft tissue sarcomas of the extremity or chest wall were treated with preoperative radiation +/- chemotherapy followed by limb-sparing resection. Of those, 191 (64%) patients had demographic, treatment, and postoperative variables and wound outcomes available; these patients' results were retrospectively evaluated. None of the 191 patients were lost to followup. Early morning blood glucose levels on postoperative day (POD) 1 were available in all patients. Wound complications were defined as those resulting in an operative procedure or prolonged wound care for 6 months postresection. Variables that may be associated with wound complications were evaluated using logistic regression for multivariate analysis. Receiver operative curve (ROC) analysis was used to assess the early morning blood glucose level that best was associated postoperative wound complications. RESULTS: After controlling for potentially relevant confounding variables such as patient comorbidities, tumor size, and location, lower extremity soft tissue sarcomas (p = 0.002, odds ratio [OR], 6.4; 95% confidence interval [CI], 1.97-20.84) and elevated POD 1 early morning blood sugars (p < 0.001; OR, 1.1; 95% CI, 1.04-1.11) were associated with increased wound complications postoperatively. ROC analysis revealed that early morning POD 1 blood glucose of > 127 mg/dL was associated with postoperative wound complications with a sensitivity of 89% (area under the curve 0.898, p < 0.001). Median POD 1 early morning blood glucose in patients without diabetes was 118 mg/dL and 153 mg/dL in patients with diabetes (p = 0.023). However, with the numbers available, there was no increase in wound complications in patients with diabetes compared with those without it. CONCLUSIONS: Our study provides preliminary information suggesting that POD 1 early morning blood glucose in patients with soft tissue sarcomas may be associated with a slightly increased risk of postoperative wound complications. An early morning blood glucose of > 127 mg/dL may be a threshold associated with this outcome. Although patients with diabetes had higher POD 1 early morning blood glucose levels, diabetes itself was not associated with the development of wound complications. We cannot conclude that better glycemic control will reduce wound complications in patients who receive preoperative radiation, but our data suggest this should be further studied in a larger, prospective study. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529646 TI - CORR Insights(r): Postoperative Day 1 Glucose May Be Associated With Wound Complications in Sarcomas Treated With Preoperative Radiation. PMID- 29529647 TI - Synovial Sarcoma Is Not Associated With a Higher Risk of Lymph Node Metastasis Compared With Other Soft Tissue Sarcomas. AB - BACKGROUND: Reported rates of the incidence of lymph node metastasis in soft tissue sarcoma vary considerably. Many are based on single-institution series and small patient populations. Certain sarcoma subtypes, including synovial sarcoma, have been associated with a higher risk of lymph node involvement. Most single centers have insufficient numbers of patients to assess lymph node metastasis accurately, but larger national databases may allow a more accurate estimation. QUESTIONS/PURPOSES: We queried a large national database and asked the following questions: (1) What proportion of patients with soft tissue sarcoma have lymph node metastasis and distant metastasis? (2) What histologic subtypes are associated with increased risk of nodal metastasis? (3) What is the impact of lymph node metastases and histologic subtype on survival? (4) Does lymph node excision improve survival of patients with soft tissue sarcoma? METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program is a national database that covers a geographic cross-section representing approximately 28% of the US population across demographic groups. Using the SEER database, we identified 15,525 adults diagnosed with histologically confirmed soft tissue sarcoma from 2004 to 2013. Proportions of patients with lymph node or distant metastases were calculated using descriptive statistics. Overall survival was computed using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazard regression to calculate the association of lymph node metastasis with overall survival while controlling for patient age, sex, race, tumor size, and tumor location. RESULTS: A total of 820 of 15,525 patients had lymph node metastasis at the time of diagnosis, yielding an overall proportion of 5.3% (95% confidence interval [CI], 4.9%-5.6%). Histologic subtypes that most frequently developed nodal metastasis were rhabdomyosarcoma, clear cell sarcoma, epithelioid sarcoma, and myxoid/round cell liposarcoma. Despite frequent reports regarding its association with lymph node metastasis, the proportion of patients with lymph node metastasis among 885 patients with synovial sarcoma (4.2%) was not different from the proportion with nodal metastasis in the overall soft tissue sarcoma population. For all soft tissue sarcomas, distant metastatic disease was present at diagnosis in 1869 (12%) patients (95% CI, 11.5%-12.6%). After controlling for relevant covariates, lymph node metastasis was associated with poorer overall survival (hazard ratio [HR], 1.34; 95% CI, 1.22-1.48; p < 0.001) as was distant metastasis (HR, 2.87; 95% CI, 2.66-3.09; p < 0.001). When comparing the subgroup of patients with positive lymph nodes, lymphadenectomy in conjunction with local excision/limb salvage was associated with the highest overall 5-year survival (HR, 0.46; 95% CI, 0.31-0.67; p < 0.001). CONCLUSIONS: In clarifying the overall proportion of patients with soft tissue sarcoma with nodal metastases, the current study indicates that lymph node metastases occur at a higher proportion than previous studies have suggested and that synovial sarcoma is not associated with a higher risk of lymphatic spread compared with soft tissue sarcoma overall. Patients with lymph node metastases are associated with poorer survival than those without metastases. Further investigation is needed to clarify the apparent improved overall survival after lymphadenectomy in the setting of nodal metastasis from soft tissue sarcoma. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 29529648 TI - CORR Insights(r): Synovial Sarcoma Is Not Associated With a Higher Risk of Lymph Node Metastasis Compared With Other Soft Tissue Sarcomas. PMID- 29529649 TI - Editorial Comment: 2017 Hip Society Proceedings. PMID- 29529650 TI - John Charnley Award: Randomized Clinical Trial of Direct Anterior and Miniposterior Approach THA: Which Provides Better Functional Recovery? AB - BACKGROUND: The choice of surgical approach for THA remains controversial. Some studies suggest that the direct anterior approach (DAA) leads to less muscle damage than the miniposterior approach (MPA), but there is little high-quality evidence indicating whether this accelerates recovery, or whether this approach which may be technically more demanding-is associated with component malposition or more complications. QUESTIONS/PURPOSES: (1) Does the DAA result in faster return to activities of daily living than the MPA? (2) Does the DAA have superior patient-reported outcome measures than the MPA? (3) Does the DAA result in improved radiographic outcomes than the MPA? (4) Does the DAA have a higher risk of complications than the MPA? METHODS: Between March 1, 2013, and May 31, 2016, 116 patients undergoing primary unilateral THA were randomized to either the DAA or MPA; 15 patients withdrew after randomization, and one died 6 months after surgery from a stroke unrelated to the procedure. Recruitment stopped when 52 patients had been randomized into the DAA group and 49 in the MPA group (n = 101). After patient randomization, one high-volume surgeon performed all of the DAAs and three high-volume surgeons performed the MPA THAs. The groups did not differ in age (65 years; SD 11; range, 38-86 years), sex (52% women), or body mass index (mean 29 kg/m; SD 6 kg/m; range, 21-40 kg/m; all p > 0.40). Functional results included time to discontinue gait aids, discontinue all narcotics, and independence with various activities of daily living; accelerometer data evaluated activity level. Clinical and radiographic outcomes, Hip disability and Osteoarthritis Outcome Score, SF-12, and Harris hip scores to 1 year were also tabulated. The minimum followup was 365 days (mean +/- SD, 627 +/- 369 days). RESULTS: There were slight differences in early functional recovery that favored the DAA versus the MPA: time to discontinue walker use (10 versus 15 days, p = 0.01) and time to discontinue all gait aids (17 versus 24 days, p = 0.04). There were no other differences in early functional milestones, although at 2 weeks after surgery, mean steps per day were 3897 (SD 2258; range, 737-11,010) for the DAA versus 2235 for the MPA (SD 1688; range, 27-7450; p < 0.01). There was no difference in activity monitoring at 1 year. There were no differences in patient reported outcome scores between the groups. There was no difference in the radiographic parameters measured in the two groups, including leg length discrepancy, component position, or offset, and there was no subsidence observed in any hip. There was no difference in complications between the DAA and the MPA groups (8% [four of 52] versus 10% [five of 49]; p = 0.33). CONCLUSIONS: Both the DAA and MPA approaches provided excellent early recovery with a low risk of complications. Patients undergoing the DAA had a slightly faster recovery, as measured by milestones of function and quantified by activity monitor data, but no substantive differences were evident at 2 months. Because the DAA is the less studied approach, longer term (> 1 year) complications may yet accrue, will be important to quantify, and may offset early benefits. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 29529651 TI - Frank Stinchfield Award: Identification of the At-risk Genotype for Development of Pseudotumors Around Metal-on-metal THAs. AB - BACKGROUND: Once touted as the future of hip arthroplasty, metal-on-metal (MoM) bearing surfaces have fallen sharply from favor with the emergence of a strong body of evidence demonstrating unacceptably high premature implant failure rates. The previously unpredictable development of adverse local tissue reactions (ALTRs) has been a substantive contributor to this. Although the underlying pathophysiology of these so-called "pseudotumors" is now well understood, the fundamental predisposing patient risk factors have remained elusive. QUESTIONS/PURPOSES: The aim of this research, as a clinical-genotype correlation analysis, was to identify specific alleles (genes) associated with the development of ALTRs in patients with in situ MoM THAs. METHODS: A case-control study of patients who received a large-head, primary MoM THA between 2005 and 2008 was performed with a minimum followup of 5 years. Twenty-six patients who had undergone revision of a primary MoM THA secondary to symptomatic ALTRs were recruited. The mean timeframe from primary MoM THA to symptomatic revision was 5.5 years (range, 1-10 years). Twenty-eight control subjects were randomly selected asymptomatic patients with no evidence of ALTRs on protocol-specific screening. Baseline demographics and high-resolution genotype (human leukocyte antigen [HLA] Class II) were collected for all patients. Cohorts were similar with respect to age at the time of primary MoM THA (mean, 54.8 versus 54.9 years, p = 0.95) and serum cobalt (mean, 5.5 versus 8.5 MUg/L, p = 0.09) and chromium concentrations (mean, 2.9 versus 4.2 MUg/L, p = 0.27). The association between genotype and revision surgery secondary to ALTRs was determined with gender as a covariate. RESULTS: The prevalence of the risk genotype was 30% (16 of 54) among the entire cohort. Adjusting for sex, the odds of revision were 6.1 times greater among patients with the risk genotype present than among patients without (95% confidence interval [CI], 1.5-25.4; p = 0.01). Among females, the specificity of the risk genotype was 1.0 (95% CIexact, 0.5-1.0; pexact = 0.03), and for males, it was 0.8 (95% CIexact, 0.6-0.9; pexact < 0.01). CONCLUSIONS: The findings of this study suggest that, among patients with a primary MoM THA, allelic variation within the HLA Class II loci may be a strong, independent risk factor associated with the need for subsequent revision surgery secondary to pseudotumor formation. CLINICAL RELEVANCE: Given the hypothesis-generating nature of this novel undertaking, confirmatory prospective clinical studies are required to further elucidate this correlation and to explore the clinical utility of targeted genetic screening in this specific population. This research may, however, represent a key missing piece in the puzzle that is metal ion-induced pseudotumor formation. PMID- 29529652 TI - CORR Insights(r): Frank Stinchfield Award: Identification of the At-risk Genotype for Development of Pseudotumors Around Metal-on-metal THAs. PMID- 29529654 TI - CORR Insights(r): Outcomes After Metal-on-metal Hip Revision Surgery Depend on the Reason for Failure: A Propensity Score-matched Study. PMID- 29529653 TI - Outcomes After Metal-on-metal Hip Revision Surgery Depend on the Reason for Failure: A Propensity Score-matched Study. AB - BACKGROUND: Metal-on-metal hip replacement (MoMHR) revision surgery for adverse reactions to metal debris (ARMD) has been associated with an increased risk of early complications and reoperation and inferior patient-reported outcome scores compared with non-ARMD revisions. As a result, early revision specifically for ARMD with adoption of a lower surgical threshold has been widely recommended with the goal of improving the subsequent prognosis after ARMD revisions. However, no large cohorts have compared the risk of complications and reoperation after MoMHR revision surgery for ARMD (an unanticipated revision indication) with those after non-ARMD revisions (which represent conventional modes of arthroplasty revision). QUESTIONS/PURPOSES: (1) Does the risk of intraoperative complications differ between MoMHRs revised for ARMD compared with non-ARMD indications? (2) Do mortality rates differ after MoMHRs revised for ARMD compared with non-ARMD indications? (3) Do rerevision rates differ after MoMHRs revised for ARMD compared with non-ARMD indications? (4) How do implant survival rates differ after MoMHR revision when performed for specific non-ARMD indications compared with ARMD? METHODS: This retrospective observational study involved all patients undergoing MoMHR from the National Joint Registry (NJR) for England and Wales subsequently revised for any indication between 2008 and 2014. The NJR achieves high levels of patient consent (93%) and linked procedures (ability to link serial procedures performed on the same patient and hip; 95%). Furthermore, recent validation studies have demonstrated that when revision procedures have been captured within the NJR, the data completion and accuracy were excellent. Revisions for ARMD and non-ARMD indications were matched one to one for multiple potential confounding factors using propensity scores. The propensity score summarizes the many patient and surgical factors that were used in the matching process (including sex, age, type of primary arthroplasty, time to revision surgery, and details about the revision procedure performed such as the approach, specific components revised, femoral head size, bearing surface, and use of bone graft) using one single score for each revised hip. The patient and surgical factors within the ARMD and non-ARMD groups subsequently became much more balanced once the groups had been matched based on the propensity scores. The matched cohort included 2576 MoMHR revisions with each study group including 1288 revisions (mean followup of 3 years for both groups; range, 1-7 years). Intraoperative complications, mortality, and rerevision surgery were compared between matched groups using univariable regression analyses. Implant survival rates in the non-ARMD group were calculated for each specific revision indication with each individual non-ARMD indication subsequently compared with the implant survival rate in the ARMD group using Cox regression analyses. RESULTS: There was no difference between the ARMD and non-ARMD MoMHR revisions in terms of intraoperative complications (odds ratio, 0.97; 95% confidence interval [CI], 0.59-1.59; p = 0.900). Mortality rates were lower after ARMD revision compared with non-ARMD revision (hazard ratio [HR], 0.43; CI, 0.21-0.87; p = 0.019); however, there was no difference when revisions performed for infection were excluded from the non-ARMD indication group (HR, 0.69; CI, 0.35-1.37; p = 0.287). Rerevision rates were lower after ARMD revision compared with non-ARMD revision (HR, 0.52; CI, 0.36-0.75; p < 0.001); this difference persisted even after removing revisions performed for infection (HR, 0.59; CI, 0.40-0.89; p = 0.011). Revisions for infection (5-year survivorship = 81%; CI, 55%-93%; p = 0.003) and dislocation/subluxation (5-year survivorship = 82%; CI, 69%-90%; p < 0.001) had the lowest implant survival rates when compared with revisions for ARMD (5-year survivorship = 94%; CI, 92%-96%). CONCLUSIONS: Contrary to previous observations, MoMHRs revised for ARMD have approximately half the risk of rerevision compared with non-ARMD revisions. We suspect worldwide regulatory authorities have positively influenced rerevision rates after ARMD revision by recommending that surgeons exercise a lower revision threshold and that such revisions are now being performed at an earlier stage. The high risk of rerevision after MoMHR revision for infection and dislocation is concerning. Infected MoMHR revisions were responsible for the increased mortality risk observed after non-ARMD revision, which parallels findings in non-MoMHR revisions for infection. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529655 TI - Five Hundred Fifty-five Retrieved Metal-on-metal Hip Replacements of a Single Design Show a Wide Range of Wear, Surface Features, and Histopathologic Reactions. AB - BACKGROUND: In 2010, a widely used metal-on-metal hip implant design was voluntarily recalled by the manufacturer because of higher than anticipated failure rates at 5 years. Although there was a large published range of revision rates, numerous studies had reported a higher risk of revision for excessive wear and associated adverse tissue reactions when compared with other metal-on-metal total hips. The reasons for this were suggested by some to be related to cup design features. QUESTIONS/PURPOSES: From retrievals of ASR metal-on-metal implants and tissue samples obtained at revision surgery, we asked the following questions: (1) What were the common and uncommon surface features? (2) What were the common and uncommon linear and volumetric wear characteristics? (3) Were there common taper corrosion characteristics? (4) What aseptic lymphocytic vasculitis-associated lesion (ALVAL) features were present in the tissues? METHODS: Five hundred fifty-five ASRs, including 23 resurfacings, were studied at one academic research center. Features of wear (eg, light and moderate scratching), damage (eg, deposits, gouges), and bone attachment on the porous coating were semiquantitatively ranked from 0 (none) to 3 (> 75%) based on the amount of a feature in each region of interest by the same experienced observer throughout the study. Visible features of head taper corrosion were ranked (Goldberg score) from 1 (none) to 4 (severe) by the same observer using a previously published scoring method. An experienced tribologist measured component wear depth using a coordinate measuring machine and quantified wear volume using previously validated methods. All available tissues were sampled and examined for features of ALVAL and scored from 0 to 10 by a single observer using a method they previously developed and published. A score from 0 to 4 is considered low, 5 to 8 is considered moderate, and 9 or 10 is considered high with regard to the risk of metal hypersensitivity features in the tissues. RESULTS: The most common bearing surface features were light and moderate scratches and removal or postremoval damage. Discoloration and deposits were commonly observed on femoral heads (55% [305 of 553]) and less commonly on cups (30% [165 of 546]). There was no evidence of impingement or dislocation damage. There was typically a small amount of bone attachment in at least one of eight designated regions of interest (84% [460 of 546]); extensive or no bone attachment was uncommon. Edge wear was highly prevalent. The maximum wear of 469 cups (88%) occurred near the edge, whereas the maximum wear of 508 femoral heads (94%) occurred between the pole and 45 degrees from the pole. The median combined head-cup wear volume was 14 mm (range, 1-636 mm). One hundred sixty-nine pairs (32%) had a combined wear volume of < 10 mm, 42 pairs (8%) had volumetric wear of > 100 mm, and 319 pairs (60%) had wear volume between 10 and 100 mm3. Seventy-four percent of tapers (390 of 530) received a Goldberg score of 4, 22% (116 of 530) a score of 3, < 5% (24 of 530) a score of 2, and none received a score of 1. The most frequent ALVAL score was 5 out of 10 (35 of 144 hips [24%]) and ranged from 2 (one hip) to 10 (nine hips); 92 of 144 (64%) had a moderate score, 17 of 144 (12%) had a high score, and 35 (24%) had a low score. CONCLUSIONS: Although edge wear was prevalent, in most cases, this was not associated with high wear. The increased diameter and decreased coverage angle of the ASR design may have resulted in the observed high incidence of edge wear while perhaps decreasing the risk for impingement and dislocation. CLINICAL RELEVANCE: The role of bearing wear in the revisions of metal-on-metal implants is controversial, because it is known that there is a large range of in vivo wear rates even within the same implant type and that patient variability affects local tissue responses to wear debris. The observations from our study of 555 retrieved ASR implant sets indicate that there was a wide range of wear including a subset with very high wear. The results suggested that the failure of the ASR and ASR XL was multifactorial, and the failure of different subgroups such as those with low wear may be the result of mechanisms other than reaction to wear debris. PMID- 29529656 TI - Otto Aufranc Award: Crosslinking Reduces THA Wear, Osteolysis, and Revision Rates at 15-year Followup Compared With Noncrosslinked Polyethylene. AB - BACKGROUND: Crosslinked polyethylene (XLPE) liners used for primary THA have demonstrated lower wear rates than noncrosslinked, conventional polyethylene (CPE) liners through the first decade of clinical service. However, little high quality evidence is currently available regarding the second decade performance of these implants and it remains uncertain whether the onset of osteolysis has simply been delayed or if the wear associated with XLPE liners will remain low enough that osteolysis will not occur. It is also unknown how the potential reductions in wear and osteolysis will influence long-term revision rates. QUESTIONS/PURPOSES: Do patients who underwent THA with XLPE liners demonstrate (1) a lower rate of revision for wear-related complications; (2) a reduced wear rate; and (3) a lower frequency of osteolysis compared with those with CPE liners? METHODS: Over an 18-month period from 1999 to 2000, 226 patients who had 236 primary THAs consented to participate in a randomized controlled trial conducted at one institution. To be eligible for intraoperative randomization, patients had to be implanted with a 28-mm cobalt-chrome alloy femoral head, a 4 mm lateralized liner, and the same cup and stem design. Six patients with six THAs were excluded intraoperatively because they did not receive study components for reasons unrelated to the liner material. The remaining 230 THAs among 220 patients were randomized to XLPE liners or CPE liners. The mean age at surgery was 62 +/- 11 years and there were no differences in age, gender, or body mass index among the groups. There was no differential loss to followup between the study groups; among patients not known to be deceased or having undergone revision, minimum 14-year radiographic followup is available for 85 THAs including 46 with XLPE and 39 with CPE liners. Polyethylene wear was measured radiographically using Martell's Hip Analysis Suite and areas of osteolysis were evaluated before revision or at most recent followup. Revision rates at 15 years using reoperation for any reason and revision for wear or osteolysis were calculated using cumulative incidence considering patient death as a competing risk. RESULTS: The cumulative incidence of revision at 15 years using reoperation for wear-related complications as an endpoint was lower in the XLPE group than the CPE group (0%, 95% confidence interval [CI], 0%-0% versus 12%, 95% CI, 7% 19%; p < 0.001). Among unrevised THAs with minimum 14-year radiographic followup, the mean steady-state linear wear rate for THAs with XLPE liners was lower than the mean linear wear rate for the THAs with CPE liners (0.03 +/- 0.05 versus 0.17 +/- 0.09 mm/year; mean difference, 0.14; 95% CI, 0.11-0.17; p < 0.001). Osteolysis of any size was noted among 9% (four of 46) of the hips in the XLPE group and 46% (18 of 39) of the hips in the CPE group (odds ratio, 0.19; 95% CI, 0.07-0.51; p < 0.001). CONCLUSIONS: This randomized study with followup into the second decade demonstrated reductions in revision, wear, and osteolysis associated with the use of XLPE. The low wear rates and absence of any mechanical failures among the XLPE liners at long-term followup affirm the durability of these components that did not incorporate antioxidants. Although osteolysis has not been eliminated, it occurs infrequently and has not caused any clinical problems to date. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 29529657 TI - CORR Insights(r): Otto Aufranc Award: Crosslinking Reduces THA Wear, Osteolysis, and Revision Rates at 15-year Followup Compared With Noncrosslinked Polyethylene. PMID- 29529658 TI - Otto Aufranc Award: Dual-mobility Constructs in Revision THA Reduced Dislocation, Rerevision, and Reoperation Compared With Large Femoral Heads. AB - BACKGROUND: Dislocation is one of the most common complications after revision THA. Dual-mobility constructs and large femoral heads (ie, 40 mm) are two contemporary, nonconstrained bearing options used in revision THA to minimize the risk of dislocation; however, it is not currently established if there is a clear benefit to using dual-mobility constructs over large femoral heads in the revision setting. QUESTIONS/PURPOSES: We sought to determine if dual-mobility constructs would provide a reduction in dislocation, rerevision for dislocation, and reoperation or other complications as compared with large femoral heads in revision THA. METHODS: From 2011 to 2014, a series of 355 THAs underwent revision for any reason and received either a dual-mobility construct (146 THAs) or a 40 mm large femoral head (209 THAs). Indications for either construct were based on surgeon judgment; however, there is a preference to use dual-mobility constructs in patients believed to be at higher risk of dislocation. In the dual-mobility group, 20 of 146 (14%) were excluded because of loss of followup before 2 years or because they had a dual-mobility shell cemented into a preexisting acetabular component. In the large head group, 33 of 209 (16%) were lost to followup before 2 years. Followup in the dual-mobility group was 3.3 +/- 0.8 years and followup in the large head group was 3.9 +/- 0.9 years. Primary endpoints included dislocation, rerevisions for dislocation, and reoperations, which were determined through our institution's total joint registry and verified by individual patient chart review. Age and body mass index were not different with the numbers available between the groups, but there was a slight predominance of females in the dual-mobility group (52% [66 of 126] female) versus the 40-mm large head group (41% [72 of 176] female) (p = 0.05). Notably, 33% (41 of 126) of patients receiving the dual-mobility constructs had the index revision THA done for a diagnosis of recurrent dislocation versus 9% (17 of 176) in the 40-mm large head group. Mean effective head size in the dual-mobility group was 47 mm (range, 38 58 mm). RESULTS: The subsequent frequency of dislocation in the dual-mobility construct group was less (3% [four of 126] dual-mobility versus 10% [17 of 176] in the 40-mm large head group; hazard ratio, 3.2 [1.1-9.4]; p = 0.03). Rerevision for dislocation in the dual-mobility construct group was less frequent (1% [one of 126] dual-mobility versus 6% [10 of 176] in the 40-mm large head group; hazard ratio, 7.1 [0.9-55.6]; p = 0.03). Reoperation for any cause in the dual-mobility construct group was less frequent (6% [eight of 126] dual-mobility versus 15% [27 of 176] in the 40-mm large head group; hazard ratio, 2.5 [1.1-5.5]; p = 0.02); there were no differences between the groups in terms of the overall percentage of complications in each group. CONCLUSIONS: When compared with patients treated with a 40-mm large femoral head, patients undergoing revision THA who received a dual-mobility construct had a lower risk of subsequent dislocation, rerevision for dislocation, and reoperation for any reason in the first several years postoperatively. Those findings were present despite selection bias in this study to use the dual-mobility construct in patients at the highest risk for subsequent dislocation. Given the lower risk of subsequent dislocation, rerevision, and reoperation with the dual-mobility construct, some surgeons may wish to consider whether the role of dual-mobility should be judiciously expanded in contemporary revision THA. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529659 TI - CORR Insights(r): Otto Aufranc Award: Dual-mobility Constructs in Revision THA Reduced Dislocation, Rerevision, and Reoperation Compared With Large Femoral Heads. PMID- 29529660 TI - Can Dislocation of a Constrained Liner Be Salvaged With Dual-mobility Constructs in Revision THA? AB - BACKGROUND: Revision THA to treat recurrent instability can itself be complicated by recurrent instability, and when this occurs, this problem is difficult to treat. Some patients' THAs will continue to dislocate despite use of a constrained liner. One option in this difficult-to-treat group is conversion to a dual-mobility (DM) construct, but there are few data on this approach. QUESTIONS/PURPOSES: (1) What were the Harris hip scores in a small group of patients whose constrained liners were converted to DM constructs to treat recurrent dislocation? (2) What were the redislocation, rerevision, and DM construct retention rates in these patients? METHODS: We conducted a retrospective analysis of a longitudinally maintained institutional database maintained by individuals other than the treating surgeons to identify patients undergoing conversion of constrained liners to DM constructs in revision THA from 2011 to 2014. We identified 16 patients who underwent revision of dislocated constrained liners to DM constructs. Two patients died before 2-year followup, leaving 14 patients available for followup at a minimum of 24 months and a median of 37 months (range, 24-71 months). Indications for conversion to DM constructs included patients with dislocation of multiple prior constrained liners, patients with at least partial abductor functioning and soft tissue tensioning, and patients at very high risk for recurrent instability as an alternative to resection arthroplasty. Ten patients (10 of 14) underwent DM conversion at the time of cup revision, whereas four patients (four of 14) had a DM construct cemented into a preexisting cup. Median age was 65 years (range, 53-93 years). Median number of prior hip surgeries was five (range, three to 10) and seven patients (seven of 14) had dislocated more than one constrained liner. RESULTS: Harris hip score improved from a median of 57 (range, 55-67) to 84 (range, 68-96) postoperatively (p < 0.001). Three patients (three of 14) experienced a redislocation. Two (two of 14) of these patients were closed reduced and treated successfully nonoperatively; one (one of 14) patient experienced an intraprosthetic dislocation and underwent modular exchange. One patient (one of 14) underwent early resection arthroplasty for acetabular loosening after complex acetabular reconstruction. Overall, all other patients (13 of 14) retained a DM construct at final followup. CONCLUSIONS: Conversion to a DM construct shows promise as a salvage option in high-risk, multiply operated on patients with dislocated constrained liners undergoing revision THA for recurrent instability. The ability to close reduce a dislocated DM construct is a distinct advantage over constrained liners. However, longer followup is required given that three of 14 redislocated, and one of those underwent revision for persistent instability at short-term followup. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29529661 TI - CORR Insights(r): Can Dislocation of a Constrained Liner Be Salvaged With Dual mobility Constructs in Revision THA? PMID- 29529662 TI - Novel Acetabular Cup for Revision THA Improves Hip Center of Rotation: A Radiographic Evaluation. AB - BACKGROUND: Bone loss in patients undergoing revision THA poses a considerable challenge for orthopaedic surgeons. Often, to achieve better fixation in remaining bone, larger diameter acetabular components and reaming superiorly may be necessary. However, this is likely to raise the hip center of rotation, which may lead to altered biomechanics, specifically, insufficiency of the abductor muscles, altered gait, and increased risk of dislocation from impingement. More recently, a newer acetabular shell has been designed to more closely replicate the native hip center of rotation in these circumstances while maintaining adequate fixation. QUESTIONS/PURPOSES: The purpose of this study was to compare the radiographic parameters of this newer design with conventional hemispheric cups in revision THA. Specifically, we assessed the differences in (1) vertical center of rotation (COR) displacement and (2) horizontal COR displacement. METHODS: Between January 2016 and April 2016, five reconstructive surgeons at five institutions utilized a newer highly porous acetabular shell designed with peripheral screw holes and vertically eccentric COR to allow for restoration of center of hip rotation in revision THA. We included all patients who received this device. During this time, the general indications at these sites for using the new device included Paprosky Stage IIA, IIB, IIC, or IIIA acetabular defects. This yielded 29 patients who were subsequently matched (one to two) by cup size and sex to a cohort who underwent revision THA with conventional hemispheric cups between January 2015 and May 2016. To determine hip COR, radiographic measurements were performed. A circle contiguous to the acetabulum was drawn and the center was determined as the hip COR. All measurements were made from the interteardrop line for both the revised and native hips. A line through the teardrops was used for all horizontal measurements. Center position adjustments were made based on the manufacturer-specified values. Comparisons were performed using chi-square tests for categorical and t-tests for continuous variables. There was no difference in the severity of bone loss before the revision in the groups, as evidenced by Paprosky staging of preoperative radiographs. RESULTS: The mean vertical COR displacement was smaller in patients who had the novel cup (3.5 mm; range, -12 to 15 mm; mean difference, -7.3 mm; 95% confidence interval [CI], -13.2 to -1.5) as compared with those who had the conventional cup (10.5 mm; range, -4 to 50 mm; mean difference, 7.3 mm; 95% CI, -12.5 to -2.2; p = 0.003). There was no difference in mean horizontal displacement between the two groups (-0.06 +/- 6.1 versus 1.7 +/- 7.1; mean difference, -1.8; p = 0.903). CONCLUSIONS: Although hip COR was improved based on radiographic measurements with the use of this novel acetabular design, and although this may improve hip biomechanics, more studies are required before its widespread adoption for revision cases of this nature can be recommended. Both implant costs and the risks associated with using a new design in practice will have to be justified by studies that evaluate fixation, clinical function and implant survival, and patient-reported outcome scores, all of which were beyond the scope of this preliminary report. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529663 TI - CORR Insights(r): Novel Acetabular Cup for Revision THA Improves Hip Center of Rotation: A Radiographic Evaluation. PMID- 29529664 TI - The Safe Zone Range for Cup Anteversion Is Narrower Than for Inclination in THA. AB - BACKGROUND: Cup malposition is a common cause of impingement, limitation of ROM, acceleration of bearing wear, liner fracture, and instability in THA. Previous studies of the safe zone based on plain radiographs have limitations inherent to measuring angles from two-dimensional projections. The current study uses CT to measure component position in stable and unstable hips to assess the presence of a safe zone for cup position in THA. QUESTIONS/PURPOSES: (1) Does acetabular component orientation, when measured on CT, differ in stable components and those revised for recurrent instability? (2) Do CT data support historic safe zone definitions for component orientation in THA? METHODS: We identified 34 hips that had undergone revision of the acetabulum for recurrent instability that also had a CT scan of the pelvis between August 2003 and February 2017. We also identified 175 patients with stable hip replacements who also had a CT study for preoperative planning and intraoperative navigation of the contralateral side. For each CT study, one observer analyzed major factors including acetabular orientation, femoral anteversion, combined anteversion (the sum of femoral and anatomic anteversion), pelvic tilt, total offset difference, head diameter, age, sex, and body mass index. These measures were then compared among stable hips, hips with cup revision for anterior instability, and hips with cup revision for posterior instability. We used a clinically relevant measurement of operative anteversion and inclination as opposed to the historic use of radiographic anteversion and inclination. The percentage of unstable hips in the historic Lewinnek safe zone was calculated, and a new safe zone was proposed based on an area with no unstable hips. RESULTS: Anteriorly unstable hips compared with stable hips had higher operative anteversion of the cup (44 degrees +/- 12 degrees versus 31 degrees +/- 11 degrees , respectively; mean difference, 13 degrees ; 95% confidence interval [CI], 5 degrees -21 degrees ; p = 0.003), tilt adjusted operative anteversion of the cup (40 degrees +/- 6 degrees versus 26 degrees +/- 10 degrees , respectively; mean difference, 14 degrees ; 95% CI, 10 degrees -18 degrees ; p < 0.001), and combined tilt-adjusted anteversion of the cup (64 degrees +/- 10 degrees versus 54 degrees +/- 19 degrees , respectively; mean difference, 10 degrees ; 95% CI, 1 degrees -19 degrees ; p = 0.028). Posteriorly unstable hips compared with stable hips had lower operative anteversion of the cup (19 degrees +/- 15 degrees versus 31 degrees +/- 11 degrees , respectively; mean difference, -12 degrees ; 95% CI, -5 degrees to -18 degrees ; p = 0.001), tilt-adjusted operative anteversion of the cup (19 degrees +/- 13 degrees versus 26 degrees +/- 10 degrees , respectively; mean difference, -8 degrees ; 95% CI, -14 degrees to -2 degrees ; p = 0.014), pelvic tilt (0 degrees +/- 6 degrees versus 4 degrees +/- 6 degrees , respectively; mean difference, -4 degrees ; 95% CI, -7 degrees to -1 degrees ; p = 0.007), and anatomic cup anteversion (25 degrees +/- 18 degrees versus 34 degrees +/- 12 degrees , respectively; mean difference, -9 degrees ; 95% CI, -1 degrees to -17 degrees ; p = 0.033). Thirty-two percent of the unstable hips were located in the Lewinnek safe zone (11 of 34; 10 posterior dislocations, one anterior dislocation). In addition, a safe zone with no unstable hips was identified within 43 degrees +/- 12 degrees of operative inclination and 31 degrees +/- 8 degrees of tilt-adjusted operative anteversion. CONCLUSIONS: The current study supports the notion of a safe zone for acetabular component orientation based on CT. However, the results demonstrate that the historic Lewinnek safe zone is not a reliable predictor of future stability. Analysis of tilt-adjusted operative anteversion and operative inclination demonstrates a new safe zone where no hips were revised for recurrent instability that is narrower for tilt-adjusted operative anteversion than for operative inclination. Tilt-adjusted operative anteversion is significantly different between stable and unstable hips, and surgeons should therefore prioritize assessment of preoperative pelvic tilt and accurate placement in operative anteversion. With improvements in patient specific cup orientation goals and acetabular component placement, further refinement of a safe zone with CT data may reduce the incidence of cup malposition and its associated complications. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 29529665 TI - Tantalum Components in Difficult Acetabular Revisions Have Good Survival at 5 to 10 Years: Longer Term Followup of a Previous Report. AB - BACKGROUND: The best method for acetabular revisions in patients with severe bone loss remains controversial; typical approaches include jumbo cups, cages, cup cages, and custom components. Tantalum (TM) components have good results at midterm followup, but the longer term survival and complications are not available. We previously reported on a series of such reconstructions; here we provide additional followup on that group along with a larger study cohort. QUESTIONS/PURPOSES: (1) What is the survival at a minimum followup of 5 years of these components implanted in difficult revisions and what is the mechanism of failure? (2) What is the most common complication of these reconstructions, and what hip scores did these patients achieve? METHODS: Between 2001 and 2010, one surgeon performed 150 acetabular revisions, of which 74 (49%) were done using TM components. The general indication for use of these devices was the surgeon's perception that there was sufficient bone loss to place the reconstruction at a high risk of mechanical failure (generally Paprosky Type 3 or 4 or lower Paprosky type with < 50% host bone coverage or morbid obesity). No cages were used during this time. Fifteen patients died and 11 were lost or did not return, leaving 48 hips (46 patients) with a mean followup of 8 years (range, 5-14 years). Of these, 39 were reported on in our previous series, and nine are new in the present series; the overall group here has an additional median of 5 years followup (range, 3-7 years). Five hips had six augments placed to obtain stability. Patients were evaluated by the Harris hip score and standard radiographs; survivorship was estimated using the cumulative incidence competing risks survival analysis. The primary outcome was fixation and survival of the TM component and the secondary outcome was complications. RESULTS: Cumulative incidence competing risks estimate survival free from aseptic loosening was 92% at 10 years (95% confidence interval [CI], 0.81-0.98). Dislocation, the most common complication, occurred in seven of 48 (15%) patients, and five of 48 (10%) had a reoperation for it. Survival free from any reoperation was 84% at 10 years (95% CI, 0.72-0.92). The Harris hip score improved from a mean of 50 points (SD 17) before surgery to 85 points (SD 10; p < 0.001) at latest followup. CONCLUSIONS: Given the findings of this study, TM components appear to provide durable fixation at midterm followup in complex acetabular revisions. Steps to minimize dislocation, the most frequent complication of these revisions, may include the routine use of larger femoral heads. Future studies likely will need to be multisurgeon or multicenter and should evaluate different techniques and components for long-term fixation and the prevention of dislocation. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29529666 TI - CORR Insights(r): Tantalum Components in Difficult Acetabular Revisions Have Good Survival at 5 to 10 Years: Longer Term Followup of a Previous Report. PMID- 29529667 TI - Late Reinfection May Recur More Than 5 Years After Reimplantation of THA and TKA: Analysis of Pathogen Factors. AB - BACKGROUND: Two-stage reimplantation has consistently yielded high rates of success for patients with chronic prosthetic joint infection, although results more than 5 years after reimplantation are not commonly reported. Numerous factors may contribute to the risk of reinfection, although these factors-as well as the at-risk period after reimplantation-are not well characterized. QUESTIONS/PURPOSES: (1) What is the risk of reinfection after reimplantation for prosthetic joint infection at a minimum of 5 years? (2) Is the bacteriology of the index infection associated with late reinfection? (3) Is the presence of bacteria at the time of reimplantation associated with late reinfection? METHODS: Between 1995 and 2010, we performed 97 two-stage revisions in 93 patients for prosthetic joint infection of the hip or knee, and all are included in this retrospective study. During that time, the indications for this procedure generally were (1) infections occurring more than 3 months after the index arthroplasty; and (2) more acute infections associated with prosthetic loosening or resistant organisms. One patient (1%) was lost to followup; all others have a minimum of 5 years of followup (mean, 11 years; range, 5-20 years) and all living patients have been seen within the last 2 years. Patients were considered free from infection if they did not have pain at rest or constitutional symptoms such as fever, chills, or malaise. The patients' bacteriology and resistance patterns of these organisms were observed with respect to recurrence of infection. Odds ratios and Fisher's exact test were performed to analyze the data. The incidence of reinfection was determined using cumulative incidence methods that considered death as a competing event. RESULTS: Reinfection occurred in 12 of the 97 joints resulting in implant revision. The estimated 10-year cumulative incidence of infection was 14% (95% confidence interval [CI], 7%-23%) and incidence of infection from the same organism was 5% (95% CI, 1%-11%). Five occurred early or within 2 years and three were resistant pathogens (methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, or vancomycin-resistant Enterococcus). Seven late hematogenous infections occurred and all were > 4 years after reimplantation and involved nonresistant organisms. Three of the five (60%) early infections were caused by resistant bacteria, whereas all seven late infections were caused by different organisms or a combination of different organisms than were isolated in the original infection. The early reinfections were more often caused by resistant organisms, whereas late infections involved different organisms than were isolated in the original infection and none involved resistant organisms. With the numbers available, we found no difference between patients in whom bacteria were detected at the time of reimplantation and those in whom cultures were negative in terms of the risk of reinfection 5 years after reimplantation (18.6% [18 of 97] versus 81.4% [79 of 97], odds ratio 1.56 [95% CI, 0.38-6.44]; p = 0.54); however, with only 93 patients, we may have been underpowered to make this analysis. CONCLUSIONS: In our study, resistant organisms were more often associated with early reinfection, whereas late failures were more commonly associated with new pathogens. We believe the most important finding in our study is that substantial risk of late infection remains even among patients who seemed free from infection 2 years after reimplantation for prosthetic joint infections of the hip or knee. This highlights the importance of educating our patients about the ongoing risk of prosthetic joint infection. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529668 TI - CORR Insights(r): Late Reinfection May Recur More Than 5 Years After Reimplantation of THA and TKA: Analysis of Pathogen Factors. PMID- 29529669 TI - Risk of Complications After THA Increases Among Patients Who Are Coinfected With HIV and Hepatitis C. AB - BACKGROUND: Individuals coinfected with both hepatitis C virus (HCV) and HIV represent a unique and growing population of patients undergoing orthopaedic surgical procedures. Data regarding complications for HCV monoinfection or HIV monoinfection are robust, but there are no data available, to our knowledge, on patients who have both HCV and HIV infections. QUESTIONS/PURPOSES: We sought to determine whether patients with coinfection differed in terms of baseline demographics and comorbidity burden as compared with patients without coinfection and whether these potential differences were translated into varying levels of postoperative complications, mortality, and hospital readmission risk. Specifically, we asked: (1) Are there demonstrable differences in baseline demographic variables between patients infected with HCV and HIV and those who do not have those infections (age, sex, race, and insurance status)? (2) Do patients with HCV and HIV infection differ from patients without those infections in terms of other medical comorbidities? (3) Do patients with HCV/HIV coinfection have a higher incidence of early postoperative complications and mortality than patients without coinfection? (4) Is the frequency of readmission greater for patients with HCV/HIV coinfection than those without? METHODS: The New York Statewide Planning and Research Cooperative System (SPARCS) database was used to identify patients undergoing THA between 2010 and 2014. The SPARCS database is particularly useful because it captures 100% of all New York State inpatient admissions while providing detailed demographic and comorbidity data for a large, heterogeneous patient population with long-term followup. Patients were stratified into four groups based on HCV/HIV status: control patients without disease, HCV monoinfection, HIV monoinfection, and coinfection. We sought to determine whether patients coinfected with HCV and HIV would differ in terms of demographics from patients without those infections and whether patients with HCV and HIV would have a greater risk of complications, longer length of stay, and hospital readmission. A total of 80,722 patients underwent THA between 2010 and 2014. A total of 98.55% (79,554 of 80,722) of patients did not have either HCV or HIV, 0.66% (530 of 80,722) had HCV monoinfection, 0.66% (534 of 80,722) HIV monoinfection, and 0.13% (104 of 80,722) were coinfected with both HCV and HIV. Multivariate analysis was performed controlling for age, sex, insurance, residency status, diagnosis, and comorbidities to allow for an equal comparison between groups. RESULTS: Patients with coinfection were more likely to be younger, male (odds ratio [OR], 2.90; 95% confidence interval [CI], 2.20-3.13; p < 0.001), insured by Medicaid (OR, 6.43; 4.41-7.55; p < 0.001), have a history of avascular necrosis (OR, 8.76; 7.20-9.53; p < 0.001), and to be homeless (OR, 6.95; 5.31-7.28; p < 0.001) as compared with patients without HIV or HCV. Additionally, patients with coinfection had the highest proportion of alcohol abuse, drug abuse, and tobacco use along with a high proportion of psychiatric disorders, including depression. HCV and HIV coinfection were independent risk factors for increased length of stay (OR, 1.97; 95% CI, 1.29-3.01; p < 0.001), having two or more in-hospital complications (OR, 1.64; 1.01-2.67; p < 0.001), and 90-day readmission rates (OR, 2.97; 1.86-4.77; p < 0.001). CONCLUSIONS: As the prevalence of HCV and HIV coinfectivity continues to increase, orthopaedic surgeons will encounter a greater number of these patients. Awareness of the demographic and socioeconomic factors leading to increased complications after THA will allow physicians to consider interventions such as in-hospital psychiatric counseling, advanced discharge planning, and coordination with social work and collaboration with HCV/HIV infectious disease specialists to improve patient health status to improve outcomes and reduce costs. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529670 TI - CORR Insights(r): Risk of Complications After THA Increases Among Patients Who Are Coinfected With HIV and Hepatitis C. PMID- 29529672 TI - CORR Insights(r): Changing Patient Expectations Decreases Length of Stay in an Enhanced Recovery Program for THA. PMID- 29529671 TI - Changing Patient Expectations Decreases Length of Stay in an Enhanced Recovery Program for THA. AB - BACKGROUND: The implementation of care pathways in hip arthroplasty programs has been shown to result in a decreased length of stay (LOS), but often multiple elements of a care pathway are implemented at the same time. As a result, it is difficult to understand the impact each of the individual modifications has made to the patient's prepathway care. In particular, it is unknown what the role of patient expectations pertaining to anticipated LOS alone is on the LOS after primary THA. QUESTIONS/PURPOSES: (1) Does changing the patient's expectations regarding his or her anticipated LOS, without intentionally changing the rest of the care pathway, result in a change in the patient's LOS after primary THA? (2) Is the resultant LOS associated with the patient's age, gender, or day of the week the surgery was performed? METHODS: We retrospectively compared the LOS in 100 consecutive patients undergoing THA immediately after the implementation of a 4-day care pathway (4-day Group) with 100 consecutive patients, 3 months later, who were also in the same pathway but were told by their surgeon preoperatively and in the hospital to expect a LOS of 2 days (2-day Group). Aside from reeducation by the surgeon, there was no difference in the surgery or intentional changes to the intraoperative or postoperative management of the two groups. Only the patient and the surgeon were made aware of the accelerated discharge plan. We compared the LOS between the two groups and the number of patients who met their discharge goal. As well, the ability to meet the discharge goal for each group was further determined based on age, gender, and day of the week the surgery was performed. RESULTS: Overall, patients in the 2-day Group had a shorter LOS than those in the 4-day Group (2.9 +/- 0.88 days versus 3.9 +/- 1.71 days; mean difference 1 day; 95% confidence interval [CI], 0.60-1.36; p = 0.001). In the 2 day Group, the LOS was 2 days in 32% compared with 8% in the 4-day Group (odds ratio, 4.0; 95% CI, 1.76-9.11; p < 0.001). Men in the 4-day Group had a shorter LOS than women (3.4 +/- 1.22 days versus 4.2 +/- 1.89 days; mean difference 0.8 days; 95% CI, 0.17-1.78; p = 0.019), but there was no difference in LOS by gender in the 2-day Group (2.8 +/- 0.81 days versus 3.1 +/- 0.93 days; mean difference 0.3 days; 95% CI, -0.14 to 0.61; p = 0.219). For all patients > 40 years and < 90 years of age, a greater percentage of patients in the 2-day Group went home by postoperative day 2 than those in the 4-day Group (32% compared with 7%; odds ratio, 4.6; p < 0.001). In both groups, there was no difference in the LOS if the surgery was on Friday compared with an earlier day of the week (4-day Group: 3.4 +/- 0.67 days versus 4.0 +/- 1.80 days; p = 0.477 and 2-day Group: 2.8 +/- 0.62 days versus 3.0 +/- 0.93 days; p = 0.547). CONCLUSIONS: We found that a surgeon who sets a clear expectation in terms of LOS could achieve a reduction in this parameter. Although it is impossible to be certain in the context of a retrospective study whether other caregivers adjusted the pathway in response to the surgeon's preferences, and we suspect this probably did occur, this still points to an opportunity on the topic of expectations setting that future studies should explore. This study highlights the influence patient education and expectations has on the effectiveness of care pathways in THA as well as the importance of continuous reinforcement of discharge planning both preoperatively and in the hospital. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529673 TI - Mobile Compression Reduces Bleeding-related Readmissions and Wound Complications After THA and TKA. AB - BACKGROUND: The use of chemoprophylaxis to prevent thromboembolic disease after primary THA and TKA can be associated with postoperative bleeding complications. Mechanical prophylaxis has been studied as an alternative to chemoprophylaxis with greater safety in patients undergoing THA, but no data have been published comparing the safety of chemoprophylaxis versus mechanical methods for patients undergoing TKA. The risk of readmission resulting from bleeding and venous thromboembolism (VTE) has also not been determined for patients undergoing THA or TKA when treated with low-molecular-weight heparin (LMWH) alone compared with mechanical prophylaxis plus aspirin (ASA). QUESTION/PURPOSES: We sought to answer four questions: For the THA and TKA cohorts, respectively, (1) was the incidence of readmission resulting from VTE and bleeding complications higher with LMWH than mobile compression plus ASA; and (2) was the incidence of wound bleeding complications higher with LMWH than mechanical compression plus ASA? For the TKA cohort specifically, (3) was the frequency of systemic bleeding events and complications related to chemical prophylaxis higher with LMWH compared with mechanical compression plus ASA? (4) Was there a difference in symptomatic VTEs between LMWH and mechanical compression plus ASA? METHODS: Between November 2008 and April 2011, 632 patients underwent primary THA and TKA. Seventy-two patients (11%) were identified before surgery as being at high risk for VTE (31 patients) or bleeding (41 patients) and were excluded from the study. Five hundred sixty patients (89%) were considered to be at standard risk for VTE and bleeding and comprise the study cohort. Between November 2008 and November 2009, 252 patients (76 THAs, 176 TKAs) underwent THA and TKA and were treated with LMWH (5 mg dalteparin given subcutaneously daily for 14 days) and in-hospital nonmobile mechanical compression. Between November 2009 and April 2011, a total of 308 patients undergoing THA and TKA (108 THAs, 200 TKAs) were treated using a mobile compression device plus oral aspirin once daily for 2 weeks after surgery. All complications and readmissions that occurred within 6 weeks of surgery were noted. There were no differences between the VTE treatment groups with regard to age, sex, or body mass index. RESULTS: For the THA cohort, there was no difference in the frequency of readmission for a bleeding complication (wound or systemic) between the two groups (2.6% for LMWH versus 0.9% for mobile compression; p = 0.57; odds ratio [OR], 2.9). Patients undergoing TKA treated with LMWH had higher readmission rates within 6 weeks of surgery because of a bleeding complication, a wound infection, or the development of a VTE (6.8% for LMWH versus 1.5% for mobile compression; p = 0.015; OR, 4.8). For the THA cohort, there was higher wound bleeding complication frequency with LMWH (9.2% for LMWH versus 0.9% for mechanical compression; p = 0.009; OR, 10.9). Patients undergoing TKA treated with LMWH had a higher frequency of wound bleeding complications or infection (3.9% for LMWH versus 0.5% for mobile compression; p = 0.028; OR, 8.2). Patients undergoing TKA treated with LMWH had higher rates of systemic bleeding or a complication secondary to LMWH administration (2.8% for LMWH versus 0% for mobile compression; p = 0.022; OR, 12.8). No difference was noted in the rate of symptomatic VTEs between either group (for THA: 2.6% for the LMWH group versus 1.9% for the mechanical compression group; p = 1; for TKA: 1.1% versus 0%, respectively; p = 0.22). CONCLUSIONS: Based on these results, we advocate for routine use of mobile mechanical compression devices in the prevention of VTEs and complications associated with more potent chemical anticoagulants. However, more focused randomized clinical trials are needed to validate these findings. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29529674 TI - Stem Cells Combined With Platelet-rich Plasma Effectively Treat Corticosteroid induced Osteonecrosis of the Hip: A Prospective Study. AB - BACKGROUND: Randomized trials have shown the benefits of injecting bone marrow derived mesenchymal stem cells (BmMSCs) after standard hip decompression in patients with osteonecrosis of the femoral head. However, the combination of BmMSCs and platelet-rich plasma (PRP) injected into the femoral head after decompression has not been reported previously. This study reports the results in a preliminary series of patients with osteonecrosis of the femoral head treated with BmMSCs plus PRP. QUESTIONS/PURPOSES: (1) What is the survivorship free from reoperation, hip arthroplasty, and femoral head collapse in a preliminary series of patients with osteonecrosis of the femoral head treated with BmMSCs plus PRP? (2) Is there a change in the degree of femoral head involvement based on modified Kerboul angle? (3) What were the scores observed for pain and function at last followup? (4) Was there a difference in survivorship free from reoperation as a function of in vitro MSC count and viability? METHODS: Twenty-two consecutive patients (35 hips; 11 men and 11 women) with corticosteroid-induced osteonecrosis who met study inclusion criteria were enrolled; none declined participation, and none was lost to followup, although one patient (two hips) died within a year of the procedure for reasons unrelated to it, and five patients (seven hips) did not undergo MRI at the 1-year followup. All patients had precollapse osteonecrosis, rated either University of Pennsylvania Stage 1 (n = 4) or Stage 2 (n = 31 hips). Mean age and body mass index were 43 years and 31 kg/m, respectively. Patients underwent pre- and postoperative radiographs and MRI to assess femoral head involvement using the modified Kerboul angle. Absolute cell count and colony forming unit (CFU) assays were used to assess MSC abundance and viability of the bone marrow obtained at the time of surgery. Patients were followed at regular intervals to assess clinical response to treatment with a mean followup of 3 years (range, 2-4 years). The change in femoral head involvement was assessed with the modified Kerboul angle; the Harris hip score was used to assess clinical outcome; and conversion to THA, reoperation, and survivorship free from femoral head collapse were analyzed with the Kaplan-Meier method on a per-hip basis. RESULTS: Survivorship free from THA, any procedure, and femoral head collapse was 84% (95% confidence interval [CI], 75%-93%), 67% (95% CI, 55%-79%), and 93% (95% CI, 76%-98%), respectively, at 3 years postoperatively; two patients (four hips) underwent a second decompression and MSC injection for persistent pain without signs of radiographic collapse. All patients with collapse underwent THA. The mean modified Kerboul angle improved from 205 degrees +/- 47 degrees to 172 degrees +/- 48 degrees postoperatively (mean change -30 degrees +/- 6 degrees , p = 0.01). A greater proportion of patients who underwent an additional procedure had a modified Kerboul grade of 3 or 4 preoperatively (80% [four of five] versus 13% [four of 30 Grade 1 or 2; odds ratio, 26; 95% CI, 2-296; p = 0.005). Preoperatively the mean Harris hip score was 57 +/- 12, which improved to 85 +/- 15 (mean change 28 +/- 3, p < 0.001) at most recent followup. Patients undergoing a reoperation or THA had a lower mean concentration of nucleated cells/mL (5.5 x 10 +/- 2.8 x 10 cells/mL versus 2.3 x 10 +/- 2.2 x 10 cells/mL, p = 0.02) and lower mean CFUs (13 +/- 6 versus 19 +/- 7, p = 0.04) compared with those who did not. CONCLUSIONS: Core hip decompression with injection of concentrated bone marrow plus PRP improved pain and function; > 90% of hips in this series were without collapse at a minimum of 2 years. In this preliminary study, successful results were seen when nucleated cell count was high and modified Kerboul grade was low. Further randomized studies are needed to determine this procedure's efficacy versus core decompression or nonoperative treatment alone. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29529675 TI - CORR Insights(r): Stem Cells Combined With Platelet-rich Plasma Effectively Treat Corticosteroid-induced Osteonecrosis of the Hip: A Prospective Study. PMID- 29529676 TI - Evaluation of the Neurobehavioral Properties of Naringin in Swiss Mice. AB - OBJECTIVES: This study was carried out to investigate the neurobehavioral properties of naringin, a flavonoid compound formed from naringenin on behavioral models in mice. METHOD: The neurobehavioral property of naringin (2.5, 5 and 10 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced rearing, locomotor behavior using open field test; anxiolytic effect was evaluated using hole-board, light and dark box, and elevated-plus maze paradigms. The anti-depressant-like property was also assessed using forced swim test (FST), tail suspension test (TST) and social interaction test (SIT). The cognitive enhancing effect of naringin was evaluated using Y-maze test. RESULTS: Intraperitoneal administration of naringin (2.5 and 5 mg/kg) demonstrated significant (p<0.05) increase in rearing behavior but not the spontaneous motor activity in comparison to control. In the anti-depressant test, naringin (2.5, 5 and 10 mg/kg, i.p.) significantly decreased the duration of immobility in the FST and TST, and increased the % social interaction preference in the SIT relative to controls, suggesting anti-depressant-like and increased social behaviors. Moreover, naringin also exhibited anxiolytic and memory enhancing properties in mice. CONCLUSION: These findings suggest that naringin possesses anti-depressant- and anxiolytic-like activities as well as memory enhancing effect in mice. PMID- 29529677 TI - Escherichia coli and Klebsiella pneumoniae Sensitivity/Resistance Pattern Towards Antimicrobial Agents in Primary and Simple Urinary Tract Infection Patients Visiting University Hospital of Jamia Hamdard New Delhi. AB - AIM: This study was carried out to record the sensitivity/resistance pattern of Escherichia coli and Klebsiella pneumoniae towards antimicrobial drugs prescribed to urinary tract infection (UTI) patients. MATERIALS AND METHODS: A total of 68 bacteriologically proven simple UTI patients were included in the study, based on inclusion and exclusion criteria. Subjects demographics, antibiotics prescribed, sensitivity pattern of antibiotics towards the urinary pathogens were recorded in drug utilization and documentation form. RESULTS: The mean age of the patients was 29.32 years. The maximum number of patients fell under the age group 21-30 years. The maximum no of male and female patients belonged to the age group 21-30 years, 82.35% were females and 17.64% were males. E. coli found to be the most common uropathogens followed by Klebsiella pneumoniae. Nitrofurantoin was the most commonly prescribed drug followed by ciprofloxacin, levofloxacin and amoxicillin + clavulanic acid and amikacin. E. coli isolates showed high resistance for ampicillin followed by cotrimoxazole, norfloxacin, ciprofloxacin, gentamicin, tetracycline and ceftazidime and least resistance to amikacin, nitrofurantoin. Klebsiella pneumoniae isolates were highly resistant against ceftazidime, ampicilline, cotrimoxazole, nitrofurantoin, gentamicin, amoxicillin + sulbactam. Overall, the antibiotic against with high resistance found was ampicillin followed by cotrimoxazole, gentamicin, ceftazidime, norfloxacin, ciprofloxacin, tetracycline, levofloxacin, cefepime and least resistance to amikacin, netilmicin and nitrofurantoin. CONCLUSION: Majority of UTIs in this study were caused by E. coli followed by Klebsiella pneumoniae. The high resistance was found with ampicillin (75%). Nitrofurantoin was the most commonly prescribed drug followed by other flouroquinolones. PMID- 29529678 TI - Pseudometastatic Conjunctival Vegetative Foreign Bodies: A Case Report and Review of the Literature. PMID- 29529679 TI - Fluorescein Staining of Intraocular Lenses. AB - BACKGROUND: Recent case reports have indicated that intraocular lenses may be discoloured by systemically or locally applied fluorescein. Since very few data are available on the susceptibility of intraocular lenses to fluorescein, an experimental survey on lens discolouration was performed. MATERIAL AND METHODS: Intraocular lenses fabricated from polmethylmethacrylate (PMMA), silicone, hydrophobic acrylic copolymers, and hydrophilic acrylic copolymers were exposed to 10% fluorescein. Staining effects were determined by standardised quantification of light transmission. RESULTS: Intraocular lenses fabricated from PMMA, silicone, or hydrophobic acrylic copolymer did not exhibit any measurable dye uptake after exposure to fluorescein. Intensive and rapid discolouration occurred in hydrophilic acrylic intraocular lenses. The transmission of blue light was reduced by 22% after 1 second and by 74% after 10 minutes of dye exposure. CONCLUSIONS: The results indicate that hydrophilic acrylic intraocular lenses develop rapid and intensive discolouration and reduced light transmission after exposure to fluorescein. Lenses fabricated from other materials (PMMA, silicone, hydrophobic acrylic copolymers) were not discoloured by fluorescein staining. PMID- 29529680 TI - [Gallstones and "liver obstruction" in medical texts of antiquity]. AB - INTRODUCTION: Gallstones are rarely mentioned in the medical texts of antiquity. The physician, Alexander of Tralles mentions-for the first time-stones in the gallbladder as a possible cause for obstructive jaundice. This designation is found in his textbook on medicine under the heading "obstruction of the liver". Based on that observation, we describe the ancient history of hepatic obstruction and investigate the connection with the rare reference of gallstones in the medical texts of antiquity. METHODS: First, we evaluated the medico-historical literature on bile-stones and liver obstruction in antiquity, which has been published since 1900. The identified ancient sources we have analyzed for the purposes of etiology, diagnostics and therapy. Second, we searched for additional ancient sources with a combined keyword search in Greek and Latin text databases to check the completeness of the mentions of gallstones and liver obstructions known from the research literature. RESULTS: There are two mentions of stones in the liver and gallbladder: Aristotle probably describes stones in the liver of slaughtered sacrificial animals and the late-antique physician, Alexander of Tralles, in the gallbladder of humans. The mechanical obstruction of the bile ducts as a cause of jaundice has been known since Diocles of Karystos (4th century BC). For the first time, Galen of Pergamon describes the disease pattern of a liver obstruction (2nd century AC). This was due to the coagulation of the yellow bile, one of the four humors of ancient humoral pathology. CONCLUSION: Although gallstones were rarely mentioned, the clinical presentation of gallstone disease was known to ancient authors of medical texts and was referred to as liver obstruction. PMID- 29529681 TI - Severe complication during remission of Crohn's disease: hemophagocytic lymphohistiocytosis due to acute cytomegalovirus infection. AB - INTRODUCTION: Immunosuppressive therapy is today's standard treatment of patients with moderate to severe inflammatory bowel disease (IBD). The risk for opportunistic infections is increased due to this therapy and is a concern in the management of patient with IBD undergoing such a treatment. CASE REPORT: In this paper, we describe a case of an acute cytomegalovirus (CMV) infection in a 35 year-old male patient with Crohn's disease being in remission while receiving azathioprine therapy. His clinical presentation was high-grade fever, night sweats, skin rash, and abdominal pain.Laboratory findings showed pancytopenia, elevated liver enzymes, and high ferritin levels. Sonographic examination revealed splenomegaly and serological analysis proved an acute CMV infection. The severity of the acute illness and these results in the setting of immunosuppressive treatment with azathioprine were highly suspicious of hemophagocytic lymphohistiocytosis (HLH).Further investigations including bone marrow biopsy, analysis of natural killer cell function, and measurement of T cell activity confirmed the suspected diagnosis. Treatment consisted of antiviral and symptomatic therapy. DISCUSSION AND CONCLUSION: HLH is a rare and severe condition triggered by uncontrolled stimulation of histiocytes and lymphocytes, resulting in abnormal cytokine production. The causes can be primary (genetic) or secondary due to acquired immunodeficiency or viral infections such as CMV. Several symptoms of this condition are unspecific, but the summary of clinical symptoms and signs are diagnostic. Treatment consists of specific intervention if possible and application of immunosuppressive drugs such as corticosteroids. PMID- 29529682 TI - [Second Austrian consensus on the safe use of anti-TNFalpha-antibodies in patients with inflammatory bowel diseases]. AB - Anti-TNFalpha-antibodies have revolutionized the therapy of inflammatory bowel diseases and other immune-mediated inflammatory diseases. Due to the increasing application of these substances, the Working Group of Inflammatory Bowel Diseases of the Austrian Association of Gastroenterology and Hepatology intended to update their consensus report on the safe use of Infliximab (published in 2010) and to enlarge its scope to cover all anti-TNFalpha-antibodies. The present consensus report summarizes the current evidence on the safe use of anti-TNFalpha antibodies and covers the following topics: general risk of infection, bacterial infections (i. e., Clostridium difficile, Tuberculosis, food hygiene), Pneumocystis jiroveci, viral infections (i. e., Hepatitis B, Hepatitis C, HIV, CMV, VZV), vaccination in general and recommendation for vaccines, gastrointestinal aspects (i. e., perianal fistula, abdominal fistula, intestinal strictures, stenosis and bowel obstruction), dermatologic aspects (skin malignancies, eczema-like drug-related skin eruption), infusion reactions and immunogenicity, demyelinating diseases, hepatotoxicity, haematotoxicity, congestive heart failure, risk and history of malignancies, and pregnancy and breast feeding. For practical reasons, the relevant aspects are summarized in a checklist which is divided into two parts: issues to be addressed before therapy and issues to be addressed during therapy. PMID- 29529683 TI - [Non-invasive quantification of liver fat]. PMID- 29529684 TI - [Influence of anti-TNF antibodytherapy on the serum concentration of newborns and the effect on infections]. PMID- 29529686 TI - Erratum to: Role of Negative Pressure Therapy as Damage Control in Soft Tissue Reconstruction for Open Tibial Fractures. PMID- 29529687 TI - Erratum to: Staged Reconstruction (Delayed-Immediate) of the Maxillectomy Defect Using CAD/CAM Technology. PMID- 29529688 TI - Levels of Nitric Oxide Metabolites and Myeloperoxidase in Subjects with Type 2 Diabetes Mellitus on Metformin Therapy . AB - INTRODUCTION: Endothelial dysfunction is involved in the pathogenesis of insulin resistance, diabetes mellitus type 2, diabetic complications and preceded clinical manifestation of cardiovascular complications. Increased myeloperoxidase activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. The aim of this study was to compare concentrations of metabolite nitric oxide and myeloperoxidase in the plasma of diabetes mellitus type 2 patients on metformin therapy, without clinical signs of cardiovascular disease and healthy subjects, as well as evaluation of concentrations of analytes in association with glycemic control. MATERIALS AND METHODS: Forty four study subjects with diabetes mellitus type 2 and thirty healthy subjects were included in this study. The concentration of myeloperoxidase was determined by enzyme-linked immunosorbent assay, the concentration of nitrate and nitrite with high performance liquid chromatography method. Student's t test, Mann-Whitney U test, Chi-square test and Fisher's exact test were used for statistical analysis. RESULTS: The mean concentration of myeloperoxidase was significantly higher in the diabetic group compared to the control group (16.2+/-4.9 vs. 3.7+/-1.8; P<0.001).The nitrite concentration was comparable in both groups while the concentration of nitrate was significantly higher in the diabetic group (41.2 [42.9] vs 31.9 [23]; P=0.017). In this study, plasma myeloperoxidase (Spearman's rho=0.421; P=0.004) and nitrate concentration was significantly positively associated with the HbA1c levels while nitrate concentration (Spearman's rho=- 0.308; P=0.047) were was significantly positively negatively associated with the HbA1c levels. CONCLUSION: Concertation of MPO and nitric oxide were significantly increased in a T2DM subject even when on metformin therapy. However, increased concentration of NO strongly correlates with lower levels of HbA1c showing a postive effect of a gylcemic control on endothelial dysfuction. Increased concentrations of NO3- in T2DM subject compared to control, indicates the variety of NO pathways that should be taken into consideration win relation to endothelial function. PMID- 29529689 TI - Frequency of Blood Pressure and Estimated Glomerular Filtration Rate Testing in type 2 Diabetes Mellitus: A Retrospective Study with 43,509 Patients. AB - BACKGROUND: The goal of this study was to analyze the frequency of blood pressure (BP) and estimated glomerular filtration rate (eGFR) testing in type 2 diabetes mellitus (T2DM) patients followed in general and diabetological practices in Germany. METHODS: The study included individuals who had at least two concultations due to T2DM diagnosis (ICD-10: E11) between January and December 2016. Patients were followed in 557 general and diabetological practices. The primary outcome was the frequency of BP and eGFR testing in T2DM patients in 2016. The association between several demographic and clinical variables and the odds of receiving>=2 BP and>=1 eGFR tests in the year 2016 was analyzed using multivariate logistic regression models. RESULTS: A total of 43,509 individuals were available for analysis. The mean age of the population was 68.6 years (SD=12.4 years). The mean number of measurements was 2.9 (SD=3.5) for BP and 0.4 (SD=1.1) for eGFR. 52.3% of patients were tested at least twice for BP and 15.3% of them at least once for eGFR in 2016. Older patients, individuals followed in diabetological practices, people receiving antihyperglycemic medications, and those affected by chronic conditions (i. e. hypertension, renal complications, or neuropathy) displayed higher odds of receiving>=2 BP and>=1 eGFR tests, whereas patients with a diabetes duration of>1 year displayed lower odds. CONCLUSIONS: The frequency of BP and eGFR testing was low in T2DM patients in Germany in 2016. Several demographic and clinical variables were associated with this frequency. PMID- 29529690 TI - The Effect of Metformin on Serum Gonadotropin Levels in Postmenopausal Women with Diabetes and Prediabetes: A Pilot Study. AB - BACKGROUND: Metformin was found to decrease serum levels of prolactin and thyrotropin. The aim of this study was to investigate the effect of this drug on hypothalamic-pituitary-ovarian axis activity in postmenopausal women with recently diagnosed and untreated glucose metabolism abnormalities. METHODS: The study included three matched groups of postmenopausal women: patients with type 2 diabetes (group A, n=16), women with prediabetes (group B, n=14), and individuals with normal glucose metabolism (group C, n=14). Women with diabetes were then treated with high-dose metformin (3 g daily), while women with prediabetes received moderate doses of this agent (1.7 g daily). Glucose homeostasis markers, as well as serum levels of FSH, LH, thyrotropin, prolactin, estradiol and creatinine were measured at baseline and after 16 weeks of metformin treatment. RESULTS: In both groups of metformin-treated women, the drug improved glucose homeostasis. High-dose metformin treatment reduced circulating levels of FSH and tended to reduce serum levels of LH, and these effects correlated with an improvement in insulin sensitivity. No changes in gonadotropin levels were observed in prediabetic women receiving moderate doses of metformin. Serum levels of thyrotropin, prolactin and estradiol, as well as the estimated glomerular filtration rate remained at a similar level throughout the study. CONCLUSIONS: Our study shows that the effect of metformin on hypothalamic-pituitary-ovarian axis activity in postmenopausal women depends on its dose and the magnitude of insulin resistance. PMID- 29529691 TI - Do Postpartum Levels of Apolipoproteins Prospectively Predict the Development of Type 2 Diabetes in Women with Previous Gestational Diabetes Mellitus? AB - AIMS: The risk of developing type 2 diabetes is greater in women with previous gestational diabetes mellitus (GDM). Apolipoprotein (Apo) species have been associated with the development of type 2 diabetes in the general population. The aim of this study was to determine if circulating levels of Apo species can predict development of type 2 diabetes in women with previous GDM. METHODS: Apo AI, Apo AII, Apo B, Apo CII, Apo CIII and Apo E levels were measured in 95 women with normal glucose tolerance, 12 weeks following an index GDM pregnancy. Women were assessed for up to 10 years for the development of type 2 diabetes. RESULTS: Postpartum Apo CIII levels, and Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, Apo CIII/Apo E and Apo E/Apo CIII ratios were significantly and positively associated with the development of type 2 diabetes. After controlling for age and BMI, these associations, except for the Apo E/Apo CIII ratio, remained significant. In a clinical model of prediction of type 2 diabetes that included age, BMI, and pregnancy and postnatal fasting glucose, the addition of Apo CIII levels, Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, and Apo CIII/Apo E resulted in a net reclassification improvement of 16.2%. CONCLUSIONS: High Apo CIII levels and the Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, and Apo CIII/Apo E ratios are all significant risk factors for the development of type 2 diabetes in women with a previous GDM pregnancy. PMID- 29529692 TI - Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1. AB - BACKGROUND: miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated. METHODS: In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Immunohistochemical staining was performed to measure NOTCH1 expression in the diabetic endothelium. RESULTS: miR-34a was significantly up-regulated, and NOTCH1 down-regulated, in the thoracic aorta from STZ-induced diabetic rats compared with control group. As compared to model group, the mRNA of NOTCH1 was significantly decreased or increased by miR-34a mimics or inhibitors ex vivo, respectively. Bioinformatics methods further demonstrated that NOTCH1 was a potential target of miR-34a, which was confirmed by dual luciferase reporter assay. Moreover, both serum ET and NO were significantly increased in diabetic rats as compared to control group. miR-34a inhibitors ex vivo treatment resulted in significant down-regulation ofserum ET and NO levels in diabetic rats as compared to model group. CONCLUSION: These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction. PMID- 29529693 TI - [Implementation of Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Germany]. AB - INTRODUCTION: For several years, hyperthermic intrathoracic chemotherapy (HITHOC) has been performed in a few departments for thoracic surgery in a multimodality treatment regime in addition to surgical cytoreduction. Specific data about HITHOC in Germany are still lacking. METHODS: Survey in written form to all departments of thoracic surgery in Germany. The objective is the evaluation of HITHOC with respect to number, indications, technique, perioperative protection measure and complications. RESULTS: A total of 116 departments of thoracic surgery were contacted, with a return rate of 43% (n = 50). HITHOC was not performed in 33 departments, due to lack of resources or experience (n = 17), missing efficacy of the procedure (n = 8) and fear of excessive complication rates (n = 3). Since 2008, a total of 343 HITHOC procedures have been performed in 17 departments. Eight departments have their own perfusion machine, whereas the remaining departments borrow the perfusion machine. Indications were malignant pleural mesothelioma in all departments (n = 17), thymoma with pleural spread (n = 11) and secondary pleural carcinosis (n = 7). The HITHOC was performed in nearly all departments after closing the chest (n = 16), with a temperature of 42 degrees C (n = 12) and for 60 minutes (n = 15). Cisplatin was always used, either alone (n = 9) or in combination (n = 8). In all the participating departments, the aims of the HITHOC were improvement in local tumor control and prolonged recurrence-free and overall survival. Relevant HITHOC associated complications were low. CONCLUSIONS: HITHOC is performed in at least 17 departments of thoracic surgery in Germany, and is widely standardised with protective measures and a low rate of complications. The aims of the HITHOC are improvement in local tumor control in pleural malignancies combined with prolonged overall survival and better quality of life. PMID- 29529694 TI - Injuries in Austrian football players: Are they an issue? AB - PURPOSE AND HYPOTHESIS: With its load characteristics, the team sport of football places high physical demands on players and thus is associated with a high risk of injury. Therefore, the purpose of this study was to collect information about injuries suffered by football players in Austria during training or matches to enable participating clubs to learn about injuries. METHODS: One hundred and forty-five players from seven teams with age ranging from 16 to 38 years participated in this prospective study during the 2015/16 season. Injury surveillance was conducted according to the consensus statement of Fuller et al. (2006). RESULTS: During the period of study, a total of 83 injuries were recorded, which represents an overall incidence of 4.5 injuries/1000 hours (2.3 injuries/1000 hours in training and 14.2 injuries/1000 hours of match play). There was a significant difference for older age in injured players compared to non-injured players (p = 0.019). No differences in BMI were detected (p = 0.427). Ninety-four percent of all injuries occurred in the lower extremity, with the thigh (25.8 %), ankle (19.3 %) and knee (13.3 %) being the major locations of injuries. Muscle tendon injuries were the most common non contact injuries (78.9 %). CONCLUSION: Lower extremity injuries are the most common injury in Austrian football. The incidence of muscle injuries is high, especially injuries of the posterior thigh. There are promising preventive strategies for the most common injury types. The implementation of these strategies is essential in order to reduce the incidence or recurrence of these football injuries. PMID- 29529695 TI - [S2k-Guideline on Meniscal Disease: Non-operative and Surgical Management]. AB - A meniscal injury should not automatically lead to surgery. Even in light of all the developments in arthroscopic surgery, non-operative management still has a place in the treatment algorithms for lesions around the knee. In this second publication of the German guidelines for meniscal surgery, the authors describe the various treatment possibilities, their indications and offer critical insight into the various therapeutic options. This will allow the patient and physician alike to make the proper individual decisions. Various German speaking associations addressing topics surrounding the knee have joined forces to develop these guidelines for meniscal lesions. The hope is that these two publications on the topic will shed light on the ongoing debate and offer some guidance. PMID- 29529696 TI - [Basic Clinical Examination of the Shoulder]. AB - OBJECTIVE: Successful treatment of shoulder disease requires an accurate diagnosis. In addition to differentiated history taking, clinical examination is the most important component in the diagnosis of shoulder diseases. METHOD: The present video explains the common provocation tests and functional tests that are used in the basic clinical examination of the shoulder. In addition to general inspection and palpation, the focus is on different diagnostic tests and clinical signs that improve diagnostic accuracy. CONCLUSION: The present basic clinical examination methods allow a structured approach to clinical issues and can be a good basis, if supplemented by further specific and individual tests. PMID- 29529697 TI - [Basic Clinical Examination of the Knee Joint]. AB - OBJECTIVE: Successful treatment of knee joint disease requires an accurate diagnosis. In addition to a differentiated history, clinical examination is the most important component in the diagnosis of knee joint diseases. METHOD: The present video explains the common provocation and functional tests that are used in the basic clinical examination of the knee joint. In addition to general inspection and palpation, the focus here is on the individual region's patella, menisci, cruciate ligaments and collateral ligaments. CONCLUSION: The present methods of basic clinical examination allow a structured approach to clinical issues and can be a good basis for the diagnosis of knee joint diseases, if supplemented by further specific and individual tests. PMID- 29529698 TI - Successful Treatment of a Child With Generalized Lichen Ruber Planus. PMID- 29529699 TI - ? PMID- 29529700 TI - Articulating Spacers as a Modified One-Stage Revision Total Knee Arthroplasty: A Preliminary Analysis. AB - INTRODUCTION: Periprosthetic joint infection (PJI) following primary total knee arthroplasty (TKA) is a challenging complication for surgeons and patients alike. Although two-stage revision arthroplasty remains the gold standard PJI management in the United States, one-stage revision has had success in many parts of Europe. The aim of this study was to retrospectively review: 1) ultimate treatment success; 2) necessary antibiotic duration; 3) change in knee range of motion (ROM); and 4) final Knee Society Scores (KSS) in a case series of patients managed with retention of articulating antibiotic spacers following PJI. MATERIALS AND METHODS: A retrospective review was performed on all patients treated for chronic PJI after primary TKA with retention of articulating antibiotic spacers at a minimum of one-year follow-up. Descriptive analysis was utilized to evaluate demographic characteristics, discharge destination, follow up and antibiotic durations, Knee Society Score (KSS), and rates of treatment failure. Paired-Samples t-Tests were utilized to evaluate mean changes in flexion and extension between the preoperative and postoperative time periods. RESULTS: Our final cohort included 29 patients who were managed with articulating spacer retention at a mean follow-up of 16.8 (range, 12.0 to 23.1) months, with 21 patients (72.4%) medically unfit for multiple surgeons and eight patients (27.6%) satisfied with their function. Mean age was 61.3 (range, 41 to 85) years and mean Charlson Comorbidity Index (CCI) was 6.1 (mean, 0 to 12). The predominant infecting organism was Methicillin-Resistant Staphylococcus aureus (MRSA), which was involved in eight patients (27.6%). There was a significant increase in postoperative knee flexion (+14.7 degrees ; p<0.001) and no decrease in postoperative knee extension (+2.3 degrees ; p=0.361). Treatment success in our cohort was 79.3% (23 patients), with four patients (13.8%) having chronic wound drainage and two patients (6.9%) requiring multiple spacer exchanges. Sixteen patients (55.2%) were able to complete their antibiotic regimen, with the remaining patients unable to discontinue their antibiotics by latest clinic follow-up. DISCUSSION: One-stage exchange arthroplasty offers the advantage of a single procedure with analogous failure rates compared to two-stage exchange, decreases hospitalization, and improves cost-effectiveness, which is paramount in today's healthcare environment. To our knowledge, this is the first study in the United States to evaluate outcome scores, function, and success rate of a modified one-stage revision TKA technique. Although we are unable to make definitive conclusions based on the small sample size, the outcomes in this study are encouraging. PMID- 29529701 TI - Cost Analysis of All-Polyethylene Compared to Metal-Backed Implants in Total Knee Arthroplasty. AB - INTRODUCTION: The growing trends of total knee arthroplasty (TKA) foreshadow an inevitable increase in the financial burden on healthcare expenditure estimated to almost nine billion dollars annually. This study aims to demonstrate the potential savings when using all-polyethylene (AP) compared to metal-backed (MB) tibial components and describes the cost variability amongst three major commercially available implants. MATERIALS AND METHODS: The cost of AP versus MB implants was analyzed using a large nationwide database, Emergency Care Research Institute (ECRI). Cost of femoral components and patellar buttons were excluded. The three manufacturers included in the study were DePuy, Smith&Nephew, and Stryker (Zimmer data was not available for analysis). RESULTS: Our results show that AP components were significantly less costly in comparison to other manufacturers, and the average AP price was $1,009. The average MB (baseplate plus liner) price was $2,054 (p<0.01). Analysis of variance (ANOVA) of the means of the AP components showed no significant difference in prices among the three studied manufacturers (p=0.946). DISCUSSION: Our results demonstrate that, regardless of the manufacturing company, AP tibial components are significantly cheaper than their MB counterparts. A literature review revealed that, when indicated, AP implants are not inferior to MB in terms of survivorship or outcome. The average savings was more than $1,000 per TKA when multiplied even by a small portion of the large volume of TKAs completed annually. This can translate into millions of dollars in savings in healthcare expenditures. With the impending legislation of the bundled-payment initiative, orthopaedic surgeons should be aware of less costly implant options that can positively impact outcomes and/or quality of care. PMID- 29529702 TI - Complex Fibular Head Avulsion Fracture: Surgical Management of a Case. AB - Fibular head avulsion fractures are rare injuries determined by traction of the fibular attachment of the lateral collateral ligament (LCL). Surgical treatment is often recommended with different techniques such as tension band fixation or lag screws stabilization. In this article, we describe a fixation technique of fibular head fractures obtained through the use of anchors. A 45-year-old athletic patient came to our attention in our traumatologic service after a motorcycle accident. He reported a complex injury of the posterolateral corner with an avulsion fracture of the left fibular head. We performed a clinical evaluation at the final follow-up visit (six months). We demonstrated that the use of suture anchors may be an effective technique of fixation in avulsion fracture of the fibular head associated with combined posterolateral corner injuries. PMID- 29529703 TI - Antimicrobial Efficacy of a Silver Impregnated Hydrophilic PU Foam. AB - A novel hydrophilic polyurethane (PU) foam dressing which is impregnated with silver chloride, Optifoam(r) Gentle (OG) Ag+ (Medline Industries Inc., Chicago, Illinois), was evaluated in this study. The aims of this study were to determine the rate of elution of silver from the foam dressing over a period of 168 hours into simulated wound fluid and an evaluation of antimicrobial efficacy using zone of inhibition (ZOI), direct kill, and time-kill viability. Thirty-two microorganisms associated with wounds including Pseudomonas aeruginosa, Methicillin sensitive Staphylococcus aureus (MSSA), Acinetobacter baumannii, Candida albicans, and antibiotic-resistant strains (Methicillin-resistant S. aureus [MRSA] and Vancomycin-resistant Enterococci [VRE]) were evaluated. Silver release from the wound dressing showed an exponential curve with a stable sustained release of 25ppm achieved after 24 hours, which was maintained for the full duration of the study. OG Ag+ caused inhibition zones ranging from 4-16mm after a 24-hour contact time. In the direct kill assay, OG Ag+ reduced the microbial numbers below the limit of detection and reduced viability by a log of four within 24 hours. For the time-kill viability studies, the results support the use of this hydrophilic polyurethane foam as a wound dressing for use in wounds at risk of infection or infected by achieving a four log kill within six hours and a six log kill in 16 hours. In conclusion, OG Ag+ was shown to be an effective wound dressing in the killing of a range of important opportunistic pathogens of relevance to wound healing and infections. Achieving a six log kill against S. aureus and E.coli, within 16 hours in the time kill assay, (ASTM E2315 03) demonstrates that OG Ag+ should be an important addition to the armoury available for the management of acute and chronic wounds at risk of infection or clinically infected. PMID- 29529704 TI - Early Experience with a Short, Tapered Titanium Porous Plasma Sprayed Stem with Updated Design. AB - INTRODUCTION: Short stem femoral components in primary total hip arthroplasty (THA) have increased in popularity since the advent of minimally invasive surgical techniques. The concept of a short stem is particularly compatible with tapered designs where the goal is to offload forces proximally in the femur. The purpose of this retrospective review was to review our early experience with a short, tapered titanium femoral component with updated design features. MATERIALS AND METHODS: Beginning in November 2011 through February 2012, 92 consented patients (93 hips), at a single center, were treated with primary cementless THA using a short stem, tapered femoral component (Taperloc(r) Complete Microplasty; Zimmer Biomet, Warsaw, Indiana) and were available for review with a minimum two year follow-up. Mean patient age at surgery was 63.2 years and body mass index (BMI) was 30.8 kg/m2. Mean stem length used was 110.3mm (range, 95-125). RESULTS: Mean follow-up was 4.5 years (2-6). Harris hip scores improved from 52.5 preoperatively to 84.7 at most recent. One stem was revised the same day for periprosthetic fracture. One patient with early infection was treated with single stage exchange followed by recurrence that was treated successfully with two stage exchange. A non-healing wound in one patient was treated with incision and debridement. Radiographic assessment demonstrated no evidence of loosening, osteolysis, distal hypertrophy, or pedestal formation in any hip, and all components appeared well fixed and in appropriate alignment. CONCLUSION: In this series of patients treated with primary THA using a short, tapered titanium porous plasma-sprayed femoral component with updated design features, good results were achieved with a low incidence of complications and revision. No aseptic loosening or osteolysis has occurred. Radiographic assessment was excellent for all patients. PMID- 29529705 TI - Video-Assisted Subcutaneous Destruction of the Sinus Tract with Vessel-Loop Drainage as Minimally-Invasive Surgical Treatment for Pilonidal Sinus Disease. AB - The video-assisted subcutaneous destruction of the sinus tract (VADST) is a novel, minimally-invasive technique for the treatment of pilonidal sinus disease (PSD). This is an advancement of the previously described subcutaneous destruction of the sinus tract and the removal of hairs as well as the long-term vessel-loop drainage of the wound channel (DST). Although the first results of this operation seemed to be promising, some of my colleagues felt that the blind approach to this procedure could be its potential "weak point". As a result of this critique, the procedure was enhanced with the subcutaneous video-assisted inspection of the natal cleft. Throughout most steps of VADST, like the widening of pilonidal pits with mosquito and/or Pean clamps, the subcutaneous destroying of the sinus tract, lifting the skin in a natal cleft with a curette, removing the hair with a Pean clamp and a subcutaneous vessel-loop drainage, were found to be similar to DST. The new steps involve the possibility of the video-assisted control of hair vestiges and bleedings as well as the removal of hair and debris under visual control. A rigid choledochoscope from Berci (Firma Richard Wolf GmbH, Knittlingen, Germany) was used for the subcutaneous endoscopic examination of the natal cleft area. Neither gas application nor water perfusion were necessary for this step. Three patients with simple forms of PSD, and one patient with an acute abscess formation, underwent the VADST procedure. The patients with simple forms of PSD had no adverse events during the first eight weeks postoperatively. The patient with an acute abscess formation developed a purulent inflammation that required a wide local excision with an open-wound healing. Due to the very small number of patients in this report, we were not able to asses this technique properly. Contrary to DST, we intend to use VADST, not only for the treatment of patients with simple forms (primary pilonidal sinus without abscessed inflammation with maximal three orifices, all of them inside the navicular area), but also for the treatment of complex PSD forms. PMID- 29529706 TI - Using Multi-Layer Foam Dressing to Prevent Pressure Injury in a Long-Term Care Setting. AB - Maintaining skin integrity is espoused by several international authorities as a benchmark for patient safety and quality of care. National guidelines advocate the use of prophylactic multi-layer foam dressings over bony prominences for the prevention of pressure ulcers or injuries. The purpose of this study was to evaluate the implementation of best practice guidelines including the use of multi-layer foam dressings for the prevention of pressure injuries. The analysis involved data from a total number of 62 unique patients. The incidence rate prior to the implementation of best practices was 5.2%. The incidence after the implementation was 0%. PMID- 29529707 TI - Detectability of fentanyl and designer fentanyls in urine by 3 commercial fentanyl immunoassays. AB - In recent times, structural variants of fentanyl (designer fentanyls) have appeared on the recreational drug market for new psychoactive substances (NPS). These potent opioids have caused harmful intoxications and increased opioid related mortality in many countries. This work evaluated 3 commercial immunoassays for fentanyl screening in urine and investigated whether they are useful also for screening of designer fentanyls. The assays examined were the Thermo DRI(r) Fentanyl Enzyme Immunoassay, the ARKTM Fentanyl Assay homogeneous enzyme immunoassay, and the Immunalysis(r) Fentanyl Urine SEFRIATM Drug Screening Kit. A liquid chromatography-high-resolution mass spectrometry method was used as reference. The DRI fentanyl immunoassay generated somewhat higher assay imprecision values (%CV) compared with the ARKTM and SEFRIATM assays, but all assays showed %CV values acceptable for routine use. The 3 assays showed overall good detectability (33%-95% cross-reactivity) for blank urine samples spiked with acetylfentanyl, acrylfentanyl, butyrfentanyl, 4-chloroisobutyrfentanyl, 4 fluorobutyrfentanyl, 4-fluorofentanyl, 4-fluoroisobutyrfentnyl, isobutyrfentanyl, methoxyacetylfentanyl, or tetrahydrofuranfentanyl, whereas 4-methoxybutyrfentanyl (all assays) and 2-fluorofentanyl (DRI assay) showed low cross-reactivity. A good detectability of designer fentanyls was confirmed in urine samples from authentic acute intoxications. In conclusion, the present results demonstrate that the urinary fentanyl immunoassays are generally useful also for preliminary screening of fentanyl analogs sold as NPS. When the SEFRIATM assay was applied for testing of 980 urine samples from patients treated for drug dependence in Sweden, only 1 sample was confirmed positive for fentanyl. PMID- 29529708 TI - An optimized radiosynthesis of [18 F]FNDP, a positron emission tomography radiotracer for imaging soluble epoxide hydrolase (sEH). AB - In this concise practitioner protocol, the radiochemical synthesis of [18 F]FNDP suitable for human positron emission tomography studies is described and the results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice requirements. PMID- 29529710 TI - Five criteria for using a surrogate endpoint to predict treatment effect based on data from multiple previous trials. PMID- 29529711 TI - Developing points-based risk-scoring systems in the presence of competing risks. PMID- 29529709 TI - A validated LC-MS/MS method for the simultaneous determination of thalidomide and its two metabolites in human plasma: Application to a pharmacokinetic assay. AB - An accurate and sensitive LC-MS/MS method for determining thalidomide, 5-hydroxy thalidomide and 5'-hydroxy thalidomide in human plasma was developed and validated using umbelliferone as an internal standard. The analytes were extracted from plasma (100 MUL) by liquid-liquid extraction with ethyl acetate and then separated on a BETASIL C18 column (4.6 * 150 mm, 5 MUm) with mobile phase composed of methanol-water containing 0.1% formic acid (70:30, v/v) in isocratic mode at a flow rate of 0.5 mL/min. The detection was performed using an API triple quadrupole mass spectrometer in atmospheric pressure chemical ionization mode. The precursor-to-product ion transitions m/z 259.1 -> 186.1 for thalidomide, m/z 273.2 -> 161.3 for 5-hydroxy thalidomide, m/z 273.2 -> 146.1 for 5'-hydroxy thalidomide and m/z 163.1 -> 107.1 for umbelliferone (internal standard, IS) were used for quantification. The calibration curves were obtained in the concentrations of 10.0-2000.0 ng/mL for thalidomide, 0.2-50.0 ng/mL for 5 hydroxy thalidomide and 1.0-200.0 ng/mL for 5'-hydroxy thalidomide. The method was validated with respect to linear, within- and between-batch precision and accuracy, extraction recovery, matrix effect and stability. Then it was successfully applied to estimate the concentration of thalidomide, 5-hydroxy thalidomide and 5'-hydroxy thalidomide in plasma samples collected from Crohn's disease patients after a single oral administration of thalidomide 100 mg. PMID- 29529712 TI - New research strategy with ambiguous implications: A comment on "Planning future studies based on the conditional power of a meta-analysis". PMID- 29529713 TI - Routine screening and related interventions significantly improve the effectiveness of emergency department detection and management of alcohol withdrawal syndrome. AB - OBJECTIVE: To evaluate the effectiveness of a routine screening and triage tool for alcohol withdrawal syndrome (AWS) in improving clinical care delivery in an ED setting. METHODS: In a regional ED in Australia, a screening and triage tool for AWS was introduced to routine ED assessment for a 13 week period. Subjects were all presentations to ED aged 16 and above with relevant presenting problems during the pre-intervention phase (1 January 2015-31 December 2016) and the post intervention phase (8 August 2016-4 November 2016). Key clinical care delivery elements related to AWS in patients presenting to ED were compared pre- and post intervention, namely proportion of presentations: (i) meeting criteria for AWS; (ii) receiving appropriate management for AWS; and (iii) with alcohol documentation in patient notes. RESULTS: A total of 5.8% of total ED presentations in the post-intervention phase and 4.5% in the pre-intervention 1 year phase had relevant presenting problems. Compared to the 1 year pre intervention phase, post-intervention showed: (i) a significant decrease in the number of presentations meeting criteria for AWS (chi2 = 6.56, P = 0.01); (ii) a significant increase in appropriate management of AWS (chi2 = 17.09, P < 0.001); and (iii) a significant increase in alcohol documentation in notes (chi2 = 13.29, P < 0.001). CONCLUSIONS: Detection and appropriate management of AWS and documentation of alcohol use can be improved significantly through adoption of a brief screening and triage tool, and related interventions to increase awareness of alcohol-related problems. PMID- 29529714 TI - Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas. AB - BACKGROUND: Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population. METHODS: DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families. RESULTS: Germline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were "loss-of-function" and two novel hotspots in EXT2 gene were observed in our study. CONCLUSION: The prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil. PMID- 29529715 TI - Interventions for preventing high altitude illness: Part 2. Less commonly-used drugs. AB - BACKGROUND: High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (~ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this second review, in a series of three about preventive strategies for HAI, we assessed the effectiveness of five of the less commonly used classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of five of the less commonly used pharmacological interventions for preventing acute HAI in participants who are at risk of developing high altitude illness in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in May 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials. SELECTION CRITERIA: We included randomized controlled trials conducted in any setting where one of five classes of drugs was employed to prevent acute HAI: selective 5-hydroxytryptamine(1) receptor agonists; N-methyl-D-aspartate (NMDA) antagonist; endothelin-1 antagonist; anticonvulsant drugs; and spironolactone. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with and without a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent or after ascent. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures employed by Cochrane. MAIN RESULTS: We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full-text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias.We report results for the following four main comparisons.Sumatriptan versus placebo (1 parallel study; 102 participants)Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan.Magnesium citrate versus placebo (1 parallel study; 70 participants)The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE.Spironolactone versus placebo (2 parallel studies; 205 participants)Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I2 = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.Acetazolamide versus spironolactone (1 parallel study; 232 participants)Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. AUTHORS' CONCLUSIONS: This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review. PMID- 29529716 TI - Cross-linked peptide identification: A computational forest of algorithms. AB - Chemical cross-linking analyzed by mass spectrometry (XL-MS) has become an important tool in unravelling protein structure, dynamics, and complex formation. Because the analysis of cross-linked proteins with mass spectrometry results in specific computational challenges, many computational tools have been developed to identify cross-linked peptides from mass spectra and subsequently interpret the identified cross-links within their structural context. In this review, we will provide an overview of the different tools that are currently available to tackle the computational part of an XL-MS experiment. First, we give an introduction on the computational challenges encountered when processing data from a cross-linking experiment. We then discuss available tools to identify peptides that are linked by intact or MS-cleavable cross-linkers, and we provide an overview of tools to interpret cross-linked peptides in the context of protein structure. Finally, we give an outlook on data management and dissemination challenges and opportunities for cross-linking experiments. PMID- 29529717 TI - Femtosecond laser eraser for controllable removing periodic microstructures on Fe based metallic glass surfaces. AB - Using two beams of femtosecond laser pulses linearly polarized in different directions, we demonstrate a new phenomenon of eliminating the periodic subwavelength surface structures recorded on Fe-based metallic glass. It is found that such femtosecond laser erasing process can be efficiently controlled by varying the temporal delay between two laser beams while maintaining the amorphous properties of the sample surface. The underlying mechanisms are substantially attributed to the transient enhancement of the surface mobility of the sample by two laser-matter interactions. These investigations may be helpful in high precision manipulation of the material surface for rewritable applications. PMID- 29529718 TI - High efficiency ultraviolet GaN-based vertical light emitting diodes on 6-inch sapphire substrate using ex-situ sputtered AlN nucleation layer. AB - We demonstrated the growth of crack-free high-quality GaN-based UV vertical LEDs (VLEDs) (lambda = 365 nm) on 6-inch sapphire substrates by using an ex-situ sputtered AlN nucleation layer (NL) and compared their performance with that of UV VLEDs with an in situ low temperature (LT) AlGaN NL. The X-ray diffraction (XRD) results showed that the ex-situ AlN sample contained lower densities of screw-type and edge-type threading dislocations than the in situ AlGaN NL sample. The micro-Raman results revealed that the ex-situ AlN sample was under more compressive stress than the in situ AlGaN sample. As the current was increased, the electroluminescence peaks of both of the samples blue-shifted, reached a minimum wavelength at 1000 mA, and then slightly red-shifted. Packaged VLEDs with the ex-situ AlN NL yielded 6.5% higher light output power at 500 mA than that with the in situ AlGaN NL. The maximum EQEs of the VLED with the in situ AlGaN and ex-situ AlN NLs were 43.7% and 48.2%, respectively. Based on the XRD and Raman results, the improved light output power of the ex-situ AlN sample is attributed to the lower density of TDs. PMID- 29529719 TI - Nanoscale orbital angular momentum beam instabilities in engineered nonlinear colloidal media. AB - Colloidal media with well-defined optical properties have been widely used as model systems in many fundamental and applied studies of light-matter interactions in complex media. Recent progress in the field of engineered nanoscale optical materials with fundamentally new physical properties opens new opportunities for tailoring the properties of colloids. In this work, we experimentally demonstrate the evolution of the optical vortex beams of different topological charges propagating in engineered nano-colloidal suspension of negative polarizability with saturable nonlinearities. Due to the high power of the incident beam, the modulation instability leads to an exponential growth of weak perturbations and thus splits the original vortex beam into a necklace beam consisting of several bright spots. At a fixed power, the number of observed bright spots is intrinsically determined by the topological charge of the incident beam and agrees well with the predictions of our linear stability analysis and numerical simulations. Besides contributing to the fundamental science of light-matter interactions in engineered soft-matter media, this work opens new opportunities for dynamic optical manipulation and transmission of light through scattering media as well as formation of complex optical patterns and light filamentation in naturally existing colloids such as fog and clouds. PMID- 29529720 TI - Brillouin optical time domain analyzer sensors assisted by advanced image denoising techniques. AB - We have experimentally analyzed and compared the performance of Brillouin optical time-domain analyzer (BOTDA) sensors assisted by non-local means (NLM) and wavelet denoising (WD) techniques in terms of measurement accuracy and experimental spatial resolution, respectively. Degradation of the measurement accuracy and experimental spatial resolution after denoising by NLM and WD are observed, which originate from the fact that higher signal-to-noise ratio (SNR) improvement is achieved at the expense of sacrificing the details of BOTDA data, and smaller data sampling point number (SPN) gives rise to insufficient redundant information for denoising. The two parameters degrade to different extents depending on the amount of SNR improvement and SPN adopted in data acquisition. Compared with WD, NLM relies more on the features of the raw data, which makes its performance highly dependent on the level of neighbouring data similarity. Also, for the first time we propose and demonstrate a BOTDA assisted by advanced Block-Matching and 3D filtering (BM3D) denoising technique, which minimizes the degradation of the two parameters even under higher SNR improvement and smaller SPN. BM3D takes the advantage of NLM and WD and utilizes the spatial-domain non local principle to enhance the denoising in the transform domain, thus it shows the least degradation of measurement accuracy/experimental spatial resolution after denoising. Thus the BOTDA assisted by BM3D maintains the best measurement accuracy/experimental spatial resolution compared with those by NLM and WD. We also show that BM3D has the advantage of temperature independent performance, unlike NLM where the accuracy is affected by the temperature value. We believe BM3D would be an excellent denoising technique for state-of-the-art BOTDA sensors. In addition, this work is also valuable for practical applications of image denoising techniques in BOTDA sensors with respect to the appropriate choice of image denoising techniques, design of SNR improvement and the adoption of SPN to maintain optimal measurement accuracy/experimental spatial resolution/data acquisition speed. PMID- 29529721 TI - 2-GHz carbon nanotube mode-locked Yb:YAG channel waveguide laser. AB - We demonstrate GHz-repetition rate mode-locked operation of a femtosecond-laser inscribed Yb:YAG channel waveguide laser using single-walled carbon nanotube saturable absorber mirror (SWCNT-SAM). A 6.3-mm-long, type II Yb:YAG waveguide laser with an extended cavity configuration delivers mode-locked picosecond (ps) pulses at GHz repetition rates. The dispersion of the laser cavity is compensated by the combination of a multi-functional output coupler and the Gires-Tournois interferometer (GTI) effect arising from an air-gap between the facet of the waveguide and the output coupler. The incident beam fluence on the SWNCNT-SAM is controlled by adjusting two intracavity lenses to avoid optical damage on the polymer nanocomposite matrix containing the SWCNTs. The average output power of our mode-locked waveguide laser is 322 mW at a pump power of 3.2 W. Nearly Fourier-limited, stable 2-ps-short pulses are generated at a repetition rate of 2.08 GHz. PMID- 29529722 TI - Orientation-insensitive azimuthally asymmetric mode rotator using chirally coupled-core fiber. AB - We propose orientation-insensitive azimuthally asymmetric mode rotators (OI-AAMR) using chirally-coupled-core fiber. The proposed mode rotator can convert azimuthally asymmetric mode to the orthogonal degenerate mode without the requirement for angle alignment. An LP11 mode rotator with a rotation efficiency and an extinction ratio as high as 97% and 17 dB over C-band respectively, has been successfully demonstrated for any incident lobe orientation for the first time to the best of our knowledge. Owing to its circular center core structure, low insertion loss and crosstalk at the connection with few-mode fibers (FMF) can be expected. The proposed OI-AAMR has good scalability to higher-order modes and a mode rotator for LP21 mode has been demonstrated as an example. The proposed mode rotators are promising for mode rotating applications in mode division multiplexing transmission. PMID- 29529723 TI - Long-wave infrared picosecond parametric amplifier based on Raman shifter technology. AB - A new method for a long-wave infrared (LWIR), picosecond difference frequency generation (DFG) source using one near-infrared laser and a Raman shifter is experimentally tested and characterized. The signal seed for DFG is a Stokes pulse generated via transient stimulated Raman scattering in a nonlinear medium with a Raman frequency in the 2-20 um range. A study of the dynamics of the transient Raman regime in liquid C6D6 has shown that the efficiency of Stokes production can be increased and the central wavelength can be controlled by chirping the pump pulse in order to compensate for chirping caused by self-phase modulation. High energy, >=3 uJ, picosecond pulses at 10.6 um have been generated in a GaSe crystal pumped by 1 mJ pulses of 1060 nm light from a Nd:glass laser. PMID- 29529724 TI - Novel approach to improve the attitude update rate of a star tracker. AB - The star tracker is widely used in attitude control systems of spacecraft for attitude measurement. The attitude update rate of a star tracker is important to guarantee the attitude control performance. In this paper, we propose a novel approach to improve the attitude update rate of a star tracker. The electronic Rolling Shutter (RS) imaging mode of the complementary metal-oxide semiconductor (CMOS) image sensor in the star tracker is applied to acquire star images in which the star spots are exposed with row-to-row time offsets, thereby reflecting the rotation of star tracker at different times. The attitude estimation method with a single star spot is developed to realize the multiple attitude updates by a star image, so as to reach a high update rate. The simulation and experiment are performed to verify the proposed approaches. The test results demonstrate that the proposed approach is effective and the attitude update rate of a star tracker is increased significantly. PMID- 29529725 TI - Investigation of channel model for weakly coupled multicore fiber. AB - We investigate the evolution of the decorrelation bandwidth of intercore crosstalk (IC-XT) based on the modified mode-coupled equations (MCEs) in homogeneous weakly coupled multicore fibers (WC-MCFs). The modified MCEs are numerically solved by combining the fourth order Runge-Kutta method with the compound Simpson integral method. It can be theoretically and numerically observed that the decorrelation bandwidth of IC-XT decreases with transmission distance by fractional linear function. The evolution rule of IC-XT's decorrelation bandwidth is further confirmed by experiments, which can be used as an evaluation criterion for the channel model. Finally, we propose a new channel model with the coupling matrix of IC-XT generated directly from the phase transfer function (PTF), which is in good agreement with the above evaluation criterion. We believe the proposed channel model can provide a good simulation platform for homogeneous WC-MCF based communication systems. PMID- 29529726 TI - Multi-frame linear regressive filter for the measurement of infrared pixel spatial response and MTF from sparse data. AB - A challenging point in the prediction of the image quality of infrared imaging systems is the evaluation of the detector modulation transfer function (MTF). In this paper, we present a linear method to get a 2D continuous MTF from sparse spectral data. Within the method, an object with a predictable sparse spatial spectrum is imaged by the focal plane array. The sparse data is then treated to return the 2D continuous MTF with the hypothesis that all the pixels have an identical spatial response. The linearity of the treatment is a key point to estimate directly the error bars of the resulting detector MTF. The test bench will be presented along with measurement tests on a 25 MUm pitch InGaAs detector. PMID- 29529727 TI - Phase measurement of a segmented wave front using PISton and TILt interferometry (PISTIL). AB - New architectures for telescopes or powerful lasers require segmented wave front metrology. This paper deals with a new interferometric wave front sensing technique called PISTIL (PISton and TILt), able to recover both piston and tilts of segment beams. The main advantages of the PISTIL technique are the absence of a reference arm and an access to the tilt information. An explanation of the principle, as well as an experimental implementation and the use of a segmented active mirror, are presented. Measurement errors of lambda/200 for piston and 40 urad for tilts have been achieved, well beyond performances requested for the above mentioned applications. PMID- 29529728 TI - Compressive optical interferometry under structural constraints. AB - Compressive sensing (CS) combines data acquisition with compression coding to reduce the number of measurements required to reconstruct a sparse signal. In optics, this usually takes the form of projecting the field onto sequences of random spatial patterns that are selected from an appropriate random ensemble. We show here that CS can be exploited in 'native' optics hardware without introducing added components. Specifically, we show that random sub-Nyquist sampling of an interferogram suffices to reconstruct the field modal structure despite the structural constraints of the measurement system set by its limited degrees of freedom. The distribution of the reduced (and structurally constrained) sensing matrices corresponding to random measurements is provably incoherent and isotropic, which helps us carry out CS successfully. We implement compressive interferometry using a generalized Mach-Zehnder interferometer in which the traditional temporal delay is replaced with a linear transformation corresponding to a fractional transform. By randomly sampling the order of the fractional transform, we efficiently reconstruct the modal content of the input beam in the Hermite-Gaussian and Laguerre-Gaussian bases. PMID- 29529729 TI - In situ 3-D temperature mapping of high average power cryogenic laser amplifiers. AB - Heat generation is a key obstacle to scaling high energy solid-state lasers to the multi-kilowatt average powers required for several key applications. We demonstrate an accurate, in situ, noninvasive optical technique to that makes three-dimensional (3-D) temperature maps within cryogenic amplifiers operating at high average power. The temperature is determined by analyzing the fluorescence spectra with a neural network function. The accuracy of the technique relies on a calibration that does not depend on simulations. Results are presented for a cryogenic Yb:YAG active mirror laser amplifier operating at different pump conditions. The technique is applicable to other solid-state lasers materials. PMID- 29529730 TI - Bistable enhanced total reflection in Kretschmann configuration containing a saturable gain medium. AB - The reflection of a TM-polarized light beam from a Kretschmann configuration with a saturable gain medium is investigated theoretically. Here, the dielectric constant of the gain medium is described by a classical Lorentzian oscillator model. When surface plasmon polaritons are effectively excited in this structure, it is demonstrated that the curves of enhanced total reflection (ETR) show different shaped hysteresis loops associated with optical bistability owing to gain saturation effect. The effects of the angle of incidence, the thickness of metal film, and the value of small-signal gain on bistable ETR are discussed in detail in a homogeneously broadened (HB) gain medium at line center. Analogous results can also be obtained in an inhomogeneously broadened (inHB) gain medium, while the two switch thresholds and the width of optical bistability hysteresis in an inHB gain medium are significantly different from those in a HB gain medium. PMID- 29529731 TI - Investigation on strain relaxation distribution in GaN-based MULEDs by Kelvin probe force microscopy and micro-photoluminescence. AB - GaN/InGaN multi-quantum-wells (MQWs) micron light emitting diodes (uLEDs) with the size ranging from 10 to 300 um are fabricated. Effects of strain relaxation on the performance of uLEDs have been investigated both experimentally and numerically. Kelvin probe force microscopy (KPFM) and micro-photoluminescence (uPL) are used to characterize the strained area on micron pillars. Strain relaxation and reducing polarization field in MQWs almost affects the whole mesa for 10 um LEDs and about 4% area around the lateral for 300 um LEDs. It makes a great contribution to high performance for smaller size uLEDs. Moreover, an indirect nanoscale strain measurement for uLEDs are provided. PMID- 29529732 TI - High order cascaded Raman random fiber laser with high spectral purity. AB - An up to 8th order cascaded Raman random fiber laser with high spectral purity is achieved with the pumping of a narrow linewidth amplified spontaneous emission source. The spectral purity is over 90% for all the 8 Stokes orders. The highest output power is 6.9 W at 1691.6 nm with an optical conversion efficiency of 21% from 1062.0 nm. As a comparison, with conventional FBG-based fiber oscillator as pump source, only 47% spectral purity is achieved at 8th order. The temporal stability of the pump laser is proved to play a key role, because the time fluctuation of pump laser is transferred directly to Raman outputs and results in power distribution among different Stokes orders. PMID- 29529733 TI - Dynamically reconfigurable holographic metasurface aperture for a Mills-Cross monochromatic microwave camera. AB - We present a reconfigurable, dynamic beam steering holographic metasurface aperture to synthesize a microwave camera at K-band frequencies. The aperture consists of a 1D printed microstrip transmission line with the front surface patterned into an array of slot-shaped subwavelength metamaterial elements (or meta-elements) dynamically tuned between "ON" and "OFF" states using PIN diodes. The proposed aperture synthesizes a desired radiation pattern by converting the waveguide-mode to a free space radiation by means of a binary modulation scheme. This is achieved in a holographic manner; by interacting the waveguide-mode (reference-wave) with the metasurface layer (hologram layer). It is shown by means of full-wave simulations that using the developed metasurface aperture, the radiated wavefronts can be engineered in an all-electronic manner without the need for complex phase-shifting circuits or mechanical scanning apparatus. Using the dynamic beam steering capability of the developed antenna, we synthesize a Mills-Cross composite aperture, forming a single-frequency all-electronic microwave camera. PMID- 29529734 TI - Refractive-index-modified-dot Fabry-Perot fiber probe fabricated by femtosecond laser for high-temperature sensing. AB - An optical fiber Fabry-Perot probe sensor for high-temperature measurement is proposed and demonstrated, which is fabricated by inducing a refractive-index modified-dot (RIMD) in the fiber core near the end of a standard single mode fiber (SMF) using a femtosecond laser. The RIMD and the SMF end faces form a Fabry-Perot interferometer (FPI) with a high-quality interference fringe visibility (>20dB). As a high-temperature sensor, such an FPI exhibits a sensitivity of 13.9pm/ degrees C and 18.6pm/ degrees C in the range of 100-500 degrees Cand 500-1000 degrees C,respectively. The fabrication process of this device is quite straightforward, simple, time saving, and the sensor features small size, ease of fabrication, low cost, assembly-free, good mechanical strength, and high linear sensitivity. PMID- 29529735 TI - Escape from an Optoelectronic Tweezer Trap: experimental results and simulations. AB - Optoelectronic tweezers (OET) are a microsystem actuation technology capable of moving microparticles at mm s-1 velocities with nN forces. In this work, we analyze the behavior of particles manipulated by negative dielectrophoresis (DEP) forces in an OET trap. A user-friendly computer interface was developed to generate a circular rotating light pattern to control the movement of the particles, allowing their force profiles to be conveniently measured. Three dimensional simulations were carried out to clarify the experimental results, and the DEP forces acting on the particles were simulated by integrating the Maxwell stress tensor. The simulations matched the experimental results and enabled the determination of a new "hopping" mechanism for particle-escape from the trap. As indicated by the simulations, there exists a vertical DEP force at the edge of the light pattern that pushes up particles to a region with a smaller horizontal DEP force. We propose that this phenomenon will be important to consider for the design of OET micromanipulation experiments for a wide range of applications. PMID- 29529736 TI - Parametric numerical study of the modulation transfer function in small-pitch InGaAs/InP infrared arrays with refractive microlenses. AB - We report on the modulation transfer function (MTF) in short-wave infrared indium gallium arsenide (InGaAs) on indium phosphide (InP) planar photodetector arrays. Our two-dimensional numerical method consists of optical simulations using the finite-difference time domain method and drift-diffusion simulations using the finite-element method. This parametric study investigates MTF dependence on pitch, the addition of refractive microlenses, the thickness of the InGaAs absorber, and the doping concentration of the InGaAs absorber. A focus is placed on the connection between the lateral diffusion of photogenerated holes in InGaAs and the MTF. It is found that the MTF of small-pitch arrays exhibit sub-ideal behavior due to pixel cross-talk resulting from a long minority carrier diffusion length. By incorporating monolithic microlenses with the InP substrate, the MTF response is improved for all pitches investigated, particularly for spatial frequencies near the respective cutoff frequencies. We also find a strong dependence of the MTF on the thickness and doping concentration in the absorbing region. Trends in dark current and quantum efficiency are reported. PMID- 29529737 TI - Superresolution reflection microscopy via absorbance modulation: a theoretical study. AB - Absorbance modulation enables lateral superresolution in optical lithography and transmission microscopy by generating a dynamic aperture within a photochromic absorbance-modulation layer (AML) coated on a substrate or a specimen. The applicability of this concept to reflection microscopy has not been addressed so far, although reflection imaging exhibits the important ability to image a wide range of samples, transparent or opaque, dielectric or metallic. In this paper, a simulation model for absorbance-modulation imaging (AMI) in confocal reflection microscopy is presented and it is shown that imaging well beyond the diffraction limit is feasible. In addition, we derive analytical design equations and estimate the dependence of the achievable resolution and pixel dwell time on relevant parameters, such as the AML properties and the applied light powers. We prove the validity of these equations through a comparison with the simulation results and we show that a resolution enhancement down to 1/5 of the diffraction limit is possible. PMID- 29529738 TI - VO2 as a natural optical metamaterial. AB - VO2 is a unique phase change material with strongly anisotropic electronic properties. Recently, samples have been prepared that present a co-existence of phases and thus form metal-insulator junctions of the same chemical compound. Using first principles calculations, the optical properties of metallic and semiconducting VO2 are here discussed to design self-contained natural optical metamaterials, avoiding coupling with other dielectric media. The analysis of the optical properties complements the experiments in the description of the vast change in reflectance and metallicity for both disordered and planar compounds. The present results also predict the possibility to realize ordered VO2 junctions operating as efficient hyperbolic metamaterials in the THz-visible range, by simply adjusting the ratio between metallic and insulating VO2 content. The possibility to excite propagating volume plasmom polariton across the metamaterial is finally discussed. PMID- 29529739 TI - Terahertz frequency modulated continuous wave imaging advanced data processing for art painting analysis. AB - Reflection terahertz frequency modulated continuous waves scanner (300 GHz) has been proficiently optimized for imaging two easel paintings of different age. The information content of the obtained THz images has been fully inspected by selecting the appropriate THz image parameter. At the same time, a new data processing has been developed for improving the level of detail held by the axial parametric THz images by means of Gaussian fit of the reflected signals. By carefully weighting the reflected signals as a function of the optical path, the reflected amplitude has been corrected for the positioning of the object surface with respect to the beam focal point. The artifact affecting the THz images recorded from an uneven painting surface have been resolved and the obtained images fairly represent to the original painting. PMID- 29529740 TI - Widely tunable, efficient 2 MUm laser in monocrystalline Tm3+:SrF2. AB - We report on the growth, spectroscopy, and laser operation of monocrystalline Tm3+:SrF2. Spectroscopic investigations confirmed the presence of broad absorption and emission bands caused by inequivalent doped sites, introduced by charge compensation effects which also caused the clusterization of doping ions in the lattice. We obtained continuous-wave laser emission at about 2 MUm, with efficiencies comparable with other Tm-doped crystals. We also achieved an uninterrupted tuning range of 180 nm between 1.8 and 2 MUm. This characterization indicates that SrF2 enhances the cooperative mechanisms between Tm ions, helping to obtain remarkable laser performances at low doping concentrations. PMID- 29529741 TI - Speckle reduction method for image-based coherent stereogram generation. AB - We propose a speckle noise reduction method for generation of coherent holographic stereograms. The method employs densely sampled light field (DSLF) of the scene together with depth information acquired for each ray in the captured DSLF. Speckle reduction is achieved based on the ray separation technique where the scene is first described as a superposition of sparse sets of point sources corresponding to separated sets of rays and then the holographic reconstructions corresponding to these sparse sets of point sources are added incoherently (intensity-wise) to obtain the final reconstruction. The proposed method handles the light propagation between the sparse scene points and hologram elements accurately by utilizing ray resampling based on the notion of DSLF. As a result, as demonstrated via numerical simulations, significant speckle suppression is achieved at no cost of sampling related reconstruction artifacts. PMID- 29529742 TI - Silicon photonic dual-drive MIM based 56 Gb/s DAC-less and DSP-free PAM-4 transmission. AB - We report two designs of silicon photonic dual-drive Michelson interferometric modulators (MIMs) suitable for four-level pulse amplitude modulation (PAM-4) that do not require digital-to-analog converters or digital signal processing. The PN junctions in MIM-1 have an asymmetric geometry and 4 doping concentrations, while those in MIM-2 have a symmetric geometry and 6 doping concentrations. We simulate and experimentally demonstrate that MIM-2 has a larger modulation efficiency and a better electro-optic (EO) bandwidth than MIM-1. The measured VpiLpi of MIM-2 at -2 V bias is 0.8 V-cm, and the measured 3-dB EO bandwidth at 0 V bias is 9.3 GHz. By carefully choosing the bias conditions of the device and the driving binary radio-frequency signals applied on each phase shifter, PAM-4 signals with even spacings are generated. Successful 56 Gb/s PAM-4 transmission over 2 km of standard single mode fiber is presented, with an estimated bit error rate below the hard-decision forward error correction threshold of 3.8 * 10-3. PMID- 29529743 TI - Hybrid graphene/GaN ultraviolet photo-transistors with high responsivity and speed. AB - In this work, we explore the possibility of using hybrid graphene/GaN phototransistors to get high responsivity, high speed, and large photosensitive area. The responsivity of our hybrid graphene/GaN phototransistors with a relatively large 15.2 mm2 active area reaches 361 mA/W at 10 V and the response time is ~5 ms, much better performance than traditional GaN photodetectors. This is because graphene acts as the carrier transport channel with a high mobility and greatly increases the charge collection efficiency. Our results should shed more light on the role of graphene in hybrid phototransistors and open a feasible pathway to develop large area ultraviolet photodetectors with high responsivity and high speed. PMID- 29529744 TI - Effects of water-absorption and thermal drift on a polymeric photonic crystal slab sensor. AB - A photonic crystal slab (PCS) sensor is a universal refractive index sensor with possibilities and performance very similar to surface plasmon resonance (SPR), which represents the gold standard of biosensing. Cheap PCS sensors can be made vacuum-free entirely out of polymers, but come with additional challenges, besides those relating to temperature-variations, which must be considered in any refractive index based method: The polymeric waveguide core was found to swell by ~0.3% as water absorbed into the waveguide core over ~1.5 h. This was investigated by monitoring the wavelength of resonant reflection during absorption, by monitoring the release of water using ellipsometry, and by rigorous coupled-wave analysis (RCWA). The approach presented here enables monitoring of water uptake and thermal fluctuations, for drift-free, high performance operation of a polymeric PCS sensor. PMID- 29529745 TI - Magnified Image Spatial Spectrum (MISS) microscopy for nanometer and millisecond scale label-free imaging. AB - Label-free imaging of rapidly moving, sub-diffraction sized structures has important applications in both biology and material science, as it removes the limitations associated with fluorescence tagging. However, unlabeled nanoscale particles in suspension are difficult to image due to their transparency and fast Brownian motion. Here we describe a novel interferometric imaging technique referred to as Magnified Image Spatial Spectrum (MISS) microscopy, which overcomes these challenges. The MISS microscope provides quantitative phase information and enables dynamic light scattering investigations with an overall optical path length sensitivity of 0.95 nm at 833 frames per second acquisition rate. Using spatiotemporal filtering, we find that the sensitivity can be further pushed down to 10-3-10-2 nm. We demonstrate the instrument's capability through colloidal nanoparticle sizing down to 20 nm diameter and measurements of live neuron membrane dynamics. MISS microscopy is implemented as an upgrade module to an existing microscope, which converts it into a powerful light scattering instrument. Thus, we anticipate that MISS will be adopted broadly for both material and life sciences applications. PMID- 29529746 TI - Wavenumber synthesis approach to high-resolution wavenumber scanning interference using a mode-hoped laser. AB - A new method for the synthesis of wavenumber series before and after mode hopping is proposed for depth-resolved wavenumber scanning interferometry. The classical Fourier transform is not suitable for mode hopping; consequently, the wavenumber scanning range of diode lasers is rather narrow, reducing the depth resolution and measurement accuracy. We show that the discontinuity in wavenumber domain interferograms caused by mode hopping can be removed by introducing the phase compensation of the interference spectrum. Thus, the wavenumber series before and after mode hopping can be synthesized. Experiments and numerical simulations validate the proposed method, and the measurement error is within 5nm. PMID- 29529747 TI - Electrically controlled enhancement in plasmonic mid-infrared photodiode. AB - Surface plasmon polaritons (SPPs) have been attracting tremendous attention in application of enhanced optoelectronic devices owing to their capability of localizing electromagnetic waves in deep subwavelength scale. We propose a plasmonic mid-infrared InAsSb-based n-i-p photodiode with electrically-controlled photocurrent enhancement achieved by controlling the overlap between SPP depth and the absorption layer, from which maximum electrically controlled enhancement factors of ~5x and ~6x have been achieved for room temperature (293 K) and 77 K operation, respectively, corresponding to electrical tuning factors of 11.9 and 26. The maximum detectivities obtained at the two temperatures are 0.8 * 1010 Jones and 5 * 1011 Jones, respectively. This electrically controlled enhancement expands the application capability of plasmonic photodiodes. PMID- 29529748 TI - Polarization-based dynamic manipulation of Bessel-like surface plasmon polaritons beam. AB - Taking advantage of the phase modulation of surface plasmon polaritons (SPPs) generated by subwavelength slits, we elaborately designed an axicon-shaped slit array to dynamically manipulate the profiles of Bessel-like SPPs beams by changing the polarization of the incident light. As the polarization direction of linearly polarized light changes from horizontal to vertical, the profile of SPPs beam will evolve from the zeroth-order Bessel function to the first-order Bessel function. For circularly polarized light, the geometry Pancharatnam-Berry (PB) phase is introduced and can lead to the transverse shift of the main lobe of SPPs beam. The evolution of the beam profile and the distance of the transverse shift are theoretically illustrated by analyzing the phase distribution of SPPs. The proposed versatile approach suggests charming applications including on-chip communications, polarization-controlled particle manipulation and the design of polarization-based dynamic SPPs devices. PMID- 29529749 TI - Biaxial hyperbolic metamaterials using anisotropic few-layer black phosphorus. AB - Most of hyperbolic metamaterials (HMMs) investigated to date are based on isotropic materials resulting in uniaxial HMMs in which dielectric permittivities perpendicular to the propagation direction are the same. Using an anisotropic material constituent to form a HMM is a promising research direction providing opportunities to control the dielectric permittivity in all three directions independently. Herein, we propose and theoretically demonstrate novel biaxial HMMs composed of multilayer stacks of few-layer black phosphorus (BP) and Au thin films. Black phosphorus is an anisotropic material exhibiting crystal axis dependent dielectric permittivity due to its puckered crystal structure. The proposed HMM provides previously unattained hyperbolic dispersion relations in which the dielectric permittivity in Z-direction of the structure shows opposite sign from that in X- and Y-directions in the most wavelengths from 400~900nm. Furthermore, we calculated the Purcell factor of the proposed biaxial HMMs using full-field electromagnetic simulations. PMID- 29529750 TI - Distortion optimization for wide-angle computational cameras. AB - An imaging system design procedure for miniature wide-angle computational cameras with subsequent software correction of distortion is described. Such miniature wide-angle computational cameras have a broad range of applications, including eye-tracked extraocular cameras for retinal prostheses, and also wearable visual aids for the blind and those with low vision. As significant (typically barrel) distortion is commonplace in wide-field-of-view imaging systems, digital post processing is often employed to generate rectilinear output images. Relaxation of the constraint on distortion during the optical system design process is shown to allow for improved optimization of other image-degrading aberrations. Analysis of the effects of distortion on the software-corrected final image during optical design is accomplished by using comprehensive image quality metrics such as the correlation coefficient and the spatial frequency response. Selection of a surprisingly large exact initial distortion value as a constraint allows for the design of a miniature wide-angle imaging system that yields significantly enhanced final image quality. PMID- 29529751 TI - Tunable terahertz/infrared coherent perfect absorption in a monolayer black phosphorus. AB - Black phosphorus (BP), a promising new two-dimensional (2D) material, has drawn a lot of attentions in academia and industry due to its extraordinary physical and chemical properties. In this paper, we theoretically demonstrate a monolayer BP that achieves coherent perfect absorption (CPA) at the THz/infrared band. It is found that quasi-CPA point does exist at the THz/infrared band. The CPA, which has a relative bandwidth of 141.3% and a coherent absorptivity of more than 90%, can be implemented at the quasi-CPA wavelength through a proper phase modulation. Moreover, the coherent absorptivity can be modulated with a high modulation depth by means of the phase difference between the two coherent counter-propagating beams. The angular selectivity of the monolayer BP is also investigated. The CPA wavelength is divided into two wavelength branches for TE and TM polarization at oblique incidence. In addition, the CPA wavelength can be tuned from THz to infrared band by adjusting the electron doping of the BP while maintaining the modulation depth of 104. Hence, our results may be potentially used for coherent modulations in terahertz/infrared detections and signal processing with 2D materials. PMID- 29529752 TI - Beam quality measurement of a static-cell cesium DPAL with a stable resonator. AB - We performed a measurement of the beam quality of an optimized moderate power cesium Diode Pumped Alkali Laser (DPAL). The DPAL used a stable resonator and operated in continuous wave mode using a static cell filled with metallic cesium and a mixture of methane and helium at 200 and 400 torr respectively. In this work, we characterized the spatial quality of the DPAL output beam. As a result of these experiments we determined the output beam quality was excellent (M2 < 1.2) in the whole range of pump power used (up to 11.5W) and pump intensities reaching 1.5 kW/cm2. The optical conversion efficiency of this laser was 51% and the slope efficiency was 61%. PMID- 29529753 TI - Edge detection based on single-pixel imaging. AB - In the paper, we propose a new edge detection schemes, based on a single-pixel imaging in the frequency domain. In SCHEME-I, special sinusoidal patterns for the x-direction edge and also y-direction edge of the unknown object are first designed. The frequency spectrum for the edge is then obtained using the a four step phase-shifting technique with the designed sinusoidal patterns in a single pixel imaging system. In SCHEME-II, the frequency spectrum of the unknown object is first obtained, then the frequency spectrum for the edge is obtained by calculations. The resulting edges are finally obtained by the inverse Fourier transform on their frequency spectrum. We have also verified the proposed schemes by experiments and numerical simulations. The results show that the proposed schemes can produce higher quality edges of character and also image objects. Comparing with SCHEME-II, the application of SCHEME-I to high frequency components has greatly improved signal-to-noise ratio of the received data in the bucket detector, resulting in better experimental results. Comparing with the edge detection scheme by speckle-shifting in ghost imaging systems, the proposed SCHEME-I shows an improvement in the signal-to-noise ratio. Since a single-pixel imaging system is used, the proposed schemes are capable of reconstructing edges from indirect measurements. The number of measurements required can be effectively reduced due to the sparsity of natural images in the Fourier domain and the conjugate symmetry of real-valued signals' Fourier spectrum. PMID- 29529754 TI - Active pump-seed-pulse synchronization for OPCPA with sub-2-fs residual timing jitter: erratum. AB - In the original manuscript, a residual RMS timing jitter below 2 fs between pump and seed pulses in the stabilized case was claimed. Following a reevaluation of the data, this was underestimated. Due to a rounding error in the calibration routine, a miscalculated calibration factor was extracted. By using a higher precision, the updated residual timing jitter amounts to 2.76 fs, or sub-3 fs. In this erratum, the calibration routine is briefly reviewed and Fig. 4, which presents the timing jitter in the stabilized and unstabilized case, is updated. All other results remain unaffected. PMID- 29529755 TI - Spectral classification of sparse photon depth images. AB - By illumination of target scenes using a set of different wavelengths, we demonstrate color classification of scenes, as well as depth estimation, in photon-starved images. The spectral signatures are classified with a new advanced statistical image processing method from measurements of the same scene, in this case using combinations of 33, 16, 8 or 4 different wavelengths in the range 500 820 nm. This approach makes it possible to perform color classification and depth estimation on images containing as few as one photon per pixel, on average. Compared to single wavelength imaging, this approach improves target discrimination by extracting more spectral information, which, in turn, improves the depth estimation since this approach is robust to changes in target reflectivity. We demonstrate color classification and depth profiling of complex targets at average signal levels as low as 1.0 photons per pixel from as few as 4 different wavelength measurements. PMID- 29529756 TI - Comparison of phase quadrature squeezed states generated from degenerate optical parametric amplifiers using PPKTP and PPLN. AB - Phase quadrature squeezed states at 1550 nm generated from degenerate optical parametric amplifiers (DOPAs) using periodically poled KTiOPO4 (PPKTP) and periodically poled lithium niobate (PPLN) are compared. A squeezing of 6.8 dB was produced from the DOPA using PPKTP with the phase matching temperature of 34.5 degrees C. By contrast, a measured squeezing of 4.9 dB was generated using PPLN with the phase matching temperature of 135.2 degrees C. The degradation of squeezing using a nonlinear crystal with a high phase matching temperature is explained by a theoretical model of DOPAs including the extra phase noise caused by the guided acoustic wave Brillouin scattering within the nonlinear crystal. PMID- 29529757 TI - High-resolution depth profiling using a range-gated CMOS SPAD quanta image sensor. AB - A CMOS single-photon avalanche diode (SPAD) quanta image sensor is used to reconstruct depth and intensity profiles when operating in a range-gated mode used in conjunction with pulsed laser illumination. By designing the CMOS SPAD array to acquire photons within a pre-determined temporal gate, the need for timing circuitry was avoided and it was therefore possible to have an enhanced fill factor (61% in this case) and a frame rate (100,000 frames per second) that is more difficult to achieve in a SPAD array which uses time-correlated single photon counting. When coupled with appropriate image reconstruction algorithms, millimeter resolution depth profiles were achieved by iterating through a sequence of temporal delay steps in synchronization with laser illumination pulses. For photon data with high signal-to-noise ratios, depth images with millimeter scale depth uncertainty can be estimated using a standard cross correlation approach. To enhance the estimation of depth and intensity images in the sparse photon regime, we used a bespoke clustering-based image restoration strategy, taking into account the binomial statistics of the photon data and non local spatial correlations within the scene. For sparse photon data with total exposure times of 75 ms or less, the bespoke algorithm can reconstruct depth images with millimeter scale depth uncertainty at a stand-off distance of approximately 2 meters. We demonstrate a new approach to single-photon depth and intensity profiling using different target scenes, taking full advantage of the high fill-factor, high frame rate and large array format of this range-gated CMOS SPAD array. PMID- 29529758 TI - Highly-efficient mid-infrared CW laser operation in a lightly-doped 3 at.% Er:SrF2 single crystal. AB - 3 at.% Er:SrF2 laser crystals with high optical quality were successfully grown using the temperature gradient technique (TGT). The intense mid-infrared emission was observed around 2.7 MUm with excitation by a 970 nm LD. Based on the Judd Ofelt theory, the emission cross-sections of the 4I13/2-4I11/2 transition were calculated by using the Fuchtbauer-Ladenburg (FL) method. Efficient continuous wave laser operation at 2.8 um was achieved with the lightly-doped 3 at.% Er:SrF2 crystal pumped by a 970 nm laser diode. The laser output power reached up to 1.06 W with a maximum slope efficiency of 26%. PMID- 29529759 TI - Dynamics of soliton explosions in ultrafast fiber lasers at normal-dispersion. AB - We found two kinds of soliton explosions based on the complex Ginzburg-Landau equation without nonlinearity saturation and high-order effects, demonstrating the soliton explosions as an intrinsic property of the dissipative systems. The two kinds of soliton explosions are caused by the dual-pulsing instability and soliton erupting, respectively. The transformation and relationship between the two kinds of soliton explosions are discussed. The parameter space for the soliton explosion in a mode-locked laser cavity is found numerically. Our results can help one to obtain or avoid the soliton explosions in mode-locked fiber lasers and understand the nonlinear dynamics of the dissipative systems. PMID- 29529760 TI - Scanning fiber microdisplay: design, implementation, and comparison to MEMS mirror-based scanning displays. AB - In this study, we propose a compact, lightweight scanning fiber microdisplay towards virtual and augmented reality applications. Our design that is tailored as a head-worn-display simply consists of a four-quadrant piezoelectric tube actuator through which a fiber optics cable is extended and actuated, and a reflective (or semi-reflective) ellipsoidal surface that relays the moving tip of the fiber onto the viewer's retina. The proposed display, offers significant advantages in terms of architectural simplicity, form-factor, fabrication complexity and cost over other fiber scanner and MEMS mirror counterparts towards practical realization. We demonstrate the display of various patterns with ~VGA resolution and further provide analytical formulas for mechanical and optical constraints to compare the performance of the proposed scanning fiber microdisplay with that of MEMS mirror-based microdisplays. Also we discuss the road steps towards improving the performance of the proposed scanning fiber microdisplay to high-definition video formats (such as HD1440), which is beyond what has been achieved by MEMS mirror based laser scanning displays. PMID- 29529761 TI - Development of high performance green c-plane III-nitride light-emitting diodes. AB - The effect of employing an AlGaN cap layer in the active region of green c-plane light-emitting diodes (LEDs) was studied. Each quantum well (QW) and barrier in the active region consisted of an InGaN QW and a thin Al0.30Ga0.70N cap layer grown at a relatively low temperature and a GaN barrier grown at a higher temperature. A series of experiments and simulations were carried out to explore the effects of varying the Al0.30Ga0.70N cap layer thickness and GaN barrier growth temperature on LED efficiency and electrical performance. We determined that the Al0.30Ga0.70N cap layer should be around 2 nm and the growth temperature of the GaN barrier should be approximately 75 degrees C higher than the growth temperature of the InGaN QW to maximize the LED efficiency, minimize the forward voltage, and maintain good morphology. Optimized Al0.30Ga0.70N cap growth conditions within the active region resulted in high efficiency green LEDs with a peak external quantum efficiency (EQE) of 40.7% at 3 A/cm2. At a normal operating condition of 20 A/cm2, output power, EQE, forward voltage, and emission wavelength were 13.8 mW, 29.5%, 3.5 V, and 529.3 nm, respectively. PMID- 29529762 TI - Narrow-linewidth, quasi-continuous-wave ASE source based on a multiple-pass Nd:YAG zigzag slab amplifier configuration. AB - We present investigations into a narrow-linewidth, quasi-continuous-wave pulsed all-solid-state amplified spontaneous emission (ASE) source by use of a novel multiple-pass zigzag slab amplifier. The SE fluorescence emitted from a Nd:YAG slab active medium acts as the seed and is amplified back and forth 8 times through the same slab. Thanks to the angular multiplexing nature of the zigzag slab, high-intensity 1064-nm ASE output can be produced without unwanted self lasing in this configuration. Experimentally, the output energy, optical conversion efficiency, pulse dynamics, spectral property, and beam quality of the ASE source are studied when the Nd:YAG slab end-pumped by two high-brightness laser diode arrays. The maximum single pulse energy of 347 mJ is generated with an optical efficiency of ~5.9% and a beam quality of 3.5/17 in the thickness/width direction of the slab. As expected, smooth pulses without relaxing spikes and continuous spectra are achieved. Moreover, the spectral width of the ASE source narrows versus the pump energy, getting a 3-dB linewidth of as narrow as 20 pm (i.e. 5.3 GHz). Via the sum frequency generation, high-intensity, smooth-pulse, and narrow-linewidth ASE sources are preferred for solving the major problem of saturation of the mesospheric sodium atoms and can create a much brighter sodium guide star to meet the needs of adaptive imaging applications in astronomy. PMID- 29529763 TI - High peak power 2.8 MUm Raman laser in a methane-filled negative-curvature fiber. AB - We demonstrate a 2.8 MUm gas Raman laser in a methane-filled hollow-core negative curvature fiber with average power of 113 mW, pulse energy of 113 MUJ and estimated peak power of 9.5 MW. Raman quantum efficiency of 40% has been reached from the pump source at 1.064 MUm to the 2nd order vibrational Stokes at 2.812 MUm using 1.8 MPa methane gas. To our knowledge, this is the first high peak power fiber-based gas Raman laser in mid-infrared region and a range of applications in supercontinuum generation, laser surgery, molecular tracing and gas detection are in prospect. PMID- 29529764 TI - Wavelength-selective mid-infrared metamaterial absorbers with multiple tungsten cross resonators. AB - Wavelength-selective metamaterial absorbers in the mid-infrared range are demonstrated by using multiple tungsten cross resonators. By adjusting the geometrical parameters of cross resonators in single-sized unit cells, near perfect absorption with single absorption peak tunable from 3.5 um to 5.5 um is realized. The combination of two, three, or four cross resonators of different sizes in one unit cell enables broadband near-perfect absorption at mid-infrared range. The obtained absorption spectra exhibit omnidirectionality and weak dependence on incident polarization. The underlying mechanism of near-perfect absorption with cross resonators is further explained by the optical mode analysis, dispersion relation and equivalent RLC circuit model. Moreover, thermal analysis is performed to study the heat generation and temperature increase in the cross resonator absorbers, while the energy conversion efficiency is calculated for the thermophotovoltaic system made of the cross resonator thermal emitters and low-bandgap semiconductors. PMID- 29529765 TI - Broadband polarization resolving based on dielectric metalenses in the near infrared. AB - We demonstrate a novel polarization-resolved device (PRD) with the ability to accurately resolve the polarization states via a simple measurement process. The PRD is composed of two elaborately designed metalenses, which are capable of focusing the two circularly polarized (CP) lights. Therefore, for an arbitrary polarized light (treated as a combination of the two CP lights), a discrepancy is exhibited on focusing efficiency, which inversely provides a way to calculate the ellipticity. With such a strategy, the generalized form for polarization resolving is derived, with which the ellipticity of the incident polarized light can be calculated (through just measuring the efficiencies of the two spots). This process is accomplished by utilizing the numerical simulations and theoretical analysis. Moreover, resolving the polarization states can be achieved within a wavelength range of 400nm, due to the broadband effect of the designed metalenses. With the merits of compact configuration, broadband and compatibility with the existing semiconductor technology, the designed PRD holds potential applications in characterizing the polarization states. PMID- 29529766 TI - Response of an optical cavity to phase-controlled incomplete power switching of nearly resonant incident light. AB - The response of an optical cavity to incomplete extinction of nearly resonant incident light was experimentally examined. Measurements were performed using a Pound-Drever-Hall-locked frequency-stabilized cavity ring-down spectrometer (CRDS) that allowed the laser frequency detuning from the cavity resonance center to be controlled at Hz-level resolution. It is shown that an insufficient laser light extinction ratio combined with a phase shift and frequency detuning may lead to non-exponential cavity pumping and decay signals. The experimental results can be explained with a simple analytical model. The non-exponential decay can lead to a systematic shift as high as 0.5% in the ring-down time constants, dependent on the laser frequency detuning from the cavity mode center and on the extinction ratio. This can lead to appreciable systematic errors in the absorption coefficients determined with the CRDS technique. PMID- 29529767 TI - Depth estimation method using depth-of-field imaging with a retroreflector. AB - We propose a method for depth estimation using a tilted retroreflective structure, which consists of a beam splitter and a micro-corner cube array. Existing depth estimation methods commonly use an active light source to detect the depth of an object. However, sunlight interferes with their depth measurements and decreases their accuracy outdoors. The proposed method does not need any active light source because depth information is obtained in the image domain, not in the object domain. The depth of field imaging by a retroreflector indicates the depth position of the object image, immediately. We believe that the proposed method can be applied to depth measurement systems such as LIDAR and time of flight cameras. An experiment is performed, whose results are compared with theoretical calculations, which confirms the feasibility of the proposed method. PMID- 29529768 TI - Graphene on metal-insulator-metal-based plasmonic metamaterials at infrared wavelengths. AB - Metal-insulator-metal-based plasmonic metamaterial absorbers (MIM-PMAs) generate strong localized surface plasmon resonance (LSPR) on their surfaces. Therefore, MIM-PMAs are expected to enhance the absorption of graphene coated on their surfaces. Graphene-coated MIM-PMAs (GMIM-PMAs) were developed and their optical properties were investigated both experimentally and numerically at infrared wavelengths. Significant modification of the absorption of GMIM-PMAs was achieved only in the main LSPR wavelength region, where the insulator is lossless. The enhancement of the absorption of graphene could be maximized by the optimization of the insulator thickness of the MIM-PMAs. The results obtained here are expected to contribute to the development of high-responsivity graphene-based photodetectors and optoelectronic devices. PMID- 29529769 TI - 8 kHz linewidth, 50 mW output, full C-band wavelength tunable DFB LD array with self-optical feedback. AB - We describe a 1.5 MUm, narrow linewidth, high output power wavelength tunable LD that employs a self-optical feedback circuit. By incorporating an optical circulator-based feedback circuit in a DFB LD array, we have successfully reduced the oscillation linewidth from several MHz to less than 8 kHz over the full C band range. A high output power of approximately 50 mW and a low relative intensity noise of less than -130 dB/Hz were simultaneously achieved. Furthermore, by employing a partial reflection mirror as a self-optical feedback circuit, we have also realized a full C-band wavelength tunable LD with a linewidth of less than 11 kHz and a simple laser configuration. PMID- 29529770 TI - Ultra-broadband absorber from visible to near-infrared using plasmonic metamaterial. AB - We propose a design of an ultra-broadband absorber based on a thin metamaterial nanostructure composed of a periodic array of titanium-silica (Ti-SiO2) cubes and an aluminum (Al) bottom film. The proposed structure can achieve nearly perfect absorption with an average absorbance of 97% spanning a broad range from visible to near-infrared (i.e., from 354 nm to 1066 nm), showing a 90% absorption bandwidth over 712 nm, and the peak absorption is up to 99.8%. The excitation of superior surface plasmon resonance combined with the resonance induced by the metal-insulator-metal Fabry-Perot (FP) cavity leads to this broadband perfect absorption. The polarization and angle insensitivity is demonstrated by analyzing the absorption performance with oblique incidences for both TE- and TM-polarized waves. In addition, we discuss the impact of various metal materials and geometry structure on absorption performance in detail. The proposed broadband metamaterial absorber shows a promising prospect in applications such as solar cell, infrared detection, and imaging. Moreover, the use of a thin titanium cap and an aluminum film instead of noble metals has the potential to reduce production cost in applications. PMID- 29529771 TI - Spectrally narrow features in a supercontinuum generated by shaped pulse trains. AB - Supercontinuum generation using photonic crystal fibers is a useful technique to generate light spanning a broad wavelength range, using femtosecond laser pulses. For some applications, one may desire higher power density at specific wavelengths. Increasing the pump power results primarily in further broadening of the output spectrum and is not particularly useful for this purpose. In this paper we demonstrate that by applying a periodic spectral phase modulation to the input pulse using a pulse shaper, the spectral energy density of the output supercontinuum can be enhanced by nearly an order of magnitude at specific wavelengths, which are tunable. PMID- 29529772 TI - Pulse-shape dependence of stimulated Brillouin scattering pulse compression to sub-phonon lifetime. AB - A new approach to sub-phonon lifetime pulse compression by stimulated Brillouin scattering (SBS) is presented. Triangular and step pulse pumps are both used as a pump source in a single-cell SBS compression setup. Compared with a Gaussian pump (shortest compressed pulse is the phonon lifetime with the highest energy conversion, approximately 60% under the same conditions), the compression ratio is significantly improved in the case of triangular and step pulse pumps, and there is some improvement in the energy conversion when a step pulse pump is used. A pulse as short as a quarter of a phonon lifetime is produced by a triangular pulse pump, with an energy conversion above 30%. The pump pulse shape is identified as the key parameter in achieving sub-phonon lifetime pulse compression. By using a step pulse shape, a 4.5 ns pump pulses with a 60mJ at 1064-nm are compressed down to 292 ps (below semi-phonon-lifetime) in 3M Fluorinert Electronic Liquid FC-770 with an energy conversion above 65%. This work presents a route to reliable generation of sub-semi-phonon-lifetime pulses by SBS compression. PMID- 29529773 TI - One-step fabrication of hierarchical multiscale surface relief gratings by holographic lithography of azobenzene polymer. AB - We present one-step method of fabricating hierarchical multiscale grating patterns by using holographic lithography on azobenzene thin films. In this study, we investigate the growth behavior of surface relief gratings in terms of surface morphology change regarding various optical conditions of different fringe visibility, exposure dose and polarization modes of the light interference pattern. The results reveal that different-sized diffractive gratings could be fabricated orthogonally at the same time. We also explain that these orthogonal gratings were developed through the different light-induced deformation mechanism. PMID- 29529774 TI - Experimental characterization of continuous-variable orbital angular momentum entanglement using Stokes-operator basis. AB - The continuous-variable (CV) orbital angular momentum (OAM) entanglement is very different to the traditional quadrature entanglement. The Stokes-operators directly reflect the character of OAM light. Here, we report the first direct experimental demonstration the Stokes-operator entanglement of continuous variable OAM entanglement. Generated by transforming quadrature entanglement in the HG01 mode onto the orbital Stokes-operator basis, the entanglement is measured in the Stokes-operator basis using a self-designed detection scheme. An inseparability of I(O^2,O^3)<1 is achieved over a wide analyzing frequency of 1 10 MHz. Moreover, experimental fluctuations at 5.0 MHz are visualized using the quantum orbital Poincare sphere representation. The OAM entanglement with Stokes operators measurement has a promising application in certain nonlocal quantum information protocols and rotational optomechanics by interacting with nanoparticle or atoms. PMID- 29529775 TI - Inter-channel nonlinear phase noise compensation using optical injection locking. AB - We propose optical injection locking (OIL) to enable compensation of the inter channel nonlinear phase noise, which is dominated by cross-phase modulation (XPM). In this paper, injection locking is used to create a local oscillator for a homodyne receiver from a residual carrier. The locking is fast enough to follow XPM-phase distortion, but slow enough to reject the signal bands, which are spaced slightly away from the pilot. The homodyne receiver thus partially cancels XPM, as it is common to the signals and the pilot. An experimental 7-channel WDM system gives 1-dB (0.7-dB) improvement in the peak Q of the center channel, for QPSK (16-QAM) modulated OFDM subcarriers, and increased the transmission reach by 320 km. The optimum performance was achieved at an injection ratio of -45 dB, with the injected power as low as -24.5 dBm. PMID- 29529776 TI - Synthetic-wavelength-based dual-comb interferometry for fast and precise absolute distance measurement. AB - We present an absolute distance measurement system using a phase-stable dual-comb system with 56.09 MHz repetition rate and 2 kHz repetition rate difference. A relative phase stability of 0.1 rad in 0.5 ms between two combs is achieved using a mutual locking scheme. The dual-comb ranging system combines the time-of-flight (TOF) method, synthetic-wavelength interferometry (SWI), and carrier wave interferometry (CWI). Each method provides a particular ambiguity range and resolution, and they can be applied simultaneously and linked to enhance the precision and measurement rate of the ranging system. The experimental results demonstrate that a precision of 1.2 MUm is obtained without time averaging, and the precision can be improved to 3 nm with only 10 ms averaging time using the SWI method described in this study. The precision reaches a sub-nanometer when the averaging time exceeds 0.1 s. A system with high accuracy and short averaging time would enhance fast measurement performance in various industrial applications. The ambiguity range is about 2.67 m in our system, we test the performance of the system with 1.5 mm range at 1.5 m distance. PMID- 29529777 TI - Manipulating the wavelength-drift of a Tm laser for resonance enhancement in an intra-cavity pumped Ho laser. AB - We demonstrate an enhancement mechanism and thermal model for intra-cavity pumped lasers, where resonance enhancement in intra-cavity pumped Ho laser was achieved by manipulating the wavelength-drift nature of the Tm laser for the first time. Optical conversion efficiency of 37.5% from an absorbed 785 nm diode laser to a Ho laser was obtained with a maximum output power of 7.51 W at 2122 nm, which is comparable to the conversion efficiency in 1.9 MUm LD pumped Ho lasers. Meanwhile, more severe thermal effects in the Ho-doped gain medium than the Tm doped one at high power operation were verified based on the built thermal model. This work benefits the design or evaluation of intra-cavity pumped lasers, and the resonance enhancement originated from the difference in reabsorption loss between stark levels at the lasing manifolds of quasi-three-level rare-earth ions has great interest to improve the existing intra-cavity pumped lasers or explore novel lasers. PMID- 29529778 TI - Liquid crystal terahertz modulator with plasmon-induced transparency metamaterial. AB - An electrically tunable terahertz (THz) modulator with large modulation depth and low insertion loss is performed with liquid crystal (LC) metamaterial. The modulation depth beyond 90% and insertion loss below 0.5 dB are achievable at normal incidence by exploiting plasmon-induced transparency (PIT) effect. The PIT spectra can be manipulated by actively controlling the interference between dipole mode and nonlocal surface-Bloch mode with LC. The incident angle tuning effect on PIT spectra shows that the large modulation depth and low insertion loss can remain over a wide range of working angles. The superior property and simplicity of design make this modulator promising in advanced terahertz communication. PMID- 29529779 TI - Impact of input mask signals on delay-based photonic reservoir computing with semiconductor lasers. AB - We experimentally investigate delay-based photonic reservoir computing using semiconductor lasers with optical feedback and injection. We apply different types of temporal mask signals, such as digital, chaos, and colored-noise mask signals, as the weights between the input signal and the virtual nodes in the reservoir. We evaluate the performance of reservoir computing by using a time series prediction task for the different mask signals. The chaos mask signal shows superior performance than that of the digital mask signals. However, similar prediction errors can be achieved for the chaos and colored-noise mask signals. Mask signals with larger amplitudes result in better performance for all mask signals in the range of the amplitude accessible in our experiment. The performance of reservoir computing is strongly dependent on the cut-off frequency of the colored-noise mask signals, which is related to the resonance of the relaxation oscillation frequency of the laser used as the reservoir. PMID- 29529780 TI - Unfolding displacement measurement method for the aliasing interferometer signal of a wavelength-comb-swept laser. AB - We demonstrate an unfolding displacement measurement method to overcome the aliasing problem of wavelength-comb-swept laser (WCSL). Compared to the conventional wavelength-swept laser (WSL), the WCSL exhibits an extended coherence length, owing to the narrowing spectral linewidth of the etalon filter. However, the aliasing interference signal induces an unexpected back-bounced phenomenon during displacement measurement because of the discretely distributed comb-like periodic spectra of the etalon filter. By using the dual-reference interferometry method, the back-bounced displacement measurement can be successfully unfolded to extend the measurement range by two times. In addition, we demonstrate a longer-range surface profiling image over 18 mm within the 200 mm of measurement range using a line-field beam of a parallel-swept source optical coherence tomography system. PMID- 29529781 TI - Demonstration of versatile whispering-gallery micro-lasers for remote refractive index sensing. AB - We developed chip-scale remote refractive index sensors based on Rhodamine 6G (R6G)-doped polymer micro-ring lasers. The chemical, temperature, and mechanical sturdiness of the fused-silica host guaranteed a flexible deployment of dye-doped polymers for refractive index sensing. The introduction of the dye as gain medium demonstrated the feasibility of remote sensing based on the free-space optics measurement setup. Compared to the R6G-doped TZ-001, the lasing behavior of R6G doped SU-8 polymer micro-ring laser under an aqueous environment had a narrower spectrum linewidth, producing the minimum detectable refractive index change of 4 * 10-4 RIU. The maximum bulk refractive index sensitivity (BRIS) of 75 nm/RIU was obtained for SU-8 laser-based refractive index sensors. The economical, rapid, and simple realization of polymeric micro-scale whispering-gallery-mode (WGM) laser-based refractive index sensors will further expand pathways of static and dynamic remote environmental, chemical, biological, and bio-chemical sensing. PMID- 29529782 TI - Upper-limited angular Goos-Hanchen shifts of Laguerre-Gaussian beams. AB - The angular Goos-Hanchen shift of vortex beam is investigated theoretically when a Laguerre-Gaussian (LG) beam is reflected by an air-metamaterial interface. The upper limit of the angular GH shift is found to be half of the divergence angle of the incident beam, i.e., |Thetaup| = (|l| + 1)1/2/k0w0, with l, k0, and w0 being the vortex charge, wavenumber in vacuum, and beam waist, respectively. Interestingly, the upper limited angular GH shift is accompanied by the upper limited spatial IF shift. A parameter F is introduced to compare the total beam shift with the beam size. F varies with the vortex charge l and the propagation distance zr. The values of F at zr = infinity plane can approach 0.5, which are always larger than those at zr = 0 plane. These findings provide a deeper insight into optical beam shifts, and they may have potential application in precision metrology. PMID- 29529783 TI - Multi-wavelength bright-dark pulse pair fiber laser based on rhenium disulfide. AB - As a new member of transition metal dichalcogenides (TMDs), rhenium disulfide (ReS2), with a nearly unchanged direct bandgap from bulk to monolayer form, is attractive in physics and material fields. By using the optically driving deposition method, the ReS2 saturable absorber (SA) has been fabricated with a modulation depth and saturation fluence of 6.9% and 27.5 MUJ/cm2, respectively. Based on the ReS2-SA, a multi-wavelength bright-dark pulse pair from a mode locked fiber laser has been observed experimentally for the first time, to the best of our knowledge. The saturable absorbing ability of the ReS2 is attributed to the formation of the bright pulses and the dark pulses. The cross-phase modulation (XPM) caused by different wavebands of bright pulse and dark pulse support the coexisting of the bright-dark pulse pair. PMID- 29529784 TI - Low dark current broadband 360-1650 nm ITO/Ag/n-Si Schottky photodetectors. AB - This work designed an ITO/Ag/n-Si Schottky photodetector with broad wavelength detection and low dark current. The introduction of Ag interfacial layer and post rapid thermal annealing dramatically increase the barrier height of ITO/n-Si Schottky diode by 0.32 eV, leading to the 2300 * reduction of dark current. A well-behaved ITO/Ag (8 nm)/n-Si Schottky diode with a high rectification ratio ( +/- 1 V) of 4 * 105 and low dark current (-1 V) of 9.2 nA was achieved. Such low dark current device spontaneously provides high sensitivity for visible/near infrared wavelength detection, in which substantial responsivity for wavelengths from 360 to 1650 nm was realized through both inter-band and internal photoemission. The design here provides an encouraging strategy for monolithically integrated pure Si photodetectors operating at long wavelength up to 1650 nm. PMID- 29529785 TI - Efficient second harmonic generation in gold-silicon core-shell nanostructures. AB - We theoretically investigate the properties of second-harmonic generation (SHG) in gold-silicon core-shell nanostructures. We first study a concentric structure. This structure exhibits strong electric field enhancement in the silicon shell due to the combined toroidal dipole mode and electric dipole mode. Efficient SHG can be obtained and the SHG signal is about 5 times as strong as that of the individual Si shell. Further calculations show that the contribution from a surface nonlinear susceptibility at the inner surface of the silicon shell dominates the SHG signal of the core-shell structure. The SHG as a function of wavelength is considered and it shows a resonance behavior. The cases of nonconcentric core-shell structures have also been considered. The SHG is further enhanced in this kind of configuration and the SHG signal can reach about 10 times as strong as that of the concentric case. Our results reveal the strong modification of the SHGs in dielectric nanostructures by using the metal dielectric hybrid configurations, and could find applications in nanoscale nonlinear devices. PMID- 29529786 TI - Paraxial propagation of the first-order chirped Airy vortex beams in a chiral medium. AB - We introduce the propagation of the first-order chirped Airy vortex beams (FCAiV) in a chiral medium analytically. Results show that the FCAiV beams split into the left circularly polarized vortex (LCPV) beams and the right circularly polarized vortex (RCPV) beams, which have totally different propagation trajectories in the chiral medium. In this paper, we investigate the effects of the first-order chirped parameter beta, the chiral parameter gamma and the optical vortex on the propagation process of the FCAiV beams. It is shown that the propagation trajectory of the FCAiV beams declines with the chirped parameter increasing. Besides, the increase of the chiral parameter acting on the LCPV beams makes the relative position between the main lobe and the optical vortex further while the effect on the RCPV beams is the opposite. Furthermore, the relative position between the main lobe and the optical vortex contributes to the position of the intensity focusing. Meanwhile, with the chiral parameter increasing, the maximum gradient and scattering forces of the LCPV beams decrease but those of the RCPV beams will increase during the propagation. It is significant that we can control the propagation trajectory, the intensity focusing position and the radiation forces of the FCAiV beams by varying the chirped parameter and the chiral parameter. PMID- 29529787 TI - Model-independent noise-robust extension of ptychography. AB - A noise-robust extension of iterative phase retrieval algorithms that does not need to assume a noise model is proposed. It works by adapting the intensity constraints using the reconstructed object. Using a proof-of-principle ptychographic experiment with visible light and a spatial light modulator to create an object, the proposed method is tested and it compares favorably to the Extended Ptychographic Iterative Engine (ePIE) with reduced step size. The method is general, so it can also be applied to other iterative reconstruction schemes such as phase retrieval using focus variation. PMID- 29529788 TI - Random technique to encode complex valued holograms with on axis reconstruction onto phase-only displays. AB - A new technique for encoding the amplitude and phase of diffracted fields in digital holography is proposed. It is based on a random spatial multiplexing of two phase-only diffractive patterns. The first one is the phase information of the intended pattern, while the second one is a diverging optical element whose purpose is the control of the amplitude. A random number determines the choice between these two diffractive patterns at each pixel, and the amplitude information of the desired field governs its discrimination threshold. This proposed technique is computationally fast and does not require iterative methods, and the complex field reconstruction appears on axis. We experimentally demonstrate this new encoding technique with holograms implemented onto a flicker free phase-only spatial light modulator (SLM), which allows the axial generation of such holograms. The experimental verification includes the phase measurement of generated patterns with a phase-shifting polarization interferometer implemented in the same experimental setup. PMID- 29529789 TI - Stochastic process design kits for photonic circuits based on polynomial chaos augmented macro-modelling. AB - Fabrication tolerances can significantly degrade the performance of fabricated photonic circuits and process yield. It is essential to include these stochastic uncertainties in the design phase in order to predict the statistical behaviour of a device before the final fabrication. This paper presents a method to build a novel class of stochastic-based building blocks for the preparation of Process Design Kits for the analysis and design of photonic circuits. The proposed design kits directly store the information on the stochastic behaviour of each building block in the form of a generalized-polynomial-chaos-based augmented macro-model obtained by properly exploiting stochastic collocation and Galerkin methods. Using these macro-models, only a single deterministic simulation is required to compute the stochastic moments of any arbitrary photonic circuit, without the need of running a large number of time-consuming circuit simulations thereby dramatically improving simulation efficiency. The effectiveness of the proposed approach is verified by means of classical photonic circuit examples with multiple uncertain variables. PMID- 29529790 TI - Effects of integration time on in-water radiometric profiles. AB - This work investigates the effects of integration time on in-water downward irradiance Ed, upward irradiance Eu and upwelling radiance Lu profile data acquired with free-fall hyperspectral systems. Analyzed quantities are the subsurface value and the diffuse attenuation coefficient derived by applying linear and non-linear regression schemes. Case studies include oligotrophic waters (Case-1), as well as waters dominated by Colored Dissolved Organic Matter (CDOM) and Non-Algal Particles (NAP). Assuming a 24-bit digitization, measurements resulting from the accumulation of photons over integration times varying between 8 and 2048ms are evaluated at depths corresponding to: 1) the beginning of each integration interval (Fst); 2) the end of each integration interval (Lst); 3) the averages of Fst and Lst values (Avg); and finally 4) the values weighted accounting for the diffuse attenuation coefficient of water (Wgt). Statistical figures show that the effects of integration time can bias results well above 5% as a function of the depth definition. Results indicate the validity of the Wgt depth definition and the fair applicability of the Avg one. Instead, both the Fst and Lst depths should not be adopted since they may introduce pronounced biases in Eu and Lu regression products for highly absorbing waters. Finally, the study reconfirms the relevance of combining multiple radiometric casts into a single profile to increase precision of regression products. PMID- 29529791 TI - Resource allocation in a multi-color DS-OCDMA VLC cellular architecture. AB - In this paper we present two resource allocations techniques in a visible light communication network with overlapping coverage areas due to the use of access points. Particularly, the first approach exploits the rate maximization criteria, and then aims at maximizing the network rate under constraints on minimum and maximum rates, while the other procedure focuses on achieving fairness in the rate of each user accessing the network. The proposed system relays on optical code division multiple access mechanism, and resource allocation is intended in terms of codes assigned to a given user. Simulation results have been addressed in terms of achievable data rates, outage probability and percentage of accessing users. PMID- 29529792 TI - High power sub 100-fs Kerr-lens mode-locked Yb:YSO laser pumped by single-mode fiber laser. AB - We report on a Kerr-lens mode-locked Yb:YSO lasers for the first time. Pumped by a single-mode fiber laser with high brightness and linear polarization, the Yb:YSO laser can deliver as high as 2 W average power with as short as 95 fs pulse duration at the repetition rate of 137.2 MHz, resulting in the single pulse energy of 14.8 nJ and the peak power of 155.7 kW. This work proves the potential on generation of sub-100 fs pulses with multi-watt level average power with the Yb doped oxyorthosilicates crystals. PMID- 29529793 TI - Collective plasmonic modes excited in Al nanocylinder arrays in the UV spectral region. AB - A periodic array of plasmonic nanocylinders can sustain both surface plasmon polaritons (SPPs) and optical diffraction in the plane of the array. Thus the optical energy can be efficiently trapped in the plane of the array, providing a good platform for controlling light. Plasmonic arrays have been investigated in the visible range, while studies in the ultraviolet (UV) range have been limited due to material-related restrictions and higher precision required for optical diffraction in the UV compared to that in the visible range. In this study, we fabricated periodic arrays of Al nanocylinders with periods comparable to optical wavelengths in the UV for simultaneous excitation of both SPPs and optical diffraction in the UV spectral region. We deposited UV-absorbing and highly luminous dielectric films on the arrays, observed enhanced photoluminescence of the film under UV laser excitation, and demonstrated that such periodic arrays can trap the UV light energy. Our findings show that periodic arrays of Al nanocylinders are useful for controlling UV light. PMID- 29529794 TI - Low loss poly-silicon for high performance capacitive silicon modulators. AB - Optical properties of poly-silicon material are investigated to be integrated in new silicon photonics devices, such as capacitive modulators. Test structure fabrication is done on 300 mm wafer using LPCVD deposition: 300 nm thick amorphous silicon layers are deposited on thermal oxide, followed by solid phase crystallization anneal. Rib waveguides are fabricated and optical propagation losses measured at 1.31 um. Physical analysis (TEM ASTAR, AFM and SIMS) are used to assess the origin of losses. Optimal deposition and annealing conditions have been defined, resulting in 400 nm-wide rib waveguides with only 9.2-10 dB/cm losses. PMID- 29529795 TI - Photon statistics and bunching of a chaotic semiconductor laser. AB - The photon statistics and bunching of a semiconductor laser with external optical feedback are investigated experimentally and theoretically. In a chaotic regime, the photon number distribution is measured and undergoes a transition from Bose Einstein distribution to Poisson distribution with increasing the mean photon number. The second order degree of coherence decreases gradually from 2 to 1. Based on Hanbury Brown-Twiss scheme, pronounced photon bunching is observed experimentally for various injection currents and feedback strengths, which indicates the randomness of the associated emission light. Near-threshold injection currents and strong feedback strengths modify exactly the laser performance to be more bunched. The macroscopic chaotic dynamics is confirmed simultaneously by high-speed analog detection. The theoretical results qualitatively agree with the experimental results. It is potentially useful to extract randomness and achieve desired entropy source for random number generator and imaging science by quantifying the control parameters. PMID- 29529796 TI - Absolute gas density profiling in high-order harmonic generation. AB - We propose and implement a method to determine the absolute density profile of a gas jet producing high-order harmonics. By measuring the transverse profile of the fluorescence emitted by the plasma, we retrieve the local density in the gas jet. We use this technique during the optimization of the high-harmonics of 515 nm, 10 uJ, 130 fs pulses at 500 kHz and find that we can generate in absorption limited conditions. PMID- 29529797 TI - Integrating quantum key distribution with classical communications in backbone fiber network. AB - Quantum key distribution (QKD) provides information-theoretic security based on the laws of quantum mechanics. The desire to reduce costs and increase robustness in real-world applications has motivated the study of coexistence between QKD and intense classical data traffic in a single fiber. Previous works on coexistence in metropolitan areas have used wavelength-division multiplexing, however, coexistence in backbone fiber networks remains a great experimental challenge, as Tbps data of up to 20 dBm optical power is transferred, and much more noise is generated for QKD. Here we present for the first time, to the best of our knowledge, the integration of QKD with a commercial backbone network of 3.6 Tbps classical data at 21 dBm launch power over 66 km fiber. With 20 GHz pass-band filtering and large effective core area fibers, real-time secure key rates can reach 4.5 kbps and 5.1 kbps for co-propagation and counter-propagation at the maximum launch power, respectively. This demonstrates feasibility and represents an important step towards building a quantum network that coexists with the current backbone fiber infrastructure of classical communications. PMID- 29529798 TI - Do it yourself hyperspectral imager for handheld to airborne operations. AB - This study describes rapid prototype construction of small and lightweight push broom Hyper Spectral Imagers (HSI). The dispersive element housings are printed by a thermoplastic 3D printer combined with S-mount optical components and commercial off-the-shelf camera heads. Four models with a mass less than 200 g are presented with a spectral range in the visible to the near-infrared part of the electromagnetic spectrum. The bandpass is in the range from 1.4 - 5 nm. Three test experiments with motorized gimbals to stabilize attitude show that the instruments are capable of push broom spectral imaging from various platforms, including airborne drone to handheld operations. PMID- 29529799 TI - Decoupling phase-matching bandwidth and interaction geometry using non-collinear quasi-phase-matching gratings. AB - In optical parametric amplification (OPA) of broadband pulses, a non-collinear angle between the interacting waves is typically introduced in order to achieve broadband phase-matching. Consequently, bandwidth and beam geometry are closely linked. This coupling restricts the geometrical layout of an OPA system. Here, we demonstrate a quasi-phase-matching (QPM) geometry for broadband OPA in which a transverse component is introduced to the QPM grating to impose an additional momentum on the generated wave. This momentum shift detunes the wavelength where the signal and the idler are group-velocity matched, thereby allowing for broadband phase-matching without having to add a non-collinear angle between the interacting waves. We present two experimental configurations making use of this principle, and propose a third configuration with the potential to further simplify ultra-broadband OPA system architectures. PMID- 29529800 TI - Fabrication and characterization of SiNx/Au cavities with colloidal nanocrystals. AB - We demonstrate the fabrication and characterization of on-chip vertically emitting SiNx/Au nanopatch cavities containing a monolayer of colloidal quantum dots. The fabrication process is based on electron-beam lithography and deterministically positions both the cavity and the emitters within the cavity with an accuracy of 10 nm. The Purcell enhancement of the spontaneous emission of the quantum dots is studied theoretically and experimentally. The fabrication technique makes it possible to pattern the quantum dot monolayer such that the quantum dots only occupy the center of the nanopatch cavity where a Purcell factor up to 7 can be reached. The work paves the way towards scalable fabrication of bright and directive single-photon sources. PMID- 29529801 TI - Temperature stability of static and dynamic properties of 1.55 um quantum dot lasers. AB - Static and dynamic properties of InP-based 1.55 um quantum dot (QD) lasers were investigated. Due to the reduced size inhomogeneity and a high dot density of the newest generation of 1.55 um QD gain materials, ridge waveguide lasers (RWG) exhibit improved temperature stability and record-high modulation characteristics. Detailed results are shown for the temperature dependence of static properties including threshold current, voltage-current characteristics, external differential efficiency and emission wavelength. Similarly, small and large signal modulations were found to have only minor dependences on temperature. Moreover, we show the impact of the active region design and the cavity length on the temperature stability. Measurements were performed in pulsed and continuous wave operation. High characteristic temperatures for the threshold current were obtained with T0 values of 144 K (15 - 60 degrees C), 101 K (60 - 110 degrees C) and 70 K up to 180 degrees C for a 900-um-long RWG laser comprising 8 QD layers. The slope efficiency in these lasers is nearly independent of temperature showing a T1 value of more than 900 K up to 110 degrees C. Due to the high modal gain, lasers with a cavity length of 340 um reached new record modulation bandwidths of 17.5 GHz at 20 degrees C and 9 GHz at 80 degrees C, respectively. These lasers were modulated at 26 GBit/s in the non-return to zero format at 80 degrees C and at 25 GBaud using a four-level pulse amplitude format at 21 degrees C. PMID- 29529802 TI - All-dielectric planar chiral metasurface with gradient geometric phase. AB - Planar optical chirality of a metasurface measures its differential response between left and right circularly polarized (CP) lights and governs the asymmetric transmission of CP lights. In 2D ultra-thin plasmonic structures the circular dichroism is limited to 25% in theory and it requires high absorption loss. Here we propose and numerically demonstrate a planar chiral all-dielectric metasurface that exhibits giant circular dichroism and transmission asymmetry over 0.8 for circularly polarized lights with negligible loss, without bringing in bianisotropy or violating reciprocity. The metasurface consists of arrays of high refractive index germanium Z-shape resonators that break the in-plane mirror symmetry and induce cross-polarization conversion. Furthermore, at the transmission peak of one handedness, the transmitted light is efficiently converted into the opposite circular polarization state, with a designated geometric phase depending on the orientation angle of the optical element. In this way, the optical component sets before and after the metasurface to filter the light of certain circular polarization states are not needed and the metasurface can function under any linear polarization, in contrast to the conventional setup for geometry phase based metasurfaces. Anomalous transmission and two-dimensional holography based on the geometric phase chiral metasurface are numerically demonstrate as proofs of concept. PMID- 29529803 TI - Economic fabrication of a novel hybrid planar Grating/Fresnel lens for miniature spectrometers. AB - We propose a new technique to fabricate a highly specialized optical element, a hybrid planar Grating/Fresnel lens (G-Fresnel), which is particularly useful to improve or enable more-affordable miniature/portable spectrometers. Both the Fresnel and the grating surface are fabricated simultaneously by sandwiching soft PDMS between a hard grating and a pre-replicated negative Fresnel surface. Several adhesion reduction techniques are also investigated that help improve both fabrication and cost efficiency (by reducing the solidification time) as well as the lifetime of the mold. Alignment errors are systematically analyzed, and their effects on the G-Fresnel lens evaluated. A compact fabrication platform was built, which is smaller than a volume of 160?140?106 mm3 to fit into a conventional vacuum drying oven, for the fabrication of a G-Fresnel lens with a diameter of 25.4 mm, an equivalent focal length of 25 mm, and a blazed grating pattern with 600 lines/mm spacing. The solidification time was reduced to 2 hours thanks to the improved adhesion reduction technique that permits a PDMS drying temperature as high as 65 degrees C. The fabricated G-Fresnel lens was evaluated with regard to both geometrical fabrication precision and optical performance. The measured results, using a step gauge and atomic force microscopy, confirm that this replication technique produces high-quality replicates of the master surface-profile. Furthermore, a prototype spectrometer that uses a G-Fresnel lens was built and evaluated. The spectrometer fits within a volume of about 100 mm?50 mm?30 mm, and it operates across a wide wavelength spectrum (450 nm to 650 nm). Both the calculation based on the optical software ZEMAX and the experimental measurements are consistent and confirm that the spectrometer with the G-Fresnel lens can provide a spectral resolution of better than 1.2nm. PMID- 29529804 TI - Aspherical high-speed varifocal mirror for miniature catadioptric objectives. AB - We present a varifocal mirror based on a piezo-actuated glass membrane that can be used as a secondary mirror in miniature Cassegrain-type mirror- or catadioptric objectives. The mirror section has a diameter of 10 mm on a clear membrane diameter of 23 mm, with a focal range of +/-8 m-1 and a response time on the millisecond-scale. The two piezo layers enable an aspherical tuning range that covers the elliptic, parabolic and hyperbolic regime over most of the focal range. We demonstrate the application of the mirror in a simple catadioptric telefocus objective with a focal length of 68 mm at an aperture of 22 mm and a thickness of 16.6 mm. PMID- 29529805 TI - Optical puff mediated laminar-turbulent polarization transition. AB - Various physical structures exhibit a fundamentally probabilistic nature over diverse scales in space and time, to the point that the demarcation line between quantum and classic laws gets blurred. Here, we characterize the probability of intermittency in the laminar-turbulence transition of a partially mode-locked fiber laser system, whose degree of coherence is deteriorated by multiple mode mixing. Two competing processes, namely the proliferation and the decay of an optical turbulent puff, determine a critical behavior for the onset of turbulence in such a nonlinear dissipative system. A new kind of polarization rogue waves is introduced at the point of transition to polarization turbulence. The probabilistic description of the puff-mediated laminar-turbulence polarization transition provides an additional degree of freedom for our understanding of the complex physics of lasers. PMID- 29529806 TI - Optical performance of large-area crystalline coatings. AB - Given their excellent optical and mechanical properties, substrate-transferred crystalline coatings are an exciting alternative to amorphous multilayers for applications in precision interferometry. The high mechanical quality factor of these single-crystal interference coatings reduces the limiting thermal noise in precision optical instruments such as reference cavities for narrow-linewidth laser systems and interferometric gravitational wave detectors. In this manuscript, we explore the optical performance of GaAs/AlGaAs crystalline coatings transferred to 50.8-mm (2-inch) diameter fused silica and sapphire substrates. We present results for the transmission, scattering, absorption, and surface quality of these prototype samples including the defect density and micro roughness. These novel coatings exhibit optical performance on par with state-of the-art dielectric structures, encouraging further work focused on the fabrication of larger optics using this technique. PMID- 29529807 TI - Time-resolved retardance and optic-axis angle measurement system for characterization of flexoelectro-optic liquid crystal and other birefringent devices. AB - A new polarimeter is presented which gives time-resolved measurements of both the optic-axis angle and the linear phase retardation for modulated birefringent optical devices. It is suitable for characterizing dynamic waveplate devices based on liquid crystal and other materials. It is fully automated and requires no angular alignment of the device under test. The system has an absolute angle error of < +/- 0.3 degrees and a retardance error of < +/- 0.44 degrees , with considerably better relative accuracy. The method has been tested with a chiral nematic liquid crystal device exhibiting flexoelectro-optic switching at 3 kHz in the uniform lying helix mode. These results represent the first time-resolved tilt-angle and phase retardation measurements for a liquid crystal device operating at fast switching frequencies. PMID- 29529808 TI - Ground-state cooling of rotating mirror in double-Laguerre-Gaussian-cavity with atomic ensemble. AB - A scheme is proposed to cool a rotating mirror close to its ground state in a double-Laguerre-Gaussian-cavity optomechanical system, where an auxiliary cavity and a two-level atomic ensemble simultaneously couple to the original optomechanical cavity. By choosing parameters reasonably, we find that the cooling process of the rotating mirror can be strengthened greatly while the heating process can be suppressed effectively. We show that the proposed ground state cooling scheme can work well no matter whether in the weak or strong coupling regime for the atomic ensemble and original cavity. Compared with previous related schemes, our scheme works in the unresolved sideband regime with fewer strict limitations for the auxiliary systems. PMID- 29529809 TI - Dimensioning of a multibeam coherent photonic beamformer fed by a phased array antenna. AB - The design and dimensioning of a photonic-aided payload for a multi-beam high throughput communications satellite is a complex problem in which the antenna, RF and photonic subsystems must be considered as a whole for achieving best performance with lowest mass and power consumption. In this paper, we propose and dimension the receiving stage of a communications satellite comprising a phased array antenna (PAA) feeding a multibeam photonic beamforming system (PBS). The PBS uses a single wavelength and resorts to heterodyne detection such that the retrieved beams are frequency downconverted. End-to-end system modeling shows that the complexity of the PAA and PBS can be traded-off for signal-to-noise ratio (SNR) or power consumption without compromising the beam width. The dimensioning of a realistic scenario is presented, showing that an SNR and beam crosstalk on the order of 20 dB are achievable with a total power consumption below 1 kW for a typical number of 100 antenna elements (AEs). PMID- 29529810 TI - Low-cost and miniaturized 100-Gb/s (2 * 50 Gb/s) PAM-4 TO-packaged ROSA for data center networks. AB - We design and implement a cost-effective and compact 100-Gb/s (2 * 50 Gb/s) PAM-4 receiver optical sub-assembly (ROSA) by using a TO-can package instead of an expensive box-type package. It consists of an optical demultiplexer, two PIN-PDs and a 2-channel linear transimpedance amplifier. The components are passively aligned and assembled using alignment marks engraved on each part. With a real time PAM-4 DSP chip, we measured the back-to-back receiver sensitivities of the 100-Gb/s ROSA based on TO-56 to be less than -13.2 dBm for both channels at a bit error rate of 2.4e-4. The crosstalk penalty due to the adjacent channel interference was observed around 0.1 dB. PMID- 29529811 TI - Quantitative visualisation of the continuous whole-field stress evolution in complex pore structures using photoelastic testing and 3D printing methods. AB - Providing a quantitative description of the whole-field stress evolution in complex structures subjected to continuous loading processes using traditional photoelastic approaches is a significant challenge because of the difficulties with fabricating complex structures, identifying the stress distribution and evolution, and unwrapping isochromatic phase maps. To overcome the challenges, we proposed a novel method to quantify the continuous whole-field stress evolution in a complex porous structure that was fabricated with 3D printing technology. The stress fringes were identified by analysing a series of continuous frames extracted from a video recording of the fringe changes and determining the valleys of the light intensity change curve over the entire loading process. The experimental data were compared with the numerical results of the complex model with identical pore geometries, physical properties, and loading conditions to evaluate the accuracy and effectiveness of the method. In principle, the applicability of the reported method for identifying and unwrapping the continuous whole-field stress is not affected by the complexity of a structure. PMID- 29529812 TI - Tunable optical forces enhanced by plasmonic modes hybridization in optical trapping of gold nanorods with plasmonic nanocavity. AB - The optomechanical interaction between a plasmonic nanocavity and a gold nanorod through optical forces is demonstrated. It is revealed that strong localized plasmon resonance mode hybridization induced by a gold nanorod results in the resonance mode of the nanocavity splitting into two different plasmon resonance modes (bonding plasmon resonance mode and antibonding plasmon resonance mode). When the whole system (gold nanorod and gold nanocavity) is excited at the antibonding plasmon mode, the gold nanorod can receive an optical pushing force and be pushed away from the gold nanocavity. On the other hand, an optical pulling force acts on the gold nanorod and the gold nanorod can be trapped by the gold nanocavity when the plasmonic tweezers work at the bonding mode. The optical pulling force acting on the gold nanorod can be enhanced by two orders of magnitude larger than that of the same sized dielectric nanorod, which benefits from the strong resonant nearfield interaction between the gold nanorod and the gold nanocavity. More importantly, the shape and the position of the optical potential can be tuned by tailoring the wavelength of the laser used in the optical trapping, which can be used to manipulate the gold nanorod within a nanoscale region. Our findings have important implications for optical trapping, manipulation, sorting, and sieving of plasmonic nanoparticles with plasmonic tweezers. PMID- 29529813 TI - Mode energy of graphene plasmons and its role in determining the local field magnitudes. AB - We theoretically study the mode energy of graphene plasmons and its fundamental role in determining the local field magnitudes. While neglecting the magnetic field energy of the mode, we derive a concise expression for the total mode energy, which is independent on the details of the mode field distributions and valid for both propagating and localized modes. We find that the mean square of the local electric fields of a graphene plasmonic mode scales linearly with the light absorption rate of the mode and the electron relaxation time of graphene. The possible strategies for improving the local field magnitudes of graphene plasmons are also discussed. Our theoretical analysis presented here may benefit the design of various graphene-based optical and optoelectronic devices for light harvesting or energy conversion. PMID- 29529814 TI - Deep learning based transceiver design for multi-colored VLC systems. AB - This paper presents a deep-learning (DL) based approach to the design of multi colored visible light communication (VLC) systems where RGB light-emitting diode (LED) lamps accomplish multi-dimensional color modulation under color and illuminance requirements. It is aimed to identify a pair of multi-color modulation transmitter and receiver leading to efficient symbol recovery performance. To this end, an autoencoder (AE), an unsupervised deep learning technique, is adopted to train the end-to-end symbol recovery process that includes the VLC transceiver pair and a channel layer characterizing the optical channel along with additional LED intensity control features. As a result, the VLC transmitter and receiver are jointly designed and optimized. Intensive numerical results demonstrate that the learned VLC system outperforms existing techniques in terms of the average symbol error probability. This framework sheds light on the viability of DL techniques in the optical communication system design. PMID- 29529815 TI - High-quality laser beam diagnostics using modified coherent phase modulation imaging. AB - Coherent modulation imaging (CMI) is a promising technique for online laser beam diagnostics; however, obvious speckle noise is always generated in the reconstruction, seriously degrading the spatial resolution and, accordingly, the accuracy. To solve this problem, both the optical setup of the common CMI and its reconstruction algorithm are slightly modified, and the performance of CMI in laser beam diagnostics can be obviously improved. By adding the second detector to record additional intensity distribution and using it to strengthen the intensity constraint of common CMI algorithm, the speckle noise in the reconstructed image can be distinctively reduced, and thus both the spatial resolution and the measurement accuracy are improved significantly. The feasibility of this proposed method is verified by proof-of-principle experiments. PMID- 29529816 TI - Room temperature operation of mid-infrared InAs0.81Sb0.19 based photovoltaic detectors with an In0.2Al0.8Sb barrier layer grown on GaAs substrates. AB - In this paper, InAs0.81Sb0.19-based hetero-junction photovoltaic detector (HJPD) with an In0.2Al0.8Sb barrier layer was grown on GaAs substrates. By using technology computer aided design (TCAD), a design of a barrier layer that can achieve nearly zero valance band offsets was accomplished. A high quality InAs0.81Sb0.19 epitaxial layer was obtained with relatively low threading dislocation density (TDD), calculated from a high-resolution X-ray diffraction (XRD) measurement. This layer showed a Hall mobility of 15,000 cm2/V?s, which is the highest mobility among InAsSb layers with an Sb composition of around 20% grown on GaAs substrates. Temperature dependence of dark current, photocurrent response and responsivity were measured and analyzed for fabricated HJPD. HJPD showed the clear photocurrent response having a long cutoff wavelength of 5.35 MUm at room temperature. It was observed that the dark current of HJPDs is dominated by the diffusion limited current at temperatures ranging from 200K to room temperature from the dark current analysis. Peak responsivity of HJPDs exhibited the 1.18 A/W and 15 mA/W for 83K and a room temperature under zero bias condition even without anti-reflection coating (ARC). From these results, we believe that HJPDs could be an appropriate PD device for future compact and low power dissipation mid-infrared on-chip sensors and imaging devices. PMID- 29529817 TI - High optical gain in erbium-doped potassium double tungstate channel waveguide amplifiers. AB - We report on the optical-gain properties of channel waveguides patterned into lattice-matched KGdxLuyEr1-x-y(WO4)2 layers grown onto undoped KY(WO4)2 substrates by liquid phase epitaxy. A systematic investigation of gain is performed for five different Er3+ concentrations in the range of 0.75 to 10at.% and different pump powers and signal wavelengths. In pump-probe-beam experiments, relative internal gain, i.e., signal enhancement minus absorption loss of light propagating in the channel waveguide, is experimentally demonstrated, with a maximum value of 12 +/- 5 dB/cm for signals at the peak-emission wavelength of 1534.7 nm. PMID- 29529818 TI - Creation of stable dark and anti-dark solitons in polariton dyad. AB - By designing an appropriate defect potential in a nonresonantly pumped exciton polariton condensate, the polariton dyad consisting of two spatially separated condensates with phase locking can be realized. We use the phase coupling of the polariton dyad to investigate the existence of both dark and anti-dark solitons in the condensates. Surprisingly, these dissipative solitons appear to be stable and are not affected by the noise both from the initial condition and from the propagation. We show that these stable solitons are transformed from a spontaneously created metastable states by choosing the state with the highest particle number. PMID- 29529819 TI - Silicon photonic 8 * 8 cyclic Arrayed Waveguide Grating Router for O-band on-chip communication. AB - We report an 8 * 8 silicon photonic integrated Arrayed Waveguide Grating Router (AWGR) targeted for WDM routing applications in O-band. The AWGR was designed for cyclic-frequency operation with a channel spacing of 10 nm. The fabricated AWGR exhibits a compact footprint of 700 * 270 MUm2. Static device characterization revealed 3.545 dB maximum channel loss non-uniformity with 2.5 dB best-case channel insertion losses and 11 dB channel crosstalk, in good agreement with the simulated results. Successful data routing operation is demonstrated with 25 Gb/s signals for all 8 * 8 AWGR port combinations with a maximum power penalty of 2.45 dB. PMID- 29529820 TI - Temporal rocking in a nonlinear hybrid optomechanical system. AB - We explore theoretically the optomechanical interaction between a light field and a mechanical mode mediated by a Kerr nonlinear medium inside a Fabry-Perot cavity. When the system is driven by a strong and fast amplitude-modulated light field, i.e., in the so-called temporal rocking region, the cavity field and the mechanical oscillator show the characteristics of multistability. The rocking breaks down the continuous phase symmetry of the cavity field to a bistable case of two equivalent states with exact pi phase difference. In addition, the rocking can significantly enhance the optomechanical coupling between the light field and the mechanical oscillator, which can be used as a new handle to control the normal mode splitting of the mechanical spectrum. Moreover, the optomechanical cooling rate can be greatly modified by the rocking. With the optimized rocking parameters, the mechanical oscillator can be cooled down to its ground state more efficiently. Such a temporal rocking optomechanical system has potential applications in all-optical switching and enhancement of quantum effects. PMID- 29529821 TI - Diagnosis of warm dense conditions in foil targets heated by intense femtosecond laser pulses using Kalpha imaging spectroscopy. AB - Warm dense conditions in titanium foils irradiated with intense femtosecond laser pulses are diagnosed using an x-ray imaging spectroscopy technique. The line shapes of radially resolved titanium Kalpha spectra are measured with a toroidally bent GaAs crystal and an x-ray charge-coupled device. Measured spectra are compared with the K-shell emissions modeled using an atomic kinetics - spectroscopy simulation code. Kalpha line shapes are strongly affected by warm (5 40 eV) bulk electron temperatures and imply multiple temperature distributions in the targets. The spatial distribution of temperature is dependent on the target thickness, and a thin target shows an advantage to generate uniform warm dense conditions in a large area. PMID- 29529822 TI - Ultrafast imaging on the formation of periodic ripples on a Si surface with a prefabricated nanogroove induced by a single femtosecond laser pulse. AB - This paper reports the ultrafast imaging on the formation of periodic surface ripples induced by a single 800 nm, 50 fs laser pulse. The evolution process is observed on a Si surface with a prefabricated nanogroove. The ripples emerge very quickly, only 3 ps after the laser pulse with a fluence of 0.18 J/cm2 irradiating on the surface, and last for several hundreds of picoseconds. The ultrafast dynamics of laser-matter interaction, such as free carrier excitation, carrier and lattice heating, surface plasmon polariton (SPP) excitation, etc, are studied theoretically. The theoretical and experimental results support that the periodic ripples are caused by the periodic energy deposition due to SPP excitation. The emerge time could identify the surface melting causing the formation of periodic ripples, and exclude the other thermal effects, for example, hydrodynamics. PMID- 29529823 TI - Experimental validation of active holographic metasurface for electrically beam steering. AB - In this paper, a holographic metasurface possessing beam scanning capability at fixed frequency is presented. The desired radiation beam is obtained by using a reference wave to excite a sinusoidally-modulated impedance surface, which is equivalent to the interference pattern between the radiation wave and reference wave. By changing the bias voltage of varactor diodes loaded on the sub wavelength unit cells, the variation range of the modulated impedance can be tuned, resulting in the change of radiation angle. Both the simulation and experimental results demonstrate that the direction of the radiation beam can be tuned in the range from 23 degrees to 50 degrees at 5.5 GHz. The proposed holographic metasurface shows great potential applications in constructing planar beam scanning antenna for integrated microwave system. PMID- 29529824 TI - Formation of laser induced periodic structures on stainless steel using multi burst picosecond pulses. AB - The formation of periodic structures on stainless steel under linearly polarized multi-burst picosecond laser pulses irradiation was experimentally investigated. The resulting structures were characterized by scanning electron microscopy (SEM) analysis. This analysis of images revealed four distinctive (quasi-) periodic structures depending on the laser irradiation parameters, i.e., LSFLs, HSFLs, micro-grooves and nano-holes. It is demonstrated that the multi-burst picosecond pulses technique is capable of fabricating periodic structures with different scales and shapes. PMID- 29529825 TI - Determination of dynamic variations in the optical properties of graphene oxide in response to gas exposure based on thin-film interference. AB - We present an effective yet simple approach to study the dynamic variations in optical properties (such as the refractive index (RI)) of graphene oxide (GO) when exposed to gases in the visible spectral region, using the thin-film interference method. The dynamic variations in the complex refractive index of GO in response to exposure to a gas is an important factor affecting the performance of GO-based gas sensors. In contrast to the conventional ellipsometry, this method alleviates the need of selecting a dispersion model from among a list of model choices, which is limiting if an applicable model is not known a priori. In addition, the method used is computationally simpler, and does not need to employ any functional approximations. Further advantage over ellipsometry is that no bulky optics is required, and as a result it can be easily integrated into the sensing system, thereby allowing the reliable, simple, and dynamic evaluation of the optical performance of any GO-based gas sensor. In addition, the derived values of the dynamically changing RI values of the GO layer obtained from the method we have employed are corroborated by comparing with the values obtained from ellipsometry. PMID- 29529826 TI - Theoretical analysis of single-cycle self-compression of near infrared pulses using high-spatial modes in capillary fibers. AB - Soliton self-compression is demonstrated during the propagation of high spatial modes in hollow core fibers in the near-infrared spectral region, taking advantage of their negative dispersion response. We have found that there is always an optimum spatial mode to observe this phenomenon, compressing the pulses down to the single-cycle regime without needing any external compression device and with a consequent increase in the output peak power. Our result is relevant for any ultrashort laser application in which few- or single-cycle pulses are crucial. PMID- 29529827 TI - Integration of high-speed GaAs metal-semiconductor-metal photodetectors by means of transfer printing for 850 nm wavelength photonic interposers. AB - We propose and demonstrate the integration of 850 nm GaAs-based metal semiconductor-metal (MSM) photodetectors (PDs) based on transfer printing for application in photonic interposers. Both devices that directly interface with a multimode optical fiber (with device dimensions of 70 MUm * 70 MUm) as well as devices that interface with a SiN waveguide layer through a grating coupler (with device dimensions of 30 MUm * 30 MUm) are demonstrated. The dark currents are measured to be 22 nA and 7.2 nA at 2 V bias for the larger and smaller PDs respectively. For 850 nm wavelength, the external responsivities are measured to be 0.117 A/W and 0.1 A/W at 2 V bias. 20 GHz bandwidth is measured. Open 40 Gb/s eye diagrams are realized. PMID- 29529828 TI - Ultra-broadband infrared absorption by tapered hyperbolic multilayer waveguides. AB - Ultra-broadband strong absorption over 92% covering the infrared wavelength range of 1~6MUm is demonstrated by using the tapered hyperbolic Au-SiO2 multilayer waveguides on glass substrates. Such broadband absorption is formed by the stop light modes at various wavelengths located at different waveguide widths. A planar hyperbolic waveguide model is built to determine the stop-light modes by considering both forward and backward guided modes. The stop-light modes located inside the Au-SiO2 multilayer waveguide are simulated at the absorption peaks by reducing the Au loss. Tapered multilayer waveguides with varying top widths are further simulated, fabricated and measured, indicating the almost linear relation between the waveguide width and the stop-light wavelength. Moreover, the broadband absorption of tapered waveguide is proved to be angle-insensitive and polarization-independent, and the heat generation and temperature increase are also discussed. PMID- 29529829 TI - Automatic evaluation of traumatic brain injury based on terahertz imaging with machine learning. AB - The imaging diagnosis and prognostication of different degrees of traumatic brain injury (TBI) is very important for early care and clinical treatment. Especially, the exact recognition of mild TBI is the bottleneck for current label-free imaging technologies in neurosurgery. Here, we report an automatic evaluation method for TBI recognition with terahertz (THz) continuous-wave (CW) transmission imaging based on machine learning (ML). We propose a new feature extraction method for biological THz images combined with the transmittance distribution features in spatial domain and statistical distribution features in normalized gray histogram. Based on the extracted feature database, ML algorithms are performed for the classification of different degrees of TBI by feature selection and parameter optimization. The highest classification accuracy is up to 87.5%. The area under the curve (AUC) scores of the receiver operating characteristics (ROC) curve are all higher than 0.9, which shows this evaluation method has a good generalization ability. Furthermore, the excellent performance of the proposed system in the recognition of mild TBI is analyzed by different methodological parameters and diagnostic criteria. The system can be extensible to various diseases and will be a powerful tool in automatic biomedical diagnostics. PMID- 29529830 TI - Compact high-resolution spectrometer using two plane gratings with triple dispersion. AB - We demonstrate a compact high-resolution spectrometer scheme using two plane gratings. In this approach, the rays are first diffracted by a fixed grating, then incident on a rotating grating at the Littrow diffraction angle, and are finally diffracted and reflected back to the fixed grating again. Thus, triple dispersion (TD) occurs during measurement, increasing the resolution. The formulae of this compact high-resolution spectrometer are rigorously derived. A design simulation with two gratings of 1050 lines/mm is performed and discussed. In addition, a prototype of this spectrometer has been built and tested. Its spectral resolution reaches a precision of 36 pm. PMID- 29529831 TI - Dynamic balance of heat and mass in high power density laser welding. AB - An experimental system to observe the inner phenomenon of keyhole and molten pool through glass plate by high speed camera and spectrometer in high power density laser welding was set up. Two circular flows in the molten pool were observed by high speed camera, which transferred the mass from the front to the rear of the keyhole to keep the mass balance. Temperature distribution in the molten pool was firstly detected by spectrometer, which indicated that the circular flows acted as the cooling system to take heat away from the keyhole. The porosity formation process was also observed and the mechanism was discussed. PMID- 29529832 TI - Nonlinearities in GaAs cavities with high CW input powers enabled by photo oxidation quenching through ALD encapsulation. AB - We demonstrate that conformal encapsulation using atomic layer deposition of GaAs nano-cavity resonator made of photonic crystal cavity prevents photo-induced oxidation. This improvement allows injecting a large quantity of energy in the resonator without any degradation of the material, thus enabling spectral stability of the resonance. We prove second harmonic and third harmonic generation over more than one decade of pump power variation, thanks to this encapsulation, with a total efficiency (etaSHG = 8.3 * 10-5 W-1 and etaTHG = 1.2 * 10-3 W-2 ) and a large net output energy for both operations (PSHGout=0.2nW and PTHGout=8pW). PMID- 29529833 TI - Extended depth of field imaging through multicore optical fibers. AB - Compact microendoscopes use multicore optical fibers (MOFs) to visualize hard-to reach regions of the body. These devices typically have a large numerical aperture (NA) and are fixed-focus, leading to blurry images from a shallow depth of field with little focus control. In this work, we demonstrate a method to digitally adjust the collection aperture and therefore extend the depth of field of lensless MOF imaging probes. We show that the depth of field can be more than doubled for certain spatial frequencies, and observe a resolution enhancement of up to 78% at a distance of 50MUm from the MOF facet. Our technique enables imaging of complex 3D objects at a comparable working distance to lensed MOFs, but without the requirement of lenses, scan units or transmission matrix calibration. Our approach is implemented in post processing and may be used to improve contrast in any microendoscopic probe utilizing a MOF and incoherent light. PMID- 29529834 TI - Photodarkening as a heat source in ytterbium doped fiber amplifiers. AB - Theoretical and experimental evaluation of the photodarkening effect as a heat source in ytterbium doped fibers is presented. An additional non-radiative decay channel that opens after photodarkening the fiber is identified via fluorescence lifetime reduction and as an additional heat source proportional to inversion. It is included in the heat source model which was tested on a core-pumped fiber amplifiers. High temperature elevation at low pump powers shows potential heat related problems in high inversion systems that are more susceptible to photodarkening. PMID- 29529835 TI - Pre-chirp managed, core-pumped nonlinear PM fiber amplifier delivering sub-100-fs and high energy (10 nJ) pulses with low noise. AB - We demonstrate a pre-chirp managed amplification (PCMA) system that is based on two stages of core-pumped, polarization maintaining (PM) fiber amplifiers. It produces output pulses with <65 fs duration and >10 nJ pulse energy from single mode fibers. Tailoring of the spectra in the amplification chain enables pulse compression to near-perfect transform limited pulses (Strehl-ratio >0.9) and low intensity noise levels (0.008%) despite B-integrals >40 rad in the PCMA amplifier. Design strategies are presented. We expect this PCMA system to become an easy to implement add-on to a variety of existing sources while maintaining the advantages of the robustness of the PM standard fiber format. PMID- 29529836 TI - Extinction measurements of metallic nanoparticles arrays as a way to explore the single nanoparticle plasmon resonances. AB - The optical characterization of a single metallic nanostructure has a strong interest in the scientific community owing to its localized surface plasmon resonances. For a single nano-object, the simplest and the accepted optical characterization technique is dark-field spectroscopy, even if there are many drawbacks and a certain complexity to operate it. We propose here using extinction spectroscopy of nanoparticles ensembles to characterize optically a single nanostructure. The scattering spectrum of a single gold nanocylinder and the extinction spectrum of a well-chosen array show similar results. We perform an experimental and numerical comparative study to draw parallels between both techniques. PMID- 29529837 TI - High power tunable mid-infrared optical parametric oscillator enabled by random fiber laser. AB - Random fiber laser, as a kind of novel fiber laser that utilizes random distributed feedback as well as Raman gain, has become a research focus owing to its advantages of wavelength flexibility, modeless property and output stability. Herein, a tunable optical parametric oscillator (OPO) enabled by a random fiber laser is reported for the first time. By exploiting a tunable random fiber laser to pump the OPO, the central wavelength of idler light can be continuously tuned from 3977.34 to 4059.65 nm with stable temporal average output power. The maximal output power achieved is 2.07 W. So far as we know, this is the first demonstration of a continuous-wave tunable OPO pumped by a tunable random fiber laser, which could not only provide a new approach for achieving tunable mid infrared (MIR) emission, but also extend the application scenarios of random fiber lasers. PMID- 29529838 TI - Effective bandwidth of terahertz antiresonant reflecting pipe waveguide. AB - We numerically investigate the transmission of the antiresonant-reflection-based terahertz (THz) pipe waveguide in which the cladding layer is very thin or the cladding index is close to one. It is found that robustness of the waveguide confinement is maintained when the cladding thickness is small, while the guiding ability deteriorates when the cladding index approaches to one. Hence, to increase the effective bandwidth of the pipe waveguide, reducing the cladding thickness is more desirable. Moreover, we also examine the effective bandwidth under the condition that the pipe waveguide is subject to a fixed ratio of core diameter to cladding thickness. Numerical result indicates that, as the ratio increases, the effective bandwidth increases as well. PMID- 29529839 TI - Achromatic electromagnetic metasurface for generating a vortex wave with orbital angular momentum (OAM). AB - The vortex wave that carries orbital angular momentum has attracted much attention due to the fact that it can provide an extra degree of freedom for optical communication, imaging and other applications. In spite of this, the method of OAM generation at high frequency still suffers from limitations, such as chromatic aberration and low efficiency. In this paper, an azimuthally symmetric electromagnetic metasurface with wide bandwidth is designed, fabricated and experimentally demonstrated to efficiently convert a left-handed (right handed) circularly polarized incident plane wave (with a spin angular momentum (SAM) of tsh) to a right-handed (left-handed) circularly polarized vortex wave with OAM. The design methodology based on the field equivalence principle is discussed in detail. The simulation and measurement results confirm that the proposed method provides an effective way for generating OAM-carrying vortex wave with comparative performance across a broad bandwidth. PMID- 29529840 TI - Platelet count is associated with sustained virological response rates in treatments for chronic hepatitis C. AB - Background/Aims: This study was conducted to clarify the sustained virological response (SVR) prediction ability of baseline and treatment-related factors in patients with chronic hepatitis C virus (HCV) infection. Methods: This retrospective study collected data at four tertiary referral hospitals between June 2004 and July 2012. Out of 476 patients, 330 treatment-naive patients with chronic HCV infection were recruited. Pegylated interferon alpha-2a/- 2b plus ribavirin was administered for either 24 or 48 weeks depending on the HCV genotype. The baseline and treatment-related predictive factors of SVR were evaluated by analyzing data measured before treatment (i.e., baseline) and during treatment. Results: SVR rates for genotypes 1 and 2 were 63% (97/154) and 79.5% (140/176), respectively (p = 0.001). Multivariate analysis for baseline factors revealed that young age (p = 0.009), genotype 2 (p = 0.001), HCV RNA level of < 800,000 IU/mL (p < 0.001), and a baseline platelet count of > 150 * 103 /uL (p < 0.001) were significant SVR predictors, regardless of the genotype. In particular, predictive accuracy for achievement of SVR was 87.3% for a baseline platelet count of > 150 * 103 /uL. In multivariate analysis for treatment-related factors, SVR was associated with achievement of a rapid virological response (RVR; p < 0.001), treatment adherence of >= 80/80/80 (p < 0.001). Conclusions: Young age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. In addition, platelet count was an independent predictive factor for SVR. Therefore, platelet count could be used to develop individualized treatment regimens and to optimize treatment outcomes in patients with chronic HCV infection. PMID- 29529841 TI - Outcome of donor biliary complications following living donor liver transplantation. AB - Background/Aims: Biliary complications are the most common donor complication following living donor liver transplantation (LDLT). The aim of this study is to investigate the long-term outcomes of biliary complications in right lobe adult to-adult LDLT donors, and to evaluate the efficacy of endoscopic treatment of these donors. METHODS: The medical charts of right lobe donors who developed biliary complications between June 2000 and January 2008 were retrospectively reviewed. RESULTS: Of 337 right lobe donors, 49 developed biliary complications, including 36 diagnosed with biliary leakage and 13 with biliary stricture. Multivariate analysis showed that biliary leakage was associated with the number of right lobe bile duct orifices. Sixteen donors, five with leakage and 11 with strictures, underwent endoscopic retrograde cholangiography (ERC). ERC was clinically successful in treating eight of the 11 strictures, one by balloon dilatation and seven by endobiliary stenting. Of the remained three, two were treated by rescue percutaneous biliary drainage and one by conservative care. Of the five patients with leakage, four were successfully treated using endobiliary stents and one with conservative care. In overall, total 35 improved with conservative treatment. All inserted stents were successfully retrieved after a median 264 days (range, 142 to 502) and there were no recurrences of stricture or leakages during a median follow-up of 10.6 years (range, 8 to 15.2). Conclusions: All donors with biliary complications were successfully treated non-surgically, with most improving after endoscopic placement of endobiliary stents and none showing recurrence on long term follow-up. PMID- 29529842 TI - Risk factors for hypothyroidism in euthyroid thyroid nodule patients with lymphocytic thyroiditis on fine needle aspiration cytology. AB - Background/Aims: Lymphocytic thyroiditis as cytology diagnosis from fine needle aspiration (FNA) is frequently detected in patients with thyroid nodules. However, the clinical outcome for upcoming hypothyroid events has been rarely clarified in euthyroid patients. Methods: We retrospectively reviewed the data of patient who had lymphocytic thyroitidis on FNA cytology of thyroid nodule from January 2005 to December 2010 at a tertiary referral hospital. In total, 109 patients with follow-up thyroid function tests (TFT) were enrolled. Final outcomes included overt and subclinical hypothyroidism with thyroid stimulating hormone (TSH) levels >= 10 mIU/L. Potential parameters predicting clinical hypothyroidism were analyzed by multivariate analysis. Results: Over the mean follow-up duration of 51.6 months, 14 out of 109 patients (12.8%) developed clinical hypothyroidism that required thyroid hormone replacement. The median onset time to hypothyroidism was 16 months (range, 3 to 88) and >= 60% of patients experienced clinical hypothyroidism within 1 year. By multivariate analysis, background thyroiditis (relative risk [RR], 9.78; p = 0.004), thyroid peroxidase antibody positivity (RR, 9.90; p = 0.003), nodule size (RR, 1.24; p < 0.001), and initial TSH (RR, 1.47; p = 0.009) were the independent risk factors for predicting hypothyroidism in euthyroid patients. Conclusions: Hypothyroidism frequently occurs during the follow-up in euthyroid patients with thyroid nodules which show lymphocytic thyroiditis on FNA cytology. Close surveillance and regular TFT are needed in high-risk patients for upcoming clinical hypothyroidism. PMID- 29529843 TI - Clinical significance of nuclear factor erythroid 2-related factor 2 in patients with chronic obstructive pulmonary disease. AB - Background/Aims: Several studies have identified a role for nuclear factor erythroid 2-related factor 2 (Nrf2) in the development of chronic obstructive pulmonary disease (COPD). However, the relationship between the plasma Nrf2 level and the extent of systemic inflammation associated with COPD status remains unclear. METHODS: Patients diagnosed with COPD were recruited from St. Paul's Hospital, The Catholic University of Korea, between July 2009 and May 2012. Patients were classified into two groups according to the severity of their symptoms on initial presentation, a COPD-stable group (n = 25) and a COPD exacerbation group (n = 30). Seventeen patients were enrolled as a control group (n = 17). The plasma levels of Nrf2 and other systemic inf lammatory biomarkers, including interleukin 6 (IL-6), surfactant protein D (SP-D), and C-reactive protein (CRP), were measured. We collected clinical data including pulmonary function test results, and analyzed the relationships between the biomarker levels and the clinical parameters. RESULTS: Plasma Nrf2 and CRP levels significantly increased in a stepwise manner with an increase in inflammatory status (control vs. COPD-stable vs. COPD-exacerbation) (p = 0.002, p < 0.001). Other biomarkers of systemic inflammation (IL-6, SP-D) exhibited similar tendencies, but significant differences were not apparent. Furthermore, we observed negative correlations between the plasma level of Nrf2 and both the forced expiratory volume in 1 second (FEV1) (r = -0.339, p = 0.015) and the forced expiratory ratio (FEV1/forced vital capacity [FVC]) (r = -0.342, p = 0.014). However, CRP level was not correlated with any measured parameter. Conclusions: Plasma Nrf2 levels gradually increased in line with disease severity and the extent of systemic inflammation in patients with COPD. PMID- 29529844 TI - Pyruvate Protects Giardia Trophozoites from Cysteine-Ascorbate Deprived Medium Induced Cytotoxicity. AB - Giardia lamblia, an anaerobic, amitochondriate protozoan parasite causes parasitic infection giardiasis in children and young adults. It produces pyruvate, a major metabolic product for its fermentative metabolism. The current study was undertaken to explore the effects of pyruvate as a physiological antioxidant during oxidative stress in Giardia by cysteine-ascorbate deprivation and further investigation upon the hypothesis that oxidative stress due to metabolism was the reason behind the cytotoxicity. We have estimated intracellular reactive oxygen species generation due to cysteine-ascorbate deprivation in Giardia. In the present study, we have examined the effects of extracellular addition of pyruvate, during oxidative stress generated from cysteine-ascorbate deprivation in culture media on DNA damage in Giardia. The intracellular pyruvate concentrations at several time points were measured in the trophozoites during stress. Trophozoites viability under cysteine-ascorbate deprived (CAD) medium in presence and absence of extracellular pyruvate has also been measured. The exogenous addition of a physiologically relevant concentration of pyruvate to trophozoites suspension was shown to attenuate the rate of ROS generation. We have demonstrated that Giardia protects itself from destructive consequences of ROS by maintaining the intracellular pyruvate concentration. Pyruvate recovers Giardia trophozoites from oxidative stress by decreasing the number of DNA breaks that might favor DNA repair. PMID- 29529845 TI - Molecular Method Confirms Canine Leishmania Infection Detected by Serological Methods in Non-Endemic Area of Brazil. AB - In Brazil, visceral leishmaniasis (VL) is expanding and becoming urbanized, especially in non-endemic areas such as the State of Rio Grande do Sul. Considering that infected dogs are the main reservoir for zoonotic VL, this study evaluated the prevalence of canine visceral leishmaniasis (CVL) in the metropolitan area of Porto Alegre, a new area of expansion of VL in Brazil. Serum and plasma from 405 asymptomatic dogs from the municipalities of Canoas (n=107), Sao Leopoldo (n=216), and Novo Hamburgo (n=82) were tested for CVL using immunochromatographic (DPP(r)) and ELISA EIE(r) assays (2 assays officially adopted by the Brazilian government for the diagnosis of CVL) and real-time PCR to confirm the results. There was no agreement among serological and real-time PCR results, indicating that the Leishmania infection in asymptomatic animals with low parasite load, confirmed by negative parasitological tests (smears and parasite culture), need to be evaluated by molecular methods. The prevalence of LVC in the metropolitan region of Porto Alegre, confirmed by real-time PCR was 4% (5.6% in Canoas and 4.6% in Sao Leopoldo). The use of molecular method is essential for accurate diagnosis of CVL, especially in asymptomatic dogs in non endemic areas. PMID- 29529846 TI - Epidemiological Aspects of Cutaneous Leishmaniasis during 2009-2016 in Kashan City, Central Iran. AB - Cutaneous leishmaniasis (CL) can be seen in 2 forms, zoonotic and anthroponotic, in Iran. In this study, epidemiological aspects of CL were studied during an 8 year period (2009-2016) in city of Kashan, central Iran. The demographic and epidemiological data, including age, sex, occupation, number and site of the lesions, treatment regimen, past history of CL, and season of all patients were gathered from the health centers. Descriptive statistics were used to describe features of the study data. Total 2,676 people with CL were identified. The highest annual incidence was estimated to be 182 per 100,000 population in 2009 and the least was in 2016 (47 per 100,000 population). The highest frequency affected age groups were observed in 20-29 year-old patients (20.9%). More than 51% of the patients were under 30 years old. The maximum frequency of the disease, 1,134 (43.3%), was seen in autumn. The most common location of lesions was hands (61.4%). Most of the patients (81.6%) were treated by systemic glucantime regimen. In the city of Kashan, the incidence rate of the CL disease is significantly higher than many other regions of Iran. To reduce the risk of disease, control of reservoir hosts and vectors of disease, and education of individual protection are strongly recommended. PMID- 29529847 TI - An Alternative Method for Extracting Plasmodium DNA from EDTA Whole Blood for Malaria Diagnosis. AB - Molecular techniques have been introduced for malaria diagnosis because they offer greater sensitivity and specificity than microscopic examinations. Therefore, DNA isolation methods have been developed for easy preparation and cost effectiveness. The present study described a simple protocol for Plasmodium DNA isolation from EDTA-whole blood. This study demonstrated that after heating infected blood samples with Tris-EDTA buffer and proteinase K solution, without isolation and purification steps, the supernatant can be used as a DNA template for amplification by PCR. The sensitivity of the extracted DNA of Plasmodium falciparum and Plasmodium vivax was separately analyzed by both PCR and semi nested PCR (Sn-PCR). The results revealed that for PCR the limit of detection was 40 parasites/MUl for P. falciparum and 35.2 parasites/MUl for P. vivax, whereas for Sn-PCR the limit of detection was 1.6 parasites/MUl for P. falciparum and 1.4 parasites/MUl for P. vivax. This new method was then verified by DNA extraction of whole blood from 11 asymptomatic Myanmar migrant workers and analyzed by Sn PCR. The results revealed that DNA can be extracted from all samples, and there were 2 positive samples for Plasmodium (P. falciparum and P. vivax). Therefore, the protocol can be an alternative method for DNA extraction in laboratories with limited resources and a lack of trained technicians for malaria diagnosis. In addition, this protocol can be applied for subclinical cases, and this will be helpful for epidemiology and control. PMID- 29529848 TI - Prevalence of Intestinal Parasites and Associated Risk Factors for Infection among Rural Communities of Chachoengsao Province, Thailand. AB - Intestinal parasitic infections remain a major public health problem in many parts of Thailand, particularly in rural areas. This study aimed to determine the prevalence of intestinal parasitic infections and associated risk factors among the people living in Huai Sai sub-district, Bang Khla district, Chachoengsao Province, central Thailand. A cross-sectional survey was carried out from June 2017 to August 2017 which included a total of 224 participants. Stool samples were examined using a simple direct smear and formalin ethyl acetate concentration technique. Association between risk factors and intestinal parasitic infections was assessed using multivariate logistic regression analysis. The overall prevalence of intestinal parasitic infections was 16.1%. Soil-transmitted helminth infections (14.3%) were more common than protozoan infections (1.8%). The most common intestinal parasites were hookworms (6.7%) followed by Strongyloides stercoralis, (5.0%), Ascaris lumbricoides (1.3%) and Trichuris trichiura (1.3%). Entamoeba histolytica/dispar (1.0%), Giardia intestinalis (0.4%), and Blastocystis hominis (0.4%) were the protozoans identified. A high prevalence of infections was found in male participants of >=40 years who raised dogs in the households and did not wear boots while working fields. Multivariate analysis showed a significant association of intestinal parasitic infections with gender with the adjusted odds ratio (OR) of 2.4 and 95% confidence interval (CI) of 1.1-5.2 (P=0.020). The results showed a high prevalence of soil-transmitted helminth infections among adults in rural communities which were particularly apparent regarding the skin-penetrating species of nematodes. A greater focus on intervention is required by improving sanitation and personal hygiene to prevent the spread of intestinal parasitic infections. PMID- 29529849 TI - Prevalence and Intensity of Clonorchis sinensis Metacercariae in Freshwater Fish from Wicheon Stream in Gunwi-gun, Gyeongsangbuk-do, Korea. AB - The infection status of Clonorchis sinensis metacercariae (CsMc) was examined in freshwater fish from a highly prevalent site, Wicheon (a branch of Nakdong-gang), which is located in Gunwi-gun, Gyeongsangbuk-do, the Republic of Korea. Total 1,162 fish in 32 species were examined by the artificial digestion method through 6 years. CsMc were detected in 720 (67.5%) out of 1,067 fish (26 spp.) and their density was 610 per fish infected. In the susceptible gobioninid fish group, i.e., Pungtungia herzi, Squalidus gracilis majimae, Squalidus japonicus coreanus, Sarcocheilichthys variegatus wakiyae and Pseudorasbora parva, all of 323 fish were infected with an average of 1,310 CsMc. Total 23 (95.8%) gobioninid fish, i.e., Pseudogobio esocinus, Abbottina springeri, Hemibarbus longirostris, Microphysogobio koreensis, and Microphysogobio jeoni, were infected with 127 CsMc in average. In the acheilognathinid fish (bitterlings) group, the prevalence was 77.0%, and the density was 50 CsMc per fish infected. In the rasborinid fish (chubs) group, i.e., Zacco platypus, Zacco temminckii, Zacco koreanus, and Opsariichthys uncirostris amurensis, 147 (36.5%) out of 403 fish examined were infected with 15 CsMc in average. The susceptibility indices of CsMc were 412 in the overall positive fish group, 1,310 in the gobioninid group-1, 122 in the gobioninid group-2, 38.5 in the acheilognathinid group, and 5.5 in the rasborinid fish group. Conclusively, it was confirmed that CsMc are highly prevalent in fish from Wicheon, and their infection tendency varied according to the subfamily groups in Cyprinidae fish hosts. PMID- 29529850 TI - New Record of Thapariella anastomusa (Trematoda: Thapariellidae) Metacercariae in Northern Thailand. AB - The family Thapariellidae has been reported in only 3 countries since 1990. The objective of this study was to identify Thapariella anastomusa metacercariae in snails in Thailand based on morphological traits using a light (LM) and a scanning electron microscope (SEM). A total of 94 Filopaludina snails were collected and identified as 50 F. martensi martensi and 44 F. doliaris. Metacercariae of T. anastomusa were recovered from the snails by the crushing method. The overall prevalence was 22.3% (21/94), and the mean intensity was 17.0 per snail. The prevalence in F. martensi martensi was 24.0% (12/50) and F. doliaris 20.5% (9/44) with the mean intensity of 18.8 and 14.8 per snail, respectively. SEM revealed traits such as a concave ventral body and well developed oral and ventral suckers. This study represents the first report of T. anastomusa in South East Asia. While LM and SEM observations provide novel insights into T. anastomusa metacercarial morphology and life history, the trematode's life cycle remains unclear. To date, there has been no report of T. anastomusa causing infections in humans. However, the snails F. martensi martensi and F. doliaris carrying the infective stages of T. anastomosa are frequently consumed by Thai people. This consumption, particularly uncooked snails, may present a risk of Thapariella infections in humans. PMID- 29529851 TI - Expression Patterns of Host Inflammatory Cytokine Genes during Infestation with Haemaphysalis longicornis, a Zoonotic Vector, in Blood Sucking Periods. AB - Tick saliva is critically important for continuous attachment to the host, blood feeding for days, and transmission of tick-borne pathogens. To characterize the patterns of inflammatory cytokine gene expression during its attachment and blood sucking time, peripheral blood samples of rabbits infested with Haemaphysalis longicornis ticks were collected at different intervals. Blood histamine concentration was evaluated as well as gene encoding IFN-gamma, TNF-alpha, IL-2, IL-6, IL-4, and IL-10 were compared with non-infested rabbits. Blood histamine concentration of tick-infested rabbits during fast feeding time was significantly higher than that of non-infested rabbits. In both nymph and adult tick infested rabbits, expression of TNF-alpha and IFN-gamma genes were decreased significantly (P<0.05), while expression of IL-4, IL-6, and IL-10 were increased 1.3 to 7 folds in adult infested rabbits with the exception of IL-6 that was significantly (P<0.05) decreased in nymph infested rabbits. IL-2 was not expressed in either nymph or adult infestation. H. longicornis saliva is capable of modulate host responses through a complex correlation with histamine and Th1, Th2 mediated cytokines that suppress the inflammatory responses directed toward inflammatory mediators introduced into the host during tick feeding. PMID- 29529852 TI - Development of a Rapid Diagnostic Test Kit to Detect IgG/IgM Antibody against Zika Virus Using Monoclonal Antibodies to the Envelope and Non-structural Protein 1 of the Virus. AB - We developed a Rapid Diagnostic Test (RDT) kit for detecting IgG/IgM antibodies against Zika virus (ZIKV) using monoclonal antibodies to the envelope (E) and non structural protein 1 (NS1) of ZIKV. These proteins were produced using baculovirus expression vector with Sf9 cells. Monoclonal antibodies J2G7 to NS1 and J5E1 to E protein were selected and conjugated with colloidal gold to produce the Zika IgG/IgM RDT kit (Zika RDT). Comparisons with ELISA, plaque reduction neutralization test (PRNT), and PCR were done to investigate the analytical sensitivity of Zika RDT, which resulted in 100% identical results. Sensitivity and specificity of Zika RDT in a field test was determined using positive and negative samples from Brazil and Korea. The diagnostic accuracy of Zika RDT was fairly high; sensitivity and specificity for IgG was 99.0 and 99.3%, respectively, while for IgM it was 96.7 and 98.7%, respectively. Cross reaction with dengue virus was evaluated using anti-Dengue Mixed Titer Performance Panel (PVD201), in which the Zika RDT showed cross-reactions with DENV in 16.7% and 5.6% in IgG and IgM, respectively. Cross reactions were not observed with West Nile, yellow fever, and hepatitis C virus infected sera. Zika RDT kit is very simple to use, rapid to assay, and very sensitive, and highly specific. Therefore, it would serve as a choice of method for point-of-care diagnosis and large scale surveys of ZIKV infection under clinical or field conditions worldwide in endemic areas. PMID- 29529853 TI - Serodiagnosis of Extraintestinal Amebiasis: Retrospective Evaluation of the Diagnostic Performance of the Bordier(r) ELISA Kit. AB - Soluble antigens from an axenic culture of Entamoeba histolytica were used to develop a commercial ELISA kit to quantify anti-E. histolytica antibodies in sera of patients with extraintestinal amebiasis in non-endemic settings. The diagnostic specificity and sensitivity of the test were assessed retrospectively using 131 human serum samples with amoebic serologic status available. They were selected according to their results in immunofluorescence (IFAT) and were separated in 2 sample categories: 64 sera with positive results by IFAT and 67 with negative results by IFAT. The sensitivity and specificity of the ELISA kit were assessed at 95.0% and 94.0% compared to the IFAT. The test can be useful to exclude a potential diagnosis of amebiasis and could be used as a screening method since ELISA is an automated technique. PMID- 29529854 TI - Echinostoma ilocanum Infection in Two Residents of Savannakhet Province, Lao PDR. AB - Adult specimens of Echinostoma ilocanum (Garrison, 1908) Odhner, 1911 (Trematoda: Echinostomatidae) were recovered from 2 riparian people who resided along the Mekong River in Savannakhet Province, Lao PDR. In fecal examinations done by the Kato-Katz technique, they revealed echinostome eggs together with eggs of Opisthorchis viverrini (and minute intestinal fluke eggs) and hookworms. To recover the adult flukes, they were treated with praziquantel 30-40 mg/kg in a single dose and purged with magnesium salts. A total of 658 adult fluke specimens were recovered from the 2 people; 456 from case 1 and 202 from case 2. Specimens from case 1 consisted of 335 echinostomes (301 E. ilocanum and 34 species undetermined), 120 O. viverrini, and 1 Haplorchis taichui, and those from case 2 consisted of 36 E. ilocanum, 134 O. viverrini, and 32 H. taichui. Thus, the number of E. ilocanum specimens was 337 in total (average per person, 168.5). From this study, it is suggested that foodborne intestinal flukes and liver flukes are highly prevalent along the Mekong River in Savannakhet Province. The present report describes for the first time human infections with E. ilocanum in Lao PDR. PMID- 29529855 TI - Comparative Characterization of Four Calcium-Binding EF Hand Proteins from Opisthorchis viverrini. AB - Four isoforms of calcium binding proteins containing 2 EF hand motifs and a dynein light chain-like domain in the human liver fluke Opisthorchis viverrini, namely OvCaBP1, 2, 3, and 4, were characterized. They had molecular weights of 22.7, 21.6, 23.7, and 22.5 kDa, respectively and showed 37.2-42.1% sequence identity to CaBP22.8 of O. viverrini. All were detected in 2- and 4-week-old immature and mature parasites. Additionally, OvCaBP4 was found in newly excysted juveniles. Polyclonal antibodies against each isoform were generated to detect the native proteins in parasite extracts by Western blot analysis. All OvCaBPs were detected in soluble and insoluble crude worm extracts and in the excretory secretory product, at approximate sizes of 21-23 kDa. The ion-binding properties of the proteins were analyzed by mobility shift assays with the divalent cations Ca2+, Mg2+, Zn2+, and Cu2+. All OvCaBPs showed mobility shifts with Ca2+ and Zn2+. OvCaBP1 showed also positive results with Mg2+ and Cu2+. As tegumental proteins, OvCaBP1, 2, and 3 are interesting drug targets for the treatment of opisthorchiasis. PMID- 29529856 TI - Spirometra decipiens (Cestoda: Diphyllobothriidae) Collected in A Heavily Infected Stray Cat from the Republic of Korea. AB - Morphological and molecular characteristics of spirometrid tapeworms, Spirometra decipiens, were studied, which were recovered from a heavily infected stray cat road-killed in Eumseong-gun, Chungcheongbuk-do (Province), the Republic of Korea (=Korea). A total of 134 scolices and many broken immature and mature proglottids of Spirometra tapeworms were collected from the small intestine of the cat. Morphological observations were based on 116 specimens. The scolex was 22.8-32.6 mm (27.4 mm in average) in length and small spoon-shape with 2 distinct bothria. The uterus was coiled 3-4 times, the end of the uterus was ball-shaped, and the vaginal aperture shaped as a crescent moon was closer to the cirrus aperture than to the uterine aperture. PCR amplification and direct sequencing of the cox1 target fragment (377 bp in length and corresponding to positions 769-1,146 bp of the cox1 gene) were performed using total genomic DNA extracted from 134 specimens. The cox1 sequences (377 bp) of the specimens showed 99.0% similarity to the reference sequence of S. decipiens and 89.3% similarity to the reference sequence of S. erinaceieuropaei. In the present study, we report a stray cat heavily infected with S. decipiens identified by mitochondrial cox1 sequence analysis and morphological examinations of the adult worms. PMID- 29529857 TI - Endoparasites of Small Mammals in Edo State, Nigeria: Public Health Implications. AB - Some small mammals occur as household pests and harbour a number of parasites that could be of public health importance. This study profiled the helminth and protozoan parasites in trapped small mammals within and around human dwelling places (houses) located across 4 major towns (Auchi, Benin, Ekpoma, and Uromi) and environs in Edo state, Nigeria. Six genera (Apodemus sp., Crocidura sp., Mastomys natalensis, Mus musculus, Rattus sp., and Sorex sp.) were identified from 502 trapped small mammals. Overall, M. musculus (71.9%) and Rattus rattus (20.1%) were the most frequently trapped. In total, on examination of blood, gastrointestinal contents, and brain tissues, 12 helminth taxa (Angiostrongylus sp., Aspicularis sp., Capillaria sp., Gongylonema sp., Heterakis spumosa, Hymenolepis diminuta, Hymenolepis nana, Mastophorus muris, Moniliformis moniliformis, Nippostrongylus brasiliensis, Strongyloides sp., Trichosomoides sp., and Trichuris sp.), and 6 protozoan parasites (Babesia sp., Trypanosoma lewisi, Plasmodium sp., Eimeria sp., Isospora sp., and Toxoplasma gondii) were isolated. Most prevalent helminths with relatively heavy mean intensity were Strongyloides sp. and Heterakis spumosa, while Plasmodium, Eimeria, and Isospora were the most prevalent protozoan parasites. Generally, intrinsic factors like sex and age had marginal influence on the rate and burden of infection in M. musculus and R. rattus. Although the infection rate and prevalence of zoonotic parasites were low, they were largely recovered in rodents from Ekpoma. This study elucidates the public health implication of the presence of zoonotic parasites in these small mammals. PMID- 29529858 TI - Randomized Phase III Trial of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin in Chemotherapy-Naive Korean Patients with Extensive-Disease Small Cell Lung Cancer. AB - Purpose: This randomized phase III study was designed to compare the efficacy and safety of irinotecan plus cisplatin (IP) over etoposide plus cisplatin (EP) in Korean patients with extensive-disease small-cell lung cancer (SCLC). Materials and Methods: Patients were randomly assigned to receive IP, composed of irinotecan 65 mg/m2 intravenously on days 1 and 8 + cisplatin 70 mg/m2 intravenously on day1 every 3 weeks, or EP, composed of etoposide 100 mg/m2 intravenously on days 1, 2, 3+cisplatin 70 mg/m2 intravenously on day 1, every 3 weeks for a maximum of six cycles, until disease progression, or until unacceptable toxicity occurred. The primary endpoint was overall survival. Results: A total of 362 patients were randomized to IP (n=173) and EP (n=189) arms. There were no significant differences between IP and EP arms for the median overall survival (10.9 vs. 10.3 months, p=0.120) and the median progression-free survival (6.5 vs. 5.8 months, p=0.1125). However, there was a significant difference in response rate (62.4 vs. 48.2%, p=0.0064). The pre-planned subgroup analyses showed that IP was associated with longer overall survival in male (11.3 vs. 10.1 months, p=0.0361), <65 years old (12.7 vs. 11.3 months, p=0.0240), and ECOG performance status 0/1 (12.4 vs. 10.9 months, p=0.0407) patient groups. The severity of treatment-related adverse events such as grade 3/4 anemia, nausea and diarrhea was more frequent in patients treated with IP. Conclusion: The IP chemotherapy did not significantly improve the survival compared with EP chemotherapy in Korean patients with extensive-disease SCLC. (ClinicalTrials.gov Identifier: NCT00349492). PMID- 29529859 TI - The effects of water-pipe smoking on birth weight: a population-based prospective cohort study in southern Iran. AB - OBJECTIVES: Consecutive community health assessments revealed that water-pipe smoking in women and impaired growth in children were among the main health concerns in suburban communities in southern Iran. The aim of the present study was to identify the effects of water-pipe smoking during pregnancy on birth weight. METHODS: Data from a population-based prospective cohort study of 714 singleton live pregnancies in the suburbs of Bandar Abbas in southern Iran in 2016-2018 were used in this study. Data about water-pipe smoking patterns and birth weight were collected by questionnaires during and after the pregnancy. Low birth weight (LBW) was defined as a birth weight below 2,500 g. Statistical analyses were performed using generalized linear models, and the results were presented in terms of relative risk (RR) and 95% confidence intervals (CI). RESULTS: Fifty (8.2%) of the study subjects smoked water-pipe. The adjusted risk of LBW increased 2-fold in water-pipe smokers (adjusted RR [aRR], 2.09; 95% CI, 1.18 to 3.71), and by 2.0% for each 1-year increase in the duration of water-pipe smoking (aRR, 1.02; 95% CI, 0.99 to 1.05). CONCLUSIONS: Our results showed that water-pipe smoking during pregnancy was an important risk factor for LBW in this population sample from southern Iran. The introduction of regulations onto prevent water-pipe smoking and the implementation of community health action plans aiming at empowering women and increasing women's knowledge and awareness regarding the health consequences of water-pipe smoking are proposed. PMID- 29529860 TI - Application of an artificial neural network model for diagnosing type 2 diabetes mellitus and determining the relative importance of risk factors. AB - OBJECTIVES: To identify the most important demographic risk factors for a diagnosis of type 2 diabetes mellitus (T2DM) using a neural network model. METHODS: This study was conducted on a sample of 234 individuals, in whom T2DM was diagnosed using hemoglobin A1c levels. A multilayer perceptron artificial neural network was used to identify demographic risk factors for T2DM and their importance. The DeLong method was used to compare the models by fitting in sequential steps. RESULTS: Variables found to be significant at a level of p<0.2 in a univariate logistic regression analysis (age, hypertension, waist circumference, body mass index [BMI], sedentary lifestyle, smoking, vegetable consumption, family history of T2DM, stress, walking, fruit consumption, and sex) were entered into the model. After 7 stages of neural network modeling, only waist circumference (100.0%), age (78.5%), BMI (78.2%), hypertension (69.4%), stress (54.2%), smoking (49.3%), and a family history of T2DM (37.2%) were identified as predictors of the diagnosis of T2DM. CONCLUSIONS: In this study, waist circumference and age were the most important predictors of T2DM. Due to the sensitivity, specificity, and accuracy of the final model, it is suggested that these variables should be used for T2DM risk assessment in screening tests. PMID- 29529861 TI - 3D Protein-Based Bilayer Artificial Skin for the Guided Scarless Healing of Third Degree Burn Wounds in Vivo. AB - Severe burn injuries can lead to delays in healing and devastating scar formation. Attempts have been made to develop a suitable skin substitute for the scarless healing of such skin wounds. Currently, there is no effective strategy for completely scarless healing after the thermal injuries. In our recent work, we fabricated and evaluated a 3D protein-based artificial skin made from decellularized human amniotic membrane (AM) and electrospun nanofibrous silk fibroin (ESF) in vitro. We also characterized both biophysical and cell culture investigation to establish in vitro performance of the developed bilayer scaffolds. In this report, we evaluate the appropriate utility of this fabricated bilayered artificial skin in vivo with particular emphasis on healing and scar formation due to the biochemical and biomechanical complexity of the skin. For this work, AM and AM/ESF membranes alone or seeded with adipose-tissue-derived mesenchymal stem cells (AT-MSCs) are implanted on full-thickness burn wounds in mice. The healing efficacy and scar formation are evaluated at 7, 14, and 28 days post-implantation in vivo. Our data reveal that ESF accelerates the wound-healing process through the early recruitment of inflammatory cells such as macrophages into the defective site as well as the up-regulation of angiogenic factors from the AT-MSCs and the facilitation of the remodeling phase. In vivo application of the prepared AM/ESF membrane seeded with the AT-MSCs reduces significantly the post-burn scars. The in vivo data suggest that the potential applications of the AM/ESF bilayered artificial skin may be considered a clinical translational product with stem cells to guide the scarless healing of severe burn injuries. PMID- 29529862 TI - Targeting Ligandable Pockets on Plant Homeodomain (PHD) Zinc Finger Domains by a Fragment-Based Approach. AB - Plant homeodomain (PHD) zinc fingers are histone reader domains that are often associated with human diseases. Despite this, they constitute a poorly targeted class of readers, suggesting low ligandability. Here, we describe a successful fragment-based campaign targeting PHD fingers from the proteins BAZ2A and BAZ2B as model systems. We validated a pool of in silico fragments both biophysically and structurally and solved the first crystal structures of PHD zinc fingers in complex with fragments bound to an anchoring pocket at the histone binding site. The best-validated hits were found to displace a histone H3 tail peptide in competition assays. This work identifies new chemical scaffolds that provide suitable starting points for future ligand optimization using structure-guided approaches. The demonstrated ligandability of the PHD reader domains could pave the way for the development of chemical probes to drug this family of epigenetic readers. PMID- 29529863 TI - Targeting of G-Quadruplex Harboring Pre-miRNA 92b by LNA Rescues PTEN Expression in NSCL Cancer Cells. AB - Since the elevated levels of microRNAs (miRNAs) often cause various diseases, selective inhibition of miRNA maturation is an important therapeutic strategy. Commonly used anti-miRNA strategies are limited to targeting of mature miRNAs, as the upstream targeting of miRNA maturation with an oligonucleotide is challenging due to the presence of a stable pre-miRNA stem-loop structure. Previously, we reported that about 16% of known human pre-miRNAs have the potential to adopt G quadruplex (GQ) structures alternatively to canonical stem-loops. Herein, we showed that a rationally designed locked nucleic acid (LNA) binds specifically the GQ conformation of pre-miRNA 92b and inhibits pre-miRNA maturation. Further, we showed that the LNA treatment rescues PTEN expression in non-small-cell lung cancer (NSCLC) cells, which is suppressed by the elevated level of miRNA 92b. Treatment of LNA significantly decreases the IC50 of doxorubicin for NSCLC cells. This strategy can be developed as a novel anti-miRNA therapeutic approach to target GQ harboring miRNAs. This can potentially be a more powerful approach than targeting of the mature miRNA, as it is an upstream targeting and can reduce both 3' and the 5' mature miRNA levels at once. PMID- 29529864 TI - A Thermoresponsive Cationic Comb-Type Copolymer Enhances Membrane Disruption Activity of an Amphiphilic Peptide. AB - Membrane active peptides (MAPs) have potential applications in drug delivery systems and as antimicrobials. We previously showed that a cationic comb-type copolymer, poly(allylamine)- graft-dextran (PAA- g-Dex), forms a soluble inter polyelectrolyte complex with an anionic MAP, the E5 peptide, resulting in significant enhancement of the membrane disruption activity of E5. In this study, we designed a novel comb-type cationic copolymer composed of a PAA main chain and thermoresponsive poly( N-isopropylacrylamide) graft chains (PAA- g-PNIPAAm). We hypothesized that the thermoresponsive hydrophilic/hydrophobic transition of the grafted polymer would regulate the membrane disruption activity of E5 peptide. Both the binding affinity of the complex and the membrane disruption activity of E5/PAA- g-PNIPAAm were found to be enhanced above the phase transition temperature of the grafted chain. Our analysis suggests that the hydrophilic/hydrophobic environment around the cationic polymer chain plays important roles in the enhancement of the activity of the anionic peptide. PMID- 29529865 TI - Elements of a Workplace Culture of Health, Perceived Organizational Support for Health, and Lifestyle Risk. AB - PURPOSE: We investigated the impact of elements of a workplace culture of health (COH) on employees' perceptions of employer support for health and lifestyle risk. DESIGN: We used 2013 and 2015 survey data from the National Healthy Worksite Program, a Centers for Disease Control and Prevention (CDC)-led initiative to help workplaces implement health-promoting interventions. SETTING: Forty-one employers completed the CDC Worksite Health Scorecard to document organizational changes. PARTICIPANTS: Eight hundred twenty-five employees provided data to evaluate changes in their health and attitudes. MEASURES: We defined elements of a COH as environmental, policy, and programmatic supports; leadership and coworker support; employee engagement (motivational interventions); and strategic communication. Outcomes included scores of employees' perceptions of employer support for health and lifestyle risk derived from self-reported physical activity, nutrition, and tobacco use. ANALYSIS: We estimated effects using multilevel regression models. RESULTS: At the employee level and across time, regression coefficients show positive associations between leadership support, coworker support, employee engagement, and perceived support for health ( P < .05). Coefficients suggest a marginally significant negative association between lifestyle risk and the presence of environmental and policy supports ( P < .10) and significant associations with leadership support in 2015 only ( P < .05). CONCLUSION: Relational elements of COH (leadership and coworker support) tend to be associated with perceived support for health, while workplace elements (environmental and policy supports) are more associated with lifestyle risk. Employers need to confront relational and workplace elements together to build a COH. PMID- 29529866 TI - Experiences in Physical Education: Exploring the Intersection of Visual Impairment and Maleness. AB - The purpose of this study was to adopt an explicitly intersectional approach to examine the embodied perspectives of males with visual impairments about physical education. An interpretative phenomenological analysis research approach was used, and six adults (18-33 years) who identified as males with visual impairments acted as participants. The primary sources of data were semistructured, audiotaped, telephone interviews and reflective field notes. Thematic development utilized a four-step interpretative phenomenological analysis-guided analytical process. Based on the data analysis, the following three interrelated themes emerged: (a) "I didn't feel very integrated": Noninclusionary experiences based on blindness; (b) "Oh great, where's my cane now?": Bullying, blindness, and maleness; and (c) "Okay, just do what you can": Competitive culture glass ceiling. The themes highlight several issues that have been faced by males with visual impairments, which should be considered by physical education and adapted physical education personnel to enhance the quality of education for this population. PMID- 29529867 TI - Social Effects of Tears and Small Pupils Are Mediated by Felt Sadness: An Evolutionary View. AB - Small pupils elicit empathic socioemotional responses comparable to those found for emotional tears. This might be understood in an evolutionary context. Intense emotional tearing increases tear film volume and disturbs tear layer uniformity, resulting in blurry vision. A constriction of the pupils may help to mitigate this handicap, which in turn may have resulted in a perceptual association of both signals. However, direct empirical evidence for a role of pupil size in tearful emotional crying is still lacking. The present study examined socioemotional responses to different pupil sizes, combined with the presence (absence) of digitally added tears superimposed upon expressively neutral faces. Data from 50 subjects showed significant effects of observing digitally added tears in avatars, replicating previous findings for increased perceived sadness elicited by tearful photographs. No significant interactions were found between tears and pupil size. However, small pupils likewise elicited a significantly greater wish to help in observers. Further analysis showed a significant serial mediation of the effects of tears on perceived wish to help via perceived and then felt sadness. For pupil size, only felt sadness emerged as a significant mediator of the wish to help. These findings support the notion that pupil constriction in the context of intense sadness may function to counteract blurry vision. Pupil size, like emotional tears, appears to have acquired value as a social signal in this context. PMID- 29529868 TI - Prevention Diaries. AB - Disease prevention is an effective means for improving health outcomes and reducing the cost burden of chronic diseases. Prevention Diaries is a collection of short accounts and learnings with the goal of making the case for prevention as a transformative tool to drive health and social change. The book provides insight from the field and outlines why prevention is the solution to many social challenges and provides innovative ideas that are needed to advance the prevention agenda. The book was designed for newcomers to public health and students of health and related fields, and is also a tool for health leaders and health practitioners interested in moving the needle from crisis intervention to community-level prevention. PMID- 29529869 TI - Service Learning Trips Abroad Benefit Both Communities and Seasoned Health Educators. AB - Service learning experiences abroad provide an excellent opportunity for seasoned health educators to share their skills with underresourced communities in other parts of the world while enriching their own professional development. Health educators have not traditionally participated in short-term medical service trips, which have become a popular humanitarian effort, yet their contributions can expand the scope of these efforts. With our responsibilities often focused on assessing needs, planning, implementing, and evaluation, seasoned health educators can provide guidance for new initiatives and share health promotion materials and other resources with communities in other parts of the world. In this commentary, I detail my experience as the first health educator to volunteer with a medical brigade that has served a rural community in Honduras for nearly two decades, and describe my added contribution of a brief intervention to address teen pregnancy during the brigade's annual, medically oriented visit. I also reflect on the benefits to my professional growth from this opportunity to immerse myself in four very familiar areas of responsibility for health education in a new and unknown setting. PMID- 29529870 TI - Six hours of task-oriented training optimizes walking competency post stroke: a randomized controlled trial in the public health-care system of South Africa. AB - OBJECTIVE: To evaluate a minimal dose intervention of six 1-hour sessions of task oriented circuit gait training including a caregiver over a 12-week period to persons post stroke in the South African public health sector. DESIGN: Stratified, single blinded, randomized controlled trial with three intervention groups. PARTICIPANTS: Persons post stroke ( n = 144, mean age 50 years, 72 women), mean 9.5 weeks post stroke. INTERVENTIONS: Task group ( n = 51) accompanied by a caregiver; task-oriented circuit gait training (to improve strength, balance, and task performance while standing and walking). Strength group ( n = 45); strength training of lower extremities while sitting and lying. Control group ( n = 48); one 90-minute educational session on stroke management. MEASURES: The six-minute walk test (6MinWT) was the primary outcome; the secondary outcomes included comfortable and fast gait speeds, Berg Balance Scale (BBS), and Timed Up and Go (TUG). Particpants evaluated at baseline, post intervention (12 weeks), and at follow-up 12 weeks later. Change scores were compared using generalized repeated measures analysis of variance (ANOVA). RESULTS: Task group change scores for all outcomes post intervention and at follow-up were improved compared to the other groups ( P-values between 0.000005 and 0.04). The change scores (mean, 1SD) between baseline and follow-up for the Task, Strength, and Control groups, respectively, were as follows: 6MinWT:119.52 m (81.92), 81.05 m (79.53), and 60.99 m (68.38); comfortable speed 0.35 m/s (0.23), 0.24 m/s (0.22), and 0.19 m/s (0.21); BBS: 9.94 (7.72), 6.93 (6.01), and 5.19 (4.80); and TUG: -14.24 seconds (16.86), -6.49 seconds (9.88), and -5.65 seconds (8.10). CONCLUSION: Results support the efficacy of a minimal dose task oriented circuit training program with caregiver help to enhance locomotor recovery and walking competency in these persons with stroke. PMID- 29529871 TI - Assessment of the content reporting for therapeutic exercise interventions among existing randomized controlled trials on knee osteoarthritis. AB - : Purpose/Rationale: Physical exercise interventions for the management of knee osteoarthritis are well known to be effective and accessible forms of rehabilitation and symptom management. However, without adequate reporting of these interventions, accurate replication and clinical use is negatively impacted. OBJECTIVES: The main objective of this article was to assess content reporting using The Consensus on Exercise Reporting Template list and 2016 American College of Sports Medicine guidelines among moderate- to high-quality exercise interventions randomized controlled trials (total score of >=6/10 on the PEDro scale) involving individuals with knee osteoarthritis. RESULTS: The Consensus on Exercise Reporting Template mean total score for all 47 included randomized controlled trials was 4.42 out of 19, demonstrating generally low quality of reporting. The Consensus on Exercise Reporting Template list and the 2016 American College of Sports Medicine guidelines scores were moderately correlated (based on 95% confidence interval, intraclass correlation coefficient = 0.508) for aerobic interventions only. CONCLUSION: The content analysis of exercise interventions in knee osteoarthritis demonstrated low scores for moderate- to high-quality trials. Improved standardized reporting is recommended to ensure knowledge transfer and replication of effective exercise programs for individuals with knee osteoarthritis. PMID- 29529872 TI - Retained primitive reflexes: Perceptions of parents who have used Rhythmic Movement Training with their children. AB - This article reports on a qualitative phenomenological research project that investigated the use of Rhythmic Movement Training (RMT) as an intervention for retained primitive reflexes. Participants were from seven families who each had a child between the ages of 7 years and 12 years. Through semi-structured interviews, parents described their reasons for seeking additional help with their child's development issues. They talked about finding RMT, using RMT within their family routine and their views on the costs and the benefits they experienced, both financial and time. While there has been a small amount of research into movement programmes targeting retained primitive reflexes, to date there appears to have been no studies completed on RMT. The data collected described searches for help, the stress and frustrations associated with the search and the range of interventions these parents tried. The families in this research found that RMT was easy to use within their daily routine and that it was a cost-effective, low-impact intervention. The families noticed a range of benefits for children who had completed the movements. The findings provide encouraging evidence to proceed with further study that will investigate the academic, social and emotional development of children using RMT. PMID- 29529873 TI - Cosmogenic beryllium-7 in soil, rainwater and selected plant species to evaluate the vegetal interception of atmospheric fine particulate matter. AB - Beryllium-7 is a radionuclide produced in the upper atmosphere by cosmic-ray spallation with ions of carbon, oxygen and nitrogen. It is one of radionuclides that can be used to trace the fine particulate matter of 2.5-um diameter (PM2.5) and smaller. In this work, 7Be was determined in leaves of 10 plant species collected from streets, parks and open land and in 5 consecutive rains over Alexandria, Egypt. 7Be levels were also measured in soil covered by each type of plant as well as in the nearest uncovered soil to be reference values to determine its intercepted amount and consequently PM2.5. The lowest interception, 17.7 %, was by Ficus elastica L., while Ficus retusa L. intercepted about 45 %. Radiologically, the annual effective dose due to the usage of Thymelea hirsute plant leaves as a medicine and Nicotiana glauca Graham for smoking were 0.013 and 0.66 uSv, respectively. The observed levels in rainwater indicated that 7Be decreased consecutively from 3.1 Bq kg-1 in the first rain to 0.71 Bq kg-1 in the last one during the 2016/2017 rain season. The wet deposition of 7Be is less than 1 % of its total deposition on the ground. PMID- 29529874 TI - In Response to a Previous Letter to the Editor Titled, "Accuracy of a Blood Glucose Monitoring System". PMID- 29529875 TI - The Use of Botulinum Toxin Injection for Brachial Plexus Birth Injuries: A Systematic Review of the Literature. AB - BACKGROUND: Most brachial plexus birth injuries (BPBI) are caused by traction on the brachial plexus during a difficult delivery. Fortunately, the possibility of complete recovery from such an incident is relatively high, with only 10% to 30% of patients having prolonged and persistent disability. These patients have muscle imbalances and co-contractions typically localized around the shoulder and elbow. These imbalances and co-contractures cause abnormal motor performances and bone/joint deformities. Typically, physical/occupational therapies are the conventional therapeutic modalities but are often times inadequate. Botulinum toxin A (BTX-A) injections into targeted muscles have been used to combat the muscular imbalances and co-contractions. METHODS: With compliance to PRISMA guidelines, a systematic review was performed to identify studies published between 2000 and 2017 that used BTX-A to treat neonatal brachial plexus palsies. RESULTS: Ten studies were included, involving 325 patients. Three groups of indications for the use of BTX-A were identified: (1) internal rotation/adduction contracture of the shoulder; (2) elbow flexion lag/elbow extension lag; and (3) forearm pronation contracture. CONCLUSIONS: The included studies show an overall beneficial effect of BTX-A in treating co-contractures seen in patients with BPBI. Specifically, BTX-A is shown to reduce internal rotation/adduction contractures of the shoulder, elbow flexion/extension contractures, and forearm pronation contractures. These beneficial effects are blunted when used in older patients. Nevertheless, BTX-A is a useful treatment for BPBI with a relatively low-risk profile. PMID- 29529876 TI - Litigation Following Carpal Tunnel Release. AB - BACKGROUND: Carpal tunnel release (CTR) is the most common hand surgery operation performed in the United States. While serious complications are rare, they can be life-altering to patients. In some cases, patients will pursue malpractice claims against the surgeon. This study aimed to understand the patient, procedure, and surgeon factors involved in CTR malpractice litigation. METHODS: The Westlaw legal database was queried for all recorded CTR malpractice cases resulting in jury verdicts and settlements. Only cases directly related to injury after CTR were included in this study. Cases were reviewed to determine plaintiff demographics, defendant training, liability, injury, outcomes, and monetary awards. RESULTS: Ninety-two unique cases were identified. Plaintiffs were predominantly female (n = 65, 71%). Most surgeons were orthopedic-trained (n = 37, 52%). Only 27% of defendants (n = 19) were hand fellowship-trained. Only 19% of cases resulting in a monetary award were against surgeons who had hand fellowship training. The majority of cases (n = 61, 66%) were found in favor of the defendant. Monetary awards averaged $305 923 (range = $12 000-1 338 147), while settlements averaged $266 250. Alleged liability was most for surgeon negligence (n = 69, 75%) with a third of cases resulting in monetary awards. Median nerve injury was claimed in 41 cases (45%), with 17 (41%) resulting in monetary awards. CONCLUSION: Although CTR is generally safe and effective, some patients will experience complications. Median nerve injury was the most common reason for successful litigation in this study. Adequate training and experience in hand surgery may lower the risk of injuries resulting in successful malpractice suits. PMID- 29529877 TI - Digoxin use in systemic light-chain (AL) amyloidosis: contra-indicated or cautious use? AB - AIM: Digoxin is considered contraindicated in light-chain (AL) amyloidosis, given reports of increased toxicity published 30-50 years ago. We sought to determine the frequency of digoxin toxicity in patients with AL. METHODS: We identified 107 patients with AL amyloidosis who received digoxin between 2000 and 2015. RESULTS: The median age was 65 and the median digoxin dose and estimated glomerular filtration rate were 0.125 mg/d and 55 ml/min/1.73 m2, respectively. Digoxin dose was reduced in 16% of the patients, mainly due to high serum drug concentration or worsening renal function. The median duration of therapy was 5 months, with half of the patients stopping treatment, primarily due to physician preference. Significant arrhythmias developed in 11% of patients, almost exclusively in newly diagnosed patients. Arrhythmias presented as terminal events in five patients; four with bradycardia followed by pulseless electrical activity (PEA) with ventricular tachycardia/fibrillation (VT/VF) during resuscitation; all patients had acute renal failure and severe, decompensated heart failure. One patient had ventricular tachycardia as a terminal event. Only one patient was treated with digoxin antibody therapy. CONCLUSIONS: Digoxin may be cautiously utilized in AL amyloidosis patients. We suggest its use in lower doses and frequent drug concentration monitoring along with close monitoring of electrolytes and renal function. Nonetheless, toxicity at low serum concentration cannot be excluded due to potential for toxic concentration at the tissue level and should be taken under consideration when prescribing digoxin for these patients. Studies with higher-level evidence are needed to confirm these findings. PMID- 29529879 TI - Comparative analysis of the psychometric parameters of two quality-of-life questionnaires, the SGRQ and CAT, in the assessment of patients with COPD exacerbations during hospitalization: A multicenter study. AB - The aim of this study was to assess health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) and to discuss the different tools available for its assessment. The most widely used assessments are the St. George respiratory questionnaire (SGRQ) and the COPD assessment test (CAT) questionnaire. Both have a different difficulty in exam completion, calculation, and scoring. No studies exist that analyze the validity and internal consistency of using both questionnaires on patients admitted to the hospital for a COPD exacerbation. A multicenter, cross-sectional analytic observational study of patients admitted to the hospital due to a COPD exacerbation (CIE 491.2). During their hospital stay, they were administered the SGRQ and the CAT questionnaire within the framework of a therapeutic education program (APRENDEPOC). Descriptive and comparative analysis, correlations between the scales (Pearson's correlation index), consistency and reliability calculations (Cronbach's alpha), and a forward stepwise multiple linear regression were performed, with significant correlations in both questionnaires considered p < 0.01 with the total scores. A statistical significance of p < 0.05 was assumed. Altogether, 231 patients were admitted for a COPD exacerbation ( n = 77) at Hospital Clinic of Barcelona (HCB) and ( n = 154) at Hospital Universitario General of Castellon (HUGC). The sample profile was not homogeneous between both centers, with significant differences in HRQL between hospitals. Correlation were noted between both scales ( p < 0.01), along with high levels of internal consistency and reliability (CAT 0.836 vs. SGRQ 0.827). The HRQL is related to dyspnea, wheezing, daytime drowsiness, and edema, as well as to the need to sleep in a sitting position, anxiety, depression, and dependence on others in the execution of daily activities. Our regression analysis showed that the SGRQ questionnaire could predict more changes in HRQL with a higher number of variables. PMID- 29529880 TI - Intradialytic neuromuscular electrical stimulation reduces DNA damage in chronic kidney failure patients: a randomized controlled trial. AB - BACKGROUND: Chronic kidney failure (CKF) patients on renal replacement therapies exhibit elevated levels of DNA lesions and this is directly related to high mortality. OBJECTIVE: This study aimed to evaluate the effect of neuromuscular electrical stimulation (NMES) on genomic damage in CKF patients on conventional haemodialysis (HD). METHODS: Twenty-one patients with CKF on HD were randomized into control (CG =10) or neuromuscular electrical stimulation (NMESG = 11) groups. NMES was applied on the quadriceps muscle during the HD session, three times a week, for 8 weeks in NMESG. DNA damage in blood was evaluated by the alkaline comet assay prior to follow-up, after 4 and 8 weeks of intervention. RESULTS: Intradialytic NMES in CKF patients induced a significant decrease in DNA damage after four [49.9 (3.68) vs 101.5 (6.53); p = 0.000] than eight [19.9 (2.07) vs 101.5 (6.53); p = 0.000] weeks compared to baseline. Genomic damage was also significantly less after four [NMESG: 49.9 (3.68) vs CG: 92.9 (12.61); p = 0.001] than after eight [NMESG: 19.9 (2.07) vs CG: 76.4 (11.15); p = 0.000] weeks compared to CG. CONCLUSIONS: This study demonstrates for the first time that intradialytic NMES is able to reduce DNA damage in blood of CKF patients. PMID- 29529881 TI - Where and how does physical therapy fit? Integrating physical therapy into interprofessional HIV care. AB - PURPOSE: To investigate the role of physical therapy in HIV care from the perspective of people living with HIV and health care professionals with expertise in HIV care. METHODS: We conducted a qualitative descriptive study using semistructured interviews (with health care professionals) and focus groups (with people living with HIV). We purposively sampled health care professionals and recruited people living with HIV in collaboration with an HIV-specialty hospital. We asked participants about their knowledge of and experiences with physical therapy, and perceptions of the physical therapy role in interprofessional HIV care. We analyzed data using content analytical techniques. RESULTS: Thirteen people living with HIV and 12 health care professionals conceptualized physical therapy as positively influencing independence and social participation, and as a valuable ally in interprofessional collaboration. The Framework of Physical Therapy Role in HIV Care consists of two components: (1) multidimensional and client-centered roles of physical therapy addressing physical, psychological and social health domains; and (2) contextual factors important to consider for the role of physical therapy: aging, episodic nature of HIV, multimorbidity, competing priorities, continuity of care, stigma, resource security and social isolation. The interaction between contextual factors and health domains can influence the role of physical therapy. CONCLUSION: The role of physical therapy in HIV is multidimensional and client-centered. This Framework can be used by rehabilitation professionals working with people living with HIV. Implications for Rehabilitation Participants living with HIV in this study experienced physical therapy as a means of addressing rehabilitation goals that positively influenced physical health and social participation. The role of physical therapy in HIV care is multidimensional and client-centered and can address health challenges in physical, social and psychological health domains. The presence and interaction of contextual factors including aging, episodic nature of HIV, multimorbidity, competing priorities, continuity of care, stigma, resource security and social isolation are important for clinicians to consider in order to optimize healthcare for people living with HIV. The Framework describing the role of physical therapy in HIV care can be used by rehabilitation professionals to help inform their approach for providing client-centered HIV care. PMID- 29529882 TI - Response: Atrial impairment in transthyretin cardiac amyloidosis: an early marker of cardiac involvement and a prognostic factor. PMID- 29529883 TI - Psychometric Properties of the FACIT-Pal 14 Administered in an Outpatient Palliative Care Clinic. AB - BACKGROUND: The Functional Assessment of Chronic Illness Therapy-Palliative (FACIT-Pal) 14 instrument measures the quality of life in palliative care patients but its psychometric properties are not well characterized. OBJECTIVES: To establish the reliability and validity of the FACIT-Pal 14 in an outpatient palliative care clinic population. METHODS: The FACIT-Pal 14 was administered to 227 patients in an outpatient palliative care clinic at a large, urban academic medical center. Internal consistency reliability was assessed with Crohnbach's alpha, and principal component analysis was used to investigate for multiple underlying latent variables. Construct validity was tested by comparing mean scores in various subgroups. RESULTS: The FACIT-Pal 14 has Crohnbach's alpha of 0.76, which increases to 0.79 if 2 items are removed. Principal component analysis supports a single latent variable underlying the instrument. Significantly lower mean scores were found in patients with Eastern Cooperative Oncology Group (ECOG) functional status 3 to 4 compared with patients with ECOG functional status 1-2 ( P = .007), in patients with life expectancy under 6 months compared to those with 6 months or greater ( P = .003), and in patients referred to clinic for pain and symptom management compared with patients referred for other reasons ( P = .038). Instrument scores did not significantly differ between men and women or between white and nonwhite patients ( P = .525 and P = .263, respectively). CONCLUSIONS: In an outpatient palliative care clinic population, the FACIT-Pal 14 has good internal consistency, but removal of 2 items would improve consistency. One latent variable underlies the instrument and there is evidence of construct validity. PMID- 29529884 TI - Provider Tools for Advance Care Planning and Goals of Care Discussions: A Systematic Review. AB - BACKGROUND: Advance care planning and goals of care discussions involve the exploration of what is most important to a person, including their values and beliefs in preparation for health-care decision-making. Advance care planning conversations focus on planning for future health care, ensuring that an incapable person's wishes are known and can guide the person's substitute decision maker for future decision-making. Goals of care discussions focus on preparing for current decision-making by ensuring the person's goals guide this process. AIM: To provide evidence regarding tools and/or practices available for use by health-care providers to effectively facilitate advance care planning conversations and/or goals of care discussions. DATA SOURCES: A systematic review was conducted focusing on guidelines, randomized trials, comparative studies, and noncomparative studies. Databases searched included MEDLINE, EMBASE, and the proceedings of the International Advance Care Planning Conference and the American Society of Clinical Oncology Palliative Care Symposium. CONCLUSIONS: Although several studies report positive findings, there is a lack of consistent patient outcome evidence to support any one clinical tool for use in advance care planning or goals of care discussions. Effective advance care planning conversations at both the population and the individual level require provider education and communication skill development, standardized and accessible documentation, quality improvement initiatives, and system-wide coordination to impact the population level. There is a need for research focused on goals of care discussions, to clarify the purpose and expected outcomes of these discussions, and to clearly differentiate goals of care from advance care planning. PMID- 29529885 TI - Palliative Chemotherapy Near the End of Life in Oncology Patients. AB - BACKGROUND: Although palliative chemotherapy during end-of-life (EOL) care is used to relieve symptoms in patients with metastatic cancer, chemotherapy may lead to more aggressive EOL care. We evaluated the use of and variables associated with chemotherapy at EOL. METHODS: This study included data from patients who died from advanced cancer and underwent palliative chemotherapy between April 2007 and May 2017 at the Department of Palliative Care of Fudan University, Shanghai Cancer Center. Data were collected from hospital medical records. Univariate and multivariate analyses were conducted to identify the variables that independently predicted the use of palliative chemotherapy. RESULTS: Among the 542 patients in the study, 85 (15.7%) underwent palliative chemotherapy during the last month and 28 (5.2%) underwent it during the last 2 weeks of life. Age <59 years (odds ratio [OR] = 1.82, 95% confidence interval [CI]: 1.51-2.61), performance status <3 (OR = 3.73, 95% CI: 1.46-4.67), and cardiopulmonary resuscitation (OR = 3.88, 95% CI: 3.01-5.34) were independently associated with the use of chemotherapy. The use of palliative chemotherapy during the last year of life differed significantly by patient age ( P < .001). CONCLUSION: The observed chemotherapy rates of 15.7% during the last month of life and 5.2% during the last 2 weeks of life are in line with international recommendations. This study showed that palliative chemotherapy is associated with more aggressive EOL care and indicates that younger patients and those with lower performance status are more likely to receive palliative chemotherapy. Significant variations in EOL treatment strategies among different age groups during the last year of life were also identified. PMID- 29529886 TI - A weak scientific basis for gaming disorder: Let us err on the side of caution. AB - We greatly appreciate the care and thought that is evident in the 10 commentaries that discuss our debate paper, the majority of which argued in favor of a formalized ICD-11 gaming disorder. We agree that there are some people whose play of video games is related to life problems. We believe that understanding this population and the nature and severity of the problems they experience should be a focus area for future research. However, moving from research construct to formal disorder requires a much stronger evidence base than we currently have. The burden of evidence and the clinical utility should be extremely high, because there is a genuine risk of abuse of diagnoses. We provide suggestions about the level of evidence that might be required: transparent and preregistered studies, a better demarcation of the subject area that includes a rationale for focusing on gaming particularly versus a more general behavioral addictions concept, the exploration of non-addiction approaches, and the unbiased exploration of clinical approaches that treat potentially underlying issues, such as depressive mood or social anxiety first. We acknowledge there could be benefits to formalizing gaming disorder, many of which were highlighted by colleagues in their commentaries, but we think they do not yet outweigh the wider societal and public health risks involved. Given the gravity of diagnostic classification and its wider societal impact, we urge our colleagues at the WHO to err on the side of caution for now and postpone the formalization. PMID- 29529888 TI - Executive Functioning, Reward/Punishment Sensitivity, and Conduct Problems in Boys With Callous-Unemotional Traits. AB - Callous-unemotional (CU) traits are thought to characterize children exhibiting persistent and severe conduct problems (CPs). Reward and punishment sensitivity have often been investigated, yet executive function problems have mostly been studied in adults. Moreover, the level of co-occurring CPs is important to take into account. Therefore, the current study investigated differences in reward responsivity, punishment sensitivity, and executive functioning (EF) between four subgroups of general community boys ( N = 346, Mage = 14.01 years, SD = 1.19): high CU/high CP, low CU/high CP, high CU/low CP, and low CU/low CP. Boys with high CU/high CP showed significantly more EF problems, but similar reward and punishment sensitivity as low CU/high CP boys. Boys with high CU/low CP did not differ from low CU/low CP boys. Severity of executive function problems appears to distinguish boys who show a combination of CU-traits and CPs from boys with CPs alone. PMID- 29529887 TI - Gray matter differences in the anterior cingulate and orbitofrontal cortex of young adults with Internet gaming disorder: Surface-based morphometry. AB - Background and aims Altered risk/reward decision-making is suggested to predispose individuals with Internet gaming disorder (IGD) to pursue short-term pleasure, despite long-term negative consequences. The anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC) play important roles in risk/reward decision-making. This study investigated gray matter differences in the ACC and OFC of young adults with and without IGD using surface-based morphometry (SBM). Methods We examined 45 young male adults with IGD and 35 age-matched male controls. We performed region of interest (ROI)-based analyses for cortical thickness and gray matter volume (GMV) in the ACC and OFC. We also conducted whole-brain vertex-wise analysis of cortical thickness to complement the ROI based analysis. Results IGD subjects had thinner cortices in the right rostral ACC, right lateral OFC, and left pars orbitalis than controls. We also found smaller GMV in the right caudal ACC and left pars orbitalis in IGD subjects. Thinner cortex of the right lateral OFC in IGD subjects correlated with higher cognitive impulsivity. Whole-brain analysis in IGD subjects revealed thinner cortex in the right supplementary motor area, left frontal eye field, superior parietal lobule, and posterior cingulate cortex. Conclusions Individuals with IGD had a thinner cortex and a smaller GMV in the ACC and OFC, which are critical areas for evaluating reward values, error processing, and adjusting behavior. In addition, in behavioral control-related brain regions, including frontoparietal areas, they also had thinner cortices. These gray matter differences may contribute to IGD pathophysiology through altered risk/reward decision-making and diminished behavioral control. PMID- 29529889 TI - Beyond Ability to Pay: Procedural Justice and Offender Compliance With Restitution Orders. AB - Restitution to victims is rarely paid in full. One reason for low rates of payments is that offenders lack financial resources. Beyond ability to pay, however, we argue that fair treatment has implications for offender behavior. This study, a survey of probationers who owed restitution, investigated the links between (a) ability to pay, (b) beliefs about restitution and the criminal justice system, and (c) restitution payment, both the amount paid and number of payments. Results indicate that perceived fair treatment by probation staff-those most directly involved with the collection of restitution payments-was significantly associated with greater payment, net of past payment behavior, intention to pay, and ability to pay. Because restitution has potentially rehabilitative aspects if offenders pay more of the court-ordered amount and if they make regular monthly payments, how fairly probation staff treat probationers has implications for both victims and for the criminal justice system. PMID- 29529890 TI - Engendering a conducive environment for university students with physical disabilities: assessing availability of assistive facilities in Nigeria. AB - PURPOSE: This study assessed awareness and availability of assistive facilities in a Nigerian public university. METHODS: Study was conducted in Obafemi Awolowo University (OAU), Ile Ife Nigeria using a mixed methods approach. Fifty two students with disability (SWD) were interviewed with a semistructured, self administered questionnaire. A checklist was used to assess assistive facilities on campus while in-depth interviews (IDI) were conducted with university officials, to assess their perspectives about the availability and use of assistive facilities in the university. RESULTS: Almost three-thirds (57.7%) of SWD were male while more than two-thirds were aged between 21 and 30 years. About seven in 10 (71.1%) respondents, had mobility impairment, while two-fifth had visual impairment (40.8%) and a few had hearing impairment. Only the university's administrative building had a functioning elevator. Slightly more than half (54.5%) of the lecture theatres have public address systems, while only two have special entrances and exits with ramps for SWD. Almost all respondents were unaware of facilities that aid learning (96.2%) and facilities for library use (90.4%). University officials were aware of assistive facilities for SWD but do not know the actual number of SWD. CONCLUSION: Assistive facilities for SWD on campus are limited. More assistive facilities need to be provided alongside increased awareness about these facilities and a disability register should be open for students on campus. Assistive facilities to aid learning and make SWD more comfortable are required. Implications for Rehabilitation Universities should have an official policy on students with disabilities and implement it, such a policy should address special considerations for disabled students, such as having an updated register for students with disability, having examination questions in large fonts for students with visual disabilities, giving them extra time for examinations and providing special counselling services for students with disabilities. Awareness about assistive facilities in tertiary institutions for students with disability should be increased so that they can utilize the ones available and demand for such if non-existent. The design of buildings on university campus should be made disability friendly. A disability register should be open for SWD on campus. PMID- 29529891 TI - Peritoneal Pulse Granulomas With Spiral Bodies Mimicking Peritoneal Carcinomatosis: A Case Report. AB - Pulse (hyaline ring) granuloma, a rare entity first described in lung and oral cavity, has been reported under various names before the identification of hyaline rings as fragments of pulses (the edible seeds of legumes). Similar lesions were thereafter described in extra-oral localizations, mainly the gastrointestinal tract, or localizations having potential communication with the gastrointestinal tract. Recently, 2 reports described "spiral bodies" surrounded by foreign body-type multinucleated giant cell reaction in pulse granulomas, corresponding to remnant plant vascular structures (helical xylem elements). In this article, we report a case of a 70-year-old male patient presenting to our hospital for an incisional hernia repair. He had a history of antrectomy 2 years previously for perforated duodenal ulcer complicated with fecal peritonitis. During the hernia repair procedure, multiple peritoneal whitish nodules and one subserosal appendiceal nodule were found. Appendectomy and biopsy of a peritoneal nodule were performed. Microscopic examination showed nodular lesions located in the subserosa to be pulse granulomas. Also surrounded by histiocytes, spiraled thin and rigid foreign bodies were identified. In this article, we report a case of pulse granuloma with spiral bodies complicating perforated duodenal ulcer and mimicking a peritoneal carcinomatosis. We also provide a discussion on the origin of spiral bodies in light of relevant literature. PMID- 29529893 TI - The impact of musculoskeletal diseases on the presence of locomotive syndrome. AB - OBJECTIVES: We assessed the impact of musculoskeletal diseases, depressive mental state, and hypertension on locomotive syndrome, a condition of reduced mobility requiring nursing care. Since locomotive syndrome is a major public health issue that needs attention, its relationship with functional inconvenience in performing daily activities was also investigated. METHODS: We conducted a cross sectional study using an Internet panel survey, comprising 747 persons aged 30-90 years. Demographics, personal medical history, and daily activity data were assessed. The 25-question Geriatric Locomotive Function Scale was used to diagnose locomotive syndrome. Stepwise linear regression analysis and logistic regression analysis were conducted to evaluate the association between locomotive syndrome, musculoskeletal diseases, and functional inconvenience. RESULTS: Aging, osteoporosis, and low back pain significantly increased the risk of locomotive syndrome, followed by knee osteoarthritis and lumbar spinal stenosis. Locomotive syndrome was significantly related to depressive mental state and hypertension, and led to functional inconvenience in Seiza sitting, cleaning, shopping, and strolling. CONCLUSION: Locomotive syndrome was associated with functional inconvenience in performing common daily activities involving the lower extremities and spine. Osteoporosis and aging were significantly associated with locomotive syndrome. The risk of locomotive syndrome may be decreased by treating comorbid osteoporosis and instituting exercise and diet-related modifications. PMID- 29529894 TI - Evaluation of systemic activity of pediatric primary Sjogren's syndrome by EULAR Sjogren's syndrome disease activity index (ESSDAI). AB - OBJECTIVES: The purpose of this study is to evaluate systemic disease activity of pediatric Sjogren's syndrome (SS) using European League Against Rheumatism (EULAR) Sjogren's syndrome disease activity index (ESSDAI). METHODS: We retrospectively reviewed medical records of patients with SS who have been diagnosed according to 1999 Japanese diagnostic criteria for SS before 16 years old at KKR Sapporo Medical Center, Hokkaido University Hospital, and affiliated hospitals. We analyzed clinical and laboratory data and calculated ESSDAI at both diagnosis and peak activity. RESULTS: Twenty-five patients (2 boys and 23 girls) were enrolled. Only 4 patients had sicca symptoms at diagnosis. Mean ESSDAI scores at diagnosis and peak activity were 12.68 (2-31) and 15.08 (2-38), respectively. Only 3 patients were inactive (ESSDAI score <5) at diagnosis. Frequently involved domains at diagnosis were the biological (96%) followed by the constitutional (68%), glandular (44%), articular (44%), cutaneous domains (28%), renal (16%), and central nervous system (12%). At peak activity, biological domain (96%) was followed by the constitutional (72%), glandular (60%), articular (44%), cutaneous (28%), central nervous system (20%), and renal domains (16%). CONCLUSION: Pediatric SS is suspected from active systemic manifestations. The items of ESSDAI are useful clues to the diagnosis of pediatric SS. PMID- 29529895 TI - Virtual reality exergaming as adjunctive therapy in a sub-acute stroke rehabilitation setting: facilitators and barriers. AB - PURPOSE: To identify the facilitators and barriers perceived by clinicians to using an Exergaming Room as adjunct to conventional therapy. DESIGN: Phenomenological qualitative study using an interpretive description methodology. SUBJECTS: Ten clinicians (four physical therapists, six occupational therapists) from the Stroke Program at the Jewish Rehabilitation Hospital (nine female, one male, age range 25-50 years old) who referred clients to the Exergaming Room. METHODS: Ten to twenty minute semi-structured interviews were conducted with each clinician. Convenience sampling was used. A thematic analysis was performed on the data collected by grouping all the open codes into facilitators and barriers, and then categorized into levels, themes and subthemes. RESULTS: Facilitators and barriers were divided into three levels: organizational, individual and technological. Major facilitators at the organizational level were: institutional support; at the individual level: personal experience of referring clinician, presence of an expert clinician, and relevance of the Exergaming Room for stroke clients; and at the technological level: perceived ease of use of the exergames and possibility of providing additional therapy. Key barriers to successful implementation of the Exergaming Room at the organizational level were: scheduling difficulties and lack of staffing; at the individual level: client functional limitations; at the technological level: low precision in motion capture of the exergame systems. CONCLUSIONS: Multiple factors affect the implementation of new technology in rehabilitation settings. In order to successfully integrate exergame systems into practice, institutions are encouraged to take the identified factors (facilitators and barriers) into account. Implications for Rehabilitation Clinicians who have referred individuals with stroke to an "exergames" room over a 1-year period at a rehabilitation hospital have found the service to be highly relevant to their clients. The presence of an expert clinician, who evaluates the clients and builds an exergames activity program, was seen as an important facilitator by referring clinicians in the use of this service. An ideal Exergames Room should offer a wide variety of activities, including some that focus on motor, cognitive and/or communications abilities. PMID- 29529892 TI - Profiling donepezil template into multipotent hybrids with antioxidant properties. AB - Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease. PMID- 29529896 TI - Honeycomb-like structure in the right coronary artery treated with a drug-eluting stent: a case report and literature review. AB - A honeycomb-like structure (HLS) is a rare entity encountered in catheterization laboratories. The etiology of HLS remains elusive. Moreover, no treatment guideline or consensus for HLS has been proposed. However, with more frequent adoption of intravascular imaging modalities, the number of cases of HLS is rising. We herein present a case of HLS and summarize previous reports in the literature with the aim of providing useful information for interventional cardiologists and promoting further research. PMID- 29529897 TI - Add-on tocilizumab versus conventional treatment for systemic sclerosis, and cytokine analysis to identify an endotype to tocilizumab therapy. AB - OBJECTIVES: To evaluate the anti-interleukin (IL)-6 receptor antibody tocilizumab (TCZ) as a treatment of systemic sclerosis (SSc), a randomised parallel group study was conducted, and compared their results and baseline cytokine/chemokine profiles. METHODS: Patients were assigned to a TCZ add-on group (TCZ group, n = 7) and a conventional therapy group (Conv group, n = 6). TCZ (8 mg/kg/month) for 6 months, and the modified Rodnan total skin score (mRSS) were used to compare the efficacy. The association of medical history, baseline pulmonary function tests, blood cell counts, serum C-reactive protein (CRP) and 26 cytokines/chemokines and decrease in mRSS were analysed. RESULTS: The mean change in mRSS was larger in the TCZ group (6.3) than in the Conv group (3.4), but the difference was not statistically significant because of high variance in the TCZ group. Patients with shorter disease histories and higher CRP had larger decreases in mRSS, and the decrease in mRSS was negatively correlated with IL-13 and C-C motif chemokine ligand (CCL)5. CONCLUSION: Although significant between group differences were not observed, some patients had a decrease in mRSS. Short disease duration, high CRP, low IL-13 and low CCL5 may represent an SSc endotype responsive to TCZ therapy. PMID- 29529898 TI - Improved quantification of a commercial enzyme-linked immunosorbent assay kit for measuring anti-MDA5 antibody. AB - OBJECTIVES: To compare the quantitative performance for measuring anti-MDA5 antibody titer of two enzyme-linked immunosorbent assay (ELISA) systems: an in house ELISA and the commercial MESACUPTM anti-MDA5 test. METHODS: Anti-MDA5 antibody titer was measured in sera from 70 patients with dermatomyositis using an in-house ELISA and the MESACUPTM anti-MDA5 test side-by-side. For the commercial ELISA kit, serum samples diluted 1:101 were used according to the manufacturer's protocol, but serial dilutions of sera were also examined to identify the optimal serum dilution for quantification. RESULTS: The anti-MDA5 antibody titers measured by the in-house and commercial ELISAs were positively correlated with each other (r = 0.53, p = .0001), but the antibody titer measured by the commercial ELISA was less sensitive to change after medical treatment, and 37 (80%) of 46 anti-MDA5-positive sera had antibody titer exceeding the quantification range specified by the manufacturer (>=150 index). Experiments using diluted serum samples revealed that diluting the sera 1:5050 improved the quantitative performance of the MESACUPTM anti-MDA5 test, including a better correlation with the in-house ELISA results and an increased sensitivity to change. CONCLUSION: We improved the ability of the commercial ELISA kit to quantify anti-MDA5 antibody titer by altering its protocol. PMID- 29529899 TI - Awareness of Hearing Loss in Older Adults: Results of a Survey Conducted in 500 Subjects Across 5 European Countries as a Basis for an Online Awareness Campaign. AB - The objectives of this study were to assess the factors which contribute to individuals' health motivation to address hearing loss and to gather baseline data that could then be used to measure the impact of an awareness campaign. An online questionnaire with 13 closed set questions was completed by 100 subjects in each country including Austria, Germany, France, Sweden, and the United Kingdom. The questionnaire was based around the Health Belief Model, which describes how, in order to take action to address a medical problem, the individual must perceive that the condition presents a threat to their well-being that exceeds any barriers to treatment. Good hearing was regarded as being important in all countries. There was agreement that the main sign of hearing loss was turning up the TV or radio. In most countries, hearing aids were thought to be not particularly visible, not require much maintenance, a hindrance while doing sport, and must be removed before bed. Perceptions of hearing implants were that they were permanently fitted, not externally visible, and do not need to be removed before bed. Medical issues were mostly researched through a doctor and then via the Internet. In this sample, there was a good understanding of the consequences and signs of hearing loss, but although hearing implants were viewed as being different to hearing aids, there was little understanding that the external speech processor was similar to a hearing aid in its physical characteristics. When actions were taken, the key professionals consulted about hearing problems were the general practitioner and ear, nose, and throat specialist. PMID- 29529900 TI - Association of low penetrance vitamin D receptor Tru9I (rs757343) gene polymorphism with risk of premenopausal breast cancer. AB - Objective The aim of this study was to determine whether a novel polymorphism ( Tru9I) in the low penetrance vitamin D receptor (VDR) gene is associated with risk of premenopausal breast cancer (BC). Methods This case-control study included 228 patients with BC and 503 healthy women living in Pakistan who were analyzed for the VDR Tru9I (rs757343) single nucleotide polymorphism. BC cases were histopathologically confirmed, and all healthy controls were age-matched with patients (age range, 20-45 years). DNA was extracted, and the polymerase chain reaction and restriction fragment length polymorphism assays were performed. Results The VDR Tru9I polymorphism was not significantly associated with premenopausal BC. However, the risk of BC was associated with the 'uu' genotype (odds ratio [OR], 1.141; 95% confidence interval [95% CI], 0.206-6.317). Further, mutant Tru9I was significantly associated with Grade IV carcinoma (OR, 5.36; 95% CI, 1.181-24.338). Conclusion The VDR Tru9I 'uu' genotype may increase the risk of premenopausal BC. PMID- 29529902 TI - BioPepDB: an integrated data platform for food-derived bioactive peptides. AB - Food-derived bioactive peptides play critical roles in regulating most biological processes and have considerable biological, medical and industrial importance. However, a large number of active peptides data, including sequence, function, source, commercial product information, references and other information are poorly integrated. BioPepDB is a searchable database of food-derived bioactive peptides and their related articles, including more than four thousand bioactive peptide entries. Moreover, BioPepDB provides modules of prediction and hydrolysis simulation for discovering novel peptides. It can serve as a reference database to investigate the function of different bioactive peptides. BioPepDB is available at http://bis.zju.edu.cn/biopepdbr/ . The web page utilises Apache, PHP5 and MySQL to provide the user interface for accessing the database and predict novel peptides. The database itself is operated on a specialised server. PMID- 29529901 TI - Evaluation of risk factors for false-negative results with an antigen-specific peripheral blood-based quantitative T cell assay (T-SPOT(r). TB) in the diagnosis of active tuberculosis: A large-scale retrospective study in China. AB - Objective To investigate the diagnostic efficacy of an interferon-gamma release assay, T-SPOT(r). TB, for diagnosing active tuberculosis (TB) and to identify risk factors for false-negative results. Methods This retrospective study enrolled consecutive patients with active TB and with non-TB respiratory diseases to evaluate the risk factors for false-negative results when using the T-SPOT(r). TB assay for the diagnosis of active TB. Patients with active TB were categorized as having confirmed pulmonary TB, clinically diagnosed pulmonary TB or extrapulmonary TB (EPTB). Results This study analysed 4964 consecutive patients; 2425 with active TB and 2539 with non-TB respiratory diseases. Multivariate logistic regression analyses identified the following five factors that were all associated with an increased false-negative rate with the T-SPOT(r). TB assay: increased age (odds ratio [OR] 1.018; 95% confidence interval [CI] 1.013, 1.024); decreased CD8+ count (OR 0.307; 95% CI 0.117, 0.803); negative sputum acid-fast bacilli (AFB) smear staining (OR 1.821; 95% CI 1.338, 2.477); negative mycobacterial cultures (OR 1.379; 95% CI 1.043, 1.824); and absence of EPTB (OR 1.291; 95% CI 1.026, 1.623). Conclusions Increased age, decreased CD8+ count, negative sputum AFB smear results, negative sputum mycobacterial cultures and absence of EPTB might lead to an increased false-negative rate when using the T SPOT(r). TB assay. PMID- 29529903 TI - Design and analysis of an original powered foot clearance creator mechanism for walking in patients with spinal cord injury. AB - BACKGROUND: The aim of this study was to assess the performance of an original powered foot clearance creator (PFCC) mechanism worn in conjunction with an isocentric reciprocal gait orthosis (IRGO) and evaluate its effect on trunk compensatory movements and spatiotemporal parameters in nine healthy subjects. METHOD: A PFCC motorized mechanism was designed that incorporated twin sole plates, the movements of which enabled increased toe to floor clearance during swing phase. A prototype was constructed in combination with an IRGO, and hence was re-named as an IRGO-PFCC orthosis. The effects of IRGO-PFCC usage on the spatiotemporal parameters and trunk compensatory movements during walking were then analyzed under two conditions, firstly with the PFCC 'active' i.e., with the motorized device functioning, and secondly inactive, where floor clearance was standard. RESULTS: Ambulating with IRGO-PFCC orthosis resulted in reduction in the spatiotemporal parameters of gait (speed of walking, cadence and stride length) in nine healthy subjects. Walking with IRGO-PFCC orthosis led to significant differences in lateral (p = .007) and vertical (p = .008) trunk compensatory movements. In other words, through using IRGO-PFCC orthosis, the lateral and vertical trunk compensatory movements decreased by 51.32% and 42.7%, respectively. CONCLUSION: An adapted PFCC mechanism, with a relatively small motor and power supply could effectively increase toe to floor clearance during swing phase and thereby decrease trunk compensatory motions and potentially improve energy consumption. Implications for rehabilitations *The High rejection rates of reciprocal gait orthoses are related to the increasing in energy expenditure and burden loads on the upper limb joints during walking following trunk compensatory movements.*An original powered foot clearance creator mechanism was designed and constructed to assisting floor clearance capability and reduce trunk compensatory movements in subjects with spinal cord injury during swing phase of gait.*This original powered foot clearance creator mechanism by using moveable soleplates and motorized actuation could decrease the trunk compensatory motions during the ambulation of nine healthy subjects.*More experiments are needed to investigate this mechanism on trunk compensatory movements of SCI subjects. PMID- 29529904 TI - Understanding the characteristics of friendship quality, activity participation, and emotional well-being in Taiwanese adolescents with autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is a lifelong developmental disability characterized by deficits in social communication and social interaction across multiple contexts. Existing literature on social relationships and well-being among adolescents with ASD in Asian countries is scant. AIMS: This study compared the perceptions of adolescents with ASD with those of their neurotypical peers toward their friendship quality, activity participation, and emotional well being, and examined the relationships between friendship quality, activity participation, and emotional well-being. METHODS: The study participants-101 adolescents with ASD and 101 neurotypical peers, aged 10-19 years-completed the following self-administered questionnaires: the Friendship Quality Questionnaire, the Child and Adolescent Scale of Participation, the Beck Anxiety Inventory, and the short-form UCLA loneliness scale. RESULTS: Adolescents with ASD reported lower friendship quality, lower school participation, and higher levels of anxiety and loneliness compared to their neurotypical peers. Loneliness correlated negatively with friendship quality and school participation and positively with anxiety. Adolescents with ASD experienced increased levels of anxiety when low friendship quality was accompanied by greater loneliness. CONCLUSIONS AND SIGNIFICANCE: These findings reveal that friendship quality, school participation, and loneliness have a considerable effect on the emotional well-being of adolescents with ASD, thus indicating the need for therapeutic interventions that address interpersonal relationships and emotional well-being. PMID- 29529905 TI - Emotional working memory in patients with major depressive disorder. AB - Objective This study was performed to examine the working memory (WM) encoding and retrieval abilities in patients with major depressive disorder (MDD) and determine whether a mood-congruent memory effect is present. Methods The modified Sternberg WM paradigm with positive, negative, and neutral emotional pictures was used to investigate the WM abilities of 26 patients with MDD and 26 healthy controls (HCs). Results No significant difference in picture WM was found between the MDD and HC groups; however, the accuracy of picture position WM was significantly lower and the response time was significantly longer in the MDD than HC group, regardless of the picture or position WM. Additionally, in the MDD group, the accuracy of negative picture/position WM was significantly higher than that of positive picture/position WM. Conclusions These results suggest that in patients with MDD, spatial WM impairment was more severe than object WM. In addition, these patients' WM retrieval was impaired, resulting in a decrease in WM retrieval ability, which may be an important cause of the slow thought in patients with MDD. Moreover, patients with depression have a mood-congruent memory effect, which may be an important factor in the occurrence and maintenance of depression. PMID- 29529906 TI - Localized ridge augmentation in the anterior maxilla using titanium mesh, an alloplast, and a nano-bone graft: a case report. AB - Alveolar ridge deficiency is considered a major limitation for successful implant placement, as well as for the long-term success rate, especially in the anterior maxillary region. Various approaches have been developed to increase bone volume. Among those approaches, inlay and onlay grafts, alveolar ridge distraction, and guided bone regeneration have been suggested. The use of titanium mesh is a reliable method for ridge augmentation. We describe a patient who presented with a localized, combined, horizontal and vertical ridge defect in the anterior maxilla. The patient was treated using titanium mesh and alloplast material mixed with a nano-bone graft to treat the localized ridge deformity for future implant installation. The clinical and radiographic presentation, as well as relevant literature, are presented. PMID- 29529908 TI - Withdrawal: Plews and Laursen (2017). AB - We, the Editors and Publishers of the International Journal of Sports Physiology and Performance, have withdrawn the following article in whole: Plews, DJ, Laursen, PB. Training intensity distribution over a four-year cycle in Olympic champion rowers: different roads lead to Rio [version of record published online ahead of print September 27, 2017]. Int J Sports Physiol Perform. doi: 10.1123/ijspp.2017-0343 . The Editorial Office was contacted with the request to withdraw this article informing the Editor-in-Chief that the data in this article were not permissible to use due to undisclosed contractual obligations. PMID- 29529907 TI - High serum uric acid levels are a protective factor against unfavourable neurological functional outcome in patients with ischaemic stroke. AB - Objective We aimed to evaluate the association between serum uric acid levels at the onset and prognostic outcome in patients with acute ischaemic stroke. Methods We retrospectively analysed the outcomes of 1166 patients with ischaemic stroke who were hospitalized in our centre during August 2008 to November 2012. Correlations of serum uric acid levels and prognostic outcomes were analysed. Results Men had higher serum uric acid levels and better neurological functional outcomes compared with women. There was a strong negative correlation between serum uric acid levels and unfavourable neurological functional outcomes. Generalized estimated equation analysis showed that a higher serum uric acid level (>237 umol/L) was a protective factor for neurological functional outcome in male, but not female, patients. Among five trial of ORG 10172 in acute stroke treatment classification subtypes, only patients with the large-artery atherosclerosis subtype had a significant protective effect of serum uric acid levels on neurological outcome. Conclusions Our study shows that high serum uric acid levels are a significant protective factor in men and in the large-artery atherosclerosis subtype in patients with ischaemic stroke. This is helpful for determining the prognostic value of serum uric acid levels for neurological outcome of acute ischaemic stroke. PMID- 29529909 TI - Incidence and Risk Factors for Overweight and Obesity after Initiation of Antiretroviral Therapy in Dar es Salaam, Tanzania. AB - OBJECTIVE: To describe the incidence of and risk factors for overweight and obesity following antiretroviral therapy (ART) initiation. METHODS: We used Cox proportional hazards models to investigate risk factors for incident overweight and obesity in 79 074 individuals aged 15 years or older who initiated ART in Dar es Salaam, Tanzania. RESULTS: Twenty-five percent of the patients became overweight and 10% became obese. The incidence rate of obesity was 3.2 per 100 person-years (95% confidence interval [CI]: 3.1-3.3) in patients who were of normal weight before starting ART and 22.6 per 100 person-years (95% CI: 21.9 23.3) in those who were overweight. Lower CD4 count was associated with a higher risk of overweight and obesity ( P value for trend < .0001). CONCLUSION: There is a high burden of overweight and obesity after starting ART, leading to proportions of these 2 conditions that are similar to those in the general population. PMID- 29529910 TI - Safety and Efficacy of Dolutegravir Plus Rilpivirine in Treatment-Experienced HIV Infected Patients: The DORIVIR Study. AB - OBJECTIVES: To analyze the efficacy and safety of dolutegravir/rilpivirine (DTG/RPV) in HIV-infected patients who switched from any other antiretroviral therapy (ART). METHODS: Open-label, multicenter study including patients who switched to DTG/RPV between February 2015 and February 2016. Efficacy (HIV RNA <50 copies/mL), adverse events, and metabolic changes at 24 weeks were analyzed. RESULTS: A total of 104 participants were included, who switched for the following reasons: toxicity/intolerance (42.3%), convenience (27.8%), and drug interactions (17.3%). Prior regimens are protease inhibitor (56.7%), integrase strand transfer inhibitor (26.9%), and non-nucleoside reverse transcriptase inhibitor (16.3%). Efficacy at 24 weeks was 88.4% (intention to treat) and 96.8% (per protocol). Triglyceride levels were reduced, on average, by 12.7% and a mean decrease of 9.0% in the glomerular filtration rate was observed as well ( P values of .003 and .002, respectively), whereas total cholesterol, HDL cholesterol, LDL cholesterol, creatinine, and glutamic-pyruvic transaminase remained unchanged. No patient discontinued due to adverse events. CONCLUSIONS: Dolutegravir/RPV is effective and safe in long-term HIV-infected patients under any prior ART. Toxicity, convenience, and interactions were the main reasons for changing. At 24 weeks, the lipid profile improved with a decrease in triglycerides. PMID- 29529911 TI - Endometrial Pneumatosis. PMID- 29529912 TI - Innovative Interventions and Models for People Living With Dementia and Their Care Partners. PMID- 29529913 TI - Smartphone-assisted minimally invasive neurosurgery. AB - OBJECTIVE Advances in video and fiber optics since the 1990s have led to the development of several commercially available high-definition neuroendoscopes. This technological improvement, however, has been surpassed by the smartphone revolution. With the increasing integration of smartphone technology into medical care, the introduction of these high-quality computerized communication devices with built-in digital cameras offers new possibilities in neuroendoscopy. The aim of this study was to investigate the usefulness of smartphone-endoscope integration in performing different types of minimally invasive neurosurgery. METHODS The authors present a new surgical tool that integrates a smartphone with an endoscope by use of a specially designed adapter, thus eliminating the need for the video system customarily used for endoscopy. The authors used this novel combined system to perform minimally invasive surgery on patients with various neuropathological disorders, including cavernomas, cerebral aneurysms, hydrocephalus, subdural hematomas, contusional hematomas, and spontaneous intracerebral hematomas. RESULTS The new endoscopic system featuring smartphone endoscope integration was used by the authors in the minimally invasive surgical treatment of 42 patients. All procedures were successfully performed, and no complications related to the use of the new method were observed. The quality of the images obtained with the smartphone was high enough to provide adequate information to the neurosurgeons, as smartphone cameras can record images in high definition or 4K resolution. Moreover, because the smartphone screen moves along with the endoscope, surgical mobility was enhanced with the use of this method, facilitating more intuitive use. In fact, this increased mobility was identified as the greatest benefit of the use of the smartphone-endoscope system compared with the use of the neuroendoscope with the standard video set. CONCLUSIONS Minimally invasive approaches are the new frontier in neurosurgery, and technological innovation and integration are crucial to ongoing progress in the application of these techniques. The use of smartphones with endoscopes is a safe and efficient new method of performing endoscope-assisted neurosurgery that may increase surgeon mobility and reduce equipment costs. PMID- 29529914 TI - Percutaneous transluminal angioplasty for central venous stenosis or occlusion in hemodialysis patients. AB - The objectives of central venous percutaneous transluminal angioplasty are to dilate the venous lesion and to extend the life of arteriovenous fistula for hemodialysis. It is reasonable to perform percutaneous transluminal angioplasty for central venous lesions if this interventional therapy is required to maintain stable dialysis therapy. However, the presence of large fresh thrombus at central venous lesion site represents a contraindication to percutaneous transluminal angioplasty unless the thrombus can first be removed by thrombectomy. Balloon angioplasty is a basic treatment for central venous lesion, but stent implantation is sometimes required. The self-expandable or balloon-expandable stent is chosen by the lesion location and characteristics. The lesion in subclavian vein is generally treated by self-expandable stent and right brachiocephalic vein is treated by balloon-expandable stent. The organic lesion of innominate vein with plaque is treated by self-expandable stent. Note that the innominate venous stenosis is sometimes caused by compression between the right brachiocephalic artery and the sternum, and this lesion is treated by balloon expandable stent because the radial force of balloon-expandable stent is stronger than self-expandable stent. It is important to understand the indication and stent selection for central venous percutaneous transluminal angioplasty. PMID- 29529915 TI - Combining Ultrasound-Guided Vascular Access With Ultrasound-Guided Analgesia for Single Skin and Vessel Puncture. AB - PURPOSE: To describe a single skin puncture technique combining subcutaneous injection of anesthetic to the depth of the vessel wall with venipuncture in the same movement. TECHNIQUE: Using ultrasound guidance, controlled anesthetic instillation along the needle tract and outer vessel wall with a 21-G vascular access needle can be combined with vessel puncture. This technique reduces the number of skin punctures and ensures accurate anesthetic instillation. The maximum inadvertent intravascular dose of commercial local anesthetic preparations that can be delivered with a small syringe is far below toxicity thresholds. CONCLUSION: A technique for combining anesthetic administration and vascular access with a 21-G needle and ultrasound guidance is feasible. PMID- 29529916 TI - Reasons of unsuccessful implantation of short-term hemodialysis catheters in jugular veins using real-time ultrasound. AB - PURPOSE: Real-time ultrasound is indicated for hemodialysis catheters' insertion in internal jugular veins. We evaluated unsuccessful implantation of short-term hemodialysis catheters in internal jugular veins using real-time ultrasound between patients with and without previous short-term catheters. METHODS: Observational open-label study of unsuccessful implantation of short-term hemodialysis catheters in internal jugular veins using real-time ultrasound from July 2013 to August 2014. RESULTS: A total of 185 procedures were compared in 122 individuals; 120 (64.86%) had previously used short-term catheters. There were 5 (8%) unsuccessful implantation among 62 catheterizations without previous short term catheter and 41 (33.6%) among 122 with previous short-term catheter (p = 0.001 Pearson's chi-squared, odds ratio = 5.77, 95% confidence interval = 2.15 15.50, p = 0.001). Non-progressing guidewire occurred in 2 (3.2%) of 62 patients without previous short-term catheter and in 18 (14.8%) of 122 with previous short term catheter (p = 0.018 Pearson's chi-squared, odds ratio = 5.19, 95% confidence interval = 1.16-23.15, p = 0.031). No difference was observed between size of the veins with or without non-progressing guidewire. All 11 cases of venous thrombosis occurred in patients who had previous short-term catheter removed due to infection. CONCLUSION: Previous use of short-term catheter is pivotal in the occurrence of unsuccessful implantation of short-term catheter in internal jugular veins using real-time ultrasound. PMID- 29529917 TI - Ultrasound-guided intravenous access in adults using SonoStik(r), a novel encapsulated sterile guidewire: A prospective cohort trial. AB - PURPOSE: We evaluated the performance of an encapsulated guidewire designed for single-handed use with ultrasound-guided vascular access (SonoStik) with Seldinger technique, as compared with conventional intravenous catheters placed under ultrasound guidance in healthy subjects. METHODS: This is a prospective cohort trial in healthy subjects in which each subject served as his/her own control by having a SonoStik ultrasound intravenous cannulation placed in one arm and a conventionally placed, standard ultrasound intravenous cannulation placed in the other arm. The basilic vein was used because it is a non-visible and non palpable vein. Emergency department technicians with extensive experience in ultrasound-guided intravenous access performed the procedures. The first-attempt success rate of intravenous-guided intravenous by using the SonoStik was compared to the standard ultrasound intravenous cannulation in adult healthy subjects. The secondary outcomes including time of procedure, technicians' and subjects' satisfaction, and complications were compared in both arms of the study. RESULTS: A total of 24 volunteers with a mean age of 22.7 years were enrolled. Four emergency department technicians with extensive prior experience with ultrasound guided intravenous access but with no prior experience using the SonoStik device performed the procedures. The first-attempt success was 83.3% with the use of SonoStik ultrasound intravenous cannulation compared to 95.8% with the standard ultrasound intravenous cannulation. There was a mean of 1.14 insertions per each successful placement in the SonoStik group compared to 1.04 insertions by using the standard catheters (mean differences = -0.1; 95% confidence interval = -0.6 to 0.4). There were no complications in either SonoStik or the standard ultrasound intravenous cannulation group. The mean time of insertion using SonoStik was slightly longer compared to standard ultrasound intravenous cannulation (143.3 vs 109.7 s). CONCLUSION: This study demonstrated that emergency department technicians skilled in ultrasound-guided intravenous access could successfully place SonoStik 83.3% of the time in vessels that were unable to be palpated or visualized. Compared to standard ultrasound intravenous cannulation, the odds ratio of successful cannulation with SonoStik was 0.91 (95% confidence interval = 0.04-17.5). In all cases, the time required to successfully insert SonoStik was less than 4 min from tourniquet application to catheter advancement to hub, with a mean time of less than 2.5 min. PMID- 29529918 TI - Establishing the Value of Diagnostic and Prognostic Tests in Health Technology Assessment. AB - In recent years, Health Technology Assessment (HTA) processes specific to diagnostics and prognostic tests have been created in response to the increased pressure on health systems to decide not only which tests should be used in practice but also the best way to proceed, clinically, from the information they provide. These technologies differ in the way value is accrued to the population of users, depending critically on the value of downstream health care choices. This paper defines an analytical framework for establishing the value of diagnostic and prognostic tests for HTA in a way that is consistent with methods used for the evaluation of other health care technologies. It assumes a linked evidence approach where modeling is required, and incorporates considerations regarding several different areas of policy, such as personalized medicine. We initially focus on diagnostic technologies with dichotomous results, and then extend the framework by considering diagnostic tests that provide more complex information, such as continuous measures (for example, blood glucose measurements) or multiple categories (such as tumor classification systems). We also consider how the methods of assessment differ for prognostic information or for diagnostics without a reference standard. Throughout, we propose innovative graphical ways of summarizing the results of such complex assessments of value. PMID- 29529919 TI - Effects of Kinect-based virtual reality game training on upper extremity motor recovery in chronic stroke. AB - BACKGROUND: Therapeutic benefits of Kinect-based virtual reality (VR) game training in rehabilitation encourage its use to improve motor function. OBJECTIVE: To assess the effects of Kinect-based VR training on motor recovery of the upper extremity and functional outcomes in patients with chronic stroke. METHODS: In this randomized controlled trial, group A received 20 sessions of physical therapy (PT) + 20 sessions of Kinect-based VR training and group B received only 20 sessions of PT. Clinical outcome measures were assessed at baseline and at the end of the treatments. Primary outcome measures that assess stroke patients' motor function included upper extremity (UE) Fugl-Meyer Assessment (FMA). Secondary outcome measures were Brunnstrom Recovery Stages (BRS), Modified Ashworth Scale (MAS), Box and Block test (BBT), Motricity index (MI), and active range of motion (AROM) measurement. RESULTS: Statistically significant improvements in game scores (p < 0.05) were observed in group A. In within-group analysis, there were statistically significant improvements in all clinical outcome measures except for the BRS-hand, MAS-distal, and MAS-hand in group A; MAS-(proximal, distal, hand) and BRS-(UE, hand) in group B compared with baseline values. Differences from baseline of FMA, MI, and AROM (except adduction of shoulder and extension of elbow) were greater in group A (p < 0.05). CONCLUSIONS: To conclude, our results suggest that the adjunct use of Kinect based VR training may contribute to the improvement of UE motor function and AROM in chronic stroke patients. Further studies with a larger number of subjects with longer follow-up periods are needed to establish its effectiveness in neurorehabilitation. PMID- 29529920 TI - Utility of Eating Assessment Tool-10 in Predicting Aspiration in Patients with Unilateral Vocal Fold Paralysis. AB - Objective Examine the incidence of penetration/aspiration in patients with unilateral vocal fold immobility and investigate the relationship with self reported perception of dysphagia. Study Design Case series with chart review. Setting Academic cancer center. Subjects and Methods Adult patients with unilateral vocal fold immobility diagnosed between 2014 and 2016 were reviewed. Patients were stratified into an aspiration group and a nonaspiration group using objective findings on flexible endoscopic evaluation of swallowing, as scored using Rosenbek's Penetration Aspiration Scale. Objective findings were compared to patient perception of dysphagia. Bivariate linear correlation analysis was performed to evaluate correlation between Eating Assessment Tool-10 scores and presence of aspiration. Tests of diagnostic accuracy were calculated to investigate the predictive value of Eating Assessment Tool-10 scores >9 on aspiration risk. Results Of the 35 patients with new-onset unilateral vocal fold immobility were evaluated, 25.7% (9/35) demonstrated tracheal aspiration. Mean +/ SD Eating Assessment Tool-10 scores were 19.2 +/- 13.7 for aspirators and 7.0 +/ 7.8 for nonaspirators ( P = .016). A statistically significant correlation was demonstrated between increasing Eating Assessment Tool-10 scores and Penetration Aspiration Scale scores ( r = 0.511, P = .002). Diagnostic accuracy analysis for aspiration risk in patients with an Eating Assessment Tool-10 score >9 revealed a sensitivity of 77.8% and a specificity of 73.1%. Conclusion Patient perception of swallowing difficulty may have utility in predicting aspiration risk. An EAT-10 of >9 in patients with unilateral vocal fold immobility may portend up to a 5 times greater risk of aspiration. Routine swallow testing to assess for penetration/aspiration may be indicated in patients with unilateral vocal fold immobility. PMID- 29529921 TI - 'That is how the real mad people behave': Beliefs about and treatment of mental disorders by traditional medicine-men in Accra, Ghana. AB - BACKGROUND: Traditional healing methods are considered central to mental health care in low-income countries such as Ghana, because they are perceived to be more easily accessible, more affordable and generally ascribe similar causal beliefs to those of the patients. However, not much is known about the work of traditional healers largely because their methods are shrouded in mysticism and secrecy. There is a need to understand the ideology and beliefs of traditional healers surrounding mental disorders, including knowledge about their practices in mental health care. AIMS: In this article, we discuss the causal beliefs and treatment methods of traditional medicine-men from Accra, Ghana. We also describe their diagnostic and treatment methods for mental disorders. METHODS: Eight medicine-men, indigenous to the Greater Accra Region, were interviewed through individual semi-structured interviews. The data were analysed through thematic analysis. RESULTS: The medicine-men's beliefs about mental illness were dominated by supernatural ideas. Mental illness was also seen as a form of punishment or resulting from envy, and there was a strong reliance on spiritual direction from the gods for diagnosis and treatment. CONCLUSION: These themes are discussed with emphasis on their potential implications for patients, as well as for collaborative efforts. PMID- 29529922 TI - Assessing the antecedents and consequences of threat appraisal of an acute psychosocial stressor: the role of optimism, displacement behavior, and physiological responses. AB - The feeling of stress is increasing in today's societies, particularly in young adults subjected to social evaluative situations in highly competitive academic and work contexts. Threat appraisal is a primary and fundamental reaction when people face a stressful situation. The aim of this study was to investigate the role of dispositional optimism as an antecedent and displacement behavior as a consequence of threat appraisal of a social-evaluative situation of stress. A second objective was to verify the moderating role of physiological responses to stress (heart rate and cortisol reactivity) in the relationship between threat appraisal and displacement behavior. To do this, we combined the Trier Social Stress Test (TSST) with ethological analysis, self-report questionnaires, and physiological data. As expected, people who scored higher on dispositional optimism perceived stress as less threatening, and a higher perception of threat was positively related to displacement behavior patterns. Moreover, the results showed that threat appraisal fully mediates the relationship between dispositional optimism and displacement behavior, and that only heart rate reactivity (not cortisol) moderates the relationship between threat appraisal and displacement behavior. PMID- 29529923 TI - Decision Criterion and Value of Information Analysis: Optimal Aspirin Dosage for Secondary Prevention of Cardiovascular Events. AB - BACKGROUND: In value of information (VOI) calculations, such as the expected value of perfect information (EVPI), partial perfect information (EVPPI), sample information (EVSI) or implementation (EVIM), the maximum expected value criterion defines the decision making criterion for the adoption of decisions for treatments. However, because decision makers are often risk averse, the uncertainty that accompanies a decision problem may influence adoption decisions. METHODS: VOI estimates were studied based on 2 alternate decision making criteria: 1) maximum expected value and 2) 95% credible intervals. These criteria were applied to a probabilistic minimal lifetime model of incident cardiovascular events and mortality among target patients comparing 2 daily doses of aspirin (81 mg and 325 mg). Model parameters were based on literature reviews and data analyses. RESULTS: Expected life-years under 81 v. 325 mg of aspirin were estimated to be 14.86 (SE, 0.10) and 14.72 (0.31) respectively, with a difference of 0.14 (0.29). The probability that 81 mg was optimal was estimated to be 67%. Under Decision Criterion 1, EVIM and EVPI were about 233-thousand and 411 thousand years, respectively. Under Criterion 2, EVIM was undefined, as there remains ambiguity about what to implement. Consequently, EVPI becomes the entire 644-thousand years. Also, under Criterion 1, EVSI reaches an asymptote at a sample size of 10,000 per arm, with minimal gains in value beyond a 5,000 person per arm trial. With Criterion 2, a sample size of 10,000 per arm or higher is substantially more valuable than lower sample sizes. CONCLUSION: Alternative decision criteria for treatment adoption change the VOI. Decision criteria should be justified for VOI analyses. If multiple criteria may be relevant, analysts should complete VOI estimates using multiple criteria. PMID- 29529924 TI - The Ubiquitin-Proteasome System and Memory: Moving Beyond Protein Degradation. AB - Cellular models of memory formation have focused on the need for protein synthesis. Recently, evidence has emerged that protein degradation mediated by the ubiquitin-proteasome system (UPS) is also important for this process. This has led to revised cellular models of memory formation that focus on a balance between protein degradation and synthesis. However, protein degradation is only one function of the UPS. Studies using single-celled organisms have shown that non-proteolytic ubiquitin-proteasome signaling is involved in histone modifications and DNA methylation, suggesting that ubiquitin and the proteasome can regulate chromatin remodeling independent of protein degradation. Despite this evidence, the idea that the UPS is more than a protein degradation pathway has not been examined in the context of memory formation. In this article, we summarize recent findings implicating protein degradation in memory formation and discuss various ways in which both ubiquitin signaling and the proteasome could act independently to regulate epigenetic-mediated transcriptional processes necessary for learning-dependent synaptic plasticity. We conclude by proposing comprehensive models of how non-proteolytic functions of the UPS could work in concert to control epigenetic regulation of the cellular memory consolidation process, which will serve as a framework for future studies examining the role of the UPS in memory formation. PMID- 29529925 TI - Broad Consent for Head and Neck Cancer Research. PMID- 29529926 TI - Validity of administrative database code algorithms to identify vascular access placement, surgical revisions, and secondary patency. AB - BACKGROUND:: We assessed the validity of physician billing codes and hospital admission using International Classification of Diseases 10th revision codes to identify vascular access placement, secondary patency, and surgical revisions in administrative data. METHODS:: We included adults (>=18 years) with a vascular access placed between 1 April 2004 and 31 March 2013 at the University Health Network, Toronto. Our reference standard was a prospective vascular access database (VASPRO) that contains information on vascular access type and dates of placement, dates for failure, and any revisions. We used VASPRO to assess the validity of different administrative coding algorithms by calculating the sensitivity, specificity, and positive predictive values of vascular access events. RESULTS:: The sensitivity (95% confidence interval) of the best performing algorithm to identify arteriovenous access placement was 86% (83%, 89%) and specificity was 92% (89%, 93%). The corresponding numbers to identify catheter insertion were 84% (82%, 86%) and 84% (80%, 87%), respectively. The sensitivity of the best performing coding algorithm to identify arteriovenous access surgical revisions was 81% (67%, 90%) and specificity was 89% (87%, 90%). The algorithm capturing arteriovenous access placement and catheter insertion had a positive predictive value greater than 90% and arteriovenous access surgical revisions had a positive predictive value of 20%. The duration of arteriovenous access secondary patency was on average 578 (553, 603) days in VASPRO and 555 (530, 580) days in administrative databases. CONCLUSION:: Administrative data algorithms have fair to good operating characteristics to identify vascular access placement and arteriovenous access secondary patency. Low positive predictive values for surgical revisions algorithm suggest that administrative data should only be used to rule out the occurrence of an event. PMID- 29529927 TI - Textured insoles reduce vertical loading rate and increase subjective plantar sensation in overground running. AB - The effect of textured insoles on kinetics and kinematics of overground running was assessed. 16 male injury-free-recreational runners attended a single visit (age 23 +/- 5 yrs; stature 1.78 +/- 0.06 m; mass 72.6 +/- 9.2 kg). Overground 15 m runs were completed in flat, canvas plimsolls both with and without textured insoles at self-selected velocity on an indoor track in an order that was balanced among participants. Average vertical loading rate and peak vertical force (Fpeak) were captured by force platforms. Video footage was digitised for sagittal plane hip, knee and ankle angles at foot strike and mid stance. Velocity, stride rate and length and contact and flight time were determined. Subjectively rated plantar sensation was recorded by visual scale. 95% confidence intervals estimated mean differences. Smallest worthwhile change in loading rate was defined as standardised reduction of 0.54 from a previous comparison of injured versus non-injured runners. Loading rate decreased (-25 to -9.3 BW s-1; 60% likely beneficial reduction) and plantar sensation was increased (46-58 mm) with the insole. Fpeak (-0.1 to 0.14 BW) and velocity (-0.02 to 0.06 m s-1) were similar. Stride length, flight and contact time were lower (-0.13 to -0.01 m; 0.02 to-0.01 s; -0.016 to -0.006 s) and stride rate was higher (0.01-0.07 steps s 1) with insoles. Textured insoles elicited an acute, meaningful decrease in vertical loading rate in short distance, overground running and were associated with subjectively increased plantar sensation. Reduced vertical loading rate could be explained by altered stride characteristics. PMID- 29529928 TI - In Vitro Susceptibility of Ciprofloxacin-Resistant Methicillin-Resistant Staphylococcus aureus to Ototopical Therapy. AB - Objective Despite the rising incidence of methicillin-resistant Staphylococcus aureus (MRSA) otologic infections, choice of treatment remains controversial. Only fluoroquinolone-containing ototopical preparations are approved by the US Food and Drug Administration for middle ear application. Furthermore, American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines advocate ototopical monotherapy for both tympanostomy tube otorrhea and acute otitis externa. Unfortunately, MRSA may be ciprofloxacin resistant. This causes confusion regarding antibiotic selection, because susceptibility profiles reflect a minimum inhibitory concentration (MIC), referenced against systemic, not ototopical, drug delivery dosing. The goal of this study is to determine the ciprofloxacin MIC for ciprofloxacin-resistant MRSA isolates from otologic infections and compare that value to the expected drug concentration achieved by fluoroquinolone ear drops and determine MRSA genotype for each isolate. Study Design In vitro assay with retrospective medical record review. Setting Tertiary care university hospital. Subjects and Methods Thirty otologically sourced ciprofloxacin-resistant MRSA isolates collected from adult and pediatric patients. MICs were calculated by broth dilution method. Isolates underwent multilocus sequence typing and polymerase chain reaction for arcA and Panton Valentine leukocidin to establish the genotype. Results MICs ranged from 16 to 1025 ug/mL. There was a relationship between MIC and genotype; of the 7 isolates with an MIC value greater than 512 ug/mL, 6 were sequence type (ST)8. Conclusion These findings support the practice of ototopical monotherapy for patients with uncomplicated ciprofloxacin-resistant MRSA otitis externa. However, they raise concern that ototopical therapy may not be adequate to treat highly resistant strains of MRSA infecting the middle ear space. PMID- 29529929 TI - Corrigendum. AB - Ferrandino R, Roof S, Ma Y, et al. Unplanned 30-day readmissions after parathyroidectomy in patients with chronic kidney disease: a nationwide analysis. Otolaryngol Head Neck Surg. 2017;157:955-965. (Original DOI: 10.1177/0194599817721154) In this article, the funding information was not included. The funding source section should have read as follows: "R.F. was supported by the National Center for Advancing Translational Sciences under award 1TL1TR001434-03. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health." PMID- 29529931 TI - Vascular access donor artery dilatation: Considerations about the formation mechanism in immunosuppressed patient. PMID- 29529930 TI - Exchange over the guidewire from non-tunneled to tunneled hemodialysis catheters can be performed without patency loss. AB - PURPOSE: The exchange from a non-tunneled hemodialysis catheter to a tunneled one over a guidewire using a previous venotomy has been reported to be safe. However, some concerns that it may increase infection risk prevent its clinical application. This approach seems particularly useful for acute kidney injury patients requiring initial renal replacement therapy, in whom we frequently worry about the choice of non-tunneled versus tunneled catheters. MATERIALS AND METHODS: From March 2012 to February 2016, 88 cases to receive the over-the guidewire exchange method from a non-tunneled to a tunneled catheter and 521 cases to receive de novo tunneled catheter placement from the hemodialysis vascular access cohort were compared retrospectively. RESULTS: The immediate complication, later catheter dysfunction requiring replacement, and infection rates were comparable between the two groups. Newly placed tunneled catheter survival in the over-the-guidewire exchange group was comparable with survival in the de novo tunneled catheter group (p = 0.24). In addition, when we compared the same two methods among only intensive care unit patients; they remained similar (p = 0.19). CONCLUSION: An exchange with the over-the-guidewire method from a non tunneled to a tunneled catheter was comparable to a de novo catheter placement technique. Therefore, this method should be viewed more favorably and should especially be considered for acute kidney injury patients. PMID- 29529932 TI - Ethical Research Practice or Undue Influence? Symbolic Power in Community- and Individual-Level Informed Consent Processes in Community-Based Participatory Research in Swaziland. AB - In community-based participatory research (CBPR), community-level consent is assumed to enhance ethical rigor, when obtained prior to individual informed consent. However, community leaders' permission to conduct research may influence individuals' agency to decline participation. This article presents findings of a Bourdieusian analysis of ethnographic data documenting CBPR in rural Swaziland. The findings reveal that the "symbolic power" of leaders who provide community level consent constrains individual agency and reproduces existing relations of power, if individual informed consent is simply a procedure. However, when informed consent is a process that introduces notions of autonomy and rights, it can disrupt power relations. Implications for ethical CBPR practice, and ethnography's value for developing theory from real-world research ethics practice, are discussed. PMID- 29529933 TI - Fretting-corrosion at the modular tapers interface: Inspection of standard ASTM F1875-98. AB - Interest in the degradation mechanisms at the modular tapers interfaces has been renewed due to increased reported cases of adverse reactions to metal debris and the appearance of wear and corrosion at the modular tapers interfaces at revision. Over the past two decades, a lot of research has been expended to understand the degradation mechanisms, with two primary implant loading procedures and orientations used consistently across the literature. ASTM F1875 98 is often used as a guide to understand and benchmark the tribocorrosion processes occurring within the modular tapers interface. This article presents a comparison of the two methods outlined in ASTM F1875-98 as well as a critique of the standard considering the current paradigm in pre-clinical assessment of modular tapers. PMID- 29529934 TI - Screening of potential lead molecules against prioritised targets of multi-drug resistant-Acinetobacter baumannii - insights from molecular docking, molecular dynamic simulations and in vitro assays. AB - Acinetobacter baumannii, an opportunistic pathogen, has become multi-drug resistant (MDR) to major classes of antibacterial and poses grave threat to public health. The current study focused to screen novel phytotherapeutics against prioritised targets of Acinetobacter baumannii by computational investigation. Fourteen potential drug targets were screened based on their functional role in various biosynthetic pathways and the 3D structures of 9 targets were retrieved from Protein Data Bank and others were computationally predicted. By extensive literature survey, 104 molecules from 48 herbal sources were screened and subjected to virtual screening. Ten clinical isolates of A. baumannii were tested for antibiotic susceptibility towards clinafloxacin, imipenem and polymyxin-E. Computational screening suggested that Ajmalicine ((19alpha)-16, 17-didehydro-19-methyloxayohimban-16-carboxylic acid methyl ester from Rauwolfia serpentina), Strictamin (Akuammilan-17-oic acid methyl ester from Alstonia scholaris) and Limonin (7, 16-dioxo-7, 16-dideoxylimondiol from Citrus sps) exhibited promising binding towards multiple drug targets of A. baumannii in comparison with the binding between standard drugs and their targets. Limonin displayed promising binding potential (binding energy -9.8 kcal/mol) towards diaminopimelate epimerase (DapF) and UDP-N-acetylglucosamine 1 carboxyvinyltransferase (MurA). Ajmalicine and Strictamin demonstrated good binding potential (-9.5, -8.5 kcal/mol, respectively) towards MurA and shikimate dehydrogenase (-7.8 kcal/mol). Molecular dynamic simulations further validated the docking results. In vitro assay suggested that the tested isolates exhibited resistance to clinafloxacin, imipenem and polymyxin-E and the herbal preparations (crude extract) demonstrated a significant antibacterial potential (p <= .05). The study suggests that the aforementioned lead candidates and targets can be used for structure-based drug screening towards MDR A. baumannii. PMID- 29529935 TI - Letters From Peplau. AB - BACKGROUND: Dr. Hildegard Peplau, considered to be our first modern Nurse theorist and the Mother of Psychiatric Nursing, was a prolific writer, engaging in correspondence with colleagues and students who sought her professional and theoretical expertise. Through these letters, she influenced psychiatric nursing while maintaining a broad international network of professional colleagues. OBJECTIVES: An analysis of letters, written between 1990 and 1998, provides insights into Peplau's last decade of professional life and a model of how to support the next generation of nurse scholars. DESIGN: Using content analysis, 24 letters received between 1990 and 1998 were read, reread, and coded. Recurring themes were identified. RESULTS: Three themes were identified. These include Peplau, the Person: Living a Life of Professional Balance; Lighting a Spark: Investing in the Next Generation; and Work in the Vineyards of Nursing: Maintaining a Life of Scholarship. The letters depict Peplau's keen intellect, her wide professional network, her leisure time spent with family and friends, and her own work to assure that her theoretical legacy continued. CONCLUSIONS: Peplau's insights continue to be relevant as psychiatric mental health nursing leaders engage in activities to support the next generation of scholars and leaders. PMID- 29529936 TI - Aflatoxin M1 in fresh milk collected from local markets of Karachi, Pakistan. AB - During 2016-2017, 156 samples of fresh milk samples were collected from local markets of Karachi, Pakistan and analysed for aflatoxin M1 (AFM1) contamination using ELISA technique. AFM1 was detected in 143 (91.7%) samples, ranged from 20 to 3090 ng L-1 with a mean level of 346.2 ng L-1. In 125 (80.1%) samples, the AFM1 contamination was greater than the maximum limit (ML = 50 ng L-1) set by EU. However, in 51 (32.7%) samples, the AFM1 level was higher than the ML of 500 ng L 1 as assigned by the USA. Statistical analysis showed that the AFM1 level in milk samples from summer was significantly (p < 0.05) higher than that obtained in winter. It was concluded that the AFM1 levels in the tested samples appear to be a serious public health problem. Therefore, immediate measures should be taken and re-evaluation done for the procedures for farming, transportation, refrigeration, and storage for the control of AFM1 level in milk samples. PMID- 29529937 TI - Implications of healing power and positioning for collaboration between formal mental health services and traditional/alternative medicine: the case of Ghana. AB - BACKGROUND: Many current debates about global mental health have increasingly called for collaboration between biomedical and traditional medical health systems. Despite these calls, not much has been written about the variables that would influence such collaboration. To a large extent, collaboration dialogues have considered biomedicine on the one hand, and a wide range of traditional and faith-based treatments on the other hand. However, this dualistic bifurcation does not reflect the plurality of healing systems in operation in many contexts, and the diverse investments that different non-biomedical healing approaches may have in their own power to heal. OBJECTIVE: We set out to explore the diversity of different healers' perceptions of power, and the relationship between that power and the perceived power of biomedical approaches. METHODS: Through a qualitative design, and using the case of medical pluralism in urban Ghana as an example, we conducted interviews among different categories of traditional and alternative medicine (TAM) practitioners living and/or working in the Greater Accra Region of Ghana. RESULTS: Through thematic analyses, differences in the notions about collaboration between the different categories of healers were identified. Their perceptions of whether collaboration would be beneficial seemed, from this study, to co-occur with their perceptions of their own power. CONCLUSIONS: We suggest that an important way to move debates forward about collaboration amongst different sectors is to examine the notions of power and positioning of different categories of TAM healers in relation to biomedicine, and the attendant implications of those notions for integrative mental healthcare. PMID- 29529938 TI - Psychophysiological effects of audiovisual stimuli during cycle exercise. AB - Immersive environments induced by audiovisual stimuli are hypothesised to facilitate the control of movements and ameliorate fatigue-related symptoms during exercise. The objective of the present study was to investigate the effects of pleasant and unpleasant audiovisual stimuli on perceptual and psychophysiological responses during moderate-intensity exercises performed on an electromagnetically braked cycle ergometer. Twenty young adults were administered three experimental conditions in a randomised and counterbalanced order: unpleasant stimulus (US; e.g. images depicting laboured breathing); pleasant stimulus (PS; e.g. images depicting pleasant emotions); and neutral stimulus (NS; e.g. neutral facial expressions). The exercise had 10 min of duration (2 min of warm-up + 6 min of exercise + 2 min of warm-down). During all conditions, the rate of perceived exertion and heart rate variability were monitored to further understanding of the moderating influence of audiovisual stimuli on perceptual and psychophysiological responses, respectively. The results of the present study indicate that PS ameliorated fatigue-related symptoms and reduced the physiological stress imposed by the exercise bout. Conversely, US increased the global activity of the autonomic nervous system and increased exertional responses to a greater degree when compared to PS. Accordingly, audiovisual stimuli appear to induce a psychophysiological response in which individuals visualise themselves within the story presented in the video. In such instances, individuals appear to copy the behaviour observed in the videos as if the situation was real. This mirroring mechanism has the potential to up-/down regulate the cardiac work as if in fact the exercise intensities were different in each condition. PMID- 29529939 TI - Thomas Reid on Mathematics and Natural Philosophy. PMID- 29529940 TI - A Novel Technique for Synchronous Laparoscopic Splenectomy and Azygoportal Disconnection With Hepatectomy. AB - BACKGROUND: Liver resection was not formerly recommended in patients with both hepatocellular carcinoma (HCC) and portal hypertension because of difficult perioperative bleeding control and postoperative liver failure. Splenectomy is a proven method with which to overcome these problems. To investigate the safety and feasibility of synchronous laparoscopic splenectomy and azygoportal disconnection with hepatectomy (LSDH) for treatment of portal hypertension accompanied with HCC, we describe a clinical cohort of 10 patients who underwent a new technique of synchronous LSDH. METHODS: A cohort of 10 cirrhotic patients with HCC, esophageal/gastric variceal bleeding, and hypersplenism received LSDH. A 6-port method was used for LSDH. This procedure comprises 5 steps: laparoscopic splenectomy, intraoperative splenic blood salvage, laparoscopic azygoportal disconnection, laparoscopic partial hepatectomy, and removal of spleen and liver specimens. Intraoperative autologous cell salvage was performed before hepatectomy. RESULTS: LSDH was successful in all patients. There was no conversion to open operations. The operative time was 220.5 +/- 19.8 minutes, blood loss was 264.0 +/- 160.3 mL, and postoperative hospital stay was 10.2 +/- 1.8 days. CONCLUSIONS: Selective synchronous LSDH is a feasible, effective, and safe surgical procedure with satisfactory short-term efficacy. It is a promising minimally invasive treatment option for patients with cirrhotic HCC and portal hypertension. PMID- 29529941 TI - Melatonin preserves ovarian tissues of rats exposed to chronic TCDD: An electron microscopic approach to effects of TCDD on ovarian cells. AB - 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is a toxic agent and has disruptive effects on reproductive tissues in females. TCDD disrupts the hormonal regulation of the body and decreases the production of melatonin. In this study, we investigated the protective effects of melatonin supplements against the toxic effects of TCDD on ovaries of female rats. TCDD caused a significant decrease in the average number of corpora lutea and follicles per tissue section (2.1 +/- 0.7; 2.3 +/- 0.8, respectively), whereas these numbers were maintained in the melatonin supplemented group (5.0 +/- 0.8; 5.1 +/- 0.8, respectively) and were similar to the control group (5.3 +/- 1.0; 5.9 +/- 0.9, respectively). Electron microscopic analysis showed that the disruption of ultrastructure components such as cell membrane and organelles due to TCDD exposure was inhibited by melatonin supplements. This study suggested that melatonin has a protective and a possible ameliorative effect over histopathological damage of rat ovaries exposed to TCDD. PMID- 29529942 TI - Abnormal spermatogenesis following sodium fluoride exposure is associated with the downregulation of CREM and ACT in the mouse testis. AB - cAMP response element modulator (CREM) is involved in regulating gene expression in normal spermatogenesis. The transcriptional activity of CREM is partly regulated by activator of CREM in the testis (ACT). To investigate the effects of different concentrations of sodium fluoride (NaF) on the gene and protein expression of CREM and ACT in the mouse testis, sexually mature male Kunming mice were exposed to 50, 100, or 150 mg/L NaF in their drinking water for 90 days. NaF reduced the sperm count and viability and increased the percentage of malformed sperm in a dose-dependent manner. The mRNA expression of CREM and ACT was markedly downregulated in the NaF-treated groups. Furthermore, immunohistochemistry revealed that CREM and ACT proteins were decreased significantly in the 50, 100, and 150 mg/L NaF-treated groups compared to the control group. These findings indicate that the decreased gene and protein expression of CREM and ACT in the testis is associated with an impairment of reproductive functions by NaF. PMID- 29529943 TI - Protective activity of pyruvate against vanadium-dependent cytotoxicity in Chinese hamster ovary (CHO-K1) cells. AB - With increasing human exposure to vanadium-containing compounds and growing concern over their impact on human health, identification of safe methods for efficient treatment of vanadium poisoning may be of value. In this study, using Chinese hamster ovary (CHO-K1) cells, we show that the toxicity of vanadyl sulphate (VOSO4) is mitigated in the presence of sodium pyruvate. The exposure of CHO-K1 cells to 100 MUM VOSO4 for 48 h induced significant cytotoxicity (measured with a resazurin assay) and elevation of the contents of malondialdehyde (MDA), a lipid peroxidation product, in the examined cells. When added simultaneously with VOSO4 to the culture medium, pyruvate (4.5 mM) reduced VOSO4-mediated cytotoxicity by twofold and inhibited MDA formation. Phase-contrast microscopy confirmed that the general morphology of cell cultures treated with 100 MUM VOSO4 and 4.5 mM pyruvate was improved compared to VOSO4-only treated cells. The two way analysis of variance revealed that the reduction of the adverse effects of VOSO4 in the presence of pyruvate was due to the independent action of pyruvate as well as antagonistic interaction between VOSO4 and pyruvate. From these data, it can be concluded that the pyruvate treatment may play a beneficial role in reducing vanadium-triggered health hazards. PMID- 29529944 TI - Total mercury levels in crustacean species from Italian fishery. AB - This study investigated mercury contamination levels in eight commercially valuable crustacean species caught off the Central Adriatic and Tyrrhenian coasts of Italy. Total mercury levels were measured by Thermal Decomposition Amalgamation-Atomic Absorption Spectrophotometry. Results showed a high variability among species with values ranging from 0.070 to 1.24 (mg kg-1 wet weight). The lowest mercury levels were detected in caramote prawn (Penaeus kerathurus), warty crab (Eriphia verrucosa) and European spider crab (Maja squinado), decapods living in shallow waters. Levels exceeding the limits established by the European Commission were found in species living in close contact with bottom sediments: deepwater rose shrimp (Parapenaeus longirostris), blue and red shrimp (Aristeus antennatus) and Norway lobster (Nephrops norvegicus). For shrimps, the inter-individual variability observed was mostly related to the body size, indicating the accumulation of mercury with age. An estimation of the human intake of mercury associated to the consumption of the crustaceans sampled and its comparison with the Tolerable Weekly Intake are provided. PMID- 29529945 TI - Successful and stable orthodontic camouflage of a mandibular asymmetry with sliding jigs. AB - The purpose of this paper is to present and discuss a simple and low-cost clinical approach to correct an asymmetric skeletal Class III combined to an extensive dental open bite that significantly compromised the occlusal function and smile aesthetics of an adult male patient. The patient did not accept the idealistic surgical-orthodontic treatment option, neither the use of temporary anchorage devices to facilitate the camouflage of the asymmetrical skeletal Class III/open bite. Therefore, a very simple and inexpensive biomechanical approach using sliding jigs in the mandibular arch was implemented as the compensatory treatment of the malocclusion. Although minor enhancements in facial aesthetics were obtained, the occlusal function and dental aesthetics were significantly improved. Furthermore, the patient was very satisfied with his new smile appearance. Some advantages of this treatment option included the small invasiveness and the remarkably low financial costs involved. Moreover, the final results fulfilled all realistic treatment objectives and the patient's expectations. Results remained stable 5 years post-treatment demonstrating that excellent results can be obtained when simple and low cost, but well-controlled mechanics are conducted. PMID- 29529946 TI - Correlation Between Raf/MEK/ERK Signaling Pathway and Clinicopathological Features and Prognosis for Patients With Breast Cancer Having Axillary Lymph Node Metastasis. AB - OBJECTIVE: This study aims to investigate the correlations between rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway and clinicopathological features and prognosis for patients with breast cancer having axillary lymph node metastasis. METHODS: A total of 118 breast cancer tissues with axillary lymph node metastasis (axillary lymph node metastasis group), 150 breast cancer tissues with non-axillary lymph node metastasis (non-axillary lymph node metastasis group), and 216 normal breast tissues (normal group) were enrolled in this study. The messenger RNA and protein expressions of rapidly accelerated fibrosarcoma, MEK, extracellular signal-regulated kinase, and their phosphorylated (p-) proteins were examined by reverse transcriptase quantitative polymerase chain reaction and immunohistochemistry, respectively. All patients received a 1-year follow-up, and the clinical follow-up data were collected. The multiple factors on the prognosis of patients with breast cancer having axillary lymph node metastasis were tested by Cox regression analysis. RESULTS: The messenger RNA expressions of rapidly accelerated fibrosarcoma, MEK, and extracellular signal-regulated kinase and positive rates of rapidly accelerated fibrosarcoma, MEK, phosphorylated MEK, extracellular signal-regulated kinase, and p-extracellular signal-regulated kinase in the axillary lymph node metastasis group were higher than in the non-axillary lymph node metastasis and normal groups (all P < .05). The protein expressions of rapidly accelerated fibrosarcoma, MEK, phosphorylated MEK, extracellular signal-regulated kinase, and p-extracellular signal-regulated kinase were associated with tumor size, clinical stage, and axillary lymph node metastasis number (all P < .05). Rapidly accelerated fibrosarcoma, MEK, and extracellular signal-regulated kinase expressions were significantly correlated with the prognosis of patients with breast cancer (all P < .05). Patients with BC having positive rapidly accelerated fibrosarcoma, MEK, phosphorylated MEK, extracellular signal-regulated kinase, and phosphorylated ERK expressions had a higher survival rate than patients with BC having the negative ones (all P < .05). Rapidly accelerated fibrosarcoma and extracellular signal-regulated kinase protein expressions, clinical stage, pathological grade, and axillary lymph node metastasis number were independent prognostic factors in patients with breast cancer having axillary lymph node metastasis (all P < .05). CONCLUSION: Our study proved that rapidly accelerated fibrosarcoma/MEK/extracellular signal-regulated kinase signaling pathway is significantly correlated with the clinicopathological features and prognosis for patients with BC having axillary lymph node metastasis. Rapidly accelerated fibrosarcoma and extracellular signal-regulated kinase protein expressions are independent prognostic factors for patients with breast cancer having axillary lymph node metastasis. PMID- 29529947 TI - Use of Severity Grades to Characterize Histopathologic Changes. AB - The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions. PMID- 29529948 TI - Controlled Donation After Circulatory Determination of Death: Ethical Issues in Withdrawing Life-Sustaining Therapy. PMID- 29529949 TI - Author's Reponse to Kompanje Letter to the Editor. PMID- 29529950 TI - The plasma interleukin-6 response to acute psychosocial stress in humans is detected by a magnetic multiplex assay: comparison to high-sensitivity ELISA. AB - Circulating concentrations of interleukin (IL)-6, an inflammatory biomarker widely assessed in humans to study the inflammatory response to acute psychological stress, have for decades been quantified using enzyme-linked immunosorbent assay (ELISA). However, biobehavioral researchers are increasingly using cytokine multiplex assays instead of ELISA to measure IL-6 and other cytokines. Despite this trend, multiplex assays have not been directly compared to ELISA for their ability to detect subtle stress-induced changes of IL-6. Here, we tested the prediction that a high-sensitivity multiplex assay (human Magnetic Luminex Performance Assay, R&D Systems, Minneapolis, MN) would detect changes in IL-6 as a result of acute stress challenge in a manner comparable to high sensitivity ELISA. Blood was collected from 12 healthy adults immediately before and then 90 and 210 min after the start of the Trier Social Stress Test (TSST), an acute laboratory psychosocial stress challenge. In addition to quantifying IL 6 concentrations in plasma with both multiplex and ELISA, we also assessed concentrations of tumor necrosis factor-alpha, IL-8, IL-10, IL-5, and IL-2 with multiplex. The multiplex detected IL-6 in all samples. Concentrations strongly correlated with values determined by ELISA across all samples (r = 0.941, p < .001) as well as among samples collected at individual TSST time points. IL-6 responses to the TSST (i.e. area under the curve) captured by multiplex and ELISA were also strongly correlated (rs = 0.937, p < .001). While other cytokines were detected by multiplex, none changed as a result of TSST challenge at time points examined. These results suggest high-sensitivity magnetic multiplex assay is able to detect changes in plasma concentrations of IL-6 as a result of acute stress in humans. PMID- 29529951 TI - Effects of tennis play on executive function in 6-11-year-old children: a 12 month longitudinal study. AB - The present study aimed to assess the effects of 12 months of frequent tennis play on executive functions and the relationships of daily moderate-to-vigorous physical activity (MVPA), physical competence, and enjoyment of playing tennis to executive functions in children. Thirty-two children (6-11 years old) who had regularly played tennis (once a week; mean = 3 years, range = 0-6 years) before the study were enrolled in a 12-month intervention. Participants were allocated into two groups: low-dose (maintain current frequency of tennis play, N = 19) or high-dose (increased frequency of tennis play to four times per week, N = 13). Participants' MVPA, physical competence, enjoyment of playing tennis, and executive functions (i.e. inhibitory control, working memory, and cognitive flexibility) were evaluated before and after this intervention. The high-dose group demonstrated a greater improvement in working memory than the low-dose group, while there was no group difference in MVPA, physical competence, and enjoyment of playing tennis. Changes in MVPA were associated with improvements in cognitive flexibility. Changes in physical competence were associated with improvements in working memory and cognitive flexibility. Changes in the enjoyment of playing tennis were associated with improvements in inhibitory control. The current findings suggest that replacement of MVPA with sports activity, such as tennis enhances executive functions development, and suggest that sports programmes that seek to build competence and enjoyment might help support the development of executive functions in children. PMID- 29529952 TI - Surgically induced weight loss results in a rapid and consistent improvement of female pelvic floor symptoms. AB - OBJECTIVE: The aim of this study was to evaluate the effect over time of bariatric surgery on female pelvic floor symptoms. METHODS: In total, 160 consecutive adult women were requested to complete four anonymous questionnaires [International Consultation on Incontinence Questionnaire (ICIQ), Bristol Female Lower Urinary Tract Symptoms (BFLUTS), Pelvic Floor Distress Inventory (PFDI-20) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12)] before bariatric surgery and at 3-6 months and 12-24 months postoperatively. Strict criteria were used to define clinically significant urinary incontinence (UI), pelvic organ prolapse (POP) and colorectal-anal (CRA) symptoms. Statistical analyses were performed using paired, two-sided, Student's t test for continuous data, and Fisher's exact test for categorical data. RESULTS: Altogether, 101 women (67%, mean age 41.6 +/- 11.8 years, mean preoperative body mass index 41.6 +/- 4.6 kg/m2) completed all questionnaires. In women who had preoperative UI (42.6%), mean ICIQ score decreased from 9.5 +/- 4.0 at baseline to 3.0 +/- 3.6 (p < .001) and 2.9 +/- 3.9 (p < .001) at 3-6 and 12-24 months postoperatively, respectively. In women who had preoperative POP symptoms (17.8%), mean PFDI 20/POP score decreased from 23.8 +/- 10.9 at baseline to 12.7 +/- 12.9 (p = .010) and 13.7 +/- 17.1 (p = .025) at 3-6 and 12-24 months postoperatively. In women who had preoperative CRA symptoms (35.6%), mean PFDI-20/CRA score decreased from 26.0 +/- 14.9 at baseline to 15.4 +/- 15.1 (p = .001) and 18.8 +/- 15.4 (p = .045) at 3-6 and 12-24 months postoperatively. De novo postoperative POP and CRA symptoms were reported by up to 16% of patients. CONCLUSIONS: Surgically induced weight loss is associated with significant improvements in UI, POP and CRA symptoms. The maximal clinical effect was achieved within 3-6 months, and remained constant throughout the second postoperative year. Nevertheless, de novo POP and CRA symptoms are expected in up to 16% of patients. PMID- 29529953 TI - Sternoclavicular joint replacement case report. AB - INTRODUCTION: This report describes the first known sternoclavicular joint (SCJ) replacement with a custom-made prosthesis. HISTORY: A 42-year-old male who presented post left medial clavicular excision with significant pain and limited range of motion impeding his daily activities and ability to work. The patient subsequently underwent a left SCJ arthroplasty with a custom-made prosthesis. Postoperatively, the patient suffered an anterior dislocation of the prosthetic joint which was successfully rectified and stabilized with soft tissue reconstruction, creating a pseudo-capsule from adjacent tissues of the joint. Thereafter, the patient required a final procedure to remove prominent sutures. RESULTS: Currently, the patient has regained full range of motion and is pain free during most activities and has now returned to work, with a plan to review his progress in 1 year. These initial promising results post SCJ replacement with the custom-made prosthesis could potentially lead SCJ reconstruction in an exciting new direction. DISCUSSION: More research should be encouraged regarding this nascent operative option, in order to identify the indications, parameters, and effectiveness of SCJ arthroplasty. PMID- 29529954 TI - Comparative study on clinical results of arthroscopic repair of anteroinferior, superior, and combined glenoid labral tear. AB - BACKGROUND: The purpose of this prospective study is to compare and correlate the clinical results of arthroscopic repair of a combined anteroinferior and superior labral lesion with those of an isolated anteroinferior labral lesion or type II superior labral tear from anterior to posterior (SLAP) lesion. METHODS: A comparative study involving patients who underwent arthroscopic labral repairs in a tertiary hospital between 2010 and 2014 was conducted. A total of 96 patients were divided into three groups: Group A consisted of 61 patients with the anteroinferior labral lesion, group B consisted of 16 patients with the type II SLAP lesion, and group C consisted of 19 patients with the combined anteroinferior and superior labral lesion. Patient demographics, preoperative and postoperative pain scores, shoulder functional scores (Constant Shoulder Score, UCLA (University of California at Los Angeles) Shoulder Score, and Oxford Instability Score), and shoulder ranges of motion were measured and compared. RESULTS: Except that patients from group B were generally older (28.8 vs. 22.2 for group A and 22.0 for group C, p = 0.04) at the time of surgery, no significant differences exist among the three groups in patient demographics and relevant clinical data. Preoperative and 2-year postoperative clinical outcomes, as well as the improvements, were comparable among the three groups. Low failure rates were observed for all three groups (6% vs. 10% vs. 11%, p = 0.999). CONCLUSIONS: Patients with the type II SLAP lesion underwent surgery at an older age. With appropriate surgical procedures, equivalent postoperative results can be expected for combined anteroinferior and superior labral lesion repair compared to isolated labral lesion repair. PMID- 29529955 TI - Hand function and recurrence after limited fasciectomy for Dupuytren's contracture: Long-term follow-up. AB - PURPOSE: The aim of this study was to analyze long-term results after limited fasciectomy for Dupuytren's contracture. METHODS: The study included 34 patients (52 rays), with an average follow-up of 9.5 years (range: 7-13 years). Range of motion, functional status, recurrence, and complications were recorded. RESULTS: Preoperative metacarpophalangeal joint (MCPJ) contracture (median: 35 degrees , range: 0-90 degrees ) improved postoperatively to full extension in all but one patient, with no recurrence at the most recent follow-up. Preoperative proximal interphalangeal joint (PIPJ) contractures (median: 52 degrees , range: 5-100 degrees ) were initially corrected, but recurred with time (median: 25 degrees , range 0 degrees -80 degrees ). Hand function was assessed using the Disabilities of the Arm, Shoulder and Hand questionnaire. Postoperative hand function improved (median: 0, range: 0-27), compared to preoperative function (median: 20, range: 0 51). Hand function worsened with time (at most recent follow-up: median: 3, range: 0-40), mainly due to PIPJ contracture recurrence, but function remained better than before surgery. CONCLUSION: Limited fasciectomy is an effective treatment method for MCPJ, with full correction achievable in both the short and long term. Regarding the PIPJ, treatment outcomes seem to be multifactorial. Further clarification is required to distinguish between local recurrence and remaining contracture of the PIPJ. PMID- 29529956 TI - The peritrapezial view: New radiograph for evaluating joints around trapezium. AB - PURPOSE: The purpose of this study was to present a new radiograph of peritrapezial view and examine whether this view could supply clear and reliable radiographs of the joints around trapezium. METHODS: The radiographs of peritrapezial and Robert views were taken on both hands of the 30 healthy volunteers (15 men and 15 women). The four peritrapezial joints were evaluated by two trained hand surgeons to find out whether these views could clearly show the joint spaces around the trapezium. Intra- and interobserver agreement for evaluation of each joint space and the ratio of joints which both of the two observers rated as clear joint space were compared between peritrapezial and Robert views. RESULTS: The kappa values of inter- and intra-observer reliability were, respectively, 0.559 and 0.715 in peritrapezial view and 0.462 and 0.355 in Robert view. The ratios of joints, which both of the two observers rated as clear joint space in each of the two time evaluations, were slightly higher in peritrapezial view than Robert view for the thumb carpometacarpal (100% vs. 96.7%) and scaphoid-trapezium joints (100% vs. 93.3%). In addition, these ratios were significantly higher in peritrapezial view than Robert view for the trapezium-index metacarpal (90.0% vs. 46.7%, p < 0.001) and trapezium-trapezoid joints (93.3% vs. 50.0%, p < 0.001). CONCLUSION: The peritrapezial view clearly shows the joint spaces around the trapezium. This view showed better inter- and intra-observer reliability for peritrapezial joints than Robert view especially in trapezium-index metacarpal and trapezium-trapezoid joint. This radiograph could provide a preliminary step for evaluating and managing pathologies of the peritrapezial joints. PMID- 29529957 TI - Circulating cell-free DNA does not harbour a diagnostic benefit in cats with feline diffuse iris melanomas. AB - Objectives Feline diffuse iris melanoma (FDIM) is the most common malignant primary intraocular tumour in cats, with reported metastases rates between 19% and 63%. Currently, the only available diagnostic tool for a tentative diagnosis is histopathological examination of the enucleated eye. Therefore, the veterinary ophthalmologist is often faced with the dilemma of whether to enucleate an oftentimes visual eye or to continue monitoring, with the risk of metastases developing. In the past, cell-free DNA (cfDNA) gained more attention in human medicine, especially in the field of oncology. Prior studies have shown the use of cfDNA as diagnostic or prognostic markers in canine and human cancer patients. Therefore, the aim of this study was to investigate cfDNA concentration and integrity in cats with FDIMs compared with cats with benign iris naevi and without ocular abnormalities. Methods cfDNA from plasma of cats with iris melanoma (n = 34), iris naevus (n = 30) and without ocular abnormalities (n = 32) were extracted. Primer and probes for feline amyloid beta precursor protein ( APP) and beta actin ( ACTB) were designed for amplicons of various lengths and quantitative PCRs of extracted cfDNA were performed to measure cfDNA concentration and integrity of the plasma samples. Differences of cfDNA concentrations and integrity levels between the three groups (iris melanoma, iris naevi and controls) were analysed using the Mann-Whitney U-test. Results cfDNA concentration and integrity analysis revealed no significant differences between the cats with iris melanoma, iris naevus or the control group ( P >0.01). Cats with metastases showed similar cfDNA concentration and integrity to cats without metastases. Conclusions and relevance cfDNA concentration and integrity seem to be insufficient as a diagnostic or prognostic marker in cats with FDIMs. PMID- 29529958 TI - A survey of vaccine history in German cats and owners' attitudes to vaccination. AB - Objectives Vaccination is the most important measure for prevention of feline infectious diseases. Cat owner compliance with vaccination recommendations has been investigated in the UK but not in other European countries. The aim of the present study was to determine cat owners' attitudes towards vaccination in cats in Germany, to identify factors that are associated with the vaccination status of their cats and to compare the results with those of the UK survey. Methods The survey was conducted using an online questionnaire and was aimed at respondents throughout Germany. Respondents under 16 years of age, cats that were less than 9 weeks old and veterinarians were excluded. A total of 920 questionnaires were evaluated, and information about cats and respondents was assessed with respect to the current vaccination status of the cats using a linear logistic regression model. Results The majority of cats (77.9%; n = 717) were vaccinated according to current guidelines; only 5.4% (n = 50; 95% confidence interval [CI] 5.00-9.00) of cats had never received a vaccine. Having visited a cattery, a cat show or travelled abroad in the past 12 months (n = 96/773; odds ratio [OR] 6.95; 95% CI 1.65-52.19) had the highest positive impact on the vaccination status of cats. In addition, detailed veterinary advice about vaccination had a positive impact (n = 275/773; OR 2.09; 95% CI 0.67-6.25) on the attitude of owners towards vaccinating their cats. Conclusions and relevance A history of travelling abroad or visiting cat shows or a cattery, and thus regulatory requirements, had the greatest positive impact on the current vaccination status of the cats. Veterinary consultation on preventive measures, including vaccination, is crucial for protecting the cat population against infectious diseases. PMID- 29529959 TI - Impact of prolonged utilization of neprilysin inhibition on the cognitive function of heart failure patients. PMID- 29529960 TI - Hemodialysis Reliable Outflow graft radiopaque tip detachment and embolization during implantation. PMID- 29529961 TI - Role of stents in hemodialysis vascular access. AB - Stents are ubiquitously utilized in coronary and peripheral arterial disease. Interventional nephrologists, however, place stents in the venous outflow of the arteriovenous access. Stenosis is the predominant pathology that causes access dysfunction and will ultimately lead to thrombosis if uncorrected. Angioplasty and stent deployment are the current techniques available to combat stenosis. From initial bare metal stainless steel stents, the current generations of stents used are predominately covered nitinol stents. The latest randomized control trials reveal that stents decrease the number of interventions required to maintain patency but do not improve the overall access survival. Furthermore, bare metal stents have been shown to be inferior to stent grafts. This review discusses indications for stent deployment in the hemodialysis access, the current evidence for their use, and briefly touches on their complications. PMID- 29529962 TI - Angioplasty to promote arteriovenous fistula maturation and maintenance. AB - The arteriovenous fistula is currently the best permanent access for the hemodialysis patient. Unfortunately, stenosis impairs maturation, long-term survival, and function of the arteriovenous fistula. Angioplasty currently is the best procedure for the treatment of immature and dysfunctional arteriovenous fistulas. In this review, the authors discuss the optimum time to evaluate arteriovenous fistulas for maturity, methods of evaluation for maturity, and the role of angioplasty in salvaging immature arteriovenous fistulas. The review also discusses the effect of stenosis on dysfunction in mature arteriovenous fistulas and the role of angioplasty to treat this complication. Finally, the impact of cutting balloons and drug-eluting balloons in the treatment of resistant and recurrent stenosis, respectively, is also discussed. PMID- 29529963 TI - Vein rupture by Arrow-Trerotola percutaneous thrombolytic device in a treatment of thrombosed arteriovenous graft. AB - INTRODUCTION: We report a case of vein rupture by Arrow-Trerotola percutaneous thrombolytic device (Trerotola PTD) during a treatment of thrombosed arteriovenous graft (AVG). CASE DESCRIPTION: A 77-year-old woman with a problem of thrombosed AVG underwent an endovascular treatment including a procedure of angioplasty of axillary vein. After angioplasty of axillary vein, we found a newly developed thrombus in axillary vein and performed thrombolysis using an over-the-wire 7F Trerotola PTD. When the rotating cage of the device arrived at axillary vein, it suddenly stopped, fixed at the angioplasty site, and didn't move at all. Venogram showed an extravasation of contrast media at axillary vein, suggesting vein rupture. The patient underwent an emergency operation. CONCLUSIONS: It could be dangerous to use Trerotola PTD in a native vein immediately after angioplasty. PMID- 29529965 TI - After peritoneal dialysis discontinuation: When will we remove peritoneal dialysis catheter? AB - Most of the peritoneal dialysis patients stop their peritoneal dialysis therapy and transfer to hemodialysis or kidney transplantation. In Japan, most end-stage kidney disease patients select hemodialysis after peritoneal dialysis discontinuation. Peritoneal dialysis catheter will be removed after stopping peritoneal dialysis. If peritoneal dialysis patients suffer from refractory peritonitis or severe tunnel infection, we remove the peritoneal dialysis catheter immediately. However, the causes of peritoneal dialysis discontinuation are ultrafiltration failure or peritoneal membrane dysfunction, and we have to consider the timing of peritoneal dialysis catheter removal. Encapsulating peritoneal sclerosis is the most important adverse event of peritoneal dialysis. And encapsulating peritoneal sclerosis often develops after stopping peritoneal dialysis. Risk factors associated with encapsulating peritoneal sclerosis are high peritoneal equilibration test values, longer peritoneal dialysis period, frequent peritonitis, and so on. There is no evidence to prevent encapsulating peritoneal sclerosis completely. Therefore, we can preserve the peritoneal dialysis catheter and assess the changes of peritoneal function after peritoneal dialysis discontinuation, if patient is suspected to have high risk of encapsulating peritoneal sclerosis. PMID- 29529964 TI - Prevalence of chronic kidney disease among patients undergoing transradial percutaneous coronary interventions. AB - BACKGROUND: While transradial approach to conduct percutaneous coronary interventions offers multiple advantages, the procedure can cause radial artery damage and occlusion. Because radial artery is the preferred site for the creation of an arteriovenous fistula to provide dialysis, patients with chronic kidney disease are particularly dependent on radial artery for their long-term survival. METHODS: In this retrospective study, we investigated the prevalence of chronic kidney disease in patients undergoing coronary interventions via radial artery. Stage of chronic kidney disease was based on estimated glomerular filtration rate and National Kidney Foundation - Kidney Disease Outcomes Quality Initiative guidelines. RESULTS: A total of 497 patients undergoing transradial percutaneous coronary interventions were included. Over 70.4% (350/497) of the patients had chronic kidney disease. Stage II chronic kidney disease was observed in 243 (69%) patients (estimated glomerular filtration rate = 76.0 +/- 8.4 mL/min). Stage III was observed in 93 (27%) patients (estimated glomerular filtration rate = 49 +/- 7.5 mL/min). Stage IV chronic kidney disease was observed in 5 (1%) patients (estimated glomerular filtration rate = 25.6 +/- 4.3 mL/min) and Stage V chronic kidney disease was observed in 9 (3%) patients (estimated glomerular filtration rate = 9.3 +/- 3.5 mL/min). Overall, 107 of 350 patients (30%) had advanced chronic kidney disease, that is, stage III-V chronic kidney disease. Importantly, 14 of the 107 (13%) patients had either stage IV or V chronic kidney disease. CONCLUSION: This study finds that nearly one-third of the patients undergoing transradial percutaneous coronary interventions have advanced chronic kidney disease. Because many of these patients may require dialysis, the use of radial artery to conduct percutaneous coronary interventions must be carefully considered in chronic kidney disease population. PMID- 29529966 TI - Ultrasound-guided internal jugular vein cannulation in the obese patient in a forced semi-sitting position. AB - INTRODUCTION: Central venous cannulation may be difficult in morbidly obese patients. We present a case of successful right internal jugular vein catheterization under real-time ultrasound guidance in an obese patient in a forced semi-sitting position. CASE REPORT: A 43-year-old male patient with body mass of 182 kg (body mass index, 52.2 kg/m2) was admitted to the clinic 48 h after the trauma. The patient was in a forced semi-sitting position (37 degrees head elevation). The patient was not able to perform the Valsalva maneuver. In the reported case, the lateral access for right internal jugular vein catheterization was chosen. We selected a lateral-oblique probe position for the ultrasound-guided internal jugular vein cannulation. Internal jugular vein catheterization was successful at the first attempt. CONCLUSION: Ultrasound imaging enables us to choose a desirable access for successful internal jugular vein cannulation in the obese patient without head-down tilt position. The lateral-oblique probe position for internal jugular vein cannulation may have advantages in certain clinical situations. PMID- 29529967 TI - Central venous catheterization for acute trauma resuscitation: Tip position analysis using routine emergency computed tomography. AB - PURPOSE: Central venous catheter insertion for acute trauma resuscitation may be associated with mechanical complications, but studies on the exact central venous catheter tip positions are not available. The goal of the study was to analyze central venous catheter tip positions using routine emergency computed tomography. METHODS: Consecutive acute multiple trauma patients requiring large bore thoracocervical central venous catheters in the resuscitation room of a university hospital were enrolled retrospectively from 2010 to 2015. Patients who received a routine emergency chest computed tomography were analyzed regarding central venous catheter tip position. The central venous catheter tip position was defined as correct if the catheter tip was placed less than 1 cm inside the right atrium relative to the cavoatrial junction, and the simultaneous angle of the central venous catheter tip compared with the lateral border of the superior vena cava was below 40 degrees . RESULTS: During the 6-year study period, 97 patients were analyzed for the central venous catheter tip position in computed tomography. Malpositions were observed in 29 patients (29.9%). Patients with malpositioned central venous catheters presented with a higher rate of shock (systolic blood pressure <90 mmHg) at admission (58.6% vs 33.8%, p = 0.023) and a higher mean injury severity score (38.5 +/- 15.7 vs 31.6 +/- 11.8, p = 0.041) compared with patients with correctly positioned central venous catheter tips. Logistic regression revealed injury severity score as a significant predictor for central venous catheter malposition (odds ratio = 1.039, 95% confidence interval = 1.005-1.074, p = 0.024). CONCLUSION: Multiple trauma patients who underwent emergency central venous catheter placement by experienced anesthetists presented with considerable tip malposition in computed tomography, which was significantly associated with a higher injury severity. PMID- 29529968 TI - Use of 8-cm 22G-long peripheral cannulas in pediatric patients. AB - INTRODUCTION: Medium-term intravenous access in children is normally achieved by means of repeated multiple peripheral intravenous cannula insertions or peripherally inserted central catheters. Long peripheral cannulas might offer an alternative to these devices in children. Our aim was to clarify whether long peripheral cannulas provide reliable medium-term intravenous access avoiding the need for multiple peripheral intravenous cannulations or peripherally inserted central catheter insertion in children undergoing surgery. METHODS: Following ethical approval, we prospectively collected data in children requiring medium term intravenous access. The 22G-8-cm-long peripheral cannulas were inserted with a Seldinger technique in a peripheral vein. Position was checked by flushing and aspirating the catheter. Results are reported as mean +/- standard deviation. RESULTS: A total of 18 children were included. Indications for medium-term intravenous therapy included perforated appendicitis (n = 14), infected central venous port (n = 2), fungal infection (n = 1) and septic arthritis (n = 1). In all, 15 (83%) patients underwent the procedure under general anaesthetic. The procedure failed in an 8-year-old patient. Insertion time was 8 +/- 3.7 min. Age at insertion was 6.3 +/- 4.9 years. Duration of intravenous therapy was 6.4 +/- 5.1 days. About 13 (76%) patients completed the treatment with no complications. Three (17%) lines occluded by day 3 needed removal; one (7%) line needed removal on day 3 because of redness/pain noted around the insertion site. CONCLUSION: Long peripheral cannulas represent a valid option for medium-term intravenous access in children undergoing surgery. Majority of patients will be successfully treated with one long peripheral cannula for the duration of their treatment without the need for further cannulation. PMID- 29529969 TI - Subclavian steal syndrome in a hemodialysis patient after percutaneous transluminal angioplasty of arteriovenous access. AB - INTRODUCTION: We describe a hemodialysis patient who developed subclavian steal syndrome via an arteriovenous fistula after percutaneous transluminal angioplasty. CASE DESCRIPTION: A 55-year-old female with end-stage renal failure due to polycystic kidney disease had been treated with hemodialysis for 10 years. Because of an autologous arteriovenous fistula stenosis, percutaneous transluminal angioplasty was performed. After successful treatment with percutaneous transluminal angioplasty, the patient developed dizziness. Magnetic resonance imaging with angiography of the brain and neck revealed normal bilateral subclavian and carotid arteries. However, flow in the left vertebral artery was not detected in time-of-flight magnetic resonance angiography. The left vertebral artery showed completely reversed blood flow as detected by color duplex ultrasound. We also confirmed anterograde flow in the left vertebral artery by color duplex ultrasound with arteriovenous fistula compression. Arteriovenous flows before the arteriovenous fistula stenosis and post percutaneous transluminal angioplasty were 1146 and 2239 mL/min, respectively. These findings suggested high-flow arteriovenous fistula led to the subclavian steal syndrome. The patient was subsequently treated by a flow reduction in the high-flow arteriovenous access using a modified graft inclusion technique. We decreased the arteriovenous fistula flow to 851 mL/min, which remained under 850 mL/min, 1 year later. The brain natriuretic peptide level and right-ventricular pressure also decreased after treatment. A modified graft inclusion technique was successful in decreasing the high flow of the arteriovenous fistula, and improved subclavian steal syndrome symptom and cardiac overload. CONCLUSION: This case shows that percutaneous transluminal angioplasty for an arteriovenous fistula may induce subclavian steal syndrome, and a modified graft inclusion technique was useful in improving the high flow of an arteriovenous fistula. PMID- 29529971 TI - Framing tomorrow's ethics education: Two steps back and three steps forward. PMID- 29529972 TI - Incivility experiences of nursing students in South Korea. AB - BACKGROUND: Incivility behaviors are negative social behaviors that can create conflict and disrespect among the persons involved. In a learning environment, incivility negatively affects learning by reducing academic motivation, lowering satisfaction with the education program, and interrupting the learning process. In addition, incivility causes those involved to feel negative emotions, such as anger, depression, and anxiety. RESEARCH QUESTION: What are the incivility experiences of nursing students during their nursing education? In what context do nursing students experience incivility during their education? RESEARCH DESIGN: This study used an exploratory qualitative methodology. Participants and research context: Participants (n = 34) were nursing students at three universities in South Korea. Data were collected during focus group interviews of 34 participants between 20 March and 26 June 2015 and were examined using a qualitative content analysis. Ethical consideration: The institutional review board approved this study. FINDINGS: The analysis revealed four learning contexts in which participants experienced incivility: (a) in the classroom, (b) outside the classroom, (c) clinical settings, and (d) related to technology use. Five themes were identified: student non-adherence to classroom standards, faculty non adherence to classroom standards, lack of helping-trusting relationships with peers, lack of dedication to teaching and learning in a clinical setting, and inappropriate use of technology. CONCLUSION: Nursing students experience incivility in a variety of situations and settings and expect a safer, more positive learning environment. The incivility experienced by nursing students during their education affects their goal of becoming professional nurses. PMID- 29529970 TI - Antibacterial effects of 18 medicinal plants used by the Khyang tribe in Bangladesh. AB - CONTEXT: The resistance of bacteria to antibiotics is raising serious concern globally. Asian medicinal plants could improve the current treatment strategies for bacterial infections. The antibacterial properties of medicinal plants used by the Khyang tribe in Bangladesh have not been investigated. OBJECTIVE: The present study examines the antibacterial properties of 18 medicinal plants used by the Khyang tribe in day-to-day practice against human pathogenic bacteria. MATERIALS AND METHODS: Leaves, bark, fruits, seeds, roots and rhizomes from collected plants were successively extracted with hexane, ethyl acetate and ethanol. The corresponding 54 extracts were tested against six human pathogenic bacteria by broth microdilution assay. The antibacterial mode of actions of phytoconstituents and their synergistic effect with vancomycin and cefotaxime towards MRSA was determined by time-killing assay and synergistic interaction assay, respectively. RESULTS AND DISCUSSION: Hexane extract of bark of Cinnamomum cassia (L.) J. Presl. (Lauraceae) inhibited the growth of MRSA, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii with MIC values below 100 ug/mL. From this plant, cinnamaldehyde evoked at 4 * MIC in 1 h an irreversible decrease of MRSA count Log10 (CFU/mL) from 6 to 0, and was synergistic with vancomycin for MRSA with fractional inhibitory concentration index of 0.3. CONCLUSIONS: Our study provides evidence that the medicinal plants in Bangladesh have high potential to improve the current treatment strategies for bacterial infection. PMID- 29529973 TI - Ethics case reflection sessions: Enablers and barriers. AB - BACKGROUND: In previous research on ethics case reflection (ECR) sessions about specific cases, healthcare professionals in childhood cancer care were clarifying their perspectives on the ethical issue to resolve their main concern of consolidating care. When perspectives were clarified, consequences in the team included 'increased understanding', 'group strengthening' and 'decision grounding'. Additional analysis of the data was needed on conditions that could contribute to the quality of ECR sessions. OBJECTIVE: The aim of this study was to explore conditions for clarifying perspectives during ECR sessions. RESEARCH DESIGN: Data were collected from observations and interviews and the results emerged from an inductive analysis using grounded theory. Participants and research context: Six observations during ECR sessions and 10 interviews were performed with healthcare professionals working in childhood cancer care and advanced paediatric homecare. Ethical considerations: The study was approved by a regional ethical review board. Participants were informed about their voluntary involvement and that they could withdraw their participation without explaining why. FINDINGS: Two categories emerged: organizational enablers and barriers and team-related enablers and barriers. Organizational enablers and barriers included the following sub-categories: the timing of the ECR session, the structure during the ECR session and the climate during the ECR session. Sub-categories to team related enablers and barriers were identified as space for inter-professional perspectives, varying levels of ethical skills and space for the patient's and the family's perspectives. DISCUSSION: Space for inter-professional perspectives included the dominance of a particular perspective that can result from hierarchical positions. The medical perspective is relevant for understanding the child's situation but should not dominate the ethical reflection. CONCLUSION: Conditions for ECR sessions have been explored and the new knowledge can be used when training facilitators as well as for those who organize/implement ECR sessions. Awareness of space for different perspectives, including the possible medical advantage over the nursing perspective, could reduce the somewhat unilateral attention and contribute to an inter-professionally shared reflection. PMID- 29529974 TI - The electrocardiographic manifestations of athlete's heart and their association with exercise exposure. AB - OBJECTIVE: The aim of this study was to define the minimum amount of exercise per week ('current exposure') and the total amount of exercise ('lifetime exposure') needed to lead to the electrocardiographic changes fitting athlete's heart. METHODS: All the pre-participation screenings (including electrocardiograms (ECGs)) from collegiate athletes performed at University Sports Medical Center in 2013 and 2014 were collected. Data on height, weight, sex, age, current sport(s) participation and lifetime sport(s) participation were collected. Current exposure was categorised into 0-3, 3-6, 6-10 and >10 hours/week. Lifetime sport exposure was divided into five categories: 0-1000, 1001-2000, 2001-3000, 3001 4000 and >4000 hours. RESULTS: The study population consisted of 1229 athletes (current exposure) and 1104 athletes (lifetime exposure). Current sport exposure: There was a significant increase in training-related ECG changes in the category 3-6 vs. <3 hours/week. When looking at individual parameters, we found an association with a significant difference in sinus bradycardia and QRS voltage (<3 vs. 3-6 hours/week) and first-degree AV-block (<3 vs. >10 hours/week).Lifetime sport exposure: There was an increase in training-related ECG changes that reached significance at an exposure >3000 hours. When looking at individual parameters, we found an association with a significant difference in sinus bradycardia (0-1000 vs. 2001-3000), QRS voltage (0-1000 vs. 3001-4000) and first-degree AV-block (0-1000 vs. >4000). CONCLUSION: A minimum of >=3 hours/week of current exposure and a lifetime exposure of >3000 hours is needed to lead to the electrocardiographic changes fitting athlete's heart. PMID- 29529975 TI - Randomized Trial of Modified Stretching Exercise Program for Menstrual Low Back Pain. AB - This study aimed to examine the effectiveness of a modified stretching exercise program on young women with menstrual low back pain. Overall, 127 young women were randomly assigned to the experimental ( n = 63) and control ( n = 64) groups. The experimental group followed the modified stretching exercise program, whereas the control group performed their usual activities. At 1, 4, 8, and 12 months, the experimental group had significantly lower scores on the visual analog scale for pain (95% confidence interval [CI] = [0.73, 1.96]; p < .05) and the Oswestry Low Back Pain Disability Questionnaire than the control group (95% CI = [0.68, 2.03]; p < .001). At 12 months, the experimental group showed significantly higher exercise self-efficacy than the control group (95% CI = [ 6.87, 0.62]; p = .003). These findings can be used to enhance self-care capabilities by using the modified stretching exercise program for young women with menstrual low back pain. PMID- 29529976 TI - Patient Identification of Health Risk. PMID- 29529977 TI - Routine CT scanning of patients retrieved to a tertiary centre on veno-venous extracorporeal membrane oxygenation: a retrospective risk benefit analysis. AB - INTRODUCTION: Comprehensive clinical examination can be compromised in patients on veno-venous extracorporeal membrane oxygenation (VV-ECMO). Adjunctive diagnostic imaging strategies range from bedside imaging only to routine computed tomography (CT). The risk-benefit of either approach remains to be evaluated. Patients retrieved to the Royal Brompton Hospital (RBH) on VV-ECMO routinely undergo admission CT imaging of head, chest, abdomen and pelvis. This study aimed to identify how frequently changes in therapy or adverse events could be attributed to routine CT scanning. METHODS: Demographic and clinical data were gathered retrospectively from patients retrieved to RBH on VV-ECMO (January 2014 2016). Scans were categorized as 'routine' or requested to clarify a specific clinical uncertainty. Clinical records were reviewed to identify attributable management changes and CT- related adverse events. Seventy-two patients were retrieved on VV-ECMO (median age 44 years) and 65 scanned on admission (mean radiation dose 2344mGy-cm). Routine head CT head yielded novel clinical information in 11 patients, 10 of whom had unexpected intracranial haemorrhage and, subsequently, had their anticoagulation withheld. Routine thoracic CT identified unexpected positive findings in three patients (early fibrosis, pulmonary vasculitis, pneumomediastinum), eliciting management variation in one (steroid administration). Routine abdomen/pelvis CT identified new information in three patients (adrenal haemorrhage, hepatosteatosis, splenic infarction), changing the management in one (withholding anticoagulation). RESULTS: CT scanning was not associated with consequential adverse events (e.g. accidental decannulation, gas entrainment into the circuit, hypoxia, hypotension). Median transfer/scan time was 78 minutes, requiring five ITU staff-members. In our cohort, a policy of routine head CT changed the management in 17% of patients; the yield from routine chest, abdomen and pelvis CT was modest. CT transfer was safe, but resource intensive. CONCLUSION: Prospective studies should evaluate whether routine CT impacts outcome. PMID- 29529979 TI - Obituary. PMID- 29529978 TI - Gene Editing: A View Through the Prism of Inherited Metabolic Disorders. AB - Novel technological developments mean that gene editing - making deliberately targeted alterations in specific genes - is now a clinical reality. The inherited metabolic disorders, a group of clinically significant, monogenic disorders, provide a useful paradigm to explore some of the many ethical issues that arise from this technological capability. Fundamental questions about the significance of the genome, and of manipulating it by selection or editing, are reviewed, and a particular focus on the legislative process that has permitted the development of mitochondrial donation techniques is considered. Ultimately, decisions about what we should do with gene editing must be determined by reference to other non genomic texts that determine what it is to be human - rather than simply to undertake gene editing because it can be done. PMID- 29529980 TI - Scientific and Ethical Issues in Mitochondrial Donation. AB - The development of any novel reproductive technology involving manipulation of human embryos is almost inevitably going to be controversial and evoke sincerely held, but diametrically opposing views. The plethora of scientific, ethical and legal issues that surround the clinical use of such techniques fuels this divergence of opinion. During the policy change that was required to allow the use of mitochondrial donation in the UK, many of these issues were intensely scrutinised by a variety of people and in multiple contexts. This extensive process resulted in the publication of several reports that informed the recommendations made to government. We have been intrinsically involved in the development of mitochondrial donation, from refining the basic technique for use in human embryos through to clinical service delivery, and have taken the opportunity in this article to offer our own perspective on the issues it raises. PMID- 29529981 TI - Gene Editing and Journal Editing. PMID- 29529982 TI - Germline Modification and Policymaking: The Relationship between Mitochondrial Replacement and Gene Editing. AB - 'Mitochondrial replacement' and 'germline gene editing' are relatively new techniques that represent a significant moral, technological, and legal threshold, as they would introduce permanent and heritable changes to the human gene pool. This article examines the close relationship between these two technologies over time, considering what regulatory lessons can be learned from the former as attention turns to the latter. It argues that the UK's 'mitochondrial replacement' approval process should not be taken as a model for the wider regulation of germline gene editing, and that policy-making needs to contend with a comprehensive picture of the social and political meaning of these technologies in the world. PMID- 29529983 TI - Selecting for Disabilities: Selection Versus Modification. AB - This essay considers one argument used to defend parents who use preimplantation genetic diagnosis (PGD) to select for deafness and other disabilities. Some bioethicists have argued that a distinction should be drawn between genetically modifying embryos to possess disabilities and using PGD to select embryos that already present markers of them, and that the former is unethical because it inflicts avoidable harms onto the resulting children, whereas the latter is permissible because it allows children with potentially impaired abilities to exist. This essay raises doubts about whether a meaningful moral distinction can be drawn between modification and selection. Arguments which distinguish modification from selection can be understood in two ways. One is to read them as presenting a No Harm, No Foul argument. Another is to read them as presenting a Harming Versus Letting Be argument. Neither succeeds, however, either in establishing a meaningful moral distinction between modification and selection, or in showing that the second is morally permissible in contradistinction to the first. PMID- 29529984 TI - In the Beginning was the Genome: Genomics and the Bi-textuality of Human Existence. AB - This paper addresses the cultural impact of genomics and the Human Genome Project (HGP) on human self-understanding. Notably, it addresses the claim made by Francis Collins (director of the HGP) that the genome is the language of God and the claim made by Max Delbruck (founding father of molecular life sciences research) that Aristotle must be credited with having predicted DNA as the soul that organises bio-matter. From a continental philosophical perspective I will argue that human existence results from a dialectical interaction between two types of texts: the language of molecular biology and the language of civilisation; the language of the genome and the language of our socio-cultural, symbolic ambiance. Whereas the former ultimately builds on the alphabets of genes and nucleotides, the latter is informed by primordial texts such as the Bible and the Quran. In applied bioethics deliberations on genomics, science is easily framed as liberating and progressive, religious world-views as conservative and restrictive (Zwart 1993). This paper focusses on the broader cultural ambiance of the debate to discern how the bi-textuality of human existence is currently undergoing a transition, as not only the physiological, but also the normative dimension is being reframed in biomolecular and terabyte terms. PMID- 29529986 TI - Ethical Judgments: Re-writing Medical Law. PMID- 29529985 TI - Why Human Germline Editing is More Problematic than Selecting Between Embryos: Ethically Considering Intergenerational Relationships. AB - Do we have a moral obligation to genetically cure embryos rather than selecting between them? Such an obligation would be an ethical argument for human germline gene editing (hGGE) to avoid the inheritance of genetic conditions instead of using pre-implantation genetic diagnosis (PGD). In this article, the intuition that we do have such a moral obligation is critically evaluated. The article first develops a theoretical framework for discussing the ethical questions of hGGE. This framework is based on an exploration of the phenomenology of the germline, from both biological and philosophical points of view. It interprets the germline as an embodied intergenerational relationship that carries meanings for the parents and for the children-to-be. It relates them to previous family generations, and to their own children. Hence, the germline is a phenomenologically much richer concept than just the line of cells that carry the inheritable genetic information. Against this background, selection is compared with editing and a key moral difference is identified: editing is in effect an act of co-constructing the genome, which necessarily assumes a wider range of responsibilities that include those parts that are left unedited. Introducing hGGE into societies would hence significantly affect and change the moral structure of the intergenerational relationships. Selective implantation, on the other hand (in the context of PGD), is based on a moral choice in favour of the embryo which is to be unaffected by a disease or disability that causes suffering, rather than selecting knowingly the affected one. The claim that hGGE is in the best interests of the child-to-be counterfactually assumes the presence of a patient who has an interest in being cured. The embryo (a potential future patient) is, however, brought into existence by the same act that is also the treatment. The future children who would result from treatment by hGGE may rather have an interest in not having been treated by hGGE, since it makes the intergenerational relationships more complicated and burdensome. The question 'Is hGGE justified, or even an obligation?' is answered with a No. PMID- 29529987 TI - Potential benefits of dietary nitrate ingestion in healthy and clinical populations: A brief review. AB - This article provides an overview of the current literature relating to the efficacy of dietary nitrate (NO3-) ingestion in altering aspects of cardiovascular and metabolic health and exercise capacity in healthy and diseased individuals. The consumption of NO3--rich vegetables, such as spinach and beetroot, have been variously shown to promote nitric oxide bioavailability, reduce systemic blood pressure, enhance tissue blood flow, modulate muscle O2 utilisation and improve exercise tolerance both in normoxia and in hypoxia, as is commonly observed in a number of disease states. NO3- ingestion may, therefore, act as a natural means for augmenting performance and attenuating complications associated with limited O2 availability or transport, hypertension and the metabolic syndrome. Recent studies indicate that dietary NO3- might also augment intrinsic skeletal muscle contractility and improve the speed and power of muscle contraction. Moreover, several investigations suggest that NO3- supplementation may improve aspects of cognitive performance both at rest and during exercise. Collectively, these observations position NO3- as more than a putative ergogenic aid and suggest that increasing natural dietary NO3- intake may act as a prophylactic in countering the predations of senescence and certain cardiovascular-metabolic diseases. PMID- 29529988 TI - On the shoulders of giants. The story behind the 'Pioneers of Nephrology' project. AB - This editorial introduces a series of interviews with the pioneers of Nephrology. It's a story that speaks by itself, given the thousands of people that are now alive thanks to the remarkable advances in renal replacement therapies such as dialysis, and kidney transplantation but also the many scientific advances in our understanding of the pathophysiology and treatment of kidney diseases worldwide.The interviews that we have selected for this series are, however, not dealing with their achievements, and their success; they try to pass on to future generations the idea of how they were, why they were passionate, what they loved, and, not last, where they found poetry in our profession.At a time in which narrative medicine points out the importance of the different life experiences in understanding diseases, we would invite you to discover a narrative portrait of the men and women who made our discipline what it is now. PMID- 29529989 TI - S100B polymorphisms are associated with age of onset of Parkinson's disease. AB - BACKGROUND: In this study we investigated the association between SNPs in the S100B gene and Parkinson's disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. METHODS: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar(r) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. RESULTS: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. CONCLUSIONS: rs9722, a functional SNP in the 3'-UTR of the S100B gene, was strongly associated with age of onset of PD. PMID- 29529990 TI - Gender differences in the psychophysiological effects induced by VOCs emitted from Japanese cedar (Cryptomeria japonica). AB - BACKGROUND: Wood is a valuable material for interiors, and the psychophysiological relaxation effects of volatile organic compounds (VOCs) from wood chips and essential oils have been reported. However, few studies have identified the odors in full-scale wooden environment, and also, differences in gender have not been clarified. In this study, we aimed to confirm the effects of VOCs emitted from interior wood walls in both human male and female participants. METHODS: We used Japanese cedar timber and analyzed VOCs in the experimental rooms with and without Japanese cedar timber by gas chromatography-mass spectrometry (GC-MS). The physiological effects were measured using neuroendocrinological and immunological parameters in saliva. A questionnaire was used to evaluate the subjective responses to each odor in the experimental rooms. RESULTS: The main compound emitted from Japanese cedar timber was delta-cadinene, and the total volume of VOCs in the wood condition (presence of VOCs emitted from Japanese cedar) was 282.4 (MUg/m3). Significant differences between genders in salivary parameters were shown that there were decreases of alpha-amylase in wood condition and increases of cortisol in the control (absence of VOCs) condition in female participants compared to male participants. The results demonstrated that VOCs in the experimental room with Japanese cedar timber tend to suppress the activation of the sympathetic nervous activity and non-VOCs of Japanese cedar in the control room increase cortisol in female participants. CONCLUSIONS: These results suggest that an indoor environment with wood interior materials has the potential to be useful for health management, especially women's health. PMID- 29529991 TI - Inferring RNA sequence preferences for poorly studied RNA-binding proteins based on co-evolution. AB - BACKGROUND: Characterizing the binding preference of RNA-binding proteins (RBP) is essential for us to understand the interaction between an RBP and its RNA targets, and to decipher the mechanism of post-transcriptional regulation. Experimental methods have been used to generate protein-RNA binding data for a number of RBPs in vivo and in vitro. Utilizing the binding data, a couple of computational methods have been developed to detect the RNA sequence or structure preferences of the RBPs. However, the majority of RBPs have not yet been experimentally characterized and lack RNA binding data. For these poorly studied RBPs, the identification of their binding preferences cannot be performed by most existing computational methods because the experimental binding data are prerequisite to these methods. RESULTS: Here we propose a new method based on co evolution to predict the sequence preferences for the poorly studied RBPs, waiving the requirement of their binding data. First, we demonstrate the co evolutionary relationship between RBPs and their RNA partners. We then present a K-nearest neighbors (KNN) based algorithm to infer the sequence preference of an RBP using only the preference information from its homologous RBPs. By benchmarking against several in vitro and in vivo datasets, our proposed method outperforms the existing alternative which uses the closest neighbor's preference on all the datasets. Moreover, it shows comparable performance with two state-of the-art methods that require the presence of the experimental binding data. Finally, we demonstrate the usage of this method to infer sequence preferences for novel proteins which have no binding preference information available. CONCLUSION: For a poorly studied RBP, the current methods used to determine its binding preference need experimental data, which is expensive and time consuming. Therefore, determining RBP's preference is not practical in many situations. This study provides an economic solution to infer the sequence preference of such protein based on the co-evolution. The source codes and related datasets are available at https://github.com/syang11/KNN . PMID- 29529993 TI - Epidemiologic analysis of respiratory viral infections among Singapore military servicemen in 2016. AB - BACKGROUND: Respiratory illnesses have been identified as a significant factor leading to lost training time and morbidity among Singapore military recruits. A surveillance programme has been put in place to determine etiological agents responsible for febrile, as well as afebrile respiratory illnesses in a military camp. The goal of the study is to better understand the epidemiology of these diseases and identify potential countermeasures to protect military recruits against them. METHODS: From Jan 2016 - Jan 2017, a total of 2647 respiratory cases were enrolled into the surveillance programme. The cases were further stratified into Febrile Respiratory Illness (FRI, with body temperature > 37.5 degrees C) or Acute Respiratory Illness (ARI, with body temperature < 37.5 degrees C). Nasal washes were collected and tested by multiplex PCR to detect 26 different pathogens. RESULTS: One thousand ninety five cases (41% of total cases) met the criteria of FRI in which 932 cases (85% of FRI cases) were screened positive for at least one virus. The most common etiological agents for FRI mono infection cases were Adenovirus E and Rhinovirus. Recruits infected with H3N2 influenza, Influenza B and Adenovirus E viruses were most likely presented as FRI cases. Notably, H3N2 influenza resulted in the greatest rise in body temperature. The remaining 1552 cases (59% of total cases) met the criteria of ARI in which 1198 cases (77% of ARI cases) were screened positive for at least one virus. The most common etiological agent for ARI mono-infection was Rhinovirus. The distribution pattern for dual infections was different for ARI and FRI cases. Maximum number of pathogens detected in a sample was five for both groups. CONCLUSION: Previous studies on respiratory diseases in military focused largely on FRI cases. With the expanded surveillance to ARI cases, this study allows unbiased evaluation of the impact of respiratory disease pathogens among recruits in a military environment. The results show that several pathogens have a much bigger role in causing respiratory diseases in this cohort. PMID- 29529992 TI - Molecular epidemiology and virulence characteristics of Staphylococcus aureus nasal colonization in medical laboratory staff: comparison between microbiological and non-microbiological laboratories. AB - BACKGROUND: Medical laboratory staff are a high-risk population for colonization of Staphylococcus aureus (S. aureus) due to direct and dense contact with the pathogens; however, there is limited information about this colonization. This study sought to determine the prevalence and molecular characteristics of nasal colonization by S. aureus in medical laboratory staff in Guangzhou, southern China, and to compare the differences between microbiological laboratory (MLS) and non-microbiological laboratory (NMLS) staff. METHODS: S. aureus colonization was assessed by nasal swab cultures from 434 subjects, including 130 MLSs and 304 NMLSs from 33 hospitals in Guangzhou. All S. aureus isolates underwent the antimicrobial susceptibility test, virulence gene detection and molecular typing. RESULTS: The overall prevalence of S. aureus carriage was 20.1% (87/434), which was higher in MLSs than in NMLSs (26.2% vs. 17.4%, P < 0.05), while the prevalence of Methicillin-resistant S. aureus (MRSA) was similar. Living with hospital staff was associated with S. aureus carriage. The majority of the isolates harboured various virulence genes, and those in MLSs appeared less resistant to antibiotics and more virulent than their counterparts. A total of 37 different spa types were detected; among these, t338, t437, t189 and t701 were the most frequently encountered types. T338 was the main spa type contributing to nasal colonization Methicillin-sensitive S. aureus (MSSA) (13.0%), and t437 SCCmec IV was predominant in MRSA isolates (40%). CONCLUSIONS: These findings provide insight into the risk factors, molecular epidemiology and virulence gene profiles of S. aureus nasal carriage among the medical laboratory staff in Guangzhou. PMID- 29529994 TI - UCP2 and UCP3 variants and gene-environment interaction associated with prediabetes and T2DM in a rural population: a case control study in China. AB - BACKGROUND: There are disparities for the association between uncoupling proteins (UCP) and type 2 diabetes (T2DM). The study was to examine the associations of genetic variants of UCP2 and UCP3 with prediabetes and T2DM in a rural Chinese population. METHODS: A population-based case-control study of 397 adults with T2DM, 394 with prediabetes and 409 with normal glucose tolerance (NGT) was carried out in 2014 in a rural community in eastern China. Three groups were identified through a community survey and the prediabetes and NGT groups were frequently matched by age and gender with the T2DM group and they were not relatives of T2DM subjects. With r2 >= 0.8 and minor allele frequency (MAF) >=0.05 for tag single nucleotide polymorphisms (SNPs) with potential function, three (rs660339, rs45560234 and rs643064) and six (rs7930460, rs15763, rs647126, rs1800849, rs3781907 and rs1685356) SNPs were selected respectively for UCP2 and UCP3 and genotyped in real time using the MassARRAY system (Sequenom; USA). The haplotypes, gene-environmental interaction and association between genetic variants of UCP2 and UCP3 and prediabetes or T2DM were explored. RESULTS: There were no significant differences in age and sex among three study groups. After the adjustment for possible covariates, the A allele of rs1800849 in UCP3 was significantly associated with prediabetes (aORAA vs GG = 1.68, 95% CI: 1.02 2.78), and the association was also significant under the recessive model (aOR AA vs GA + GG = 1.64, 95% CI: 1.02-2.66). Also, rs15763 was found to be marginally significantly associated with T2DM under dominant model (ORGA + AA vs GG = 0.73, 95% CI: 0.52-1.03, P = 0.072). No haplotype was significantly associated with prediabetes or T2DM. Multiplicative interactions for rs660339-overweight on T2DM were observed. In addition, the AA genotype of rs660339 was associated with an increased risk of T2DM in overweight subjects (OR = 1.48, 95%CI: 0.87-2.52) but with a decreased risk in those with normal weight (OR = 0.54, 95%CI: 0.28-1.05). CONCLUSIONS: Rs1800849 in UCP3 was significantly associated with prediabetes. Overweight might modify the effects of rs660339 of UCP2 on T2DM. PMID- 29529996 TI - Celiac disease and risk of myasthenia gravis - nationwide population-based study. AB - BACKGROUND: Case reports suggest there may be an association between celiac disease (CD) and myasthenia gravis (MG). METHODS: We identified 29,086 individuals with CD in Sweden from 1969 to 2008. We compared these individuals with 144,480 matched controls. Hazard ratios (HRs) for future MG (identified through ICD codes) were estimated using Cox regression. RESULTS: During 326,376 person-years of follow-up in CD patients, there were 7 MG cases (21/million person-years) compared to 22 MG cases in controls during 1,642,273 years of follow-up (14/million person-years) corresponding to a HR of 1.48 (95% CI = 0.64 3.41). HRs did not differ when stratifying for age, sex or calendar period. HRs were highest in the first year after follow-up, though insignificant. Individuals with CD were at no increased risk of MG more than 5 years after CD diagnosis (HR = 0.70; 95% CI = 0.16-3.09). CONCLUSION: This study found no increased risk of MG in patients with CD. PMID- 29529995 TI - Dissecting the pathobiology of altered MRI signal in amyotrophic lateral sclerosis: A post mortem whole brain sampling strategy for the integration of ultra-high-field MRI and quantitative neuropathology. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegenerative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Magnetic resonance imaging (MRI) has demonstrated its potential for detecting the pathological signature and tracking disease progression in ALS. However, the microstructural and molecular pathological substrate is poorly understood and generally defined histologically. One route to understanding and validating the pathophysiological correlates of MRI signal changes in ALS is to directly compare MRI to histology in post mortem human brains. RESULTS: The article delineates a universal whole brain sampling strategy of pathologically relevant grey matter (cortical and subcortical) and white matter tracts of interest suitable for histological evaluation and direct correlation with MRI. A standardised systematic sampling strategy that was compatible with co-registration of images across modalities was established for regions representing phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) patterns that were topographically recognisable with defined neuroanatomical landmarks. Moreover, tractography-guided sampling facilitated accurate delineation of white matter tracts of interest. A digital photography pipeline at various stages of sampling and histological processing was established to account for structural deformations that might impact alignment and registration of histological images to MRI volumes. Combined with quantitative digital histology image analysis, the proposed sampling strategy is suitable for routine implementation in a high-throughput manner for acquisition of large-scale histology datasets. Proof of concept was determined in the spinal cord of an ALS patient where multiple MRI modalities (T1, T2, FA and MD) demonstrated sensitivity to axonal degeneration and associated heightened inflammatory changes in the lateral corticospinal tract. Furthermore, qualitative comparison of R2* and susceptibility maps in the motor cortex of 2 ALS patients demonstrated varying degrees of hyperintense signal changes compared to a control. Upon histological evaluation of the same region, intensity of signal changes in both modalities appeared to correspond primarily to the degree of microglial activation. CONCLUSION: The proposed post mortem whole brain sampling methodology enables the accurate intraindividual study of pathological propagation and comparison with quantitative MRI data, to more fully understand the relationship of imaging signal changes with underlying pathophysiology in ALS. PMID- 29529997 TI - Possible association between androgenic alopecia and risk of prostate cancer and testicular germ cell tumor: a systematic review and meta-analysis. AB - BACKGROUND: A number of studies have investigated the association between androgenic alopecia (AGA) and cancer risk, but they have yielded inconsistent results. Therefore, this study was conducted to explore this controversial subject. METHODS: A literature database search was performed according to predefined criteria. An odds ratio (OR) or a hazard ratio (HR) with 95% confidence intervals (CIs) was retained to evaluate the relationship between the incidence of cancer or cancer-specific mortality and categories of AGA. Then a pooled OR or HR was derived. RESULTS: The pooled results showed that no specific degree of baldness had an influence on the incidence of cancer or cancer-specific mortality. However, AGA, especially frontal baldness, with the incidence of testicular germ cell tumor (TGCT) (OR = 0.69; 95% CI = 0.58-0.83). A significant increase of risk was observed in relation to high grade prostate cancer (PC) (OR = 1.42; 95% CI 1.02-1.99) and vertex with/without frontal baldness was associated with PC risk. CONCLUSIONS: The study results supported the hypothesis that AGA is negatively associated with TGCT risk and suggested an overlapping pathophysiological mechanism between them, while the viewpoint that AGA can be used as a phenotypic marker for PC risk was poorly supported. PMID- 29529998 TI - Neighborhood social capital and sleep duration: a population based cross sectional study in a rural Japanese town. AB - BACKGROUND: Studies on social capital and health outcomes have become common, but the relationship between neighborhood social capital and sleep duration by gender is still unclear. We examined the relationship between neighborhood social capital and sleep duration by gender in adults living in a rural community in Japan. METHOD: We conducted a cross-sectional survey of 12,321 residents aged >=20 years in a town in Mie Prefecture in January-March 2013. Self-completed questionnaires were collected from the residents (n = 7782; valid participation rate, 63.2%). We used five items to assess the neighborhood social capital (Cronbach's alpha = 0.86). We summed up the scores of each item, and then divided the participants into four groups by quartile of total scores of neighborhood social capital (lowest, low, high, and highest). Sleep duration of < 7 h/day was defined as insufficient sleep duration according to previous studies. To adjust for potential confounders, we performed a multiple log-binominal regression analysis and estimated the prevalence ratios (PRs) and 95% confidence intervals (CIs) for insufficient sleep. RESULTS: Overall 42% of the men and 45% of the women had insufficient sleep. In the men, the lowest group of neighborhood social capital presented a 22% higher prevalence of insufficient sleep (PR 1.22; 95% CIs 1.08-1.38) compared to the highest group of neighborhood social capital. Similarly the low group of neighborhood social capital and the high group of neighborhood social capital had 20 and 19% higher prevalence of insufficient sleep (PR 1.20; 95% CIs 1.06-1.36; PR 1.19; 95% CIs 1.06-1.34, respectively) compared to the highest group of neighborhood social capital. For women there was no significant association between neighborhood social capital and insufficient sleep after controlling for all potential confounders. CONCLUSION: Having lower neighborhood social capital was associated with insufficient sleep among Japanese adults, particularly in the men. This suggests that the context of neighborhood social capital by gender should be considered to promote healthier behaviors with regard to getting enough sleep. PMID- 29529999 TI - Prevalence of pre-transplant anti-HLA antibodies and their impact on outcomes in lung transplant recipients. AB - BACKGROUND: Previous studies have suggested that antibodies against human leukocyte antigen (HLA) are associated with worse outcomes in lung transplantation. However, little is known about the factors associated with outcomes following lung transplantation in Asia. Accordingly, we investigated the prevalence of anti-HLA antibodies in recipients before transplantation and assessed their impact on outcomes in Korea. METHODS: A single-center retrospective study was conducted. The study included 76 patients who received a lung transplant at a tertiary hospital in South Korea between January 2010 and March 2015. RESULTS: Nine patients (11.8%) had class I and/or class II panel reactive antibodies greater than 50%. Twelve patients (15.8%) had anti-HLA antibodies with a low mean fluorescence intensity (MFI, 1000-3000), 7 (9.2%) with a moderate MFI (3000-5000), and 12 (15.8%) with a high MFI (> 5000). Ten patients (13.2%) had suspected donor-specific antibodies (DSA), and 60% (6/10) of these patients had antibodies with a high MFI. In an analysis of outcomes, high-grade (>=2) primary graft dysfunction (PGD) was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI values than in patients with low MFI values (39.4% vs. 14.0%, p = 0.011). Of 20 patients who survived longer than 2 years and evaluated for pBOS after transplant, potential bronchiolitis obliterans syndrome (pBOS) or BOS was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI than in patients with low MFI, although this difference was not statistically significant (50.0% vs. 14.3%, p = 0.131). CONCLUSIONS: The prevalence of anti-HLA antibodies with high MFI was not high in Korea. However, the MFI was relatively high in patients with DSA. Anti-HLA antibodies with moderate-to-high MFI values were related to high-grade PGD. Therefore, recipients with high MFI before lung transplantation should be considered for desensitization and close monitoring. PMID- 29530000 TI - Relationship between the genetic polymorphisms of vicR and vicK Streptococcus mutans genes and early childhood caries in two-year-old children. AB - BACKGROUND: The VicRK two-component signalling system regulates virulence and cariogenicity in Streptococcus mutans (S. mutans). The purpose of this study was to explore the genetic polymorphisms of the vicR and vicK genes, which are associated with dental caries in children with S. mutans. METHODS: In this study, 121 (from each group) clinical S. mutans strains were isolated from caries-free children and children with high-severity caries to sequence the vicR and vicK genes. Genomic DNA was extracted from S. mutans strains and amplified using PCR. The PCR products were purified and sequenced. A chi-squared test and ABI Variant Reporter software were used to analyse the sequencing results. RESULTS: The 242 clinically isolated S. mutans strains contained the full-length vicR and vicK genes. No nucleotide sequence insertions or deletions were observed in the two genes. Four silent point mutations were identified in the vicR genes, and no missense mutations could be detected. Forty-one mutations were identified in the vicK genes. In addition to 32 silent mutations, 9 missense mutations at the 173, 337, 470, 1051, 1132, 1258, 1260, 1277, and 1348 bp positions were found. The distribution frequencies of the missense mutations were not significantly different between the groups, except for the C470T mutation. The frequency of the C470T missense mutation was higher in the high-severity caries group than in the caries-free group. CONCLUSIONS: vicR sequences are highly conserved in S. mutans clinical isolates. The locus 470 missense mutation of the vicK gene may be related to caries in children with S. mutans. PMID- 29530001 TI - Diagnostic and prognostic implications of ribosomal protein transcript expression patterns in human cancers. AB - BACKGROUND: Ribosomes, the organelles responsible for the translation of mRNA, are comprised of four rRNAs and ~ 80 ribosomal proteins (RPs). Although canonically assumed to be maintained in equivalent proportions, some RPs have been shown to possess differential expression across tissue types. Dysregulation of RP expression occurs in a variety of human diseases, notably in many cancers, and altered expression of some RPs correlates with different tumor phenotypes and patient survival. Little work has been done, however, to characterize overall patterns of RP transcript (RPT) expression in human cancers. METHODS: To investigate the impact of global RPT expression patterns on tumor phenotypes, we analyzed RPT expression of ~ 10,000 human tumors and over 700 normal tissues from The Cancer Genome Atlas (TCGA) using t-distributed stochastic neighbor embedding (t-SNE). Clusters of tumors identified by t-SNE were then analyzed with chi squared and t-tests to compare phenotypic data, ANOVA to compare individual RPT expression, and Kaplan-Meier curves to assess survival differences. RESULTS: Normal tissues and cancers possess distinct and readily discernible RPT expression patterns that are independent of their absolute levels of expression. In tumors, RPT patterning is distinct from that of normal tissues, identifies heretofore unrecognized tumor subtypes, and in many cases correlates with molecular, pathological, and clinical features, including survival. CONCLUSIONS: RPT expression patterns are both tissue-specific and tumor-specific. These could be used as a powerful and novel method of tumor classification, offering a potential clinical tool for prognosis and therapeutic stratification. PMID- 29530002 TI - Time to diagnosis and associated costs of an outpatient vs inpatient setting in the diagnosis of lymphoma: a retrospective study of a large cohort of major lymphoma subtypes in Spain. AB - BACKGROUND: Mainly because of the diversity of clinical presentations, diagnostic delays in lymphoma can be excessive. The time spent in primary care before referral to the specialist may be relatively short compared with the interval between hospital appointment and diagnosis. Although studies have examined the diagnostic intervals and referral patterns of patients with lymphoma, the time to diagnosis of outpatient compared to inpatient settings and the costs incurred are unknown. METHODS: We performed a retrospective study at two academic hospitals to evaluate the time to diagnosis and associated costs of hospital-based outpatient diagnostic clinics or conventional hospitalization in four representative lymphoma subtypes. The frequency, clinical and prognostic features of each lymphoma subtype and the activities of the two settings were analyzed. The costs incurred during the evaluation were compared by microcosting analysis. RESULTS: A total of 1779 patients diagnosed between 2006 and 2016 with classical Hodgkin, large B-cell, follicular, and mature nodal peripheral T-cell lymphomas were identified. Clinically aggressive subtypes including large B-cell and peripheral T-cell lymphomas were more commonly diagnosed in inpatients than in outpatients (39.1 vs 31.2% and 18.9 vs 13.5%, respectively). For each lymphoma subtype, inpatients were older and more likely than outpatients to have systemic symptoms, worse performance status, more advanced Ann Arbor stages, and high-risk prognostic scores. The admission time for diagnosis (i.e. from admission to excisional biopsy) of inpatients was significantly shorter than the time to diagnosis of outpatients (12.3 [3.3] vs 16.2 [2.7] days; P < .001). Microcosting revealed a mean cost of ?4039.56 (513.02) per inpatient and of ?1408.48 (197.32) per outpatient, or a difference of ?2631.08 per patient. CONCLUSIONS: Although diagnosis of lymphoma was quicker with hospitalization, the outpatient approach seems to be cost-effective and not detrimental. Despite the considerable savings with the latter approach, there may be hospitalization-associated factors which may not be properly managed in an outpatient unit (e.g. aggressive lymphomas with severe symptoms) and the cost analysis did not account for this potentially added value. While outcomes were not analyzed in this study, the impact on patient outcome of an outpatient vs inpatient diagnostic setting may represent a challenging future research. PMID- 29530003 TI - Reproductive risk factors in breast cancer and genetic hormonal pathways: a gene environment interaction in the MCC-Spain project. AB - BACKGROUND: Reproductive factors are well known risk factors for breast cancer; however, little is known about how genetic variants in hormonal pathways interact with that relationship. METHODS: One thousand one hundred thirty nine cases of breast cancer in women and 1322 frequency-matched controls were compared. Genetic variants in hormonal pathways (identified in the Kyoto Encyclopedia of Genes and Genomes) were screened according to their relationship with breast cancer using the Cochran-Armitage statistic. Information on reproductive factors was obtained using a face-to-face questionnaire. The interaction among the selected genetic variants and reproductive factors was tested with logistic regression. RESULTS: Concerning C allele in rs2229712, compared to nulliparity in non-carriers the ORs for 1-2 and > 2 deliveries were 0.48 (0.28-0.81) and 0.34 (0.19-0.59), and in C carriers they were 0.92 (0.42-1.98) and 0.71 (0.31-1.61). Similar results were found in women carrying the C allele in rs1269851. Carriers of Allele T in rs35652107 and allele C in rs6018027 had the delivery number effect more pronounced. CONCLUSIONS: The number of deliveries had a dose-response protective effect on breast cancer; women carrying C allele in rs2229712 did not benefit from this protective effect. PMID- 29530004 TI - Effect of infant feeding practices on iron status in a cohort study of Bolivian infants. AB - BACKGROUND: Iron deficiency (ID) is the most common micronutrient deficiency worldwide, with potentially severe consequences on child neurodevelopment. Though exclusive breastfeeding (EBF) is recommended for 6 months, breast milk has low iron content. This study aimed to estimate the effect of the length of EBF on iron status at 6 - 8 months of age among a cohort of Bolivian infants. METHODS: Mother-infant pairs were recruited from 2 hospitals in El Alto, Bolivia, and followed from one through 6 - 8 months of age. Singleton infants > 34 weeks gestational age, iron-sufficient at baseline, and completing blood draws at 2 and 6 - 8 months of age were eligible for inclusion (N = 270). Ferritin was corrected for the effect of inflammation. ID was defined as inflammation-corrected ferritin < 12 MUg/L, and anemia was defined as altitude-corrected hemoglobin < 11 g/dL; IDA was defined as ID plus anemia. The effect of length of EBF (infant received only breast milk with no other liquids or solids, categorized as < 4, 4 - 6, and > 6 months) was assessed for ID, IDA, and anemia (logistic regression) and ferritin (Fer) and hemoglobin (Hb, linear regression). RESULTS: Low iron status was common among infants at 6 - 8 months: 56% of infants were ID, 76% were anemic, and 46% had IDA. EBF of 4 months and above was significantly associated with ID as compared with EBF < 4 months (4 - 6 months: OR 2.0 [1.1 - 3.4]; > 6 months: 3.3 [1.0 - 12.3]), but not with IDA (4 - 6 months: OR 1.4 [0.8 - 2.4]; > 6 months: 2.2 [0.7 - 7.4]), or anemia (4 - 6 months: OR 1.4 [0.7 - 2.5]; > 6 months: 1.5 [0.7 - 7.2]). Fer and Hb concentrations were significantly lower with increasing months of EBF. CONCLUSIONS: Results suggest a relationship between prolonged EBF and ID, but are not sufficient to support changes to current breastfeeding recommendations. More research is needed in diverse populations, including exploration of early interventions to address infant IDA. PMID- 29530005 TI - Risk factors for progression of radiographic knee osteoarthritis in elderly community residents in Korea. AB - BACKGROUND: Knee osteoarthritis (OA) is the most common form of arthritis affecting the elderly. Understanding the risk factors for knee OA has been derived from cross sectional studies. There have been few longitudinal studies of risk factors for knee OA among Asian populations. The purpose of this study was to evaluate the risk factors for knee OA in elderly Korean community residents. METHODS: This prospective, population-based study was conducted on residents over 50 years of age in Chuncheon who participated in the Hallym Aging Study. Standardized weight-bearing semi-flexed knee anteroposterior radiographs were obtained in 2007 and in 2010. Of 504 participants at baseline, 322 participants (male: female = 150:172) underwent follow-up knee radiographs. Radiographic knee OA was defined as Kellgren/Lawrence (K-L) grade of >= 2. Risk factors assessed at baseline were tested for their association with incidence, progression, and worsening of radiographic knee OA by logistic regression analysis. RESULTS: The median age of these participants at follow-up was 71 years (interquartile range 66-75 years). Incident OA was observed in 33 (10.2%) and progression of OA (defined as an increase of Kellgren-Lawrence (K-L) grade at follow-up, from grades 2 or 3 at baseline) in 43 (13.55%) participants. In multivariate logistic regression analysis, only females were significantly associated with the progression of radiographic knee OA (odds ratio [OR] = 4.41, 95% confidence interval [CI] 1.32-14.77). CONCLUSIONS: In this 3-year longitudinal study, the yearly incidence and progression of knee OA was higher than those previously reported in Western populations. PMID- 29530006 TI - The prognostic value of microvascular invasion in early-intermediate stage hepatocelluar carcinoma: a propensity score matching analysis. AB - BACKGROUND: Microvascular invasion (MVI) is well established as a negative prognostic factor for hepatocelluar carcinoma (HCC). However, its prognostic value in different subgroups of Barcelona Clinical Liver Cancer (BCLC) stages remains to be elucidated. METHODS: Four hundred fifty-eight MVI-negative and 204 MVI-positive patients who underwent hepatectomy were retrospectively analyzed. After propensity score matching (PSM) analysis, 187 pairs of matched patients were generated. Long-term survival was compared by the Kaplan-Meier method. RESULTS: Patients with MVI commonly had more advanced tumors. All the patients with MVI had significantly worse survival rate compared to the patients without MVI before and after PSM(p < 0.001). In the subgroup analysis, BCLC stage A HCC patients without MVI had better prognosis than those with MVI before and after PSM (p < 0.001 and p = 0.024). For BCLC stage B HCCs, long-term survival was significantly better for patients without MVI before PSM(p = 0.001). However, the overall survival (OS) rate was comparable between both groups after PSM (p = 0.682), although MVI-positive group had a higher rate of recurrence (p = 0.011).. Surgery type, satellite lesions, tumor size, and serum ALT level were statistically significant factors associated with survival in MVI-positive group. Tumor number, tumor size and neutrophil to lymphocyte ratio (NLR) were predictors of survival in MVI-negative group. CONCLUSIONS: Its prognostic value in different subgroups of BCLC stages differed. MVI is an independent predictor of prognosis in patients with BCLC stage A. For BCLC stage B HCCs, MVI-positive group had poor prognosis through more advanced HCCs. PMID- 29530007 TI - Elevated alpha-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease. AB - BACKGROUND: Interstitial lung disease (ILD) is a prognostic indicator of poor outcome in myositis. Although the pathogenesis of myositis-associated ILD is not well understood, neutrophils are thought to play a pivotal role. Neutrophils store azurophil granules that contain defensins, which are antimicrobial peptides that regulate the inflammatory response. Here, we evaluated levels of the human neutrophil peptides (HNPs) alpha-defensin 1 through 3 in patients with myositis associated ILD to determine whether HNPs represent disease markers and play a role in the pathogenesis of myositis-associated ILD. METHODS: HNP levels were measured in the plasma and bronchoalveolar lavage fluid (BALF) of 56 patients with myositis-associated ILD and 24 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Analysis revealed significantly higher HNP levels in plasma and BALF samples from patients with myositis-associated ILD as compared to those of healthy controls; however, plasma HNPs were significantly correlated with total cell counts in BALF. Additionally, BALF HNP levels were positively correlated with serum surfactant protein-A and the percentage of neutrophils in BALF, and BALF HNP levels correlated with the percentage of reticular opacities in high-resolution computed tomography results for patients with anti-aminoacyl tRNA synthetase (ARS) antibody positive myositis-associated ILD. Survival did not differ between patients with higher and lower levels of plasma and BALF HNPs. CONCLUSIONS: Plasma and BALF HNPs might reflect the disease activities of myositis-associated ILD, especially in patients with anti-ARS antibody positive myositis-associated ILD. However further studies are necessary to clarify whether HNPs represent disease markers and play roles in disease pathogenesis. PMID- 29530008 TI - Hyperglycemia-related central pontine demyelinization after a binge-eating attack in a patient with type-2 diabetes: a case report. AB - BACKGROUND: Here, we report a case of central pontine demyelinization in a type-2 diabetes patient with hyperglycemia after a binge-eating attack in the absence of a relevant hyponatremia. CASE PRESENTATION: A 55-year-old, male type-2 diabetic patient with liver cirrhosis stage Child-Pugh B was admitted due to dysmetria of his right arm, gait disturbance, dizziness, vertigo, and polyuria, polydipsia after a binge-eating attack of sweets (a whole fruit cake and 2 Liters of soft drinks). A recently initiated insulin therapy had been discontinued for 8 months. A serum glucose measurement obtained 5 days prior to hospitalisation was 38.5 mmol/l (694 mg/dl). The patient graved for sweets since stopping alcohol consumption 8 months earlier. On admission, venous-blood glucose was 29.1 mmol/l (523.8 mg/dl), glycated hemoglobin was 168.0 mmol/mol or 17.6%. No supplementation of sodium chloride was reported. Laboratory exams revealed an elevated serum ammonia level (127.1 MUmol/l), rendering a hepatic encephalopathy very likely. After initiation of insulin therapy, capillary glucose normalized, and serum sodium rose from 133 on admission to 144 mmol/l during the hospital stay. In retrospect, the mild hyponatremia on admission was classified as pseudohyponatremia due to hyperglycemia. The patient had an insulin resistance (HOMA-IR 7.8 (normal range < 2.5)). A T2-weighted magnetic resonance imaging (MRI) of the head and a cranial computed tomography scan were obtained demonstrating a symmetric central pontine demyelinization. After 26 days in hospital, the patient was discharged with an inkretin-mimetic therapy (dulaglutide SC, 1.5 mg/week) and an intensified conventional insulin therapy (insulin aspart: 14 units/d in euglycemia, insulin glargin 20 units/d). CONCLUSIONS: Central pontine and/or cerebellar myelinolysis can be caused by sudden, severe, and sustained hyperglycemia, especially when another risk factor (in this case, liver cirrhosis) is present. Functional neurological deficits in the context of hyperglycemia should prompt for the consideration of this differential diagnosis in all diabetes patients. PMID- 29530009 TI - Kidney stone formers have more renal parenchymal crystals than non-stone formers, particularly in the papilla region. AB - BACKGROUND: We investigated the renoprotective ability of healthy people against kidney stone formation. To clarify intratubular crystal kinetics and processing in human kidneys, we performed a quantitative and morphological observation of nephrectomized renal parenchyma tissues. METHODS: Clinical data and pathological samples from 60 patients who underwent radical nephrectomy for renal cancer were collected from June 2004 to June 2010. The patients were retrospectively classified as stone formers (SFs; n = 30, kidney stones detected by preoperative computed tomography) and non-stone formers (NSFs; n = 30, no kidney stone history). The morphology of parenchymal intratubular crystals and kidney stone related gene and protein expression levels were examined in noncancerous renal sections from both groups. RESULTS: SFs had a higher smoking rate (P = 0.0097); lower red blood cell, hemoglobin, and hematocrit values; and higher urinary red blood cell, white blood cell, and bacterial counts than NSFs. Scanning electron microscopy revealed calcium-containing crystal deposits and crystal attachment to the renal tubular lumen in both groups. Both groups demonstrated crystal transmigration from the tubular lumen to the interstitium. The crystal diffusion analysis indicated a significantly higher crystal existing ratio in the medulla and papilla of SFs and a significantly higher number of papillary crystal deposits in SFs than NSFs. The expression analysis indicated relatively high osteopontin and CD68, low superoxide dismutase, and significantly lower Tamm Horsfall protein expression levels in SFs. Multivariate logistic regression analysis involving the above factors found the presence of renal papillary crystals as a significant independent factor related to SFs (odds ratio 5.55, 95% confidence interval 1.08-37.18, P = 0.0395). CONCLUSIONS: Regardless of stone formation, intratubular crystals in the renal parenchyma seem to transmigrate to the interstitium. SFs may have reduced ability to eliminate renal parenchymal crystals, particularly those in the papilla region, than NSFs with associated gene expression profiles. PMID- 29530010 TI - The fundamental association between mental health and life satisfaction: results from successive waves of a Canadian national survey. AB - BACKGROUND: A self-reported life satisfaction question is routinely used as an indicator of societal well-being. Several studies support that mental illness is an important determinant for life satisfaction and improvement of mental healthcare access therefore could have beneficial effects on a population's life satisfaction. However, only a few studies report the relationship between subjective mental health and life satisfaction. Subjective mental health is a broader concept than the presence or absence of psychopathology. In this study, we examine the strength of the association between a self-reported mental health question and self-reported life satisfaction, taking into account other relevant factors. METHODS: We conducted this analysis using successive waves of the Canadian Community Health Survey (CCHS) collected between 2003 and 2012. Respondents included more than 400,000 participants aged 12 and over. We extracted information on self-reported mental health, socio-demographic and other factors and examined correlation with self-reported life satisfaction using a proportional ordered logistic regression. RESULTS: Life satisfaction was strongly associated with self-reported mental health, even after simultaneously considering factors such as income, general health, and gender. The poor-self reported mental health group had a particularly low life satisfaction. In the fair-self-reported mental health category, the odds of having a higher life satisfaction were 2.35 (95% CI 2.21 to 2.50) times higher than the odds in the poor category. In contrast, for the "between 60,000 CAD and 79,999 CAD" household income category, the odds of having a higher life satisfaction were only 1.96 (95% CI 1.90 to 2.01) times higher than the odds in the "less than 19,999 CAD" category. CONCLUSIONS: Subjective mental health contributes highly to life satisfaction, being more strongly associated than other selected previously known factors. Future studies could be useful to deepen our understanding of the interplay between subjective mental health, mental illness and life satisfaction. This may be beneficial for developing public health policies that optimize mental health promotion, illness prevention and treatment of mental disorders to enhance life satisfaction in the general population. PMID- 29530011 TI - Clinical and misdiagnosed analysis of primary pulmonary lymphoma: a retrospective study. AB - BACKGROUND: The primary pulmonary lymphoma (PPL), with a low incidence, was highly misdiagnosed in clinic. The present study analyzes the clinical features, laboratory and imaging data, pathologic characteristics, and summarizes misdiagnosis reasons of PPL cases, aims to provide a better understanding and increase the accuracy of early diagnosis and minimize the misdiagnosis of PPL. METHODS: The clinical data of 19 cases were collected from the first affiliated hospital of Wenzhou medical university (PRC) from April 2010 to May 2016. All cases were confirmed by pathology. The process of misdiagnosis was described. This study retrospectively analyzed the incidence, clinical presentation, laboratory examination, Chest CT scan and diagnosis of the cases. RESULTS: The symptoms of the 19 cases were dyspnea, fever, hemoptysis, chest pain or physical findings without obvious symptoms. Five patients were pneumonia-like, nine patients had lung single nodule or mass and four patients got pleural effusion, which were reported by computed tomography (HRCT) scan. There were 2 cases of Hodgkin lymphoma (HL), and 17 cases of non-Hodgkin lymphoma (NHL). In NHL cases, 12 cases were confirmed mucosa associated lymphoid tissue B lymphoma type, 3 cases were confirmed diffuse large B-cell lymphoma, angioimmunoblastic T-cell lymphoma and ALK positive anaplastic large cell lymphoma were one case separately. Clinical and imaging manifestation of PPL is untypical, but there are still some hints: 1) Fuzzy shadow at the edge of lung mass with air bronchogram; 2) Lung mass shadow stable for a long time; 3) Pneumonia-like changing without infections clinical and lab manifestation. Thirteen patients (68.4%) were misdiagnosed as pneumonia, lung cancer and tuberculosis initially. The term between initial diagnosis and final diagnosis lasted for half a month up to 2 years, with median time of 6 months. Two cases were misdiagnosed as tuberculosis. One case was misdiagnosed as small cell lung cancer. CONCLUSION: Clinical and imaging manifestation of PPL is untypical. Biopsies should be taken actively if the imaging findings don't match the symptoms or the anti-infection treatments to "lung infection" don't work. Accurate diagnosis requires adequate tissue sampling with appropriate ancillary pathologic studies. If clinical manifestation and the diagnosis don't match, repeated biopsy should be ordered. PMID- 29530012 TI - Sepsis increases perioperative metastases in a murine model. AB - BACKGROUND: Cancer surgery can promote tumour metastases and worsen prognosis, however, the effect of perioperative complications on metastatic disease remains unclear. In this study we sought to evaluate the effect of common perioperative complications including perioperative blood loss, hypothermia, and sepsis on tumour metastases in a murine model. METHODS: Prior to surgery, pulmonary metastases were established by intravenous challenge of CT26LacZ colon cancer cells in BALB/c mice. Surgical stress was generated through partial hepatectomy (PH) or left nephrectomy (LN). Sepsis was induced by puncturing the cecum to express stool into the abdomen. Hemorrhagic shock was induced by removal of 30% of total blood volume (i.e. stage 3 hemorrhage) via the saphenous vein. Hypothermia was induced by removing the heating apparatus during surgery and lowering core body temperatures to 30 degrees C. Lung tumour burden was quantified 3 days following surgery. RESULTS: Surgically stressed mice subjected to stage 3 hemorrhage or hypothermia did not show an additional increase in lung tumour burden. In contrast, surgically stressed mice subjected to intraoperative sepsis demonstrated an additional 2-fold increase in the number of tumour metastases. Furthermore, natural killer (NK) cell function, as assessed by YAC-1 tumour cell lysis, was significantly attenuated in surgically stressed mice subjected to intraoperative sepsis. Both NK cell-mediated cytotoxic function and lung tumour burden were improved with perioperative administration of polyI:C, which is a toll-like receptor (TLR)-3 ligand. CONCLUSIONS: Perioperative sepsis alone, but not hemorrhage or hypothermia, enhances the prometastatic effect of surgery in murine models of cancer. Understanding the cellular mechanisms underlying perioperative immune suppression will facilitate the development of immunomodulation strategies that can attenuate metastatic disease. PMID- 29530014 TI - How much do combined affective and cognitive impairments worsen rehabilitation outcomes after hip fracture ? AB - BACKGROUND: To investigate the association between isolated and combined affective and cognitive impairments with functional outcomes and discharge destination in older patients admitted to rehabilitation after a hip fracture. METHODS: Prospective study in 612 community-dwelling patients aged 65 years and over, admitted to rehabilitation after surgery for hip fracture. Information on socio-demographics, medical, functional, affective, and cognitive status was systematically collected at admission. Functional status, length of stay and destination were assessed at discharge. Functional improvement was defined as any gain on the Barthel Index score between admission and discharge from rehabilitation. RESULTS: At admission, 8.2% of the patients had isolated affective impairment, 27.5% had cognitive impairment only, and 7.5% had combined impairments. Rate of functional improvement steadily decreased from 91.2% in patients with no cognitive nor affective impairment to 73.8% in those with combined impairments. Compared to patients without any impairment, those with combined impairments had lower odds of functional improvement, even after adjustment for age, gender, health and functional status at admission (adjOR: 0.40; 95%CI: 0.16-1.0; p = .049). The proportion of patients discharged back home gradually decreased from 82.8% among patients without any impairment to only 45.6% in patients with combined impairments. In multivariate analysis, the odds of returning home remained significantly reduced in these latter patients (adjOR: 0.31; 95%CI:0.15-0.66; p = .002). CONCLUSIONS: Affective and cognitive impairments had both independent, and synergistic negative association with functional outcome and discharge destination in patients admitted to rehabilitation after a hip fracture. Nevertheless, patients with combined affective and cognitive impairments still achieved significant functional improvement, even though its magnitude was reduced. Further studies should investigate whether these patients would benefit from better targeted, longer, or more intensive rehabilitation interventions to optimize their functional recovery. PMID- 29530013 TI - Symbiont interactions with non-native hosts limit the formation of new symbioses. AB - BACKGROUND: Facultative symbionts are common in eukaryotes and can provide their hosts with significant fitness benefits. Despite the advantage of carrying these microbes, they are typically only found in a fraction of the individuals within a population and are often non-randomly distributed among host populations. It is currently unclear why facultative symbionts are only found in certain host individuals and populations. Here we provide evidence for a mechanism to help explain this phenomenon: that when symbionts interact with non-native host genotypes it can limit the horizontal transfer of symbionts to particular host lineages and populations of related hosts. RESULTS: Using reciprocal transfections of the facultative symbiont Hamiltonella defensa into different pea aphid clones, we demonstrate that particular symbiont strains can cause high host mortality and inhibit offspring production when injected into aphid clones other than their native host lineage. However, once established, the symbiont's ability to protect against parasitoids was not influenced by its origin. We then demonstrate that H. defensa is also more likely to establish a symbiotic relationship with aphid clones from a plant-adapted population (biotype) that typically carry H. defensa in nature, compared to clones from a biotype that does not normally carry this symbiont. CONCLUSIONS: These results provide evidence that certain aphid lineages and populations of related hosts are predisposed to establishing a symbiotic relationship with H. defensa. Our results demonstrate that host-symbiont genotype interactions represent a potential barrier to horizontal transmission that can limit the spread of symbionts, and adaptive traits they carry, to certain host lineages. PMID- 29530015 TI - Smoking during pregnancy and harm reduction in birth weight: a cross-sectional study. AB - BACKGROUND: Different studies have shown the advantages of abstinence from cigarette smoking during pregnancy to promote full fetal development. Given that pregnant women do not always abstain from smoking, this study aimed to analyze the effect of different intensities of smoking on birth weight of the newborn. METHODS: A cross-sectional study was adopted to explore smoking in a population of pregnant women from a medium-sized city in Sao Paulo state, Brazil, who gave birth between January and June of 2012. Data were collected from maternal and pediatric medical files and, where data were absent, they were collected by interview during hospitalization for delivery. For data analysis, the effect of potential confounding variables on newborn birth weight was estimated using a gamma response model. The effect of the identified confounding variables was also estimated by means of a gamma response regression model. RESULTS: The prevalence of smoking during pregnancy was 13.4% in the study population. In full-term infants, birth weight decreased as the category of cigarette number per day increased, with a significant weight reduction as of the category 6 to 10 cigarettes per day. Compared with infants born to non smoking mothers, mean birth weight was 320 g lower in infants whose mothers smoked 6 to 10 cigarettes per day and 435 g lower in infants whose mothers smoked 11 to 40 cigarettes per day during pregnancy. CONCLUSIONS: Based on the study results and the principle of harm reduction, if a pregnant woman is unable to quit smoking, she should be encouraged to reduce consumption to less than six cigarettes per day. PMID- 29530016 TI - Role of working conditions in the explanation of occupational inequalities in work injury: findings from the national French SUMER survey. AB - BACKGROUND: Social inequalities in work injury have been observed but explanations are still missing. The objectives of this study were to evaluate the contribution of working conditions in the explanation of social inequalities in work injury in a national representative sample of employees. METHODS: The study was based on the cross-sectional sample of the national French survey SUMER 2010 including 46,962 employees, 26,883 men and 20,079 women. The number of work injuries within the last 12 months was studied as the outcome. Occupation was used as a marker of social position. Psychosocial work factors included various variables related to the classical job strain model, psychological demands, decision latitude, social support, and other understudied variables related to reward, job insecurity, job promotion, esteem, working time and hours and workplace violence. Occupational exposures of chemical, biological, physical and biomechanical nature were also studied. Weighted age-adjusted Poisson regression analyses were performed. RESULTS: Occupational gradients were observed in the exposure of most psychosocial work factors and occupational exposures. Strong occupational differences in work injury were found, blue-collar workers being more likely to have work injury. Chemical, biological, physical and biomechanical exposures contributed to explain the occupational differences in work injury substantially. Noise, thermic constraints, manual materials handling, postural/articular constraints and vibrations had significant contributions. Psychosocial work factors also contributed to explain the differences especially among women. CONCLUSION: Prevention policies oriented toward chemical, biological, physical, biomechanical and psychosocial work exposures may contribute to reduce the magnitude of occupational differences in work injury. PMID- 29530017 TI - Microencapsulation extends mycelial viability of Streptomyces lividans 66 and increases enzyme production. AB - BACKGROUND: Filamentous bacteria of the genus Streptomyces produce a large arsenal of industrially relevant antibiotics and enzymes. The industrial production of these molecules occurs in large fermenters, where many streptomycetes form dense mycelial networks called pellets. Pellets are characterized by slow growth and inefficient nutrient transfer and therefore regarded as undesirable from the perspective of productivity. Although non pelleting strains have increased growth rates, their morphology also leads to a dramatic increase in the viscosity of the culture broth, which negatively impacts the process dynamics. RESULTS: Here, we applied immobilization of Streptomyces lividans 66 using alginate as semi-solid matrix. This alginate-mediated micro encapsulation increased the production of the extracellular enzyme tyrosinase more than three-fold. The increased production was accompanied by extended viability of the mycelium and a dramatic reduction in the release of intracellular proteins into the culture broth. CONCLUSIONS: Our data demonstrate the utility of micro-encapsulation as a powerful technique to achieve higher yields and lower downstream-processing costs of streptomycetes. PMID- 29530018 TI - Prevalence and stability of mental disorders among young adults: findings from a longitudinal study. AB - BACKGROUND: Mental disorders often have onset early in life, contribute substantially to the global disease burden, and may interfere with young people's ability to complete age-relevant tasks in important developmental periods. However, knowledge about prevalence and course of mental disorders in young adulthood is sparse. The aim of the current study was to estimate prevalence and stability of mental disorders from the twenties to the thirties/forties. METHODS: DSM-IV mental disorders were assessed with the Composite International Diagnostic Interview in two waves (1999-2004 and 2010-2011) in 1623 young adult Norwegian twins (63.2% women, aged 19-29 years in wave 1). RESULTS: In wave 1, the 12-month prevalence of any mental disorder among people in the twenties was 19.8% (men) and 32.4% (women), anxiety disorders: 9.6% (men) and 26.7% (women), anxiety disorders excluding specific phobias: 2.5% (men) and 6.9% (women), major depressive disorder (MDD): 4.4% (men) and 7.2% (women), and alcohol use disorder (AUD): 8.7% (men) and 4.4% (women). The prevalence of any mental disorder decreased from the twenties to the thirties/forties. This was due to a decrease in AUD and specific phobias. Anxiety disorders in the twenties predicted anxiety disorders and MDD ten years later, even when controlling for the association between these disorders in the twenties. MDD in the twenties predicted MDD ten years later. At both ages, two-week and 12-month prevalence estimates differed markedly for MDD - indicating an episodic course. CONCLUSIONS: Common mental disorders are highly prevalent among young adults in the twenties, and somewhat less prevalent in the thirties/forties. Those who suffer from one mental disorder in the twenties are at considerably increased risk for suffering from a disorder ten years later as well. This may have significant implications for young people's ability to attain education, establish a family, and participate in occupational life. PMID- 29530019 TI - Multiple midline defects identified in a litter of golden retrievers following gestational administration of prednisone and doxycycline: a case series. AB - BACKGROUND: The teratogenic effects of immunomodulatory and certain antimicrobial therapies are described in small rodents and humans. While the described teratogenic effects in small rodents have been extrapolated to make conclusions about its use in the pregnant dam, teratogenic effects of prednisone and doxycycline have not yet been reported in the dog. Here we report and describe midline defects observed in a litter of golden retriever puppies exposed to mid gestational immunosuppressive and antimicrobial therapy. CASE PRESENTATION: Twenty-one days into gestation, the dam of a litter of eight golden retriever puppies was administered prednisone, doxycycline, and tramadol as treatment for immune-mediated polyarthritis. The individuals in the litter were subsequently diagnosed with a variety of midline defects and congenital cardiac defects. This case series describes the variety of identified defects and presents a descriptive account of complex congenital abnormalities that are likely secondary to teratogenic effects of one or more drugs administered during gestation. The available puppies, dam, and grand dam underwent thorough physical examination, complete echocardiogram, and where indicated, advanced imaging with various surgical corrections when possible. Numerous midline congenital defects and congenital heart disease were identified in the puppies evaluated. Ultimately 5 of 8 puppies born to the dam were presented for thorough evaluation. The midline defects include: gastroschisis (1), peritoneopericardial diaphragmatic hernias (4, PPDH), umbilical hernia (4), unilateral cryptorchidism (1 of 4 males), cleft palate (1), renal agenesis (1), renal abnormalities (1), sternal and vertebral abnormalities (3), remnant liver lobe (1) and malformations consistent with ductal plate malformations with congenital hepatic fibrosis (1). The congenital cardiac defects include: ventricular septal defect (4, VSD) and subaortic stenosis (4, SAS). The presence of greater than one congenital defect was noted in all 5 of the dogs evaluated. Surgical correction was necessary for PPDH in 4 puppies. Medical intervention was recommended for congenital cardiac disease in 1 puppy. CONCLUSION: This case report is the first to describe midline defects in dogs that have been exposed to immunomodulatory therapy during gestation. A causative relationship between mid-gestational immunomodulatory exposure and midline defects cannot be proven, however, this case supports a clear association and provides case-based evidence to support its avoidance when possible. PMID- 29530020 TI - Fatty fish intake and cognitive function: FINS-KIDS, a randomized controlled trial in preschool children. AB - BACKGROUND: Marine resources including fatty fish are important sources of n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), which are important for brain development. To our knowledge, this is the first randomized controlled trial (RCT) investigating the impact of fatty fish on cognition in preschool children. The purpose of the trial was to investigate whether an increased intake of fatty fish compared to meat improves cognitive function in children 4-6 years old. METHODS: The children (n = 232) in this two-armed RCT, Fish Intervention Studies-KIDS (FINS-KIDS) were recruited from 13 kindergartens in Bergen, Norway. They were randomly assigned to lunch meals with fatty fish (herring/mackerel) or meat (chicken/lamb/beef) three times a week for 16 weeks. The fish and meat were weighed before and after the meals to record the exact consumption (dietary compliance). The primary outcome was cognitive function measured by the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III) and fine motor coordination measured by the 9-Hole Peg Test (9-HPT) at pre- and post intervention. Biological samples (blood, urine, hair), and questionnaires to the caregivers were included at both time points. Linear mixed effect models with a random intercept for kindergarten were used to analyze changes from pre- to post intervention in the primary outcome variables. RESULTS: There were 218 children included in the trial (105 in the fish, and 113 in the meat group). The children consumed a mean (standard deviation) of 2070 (978) g fish or 2675 (850) g meat from the study meals (p < 0.0001). The fish group had a significant increase of red blood cell n-3 LC-PUFAs. The intervention had no effect on the WPPSI-III scores (mean change total raw score; fish group 17.7, 95% confidence interval (CI) 14.8-20.7 vs meat group 17.8, 95% CI 15.0-20.6, p = 0.97) in the main analyses. In the sub-analyses, adjusting for dietary compliance, the fish group showed a higher improvement on total raw score (20.4, 95% CI 17.5-23.3) compared to the meat group (15.2, 95% CI 12.4-18.0, p = 0.0060); docosahexaenoic acid mediated this effect. CONCLUSIONS: There was no beneficial effect of fatty fish compared to meat on cognitive functioning in the preschool children. When considering dietary compliance, we found a beneficial effect of fatty fish on cognitive scores. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02331667 December 17, 2014. PMID- 29530021 TI - Factors associated with emergency services use in Taiwanese advanced cancer patients receiving palliative home care services during out-of-hours periods: a retrospective medical record study. AB - BACKGROUND: For patients receiving palliative home care, the need to visit the emergency department is considered to be an indicator of poor quality care. The situation can be particularly distressing when it occurs outside of normal hours of palliative home care service. The aim of this study was to investigate the factors for emergency department use during out-of-hours periods of palliative home care service among advanced cancer patients in Taiwan. METHODS: This case control study was based on a retrospective medical chart review (January 2010 to December 2012) of advanced cancer patients who were receiving palliative home care in a community hospital in south Taiwan. The use of emergency medical services by these patients was dichotomized into either normal hours (8 a.m. to midnight, Monday to Friday, excluding public holidays) of palliative home care or outside normal hours. Logistic regression analyses were performed to evaluate factors associated with emergency services use during out-of-hours period of palliative home care. RESULTS: Of the 94 patients receiving palliative home care, 65 had used emergency services at least once during the 3-year study period. Of these 65 patients, 40% used emergency services during out-of-hours of palliative home care. Patients with distressing conditions (defined as the occurrence of any two conditions of dyspnea, change of consciousness, or gastrointestinal bleeding) were significantly more likely to use emergency services during out-of-hours of palliative home care. CONCLUSIONS: Patients at risk of developing dyspnea, change of consciousness, or gastrointestinal bleeding should be provided with relevant information regarding these symptoms and signs. PMID- 29530022 TI - In vitro investigation of cytotoxic and antioxidative activities of Ardisia crispa against breast cancer cell lines, MCF-7 and MDA-MB-231. AB - BACKGROUND: Ardisia crispa Thunb. D.C is used mostly in some parts of the Asian region by traditional practitioners to treat certain diseases associated with oxidative stress and inflammation including cancer and rheumatism. In Malaysia, it is popularly known as 'Mata Ayam' and local traditional practitioners believed that the root of the plant is therapeutically beneficial. METHODS: The cytotoxic effect of hydromethanolic extract of A. crispa and its solvents partitions (ethyl acetate and aqueous extracts) against breast cancer cells were evaluated by using MTT assay. The cells were treated with concentration of extracts ranging from 15.63 MUg/mL- 1000 MUg/mL for 72 h. The quantification of phenolic and flavonoid contents of the extracts were carried out to determine the relationship between of phytochemical compounds responsible for cytotoxic and antioxidative activities. The antioxidant capacity was measured by DPPH and ABTS free radical scavenging assay and expressed as milligram (mg) Trolox equivalent antioxidant capacity per 1 g (g) of tested extract. RESULTS: The hydromethanolic and ethyl acetate extracts showed moderate cytotoxic effect against MCF-7 with IC50 values of 57.35 +/- 19.33 MUg/mL, and 54.98 +/- 14.10 MUg/mL, respectively but aqueous extract was inactive against MCF-7. For MDA-MB-231, hydromethanolic, ethyl acetate and aqueous extracts exhibited weak cytotoxic effects against MDA-MB-231 with IC50 values more than 100 MUg/mL. The plant revealed high total phenolic content, total flavonoid and antioxidant capacity. CONCLUSION: The response of different type of breast cancer cell lines towards A. crispa extract and its partitions varied. Accordingly, hydromethanolic and ethyl acetate extracts appear to be more cytotoxic to oestrogen receptor (ER) positive breast cancer than oestrogen receptor (ER) negative breast cancer. However, aqueous extract appears to have poor activity to both types of breast cancer. Besides that, hydromethanolic and ethyl acetate extracts exhibit higher TPC, TFC and antioxidant capacity compared to aqueous extract. Synergistic effect of anticancer and antioxidant bioactives compounds of A. crispa plausibly contributed to the cytotoxic effects of the extract. PMID- 29530023 TI - Effects and mechanisms of apolipoprotein A-V on the regulation of lipid accumulation in cardiomyocytes. AB - BACKGROUND: Apolipoprotein (apo) A-V is a key regulator of triglyceride (TG) metabolism. We investigated effects of apoA-V on lipid metabolism in cardiomyocytes in this study. METHODS: We first examined whether apoA-V can be taken up by cardiomyocytes and whether low density lipoprotein receptor family members participate in this process. Next, triglyceride (TG) content and lipid droplet changes were detected at different concentrations of apoA-V in normal and lipid-accumulation cells in normal and obese animals. Finally, we tested the levels of fatty acids (FAs) taken up into cardiomyocytes and lipid secretion through [14C]-oleic acid. RESULTS: Our results show that heart tissue has apoA-V protein, and apoA-V is taken up by cardiomyocytes. When HL-1 cells were transfected with low density lipoprotein receptor (LDLR)-related protein 1(LRP1) siRNA, apoA-V intake decreased by 53% (P<0.05), while a 37% lipid accumulation in HL-1 cells remain unchanged. ApoA-V localized to the cytoplasm and was associated with lipid droplets in HL-1 cells. A 1200 and 1800 ng/mL apoA-V intervention decreased TG content by 28% and 45% in HL-1 cells, respectively and decreased TG content by 39% in mouse heart tissue (P<0.05). However, apoA-V had no effects on TG content in either normal HL-1 cells or mice. The levels of FAs taken up into cardiomyocytes decreased by 43% (P < 0.05), and the levels of TG and cholesterol ester secretion increased by 1.2-fold and 1.6-fold, respectively (P < 0.05). CONCLUSION: ApoA-V is a novel regulator of lipid metabolism in cardiomyocytes. PMID- 29530024 TI - Chinese translation and psychometric testing of the cardiac self-efficacy scale in patients with coronary heart disease in mainland China. AB - BACKGROUND: A person's self-efficacy plays a critical role during the chronic management process of a health condition. Assessment of self-efficacy for patients with heart diseases is essential for healthcare professionals to provide tailored interventions to help patient to manage the disease. OBJECTIVE: To translate and test the psychometric properties of the Chinese version of Cardiac Self-efficacy Scale (C-CSES) as a disease-specific instrument for patients with coronary heart disease (CHD) in mainland China. METHODS: The original English version of the CSES was translated into Chinese using a forward-backward translation approach. A convenience sample consisting of 224 Chinese patients with CHD were recruited from a university-affiliated hospital in Shiyan, China. The C-CSES and the General Self-efficacy Scale (GSES) were used in this study. The factor structure, convergent and discriminative validities, and internal consistency of the C-CSES were evaluated. RESULTS: The confirmatory factor analysis (CFA) supported a three-factor high-order structure of the C-CSES with model fit indexes (RMSEA = 0.084, CFI = 0.954, NNFI = 0.927, IFI = 0.954 and chi 2 /df = 2.572). The C-CSES has good internal consistency with a Cronbach's alpha of 0.926. The convergent validity of the C-CSES was established with significantly moderate correlations between the C-CSES and the Chinese version of the GSES (p < 0.001). The C-CSES has also shown good discriminative validity with significant differences of cardiac self-efficacy being found between patients with and without comorbidities of hypertension, diabetes, or heart failure. CONCLUSION: The empirical data supported that the C-CSES is a valid and reliable disease-specific instrument for assessing the self-efficacy of Chinese patients with CHD. PMID- 29530025 TI - Carotid DSA based CFD simulation in assessing the patient with asymptomatic carotid stenosis: a preliminary study. AB - BACKGROUND: Cerebrovascular events are frequently associated with hemodynamic disturbance caused by internal carotid artery (ICA) stenosis. It is challenging to determine the ischemia-related carotid stenosis during the intervention only using digital subtracted angiography (DSA). Inspired by the performance of well established FFRct technique in hemodynamic assessment of significant coronary stenosis, we introduced a pressure-based carotid arterial functional assessment (CAFA) index generated from computational fluid dynamic (CFD) simulation in DSA data, and investigated its feasibility in the assessment of hemodynamic disturbance preliminarily using pressure-wired measurement and arterial spin labeling (ASL) MRI as references. METHODS: The cerebral multi-delay multi parametric ASL-MRI and carotid DSA including trans-stenotic pressure-wired measurement were implemented on a 65-year-old man with asymptomatic unilateral (left) ICA stenosis. A CFD simulation using simplified boundary condition was performed in DSA data to calculate the CAFA index. The cerebral blood flow (CBF) and arterial transit time (ATT) of ICA territories were acquired. RESULTS: CFD simulation showed good correlation (r = 0.839, P = 0.001) with slight systematic overestimation (mean difference - 0.007, standard deviation 0.017) compared with pressure-wired measurement. No significant difference was observed between them (P = 0.09). Though the narrowing degree of in the involved ICA was about 70%, the simulated and measured CAFA (0.942/0.937) revealed a functionally nonsignificant stenosis which was also verified by a compensatory final CBF (fronto temporal/fronto-parietal region: 51.58/45.62 ml/100 g/min) and slightly prolonged ATT (1.23/1.4 s) in the involved territories, together with a normal left-right percentage difference (2.1-8.85%). CONCLUSIONS: The DSA based CFD simulation showed good consistence with invasive approach and could be used as a cost-saving and efficient way to study the relationship between hemodynamic disorder caused by ICA stenosis and subsequent perfusion variations in brain. Further research should focus on the role of noninvasive pressure-based CAFA in screening asymptomatic ischemia-causing carotid stenosis. PMID- 29530026 TI - Factors associated with seeking preventive dental care: an integrative model exploration of behaviors in Mexican immigrants in Midwest America. AB - BACKGROUND: Mexican immigrants in the United States suffer from poor oral health. The objective of the current study was to explore the utility of applying theory based factors associated with seeking preventive dental care in a sample of Mexican American adults. METHODS: Data were collected from a cross-sectional survey of a sample of 157 people of Mexican origin (64% female; age 34 +/- 11 years) recruited primarily from church congregations and lay community organizations in Central Indiana. Using the Integrative Model of Behavioral Prediction as the guiding framework, structural equation modeling was used to test factors associated with intention to seek preventive dental care. RESULTS: Attitude towards seeking preventive dental care (estimate = 0.37; p < .0001) and self-efficacy for seeking preventive dental care (estimate = 0.68; p < .0001) were associated with intention to seek preventive dental care. The association between dental beliefs and intention to seek preventive dental care was mediated by attitude and self-efficacy (indirect effect = 0.26, p = .002), and the association between past behavior and intention to seek preventive dental care was mediated by self-efficacy (indirect effect = 0.26, p = .003). CONCLUSIONS: These findings suggest that interventions to increase preventive dental care seeking behavior among Mexican Americans should focus on changing attitudes toward seeking preventive dental care and on increasing self-efficacy to seek preventive dental care. Findings also support the use of interventions to influence dental beliefs. PMID- 29530027 TI - Inhibition of lipopolysaccharide (LPS)-induced neuroinflammatory response by polysaccharide fractions of Khaya grandifoliola (C.D.C.) stem bark, Cryptolepis sanguinolenta (Lindl.) Schltr and Cymbopogon citratus Stapf leaves in raw 264.7 macrophages and U87 glioblastoma cells. AB - BACKGROUND: Khaya grandifoliola (C.D.C.) stem bark, Cymbopogon citratus (Stapf) and Cryptolepis sanguinolenta (Lindl.) Schltr leaves are used in Cameroonian traditional medicine for the treatment of inflammatory diseases. Several studies have been performed on the biological activities of secondary metabolites extracted from these plants. However, to the best of our knowledge, the anti neuro inflammatory and protective roles of the polysaccharides of these three plants have not yet been elucidated. This study aimed at investigating potential use of K. grandifoliola, C. sanguinolenta and C. citratus polysaccharides in the prevention of chronic inflammation. METHODS: Firstly, the composition of polysaccharide fractions isolated from K. grandifoliola stem bark (KGF), C. sanguinolenta (CSF) and C. citratus (CCF) leaves was assessed. Secondly, the cytotoxicity was evaluated on Raw 264.7 macrophages and U87-MG glioblastoma cell lines by the MTT assay. This was followed by the in vitro evaluation of the ability of KGF, CSF and CCF to inhibit lipopolysaccharides (LPS) induced overproduction of various pro-inflammatory mediators (NO, ROS and IL1beta, TNFalpha, IL6, NF-kB cytokines). This was done in Raw 264.7 and U87-MG cells. Finally, the in vitro protective effect of KGF, CSF and CCF against LPS-induced toxicity in the U87-MG cells was evaluated. RESULTS: CCF was shown to mostly contain sugar and no polyphenol while KGP and CSP contained very few amounts of these metabolites (<= 2%). The three polysaccharide fractions were non-toxic up to 100 MUg.mL- 1. All the polysaccharides at 10 MUg/mL inhibited NO production, but only KGF and CCF at 12.5 MUg/mL down-regulated LPS-induced ROS overproduction. Finally, 100 MUg/mL LPS reduced 50% of U87 cell viability, and pre-treatment with the three polysaccharides significantly increased the proliferation. CONCLUSION: These results suggest that the polysaccharides of K. grandifoliola, C. citratus and C. sanguinolenta could be beneficial in preventing/treating neurodegenerative diseases in which neuroinflammation is part of the pathophysiology. PMID- 29530028 TI - Patients' knowledge and attitudes to the Wise List - a drug formulary from the Stockholm Drug and Therapeutic committee. AB - BACKGROUND: Involving patients in decisions about their pharmacotherapy is crucial for a satisfactory treatment outcome. Information and opinions about medicines are available from a variety of sources. The Wise List is the drug formulary of recommended essential medicines for the Stockholm healthcare region and is issued by the Drug and Therapeutics Committee (DTC). To inform the public about treatment for common diseases and the concept of recommended medicines, a patient edition of the Wise List was developed. The aim of this study was to explore patients' knowledge, needs and attitudes to the Wise List, DTC and information about medicines in general. METHODS: To examine patient knowledge about recommended medicines a survey (n = 312) was carried out at four large primary healthcare centres in Stockholm, Sweden. To further elucidate the patients' needs of the information on recommended medicines and medicines in general, three focus group discussions (FGDs) were performed. RESULTS: Of the respondents 57% did not recognise the Wise List, 26% recognised but did not use it and 17% used it. A total of 63% reported that they search for information about medicines. The most common information source was "asking their doctor" (36%) followed by searching the internet (31%). The FGDs revealed that the patients were not interested in medicines in general, only in the medicines they use themselves. They did not understand the aim of the Wise List or how they could benefit from information about recommended medicines. The patients expressed a wish to access all information they need about their own care as well as public healthcare information at one location. CONCLUSION: The intended aim of the DTC with providing information to the public was not achieved as the patients have difficulties to understand the information and how they should use it. The patients were not interested in medicines in general, they wanted information tailored to their specific needs. The findings highlight the importance of creating tools for patients in collaboration with them and evaluate the concept continuously. PMID- 29530029 TI - Effect of clinical decision rules, patient cost and malpractice information on clinician brain CT image ordering: a randomized controlled trial. AB - BACKGROUND: The frequency of head computed tomography (CT) imaging for mild head trauma patients has raised safety and cost concerns. Validated clinical decision rules exist in the published literature and on-line sources to guide medical image ordering but are often not used by emergency department (ED) clinicians. Using simulation, we explored whether the presentation of a clinical decision rule (i.e. Canadian CT Head Rule - CCHR), findings from malpractice cases related to clinicians not ordering CT imaging in mild head trauma cases, and estimated patient out-of-pocket cost might influence clinician brain CT ordering. Understanding what type and how information may influence clinical decision making in the ordering advanced medical imaging is important in shaping the optimal design and implementation of related clinical decision support systems. METHODS: Multi-center, double-blinded simulation-based randomized controlled trial. Following standardized clinical vignette presentation, clinicians made an initial imaging decision for the patient. This was followed by additional information on decision support rules, malpractice outcome review, and patient cost; each with opportunity to modify their initial order. The malpractice and cost information differed by assigned group to test the any temporal relationship. The simulation closed with a second vignette and an imaging decision. RESULTS: One hundred sixteen of the 167 participants (66.9%) initially ordered a brain CT scan. After CCHR presentation, the number of clinicians ordering a CT dropped to 76 (45.8%), representing a 21.1% reduction in CT ordering (P = 0.002). This reduction in CT ordering was maintained, in comparison to initial imaging orders, when presented with malpractice review information (p = 0.002) and patient cost information (p = 0.002). About 57% of clinicians changed their order during study, while 43% never modified their imaging order. CONCLUSION: This study suggests that ED clinician brain CT imaging decisions may be influenced by clinical decision support rules, patient out-of-pocket cost information and findings from malpractice case review. TRIAL REGISTRATION: NCT03449862 , February 27, 2018, Retrospectively registered. PMID- 29530030 TI - Chemical composition and antibacterial activity of oils from Chrysicthys nigrodigitatus and Hepsetus odoe, two freshwater fishes from Yabassi, Cameroon. AB - BACKGROUNDS: Oils of fish origin are a very rich source of Omega - 3 and Omega - 6 fatty acids. They have been suggested to provide numerous health benefits for humans involving antimicrobial properties. Chrysichthys nigrodigitatus and Hepsetus odoe are two fishes well known in Cameroon. The chemical composition and the antibacterial activity of these fishes derived oils are unknown. The study was designed to valorise C. nigrodigitatus and H.s odoe oils activity against food poisoning bacteria. METHODS: Oils were extracted by pressing and maceration methods. Their quality was assessed by analysing quality indexes including peroxides, acid, iodine, anisidine and thiobarbituric acid values. Chemical analysis was established by gas chromatography coupled to flame ionization detector. Antibacterial activity was evaluated by broth microdilution method. RESULTS: C. nigrodigitatus oil obtained by maceration exhibited highest acid (7.33 +/- 0.00 mg KOH/g), anisidine (34.5 +/- 1.84) and thiobarbituric acid (7.50 +/- 0.30 MUmol MDA/Kg) values compared to that obtained by pressing method (9.13 +/- 0.64 and 6.72 +/- 0.34 MUmol MDA/Kg) respectively. H. odoe oil obtained by pressing method showed highest peroxide value (6.22 +/- 1.31 meq O2/kg). Oil chemical analysis revealed long chain polyunsaturated fatty acids of the omega-3 family: linolenic acid (C18:3); eicosapentaenoic acid (C20:5) and docosahexaenoic acid (C22:6) and omega-6 family; arachidonic acid (C20:4). In addition, C. nigrodigitatus oil obtained by pressing and maceration methods showed Minimum Inhibitory Concentrations (MIC) values ranging from 32 to 64 mg/ml. H. odoe oil obtained by pressing method revealed MIC values ranging between 8 and 64 mg/ml. CONCLUSIONS: C. nigrodigitatus and H. odoe oils have activity against food poisoning bacteria, due to their chemical composition. PMID- 29530031 TI - Attitudes towards help-seeking for sexual and gender-based violence in humanitarian settings: the case of Rwamwanja refugee settlement scheme in Uganda. AB - BACKGROUND: Sexual and gender-based violence (SGBV) remains a silent epidemic in many humanitarian settings with many survivors concealing their experiences. Attitudes towards help-seeking for SGBV is an important determinant of SGBV service use. This paper examined the association between attitudes towards seeking care and knowledge and perceptions about SGBV among men and women in a humanitarian setting in Uganda. METHODS: A cross-sectional survey was conducted from May to June 2015 among 601 heads of refugee households (261 females and 340 males) in Rwamwanja Refugees Settlement Scheme, South West Uganda. Analysis entails cross-tabulation with chi-square test and estimation of a multivariate logistic regression model. RESULTS: Results showed increased odds of having a favorable attitude toward seeking help for SGBV among women with progressive attitudes towards SGBV (OR = 2.78, 95% CI: 1.56-4.95); who felt that SBGV was not tolerated in the community (OR = 2.03, 95% CI: 1.03-4.00); those who had not experienced violence (OR = 2.08, 95% CI: 1.06-4.07); and those who were aware of the timing for post-exposure prophylaxis (OR = 3.08, 95% CI: 1.57-6.04). In contrast, results for men sample showed lack of variations in attitude toward seeking help for SGBV for all independent variables except timing for PEP (OR = 2.57, 95% CI: 1.30-5.10). Among individuals who had experienced SGBV, the odds of seeking help was more likely among those with favorable attitude towards seeking help (OR = 4.22, 95% CI: 1.47-12.06) than among those with unfavorable help seeking attitudes. CONCLUSION: The findings of the paper suggest that targeted interventions aimed at promoting awareness and progressive attitudes towards SGBV are likely to encourage positive help-seeking attitudes and behaviors in humanitarian contexts. PMID- 29530032 TI - Married women's autonomy and post-delivery modern contraceptive use in the Democratic Republic of Congo. AB - BACKGROUND: Although use of modern contraception is considered beneficial in lowering maternal and child mortality rates, the prevalence of contraceptive use remains low in the Democratic Republic of Congo. This study examined modern contraceptive use and its linkage to women's autonomy. METHODS: Data were drawn from the 2013-2014 Democratic Republic of Congo Demographic and Health Survey. We selected unsterilized and non-pregnant married women who have given birth in the last three years (N = 6680). Logistic regression models were fitted to explore the relationship between women's autonomy and modern contraceptive use. RESULTS: The study found that only 7.1% of married women who had delivered within three years used modern contraceptive methods. After controlling for socioeconomic and demographic factors, the association between women's autonomy and modern contraceptive use remained positively significant (OR = 1.16; 95% CI = 1.05, 1.29). CONCLUSION: The findings from this study indicate that it is not enough to provide women with educational and employment opportunities to increase the uptake of modern contraception, but also to enhance women's assertiveness to make their own decisions regardless of their partners' preferences within household settings. It is critical for government and other stakeholders to roll out programs aimed at reducing gender inequality and improving women's autonomy in decision-making about reproductive health. PMID- 29530033 TI - Translation and validation of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) version 4 quality of life instrument into Arabic language. AB - BACKGROUND: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT BMT) has been translated from English into several languages. Currently, there is no validated translation of FACT-BMT in Arabic. Here, we are reporting the first Arabic translation and validation of the FACT-BMT. METHODS: The study was approved by the Institutional Research Advisory Council. The Arabic translation followed the standard Functional Assessment of Chronic Illness Therapy (FACIT.org) translation methodology (with permission). Arabic FACT-BMT (50- items) was statistically validated. Cronbach's alpha for internal consistency, Spearman's rank correlation coefficients method for Inter-scale correlations and Principal Component Analysis for factorial construct validity was used. RESULTS: One hundred and eight consecutive relapsed /refractory lymphoma patients who underwent high dose chemotherapy and autologous stem cell transplant were enrolled. There were 68 males (63%) and 40 females (37%) with a median age of 29 years (range 14-62). After Arabic questionnaire pre-testing (Cronbach's alpha 0.744), the study included 108 patients. Cronbach's alpha for the entire FACT-BMT indicated an excellent internal consistency (0.90); range (0.67 to 0.91). Cronbach's alpha for sub-groups of social (0.78), emotional (0.67) and functional wellbeing was (0.88). Cronbach's alpha for bone marrow transplant (0.81), FACT General (0.89), and FACT- Trial Outcome Index (TOI); (0.91) also revealed excellent internal consistency. Patients had high scores in all domains of quality of life, indicating that most patients were leading a normal life. This translation of FACT-BMT in Arabic was reviewed and approved for submission by the FACIT.org. CONCLUSIONS: Our data reports the first translated, validated and approved Arabic version of FACT-BMT. This will help large numbers of Arabic speaking patients undergoing stem cell/bone marrow transplantation, across the globe. PMID- 29530034 TI - The use of complementary and alternative medicine by patients with cancer: a cross-sectional survey in Saudi Arabia. AB - BACKGROUND: A significant proportion of cancer patients use complementary and alternative medicine (CAM) along with conventional therapies (CT), whereas a smaller proportion delay or defer CT in favor of CAM. Previous studies exploring CAM use among cancer patients in the Middle East region have shown discrepant results. This study investigates the prevalence and pattern of CAM use by Saudi cancer patients. It also discusses the possible benefits and harm related to CAM use by cancer patients, and it explores the beliefs patients hold and their transparency with health care providers regarding their CAM use. METHODS: A cross sectional study was conducted in oncology wards and outpatient clinics by using face-to-face interviews with the participants. RESULTS: A total of 156 patients with a median age of 50 years (18-84) participated in the study. The prevalence of CAM use was 69.9%; the most prominent types of CAM were those of a religious nature, such as supplication (95.4%), Quran recitation (88.1%), consuming Zamzam water (84.4%), and water upon which the Quran has been read (63.3%). Drinking camel milk was reported by 24.1% of CAM users, whereas camel urine was consumed by 15.7%. A variety of reasons were given for CAM use: 75% reported that they were using CAM to treat cancer, enhance mood (18.3%),control pain (11.9%), enhance the immune system (11%),increase physical fitness (6.4%), and improve appetite (4.6%). Thirty percent of CAM users had discussed the issue with their doctors; only 7.7% had done so with their nurses. CONCLUSIONS: The use of CAM, including camel products, is highly prevalent among cancer patients in the Middle East, but these patients do not necessarily divulge their CAM use to their treating physicians and nurses. Although CAM use can be beneficial, some can be very harmful, especially for cancer patients. Association is known between camel products and brucellosis and Middle East respiratory syndrome coronavirus (MERS CoV). Both can lead to tremendous morbidity in immune-compromised patients. Doctor-patient communication regarding CAM use is of paramount importance in cancer care. PMID- 29530036 TI - Determinants of family planning use among married women in bale eco-region, Southeast Ethiopia: a community based study. AB - BACKGROUND: Family planning is the ability of individuals and couples to anticipate and attain their desired number of children and the spacing and timing of their births. Providing family planning could prevent maternal deaths by allowing women to delay motherhood, space births, avoid unintended pregnancies and abortions, and stop childbearing when they reach their desired family size. Despite the fact that family planning is advantageous for maternal and newborn health and the services and commodities are free of charge, the reason of not using modern family planning methods is unclear in Bale Eco-Region. Therefore, this study assessed the contraceptive prevalence rate and its determinants among women in Bale Eco-Region, Ethiopia. METHODS: A community-based cross-sectional study design (both quantitative and qualitative methods) was conducted from December 2016 to February 2017. Five hundred sixty-seven women were successfully interviewed using structured and pre-tested questionnaire. A multistage sampling technique was employed. Data were entered into Epi-data version 3.1 and exported to SPSS version 21. Logistic regression analyses were done and a significant association was declared at p-value less than 0.05. All focus group discussions and key informant interviews were recorded and analyzed thematically. RESULTS: The overall contraceptive prevalence rate was 41.5%. Injectable (48.1%), implants (22.6%) and pills (20.0%) were the most contraceptive methods utilized by study participants. Spousal (husband's) opposition (38.8%), religious beliefs (17.7%), concern and fear of side effects (14.8%), and distance of family planning service (5.9%) were the reasons for not using contraceptive methods. Having more than seven deliveries (AOR = 2.98, CI = 1.91-6.10, P = 0.000) and having birth interval less than 24 months between the last two children (AOR = 3.8, CI = 13.41 21.61, P = 0.003) were significantly associated with utilization of contraceptive methods. CONCLUSION: Low contraceptive prevalence rate might be attributed by husband opposition, religious beliefs, concern and fear of side effects. Having more than seven deliveries and birth interval less than 24 months between the last two children were determinants of contraceptive use. Family planning consultation opportunities should be created to make male's involved and to increase their responsibility for family planning use. PMID- 29530035 TI - Efficacy of the unified protocol for the treatment of emotional disorders in the Spanish public mental health system using a group format: study protocol for a multicenter, randomized, non-inferiority controlled trial. AB - BACKGROUND: Emotional disorders, which include both anxiety and depressive disorders, are the most prevalent psychological disorders according to recent epidemiological studies. Consequently, public costs associated with their treatment have become a matter of concern for public health systems, which face long waiting lists. Because of their high prevalence in the population, finding an effective treatment for emotional disorders has become a key goal of today's clinical psychology. The Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders might serve the aforementioned purpose, as it can be applied to a variety of disorders simultaneously and it can be easily performed in a group format. METHODS: The study is a multicenter, randomized, non-inferiority controlled clinical trial. Participants will be 220 individuals with emotional disorders, who are randomized to either a treatment as usual (individual cognitive behavioral therapy) or to a Unified Protocol condition in group format. Depression, anxiety, and diagnostic criteria are the primary outcome measures. Secondary measures include the assessment of positive and negative affect, anxiety control, personality traits, overall adjustment, and quality of life. An analysis of treatment satisfaction is also conducted. Assessment points include baseline, post-treatment, and three follow-ups at 3, 6, and 12 months. To control for missing data and possible biases, intention-to-treat and per-protocol analyses will be performed. DISCUSSION: This is the first randomized, controlled clinical trial to test the effectiveness of a transdiagnostic intervention in a group format for the treatment of emotional disorders in public settings in Spain. Results obtained from this study may have important clinical, social, and economic implications for public mental health settings in Spain. TRIAL REGISTRATION: Retrospectively registered at https://clinicaltrials.gov/ . Trial NCT03064477 (March 10, 2017). The trial is active and recruitment is ongoing. Recruitment is expected to finish by January 2020. PMID- 29530037 TI - Molecular iodine/doxorubicin neoadjuvant treatment impair invasive capacity and attenuate side effect in canine mammary cancer. AB - BACKGROUND: Mammary cancer has a high incidence in canines and is an excellent model of spontaneous carcinogenesis. Molecular iodine (I2) exerts antineoplastic effects on different cancer cells activating re-differentiation pathways. In co administration with anthracyclines, I2 impairs chemoresistance installation and prevents the severity of side effects generated by these antineoplastic drugs. This study is a random and double-blind protocol that analyzes the impact of I2 (10 mg/day) in two administration schemes of Doxorubicin (DOX; 30 mg/m2) in 27 canine patients with cancer of the mammary gland. The standard scheme (sDOX) includes four cycles of DOX administered intravenously for 20 min every 21 days, while the modified scheme (mDOX) consists of more frequent chemotherapy (four cycles every 15 days) with slow infusion (60 min). In both schemes, I2 or placebo (colored water) was supplemented daily throughout the treatment. RESULTS: mDOX attenuated the severity of adverse events (VCOG-CTCAE) in comparison with the sDOX group. The overall tumor response rate (RECIST criteria) for all dogs was 18% (interval of reduction 48-125%), and no significant difference was found between groups. I2 supplementation enhances the antineoplastic effect in mDOX, exhibiting a significant decrease in the tumor epithelial fraction, diminished expression of chemoresistance (MDR1 and Survivin) and invasion (uPA) markers and enhanced expression of the differentiation factor known as peroxisome proliferator-activated receptors type gamma (PPARgamma). Significant tumor lymphocytic infiltration was also observed in both I2-supplemented groups. The ten-month survival analysis showed that the entire I2 supplementation (before and after surgery) induced 67-73% of disease-free survival, whereas supplementation in the last period (only after surgery) produced 50% in both schemes. CONCLUSIONS: The mDOX+I2 scheme improves the therapeutic outcome, diminishes the invasive capacity, attenuates the adverse events and increases disease-free survival. These data led us to propose mDOX+I2 as an effective treatment for canine mammary cancer. PMID- 29530038 TI - SCOPEOUT: sustainability and spread of quality improvement activities in long term care- a mixed methods approach. AB - BACKGROUND: Interventions to improve quality of care for residents of long-term care facilities, and to examine the sustainability and spread of such initiatives, remain a top research priority. The purpose of this exploratory study was to assess the extent to which activities initiated in a quality improvement (QI) collaborative study using care aide led teams were sustained or spread following cessation of the initial project and to identify factors that led to its success. METHODS: This study used an exploratory mixed methods study design and was conducted in seven residential long-term care facilities in two Canadian provinces. Sustainability and spread of QI activities were assessed by a questionnaire over five time points for 18 months following the collaborative study with staff from both intervention with non-intervention units. Semi structured interviews were conducted with care managers at six and 12 months. QI team success in applying the QI model was ranked as high, medium, or low using criteria developed by the research team. Descriptive statistics, bivariate analyses, and General Estimating Equations were used to analyze the data. Interview data were analyzed using thematic analysis. RESULTS: In total, 683 surveys were received over the five time periods from 476 unique individuals on a facility unit. Seven managers were interviewed. A total of 533 surveys were analyzed. While both intervention and non-intervention units experienced a decline over time in all outcome measures, this decline was significantly less pronounced on intervention units. Facilities with medium and high success ranking had significantly higher scores in all four outcomes than facilities with a low success ranking. Care aides reported significantly less involvement of others in QI activities, less empowerment and less satisfaction with the quality of their work life than regulated care providers. Manager interviews provided evidence of sustainability of QI activities on the intervention units in four of the seven facilities up to 18 months following the intervention and demonstrated the need for continued staff and leadership engagement. CONCLUSION: Sustainability of a QI project which empowers and engages care aides is possible and achievable, but requires ongoing staff and leadership engagement. PMID- 29530039 TI - Effect of protraction facemask on the temporomandibular joint: a systematic review. AB - BACKGROUND: The aim of this study was to assess the influence of protraction facemask (PFM) on temporomandibular joint (TMJ) of skeletal Class III malocclusion patients. METHOD: Literature searches were carried out electronically in five English and three Chinese databases (Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed, Embase, MEDLINE (via Ovid), Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and VIP Database). The date of the most recent search was 22 March 2017. Randomized controlled trials, controlled clinical trials, cohort studies, and before-after studies comparing the effect of PFM and other treatments on TMJ were included. The data were collected and extracted by three authors. The risk of bias in the RCTs was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. For the nonrandomized studies, the risk of bias was judged with Newcastle-Ottawa Scale. RESULTS: For the 261 articles identified, 13 studies with 522 participants were included for the final qualitative analysis. Three studies were graded as high value of evidence, while seven studies and the other three studies were graded as moderate value and low value respectively. According to the available evidence, PFM contributed to the significant increase of CondAx-SBL and the significant decrease of CondAx-ML. Thin-plate spline (TPS) analysis showed a horizontal compression in condyles. Condyles tended to move superiorly and posteriorly. Concerning the occurrence of temporomandibular disorders (TMD), PFM was not involved in aggravating TMJ symptoms and signs. CONCLUSIONS: Clinical evidence suggests that PFM might contribute to the morphologic adaptation of TMJs and displacement of condyles, and PFM may well be not a risk factor for the development of TMD. PMID- 29530040 TI - Quantitative evaluation of canine urinary bladder transitional cell carcinoma using contrast-enhanced ultrasonography. AB - BACKGROUND: In veterinary medicine, contrast-enhanced ultrasonography allowed the accurate quantification of liver, splenic and kidney vascularization in healthy dogs and the differentiation between malignant and benign hepatic, renal, and splenic nodules in dogs and cats based on perfusion patterns. The utility of contrast-enhanced ultrasonography in other applications is still under study. The aim of this study was to develop diagnostic criteria by contrast-enhanced ultrasonography in 8 client-owned adult dogs affected by urinary bladder transitional cell carcinoma with definitive diagnosis made by cytopathologic evaluation after suction biopsy. The contrast enhancement pattern and the quantification of blood flow parameters of this tumor were reported. RESULTS: Examinations with B-mode, Doppler ultrasonography and contrast-enhanced ultrasonography were performed in all not sedated dogs. Assessments of bladder masses and bladder wall infiltration were performed. Each dog received 2 bolus injections of sulfur hexafluoride during the contrast-enhanced ultrasonography. Quantitative analysis of the contrast-enhanced ultrasonography images were performed. For each dog, one region of interest was manually drawn around the entire tumor. Software analysis of contrast-enhanced time-intensity curves was used to identify peak enhancement, time to peak enhancement, regional blood volume, regional blood flow, and mean transit time. Contrast-enhanced ultrasonography showed an avid enhancement of the tumour tissue, with a heterogeneous or homogeneous pattern. The exam also showed the loss of planes between the lesion and the muscular layer. The presence of vascularized tissue through the bladder wall confirms the infiltrative feature of the tumour. Post processing quantitative analysis showed a time-intensity curve with a rapid wash in, a low level of signal intensity and a slow wash-out. CONCLUSIONS: Contrast enhanced ultrasonography provided useful clinical information and defined a vascular enhancement patterns and calculated parameters associated with TCC. It may be a useful, noninvasive and reproducible tool for detecting these tumors in dogs. PMID- 29530041 TI - Syrian refugees in Greece: experience with violence, mental health status, and access to information during the journey and while in Greece. AB - BACKGROUND: Since 2015, Europe has been facing an unprecedented arrival of refugees and migrants: more than one million people entered via land and sea routes. During their travels, refugees and migrants often face harsh conditions, forced detention, and violence in transit countries. However, there is a lack of epidemiological quantitative evidence on their experiences and the mental health problems they face during their displacement. We aimed to document the types of violence experienced by migrants and refugees during their journey and while settled in Greece, and to measure the prevalence of anxiety disorders and access to legal information and procedures. METHODS: We conducted a cross-sectional population-based quantitative survey combined with an explanatory qualitative study in eight sites (representing the range of settlements) in Greece during winter 2016/17. The survey consisted of a structured questionnaire on experience of violence and an interviewer-administered anxiety disorder screening tool (Refugee Health Screener). RESULTS: In total, 1293 refugees were included, of whom 728 were Syrians (41.3% females) of median age 18 years (interquartile range 7-30). Depending on the site, between 31% and 77.5% reported having experienced at least one violent event in Syria, 24.8-57.5% during the journey to Greece, and 5-8% in their Greek settlement. Over 75% (up to 92%) of respondents >=15 years screened positive for anxiety disorder, which warranted referral for mental health evaluation, which was only accepted by 69-82% of participants. Access to legal information and assistance about asylum procedures were considered poor to non-existent for the majority, and the uncertainty of their status exacerbated their anxiety. CONCLUSIONS: This survey, conducted during a mass refugee crisis in a European Community country, provides important data on experiences in different refugee settings and reports the high levels of violence experienced by Syrian refugees during their journeys, the high prevalence of anxiety disorders, and the shortcomings of the international protective response. PMID- 29530042 TI - The impact of a human papillomavirus (HPV) vaccination campaign on routine primary health service provision and health workers in Tanzania: a controlled before and after study. AB - BACKGROUND: The burden of cervical cancer and shortage of screening services in Tanzania confers an urgent need for human papillomavirus (HPV) vaccination. However, the sustainability and impact of another new vaccine campaign in an under-resourced health system requires consideration. We aimed to determine the impact of the government's school-based HPV vaccine campaign in Kilimanjaro region on the provision of routine primary health services and staff workload. METHODS: Data on daily numbers of consultations were collected from health facility register books in 63 dispensaries and health centres in North-West Tanzania for 20 weeks in 2014. Changes in outpatient, antenatal care (ANC), family planning (FP) and immunisation service activity levels before, during and after the two HPV vaccination campaigns in 2014 in 30 facilities within Kilimanjaro region ('intervention facilities') were compared with changes in activity levels in 33 facilities in Arusha region ('controls'). Qualitative interviews were conducted with health workers in Kilimanjaro region who delivered HPV vaccination and those who remained at the facility during in-school HPV vaccine delivery to explore perceptions of workload and capacity. RESULTS: Health facility activity levels were low and very variable in both regions. Controlling for district, facility type, catchment population, clinical staff per 1000 catchment population and the timing of other campaigns, no evidence of a decrease in consultations at the health facility during HPV vaccination week was found across outpatient, ANC, routine immunisation and FP services. However, compared to the average week before and after the campaign, health workers reported longer working hours and patient waiting times, feeling over-stretched and performing duties outside their normal roles whilst colleagues were absent from the facility conducting the HPV vaccine campaign. CONCLUSION: Qualitative interviews with health workers revealed that staff absence from the health facility is common for a number of reasons, including vaccination campaigns. Health workers perceived that the absence of their colleagues increased the workload at the health facility. The numbers of consultations for each service on 'normal days' were low and highly variable and there was no clear detrimental effect of the HPV vaccination campaign on routine health service activity. PMID- 29530043 TI - Inflammatory markers before and after farrowing in healthy sows and in sows affected with postpartum dysgalactia syndrome. AB - BACKGROUND: The pathogenesis of postpartum dysgalactia syndrome (PDS) in sows is not fully elucidated and affected sows often present vague clinical signs. Accurate and timely diagnosis is difficult, and PDS is often recognized with a delay once piglets begin to starve. Increased rectal temperature of the sow is an important diagnostic parameter, but it may also be influenced by a number of other parameters and is thus difficult to interpret. Inflammatory markers may be important adjuncts to the clinical assessment of sows with PDS, but such markers have only been studied to a limited extent. The objective was to characterize the inflammatory response in healthy sows and in sows suffering from PDS, and to identify biomarkers that may assist in early identification of PDS-affected sows. RESULTS: Thirty-eight PDS-affected (PDS+) and 38 healthy (PDS-) sows underwent clinical examination and blood sampling every 24 h, from 60 h before the first piglet was born to 36 h after parturition. In both groups, inflammatory markers changed in relation to parturition. Most inflammatory markers changed 12-36 h after parturition [white blood cell counts (WBC), neutrophil counts, lymphocyte counts, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), serum amyloid A (SAA), C-reactive protein (CRP), haptoglobin (Hp), iron (Fe) and albumin (ALB)]. Changes in neutrophil counts, lymphocyte counts, CRP, Fe and ALB were observed -12 to 0 h before parturition. WBC, neutrophil and lymphocyte counts, serum concentrations of TNF-alpha, IL-6, Hp and Fe differed between PDS+ and PDS- sows. These differences were mainly apparent 12 to 36 h after parturition, but already at 12 h before parturition, PDS+ sows had lower lymphocyte counts than PDS- sows. CONCLUSIONS: Parturition itself caused significant inflammatory changes, but PDS+ sows showed a more severe response than PDS- sows. WBC, neutrophil and lymphocyte counts, and concentrations of TNF alpha, IL-6, Hp and Fe can be potential biomarkers for PDS. Lymphocyte counts may be used to detect PDS at pre-partum. To assess their diagnostic potential, these markers must be investigated further and most likely combined with assessment of clinical parameters and other biomarkers for improved identification of sows at risk of developing PDS. PMID- 29530044 TI - Uptake of intermittent preventive treatment and pregnancy outcomes: health facilities and community surveys in Chokwe district, southern Mozambique. AB - BACKGROUND: Malaria in pregnancy leads to serious adverse effects on the mother and the child and accounts for 75,000-200,000 infant deaths every year. Currently, the World Health Organization recommends intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) at each scheduled antenatal care (ANC) visit. This study aimed to assess IPTp-SP coverage in mothers delivering in health facilities and at the community. In addition, factors associated with low IPTp-SP uptake and malaria adverse outcomes in pregnancy were investigated. METHODS: A community and a health facility-based surveys were conducted in mothers delivering in Chokwe district, southern Mozambique. Social-demographic data, malaria prevention practices and obstetric history were recorded through self-report and antenatal records. For women delivering at health facilities, a clinical examination of mother and child was performed, and malaria infection at delivery was determined by rapid diagnostic test, microscopy, quantitative PCR and placental histology. RESULTS: Of 1141 participants, 46.6, 30.2, 13.5 and 9.6% reported taking >= 3, two, one and none SP doses, respectively. Low IPTp uptake (< 3 doses) was associated with non institutional deliveries (AOR = 2.9, P < 0.001), first ANC visit after week 28 (AOR = 5.4, P < 0.001), low awareness of IPTp-SP (AOR = 1.6, P < 0.002) and having no or only primary education (AOR = 1.3, P = 0.041). The overall prevalence of maternal malaria (peripheral and/or placental) was 16.8% and was higher among women from rural areas compared to those from urban areas (AOR = 1.9, P < 0.001). Younger age (< 20 years; AOR = 1.6, P = 0.042) and living in rural areas (AOR = 1.9, P < 0.001) were predictors of maternal malaria at delivery. Being primigravidae (AOR = 2.2, P = 0.023) and preterm delivery (AOR = 2.6, P < 0.001) predicted low birth weight while younger age was also associated with premature delivery (AOR = 1.4, P = 0.031). CONCLUSION: The coverage for two and >= 3 doses of IPTp-SP is moderately higher than estimates from routine health facility records in Gaza province in 2015. However, this is still far below the national target of 80% for >= 3 doses. Ongoing campaigns aiming to increase the use of malaria prevention strategies during pregnancy should particularly target rural populations, increasing IPTp-SP knowledge, stimulate early visits to ANC, improve access to health services and the quality of the service provided. PMID- 29530045 TI - Porous safety net: catastrophic health expenditure and its determinants among insured households in Togo. AB - BACKGROUND: In Togo, about half of health care costs are paid at the point of service, which reduces access to health care and exposes households to catastrophic health expenditure (CHE). To address this situation, the Togolese government introduced a National Health Insurance Scheme (NHIS) in 2011. This insurance currently covers only employees and retirees of the State as well as their dependents, although plans for extension exist. This study is the first attempt to examine the extent to which Togo's NHIS protects its members financially against the consequences of ill-health. METHODS: Data was obtained from a cross-sectional representative households' survey involving 1180 insured households that had reported illness in the household in the 4 weeks preceding the survey or hospitalization in the 12 months preceding the survey. The incidence and intensity of CHE were measured by the catastrophic health payment method. A logistic regression was used to analyse determinants of CHE. RESULTS: The results indicate that the proportion of insured households with CHE varies widely between 3.94% and 75.60%, depending on the method and the threshold used. At the 40% threshold, health care cost represents 60.95% of insured households' total monthly non-food expenditure. This study showed that the socioeconomic status, the type of health facility used, hospitalization and household size were the highest predictors of CHE. Whatever the chosen threshold, care in referral and district hospitals significantly increases the likelihood of CHE. In addition, the proportion of households facing CHE is higher in the lowest income groups. The behaviour of health care providers, poor quality of care and long waiting time were the main factors leading to CHE. CONCLUSION: A sizable proportion of insured households face CHE, suggesting gaps in the coverage. To limit the impoverishment of insured households with low income, policies for free or heavily subsidized hospital services should be considered. The results call for an equitable health insurance scheme, which is affordable for all insured households. PMID- 29530046 TI - The D113N mutation in the RING E3 ubiquitin protein ligase gene is not associated with ex vivo susceptibility to common anti-malarial drugs in African Plasmodium falciparum isolates. AB - BACKGROUND: Plasmodium falciparum resistance to artemisinin-based combination therapy has emerged and spread in Southeast Asia. In areas where artemisinin resistance is emerging, the efficacy of combination is now based on partner drugs. In this context, the identification of novel markers of resistance is essential to monitor the emergence and spread of resistance to these partner drugs. The ubiquitylation pathway could be a possible target for anti-malarial compounds and might be involved in resistance. Polymorphisms in the E3 ubiquitin protein ligase (PF3D7_0627300) gene could be associated with decreased in vitro susceptibility to anti-malarial drugs. METHODS: Plasmodium falciparum isolates were collected from patients hospitalized in France with imported malaria from a malaria-endemic country from January 2015 to December 2016 and, more particularly, from African French-speaking countries. In total, 215 isolates were successfully sequenced for the E3 ubiquitin-protein ligase gene and assessed for ex vivo susceptibility to anti-malarial drugs. RESULTS: The D113N mutation in the RING E3 ubiquitin-protein ligase gene was present in 147 out of the 215 samples (68.4%). The IC50 values for the ten anti-malarial drugs were not significantly different between the wild-type and mutant parasites (p values between 0.225 and 0.933). There was no significant difference in terms of the percentage of parasites with decreased susceptibility between the D113 wild-type and the 133N mutated P. falciparum strains (p values between 0.541 and 1). CONCLUSION: The present data confirmed the absence of the association between polymorphisms in the RING E3 ubiquitin-protein ligase gene and the ex vivo susceptibility to common anti-malarial drugs in African P. falciparum isolates. PMID- 29530047 TI - Building the evidence base on the HIV programme in India: an integrated approach to document programmatic learnings. AB - BACKGROUND: The Knowledge Network project was launched in 2010 to build evidence on the HIV epidemic by using the data generated by HIV programme implementing organisations in India. This paper describes the implementation of the programme and the strategies adopted to enhance the capacity of individuals to document and publish HIV prevention programme learnings. Further, it discusses the outcomes of the initiative. METHODS: A multipronged approach was adopted, where a group of experts were brought together to collaborate with programme implementing organisations, review available data, develop research questions and guide peer reviewed publications. Further, scientific writing courses were conducted to support individuals from HIV programme implementing organisations as well as educational and government organisations (mentees) to build the documentation capacity of individuals leading programme implementation and current and future researchers. The impact and quality of evidence generated was measured by examining the number of papers published, the number of citations, and the number of papers with at least 10 citations. Additionally, course participants' responses to open-ended questions in the anonymous course evaluation questionnaires are presented as verbatim quotes. RESULTS: Overall, 99 papers on HIV programmatic learnings from India were finalised under the programme, of which 95 have been published. In all, 67 papers were co-authored by mentees. Most papers were published in high-impact factor (1 or more) journals and 72% were cited at least once in the literature. The main themes documented include key populations' HIV risk, HIV risk of general population groups, HIV/STI service delivery models and community mobilisation interventions. CONCLUSION: The study demonstrates that an integrated approach, involving partnership, capacity building and mentorship, can maximise the use of available data and build the evidence base on HIV programmatic learnings. The capacity-building model adopted in the programme can be used to build scientific writing and documentation capacity in other public health programmes that are implemented at scale. PMID- 29530048 TI - Vitamin D deficiency is associated with poorer satisfaction with diabetes-related treatment and quality of life in patients with type 2 diabetes: a cross-sectional study. AB - BACKGROUND: In this cross-sectional study, we assessed the possible association of vitamin D deficiency with self-reported treatment satisfaction and health related quality of life in patients with type 2 diabetes. METHODS: We performed a sub-analysis of a previous study and included a total of 292 type 2 diabetic patients. We evaluated treatment satisfaction and health-related quality of life through specific tools: the Diabetes Treatment Satisfaction Questionnaire and the Audit of Diabetes-Dependent Quality of Life. Vitamin D deficiency was defined as 25 (OH) D serum levels < 15 ng/mL. RESULTS: Multivariable linear regression models were used to estimate the relationship of vitamin D deficiency with both outcomes once adjusted for self-reported patient characteristics. Vitamin D deficiency was significantly associated with the final score of the Diabetes Treatment Satisfaction Questionnaire and the single "diabetes-specific quality of life" dimension of the Audit of Diabetes-Dependent Quality of Life (p = 0.0198 and p = 0.0070, respectively). However, lower concentrations of 25-OH vitamin D were not associated with the overall quality of life score or the perceived frequency of hyperglycaemia and hypoglycaemia. CONCLUSIONS: Our study shows the association between vitamin D deficiency and both the self-reported diabetes treatment satisfaction and the diabetes-specific quality of life in patients with type 2 diabetes. PMID- 29530050 TI - Sulforaphane rescues amyloid-beta peptide-mediated decrease in MerTK expression through its anti-inflammatory effect in human THP-1 macrophages. AB - BACKGROUND: Mer tyrosine kinase (MerTK) activity necessary for amyloid-stimulated phagocytosis strongly implicates that MerTK dysregulation might contribute to chronic inflammation implicated in Alzheimer's disease (AD) pathology. However, the precise mechanism involved in the regulation of MerTK expression by amyloid beta (Abeta) in proinflammatory environment has not yet been ascertained. METHODS: The objective of this study was to determine the underlying mechanism involved in Abeta-mediated decrease in MerTK expression through Abeta-mediated regulation of MerTK expression and its modulation by sulforaphane in human THP-1 macrophages challenged with Abeta1-42. We used protein preparation, Ca2+ influx fluorescence imaging, nuclear fractionation, Western blotting techniques, and small interfering RNA (siRNA) knockdown to perform our study. RESULTS: Abeta1-42 elicited a marked decrease in MerTK expression along with increased intracellular Ca2+ level and induction of proinflammatory cytokines such as IL-1beta and TNF alpha. Ionomycin A and thapsigargin also increased intracellular Ca2+ levels and production of IL-1beta and TNF-alpha, mimicking the effect of Abeta1-42. In contrast, the Abeta1-42-evoked responses were attenuated by depletion of Ca2+ with ethylene glycol tetraacetic acid. Furthermore, recombinant IL-1beta or TNF alpha elicited a decrease in MerTK expression. However, immunodepletion of IL 1beta or TNF-alpha with neutralizing antibodies significantly inhibited Abeta1-42 mediated downregulation of MerTK expression. Notably, sulforaphane treatment potently inhibited Abeta1-42-induced intracellular Ca2+ level and rescued the decrease in MerTK expression by blocking nuclear factor-kappaB (NF-kappaB) nuclear translocation, thereby decreasing IL-1beta and TNF-alpha production upon Abeta1-42 stimulation. Such adverse effects of sulforaphane were replicated by BAY 11-7082, a NF-kappaB inhibitor. Moreover, sulforaphane's anti-inflammatory effects on Abeta1-42-induced production of IL-1beta and TNF-alpha were significantly diminished by siRNA-mediated knockdown of MerTK, confirming a critical role of MerTK in suppressing Abeta1-42-induced innate immune response. CONCLUSION: These findings implicate that targeting of MerTK with phytochemical sulforaphane as a mechanism for preventing Abeta1-42-induced neuroinflammation has potential to be applied in AD therapeutics. PMID- 29530049 TI - Guidelines on pediatric day surgery of the Italian Societies of Pediatric Surgery (SICP) and Pediatric Anesthesiology (SARNePI). AB - The Italian Society of Pediatric Surgery (SICP) together with The Italian Society of Pediatric Anesthesia (SARNePI) through a systematic analysis of the scientific literature, followed by a consensus conference held in Perugia on 2015, have produced some evidence based guidelines on the feasibility of day surgery in relation to different pediatric surgical procedures. The main aspects of the pre operative assessment, appropriacy of operations and discharge are reported. PMID- 29530051 TI - Serum proton NMR metabolomics analysis of human lung cancer following microwave ablation. AB - BACKGROUND: To find potential serum biomarkers of microwave ablation (MWA) for treatment of human lung cancer by 1H nuclear magnetic resonance (NMR)-based metabolomics analysis. METHODS: Serum specimens collected from 43 healthy individuals, 39 patients with advanced non-small cell lung cancer (NSCLC) and 38 NSCLC patients treated with MWA, were subjected to 1H NMR-based metabolomics analysis. Partial least squares discriminant analysis was used to analyze the data. RESULTS: Compared with healthy controls, NSCLC patients showed significantly elevated serum levels of lactate, alanine, glutamate, proline, glycoprotein, phenylalanine, tyrosine and tryptophan, and markedly decreased serum levels of glucose, taurine, glutamine, glycine, phosphocreatine and threonine (p < 0.05). MWA treatment reversed the metabolic profiles of NSCLC patients towards the control group. CONCLUSIONS: 1H NMR-based metabolomics analysis enhanced the current understanding of the mechanisms involved in NSCLC, and uncovered the therapeutic potential of MWA for treatment of NSCLC. The above disturbed serum metabolites were proposed to be the potential biomarkers that may help to predict NSCLC and to evaluate the efficacy of MWA in the treatment of NSCLC. PMID- 29530052 TI - Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway. AB - BACKGROUND: Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. miR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and its underlying mechanisms of transforming sensitive cell to resistant cell. METHODS: We detected the expression of miR-32-5p and PTEN in the multidrug-resistant cell line (Bel/5 FU) and the sensitive cell line (Bel7402), HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes from sensitive and multidrug resistant cell line were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss of-function experiments, rescue experiments, a PI3K/Akt pathway inhibitor, an exosome biogenesis inhibitor, and nude mice xenograft models were used to determine the underlying mechanisms of miR-32-5p and PTEN, as well as exosomal miR-32-5p in inducing multidrug resistance in vitro and in vivo. RESULTS: miR-32 5p was significantly elevated but PTEN was reduced in Bel/5-FU. An inverse correlation between miR-32-5p and PTEN was confirmed in HCC cell lines and patients; moreover, high expression of miR-32-5p and low expression of PTEN were positively associated with poor prognosis. Over-expression of miR-32-5p activated the PI3K/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition (EMT). CONCLUSIONS: Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosomes and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT. PMID- 29530053 TI - Automatic application of neural stimulation during wheelchair propulsion after SCI enhances recovery of upright sitting from destabilizing events. AB - BACKGROUND: The leading cause of injury for manual wheelchair users are tips and falls caused by unexpected destabilizing events encountered during everyday activities. The purpose of this study was to determine the feasibility of automatically restoring seated stability to manual wheelchair users with spinal cord injury (SCI) via a threshold-based system to activate the hip and trunk muscles with electrical stimulation during potentially destabilizing events. METHODS: We detected and classified potentially destabilizing sudden stops and turns with a wheelchair-mounted wireless inertial measurement unit (IMU), and then applied neural stimulation to activate the appropriate muscles to resist trunk movement and restore seated stability. After modeling and preliminary testing to determine the appropriate inertial signatures to discriminate between events and reliably trigger stimulation, the system was implemented and evaluated in real-time on manual wheelchair users with SCI. Three participants completed simulated collision events and four participants completed simulated rapid turns. Data were analyzed as a series of individual case studies with subjects acting as their own controls with and without the system active. RESULTS: The controller achieved 93% accuracy in detecting collisions and right turns, and 100% accuracy in left turn detection. Two of the three subjects who participated in collision testing with stimulation experienced significantly decreased maximum anterior posterior trunk angles (p < 0.05). Similar results were obtained with implanted and surface stimulation systems. CONCLUSIONS: This study demonstrates the feasibility of a neural stimulation control system based on simple inertial measurements to improve trunk stability and overall safety of people with spinal cord injuries during manual wheelchair propulsion. Further studies are required to determine clinical utility in real world situations and generalizability to the broader SCI or other population of manual or powered wheelchair users. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01474148 . Registered 11/08/2011 retrospectively registered. PMID- 29530054 TI - Physical basis of the 'magnification rule' for standardized Immunohistochemical scoring of HER2 in breast and gastric cancer. AB - BACKGROUND: Detection of HER2/neu receptor overexpression and/or amplification is a prerequisite for efficient anti-HER2 treatment of breast and gastric carcinomas. Immunohistochemistry (IHC) of the HER2 protein is the most common screening test, thus precise and reproducible IHC-scoring is of utmost importance. Interobserver variance still is a problem; in particular in gastric carcinomas the reliable differentiation of IHC scores 2+ and 1+ is challenging. Herein we describe the physical basis of what we called the 'magnification rule': Different microscope objectives are employed to reproducibly subdivide the continuous spectrum of IHC staining intensities into distinct categories (1+, 2+, 3+). METHODS: HER2-IHC was performed on 120 breast cancer biopsy specimens (n = 40 per category). Width and color-intensity of membranous DAB chromogen precipitates were measured by whole-slide scanning and digital morphometry. Image analysis data were related to semi-quantitative manual scoring according to the magnification rule and to the optical properties of the employed microscope objectives. RESULTS: The semi-quantitative manual HER2-IHC scores are correlated to color-intensity measured by image-analysis and to the width of DAB precipitates. The mean widths +/-standard deviations of precipitates were: IHC score 1+, 0.64 +/- 0.1 MUm; score 2+, 1.0 +/- 0.23 MUm; score 3+, 2.14 +/- 0.4 MUm. The width of precipitates per category matched the optical resolution of the employed microscope objective lenses: Approximately 0.4 MUm (40*), 1.0 MUm (10*) and 2.0 MUm (5*). CONCLUSIONS: Perceived intensity, width of the DAB chromogen precipitate, and absolute color-intensity determined by image-analysis are linked. These interrelations form the physical basis of the 'magnification rule': 2+ precipitates are too narrow to be observed with 5* microscope objectives, 1+ precipitates are too narrow for 10* objectives. Thus, the rule uses the optical resolution windows of standard diagnostic microscope objectives to derive the width of the DAB-precipitates. The width is in turn correlated with color intensity. Hereby, the more or less subjective estimation of IHC scores based only on the staining-intensity is replaced by a quasi-morphometric measurement. The principle seems universally applicable to immunohistochemical stainings of membrane-bound biomarkers that require an intensity-dependent scoring. PMID- 29530055 TI - Evaluation of Communities of Practice performance developing implementation research to enhance maternal health decision-making in Mexico and Nicaragua. PMID- 29530056 TI - Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF alpha, Ripoptosome and autophagy mediated cell death pathway. AB - BACKGROUND: Ovarian cancer is a deadly disease. Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian cancer. METHODS: CCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescence microscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFalpha protein. Caspase activity assay was used for caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian cancer cell xenograft nude mice model was used for in vivo efficacy evaluation. RESULTS: APG-1387 demonstrated potent inhibitory effect on ovarian cancer cell growth and clonogenic cell survival. APG 1387 induced RIP1- and TNFalpha-dependent apoptotic cell death in ovarian cancer through downregulation of IAPs proteins and induction of caspase-8/FADD/RIP1 complex, which drives caspase-8 activation. NF-kappaB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-kappaB activation. APG-1387 induced cytoprotective autophagy while triggering apoptosis in ovarian cancer cells and inhibition of autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian cancer xenografts. CONCLUSIONS: Our results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian cancer. PMID- 29530057 TI - LncRNA-TUSC7/miR-224 affected chemotherapy resistance of esophageal squamous cell carcinoma by competitively regulating DESC1. AB - BACKGROUND: This study aims to clarify the underlying mechanism for the tumor suppressive function of lnc TUSC7 in chemotherapy resistance of esophageal squamous cell carcinoma (ESCC). METHODS: TUSC7, miR-224 and DESC1 expressions in ESCC tissues and cells were detected by qRT-PCR. Protein level of DESC1, EGFR and p-AKT were observed by Western blot. Overall survival was calculated using the Kaplan-Meier method. Dual-luciferase reporter gene assay and RIP assay were used to comfirm TUSC7 binding to miR-224, and miR-224 binding to DESC1. Cell proliferation, apoptosis, and colony formation was detected by MTT, Flow Cytometry and Colony formation assays. RESULTS: TUSC7 was downregulated in ESCC tissues and cells, and low TUSC7 indicated worse overall survival. The analysis of bioinformatics softwares showed that TUSC7 specifically bound to miR-224, and we proved miR-224 was upregulated in ESCC and negatively correlated with TUSC7 expression. Overexpression of TUSC7/inhibition of miR-224 suppressed cell proliferation, colony formation and chemotherapy resistance of ESCC cells, and promoted cell apoptosis. In addition, we confirmed that miR-224 specifically bound to DESC1, and negatively correlated with DESC1. TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224. We also confirmed DESC1 inhibited chemotherapy resistance of ESCC cells via EGFR/AKT. Finally, in vivo experiments demonstrated that overexpression of TUSC7 decreased tumor growth and chemotherapy resistance. CONCLUSION: These findings suggested TUSC7 suppressed chemotherapy resistance of ESCC by downregulating miR-224 to modulate DESC1/EGFR/AKT pathway. PMID- 29530058 TI - Molecular detection of Anaplasma bovis in Holstein cattle in the Republic of Korea. AB - Anaplasmosis is a tick-borne infectious disease that affects both human and animal health. This study was performed to characterize and investigate the prevalence of infection with Anaplasma bovis in Holstein cattle originating from two regions in the Republic of Korea (ROK). Blood samples (n = 151; 80 from Namwon and 71 from Jeju Island) were analyzed by polymerase chain reaction, and the prevalence of A. bovis infection was compared before and after grazing. In Namwon, A. bovis infection was not detected, while in the Jeju Island, A. bovis infection was detected in three of 13 animals after grazing. Phylogenetic analysis revealed that the A. bovis isolates had homology (97.1-99.7%) with a Korean spotted deer (Cervus nippon) isolate and Haemaphysalis longicornis tick isolates identified in the ROK. A. bovis infection has not previously been diagnosed in cattle in the ROK. This study shows that A. bovis infection in the Jeju Island is closely related to grazing. PMID- 29530059 TI - Monitoring variables affecting positron emission tomography measurements of cerebral blood flow in anaesthetized pigs. AB - BACKGROUND: Positron emission tomography (PET) imaging of anaesthetized pig brains is a useful tool in neuroscience. Stable cerebral blood flow (CBF) is essential for PET, since variations can affect the distribution of several radiotracers. However, the effect of physiological factors regulating CBF is unresolved and therefore knowledge of optimal anaesthesia and monitoring of pigs in PET studies is sparse. The aim of this study was therefore to determine if and how physiological variables and the duration of anaesthesia affected CBF as measured by PET using [15O]-water in isoflurane-N2O anaesthetized domestic female pigs. First, we examined how physiological monitoring parameters were associated with CBF, and which parameters should be monitored and if possible kept constant, during studies where a stable CBF is important. Secondly, we examined how the duration of anaesthesia affected CBF and the monitoring parameters. RESULTS: No significant statistical correlations were found between CBF and the nine monitoring variables. However, we found that arterial carbon dioxide tension (PaCO2) and body temperature were important predictors of CBF that should be observed and kept constant. In addition, we found that long-duration anaesthesia was significantly correlated with high heart rate, low arterial oxygen tension, and high body temperature, but not with CBF. CONCLUSIONS: The findings indicate that PaCO2 and body temperature are crucial for maintaining stable levels of CBF and thus optimizing PET imaging of molecular mechanisms in the brain of anaesthetized pigs. Therefore, as a minimum these two variables should be monitored and kept constant. Furthermore, the duration of anaesthesia should be kept constant to avoid variations in monitoring variables. PMID- 29530060 TI - Mechanisms of implementing public health interventions: a pooled causal mediation analysis of randomised trials. AB - BACKGROUND: The World Health Organization recommends that nations implement evidence-based nutritional guidelines and policies in settings such as schools and childcare services to improve public health nutrition. Understanding the causal mechanism by which implementation strategies exert their effects could enhance guideline implementation. The aim of this study was to assess the mechanisms by which implementation strategies improved schools and childcare services' adherence to nutrition guidelines. METHODS: We conducted a mechanism evaluation of an aggregated dataset generated from three randomised controlled trials conducted in schools and childcare services in New South Wales, Australia. Each trial examined the impact of implementation strategies that targeted Theoretical Domains Framework constructs including knowledge, skills, professional role and identity, environmental context and resources. We pooled aggregated organisation level data from each trial, including quantitative assessments of the Theoretical Domains Framework constructs, as well as measures of school or childcare nutrition guideline compliance, the primary implementation outcome. We used causal mediation analysis to estimate the average indirect and direct effects of the implementation strategies and assessed the robustness of our findings to varying levels of unmeasured and unknown confounding. RESULTS: We included 121 schools or childcare services in the pooled analysis: 79 allocated to receive guideline and policy implementation strategies and 42 to usual practice. Overall, the interventions improved compliance (odds ratio = 6.64; 95% CI [2.58 to 19.09]); however, the intervention effect was not mediated by any of the four targeted Theoretical Domains Framework constructs (average causal mediation effects through knowledge = - 0.00 [- 0.05 to 0.04], skills = 0.01 [- 0.02 to 0.07], professional role and identity = 0.00 [- 0.03 to 0.03] and environmental context and resources = 0.00 [- 0.02 to 0.06]). The intervention had no significant effect on the four targeted Theoretical Domains Framework constructs, and the constructs were not associated with school or childcare nutrition guideline compliance. Potentially, this lack of effect could be explained by imprecise measurement of the mediators. Alternatively, it is likely that that the interventions were operating via alternative mechanisms that were not captured by the four Theoretical Domains Framework constructs we explored. CONCLUSIONS: Even though public health implementation strategies led to meaningful improvements in school or childcare nutrition guideline compliance, these effects were not mediated by key targeted constructs of the Theoretical Domains Framework. Future research should explore the mechanistic role of other Theoretical Domains Framework constructs and evaluate system-level mechanisms informed by an ecological framework. TRIAL REGISTRATION: All trials were prospectively registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12613000543785 . Registered 15/05/2013; ACTRN12614001148662 . Registered 30/10/2014; ACTRN12615001032549 . Registered 1/10/2015). PMID- 29530061 TI - Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN. AB - BACKGROUND: Diabetic patients have a higher risk factor for colorectal cancer (CRC) metastasis. Stearoyl-CoA desaturase 1 (SCD1), the main enzyme responsible for producing monounsaturated fatty acids(MUFA) from saturated fatty acids, is frequently deregulated in both diabetes and CRC. The function and mechanism of SCD1 in metastasis of CRC and its relevance to glucose remains largely unknown. METHODS: SCD1 expression levels were analyzed in human CRC tissues and the Cancer Browser database ( https://genome-cancer.ucsc.edu/ ). CRC cell lines stably transfected with SCD1 shRNAs or vector were established to investigate the role of SCD1 in modulating migration and invasion of CRC cells. A glucose concentration gradient was set to investigate regulation of SCD1 in CRC relevant to diabetic conditions. RESULTS: The clinical data analysis showed high expression of SCD1 in CRC tissues with a negative correlation with the prognosis of CRC. In vitro experiments revealed that SCD1 increased CRC progression through promoting epithelial-mesenchymal transition (EMT). Lipidomic analysis demonstrated that SCD1 increased MUFA levels and MUFA administration could rescue migration and invasion defect of CRC cells induced by SCD1 knockdown. Furthermore, SCD1-mediated progression of CRC was promoted by carbohydrate response-element binding protein (ChREBP) in response to high glucose. Mechanistically, hyperglycemia-SCD1-MUFA induced CRC cell migration and invasion by regulating PTEN. CONCLUSIONS: Our findings show that SCD1 promotes metastasis of CRC cells through MUFA production and suppressing PTEN in response to glucose, which may be a novel mechanism for diabetes-induced CRC metastasis. PMID- 29530063 TI - The efficacy of synovectomy for total knee arthroplasty: a meta-analysis. AB - BACKGROUND: Many studies have proposed synovectomy during total knee arthroplasty (TKA) to reduce pain after TKA. The aim of this study was to assess the outcomes of synovectomy for treating of TKA through a meta-analysis. METHODS: Relevant clinical studies on synovectomy and without synovectomy were retrieved through searching the databases PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials up to January 2018. Studies that investigated the comparison of pain scores, total blood loss, range of motion, functional Knee Society Scores (KSSs), clinical KSSs, and operating time and provided sufficient data of interest were included in this meta-analysis. Stata 12.0 was used for meta-analysis. RESULTS: Ten randomized controlled trials (RCTs) were finally included in this meta-analysis. Final results indicated that there was no significant difference between the pain scores, range of motion, functional Knee Society Scores (KSSs), and clinical KSSs (P > 0.05). However, synovectomy was associated with an increase of the total blood loss compared to patients without synovectomy (weighted mean difference (WMD) = 116.71, 95% confidence interval (CI) 78.63, 154.79, P = 0.000). Pooled results indicated that synovectomy was associated with an increase of the operating time (WMD = 15.44, 95% CI 2.67, 28.21, P = 0.018). CONCLUSIONS: Current evidence indicates that synovectomy has no effects on the final clinical outcomes for patients undergoing TKA. It will increase the total blood loss and the operating time during TKA. PMID- 29530062 TI - Potential mediators of in ovo delivered double stranded (ds) RNA-induced innate response against low pathogenic avian influenza virus infection. AB - BACKGROUND: Toll like receptor (TLR) 3 is a critically important innate pattern recognizing receptor that senses many viral infections. Although, it has been shown that double stranded (ds) RNA can be used for the stimulation of TLR3 signaling pathway in a number of host-viral infection models, it's effectiveness as an antiviral agent against low pathogenic avian influenza virus (LPAIV) needs further investigation. METHODS: In this study, first, we delivered TLR3 ligand, dsRNA, in ovo at embryo day (ED)18 since in ovo route is routinely used for vaccination against poultry viral and parasitic infections and infected with H4N6 LPAIV 24-h post-treatment. A subset of in ovo dsRNA treated and control groups were observed for the expressions of TLR3 and type I interferon (IFN)s, mRNA expression of interleukin (IL)-1beta and macrophage recruitment coinciding with the time of H4N6 LPAIV infection (24 h post-treatment). Additionally, Day 1 chickens were given dsRNA intra-tracheally along with a control group and a subset of chickens were infected with H4N6 LPAIV 24-h post-treatment whereas the rest of the animals were observed for macrophage and type 1 IFN responses coinciding with the time of viral infection. RESULTS: Our results demonstrate that the pre-hatch treatment of eggs with dsRNA reduces H4N6 replication in lungs. Further studies revealed that in ovo delivery of dsRNA increases TLR3 expression, type I IFN production and number of macrophages in addition to mRNA expression of IL-1beta in lung 24-h post-treatment. The same level of induction of innate response was not evident in the spleen. Moreover, we discovered that dsRNA elicits antiviral response against LPAIV correlating with type I IFN activity in macrophages in vitro. Post-hatch, we found no difference in H4N6 LPAIV genome loads between dsRNA treated and control chickens although we observed higher macrophage recruitment and IFN-beta response coinciding with the time of viral infection. CONCLUSIONS: Our findings imply that the TLR3 ligand, dsRNA has antiviral activity in ovo and in vitro but not in chickens post-hatch and dsRNA-mediated innate host response is characterized by macrophage recruitment and expressions of TLR3 and type 1 IFNs. PMID- 29530064 TI - Dynamic fetal cardiovascular magnetic resonance imaging using Doppler ultrasound gating. AB - BACKGROUND: Fetal cardiovascular magnetic resonance (CMR) imaging may provide a valuable adjunct to fetal echocardiography in the evaluation of congenital cardiovascular pathologies. However, dynamic fetal CMR is difficult due to the lack of direct in-utero cardiac gating. The aim of this study was to investigate the effectiveness of a newly developed Doppler ultrasound (DUS) device in humans for fetal CMR gating. METHODS: Fifteen fetuses (gestational age 30-39 weeks) were examined using 1.5 T CMR scanners at three different imaging sites. A newly developed CMR-compatible DUS device was used to generate gating signals from fetal cardiac motion. Gated dynamic balanced steady-state free precession images were acquired in 4-chamber and short-axis cardiac views. Gating signals during data acquisition were analyzed with respect to trigger variability and sensitivity. Image quality was assessed by measuring endocardial blurring (EB) and by image evaluation using a 4-point scale. Left ventricular (LV) volumetry was performed using the single-plane ellipsoid model. RESULTS: Gating signals from the fetal heart were detected with a variability of 26 +/- 22 ms and a sensitivity of trigger detection of 96 +/- 4%. EB was 2.9 +/- 0.6 pixels (4 chamber) and 2.5 +/- 0.1 pixels (short axis). Image quality scores were 3.6 +/- 0.6 (overall), 3.4 +/- 0.7 (mitral valve), 3.4 +/- 0.7 (foramen ovale), 3.6 +/- 0.7 (atrial septum), 3.7 +/- 0.5 (papillary muscles), 3.8 +/- 0.4 (differentiation myocardium/lumen), 3.7 +/- 0.5 (differentiation myocardium/lung), and 3.9 +/- 0.4 (systolic myocardial thickening). Inter observer agreement for the scores was moderate to very good (kappa 0.57-0.84) for all structures. LV volumetry revealed mean values of 2.8 +/- 1.2 ml (end diastolic volume), 0.9 +/- 0.4 ml (end systolic volume), 1.9 +/- 0.8 ml (stroke volume), and 69.1 +/- 8.4% (ejection fraction). CONCLUSION: High-quality dynamic fetal CMR was successfully performed using a newly developed DUS device for direct fetal cardiac gating. This technique has the potential to improve the utility of fetal CMR in the evaluation of congenital pathologies. PMID- 29530066 TI - Preventing sensationalistic science and fake news about substance use. PMID- 29530065 TI - Predictive factors for sentinel node metastases in primary invasive breast cancer: a population-based cohort study of 2552 consecutive patients. AB - BACKGROUND: Axillary lymph node status is one of the most important prognostic factors for breast cancer. The aim of this study was to determine predictive factors for metastasis to sentinel node (SN) in primary invasive breast cancer. METHOD: This is a study of 3979 patients with primary breast cancer during 2008 2013 in Malmo and Lund scheduled for surgery and included in the information retrieved from Information Network for Cancer Care (INCA). The final study population included 2552 patients with primary invasive breast cancer. The risk of metastases to SN were examined in relation to potential clinicopathological factors such as age, screening mammography, tumor size, tumor type, histological grade, estrogen status, progesterone status, Her-2 status, multifocality, and lymphovascular invasion. Binary logistic regression was used; adjusted analyses yielded odds ratio (OR) with 95% confidence interval. RESULTS: Tumors detected by mammography screening were less likely to be associated with metastases to SN compared to those not found by mammography screening (0.63; 0.51-0.80). Negative hormonal status for estrogen associated with lower risk for SN metastases compared to tumor with positive estrogen status (0.64; 0.42-0.99). Tumors with a size more than 20 mm had higher risk to metastasize to SN (1.84; 1.47-2.33) compared to tumors less than 20 mm. Multifocality (1.90; 1.45-2.47) and lymphovascular invasion (3.74; 2.66-5.27) were also strong predictive factors for SN metastases. CONCLUSION: SN metastasis is less likely to occur in women with invasive breast cancer diagnosed by screening mammogram. Tumors with negative estrogen status are associated with low risk for SN metastases. Tumors larger than 20 mm, multifocality, or lymphovascular invasion are also factors associated with high risk for SN metastases. PMID- 29530067 TI - The effectiveness of Chance UK's mentoring programme in improving behavioural and emotional outcomes in primary school children with behavioural difficulties: study protocol for a randomised controlled trial. AB - BACKGROUND: There is a need to build the evidence base of early interventions to promote children's health and development in the UK. Chance UK is a voluntary sector organisation based in London that delivers a 12-month mentoring programme for primary school children identified by teachers and parents as having behavioural and emotional difficulties. The aim of the study is to determine the effectiveness of the programme in terms of children's behaviour and emotional well-being; this is the primary outcome of the trial. METHODS/DESIGN: A randomised controlled trial will be conducted in which participants are randomly allocated on a dynamic basis to one of two possible arms: the intervention arm (n = 123) will be offered the mentoring programme, and the control arm (n = 123) will be offered services as usual. Outcome data will be collected at three points: pre-intervention (baseline), mid-way through the mentoring year (c.9 months after randomisation) and post- mentoring programme (c.16 months after randomisation). DISCUSSION: This study will further enhance the evidence for early intervention mentoring programmes for child behaviour and emotional well being in the UK. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47154925 . Retrospectively registered 9 September 2014. PMID- 29530068 TI - Deregulated microRNA and mRNA expression profiles in the peripheral blood of patients with Marfan syndrome. AB - BACKGROUND: MicroRNAs (miRNAs) are small RNAs regulating gene expression post transcriptionally. While acquired changes of miRNA and mRNA profiles in cancer have been extensively studied, little is known about expression changes of circulating miRNAs and messenger RNAs (mRNA) in monogenic constitutional anomalies affecting several organ systems, like Marfan syndrome (MFS). We performed integrated miRNA and mRNA expression profiling in blood samples of Marfan patients in order to investigate deregulated miRNA and mRNA networks in these patients which could serve as potential diagnostic and prognostic tools for MFS therapy. METHODS: MiRNA and mRNA expression profiles were determined in blood samples from MFS patients (n = 7) and from healthy volunteer controls (n = 7) by microarray analysis. Enrichment analyses of altered mRNA expression were identified using bioinformatic tools. RESULTS: A total of 28 miRNAs and 32 mRNAs were found to be significantly altered in MFS patients compared to controls (> 2.0-fold change, adjusted P < 0.05). The expression of 11 miRNA and 6 mRNA candidates was validated by RT-qPCR in an independent cohort of 26 MFS patients and 26 matched HV controls. Significant inverse correlations were evident between 8 miRNAs and 5 mRNAs involved in vascular pathology, inflammation and telomerase regulation. Significant positive correlations were present for 7 miRNAs with age, for 2 miRNAs with the MFS aortic root status (Z-score) and for 7 miRNAs with left ventricular end-diastolic diameter in MFS patients. In addition, miR-331-3p was significantly up-regulated in MFS patients without mitral valve prolapse (MVP) as compared with patients with MVP. CONCLUSIONS: Our data show deregulated gene and miRNA expression profiles in the peripheral blood of MFS patients, demonstrating several candidates for prognostic biomarkers for cardiovascular manifestations in MFS as well as targets for novel therapeutic approaches. A deregulation of miRNA expression seems to play an important role in MFS, highlighting the plethora of effects on post-transcriptional regulation of miRNAs and mRNAs initiated by constitutional mutations in single genes. Trial registration Nr: EA2/131/10 . Registered 28 December, 2010. PMID- 29530069 TI - Inhibition of CREB binding protein-beta-catenin signaling down regulates CD133 expression and activates PP2A-PTEN signaling in tumor initiating liver cancer cells. AB - BACKGROUND: The WNT-beta-catenin pathway is known to regulate cellular homeostasis during development and tissue regeneration. Activation of WNT signaling increases the stability of cytoplasmic beta-catenin and enhances its nuclear translocation. Nuclear beta-catenin function is regulated by transcriptional co-factors such as CREB binding protein (CBP) and p300. Hyper activated WNT-beta-catenin signaling is associated with many cancers. However, its role in inducing stemness to liver cancer cells, its autoregulation and how it regulates tumor suppressor pathways are not well understood. Here we have investigated the role of CBP-beta-catenin signaling on the expression of CD133, a known stem cell antigen and PP2A-PTEN pathway in tumor initiating liver cancer cells. METHODS: Human hepatoblastoma cell line HepG2 and clonally expanded CD133 expressing tumor initiating liver cells (TICs) from premalignant murine liver were used in this study. CBP-beta-catenin inhibitor ICG001 was used to target CBP beta catenin signaling in liver cancer cells in vitro. Western blotting and real time PCR (qPCR) were used to quantify protein expression/phosphorylation and mRNA levels, respectively. CBP and CD133 gene silencing was performed by siRNA transfection. Fluorescence Activated Cell Sorting (FACS) was performed to quantify CD133 positive cells. Protein Phosphatase (PP2A) activity was measured after PP2AC immunoprecipitation. RESULTS: CBP inhibitor ICG001 and CBP silencing significantly reduced CD133 expression and anchorage independent growth in HepG2 and murine TICs. CD133 silencing in TICs decreased cell proliferation and expression levels of cell cycle regulatory genes, CyclinD1 and CyclinA2. ICG001 treatment and CBP silencing reduced the levels of phosphoSer380/Tyr382/383PTEN, phosphoSer473-AKT, Phospho-Ser552beta-catenin in TICs. ICG001 mediated de phosphorylation of PTEN in TICs was PP2A dependent and partly prevented by co treatment with PP2A inhibitor okadaic acid. CONCLUSIONS: CBP-beta-catenin signaling promotes stemness via CD133 induction and cell proliferation in TICs. We found a novel functional link between CBP-beta-catenin and PP2A-PTEN-AKT pathway in liver TICs. Therefore, CBP-beta-catenin-PP2A-PTEN-AKT signaling axis could be a novel therapeutic target to prevent liver tumor initiation and cancer recurrence. PMID- 29530070 TI - Correction to: PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. AB - The original article [1] contained an error in Table 1 whereby the 'Positive' column in the 'PD-L1' Tumor type group of columns was mistakenly included at the beginning of the 'PD-L2' Tumor type group of columns. PMID- 29530071 TI - A multidisciplinary team-oriented intervention to increase guideline recommended care for high-risk prostate cancer: A stepped-wedge cluster randomised implementation trial. AB - BACKGROUND: This study assessed whether a theoretically conceptualised tailored intervention centred on multidisciplinary teams (MDTs) increased clinician referral behaviours in line with clinical practice guideline recommendations. METHODS: Nine hospital Sites in New South Wales (NSW), Australia with a urological MDT and involvement in a state-wide urological clinical network participated in this pragmatic stepped wedge, cluster randomised implementation trial. Intervention strategies included flagging of high-risk patients by pathologists, clinical leadership, education, and audit and feedback of individuals' and study Sites' practices. The primary outcome was the proportion of patients referred to radiation oncology within 4 months after prostatectomy. Secondary outcomes were proportion of patients discussed at a MDT meeting within 4 months after surgery; proportion of patients who consulted a radiation oncologist within 6 months; and the proportion who commenced radiotherapy within 6 months. Urologists' attitudes towards adjuvant radiotherapy were surveyed pre- and post-intervention. A process evaluation measured intervention fidelity, response to intervention components and contextual factors that impacted on implementation and sustainability. RESULTS: Records for 1071 high-risk post-RP patients operated on by 37 urologists were reviewed: 505 control-phase; and 407 intervention-phase. The proportion of patients discussed at a MDT meeting increased from 17% in the control-phase to 59% in the intervention-phase (adjusted RR = 4.32; 95% CI [2.40 to 7.75]; p < 0.001). After adjustment, there was no significant difference in referral to radiation oncology (intervention 32% vs control 30%; adjusted RR = 1.06; 95% CI [0.74 to 1.51]; p = 0.879). Sites with the largest relative increases in the percentage of patients discussed also tended to have greater increases in referral (p = 0.001). In the intervention phase, urologists failed to provide referrals to more than half of patients whom the MDT had recommended for referral (78 of 140; 56%). CONCLUSIONS: The intervention resulted in significantly more patients being discussed by a MDT. However, the recommendations from MDTs were not uniformly recorded or followed. Although practice varied markedly between MDTs, the intervention did not result in a significant overall change in referral rates, probably reflecting a lack of change in urologists' attitudes. Our results suggest that interventions focused on structures and processes that enable health system-level change, rather than those focused on individual-level change, are likely to have the greatest effect. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12611001251910 ). Registered 6 December 2011. PMID- 29530072 TI - Circulating stem cells, HIF-1, and SDF-1 in septic abdominal surgical patients: randomized controlled study protocol. AB - BACKGROUND: Sepsis caused by complicated intra-abdominal infection is associated with high mortality. Loss of endothelial barrier integrity, inflammation, and impaired cellular oxygen have been shown to be primary contributors to sepsis. To date, little is known regarding the pathway for the mobilization of endothelial progenitor cells (EPCs) from the bone marrow in sepsis whereas stromal-cell derived factor 1a (SDF-1a) and hypoxia inducible factor 1 (HIF-1) seem to have a role in the EPC response to hypoxic microenvironments. The aims of the study are: (a) to determine the time course of the levels of circulating EPCs (CD133/CD34), SDF-1a, and HIF-1 in septic patients undergoing major abdominal surgery (group S), (b) to investigate the relationship between CD133/CD34, HIF-1, and SDF-1a, and (c) to investigate the relationship of these factors with the outcome of group S patients treated with standard conventional therapy alone (CT) or with the addition of extracorporeal hemoperfusion therapy (HCT). METHODS/DESIGN: Patients undergoing major abdominal surgery will be allocated into groups: postoperative non-septic patients in an emergency surgical ward (group C) and postoperative septic patients in an intensive care unit (group S). The latter will be randomized to receive CT alone (S1) or with HCT (S2). Healthy volunteers (group H) will be recruited at University Hospital Foggia. Peripheral blood (PB) samples will be collected preoperatively (T0), at 24 h (T1), 72 h (T2), 7 (T3), and 10 (T4) postoperative days in groups S and C, and at T0 in group H. The CD34/133 cells and HIF-1 counts will be determined by flow cytometer analysis. The concentration of SDF-1a in plasma will be calculated by enzyme-linked immunosorbent assay analysis (ELISA). DISCUSSION: This prospective randomized clinical trial is designed to investigate circulating stem cells, levels of HIF-1 and SDF-1a, and their interrelationship in septic postoperative abdominal surgical patients treated with CT alone or with HCT. The rationale is that an integrated understanding of the role of hypoxia-related factors and EPCs in PB of septic patients could indicate which molecular processes need to be regulated to recover the innate immunity homeostasis. Understanding the function of EPCs in sepsis may provide innovative diagnostic and therapeutic approaches to improve the prognosis of this syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02589535 . Registered on 28 October 2015. PMID- 29530073 TI - Rethinking the extrinsic incubation period of malaria parasites. AB - The time it takes for malaria parasites to develop within a mosquito, and become transmissible, is known as the extrinsic incubation period, or EIP. EIP is a key parameter influencing transmission intensity as it combines with mosquito mortality rate and competence to determine the number of mosquitoes that ultimately become infectious. In spite of its epidemiological significance, data on EIP are scant. Current approaches to estimate EIP are largely based on temperature-dependent models developed from data collected on parasite development within a single mosquito species in the 1930s. These models assume that the only factor affecting EIP is mean environmental temperature. Here, we review evidence to suggest that in addition to mean temperature, EIP is likely influenced by genetic diversity of the vector, diversity of the parasite, and variation in a range of biotic and abiotic factors that affect mosquito condition. We further demonstrate that the classic approach of measuring EIP as the time at which mosquitoes first become infectious likely misrepresents EIP for a mosquito population. We argue for a better understanding of EIP to improve models of transmission, refine predictions of the possible impacts of climate change, and determine the potential evolutionary responses of malaria parasites to current and future mosquito control tools. PMID- 29530074 TI - Trypanosoma cruzi load in synanthropic rodents from rural areas in Chile. AB - BACKGROUND: Trypanosoma cruzi is the agent of Chagas disease, a major public health problem in Latin America. Many wild and domestic animals are naturally infected with T. cruzi; rodents are one of the groups which have been consistently detected infected in different countries. The aim of this work was to characterize blood T. cruzi load in naturally infected rodents from a Chagas disease endemic region in Chile. METHODS: Baited traps were set in domestic and peridomestic areas of rural dwellings. The rodents were anesthetized and blood sampled; DNA was extracted and the parasite load was quantified by T. cruzi satellite DNA real-time PCR assays. RESULTS: Seventy-one rodents of four species, Rattus rattus, Mus musculus, Phyllotis darwini and Octodon degus, were captured; R. rattus was the most abundant species. Fifty-nine samples (83.1%) were T. cruzi positive and the median value of the parasite load was 2.99 parasite equivalents (par-eq)/ml. The comparison of frequency of infection or parasite load by species showed no differences. However, one R. rattus presented very elevated parasitemia (1644 par-eq/ml). CONCLUSIONS: The overall levels of parasitemia were similar to those found in humans in Chile. The high infection levels in exotic and endemic rodents very near to rural settlements increases their relevance as T. cruzi hosts. PMID- 29530075 TI - Prospective associations between pulse pressure and cognitive performance in Chinese middle-aged and older population across a 5-year study period. AB - BACKGROUND: Substantial evidence indicates that the relationship between blood pressure (BP) measures and cognitive functioning is inconsistent, complex, and age-related. Pulse pressure (PP), which can not only reflect arterial stiffness and but also represent the chronic effects of hypertension other than BP itself, has been considered as a better predictor of cognitive impairment. However, evidence on the association of cognitive function with PP has not been investigated extensively. We examined this relationship in a longitudinal study based on the latent growth model (LGM). METHODS: This study was based on a nationally representative sample of Chinese middle-aged and older participants from the China Health and Retirement Longitudinal Study (CHARLS), a prospective observational study conducted from 2011 to 2016. Cognitive performance was assessed on the basis of three measures of cognition. The PP was calculated as the difference of the average values of three systolic and diastolic BP readings. A series of potential confounders were collected in this research. The LGM was used to examine the effects of PP on cognitive performance at three time points. To test the independent effects of PP on the initial level and the subsequent development of cognition, unconditional and conditional models were compared sequentially. RESULTS: After excluding respondents with missing key variables, we ultimately included 9750 participants in the analysis. Cognitive performance scores and PP showed significant differences across time. After adjustment for the confounders, the standardized coefficients of PP in the LGM indicated negative effects on cognitive performance in elderly Chinese participants at wave 2 and wave 3 (P < 0.01). The initial level of PP in the unconditional model was negatively associated with the initial level (beta = - 0.25) and the slope (beta = - 0.16) of cognition, whereas these effects were attenuated and the association between intercept of PP and slope of cognition became nonsignificant after controlling for the confounders. CONCLUSIONS: The implications of these results demonstrate that a higher PP lowers the cognitive performance of middle-aged and elderly persons independent of a comprehensive set of covariates, but it is not a contributor to the rate of change in cognition. PMID- 29530076 TI - Identification, characterization and heparin binding capacity of a spore-wall, virulence protein from the shrimp microsporidian, Enterocytozoon hepatopenaei (EHP). AB - BACKGROUND: The microsporidian Enterocytozoon hepatopenaei (EHP) is a spore forming, intracellular parasite that causes an economically debilitating disease (hepatopancreatic microsporidiosis or HPM) in cultured shrimp. HPM is characterized by growth retardation and wide size variation that can result in economic loss for shrimp farmers. Currently, the infection mechanism of EHP in shrimp is poorly understood, especially at the level of host-parasite interaction. In other microsporidia, spore wall proteins have been reported to be involved in host cell recognition. For the host, heparin, a glycosaminoglycan (GAG) molecule found on cell surfaces, has been shown to be recognized by many parasites such as Plasmodium spp. and Leishmania spp. RESULTS: We identified and characterized the first spore wall protein of EHP (EhSWP1). EhSWP1 contains three heparin binding motifs (HBMs) at its N-terminus and a Bin-amphiphysin-Rvs-2 (BAR2) domain at its C-terminus. A phylogenetic analysis revealed that EhSWP1 is similar to an uncharacterized spore wall protein from Enterospora canceri. In a cohabitation bioassay using EHP-infected shrimp with naive shrimp, the expression of EhSWP1 was detected by RT-PCR in the naive test shrimp at 20 days after the start of cohabitation. Immunofluorescence analysis confirmed that EhSWP1 was localized in the walls of purified, mature spores. Subcellular localization by an immunoelectron assay revealed that EhSWP1 was distributed in both the endospore and exospore layers. An in vitro binding assay, a competition assay and mutagenesis studies revealed that EhSWP1 is a bona fide heparin binding protein. CONCLUSIONS: Based on our results, we hypothesize that EhSWP1 is an important host-parasite interaction protein involved in tethering spores to host-cell surface heparin during the process of infection. PMID- 29530078 TI - Sociodemographic correlates of prospective dog owners' intentions to participate in controlled trials of dog ownership and human health. AB - OBJECTIVE: Dog ownership is popular, with research suggesting improvements in physical and psychological health of dog owners. However, majority of these studies were not investigator-controlled. Ethical and practical implications arising from the intervention exposure (dog ownership) result in recruitment difficulties. A fit-for-purpose design, such as delaying dog adoption until after data collection, could alleviate such issues. The purpose of this study was to explore intentions and possible incentives for participation in investigator controlled trials examining the effects of dog ownership on human physical and psychological health. RESULTS: Female (OR 1.64, 95% CI 1.31-2.04) and older (OR 65+ years 1.49, 95% CI 1.06-2.10) participants were more likely to be interested in taking part in a study investigating the health benefits of dog ownership. Majority reported no incentive was necessary for participation (57%), while others preferred pet food supplies (37%), or vouchers for veterinary care (32%). Over half of participants (53%) were willing postpone adoption for up to 3 months to participate in an investigator-controlled trial. The results of the study, showing majority of participants interested in participating in future studies examining the health benefits of dog ownership and without incentives, provides insight to methodical directions for future studies. PMID- 29530077 TI - Microarray analysis of long non-coding RNA expression profiles uncovers a Toxoplasma-induced negative regulation of host immune signaling. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite that can infect mammalian cells and thereby regulate host gene expression. The long non-coding RNAs (lncRNAs) have been demonstrated to be an important class of RNA molecules that regulate many biological processes, including host-pathogen interactions. However, the role of host lncRNAs in the response to T. gondii infection remains largely unknown. METHODS: We applied a microarray approach to determine the differential expression profiles of both lncRNAs and mRNAs in the human foreskin fibroblast (HFF) cells after T. gondii infection. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to reveal the potential functions of T. gondii-induced genes. Based on the co-expression networks of lncRNAs and immune-related genes, the role of NONSHAT022487 on the regulation of UNC93B1 related immune signaling was investigated by the knockdown and over-expression of lncRNA in human macrophage derived from the PMA-induced promonocytic cell line THP-1. RESULTS: Our data showed that 996 lncRNAs and 109 mRNAs in HFF cells were significantly and differentially expressed following T. gondii infection (fold change >= 5, P < 0.05). The results from the GO and KEGG pathway analyses indicated that the mRNAs with differential expression were mainly involved in the host immune response. Remarkably, we identified a novel lncRNA, NONSHAT022487, which suppresses the expression of the immune-related molecule UNC93B1. After T. gondii infection, NONSHAT022487 impaired the secretion of the cytokines IL-12, TNF-alpha, IL-1beta and IFN-gamma by downregulating UNC93B1 expression in human macrophage cells. CONCLUSIONS: Our study identified infection-induced lncRNA expression as a novel mechanism by which the Toxoplasma parasite regulates host immune signaling, which advances our understanding of the interaction of T. gondii parasites and host cells. PMID- 29530079 TI - Identifying non-traditional stakeholders with whom to engage, when mitigating antimicrobial resistance in foodborne pathogens (Canada). AB - OBJECTIVE: Antimicrobial resistance (AMR) is a critical public health issue that involves interrelationships between people, animals, and the environment. Traditionally, interdisciplinary efforts to mitigate AMR in the food chain have involved public health, human and veterinary medicine, and agriculture stakeholders. Our objective was to identify a more diverse range of stakeholders, beyond those traditionally engaged in AMR mitigation efforts, via diagramming both proximal and distal factors impacting, or impacted by, use and resistance along the Canadian food chain. RESULTS: We identified multiple stakeholders that are not traditionally engaged by public health when working to mitigate AMR in the food chain, including those working broadly in the area of food (e.g., nutrition, food security, international market economists) and health (e.g., health communication, program evaluation), as well as in domains as diverse as law, politics, demography, education, and social innovation. These findings can help researchers and policymakers who work on issues related to AMR in the food chain to move beyond engaging the 'traditional' agri-food stakeholders (e.g., veterinarians, farmers), to also engage those from the wider domains identified here, as potential stakeholders in their AMR mitigation efforts. PMID- 29530080 TI - Substance use and the HIV care continuum: important advances. PMID- 29530081 TI - Evaluating optimal utilisation of technology in type 1 diabetes mellitus from a clinical and health economic perspective: protocol for a systematic review. AB - BACKGROUND: Technology has been implemented since the 1970s with the hope of improving glycaemic control and reducing the burden of complications for those living with type 1 diabetes. A clinical and cost-effectiveness comparison of all available technologies including continuous subcutaneous insulin infusion (CSII), continuous glucose monitors (CGMs), sensor-augmented pump therapy (including either low-glucose suspend or predictive low-glucose suspend), hybrid closed-loop systems, closed-loop (single-hormone or dual-hormone) systems, flash glucose monitoring (FGM), insulin bolus calculators, and 'smart-device' applications is currently lacking. This systematic review, network meta-analysis, and narrative synthesis aims to summarise available evidence regarding the clinical and cost effectiveness of available technologies in the management of patients with type 1 diabetes. METHODS: Relevant studies will be searched using a comprehensive strategy through MEDLINE, MEDLINE in-process and other non-indexed citations, EMBASE, PubMed, all evidenced-based medicine reviews, EconLit, Cost-effectiveness Analysis Registry, Research Papers in Economics, Web of Science, PsycInfo, CINAHL, and PROSPERO for randomised controlled trials and economic evaluations. The search strategy will assess if there are combinations of currently available technologies that are superior to each other or to insulin injections and capillary blood glucose testing with regard to glycaemic control, morbidity/mortality, quality of life, and cost-effectiveness. Two reviewers will screen all articles for eligibility and then independently evaluate risk of bias, complete quality assessment, and extract data for included studies. Network meta analyses will be performed where there is sufficient homogenous clinical data. Narrative synthesis will be performed for heterogeneous clinical data that cannot be pooled for network meta-analysis with critical appraisal of economic evaluations. DISCUSSION: This systematic review protocol utilises rigorous methodology and pre-determined eligibility criteria to provide a uniquely comprehensive search for a broad spectrum of clinical and economic outcomes in comparing multiple currently available technologies for managing type 1 diabetes. Evidence on which technologies may be most appropriate for particular patient groups will be examined as well as the economic justification for funding of different technologies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ( CRD42017077221 ). PMID- 29530082 TI - The role of gender relations in uptake of mass drug administration for lymphatic filariasis in Alor District, Indonesia. AB - BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis has set 2020 as a target to eliminate lymphatic filariasis (LF) as a public health problem through mass drug administration (MDA) to all eligible people living in endemic areas. To obtain a better understanding of compliance with LF treatment, a qualitative study using 43 in-depth interviews was carried out in Alor District, Indonesia to explore factors that motivate uptake of LF treatment, including the social and behavioural differences between compliant and non-compliant individuals. In this paper, we report on the findings specific to the role of family and gender relations and how they affect compliance. RESULTS: The sample comprised 21 men and 22 women; 24 complied with treatment while 19 did not. Gender relations emerged as a key theme in access, uptake and compliance with MDA. The view that the husband, as head of household, had the power, control, and in some cases the responsibility to influence whether his wife took the medication was common among both men and women. Gender also affected priorities for health care provision in the household as well as overall decision making regarding health in the household. Four models of responsibility for health decision making emerged: (i) responsibility resting primarily with the husband; (ii) responsibility resting primarily with the wife; (iii) responsibility shared equally by both husband and wife; and (iv) responsibility autonomously assumed by each individual for his or her own self, regardless of the course of action of the other spouse. CONCLUSIONS: (i) Gender relations and social hierarchy influence compliance with LF treatment because they inherently affect decisions taken within the household regarding health; (ii) health care interventions need to take account of the complexity of gender roles; (iii) the fact that women's power tends to be implicit and not overtly recognised in the household or the community has important implications for health care interventions; (iv) campaigns and other preventive interventions need to take account of the diversity of patterns of health care decision-making and responsibility in specific communities so that social mobilisation messages can be tailored appropriately. PMID- 29530083 TI - Schwannoma with chondroid metaplasia of the external auditory canal - a rare finding in a rare location: a case report. AB - BACKGROUND: Schwannomas are uncommon tumors of the external auditory canal. In the English literature, very few cases of schwannomas originating in the external auditory canal were reported and none of them showed chondroid metaplasia. We report the first case of schwannoma with chondroid metaplasia in this location. CASE PRESENTATION: In this report, we described a 22-year-old white man who presented with an external auditory slow growing mass. A computed tomography scan of the temporal bone demonstrated a well-circumscribed, soft tissue mass narrowing most of the external auditory canal. A surgical biopsy was performed and the histological examination showed a schwannoma with chondroid metaplasia. CONCLUSION: Schwannoma should be considered in the differential diagnosis of benign or malignant tissue masses involving the external ear canal. PMID- 29530084 TI - Genetic diversity within dominant Enterocytozoon bieneusi genotypes in pre-weaned calves. AB - BACKGROUND: Cattle are commonly infected with the microsporidian parasite Enterocytozoon bieneusi. Sequence characterization of E. bieneusi in these animals at the ribosomal internal transcribed spacer (ITS) locus had identified I, J and BEB4 as the dominant genotypes. However, current studies on E. bieneusi in dairy cattle are mostly on infection rates and genotype distribution. This study aims to examine the intragenotypic diversity within dominant E. bieneusi genotypes in pre-weaned dairy calves in Shanghai, China. METHODS: Enterocytozoon bieneusi genotypes and subtypes were identified by PCR sequence analysis of ITS and multilocus sequence typing (MLST), based on material from farms. Chi-square test was used to examine differences in E. bieneusi infection rates between farms or age groups. RESULTS: The overall infection rate of E. bieneusi was 26.5% (214/809), ranging from 12.6% (Farm 5) to 38.5% (Farm 4). Infection rates increased with age during early life, with the peak infection rate (43.0%; 43/100) occurring at six weeks. Four genotypes were present, including J (n = 145, 67.8%), BEB4 (n = 59, 27.6%), CHN4 (n = 4, 1.9%) and CHN15 (n = 1, 0.5%), with the former two belonging to Group 2 and the latter two belonging to Group 1. Differences were detected in the distribution of the dominant genotypes J and BEB4 among five study farms. Altogether, 10 multilocus genotypes (MLGs) were identified in the two dominant ITS genotypes, including MLG-J1 to MLG-J8 of genotype J and MLG-B1 to MLG-B2 of genotype BEB4. MLG-B1 and MLG-B2 were recovered in Farms 1, 2 and 5, whereas MLG-J1 to MLG-J5 and MLG-J6 to MLG-J8 were found in Farms 3 and 4, respectively. CONCLUSIONS: There is extensive genetic heterogeneity within the dominant E. bieneusi genotypes J and BEB4 in dairy calves in Shanghai, China, and MLST should be used in molecular epidemiological studies of E. bieneusi in cattle. PMID- 29530085 TI - Spherical Body Protein 2 truncated copy 11 as a specific Babesia bovis attenuation marker. PMID- 29530086 TI - Seroprevalence and determinants of transfusion transmissible infections among voluntary blood donors in Homabay, Kisumu and Siaya counties in western Kenya. AB - OBJECTIVE: Since the implementation of a series of blood donation safety improvements in Kenya, information about seroprevalence and determinants of transfusion transmissible infections among voluntary blood donors especially in high HIV burden regions of Homabay, Kisumu and Siaya counties remain scanty. A cross-sectional study examining HIV, syphilis, hepatitis B and C virus sero markers and associated determinants was conducted among voluntary blood donors. Their demographic characteristics and previous risk exposure were recorded in a pre-donation questionnaire, while blood samples collected were screened for hepatitis B, hepatitis C, human immunodeficiency viruses by ELISA and RPR (syphilis), then confirmed using CMIA. RESULTS: Overall TTIs seroprevalence was 114 (9.4%), distributed among HIV, HBV, HCV and syphilis at 14 (1.15%), 42 (3.46%), 39 (3.21%) and 19 (1.56%), respectively, with co-infections of 3 (0.25%). There were no significant differences in proportions distributions among demographic variables. However, high risk sex was significantly associated with higher odds of HBV infections [> 1 partner vs. 0-1 partner; odd ratio (OR) 2.60; 95% confidence interval (CI) 1.098-6.86; p = 0.046]. In conclusion, a substantial percentage of blood donors still harbor transfusion transmissible infections despite recent safety improvements with greater majority cases caused by HBV infections arising from previous exposure to high risk sex. PMID- 29530087 TI - Analysis of microRNA profile of Anopheles sinensis by deep sequencing and bioinformatic approaches. AB - BACKGROUND: microRNAs (miRNAs) are small non-coding RNAs widely identified in many mosquitoes. They are reported to play important roles in development, differentiation and innate immunity. However, miRNAs in Anopheles sinensis, one of the Chinese malaria mosquitoes, remain largely unknown. METHODS: We investigated the global miRNA expression profile of An. sinensis using Illumina Hiseq 2000 sequencing. Meanwhile, we applied a bioinformatic approach to identify potential miRNAs in An. sinensis. The identified miRNA profiles were compared and analyzed by two approaches. The selected miRNAs from the sequencing result and the bioinformatic approach were confirmed with qRT-PCR. Moreover, target prediction, GO annotation and pathway analysis were carried out to understand the role of miRNAs in An. sinensis. RESULTS: We identified 49 conserved miRNAs and 12 novel miRNAs by next-generation high-throughput sequencing technology. In contrast, 43 miRNAs were predicted by the bioinformatic approach, of which two were assigned as novel. Comparative analysis of miRNA profiles by two approaches showed that 21 miRNAs were shared between them. Twelve novel miRNAs did not match any known miRNAs of any organism, indicating that they are possibly species specific. Forty miRNAs were found in many mosquito species, indicating that these miRNAs are evolutionally conserved and may have critical roles in the process of life. Both the selected known and novel miRNAs (asi-miR-281, asi-miR-184, asi-miR 14, asi-miR-nov5, asi-miR-nov4, asi-miR-9383, and asi-miR-2a) could be detected by quantitative real-time PCR (qRT-PCR) in the sequenced sample, and the expression patterns of these miRNAs measured by qRT-PCR were in concordance with the original miRNA sequencing data. The predicted targets for the known and the novel miRNAs covered many important biological roles and pathways indicating the diversity of miRNA functions. We also found 21 conserved miRNAs and eight counterparts of target immune pathway genes in An. sinensis based on the analysis of An. gambiae. CONCLUSIONS: Our results provide the first lead to the elucidation of the miRNA profile in An. sinensis. Unveiling the roles of mosquito miRNAs will undoubtedly lead to a better understanding of mosquito biology and mosquito-pathogen interactions. This work lays the foundation for the further functional study of An. sinensis miRNAs and will facilitate their application in vector control. PMID- 29530089 TI - Transcriptome analysis of pig intestinal cell monolayers infected with Cryptosporidium parvum asexual stages. AB - BACKGROUND: Human cryptosporidiosis is caused primarily by two species of apicomplexan protozoa, Cryptosporidium parvum and C. hominis. In cultured cell monolayers, the parasite undergoes two generations of asexual multiplication (merogony). However, the proportion of parasites completing the life-cycle is low and insufficient to sustain continuous propagation. Due to the intracellular location of meronts and later life-cycle stages, oocyst and sporozoites are the only forms of the parasite that can readily be isolated. RESULTS: Research on the replicating forms of Cryptosporidium parasites and their interaction with the host cell remains challenging. Based on an RNA-Seq analysis of monolayers of pig epithelial cells infected with C. parvum, here we report on the impact of merogony on the host's gene regulation. Analysis of the transcriptome of infected and uninfected monolayers demonstrates a significant impact of the infection on host cell gene expression. A total of 813 genes were differentially expressed. Functional terms significantly altered in response to infection include phosphoprotein, RNA binding and acetylation. Upregulation of cell cycle pathways indicates an increase in mitosis. Notably absent from differentially enriched functional categories are stress- and apoptosis-related functions. The comparison of the combined host-parasite transcriptome reveals that C. parvum gene expression is less diverse than the host cell transcriptome and is highly enriched for genes encoding ribosomal functions, such as ribosomal proteins. CONCLUSIONS: These results indicate that C. parvum infection significantly changes host biological functions and provide new insight into gene functions driving early C. parvum intracellular development. PMID- 29530088 TI - Investigations on the interplays between Schistosoma mansoni, praziquantel and the gut microbiome. AB - BACKGROUND: Schistosomiasis is a neglected tropical disease burdening millions of people. One drug, praziquantel, is currently used for treatment and control. Clinically relevant drug resistance has not yet been described, but there is considerable heterogeneity in treatment outcomes, ranging from cure to only moderate egg reduction rates. The objectives of this study are to investigate potential worm-induced dysbacteriosis of the gut microbiota and to assess whether a specific microbiome profile could influence praziquantel response. METHODS: Using V3 and V4 regions of 16S rRNA genes, we screened the gut microbiota of 34 Schistosoma mansoni infected and uninfected children from Cote d'Ivoire. From each infected child one pre-treatment, one 24-hour and one 21-day follow-up sample after administering 60 mg/kg praziquantel or placebo, were collected. RESULTS: Overall taxonomic profiling and diversity indicators were found to be close to a "healthy" gut structure in all children. Slight overall compositional changes were observed between S. mansoni-infected and non-infected children. Praziquantel treatment was not linked to a major shift in the gut taxonomic profiles, thus reinforcing the good safety profile of the drug by ruling out off targets effects on the gut microbes.16S rRNA gene of the Fusobacteriales order was significantly more abundant in cured individuals, both at baseline and 24 hours post-treatment. A real-time qPCR confirmed the over-abundance of Fusobacterium spp. in cured children. Fusobacterium spp. abundance could also be correlated with treatment induced S. mansoni egg-reduction. CONCLUSIONS: Our study suggests that neither a S. mansoni infection nor praziquantel administration triggers a significant effect on the microbial composition and that a higher abundance of Fusobacterium spp., before treatment, is associated with higher efficacy of praziquantel in the treatment of S. mansoni infections. TRIAL REGISTRATION: International Standard Randomised Controlled Trial, number ISRCTN15280205 . PMID- 29530090 TI - Adherence to standardized assessments through a complexity-based model for categorizing rehabilitation(c): design and implementation in an acute hospital. AB - BACKGROUND: The use of measurement instruments has become a major issue in physical therapy, but their use in daily practice is rare. The aim of this paper is to describe adherence to standardized assessments by physical therapists using a complexity-based model for categorizing rehabilitation (CMCR) at the Clinica Alemana of Santiago, an acute hospital in Chile. METHODS: This retrospective cohort study used 145,968 participant records that were stored in the inpatient database between July 2011 and December 2015. Adherence to the CMCR by 31 physical therapists working with intensive care unit (ICU) and non-ICU inpatients was assessed every quarter using the electronic patient records (EPR). This instrument (CMCR) linked clinical functional assessment to the degree of severity, thereby setting a score used to categorize patients as low, medium and high complexity. 96,400 instances of inpatient care where the physician recommended physical therapy were categorized. This was from a total of 145,968 instances of inpatient care recorded throughout the duration of the study (17 quarters). Trends in adherence were analyzed using a Prais-Winsten regression (a first-order autoregressive model). The trends were compared using a repeated measures ANOVA for mixed models with a significance level of 0.05. The use of the CMCR was included as one of the organization's quality indicators associated with the hospital's accreditation processes. RESULTS: Adherence increased by 1.48% every quarter (p = 0.005) for both ICU and non-ICU patients. On average, adherence with ICU patients was 16.98% greater than with non-ICU patients. Although adherence was always greater with ICU patients, the rate of increase with non-ICU patients was significantly greater: 1.62% (p = 0.007) vs. 1.28% (p = 0.003), respectively. CONCLUSION: The CMCR facilitated adherence to standardized assessments by physical therapists working with ICU and non-ICU inpatients in an acute hospital, while linking this instrument to the organization's quality management process proved to be an effective strategy for the duration of this study (17 quarters). PMID- 29530092 TI - Adaptation and assessments of the Chinese version of the ICECAP-A measurement. AB - BACKGROUND: This study adapts the ICECAP measure for Adults (ICECAP-A) to assess its capacity to measure the quality of life in China for economic evaluation. METHODS: Qualitative and quantitative methods were used to translate the ICECAP-A measure for wellbeing, established by the University of Birmingham, UK, to the Chinese cultural context. A focus group discussion solved the appropriateness and wording of the ICECAP attributes in Chinese; and a randomly selected sample of 1000 adults aged over 18 years were online surveyed. We conducted psychometric tests and compared the factors influencing the ICECAP-A measure with those influencing EQ-5D-3 L. RESULTS: Members of the focus group discussion agreed that the five attributes of the ICECAP-A measure are sufficient to evaluate wellbeing in China. However, the terms "being settled" and "friendship" were changed to "stability" and "kindness" for the Chinese cultural context. Our results show that the Chinese version of ICECAP-A has good internal consistency with an overall Cronbach's Alpha coefficient of 0.7999. The concurrent validity indicates that ICECAP-A is moderately correlated with EQ-5D-3 L (r <= 0.52). CONCLUSIONS: The ICECAP-A measure can be adapted to evaluate wellbeing in China, but cultural changes to the wording are necessary. It is a valid measurement of wellbeing and can complement the EQ-5D already used in China. However, further work is still needed to evaluate the sensitivity of the ICECAP-A measure in relation to public health and social care. PMID- 29530091 TI - Integrating palliative care in long-term care facilities across Europe (PACE): protocol of a cluster randomized controlled trial of the 'PACE Steps to Success' intervention in seven countries. AB - BACKGROUND: Several studies have highlighted the need for improvement in palliative care delivered to older people long-term care facilities. However, the available evidence on how to improve palliative care in these settings is weak, especially in Europe. We describe the protocol of the PACE trial aimed to 1) evaluate the effectiveness and cost-effectiveness of the 'PACE Steps to Success' palliative care intervention for older people in long-term care facilities, and 2) assess the implementation process and identify facilitators and barriers for implementation in different countries. METHODS: We will conduct a multi-facility cluster randomised controlled trial in Belgium, Finland, Italy, the Netherlands, Poland, Switzerland and England. In total, 72 facilities will be randomized to receive the 'Pace Steps to Success intervention' or to 'care as usual'. Primary outcome at resident level: quality of dying (CAD-EOLD); and at staff level: staff knowledge of palliative care (Palliative Care Survey). SECONDARY OUTCOMES: resident's quality of end-of-life care, staff self-efficacy, self-perceived educational needs, and opinions on palliative care. Economic outcomes: direct costs and quality-adjusted life years (QALYs). Measurements are performed at baseline and after the intervention. For the resident-level outcomes, facilities report all deaths of residents in and outside the facilities over a previous four month period and structured questionnaires are sent to (1) the administrator, (2) staff member most involved in care (3) treating general practitioner, and (4) a relative. For the staff-level outcomes, all staff who are working in the facilities are asked to complete a structured questionnaire. A process evaluation will run alongside the effectiveness evaluation in the intervention group using the RE-AIM framework. DISCUSSION: The lack of high quality trials in palliative care has been recognized throughout the field of palliative care research. This cross-national cluster RCT designed to evaluate the impact of the palliative care intervention for long-term care facilities 'PACE Steps to Success' in seven countries, will provide important evidence concerning the effectiveness as well as the preconditions for optimal implementation of palliative care in nursing homes, and this within different health care systems. TRIAL REGISTRATION: The study is registered at www.isrctn.com - ISRCTN14741671 (FP7-HEALTH-2013 INNOVATION-1 603111) Registration date: July 30, 2015. PMID- 29530093 TI - Femorotibial kinematics in dogs with cranial cruciate ligament insufficiency: a three-dimensional in-vivo fluoroscopic analysis during walking. AB - BACKGROUND: Cranial cruciate ligament (CrCL) insufficiency is a degenerative condition that is a common cause of pelvic limb lameness and osteoarthritis in dogs. Surgical therapies developed to treat dogs with naturally occurring CrCL insufficiency aim to address the resultant instability, but the in-vivo alterations in stifle kinematics associated with CrCL insufficiency have not been accurately defined. The objective of this study was to quantify the 3-dimensional femorotibial joint kinematics of dogs with naturally occurring cranial cruciate ligament (CrCL) insufficiency during ambulation. Eighteen client-owned dogs (20 40 kg) with natural unilateral complete CrCL rupture were included. Computed tomographic scans were used to create digital 3-dimensional models of the femur and tibia bilaterally for each dog. Lateral fluoroscopic images were obtained during treadmill walking and 3 complete gait cycles were analyzed. Stifle flexion/extension angle, craniocaudal translation, and internal/external rotation were calculated throughout the gait cycle using a previously described 3D-to-2D image registration process. Results were compared between the pre-operative CrCL deficient and 6-month post-operative contralateral stifles (control). RESULTS: CrCL-deficient stifles were maintained in greater flexion throughout the gait cycle. Cranial tibial subluxation was evident in CrCL-deficient stifles at all time points throughout the gait cycle [9.7 mm at mid-stance (P < 0.0001); 2.1 mm at mid-swing (P < 0.0017)], and the magnitude of cranial tibial subluxation was greater at mid-stance phase than at mid-swing phase (P < 0.0001). Greater internal tibial rotation was present in CrCL-deficient stifles during stance phase (P < 0.0022) but no difference in axial rotation was evident during swing phase. CONCLUSIONS: Naturally occurring CrCL rupture causes profound craniocaudal translational and axial rotational instability, which is most pronounced during the stance phase of gait. Surgical stabilization techniques should aim to resolve both craniocaudal subluxation and axial rotational instability. PMID- 29530094 TI - The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice. AB - BACKGROUND: Noise-induced hearing loss (NIHL) is the most prevalent form of acquired hearing loss and affects about 40 million US adults. Among the suggested therapeutics tested in rodents, suberoylanilide hydroxamic acid (SAHA) has been shown to be otoprotective from NIHL; however, these results were limited to male mice. METHODS: Here we tested the effect of SAHA on the hearing of 10-week-old B6CBAF1/J mice of both sexes, which were exposed to 2 h of octave-band noise (101 dB SPL centered at 11.3 kHz). Hearing was assessed by measuring auditory brainstem responses (ABR) at 8, 16, 24, and 32 kHz, 1 week before, as well as at 24 h and 15-21 days following exposure (baseline, compound threshold shift (CTS) and permanent threshold shift (PTS), respectively), followed by histologic analyses. RESULTS: We found significant differences in the CTS and PTS of the control (vehicle injected) mice to noise, where females had a significantly smaller CTS at 16 and 24 kHz (p < 0.0001) and PTS at 16, 24, and 32 kHz (16 and 24 kHz p < 0.001, 32 kHz p < 0.01). This sexual dimorphic effect could not be explained by a differential loss of sensory cells or synapses but was reflected in the amplitude and amplitude progression of wave I of the ABR, which correlates with outer hair cell (OHC) function. Finally, the frequency of the protective effect of SAHA differed significantly between males (PTS, 24 kHz, p = 0.002) and females (PTS, 16 kHz, p = 0.003), and the magnitude of the protection was smaller in females than in males. Importantly, the magnitude of the protection by SAHA was smaller than the effect of sex as a biological factor in the vehicle-injected mice. CONCLUSIONS: These results indicate that female mice are significantly protected from NIHL in comparison to males and that therapeutics for NIHL may have a different effect in males and females. The data highlight the importance of analyzing NIHL experiments from males and females, separately. Finally, these data also raise the possibility of effectors in the estrogen signaling pathway as novel therapeutics for NIHL. PMID- 29530095 TI - Identification of matrix metalloproteinase-2 and -9 activities within the intestinal mucosa of dogs with chronic enteropathies. AB - BACKGROUND: Matrix metalloproteinases (MMPs) 2 and 9 are zinc- and calcium dependent endopeptidases involved in the breakdown and reconstitution of extracellular matrix under both physiological and pathological conditions. Mucosal MMP-2 and -9 activities have been reported to be upregulated in the intestine of humans with inflammatory bowel disease (IBD), and in animal models of IBD. However, their involvement in the pathogenesis of canine chronic enteropathies (CE) is unknown. This study investigated mucosal pro- and active MMP-2 and -9 activities in dogs with CE and healthy dogs using gelatin zymography, and also to determine the association of their activities in dogs with CE with the canine IBD activity index (CIBDAI), histopathologic findings, the clinical outcome, and hypoalbuminemia. Intestinal mucosal samples from duodenum, ileum, colon, and cecum were collected from 40 dogs with CE and 18 healthy Beagle dogs. RESULTS: In dogs with CE, the number of samples positive for mucosal pro- and active MMP-2 was significantly higher in the duodenum (P < 0.0001 and P = 0.011, respectively), ileum (P = 0.002 and P = 0.018, respectively), and colon (P < 0.0001 and P = 0.002, respectively), compared with healthy controls. Mucosal pro-MMP-9-positive samples in the duodenum and colon were significantly more frequent in dogs with CE than in healthy dogs (P = 0.0004 and P = 0.001, respectively). Despite the presence of mucosal samples positive for active MMP-9 in the intestinal segments of dogs with CE, the difference compared to healthy controls did not reach statistical significance. None of the intestinal mucosal samples in healthy dogs showed gelatinolytic activity corresponding to the control bands of active MMP-2 and -9. Mucosal active MMP-9 activities displayed a significant positive association with the severity of neutrophil infiltration in the duodenum (P = 00.040), eosinophils in the cecum (P = 00.037), and the CIBDAI score for ileum samples (P = 0.023). There was no significant association of pro- and active MMP-2 and -9 levels with the clinical outcome or hypoalbuminemia. CONCLUSIONS: This study is the first to demonstrate upregulation of mucosal pro- and active MMP-2 and pro-MMP-9 in the intestine of dogs with CE compared to healthy dogs. The results provide supporting evidence for the possible involvement of MMP-2 and -9 in the pathogenesis of canine CE. PMID- 29530096 TI - Laparoscopic and endoscopic cooperative surgery for intra-mucosal gastric carcinoma adjacent to the ulcer scars. AB - BACKGROUND: Laparoscopic and endoscopic cooperative surgery (LECS) was performed for the local resection of gastrointestinal stromal tumors (GIST). LECS enables less resection of the lesion area and preserves function. Furthermore, LECS can be safely performed and independent of tumor location. However, LECS is not usually used for cases involving gastric carcinoma because it may seed tumor cells into the peritoneal cavity when the gastric wall is perforated. Here, we report seven cases of LECS for intra-mucosal gastric carcinoma, which were difficult to carry out by endoscopic submucosal dissection (ESD) because of ulcer scars. METHODS: We performed LECS (classical LECS and inverted LECS) in seven cases of intra-mucosal gastric carcinoma. All cases had ulcer scars beside the tumor. LECS was chosen because ESD was thought to be difficult because of the ulcer scars. We only selected cases in which the patients did not prefer gastrectomy and endoscopic examination was indicative of intra-mucosal gastric carcinoma. RESULTS: In all cases, LECS was performed without severe complications including postoperative stenosis. Histopathology findings proved that the tumors were intra-mucosal carcinoma and had been resected completely. Furthermore, there were ulcer scars (Ul IIIs-IVs) beside the tumor. Currently, dissemination and recurrence have not been apparent. CONCLUSIONS: LECS for intra-mucosal gastric carcinoma is an efficient procedure, but strict observation is necessary because of the possibility of peritoneal dissemination. Results suggest that LECS is likely to be effective for cases involving intra-mucosal gastric carcinoma that are difficult to treat by ESD due to ulcer scars. PMID- 29530097 TI - Technology-assisted title and abstract screening for systematic reviews: a retrospective evaluation of the Abstrackr machine learning tool. AB - BACKGROUND: Machine learning tools can expedite systematic review (SR) processes by semi-automating citation screening. Abstrackr semi-automates citation screening by predicting relevant records. We evaluated its performance for four screening projects. METHODS: We used a convenience sample of screening projects completed at the Alberta Research Centre for Health Evidence, Edmonton, Canada: three SRs and one descriptive analysis for which we had used SR screening methods. The projects were heterogeneous with respect to search yield (median 9328; range 5243 to 47,385 records; interquartile range (IQR) 15,688 records), topic (Antipsychotics, Bronchiolitis, Diabetes, Child Health SRs), and screening complexity. We uploaded the records to Abstrackr and screened until it made predictions about the relevance of the remaining records. Across three trials for each project, we compared the predictions to human reviewer decisions and calculated the sensitivity, specificity, precision, false negative rate, proportion missed, and workload savings. RESULTS: Abstrackr's sensitivity was > 0.75 for all projects and the mean specificity ranged from 0.69 to 0.90 with the exception of Child Health SRs, for which it was 0.19. The precision (proportion of records correctly predicted as relevant) varied by screening task (median 26.6%; range 14.8 to 64.7%; IQR 29.7%). The median false negative rate (proportion of records incorrectly predicted as irrelevant) was 12.6% (range 3.5 to 21.2%; IQR 12.3%). The workload savings were often large (median 67.2%, range 9.5 to 88.4%; IQR 23.9%). The proportion missed (proportion of records predicted as irrelevant that were included in the final report, out of the total number predicted as irrelevant) was 0.1% for all SRs and 6.4% for the descriptive analysis. This equated to 4.2% (range 0 to 12.2%; IQR 7.8%) of the records in the final reports. CONCLUSIONS: Abstrackr's reliability and the workload savings varied by screening task. Workload savings came at the expense of potentially missing relevant records. How this might affect the results and conclusions of SRs needs to be evaluated. Studies evaluating Abstrackr as the second reviewer in a pair would be of interest to determine if concerns for reliability would diminish. Further evaluations of Abstrackr's performance and usability will inform its refinement and practical utility. PMID- 29530098 TI - Identification and genetic characterization of Sarcocystis arctica and Sarcocystis lutrae in red foxes (Vulpes vulpes) from Baltic States and Spain. AB - BACKGROUND: Typically, carnivores serve as definitive hosts for Sarcocystis spp. parasites; currently, their role as intermediate hosts is being elucidated. The present study aimed to identify and molecularly characterize Sarcocystis cysts detected in striated muscle of red foxes from different populations in Latvia, Lithuania and Spain. METHODS: Muscle samples from 411 red foxes (Vulpes vulpes) and 269 racoon dogs (Nyctereutes procyonoides) from Latvia, 41 red foxes from Lithuania and 22 red foxes from Spain were examined for the presence of Sarcocystis sarcocysts by light microscopy (LM). Sarcocystis spp. were identified by transmission electron microscopy (TEM) and molecular biology techniques. RESULTS: Sarcocystis cysts were detected in 11/411 (2.7%) Latvian, 3/41 (7.3%) Lithuanian, and 6/22 (27.3%) Spanish red foxes, however, cysts were not observed in the muscles of racoon dogs. Based on LM, TEM, 18S rDNA, 28S rDNA, ITS1, cox1 and rpoB sequences, Sarcocystis arctica and Sarcocystis lutrae cysts were identified in red fox muscles from Latvia and Lithuania, whereas only S. arctica was detected in Spain. The 18S rDNA, 28S rDNA and ITS1 sequences from the 21 isolates of S. arctica from Latvia, Lithuania and Spain were identical. By contrast, two and four haplotypes were determined based on mtDNA cox1 and apicoplast rpoB sequences, respectively. Polymorphisms were not detected between the two isolates of S. lutrae from Latvia and Lithuania. Based on phylogenetic results, S. arctica and S. lutrae were most closely related to Sarcocystis spp. using predatory mammals as intermediate hosts and to Sarcocystis species with a bird-bird life-cycle. CONCLUSIONS: Based on current knowledge, the red fox and Arctic fox (Vulpes lagopus) could act as intermediate host for the same two Sarcocystis species. Molecular results suggest the existence of two genetic lineages of S. arctica, and such divergence relies on its geographical distribution but not on their intermediate host species. PMID- 29530099 TI - Protection induced by a gp90 protein-based vaccine derived from a Reticuloendotheliosis virus strain isolated from a contaminated IBD vaccine. AB - BACKGROUND: Reticuloendotheliosis is an immunosuppressive disease caused by avian reticuloendotheliosis virus (REV). It is commonly found in poultry farms and has caused a notable economic loss worldwide. Despite this, there is currently no effective vaccine available to protect against REV infection. METHOD: In this study, gp90 protein derived from an REV isolated from a contaminated vaccine was co-administered with cytosine-phosphate-guanine oligodeoxynucleotide (CpG-ODN) adjuvant to hens to determine if it protects their chicks against REV infection. To synthesize the gp90 protein, the gp90 gene was amplified using polymerase chain reaction, expressed in Escherichia coli, and purified. The resulting recombinant protein was injected intramuscularly into breeder hens along with CpG ODN adjuvant and then serum antibody levels were regularly evaluated. After the fertilized eggs from these vaccinated hens had hatched, the resulting chicks were challenged with a 102.7 50% tissue culture infectious dose (TCID50) of REV at 1 day old and the REV antibody levels in these hatched chickens were evaluated before and after the challenge. Viremia and growth rate were measured weekly and statistically analyzed. RESULTS: The results suggest that the gp90 recombinant protein was successfully prepared and, when used with CpG-ODN adjuvant to immunize breeder hens, induced serological antibody production against REV in both hens and their hatched chicks. In addition, the maternal antibodies induced by the gp90 protein vaccine effectively protected majority of the chicks from REV infection. CONCLUSIONS: Overall, we found the gp90 protein obtained in this study may be a potential vaccine candidate that had good immunogenicity and could be an auxiliary measure to accelerate the eradication of REV. PMID- 29530100 TI - Prevalence of Plasmodium falciparum delayed clearance associated polymorphisms in adaptor protein complex 2 mu subunit (pfap2mu) and ubiquitin specific protease 1 (pfubp1) genes in Ghanaian isolates. AB - BACKGROUND: Plasmodium falciparum delayed clearance with the use of artemisinin based combination therapy (ACTs) has been reported in some African countries. Single nucleotide polymorphisms (SNPs) in two genes, P. falciparum adaptor protein complex 2 mu subunit (pfap2mu) and ubiquitin specific protease 1 (pfubp1), have been linked to delayed clearance with ACT use in Kenya and recurrent imported malaria in Britain. With over 12 years of ACT use in Ghana, this study investigated the prevalence of SNPs in the pfap2mu and pfubp1 in Ghanaian clinical P. falciparum isolates to provide baseline data for antimalarial drug resistance surveillance in the country. METHODS: Filter paper blood blots collected in 2015-2016 from children aged below 9 years presenting with uncomplicated malaria at hospitals in three sentinel sites Begoro, Cape Coast and Navrongo were used. Parasite DNA was extracted from 120 samples followed by nested polymerase chain reaction (nPCR). Sanger sequencing was performed to detect and identify SNPs in pfap2mu and pfubp1 genes. RESULTS: In all, 11.1% (9/81) of the isolates carried the wildtype genotypes for both genes. A total of 164 pfap2mu mutations were detected in 67 isolates whilst 271 pfubp1 mutations were observed in 72 isolates. The majority of the mutations were non synonymous (NS): 78% (128/164) for pfap2mu and 92.3% (250/271) for pfubp1. Five unique samples had a total of 215 pfap2mu SNPs, ranging between 15 and 63 SNPs per sample. Genotypes reportedly associated with ART resistance detected in this study included pfap2mu S160N (7.4%, 6/81) and pfubp1 E1528D (7.4%, 6/81) as well as D1525E (4.9%, 4/81). There was no significant difference in the prevalence of the SNPs between the three ecologically distinct study sites (pfap2mu: chi2 = 6.905, df = 2, P = 0.546; pfubp1: chi2 = 4.883, df = 2, P = 0.769). CONCLUSIONS: The detection of pfap2mu and pfubp1 genotypes associated with ACT delayed parasite clearance is evidence of gradual nascent emergence of resistance in Ghana. The results will serve as baseline data for surveillance and the selection of the genotypes with drug pressure over time. The pfap2mu S160N, pfubp1 E1528D and D1525E must be monitored in Ghanaian isolates in ACT susceptibility studies, especially when cure rates of ACTs, particularly AL, is less than 100%. PMID- 29530101 TI - Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma. AB - BACKGROUND: Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). METHODS: The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ctDNA was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease. RESULTS: RAS/RAF mutations were detected in the plasma from 77 patients. Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of mutated DNA in plasma was correlated with poor overall survival. A low level of ctDNA after the first cycle of chemotherapy was associated with a low risk of progression. On the other hand, a significant increase of ctDNA at any time during the treatment course was associated with a high risk of progression on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. CONCLUSIONS: The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated with a prolonged progression free interval, whereas a significant increase gave notice of early progression with a relevant lead time. PMID- 29530102 TI - The role of metalloproteases in Leishmania species infection in the New World: a systematic review. AB - This is a systematic review on the role of metalloproteases in the pathogenicity of the American tegumentary leishmaniasis (ATL) caused by New World Leishmania species. The review followed the PRISMA method, searching for articles in PubMed, EMBASE, LILACS and ISI Web of Science, by employing the following terms: 'leishmaniasis', 'cutaneous leishmaniasis', 'mucocutaneous leishmaniasis', 'diffuse cutaneous leishmaniasis', 'Leishmania' and 'metalloproteases'. GP63 of New World Leishmania species is a parasite metalloproteases involved in the degradation and cleavage of many biological molecules as kappa-B nuclear factor, fibronectin, tyrosine phosphatases. GP63 is capable of inhibiting the activity of the complement system and reduces the host's immune functions, allowing the survival of the parasite and its dissemination. High serological/tissue levels of host matrix metalloproteases (MMP)-9 have been associated with tissue damage during the infection, while high transcriptional levels of MMP-2 related with a satisfactory response to treatment. Host MMPs serological and tissue levels have been investigated using Western Blot, zymography, and Real Time polymerase chain reaction. GP63 detection characterizes species and virulence in promastigotes isolated from lesions samples using techniques mentioned previously. The monitoring of host MMPs levels and GP63 in Leishmania isolated from host samples could be used on the laboratory routine to predict the prognostic and treatment efficacy of ATL. PMID- 29530103 TI - Proximity to parasites reduces host fitness independent of infection in a Drosophila-Macrocheles system. AB - Parasites are known to have direct negative effects on host fitness; however, the indirect effects of parasitism on host fitness sans infection are less well understood. Hosts undergo behavioural and physiological changes when in proximity to parasites. Yet, there is little experimental evidence showing that these changes lead to long-term decreases in host fitness. We aimed to determine if parasite exposure affects host fitness independent of contact, because current approaches to parasite ecology may underestimate the effect of parasites on host populations. We assayed the longevity and reproductive output of Drosophila nigrospiracula exposed or not exposed to ectoparasitic Macrocheles subbadius. In order to preclude contact and infection, mites and flies were permanently separated with a mesh screen. Exposed flies had shorter lives and lower fecundity relative to unexposed flies. Recent work in parasite ecology has argued that parasite-host systems show similar processes as predator-prey systems. Our findings mirror the non-consumptive effects observed in predator-prey systems, in which prey species suffer reduced fitness even if they never come into direct contact with predators. Our results support the perspective that there are analogous effects in parasite-host systems, and suggest new directions for research in both parasite ecology and the ecology of fear. PMID- 29530104 TI - The association between school exam grades and subsequent development of bipolar disorder. AB - OBJECTIVE: Prior studies have indicated that both high and low school grades are associated with development of bipolar disorder (BD), but these studies have not adjusted for parental history of mental disorder, which is a likely confounder. Furthermore, the association between school grades and bipolar I disorder (BD-I) has not been studied. Therefore, we aimed to study the association between school exam grades and subsequent development of BD and BD-I while adjusting for parental history of mental disorder. METHODS: We conducted a register-based nationwide cohort study following 505 688 individuals born in Denmark between 1987 and 1995. We investigated the association between school exam grades and development of BD or BD-I with a Cox model adjusting for family history of mental disorder and other potential confounders. RESULTS: During follow-up, 900 individuals were diagnosed with BD and 277 of these with BD-I. The risk for BD and BD-I was significantly increased for individuals not having completed the exams at term [adjusted hazard ratio (aHR) for BD (aHR=1.71, 95% CI: 1.43-2.04) and for BD-I (aHR=1.57, 95% CI: 1.13-2.19)]. Also, having low exam grades in mathematics was associated with increased risk of both BD (aHR=2.41, 95% CI: 1.27 4.59) and BD-I (aHR=2.71, 95% CI: 1.41-5.21). Females with very high exam grades in Danish (percentile group>97.7) had a significantly increased risk of BD-I (aHR=2.49, 95% CI: 1.19-5.23). CONCLUSIONS: The potential to develop BD seems to affect the school results of individuals negatively even before BD is diagnosed - with females having the potential to develop BD-I as a possible exception. PMID- 29530105 TI - A Descriptive Analysis of Care Provided by Law Enforcement Prior to EMS Arrival in the United States. AB - : Study Objectives Law enforcement is increasingly viewed as a key component in the out-of-hospital chain of survival, with expanded roles in cardiac arrest, narcotic overdose, and traumatic bleeding. Little is known about the nature of care provided by law enforcement prior to the arrival of Emergency Medical Services (EMS) assets. The purpose of the current study was to perform a descriptive analysis of events reported to a national EMS database. METHODS: This study was a descriptive analysis of the 2014 National Emergency Medical Services Information System (NEMSIS) public release research data set, containing EMS emergency response data from 41 states. Code E09_02 1200 specifically identifies care provided by law enforcement prior to EMS arrival. RESULTS: A total of 25,835,729 unique events were reported. Of events in which pre-arrival care was documented, 2.0% received prior aid by law enforcement. Patients receiving law enforcement care prior to EMS arrival were more likely to be younger (52.8 [SD=23.3] years versus 58.7 [SD=23.3] years), male (54.8% versus 46.7%), and white (80.3% versus 77.5%). Basic Life Support (BLS) EMS response was twice as likely in patients receiving prior aid by law enforcement. Multiple-casualty incidents were five times more likely with prior aid by law enforcement. Compared with prior aid by other services, law enforcement pre-arrival care was more likely with motor vehicle accidents, firearm assaults, knife assaults, blunt assaults, and drug overdoses, and less likely at falls and childbirths. Cardiac arrest was significantly more common in patients receiving prior aid by law enforcement (16.5% versus 2.6%). Tourniquet application and naloxone administration were more common in the law enforcement prior aid group. CONCLUSION: Where noted, law enforcement pre-arrival care occurs in 2.0% of EMS patient encounters. The majority of cases involve cardiac arrest, motor vehicle accidents, and assaults. Better understanding of the nature of law enforcement care is required in order to identify potential barriers to care and to develop appropriate training and policy recommendations. Klassen AB , Core SB , Lohse CM , Sztajnkrycer MD . A descriptive analysis of care provided by law enforcement prior to EMS arrival in the United States. Prehosp Disaster Med. 2018;33(2):165 170. PMID- 29530106 TI - Molecular identification of potential intermediate hosts of Aulonocephalus pennula from the order Orthoptera. AB - Aulonocephalus pennula is a heteroxenous nematode that commonly infects a declining game bird, the northern bobwhite quail (Colinus virginianus). There is a lack of information on the life cycle of A. pennula and the potential effects of infection on bobwhites. In order to better understand the life cycle of this parasite, various species from the order Orthoptera were collected from a field site in Mitchell County, Texas. Using polymerase chain reaction (PCR), nine potential intermediate hosts were identified from the 35 orthopteran species collected. Later, ten live specimens were collected to identify larvae within the potential intermediate hosts. Larvae were present in three of these and were sent for sequencing. Similarly, the presence of larvae was confirmed from extra tissues of samples identified as positive with PCR. This was the first study to document potential intermediate hosts, but future studies are needed to confirm that these species are capable of transmitting infection to bobwhite. However, this study demonstrates that PCR has increased sensitivity and may be a valuable tool when determining intermediate hosts. PMID- 29530107 TI - Effects of an Appearance-Focused Interpretation Training Intervention on Eating Disorder Symptoms. AB - BACKGROUND: Previous research suggests that computerized interpretation bias modification (IBM) techniques may be useful for modifying thoughts and behaviours relevant to eating pathology; however, little is known about the utility of IBM for decreasing specific eating disorder (ED) symptoms (e.g. bulimia, drive for thinness). AIMS: The current study sought to further examine the utility of IBM for ED symptoms via secondary analyses of an examination of IBM for individuals with elevated body dysmorphic disorder (BDD) symptoms (see Summers and Cougle, 2016), as these disorders are both characterized by threat interpretation biases of ambiguous appearance-related information. METHOD: We recruited 41 participants for a randomized trial comparing four sessions of IBM aimed at modifying problematic social and appearance-related threat interpretation biases with a placebo control training (PC). RESULTS: At 1-week post-treatment, and relative to the PC, the IBM group reported greater reductions in negative/threat interpretations of ambiguous information in favour of positive/benign biases. Furthermore, among individuals with high pre-treatment bulimia symptoms, IBM yielded greater reductions in bulimia symptoms compared with PC at post treatment. No treatment effects were observed on drive for thinness symptoms. CONCLUSIONS: The current study suggests that cognitive interventions for individuals with primary BDD symptoms may improve co-occurring ED symptoms such as bulimia. PMID- 29530108 TI - Long-term effects of stimulant treatment on ADHD symptoms, social-emotional functioning, and cognition. AB - BACKGROUND: Methodological and ethical constraints have hampered studies into long-term lasting outcomes of stimulant treatment in individuals with attention deficit/hyperactivity disorder (ADHD). Lasting effects may be beneficial (i.e. improved functioning even when treatment is temporarily ceased) or detrimental (i.e. worse functioning while off medication), but both hypotheses currently lack empirical support. Here we investigate whether stimulant treatment history predicts long-term development of ADHD symptoms, social-emotional functioning or cognition, measured after medication wash-out. METHODS: ADHD symptoms, social emotional functioning and cognitive test performance were measured twice, 6 years apart, in two ADHD groups (stimulant-treated versus not stimulant-treated between baseline and follow-up). Groups were closely matched on baseline clinical and demographic variables (n = 148, 58% male, age = 11.1). A matched healthy control group was included for reference. RESULTS: All but two outcome measures (emotional problems and prosocial behaviour) improved between baseline and follow up. Improvement over time in the stimulant-treated group did not differ from improvement in the not stimulant-treated group on any outcome measure. CONCLUSIONS: Stimulant treatment is not associated with the long-term developmental course of ADHD symptoms, social-emotional functioning, motor control, timing or verbal working memory. Adolescence is characterised by clinical improvement regardless of stimulant treatment during that time. These findings are an important source to inform the scientific and public debate. PMID- 29530109 TI - The Nature of Nurture: Using a Virtual-Parent Design to Test Parenting Effects on Children's Educational Attainment in Genotyped Families. AB - Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (beta = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (beta = 0.20), and parental SES and offspring EA were significantly associated (beta = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry. PMID- 29530111 TI - Celebrating the 40th anniversary of the Italian Mental Health reform. PMID- 29530110 TI - Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design. AB - BACKGROUND: The genetic component of Cannabis Use Disorder may overlap with influences acting more generally on early stages of cannabis use. This paper aims to determine the extent to which genetic influences on the development of cannabis abuse/dependence are correlated with those acting on the opportunity to use cannabis and frequency of use. METHODS: A cross-sectional study of 3303 Australian twins, measuring age of onset of cannabis use opportunity, lifetime frequency of cannabis use, and lifetime DSM-IV cannabis abuse/dependence. A trivariate Cholesky decomposition estimated additive genetic (A), shared environment (C) and unique environment (E) contributions to the opportunity to use cannabis, the frequency of cannabis use, cannabis abuse/dependence, and the extent of overlap between genetic and environmental factors associated with each phenotype. RESULTS: Variance components estimates were A = 0.64 [95% confidence interval (CI) 0.58-0.70] and E = 0.36 (95% CI 0.29-0.42) for age of opportunity to use cannabis, A = 0.74 (95% CI 0.66-0.80) and E = 0.26 (95% CI 0.20-0.34) for cannabis use frequency, and A = 0.78 (95% CI 0.65-0.88) and E = 0.22 (95% CI 0.12 0.35) for cannabis abuse/dependence. Opportunity shares 45% of genetic influences with the frequency of use, and only 17% of additive genetic influences are unique to abuse/dependence from those acting on opportunity and frequency. CONCLUSIONS: There are significant genetic contributions to lifetime cannabis abuse/dependence, but a large proportion of this overlaps with influences acting on opportunity and frequency of use. Individuals without drug use opportunity are uninformative, and studies of drug use disorders must incorporate individual exposure to accurately identify aetiology. PMID- 29530112 TI - The risk of developing major depression among individuals with subthreshold depression: a systematic review and meta-analysis of longitudinal cohort studies. AB - BACKGROUND: Studies have consistently shown that subthreshold depression is associated with an increased risk of developing major depression. However, no study has yet calculated a pooled estimate that quantifies the magnitude of this risk across multiple studies. METHODS: We conducted a systematic review to identify longitudinal cohort studies containing data on the association between subthreshold depression and future major depression. A baseline meta-analysis was conducted using the inverse variance heterogeneity method to calculate the incidence rate ratio (IRR) of major depression among people with subthreshold depression relative to non-depressed controls. Subgroup analyses were conducted to investigate whether IRR estimates differed between studies categorised by age group or sample type. Sensitivity analyses were also conducted to test the robustness of baseline results to several sources of study heterogeneity, such as the case definition for subthreshold depression. RESULTS: Data from 16 studies (n = 67 318) revealed that people with subthreshold depression had an increased risk of developing major depression (IRR = 1.95, 95% confidence interval 1.28-2.97). Subgroup analyses estimated similar IRRs for different age groups (youth, adults and the elderly) and sample types (community-based and primary care). Sensitivity analyses demonstrated that baseline results were robust to different sources of study heterogeneity. CONCLUSION: The results of this study support the scaling up of effective indicated prevention interventions for people with subthreshold depression, regardless of age group or setting. PMID- 29530113 TI - [Application of real world study in neonatal medicine]. AB - Real world study (RWS) has attracted more and more attention of neonatologists since it involves less clinical intervention and is closer to actual clinical conditions. Generally speaking, RWS means to select treatment measures based on the internal efficacy and safety verified by randomized controlled trials (RCTs), more representative samples, and patients' actual conditions and their guardians' will and conduct follow-up evaluation of short- and long-term outcomes, in order to further evaluate the external efficacy and safety of interventional measures. Most guidelines for clinical practice are based on RCTs and lack the support of real world data. Strengthening of neonatal RWS helps to make these guidelines more practical and thus promotes the development of neonatal medicine. PMID- 29530114 TI - [Risk factors for elevated serum total bile acid in preterm infants]. AB - OBJECTIVE: To study the risk factors for elevated serum total bile acid (TBA) in preterm infants. METHODS: A retrospective analysis was performed for the clinical data of 216 preterm infants who were admitted to the neonatal intensive care unit. According to the presence or absence of elevated TBA (TBA >24.8 MUmol/L), the preterm infants were divided into elevated TBA group with 53 infants and non elevated TBA group with 163 infants. A univariate analysis and an unconditional multivariate logistic regression analysis were used to investigate the risk factors for elevated TBA. RESULTS: The univariate analysis showed that there were significant differences between the elevated TBA group and the non-elevated TBA group in gestational age at birth, birth weight, proportion of small-for gestational-age infants, proportion of infants undergoing ventilator-assisted ventilation, fasting time, parenteral nutrition time, and incidence of neonatal respiratory failure and sepsis (P<0.05). The unconditional multivariate logistic regression analysis showed that low birth weight (OR=3.84, 95%CI: 1.53-9.64) and neonatal sepsis (OR=2.56, 95%CI: 1.01-6.47) were independent risk factors for elevated TBA in preterm infants. CONCLUSIONS: Low birth weight and neonatal sepsis may lead to elevated TBA in preterm infants. PMID- 29530115 TI - [Relationship between vitamin D deficiency and necrotizing enterocolitis in preterm infants]. AB - OBJECTIVE: To evaluate the relationship of vitamin D level with the development of necrotizing enterocolitis (NEC) in preterm infants. METHODS: A total of 429 preterm infants with a gestational age of <36 weeks, who were admitted to the department of neonatology within 2 hours after birth between January and December, 2016, were enrolled in the study. According to whether these infants developed NEC, the 429 subjects were divided into NEC group (n=22) and non-NEC group (n=407). Peripheral venous blood was collected from these preterm infants and their mothers at admission to measure the level of 25-hydroxyvitamin D (25 OHD). The two groups were compared in terms of the serum 25-OHD levels of preterm infants and their mothers. Pearson correlation analysis was used to investigate the correlation between the serum 25-OHD levels of preterm infants and their mothers. The distribution of vitamin D levels in preterm infants was compared between the two groups. The univariate logistic regression analysis was used to determine the risk factors for NEC in preterm infants. RESULTS: The serum 25-OHD levels of preterm infants and their mothers in the NEC group were significantly lower than in the non-NEC group (P<0.001). In both groups, the serum 25-OHD levels of mothers and preterm infants were positively correlated with each other (P<0.001). The distribution of vitamin D levels (normal vitamin D level, low vitamin D level, vitamin D deficiency, and severe vitamin D deficiency) was significantly different between the NEC and non-NEC groups (P<0.001). The univariate logistic regression analysis showed that gestational age, birth weight, 25-OHD levels of preterm infants and their mothers, the duration of mechanical ventilation, the duration of oxygen inhalation, and the length of hospital stay were associated with the development of NEC (P<0.05). CONCLUSIONS: The serum 25-OHD levels of preterm infants and their mothers may be related to the development of NEC in preterm infants, suggesting that vitamin D supplementation during pregnancy is important for preventing the development of NEC in preterm infants. PMID- 29530116 TI - [Differences in intrauterine growth levels between full-term neonates born to primiparous or multiparous women]. AB - OBJECTIVE: To establish the intrauterine growth percentile curves of full-term neonates with different gestational ages (GAs) born to primiparous or multiparous women, and to investigate the influence of parity on intrauterine growth potential. METHODS: Cross-sectional cluster sampling was performed from April 2013 to September 2015 to measure physical growth in full-term singleton infants with a GA of 37-41 weeks in two hospitals in Shenzhen, China. The Lambda-Mu-Sigma method was used for curve fitting. RESULTS: The mean values of birth weight, body length, head circumference, chest circumference, and crown-rump length were obtained in 14 529 full-term infants. The 10th, 25th, 50th, 75th, and 90th percentile curves of the five indices were established. The full-term infants born to multiparous women had similar patterns and growth trends of the five percentile curves of the above five indices to those born to primiparous women, while the full-term infants with a GA of 37-41 weeks born to multiparous women had higher mean values and percentile curve values of the above five indices than those born to primiparous women. In the group with a GA of 41 weeks, there was no significant difference in the crown-rump length between the infants born to primiparous women and those born to multiparous women, but there were significant differences in the means of the above five indices in all the other GA groups between the two group infants (P<0.05). CONCLUSIONS: Full-term infants with a GA of 37-41 weeks born to multiparous women have higher intrauterine growth levels of birth weight, body length, head circumference, chest circumference, and crown rump length than those born to primiparous women, suggesting that parity is an important influencing factor for intrauterine growth potential. PMID- 29530117 TI - [An assessment of nutritional status in children on maintenance hemodialysis due to stage 5 chronic kidney disease]. AB - OBJECTIVE: To investigate the nutritional status of children on maintenance hemodialysis due to stage 5 chronic kidney disease (CKD) and the clinical significance of nutritional assessment indices. METHODS: A total of 21 children on maintenance hemodialysis due to stage 5 CKD were grouped according to body mass index. The nutritional status was assessed based on anthropometric parameters, biochemical parameters, inflammatory factors, residual renal function, indices of dialysis adequacy, and resting energy expenditure. Related indices were compared between the children with malnutrition and those with normal nutritional status. RESULTS: Of the 21 children, 10 had malnutrition and 11 had normal nutritional status. There were significant differences between the two groups in anthropometric parameters, levels of leptin, insulin-like growth factor-1, interleukin-1, interleukin-6, and tumor necrosis factor-alpha, and mean 24-hour residual urine volume (P<0.05), while there were no significant differences in albumin, prealbumin, CONCLUSIONS: urea clearance index (Kt/V), and measured resting energy expenditure. CONCLUSIONS: Anthropometric parameters, biochemical parameters, residual renal function, and inflammatory factors have an important value in evaluating the nutritional status of children with stage 5 CKD on maintenance hemodialysis. Further studies are needed to investigate the value of the measurement of resting energy expenditure in the evaluation and monitoring of nutritional status in children with stage 5 CKD on maintenance hemodialysis. PMID- 29530118 TI - [Current status of vitamin A deficiency in preschool children in Dongguan, China and the effect of vitamin A on serum ferritin and red blood cell parameters]. AB - OBJECTIVE: To investigate the current status of vitamin A deficiency in preschool children in Dongguan, China, as well as the effect of vitamin A on serum ferritin, red blood cell, and reticulocyte parameters. METHODS: Cluster sampling was performed from April 2015 to December 2016 to select 2 085 preschool children (3-6 years old) without any disease in Dongguan. Routine blood test, reticulocyte count, serum ferritin measurement, hemoglobin electrophoresis, and vitamin A measurement were performed for all children. The associations of age and sex with vitamin A and serum ferritin concentrations were analyzed. The effect of vitamin A concentration on serum ferritin, red blood cell, and reticulocyte parameters and the effect of reduced iron storage caused by vitamin A deficiency on red blood cell parameters were evaluated. RESULTS: Of the 2 085 children, 140 (6.71%) had reduced iron storage, and 678 (32.52%) had vitamin A deficiency. Among the 678 children with vitamin A deficiency, 647 (95.4%) had subclinical deficiency and 31 (4.6%) had clinical deficiency. There was no significant difference in vitamin A concentration between boys and girls, however girls had a significantly higher serum ferritin concentration than boys (P<0.05). The clinical vitamin A deficiency group had a significantly higher serum ferritin concentration than the subclinical vitamin A deficiency group and the normal group (P<0.05). In cases of vitamin A deficiency, the reduced iron storage group had significant reductions in mean corpuscular volume and mean corpuscular hemoglobin than the normal iron storage group (P<0.05). Compared with the normal vitamin A group, the vitamin A deficiency group had significantly lower hemoglobin concentration, mean corpuscular hemoglobin, red blood cell count, hematocrit, absolute reticulocyte count, reticulocyte percentage, and reticulocyte hemoglobin content, as well as a significantly higher mean corpuscular volume (P<0.05). CONCLUSIONS: Vitamin A deficiency is prevalent in preschool children in Dongguan, China, and it may adversely affect serum ferritin, red blood cell, and reticulocyte parameters. PMID- 29530119 TI - [Clinical features of Enterococcus faecium meningitis in children]. AB - OBJECTIVE: To summarize the clinical features of Enterococcus faecium meningitis in children. METHODS: The clinical data of nine children with Enterococcus faecium meningitis were analyzed. RESULTS: In all the nine children, Enterococcus faecium was isolated from blood, cerebrospinal fluid, or peripherally inserted central catheters; 6 (67%) patients were neonates, 2 (22%) patients were younger than 6 months, and 1 (11%) patient was three years and four months of age. In those patients, 56% had high-risk factors before onset, which included intestinal infection, resettlement of drainage tube after surgery for hydrocephalus, skull fracture, perinatal maternal infection history, and catheter-related infection. The main symptoms were fever and poor response. In those patients, 22% had seizures; no child had meningeal irritation sign or disturbance of consciousness. The white blood cell count and level of C-reactive protein were normal or increased; the nucleated cell count in cerebrospinal fluid was normal or mildly elevated; the protein level was substantially elevated; the glucose level was decreased. The drug sensitivity test showed that bacteria were all sensitive to vancomycin and the vancomycin treatment was effective. Only one child had the complication of hydrocephalus. CONCLUSIONS: Enterococcus faecium meningitis occurs mainly in neonates and infants. The patients have atypical clinical features. A high proportion of patients with Enterococcus faecium meningitis have high-risk factors. Enterococcus faecium is sensitive to vancomycin. PMID- 29530120 TI - [Percentages of peripheral blood gammadelta T cells and regulatory T cells and expression of associated cytokines in infants with human cytomegalovirus infection]. AB - OBJECTIVE: To investigate the percentages of peripheral blood gammadelta T cells and regulatory T cells (Treg) and the expression of associated cytokines, interleukin 17 (IL-17) and transforming growth factor-beta1 (TGF-beta1), in infants with human cytomegalovirus (HCMV) infection. METHODS: Twenty-two infants with HCMV infection (HCMV group) and 22 healthy infants who underwent physical examination (control group) were enrolled in this study. The percentages of peripheral blood gammadelta T cells and Treg cells were determined by flow cytometry. The levels of IL-17 and TGF-beta1 in plasma were measured using ELISA. RESULTS: Compared with the control group, the HCMV group had significantly higher percentage of gammadelta T cells and IL-17 level (P<0.01) and significantly lower percentage of Treg cells and TGF-beta1 level (P<0.01). In the HCMV group, the percentage of gammadelta T cells was negatively correlated with the percentage of Treg cells and TGF-beta1 level (P<0.05), but positively correlated with IL-17 level (P<0.05); the percentage of Treg cells was positively correlated with TGF beta1 level (P<0.05), but negatively correlated with IL-17 level (P<0.05); there was no correlation between IL-17 level and TGF-beta1 level (P>0.05). CONCLUSIONS: There is an imbalance between gammadelta T cells and Treg cells in the peripheral blood of infants with HCMV infection, and gammadelta T cells may be involved in the secretion of IL-17. PMID- 29530121 TI - [Glucose transporter 1 deficiency syndrome: features of movement disorders, diagnosis and treatment]. AB - OBJECTIVE: To investigate the clinical features, diagnosis and treatment of glucose transporter 1 deficiency syndrome (GLUT1-DS), as well as the diagnostic value of movement disorders. METHODS: The clinical data of four children with GLUT1-DS were collected, and their clinical features, treatment, and follow-up results were analyzed. RESULTS: There were two boys and two girls, with an age of onset of 2-15 months. Clinical manifestations included movement disorders, seizures, and developmental retardation. Seizures were the cause of the first consultation in all cases. The four children all had persistent ataxia, dystonia, and dysarthria; two had persistent tremor, two had paroxysmal limb paralysis, and two had eye movement disorders. Paroxysmal symptoms tended to occur in fatigue state. All four children had reductions in the level of cerebrospinal fluid glucose and its ratio to blood glucose, as well as SLC2A1 gene mutations. The four children were given a ketogenic diet, at a ketogenic ratio of 2:1 to 3:1, and achieved complete remission of paroxysmal symptoms within 5 weeks. CONCLUSIONS: GLUT1-DS should be considered for epileptic children with mental retardation and motor developmental delay complicated by various types of movement disorders. The ketogenic diet is effective at a ketogenic ratio of 2:1 to 3:1 for the treatment of GLUT1-DS. PMID- 29530122 TI - [Expression of TOPK/PBK in children with malignant lymphoma or reactive lymphoid hyperplasia]. AB - OBJECTIVE: To study the difference in expression of TOPK/PBK in lymph nodes between children with malignant lymphoma and those with reactive lymphoid hyperplasia. METHODS: Eighty children with malignant lymphoma and twenty children with reactive lymphoid hyperplasia were enrolled as subjects. Immunohistochemistry was used to determine the expression of TOPK/PBK in all the subjects. The expression of TOPK/PBK was compared between the two groups. RESULTS: The TOPK/PBK-positivity rate was significantly higher in children with malignant lymphoma than in those with reactive lymphoid hyperplasia (P<0.05). There was no significant difference in the TOPK/PBK-positivity rate between the children with Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). There were significant differences in the TOPK/PBK-positivity rate among children with different pathological types of NHL (P<0.05): the children with lymphoblastic lymphoma showed the highest TOPK/PBK-positivity rate and those with mature B-cell lymphoma and mature T/NK-cell lymphoma had a similar TOPK/PBK-positivity rate. CONCLUSIONS: The expression of TOPK/PBK is up-regulated in the lymph nodes of children with malignant lymphoma. The expression level of TOPK/PBK may be related to the pathological type of NHL. PMID- 29530123 TI - [A Meta analysis of risk factors for asthma in Chinese children]. AB - OBJECTIVE: To investigate the main risk factors for asthma in Chinese children, and to provide a reference for the prevention and treatment of asthma. METHODS: The databases including CNKI, Wanfang Data, China Biology Medicine disc, VIP Database for Chinese Technical Periodicals, Web of Science, and PubMed were searched for studies on risk factors for asthma in Chinese children published up to September 2017. Stata 12.0 was used for the Meta analysis. RESULTS: A total of 24 case-control studies were included, with 5 309 cases in the case group and 6 404 cases in the control group. The Meta analysis showed that a family history of asthma (OR=5.246, 95%CI: 3.435-8.011), a family history of allergy (OR=4.627, 95%CI: 2.450-8.738), atopic constitution (OR=4.659, 95%CI: 2.511-8.644), allergic rhinitis (OR=11.510, 95%CI: 6.769-19.574), a history of eczema/dermatitis (OR=4.919, 95%CI: 3.514-6.886), a history of allergies (OR=4.732, 95%CI: 2.802 7.989), a history of food allergies (OR=5.890, 95%CI: 3.412-10.166), a history of drug allergies (OR=4.664, 95%CI: 2.637-8.252), mold contamination at home (OR=2.483, 95%CI: 1.671-3.690), flowers at home (OR=1.748, 95%CI: 1.383-2.209), a history of house decoration (OR=2.823, 95%CI: 2.206-3.935), and cesarean section (OR=1.894, 95%CI: 1.166-3.077) were risk factors for asthma in children, while breastfeeding was a protective factor against asthma (OR=0.508, 95%CI: 0.396 0.653). CONCLUSIONS: The development of asthma in Chinese children is associated with a variety of factors, among which a family history of asthma, a family history of allergy, atopic constitution, a history of allergies, allergic comorbidities, cesarean section, and bad family environment can increase the risk of asthma in children, while breastfeeding can reduce the risk. PMID- 29530124 TI - [Effect of Bifidobacterium on the expression of beta-defensin-2 in intestinal tissue of neonatal rats with necrotizing enterocolitis]. AB - OBJECTIVE: To study the effect of Bifidobacterium on the expression of beta defensin-2 (BD-2) in intestinal tissue of neonatal rats with necrotizing enterocolitis (NEC). METHODS: A total of 40 rats were randomly divided into four groups: normal control, Bifidobacterium control, NEC model, and Bifidobacterium treatment, with 10 rats in each group. A rat model of NEC was induced by hypoxia, cold stimulation, and artificial feeding. The rats in the Bifidobacterium control and Bifidobacterium treatment groups were given Bifidobacterium via the gastric tube after cold stimulation once a day for three consecutive days. The morphological changes of the terminal ileum were observed under a light microscope and the intestinal injury score was determined. Immunohistochemistry and qRT-PCR were used to measure the protein and mRNA expression of BD-2 in the ileal mucosal tissue. RESULTS: The NEC model group had a significantly higher intestinal injury score than the normal control, Bifidobacterium control, and Bifidobacterium treatment groups (P<0.05). The Bifidobacterium treatment group had a significantly higher intestinal injury score than the normal control and Bifidobacterium control groups (P<0.05). The mRNA and protein expression of BD-2 in the normal control group was significantly lower than in the Bifidobacterium control, NEC model, and Bifidobacterium treatment groups (P<0.05). The Bifidobacterium control group had significantly higher mRNA and protein expression of BD-2 than the NEC model and Bifidobacterium treatment groups (P<0.05). The Bifidobacterium treatment group had significantly higher mRNA and protein expression of BD-2 than the NEC model group (P<0.05). CONCLUSIONS: Bifidobacterium can induce the expression of BD-2 in intestinal tissue of rats and reduce inflammatory response by increasing the expression of BD-2. This provides a protective effect on neonatal rats with NEC. PMID- 29530125 TI - [Protective effect of prostaglandin E1 against brain injury induced by hyperoxia in neonatal rats]. AB - OBJECTIVE: To investigate the protective effect of prostaglandin E1 (PGE-1) against brain injury induced by hyperoxia in neonatal rats and observe the changes in the expression of glucose-regulated protein 78 (GRP78) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and to provide a theoretical basis for the clinical application of PGE-1 in the treatment of neonatal brain injury induced by hyperoxia. METHODS: Sixty neonatal Wistar rats were randomly divided into air control group, hyperoxic brain injury model group, and hyperoxic brain injury+PGE-1 group. All rats except those in the air control group were treated to establish a hyperoxic brain injury model. From the first day of modeling, the rats in the hyperoxia brain injury+PGE-1 group were intraperitoneally injected with PGE-1 2 MUg/kg daily for 7 consecutive days, while the other two groups were treated with normal saline instead. The water content of brain tissue was measured; the pathological changes of brain tissue were evaluated by hematoxylin-eosin staining; the apoptosis of brain cells was assessed by nuclear staining combined with TUNEL staining; the protein expression of GRP78 and CHOP in brain tissue was measured by Western blot. RESULTS: The water content of brain tissue in the hyperoxic brain injury model group was significantly higher than that in the hyperoxic brain injury+PGE-1 group and air control group (P<0.05); the water content of brain tissue in the hyperoxic brain injury+PGE-1 group was significantly higher than that in the air control group (P<0.05). The pathological section of brain tissue showed inflammatory cell infiltration and mild cerebrovascular edema in the brain parenchyma in the hyperoxic brain injury model group; the periparenchymal inflammation and edema in the hyperoxic brain injury+PGE-1 group were milder than those in the hyperoxic brain injury model group. The apoptosis index of brain tissue in the hyperoxic brain injury model group was significantly higher than that in the hyperoxic brain injury+PGE-1 group and air control group (P<0.05); the apoptosis index of brain tissue in the hyperoxic brain injury+PGE-1 group was significantly higher than that in the air control group (P<0.05). The protein expression of GRP78 and CHOP in brain tissue was significantly higher in the hyperoxic brain injury model group than in the hyperoxic brain injury+PGE-1 group and air control group (P<0.05); the protein expression of GRP78 and CHOP was significantly higher in the hyperoxic brain injury+PGE-1 group than in the air control group (P<0.05). CONCLUSIONS: PGE-1 has a protective effect against hyperoxia-induced brain injury in neonatal rats, which may be related to the inhibition of cell apoptosis by down-regulating the expression of GRP78 and CHOP. PMID- 29530126 TI - [Advances in application of Jurkat cell model in research on infectious diseases]. AB - Infectious diseases can be caused by multiple pathogens, which can produce specific immune response in human body. The immune response produced by T cells is cellular immunity, which plays an important role in the anti-infection process of human body, and can participate in immunological protection and cause immunopathology. The outcome of various infectious diseases is closely related to cellular immune function, especially the function of T cells. Jurkat cells belong to the human acute T lymphocyte leukemia cell line. Jurkat cell model can simulate the function T lymphocytes, so it is widely used in the in vitro studies of T cell signal transduction, cytokines, and receptor expression, and can provide reference and guidance for the treatment of various infectious diseases and the research on their pathogenesis. The Jurkat cell model has been widely used in the in vitro studies of viral diseases and atypical pathogens, but parasitic infection studies using the Jurkat cell model are still rare. This article reviews advances in the application of Jurkat cell model in the research on infectious diseases. PMID- 29530127 TI - [Advances in genetic research of congenital hypothyroidism in China]. AB - Congenital hypothyroidism (CH), which results from insufficient thyroid hormone biosynthesis, is one of the most common neonatal endocrine disorders. Thyroid dysgenesis and thyroid dyshormonogenesis are the two causes of CH and either one will lead to deficiencies of enzymes during thyroid hormone biosynthesis and insufficient thyroid hormone biosynthesis. Recently, researchers have performed extensive studies on genetics of CH. This paper reviews genes reported to be associated with CH in China. PMID- 29530128 TI - [Research advances in the role of neutrophil extracellular traps in childhood onset systemic lupus erythematosus]. AB - Neutrophil extracellular traps (NETs) represent a form of cell death distinct from apoptosis or necrosis. The imbalance between the formation and degradation of NETs has long been considered to be closely associated with the activity of autoimmune diseases such as systemic lupus erythematous (SLE). Reactive oxygen species derived from the nicotinamide adenine dinucleotide phosphate oxidase pathway or mitochondrial DNA pathway play a key role in the primary stage of NETs formation. The exposure or delayed degradation of abundant autoantigens, such as double-strand DNA, caused by abnormal activation of neutrophils can induce autoantibody to form immune complexes that deposit in local tissues and then induce the plasmacytoid dendritic cells to secrete the interferon alpha and other inflammatory factors. Those inflammatory factors will eventually cause endothelial cell injury. In order to provide a theoretical basis for targeted therapy and diagnosis of childhood-onset SLE, this paper reviews the role of NETs in the pathogenesis of SLE. PMID- 29530130 TI - From the Editor: Keeping on our toes. PMID- 29530131 TI - Guest Editorial: The journey of patient portals in New Zealand general practice: early learnings and key challenges. PMID- 29530132 TI - Patient portals and young people: addressing the privacy dilemma of providing access to health information. AB - Patient portals enable people to access their health information electronically, but concerns about confidentiality and privacy breaches, particularly for young people, may be impeding portal adoption in New Zealand. This paper considers the legal and ethical framework relating to health information privacy and informed consent in New Zealand, and proposes an approach to implementing patient portals for young people. Shared portal access (where both a young person and their parent or guardian have access to the young person's portal) may be appropriate for young children whose parents or guardians are responsible for their health care. However, as children mature and their capacity to make health care decisions increases, general practitioners will need to consider shifting to independent portal access by competent young people. The circumstances of each young person, including their best interests and rights, cultural needs and their views on information disclosure should be taken into account. PMID- 29530133 TI - To report or not to report? That is the question. PMID- 29530134 TI - New screen on the block: non-invasive prenatal testing for fetal chromosomal abnormalities. AB - Non-invasive prenatal testing (NIPT) is a new screen for fetal chromosomal abnormalities. It is a screening test based on technology that involves the analysis of feto-placental DNA that is present in maternal blood. This DNA is then analysed for abnormalities of specific chromosomes (eg 13, 18, 21, X, Y). NIPT has a much higher screening capability for chromosomal abnormalities than current combined first trimester screening, with ~99% sensitivity for trisomy 21 (Down syndrome) and at least a 10-fold higher positive predictive value. The low false-positive rate (1-3%) is one of the most advertised advantages of NIPT. In practice, this could lead to a significant reduction in the number of false positive tests and the need for invasive diagnostic procedures. NIPT is now suitable for singleton and twin pregnancies and can be performed from ~10 weeks in a pregnancy. NIPT is not currently publicly funded in most countries. However, the increasing availability of NIPT commercially will likely lead to an increase in demand for this as a screening option. Given the high numbers of women who visit a general practitioner (GP) in their first trimester, GPs are well-placed to also offer NIPT as a screening option. A GP's role in facilitating access to this service will likely be crucial in ensuring equity in access to this technology, and it is important to ensure that they are well supported to do so. PMID- 29530135 TI - Improved prospects for food allergy prevention. AB - Three recent publications from Professor Gideon Lack have fundamentally changed our understanding of how to prevent food allergy. His team has shown that early introduction of allergenic foods may prevent food allergy in most but not all high-risk children. Various allergy and paediatric societies around the world are changing their recommendations based on these three studies. It appears there is a window of opportunity to safely introduce allergenic foods to high-risk children. This has resource implications, as some of these children will need testing and food challenges. PMID- 29530136 TI - The Cynefin framework: applying an understanding of complexity to medicine. PMID- 29530137 TI - Patients' experience and understanding of E-portals in rural general practice: an ethnographic exploration. AB - AIM This exploratory qualitative study provides insight into E-portal use in rural primary care. INTRODUCTION As of February 2017, almost 300,000 New Zealanders were using E-portals, offered in over 455 general practices. Patient portals are intended to give patients convenient and secure electronic access to their health information and increase their ability to manage their own health care. Early patient experience of E-portal use in New Zealand has not yet been studied. METHODS Thirty-three patients from three rural general practice sites were interviewed between December 2015 and June 2016. Eleven patients were not using a portal. Data were analysed using ethnograph and comparative analysis between two researchers. RESULTS Four major themes emerged from the data: (i) technology acceptance, (ii) activation to full engagement with E-portals, (iii) benefits and concerns, and (iv) the impact of rural contextual understandings for these 33 patients. DISCUSSION Portal use in New Zealand is in its infancy, but signs suggest that New Zealanders are ready and enthusiastic adopters of such technology. Engagement levels are variable and it is too soon to fully explore the impact of E-portals on the general practice culture, provider relationships and the degree to which portals increase personal self-efficacy in relation to health care. PMID- 29530138 TI - Unmet need for referred services as measured by general practice. AB - INTRODUCTION Unmet needs are a key indicator of the success of a health system. Clinicians and funders in Christchurch, Canterbury, New Zealand were concerned that unmet health need was hidden. AIM The aim of this survey was to estimate the proportion of patients attending general practice who were unable to access clinically indicated referred services. METHODS The survey used a novel method to estimate unserviced health needs. General practitioners (GPs, n = 54) asked their patients (n = 2135) during a consultation about any health needs requiring a referred service. If both agreed that a service was potentially beneficial and not available, this was documented on an e-referral system for review. The outcomes of actual referrals were also reviewed. RESULTS The patient group was broadly representative of the Canterbury population, but over-sampled female and middle-aged people and under-sampled Maori. Data adjusted to regional demographics showed that 3.6% of patients had a GP-confirmed unserviced health need. Elective orthopaedic surgery, general surgery and mental health were areas of greatest need. Unserviced health needs were significantly (P <= 0.05) associated with greater deprivation, middle-age, and receiving high health-use subsidies. DISCUSSION To our knowledge, this is the first survey of GP and patient agreement on unserviced referred health needs. Measuring unserviced health needs in this way is directly relevant to service planning because the gaps identified reflect clinically indicated services that patients want and need. The survey method is an improvement on declined referral rates as a measure of need. Key factors in the method were using a patient-initiated GP consultation and an e-referral system to collect data. PMID- 29530139 TI - Caring for self-harming patients in general practice. AB - INTRODUCTION Intentional self-harm is an international public health issue with high personal, social and financial costs to society. Poor relationship dynamics are known to have a negative influence on the psyche of people who self-harm, and this can increase anxiety and decrease self-esteem, both shown to be significant contributors to self-harm behaviours. Positive and functional social supports have been proposed as a cost-effective and constructive approach in diminishing self-harming behaviours. AIM This qualitative study investigated the aspects of professional, social, familial and romantic relationships that people who have self-harmed identified as having a positive and constructive effect on their self harm behaviour. METHODS Twelve participants with a history of self-harming behaviours were recruited through free press advertising in primary care and interviewed. The participants ranged in age from 19 to 70 years, and represented New Zealand (NZ) European and Maori from across the Southern region of NZ. RESULTS This study shows that constructive relationships that inhibit self-harm behaviours are characterised by participants' perceptions of authenticity in their relationships, and knowing that other people genuinely care. Feeling cared for within an authentic therapeutic relationship enabled participants to overcome their perception of being damaged selves and gave them the skills and confidence to develop functional relationships within their communities. A relationship centred care approach may be useful for general practitioners seeking to develop more effective therapeutic relationships with patients who deliberately self harm. PMID- 29530140 TI - Self-care of Canterbury general practitioners, nurse practitioners, practice nurses and community pharmacists. AB - INTRODUCTION Pastoral care is recognised as an important aspect of a mature primary care network. Pegasus Health is now in its 25th year and has had a formal Pastoral Care Programme for doctors since 2009. AIM This study aimed to collect local data on the self-care of Canterbury (Christchurch, New Zealand) general practitioners (GPs), nurse practitioners (NPs), practice nurses (PNs) and community pharmacists (CPs). METHODS The survey was open to all participants in the Pegasus Small Group Education Programme in Canterbury. From a survey circulated to approximately 1100 primary care professionals, 504 responses were collected either electronically or as hard copies. RESULTS The themes that emerged were similar among all the health professional groups. A significant proportion of health professionals took minimal annual leave and even more worked while ill. CPs were the group with the highest rates in both these areas. Reasons given for this focused largely on a lack of locum cover. DISCUSSION Locum cover is a significant issue in Canterbury for all health professional groups in the study. The issue of locums is now being reviewed in Canterbury partly as a result of this study. Consideration is also being given to how the Pastoral Care Programme can be made more widely available. PMID- 29530141 TI - A model of multidisciplinary professional development for health professionals in rural Canterbury, New Zealand. AB - INTRODUCTION Pegasus Health Charitable Ltd, a Christchurch Primary Health Organisation, is contracted by the Canterbury District Health Board to provide continuing professional development for primary care practitioners in the region. Rurally located health practitioners have largely been unable to participate because of the travel time and distances involved. AIM The initiative reported in this paper aimed to fill this gap by developing an accessible and high-quality multidisciplinary model of professional development for general practitioners, nurse practitioners, practice nurses and community pharmacists in rural areas of North Canterbury, New Zealand. METHODS A survey was conducted to learn from the experiences of 14 health professionals in an existing multidisciplinary group, which had developed as a local initiative in one rural community. RESULTS The survey had an 86% response rate. All respondents believed the multidisciplinary format worked well, had improved collaborative working and increased the consistency of patient care. Access to professional development had improved and the meetings provided a useful forum for the mostly part-time staff to interact as a group. The main caution noted was the potential to become inward looking without being exposed to fresh ideas from other practices. DISCUSSION The multidisciplinary model was considered workable and valuable by the survey respondents. Based on our findings, the multidisciplinary model has been formalised by the Pegasus team responsible, and three new groups are now operating successfully in rural areas of North Canterbury. PMID- 29530142 TI - Beyond the four walls: an exploratory survey of location, employment and roles of pharmacists in primary health care. AB - INTRODUCTION Recognition of the need to reduce harm and optimise patient outcomes from the use of medicines is contributing to an evolution of pharmacy practice in primary health care internationally. This evolution is changing community pharmacy and leading to new models of care that enable pharmacist contribution beyond traditional realms. There is little information about the extent of these changes in New Zealand. AIM The aim of this study was to investigate emerging roles of pharmacists in primary health care. METHODS A 10-question electronic survey was used to collect quantitative data about location, employment and roles of pharmacists practising in primary health care. RESULTS There were 467 survey responses. Although most pharmacists are employed by (78%, n = 357/458) and located in (84%, n = 393/467) community pharmacies, small numbers are dispersed widely across the primary health care sector. Of the 7% (n = 31/467) working in general practices, most are employed by Primary Health Organisations or District Health Boards. Limited cognitive pharmacy service provision is evident in the sector overall, but is much greater for pharmacists spending time located within general practices. DISCUSSION The large proportion of pharmacists practising in community pharmacies emphasises the importance of the Community Pharmacy Services Agreement in facilitating increased cognitive pharmacy service provision to optimise patient outcomes. The small numbers of pharmacists located elsewhere in the primary health care sector suggest there is scope to improve collaboration and integration in these areas. Flexible funding models that promote innovation and support sustainable practice change are key. PMID- 29530143 TI - Falls and depression in octogenarians - life and living in advanced age: a cohort study in New Zealand. AB - INTRODUCTION Falls and injury have the most devastating consequences for very old people. Depression may be a significant cause and consequence of falls. AIM To examine the association between falls and depression in octogenarians. METHODS LiLACS NZ (Life and Living in Advanced Age: A Cohort Study in New Zealand), cohort study data of Maori (aged 80-90 years, 11-year age band) and non-Maori (aged 85 years, 1-year age band) followed for 3 years was used to describe the incidence and prevalence of falls and depression. Falls by self-report were accumulated over 3 years. Geriatric depression score (GDS) was ascertained at baseline. RESULTS Over 3 years, fewer Maori (47%) than non-Maori (57%) fell; 19% of non-Maori and 20% of Maori scored 5+ (depressed) on the GDS. For non-Maori and Maori, people with depression were more likely to fall than Maori not diagnosed with depression (OR 2.72, CI 1.65-4.48 for non-Maori and OR 2.01, CI 1.25-3.25 for Maori). This remained significant, adjusted for age and sex. Depression was a significant predictor of hospitalisations from falls for Maori (OR 5.59, CI 2.4 12.72, adjusted for age and sex) and non-Maori (OR 4.21, 2.3-7.44, adjusted for sex). CONCLUSION Depression and falls are common and co-exist in octogenarians. GPs thinking about falls should also think about depression and vice versa. PMID- 29530144 TI - Association of aspartate aminotransferase in statin-induced rhabdomyolysis. AB - INTRODUCTION The risk of rhabdomyolysis in the general population is elevated by the increased prevalence of statin use. As the presentation of rhabdomyolysis is varied, there is a risk of delayed diagnosis leading to patient complications and increased healthcare costs. Creatine kinase (CK) alone is not sufficiently predictive for risk stratification. Beyond serum CK, other biomarkers such as transaminases may be used as surrogates to evaluate rhabdomyolysis severity and predict complication risks. AIM To assess if other biomarkers are associated with peak CK and severity of rhabdomyolysis to aid in clinical diagnosis of rhabdomyolysis. METHODS A retrospective study was conducted at an acute care hospital from 2008 to 2011. Inclusion criteria were: (1) patients diagnosed with statin-induced rhabdomyolysis; and (2) peak CK levels of >=1000 IU/L. Patients with post-operational rhabdomyolysis, acute myocardial infarction and who had suffered from road traffic accidents were excluded. A total of 24,332 patients were screened, and 78 patients fulfilled our inclusion criteria. RESULTS Aspartate aminotransferase (AST) was found to be positively associated with peak CK levels in the multivariable linear regression model after adjusting for alanine aminotransferase (ALT) levels (P = 0.002; beta = 83.18). Aspartate aminotransferase was found to be associated with severity of rhabdomyolysis in the multivariable logistics regression model after adjusting for ALT levels (P = 0.015; OR = 1.01). DISCUSSION Aspartate transferase is associated with raised peak CK levels and severity of rhabdomyolysis. Clinicians may consider ordering AST to aid in the clinical diagnosis of rhabdomyolysis. PMID- 29530146 TI - Cochrane Corner: What is the best oral treatment for those nasty looking toes? PMID- 29530145 TI - A project to improve the quality of care for overweight and obese patients in a Nelson general practice. AB - INTRODUCTION Local guidelines exist in Nelson to assist general practitioners (GPs) in supporting overweight and obese patients with weight loss and improvements in their overall health. This audit measures whether this role is fulfilled in a Very Low Cost Access practice in Nelson, in which 76% of enrolled patients reside in New Zealand social deprivation index quintiles 4 and 5. AIM This study measured whether Nelson Marlborough District Health Board Health Pathways and the Ministry of Health Clinical Guidelines are followed in identifying risk and initiating management, including treatment of additional risk factors, lifestyle modification and dietitian referral. RESULTS Although limited by sample size and consecutive patient screening methodology, the results of this study indicate that overweight and obesity rates in this practice are comparable with the national average, with Maori and Pacific Island populations more likely to be affected compared to their New Zealand European counterparts. Of the patients who had their body mass index recorded, 65% were overweight or obese. Risk factors were assessed and treated in all, green prescriptions were issued in 4%, and 23% were referred to a dietitian. DISCUSSION Audit findings were presented at an intervention session where strategies for improvement were considered including routine waist circumference measurement, dietitian referral, exercise on prescription and providing individualised tailored approaches that integrate patients' cultural and social context. While risk factors are being managed appropriately, improvements can be made in identifying high-risk patients, promoting lifestyle modifications and early dietitian referral. PMID- 29530149 TI - From the Editor: Forces of nature. PMID- 29530150 TI - Guest Editorial: Rethinking how we see and respond to fatness. PMID- 29530151 TI - Principles of family medicine and general practice - defining the five core values of the specialty. AB - The principles of general practice and family medicine are the defining characteristics of the speciality. The five principles are: compassionate care - a caring attitude towards patients and their families shown as kindness and a desire to help; generalist approach - a perspective on the whole person and the context of illness including family, culture and society; continuity of relationship - the interpersonal bond of trust and respect between family physicians, patients, and their families that develops over the life course; reflective mindfulness- doctors' awareness of their thoughts and emotions manifested as a sense of presence and attentiveness towards self and others; and lifelong learning - a commitment to personal and professional development by participating in learning activities and practice-based research that leads to better patient outcomes. Concepts such as care coordination, preventive care, access to care, professional competence, resource management and community-based care, are part of the principles above. The term 'comprehensive care' is should be avoided as it misinterprets the scope of family medicine. PMID- 29530152 TI - Evaluation of general practice house officer attachments in Counties Manukau: insights and benefits. AB - BACKGROUND The Medical Council of New Zealand requires graduating doctors to have community attachments within their first two years of practice by 2020. Counties Manukau Health has developed a programme where house officers (HOs) are attached to a general practice for three months. AIM This study aimed to establish the value of four HO general practice attachments in Counties Manukau and describe how HOs are being used in these practices. METHODS A mixed-methods design was used to evaluate three attachment runs. Two practices provided the number of patients seen by HOs. Fifty-eight patients were surveyed to assess patient perceptions of the HOs. Six HOs, four supervising general practitioners, two PHO senior staff and one practice manager participated in semi-structured interviews. Focus groups were held with nurses, doctors and administrative staff at all four practices. FINDINGS HOs saw 300-600 patients in one practice and 800-1000 in the other during their attachment. Practices developed their own approach to mentoring and teaching HOs. Most patients reported positive perceptions of the HOs. Themes from interviews and focus groups were consistent among participants and included: improved HO confidence, clinical skills and understanding of general practice; extra capacity and improved quality of care and staff satisfaction among practices. CONCLUSION HOs and practices viewed HO attachments in general practice positively. HOs developed clinical skills and understanding of primary health care. Practice teams enjoyed the energy and enthusiasm of the HOs, while providing clinical support to ensure quality patient care. PMID- 29530153 TI - Australian general practice trainees' exposure to ophthalmic problems and implications for training: a cross-sectional analysis. AB - INTRODUCTION Eye conditions are common presentations in Australian general practice, with the potential for serious sequelae. Pre-vocational ophthalmology training for General Practitioner (GP) trainees is limited. AIM To describe the rate, nature and associations of ophthalmic problems managed by Australian GP trainees, and derive implications for education and training. METHODS Cross sectional analysis from an ongoing cohort study of GP trainees' clinical consultations. Trainees recorded demographic, clinical and educational details of consecutive patient consultations. Descriptive analyses report trainee, patient and practice demographics. Proportions of all problems managed in these consultations that were ophthalmology-related were calculated with 95% confidence intervals (CI). Associations were tested using simple logistic regression within the generalised estimating equations (GEE) framework. RESULTS In total, 884 trainees returned data on 184,476 individual problems or diagnoses from 118,541 encounters. There were 2649 ophthalmology-related problems, equating to 1.4% (95% CI: 1.38-1.49) of all problems managed. The most common eye presentations were conjunctivitis (32.5% of total problems), eyelid problems (14.9%), foreign body (5.3%) and dry eye (4.7%). Statistically significant associations were male trainee; male patient and patient aged 14 years or under; the problem being new and the patient being new to both trainee and practice; urban and of higher socioeconomic status practice location; the practice nurse not being involved; planned follow up not arranged; referral made; in-consultation information sought; and learning goals generated. DISCUSSION Trainees have comparable ophthalmology exposure to established GPs. However, associations with referral and information-seeking suggest GP trainees find ophthalmic problems challenging, reinforcing the critical importance of appropriate training. PMID- 29530154 TI - Cracking open death: death conversations in primary care. AB - INTRODUCTION Research supports talking about death outside the end-of-life context. Benefits include allaying death anxiety to increased engagement in health promotion interventions. Nonetheless, the focus on death conversations remains centred on the imminently dying. This qualitative study investigated New Zealanders' perspectives on the value of, opportunities for, and barriers to death conversations in primary healthcare. METHODS Twenty-one participants were interviewed. Participants were young older adults (54-65 years) not receiving palliative care or diagnosed with a terminal illness. Most were women who identified ethnically as New Zealand European. An immersion-crystallisation approach to thematic development was used to accommodate the multidisciplinary research framework. RESULTS Four core themes were identified: 'a need to talk about death'; 'the role of the GP'; 'broaching the topic'; and 'media'. CONCLUSION A cultural silence on death has rendered both the medical and lay community insufficiently prepared for frank and meaningful engagement with the topic, exacerbated by restricted consultation timeframes. The ease of death conversations may be facilitated by taking a family-centred approach, using community organisations and settings, and harnessing conversation entry points provided by the media. Future research should aim to develop tailored resources and frameworks to support general practitioners' meaningful engagement with the topic of death both within and outside of the end-of-life context. PMID- 29530155 TI - What supports are needed by New Zealand primary care to improve equity and quality? AB - While some primary care practices have found ways to deliver quality care more equitably to their Maori and Pacific patients, others have struggled to get started or be successful. Quality Symposium attendees shared their views on barriers and success factors, both within the practice and beyond. When practices have collaborated and used their own ethnic-specific data in quality improvement techniques, they have improved Maori and Pacific health and equity. Attendees asked for greater practical support and guidance from the profession and sector. They report a funding gap for services needed by their patients to enable primary care to deliver equitable services for Maori and Pacific people. PMID- 29530156 TI - Agreement between parental perception of child weight status and actual weight status is similar across different ethnic groups in New Zealand. AB - INTRODUCTION Accurate parental perception of their child's weight is poor. Accuracy may be influenced by differences in ethnicity but this is currently unknown. AIM To determine whether agreement between parental perception of child weight status and actual child weight status differs according to ethnic group (NZ European, Maori, Pacific, Asian), and to investigate whether it is influenced by various demographic and behavioural factors. METHODS A total of 1093 children (4-8 years old) attended a weight screening initiative. Parents completed questionnaires on demographics, beliefs about child weight, parenting style, parental feeding practices and social desirability. Actual measured weight status was compared with parental perception of weight status (underweight, normal weight, overweight). RESULTS Agreement about child weight status was apparent in 85% of NZ European, 84% of Maori, 82% of Pacific and 88% of Asian children. However, adjusting for chance led to kappas of 0.34, 0.38, 0.41 and 0.53, respectively, indicating only fair-to-moderate agreement. Overall, agreement between measured body mass index and parental perception was not related to ethnic group, child sex and age, maternal age and education, and household deprivation (k ranged from 0.16 to 0.47). However, agreement about weight status was higher in parents who reported higher levels of restrictive feeding than in parents who reported less restriction (P < 0.01) but agreement was only fair. CONCLUSION Agreement between parental perception and actual weight status was fair and did not differ between the ethnic groups examined. PMID- 29530157 TI - Antidepressants for treatment of depression in primary care: a systematic review and meta-analysis. AB - INTRODUCTION Evidence for the effectiveness of drug treatment for depression in primary care settings remains limited, with little information on newer antidepressant classes. AIM To update an earlier Cochrane review on the effectiveness of antidepressants in primary care to include newer antidepressant classes, and to examine the efficacy of individual agents. METHODS Selection criteria included antidepressant studies with a randomly assigned placebo group where half or more subjects were recruited from primary care. The Cochrane Collaboration Depression, Anxiety and Neurosis (CCDAN) group searched multiple databases to identify eligible studies. Data extraction was performed independently by two reviewers. Data were analysed using Revman version 5.3.5. RESULTS In total, 17 papers and 22 comparisons were included for analysis. Significant benefits in terms of response were found for tricyclic antidepressants (TCA) with a relative risk (RR) = 1.23 (95% CI, 1.01-1.48), and serotonin selective reuptake inhibitors (SSRI) with a RR = 1.33 (95% CI, 1.20 1.48). Mianserin was effective for continuous outcomes. Numbers needed to treat (NNT) for TCA = 8.5; SSRI = 6.5; and venlafaxine = 6. Most studies were industry funded and of a brief duration (<= 8 weeks). There was evidence of publication bias. There were no studies comparing newer antidepressants against placebo. CONCLUSION Antidepressants such as TCA, SSRI, SNRI (serotonin-norepinephrine reuptake inhibitor) and NaSSA (noradrenergic and specific serotonergic antidepressant) classes appear to be effective in primary care when compared with placebo. However, in view of the potential for publication bias and that only four studies were not funded by industry, caution is needed when considering their use in primary care. PMID- 29530158 TI - Quality use of antipsychotic medicines inresidential aged care facilities in New Zealand. AB - INTRODUCTION Antipsychotic medicines are used regularly or when required in residential aged care facilities to treat symptoms of dementia, but have been associated with several adverse effects. AIM The aim of this study was to examine 'quality use' of antipsychotic medicines in residential aged care facilities in New Zealand, by surveying nurse managers. METHODS A cross-sectional survey was mailed to 318 nurse managers working in a nationally representative sample of aged care facilities. A purpose-developed, pre-tested, 22-item structured questionnaire was used to explore practice related to the quality use of antipsychotic medicines. RESULTS Overall, 31.4% of nurse managers responded to the survey. They mostly (88%) had >= 1 year's relevant work experience and 83% of facilities provided care for those within the range of 21 to 100 residents. Respondents reported that staff education on dementia management occurred early in employment. Two-thirds of participants reported non-pharmacological interventions were commonly used for managing challenging behaviours, while less than half (45%) cited administering antipsychotic medicine. Respondents reported 'managing behavioural symptoms' (81%) as one of the main indications for antipsychotic use. Frequently identified adverse effects of antipsychotic medicines were drowsiness or sedation (64%) and falls (61%). Over 90% reported general practitioners reviewed antipsychotic use with respect to residents' target behaviour 3-monthly, and two-thirds used an assessment tool to appraise residents' behaviour. DISCUSSION Staff education on dementia management soon after employment and resident 3-monthly antipsychotic medicine reviews were positive findings. However, a wider use of behavioural assessment tools might improve the care of residents with dementia and the quality use of antipsychotic medicines. PMID- 29530159 TI - Reasons for use and non-use of the pertussis vaccine during pregnancy: an interview study. AB - INTRODUCTION In New Zealand, pertussis vaccination is recommended and government funded during every pregnancy to protect the infant after birth. However, uptake is low and needs to be increased. AIM To investigate enablers and barriers for uptake of the pertussis vaccination by pregnant women in New Zealand, and explore the acceptability of provision in pharmacies. METHODS Women with infants were recruited in selected pharmacies and interviewed using abrief structured interview. Transcripts were analysed using a framework approach. RESULTS Thirty seven women aged 18-43 years provided data for analysis. Seventeen women reported receiving a pertussis vaccination during their pregnancy. Information from health professionals appeared important to encourage vaccination, but other sources of information (eg antenatal groups and media) were also cited. Non-vaccination arose from being unaware of the need for pertussis vaccination during pregnancy, concerns about safety, and misinformation. Participants supported pertussis vaccination in pharmacies to help access or increase the opportunity for health professionals to inform women. DISCUSSION The information received by participants affected their uptake of the pertussis vaccine during pregnancy. Education of the public and health professionals about the pertussis vaccine during pregnancy is necessary. PMID- 29530160 TI - Text messaging between clinicians and patients - Hve we got thngs unda cntrl? AB - INTRODUCTION Patients are interested in receiving text messages (texts) related to their health care. However, anecdotes are emerging of associated problems and it is possible that many of the potential pitfalls are not recognised. AIM To assess clinicians' attitudes and behaviours towards text messaging (texting) with patients. METHODS A voluntary, anonymous, online survey was created and distributed to general practitioners and physiotherapists in New Zealand and to Sports Medicine Fellows and Sports Medicine Registrars in New Zealand and Australia. RESULTS In total, 322 clinicians completed the survey. Texting behaviours relating to accuracy, privacy and security were identified. A range of sensitive and important medical information was frequently conveyed and at times forwarded to third parties. The clinicians generally felt uneasy communicating this way and some felt pressured into it. Most thought that guidelines are insufficient and that they had not received sufficient education on the issues. Most were interested in further education. CONCLUSION This study has demonstrated frequent texting between clinicians and patients. It has highlighted potential risks to the privacy, accuracy and security of medical information. Current guidelines and education may be insufficient. Clinicians were interested in receiving readily available best practice guidelines and education regarding texting. PMID- 29530161 TI - General practitioners' views on providing nutrition care to patients with chronic disease: a focus group study. AB - INTRODUCTION Nutrition care refers to practices conducted by health professionals to support patients to improve their dietary intake. General practitioners (GPs) are expected to provide nutrition care to patients for prevention and management of chronic disease. AIM This study explores GPs' opinions regarding nutrition care provision to patients with chronic disease. METHODS An interpretive descriptive approach to qualitative research using seven semi-structured focus groups with 48 GPs in Auckland was used. Focus groups investigated how GPs felt about providing nutrition care; the perceived barriers to and support required for this care; the development of further nutrition knowledge and skills; and possible roles for Practice Nurses. Recorded interviews were transcribed verbatim and analysed using a thematic approach. RESULTS GPs indicated routine provision of basic nutrition care to patients with chronic disease, but perceived their limited consultation time and nutrition competence constrained their capacity to provide nutrition care. GPs felt they needed further information to provide culturally, socially and economically sensitive nutrition care. GPs displayed variable opinions on the benefits of developing their nutrition knowledge and skills, and the idea of Practice Nurses providing nutrition care. CONCLUSIONS Despite perceiving that nutrition care is important for patients with chronic disease and facing barriers to providing nutrition care, GPs appear reluctant to further develop their knowledge and skills and for Practice Nurses to provide this care. Strategies to enhance GPs' nutrition-related self-efficacy, nutrition cultural competence and attitudes towards further training care may be warranted. PMID- 29530162 TI - "Basically you wait for an 'in''': community pharmacist views on their role in weight management in New Zealand. AB - INTRODUCTION Obesity is now widely regarded as the main contributor to poor health globally, overtaking tobacco as the leading potentially modifiable risk to health. Community pharmacists are delivering an increasing number of extended services and are potentially well placed to contribute to obesity management strategies. No studies to date have investigated the views of community pharmacists in New Zealand about their role in weight management. AIM To explore the views of community pharmacists in one region of New Zealand about their role in weight management, including the perceived barriers and facilitators to their involvement. METHODS Qualitative, face-to-face, semi-structured interviews were undertaken with 11 community pharmacists from the Greater Wellington region. Interviews were transcribed verbatim and analysed thematically using an inductive approach. RESULTS Four key themes were identified from data analysis. These were: (i) perceptions of obesity; (ii) perceptions of weight management treatment options; (iii) the unique position of the community pharmacist; and (iv) barriers to involvement. The main barriers described included: (i) a lack of time and remuneration; (ii) the absence of an appropriate space within the pharmacy to discuss weight-related matters; (iii) and a lack of awareness of who to contact for specialist support. DISCUSSION Community pharmacists in Greater Wellington believe that they have a distinct role in their local community and can contribute to a multidisciplinary approach to reduce levels of obesity. Further work is required to determine the most appropriate role for community pharmacy in weight management and the training needs for pharmacy staff to optimally fulfil this role. PMID- 29530163 TI - Integrating dietitians into primary health care: benefits for patients, dietitians and the general practice team. AB - INTRODUCTION Dietetic service delivery in primary health care is an emerging area of dietetic practice in New Zealand. AIM This paper aims to describe the dietetic services being delivered in this setting and dietitians' perceptions of the factors that have an effect on their ability to deliver an optimal service. METHODS Individual, qualitative, semi-structured, face-to-face interviews were conducted with 12 primary healthcare dietitians from a range of age, ethnicity and professional backgrounds. Interviews were audio-recorded, transcribed verbatim and analysed using inductive thematic analysis. RESULTS Participants were delivering a range of services including: providing nutrition care directly to patients, helping to upskill other primary health care professionals in nutrition, and delivering health promotion initiatives to their local community. Three key factors were identified that participants perceived as having an effect on their ability to deliver effective dietetic services in primary health care: being part of a multidisciplinary general practice team, having flexible service delivery contracts appropriate for the setting and that supported integration, and having an adequate level of dietetic experience. DISCUSSION Dietitians working in primary health care recognise the importance of being well integrated into a multidisciplinary general practice team. This enables them to deliver more collaborative and coordinated nutrition care alongside their colleagues, to benefit patient care. Establishing flexible dietetic service delivery contracts, which support integration and take into account funding and workforce capacity requirements, may help ensure that the unique skill set of a dietitian is utilised to best effect. PMID- 29530164 TI - Potion or Poison? Green Tea. PMID- 29530166 TI - Guest Editorial: Business of Care: Global perspectives. PMID- 29530167 TI - Cheques and challenges: business performance in New Zealand general practice. AB - INTRODUCTION New Zealand general practice mainly functions as small businesses, usually owned by a single or small group of doctors. Consequently, owners often have to balance the provision of patient care with varying funding priorities, changing patient needs and the pressures of running a sustainable business. Such balancing inevitably leads to tensions developing between these factors. AIM To explore and understand these tensions and responses to them, by examining the business performance measurements used by general practice. METHODS For this study, the unit of analysis and focus were individual practices, but qualitative semi-structured interviews with general practitioners (GPs) and practice managers were used to gather the data. RESULTS All participating practices had some form of governance or board review, where high-level aggregated business performance data were presented. More sophisticated business performance measures were evident in the larger, more developed practices and in practices functioning as community trusts. Examples of such measures included doctor utilisation and efficiency, appraisal of risk, patient satisfaction with services and responses to changes in patient demand. DISCUSSION As the number of general practices based on the traditional model decrease, a corresponding increase is likely in the establishment and development of 'super practices' based on a corporatized, multi service, single-location model. Consequently, service delivery will become increasingly complex and will drive a need for increased sophistication in how general practice measures its business performance, thus ensuring a balance between high-quality, safe patient care and the maintenance of a sustainable business. PMID- 29530169 TI - Not-for-profit health services and hybridisation. PMID- 29530168 TI - Through the looking glass: the perspective of a nurse and practice manager-owned general practice. PMID- 29530170 TI - Releasing the potential of Nursing. PMID- 29530171 TI - Navigating payer heterogeneity in the United States: lessons for primary care. AB - With most providers accepting private and public funding, the US exemplifies hybridization, which results in both systemic benefits and harms. While this practice stimulates innovation, encourages practices to be efficient, and increases choice, it has also been linked to gaps in patient safety and overtreatment. We propose three lessons from the US for navigating a public and private system: hybridization allows for innovation; hybridization leads to administrative complexity; and if the costs of participation outweigh the benefits, practices may undergo dehybridization. PMID- 29530172 TI - English general practice: once, twice, three times a hybrid. PMID- 29530173 TI - Exploration of funding models to support hybridisation of Australian primary health care organisations. AB - Primary Health Care (PHC) funding in Australia is complex and fragmented. The focus of PHC funding in Australia has been on volume rather than comprehensive primary care and continuous quality improvement. As PHC in Australia is increasingly delivered by hybrid style organisations, an appropriate funding model that matches this set-up while addressing current issues with PHC funding is required. This article discusses and proposes an appropriate funding model for hybrid PHC organisations. PMID- 29530174 TI - Do out-of-hours general practitioner services and emergency departments cost more by collaborating or by working separately? A cost analysis. AB - INTRODUCTION In the Netherlands, general practitioners (GPs) and emergency departments (EDs) collaborate increasingly in urgent care collaborations (UCCs) in which the two services share one combined entrance and joint triage. AIM The objective of this study is to determine if UCCs are cost-effective compared to the usual care setting where out-of-hours GP services and EDs work separately. METHODS This observational study compared UCCs with the usual care setting on costs by performing linear regression analyses. These costs were also combined with two performance indicators: level of patient satisfaction and the length of stay. A non-parametric bootstrap (resampling) method was performed in order to analyze the cost-effect pairs. RESULTS During the study period, 122,061 patients visited EDs and the out-of-hours GP services. Total mean costs per episode were substantially higher in UCCs: ?480 versus ?392 respectively. In this study, two factors that contributed to higher costs in UCCs compared to usual care were identified. First, there was a higher proportion of GP consultations instead of cheaper medical advice for self-care in UCCs. Second, in UCCs there were more often double costs per episode, as more patients were referred to an ED after triage or consulting GP services. The cost-effectiveness analyses show that UCCs were not dominant on cost-effectiveness compared to the usual care setting. DISCUSSION A substitution of, often self-referring, patients from EDs to GP services does not result in lower costs to society, a shorter length of stay or a higher level of patient satisfaction. PMID- 29530175 TI - General practice evolution in New Zealand: hybridisation in action. AB - This viewpoint outlines a brief history of primary care health reforms over the last 25 years, and how this history has influenced the business of caring. It also suggests where we should next look to improve the provision of equitable patient-centred care in the current climate of fiscal constraint, while meeting the challenges of an ageing population and increasing multimorbidity. PMID- 29530176 TI - Pegasus Health Pastoral Care Programme. AB - INTRODUCTION In New Zealand, 41% of general practitioners (GPs) intend to retire by 2025. Increasing workforce shortages and other stressors are putting doctors at risk of burnout, which in turn can put patients at risk of harm. Offering a range of resources can signal an organisation's commitment to physician wellness while improving patient safety and organisational stability. AIM To replace the current reactive approach to impaired doctors with a proactive system of monitoring performance with the goal of identifying problems early. METHODS This paper reports on an initiative of Pegasus Health Charitable to provide pastoral care to GPs in Canterbury experiencing increased stress, burnout or problems leading to impaired performance. RESULTS The pastoral care programme has been running successfully for 9 years and has helped 32 GPs. Because of the low numbers, the programme needs to be individualised and confidential. CONCLUSION Recent developments have seen Pegasus Health adopt a systematic approach to monitoring and supporting health practitioners. This includes the monitoring of available data on GPs at risk. Data collection is being used to manage the "psychological health" of doctors, including complaints, prescribing, referral data and attendance at education sessions. PMID- 29530177 TI - From good to great: the potential for the Health Care Home model to improve primary health care quality in New Zealand. PMID- 29530179 TI - From the Editor: One job, two jobs, three jobs, four .... PMID- 29530180 TI - Guest Editorial: Personhood, values, and work. PMID- 29530181 TI - Clinical leadership: what is it and how do we facilitate it? AB - Clinical leadership has been on the New Zealand policy agenda since the launch of the 2009 In Good Hands report, yet performance in supporting its development has been variable. The 2016 New Zealand Health Strategy renews the emphasis on clinical leadership, but with few details for what this is, what the expectations are and how clinical leadership might be supported. This article backgrounds the field and provides some pointers for policymakers and the sector if New Zealand is to take the lead on clinical leadership. PMID- 29530182 TI - General Practitioners providing obstetric care in New Zealand. What differentiates GPs who continue to deliver babies? AB - AIM To identify factors that have enabled some New Zealand general practitioner obstetricians (GPOs) to continue providing maternity care and factors implicated in decisions to withdraw from maternity care. METHOD Semi-structured interviews and one focus group (n = 3) were conducted with 23 current and former GPOs. Interviews were transcribed and analysed thematically. RESULTS Current and former GPOs practiced maternity care because they enjoyed being involved in the birth process and delivery suite environment. Their maternity practice was framed by a philosophy of lifelong continuity of care for patients. CONCLUSION GPOs still practicing in New Zealand do so because they find maternity care highly rewarding despite their perceptions that the current maternity care model is incompatible with general practice. They have often developed local solutions that support their practice, particularly around shared care arrangements. PMID- 29530183 TI - Initial perspectives of New Zealand doctors: developing capacity and a training programme in the Cook Islands. AB - From 2012 to 2014, 18 New Zealand general and rural medical practitioners worked in the Cook Islands on a visiting programme to achieve the following objectives: (1) assess and assist with the capacity of the Cook Islands medical workforce; (2) assist with the infrastructure to improve clinical records and audit; (3) assist with developing a General Practice training programme for the Cook Islands; and (4) develop a training post for the Division of Rural Hospital Medicine in the Cook Islands. Each visiting doctor spent a minimum of 4 weeks in the Cook Islands. This study presents the results of a questionnaire undertaken to evaluate their experiences. There were challenges, but for most, the experience was overwhelmingly positive. There were synergies with rural practice in New Zealand. Working alongside local clinicians and being immersed in the Cook Islands health system led to better understanding of the Cook Islands perspective of rural and remote medicine. The findings provide insight into the early phase of an ongoing programme between the Cook Islands Ministry of Health and New Zealand, which has led to the development of a reciprocal training programme for generalist doctors. PMID- 29530184 TI - 'By the way....how's your sex life?' - A descriptive study reporting primary health care registered nurses engagement with youth about sexual health. AB - INTRODUCTION Youth rates of sexually transmitted infections in New Zealand are among the highest in the Organisation for Economic Cooperation and Development. Registered nurses employed in primary healthcare settings (PHC RNs) may lack confidence engaging with youth about their sexual health. AIM To identify what facilitates PHC RNs to discuss sexual health with youth. METHODS This descriptive study was undertaken in two phases. In phase one, 23 PHC RNs completed an online survey. Phase two followed up the survey with semi-structured interviews with seven PHC RNs. RESULTS Most PHC RNs are female, aged between 40 and 60 years old and identify with New Zealand or other European ethnicity. Participants identified specific educational needs relating to youth sexual health that are not being met: legal and ethical issues (65%); cultural issues (65%); youth sexual (44%) and psychological (52%) development; and working with gay, lesbian, bisexual or transsexual youth (48%). Lack of time was cited as a barrier to engaging with youth about sexual health by 30% of the participants. Ongoing support practices such as regular debriefing, reflections of practice and case reviews with colleagues (74%); support from other sexual health providers (87%); and access to educational materials about youth sexual health aimed at health professionals (100%) were perceived to be useful to increase confidence in discussing sexual health with youth. DISCUSSION The PHC RNs lacked knowledge and confidence engaging with youth about sexual health. PHC RNs need resourcing to provide culturally safe, effective sexual health care to youth. PMID- 29530185 TI - Building and expanding interprofessional teaching teams. AB - INTRODUCTION Interprofessional education (IPE) aims to prepare learners to work in collaborative health-care teams. The University of Otago, Wellington has piloted, developed and expanded an IPE programme since 2011. An interprofessional teaching team has developed alongside this programme. AIMS This study aimed to understand the development of a university-based interprofessional teaching team over a 4-year period and generate insights to aid the development of such teams elsewhere. METHODS Two semi-structured audio-recorded educator focus groups were conducted at key times in the development of the IPE programme in 2011 and 2014. The programme focused on long-term condition management and involved students from dietetics, medicine, physiotherapy and radiation therapy. Focus group transcripts were independently analysed by two researchers using Thematic Analysis to identify broad themes. Initial themes were compared, discussed and combined to form a thematic framework. The thematic framework was verified by the education team and subsequently updated and reorganised. RESULTS Three key themes emerged: (i) development as an interprofessional educator; (ii) developing a team; and (iii) risk and reward. Teaching in an interprofessional environment was initially daunting but confidence increased with experience. Team teaching highlighted educators' disciplinary roles and skill sets and exposed educators to different teaching approaches. Educators perceived they modelled team development processes to students through their own development as a team. Interprofessional teaching was challenging to organise but participation was rewarding. Programme expansion increased the risks and complexity, but also acted as a stimulus for development and energised the teaching team. DISCUSSION Interprofessional teaching is initially challenging but ultimately enriching. Interprofessional teaching skills take time to develop and perspectives of role change over time. Educator team development is aided by commitment, understanding, enthusiasm, leadership and trust. PMID- 29530186 TI - Changing perspectives of the role of community pharmacists: 1998 - 2012. AB - INTRODUCTION In New Zealand, extended medicines management roles proposed for pharmacists include the optimisation and monitoring of medicines in patients with long-term conditions through greater collaboration with general practitioners (GPs). Although some collaborative roles have been successfully implemented in hospitals, barriers for both pharmacists and GPs hinder interprofessional working relationships in the community. AIM To compare data from a 2012 study with two previous studies (1998, 2002) examining perceptions of community pharmacists and GPs of the expanding medicines management roles of community pharmacists. METHODS In 2012, a survey, modelled on the 1998 and 2002 studies, was sent to 600 community pharmacists and 600 GPs. Analyses considered the five-point Likert scale to be a continuous variable. A change of >= 10% between any two surveys indicated a relevant change for comparison. RESULTS Increasing agreement, which differed considerably between professions, was apparent for most expanding medicine management roles over the 14 study years. In all three studies, pharmacists were open to expanding their roles to include monitoring, screening, advisory and prescribing roles. GPs were most accepting of the traditional dispensing role with a positive shift towards pharmacists' involvement in medicines management over time. DISCUSSION Over 14 years, GPs became more accepting of community pharmacists' involvement in extended medicines management roles, although still had low acceptance of the more clinical roles. Pharmacists considered increased involvement in medicines management as their role, but appeared to lack confidence in their ability to do this role. PMID- 29530187 TI - Standing order use in general practice: the views of medicine, nursing and pharmacy stakeholder organisations. AB - INTRODUCTION Standing orders are used by many general practices in New Zealand. They allow a practice nurse to assess patients and administer and/or supply medicines without needing intervention from a general practitioner. AIM To explore organisational strategic stakeholders' views of standing order use in general practice nationally. METHODS Eight semi-structured, qualitative, face-to face interviews were conducted with participants representing key primary care stakeholder organisations from nursing, medicine and pharmacy. Data were analysed using a qualitative inductive thematic approach. RESULTS Three key themes emerged: a lack of understanding around standing order use in general practice, legal and professional concerns, and the impact on workforce and clinical practice. Standing orders were perceived to extend nursing practice and seen as a useful tool in enabling patients to access medicines in a safe and timely manner. DISCUSSION The variability in understanding of the definition and use of standing orders appears to relate to a lack of leadership in this area. Leadership should facilitate the required development of standardised resources and quality assurance measures to aid implementation. If these aspects are addressed, then standing orders will continue to be a useful tool in general practice and enable patients to have access to health care and, if necessary, to medicines without seeing a general practitioner. PMID- 29530188 TI - Measuring doctor appointment availability in Northland general practice. AB - INTRODUCTION Primary care access is associated with improved patient outcomes. Availability of appointments in general practice is one measure of access. Northland's demographics and high ambulatory sensitive hospitalisation rates may indicate constrained appointment availability. Our study aims were to determine appointment availability and establish the feasibility of measuring appointment availability through an automated process. METHODS An automated electronic query was created, run through a third party software programme that interrogated Northland general practice patient management systems. The time to third next available appointment (TNAA) was calculated for each general practitioner (GP) and a mean calculated for each practice and across the region. A research assistant telephone request for an urgent GP appointment captured the time to the urgent appointment and type of urgent appointment used to fit patients in. Regression analysis was used to determine the relationships between deprivation, patients per GP, and the use of walk-in clinics. RESULTS The mean TNAA was 2.5 days. 12% of practices offered walk-in clinics. There was a significant relationship between TNAA and increasing number of walk-in clinics. CONCLUSION The TNAA of 2.5 days indicates the possibility that routine appointments are constrained in Northland. However, TNAA may not give a reliable measure of urgent appointment availability and the measure needs to be interpreted by taking into account practice characteristics. Walk-in clinics, although increasing the availability of urgent appointments, may lead to more pressure on routine appointments. Using an electronic query is a feasible way to measure routine GP appointment availability. PMID- 29530189 TI - Outreach immunisation services in NewZealand: a review of service delivery models. AB - INTRODUCTION Outreach Immunisation Services (OIS) enable children who have not been immunised on time at general practice to be immunised in the community, thereby improving immunisation coverage and reducing equity gaps. AIM To identify the most effective service delivery models and make recommendations for more effective and cost-efficient OIS delivery in New Zealand. METHODS Data collection and thematic analysis through a detailed review of OIS contracts and service specifications, an online survey and in-depth interviews with stakeholders and providers, and an analysis of cost data was conducted. RESULTS In total, 28 OIS providers completed survey questionnaires, 28 OIS staff were interviewed, and cost effectiveness data were obtained from 11 providers. The surveys and interviews identified key themes around identifying clients with the highest needs, effective engagement strategies, staffing requirements, and service challenges. On average, each OIS referral costs NZ$361 (median NZ$257), and each vaccination event costs NZ$636, ranging from NZ$145 to NZ$2403. Characteristics for two separate models of service delivery were identified based on provider size. CONCLUSION There is considerable range in costs and style of OIS delivery, and efficiencies can be gained. Models need to fit with locality needs and include adequate resourcing, staff with good local knowledge, close relationships with other key child health services and preferably co-location, sustainable funding, and regular service reviews. OIS are part of an effective integrated service that relies on accurate data, positive relationships and a rapid response when children fail to present for vaccination in a timely fashion. PMID- 29530190 TI - Identifying factors behind the general practice use of the term 'decline' for the childhood immunisation programme in New Zealand. AB - INTRODUCTION The role of healthcare providers and their use of systems is one of the most important factors in vaccination uptake. AIM To identify reasons and find patterns behind why immunisation providers code the word 'decline' in their system for childhood immunisation events. METHODS A qualitative study involving face-to-face semi-structured interviews with staff members involved in immunisation delivery. General practices were purposively selected for having either high or low rates of registered children coded on the electronic practice management system as having declined immunisation events. Thematic analysis was undertaken using an inductive approach to link themes to the data. RESULTS A total of 35 interviews were conducted with practice nurses; 21 were from practices with high rates of registered children recorded as having declining immunisation events, and 14 practices with low rates of declining. Common themes were: effective use of systems, early and ongoing engagement, adequate health care practitioner time and practitioner experience. Practices with low rates of coded decliners had stronger approaches for early and ongoing engagement, and were less likely to use formalised decline forms. As practice immunisation coverage rates improved over time, there was perceived to be less expressed vaccine hesitancy from families. CONCLUSIONS The reasons for coding individuals as 'decliners' are a complex mixture of individual, community, practitioner and practice systems. Front-line providers need adequate tools, time and resourcing to support effective and ongoing engagement with families. Community factors have influence but can change over time. PMID- 29530191 TI - Usual primary care of older people in New Zealand: association between practice characteristics and practice activities. AB - INTRODUCTION Information on the processes used by primary care practices to help identify older patients in need of assistance are limited in New Zealand. AIM To describe the processes used to promote early problem detection in older patients in primary care and the practice characteristics associated with the use of these proactive processes. METHODS Sixty practices were randomly selected from all primary care practices in three regions (52% response rate) and surveyed in 2010 to identify characteristics of practices performing the following activities: using assessment tools; auditing the practice; conducting specific clinics; providing home visits; and providing active patient follow-up. Practice level variables were examined. RESULTS Only 4 (7%) of 57 practices did not perform any of the activities. We found the following associations in the many comparisons done: no activities and greater level of deprivation of practice address (p = 0.048); more activities in main urban centres (p = 0.034); more main urban centre practices doing home visits (p = 0.001); less Canterbury practices conducting specific clinics for frail older patients (p = 0.010); and more Capital and Coast practices following-up patients who do not renew their prescriptions (p = 0.019). DISCUSSION There are proactive processes in place in most New Zealand practices interested in a trial about care of older people. Future research should determine whether different types of practices or the activities that they undertake make a difference to older primary care patients' outcomes. PMID- 29530192 TI - Exploring access to vasectomy services: a case study of funding in Counties Manukau. AB - INTRODUCTION Although vasectomy rates in New Zealand have been reported as among the highest worldwide, there is limited information about who is receiving these services and how they are being accessed. This information is needed to develop equitable access to vasectomy services. AIM To describe the ethnicity and socioeconomic status of men accessing District Health Board-funded and self funded vasectomies in Counties Manukau. METHODS A retrospective cohort analysis of provider data linked to ethnicity and area deprivation as an indicator of socioeconomic status. RESULTS Of 332 vasectomies, 66% were for New Zealand European men. Socioeconomic status was not associated with the number of procedures for New Zealand European men, but of the Maori and Pacific men who underwent vasectomies, most lived in the greatest areas of deprivation; 58% (18/31) and 50% (12/24), respectively. When vasectomies were funded, the number of procedures doubled for men from areas of high deprivation. The number of procedures was low for men of other ethnicities. DISCUSSION Our findings indicate differential access to vasectomies by ethnicity and socioeconomic status. Funding vasectomies may provide community benefits in terms of improving equity in access and alleviating a financial burden for many families living in areas of high deprivation. PMID- 29530193 TI - Topical corticosteroid addiction and withdrawal in a 6 year old. PMID- 29530194 TI - String of PEARLS about Mental health update. PMID- 29530196 TI - Breeding in the fat-tailed dunnart following ovarian suppression with the gonadotrophin-releasing hormone agonist Lucrin(r) Depot. AB - Lucrin Depot (AbbVie), a 1-month microsphere gonadotrophin-releasing hormone (GnRH) agonist preparation, was investigated as a potential agent to synchronise cycling in the fat-tailed dunnart (Sminthopsis crassicaudata). Forty-eight randomly selected females were treated with 5 or 10mgkg-1 Lucrin Depot (n=24 per dose). Eighteen females per treatment had their reproductive activity scored at 4, 8, 12 and 16 weeks using two ovarian (Graafian follicle and corpus luteum status) and two reproductive tract (uterine and vaginal muscularity and vascularity) parameters that formed a reproductive activity score. Six females per treatment were paired with a male at 4 weeks. Fertility was assessed between 8 and 16 weeks by pouch check, and thereafter by dissection. The effects of the 5 and 10mgkg-1 doses were statistically equivalent. Females showed suppression at 4 8 weeks, an increase in reproductive activity at 8-12 weeks and all were cycling normally at 16 weeks. Six pouch young were born at 12 weeks to two females treated with the 5mgkg-1 dose. Nine embryos were recovered at 16 weeks from two females treated with the 10mgkg-1 dose. In conclusion, Lucrin Depot can suppress breeding, and fertile mating can occur in subsequent cycles in the dunnart. There is potential for Lucrin Depot to be used as an assisted breeding tool, but it may need to be combined with ovarian stimulation treatment to achieve practical levels of synchronisation in the fat-tailed dunnart. PMID- 29530198 TI - From the Editor: We all benefit from caring about rural health. PMID- 29530200 TI - Guest Editorial: Providing health care across distance - Scottish solutions to rural challenges. PMID- 29530199 TI - Guest Editorial: What is rural health and why does it matter? PMID- 29530201 TI - General practice: balancing business and care. PMID- 29530202 TI - The rural medical generalist workforce: The Royal New Zealand College of General Practitioners' 2014 workforce survey results. AB - INTRODUCTION Previous surveys have revealed a New Zealand rural medical generalist workforce that is mainly male, older and dependent on international medical graduates (IMGs). AIMS To provide a snapshot of the New Zealand rural medical generalist workforce in 2014 and to make comparisons with the urban medical generalist workforce. To assess future workforce losses and find ways to address them. METHODS In March/April 2014, a survey of members of The Royal New Zealand College of General Practitioners used the SurveyMonkey tool. A comparative analysis was undertaken ofself-identified rural and urban respondents. RESULTS The response rate was 55.9% (2525/4514). Of the 2203 working respondents, 17.1% self-identified as rural, working in rural general practice or rural hospital medicine. Compared with urban respondents, more rural generalists were male (57.5% rural vs 45.5% urban; P < 0.01), aged >= 55 years (38.2% rural vs 32.6% urban; P = 0.04) and involved in teaching (53.0% rural vs 30.0% urban; P < 0.01). IMGs were an integral part of the rural generalist workforce (52.8% rural vs 38.7% urban; P < 0.01). More rural generalists worked >= 36 h per week (66.8% rural vs 50.4% urban; P < 0.01) and they were more likely to retire within the next 10 years (40.4% rural vs 34.7% urban; P = 0.0417). DISCUSSION The rural medical generalist workforce continues to be mainly male, older and consist of a high proportion of IMGs. Findings confirm the fragility of this workforce and highlight the need for renewed efforts to improve recruitment and retention. PMID- 29530203 TI - The price of 'free'. Quantifying the costs incurred by rural residents attending publically funded outpatient clinics in rural and base hospitals. AB - INTRODUCTION Rural living is associated with increased costs in many areas, including health care. However, there is very little local data to quantify these costs, and their unknown quantity means that costs are not always taken into account in health service planning and delivery. AIM The aim of this study was to calculate the average time and travel costs of attending rural and base hospital outpatient clinics for rural Central Otago residents. METHODS A survey of 51 people attending rural hospital outpatient clinics. Individual costs in terms of travel and time were quantified and an average cost of both rural and base hospital attendance was calculated. RESULTS The average travel and lost time cost of attending a rural outpatient clinic was NZ$182 and 61% of respondents reported this cost had a significant effect on their weekly budget. The average cost incurred by residents associated with a base hospital attendance in Dunedin was NZ$732. DISCUSSION This study data show that costs are substantial and probably higher than most people might expect for both rural and base hospital attendances. It seems likely that these costs are a potential barrier to service access. However, the full implications of the personal costs incurred by rural residents in accessing health services are largely unstudied and therefore remain unknown in New Zealand. PMID- 29530204 TI - Interprofessional education in a rural community: the perspectives of the clinical workplace providers. AB - INTRODUCTION Interprofessional education is internationally recognised as a key element in preparing a collaborative practice-ready health workforce, for improving health care outcomes and patient-centred practice. The Tairawhiti interprofessional education (TIPE) programme was introduced in 2012 in a rural area with a high Maori population. Students from seven health professions: dentistry, dietetics, medicine, nursing, occupational therapy, pharmacy and physiotherapy participated in clinical rotations as well as working in Maori communities with Maori health providers. AIM The primary aim was to retrospectively investigate clinical workplace providers' perspectives on their participation in the TIPE project over its first 3 years. METHODS Face-to-face, semi-structured interviews were completed with 16 clinical workplace providers involved in TIPE. A qualitative approach using template analysis methodology and a priori themes was used to identify predominant themes from the providers' perspectives. RESULTS All 16 providers reported positive experiences during their involvement in TIPE and wished to continue with this educational model. Benefits described included greater interprofessional collaboration at the workplace; improved engagement between students and providers; enhanced patient-centred care, particularly with Maori and whanau; and positive outcomes from community projects undertaken by the students. Although providers acknowledged additional costs on time, pressure on staff and extra workloads, all confirmed that the benefits from the project far outweighed the costs. CONCLUSION From the providers' perspectives, the TIPE project met its objectives. Furthermore, providers noted several students had re-located back to Tairawhiti to work as health professionals, which suggests that investment in TIPE adds long-term value to the community. PMID- 29530205 TI - Rural women's perspectives of maternity services in the Midland Region of New Zealand. AB - INTRODUCTION Rural women face many challenges with regards to maternity services. Many rural primary birthing facilities in New Zealand have closed. The Lead Maternity Carer (LMC) model of maternity care, introduced in 1990, has moved provision of rural maternity care from doctors to independent midwifery services. Shortages of rural midwives in the Midland region led to rural maternity care being seen as a vulnerable service. AIM To understand the views and experiences of rural women concerning maternity care, to inform the future design and provision of rural maternity services. METHODS Participants were drawn from areas purposively selected to represent the five District Health Boards comprising the Midland health region. A demographic questionnaire, focus groups and individual interviews explored rural women's perspectives of antenatal care provision. These were analysed thematically. RESULTS Sixty-two women were recruited. Key themes emerging from focus groups and interviews included: access to services, the importance of safety and quality of care, the need for appropriate information at different stages, and the role of partners, family and friends in the birthing journey. While most women were happy with access to services, quality of care, provision of information, and the role of family in their care, for some women, this experience could be enhanced. CONCLUSION Midwives are the frontline service for women seeking antenatal services. Support for rural midwives and for local birthing units is needed to ensure rural women receive services equal to that of their urban counterparts. PMID- 29530206 TI - Risk stratification of New Zealand general practice patients for emergency admissions in the next year: adapting the PEONY model for use in New Zealand. AB - INTRODUCTION Patient-centred case management programmes in general practice are needed for patients at high risk for emergency admissions to hospital. AIM To adapt and assess the Predicting Emergency Admissions Over the Next Year (PEONY) model for use in New Zealand to provide risk stratification of general practice patients aged >=40 years for emergency hospital admissions in the next year. METHODS A retrospective observational cohort study modelling 2008-2010 hospital utilisation and medicine use was undertaken to estimate for each patient a risk of emergency admissions in 2011. Health care data were integrated from four national data collections relating to general practice patient registers, hospital admissions, pharmacy dispensed medicines, and mortality. Logistic regression was used to estimate coefficients for variables in the model. Model performance was assessed by calculating its positive predictive value (PPV), sensitivity, and specificity at incremental risk thresholds and receiver operating characteristic. RESULTS The patient cohort included 1,409,506 registered patients; 154,892 (11.0%) had an emergency admission in the follow-up year. Patient age, sex, ethnic group, deprivation status, prior emergency admissions and use of medicines for chronic conditions were all strong predictors of admissions in the next year. The model's PPV for the validation dataset was 58.2% for patients with risk >= 50%, and the area under its receiver operating curve = 0.72. DISCUSSION The PEONY model provides an effective methodology for stratifying New Zealand general practice patients' risk for future emergency admissions. High-risk patients may benefit from patient-centred case management programs to address risk and reduce unplanned admissions. PMID- 29530207 TI - Initiation and maintenance of statins and aspirin after acute coronary syndromes (ANZACS-QI 11). AB - INTRODUCTION Prior New Zealand studies suggest that only approximately two-thirds of patients who present with an acute coronary syndrome (ACS) are maintained on a statin/aspirin post-discharge. This could be due to sub-optimal initiation or poor longer-term adherence. AIM To identify the pattern of statin/aspirin maintenance following ACS from initial prescription to 3 years post-discharge. METHODS All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry data for consecutive New Zealand residents (2007-2011), who were hospitalised with ACS, were anonymously linked to national datasets to derive a medication possession ratio (MPR) to assess medication maintenance. An MPR >= 0.8 is considered adequate maintenance. RESULTS Of the 1846 patients discharged alive, 95% were prescribed a statin at discharge and 92% were dispensed a statin within 3 months, but only 75% had a MPR >= 0.8 in the first year, and 67% in year 3. In the same cohort, 98% were prescribed aspirin and 88% were dispensed aspirin within the 3 months of discharge. In the first year, 72% had an aspirin MPR >= 0.8 and 71% maintained this in year 3. Fifty-nine percent were maintained on both aspirin and a statin in the third year, but 20% were maintained on neither. Regression analysis identified the independent predictors of inadequate maintenance in the third year as age < 45 years, no prior statin, and Maori and Pacific ethnicity. CONCLUSION Longer-term maintenance of evidenced-based secondary prevention medications after ACS is suboptimal despite high levels of initial prescribing and dispensing. Understanding the barriers to longer-term maintenance is required to improve patient outcomes. PMID- 29530208 TI - Exercise treadmill tests in patients with low cardiovascular risk: are we wasting our time? AB - INTRODUCTION The efficacy and cost-effectiveness of exercise treadmill testing for patients with low cardiovascular risk is unclear. This is due to the low incidence of coronary artery disease in this population and the potential for false-positive results leading to additional invasive and expensive investigation. AIM To investigate the value of exercise treadmill testing (ETT) as a predictor of coronary artery disease in patients with different levels of cardiovascular risk. METHODS An observational study was completed on an outpatient population from a chest pain clinic (n = 529). Cross-tabulations and binary logistic regressions were used to examine relationships between variables. RESULTS A negative ETT result was recorded for 72.5% of patients with low cardiovascular risk compared to 54.3% of those with moderate or high risk. Within the low cardiovascular risk group, patients with symptoms atypical for cardiac ischaemia were 11.1-fold more likely to have a negative ETT result. Of the patients with positive or equivocal ETT results, coronary artery disease was subsequently confirmed in only 23.1% of the low cardiovascular risk group compared to 77.2% of those with moderate or high cardiovascular risk. DISCUSSION Results show low cardiovascular risk patients are significantly more likely to return negative ETT results, particularly when associated with atypical symptoms. Similarly, positive or equivocal ETTs in this group are significantly more likely to be false positives. This suggests the ETT is not efficacious in predicting coronary artery disease in patients with low cardiovascular risk. Is it therefore appropriate to offer exercise testing to this cohort or should alternative management strategies be considered? PMID- 29530209 TI - Measuring care alignment in general practice consultations for people with long term conditions: an exploratory study. AB - INTRODUCTION Chronic care Model (CCM) aims to make the care of people with long term conditions (LTC) planned, proactive and patient-centred. The patient assessment of chronic care (PACIC) and our recently developed modified PACIC (MPACIC) allow patient and provider views to be compared. AIM To explore the use of measures of care provision and receipt in primary care long-term conditions management and to assess congruity between patient and provider views of support. METHODS For this observational self-report study, 13 pairs of matched patient and provider dyads (patient/general practitioner and patient/practice nurse) were recruited from general practice. Patients with long-term conditions were asked to rate the support provided by their general practitioner and practice nurse, separately, using the PACIC instrument, a measure of care processes. The modified version for providers (MPACIC) was similarly administered, with GPs and PNs (herein referred to as practitioners) rating the care specifically provided to the 13 patients. Aggregated scores were compared and a case study example was used. RESULTS For 67% of ratings, patients and practitioners agreed (0 or 1 category difference) on the frequency of self-management support provision. Some disagreement was found for 19% of ratings, and considerable disagreement was found for 15%. The strongest agreement was found with Delivery System Design and the least with Goal Setting. Generally, there was little difference between patient/doctor and patient/nurse agreement. DISCUSSION Agreement between patients and practitioners regarding the level of self-management support received and provided was relatively high. This study demonstrates ways the PACIC and MPACIC can be used together to measure patient/practitioner agreement about long-term condition care provision. PMID- 29530210 TI - Adherence to modified constraint-induced movement therapy: the case for meaningful occupation. AB - INTRODUCTION Modified constraint-induced movement therapy (mCIMT) has been shown to improve function of an affected upper limb post stroke. However, factors influencing adherence of individuals undertaking a mCIMT protocol require further investigation. AIM To explore the experience of two participants undergoing a mCIMT protocol and examine factors influencing adherence to the protocol. METHODS A qualitative case study design was used. Two participants with upper limb hemiparesis following a stroke were recruited and received mCIMT (two hours of therapy, three days per week for a total of two weeks). During the treatment period, participants were also encouraged to wear the restraint mitt for four hours per day at home. RESULTS Participants reported increased confidence and self-esteem following participation, as well as improvements in bi-lateral upper limb function. Participants reported the mCIMT protocol as being highly frustrating. However, motivation to adhere to the protocol was positively influenced by the meaningfulness of the occupations attempted. CONCLUSION Although mCIMT can prove frustrating, meaningful occupations may act as a powerful motivator towards adherence to a mCIMT protocol. Further research is required. PMID- 29530211 TI - Audit of a Services to Improve Access project to improve access for skin cancer surgery. AB - Like many general practices in low decile communities with a high percentage of elderly patients, the Paeroa Medical Centre was relying heavily on secondary care to provide skin cancer surgical services, which led to delays in treatment and under-utilisation of the skills available in primary care. A new system utilising Services to Improve Access (SIA) funding was developed to provide partially funded skin cancer surgery within primary care. A 6-month period of this work by one general practitioner (GP) was audited. This has demonstrated that the majority of minor dermatological surgery can be successfully managed in primary care, with more timely and convenient treatment and substantial cost savings to the health system. PMID- 29530212 TI - Elderly disempowerment and do the means justify the end? PMID- 29530213 TI - Potion or Poison? Manuka Honey. PMID- 29530214 TI - String of PEARLS about pain. PMID- 29530216 TI - Corrigendum to: Paternal priming of maternal tissues to optimise pregnancy success. AB - The question of 'how does the allogeneic fetus survive gestation in the face of the maternal immune system?' has yet to be definitively answered. Several acceptable mechanisms exist to facilitate survival of the semi-allogeneic fetus in various species; paramount is the immunological separation of maternal and fetal tissues during gestation. However, keen observation of the maternal immune system during pregnancy has noted maternal immune tolerance to paternal-specific antigens. A mechanism by which the maternal immune system tolerates specific paternal antigens expressed on the fetus would be far more beneficial than the previously proposed immune indolence that would leave the mother susceptible to infection. In species like human or rodent, implantation occurs days after fertilisation and, as such, the mechanisms to establish antigen-specific tolerance must be initiated very early during pregnancy. We and others propose that these mechanisms are initiated at the time of insemination when paternal antigens are first introduced to the maternal immune system. Indeed, a new paradigm demonstrating the importance of paternal-maternal communication at the time of insemination is becoming evident as it relates to maternal tolerance to fetal antigen and ultimately pregnancy success. PMID- 29530219 TI - Guest Editorial: How valuable are systematic reviews for primary health care practitioners? PMID- 29530218 TI - From the Editor: Kindness and positive deviance. PMID- 29530220 TI - The Oral Cavity; an overlooked window into Diabetes Mellitus. PMID- 29530221 TI - Narrating Our Selves: Eric Elder Lecture Presented at the annual conference of the Royal New Zealand College of General Practitioners, July 2016. PMID- 29530222 TI - Should we switch from bendrofluazide to chlorthalidone as the initial treatment for hypertension? A review of the available medication. AB - INTRODUCTION Thiazide diuretics are commonly prescribed in the treatment of hypertension. However, thiazide diuretics may not all be equal in their ability to reduce cardiovascular disease outcomes. AIM To determine if bendroflumethiazide/bendrofluazide, the most commonly used diuretic for hypertension in New Zealand, is as effective as other diuretics in terms of cardiovascular disease outcomes. METHODS Using recent reviews of thiazide-like (chlorthalidone or indapamide) and thiazide-type diuretics (hydrochlorothiazide and bendrofluazide) and a separate search of bendrofluazide, data on cardiovascular disease outcomes was extracted. RESULTS Nineteen relevant papers with 21 comparisons were found. All thiazide-based diuretics have been reported in at least one trial showing them to be more effective than placebo for cardiovascular disease outcomes, with the exception of chlorothiazide. There were no comparisons of bendrofluazide alone with other medications, but there were two studies with either bendrofluazide or hydrochlorothiazide compared with beta blockers; however, the pooled relative risk (RR) was not significant (RR = 1.10 (95% CI, 0.84-1.43)). For chlorthalidone, there were four comparisons with other medications, and the summary RR was statistically significant for cardiovascular disease outcomes (RR = 0.91 (95% CI, 0.85-0.98)). Chlorthalidone was significantly more effective for some cardiovascular disease outcomes when compared with doxazosin, amlodipine and lisinopril. CONCLUSIONS All thiazide based medicines available in New Zealand are effective in terms of cardiovascular disease outcomes compared with placebo when used for treating hypertension, with the exception of chlorothiazide. Of the diuretics available in New Zealand for hypertension, only chlorthalidone has been shown to be more effective than other blood pressure-lowering medicines. It may be time to change from using bendrofluazide and start using chlorthalidone as a treatment for hypertension. PMID- 29530223 TI - Diagnosis and management of transient ischemic attacks in primary care: a systematic review. AB - INTRODUCTION Many patients who suffer a transient ischaemic attack (TIA) present to their general practitioner (GP). Early identification and treatment reduces the risk of subsequent stroke, disability and mortality. AIM To review the accuracy of TIA diagnosis in primary care, immediate management and interventions to assist GPs with the condition. METHODS This study included the search of Medline, Embase, Web of Science and Scopus databases (1995-2015). Relevant titles and abstracts were obtained using structured criteria (diagnosis, immediate management or intervention of TIAs in primary care), with full review and data extraction for eligible publications. RESULTS Most studies found limitations in GPs' knowledge and ability to diagnose TIAs to varying extent over time and between countries. GPs tended to over-interpret non-specific symptoms (e.g. isolated vertigo) when considering a TIA diagnosis. Reported referral behaviour varied between countries, with some favouring admission and others preferring outpatient management. Consistent under-referral and under-use of effective medication was reported. However, GPs may refer some patients to exclude rather than confirm a final diagnosis. This, alongside evidence of under-referral, suggests the need for education and decision support tools to enhance referral patterns. Intervention studies suggested that electronic decision support may increase referrals and timely management. CONCLUSION This review revealed deficiencies in knowledge and clinical practice, and identified potential avenues to addressing these. Issues for future research were also identified. PMID- 29530224 TI - Appropriateness of general practitioner imaging requests for transient ischaemic attack patients: secondary analysis of a cluster randomised controlled trial. AB - AIMS Many transient ischaemic attack (TIA) patients receive initial assessments by general practitioners (GPs). In a randomised controlled trial (RCT) we showed that BPAC Inc. TIA/stroke electronic decision support (EDS) for GPs improves patient outcomes and guideline adherence. This secondary analysis assesses the impact of trial associated enhanced GP access to radiological investigation. METHODS Post-hoc analysis of a multi-centre, single blind, parallel group, cluster RCT comparing TIA/stroke EDS guided GP management with usual care to assess whether imaging requests and their appropriateness differed between study groups. RESULTS GPs requested 15/291 (5.2%) carotid ultrasounds and 19/291 (6.5%) computed tomography (CT) head scans. Scans were obtained more frequently in the intervention group (ultrasound cluster adjusted OR (95% CI) 1.41 (0.44 to 4.49), P = 0.56 and CT 13.8 (1.7 to 110.7), P < 0.001). All CTs were clinically appropriate. More ultrasounds were appropriate in the EDS group (cluster adjusted OR (95% CI) of 8.4 (0.39 to 92.3), P = 0.18). Overall investigation costs did not differ between groups (P = 0.83). Some apparent avoidable imaging duplication occurred where patients were subsequently assessed by secondary services. CONCLUSION In the setting of a RCT assessing GP electronic decision support, frequency of GP initiated imaging requests was low and largely appropriate especially in the setting of EDS use. Thus enhanced GP imaging access as part of the EDS tool did not result in inappropriate or excessive GP imaging requests. However, some duplication occurred and practitioners need to ensure that test referrals and results are adequately communicated between sectors. PMID- 29530225 TI - Overcoming challenges associated with partner notification following chlamydia and gonorrhoea diagnosis in primary care: a postal survey of doctors and nurses. AB - INTRODUCTION Sexual health guidelines recommend that partner notification and testing for reinfection are undertaken when individuals are diagnosed with bacterial sexually transmitted infections (STIs). AIM To understand factors influencing the effective delivery of partner notification and follow up after diagnosis of STIs in primary care, and to identify strategies that might facilitate these processes. METHODS A postal survey was sent to 216 primary care doctors and nurses working in 72 Wellington primary care settings. Eligible clinicians were identified from laboratory testing data, and included clinicians who had diagnosed relatively high numbers of chlamydia and/or gonorrhoea cases during a 12-month period. Response frequencies were tabulated and chi-squared testing was used to test for significant differences between doctor and nurse responses for selected items. RESULTS In total, 121 surveys were completed (56% response rate) by 78 doctors and 43 nurses, from 55 primary care settings (76% of sites surveyed). Responding health professionals thought that patients were open to partner notification discussion, but appreciated that this sometimes raised difficult issues for patients. Lack of time or resources to follow up, and difficulty getting hold of patients, were cited as key factors that limit assessment of partner notification success. Factors deemed likely to facilitate partner notification included readily available patient resources, training to upskill practice team members, guidance on what to say and record, and access to external advice and assistance. DISCUSSION This study provides insight into provider- and patient-level factors perceived to be hindering successful partner notification. Strategies that could facilitate partner notification were identified, and suggestions made as to how these could be integrated into practice. PMID- 29530226 TI - Safer Prescribing and Care for the Elderly (SPACE): feasibility of audit and feedback plus practice mail-out to patients with high-risk prescribing. AB - INTRODUCTION High-risk prescribing in general practice is common and places patients at increased risk of adverse events. AIM The Safer Prescribing and Care for the Elderly (SPACE) intervention, comprising audit and feedback plus practice mail-out to patients with high-risk prescribing, was designed to promote medicines review and support safer prescribing. This study aims to test the SPACE intervention feasibility in general practice. METHODS This feasibility study involved an Auckland Primary Health Organisation (PHO), a clinical advisory pharmacist, two purposively sampled urban general practices, and seven GPs. The acceptability and utility of the SPACE intervention were assessed by semi- structured interviews involving study participants, including 11 patients with high-risk prescribing. Interviews were audio-recorded, transcribed verbatim and analysed using a general inductive approach to identify emergent themes. RESULTS The pharmacist said the SPACE intervention facilitated communication with GPs, and provided a platform for their clinical advisory role at no extra cost to the PHO. GPs said the feedback session with the pharmacist was educational but added to time pressures. GPs selected 29 patients for the mail-out. Some GPs were concerned the mail-out might upset patients, but patients said they felt cared for. Some patients intended to take the letter to their next appointment and discuss their medicines with their GP; others said there were already many things to discuss and not enough time. Some patients were confused by the medicines information brochure. DISCUSSION The SPACE intervention is feasible in general practice. The medicines information brochure needs simplification. Further research is needed to test the effect of SPACE on high-risk prescribing. PMID- 29530227 TI - Social networks of patients with multimorbidity: a qualitative study of patients' and supporters' views. AB - INTRODUCTION Multimorbidity impacts on patients' health and wellbeing, but relationships experienced within social networks can support people to live well. AIM This study sought to elicit the views of New Zealanders with multimorbidity about their social networks and the views of their nominated supporters. METHODS Ten patients with multimorbidity and their nominated supporters each independently recorded their views of the patient's social network on a five concentric-circle template, indicating supporting role and importance to each patient. Sets of patients' and nominated supporters' templates were compared followed by comparing matched pairs of patient-supporter templates. Nominated supporters' views about the patients' networks and why they were nominated were collated. RESULTS Three patients nominated family members as supporters and seven nominated health professionals. Nominated family members identified a greater range of supporters than nominated health professionals. Nominated family members perceived that they played an integral role, whereas health professionals were less comfortable viewing relationships with patients in this way. Family members were not surprised to be nominated as supporters, and some described a considerable burden of care. Health professionals described themselves as coordinators of support and having positive relationships with patients. DISCUSSION Patients with multimorbidity have rich and diverse social networks. They view partners, family and health professionals as providing significant support. Family members are more aware of their role and have a deeper understanding of other network members than health professionals. Further research is needed on the use of social networks in clinical practice to support the health and wellbeing of those with multimorbidity. PMID- 29530228 TI - The use of CT in the management of minor head injuries in Queenstown. AB - AIM This study retrospectively reviewed the management of head injury at Lakes District Hospital in Queenstown, New Zealand. The aim is to describe the management of minor head injury with particular reference to the current Traumatic Brain Injury guidelines of the New Zealand Guidelines Group. METHODS We identified all patients with head injury as a primary diagnosis who were seen in the Emergency Department at Lakes District Hospital during 2013-2015. We recorded clinical criteria indicating need for computed tomography (CT) scanning according to current guidelines for management of minor head injury. RESULTS A total of 883 patients were seen with head injury as their primary diagnosis: 280 patients aged >15 years had a minor head injury that met current criteria for immediate CT scanning. Of these, 66 (23.6%) actually had a CT head scan. CONCLUSION The rate of CT head scanning for minor head injury in Queenstown does not comply with current New Zealand guidelines. PMID- 29530229 TI - Breast cancer information communicated on a public online platform: an analysis of 'Yahoo! Answer Japan'. AB - INTRODUCTION Japan is a developed country with high use of Internet and online platforms for health information. 'Yahoo! Answer Japan' is the most commonly used question-and-answer service in Japan. AIM To explore the information users seek regarding breast cancer from the 'Yahoo! Answer Japan' web portal. METHODS The 'Yahoo! Answer Japan' portal was searched for the key word 'breast cancer' and all questions searched for the period of 1 January to 31 December 2014 were obtained. The selected questions related to human breast cancer and were not advertisements or promotional material. The questions were categorized using a coding schema. High and low access of the questions were defined by the number of view-counts. RESULTS Among the 2392 selected questions, six major categories were identified; (1) suspected breast cancer, (2) breast cancer screening, (3) treatment of breast cancer, (4) life with breast cancer, (5) prevention of breast cancer and (6) others. The highest number of questions were treatment related (28.8%) followed by suspected breast cancer-related questions (23.4%) and screening-related questions (20%). Statistical analysis revealed that the treatment-related questions were more likely to be highly accessed. CONCLUSION Content analysis of Internet question-answer communities is important, as questions posted on these sites would serve as a rich source of direct reflection regarding the health-related information needs of the general population. PMID- 29530231 TI - Potion or Poison? Probiotics in eczema. PMID- 29530230 TI - Breastfeeding peer support in rural New Zealand: the views of peer supporters. AB - BACKGROUND New Zealand (NZ) has a high rate of breastfeeding initiation, declining sharply during the first six months. Although there is a range of support available to breastfeeding mothers, access can be problematic in rural areas. To extend the accessibility of breastfeeding support to rural women, a Primary Health Organisation established a breastfeeding peer supporters (BPS) programme (Mum4Mum - M4M). OBJECTIVES The objective of this study was to gain an understanding of the impact of the BPS training programme on participants, as well as understanding how they utilised the information, both personally and in their communities. METHODS All women who had completed the M4M training and for whom current contact details were available were contacted and invited to complete an online survey. The text data contained in returned surveys was collated and analysed using a general inductive thematic approach. RESULTS Forty one out of 100 BPS graduates completed the survey. Five key themes emerged from the qualitative analysis: knowledge gained and shared; increased confidence; role of peer support; acceptance; personal satisfaction. CONCLUSION The M4M programme improved the personal knowledge and skills of participants and enhanced confidence in breastfeeding ability, which in turn empowered responding participants to successfully support other women to breastfeed in their communities. As a consequence, respondents reported experiencing a heightened sense of personal satisfaction. Furthermore, the initiative successfully established a network of BPS across a sparsely populated rural area of NZ. PMID- 29530232 TI - String of PEARLS about Pregnancy. PMID- 29530233 TI - Cochrane Corner: Chocolate and cocoa: at last some good news for chocolate addicts. PMID- 29530234 TI - [Heart valve disease evaluated with MRI]. AB - Patients with heart valve disease are evaluated with non-invasive imaging techniques notably echocardiography. Cardiovascular MRI (CMR) is increasingly applied, not only in case of a poor echocardiographic window, but also as a consequence of CMR's possibilities of precise determination of regurgitation volumes in insufficiency and precise determination of the impact of valve disease on corres-ponding heart chambers including chamber volumes, myocardial masse and fibrosis. In this paper, the emerging role of CMR in evaluation of patients with heart valve disease is reviewed. PMID- 29530235 TI - [New psychoactive substances require a paradigm shift in drug testing in Denmark]. AB - The emergence of an increasing number of new psychoactive substances (NPS) on the drug market requires a paradigm shift in drug testing. Immunoassay screening needs to be replaced with highly specific and sensitive analytical methods based on chromatography and mass spectrometry to produce accurate results, promote health and patient safety and collect data on the prevalence of NPS use, impact on public health and clinical aspects of NPS in Denmark. Development and implementation of new analytical methods currently present a major challenge for both clinical and forensic laboratories. PMID- 29530236 TI - [Diagnosis of developmental dyspraxia]. AB - In the absence of any known neurological condition or intellectual impairment, dyspraxia, also known as developmental coordination disorder, should be considered. Dyspraxia is the inability to plan, organize and execute movements. At all ages, dyspraxia can be congenital or acquired. While some learn to cope with their motor difficulties over the years, the majority will retain them as adults. Children with significant functional impairment should be identified and assessed as early as possible, since failure to address the motor and other commonly associated (co-morbid) features may have major consequences in adult life. PMID- 29530237 TI - [Trichobezoar as cause of ileus with several perforations of the small intestine in a 15-year-old girl]. AB - A 15-year-old girl was admitted to the paediatric ward due to abdominal pain, vomiting and diarrhoea. Her symptoms could not be explained by the clinical examinations, blood samples or ultrasound, but she had a history of tricho phagia. A CT-scan showed gastric retention, and an endoscopy revealed a trichobezoar, which was removed by a laparotomy. Furthermore, a smaller bezoar and three perforations were found in the proximal part of the small intestine. The treatment of trichobezoars should include surgery as well as multidisciplinary involvement to prevent future trichophagia. PMID- 29530238 TI - [The first Danish patient with a recognisable genetic KBG syndrome]. AB - KBG syndrome is a rare condition characterised by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement including global developmental delay, seizures, and intellectual disability. This is a case report of a seven-year-old boy, who presented with symptoms fulfilling the diagnostic criteria of KBG syndrome, molecularly confirmed by detection of a heterozygous mutation in ANKRD11. To our knowledge, this is the first patient diagnosed with KBG syndrome in Denmark. The aim of this study is to raise awareness of this recognisable syndrome. PMID- 29530239 TI - [Haemorrhagic proctocolitis as primary manifestation of lymphogranuloma venereum in an HIV-positive male]. AB - This is a case report of lymphogranuloma venereum (LGV) manifesting as haemorrhagic proctocolitis in a homosexual HIV-positive male. The primary symptom was a rectal abscess, which was initially surgically treated and subsequently insufficiently treated with single-dose tablet azithromycin. The patient's symptoms were successfully treated after a 21-day doxycycline regime. LGV is a sexually transmitted infection with a rising incidence among persons with risk behaviour. This case report underlines the importance, that all positive rectal screenings for Chlamydia trachomatis should be routinely serotyped. PMID- 29530240 TI - Foreword. PMID- 29530241 TI - Assessing the Value of Moving More-The Integral Role of Qualified Health Professionals. AB - Being physically active or, in a broader sense, simply moving more throughout each day is one of the most important components of an individual's health plan. In conjunction with regular exercise training, taking more steps in a day and sitting less are also important components of one's movement portfolio. Given this priority, health care professionals must develop enhanced skills for prescribing and guiding individualized movement programs for all their patients. An important component of a health care professional's ability to prescribe movement as medicine is competency in assessing an individual's risk for untoward events if physical exertion was increased. The ability to appropriately assess one's risk before advising an individual to move more is integral to clinical decision-making related to subsequent testing if needed, exercise prescription, and level of supervision with exercise training. At present, there is a lack of clarity pertaining to how a health care professional should go about assessing an individual's readiness to move more on a daily basis in a safe manner. Therefore, this perspectives article clarifies key issues related to prescribing movement as medicine and presents a new process for clinical assessment before prescribing an individualized movement program. PMID- 29530242 TI - Let Us Talk About Moving: Reframing the Exercise and Physical Activity Discussion. AB - Noncommunicable and chronic disease are interchangeable terms. According to the World Health Organization, "they are of long duration and generally slow progression. The 4 main types of chronic diseases are cardiovascular diseases (ie, heart attacks and stroke), cancers, chronic respiratory diseases (such as chronic obstructive pulmonary disease and asthma), and diabetes." We have known about the benefits of physical activity (PA) for thousands of years. Perhaps our approach, from public health messaging to the individual clinical encounter, as to how PA and exercise are discussed and prescribed can be improved upon, with the ultimate goal of increasing the likelihood that an individual moves more; ultimately moving more should be the goal. In fact, there is an incongruence between the evidence for the benefits of physical movement and how we message and integrate PA and exercise guidance into health care, if it is discussed at all. Specifically, evidence clearly indicates any migration away from the sedentary phenotype toward a movement phenotype is highly beneficial. As we necessarily move to a proactive, preventive healthcare model, we must reconceptualize how we evaluate and treat conditions that pose the greatest threat, namely chronic disease; there is a robust body of evidence supporting the premise of movement as medicine. The purpose of this perspective paper is to propose an alternate model for promoting, assessing, discussing, and prescribing physical movement. PMID- 29530243 TI - The management of emotions in clinical practice. An intelligent and healing way to improve the health of people. PMID- 29530244 TI - Retraction notice to "BEBT-908: A novel potent PI3K/HDAC inhibitor against diffuse large B-cell lymphoma" [Biochem. Biophys. Res. Commun. 491 (2017) 939 945]. PMID- 29530245 TI - Retraction notice to "Association of angiotensin II receptor 1 and lectin-like oxidized low-density lipoprotein receptor-1 mediates the cardiac hypertrophy induced by oxidized low-density lipoprotein" [Biochem. Biophys. Res. Commun. 490 (1) (2017) 55-61]. PMID- 29530246 TI - Retraction notice to "Reciprocal regulation of miR-1254 and c-Myc in oral squamous cell carcinoma suppresses EMT-mediated metastasis and tumor-initiating properties through MAPK signaling" [Biochem. Biophys. Res. Commun. 484 (4) (2017) 801-807]. PMID- 29530247 TI - Low-voltage driven portable paper bipolar electrode-supported electrochemical sensing device. AB - Aiming to overcome the obstacles of power supply requirement and chip usefulness in practice, a low-cost and convenient portable electrochemical sensing device is introduced for the first time, featuring bipolar electrode system, LED read-out, laminated paper-based devices, and low-voltage button cells. The electric circuits of this practical device are constructed on laminating films with copper and conductive carbon tapes, and the reservoirs facilitating chemical reactions are made with chromatography paper. The device is sensitive to electrochemical responses, validated by the demonstrative hydrogen peroxide and enzyme-assisted glucose detection. The business-card-size chip achieves sensitive analyte detection by naked eyes as well as further image processing in both laboratory samples and human serum samples testing, featuring detection limit as low as 1.79 MUM and a dynamic range from 10 MUM to 10 mM. This new practical design of point of-care sensing chip entails the properties of facile fabrication, simple usage, high robustness, low power consumption, and accurate sensing showing the attainability of fabricating a useful and portable analytical device. PMID- 29530248 TI - A graphene oxide-based polymer composite coating for highly-efficient solid phase microextraction of phenols. AB - Sensitivity and selectivity of the solid phase microextraction (SPME) in analysis are mostly determined by the coating material of the fiber used. Graphene oxide (GO) has attracted great attention because of its large specific surface area, rich oxygen functional groups, good dispersibility in aqueous solution and high reactivity. However, the low thermal stability of the functional groups limits the wide application of GO in SPME coating design. Highly cross-linked polyoxyethylene (POE) is a substrate widely used for composite material construction, which could significantly improve the thermal stability, water resistance as well as biocompatibility of the functional materials. In this study, we incorporated GO with highly cross-linked POE as a novel fiber coating material for SPME through the gluing approach. The obtained fiber possessed a wrinkled shape surface, which could increase the accessible surface area. In addition, the thermal and chemical stability of the fiber coating were also improved, rendering the fiber rigid enough for more than 100 repetitive extraction cycles. The performance of this developed SPME method for phenols was evaluated by headspace extraction of phenols in aqueous samples. Compared with three commercial fibers, the home-made fiber showed excellent extraction efficiencies towards phenols. Under the optimized conditions, it showed low detection limits (0.12-1.36 ng. L-1), good precision (<8.4%), good fiber-to-fiber repeatability (3.1%-8.1%), wide linear range (almost 5-1000 ng.L-1and correlation coefficients (R2) >99%), as well as good enrichment efficiencies (enrichment factors (EFs), 172-1752). Furthermore, the method was successfully applied in simultaneous analyses of five phenols for real water samples with satisfactory recoveries (81-113% for the Pearl River samples). PMID- 29530249 TI - Polyphenylene core-conjugated microporous polymer coating for highly sensitive solid-phase microextraction of polar phenol compounds in water samples. AB - The high performance separation and pre-concentration of polar phenols from aqueous matrices is difficult because of the strong interactions between phenols and water molecules. Conjugated microporous polymers (CMPs) are a kind of novel porous organic materials. Polyphenylene core-conjugated microporous polymers (PPc CMPs) were used as a novel coating material in the solid-phase microextraction of polar phenols in water samples for the first time. The novel PPc-CMPs fibers exhibited good thermal stability (>450 degrees C), high enrichment factors (519 2372), low limits of detection (0.02-0.05 ng L-1), wide linearity (0.1-1000 ng L 1), and good repeatability (2.5%-8.1%) for polar phenols. The new coating was successfully used in the analysis of phenols in real environmental water samples. PPc-CMPs as a polar solid-phase microextraction coating material was excellent for the rapid and sensitive analysis of phenols at trace levels in the environment. PMID- 29530250 TI - Analysis of globotriaosylceramide (Gb3) isoforms/analogs in unfractionated leukocytes, B lymphocytes and monocytes from Fabry patients using ultra-high performance liquid chromatography/tandem mass spectrometry. AB - Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb3) isoforms/analogs, globotriaosylsphingosine (lyso-Gb3) and analogs, and galabiosylceramide (Ga2) isoforms/analogs may accumulate in biological fluids and different organs. The aims of this study were to: 1) develop/validate a novel UHPLC-MS/MS method for relative quantitation of Gb3 in leukocytes (unfractionated white blood cells), B lymphocytes and monocytes; 2) evaluate these biomarkers in a cohort of Fabry patients and healthy controls; and 3) assess correlations between these biomarkers, treatment and genotype. Whole blood, plasma and urine samples from 21 Fabry patients and 20 healthy controls were analyzed. Samples were purified by liquid-liquid extraction and analyzed by UHPLC-MS/MS in positive electrospray ionization. Methylated Gb3 isoforms were detected, showing that a methylation process occurs at the cellular level. Our results show that there were no significant differences in the distribution of the different Gb3 isoforms/analogs in blood cells between Fabry patients and healthy controls. In leukocyte, Gb3[(d18:1)(C14:0)], Gb3[(d18:1)(C16:0)], Gb3 [(d18:1)(C16:0)]Me, Gb3 [(d18:1)(C16:1)], Gb3 [(d18:1)(C18:0)], Gb3 [(d18:1)(C18:1)], Gb3 [(d18:1)(C20:1)], Gb3 [(d18:1)(C24:2)], Gb3 [(d18:1)(C26:1)] and total Gb3 allowed good discrimination between male Fabry patients and male controls, patients having higher biomarker levels than controls. Regarding B lymphocytes and monocytes, the same tendency was observed without reaching statistical significance. A positive concordance between mutation types and biomarker levels in white blood cells was established. Our results might provide a deeper mechanistic comprehension of the underlying biochemical processes of Gb3 biomarkers in white blood cells of Fabry patients. PMID- 29530251 TI - MassImager: A software for interactive and in-depth analysis of mass spectrometry imaging data. AB - Mass spectrometry imaging (MSI) has become a powerful tool to probe molecule events in biological tissue. However, it is a widely held viewpoint that one of the biggest challenges is an easy-to-use data processing software for discovering the underlying biological information from complicated and huge MSI dataset. Here, a user-friendly and full-featured MSI software including three subsystems, Solution, Visualization and Intelligence, named MassImager, is developed focusing on interactive visualization, in-situ biomarker discovery and artificial intelligent pathological diagnosis. Simplified data preprocessing and high throughput MSI data exchange, serialization jointly guarantee the quick reconstruction of ion image and rapid analysis of dozens of gigabytes datasets. It also offers diverse self-defined operations for visual processing, including multiple ion visualization, multiple channel superposition, image normalization, visual resolution enhancement and image filter. Regions-of-interest analysis can be performed precisely through the interactive visualization between the ion images and mass spectra, also the overlaid optical image guide, to directly find out the region-specific biomarkers. Moreover, automatic pattern recognition can be achieved immediately upon the supervised or unsupervised multivariate statistical modeling. Clear discrimination between cancer tissue and adjacent tissue within a MSI dataset can be seen in the generated pattern image, which shows great potential in visually in-situ biomarker discovery and artificial intelligent pathological diagnosis of cancer. All the features are integrated together in MassImager to provide a deep MSI processing solution at the in-situ metabolomics level for biomarker discovery and future clinical pathological diagnosis. PMID- 29530252 TI - Two dimensional alpha-MoO3-x nanoflakes as bare eye probe for hydrogen peroxide in biological fluids. AB - We report a rapid and facile method for detection of hydrogen peroxide (H2O2) in biological fluids using sub-stoichiometric two-dimensional (2D) molybdenum trioxide (alpha-MoO3-x) nanoflakes. The two-dimensional nanoflakes, initially blue in color, is oxidized after interaction with hydrogen peroxide thereby changing its oxidation state to form alpha-MoO3. The change in oxidation state of nanoflakes transforms from blue to a visually distinct hazy blue color with change in absorption spectrum. The phenomenal property is explored here in sensing up to 34 nM as limit of detection. The efficacy of the detection system was analyzed by "zone of inhibition" based agar diffusion assay with different concentrations of H2O2. The current approach is highly accurate, effective and reproducible for quantification of physiological concentration of H2O2 in biological fluid such as human urine. PMID- 29530253 TI - A multifunctional material based on co-electrospinning for developing biosensors with optical oxygen transduction. AB - A multifunctional material based on co-electrospinning has been developed as a basic material for the development of biosensors with optical oxygen transduction. It is based on coaxial nanofibres: inner fibres containing an oxygen sensitive dye and outer fibres containing aldehyde groups to allow the formation of Schiff bases with the amino groups of the enzyme. The resulting material preserves the oxygen sensing properties of the inner optical transducer as well as exhibits a high capacity for immobilizing molecules on its surface. Uricase has been selected as model enzyme and several parameters (temperature, pH, reaction time, buffer, and enzyme concentration) have been optimised to demonstrate the versatility of this novel multifunctional material in the development of biosensors with optical oxygen transduction for determining uric acid in serum samples. It suggests that the proposed multifunctional material can provide a promising multifunctional platform for biosensing applications. PMID- 29530254 TI - Digital ELISA for the quantification of attomolar concentrations of Alzheimer's disease biomarker protein Tau in biological samples. AB - The close correlation between Tau pathology and Alzheimer's disease (AD) progression makes this protein a suitable biomarker for diagnosis and monitoring of the disorder evolution. However, the use of Tau in diagnostics has been hampered, as it currently requires collection of cerebrospinal fluid (CSF), which is an invasive clinical procedure. Although measuring Tau-levels in blood plasma would be favorable, the concentrations are below the detection limit of a conventional ELISA. In this work, we developed a digital ELISA for the quantification of attomolar protein Tau concentrations in both buffer and biological samples. Individual Tau molecules were first captured on the surface of magnetic particles using in-house developed antibodies and subsequently isolated into the femtoliter-sized wells of a 2 * 2 mm2 microwell array. Combination of high-affinity antibodies, optimal assay conditions and a digital quantification approach resulted in a 24 +/- 7 aM limit of detection (LOD) in buffer samples. Additionally, a dynamic range of 6 orders of magnitude was achieved by combining the digital readout with an analogue approach, allowing quantification from attomolar to picomolar levels of Tau using the same platform. This proves the compatibility of the presented assay with the wide range of Tau concentrations encountered in different biological samples. Next, the developed digital assay was applied to detect total Tau levels in spiked blood plasma. A similar LOD (55 +/- 29 aM) was obtained compared to the buffer samples, which was 5000-fold more sensitive than commercially available ELISAs and even outperformed previously reported digital assays with 10-fold increase in sensitivity. Finally, the performance of the developed digital ELISA was assessed by quantifying protein Tau in three clinical CSF samples. Here, a high correlation (i.e. Pearson coefficient of 0.99) was found between the measured percentage of active particles and the reference protein Tau values. The presented digital ELISA technology has great capacity in unlocking the potential of Tau as biomarker for early AD diagnosis. PMID- 29530255 TI - Voltammetric fingerprinting of oils and its combination with chemometrics for the detection of extra virgin olive oil adulteration. AB - In the present work, two approaches for the voltammetric fingerprinting of oils and their combination with chemometrics were investigated in order to detect the adulteration of extra virgin olive oil with olive pomace oil as well as the most common seed oils, namely sunflower, soybean and corn oil. In particular, cyclic voltammograms of diluted extra virgin olive oils, regular (pure) olive oils (blends of refined olive oils with virgin olive oils), olive pomace oils and seed oils in presence of dichloromethane and 0.1 M of LiClO4 in EtOH as electrolyte were recorded at a glassy carbon working electrode. Cyclic voltammetry was also employed in methanolic extracts of olive and seed oils. Datapoints of cyclic voltammograms were exported and submitted to Principal Component Analysis (PCA), Partial Least Square- Discriminant Analysis (PLS-DA) and soft independent modeling of class analogy (SIMCA). In diluted oils, PLS-DA provided a clear discrimination between olive oils (extra virgin and regular) and olive pomace/seed oils, while SIMCA showed a clear discrimination of extra virgin olive oil in regard to all other samples. Using methanolic extracts and considering datapoints recorded between 0.6 and 1.3 V, PLS-DA provided more information, resulting in three clusters-extra virgin olive oils, regular olive oils and seed/olive pomace oils-while SIMCA showed inferior performance. For the quantification of extra virgin olive oil adulteration with olive pomace oil or seed oils, a model based on Partial Least Square (PLS) analysis was developed. Detection limit of adulteration in olive oil was found to be 2% (v/v) and the linearity range up to 33% (v/v). Validation and applicability of all models was proved using a suitable test set. In the case of PLS, synthetic oil mixtures with 4 known adulteration levels in the range of 4-26% were also employed as a blind test set. PMID- 29530256 TI - Honoring the Past, Envisioning the Future: ABCT's 50th Anniversary Presidential Address. AB - The theme of the Association for Behavioral and Cognitive Therapies (ABCT) 50th Anniversary was to honor the past and envision the future. From the wisdom, foresight, and determination of the pioneers of our organization, and the continuous upholding of the scientific method over the last 50 years, cognitive behavioral therapy (CBT) has become the most empirically supported psychological treatment for a wide array of mental health problems. Yet, we still have a long way to go. This address outlines a vision for the future of CBT, which involves greater collaborative science, with all minds working together on the same problem, and greater attention to the risk factors and critical processes that underlie psychopathology and explain treatment change. Such knowledge generation can inform the development of new, more efficient and more effective therapies that are tailored with more precision to the needs of each person. Latest technologies provide tools for a precision focus while at the same time increasing the reach of our treatments to the many for whom traditional therapies are unavailable. Our impact will be greatly enhanced by large samples with common methods and measures that inform a precision approach. We have come a long way since ABCT was founded in 1966, and we are poised to make even larger strides in our mission to enhance health and well-being by harnessing science, our major guiding principle. PMID- 29530257 TI - Combined Audience and Video Feedback With Cognitive Review Improves State Anxiety and Self-Perceptions During Speech Tasks in Socially Anxious Individuals. AB - This study investigated the effects of combined audience feedback with video feedback plus cognitive preparation, and cognitive review (enabling deeper processing of feedback) on state anxiety and self-perceptions including perception of performance and perceived probability of negative evaluation in socially anxious individuals during a speech performance. One hundred and forty socially anxious students were randomly assigned to four conditions: Cognitive Preparation + Video Feedback + Audience Feedback + Cognitive Review (CP+VF+AF+CR), Cognitive Preparation + Video Feedback + Cognitive Review (CP+VF+CR), Cognitive Preparation + Video Feedback only (CP+VF), and Control. They were asked to deliver two impromptu speeches that were evaluated by confederates. Participants' levels of anxiety and self-perceptions pertaining to the speech task were assessed before and after feedback, and after the second speech. Compared to participants in the other conditions, participants in the CP+VF+AF+CR condition reported a significant decrease in their state anxiety and perceived probability of negative evaluation scores, and a significant increase in their positive perception of speech performance from before to after the feedback. These effects generalized to the second speech. Our results suggest that adding audience feedback to video feedback plus cognitive preparation and cognitive review may improve the effects of existing video feedback procedures in reducing anxiety symptoms and distorted self-representations in socially anxious individuals. PMID- 29530258 TI - Treating Procrastination Using Cognitive Behavior Therapy: A Pragmatic Randomized Controlled Trial Comparing Treatment Delivered via the Internet or in Groups. AB - Procrastination is a common problem among university students, with at least half of the population reporting great difficulties initiating or completing tasks and assignments. Procrastination can have a negative impact on course grades and the ability to achieve a university degree, but can also lead to psychological distress. Cognitive behavior therapy (CBT) is believed to reduce procrastination, but few studies have investigated its effectiveness in a regular clinical setting. The current study explored its effects using a pragmatic randomized controlled trial comparing treatment delivered during 8 weeks as self-guided CBT via the Internet (ICBT) or as group CBT. In total, 92 university students with severe procrastination were included in the study (registered as a clinical trial on Clinicaltrials.gov: NCT02112383). Outcome measures on procrastination, depression, anxiety, and well-being were distributed at pre- and posttreatment as well as 6-month follow-up. An outcome measure of procrastination was administered weekly. Linear mixed and fixed effects models were calculated, along with improvement and deterioration rates. The results showed large within-group effect sizes on procrastination, Cohen's d of 1.29 for ICBT, 95% Confidence Interval (CI) [0.81, 1.74], and d of 1.24 for group CBT, 95% CI [0.76, 1.70], and small to moderate benefits for depression, anxiety, and well-being. In total, 33.7% were regarded as improved at posttreatment and 46.7% at follow-up. No differences between conditions were observed after the treatment period, however, participants in group CBT continued or maintained their improvement at follow-up, while participants in self-guided ICBT showed some signs of deterioration. The findings from the current study suggest that CBT might be an effective treatment for those struggling with severe procrastination, but that a group format may be better for some to sustain their benefits over time and that the clinical significance of the results need to be investigated further. PMID- 29530259 TI - Modification of Hostile Interpretation Bias in Depression: A Randomized Controlled Trial. AB - Interpretation Bias Modification (IBM) is gaining attention in the literature as an intervention that alters cognitive biases and reduces associated symptoms. Forty, primarily college-aged, non-treatment-seeking adults with major depressive disorder (MDD) were randomly assigned to receive either IBM targeting hostile interpretation bias (IBM-H) or a healthy video control (HVC) condition. Compared to those in HVC, participants in IBM-H reported more benign interpretations and fewer hostile interpretations at posttreatment. No difference in depressive interpretation bias was found between groups at posttreatment. IBM-H led to improved anger control at posttreatment and follow-up compared to HVC, though no effects of condition were found on trait anger or depressive symptoms. The IBM-H group perceived their treatment as less credible than the HVC group. For individuals with high expectancy of treatment success, IBM-H led to lower posttreatment depressive symptoms compared to HVC, while findings trended in the opposite direction for those with low expectancy of success. Overall, these preliminary findings point to boundary conditions for the efficacy of IBM protocols for anger and depression and potential improvements to be made to future IBM protocols. PMID- 29530260 TI - Using Retrieval Cues to Attenuate Return of Fear in Individuals With Public Speaking Anxiety. AB - Even after successful exposure, relapse is not uncommon. Based on the retrieval model of fear extinction (e.g., Vervliet, Craske, & Hermans, 2013), return of fear can occur after exposure due to an elapse of time (spontaneous recovery) or change in context (contextual renewal). The use of external salient stimuli presented throughout extinction (i.e., retrieval cues [RCs]) has been suggested as a potential solution to this problem (Bouton, 2002). The current study examined whether RCs attenuated return of fear in individuals with public speaking anxiety. Sixty-five participants completed a brief exposure while presented with two RC stimuli aimed at a variety of senses (visual, tactile, olfactory, and auditory). Later, half the participants were tested for return of fear in a context different from the exposure context, and the other half in the same context. Half of each context group were presented with the same cues as in exposure, while the other half were not. Return of fear due to an elapse of time, change in context, and effects of RCs were evaluated on subjective, behavioral, and physiological measures of anxiety. Although contextual renewal was not observed, results supported effects of RCs in reducing spontaneous recovery on behavioral and physiological measures of anxiety. There was also evidence that participants who were reminded of feeling anxious during exposure by the RCs benefited more from using them at follow-up, whereas those who perceived the cues as comforting (safety signals) benefited less. Clinical implications of the findings are discussed. PMID- 29530261 TI - Prospective Associations of Coping Styles With Depression and Suicide Risk Among Psychiatric Emergency Patients. AB - Suicide is the second leading cause of death for those ages 13-25 in the United States. Coping is a mediator between stressful life events and adverse outcomes, and coping skills have been incorporated into interventions (e.g., cognitive behavioral therapy, dialectical behavior therapy, safety-planning interventions) for suicidal populations. However, longitudinal research has not directly examined the prospective associations between multiple coping styles and suicide related outcomes in high-risk samples. This study identified cross-sectional and 4-month longitudinal associations of coping styles with suicide risk factors (i.e., depression, suicidal ideation, suicidal behavior) in a sample of 286 adolescent and young adult psychiatric emergency patients. Positive reframing was the coping style most consistently associated with positive outcomes, whereas self-blame and disengagement were consistently associated with negative outcomes. Active coping protected against suicidal behavior for males, but not for females. This was the first study to examine longitudinal relationships between coping and suicide-related outcomes in a high-risk clinical sample. Findings suggest that clinical interventions with suicidal adolescents and young adults may benefit from a specific focus on increasing positive reframing and reducing self-blame. PMID- 29530262 TI - Predicting Response to an Internet-Delivered Parenting Program for Anxiety in Early Childhood. AB - Previous research has identified factors related to outcome in child anxiety treatment and parent training programs for child behavior problems. However, it is unclear what factors predict outcomes in interventions delivered online to parents of young children at risk of anxiety. This study investigated predictors of child anxiety outcomes among 433 families with young children (3-6 years) who participated in a randomized controlled trial of Cool Little Kids Online, an eight-module early intervention program for child anxiety based on cognitive behavioral therapy (CBT). Potential predictors included baseline demographic factors, child and parent mental health factors, and indicators of program use, including number of online modules completed and frequency of homework practice. Results showed that only access to a printer moderated intervention effectiveness. Printer access predicted lower child anxiety in the Cool Little Kids Online group, but had no effect on outcomes in the wait-list group. In both groups, higher levels of child anxiety symptoms, child-inhibited temperament, and poorer parent mental health at baseline predicted higher levels of child anxiety symptoms at 6-month follow-up. The amount of online program use was not related to improvements in child anxiety symptoms. However, parents who reported practicing the program skills more frequently showed greater reductions in child anxiety, and access to a printer was related to frequency of program skills practice. These findings provide empirical support for the important role of skills practice in online CBT interventions, and suggest that practicing program skills may be more important than completing the online modules. PMID- 29530263 TI - Consumer Smartphone Apps Marketed for Child and Adolescent Anxiety: A Systematic Review and Content Analysis. AB - Anxiety disorders are collectively the most prevalent mental health problems affecting youth. To increase the reach of mental health care, recent years have seen increasing enthusiasm surrounding mobile platforms for expanding treatment delivery options. Apps developed in academia and supported in clinical trials are slow to reach the consumer marketplace. Meanwhile, proliferation of industry developed apps on consumer marketplaces has been high. The present study analyzed content within mobile products prominently marketed toward consumers for anxiety in youth. Systematic inventory of the Google Play Store and Apple Store using keyword searches for child and adolescent anxiety yielded 121 apps, which were evaluated on the basis of their descriptive characteristics, mobile functionalities, and adherence to evidence-based treatment principles. Findings revealed that evidence-based treatment content within the sample is scant and few comprehensive anxiety self-management apps were identified. Advanced features that leverage the broader functionalities of smartphone capabilities (e.g., sensors, ecological momentary assessments) were rarely present. Findings underscore the need to increase the prominence and accessibility of quality child anxiety intervention products for consumers. Strategies for improving marketing of supported apps to better penetrate consumer markets are discussed. PMID- 29530265 TI - Racial Differences in Attributions, Perceived Criticism, and Upset: A Study With Black and White Community Participants. AB - The primary aims of the current investigation were (a) to examine the relationships among attributions, perceived constructive and destructive criticism, and upset due to criticism and (b) to explore racial differences in mean levels of attributions, perceived criticism, upset due to criticism, and warmth in a community sample of Blacks and Whites (N = 272). The Attributions of Criticism Scale (ACS) was used to measure participants' attributions regarding criticism from their relatives. No racial differences were found in mean levels of attributions or type of perceived criticism. However, Blacks were significantly less upset by perceived criticism from their relatives than Whites. When the relationships between attributions, perceived criticism, and upset were explored, results showed that positive attributions were associated with greater perceived constructive criticism and less upset due to criticism, whereas negative attributions were associated with greater perceived destructive criticism and more upset. Perceptions of relatives' warmth were also associated with greater perceived constructive criticism and less perceived destructive criticism, but warmth was only related to less upset for Blacks and not Whites. Findings suggest that attributions and warmth play an important role in the perception of criticism and the extent to which individuals become upset in response to criticism from loved ones. Results also point to potential racial differences in mean levels of these variables and the associations among them. PMID- 29530264 TI - Visual Attention to Pictorial Food Stimuli in Individuals With Night Eating Syndrome: An Eye-Tracking Study. AB - Night eating syndrome (NES) is characterized by excessive evening and/or nocturnal eating episodes. Studies indicate an attentional bias towards food in other eating disorders. For NES, however, evidence of attentional food processing is lacking. Attention towards food and non-food stimuli was compared using eye tracking in 19 participants with NES and 19 matched controls without eating disorders during a free exploration paradigm and a visual search task. In the free exploration paradigm, groups did not differ in initial fixation position or gaze duration. However, a significant orienting bias to food compared to non-food was found within the NES group, but not in controls. A significant attentional maintenance bias to non-food compared to food was found in both groups. Detection times did not differ between groups in the search task. Only in NES, attention to and faster detection of non-food stimuli were related to higher BMI and more evening eating episodes. The results might indicate an attentional approach avoidance pattern towards food in NES. However, further studies should clarify the implications of attentional mechanisms for the etiology and maintenance of NES. PMID- 29530266 TI - Profile Analysis of Psychological Symptoms Associated With Misophonia: A Community Sample. AB - Misophonia is characterized by extreme aversive reactions to certain classes of sounds. It has recently been recognized as a condition associated with significant disability. Research has begun to evaluate psychopathological correlates of misophonia. This study sought to identify profiles of psychopathology that characterize misophonia in a large community sample. A total of N = 628 adult participants completed a battery of measures assessing anxiety and anxiety sensitivity, depression, stress responses, anger, dissociative experiences, obsessive-compulsive symptoms and beliefs, distress tolerance, bodily perceptions, as well as misophonia severity. Profile Analysis via Multidimensional Scaling (PAMS) was employed to evaluate profiles associated with elevated misophonia and those without symptoms. Three profiles were extracted. The first two accounted for 70% total variance and did not show distinctions between groups. The third profile accounted for 11% total variance, and showed that misophonia is associated with lower obsessive-compulsive symptoms for neutralizing, obsessions generally, and washing compared to those not endorsing misophonia, and higher levels of obsessive-compulsive symptoms associated with ordering and harm avoidance. This third profile extracted also showed significant differences between those with and without misophonia on the scale assessing physical concerns (that is, sensitivity to interoceptive sensations) as assessed with the ASI-3. Further research is called for involving diagnostic interviewing and experimental methods to clarify these putative mechanisms associated with misophonia. PMID- 29530268 TI - Corrigendum to "Intervention Effectiveness of The Incredible Years: New Insights Into Sociodemographic and Intervention-Based Moderators" [Behavior Therapy 48 (2017) 1-18]. PMID- 29530269 TI - CS Frojan et al. in response to the article by SK Lim et al.: Biotin interferes with free thyroid hormone and thyroglobulin, but not TSH measurements using Beckman-Access immunoassays. Lim SK, Pilon A, Guechot J. Ann Endocrinol (Paris) 2017;78(3):186-7. PMID- 29530267 TI - Efficacy of Guided iCBT for Depression and Mediation of Change by Cognitive Skill Acquisition. AB - Guided internet CBT (iCBT) is a promising treatment for depression; however, it is less well known through what mechanisms iCBT works. Two possible mediators of change are the acquisition of cognitive skills and increases in behavioral activation. We report results of an 8-week waitlist controlled trial of guided iCBT, and test whether early change in cognitive skills or behavioral activation mediated subsequent change in depression. The sample was 89 individuals randomized to guided iCBT (n = 59) or waitlist (n = 30). Participants were 75% female, 72% Caucasian, and 33 years old on average. The PHQ9 was the primary outcome measure. Mediators were the Competencies of Cognitive Therapy Scale-Self Report and the Behavioral Activation Scale for Depression-Short Form. Treatment was Beating the Blues plus manualized coaching. Outcomes were analyzed using linear mixed models, and mediation with a bootstrap resampling approach. The iCBT group was superior to waitlist, with large effect sizes at posttreatment (Hedges' g = 1.45). Dropout of iCBT was 29% versus 10% for waitlist. In the mediation analyses, the acquisition of cognitive skills mediated subsequent depression change (indirect effect = -.61, 95% bootstrapped biased corrected CI: -1.47, 0.09), but increases in behavioral activation did not. iCBT is an effective treatment for depression, but dropout rates remain high. Change in iCBT appears to be mediated by improvements in the use of cognitive skills, such as critically evaluating and restructuring negative thoughts. PMID- 29530270 TI - Prostate adenocarcinoma in a young patient with multiple endocrine neoplasia 2B. PMID- 29530271 TI - Decreased sensitivity of thyrotropin-thyroid hormone feedback control in hypothyroid and athyreotic patients treated with levothyroxine. Is serum triiodothyronine involved? AB - OBJECTIVES: The search for optimal therapy for hypothyroidism is challenging and complex and is still going on. We investigated TSH-thyroid hormone feedback control in hypothyroid and athyreotic patients properly treated with levothyroxine (LT4), based on normal TSH values. MATERIAL AND METHODS: We randomly selected 150 hypothyroid, 110 athyreotic and 210 euthyroid subjects, determined their serum T4, T3 and TSH values and calculated T4/TSH and T3/T4 ratios. RESULTS: The TSH distribution in hypothyroidism was significantly shifted to the higher and that in athyreosis to the lower values from the normal distribution in euthyroid controls. This TSH-thyroid hormone dissociation in hypothyroidism was characterized with higher T4 and higher matched TSH values. We found 5% hypothyroid and 10% athyreotic patients normalize TSH only with hyperthyroxinemia. Serum T3 was lower in both hypothyroid groups and unaffected by a higher LT4 dose and higher serum T4 in athyreosis. CONCLUSION: Our results suggest that the decreased serum T3 is a major cause of impaired TSH-thyroid hormone feedback control in hypothyroidism treated with LT4. PMID- 29530272 TI - J. Vouillarmet et al. in response to V. Aboyans et al. concerning the article by M. Helfre et al.: Usefulness of a systematic screening of carotid atherosclerosis in asymptomatic people with type 2 diabetes for cardiovascular risk reclassification. Ann Endocrinol (Paris). 2017;78:14-19. PMID- 29530273 TI - Anisotropic surface chemistry properties and adsorption behavior of silicate mineral crystals. AB - Anisotropic surface properties of minerals play an important role in a variety of fields. With a focus on the two most intensively investigated silicate minerals (i.e., phyllosilicate minerals and pegmatite aluminosilicate minerals), this review highlights the research on their anisotropic surface properties based on their crystal structures. Four surface features comprise the anisotropic surface chemistry of minerals: broken bonds, energy, wettability, and charge. Analysis of surface broken bond and energy anisotropy helps to explain the cleavage and growth properties of mineral crystals, and understanding surface wettability and charge anisotropy is critical to the analysis of minerals' solution behavior, such as their flotation performance and rheological properties. In a specific reaction, the anisotropic surface properties of minerals are reflected in the adsorption strengths of reagents on different mineral surfaces. Combined with the knowledge of mineral crushing and grinding, a thorough understanding of the anisotropic surface chemistry properties and the anisotropic adsorption behavior of minerals will lead to the development of effective relational models comprising their crystal structure, surface chemistry properties, and targeted reagent adsorption. Overall, such a comprehensive approach is expected to firmly establish the connection between selective cleavage of mineral crystals for desired surfaces and designing novel reagents selectively adsorbed on the mineral surfaces. As tools to characterize the anisotropic surface chemistry properties of minerals, DLVO theory, atomic force microscopy (AFM), and molecular dynamics (MD) simulations are also reviewed. PMID- 29530274 TI - [Cardiovascular risk factors in Algeria. Analysis of the subgroup from the "Africa/Middle East Cardiovascular Epidemiological" Study]. AB - OBJECTIVES: This cross-sectional epidemiological study aimed at determining the prevalence of cardiovascular risk factors (CVRF; including obesity, dyslipidaemia, hypertension, diabetes and smoking), among patients from the Algerian sub-population of the "Africa/Middle East Cardiovascular Epidemiological" study attending general practitioners at primary healthcare facilities, and stratified according to their environment (rural/urban), sex and age. PATIENTS AND METHODS: The study sites, located in 10 wilayas (administrative regions), were situated in urban and rural areas (rural populations defined as living at least 50km away from urban centres, or lacking access to suburban transport). RESULTS: Four hundred and ten subjects (262 female, 148 male) were enrolled; 287 subjects were from an urban environment and 123 from a rural environment. Mean age was 50.4 years. Ninety one point eight percent of patients had >=1 CVRF; 48.2% had >=3 CVRF. Prevalence for the different CVRF was: 61.7% for dyslipidaemia; 39.5% for hypertension; 25.0% for diabetes; 10.0% for smoking, 70.0% for abdominal obesity and 32.0% for a body mass index >=30kg/m2. CONCLUSION: The high prevalence of all CVRF observed in the Algeria sub-group, especially among the rural population, should encourage us to develop a carefully planned strategy for primary prevention, opportunistic screening and early management, in both urban and rural settings, and with particular attention to young adults. These actions should involve all state bodies and those active in civil society, in order to guarantee full achievement of set goals. The ACE trial is registered under NCT01243138. PMID- 29530276 TI - The evolution of familial polyposis coli. PMID- 29530275 TI - Stoma reversal after surgery for complicated acute diverticulitis: A multicentre retrospective study. AB - : INTRODUCTION THE AIM: was to analyse the stoma reversal rate after surgery for complicated acute diverticulitis (CAD), and more specifically the end-stoma reversal, as well as the delay, feasibility, complications and risk factors for stoma maintenance. METHODS: A multicentre retrospective study of patients who had undergone urgent surgery for CAD with stoma formation in ten hospitals during a period of 6 years. The frequency of reversal over time and the factors affecting the decision for reversal were analysed. RESULTS: Out of 385 patients operated for CAD, 312 underwent stoma creation: 292 end colostomies and 20 diverting stomas. During follow-up, stoma reversal surgery was performed in 161 patients (51.6%) after a median of 9 months. The main causes for not performing stoma reversal were comorbidities and the death of the patient. Advanced age was an adverse factor in the multivariate analysis, and the actuarial rate of reversal was higher in men and in patients with no previous Hartmann's operation. Stoma reversal surgery was completed in all but one patient, and a loop ileostomy was associated in four. Morbidity and mortality rates were 35.7% and 1.9%, respectively. A total of 8.4% of patients underwent re-operation, and 6% experienced an anastomotic leak. Twelve patients remained with a stoma after the attempted reconstruction surgery. CONCLUSIONS: Surgery for CAD is frequently associated with an end stoma, which will ultimately not be reversed in almost 50% of patients. Moreover, reversal surgery is frequently delayed and is associated with significant morbidity and mortality. PMID- 29530277 TI - The cervical spine can be cleared without MRI after blunt trauma:A retrospective review of a single level 1 trauma center experience over 8 years. AB - BACKGROUND: The newest CT scanners provide resolution comparable to MRIs leading many to question when and whether cervical spine MRIs are warranted. METHODS: An 8 year retrospective review identified 241 patients who underwent CT scan and MRI of the cervical spine. The initial clinical examination, cervical spine CT scan, and cervical spine MRI were compared to identify cervical spine injuries that would have been missed had the MRI not been performed. RESULTS: The CT scans were normal in 153 patients, and abnormal in 88. Of the 88 abnormal CT scans, the MRIs were abnormal in 65, and normal in the other 23. The indications for MRI in patients with normal CT scans were neck pain, an abnormal neurologic examination, and/or altered mental status. Of the 13 patients with abnormal MRIs, none were pain free with a normal clinical examination. CONCLUSION: In the absence of focal signs of neurologic injury, the cervical spine can be cleared without a clinical exam or MRI if the cervical CT scan does not demonstrate injury or abnormality. PMID- 29530278 TI - A 15 year cohort review of in-hospital pediatric trauma center mortality: A catalyst for injury prevention programming. AB - BACKGROUND: The objective of our study was to identify the most common mechanisms of injury leading to death in our pediatric population. METHODS: A retrospective cohort of fatally injured children 0-17 years old treated at our trauma center during 2000-2015. RESULTS: The mortality rate in our population was 8% (n = 103). Fifty-five percent were male. The majority (76%) of fatal injuries were blunt. Overall, motor vehicle collisions (MVCs) were the most common mechanism of injury (61%), followed by assault/abuse (9%). Of the deaths caused by MVCs, 37 (59%) were occupants, 11 (17%) were pedestrians, and 6 (10%) were cyclists. In the infant sub-population, assault/abuse was the most common mechanism of injury. CONCLUSION: MVCs were the leading cause of death in this population. In the infant subpopulation (<1 year), abusive head trauma emerged as the leading mechanism. Injury prevention programming should target abusive head trauma in infants and teen road safety. PMID- 29530279 TI - Air Pollution Exposure During Fetal Life, Brain Morphology, and Cognitive Function in School-Age Children. AB - BACKGROUND: Air pollution exposure during fetal life has been related to impaired child neurodevelopment, but it is unclear if brain structural alterations underlie this association. The authors assessed whether air pollution exposure during fetal life alters brain morphology and whether these alterations mediate the association between air pollution exposure during fetal life and cognitive function in school-age children. METHODS: We used data from a population-based birth cohort set up in Rotterdam, The Netherlands (2002-2006). Residential levels of air pollution during the entire fetal period were calculated using land-use regression models. Structural neuroimaging and cognitive function were performed at 6 to 10 years of age (n = 783). Models were adjusted for several socioeconomic and lifestyle characteristics. RESULTS: Mean fine particle levels were 20.2 MUg/m3 (range, 16.8-28.1 MUg/m3). Children exposed to higher particulate matter levels during fetal life had thinner cortex in several brain regions of both hemispheres (e.g., cerebral cortex of the precuneus region in the right hemisphere was 0.045 mm thinner (95% confidence interval, 0.028-0.062) for each 5 MUg/m3 increase in fine particles). The reduced cerebral cortex in precuneus and rostral middle frontal regions partially mediated the association between exposure to fine particles and impaired inhibitory control. Air pollution exposure was not associated with global brain volumes. CONCLUSIONS: Exposure to fine particles during fetal life was related to child brain structural alterations of the cerebral cortex, and these alterations partially mediated the association between exposure to fine particles during fetal life and impaired child inhibitory control. Such cognitive impairment at early ages could have significant long-term consequences. PMID- 29530280 TI - ConVes: The Sutureless Aortic Graft Anastomotic Device. AB - PURPOSE: Less invasive left ventricular assist device implantation became feasible with the development of smaller devices. This study evaluated a sutureless aortic anastomosis device to facilitate the implant procedure. DESCRIPTION: The novel anastomotic device deploys and anchors an acute-angled stent in the aortic wall to create a sutureless outflow graft anastomosis in the ascending aorta. Four aortic anastomoses were performed on the beating hearts of two pigs without cross-clamping or cardiopulmonary bypass. EVALUATION: The procedure was fast and simple. The time of anastomosis averaged 8.1 minutes, with merely oral instructions to the operating surgeon. The design of the stent allowed the outflow graft to be implanted with the intended angulation of 45 degrees. CONCLUSIONS: This proof-of-concept study demonstrates the feasibility and short-term success of the proposed sutureless anastomotic device. Further preclinical studies are necessary to evaluate long-term durability of the anastomosis. PMID- 29530282 TI - ? PMID- 29530281 TI - Single-nephron proteomes connect morphology and function in proteinuric kidney disease. AB - In diseases of many parenchymatous organs, heterogeneous deterioration of individual functional units determines the clinical prognosis. However, the molecular characterization at the level of such individual subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Proteinuric glomerular kidney diseases are frequent and assorted diseases affecting a fraction of glomeruli and their draining tubules to variable extents, and for which no specific treatment exists. Here, we developed and applied a mass spectrometry-based methodology to investigate heterogeneity of proteomes from individually isolated nephron segments from mice with proteinuric kidney disease. In single glomeruli from two different mouse models of sclerotic glomerular disease, we identified a coherent protein expression module consisting of extracellular matrix protein deposition (reflecting glomerular sclerosis), glomerular albumin (reflecting proteinuria) and LAMP1, a lysosomal protein. This module was associated with a loss of podocyte marker proteins while genetic ablation of LAMP1-correlated lysosomal proteases could ameliorate glomerular damage in vivo. Furthermore, proteomic analyses of individual glomeruli from patients with genetic sclerotic and non-sclerotic proteinuric diseases revealed increased abundance of lysosomal proteins, in combination with a decreased abundance of mutated gene products. Thus, altered protein homeostasis (proteostasis) is a conserved key mechanism in proteinuric kidney diseases. Moreover, our technology can capture intra-individual variability in diseases of the kidney and other tissues at a sub-biopsy scale. PMID- 29530283 TI - ? PMID- 29530284 TI - [Improving the prevention of rehospitalisation]. AB - International literature endorses an organisation of care which links up the hospital and the usual living environment of the elderly person as well as interdisciplinarity in the pathway of these vulnerable patients. The internal medicine and vascular diseases department of Angers university hospital favours these two principles and wishes to strenghten this strategy thanks to the intervention of a dedicated nurse and an occupational therapist. The aim is to prevent the early rehospitalisation of elderly people. PMID- 29530285 TI - [Organising a successful return home]. AB - Discharge from hospital is a major component of the quality and efficiency of the healthcare system. The failures of the return home of elderly people testify to the difficulties of applying guidelines in the area of hospital discharge. The action plan decided in the hospital for a successful return home can be jeopardised for personal, relational, functional and structural reasons originating from the different players involved in the hospital discharge. PMID- 29530286 TI - [The suitability of sending nursing home residents over 75 to emergency departments]. AB - The care provided to elderly people aged over 75 must be specific and multidisciplinary. An emergency department, which is seeing increasing numbers of patients passing through its doors, notably with the provision of an ambulatory care service, would not appear to be a suitable place for this fragile population, often with multiple pathologies. A study is looking at the suitability of the emergency department for nursing home residents, who have regular access to medical care, unlike elderly people living at home. PMID- 29530287 TI - [When the disabled sector meets that of gerontology]. AB - Denis is a 62-year-old man with Down syndrome. He lives in a residential home and is retired from a supported employment service centre. Since suffering a stroke, Denis has been relatively immobile, looking on as a spectator in the medical social centre where he is living. Anticipating his advancing years, the team has turned to a gerontological team which will intervene in a centre for people with disabilities. PMID- 29530288 TI - [Living wills in a nursing home, guaranteeing freedom of expression]. AB - The drawing up of a living will in a nursing home for elderly people is a complex process. Not only must the resident think about the end of life, which is not easy, but the institution must be fully aware of the law. Guaranteeing the resident's expression is essential. A study enabled this subject to be reviewed in a nursing home where different players are present around the resident. It enabled professionals to reflect on their practices. PMID- 29530289 TI - [Humour therapy, laughter and the intervention of clowns in gerontology]. AB - Confronted with the growing incidence of age-related pathologies and the limits of so-called traditional medicine oriented towards the prescribing of medicines, non-pharmacological approaches have grown considerably in the geriatric community. A literature review focused on the therapeutic benefit of humour, laughter and the use of clowns on the physical and psychological health of elderly people. PMID- 29530290 TI - ? PMID- 29530291 TI - ? PMID- 29530292 TI - Feasibility of mobile mental wellness training for older adults. AB - Mobile technology has been increasingly adopted in promotion of mental health among older people. This study assessed the feasibility of a mobile mental wellness training application for individual use and for group work from the perspectives of older adults and social care professionals. The older individuals recruited for the study were participants in a Circle of Friends group and family caregivers' peer support group offered by the communal senior services. The qualitative and quantitative results of interviews, questionnaires, observation, and application usage were reported. Seven older adults started using the application independently at home in parallel with the group activity. This study revealed new information regarding the barriers to the older adults' full adoption of such mobile technologies. The results indicated that there may be potential in the incorporation of mobile technologies in promotion of mental health of older people at group settings. PMID- 29530293 TI - Practical non-pharmacological intervention approaches for sleep problems among older adults. AB - Poor sleep is common among older adults, often caused by multiple underlying factors such as chronic stress. Poor sleep is subsequently associated with negative health outcomes including higher morbidity and mortality. Our primary purpose is to explore practical non-pharmacological intervention approaches integrating stress management to improve sleep quality among older adults. In doing so, we highlight approaches that appear to hold promise in real-world settings with older individuals. We conducted a tailored literature review specifically on approaches to improve sleep quality among older adults, with emphasis on those integrating stress management. Online search engines were reviewed to identify research in these areas. Various non-pharmacological intervention approaches, such as mindfulness and cognitive behavioral therapy, have shown promise in improving sleep quality and health outcomes within this population. Those integrating chronic stress management appear to be particularly successful. Thus further development of multidimensional sleep interventions integrating stress management with seniors is warranted. PMID- 29530294 TI - Regarding "Epidemiology and risk factors for Clostridium difficile-associated diarrhea in adult inpatients in a university hospital in China: Methodologic issues". PMID- 29530295 TI - 'One size does not fit all' - customizing hand hygiene agents, messages, and interventions. PMID- 29530296 TI - Sweet's syndrome with ocular involvement. PMID- 29530297 TI - [Giant retroperitoneal liposarcoma]. PMID- 29530298 TI - [Association of chromhidrosis and segmental neurofibromatosis]. PMID- 29530299 TI - [Schistosomiasis: in France too]. PMID- 29530300 TI - [Breast calciphylaxis: An uncommon and difficult pathology]. PMID- 29530301 TI - Is It Feasible to Identify Natural Clusters of TSC-Associated Neuropsychiatric Disorders (TAND)? AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with multisystem involvement. The lifetime prevalence of TSC-Associated Neuropsychiatric Disorders (TAND) is in the region of 90% in an apparently unique, individual pattern. This "uniqueness" poses significant challenges for diagnosis, psycho-education, and intervention planning. To date, no studies have explored whether there may be natural clusters of TAND. The purpose of this feasibility study was (1) to investigate the practicability of identifying natural TAND clusters, and (2) to identify appropriate multivariate data analysis techniques for larger-scale studies. METHODS: TAND Checklist data were collected from 56 individuals with a clinical diagnosis of TSC (n = 20 from South Africa; n = 36 from Australia). Using R, the open-source statistical platform, mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. RESULTS: Ward's method rendered six TAND clusters with good face validity and significant convergence with a six-factor exploratory factor analysis solution. The "bottom up" data-driven strategies identified a "scholastic" cluster of TAND manifestations, an "autism spectrum disorder-like" cluster, a "dysregulated behavior" cluster, a "neuropsychological" cluster, a "hyperactive/impulsive" cluster, and a "mixed/mood" cluster. CONCLUSIONS: These feasibility results suggest that a combination of cluster analysis and exploratory factor analysis methods may be able to identify clinically meaningful natural TAND clusters. Findings require replication and expansion in larger dataset, and could include quantification of cluster or factor scores at an individual level. PMID- 29530303 TI - Time series modeling in traffic safety research. AB - The use of statistical models for analyzing traffic safety (crash) data has been well-established. However, time series techniques have traditionally been underrepresented in the corresponding literature, due to challenges in data collection, along with a limited knowledge of proper methodology. In recent years, new types of high-resolution traffic safety data, especially in measuring driver behavior, have made time series modeling techniques an increasingly salient topic of study. Yet there remains a dearth of information to guide analysts in their use. This paper provides an overview of the state of the art in using time series models in traffic safety research, and discusses some of the fundamental techniques and considerations in classic time series modeling. It also presents ongoing and future opportunities for expanding the use of time series models, and explores newer modeling techniques, including computational intelligence models, which hold promise in effectively handling ever-larger data sets. The information contained herein is meant to guide safety researchers in understanding this broad area of transportation data analysis, and provide a framework for understanding safety trends that can influence policy-making. PMID- 29530304 TI - Data and methods for studying commercial motor vehicle driver fatigue, highway safety and long-term driver health. AB - This article summarizes the recommendations on data and methodology issues for studying commercial motor vehicle driver fatigue of a National Academies of Sciences, Engineering, and Medicine study. A framework is provided that identifies the various factors affecting driver fatigue and relating driver fatigue to crash risk and long-term driver health. The relevant factors include characteristics of the driver, vehicle, carrier and environment. Limitations of existing data are considered and potential sources of additional data described. Statistical methods that can be used to improve understanding of the relevant relationships from observational data are also described. The recommendations for enhanced data collection and the use of modern statistical methods for causal inference have the potential to enhance our understanding of the relationship of fatigue to highway safety and to long-term driver health. PMID- 29530305 TI - [Theoretical and practical assessment of Lille general practice and pharmacy students' knowledge about use of inhaler devices for asthma control]. AB - INTRODUCTION: Asthma is a potentially serious chronic respiratory disease impacting patients quality of life. Satisfactory control requires proper use of inhaled devices. This study assesses general medical residents and pharmacy students knowledge about proper use of inhaled asthma devices. MATERIALS AND METHODS: We evaluated knowledge of 43 general practice students and 43 pharmacy students in Lille for three inhaler devices (metered-dose inhaler, Turbuhaler(r) and Diskus(r)) during individual interviews. Students were assessed on 8 proper use criterias for each device. RESULTS: General practice and pharmacy students are unfamiliar with proper use of inhaler devices. However, pharmacy students get better average scores than general practice students for all devices included in this study: 6.3/8 respected criterias against 5/8 for metered-dose inhaler; 5.3/8 against 3.2/8 for Turbuhaler(r); and 6/8 against 4.3/8 for Diskus(r). Pharmacy students more frequently perform a demonstration of proper use to patients when a device is first prescribed or when a prescription is renewed; general practice students more frequently ask patients themselves to perform a demonstration of proper use. CONCLUSION: Introducing trainings workshops for inhaler devices to pharmacy and general practice students appears appropriate in order to promote therapeutic patient education, to increase asthma control and better patients life quality. PMID- 29530306 TI - Contemporary Burn Survival. AB - BACKGROUND: The standard of burn treatment today reflects major advances. We sought to quantitate the impact of these advances on burn survival via age stratified mortality ratios compared with other reported mortality analyses in burns. STUDY DESIGN: Age, percent of the total body surface area (TBSA) burned, presence of inhalation injury, length of stay, and survival status were recorded at admission and at discharge for all new burn admissions between 1989 and 2017. The expected mortality probability was calculated using historical multiple regression techniques and compared with observed data. We developed a prediction model for our observed data. RESULTS: Between 1989 and 2017, there were 10,384 consecutive new burn admissions, with 355 mortalities (median age, 13 years; median percent TBSA burn, 11%). We saw a significant decrease in our observed mortality data compared to historical predictions (p < 0.0001), and a 2% reduction per year in mortality during the 3 decades. The prediction model of mortality for the data is as follows: Pr(dying) = ex/(1 + ex) where x = -6.44 - 0.12 age + 0.0042 age2 - 0.0000283 age3 + 0.0499 TBSA + 1.21 Inhalation Injury + 0.015 third degree TBSA. CONCLUSIONS: The reduction in mortality over time may be attributed to successful changes in standard of care protocols in the burn center that improved the outlook for burned individuals, including protocols for management of inhalation injury, nutrition, resuscitation, and early excision and grafting. PMID- 29530307 TI - Parasites of the Giant Panda: A Risk Factor in the Conservation of a Species. AB - The giant panda, with an estimated population size of 2239 in the world (in 2015), is a global symbol of wildlife conservation that is threatened by habitat loss, poor reproduction and limited resistance to some infectious diseases. Of these factors, some diseases caused by parasites are considered as the foremost threat to its conservation. However, there is surprisingly little published information on the parasites of the giant panda, most of which has been disseminated in the Chinese literature. Herein, we review all peer-reviewed publications (in English or Chinese language) and governmental documents for information on parasites of the giant pandas, with an emphasis on the intestinal nematode Baylisascaris schroederi (McIntosh, 1939) as it dominates published literature. The purpose of this chapter is to: (i) review the parasites recorded in the giant panda and describe what is known about their biology; (ii) discuss key aspects of the pathogenesis, diagnosis, treatment and control of key parasites that are reported to cause clinical problems and (iii) conclude by making some suggestions for future research. This chapter shows that we are only just 'scratching the surface' when it comes to parasites and parasitological research of the giant panda. Clearly, there needs to be a concerted research effort to support the conservation of this iconic species. PMID- 29530308 TI - Evolution, Systematics, and Biogeography of the Triatominae, Vectors of Chagas Disease. AB - In this chapter, we review and update current knowledge about the evolution, systematics, and biogeography of the Triatominae (Hemiptera: Reduviidae)-true bugs that feed primarily on vertebrate blood. In the Americas, triatomines are the vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Despite declining incidence and prevalence, Chagas disease is still a major public health concern in Latin America. Triatomines occur also in the Old World, where vector-borne T. cruzi transmission has not been recorded. Triatomines evolved from predatory reduviid bugs, most likely in the New World, and diversified extensively across the Americas (including the Caribbean) and in parts of Asia and Oceania. Here, we first discuss our current understanding of how, how many times, and when the blood-feeding habit might have evolved among the Reduviidae. Then we present a summary of recent advances in the systematics of this diverse group of insects, with an emphasis on the contribution of molecular tools to the clarification of taxonomic controversies. Finally, and in the light of both up-to-date phylogenetic hypotheses and a thorough review of distribution records, we propose a global synthesis of the biogeography of the Triatominae. Over 130 triatomine species contribute to maintaining T. cruzi transmission among mammals (sometimes including humans) in almost every terrestrial ecoregion of the Americas. This means that Chagas disease will never be eradicated and underscores the fact that effective disease prevention will perforce require stronger, long-term vector control-surveillance systems. PMID- 29530309 TI - Expanding the Vector Control Toolbox for Malaria Elimination: A Systematic Review of the Evidence. AB - BACKGROUND: Additional vector control tools (VCTs) are needed to supplement insecticide-treated nets (ITNs) and indoor residual spraying (IRS) to achieve malaria elimination in many settings. To identify options for expanding the malaria vector control toolbox, we conducted a systematic review of the availability and quality of the evidence for 21 malaria VCTs, excluding ITNs and IRS. METHODS: Six electronic databases and grey literature sources were searched from January 1, 1980 to September 28, 2015 to identify systematic reviews, Phase I-IV studies, and observational studies that measured the effect of malaria VCTs on epidemiological or entomological outcomes across any age groups in all malaria endemic settings. Eligible studies were summarized qualitatively, with quality and risk of bias assessments undertaken where possible. Of 17,912 studies screened, 155 were eligible for inclusion and were included in a qualitative synthesis. RESULTS: Across the 21 VCTs, we found considerable heterogeneity in the volume and quality of evidence, with 7 VCTs currently supported by at least one Phase III community-level evaluation measuring parasitologically confirmed malaria incidence or infection prevalence (insecticide-treated clothing and blankets, insecticide-treated hammocks, insecticide-treated livestock, larval source management (LSM), mosquito-proofed housing, spatial repellents, and topical repellents). The remaining VCTs were supported by one or more Phase II (n=13) or Phase I evaluation (n=1). Overall the quality of the evidence base remains greatest for LSM and topical repellents, relative to the other VCTs evaluated, although existing evidence indicates that topical repellents are unlikely to provide effective population-level protection against malaria. CONCLUSIONS: Despite substantial gaps in the supporting evidence, several VCTs may be promising supplements to ITNs and IRS in appropriate settings. Strengthening operational capacity and research to implement underutilized VCTs, such as LSM and mosquito-proofed housing, using an adaptive, learning-by-doing approach, while expanding the evidence base for promising supplementary VCTs that are locally tailored, should be considered central to global malaria elimination efforts. PMID- 29530310 TI - The Evolutionary Biology, Ecology and Epidemiology of Coccidia of Passerine Birds. AB - Coccidia are intracellular parasites of the phylum Apicomplexa that cause a range of pathologies collectively termed coccidiosis. Species of coccidia of commercial importance have been well studied, with the effect of other species on passerine birds receiving increasing attention. In this chapter, we review the literature on coccidia in passerines, with a particular focus on wild populations. The taxonomy and life cycle of passerine coccidia are covered, as is their impact on the health of passerines, their epidemiology and their role in parasite-mediated natural and sexual selection. Coccidia can pose a significant threat to the health of wild passerine populations, and high rates of mortality have been observed in some studies. We examine some of the genetic factors that influence host resistance to coccidia and discuss how these parasites may be important in relation to sexually selected traits. General patterns are beginning to emerge with regard to the epidemiology of the parasites, and the influence of different aspects of the host's ecology on the prevalence and intensity of coccidia is being revealed. We examine these, as well exceptions, in addition to the phenomenon of diurnal oocyst shedding that can bias studies if not accounted for. Finally, we discuss potential future directions for research on coccidia in passerines and the importance of understanding parasite ecology in the management of threatened species. PMID- 29530311 TI - Monogenean Parasite Cultures: Current Techniques and Recent Advances. AB - Global expansion in fish production and trade of aquatic ornamental species requires advances in aquatic animal health management. Aquatic parasite cultures permit diverse research opportunities to understand parasite-host dynamics and are essential to validate the efficacy of treatments that could reduce infections in captive populations. Monogeneans are important pathogenic parasites of captured captive fishes and exhibit a single-host life cycle, which makes them amenable to in vivo culture. Continuous cultures of oviparous monogenean parasites provide a valuable resource of eggs, oncomiracidia (larvae) and adult parasites for use in varied ecological and applied scientific research. For example, the parasite-host dynamics of Entobdella soleae (van Beneden and Hesse, 1864) and its fish host, Solea solea (Linnaeus, 1758), is one of the most well documented of all monogeneans following meticulous, dedicated study. Polystoma spp. cultures provide an intriguing model for examining evolution in monogeneans because they exhibit two alternative phenotypes depending on the age of infection of amphibians. Furthermore, assessments of the ecological, pathological and immunological effects of fish parasites in aquaculture have been achieved through cultures of Gyrodactylus von Nordmann, 1832 spp., Benedenia seriolae (Yamaguti, 1934), Neobenedenia Yamaguti, 1963 spp. and Zeuxapta seriolae (Meserve, 1938). This review critically examines methods to establish and maintain in vivo monogenean monocultures on finfish, elasmobranchs and amphibians. Four separate approaches to establish cultures are scrutinised including the collection of live infected hosts, cohabiting recipient hosts with infected stock, cohabiting hosts with parasite eggs or oncomiracidia (larvae) and direct transfer of live adult parasites onto new fish hosts. Specific parasite species' biology and behaviour permits predictive collection of parasite life stages to effectively maintain a continuous culture, while environmental parameters can be altered to manipulate parasite generation time. Parasite virulence and biosecurity are vital components of a well-managed culture to ensure appropriate animal welfare and uncontaminated surrounding environments. Contemporary approaches and techniques are reviewed to ensure optimised monogenean cultures, which ultimately can be used to further our understanding of aquatic parasitology and identify mechanisms to limit infestations in public aquaria, ornamental trade and intensive aquaculture. PMID- 29530312 TI - Molecular Epidemiology of Anisakis and Anisakiasis: An Ecological and Evolutionary Road Map. AB - This review addresses the biodiversity, biology, distribution, ecology, epidemiology, and consumer health significance of the so far known species of Anisakis, both in their natural hosts and in human accidental host populations, worldwide. These key aspects of the Anisakis species' biology are highlighted, since we consider them as main driving forces behind which most of the research in this field has been carried out over the past decade. From a public health perspective, the human disease caused by Anisakis species (anisakiasis) appears to be considerably underreported and underestimated in many countries or regions around the globe. Indeed, when considering the importance of marine fish species as part of the everyday diet in many coastal communities around the globe, there still exist significant knowledge gaps as to local epidemiological and ecological drivers of the transmission of Anisakis spp. to humans. We further identify some key knowledge gaps related to Anisakis species epidemiology in both natural and accidental hosts, to be filled in light of new 'omic' technologies yet to be fully developed. Moreover, we suggest that future Anisakis research takes a 'holistic' approach by integrating genetic, ecological, immunobiological, and environmental factors, thus allowing proper assessment of the epidemiology of Anisakis spp. in their natural hosts, in human populations, and in the marine ecosystem, in both space and time. PMID- 29530313 TI - Pharmacogenetics and application in pediatrics. AB - Identification of markers involved in drug disposition is crucial for drugs with a narrow therapeutic index. Individual genomic differences can affect the pharmacology of some drugs and participate to inter-individual variability in drug response. Pharmacogenetics is a useful tool in clinical practice for dosage adjustment and to limit drug toxicities. In pediatrics, physiological changes can also influence the disposition of drugs in infants, children and adolescents. The importance of ontogeny translates into different responses to the same drug in children and adults. Thus, interactions between the maturation of metabolism enzymes or transporters and genetics have a major impact on drug exposure leading to age-specific dosage requirements. This review aims to describe implementation of pharmacogenetics in personalized medicine and specifies pediatric characteristics with ethical considerations. PMID- 29530315 TI - Epigenetic modulation of macrophage polarization- perspectives in diabetic wounds. AB - Diabetes is a chronic metabolic disorder that poses a global burden to healthcare. Increasing incidence of diabetes-related complications in the affected population includes a delay in wound healing that often results in non traumatic limb amputations. Owing to the intricacies of the healing process and crosstalk between the multitude of participating cells, the identification of hyperglycaemia-induced changes at both cellular and molecular levels poses a challenge. Macrophages are one of the key participants in wound healing and continue to exert functional changes at the wound site since the time of injury. In the present review, we discuss the role of these cells and their aberrant functions in diabetic wounds. We have extensively studied the process of macrophage polarization (MP) and its modulation through epigenetic modifications. Data from both pre-clinical and clinical studies on diabetes have co-related hyperglycaemia induced changes in gene expression to an increased incidence of diabetic complications. Hyperglycaemia and oxidative stress, create an environment prone to changes in the epigenetic code, that is manifested as an altered inflammatory gene expression. Here, we have attempted to understand the different epigenetic modulations that possibly contribute towards dysregulated MP, resulting in delayed wound healing. PMID- 29530314 TI - Requests for post-registration studies (PRS), patients follow-up in actual practice: Changes in the role of databases. AB - Early market access of health products is associated with a larger number of requests for information by the health authorities. Compared with these expectations, the growing expansion of health databases represents an opportunity for responding to questions raised by the authorities. The computerised nature of the health system provides numerous sources of data, and first and foremost medical/administrative databases such as the French National Inter-Scheme Health Insurance Information System (SNIIRAM) database. These databases, although developed for other purposes, have already been used for many years with regard to post-registration studies (PRS). The use thereof will continue to increase with the recent creation of the French National Health Data System (SNDS [2016 health system reform law]). At the same time, other databases are available in France, offering an illustration of "product use under actual practice conditions" by patients and health professionals (cohorts, specific registries, data warehouses, etc.). Based on a preliminary analysis of requests for PRS, approximately two-thirds appeared to have found at least a partial response in existing databases. Using these databases has a number of disadvantages, but also numerous advantages, which are listed. In order to facilitate access and optimise their use, it seemed important to draw up recommendations aiming to facilitate these developments and guarantee the conditions for their technical validity. The recommendations drawn up notably include the need for measures aiming to promote the visibility of research conducted on databases in the field of PRS. Moreover, it seemed worthwhile to promote the interoperability of health data warehouses, to make it possible to match information originating from field studies with information originating from databases, and to develop and share algorithms aiming to identify criteria of interest (proxies). Methodological documents, such as the French National Authority for Health (HAS) recommendations on "Les etudes post-inscription sur les technologies de sante (medicaments, dispositifs medicaux et actes). Principes et methodes" [Post-registration studies on health technologies (medicinal products, medical devices and procedures). Principles and methods] should be updated to incorporate these developments. PMID- 29530316 TI - Selected mosquito-borne illnesses-Chikungunya. PMID- 29530317 TI - The evidence for ropivacaine wound infiltration and postsurgical pain. PMID- 29530318 TI - Morel-Lavallee lesion: diagnosis and treatment with imaging techniques. AB - OBJECTIVES: We aim to review the characteristics of Morel-Lavallee lesions and to evaluate their treatment. MATERIAL AND METHODS: We retrospectively reviewed 17 patients (11 men and 6 women; mean age, 56.1 years, range 25-81 years) diagnosed with Morel-Lavallee lesions in two different departments. All patients underwent ultrasonography, 5 underwent computed tomography, and 9 underwent magnetic resonance imaging. Percutaneous treatment with fine-needle aspiration and/or drainage with a 6F-8F catheter was performed in 13 patients. Two patients required percutaneous sclerosis with doxycycline. RESULTS: All patients responded adequately to percutaneous treatment, although it was necessary to repeat the procedure in 4 patients. CONCLUSIONS: Radiologists need to be familiar with this lesion that can be treated percutaneously in the ultrasonography suite when it is not associated with other entities. PMID- 29530319 TI - Extranuclear SUMOylation in Neurons. AB - Post-translational modification of substrate proteins by SUMO conjugation regulates a diverse array of cellular processes. While predominantly a nuclear protein modification, there is a growing appreciation that SUMOylation of proteins outside the nucleus plays direct roles in controlling synaptic transmission, neuronal excitability, and adaptive responses to cell stress. Furthermore, alterations in protein SUMOylation are observed in a wide range of neurological and neurodegenerative diseases, and several extranuclear disease associated proteins have been shown to be directly SUMOylated. Here, focusing mainly on SUMOylation of synaptic and mitochondrial proteins, we outline recent developments and discoveries, and present our opinion as to the most exciting avenues for future research to define how SUMOylation of extranuclear proteins regulates neuronal and synaptic function. PMID- 29530321 TI - Diminished fronto-limbic functional connectivity in child sexual offenders. AB - BACKGROUND: Child sexual abuse and neglect have been related to an increased risk for the development of a wide range of behavioral, psychological, and sexual problems and increased rates of suicidal behavior. Contrary to the large amount of research focusing on the negative mental health consequences of child sexual abuse, very little is known about the characteristics of child sexual offenders and the neuronal underpinnings contributing to child sexual offending. METHODS AND SAMPLE: This study investigates differences in resting state functional connectivity (rs-FC) between non-pedophilic child sexual offenders (N = 20; CSO P) and matched healthy controls (N = 20; HC) using a seed-based approach. The focus of this investigation of rs-FC in CSO-P was put on prefrontal and limbic regions highly relevant for emotional and behavioral processing. RESULTS: Results revealed a significant reduction of rs-FC between the right centromedial amygdala and the left dorsolateral prefrontal cortex in child sexual offenders compared to controls. CONCLUSION & RECOMMENDATIONS: Given that, in the healthy brain, there is a strong top-down inhibitory control of prefrontal over limbic structures, these results suggest that diminished rs-FC between the amygdala and the dorsolateral prefrontal cortex and may foster sexual deviance and sexual offending. A profound understanding of these concepts should contribute to a better understanding of the occurrence of child sexual offending, as well as further development of more differentiated and effective interventions. PMID- 29530320 TI - Chromatin Regulation of Neuronal Maturation and Plasticity. AB - Neurons are dynamic cells that respond and adapt to stimuli throughout their long postmitotic lives. The structural and functional plasticity of neurons requires the regulated transcription of new gene products, and dysregulation of transcription in either the developing or adult brain impairs cognition. We discuss how mechanisms of chromatin regulation help to orchestrate the transcriptional programs that underlie the maturation of developing neurons and the plasticity of adult neurons. We review how chromatin regulation acts locally to modulate the expression of specific genes and more broadly to coordinate gene expression programs during transitions between cellular states. These data highlight the importance of epigenetic transcriptional mechanisms in postmitotic neurons. We suggest areas where emerging methods may advance understanding in the future. PMID- 29530322 TI - Early outcomes using hepatitis C-positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies. AB - BACKGROUND: Given the shortage of suitable donor hearts for cardiac transplantation, and the favorable safety and efficacy of current agents used to treat hepatitis C virus (HCV), our institution recently piloted transplantation of select patients using HCV-positive donors. METHODS: Between September 2016 and March 2017, 12 HCV-naive patients and 1 patient with a history of treated HCV underwent heart transplantation (HT) using hearts from HCV-positive donors after informed consent. Patients who acquired HCV were referred to hepatology and treated with direct-acting anti-viral therapies (DAAs). Data collection and analysis were performed with institutional review board approval. RESULTS: At the time of HT, mean age of recipients was 53 +/- 10 years, and 8 patients (61.5%) were on left ventricular assist device support. After consent to consider an HCV positive heart, mean time to HT was 11 +/- 12 days. Nine of 13 patients (69%) developed HCV viremia after transplant, including 8 who completed DAA treatment and demonstrated cure, as defined by a sustained virologic response 12 weeks after treatment. One patient died during Week 7 of his treatment due to pulmonary embolism. DAAs were well tolerated in all treated patients. CONCLUSIONS: In the era of highly effective DAAs, the use of HCV-positive donors represents a potential approach to safely expand the donor pool. Additional follow-up is needed to elucidate long-term outcomes. PMID- 29530323 TI - Economics of MRI Operations After Implementation of Interpersonal Skills Training. AB - PURPOSE: Examine the cost of MRI operations before and after implementation of interpersonal skills training to reduce unanticipated patient-related events in an academic medical center. METHODS: Teams at four MRI sites (two hospital-based, two freestanding) were trained in evidence-based communication skills in February to April 2015. Training was designed to enable staff members to help patients mobilize their innate coping skills in response to any distress they experienced during their MRI visit. Data were collected before training and afterward from January to June 2016. Staff reported the incidence of disruptive motion, sedation use, MRI delays, incomplete examinations, and no-shows. Cost and revenue associated with MRI operations and staff and physician costs were estimated using Medicare and private insurance rates and data from the US Bureau of Labor Statistics. RESULTS: The study included 12,930 outpatient MRI visits. From baseline to follow-up, average monthly patient volume increased from 1,105 to 1,463 at hospital MRI sites and from 245 to 313 at freestanding MRI sites. Patient factors necessitating sedation or interfering with image progression or quality decreased from 9.0% to 5.5% at hospital sites and from 3.1% to 1.2% at freestanding sites. These changes translated into a reduction in operational costs of $4,600 per 1,000 scheduled patients and an increase in profit of $8,370 per 1,000 scheduled patients in hospital MRI sites, and a corresponding increase in operational costs of $1,570 per 1,000 scheduled-patients and an increase in profit of $12,800 per 1,000 scheduled patients in freestanding MRI sites. CONCLUSIONS: We found significant improvements in MRI operational efficiency after interpersonal skills team training, which were associated with reductions in costs and growth in revenue. PMID- 29530324 TI - 2017 Presidential Address: Staying Ahead of the Curve. AB - The practice of the radiological sciences has always been dynamic. From economics and payment policy to imaging appropriateness, the ACR has led the way in keeping our specialty ahead of the curve. However, being ahead of the curve is a fragile place, and constant diligence is needed to remain there. There will always be major changes on our horizon, and the ACR will be there to empower us to adapt to change. PMID- 29530325 TI - Measuring on the go: Response to Morra, Panesi, Traverso, and Usai. AB - Morra, Panesi, Traverso, and Usai's (Journal of Experimental Child Psychology, 2017, Vol. 167, pp. 246-258) effort to clarify theoretical models and nomenclature confusion surrounding young children's executive functions development is laudable and important. In this article, we address some of the points these authors raised regarding our previous article (Journal of Experimental Child Psychology, 2017, Vol. 159, pp. 199-218). Although we agree that the Multidimensional Card Selection Task makes working memory demands, it goes beyond working memory to measure concurrent cognitive flexibility in preschoolers. Using this task will allow researchers to fine-tune our models of cognitive flexibility and executive functions development. PMID- 29530326 TI - Preschoolers' selective sustained attention and numeracy skills and knowledge. AB - This brief report addresses preschoolers' selective sustained attention (SSA) and early numeracy skills and knowledge. Past research indicates that children's attention and early numeracy are positively associated, yet some concerns have emerged about the age appropriateness of tools used to measure preschoolers' SSA. This study used a new measure-the Track-It Task-that demonstrates strong psychometric properties. In total, 31 at-risk preschoolers (Mage = 46.6 months) participated and were assessed on SSA, nonsymbolic quantity discrimination, and symbolic quantitative skills and knowledge. The ability to sustain attention in the face of distractions was positively correlated with preschoolers' verbal counting and one-to-one correspondence, Arabic numeral recognition, and cardinal principle knowledge. SSA was not significantly associated with child age or performance on a memory task. This study provides preliminary evidence that SSA may facilitate the process whereby young children become reliable counters and learn that the symbol system of numbers represents specific quantities. PMID- 29530327 TI - Laryngeal injury in closed cervical traumatism. PMID- 29530328 TI - Clinical characteristics, prevalence, and factors related to delirium in children of 5 to 14 years of age admitted to intensive care. AB - OBJECTIVE: To evaluate the clinical characteristics, prevalence and factors associated with delirium in critical patients from 5 to 14 years of age. DESIGN: An analytical, cross-sectional observational study was made. Delirium was assessed with the Pediatric-Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU) and motor classification was established with the Delirium Rating Scale Revised-98. SETTING: A pediatric Intensive Care Unit. PATIENTS: All those admitted over a one-year period were assessed during the first 24-72h, or when possible in deeply sedated patients. EXCLUSION CRITERIA: Patients in stupor or coma, with severe communication difficulty, subjected to deep sedation throughout admission, and those with denied consent. RESULTS: Twenty-nine of the 156 assessed patients suffered delirium (18.6%) and 55.2% were hypoactive. The neurocognitive alterations evaluated by the pCAM-ICU were similar in the three motor groups. Intellectual disability (OR=17.54; 95%CI: 3.23-95.19), mechanical ventilation (OR=18.80; 95%CI: 4.29-82.28), liver failure (OR=54.88; 95%CI: 4.27 705.33), neurological disease (OR=4.41; 95%CI: 1.23-15.83), anticholinergic drug use (OR=3.23; 95%CI: 1.02-10.26), different psychotropic agents (OR=4.88; 95%CI: 1.42-16.73) and tachycardia (OR=4.74; 95%CI: 1.21-18.51) were associated to delirium according to the logistic regression analysis. CONCLUSION: The frequency of delirium and hypoactivity was high. It is therefore necessary to routinely evaluate patients with standardized instruments. All patients presented with important neurocognitive alterations. Several factors related with the physiopathology of delirium were associated to the diagnosis; some of them are modifiable through the rationalization of medical care. PMID- 29530329 TI - Cardiovascular disease in ANCA-associated vasculitis: The danger lurking beneath the surface! PMID- 29530330 TI - Reducing glucocorticoid duration in ANCA-associated vasculitis: A pilot trial. AB - OBJECTIVE: Therapeutic advances in ANCA-associated vasculitis (AAV) have improved patient survival, but mortality rates remain higher than the general population. Glucocorticoids contribute to AAV morbidity and mortality. We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. METHODS: Patients with active AAV received an 8-week prednisone taper and RTX 375mg/m2 weekly for 4 weeks. Patients with severe glomerulonephritis or diffuse alveolar hemorrhage requiring mechanical ventilation were excluded. In-person and telephone visits were scheduled for disease activity assessment. The primary endpoint was complete remission at 24 weeks (no disease activity while being off prednisone with no intercedent relapses). Secondary analysis included comparing study outcomes to historical controls from the Rituximab in AAV (RAVE) trial. RESULTS: Fourteen of 20 patients (70%) achieved the primary outcome. The patients in our trial achieved the primary outcome at a rate similar to that of controls from the RAVE trial (adjusted OR 1.31 [0.26-6.56]), had fewer median adverse events per patient (2 versus 8, p < 0.001) but were more likely to relapse (30% versus 7%, p = 0.03). Most relapses occurred in patients who had severe vasculitic manifestations at trial entry. Disease damage did not differ between the two trial populations. CONCLUSION: An 8-week course of prednisone with RTX resulted in a similar rate of complete remission at 6 months as in the RAVE trial, with fewer adverse events but more frequent relapses. Further study of this protocol is warranted in selected patient populations. PMID- 29530331 TI - Immunobiochemical pathways of neopterin formation and tryptophan breakdown via indoleamine 2,3-dioxygenase correlate with circulating tumor cells in ovarian cancer patients- A study of the OVCAD consortium. AB - OBJECTIVE: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown. METHODS: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two tailed Chi2 or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis. RESULTS: In EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC positive patients, both at diagnosis and at follow-up in platinum-sensitive disease. CONCLUSIONS: We observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation. PMID- 29530332 TI - Adjuvant chemoradiotherapy versus radiotherapy alone in high-risk endometrial cancer: A systematic review and meta-analysis. AB - BACKGROUND: The benefits of adjuvant chemoradiotherapy (CRT) for high-risk endometrial cancer (HREC) in International Federation of Gynecology and Obstetrics (FIGO) stages I-III remain controversial. A systematic review and meta analysis was conducted to evaluate the clinical effectiveness and safety of postoperative CRT over radiotherapy (RT) alone, exclusively for patients with HREC for the following key endpoints: overall survival (OS), progression-free survival (PFS), the local recurrence rate, the distant metastasis rate, cancer specific survival (CSS), grade III/IV acute and late toxicities, and the small bowel obstruction rate. METHODS: Five databases, namely, PubMed, EMBASE, Cochrane Library, Web of Science and ClinicalTrials.gov, were systematically explored and supplemented by manual searching to identify relevant studies published before Dec 9, 2017. Only prospective randomized controlled trials (RCTs) conducted for HREC comparing CRT and RT alone after surgery were included. All statistical analyses were performed using RevMan Version 5.3 software. RESULTS: Six eligible trials involving 2105 patients were identified for the final meta-analysis (CRT: n = 1064; RT: n = 1041). No statistically significant differences were evident between the CRT and RT groups regarding OS (n = 2105, RR = 1.02, 95% CI 0.98 1.06, P = 0.40). Additionally, no differences were apparent in terms of the local recurrence rate (n = 690, RR = 0.48, 95% CI 0.19-1.18, P = 0.11) or distant metastasis rate (n = 1445, RR = 0.94, 95% CI 0.72-1.23, P = 0.67). However, CRT significantly prolonged overall five-year PFS (80.2% vs. 74.5%, +5.7%; RR = 1.08, P = 0.005) and five-year CSS (86.1% vs. 79.0%, +7.1%; RR = 1.09, P = 0.03). A higher incidence of grade III/IV toxicities (P < 0.00001) was evident with CRT, while grade III/IV late toxicities and the small bowel obstruction rate were not significantly different between the two groups. CONCLUSIONS: For patients with endometrial cancers with stage I-III risk factors, adjuvant CRT can significantly improve PFS and CSS compared with RT. With the exception of increased acute toxicities, CRT is well accepted and tolerated in HREC patients. PMID- 29530333 TI - Department of Error. PMID- 29530334 TI - DFN-M field characterization of sandstone for a process-based site conceptual model and numerical simulations of TCE transport with degradation. AB - Plumes of trichloroethene (TCE) with degradation products occur at a large industrial site in California where TCE as a dense non-aqueous phase liquid (DNAPL) entered the fractured sandstone bedrock at many locations beginning in the late 1940s. Groundwater flows rapidly in closely spaced fractures but plume fronts are strongly retarded relative to groundwater flow velocities owing largely to matrix diffusion in early decades and degradation processes in later decades and going forward. Multiple data types show field evidence for both biotic and abiotic dechlorination of TCE and its degradation products, resulting in non-chlorinated compounds. Analyses were conducted on groundwater samples from hundreds of monitoring wells and on thousands of rock samples from continuous core over depths ranging from 6 to 426 metres below ground surface. Nearly all of the present-day mass of TCE and degradation products resides in the water saturated, low-permeability rock matrix blocks. Although groundwater and DNAPL flow primarily occur in the fractures, DNAPL dissolution followed by diffusion and sorption readily transfers contaminant mass into the rock matrix. The presence of non-chlorinated degradation products (ethene, ethane, acetylene) and compound specific isotope analysis (CSIA) of TCE and cis-1,2-dichloroethene (cDCE) indicate at least some complete dechlorination by both biotic and abiotic pathways, consistent with the observed mineralogy and hydrogeochemistry and with published results from crushed rock microcosms. The rock matrix contains abundant iron-bearing minerals and solid-phase organic carbon with large surface areas and long contact times, suggesting degradation processes are occurring in the rock matrix. Multiple, high-resolution datasets provide strong evidence for spatially heterogeneous distributions of TCE and degradation products with varying degrees of degradation observed only when using new methods that achieve better detection of dissolved gases (i.e., Snap SamplerTM) and contaminant mass stored in the low permeability rock matrix (i.e., CORE-DFNTM). Simulations using a discrete fracture-matrix (DFN-M) numerical model capable of rigorously simulating flow and transport in both the fractures and matrix, including interactions, show that even slow, first-order degradation rates (i.e., 5- to 20-year half-lives) informed by site-derived parameters can contribute strongly to natural attenuation, resulting in TCE plumes that become stationary in space and might even retreat after 50 to 100 years, if the DNAPL sources become depleted due to the combination of diffusion and degradation processes. PMID- 29530335 TI - A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. AB - BACKGROUND: FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet. PATIENTS AND METHODS: This study was an open-label, single-arm, multi centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety. RESULTS: A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004). CONCLUSIONS: FOLFOXIRI plus bevacizumab is considered an effective first line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered. PMID- 29530336 TI - Liverpool Adverse Events Profile: Italian validation and predictive value for dropout from antiepileptic treatment in people with epilepsy. AB - INTRODUCTION: Adverse events (AEs) of antiepileptic drugs (AEDs) affect patient compliance and dropout. No questionnaire measuring AEs of AEDs is available for Italian-speaking people with epilepsy. Moreover, no questionnaire has been shown to predict patient dropout. OBJECTIVE: The aim of this study was to provide a validated Italian version of the Liverpool Adverse Events Profile (iLAEP) and to define iLAEP reliability in AE monitoring and dropout risk prediction. METHODS: The original LAEP was translated and tested for internal consistency and reliability. Patients with epilepsy who are on stable AED regimen completed the questionnaire as well as a 3-month follow-up to assess dropouts. RESULTS: Overall, 204 patients with epilepsy were enrolled (mean age: 47.1+/-21.5). High internal consistency (Cronbach's alpha=0.88) was demonstrated, and very quick completion time was registered (mean=9min). A 3-month follow-up was performed to assess treatment discontinuation and potential predictive value of the iLAEP score. Treatment was discontinued in 33.3% of the cohort. Moreover, iLAEP scores (mean=30.71) significantly differed between patients interrupting (39.15+/-5.66) and those prosecuting treatment (29.4+/-6.54, p<.001). A cutoff of 36.5 had an 85% accuracy in predicting treatment discontinuation (85% sensitivity, 79% specificity). Scores >36.5 were associated with a 20.27-fold increase in dropout relative risk (RR), with a 66% positive predictive value. CONCLUSIONS: The iLAEP represents a reliable, quick, and inexpensive assessment tool for patient reported AEs of AEDs. An iLAEP cutoff of 36.5 differentiates patients unlikely to interrupt treatment from those more prone to stop AEDs in the following 3months. The iLAEP might help clinicians in weighting the risk of dropout and better tailor treatment to patients. PMID- 29530338 TI - Experimental validation of predictor-corrector approach based control schemes on the laboratory scale non-linear system. AB - In this work, the authors have designed and implemented predictor-corrector approach based control schemes for a single input-single output nonlinear system. The controller output is computed in two steps. The first step explicitly uses a non-linear model or multiple-linear models weighted using fuzzy membership function to compute the value of the controller output. The second step is based on the measurement, where the value of the controller output computed in first step is updated. The extensive simulation studies show that the set-point tracking and disturbance rejection capability of the proposed control schemes are found to be satisfactory in the absence and presence of Model-plant mismatch. The performances of the proposed control schemes have been compared with that of a gain-scheduled PI controller. In addition, the control schemes are experimentally validated on the laboratory scale conical tank experimental setup. PMID- 29530337 TI - Cysteine Metabolism in Neuronal Redox Homeostasis. AB - Besides its essential role in protein synthesis, cysteine plays vital roles in redox homeostasis, being a component of the major antioxidant glutathione (GSH) and a potent antioxidant by itself. In addition, cysteine undergoes a variety of post-translational modifications that modulate several physiological processes. It is becoming increasingly clear that redox-modulated events play important roles not only in peripheral tissues but also in the brain where cysteine disposition is central to these pathways. Dysregulated cysteine metabolism is associated with several neurodegenerative disorders. Accordingly, restoration of cysteine balance has therapeutic benefits. This review discusses metabolic signaling pathways pertaining to cysteine disposition in the brain under normal and pathological conditions, highlighting recent findings on cysteine metabolism during aging and in neurodegenerative conditions such as Huntington's disease (HD) and molybdenum cofactor (MoCo) deficiency (MoCD) among others. PMID- 29530339 TI - Spinogenesis and Plastic Changes in the Dendritic Spines of Spinal Cord Motoneurons After Traumatic Injury in Rats. AB - BACKGROUND: Spinal cord injury (SCI) is highly incapacitating, and the neurobiological factors involved in an eventual functional recovery remain uncertain. Plastic changes to dendritic spines are closely related with the functional modifications of behavior. AIM OF THE STUDY: To explore the plastic response of dendritic spines in motoneurons after SCI. METHODS: Female rats were assigned to either of three groups: Intact (no manipulations), Sham (T9 laminectomy), and SCI (T9 laminectomy and spinal cord contusion). RESULTS: Motor function according to a BBBscale was progressively recovered from 2 week through 8 week postinjury, reaching a plateau through week 16. Dendritic spine density was greater in SCI vs. control groups, rostral as well as caudal to the lesion, at 8 and 16 weeks postinjury. Thin and stubby/wide spines were more abundant at both locations and time points, whereas mushroom spines predominated at 2 and 4 months in rostral to the lesion. Filopodia and atypical structures resembling dendritic spines were observed. Synaptophysin expression was lower in SCI at the caudal portion at 8 weeks, and was higher at week 16. CONCLUSION: Spinogenesis in spinal motoneurons may be a crucial plastic response to favor spontaneous recovery after SCI. PMID- 29530341 TI - Corrigendum to 'Tumor-targeting peptides from combinatorial libraries' [Adv Drug Deliv Rev.110-111 (2017) 13-37]. PMID- 29530340 TI - Efficacy and safety of topical SR-T100 gel in treating actinic keratosis in Taiwan: A Phase III randomized double-blind vehicle-controlled parallel trial. AB - BACKGROUND: Currently available topical treatments for actinic keratosis (AK) are associated with substantial side-effects. OBJECTIVES: To evaluate the efficacy and safety of topical SR-T100 gel in treating AK. METHODS: A multicenter, randomized, double-blinded phase III trial was conducted. Patients with at least two clinically visible AK were enrolled and a punch biopsy was performed on one of the AK to confirm the diagnosis. This study consisted of up to 16-week treatment and 8-week post-treatment periods. Medication was applied daily with occlusive dressing. RESULTS: 123 subjects were recruited and 113 were randomized. 76 subjects were in the SR-T100 and 37 in the vehicle arms. In SR-T100 and vehicle groups, 32.39% and 17.14% of subjects achieved complete clearance, respectively. For 75% partial clearance of lesions, 71.83% and 37.1% of subjects achieved this goal in SR-T100 and vehicle group, respectively. When comparing SR T100 to vehicle, the odds ratio of complete clearance was 2.14 (p = 0.111), and odds ratio of partial clearance was 4.36 (p < 0.001). Severe local reactions were reported by only one subject using SR-T100. CONCLUSION: The imitation of the study was that not all the treated AK lesions were confirmed by histopathology. The diagnostic uncertainty may contribute to the high partial clearance rate in the vehicle group since the clinical-diagnosed AK showed higher clearance rate compared to histopathology-confirmed AK. The use of occlusive dressing was another possible explanation for high placebo effects. The results suggested that topical SR-T100 gel may be an effective and safe treatment for field therapy of AK. PMID- 29530342 TI - Pancreaticopleural fistula associated with choledocholithiasis: An infrequent complication of acute pancreatitis. PMID- 29530343 TI - Variability in diagnosis and management of acquired cold-induced urticaria. PMID- 29530344 TI - Anesthetic technique for cancer surgery: Harm or benefit for cancer recurrence? PMID- 29530345 TI - Inflammation and cancer: What a surgical oncologist should know. AB - Chronic inflammation is an aberrantly prolonged form of a protective response to a loss of tissue homeostasis and it is involved in several steps of the carcinogenesis process. As a result, many cancers are inflammation-related. The systemic inflammatory response is associated with survival in advanced and localized cancers. Two categories of scores have been proposed to monitor the systemic inflammatory response, those derived from protein measurement and those based on counting inflammatory cells. This review aims to provide a critical appraisal of these 2 categories of surrogate markers. The 3 scale modified Glasgow prognostic score (mGPS) is based on the combination of C-reactive protein and albumin and is graded 0 to 2. It has been validated worldwide showing an independent prognostic value in patients with cancer in a variety of tumour types and tumour stages. Leukocytes-based scores are mainly neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR). Elevated NLR and/or PLR and lower LMR seem to be associated with decreased survival, but the studies about these markers are very heterogeneous. The main limit is the variety of thresholds used to dichotomize patients, so that reproducibility and reliability of leukocytes-based scores can be questioned. Hence, there is no sufficient evidence to support their use in clinical practice. Comprehensive management of patients with operable and advanced cancer should integrate the host systemic inflammatory response by calculating the mGPS. It could be a helpful tool to tailor patients' management. PMID- 29530346 TI - Quality of life and cost effectiveness in a randomized trial of patients with colorectal cancer and peritoneal metastases. AB - BACKGROUND: The aim was to compare health-related quality-of-life (HRQOL) and cost-effectiveness between cytoreductive surgery with intraperitoneal chemotherapy (CRS + IPC) and systemic chemotherapy for patients with colorectal peritoneal metastases. METHODS: Patients included in the Swedish Peritoneal Trial comparing CRS + IPC and systemic chemotherapy completed the EORTC QLQ-C30 and SF 36 questionnaires at baseline, 2, 4, 6, 12, 18, and 24 months. HRQOL at 24 months was the primary endpoint. EORTC sum score, SF-36 physical and mental component scores at 24 months were calculated and compared for each arm and then referenced against general population values. Two quality-adjusted life-year (QALY) indices were applied (EORTC-8D and SF-6D) and an incremental cost-effectiveness ratio (ICER) per QALY gained was calculated. A projected life-time ICER per QALY gained was calculated using predicted survival according to Swedish population statistics. RESULTS: No statistical differences in HRQOL between the arms were noted at 24 months. Descriptively, survivors in the surgery arm had higher summary scores than the general population at 24 months, whereas survivors in the chemotherapy arm had lower scores. The projected life-time QALY benefit was 3.8 QALYs in favor of the surgery arm (p=0.06) with an ICER per QALY gained at 310,000 SEK (EORTC-8D) or 362,000 SEK (SF-6D) corresponding to 26,700-31,200 GBP. CONCLUSION: The HRQOL in patients with colorectal peritoneal metastases undergoing CRS + IPC appear similar to those receiving systemic chemotherapy. Two year survivors in the CRS + IPC arm have comparable HRQOL to a general population reference. The treatment is cost-effective according to NICE guidelines. PMID- 29530347 TI - Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation. AB - Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines. PMID- 29530348 TI - Synthesis and fungicidal activity of novel imidazole-based ketene dithioacetals. AB - Novel imidazole-based ketene dithioacetals show impressive in planta activity against the economically important plant pathogens Alternaria solani, Botryotinia fuckeliana, Erysiphe necator and Zymoseptoria tritici. Especially derivatives of the topical antifungal lanoconazole, which bear an alkynyloxy or a heteroaryl group in the para-position of the phenyl ring, exhibit excellent control of the mentioned phytopathogens. These compounds inhibit 14alpha -demethylase in the sterol biosynthesis pathway of the fungi. Synthesis routes starting from either benzaldehydes or acetophenones as well as structure-activity relationships are discussed in detail. PMID- 29530349 TI - Diagnostic aptitude of West Nile virus-like particles expressed in insect cells. AB - West Nile virus is a globally spread zoonotic arbovirus. The laboratory diagnosis of WNV infection relies on virus identification by RT-PCR or on specific antibody detection by serological tests, such as ELISA or virus-neutralization. These methods usually require a preparation of the whole virus as antigen, entailing biosafety issues and therefore requiring BSL-3 facilities. For this reason, recombinant antigenic structures enabling effective antibody recognition comparable to that of the native virions, would be advantageous as diagnostic reagents. WNV virions are enveloped spherical particles made up of 3 structural proteins (C, capsid; M, membrane and E, envelope) enclosing the viral RNA. This study describes the co-expression of these 3 proteins yielding non-infectious virus-like particles (VLPs) and the results of the initial assessment of these VLPs, used instead of the whole virus, that were shown to perform correctly in two different ELISAs for WNV diagnosis. PMID- 29530350 TI - Telemedicine in Sleep Apnea: A Simple Approach for Nasal Pressure (CPAP) Treatment. PMID- 29530351 TI - GOLD Staging System is Appropriate to Predict Mortality in Older People With Chronic Obstructive Pulmonary Disease. AB - INTRODUCTION: In the new GOLD classification the reduction of FEV1, expressed as percentage of predicted value (FEV1PP), is considered an important prognostic factor. However, the use of FEV1PP may introduce bias, especially if based on equations derived from populations different from the one under study. We evaluated how well the GOLD classification stratifies the mortality risk when FEV1PP is based on an equation developed in the same population that gave rise to cases, externally developed equations, or as FEV1 divided by cubed height (FEV1/Ht3). METHODS: We studied 882 participants aged >=65 years. Bronchial obstruction was defined using a fixed cut-off of 0.7 for FEV1/FVC. Predicted values of FEV1 were derived from equations based on the same sample of the cases included in this study and from the European Respiratory Society equations. Severity of bronchial obstruction was also classified according to quartiles of FEV1/Ht3. RESULTS: All the classification systems showed a non-statistically significant linear tendency with 5-years mortality risk. For the 15-years mortality, the linear trend across severity stages is more evident for GOLD classifications, with significant increments in the hazard ratio. Stratification by FEV1/Ht3 could better discriminate the functional status of participants. CONCLUSION: The severity of bronchial obstruction according to GOLD classes may stratify mortality risk better than quartiles of FEV1/Ht3, whereas the second seems to be more suited to stratify the risk of clinical outcomes. Concerns about the use of externally developed reference values to calculate FEV1PP do not seem confirmed, at least for GOLD classification. PMID- 29530352 TI - Primary Pleural Synovial Sarcoma: Differential Diagnosis with Small Cell Lung Carcinoma. PMID- 29530353 TI - High-definition colonoscopy versus Endocuff versus EndoRings versus full-spectrum endoscopy for adenoma detection at colonoscopy: a multicenter randomized trial. AB - BACKGROUND AND AIMS: Devices used to improve polyp detection during colonoscopy have seldom been compared with each other. METHODS: We performed a 3-center prospective randomized trial comparing high-definition (HD) forward-viewing colonoscopy alone to HD with Endocuff to HD with EndoRings to the full spectrum endoscopy (FUSE) system. Patients were age >=50 years and had routine indications and intact colons. The study colonoscopists were all proven high-level detectors. The primary endpoint was adenomas per colonoscopy (APC). RESULTS: Among 1188 patients who completed the study, APC with Endocuff (APC mean +/- standard deviation: 1.82 +/- 2.58), EndoRings (1.55 +/- 2.42), and standard HD colonoscopy (1.53 +/- 2.33) were all higher than FUSE (1.30 +/- 1.96; P < .001 for APC). The APC for Endocuff was higher than standard HD colonoscopy (P = .014). Mean cecal insertion times with FUSE (468 +/- 311 seconds) and EndoRings (403 +/- 263 seconds) were both longer than with Endocuff (354 +/- 216 seconds; P = .006 and .018, respectively). CONCLUSIONS: For high-level detectors at colonoscopy, forward-viewing HD instruments dominate the FUSE system, indicating that for these examiners image resolution trumps angle of view. Further, Endocuff is a dominant strategy over EndoRings and no mucosal exposure device on a forward viewing HD colonoscope. (Clinical trial registration number: NCT02345889.). PMID- 29530354 TI - Does Posterior Tibial Slope Affect Graft Rupture Following Anterior Cruciate Ligament Reconstruction? AB - PURPOSE: The purpose of this study was to evaluate the association between posterior tibial slope (PTS) and anterior cruciate ligament (ACL) graft rupture in patients who have undergone ACL reconstruction by comparing results in patients who experienced graft rupture and a matched control group. METHODS: The study included 64 knees of 64 patients (58 men and 6 women), of mean age 31 years (range, 18-60 years) who underwent revision ACL reconstruction for ACL graft rupture, as well as a control group without ACL graft rupture matched for age, sex, body mass index (BMI), and left or right side. The mean time to failure in study group was 48.5 months, and after revision surgeries, the mean follow-up period was 37.7 months. The graft used for the primary surgery was autograft in 3 patients (4.7%) and allograft in 49 patients (76.6%). The type of graft could not be confirmed in the remaining 12 patients (18.7%). PTS was measured on plain radiographs and compared in the 2 groups. RESULTS: Mean PTS was significantly higher in patients with (13.2 degrees +/- 2.5 degrees ; range, 8.5 degrees -18.2 degrees ) than without (10.9 degrees +/- 3.1 degrees ; range, 4.9 degrees -13.6 degrees ) rerupture (P < .01). When mean PTS was compared in the 37 patients who underwent primary surgery by the same surgeon, it was significantly higher in patients with (13.5 degrees +/- 2.5 degrees ; range, 8.5 degrees -18.2 degrees ) than without (11.1 degrees +/- 2.9 degrees ; range, 5.1 degrees -13.6 degrees ) rerupture (P < .01). PTS in patients with rerupture was not significantly associated with age, gender, BMI, and right or left side. The odds ratio of ACL graft rupture in knees with PTS >=12 degrees was 4.52 (P < .001). CONCLUSIONS: This study showed that mean PTS was significantly greater in patients with than without noncontact ACL graft rerupture (13.2 degrees vs 10.9 degrees , P < .01). The failure of ACL reconstruction appears to be associated with increased PTS, with PTS >=12 degrees a risk factor for the failure of ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29530355 TI - Evaluation for occult sepsis incorporating NIRS and emergency sonography. AB - PURPOSE: We aim to determine whether the combination of regional tissue oxygen saturation (StO2) measurement using near-infrared spectroscopy (NIRS), inferior vena cava (IVC) collapsibility and ejection fraction (EF) is able to detect occult sepsis. METHODS: We included adult patients in the emergency department with at least one of the following: fever; any one component of the quick sepsis related organ function assessment (SOFA) score; heart rate>=100 beats per minute; or white cell count <4.0*109/L or >12.0*109/L. StO2 parameters, IVC collapsibility and EF were assessed. Primary outcome was composite of admission to intensive care unit, hypotension requiring fluid resuscitation or vasopressor use, and antibiotic escalation. RESULTS: We included 184 patients with mean age of 55.4years and slight male predominance (51.6%). Increase in temperature (adjusted odds ratio [aOR] 3.05; 95% confidence interval [CI] 1.16 to 8.02), higher white cell counts (aOR 1.10; 95% CI 1.03 to 1.19), increase in time taken to new StO2 baseline (aOR 1.03; 95% CI 1.01 to 1.06) and reduced EF (aOR 33.9; 95% CI 2.19 to 523.64) had higher odds of achieving the primary outcome. CONCLUSION: Change in StO2 and time taken to reach new StO2 baseline, combined with EF could potentially predict sepsis among patients with infection. PMID- 29530356 TI - Characterization of pediatric golf cart injuries to guide injury prevention efforts. AB - BACKGROUND: Golf cart injuries represent an increasing source of morbidity and mortality in the United States. Characterization of the circumstances of these injuries can inform injury prevention efforts. METHODS: This study retrospectively reviews a prospective trauma registry at a level-one pediatric trauma center for golf cart-related injuries in patients under 18years of age admitted to the hospital between 2008 and 2016. RESULTS: The 40 identified crashes were associated with 82 hospital days, 17 ICU days, and more than $1 million in hospital charges over the study period. The median hospital stay was 1.5days, and the median hospital charge was $20,489. Severe injuries with an Injury Severity Score of >15 were identified in 25% of patients, and moderate injuries with scores between nine and 15 were identified in an additional 30%. The most common injures were head and neck (60%) and external injuries to the body surface (52.5%). Only a single child was wearing a seatbelt, and the vast majority was not using any safety equipment. Children as young as nine years old were driving golf carts, and child drivers were associated with the cart overturning (p=0.007). CONCLUSIONS: Golf cart crashes were a source of substantial morbidity at a level-one trauma center. Increased safety measures, such as higher hip restraints, seatbelts, and front-wheel breaks could substantially increase the safety of golf carts. Increased regulation of driving age as well as driver education may also reduce these injuries. PMID- 29530357 TI - Medical toxicology education in US emergency medicine residencies. PMID- 29530358 TI - Embolization of a contraceptive implant into the pulmonary vasculature in an adolescent female. AB - Nexplanon is a long-acting 4cm radio-opaque rod shaped contraceptive device implanted in the subdermal layer of the inner, upper arm. Complications from implantation are uncommon and mostly local and minor, including infection at the implantation site with resulting cellulitis or abscess, hematoma, abnormal scar formation, or local damage to nerves and blood vessels. Intravascular insertion is estimated to be at 1.3 per million Nexplanon implants, and migration and embolization is a rare complication of this device. We present a case report of a 16year old female who presented to the pediatric emergency department with subjective dyspnea and an embolized contraceptive device within a subsegmental branch of the left lower lobe pulmonary artery. After discussion with consultants, interventional radiology was able to successful retrieve the device without complication. PMID- 29530359 TI - Suicide screening scales may not adequately predict disposition of suicidal patients from the emergency department. AB - BACKGROUND: Suicide screening scales have been advocated for use in the ED setting. However, it is currently unknown whether patients classified as low-risk on these scales can be safely discharged from the emergency department. This study evaluated the utility of three commonly-used suicide screening tools in the emergency department to predict ED disposition, with special interest in discharge among low-risk patients. METHODS: This prospective observational study enrolled a convenience sample of patients who answered "yes" to a triage suicidal ideation question in an urban academic emergency department. Patients were administered the weighted modified SADPERSONS Scale, Suicide Assessment Five-step Evaluation and Triage, and Columbia-Suicide Severity Rating Scale. Patients who subsequently received a psychiatric evaluation were included, and the utility of these screening tools to predict disposition was evaluated. RESULTS: 276 subjects completed all three suicide screening tools and were included in data analyses. Eighty-two patients (30%) were admitted or transferred. Three patients (1%) died by suicide within one year of enrollment; one was hospitalized at the end of his or her enrollment visit, dying by suicide seven months later and the other two were discharged, dying by suicide nine and ten months later, respectively. The screening tools exhibited modest negative predictive values (range: 0.66-0.73). CONCLUSION: Three suicide screening tools displayed modest ability to predict the disposition of patients who presented to an emergency department with suicidal ideation. This study supports the current ACEP clinical policy on psychiatric patients which states that screening tools should not be used in isolation to guide disposition decisions of suicidal patients from the ED. PMID- 29530360 TI - Utility of initial procalcitonin values to predict urinary tract infection. AB - BACKGROUND: Urinary tract infections (UTIs) are one of the most common reasons women seek treatment in the emergency department (ED). The biomarker procalcitonin (PCT) has gained popularity over the last decade to improve the diagnosis of bacterial infections and reduce unnecessary exposure to antibiotics. PCT has been extensively studied in patients with pneumonia and sepsis and may have additional role in UTI. METHODS: A retrospective study of patients who presented to the ED in which a urinalysis test and a PCT level was obtained within the first 24h of presentation. Signs and symptoms of UTI and urine cultures were reviewed to determine a positive diagnosis of UTI. The area under the receiver operating curve was used to calculate the test characteristics of PCT. Different breakpoints were analyzed to determine which PCT level corresponded to the highest sensitivity and specificity. RESULTS: 293 patients were included in this single center, retrospective study. The AUC of PCT to predict UTI was 0.717; 95% CI: 0.643-0.791 (p<0.001). A PCT threshold of 0.25ng/ml corresponded to the best combination of sensitivity (67%) and specificity (63%), with a positive predictive value and negative predictive value of 26% and 91%, respectively. CONCLUSIONS: A PCT threshold <0.25ng/ml was a strong predictor of the absence of UTI. The high negative predictive value of PCT may be useful as an adjunct to urinalysis results to rule out UTI and facilitate noninitiation or earlier discontinuation of empiric antibiotics. PMID- 29530361 TI - Strategies for endovascular treatment of complicated splenic artery aneurysms. AB - OBJECTIVE: Endovascular treatment (ET) is being increasingly used for splenic artery aneurysms (SAAs), but systematic treatment strategies have not been defined. We set out to investigate the optimal strategies for ET of complicated SAAs (CSAAs). METHODS: CSAAs were classified into three types: type I, rupture or impending rupture; type II, at the origin of the splenic artery; and type III, having an aberrant splenic artery from the splenomesenteric trunk (type IIIA) or celiacomesenteric trunk (type IIIB). SAAs treated at our center during the last decade were reviewed, and CSAAs were selected for analysis. Patients' demographics, clinical manifestations, aneurysm characteristics, ET strategies, and outcomes were analyzed. RESULTS: A total of 154 SAAs were identified, with 24 (15.6%) being CSAAs. Open surgery was employed in two patients, whereas 22 patients underwent ET. There were 3 patients with type I (type IIIA co-occurred in one of them), 5 with type II, and 15 with type III CSAAs. Treatment strategies included the following: immediate and thorough exclusion with embolization of the collaterals for type I; and dense embolization of the sac and outflow artery, with or without embolization of the inflow artery, or covered stent placement in the splenomesenteric trunk or celiacomesenteric, for types II and III. Technical success was achieved in 21 patients (95.5%). Mean follow-up was 33.7 +/- 31.2 months (range, 1.5-117.0 months). The aneurysms remained completely thrombosed and unenlarged in 21 patients (95.5%). Reintervention was needed in one patient (4.5%) for persistent sac enlargement. The covered stent was asymptomatically occluded in one patient (11.1%). No hepatic or intestinal ischemia or death developed perioperatively or during the follow-up period. CONCLUSIONS: With reasonable strategies toward the urgency and thoroughness needed for aneurysm exclusion as well as the anatomic challenges, ET appeared to be feasible, safe, and effective in the management of CSAAs. PMID- 29530362 TI - The OptiflowTM interface for chronic CPAP use in children. AB - Continuous positive airway pressure (CPAP) is being increasingly used in children of all age ranges. The limited number of commercially available masks especially in infants and young children may complicate its use and compliance. In this report, we describe our experience with the use of the OptiflowTM (Fisher and Paykel Healthcare) Nasal Cannula attached to a regular CPAP device in the setting of chronic CPAP use. This interface consists of a nasal cannula and was originally designed for the delivery of high-flow oxygen therapy. We could show an objective improvement in breathing parameters in several children selected for CPAP mainly because of obstructive sleep apnea syndrome (OSAS). However, this interface cannot be used for bilevel non-invasive ventilation due to insufficient triggering. PMID- 29530363 TI - Comprehensive assessment of the impact of life habits on sleep disturbance, chronotype, and daytime sleepiness among high-school students. AB - OBJECTIVE: Sleep affects adolescents in various ways. However, the effects of multiple factors on sleep hygiene remain unclear. A comprehensive assessment of the effects of life habits on sleep in high-school students was conducted. METHODS: A cross-sectional survey of 344 high school students (age range 15-17; 171 boys, 173 girls) in Tokyo, Japan was conducted in 2015. Complete responses were provided by 294 students. Demographic variables, Pittsburgh Sleep Quality Index (PSQI), diurnal type scale, Pediatric Daytime Sleepiness Scale (PDSS), and life habits such as dinnertime, viewing electronic displays, caffeine intake, sunlight in the morning, and the brightness of the room in the night were asked. RESULTS: The mean scores were PSQI: 5.9 (+/-2.3), PDSS: 19.0 (+/-5.8), and the diurnal type scale: 16.7 (+/-3.4). Using an electronic display in bed (OR = 3.01; (95%CI) 1.24-7.30), caffeine intake at night always (OR = 2.22; 1.01-4.90), and waking up before dawn (OR = 3.25; 1.34-7.88) were significantly associated with sleep disturbance. Irregular timing of the evening meal (OR = 2.06; 1.10-3.84) and display viewing within 2 h before bedtime (OR = 2.50; 1.01-6.18) or in bed (OR = 3.60; 1.41-9.21) were significantly associated with excessive daytime sleepiness. Using an electronic display within 2 h before bedtime (OR = 2.64; 1.10-6.38) or in bed (OR = 3.50; 1.40-8.76) and a living room which is bright at night (OR = 1.89; 1.06-3.36) were significantly associated with eveningness. CONCLUSION: Each type of sleep-related problem had its own associated life habit factors. PMID- 29530364 TI - Multiple nights of partial sleep deprivation do not affect prospective remembering at long delays. AB - Prospective memory is defined as remembering to do something at a particular moment in the future and may be modulated by sleep. Here, we investigated whether multiple nights of partial sleep deprivation would affect the successful retrieval of intentions. Fifty-nine adolescents (mean age +/- SD: 16.1 +/- 0.6 years) were instructed to remember to press specific keys in response to the target words presented during a semantic categorization task in the future. Their memory was tested after five nights of either 5-h (sleep restriction group) or 9 h time-in-bed (control group). The average percentage of target words correctly responded to was small and did not significantly differ between the two groups (mean +/- SEM for the sleep restriction group: 15.52 +/- 6.61%; the control group: 23.33 +/- 7.48%, p = 0.44). Thus, after the extended retention interval, prospective remembering was poor and did not appear to be affected by post learning sleep restriction. These findings suggest a temporal boundary beyond which intentions fall below requisite levels of activation, potentially masking any benefits for retrieval conferred by sleep. PMID- 29530365 TI - The effect of light exposure on insomnia and nocturnal movement in Parkinson's disease: an open label, retrospective, longitudinal study. AB - Insomnia, hypersomnia and REM Sleep Behavior Disorder (RSBD) during sleep are major problems for patients suffering from Parkinson's disease (PD) but they are also used to predict its onset. While these secondary symptoms detract from the quality of life in PD patients, few treatment options are available due to limited efficacy or risk of complicating the treatment regimen. Light therapy (LT) has been suggested as a strategy for sleep disorders but it has only been implemented recently for use in PD. An open label, retrospective study was undertaken where PD patients had been undergoing LT, using polychromatic light, for four months to 15 years prior. It was found that 1 h exposure to light, just prior to retiring, significantly improved insomnia and reduced RSBD in as little as one month after commencing LT. In addition, the improvement was maintained as long as LT was continued over a four to six year period. The efficacy of LT in alleviating these sleep related conditions was not compromised by time since diagnosis or age of the patient. These results intimate the value of long term application of non-invasive techniques such as LT for treating sleep disorders in PD and justify further controlled trials on the long term efficacy of LT. PMID- 29530367 TI - RBD: a red flag for cognitive impairment in Parkinson's disease? AB - Increasing evidence indicates a strong association between rapid eye movement sleep behavior disorder (RBD) and Parkinson's disease - cognitive impairment (PD CI). Numerous longitudinal and cross-sectional studies have shown that RBD may be an important risk factor and predictor of Parkinson's disease - mild cognitive impairment (PD-MCI) and Parkinson's disease dementia (PDD); which may be explained by the association of mechanisms between RBD and PD-CI, including neurotransmitter alterations, genetic mutation, neuroinflammation, alpha synuclein inclusion, abnormal cerebral metabolism and cortical activity slowing. Understanding the role of RBD in cognition of PD, we may predict and prevent the presence of PD-CI. The purpose of our comprehensive narrative review was to investigate the role of RBD in cognition of PD patients and its possible mechanism with lights from clinical epidemiological evidence, neuroimaging and electrophysiology studies. PMID- 29530366 TI - Joint effects of OSA and self-reported sleepiness on incident CHD and stroke. AB - BACKGROUND: Although excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA), and both EDS and OSA have separately been associated with increased risk of cardiovascular disease (CVD), their joint association with CVD risk is unknown. METHODS: Among 3874 Sleep Heart Health Study (SHHS) participants without prevalent CVD, moderate to severe OSA was defined by an apnea hypopnea index (AHI) >= 15 on an in-home polysomnography. EDS was defined as an Epworth Sleepiness Scale score >=11. Incident CVD events included total CVD events (coronary heart disease (CHD) and stroke), as well as CHD and stroke separately. Cox proportional hazards models adjusted for age, sex, alcohol, smoking, and body mass index. RESULTS: Compared to those with AHI <15, the hazard ratios (95% CI) for the association of moderate-severe OSA (AHI >=15) were as follows: CVD 1.06 (0.85-1.33); CHD 1.08 (0.85-1.33); and stroke 1.18 (0.75-1.84). Weak associations between EDS and CVD risk = [1.22 (1.01-1.47)] and CHD risk [1.25 (1.02-1.53)] were present, however there were none for stroke risk [1.10 (0.75-1.63)]. When jointly modeled, both AHI >=15 and EDS (compared with having AHI <15 and no EDS) was associated with HRs of 1.26 (0.91-1.73) for CVD, 1.24 (0.87-1.75) for CHD and 1.49 (0.78-2.86) for stroke. There were no statistically significant interactions between daytime sleepiness and OSA on the multiplicative or additive scales. CONCLUSIONS: Having both EDS and moderate severe OSA was not associated with an increased risk of CVD in the SHHS data. PMID- 29530368 TI - Association between nighttime sleep duration, midday naps, and glycemic levels in Japanese patients with type 2 diabetes. AB - OBJECTIVES: To clarify the relationship between nighttime sleep duration, midday naps, and glycemic control in Japanese patients diagnosed with type 2 diabetes (n = 355) or impaired glucose tolerance (n = 43). METHODS: A total of 398 patients completed a self-administered questionnaire on sleep duration/quality and were divided into five groups according to their self-reported nighttime sleep duration: <5 h, 5-6 h, 6-7 h, 7-8 h, and >8 h. Each group was further divided into two subgroups each according to the presence or absence of midday naps. Poor glycemic control was defined as HbA1c >= 7.0%. RESULTS: Short nighttime sleep (<5 h), poor sleep induction, daytime sleepiness, and low sleep satisfaction were associated with high HbA1c levels. HbA1c was higher in the short nighttime sleep/no nap group than in non-nappers with different nighttime sleep duration, whereas the short nighttime sleep/nap group showed similar HbA1c levels to the other nap subgroups. In multivariate logistic regression models, after adjusting for a number of potential confounders, short (<5 h) nighttime sleep without nap was significantly associated with poor glycemic control compared with 6-7 h nighttime sleep without nap (OR [95% CI]: 7.14 [2.20-23.20]). However, taking naps reduced this risk for poor glycemic control in short sleepers. Other risk factors for poor glycemic control were low sleep satisfaction (1.73 [1.10-2.70]) and poor sleep induction (1.69 [1.14-2.50]). CONCLUSIONS: Poor sleep quality and quantity could aggravate glycemic control in type 2 diabetes. Midday naps could mitigate the deleterious effects of short nighttime sleep on glycemic control. CLINICAL TRIALS REGISTRATION: UMIN 000017887. PMID- 29530369 TI - Adherence and persistence to ropinirole, pramipexole, and gabapentin in patients with newly diagnosed restless legs syndrome. AB - STUDY OBJECTIVES: The objective of this study is to assess adherence and persistence of ropinirole, pramipexole, and gabapentin; to investigate factors associated with non-adherence and non-persistence in restless legs syndrome (RLS) patients. METHODS: We used the 2008-2014 Marketscan(r) Research Databases to conduct a retrospective data analysis. The study included newly diagnosed RLS patients who initiated ropinirole, pramipexole, or gabapentin therapy. During 365 days of follow-up, mean medication possession ratios (MPRs) for adherence and the proportion of adherent users were calculated. The mean persistence (time to discontinuation) and the proportion of persistent users were also assessed during the same follow-up period. Factors associated with non-adherence and non persistence were analyzed using multivariate logistic regression. RESULTS: This study included 5163 ropinirole, 3380 pramipexole, and 1353 gabapentin users. The mean MPRs for ropinirole, pramipexole, and gabapentin were 0.52, 0.52, and 0.48, respectively. The proportions of adherent users were 33.2%, 34.6%, and 27.4%, respectively. Mean time to treatment discontinuation was 158 days, 158 days, and 145 days, respectively. The proportions of persistent users at 365 days were 25.0%, 25.8%, and 20.6%, respectively. Younger age, higher number of concomitant medications, and gabapentin use (vs. ropinirole or pramipexole use) were positively associated with non-adherence and non-persistence. Additionally, retail pharmacy use (vs. mail order pharmacy use) and use of benzodiazepines were positively associated with non-adherence. CONCLUSION: Adherence and persistence to ropinirole, pramipexole, and gabapentin were low in newly diagnosed RLS patients during 365 days of follow-up. Certain patient characteristics were predictors of non-adherence and non-persistence. PMID- 29530370 TI - Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease. AB - BACKGROUND: Type 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course. METHODS: Immune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses. RESULTS: The NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4+ terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4+ terminally differentiated effector memory T cells and an increased frequency of NK CD56bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4+ terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls. CONCLUSIONS: Significant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology. PMID- 29530371 TI - Exploring sleep quality of young children with autism spectrum disorder and disruptive behaviors. AB - BACKGROUND AND PURPOSE: Sleep disturbances in autism spectrum disorder (ASD) are common and may impair daytime functioning as well as add to parental burden. In this well characterized sample of young children with ASD and disruptive behaviors, we examine the association of age and IQ in sleep disturbances using the Child Sleep Habits Questionnaire modified for ASD (CSHQ-ASD). We also test whether children with poor sleep have greater daytime behavioral problems than those with better sleep. Finally, we examine whether parental stress is higher in children with greater disruptive behaviors and sleep disturbances. PARTICIPANTS AND METHODS: One hundred and seventy-seven children with complete data out of 180 (mean age 4.7) with ASD participated in a randomized clinical trial. Parents completed the CSHQ-ASD and several other measures at study enrollment. The sample was divided into "poor sleepers" (upper quartile on the total score of the CSHQ ASD) and "good sleepers" (lower quartile) for comparisons. Analyses were conducted to evaluate group differences on age, IQ, daytime disruptive behavior, social disability and parental stress. RESULTS: The two groups of young children with ASD, good sleepers versus poor sleepers, were not different on age or cognitive level. Children in the poor sleeping group had significantly higher daytime behavioral problems including irritability, hyperactivity, social withdrawal and stereotypical behaviors. Parents in this group reported significantly higher levels of stress. CONCLUSIONS: The finding of no age difference between good and poor sleepers in young children with ASD and disruptive behaviors suggests that sleep problems are unlikely to resolve as might be expected in typically developing children. Likewise, the good and poor sleepers did not significantly differ in IQ. These findings add strong support for the need to screen for sleep disturbances in all children with ASD, regardless of age and cognitive level. Poor sleepers exhibited significantly greater daytime behavioral problems and parents of children in this group reported significantly higher levels of stress. Above and beyond the co-occurring disruptive behavior, poor sleep quality appears to pose substantial additive burden on child and parents. PMID- 29530372 TI - Characteristics and correlates of sleep duration, daytime napping, snoring and insomnia symptoms among 0.5 million Chinese men and women. AB - BACKGROUND: Inadequate sleep duration and insomnia can affect both physical and mental health. There is limited evidence, however, on characteristics and correlates of sleep patterns and insomnia in urban and rural China. METHODS: This cross-sectional study, involving 512,891 adults aged 30-79 years from ten (five urban and five rural) diverse areas in China, recorded detailed information, using interviewer-administered laptop-based questionnaires, on sleep patterns (duration, daytime napping and snoring) and insomnia symptoms. Logistic regression was used to examine the associations of sleep patterns and insomnia symptoms with a range of socio-economic, lifestyle, behaviour and health-related factors. RESULTS: Overall, the mean (SD) sleep duration was 7.38 (1.37) h, with 23% reporting short (<=6 h) and 16% reporting long (>=9 h) sleep duration, 21% taking daytime naps and 22% having frequent snoring. Overall, 17% reported having insomnia symptoms, with a higher proportion in women than in men (19% vs 13%), in rural than in urban residents (19% vs 15%), and in individuals who were living alone (23%). The adjusted odds ratios (ORs) of having insomnia symptoms were significantly higher among people with major depressive episodes (6.10, 95% CI: 5.69-6.55), generalised anxiety disorders (7.46, 6.65-8.37) and any chronic diseases (1.46; 1.44-1.49). In contrast, the ORs of insomnia symptoms were significantly lower among those reporting napping (0.77, 0.75-0.78) and frequent snoring (0.86, 0.84-0.87). CONCLUSIONS: Among Chinese adults, sleep patterns varied greatly by socio-economic, lifestyle and health-related factors. The risk of insomnia symptoms was associated with both poor mental and physical health status. PMID- 29530373 TI - Sleep disorder risk factors among student athletes. AB - OBJECTIVE: To clarify sleep disorder risk factors among student athletes, this study examined the relationship between lifestyle habits, competition activities, psychological distress, and sleep disorders. METHODS: Student athletes (N = 906; male: 70.1%; average age: 19.1 +/- 0.8 years) in five university sports departments from four Japanese regions were targeted for analysis. Survey items were attributes (age, gender, and body mass index), sleep disorders (recorded through the Pittsburgh Sleep Quality Index), lifestyle habits (bedtime, wake-up time, smoking, drinking alcohol, meals, part-time jobs, and use of electronics after lights out), competition activities (activity contents and competition stressors), and psychological distress (recorded through the K6 scale). The relation between lifestyle habits, competition activities, psychological distress, and sleep disorders was explored using logistic regression analysis. RESULTS: Results of multivariate logistic regression analysis with attributes as adjustment variables showed that "bedtime," "wake-up time," "psychological distress," "part-time jobs," "smartphone/cellphone use after lights out," "morning practices," and "motivation loss stressors," were risk factors that were independently related to sleep disorders. CONCLUSIONS: Sleep disorders among student athletes are related to lifestyle habits such as late bedtime, early wake up time, late night part-time jobs, and use of smartphones/cellphones after lights out; psychological distress; and competition activities such as morning practices and motivation loss stressors related to competition. Therefore, this study suggests the importance of improving these lifestyle habits, mental health, and competition activities. PMID- 29530375 TI - Lower plasma choline levels are associated with sleepiness symptoms. AB - : Sleepiness and cardiovascular disease share common molecular pathways; thus, metabolic risk factors for sleepiness may also predict cardiovascular disease risk. Daytime sleepiness predicts mortality and cardiovascular disease, although the mechanism is unidentified. This study explored the associations between subjective sleepiness and metabolite concentrations in human blood plasma within the oxidative and inflammatory pathways, in order to identify mechanisms that may contribute to sleepiness and cardiovascular disease risk. METHODS: An exploratory case-control sample of 36 subjects, categorized based on the Epworth Sleepiness Scale (ESS) questionnaire as sleepy (ESS >= 10) or non-sleepy (ESS < 10), was recruited among subjects undergoing an overnight sleep study for suspected sleep apnea at the University of Pennsylvania Sleep Center. The average age was 42.4 +/ 10.5 years, the mean body mass index (BMI) was 40.0 +/- 9.36 kg/m2, median Apnea Hypopnea Index (AHI) was 8.2 (IQR: 2.5-26.5), and 52% were male. Fasting morning blood plasma samples were collected after an overnight sleep study. Biomarkers were explored in subjects with sleepiness versus those without using the multiple linear regression adjusting for age, BMI, smoking, Apnea Hypopnea Index (sleep apnea severity), study cohort, and hypertension. RESULTS: The level of choline is significantly lower (P = 0.003) in sleepy subjects (N = 18; mean plasma choline concentration of 8.19 +/- 2.62 MUmol/L) compared with non-sleepy subjects (N = 18; mean plasma choline concentration of 9.14 +/- 2.25 MUmol/L). Other markers with suggestive differences (P < 0.1) include isovalerylcarnitine, Alpha-Amino apidipic acid, Spingosine 1 Phosphate, Aspartic Acid, Propionylcarnitine, and Ceramides (fatty acids; C14-C16 and C-18). CONCLUSION: This pilot study is the first to show that lower levels of plasma choline metabolites are associated with sleepiness. Further exploration of choline and other noted metabolites and their associations with sleepiness will guide targeted symptom management. PMID- 29530374 TI - Factors associated with insomnia and complementary medicine use in children: results of a national survey. AB - OBJECTIVES: Sleep difficulties are a serious health problem in children, and interest in using complementary and alternative medicine (CAM) therapies to treat sleep is growing. In this study, we aimed to identify: the prevalence of sleep difficulties in children, and the prevalence and patterns of CAM use among children with trouble sleeping. METHODS: We used the 2012 National Health Interview Survey (NHIS) dataset to estimate the prevalence of sleep difficulties and CAM use in children ages 6-17 years. Prevalence estimates were weighted to reflect the survey's sampling design. We used logistic regression to explore associations between sleep difficulties, psychosocial factors, comorbidities and CAM use. RESULTS: 6.4% of children in the 2012 NHIS dataset reported regular difficulty sleeping in the last year, corresponding to an estimated 1.5 million children in the US. Older age, poorer health status, more missed school days, and multiple comorbidities were all associated with sleep difficulties (p <= 0.001). Among children with sleep difficulties, 29% used at least one CAM therapy. Of the CAM therapies surveyed, non-vitamin, non-mineral supplements were the most commonly used (14.6%), followed by manipulation therapies (9.2%) and mind-body techniques (8.8%). Parental education and CAM use were most strongly associated with child CAM use (p <= 0.001). CONCLUSIONS: CAM therapies, particularly non vitamin, non-mineral supplements, are commonly used among children with sleeping problems. More research is needed to characterize the safety and efficacy of CAM therapies for sleep in this population. PMID- 29530376 TI - A comparative study of methods for automatic detection of rapid eye movement abnormal muscular activity in narcolepsy. AB - OBJECTIVE: To evaluate rapid eye movement (REM) muscular activity in narcolepsy by applying five algorithms to electromyogram (EMG) recordings, and to investigate its value for narcolepsy diagnosis. PATIENTS/METHODS: A modified version of phasic EMG metric (mPEM), muscle activity index (MAI), REM atonia index (RAI), supra-threshold REM EMG activity metric (STREAM), and Frandsen method (FR) were calculated from polysomnography recordings of 20 healthy controls, 18 clinic controls (subjects suspected with narcolepsy but finally diagnosed without any sleep abnormality), 16 narcolepsy type one without REM sleep behavior disorder (RBD), nine narcolepsy type one with RBD, and 18 narcolepsy type two. Diagnostic value of metrics in differentiating between groups was quantified by area under the receiver operating characteristic curve (AUC). Correlations among the metrics and cerebrospinal fluid hypocretin-1 (CSF hcrt-1) values were calculated using linear models. RESULTS: All metrics excluding STREAM found significantly higher muscular activity in narcolepsy one cases versus controls (p < 0.05). Moreover, RAI showed high sensitivity in the detection of RBD. The mPEM achieved the highest AUC in differentiating healthy controls from narcoleptic subjects. The RAI best differentiated between narcolepsy 1 and 2. Lower CSF-hcrt-1 values correlated with high muscular activity quantified by mPEM, sMAI, lMAI, PEM and FR (p < 0.05). CONCLUSIONS: This automatic analysis showed higher number of muscle activations in narcolepsy 1 compared to controls. This finding might play a supportive role in diagnosing narcolepsy and in discriminating narcolepsy subtypes. Moreover, the negative correlation between CSF-hcrt-1 level and REM muscular activity supported a role for hypocretin in the control of motor tone during REM sleep. PMID- 29530377 TI - Autonomously Controlled Magnetic Flexible Endoscope for Colon Exploration. PMID- 29530378 TI - Dimensions of insight in schizophrenia: Exploratory factor analysis of items from multiple self- and interviewer-rated measures of insight. AB - OBJECTIVE: Insight in schizophrenia is regarded as a multidimensional construct that comprises aspects such as awareness of the disorder and recognition of the need for treatment. The proposed number of underlying dimensions of insight is variable in the literature. In an effort to identify a range of existing dimensions of insight, we conducted a factor analysis on combined items from multiple measures of insight. METHOD: We recruited 165 participants with enduring schizophrenia (treated for >3years). Exploratory factor analysis was conducted on itemized scores from two interviewer-rated measures of insight: the Schedule for the Assessment of Insight-Expanded and the abbreviated Scale to assess Unawareness of Mental Disorder; and two self-report measures: the Birchwood Insight Scale and the Beck Cognitive Insight Scale. RESULTS: A five-factor solution was selected as the best-fitting model, with the following dimensions of insight: 1) awareness of illness and the need for treatment; 2) awareness and attribution of symptoms and consequences; 3) self-certainty; 4) self reflectiveness for objectivity and fallibility; and 5) self-reflectiveness for errors in reasoning and openness to feedback. CONCLUSIONS: Insight in schizophrenia is a multidimensional construct comprised of distinct clinical and cognitive domains of awareness. Multiple measures of insight, both clinician- and self-rated, are needed to capture all of the existing dimensions of insight. Future exploration of associations between the various dimensions and their potential determinants will facilitate the development of clinically useful models of insight and effective interventions to improve outcome. PMID- 29530379 TI - A Bypass in Jasmonate Biosynthesis - the OPR3-independent Formation. AB - For the first time in 25 years, a new pathway for biosynthesis of jasmonic acid (JA) has been identified. JA production takes place via 12-oxo-phytodienoic acid (OPDA) including reduction by OPDA reductases (OPRs). A loss-of-function allele, opr3-3, revealed an OPR3-independent pathway converting OPDA to JA. PMID- 29530380 TI - Gibberellin Localization and Transport in Plants. AB - Distribution patterns and finely-tuned concentration gradients of plant hormones govern plant growth and development. Gibberellin (GA) is a plant hormone regulating key processes in plants; many of them are of significant agricultural importance, such as seed germination, root and shoot elongation, flowering, and fruit patterning. Although studies have demonstrated that GA movement is essential for multiple developmental aspects, how GAs are transported throughout the plant and where exactly they accumulate remain largely unknown. Here, we summarize recent findings from studies of GA movement and localization, and discuss the importance of GA intermediates in long- and short-distance movement. We further review recently identified Arabidopsis GA transporters and highlight their complex specialization and robust functional redundancy in GA transport activity. PMID- 29530381 TI - Commercialization, Altruism, Clinical Practice: Seeking Explanation for Similarities and Differences in Californian and Canadian Gestational Surrogacy Outcomes. AB - BACKGROUND: Surrogacy is growing worldwide. Although recently some countries have sought to ban it, between 2010 and 2014 the number of babies born to gestational surrogates having in vitro fertilization treatment in California doubled, and in Canada it grew by 35%. This work seeks to fill identified knowledge gaps about the similarities and differences in the practices and outcomes of gestational surrogacy, which in California operates on a commercial basis, whereas in Canada it is illegal to pay a surrogate. The paper focusses on the period from 2010 to 2014, for which comparable American and Canadian national assisted reproduction technology information exist. STUDY DESIGN: A retrospective data analysis was performed using information on gestational surrogate multiple births obtained from the Centers for Disease Control and Prevention National Assisted Reproductive Technology Surveillance System (NASS) and Canada's Assisted Reproduction Registry-Better Outcomes Registry and Network (CARTR-BORN). Multiple birth rates and transfers of multiple embryos were compared using relative risk analysis. Adherence to voluntary American Society for Reproductive Medicine Society for Assisted Reproductive Technology and Canadian Fertility and Andrology Society embryo transfer guidelines was modelled. FINDINGS: Among gestational surrogates, when donor ova embryos obtained from women aged less than 35 years were used, embryo transfer guideline adherence was 42% in California and 48% in Canada. CONCLUSIONS: Regardless of where on the commercial/noncommercial boundary North American surrogates reside, they are more likely to receive more donor ova embryos per in vitro fertilization transfer than other in vitro fertilization patients. An altruistic desire to assist childless couples and individuals create families along with clinic practices seem to play major roles in treatment decisions privileging the transfer two or more embryos. PMID- 29530382 TI - Life Course Adversity and Prior Miscarriage in a Pregnancy Cohort. AB - BACKGROUND: Prior studies indicate associations between preconception adversities and risk of miscarriage, but few have considered type (e.g., financial, substance use, abuse) or timing (e.g., childhood, adulthood) of adversities. We examined relationships between life course adversities in multiple domains and probability of miscarriage. METHODS: Data came from women with at least one previous pregnancy in the Pregnancy Outcomes and Community Health (1998-2004) study (n = 2,106). Life course adversities in domains of abuse/witnessing violence, loss of someone close, economic hardship, and substance abuse were assessed via questionnaire and categorized as occurring during childhood only, adulthood only, both childhood and adulthood, or neither. We also calculated a cumulative adversity score. We used logistic regression models to estimate associations between life course adversity measures and the probability of miscarriage, and examined effect modification by race/ethnicity and maternal education. All models were adjusted for maternal age, race/ethnicity, education, and marital status. RESULTS: The odds of miscarriage were higher among women experiencing legal adversities during both childhood and adulthood (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.3-2.8) compared with women not experiencing legal adversities, and higher among women experiencing substance use adversities in childhood only (OR, 1.4; 95% CI, 1.1-1.7) compared with women not experiencing substance use adversities. Each additional adversity was marginally significantly associated with a 10% increase in odds of preterm birth (OR, 1.1; 95% CI, 1.0 1.1). Among women with only one prior miscarriage, no adversity measures were associated with miscarriage. CONCLUSIONS: Exposure to adversity in certain domains and across the life course modestly increased the odds of miscarriage. PMID- 29530383 TI - High-resolution magnetization transfer MRI in patients with cervical spondylotic myelopathy. AB - Magnetization transfer (MT) contrast has been established as a marker of myelin integrity, and cervical spondylotic myelopathy is known to cause demyelination. Ten patients with clinical and magnetic resonance imaging (MRI) manifestations of cervical spondylotic myelopathy (CSM) were compared to the MRIs of seven historic healthy controls, using the magnetization transfer ratio (MTR) and Nurick scores as the primary metrics. Transverse slices through the intervertebral discs of the cervical spine were acquired using a gradient echo sequence (MEDIC) with and without an MT saturation pulse on a 3 Tesla Siemens Prisma scanner (TR = 300 ms, TEeff = 17 ms, flip angle = 30 degrees , in-plane resolution = 0.47 * 0.47 mm2). The CSM patients tended to have a lower mean MTR (30.4 +/- 6.5) than the controls (34.8 +/- 3.8), but the difference was not significant (independent samples t test, p = 0.110, Cohen's d = 0.80). The mean MTR across all intervertebral disc levels was not significantly correlated to the Nurick score (Spearman's rho = 0.489, p = 0.151). The intervertebral level with the lowest MTR in each cohort was not significantly different between groups (equal variances not assumed, t = 1.965, dof = 14.8, p = 0.068, Cohen's d = 0.88), but the CSM patients tended to have a lower MTR. The mean MTR at this level was negatively correlated to the Nurick score among CSM patients (Spearman's rho = -0.725, p = 0.018). CSM patients tended to have decreased MTR indicating myelin degradation compared to our healthy subjects, and MTR was negatively correlated with the severity of CSM. PMID- 29530384 TI - Awake craniotomy for excision of arteriovenous malformations? A qualitative comparison study with stereotactic radiosurgery. AB - Treatment of arteriovenous malformations (AVM) located at the eloquent area has been a challenge. Awake brain mapping allows identification of a non-eloquent gyrus for intervention and can potentially facilitate resection with preservation of functions. An alternative treatment option is stereotactic radiosurgery (SRS). The objective of this study was to perform a qualitative comparison of the treatment outcome of awake AVM excision versus SRS. We conducted a 13-year retrospective review of AVM excision under awake craniotomy performed at Prince of Wales Hospital, Hong Kong, from 2003 to 2016. Patients' presentation, Spetzler Martin (SM) grading, rate of obliteration and complication were reviewed and analyzed with the modified radiosurgery-based AVM score (RS score). Six patients had excision of AVM under awake mapping during this period of time. Two were SM Grade II and four were SM Grade III. Five located at the peri-rolandic region while one at the temporal language area. None had failed mapping. Five out of six achieved complete obliteration (83.3%). Qualitative comparative analysis had revealed better treatment outcome with awake AVM excision as compared to SRS with the obliteration rate of 100% versus 96% for RS score <=1.00, 100% versus 78% for RS score 1.01-1.50, and 66% versus 50% for RS score >2.00 respectively. In conclusion, awake mapping and excision of AVMs at the eloquent area is feasible. Qualitative comparative analysis had revealed higher obliteration rate with awake AVM excision as compared to SRS. PMID- 29530385 TI - A qualitative evaluation of a physician-delivered pedometer-based step count prescription strategy with insight from participants and treating physicians. AB - AIMS: The integration of pedometers into clinical practice has the potential to enhance physical activity levels in patients with chronic disease. Our SMARTER randomized controlled trial demonstrated that a physician-delivered step count prescription strategy has measurable effects on daily steps, glycemic control, and insulin resistance in patients with type 2 diabetes and/or hypertension. In this study, we aimed to understand perceived barriers and facilitators influencing successful uptake and sustainability of the strategy, from patient and physician perspectives. METHODS: Qualitative in-depth interviews were conducted in a purposive sample of physicians (n = 10) and participants (n = 20), including successful and less successful cases in terms of pedometer-assessed step count improvements. Themes that achieved saturation in either group through thematic analysis are presented. RESULTS: All participants appreciated the pedometer-based monitoring combined with step count prescriptions. Accountability to physicians and support offered by the trial coordinator influenced participant motivation. Those who increased step counts adopted strategies to integrate more steps into their routines and were able to overcome weather-related barriers by finding indoor alternative options to outdoor steps. Those who decreased step counts reported difficulty in overcoming weather-related challenges, health limitations and work constraints. Physicians indicated the strategy provided a framework for discussing physical activity and motivating patients, but emphasized the need for support from allied professionals to help deliver the strategy in busy clinical settings. CONCLUSION: A physician-delivered step count prescription strategy was feasibly integrated into clinical practice and successful in engaging most patients; however, continual support is needed for maximal engagement and sustained use. PMID- 29530386 TI - Steroid-induced hyperglycemia: An underdiagnosed problem or clinical inertia? A narrative review. AB - Corticosteroids are widely diffused drugs. An important side effect is the impairment of glycemic control both in patients with known diabetes and in normoglycemic ones potentially leading to steroid-induced diabetes mellitus (SIDM). In this review based on papers released on PubMed, MEDLINE, and EMBASE from January 2015 to October 2017, we summarized and discussed main updates about the definition, the diagnosis, and the pathophysiology of steroid-induced hyperglycemia (SIH), with a look to new therapies. Main alterations responsible for the diabetogenic effect of corticosteroids are a negative impact on insulin sensitivity along with a derangement on insulin secretion, explaining the typical post-prandial hyperglycemia linked to the promotion of gluconeogenesis. An early and precise diagnosis of SIH and/or SIDM is necessary, but current criteria do not seem sensible enough. As an afterthought, the treatment should be reasoned and tailored according to proposed glycemic thresholds and patient comorbidities, choosing between antidiabetic oral drugs and insulin, the latter being preferable among hospitalized patients. SIDM and SIH are frequent problems, but often underdiagnosed due to old diagnostic criteria. Dedicated guidelines universally shared are mandatory in order to harmonize the treatment of these conditions, thus overtaking single therapeutic strategies mostly arising from literature. PMID- 29530387 TI - Access to artemisinin-based combination therapies and other anti-malarial drugs in Kinshasa. AB - OBJECTIVE: Artemisinin-based combination therapies have been available since 2005 in the Democratic Republic of the Congo to treat malaria and to overcome the challenge of anti-malarial drug resistance as well as to improve access to effective treatments. The private sector is the primary distribution source for anti-malarial drugs and thus, has a key position among the supply chain actors for a rational and proper use of anti-malarial drugs. We aimed to assess access to nationally recommended anti-malarial drugs in private sector pharmacies of the capital-city of Kinshasa. METHOD: We performed a cross-sectional survey of 404 pharmacies. RESULTS: Anti-malarial drugs were stocked in all surveyed pharmacies. Non-artemisinin-based anti-malarial therapies such as quinine or sulfadoxine pyrimethamine, were the most frequently stocked drugs (93.8% of pharmacies). Artemisinin-based combination therapies were stocked in 88% of pharmacies. Artemether-lumefantrine combinations were the most frequently dispensed drugs (93% of pharmacies), but less than 3% were quality-assured products. Other non officially recommended artemisinin-based therapies including oral monotherapies were widely available. CONCLUSION: Artemisinin-based combination therapies were widely available in the private pharmacies of Kinshasa. However, the private sector does not guarantee the use of nationally recommended anti-malarial drugs nor does it give priority to quality-assured anti-malarial drugs. These practices contribute to the risk of emergence and spread of resistance to anti-malarial drugs and to increasing treatment costs. PMID- 29530388 TI - A review of the 1918 herald pandemic wave: importance for contemporary pandemic response strategies. AB - Mounting epidemiological evidence supports the occurrence of a mild herald pandemic wave in the spring and summer of 1918 in North America and Europe, several months before the devastating autumn outbreak that killed an estimated 2% of the global population. These epidemiological findings corroborate the anecdotal observations of contemporary clinicians who reported widespread influenza outbreaks in spring and summer 1918, with sporadic occurrence of unusually severe clinical manifestations in young adults. Initially seen as controversial, these findings were eventually confirmed by retrospective identification of influenza specimens collected from U.S. soldiers who died from acute respiratory infections in May-August 1918. Other studies found that having an episode of influenza illness during the spring herald wave was highly protective in the severe autumn wave. Here, we conduct a systematic review of the clinical, epidemiological, and virological evidence supporting the global occurrence of mild herald waves of the 1918 pandemic and place these historic observations in the context of pandemic preparedness. Taken together, historic experience with the 1918 and subsequent pandemics shows that increased severity in second and later pandemic waves may be the rule rather than the exception. Thus, a sustained pandemic response in the first years following a future pandemic is critical; conversely, multiwave pandemic patterns allow for more time to rollout vaccines and antivirals. PMID- 29530389 TI - Report of final results regarding brain and heart tumors in Sprague-Dawley rats exposed from prenatal life until natural death to mobile phone radiofrequency field representative of a 1.8 GHz GSM base station environmental emission. AB - BACKGROUND: In 2011, IARC classified radiofrequency radiation (RFR) as possible human carcinogen (Group 2B). According to IARC, animals studies, as well as epidemiological ones, showed limited evidence of carcinogenicity. In 2016, the NTP published the first results of its long-term bioassays on near field RFR, reporting increased incidence of malignant glial tumors of the brain and heart Schwannoma in rats exposed to GSM - and CDMA - modulated cell phone RFR. The tumors observed in the NTP study are of the type similar to the ones observed in some epidemiological studies of cell phone users. OBJECTIVES: The Ramazzini Institute (RI) performed a life-span carcinogenic study on Sprague-Dawley rats to evaluate the carcinogenic effects of RFR in the situation of far field, reproducing the environmental exposure to RFR generated by 1.8 GHz GSM antenna of the radio base stations of mobile phone. This is the largest long-term study ever performed in rats on the health effects of RFR, including 2448 animals. In this article, we reported the final results regarding brain and heart tumors. METHODS: Male and female Sprague-Dawley rats were exposed from prenatal life until natural death to a 1.8 GHz GSM far field of 0, 5, 25, 50 V/m with a whole-body exposure for 19 h/day. RESULTS: A statistically significant increase in the incidence of heart Schwannomas was observed in treated male rats at the highest dose (50 V/m). Furthermore, an increase in the incidence of heart Schwann cells hyperplasia was observed in treated male and female rats at the highest dose (50 V/m), although this was not statistically significant. An increase in the incidence of malignant glial tumors was observed in treated female rats at the highest dose (50 V/m), although not statistically significant. CONCLUSIONS: The RI findings on far field exposure to RFR are consistent with and reinforce the results of the NTP study on near field exposure, as both reported an increase in the incidence of tumors of the brain and heart in RFR-exposed Sprague-Dawley rats. These tumors are of the same histotype of those observed in some epidemiological studies on cell phone users. These experimental studies provide sufficient evidence to call for the re evaluation of IARC conclusions regarding the carcinogenic potential of RFR in humans. PMID- 29530390 TI - Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery. AB - Human serum albumin (HSA) is a superior carrier for delivering extracellular drugs. However, the development of a cell-penetrating HSA remains a great challenge due to its low membrane permeability. We report herein on the design of a series of palmitoyl-poly-arginine peptides (CPPs) and an evaluation of their cell-penetrating effects after forming a complex with HSA for use in intracellular drug delivery. The palmitoyl CPPs forms a stable complex with HSA by anchoring itself to the high affinity palmitate binding sites of HSA. Among the CPPs evaluated, a cyclic polypeptide composed of D-dodecaarginines, palmitoyl cyclic-(D-Arg)12 was the most effective for facilitating the cellular uptake of HSA by HeLa cells. Such a superior cell-penetrating capability is primarily mediated by macropinocytosis. The effect of the CPP on pharmacological activity was examined using three drugs loaded in HSA via three different methods: a) an HSA-paclitaxel complex, b) an HSA-doxorubicin covalent conjugate and c) an HSA thioredoxin fusion protein. The results showed that cell-penetrating efficiency was increased with a corresponding and significant enhancement in pharmacological activity. In conclusion, palmitoyl-cyclic-(D-Arg)12/HSA is a versatile cell penetrating drug delivery system with great potential for use as a nano-carrier for a wide diversity of pharmaceutical applications. PMID- 29530391 TI - Editorial: Improving healthcare for our homeless patients matters. PMID- 29530392 TI - Effectiveness of an Interprofessional Glycemic Optimization Clinic on Preoperative Glycated Hemoglobin Levels for Adult Patients With Type 2 Diabetes Undergoing Bariatric Surgery. AB - OBJECTIVES: Bariatric surgery is an effective treatment for patients with type 2 diabetes and refractory obesity; however, many patients have nonoptimal glycemic control preoperatively. We created an interprofessional bariatric glycemic optimization clinic. Patients were seen monthly and received weekly phone calls. We analyzed the effectiveness in assisting patients reach a preoperative glycated hemoglobin (A1C) level of <7.5%. METHODS: Data were analyzed for the first 75 patients. The primary outcome measure was percentage of patients reaching target A1C levels. RESULTS: Mean age was 51+/-8.3 years; 64% were women. Mean baseline weight was 134.4+/-29.2 kg. Baseline body mass index was 48.2+/-8.3 kg/m2. Duration of diabetes was 9+/-7.9 years. Baseline A1C level was 9.0+/-1.2%. Number of antihyperglycemic agents at baseline was 2.7+/-0.96. Seventy-five percent reached a target A1C level of <=7.5%, 92% reached a target of <=8.0% and 95% reached a target of <=8.5%; 32% had achieved A1C levels <=7.5% at 1 month, 59% at 2 months, 70% at 3 months, 73% at 4 months and 75% at 5 months. Mean number of antihyperglycemic agents at target A1C levels was 3.6+/-1.1. Mean absolute decrease in A1C levels from baseline to target A1C levels was 1.7+/-1.2. Mean absolute change in weight was -1.9+/-8.0 kg. Percent change in body weight from baseline to target A1C level was -1.3+/-4.9%. CONCLUSIONS: Glycemic optimization for candidates with diabetes for bariatric surgery is possible in a short time by an interprofessional diabetes team and without weight gain. Further research is needed to determine whether better preoperative glycemic control improves bariatric surgery outcomes. PMID- 29530393 TI - Chemotherapy and targeted therapy in the management of cervical cancer. AB - Management of cervical cancer has undergone refinement in the past two decades; concurrent chemo-radiation (CCRT) (with cisplatin alone or in combination) is currently the standard treatment approach for patients with locally advanced disease (FIGO stage IIB-IVA). About 30%-40% of such patients fail to achieve complete response; alternative approaches are needed to improve outcome for them. Treatment with bevacizumab (an inhibitor of vascular endothelial growth factor) along with chemotherapy is associated with improved survival in patients with recurrent or metastatic cervical cancer. Weekly paclitaxel and carboplatin for 4 6 weeks as dose dense chemotherapy prior to CCRT is currently under study in a phase III, multicentric trial. Role of adjuvant chemotherapy after CCRT in patients with positive lymph nodes, larger tumor volume and those with stage III IVA disease needs further exploration. Novel agents targeting molecular pathways are currently being studied. Recent development of immune check point inhibitors is exciting, results of ongoing studies are awaited with interest. PMID- 29530394 TI - Primary squamous cell carcinoma arising from endometriosis of the ovary: A case report and literature review. AB - Cases of squamous cell carcinoma (SCC) arising from ovarian endometriosis have been rarely reported. Most of the patients show a poor prognosis and present with a diminished survival time. We present a SCC case arising from endometriosis, and analyzed the clinical, therapeutic, and pathologic features through a comprehensive literature review. A 43-year premenopausal woman (gravida 2, para 1) presented to our hospital due to sudden pain in lower abdomen. Exploratory laparotomy indicated rupture of left ovarian cyst and intra-abdominal hemorrhage were observed. Frozen section pathologic examination indicated malignant ovarian (left-sided) epithelial tumor (poorly differentiated squamous carcinoma). She received hysterectomy, adnexectomy, and omentectomy. Initially, the patient received 3 cycles of chemotherapy using paclitaxel and cisplatin via peritoneal injection. Subsequently, the regimen was altered to 2 cycles of paclitaxel or cisplatin chemotherapy through intravenous injection due to poor tolerance. Upon diagnosis of vaginal metastasis, 2 cycles of chemotherapy was performed using cisplatin, doxorubicin, and cyclophosphamide. Pathologic analysis revealed massive poorly differentiated squamous carcinoma in the fibrous tissues. Besides, cancer embolus was noticed in the lymphatic vessels. Besides our case, 20 cases of infiltrating SCC of the ovary associated with or arising from endometriosis were found. The tumor was associated with 80% patient mortality in the first few months. Adjuvant chemotherapy with paclitaxel and carboplatin or cisplatin appeared to contribute to the survival duration. The best outcomes were obtained in patients received paclitaxel and carboplatin or cisplatin after radical surgery. In future, further studies are needed to validate the efficiency of such regimen. PMID- 29530395 TI - Hypercoagulability - The Underdiagnosed and Undertreated Nemesis of Congenital Heart Surgery. PMID- 29530396 TI - Acute Risk Change: An Innovative Measure of Operative Adverse Events and Perioperative Team Performance. AB - OBJECTIVES: Cardiac surgical risk models predict mortality preoperatively, whereas intensive care unit (ICU) models predict mortality postoperatively. Finding a large difference between the 2 (an acute risk change [ARC]) may reflect an alteration in the status of the patient related to the surgery. An adverse ARC was associated with morbidity and mortality in an Australian population. The aims of this study were to validate ARC in a UK population and to investigate the possible mechanisms behind ARC. DESIGN: This was a retrospective case-control study. SETTING: Single, high-volume cardiothoracic hospital. PARTICIPANTS: Data from 4,842 cardiac surgical patients were collected between 2013 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EuroSCORE was recalibrated to each preceding year's data. ARC was defined as postoperative minus preoperative percentage mortality risk. Association among ARC, morbidity, and mortality was tested. Cases with large adverse ARC (greater than +15%) were compared with cases with large favorable ARC (less than -10%) with regard to intraoperative adverse events, unmeasured patient risk factors, and postoperative events. Adverse ARC was associated with hospital mortality, ICU stay, ICU readmission, renal support, prolonged intubation and return to the operating room (p < 0.001). Intraoperative adverse events occurred in 23 of 33 patients with adverse ARC; however, only 2 of 17 patients with favorable ARC reported adverse events (p < 0.001). Unmeasured risk factors were present in 48% of patients in the adverse ARC group. CONCLUSION: ARC is a readily available and sensitive marker that correlates strongly with morbidity and mortality. The use of ARC in local and national quality monitoring could identify areas for improvement of the quality of cardiac surgical care. PMID- 29530397 TI - Can I Go Home With That Balloon Pump? PMID- 29530398 TI - Outcomes of Patients With COPD Undergoing Cardiac Surgery: Don't Hold Your Breath. PMID- 29530399 TI - Response: "Confounding and Adjustment Factors in the Effect of Intravenous Parecoxib on Shoulder Pain After Thoracotomy?" PMID- 29530401 TI - Shifting Sands of Surgical Education. PMID- 29530400 TI - Ischemic Postconditioning and Milrinone. PMID- 29530402 TI - Is egg freezing a good response to socioeconomic and cultural factors that lead women to postpone motherhood? AB - In western societies, a growing number of women are currently turning to social egg freezing, a technique that makes it possible to freeze oocytes and thus preserve female reproductive possibilities. The current ethical debate has focused on normative aspects concerning the question of whether social egg freezing empowers women's reproductive autonomy. Due to this narrow focus on autonomy, deeper questions concerning the socio-economic conditions and cultural factors that lead women to delay reproduction, to feel pressured by their biological clock, and thus to consider social egg freezing have not yet received sufficient attention and analysis. The aim of this study was to broaden the ethical debate by focusing on whether social egg freezing is a good response to the socioeconomic and cultural constraints that lead women to postpone motherhood, and therefore whether it can be seen as a means of achieving what in virtue ethics is known as a 'good life'. I will argue that while social egg freezing can be seen as a means to empower women to adapt to current socioeconomic constraints, it is not an adequate response to cultural factors, as these cannot be solved by simply extending a woman's fertility. PMID- 29530403 TI - Magnetic molecularly imprinted polymers for the selective determination of cocaine by ion mobility spectrometry. AB - Magnetic molecularly imprinted polymers (MMIPs) were prepared for cocaine recognition by bulk polymerization in the presence of magnetic nanoparticles (MNPs). Two reagents (polyethylene glycol (PEG) and 3-(trimethoxysilyl)propyl methacrylate (V)) were used for MNPs modification. MMIPs were characterized and compared in terms of loading capacity, reusability, accuracy and precision for the extraction of cocaine from saliva samples. It was observed that V-MMIPs gave higher physical stability than PEG-MMIPs. Thus, V-MMIP were used for the analysis of cocaine users saliva. The developed procedure based on ion mobility spectrometry (IMS) provided limits of detection and quantification of 4 and 14 MUg L-1, respectively, and recoveries in cocaine free saliva samples spiked at 80, 270 and 560 MUg L-1 ranging from 80 to 99%. Results found by the proposed method were statistically comparable to those obtained by two reference procedures; a lateral flow immunoassay and an ultra-high performance liquid chromatography coupled with tandem mass spectrometry. Therefore, MMIP-IMS can be considered as a fast, selective and sensitive alternative to reference methods with affordable cost avoiding the requirement of skilled operator. PMID- 29530404 TI - In-line Fourier-transform infrared spectroscopy as a versatile process analytical technology for preparative protein chromatography. AB - Fourier-transform infrared spectroscopy (FTIR) is a well-established spectroscopic method in the analysis of small molecules and protein secondary structure. However, FTIR is not commonly applied for in-line monitoring of protein chromatography. Here, the potential of in-line FTIR as a process analytical technology (PAT) in downstream processing was investigated in three case studies addressing the limits of currently applied spectroscopic PAT methods. A first case study exploited the secondary structural differences of monoclonal antibodies (mAbs) and lysozyme to selectively quantify the two proteins with partial least squares regression (PLS) giving root mean square errors of cross validation (RMSECV) of 2.42 g/l and 1.67 g/l, respectively. The corresponding Q2 values are 0.92 and, respectively, 0.99, indicating robust models in the calibration range. Second, a process separating lysozyme and PEGylated lysozyme species was monitored giving an estimate of the PEGylation degree of currently eluting species with RMSECV of 2.35 g/l for lysozyme and 1.24 g/l for PEG with Q2 of 0.96 and 0.94, respectively. Finally, Triton X-100 was added to a feed of lysozyme as a typical process-related impurity. It was shown that the species could be selectively quantified from the FTIR 3D field without PLS calibration. In summary, the proposed PAT tool has the potential to be used as a versatile option for monitoring protein chromatography. It may help to achieve a more complete implementation of the PAT initiative by mitigating limitations of currently used techniques. PMID- 29530405 TI - The use of historical platelet counts from blood donors to program apheresis platelet donation: An Australian perspective. AB - BACKGROUND: For Australian apheresis platelet donations, in-centre haematology analysers provided the platelet count used to program the platelet collection machines. When the haematology analysers were not functional, historical platelet counts from previous donations were used. This study aimed to confirm that the routine use of historical platelet counts for programming apheresis collection machines would maintain platelet yields within the donated units and that haematology analysers could be removed. STUDY DESIGN: A staggered implementation for the routine use of mean historical platelet counts to program apheresis platelet collection machines was conducted. The donors' full blood counts following donation were tested centrally for comparison to the historical mean. The component yields when using on-the-day platelet counts to program platelet collection were compared with those collected using historical platelet counts. For historical platelet counts to be deemed successful, the target was for 90% of the mean historical donor platelet counts to have less than 20% variance from the on-the-day platelet count. RESULTS: Over 96% of the mean historical platelet counts were within 20% variance of the platelet count on the day of donation. The component yield (platelet count x109 cell/unit) before analyser removal was 273.3 +/- 32.0 (n = 2639) and post-removal was 282.8 +/- 38.8 (n = 2689). CONCLUSION: The removal of haematology analysers from donor centres and replacement with mean historical platelet counts was successful in maintaining platelet yields. Replacement of the haematology analysers with historical platelet counts simplified regulatory compliance, reduced staff workload and costs associated with analyser registration. PMID- 29530406 TI - Unified infusion rates for 10% intravenous immunoglobulin. AB - Although manufacturers recommend varying infusion rates for differing intravenous immunoglobulin products (IVIg), there may be improved efficiency and reduced potential for error with the application of a single infusion policy for all IVIg products. During the transition from a 6% to a 10% IVIg, we prospectively evaluated patient reported adverse reactions to IVIg with the 10% product (Intragam 10) given at a rate faster than recommended by the manufacturer. While there was a significant increase in the rate of immediate infusion reactions when compared with the previous IVIg preparation (Intragam P), there was no increase in the rate of reactions post infusion. The rate of reactions was within previously reported expectations for other IVIg products. All reactions were minor, requiring no or minimal intervention and few impacted significantly on the quality of life. Despite an active haemovigilance program, minor adverse reactions were generally not reported. Our results suggest that a fast single rate of IVIg infusion is safe, and may minimise patient attendance and hospital resources with acceptable safety. In implementing a strategy to increase IVIg infusion rates an active process to monitor safety is preferred over standard haemovigiliance or pharmacovigilance processes. PMID- 29530407 TI - Has the robot caught up? National trends in utilization, perioperative outcomes, and cost for open, laparoscopic, and robotic pediatric pyeloplasty in the United States from 2003 to 2015. AB - INTRODUCTION: Since 2010, there have been few new data comparing perioperative outcomes and cost between open (OP) and robotic pyeloplasty (RP). In a post adoption era, the value of RP may be converging with that of OP. OBJECTIVE: To 1) characterize national trends in pyeloplasty utilization through 2015, 2) compare adjusted outcomes and median costs between OP and RP, and 3) determine the primary cost drivers for each procedure. STUDY DESIGN: We performed a retrospective cohort study using the Premier database, which provides a nationally representative sample of U.S. hospitalizations between 2003 and 2015. ICD9 codes and itemized billing were used to abstract our cohorts. Trends in utilization and cost were calculated and then stratified by age. We used propensity scores to weight our cohorts and then applied regression models to measure differences in the probability of prolonged operative time (pOT), prolonged length of stay (pLOS), complications, and cost. RESULTS: During the study period 11,899 pyeloplasties were performed: 75% open, 10% laparoscopic, and 15% robotic. The total number of pyeloplasty cases decreased by 7% annually; OP decreased by a rate of 10% while RP grew by 29% annually. In 2015, RP accounted for 40% of cases. The largest growth in RPs was among children and adolescents. The average annual rate of change in cost for RP and OP was near stagnant: -0.5% for open and -0.2% for robotic. The summary table provides results from our regression analyses. RP conferred an increased likelihood of pOT, but a reduced likelihood of pLOS. The odds of complications were equivalent. RP was associated with a significantly higher median cost, but the absolute difference per case was $1060. DISCUSSION: Despite advantages in room and board costs for RP, we found that the cost of equipment and OR time continue to make it more expensive. Although the absolute difference may be nominal, we likely underestimate the true cost because we did not capture amortization, hidden or down-stream costs. In addition, we did not measure patient satisfaction and pain control, which may provide the non-monetary data needed for comparative value. CONCLUSION: Despite an overall decline in pyeloplasties, RP utilization continues to increase. There has been little change in cost over time, and RP remains more expensive because of equipment and OR costs. The robotic approach confers a reduced likelihood of pLOS, but an increased likelihood of pOT. Complication rates are low and similar in each cohort. PMID- 29530408 TI - Role of neuropeptide Y (NPY) in the differentiation of Trpm-5-positive olfactory microvillar cells. AB - The mouse olfactory neuroepithelium (ON) is comprised of anatomically distinct populations of cells in separate regions; apical (sustentacular and microvillar), neuronal (olfactory sensory neurons) and basal (horizontal and globose basal cells). The existence of microvillar cells (MVCs) is well documented but their nature and function remains unclear. An important transcription factor for the differentiation of MVCs is Skn-1a, with loss of function of Skn-1a in mice resulting in a complete loss of Trpm-5 expressing MVCs, while olfactory sensory neuron differentiation is normal. Our previous research has shown that neuropeptide Y (NPY) is expressed in MVCs and is important in the neuroproliferation of olfactory precursors. This study showed that following X ray irradiation of the snout of wildtype mice, which decreases the proliferation of basal precursor cells, the numbers of Trpm-5-positive MVCs is increased at 2 and 5 weeks post-irradiation compared to controls. Skn-1a expression in the ON following X-ray irradiation also increases at 2 weeks post-irradiation in a regionally specific manner matching the expression pattern of Trpm-5-positive MVCs. In parallel, NPYCre knock-in mice were used to examine the expression of Skn-1a following activation of NPY unilaterally in the ON (unilateral nasal irrigation of AAV-NPY-FLEX). These experiments demonstrated that Skn-1a is only expressed when NPY is activated in MVCs. Therefore the expression of NPY is necessary for the transcription factor-mediated differentiation of olfactory MVCs. PMID- 29530409 TI - [Misuse and dependence on prescription opioids: Prevention, identification and treatment. Rolland B. et al. Rev Med Interne 2017;38:539-546]. PMID- 29530410 TI - High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells. AB - Alarmins are preformed, endogenous molecules that can be promptly released to signal cell or tissue stress or damage. The ubiquitous nuclear molecule high mobility group box 1 protein (HMGB1) is a prototypical alarmin activating innate immunity. HMGB1 serves a dual alarmin function. The protein can be emitted to alert adjacent cells about endangered homeostasis of the HMGB1-releasing cell. In addition to this expected path of an alarmin, extracellular HMGB1 can be internalized via RAGE-receptor mediated endocytosis to the endolysosomal compartment while attached to other extracellular proinflammatory molecules. The endocytosed HMGB1 may subsequently destabilize lysosomal membranes. The HMGB1 bound partner molecules depend on the HMGB1-mediated transport and the induced lysosomal leakage to obtain access to endosomal and cytosolic reciprocal sensors to communicate extracellular threat and to initiate the proper activation pathways. PMID- 29530411 TI - Masticatory performance of the elderly as seen from differences in occlusal support of residual teeth. AB - PURPOSE: To clarify whether the occlusal state affects the masticatory performance of elderly adults. METHODS: Elderly women were asked to chew a gummy jelly, and the amount of glucose extraction was measured as the parameter for masticatory performance. Subjects were divided into five groups depending on occlusal support on the habitual chewing side (G1: no occlusal support of posterior teeth, G2: occlusal support of first premolar, G3: occlusal support of premolars, G4: occlusal support from first premolar to first molar, and G5: occlusal support from first premolar to second molar). It was also investigated whether or not the subjects were wearing dentures. The amount of glucose extraction was compared among the five groups and then between subjects with removable denture and subjects without removable denture. The relationship between age and glucose extraction were also investigated. RESULTS: The amount of glucose extraction progressively increased with increase in number of occlusal support. There were no fixed tendencies between age and glucose extraction, when occlusal state was taken into account. The amount of glucose extraction of subjects without removable denture was significantly larger than that of subjects with removable denture. It was also found that 67 % of subjects with removable denture were within the normal range when it was set based on G5 data. CONCLUSIONS: It was suggested that the occlusal state affected the masticatory performance of elderly adults. PMID- 29530412 TI - Who benefits from psychosocial support interventions in humanitarian settings? PMID- 29530413 TI - Effectiveness of an education-based control option for human cysticercosis. PMID- 29530414 TI - Sexual violence against children and adolescents in South Africa: making the invisible visible. PMID- 29530415 TI - Diabetes Academy Africa: training the next generation of researchers in sub Saharan Africa. PMID- 29530416 TI - Female community health volunteers to reduce blood pressure: feasible and sustainable? PMID- 29530417 TI - Female community health volunteers to reduce blood pressure: feasible and sustainable? - Authors' reply. PMID- 29530418 TI - Reducing antibiotic overuse in rural China. PMID- 29530419 TI - Reducing antibiotic overuse in rural China. PMID- 29530420 TI - MicroResearch: an effective approach to local research capacity development. PMID- 29530421 TI - Correction to Lancet Glob Health 2018; 6: e242-43. PMID- 29530422 TI - Focused psychosocial interventions for children in low-resource humanitarian settings: a systematic review and individual participant data meta-analysis. AB - BACKGROUND: Results from studies evaluating the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in humanitarian settings in low-income and middle-income countries have been inconsistent, showing varying results by setting and subgroup (eg, age or gender). We aimed to assess the effectiveness of these interventions, and to explore which children are likely to benefit most. METHODS: We did a systematic review and meta-analysis of individual participant data (IPD) from 3143 children recruited to 11 randomised controlled trials of focused psychosocial support interventions versus waiting list. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, PsycArticles, Web of Science, and the main local low-income and middle-income countries (LMICs) databases according to the list of databases relevant to LMIC developed collaboratively by Cochrane and WHO Library, up to November, 2016. We included randomised controlled trials that assessed the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in LMICs, compared with waiting lists (eg, inactive controls). We excluded quasi-randomised trials, studies that did not focus on psychosocial support interventions, and studies that compared two active interventions without control conditions. We requested anonymised data from each trial for each of the prespecified variables for each child who was randomly assigned. The main outcomes considered were continuous scores in post-traumatic stress disorder (PTSD) symptoms, depressive symptoms, and anxiety symptoms assessed with rating scales administered immediately (0-4 weeks) after the intervention. We harmonised all individual items from rating scales using item response theory methods. This study is registered with PROSPERO, number CRD42013006960. FINDINGS: We identified a beneficial effect of focused psychosocial support interventions on PTSD symptoms (standardised mean difference [SMD] -0.33, 95% CI -0.52 to -0.14) that was maintained at follow-up (-0.21, 0.42 to -0.01). We also identified benefits at the endpoint for functional impairment (-0.29, -0.43 to -0.15) and for strengths: coping (-0.22, -0.43 to 0.02), hope (-0.29, -0.48 to -0.09), and social support (-0.27, -0.52 to -0.02). In IPD meta-analyses focused on age, gender, displacement status, region, and household size we found a stronger improvement in PTSD symptoms in children aged 15-18 years (-0.43, -0.63 to -0.23), in non-displaced children (-0.40, -0.52 to 0.27), and in children living in smaller households (<6 members; -0.27, -0.42 to 0.11). INTERPRETATION: Overall, focused psychosocial interventions are effective in reducing PTSD and functional impairment, and in increasing hope, coping, and social support. Future studies should focus on strengthening interventions for younger children, displaced children, and children living in larger households. FUNDING: European Commission FP7th Framework Programme for Research (Marie Curie International Outgoing Fellowship) and the National Institute on Aging. PMID- 29530424 TI - Sexual violence against children in South Africa: a nationally representative cross-sectional study of prevalence and correlates. AB - BACKGROUND: We aimed to complete a nationally representative study of sexual violence against children in South Africa, and its correlates, since we could identify no other such study. METHODS: For this nationally representative, cross sectional study in South Africa, households were selected by use of a multistage sampling frame, stratified by province, urban or rural setting, and race group, and schools were selected on the basis that they were closest to the area in which households were selected. Interviews and self-administered questionnaires in each location inquired into lifetime and last-year prevalence of sexual abuse, and its correlates among children aged 15-17 years, whose parents gave informed consent and they themselves gave informed assent. FINDINGS: The final household sample was 5631 (94.6% participation rate). 9.99% (95% CI 8.65-11.47) of boys and 14.61% (95% CI 12.83-16.56) of girls reported some lifetime sexual victimisation. Physical abuse, emotional abuse, neglect, family violence, and other victimisations were all strongly associated with sexual victimisation. The following were associated with greater risk of sexual abuse (adjusted odds ratio [OR]); school enrolment (OR 2.12, 95% CI 1.29-3.48); rural dwelling (0.59; 0.43 0.80); having a flush toilet (1.43, 1.04-1.96); parental substance misuse (2.37, 1.67-3.36); being disabled (1.42, 1.10-1.82); female (but not male) caregivers' poor knowledge of the child's whereabouts, friends, and activities (1.07, 0.75 1.53) and poor quality of the relationship with the child (ie, poor acceptance; 1.20, 0.55-2.60). The child's own substance misuse (4.72, 3.73-5.98) and high risk sexual behaviour (3.71, 2.99-4.61) were the behaviours most frequently associated with sexual abuse, with mental health conditions found to be less prevalent than these factors but still strongly associated with sexual victimisation (post-traumatic stress disorder 2.81, 1.65-4.78; depression 3.43, 2.26-5.19; anxiety 2.48, 1.61-3.81). INTERPRETATION: Sexual violence is widespread among both girls and boys, and is associated with serious health problems. Associated factors require multisectoral responses to prevent sexual violence or mitigate consequences. FUNDING: UBS Optimus Foundation. PMID- 29530423 TI - Effectiveness of a community-based educational programme in reducing the cumulative incidence and prevalence of human Taenia solium cysticercosis in Burkina Faso in 2011-14 (EFECAB): a cluster-randomised controlled trial. AB - BACKGROUND: The effectiveness of drug-free interventions in controlling human cysticercosis is not well known. We aimed to estimate the effectiveness of a community-based educational intervention in reducing the frequency of human cysticercosis in Burkina Faso. METHODS: We did a cluster-randomised controlled trial between 2011 and 2014. 60 eligible villages from three provinces (Boulkiemde, Sanguie, and Nayala) were randomly allocated to the intervention or control group. Villages raising pigs, that were not a regional capital or located on a main road, that were more than 20 km from Ouagadougou or 5 km from one another, were eligible. In each village, 60 participants were asked for blood samples at baseline, 18 months later (before randomisation), and 18 months after randomisation. Villages were block randomised (1:1) by pig-raising department immediately after the pre-randomisation visit. The intervention aimed to improve knowledge of Taenia solium transmission and control through screening and structured discussion of a 52-min movie, and to increase community self-efficacy through a Self-esteem, Associative strengths, Resourcefulness, Action planning, Responsibility (SARAR) approach via the Participatory Hygiene and Sanitation Transformation (PHAST) model. The primary outcome was active cysticercosis, defined as the presence of circulating antigens detected by use of B158/B60 ELISA. Effectiveness measured at the village level was estimated by use of three Bayesian hierarchical models. This study is registered with ClinicalTrials.gov, number NCT0309339. FINDINGS: Two villages in the same randomisation block were excluded, resulting in a final sample size of 58 villages. Overall, the intervention tended towards a decrease in the cumulative incidence of active cysticercosis from baseline to after randomisation (adjusted cumulative incidence ratio 0.65, 95% Bayesian credible interval [95% CrI] 0.39-1.05) and a decrease in active cysticercosis prevalence from baseline to after randomisation (adjusted prevalence proportion ratio 0.84; 95% CrI 0.59-1.18). The intervention was shown to be effective in Nayala and Sanguie but not in Boulkiemde. INTERPRETATION: Community-engaged participatory interventions can be effective at reducing the incidence and prevalence of cysticercosis in some low-resource settings. FUNDING: US National Institutes of Health (National Institute of Neurological Disorders and Stroke, Fogarty International Center, and National Institute of General Medical Sciences). PMID- 29530425 TI - Medical treatment of endometriosis-related pain. AB - Available medical treatments for symptomatic endometriosis act by inhibiting ovulation, reducing serum oestradiol levels, and suppressing uterine blood flows. For this, several drugs can be used with a similar magnitude of effect, in terms of pain relief, independently of the mechanism of action. Conversely, safety, tolerability, and cost differ. Medications for endometriosis can be categorized into low-cost drugs including oral contraceptives (OCs) and most progestogens, and high-cost drugs including dienogest and GnRH agonists. As the individual response to different drugs is variable, a stepwise approach is suggested, starting with OCs or low-cost progestogens, and stepping up to high-cost drugs only in case of inefficacy or intolerance. OCs may be used in women with dysmenorrhea as their main complaint, and when only superficial peritoneal implants or ovarian endometriomas <5 cm are present, while progestogens should be preferred in women with severe deep dyspareunia and when infiltrating lesions are identified. PMID- 29530426 TI - The significance and evolution of menstruation. AB - Historically, the evolutionary origins of menstruation have been based on two theories: the ability to eliminate infectious agents carried to the uterus with spermatozoa and the comparative conservation of energy with menstruation compared to its absence. In the menstruating species, more recent theories have identified spontaneous decidualization as the key adaptive mechanism. Spontaneous decidualization is seen as a mechanism to provide the mother with protection from the invasive characteristics of the embryo. Physiologically, menstruation involves complex interactions of inflammation and vascular mechanisms to stabilize the endometrium and allow a regulated loss of endometrial tissues and blood. A variety of human illnesses can be better understood as vulnerabilities associated with these evolutionary developments, including recurrent pregnancy loss, placenta accreta, ectopic pregnancy, endometriosis, adenomyosis, dysmenorrhea, and chronic pelvic pain. While the evolutionary aspects of these diseases indicate why such illnesses can occur, in some instances, they also provide a basis for treatment, prevention and future research direction. PMID- 29530427 TI - The association between otogenic lateral sinus thrombosis and thrombophilia - A long-term follow-up. AB - PURPOSE: Otogenic lateral sinus thrombosis (OLST) is an intracranial, potentially life-threatening complication of acute and chronic otitis media. Since congenital thrombophilic disorders are risk factors for cerebral venous thrombosis, OLST may be related to thrombophilia. The aim of our study was twofold: to evaluate whether patients who suffered from OLST in childhood also have thrombophilia, and whether these patients experienced thromboembolic episodes in future years. STUDY DESIGN: Retrospective case series. METHODS: The medical charts of all children hospitalized for OLST at Soroka University Medical Center of Israel, a tertiary referral hospital, from January 1983 to September 2014 were reviewed. The patients were invited for a follow-up visit and comprehensive medical history was taken along with a physical examination and laboratory work-up for thrombophilia. MAIN FINDINGS: Seven patients were included in the study. Of these, 3 (43%) had results suggesting thrombophilic disorders manifested by elevated levels of factor IX and decreased levels of protein S activity (n = 1), decreased levels of proteins C and S activity (n = 1), and elevated levels of antibodies to cardiolipin (n = 1). No patients experienced clear thrombophilic events; however, 2 patients (29%) with later proven thrombophilia suffered neurologic sequelae, possibly suggesting thrombophilic events. CONCLUSIONS: Pediatric OLST secondary to acute otitis media and mastoiditis may reflect an underlying thrombophilia. Laboratory work-up for thrombophilia should be performed, and anticoagulant treatment may be warranted in managing these patients. PMID- 29530428 TI - Partial parotidectomy under local anesthesia for benign parotid tumors - An experience of 50 cases. AB - PURPOSE: Benign parotid tumors are adequately treated with partial parotidectomy, which is often performed under general anesthesia (GA). We have reported our preliminary results on the feasibility to perform parotidectomy under local anesthesia (LA). We hereby present our accumulated experience of partial parotidectomy under LA to further consolidate its feasibility, efficacy and safety in a larger series. MATERIALS AND METHODS: Case series review was carried out using our own center patients' database. 50 patients with parotid tumors were treated with partial parotidectomy under LA, using a retrograde nerve dissection approach from January 2006 to October 2016. The inclusion criteria encompassed mobile parotid nodules primarily operated after non-suspicious fine-needle aspiration cytology. Their demographics, complications and outcomes were evaluated. RESULTS: No procedure required conversion to GA. There were 48 benign tumors and 2 lymphomas based on the histopathologic examination. The commonest pathologies were pleomorphic adenoma (40%), Warthin's tumor (38%) and cyst (8%). The mean tumor size was 2.68 +/- 1.5 cm and the mean operative time was 91.5 +/- 34.7 min. Forty-two operations were done as day cases. Ten (20%) patients suffered from transient ear lobe numbness and two (4%) patients had sialocele. Transient facial palsy occurred in 2(4%) patients while another patient (2%) had persistent House-Brackmann grade II facial palsy. No tumor recurrence was noted during follow-up period. CONCLUSIONS: Partial parotidectomy adopting a retrograde nerve dissection under LA is feasible and minimally invasive in treating benign parotid tumors. It can avoid the adverse effects of general anesthesia and promote day surgery or minimize hospital stay. PMID- 29530429 TI - Audiological profiling in postmenopausal women with osteoporosis. AB - OBJECTIVES: To compare the audiological profiles in postmenopausal women with and without osteoporosis and to study the pattern of hearing loss in osteoporotic patients. MATERIALS AND METHODS: 80 postmenopausal women were evaluated at a tertiary referral center and were divided into normal, osteopenic and osteoporotic based on BMD results. The hearing evaluation was done using PTA, Impedance audiometry and DPOAE and the results were compared between the groups and analyzed. RESULTS: Osteoporotic patients had higher incidence of sensorineural hearing loss than normal and osteopenic patients and the results were statistically significant (P <=0.001) on PTA and DPOAE testing. The mean pure tone thresholds were significantly higher in osteoporotic patients in comparison with normal and osteopenic patients. The average hearing loss in osteoporotic patients with sensorineural loss was of mild degree. CONCLUSION: The data reveal that osteoporosis is associated with sensorineural hearing loss in postmenopausal women. The underlying mechanism needs further research but cochlear dysfunction could be an important factor. PMID- 29530431 TI - Application of new instruments for beginner lymphatic supermicrosurgeon. PMID- 29530430 TI - Detection of GSK-3beta activation index in pediatric chronic tonsillitis is an indicator for chronic recurrent inflammation. AB - PURPOSE: Chronic tonsillitis (TC) is among the most common bacterial diseases in pediatric otolaryngology. We aimed to evaluate the expression of glycogen synthase kinase 3beta (GSK-3beta) in a cohort of children with chronic tonsillitis (TC), and the correlation between GSK-3beta activity index and inflammatory profiles of TC. MATERIALS AND METHODS: The expression of GSK-3beta was comparably evaluated between children with TC (n = 26) and tonsillar hypertrophy (TH, n = 26). GSK-3beta expression was detected by immunohistochemistry, RT-qPCR, and Western blot. The inflammatory profiles between the TC and TH groups were also evaluated. RESULTS: We found that while GSK-3beta was highly expressed in both TC and TH groups, no significant difference were detected at mRNA and protein levels between groups. The protein level of p-GSK-3beta was significantly lower in the TC group as compared to the TH group. Additionally, the inflammatory markers, including NF-kappaB, T-bet, and IFN-gamma were higher in the TC group compared to TH group. The GSK-3beta activation index was positively correlated with the levels of NF-kappaB, T-bet, and IFN-gamma in the TC group. CONCLUSIONS: Our findings suggested that GSK-3beta activation index was demonstrated to be a clinically applicable indicator for chronic recurrent inflammation in pediatric TC. PMID- 29530432 TI - High lymphocyte count during neoadjuvant chemoradiotherapy is associated with improved pathologic complete response in esophageal cancer. AB - BACKGROUND AND PURPOSE: Neoadjuvant chemoradiation (nCRT) can reduce tumor infiltrating lymphocytes. We examined absolute lymphocyte count (ALC) nadir during nCRT for esophageal cancer (EC) and pathologic complete response (pCR). MATERIALS AND METHODS: Patients with stage I-IVA EC (n = 313) treated 2007-2013 with nCRT followed by surgery were analyzed. ALC was obtained before, during/weekly, and one month after CRT. pCR was defined as no viable tumor cells at surgery. High ALC was defined as nadir of >=0.35 * 103/MUL (highest tertile). Comparison of continuous and categorical variables by pCR was assessed by ANOVA and Pearson's chi-square. Univariate/multivariate logistic regression was used to assess predictors of pCR and high ALC nadir. RESULTS: Eighty-nine patients (27.8%) achieved a complete pathological response (pCR). For patients with pCR, median ALC nadir was significantly higher than those without (0.35 * 103/MUL vs 0.29 * 103/MUL, p = 0.007). Patients maintaining high ALC nadir had a higher pCR rate (OR1.82, 95%CI 1.08-3.05, p = 0.024). Predictors of high ALC included treatment with proton therapy vs. IMRT (OR4.18, 95%CI 2.34-7.47, p < 0.001), smoking at diagnosis (OR2.80, 95%CI 1.49-5.25, p = 0.001), early stage I-II disease (OR2.33, 95%CI 1.32-4.17, p = 0.005), and SCC histology (OR3.70, 95%CI 1.01-14.29, p = 0.048). Mean body dose (MBD) was inversely related to high ALC nadir (OR0.77 per Gy, 95%CI 0.70-0.84, p < 0.001). CONCLUSION: A higher ALC level during nCRT is associated with a higher rate of pCR for esophageal cancer patients undergoing trimodality therapy. PMID- 29530434 TI - Meta-Analysis: Contrast-Enhanced Ultrasound Versus Conventional Ultrasound for Differentiation of Benign and Malignant Breast Lesions. AB - This meta-analysis aimed to compare the diagnostic performance of contrast enhanced ultrasound (CEUS), conventional ultrasound (US) combined with CEUS (US + CEUS) and US for distinguishing breast lesions. From thorough literature research, studies that compared the diagnostic performance of CEUS versus US or US + CEUS versus US, using pathology results as the gold standard, were included. A total of 10 studies were included, of which 9 compared the diagnostic performance of CEUS and US, and 5 studies compared US + CEUS and US. In those comparing CEUS versus US, the pooled sensitivity was 0.93 (95% CI: 0.91-0.95) versus 0.87 (95% CI: 0.85-0.90) and pooled specificity was 0.86 (95% CI: 0.84 0.88) versus 0.72 (95% CI: 0.69-0.75). In studies comparing US + CEUS versus US, the pooled sensitivity was 0.94 (95% CI: 0.92-0.96) versus 0.87 (95% CI: 0.84 0.90) and pooled specificity was 0.86 (95% CI: 0.82-0.89) versus 0.80 (95% CI: 0.76-0.84). In terms of diagnosing breast malignancy, areas under the curve of the summary receiver operating characteristic (of both CEUS (p = 0.003) and US + CEUS (p = 0.000) were statistically higher than that of US. Both CEUS alone and US + CEUS had better diagnostic performance than US in differentiation of breast lesions, and US + CEUS also had low negative likelihood ratio. PMID- 29530433 TI - Inter-institutional analysis demonstrates the importance of lower than previously anticipated dose regions to prevent late rectal bleeding following prostate radiotherapy. AB - PURPOSE: To investigate whether inter-institutional cohort analysis uncovers more reliable dose-response relationships exemplified for late rectal bleeding (LRB) following prostate radiotherapy. MATERIAL AND METHODS: Data from five institutions were used. Rectal dose-volume histograms (DVHs) for 989 patients treated with 3DCRT or IMRT to 70-86.4 Gy@1.8-2.0 Gy/fraction were obtained, and corrected for fractionation effects (alpha/beta = 3 Gy). Cohorts with best-fit Lyman-Kutcher-Burman volume-effect parameter a were pooled after calibration adjustments of the available LRB definitions. In the pooled cohort, dose-response modeling (incorporating rectal dose and geometry, and patient characteristics) was conducted on a training cohort (70%) followed by final testing on the remaining 30%. Multivariate logistic regression was performed to build models with bootstrap stability. RESULTS: Two cohorts with low bleeding rates (2%) were judged to be inconsistent with the remaining data, and were excluded. In the remaining pooled cohorts (n = 690; LRB rate = 12%), an optimal model was generated for 3DCRT using the minimum rectal dose and the absolute rectal volume receiving less than 55 Gy (AUC = 0.67; p = 0.0002; Hosmer-Lemeshow p-value, pHL = 0.59). The model performed nearly as well in the hold-out testing data (AUC = 0.71; p < 0.0001; pHL = 0.63), indicating a logistically shaped dose-response. CONCLUSION: We have demonstrated the importance of integrating datasets from multiple institutions, thereby reducing the impact of intra-institutional dose volume parameters explicitly correlated with prescription dose levels. This uncovered an unexpected emphasis on sparing of the low to intermediate rectal dose range in the etiology of late rectal bleeding following prostate radiotherapy. PMID- 29530435 TI - Transient contrast-induced encephalopathy after internal carotid artery embolisation prior to surgery for nasopharyngeal carcinoma. PMID- 29530436 TI - Observational multicentre study into the use of antiepileptic drugs in Spanish neurology consultations. AB - INTRODUCTION: The study aims to quantify the types of antiepileptic drugs (AED) prescribed in neurology consultations. MATERIAL AND METHOD: This descriptive, observational study included a sample of 559 patients older than 14 years, diagnosed with epilepsy, and receiving pharmacological treatment. Data were collected at outpatient consultations by 47 Spanish neurologists in May 2016. Epilepsy was defined based on the International League Against Epilepsy classification. According to the year of marketing, AEDs were categorised as classic (before 1990) or new (after 1990). We performed a descriptive analysis of qualitative and quantitative variables. RESULTS: Female patients accounted for 54.6% of the sample. Mean age was 42.7 years; mean age of onset was 22.4. Regarding epilepsy type, 75.7% of patients experienced partial seizures, 51.5% were symptomatic,32.4% had refractory epilepsy, 35.6% had been seizure-free for the previous year, and 59.2% had associated comorbidities.A total of 1103 AED prescriptions were made; 64.6% of prescriptions were for new AEDs; 85.4% of patients received new AEDs. Patients received a mean of 2 AEDs (range, 1-5). A total of 59.6% of patients received polytherapy.The most frequently prescribed AEDs were levetiracetam (42.6%), valproic acid (25.4%), lamotrigine (19.5%), carbamazepine (17.9%), and lacosamide (17.5%). No AED was employed exclusively as monotherapy. The most frequently prescribed AEDs for generalised and partial seizures were valproic acid (48.2%) and levetiracetam (43.2%), respectively. Valproic acid was less frequently prescribed to female patients. Patients with refractory epilepsy or with associated comorbidities were more frequently prescribed a combination of new and classic AEDs (48.7% and 45.6%, respectively) than only one type of AED. CONCLUSIONS: The majority of patients received new AEDs. The combination of classic and new AEDs was more frequently prescribed to patients with refractory epilepsy or with associated comorbidities. PMID- 29530437 TI - Double cortex syndrome in a male patient without lissencephaly. PMID- 29530438 TI - The Road Map for National Health Service Proton Beam Therapy. AB - Proton Beam Therapy is one of the key elements in a major improvement in access to advanced radiotherapy in the UK. An overseas programme has treated significant numbers of children and young adults and skull base tumours since 2008. A major government investment has resulted in building two proton centres in England sited in academic major cancer centres. A weak evidence base for most adult indications means that the NHS will use clinical trials and studies to explore the future role of Protons. PMID- 29530439 TI - [Data sources, the data used, and the modality for collection]. AB - The hospital costing process implies access to various sources of data. Whether a micro-costing or a gross-costing approach is used, the choice of the methodology is based on a compromise between the cost of data collection, data accuracy, and data transferability. This work describes the data sources available in France and the access modalities that are used, as well as the main advantages and shortcomings of: (1) the local unit costs, (2) the hospital analytical accounting, (3) the Angers database, (4) the National Health Cost Studies, (5) the INTER CHR/U databases, (6) the Program for Medicalizing Information Systems, and (7) the public health insurance databases. PMID- 29530440 TI - [Integrating the touch-screen into oral health prevention programs for people with cognitive disabilities: An exploratory study in children]. AB - BACKGROUND: The oral diseases of people with disabilities are the same as those observed in the general population but occur earlier and more intensely. Primary prevention, especially toothbrushing, is at the forefront of the appropriate management of these patients. The aim of this study is to evaluate the use of a digital application on iPad(r) as mediator for learning toothbrushing in children with disabilities. METHODS: Twelve children from a care-center were included in this preliminary study. A training program for toothbrushing was conducted, using a visual activity schedule on iPad(r). Quotation grids enabled to assess the initial situation and the program efficacy over an 11-month period. RESULTS: The children progressed over time in their autonomy and in their compliance during toothbrushing. Wilcoxon's analysis showed that these progresses were significant, although some steps remained more difficult to achieve. Three months after the end of the program, the children maintained their skills. CONCLUSIONS: The integration of the iPad(r) as a support for visual pedagogy and learning is useful in a dental context, for children with cognitive disabilities. PMID- 29530441 TI - [An assessment of the direct costs of healthcare for victims of sexual assaults in hospital emergency units]. AB - BACKGROUND: The Forensic medicine reform in 2011 enabled the development of forensic units specialized in multidisciplinary care of victims of criminal offences. Thanks to an annual budgetary allocation, the Ministry of Justice handles the financing of judicial acts, while the health care facilities assume the medical, psychological and social aspects. The objective of this study was to determine the direct costs of medical care provided to rape victims (such as defined in the article 222-23 of the Penal Code) in order to see how its funding could be reconsidered to prevent any additional cost that could be caused by non sufficient medical, psychological and social care. Furthermore, this first assessment may serve as a basis for further reflection on creating other medical judicial units but also for reviewing existing structures. METHODS: The direct costs for medical care of a recent rape victim (<48hours) was quantified by including staff and consumables costs, treatments, biological tests and other expenses. RESULTS: The overall time for the entire medical care procedure was approximately three hours, for an overall cost of 673.92?, of which 41.5 % (279.90?) was paid by the Ministry of Justice. The medical, psychological and social aspects stood for the major expenditure items (394.02?), attributable mainly to the biological screening tests for sexually transmissible infections (STIs). CONCLUSION: These frequent situations require the convergence of human and material needs with a financial burden shared between the Ministry of Justice and health establishments. Authors suggest that in the annual hospital budgetary allocation allotted by the Ministry of Justice, the care of victims of sexual assault be based on the rate of day hospitalization "Medicine, medical specialties part time day or night common regime", allowing to provide optimal multidisciplinary care, which lessens the risks of complications and reduces the global cost created by these situations. PMID- 29530442 TI - [Methods for the analysis and treatment of cost data by micro- and gross-costing approaches]. AB - This work addresses the analysis of individual cost data in the setting of interventional or observational studies using statistical analysis software once the costs per patient have been estimated. It is in fact necessary to be able to present and describe data in an appropriate manner in each of the studied health strategies and to test whether the difference in costs observed between treatment groups is due to chance or not. Furthermore, cost analysis differs from conventional statistical analysis in that cost data have a certain number of specific properties, including their use by health decision-makers. This work also addresses the difficulties that generally arise in regard to the distribution of cost; it explains why the mathematical average constitutes the only relevant measure for economists; and it outlines which analyses are required for inter-strategy cost comparisons. It also covers the issue of missing or censored data, features that are inherent to information collected regarding costs and to sensitivity analyses. PMID- 29530443 TI - Post-depositional behaviour of mercury and arsenic in submarine mine tailings deposited in Buyat Bay, North Sulawesi, Indonesia. AB - The post-depositional geochemical behaviour of mercury and arsenic in submarine mine tailings from the Mesel Gold Mine in Buyat Bay, North Sulawesi, Indonesia was assessed by in situ sampling of tailings porewaters using dialysis arrays and seawater and fish monitoring. Under steady-state conditions one year after cessation of tailings discharge, the calculated arsenic efflux incrementally added 0.8 MUg/L of arsenic to the overlying seawater. The mercury efflux across the tailings-seawater interface was negligible. The arsenic and mercury concentration in seawater bottom samples monitored biannually during a 9-year post-closure program were 1.54 MUg/L and <0.05 MUg/L, respectively. Analysis of 650 fish tissue samples, from the post-closure monitoring had mean mercury and arsenic concentrations consistently below the FAO/WHO CODEX, and Australian and New Zealand National Food Standards, respectively. The results of the porewater, seawater and fish tissue demonstrate that the arsenic and mercury-bearing bearing compounds in the tailings are geochemically stable. PMID- 29530444 TI - Technology-Enhanced Simulation Improves Trainee Readiness Transitioning to Cardiothoracic Training. AB - OBJECTIVE: Transitioning from medical school and general surgery training to cardiothoracic (CT) surgical training poses unique challenges for trainees and patient care. We hypothesized that participation in technology-enhanced simulation modules that provided early exposure to urgent/emergent CT patient problems would improve cognitive skills and readiness to manage common urgencies/emergencies. DESIGN: Traditional and integrated cardiothoracic residents at our institution participated in a technology-enhanced simulation curriculum. The course comprised of didactics, hands-on simulation, virtual models, and mock oral examinations. Residents also were given a validated pretest and post-test to evaluate knowledge retention and integration. Resident performance was graded using a previously validated objective structured clinical examination. Resident perception of course usefulness and relevance was determined through the completion of a perception survey. SETTING: This study occurred at the University of Pittsburgh School of Medicine with the Department of Cardiothoracic Surgery. The facility used was the Peter Winter Institute for Simulation, Education and Research. PARTICIPANTS: From 2013 to 2015, 25 traditional and integrated cardiothoracic residents participated in these training modules who have completed all portions of the simulation were used for analysis. RESULTS: For our participants, knowledge base significantly increased by 7.9% (pretest = 76.0% vs. post-test = 83.9%, p < 0.01). According to trained rater evaluation, 93.6% of responses to the 11 objective structured clinical examination competencies were deemed adequate. Postcourse perception survey demonstrated 92% of participants scoring the sessions as important or very important toward development and confidence in managing the cardiothoracic scenarios. These findings were present despite historical assumption that these learners were prepared for complex patient care. CONCLUSIONS: After completing a technology-enhanced course combining didactics, simulation, and real-time assessment, residents demonstrated objective improvements in cognitive skills and readiness in managing CT patients. Resident postcourse feedback indicated enhanced confidence, suggesting increased preparedness transitioning to CT surgery. This has strong implications for improved patient safety during these potentially labile transition periods. PMID- 29530445 TI - Coding Discrepancies Between Medical Student and Physician Documentation. AB - OBJECTIVE: Accurate medical documentation is a core competency in medical education and is critical to successful surgical practice. The following study aims to assess the coding accuracy of medical student documentation. DESIGN: Retrospective chart review identified patient encounters in a surgery clinic that contained documentation by both a faculty member and a third-year medical student. Records were de-identified and assigned a level of service (LOS) and diagnostic code by trained, expert coders. Differences in LOS and diagnostic code were then compared between medical student and faculty documentation. SETTING: A single academic health system. PARTICIPANTS: Third-year medical students. RESULTS: 80 full patient evaluations and 20 postoperative visits were analyzed. Median faculty and student LOS was 4 (range 3-4) and 3 (range 0-4) respectively (p < 0.001). Students failed to document a sufficient number of elements in the evaluation, failed to specify studies ordered, and documented low medical decision making. Diagnostic code was concordant between students and faculty for only 31% of documentation. CONCLUSION: Student documentation of clinical encounters is coded at a lower LOS than faculty documentation. These results likely reflect the lack of education regarding E/M coding in medical school, which is integral to real world practice. SUMMARY: Accurate medical documentation is critical to the correct diagnostic coding and billing of a medical encounter. We found that compared to faculty documentation of the same patient evaluations, student documentation was typically coded at a lower level of service and assigned a different diagnostic code by professional medical coders. Addressing these topics in medical school may better prepare students for real-world practice. PMID- 29530446 TI - Plasmodium vivax Infections of Duffy-Negative Erythrocytes: Historically Undetected or a Recent Adaptation? AB - Plasmodium vivax is the main cause of malarial disease in Asia and South America. Plasmodium vivax infection was thought to be absent in African populations who are Duffy blood group antigen negative (Duffy-negative). However, many cases of P. vivax infection have recently been observed in Duffy-negative Africans. This raises the question: were P. vivax infections in Duffy-negative populations previously missed or has P. vivax adapted to infect Duffy-negative populations? This review focuses on recent P. vivax findings in Africa and reports views on the parasite ligands that may play a role in Duffy-negative P. vivax infections. In addition, clues gained from studying P. vivax infection of reticulocytes are presented, which may provide possible avenues for establishing P. vivax culture in vitro. PMID- 29530447 TI - Single pulse TMS to the DLPFC, compared to a matched sham control, induces a direct, causal increase in caudate, cingulate, and thalamic BOLD signal. AB - BACKGROUND: In the 20 years since our group established the feasibility of performing interleaved TMS/fMRI, no studies have reported direct comparisons of active prefrontal stimulation with a matched sham. Thus, for all studies there is concern about what is truly the TMS effect on cortical neurons. OBJECTIVE: After developing a sham control for use within the MRI scanner, we used fMRI to test the hypothesis of greater regional BOLD responses for active versus control stimulation. METHODS: We delivered 4 runs of interleaved TMS/fMRI with a limited field of view (16 slices, centered at AC-PC) to the left DLPFC (2 active, 2 control; counterbalanced) of 20 healthy individuals (F3; 20 pulses/run, interpulse interval:10-15sec, TR:1sec). In the control condition, 3 cm of foam was placed between the TMS coil and the scalp. This ensured magnetic field decay, but preserved the sensory aspects of each pulse (empirically evaluated in a subset of 10 individuals). RESULTS: BOLD increases in the cingulate, thalamus, insulae, and middle frontal gyri (p < 0.05, FWE corrected) were found during both active and control stimulation. However, relative to control, active stimulation caused elevated BOLD signal in the anterior cingulate, caudate and thalamus. No significant difference was found in auditory regions. CONCLUSION(S): This TMS/fMRI study evaluated a control condition that preserved many of the sensory features of TMS while reducing magnetic field entry. These findings support a relationship between single pulses of TMS and activity in anatomically connected regions, but also underscore the importance of using a sham condition in future TMS/fMRI studies. PMID- 29530448 TI - Deja-reve: Prior dreams induced by direct electrical brain stimulation. AB - BACKGROUND: Epileptic patients sometimes report experiential phenomena related to a previous dream they had during seizures or electrical brain stimulation (EBS). This has been alluded to in the literature as "deja-reve" ("already dreamed"). However, there is no neuroscientific evidence to support its existence and this concept is commonly mixed up with deja-vu. We hypothesized that deja-reve would be a specific entity, i.e., different from other experiential phenomena reported in epileptic patients, induced by EBS of specific brain areas. METHODS: We collected all experiential phenomena related to dreams induced by electrical brain stimulations (EBS) in our epileptic patients (2003-2015) and in a review of the literature. The content of these deja-reve and the location of EBS were analyzed. RESULTS: We collected 7 deja-reve in our database and 35 from the literature, which corresponds to an estimated prevalence of 0.30/00 of all EBS inducing deja-reve. Deja-reve is a generic term for three distinct entities: it can be the recollection of a specific dream ("episodic-like"), reminiscence of a vague dream ("familiarity-like") or experiences in which the subject feels like they are dreaming (literally "a dreamy state"). EBS-inducing "episodic-like" and "familiarity-like" deja-reve were mostly located in the medial temporal lobes. "Dreamy states" were induced by less specific EBS areas although still related to the temporal lobes. CONCLUSIONS: This study demonstrates that deja-reve is a heterogeneous entity that is different from deja-vu, the historical "dreamy state" definition and other experiential phenomena. This may be relevant for clinical practice as it points to temporal lobe dysfunction and could be valuable for studying the neural substrates of dreams. PMID- 29530449 TI - Combined effects of rTMS and botulinum toxin therapy in benign essential blepharospasm. PMID- 29530450 TI - Comments on: "Safety of repeated sessions of transcranial direct current stimulation: A systematic review". PMID- 29530452 TI - The Impact of Gadolinium Deposition on Radiology Practice: An International Survey of Radiologists. AB - RATIONALE AND OBJECTIVES: Brain deposition of gadolinium following the administration of gadolinium-based contrast agents (GBCAs) was initially reported in 2014. Gadolinium deposition is now recognized as a dose-dependent consequence of exposure. The potential clinical implications are not yet understood. The purpose of this study was to determine radiologists' reporting practices in response to gadolinium deposition. MATERIALS AND METHODS: An electronic survey querying radiologists' practices regarding gadolinium deposition was distributed by Radiopaedia.org from November-December 2015. RESULTS: Our study sample included 94 total respondents (50% academic; 27% private practice; 23% hybrid) from 30 different countries (USA 18%). Fifty-seven (62%) radiologists had observed brain gadolinium deposition on MRI brain studies howerver more than half of these (30 of 57) reported detecting dentate T1 shortening only rarely (<1/month). Among respondents, 58% (52 of 89) do not or would not include the finding in the radiology report; only 12 (13%) report the finding in the impression of their reports. The most common reason for not reporting gadolinium deposition was the risk of provoking unnecessary patient anxiety (29%, 20 of 70). Recent data on gadolinium deposition has led to a reported practice change in 24 of 87 (28%) of respondents. CONCLUSION: Recognition of, and attitudes toward, brain gadolinium deposition were inconsistent in this worldwide sample. Most surveyed radiologists do not routinely report dentate T1shortening as a marker of gadolinium deposition. Fear of provoking patient/clinician anxiety and an incomplete understanding of the implications of gadolinium deposition contribute to inconsistencies in reporting. PMID- 29530453 TI - Bronchiectasis Revisited: Imaging-Based Pattern Approach to Diagnosis. AB - BACKGROUND: Bronchiectasis is one of the causes of non-resolving, persistent or recurrent pulmonary infection which, if uncorrected may have deleterious consequences on the lung parenchyma and pulmonary circulation. High-resolution computed tomography (HRCT) is needed for the confirmation, localization and directing management accordingly. CONTENTS: Bronchiectasis is one of the major cause of morbidity worldwide. Chest radiograph is done at the initial suspicion which is supplemented by HRCT to confirm the diagnosis. Imaging diagnosis supplemented by the recognition of the pattern of involvement is essential to outline the differential diagnosis, map the complications and, hence, guiding the further management. Identification of the causative aetiology may not only prevent its further progression but obviate recurrent insults to the lung parenchyma as well. This article focuses on an algorithmic approach to bronchiectasis based on the distribution on imaging. PMID- 29530454 TI - Neuropharmacological evaluation on four traditional herbs used as nervine tonic and commonly available as Shankhpushpi in India. AB - OBJECTIVE: The present study was undertaken to evaluate the neuropharmacological effect of four herbs commonly identified as source of Shankhpushpi. BACKGROUND: Shankhpushpi is an Ayurvedic drug, widely used for its actions on the central nervous system, especially to improve intellect and boost memory. Four botanicals viz. Canscora decussata Schult. (CD), Clitorea ternatea Linn. (CT), Convolvulus pluricaulis Choisy. (CP) and Evolvulus alsinoides Linn. (EA) are considered as sources of Shankhpushpi by Indian practitioners on the basis of their morphological descriptions given in ancient texts. MATERIALS AND METHODS: Methanol extracts of all four varieties were tested and evaluated in vitro and in vivo for their neuropharmacological effects. Experiments such as protection against beta-amyloid induced neurotoxicity on brain cell line (Neuro 2A), antioxidant potential, AchE (acetylcholinesterase enzyme) inhibition, and 5-LOX (lipoxygenase) enzyme inhibition were conducted for in vitro evaluation. For in vivo evaluation, scopolamine (0.3 mg/kg i.p.) induced memory retrieval using pole climbing apparatus and Morris water maze were performed in rat models. RESULTS: It was found that protective effects of EA and CD against beta-amyloid induced neurotoxicity in Neuro 2A cells were significantly higher than CT and CP. EA proved to be superior than other varieties on the basis of antioxidant activity, AchE inhibitory and LOX inhibitory activities. The preventive activity of EA on scopolamine induced memory retrieval in pole climbing and Morris water maze task in rats was found to be higher than that of CD, CT and CP. CONCLUSION: EA has remarkable neuropharmacological effect as compared to other three varieties of Shankhpushpi. This effect may be attributed due to the presence of steroids (stigmasterol and betulinic acid), coumarins (scopoletin) and flavonoids (beta carotene and chlorogenic acid). Hence it can be used as a promising lead in development and management of neuronal disorders including Alzheimer's disease. PMID- 29530451 TI - Pitx1 regulates cement gland development in Xenopus laevis through activation of transcriptional targets and inhibition of BMP signaling. AB - The cement gland in Xenopus laevis has long been used as a model to study the interplay of cell signaling and transcription factors during embryogenesis. It has been shown that an intermediate level of Bone Morphogenetic Protein (BMP) signaling is essential for cement gland formation. In addition, several transcription factors have been linked to cement gland development. One of these, the homeodomain-containing protein Pitx1, can generate ectopic cement gland formation; however, the mechanisms underlying this process remain obscure. We report here, for the first time, a requirement for Pitx proteins in cement gland formation, in vivo: knockdown of both pitx1 and the closely related pitx2c inhibit endogenous cement gland formation. Pitx1 transcriptionally activates cement gland differentiation genes through both direct and indirect mechanisms, and functions as a transcriptional activator to inhibit BMP signaling. This inhibition, required for the expression of pitx genes, is partially mediated by Pitx1-dependent follistatin expression. Complete suppression of BMP signaling inhibits induction of cement gland markers by Pitx1; furthermore, we find that Pitx1 physically interacts with Smad1, an intracellular transducer of BMP signaling. We propose a model of cement gland formation in which Pitx1 limits local BMP signaling within the cement gland primordium, and recruits Smad1 to activate direct downstream targets. PMID- 29530455 TI - Reflections on Oncotherapies. PMID- 29530456 TI - An Overview of Immune Checkpoint Inhibitors in Gynecologic Cancers. AB - PURPOSE: The goal of this study was to compile a review of topics pertinent to the use of immune checkpoint inhibitors in gynecologic malignancies, including foundation for use, current agents available and trials in gynecologic cancers, special populations of interest, identification and management of toxicities, and considerations in predictive biomarkers and response assessment. METHODS: A literature review of selected topics in reference to immune checkpoint inhibitors and gynecologic cancers was conducted on PubMed and the US Food and Drug Administration drug search application. A review of current and ongoing clinical trials was performed in clinicaltrials.gov, and selected preliminary results reported in PubMed abstracts and through the American Society of Clinical Oncologists were compiled. FINDINGS: Although immunotherapy in gynecologic malignancy is relatively new, 7 agents are currently approved for use in other oncologic indications, and a multitude of trials in gynecologic cancer are ongoing. Immunotherapy has a specific set of drug toxicities that manifest and are managed unlike traditional cytotoxic therapies. IMPLICATIONS: Application of the knowledge of immune checkpoint inhibitor use in gynecologic cancers will improve care for women with cancers of the female reproductive tract. As more complex and newer immunotherapies evolve, it will be vital to accurately characterize each specific drug class and management thereof. PMID- 29530457 TI - Patient Characteristics and Costs in Recurrent or Refractory Head and Neck Cancer: Retrospective Analysis of a Community Oncology Database. AB - PURPOSE: The goal of this study was to describe patient characteristics, health resource utilization (HRU), and costs associated with treating recurrent or refractory head and neck cancer (HNC) among patients with disease progression in the community oncology setting. METHODS: This retrospective observational study was conducted by using data from the Vector Oncology Data Warehouse. Patients had been diagnosed with locally advanced or metastatic (stage III-IVc) HNC between January 1, 2007, and October 1, 2015. Patients also had evidence of at least 1 systemic anticancer therapy regimen following the diagnosis of advanced HNC, with at least 1 disease progression. Costs, treatment patterns, and HRU were evaluated beginning with diagnosis of advanced HNC through 3 lines of therapy. Costs of surgery or radiation were not available for inclusion in the analysis. Total cost for the study period and cost per month were analyzed by using a generalized linear regression model. FINDINGS: The study included 462 patients (median age, 61 years; range, 26-99 years); of these, 81% were male, 77% were white, and 21% were black. At initial diagnosis, the most frequent tumor locations were the hypopharynx/larynx (31%) and the oropharynx (31%). Human papilloma virus testing was most frequent among the oropharynx group (22% tested, 52% positive). Overall, 42% were current tobacco users and 22% were current or past alcohol abusers/excessive users. Platinum-based combination therapies were the most frequently administered chemotherapy in both first (42%) and second (40%) lines of treatment. Through the overall study period (mean, 20.5 months), 74% of patients were hospitalized, 19% had an emergency department visit, and 100% had an office visit. The overall mean (SD) duration of hospital stay was 12.6 days, and the median number of office visits per patient was 35. The mean monthly health care cost for the overall study period was $14,391 (95% CI, 12,739 16,044). Hospitalization costs represented ~57% of the total expenditures. Statistically significant predictors of higher overall cost included primary tumor location in the oral cavity, history of alcohol abuse/excess use, use of cetuximab, and higher comorbidity index. Older age and being stage IV versus other stages of disease at diagnosis were associated with lower overall cost. IMPLICATIONS: These data suggest that costs of care in patients with recurrent or refractory HNC are related to patient characteristics and treatment patterns. Identification of factors contributing to the costs of care in HNC may provide a useful foundation for developing strategies to control rising costs. PMID- 29530458 TI - [From pediatric care to adult medicine: Transition of sickle cell patients, a French monocentric study]. AB - Sickle cell disease, a hemoglobin disorder with autosomal recessive transmission, is one of the most common genetic diseases screened in France. Thanks to early management, 95% of sickle cell patients reach adulthood and require transition from pediatric care to adult care. Through a retrospective study of records from serious sickle cell patients over 17 years old, followed in the hematology oncology pediatric unit of Reims University Hospital Center in France, we analyzed transition conditions, compared pediatric and adult management, and proposed a plan for transition care. As of 1 January 2016, out of 19 sickle cell patients meeting the inclusion criteria, 12 had made the transition from pediatric care to adult medicine. Among the transition group, the transition was proposed by the pediatrician in 92% of cases. The average age of transition was 19.4 years. The time between receiving the information and the last pediatric visit was 2.4 months. Seven out of the 12 patients were informed of their transition during the last pediatric visit. The age of the first adult visit was 20.3 years. There was no alternate or joint consultation. The treatments prescribed during the last pediatric visit were not modified during the first adult visit. The average number of hospitalizations per patient was 2.7 in pediatric care and 3.4 in adult care with a median value of 2 in both groups. Three out of 12 patients died, the average age of death being 26.7 years. Transition is an important milestone in chronic disease patients. More than age, the maturity of the patient must be taken into account. The transition to the adult structure requires early preparation in the teenage years and investment of the adolescent and his family as well as investment of pediatric and adult caregivers. This study points out the need to establish a transition plan within our hospital in collaboration with adult physicians. Continuity of care is necessary to increase the quality of managing patients and cannot be done without a close relationship between pediatric specialists and adult physicians. PMID- 29530459 TI - High-Resolution Magnetic Resonance Imaging Confirmed Atherosclerosis of an Intracranial Penetrating Artery: A Case Report. AB - Intracranial branch atheromatous disease is an atheromatous pathophysiological process associated with occlusion or stenosis at the orifice of a deep penetrating artery. However, apart from autopsy, atherosclerosis in the penetrating artery has not been confirmed in vivo. In this case, we confirmed that the ostium was located in the parent artery plaque and demonstrated the atherosclerosis of the proximal penetrating artery by using high-resolution magnetic resonance imaging. HR-MRI can be used to identify the pathological changes in penetrating arteries and provides more reliable basic information for the clinical subclassification and optimal medical treatment of penetrating artery infarction. PMID- 29530460 TI - Nationwide Healthcare Expenditures among Hypertensive Individuals with Stroke: 2003-2014. AB - BACKGROUND: Of all the various clinical entities, hypertension is arguably most strongly linked to the occurrence of stroke. However, the impact of stroke on health-care expenditures in patients with hypertension has not been previously evaluated. METHODS: We analyzed data from the Medical Expenditure Panel Survey Household Component, 2003-2014 data. Adults aged 18 years or greater were included in this analysis. We used a 2-part model (adjusting for demographic, comorbidity, and time) to estimate the incremental health-care expenditures incurred by stroke among individuals with hypertension. RESULTS: On average, $4057 more dollars (adjusted incremental health-care expenditure) was spent on individuals with hypertension plus stroke versus no history of stroke. Overall unadjusted mean medical expenditure in those with a comorbid diagnosis of stroke was twice as high as in those without a diagnosis of stroke ($16,668 versus 8374; P < .001). Inpatient expenditures (37.4%), outpatient expenditures, and prescription expenditures (nearly 23% each) accounted for almost 80% of the total mean unadjusted direct expenditures. Annual average unadjusted aggregate costs among individuals with hypertension and stroke were $98.3 billion, while annual adjusted aggregate incremental costs were higher by $24 billion among patients with stroke versus those without stroke. CONCLUSION: Among individuals with hypertension in the United States, those who have experienced a stroke incur tens of billions of dollars in higher health-care expenditures compared with those without known stroke. Greater emphasis on stroke prevention strategies and cost control initiatives (wherever appropriate) are warranted. PMID- 29530461 TI - Long-Term Outcome of Balloon Angioplasty Without Stenting for Symptomatic Middle Cerebral Artery Stenosis. AB - PURPOSE: A recent randomized controlled trial demonstrated that aggressive medical management was superior to angioplasty with stenting for intracranial stenosis. The purpose of this study was to assess initial and long-term outcomes of balloon angioplasty without stenting for symptomatic middle cerebral artery (MCA) stenosis. METHODS: We retrospectively analyzed the clinical data of 72 patients (mean age, 58.9 years old) with 84 balloon angioplasties without stenting for high-grade (>70%) atherosclerotic stenosis of the main trunk of the MCA. All patients had experienced recurrent transient ischemic attack or minor stroke resistant to medical treatment. We assessed perioperative and long-term outcomes such as restenosis and the recurrence of strokes. The follow-up period was a median of 63 months (range, 6-171 months). RESULTS: Balloon angioplasty was successful in 97% of procedures. During the 30-day perioperative period, a total of 3 patients suffered from stroke (4.2%) without death. A total of 23 (31.9%) patients had restenosis at a time point that varied from 6 to 111 months. Diabetes mellitus (DM) was noted significantly more often in the restenosis group (39%) than in the nonrestenosis group (13%). Multivariate logistic regression analysis revealed DM (odds ratio, 4.84; 95% confidence interval, 1.196-19.62; P = .027) as an independent predictor of restenosis. Restenosis and DM were indicated as independent predictors of the recurrence of ischemic stroke and transient ischemic attack. CONCLUSIONS: Balloon angioplasty without stenting for symptomatic MCA stenosis can be performed with a high successful rate and a low risk of complications. Long-term outcome data suggest that this procedure reduces the risk of further strokes. PMID- 29530462 TI - Lifestyle Factors and Gender-Specific Risk of Stroke in Adults with Diabetes Mellitus: A Case-Control Study. AB - BACKGROUND: The lifestyle interventions are effective preventive measures for stroke in general population, and the stroke risk with lifestyle factors may be modified by gender, health conditions, etc. Therefore, we conducted a case control study to investigate the gender-specific association between stroke risk and lifestyle factors in adults with diabetes based on the China National Stroke Screening Survey. METHODS: Structured questionnaires were used to collect demographic data and information regarding lifestyle factors, history of chronic medical conditions, and family history of stroke and the status of treatment. The case group comprised individuals diagnosed with first-ever stroke in 2013-2014 screening period. Their corresponding controls (frequency-matched for age group and urban/rural ratio) were randomly selected from individuals with diabetes without stroke. RESULTS: There were 170 total stroke cases (500 controls) and 152 ischemic stroke cases (456 controls) among men with diabetes, and 183 total stroke cases (549 controls) and 168 ischemic stroke cases (504 controls) among women with diabetes. We found that physical inactivity was significantly associated with increased risk of total stroke (odds ratio [OR] = 1.50, 95% confidence interval [CI] 1.02-2.21) and of ischemic stroke (OR = 1.57, 95% CI 1.04-2.36) in women with diabetes. We found no significant association of smoking, overweight/obesity, or physical inactivity with risk of total or ischemic stroke in men with diabetes. CONCLUSION: Among the lifestyle factors of smoking, overweight/obesity, and physical inactivity, physical inactivity might increase the risk of total and ischemic stroke in women with diabetes. PMID- 29530463 TI - Hypotension in hemodialysis secondary to a reaction to synthetic membranes. PMID- 29530464 TI - Role of gene polymorphisms/haplotypes and serum levels of interleukin-17A in susceptibility to viral myocarditis. AB - Interleukin-17A (IL-17A) has been implicated in the pathogenesis of viral myocarditis (VMC). However, the role of IL-17A polymorphisms in susceptibility to VMC has not been reported to date. The aim of this study was to explore the association between IL-17A variants as well as serum IL-17 levels with VMC. Three single-nucleotide polymorphisms (SNPs) (rs2275913, rs3819025, and rs3748067) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in 236 VMC patients and 259 controls from China. Serum IL-17A levels were measured by enzyme-linked immunosorbent assay kits. Multivariable logistic regression analysis that the rs2275913 AA genotype and the haplotype 197A/+45G/+1249G (AGG) were associated with an increased risk of VMC (all P < 0.05). Consistent with these findings, the rs2275913 AA genotype was linked to higher serum IL-17A compared to GG/AG genotype (all P < 0.001). We observed no associations between the other two SNPs and risk of VMC. Serum IL-17A levels were significantly higher in the VMC group than controls (P < 0.001) and gradually increased with the increase of New York Heart Association grade in VMC patients (P < 0.05). Spearman correlation test revealed that the serum IL-17A level was correlated with the cardiac damage and left ventricular systolic functions among VMC patients (all P < 0.05). Our study reveals that IL-17A expression may contribute to the development and severity of VMC. The SNP rs2275913 in the IL 17A gene might exert influence on susceptibility to VMC via linking with the serum IL-17A level. PMID- 29530465 TI - Does switching the bacillus Calmette-Guerin strain affect clinical outcome in patients with recurrent non-muscle-invasive bladder cancer after initial bacillus Calmette-Guerin therapy? AB - PURPOSE: It is still unknown whether switching the bacillus Calmette-Guerin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). MATERIALS AND METHODS: We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). RESULT: The 5-year recurrence-free survival rate of the switching group was 64.7 +/- 9.6%, which was not significantly different from that of the non-switching group (54.8 +/- 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 +/- 2.6%, which was also not significantly different from that of the non-switching group (96.0 +/- 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. CONCLUSIONS: The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain. PMID- 29530466 TI - Circulating tumor cells in bladder cancer: Emerging technologies and clinical implications foreseeing precision oncology. AB - CONTEXT: Circulating tumor cells (CTC) in peripheral blood of cancer patients provide an opportunity for real-time liquid biopsies capable of aiding early intervention, therapeutic decision, response to therapy, and prognostication. Nevertheless, the rare and potentially heterogeneous molecular nature of CTC has delayed the standardization of robust high-throughput capture/enrichment and characterization technologies. OBJECTIVE: This review aims to systematize emerging solutions for CTC analysis in bladder cancer (BC), their opportunities and limitations, while providing key insights on specific technologic aspects that may ultimately guide molecular studies and clinical implementation. EVIDENCE ACQUISITION: State-of-the-art screening for CTC technologies and clinical applications in BC was conducted in MEDLINE through PubMed. EVIDENCE SYNTHESIS: From 200 records identified by the search query, 25 original studies and 1 meta analysis met the full criteria for selection. A significant myriad of CTC technological platforms, including immunoaffinity, biophysical, and direct CTC detection by molecular methods have been presented. Despite their preliminary nature and irrespective of the applied technology, most studies concluded that CTC counts in peripheral blood correlated with metastasis. Associations with advanced tumor stage and grade and worst prognosis have been suggested. However, the unspecific nature, low sensitivity, and the lack of standardization of current methods still constitutes a major drawback. Moreover, few comprehensive molecular studies have been conducted on these poorly known class of malignant cells. CONCLUSION: The current rationale supports the importance of moving the CTC field beyond proof of concept studies toward molecular-based solutions capable of improving disease management. The road has been paved for identification of highly specific CTC biomarkers and novel targeted approaches, foreseeing successful clinical applications. PMID- 29530467 TI - Tick microbial communities within enriched extracts of Amblyomma maculatum. AB - Our objective of this study was to explore the bacterial microbiome in fresh or fresh-frozen adult Amblyomma maculatum (Gulf Coast ticks) using extracts enriched for microbial DNA. We collected 100 questing adult A. maculatum, surface disinfected them, and extracted DNA from individual ticks collected the same day or after storage at -80 degrees C. Because only extracts with microbial DNA concentrations above 2 ng/MUL were considered suitable for individual analysis, we expected fewer samples to meet these requirements. Of individual ticks extracted, 48 extracts met this minimum concentration. We pooled 20 additional extracts that had lower concentrations to obtain seven additional pools that met the minimum DNA concentration. Libraries created from these 55 samples were sequenced using an Illumina MiSeq platform, and data sets were analyzed using QIIME to identify relative abundance of microorganisms by phylum down to genus levels. Proteobacteria were in greatest abundance, followed by Actinobacteria, Firmicutes, and Bacteroidetes, at levels between 1.9% and 6.4% average relative abundance. Consistent with the Francisella-like endosymbiont known to be present in A. maculatum, the genus Francisella was detected at highest relative abundance (72.9%; SE 0.02%) for all samples. Among the top ten genera identified (relative abundance >= 0.5%) were potential extraction kit contaminants, Sphingomonas and Methylobacterium, the soil bacterium Actinomycetospora, and the known A. maculatum-associated genus, Rickettsia. Four samples had Rickettsia at greater than 1% relative abundance, while nine additional samples had Rickettsia at low (0.01-0.04%) relative abundance. In this study, we used the entire microbe enriched DNA extract for whole ticks for microbiome analysis. A direct comparison of the microbiome in microbe-enriched DNA and total genomic DNA extracts from halves of the same tick would be useful to determine the utility of this extraction method in this system. We anticipate that future tick microbiome studies will be valuable to explore the influence of microbial diversity on pathogen maintenance and transmission, and to evaluate niche-specific microbiomes within individual tick tissues. PMID- 29530468 TI - Geographical distribution and phylogenetic analysis of Rhipicephalus sanguineus sensu lato in northern and central Chile. AB - The presented study analyzed the presence and geographical distribution of the tropical and temperate lineages of Rhipicephalus sanguineus sensu lato in Chile. R. sanguineus s.l. ticks were collected from dogs at 14 sites in northern and central Chile for morphological and genetic analysis based on the 16S rDNA gene. Phylogenetic studies proved the existence of both, the tropical and the temperate lineages. The former was represented by a single haplotype and occurred in the far north; the latter included four haplotypes and was observed from the Tarapaca Region southwards. In four sites at latitudes from 20 degrees S to 22 degrees S, both lineages were found to coexist. Our study discovered for the first time the existence of the tropical lineage in Chile and demonstrated that distributions of the tropical and temperate lineages overlap, forming a transitional zone of approximately 200 km in northern coastal Chile. PMID- 29530469 TI - Close Encounter With a Prickly Soccer Ball: An Injury From an Indian Crested Porcupine. AB - The Indian crested porcupine, Hystrix indica, is a large rodent with the unique feature of long quills. These quills are an integral part of its defense mechanism against predators. Injuries resulting from human contact with quills may cause pain, bleeding, and swelling. Quill-related injuries are common among animals such as dogs, cats, and some wild animals. The mechanism of injury, consequences, and management of injuries to humans from H indica quills are rarely described. In this report, we describe the injuries and management of a man who sustained injury from H indica quills. PMID- 29530470 TI - Snakebites Treated in North Carolina Emergency Departments, October 2013 September 2015. AB - INTRODUCTION: North Carolina (NC) is home to more than 30 species of indigenous venomous and nonvenomous snakes. Snakebites can cause debilitating and potentially fatal injuries. However, there is a lack of current information available describing the incidence of snakebites in NC. Therefore, we performed this study of snakebites treated in NC emergency departments (EDs) using the statewide syndromic surveillance system, the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT). METHODS: This was a descriptive epidemiologic study characterizing NC ED visits collected by NC DETECT between October 1, 2013 and September 30, 2015 with an assigned International Classification of Diseases, 9th Revision, Clinical Modification code or keyword indicating a snakebite. RESULTS: Over the 2-year period, the absolute count of snakebite-related ED visits was 2080 visits with an incidence rate of 10.4 visits per 100 000 person-years (95% confidence interval: 10.0 10.9). The frequency of snakebite was highest during the summer months and evening hours. Men had higher incidence rates of snakebite-related ED visits than women, and residents of the Coastal Plain geographic region of NC had higher incidence rates than persons in other regions. CONCLUSIONS: The current study indicated that snakebites are common injuries treated at NC EDs, with a strong seasonal and geographic component. Additional research is needed to further characterize the circumstances associated with snakebites for the development of preventive measures and public health education. PMID- 29530471 TI - Whiptail Stingray Injury. AB - Stingray injuries to the chest are rare but potentially life-threatening. They may occur in remote areas where advanced emergency healthcare services are unavailable. We describe the case of a 24-year-old man with tension pneumothorax due to a Himantura fai stingray injury to the left chest. The chest wound was unremarkable, with no external bleeding or evidence of a foreign body. Decompression was performed at the scene with an improvised knife procedure and a hollow writing pen, which served as a chest tube. At the local hospital, a standard-sized chest tube was inserted, the wound cleaned, and the patient given antibiotics active against marine organisms. Computed tomography visualized the stinger and revealed hemopneumothorax and pneumomediastinum. The local hospital did not have a thoracic surgeon, and the patient was transferred to a larger hospital with a thoracic surgery center. After surgical removal of the stinger, segmental lung resection was required to control bleeding. Management of life threatening stingray injuries to the chest should begin at the scene. After stabilization, the patient should be transferred to a hospital equipped for cardiovascular and thoracic surgery. Surgery may be required to remove the retroserrated stinger and can be challenging. PMID- 29530472 TI - Medical Services at an International Summer Camp Event Under Hot and Humid Conditions: Experiences From the 23rd World Scout Jamboree, Japan. AB - INTRODUCTION: The 23rd World Scout Jamboree (WSJ) was a 10-day summer camp held in Japan in 2015 under hot and humid conditions. The attendees comprised 33,628 people from 155 countries and territories. The aim of this study was to examine the provision of medical services under such conditions and to identify preventive factors for major diseases among long-term campers. METHODS: Data were obtained from WSJ medical center records and examined to clarify the effects of age, sex, and period on visit frequencies and rates. RESULTS: Medical records from 3215 patients were examined. Daytime temperatures were 31.5+/-3.2 degrees C and relative humidity was 61+/-13% (mean+/-SD). The initial visit rates among scouts and adults were 72.2 and 77.2 per 1000 persons, respectively. No significant age difference was observed in the initial visit rate; however, it was significantly higher among female patients than male patients. Significant differences were also seen in the adjusted odds ratios by age, sex, and period for disease distributions of initial visit frequencies. In addition, a higher initial visit frequency for heat strain-related diseases was seen among the scouts. Initial visit frequencies for heatstroke and/or dehydration increased just after opening day and persisted until closing day. CONCLUSIONS: Our findings suggest the importance of taking effective countermeasures against heat strain, fatigue, and unsanitary conditions at the WSJ. Medical services staff should take attendees' age, sex, and period into consideration to prevent heat strain-related diseases during such camps under hot and humid conditions. PMID- 29530473 TI - Agathisflavone and GABAA receptors in the biflavone-mediated action on rat primary cortical neurons. PMID- 29530474 TI - Streptococcus salivarius-mediated CD8+ T cell stimulation required antigen presentation by macrophages in oral squamous cell carcinoma. AB - It has been shown that the peripheral blood mononuclear cells (PBMCs) from oral squamous cell carcinoma (OSCC) patients presented cytotoxic CD8 T cell response against Streptococcus salivarius (S. salivarius), of which the frequency was positively associated with recurrence-free survival in OSCC patients. To identify the conditions required for regulating S. salivarius-specific CD8 T cell-mediated cytotoxicity, we selectively depleted individual components of the PBMCs, and observed that the depletion of monocytes/macrophages, but not other immune cell subsets, significantly downregulated the S. salivarius-specific CD8 T cell cytotoxicity. Monocyte/macrophage alone was sufficient to reconstitute optimal granzyme B expression from S. salivarius-specific CD8 T cells. Also, both the memory and the naive CD8 T cells reacted to S. salivarius-stimulation, with the memory CD8 T cells presenting significantly higher S. salivarius-reactivity. Using M1- and M2-polarized macrophages from circulating monocytes, we found that M1-polarized macrophages, with significantly higher IL-12 expression and significantly lower IL-10 and MHC class II molecule expression, was more effective at promoting granzyme B responses in CD8 T cells, and required CD80/CD86 costimulating molecules for optimal responses. Interestingly, the tumor associated macrophages (TAMs) from resected tumors presented characteristics of M2-polarized macrophages with high MHC class II expression and low IL-12 secretion. The frequency of tumor-infiltrating S. salivarius-specific cytotoxic CD8 T cell was inversely correlated with the level of IL-10 secretion and the MHC class II molecule expression in autologous TAMs. Together, we demonstrated that monocyte/macrophages presented essential antigen-presentation and costimulatory roles in CD8 T cell-mediated S. salivarius-specific granzyme B responses, and the polarization of macrophages could influence the potency of CD8 T cell responses. PMID- 29530475 TI - MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2-STAT3 signaling axis. AB - Cholangiocarcinoma (CCA) is a lethal cancer associated with chronic inflammation that has increased in prevalence in recent decades. The dysregulated expression of microRNAs (miRNAs) has been detected in various types of malignancies, and depending on the target genes this can result in miRNAs functioning as tumor suppressors or oncogenes. In this study, we investigated the role of miR-124 in cholangiocarcinoma (CCA) and found that its expression was significantly downregulated in the tumor tissue of patients and in CCA cell lines. Our results provided evidence that miR-124 induces apoptotic cell death and triggers the autophagic flux in CCA cells. EZH2 and STAT3 were identified as direct targets of miR-124. The effect of miR-124 on EZH2 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Silencing of EZH2 restored the effects of miR-124, whereas overexpression of EZH2 abrogated the effects of miR-124. Silencing of Beclin1 or ATG5 abrogated the effects of miR-124 or siEZH2. In vivo, overexpression of miR 124 dramatically induced autophagy-related cell death and suppressed tumorigenicity. Taken together, our findings indicated that downregulation of miR 124 expression was associated with disease progression in human CCA and we revealed that miR-124 exerts a tumor suppressive function in CCA by inducing autophagy-related cell death via direct targeting of the EZH2-STAT3 signaling axis. PMID- 29530476 TI - Erratum to "Cloaca reconstruction: A new algorithm which considers the role of urethral length in determining surgical planning" [YJPSU 53/1 (2018) 90-95]. PMID- 29530477 TI - Lessons learned from 29 lymphoepithelial cysts of the pancreas: institutional experience and review of the literature. AB - BACKGROUND: Lymphoepithelial cysts (LECs) are rare pancreatic cystic lesions. Since LECs are benign, preoperative diagnosis is important to differentiate from a cystic neoplasm and avoid unnecessary surgery. The aim of this study was to identify clinical, radiographic and cytopathologic features associated with LECs. METHODS: A retrospective review was performed of patients diagnosed with LEC between 1995 and 2017 at our hospital. Clinicopathologic and radiographic imaging features were documented. RESULTS: Of 29 patients with pancreatic LEC, 22 underwent surgical resection. The majority were male (n = 24) with a median age of 55 years (range, 21-74). During the evaluation, all patients underwent a CT, with endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) biopsy (n = 22) and/or MRI/MRCP (n = 11) performed in a smaller number of patients. A combination of exophytic tumor growth on imaging and the presence of specific cytomorphologic features on the EUS-FNA cytology biopsy led to the correct diagnosis of LEC and prevention of unnecessary surgery in 7 patients. DISCUSSION: Differentiating LECs from premalignant pancreatic cystic neoplasms remains difficult. Findings of an exophytic growth pattern of the lesion on abdominal imaging and the presence of specific cytomorphologic features in the EUS-FNA biopsy could help clinicians diagnose LEC preoperatively. PMID- 29530478 TI - Cross-cultural adaptation of Kerlan-Jobe Orthopaedic Clinic shoulder and elbow score: Reliability and validity in Turkish-speaking overhead athletes. AB - OBJECTIVE: Kerlan-Jobe Orthopaedic Clinic Shoulder and Elbow Score (KJOC-SES) is a subjective assessment tool to measure functional status of the upper extremities in overhead athletes. The aim was to translate and culturally adapt the KJOC-SES and to evaluate the psychometric properties of the Turkish version (KJOC-SES-Tr) in overhead athletes. METHODS: The forward and back-translation method was followed. One hundred and twenty-three overhead athletes completed the KJOC-SES-Tr, the Disabilities of the Arm, Shoulder, and Hand (DASH), and the American Shoulder and Elbow Surgeons Evaluation Form (ASES). Participants were assigned to one of the following subgroups: asymptomatic (playing without pain) or symptomatic (playing with pain, or not playing due to pain). Internal consistency, reliability, construct validity, discriminant validity, and content validity of the KJOC-SES-Tr were tested. RESULTS: The test-retest reliability of the KJOC-SES-Tr was excellent with an interclass coefficient of 0.93. There was a strong correlation between the KJOC-SES-Tr and the DASH and the ASES, indicating that the construct validity was good for all participants. Results of the KJOC SES-Tr significantly differed between different subgroups and categories of athletes. The floor and ceiling effects were acceptable for symptomatic athletes. CONCLUSION: The KJOC-SES-Tr was shown to be valid, reliable tool to monitor the return to sports following injuries in athletes. PMID- 29530479 TI - How do mental health first aid TM interventions influence patient help-seeking behaviours? A dilemma for pharmacist mental health first aid responders. AB - In any given year approximately 34% of the 130 million adults in the United States suffer from a mental health condition or disorder. Anxiety and depressive disorders are the most common followed by substance use disorder. Many people who suffer from a mental illness do not seek help. Studies have shown that the stigma of being perceived as having a mental illness prevents many adults from seeking help. Mental Health First Aid TM (MHFA) is an educational program geared towards educating MHFA responders to assist those who may be experiencing a mental health condition or disorder. Pharmacists are the most accessible healthcare professionals, and many are trained in delivering MHFA. The literature on MHFA suggests that it is an effective educational program for those that take the training course. What is lacking is evidence that MHFA interventions positively affect help-seeking behaviours after an intervention has occurred between a mental health first air responder and an individual requiring MHFA. This paper highlights this issue and provides suggestions for future research. PMID- 29530480 TI - Janus kinase-1 and 3 in ankylosing spondylitis. AB - BACKGROUND/PURPOSE: To investigate the Janus kinase-1 and 3 (JAK-1 and 3) expression in peripheral blood mononuclear cells (PBMCs) in ankylosing spondylitis (AS). METHODS: The levels of JAK-1 and JAK-3 mRNA in PBMCs, CD3+ T cells and CD14+ monocytes were measured by RT-PCR in 52 AS patients and 31 healthy controls (HCs). The demographic features, BASDAI, BASFI, HLA-B27, ESR, CRP and serum immunoglobulin A (IgA) level were recorded and correlated with the JAK-1 & JAK-3 transcripts in patients and HCs as appropriate. RESULTS: JAK-1 and JAK-3 expression in PB CD3+ T cells plus CD14+ monocytes was significantly higher in AS patients than in HCs (p < 0.05). There is a positive correlation between JAK-1 expression in CD3+ T cells plus CD14+ monocytes and ESR, CRP, IgA, HLA-B27, peripheral arthritis, enthesitis and uveitis (all p < 0.05), respectively. JAK-1 transcript was also increased in CD14+ monocytes from patients and correlated well with ESR and CRP as the disease deteriorated. Conversely, JAK-1 was negatively correlated to chest expansion. Area under the curve of standard receiver operating characteristic suggested that JAK-1 transcript in CD3+ T cells plus CD14+ monocytes is better to predict the higher BASDAI (>4) and BASFI (>4) than ESR or CRP in AS patients. CONCLUSION: In AS, JAK-1 expression in PB cells rather than ESR or CRP might be regarded as a bio-marker for monitoring disease activity and functional index in AS. These findings have also suggested that JAK 1 and JAK-3 expression may play a role in the inflammatory processes in patients with AS. PMID- 29530481 TI - Lanai: A small, fast growing tomato variety is an excellent model system for studying geminiviruses. AB - Geminiviruses are devastating single-stranded DNA viruses that infect a wide variety of crops in tropical and subtropical areas of the world. Tomato, which is a host for more than 100 geminiviruses, is one of the most affected crops. Developing plant models to study geminivirus-host interaction is important for the design of virus management strategies. In this study, "Florida Lanai" tomato was broadly characterized using three begomoviruses (Tomato yellow leaf curl virus, TYLCV; Tomato mottle virus, ToMoV; Tomato golden mosaic virus, TGMV) and a curtovirus (Beet curly top virus, BCTV). Infection rates of 100% were achieved by agroinoculation of TYLCV, ToMoV or BCTV. Mechanical inoculation of ToMoV or TGMV using a microsprayer as well as whitefly transmission of TYLCV or ToMoV also resulted in 100% infection frequencies. Symptoms appeared as early as four days post inoculation when agroinoculation or bombardment was used. Symptoms were distinct for each virus and a range of features, including plant height, flower number, fruit number, fruit weight and ploidy, was characterized. Due to its small size, rapid growth, ease of characterization and maintenance, and distinct responses to different geminiviruses, "Florida Lanai" is an excellent choice for comparing geminivirus infection in a common host. PMID- 29530482 TI - Recent computational studies of membrane interaction and disruption of human islet amyloid polypeptide: Monomers, oligomers and protofibrils. AB - The amyloid deposits of human islet amyloid polypeptide (hIAPP) are found in type 2 diabetes patients. hIAPP monomer is intrinsically disordered in solution, whereas it can form amyloid fibrils both in vivo and in vitro. Extensive evidence suggests that hIAPP causes the disruption of cellular membrane, and further induces cytotoxicity and the death of islet beta-cells in pancreas. The presence of membrane also accelerates the hIAPP fibril formation. hIAPP oligomers and protofibrils in the early stage of aggregation were reported to be the most cytotoxic, disrupting the membrane integrity and giving rise to the pathological process. The detailed molecular mechanisms of hIAPP-membrane interactions and membrane disruption are complex and remain mostly unknown. Here in this review, we focus on recent computational studies that investigated the interactions of full length and fragmentary hIAPP monomers, oligomers and protofibrils with anionic, zwitterionic and mixed anionic-zwitterionic lipid bilayers. We mainly discuss the binding orientation of monomers at membrane surface, the conformational ensemble and the oligomerization of hIAPP inside membranes, the effect of lipid composition on hIAPP oligomers/protofibrils-membrane interactions, and the hIAPP-induced membrane perturbation. This review provides mechanistic insights into the interactions between hIAPP and lipid bilayers with different lipid composition at an atomistic level, which is helpful to understand the hIAPP cytotoxicity mediated by membrane. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29530483 TI - Exosomal alphavbeta6 integrin is required for monocyte M2 polarization in prostate cancer. AB - Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described alphavbeta6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel alphavbeta6-mediated signaling pathway that has profound effects on the microenvironment. We show that alphavbeta6 is transferred from cancer cells to monocytes, including beta6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express alphavbeta6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas alphavbeta6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, alphavbeta6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc-/- prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that alphavbeta6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of alphavbeta6 from cancer cells to monocytes through exosomes. PMID- 29530485 TI - Genomic Profiling and Metabolic Homeostasis in Primary Liver Cancers. AB - Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), the two most common primary liver cancers, represent the second most common cancer related cause of death worldwide, with most cases being diagnosed at an advanced stage. Recent genome-wide studies have helped to elucidate the molecular pathogenesis and genetic heterogeneity of liver cancers. This review of the genetic landscape of HCC and iCCA discusses the most recent findings from genomic profiling and the current understanding of the pathways involved in the initiation and progression of liver cancer. We highlight recent insights gained from metabolic profiling of HCC and iCCA. This knowledge will be key to developing clinically useful diagnostic/prognostic profiles, building targeted molecular and immunologic therapies, and ultimately curing these complex and heterogeneous diseases. PMID- 29530486 TI - Qualitative CT Criterion for Subsolid Nodule Subclassification: Improving Interobserver Agreement and Pathologic Correlation in the Adenocarcinoma Spectrum. AB - RATIONALE AND OBJECTIVES: The main aim of this study was to evaluate the clinical validity and correlation with pathologic invasiveness in the pulmonary adenocarcinoma spectrum based on the novel qualitative computed tomography criterion for subsolid nodule (SSN) classification, which classified SSN into pure ground-glass nodule, heterogeneous ground-glass nodule, and part-solid nodule. In addition, we compared the performance of the conventional and novel classifications. MATERIALS AND METHODS: The computed tomography images of 41 SSN nodules were interpreted by six observers independently, and the SSN characteristics were classified according to both the conventional and the novel classification systems. Each observer assessed 41 nodules in two different classifications separated by a minimum of 8 weeks. The kappa (kappa) coefficient test was used to determine the reliability. The correlation between pulmonary adenocarcinoma spectrum and the SSN classification was analyzed with Spearman correlation coefficients. RESULTS: Interobserver agreement (kappa) was 0.702 (range 0.42-0.89) and 0.707 (range 0.58-0.88) for the conventional and the novel classifications for SSN, respectively, and intraobserver agreement (kappa) was 0.92 and 0.88 for the conventional and the novel classifications for SSN, respectively. The novel SSN classification (correlation coefficient range 0.622 0.732) is more strongly correlated with the pathologic invasiveness degree of lesions in adenocarcinoma spectrum than the conventional SSN classification (correlation coefficient range 0.458-0.644). CONCLUSIONS: The agreement between observers on the novel SSN classification system was good and had better correlation with pathologic invasiveness than the conventional SSN classification. Further studies are needed to confirm these results on interobserver agreement. PMID- 29530484 TI - Cartilage oligomeric matrix protein: COMPopathies and beyond. AB - Cartilage oligomeric matrix protein (COMP) is a large pentameric glycoprotein that interacts with multiple extracellular matrix proteins in cartilage and other tissues. While, COMP is known to play a role in collagen secretion and fibrillogenesis, chondrocyte proliferation and mechanical strength of tendons, the complete range of COMP functions remains to be defined. COMPopathies describe pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), two skeletal dysplasias caused by autosomal dominant COMP mutations. The majority of the mutations are in the calcium binding domains and compromise protein folding. COMPopathies are ER storage disorders in which the retention of COMP in the chondrocyte ER stimulates overwhelming cellular stress. The retention causes oxidative and inflammation processes leading to chondrocyte death and loss of long bone growth. In contrast, dysregulation of wild-type COMP expression is found in numerous diseases including: fibrosis, cardiomyopathy and breast and prostate cancers. The most exciting clinical application is the use of COMP as a biomarker for idiopathic pulmonary fibrosis and cartilage degeneration associated osteoarthritis and rheumatoid and, as a prognostic marker for joint injury. The ever expanding roles of COMP in single gene disorders and multifactorial diseases will lead to a better understanding of its functions in ECM and tissue homeostasis towards the goal of developing new therapeutic avenues. PMID- 29530487 TI - Attitudes of Radiology Program Directors Toward MD-PhD Trainees, Resident Research Productivity, and Dedicated Research Time. AB - RATIONALE AND OBJECTIVES: The percentage of clinical scientists in radiology has historically been low. Increasing the pipeline of trainees interested in research could occur by recruiting MD-PhD trainees and providing protected research time during residency. The purpose of this work is to assess the attitudes of radiology program directors toward MD-PhD trainees, resident research productivity, and dedicated research time. METHODS: An online survey was sent to residency program directors of all diagnostic radiology departments that received National Institutes of Health (NIH) awards in 2014 (n = 63). Survey questions included program size; perception of overall performance, clinical performance, and research productivity of MD-PhD residents compared to non-PhD residents; and presence of dedicated research time. Responses comparing MD-PhD residents to non PhD residents were reported as a five-point Likert scale. Student t test was used to assess for significance (alpha = 0.05). RESULTS: Response rate was 37%. Clinical performance of MD-PhD residents was judged inferior (P < .05) to non-PhD residents, although that of all residents engaged in research trended toward superiority compared to those not involved in research. Dedicated research time is offered by 61% of programs in years R1-R3 and all programs in year R4. Research productivity during residency was judged to be similar (P = .5) between MD-PhD and non-PhD residents. CONCLUSIONS: Survey results suggest that clinical performance during residency and research involvement is often individually based and difficult to generalize based on prior PhD training. All programs offered dedicated research time, and the vast majority of residents were reported to engage in research during residency, which may increase the pipeline of trainees interested in an academic career. PMID- 29530488 TI - Modified Lung-RADS Improves Performance of Screening LDCT in a Population with High Prevalence of Non-smoking-related Lung Cancer. AB - OBJECTIVES: We proposed a modification of the ACR Lung Imaging Reporting and Data System (Lung-RADS) to clarify the characteristics of subsolid nodules with categories 1-11, and to compare the diagnostic accuracy with Lung-RADS and National Lung Screening Trial criteria in an Asian population with high prevalence of adenocarcinoma. METHODS: We analyzed a retrospective cohort of 1978 consecutive healthy subjects (72.8% nonsmoker) who underwent low-dose computed tomography from August 2013 to October 2014 (1084 men, 894 women). Lung-RADS categories 2 and 3 were modified to include subcategories of 2A/2B/2C and 3A/3B/3C, respectively. Clinical information and nodule characteristics were recorded. Receiver operating characteristic curves were used to compare diagnostic accuracy at different cutoffs. RESULTS: Thirty-two subjects (30 nonsmokers) had pathology-proven adenocarcinoma spectrum lesions in the follow-up period (1.6 +/- 0.5 years). Modified Lung-RADS, using modified Lung-RADS category 2C as cutoff, had an area under the curve (AUC) of 0.973 in predicting adenocarcinoma spectrum lesions (sensitivity of 100%, specificity of 89.3%), which was significantly higher than that of Lung-RADS (AUC = 0.815, P < .001) and National Lung Screening Trial (AUC = 0.906, P < .001). Furthermore, modified Lung RADS showed an AUC of 0.992 in predicting invasive adenocarcinoma (sensitivity of 95%, specificity of 97.8%) when category 3B was used as cutoff. CONCLUSIONS: Modified Lung-RADS may substantially improve sensitivity while maintaining specificity for detection of adenocarcinoma spectrum lesions in an Asian population. Compared to Lung-RADS, it has enhanced ability to differentiate invasive from indolent adenocarcinoma by more refined subclassification of subsolid nodules using two cutoff values of category 2C and 3B. The effect of using modified Lung-RADS in clinical practice must be carefully studied in prospective large cohort studies. PMID- 29530489 TI - Abnormal ventral tegmental area-anterior cingulate cortex connectivity in Parkinson's disease with depression. AB - Neuropathology suggests that Parkinson's disease (PD) with depression may involve a progressive degeneration of the nigrostriatal and mesocorticolimbic dopaminergic systems. Previous positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies have shown that dopamine changes in individual brain regions constituting the nigrostriatal and mesocorticolimbic circuits are associated with depression in PD. However, few studies have been conducted on the circuit-level alterations in this disease. The present study used resting-state fMRI and seed-based functional connectivity of putative dopaminergic midbrain regions (i.e., substantia nigra (SN) and ventral tegmental area (VTA)) to investigate the circuit-related abnormalities in PD with depression. The results showed that depressed PD (DPD) patients relative to healthy controls (HC) and non-depressed PD (NDPD) patients had increased functional connectivity between VTA and anterior cingulate cortex (ACC), demonstrating that dysfunctional mesocorticolimbic dopaminergic neurotransmission may be associated with depression in PD. Compared with HC, DPD and NDPD patients showed increased functional connectivity from SN to sensorimotor cortex, validating that alterations in the nigrostriatal circuitry could be responsible for cardinal motor features in PD. In addition, aberrant connectivity between VTA and ACC was correlated with the severity of depression in PD patients, further supporting that abnormal mesocorticolimbic system may account for depressive symptoms in PD. These results have provided potential circuit-level biomarkers of depression in PD, and suggested that resting state functional connectivity of midbrain dopaminergic nuclei may be useful for understanding the underlying pathology in PD with depression. PMID- 29530490 TI - Spectroscopic studies on the interactions of 5-ethyl-6-phenyl-3,8-bis((3 aminoalkyl)propanamido)phenanthridin-5-ium derivatives with G-quadruplex DNA. AB - An improved microwave-induced synthesis of five ethidium derivatives (Ethidium derivatives, 2a-d) is presented. As the derivatives 2a-d have been proposed previously to be telomerase inhibitors, the binding interactions of these ethidium derivatives with G-quadruplex DNA were evaluated by means of photometric and fluorimetric titration, thermal DNA denaturation, CD and 1H NMR spectroscopy. In particular, the compound bearing 3,8-bis(pyrrolidin-1-yl)propanamido substituent 2a exhibits high selectivity for G-quadruplex DNA relative to duplex DNA. PMID- 29530491 TI - Pain-motor integration and chronic pain: One step ahead. PMID- 29530492 TI - Agmatine inhibits nicotine withdrawal induced cognitive deficits in inhibitory avoidance task in rats: Contribution of alpha2-adrenoceptors. AB - Nicotine abstinence following chronic exposure is associated with impairments in memory and variety of cognitive functions. Daily nicotine (2 mg/kg, sc, four times daily) administration for 14 days and its abrupt withdrawal significantly impaired avoidance learning in inhibitory avoidance task as indicated by a significant decrease in the step through latency. Animals injected with agmatine (10-40 MUg/rat, icv) from day 7 to 14 before the first daily dose of nicotine (2 mg/kg, sc) showed increased step through latencies during retrieval test. Similarly Intracerebroventricular injection of l-arginine (25-100 MUg/rat), a biosynthetic precursor of agmatine and arcaine (50 MUg -100 MUg/rat), an agmatinase inhibitor, also increased the step through latency during retrieval test in nicotine withdrawn animals. In separate experiments, alpha2-adrenoceptor agonist, clonidine (0.5-1 MUg/rat, icv) not only demonstrated significant increase in the step through latency as in nicotine withdrawn rats but also potentiated the pharmacological effect of agmatine. In contrast, pre-treatment of alpha2-adrenoceptor antagonist, yohimbine (0.5 MUg/rat, icv) antagonized the memory enhancing effect of agmatine (20 MUg/rat, icv) in nicotine withdrawn rats. In addition, brain agmatine analysis carried out at 72 h time point of nicotine withdrawal showed marked decrease in basal brain agmatine content as compared to control. Overall, the data indicate that agmatine attenuates nicotine withdrawal induced memory impairment through modulation of alpha2adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of cognitive deficits following nicotine withdrawal. PMID- 29530493 TI - Neurocognitive deficits in older patients with cancer. AB - OBJECTIVE: To assess cognitive function in older adults undergoing cancer care. MATERIALS AND METHODS: This is a cross-sectional study, in the University of Texas MD Anderson Cancer Center, in older adults undergoing cancer care. Comprehensive geriatric assessments were conducted prior to surgery, chemotherapy or allogeneic stem cell transplantation, at the Program for Healthy Aging from January 1, 2013 through March 31, 2015. Cognitive assessment was conducted through personal and family interview, and the Montreal cognitive assessment (MoCA). Functional, physical, nutritional, social support, comorbidity assessment and medication review were conducted. ANALYSIS: Patients with mild cognitive impairment (MCI) or dementia were compared to patients who were cognitively intact. RESULTS: One hundred and ninety-two patients underwent geriatric assessment, mean (+/-SD) age was 78 +/- 7 years, 121 (63%) had some degree of neurocognitive deficit, with 64 patients (33%) presenting with major neurocognitive deficit (dementia), and 57 cases (30%), minor neurocognitive deficit (MCI). Early stage dementia was evident in 50% of cases, moderate stage in 32%, and severe stage in 18%. The prevalence of dementia and MCI were higher than in the general population studies (70-79 years). Associated factors for neurocognitive deficits as compared to older patients with cancer with normal cognition, included a higher comorbidity index (p = 0.04), stroke (p = 0.03), metastatic disease (p = 0.04), and warfarin use (p = 0.03). CONCLUSION: Neurocognitive deficits (MCI and dementia) are more common in older adults with cancer. Factors associated with neurocognitive deficits include high comorbidity, stroke, warfarin use and metastatic cancer. Identification and management of these conditions is of great relevance in the course of cancer therapy. PMID- 29530494 TI - Nivolumab in routine practice for older patients with advanced or metastatic non small cell lung cancer. AB - BACKGROUND: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a "real world" older population. PATIENTS AND METHODS: We retrospectively collected data from older patients (>=70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period. RESULTS: From July 2015 to September 2016, 30 patients were enrolled with a median age of 75.2. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 3.3 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects. CONCLUSIONS: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC. PMID- 29530495 TI - Geriatric assessment-driven polypharmacy discussions between oncologists, older patients, and their caregivers. AB - OBJECTIVES: Polypharmacy (PP) and potentially inappropriate medications (PIM) are common in older adults with cancer, increasing the risk of adverse outcomes. Approaches to identifying and addressing PP/PIM are needed. MATERIALS AND METHODS: Patients >=70 years with advanced cancer were enrolled in this cluster randomized study. All underwent geriatric assessment (GA), and oncologists randomized to the intervention arm received GA-driven recommendations; no information was provided to oncologists at usual care sites. For patients with PP (>=5 medications or >=1 high-risk medication), clinic visits with treating oncologists were audiorecorded and transcribed, and discussions regarding PP/PIM identified. Quality of provider response was coded as dismissed, mentioned, acknowledged, or addressed. RESULTS: Forty patient transcripts were analyzed (20 per arm). More discussions occurred in the intervention group (n = 81) versus the usual care group (n = 51). More concerns per patient were brought up in the intervention group (4.1 vs. 2.6, p = 0.07). Physician-initiated discussions were higher in the intervention group (73% vs. 49%, p = 0.006). More PP concerns were "addressed" in the intervention group (59% vs. 45%, p = 0.1). Oncology supportive care medication concerns were more often addressed in the usual care group (58% vs. 18%, p = 0.008), but medication management concerns were addressed more commonly in the intervention group (38% vs. 79%, p = 0.003). CONCLUSION: In this secondary analysis, a GA-driven intervention increased PP discussions, particularly about total number of medications and medication management. PP/PIM concerns were more commonly addressed in the intervention group, except for the subset of conversations about supportive care medications. PMID- 29530496 TI - Preoperative frailty is a risk factor for non-home discharge in patients undergoing surgery for endometrial cancer. AB - OBJECTIVE: Our objective was to examine the association of the modified frailty index (mFI) and non-home discharge in patients undergoing surgery for endometrial cancer (EMCA). METHODS: Patients who underwent surgery for EMCA from 2011 to 2012 were identified from the American College of Surgeons - Nastional Surigical Quality Improvement Project (ACS-NSQIP) database. Current Procedural Terminology (CPT) codes were used to identify surgical characteristics. We excluded patients who were already living in a non-home facility. To determine frailty, we used the NSQIP frailty index. For analysis purposes, patients with an mFI score >=0.18 were defined as frail. Patients were divided into groups based on discharge destination. Logistic regression were used to identify predictors of post operative non-home discharge. RESULTS: 1216 patients were identified. 26 (2.1%) were discharged to a non-home facility. On multivariate analysis, patients who were discharged to a non-home facility were older (OR 1.09, 95% CI 1.04-1.14, p < 0.001), had a higher Body Mass Index (BMI) (OR 1.08, 95% CI 1.04-1.12, p < 0.001), were more likely to have disseminated cancer (OR 10.02, 95% CI 2.28-44.1, p = 0.002), and were frail (OR 1.95, 95% CI 1.91-5.01, p = 0.008). Undergoing minimally-invasive surgery was independently associated with discharge to home (OR 0.165, 95% CI 0.059-0.458, p = 0.001). CONCLUSION: Frailty is associated with increased risk of non-home discharge in patients undergoing surgery for EMCA. The mFI can be easily calculated using patient characteristics that are readily available pre-operatively. This information can be used for pre-op counseling and to facilitate appropriate and timely discharge planning. PMID- 29530497 TI - Colistin-resistant carbapenemase-producing isolates among Klebsiella spp. and Acinetobacter baumannii in Tripoli, Libya. PMID- 29530498 TI - SVDquest: Improving SVDquartets species tree estimation using exact optimization within a constrained search space. AB - Species tree estimation from multi-locus datasets is complicated by processes such as incomplete lineage sorting (ILS) that result in different loci having different trees. Summary methods, which estimate species trees by combining gene trees, are popular but their accuracy is impaired by gene tree estimation error. Other approaches have been developed that only use the site patterns to estimate the species tree, and so are not impacted by gene tree estimation issues. In particular, PAUP* provides a method in which SVDquartets is used to compute a set Q of quartet trees (i.e., trees on four leaves), and then a heuristic search is used to combine the quartet trees into a species tree T, seeking to maximize the number of quartet trees in Q that agree with T. The PAUP* method based on SVDquartets (henceforth referred to as SVDquartets + PAUP*) is increasingly used in phylogenomic studies due to its ability to reconstruct species trees without needing to estimate accurate gene trees. We present SVDquest*, a new method for constructing species trees using site patterns that is guaranteed to produce species trees that satisfy at least as many quartet trees as SVDquartets + PAUP*. We show that SVDquest* is competitive with ASTRAL and ASTRID (two leading summary methods) in terms of topological accuracy, and tends to be more accurate than ASTRAL and ASTRID under conditions with relatively high gene tree estimation error. SVDquest* is available in open source form at https://github.com/pranjalv123/SVDquest. PMID- 29530499 TI - Large-scale phylogenetic analyses provide insights into unrecognized diversity and historical biogeography of Asian leaf-litter frogs, genus Leptolalax (Anura: Megophryidae). AB - Southeast Asia and southern China (SEA-SC) harbor a highly diverse and endemic flora and fauna that is under increasing threat. An understanding of the biogeographical history and drivers of this diversity is lacking, especially in some of the most diverse and threatened groups. The Asian leaf-litter frog genus Leptolalax Dubois 1980 is a forest-dependent genus distributed throughout SEA-SC, making it an ideal study group to examine specific biogeographic hypotheses. In addition, the diversity of this genus remains poorly understood, and the phylogenetic relationships among species of Leptolalax and closely related Leptobrachella Smith 1928 remain unclear. Herein, we evaluate species-level diversity based on 48 of the 53 described species from throughout the distribution of Leptolalax. Molecular analyses reveal many undescribed species, mostly in southern China and Indochina. Our well-resolved phylogeny based on multiple nuclear DNA markers shows that Leptolalax is not monophyletic with respect to Leptobrachella and, thus, we assign the former to being a junior synonym of the latter. Similarly, analyses reject monophyly of the two subgenera of Leptolalax. The diversification pattern of the group is complex, involving a high degree of sympatry and prevalence of microendemic species. Northern Sundaland (Borneo) and eastern Indochina (Vietnam) appear to have played pivotal roles as geographical centers of diversification, and paleoclimatic changes and tectonic movements seem to have driven the major divergence of clades. Analyses fail to reject an "upstream" colonization hypothesis, and, thus, the genus appears to have originated in Sundaland and then colonized mainland Asia. Our results reveal that both vicariance and dispersal are responsible for current distribution patterns in the genus. PMID- 29530500 TI - Cluster-based upper body marker models for three-dimensional kinematic analysis: Comparison with an anatomical model and reliability analysis. AB - Quantifying angular joint kinematics of the upper body is a useful method for assessing upper limb function. Joint angles are commonly obtained via motion capture, tracking markers placed on anatomical landmarks. This method is associated with limitations including administrative burden, soft tissue artifacts, and intra- and inter-tester variability. An alternative method involves the tracking of rigid marker clusters affixed to body segments, calibrated relative to anatomical landmarks or known joint angles. The accuracy and reliability of applying this cluster method to the upper body has, however, not been comprehensively explored. Our objective was to compare three different upper body cluster models with an anatomical model, with respect to joint angles and reliability. Non-disabled participants performed two standardized functional upper limb tasks with anatomical and cluster markers applied concurrently. Joint angle curves obtained via the marker clusters with three different calibration methods were compared to those from an anatomical model, and between-session reliability was assessed for all models. The cluster models produced joint angle curves which were comparable to and highly correlated with those from the anatomical model, but exhibited notable offsets and differences in sensitivity for some degrees of freedom. Between-session reliability was comparable between all models, and good for most degrees of freedom. Overall, the cluster models produced reliable joint angles that, however, cannot be used interchangeably with anatomical model outputs to calculate kinematic metrics. Cluster models appear to be an adequate, and possibly advantageous alternative to anatomical models when the objective is to assess trends in movement behavior. PMID- 29530501 TI - Day-to-day reliability of gait characteristics in rats. AB - The purpose of the present study was to determine the day-to-day reliability in stride characteristics in rats during treadmill walking obtained with two dimensional (2D) motion capture. Kinematics were recorded from 26 adult rats during walking at 8 m/min, 12 m/min and 16 m/min on two separate days. Stride length, stride time, contact time, swing time and hip, knee and ankle joint range of motion were extracted from 15 strides. The relative reliability was assessed using intra-class correlation coefficients (ICC(1,1)) and (ICC(3,1)). The absolute reliability was determined using measurement error (ME). Across walking speeds, the relative reliability ranged from fair to good (ICCs between 0.4 and 0.75). The ME was below 91 mm for strides lengths, below 55 ms for the temporal stride variables and below 6.4 degrees for the joint angle range of motion. In general, the results indicated an acceptable day-to-day reliability of the gait pattern parameters observed in rats during treadmill walking. The results of the present study may serve as a reference material that can help future intervention studies on rat gait characteristics both with respect to the selection of outcome measures and in the interpretation of the results. PMID- 29530502 TI - [Angiosarcoma in primary lymphoedema: A rare complication]. AB - BACKGROUND: Chronic lymphoedema is classically complicated by recurring episodes of cellulitis. Degeneration to the angiosarcoma form (Stewart-Treves syndrome) is much less common. It occurs mainly in the upper limbs following surgery or radiotherapy for mammary neoplasia. Herein we report a rare case of Stewart Treves syndrome (STS) of the lower limb as a complication of congenital lymphoedema. PATIENTS AND METHODS: A 69-year-old woman treated for bilateral lower-limb oedema present for 30years developed painful necrotic lesions in her left lower limb. A diagnosis of angiosarcoma was made based on biopsy of a nodular lesion. Since surgical excision was precluded by the extent of the lesions, chemotherapy was initiated with paclitaxel 175mg/m2 every 21days. The outcome was rapidly unfavourable and the patient died at her home during the third course of treatment. DISCUSSION: Angiosarcoma is an extremely rare complication of primary lymphoedema; treatment is poorly codified and the prognosis is unfavourable. PMID- 29530503 TI - Vitamin D deficiency and vitamin D receptor variants in mothers and their neonates are risk factors for neonatal sepsis. AB - BACKGROUND AND AIM: Increasing prevalence of neonatal sepsis in recent years catch attention to early prevention and management. Vitamin D receptor (VDR) polymorphism can modulate VDR expression level that greatly influences immunity and susceptibility to microbial infections. We aimed to investigate the association of VDR polymorphism at FokI, rs2228570 T/C, and TaqI, rs731236 C/T gene with serum 25-hydroxyvitamin D level and risk of neonatal sepsis. METHODS: This work carried on 160 subjects classified into 80 cases (40 mothers and their 40 septic neonates) and 80 healthy controls (40 volunteer mothers and their 40 healthy neonates). Genotyping of VDR polymorphisms were assayed by real-time PCR and serum 25-hydroxyvitamin D level and hs-CRP were measured by ELISA. RESULTS: Vitamin D deficiency was observed in mothers of cases compared with healthy ones (p = <0.001) and in septic neonates versus healthy ones (p = <0.001). Septic neonates had much higher VDR FokI TT genotype (p = 0.014) and T allele (p = 0.003) versus healthy ones. TT genotype and T allele could increase the risk of sepsis with OR 95% CI [4.804 (1.4-16.4)] and [2.786 (1.4-5.7)] respectively while VDR TaqI showed no association with sepsis. There was a strong LD between FokI and TaqI in sepsis cases. In sepsis, T/T genotype at FokI had significantly lower vitamin D (p = <0.001). CONCLUSION: Vitamin D deficiency in mothers/neonates is a risk factor for neonatal sepsis. VDR FokI T allele had lower 25-hydroxyvitamin D level that may predispose to sepsis hazards. PMID- 29530504 TI - Quantifying spatial and temporal variations of the cell membrane ultra-structure by bimFCS. AB - It has been long recognized that the cell membrane is heterogeneous on scales ranging from a couple of molecules to micrometers in size and hence diffusion of receptors is length scale dependent. This heterogeneity modulates many cell membrane-associated processes requiring transient spatiotemporal separation of components. The transient increase in local concentration of interacting signal components enables robust signaling in an otherwise thermally noisy system. Understanding how lipids and proteins self-organize and interact with the cell cortex requires quantifying the motion of the components. Multi-length scale diffusion measurements by single particle tracking, fluorescence correlation spectroscopy (FCS) or related techniques are able to identify components being transiently trapped in nanodomains, from freely moving one and from ones with reduced long-scale diffusion due to interaction with the cell cortex. One particular implementation of multi-length scale diffusion measurements is the combination of FCS with a spatially resolved detector, such as a camera and two dimensional extended excitation profile. The main advantages of this approach are that all length scales are interrogated simultaneously, uniquely permits quantifying changes to the membrane structure caused by extrenal or internal perturbations. Here, we review how combining total internal reflection microscopy (TIRF) with FC resolves the membrane organization in living cells. We show how to implement the method, which requires only a few seconds of data acquisition to quantify membrane nanodomains, or the spacing of membrane fences caused by the actin cortex. The choice of diffusing fluorescent probe determines which membrane heterogeneity is detected. We review the instrument, sample preparation, experimental and computational requirements to perform such measurements, and discuss the potential and limitations. The discussion includes examples of spatial and temporal comparisons of the membrane structure in response to perturbations demonstrating the complex cell physiology. PMID- 29530506 TI - Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists. AB - The atypical chemokine receptor ACKR3/CXCR7 plays crucial roles in numerous physiological processes but also in viral infection and cancer. ACKR3 shows strong propensity for activation and, unlike classical chemokine receptors, can respond to chemokines from both the CXC and CC families as well as to the endogenous peptides BAM22 and adrenomedullin. Moreover, despite belonging to the G protein coupled receptor family, its function appears to be mainly dependent on beta-arrestin. ACKR3 has also been shown to continuously cycle between the plasma membrane and the endosomal compartments, suggesting a possible role as a scavenging receptor. So far, the molecular basis accounting for these atypical binding and signalling properties remains elusive. Noteworthy, ACKR3 extracellular domains bear three disulphide bridges. Two of them lie on top of the two main binding subpockets and are conserved among chemokine receptors, and one, specific to ACKR3, forms an intra-N terminus four-residue-loop of so far unknown function. Here, by mutational and functional studies, we examined the impact of the different disulphide bridges for ACKR3 folding, ligand binding and activation. We showed that, in contrast to most classical chemokine receptors, none of the extracellular disulphide bridges was essential for ACKR3 function. However, the disruption of the unique ACKR3 N-terminal loop drastically reduced the binding of CC chemokines whereas it only had a mild impact on CXC chemokine binding. Mutagenesis also uncovered that chemokine and endogenous non-chemokine ligands interact and activate ACKR3 according to distinct binding modes characterized by different transmembrane domain subpocket occupancy and N terminal loop contribution, with BAM22 mimicking the binding mode of CC chemokine N terminus. PMID- 29530507 TI - Impairing energy metabolism in solid tumors through agents targeting oncogenic signaling pathways. AB - Cell metabolic reprogramming is one of the main hallmarks of cancer and many oncogenic pathways that drive the cancer-promoting signals also drive the altered metabolism. This review focuses on recent data on the use of oncogene-targeting agents as potential modulators of deregulated metabolism in different solid cancers. Many drugs, originally designed to inhibit a specific target, then have turned out to have different effects involving also cell metabolism, which may contribute to the mechanisms underlying the growth inhibitory activity of these drugs. Metabolic reprogramming may also represent a way by which cancer cells escape from the selective pressure of targeted drugs and become resistant. Here we discuss how targeting metabolism could emerge as a new effective strategy to overcome such resistance. Finally, accumulating evidence indicates that cancer metabolic rewiring may have profound effects on tumor-infiltrating immune cells. Modulating cancer metabolic pathways through oncogene-targeting agents may not only restore more favorable conditions for proper lymphocytes activation, but also increase the persistence of memory T cells, thereby improving the efficacy of immune-surveillance. PMID- 29530505 TI - Methods for construction and characterization of simple or special multifunctional RNA nanoparticles based on the 3WJ of phi29 DNA packaging motor. AB - The field of RNA nanotechnology has developed rapidly over the last decade, as more elaborate RNA nanoarchitectures and therapeutic RNA nanoparticles have been constructed, and their applications have been extensively explored. Now it is time to offer different levels of RNA construction methods for both the beginners and the experienced researchers or enterprisers. The first and second parts of this article will provide instructions on basic and simple methods for the assembly and characterization of RNA nanoparticles, mainly based on the pRNA three-way junction (pRNA-3WJ) of phi29 DNA packaging motor. The third part of this article will focus on specific methods for the construction of more sophisticated multivalent RNA nanoparticles for therapeutic applications. In these parts, some simple protocols are provided to facilitate the initiation of the RNA nanoparticle construction in labs new to the field of RNA nanotechnology. This article is intended to serve as a general reference aimed at both apprentices and senior scientists for their future design, construction and characterization of RNA nanoparticles based on the pRNA-3WJ of phi29 DNA packaging motor. PMID- 29530508 TI - Differential expression of CD73, CD86 and CD304 in normal vs. leukemic B-cell precursors and their utility as stable minimal residual disease markers in childhood B-cell precursor acute lymphoblastic leukemia. AB - BACKGROUND: Optimal discrimination between leukemic blasts and normal B-cell precursors (BCP) is critical for treatment monitoring in BCP acute lymphoblastic leukemia (ALL); thus identification of markers differentially expressed on normal BCP and leukemic blasts is required. METHODS: Multicenter analysis of CD73, CD86 and CD304 expression levels was performed in 282 pediatric BCP-ALL patients vs. normal bone marrow BCP, using normalized median fluorescence intensity (nMFI) values. RESULTS: CD73 was expressed at abnormally higher levels (vs. pooled normal BCP) at diagnosis in 71/108 BCP-ALL patients (66%), whereas CD304 and CD86 in 119/202 (59%) and 58/100 (58%) patients, respectively. Expression of CD304 was detected at similar percentages in common-ALL and pre-B-ALL, while found at significantly lower frequencies in pro-B-ALL. A significant association (p = 0.009) was found between CD304 expression and the presence of the ETV6-RUNX1 fusion gene. In contrast, CD304 showed an inverse association with MLL gene rearrangements (p = 0.01). The expression levels of CD73, CD86 and CD304 at day 15 after starting therapy (MRD15) were stable or higher than at diagnosis in 35/37 (95%), 40/56 (71%) and 19/41 (46%) cases investigated, respectively. This was also associated with an increased mean nMFI at MRD15 vs. diagnosis of +24 and +3 nMFI units for CD73 and CD86, respectively. In addition, gain of expression of CD73 and CD86 at MRD15 for cases that were originally negative for these markers at diagnosis was observed in 16% and 18% of cases, respectively. Of note, CD304 remained aberrantly positive in 63% of patients, despite its levels of expression decreased at follow-up in 54% of cases. CONCLUSIONS: Here we show that CD73, CD86 and CD304 are aberrantly (over)expressed in a substantial percentage of BCP-ALL patients and that their expression profile remains relatively stable early after starting therapy, supporting their potential contribution to improved MRD analysis by flow cytometry. PMID- 29530509 TI - Menopause in CKD. AB - Most women with dialysis-dependent chronic kidney disease (CKD) stage 5 (CKD stage 5D) are in the postmenopausal age group. Early menopause is reported for all CKD stages (stages 3-5D). The traditional definition of menopause is not applicable in CKD stage 5(D) because menses can resume with hormone replacement therapy or kidney transplantation. Treatment of vasomotor symptoms continues to be the primary indication for hormone replacement therapy, with no dosing studies done specifically for CKD or kidney transplantation populations. Similarly, the risk for cardiovascular disease and osteoporosis in menopause is well described in healthy women, but the role that menopause plays in accelerating the risk further in CKD/kidney transplantation is yet to be explored. Lack of data and specific guidance on management make the long-term effects of menopause one of the most under-recognized and neglected patient problems in clinical nephrology. The efficacy and side effects of widely available therapeutic options in healthy women for menopause-related clinical manifestations, be it hormone replacement therapy for vasomotor symptoms or antiresorptive agents for osteoporosis, are to be tested in kidney transplantation and CKD populations. Longitudinal clinical trials are in need to define menopause in CKD and determine the role that CKD plays in menopause transition and menopause on CKD manifestations. PMID- 29530510 TI - Exploring the interaction of silver nanoparticles with pepsin and its adsorption isotherms and kinetics. AB - The interaction of nanoparticles (NPs) with proteins is a topic of high relevance for the medical application of nanomaterials. In the study, a comprehensive investigation was performed for the binding properties of silver nanoparticles (AgNPs) to pepsin. The results indicate that the binding of AgNPs to pepsin may be a static quenching mechanism. Thermodynamic analysis reveals that AgNPs binds to pepsin is synergistically driven by enthalpy and entropy, and the major driving forces are hydrophobic and electrostatic interactions. Synchronous fluorescence spectroscopy shows that AgNPs may induce microenvironmental changes of pepsin. The hydrophobicity of Trp is increased while the hydrophility of Tyr is increased. The adsorption of pepsin on AgNPs was analyzed by Langmuir and Freundlich models, suggesting that the equilibrium adsorption data fit well with Freundlich model. The equilibrium adsorption data were modeled using the pseudo first-order and pseudo-second-order kinetic equations. The results indicate that pseudo-second-order kinetic equation better describes the adsorption kinetics. The study provides an accurate and full basic data for clarifying the binding mechanism, adsorption isotherms and kinetic behaviors of AgNPs with pepsin. These fundamental works will provide some new insights into the safe and effective application of AgNPs in biological and medical areas. PMID- 29530511 TI - Virtual simulation of an osseointegrated trans-humeral prosthesis: A falling scenario. AB - INTRODUCTION: Traditional prosthetic solutions expose the amputee to numerous problems that limit his ability to safely perform the normal activities of daily life. In order to eliminate the problems related to the use of the traditional prosthesis with socket, a new technique was developed for fixing the prosthesis to the amputees based on the principle of osseointegration. The aim of this paper is to study and analyze the stress distribution on the interface between a trans humeral osseointegrated prosthetic implant and the residual bone, identifying the most stressed areas and thus foreseeing possible failure phenomena of the entire prosthetic system and, after, to compare the stress distribution on three different prosthetic designs that differ from each other for some geometric characteristics. MATERIALS AND METHODS: A healthy individual mimics two fall scenarios of which the trans-humeral amputees can most likely be victims: Static fall and Dynamic fall. A force platform (P-6000, BTS Bioengineering) is required for load data acquisition. The CAD model of the trans-humeral osseointegrated implant was created following the guidelines of the OPRA implant. The bone model was created starting from the CAT scan of a left humerus. The FEM simulation was conducted throught a linear analysis. RESULTS: Both during static fall and dynamic fall, similar trends have been observed for the reaction force Fz, the torque moment Tz, the bending moments Mx and My. From the analysis of the von Mises stress distribution it was found that the stress distribution is more homogeneous in the case where the thread of the fixture is made by a triangular profile with height of the thread equal to 0.5 mm. However, it can be seen that, when passing from a thread with height of 0.5 mm to a 1 mm, there is a slight decrease in the stress on the whole contact zone between the fixture and the humerus. The same improvement can also be seen in the case of trapezoidal threading. CONCLUSION: By modifying the height and/or by varying the thread profile, are obtained slightly better results with respect to the case with a 0.5 mm height triangular thread. PMID- 29530512 TI - A prospective injury surveillance study in canyoning. AB - INTRODUCTION: Little is known about injuries in canyoning. It was the purpose of this study to determine injury rates, patterns, causes and risk factors in canyoning; and to identify targets for future injury prevention strategies. METHODS: From May to October 2015, 109 participants from 17 different countries were prospectively followed via a monthly e-mail-based questionnaire. RESULTS: During 13,690 h of canyoning, 57 injury-events occurred. The overall injury-rate was 4.2 injuries/1000 h of canyoning. The hand (23%) and lower leg and foot (25%) were most frequently involved. Most of the injuries were mild (n = 27, 49%) and limited to the soft-tissue. There were seven severe injuries (12%) with two lateral malleolar fractures, both necessitating surgery. The majority of injuries were due to material failure (44%) and significantly more injury-events were reported when the tour included rappelling (p = 0.037). Canyoning guides suffered from significantly less injuries compared to beginners and advanced canyoneers (p < 0.001). CONCLUSIONS: The majority of canyoning injuries are mild. On the other side, roughly one-tenth suffered from severe injury. Canyoning guides are less prone to injury-events and beginners should consider performing tours with experienced guides. Notwithstanding, rappelling was the most common activity associated with an injury and the material used was deemed causative for an injury-event in almost half of all cases. Further improvement in canyoning equipment, frequent equipment service, and instructional courses to ensure adequate employment of equipment might minimize the risk of getting injured. PMID- 29530513 TI - Minimally invasive plate osteosynthesis has equal safety to reamed intramedullary nails in treating Gustilo-Anderson type I, II and III-A open tibial shaft fractures. AB - OBJECTIVES: The best fixation method for open tibial fractures has long been a matter of debate, many studies have recommended the use of intramedullary nails over external fixation for treating such fractures, recent studies also showed favorable results for the use of plates in managing open tibial fractures. However, there are very few (if any) reports in the literature comparing the use of minimally invasive plate osteosynthesis to reamed intramedullary nails in the fixation of open tibial fractures. The aim of this study was to compare the safety & efficiency of minimally invasive plate osteosynthesis to reamed intramedullary nails in treating open tibial shaft fractures. DESIGN: A single center, parallel group, prospective, randomized study. SETTING: Academic Level 1 Trauma Center, during the period from October 2014 to December 2016. PATIENTS: A total of 60 patients with open tibial fractures were randomized to reamed intra medullary nails (R-IMN) (group A) or minimally invasive plate osteosynthesis (MIPO) (group B). OUTCOME MEASUREMENT: Patients were assessed for union (clinical & radiographic) & complications (e.g.; non-union, infection). RESULTS: No statistically significant differences were found between the 2 methods in term of the incidence of infection or non-union. Time to full union was shorter for the R IMN group when compared to that of the MIPO group & that was found to be statistically significant. CONCLUSION: MIPO technique has equal safety to R-IMN technique in treating Gustilo-Anderson type I, II and III-A open tibial shaft fractures, as both techniques have similar rate of infection & non-union. These findings suggest that the MIPO technique can be considered a valid treatment alternative for such fractures. LEVEL OF EVIDENCE: Level II, Therapeutic study. PMID- 29530514 TI - Functional outcomes following ultrasound-guided botulinum toxin type A injections to reduce spastic equinovarus in adult post-stroke patients. AB - OBJECTIVE: The aim of this study is to identify the effect on spasticity and walking of US-guided botulinum toxin type A (BoNT-A) injections administered to improve equinovarus walking pattern commonly observed in patients after stroke. MATERIAL AND METHOD: Twenty-three patients with post-stroke spastic equinovarus deformity were recruited. The US-guided BoNT-A injections were administered into the spastic muscles (including gastrocnemius; GK, soleus; S and tibialis posterior; TP) using a specific approach, and all of the patients were enrolled in rehabilitation programmes after the injections. Modified Ashworth Scale (MAS), Brunnstrom stage of lower limb, Functional Ambulation Score (FAS), Preferred Gait Speed (PGS) and the six-minute walk test (6MWT) were assessed at the baseline, 4 and 12 weeks after the BoNT-A injection. RESULTS: Significant decreases in the MAS scores of the lower limb muscle (GK, S and TP) tone were measured 4 and 12 weeks after the BoNT-A injection when compared to the baseline scores (p < 0.05). In parallel with a reduction in spasticity there was an increase in 6MWT and PGS in the 4th and 12th weeks. Increases in motor improvement and functional ambulation score were ensured in the 12th week (p < 0.05). CONCLUSION: Spastic equinovarus deformity observed in patients after stroke creates significant limitations in the patient's functional walking speed and distance. As a result, when BoNT-A injections accompanied by ultrasound to improve equinovarus deformity considering the innervation zones of the muscles with a specific approach are administered directly into the muscle at the correct point, we can say it provides hopeful results from a functional point of view. PMID- 29530515 TI - Use of Virtual Technology as an Intervention for Wheelchair Skills Training: A Systematic Review. AB - OBJECTIVE: To provide a comprehensive description of the current state of knowledge regarding the use of virtual technology (VT) for wheelchair skills training. DATA SOURCES: The Cochrane Library, MEDLINE, CINAHL, Embase, ACM, IEEE Xplore, Inspec, and Web of Science databases were searched for relevant articles from 1990 to February 2016. STUDY SELECTION: We included peer-reviewed studies or long conference proceedings that examined the use of VT as a medium to provide a wheelchair skills training intervention for any population with any diagnosis using any research design. One investigator screened the titles and abstracts, then 2 investigators independently reviewed the full-text articles. Disagreements regarding inclusion were resolved by consensus or a third reviewer. Ten studies were included out of 4994 initially identified. DATA EXTRACTION: Two investigators extracted data to systematically assess the studies' findings into 5 tables (study design and participant characteristics, equipment and technology used, intervention characteristics, outcome measures, and outcomes). DATA SYNTHESIS: Most studies demonstrated that VT wheelchair skills training showed improved outcomes (eg, simulation score, completion time, number of collisions) in the virtual environment and/or in the real world. However, subject characteristics, equipment, virtual environment, intervention tasks, and outcome measures varied across the studies. CONCLUSIONS: There are a variety of studies using VT as an intervention for wheelchair skills training. Given the positive outcomes for most of the studies, it appears as though VT may indeed be a solution that can help to alleviate barriers to wheelchair skills training and subsequently improve wheelchair user skill. PMID- 29530516 TI - Fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants. AB - The study of fear extinction represents an important example of translational neuroscience in psychiatry and promises to improve the understanding and treatment of anxiety and fear-related disorders. We present the results of a set of meta-analyses of human fear extinction studies in healthy participants, conducted with functional magnetic resonance imaging (fMRI) and reporting whole brain results. Meta-analyses of fear extinction learning primarily implicate consistent activation of brain regions linked to threat appraisal and experience, including the dorsal anterior cingulate and anterior insular cortices. An overlapping anatomical result was obtained from the meta-analysis of extinction recall studies, except when studies directly compared an extinguished threat stimulus to an unextinguished threat stimulus (instead of a safety stimulus). In this latter instance, more consistent activation was observed in dorsolateral and ventromedial prefrontal cortex regions, together with other areas including the hippocampus. While our results partially support the notion of a shared neuroanatomy between human and rodent models of extinction processes, they also encourage an expanded account of the neural basis of human fear extinction. PMID- 29530517 TI - Factors influencing spatial frequency extraction in faces: A review. AB - JEANTET, C., Caharel, S., Schwan, R., Lighezzolo-Alnot, J., and Laprevote, V. Factors influencing spatial frequencies extraction in faces: a review. NEUROSCI BIOBEHAV REV XX(X) XXX-XXX, 2017. Spatial frequency is an elementary aspect of visual perception. Moreover, faces elicit distinct responses by the human visual system when compared to other visual objects. This review examines the factors influencing spatial frequency processing in faces. Visual perception of a face results from the interaction between the physical properties of the stimulus and the human visual system. We first review the methodology of visual stimulus production and presentation in the assessment of spatial frequency processing in faces. Image properties interact with the physical constraints of the visual system. Other cognitive phenomena also drive the processing of spatial frequencies in faces. Finally, the observer's characteristics may further influence this spatial processing. Overall, the studies indicate that spatial frequency processing in faces is not a fixed process, conditioned by physical constraints alone, but a flexible process, dependent of various cognitive constraints, developmental, and health conditions. Finally, limitations and new challenges are discussed. PMID- 29530518 TI - Economic Evaluation of Antibacterial Coatings on Healthcare Costs in First Year Following Total Joint Arthroplasty. AB - BACKGROUND: Antibacterial coatings (ABCs) of implants have proven safe and effective to reduce postsurgical infection, but little is known about their possible economic impact on large-scale use. This study evaluated the point of economic balance, during the first year after surgery, and the potential overall annual healthcare cost savings of 3 different antibacterial technologies applied to joint arthroplasty: a dual-antibiotic-loaded bone cement (COPAL G + C), an antibacterial hydrogel coating (DAC), and a silver coating (Agluna). METHODS: The variables included in the algorithm were average cost and number of primary joint arthroplasties; average cost per patient of the ABC; incidence of periprosthetic joint infections and expected reduction using the ABCs; average cost of infection treatment and expected number of cases. RESULTS: The point of economic balance for COPAL G + C, DAC, and Agluna in the first year after surgery was reached in patient populations with an expected postsurgical infection rate of 1.5%, 2.6%, and 19.2%, respectively. If applied on a national scale, in a moderately high risk population of patients with a 5% expected postsurgical infection rate, COPAL G + C and DAC hydrogel would provide annual direct cost savings of approximately ?48,800,000 and ?43,200,000 (?1220 and ?1080 per patient), respectively, while the silver coating would be associated with an economic loss of approximately ?136,000,000. CONCLUSION: This economic evaluation shows that ABC technologies have the potential to decrease healthcare costs primarily by decreasing the incidence of surgical site infections, provided that the technology is used in the appropriate risk class of patients. PMID- 29530519 TI - Systematic Review of Three Electrical Stimulation Techniques for Rehabilitation After Total Knee Arthroplasty. AB - BACKGROUND: The comparative effectiveness of neuromuscular electrical stimulation (NMES), transcutaneous electrical nerve stimulation (TENS), and electroacupuncture (EA) for improving patient rehabilitation following total knee arthroplasty (TKA) is controversial. Therefore we conducted this systematic review to assess the available evidence. METHODS: The PubMed, OVID, and ScienceDirect databases were comprehensively searched and studies were selected and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Data were extracted and qualitatively synthesized for several outcomes. RESULTS: Data were analyzed from 17 randomized controlled trials involving 1285 procedures: 8 NMES studies (608 procedures), 7 TENS studies (560 procedures), and 2 EA studies (117 procedures). Qualitative analysis suggested that NMES was associated with higher quadriceps strength and functional recovery after TKA. Recovery benefits were maximal when the stimulation was performed once or twice a day for 4-6 weeks at an intensity of 100-120 mA and frequency of 30-100 Hz. The electrode should be sufficiently large (100-200 cm2) to reduce discomfort. TENS at an intensity of 15-40 mA and frequency of 70-150 Hz provided effective analgesia after TKA. EA at an intensity of 2 mA and frequency of 2 Hz may also provide postoperative analgesia of TKA. CONCLUSION: As adjunct modalities, NMES and TENS can effectively improve rehabilitation after TKA without triggering significant intolerance, and maximal benefits depend on optimized parameters and intervention protocols. EA may be an effective adjunct modality for analgesia after TKA. PMID- 29530520 TI - Influence of Assembly Force and Distraction on the Femoral Head-Taper Junction. AB - BACKGROUND: This study investigates if the placement of femoral heads (trials and actual implants) using varying impaction forces causes physical compromise to the trunnion. METHODS: Trunnion and head taper wear patterns were evaluated after impaction and removal of new femoral stem trunnions and ceramic heads at various impaction loads (2 kN, 4 kN, or 6 kN, n = 6/group). In addition, trunnion wear patterns were measured after plastic trials were hand-placed on new trunnions and underwent range of motion testing in a Hip Simulator (n = 5). RESULTS: There was no significant difference in trunnion or head surface deviation, taper angle, or surface roughness in any groups preimpaction and postimpaction and removal. There was no significant surface trunnion damage from assembly and range of motion testing of the plastic femoral head trial. CONCLUSIONS: The use of femoral head trials and the concurrent impaction and removal of a new femoral head were not associated with significant trunnion surface damage for the impaction loads observed in this study. PMID- 29530521 TI - Puncture Protocol in the Diagnostic Work-Up of a Suspected Chronic Prosthetic Joint Infection of the Hip. AB - BACKGROUND: Diagnosing a chronic prosthetic joint infection (PJI) can be challenging. We hypothesized that obtaining preoperative tissue samples for culture in hip arthroplasty will increase the likelihood of diagnosing an infection before revision surgery. The aim of this cohort study was to determine the diagnostic accuracy of 2 tissue acquiring biopsy strategies to diagnose a PJI. METHODS: Patients with a painful hip arthroplasty, in which a chronic PJI was suspected, were included. Tissue samples were obtained either by ultrasound guidance with a 16-Gauge needle (2012-2013) or in the operating room with a thick bore needle (2013-2016). Revision surgery tissue biopsies were used as the gold standard. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio were calculated. RESULTS: A total of 16 patients in the ultrasound cohort and 29 patients in the surgical cohort were included. Thirty-one percent (n = 14) were finally diagnosed with a PJI. The addition of thick bore needle tissue biopsies resulted in 9% more diagnosed PJIs compared with synovial fluid alone. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio was 33%, 85%, 33%, 85%, 2.2, and 0.8, respectively, for the ultrasound-guided biopsy cohort and 82%, 100%, 100%, 90%, infinite, and 0.2, respectively, for the surgical biopsy cohort. CONCLUSION: Obtaining multiple good quality tissue biopsies in a sterile environment will contribute to the diagnosis of a chronic PJI of the hip, with a higher diagnostic accuracy compared with ultrasound-guided thin needle biopsies and compared with synovial fluid culture alone. PMID- 29530522 TI - Evidence-Based Validation of Diagnostic Criteria for Periprosthetic Joint Infection: A Major Step Forward! PMID- 29530523 TI - Electrocardiographic changes and conduction disturbances after transfemoral aortic valve implantation with Edwards Sapien 3 prosthesis. AB - OBJECTIVES: The aim of this study is to describe electrocardiographic changes and conduction abnormalities in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: 76 patients who underwent TAVI using Edwards Sapien 3 prosthesis were included, comparing electrocardiographic registries at admission, post-procedure and before discharge. RESULTS: Patients after TAVI presented a longer PR interval, a wider QRS, and a longer corrected QT, with a left deviation of QRS axis and T waves; reversible changes that tended to correct in the following days after TAVI. Complete atrioventricular block incidence was 2.9%. New-onset left bundle branch block (LBBB) incidence was 39%, although solved in almost half of patients before discharge. CONCLUSIONS: TAVI was associated with different reversible electrocardiographic changes that suggest a transient impact on the conduction system. One of every five patients presented permanent LBBB after valve implant. PMID- 29530524 TI - Translational Control by Prion-like Proteins. AB - Prion-like proteins overlap with intrinsically disordered and low-complexity sequence families. These proteins are widespread, especially among mRNA-binding proteins. A salient feature of these proteins is the ability to form protein assemblies with distinct biophysical and functional properties. While prion-like proteins are involved in myriad of cellular processes, we propose potential roles for protein assemblies in regulated protein synthesis. Since proteins are the ultimate functional output of gene expression, when, where, and how much of a particular protein is made dictates the functional state of a cell. Recent finding suggests that the prion-like proteins offer unique advantages in translation regulation and also raises questions regarding formation and regulation of protein assemblies. PMID- 29530525 TI - Porphyromonas gingivalis is highly sensitive to inhibitors of a proton-pumping ATPase. AB - Porphyromonas gingivalis is a well-known Gram-negative bacterium that causes periodontal disease. The bacterium metabolizes amino acids and peptides to obtain energy. An ion gradient across its plasma membrane is thought to be essential for nutrient import. However, it is unclear whether an ion-pumping ATPase responsible for the gradient is required for bacterial growth. Here, we report the inhibitory effect of protonophores and inhibitors of a proton-pumping ATPase on the growth of P. gingivalis. Among the compounds examined, curcumin and citreoviridin appreciably reduced the bacterial growth. Furthermore, these compounds inhibited the ATPase activity in the bacterial membrane, where the A-type proton-pumping ATPase (A-ATPase) is located. This study suggests that curcumin and citreoviridin inhibit the bacterial growth by inhibiting the A-ATPase in the P. gingivalis membrane. PMID- 29530526 TI - Levels of tight junction protein CLDND1 are regulated by microRNA-124 in the cerebellum of stroke-prone spontaneously hypertensive rats. AB - The claudin family shows organ- and tissue-specific expression of individual members. Deficiency or aberrant expression of distinct claudins has been reported to be associated with severe pathophysiological consequences. Claudin domain containing 1 (CLDND1), also known as claudin-25, shows homology to this family of proteins. Furthermore, serum CLDND1-derived peptide antibody levels are elevated in patients with cerebral infarction, as compared with healthy controls. We previously reported that, in the adult murine brain, CLDND1 is abundantly expressed in the cerebellum in common sites of intracerebral hemorrhage, and CLDND1 levels are transiently decreased after hemorrhagic insult. However, regulation of CLDND1 expression levels in cerebrovascular disease is poorly studied, and most regulatory microRNAs remain to be defined. We assessed its expression level, according to the presence of early signs of cerebrovascular disease, in the brain of stroke-prone spontaneously hypertensive rats (SHRSPs) and investigated the microRNA regulation of Cldnd1 mRNA. We investigated the post transcriptional regulation of Cldnd1 by examining the subcellular distribution of its mRNA and evaluating its translational regulation by microRNA in human brain endothelial cells (HBECs) and in the brain of SHRSPs. Using bioinformatics, we identified a conserved microRNA-124 (miR-124)-binding site in the 3'-untranslated region of Cldnd1 and demonstrated that miR-124 regulates the translation of Cldnd1 mRNA reporters in a sequence-specific manner in luciferase assays. HBECs transfected with an miR-124 mimic showed decreased levels of CLDND1 mRNA in reverse transcription quantitative PCR. miR-124 levels were markedly lower in SHRSP than in Wister Kyoto rat brains, whereas Cldnd1 mRNA and protein levels were significantly higher. In SHRSP brains, Cldnd1 mRNA levels increased with a decrease in miR-124. Therefore, by interacting with Cldnd1 mRNA, miR-124 influences CLDNL1 levels in the brain, thus playing a role in the development of cerebrovascular disease in SHRSPs. PMID- 29530527 TI - Stimulation of white adipose tissue lipolysis by xenin, a neurotensin-related peptide. AB - Xenin is a gastrointestinal hormone that belongs to the neurotensin family. Central administration of xenin to obese mice reduces food intake and body weight gain and causes alterations in the expression of lipid metabolism-related genes and proteins in white adipose tissue (WAT). However, it has not been tested whether or not xenin directly acts on adipose tissue and alters lipid metabolism. The present study was performed to address this possibility by examining the effect of xenin treatment on the levels of glycerol and free fatty acids (FFA) and expression levels of lipolysis marker proteins ex vivo in cultured mouse WAT. Xenin treatment significantly increased concentrations of glycerol and FFA in culture media and increased phosphorylation of hormone sensitive lipase (HSL) in ex vivo cultured WAT. These findings support the hypothesis that xenin directly acts on adipose tissues and stimulates lipolysis. Thus, enhancement of xenin action and its downstream signaling may offer a novel and effective therapy for obese patients by reducing the amount of stored fat in adipose tissue. PMID- 29530528 TI - Regulation by commensal bacteria of neurogenesis in the subventricular zone of adult mouse brain. AB - In the mouse olfactory bulb (OB), interneurons such as granule cells and periglomerular cells are continuously replaced by adult-born neurons, which are generated in the subventricular zone (SVZ) of the brain. We have now investigated the role of commensal bacteria in regulation of such neuronal cell turnover in the adult mouse brain. Administration of mixture of antibiotics to specific pathogen-free (SPF) mice markedly attenuated the incorporation of bromodeoxyuridine (BrdU) into the SVZ cells. The treatment with antibiotics also reduced newly generated BrdU-positive neurons in the mouse OB. In addition, the incorporation of BrdU into the SVZ cells of germ-free (GF) mice was markedly reduced compared to that apparent for SPF mice. In contrast, the reduced incorporation of BrdU into the SVZ cells of GF mice was recovered by their co housing with SPF mice, suggesting that commensal bacteria promote the incorporation of BrdU into the SVZ cells. Finally, we found that administration of ampicillin markedly attenuated the incorporation of BrdU into the SVZ cells of SPF mice. Our results thus suggest that ampicillin-sensitive commensal bacteria regulate the neurogenesis in the SVZ of adult mouse brain. PMID- 29530529 TI - Lamellipodial wrinkles in fish keratocytes as markers of imperfect coordination between extension and retraction during cell migration. AB - Cell migration involves the precise coordination between extension at the front of the cell and retraction at the rear. This coordination is particularly evident in fast moving cells such as fish keratocytes, where it leads to highly stable gliding motion, propelled at the front by broad, 0.1-0-2 MUm thick lamellipodia. Transient uncoupling between extension and retraction can occur if the rear is temporarily stuck, which might eventually lead to cell shape instabilities. We have frequently observed in fish keratocytes the presence of lamellipodial radial wrinkles, detected by confocal, scanning electron and side-view microscopy as folds in the lamellipodium up to 2 MUm in height. Using a linear finite elements analysis, we simulated the displacement of cells either with perfect coordination between extension and retraction or with the rear transiently stuck while the front continues extending, and we observed that in this last condition compression stresses arise in the lamellipodium which predict the formation of the observed pattern of lamellipodial wrinkles. In support of the numerical modeling findings, we observed that the transient halting of retraction at the rear using micromanipulation induced the formation of lamellipodial wrinkles in previously flat lamellipodia. The obtained results suggest that the conspicuous lamellipodial wrinkles observed in migrating fish keratocytes are the product of transient imbalances between front and rear displacements, and are therefore useful markers of the short scale dynamics of extension and retraction coordination during cell migration. PMID- 29530530 TI - Membrane-acting bacteriocin purified from a soil isolate Pediococcus pentosaceus LB44 shows broad host-range. AB - Bacteriocin LB44 was purified from cell-free supernatant (CFS) of Pediococcus pentosaceus LB44 using activity-guided chromatography techniques. It was stable up to 121 degrees C, pH 2.0-6.0, sensitive to proteinase K, papain and trypsin, and retained complete activity in the presence of organic solvents tested. The molecular weight of bacteriocin was ~6 kDa and initial ten amino acid residues (GECGMCXECG) suggested a new compound. The loss in viable cell count and K+ ion efflux of target cells of Micrococcus luteus suggested bactericidal activity. The cell membrane of bacteriocin-treated cells was found to be ruptured which was further confirmed by Fourier Transform Infrared (FTIR) analysis suggesting interaction of bacteriocin with phospholipids in cell membrane. It showed broad host-range and inhibited the growth of Lactobacillus delbrueckii NRRL B-4525, L. plantarum NRRL B-4496, L. acidophilus NRRL B-4495, Enterococcus hirae LD3, Weissella confusa LM85, Staphylococcus aureus, Salmonella typhi ATCC 13311, Serratia marcescens ATCC 27137, Pseudomonas aeruginosa ATCC 27853, Proteus vulgaris ATCC 29905, Haloferax larsenii HA1, HA3, HA8, HA9 and HA10. These properties suggested a new bacteriocin from soil isolate P. pentosaceus LB44 which may offers possible applications in food-safety and therapeutics. PMID- 29530531 TI - Alpha-helical domain from IL-8 of salmonids: Mechanism of action and identification of a novel antimicrobial function. AB - In this work, the potential antimicrobial role and mechanism of action of alpha helix domain of trout and salmon IL-8 against Eschericia coli, Pseudomonas aeruginosa and Staphylococcus aureus was investigated. By an in silico analysis of the primary structure of IL-8 from Oncorhynchus mykiss and salmo salar, it was evidenced that gamma-core motif was present, as in the vast majority of kinocidins. The alpha-helix domain of IL-8 (alphaIL-8) was synthesized by solid phase peptide synthesis and showed a tendency to form an alpha-helix conformation, as revealed by circular dichroism. Additionally, it was demonstrated that alphaIL-8 from both species showed antimicrobial activity against E. coli, P. aeruginosa and S. aureus. Membrane permeabilization and co localization assay, as well as scanning electron microscopy, showed that these peptides were accumulated on the cell surface and in the cytoplasm, suggesting that they were capable of permeabilizing and disrupt the bacterial membranes and interact with cytoplasmic components. Our results represent the first analysis on the antimicrobial function of IL-8-derived peptide from salmonids. PMID- 29530532 TI - The dilemma of diagnosing coenzyme Q10 deficiency in muscle. AB - BACKGROUND: Coenzyme Q10 (CoQ10) is an important component of the mitochondrial respiratory chain (RC) and is critical for energy production. Although the prevalence of CoQ10 deficiency is still unknown, the general consensus is that the condition is under-diagnosed. The aim of this study was to retrospectively investigate CoQ10 deficiency in frozen muscle specimens in a cohort of ethnically diverse patients who received muscle biopsies for the investigation of a possible RC deficiency (RCD). METHODS: Muscle samples were homogenized whereby 600 *g supernatants were used to analyze RC enzyme activities, followed by quantification of CoQ10 by stable isotope dilution liquid chromatography tandem mass spectrometry. The experimental group consisted of 156 patients of which 76 had enzymatically confirmed RCDs. To further assist in the diagnosis of CoQ10 deficiency in this cohort, we included sequencing of 18 selected nuclear genes involved with CoQ10 biogenesis in 26 patients with low CoQ10 concentration in muscle samples. RESULTS: Central 95% reference intervals (RI) were established for CoQ10 normalized to citrate synthase (CS) or protein. Nine patients were considered CoQ10 deficient when expressed against CS, while 12 were considered deficient when expressed against protein. In two of these patients the molecular genetic cause could be confirmed, of which one would not have been identified as CoQ10 deficient if expressed only against protein content. CONCLUSION: In this retrospective study, we report a central 95% reference interval for 600 *g muscle supernatants prepared from frozen samples. The study reiterates the importance of including CoQ10 quantification as part of a diagnostic approach to study mitochondrial disease as it may complement respiratory chain enzyme assays with the possible identification of patients that may benefit from CoQ10 supplementation. However, the anomaly that only a few patients were identified as CoQ10 deficient against both markers (CS and protein), while the majority of patients where only CoQ10 deficient against one of the markers (and not the other), remains problematic. We therefore conclude from our data that, to prevent possibly not diagnosing a potential CoQ10 deficiency, the expression of CoQ10 levels in muscle on both CS as well as protein content should be considered. PMID- 29530533 TI - Fabry disease revisited: Management and treatment recommendations for adult patients. AB - Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient alpha-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team. PMID- 29530534 TI - Plasma chitotriosidase activity versus plasma glucosylsphingosine in wide spectrum of Gaucher disease phenotypes - A statistical insight. AB - Deficiency of beta-glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Macrophages activated by accumulated GlcCer secrete chitotriosidase. Plasma chitotriosidase activity is significantly elevated in patients with active GD and has been suggested to indicate total body Gaucher cell load. There are two biomarkers used to assess the severity of GD - chitotriosidase has been measured for over 20 years, and deacylated GlcCer, known as glucosylsphingosine (GlcSph) is thought to be even more adequate, as it is almost a direct storage substrate. In this paper we focused entirely on statistical analysis, performing a thorough search of possible relations, dependencies and differences in the levels of these two biomarkers in a cohort of 64 Polish GD patients. We found that the treatment of GD with enzyme replacement therapy (ERT) changes the distribution of the disease biomarkers; their levels follow a normal distribution only in untreated patients. The variable "disease biomarker level" was found dependent of the binary variable "treated with ERT or not". It was found independent of the following variables: "disease type", "splenectomized or not", and "heterozygous for 24-bp duplication for CHIT1 variant" or "CHIT1 wild type". An almost perfect linear correlation (coefficient of determination R2 = 0.99) between the chitotriosidase activity and GlcSph level was revealed in splenectomized patients. PMID- 29530535 TI - High Expression of Collagen XVII Compensates for its Depletion Induced by Pemphigoid IgG in the Oral Mucosa. AB - The basement membrane zone consists of multiple components, including collagen XVII (COL17), which is the target of bullous pemphigoid. To our knowledge, no research has addressed the differences in basement membrane zone components between the skin and oral mucosa; therefore, we investigated the basement membrane zone proteins, with a focus on COL17. The mRNA and protein expression levels of COL17 were significantly higher in oral keratinocytes than in skin keratinocytes. Hemidesmosomal COL17 expression was markedly higher in oral keratinocytes than in skin keratinocytes, and its level was associated with adhesion strength. Oral keratinocytes adhered to the extracellular matrix more tightly than did skin keratinocytes in vitro. Based on these results, we attempt to explain the clinical diversity of bullous pemphigoid. COL17 depletion was more prominent in skin keratinocytes than in oral keratinocytes after treatment with COL17-NC16A mAbs, which have in vivo pathogenicity. COL17 C-terminus mAbs, which are not pathogenic, facilitated COL17 depletion in combination treatment with COL17-NC16A mAbs in both types of keratinocytes. In summary, the greater amount of COL17 in oral keratinocytes than in skin keratinocytes is associated with the higher strength of oral keratinocyte hemidesmosomal adhesion at the basement membrane zone. Our results may explain why bullous pemphigoid blistering tends to be more prevalent in the skin than in the oral mucosa. PMID- 29530536 TI - GPCR Kinase (GRK)-2 Is a Key Negative Regulator of Itch: l-Glutamine Attenuates Itch via a Rapid Induction of GRK2 in an ERK-Dependent Way. AB - Many itch mediators activate GPCR and trigger itch via activation of GPCR mediated signaling pathways. GPCRs are desensitized by GPCR kinases (GRKs). The aim of this study is to explore the role of GRKs in itch response and the link between GRKs and glutamine, an amino acid previously shown to be an itch reliever. Itch responses were evoked by histamine, chloroquine, and dinitrochlorobenzene-induced contact dermatitis (CD). Phosphorylation and protein expression were detected by immunofluorescent staining and Western blotting. GRK2 knockdown using small interfering RNA enhanced itch responses evoked by histamine, chloroquine, and dinitrochlorobenzene-induced CD, whereas GRK2 overexpression using GRK2-expressing adenovirus reduced the itch responses. Glutamine reduced all itch evoked by histamine, chloroquine, and dinitrochlorobenzene-induced CD. Glutamine-mediated inhibition of itch was abolished by GRK2 knockdown. Glutamine application resulted in a rapid and strong expression of GRK2 in not only dinitrochlorobenzene-induced CD (within 10 minutes) but also cultured rat dorsal root ganglion cells, F11 (within 1 minute). ERK inhibitor abrogates glutamine-mediated GRK2 expression and inhibition of itch in dinitrochlorobenzene-induced CD. Our data indicate that GRK2 is a key negative regulator of itch and that glutamine attenuates itch via a rapid induction of GRK2 in an ERK-dependent way. PMID- 29530537 TI - Effect-based monitoring of the Danube River using mobile passive sampling. AB - Many aquatic pollutants can be present at low concentrations, but their mixtures can still affect health or behavior of exposed organisms. In this study, toxicological and chemical analyses were combined for spatial contamination profiling using an innovative passive sampling approach. A novel Dynamic Passive Sampler (DPS) was employed as a mobile sampler from a ship cruising along 2130km of the Danube river during the Joint Danube Survey 3 (JDS3). The sampling was performed in eight subsequent river stretches with two types of complementary passive samplers: silicone rubber sheets (SR) used for non-polar chemicals and SDB-RPS EmporeTM disks (ED) for more hydrophilic compounds. Besides extensive chemical analyses, the bioactivity of samples was characterized by a battery of reporter gene bioassays. Cross-calibration of the employed passive samplers enabled robust estimation of water concentrations applicable for compounds with a wide range of physicochemical properties. DPS was suitable for sampling of water contaminants even at pgL-1 levels, with 209 of 267 analyzed compounds detected in the samples. Biological effects were detected in both ED and SR extracts across all river stretches by bioassays focused on xenobiotic metabolism mediated by the aryl hydrocarbon and pregnane X receptors, endocrine disruptive potential mediated by estrogen and androgen receptors and the oxidative stress response. The bioassay responses expressed as bioanalytical equivalent concentrations (BEQbio) were comparable with data obtained from large volume active sampling. The extracts of the ED samplers were more biologically active than extracts of SR samplers. Except of estrogenicity, where the analyzed chemicals explained on average 62% of the effects in ED samples, the detected chemicals explained <8% of BEQbio values. The study shows the utility of the combination of the innovative passive sampling approach with effect-based tools for efficient and fast monitoring even in water bodies with relatively low levels of contamination. PMID- 29530538 TI - Fooled by savouriness? Investigating the relationship between savoury taste and protein content in familiar foods. AB - Selecting savoury foods after consuming a protein depleted diet has been suggested to reflect protein seeking behaviour. The modern diet contains a large number of processed foods, many of which are highly savoury to taste, but not necessarily high in protein. The present two studies aimed to investigate the relationship between savoury taste and protein content (actual and participant estimated). Participants (S1 n = 20, S2 n = 37) completed 100 mm VAS ratings of sensory and nutritional qualities of 18 familiar foods, categorised as sweet low protein, savoury low protein and savoury high protein. In study 2, the individual foods were blended to a fine consistency to disguise their identity and ensure ratings were based primarily on taste. Multilevel linear regression was used to test associations between savoury taste and actual protein content. Protein content did not predict savoury taste rating, irrespective of category. The results also indicated that participants were generally accurate at estimating the protein content of foods, although there was a tendency towards overestimation. The magnitude of this error was increased in low protein savoury foods. Specifically, there was a shift in the spread of estimation scores which showed a greater level of overestimation in some blended compared to unblended foods, and predominantly in savoury foods which participants could not identify. These results provide evidence that savoury taste and protein content are not well linked in the current food environment, but taste may guide nutrient estimations about certain unidentified foods. PMID- 29530539 TI - Focal immune-related pancreatitis occurring after treatment with programmed cell death 1 inhibitors: a distinct form of autoimmune pancreatitis? PMID- 29530540 TI - Immune checkpoint therapy in proteinuric kidney disease. PMID- 29530541 TI - Comparison of feature representations in MRI-based MCI-to-AD conversion prediction. AB - Alzheimer's disease (AD) is a progressive neurological disorder in which the death of brain cells causes memory loss and cognitive decline. The identification of at-risk subjects yet showing no dementia symptoms but who will later convert to AD can be crucial for the effective treatment of AD. For this, Magnetic Resonance Imaging (MRI) is expected to play a crucial role. During recent years, several Machine Learning (ML) approaches to AD-conversion prediction have been proposed using different types of MRI features. However, few studies comparing these different feature representations exist, and the existing ones do not allow to make definite conclusions. We evaluated the performance of various types of MRI features for the conversion prediction: voxel-based features extracted based on voxel-based morphometry, hippocampus volumes, volumes of the entorhinal cortex, and a set of regional volumetric, surface area, and cortical thickness measures across the brain. Regional features consistently yielded the best performance over two classifiers (Support Vector Machines and Regularized Logistic Regression), and two datasets studied. However, the performance difference to other features was not statistically significant. There was a consistent trend of age correction improving the classification performance, but the improvement reached statistical significance only rarely. PMID- 29530542 TI - Re: Almassi et al.: Use of 99mTc-Sestamibi Single-photon Emission Computed Tomography / X-ray Computed Tomography in the Diagnosis of Hybrid Oncocytic / Chromophobe Tumor in a Pediatric Patient. (Urology 2018;113:206-208). PMID- 29530543 TI - Nurse-Led HIV PEP Program Used by Men at High Risk for HIV Seroconversion. AB - We trialed a nurse-led HIV postexposure prophylaxis (PEP) program in two sexually transmitted infection clinics in Ottawa, Canada. From September 5, 2013 to September 4, 2015, 112 persons sought PEP: 103 were male, of whom 84 were men who have sex with men (MSM). Seventy-two patients (59 MSM) initiated PEP; 11 were diagnosed with HIV: 6 diagnoses occurred during initial assessment (all MSM; 1 also shared injection equipment); 5 MSM were diagnosed with HIV within 1 year of seeking PEP. This level of positivity indicated that, when access is facilitated, individuals at high risk of HIV seek PEP. However, the 8.5% of MSM who seroconverted within a year of taking PEP demonstrated that this group remained at risk and needed additional prevention services. Delivery of PEP should include provision of medication, as well as an opportunity to address individual-level HIV risk strategies and population-level syndemic conditions that contribute to ongoing HIV transmission among MSM. PMID- 29530544 TI - Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan - Results of a randomised, multicentre phase 3 study. AB - The objective of this open-label, randomised (i.e. 2:1 ratio), Phase 3 study was to compare the efficacy and safety of tedizolid phosphate 200 mg, once-daily treatment with that of linezolid 600 mg, twice-daily treatment for 7-14 days in Japanese adult patients (N = 125) with skin and soft tissue infections (SSTIs) and/or for 7-21 days for those with SSTI-related bacteraemia, caused by confirmed or highly suspected methicillin-resistant Staphylococcus aureus (MRSA). Primary outcome was clinical cure rate at test-of-cure (TOC, in SSTI: 7-14 days, in bacteraemia: 4-6 weeks after end-of-therapy [EOT]) time point in the microbiologically evaluable MRSA (ME-MRSA) population (N = 39). Secondary endpoints were clinical and microbiological response rates at EOT. Safety parameters were evaluated in the safety analysis population up to follow up. Data analysis was descriptive in nature. Baseline characteristics of patients were similar between treatment groups. At TOC in the ME-MRSA population, clinical cure rate was similar in tedizolid phosphate (92.6%) and linezolid (88.9%) groups. At EOT, clinical cure (tedizolid phosphate: 93.1%, linezolid: 90.0%) and microbiological success (tedizolid phosphate: 93.1%, linezolid: 100.0%) rates were similar in the ME-MRSA population. Both treatments were well tolerated; overall treatment-emergent adverse events (TEAEs) in tedizolid phosphate (79.5%) and linezolid (75.6%) treatment groups were similar. Drug-related TEAEs were numerically lower with tedizolid phosphate versus linezolid (30.1%; 39.0%, respectively), as well as gastrointestinal (21.7%; 26.8%) and myelosuppression related (2.4%; 22.0%) TEAEs. One death occurred in the linezolid group. Tedizolid phosphate may be an appropriate antibiotic for the treatment of SSTIs in Japanese adult patients. International clinical trial registration number: NCT01967225. Japanese clinical trial registration number: JapicCTI-132308. PMID- 29530545 TI - Biomimetic synthesis and evaluation of histidine-derivative templated chiral mesoporous silica for improved oral delivery of the poorly water-soluble drug, nimodipine. AB - In this study, spherical shaped chiral mesoporous silica nanoparticles (CMS) was biomimetic synthesized using histidine derivatives (C16-L-histidine) as template via the sol-gel reaction and employed as poorly water-soluble drug nimodipine (NMP) carrier. Characteristics of CMS and its application as drug carrier were intensively investigated and compared with MCM41. Then NMP was respectively loaded into CMS and MCM41 with the drug: carrier weight ratio of 2:1. Structural features of NMP before and after drug loading were systemically characterized. The results demonstrated that hydrogen bonds were formed between NMP and carriers during the drug loading process. After drug loading, crystalline state of NMP effectively converted into modification L and amorphous state, and the first form turned out to be easily removed by washing. On the other hand, drug dissolution rate was significantly improved after drug loading, and the best result came from NMP-C3 sample. It was able to release 17.83% of drug within 60 min, which was 6.8 fold higher than the release amount of pure NMP. Undoubtedly, NMP-C3 presented the highest relative bioavailability (386.22%), and the best therapeutic effect. Meanwhile, CMS improved the brain distribution of NMP in vivo. PMID- 29530546 TI - Body mass index represents a good predictor of vitamin D status in women independently from age. AB - BACKGROUND & AIMS: Vitamin D is a pleiotropic hormone targeting several tissues and is involved in basic homeostatic processes, including bone mineralization, immune response and muscle strength. Although hypovitaminosis D is common in Europe and North America, representing a risk factor for several chronic diseases, the contribution of factors other than sun exposure is largely underestimated. METHODS: In our study, we retrospectively collected data from medical records of women with age between 19 and 80 screened in Central Italy (42 degrees N) for increased risk of metabolic syndrome. Vitamin D status was evaluated by serum 25-hydroxyvitamin D (25(OH)D) measurement and the association among vitamin D status and anthropometric and clinic variables was tested by multivariate logistic analysis. RESULTS: More than 80% of women presented serum 25(OH)D concentration lower than 30 ng/mL (75 nM), with the majority of values falling between 10 and 20 ng/mL. 25(OH)D concentration was dependent on season, with the highest 25(OH)D mean value measured in September and the lowest mean value in March. Among different clinical characteristics, body mass index (BMI) demonstrated the highest significant inverse correlation with serum 25(OH)D values, independently from season and age. Serum 25(OH)D values demonstrated a seasonal-directed sinusoidal trend and they raised during spring/summer in a similar manner in both obese and non-obese women. However, the obese group had lower mean values of vitamin D respect to overweight and to normal weight groups in both winter and summer, reaching frequently the status of vitamin D deficiency (<10 ng/mL). CONCLUSIONS: In conclusion, at our latitude, seasonal UV irradiance availability determines an obligate sinusoidal trend in vitamin D status. However, body mass is able to reduce proportionally circulating vitamin D over calendar months determining vitamin D deficiency. These results suggest taking in particular account BMI in clinical management of vitamin D status in overweight and obese women. PMID- 29530547 TI - Selenium intake and metabolic syndrome: A systematic review. AB - BACKGROUND & AIMS: Metabolic syndrome is a multi-causal disease. Its treatment includes lifestyle changes with a focus on weight loss. This systematic review assessed the association between Selenium intake and metabolic syndrome. METHODS: Data were collected mainly from four databases: PubMed, CENTRAL (Cochrane), Scopus and Web of Knowledge. Keywords related to metabolic syndrome, selenium, as well as metabolic syndrome features were searched. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. A systematic review protocol was registered at PROSPERO (n. 42016046321). Two reviewers independently screened 2957 abstracts. Six studies were included to perform data extraction with standardized spreadsheets. The risk of bias was assessed by using specific tools according to the design of the relevant studies. An assessment was carried out based on the appropriateness of the study reports accordingly to STROBE and the CONSORT-based checklist for each study design. RESULTS: Three studies found no association between Selenium intake and metabolic syndrome; two of them found an inverse association; and one study found a direct association between Selenium intake and metabolic syndrome. One study also showed an inverse association between Selenium intake and the prevalence of high waist circumference, high diastolic blood pressure, and hyperglycaemia in women. CONCLUSIONS: Overall, based on the argumentation and results of this study, it is possible to conclude that Selenium intake and metabolic syndrome are not clearly associated in adults and elderly. PMID- 29530548 TI - Chinese mitten crab (Eriocheir sinensis) iron-sulphur cluster assembly protein 2 (EsIscA2) is differentially regulated after immune and oxidative stress challenges. AB - Iron-sulphur clusters (ISCs), one of the oldest and most versatile cofactors of proteins, are involved in catalysis reactions, electron transport reactions, regulation processes as well as sensing of ambient conditions. Iron-sulphur cluster assembly protein (IscA) is a scaffold protein member of ISC formation system, which plays a significant role in the assembly and maturation process of ISC proteins. In the present study, the cDNA sequence of iron-sulphur cluster assembly protein 2 (designated as EsIscA2) was cloned from Eriocheir sinensis. The open reading frame (ORF) of EsIscA2 was of 507 bp, encoding a peptide of 168 amino acids with a typically conserved Fe-S domain. A tetrameric form was predicated by the SWISS-MODEL prediction algorithm, and three conserved cysteine residues (Cys-93, Cys-158, Cys-160) from each IscA monomer were predicted to form a 'cysteine pocket'. The deduced amino acid sequence of EsIscA2 shared over 50% similarity with that of other IscAs. EsIscA2 was clustered with IscA2 proteins from invertebrates and vertebrates, indicating that the protein was highly conservative in the evolution. rEsIscA2 exhibited a high iron binding affinity in the concentration ranging from 2 to 200 MUM. EsIscA2 transcripts were detected in all the tested tissues including gonad, hemocytes, gill, muscle, heart, hepatopancreas and eyestalk, and EsIscA2 protein was detected in the mitochondria of hemocytes. The highest mRNA expression level of EsIscA2 was detected in muscle and hepatopancreas, which was about 34.66-fold (p < 0.05) and 27.07-fold (p < 0.05) of that in hemocytes, respectively. After Aeromonas hydrophila and lipopolysaccharide (LPS) stimulations, the mRNA expression of EsIscA2 in hemocytes was down-regulated and reached the lowest level at 24 h (0.31-fold, p < 0.05) and 48 h (0.29-fold, p < 0.05) compared to control group, respectively. And the expression of EsIscA2 mRNA in hepatopancreas was repressed from 6 h to 48 h post stimulation (p < 0.05). When the primary cultured crab hemocytes were incubated with different concentrations of H2O2 for 15 min, the expression level of EsIscA2 mRNA was significantly repressed to the 0.34-0.44-fold of that in the control group. After A. hydrophila stimulation, the mRNA expression of EsGrx2 was up-regulated at 3 h (3.22-fold compared to control group, p < 0.05) and reached the peak at 12 h (4.88-fold, p < 0.05). All these results suggested that EsIscA2 had iron-binding capabilities as observed in IscA proteins from other organisms, supporting the role of EsIscA2 as a mitochondrial iron donor for ISC synthesis in Chinese mitten crab. Its differential mRNA expression after immune and oxidative stress challenges suggested the adaptations of ISC synthesis rates to these stress conditions. PMID- 29530549 TI - Glucocorticoid receptor selectively mediates stress-induced suppression of innate immunity in the House Sparrow, Passer domesticus. AB - Stress-induced inhibition of innate immune activity is widespread in free-ranging birds, but the mechanisms that are responsible for this inhibition are poorly understood. We previously demonstrated that an increase in plasma corticosterone (CORT), the primary avian glucocorticoid, is necessary for the inhibition of natural antibody- and complement-mediated as well as bactericidal activities to occur during stress. Here we investigated the role of glucocorticoid receptors in stress-induced inhibition of natural antibody- and complement-mediated activities and bactericidal activity within non-genomic (<10 min) and genomic (<120 min) time frames in male House Sparrows, Passer domesticus. Treatment with the selective glucocorticoid receptor antagonist mifepristone (RU486) attenuated stress-induced suppression of natural antibody-mediated activity within 10 min and 120 min of experimental stress. By contrast, this treatment did not influence stress-induced suppression of complement-mediated or bactericidal activity. These results suggest that stress-induced elevated plasma CORT inhibits natural antibody-mediated activity, but not complement-mediated or bactericidal activity, by activating glucocorticoid receptors, and that both non-genomic and genomic mechanisms underlie this activation. Additional research is needed to identify the receptors that regulate inhibitory effects of elevated plasma CORT on complement-mediated and bactericidal activity. PMID- 29530550 TI - Fingolimod inhibits brain atrophy and promotes brain-derived neurotrophic factor in an animal model of multiple sclerosis. AB - Longitudinal brain atrophy quantification is a critical efficacy measurement in multiple sclerosis (MS) clinical trials and the determination of No Evidence of Disease Activity (NEDA). Utilising fingolimod as a clinically validated therapy we evaluated the use of repeated brain tissue volume measures during chronic experimental autoimmune encephalomyelitis (EAE) as a new preclinical efficacy measure. Brain volume changes were quantified using magnetic resonance imaging (MRI) at 7 Tesla and correlated to treatment-induced brain derived neurotrophic factor (BDNF) measured in blood, cerebrospinal fluid, spinal cord and brain. Serial brain MRI measurements revealed slow progressive brain volume loss in vehicle treated EAE mice despite a stable clinical score. Fingolimod (1 mg/kg) significantly ameliorated brain tissue atrophy in the cerebellum and striatum when administered from established EAE disease onwards. Fingolimod-dependent tissue preservation was associated with induction of BDNF specifically within the brain and co-localized with neuronal soma. In contrast, therapeutic teriflunomide (3 mg/kg) treatment failed to inhibit CNS autoimmune mediated brain degeneration. Finally, weekly anti-IL-17A antibody (15 mg/kg) treatment was highly efficacious and preserved whole brain, cerebellum and striatum volume. Fingolimod-mediated BDNF increases within the CNS may contribute to limiting progressive tissue loss during chronic neuroinflammation. PMID- 29530551 TI - Re-thinking the paradox as catalyzed processing: Enjoyment of sadness in music as facilitated emotional processing: Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29530552 TI - Sad music and self-reflection: Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29530553 TI - [Extragenital endometriosis: Parietal, thoracic, diaphragmatic and nervous lesions. CNGOF-HAS Endometriosis Guidelines]. AB - According to some studies, extragenital endometriosis represents 5% of the localisations. Its prevalence seems to be underestimated. The extra pelvic localisation can make the diagnosis more difficult. Nevertheless, the recurrent and catamenial symptomatology can evoke this pathology. Surgery seems to be the unique efficient treatment for parietal lesions. Pain linked to nervous lesions (peripheric and sacral roots) seems to be underestimated and difficult to diagnose because of various localisations. Neurolysis seems to have encouraging results. Diaphragmatic lesions are often discovered either incidentally during laparoscopy, or by pulmonary symptomatology as recurrent catamenial pneumothorax or cyclic thoracic pain. Surgical treatment seems as well to be efficient. PMID- 29530554 TI - [Expectations of women with endometriosis: What information to deliver? CNGOF-HAS Endometriosis Guidelines]. AB - Women with endometriosis often say that the information doctors give them should be improved. Patient support groups can provide missing information but may lack objectivity, or reliability, and may even generate anxiety or even harm their health. Clear unbiased medical information is the ideal. New patients with endometriosis wish to be taken seriously by primary care physicians, and be referred quickly to a specialist without further unnecessary investigation or delay. The diagnosis of endometriosis should ideally be made quickly, and should clearly specify the nature of the disease, its evolution, and its consequences on quality of life, relationships, and fertility. When choosing a treatment, information should state the risks of each treatment, the risks of recurrence long term, and the therapeutic alternatives. These should include conventional medical treatment, lifestyle adaptation, or alternative therapies. In case of surgery, prior written information should be provided, the likely scar appearance, the short and long term consequences in terms of pain, postoperative recovery time and complication rates. Once the surgery is performed, the degree of endometriotic involvement and the treatment undertaken should be explained. At discharge, patients should be told the expected recovery time, and the consequences of the operation on daily life. PMID- 29530555 TI - [Interest of hysterectomy with or without bilateral oophorectomy in the surgical treatment of endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - OBJECTIVE: In women with symptomatic endometriosis and no desire for pregnancy, hysterectomy with or without bilateral oophorectomy is often presented as a definitive solution to their symptoms. Despite this radical treatment, it should be known that nearly 15% of these patients will have persistent pain. Thus the objective of this review was to determine the interest of total hysterectomy with or without bilateral oophorectomy for the treatment of deep endometriosis. METHOD: The research was conducted from the US National Library of Medicine's National Institutes of Health from the following keywords: endometriosis, hysterectomy, oophorectomy, ovariectomy, radical treatment. Only articles written in English have been selected. RESULTS AND RECOMMENDATIONS: Hysterectomy with or without bilateral oophorectomy, associated with endometriotic lesions exeresis could decrease the rate of recurrence and surgical reoperations compared to resection alone endometriosis lesions (NP4). In women with no desire for pregnancy, the benefit-risk balance of a hysterectomy, with or without bilateral oophorectomy, may be discussed in order to reduce the risk of recurrence of endometriotic disease (Expert Agreement). Taking into account the multiple adverse effects of early menopause on expectancy and quality of life (NP2), ovarian preservation should be discussed with the patient in case of hysterectomy for deep endometriosis (Expert Agreement). The use of menopausal hormone therapy (THM) does not appear to increase the symptoms of endometriosis after surgical castration (NP3). THM is not contraindicated in postmenopausal women with endometriosis (grade C). PMID- 29530556 TI - [Endometriosis and fertility preservation: CNGOF-HAS Endometriosis Guidelines]. AB - Fertility preservation (FP) techniques are progressing rapidly these past few years thanks to the oocyte vitrification. Indication of FP techniques is now extended to non-oncological situation that may induce risk of premature ovarian failure. Ovarian endometriosis can lead to premature ovarian failure and further infertility due to the high risk of ovarian cysts recurrence and surgery. To date, there is no cohort study regarding FP and endometriosis as well as no recommendation. Our purpose is to review the arguments in favor of FP in this specific area and to elaborate strategies according to each clinical form. PMID- 29530557 TI - [Endometriosis medical treatment: Hormonal treatment for the management of pain and endometriotic lesions recurrence. CNGOF-HAS Endometriosis Guidelines]. AB - The available literature, from 2006 to 2017, on hormonal treatment has been analysed as a contribution to the HAS-CNGOF task force for the treatment of endometriosis. Available data are heterogeneous and the general level of evidence is moderate. Hormonal treatment is usually offered as the primary option to women suffering from endometriosis. It cannot be used in women willing to conceive. In women who have not been operated, the first line of hormonal treatment includes combined oral contraceptives (COC) and the levonorgestrel-releasing intra uterine system (52mg LNG-IUS). As a second line, desogestrel progestin only pills, etonogestrel implants, GnRH analogs (GnRHa) with add back therapy and dienogest can be offered. Add back therapy should include estrogens to prevent bone loss and improve quality of life, it can be introduced before the third month of treatment to prevent side effects. The literature does not support preoperative hormonal treatment for the sole purpose of reducing complications or recurrence, or facilitating surgical procedures. After surgical treatment, hormonal treatment is recommended to prevent pain recurrence and improve quality of life. COCs or LNG IUS are recommended as a first line. To prevent recurrence of endometriomas COC is advised and maintained as long as tolerance is good in the absence of pregnancy plans. In case of dysmenorrhea, postoperative COC should be used in a continuous scheme. GnRHa are not recommended in the sole purpose of reducing endometrioma recurrence risk. PMID- 29530558 TI - [New medical treatments for painful endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - OBJECTIVE: The objective of this work is to evaluate the place of new treatments in the management of endometriosis outside the context of infertility. METHODS: A review of the literature was conducted by consulting Medline data until July 2017. RESULTS: Dienogest is effective compared to placebo in short term (NP2) and long term (NP4) for the treatment of painful endometriosis. In comparison with GnRH agonists, dienogest is also effective in terms of decreased pain and improved quality of life in non-operated patients (NP2) as well as for recurrence of lesions and symptomatology postoperatively (NP2). Data on GnRH antagonists, selective progesterone receptor modulators as well as selective inhibitors (anti TNF-alpha, matrix metalloprotease inhibitors, angiogenesis growth factor inhibitors) are insufficient to provide evidence of interest in clinical practice for the management of painful endometriosis (NP3). CONCLUSION: Dienogest is recommended as second-line therapy for the management of painful endometriosis (Grade B). Because of lack of evidence, aromatase inhibitors, elagolix, SERM, SPRM and anti-TNF-alpha are not recommended for the management of painful endometriosis (Grade C). PMID- 29530559 TI - [Specific clinical signs suggestive of endometriosis (excluding adenomyosis) and questionnaires of symptoms, pain and quality of life: CNGOF-HAS Endometriosis Guidelines]. AB - In case of consultation for chronic pelvic pain or suspicion of endometriosis, it is recommended to evaluate the pain (intensity, resonance) and to search out the evocative and localizing symptoms of endometriosis (Grade B). The main symptoms suggestive of endometriosis are: severe dysmenorrhea (NP2), deep dyspareunia (NP2), painful defecation during menstruation (NP2), urinary tract symptoms during menstruation (NP2) and infertility (NP2). In patients with chronic pelvic pain, it is recommended to search deep infiltrating endometriosis in patients with painful defecation during menstruation or severe deep dyspareunia (Grade B). It is recommended to search symptoms suggestive of sensitization in painful patients with endometriosis (Grade B). When suggestive symptoms of endometriosis are present, a directed gynecological examination is recommended, where possible, including examination of the posterior vaginal cul-de-sac (Grade C). In assessing pain intensity or evaluating analgesic effectiveness of a treatment, it is recommended to use a scale to measure the intensity of pain (Grade A). In the management of symptomatic endometriosis, it is recommended to evaluate the quality of life (Grade C). PMID- 29530561 TI - [Erratum to "Neonatal herpes: Epidemiology, clinical manifestations and management. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)" [Gynecol Obstet Fertil Senol 45 (2017) 691-704]]. PMID- 29530560 TI - [Diagnosis accuracy of endoscopy (laparoscopy, hysteroscopy, fertiloscopy, cystoscopy, colonoscopy) in case of endometriosis: CNGOF-HAS Endometriosis Guidelines]. AB - OBJECTIVE: To provide clinical practice guidelines from the French college of obstetrics and gynecology (CNGOF) with the Haute Autorite de sante (HAS), based on the best evidence available, concerning the diagnosis accuracy of endoscopy (laparoscopy, hysteroscopy, fertiloscopy, cystoscopy, colonoscopy) in case of endometriosis. MATERIAL AND METHODS: English and French review of literature about the diagnosis accuracy of endoscopy in case of endometriosis. RESULTS AND CONCLUSION: Laparoscopy is useful in case of suspected endometriosis in patients with symptoms or infertility when appropriate preoperative assessment is negative (grade C). Biopsies during diagnosis laparoscopy are recommended in case of typical or atypical lesions to confirm endometriosis (grade B). It is not recommended to perform fertiloscopy in case of suspected endometriosis (grade C). Hysteroscopy could be performed in case of suspected endometriosis and infertility to eliminate endometrial polyp or septate uterus (grade C). Colonoscopy is not recommended in case of suspected deep posterior endometriosis (grade C). PMID- 29530562 TI - Novel medium-throughput technique for investigating drug-cyclodextrin complexation by pH-metric titration using the partition coefficient method. AB - The present study was aimed to develop a medium-throughput screening technique for investigation of cyclodextrin (CD)-active pharmaceutical ingredient (API) complexes. Dual-phase potentiometric lipophilicity measurement, as gold standard technique, was combined with the partition coefficient method (plotting the reciprocal of partition coefficients of APIs as a function of CD concentration). A general equation was derived for determination of stability constants of 1:1 CD API complexes (K1:1,CD) based on solely the changes of partition coefficients (logPo/wN-logPappN), without measurement of the actual API concentrations. Experimentally determined logP value (-1.64) of 6-deoxy-6[(5/6) fluoresceinylthioureido]-HPBCD (FITC-NH-HPBCD) was used to estimate the logP value (~ -2.5 to -3) of (2-hydroxypropyl)-beta-cyclodextrin (HPBCD). The results suggested that the amount of HPBCD can be considered to be inconsequential in the octanol phase. The decrease of octanol volume due to the octanol-CD complexation was considered, thus a corrected octanol-water phase ratio was also introduced. The K1:1,CD values obtained by this developed method showed a good accordance with the results from other orthogonal methods. PMID- 29530563 TI - Establishing an in vitro permeation model to predict the in vivo sex-related influence of PEG 400 on oral drug absorption. AB - The notion that certain formerly regarded "inert" pharmaceutical excipients are capable of modifying the bioavailability of oral drugs has gained increasing attention in recent years. For instance, the commonly-used solubilizing agent polyethylene glycol 400 (PEG 400) exhibits a sex-specific effect on the bioavailability of ranitidine in both humans and rats, mediated by the efflux transporter P-glycoprotein (P-gp). To determine whether such in vivo effect could be predicted by in vitro tests, an in vitro/ex vivo model was established using tissues from male and female rats to characterize the influence of PEG 400 on the intestinal transport of ranitidine in the absence and/or presence of a Pgp inhibitor, cyclosporine A (CsA). We found the absorptive permeability of ranitidine in the small intestine (duodenum, jejunum, ileum) and colon was higher in females compared with males. PEG 400 significantly increased the absorption and decreased the secretion of ranitidine in the intestine of male rats (p < 0.05), but no such effects were observed in female intestines. In addition, while the P-gp inhibitor CsA increased the intestinal uptake of ranitidine in both male and female rats, a greater extent of intestinal transport modulation was observed in males compared to females. These in vitro data on the influence of PEG 400 on the intestinal transport of ranitidine in a sex-dependent manner are in agreement with previously published in vivo data. This good in vivo-in vitro correlation means that the in vitro method will be quicker, cheaper and easier to investigate any sex-related influence of pharmaceutical excipients on oral drug bioavailability. PMID- 29530564 TI - Enolase from Trypanosoma cruzi is inhibited by its interaction with metallocarboxypeptidase-1 and a putative acireductone dioxygenase. AB - Purification of enolase (ENO) from the cytosol of Trypanosoma cruzi indicated that it may interact with at least five other proteins. Two of them were identified as metallocarboxypeptidase-1 (TcMCP-1) and a putative acireductone dioxygenase (ARDp). Subcellular localization studies confirmed the presence of ARDp in the cytosol, as is the case for ENO and TcMCP-1. Analysis of the ARDp sequence showed that this protein has two domains, an N-terminal ARD and a C terminal TRP14 (thioredoxin-related protein) domain. The interactions between ENO, TcMCP-1 and ARDp were confirmed for the natural proteins from the trypanosome (using size-exclusion chromatography and co-immunoprecipitation from a cytosolic fraction) and recombinant forms (using ELISA ligand-binding assay and ENO activity assays). The ELISA ligand-binding assays permitted to verify the optimal physicochemical conditions for the interactions (representative for the physiological conditions) and to determine the affinity constants (Kd): ENO/ARDp: 9.54 +/- 0.82 nM, ARDp/ENO 10.05 +/- 1.11 nM, and ENO/TcMCP-1: 5.66 +/- 0.61 nM. The data also show that the interaction between TcMCP-1 and ARDp is mediated by ENO acting as a "bridge". Furthermore, considerable inhibition of the ENO activity, up to 85%, is observed when the enzyme interacts with TcMCP-1 and ARDp simultaneously. All these data confirm that the interaction between ENO, TcMCP-1 and ARDp, occurring in T. cruzi's cytosol, modulates the ENO activity and suggest a possible physiological mechanism for regulation of the ENO activity by the protein-protein interaction. PMID- 29530565 TI - D-Amino acids in protein: The mirror of life as a molecular index of aging. AB - Proteins are composed exclusively of l-amino acids. Among elderly individuals, however, d-aspartic acid (d-Asp) residues have been found in eye lens and brain, as well as in other tissues. The presence of d-Asp may change the higher-order structure of a protein, which in turn may have a role in age-related disorders such as cataract and Alzheimer's disease. d-Asp results from the spontaneous racemization of Asp residues in susceptible proteins. During aging, natural lalpha-Asp residues in proteins are non-enzymatically isomerized via a succinimidyl intermediate to l-beta-, d-alpha- and d-beta-isomers. This isomerization does not happen uniformly, but instead occurs at specific residues that are susceptible to isomerization due to their sequence or structural context. Thus, it is necessary to establish the nature of each individual Asp residue in susceptible proteins. Recently, a new method based on LC-MS/MS for the analysis of Asp isomerization at specific protein sites has been described. In this review, we first show that the homochirality of amino acids in proteins is not guaranteed throughout life. We then describe the development of a new method for protein-bound d-amino acid analysis, and discuss the negative influence that d-Asp has on protein structure and function. PMID- 29530566 TI - Heart failure with preserved ejection fraction as an independent risk factor of mortality after cardiothoracic surgery. AB - BACKGROUND: The prognostic role of heart failure with preserved ejection fraction (HFpEF) remains unclear. This study aimed to assess HFpEF prognostic value after cardiothoracic surgery, adjusting for European System for Cardiac Operative Risk (EuroSCORE II) criteria. METHODS: Patients with left ventricular ejection fraction (LVEF) >= 50% undergoing cardiothoracic surgery between 2012 and 2016 were included. Patients with HFpEF were compared to control patients with LVEF >= 50%. HFpEF was defined following 2016 European Society of Cardiology guidelines: LVEF >= 50%, symptomatic HF with New York Heart Association (NYHA) class 2 or greater, elevated brain natriuretic peptide (BNP) and relevant echocardiographic findings (LV hypertrophy, LA enlargement, or diastolic filling anomaly). The primary endpoint was in-hospital mortality, and the secondary endpoint was postoperative shock. Multivariate analyses were performed to determine mortality and shock risk-factors. RESULTS: Among 1743 patients, 427 (24.5%) presented HFpEF. HFpEF was highly associated with in-hospital mortality (hazard ratio = 1.86; 95% confidence interval [CI], 1.16-2.98; P = .01). This association remained independent when adjusting for EuroSCORE II (adjusted hazard ratio = 1.6; 95% CI, 1.0-2.6; P = .049). Postoperative shock occurred more in HFpEF than in control patients (17.8% vs 6.7%; P < .001). HFpEF was an independent risk factor of postoperative shock (adjusted odds ratio = 2.9; 95% CI, 1.5-3.0; P < .001). CONCLUSIONS: HFpEF was an independent risk-factor of mortality and postoperative shock after cardiothoracic surgery, after adjustment regarding EuroSCORE II. PMID- 29530567 TI - Induction therapy for locally advanced distal esophageal adenocarcinoma: Is radiation Always necessary? AB - OBJECTIVE: To compare outcomes between induction chemotherapy alone (ICA) and induction chemoradiation (ICR) in patients with locally advanced distal esophageal adenocarcinoma. METHODS: Patients in the National Cancer Database treated with ICA or ICR followed by esophagectomy between 2006 and 2012 for cT1 3N1M0 or T3N0M0 adenocarcinoma of the distal esophagus were compared using logistic regression, Kaplan-Meier analysis, and Cox proportional hazards methods. RESULTS: The study group included 4763 patients, of whom 4323 patients (90.8%) received ICR and 440 patients (9.2%) received ICA. There were no differences in age, sex, race, Charlson Comorbidity Index, treatment facility type, clinical T or N status between the 2 groups. Tumor size >=5 cm (odds ratio, 1.46; P = .006) was the only factor that predicted ICR use. Higher rates of T downstaging (39.7% vs 33.4%; P = .012), N downstaging (32.0% vs 23.4%; P < .001), and complete pathologic response (13.1% vs 5.9%; P < .001) occurred in ICR patients. Positive margins were seen more often in ICA patients (9.6% vs 5.5%; P = .001), but there was no difference in 5-year survival (ICR 35.9% vs ICA 37.2%; P = .33), and ICR was not associated with survival in multivariable analysis (hazard ratio = 1.04; P = .61). CONCLUSIONS: ICR for locally advanced distal esophageal adenocarcinoma is associated with a better local treatment effect, but not improved survival compared with ICA, which suggests that radiation can be used selectively in this clinical situation. PMID- 29530568 TI - Acute aortic dissection: The conundrum of severity of disease, extent of surgery and end-organ function. PMID- 29530569 TI - Type A aortic dissection: Are we any nearer to taming the beast? PMID- 29530570 TI - Food fight: Perhaps there is a benefit to being fat and happy. PMID- 29530571 TI - The root cause of anxiety during reoperative aortic valve surgery. PMID- 29530572 TI - Predicting Fontan failure: Why a chylothorax matters. PMID- 29530573 TI - All that glitters may not be gold: Changes in serum creatinine may not be the criterion standard for acute kidney injury. PMID- 29530574 TI - Ultrasound, endoscopy, and the recurrent nerve. PMID- 29530575 TI - Discussion. PMID- 29530576 TI - Polytetrafluoroethylene valved conduits for right ventricle-pulmonary artery reconstruction: Do they outperform xenografts and allografts? PMID- 29530577 TI - Sliding esophagoplasty in esophageal obstruction after endovascular stent grafting of thoracic aortic aneurysm. PMID- 29530578 TI - Spiral suspension, a novel repair technique for severe functional tricuspid regurgitation. PMID- 29530579 TI - What goes around comes around...possibly. PMID- 29530580 TI - Thoracic surgery without intubation: Revisiting the challenges of a previous century. PMID- 29530581 TI - A systematic approach to the formulation of anti-onychomycotic nail patches. AB - Nail patches have a potential role as drug carriers for the topical treatment of nail diseases such as onychomycosis, a common condition. Our aim was therefore to develop a systematic and novel approach to the formulation of a simple drug-in adhesive ungual patch. Twelve pressure-sensitive adhesives (PSAs), four backing membranes, two release liners and three drugs were screened for pharmaceutical and mechanical properties. From this initial screening, two PSAs, two drugs, one backing membrane and one release liner were selected for further investigation. Patches were prepared by solvent-casting and characterised. The patches had good uniformity of thickness and of drug content, and showed minimal drug crystallisation during six months of storage. Meanwhile, the drug stability in the patch upon storage and patch adhesion to the nail was influenced by the nature of the drug, the PSA and the backing membrane. The reported methodology paves the way for a systematic formulation of ungual nail patches to add to the armamentarium of nail medicines. Further, from this work, the best patch formulation has been identified. PMID- 29530583 TI - Sleep Disturbances, Psychosocial Difficulties, and Health Risk Behavior in 16,781 Dutch Adolescents. AB - OBJECTIVE: To investigate the prevalence of adolescent sleep disturbances and their relation to psychosocial difficulties and health risk behaviors with the use of data from a province-wide health survey (n = 16,781). METHODS: Psychosocial difficulties were measured with the Strength and Difficulties Questionnaire. Additional assessments included self-reported sleep disturbances, suicidality, and health risk behaviors including current use of tobacco, alcohol, and drugs, physical inactivity, and compulsive use of multimedia. We used multilevel analyses to investigate the relationhips, including differences, between boys and girls, as well as the mediating role of emotional problems. RESULTS: Just under 20% of adolescents reported sleep disturbances in the previous month. These sleep disturbances were associated with psychosocial problems (odds ratio [OR], 6.42; P < .001), suicidality (OR, 3.90-4.14; P < .001), and all health risk behaviors (OR, 1.62-2.66; P < .001), but not with physical inactivity. We found moderation by gender for the relations between sleep and suicide attempts (OR, 0.38; P < .002) and between sleep and cannabis use (OR, 0.52; P = .002), indicating attenuated relationships in girls compared with boys. Emotional problems partially mediated the relationships between sleep disturbances and multimedia use. CONCLUSIONS: This study reiterates the high prevalence of sleep disturbances during adolescence. These sleep disturbances were strongly related to psychosocial problems and a wide range of health risk behaviors. Although the direction of causality cannot be inferred, this study emphasizes the need for awareness of impaired sleep in adolescents. Moreover, the gender differences in associated suicide attempts and cannabis use call for further research into tailored intervention strategies. PMID- 29530582 TI - Heat shock protein A12A encodes a novel prosurvival pathway during ischaemic stroke. AB - Heat shock protein A12A (HSPA12A) is a newly discovered member of the Hsp70 family. The biological characteristics and functional roles of HSPA12A are poorly understood. This study investigated the effects of HSPA12A on ischaemic stroke in mice. Ischaemic stroke was induced by left middle cerebral artery occlusion for 1 h followed by blood reperfusion. We observed that HSPA12A was highly expressed in brain neurons, and neuronal HSPA12A expression was downregulated by ischaemic stroke and stroke-associated risk factors (aging, obesity and hyperglycaemia). To investigate the functional requirement of HSPA12A in protecting ischaemic brain injury, HSPA12A knockout mice (Hspa12a-/-) were generated. Hspa12a-/- mice exhibited an enlarged infarct volume and aggravated neurological deficits compared to their wild-type (WT) littermates after stroke. These aggravations in Hspa12a-/- mice were accompanied by more apoptosis and severer hippocampal morphological abnormalities in ischaemic hemispheres. Long-term examination revealed impaired motor function recovery and neurogenesis in stroke-affected Hspa12a-/- mice compared to stroke-affected WT controls. Significant reduced activation of GSK-3beta/mTOR/p70S6K signalling was also observed in ischaemic hemispheres of Hspa12a-/- mice compared to WT controls. Administration with lithium (non-selective GSK-3beta inhibitor) activated GSK-3beta/mTOR/p70S6K signalling in stroke-affected Hspa12a-/- mice. Notably, lithium administration attenuated the HSPA12A deficiency-induced aggravation in infarct size, neurological deficits and neuronal death in Hspa12a-/- mice after stroke. Altogether, the findings suggest that HSPA12A expression encodes a critical novel prosurvival pathway during ischaemic stroke. We identified HSPA12A as a novel neuroprotective target for stroke patients. PMID- 29530584 TI - Using a Community Bus Tour for Pediatric Residents to Increase Their Knowledge of Health Disparities. AB - A community bus tour with a focus on social determinants of health created through a partnership between the pediatric residency program and the hospital's Child Health Advocacy Institute was shown to increase knowledge of health disparities among pediatric interns. PMID- 29530585 TI - Omission of Adjuvant Radiotherapy in the Elderly Breast Cancer Patient: Missed Opportunity? AB - PURPOSE: We used the National Cancer Data Base to analyze practice patterns of adjuvant breast radiotherapy (RT) in elderly patients to see if a difference in overall survival (OS) could be detected. Additionally, we investigated factors that affected OS in these patients. PATIENTS AND METHODS: Women aged >= 65 years with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative pathologic T1-T2N0M0 invasive breast cancer measuring up to 3 cm who were treated with breast conservation and adjuvant endocrine therapy without adjuvant chemotherapy were identified and stratified by use of adjuvant RT. Multivariable Cox proportional hazards modeling was used to examine the association of treatment and mortality adjusting for demographic, socioeconomic, and clinicopathologic factors. Kaplan-Meier analysis was used to estimate overall 5-year survival in patients who did or did not receive adjuvant RT, and to compare those groups. RESULTS: A total of 61,395 patients with a median follow-up of 48.7 months (range, 0-107 months) were identified. On Cox regression analysis, improved OS was associated with treatment at an academic facility, younger age, higher income level, lower Charlson-Deyo comorbidity index, and receipt of adjuvant RT (all P < .05). The overall 5-year survival rate was 93.0% (95% confidence interval 92.7-93.3) in the adjuvant RT group and 83.6% (95% confidence interval 82.5-84.7) in the nonadjuvant RT group (P < .0001). CONCLUSION: Improved survival is associated with the receipt of adjuvant RT for older women with early stage hormone receptor-positive HER2-negative breast cancer who received adjuvant endocrine therapy. However, there are many limitations inherent to a retrospective database study such as ours, so the findings should be taken with caution. PMID- 29530586 TI - Screening for Binge Eating Disorder in people with obesity. AB - The Risk factors for Binge Eating Disorder in Overweight (REO) questionnaire is a screening tool for nutritionists to discriminate between individuals with obesity with and without Binge Eating Disorder (BED). The first study tested the discriminative ability of the REO and identified an optimal cut-off value. In the second study this cut-off value was used to identify individuals with and without BED from a sample of individuals with obesity visiting a nutritionist and compared clinical and personality characteristics with a group of individuals officially diagnosed with BED. Results showed that the REO has a sensitivity of 95.1%, specificity of 81.5%, a good internal consistency of alpha=.96, and an exploratory factor analysis showed four underlying factors of the REO that explained a total variance of 63.7%. Characteristics of individuals with BED symptoms identified by the REO and those officially diagnosed with BED were comparable and differed from individuals with obesity without BED symptoms. By screening individuals with obesity with the REO those presenting with BED symptoms are more easily identified, and can be referred to psychological treatment facilities for further assessment and appropriate treatment. PMID- 29530587 TI - Clonal emergence of Klebsiella pneumoniae ST14 co-producing OXA-48-type and NDM carbapenemases with high rate of colistin resistance in Dubai, United Arab Emirates. AB - Few studies have addressed the molecular epidemiology of carbapenem-resistant Enterobacteriaceae (CRE) isolates in the Arabian Peninsula, and such investigations have been missing from Dubai, a major economical, tourism and medical centre of the region. The antibiotic susceptibility, the carbapenemase type produced, and the clonality of 89 CRE strains isolated in five major Dubai hospitals in June 2015 to June 2016 were determined. Thirty-three percent of the collection of 70 Klebsiella pneumoniae, 13 Escherichia coli and 6 other Enterobacteriaceae were extremely drug resistant, 27% were resistant to colistin, and 4.5% (4 K. pneumoniae isolates) were resistant to all antibiotics tested. The colistin resistance rate in K. pneumoniae was 31.4%. None of the isolates carried mobile colistin resistance genes. Seventy-seven isolates produced carbapenemase: 53.3% OXA-48-like, 24.7% NDM and 22.1% both OXA-48-like and NDM, respectively. Pulsed-field gel electrophoresis clustered 50% of K. pneumoniae into a 35 membered group, which showed significant association with double carbapenemase production, with extreme drug resistance, and with being isolated from Emirati patients. Members of the cluster belonged to sequence type ST14. The rate of colistin resistance in K. pneumoniae ST14 was 37.1% vs. 27.1% of K. pneumoniae isolates outside of the cluster. Two of the panresistant K. pneumoniae isolates also belonged to ST14, whereas the other two were ST15 and ST231, respectively. In conclusion, beyond the overall high colistin resistance rate in CRE, the emergence of a highly resistant clone of K. pneumoniae ST14 in all Dubai hospitals investigated is a serious problem requiring immediate attention. PMID- 29530588 TI - Can the quorum sensing inhibitor resveratrol function as an aminoglycoside antibiotic accelerant against Pseudomonas aeruginosa? AB - Pseudomonas aeruginosa infection is a serious disease in cystic fibrosis patients and is difficult to treat owing to biofilm persistence and emerging multidrug resistance. Considering the essential role of quorum sensing (QS) in P. aeruginosa infections, the enhanced effects between the quorum sensing inhibitor (QSI) resveratrol and several antibiotics against P. aeruginosa PAO1 were investigated. Crystal violet staining assay revealed that biofilms of P. aeruginosa PAO1 grown in the presence of resveratrol were more susceptible to aminoglycoside antibiotics. Scanning electron and fluorescence microscopy showed architectural disruption of the biofilms when treated with resveratrol and aminoglycoside antibiotics. Furthermore, quantitative reverse transcription PCR (qRT-PCR) analysis demonstrated that expression of lasI and rhlI, two genes encoding enzymes that synthesise signal molecules in QS systems, were inhibited in the P. aeruginosa PAO1 biofilms by resveratrol. These results indicate that the QSI resveratrol can significantly enhance the effects of aminoglycoside antibiotics (e.g. tobramycin, gentamicin, amikacin and netilmicin) on P. aeruginosa PAO1 biofilms. These findings suggest that resveratrol is a potential accelerant in the treatment of P. aeruginosa biofilms and can restore or enhance the efficacy of aminoglycoside antibiotics. PMID- 29530589 TI - Cisplatin-induced gastrointestinal toxicity: An update on possible mechanisms and on available gastroprotective strategies. AB - Cisplatin (cis-diamminedichloroplatinum [II], CP) is most widely prescribed in chemotherapy and efficaciously treats diverse human cancers, with remission rates > 90% in testicular cancers. However, clinical use of CP is associated with numerous untoward side effects, in particular, at the gastrointestinal level that reduces the therapeutic efficacy of CP and often results in withdrawal of its clinical usage in long term cancer chemotherapy. Substantial strides have been made to identify effective protective strategies against CP-induced nephrotoxicity, hepatotoxicity and ototoxicity. Unfortunately, very limited studies have focused on CP-induced gastrointestinal toxicity and advances in developing potent gastroprotective strategies/agents are still lacking. The current article reviews the metabolism and pharmacokinetics of CP, mechanisms underlying CP-induced gastrointestinal toxicity and lastly displays the potential approaches including plant-derived agents (phytochemicals) utilized to counteract CP-induced gastrointestinal dysfunction. Furthermore, the gastroprotective agents described in the experimental literature have shown partial protection against CP induced intestinal damage. This stresses the need to ascertain new information on the underlying mechanism and to discover novel combinatorial strategies for the abrogation of CP-induced gastrointestinal toxicity. PMID- 29530591 TI - Effects of pregabalin and duloxetine on neurotransmitters in the dorsal horn of the spinal cord in a rat model of fibromyalgia. AB - Dysfunction of the monoamine systems in the nervous system is associated with the clinical symptoms of fibromyalgia. Reserpine-induced myalgia (RIM) rats are a putative model of fibromyalgia in which muscle pressure thresholds and monoamine content is reduced in the brain and spinal cord. We examined the effects of pregabalin and duloxetine, drugs approved for fibromyalgia treatment, on the levels of extracellular neurotransmitters in the dorsal horn of the spinal cord in RIM rats using microdialysis. Male SD rats were used for all experiments. To generate RIM rats, reserpine was injected at 1 mg/kg subcutaneously once daily for three consecutive days. The pressure threshold of the mid-gastrocnemius muscle was measured using a Randall-Selitto apparatus. Norepinephrine, dopamine, and serotonin were detected using high-performance liquid chromatography with electrochemical detection, and glutamate and gamma-aminobutyric acid (GABA) were detected using liquid chromatography-mass spectrometry. The muscle pressure threshold in RIM rats was significantly lower than that in normal rats. While the levels of monoamines and glutamate were lower in the spinal cord of RIM rats than in normal rats, levels of GABA did not markedly differ. Duloxetine increased the levels of all three monoamines in normal and RIM rats in a dose-dependent manner. In contrast, pregabalin only increased norepinephrine levels in RIM rats. These results indicate that while both pregabalin and duloxetine ameliorate muscle pressure thresholds in RIM rats, their effects on the levels of extracellular neurotransmitters in the spinal cord differ considerably. PMID- 29530590 TI - In vitro and in vivo functional profile characterization of 17-cyclopropylmethyl 3,14beta-dihydroxy-4,5alpha-epoxy-6alpha-(isoquinoline-3-carboxamido)morphinan (NAQ) as a low efficacy mu opioid receptor modulator. AB - Evidence has shown that downstream signaling by mu opioid receptor (MOR) agonists that recruit beta-arrestin2 may lead to the development of tolerance. Also, it has been suggested that opioid receptor desensitization and cyclic AMP overshoot contributes to the development of tolerance and occurrence of withdrawal, respectively. Therefore, studies were conducted with 17-cyclopropylmethyl 3,14beta-dihydroxy-4,5alpha-epoxy-6alpha-(isoquinoline-3-carboxamido)morphinan (NAQ), a MOR selective partial agonist discovered in our laboratory, to characterize its effect on beta-arrestin2 recruitment and precipitation of a cyclic AMP overshoot. DAMGO, a MOR full agonist dose-dependently increased beta arrestin2 association with the MOR, whereas NAQ did not. Moreover, NAQ displayed significant, concentration-dependent antagonism of DAMGO-induced beta-arrestin2 recruitment. After prolonged morphine treatment of mMOR-CHO cells, there was a significant overshoot of cAMP upon exposure to naloxone, but not NAQ. Moreover, prolonged incubation of mMOR-CHO cells with NAQ did not result in desensitization nor downregulation of the MOR. In functional studies comparing NAQ with nalbuphine in the cAMP inhibition, Ca2+ flux and [35S]GTPgammaS binding assays, NAQ did not show agonism in the Ca2+ flux assay but showed partial agonism in the cAMP and [35S]GTPgammaS assays. Also, NAQ significantly antagonized DAMGO-induced intracellular Ca2+ increase. In conclusion, NAQ is a low efficacy MOR modulator that lacks beta-arrestin2 recruitment function and does not induce cellular hallmarks of MOR adaptation and fails to precipitate a cellular manifestation of withdrawal in cells pretreated with morphine. These characteristics are desirable if NAQ is pursued for opioid abuse treatment development. PMID- 29530592 TI - Postural Orthostatic Tachycardia Syndrome (POTS) in Denmark: Increasingly recognized or new epidemic? AB - AIMS: The incidence of Postural Orthostatic Tachycardia Syndrome (POTS) has grown in recent years. Whether this is an emerging epidemic or increasing recognition is unclear. METHODS: We retrospectively examined 8790 tilt-table tests (HUT) performed between 1997 and 2014 in patients with orthostatic intolerance and/or suspected syncope. Tests were reclassified according to the current diagnostic criteria for POTS. The number of POTS diagnoses in proportion to the number of tilt tests performed per year was calculated. The number of papers published with the term "Postural Orthostatic Tachycardia Syndrome" 1997-2014 was retrieved from PubMed and related to yearly POTS incidence. RESULTS: Eight-hundred-and-seventy five tests with suspected POTS were thoroughly evaluated. The reclassification of test results yielded 243 POTS diagnoses (age, 27.0 +/- 11.8 years). An increase in total number of POTS diagnoses was observed but the proportion of POTS positive tests per year was relatively constant (~2-3%) except for the period 2013-2014 (~7%). The increase in POTS diagnoses was preceded by an increase in number of POTS-related papers in PubMed. CONCLUSION: The proportion of POTS diagnoses among patients investigated for suspected syncope and/or orthostatic intolerance was relatively constant 1997-2012. The growing number of POTS-related publications in PubMed preceded the steep increase in diagnostic rate of POTS observed after 2012. PMID- 29530593 TI - Interpretation of cytochrome P450 monooxygenase kinetics by modeling of thermodynamic activity. AB - The experimentally determined Michaelis constant Kmc results from a combination of two effects: the recognition of the substrate by the enzyme and the molecular interactions between substrate and solvent. By separating substrate recognition from solvent effects, the thermodynamic activity-based Michaelis constant Kma allows for an unambiguous comparison of how different substrates fit into the substrate binding site. Kma of a poorly water-soluble substrate is calculated from the experimentally determined concentration-based Michaelis constant Kmc and its activity coefficient at infinite dilution gammainfinity. Comparing the Kma of different substrates instead of the experimentally determined Kmc prevents misinterpretations of the molecular basis of enzyme-substrate interactions. While n-octane showed the lowest Kmc value of six P450BM-3 substrates, its Kma was 500 fold higher than aniline, indicating that the binding of n-octane is mainly driven by its low water solubility, while binding of aniline is driven by its shape complementarity. For three substrates (aniline, oct-1-yne, n-octane), gammainfinity was reliably calculated by molecular dynamics simulations, either in binary substrate-water mixtures or in ternary mixtures including DMSO as cosolvent. It is demonstrated that the widely used DMSO has a considerable effect on the measured Kmc value. Depending on the substrate, addition of 10% v/v DMSO increases Kmc by up to a factor of 11. To make biocatalytic experiments reproducible, it is therefore of utmost importance to carefully report the reaction conditions. The reliable simulation of activity coefficients in complex mixtures allows for an unambiguous comparison of enzyme-substrate interactions and provides a predictive tool for the design of biocatalytic processes. PMID- 29530594 TI - Humanlike substitutions to Omega-loop D of yeast iso-1-cytochrome c only modestly affect dynamics and peroxidase activity. AB - Structural studies of yeast iso-1-cytochrome c (L.J. McClelland, T.-C. Mou, M.E. Jeakins-Cooley, S.R. Sprang, B.E. Bowler, Proc. Natl. Acad. Sci. U.S.A. 111 (2014) 6648-6653) show that modest movement of Omega-loop D (residues 70-85, average RMSD versus the native structure: 0.81 A) permits loss of Met80-heme ligation creating an available coordination site to catalyze the peroxidase activity mediated by cytochrome c early in apoptosis. However, Ala81 and Gly83 move significantly (RMSDs of 2.18 and 1.26 A, respectively). Ala81 and Gly83 evolve to Ile and Val, respectively, in human cytochrome c and peroxidase activity decreases 25-fold relative to the yeast protein at pH 7. To test the hypothesis that these residues evolved to restrict the peroxidase activity of cytochrome c, A81I and G83V variants of yeast iso-1-cytochrome c were prepared. For both variants, the apparent pKa of the alkaline transition increases by 0.2 to 0.3 relative to the wild type (WT) protein and the rate of opening the heme crevice is slowed. The cooperativity of acid unfolding is decreased for the G83V variant. At pH 7 and 8, the catalytic rate constant, kcat, for the peroxidase activity of both variants decreases relative to WT, consistent with the effects on alkaline isomerization. Below pH 7, the loss in the cooperativity of acid unfolding causes kcat for peroxidase activity to increase for the G83V variant relative to WT. Neither variant decreases kcat to the level of the human protein, indicating that other residues also contribute to the low peroxidase activity of human cytochrome c. PMID- 29530595 TI - CW EPR parameters reveal cytochrome P450 ligand binding modes. AB - Cytochrome P450 (CYP) monoxygenses utilize heme cofactors to catalyze oxidation reactions. They play a critical role in metabolism of many classes of drugs, are an attractive target for drug development, and mediate several prominent drug interactions. Many substrates and inhibitors alter the spin state of the ferric heme by displacing the heme's axial water ligand in the resting enzyme to yield a five-coordinate iron complex, or they replace the axial water to yield a nitrogen ligated six-coordinate iron complex, which are traditionally assigned by UV-vis spectroscopy. However, crystal structures and recent pulsed electron paramagnetic resonance (EPR) studies find a few cases where molecules hydrogen bond to the axial water. The water-bridged drug-H2O-heme has UV-vis spectra similar to nitrogen-ligated, six-coordinate complexes, but are closer to "reverse type I" complexes described in older liteature. Here, pulsed and continuous wave (CW) EPR demonstrate that water-bridged complexes are remarkably common among a range of nitrogenous drugs or drug fragments that bind to CYP3A4 or CYP2C9. Principal component analysis reveals a distinct clustering of CW EPR spectral parameters for water-bridged complexes. CW EPR reveals heterogeneous mixtures of ligated states, including multiple directly-coordinated complexes and water-bridged complexes. These results suggest that water-bridged complexes are under represented in CYP structural databases and can have energies similar to other ligation modes. The data indicates that water-bridged binding modes can be identified and distinguished from directly-coordinated binding by CW EPR. PMID- 29530596 TI - Patients' preferences for information in bariatric surgery. AB - BACKGROUND: The decision to undergo bariatric surgery is multifactorial and made both by patient and doctor. Information is of the utmost importance for this decision. OBJECTIVE: To investigate the bariatric surgery patient's preferences regarding information provision in bariatric surgery. SETTING: A teaching hospital, bariatric center of excellence in Amsterdam, the Netherlands. METHODS: All patients who underwent a primary laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy between September 2013 and September 2014 were approached by mail to participate. A questionnaire was used to elicit patient preferences for the content and format of information. Sociodemographic characteristics, clinicopathologic factors, and psychologic factors were explored as predictors for specific preferences. RESULTS: Of the 356 eligible patients, 112 (31.5%) participated. The mean age was 49.2 (+/-10.7) years, and 91 (81.3%) patients were female. Patients deemed the opportunity to ask questions (96.4%) the most important feature of the consult, followed by a realistic view on expectations for example, results of the procedure (95.5%) and information concerning the consequences of surgery for daily life (89.1%). Information about the risk of complications on the order of 10% was desired by 93% of patients; 48% desired information about lower risks (.1%). Only 25 patients (22.3%) desired detailed information concerning their weight loss after surgery. CONCLUSION: Bariatric patients wished for information about the consequences of surgery on daily life, whereas the importance of information concerning complications decreased when their incidence lessened. PMID- 29530597 TI - The incidence of complications associated with loop duodeno-ileostomy after single-anastomosis duodenal switch procedures among 1328 patients: a multicenter experience. AB - BACKGROUND: The single-anastomosis duodenal switch procedure is a type of duodenal switch that involves a loop anastomosis rather than traditional Roux-en Y reconstruction. To date, there have been no multicenter studies looking at the complications associated with post-pyloric loop reconstruction. OBJECTIVES: The aim of the study was to report the incidence of complications associated with loop duodeno-ileostomy (DI) following single-anastomosis duodenal switch (SADS) procedures. SETTING: Mixed of private and teaching facilities. METHODS: The medical records of 1328 patients who underwent primary SADS procedure (single anastomosis duodeno-ileal bypass with sleeve gastrectomy or stomach intestinal pylorus-sparing surgery) by 17 surgeons from 3 countries (United States, Spain, and Australia) at 9 centers over a 6-year period were retrospectively reviewed, and their results were compared with articles in the literature. RESULTS: Mean preoperative body mass index was 51.6 kg/m2. Of 1328 patients, 123 patients received a linear stapled duodeno-ileostomy (DI) and 1205 patients a hand-sewn DI. In the overall series, the anastomotic leak, ulcer, and bile reflux occurred in .6% (9/1328), .1% (2/1328), and .1% (2/1328), respectively. None of our patients experienced volvulus at the DI or an internal hernia. Overall, 5 patients (.3%) (3/123 [2.4%] with linear stapled DI versus 2/1205 [.1%] with hand sewn DI [P<.05]) experienced stricture at the DI in this series. CONCLUSIONS: The overall incidence of complications associated with loop DI was lower than the reported incidence of anastomotic complications after Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch. SADS procedures may cause much fewer anastomotic complications compared with Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch. PMID- 29530598 TI - Disruption of TFGbeta-SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand. AB - : Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in an injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation. While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist. METHODS: Liver Fibrosis was induced in mice by carbon tetrachloride (CCl4). MAIN RESULTS: In transactivation assay BAR704 activated FXR with and EC50 of 967 nM while exerted no agonistic activity on other receptors including GPBAR1. In naive mice, BAR704 modulated the expression of FXR target genes in the liver of wild type mice but not in FXR-/- mice. In cirrhotic mice, administration of BAR704, 15 mg/kg for 9 weeks, spared the liver biosynthetic activity (bilirubin and albumin plasma levels), reduced liver fibrosis score (Sirius red staining), expression of pro-fibrogenetic (Colalpha1alpha, TGFbeta and alphaSMA) and inflammatory genes (IL-1beta, TNFalpha) and portal pressure. From mechanistic stand point, we have found that exposure of LX2 cells, a human HSCs line, to BAR704 increased the transcription of the short heterodimer partner (SHP) and induced the binding of this nuclear receptor to SMAD3, thus abrogating the binding of phosho-SMAD3 to the TGFbeta promoter. CONCLUSIONS AND APPLICATIONS: BAR704 is a selective FXR agonist that reduces liver fibrosis by interfering with the TGFbeta-SMAD3 pathway in HSCs. Selective FXR agonists may represent an attractive strategy for the treatment of liver fibrosis. PMID- 29530599 TI - The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis. AB - Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-beta1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type I alpha 1 (Col1alpha1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (alpha-SMA), and downregulation of E cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-beta1 and its receptor (TGF-beta1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK 52E cells were induced by TGF-beta1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-beta1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-beta1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF beta1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis. PMID- 29530600 TI - The hypotensive effect of activated apelin receptor is correlated with beta arrestin recruitment. AB - The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids. In HEK293 cells expressing APJ, we evaluated the relative efficacy of these compounds to activate Galphai1 and GalphaoA G-proteins, recruit beta-arrestins 1 and 2 (betaarrs), and inhibit cAMP production. Calculating the transduction ratio for each pathway allowed us to identify several analogs with distinct signaling profiles. Furthermore, we found that these analogs delivered i.v. to Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two compounds lost their ability to lower blood pressure, while other analogs significantly reduced blood pressure as apelin-13. Interestingly, analogs that did not lower blood pressure were less effective at recruiting betaarrs. Finally, using Spearman correlations, we established that the hypotensive response was significantly correlated with betaarr recruitment but not with G protein-dependent signaling. In conclusion, our results demonstrated that the betaarr recruitment potency is involved in the hypotensive efficacy of activated APJ. PMID- 29530601 TI - Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms. AB - The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L1 (linker between the two halves of the exporter); L0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics. PMID- 29530602 TI - Drug-induced xenogenization of tumors: A possible role in the immune control of malignant cell growth in the brain? AB - In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient's survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses. Several years ago we discovered that in vivo treatment of leukemic mice with triazene compounds (TZC) produces a marked increase of leukemia cell immunogenicity [a phenomenon termed Drug-Induced Xenogenization (DIX)] through point mutations able to generate strong tumor neoantigens (Drug-Induced Neoantigens, DIN). Immunogenic mutations are produced by TZC-dependent methylation of O6-guanine of DNA, that is suppressed by the DNA repair protein methyl-guaninemethyltransferase (MGMT). This minireview illustrates preclinical investigations conducted in animal models where DIN-positive murine leukemia cells were inoculated intracerebrally into histocompatible mice. The analysis of the literature indicates that the growth of xenogenized malignant cells is controlled by anti-DIN graft responses and by intra-cerebral or intravenous adoptive transfer of anti-DIN cytotoxic T lymphocytes. This survey reminds also that PARP inhibitors increase substantially the antitumor activity of TZC and can be administered with the intent of suppressing more efficiently tumor load and possibly reducing ITH through downsizing the polyclonality of xenogenized tumor cell population. Finally, the present report illustrates a hypothetical clinical protocol that could be considered as an example of future development of DIXbased tumor immuno chemotherapy in brain malignancies. The protocol involves oral or intravenous administration of TZC along with loco-regional (i.e. intracerebral "wafer") treatment with agents able to increase tumor cell sensitivity to the cytotoxic and xenogenizing effects of TZC (i.e. MGMT and PARP inhibitors) without enhancing the systemic toxicity of these DNA methylating compounds. PMID- 29530603 TI - Modulation of the endocrine transcriptional program by targeting histone modifiers of the H3K27me3 mark. AB - Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells. Previously, we showed that Neurogenin3 promoted the removal of H3K27me3 marks at target gene promoters in vitro, suggesting a functional connection between this factor and regulators of this chromatin mark. In the present study, we aimed to specifically evaluate whether targeting the activity of these histone modifiers can be used to modulate pancreatic endocrine differentiation. Our data show that chemical inhibition of the H3K27me3 demethylases Jmjd3/Utx blunts Neurogenin3-dependent gene activation in vitro. Conversely, inhibition of the H3K27me3 methyltransferase Ezh2 enhances both the transactivation ability of Neurogenin3 in cultured cells and the formation of insulin-producing cells during directed differentiation from pluripotent cells. These results can help improve current protocols aimed at generating insulin producing cells for beta cell replacement therapy in diabetes. PMID- 29530604 TI - [Risk of falls and consumption of medicines in an elderly population]. AB - OBJECTIVES: To describe the risk factors and the effect of medication use on the risk of falls in a population of 65 years or older. MATERIAL AND METHODS: Descriptive study of falls in the elderly population. The risk factors and consequences of the fall were recorded. Hypnotic and sedative risk drugs, opioids, and the simultaneous consumption of six or more drugs were considered. Diuretics were also included. The cumulative incidence for each group and the corresponding relative risks of falls were analysed from the cases registered between June and November 2016. RESULTS: During the study period, 60 falls were reported, of which 66% were by women and 34% by men. The cumulative incidence of falls was 3 per thousand women (95% CI: 2.22-4.08), and 2 per thousand men (95% CI: 1.44-3.41). The majority (71%) had consumed risk medication. Six or more medications were taken by 40% of the men and 62.5% of the women, and 97.6% was risk medication. The relative risk of falls in people using hypnotics, sedatives and opioids compared to non-users was 8.7 in men and 7.1 in women. In people who took diuretics, the relative risk was 4.6 for both genders. In women on multiple medications the relative risk was 3.7 compared to 1.7 in men. CONCLUSIONS: Polypharmacy and the use of hypnotic and sedative drugs and opioids and diuretics are an important public health problem, due to being risk factors for falls in this population, with a greater impact for women. PMID- 29530605 TI - [Absenteeism and associated factors in scheduled visits to a Preventive Medicine outpatient clinic]. AB - BACKGROUND: Patient absenteeism in outpatient clinics represents a significant obstacle to the cost-effectiveness of healthcare. The aim of this study was to assess the frequency of absence of patients and its associated factors in scheduled visits to a Preventive Medicine department. PATIENTS AND METHODS: The cross-sectional study was carried out in the Service of Preventive Medicine of the Lozano Blesa University Clinical Hospital of Zaragoza. It included all the visits scheduled from 3 January to 31 March 2017. For each visit, the date and time were registered, together with the type (first or consecutive appointments), age, gender, town of residence, country of birth, and underlying disease. The Chi squared test was used to determine the association between the variables and making the visit, with a multiple logistic regression analysis being performed on the variables in which a significant association was found. RESULTS: Of the total of 582 appointments studied, the absenteeism rate was 12.5% (73 out of 582; 13.7% for first appointments and 11.7% for consecutive appointments). Variables that revealed a significant association with patients not attending were: time (9.00 11:15 a. m.; OR=1.84; 95%CI: 1.10-3.08), day of the week (Mondays-Thursdays; OR=3.19; 95%CI: 1.12-9.07), country of birth (outside of Spain; OR=2.09; 95%CI:1.09-3.99), vaccination group (chronic kidney disease during pre-dialysis or dialysis; OR=3.59; 95%CI: 1.57-8.18), and age group (under 52 years old; OR=1.85; 95%CI: 1.08-3.19). CONCLUSIONS: The rate of absenteeism is at an intermediate position compared to the outpatient visits for other departments. The detection of associated factors makes it possible to plan specific measures for improvements that may reduce absences. PMID- 29530606 TI - Achieving a Predictive Understanding of Antimicrobial Stress Physiology through Systems Biology. AB - The dramatic spread and diversity of antibiotic-resistant pathogens has significantly reduced the efficacy of essentially all antibiotic classes, bringing us ever closer to a postantibiotic era. Exacerbating this issue, our understanding of the multiscale physiological impact of antimicrobial challenge on bacterial pathogens remains incomplete. Concerns over resistance and the need for new antibiotics have motivated the collection of omics measurements to provide systems-level insights into antimicrobial stress responses for nearly 20 years. Although technological advances have markedly improved the types and resolution of such measurements, continued development of mathematical frameworks aimed at providing a predictive understanding of complex antimicrobial-associated phenotypes is critical to maximize the utility of multiscale data. Here we highlight recent efforts utilizing systems biology to enhance our knowledge of antimicrobial stress physiology. We provide a brief historical perspective of antibiotic-focused omics measurements, highlight new measurement discoveries and trends, discuss examples and opportunities for integrating measurements with mathematical models, and describe future challenges for the field. PMID- 29530607 TI - Advantages of submandibular gland preservation surgery over submandibular gland resection for proximal submandibular stones. AB - OBJECTIVES: This study sought to compare surgical outcomes after the removal of submandibular gland (SMG) stones via 2 different surgical methods. MATERIALS AND METHODS: From June 2015 to July 2016, a total of 40 patients with SMG stones were selected from the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University (Shenyang, China), and were randomly assigned to 2 groups. Twenty patients underwent sialendoscopy-assisted stone removal via extraoral incision with preservation of the SMG, and 20 patients underwent traditional SMG resection. The outcomes of the 2 surgical procedures were assessed. RESULTS: The operation time and hospital stay were shorter in the SMG preservation group than the SMG resection group. There were no significant differences in stone size or location between the groups. The mean visual analog scale (VAS) score was lower in the SMG preservation group than the SMG resection group. All patients in the SMG resection group exhibited varying degrees of scarring and concave deformity on the face and neck, whereas all patients in the SMG preservation group retained intact facial morphology. CONCLUSIONS: Sialendoscopy-assisted stone removal with preservation of the SMG exhibited many advantages relative to traditional SMG resection. PMID- 29530608 TI - Frankincense and myrrh essential oils and burn incense fume against micro inhabitants of sacral ambients. Wisdom of the ancients? AB - ETHNOPHARMACOLOGICAL RELEVANCE: Essential oils obtained from resins of Boswellia carteri Birdw. and Commiphora myrrha (Nees) Engl., commonly known as frankincense and true myrrh respectively, have been used extensively since 2800 BCE for the treatment of skin sores, wounds, teeth, inflammation, and urinary tract diseases in traditional medicine; for preparation of mummification balms and unguents; and also as incense and perfumes. Since ancient times, burning of frankincense and myrrh in places of worship for spiritual purposes and contemplation (a ubiquitous practice across various religions) had hygienic functions, to refine the smell and reduce contagion by purifying the indoor air. AIM OF THE STUDY: The general purpose of the study was to assess the in vitro antimicrobial potential of the liquid and vapour phases of B. carteri and C. myrrha essential oils and burn incense, as well as to test the effectiveness of their in situ application to cleanse microbially-contaminated air within the ambient of an investigated 17th century church. MATERIALS AND METHODS: The chemical composition of B. carteri and C. myrrha essential oils, obtained by hydrodistillation of frankincense and true myrrh oleo gum resins was determined using GC/MS, and antimicrobial properties of their liquid and vapour phases were assessed by the broth microdilution and microatmosphere diffusion methods. Chemical analysis of burn incense fume obtained using bottle gas washing with dichloromethane as a solvent was performed by GC/MS, while its antimicrobial activity was evaluated using a modified microatmosphere diffusion method to evaluate germination inhibition for fungi and CFU count reduction for bacteria. The in situ antimicrobial activity of B. carteri burn incense and essential oil vapour phase was assessed in the sealed nave and diaconicon of the church, respectively. RESULTS: The dominant compounds of B. carteri EO were alpha-pinene (38.41%) and myrcene (15.21%), while C. myrrha EO was characterized by high content of furanoeudesma-1,3-diene (17.65%), followed by curzerene (12.97%), beta-elemene (12.70%), and germacrene B (12.15%). Burn incense fume and soot had alpha-pinene (68.6%) and incensole (28.6%) as the most dominant compounds, respectively. In vitro antimicrobial assays demonstrated high bacterial and fungal sensitivity to the liquid and vapour phases of EOs, and burn incense fume. In situ application of B. carteri EO vapour and incense fume resulted in reduction of air-borne viable microbial counts by up to 45.39 +/- 2.83% for fungi and 67.56 +/- 3.12% for bacteria (EO); and by up to 80.43 +/- 2.07% for fungi and 91.43 +/- 1.26% for bacteria (incense fume). CONCLUSIONS: The antimicrobial properties of essential oil derived from frankincense, a compound with well-known traditional use, showed that it possesses a clear potential as a natural antimicrobial agent. Moreover, the results suggest possible application of B. carteri EO vapour and incense fume as occasional air purifiers in sacral ambients, apart from daily church rituals. PMID- 29530609 TI - Protective effect of Sesbania grandiflora on acetic acid induced ulcerative colitis in mice by inhibition of TNF-alpha and IL-6. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plant Sesbania grandiflora (Linn) belonging to the family Fabaceae is commonly known as sesbania, agathi, and katurai. The plant is accredited for alleviating a spectrum of ailments including inflammation, colitis, diarrhea, dysentery, leprosy, gout, rheumatism, jaundice, bronchitis, convulsion and anxiety. It is also used as antitumour, anthelmintic, and laxatives in Ayurveda and Siddha system of Indian traditional medicine. AIM: To reveal protective effect of Sesbania grandiflora in acetic acid induced ulcerative colitis in mice. MATERIALS AND METHOD: Polyphenol, flavonoid and flavanone contents of different extracts of S. grandiflora leaves were quantified and correlated with their antioxidant capacity in-vitro (DPPH assay) for identification of potential fraction. In further studies hydroalocholic extract (HASG, 100 and 200 mg/kg) was evaluated for protective effect towards acetic acid induced ulcerative colitis (UC) animals administered with 150 ul of 5% acetic acid once, intrarectally. The colonic mucosal injury was assessed by estimating disease activity index (DAI), which took into account weight loss, stool consistency and occult/gross bleeding. Macroscopic changes like colon length, spleen weights, ulcer area and ulcer index were determined. Haematological parameters like WBC count, RBC count, Hb (g/dL), HCT (%), PLT count and FFA level were determined. Biochemical analysis was carried out for asserting the levels of tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation in UC induced and treated animals. The cardinal inflammatory biomarkers like nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL-6) were determined. Histopathological investigation was carried out and scores were calculated. RESULTS: HASG showed presence of highly polymerized polyphenols and flavonoids amongst other extracts of S. grandiflora, which is correlated to its rich antioxidant potential (IC50 =19.21). HPLC fingerprinting quantifies the presence of quercetin in concentration of 81.7 ug/mg of HASG. HASG (200 mg/kg) and Prednisolone (2 mg/kg) significantly reduced DAI and macroscopic scores. The haematological changes in experimental animals were restored upon treatment with HASG and Prednisolone. HASG showed potent antioxidant activity (In-vivo) by restoring the levels of SOD, GSH, MPO, MDA and NO. HASG was found to inhibit FFA levels, which may indicate inhibition of TLR4 receptor mediated inflammation. The levels of serological biomarkers like TNF alpha and IL-6 were found to be suppressed. Histopathological investigation reveals decrease signs of ulceration, necrosis, cellular infiltration, hyperaemia in HASG treated animals. The results of HASG (200 mg/kg) were found to be comparable with Prednisolone (2 mg/kg) significantly. CONCLUSION: The protective action of HASG against acetic acid induced UC is attributed to the antioxidant like action (In-vitro and In-vivo) of highly polymerized polyphenols and flavonoids especially quercetin. Also HASG was found to reduce the levels of TNF alpha and IL-6, thereby suppressing their inflammatory response in UC. PMID- 29530610 TI - Effects of Chinese herbal medicine on hyperlipidemia and the risk of cardiovascular disease in HIV-infected patients in Taiwan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Due to the development of antiretroviral therapy (ART), HIV/AIDS is now regarded as a treatable chronic disease. Chinese herbal medicine (CHM) is a type of complementary and alternative medicine (CAM) that has been widely applied in the healthcare system in Taiwan. AIM OF THE STUDY: The aim of this study was to investigate the frequency of use and patterns of prescription for the CHM-based treatment of HIV-infected patients and to assess the long-term effects of CHM on hyperlipidemia and cardiovascular disease events in these patients. MATERIALS AND METHODS: We identified 21,846 HIV-infected patients (ICD-9-CM: 042-044, 079, and V08 codes). Of these, 1083 and 2166 patients who used CHM and were non-users, respectively, were matched for age, gender, and ART use before CHM. The chi-squared test, Cox proportional hazard model, Kaplan-Meier method, and the log-rank test were used for comparisons between these two groups. RESULTS: CHM users had a lower risk of hyperlipidemia compared with non-users after adjusting for comorbidities by using a multivariate Cox proportional hazard model (P = 0.0011; HR: 0.66, 95% CI: 0.52-0.85). In addition, the CHM users had a lower risk of cardiovascular disease compared with non-users after adjusting for comorbidities (P = 0.0004; HR: 0.67, 95% CI: 0.53 0.83). The 10-year cumulative incidences of hyperlipidemia and cardiovascular disease were lower in the CHM group (P < 0.0001 for both, log rank test). Among the 12 most commonly used CHMs in these patients, Jia-Wei-Xiao-Yao-San (JWXYS) (46.1%), Ge-Gen-Tang (GGT) (40.6%), and Yin-Qiao-San (YQS) (38.0%) were the most common herbal formulas used. Huang-Qin (HQin) (44.6%), Yan-Hu-Suo (YHS) (40.5%), and Jie-Geng (JG) (39.5%) were the most commonly used single herbs. A CHM network analysis showed that JG was the core CHM in one cluster, and BM, MXSGT, and HQin were important CHMs in that cluster. In the other cluster, YHS was the core CHM, and SYGCT and JWXYS were important CHMs. CONCLUSION: CHM as adjunctive therapy may reduce hyperlipidemia and the risk for cardiovascular disease in HIV-infected patients. The list of the comprehensive herbal medicines that the patients used might be useful in further scientific investigations or therapeutic interventions for preventing atherosclerosis among HIV-infected patients. PMID- 29530611 TI - Anethum graveolens (dill) - A medicinal herb induces apoptosis and cell cycle arrest in HepG2 cell line. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal herb, Anethum graveolens L. (dill) is one of the potent culinary herbs used as an alternative form of medicine worldwide. The unguent topical Oil from the aerial parts of A. graveolens was found to be effective in the management of uterus cancer in ethnomedicine has been reported. BACKGROUND: The incidence and mortality rates of Hepatocellular carcinoma (HCC) are steadily rising worldwide, especially, in underdeveloped and developing countries. Moreover, HCC develops rapidly in patients with chronic cirrhosis or hepatitis, where the solid tumours/malignancies coexist with the inflammation. Recent studies have shown that the medicinal herb, Anethum graveolens, holds anticancer potential, which could be a promising approach for the treatment of various tumours. AIM: In the current study, we have analysed the antiproliferative effect of ethyl acetate fraction of Dill Seeds (EAFD) on HepG2 cell line. METHODS: Cell viability and proliferation were observed by MTT assay; Morphological changes were studied using fluorescent stains like Hoechst 33342, acridine orange/ethidium bromide and JC-1 dye. Further, the pro-apoptotic activity was demonstrated through Annexin-V-FITC/ PI assay and cell cycle analysis. Different concentrations (0.1, 0.2, 0.4, 0.6, 0.8 mg/ml) of EAFD were studied. RESULTS: EAFD markedly suppressed the proliferation of HepG2 cells in a dose and time-dependent manner. The phase contrast and fluorescence microscopy revealed the morphological alterations like disruption, shrinkage, detachment and blebbing of cell membrane accompanied by nuclear condensation after exposure to EAFD. Radical scavenging activity was evidenced by measurement of ROS levels post treatment. Modulation of mitochondrial membrane potential was exhibited leading to the activation of caspases 3/7 and 9 which is a committed step towards apoptosis. Annexin V-FITC/ PI assay and cell cycle, later confirmed the apoptosis and cell cycle arrest in 'G2/M' phase through flow cytometric analysis. CONCLUSION: In conclusion, a significant apoptogenic effect was exhibited by EAFD against HepG2 cells in inducing apoptosis and cell cycle arrest. Our findings indicate that the medicinal herb- Anethum graveolens, holds potential in treating hepatocellular carcinoma effectively. PMID- 29530612 TI - A New Critical Conformational Determinant of Multidrug Efflux by an MFS Transporter. AB - Secondary multidrug (Mdr) transporters utilize ion concentration gradients to actively remove antibiotics and other toxic compounds from cells. The model Mdr transporter MdfA from Escherichia coli exchanges dissimilar drugs for protons. The transporter should open at the cytoplasmic side to enable access of drugs into the Mdr recognition pocket. Here we show that the cytoplasmic rim around the Mdr recognition pocket represents a previously overlooked important regulatory determinant in MdfA. We demonstrate that increasing the positive charge of the electrically asymmetric rim dramatically inhibits MdfA activity and sometimes even leads to influx of planar, positively charged compounds, resulting in drug sensitivity. Our results suggest that unlike the mutants with the electrically modified rim, the membrane-embedded wild-type MdfA exhibits a significant probability of an inward-closed conformation, which is further increased by drug binding. Since MdfA binds drugs from its inward-facing environment, these results are intriguing and raise the possibility that the transporter has a sensitive, drug-induced conformational switch, which favors an inward-closed state. PMID- 29530613 TI - Shikimate Induced Transcriptional Activation of Protocatechuate Biosynthesis Genes by QuiR, a LysR-Type Transcriptional Regulator, in Listeria monocytogenes. AB - Listeria monocytogenes is a common foodborne bacterial pathogen that contaminates plant and animal consumable products. The persistent nature of L. monocytogenes is associated with millions of dollars in food recalls annually. Here, we describe the role of shikimate in directly modulating the expression of genes encoding enzymes for the conversion of quinate and shikimate metabolites to protocatechuate. In L. monocytogenes, these genes are found within two operons, named qui1 and qui2. In addition, a gene named quiR, encoding a LysR-Type Transcriptional Regulator (QuiR), is located immediately upstream of the qui1 operon. Transcriptional lacZ-promoter fusion experiments show that QuiR induces gene expression of both qui1 and qui2 operons in the presence of shikimate. Furthermore, co-crystallization of the QuiR effector binding domain in complex with shikimate provides insights into the mechanism of activation of this regulator. Together these data show that upon shikimate accumulation, QuiR activates the transcription of genes encoding enzymes involved in shikimate and quinate utilization for the production of protocatechuate. Furthermore, the accumulation of protocatechuate leads to the inhibition of Listeria growth. Since protocatechuate is not known to be utilized by Listeria, its role is distinct from those established in other bacteria. PMID- 29530614 TI - Food safety evaluation for R-proteins introduced by biotechnology: A case study of VNT1 in late blight protected potatoes. AB - Resistance genes (R-genes) from wild potato species confer protection against disease and can be introduced into cultivated potato varieties using breeding or biotechnology. The R-gene, Rpi-vnt1, which encodes the VNT1 protein, protects against late blight, caused by Phytophthora infestans. Heterologous expression and purification of active VNT1 in quantities sufficient for regulatory biosafety studies was problematic, making it impractical to generate hazard characterization data. As a case study for R-proteins, a weight-of-evidence, tiered approach was used to evaluate the safety of VNT1. The hazard potential of VNT1 was identified from relevant safety information including history of safe use, bioinformatics, mode of action, expression levels, and dietary intake. From the assessment it was concluded that Tier II hazard characterization was not needed. R-proteins homologous to VNT1 and identified in edible crops, have a history of safe consumption. VNT1 does not share sequence identity with known allergens. Expression levels of R-proteins are generally low, and VNT1 was not detected in potato varieties expressing the Rpi-vnt1 gene. With minimal hazard and negligible exposure, the risks associated with consumption of R-proteins in late blight protected potatoes are exceedingly low. R-proteins introduced into potatoes to confer late blight protection are safe for consumption. PMID- 29530615 TI - Skin sensitization quantitative risk assessment for occupational exposure of hairdressers to hair dye ingredients. AB - Occupational exposure of hairdressers to hair dyes has been associated with the development of allergic contact dermatitis (ACD) involving the hands. p Phenylenediamine (PPD) and toluene-2,5-diamine (PTD) have been implicated as important occupational contact allergens. To conduct a quantitative risk assessment for the induction of contact sensitization to hair dyes in hairdressers, available data from hand rinsing studies following typical occupational exposure conditions to PPD, PTD and resorcinol were assessed. By accounting for wet work, uneven exposure and inter-individual variability for professionals, daily hand exposure concentrations were derived. Secondly, daily hand exposure was compared with the sensitization induction potency of the individual hair dye defined as the No Expected Sensitization Induction Levels (NESIL). For PPD and PTD hairdresser hand exposure levels were 2.7 and 5.9 fold below the individual NESIL. In contrast, hand exposure to resorcinol was 50 fold below the NESIL. Correspondingly, the risk assessment for PPD and PTD indicates that contact sensitization may occur, when skin protection and skin care are not rigorously applied. We conclude that awareness of health risks associated with occupational exposure to hair dyes, and of the importance of adequate protective measures, should be emphasized more fully during hairdresser education and training. PMID- 29530616 TI - Safety evaluation of mulberry leaf extract: Acute, subacute toxicity and genotoxicity studies. AB - Mulberry (Morus alba L.) leaves are of broad popular use for food or remedy purposes due to their bioactive properties, especially antidiabetic activity and antioxidative activity. The present study aimed to assess the toxicological profile of mulberry leaf extract (MLE), through acute, subacute toxicity and genotoxicity tests. Male and female rats received by gavage 15.0 g/kg bw of MLE in the acute toxicity test, and 0, 1.88, 3.75 and 7.50 g/kg bw/d of MLE for subacute toxicity test. In the acute toxicity study, no mortality or behavioral changes were observed, indicating the LD50 is higher than 15.0 g/kg bw. In the subacute toxicity test, no significant changes were observed in hematological, biochemical or histopathological parameters in the animals exposed. The no observed-adverse-effect level in the subacute toxicity study was considered to be 7.50 g/kg bw/d, the highest dose tested. In the genotoxicity study, MLE showed no mutagenic activity in the Ames assay and no evidence of potential to induce chromosome aberrations or sperm abnormalities in mice exposed to 10 g/kg bw. Collectively, aqueous extract of mulberry leaves could be considered safe, and the results support the application of MLE as novel food ingredient or product. PMID- 29530617 TI - Neural Parallel Engine: A toolbox for massively parallel neural signal processing. AB - BACKGROUND: Large-scale neural recordings provide detailed information on neuronal activities and can help elicit the underlying neural mechanisms of the brain. However, the computational burden is also formidable when we try to process the huge data stream generated by such recordings. NEW METHOD: In this study, we report the development of Neural Parallel Engine (NPE), a toolbox for massively parallel neural signal processing on graphical processing units (GPUs). It offers a selection of the most commonly used routines in neural signal processing such as spike detection and spike sorting, including advanced algorithms such as exponential-component-power-component (EC-PC) spike detection and binary pursuit spike sorting. We also propose a new method for detecting peaks in parallel through a parallel compact operation. RESULTS: Our toolbox is able to offer a 5* to 110* speedup compared with its CPU counterparts depending on the algorithms. A user-friendly MATLAB interface is provided to allow easy integration of the toolbox into existing workflows. COMPARISON WITH EXISTING METHODS: Previous efforts on GPU neural signal processing only focus on a few rudimentary algorithms, are not well-optimized and often do not provide a user friendly programming interface to fit into existing workflows. There is a strong need for a comprehensive toolbox for massively parallel neural signal processing. CONCLUSIONS: A new toolbox for massively parallel neural signal processing has been created. It can offer significant speedup in processing signals from large scale recordings up to thousands of channels. PMID- 29530619 TI - O-GlcNAcylation of cardiac Nav1.5 contributes to the development of arrhythmias in diabetic hearts. AB - BACKGROUND: Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias. METHODS AND RESULTS: In this study, Sprague-Dawley rats (male, 200 230 g) were treated with a single high-dose of streptozotocin (STZ, 80 mg/kg) to generate a rat model of diabetes. STZ-induced 3-month diabetic rats displayed increased susceptibility to ventricular arrhythmias. The elevated O-GlcNAc modification was correlated with decreases in both total and cytoplasmic Nav1.5 expression in vivo and in vitro. In addition, both co-immunoprecipitation and immunostaining assays demonstrated that hyperglycemia could increase the O-GlcNAc modified Nav1.5 levels and decrease the interaction between Nav1.5 and Nav1.5 binding proteins Nedd4-2/SAP-97. Furthermore, patch-clamp measurements in HEK-293 T cells showed that Nav1.5 current densities decreased by 30% after high-glucose treatment, and the sodium currents increased via O-GlcNAc inhibition. CONCLUSION: Our data suggested that hyperglycemia increased the O-GlcNAc modification of Nav1.5 expression and decreased the interaction between Nav1.5 and Nedd4-2/SAP 97, which led to the abnormal expression and distribution of Nav1.5, loss of function of the sodium channel, and prolongation of the PR/QT interval. Excessive O-GlcNAc modification of Nav1.5 is a novel signaling event, which may be an underlying contributing factor for the development of the arrhythmogenesis in DH. PMID- 29530618 TI - CT derived left atrial size identifies left heart disease in suspected pulmonary hypertension: Derivation and validation of predictive thresholds. AB - BACKGROUND: Patients with pulmonary hypertension due to left heart disease (PH LHD) have overlapping clinical features with pulmonary arterial hypertension making diagnosis reliant on right heart catheterization (RHC). This study aimed to investigate computed tomography pulmonary angiography (CTPA) derived cardiopulmonary structural metrics, in comparison to magnetic resonance imaging (MRI) for the diagnosis of left heart disease in patients with suspected pulmonary hypertension. METHODS: Patients with suspected pulmonary hypertension who underwent CTPA, MRI and RHC were identified. Measurements of the cardiac chambers and vessels were recorded from CTPA and MRI. The diagnostic thresholds of individual measurements to detect elevated pulmonary arterial wedge pressure (PAWP) were identified in a derivation cohort (n = 235). Individual CT and MRI derived metrics were tested in validation cohort (n = 211). RESULTS: 446 patients, of which 88 had left heart disease. Left atrial area was a strong predictor of elevated PAWP>15 mm Hg and PAWP>18 mm Hg, area under curve (AUC) 0.854, and AUC 0.873 respectively. Similar accuracy was also identified for MRI derived LA volume, AUC 0.852 and AUC 0.878 for PAWP > 15 and 18 mm Hg, respectively. Left atrial area of 26.8 cm2 and 30.0 cm2 were optimal specific thresholds for identification of PAWP > 15 and 18 mm Hg, had sensitivity of 60%/53% and specificity 89%/94%, respectively in a validation cohort. CONCLUSIONS: CTPA and MRI derived left atrial size identifies left heart disease in suspected pulmonary hypertension with high specificity. The proposed diagnostic thresholds for elevated left atrial area on routine CTPA may be a useful to indicate the diagnosis of left heart disease in suspected pulmonary hypertension. PMID- 29530620 TI - Influence of vitamin K antagonists and direct oral anticoagulation on coronary artery disease: A CTA analysis. AB - OBJECTIVE: Vitamin K antagonists (VKA) are associated with increased vascular calcification which may lead to an elevated cardiovascular risk. If the direct anticoagulants (DOACs) have similar negative vascular effects is unknown. We evaluated the influence of different anticoagulation strategies on coronary artery disease (CAD) using coronary computed tomography angiography (CTA). METHODS: Overall 702 consecutive patients with non-valvular atrial fibrillation (AF) who underwent CTA for AF ablation planning were enrolled and stratified according to their anticoagulation into VKA, DOAC (all agents) and a control group without oral anticoagulation. Patients were propensity score matched 1:1:1, significant structural heart disease and comorbidities were excluded. CT images were evaluated for plaque burden (calcium score, segment involvement score (SIS) and non-calcified SIS, stenosis grading) and plaque morphology (high risk plaque features: low attenuation, positive remodeling, napkin-ring sign, spotty calcification). RESULTS: Final analysis included 303 patients (101 patients each group) and showed increased overall plaque burden in patients using VKA compared to DOAC users and the control group (mean affected segments 2.58 vs 1.58 vs 2.100, p = 0.008), and a higher prevalence of high-risk plaque (HRP) features (42.6% vs 13.9% vs 26.7%, p < 0.0001). Patients treated with DOACs did not differ in conventional CT findings from the control group and showed an even lower prevalence of selected HRP features compared to the control group: low attenuation plaques (4.0% vs. 14.4%, p = 0.014) and napkin-ring sign (0 vs. 5.0%, p = 0.029). CONCLUSION: Vitamin K antagonists are associated with a higher plaque burden and increased high-risk plaque features, whereas DOACs may yield a benefit in cardiovascular atherosclerosis. PMID- 29530621 TI - Right ventricular systolic dysfunction at rest is not related to decreased exercise capacity in patients with a systemic right ventricle. AB - BACKGROUND: To evaluate the relationship between right ventricular (RV) systolic dysfunction at rest and reduced exercise capacity in patients with a systemic RV (sRV). METHODS: All patients with congenitally corrected transposition of the great arteries (ccTGA) or complete TGA after atrial switch (TGA-Mustard/Senning) followed in our institution between July 2011 and September 2017 who underwent cardiac imaging within a six-month time period of cardiopulmonary exercise testing (CPET) were analyzed. We assessed sRV systolic function with TAPSE and fractional area change on echocardiogram and, if possible, with ejection fraction, global longitudinal and circumferential strain on cardiac magnetic resonance (CMR) imaging. RESULTS: We studied 105 patients with an sRV (median age 34 [IQR 28-42] years, 29% ccTGA and 71% TGA-Mustard/Senning) of which 39% had either a pacemaker (n = 17), Eisenmenger physiology (n = 6), severe systemic atrioventricular valve regurgitation (n = 14), or peak exercise arterial oxygen saturation < 92% (n = 17). Most patients were asymptomatic or mildly symptomatic (NYHA class I/II/III in 71/23/6%). Sixty-four percent had evidence of moderate or severe sRV dysfunction on cardiac imaging. Mean peak oxygen uptake (pVO2) was 24.1 +/- 7.4 mL/kg/min, corresponding to a percentage of predicted pVO2 (%ppVO2) of 69 +/- 17%. No parameter of sRV systolic function as evaluated on echocardiography (n = 105) or CMR (n = 46) was correlated with the %ppVO2, even after adjusting for associated cardiac defects or pacemakers. CONCLUSIONS: In adults with an sRV, there is no relation between echocardiographic or CMR-derived sRV systolic function parameters at rest and peak oxygen uptake. Exercise imaging may be superior to evaluate whether sRV contractility limits exercise capacity. PMID- 29530622 TI - Acute administration of capsaicin increases resting energy expenditure in young obese subjects without affecting energy intake, appetite, and circulating levels of orexigenic/anorexigenic peptides. AB - Although capsaicin has been reported to reduce energy intake and increase energy expenditure in an adult (normal weight or overweight) population, thus resulting in a net negative energy balance and weight loss, these beneficial effects have not been investigated in young obese subjects. We hypothesize that capsaicin acutely administered in young obese subjects exerts the same effects on energy balance and that these effects are mediated by changes in gastrointestinal peptides regulating appetite. Thus, the aim of the present study was to evaluate the acute effects of capsaicin (2 mg) or placebo on energy intake, hunger, and satiety in obese adolescents and young adults (female-male ratio: 4:6, age: 21.0 +/- 5.8 years; body mass index: 41.5 +/- 4.3 kg/m2) provided an ad libitum dinner. Furthermore, circulating levels of some orexigenic (ghrelin) and anorexigenic (glucagon-like peptide 1 and peptide YY) peptides were measured after a meal completely consumed (lunch), together with the evaluation of hunger and satiety and assessment of resting energy expenditure (REE) through indirect computerized calorimetry. When compared to placebo, capsaicin did not significantly change either energy intake or hunger/satiety 6 hours after its administration (dinner). No differences in circulating levels of ghrelin, glucagon-like peptide 1, and peptide YY and in hunger/satiety were found in the 3 hours immediately after food ingestion among obese subjects treated with capsaicin or placebo (lunch). By contrast, the meal significantly increased REE in the capsaicin- but not placebo-treated group (capsaicin: from 1957.2 +/- 455.1 kcal/d up to 2342.3 +/- 562.1 kcal/d, P < .05; placebo: from 2060.1 +/- 483.4 kcal/d up to 2296.0 +/- 484.5 kcal/d). The pre-post meal difference in REE after capsaicin administration was significantly higher than that observed after placebo (385.1 +/- 164.4 kcal/d vs 235.9 +/- 166.1 kcal/d, P < .05). In conclusion, although capsaicin does not exert hypophagic effects, these preliminary data demonstrate its ability as a metabolic activator in young obese subjects. PMID- 29530623 TI - Injury patterns of fatal bear attacks in Japan: A description of seven cases. AB - In recent years, the number of bear attacks has risen in Akita prefecture, Japan. Here, we present the injury patterns of seven fatal bear attacks, and discuss the implication of these findings. We included five cases of Asiatic black bear attacks and two cases of Ezo brown bear attacks. In all cases, the injuries, 2-5 parallel linear lacerations with severe hemorrhaging and decollement, were mainly located on the upper body. These injuries were thought to be fatal as, upon a first encounter, bears often stand and first attack the victim's head and face using their claws. Four lacerations were located at the vertex of the trapezoid in all cases, without severe hemorrhaging on the neck, extremities, or around the antemortem injuries. These injuries were thought to be bite marks incurred by the bears' four large canines, mainly occurring postmortem during the process of predation. These findings differed from those of fatal biting around the neck by other animals such as lions, mountain lions, or large-sized dogs. Further, laceration with avulsion of the skin was found in the inguinal region, without severe hemorrhaging. In some cases, the intestine had been removed from the inguinal injury for predation. In conclusion, the injuries of bear attacks are different from those caused by other animals, owing to the characteristics of bears. By investigating the injuries caused by fatal bear attacks, we can better understand the patterns of such injuries. Especially, the diameter between the canines is sometimes useful to estimate the size and the number of offending bears. PMID- 29530624 TI - The skeletal trauma resulting from a fatal B.A.S.E jump: A case study showing the impact of landing feet-first under extreme vertical deceleration. AB - The term 'B.A.S.E jump' refers to jumping from a building, antenna, span (i.e., bridge) or earth (i.e., cliff) structure, and parachuting to the ground. There are numerous hazards associated with B.A.S.E jumps which often result in injury and, occasionally, fatality. This case report details the skeletal trauma resulting from a fatal B.A.S.E jump in Australia. In this case, the jumper impacted the ground from a fall of 439m in a feet-first landing position, as a result of a partially deployed parachute, under extreme vertical deceleration. Skeletal trauma was analyzed using full-body post mortem computed tomography (PMCT) and contextual information related to the circumstances of the jump as reported by the Coroner. Trauma to 61 skeletal elements indicates the primary impact was to the feet (i.e., feet-first landing), followed by an anterior impact to the body (i.e., fall forwards). Details of the individual fracture morphologies indicate the various forces and biomechanics involved in this fall event. This case presents the types of fractures that result from a B.A.S.E jump, and highlights the value of using PMCT and coronial data as tools to augment skeletal trauma interpretations. PMID- 29530625 TI - Non-pharmacological techniques for the extremes of the cough spectrum. AB - Cough can be viewed as a continuum where extremes represent disease phenotypes. Under this unified concept, non-pharmacological treatment for the extremes of the cough spectrum includes both cough augmentation and cough control techniques. Supporting the cough motor output and exercising the cognitive control on coughing are the main directions of these techniques. Cough augmentation can be provided to patients who present low ability to generate adequate peak cough flows, with the aim to develop the sheering forces that are essential for effective airway clearance. On the other hand, individuals with high cough sensitivity or frequency can practice techniques for cough control, which incorporates a combination of education, retraining and psychological support. These techniques aim to empower patients to increase their supramedulary control on cough. Although hypotheses that are generated by the physiology of cough can support most non-pharmacological techniques, their exact mechanisms of effectiveness remain unclear. PMID- 29530626 TI - Standardized EEG interpretation in patients after cardiac arrest: Correlation with other prognostic predictors. AB - INTRODUCTION: Standardized EEG patterns according to the American Clinical Neurophysiology Society (ACNS) ("highly malignant", "malignant" and "benign") demonstrated good correlation with outcome after cardiac arrest (CA). However, this approach relates to EEGs after target temperature management (TTM), and correlation to other recognized outcome predictors remains unknown. OBJECTIVES: To investigate the relationship between categorized EEG and other outcome predictors, during and after TTM, at different temperatures. METHODS: In a prospective adult CA registry between 01.2014 and 06.2017, EEG at day one and two after CA were reclassified into pre-defined categories. Correlations between EEG and clinical, biochemical, neurophysiological outcome predictors, and prognosis (CPC at three months; good: 1-2), were assessed. RESULTS: Of 203 CA episodes, 31.5% were managed targeting 33 degrees C, 60.6% targeting 36 degrees C, and 7.9% with spontaneous temperature. "Highly malignant" EEG was found in 36.7% of patients at day one (predicting poor prognosis with 91% specificity -95%CI: 83% 97%-, and 63% sensitivity -95% CI: 53%-72%), and 27.1% at day two. "Benign" EEG occurred in 19.2% at day one (sensitivity to good prognosis: 35% -95%CI: 26%-46% , positive predictive value: 89% -95% CI: 75%-97%), and in 33.2% at day two. Categorized EEG showed robust correlations with all prognostic predictors. Results were similar between EEGs recorded at day one or two, and, especially for poor prognosis, across TTM targets. DISCUSSION: Standardized EEG categorization after CA shows strong correlation with other outcome predictors, without marked variation across EEG recording time or TTM targets, underscoring its prognostic role in a multimodal approach. PMID- 29530627 TI - Consensus document on osteoporosis in males. AB - OBJECTIVE: To provide practical recommendations to assess and treat osteoporosis in males. PARTICIPANTS: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. METHODS: Recommendations were formulated using the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in Medline (PubMed) using the following associated terms: "osteoporosis", "men", "fractures", "bone mineral density", "treatment", "hypogonadism", and "prostate cancer". Papers in English and Spanish with publication date before 30 August 2017 were included. Current evidence for each disease was reviewed by 2group members. Finally, recommendations were discussed in a meeting of the working group. CONCLUSIONS: The document provides evidence-based practical recommendations for diagnosis, assessment, and management of osteoporosis in men and special situations such as hypogonadism and prostate cancer. PMID- 29530628 TI - Critical flicker frequency test predicts overt hepatic encephalopathy and survival in patients with liver cirrhosis. AB - BACKGROUND: A critical flicker frequency (CFF) <=39 Hz identifies cirrhotic patients with minimal hepatic encephalopathy (mHE) and predicts the risk of both overt hepatic encephalopathy (oHE) and mortality in patients with previous episodes of decompensation and/or oHE. AIMS: Herein, we evaluated the effectiveness of CFF in predicting the first episode of oHE and survival in cirrhotics who had never experienced an episode of oHE. METHODS: Our cohort study of 134 patients and 150 healthy subjects were examined. A CFF > 39 Hz was considered normal and pathological when <=39 Hz. The median follow up was 36 months. RESULTS: At baseline, all controls had CFF > 39 Hz. Ninety-three patients had a CFF > 39 Hz and 41 had a CFF <= 39 Hz. The prevalence of CFF <= 39 Hz significantly increased with the progression of the Child-Pugh class (p = 0.003). Moreover, the risk of oHE was increased by CFF <= 39 (p < 0.001, by log-rank test) [HR = 7.57; CI(3.27-17.50); p < 0.0001, by Cox model] and ammonia [HR = 1.02 CI(1.01-1.03), p = 0.0009]. Both a CFF value <= 39 Hz and Child-Pugh class were independent predictors of mortality by Cox model [HR = 1.97; CI(1.01-3.95), p = 0.049; HR = 3.85 CI(1.68-8.83), p = 0.003]. CONCLUSIONS: CFF predicts the first episode of oHE in cirrhotics that had never experienced oHE, and predicts mortality risk. These findings suggest that cirrhotic patients should be routinely screened by CFF. PMID- 29530629 TI - Three-dimensional Navigation for Thoracoscopic Sublobar Resection Using a Novel Wireless Marking System. AB - We developed a novel localization technique for small intrapulmonary lesions using radiofrequency identification (RFID) technology. Micro-RFID markers with nickel-titanium coils were designed to be placed from subsegmental bronchi to the peripheral parenchyma. In this preclinical study, thoracoscopic subsegmentectomy of a canine pseudotumor model was performed to demonstrate the feasibility and three-dimensional positional accuracy of the system. To recover subcentimeter pseudotumors, markers were bronchoscopically placed to determine the resection line: (1) next to the pseudotumor; (2) in the responsible subsegmental bronchi as the central margin; and (3) on the intersubsegmental plane as the lateral margin. Specific marker positions were located by wireless communication using a wand shaped probe with a 30-mm communication range, with the distance to the marker indicated by gradual changes in sound pitch. Thirty-four markers were placed for 10 pseudotumors (14.6 mm from the pleura) in 10 canines. Three markers were placed at a mean distance of 5.5 mm from the pseudotumors, and 11 central and 20 lateral markers were placed at mean distances of 17.2 and 20.7 mm from the pseudotumors, respectively. Central markers (20.5 mm from the pleura) were detected within 16.0 seconds in 2.9-mm-diameter bronchi. All resection stumps were within 5.4 mm (range 2-8 mm) from each marker, and pseudotumors were removed with adequate surgical margins toward the central (11.5 mm; range 7-16 mm) and lateral (12.4 mm; range 9-17 mm) directions. RFID wireless markers provided precise three-dimensional positional information and are a potential viable alternative to conventional markers. PMID- 29530630 TI - Evolution of the mating types and mating strategies in prominent genera in the Botryosphaeriaceae. AB - Little is known regarding mating strategies in the Botryosphaeriaceae. To understand sexual reproduction in this fungal family, the mating type genes of Botryosphaeria dothidea and Macrophomina phaseolina, as well as several species of Diplodia, Lasiodiplodia and Neofusicoccum were characterized from whole genome assemblies. Comparisons between the mating type loci of these fungi showed that the mating type genes are highly variable, but in most cases the organization of these genes is conserved. Of the species considered, nine were homothallic and seven were heterothallic. Mating type gene fragments were discovered flanking the mating type regions, which indicates both ongoing and ancestral recombination occurring within the mating type region. Ancestral reconstruction analysis further indicated that heterothallism is the ancestral state in the Botryosphaeriaceae and this is supported by the presence of mating type gene fragments in homothallic species. The results also show that at least five transitions from heterothallism to homothallism have taken place in the Botryosphaeriaceae. The study provides a foundation for comparison of mating type evolution between Botryosphaeriaceae and other fungi and also provides valuable markers for population biology studies in this family. PMID- 29530631 TI - What's New in Rezum? AB - : Management of benign prostatic hyperplasia focuses on relief of lower urinary tract symptoms (LUTSs), improvement of quality of life, and prevention of symptom progression. Minimally invasive surgical treatments (MISTs) offer potential for rapid symptomatic relief, medication independence, and less perioperative risk. The Rezum system is a novel MIST that uses water vapor thermal therapy to ablate obstructive prostate tissue. In this review, we summarize the data revealing that water vapor thermal therapy provides clinically meaningful, rapid, and durable relief of LUTSs in both storage and voiding functions while providing a minimal impact on sexual function. PATIENT SUMMARY: The expanding body of literature examining Rezum water vapor thermal therapy suggests that it is a safe, efficacious, and durable treatment modality for lower urinary tract symptoms that can be offered to a wide selection of patients. PMID- 29530632 TI - Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi institutional Case-control Study. AB - BACKGROUND: Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. OBJECTIVE: To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). DESIGN, SETTING, AND PARTICIPANTS: PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. INTERVENTION: The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography detected nodal recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS AND LIMITATIONS: At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. CONCLUSIONS: MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis generating and inform future randomized trials in this setting. PATIENT SUMMARY: Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes. PMID- 29530633 TI - Chicken immune response following in ovo delivery of bacterial flagellin. AB - In ovo immunization of chicken embryos with live vaccines is an effective strategy to protect chickens against several viral pathogens. We investigated the immune response of chicken embryos to purified recombinant protein. In ovo delivery of Salmonella flagellin to 18-day old embryonated eggs resulted in elevated pro-inflammatory chIL-6 and chIL-8 (CXCL8-CXCLi2) cytokine transcript levels in the intestine but not in the spleen at 24 h post-injection. Analysis of the chicken Toll-like receptor (TLR) repertoire in 19-day old embryos revealed gene transcripts in intestinal and spleen tissue for most chicken TLRs, including TLR5 which recognizes Salmonella flagellin (FliC). The in ovo administration of FliC did not alter TLR transcript levels, except for an increase in intestinal chTLR15 expression. Measurement of the antibody response in sera collected at day 11 and day 21 post-hatch demonstrated high titers of FliC-specific antibodies for the animals immunized at the late-embryonic stage in contrast to the mock-treated controls. The successful in ovo immunization with purified bacterial antigen indicates that the immune system of the chicken embryo is sufficiently mature to yield a strong humoral immune response after single exposure to purified protein. This finding strengthens the basis for the development of in ovo protein-based subunit vaccines. PMID- 29530635 TI - Post stem cell transplantation revaccination: A survey of the current practices in India. AB - BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients are more susceptible to infections from vaccine preventable diseases (VPDs) than the general population. Indian stem cell transplant registry (ISCTR) post-BMT vaccination guidelines were formulated in 2015. The objective of the survey was to assess the compliance to these guidelines among transplant physicians in India. MATERIALS AND METHODS: This is a cross-sectional survey executed as the quantitative research strategy to explore the various aspects of vaccination practices among transplant physicians in India. The 'data collection tool' included 36 predetermined questions related to vaccination of the patients and their close contacts. Theoretical construct of the questionnaire was face validated and questionnaire survey forms were emailed individually as attachments or by google forms. This study is being reported based on the checklist for reporting results of internet e-surveys statement guidelines. RESULTS: Survey forms were sent to 105 transplant physicians in India, 62% of whom responded representing 78.8% of transplant centers in India. More than 90% of allogeneic transplant physicians and 64% of autologous transplant physicians offered vaccination. Over two third of the physicians responded that they would discontinue vaccination at the onset of cGVHD. Fewer than one third physicians offered vaccination against Hepatitis A, Typhoid or Meningococcal infections. Forty two percent of respondents were unaware of the ISCTR post-BMT vaccination protocol. Only 47% of respondents reported complete adherence to any of the protocols they were following. Immune reconstitution to guide vaccination was available only to 13.3 percent of respondents. CONCLUSION: There is a need to improve the implementation strategies of vaccination in HSCT recipients to increase the adherence and continuation of it even in the presence of GVHD. There is also a need to extend the vaccination among VPDs especially prevalent in India. PMID- 29530634 TI - Early and long term anamnestic response to HBV booster dose among fully vaccinated Egyptian children during infancy. AB - OBJECTIVE: To evaluate early and long term anamnestic response to a booster dose of HBV vaccine among non-seroprotected children. SUBJECTS AND METHOD: A national community based project was carried out on 3600 children aged 9 months to 16 years, fully vaccinated during infancy. They were recruited from 6 governorates representing Egypt. It revealed that 1535 children (42.8%) had non sero protective anti-HBs (<10 IU/L) and were HBsAg or anti-HBc negative. A challenging dose of 10 MUg of mono-valent Euvax HBV vaccine was given to 1121/1535 children. Quantitative assessment of anti-HBs was performed to detect early (2-4 weeks) and long term (one year) anamnestic responses. RESULTS: Early anamnestic response developed among 967/1070 children (90.3%).Children having detectable anti-HBs (1 9 IU/L) significantly developed early anamnestic response (90%) compared to 85% with undetectable anti-HBs (<1 IU/L), P < 0.001. Multiple logistic analysis revealed that undetectable anti-HBs, living in rural residence and children aged 15-16 years were the most significant predicting risk factors for the absence of early anamnestic response (<10 IU/L), with AOR 2.7, 2.7 & 4.7 respectively. After one year, long term anamnestic response was absent among 15% of children who previously showed early response. Poor early anamnestic response and undetectable pre-booster anti-HBs were the significant predicting risk factors for absent long term anamnestic response, with AOR 18.7 & 2.7 respectively. CONCLUSION: Immunological memory for HBV vaccine outlasts the presence of anti- HBs and HBV vaccination program provides effective long term protection even in children showing waning or undetectable concentrations of anti-HBs. This signifies no need for a booster dose especially to healthy children. PMID- 29530636 TI - Complex Polygenic Nature of Testicular Germ Cell Cancer Suggests Multifactorial Aetiology. PMID- 29530638 TI - Metabolism and disposition of arsenic species after repeated oral dosing with sodium arsenite in drinking water. II. Measurements in pregnant and fetal CD-1 mice. AB - Arsenic is ubiquitous in the earth's crust, and human diseases are linked with exposures that are similar to dietary intake estimates. Metabolic methylation of inorganic arsenic facilitates excretion of pentavalent metabolites and decreases acute toxicity; however, tissue binding of trivalent arsenic intermediates is evidence for concomitant metabolic activation. Pregnant and fetal CD-1 mice comprise a key animal model for arsenic carcinogenesis since adult-only exposures have minimal effects. This study evaluated inorganic arsenic and its metabolites in pentavalent and trivalent states in blood and tissues from maternal and fetal CD-1 mice after repeated administration of arsenite through drinking water. After 8 days of exposure, DMA species were ubiquitous in dams and fetuses. Despite the presence of MMAIII in dams, none was observed in any fetal sample. This difference may be important in assessing fetal susceptibility to arsenic toxicity because MMA production has been linked with human disease. Binding of DMAIII in fetal tissues provided evidence for metabolic activation, although the role for such binding in arsenic toxicity is unclear. This study provides links between administered dose, metabolism, and internal exposures from a key animal model of arsenic toxicity to better understand risks from human exposure to environmental arsenic. PMID- 29530637 TI - Colonic metabolites from flavanols stimulate nitric oxide production in human endothelial cells and protect against oxidative stress-induced toxicity and endothelial dysfunction. AB - Oxidative stress is involved in endothelial dysfunction, the key player in the development of vascular events. Flavanols, the major antioxidants in cocoa have been related to vascular protection and lower cardiovascular risk. However, the bioavailability of cocoa flavanols is very low and their bioactivity in vivo seems to be greatly mediated by the derived phenolic metabolites formed by intestinal microbiota. Hence, we investigated whether microbial-derived flavanol metabolites 3,4-dihydroxyphenylacetic acid (DHPAA), 2,3-dihydroxybenzoic acid (DHBA), 3-hydroxyphenylpropionic acid (HPPA) and a mix of them could influence endothelial function and prevent oxidative stress in human endothelial cells (Ea.hy926). Our results revealed that a mixture of flavanol colonic metabolites significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. By using specific inhibitors, we also established the participation of the adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) in eNOS activation. Likewise, flavanol metabolite mix protected against oxidative stress-induced endothelial dysfunction and cell death by preventing increased ROS generation and activation of signaling pathways related to oxidative stress. We concluded that flavanol colonic metabolites could exert beneficial effects in endothelial cells and prevent oxidative stress-induced vascular dysfunction. PMID- 29530639 TI - A subchronic feeding safety evaluation of transgenic milk containing human beta defensin 3 on reproductive system of C57BL/6J mouse. AB - Bovine mastitis is an infectious disease of the mammary gland which has been generally treated by antibiotic delivery. While the increasing drug-resistant bacteria and the high consumption of the antibiotic had become a noticeable concern. In a previous study, a mammary special vector expressing human beta defensin 3 (hBD3) was transfected into bovine fetal fibroblasts to produce mastitis-resistant bovine. This investigation focused on potential unintended effects of transgenic milk containing hBD3 produced by these mastitis-resistant bovine on the reproductive system of C57BL/6J mice. Mice were fed with diets containing transgenic milk or conventional milk, nutritionally balanced to an AIN93G diet for 90 days, and non-milk diet was selected as the negative group. The reproductive system was given special attention including reproductive organ/body ratios, necropsy and histopathology, serum sex hormone, sperm parameters, estrus cycle and the expression level of some specific genes which could indicate the development and function of reproductive system. No diet related significant differences were observed among three groups in this 90-day feeding study. The results indicated that hBD3 milk does not appear to exert any effect on the reproductive system in C57BL/6J rats compared with conventional milk or the control diet. PMID- 29530640 TI - Beauvericin and enniatin B effects on a human lymphoblastoid Jurkat T-cell model. AB - Several mycotoxins exert their effect on the immunological system; some are classified as immunotoxic. Jurkat T-cells were used to study toxic effects of beauvericin (BEA) and enniatin B (ENN B). Both are not legislated mycotoxins with increasing presence in feed and food. Concentrations studied were from 1 to 15 MUM at 24, 48 and 72 h. Cell death by increasing the percentage of apoptotic/necrotic cells was: BEA > ENN B. IC50 values ranged from 3 to 7.5 MUM for BEA. ENN B 15 MUM decreased viability (21-29%). The percentage of apoptotic/necrotic cells was BEA > ENN B at 24 h but not at 48 h. Caspase-3&7 activation profile varied, although both mycotoxins increased this activation. No difference in ROS production for any mycotoxin was observed. Arrest in S phase for both mycotoxins was obtained. BEA increased the percentage of DNA in the tail (18% and 20%) with respect to the control, whereas not for ENN B. In summary, cytotoxicity of BEA involved mitochondrial alterations; while ENN B only at highest concentrations and time assayed. BEA had cell cycle disturbances and apoptotic and apoptotic/necrotic cells increased; for ENN B these were not evident. Different toxic responses in Jurkat T-cells may be involved in BEA and ENN B toxicity. PMID- 29530641 TI - Body mass index and clinical outcomes in trastuzumab-treated metastatic breast cancer patients: An alternative explanation for the lack of association. PMID- 29530642 TI - Transient anoxia during Metarhizium robertsii growth increases conidial virulence to Tenebrio molitor. AB - Little is known about the phenotypic effects of hypoxia and transient anoxia on the virulence of an entomopathogenic fungus. Conidia of Metarhizium robertsii were produced on: (1) potato dextrose agar medium (PDA) under normoxia; (2) PDA medium under continuous hypoxia; (3) PDA medium under transient anoxia; and (4) minimal medium with lactose (MML) under normoxia. Conidia produced under transient anoxia and produced on MML were the most virulent to Tenebrio molitor. Conidia produced under normoxia and hypoxia were the least virulent. Conidial production and germination speed of conidia produced under normoxia, hypoxia, and transient anoxia were similar; however, MML produced less conidia, but germinated faster than any other treatments. PMID- 29530643 TI - Zika virus: from an obscurity to a priority. AB - Despite being discovered approximately 70 years ago, Zika virus (ZIKV) has received little attention, until the occurrence of alarming epidemics in the Pacific Islands and Latin America between 2013 and 2016. These series of outbreaks resulted in crippling neurological complications in adults, and congenital deformities in new-borns. The dire outcomes marked ZIKV as a re emerging pathogen of public health concern. Over a period of two years, extensive studies have been conducted to understand different aspects of ZIKV from pathogen biology to infection, including the immune response during virus-host interplay in established animal models, as well as potential therapeutics against ZIKV infection. The vast diversity of novel findings has added value to ZIKV research, and a strategic consolidation is crucial to encompass the latest advances and developments, as well as missing pieces of the puzzle. This review thus aims to provide a concise yet extensive update on current ZIKV studies. PMID- 29530644 TI - Do clinicians want recommendations? A multicenter study comparing evidence summaries with and without GRADE recommendations. AB - OBJECTIVES: Evidence-based clinical practice guidelines provide recommendations to assist clinicians in decision-making and to reduce the gap between best current research evidence and clinical practice. However, some argue that providing preappraised evidence summaries alone, rather than recommendations, is more appropriate. The objective of the study is to evaluate clinicians' preferences, and understanding of the evidence and intended course of action in response to evidence summaries with and without recommendations. STUDY DESIGN SETTING: We included practicing clinicians attending educational sessions across 10 countries. Clinicians were randomized to receive relevant clinical scenarios supported by research evidence of low or very low certainty and accompanied by either strong or weak recommendations developed with the GRADE system. Within each group, participants were further randomized to receive the recommendation plus the corresponding evidence summary or the evidence summary alone. We evaluated participants' preferences and understanding for the presentation strategy, as well as their intended course of action. RESULTS: One hundred eighty nine of 219 (86%) and 201 of 248 (81%) participants preferred having recommendations accompanying evidence summaries for both strong and weak recommendations, respectively. Across all scenarios, less than half of participants correctly interpreted information provided in the evidences summaries (e.g., estimates of effect, certainty in the research evidence). The presence of a recommendation resulted in a more appropriate intended course of action for two scenarios involving strong recommendations. CONCLUSION: Evidence summaries alone are not enough to impact clinicians' course of action. Clinicians clearly prefer having recommendations accompanying evidence summaries in the context of low or very low certainty of evidence (Trial registration NCT02006017). PMID- 29530645 TI - Is there more to the clinical outcome in posttraumatic reconstruction of the inferior and medial orbital walls than accuracy of implant placement and implant surface contouring? A prospective multicenter study to identify predictors of clinical outcome. AB - PURPOSE: Reconstruction of orbital wall fractures is demanding and has improved dramatically with the implementation of new technologies. True-to-original accuracy of reconstruction has been deemed essential for good clinical outcome, and reasons for unfavorable clinical outcome have been researched extensively. However, no detailed analysis on the influence of plate position and surface contour on clinical outcome has yet been published. MATERIALS AND METHODS: Data from a previous study were used for an ad-hoc analysis to identify predictors for unfavorable outcome, defined as diplopia or differences in globe height and/or globe projection of >2 mm. Presumed predictors were implant surface contour, aberrant implant dimension or position, accuracy of reconstructed orbital volume, and anatomical fracture topography according to the current AO classification. RESULTS: Neither in univariable nor in multivariable regression models were unfavorable clinical outcomes associated with any of the presumed radiological predictors, and no association of the type of implant, i.e., standard preformed, CAD-based individualized and non-CAD-based individualized with its surface contour could be shown. CONCLUSION: These data suggest that the influence of accurate mechanical reconstruction on clinical outcomes may be less predictable than previously believed, while the role of soft-tissue-related factors may have been underestimated. PMID- 29530646 TI - Morpholino-mediated in vivo silencing of Cryptosporidium parvum lactate dehydrogenase decreases oocyst shedding and infectivity. AB - Cryptosporidium is a highly prevalent protozoan parasite that is the second leading cause of childhood morbidity and mortality due to diarrhoea in developing countries, and causes a serious diarrheal syndrome in calves, lambs and goat kids worldwide. Development of fully effective drugs against Cryptosporidium has mainly been hindered by the lack of genetic tools for functional characterization and validation of potential molecular drug targets in the parasite. Herein, we report the development of a morpholino-based in vivo approach for Cryptosporidium parvum gene knockdown to facilitate determination of the physiological roles of the parasite's genes in a murine model. We show that, when administered intraperitoneally at non-toxic doses, morpholinos targeting C. parvum lactate dehydrogenase (CpLDH) and sporozoite 60K protein (Cp15/60) were able to specifically and sustainably down-regulate the expression of CpLDH and Cp15/60 proteins, respectively, in C. parvum-infected interferon-gamma knockout mice. Over a period of 6 days of daily administration of target morpholinos, CpLDH and Cp15/60 proteins were down-regulated by 20- to 50-fold, and 10- to 20-fold, respectively. Knockdown of CpLDH resulted in approximately 80% reduction in oocyst load in the feces of mice, and approximately 70% decrease in infectivity of the sporozoites excysted from the shed oocysts. Cp15/60 knockdown did not affect oocyst shedding nor infectivity but, nevertheless, provided a proof-of principle for the resilience of the morpholino-mediated C. parvum gene knockdown system in vivo. Together, our findings provide a genetic tool for deciphering the physiological roles of C. parvum genes in vivo, and validate CpLDH as an essential gene for the growth and viability of C. parvum in vivo. PMID- 29530647 TI - Diversity of Entamoeba spp. in African great apes and humans: an insight from Illumina MiSeq high-throughput sequencing. AB - Understanding the complex Entamoeba communities in the mammalian intestine has been, to date, complicated by the lack of a suitable approach for molecular detection of multiple variants co-occurring in mixed infections. Here, we report on the application of a high throughput sequencing approach based on partial 18S rDNA using the Illumina MiSeq platform. We describe, to our knowledge, for the first time, the Entamoeba communities in humans, free-ranging western lowland gorillas and central chimpanzees living in the Dja Faunal Reserve in Cameroon. We detected 36 Entamoeba haplotypes belonging to six haplotype clusters, containing haplotypes possessing high and low host specificity. Most of the detected haplotypes belonged to commensal Entamoeba, however, the pathogenic species (Entamoeba histolytica and Entamoeba nuttalli) were also detected. We observed that some Entamoeba haplotypes are shared between humans and other hosts, indicating their zoonotic potential. The findings are important not only for understanding the epidemiology of amoebiasis in humans in rural African localities, but also in the context of wild great ape conservation. PMID- 29530648 TI - Refined ab initio gene predictions of Heterorhabditis bacteriophora using RNA seq. AB - Interest has recently grown in developing the entomopathogenic nematode Heterorhabditis bacteriophora as a model to genetically dissect the process of parasitic infection. Despite the availability of a full genome assembly, there is substantial variation in gene model accuracy. Here, a methodology is presented for leveraging RNA-seq evidence to generate improved annotations using ab initio gene prediction software. After alignment of reads and subsequent generation of a RNA-seq supported annotation, the new gene prediction models were verified on a selection of genes by comparison with sequenced 5' and 3' rapid amplification of cDNA ends products. By utilising a whole transcriptome for genome annotation, the current reference annotation was enriched, demonstrating the importance of coupling transcriptional data with genome assemblies. PMID- 29530649 TI - Metaplastic woven bone in bone metastases: A Fourier-transform infrared analysis and imaging of bone quality (FTIR). AB - Most osteolytic tumors are in fact mixed and contain an osteoblastic component associated with the predominant osteolytic areas. This metaplastic woven bone is always evidenced by histological analysis even in the absence of radiological expression. Metaplastic bone formation reflects the activation of new osteoblasts coming from the stimulation of the dormant lining cells. Twelve patients with secondary metastases of the iliac crest evidenced by hot spots on a 99Tc-MBP san were diagnosed by histomorphometry on bone biopsies. Fourier Transformed InfraRed analysis and Imaging (FTIRI) was used on 4MUm thick sections of undecalcified bone. The mineralization degree, carbonate substitution, crystallinity and the cross-links ratio of collagen (1660/1690cm-1 bands) were determined. The matrix characteristics were analyzed and imaged in the pre-existing residual bone and in the metaplastic woven bone in the vicinity of the tumor cells. FTIRI provided images of the phosphate, amide and combination of peak ratio after having selected the peaks of interest. In addition, the matrix properties can be measured and compared between the old and newly-formed bones. Woven bone appeared poorly calcified with a low phosphate/amide ratio (P=0.03) crystallinity (P<0.0001) and carbonate substitution (P=0.003). Collagen was less mature as evidenced by lower cross-links (P=0.01). Woven bone associated with bone metastasis appears poorly mineralized and rapidly elaborated by osteoblasts. The collagenous phase of the bone matrix has a low level of reticulation. FTIRI is a powerful tool to measure and visualize the various components of the bone matrix in human diseases. PMID- 29530650 TI - Ovarian hormones mediate running-induced changes in high fat diet choice patterns in female rats. AB - Physical inactivity and increased consumption of energy dense, high fat (HF) foods often leads to a state of positive energy balance. Regular exercise can facilitate the maintenance of a healthy body weight and mediate changes in dietary selection. Past studies using a two-diet choice (chow vs. HF) and voluntary wheel running paradigm found that when a novel HF diet and wheel running are simultaneously introduced, male rats show complete and persistent HF diet avoidance whereas the majority of females show HF diet avoidance for a few days, but then revert to HF diet preference. Ovariectomy (OVX) appears to decrease preference for the HF diet bringing it closer to that of males. Given that estradiol but not progesterone mediates changes in food intake and energy balance, we hypothesized that estradiol signaling is required for the reversal of HF diet avoidance in female rats. Accordingly, Experiment 1 compared the persistency of running-induced HF diet avoidance in males, sham-operated females, and OVX rats with replacement of oil vehicle, estradiol benzoate (E), progesterone (P), or both (E + P). The number of wheel running rats that either avoided or preferred the HF diet varied with hormone treatment. The reversal of HF diet avoidance in running females and OVX E + P rats occurred more rapidly and frequently than male running rats. E + P but not E or P replaced OVX wheel running rats significantly reversed HF diet avoidance. OVX oil rats avoided HF diet to the same extent as male rats for the first 11 days of diet choice and then rapidly increased HF diet intake and began preferring it. This incomplete elimination of sex differences suggests that developmental factors or androgens might play a role in sustaining running-induced HF diet avoidance. Subsequently, Experiment 2 aimed to determine the role of androgens in the persistency of running-associated HF diet avoidance with sham-operated and orchiectomized (GDX) male rats. Both intact and GDX male running rats persistently avoided the HF diet to the same extent. Taken together, these results suggest that activational effects of ovarian hormones play a role in female specific running-induced changes in diet choice patterns. Furthermore, the activational effects of androgens are not required for the expression of HF diet avoidance in males. PMID- 29530653 TI - Implementation of a Clinical Bundle to Reduce Out-of-Hospital Peri-intubation Hypoxia. AB - STUDY OBJECTIVE: Peri-intubation hypoxia is an important adverse event of out-of hospital rapid sequence intubation. The aim of this project is to determine whether a clinical bundle encompassing positioning, apneic oxygenation, delayed sequence intubation, and goal-directed preoxygenation is associated with decreased peri-intubation hypoxia compared with standard out-of-hospital rapid sequence intubation. METHODS: We conducted a retrospective, before-after study using data from a suburban emergency medical services (EMS) system in central Texas. The study population included all adults undergoing out-of-hospital intubation efforts, excluding those in cardiac arrest. The before-period intervention was standard rapid sequence intubation using apneic oxygenation at flush flow, ketamine, and a paralytic. The after-period intervention was a care bundle including patient positioning (elevated head, sniffing position), apneic oxygenation, delayed sequence intubation (administration of ketamine to facilitate patient relaxation and preoxygenation with a delayed administration of paralytics), and goal-directed preoxygenation. The primary outcome was the rate of peri-intubation hypoxia, defined as the percentage of patients with a saturation less than 90% during the intubation attempt. RESULTS: The before group (October 2, 2013, to December 13, 2015) included 104 patients and the after group (August 8, 2015, to July 14, 2017) included 87 patients. The 2 groups were similar in regard to sex, age, weight, ethnicity, rate of trauma, initial oxygen saturation, rates of initial hypoxia, peri-intubation peak SpO2, preintubation pulse rate and systolic blood pressure, peri-intubation cardiac arrest, and first pass and overall success rates. Compared with the before group, the after group experienced less peri-intubation hypoxia (44.2% versus 3.5%; difference -40.7% [95% confidence interval -49.5% to -32.1%]) and higher peri-intubation nadir SpO2 values (100% versus 93%; difference 5% [95% confidence interval 2% to 10%]). CONCLUSION: In this single EMS system, a care bundle encompassing patient positioning, apneic oxygenation, delayed sequence intubation, and goal-directed preoxygenation was associated with lower rates of peri-intubation hypoxia than standard out-of-hospital rapid sequence intubation. PMID- 29530652 TI - Informing Medicare's Two-Midnight Rule Policy With an Analysis of Hospital-Based Long Observation Stays. AB - STUDY OBJECTIVE: Outpatient observation stays are increasingly substituting for standard inpatient hospitalizations. In 2013, the Centers for Medicare & Medicaid Services adopted the controversial Two-Midnight Rule policy to curb long observation stays and better define the use of hospital-based observation services versus inpatient hospitalizations. We seek to determine the extent to which Medicare beneficiaries exposed to long observation stays (>48 hours) are clinically similar to those with short observation stays (<=48 hours) because this has relevance to the Two-Midnight Rule. METHODS: Using 100% Medicare claims data from 2008 to 2010, we identified all patients with long observation stays (>48 hours) who were admitted through the emergency department (ED). We report beneficiary characteristics, as well as crude and risk-adjusted 30-day rates of mortality, readmissions, and return ED visits stratified by observation stay length. RESULTS: Seven percent of 2.8 million observation stays were greater than 48 hours. Beneficiaries with long observation stays tended to be older, women, nonwhite, and urban residents, with a greater number of comorbid conditions. Crude rates increased with observation stay length for all 3 outcomes. However, after directly standardizing the rates, we observed the reverse trend because all adjusted rates decreased stepwise with observation stay length greater than 48 hours in a dose-response pattern. CONCLUSION: Patients with observation stays lasting longer than 48 hours are a clinically distinct population. Our findings support the conceptual underpinnings of the Two-Midnight Rule, but suggest that observation versus inpatient determinations should be based on actual length of stay rather than prospective prediction to reduce the administrative ambiguity this policy has created. PMID- 29530651 TI - Immunology of Uterine and Vaginal Mucosae: (Trends in Immunology 39, 302-314, 2018). PMID- 29530654 TI - Safety of a Brief Emergency Department Observation Protocol for Patients With Presumed Fentanyl Overdose. AB - STUDY OBJECTIVE: Fentanyl overdoses are increasing and few data guide emergency department (ED) management. We evaluate the safety of an ED protocol for patients with presumed fentanyl overdose. METHODS: At an urban ED, we used administrative data and explicit chart review to identify and describe consecutive patients with uncomplicated presumed fentanyl overdose (no concurrent acute medical issues) from September to December 2016. We linked regional ED and provincial vital statistics databases to ascertain admissions, revisits, and mortality. Primary outcome was a composite of admission and death within 24 hours. Other outcomes included treatment with additional ED naloxone, development of a new medical issue while in the ED, and length of stay. A prespecified subgroup analysis assessed low-risk patients with normal triage vital signs. RESULTS: There were 1,009 uncomplicated presumed fentanyl overdose, mainly by injection. Median age was 34 years, 85% were men, and 82% received out-of-hospital naloxone. One patient was hospitalized and one discharged patient died within 24 hours (combined outcome 0.2%; 95% confidence interval [CI] 0.04% to 0.8%). Sixteen patients received additional ED naloxone (1.6%; 95% CI 1.0% to 2.6%), none developed a new medical issue (0%; 95% CI 0% to 0.5%), and median length of stay was 173 minutes (interquartile range 101 to 267). For 752 low-risk patients, no patients were admitted or developed a new issue, and one died postdischarge; 3 (0.4%; 95% CI 0.01% to 1.3%) received ED naloxone. CONCLUSION: In our cohort of ED patients with uncomplicated presumed fentanyl overdose-typically after injection-deterioration, admission, mortality, and postdischarge complications appear low; the majority can be discharged after brief observation. Patients with normal triage vital signs are unlikely to require ED naloxone. PMID- 29530655 TI - Triage, Machine Learning, Algorithms, and Becoming the Borg. PMID- 29530656 TI - Tetracaine Challenges Old Dogma for Emergency Department Management of Corneal Abrasion Pain and Beckons a Definitive Study. PMID- 29530657 TI - Is Loop Drainage Technique More Effective for Treatment of Soft Tissue Abscess Compared With Conventional Incision and Drainage? PMID- 29530658 TI - Systemic Antibiotics for the Treatment of Skin and Soft Tissue Abscesses: A Systematic Review and Meta-Analysis. AB - STUDY OBJECTIVE: The addition of antibiotics to standard incision and drainage is controversial, with earlier studies demonstrating no significant benefit. However, 2 large, multicenter trials have recently been published that have challenged the previous literature. The goal of this review was to determine whether systemic antibiotics for abscesses after incision and drainage improve cure rates. METHODS: PubMed, the Cumulative Index of Nursing and Allied Health Literature, Scopus, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and bibliographies of selected articles were assessed for all randomized controlled trials comparing adjuvant antibiotics with placebo in the treatment of drained abscesses, with an outcome of treatment failure assessed within 21 days. Data were dual extracted into a predefined worksheet and quality analysis was performed with the Cochrane Risk of Bias tool. RESULTS: Four studies (n=2,406 participants) were identified. There were 89 treatment failures (7.7%) in the antibiotic group and 150 (16.1%) in the placebo group. The calculated risk difference was 7.4% (95% confidence interval [CI] 2.8% to 12.1%), with an odds ratio for clinical cure of 2.32 (95% CI 1.75 to 3.08) in favor of the antibiotic group. There was also a decreased incidence of new lesions in the antibiotic group (risk difference -10.0%, 95% CI -12.8% to -7.2%; odds ratio 0.32, 95% CI 0.23 to 0.44), with a minimally increased risk of minor adverse events (risk difference 4.4%, 95% CI 1.0% to 7.8%; odds ratio 1.29, 95% CI 1.06 to 1.58). CONCLUSION: The use of systemic antibiotics for skin and soft tissue abscesses after incision and drainage resulted in an increased rate of clinical cure. Providers should consider the use of antibiotics while balancing the risk of adverse events. PMID- 29530659 TI - Emergence of novel reassortant H6N2 avian influenza viruses in ducks in India. AB - The recent reports of human infection due to H6 subtype avian influenza viruses (AIV), which are prevalent in terrestrial poultry, indicate evolution of the virus to a possible pandemic strain. Here, we report antigenic and genetic characterization of two H6N2 viruses isolated from apparently healthy domestic ducks in Kerala and Assam, India during 2014 and 2015, respectively. Hemagglutination inhibition assay revealed antigenic divergence between the two isolates, which was corroborated by amino acid differences at 55 positions (15.98%) between their hemagglutinin (HA) 1.The sequence analyses indicated that both the viruses are avian origin with avian receptor specificity, low pathogenic to poultry and sensitive to oseltamivir. However, Kerala14 had V27I mutation marker for amantadine resistance in M2. The Assam15 virus had an additional N linked glycosylation on HA2 (position 557) compared to Kerala14 virus. Phylogenetic analysis of the HA gene revealed that both the viruses belonged to distinct lineages (Eurasian and Asia II). Phylogeny of neuraminidase and internal gene segments revealed that both the viruses are novel reassortants and are genetically distinct with different gene constellations. The results suggest independent introductions of the two H6N2 viruses into India and migratory wild birds in the Central Asian flyway might be the source of H6N2 viruses in ducks in India. Therefore, continued AIV surveillance in poultry and wild birds is essential for early detection of emergence of novel strains with pandemic potential and control of their spread. PMID- 29530660 TI - Streptococcal pharyngitis and rheumatic heart disease: the superantigen hypothesis revisited. AB - Streptococcus pyogenes is a human-specific and globally prominent bacterial pathogen that despite causing numerous human infections, this bacterium is normally found in an asymptomatic carrier state. This review provides an overview of both bacterial and human factors that likely play an important role in nasopharyngeal colonization and pharyngitis, as well as the development of acute rheumatic fever and rheumatic heart disease. Here we highlight a recently described role for bacterial superantigens in promoting acute nasopharyngeal infection, and discuss how these immune system activating toxins could be crucial to initiate the autoimmune process in rheumatic heart disease. PMID- 29530661 TI - First genetic characterization of Toxoplasma gondii infection in donkey meat slaughtered for human consumption in Shandong province, eastern China. AB - Until now, limited information on the molecular epidemiology and genotypes of Toxoplasma gondii infection in donkeys is available in China. Thus, the present study was conducted to characterize T. gondii genotypes in donkeys, intended for human consumption in Shandong province, eastern China. A total of 618 muscle tissue samples of donkeys was collected in Shandong province from January 2016 to August 2017 and were used to detect the T. gondii B1 gene by a semi-nested PCR, and the positive samples were genotyped at 10 nuclear loci (i.e., SAG1, alternative SAG2, 5'-and 3'-SAG2, SAG3, L358, BTUB, c22-8, GRA6, c29-2, PK1) and an apicoplast locus Apico by multi-locus PCR-RFLP method. Fifty-seven (9.22%) samples out of 618 donkey meat samples were examined T. gondii B1 gene positive. In this study, no risk factor was found to be associated with T. gondii infection in donkeys. Moreover, two genotypes (ToxoDB#9 and ToxoDB#1) were identified. This is the first genetic characterization of T. gondii isolated from donkey meat that would intend for human consumption in Shandong province, eastern China and also the first report of genotype ToxoDB#1 found in donkeys in China, which may be useful for preventing and controlling T. gondii infection in donkeys, other animals and humans. PMID- 29530662 TI - Recycling processes and quality of secondary materials: Food for thought for waste-management-oriented life cycle assessment studies. PMID- 29530663 TI - Maternal breastfeeding: indicators and factors associated with exclusive breastfeeding in a subnormal urban cluster assisted by the Family Health Strategy. AB - OBJECTIVE: To describe and analyze indicators of feeding practices related to breastfeeding and factors associated with exclusive breastfeeding (EBF) in a subnormal urban cluster (slums) in Pernambuco, Brazil. METHODS: Four breastfeeding indicators were used to interview mothers of children under 3 years of age. An inventory of the families' socioeconomic and environmental factors, maternal obstetric history, and basic health care access was undertaken. The sample consisted of all 310 children under the age of 3 years from Coelhos, PE, Brazil. Spearman's correlation was carried out, as well as crude and adjusted prevalence ratios for a final statistical model that showed associated factors with the main outcome at a level of 0.05. RESULTS: The prevalence of breastfeeding in the first hour of life, exclusive breastfeeding up to 6 months, continued breastfeeding at 1 year, and continued breastfeeding at 2 years were 60.2%, 32.9%, 45.9, and 35.9%, respectively. A correlation was observed between start of pacifier use and duration of either exclusive (rs=0.358 [p<0.001]) or non-exclusive breastfeeding (rs=0.248 [p=0.006]). Maternal age over 35 years (p<0.001), home visit in the first week after birth (p=0.003), having had a male baby (p=0.029), and not using a pacifier (p<0.001) remained protective factors in the final model. CONCLUSION: The prevalence rates of exclusive breastfeeding at 6 months were well above the results obtained by other Brazilian authors. Home visit and maternal age prevailed as protective factors, while pacifier use was shown to be a discouraging practice. PMID- 29530664 TI - Vulvar field resection based on ontogenetic cancer field theory for surgical treatment of vulvar carcinoma: a single-centre, single-group, prospective trial. AB - BACKGROUND: The incidence of vulvar cancer is increasing, but surgical treatment the current standard of care-often leads to unsatisfactory outcomes, especially in patients with node-positive disease. Preliminary results at our centre showed that locoregional spread of vulvar carcinoma occurs within tissue domains defined by stepwise embryonic and fetal development (ontogenetic cancer fields and associated lymph node regions). We propose that clinical translation of these insights into practice could improve outcomes of surgical treatment of vulvar cancer. METHODS: We did a single-centre prospective trial at the University of Leipzig's Cancer Center. Eligible patients were aged 18 years or older, had ontogenetic stage 1-3b histologically proven primary carcinoma of the vulva, and had not undergone previous surgical or radiotherapy treatment for vulvar cancer or any other major perineal or pelvic disease. In view of staged morphogenesis of the vulva from the cloacal membrane endoderm at Carnegie stage 11 to adulthood, we defined the tissue domains of tumour spread according to the theory of ontogenetic cancer fields. On the basis of ontogenetic staging, patients were treated locally with partial, total, or extended vulvar field resection; regionally with therapeutic inguinopelvic lymph node dissection; and anatomical reconstruction without adjuvant radiotherapy. The primary endpoints were recurrence-free survival, disease-specific survival, and early postoperative complications. Analysis of tumour spread and early postoperative surgical complications was done by intention to treat (ie, all patients were included), whereas outcome analyses were done per protocol. This ongoing trial is registered with the German Clinical Trials Register, number DRKS00013358. FINDINGS: Between March 1, 2009, and June 8, 2017, 97 consecutive patients were included in the study, of whom 94 were treated per protocol with vulvar field resection, therapeutic inguinopelvic lymph node dissection, and anatomical reconstruction without adjuvant radiotherapy. 46 patients had moderate or severe postoperative complications, especially infectious perineal and inguinal wound dehiscence. 3 year recurrence-free survival in all patients was 85.1% (95% CI 76.9-93.3), and 3 year disease-specific survival was 86.0% (78.2-93.8). INTERPRETATION: Our results support the theory of ontogenetic cancer fields for vulvar carcinoma, accord with our previous findings in cervical cancer, and suggest the general applicability of the theory. Application of the concept of cancer field resection could improve outcomes in patients with vulvar carcinoma, but needs to be investigated further in multicentre randomised controlled trials. FUNDING: Leipzig School of Radical Pelvic Surgery and Gynecologic Oncology Research Foundation. PMID- 29530665 TI - Vulvar field resection: innovative procedure or same old? PMID- 29530666 TI - Aiming for complete responses in renal-cell carcinoma. PMID- 29530667 TI - Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. AB - BACKGROUND: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. METHODS: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (>=20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. FINDINGS: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. INTERPRETATION: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. FUNDING: Pfizer and Merck. PMID- 29530668 TI - Cleavage of poly(cis-1,4-isoprene) rubber as solid substrate by cultures of Gordonia polyisoprenivorans. AB - Potential biotechnological recycling processes for rubber products include the bacterial degradation of poly(cis-1,4-isoprene) (IR) in order to achieve its total biodegradation or its biotransformation into useful products. The actinomycete Gordonia polyisoprenivorans strain VH2 catalyzes the degradation of IR and enables its use as a sole carbon source via beta-oxidation. The initial cleavage reaction is catalyzed by the extracellular latex clearing protein (Lcp). This dioxygenase is the key enzyme for the formation of oligo(cis-1,4-isoprene) molecules with different lengths, i.e., numbers of isoprene units. For the first time, IR was used as a solid substrate in 2-l fermenters. Two different particle size fractions (63-500 and 500-1000 MUm) and three stirring rates (300, 400 and 500 rpm) were evaluated in the process. An increase of the cell concentration was achieved by using smaller particles and by using lower stirring rates, reaching a final biomass concentration of 0.52 g l-1 at 300 rpm after 12 days of cultivation. In order to enhance the formation of oligo(cis-1,4-isoprene) molecules, a transposon insertion mutant (TH5) of G. polyisoprenivorans strain VH2 that has lost the ability to transport the partial degradation products into the cells was used, thereby allowing the accumulation of the degradation products in the culture supernatants. Propionate, glucose and glycerol were evaluated as additional carbon sources besides IR, and the highest yields were observed on propionate. In 2-l bioreactors with pH control, different feeding regimes were performed during cultivation by the addition of propionate every 24 or 48 h for 16 days. After liquid-liquid extraction and a derivatization with Girard's T reagent, the oligo(cis-1,4-isoprene) molecules were detected by ESI-MS. The mass distribution of the degradation products was affected by the selection of the extraction solvent, but no influence of longer cultivation periods was detected. PMID- 29530669 TI - Liposomal bupivacaine to improve pain after retropubic sling placement. PMID- 29530671 TI - Reply. PMID- 29530672 TI - The effect of customization and use of a fetal growth standard on the association between birthweight percentile and adverse perinatal outcome: methodologic issues. PMID- 29530673 TI - Reply. PMID- 29530670 TI - Policy change is not enough: engaging provider champions on immediate postpartum contraception. AB - Rates of short-interval pregnancies that result in unintended pregnancies remain high in the United States and contribute to adverse reproductive health outcomes. Long-acting reversible contraception methods have annual failure rates of <1%, compared with 9% for oral contraceptive pills, and are an effective strategy to reduce unintended pregnancies. To increase access to long-acting reversible contraception in the immediate postpartum period, several State Medicaid programs, which include those in Iowa and Louisiana, recently established reimbursement policies to remove the barriers to reimbursement of immediate postpartum long-acting reversible contraception insertion. We used a mixed methods approach to analyze 2013-2015 linked Medicaid and vital records data from both Iowa and Louisiana and to describe trends in immediate postpartum long acting reversible contraception provision 1 year before and after the Medicaid reimbursement policy change. We also used data from key informant interviews with state program staff to understand how provider champions affected policy uptake. We found that the monthly average for the number of insertions in Iowa increased from 4.6 per month before the policy to 6.6 per month after the policy; in Louisiana, the average number of insertions increased from 2.6 per month before the policy to 45.2 per month. In both states, the majority of insertions occurred at 1 academic/teaching hospital. In Louisiana, the additional increase may be due to the engagement of a provider champion who worked at both the state and facility level. Recruiting, training, engaging, and supporting provider champions, as facilitators, with influence at state and facility levels, is an important component of a multipart strategy for increasing successful implementation of state-level Medicaid payment reform policies that allow reimbursement for immediate postpartum long-acting reversible contraception insertions. PMID- 29530674 TI - All-cause death in young women with endometrial cancer who receive progesterone therapy. PMID- 29530675 TI - The Conscience of an MFM. AB - Much has been written about conscience-based objections to the provision of reproductive abortion services. Nevertheless, conscience may drive providers in the other direction as well: OB/GYNs may, in fact, decide to provide these services because of their well-considered moral, ethical, and religious convictions. PMID- 29530676 TI - Reply. PMID- 29530677 TI - Myxoma of the mandibular condyle: Report of a rare case and review of the literature. AB - This report describes an extremely rare case of myxoma of the mandibular condyle. The tumor occurred in the left mandibular condyle of a 42-year-old woman, which was identified in a routine radiographic examination. The clinico-radiographic and histopathological features, and histogenesis of the lesion are discussed. A review of the literature and differential diagnosis of radiolucent condylar lesions are also presented. PMID- 29530678 TI - Human follicular fluid proteomic and peptidomic composition quantitative studies by SWATH-MS methodology. Applicability of high pH RP-HPLC fractionation. AB - : Analysis of proteomic composition of human follicular fluid (hFF) has been previously proposed as a potential tool of oocyte quality evaluation. In order to develop an efficient method to investigate the hFF proteome and peptidome components, we applied and tested a few prefractionation schemes of hFF material consisting of ultrafiltration, optional immunodepletion, and high pH RP-HPLC separation by building spectral libraries and comparing their quantification capabilities of unfractionated samples. Low Molecular-Weight Fraction peptides (LMWF, <10 kDa) and High Molecular-Weight Fraction proteins (HMWF, >10 kDa) resulting from ultrafiltration were analyzed separately. We identified 302 proteins in HMWF and 161 proteins in LMWF in all qualitative experiments. All LMWF peptidomic libraries turned out to be of poor quantification quality, however they enabled measurement of higher numbers of peptides with increasing input of experiment data, in contrast to HMWF proteomic libraries. We were able to quantify a total of 108 HMWF proteins and 250 LMWF peptides (from 84 proteins) in all experiments. Employment of high RP-HPLC fractionation allowed for identification of a much broader set of proteins, however did not significantly improve the quantification capabilities of the applied method. Data are available via ProteomeXchange with identifier PXD008073. SIGNIFICANCE: In the search of biomarkers for assessment of oocyte quality in assisted reproductive technology, many studies are devoted to analysis of follicular fluid composition. Candidates for such biomarkers can be located in both the proteome and the recently investigated peptidome of hFF. Reliable qualitative and especially quantitative analysis of complex mixtures such as hFF, requires development of a fast and preferably inexpensive analytical procedure. The powerful SWATH-MS technique is well suited for quantitative label-free analysis of complex protein and peptide mixtures. However, for efficient usage it needs well designed and constructed MS spectral libraries as well as a proper protocol for sample preparation. We investigated the influence of the size and quality of MS-spectral libraries (different spectral libraries are constructed using various sample prefractionation protocols) on SWATH experiments on hFF proteome and peptidome. In the case of peptidome investigation, increasing the size of spectral libraries led to quantification of more peptides in a single experiment. For the proteome, increasing the size of spectral libraries improved quantification only to a limited extend, and further extension of spectral libraries even worsened results. Nevertheless, using the best selected prefractionation schemes and spectral libraries we were able to quantify as many as 79 proteins of hFF proteome and 106 peptides (from 53 proteins) of hFF peptidome in single experiments. The spectral libraries and prefractionation protocols we developed allow for a large scale fast scan of hundreds of clinical hFF samples in the search for biomarkers for evaluation of oocyte quality. PMID- 29530679 TI - Serum proteome profiling in canine idiopathic dilated cardiomyopathy using TMT based quantitative proteomics approach. AB - : Idiopathic dilated cardiomyopathy (iDCM) is a primary myocardial disorder with an unknown aetiology, characterized by reduced contractility and ventricular dilation of the left or both ventricles. Naturally occurring canine iDCM was used herein to identify serum proteomic signature of the disease compared to the healthy state, providing an insight into underlying mechanisms and revealing proteins with biomarker potential. To achieve this, we used high-throughput label based quantitative LC-MS/MS proteomics approach and bioinformatics analysis of the in silico inferred interactome protein network created from the initial list of differential proteins. To complement the proteomic analysis, serum biochemical parameters and levels of know biomarkers of cardiac function were measured. Several proteins with biomarker potential were identified, such as inter-alpha trypsin inhibitor heavy chain H4, microfibril-associated glycoprotein 4 and apolipoprotein A-IV, which were validated using an independent method (Western blotting) and showed high specificity and sensitivity according to the receiver operating characteristic curve analysis. Bioinformatics analysis revealed involvement of different pathways in iDCM, such as complement cascade activation, lipoprotein particles dynamics, elastic fibre formation, GPCR signalling and respiratory electron transport chain. SIGNIFICANCE: Idiopathic dilated cardiomyopathy is a severe primary myocardial disease of unknown cause, affecting both humans and dogs. This study is a contribution to the canine heart disease research by means of proteomic and bioinformatic state of the art analyses, following similar approach in human iDCM research. Importantly, we used serum as non-invasive and easily accessible biological source of information and contributed to the scarce data on biofluid proteome research on this topic. Bioinformatics analysis revealed biological pathways modulated in canine iDCM with potential of further targeted research. Also, several proteins with biomarker potential have been identified and successfully validated. PMID- 29530680 TI - Recurrent encephalopathy in milliary neurocysticercosis: An uncommon manifestation of a common infection. AB - Neurocysticercosis is a common parasitic infection in children in developing countries and neurological symptoms such as seizures are the most common manifestations. However, symptoms of encephalopathy are an unusual presentation in children. A 4-year-old boy presented with recurrent episodes of febrile encephalopathy. His magnetic resonance imaging of the brain was suggestive of milliary neurocysticercosis of various stages. Reports on recurrent encephalopathy following neurocysticercosis are scarce in literature. Hence, we report this case who presented with recurrent episodes of encephalopathy. PMID- 29530681 TI - Strategies in Traumatic Brain Injury and Alcohol Consumption: A Professional's Survey. AB - BACKGROUND: Traumatic brain injury associated with alcohol consumption is a global public health problem. It is important to identify and rethink the strategies to approach this challenge for health care institutions from a professional perspective. METHODS: An online survey, created with Google Forms, was sent to professional neurosurgeons in Mexico and Latin America. Participation was voluntary, and responses were anonymous and confidential. Data were captured after 1 month and subjected to descriptive statistical analysis using Fisher exact and chi2 tests. RESULTS: There were 83 questionnaires answered by certified neurosurgeons with a response rate of 52.9%. Responses indicated that 78% of hospitals have no specific management guidelines for patients with TBI and alcohol intoxication. In 90% of cases, no triage strategies are defined for the case, and at hospital admission, there are no specific identified strategies for extraordinary surveillance of risks in these patients (P = 0.062). CONCLUSIONS: These findings confirm a lack of systematic strategies for management of patients with TBI and associated comorbidity of alcohol intoxication in the acute phase. It is important to define specific management guidelines to improve treatment efficacy and limit complications in patients with TBI and alcohol intoxication. PMID- 29530682 TI - Pathogenesis of Idiopathic Ventral Herniation of Spinal Cord: Neuropathologic Analysis. AB - BACKGROUND: Idiopathic ventral herniation of the spinal cord is rarely seen as a cause of gradually increasing neurologic deficit. Its cause has never been clarified. It could be the result of a developmental disorder at 30- to 60-day gestational age. Neuropathologic analysis of herniated spinal cord tissue could probably support this hypothesis. CASE DESCRIPTION: In a patient suffering from idiopathic ventral herniation of the spinal cord, a biopsy was performed in order to reduce the space-occupying effect. The biopsy was taken while intraoperative neuromonitoring was used. The patient recovered uneventfully without any additional deficit. Tissue analysis included histopathologic, immunohistochemical, and molecular examination (methylation profiling). The tissue did not appear as a normally functioning spinal cord; instead, a non neoplastic glio-(neuronal) proliferation was found. CONCLUSION: These findings support a developmental disorder as a cause for idiopathic ventral spinal cord herniation. PMID- 29530683 TI - Comparison of Clinical and Radiographic Results Between Posterior Pedicle-Based Dynamic Stabilization and Posterior Lumbar Intervertebral Fusion for Lumbar Degenerative Disease: A 2-Year Retrospective Study. AB - OBJECTIVE: To compare outcomes between K-rod dynamic stabilization system (KDSS) and posterior lumbar intervertebral fusion (PLIF) for lumbar degenerative disease. METHODS: This study retrospectively reviewed 98 patients who underwent lumbar surgery from March 2012 to June 2014, including 48 in the KDSS group and 50 in the PLIF group. All patients were followed up for at least 2 years. Duration of operation, blood loss, hospital stay, complications, and patient satisfaction were recorded and analyzed. Clinical outcomes were evaluated by visual analog scale and Oswestry Disability Index. Radiographic results including disk height index, foraminal height, and range of motion (ROM) were compared between groups. RESULTS: Compared with PLIF group, KDSS group had shorter duration of operation and less blood loss (P < 0.001). There were no differences in hospital stay, complications, and patient satisfaction. Both groups demonstrated significant improvement in visual analog scale back and leg pain and Oswestry Disability Index. No significant difference was found between groups at any time point (P > 0.05). Postoperative disk height index and foraminal height increased significantly compared with preoperatively (P < 0.05). Although disk height index and foraminal height in KDSS group were smaller than PLIF group values, there were no significant differences between groups. ROM of total lumbar and implanted segment was decreased compared with preoperative ROM in both groups (P < 0.05), but the 2 values were higher in KDSS group (P < 0.05). CONCLUSIONS: Both KDSS and PLIF can improve clinical and radiographic outcomes for early-stage lumbar degenerative disease. Compared with PLIF, KDSS has better operative time, less blood loss, and better preservation of ROM, but prospective, randomized, controlled trials with larger sample size and longer follow-up are required. PMID- 29530684 TI - Arterial Spin Labeling Method as a Supplemental Predictor to Distinguish Between High- and Low-Grade Gliomas. AB - BACKGROUND: Preoperative evaluation of malignancy in gliomas is important for surgical planning, particularly to determine whether a 1,3-bis-2-chloroethyl-1 nitrosourea wafer should be placed into the tumor cavity. In some cases, the intraoperative pathologic diagnosis of World Health Organization grade differs from the final diagnosis. Supplemental methods in addition to the routine contrast tomography or magnetic resonance imaging sequences may provide a more accurate preoperative diagnosis. Because tumor vascularity has been useful in distinguishing between low- and high-grade gliomas, we evaluated the accuracy of the arterial spin labeling (ASL) method, which could measure the cerebral blood flow (CBF) without using contrast medium, to determine the malignancy of gliomas. METHODS: This study included 102 patients with glioma (grade II, n = 40; grade III, n = 18; grade IV, n = 44). All patients underwent ASL to determine the tumor blood flow (TBF) and CBF in the middle cerebral region. The relative tumor vascular index (tVI), which is calculated as TBF divided by CBF in the contralateral middle cerebral region, was used to avoid dispersion of the absolute TBF value. RESULTS: tVI was significantly greater (1.46 +/- 0.751) in high-grade gliomas than in low-grade gliomas (1.05 +/- 0.343) (P = 0.003). As for each grade, tVI was statistically higher in grade IV than in grade II (P = 0.03) gliomas. CONCLUSIONS: The noninvasive ASL method provides additional information to distinguish high-grade glioma from low-grade gliomas without using contrast medium. PMID- 29530685 TI - Computed Tomography Imaging Study of Basilar Invagination and Atlantoaxial Dislocation. AB - OBJECTIVE: We sought to analyze axis deformities and the biomechanics related to atlantoaxial dislocation (AAD) in patients with basilar invagination (BI). METHODS: Seventy-six patients were retrospectively analyzed including 21 patients who had BI (group B), 32 patients with BI and AAD (group C), and 23 nondeformity control subjects (group A). Using 3-dimensional computed tomography imaging the distance from the tip of the dens above the Chamberlain line in the sagittal plane, atlantodental interval, sagittal inclination, coronal inclination, and craniocervical tilt, the height of the odontoid and ratio of the height to the odontoid basal width were measured in each patient. We statistically analyzed the resulting data for correlations among physiologic measurements and disease state. RESULTS: The height of the odontoid process in groups A, B, and C was 13.38 +/- 1.50 mm, 10.87 +/- 1.48 mm, and 8.49 +/- 2.49 mm, respectively. The ratio of height-to-basal width of the odontoid in groups A, B, and C was 1.32 +/- 0.21, 0.91 +/- 0.21, and 0.65 +/- 0.17, respectively. The sagittal inclination in groups A, B, and C was 85.85 +/- 4.55 degrees, 105.76 +/- 10.72 degrees, and 123.48 +/-12.43 degrees, and the coronal inclination was 108.95 +/- 24.09 degrees, 105.40 +/- 25.16 degrees, and 108.82 +/- 21.41 degrees, respectively. The craniocervical tilt in groups A, B, and C was 60.31 +/- 6.98 degrees, 84.53 +/- 18.94 degrees, and 71.79 +/- 11.69 degrees, respectively. The height of the odontoid, height-to-basal width, and sagittal inclination were significantly correlated with both BI and AAD (P < 0.001). Odontoid height and height-to-basal width ratio were significantly correlated with BI, AAD, and sagittal inclination (P < 0.001). Finally, craniocervical tilt was correlated only with the BI severity (P < 0.001). CONCLUSION: This study confirms that deformities of the odontoid process and the lateral joint correlate with severity of BI, while deformity of the odontoid process may be a primary factor in AAD for patients with BI. PMID- 29530686 TI - Piezoelectric Surgery for Dorsal Spine. AB - BACKGROUND: Laminoplasty and laminectomy are 2 common surgical procedures used in treating degenerative and neoplastic diseases of the spinal canal. Routinely used instruments, such as the Kerrison rongeur and high-speed drill, can result in potentially serious complications, such as dural injury and thermal and mechanical damage to neurovascular structures. We adopted piezoelectric bone surgery, which permits a selective cut of mineralized tissues, to perform posterior procedures on the thoracic spine, where the relationship between bone and the spinal cord is critical. The aim of this article was to evaluate the use of piezoelectric surgery for performing dorsal spine laminectomy and laminoplasty. METHODS: The Mectron piezosurgery device was developed for cutting bone with microvibrations that are created by the piezoelectric effect. This instrument allows a safe and precise bone cut, and it is characterized by no heat generation, thus avoiding thermal injury to bone and soft tissues. We used this device to perform 8 laminoplasties for tumors of the dorsal spine and 2 laminectomies for thoracic spinal stenosis in 10 patients. RESULTS: There were no procedure-related intraoperative complications, such as dural injury or damage to neural structures. CONCLUSIONS: The piezoelectric device showed excellent results in terms of safety and precise bone cutting properties when performing posterior surgical procedures in the dorsal spine, where thermal injury produced by the conventionally used drill may damage the spinal cord closer to bony elements. PMID- 29530687 TI - Neurologic Status on Presentation as Predictive Measurement in Success of Closed Reduction in Traumatic Cervical Facet Fractures. AB - BACKGROUND: Dislocations to cervical facets resulting from traumatic injury often lead to neurologic impairment and can be treated both surgically and in a closed manner. OBJECTIVE: We sought to evaluate the utilization of closed reduction in the initial management of bilateral facet dislocations over the past 10 years at our institution. METHODS: We retrospectively reviewed the charts of patients who experienced subaxial cervical facet injury within the Penn Health System between 1 June 2006 and 1 June 2016 to identify patients with bilateral jumped/perched facets. The neurologic injury was identified on the basis of the American Spinal Injury Association (ASIA) spinal cord injury score. Analysis of variance and 2 sample t-tests were used to compare continuous distributions, and chi-square tests were used to compare categorical distributions. RESULTS: We focused our analyses on patients who presented with bilateral jumped/perched facets with (ASIA A and B) or without (ASIA C, D, E) complete voluntary motor deficit and underwent attempted closed reduction. We found that the rate of successful closed reduction was significantly higher in incomplete motor deficits (5/5, P = 0.04, chi-square test) as compared with complete motor deficits (n = 2/11). CONCLUSION: Our results demonstrate a significant difference in the success rate of closed reduction in patients with good neurologic status on presentation (ASIA A or B), compared with those with poor neurologic status (ASIA C, D, and E). These results suggest that closed reduction should be attempted in patients with good motor examinations on presentation, whereas those with significant deficits may benefit from earlier surgical intervention. PMID- 29530688 TI - Risk Factors for Postoperative Delirium After Deep Brain Stimulation Surgery for Parkinson Disease. AB - OBJECTIVE: The aim of this study was to investigate the incidence of and risk factors for postoperative delirium (POD) after deep brain stimulation (DBS) surgery in patients with Parkinson disease. METHODS: We analyzed the preoperative T1-weighted magnetic resonance imaging data of 71 patients with Parkinson disease who underwent DBS surgery. Multiple regression analysis was performed with age, l dopa equivalent daily dose, laterality of the surgery, target regions, number of electrode trajectories tried, gray matter volume, and white matter (WM) volume as explanatory variables and the duration (number of days) of POD as the response variable. In addition, regional brain atrophy associated with POD was investigated by means of voxel-based morphometry. RESULTS: Excluding patients with outliers, 61 patients were included in the analyses. POD had occurred in 26 of the 61 patients (42.6%). Age and total WM volume were shown by multiple regression analysis to correlate significantly with the duration of POD (P < 0.05 and < 0.01, respectively). WM was significantly reduced in the temporal stem, and the reduction in volume correlated significantly with the duration of POD (P < 0.001). Gray matter atrophy was not associated with POD. CONCLUSIONS: We found that age and WM atrophy in the temporal stem are factors predictive of POD after DBS surgery. In aged patients with temporal stem atrophy, surgical procedures and postoperative management should be carefully explored to reduce the risk of postoperative delirium. PMID- 29530689 TI - Circle of Willis Collateral Flow in Carotid Artery Occlusion Is Depicted by 4D CTA. AB - BACKGROUND: In case of carotid artery occlusion, the risk and extent of ischemic cerebral damage are highly dependent on the pathways of collateral flow including the anatomy of the circle of Willis. In this report, cases are presented to illustrate that 4-dimensional computed tomography angiography (4D-CTA) can be considered as a noninvasive alternative to digital subtraction angiography for the evaluation of circle of Willis collateral flow. CASE DESCRIPTION: Five patients with unilateral internal carotid artery (ICA) occlusion underwent 4D-CTA for the evaluation of intracranial hemodynamics. Next to a visual evaluation of 4D-CTA, temporal information was visualized using a normalized color scale on the cerebral vasculature, which enabled quantification of the contrast bolus arrival time. In these patients, 4D-CTA demonstrated dominant middle cerebral artery blood supply on the side of ICA occlusion originating from either the contralateral ICA or posterior circulation via the communicating arteries. CONCLUSIONS: Temporal dynamics of collateral flow in the circle of Willis can be depicted with 4D-CTA in patients with a unilateral carotid artery occlusion. PMID- 29530690 TI - Intraventricular Hemorrhage After Head Injury: A Multicenter, Retrospective, Cohort Study. AB - BACKGROUND: Data on traumatic intraventricular hemorrhage (IVH) are currently limited, and therefore, the condition is not fully understood. The aim of this study was to determine the epidemiology of traumatic IVH and its effects on outcome in patients with blunt head trauma. METHODS AND MATERIALS: Using a nationwide trauma registry-the Japan Trauma Data Bank, we identified patients who underwent head computed tomography (CT) after blunt head trauma and had intracranial injuries between 2004 and 2015. The endpoint was in-hospital mortality. We compared patients with IVH and without IVH and adjusted for potential confounders using a multivariate logistic regression model. RESULTS: A total of 236,698 patients were registered in the database. Of the 139,058 patients who underwent head CT after blunt trauma, 906 (0.7%) had traumatic IVH. Among the 53,618 patients who were eligible for analysis, 871 had IVH. Traumatic IVH was associated with the occurrence of traffic accidents that caused trauma and severe injuries. Mortality was significantly higher in patients with IVH than in those without IVH (33.5% vs. 18.5%; P < 0.001); however, the difference was not significant after adjusting for confounding factors, with an adjusted odds ratio of 1.13 (95% confidence interval: 0.91-1.40). CONCLUSIONS: Traumatic IVH is associated with a high mortality. However, the outcome in patients with traumatic IVH was worse than that in patients without IVH, which could be a result of factors associated with IVH rather than of IVH alone. PMID- 29530691 TI - Evaluation of the Relevance of Surgery in Patients with Multiple Myeloma Harboring Symptomatic Spinal Involvement: A Retrospective Case Series. AB - BACKGROUND: Multiple myeloma spinal involvement can lead to bone fractures and neurologic impairment that can severely alter quality of life. The role of surgery is controversial, given its high morbidity, and the lack of evidence. We hereby aim to evaluate efficacy and safety of surgery in the management of symptomatic spinal lesions in patients with multiple myeloma. METHODS: We included all patients operated on for a myeloma-related spinal lesion in our institution between 2007 and 2015. Demographic, clinical, and surgical data were collected as well as hematologic profiles. We retrospectively assessed the surgical success of the procedures, if at 3 months the patient fulfilled the following 4 criteria: pain relief, ability to walk, spinal stability, and no relevant morbidity. RESULTS: Thirty-six men and 19 women, with a median age of 62 years, were included. Seventeen patients underwent an emergency intervention, whereas 38 patients underwent elective surgery. At 3 months, 88.2% and 96.1%, respectively, of patients experienced pain relief and were able to walk. Spinal stability was considered satisfactory for 94.1% of patients. We reported 8 major complications in 8 patients. Altogether, 34 patients (61.8%) fulfilled all criteria for surgical success. An International Staging System score of 1 and the absence of previous chemotherapy were significantly associated with surgical success. CONCLUSIONS: Management of myeloma-related spine lesions requires a multidisciplinary approach. Surgery rapidly provides both decompression and stabilization. Using a strict patient-specific evaluation, we reported rewarding functional results, with acceptable morbidity. Surgery for multiple myeloma vertebral lesions seems to be a valuable option for carefully selected patients. PMID- 29530692 TI - Pathologic Findings and Clinical Course of Midline Paraventricular Gliomas Diagnosed Using a Neuroendoscope. AB - INTRODUCTION: Removal of midline paraventricular gliomas is difficult because of their deep localization and invasive character, requiring biopsy for pathologic diagnosis. This study aimed to assess the pathologic findings and clinical course of midline paraventricular gliomas diagnosed using a neuroendoscope. METHODS: This study was performed as a retrospective investigation using a neuroendoscope of 26 patients whose tumors were diagnosed as midline paraventricular gliomas. The main loci of the lesions were the thalamus (11 patients), tectum (6 patients), and other areas (9 patients). Of these 26 patients, 21 (81%) had accompanying obstructive hydrocephalus. Surgery was performed via the lateral ventricle using a flexible scope. For patients with obstructive hydrocephalus, we added endoscopic third ventriculostomy, septostomy, and/or plasty of the foramen of Monro. Pathologic diagnosis was determined according to hematoxylin-eosin staining and immunohistochemistry using anti-GFAP, anti-Ki-67, anti-H3-K27M, and anti-IDH1-R132H antibodies. RESULTS: The pathologic diagnoses were grade I (5 patients), grade II (3 patients), grade III (6 patients), and grade IV (4 patients) gliomas. Six patients were diagnosed as having high-grade glioma, which was difficult to distinguish between grade III and grade IV. Two patients were undiagnosable. H3-K27M was strongly positive in 8 of 15 patients with high-grade glioma. All patients with high-grade gliomas died or received best supportive care within 2 years after surgery. CONCLUSIONS: Neuroendoscopic surgery is useful for midline paraventricular gliomas in terms of the treatment of obstructive hydrocephalus, as well as pathologic diagnosis and genetic analysis, which are required under the World Health Organization 2016 classification. PMID- 29530693 TI - Anterior Unilateral Plagiocephaly in Patient with Alagille Syndrome: Case Report. AB - BACKGROUND: The polymalformative syndromes and craniofacial anomalies association is a well-known phenomenon in patients with Crouzon, Pfeiffer, Apert, or Muenke disease. Recently, other less frequent pathologies, such as Alagille syndrome, have shown an association with alterations in the development of cranial sutures, resulting in serious cosmetic defects and neurologic disorders. CASE DESCRIPTION: We report an exceptional case of a 30-month-old girl, a nephroblastoma survivor diagnosed with Alagille syndrome, who was referred to our department with progressive anterior plagiocephaly and premature left coronal suture closure associated with a large compensating right bossing. Despite the patient's age, we offered aggressive surgical treatment performing a new forehead harvested from the skull vertex with orbital rim reconstruction. CONCLUSIONS: Alagille syndrome is a complex multisystem pathology with a poor craniosynostosis association and only 3 cases have been described in the literature. PMID- 29530694 TI - Repeated Spontaneous Intracranial Epidural Hemorrhage After Hysterical Crying. AB - BACKGROUND: Spontaneous epidural hemorrhage (EDH) is a rare occurrence that may be caused by vascular anomalies, infections, coagulopathies, or tumors. Spontaneous EDH occurring in patients without specific underlying disease has been reported only as intraspinal lesion but has never been demonstrated in the intracranial area. This study presents a 19-year-old patient with repeated spontaneous intracranial EDH caused twice by hysterical crying. CASE DESCRIPTION: The patient had spontaneous left frontal EDH after hysterical crying. Two years later, she had a similar episode after crying and a new spontaneous right frontal EDH was revealed. There was no obvious risk factor revealed by laboratory and radiologic survey. We postulated that hyperventilation during crying resulted in a sudden decrease in intracranial pressure. The intracranial hypotension induced detachment of the dura from the skull and spontaneous EDH occurred. CONCLUSIONS: Crying or hyperventilation may trigger spontaneous EDH and should be suspected when there are signs of persisting headache and increased intracranial pressure. The prognosis is excellent if early diagnosis and surgical decompression are achieved. PMID- 29530695 TI - Revisiting Ligament-Sparing Lumbar Microdiscectomy: When to Preserve Ligamentum Flavum and How to Evaluate Radiological Results for Epidural Fibrosis. AB - OBJECTIVE: Preserving the ligamentum flavum (LF) during lumbar spine surgery can help to limit the extent of postoperative epidural fibrosis (EF), which is a potential cause of persistent leg pain. We present a retrospective analysis of microdiscectomy with preservation of the LF to evaluate the effects of the two LF mobilizing techniques (reflecting inferiorly or medially vs. removing completely) on EF and clinical outcomes. METHODS: Microdiscectomy was performed through a unilateral laminotomy in 93 patients (52 male, 41 female; mean age, 46 years; range, 25-65 years) with L3-L4 (n = 3), L4-L5 (n = 40), and L5-S1 (n = 50) lumbar disc herniation. Patients whose LF was removed were assigned to group 1 (n=42), and patients whose LF was preserved by mobilizing it medially (n = 31) or inferiorly (n = 20) were assigned to groups 2 and 3, respectively. Follow-up visual analog scale (VAS) scores and magnetic resonance images were evaluated. RESULTS: EF scores, particularly for the anterior quadrants, were significantly higher in group 1 than in groups 2 (P = 0.012) and 3 (P = 0.001). Likewise, postoperative VAS scores in group 1 were also significantly higher than in groups 2 (P = 0.009) and 3 (P = 0.044). CONCLUSIONS: Our results demonstrate that 1) preserving the LF during lumbar microdiscectomy reduces the formation of postoperative EF and improves clinical outcomes; 2) EF in the anterior, rather than the posterior epidural space, is correlated with clinical results; and 3) the ligament mobilizing technique used should be individually tailored on the basis of the features of disc herniation. PMID- 29530696 TI - Follow-Up Outcomes After Re-Embolization for Recanalized Aneurysms After Initial Coiling: Further Recurrence Rates and Related Risk Factors. AB - BACKGROUND: Although it is well known that coiled aneurysms can recanalize over time, long-term outcomes of re-embolization for recurred aneurysms have not been adequately investigated. We studied the retreatment outcomes of re-embolized aneurysms during follow-up monitoring and assessed the risk factors related to further recanalization. METHODS: A total of 129 patients with 133 aneurysms were retrospectively reviewed. Each aneurysm was subjected to re-embolization because of major recanalization after initial coil embolization and underwent midterm and extended monitoring after retreatment. Cumulative medical records and radiologic data were assessed. Repeat recurrence rates and related risk factors were assessed by binary logistic regression analysis. RESULTS: A total of 47 aneurysms (35.3%) showed re-recanalization at 6 months after re-embolization, with 17 and 30 instances of minor and major recanalization, respectively. Multivariate analysis indicated that posterior circulation (hazard ratio [HR], 6.129; P = 0.010), large aneurysm (>7 mm) (HR, 13.598; P < 0.001), and incomplete occlusion at the second coiling (HR, 9.975; P = 0.001) were significant factors for repeat recanalization. Of 86 aneurysms showing complete occlusion at the midterm, 76 were further evaluated (>=12 months), showing 18 aneurysms (23.7%) of delayed re recanalization during a follow-up of 230.1 aneurysm-years. Of 15 aneurysms with minor recanalization at 6 months, 6 (40.0%) progressed to major recanalization during a follow-up of 44.0 aneurysm-years. CONCLUSIONS: Most re-coiled aneurysms (64.7%) showed complete occlusion at the 6-month follow-up. However, posterior circulation, large aneurysm (>7 mm), and incomplete occlusion at the second coiling were risks for further recanalization. The midterm and delayed re recanalization rates of the re-embolized aneurysms seem to be higher than those of the initial aneurysms. PMID- 29530697 TI - Strictly Limited Orbital Pain as Sentinel Headache of Subarachnoid Hemorrhage. AB - BACKGROUND: The headache preceding an intracranial aneurysm rupture is called a sentinel headache (SH), and it is characterized by a sudden, intense, and persistent headache. As subarachnoid hemorrhage (SAH) often develops within several weeks of SH, its rapid diagnosis and treatment can improve the prognosis. CASE DESCRIPTION: A 52-year-old woman with migraine in her medical history visited the outpatient clinic due to left orbital pain. There was no neurologic deficit. Although magnetic resonance imaging examination found no SAH, a left internal carotid artery-posterior communicating artery bifurcation aneurysm was detected by magnetic resonance angiography. Ten days after the onset of orbital pain, the patient consulted our hospital for a second opinion. We scheduled an elective clipping because the irregular shape of the aneurysm had a high risk of rupture. On the day before surgery, the aneurysm ruptured and led to SAH. Clipping was performed immediately. The patient was discharged with no neurologic deficit. CONCLUSION: Clinicians must take into consideration that unilateral orbital pain, though atypical, may be a symptom of SH. PMID- 29530698 TI - Neurocutaneous Melanosis in an Adult Patient with Intracranial Primary Malignant Melanoma: Case Report and Review of the Literature. AB - BACKGROUND: To explore the clinical characteristics of neurocutaneous melanosis (NCM) in adult patients to help improve diagnosis and treatment of this disease, we present a rare case of an adult patient suffering from NCM with malignant melanoma, as well as a review of the relevant Chinese and English literature. CASE DESCRIPTION: The patient reported here plus the patients identified in our literature review total 30 adults with NCM (20 males [66.7%] and 10 females [33.3%]), age 19-65 years (average, 27.9 years). These include 24 cases of malignant melanoma (80.0%), 3 cases of melanocytoma (10.0%), 2 cases of diffuse melanocytosis (6.7%), and 1 case of unknown pathology (3.3%). Satellite nevi were reported in 25 cases (83.3%) and in 5 cases their presence was unknown (16.7%). Intracranial lesions were present in 28 cases (93.3%), and intraspinal lesions were present in 2 cases (6.7%). There are 4 cases of combined hydrocephalus (13.3%), and 2 cases of combined Dandy-Walker deformity (6.7%). CONCLUSIONS: NCM is a rare disease, especially in adults. With the onset of symptoms, the diagnosis is generally confirmed. In children with congenital giant nevus, regular periodic surveys of the central nervous system (brain and spinal cord) with magnetic resonance imaging or cerebrospinal fluid analysis should be performed to diagnose NCM. Active treatment should be undertaken to improve the prognosis. PMID- 29530699 TI - Combination Treatment with Bromocriptine and Metformin in Patients with Bromocriptine-Resistant Prolactinomas: Pilot Study. AB - BACKGROUND: Prolactinomas are the most common functional pituitary adenomas and dopamine agonists are the primary therapy. However, some patients are resistant to dopamine agonists. Recently, metformin has been proposed as a cancer treatment. CASE DESCRIPTION: This study is a retrospective review of 2 cases including 1 patient with prolactinoma who was resistant to bromocriptine, diagnosed with impaired glucose tolerance, and administered metformin. Surprisingly, combining the patient's treatment with metformin decreased prolactin (PRL) levels to 12 ng/mL and significantly decreased the size of the tumor after 1 year of combination therapy. As menstruation resumed and galactorrhea resolved, the patient became pregnant and stopped using metformin but continued taking bromocriptine. She gave birth to a healthy boy in August 2016. After delivery, she decided to breastfeed the baby and only took bromocriptine. After 14 months of using bromocriptine alone, her PRL level increased to 208 ng/mL and the tumor reappeared (7 mm * 8 mm * 9 mm). Interestingly, the patient's PRL level decreased from 208 ng/mL to 150 ng/mL 2 months after using combination treatment with bromocriptine and metformin. On the basis of these findings, a second bromocriptine-resistant patient was recruited. After 3 months of combined treatment with bromocriptine and metformin, the patient's PRL level decreased to 2.08 ng/mL, testosterone levels increased significantly, and the tumor size decreased. CONCLUSIONS: Although more cases and investigations into the mechanisms underlying these effects are needed, these 2 cases support the hypothesis that the combination of metformin and bromocriptine might be a new treatment for resistant prolactinomas. PMID- 29530700 TI - Effect of Riluzole on Spinal Cord Regeneration with Hemisection Method Before Injury. AB - OBJECTIVE: The pathophysiology of spinal cord injury (SCI) with the information obtained to date has not been elucidated fully. A safe drug or treatment protocol that results in cell regeneration for SCI remains unknown. Neuroprotective and neuroregenerative effects of riluzole, administered after a SCI, have been shown in experimental studies. This study aimed to investigate the effect of riluzole on neural regeneration in a rat SCI model. METHODS: Thirty-two rats were divided into 8 groups, with 4 rats in each group. Hemisection method was performed after T7-T9 laminectomy. Rats were intraperitoneally aministered with riluzole (6 mg/kg). Locomotor recovery of the rats was assessed at 1 day, and 1, 2, 3, and 4 weeks after the 21-point Basso, Beattie, and Bresnahan test. Subsequently, the spinal cords of the rats were scored according to a semiquantitative grading system using a light microscope, and the numbers of myelinated axons, neurons, and glial cells were calculated. RESULTS: Basso, Beattie, and Bresnahan test changes were statistically significant when groups 4-6 and 8 were compared with the other groups (P < 0.05, P < 0.00625). The results of the numbers of neurons, glial cells, and myelinated axons were statistically significant. Especially group 8, in which riluzole was administered 5 days before injury, more positive clinical and histopathologic results were obtained. CONCLUSIONS: Riluzole treatment is more effective when provided before injury. Riluzole may contribute to functional recovery when used in the preoperative period in patients who are at a high risk for permanent neurologic deficit. PMID- 29530701 TI - Planned Subtotal Resection of Vestibular Schwannoma Differs from the Ideal Radiosurgical Target Defined by Adaptive Hybrid Surgery. AB - OBJECTIVE: To retrospectively compare ideal radiosurgical target volumes defined by a manual method (surgeon) to those determined by Adaptive Hybrid Surgery (AHS) operative planning software in 7 patients with vestibular schwannoma (VS). METHODS: Four attending surgeons (3 neurosurgeons and 1 ear, nose, and throat surgeon) manually contoured planned residual tumors volumes for 7 consecutive patients with VS. Next, the AHS software determined the ideal radiosurgical target volumes based on a specified radiotherapy plan. Our primary measure was the difference between the average planned residual tumor volumes and the ideal radiosurgical target volumes defined by AHS (dRVAHS-planned). RESULTS: We included 7 consecutive patients with VS in this study. The planned residual tumor volumes were smaller than the ideal radiosurgical target volumes defined by AHS (1.6 vs. 4.5 cm3, P = 0.004). On average, the actual post-operative residual tumor volumes were smaller than the ideal radiosurgical target volumes defined by AHS (2.2 cm3 vs. 4.5 cm3; P = 0.02). The average difference between the ideal radiosurgical target volume defined by AHS and the planned residual tumor volume (dRVAHS-planned) was 2.9 +/- 1.7 cm3, and we observed a trend toward larger dRVAHS-planned in patients who lost serviceable facial nerve function compared with patients who maintained serviceable facial nerve function (4.7 cm3 vs. 1.9 cm3; P = 0.06). CONCLUSIONS: Planned subtotal resection of VS diverges from the ideal radiosurgical target defined by AHS, but whether that influences clinical outcomes is unclear. PMID- 29530702 TI - Dynamic Cervical Radiographs in Patients with Hirayama Disease: An Unneglectable Factor on the Choice of Surgery Options. AB - OBJECTIVE: To evaluate the cervical spine alignment and range of motion (ROM) of neck flexion in patients with Hirayama disease. METHODS: Fifty male patients were included, with dynamic radiographs and magnetic resonance imaging (MRI) analyzed retrospectively. The Cobb angles for the entire cervical spine (C2-C7) and each level (C2/3-C6/7) were measured, and the neck flexion ROM was defined as the neutral Cobb angle minus the flexion Cobb angle. Paired t tests and Wilcoxon signed-rank tests were used to compare the Cobb angles and ROM between radiographs and MRI. RESULTS: The neutral and flexion Cobb angles decreased from C2/3 to C5/6 but increased at C6/7 on radiographs and MRI. The neutral Cobb angle of C2-C7 from radiographs was significantly larger than that seen on MRI (5.27 degrees vs. -3.26 degrees ; P < 0.0001). Neck flexion ROM seen with MRI tended to be lower than those of corresponding levels on radiographs. The ROM of C2-C7, C3/4, and C6/7 on radiographs was significantly larger than that seen with MRI (37.86 degrees vs. 26.59 degrees , P < 0.0001; 7.46 degrees vs. 5.10 degrees , P = 0.0071; and 10.45 degrees vs. 7.03 degrees , P = 0.0023, respectively). For the lower cervical levels, the largest and second largest ROM were seen in C5/6 and C6/7 on the radiographs but C5/6 and C4/5 on MRI. CONCLUSIONS: The cervical spine alignment and neck flexion ROM in Hirayama disease differed between radiographs and MRI. Both imaging techniques should be examined comprehensively when planning an operation. PMID- 29530703 TI - Mechanism of Pediatric Traumatic Brain Injury in Southwestern Uganda: A Prospective Cohort of 100 Patients. AB - BACKGROUND: Road traffic incidents (RTIs), falls, and violence contribute to more than two thirds of pediatric traumatic brain injuries in sub-Saharan Africa. In this study, we sought to assess mechanisms of pediatric traumatic brain injury in an effort to propose interventions for more effective pediatric head injury prevention. METHODS: A cohort of 100 patients who were <18 years treated at Mbarara Regional Referral Hospital between November 2016 and June 2017 were enrolled in the study. Information on etiology of injury was obtained via a questionnaire administered to patient caretakers at the time of admission. RESULTS: The mean age was found to be 7.5 years (standard deviation 5.2) and 38% were female. In our sample, 61% had computed tomography imaging done, of whom 88.5% had a positive finding. A majority of patients presented with a mild head injury (55%). RTIs were the predominant mechanism of injury across age groups (75%). Across all age groups, falls were responsible for a greater proportion of injuries in children aged 10-14 years (13.3%), whereas the greatest proportion of intentional injuries was reported in age group 10-14 and 15-17 years, 20% and 31.3%, respectively. Patients involved in pedestrian RTIs were significantly younger compared with those injured in nonpedestrian RTIs. Most parents (87.9%) were not with their children at the time of a pedestrian RTI. CONCLUSIONS: In Southwestern Uganda, the majority of pediatric neurotrauma patients are injured pedestrians, with no adult supervision at the time of the injury. Conducting a public awareness and education campaign on the necessity of child supervision is critical to decreasing pediatric head injuries in Uganda. PMID- 29530704 TI - PHASES and ELAPSS Scores Are Associated with Aneurysm Growth: A Study of 431 Unruptured Intracranial Aneurysms. AB - BACKGROUND: Understanding risk factors for intracranial aneurysm growth is important for patient management. We performed a retrospective study examining risk factors for the growth of unruptured intracranial aneurysms followed at our institution, evaluating both traditional risk factors and the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score. METHODS: We retrospectively reviewed a consecutive series of unruptured intracranial aneurysms followed at our institution for a minimum of 6 months over a 15-year period. The primary outcome of this study was aneurysm growth, defined as a >=1 mm increase in maximum diameter. Risk factors studied included PHASES score, ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age, Population, Size, and Shape) score, demographics, multiple aneurysms, previous subarachnoid hemorrhage, family history of aneurysm or subarachnoid hemorrhage, smoking, hypertension, and aneurysm shape, size, and location. The chi2 test was used for comparison of categorical variables, and the Student t test was used for continuous variables. RESULTS: The study cohort comprised 352 patients with a total of 431 unruptured intracranial aneurysms. The mean duration of follow-up was 4.8 years, and there was a total of 2100 aneurysm-years of follow-up. Forty aneurysms (9.3%) grew, for an annualized growth rate of 2.0% of aneurysms/year. Current smoking status was the sole modifiable risk factor associated with growth (growth rate of 5.1%/year compared with 1.5%/year for never smokers; P = 0.0004). Increasing size (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.11-1.33; P < 0.0001), ELAPSS score (OR, 1.10; 95% CI, 1.09-1.11; P < 0.0001), and PHASES score (OR, 1.24; 95% CI, 1.20-1.28; P < 0.0001) were associated with growth as well. Age, location, previous subarachnoid hemorrhage, and hypertension were not independently associated with aneurysm growth. CONCLUSIONS: Our retrospective study suggests that aneurysm size, smoking status, PHASES score, and ELAPSS score are associated with aneurysm growth. PMID- 29530705 TI - The Optimum Operative Time of Revascularization for Patients with Moyamoya Disease Following Acute Onset. AB - OBJECTIVE: Whether surgery should be performed in patients with acute onset of moyamoya disease (MMD) is controversial. This study aimed to determine optimum operative time for patients with MMD. METHODS: We retrospectively analyzed 57 patients with MMD admitted between January 2016 and June 2017. All patients consented to combined revascularization. Considering the time interval between acute onset of MMD and surgery, we divided all patients into an early group and later group (>90 days between MMD onset and surgery). We compared postoperative complications, neurologic improvement, and favorable outcome between groups to estimate optimum operative time of revascularization. RESULTS: More patients in the early group presented with ischemic events compared with the later group (18/28 vs. 11/29, P = 0.047). The difference in worst preoperative mRS score (>=3) between groups was not statistically significant (3/28 vs. 3/29, P = 0.964). Rate of postoperative complications in the early group was significantly higher than in the later group (39.2% vs. 13.7%, P = 0.029). There was neurologic improvement in 50.0% of patients in the early group and 75.9% of patients in the later group (P = 0.043). The rate of favorable outcome after revascularization in the later group (89.7%) was higher than in the early group (78.6%), but there was no significant difference (P = 0.251). CONCLUSIONS: It seems more reasonable to opt for delayed revascularization for patients with acute-onset MMD, but the decision must take into account the morbidity of ongoing ischemic or hemorrhagic events. PMID- 29530706 TI - Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Moyamoya Disease: Region-Symptom Mapping and Estimating a Critical Threshold. AB - BACKGROUND: Cerebral hyperperfusion complicates the postoperative course of patients with moyamoya disease after direct revascularization surgery. There is no clear distinction between cerebral hyperperfusion syndrome and benign postoperative increase in regional cerebral blood flow (rCBF). OBJECTIVE: The present study aimed to determine clinically relevant changes in rCBF, anatomical correlations, and factors associated with transient neurologic symptoms after revascularization surgery in moyamoya disease. METHODS: Whole-brain voxel-based perfusion mapping was used to identify regions involved in cerebral hyperperfusion and quantify the changes in 105 hemispheric surgeries with the use of single-photon computed tomography acquired on postoperative day 7. The changes in rCBF were quantitatively analyzed, and associations with cerebral hyperperfusion syndrome were determined. RESULTS: Transient neurologic symptoms appeared with rCBF increase in 37.9% of adults. Speech impairments were associated with an increase in rCBF in the operculo-insula region. Cheiro-oral syndrome was associated with the posterior insula as well as the prefrontal region. A receiver operating curve analysis yielded transient neurologic symptoms with maximum accuracy at >15.5% increase from baseline. Age and preoperative rCBF were independently associated with transient neurologic symptoms (P < 0.001). CONCLUSIONS: Areas showing rCBF increase during the experience of transient neurologic symptoms were spatially compatible with the known functional anatomy of the brain. An increase of approximately 15% from baseline was found to be critical, which is a far lower threshold than what has been reported previously. Increasing age was significantly associated with the occurrence of symptomatic hyperperfusion. Furthermore, patients with preserved rCBF also showed symptomatic hyperperfusion. PMID- 29530707 TI - Transient Focal Magnetic Resonance Imaging Abnormalities After Status Epilepticus Showed 11C-Methionine Uptake with Positron Emission Tomography in a Patient with Cerebral Cavernous Malformation. AB - BACKGROUND: Transient focal magnetic resonance imaging (MRI) abnormalities after status epilepticus (SE) are rarely seen in patients with benign brain tumors, and the underlying mechanism is still unknown. We report a rare case of cerebral cavernous malformation with transient focal MRI abnormalities around the tumor and accumulation of 11C-methionine on positron emission tomography (PET) after SE. These findings mimicked those of a glioma because the MRI and methionine PET findings were similar. We also speculate about the cause of this phenomenon in relation to pathologic findings of this case. CASE DESCRIPTION: A 51-year-old man suffered from SE. MRI demonstrated a focal T2/fluid-attenuated inversion recovery hyperintense area. 11C-methionine PET showed high accumulation of methionine in the same lesion. The initial diagnosis was low-grade glioma. However, these MRI abnormalities were transient and completely resolved. The patient underwent surgical removal of the tumor, and the histologic diagnosis was typical cavernous malformation. Pathologic findings of the gyrus around the tumor revealed mild gliosis with proliferating astrocytes but no evidence of glioma. CONCLUSIONS: This case suggests that transient focal MRI abnormalities after SE may indicate reversible cortical brain edema. Accumulation of 11C-methionine on PET could occur in the corresponding lesion even if no malignant tumor is present. Because distinguishing transient MRI abnormalities after SE from a glioma is difficult, repeated imaging studies should be performed in patients with brain tumor-related seizures. PMID- 29530708 TI - Improvement in Sagittal Balance After Decompression Surgery without Fusion in Patients with Degenerative Lumbar Stenosis: Clinical and Radiographic Results at 1 Year. AB - OBJECTIVE: To evaluate modifications in static spinal status after posterior decompression surgery without fusion in patients with symptomatic central canal stenosis. METHODS: From November 2014 to May 2016, 72 patients who underwent isolated decompression for lumbar spinal stenosis were enrolled prospectively in this single-center study. All of the patients had lateral full-body x-ray scans with the EOS system (EOS Imaging, Paris, France) before surgery and after 12 months of follow-up. Patients were classified into 3 groups according to their preoperative sagittal vertical axis (<50 mm, >=50 mm, and <100 mm, >=100 mm). RESULTS: SVA decreased significantly (SVA preoperative: 72.3 +/- 43.1; SVA postoperative: 48.3 +/- 46.8. P < 0.001). Lumbar lordosis increased significantly from 41.9 +/- 13.4 in the preoperative period to 46.5 +/- 14.8 at the last follow up (P < 0.001). In the imbalance groups, the mean postoperative SVA decreased significantly compared with preoperative SVA (P = 0.004). Surgery led to a significant increase in lumbar lordosis in the 3 groups (P < 0.05). Nonetheless, a certain degree of residual imbalance persisted in the major imbalance group. In all of the groups, decompression surgery led to a significant improvement in clinical scores (P < 0.05). CONCLUSIONS: Our study showed an improvement in sagittal balance and lumbar lordosis after decompression surgery without fusion, even in patients with a preoperative SVA >100 mm. However, a certain degree of sagittal imbalance may persist after surgery in patients with major initial imbalance (SVA >100 mm). Nonetheless, after surgery, these patients experienced a clinical benefit comparable with that in the other groups. PMID- 29530709 TI - Predominance of methicillin-resistant Staphylococcus aureus in the residents and environments of long-term care facilities in Taiwan. AB - BACKGROUND/PURPOSE: This study investigated the distribution and persistence of multidrug resistant organisms (MDROs) including methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and multidrug-resistant Acinetobacter baumannii (MDRAB) in six long-term care facilities (LTCFs). METHODS: We investigated the distribution of MDROs in residents of six LTCFs and their environments from January to December 2016 (intervention period). Active surveillance of colonization of MDROs was performed by culturing rectal and nasal swab samples from the residents every three months. Multilocus sequence typing (MLST) was conducted, and genes for panton-valentine leukocidin (PVL) from MRSA isolates were determined. RESULTS: A total of 521 samples were positive for MDROs, and MRSA was the most common organism (65.1%), followed by MDRAB (11.3%), carbapenem-resistant Klebsiellapneumoniae (11.1%), carbapenem-resistant Escherichiacoli (4.6%), and carbapenem-resistant P. aeruginosa (2.1%, n = 11). By a linear regression model, positive MRSA isolates from the environment were found to be statistically significant and associated with the number of colonized LTCF residents (p = 0.01), while the timing of the surveillance culture was not (p = 0.227). The main MLST types associated with PVL-production were sequence type (ST) 59, (40.0%, 24/60), ST30 (21.4%, 3/14), ST8 (87.5%, 14/16), and ST45 (3.6%, 1/28). The susceptibility rates of tetracycline (96.7%), trimethoprim sulfamethoxazole (96.7%), and ciprofloxacin (81.7%) were statistically significant and higher in MRSA ST59, compared to the rates in MRSA ST45 isolates. CONCLUSIONS: MRSA was the most commonly colonized MDRO, both in the LTCF residents and in the environment, followed by MDRAB and carbapenem-resistant K. pneumoniae. PMID- 29530710 TI - New Technologies for Treating Type I Diabetes in Pediatrics. PMID- 29530711 TI - Mapping and neuromodulation of lower urinary tract function using spinal cord stimulation in female rats. AB - Spinal cord epidural stimulation (SCS) represents a form of neuromodulation for the management of spasticity and pain. This technology has recently emerged as a new approach for potentially augmenting locomotion and voiding function in humans and rodents after spinal cord injury. However, the effect of SCS on micturition has not been studied extensively. Here, SCS was first applied as a direct stimulus onto individual segmental levels of the lumbar spinal cord in rats to map evoked external urethral sphincter (EUS) electromyography activity and SCS induced voiding contractions. SCS of L2-3 inhibited EUS tonic activity, and SCS on L3 (L3/SCS) inhibited EUS tonic activity and elicited EUS bursting. In contrast, SCS of L1 and L4-6 evoked EUS tonic contractions, which resembled the urethral guarding reflex during bladder storage. Next, the effects of a bilateral pelvic nerve crush (PNC) injury on urodynamic function were examined at 14 days post-operatively. The PNC injury resulted in decreased voiding efficiency and maximum intravesical pressure, whereas the post-voiding residual volume was increased, suggestive of an underactive bladder. Finally, L3/SCS was performed to induce a voiding contraction and enable voiding in rats with a PNC injury. Voiding efficiency was significantly increased, and the residual volume was decreased by L3/SCS in rats after the PNC injury. We conclude that L3/SCS may be used to induce micturition reflexes in a partially filled bladder, reduce urethral resistance, and augment bladder emptying after PNC injury. PMID- 29530712 TI - Genetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and l-Dopa-induced dyskinesia in experimental Parkinson's disease. AB - Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiology of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and l-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic l-Dopa in wild type and Nr4a1-deficient rats, respectively. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and l-Dopa-induced dyskinesia in experimental PD. PMID- 29530713 TI - DREADDed microglia in pain: Implications for spinal inflammatory signaling in male rats. AB - The absence of selective pharmacological tools is a major barrier to the in vivo study of microglia. To address this issue, we developed a Gq- and Gi-coupled Designer Receptor Exclusively Activated by a Designer Drug (DREADD) to enable selective stimulation or inhibition of microglia, respectively. DREADDs under a CD68 (microglia/macrophage) promoter were intrathecally transfected via an AAV9 vector. Naive male rats intrathecally transfected with Gq (stimulatory) DREADDs exhibited significant allodynia following intrathecal administration of the DREADD-selective ligand clozapine-N-oxide (CNO), which was abolished by intrathecal interleukin-1 receptor antagonist. Chronic constriction injury induced allodynia was attenuated by intrathecal CNO in male rats intrathecally transfected with Gi (inhibitory) DREADDs. To explore mechanisms, BV2 cells were stably transfected with Gq or Gi DREADDs in vitro. CNO treatment induced pro inflammatory mediator production per se from cells expressing Gq-DREADDs, and inhibited lipopolysaccharide- and CCL2-induced inflammatory signaling from cells expressing Gi-DREADDs. These studies are the first to manipulate microglia function using DREADDs, which allow the role of glia in pain to be conclusively demonstrated, unconfounded by neuronal off-target effects that exist for all other drugs that also inhibit glia. Hence, these studies are the first to conclusively demonstrate that in vivo stimulation of resident spinal microglia in intact spinal cord is a) sufficient for allodynia, and b) necessary for allodynia induced by peripheral nerve injury. DREADDs are a unique tool to selectively explore the physiological and pathological role of microglia in vivo. PMID- 29530714 TI - Mesoporous Pravastatin Solid Dispersion Granules Incorporable Into Orally Disintegrating Tablets. AB - Herein, we aimed to prepare porous granules of pravastatin and evaluate their applicability to orally disintegrating tablets (ODTs). Pravastatin solid dispersion granules (PSDGs-A) were prepared by dispersing pravastatin sodium in D mannitol (the dispersion medium) in the presence of ammonium bicarbonate (the sublimation agent) using a spray-drying process. The PSDGs-A were round, irregularly shaped, mesoporous agglomerates with appropriate particle size, bulk density, and flowability for the tableting process. The mesopore formation in PSDGs-A resulted from the complete sublimation of ammonium bicarbonate during spray-drying and resulted in a notably high surface area. When the PSDGs-A were blended with ODT excipients and then directly compressed into ODTs (PSDGs-A ODTs), they were readily incorporated into ODTs without tableting problems and had desirable ODT characteristics. They demonstrated rapid disintegration times because of the fast water uptake of mesoporous PSDGs-A caused by their high surface area. This rapid disintegration of PSDGs-A-ODTs was reflected also by their quick initial dissolution. The mesoporous PSDGs-A prepared with ammonium bicarbonate using the spray-drying process can be used to develop pravastatin ODTs. This spray-dried, mannitol-based solid dispersion of drugs using sublimation solids is a potential formulation technology for ODT product development. PMID- 29530715 TI - The patterns of colonization and antifungal susceptibility of Candida, isolated from preterm neonates in Khorramabad, South West of Iran. AB - OBJECTIVE: Usually, 7-20% of preterm neonates colonized by Candida species present invasive candidiasis. Candida albicans, and several non-albicans species cause invasive infection with C. albicans being the most dominant agent. In the last two decades, infection due to non-albicans have been increased dramatically due to their low sensitivity to antifungal drugs such as fluconazole. The aim of present study was to evaluate Candida colonization pattern and antifungal susceptibility among preterm neonates from Khorramabad, South west of Iran. MATERIALS AND METHODS: Samples were collected from 80 preterm neonates, cultured on CHROMagar Candida and incubated at 37 degrees C. All recovered isolates were primarily screened based on classical methods and identified by PCR-RFLP targeting the ITS-rDNA regions. Antifungal susceptibility testing of all isolates was performed according to the CLSI method against amphotericin B, caspofungin, itraconazole, fluconazole and voriconazole. RESULTS: Totally 23 isolates of Candida species were recovered from 20 patients (female: male, 50:50) including, C. albicans (18), C. parapsilosis (2) and C. glabrata (1). Furthermore, the blood cultures from two patients were yielded C. albicans and C. parapsilosis so that patient with C. albicans died after five days. Generally, in this study, 9 (39.1%) isolates were resistant to amphotericin B including; 7 (30.4%) C. albicans and 2 (8.7%) C. parapsilosis. In addition, 2 (8.7%) and 4 (17.4%) isolates were also resistant to itraconazole and caspofungin, respectively. CONCLUSION: In conclusion, Candida colonization among preterm neonates is still an important issue in hospitals. In addition, in spite of a significant amphotericin B resistant Candida, voriconazole, fluconazole, and itraconazole are valuable antifungals, due to fully sensitivity to Candida. PMID- 29530716 TI - Critically Appraised Papers: Moderate-intensity walking for people with severe knee osteoarthritis does not decrease pain but may have cardiovascular benefits [synopsis]. PMID- 29530717 TI - Expression profile of glucose transport-related genes under chronic and acute exposure to growth hormone in zebrafish. AB - The brain is a highly demanding organ in terms of energy requirements, and precise regulatory mechanisms must operate to ensure adequate energy delivery to maintain normal neuronal activity. Of the energy-promoting substrates present in the circulation, glucose is preferred by the brain, and as with all other substrates, its utilization depends on the presence of humoral factors such as hormones including growth hormone (GH). Glucose enters the cells though specific transport proteins. Among all transporter families and subtypes described to date, the most studied ones are the glucose transporters (GLUTs). The aim of this study is to determine a possible relationship between GH and GLUTs. Therefore, we evaluated the effect of GH-transgenesis and recombinant GH injections upon GLUT expression in the brain of male zebrafish. Overall, the results demonstrated that increasing the GH concentrations above the normal level, via transgenesis or injection, in the fish may impair energy uptake by the brain. This appeared to occur through downregulation of most of the analyzed GLUTs. PMID- 29530718 TI - French national survey on infective endocarditis and the MelodyTM valve in percutaneous pulmonary valve implantation. AB - BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) is a routine treatment for dysfunctional right ventricular outflow tract. Infective endocarditis (IE) is a major concern. AIM: To report French experience with the MelodyTM valve (Medtronic Inc., Minneapolis, MN, USA). METHODS: All patients who underwent PPVI were recorded in a multicentre French national survey. Demographic and procedural data were collected from patients with IE. Bacterial identification, diagnostic tools and outcome were recorded. RESULTS: Forty-five cases of IE were diagnosed in 43 patients. The cumulative IE incidence was 11.8% (95% confidence interval [CI] 8.5-15.9). The annualized IE incidence was 3.6% (95% CI 0-4.8). Freedom from IE was 96.3% and 85.8% at 12 months and 60 months, respectively. IE incidence did not change during the study period. The mean interval between PPVI and IE was 2.6+/-2.1 years (range, 5 days to 7.3 years). Fifteen patients with IE required intravenous antibiotics only. Seven patients had early interventional cardiac catheterization to relieve severe right ventricular outflow tract obstruction. Twenty-four patients had surgical valve replacement (six urgently; nine semi-urgently; nine electively). Staphylococcus aureus IE required surgery in all but one patient. Three patients died before any treatment. Three additional patients died, giving a mortality rate of 14%. Global survival in the total cohort of patients who received a Melody valve was excellent (96.5% at 5 years). When comparing survival curves between the IE and non-IE groups, death and cardiovascular events were statistically significantly higher in the IE group (log-rank P<0.0001). CONCLUSION: Melody valve IE is a severe complication following PPVI. The annualized IE incidence in this cohort was similar to rates reported in other studies. With rapid diagnosis and adequate treatment, outcome has improved, and unfavourable outcome is mainly associated with S. aureus. PMID- 29530719 TI - Rescue of a cherubism bone marrow stromal culture phenotype by reducing TGFbeta signaling. AB - We utilized a bone marrow stromal culture system to investigate changes in TGFbeta signaling in a mouse model for cherubism (Sh3bp2KI/KI). Interestingly, bone marrow cultures derived from cherubism mice not only displayed impaired osteoblast differentiation, but also had spontaneous osteoclast formation. PAI1, a target gene of TGFbeta signaling, was elevated 2-fold in cherubism CD11b-,CD45- cells compared to wild type cells, while the expression of BAMBI, an inhibitor of TGFbeta signaling, was down-regulated. We also discovered that treatment of cherubism cultures with antagonists of the TGFbeta signaling pathway could largely rescue osteoblast differentiation and markedly reduce spontaneous osteoclast formation. Treatment with the type I TGFbeta receptor small molecule inhibitor SB505124 increased osteoblast reporter gene Col1a1-2.3 expression 24 fold and increased the expression of osteoblast gene markers Osterix (Sp7) 25 fold, Bone Sialoprotein (BSP) 7-fold, Osteocalcin (Bglap1) 100-fold, and Dentin Matrix Protein 1 (DMP1) 35-fold. In contrast, SB505124 treatment resulted in a significant reductions in osteoclast number and size. Gene expression analyses for RANKL, a positive regulator of osteoclast formation was 2.5-fold higher in osteoblast cultures derived from Sh3bp2KI/KI mice compared to wild type cultures, whereas OPG, an inhibitor of RANKL was 5-fold lower. However, SB505124 treatment reduced RANKL almost back down to wild type levels, while increasing OPG expression. Our studies also implicate a role for TGFbeta ligands in the etiology of cherubism. Blocking of TGFbeta ligands with the monoclonal antibody 1D11 increased Col1a1-2.3 reporter expression 4-fold and 13-fold in cultures derived from Sh3bp2KI/+ and Sh3bp2KI/KI mice, respectively. Serum levels of latent TGFbeta1 were also 2-fold higher in SH3BP2KI/KI mice compared to wild type littermates. Taken together, these studies provide evidence that elevated levels of TGFbeta signaling may contribute to the disease phenotype of cherubism and a reduction in pathway activity may be an effective therapeutic approach to treat this rare disease. PMID- 29530720 TI - Differential effects of high-physiological oestrogen on the degeneration of mandibular condylar cartilage and subchondral bone. AB - The striking predilection of temporomandibular disorders (TMD) in women, especially during gonad-intact puberty or reproductive years, indicates that oestrogen plays an important role in the progression of TMD, but the underlying mechanism remains unclear. In this study, unilateral anterior crossbite (UAC) was used to create temporomandibular joint osteoarthritis (TMJ OA) models in rats, while 17beta-estradiol (E2) injections were applied to mimic patients with high physiological levels of oestrogen. Micro-CT scanning, histological staining and real-time PCR assays were preformed to observe the degenerative changes in the mandibular condylar cartilage and subchondral bone. The results showed that obvious degradation was found in the condylar cartilage and subchondral bone of rats with UAC procedure, including decreased cartilage thickness, loss of extracellular matrix, increased apoptotic chondrocytes and expression of pro inflammatory and catabolic factors, decreased bone mineral density and increased osteoclast activity. E2 supplements aggravated the condylar cartilage degradation but reversed the abnormal bone resorption in the subchondral bone induced by UAC. Our results revealed that high-physiological oestrogen plays a destructive role in condylar cartilage but a protective role in subchondral bone at the early stage of TMJ OA. These dual and distinct effects should be given serious consideration in future OA treatments. PMID- 29530721 TI - Trends in calcium supplementation, National Health and Nutrition Examination Survey (NHANES) 1999-2014. AB - BACKGROUND: Long-term outcomes of supplemental calcium are inadequately understood. Recent research suggests that calcium from supplements may not be entirely free from unintended health consequences. Consequently, it is important to understand patterns and trends in use of calcium supplements. OBJECTIVE: To report trends in supplemental calcium intake between 1999 and 2014, using NHANES data, overall and stratified by sex, race/ethnicity and age. METHODS: A total of 42,038 adult NHANES participants were included in this analysis. For each survey period, we calculated the prevalence of calcium supplement use exceeding the Estimated Average Requirement (EAR) and Tolerable Upper Intake Levels (UL), and mean daily supplemental calcium dose among calcium-containing supplement users. Sample weights were applied. Linear regression was used to examine trends. RESULTS: Overall, the prevalence of calcium supplement use at a dose >=EAR increased between 1999 and 2000 and 2013-2014, from 2.5% (95% CI: 1.9-3.3%) to 4.6% (3.8-5.5%). Use >=EAR peaked in 2003-2004 at 6.7% (5.3-8.5%) (p-quadratic trend<0.001). Mean supplemental calcium intake peaked in 2007-2008, thereafter decreasing (p-quadratic trend<0.001). The overall prevalence of intake >=UL from supplemental calcium in 2013-2014 was 0.4% (0.2-0.8%). Use of supplemental calcium >=UL peaked during 2007-2008 at 1.2% (0.7-2.0%). In all time periods, supplemental calcium intake tended to be greater among women, non-Hispanic whites and adults >60years. CONCLUSIONS: We described the prevalence of U.S. adults consuming supplemental calcium >=UL and >= EAR. While few were consuming supplemental calcium >=UL, consumption >=EAR was not uncommon, especially among women, non-Hispanic whites and older adults. PMID- 29530722 TI - Mutation of adjacent cysteine residues in the NSs protein of Rift Valley fever virus results in loss of virulence in mice. AB - The NSs protein encoded by the S segment of Rift Valley fever virus (RVFV) is the major virulence factor, counteracting the host innate antiviral defence. It contains five highly conserved cysteine residues at positions 39, 40, 149, 178 and 194, which are thought to stabilize the tertiary and quaternary structure of the protein. Here, we report significant differences between clinical, virological, histopathological and host gene responses in BALB/c mice infected with wild-type RVFV (wtRVFV) or a genetic mutant having a double cysteine-to serine substitution at residues 39 and 40 of the NSs protein (RVFV-C39S/C40S). Mice infected with the wtRVFV developed a fatal acute disease; characterized by high levels of viral replication, severe hepatocellular necrosis, and massive up regulation of transcription of genes encoding type I and -II interferons (IFN) as well as pro-apoptotic and pro-inflammatory cytokines. The RVFV-C39S/C40S mutant did not cause clinical disease and its attenuated virulence was consistent with virological, histopathological and host gene expression findings in BALB/c mice. Clinical signs in mice infected with viruses containing cysteine-to-serine substitutions at positions 178 or 194 were similar to those occurring in mice infected with the wtRVFV, while a mutant containing a substitution at position 149 caused mild, non-fatal disease in mice. As mutant RVFV-C39S/C40S showed an attenuated phenotype in mice, the molecular mechanisms behind this attenuation were further investigated. The results show that two mechanisms are responsible for the attenuation; (1) loss of the IFN antagonistic propriety characteristic of the wtRVFV NSs and (2) the inability of the attenuated mutant to degrade Proteine Kinase R (PKR). PMID- 29530723 TI - Role of cellular prion protein in interneuronal amyloid transmission. AB - Several studies have indicated that certain misfolded amyloids composed of tau, beta-amyloid or alpha-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of beta-amyloid oligomers and cellular prion protein (PrPC) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, beta-amyloid/PrPC interaction takes place in two differently charged clusters of PrPC. In addition to beta-amyloid, participation of PrPC in alpha-synuclein binding and brain spreading also appears to be relevant in alpha-synucleopathies. This review summarizes current knowledge about PrPC as a putative receptor for amyloid proteins and the physiological consequences of these interactions. PMID- 29530724 TI - Genetic and functional characters of GRN p.T487I mutation in Taiwanese patients with atypical parkinsonian disorders. AB - BACKGROUND: Mutations in the GRN (granulin precursor) are a frequent cause of frontotemporal dementia (FTD) and other atypical parkinsonian disorders. However, the frequency of GRN mutations in Asian patients with atypical parkinsonian disorders is still uncertain. METHODS: We screened GRN mutations by sequencing cDNA from 98 patients with FTD or atypical parkinsonian disorders. The functional properties of the identified mutation were evaluated by overexpression in human embryonic kidney (HEK)-293 cells. RESULTS: We identified a new missense (GRN p.T487I) mutation in a female patient with undefined atypical parkinsonism. The overexpression experiment further demonstrated that p.T487I mutation reduced the progranulin protein level and stability in HEK-293 cells. CONCLUSION: GRN p.T487I mutation, which decreases the stability of progranulin protein, could be a new causative mutation in patients with atypical parkinsonian disorders. PMID- 29530725 TI - Movement disorders in multiple sclerosis and neuromyelitis optica: A clinical marker of neurological disability. AB - INTRODUCTION: Movement disorders are not rare in demyelinating diseases but there are few studies comparing their frequency between multiple sclerosis and neuromyelitis optica spectrum disorder. Our aim was to determine the frequency and the related features of movement disorders in a cohort of patients with multiple sclerosis and neuromyelitis optica spectrum disorder. METHODS: It is a cross-sectional study of patients with multiple sclerosis and neuromyelitis optica spectrum disorder. Patients were evaluated by a movement disorder specialist. Data from a personal interview and neurological examination were collected. Fahn-Tolosa-Marin tremor rating scale was used for tremor evaluation. Health-related quality of life was assessed using EuroQol instrument. RESULTS: Two hundred fifty-three patients were included (mean [SD] age, 40 [12] years; 74.3% female; median [IQR] EDSS score 2.5 [1.0-6.0]); 26% presented with movement disorders. Paroxysmal dystonia (n = 32) and tremor (n = 27) were the most common movement disorders. Patients with multiple sclerosis and low Expanded Disability Status Scale score (below 4.0) have fewer movement disorders than patients with neuromyelitis optica spectrum disorder. The diagnosis of neuromyelitis optica spectrum disorder was strongly associated with paroxysmal dystonia (OR = 22.07, 95% CI = 2.56-189.78; p = 0.005). Patients with multiple sclerosis and patients without movement disorders have a slightly better quality of life. CONCLUSIONS: Paroxysmal dystonia was the most common movement disorder in demyelinating diseases and strongly associated with neuromyelitis optica spectrum disorder. PMID- 29530726 TI - Minimal clinically important change in the Toronto Western Spasmodic Torticollis Rating Scale. AB - OBJECTIVES: To characterize the minimal clinically important change (MCIC) after treatment in cervical dystonia patients using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). METHODS: Changes in the TWSTRS from an observational study of abobotulinumtoxinA in the routine management of cervical dystonia (NCT01314365) were analyzed using the Patient Global Impression of Change (PGIC) as anchor. RESULTS: For the overall population (N = 304, baseline TWSTRS-Total score 43.4 +/- 19.4), the MCIC for the TWSTRS Total score was -11.9 (95%CI: -13.9, -10.0; p < 0.0001). However, thresholds ranged from -3.2 to -18.0 dependent on baseline severity. TWSTRS-Total scores improved linearly by 3 points for every one-point PGIC increase. There was similar linearity between the graded PGIC categories and TWSTRS subscale scores (severity, disability, and pain). CONCLUSIONS: A 3-point change is the minimal clinically important change after treatment using TWSTRS as endpoint with higher cutoffs for greater baseline disease severity. For an average trial population (TWSTRS-total: 40-45), a 12 point decrease is clinically meaningful. PMID- 29530727 TI - Please Say Thank You. PMID- 29530728 TI - Sepsis-Associated Encephalopathy with Multiple Microbleeds in Cerebral White Matter. PMID- 29530729 TI - Assessing Resident Attitudes and Confidence after Integrating Geriatric Education Into a Primary Care Resident Clinic. PMID- 29530730 TI - Social Media and Physician Conflict of Interest. PMID- 29530731 TI - Hypertriglyceridemia-Induced Acute Pancreatitis with Normal Pancreatic Enzymes. PMID- 29530732 TI - Clinical and Molecular Predictors of PD-L1 Expression in Non-Small-Cell Lung Cancer: Systematic Review and Meta-analysis. AB - Clinicopathologic and molecular characteristics of non-small-cell lung cancers (NSCLCs) associated with a strong expression of programmed death ligand 1 (PD-L1+ in > 5% of cells) have not been well elucidated. Expression of PD-L1 is a poor prognostic factor, but NSCLCs with higher levels of PD-L1 have greater benefit when treated with immunotherapy. We have performed a systematic review to synthesize the available evidence regarding clinicopathologic and molecular variables associated with PD-L1 expression in NSCLC. PubMed, EMBASE, SCOPUS, Web of Science and Cochrane Library databases were searched for relevant articles assessing predictors of PD-L1 expression in > 5% cells. Data were reported as odds ratio (OR) of events. Fifty-two studies (for a total of 5066 PD-L1+ out of 13,279 NSCLC patients) were included in this meta-analysis. Factors associated with PD-L1 expression were: smoking status (OR 5.48; 95% confidence interval (CI) 2.8-10.4; P < .001), male gender (OR 4.8; 95% CI 3.2-7.2; P < .001), adenocarcinoma histology (OR 2.75; 95% CI, 1.5-4.8; P < .001), Epidermal growth factor receptor (EGFR) wild type (OR 4.83; 95% CI, 2.1-11.1; P < .001), ALK mutation negative (OR 388.6; 95% CI, 222.5-678.7; P < .001), ROS mutation negative (OR 1904.8; 95% CI, 630-5757; P < .001), and KRAS wild type (OR 19.8; 95% CI, 7.6-51.6; P < .001). Conversely higher pT stages (OR 0.16; 95% CI, 0.04 0.7; P = .01), pN+ stages (OR 0.29; 95% CI, 0.17-0.5; P < .001) are inversely associated with PD-L1 expression in > 5% cells. Expression of PD-L1 is more common in male smokers, with adenocarcinoma histology and not carriers of EGFR/ALK/ROS/KRAS mutations. These data could be useful to screening of PD-L1 expression and to select patients for immunotherapy. PMID- 29530733 TI - An arboreal spider protects its offspring by diving into the water of tank bromeliads. AB - Cupiennius salei (Ctenidae) individuals frequently live in association with tank bromeliads, including Aechmea bracteata, in Quintana Roo (Mexico). Whereas C. salei females without egg sacs hunt over their entire host plant, females carrying egg sacs settle above the A. bracteata reservoirs they have partially sealed with silk. There they avoid predators that use sight to detect their prey, as is known for many bird species. Furthermore, if a danger is more acute, these females dive with their egg sacs into the bromeliad reservoir. An experiment showed that this is not the case for males or females without egg sacs. In addition to the likely abundance of prey found therein, the potential of diving into the tank to protect offspring may explain the close association of this spider with bromeliads. These results show that, although arboreal, C. salei evolved a protective behavior using the water of tank bromeliads to protect offspring. PMID- 29530734 TI - Neurophysiological processes and functional neuroanatomical structures underlying proactive effects of emotional conflicts. AB - There is a strong inter-relation of cognitive and emotional processes as evidenced by emotional conflict monitoring processes. In the cognitive domain, proactive effects of conflicts have widely been studied; i.e. effects of conflicts in the n-1 trial on trial n. Yet, the neurophysiological processes and associated functional neuroanatomical structures underlying such proactive effects during emotional conflicts have not been investigated. This is done in the current study combining EEG recordings with signal decomposition methods and source localization approaches. We show that an emotional conflict in the n-1 trial differentially influences processing of positive and negative emotions in trial n, but not the processing of conflicts in trial n. The dual competition framework stresses the importance of dissociable 'perceptual' and 'response selection' or cognitive control levels for interactive effects of cognition and emotion. Only once these coding levels were isolated in the neurophysiological data, processes explaining the behavioral effects were detectable. The data show that there is not only a close correspondence between theoretical propositions of the dual competition framework and neurophysiological processes. Rather, processing levels conceptualized in the framework operate in overlapping time windows, but are implemented via distinct functional neuroanatomical structures; the precuneus (BA31) and the insula (BA13). It seems that decoding of information in the precuneus, as well as the integration of information during response selection in the insula is more difficult when confronted with angry facial emotions whenever cognitive control resources have been highly taxed by previous conflicts. PMID- 29530735 TI - Anterior pedicle temporalis muscle flap interposition in the treatment of TMJ disorders. AB - : Temporomandibular joint (TMJ) disorders are a common reason for consultation. Failure of medical treatments sometimes leads to the need for one of many surgical alternatives. Our purpose was to evaluate the results of anterior pedicle temporalis muscle flap interposition in the treatment of TMJ disorders. MATERIAL AND METHODS: For this prospective study, we selected 18 patients who underwent TMJ surgery involving the interposition of a temporalis muscle flap according to a standardized technique, between January 1, 2009 and August 31, 2014. CT imaging was performed on all patients prior to surgery. We documented the etiology of TMJ dysfunction, pre and postoperative pain using a visual analogue scale (VAS), pre and postoperative (last consultation) mouth opening, and complications. We used the Wilcoxon test for our statistical analysis. RESULTS: We observed a significant variation in preoperative and postoperative pain and mouth opening, with an average decrease in VAS values of 4.9/10 and an average increase of mouth opening of 11.1mm. No major complications were observed. DISCUSSION: The interposition of an anterior pedicle temporalis muscle flap in the treatment of temporomandibular joint disorder is a simple and effective technique. PMID- 29530736 TI - Hubner's tarsomarginal grafts in eyelid reconstruction: 94 cases. AB - BACKGROUND: Preserving the integrity of the eyelid margin in eyelid reconstruction remains a challenge for plastic surgeons. In 1976, Hubner described a technique to repair full-thickness eyelid defects using a tarsomarginal graft covered with a local flap. This simple technique addresses both functional and aesthetic requirements of eyelid reconstruction by using tissue from the contralateral eyelid. The aim of this study was to determine the appropriate role of this uncommon technique in eyelid reconstruction. METHOD: In total, 94 tarsomarginal grafts were performed on 70 patients. Eight surgeons participated in this study. Data were retrospectively collected from patients' charts and all information regarding surgical indications, histology, defect size and topography, operative time, immediate result, and potential complications were recorded. RESULTS: Only one of the patients suffered total necrosis. Partial wound dehiscence occurred in one case and partial necrosis occurred in 6 cases. No major sequelae were observed in the donor eyelids. In 100% of cases, eyelid margin integrity was otherwise preserved. Four patients required revision surgery for insufficient malignancy resection and 13 patients for long-term eyelid ectropion or scar retraction. CONCLUSION: This simple and reliable technique ensured the closure of full-thickness eyelid defects covering up to 3/4 of the eyelid length. The procedure should be more widely used as it guarantees high quality eyelid reconstruction. PMID- 29530737 TI - Clinical characteristics and immunohistochemical analysis of p53, Ki-67 and cyclin D1 in 80 odontogenic keratocysts. AB - OBJECTIVE: The aim of this study was to evaluate clinical parameters and expression patterns of Ki-67, cyclin D1 and p53 in odontogenic keratocysts. MATERIAL AND METHODS: In this study, fifty-three patients with 80 odontogenic keratocysts were included. The medical records of these patients were reviewed retrospectively. To elucidate the molecular pathogenesis of the disease, the expression of p53, Ki-67 and cyclin D1 was analyzed using immunohistochemistry. RESULTS: A total of 53 patients (mean age 38 years) with a median follow-up of 4.2 years (ranging from 4 days to 14.4 years) were evaluated. The rates of recurrence and post-operative complications varied depending on the surgical approach: cystectomy and peripheral ostectomy led to manageable low rates of complications and recurrence frequency. Immunohistochemical evaluation revealed that all lesions were positive for Ki-67 and cyclin D1 expression. The expression of Ki-67 was associated with the degree of inflammation. Cyclin D1 was expressed significantly higher in syndrome-associated keratocystic lesions. In contrast to non-syndromal lesions, all syndromal lesions expressed p53. CONCLUSION: This investigation demonstrates that the pathogenesis of syndromal keratocysts appears to differ from sporadic odontogenic keratocysts. Additionally, the primary and recurrent non-syndromal keratocysts have a similar etiology, as no differences in the expression patterns of Ki-67, p53 and cyclin D1 were observed. PMID- 29530738 TI - Use of omental free flap for craniofacial reconstruction in unfavorable wound bed: A case report. AB - INTRODUCTION: The omental free flap is an effective tool for craniofacial reconstruction. However it is generally under-utilised by a large number of practitioners. This paper's goal is to increase awareness of this free flap's accessibility and to demonstrate that it can be an attractive option for reconstructive surgery. CLINICAL REPORT: This article outlines the details of a 57-year-old patient who required coverage of a fronto-parietal wound with dura mater exposure. After previous failed conventional free flap attempts, a procedure using the omental free flap was finally performed on this severe wound. The omentum was harvested via a 8cm laparotomy and anastomosed to the temporal vessels. The final result was successful, with a favorable aesthetic result. DISCUSSION: The omental free flap has many advantages: the pedicle length is long, it allows coverage of a large wound, it can be applied to a wound bed previously irradiated and infected, it has a low morbidity rate to the donor site, the surgical technique of harvesting is easy, the aesthetic result is satisfactory. However, the absence of skin slice is a disadvantage of the omental free flap because it makes monitoring difficult and it requires a skin graft in a second procedure. Laparoscopic harvest of omentum free flaps is a safe and effective tool in the reconstructive armamentarium. Every maxillofacial and plastic surgeon should aim to master and use this method as a legitimate option in some infrequent but appropriated cases. PMID- 29530739 TI - Re-programming immunosurveillance in persistent non-infectious ocular inflammation. AB - Ocular function depends on a high level of anatomical integrity. This is threatened by inflammation, which alters the local tissue over short and long time-scales. Uveitis due to autoimmune disease, especially when it involves the retina, leads to persistent changes in how the eye interacts with the immune system. The normal pattern of immune surveillance, which for immune privileged tissues is limited, is re-programmed. Many cell types, that are not usually present in the eye, become detectable. There are changes in the tissue homeostasis and integrity. In both human disease and mouse models, in the most extreme cases, immunopathological findings consistent with development of ectopic lymphoid-like structures and disrupted angiogenesis accompany severely impaired eye function. Understanding how the ocular environment is shaped by persistent inflammation is crucial to developing novel approaches to treatment. PMID- 29530740 TI - Ductus arteriosus and fetal echocardiography: Implications for practice. AB - The ductus arteriosus (DA) is a crucial part of the fetal circulation, both in the normal fetus and in critical congenital heart disease (CHD). It allows shunting between the pulmonary and systemic circulations. In physiological prenatal conditions, the DA lets the majority of right ventricular output bypass the fluid-filled, high-resistance lungs. The DA can cause hemodynamic compromise in the fetus and neonate when constricted or absent (in isolation or in patients with CHD) and may lead to pre- or postnatal sequelae within other systems when forming part of a vascular ring. In CHD, the DA can be interrogated by fetal echocardiography to infer information regarding severity of pulmonary outflow tract obstruction, adequacy of the sub-pulmonary ventricle to supply pulmonary blood flow, and to predict the likelihood of atrial septum restriction in transposition of the great arteries. A good understanding of the DA is crucial for fetal cardiologists. PMID- 29530741 TI - An evaluation of a toolkit for the early detection, management, and control of carbapenemase-producing Enterobacteriaceae: a survey of acute hospital trusts in England. AB - BACKGROUND: Following hospital outbreaks of carbapenemase-producing Enterobacteriaceae (CPE), Public Health England published a toolkit in December 2013 to promote the early detection, management, and control of CPE colonization and infection in acute hospital settings. AIM: To examine awareness, uptake, implementation and usefulness of the CPE toolkit and identify potential barriers and facilitators to its adoption in order to inform future guidance. METHODS: A cross-sectional survey of National Health Service (NHS) acute trusts was conducted in May 2016. Descriptive analysis and multivariable regression models were conducted, and narrative responses were analysed thematically and informed using behaviour change theory. FINDINGS: Most (92%) acute trusts had a written CPE plan. Fewer (75%) reported consistent compliance with screening and isolation of CPE risk patients. Lower prioritization and weaker senior management support for CPE prevention were associated with poorer compliance. Awareness of the CPE toolkit was high and all trusts with patients infected or colonized with CPE had used the toolkit either as provided (32%), or to inform (65%) their own local CPE plan. Despite this, many respondents (80%) did not believe that the CPE toolkit guidance offered an effective means to prevent CPE or was practical to follow. CONCLUSION: CPE prevention and control requires robust IPC measures. Successful implementation can be hindered by a complex set of factors related to their practical execution, insufficient resources and a lack of confidence in the effectiveness of the guidance. Future CPE guidance would benefit from substantive user involvement, processes for ongoing feedback, and regular guidance updates. PMID- 29530742 TI - Reducing the risk of iatrogenic Creutzfeldt-Jakob disease by improving the cleaning of neurosurgical instruments. AB - BACKGROUND: In all, there have been 178 variant Creutzfeldt-Jakob disease (vCJD) patients diagnosed in the UK, with an estimated maximum 1:2000 carriage rate based on archived appendix and tonsil tissue, implying that infection may be rare but carriage relatively frequent. Previous workers have identified that maintenance of surgical instruments in a humid atmosphere after use and prior to cleaning assists cleaning efficacy. Recently the Department of Health/Advisory Committee on Dangerous Pathogens UK have recommended a surgical instrument cleanliness threshold post cleaning of <5 MUg protein per instrument side. AIM: To quantify cleanliness of neurosurgical instruments and to investigate cost effective measures for improved cleaning. METHODS: Two instrument protein quantification methods were used: one based on the International Standard (15883 series) using sodium dodecyl sulphate elution and ortho-phthalaldehyde reaction, and a second in-situ protein fluorescence detection system (ProReveal) providing results per instrument side. In-vitro investigation of the efficacy of some commercial and in-house pre-clean wetting agents was undertaken using artificial test soil and stainless steel discs under standard conditions. In-vivo evaluation of best-performing in-vitro agents was undertaken on craniotomy sets. FINDINGS: ProReveal technology demonstrated that 163 out of 187 (87%) neurosurgical instruments had <5 MUg residual protein per instrument side. The use of proprietary National Health Service plastic bags and sterile water-soaked wound pads were equivalent in efficacy to commercial pre-cleaning wetting products and significantly less expensive. CONCLUSION: Although we demonstrate low in-situ protein levels on neurosurgical instruments and the beneficial effects of keeping instruments moist, other cleaning critical-control points such as instrument loading patterns should also be monitored. PMID- 29530743 TI - Epidemiology, risk factors and outcomes of multi-drug-resistant bloodstream infections in haematopoietic stem cell transplant recipients: importance of previous gut colonization. AB - BACKGROUND: Bloodstream infections (BSI) are a major complication in the early phase of a haematopoietic stem cell transplant (HSCT). AIM: To describe the incidence and risk factors for BSI occurring in the pre-engraftment phase of HSCT, and its impact on mortality. METHODS: Clinical variables of 232 HSCT patients were analysed retrospectively between 2014 and 2015. Univariate Cox regression analyses were performed to test the association between each covariate and the outcome. Covariates with P < 0.10 on univariate analysis were included in a multiple Cox regression analysis using a backward elimination method. FINDINGS: The cumulative incidence of BSI was 25.4%, mainly caused by Gram-negative bacteria (GNB) (55.2%). Approximately 40.5% of the patients had gut colonization by multi-drug-resistant (MDR) bacteria (vancomycin-resistant enterococcus and carbapenem-resistant GNB). Among patients colonized by MDR GNB, 20% developed an overt BSI due to MDR bacteria with the same pattern of sensitivity. Of the 13 deaths related to infection, 10 were patients with BSI caused by MDR GNB. The independent risk factors for BSI were gut colonization by MDR bacteria including GNB (P < 0.001) and duration of neutropenia >10 days (P = 0.005), and those associated with BSI caused by MDR bacteria were age >62 years (P = 0.03), use of total parenteral nutrition (TPN) (P < 0.001) and previous gut colonization by MDR GNB (P = 0.002). CONCLUSIONS: Previous gut colonization by MDR was an independent risk factor for BSI, together with TPN and age, and had an impact on outcome. These findings suggest that gut decolonization may be a potential strategy to prevent BSI. PMID- 29530744 TI - Links between global and local shape perception, coloured backgrounds, colour discrimination, and non-verbal IQ. AB - This study explored associations between local and global shape perception on coloured backgrounds, colour discrimination, and non-verbal IQ (NVIQ). Five background colours were chosen for the local and global shape tasks that were tailored for the cone-opponent pathways early in the visual system (cardinal colour directions: L-M, loosely, reddish-greenish; and S-(L + M), or tritan colours, loosely, blueish-yellowish; where L, M and S refer to the long, middle and short wavelength sensitive cones). Participants also completed the Farnsworth Munsell 100-hue test (FM100) to determine whether performance on the local and global shape tasks correlated with colour discrimination overall, or with performance on the L-M and tritan subsets of the FM100 test. Overall performance on the local and global shape tasks did correlate with scores on the FM100 tests, despite the colour of the background being irrelevant to the shape tasks. There were also significantly larger associations between scores for the L-M subset of the FM100 test, compared to the tritan subset, and accuracy on some of the shape tasks on the reddish, greenish and neutral backgrounds. Participants also completed the non-verbal components of the WAIS and the SPM+ version of Raven's progressive matrices, to determine whether performance on the FM100 test, and on the local and global shape tasks, correlated with NVIQ. FM100 scores correlated significantly with both WAIS and SPM+ scores. These results extend previous work that has indicated FM100 performance is not purely a measure of colour discrimination, but also involves aspects of each participant's NVIQ, such as the ability to attend to local and global aspects of the test, part-whole relationships, perceptual organisation and good visuomotor skills. Overall performance on the local and global shape tasks correlated only with the WAIS scores, not the SPM+. These results indicate that those aspects of NVIQ that engage spatial comprehension of local-global relationships and manual manipulation (WAIS), rather than more abstract reasoning (SPM+), are related to performance on the local and global shape tasks. Links are presented between various measures of NVIQ and performance on visual tasks, but they are currently seldom addressed in studies of either shape or colour perception. Further studies to explore these issues are recommended. PMID- 29530745 TI - The hemoglobin degradation pathway in patients with preeclampsia - Fetal hemoglobin, heme, heme oxygenase-1 and hemopexin - Potential diagnostic biomarkers? AB - OBJECTIVE: The aim of this study was to investigate how maternal cell-free fetal hemoglobin and heme impact the scavenger enzyme systems Hemopexin and Heme Oxygenase-1 in patients with preeclampsia (PE). The secondary aims were to evaluate these proteins as biomarkers for severity of the clinical manifestation i.e. hypertension, in early- and late onset PE. MATERIAL AND METHODS: Plasma samples taken within the last 24 h before delivery from 135 patients were analyzed, 89 PE and 46 normal pregnancies. All samples were analyzed for cell free fetal hemoglobin (HbF), heme, hemopexin enzymatic activity (Hx activity), hemopexin concentration (Hx), and heme oxygenase 1 concentration (HO-1). Logistic regression analysis with ROC-curve analysis was performed to evaluate the possible use as biomarkers for preeclampsia. RESULTS: There were significantly higher levels of HbF (p = 0.01) and heme (0.01) but significantly lower Hx activity (p = 0.02), Hx (p < 0.0001) and HO-1 (p = 0.03) in PE plasma as compared to plasma of normal pregnancies. The Hx activity was significantly inversely correlated (p = 0.04) to the diastolic blood pressure. The HO-1 concentration was significantly inversely correlated to both the systolic and diastolic blood pressure (p = 0.01 and p = 0.003). ROC-curve analysis showed a combined detection rate for these biomarkers of 84% at 10% false positive rate. CONCLUSIONS: Increased maternal plasma levels of heme and HbF in PE are associated with decreased HO-1 and hemopexin protein levels as well as reduced hemopexin activity. By measuring the consumption of the scavenger protein Hx, and the proteins in the Hb degradation system, clinical information about the dynamics of the disease can be obtained. PMID- 29530746 TI - Myopericytoma of the Lip: A Case Report of This Rare Lesion. AB - Myopericytomas are rare benign tumors that show a distinctive, concentric perivascular proliferation of oval to spindle-shaped myoid-appearing cells that are predominantly arranged concentrically around thin-walled vascular channels. These lesions are similar in histologic appearance to hemangiopericytomas, myofibromas, and glomus tumors. The myopericytoma is usually found in the distal extremities, but a handful of reports have shown the lesion to be present in the oral cavity. A review of the literature to date shows only 4 other reported cases of myopericytomas occurring in the lips. We describe a case of myopericytoma in the lower lip of a 42-year-old woman. PMID- 29530747 TI - Use of Intravenous Acetaminophen in Postoperative Pain Management After Partial and Full Bony Impacted Third Molar Extractions: A Randomized Double-Blind Controlled Trial. AB - PURPOSE: Currently, there is a concern at the national level of the overuse of both prescription and nonprescription opioid use. The purpose of this study was to identify whether the use of the intravenous (IV) formulation of acetaminophen (Ofirmev; Mallinckrodt Pharmaceuticals, Staines-upon-Thames, United Kingdom) is an effective tool in the reduction of postoperative pain, with a secondary goal of reduction of postoperative narcotic use. MATERIALS AND METHODS: A total of 72 patients with previously diagnosed either partial bony or complete bony impacted third molars were selected with care to avoid long-acting local anesthetics or dissociative anesthetic agents. The patients' postoperative pain scores at 4 and 24 hours were collected via a verbal rating scale by the primary investigator. The exclusion criteria included administration of bupivacaine or ketamine, hepatic or renal impairment, pregnancy, or allergy to any of the normally administered sedation medications. RESULTS: At all postoperative increments (immediately, 4 hours, and 24 hours), there was no significant difference at P < .05 between scores for either the IV acetaminophen or placebo group. Although there was a recorded difference in reduction of pain at both 4 and 24 hours postoperatively, these were not statistically significant variables. CONCLUSIONS: The use of IV acetaminophen showed no statistically significant decrease in patient pain at either 4 or 24 hours postoperatively. Although there are not representative data suggesting the routine use of IV acetaminophen, on the basis of the abundance of literature on the treatment of pain for other procedures, this medication should not be discarded as ineffective. PMID- 29530748 TI - Protocol for Single-Stage Bilateral Temporomandibular Joint Replacement Using Intraoperative Navigation in Patients With Ankylosis. AB - Treatment of patients with bilateral temporomandibular joint (TMJ) ankylosis in a single-stage procedure can be challenging. The implementation of intraoperative navigation has proved beneficial by enabling faster and safer excision by providing real-time identification of vital structures. Navigation also can be used to verify site preparation for custom joint prostheses. This article seeks to establish a protocol, based on the use of intermaxillary fixation screws, to produce accurate and repeatable outcomes for the correction of bilateral TMJ ankylosis with total joint replacement in a single-stage procedure. PMID- 29530749 TI - Integrated analysis of isopentenyl pyrophosphate (IPP) toxicity in isoprenoid producing Escherichia coli. AB - Isopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental platform to study IPP toxicity in isoprenol producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability. We show that IPP toxicity selects for pathway "breakage", using proteomics to identify a reduction in phosphomevalonate kinase (PMK) as a probable recovery mechanism. Next, using multi-omics data, we demonstrate that endogenous E. coli metabolism is globally impacted by IPP accumulation, which slows nutrient uptake, decreases ATP levels, and perturbs nucleotide metabolism. We also observe the extracellular accumulation of IPP and present preliminary evidence that IPP can be transported by E. coli, findings that might be broadly relevant for the study of isoprenoid biosynthesis. Finally, we discover that IPP accumulation leads to the formation of ApppI, a nucleotide analog of IPP that may contribute to observed toxicity phenotypes. This comprehensive assessment of IPP stress suggests potential strategies for the alleviation of prenyl diphosphate toxicity and highlights possible engineering targets for improved IPP flux and high titer isoprenoid production. PMID- 29530750 TI - Exploiting endogenous CRISPR-Cas system for multiplex genome editing in Clostridium tyrobutyricum and engineer the strain for high-level butanol production. AB - Although CRISPR-Cas9/Cpf1 have been employed as powerful genome engineering tools, heterologous CRISPR-Cas9/Cpf1 are often difficult to introduce into bacteria and archaea due to their severe toxicity. Since most prokaryotes harbor native CRISPR-Cas systems, genome engineering can be achieved by harnessing these endogenous immune systems. Here, we report the exploitation of Type I-B CRISPR Cas of Clostridium tyrobutyricum for genome engineering. In silico CRISPR array analysis and plasmid interference assay revealed that TCA or TCG at the 5'-end of the protospacer was the functional protospacer adjacent motif (PAM) for CRISPR targeting. With a lactose inducible promoter for CRISPR array expression, we significantly decreased the toxicity of CRISPR-Cas and enhanced the transformation efficiency, and successfully deleted spo0A with an editing efficiency of 100%. We further evaluated effects of the spacer length on genome editing efficiency. Interestingly, spacers <= 20 nt led to unsuccessful transformation consistently, likely due to severe off-target effects; while a spacer of 30-38 nt is most appropriate to ensure successful transformation and high genome editing efficiency. Moreover, multiplex genome editing for the deletion of spo0A and pyrF was achieved in a single transformation, with an editing efficiency of up to 100%. Finally, with the integration of the alcohol dehydrogenase gene (adhE1 or adhE2) to replace cat1 (the key gene responsible for butyrate production and previously could not be deleted), two mutants were created for n-butanol production, with the butanol titer reached historically record high of 26.2 g/L in a batch fermentation. Altogether, our results demonstrated the easy programmability and high efficiency of endogenous CRISPR Cas. The developed protocol herein has a broader applicability to other prokaryotes containing endogenous CRISPR-Cas systems. C. tyrobutyricum could be employed as an excellent platform to be engineered for biofuel and biochemical production using the CRISPR-Cas based genome engineering toolkit. PMID- 29530751 TI - RARA and RARG gene downregulation associated with EZH2 mutation in acute promyelocytic-like morphology leukemia. AB - Most acute promyelocytic leukemia (APL) patients express PML-RARA fusion; in rare cases, RARA is rearranged with partner genes other than PML. To date, only 2 patients presenting features similar to APL showing the RARG gene rearrangement have been described. We report an acute myeloid leukemia patient with morphology resembling APL without involvement of the RARA gene. Molecular and fluorescent in situ hybridization analyses excluded PML-RARA fusion and variant rearrangements involving RARA and RARG loci. Targeted next-generation sequencing showed EZH2- D185H mutation. As this mutation involved the region of interaction with DNA methyltransferases, we speculate an epigenetic alteration of genes involved in the APL-like phenotype. Expression analysis by droplet digital polymerase chain reaction revealed downregulation of the RARA and RARG genes. We hypothesize a novel mechanism of EZH2 function alteration, which may be responsible for an acute myeloid leukemia with APL-like phenotype featuring dysregulation of the RARA and RARG genes. PMID- 29530752 TI - A unique evolution of the kidney phenotype in a patient with autosomal recessive Alport syndrome. AB - Alport syndrome is due to mutations in one of the genes encoding (alpha3,4,5) type IV collagen resulting in defective type IV collagen, a key component of the glomerular basement membrane (GBM). The GBM is initially thin and, with ongoing remodeling, develops a thickened basket-woven appearance. We report a unique case of a 9-year-old boy who underwent biopsy for hematuria and proteinuria, diagnosed as IgA nephropathy, with normal GBM appearance and thickness. Because of a family history of hematuria and chronic kidney disease, he subsequently underwent genetic evaluation, and a mutation of alpha3 type IV collagen (COL4A3) was detected. Additional studies of the initial biopsy demonstrated abnormal type IV collagen immunostaining. A repeat biopsy 4 years later showed characteristic glomerular basement membrane morphology of Alport syndrome and scarring consistent with sequelae of IgA nephropathy. This is the first description of this unusual transition from an initial normal appearance of the glomerular basement membrane to the classic Alport phenotype. PMID- 29530753 TI - Autopsy-detected diagnostic errors over time in the intensive care unit. AB - We evaluate the evolution over time of discrepancies between clinical diagnoses and postmortem findings in critically ill patients and assess the factors associated with these discrepancies. We conducted a prospective study of all consecutive patients who underwent autopsy in a medical-surgical intensive care unit (ICU) between January 2008 and December 2015. Among 7655 patients admitted to our ICU, 671 (8.8%) died. Clinical autopsy was performed in 215 (32%) patients. Major missed diagnoses were noted in 38 patients (17.7%). Eighteen patients (8.4%) had class I discrepancies, and 20 patients (9.3%) had class II discrepancies. The most frequently missed diagnoses were invasive aspergillosis, intestinal ischemia, myocardial infarction, cancer, and intra-abdominal abscesses. We did not find a statistically significant correlation between any premortem factor, including age, sex, severity of illness, length of hospital stay before ICU admission, length of ICU stay before death, duration of mechanical ventilation, or admitting unit, and the level of agreement between clinical and pathological diagnosis. In the last decades, the discrepancies between clinical and autopsy diagnoses persisted despite advances in medical skills and technology. Specific clinical entities such as invasive aspergillosis, mesenteric ischemia, myocardial infarction, intra-abdominal abscesses, and neoplastic diseases remain a diagnostic challenge in critically ill patients. Clinical level of diagnostic certainty does not increase with specific premortem characteristics. PMID- 29530754 TI - Investigating the metabolic alterations in a depressive-like rat model of chronic forced swim stress: An in vivo proton magnetic resonance spectroscopy study at 7T. AB - Although recent investigations of major depressive disorder (MDD) have focused on the monoaminergic system, accumulating evidences suggest that alternative pathophysiological models of MDD and treatment options for patients with MDD are needed. Animals subjected to chronic forced swim stress (CFSS) develop behavioral despair. The purpose of this study was to investigate the in vivo effects of CFSS on systems other than the monoamine system in the rat prefrontal cortex (PFC) with 7T and short-echo-time (16.3 ms) proton magnetic resonance spectroscopy (1H MRS). Ten male Wistar rats underwent 14 days of CFSS, and in vivo1H MRS and forced swim tests were performed before and after CFSS. Point-resolved spectroscopy was used to quantify metabolite levels in the rat PFC. To investigate spectral overlap in glutamate and glutamine, spectral analyses in the spectra obtained in the in vivo1H MRS, parametrically matched spectral simulation, and in vitro experiments were performed. The results of the spectral analyses showed that the glutamate/glutamine spectral overlap was not critical, which suggested that in vivo1H MRS can be used to reliably assess the glutamate system. The rats showed significantly increased immobility times and decreased climbing times in the FST after CFSS, which suggested that the rats developed behavioral despair. The pre-CFSS and post-CFSS glutamate and glutamine levels did not significantly differ (p > 0.050). The levels of myo-inositol, total choline, and N-acetylaspartate, myo-inositol/creatine, and total choline/creatine increased significantly (p < 0.050). Similar findings have been reported in patients with MDD. Taken together, these results suggest that the CFSS-induced metabolic alterations were similar to those found in patients and that high-field and short-echo-time in vivo1H MRS can be used to investigate depression-induced metabolic alterations. Such investigations might provide alternative insights into the nonmonoaminergic pathophysiology and treatment of depression. PMID- 29530755 TI - Glial glutamate transporters expression, glutamate uptake, and oxidative stress in an experimental rat model of intracerebral hemorrhage. AB - Glial glutamate transporters (EAAT1 and EAAT2), glutamate uptake, and oxidative stress are important players in the pathogenesis of ischemic brain injury. However, the changes in EAAT1 and EAAT2 expression, glutamate uptake and the oxidative profile during intracerebral hemorrhage (ICH) development have not been described. The present study sought to investigate the changes of the above mentioned variables, as well as the Na+/K+-ATPase and glutamine synthetase activities (as important contributors of glutamate homeostasis) and the percentage of neuronal cells after 6 h, 24 h, 72 h and 7 days of ICH. An injection of 0.2U of bacterial collagenase in the ipsilateral striatum was used to induce ICH in male Wistar rats; naive animals were used as controls. EAAT1 and EAAT2 expression and glutamate uptake in the ipsilateral striatum were assessed. Additionally, the percentage of MAP2+ cells, Na+/K+-ATPase and GS activities, as well as the oxidative profile were analyzed. It is shown a decrease of EAAT1 expression and glutamate uptake 6 h post-ICH, whereas EAAT2 decreased 72 h after the event; conversely EAAT2 and glutamate uptake were increased after 7 days. The oxidative stress and endogenous defense system exhibited a remarkable response at 72 h of injury. ICH also increased Na+/K+-ATPase activity and selectively decreased GS activity, variables known to be important contributors of glial glutamate transporters activities. Altogether, present findings indicate that ICH induces different temporal EAAT1 and EAAT2 responses, culminating with an imbalance of glutamate uptake capacity, increased oxidative stress and sustained neuronal loss. PMID- 29530756 TI - Axon-terminals expressing EAAT2 (GLT-1; Slc1a2) are common in the forebrain and not limited to the hippocampus. AB - : The excitatory amino acid transporter type 2 (EAAT2) represents the major mechanism for removal of extracellular glutamate. In the hippocampus, there is some EAAT2 in axon-terminals, whereas most of the protein is found in astroglia. The functional importance of the neuronal EAAT2 is unknown, and it is debated whether EAAT2-expressing nerve terminals are present in other parts of the brain. Here we selectively deleted the EAAT2 gene in neurons (by crossing EAAT2-flox mice with synapsin 1-Cre mice in the C57B6 background). To reduce interference from astroglial EAAT2, we measured glutamate accumulation in crude tissue homogenates. EAAT2 proteins levels were measured by immunoblotting. Although synapsin 1-Cre mediated gene deletion only reduced the forebrain tissue content of EAAT2 protein to 95.5 +/- 3.4% of wild-type (littermate) controls, the glutamate accumulation in homogenates of neocortex, hippocampus, striatum and thalamus were nevertheless diminished to, respectively, 54 +/- 4, 46 +/- 3, 46 +/ 2 and 65 +/- 7% of controls (average +/- SEM, n = 3 pairs of littermates). GABA uptake was unaffected. After injection of U-13C-glucose, lack of neuronal EAAT2 resulted in higher 13C-labeling of glutamine and GABA in the hippocampus suggesting that neuronal EAAT2 is partly short-circuiting the glutamate-glutamine cycle in wild-type mice. Crossing synapsin 1-Cre mice with Ai9 reporter mice revealed that Cre-mediated excision occurred efficiently in hippocampus CA3, but less efficiently in other regions and hardly at all in the cerebellum. CONCLUSIONS: (1) EAAT2 is expressed in nerve terminals in multiple brain regions. (2) The uptake catalyzed by neuronal EAAT2 plays a role in glutamate metabolism, at least in the hippocampus. (3) Synapsin 1-Cre does not delete floxed genes in all neurons, and the contribution of neuronal EAAT2 is therefore likely to be larger than revealed in the present study. PMID- 29530757 TI - Neuromuscular synapse degeneration without muscle function loss in the diaphragm of a murine model for Huntington's Disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model for HD (BACHD). We showed that the axons of the phrenic nerves were not affected in 12-months-old BACHD mice, but the axon terminals that form the neuromuscular junctions (NMJs) were more fragmented in these animals in comparison with the wild-type mice. In BACHD mice, the synaptic vesicles of the diaphragm NMJs presented a decreased exocytosis rate. Quantal content and quantal size were smaller and there was less synaptic depression whereas the estimated size of the readily releasable vesicle pool was not changed. At the ultrastructure level, the diaphragm NMJs of these mice presented fewer synaptic vesicles with flattened and oval shapes, which might be associated with the reduced expression of the vesicular acetylcholine transporter protein. Furthermore, mitochondria of the diaphragm muscle presented signs of degeneration in BACHD mice. Interestingly, despite all these cellular alterations, BACHD diaphragmatic function was not compromised, suggesting a higher resistance threshold of this muscle. A putative resistance mechanism may be protecting this vital muscle. Our data contribute to expanding the current understanding of the effects of mutated huntingtin in the neuromuscular synapse and the diaphragm muscle function. PMID- 29530759 TI - Effect of traditional Chinese medicine on skin lesions and quality of life in patients with moderate to severe eczema. PMID- 29530758 TI - Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats. AB - Hypoxic-ischemic (HI) encephalopathy is a leading cause of dire mortality and morbidity in neonates. Unfortunately, no effective therapies have been developed as of yet. Oxidative stress plays a critical role in pathogenesis and progression of neonatal HI. Previously, as a Nrf2 activator, tert-butylhydroquinone (TBHQ) has been demonstrated to exert neuroprotection on brain trauma and ischemic stroke models, as well as oxidative stress-induced cytotoxicity in neurons. It is, however, still unknown whether TBHQ administration can protect against oxidative stress in neonatal HI brain injury. This study was undertaken to determine the neuroprotective effects and mechanisms of TBHQ post-treatment on neonatal HI brain damage. Using a neonatal HI rat model, we demonstrated that TBHQ markedly abated oxidative stress compared to the HI group, as evidenced by decreased oxidative stress indexes, enhanced Nrf2 nuclear accumulation and DNA binding activity, and up-regulated expression of Nrf2 downstream antioxidative genes. Administration of TBHQ likewise significantly suppressed reactive gliosis and release of inflammatory cytokines, and inhibited apoptosis and neuronal degeneration in the neonatal rat cerebral cortex. In addition, infarct size and neuronal damage were attenuated distinctly. These beneficial effects were accompanied by improved neurological reflex and motor coordination as well as amelioration of spatial learning and memory deficits. Overall, our results provide the first documentation of the beneficial effects of TBHQ in neonatal HI model, in part conferred by activation of Nrf2 mediated antioxidative signaling pathways. PMID- 29530760 TI - Beekeeper' arthropathy. AB - An acute inflammatory arthritis of unknown cause has been described in beekeepers in relation to their work with the hives. We present the case of a beekeeper who, after a bee sting, developed arthritis of the interphalangeal joint of the first finger of his left hand. Although the subacute clinical course and the magnetic resonance imaging findings required the differential diagnosis with an infectious process, the rest of the laboratory tests. other imaging studies and the course, together with a history of a similar episode a few years earlier on a finger of the other hand after a bee sting, enabled us to diagnosis this condition. PMID- 29530761 TI - Sexuality and rheumatic diseases. PMID- 29530762 TI - Utility of urinary transferrin and ceruloplasmin in patients with systemic lupus erythematosus for differentiating patients with lupus nephritis. AB - BACKGROUND AND OBJECTIVE: Diagnosis of lupus nephritis (LN) is usually based on renal biopsy, which is an invasive technique that involves multiple risks. Therefore, different biomarkers have emerged as alternatives for the diagnosis of LN. Nonetheless, studies regarding urinary biomarkers in Latin American patients are limited. The objective of this study was to assess the diagnostic value of urinary transferrin and ceruloplasmin to differentiate patients who have renal involvement from those who do not. MATERIALS AND METHODS: Systemic lupus erythematosus (SLE) patients that met the revised American College of Rheumatology (ACR) classification criteria were recruited. Patients with another autoimmune disease, active infection (urinary tract or systemic infection), renal replacement therapy, human immunodeficiency virus infection or pregnancy were excluded. A urine sample was collected from each patient. LN was diagnosed according to ACR criteria. The activity and chronicity of LN were measured using the Austin indices. Urinary transferrin and ceruloplasmin levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits. Mann-Whitney U test and Student's t-test were used to compare data. Spearman's rank correlation was used to determine associations. Lastly, receiver operating characteristic (ROC) curves were created. RESULTS: The study involved 120 SLE patients. In all, 85% were female, 76% mestizo, the mean age was 32.8+/-12.1years and mean systemic lupus erythematosus disease activity index (SLEDAI) was 8.4+/-8.9; 64% had renal involvement. Urinary levels of the two biomarkers were significantly higher in patients with LN compared to those without LN. Similarly, urinary levels of both biomarkers were significantly higher in patients with active LN compared to those with inactive LN. Furthermore, urinary transferrin levels were significantly higher in Afro-Latin American patients. On the other hand, urinary transferrin levels correlated with SLEDAI and proteinuria, and transferrin and ceruloplasmin levels correlated with each other. The diagnostic value of ROC curves for these urinary biomarkers for LN were good. CONCLUSIONS: In our cohort of SLE patients, we found that transferrin and ceruloplasmin were potential biomarkers for LN, and can even differentiate active LN. PMID- 29530763 TI - Switch from intravenous to subcutaneous abatacept: Our experience. PMID- 29530764 TI - A computational model integrating brain electrophysiology and metabolism highlights the key role of extracellular potassium and oxygen. AB - The human brain is a small organ which uses a disproportionate amount of the total metabolic energy production in the body. While it is well understood that the most significant energy sink is the maintenance of the neuronal membrane potential during the brain signaling activity, the role of astrocytes in the energy balance continues to be the topic of a lot of research. A key function of astrocytes, besides clearing glutamate from the synaptic clefts, is the potassium clearing after neuronal activation. Extracellular potassium plays a significant role in triggering neuronal firing, and elevated concentration of potassium may lead to abnormal firing patterns, e.g., seizures, thus emphasizing the importance of the glial K+ buffering role. The predictive mathematical model proposed in this paper elucidates the role of glial potassium clearing in brain energy metabolism, integrating a detailed model of the ion dynamics which regulates neuronal firing with a four compartment metabolic model. Because of the very different characteristic time scales of electrophysiology and metabolism, care must be taken when coupling the two models to ensure that the predictions, e.g., neuronal firing frequencies and the oxygen-glucose index (OGI) of the brain during activation and rest, are in agreement with empirical observations. The temporal multi-scale nature of the problem requires the design of new computational tools to ensure a stable and accurate numerical treatment. The model predictions for different protocols, including combinations of elevated activation and ischemic episodes, are in good agreement with experimental observations reported in the literature. PMID- 29530765 TI - Complete genome sequence of Pseudomonas frederiksbergensis ERDD5:01 revealed genetic bases for survivability at high altitude ecosystem and bioprospection potential. AB - Pseudomonas frederiksbergensis ERDD5:01 is a psychrotrophic bacteria isolated from the glacial stream flowing from East Rathong glacier in Sikkim Himalaya. The strain showed survivability at high altitude stress conditions like freezing, frequent freeze-thaw cycles, and UV-C radiations. The complete genome of 5,746,824 bp circular chromosome and a plasmid of 371,027 bp was sequenced to understand the genetic basis of its survival strategy. Multiple copies of cold associated genes encoding cold active chaperons, general stress response, osmotic stress, oxidative stress, membrane/cell wall alteration, carbon storage/starvation and, DNA repair mechanisms supported its survivability at extreme cold and radiations corroborating with the bacterial physiological findings. The molecular cold adaptation analysis in comparison with the genome of 15 mesophilic Pseudomonas species revealed functional insight into the strategies of cold adaptation. The genomic data also revealed the presence of industrially important enzymes. PMID- 29530766 TI - Viral Respiratory Tract Infections in Allogeneic Hematopoietic Stem Cell Transplantation Recipients in the Era of Molecular Testing. AB - Viral respiratory tract infection (vRTI) is a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to assess the epidemiologic characteristics, risk factors, and outcomes of vRTI occurring in the period from conditioning to 100 days after allo-HSCT in the era of molecular testing. This study was a retrospective record review of patients who underwent allo-HSCT at Royal Melbourne Hospital between January 2010 and December 2015. Symptomatic patients were tested using respiratory multiplex polymerase chain reaction (PCR). Logistic regression and Kaplan-Meier analysis were used to identify risk factors for vRTI and the risk of death or intensive care unit (ICU) admission, respectively. A total of 382 patients were reviewed, and 65 episodes of vRTI were identified in 56 patients (14.7%). Rhinovirus accounted for the majority of infections (69.2%). The majority of episodes presented initially with upper respiratory tract infection (58.5%), with 28.9% of them progressing to lower respiratory tract infection. Eleven episodes (16.9%) were associated with ICU admission. There were no deaths directly due to vRTI. Previous autologous HSCT was associated with an increased risk of vRTI (odds ratio, 2.1; 95% confidence interval, 1.0 to 4.1). The risks of death (P = .47) or ICU admission (P = .65) were not significantly different by vRTI status. vRTI is common in the first 100 days after allo-HSCT and is associated with ICU admission. PMID- 29530767 TI - Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation. AB - Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disorders (EBV-PTLDs) are rare but potentially fatal complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by uncontrolled proliferation of EBV-infected lymphocytes. The most common risk factors include T cell depletion of graft, HLA mismatch, severe graft-versus-host disease (GVHD), and EBV seromismatch (recipient-negative/donor-positive), among others. EBV-PTLDs commonly manifest as fever and lymphadenopathy and may rapidly progress to multiorgan failure and even death. Histopathological evidence is indispensable for the diagnosis, and positive findings of EBV-DNA (EBV-DNAemia) and imaging are also very helpful. Active prophylaxis, such as optimization of the donor choice, conditioning regimen, and GVHD prevention, or passive prophylaxis, such as low dose of rituximab, unselected donor lymphocyte infusion (DLI), and EBV-specific cytotoxic T lymphocyte (EBV-CTLs) infusion, can decrease the incidence of EBV-DNAemia. Rituximab- based preemptive treatment can prevent EBV-DNAemia from developing into EBV-PTLDs, particularly benefiting recipients with higher loads of EBV-DNA, although the long-term outcome has not been significantly improved. To date, there is no consensus as to whether and when to initiate prophylactic or preemptive treatment. The current treatment strategies for probable and proven EBV-PTLDs include reduction of immunosuppression (RI), rituximab, adoptive cell therapy (DLI or EBV-CTLs), chemotherapy, radiotherapy, and surgery, among which rituximab plus RI is the mainstay. However, the mortality of EBV-PTLDs remains considerably high, and novel strategies merit exploration. PMID- 29530768 TI - Finite Element Analysis-Aided Design of Customized Nuss Bar in Pectus Excavatum Surgery. PMID- 29530769 TI - A Nomogram Predicting Recurrence and Guiding Adjuvant Radiation for Thymic Carcinoma After Resection. AB - BACKGROUND: Resection is an effective treatment for thymic carcinoma. We aimed to develop a nomogram for postoperative prediction of recurrence-free survival for patients with thymic carcinoma and guide adjuvant radiotherapy. METHODS: A total of 198 patients who underwent surgery were divided into training cohort (n = 152) and validation cohort (n = 46). Clinicopathologic features and independent factors for postoperative recurrence were analyzed. A predictive nomogram was developed based on the prognostic factors. Discrimination and predictive accuracy of the model were measured using the concordance index (C-index), calibration curves, and validation study. RESULTS: The overall 1-, 3-, and 5-year recurrence rate of 198 patients was 7.6%, 27.9%, and 39.9%, respectively. Independent predictors of recurrence-free survival on multivariate analysis were incorporated into the nomogram. Calibration curves for the probability of 1-, 3-, and 5-year recurrence-free survival fitted well. The C-index of the nomogram for predicting recurrence-free survival was 0.862 (95% confidence interval: 0.804 to 0.919). Internal validation supported the results optimally. Adjuvant radiotherapy was effective for patients with a total score greater than 208. CONCLUSIONS: Our nomogram for predicting recurrence-free survival had good performance. Adjuvant radiotherapy should be recommended for patients with a total score greater than 208. PMID- 29530771 TI - Novel Management of Atrial Septal Defect at Time of Lung Transplantation. AB - We present a case of a young female patient with end-stage lung failure because of pulmonary arterial hypertension who was failing maximal medical therapy and was listed for a single sequential lung transplantation. The challenge of the case was a concomitant presence of a large atrial septal defect. The novelty of our approach was a device closure of atrial septal defect before performing transplantation with the use of intraoperative venoarterial extracorporeal membrane oxygenation. PMID- 29530772 TI - Overcoming a Surgical Challenge: Inverted Aortic Prosthetic Valves in Small Mitral Annulus. PMID- 29530770 TI - Enhanced Recovery Decreases Pulmonary and Cardiac Complications After Thoracotomy for Lung Cancer. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) pathways aim to improve postoperative recovery through evidence-based practices, including early ambulation, multimodal opioid-sparing analgesia, and reduction of surgical stress. This study evaluated outcomes after implementation of ERAS in patients undergoing resection for pulmonary malignancy. METHODS: A retrospective review compared outcomes for patients undergoing pulmonary resection for primary lung cancer. Analysis was performed between three periods: pre-ERAS (January 1, 2006, to December 31, 2011), transitional period with elements of ERAS (January 1, 2012, to August 31, 2015), and full implementation of ERAS (September 1, 2015, to December 31, 2016). RESULTS: We analyzed 2,886 lung resections (pre-ERAS, n = 1615; transitional, n = 929; ERAS, n = 342). For all patients, length of stay decreased in the ERAS and transitional periods compared with pre-ERAS (4 [3] versus 4 [3] versus 5 [3] days, p < 0.001). Pulmonary complications were decreased with ERAS compared with transitional and pre-ERAS (19.9% versus 28.2% versus 28.7%, p = 0.004). Cardiac complications decreased with ERAS (12.3% versus 13.1% versus 18.1%, p = 0.001). There was less thoracic epidural use (2.9% versus 44.5% versus 75.5%, p < 0.001). There were no differences in hospital readmission (p = 0.772) or mortality rates (p = 0.417). After thoracotomy, ERAS was associated with decreased length of stay, fewer intensive care unit readmissions, and decreased frequency of pneumonia, atrial arrhythmias, and need for home oxygen (all p < 0.05). ERAS was independently associated with decreased pulmonary (p = 0.046) and cardiac (p = 0.001) complications on logistic regression after thoracotomy but not minimally invasive operations. CONCLUSIONS: ERAS was associated with improved postoperative outcomes, including decreased length of stay and pulmonary and cardiac morbidity after thoracotomy, but not after minimally invasive operations. ERAS safety was demonstrated by low rates of adverse events without effect on hospital readmission or perioperative deaths. PMID- 29530773 TI - Bronchoscopy Simulation Training as a Tool in Medical School Education. AB - BACKGROUND: Procedural simulation training is rare at the medical school level and little is known about its usefulness in improving anatomic understanding and procedural confidence in students. Our aim is to assess the impact of bronchoscopy simulation training on bronchial anatomy knowledge and technical skills in medical students. METHODS: Medical students were recruited by email, consented, and asked to fill out a survey regarding their baseline experience. Two thoracic surgeons measured their knowledge of bronchoscopy on a virtual reality bronchoscopy simulator using the Bronchoscopy Skills and Tasks Assessment Tool (BSTAT), a validated 65-point checklist (46 for anatomy, 19 for simulation). Students performed four self-directed training sessions of 15 minutes per week. A posttraining survey and BSTAT were completed afterward. Differences between pretraining and posttraining scores were analyzed with paired Student's t tests and random intercept linear regression models accounting for baseline BSTAT score, total training time, and training year. RESULTS: The study was completed by 47 medical students with a mean training time of 81.5 +/- 26.8 minutes. Mean total BSTAT score increased significantly from 12.3 +/- 5.9 to 48.0 +/- 12.9 (p < 0.0001); mean scores for bronchial anatomy increased from 0.1 +/- 0.9 to 31.1 +/- 12.3 (p < 0.0001); and bronchoscopy navigational skills increased from 12.1 +/- 5.7 to 17.4 +/- 2.5 (p < 0.0001). Total training time and frequency of training did not have a significant impact on level of improvement. CONCLUSIONS: Self driven bronchoscopy simulation training in medical students led to improvements in bronchial anatomy knowledge and bronchoscopy skills. Further investigation is under way to determine the impact of bronchoscopy simulation training on future specialty interest and long-term skills retention. PMID- 29530774 TI - Anomalous Left Coronary Artery From the Pulmonary Artery: Masquerading as Peripartum Cardiomyopathy. AB - Diagnosed with peripartum cardiomyopathy 8 years earlier, a 45-year-old woman had sudden cardiac death. After resuscitation, the patient was diagnosed with an anomalous origin of the left coronary artery from the pulmonary artery and underwent a successful coronary repair. The management of a patient with clinical features of cardiomyopathy is reviewed. PMID- 29530775 TI - Construction of an Apical Plug for Explantation of HeartWare HVAD Left Ventricular Assist Device. AB - Utilization of a left ventricular assist device as a bridge to myocardial recovery is an established therapy for acute systolic heart failure. However, device removal can present a technical challenge, with no clear consensus on preferred method. In this case report, we describe a complex patient who underwent successful explantation of a left ventricular assist device using an intraoperatively constructed apical plug. This method utilizes inexpensive and easily accessible materials, minimizes ventricular distortion during device removal, and preserves the ventricular sewing ring for future reimplantation. PMID- 29530776 TI - W. Gerald Rainer, MD, November 13, 1927 to November 14, 2017. AB - W. Gerald Rainer, the 25th president of The Society of Thoracic Surgeons and a founding member of The Society of Thoracic Surgeons, died suddenly on November 14, 2017, the day after celebrating his 90th birthday with his family. He will be remembered as a superb private practice cardiothoracic surgeon who also participated in research, had a strong commitment to the community and the University of Colorado, and a superb record of service to The Society of Thoracic Surgeons and other professional societies. PMID- 29530777 TI - Psoas Muscle Size Predicts Risk-Adjusted Outcomes After Surgical Aortic Valve Replacement. AB - BACKGROUND: Frailty is an important predictor of outcomes after cardiac surgery, but utility is limited by difficult assessment and quantification. We hypothesize that sarcopenia defined as psoas muscle cross-sectional area is a useful predictor of surgical aortic valve replacement outcomes in moderate to high-risk patients. METHODS: Moderate to high risk patients (predicted risk of mortality greater than 3%) who underwent surgical aortic valve replacement with or without coronary artery bypass were extracted from an institutional database (2009 to 2016). Psoas index was calculated as the cross-sectional area of the psoas muscle at the L4 vertebral level normalized to body surface area. Patients were stratified by sarcopenia status, defined as less than 25th sex-specific percentile. Multivariable regression analysis identified risk-adjusted associations with psoas index using The Society of Thoracic Surgeons predicted risk scores. RESULTS: Of the 240 patients included, the median predicted risk of mortality was 6%, median age 80 years, and 40% were female. Patients with (33.3%) and without (66.7%) sarcopenia had equivalent baseline risk (median predicted risk of mortality 5.7% versus 6.0%, p = 0.29). Patients with sarcopenia had higher 1-year mortality (31.9% versus 16.9% p = 0.03). Psoas index significantly predicted risk-adjusted 1-year mortality (odds ratio 0.84, p = 0.02) and long term mortality (hazard ratio 0.92, p = 0.04), as well as risk-adjusted major morbidity, prolonged ventilation, length of stay, discharge to a facility, and hospital cost. Finally, psoas index measurements were highly reproducible (Pearson correlation coefficient 0.944). CONCLUSIONS: Psoas index is an easily obtained and reproducible measure of frailty that predicts risk-adjusted resource utilization, morbidity, and long-term mortality. Psoas index may improve procedural selection and risk adjustment in high-risk patients with aortic valve disease. PMID- 29530778 TI - A Multidisciplinary Protocol-Driven Approach to Improve Extubation Times After Cardiac Surgery. AB - BACKGROUND: Prolonged intubation after cardiac surgery is associated with significant morbidity. A fast-track extubation protocol primarily driven by bedside providers was instituted for all postoperative cardiac surgery patients to facilitate safe and expeditious extubation. METHODS: A retrospective review of 1,581 cardiac surgery patients over an 8-year period was performed. Before 2011, nonprotocolized standard perioperative management was utilized (n = 807). From 2011 onward, a fast-track extubation (FTE) protocol directed by bedside providers was instituted (n = 774). Postoperatively, patients were placed on pressure regulated volume control and titrated down to minimal support to maintain peripheral capillary oxygen saturation greater than 94%. For patients deemed ready for weaning (no evidence of hypoxia, hemodynamic instability, and so forth), a 30-minute continuous positive airway pressure trial was performed. Patients meeting all neurologic, respiratory, and cardiovascular criteria were extubated. The impact of the FTE algorithm on timely extubation, clinical outcomes, and safety was assessed. RESULTS: Baseline preoperative and intraoperative characteristics were similar between pre-FTE and FTE groups. Before instituting the FTE protocol, the rate of early extubation (less than 6 hours) was 43.7%, and increased to 64.1% during the FTE era (p < 0.001). Median time to extubation was also found to be significantly decreased: 295 minutes (interquartile range: 288) versus 385 minutes (interquartile range: 362, p = 0.041). There was no statistically significant difference in reintubation rates or 30-day mortality. CONCLUSIONS: The institution of a bedside provider-directed FTE pathway reduced overall intubation times and increased the rate of early extubation, without an increase in reintubation or mortality. This program-wide multidisciplinary approach appears to promote safe and expeditious extubation of cardiac surgery patients. PMID- 29530779 TI - Granulomatosis With Polyangiitis Involving the Ascending Aorta. AB - A 58-year-old man visited the emergency department with vague anterior chest discomfort. From the computed tomographic findings, our initial suspicion was intramural hematoma in the ascending aorta. After a comprehensive discussion with relevant departments, emergent operation was planned. Intrapericardial space, however, was severely adhered, suggesting chronic inflammation. Biopsies were performed, and additional surgical procedures were discontinued. The patient was finally diagnosed as having granulomatosis with polyangiitis. Careful approach with high-degreed suspicion for granulomatosis with polyangiitis, although rare, is required when preoperative findings are similar to the present case. PMID- 29530780 TI - American Journal of Ophthalmology Contributions to Ophthalmic Genetics. AB - PURPOSE: To review the contributions to ophthalmic genetics through the American Journal of Ophthalmology (AJO). DESIGN: Perspective. METHODS: A literature search to retrieve original articles, letters, editorials, and published lectures from 1966 to 2017, providing a 50-year review. Titles were excluded that gave no reference to genetics or that presented findings related to a nongenetic ocular condition. RESULTS: From a search of the Scopus database, 719 articles were ascertained. Of these, 115 were excluded because the title did not reference a genetic condition or have a focus on genetic factors; 4 were excluded because they described animal phenotypes (1966-1967); and 4 were excluded owing to having received no citations up to and including 2015. The highest number of citations was 283 times for a single article on familial aggregation in age-related macular degeneration. The Web of Science database yielded 771 articles; of these, 118 were excluded owing to not reporting human genetic studies; 55 received no citations. The highest number of citations was 307 for a single article, a 1991 paper on Leber hereditary optic neuropathy. CONCLUSIONS: The Journal's contributions to our understanding of the heritability of human ocular traits have been broad and deep, with international reach. The development of new techniques fostered new concepts and new approaches to rapidly expand the number of known single gene disorders with a defined molecular genetic cause. Reports on Mendelian and complex traits in the AJO abound, along with 6 Edward Jackson Memorial Lectures on retinal dystrophies, Leber congenital amaurosis, age-related macular degeneration, and glaucoma. PMID- 29530781 TI - Reliability and Construct Validity of the NEI VFQ-25 in a Subset of Patients With Geographic Atrophy From the Phase 2 Mahalo Study. AB - PURPOSE: Geographic atrophy (GA) is an advanced form of age-related macular degeneration characterized by progressive, irreversible visual function loss. This analysis evaluates the psychometric properties of the 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite, near activity, and distance activity scores in patients with GA. DESIGN: Reliability and validity study. METHODS: Reliability and validity were tested with NEI VFQ-25 data collected from 100 subjects with GA from United States' sites of the phase 2 Mahalo study of lampalizumab (ClinicalTrials.gov identifier: NCT01229215). RESULTS: Strong internal consistency and reproducibility were demonstrated for the NEI VFQ-25 composite (Cronbach's alpha, 0.95; intraclass correlation coefficient [ICC], 0.86), near activity (Cronbach's alpha, 0.84; ICC, 0.80), and distance activity (Cronbach's alpha, 0.84; ICC, 0.84) scores. Convergent validity with the binocular measures, Minnesota Low-Vision Reading Test (MNRead) reading speed and Functional Reading Independence (FRI) index score, was demonstrated for baseline NEI VFQ-25 composite (Pearson correlation [r] = 0.61 and 0.69, respectively), near activities (r = 0.69 and 0.73), and distance activities (r = 0.57 and 0.64) scores. Known-group validity testing for baseline mean NEI VFQ-25 scores (composite, near activities, and distance activities) showed differences between patients with mean maximum MNRead reading speed >= 80 vs < 80 words per minute, and between mean FRI index score >= 2.5 vs < 2.5 (all P < .0001). CONCLUSIONS: Psychometric evidence supports the NEI VFQ-25 as a reliable and valid cross-sectional measure of the impact of GA on patient visual function and vision-related quality of life. PMID- 29530782 TI - Correlation of Immunocytochemistry of BRCA1-associated Protein-1 (BAP1) With Other Prognostic Markers in Uveal Melanoma. AB - PURPOSE: Prior studies have shown that nuclear reactivity for BRCA1-associated protein-1 (BAP1) yields prognostic information for paraffin-embedded uveal melanomas. Lacking are immunocytochemical studies of BAP1 on fine needle aspiration biopsies of uveal melanoma that correlate with prognosis or other markers of prognosis. Our purpose was to fill this gap. DESIGN: Experimental laboratory study. METHODS: Fine needle aspiration biopsies were performed prospectively on 113 patients with uveal melanomas, garnering limited subsets of cases for comparison. Agreement between immunocytochemistry for BAP1 nuclear staining vs chromosome 3 ploidy analysis and gene expression profiling was assessed by 2 * 2 contingency table analysis. RESULTS: The presence or absence of suppression of nuclear expression of BAP1 was strongly associated (73%, P = .000002) with monosomy and disomy chromosome 3, respectively. BAP1 nuclear expression was also correlated with gene expression profiling. Chromosome 3 ploidy analysis correlated with gene expression profiles. CONCLUSION: When adequate material is obtained, immunocytology using BAP1 is a potentially informative tool for prognostication of uveal melanoma. PMID- 29530783 TI - Protein kinase D1 conditional null mice show minimal bone loss following ovariectomy. AB - We previously found that 3- and 6-month-old male mice with conditional ablation of protein kinase D1 (PRKD1) in osteoprogenitor cells (expressing Osterix) exhibited reduced bone mass. Others have demonstrated similar effects in young female PRKD1-deficient mice. Here we examined the bone resorptive response of adult female floxed control and conditional knockout (cKO) mice undergoing sham surgery or ovariectomy (OVX). Femoral and tibial bone mineral density (BMD) values were significantly reduced upon OVX in control, but not cKO, females compared to the respective sham-operated mice. Micro-CT analysis showed that OVX significantly increased trabecular number and decreased trabecular spacing in cKO but not control mice. Finally, in control mice serum levels of a marker of bone resorption (pyridinoline crosslinks) and the osteoclast activator RANKL significantly increased upon OVX; however, no such OVX-induced increase was observed in cKO mice. Our results suggest the potential importance of PRKD1 in response to estrogen loss in bone. PMID- 29530784 TI - Testis Sparing Surgery for Benign Testicular Masses: Diagnostics and Therapeutic Approaches. AB - PURPOSE: Small benign testicular masses are often misinterpreted as germ cell tumors and immediate inguinal orchiectomy is performed. We analyzed the diagnostic and therapeutic workup of testicular masses to improve preoperative stratification algorithms. MATERIALS AND METHODS: We performed a retrospective, single center analysis of the records of 522 patients diagnosed with primary testicular masses of unknown malignant potential. RESULTS: A total of 28 patients (5%) showed a primary benign tumor after resection, including Leydig cell tumors in 9 (32%), epidermoid cysts in 9 (32%), adenomatoid tumors in 8 (29%) and Sertoli cell tumors in 2 (7%). The median volume of benign tumors was significantly less than that of malignant tumors (0.75 cm3, range 0.1 to 2.1 vs 15, range 4.5-39.9, p <=0.001). At a cutoff of 2.8 cm3 tumor volume most accurately differentiated between benign and malignant disease, and it was a predictor of malignancy with 83% sensitivity and 89% specificity (OR 1.389, 95% CI 1.035-1.864, p = 0.029). Symptom duration in patients with benign tumors was significantly longer (365 days, range 25.5 to 365 vs 20, range 7 to 42, p <=0.001). Also, tumor markers were unaltered in benign lesions. In patients with benign tumors significantly more fertility disorders or cryptorchidism were found (p <=0.001) as well as a tendency toward lower testosterone (3.9 MUg/l, range 0.9 to 4.9 vs 5.3, range 3.5 to 6.8, p = 0.084). Testis sparing surgery was performed in 22 of all patients (79%) with benign tumors. There was no case of relapse during followup. CONCLUSIONS: Nongerm cell tumors should be considered when small testicular masses have a volume of less than 2.8 cm3 and there are hormone disorders or normal tumor markers. Immediate orchiectomy should be avoided, favoring testis sparing surgery. PMID- 29530785 TI - Proteomic Signatures of Sperm Mitochondria in Varicocele: Clinical Use as Biomarkers of Varicocele Associated Infertility. AB - PURPOSE: Varicocele may disrupt testicular microcirculation and induce hypoxia ischemia related degenerative changes in testicular cells and spermatozoa. Superoxide production at low oxygen concentration exacerbates oxidative stress in men with varicocele. Therefore, the current study was designed to study the role of mitochondrial redox regulation and its possible involvement in sperm dysfunction in varicocele associated infertility. MATERIALS AND METHODS: We identified differentially expressed mitochondrial proteins in 50 infertile men with varicocele and in 10 fertile controls by secondary liquid chromatography tandem mass spectroscopy data driven in silico analysis. Identified proteins were validated by Western blot and immunofluorescence. Seminal oxidation-reduction potential was measured. RESULTS: We identified 22 differentially expressed proteins related to mitochondrial structure (LETM1, EFHC, MIC60, PGAM5, ISOC2 and import TOM22) and function (NDFSU1, UQCRC2 and COX5B, and the core enzymes of carbohydrate and lipid metabolism). Cluster analysis and 3-dimensional principal component analysis revealed a significant difference between the groups. All proteins studied were under expressed in infertile men with varicocele. Liquid chromatography-tandem mass spectroscopy data were corroborated by Western blot and immunofluorescence. Impaired mitochondrial function was associated with decreased expression of the proteins (ATPase1A4, HSPA2, SPA17 and APOA1) responsible for proper sperm function, concomitant with elevated seminal oxidation-reduction potential in the semen of infertile patients with varicocele. CONCLUSIONS: Impaired mitochondrial structure and function in varicocele may lead to oxidative stress, reduced ATP synthesis and sperm dysfunction. Mitochondrial differentially expressed proteins should be explored for the development of biomarkers as a predictor of infertility in patients with varicocele. Antioxidant therapy targeting sperm mitochondria may help improve the fertility status of these patients. PMID- 29530787 TI - Altered ureteral contractility with ageing: Role of the rho-kinase pathway. AB - This study investigated the role of calcium sensitisation in the regulation of ureteral contractility with ageing. Isolated ureteral strips from young (6-month old) and older (3-year old) pigs were mounted in Krebs bicarbonate solution and contractility induced by the alpha1-adrenoceptor agonist phenylephrine (30 and 300 MUM) and 5-HT (10 and 100 MUM), recorded in the absence and presence of the rho-kinase inhibitors Y-27632 (10 MUM) and fasudil (30 MUM). Ureteral strips developed bursts of contractile activity which was measured as area under the curve (AUC) and frequency. Maximum contraction to phenylephrine was significantly enhanced in tissues from older animals compared to younger animals (p < 0.001) while maximum contraction to 5-HT was greater in tissues from younger animals (p < 0.001). Both inhibitors significantly depressed AUC and frequency responses to both agonists in ureters from both age groups (p < 0.05). Inhibition by Y-27632 of phenylephrine (300 MUM)- and 5-HT(100 MUM)-induced contractions was greater in tissues from older animals than young (p < 0.05). Rho-kinase activity was also assayed in ureteral tissues, and basal activity was similar in ureters from both age groups. Neither phenylephrine nor 5-HT increased rho-kinase activity over basal levels. These data demonstrate the significant role rho-kinase plays in ureteral contractility and possible alterations with age. PMID- 29530786 TI - The Bladder Utility Symptom Scale: A Novel Patient Reported Outcome Instrument for Bladder Cancer. AB - PURPOSE: Health related quality of life is important in bladder cancer care and clinical decision making because patients must choose between diverse treatment modalities with unique morbidities. A patient reported outcome measure of overall health related quality of life for bladder cancer regardless of disease severity and treatment could benefit clinical care and research. MATERIALS AND METHODS: Prospective questionnaire development was completed in 3 parts. In study 1 the BUSS (Bladder Utility Symptom Scale) questions were created by experts using a conceptual framework of bladder cancer health related quality of life generated through patient focus groups. In study 2 patients with bladder cancer, including those treated with surgery, radiation and chemotherapy, completed the BUSS and 5 health related quality of life instruments at baseline and 4 weeks to assess validity and test-retest reliability. External validity was then explored in study 3 by administering the BUSS to 578 patients online and at clinics. Construct validity was assessed by whole and subscale Spearman rank correlations, and by comparisons of BUSS scores across known groups. RESULTS: The BUSS had high whole scale correlation with the FACT-Bl (Functional Assessment of Cancer Therapy Bladder) (rs = 0.82, p <0.0001) and substantial to high subscale correlations with the EQ-5DTM-3L (EuroQol 5 Dimensions Questionnaire-3 Levels) (eg emotional well-being rs = 0.69, p <0.0001). BUSS scores were lower in patients with comorbidity and advanced disease. Cognitive debriefing and the 94% completion rate suggested good comprehensibility. There was excellent test-retest reliability (ICC = 0.79). Limitations included an extended time from diagnosis in many patients. CONCLUSIONS: The BUSS is a reliable and valid patient reported outcome instrument for health related quality of life in all patients with bladder cancer regardless of the treatment received or the stage of disease. PMID- 29530788 TI - NDRG2 suppresses proliferation, migration, invasion and epithelial-mesenchymal transition of esophageal cancer cells through regulating the AKT/XIAP signaling pathway. AB - N-Myc downstream-regulated gene 2 (NDRG2) has recently revealed as a candidate tumor suppressor gene. To inhibit tumor growth and decrease morbidity of esophageal cancer (EC), this study aims to test the hypothesis that the upregulation of NDRG2 may suppress proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of EC cells by regulating the AKT/XIAP signaling pathway. Immunohistochemistry was conducted for the identification of NDRG2, protein kinase B (p-AKT), X-linked inhibitor of apoptosis protein (XIAP) in EC tissues. To identify the regulatory mechanism of NDRG2 on the AKT/XIAP signaling pathway and EMT in EC, over-expressed lentiviral vector and shRNA were applied for up-regulating and interfering NDRG2 expression, and a series of determinations on the biological behavior of EC cells were performed to validate this regulation action. The results of immunohistochemistry showed NDRG2 was lowly expressed in EC tissues while p-AKT and XIAP are highly expressed. Over expression of NDRG2 suppresses the proteins related to AKT/XIAP signaling pathway and EMT. Besides, a series of determinations shows the proliferation, migration and invasion of TE-13 cells were suppressed by over-expressed NDRG2, while the cell cycle progression was blocked and cell apoptosis was promoted. And in vivo experiment also demonstrated NDRG2 could inhibit tumor growth. Our findings demonstrate over-expression of NDRG2 works as tumor suppressive role in EC through its effects on inhibition of cell migration, invasion, and EMT by inhibiting the AKT/XIAP signaling pathway. PMID- 29530789 TI - Catalase and its mysteries. AB - Catalase is one of the firsts in every realm of biological sciences. At the same time it also has a number of unusual features. It has one of the highest turnover numbers of all enzymes. It is essential for neutralizing the noxious hydrogen peroxide both in the nature and the various industries such as dairy, textile and pharmaceutics. It also has the merit of being one of the first protein crystals to be isolated. Ironically its three-dimensional structure was discerned some forty years later. However through the times this senile enzyme has continued to intrigue the scientists by surprising facts and phenomena, such as peculiar interweaving of subunits and remarkable thermal stability. It is also known for suicide inactivation by its own substrate. Catalase is known to be implicated in various medical scenarios and its levels have served as a marker in that capacity. It has even been incorporated into several pharmaceuticals. This review strives to clarify these perspectives. It also draws attention to the biophysical contributions offered by thermodynamics and kinetics in these discoveries. The ultimate aim of this review, however, is to state that the venerable catalase will continue to bewilder us with its mysteries well into the twenty-first century. PMID- 29530790 TI - Models to assess the effects of non-identical sex ratio augmentations of Wolbachia-carrying mosquitoes on the control of dengue disease. AB - The introduction of endosymbiont Wolbachia into laboratory-reared mosquito populations, which are then released to mix with natural populations to prevent the mosquito vectors from reproducing and thus break the transmission cycle of dengue disease, is an innovative new technology. Field trials of Wolbachia carrying mosquitoes have now been implemented in many countries where there have been the outbreaks of dengue disease. A mathematical model is proposed to investigate the effects of non-identical sex ratio releases of Wolbachia-carrying mosquitoes on the control of dengue transmission. Firstly, we analyzed the existence and stability of equilibria for the system and proved the existence of forward and backward bifurcations. Secondly, bifurcation diagrams, the basins of attraction of the equilibria and the effects of mosquito augmentation for the system with imperfect and perfect transmission rates were obtained. Thirdly, three possible results for mosquito augmentation were summarized for different parameter regions. Further we explored an uncertainty and sensitivity analysis of solutions to estimate the effects of different parameter values on the success or failure of population replacement. Based on the above analysis, we considered a series of relevant issues such as (a) whether or not mosquito augmentation can ensure the success of population replacement? (b) If not, what are the parameter regions for the success or possible success of population replacement? (c) How does the initial density of natural mosquitoes and the quantity of mosquito augmentations affect the success of population replacement? (d) Whether all population replacements are effective for reducing the spread of dengue virus in the end? The results of this study will be helpful for public health authorities in designing proper strategies of mosquito augmentations for the control of dengue disease. PMID- 29530791 TI - Overexpression of miR-219 promotes differentiation of human induced pluripotent stem cells into pre-oligodendrocyte. AB - Oligodendrocytes play critical roles in the central nervous system (CNS) thorough producing myelin sheaths around axons. There are a variety of approaches to produce oligodendrocytes in vitro and in vivo which are a subject of interest in many studies. A new approach to induce this differentiation is using microRNA 219 (miR-219). However, this new approach suffers from a lack of studies regarding the effect of miR-219 on differentiating human induced pluripotent stem cells (hiPSCs) to oligodendrocytes. This study aimed to assess the impact of miR-219 overexpression on hiPSCs. Initially, hiPSCs were induced with basic fibroblast growth factor (bFGF), epidermalgrowth factor (EGF) and platelet-derived growth factor (PDGF)-AA, then, miR-219- green fluorescent protein (GFP)-expressing lentiviruses were utilized for cell infection. Microscopic observation revealed significant morphological changes and data obtained from quantitative reverse transcription PCR and immunofluorescence analysis of differentiated cells showed that the expression of various oligodendrocyte stage-specific markers such as Nestin, Olig2, Sox10, PDGFRalpha, A2B5, O4, and MBP increased. In addition, higher expressions of pre-oligodendrocyte markers were detected in the cells transduced with miR-219 lentivirus in comparison with the cells treated with triiodothyronine (T3). These results suggest that overexpression of miR-219 promotes differentiation of hiPSCs to pre-oligodendrocyte cells, providing a potential source for cell therapy by replacing and restoring the lost cell function in neurodegenerative and demyelinating diseases. PMID- 29530792 TI - Implication of regional brain serotonergic neurons in dorsal and median Raphe nuclei in adaptation to water lacking in Gerbillus tarabuli. AB - The objective of this work was to investigate the implication of serotonin (5-HT) produced in the dorsal and medial raphe nuclei (DRN and MRN) in water homeostasis in desert animal Gerbillus tarabuli. For that, we measured the density of 5-HT immunolabeled neurons in hydrated and dehydrated animals (over 1 and six months). In this work, 5-HT positive neurons showed some change in shape and colour intensity in dehydrated gerbils comparing with hydrated gerbils. Furthermore a differential increase of 5-HT neurons density was observed in DRN subregions and in MRN following 1 and 6 months of dehydration. This study suggested that neurons in DRN and MRN contain 5-HT in various amounts, thus allowing an adapted response to hydration status. These neurons could mediate one of the adaptation mechanisms of this animal to its desert biotope. PMID- 29530793 TI - Nitrite exerts antioxidant effects, inhibits the mTOR pathway and reverses hypertension-induced cardiac hypertrophy. AB - Cardiac hypertrophy is a common consequence of chronic hypertension and leads to heart failure and premature death. The anion nitrite is now considered as a bioactive molecule able to exert beneficial cardiovascular effects. Previous results showed that nitrite attenuates hypertension-induced increases in reactive oxygen species (ROS) production in the vasculature. Whether antioxidant effects induced by nitrite block critical signaling pathways involved in cardiac hypertrophy induced by hypertension has not been determined yet. The Akt/mTOR signaling pathway is responsible to activate protein synthesis during cardiac remodeling and is activated by increased ROS production, which is commonly found in hypertension. Here, we investigated the effects of nitrite treatment on cardiac remodeling and activation of this hypertrophic signaling pathway in 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral nitrite at 1 or 15 mg/kg for four weeks. Nitrite treatment (15 mg/kg) reduced systolic blood pressure and decreased ROS production in the heart tissue from hypertensive rats. This nitrite dose also blunted hypertension-induced activation of mTOR pathway and cardiac hypertrophy. While the lower nitrite dose (1 mg/kg) did not affect blood pressure, it exerted antioxidant effects and tended to attenuate mTOR pathway activation and cardiac hypertrophy induced by hypertension. Our findings provide strong evidence that nitrite treatment decreases cardiac remodeling induced by hypertension as a result of its antioxidant effects and downregulation of mTOR signaling pathway. This study may help to establish nitrite as an effective therapy in hypertension-induced cardiac hypertrophic remodeling. PMID- 29530794 TI - Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function. AB - Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting toxicity associated with cancer chemotherapy. The efficacy of antioxidant administration in OIPN is debatable, as the promising preliminary results obtained with a number of antioxidants have not been confirmed in larger clinical trials. Besides its antioxidant activity, the transcription factor, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2) plays a crucial role in the maintenance of mitochondrial homeostasis, and mitochondrial dysfunction is a key contributor to OIPN. Here, we have investigated the protective properties of Nrf2 in OIPN. Nrf2-/- mice displayed severe mechanical allodynia and cold sensitivity and thus experienced increased peripheral nervous system injury compared to Nrf2+/+ mice. Furthermore, Nrf2 knockout aggravated oxaliplatin induced reactive oxygen species production, decreased the mitochondrial membrane potential, led to abnormal intracellular calcium levels, and induced cytochrome c related apoptosis and overexpression of the TRP protein family. Sulforaphane induced activation of the Nrf2 signaling pathway alleviated morphological alterations, mitochondrial dysfunction in dorsal root ganglion neurons, and nociceptive sensations in mice. Our findings reveal that Nrf2 may play a critical role in ameliorating OIPN, through protection of mitochondrial function by alleviating oxidative stress and inhibiting TRP protein family expression. This suggests that pharmacological or therapeutic activation of Nrf2 may be used to prevent or slow down the progression of OIPN. PMID- 29530796 TI - Testosterone replacement therapy: For whom, when and how? AB - The finding of low circulating testosterone level in men is relatively frequent. The symptoms of hypogonadism are very frequent in the aging men. However, the diagnosis of hypogonadism is often neglected and the opportunity to replace low testosterone in older men is highly debated. The aim of this narrative review is to summarize the steps necessary to formulate a proper diagnosis and to guide toward an individualized treatment. While universally recognized the need to treat the young adults with known causes of pituitary or testicular failure, there are controversies on the cost-benefit of treating testosterone deficiency in older men. Discrepancies among the several available guidelines do not help to clarify the scenario, however, the recent larger clinical trials have shed some light on the fact that testosterone treatment carries some benefit, that is not free from risks. We provide an updated review of the diagnostic hallmarks, the several treatment modalities, with their advantages and disadvantages, and how to individualize and monitor treatment in order to maximize the benefits and minimize the risks. The treatment of male hypogonadism can no longer be downgraded and must become part of the cultural baggage of the endocrinologist. PMID- 29530795 TI - Amphipathic helical peptides hamper protein-protein interactions of the intrinsically disordered chromatin nuclear protein 1 (NUPR1). AB - BACKGROUND: NUPR1 is a multifunctional intrinsically disordered protein (IDP) involved, among other functions, in chromatin remodelling, and development of pancreatic ductal adenocarcinoma (PDAC). It interacts with several biomolecules through hydrophobic patches around residues Ala33 and Thr68. The drug trifluoperazine (TFP), which hampers PDAC development in xenografted mice, also binds to those regions. Because of the large size of the hot-spot interface of NUPR1, small molecules could not be adequate to modulate its functions. METHODS: We explored how amphipathic helical-designed peptides were capable of interacting with wild-type NUPR1 and the Thr68Gln mutant, inhibiting the interaction with NUPR1 protein partners. We used in vitro biophysical techniques (fluorescence, circular dichroism (CD), nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC)), in silico studies (docking and molecular dynamics (MD)), and in cellulo protein ligation assays (PLAs) to study the interaction. RESULTS: Peptide dissociation constants towards wild-type NUPR1 were ~ 3 MUM, whereas no interaction was observed with the Thr68Gln mutant. Peptides interacted with wild-type NUPR1 residues around Ala33 and residues at the C terminus, as shown by NMR. The computational results clarified the main determinants of the interactions, providing a mechanism for the ligand-capture that explains why peptide binding was not observed for Thr68Gln mutant. Finally, the in cellulo assays indicated that two out of four peptides inhibited the interaction of NUPR1 with the C-terminal region of the Polycomb RING protein 1 (C-RING1B). CONCLUSIONS: Designed peptides can be used as lead compounds to inhibit NUPR1 interactions. GENERAL SIGNIFICANCE: Peptides may be exploited as drugs to target IDPs. PMID- 29530797 TI - Metformin combined with dipeptidyl peptidase-4 inhibitors or metformin combined with sulfonylureas in patients with type 2 diabetes: A real world analysis of the South Korean national cohort. AB - AIMS: We explored the risks associated with metformin plus sulfonylurea (MET + SU) or MET plus a dipeptidyl peptidase-4 inhibitor (MET + DPP4i) for hypoglycemia, cardiovascular disease (CVD) events and all-cause mortality in type 2 diabetes (T2D) patients with comorbidities. METHODS: This retrospective cohort study is based on the South Korean National Health Insurance Service-National Sample Cohort, enrolling T2D patients with one or more diabetes-related comorbidities who switched from monotherapy to MET + SU or MET + DPP4i between July 1, 2008 and December 31, 2013. The risk of hypoglycemia, CVD events and all cause mortality was examined using Cox's proportional hazard modeling and propensity score matching. RESULTS: Overall, 5693 patients with a mean of 2.6 comorbidities in addition to diabetes were included. Compared with MET + SU, MET + DPP4i treatment was associated with a lower risk of hypoglycemia, CVD events and all-cause mortality; adjusted HRs (95% CI), 0.39 (0.18-0.83), 0.72 (0.54 0.97), and 0.64 (0.39-1.05), respectively. Propensity score matching showed comparable results. In further subgroup analyses according to comorbidity type and number, MET + DPP4i was associated with less CVD events and all-cause mortality compared to MET + SU. This increased with more complex comorbid status. CONCLUSIONS: In T2D patients with comorbidities, MET + DPP4i treatment is associated with lower risks of CVD events and all-cause mortality compared with MET + SU, independent of type or number of comorbidities. A more complex comorbid status further increases this effect. PMID- 29530799 TI - Task-induced deactivation in diverse brain systems correlates with interindividual differences in distinct autonomic indices. AB - Neuroimaging research has shown that different cognitive tasks induce relatively specific activation patterns, as well as less task-specific deactivation patterns. Here we examined whether individual differences in Autonomic Nervous System (ANS) activity during task performance correlate with the magnitude of task-induced deactivation. In an fMRI study, participants performed a continuous mental arithmetic task in a task/rest block design, while undergoing combined fMRI and heart/respiration rate acquisitions using photoplethysmograph and respiration belt. As expected, task performance increased heart-rate and reduced the RMSSD, a cardiac index related to vagal tone. Across participants, higher heart rate during task was linked to increased activation in fronto-parietal regions, as well as to stronger deactivation in ventromedial prefrontal regions. Respiration frequency during task was associated with similar patterns, but in different regions than those identified for heart-rate. Finally, in a large set of regions, almost exclusively limited to the Default Mode Network, lower RMSSD was associated with greater deactivation, and furthermore, the vast majority of these regions were task-deactivated at the group level. Together, our findings show that inter-individual differences in ANS activity are strongly linked to task-induced deactivation. Importantly, our findings suggest that deactivation is a multifaceted construct potentially linked to ANS control, because distinct ANS measures correlate with deactivation in different regions. We discuss the implications for current theories of cortical control of the ANS and for accounts of deactivation, with particular reference to studies documenting a "failure to deactivate" in multiple clinical states. PMID- 29530798 TI - Depletion of dendritic cells in perivascular adipose tissue improves arterial relaxation responses in type 2 diabetic mice. AB - BACKGROUND: Accumulation of multiple subtypes of immune cells in perivascular adipose tissue (PVAT) has been proposed to cause vascular inflammation and dysfunction in type 2 diabetes (T2DM). This study was designed to investigate specific roles for dendritic cells in PVAT in the development of vascular inflammation and impaired PVAT-mediated vasorelaxation in T2DM. METHODS AND RESULTS: Studies were performed using db/db mice (model of T2DM) and their Db heterozygote (DbHET), lean and normoglycemic controls. Dendritic cell depletion was performed by cross-breeding DbHet with Flt3l-/- (null for ligand for FMS kinase tyrosine kinase) mice. Using PCR, it was found that the majority of dendritic cells (CD11c+) were located in PVAT rather than the vascular wall. Flow cytometry similarly showed greater dendritic cell accumulation in adipose tissue from db/db mice than DbHET controls. Adipose tissue from db/db mice displayed increased mRNA levels of proinflammatory cytokines TNF-alpha and IL-6 and decreased mRNA levels of the anti-inflammatory mediator adiponectin, compared to DbHET mice. Depletion of dendritic cells in dbFlt3l-/dbFlt3l- (confirmed by flow cytometry) reduced TNF-alpha and IL-6 mRNA levels in diabetic adipose tissue without influencing adiponection expression. Moreover, in mesenteric arteries, dendritic cell depletion improved the ability of PVAT to augment acetylcholine induced vasorelaxation and anti-contractile activity. CONCLUSIONS: In a murine model of T2DM, dendritic cells accumulated predominantly in PVAT, as opposed to the vessel wall, per se. Accumulation of dendritic cells in PVAT was associated with overproduction of pro-inflammatory cytokines, which contributed to an impaired ability of PVAT to augment vasorelaxation and exert anti-contractile activity in T2DM. PMID- 29530800 TI - Neural basis of functional fixedness during creative idea generation: An EEG study. AB - Decades of problem solving and creativity research have converged to show that the ability to generate new and useful ideas can be blocked or impeded by intuitive biases leading to mental fixations. The present study aimed at investigating the neural bases of the processes involved in overcoming fixation effects during creative idea generation. Using the AU task adapted for EEG recording, we examined whether participant's ability to provide original ideas was related to alpha power changes in both the frontal and temporo-parietal regions. Critically, for half of the presented objects, the classical use of the object was primed orally, and a picture of the classical use was presented visually to increase functional fixedness (Fixation Priming condition). For the other half, only the name of the object and a picture of the object was provided to the participants (control condition). As expected, priming the classical use of an object before the generation of creative alternative uses of the object impeded participants' performances in terms of remoteness. In the control condition, while the frontal alpha synchronization was maintained across all successive time windows in participants with high remoteness scores, the frontal alpha synchronization decreased in participants with low remoteness scores. In the Fixation Priming condition, in which functional fixedness was maximal, both participants with high and low remoteness scores maintained frontal alpha synchronization throughout the period preceding their answer. Whereas participants with high remoteness scores maintained alpha synchronization in the temporo-parietal regions throughout the creative idea generation period, participants with low remoteness scores displayed alpha desynchronization in the same regions during this period. We speculate that individuals with high remoteness scores might generate more creative ideas than individuals with low remoteness scores because they rely more on internal semantic association and selection processes. PMID- 29530801 TI - The role of the human cerebellum in linguistic prediction, word generation and verbal working memory: evidence from brain imaging, non-invasive cerebellar stimulation and lesion studies. AB - Lesion studies emphasize the role of the human cerebellum in a variety of cognitive processes. To date, most evidence comes from studies investigating language-related functions, such as verbal short-term/working memory, word generation, or linguistic/semantic predictions. This review summarizes brain imaging, non-invasive cerebellar stimulation and lesion studies in this field. Converging evidence suggests a cerebellar role in error processing and memory encoding although findings are partly contradictory. Future research should focus on common principles of cerebellar processing across different forms of cognitive performance to assess basic principles of cerebellar function. PMID- 29530802 TI - Pitfalls in molecular diagnosis of Friedreich ataxia. AB - Freidreich ataxia (FRDA) is the most common hereditary ataxia, nearly 98% of patients harbouring homozygous GAA expansions in intron 1 of the FXN gene (NM_000144.4). The remaining patients are compound heterozygous for an expansion and a point mutation or an exonic deletion. Molecular screening for FXN expansion is therefore focused on (GAA)n expansion analysis, commonly performed by triplet repeat primed PCR (PT-PCR). We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4-5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients. PMID- 29530803 TI - Development of an automated phenotyping algorithm for hepatorenal syndrome. AB - OBJECTIVE: Hepatorenal Syndrome (HRS) is a devastating form of acute kidney injury (AKI) in advanced liver disease patients with high morbidity and mortality, but phenotyping algorithms have not yet been developed using large electronic health record (EHR) databases. We evaluated and compared multiple phenotyping methods to achieve an accurate algorithm for HRS identification. MATERIALS AND METHODS: A national retrospective cohort of patients with cirrhosis and AKI admitted to 124 Veterans Affairs hospitals was assembled from electronic health record data collected from 2005 to 2013. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Five hundred and four hospitalizations were selected for manual chart review and served as the gold standard. Electronic Health Record based predictors were identified using structured and free text clinical data, subjected through NLP from the clinical Text Analysis Knowledge Extraction System. We explored several dimension reduction techniques for the NLP data, including newer high-throughput phenotyping and word embedding methods, and ascertained their effectiveness in identifying the phenotype without structured predictor variables. With the combined structured and NLP variables, we analyzed five phenotyping algorithms: penalized logistic regression, naive Bayes, support vector machines, random forest, and gradient boosting. Calibration and discrimination metrics were calculated using 100 bootstrap iterations. In the final model, we report odds ratios and 95% confidence intervals. RESULTS: The area under the receiver operating characteristic curve (AUC) for the different models ranged from 0.73 to 0.93; with penalized logistic regression having the best discriminatory performance. Calibration for logistic regression was modest, but gradient boosting and support vector machines were superior. NLP identified 6985 variables; a priori variable selection performed similarly to dimensionality reduction using high-throughput phenotyping and semantic similarity informed clustering (AUC of 0.81 - 0.82). CONCLUSION: This study demonstrated improved phenotyping of a challenging AKI etiology, HRS, over ICD-9 coding. We also compared performance among multiple approaches to EHR-derived phenotyping, and found similar results between methods. Lastly, we showed that automated NLP dimension reduction is viable for acute illness. PMID- 29530804 TI - Influence of diet and dietary nanoparticles on gut dysbiosis. AB - Human gut comprises of a huge mixture of microorganisms as they had co-existed for millions of years. The change in co-existence of microbial genera leads to dysbiosis, which creates several disorders in humans. Diet and diet associated agents can have a considerable influence on host health by regulating the gut microbiome, which can thereby maintain the homeostasis of the gut. Analysis of the gut microbiome and the agents that can have an influence on the gut need a profound understanding, which is the need of the hour. The current review therefore focuses on the influence of diet and dietary nanoparticles on the gut microbiota and their positive or adverse effect. PMID- 29530805 TI - Antibacterial mechanism of artemisinin / beta-cyclodextrins against methicillin resistant Staphylococcus aureus (MRSA). AB - A new inhibitor to overcome the multi-drug resistance of MRSA was developed in this study. Artemisinin (ART) was encapsulated in beta-cyclodextrin (beta-CD) in order to enhance the solubility of ART. The molecular encapsulation of ART was confirmed by using Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-Ray Diffraction (XRD), and nuclear magnetic resonance (1H NMR) methods. The phase solubility study showed the relationship between ART solubility and beta-CD concentration. The antibacterial activity of ART/beta-CDs inclusion complexes (ART/beta-CDs-IC) (20 mg/mL) against MRSA was distinguished, with the inhibition rate of 99.94% after 4 days. The antibacterial mechanism research indicated the membrane permeability of MRSA can be increased by the complexes. Besides, the respiratory metabolism of MRSA was inhibited via Embden Meyerhof-Parnas (EMP) pathway. The conclusion was further confirmed by measuring the contents of three enzymes in the irreversible reaction in EMP pathway. The obtained results enable the potential use of ART/beta-CDs-IC in the field of antimicrobial. PMID- 29530806 TI - The association between gut microbiome, sex, age and body condition scores of horses in Maiduguri and its environs. AB - The equine gut harbours complex microbial populations which influence physiology, metabolism, nutrition and immune functions, while disruption to the gut microbiota has been linked with conditions such as lameness, diabetes and obesity. Therefore, the present study was conducted to determine the association between microbial dysbiosis, sex, age and body condition scores (BCS) of horses (Equus equus caballus) in Maiduguri and its environs. Forty horses were assessed by convenient sampling, while faecal samples were collected and analyzed to determine the microbiomes in the various age groups with variable BSC in stallions and mares. The present study revealed that there was strong and not significant association between the microbial populations in the gut of horses and the various age groups (Chi-Squared test = 11.809; df = 18; P = 0.8570). There were significant (p < 0.0001) differences in the microbiome population in the guts of the horses. There were significant (p < 0.05) differences in the microbiomes in the various body scores. There were significant (P < 0.047) differences in the microbiomes of the mares and stallions. E. coli had the highest burden of microbial populations with 30.38*103 +/- 1.04*103 in the guts of horses in the study area, while statistically there were no differences in the populations of Corynebacterium, Klebsiella, Salmonella, Staphylococcus and Streptococcus in the gut of horses in the study area relative to E. coli. This study provides information on the nature of bacterial population present in horses in Maiduguri and its Environs. Therefore, further high-throughput characterization of the faecal bacteria microbiome of horses is essential to enable comparison to disease state and thus develop diagnostic tests, prophylactic measures and appropriate treatments. PMID- 29530807 TI - WITHDRAWN: Minocycline an antimicrobial agent attenuates the mitochondrial dependent cell death and stabilizes the expression of HIF-1alpha in spinal cord injury. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29530808 TI - Biogenic synthesis of copper nanoparticles by natural polysaccharides and Pleurotus ostreatus fermented fenugreek using gamma rays with antioxidant and antimicrobial potential towards some wound pathogens. AB - Mono-dispersed copper nanoparticles (CuNPs) were constructed using cheap polysaccharides (citrus pectin, chitosan, and sodium alginate), and by appropriating aqueous fermented fenugreek powder (FFP) under the action of Pleurotus ostreatus (as reducing and preserving means), through the influence of gamma irradiation. The synthesized CuNPs are described by UV-Vis. spectroscopy TEM, DLS, XRD, and FT-IR. XRD study of the CuNPs confirmed the generation of metallic CuNPs. The nucleation and the production mechanism of CuNPs are moreover explained. TEM unveiled that, the ordinary diameter of CuNPs incorporated by various polysaccharides, and FFP taken in the range of 31.0 and 36.0 nm respectively. CuNPs size is influenced by many parameters such as the variety of stabilizer, pH within the organization and applied gamma dose. Evaluation of the antioxidant and antimicrobial activities of CuNPs was performed against some selected wound pathogens. The results showed that, CuNPs were a strong antimicrobial agents against microbes caused burn skin infection such as Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans (16.0, 15.0, and 15.0 mm ZOI, respectively). Additionally, CuNPs have a strong antioxidant with 70% scavenging activity against DPPH. So, due to unique characteristics of CuNPs (cost-effective with continued-term stabilization and effective features), they can recover reasonable potential in biomedical, industrial, agricultural, cosmetics, dermal products and pharmaceutical purposes. PMID- 29530809 TI - Expression of Salmonella typhimurium and Escherichia coli flagellin protein and its functional characterization as an adjuvant. AB - BACKGROUND: Flagellin is the major structural protein monomer of bacterial flagella. Flagellin through binding to its receptor and activation of antigen presenting cells stimulates the innate and adaptive immune responses. Flagellin is used as an effective systemic or mucosal adjuvant to stimulate the immune system. Recently, the therapeutic and protective role of flagellin in some infectious diseases and cancers has been investigated. In this study, we cloned the fliC genes from Salmonella typhimurium and Escherichia coli into pET-28a vector and investigated their expression in the prokaryotic system. METHODS: The fliC genes of S. typhimurium and E. coli were amplified by PCR with a specific oligonucleotide primer set. thse were cloned into the pET-28a vector and the recombinant pET-28a-fliC plasmids were successfully transformed into the E. coli strain BL-21(DE3). The expression of flagellin proteins in the prokaryotic cells were evaluated. Finally, Transcription of TNF-alpha mRNA was confirmed using Real time PCR. RESULTS: The expression of proteins in the prokaryotic cells were approved by SDS-PAGE and western blotting method. Further, the functional characterization of flagellin proteins were evaluated using their ability to induce increased m-RNA expression of pro-inflammatory cytokine. CONCLUSIONS: The flagellin proteins were expressed in the prokaryotic system. These proteins can be used to link target antigens as an effective adjuvant for future DNA vaccine studies. Purified recombinant proteins in this study can also be used for therapeutic and prophylactic purposes. PMID- 29530810 TI - Vascular-metabolic and GABAergic Inhibitory Correlates of Neural Variability Modulation. A Combined fMRI and PET Study. AB - Neural activity varies continually from moment to moment. Such temporal variability (TV) has been highlighted as a functionally specific brain property playing a fundamental role in cognition. We sought to investigate the mechanisms involved in TV changes between two basic behavioral states, namely having the eyes open (EO) or eyes closed (EC) in vivo in humans. To these ends we acquired BOLD fMRI, ASL, and [18F]-fluoro-deoxyglucose PET in a group of healthy participants (n = 15), along with BOLD fMRI and [18F]-flumazenil PET in a separate group (n = 19). Focusing on an EO- vs EC-sensitive region in the occipital cortex (identified in an independent sample), we show that TV is constrained in the EO condition compared to EC. This reduction is correlated with an increase in energy consumption and with regional GABAA receptor density. This suggests that the modulation of TV by behavioral state involves an increase in overall neural activity that is related to an increased effect from GABAergic inhibition in addition to any excitatory changes. These findings contribute to our understanding of the mechanisms underlying activity variability in the human brain and its control. PMID- 29530811 TI - Iron-chelating agents attenuate NMDA-Induced neuronal injury via reduction of oxidative stress in the rat retina. AB - Excitoneurotoxicity is regarded as one of the mechanisms of the death of retinal ganglion cells induced by retinal central artery occlusion and glaucoma. Oxidative stress is at least in part involved in excitoneurotoxicity. Fenton reaction, which is catalyzed by Fe2+, is known to cause formation of hydroxyl radical, one of reactive oxygen species, suggesting that chelation of iron may be protective against excitoneurotoxicity. In the present study, we histologically evaluated whether zinc-deferoxamine (Zn-DFO) and deferasirox (DFX), common iron chelating agents, were protective against N-methyl-D-aspartate (NMDA)-induced retinal injury in the rat in vivo. Male Sprague-Dawley rats were subjected to intravitreal NMDA injection (200 nmol/eye). Zn-DFO (1, 3, 10, and 30 mg/kg), Zn (0.1, 0.2 and 0.6 mg/kg) and DFX (20 mg/kg) were intraperitoneally administered. Morphometric evaluations using paraffin-embedded retinal sections, and detection of Fe2+ using SiRhoNox-1, a fluorescent probe of labile Fe2+ in the retinal frozen sections were carried out. Intravitreal NMDA resulted in strong positive signals of SiRhoNox-1 in the ganglion cell layer 24 h after NMDA injection, suggesting that intravitreal NMDA caused Fe2+ accumulation in the retinal ganglion cells. Intravitreal NMDA induced retinal ganglion cell loss 7 days after NMDA injection. Zn-DFO (1, 3, 10, and 30 mg/kg), ZnCl2 (0.2 mg/kg, a corresponding dose of 1 mg/kg Zn-DFO) and DFX (20 mg/kg) prevented the damage of retinal ganglion cells, whereas 0.6 mg/kg ZnCl2, which is a corresponding dose of 3 mg/kg Zn-DFO, did not show any protective effects. Zn-DFO (30 mg/kg) significantly decreased the intensity of the fluorescence of SiRhoNox-1 and the transferrin immunofluorescence 24 h after NMDA injection, the number of TUNEL positive cells 24 h after NMDA injection, that of 8-OHdG-positive cells, and that of 4-hydroxy-2-nonenal-positive cells 12 and 24 h after NMDA injection. These data suggest that iron-chelating agents protected retinal neurons against excitoneurotoxicity via reduction of iron content and oxidative stress in the rats in vivo. We proposed that treatment with iron-chelating agents would be a new strategy for the retinal diseases caused by excitoneurotoxicity. PMID- 29530812 TI - Histological changes underlying bupivacaine's effect on extra ocular muscle. AB - To determine the changes in the cross-sectional area (CSA) of myofibers and their subtype distribution based on the myosin isoform expression after bupivacaine (BUP) injection in the EOM of rabbits and help the understanding of strabismus correction after BUP injection in the clinical practice. A total of 32 rabbits received 0.3 mL of 1.5% BUP in the superior rectus muscle (SR) of the right eye (OD) and were sacrificed at days 7, 28, 60, and 92. Additional eight untouched rabbits were included as controls. Hematoxylin and eosin staining was performed, and ImageJ software was used to measure CSA. Immunohistochemical analysis was performed to analyze the proportion of myofibers positive for myosin types 1 (slow), 2 (fast) and embryonic. Myofiber area measurement decreased 7 days after BUP injection [SR, 1271 +/- 412 MUm2 (control) to 909 +/- 255 MUm2 (day 7)] after BUP injection, followed by an increasing trend after 28 days and normalization after 92 days [SR; 1062 +/- 363 MUm2 (day 28), 1492 +/- 404 MUm2 (day 60), 1317 +/- 334 MUm2 (day 92)]. The proportion of slow myosin-positive fibers increased in the 60-day group (88.5% +/- 16.2%). There was no statistically significant difference in fast myosin-positive fibers. The inferior rectus of both eyes showed an increase in CSA. No increase of endomysial fibrous tissue was observed after 60 and 92 days of BUP injection. Bupivacaine, when injected into the SR of rabbits, initially decreases the fiber area followed by a transient increasing trend and normalization. There is a transient increase in the proportion of slow myosin-positive fibers in the injected muscle. Muscle adaptation in untreated EOM was found with increased CSA. These findings help clarify the clinical effects of BUP in extraocular muscle. PMID- 29530813 TI - Impulsivity and behaviour problems in dogs: A Reinforcement Sensitivity Theory perspective. AB - Trait impulsivity is an increasingly relevant topic for human and non-human animal personality research. There are similarities in dog and human manifestations of trait impulsivity at the behavioural, genetic, and neurobiological level. We investigated a well-validated measure of dog impulsivity and responsivity (the Dog Impulsivity Assessment Scale, DIAS) and a neuropsychological theory of human trait approach and avoidance (the Reinforcement Sensitivity Theory of personality, RST). Owners reported their dogs' dispositional behaviour on the DIAS, an RST scale modified to describe dogs' behaviour, and a list of common dog behaviour problems. In a sample of 730 dogs, we observed convergence between the RST and the DIAS. There was a negative correlation between RST 'Behaviour Inhibition System' and DIAS impulsivity factor ('Behavioural Regulation'). RST 'Behavioural Approach System' correlated positively with DIAS 'Responsiveness'. The RST 'Fight-Flight-Freeze System' (FFFS) and the DIAS 'Aggression and response to novelty factor were both distinct from other factors. However, the DIAS 'Aggression and response to novelty' factor and the RST FFFS explained different aspects of dog behaviour problems. Importantly, whilst the DIAS factors indicated tendencies towards avoidant behaviours, the FFFS discriminated between active and passive avoidance. The findings suggest a partial overlapping between the DIAS and RST scales, and highlights the utility of personality models in investigating behaviour problems in dogs. PMID- 29530814 TI - Curcumin-loaded nanoparticles ameliorate glial activation and improve myelin repair in lyolecithin-induced focal demyelination model of rat corpus callosum. AB - Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5 mg/kg, 10 days prior to LPC injection and the injections were continued for 7 or 14 days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context. PMID- 29530815 TI - A novel p.L216I mutation in the glucocerebrosidase gene is associated with Parkinson's disease in Han Chinese patients. AB - OBJECTIVES: Pathogenic mutations in the glucocerebrosidase (GBA) gene are associated with Parkinson's disease (PD), of which L444P and N370S are the most frequently observed in patients with PD. The aim of this study was to systematically explore variations in the coding regions of GBA in Han Chinese patients with PD, as well as to expand the GBA mutation spectrum. MATERIAL AND METHODS: A total of 213 Han Chinese patients with PD and 348 controls were enrolled in the study. Whole coding regions of GBA were captured and sequenced by target region sequencing. Sanger sequencing was also used to confirm the identified variants. RESULTS: We identified a novel variant (c. C646A; p.L216I; NM_001171811.1) of GBA in two unrelated patients, which was not observed in the controls. Both patients had early-onset PD and neither exhibited any motor related symptoms. However, we did not find an L444P or N370S mutations in our patients. CONCLUSIONS: The p.L216I mutation is a novel GBA mutation, which we identified in two Han Chinese patients with PD. The patients exhibited similar characteristics, which differed from those seen in patients with other GBA mutations. Future work is needed to investigate this mutation further, as well as larger cohort studies to explore other GBA mutations associated with PD in the Han Chinese and in other populations. PMID- 29530816 TI - Structural and functional brain network of human retrosplenial cortex. AB - Retrosplenial cortex (RSC) plays a key role in various cognitive functions. The fiber connectivity of RSC had been reported in rodent and primate studies by tracer injection methods To explore structural and functional connectivity of two sub-regions of RSC, Brodmann area (BA)29 and BA30, we constructed fiber connectivity networks of two sub-regions by diffusion tensor imaging (DTI) tractography based on diffusion magnetic resonance imaging (MRI) and functional connectivity networks by resting-state functional MRI. The BA29 network showed fiber connections with auditory cortex and functional connections with BA21. Both fiber and functional connections show that BA30 network includes visual cortex. Furthermore, BA30 had fiber connections with hippocampus, thalamus, and prefrontal cortex. We suggest that (1) structural connectivity reflects functional connectivity in some degree. (2) BA29 mainly received and processed sound information from auditory cortex, while BA30 mainly received and processed scene information from visual cortex. PMID- 29530817 TI - Filling the Gaps to Solve the Extensin Puzzle. AB - Extensins (EXTs) are highly repetitive plant O-glycoproteins that require several post-translational modifications (PTMs) to become functional in plant cell walls. First, they are hydroxylated on contiguous proline residues; then they are O glycosylated on hydroxyproline and serine. After secretion into the apoplast, O glycosylated EXTs form a tridimensional network organized by inter- and intra-Tyr linkages. Recent studies have made significant progress in the identification of the enzymatic machinery required to process EXTs, which includes prolyl 4 hydroxylases, glycosyltransferases, papain-type cysteine endopeptidases, and peroxidases. EXTs are abundant in plant tissues and are particularly important in rapidly expanding root hairs and pollen tubes, which grow in a polar manner. Small changes in EXT PTMs affect fast-growing cells, although the molecular mechanisms underlying this regulation are unknown. In this review, we highlight recent advances in our understanding of EXT modifications throughout the secretory pathway, EXT assembly in cell walls, and possible sensing mechanisms involving the Catharanthus roseus cell surface sensor receptor-like kinases located at the interface between the apoplast and the cytoplasmic side of the plasma membrane. PMID- 29530818 TI - Calcium Signaling in Plant Autoimmunity: A Guard Model for AtSR1/CAMTA3-Mediated Immune Response. PMID- 29530819 TI - Effect of language experience on selective auditory attention: An event-related potential study. AB - Dual language experience has typically been shown to improve various executive control functions. We investigated with event-related brain potentials (ERPs) recorded from early (natively) bilingual speakers and control participants whether it also affects auditory selective attention. We delivered to our participants two tone streams, one to the left and one to the right ear. Both streams consisted of standard tones and two types of infrequent deviant tones which had either an enhanced duration or intensity. The participants were instructed to attend either to the right or left stream and to detect longer duration deviants in the attended stream. The results showed that the early bilinguals did not outperform the controls in target detection accuracy or speed. However, the late portion of the attention-related ERP modulation (the negative difference, Nd) was larger over the left hemisphere in the early bilinguals than in the controls, suggesting that the maintenance of selective attention or further processing of selectively attended sounds is enhanced in the bilinguals. Moreover, the late reorienting negativity (RON) in response to intensity-deviant tones was larger in the bilinguals, suggesting more efficient disengagement of attention from distracting auditory events. Hence, our results demonstrate that brain responses associated with certain aspects of auditory attention are enhanced in the bilingual adults, indicating that early dual language exposure modulates the neuronal responsiveness of auditory modality. PMID- 29530820 TI - In vitro and in vivo studies on zinc-hydroxyapatite composites as novel biodegradable metal matrix composite for orthopedic applications. AB - : Recent studies indicate that there is a great demand to optimize pure Zn with tunable degradation rates and more desirable biocompatibility as orthopedic implants. Metal matrix composite (MMC) can be a promising approach for this purpose. In this study, MMC with pure Zn as a matrix and hydroxyapatite (HA) as reinforcements were prepared by spark plasma sintering (SPS). Feasibility of novel Zn-HA composites to be used as orthopedic implant applications was systematically evaluated. After sintering, HA distributed in the Zn particle boundaries uniformly. Corrosion tests indicated that the degradation rates of Zn HA composites were adjustable due to the biphasic effects of HA. Zn-HA composites showed significantly improved cell viability of osteoblastic MC3T3-E1 cells compared with pure Zn. Both pure Zn and composites exhibited a low thrombosis risk and hemolysis rates while a Zn ion concentration-dependent effect was found on coagulation time. An effective antibacterial property was observed as well. The volume loss of pure Zn and Zn-5HA composite was 1.7% and 3.2% after 8 weeks' implantation. Histological analysis found newly formed bone surrounding pure Zn and Zn-5HA composite at week 4 and increased bone mass over time. With prolonged implantation time, Zn-5HA composite was more effective on stimulating new bone formation than pure Zn. In summary, MMC is a feasible way to design Zn based materials with adjustable degradation rates and improved biocompatibility. STATEMENT OF SIGNIFICANCE: Biodegradable zinc materials are promising candidates for the new generation of orthopedic implants. However, the slow degradation rates and unsatisfactory cytocompatibility of pure Zn in bone environments limit its future clinical applications. Generally, alloying is a common way to improve the performance of pure Zn. In this study, metal matrix composite was chosen as a novel strategy to solve the problems. Hydroxyapatite, as a bioactive component, was added into Zn matrix via spark plasma sintering. We find that Zn-HA composites exhibited adjustable degradation rates and improved biocompatibility both in vitro and in vivo. This study provides exhaustive and significant information including microstructure, mechanical performance, degradation behavior, biocompatibility, hemocompatibility and antibacterial property for the future Zn based implants design. PMID- 29530822 TI - Substrate fiber alignment mediates tendon cell response to inflammatory signaling. AB - : Healthy tendon tissue features a highly aligned extracellular matrix that becomes disorganized with disease. Recent evidence suggests that inflammation coexists with early degenerative changes in tendon, and that crosstalk between immune-cells and tendon fibroblasts (TFs) can contribute to poor tissue healing. We hypothesized that a disorganized tissue architecture may predispose tendon cells to degenerative extracellular matrix remodeling pathways, particularly within a pro-inflammatory niche. This hypothesis was tested by analyzing human TFs cultured on electrospun polycaprolactone (PCL) mats with either highly aligned or randomly oriented fiber structures. We confirmed that fibroblast morphology, phenotype, and markers of matrix turnover could be significantly affected by matrix topography. More strikingly, the TF response to paracrine signals from polarized macrophages or by stimulation with pro-inflammatory cytokines featured significant downregulation of signaling related to extracellular synthesis, with significant concomitant upregulation of gene and protein expression of matrix degrading enzymes. Critically, this tendency towards degenerative re-regulation was exacerbated on randomly oriented PCL substrates. These novel findings indicate that highly aligned tendon cell scaffolds not only promote tendon matrix synthesis, but also play a previously unappreciated role in mitigating adverse resident fibroblast response within an inflammatory milieu. STATEMENT OF SIGNIFICANCE: Use of biomaterial scaffolds for tendon repair often results in tissue formation characteristic of scar tissue, rather than the highly aligned type-1 collagen matrix of healthy tendons. We hypothesized that non optimal biomaterial surfaces may play a role in these outcomes, specifically randomly oriented biomaterial surfaces that unintentionally mimic structure of pathological tendon. We observed that disorganized scaffold surfaces do adversely affect early cell attachment and gene expression. We further identified that disorganized fiber surfaces can prime tendon cells toward pro-inflammatory signaling. These findings represent provocative evidence unstructured fiber surfaces may underlie inflammatory responses that drive aberrant collagen matrix turnover. This work could be highly relevant for the design of cell instructive biomaterial therapies that yield positive clinical outcomes. PMID- 29530821 TI - Zinc-based alloys for degradable vascular stent applications. AB - : The search for biodegradable metals with mechanical properties equal or higher to those of currently used permanent biomaterials, such as stainless steels, cobalt chromium and titanium alloys, desirable in vivo degradation rate and uniform corrosion is still an open challenge. Magnesium (Mg), iron (Fe) and zinc (Zn)-based alloys have been proposed as biodegradable metals for medical applications. Over the last two decades, extensive research has been done on Mg and Fe. Fe-based alloys show appropriate mechanical properties, but their degradation rate is an order of magnitude below the benchmark value. In comparison, alongside the insufficient mechanical performance of most of its alloys, Mg degradation rate has proven to be too high in a physiological environment and corrosion is rarely uniform. During the last few years, Zn alloys have been explored by the biomedical community as potential materials for bioabsorbable vascular stents due to their tolerable corrosion rates and tunable mechanical properties. This review summarizes recent progress made in developing Zn alloys for vascular stenting application. Novel Zn alloys are discussed regarding their microstructural characteristics, mechanical properties, corrosion behavior and in vivo performance. STATEMENT OF SIGNIFICANCE: Numerous studies on magnesium and iron materials have been reported to date, in an effort to formulate bioabsorbable stents with tailorable mechanical characteristics and corrosion behavior. Crucial concerns regarding poor ductility and remarkably rapid corrosion of magnesium, and very slow degradation of iron, seem to be still not desirably fulfilled. Zinc was introduced as a potential implant material in 2013 due to its promising biodegradability and biocompatibility. Since then, extensive investigations have been made toward development of zinc alloys that meet clinical benchmarks for vascular scaffolding. This review critically surveys the zinc alloys developed since 2013 from metallurgical and biodegradation points of view. Microstructural features, mechanical, corrosion and in vivo performances of these new alloys are thoroughly reviewed and evaluated. PMID- 29530823 TI - Protein machineries defining pathways of nanocarrier exocytosis and transcytosis. AB - : The transport of nanocarriers through barriers like the gut in a living organism involves the transcytosis of these nanocarriers through the cell layer dividing two compartments. Understanding how this process works is not only essential to further developing strategies for a more effective nanocarrier transport system but also for providing fundamental insights into the barrier function as a means of protection against micro- and nanoplastics in the food chain. We therefore set out to investigate the different uptake mechanisms, intracellular trafficking and the routes for exocytosis for small polystyrene nanoparticles (PS-NPs ca. 100 nm) as mimicking nanocarriers in a Caco-2 cell model for gut-blood transition. We used label-free, quantitative mass spectrometry (MS) for determining the proteome that adhered to transversed nanoparticles. From this rich proteomics dataset, as well as previous studies, we generated stable-transfected Caco-2 cell lines carrying the green fluorescent protein (GFP) coupled to proteins of interest for uptake, early, late and exocytotic endosomes. We detected the spatial and temporal overlap of such marked endosomes with the nanocarrier signal in confocal laser scanning and super resolution microscopy. There was a clear distinction in the time course of nanoparticle trafficking between groups of proteins for endocytosis, intracellular storage and putatively transcytosis and we identified several key transcytotic markers like Rab3 and Copine1. Moreover, we postulate the necessity of a certain protein composition on endosomes for successful transcytosis of nanocarriers. Finally, we define the two-sided impasse of the lysosome as a dead end for nano-plastic and the limit of nanocarriers in the 100 nm range. STATEMENT OF SIGNIFICANCE: Here we focus on mechanisms of transcytosis and how we can follow these with methods not used before. First, we use mass spectrometry of transcytosed nanoparticles to pick proteins of the transcytosis machinery describing key proteins involved. We can detect the complex mixtures of proteins. As this is a dynamic process involving whole families of proteins interacting with each other and as this is an orchestrated process we coined the term protein machineries for this active interplay. By genetically modifying the proteins attaching GFP we are able to follow the transcytosis pathway. We evaluate the process in a quantitative manner over time. This reveals that the most obvious obstacle to transcytosis is a routing of the nanocarriers to the lysosomes. PMID- 29530824 TI - Toxicological effects of trichlorfon on hematological and biochemical parameters in Cyprinus carpio L. following thermal stress. AB - Trichlorfon is a moderately toxic organophosphate pesticide that is widely used in aquaculture. This study investigated the effects of trichlorfon on hematological parameters, biochemical factors, and stress reaction in Cyprinus carpio L. The fish were exposed to acute concentrations of trichlorfon (0, 0.5, 1.0, 2.0, and 4.0 mg L-1) at 25 degrees C and 15 degrees C for 1 and 2 weeks, after which several parameters were evaluated to assess the effects of the pesticide. Significant decreases were observed in red blood cell (RBC) Count, hemoglobin (Hb) level, hematocrit (Ht), and plasma protein levels after each exposure period. In contrast, notable increases in mean corpuscular volume (MCV), mean cell hemoglobin (MCH), calcium, and glucose levels were observed in the trichlorfon-treated groups. Additionally, there were significant increases in the plasma levels of glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), and alkaline phosphatase (ALP) following the exposure to trichlorfon. Furthermore, the results showed a relationship between toxic stress and increment in HSP70 and cytochrome P450 1A (CYP1A) expression over time. Ht, MCV, MCH, and the value of other biochemical parameters were quite lower at 15 degrees C than their corresponding values were at 25 degrees C, which indicated the decreased physical activity at 15 degrees C. The results of the present work indicate that acute exposure to trichlorfon and thermal stimulus could damage erythropoietic tissue. Additionally, hepatocytes function and physiological mechanisms could be impaired. Ht, glucose, GOT, GPT, HSP70, and CYP1A levels might be useful biomarkers of trichlorfon toxicity in contaminated aquatic ecosystems. PMID- 29530825 TI - Plate versus Kirschner wire fixation in treatment of fourth and fifth carpometacarpal fracture-dislocations: A retrospective cohort study AB - BACKGROUND: Fourth and fifth carpometacarpal fracture-dislocations with unsatisfactory closed reduction commonly require later open reduction and internal fixation. However, the optimal method of internal fixation for these is unknown. The purpose of this study was to determine through objective clinical measures which method is superior for fourth and fifth carpometacarpal fracture dislocations: a K-wire or a plate. METHODS: We conducted a retrospective review of hospital records of patients who had received treatment for fourth and fifth carpometacarpal fracture-dislocations at one hospital between May 2007 and May 2015. A total of 86 patients who had received open reduction either with plate or K-wire fixation were included. Demographic and clinical characteristics of the two groups of patients were collected. Patients received standardised clinical tests one year after fixation. Clinical outcomes included tests of grip strength and scores on the Michigan Hand Outcomes Questionnaire and Disabilities of Arm, Shoulder, and Hand. Student's t tests and Chi-square tests were used to statistically evaluate whether plate or K-wire fixation was superior on the clinical variables. RESULTS: The two groups were statistically indistinguishable on their demographic and clinical characteristics. Generally, the clinical outcomes of internal fixation were satisfactory. The average DASH and MHQ scores of the K-wire group were superior to those of the plate group (DASH 2.3 versus 9.8, P = 0.01; MHQ 96.7 versus 86.6, P = 0.02). Grip strength was not significantly different between the two groups (89.5 +/- 5.8% versus 90.1 +/- 4.9%, P = 0.36). CONCLUSIONS: This non-randomly controlled, retrospective study suggests that clinical outcomes after K-wire fixation is superior to plate fixation for fourth and fifth carpometacarpal fracture-dislocations. This is especially the case for hand functions related to work. The present results suggest that K-wire fixation is the gold-standard technique for the treatment of fourth and fifth CMC fracture-dislocations. PMID- 29530826 TI - Preventable risk factors of mortality after hip fracture surgery: Systematic review and meta-analysis. AB - OBJECTIVE: Although many studies have reported risk factors of mortality following hip fracture surgery, the preventable risk factors of mortality following hip fracture surgery have not been well-identified. The aim of this study was to identify the preventable risk factors of mortality following hip fracture surgery. METHODS: We searched PubMed, Web of Science, Google scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases from January 1997 to March 2017 for studies reporting risk factors of mortality following hip fracture surgery. The primary outcomes assessed in this meta-analysis were time to surgery, residential status, smoking, cardiovascular disease, pulmonary disease, diabetes, and malignancy. All analyses were conducted using Stata/SE version 11.0 software. RESULTS: Sixteen studies involving 25 349 patients meeting the inclusion criteria were included. Statistically significant associations between the mortality after hip fracture surgery and the risk factors, including the time to surgery (>2days/<2days) (odds ratio[OR] = 1.91; 95%CI, 1.14-3.18; P = 0.013), residential status (nursing home/home) (OR = 1.97; 95%CI, 1.02-3.78; P = 0.043), cardiovascular disease (OR = 1.14; 95%CI, 1.03-1.26; P = 0.012), pulmonary disease (OR = 1.52; 95%CI, 1.37-1.69; P < 0.001), diabetes (OR = 1.41; 95%CI, 1.19-1.67; P < 0.001), and malignancy (OR = 2.99, 95%CI, 1.14-7.83; P = 0.013) were established. However, the available data failed to demonstrate an association between the mortality, and time to surgery (>1day/<1day) (OR = 1.25; 95%CI, 0.93-1.66; P = 0.136) and smoking (OR = 0.89; 95%CI, 0.69-1.14; P = 0.340). CONCLUSION: This meta-analysis explicitly indicated that malignancy, nursing home residence, time to surgery (>2days/<2days), pulmonary disease, diabetes, and cardiovascular disease significantly increased the risk of mortality after hip fracture surgery. These preventable risk factors may be used to create algorithms that are more effective and pertinent to reduce the mortality following hip fracture surgery. PMID- 29530827 TI - Contaminated drainage fluid and pancreatic fistula after pancreatoduodenectomy: A retrospective study. AB - BACKGROUND: Appropriate bacterial infection control in the perioperative period of a pancreaticoduodenectomy (PD) is important to prevent and manage serious complications including postoperative pancreatic fistula (POPF). In the present study, the clinical impact of bacterial contamination of intra-abdominal discharge on the rate of POPF after PD was analysed retrospectively. MATERIALS AND METHODS: The data for 82 consecutive patients who had undergone PD at our hospital between January 2009 and July 2014 were retrospectively analysed to review patient characteristics and perioperative and postoperative parameters. We compared the clinicopathologic features between patients with bacterial contamination of drainage fluid and those without bacterial contamination of drainage fluid. We also examined the relationship between POPF and bacterial contamination of drainage fluid, according to the bacterial strain involved. RESULTS: The incidence of Grade B/C POPF was significantly higher in the bacterial contamination positive group than in the bacterial contamination negative group (44.0% vs. 0.0%; p < 0.001). Soft gland texture and bacterial contamination of intra-abdominal discharge were found to be risk factors for POPF (odds ratio: 9.00, 95% confidence interval: 1.17-409.46 and odds ratio: 43.94, 95% confidence interval: 5.72-1992.04, respectively). The incidence of Grade B/C POPF was significantly higher in patients harbouring Pseudomonas aeruginosa than in patients harbouring bacteria other than Pseudomonas aeruginosa (p = 0.005). CONCLUSION: Bacterial contamination of intra-abdominal discharge is a risk factor for the development of pancreatic fistulae. Cases involving contamination with Pseudomonas aeruginosa warrant extreme caution. PMID- 29530828 TI - Central hepatectomy versus major hepatectomy for patients with centrally located hepatocellular carcinoma: A meta-analysis. AB - BACKGROUND: Both central hepatectomy (CH) and major hepatectomy (MH) are suggested surgical treatments for patients with centrally located hepatocellular carcinoma (CL-HCC). However, no consensus has been reached regarding which method is superior for managing these patients. This meta-analysis was conducted to compare the short- and long-term outcomes of CH and MH in patients with CL-HCC. METHODS: An electronic search for studies published in all years up to July 2017 in PubMed (Medline), EMBASE, Cochrane Library and Web of Science was performed. The short-term outcome was the incidence of postoperative complications, and the long-term outcomes included 1-, 3- and 5-year overall survival (OS) and corresponding disease-free survival (DFS), mortality and morbidity. The results were presented as Risk Ratios (RRs) or weighted mean differences with 95% confidence intervals. RESULTS: Four retrospective studies containing 465 patients with CL-HCC were included (248 in the CH group and 217 in the MH group). The results suggested no significant differences in the 1-, 3- and 5-year DFS, 1, 3 and 5-year OS, total morbidity or mortality between these groups. Nevertheless, the patients in the CH group presented a lower prevalence of vascular invasion (RR 0.70, 95% CI 0.52-0.93, P = 0.020) than did the MH group. In addition, CH led to a higher incidence of biliary fistula, while MH showed a higher incidence of postoperative liver failure. CONCLUSION: This study demonstrated that the long term outcomes of the patients with CL-HCC in these two groups were not significantly different. For short-term outcomes, CH resulted in a lower rate of postoperative liver failure, while MH resulted in a lower incidence of biliary fistula. Nonetheless, compared with MH, CH provided CL-HCC patients with greater future remnant liver volume without an increased risk of early intra-hepatic recurrence. More multi-centre, randomized controlled trials comparing the therapeutic efficacy of CH and MH are urgently warranted. PMID- 29530829 TI - The impact of major postoperative complications on long-term outcomes following curative resection of colon cancer. AB - PURPOSE: The objective is to analyze the impact of severe postoperative complications in patients undergoing curative surgery for colon cancer. MATERIAL AND METHODS: From a prospective database, we identified patients with stage I-III disease (AJCC) who underwent surgery between 2000 and 2014. Patients were selected with major complications (IIIb on the Clavien-Dindo classification) and with no major complications. Variables were analyzed in both groups. Local, peritoneal and distant recurrence together with overall survival and disease-free survival were analyzed. RESULTS: Of a total of 950 patients, 51 (5.3%) experienced major complications. Operative mortality was 2.6%. Age, ASA grade, urgent surgery, pre-operative hemoglobin, right-sided location, operative time, transfusion, conversion to open surgery, were all associated with major complications (all P < 0.05). With a median follow-up of 84.8 and 40 months in both groups, there was greater incidence of local recurrences in patients experiencing complications (2.4% vs 7.8%; P = 0.03 OR 3.39, 95% CI 1.12-10.24), being more marked in stage III patients (4.2% vs 21%; P = 0.005, OR 6.13 95% CI 1.74-21.56). In the stage III group, peritoneal recurrence was significantly greater in patients with complications (13.6% vs 31.6%; P = 0.04 OR 2.92 95% CI 1.04-8.18). Patients with major complications had a significantly lower overall survival (P = 0.024) than patients with no complications both at 5 years (78.9% vs 68.8%) and 10 years (74.6% vs 32.1%). The same trend was observed for disease free survival (71.6% vs 48.3% and 69.8% vs 32.2%; P = 0.013). CONCLUSION: The development of major complications following colectomy for colon cancer has a negative impact on long-term oncologic outcomes, especially in stage III disease. PMID- 29530830 TI - Transcriptome analysis of olive flounder (Paralichthys olivaceus) head kidney infected with moderate and high virulent strains of infectious viral hemorrhagic septicaemia virus (VHSV). AB - Olive flounder (Paralichthys olivaceus) is one of the most valuable marine aquatic species in South Korea and faces tremendous exposure to the viral hemorrhagic septicemia virus (VHSV). Given the growing importance of flounder, it is therefore essential to understand the host defense of P. olivaceus against VHSV infection, but studies on its immune mechanism are hindered by the lack of genomic resources. In this study, the P. olivaceus was infected with disease causing VHSV isolates, ADC-VHS2012-11 and ADC-VHS2014-5 which showed moderate virulent (20% mortality) and high virulent (65% mortality), in order to investigate the effect of difference in pathogenicity in head kidney during 1, 3, 7 days of post-infection using Illumina sequencing. After removing low-quality sequences, we obtained 144,933,160 high quality reads from thirty-six libraries which were further assembled into 53,384 unigenes with an average length of 563 bp with a range of 200 to 9605 bp. Transcriptome annotation revealed that 30,475 unigenes with a cut-off e-value of 10-5 were functionally annotated. In total, 10,046 unigenes were clustered into 26 functional categories by searching against the eggNOG database, and 22,233 unigenes to 52 GO terms. In addition, 12,985 unigenes were grouped into 387 KEGG pathways. Among the 13,270 differently expressed genes, 6578 and 6692 were differentially expressed only in moderate and high virulent, respectively. Based on our sequence analysis, many candidate genes with fundamental roles in innate immune system including, pattern recognition receptors (TLRs & RLRs), Mx, complement proteins, lectins, and cytokines (chemokines, IFN, IRF, IL, TRF) were differentially expressed. Furthermore, GO enrichment analysis for these genes revealed gene response to defense response to virus, apoptotic process and transcription factor activity. In summary, this study identifies several putative immune pathways and candidate genes deserving further investigation in the context of novel gene discovery, gene expression and regulation studies and lays the foundation for fish immunology especially in P. olivaceus against VHSV. PMID- 29530831 TI - Role for electrocardiographic imaging in cardiac resynchronization therapy? PMID- 29530832 TI - Antiarrhythmic effects of vagal nerve stimulation after cardiac sympathetic denervation in the setting of chronic myocardial infarction. AB - BACKGROUND: Neuraxial modulation with cardiac sympathetic denervation (CSD) can potentially reduce burden of ventricular tachyarrhythmia (VT). However, despite catheter ablation and CSD, VT can recur in patients with cardiomyopathy and the role of vagal nerve stimulation (VNS) in this setting is unclear. OBJECTIVE: The purpose of this study was to evaluate the electrophysiological effects of VNS after CSD in normal and infarcted hearts. METHODS: In 10 normal and 6 infarcted pigs, electrophysiological and hemodynamic parameters were evaluated before and during intermittent VNS pre-CSD (bilateral stellectomy and T2-T4 thoracic ganglia removal) as well as post-CSD. The effect of VNS during isoproterenol was also assessed pre- and post-CSD. Multielectrode ventricular activation recovery interval (ARI) recordings, a surrogate of action potential duration, were obtained. VT inducibility was tested during isoproterenol infusion after CSD with and without VNS. RESULTS: VNS increased the global ARI by 4% +/- 4% pre-CSD and by 5% +/- 6% post-CSD, with enhanced effects observed during isoproterenol infusion (10% +/- 8% pre-CSD and 12% +/- 9% post-CSD) in normal animals. In infarcted animals pre-CSD, VNS increased ARI by 6% +/- 7% before and by 13% +/- 8% during isoproterenol infusion. Post-CSD, VNS increased ARI by 6% +/- 5% before and by 11% +/- 7% during isoproterenol infusion. VT was inducible in all infarcted animals post-CSD during isoproterenol infusion; this inducibility was reduced by 67% with VNS (P = .01). In all animals, the hemodynamic effects of VNS remained after CSD. CONCLUSION: After CSD, the beneficial electrophysiological effects of VNS remain. Furthermore, VNS can reduce VT inducibility beyond CSD in the setting of circulating catecholamines, suggesting a role for additional parasympathetic modulation in the treatment of ventricular arrhythmias. PMID- 29530833 TI - Visualization of acute edema in the left atrial myocardium after radiofrequency ablation: Application of a novel high-resolution 3-dimensional magnetic resonance imaging sequence. AB - BACKGROUND: Ablation-induced left atrial (LA) edema may result in procedural failure due to reversible pulmonary vein isolation. Conventional T2-weighted magnetic resonance edema imaging is limited by low spatial resolution. OBJECTIVE: The purpose of this pilot study was to optimize and validate a 3-dimensional (3D) sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) sequence for quantification of T2 signal in the LA, and to apply it in recently ablated patients, comparing myocardial edema on T2-SPACE to tissue damage on late gadolinium enhancement (LGE) imaging. METHODS: Phantom studies were performed to identify 3D-SPACE parameters for optimal contrast between normal and edematous myocardium. Fourteen AF patients were imaged with both 3D-SPACE and dark-blood turbo-spin echo (DB-TSE) to compare image quality and signal intensity between the 2 techniques. Eight patients underwent pre- and postablation 3D-SPACE and 3D-LGE imaging. Ablation points were co-registered with corresponding myocardial sectors, and ablation-induced changes in T2 and LGE signal intensities were measured. RESULTS: Signal-to-noise ratio and contrast-to noise ratio were higher on SPACE vs DB-TSE (65.5 +/- 33.9 vs 35.7 +/- 17.9; P = .01; and 59.4 +/- 33.0 vs 32.9 +/- 17.7; P = .04, respectively). T2-signal correlated well on 3D-SPACE and DB-TSE, such that each unit increase in TSE intensity correlated with a 0.69-unit increase in SPACE intensity (95% confidence interval 0.56-0.82; P <.001). T2 and LGE signal intensities were acutely increased at ablation sites. The extent of postablation edema was higher compared to LGE, although the spatial distribution of hyperenhancement around pulmonary veins seemed similar in both modalities. CONCLUSION: T2-SPACE can be used to map the extent of acute postablation edema in the thin LA myocardium, with improved resolution and lower artifact compared to traditional DB-TSE. PMID- 29530834 TI - Radical Hysterectomy and Age: Outcomes Comparison Based on a Minimally Invasive vs an Open Approach. AB - STUDY OBJECTIVE: To compare outcomes of radical hysterectomy (RH) across age groups based on surgical approach: minimally invasive surgery (MIS) vs laparotomy (LP). DESIGN: Cross-sectional retrospective review (Canadian Task Force classification II-2). SETTING: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center. PATIENTS: Patients with early-stage cervical cancer who underwent RH at a tertiary cancer center between 1990 and 2013. INTERVENTIONS: Patients were stratified by age group (<50, 50-59, and >=60 years) and by surgical approach (minimally invasive surgery [MIS] vs laparotomy [LP]). MEASUREMENTS AND MAIN RESULTS: Patients with early-stage cervical cancer who underwent RH were retrospectively reviewed to obtain demographic data, surgical data, and clinical outcomes. We used the Fisher exact, Wilcoxon rank-sum, and Cochran-Mantel Haenszel tests to compare categorical and continuous variables stratified by surgical approach and age group. A total of 548 patients were evaluated, including 427 (77.9%) who underwent LP (age <50, 84.3%; 50-59, 11.2%; >=60, 4.5%) and 121 (22.1%) who underwent MIS (age <50, 71.9%; 50-59, 17.3%; >=60, 10.8%). In the MIS group, 71 patients (58.7%) underwent laparoscopy and 50 (41.3%) underwent robotic surgery. Patients in the MIS group were significantly older and heavier than those in the LP group. The operative time was significantly longer in the MIS group. There was no between-group difference in intraoperative complications in any of the 3 age groups. LP patients had more infectious complications (respiratory, systemic, and wound) than MIS patients in the <50-year age group (53.3% vs 21.8%). The difference between the LP and MIS groups with respect to the postoperative noninfectious complication rate was greatest in the >=60-year age group (p = .0324). CONCLUSION: The between-group difference in postoperative noninfectious complication rate in the oldest age group was twice that in either of the other 2 age groups (p = .0324), even though the MIS patients were older, heavier, and had a longer operative time compared with the LP patients. PMID- 29530835 TI - Dermatologic Manifestations of Laparoscopic Port Site Vascular Injuries. PMID- 29530836 TI - The Effect of Intramural Myomas Without an Intracavity Component on In Vitro Fertilization Outcomes in Single Fresh Blastocyst Transfer Cycles. AB - STUDY OBJECTIVE: To assess clinical pregnancy rate (CPR) and live birth rate (LBR) in the presence of non-cavity-deforming intramural myomas in single fresh blastocyst transfer cycles. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Academic fertility center. PATIENTS: A total of 929 fresh single blastocyst transfer cycles were included, 94 with only non cavity-distorting intramural myomas and 764 without myomas. Cleavage embryo transfers were excluded to reduce bias based on embryo quality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: CPR and LBR were assessed. There were no differences noted in gravidity, parity, or body mass index between patients with myomas and those without myomas. Women with myomas required higher doses of gonadotropins (mean, 2653 +/- 404 IU vs 2350 +/- 1368 IU; p = .04) than women without myomas. However, the total number of mature oocytes collected and the total number of blastocysts created were similar. CPR (47% vs 32%; p = .005) and LBR (37.8% vs 25.5%; p = .02) were lower in patients who had intramural myomas compared with those without myomas. CPR and LBR were significantly reduced in the presence of even 1 myoma (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33-0.83 and OR, 0.56; 95% CI, 0.35-0.92, respectively). In patients with myomas >1.5 cm, LBR was also significantly reduced, even after adjusting for age, smoking, quality of embryo transferred, antral follicle count, and dose of gonadotropins (OR, 0.53; 95% CI, 0.29-0.97). This LBR finding was not significant if all myomas were included (including those <1.5 cm in diameter), but CPR was still significantly reduced. CONCLUSION: Relatively small (>1.5 cm) non-cavity distorting intramural myomas negatively affect CPR and LBR in in vitro fertilization cycles, even in the presence of only 1 myoma. PMID- 29530837 TI - Epidemiology of Surgical Site Infections With Staphylococcus aureus in Europe: Protocol for a Retrospective, Multicenter Study. AB - BACKGROUND: Surgical site infections (SSIs) are among the most common hospital acquired infections. While the incidence of SSI in certain indicator procedures is the subject of ongoing surveillance efforts in hospitals and health care systems around the world, SSI rates vary markedly within surgical categories and are poorly represented by routinely monitored indicator procedures (eg, mastectomy or hernia surgery). Therefore, relying on indicator procedures to estimate the burden of SSI is imprecise and introduces bias as hospitals may take special precautions to achieve lower SSI rates. The most common cause of SSI is Staphylococcus aureus (S. aureus), as recently confirmed by a Europe-wide point prevalence study conducted by the European Centre for Disease Prevention and Control (ECDC). OBJECTIVE: The primary objective of this study is to determine the overall and procedure-specific incidence of S. aureus SSI in Europe. Secondary objectives are the overall and procedure-specific outcomes as well as the economic burden of S. aureus SSI in Europe. Explorative objectives are to characterize the composition of the surgical patient population and to estimate the number of patients at risk for S. aureus SSI. METHODS: A retrospective, multinational, multicenter cohort study (Staphylococcus aureus Surgical Site Infection Multinational Epidemiology in Europe [SALT] study) with a nested case control part will be conducted. The study will include all surgical procedures at a participating center in order to prevent selection bias and strengthen the understanding of SSI risk by determining the incidence for all common surgical procedures. Data will be assessed in the cohort population, including 150,000 adult patients who underwent any surgical procedure in 2016, and the case-control population. We will match patients establishing S. aureus SSI 1:1 with controls from the same center. Data on demographics, surgery, and microbiology will be exported from electronic files. More detailed data will be captured from the case control population. The SALT study will include 13 major or academic surgical centers in Europe, comprising 3 in France, 4 in Germany, 2 in Italy, 3 in Spain, and 1 in the United Kingdom. Sites were selected using a feasibility questionnaire. RESULTS: The SALT study is currently recruiting patients. The aim is to complete recruitment in February 2018 and to close the database in September 2018. The final results are expected by the end of 2018. CONCLUSIONS: Results of the SALT study will help to better understand the precise risk of certain procedures. They will also provide insight into the overall and procedure specific incidence and outcome as well as the economic burden of S. aureus SSI in Europe. Findings of the study may help guide the design of clinical trials for S. aureus vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03353532; https://clinicaltrials.gov/ct2/show/NCT03353532 (Archived by WebCite at http://www.webcitation.org/6xAK3gVmO). PMID- 29530838 TI - Evaluating Patient Perspectives of Provider Professionalism on Twitter in an Academic Obstetrics and Gynecology Clinic: Patient Survey. AB - BACKGROUND: One-third of Americans use social media websites as a source of health care information. Twitter, a microblogging site that allows users to place 280-character posts-or tweets-on the Web, is emerging as an important social media platform for health care. However, most guidelines on medical professionalism on social media are based on expert opinion. OBJECTIVE: This study sought to examine if provider Twitter profiles with educational tweets were viewed as more professional than profiles with personal tweets or a mixture of the two, and to determine the impact of provider gender on perceptions of professionalism in an academic obstetrics and gynecology clinic. METHODS: This study randomized obstetrics and gynecology patients at the University of Michigan Von Voigtlander Clinic to view one of six medical provider Twitter profiles, which differed in provider gender and the nature of tweets. Each participant answered 10 questions about their perception of the provider's professionalism based on the Twitter profile content. RESULTS: The provider profiles with educational tweets alone received higher mean professionalism scores than profiles with personal tweets. Specifically, the female and male provider profiles with exclusively educational tweets had the highest and second highest overall mean professionalism ratings at 4.24 and 3.85, respectively. In addition, the female provider profiles received higher mean professionalism ratings than male provider profiles with the same content. The female profile with mixed content received a mean professionalism rating of 3.38 compared to 3.24 for the male mixed-content profile, and the female profile with only personal content received a mean professionalism rating of 3.68 compared to 2.68 for the exclusively personal male provider profile. CONCLUSIONS: This study showed that in our obstetrics and gynecology clinic, patients perceived providers with educational profiles as more professional than those with a mixture of educational and personal tweets or only personal tweets. It also showed that our patient population perceived the female provider with educational tweets to be the most professional. This study will help inform the development of evidence based guidelines for social media use in medicine as it adds to the growing body of literature examining professionalism and social media. PMID- 29530839 TI - Integrating Smart Health in the US Health Care System: Infodemiology Study of Asthma Monitoring in the Google Era. AB - BACKGROUND: With the internet's penetration and use constantly expanding, this vast amount of information can be employed in order to better assess issues in the US health care system. Google Trends, a popular tool in big data analytics, has been widely used in the past to examine interest in various medical and health-related topics and has shown great potential in forecastings, predictions, and nowcastings. As empirical relationships between online queries and human behavior have been shown to exist, a new opportunity to explore the behavior toward asthma-a common respiratory disease-is present. OBJECTIVE: This study aimed at forecasting the online behavior toward asthma and examined the correlations between queries and reported cases in order to explore the possibility of nowcasting asthma prevalence in the United States using online search traffic data. METHODS: Applying Holt-Winters exponential smoothing to Google Trends time series from 2004 to 2015 for the term "asthma," forecasts for online queries at state and national levels are estimated from 2016 to 2020 and validated against available Google query data from January 2016 to June 2017. Correlations among yearly Google queries and between Google queries and reported asthma cases are examined. RESULTS: Our analysis shows that search queries exhibit seasonality within each year and the relationships between each 2 years' queries are statistically significant (P<.05). Estimated forecasting models for a 5-year period (2016 through 2020) for Google queries are robust and validated against available data from January 2016 to June 2017. Significant correlations were found between (1) online queries and National Health Interview Survey lifetime asthma (r=-.82, P=.001) and current asthma (r=-.77, P=.004) rates from 2004 to 2015 and (2) between online queries and Behavioral Risk Factor Surveillance System lifetime (r=-.78, P=.003) and current asthma (r=-.79, P=.002) rates from 2004 to 2014. The correlations are negative, but lag analysis to identify the period of response cannot be employed until short-interval data on asthma prevalence are made available. CONCLUSIONS: Online behavior toward asthma can be accurately predicted, and significant correlations between online queries and reported cases exist. This method of forecasting Google queries can be used by health care officials to nowcast asthma prevalence by city, state, or nationally, subject to future availability of daily, weekly, or monthly data on reported cases. This method could therefore be used for improved monitoring and assessment of the needs surrounding the current population of patients with asthma. PMID- 29530840 TI - Evolution of Electronic Cigarette Brands From 2013-2014 to 2016-2017: Analysis of Brand Websites. AB - BACKGROUND: The electronic cigarette (e-cigarette) industry has grown in size and organizational complexity in recent years, most notably with the entry of major tobacco companies in 2012 and the proliferation of vape shops. Many brands maintain retail websites that present e-cigarette marketing claims and sell directly to consumers. Understanding of the evolving composition of different types of e-cigarette brand websites is currently underdeveloped. OBJECTIVE: This paper presents how e-cigarette brand websites surveyed in 2013-2014 evolved by 2016-2017, and how the websites run by different types of e-cigarette producers currently differ. METHODS: In 2016-2017, we revisited 466 e-cigarette brand websites surveyed in 2013-2014, 288 of which were extant, and identified 145 new English-language websites. We compared product designs, marketing claims, and age based warnings presented by types of e-cigarette producers: major tobacco companies, independent vape shops, and independent internet-only companies. RESULTS: Among the 433 websites examined in 2016-2017, 12 were owned by major tobacco companies, 162 operated a physical vape shop, and 259 were internet-only operations. Closed-system product designs were sold by 83% (10/12) of tobacco owned brands. In comparison, 29.0% (47/162, P<.001) of vape shop and 55.2% (143/259, P=.06) of internet-only brands sold closed-system designs. Compared with vape shop and internet-only brands, tobacco-owned brands offered a smaller set of product models (P values <.001) and a narrower range of flavors (P values <.01), with greater emphasis on the traditional combustible cigarette flavors of tobacco and menthol (P values <.001). Tobacco-owned brands also offered a narrower range of nicotine options than the vape shops (P=.002) and were less likely to offer nicotine-free e-liquid compared with internet-only and vape shop brands (P values <.001). Finally, 83% (10/12) of tobacco-owned brand websites featured age verification pop-up windows. In comparison, only 50.2% (130/259) of internet-only brands (P=.01) and 60.5% (98/162) of vape shop brands (P=.06) featured age verification windows. Websites surveyed in both 2013-2014 and 2016 2017 became more likely to sell open-system mods (P<.001) and sold an increased number of product models (P<.001), flavors (P<.001), and nicotine options (P<.001). Prevalence of several types of claims decreased significantly, including indirect claims regarding smoking cessation (P<.001), claims regarding e-cigarettes as healthier (P<.001), less expensive (P<.001), and usable in more places (P<.001) compared with combustible cigarettes. CONCLUSIONS: The number of e-cigarette brands has not appeared to increase since 2014, even as website messaging evolved, with brands owned by tobacco companies and vape shops pulling in opposite directions. Brands owned by tobacco companies offered a limited range of e-cigarette products, whereas brands owned by vape shops emphasized a panoply of flavor and nicotine options. Furthermore, the Food and Drug Administration's regulatory action may influence the types of e-cigarette products offered and the market shares of various companies. PMID- 29530841 TI - TLR7 Agonists Display Potent Antiviral Effects against Norovirus Infection via Innate Stimulation. AB - Norovirus infections are a significant health and economic burden globally, accounting for hundreds of millions of cases of acute gastroenteritis every year. In the absence of an approved norovirus vaccine, there is an urgent need to develop antivirals to treat chronic infections and provide prophylactic therapy to limit viral spread during epidemics and pandemics. Toll-like receptor (TLR) agonists have been explored widely for their antiviral potential, and several are progressing through clinical trials for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and as adjuvants for norovirus viruslike particle (VLP) vaccines. However, norovirus therapies in development are largely direct-acting antivirals (DAAs) with fewer compounds that target the host. Our aim was to assess the antiviral potential of TLR7 agonist immunomodulators on norovirus infection using the murine norovirus (MNV) and human Norwalk replicon models. TLR7 agonists R-848, Gardiquimod, GS-9620, R-837, and loxoribine were screened using a plaque reduction assay, and each displayed inhibition of MNV replication (50% effective concentrations [EC50s], 23.5 nM, 134.4 nM, 0.59 MUM, 1.5 MUM, and 79.4 MUM, respectively). RNA sequencing of TLR7-stimulated cells revealed a predominant upregulation of innate immune response genes and interferon (IFN)-stimulated genes (ISGs) that are known to drive an antiviral state. Furthermore, the combination of R-848 and the nucleoside analogue (NA) 2'C methylcytidine elicited a synergistic antiviral effect against MNV, demonstrating that combinational therapy of host modulators and DAAs might be used to reduce drug cytotoxicity. In summary, we have identified that TLR7 agonists display potent inhibition of norovirus replication and are a therapeutic option to combat norovirus infections. PMID- 29530842 TI - Evaluation of Ceftolozane-Tazobactam in Combination with Meropenem against Pseudomonas aeruginosa Sequence Type 175 in a Hollow-Fiber Infection Model. AB - The aim of this study was to investigate the efficacy of ceftolozane-tazobactam in combination with meropenem against an extensively drug-resistant (XDR) Pseudomonas aeruginosa high-risk clone, sequence type 175, isolated in a Spanish university hospital. A 14-day hollow-fiber infection model was used to simulate clinical exposure of the two drug regimens alone and in combination, and serial samples were collected to determine drug concentrations and CFU counts. The untreated control failed, as did each study regimen when administered alone. However, when ceftolozane-tazobactam was administered in combination with meropenem, there was a >4-log10 CFU/ml bacterial density reduction and suppression of resistance for the duration of the study. These data suggest that ceftolozane-tazobactam plus meropenem may be a useful combination for treating XDR P. aeruginosa. PMID- 29530843 TI - Combination of Tedizolid and Daptomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for health care-associated infections, and treatment options are limited. Tedizolid (TZD) is a novel oxazolidinone antibiotic with activity against MRSA. Previously, daptomycin (DAP) has demonstrated synergy with other antibiotics against MRSA. We sought to determine the efficacy of the combination of TZD and DAP against MRSA in an in vitro model of simulated endocardial vegetations (SEVs). TZD simulations of 200 mg once daily and DAP simulations of 6 mg/kg of body weight and 10 mg/kg once daily were tested alone and in the combinations TZD plus DAP at 6 mg/kg or DAP at 10 mg/kg against two clinical strains of MRSA, 494 and 67. These regimens were tested in SEV models over 8 days to determine the antibacterial activity of the regimens and whether synergy or antagonism might be present between the agents. Against both strains 494 and 67 and at both DAP dose regimens, the combination of TZD and DAP was antagonistic at 192 h. In all cases, DAP alone was statistically superior to DAP plus TZD. When the combination was stopped after 96 h, transitioning to DAP at 6 mg/kg or DAP at 10 mg/kg alone resulted in better antibacterial activity than either of the TZD plus-DAP combinations, further demonstrating antagonistic effects. Against MRSA, we demonstrated that TZD and DAP have antagonistic activity that hinders their overall antimicrobial efficacy. The exact nature of this antagonistic relationship is still undetermined, but its presence warrants further study of the potentially harmful grouping of the two antibiotics in clinical use. PMID- 29530844 TI - Potent Activities of Luliconazole, Lanoconazole, and Eight Comparators against Molecularly Characterized Fusarium Species. AB - A collection of clinical (n = 47) and environmental (n = 79) Fusarium isolates were tested against 10 antifungal drugs, including 2 novel imidazoles. Luliconazole and lanoconazole demonstrated very low geometric mean MIC values of 0.005 and 0.013 MUg/ml, respectively, compared with 0.51 MUg/ml for micafungin, 0.85 MUg/ml for efinaconazole, 1.12 MUg/ml for natamycin, 1.18 MUg/ml for anidulafungin, 1.31 MUg/ml for voriconazole, 1.35 MUg/ml for caspofungin, 1.9 MUg/ml for amphotericin B, and 4.08 MUg/ml for itraconazole. Results show that these drugs are potential candidates for (topical) treatment of skin and nail infections due to Fusarium species. PMID- 29530845 TI - Association of Vancomycin MIC and Molecular Characteristics with Clinical Outcomes in Methicillin-Susceptible Staphylococcus aureus Acute Hematogenous Osteoarticular Infections in Children. AB - Strains of methicillin-resistant Staphylococcus aureus (MRSA), particularly those belonging to the USA300 pulsotype, have been well described to cause severe osteoarticular infections (OAIs). A vancomycin MIC of >=1.5 MUg/ml has been demonstrated to contribute to disease severity in adults with MRSA and even methicillin-susceptible S. aureus (MSSA) bacteremia. Little data exist describing the outcomes of MSSA OAIs in terms of molecular characteristics and vancomycin MIC. All patients/isolates were chosen from a surveillance study at Texas Children's Hospital (TCH). S. aureus OAI isolates were identified from 2011 to 2016 and subjected to vancomycin Etests, pulsed-field gel electrophoresis (PFGE), and PCR to determine Panton-Valentine leucocidin (PVL) production and agr group. Two hundred fifty-two cases of S. aureus OAI were identified; 183 cases were MSSA (72.6%). During the study period, a decrease in the proportion of cases secondary to MRSA was observed, declining from 37.8% to 15.9% (P = 0.02). Of the MSSA isolates, 26.2% and 23.5% were USA300 and PVL positive, respectively. An increase in the proportion of MSSA isolates with a vancomycin MIC of >=1.5 MUg/ml occurred in the study period (P = 0.004). In MSSA, an elevated vancomycin MIC was associated with multiple surgical procedures and venous thromboses, even when adjusting for empirical beta-lactam use. An increase in vancomycin MIC was noted among isolates belonging to agr group 4 during the study period. Methicillin resistance is declining among S. aureus OAI isolates at TCH. Simultaneously, vancomycin Etest MICs are increasing among MSSA isolates. Vancomycin MICs of >=2 MUg/ml are associated with adverse clinical outcomes in MSSA irrespective of antibiotic choice, suggesting that this may be a surrogate for organism virulence. PMID- 29530846 TI - Micafungin Breakthrough Fungemia in Patients with Hematological Disorders. AB - Limited data are available on micafungin breakthrough fungemia (MBF), fungemia that develops on administration of micafungin, in patients with hematological disorders. We reviewed medical and microbiological records of patients with hematological disorders who developed MBF between January 2008 and June 2015. A total of 39 patients with MBF were identified, and Candida (30 strains) and non Candida (9 strains) fungal species were recognized as causative strains. Among 35 stored strains, Candida parapsilosis (14 strains), Trichosporon asahii (7 strains), Candida glabrata (5 strains), and other fungal species (9 strains) were identified by sequencing. Neutropenia was identified as an independent predictor of non-Candida fungemia (P = 0.023). T. asahii was the most common causative strain (7/19) during neutropenia. The 14-day crude mortality rate of patients treated with early micafungin change (EMC) to other antifungal agents was lower than that of the patients not treated with EMC (14% versus 43%, P = 0.044). Most of the stored causative Candida strains were susceptible (80%) or showed wild type susceptibility (72%) to micafungin. The MICs of voriconazole for T. asahii were low (range, 0.015 to 0.12 MUg/ml), whereas the MICs of amphotericin B for T. asahii were high (range, 2 to 4 MUg/ml). MBF caused by non-Candida fungus should be considered, especially in patients with neutropenia. EMC could improve early mortality. Based on epidemiology and drug susceptibility profiling, empirical voriconazole-containing therapy might be suitable for treating MBF during neutropenia to cover for T. asahii. PMID- 29530847 TI - Increasing Resistance to Azithromycin in Neisseria gonorrhoeae in Eastern Chinese Cities: Resistance Mechanisms and Genetic Diversity among Isolates from Nanjing. AB - Azithromycin resistance (AZM-R) of Neisseria gonorrhoeae is emerging as a clinical and public health challenge. We determined molecular characteristics of recent AZM-R Nanjing gonococcal isolates and tracked the emergence of AZM-R isolates in eastern Chinese cities in recent years. A total of 384 N. gonorrhoeae isolates from Nanjing collected from 2013 to 2014 were tested for susceptibility to AZM and six additional antibiotics; all AZM-R strains were characterized genetically for resistance determinants by sequencing and were genotyped using N. gonorrhoeae multiantigen sequence typing (NG-MAST). Among the 384 isolates, 124 (32.3%) were AZM-R. High-level resistance (MIC, >=256 mg/liter) was present in 10.4% (40/384) of isolates, all of which possessed the A2143G mutation in all four 23S rRNA alleles. Low- to mid-level resistance (MIC, 1 to 64 mg/liter) was present in 21.9% (84/384) of isolates, 59.5% of which possessed the C2599T mutation in all four 23S rRNA alleles. The 124 AZM-R isolates were distributed in 71 different NG-MAST sequence types (STs). ST1866 was the most prevalent type in high-level AZM-R (HL-AZM-R) isolates (45% [18/40]). This study, together with previous reports, revealed that the prevalence of AZM-R in N. gonorrhoeae isolates in certain eastern Chinese cities has risen >4-fold (7% to 32%) from 2008 to 2014. The principal mechanisms of AZM resistance in recent Nanjing isolates were A2143G mutations (high-level resistance) and C2599T mutations (low- to mid-level resistance) in the 23S rRNA alleles. Characterization of NG-MAST STs and phylogenetic analysis indicated the genetic diversity of N. gonorrhoeae in Nanjing; however, ST1866 was the dominant genotype associated with HL-AZM-R isolates. PMID- 29530848 TI - Population Pharmacokinetics of Meropenem in Plasma and Subcutis from Patients on Extracorporeal Membrane Oxygenation Treatment. AB - The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) treatment and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 h. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed using NONMEM. Time above clinical breakpoint MIC for Pseudomonas aeruginosa (8 mg/liter) was predicted for each patient. The following targets were evaluated: time for which the free (unbound) concentration is maintained above the MIC of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4*MIC. For all dosing regimens simulated in both plasma and SCT, 40% fT>MIC was attained. However, prolonged meropenem infusion would be needed for 100% fT>MIC and 100% fT>4*MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCLCr). Simulations showed that in patients with increased eCLCr, dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40% fT>MIC for standard meropenem dosing of 1 g intravenously every 8 h is likely to provide sufficient meropenem concentration to treat the problematic pathogen P. aeruginosa for patients receiving ECMO treatment. However, for patients with an increased eCLCr, or if more aggressive targets, like 100% fT>MIC or 100% fT>4*MIC, are adopted, incremental dosing or continuous infusion may be needed. PMID- 29530850 TI - Posaconazole-Induced Pseudohyperaldosteronism. AB - A woman in her late 60s with disseminated histoplasmosis was treated with posaconazole because first-line therapies were not tolerated. She subsequently presented with decompensated heart failure, hypertension, and hypokalemia. Laboratory tests revealed low renin and aldosterone levels. A potential mechanism is inhibition of the enzyme 11beta-hydroxysteroid dehydrogenase 2, with resultant apparent mineralocorticoid excess. PMID- 29530849 TI - Imidazolopiperazines Kill both Rings and Dormant Rings in Wild-Type and K13 Artemisinin-Resistant Plasmodium falciparum In Vitro. AB - Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART resistance has been associated with mutations in the Plasmodium falciparum kelch-13 (Pfk13) propeller domain. Phenotypically, ART resistance is defined as delayed parasite clearance in patients due to the reduced susceptibility of early ring-stage parasites to the active metabolite of ART dihydroartemisinin (DHA). Early rings can enter a state of quiescence upon DHA exposure and resume growth in its absence. These quiescent rings are referred to as dormant rings or DHA-pretreated rings (here called dormant rings). The imidazolopiperazines (IPZ) are a novel class of antimalarial drugs that have demonstrated efficacy in early clinical trials. Here, we characterized the stage of action of the IPZ GNF179 and evaluated its activity against rings and dormant rings in wild-type and ART-resistant parasites. Unlike DHA, GNF179 does not induce dormancy. We show that GNF179 is more rapidly cidal against schizonts than against ring and trophozoite stages. However, with 12 h of exposure, the compound effectively kills rings and dormant rings of both susceptible and ART-resistant parasites within 72 h. We further demonstrate that in combination with ART, GNF179 effectively prevents recrudescence of dormant rings, including those bearing pfk13 propeller mutations. PMID- 29530851 TI - Inactivation of the Pseudomonas-Derived Cephalosporinase-3 (PDC-3) by Relebactam. AB - Pseudomonas aeruginosa is a prevalent and life-threatening Gram-negative pathogen. Pseudomonas-derived cephlosporinase (PDC) is the major inducible cephalosporinase in P. aeruginosa In this investigation, we show that relebactam, a diazabicyclooctane beta-lactamase inhibitor, potently inactivates PDC-3, with a k2/K of 41,400 M-1 s-1 and a koff of 0.00095 s-1 Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant P. aeruginosa clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone. Relebactam promises to increase the efficacy of imipenem-cilastatin against P. aeruginosa. PMID- 29530852 TI - Constitutive Activation of MexT by Amino Acid Substitutions Results in MexEF-OprN Overproduction in Clinical Isolates of Pseudomonas aeruginosa. AB - When overproduced, the multidrug efflux system MexEF-OprN increases the resistance of Pseudomonas aeruginosa to fluoroquinolones, chloramphenicol, and trimethoprim. In this work, we demonstrate that gain-of-function mutations in the regulatory gene mexT result in oligomerization of the LysR regulator MexT, constitutive upregulation of the efflux pump, and increased resistance in clinical isolates. PMID- 29530853 TI - Tapering Courses of Oral Vancomycin Induce Persistent Disruption of the Microbiota That Provide Colonization Resistance to Clostridium difficile and Vancomycin-Resistant Enterococci in Mice. AB - Vancomycin taper regimens are commonly used for the treatment of recurrent Clostridium difficile infections. One rationale for tapering and pulsing of the dose at the end of therapy is to reduce the selective pressure of vancomycin on the indigenous intestinal microbiota. Here, we used a mouse model to test the hypothesis that the indigenous microbiota that provide colonization resistance against C. difficile and vancomycin-resistant enterococci (VRE) is repopulated during tapering courses of vancomycin. Mice were treated orally with vancomycin daily for 10 days, vancomycin in a tapering dose for 42 days, fidaxomicin for 10 days, or saline. To assess colonization resistance, subsets of mice were challenged with 104 CFU of C. difficile or VRE at multiple time points during and after completion of treatment. The impact of the treatments on the microbiome was measured by cultures, real-time PCR for selected anaerobic bacteria, and deep sequencing. Vancomycin taper-treated mice developed alterations of the microbiota and disruption of colonization resistance that was persistent 18 days after treatment. In contrast, mice treated with a 10-day course of vancomycin exhibited recovery of the microbiota and of colonization resistance by 15 days after treatment, and fidaxomicin-treated mice maintained intact colonization resistance. These findings demonstrate that alteration of the indigenous microbiota responsible for colonization resistance to C. difficile and VRE persist during and after completion of tapering courses of vancomycin. PMID- 29530854 TI - Clinical and Genetic Risk Factors for Biofilm-Forming Staphylococcus aureus. AB - The molecular and clinical factors associated with biofilm-forming methicillin resistant Staphylococcus aureus (MRSA) are incompletely understood. Biofilm production for 182 MRSA isolates obtained from clinical culture sites (2004 to 2013) was quantified. Microbiological toxins, pigmentation, and genotypes were evaluated, and patient demographics were collected. Logistic regression was used to quantify the effect of strong biofilm production (versus weak biofilm production) on clinical outcomes and independent predictors of a strong biofilm. Of the isolates evaluated, 25.8% (47/182) produced strong biofilms and 40.7% (74/182) produced weak biofilms. Strong biofilm-producing isolates were more likely to be from multilocus sequence typing (MLST) clonal complex 8 (CC8) (34.0% versus 14.9%; P = 0.01) but less likely to be from MLST CC5 (48.9% versus 73.0%; P = 0.007). Predictors for strong biofilms were spa type t008 (adjusted odds ratio [aOR], 4.54; 95% confidence interval [CI], 1.21 to 17.1) and receipt of chemotherapy or immunosuppressants in the previous 90 days (aOR, 33.6; 95% CI, 1.68 to 673). Conversely, patients with high serum creatinine concentrations (aOR, 0.33; 95% CI, 0.15 to 0.72) or who previously received vancomycin (aOR, 0.03; 95% CI, 0.002 to 0.39) were less likely to harbor strong biofilm-producing MRSA. Beta-toxin-producing isolates (aOR, 0.31; 95% CI, 0.11 to 0.89) and isolates with spa type t895 (aOR, 0.02 95% CI, <0.001 to 0.47) were less likely to produce strong biofilms. Patient outcomes also varied between the two groups. Specifically, patients with strong biofilm-forming MRSA were significantly more likely to be readmitted within 90 days (aOR, 5.43; 95% CI, 1.69 to 17.4) but tended to have decreased 90-day mortality (aOR, 0.36; 95% CI, 0.12 to 1.06). Patients that harbored t008 and received immunosuppressants were more likely to have strong biofilm-producing MRSA isolates. Clinically, patients with strong biofilm-forming MRSA were less likely to die at 90 days but five times more likely to be readmitted. PMID- 29530855 TI - Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy. AB - Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 +/- 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 +/- 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 +/- 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.). PMID- 29530856 TI - In Vitro Antifungal Activity of Novel Triazole Efinaconazole and Five Comparators against Dermatophyte Isolates. AB - The objective of this study was to assess the in vitro activity of the novel triazole antifungal drug, efinaconazole, and five comparators (luliconazole, lanoconazole, terbinafine, itraconazole, and fluconazole) against a large collection of Trichophyton interdigitale and Trichophyton rubrum clinical isolates. The geometric mean MICs were the lowest for luliconazole (0.0005 MUg/ml), followed by lanoconazole (0.002 MUg/ml), efinaconazole (0.007 MUg/ml), terbinafine (0.011 MUg/ml), itraconazole (0.095 MUg/ml), and fluconazole (12.77 MUg/ml). It appears that efinaconazole, lanoconazole, and luliconazole are promising candidates for the treatment of dermatophytosis due to T. interdigitale and T. rubrum. PMID- 29530857 TI - Mutation in the Squalene Epoxidase Gene of Trichophyton interdigitale and Trichophyton rubrum Associated with Allylamine Resistance. AB - Dermatophytosis, the commonest superficial fungal infection, has gained recent attention due to its change of epidemiology and treatment failures. Despite the availability of several agents effective against dermatophytes, the incidences of chronic infection, reinfection, and treatment failures are on the rise. Trichophyton rubrum and Trichophyton interdigitale are the two species most frequently identified among clinical isolates in India. Consecutive patients (n = 195) with suspected dermatophytosis during the second half of 2014 were included in this study. Patients were categorized into relapse and new cases according to standard definitions. Antifungal susceptibility testing of the isolated Trichophyton species (n = 127) was carried out with 12 antifungal agents: fluconazole, voriconazole, itraconazole, ketoconazole, sertaconazole, clotrimazole, terbinafine, naftifine, amorolfine, ciclopirox olamine, griseofulvin, and luliconazole. The squalene epoxidase gene was evaluated for mutation (if any) in 15 T. interdigitale and 5 T. rubrum isolates exhibiting high MICs for terbinafine. A T1189C mutation was observed in four T. interdigitale and two T. rubrum isolates. This transition leads to the change of phenylalanine to leucine in the 397th position of the squalene epoxidase enzyme. In homology modeling the mutant residue was smaller than the wild type and positioned in the dominant site of squalene epoxidase during drug interaction, which may lead to a failure to block the ergosterol biosynthesis pathway by the antifungal drug. PMID- 29530858 TI - A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study). AB - Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a >=20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, -5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier NCT02607618.). PMID- 29530859 TI - Bacterial Adaptation to Antibiotics through Regulatory RNAs. AB - The extensive use of antibiotics has resulted in a situation where multidrug resistant pathogens have become a severe menace to human health worldwide. A deeper understanding of the principles used by pathogens to adapt to, respond to, and resist antibiotics would pave the road to the discovery of drugs with novel mechanisms. For bacteria, antibiotics represent clinically relevant stresses that induce protective responses. The recent implication of regulatory RNAs (small RNAs [sRNAs]) in antibiotic response and resistance in several bacterial pathogens suggests that they should be considered innovative drug targets. This minireview discusses sRNA-mediated mechanisms exploited by bacterial pathogens to fight against antibiotics. A critical discussion of the newest findings in the field is provided, with emphasis on the implication of sRNAs in major mechanisms leading to antibiotic resistance, including drug uptake, active drug efflux, drug target modifications, biofilms, cell walls, and lipopolysaccharide (LPS) biosynthesis. Of interest is the lack of knowledge about sRNAs implicated in Gram positive compared to Gram-negative bacterial resistance. PMID- 29530860 TI - Selection and Characterization of Rupintrivir-Resistant Norwalk Virus Replicon Cells In Vitro. AB - Human norovirus (HuNoV) is a major cause of nonbacterial gastroenteritis worldwide, yet despite its impact on society, vaccines and antivirals are currently lacking. A HuNoV replicon system has been widely applied to the evaluation of antiviral compounds and has thus accelerated the process of drug discovery against HuNoV infection. Rupintrivir, an irreversible inhibitor of the human rhinovirus 3C protease, has been reported to inhibit the replication of the Norwalk virus replicon via the inhibition of the norovirus protease. Here we report, for the first time, the generation of rupintrivir-resistant human Norwalk virus replicon cells in vitro Sequence analysis revealed that these replicon cells contained amino acid substitutions of alanine 105 to valine (A105V) and isoleucine 109 to valine (I109V) in the viral protease NS6. The application of a cell-based fluorescence resonance energy transfer (FRET) assay for protease activity demonstrated that these substitutions were involved in the enhanced resistance to rupintrivir. Furthermore, we validated the effect of these mutations using reverse genetics in murine norovirus (MNV), demonstrating that a recombinant MNV strain with a single I109V substitution in the protease also showed reduced susceptibility to rupintrivir. In summary, using a combination of different approaches, we have demonstrated that, under the correct conditions, mutations in the norovirus protease that lead to the generation of resistant mutants can rapidly occur. PMID- 29530861 TI - Discovery of a Novel Metallo-beta-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae. AB - Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of beta-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine beta-lactamases (SBLs; e.g., KPC-2 and OXA-48) and metallo-beta-lactamases (MBLs), such as NDM-1. MBL producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of beta-lactam antibiotics with beta-lactamase inhibitors are active only against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL producing CRE pathogens are urgently needed. Here we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of meropenem (MEM) against a broad range of MBL-producing CRE and restore its efficacy against an Escherichia coli NDM-1-producing strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor-carbapenem combination. This would complement the existing weaponry against CRE and address an important and growing unmet medical need. PMID- 29530863 TI - In Vitro Activity of Lefamulin against Sexually Transmitted Bacterial Pathogens. AB - The pleuromutilin antibiotic lefamulin demonstrated in vitro activity against the most relevant bacterial pathogens causing sexually transmitted infections (STI), including Chlamydia trachomatis (MIC50/90, 0.02/0.04 mg/liter; n = 15), susceptible and multidrug-resistant Mycoplasma genitalium (MIC range, 0.002 to 0.063 mg/liter; n = 6), and susceptible and resistant Neisseria gonorrhoeae (MIC50/90, 0.12/0.5 mg/liter; n = 25). The results suggest that lefamulin could be a promising first-line antibiotic for the treatment of STI, particularly in populations with high rates of resistance to standard-of-care antibiotics. PMID- 29530862 TI - Heavy Metal Susceptibility of Escherichia coli Isolated from Urine Samples from Sweden, Germany, and Spain. AB - Antimicrobial resistance is a major health care problem, with the intensive use of heavy metals and biocides recently identified as a potential factor contributing to the aggravation of this situation. The present study investigated heavy metal susceptibility and genetic resistance determinants in Escherichia coli isolated from clinical urine samples from Sweden, Germany, and Spain. A total of 186 isolates were tested for their sodium arsenite, silver nitrate, and copper(II) sulfate MICs. In addition, 88 of these isolates were subjected to whole-genome sequencing for characterization of their genetic resistance determinants and epidemiology. For sodium arsenite, the isolates could be categorized into a resistant and a nonresistant group based on MIC values. Isolates of the resistant group exhibited the chromosomal ars operon and belonged to non-B2 phylogenetic groups; in contrast, within the B2 phylogroup, no ars operon was found, and the isolates were susceptible to sodium arsenite. Two isolates also harbored the silver/copper resistance determinant pco/sil, and they belonged to sequence types ST10 (phylogroup A) and ST295 (phylogroup C). The ST295 isolate had a silver nitrate MIC of >=512 mg/liter and additionally produced extended-spectrum beta-lactamases. To our knowledge, this is the first study to describe the distribution of the arsenic resistance ars operon within phylogroups of E. coli strains isolated from patients with urinary tract infections. The arsenic resistance ars operon was present only in all non-B2 clades, which have previously been associated with the environment and commensalism in both humans and animals, while B2 clades lacked the ars operon. PMID- 29530864 TI - Substrate Selectivity Check of the Ergothioneine Transporter. AB - The candidate vitamin ergothioneine (ET) is a unique antioxidant. Expression of the ET transporter (ETT) (gene symbol SLC22A4) in distinct cells is thought to signal intracellular ET activity, since we have previously shown that the ETT is highly selective for ET. Unfortunately, some continue to hold the ETT as a relevant drug transporter, using the misleading functional name OCTN1, novel organic cation transporter. The present study was provoked by two recent reports in which new ETT substrates were declared. Astonishingly, the transport efficiencies (TEs) of ETT for saracatinib and some nucleoside drugs were as high as the TE for ET. Here we examined, based on regulated expression of ETT from human and rat in 293 cells and liquid chromatography-mass spectrometry quantification, the transport of several drugs. With the nucleosides cytarabine, gemcitabine, 2'-deoxycytidine, and 2'-deoxyadenosine, and the drugs saracatinib, ipratropium, metformin, and oxaliplatin, the uptake into cells expressing ETT was not increased over control cells. ETT-mediated uptake of gabapentin was detectable, but the TE was approximately 100-fold lower than the TE for ergothioneine (50-200 ul/min per milligram of protein). In conclusion, the ETT remains highly specific for its physiologic substrate ergothioneine. Our results contradict several reports on additional substrates. The ETT does not provide multiple substrate specificities, and it is not a transporter of cationic drugs. Only compounds that are related to ET in substructure-for example, gabapentin, carnitine, and TEA-can be transported, but with very low efficiency. Thus, ETT persists as a specific molecular indicator of ET activity. PMID- 29530866 TI - New Insights into Genomics of Pediatric Cancers. AB - Two large studies show that the genetic events driving pediatric cancers are different from those underlying adult cancers. These findings may prove useful for identifying new treatments for childhood cancers, as well as for developing tests to aid in diagnosis and the selection of therapy. PMID- 29530865 TI - Identification of Structural and Molecular Features Involved in the Transport of 3'-Deoxy-Nucleoside Analogs by Human Equilibrative Nucleoside Transporter 3. AB - Combination antiretroviral drug treatments depend on 3'-deoxy-nucleoside analogs such as 3'-azido-3'-deoxythymidine (AZT) and 2'3'-dideoxyinosine (DDI). Despite being effective in inhibiting human immunodeficiency virus replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy, and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. Although cell surface-localized nucleoside transporters, such as human equilibrative nucleoside transporter 2 (hENT2) and human concentrative nucleoside transporter 1 (hCNT1), are known to increase the carrier mediated uptake of 3'-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter (namely, hENT3) has been implicated in the mitochondrial transport of 3'-deoxy-nucleoside analogs. Using site-directed mutagenesis, generation of chimeric hENTs, and 3H-permeant flux measurements in mutant/chimeric RNA-injected Xenopus oocytes, here we identified the molecular determinants of hENT3 that dictate membrane translocation of 3' deoxy-nucleoside analogs. Our findings demonstrated that whereas hENT1 had no significant transport activity toward 3'-deoxy-nucleoside analogs, hENT3 was capable of transporting 3'-deoxy-nucleoside analogs similar to hENT2. Transport analyses of hENT3-hENT1 chimeric constructs demonstrated that the N-terminal half of hENT3 is primarily responsible for the hENT3-3'-deoxy-nucleoside analog interaction. In addition, mutagenic studies identified that 225D and 231L in the N-terminal half of hENT3 partially contribute to the ability of hENT3 to transport AZT and DDI. The identification of the transporter segment and amino acid residues that are important in hENT3 transport of 3'-deoxy-nucleoside analogs may present a possible mechanism for overcoming the adverse toxicities associated with 3'-deoxy-nucleoside analog treatment and may guide rational development of novel nucleoside analogs. PMID- 29530867 TI - Health in correctional facilities is health in our communities. PMID- 29530868 TI - The effect of provider affiliation with a primary care network on emergency department visits and hospital admissions. AB - BACKGROUND: Primary care networks are designed to facilitate access to inter professional, team-based care. We compared health outcomes associated with primary care networks versus conventional primary care. METHODS: We obtained data on all adult residents of Alberta who visited a primary care physician during fiscal years 2008 and 2009 and classified them as affiliated with a primary care network or not, based on the physician most involved in their care. The primary outcome was an emergency department visit or nonelective hospital admission for a Patient Medical Home indicator condition (asthma, chronic obstructive pulmonary disease, heart failure, coronary disease, hypertension and diabetes) within 12 months. RESULTS: Adults receiving care within a primary care network (n = 1 502 916) were older and had higher comorbidity burdens than those receiving conventional primary care (n = 1 109 941). Patients in a primary care network were less likely to visit the emergency department for an indicator condition (1.4% v. 1.7%, mean 0.031 v. 0.035 per patient, adjusted risk ratio [RR] 0.98, 95% confidence interval [CI] 0.96-0.99) or for any cause (25.5% v. 30.5%, mean 0.55 v. 0.72 per patient, adjusted RR 0.93, 95% CI 0.93-0.94), but were more likely to be admitted to hospital for an indicator condition (0.6% v. 0.6%, mean 0.018 v. 0.017 per patient, adjusted RR 1.07, 95% CI 1.03-1.11) or all-cause (9.3% v. 9.1%, mean 0.25 v. 0.23 per patient, adjusted RR 1.08, 95% CI 1.07 1.09). Patients in a primary care network had 169 fewer all-cause emergency department visits and 86 fewer days in hospital (owing to shorter lengths of stay) per 1000 patient-years. INTERPRETATION: Care within a primary care network was associated with fewer emergency department visits and fewer hospital days. PMID- 29530869 TI - Risk of stroke in patients with dengue fever: a population-based cohort study. AB - BACKGROUND: Stroke is a severe neurologic complication of dengue fever, described in only a few case reports. The incidence and risk factors for stroke in patients with dengue remain unclear. We conducted a population-based retrospective cohort study to investigate the risk of stroke in patients with dengue. METHODS: Using data from the Taiwan National Health Insurance Research Database, we included a total of 13 787 patients with dengue newly diagnosed between 2000 and 2012. The control cohort consisted of patients who did not have dengue, matched 1:1 by demographic characteristics and stroke-related comorbidities. We calculated the cumulative incidences and hazard ratios (HRs) of stroke in both cohorts using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: The overall incidence rate of stroke was 5.33 per 1000 person-years in the dengue cohort and 3.72 per 1000 person-years in the control cohort, with an adjusted HR of 1.16 (95% confidence interval [CI] 1.01-1.32). The risk of stroke among patients with dengue was highest in the first 2 months after diagnosis (25.53 per 1000 person years, adjusted HR 2.49, 95% CI 1.48-4.18). INTERPRETATION: Dengue fever was associated with an increased risk of stroke in the first few months after diagnosis. The effect of dengue on stroke may be acute rather than chronic. PMID- 29530870 TI - Evaluation of the patient with pleural effusion. PMID- 29530871 TI - Medication-overuse headache. PMID- 29530872 TI - Chronic actinic dermatitis. PMID- 29530873 TI - The 2017 Canadian opioid guideline: already time for an overhaul. PMID- 29530875 TI - Do physicians have a duty to share their views on social media? PMID- 29530874 TI - The authors respond to "The 2017 Canadian opioid guideline: already time for an overhaul". PMID- 29530876 TI - Canada isn't making the most of DIY tests for HPV. PMID- 29530877 TI - Online ratings for doctors are flawed, but "not going anywhere". PMID- 29530878 TI - Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program. AB - A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions. PMID- 29530879 TI - Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney. AB - The development of the kidney relies on the establishment and maintenance of a precise tubular diameter of its functional units, the nephrons. This process is disrupted in polycystic kidney disease (PKD), resulting in dilations of the nephron and renal cyst formation. In the course of exploring G-protein-coupled signaling in the Xenopus pronephric kidney, we discovered that loss of the G protein alpha subunit, Gnas, results in a PKD phenotype. Polycystin 1, one of the genes mutated in human PKD, encodes a protein resembling a G-protein-coupled receptor. Furthermore, deletion of the G-protein-binding domain present in the intracellular C terminus of polycystin 1 impacts functionality. A comprehensive analysis of all the G-protein alpha subunits expressed in the Xenopus pronephric kidney demonstrates that polycystin 1 recruits a select subset of G-protein alpha subunits and that their knockdown - as in the case of Gnas - results in a PKD phenotype. Mechanistically, the phenotype is caused by increased endogenous G protein beta/gamma signaling and can be reversed by pharmacological inhibitors as well as knocking down Gnb1. Together, our data support the hypothesis that G proteins are recruited to the intracellular domain of PKD1 and that this interaction is crucial for its function in the kidney. PMID- 29530882 TI - Margaret McCartney: Cancer patients should not be shamed. PMID- 29530880 TI - Polycomb group (PcG) proteins and Pax6 cooperate to inhibit in vivo reprogramming of the developing Drosophila eye. AB - How different cells and tissues commit to and determine their fates has been a central question in developmental biology since the seminal embryological experiments conducted by Wilhelm Roux and Hans Driesch in sea urchins and frogs. Here, we demonstrate that Polycomb group (PcG) proteins maintain Drosophila eye specification by suppressing the activation of alternative fate choices. The loss of PcG in the developing eye results in a cellular reprogramming event in which the eye is redirected to a wing fate. This fate transformation occurs with either the individual loss of Polycomb proteins or the simultaneous reduction of the Pleiohomeotic repressive complex and Pax6. Interestingly, the requirement for retinal selector genes is limited to Pax6, as the removal of more downstream members does not lead to the eye-wing transformation. We also show that distinct PcG complexes are required during different developmental windows throughout eye formation. These findings build on earlier observations that the eye can be reprogrammed to initiate head epidermis, antennal and leg development. PMID- 29530881 TI - Imprinted gene dysregulation in a Tet1 null mouse model is stochastic and variable in the germline and offspring. AB - Imprinted genes are expressed from one parental allele and regulated by differential DNA methylation at imprinting control regions (ICRs). ICRs are reprogrammed in the germline through erasure and re-establishment of DNA methylation. Although much is known about DNA methylation establishment, DNA demethylation is less well understood. Recently, the Ten-Eleven Translocation proteins (TET1-3) have been shown to initiate DNA demethylation, with Tet1-/- mice exhibiting aberrant levels of imprinted gene expression and ICR methylation. Nevertheless, the role of TET1 in demethylating ICRs in the female germline and in controlling allele-specific expression remains unknown. Here, we examined ICR specific DNA methylation in Tet1-/- germ cells and ascertained whether abnormal ICR methylation impacted imprinted gene expression in F1 hybrid somatic tissues derived from Tet1-/- eggs or sperm. We show that Tet1 deficiency is associated with hypermethylation of a subset of ICRs in germ cells. Moreover, ICRs with defective germline reprogramming exhibit aberrant DNA methylation and biallelic expression of linked imprinted genes in somatic tissues. Thus, we define a discrete set of genomic regions that require TET1 for germline reprogramming and discuss mechanisms for stochastic imprinting defects. PMID- 29530883 TI - Hemodynamic and Echocardiographic Comparison of the Lotus and CoreValve Transcatheter Aortic Valves in Patients With High and Extreme Surgical Risk: An Analysis From the REPRISE III Randomized Controlled Trial. AB - BACKGROUND: Comparative echocardiographic data on transcatheter aortic valve replacement systems from randomized trials are limited. The REPRISE III trial (Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System - Randomized Clinical Evaluation) is a multicenter, randomized comparison of a mechanically expanded (Lotus) versus self expanding (CoreValve) transcatheter aortic valve replacement device. This analysis rigorously assesses Doppler-derived valve hemodynamics and the impact on outcomes at 1 year in patients with extreme/high surgical risk treated with Lotus and CoreValve from REPRISE III. METHODS: REPRISE III includes patients with extreme- and high-risk aortic stenosis. Patients were enrolled at 55 centers. All transthoracic echocardiograms with Doppler were obtained following a standard protocol up to 12 months postimplant and analyzed by a core laboratory. Valve size, mean gradient, aortic valve area, and Doppler velocity index and their impact on clinical outcomes are reported. Additional parameters including paravalvular leak were evaluated using a multiparametric approach. RESULTS: A total of 912 patients were randomly assigned (2:1 ratio; 607 Lotus:305 CoreValve). Median age was 84 years, 51% of the patients were women, and the Society of Thoracic Surgeons score was 6.8+/-4.1. CoreValve demonstrated lower gradients and larger aortic valve area and Doppler velocity index than Lotus at discharge; the difference decreased in subsequent follow-up up to a year (all P<0.01). Lotus had lower rates of paravalvular leak that persisted over time (P<0.05). Similar outcomes were seen when comparing each valve type by size group (small, medium, large). The hemodynamic differences between valves did not translate into worse clinical outcomes. All-cause mortality was not different between the 2 groups in any of the 3 valve sizes. When comparing patients with normal valve gradients (<20 mm Hg, n=780) with those with abnormal gradients (>20 mm Hg, n=48) in the entire patient population, all-cause mortality was not different. This was also not significant when evaluating each valve type separately. Similarly, there were no differences for aortic valve area >1.1 cm2 or <1.1 cm2 and for Doppler velocity index >0.35 or <0.35 (all P=not significant). CONCLUSIONS: Lotus had significantly greater freedom from moderate or severe paravalvular leak and smaller valve area and higher gradients than CoreValve. The hemodynamic differences were not associated with any clinical differences in the composite end point of mortality, disabling stroke, and moderate paravalvular leak or with quality of life at 1 year of follow-up. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02202434. PMID- 29530884 TI - Inflammatory and Cholesterol Risk in the FOURIER Trial. AB - BACKGROUND: In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. It is not known whether the efficacy of evolocumab is modified by baseline inflammatory risk. We explored the efficacy of evolocumab stratified by baseline high-sensitivity C-reactive protein (hsCRP). We also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL-C concentrations. METHODS: Patients (n=27 564) with stable atherosclerotic cardiovascular disease and LDL-C >=70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8-2.5). The effects of evolocumab on the primary end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization, and the key secondary end point of cardiovascular death, myocardial infarction, or stroke were compared across strata of baseline hsCRP (<1, 1-3, and >3 mg/dL). Outcomes were also assessed across values for baseline hsCRP and 1-month LDL-C in the entire trial population. Multivariable models adjusted for variables associated with hsCRP and 1-month LDL-C were evaluated. RESULTS: A total of 7981 (29%) patients had a baseline hsCRP<1 mg/L, 11 177 (41%) had a hsCRP 1 to 3 mg/L, and 8337 (30%) had a hsCRP >3 mg/L. Median (interquartile range) baseline hsCRP was 1.8 (0.9-3.6) mg/L and levels were not altered by evolocumab (change at 48 weeks of -0.2 mg/dL [-1.0 to 0.4] in both treatment arms). In the placebo arm, patients in higher baseline hsCRP categories experienced significantly higher 3-year Kaplan-Meier rates of the primary and key secondary end points: 12.0%, 13.7%, and 18.1% for the primary end point (Ptrend<0.0001) and 7.4%, 9.1%, and 13.2% for the key secondary end point (Ptrend<0.0001) for categories of <1, 1 to 3, and >3 mg/dL, respectively. The relative risk reductions for the primary end point and key secondary end point with evolocumab were consistent across hsCRP strata (P interactions>0.15 for both). In contrast, the absolute risk reductions with evolocumab tended to be greater in patients with higher hsCRP: 1.6%, 1.8%, and 2.6% and 0.8%, 2.0%, and 3.0%, respectively, for the primary and key secondary end points across hsCRP strata. In adjusted analyses of the association between LDL-C and hsCRP levels and cardiovascular risk, both LDL-C and hsCRP were independently associated with the primary outcome (P<0.0001 for each). CONCLUSIONS: LDL-C reduction with evolocumab reduces cardiovascular events across hsCRP strata with greater absolute risk reductions in patients with higher baseline hsCRP. Event rates were lowest in patients with the lowest hsCRP and LDL C. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633. PMID- 29530885 TI - Radiofrequency Ablation of Asymptomatic Brugada Syndrome: Don't Go Burning My Heart. PMID- 29530886 TI - Hyperacute Monocyte Gene Response Patterns Are Associated With Lower Extremity Vein Bypass Graft Failure. AB - BACKGROUND: Despite being the definitive treatment for lower extremity peripheral arterial disease, vein bypass grafts fail in half of all cases. Early repair mechanisms after implantation, governed largely by the immune environment, contribute significantly to long-term outcomes. The current study investigates the early response patterns of circulating monocytes as a determinant of graft outcome. METHODS: In 48 patients undergoing infrainguinal vein bypass grafting, the transcriptomes of circulating monocytes were analyzed preoperatively and at 1, 7, and 28 days post-operation. RESULTS: Dynamic clustering algorithms identified 50 independent gene response patterns. Three clusters (64 genes) were differentially expressed, with a hyperacute response pattern defining those patients with failed versus patent grafts 12 months post-operation. A second independent data set, comprised of 96 patients subjected to major trauma, confirmed the value of these 64 genes in predicting an uncomplicated versus complicated recovery. Causal network analysis identified 8 upstream elements that regulate these mediator genes, and Bayesian analysis with a priori knowledge of the biological interactions was integrated to create a functional network describing the relationships among the regulatory elements and downstream mediator genes. Linear models predicted the removal of either STAT3 (signal transducer and activator of transcription 3) or MYD88 (myeloid differentiation primary response 88) to shift mediator gene expression levels toward those seen in successful grafts. CONCLUSIONS: A novel combination of dynamic gene clustering, linear models, and Bayesian network analysis has identified a core set of regulatory genes whose manipulations could migrate vein grafts toward a more favorable remodeling phenotype. PMID- 29530887 TI - Association Between 30-Day Episode Payments and Acute Myocardial Infarction Outcomes Among Medicare Beneficiaries. AB - BACKGROUND: Recent policy efforts have focused on improving the value of acute myocardial infarction (AMI) care. Medicare payment programs, for example, increasingly evaluate hospital performance based on spending, as determined by payments made to institutions and providers, and outcome measures for a longitudinal episode of AMI care. Little is known about the relationship between total 30-day payments-both in the inpatient and immediate postdischarge timeframe and outcomes after an admission for AMI. METHODS AND RESULTS: Using Medicare claims data, we identified Medicare fee-for-service beneficiaries >=65 years of age who were hospitalized at an acute-care hospital for AMI between July 1, 2011, and June 30, 2014, and examined the association between hospital-level 30-day payments for an episode of AMI care and patient 30-day mortality using mixed regression models with a logit link function and random hospital intercepts. Our cohort included 642 105 index hospitalizations for AMI at 2319 acute-care hospitals. Overall mean 30-day episode payments per beneficiary were $22 128 (SD, $1750). The observed 30-day mortality rate was 12.9%. Higher 30-day payments were associated with lower 30-day mortality after adjustment for patient characteristics and comorbidities (adjusted odds ratio for additional $1000 payments, 0.986; 95% confidence interval, 0.979-0.992; P<0.001). Additional adjustment for potential mediating factors, including hospital characteristics, coronary revascularization rates, and discharge disposition, did not significantly attenuate the relationship (adjusted odds ratio for additional $1000 payments, 0.987; 95% confidence interval, 0.980-0.994; P<0.001). CONCLUSIONS: Higher hospital-level 30-day payments-both inpatient and in multiple settings after discharge-for AMI care were associated with lower 30-day mortality among beneficiaries. This may have implications for payment programs that incent reduction in payments without considering value. PMID- 29530888 TI - Moving the Goalposts Into Unblinded Territory: The Larger Lessons of DEFER and FAME 2 and Their Implications for Shifting End Points in ISCHEMIA. PMID- 29530889 TI - Icarus, Blood Pressure, and the Dangers of Flying Too Close to the Sun. PMID- 29530890 TI - Addressing Acute Coronary Syndromes: New Challenges and Opportunities After the CANTOS Trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study). PMID- 29530891 TI - Non-Vitamin K Antagonist Preferred in Patients With Nonvalvular Atrial Fibrillation and Indication for Aspirin Therapy. PMID- 29530892 TI - Integrative Omics: Harnessing the Proteome to Maximize the Potential of the Genome. PMID- 29530894 TI - Alternating Bundle-Branch Block: What Is the Mechanism? PMID- 29530893 TI - Exercise Therapy and Cardiovascular Toxicity in Cancer. AB - Cardio-oncology is an emerging discipline focused predominantly on the detection and management of cancer treatment-induced cardiac dysfunction (cardiotoxicity), which predisposes to development of overt heart failure or coronary artery disease. The direct adverse consequences, as well as those secondary to anticancer therapeutics, extend beyond the heart, however, to affect the entire cardiovascular-skeletal muscle axis (ie, whole-organism cardiovascular toxicity). The global nature of impairment creates a strong rationale for treatment strategies that augment or preserve global cardiovascular reserve capacity. In noncancer clinical populations, exercise training is an established therapy to improve cardiovascular reserve capacity, leading to concomitant reductions in cardiovascular morbidity and its attendant symptoms. Here, we overview the tolerability and efficacy of exercise on cardiovascular toxicity in adult patients with cancer. We also propose a conceptual research framework to facilitate personalized risk assessment and the development of targeted exercise prescriptions to optimally prevent or manage cardiovascular toxicity after a cancer diagnosis. PMID- 29530896 TI - Letter by Tsuda Regarding Article, "A Novel alpha-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure". PMID- 29530895 TI - Widening Racial Differences in Risks for Coronary Heart Disease. PMID- 29530897 TI - Letter by Jin-shan and Xue-bin Regarding Article, "A Novel alpha-Calcitonin Gene Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure". PMID- 29530899 TI - Letter by Mutlu and Budinger Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification". PMID- 29530898 TI - Response by Aubdool et al to Letters Regarding Article, "A Novel alpha-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure". PMID- 29530900 TI - Letter by Jordan and Biaggioni Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification". PMID- 29530901 TI - Letter by Li et al Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification". PMID- 29530902 TI - Response by Li et al to Letters Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification". PMID- 29530903 TI - Letter by Poullis Regarding Article, "Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes: Insights From the Arterial Revascularization Trial". PMID- 29530904 TI - Drivers for successful long-term lifestyle change, the role of e-health: a qualitative interview study. AB - OBJECTIVES: Assisting patients in lifestyle change using collaborative e-health tools can be an efficient treatment for non-communicable diseases like diabetes, cardiovascular disease and chronic obstructive lung disease that are caused or aggravated by unhealthy living in the form of unhealthy diet, physical inactivity or tobacco smoking. In a prospective pilot study, we tested an online collaborative e-health tool in general practice. The aim of this study was to identify drivers of importance for long-term personal lifestyle changes from a patient perspective when using a collaborative e-health tool, including the support of peers and healthcare professionals. SETTING: General practice clinics in the Region of Southern Denmark. PARTICIPANTS: 10 overweight patients who had previously successfully used a hybrid online collaborative e-health tool with both face-to-face and online consultations to lose weight. RESULTS: The main themes identified were facilitators, barriers and support from family and peers. Establishment of a trustworthy relationship with the healthcare professionals was of paramount importance. It was important for the patients to monitor the measurable outcomes with realistic goals and feedback from a trusted person. Often, significant life events were identified as catalysts for successful long term lifestyle changes. Dominant barriers to change were perception of insurmountable obstacles, experience of lack of self-efficacy and excess eating of high-calorie food. Finally, experiencing of trustworthy person-to-person forums, need for acknowledgement from referent others and support from family and peers were important drivers for long-term lifestyle change. CONCLUSION: The most important driver in long-term weight loss was a strong relationship with a healthcare professional. Collaborative e-health tools can support the relationship and behavioural changes through monitoring and providing relevant feedback. The support from family and peers also matters, and long-term success depends on the ability to establish strong, positive support on a day-to-day basis. PMID- 29530905 TI - Feasibility of a blended group treatment (bGT) for major depression: uncontrolled interventional study in a university setting. AB - OBJECTIVE: This study investigated the feasibility of a novel blended (face-to face and computer-based) group intervention for the reduction of depressive symptoms in major depression. DESIGN: Patient-centred uncontrolled interventional study. SETTING: University setting in a general community sample. A multimodal recruitment strategy (public health centres and public areas) was applied. PARTICIPANTS: Based on independent interviews, 26 participants, diagnosed with major depressive disorder (81% female; 23% comorbidity >1 and 23% comorbidity >2), entered treatment. INTERVENTION: Acceptance and mindfulness based, as well as self-management and resource-oriented psychotherapy principles served as the theoretical basis for the low-threshold intervention. The blended format included face-to-face sessions, complemented with multimedia presentations and a platform featuring videos, online work sheets, an unguided group chat and remote therapist patient communication. MAIN OUTCOME MEASURES: The Center for Epidemiological Studies-Depression scale and the 12-item General Health Questionnaire. RESULTS: Large to very large within group effect sizes were found on self-reported depression (F(2, 46.37)=25.69, p<0.001; d=1.80), general health (F(2,46.73)=11.47, p<0.001; d=1.32), personal resources (F(2,43.36)=21.17, p<0.001; d=0.90) and mindfulness (F(2,46.22)=9.40, p<0.001; d=1.12) after a follow-up period of 3 months. Treatment satisfaction was high, and 69% ranked computer and multimedia use as a therapeutic factor. Furthermore, participants described treatment intensification as important advantage of the blended format. Half of the patients (48%) would have preferred more time for personal exchange. CONCLUSION: The investigated blended group format seems feasible for the reduction of depressive symptoms in major depression. The development of blended interventions can benefit from assuring that highly structured treatments actually meet patients' needs. As a next step, the intervention should be tested in comparative trials in routine care. TRIAL REGISTRATION NUMBER: DRKS00010894; Pre-results. PMID- 29530906 TI - Influence of military component and deployment-related experiences on mental disorders among Canadian military personnel who deployed to Afghanistan: a cross sectional survey. AB - OBJECTIVE: The primary objective was to explore differences in mental health problems (MHP) between serving Canadian Armed Forces (CAF) components (Regular Force (RegF); Reserve Force (ResF)) with an Afghanistan deployment and to assess the contribution of both component and deployment experiences to MHP using covariate-adjusted prevalence difference estimates. Additionally, mental health services use (MHSU) was descriptively assessed among those with a mental disorder. DESIGN: Data came from the 2013 CAF Mental Health Survey, a cross sectional survey of serving personnel (n=72 629). Analyses were limited to those with an Afghanistan deployment (population n=35 311; sampled n=4854). Logistic regression compared MHP between RegF and ResF members. Covariate-adjusted prevalence differences were computed. PRIMARY OUTCOME MEASURE: The primary outcomes were MHP, past-year mental disorders, identified using the WHO's Composite International Diagnostic Interview, and past-year suicide ideation. RESULTS: ResF personnel were less likely to be identified with a past-year anxiety disorder (adjusted OR (AOR)=0.72 (95% CI 0.58 to 0.90)), specifically both generalised anxiety disorder and panic disorder, but more likely to be identified with a past-year alcohol abuse disorder (AOR=1.63 (95% CI 1.04 to 2.58)). The magnitude of the covariate-adjusted disorder prevalence differences for component was highest for the any anxiety disorder outcome, 2.8% (95% CI 1.0 to 4.6); lower for ResF. All but one deployment-related experience variable had some association with MHP. The 'ever felt responsible for the death of a Canadian or ally personnel' experience had the strongest association with MHP; its estimated covariate-adjusted disorder prevalence difference was highest for the any (of the six measured) mental disorder outcome (11.2% (95% CI 6.6 to 15.9)). Additionally, ResF reported less past-year MHSU and more past-year civilian MHSU. CONCLUSIONS: Past-year MHP differences were identified between components. Our findings suggest that although deployment-related experiences were highly associated with MHP, these only partially accounted for MHP differences between components. Additional research is needed to further investigate MHSU differences between components. PMID- 29530907 TI - Comparison of hip function and quality of life of total hip arthroplasty and resurfacing arthroplasty in the treatment of young patients with arthritis of the hip joint at 5 years. AB - OBJECTIVE: To compare the medium-term clinical effectiveness of total hip arthroplasty and resurfacing arthroplasty. DESIGN: Single centre, two-arm, parallel group, assessor blinded, randomised controlled trial with 1:1 treatment allocation. SETTING: A large teaching hospital in England. PARTICIPANTS: 122 patients older than 18 years with severe arthritis of the hip joint, suitable for resurfacing arthroplasty of the hip. Patients were excluded if they were considered to be unable to adhere to trial procedures or complete questionnaires. INTERVENTIONS: Total hip arthroplasty (replacement of entire femoral head and neck); hip resurfacing arthroplasty (replacement of the articular surface of femoral head only, femoral neck remains intact). Both procedures replaced the articular surface of the acetabulum. OUTCOMES: The outcome measures were hip function assessed using the Oxford Hip Score (OHS) and health-related quality of life assessed using the EuroQol (EQ-5D). Patients were followed up annually for a minimum of 5 years. Outcome data were modelled using the generalised estimating equation methodology to explore temporal variations during follow-up. RESULTS: 60 patients were randomly assigned to hip resurfacing arthroplasty and 62 to total hip arthroplasty. 95 (78%) of the 122 original study participants provided data at 5 years. There was a small decrease in both hip functions and quality of life in both groups of patients each year during the 5-year follow-up period. However, there was no evidence of a significant difference between treatments group in the OHS (P=0.333) or the EQ-5D (P=0.501). CONCLUSIONS: We previously reported no difference in outcome in the first year after surgery. The current medium-term results also show no evidence of a difference in hip function or health-related quality of life in the 5 years following a total hip arthroplasty versus resurfacing arthroplasty. TRIAL REGISTRATION NUMBER: ISRCTN33354155. UKCRN 4093. PMID- 29530908 TI - Factors associated with basic and instrumental activities of daily living in elderly participants of a population-based survey: the Nord-Trondelag Health Study, Norway. AB - OBJECTIVES: To investigate factors associated with the need for assistance in basic and instrumental activities of daily living in Norwegian elderly. DESIGN: Prospective cohort study. SETTING: The Nord-Trondelag Health Study (HUNT), a large population-based health survey in Norway. PARTICIPANTS: 5050 individuals aged 60-69 years old at baseline in HUNT2 (1995-1997) who also participated in HUNT3 (2006-2008) were included in the study. 676/693 individuals were excluded in the analyses due to missing outcomes. OUTCOMES: Needing assistance in one or more basic or instrumental activities of daily living reported in HUNT3. RESULTS: In adjusted multinomial logistic regression analyses, poor self-rated health and depression were the strongest risk factors for needing assistance in one or more basic activities of daily living in HUNT3, with ORs of 2.13 (1.35 to 3.38) and 1.58 (0.91 to 2.73). Poor self-rated health and poor life satisfaction were the strongest risk factors for needing assistance in one or more instrumental activities of daily living in HUNT3, with ORs of 2.30 (1.93 to 2.74) and 2.29 (1.86 to 2.81), respectively. Excessive sitting time, short or prolonged sleeping time, and physical inactivity seemed to be the most important lifestyle risk factors for basic/instrumental activities of daily living (ADL/IADL) disability. The studied factors were, in general, greater risk factors for mortality during follow-up than for ADL/IADL disability. Smoking was the strongest risk factor for mortality during follow-up and non-participation in HUNT3. Smoking and low social participation were the strongest risk factors for non-participation in HUNT3. CONCLUSIONS: Subjective health perception, life satisfaction and depression were the strongest risk factors for needing assistance in one or more basic/instrumental activities of daily living later in life. These factors could be possible targets for prevention purposes. PMID- 29530909 TI - Understanding the role of health information in patients' experiences: secondary analysis of qualitative narrative interviews with people diagnosed with cancer in Germany. AB - OBJECTIVE: To analyse the role and meaning of health information in individuals' experiences with either breast, colorectal or prostate cancer in order to better understand unmet information needs of people with a cancer diagnosis. DESIGN: This is a secondary analysis of data from a qualitative interview study including narrative interviews and maximum variation sampling. A thematic analysis was conducted, followed by an in-depth analysis based on the principles of grounded theory. SETTING: Interviewees were sought across Germany through self-help organisations, primary care clinics, rehabilitation facilities, physicians and other healthcare professionals to develop cancer modules for the website krankheitserfahrungen.de (illness experiences.de). PARTICIPANTS: Women with a diagnosis of breast cancer, individuals with a diagnosis of colorectal cancer and men with a diagnosis of prostate cancer. RESULTS: The meaning and role of information in the illness experiences were clearly associated with gaining control in a seemingly uncontrollable situation in which others -people, the disease- take over. Four categories characterise the ways in which information helped interviewees to regain a sense of control following a diagnosis of cancer: 'becoming confident in one's treatment decision', 'taking responsibility for one's situation', 'understanding the consequences of the disease and treatment for one's life', and 'dealing with fear'. There was, however, always a fine line between information seeking and becoming overwhelmed by information. CONCLUSIONS: Information needs to be understood as a management tool for handling the disease and its (potential) consequences. Patients' unmet needs for information might not be easily solved by a simple increase in the amount of information because emotional support and respect for patient autonomy might also play a role. The evaluation of one's own information behaviour and the information received is closely linked to how the illness unfolds. This makes it challenging to document unmet information needs and satisfaction with information independent of an individual's illness trajectory over time. PMID- 29530910 TI - What factors are critical to attracting NHS foundation doctors into specialty or core training? A discrete choice experiment. AB - OBJECTIVES: Multiple personal and work-related factors influence medical trainees' career decision-making. The relative value of these diverse factors is under-researched, yet this intelligence is crucially important for informing medical workforce planning and retention and recruitment policies. Our aim was to investigate the relative value of UK doctors' preferences for different training post characteristics during the time period when they either apply for specialty or core training or take time out. METHODS: We developed a discrete choice experiment (DCE) specifically for this population. The DCE was distributed to all Foundation Programme Year 2 (F2) doctors across Scotland as part of the National Career Destination Survey in June 2016. The main outcome measure was the monetary value of training post characteristics, based on willingness to forgo additional potential income and willingness to accept extra income for a change in each job characteristic calculated from regression coefficients. RESULTS: 677/798 F2 doctors provided usable DCE responses. Location was the most influential characteristic of a training position, followed closely by supportive culture and then working conditions. F2 doctors would need to be compensated by an additional 45.75% above potential earnings to move from a post in a desirable location to one in an undesirable location. Doctors who applied for a training post placed less value on supportive culture and excellent working conditions than those who did not apply. Male F2s valued location and a supportive culture less than female F2s. CONCLUSION: This is the first study focusing on the career decision-making of UK doctors at a critical careers decision-making point. Both location and specific job-related attributes are highly valued by F2 doctors when deciding their future. This intelligence can inform workforce policy to focus their efforts in terms of making training posts attractive to this group of doctors to enhance recruitment and retention. PMID- 29530911 TI - Comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder in children and adolescents: study protocol for a systematic review and network meta-analysis. AB - INTRODUCTION: Post-traumatic stress disorder (PTSD) is common among children and adolescents who are exposed to trauma, and it is often associated with significant negative impacts on their psychosocial functioning and quality of life. Many types of psychotherapies have been found to be effective for PTSD in children and adolescents. However, due to the lack of direct comparisons between different psychotherapies, the hierarchy of treatment efficacy is still unclear. Therefore, we plan to conduct a systematic review and network meta-analysis to evaluate the efficacy and acceptability of various types of psychotherapies for PTSD in children and adolescents. METHODS AND ANALYSIS: A systematic search will be conducted among eight electronic databases, including PubMed, Cochrane, Embase, Web of Science, PsycINFO, Cumulative Index of Nursing and Allied Health, Published International Literature on Traumatic Stress (PILOTS) and ProQuest Dissertations, from inception to October 2017. Randomised controlled trials, regardless of language, publication year and publication type, comparing any psychotherapies for PTSD to any control condition or alternative treatment in children and adolescents (18 years old or less) diagnosed with full or subclinical PTSD will be included. Study duration and the number of treatment sessions will not be limited. The primary outcome will be PTSD symptom severity at post-treatment as measured by a rating scale reported by the child, parent or a clinician. The secondary outcomes will include: (1) efficacy at follow-up; (2) acceptability (all-cause discontinuation); (3) anxiety symptom severity; (4) depressive symptom severity and (5) quality of life and functional improvement. Bayesian network meta-analyses for all relative outcome measures will be performed. We will conduct subgroup and sensitivity network meta-analyses to determine whether the findings are affected by study characteristics. The quality of the evidence contributing to network estimates of the primary outcome will be evaluated by the Grading of Recommendations, Assessment, Development and Evaluations framework. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal, which will be disseminated electronically and in print. This network meta-analysis may be updated to inform and guide the clinical management of PTSD in children and adolescents. PROSPERO REGISTRATION NUMBER: CRD42016051786. PMID- 29530912 TI - National trends in emergency readmission rates: a longitudinal analysis of administrative data for England between 2006 and 2016. AB - OBJECTIVE: To assess trends in 30-day emergency readmission rates across England over one decade. DESIGN: Retrospective study design. SETTING: 150 non-specialist hospital trusts in England. PARTICIPANTS: 23 069 134 patients above 18 years of age who were readmitted following an initial admission (n=62 584 297) between April 2006 and February 2016. PRIMARY AND SECONDARY OUTCOMES: We examined emergency admissions that occurred within 30 days of discharge from hospital ('emergency readmissions') as a measure of healthcare quality. Presented are overall readmission rates, and disaggregated by the nature of the indexed admission, including whether it was elective or emergency, and by clinical health condition recorded. All rates were risk-adjusted for patient age, gender, ethnicity, socioeconomic status, comorbidities and length of stay. RESULTS: The average risk-adjusted, 30-day readmission rate increased from 6.56% in 2006/2007 to 6.76% (P<0.01) in 2012/2013, followed by a small decrease to 6.64% (P<0.01) in 2015/2016. Emergency readmissions for patients discharged following elective procedures decreased by 0.13% (P<0.05), whereas those following emergency admission increased by 1.27% (P<0.001). Readmission rates for hip or knee replacements decreased (-1.29%; P<0.001); for acute myocardial infarction ( 0.04%; P<0.49), stroke (+0.62%; P<0.05), chronic obstructive pulmonary disease (+0.41%; P<0.05) and heart failure (+0.15%; P<0.05) remained stable; and for pneumonia (+2.72%; P<0.001), diabetes (+7.09%; P<0.001), cholecystectomy (+1.86%; P<0.001) and hysterectomy (+2.54%; P<0.001) increased. CONCLUSIONS: Overall, emergency readmission rates in England remained relatively stable across the observation period, with trends of slight increases contained post 2012/2013. However, there were large variations in trends across clinical areas, with some experiencing marked increases in readmission rates. This highlights the need to better understand variations in outcomes across clinical subgroups to allow for targeted interventions that will ensure highest standards of care provided for all patients. PMID- 29530913 TI - Effect of noise tolerance on non-restorative sleep: a population-based study in Hong Kong. AB - OBJECTIVE: The aim of this study was to assess the impact of auditory noise tolerance on non-restorative sleep using an objective audiometric test in a representative sample. DESIGN: A total of 202 Chinese individuals aged 15 years and above were recruited from a population-based household survey. Their non restorative sleep was assessed by a single item, the degree of feeling refreshed on waking up, on a 0-10 scale, while noise tolerance was measured by the most comfortable level expressed in A-weighted decibels. RESULTS: The 202 individuals (106 women) had a mean degree of feeling refreshed on waking up of 6.5 on the 0 10 scale and a mean maximum comfortable sound level of 69.2 dB. A multivariable analysis showed that a 1 dB increase in noise tolerance was associated with a 0.1 unit increase in the degree of feeling refreshed after adjusting for age, education, marital status, occupation, exercise, smoking, alcohol consumption, household noise level, stress, anxiety and depression. Moreover, housewives, non smokers and individuals who were less anxious or stressed felt significantly more refreshed on waking up. CONCLUSION: People with higher levels of noise tolerance experienced more refreshing sleep. Additional clinical consideration of enhancing noise tolerance in patients with sleep complaints is needed. PMID- 29530915 TI - Correction: 2016 American college of rheumatology/European league against rheumatism criteria for minimal moderate, and major clinical response in juvenile dermatomyositis. PMID- 29530917 TI - Fresh as an Exitron: A Flower-Specific Splice Variant of AUXIN RESPONSE FACTOR8 Helps Shape the Stamen. PMID- 29530914 TI - Meta Salud Diabetes study protocol: a cluster-randomised trial to reduce cardiovascular risk among a diabetic population of Mexico. AB - INTRODUCTION: Northern Mexico has among the highest rates of cardiovascular disease (CVD) and diabetes in the world. This research addresses core gaps in implementation science to develop, test and scale-up CVD risk-reduction interventions in diabetics through a national primary care health system. METHODS AND ANALYSIS: The Meta Salud Diabetes (MSD) research project is a parallel two arm cluster-randomised clinical behavioural trial based in 22 (n=22) health centres in Sonora, Mexico. MSD aims to evaluate the effectiveness of the MSD intervention for the secondary prevention of CVD risk factors among a diabetic population (n=320) compared with the study control of usual care. The MSD intervention consists of 2-hour class sessions delivered over a 13-week period providing educational information to encourage sustainable behavioural change to prevent disease complications including the adoption of physical activity. MSD is delivered within the context of Mexico's national primary care health centre system by health professionals, including nurses, physicians and community health workers via existing social support groups for individuals diagnosed with chronic disease. Mixed models are used to estimate the effect of MSD by comparing cardiovascular risk, as measured by the Framingham Risk Score, between the trial arms. Secondary outcomes include hypertension, behavioural risk factors and psychosocial factors. ETHICS AND DISSEMINATION: This work is supported by the National Institutes of Health, National Heart Lung and Blood Institute (1R01HL125996-01) and approved by the University of Arizona Research Institutional Review Board (Protocol 1508040144) and the Research Bioethics Committee at the University of Sonora. The first Internal Review Board approval date was 31 August 2015 with five subsequent approved amendments. This article refers to protocol V.0.2, dated 30 January 2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences and will be shared through meetings with health systems officials. TRIAL REGISTRATION NUMBER: NCT0280469; Pre-results. PMID- 29530918 TI - The epidemiology of multimorbidity in primary care: a retrospective cohort study. AB - BACKGROUND: Multimorbidity places a substantial burden on patients and the healthcare system, but few contemporary epidemiological data are available. AIM: To describe the epidemiology of multimorbidity in adults in England, and quantify associations between multimorbidity and health service utilisation. DESIGN AND SETTING: Retrospective cohort study, undertaken in England. METHOD: The study used a random sample of 403 985 adult patients (aged >=18 years), who were registered with a general practice on 1 January 2012 and included in the Clinical Practice Research Datalink. Multimorbidity was defined as having two or more of 36 long-term conditions recorded in patients' medical records, and associations between multimorbidity and health service utilisation (GP consultations, prescriptions, and hospitalisations) over 4 years were quantified. RESULTS: In total, 27.2% of the patients involved in the study had multimorbidity. The most prevalent conditions were hypertension (18.2%), depression or anxiety (10.3%), and chronic pain (10.1%). The prevalence of multimorbidity was higher in females than males (30.0% versus 24.4% respectively) and among those with lower socioeconomic status (30.0% in the quintile with the greatest levels of deprivation versus 25.8% in that with the lowest). Physical-mental comorbidity constituted a much greater proportion of overall morbidity in both younger patients (18-44 years) and those patients with a lower socioeconomic status. Multimorbidity was strongly associated with health service utilisation. Patients with multimorbidity accounted for 52.9% of GP consultations, 78.7% of prescriptions, and 56.1% of hospital admissions. CONCLUSION: Multimorbidity is common, socially patterned, and associated with increased health service utilisation. These findings support the need to improve the quality and efficiency of health services providing care to patients with multimorbidity at both practice and national level. PMID- 29530919 TI - Using the electronic health record to build a culture of practice safety: evaluating the implementation of trigger tools in one general practice. AB - BACKGROUND: Identifying patients at risk of harm in general practice is challenging for busy clinicians. In UK primary care, trigger tools and case note reviews are mainly used to identify rates of harm in sample populations. AIM: This study explores how adaptions to existing trigger tool methodology can identify patient safety events and engage clinicians in ongoing reflective work around safety. DESIGN AND SETTING: Mixed-method quantitative and narrative evaluation using thematic analysis in a single East London training practice. METHOD: The project team developed and tested five trigger searches, supported by Excel worksheets to guide the case review process. Project evaluation included summary statistics of completed worksheets and a qualitative review focused on ease of use, barriers to implementation, and perception of value to clinicians. RESULTS: Trigger searches identified 204 patients for GP review. Overall, 117 (57%) of cases were reviewed and 62 (53%) of these cases had patient safety events identified. These were usually incidents of omission, including failure to monitor or review. Key themes from interviews with practice members included the fact that GPs' work is generally reactive and GPs welcomed an approach that identified patients who were 'under the radar' of safety. All GPs expressed concern that the tool might identify too many patients at risk of harm, placing further demands on their time. CONCLUSION: Electronic trigger tools can identify patients for review in domains of clinical risk for primary care. The high yield of safety events engaged clinicians and provided validation of the need for routine safety checks. PMID- 29530920 TI - Behaviour change opportunities at mother and baby checks in primary care: a qualitative investigation of the experiences of GPs. AB - BACKGROUND: Pregnancy is widely recognised as a 'teachable moment' for healthy behaviour change and the postnatal period has been identified as the opportune time to initiate this change. In the UK, all women are offered a routine health check at 6-8 weeks postpartum with their GP. This provides a potential opportunity to facilitate long-term behaviour change discussions. AIM: To explore GPs' views and experiences of using the postnatal check as a health-related behaviour change opportunity. DESIGN AND SETTING: A qualitative, inductive study in general practice. METHOD: Semi-structured telephone interviews were conducted with 18 GPs. Audiorecorded interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: One theme emerged from the data: the postnatal check is an unrealised opportunity to facilitate health-related behaviour change. This theme was organised into three subthemes: opportunity for health-related behaviour change; role responsibility; and patient-led versus GP-led behaviour change. CONCLUSION: Although GPs recognise the postnatal check as a potential opportunity for health-related behaviour change, it is underutilised as they do not perceive this to be the purpose of the check and are uncertain as to their role in facilitating lifestyle changes. To enable this long-term lifestyle behaviour change opportunity to be utilised more fully, further research is needed to understand women's expectations of the postnatal checks and the scope for further recommendations, guidance, and communication training around behaviour change. PMID- 29530921 TI - Impact of issuing longer- versus shorter-duration prescriptions: a systematic review. AB - BACKGROUND: Long-term conditions place a substantial burden on primary care services, with drug therapy being a core aspect of clinical management. However, the ideal frequency for issuing repeat prescriptions for these medications is unknown. AIM: To examine the impact of longer-duration (2-4 months) versus shorter-duration (28-day) prescriptions. DESIGN AND SETTING: Systematic review of primary care studies. METHOD: Scientific and grey literature databases were searched from inception until 21 October 2015. Eligible studies were randomised controlled trials and observational studies that examined longer prescriptions (2 4 months) compared with shorter prescriptions (28 days) in patients with stable, chronic conditions being treated in primary care. Outcomes of interest were: health outcomes, adverse events, medication adherence, medication wastage, professional administration time, pharmacists' time and/or costs, patient experience, and patient out-of-pocket costs. RESULTS: From a search total of 24 876 records across all databases, 13 studies were eligible for review. Evidence of moderate quality from nine studies suggested that longer prescriptions are associated with increased medication adherence. Evidence from six studies suggested that longer prescriptions may increase medication waste, but results were not always statistically significant and were of very low quality. No eligible studies were identified that measured any of the other outcomes of interest, including health outcomes and adverse events. CONCLUSION: There is insufficient evidence relating to the overall impact of differing prescription lengths on clinical and health service outcomes, although studies do suggest medication adherence may improve with longer prescriptions. UK recommendations to provide shorter prescriptions are not substantiated by the current evidence base. PMID- 29530922 TI - Regulation of Hypoxia-Inducible Factor 1alpha during Hypoxia by DAP5-Induced Translation of PHD2. AB - Death-associated protein 5 (DAP5) is an atypical isoform of the translation initiation scaffolds eukaryotic initiation factor 4GI (eIF4GI) and eIF4GII (eIF4GI/II), which recruit mRNAs to ribosomes in mammals. Unlike eIF4GI/II, DAP5 binds eIF2beta, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. We discovered that DAP5:eIF2beta binding depends on specific stimuli, e.g., protein kinase C (PKC)-Raf-extracellular signal-regulated kinase 1/2 (ERK1/2) signals, and determines DAP5's influence on global and template-specific translation. DAP5 depletion caused an unanticipated surge of hypoxia-inducible factor 1alpha (HIF-1alpha), the transcription factor and master switch of the hypoxia response. Physiologically, the hypoxia response is tempered through HIF 1alpha hydroxylation by the oxygen-sensing prolyl hydroxylase-domain protein 2 (PHD2) and subsequent ubiquitination and degradation. We found that DAP5 regulates HIF-1alpha abundance through DAP5:eIF2beta-dependent translation of PHD2. DAP5:eIF2-induced PHD2 translation occurred during hypoxia-associated protein synthesis repression, indicating a role as a safeguard to reverse HIF 1alpha accumulation and curb the hypoxic response. PMID- 29530923 TI - Endosomal-Lysosomal Cholesterol Sequestration by U18666A Differentially Regulates Amyloid Precursor Protein (APP) Metabolism in Normal and APP-Overexpressing Cells. AB - Amyloid beta (Abeta) peptide, derived from amyloid precursor protein (APP), plays a critical role in the development of Alzheimer's disease. Current evidence indicates that altered levels or subcellular distribution of cholesterol can regulate Abeta production and clearance, but it remains unclear how cholesterol sequestration within the endosomal-lysosomal (EL) system can influence APP metabolism. Thus, we evaluated the effects of U18666A, which triggers cholesterol redistribution within the EL system, on mouse N2a cells expressing different levels of APP in the presence or absence of extracellular cholesterol and lipids provided by fetal bovine serum (FBS). Our results reveal that U18666A and FBS differentially increase the levels of APP and its cleaved products, the alpha-, beta-, and eta-C-terminal fragments, in N2a cells expressing normal levels of mouse APP (N2awt), higher levels of human wild-type APP (APPwt), or "Swedish" mutant APP (APPsw). The cellular levels of Abeta1-40/Abeta1-42 were markedly increased in U18666A-treated APPwt and APPsw cells. Our studies further demonstrate that APP and its cleaved products are partly accumulated in the lysosomes, possibly due to decreased clearance. Finally, we show that autophagy inhibition plays a role in mediating U18666A effects. Collectively, these results suggest that altered levels and distribution of cholesterol and lipids can differentially regulate APP metabolism depending on the nature of APP expression. PMID- 29530925 TI - Changes in the Neuronal Control of the Urinary Bladder in a Model of Radiation Cystitis. AB - Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days after bladder irradiation (20 Gy), rats were sedated and the urinary bladder was cut into two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one-half of the bladder, while contractions were registered on the contralateral half of the bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit-positive interstitial cells), atropine (1 mg/kg; to block muscarinic M3 receptors), or pyridoxalphosphate-6 azophenyl-2',4'-disulfonic acid (2 mg/kg; P2X1 purinoceptor antagonist). Urinary bladders were also excised for organ bath experiments, Western blot, quantitative polymerase chain reaction, and immunohistochemistry. In vivo, EFS contractions were enhanced after irradiation, and imatinib (1-10 mg/mg) inhibited contractions by EFS and stretched dose-dependently in controls but not in irradiated bladders. In the irradiated bladder in vitro, atropine resistance was increased and imatinib (100 uM) inhibited contractions by EFS and agonists (ATP, methacholine) in irradiated bladders and controls. The urinary bladder expressions of P2X1 purinoceptors, muscarinic M3 receptor, choline acetyltransferase, c-kit, and the agonist of c-kit, stem cell factor, were not changed by irradiation. In conclusion, bladder irradiation affects several levels of neuronal control of the urinary bladder. Interstitial cells may contribute to some of the symptoms associated with radiation cystitis. PMID- 29530924 TI - Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice. AB - Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites. PMID- 29530926 TI - Meat Cooking Methods and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies. AB - OBJECTIVE: To examine open-flame and/or high-temperature cooking (grilling/barbecuing, broiling, or roasting) and doneness preferences (rare, medium, or well done) for red meat, chicken, and fish in relation to type 2 diabetes (T2D) risk among U.S. adults who consumed animal flesh regularly (>=2 servings/week). RESEARCH DESIGN AND METHODS: The prospective studies included 52,752 women from the Nurses' Health Study (NHS) (followed during 1996-2012), 60,809 women from NHS II (followed during 2001-2013), and 24,679 men from the Health Professionals Follow-Up Study (HPFS) (followed during 1996-2012) who were free of diabetes, cardiovascular disease, and cancer at baseline. Incident cases of T2D were confirmed by validated supplementary questionnaires. RESULTS: We documented 7,895 incident cases of T2D during 1.74 million person-years of follow up. After multivariate adjustments including baseline BMI and total consumption of red meat, chicken, and fish, higher frequency of open-flame and/or high temperature cooking was independently associated with an elevated T2D risk. When comparing open-flame and/or high-temperature cooking >15 times/month with <4 times/month, the pooled hazard ratio (HR) (95% CI) of T2D was 1.28 (1.18, 1.39; Ptrend <0.001). When comparing the extreme quartiles of doneness-weighted frequency of high-temperature cooking, the pooled HR (95% CI) of T2D was 1.20 (1.12, 1.28; Ptrend <0.001). These associations remained significant when red meat and chicken were examined separately. In addition, estimated intake of heterocyclic aromatic amines was also associated with an increased T2D risk. CONCLUSIONS: Independent of consumption amount, open-flame and/or high temperature cooking for both red meat and chicken is associated with an increased T2D risk among adults who consume animal flesh regularly. PMID- 29530927 TI - Epigenetic activation of meiotic recombination near Arabidopsis thaliana centromeres via loss of H3K9me2 and non-CG DNA methylation. AB - Eukaryotic centromeres contain the kinetochore, which connects chromosomes to the spindle allowing segregation. During meiosis, centromeres are suppressed for inter-homolog crossover, as recombination in these regions can cause chromosome missegregation and aneuploidy. Plant centromeres are surrounded by transposon dense pericentromeric heterochromatin that is epigenetically silenced by histone 3 lysine 9 dimethylation (H3K9me2), and DNA methylation in CG and non-CG sequence contexts. However, the role of these chromatin modifications in control of meiotic recombination in the pericentromeres is not fully understood. Here, we show that disruption of Arabidopsis thaliana H3K9me2 and non-CG DNA methylation pathways, for example, via mutation of the H3K9 methyltransferase genes KYP/SUVH4 SUVH5 SUVH6, or the CHG DNA methyltransferase gene CMT3, increases meiotic recombination in proximity to the centromeres. Using immunocytological detection of MLH1 foci and genotyping by sequencing of recombinant plants, we observe that H3K9me2 and non-CG DNA methylation pathway mutants show increased pericentromeric crossovers. Increased pericentromeric recombination in H3K9me2/non-CG mutants occurs in hybrid and inbred backgrounds and likely involves contributions from both the interfering and noninterfering crossover repair pathways. We also show that meiotic DNA double-strand breaks (DSBs) increase in H3K9me2/non-CG mutants within the pericentromeres, via purification and sequencing of SPO11-1 oligonucleotides. Therefore, H3K9me2 and non-CG DNA methylation exert a repressive effect on both meiotic DSB and crossover formation in plant pericentromeric heterochromatin. Our results may account for selection of enhancer trap Dissociation (Ds) transposons into the CMT3 gene by recombination with proximal transposon launch-pads. PMID- 29530929 TI - Separate roles for Med12 and Wnt signaling in regulation of oxytocin expression. AB - Transcriptional control of oxytocinergic cell development influences social, sexual, and appetite related behaviors and is implicated in disorders such as autism and Prader-Willi syndrome. Mediator 12 (Med12) is a transcriptional coactivator required for multiple facets of brain development including subsets of serotonergic and dopaminergic neurons. We surveyed hormone gene expression within the hypothalamo-pituitary axis of med12 mutant zebrafish embryos with a focus on oxytocin (oxt) expression. Some transcripts, such as oxt, vasopressin (avp) and corticotrophin releasing hormone (crh) are undetectable in the med12 mutant, while others are upregulated or downregulated to varying degrees. In med12 mutants, the expression patterns of upstream transcriptional regulators of oxytocinergic cell development remain largely intact in the pre-optic area, suggesting a more direct influence of Med12 on oxt expression. We show that Med12 is required for Wnt signaling in zebrafish. However, oxt expression is unaffected in Wnt-inhibited embryos indicating independence of Wnt signaling. In fact, overactive Wnt signaling inhibits oxt expression, and we identify a Wnt-sensitive period starting at 24 h post fertilization (hpf). Thus, Med12 and repression of Wnt signaling display critical but unrelated roles in regulating oxt expression. PMID- 29530928 TI - Nucleosomes and DNA methylation shape meiotic DSB frequency in Arabidopsis thaliana transposons and gene regulatory regions. AB - Meiotic recombination initiates from DNA double-strand breaks (DSBs) generated by SPO11 topoisomerase-like complexes. Meiotic DSB frequency varies extensively along eukaryotic chromosomes, with hotspots controlled by chromatin and DNA sequence. To map meiotic DSBs throughout a plant genome, we purified and sequenced Arabidopsis thaliana SPO11-1-oligonucleotides. SPO11-1-oligos are elevated in gene promoters, terminators, and introns, which is driven by AT sequence richness that excludes nucleosomes and allows SPO11-1 access. A positive relationship was observed between SPO11-1-oligos and crossovers genome-wide, although fine-scale correlations were weaker. This may reflect the influence of interhomolog polymorphism on crossover formation, downstream from DSB formation. Although H3K4me3 is enriched in proximity to SPO11-1-oligo hotspots at gene 5' ends, H3K4me3 levels do not correlate with DSBs. Repetitive transposons are thought to be recombination silenced during meiosis, to prevent nonallelic interactions and genome instability. Unexpectedly, we found high SPO11-1-oligo levels in nucleosome-depleted Helitron/Pogo/Tc1/Mariner DNA transposons, whereas retrotransposons were coldspots. High SPO11-1-oligo transposons are enriched within gene regulatory regions and in proximity to immunity genes, suggesting a role as recombination enhancers. As transposon mobility in plant genomes is restricted by DNA methylation, we used the met1 DNA methyltransferase mutant to investigate the role of heterochromatin in SPO11-1-oligo distributions. Epigenetic activation of meiotic DSBs in proximity to centromeres and transposons occurred in met1 mutants, coincident with reduced nucleosome occupancy, gain of transcription, and H3K4me3. Together, our work reveals a complex relationship between chromatin and meiotic DSBs within A. thaliana genes and transposons, with significance for the diversity and evolution of plant genomes. PMID- 29530930 TI - Degradation of cyclin B is critical for nuclear division in Trypanosoma brucei. AB - Kinetoplastids have a nucleus that contains the nuclear genome and a kinetoplast that contains the mitochondrial genome. These single-copy organelles must be duplicated and segregated faithfully to daughter cells at each cell division. In Trypanosoma brucei, although duplication of both organelles starts around the same time, segregation of the kinetoplast precedes that of the nucleus. Cytokinesis subsequently takes place so that daughter cells inherit a single copy of each organelle. Very little is known about the molecular mechanism that governs the timing of these events. Furthermore, it is thought that T. brucei lacks a spindle checkpoint that delays the onset of nuclear division in response to spindle defects. Here we show that a mitotic cyclin CYC6 has a dynamic localization pattern during the cell cycle, including kinetochore localization. Using CYC6 as a molecular cell cycle marker, we confirmed that T. brucei cannot delay the onset of anaphase in response to a bipolar spindle assembly defect. Interestingly, expression of a stabilized form of CYC6 caused the nucleus to arrest in a metaphase-like state without preventing cytokinesis. We propose that trypanosomes have an ability to regulate the timing of nuclear division by modulating the CYC6 protein level, without a spindle checkpoint. PMID- 29530931 TI - Lithobates catesbeianus (American Bullfrog) oocytes: a novel heterologous expression system for aquaporins. AB - Xenopus laevis oocytes are a valuable tool for investigating the function of membrane proteins. However, regulations around the world, specifically in Brazil, render the import of Xenopus laevis frogs impractical, and, in some cases, impossible. Here, as an alternative, we evaluate the usefulness of the North American aquatic bullfrog Lithobates catesebeianus, which is commercially available in Brazil, for the heterologous expression of aquaporin (AQP) proteins. We have developed a method that combines a brief collagenase treatment and mechanical defolliculation for isolating individual oocytes from Lithobates ovaries. We find that they have a similar size, shape, and appearance to Xenopus oocytes and can tolerate and survive following injections with cRNA or water. Furthermore, surface biotinylation, western blot analysis, and measurements of osmotic water permeability (Pf) show that Lithobates oocytes can express AQPs to the plasma membrane and significantly increase the Pf of the oocytes. In fact, the Pf values are similar to historical values gathered from Xenopus oocytes. Due to the presence of a mercury sensitive cysteine (Cys or C) in the throat of the water channel, the Pf of oocytes expressing human (h) AQP1, hAQP1FLAG [FLAG, short protein tag (DYKDDDDK) added to the N-terminus of AQP1], hAQP8, and rat (r) AQP9 was inhibited with the mercurial compound p-chloromercuribenzene sulfonate (pCMBS), whereas AQPs lacking this Cys - hAQP1C189S mutant [residue Cys 189 was replaced by a serine (Ser or S)] and hAQP7 - were mercury insensitive. Contrary to previous studies with Xenopus oocytes, rAQP3 was also found to be insensitive to mercury, which is consistent with the mercury-sensitive Cys (Cys 11) being located intracellularly. Thus, we consider Lithobates oocytes to be a readily accessible system for the functional expression and study of membrane proteins for international researchers who do not currently have access to Xenopus oocytes. PMID- 29530933 TI - Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study. AB - Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell-cycle regulation or proliferation in patients with HER2-positive early breast cancer.Experimental Design: Protein expression of TOP2A, Ki67, cyclin D1, and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 years; N = 561) and observation (N = 301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (predefined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest.Results: A significant interaction was detected between p27 and treatment (adjusted P = 0.0049). Trastuzumab effect was significant in the p27-low subgroup (<=70% p27-positive tumor cells; N = 318). HR Comb Trast vs. Obs 0.44, 95% CI, 0.29-0.65 (P < 0.001). No trastuzumab effect was observed in the p27-high subgroup N = 435; HR Comb Trast vs. Obs 0.97, 95% CI, 0.66-1.44, P = 0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27-high patients experiencing half the hazard of a DFS event compared with low ones (HR p27 High vs. Low 0.49, 95% CI, 0.32-0.75). TOP2A, Ki67, and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit.Conclusions: In TransHERA, patients with HER2-positive early breast cancer with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not. Clin Cancer Res; 24(13); 3079-86. (c)2018 AACR. PMID- 29530932 TI - Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance. AB - Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies.Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1 Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivoConclusions:EGFR mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108-18. (c)2018 AACR. PMID- 29530934 TI - Lipidomic Profiling Links the Fanconi Anemia Pathway to Glycosphingolipid Metabolism in Head and Neck Cancer Cells. AB - Purpose: Mutations in Fanconi anemia (FA) genes are common in sporadic squamous cell carcinoma of the head and neck (HNSCC), and we have previously demonstrated that FA pathway depletion in HNSCC cell lines stimulates invasion. The goal of our studies was to use a systems approach in order to define FA pathway-dependent lipid metabolism and to extract lipid-based signatures and effectors of invasion in FA-deficient cells.Experimental Design: We subjected FA-isogenic HNSCC keratinocyte cell lines to untargeted and targeted lipidomics analyses to discover novel biomarkers and candidate therapeutic targets in FA-deficient cells. Cellular invasion assays were carried out in the presence and absence of N butyldeoxynojirimycin (NB-DNJ), a biosynthetic inhibitor of the newly identified class of gangliosides, to investigate the requirement of ganglioside upregulation in FA-deficient HNSCC cells.Results: The most notable element of the lipid profiling results was a consistent elevation of glycosphingolipids, and particularly the accumulation of gangliosides. Conversely, repression of this same class of lipids was observed upon genetic correction of FA patient-derived HNSCC cells. Functional studies demonstrate that ganglioside upregulation is required for HNSCC cell invasion driven by FA pathway loss. The motility of nontransformed keratinocytes in response to FA loss displayed a similar dependence, thus supporting early and late roles for the FA pathway in controlling keratinocyte invasion through lipid regulation.Conclusions: Elevation of glycosphingolipids including the ganglioside GM3 in response to FA loss stimulates invasive characteristics of immortalized and transformed keratinocytes. An inhibitor of glycosphingolipid biosynthesis NB-DNJ attenuates invasive characteristics of FA-deficient HNSCC cells. Clin Cancer Res; 24(11); 2700-9. (c)2018 AACR. PMID- 29530935 TI - High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2 Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance). AB - Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials.Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples.Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02).Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053-8. (c)2018 AACR. PMID- 29530936 TI - B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity. AB - Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8+ tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry.Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8+ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8+ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8+ TILs and recovery of effector function. CD8+ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8+ T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction.Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8+ T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs. Clin Cancer Res; 24(11); 2653-64. (c)2018 AACR. PMID- 29530937 TI - Predicted Arabidopsis Interactome Resource and Gene Set Linkage Analysis: A Transcriptomic Analysis Resource. AB - An advanced functional understanding of omics data is important for elucidating the design logic of physiological processes in plants and effectively controlling desired traits in plants. We present the latest versions of the Predicted Arabidopsis Interactome Resource (PAIR) and of the gene set linkage analysis (GSLA) tool, which enable the interpretation of an observed transcriptomic change (differentially expressed genes [DEGs]) in Arabidopsis (Arabidopsis thaliana) with respect to its functional impact for biological processes. PAIR version 5.0 integrates functional association data between genes in multiple forms and infers 335,301 putative functional interactions. GSLA relies on this high-confidence inferred functional association network to expand our perception of the functional impacts of an observed transcriptomic change. GSLA then interprets the biological significance of the observed DEGs using established biological concepts (annotation terms), describing not only the DEGs themselves but also their potential functional impacts. This unique analytical capability can help researchers gain deeper insights into their experimental results and highlight prospective directions for further investigation. We demonstrate the utility of GSLA with two case studies in which GSLA uncovered how molecular events may have caused physiological changes through their collective functional influence on biological processes. Furthermore, we showed that typical annotation-enrichment tools were unable to produce similar insights to PAIR/GSLA. The PAIR version 5.0 inferred interactome and GSLA Web tool both can be accessed at http://public.synergylab.cn/pair/. PMID- 29530938 TI - Perception of Sunflecks by the UV-B Photoreceptor UV RESISTANCE LOCUS8. AB - Sunflecks, transient patches of light that penetrate through gaps in the canopy and transiently interrupt shade, are eco-physiologically and agriculturally important sources of energy for carbon gain, but our molecular understanding of how plant organs perceive and respond to sunflecks through photoreceptors remains limited. The UV-B photoreceptor UV RESISTANCE LOCUS8 (UVR8) is a recent addition to the list of plant photosensory receptors, and we have made considerable advances in our understanding of the physiology and molecular mechanisms of action of UVR8 and its signaling pathway. However, the function of UVR8 in the natural environment is poorly understood. Here, we show that the UVR8 dimer/monomer ratio responds quantitatively and reversibly to the intensity of sunflecks that interrupt shade in the field. Sunflecks reduced hypocotyl growth and increased CHALCONE SYNTHASE (CHS) and ELONGATED HYPOCOTYL5 gene expression and CHS protein abundance in wild-type Arabidopsis (Arabidopsis thaliana) seedlings, but the uvr8 mutant was impaired in these responses. UVR8 was also required for normal nuclear dynamics of CONSTITUTIVELY PHOTOMORPHOGENIC1. We propose that UVR8 plays an important role in the plant perception of and response to sunflecks. PMID- 29530940 TI - Acquired resistance to aromatase inhibitors: where we stand! AB - Aromatase inhibitors (AIs) are one of the principal therapeutic approaches for estrogen receptor-positive (ER+) breast cancer in postmenopausal women. They block estrogen biosynthesis through aromatase inhibition, thus preventing tumour progression. Besides the therapeutic success of the third-generation AIs, acquired resistance may develop, leading to tumour relapse. This resistance is thought to be the result of a change in the behaviour of ER in these breast cancer cells, presumably by PI3K/AKT pathway enhancement along with alterations in other signalling pathways. Nevertheless, biological mechanisms, such as apoptosis, autophagy, cell cycle modulation and activation of androgen receptor (AR), are also implicated in acquired resistance. Moreover, clinical evidence demonstrated that there is a lack of cross-resistance among AIs, although the reason is not fully understood. Thus, there is a demand to understand the mechanisms involved in endocrine resistance to each AI, since the search for new strategies to surpass breast cancer acquired resistance is of major concern. PMID- 29530941 TI - On average, a professional rugby union player is more likely than not to sustain a concussion after 25 matches. AB - OBJECTIVES: To investigate concussion injury rates, the likelihood of sustaining concussion relative to the number of rugby union matches and the risk of subsequent injury following concussion. METHODS: A four-season (2012/2013 2015/2016) prospective cohort study of injuries in professional level (club and international) rugby union. Incidence (injuries/1000 player-match-hours), severity (days lost per injury) and number of professional matches conferring a large risk of concussion were determined. The risk of injury following concussion was assessed using a survival model. RESULTS: Concussion incidence increased from 7.9 (95% CI 5.1 to 11.7) to 21.5 injuries/1000 player-match-hours (95% CI 16.4 to 27.6) over the four seasons for combined club and international rugby union. Concussion severity was unchanged over time (median: 9 days). Players were at a greater risk of sustaining a concussion than not after an exposure of 25 matches (95% CI 19 to 32). Injury risk (any injury) was 38% greater (HR 1.38; 95% CI 1.21 to 1.56) following concussion than after a non-concussive injury. Injuries to the head and neck (HR 1.34; 95% CI 1.06 to 1.70), upper limb (HR 1.59; 95% CI 1.19 to 2.12), pelvic region (HR 2.07; 95% CI 1.18 to 3.65) and the lower limb (HR 1.60; 95% CI 1.21 to 2.10) were more likely following concussion than after a non concussive injury. CONCLUSION: Concussion incidence increased, while severity remained unchanged, during the 4 years of this study. Playing more than 25 matches in the 2015/2016 season meant that sustaining concussion was more likely than not sustaining concussion. The 38% greater injury risk after concussive injury (compared with non-concussive injury) suggests return to play protocols warrant investigation. PMID- 29530942 TI - Sports-related injuries in New Zealand: National Insurance (Accident Compensation Corporation) claims for five sporting codes from 2012 to 2016. AB - OBJECTIVES: To provide epidemiological data and related costs for sport-related injuries of five sporting codes (cricket, netball, rugby league, rugby union and football) in New Zealand for moderate-to-serious and serious injury claims. METHODS: A retrospective analytical review using detailed descriptive epidemiological data obtained from the Accident Compensation Corporation (ACC) for 2012-2016. RESULTS: Over the 5 years of study data, rugby union recorded the most moderate-to-serious injury entitlement claims (25 226) and costs (New Zealand dollars (NZD$)267 359 440 (L139 084 749)) resulting in the highest mean cost (NZD$10 484 (L5454)) per moderate-to-serious injury entitlement claim. Rugby union recorded more serious injury entitlement claims (n=454) than cricket (t(4)= 66.6; P<0.0001); netball (t(4)=-45.1; P<0.0001); rugby league (t(4)=-61.4; P<0.0001) and football (t(4)=66.6; P<0.0001) for 2012-2016. There was a twofold increase in the number of female moderate-to-serious injury entitlement claims for football (RR 2.6 (95%CI 2.2 to 2.9); P<0.0001) compared with cricket, and a threefold increase when compared with rugby union (risk ratio (RR) 3.1 (95%CI 2.9 to 3.3); P<0.0001). Moderate-to-serious concussion claims increased between 2012 and 2016 for netball (RR 3.7 (95%CI 1.9 to 7.1); P<0.0001), rugby union (RR 2.0 (95% CI 1.6 to 2.4); P<0.0001) and football (RR 2.3 (95%CI 1.6 to 3.2); P<0.0001). Nearly a quarter of moderate-to-serious entitlement claims (23%) and costs (24%) were to participants aged 35 years or older. CONCLUSIONS: Rugby union and rugby league have the highest total number and costs associated with injury. Accurate sport exposure data are needed to enable injury risk calculations. PMID- 29530939 TI - Regulation of RUNX1 dosage is crucial for efficient blood formation from hemogenic endothelium. AB - During ontogeny, hematopoietic stem and progenitor cells arise from hemogenic endothelium through an endothelial-to-hematopoietic transition that is strictly dependent on the transcription factor RUNX1. Although it is well established that RUNX1 is essential for the onset of hematopoiesis, little is known about the role of RUNX1 dosage specifically in hemogenic endothelium and during the endothelial to-hematopoietic transition. Here, we used the mouse embryonic stem cell differentiation system to determine if and how RUNX1 dosage affects hemogenic endothelium differentiation. The use of inducible Runx1 expression combined with alterations in the expression of the RUNX1 co-factor CBFbeta allowed us to evaluate a wide range of RUNX1 levels. We demonstrate that low RUNX1 levels are sufficient and necessary to initiate an effective endothelial-to-hematopoietic transition. Subsequently, RUNX1 is also required to complete the endothelial-to hematopoietic transition and to generate functional hematopoietic precursors. In contrast, elevated levels of RUNX1 are able to drive an accelerated endothelial to-hematopoietic transition, but the resulting cells are unable to generate mature hematopoietic cells. Together, our results suggest that RUNX1 dosage plays a pivotal role in hemogenic endothelium maturation and the establishment of the hematopoietic system. PMID- 29530943 TI - Provider attitudes and management regarding returning to drive after concussion. PMID- 29530944 TI - DNA Damage Response in Prostate Cancer. AB - Prostatic adenocarcinoma (PCa) remains a significant health concern. Although localized PCa can be effectively treated, disseminated disease remains uniformly fatal. PCa is reliant on androgen receptor (AR); as such, first-line therapy for metastatic PCa entails suppression of AR signaling. Although initially effective, recurrent tumors reactivate AR function, leading to a lethal stage of disease termed castration-resistant PCa (CRPC). Recent findings implicate AR signaling in control of DNA repair and show that alterations in DNA damage repair pathways are strongly associated with disease progression and poor outcome. This review will address the DNA repair alterations observed in the clinical setting, explore the anticipated molecular and cellular consequence of DNA repair dysfunction, and consider clinical strategies for targeting tumors with altered DNA repair. PMID- 29530945 TI - New Opportunities for Targeting the Androgen Receptor in Prostate Cancer. AB - Recent genomic analyses of metastatic prostate cancer have provided important insight into adaptive changes in androgen receptor (AR) signaling that underpin resistance to androgen deprivation therapies. Novel strategies are required to circumvent these AR-mediated resistance mechanisms and thereby improve prostate cancer survival. In this review, we present a summary of AR structure and function and discuss mechanisms of AR-mediated therapy resistance that represent important areas of focus for the development of new therapies. PMID- 29530946 TI - Transmission and Epidemiology of Hepatitis E Virus Genotype 3 and 4 Infections. AB - Following the introduction of robust serological and molecular tools, our understanding of the epidemiology of zoonotic hepatitis E virus (HEV) has improved considerably in recent years. Current thinking suggests that consumption of pork meat products is the key route of infection in humans, but it is certainly not the only one. Other routes of infection include environmental spread, contaminated water, and via the human blood supply. The epidemiology of HEV genotype (gt)3 and gt4 is complex, as there are several sources and routes of infection, and it is likely that these vary between and within countries and over time. PMID- 29530947 TI - Transcriptional Regulation in Prostate Cancer. AB - Prostate cancer development involves corruption of the normal prostate transcriptional network, following deregulated expression or mutation of key transcription factors. Here, we provide an overview of the transcription factors that are important in normal prostate homeostasis (NKX3-1, p63, androgen receptor [AR]), primary prostate cancer (ETS family members, c-MYC), castration-resistant prostate cancer (AR, FOXA1), and AR-independent castration-resistant neuroendocrine prostate cancer (RB1, p53, N-MYC). We use functional (in vitro and in vivo) as well as clinical data to discuss evidence that unveils their roles in the initiation and progression of prostate cancer, with an emphasis on results of chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq). PMID- 29530948 TI - Hepatitis E Virus Genome Structure and Replication Strategy. AB - Hepatitis E virus (HEV) possesses many of the features of other positive-stranded RNA viruses but also adds HEV-specific nuances, making its virus-host interactions unique. Slow virus replication kinetics and fastidious growth conditions, coupled with the historical lack of an efficient cell culture system to propagate the virus, have left many gaps in our understanding of its structure and replication cycle. Recent advances in culturing selected strains of HEV and resolving the 3D structure of the viral capsid are filling in knowledge gaps, but HEV remains an extremely understudied pathogen. Many steps in the HEV life cycle and many aspects of HEV pathogenesis remain unknown, such as the host and viral factors that determine cross-species infection, the HEV-specific receptor(s) on host cells, what determines HEV chronicity and the ability to replicate in extrahepatic sites, and what regulates processing of the open reading frame 1 (ORF1) nonstructural polyprotein. PMID- 29530949 TI - Hepatitis A Virus Codon Usage: Implications for Translation Kinetics and Capsid Folding. AB - Codon usage bias is universal to all genomes. Hepatitis A virus (HAV) codon usage is highly biased and deoptimized with respect to its host. Accordingly, HAV is unable to induce cellular translational shutoff and its internal ribosome entry site (IRES) is inefficient. Codon usage deoptimization may be seen as a hawk (host cell) versus dove (HAV) game strategy for accessing transfer RNA (tRNA). HAV avoids use of abundant host cell codons and thereby eludes competition for the corresponding tRNAs. Instead, codons that are abundant or rare in cellular messenger RNAs (mRNAs) are used relatively rarely in its genome, although intermediately abundant host cell codons are abundant in the viral genome. Rare codons in the capsid coding region slow down the translation elongation rate, and in doing so intrinsically modulate capsid folding, which is critical to the stability of a virus transmitted through the fecal-oral route. HAV is a paradigmatic example of what has been proposed as a codon usage "code" for protein structure. PMID- 29530950 TI - Classification and Genomic Diversity of Enterically Transmitted Hepatitis Viruses. AB - Hepatitis A virus (HAV) and hepatitis E virus (HEV) are significant human pathogens and are responsible for a substantial proportion of cases of severe acute hepatitis worldwide. Genetically, both viruses are heterogeneous and are classified into several genotypes that differ in their geographical distribution and risk group association. There is, however, little evidence that variants of HAV or HEV differ antigenically or in their propensity to cause severe disease. Genetically more divergent but primarily hepatotropic variants of both HAV and HEV have been found in several mammalian species, those of HAV being classified into eight species within the genus Hepatovirus in the virus family Picornaviridae. HEV is classified as a member of the species Orthohepevirus A in the virus family Hepeviridae, a species that additionally contains viruses infecting pigs, rabbits, and a variety of other mammalian species. Other species (Orthohepevirus B-D) infect a wide range of other mammalian species including rodents and bats. PMID- 29530951 TI - Immunization against Hepatitis E. AB - Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in Escherichia coli Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries where the disease burden is highest. Nevertheless, the stage is set for the final act in the hepatitis E vaccine story-policymaking, advocacy, and pilot introduction of vaccine in at-risk populations, in which it is expected to be cost-effective. PMID- 29530953 TI - What's Happening in Neurology(r). PMID- 29530954 TI - What's Happening in Neurology(r)Clinical Practice. PMID- 29530952 TI - MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft versus-host disease in mice. AB - Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92 (miR-17-92) influences the survival, differentiation, and function of lymphocytes in cancer, infections, and autoimmunity. To determine whether miR 17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T cells, B cells, or both. Using murine models of allogeneic bone marrow transplantation, we demonstrate that expression of miR-17 92 in donor T and B cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T cells not only enhances the differentiation of pathogenic T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression is required for autoantibody production and immunoglobulin G deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti-miR-17, but not anti-miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation, and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD. PMID- 29530955 TI - What's Happening in Neurology(r)Genetics. PMID- 29530956 TI - What's Happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29530957 TI - What's happening in Without Borders. PMID- 29530958 TI - Charles E. Beevor's lasting contributions to neurology: More than just a sign. AB - Charles Edward Beevor (1854-1908) was a prominent English neurologist who served in a variety of positions at the National Hospital for the Paralysed and Epileptic, Queen Square, from 1883 until his sudden death due to coronary artery disease in 1908. Staunchly committed to the meticulous study of neuroanatomy and physiology and education of his fellow physicians, Beevor was an accomplished clinician-scientist. He is most well known for describing the Beevor sign (commonly known as "Beevor's sign"), which is the upward movement of the umbilicus with truncal flexion from a supine position, used to indicate a spinal cord lesion between the levels of T10 and T12. His sign has also been reported to be suggestive of facioscapulohumeral muscular dystrophy. While the initial description of the Beevor sign has traditionally been attributed to his 1903 Croonian Lectures, he actually first described his sign in his 1898 textbook Diseases of the Nervous System: A Handbook for Students and Practitioners In addition to his eponymous sign, Beevor also made significant contributions to the understanding of the representation of motor movements in the cerebral cortex, and, of more importance, utilized a novel method to identify cerebral vascular territory maps that are still utilized by neurologists today. PMID- 29530959 TI - Nigrosome 1 absence in de novo Parkinson disease. PMID- 29530961 TI - Editors' note: A new potential biomarker for dementia with Lewy bodies: Skin nerve alpha-synuclein deposits. PMID- 29530960 TI - Clinical Reasoning: A 12-year-old girl with headache and change in mental status. PMID- 29530962 TI - Reader response: A new potential biomarker for dementia with Lewy bodies: Skin nerve alpha-synuclein deposits. PMID- 29530963 TI - Author response: A new potential biomarker for dementia with Lewy bodies: Skin nerve alpha-synuclein deposits. PMID- 29530964 TI - Editors' note: Underestimation of sudden deaths among patients with seizures and epilepsy. PMID- 29530965 TI - Reader response: Underestimation of sudden deaths among patients with seizures and epilepsy. PMID- 29530966 TI - Author response: Underestimation of sudden deaths among patients with seizures and epilepsy. PMID- 29530967 TI - Clinical Reasoning: A 52-year-old woman with 3 weeks of progressive gait ataxia and dysarthria. PMID- 29530968 TI - Teaching NeuroImages: Vertebrobasilar dolichoectasia with dissection manifested as infarct and subarachnoid hemorrhage. PMID- 29530969 TI - Teaching NeuroImages: Retinal migraine in action. PMID- 29530970 TI - Economic perspective of dementia care in Pakistan. PMID- 29530971 TI - A simple model predicts energetically optimised jumping in dogs. AB - It is generally accepted that animals move in a way that minimises energy use during regular gait and there is evidence that the principle might extend more generally to locomotor behaviour and manoeuvres. Jumping during locomotion is a useful manoeuvre that contributes to the versatility of legged locomotion and is within the repertoire of many terrestrial animals. We describe a simple ballistic model that can be used to identify a single unique trajectory of the body's centre of mass that minimises the mechanical work to initiate a jump, regardless of the approach velocity or take-off position. The model was used to show that domestic dogs (Canis lupus familiaris) demonstrate complex anticipatory control of locomotor behaviour by systematically using jump trajectories close to those that minimised the mechanical energy of jumps over raised obstacles. It is unclear how the dogs acquired the complex perception and control necessary to exhibit the observed behaviour. The model may be used to investigate whether animals adopt energetically optimised behaviour in any similarly constrained ballistic task. PMID- 29530972 TI - Energetic costs of performance in trained and untrained Anolis carolinensis lizards. AB - The energetic costs of performance constitute a non-trivial component of animals' daily energetic budgets. However, we currently lack an understanding of how those costs are partitioned among the various stages of performance development, maintenance and production. We manipulated individual investment in performance by training Anolis carolinensis lizards for endurance or sprinting ability. We then measured energetic expenditure both at rest and immediately following exercise to test whether such training alters the maintenance and production costs of performance. Trained lizards had lower resting metabolic rates than controls, suggestive of a maintenance saving associated with enhanced performance as opposed to a cost. Production costs also differed, with sprint-trained lizards incurring a larger energetic performance cost and experiencing longer recovery times compared with endurance trained and control animals. Although performance training modifies metabolism, production costs are probably the key drivers of trade-offs between performance and other life-history traits in this species. PMID- 29530973 TI - The consequences of seasonal fasting during the dormancy of tegu lizards (Salvator merianae) on their postprandial metabolic response. AB - Tegu lizards (Salvator merianae) aestivate for up to 5 months during Brazil's winter, when they retreat to burrows and halt most activities. Dormant tegus reduce their gastrointestinal (GI) mass, which allows a substantial energy economy. This strategy, however, implies that the first post-dormancy digestion would be more costly than subsequent feeding episodes as a result of GI atrophy. To address this, we determined the postprandial metabolic response (SDA) of the first (M1), second (M2) and several (RM) feeding episodes after tegus' dormancy. Another group of tegus (PF) was subjected to an extra 50 day fasting period after arousal. Glucose, triglycerides and uric acid levels were checked before and after feeding. M1 digestion lasted twice as long and cost twofold more when compared with M2 or RM, in agreement with the idea that GI atrophy inflates digestion cost at the first post-dormancy meal. The SDA response was similar in M2 and RM, suggesting that the GI tract was fully reorganized after the first feeding. The SDA cost was equal in PF and RM, implying that the change in state per se (dormant to arousal) triggers the regrowth of GI, independently of feeding. Fasting tegus at M1 presented higher triglyceride and lower uric acid levels than fed tegus, indicating that fasting is mainly sustained by fat storage. Our results show that seasonal fasting imposes an extra digestion cost to tegus following their next feeding, which is fully paid during their first digestion. This surplus cost, however, is negligible compared with the overall energetic savings from GI tract atrophy during the dormancy period. PMID- 29530974 TI - The effects of lateral line ablation and regeneration in schooling giant danios. AB - Fish use multiple sensory systems, including vision and their lateral line system, to maintain position and speed within a school. Although previous studies have shown that ablating the lateral line alters schooling behavior, no one has examined how the behavior recovers as the sensory system regenerates. We studied how schooling behavior changes in giant danios, Devario aequipinnatus, when their lateral line system is chemically ablated and after the sensory hair cells regenerate. We found that fish could school normally immediately after chemical ablation, but that they had trouble schooling 1-2 weeks after the chemical treatment, when the hair cells had fully regenerated. We filmed groups of giant danios with two high-speed cameras and reconstructed the three-dimensional positions of each fish within a group. One fish in the school was treated with gentamycin to ablate all hair cells. Both types of neuromasts (canal and superficial) were completely ablated after treatment, but fully regenerated after 1 week. We quantified the structure of the school using nearest neighbor distance, bearing, elevation, and the cross-correlation of velocity between each pair of fish. Treated fish maintained a normal position within the school immediately after the lateral line ablation, but could not school normally 1 or 2 weeks after treatment, even though the neuromasts had fully regenerated. By 4-8 weeks post-treatment, the treated fish could again school normally. These results demonstrate that the behavioral recovery after lateral line ablation is a longer process than the regeneration of the hair cells themselves. PMID- 29530975 TI - Critical thermal limits of bumblebees (Bombus impatiens) are marked by stereotypical behaviors and are unchanged by acclimation, age or feeding status. AB - Critical thermal limits often determine species distributions for diverse ectotherms and have become a useful tool for understanding past and predicting future range shifts in response to changing climates. Despite recently documented population declines and range shifts of bumblebees (genus Bombus), the few measurements of thermal tolerance available for the group have relied on disparate measurement approaches. We describe a novel stereotypical behavior expressed by bumblebee individuals during entry into chill coma. This behavioral indicator of minimum critical temperature (CTmin) occurred at ambient temperatures of 3-5 degrees C (approximately 7-9 degrees C core temperatures) and was accompanied by a pronounced CO2 pulse, indicative of loss of spiracle function. Maximum critical temperature (CTmax) was indicated by the onset of muscular spasms prior to entering an unresponsive state and occurred at ambient temperatures of approximately 52-55 degrees C (42-44 degrees C core temperatures). Measurements of CTmin and CTmax were largely unaffected by acclimation, age or feeding status, but faster ramping rates significantly increased CTmax and decreased CTmin This high-throughput approach allows rapid measurement of critical thermal limits for large numbers of individuals, facilitating large-scale comparisons among bumblebee populations and species - a key step in determining current and future effects of climate on these critical pollinators. PMID- 29530976 TI - Occupational and educational inequalities in exit from employment at older ages: evidence from seven prospective cohorts. AB - OBJECTIVES: Past studies have identified socioeconomic inequalities in the timing and route of labour market exit at older ages. However, few studies have compared these trends cross-nationally and existing evidence focuses on specific institutional outcomes (such as disability pension and sickness absence) in Nordic countries. We examined differences by education level and occupational grade in the risks of work exit and health-related work exit. METHODS: Prospective longitudinal data were drawn from seven studies (n=99 164). Participants were in paid work at least once around age 50. Labour market exit was derived based on reductions in working hours, changes in self-reported employment status or from administrative records. Health-related exit was ascertained by receipt of health-related benefit or pension or from the reported reason for stopping work. Cox regression models were estimated for each study, adjusted for baseline self-rated health and birth cohort. RESULTS: There were 50 003 work exits during follow-up, of which an average of 14% (range 2-32%) were health related. Low level education and low occupational grade were associated with increased risks of health-related exit in most studies. Low level education and occupational grade were also associated with an increased risk of any exit from work, although with less consistency across studies. CONCLUSIONS: Workers with low socioeconomic position have an increased risk of health-related exit from employment. Policies that extend working life may disadvantage such workers disproportionally, especially where institutional support for those exiting due to poor health is minimal. PMID- 29530977 TI - Regulation of hepatic gluconeogenesis by nuclear factor Y transcription factor in mice. AB - Hepatic gluconeogenesis is essential to maintain blood glucose levels, and its abnormal activation leads to hyperglycemia and type 2 diabetes. However, the molecular mechanisms in the regulation of hepatic gluconeogenesis remain to be fully defined. In this study, using murine hepatocytes and a liver-specific knockout mouse model, we explored the physiological role of nuclear factor Y (NF Y) in regulating hepatic glucose metabolism and the underlying mechanism. We found that NF-Y targets the gluconeogenesis pathway in the liver. Hepatic NF-Y expression was effectively induced by cAMP, glucagon, and fasting in vivo Lentivirus-mediated NF-Y overexpression in Hepa1-6 hepatocytes markedly raised the gluconeogenic gene expression and cellular glucose production compared with empty vector control cells. Conversely, CRISPR/Cas9-mediated knockdown of NF-Y subunit A (NF-YA) attenuated gluconeogenic gene expression and glucose production. We also provide evidence indicating that CRE-loxP-mediated, liver specific NF-YA knockout compromises hepatic glucose production. Mechanistically, luciferase reporter gene assays and ChIP analysis indicated that NF-Y activates transcription of the gluconeogenic genes Pck1 and G6pc, by encoding phosphoenolpyruvate carboxykinase (PEPCK) and the glucose-6-phosphatase catalytic subunit (G6Pase), respectively, via directly binding to the CCAAT regulatory sequence motif in their promoters. Of note, NF-Y enhanced gluconeogenesis by interacting with cAMP-responsive element-binding protein (CREB). Overall, our results reveal a previously unrecognized physiological function of NF-Y in controlling glucose metabolism by up-regulating the gluconeogenic genes Pck1 and G6pc Modulation of hepatic NF-Y expression may therefore offer an attractive therapeutic approach to manage type 2 diabetes. PMID- 29530978 TI - Elucidation of the 14-3-3zeta interactome reveals critical roles of RNA-splicing factors during adipogenesis. AB - Adipogenesis involves a complex signaling network requiring strict temporal and spatial organization of effector molecules. Molecular scaffolds, such as 14-3-3 proteins, facilitate such organization, and we have previously identified 14-3 3zeta as an essential scaffold in adipocyte differentiation. The interactome of 14-3-3zeta is large and diverse, and it is possible that novel adipogenic factors may be present within it, but this possibility has not yet been tested. Herein, we generated mouse embryonic fibroblasts from mice overexpressing a tandem affinity purification (TAP) epitope-tagged 14-3-3zeta molecule. After inducing adipogenesis, TAP-14-3-3zeta complexes were purified, followed by MS analysis to determine the 14-3-3zeta interactome. We observed more than 100 proteins that were unique to adipocyte differentiation, 56 of which were novel interacting partners. Among these, we were able to identify previously established regulators of adipogenesis (i.e. Ptrf/Cavin1) within the 14-3-3zeta interactome, confirming the utility of this approach to detect adipogenic factors. We found that proteins related to RNA metabolism, processing, and splicing were enriched in the interactome. Analysis of transcriptomic data revealed that 14-3-3zeta depletion in 3T3-L1 cells affected alternative splicing of mRNA during adipocyte differentiation. siRNA-mediated depletion of RNA-splicing factors within the 14-3 3zeta interactome, that is, of Hnrpf, Hnrpk, Ddx6, and Sfpq, revealed that they have essential roles in adipogenesis and in the alternative splicing of Pparg and the adipogenesis-associated gene Lpin1 In summary, we have identified novel adipogenic factors within the 14-3-3zeta interactome. Further characterization of additional proteins within the 14-3-3zeta interactome may help identify novel targets to block obesity-associated expansion of adipose tissues. PMID- 29530979 TI - Crystal structure of a SFPQ/PSPC1 heterodimer provides insights into preferential heterodimerization of human DBHS family proteins. AB - Members of the Drosophila behavior human splicing (DBHS) protein family are nuclear proteins implicated in many layers of nuclear functions, including RNA biogenesis as well as DNA repair. Definitive of the DBHS protein family, the conserved DBHS domain provides a dimerization platform that is critical for the structural integrity and function of these proteins. The three human DBHS proteins, splicing factor proline- and glutamine-rich (SFPQ), paraspeckle component 1 (PSPC1), and non-POU domain-containing octamer-binding protein (NONO), form either homo- or heterodimers; however, the relative affinity and mechanistic details of preferential heterodimerization are yet to be deciphered. Here we report the crystal structure of a SFPQ/PSPC1 heterodimer to 2.3-A resolution and analyzed the subtle structural differences between the SFPQ/PSPC1 heterodimer and the previously characterized SFPQ homodimer. Analytical ultracentrifugation to estimate the dimerization equilibrium of the SFPQ containing dimers revealed that the SFPQ-containing dimers dissociate at low micromolar concentrations and that the heterodimers have higher affinities than the homodimer. Moreover, we observed that the apparent dissociation constant for the SFPQ/PSPC1 heterodimer was over 6-fold lower than that of the SFPQ/NONO heterodimer. We propose that these differences in dimerization affinity may represent a potential mechanism by which PSPC1 at a lower relative cellular abundance can outcompete NONO to heterodimerize with SFPQ. PMID- 29530980 TI - Impact of altered phosphorylation on loss of function of juvenile Parkinsonism associated genetic variants of the E3 ligase parkin. AB - Autosomal recessive juvenile Parkinsonism (ARJP) is an inherited neurodegenerative disease in which 50% of affected individuals harbor mutations in the gene encoding the E3 ligase parkin. Parkin regulates the mitochondrial recycling pathway, which is induced by oxidative stress. In its native state, parkin is auto-inhibited by its N-terminal ubiquitin-like (Ubl) domain, which blocks the binding site for an incoming E2~ubiquitin conjugate, needed for parkin's ubiquitination activity. Parkin is activated via phosphorylation of Ser 65 in its Ubl domain by PTEN-induced putative kinase 1 (PINK1) and a ubiquitin molecule phosphorylated at a position equivalent to Ser-65 in parkin. Here we have examined the underlying molecular mechanism of phosphorylation of parkin's Ubl domain carrying ARJP-associated substitutions and how altered phosphorylation modulates parkin activation and ubiquitination. We found that three substitutions in the Ubl domain (G12R, R33Q, and R42P) significantly decrease PINK1's ability to phosphorylate the Ubl domain. We noted that two basic loss-of-function substitutions (R33Q and R42P) are close to acidic patches in the proposed PINK1 parkin interface, indicating that ionic interactions at this site may be important for efficient parkin phosphorylation. Increased auto-ubiquitination with unique ubiquitin chain patterns was observed for two other Ubl domain substitutions (G12R and T55I), suggesting that these substitutions, along with phosphorylation, increase parkin degradation. Moreover, Ubl domain phosphorylation decreased its affinity for the potential effector protein ataxin 3, which edits ubiquitin chain building by parkin. Overall, our work provides a framework for the mechanisms of parkin's loss-of-function, indicating an interplay between ARJP-associated substitutions and phosphorylation of its Ubl domain. PMID- 29530981 TI - The proximity-labeling technique BioID identifies sorting nexin 6 as a member of the insulin-like growth factor 1 (IGF1)-IGF1 receptor pathway. AB - The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase with critical roles in various biological processes. Recent results from clinical trials targeting IGF1R indicate that IGF1R signaling pathways are more complex than previously thought. Moreover, it has become increasingly clear that the function of many proteins can be understood only in the context of a network of interactions. To that end, we sought to profile IGF1R-protein interactions with the proximity-labeling technique BioID. We applied BioID by generating a HEK293A cell line that stably expressed the BirA* biotin ligase fused to the IGF1R. Following stimulation by IGF1, biotinylated proteins were analyzed by MS. This screen identified both known and previously unknown interactors of IGF1R. One of the novel interactors was sorting nexin 6 (SNX6), a protein that forms part of the retromer complex, which is involved in intracellular protein sorting. Using co-immunoprecipitation, we confirmed that IGF1R and SNX6 physically interact. SNX6 knockdown resulted in a dramatic diminution of IGF1-mediated ERK1/2 phosphorylation, but did not affect IGF1R internalization. Bioluminescence resonance energy transfer experiments indicated that the SNX6 knockdown perturbed the association between IGF1R and the key adaptor proteins insulin receptor substrate 1 (IRS1) and SHC adaptor protein 1 (SHC1). Intriguingly, even in the absence of stimuli, SNX6 overexpression significantly increased Akt phosphorylation. Our study confirms the utility of proximity-labeling methods, such as BioID, to screen for interactors of cell-surface receptors and has uncovered a role of one of these interactors, SNX6, in the IGF1R signaling cascade. PMID- 29530982 TI - Repair of DNA double-strand breaks by mammalian alternative end-joining pathways. AB - Alternative end-joining (a-EJ) pathways, which repair DNA double-strand breaks (DSBs), are initiated by end resection that generates 3' single strands. This reaction is shared, at least in part, with homologous recombination but distinguishes a-EJ from the major nonhomologous end-joining pathway. Although the a-EJ pathways make only a minor and poorly understood contribution to DSB repair in nonmalignant cells, there is growing interest in these pathways, as they generate genomic rearrangements that are hallmarks of cancer cells. Here, we review and discuss the current understanding of the mechanisms and regulation of a-EJ pathways, the role of a-EJ in human disease, and the potential utility of a EJ as a therapeutic target in cancer. PMID- 29530983 TI - The apical anion exchanger Slc26a6 promotes oxalate secretion by murine submandibular gland acinar cells. AB - The solute carrier family 26 (SLC26) gene family encodes at least 10 different anion exchangers. SLC26 member 6 (SLC26A6 or CFEX/PAT-1) and the cystic fibrosis transmembrane conductance regulator (CFTR) co-localize to the apical membrane of pancreatic duct cells, where they act in concert to drive HCO3- and fluid secretion. In contrast, in the small intestine, SLC26A6 serves as the major pathway for oxalate secretion. However, little is known about the function of Slc26a6 in murine salivary glands. Here, RNA sequencing-based transcriptional profiling and Western blots revealed that Slc26a6 is highly expressed in mouse submandibular and sublingual salivary glands. Slc26a6 localized to the apical membrane of salivary gland acinar cells with no detectable immunostaining in the ducts. CHO-K1 cells transfected with mouse Slc26a6 exchanged Cl- for oxalate and HCO3-, whereas two other anion exchangers known to be expressed in salivary gland acinar cells, Slc4a4 and Slc4a9, mediated little, if any, Cl-/oxalate exchange. Of note, both Cl-/oxalate exchange and Cl-/HCO3- exchange were significantly reduced in acinar cells isolated from the submandibular glands of Slc26a6-/- mice. Oxalate secretion in submandibular saliva also decreased significantly in Slc26a6-/- mice, but HCO3- secretion was unaffected. Taken together, our findings indicate that Slc26a6 is located at the apical membrane of salivary gland acinar cells, where it mediates Cl-/oxalate exchange and plays a critical role in the secretion of oxalate into saliva. PMID- 29530984 TI - Cytochrome c is an oxidative stress-activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage. AB - Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl ether linkage at the sn-1 position and are highly enriched in arachidonic acid (AA) at the sn-2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive. Herein, we report that cytochrome c, in the presence of either cardiolipin (CL), O2 and H2O2, or oxidized CL and O2, catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive alpha-hydroxy fatty aldehydes. Using stable isotope labeling in synergy with strategic chemical derivatizations and high-mass-accuracy MS, we deduced the chemical mechanism underlying this long sought-after reaction. Specifically, labeling with either 18O2 or H218O, but not with H218O2, resulted in M + 2 isotopologues of the alpha-hydroxyaldehyde, whereas reactions with both 18O2 and H218O identified the M + 4 isotopologue. Furthermore, incorporation of 18O from 18O2 was predominantly located at the alpha-carbon. In contrast, reactions with H218O yielded 18O linked to the aldehyde carbon. Importantly, no significant labeling of 2-AA-lysolipids with 18O2, H218O, or H218O2 was present. Intriguingly, phosphatidylinositol phosphates (PIP2 and PIP3) effectively substituted for cardiolipin. Moreover, cytochrome c released from myocardial mitochondria subjected to oxidative stress cleaved plasmenylcholine in membrane bilayers, and this was blocked with a specific mAb against cytochrome c Collectively, these results identify the first plasmalogenase in biology, reveal the production of previously unanticipated signaling lipids by cytochrome c, and present new perspectives on cellular signaling during oxidative stress. PMID- 29530986 TI - Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel. AB - Mutations in the cereblon (CRBN) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and Drosophila G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in Crbn KO mice. In addition, paxilline treatment also restored normal cognitive behavior in Crbn KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in CRBN mutations.SIGNIFICANCE STATEMENTCereblon (CRBN), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of Crbn knock-out (KO) animals to identify the molecular mechanisms of intellectual disability. Here, we found that Crbn KO animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene CRBN and will contribute to the development of therapeutic strategies for CRBN-related intellectual disability. PMID- 29530985 TI - The transpeptidase PbpA and noncanonical transglycosylase RodA of Mycobacterium tuberculosis play important roles in regulating bacterial cell lengths. AB - The cell wall of Mycobacterium tuberculosis (Mtb) is a complex structure that protects the pathogen in hostile environments. Peptidoglycan (PG), which helps determine the morphology of the cell envelope, undergoes substantial remodeling under stress. This meshwork of linear chains of sugars, cross-linked through attached peptides, is generated through the sequential action of enzymes termed transglycosylases and transpeptidases. The Mtb genome encodes two classical transglycosylases and four transpeptidases, the functions of which are not fully elucidated. Here, we present work on the yet uncharacterized transpeptidase PbpA and a nonclassical transglycosylase RodA. We elucidate their roles in regulating in vitro growth and in vivo survival of pathogenic mycobacteria. We find that RodA and PbpA are required for regulating cell length, but do not affect mycobacterial growth. Biochemical analyses show PbpA to be a classical transpeptidase, whereas RodA is identified to be a member of an emerging class of noncanonical transglycosylases. Phosphorylation of RodA at Thr-463 modulates its biological function. In a guinea pig infection model, RodA and PbpA are found to be required for both bacterial survival and formation of granuloma structures, thus underscoring the importance of these proteins in mediating mycobacterial virulence in the host. Our results emphasize the fact that whereas redundant enzymes probably compensate for the absence of RodA or PbpA during in vitro growth, the two proteins play critical roles for the survival of the pathogen inside its host. PMID- 29530987 TI - Fractone Bulbs Derive from Ependymal Cells and Their Laminin Composition Influence the Stem Cell Niche in the Subventricular Zone. AB - Fractones are extracellular matrix structures in the neural stem cell niche of the subventricular zone (SVZ), where they appear as round deposits named bulbs or thin branching lines called stems. Their cellular origin and what determines their localization at this site is poorly studied, and it remains unclear whether they influence neural stem and progenitor cell formation, proliferation, and/or maintenance. To address these questions, we analyzed whole-mount preparations of the lateral ventricle of male and female mice by confocal microscopy using different extracellular matrix and cell markers. We found that bulbs are rarely connected to stems and that they contain laminin alpha5 and alpha2 chains, respectively. Fractone bulbs were profusely distributed throughout the SVZ and appeared associated with the center of pinwheels, a critical site for adult neurogenesis. We demonstrate that bulbs appear at the apical membrane of ependymal cells at the end of the first week after birth. The use of transgenic mice lacking laminin alpha5 gene expression (Lama5) in endothelium and in FoxJ1 expressing ependymal cells revealed ependymal cells as the source of laminin alpha5-containing fractone bulbs. Deletion of laminin alpha5 from ependymal cells correlated with a 60% increase in cell proliferation, as determined by phospho histone H3 staining, and with a selective reduction in the number of slow dividing cells. These results indicate that fractones are a key component of the SVZ and suggest that laminin alpha5 modulates the physiology of the neural stem cell niche.SIGNIFICANCE STATEMENT Our work unveils key aspects of fractones, extracellular matrix structures that are present in the SVZ that still lack a comprehensive characterization. We show that fractones extensively interact with neural stem cells, whereas some of them are located precisely at pinwheel centers, which are hotspots for adult neurogenesis. Our results also demonstrate that fractones increase in size during aging and that their interactions with neural stem and progenitor cells become more complex in old mice. Last, we show that fractone bulbs are produced by ependymal cells and that their laminin content regulates neural stem cells. PMID- 29530988 TI - Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice. AB - The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8-/- mice exhibited a fall of 0.7 degrees C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30 degrees C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. Trpm8-/- mice raised at mild cold temperatures developed late onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity.SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8 deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures. PMID- 29530989 TI - Reliability of single office blood pressure measurements. AB - OBJECTIVES: Standard operating procedures for office blood pressure measurement (OBPM) vary greatly between guidelines and studies. We aimed to compare the difference between a single OBPM and the mean of the three following measurements. Further, we studied how many patients with possible hypertension may be missed due to short-term masked hypertension (STMH) and how many might be overdiagnosed due to short-term white coat hypertension (STWCH). DESIGN AND SETTING: In this cross-sectional, single-centre trial, 1000 adult subjects were enrolled. After 5 min of rest, four sequential standard OBPMs were performed at 2 min intervals in a quiet room in sitting position. We compared the first (fBPM) to the mean of the second to fourth measurement (mBPM). STMH was defined as fBPM <140 mm Hg systolic and <90 mm Hg diastolic and mBPM systolic >=140 mm Hg or diastolic >=90 mm Hg. STWCH was defined as fBPM systolic >=140 mm Hg or diastolic >=90 mm Hg and mBPM <140 mm Hg systolic and <90 mm Hg diastolic. RESULTS: Complete measurements were available in 802 subjects. Between fBPM and mBPM, 662 (82.5%), 441 (55%) and 208 (25.9%) subjects showed a difference in systolic and 531 (66.2%), 247 (30.8%) and 51 (6.4%) in diastolic blood pressure (BP) values of >2 mm Hg, >5 mm Hg and >10 mm Hg, respectively. In 3.4% of initially normotensives STMH and in 34.3% of initially hypertensives, STWCH was apparent. CONCLUSIONS: There are significant differences between a single OBPM and the mean of consecutive BP measurements. Our study provides evidence that a single OBPM should not be the preferred method and should be discouraged in future guidelines. TRIAL REGISTRATION NUMBER: NCT02552030;Results. PMID- 29530990 TI - RASGRF1 Hypermethylation, a Putative Biomarker of Colorectal Cancer. AB - OBJECTIVE: RASGRF1 is a guanine nucleotide exchange factor, which promotes the release of GDP from inactive Ras and stabilizes the apoprotein. In this study, the methylation status of RASGRF1 promoter and its correlation with clinicopathological parameters were evaluated in colorectal cancer (CRC). METHODS: Methylation-specific PCR and bisulfate-sequencing PCR were carried out to investigate the promoter methylation status of the RASGRF1 gene in tumor tissues and adjacent non-tumor tissues of 68 CRC patients. The effect of RASGRF1 promoter hypermethylation on its mRNA and protein expression was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: RASGRF1 was methylated in 58.6% tumor tissues and negatively correlated with its mRNA or protein expression. There was a statistical relationship between the degree of differentiation, lymph node metastasis and clinical stage and RASGRF1 hypermethylation. Furthermore, RASGRF1 mRNA and protein levels in tumor tissues were both significantly decreased compared with that in adjacent non-tumor tissues. In addition, the correlations between RASGRF1 hypermethylation, mRNA or protein expression, and overall survival were statistically significant. CONCLUSIONS: Collectively, our data suggest that RASGRF1 hypermethylation is involved in an epigenetic field defect in CRC and that it might be a potential risk factor for CRC. PMID- 29530991 TI - The Diagnostic and Prognostic Value of Hematological and Chemical Abnormalities in Soft Tissue Sarcoma: A Comparative Study in Patients with Benign and Malignant Soft Tissue Tumors. AB - The value of routine blood tests in malignant soft tissue tumors remains uncertain. To determine if these tests can be used for screening, the routine pretreatment blood test findings were retrospectively investigated in 359 patients with benign and malignant soft tissue tumors. Additionally, the prognostic potential of pretreatment blood abnormalities was evaluated in patients with soft tissue sarcomas. We compared clinical factors and blood tests findings between patients with benign and malignant soft tissue tumors using univariate and multivariate analysis. Subsequently, patients with malignant tumors were divided into two groups based on blood test reference values, and the prognostic significance of each parameter was evaluated. In the univariate analysis, age, tumor size, and tumor depth were significant clinical diagnostic factors. Significant increases in the granulocyte count, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and gamma-glutamyl transpeptidase (gamma-GTP) levels were found in patients with malignant soft tissue tumors. Multiple logistic regression showed that tumor size and ESR were independent factors that predicted malignant soft tissue tumors. The Kaplan-Meier survival analysis revealed that granulocyte counts, gamma-GTP levels, and CRP levels correlated significantly with overall survival. Thus, pretreatment routine blood tests are useful diagnostic and prognostic markers for diagnosing soft tissue sarcoma. PMID- 29530992 TI - A Cumulative Analysis of Current Evidence for Association between Expression of Epithelial-Mesenchymal Transition Markers and Clinicopathological Outcomes in Patients after Radical Prostatectomy. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) was reported to have an important effect on malignant metastasis; however, it remained largely unknown if EMT marker expression of neoplastic tissue had predictive value for prognosis of prostate cancer. METHODS: We searched for published studies which measured EMT marker expression and analyzed its association with clinical outcomes of patients after Radical Prostatectomy (RP). We reviewed and pooled-analyzed the association of EMT marker expression and biochemical recurrence-free survival (BFS), as well as the difference in strong or weak expression of EMT markers in tumors of high Gleason score (>=8). RESULTS: A total of 25 studies with 14 EMT markers were included for review and meta-analysis. Only mesenchymal markers of N-cadherin, snail, twist, vimentin, and slug seemed to be significantly associated with decreased BFS in strongly expressed patients. Weak expression of epithelial markers (E-cadherin and alpha-catenin) and strong expression of mesenchymal markers (N-cadherin, snail, twist, and vimentin) seemed to be more frequent in tumors of Gleason >=8. CONCLUSION: Strong expression of mesenchymal markers (N cadherin, snail, twist, and vimentin) seemed to have significant predictive value for decreased BFS in patients after RP. PMID- 29530993 TI - Overexpression of Derlin-1 is Associated with Poor Prognosis in Patients with Non small Cell Lung Cancer. AB - BACKGROUND: Recent studies indicated that Derlin-1 has an important function in cancer progression. However, its expression pattern and relationships with clinicopathologic characteristics in non-small cell lung cancer (NSCLC) have not been completely found. In the current study, we aimed to evaluate the prognostic significance of Derlin-1 in NSCLC. METHODS: Cancer tissues and paracancer tissues were collected from 168 patients with NSCLC. The expression of Derlin-1 was detected by RT-PCR, Western blot, and immunohistochemistry. The correlation between Derlin-1 expression and various clinicopathologic features was investigated. RESULTS: The results showed that mRNA and protein of Derlin-1 was overexpressed in NSCLC and the positive rate of Derlin-1 was significantly correlated with TNM stage, histologic grade, lymph node metastasis and overall survival. CONCLUSION: Derlin-1 is overexpressed in NSCLC and promotes the malignancy of NSCLC. Derlin-1 maybe served as a potential therapeutic target for NSCLC. PMID- 29530994 TI - Establishment of a Multiplex PCR-Based Procedure for Detection of Most Common Mutations in NPM1, FLT3 in Acute Myeloid Leukemia Patients. AB - Numerous studies have identified Nucleophosmin 1 (NPM1) and Fms-like tyrosine kinase 3 (FLT3) as the most frequently mutated genes in Acute Myeloid Leukemia (AML) patients. Mutations occurring in these genes, including NPM1+4 (tetranucleotide insertions), FLT3-ITD (internal tandem duplications), and FLT3 TKD (tyrosine kinase domain point mutations) account for approximately 80% of all mutations found in normal karyotype AML (AML-NK) cases. Different methods have been established to detect the three listed mutations, in which, PCR-based techniques are the most widely used due to their efficiency. Past researches on performing multiplex PCR for simultaneous screening were successful for only two out of the three mutations of interest. In this study, from genomic DNA, we amplified three fragments corresponding to the regions containing these mutations in a single PCR reaction, digested the products with EcoRV, and then analyzed the migration pattern using 3% UltraphorTM agarose electrophoresis. In case of wild types, the results showed three and four distinct bands before and after restriction enzyme treatment, respectively; and in case of mutants, the presence of extra bands indicated suspected length mutations. This method was used to screen 20 samples, identifying a total of 6 possible mutants, including 3 NPM1+4 and 3 FLT3-ITDs, which were verified through established procedures and capillary electrophoresis. PMID- 29530995 TI - Correlation of Cystatin E/M with Clinicopathological Features and Prognosis in Triple-Negative Breast Cancer. AB - BACKGROUND: Among all kinds of breast cancer, triple-negative breast cancer (TNBC) is the most aggressive, with the poorest prognosis and highest mortality rates. Thus, novel biomarkers that personalize the therapeutic regimen and evaluate prognosis for TNBC patients should be determined. METHODS: We analyzed the cystatin E/M (CST6) expression profiles of 161 TNBC tissues and 14 noncancerous tissues through multiple statistical analyses. We also investigated the relationship of CST6 expression with clinical parameters and evaluated the prognostic value of CST6 in 161 TNBC patients. RESULTS: CST6, a member of the cystatin superfamily, was remarkably more up-regulated in TNBC tissues than in adjacent normal breast tissues. High CST6 expression was frequently observed in white people and associated with a high risk of lymph-node metastasis. Cox regression analysis confirmed that the high CST6 expression was an independent predictor of disease-free survival in TNBC. Kaplan-Meier analysis further revealed that high CST6 expression caused a low disease-free survival rate. CONCLUSION: CST6 is involved in the progression of TNBC and may act as a tumor promoter gene. A systematic literature review shows that our study is the first to explore the relationship between CST6 and TNBC. PMID- 29530996 TI - Aspirin Resistance: Risk Factors and Prognostic Significance in Patients with Cerebral Small Vessel Disease. AB - BACKGROUND: The clinical significance of aspirin resistance (AR) in patients with symptomatic cerebrovascular disease is not well known. The aim of this single center, prospective study was to examine the prevalence, risk factors and prognostic significance of AR in patients with different clinical manifestations of cerebral small vessel disease (CSVD) over 24-month follow-up. METHODS: We studied 104 patients with MRI confirmed CSVD, including those with recent lacunar stroke (LS, n=49), vascular parkinsonism (VaP, n=16) and dementia (VaD, n=39). Platelet aggregation was evaluated with electrode platelet aggregometry (Multiplate analyzer); AR was defined as a value of >=300 AUC*min. All patients had 24-h ABPM performed at baseline. Radiological progression was recognized based on repeated MRI examinations. RESULTS: The prevalence of AR was 26%, and it did not differ between LS, VaD, and VaP (22.4%, 28.2%, and 31.3%, respectively; p=0.7). The patients with AR had higher triglyceride levels (TG; 144.2+/-100 vs 109.7+/-48 mg/dl; p=0.09) and mean arterial blood pressure (MAP; 103.5+/-15.2 vs 91.7+/-10.5 mmHg; p<0.01) than did responders to aspirin (RTA). TG (OR 1.02; 95%CI 1-1.11; p=0.04) and MAP (OR 1.03; 95%CI 1.0-1.09; p=0.04) were independent of age, sex, statin and antihypertensive treatment risk factors for AR. The patients with AR more frequently experienced ischemic strokes than did those with RTA (OR 3.1; 98%CI 1.08-9.3; p=0.03) and had more radiological progression (OR 2.2; 95%CI 0.9-5.7; p=0.08). AR was independent of age, sex, baseline Fazekas score predictor of lacunar stroke (OR 3.79; 95%CI 1.19-12; p=0.02) and radiological progression (OR 2.9; 95%CI 1.04-8.3; p=0.04). CONCLUSIONS: The prevalence of AR was high and similar among the patients with LS, VaD, and VaP due to CSVD. Higher 24-h MAP and TG were independently related to the risk of AR. AR was associated with risk of radiological progression and lacunar strokes over 24 months of observation. PMID- 29530997 TI - Development of New mRNA Markers for the Identification of Menstrual Blood. AB - BACKGROUND: The aim of this study was to screen 3 mRNA markers (i.e., PAEP, LAPR3, and HOXA10) with diverse expression in different body fluids and to develop a method for the identification of menstrual blood using these mRNA markers. METHODS: Body fluid (i.e., venous blood, menstrual blood, semen, and saliva) samples were collected and prepared under differing environmental conditions (temperature, humidity and time), and RNA was extracted and reverse transcribed. The expression specificity of these markers was assessed using TaqMan probe qPCR. RESULTS: A high mean cycle threshold value corresponds to a lower expression level. The mean cycle threshold value of the LAPR3, HOXA10, and PAEP genes are 8.37, 8.73, 4.67 in menstrual blood respectively. LAPR3 and PAEP were only expressed in menstrual blood. HOXA10 were expressed in blood, menstrual blood, and semen. No significant differences were found while the mean cycle threshold of MMP11 and PAEP were compared in the menstrual blood under common environmental conditions. There were no observed differences in the expression of the target genes in women of different ages and at different menstrual phases. The sensitivity of the expression of the 3 target genes could be examined in fluid amount range from 1 to 32 ul of body fluid. The expression of PAEP differed markedly from the expression of LAPR3 and HOXA10 in menstrual blood stains tested using mRNA-based assays (p<0.001). CONCLUSIONS: These markers, particularly PAEP, can likely be used for the identification of menstrual blood in certain forensic cases. PMID- 29530998 TI - Clinical Significance of Myeloid-Related Protein 8/14 as a Predictor for Biological Treatment and Disease Activity in Rheumatoid Arthritis. AB - OBJECTIVES: To investigate the serum level of Myeloid-Related Protein 8/14 complex (MRP8/14) and to predict and monitor the response to biologic treatment in rheumatoid arthritis (RA) patients. METHODS: Each patient underwent clinical examination and blood sampling for assessment of serum high-sensitivity C reactive protein (hs-CRP) levels, erythrocyte sedimentation rate (ESR), rheumatoid factors (RF), anti-cyclic citrullinated protein antibodies (anti-CCP), and serum concentrations of MRP8/14 protein complexes (myeloid-related proteins, MRP8/14) were measured at baseline, and weeks 4 and 12 (after initiation of treatment). RESULTS: Serum MRP8/14 protein complex levels correlated with DAS28 and anti-CCP antibody. MRP8/14 protein complex levels decreased significantly after 12 weeks treatment with biological therapy: mono-rhTNFR-Fc active group. rhTNFR-Fc plus methotrexate (MTX) decreased MRP8/14 protein complex levels from 11839+/-1849 ng/ml to 5423+/-1130 ng/ml (p<0.01) a reduction of 54.2% compared with 32.9% in the rhTNFR-Fc group. CONCLUSIONS: MRP8/14 protein complex levels were increased in active stage RA patients. MRP8/14 levels were decreased with rhTNFR-Fc treatment, suggesting serum concentrations of MRP8/14 protein complex might be a promising biomarker to predict responses to biological therapy in active RA patients at baseline and could be used to monitor responses to treatment across different mechanisms of action. PMID- 29530999 TI - Performance of Sequencing in Predicting Ofloxacin Resistance in Mycobacterium tuberculosis from Positive Bactec MGIT 960 Cultures. AB - Ofloxacin (OFX) resistant Mycobacterium tuberculosis (MTB) isolates have been increasingly observed worldwide, complicating tuberculosis control. This study investigated the performance of sequencing which could predict OFX resistance in MTB isolates from positive Bactec MGIT 960 cultures. A total of 214 Bactec MGIT 960 positive cultures were identified by p-nitrobenzoic-acid and thiophene-2 carboxylic hydrazide. Drug susceptibility testing was performed using the proportion method and sequencing. The sequence results were compared with the results of the proportion method to analyze the consistency between the results. We identified a total of 204 MTB and 10 nontuberculous mycobacteria (NTM) isolates. Among the MTB isolates, 98% (200/204) carried gyrA and gyrB genes, whereas 20% (2/10) of the NTM isolates had gyrA and gyrB genes. Of the 202 MTB isolates, 7.4% (15/202) and 92.6% (187/202) were OFX-resistant and susceptible isolates, respectively. Among the OFX resistant isolates, 80% (12/15) had mutations in gyrA (n=9), gyrB (n=1), or both gyrA and gyrB (n=2). Among the OFX susceptible isolates, 2.7% (5/187) had mutations in gyrA (n=2) or gyrB (n=3). Compared with the proportion method, the sensitivity and specificity of sequencing were 78.6% and 99.5%, respectively. Sequencing had good performance for detecting OFX resistance and could be used for predicting OFX susceptibility. PMID- 29531000 TI - Analytical and Clinical Performance Evaluation of the Abbott Architect PIVKA Assay. AB - Protein induced by vitamin K absence (PIVKA) is measured using various assays and is used to help diagnose hepatocellular carcinoma. The present study evaluated the analytical and clinical performances of the recently released Abbott Architect PIVKA assay. Precision, linearity, and correlation tests were performed in accordance with the Clinical Laboratory Standardization Institute guidelines. Sample type suitability was assessed using serum and plasma samples from the same patients, and the reference interval was established using sera from 204 healthy individuals. The assay had coefficients of variation of 3.2-3.5% and intra laboratory variation of 3.6-5.5%. Linearity was confirmed across the entire measurable range. The Architect PIVKA assay was comparable to the Lumipulse PIVKA assay, and the plasma and serum samples provided similar results. The lower reference limit was 13.0 mAU/mL and the upper reference limit was 37.4 mAU/mL. The ability of the Architect PIVKA assay to detect hepatocellular carcinoma was comparable to that of the alpha-fetoprotein test and the Lumipulse PIVKA assay. The Architect PIVKA assay provides excellent analytical and clinical performance, is simple for clinical laboratories to adopt, and has improved sample type suitability that could broaden the assay's utility. PMID- 29531001 TI - Reliability of Pro-adrenomedullin and Interleukin 1beta in Predicting Severity of Community-Acquired Pneumonia in Pediatric Patients. AB - OBJECTIVES: Community-acquired pneumonia (CAP) in children is one of the most important causes of mortality and morbidity in developing countries. Therefore, it is very important for clinicians to detect the presence and severity of pneumonia. Proadrenomedullin (Pro-ADM) and Interleukin-1beta (IL-1beta) are thought to have potential for CAP evaluation in children. We sought to investigate the value of Pro-ADM and IL-1beta levels for severity assessment and outcome prediction in children with CAP. METHODS: A total of 66 hospitalized CAP patients were included in a prospective observational study. Complete blood count, serum C-reactive protein (CRP), Pro-ADM and IL-1beta levels were studied in blood samples obtained from the patients upon admission. Respiratory Clinical Score (RCS) was performed to determine the respiratory distress and severity. RESULTS: The comparison of data with laboratory-severity groups: serum CRP, Pro ADM and IL-1beta levels increased in parallel with the disease severity. Pro-ADM was the best biomarker for severity stratification. Logistic regression analysis revealed that RCS >6 points and Pro-ADM values >1.75 nmol/L combination had the most significant results (OR: 15.38, 95% CI 1.35-166.66, p=0.027). Moreover, a relationship was found between the high serum levels of IL-1beta and requirement of intervention procedures in patients with pleural effusion. CONCLUSIONS: Serum Pro-ADM and IL-1beta levels may offer additional risk/severity stratification in children with CAP. In addition, they may be helpful in predicting the development of complications, requirements for ntensive care unit admission, and intervention procedures. PMID- 29531002 TI - Validation of the Cut-points Recommended for ROMA Using the Roche Elecsys CA125 and HE4 Assays. AB - Assessing the risk of malignancy in patients with a pelvic mass helps triage women suspected of ovarian cancer to specialized gynecologic oncologists to improve treatment outcomes. To this end, several algorithms have been proposed; most notably, the Risk of Ovarian Malignancy Algorithm (ROMA) based on CA125, HE4, and menopausal status. However, appropriate decision cut-points for the ROMA score depends on the choice of analytical assays used. This study validates the use of the Roche Elecsys CA125 and HE4 assays for ROMA calculation in a cohort of 207 women who presented to Mayo Clinic with a pelvic mass. Results were compared to a definitive histologic diagnosis in each case. Clinical performance of ROMA scores derived using these assays was similar to stated claims and indicates that recommended cut-points are acceptable for clinical use. PMID- 29531003 TI - Mammary Analogue Secretory Carcinoma of Minor Salivary Glands: A Rare Case Series and Review of the Literature. AB - Mammary analogue secretory carcinoma (MASC) is a rare salivary gland tumor that recapitulates the cytomorphology, immunophenotype, and genetics of an equally rare malignancy of the breast, secretory carcinoma (SC). Here we present two cases of MASC of minor salivary glands from a single institutional experience. PMID- 29531004 TI - Five Novel COL7A1 Gene Mutations in Three Chinese Patients with Recessive Dystrophic Epidermolysis Bullosa. AB - BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is an inherited skin disorder with variable severity and heterogeneous genetic involvement. Recessive DEB (RDEB) is a rare heritable blistering skin condition caused by loss-of-function mutations in the COL7A1 gene. AIM: This study aimed to determine the genetic basis of three Chinese RDEB patients from different families and identify correlations between phenotype and genotype. METHODS: All three patients were diagnosed with RDEB based on typical phenotype. Genomic DNA from both the patients and parents was subjected to amplification of all 118 exons and flanking intron boundaries of the COL7A1 gene, followed by Sanger sequencing. RESULTS: Sanger sequencing identified six mutations in the three patients: five novel mutations (c.2321_2322insCTGA in exon 18, c.5924-5927delAACG in exon 72, c.4871delC in exon 53, c.8278G>A in exon 111, and c.1A>G in exon 1) and one recurrent mutation (c.8038G>A in exon 108). The first three novel mutations resulted in a premature termination codon (PTC), the remaining two novel mutations caused a glycine substitution and a loss of the primary ATG start codon, respectively. All patients had a heterozygous PTC mutation combined with either a glycine substitution mutation in the critical triple-helical collagenous domain or a loss of the primary ATG start codon. CONCLUSION: Our findings expand the mutation spectrum of COL7A1 leading to RDEB and confirm that the RDEB phenotype correlates with the compound heterozygous PTC mutation with a missense mutation. This study will aid the molecular diagnosis, genetic counseling and prognosis prediction of RDEB patients. PMID- 29531005 TI - A Novel Frameshift Mutation (c.5387_5388insTT) in NIPBL in Cornelia de Lange Syndrome with Severe Phenotype. AB - Cornelia de Lange syndrome (CdLS) is a developmental disorder which is characterized by typical facial features, upper extremity malformations, and growth and cognitive delays. The genes involved in CdLS encode the cohesin complex and its associated proteins; and NIPBL mutations, which account for half of the cases, result in severe CdLS phenotypes. We describe a girl with CdLS, presenting with typical facial dysmorphism, cleft palate, hypertrichosis, upper limb hypertonicity, flexion contracture of elbows, micromelia, bilateral hearing loss, gastroesophageal reflux, and severe pyloric stenosis. We detected a heterozygous frameshift mutation in NIPBL (c.5387_5388ins(TT), p.Leu1796Phefs*8) which is a novel mutation. PMID- 29531006 TI - TFE3-Expressing Epithelioid Rich Perivascular Epithelioid Cell Neoplasm (PEComa) of the Bladder with Unusual Benign Course. AB - Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor which presents with epithelioid and spindled cell morphology and is immunoreactive for myogenic and melanocytic markers. Recently, a subset of PEComas has been reported to harbor TFE3 gene rearrangement.In this case report, we describe a TFE3-expressing primary bladder PEComa in a 27-year-old male patient with acute myeloid leukaemia in remission. The tumor displayed epithelioid morphology with surrounding delicate blood vessels and was devoid of a prominent spindle cell component. Malignant features were not identified. The tumor expressed HMB45, CD117, and focal patchy positive expression for SMA. TFE3 gene translocation was confirmed by Fluorescence in-situ hybridization. RT-PCR assay confirmed the presence of SFPQ-TFE3 gene fusion.In contrast to previously reported aggressive TFE3 gene rearranged bladder PEComa cases, our case shows benign histologic and clinical features. Current clinical follow-up also shows a benign course. PMID- 29531007 TI - Uterus Septus Subtotalis Bicollis: A Rare Mullerian Duct Abnormality. AB - Mullerian duct anomalies (MDAs) are congenital defects of the female genital system that arise from abnormal embryological development of the Mullerian ducts. Septate uterus is the most common, resulting from incomplete resorption of the medial septum after fusion of the Mullerian ducts. Two main types of septate uterus exist, including septa that extend completely or partially from the uterine fundus to the cervical os. The combination of a uterine septum with a double cervix has been previously described; however, in most cases the septum was complete. We present a case of a 23-year-old female with a partial uterine septum and a double cervix. We refer to this atypical MDA as "uterus septus subtotalis bicollis". The description, characterization, and diagnosis of rare MDAs is important as they imply distinct therapeutic modalities. PMID- 29531008 TI - Late Relapse of Multiple Myeloma with Testicular Plasmacytoma after Autologous Hematopoietic Stem Cell Transplantation: A Case Report and Review of the Literature. AB - High-dose chemotherapy combined with autologous hematopoietic stem-cell transplantation (ASCT) is the first-line treatment for multiple myeloma. Yet, some patients will relapse. Testicular plasmacytoma which rarely happens can be isolated or associated with progressive multiple myeloma. Here, we report a case of multiple myeloma (MM) undergoing ASCT when the patient obtained complete remission. He developed painless right testicular swelling after nearly 3 years since the ASCT. After radical orchiectomy, histopathology showed diffuse abnormal plasma cells infiltration of the testicular tissue. At the same time, he experienced a bone marrow relapse, and relapse of multiple myeloma with plasmacytoma of testis was confirmed. It is also important to note that at the time of initial diagnosis with MM, he had no mutation of TP53 and MYC in FISH, but at a relapse with testicular plasmacytoma, some high-risk karyotypes were detected, including amplification with 1q21 and absence of p53, RB1/D13S319 and rearrangement with IGH. Similarly, the rearrangement with IGH was found in the histological sections of testicular neoplasm by FISH. The clinical characteristics and altered chromosomes of the case are discussed in the context of previous reports. In common with reports, testicular plasmacytoma with relapsed multiple myeloma had a worse outcome and our findings suggest that chromosome monitoring can be added in multiple myeloma after ASCT. PMID- 29531009 TI - Communication: Melatonin, Hyperhomocysteinemia, Thioretinaco Ozonide, Adenosylmethionine and Mitochondrial Dysfunction in Aging and Dementia. AB - The indoleamine hormone melatonin is synthesized by the pineal gland, controls circadian rhythm, and is dependent upon adenosyl methionine for enzymatic synthesis of melatonin from N-acetyl serotonin. Pineal melatonin secretion declines dramatically with aging and dementia. Elevated plasma homocysteine is a risk factor for atherosclerosis and Alzheimer's disease, and the marked decline in adenosyl methionine with aging leads to dysregulation of methionine metabolism and hyperhomocysteinemia. Thioretinaco ozonide is a disulfonium complex formed from thioretinamide, cobalamin, and ozone, which binds the alpha and gamma phosphate groups of adenosine triphosphate (ATP) and oxygen in the process of oxidative phosphorylation within mitochondria. Decreased adenosyl methionine concentrations with aging are attributed to the loss of thioretinaco ozonide from mitochondria, impairing adenosyl methionine synthesis from thioretinaco ozonide and ATP. Melatonin is present in mitochondria, where it inhibits the opening of the mitochondrial permeability transition pore, explaining its anti-oxidant and anti-apoptotic effects by reducing oxygen consumption, restoration of membrane potential and reduction of superoxide production. In aging, the enzyme cyclic nucleotide phosphodiesterase is lost from mitochondria by the opening of the permeability transition pore and disruption of the outer mitochondrial membrane, a process that is inhibited by melatonin. Thioretinaco ozonide is progressively lost from dysfunctional mitochondria by disruption of the outer mitochondrial membrane, explaining its depletion during the aging process. Accordingly, the anti-aging effects of diallyl trisulfide and metformin are attributable to inhibition of the opening of the mitochondrial permeability transition pore, preventing loss of thioretinaco ozonide from mitochondria. The hyperhomocysteinemia and suppressed immunity that are observed in atherosclerosis and dementia are attributed to the deficiency of adenosylmethionine caused by increased polyamine synthesis and decreased nitric oxide synthesis by host cells infected with pathogenic microbes. According to this analysis, the critical loss of thioretinaco ozonide from mitochondria through the opening of the permeability transition pore and disruption of the outer mitochondrial membrane by decreased melatonin secretion leads to the impaired oxidative phosphorylation, oxidative stress, calcium influx, apoptosis and mitochondrial dysfunction observed in aging and dementia. PMID- 29531010 TI - Genetics and Genomics of Social Behavior in a Chicken Model. AB - The identification of genes affecting sociality can give insights into the maintenance and development of sociality and personality. In this study, we used the combination of an advanced intercross between wild and domestic chickens with a combined QTL and eQTL genetical genomics approach to identify genes for social reinstatement, a social and anxiety-related behavior. A total of 24 social reinstatement QTL were identified and overlaid with over 600 eQTL obtained from the same birds using hypothalamic tissue. Correlations between overlapping QTL and eQTL indicated five strong candidate genes, with the gene TTRAP being strongly significantly correlated with multiple aspects of social reinstatement behavior, as well as possessing a highly significant eQTL. PMID- 29531011 TI - Mitochondrial Recombination Reveals Mito-Mito Epistasis in Yeast. AB - Genetic variation in mitochondrial DNA (mtDNA) provides adaptive potential although the underlying genetic architecture of fitness components within mtDNAs is not known. To dissect functional variation within mtDNAs, we first identified naturally occurring mtDNAs that conferred high or low fitness in Saccharomyces cerevisiae by comparing growth in strains containing identical nuclear genotypes but different mtDNAs. During respiratory growth under temperature and oxidative stress conditions, mitotype effects were largely independent of nuclear genotypes even in the presence of mito-nuclear interactions. Recombinant mtDNAs were generated to determine fitness components within high- and low-fitness mtDNAs. Based on phenotypic distributions of isogenic strains containing recombinant mtDNAs, we found that multiple loci contributed to mitotype fitness differences. These mitochondrial loci interacted in epistatic, nonadditive ways in certain environmental conditions. Mito-mito epistasis (i.e., nonadditive interactions between mitochondrial loci) influenced fitness in progeny from four different crosses, suggesting that mito-mito epistasis is a widespread phenomenon in yeast and other systems with recombining mtDNAs. Furthermore, we found that interruption of coadapted mito-mito interactions produced recombinant mtDNAs with lower fitness. Our results demonstrate that mito-mito epistasis results in functional variation through mitochondrial recombination in fungi, providing modes for adaptive evolution and the generation of mito-mito incompatibilities. PMID- 29531014 TI - March 12th Question. PMID- 29531013 TI - Predicted rise in trusts' income from private patients fails to materialise. PMID- 29531015 TI - Knockdown of MRPL42 suppresses glioma cell proliferation by inducing cell cycle arrest and apoptosis. AB - Mammalian mitochondrial ribosomal proteins are functionally involved in protein synthesis in mitochondrion. Recently numerous studies have illuminated the role of mitochondrion in cancer development. However, the precise function of mitochondrial ribosomal protein L42 (MRPL42) remains unclear. Here in the present study, we identified MRPL42 as a novel oncogene in glioma. By analyzing the Cancer Genome Atlas (TCGA) database, we first found that MRPL42 was significantly up-regulated in glioma tissues compared with normal tissues. Functionally, we silenced MRPL42 in glioma cells and revealed that MRPL42 knockdown largely blunted the proliferation of U251 and A172 cells. Mechanistically, our results suggested that MRPL42 silencing resulted in increased distribution of cell cycle in G1 and G2/M phases, while the S-phase decreased. In addition, the apoptosis and caspase3/7 activity were both activated after MRPL42 knockdown. Taken together, MRPL42 is a novel oncogene in glioma and might help us develop promising targetted therapies for glioma patients. PMID- 29531012 TI - MIB-1 Is Required for Spermatogenesis and Facilitates LIN-12 and GLP-1 Activity in Caenorhabditis elegans. AB - Covalent attachment of ubiquitin to substrate proteins changes their function or marks them for proteolysis, and the specificity of ubiquitin attachment is mediated by the numerous E3 ligases encoded by animals. Mind Bomb is an essential E3 ligase during Notch pathway signaling in insects and vertebrates. While Caenorhabditis elegans encodes a Mind Bomb homolog (mib-1), it has never been recovered in the extensive Notch suppressor/enhancer screens that have identified numerous pathway components. Here, we show that C. elegans mib-1 null mutants have a spermatogenesis-defective phenotype that results in a heterogeneous mixture of arrested spermatocytes, defective spermatids, and motility-impaired spermatozoa. mib-1 mutants also have chromosome segregation defects during meiosis, molecular null mutants are intrinsically temperature-sensitive, and many mib-1 spermatids contain large amounts of tubulin. These phenotypic features are similar to the endogenous RNA intereference (RNAi) mutants, but mib-1 mutants do not affect RNAi. MIB-1 protein is expressed throughout the germ line with peak expression in spermatocytes followed by segregation into the residual body during spermatid formation. C. elegans mib-1 expression, while upregulated during spermatogenesis, also occurs somatically, including in vulva precursor cells. Here, we show that mib-1 mutants suppress both lin-12 and glp-1 (C. elegans Notch) gain-of-function mutants, restoring anchor cell formation and a functional vulva to the former and partly restoring oocyte production to the latter. However, suppressed hermaphrodites are only observed when grown at 25 degrees , and they are self-sterile. This probably explains why mib-1 was not previously recovered as a Notch pathway component in suppressor/enhancer selection experiments. PMID- 29531016 TI - CREB3L1 and PTN expressions correlate with prognosis of brain glioma patients. AB - The present study was conducted to investigate the clinical significance of cAMP responsive element binding protein 3 like 1 (CREB3L1) and pleiotrophin (PTN) expression in prognosis of patients with brain gliomas. Human brain tissue samples were collected from normal glial tissues (control), low- and high-grade glioma tissues. CREB3L1 and PTN expression levels in cells were assessed by immunohistochemistry (IHC), and population distribution of the CREB3L1- and PTN presenting patients was examined. The CREB3L1 and PTN mRNA expression levels in three types of the brain cells was determined by RT-PCR. Survival rates for population of the CREB3L1- and PTN-presenting patients were examined. CREB3L1+ cell counts were decreased with increased PTN+ cells in the low-grade and high grade glioma tissues as compared with the control. Population proportion of the CREB3L1+-presenting patients decreased from the control to the high-grade glioma and the population of the PTN+-presenting patients increased in low- and high grade gliomas as compared with the control (both P<0.05). The decrease in the CREB3L1 mRNA expression was associated with the increase in the PTN mRNA expression in the low- and high-grade gliomas (P<0.05). Survival time for patients with CREB3L1- and PTN+ gliomas was shorter than patients with CREB3L1+ and PTN- gliomas in the investigated cohorts (both P<0.05). There was a relationship between the expression levels of both proteins and survival time. CREB3L1 and PTN expression levels serve as biomarkers with utility in grading gliomas. Absence of CREB3L1 and presence of PTN in brain glioma cells correlate with survival time of the glioma patients. PMID- 29531017 TI - Activation of M1 macrophages plays a critical role in the initiation of acute lung injury. AB - The goal of the present study was to investigate the role of M1 macrophages in acute lung injury (ALI). To address this, we used lipopolysaccharide (LPS) treated wild-type and CD11b-DTR mice, and examined their M1 macrophage levels, and the extent of their inflammation and pulmonary injuries. In addition, we evaluated pulmonary function by measuring the expressions of SP-A and SP-B in infiltrated M1 macrophages. Finally, we co-cultured the mouse type II-like alveolar epithelial cells (AT-II) and mouse pulmonary microvascular endothelial cells (PMECs) with M1 macrophages in the presence of TNF-alpha or H2O2 and assessed them for viability and apoptosis. After LPS treatment, we observed that the number of pulmonary M1/M2 macrophages and the serum levels of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and reactive oxygen species (ROS) significantly increased. Furthermore, the increase in cytokines was accompanied with the initiation of lung injury indicated by the decreased levels of SP-A and SP-B. In macrophage-depleted CD11b-DTR mice, ALI was attenuated, serum levels of IL-1beta, TNF-alpha and ROS were reduced, and lung levels of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were decreased. After administering TNF-alpha and H2O2, the proapoptotic effect of M1 macrophages on AT-II or PMECs significantly increased, the cell viabilities significantly decreased, and apoptosis significantly increased. Our results suggest that M1 macrophages are recruited to the lungs where they significantly contribute to an increase in TNF-alpha and ROS production, thus initiating ALI. PMID- 29531018 TI - The effect of earthworm extract on promoting skin wound healing. AB - Chronic nonhealing wounds pose a significant challenge to healthcare system because of its tremendous utilization of resources and time to heal. It has a well-deserved reputation for reducing the quality of life for those affected and represent a substantial economic burden to the healthcare system overall. Earthworms are used as a traditional Chinese medicine, and have been applied pharmacologically and clinically since a long time in China. However, there is paucity in data regarding its wound healing effects. Therefore, we investigated the effect of earthworm extract (EE) on skin wound healing process. The obtained data showed that EE has healing effects on local wound of mice. It decreased the wound healing time and reduced the ill-effects of inflammation as determined by macroscopic, histopathologic, hematologic, and immunohistochemistry parameters. The potential mechanism could be accelerated hydroxyproline and transforming growth factor-beta secretion-thus increasing the synthesis of collagen, promoting blood capillary, and fibroblast proliferation. It could accelerate the removal of necrotic tissue and foreign bodies by speeding up the generation of interleukin 6, white blood cells, and platelets. It thus enhances immunity, reduces the risk of infection, and promotes wound healing. All in all, the obtained data demonstrated that EE improves quality of healing and could be used as a propitious wound healing agent. PMID- 29531019 TI - Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies. AB - High grade gliomas are the most common brain tumors in adult. These tumors are characterized by a high infiltration in microglial cells and macrophages. The immunosuppressive tumor environment is known to orient immune cells toward a pro tumoral and anti-inflammatory phenotype. Therefore, the current challenge for cancer therapy is to find a way to reorient macrophages toward an antitumoral phenotype. Previously, we demonstrated that macrophages secreted antitumoral factors when they were invalidated for the proprotein converstase 1/3 (PC1/3) and treated with LPS. However, achieving an activation of macrophages via LPS/TLR4/Myd88-dependent pathway appears yet unfeasible in cancer patients. On the contrary, the antitumor drug Paclitaxel is also known to activate the TLR4 MyD88-dependent signaling pathway and mimics LPS action. Therefore, we evaluated if PC1/3 knock-down (KD) macrophages could be activated by Paclitaxel and efficient against glioma. We report here that such a treatment of PC1/3 KD macrophages drove to the overexpression of proteins mainly involved in cytoskeleton rearrangement. In support of this finding, we found that these cells exhibited a Ca2+ increase after Paclitaxel treatment. This is indicative of a possible depolymerization of microtubules and may therefore reflect an activation of inflammatory pathways in macrophages. In such a way, we found that PC1/3 KD macrophages displayed a repression of the anti-inflammatory pathway STAT3 and secreted more pro-inflammatory cytokines. Extracellular vesicles isolated from these PC1/3 KD cells inhibited glioma growth. Finally, the supernatant collected from the coculture between glioma cells and PC1/3 KD macrophages contained more antitumoral factors. These findings unravel the potential value of a new therapeutic strategy combining Paclitaxel and PC1/3 inhibition to switch macrophages toward an antitumoral immunophenotype. PMID- 29531022 TI - Retraction: "Haemophilus influenzae responds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance". AB - Chris S Earl, Teh Wooi Keong, Shi-qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole & Robert P RyanThe above article, published May 20 2015 in EMBO Molecular Medicine, has been retracted by agreement between the authors of the study, CSE, TWK, SQA, SM, YMcC, JG, JW, JMD, LY, RPR, the journal Chief Editor and the EMBO Head of Scientific Publications in accordance with the outcomes of independent investigations conducted by the University of Dundee and University College Cork.GAO'T disagrees with the text of this retraction notice, albeit not with the retraction.The following issues are noted: Table 1 contains clinical data described in the paper as being derived from a cohort of asthma patients. However, the provenance of this data is unclear. Based on the evidence available, the University of Dundee investigation concluded that the majority of the patient cohort is likely to be a subset of a cohort of cystic fibrosis patients reported in PLoS One 8(12): e82432 (https://doi.org/10.1371/journal.pone.0082432), although in a number of cases the patient's gender is at odds between the two reports.The RNAseq data are unavailable on the European Nucleotide Archive under the reported accession number ERG003569. RNAseq data were uploaded with accession number ERS654066 before publication.The paper describes use of both prednisolone and prednisone, yet only the latter was used in the study. PMID- 29531020 TI - Implementation of a Multiplex and Quantitative Proteomics Platform for Assessing Protein Lysates Using DNA-Barcoded Antibodies. AB - Molecular analysis of tumors forms the basis for personalized cancer medicine and increasingly guides patient selection for targeted therapy. Future opportunities for personalized medicine are highlighted by the measurement of protein expression levels via immunohistochemistry, protein arrays, and other approaches; however, sample type, sample quantity, batch effects, and "time to result" are limiting factors for clinical application. Here, we present a development pipeline for a novel multiplexed DNA-labeled antibody platform which digitally quantifies protein expression from lysate samples. We implemented a rigorous validation process for each antibody and show that the platform is amenable to multiple protocols covering nitrocellulose and plate-based methods. Results are highly reproducible across technical and biological replicates, and there are no observed "batch effects" which are common for most multiplex molecular assays. Tests from basal and perturbed cancer cell lines indicate that this platform is comparable to orthogonal proteomic assays such as Reverse-Phase Protein Array, and applicable to measuring the pharmacodynamic effects of clinically-relevant cancer therapeutics. Furthermore, we demonstrate the potential clinical utility of the platform with protein profiling from breast cancer patient samples to identify molecular subtypes. Together, these findings highlight the potential of this platform for enhancing our understanding of cancer biology in a clinical translation setting. PMID- 29531021 TI - Tranilast directly targets NLRP3 to treat inflammasome-driven diseases. AB - The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti-allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome related human diseases, including gouty arthritis, cryopyrin-associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3-driven diseases. PMID- 29531023 TI - Empirical confidence interval calibration for population-level effect estimation studies in observational healthcare data. AB - Observational healthcare data, such as electronic health records and administrative claims, offer potential to estimate effects of medical products at scale. Observational studies have often been found to be nonreproducible, however, generating conflicting results even when using the same database to answer the same question. One source of discrepancies is error, both random caused by sampling variability and systematic (for example, because of confounding, selection bias, and measurement error). Only random error is typically quantified but converges to zero as databases become larger, whereas systematic error persists independent from sample size and therefore, increases in relative importance. Negative controls are exposure-outcome pairs, where one believes no causal effect exists; they can be used to detect multiple sources of systematic error, but interpreting their results is not always straightforward. Previously, we have shown that an empirical null distribution can be derived from a sample of negative controls and used to calibrate P values, accounting for both random and systematic error. Here, we extend this work to calibration of confidence intervals (CIs). CIs require positive controls, which we synthesize by modifying negative controls. We show that our CI calibration restores nominal characteristics, such as 95% coverage of the true effect size by the 95% CI. We furthermore show that CI calibration reduces disagreement in replications of two pairs of conflicting observational studies: one related to dabigatran, warfarin, and gastrointestinal bleeding and one related to selective serotonin reuptake inhibitors and upper gastrointestinal bleeding. We recommend CI calibration to improve reproducibility of observational studies. PMID- 29531024 TI - Simple mechanosense and response of cilia motion reveal the intrinsic habits of ciliates. AB - An important habit of ciliates, namely, their behavioral preference for walls, is revealed through experiments and hydrodynamic simulations. A simple mechanical response of individual ciliary beating (i.e., the beating is stalled by the cilium contacting a wall) can solely determine the sliding motion of the ciliate along the wall and result in a wall-preferring behavior. Considering ciliate ethology, this mechanosensing system is likely an advantage in the single cell's ability to locate nutrition. In other words, ciliates can skillfully use both the sliding motion to feed on a surface and the traveling motion in bulk water to locate new surfaces according to the single "swimming" mission. PMID- 29531025 TI - Misrepresentation and distortion of research in biomedical literature. AB - Publication in peer-reviewed journals is an essential step in the scientific process. However, publication is not simply the reporting of facts arising from a straightforward analysis thereof. Authors have broad latitude when writing their reports and may be tempted to consciously or unconsciously "spin" their study findings. Spin has been defined as a specific intentional or unintentional reporting that fails to faithfully reflect the nature and range of findings and that could affect the impression the results produce in readers. This article, based on a literature review, reports the various practices of spin from misreporting by "beautification" of methods to misreporting by misinterpreting the results. It provides data on the prevalence of some forms of spin in specific fields and the possible effects of some types of spin on readers' interpretation and research dissemination. We also discuss why researchers would spin their reports and possible ways to avoid it. PMID- 29531027 TI - Human diets drive range expansion of megafauna-dispersed fruit species. AB - Neotropical fruit species once dispersed by Pleistocene megafauna have regained relevance in diversifying human diets to address malnutrition. Little is known about the historic interactions between humans and these fruit species. We quantified the human role in modifying geographic and environmental ranges of Neotropical fruit species by comparing the distribution of megafauna-dispersed fruit species that have been part of both human and megafauna diets with fruit species that were exclusively part of megafauna diets. Three quarters of the fruit species that were once dispersed by megafauna later became part of human diets. Our results suggest that, because of extensive dispersal and management, humans have expanded the geographic and environmental ranges of species that would otherwise have suffered range contraction after extinction of megafauna. Our results suggest that humans have been the principal dispersal agent for a large proportion of Neotropical fruit species between Central and South America. Our analyses help to identify range segments that may hold key genetic diversity resulting from historic interactions between humans and these fruit species. These genetic resources are a fundamental source to improve and diversify contemporary food systems and to maintain critical ecosystem functions. Public, private, and societal initiatives that stimulate dietary diversity could expand the food usage of these megafauna-dispersed fruit species to enhance human nutrition in combination with biodiversity conservation. PMID- 29531026 TI - Mechanistic basis for the activation of plant membrane receptor kinases by SERK family coreceptors. AB - Plant-unique membrane receptor kinases with leucine-rich repeat ectodomains (LRR RKs) can sense small molecule, peptide, and protein ligands. Many LRR-RKs require SERK-family coreceptor kinases for high-affinity ligand binding and receptor activation. How one coreceptor can contribute to the specific binding of distinct ligands and activation of different LRR-RKs is poorly understood. Here we quantitatively analyze the contribution of SERK3 to ligand binding and activation of the brassinosteroid receptor BRI1 and the peptide hormone receptor HAESA. We show that while the isolated receptors sense their respective ligands with drastically different binding affinities, the SERK3 ectodomain binds the ligand associated receptors with very similar binding kinetics. We identify residues in the SERK3 N-terminal capping domain, which allow for selective steroid and peptide hormone recognition. In contrast, residues in the SERK3 LRR core form a second, constitutive receptor-coreceptor interface. Genetic analyses of protein chimera between BRI1 and SERK3 define that signaling-competent complexes are formed by receptor-coreceptor heteromerization in planta. A functional BRI1-HAESA chimera suggests that the receptor activation mechanism is conserved among different LRR-RKs, and that their signaling specificity is encoded in the kinase domain of the receptor. Our work pinpoints the relative contributions of receptor, ligand, and coreceptor to the formation and activation of SERK dependent LRR-RK signaling complexes regulating plant growth and development. PMID- 29531029 TI - Correction for Slik et al., Phylogenetic classification of the world's tropical forests. PMID- 29531028 TI - Extrachromosomal circular DNA-based amplification and transmission of herbicide resistance in crop weed Amaranthus palmeri. AB - Gene amplification has been observed in many bacteria and eukaryotes as a response to various selective pressures, such as antibiotics, cytotoxic drugs, pesticides, herbicides, and other stressful environmental conditions. An increase in gene copy number is often found as extrachromosomal elements that usually contain autonomously replicating extrachromosomal circular DNA molecules (eccDNAs). Amaranthus palmeri, a crop weed, can develop herbicide resistance to glyphosate [N-(phosphonomethyl) glycine] by amplification of the 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene, the molecular target of glyphosate. However, biological questions regarding the source of the amplified EPSPS, the nature of the amplified DNA structures, and mechanisms responsible for maintaining this gene amplification in cells and their inheritance remain unknown. Here, we report that amplified EPSPS copies in glyphosate-resistant (GR) A. palmeri are present in the form of eccDNAs with various conformations. The eccDNAs are transmitted during cell division in mitosis and meiosis to the soma and germ cells and the progeny by an as yet unknown mechanism of tethering to mitotic and meiotic chromosomes. We propose that eccDNAs are one of the components of McClintock's postulated innate systems [McClintock B (1978) Stadler Genetics Symposium] that can rapidly produce soma variation, amplify EPSPS genes in the sporophyte that are transmitted to germ cells, and modulate rapid glyphosate resistance through genome plasticity and adaptive evolution. PMID- 29531030 TI - Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration. AB - Inherited retinal degeneration (RD) is a devastating and currently untreatable neurodegenerative condition that leads to loss of photoreceptor cells and blindness. The vast genetic heterogeneity of RD, the lack of "druggable" targets, and the access-limiting blood-retinal barrier (BRB) present major hurdles toward effective therapy development. Here, we address these challenges (i) by targeting cGMP (cyclic guanosine- 3',5'-monophosphate) signaling, a disease driver common to different types of RD, and (ii) by combining inhibitory cGMP analogs with a nanosized liposomal drug delivery system designed to facilitate transport across the BRB. Based on a screen of several cGMP analogs we identified an inhibitory cGMP analog that interferes with activation of photoreceptor cell death pathways. Moreover, we found liposomal encapsulation of the analog to achieve efficient drug targeting to the neuroretina. This pharmacological treatment markedly preserved in vivo retinal function and counteracted photoreceptor degeneration in three different in vivo RD models. Taken together, we show that a defined class of compounds for RD treatment in combination with an innovative drug delivery method may enable a single type of treatment to address genetically divergent RD type diseases. PMID- 29531031 TI - Deletion of dopamine D2 receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes. AB - Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system. PMID- 29531033 TI - Reproducibility of research: Issues and proposed remedies. PMID- 29531032 TI - Enhancing primary reports of randomized controlled trials: Three most common challenges and suggested solutions. AB - Evidence from a well-designed randomized controlled trial (RCT) is generally considered to be the gold standard that can inform clinical practice and guide decision-making. However, several deficiencies in the reporting of RCTs have frequently been identified, including incomplete, selective, and biased or inconsistent reporting. Such suboptimal reporting may lead to irreproducible results, substantial waste of resources, impaired study validity, erosion of public trust in science, and a high risk of research misconduct. In this article, we present an overview of the reporting of RCTs in the biomedical literature with a focus on the three most common reporting problems: (i) lack of adherence to reporting guidelines, (ii) inconsistencies between trial protocols or registrations and full reports, and (iii) inconsistencies between abstracts and their corresponding full reports. Unsatisfactory levels of adherence to guidelines and frequent inconsistencies between protocols or registrations and full reports, and between abstracts and full reports, were consistently found in various biomedical research fields. A variety of factors were found to be associated with these reporting challenges. Improved reporting can build public trust and credibility of science, save resources, and enhance the ethical integrity of research. Therefore, joint efforts from the various sectors of the biomedical community (researchers, journal editors and reviewers, educators, healthcare providers, and other research consumers) are needed to reduce and reverse the current suboptimal state of RCT reporting in the literature. PMID- 29531034 TI - Nanoscale view of assisted ion transport across the liquid-liquid interface. AB - During solvent extraction, amphiphilic extractants assist the transport of metal ions across the liquid-liquid interface between an aqueous ionic solution and an organic solvent. Investigations of the role of the interface in ion transport challenge our ability to probe fast molecular processes at liquid-liquid interfaces on nanometer-length scales. Recent development of a thermal switch for solvent extraction has addressed this challenge, which has led to the characterization by X-ray surface scattering of interfacial intermediate states in the extraction process. Here, we review and extend these earlier results. We find that trivalent rare earth ions, Y(III) and Er(III), combine with bis(hexadecyl) phosphoric acid (DHDP) extractants to form inverted bilayer structures at the interface; these appear to be condensed phases of small ion extractant complexes. The stability of this unconventional interfacial structure is verified by molecular dynamics simulations. The ion-extractant complexes at the interface are an intermediate state in the extraction process, characterizing the moment at which ions have been transported across the aqueous-organic interface, but have not yet been dispersed in the organic phase. In contrast, divalent Sr(II) forms an ion-extractant complex with DHDP that leaves it exposed to the water phase; this result implies that a second process that transports Sr(II) across the interface has yet to be observed. Calculations demonstrate that the budding of reverse micelles formed from interfacial Sr(II) ion-extractant complexes could transport Sr(II) across the interface. Our results suggest a connection between the observed interfacial structures and the extraction mechanism, which ultimately affects the extraction selectivity and kinetics. PMID- 29531035 TI - Stabilized supralinear network can give rise to bistable, oscillatory, and persistent activity. AB - A hallmark of cortical circuits is their versatility. They can perform multiple fundamental computations such as normalization, memory storage, and rhythm generation. Yet it is far from clear how such versatility can be achieved in a single circuit, given that specialized models are often needed to replicate each computation. Here, we show that the stabilized supralinear network (SSN) model, which was originally proposed for sensory integration phenomena such as contrast invariance, normalization, and surround suppression, can give rise to dynamic cortical features of working memory, persistent activity, and rhythm generation. We study the SSN model analytically and uncover regimes where it can provide a substrate for working memory by supporting two stable steady states. Furthermore, we prove that the SSN model can sustain finite firing rates following input withdrawal and present an exact connectivity condition for such persistent activity. In addition, we show that the SSN model can undergo a supercritical Hopf bifurcation and generate global oscillations. Based on the SSN model, we outline the synaptic and neuronal mechanisms underlying computational versatility of cortical circuits. Our work shows that the SSN is an exactly solvable nonlinear recurrent neural network model that could pave the way for a unified theory of cortical function. PMID- 29531036 TI - Substrate recognition and mechanism revealed by ligand-bound polyphosphate kinase 2 structures. AB - Inorganic polyphosphate is a ubiquitous, linear biopolymer built of up to thousands of phosphate residues that are linked by energy-rich phosphoanhydride bonds. Polyphosphate kinases of the family 2 (PPK2) use polyphosphate to catalyze the reversible phosphorylation of nucleotide phosphates and are highly relevant as targets for new pharmaceutical compounds and as biocatalysts for cofactor regeneration. PPK2s can be classified based on their preference for nucleoside mono- or diphosphates or both. The detailed mechanism of PPK2s and the molecular basis for their substrate preference is unclear, which is mainly due to the lack of high-resolution structures with substrates or substrate analogs. Here, we report the structural analysis and comparison of a class I PPK2 (ADP phosphorylating) and a class III PPK2 (AMP- and ADP-phosphorylating), both complexed with polyphosphate and/or nucleotide substrates. Together with complementary biochemical analyses, these define the molecular basis of nucleotide specificity and are consistent with a Mg2+ catalyzed in-line phosphoryl transfer mechanism. This mechanistic insight will guide the development of PPK2 inhibitors as potential antibacterials or genetically modified PPK2s that phosphorylate alternative substrates. PMID- 29531037 TI - Reintroductions of birds and mammals involve evolutionarily distinct species at the regional scale. AB - Reintroductions offer a powerful tool for reversing the effects of species extirpation and have been increasingly used over recent decades. However, this species-centered conservation approach has been criticized for its strong biases toward charismatic birds and mammals. Here, we investigated whether reintroduced species can be representative of the phylogenetic diversity within these two groups at a continental scale (i.e., Europe, North and Central America). Using null models, we found that reintroduced birds and mammals of the two subcontinents tend to be more evolutionarily distinct than expected by chance, despite strong taxonomic biases leading to low values of phylogenetic diversity. While evolutionary considerations are unlikely to have explicitly driven the allocation of reintroduction efforts, our results illustrate an interest of reintroduction practitioners toward species with fewer close relatives. We discuss how this phylogenetic framework allows us to investigate the contribution of reintroductions to the conservation of biodiversity at multiple geographic scales. We argue that because reintroductions rely on a parochial approach of conservation, it is important to first understand how the motivations and constraints at stake at a local context can induce phylogenetic biases before trying to assess the relevance of the allocation of reintroduction efforts at larger scales. PMID- 29531039 TI - Correction for Dixon et al., Heterogeneity within the frontoparietal control network and its relationship to the default and dorsal attention networks. PMID- 29531038 TI - Transcriptome landscape of a bacterial pathogen under plant immunity. AB - Plant pathogens can cause serious diseases that impact global agriculture. The plant innate immunity, when fully activated, can halt pathogen growth in plants. Despite extensive studies into the molecular and genetic bases of plant immunity against pathogens, the influence of plant immunity in global pathogen metabolism to restrict pathogen growth is poorly understood. Here, we developed RNA sequencing pipelines for analyzing bacterial transcriptomes in planta and determined high-resolution transcriptome patterns of the foliar bacterial pathogen Pseudomonas syringae in Arabidopsis thaliana with a total of 27 combinations of plant immunity mutants and bacterial strains. Bacterial transcriptomes were analyzed at 6 h post infection to capture early effects of plant immunity on bacterial processes and to avoid secondary effects caused by different bacterial population densities in planta We identified specific "immune responsive" bacterial genes and processes, including those that are activated in susceptible plants and suppressed by plant immune activation. Expression patterns of immune-responsive bacterial genes at the early time point were tightly linked to later bacterial growth levels in different host genotypes. Moreover, we found that a bacterial iron acquisition pathway is commonly suppressed by multiple plant immune-signaling pathways. Overexpression of a P. syringae sigma factor gene involved in iron regulation and other processes partially countered bacterial growth restriction during the plant immune response triggered by AvrRpt2. Collectively, this study defines the effects of plant immunity on the transcriptome of a bacterial pathogen and sheds light on the enigmatic mechanisms of bacterial growth inhibition during the plant immune response. PMID- 29531040 TI - Population genomic analysis of elongated skulls reveals extensive female-biased immigration in Early Medieval Bavaria. AB - Modern European genetic structure demonstrates strong correlations with geography, while genetic analysis of prehistoric humans has indicated at least two major waves of immigration from outside the continent during periods of cultural change. However, population-level genome data that could shed light on the demographic processes occurring during the intervening periods have been absent. Therefore, we generated genomic data from 41 individuals dating mostly to the late 5th/early 6th century AD from present-day Bavaria in southern Germany, including 11 whole genomes (mean depth 5.56*). In addition we developed a capture array to sequence neutral regions spanning a total of 5 Mb and 486 functional polymorphic sites to high depth (mean 72*) in all individuals. Our data indicate that while men generally had ancestry that closely resembles modern northern and central Europeans, women exhibit a very high genetic heterogeneity; this includes signals of genetic ancestry ranging from western Europe to East Asia. Particularly striking are women with artificial skull deformations; the analysis of their collective genetic ancestry suggests an origin in southeastern Europe. In addition, functional variants indicate that they also differed in visible characteristics. This example of female-biased migration indicates that complex demographic processes during the Early Medieval period may have contributed in an unexpected way to shape the modern European genetic landscape. Examination of the panel of functional loci also revealed that many alleles associated with recent positive selection were already at modern-like frequencies in European populations ~1,500 years ago. PMID- 29531041 TI - Structural changes of TasA in biofilm formation of Bacillus subtilis. AB - Microorganisms form surface-attached communities, termed biofilms, which can serve as protection against host immune reactions or antibiotics. Bacillus subtilis biofilms contain TasA as major proteinaceous component in addition to exopolysaccharides. In stark contrast to the initially unfolded biofilm proteins of other bacteria, TasA is a soluble, stably folded monomer, whose structure we have determined by X-ray crystallography. Subsequently, we characterized in vitro different oligomeric forms of TasA by NMR, EM, X-ray diffraction, and analytical ultracentrifugation (AUC) experiments. However, by magic-angle spinning (MAS) NMR on live biofilms, a swift structural change toward only one of these forms, consisting of homogeneous and protease-resistant, beta-sheet-rich fibrils, was observed in vivo. Thereby, we characterize a structural change from a globular state to a fibrillar form in a functional prokaryotic system on the molecular level. PMID- 29531042 TI - Requirement for intron structures in activating the Cd8a locus. AB - During differentiation of CD4+CD8+ double-positive (DP) thymocytes into the CD4 CD8+ single-positive (CD8SP) thymocytes committed to the cytotoxic T cell lineage, Cd8a transcription is temporally terminated after positive selection and is subsequently reinitiated, a process known as coreceptor reversal. Despite the identification of a transcriptional enhancer in the Cd8a gene that directs reporter transgene expression specifically in CD8SP thymocytes, the molecular mechanisms controlling reactivation of the Cd8a gene are not fully understood. Here, we show that, after positive selection, hCD2 reporter expression from the Cd8a locus, which was generated by insertion of hCD2 cDNA into the first exon of the Cd8a gene, requires the incorporation of intron sequences into the hCD2 transcript. The presence of polyadenylation signals after hCD2 cDNA inhibited hCD2 expression in mature CD8+ T cells, whereas hCD2 expression in DP thymocytes recapitulated the Cd8a expression. Incorporation of the endogenous short intron structure and heterologous intron structure of the Cd4 locus restored hCD2 expression in mature CD8+ T cells in a variegated manner. Interestingly, stage specific DNA demethylation was impaired in Cd8a reporter alleles that failed to express hCD2 in CD8+ T cells, and intron sequences lacking RNA splicing signals still restored hCD2 expression. These observations indicate that "intron-mediated enhancement" is involved in a stage-specific reactivation of the Cd8a locus harboring hCD2 cDNA. However, the Cd8a gene was transcribed in mature CD8+ T cells, albeit at a lower level, from a mutant Cd8a locus lacking intron structures, suggesting that protein-coding sequences in transcripts affect sensitivity to intron-mediated enhancement. PMID- 29531044 TI - Retraction for Maisonneuve et al., Bacterial persistence by RNA endonucleases. PMID- 29531043 TI - Structural insights into the sequence-specific recognition of Piwi by Drosophila Papi. AB - The Tudor domain-containing (Tdrd) family proteins play a critical role in transposon silencing in animal gonads by recognizing the symmetrically dimethylated arginine (sDMA) on the (G/A)R motif of the N-terminal of PIWI family proteins via the eTud domains. Papi, also known as "Tdrd2," is involved in Zucchini-mediated PIWI-interacting RNA (piRNA) 3'-end maturation. Intriguingly, a recent study showed that, in papi mutant flies, only Piwi-bound piRNAs increased in length, and not Ago3-bound or Aub-bound piRNAs. However, the molecular and structural basis of the Papi-Piwi complex is still not fully understood, which limits mechanistic understanding of the function of Papi in piRNA biogenesis. In the present study, we determined the crystal structures of Papi-eTud in the apo form and in complex with a peptide containing unmethylated or dimethylated R10 residues. Structural and biochemical analysis showed that the Papi interaction region on the Drosophila Piwi contains an RGRRR motif (R7-R11) distinct from the consensus (G/A)R motif recognized by canonical eTud. Mass spectrometry results indicated that Piwi is the major binding partner of Papi in vivo. The papi mutant flies suffered from both fertility and transposon-silencing defects, supporting the important role conferred to Papi in piRNA 3' processing through direct interaction with Piwi proteins. PMID- 29531046 TI - Correction for Kudalkar et al., From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. PMID- 29531045 TI - Complex electrophysiological remodeling in postinfarction ischemic heart failure. AB - Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell's action potential (AP) under physiologically relevant conditions using selfAP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na+ current, Ca2+-activated K+ current, Ca2+-activated Cl- current, decreased rapid delayed rectifier K+ current, and altered Na+/Ca2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca2+ current, decrease of inward rectifier K+ current, and Ca2+ release-dependent delayed after depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF. PMID- 29531047 TI - Noncatalytic aspartate at the exonuclease domain of proofreading DNA polymerases regulates both degradative and synthetic activities. AB - Most replicative DNA polymerases (DNAPs) are endowed with a 3'-5' exonuclease activity to proofread the polymerization errors, governed by four universally conserved aspartate residues belonging to the Exo I, Exo II, and Exo III motifs. These residues coordinate the two metal ions responsible for the hydrolysis of the last phosphodiester bond of the primer strand. Structural alignment of the conserved exonuclease domain of DNAPs from families A, B, and C has allowed us to identify an additional and invariant aspartate, located between motifs Exo II and Exo III. The importance of this aspartate has been assessed by site-directed mutagenesis at the corresponding Asp121 of the family B phi29 DNAP. Substitution of this residue by either glutamate or alanine severely impaired the catalytic efficiency of the 3'-5' exonuclease activity, both on ssDNA and dsDNA. The polymerization activity of these mutants was also affected due to a defective translocation following nucleotide incorporation. Alanine substitution for the homologous Asp90 in family A T7 DNAP showed essentially the same phenotype as phi29 DNAP mutant D121A. This functional conservation, together with a close inspection of phi29 DNAP/DNA complexes, led us to conclude a pivotal role for this aspartate in orchestrating the network of interactions required during internal proofreading of misinserted nucleotides. PMID- 29531049 TI - Regional pest suppression associated with widespread Bt maize adoption benefits vegetable growers. AB - Transgenic crops containing the bacterium Bacillus thuringiensis (Bt) genes reduce pests and insecticide usage, promote biocontrol services, and economically benefit growers. Area-wide Bt adoption suppresses pests regionally, with declines expanding beyond the planted Bt crops into other non-Bt crop fields. However, the offsite benefits to growers of other crops from such regional suppression remain uncertain. With data spanning 1976-2016, we demonstrate that vegetable growers benefit via decreased crop damage and insecticide applications in relation to pest suppression in the Mid-Atlantic United States. We provide evidence for the regional suppression of Ostrinia nubilalis (Hubner), European corn borer, and Helicoverpa zea (Boddie), corn earworm, populations in association with widespread Bt maize adoption (1996-2016) and decreased economic levels for injury in vegetable crops [peppers (Capsicum annuum L.), green beans (Phaseolus vulgaris L.), and sweet corn (Zea mays L., convar. saccharata)] compared with the pre-Bt period (1976-1995). Moth populations of both species significantly declined in association with widespread Bt maize (field corn) adoption, even as increased temperatures buffered the population reduction. We show marked decreases in the number of recommended insecticidal applications, insecticides applied, and O. nubilalis damage in vegetable crops in association with widespread Bt maize adoption. These offsite benefits to vegetable growers in the agricultural landscape have not been previously documented, and the positive impacts identified here expand on the reported ecological effects of Bt adoption. Our results also underscore the need to account for offsite economic benefits of pest suppression, in addition to the direct economic benefits of Bt crops. PMID- 29531050 TI - An empirical analysis of journal policy effectiveness for computational reproducibility. AB - A key component of scientific communication is sufficient information for other researchers in the field to reproduce published findings. For computational and data-enabled research, this has often been interpreted to mean making available the raw data from which results were generated, the computer code that generated the findings, and any additional information needed such as workflows and input parameters. Many journals are revising author guidelines to include data and code availability. This work evaluates the effectiveness of journal policy that requires the data and code necessary for reproducibility be made available postpublication by the authors upon request. We assess the effectiveness of such a policy by (i) requesting data and code from authors and (ii) attempting replication of the published findings. We chose a random sample of 204 scientific papers published in the journal Science after the implementation of their policy in February 2011. We found that we were able to obtain artifacts from 44% of our sample and were able to reproduce the findings for 26%. We find this policy author remission of data and code postpublication upon request-an improvement over no policy, but currently insufficient for reproducibility. PMID- 29531048 TI - The Great Recession worsened blood pressure and blood glucose levels in American adults. AB - Longitudinal, individual-specific data from the Multi-Ethnic Study of Atherosclerosis (MESA) provide support for the hypothesis that the 2008 to 2010 Great Recession (GR) negatively impacted the health of US adults. Results further advance understanding of the relationship by (i) illuminating hypothesized greater negative impacts in population subgroups exposed to more severe impacts of the GR and (ii) explicitly controlling for confounding by individual differences in age-related changes in health over time. Analyses overcome limitations of prior work by (i) employing individual-level data that avoid concerns about ecological fallacy associated with prior reliance on group-level data, (ii) using four waves of data before the GR to estimate and control for underlying individual-level age-related trends, (iii) focusing on objective, temporally appropriate health outcomes rather than mortality, and (iv) leveraging a diverse cohort to investigate subgroup differences in the GR's impact. Innovative individual fixed-effects modeling controlling for individual-level age related trajectories yielded substantively important insights: (i) significant elevations post-GR for blood pressure and fasting glucose, especially among those on medication pre-GR, and (ii) reductions in prevalence and intensity of medication use post-GR. Important differences in the effects of the GR are seen across subgroups, with larger effects among younger adults (who are likely still in the labor force) and older homeowners (whose declining home wealth likely reduced financial security, with less scope for recouping losses during their lifetime); least affected were older adults without a college degree (whose greater reliance on Medicare and Social Security likely provided more protection from the recession). PMID- 29531051 TI - Opinion: Is science really facing a reproducibility crisis, and do we need it to? AB - Efforts to improve the reproducibility and integrity of science are typically justified by a narrative of crisis, according to which most published results are unreliable due to growing problems with research and publication practices. This article provides an overview of recent evidence suggesting that this narrative is mistaken, and argues that a narrative of epochal changes and empowerment of scientists would be more accurate, inspiring, and compelling. PMID- 29531052 TI - Direct observation of ultrafast large-scale dynamics of an enzyme under turnover conditions. AB - The functional cycle of many proteins involves large-scale motions of domains and subunits. The relation between conformational dynamics and the chemical steps of enzymes remains under debate. Here we show that in the presence of substrates, domain motions of an enzyme can take place on the microsecond time scale, yet exert influence on the much-slower chemical step. We study the domain closure reaction of the enzyme adenylate kinase from Escherichia coli while in action (i.e., under turnover conditions), using single-molecule FRET spectroscopy. We find that substrate binding increases dramatically domain closing and opening times, making them as short as ~15 and ~45 us, respectively. These large-scale conformational dynamics are likely the fastest measured to date, and are ~100-200 times faster than the enzymatic turnover rate. Some active-site mutants are shown to fully or partially prevent the substrate-induced increase in domain closure times, while at the same time they also reduce enzymatic activity, establishing a clear connection between the two phenomena, despite their disparate time scales. Based on these surprising observations, we propose a paradigm for the mode of action of enzymes, in which numerous cycles of conformational rearrangement are required to find a mutual orientation of substrates that is optimal for the chemical reaction. PMID- 29531053 TI - Four millennia of Iberian biomolecular prehistory illustrate the impact of prehistoric migrations at the far end of Eurasia. AB - Population genomic studies of ancient human remains have shown how modern-day European population structure has been shaped by a number of prehistoric migrations. The Neolithization of Europe has been associated with large-scale migrations from Anatolia, which was followed by migrations of herders from the Pontic steppe at the onset of the Bronze Age. Southwestern Europe was one of the last parts of the continent reached by these migrations, and modern-day populations from this region show intriguing similarities to the initial Neolithic migrants. Partly due to climatic conditions that are unfavorable for DNA preservation, regional studies on the Mediterranean remain challenging. Here, we present genome-wide sequence data from 13 individuals combined with stable isotope analysis from the north and south of Iberia covering a four-millennial temporal transect (7,500-3,500 BP). Early Iberian farmers and Early Central European farmers exhibit significant genetic differences, suggesting two independent fronts of the Neolithic expansion. The first Neolithic migrants that arrived in Iberia had low levels of genetic diversity, potentially reflecting a small number of individuals; this diversity gradually increased over time from mixing with local hunter-gatherers and potential population expansion. The impact of post-Neolithic migrations on Iberia was much smaller than for the rest of the continent, showing little external influence from the Neolithic to the Bronze Age. Paleodietary reconstruction shows that these populations have a remarkable degree of dietary homogeneity across space and time, suggesting a strong reliance on terrestrial food resources despite changing culture and genetic make-up. PMID- 29531054 TI - Rapid growth of the US wildland-urban interface raises wildfire risk. AB - The wildland-urban interface (WUI) is the area where houses and wildland vegetation meet or intermingle, and where wildfire problems are most pronounced. Here we report that the WUI in the United States grew rapidly from 1990 to 2010 in terms of both number of new houses (from 30.8 to 43.4 million; 41% growth) and land area (from 581,000 to 770,000 km2; 33% growth), making it the fastest growing land use type in the conterminous United States. The vast majority of new WUI areas were the result of new housing (97%), not related to an increase in wildland vegetation. Within the perimeter of recent wildfires (1990-2015), there were 286,000 houses in 2010, compared with 177,000 in 1990. Furthermore, WUI growth often results in more wildfire ignitions, putting more lives and houses at risk. Wildfire problems will not abate if recent housing growth trends continue. PMID- 29531055 TI - Bilobal architecture is a requirement for calmodulin signaling to CaV1.3 channels. AB - Calmodulin (CaM) regulation of voltage-gated calcium (CaV) channels is a powerful Ca2+ feedback mechanism that adjusts Ca2+ influx, affording rich mechanistic insights into Ca2+ decoding. CaM possesses a dual-lobed architecture, a salient feature of the myriad Ca2+-sensing proteins, where two homologous lobes that recognize similar targets hint at redundant signaling mechanisms. Here, by tethering CaM lobes, we demonstrate that bilobal architecture is obligatory for signaling to CaV channels. With one lobe bound, CaV carboxy tail rearranges itself, resulting in a preinhibited configuration precluded from Ca2+ feedback. Reconstitution of two lobes, even as separate molecules, relieves preinhibition and restores Ca2+ feedback. CaV channels thus detect the coincident binding of two Ca2+-free lobes to promote channel opening, a molecular implementation of a logical NOR operation that processes spatiotemporal Ca2+ signals bifurcated by CaM lobes. Overall, a unified scheme of CaV channel regulation by CaM now emerges, and our findings highlight the versatility of CaM to perform exquisite Ca2+ computations. PMID- 29531056 TI - DEC2 modulates orexin expression and regulates sleep. AB - Adequate sleep is essential for physical and mental health. We previously identified a missense mutation in the human DEC2 gene (BHLHE41) leading to the familial natural short sleep behavioral trait. DEC2 is a transcription factor regulating the circadian clock in mammals, although its role in sleep regulation has been unclear. Here we report that prepro-orexin, also known as hypocretin (Hcrt), gene expression is increased in the mouse model expressing the mutant hDEC2 transgene (hDEC2-P384R). Prepro-orexin encodes a precursor protein of a neuropeptide producing orexin A and B (hcrt1 and hcrt2), which is enriched in the hypothalamus and regulates maintenance of arousal. In cell culture, DEC2 suppressed prepro-orexin promoter-luc (ore-luc) expression through cis-acting E box elements. The mutant DEC2 has less repressor activity than WT-DEC2, resulting in increased orexin expression. DEC2-binding affinity for the prepro-orexin gene promoter is decreased by the P384R mutation, likely due to weakened interaction with other transcription factors. In vivo, the decreased immobility time of the mutant transgenic mice is attenuated by an orexin receptor antagonist. Our results suggested that DEC2 regulates sleep/wake duration, at least in part, by modulating the neuropeptide hormone orexin. PMID- 29531057 TI - Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation. AB - The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of Smo (SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres, with SmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high-level SHH signaling compared with GCPs in the medial cerebellum (vermis), as more SmoM2 or Ptch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene-expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide insights into intrinsic differences within GCPs that impact on SHH-MB progression. PMID- 29531058 TI - Detection of amyloid fibrils in Parkinson's disease using plasmonic chirality. AB - Amyloid fibrils, which are closely associated with various neurodegenerative diseases, are the final products in many protein aggregation pathways. The identification of fibrils at low concentration is, therefore, pivotal in disease diagnosis and development of therapeutic strategies. We report a methodology for the specific identification of amyloid fibrils using chiroptical effects in plasmonic nanoparticles. The formation of amyloid fibrils based on alpha synuclein was probed using gold nanorods, which showed no apparent interaction with monomeric proteins but effective adsorption onto fibril structures via noncovalent interactions. The amyloid structure drives a helical nanorod arrangement, resulting in intense optical activity at the surface plasmon resonance wavelengths. This sensing technique was successfully applied to human brain homogenates of patients affected by Parkinson's disease, wherein protein fibrils related to the disease were identified through chiral signals from Au nanorods in the visible and near IR, whereas healthy brain samples did not exhibit any meaningful optical activity. The technique was additionally extended to the specific detection of infectious amyloids formed by prion proteins, thereby confirming the wide potential of the technique. The intense chiral response driven by strong dipolar coupling in helical Au nanorod arrangements allowed us to detect amyloid fibrils down to nanomolar concentrations. PMID- 29531059 TI - Programmable RNA recognition using a CRISPR-associated Argonaute. AB - Argonaute proteins (Agos) are present in all domains of life. Although the physiological function of eukaryotic Agos in regulating gene expression is well documented, the biological roles of many of their prokaryotic counterparts remain enigmatic. In some bacteria, Agos are associated with CRISPR (clustered regularly interspaced short palindromic repeats) loci and use noncanonical 5'-hydroxylated guide RNAs (gRNAs) for nucleic acid targeting. Here we show that using 5-bromo-2' deoxyuridine (BrdU) as the 5' nucleotide of gRNAs stabilizes in vitro reconstituted CRISPR-associated Marinitoga piezophila Argonaute-gRNA complexes (MpAgo RNPs) and significantly improves their specificity and affinity for RNA targets. Using reconstituted MpAgo RNPs with 5'-BrdU-modified gRNAs, we mapped the seed region of the gRNA and identified the nucleotides of the gRNA that play the most significant role in targeting specificity. We also show that these MpAgo RNPs can be programmed to distinguish between substrates that differ by a single nucleotide, using permutations at the sixth and seventh positions in the gRNA. Using these specificity features, we employed MpAgo RNPs to detect specific adenosine-to-inosine-edited RNAs in a complex mixture. These findings broaden our mechanistic understanding of the interactions of Argonautes with guide and substrate RNAs, and demonstrate that MpAgo RNPs with 5'-BrdU-modified gRNAs can be used as a highly specific RNA-targeting platform to probe RNA biology. PMID- 29531060 TI - Training replicable predictors in multiple studies. AB - This article considers replicability of the performance of predictors across studies. We suggest a general approach to investigating this issue, based on ensembles of prediction models trained on different studies. We quantify how the common practice of training on a single study accounts in part for the observed challenges in replicability of prediction performance. We also investigate whether ensembles of predictors trained on multiple studies can be combined, using unique criteria, to design robust ensemble learners trained upfront to incorporate replicability into different contexts and populations. PMID- 29531061 TI - Measuring discursive influence across scholarship. AB - Assessing scholarly influence is critical for understanding the collective system of scholarship and the history of academic inquiry. Influence is multifaceted, and citations reveal only part of it. Citation counts exhibit preferential attachment and follow a rigid "news cycle" that can miss sustained and indirect forms of influence. Building on dynamic topic models that track distributional shifts in discourse over time, we introduce a variant that incorporates features, such as authorship, affiliation, and publication venue, to assess how these contexts interact with content to shape future scholarship. We perform in-depth analyses on collections of physics research (500,000 abstracts; 102 years) and scholarship generally (JSTOR repository: 2 million full-text articles; 130 years). Our measure of document influence helps predict citations and shows how outcomes, such as winning a Nobel Prize or affiliation with a highly ranked institution, boost influence. Analysis of citations alongside discursive influence reveals that citations tend to credit authors who persist in their fields over time and discount credit for works that are influential over many topics or are "ahead of their time." In this way, our measures provide a way to acknowledge diverse contributions that take longer and travel farther to achieve scholarly appreciation, enabling us to correct citation biases and enhance sensitivity to the full spectrum of scholarly impact. PMID- 29531062 TI - EF-Tu and EF-G are activated by allosteric effects. AB - Many cellular processes are controlled by GTPases, and gaining quantitative understanding of the activation of such processes has been a major challenge. In particular, it is crucial to obtain reliable free-energy surfaces for the relevant reaction paths both in solution and in GTPases active sites. Here, we revisit the energetics of the activation of EF-G and EF-Tu by the ribosome and explore the nature of the catalysis of the GTPase reaction. The comparison of EF Tu to EF-G allows us to explore the impact of possible problems with the available structure of EF-Tu. Additionally, mutational effects are used for a careful validation of the emerging conclusions. It is found that the reaction may proceed by both a two-water mechanism and a one-water (GTP as a base) mechanism. However, in both cases, the activation involves a structural allosteric effect, which is likely to be a general-activation mechanism for all GTPases. PMID- 29531063 TI - Single-molecule peptide fingerprinting. AB - Proteomic analyses provide essential information on molecular pathways of cellular systems and the state of a living organism. Mass spectrometry is currently the first choice for proteomic analysis. However, the requirement for a large amount of sample renders a small-scale proteomics study challenging. Here, we demonstrate a proof of concept of single-molecule FRET-based protein fingerprinting. We harnessed the AAA+ protease ClpXP to scan peptides. By using donor fluorophore-labeled ClpP, we sequentially read out FRET signals from acceptor-labeled amino acids of peptides. The repurposed ClpXP exhibits unidirectional processing with high processivity and has the potential to detect low-abundance proteins. Our technique is a promising approach for sequencing protein substrates using a small amount of sample. PMID- 29531064 TI - Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements. AB - RNA-sequencing (RNA-seq) is commonly used to identify genetic modules that respond to perturbations. In single cells, transcriptomes have been used as phenotypes, but this concept has not been applied to whole-organism RNA-seq. Also, quantifying and interpreting epistatic effects using expression profiles remains a challenge. We developed a single coefficient to quantify transcriptome wide epistasis that reflects the underlying interactions and which can be interpreted intuitively. To demonstrate our approach, we sequenced four single and two double mutants of Caenorhabditis elegans From these mutants, we reconstructed the known hypoxia pathway. In addition, we uncovered a class of 56 genes with HIF-1-dependent expression that have opposite changes in expression in mutants of two genes that cooperate to negatively regulate HIF-1 abundance; however, the double mutant of these genes exhibits suppression epistasis. This class violates the classical model of HIF-1 regulation but can be explained by postulating a role of hydroxylated HIF-1 in transcriptional control. PMID- 29531065 TI - Blindfold learning of an accurate neural metric. AB - The brain has no direct access to physical stimuli but only to the spiking activity evoked in sensory organs. It is unclear how the brain can learn representations of the stimuli based on those noisy, correlated responses alone. Here we show how to build an accurate distance map of responses solely from the structure of the population activity of retinal ganglion cells. We introduce the Temporal Restricted Boltzmann Machine to learn the spatiotemporal structure of the population activity and use this model to define a distance between spike trains. We show that this metric outperforms existing neural distances at discriminating pairs of stimuli that are barely distinguishable. The proposed method provides a generic and biologically plausible way to learn to associate similar stimuli based on their spiking responses, without any other knowledge of these stimuli. PMID- 29531066 TI - Cross-resistance to dicamba, 2,4-D, and fluroxypyr in Kochia scoparia is endowed by a mutation in an AUX/IAA gene. AB - The understanding and mitigation of the appearance of herbicide-resistant weeds have come to the forefront of study in the past decade, as the number of weed species that are resistant to one or more herbicide modes of action is on the increase. Historically, weed resistance to auxin herbicides has been rare, but examples, such as Kochia scoparia L. Schrad (kochia), have appeared, posing a challenge to conventional agricultural practices. Reports of dicamba-resistant kochia populations began in the early 1990s in areas where auxin herbicides were heavily utilized for weed control in corn and wheat cropping systems, and some biotypes are resistant to other auxin herbicides as well. We have further characterized the auxin responses of one previously reported dicamba-resistant biotype isolated from western Nebraska and found that it is additionally cross resistant to other auxin herbicides, including 2,4-dichlorophenoxyacetic acid (2,4-D) and fluroxypyr. We have utilized transcriptome sequencing and comparison to identify a 2-nt base change in this biotype, which results in a glycine to asparagine amino acid change within a highly conserved region of an AUX/indole-3 acetic acid (IAA) protein, KsIAA16. Through yeast two-hybrid analysis, characterization of F2 segregation, and heterologous expression and characterization of the gene in Arabidopsis thaliana, we show that that the single dominant KsIAA16R resistance allele is the causal basis for dicamba resistance in this population. Furthermore, we report the development of a molecular marker to identify this allele in populations and facilitate inheritance studies. We also report that the resistance allele confers a fitness penalty in greenhouse studies. PMID- 29531067 TI - Sign of selection on mutation rate modifiers depends on population size. AB - The influence of population size (N) on natural selection acting on alleles that affect fitness has been understood for almost a century. As N declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, however, alleles experience so-called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best-studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination and mutation rates. Here, we use analytics, simulations, and experimental populations of Saccharomyces cerevisiae to examine the influence of N on indirect selection acting on alleles that increase the genomic mutation rate (mutators). Mutators experience indirect selection via genomic associations with beneficial and deleterious mutations they generate. We show that, as N declines, indirect selection driven by linked beneficial mutations is overpowered by drift before drift can neutralize the cost of the deleterious load. As a result, mutators transition from being favored by indirect selection in large populations to being disfavored as N declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on mutators exhibits a profound and qualitatively distinct dependence on N. PMID- 29531068 TI - Occurrence, evolution, and functions of DNA phosphorothioate epigenetics in bacteria. AB - The chemical diversity of physiological DNA modifications has expanded with the identification of phosphorothioate (PT) modification in which the nonbridging oxygen in the sugar-phosphate backbone of DNA is replaced by sulfur. Together with DndFGH as cognate restriction enzymes, DNA PT modification, which is catalyzed by the DndABCDE proteins, functions as a bacterial restriction modification (R-M) system that protects cells against invading foreign DNA. However, the occurrence of dnd systems across a large number of bacterial genomes and their functions other than R-M are poorly understood. Here, a genomic survey revealed the prevalence of bacterial dnd systems: 1,349 bacterial dnd systems were observed to occur sporadically across diverse phylogenetic groups, and nearly half of these occur in the form of a solitary dndBCDE gene cluster that lacks the dndFGH restriction counterparts. A phylogenetic analysis of 734 complete PT R-M pairs revealed the coevolution of M and R components, despite the observation that several PT R-M pairs appeared to be assembled from M and R parts acquired from distantly related organisms. Concurrent epigenomic analysis, transcriptome analysis, and metabolome characterization showed that a solitary PT modification contributed to the overall cellular redox state, the loss of which perturbed the cellular redox balance and induced Pseudomonas fluorescens to reconfigure its metabolism to fend off oxidative stress. An in vitro transcriptional assay revealed altered transcriptional efficiency in the presence of PT DNA modification, implicating its function in epigenetic regulation. These data suggest the versatility of PT in addition to its involvement in R-M protection. PMID- 29531069 TI - Transitions from a Kondo-like diamagnetic insulator into a modulated ferromagnetic metal in FeGa3-yGey. AB - One initial and essential question of magnetism is whether the magnetic properties of a material are governed by localized moments or itinerant electrons. Here, we expose the case for the weakly ferromagnetic system FeGa3-y Ge y , wherein these two opposite models are reconciled, such that the magnetic susceptibility is quantitatively explained by taking into account the effects of spin-spin correlation. With the electron doping introduced by Ge substitution, the diamagnetic insulating parent compound FeGa3 becomes a paramagnetic metal as early as at y=0.01, and turns into a weakly ferromagnetic metal around the quantum critical point y=0.15. Within the ferromagnetic regime of FeGa3-y Ge y , the magnetic properties are of a weakly itinerant ferromagnetic nature, located in the intermediate regime between the localized and the itinerant dominance. Our analysis implies a potential universality for all itinerant-electron ferromagnets. PMID- 29531071 TI - Universal linear and nonlinear electrodynamics of a Dirac fluid. AB - A general relation is derived between the linear and second-order nonlinear ac conductivities of an electron system in the hydrodynamic regime of frequencies below the interparticle scattering rate. The magnitude and tensorial structure of the hydrodynamic nonlinear conductivity are shown to differ from their counterparts in the more familiar kinetic regime of higher frequencies. Due to universality of the hydrodynamic equations, the obtained formulas are valid for systems with an arbitrary Dirac-like dispersion, ranging from solid-state electron gases to free-space plasmas, either massive or massless, at any temperature, chemical potential, or space dimension. Predictions for photon drag and second-harmonic generation in graphene are presented as one application of this theory. PMID- 29531070 TI - CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells. AB - Recent findings demonstrated proinflammatory functions of interleukin (IL)-9 producing T helper type (Th) 9 cells in the pathogenesis of intestinal bowel diseases (IBDs). However, also antiinflammatory properties have been ascribed to Th9 cells, pointing to a functional heterogeneity. To dissect the specific expression pattern and, especially, diversity of murine antigen-specific Th9 cells, we applied single cell transcription profiling. Th9 cells displayed reduced expression of typical activation markers, such as Cd40 ligand and Cd96, whereas expression of Cd25 and Cd83 was increased compared with other Th subsets. Importantly, we identified two subsets of Th9 cells differing above all in their CD96 expression. The heterogeneous CD96 expression was specific for Th9 cells and not observed for other Th subtypes, such as Th1 cells. Lower CD96 expression was also observed in human IL-9+ compared with IFN-gamma+ T cells. Although Il9 was highly transcribed by all Th9 cells, IL-9 mRNA and protein expression was increased in CD96low cells. Transfer of CD96low Th9 cells into recombination activating gene 1-deficient (Rag1-/- ) mice caused severe weight loss, intestinal and colonic inflammation, and destruction of allogeneic skin grafts and thus showed high inflammatory potential. This was associated with their expansion and tissue accumulation. Contrastingly, CD96high Th9 cells did not cause colitis and showed reduced expansion and migratory potential. Blockade of CD96 completely restored the expansion and inflammatory properties of CD96high Th9 cells. Collectively, our data suggest an inhibitory role for the cosignaling receptor CD96 in Th9 cells, raising new opportunities in the treatment of IL-9-associated inflammations such as IBD. PMID- 29531072 TI - Correlation analysis framework for localization-based superresolution microscopy. AB - Superresolution images reconstructed from single-molecule localizations can reveal cellular structures close to the macromolecular scale and are now being used routinely in many biomedical research applications. However, because of their coordinate-based representation, a widely applicable and unified analysis platform that can extract a quantitative description and biophysical parameters from these images is yet to be established. Here, we propose a conceptual framework for correlation analysis of coordinate-based superresolution images using distance histograms. We demonstrate the application of this concept in multiple scenarios, including image alignment, tracking of diffusing molecules, as well as for quantification of colocalization, showing its superior performance over existing approaches. PMID- 29531073 TI - Predicting cancer outcomes from histology and genomics using convolutional networks. AB - Cancer histology reflects underlying molecular processes and disease progression and contains rich phenotypic information that is predictive of patient outcomes. In this study, we show a computational approach for learning patient outcomes from digital pathology images using deep learning to combine the power of adaptive machine learning algorithms with traditional survival models. We illustrate how these survival convolutional neural networks (SCNNs) can integrate information from both histology images and genomic biomarkers into a single unified framework to predict time-to-event outcomes and show prediction accuracy that surpasses the current clinical paradigm for predicting the overall survival of patients diagnosed with glioma. We use statistical sampling techniques to address challenges in learning survival from histology images, including tumor heterogeneity and the need for large training cohorts. We also provide insights into the prediction mechanisms of SCNNs, using heat map visualization to show that SCNNs recognize important structures, like microvascular proliferation, that are related to prognosis and that are used by pathologists in grading. These results highlight the emerging role of deep learning in precision medicine and suggest an expanding utility for computational analysis of histology in the future practice of pathology. PMID- 29531074 TI - Reply to Katsu and Baker: Using zebrafish PDX to screen drug sensitivity of endocrine-dependent cancers. PMID- 29531075 TI - Progesterone activation of zebrafish mineralocorticoid receptor may influence growth of some transplanted tumors. PMID- 29531076 TI - Crisis or self-correction: Rethinking media narratives about the well-being of science. AB - After documenting the existence and exploring some implications of three alternative news narratives about science and its challenges, this essay outlines ways in which those who communicate science can more accurately convey its investigatory process, self-correcting norms, and remedial actions, without in the process legitimizing an unwarranted "science is broken/in crisis" narrative. The three storylines are: (i) quest discovery, which features scientists producing knowledge through an honorable journey; (ii) counterfeit quest discovery, which centers on an individual or group of scientists producing a spurious finding through a dishonorable one; and (iii) a systemic problem structure, which suggests that some of the practices that protect science are broken, or worse, that science is no longer self-correcting or in crisis. PMID- 29531077 TI - UBD modifies APOL1-induced kidney disease risk. AB - People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1 We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype. PMID- 29531078 TI - Chemical control over membrane-initiated steroid signaling with a DNA nanocapsule. AB - Membrane-initiated steroid signaling (MISS) is a recently discovered aspect of steroidal control over cell function that has proved highly challenging to study due to its rapidity and ultrasensitivity to the steroid trigger [Chow RWY, Handelsman DJ, Ng MKC (2010) Endocrinology 151:2411-2422]. Fundamental aspects underlying MISS, such as receptor binding, kinetics of ion-channel opening, and production of downstream effector molecules remain obscure because a pristine molecular technology that could trigger the release of signaling steroids was not available. We have recently described a prototype DNA nanocapsule which can be programmed to release small molecules upon photoirradiation [Veetil AT, et al. (2017) Nat Nanotechnol 12:1183-1189]. Here we show that this DNA-based molecular technology can now be programmed to chemically trigger MISS, significantly expanding its applicability to systems that are refractory to photoirradiation. PMID- 29531079 TI - Issues with data and analyses: Errors, underlying themes, and potential solutions. AB - Some aspects of science, taken at the broadest level, are universal in empirical research. These include collecting, analyzing, and reporting data. In each of these aspects, errors can and do occur. In this work, we first discuss the importance of focusing on statistical and data errors to continually improve the practice of science. We then describe underlying themes of the types of errors and postulate contributing factors. To do so, we describe a case series of relatively severe data and statistical errors coupled with surveys of some types of errors to better characterize the magnitude, frequency, and trends. Having examined these errors, we then discuss the consequences of specific errors or classes of errors. Finally, given the extracted themes, we discuss methodological, cultural, and system-level approaches to reducing the frequency of commonly observed errors. These approaches will plausibly contribute to the self-critical, self-correcting, ever-evolving practice of science, and ultimately to furthering knowledge. PMID- 29531081 TI - Geospatial analysis of near-term potential for carbon-negative bioenergy in the United States. AB - Bioenergy with carbon capture and storage (BECCS) is a negative-emissions technology that may play a crucial role in climate change mitigation. BECCS relies on the capture and sequestration of carbon dioxide (CO2) following bioenergy production to remove and reliably sequester atmospheric CO2 Previous BECCS deployment assessments have largely overlooked the potential lack of spatial colocation of suitable storage basins and biomass availability, in the absence of long-distance biomass and CO2 transport. These conditions could constrain the near-term technical deployment potential of BECCS due to social and economic barriers that exist for biomass and CO2 transport. This study leverages biomass production data and site-specific injection and storage capacity estimates at high spatial resolution to assess the near-term deployment opportunities for BECCS in the United States. If the total biomass resource available in the United States was mobilized for BECCS, an estimated 370 Mt CO2?y 1 of negative emissions could be supplied in 2020. However, the absence of long distance biomass and CO2 transport, as well as limitations imposed by unsuitable regional storage and injection capacities, collectively decrease the technical potential of negative emissions to 100 Mt CO2?y-1 Meeting this technical potential may require large-scale deployment of BECCS technology in more than 1,000 counties, as well as widespread deployment of dedicated energy crops. Specifically, the Illinois basin, Gulf region, and western North Dakota have the greatest potential for near-term BECCS deployment. High-resolution spatial assessment as conducted in this study can inform near-term opportunities that minimize social and economic barriers to BECCS deployment. PMID- 29531080 TI - Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. AB - Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6-/- mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis. PMID- 29531082 TI - Psychophysical evidence for auditory motion parallax. AB - Distance is important: From an ecological perspective, knowledge about the distance to either prey or predator is vital. However, the distance of an unknown sound source is particularly difficult to assess, especially in anechoic environments. In vision, changes in perspective resulting from observer motion produce a reliable, consistent, and unambiguous impression of depth known as motion parallax. Here we demonstrate with formal psychophysics that humans can exploit auditory motion parallax, i.e., the change in the dynamic binaural cues elicited by self-motion, to assess the relative depths of two sound sources. Our data show that sensitivity to relative depth is best when subjects move actively; performance deteriorates when subjects are moved by a motion platform or when the sound sources themselves move. This is true even though the dynamic binaural cues elicited by these three types of motion are identical. Our data demonstrate a perceptual strategy to segregate intermittent sound sources in depth and highlight the tight interaction between self-motion and binaural processing that allows assessment of the spatial layout of complex acoustic scenes. PMID- 29531083 TI - Archaeal acetoacetyl-CoA thiolase/HMG-CoA synthase complex channels the intermediate via a fused CoA-binding site. AB - Many reactions within a cell are thermodynamically unfavorable. To efficiently run some of those endergonic reactions, nature evolved intermediate-channeling enzyme complexes, in which the products of the first endergonic reactions are immediately consumed by the second exergonic reactions. Based on this concept, we studied how archaea overcome the unfavorable first reaction of isoprenoid biosynthesis-the condensation of two molecules of acetyl-CoA to acetoacetyl-CoA catalyzed by acetoacetyl-CoA thiolases (thiolases). We natively isolated an enzyme complex comprising the thiolase and 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (HMGCS) from a fast-growing methanogenic archaeon, Methanothermococcus thermolithotrophicus HMGCS catalyzes the second reaction in the mevalonate pathway-the exergonic condensation of acetoacetyl-CoA and acetyl-CoA to HMG-CoA. The 380-kDa crystal structure revealed that both enzymes are held together by a third protein (DUF35) with so-far-unknown function. The active-site clefts of thiolase and HMGCS form a fused CoA-binding site, which allows for efficient coupling of the endergonic thiolase reaction with the exergonic HMGCS reaction. The tripartite complex is found in almost all archaeal genomes and in some bacterial ones. In addition, the DUF35 proteins are also important for polyhydroxyalkanoate (PHA) biosynthesis, most probably by functioning as a scaffold protein that connects thiolase with 3-ketoacyl-CoA reductase. This natural and highly conserved enzyme complex offers great potential to improve isoprenoid and PHA biosynthesis in biotechnologically relevant organisms. PMID- 29531084 TI - History meets palaeoscience: Consilience and collaboration in studying past societal responses to environmental change. AB - History and archaeology have a well-established engagement with issues of premodern societal development and the interaction between physical and cultural environments; together, they offer a holistic view that can generate insights into the nature of cultural resilience and adaptation, as well as responses to catastrophe. Grasping the challenges that climate change presents and evolving appropriate policies that promote and support mitigation and adaptation requires not only an understanding of the science and the contemporary politics, but also an understanding of the history of the societies affected and in particular of their cultural logic. But whereas archaeologists have developed productive links with the paleosciences, historians have, on the whole, remained muted voices in the debate until recently. Here, we suggest several ways in which a consilience between the historical sciences and the natural sciences, including attention to even distant historical pasts, can deepen contemporary understanding of environmental change and its effects on human societies. PMID- 29531085 TI - Psychopaths fail to automatically take the perspective of others. AB - Psychopathic individuals display a chronic and flagrant disregard for the welfare of others through their callous and manipulative behavior. Historically, this behavior is thought to result from deficits in social-affective processing. However, we show that at least some psychopathic behaviors may be rooted in a cognitive deficit, specifically an inability to automatically take another person's perspective. Unlike prior studies that rely solely on controlled theory of mind (ToM) tasks, we employ a task that taps into automatic ToM processing. Controlled ToM processes are engaged when an individual intentionally considers the perspective of another person, whereas automatic ToM processes are engaged when an individual unintentionally represents the perspective of another person. In a sample of incarcerated offenders, we find that psychopathic individuals are equally likely to show response interference under conditions of controlled ToM, but lack a common signature of automatic ToM known as altercentric interference. We also demonstrate that the magnitude of this dysfunction in altercentric interference is correlated with real-world callous behaviors (i.e., number of assault charges). These findings suggest that psychopathic individuals have a diminished propensity to automatically think from another's perspective, which may be the cognitive root of their deficits in social functioning and moral behavior. PMID- 29531086 TI - Standards for design and measurement would make clinical research reproducible and usable. AB - We find standards useful in everyday life and in science, although we do not always follow them. Adopting new standards can be expensive, so there may be a strong incentive to maintain the status quo rather than adopt new standards. The scientific community has many standards encompassing both doing clinical research and reporting it, including standards for design and measurement. Although existing research standards have improved both research and its reporting, we need to unify existing standards and to fill the gaps between steps throughout the research process. Existing gaps include implementation of standards and links between standards for study registration (to know about all studies undertaken), study protocols (to identify the preplanned study design and methods), data collection (to assess outcomes that are important and comparable across studies), dissemination of findings (to know the results of previous studies), data sharing (to make best use of existing data), and evidence synthesis (to draw appropriate conclusions from the body of evidence). The scientific community must work together to harmonize existing standards, to ensure that standards are kept up to date, to check that standards are followed, and to develop standards where they are still needed. A unified system of standards will make our work more reproducible. PMID- 29531089 TI - Retraction for Skau et al., Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly. PMID- 29531087 TI - Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses. AB - Endocannabinoids (eCBs) are lipid-signaling molecules involved in the regulation of numerous behaviors and physiological functions. Released by postsynaptic neurons, eCBs mediate retrograde modulation of synaptic transmission and plasticity by activating presynaptic cannabinoid receptors. While the cellular mechanisms by which eCBs control synaptic function have been well characterized, the mechanisms controlling their retrograde synaptic transport remain unknown. Here, we demonstrate that fatty-acid-binding protein 5 (FABP5), a canonical intracellular carrier of eCBs, is indispensable for retrograde eCB transport in the dorsal raphe nucleus (DRn). Thus, pharmacological inhibition or genetic deletion of FABP5 abolishes both phasic and tonic eCB-mediated control of excitatory synaptic transmission in the DRn. The blockade of retrograde eCB signaling induced by FABP5 inhibition is not mediated by impaired cannabinoid receptor function or reduced eCB synthesis. These findings indicate that FABP5 is essential for retrograde eCB signaling and may serve as a synaptic carrier of eCBs at central synapses. PMID- 29531088 TI - Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. AB - Low-dose ketamine, an open-channel N-methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated. Using in vitro electrophysiology in acute slices of dorsal hippocampus from adult male Sprague-Dawley rats, we examined the immediate effects of a clinically relevant concentration of ketamine to directly test the disinhibition hypothesis. As a mechanistic comparison, we also tested the effects of the glycine site NMDAR partial agonist/antagonist GLYX-13 (rapastinel), the GluN2B subunit-selective NMDAR antagonist Ro 25-6981, and the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine. Low-dose ketamine, GLYX-13, and scopolamine reduced inhibitory input onto pyramidal cells and increased synaptically driven pyramidal cell excitability measured at the single-cell and population levels. Conversely, Ro 25-6981 increased the strength of inhibitory transmission and did not change pyramidal cell excitability. These results show a decrease in the inhibition/excitation balance that supports disinhibition as a common mechanism shared among those antagonists with rapid antidepressant properties. These data suggest that pyramidal cell disinhibition downstream of NMDAR antagonism could serve as a possible biomarker for the efficacy of rapid antidepressant therapy. PMID- 29531091 TI - The preregistration revolution. AB - Progress in science relies in part on generating hypotheses with existing observations and testing hypotheses with new observations. This distinction between postdiction and prediction is appreciated conceptually but is not respected in practice. Mistaking generation of postdictions with testing of predictions reduces the credibility of research findings. However, ordinary biases in human reasoning, such as hindsight bias, make it hard to avoid this mistake. An effective solution is to define the research questions and analysis plan before observing the research outcomes-a process called preregistration. Preregistration distinguishes analyses and outcomes that result from predictions from those that result from postdictions. A variety of practical strategies are available to make the best possible use of preregistration in circumstances that fall short of the ideal application, such as when the data are preexisting. Services are now available for preregistration across all disciplines, facilitating a rapid increase in the practice. Widespread adoption of preregistration will increase distinctiveness between hypothesis generation and hypothesis testing and will improve the credibility of research findings. PMID- 29531090 TI - Phosphorylation-induced unfolding regulates p19INK4d during the human cell cycle. AB - Cell cycle progression is tightly regulated by cyclin-dependent kinases (CDKs). The ankyrin-repeat protein p19INK4d functions as a key regulator of G1/S transition; however, its molecular mode of action is unknown. Here, we combine cell and structural biology methods to unravel the mechanism by which p19INK4d controls cell cycle progression. We delineate how the stepwise phosphorylation of p19INK4d Ser66 and Ser76 by cell cycle-independent (p38) and -dependent protein kinases (CDK1), respectively, leads to local unfolding of the three N-terminal ankyrin repeats of p19INK4d This dissociates the CDK6-p19INK4d inhibitory complex and, thereby, activates CDK6. CDK6 triggers entry into S-phase, whereas p19INK4d is ubiquitinated and degraded. Our findings reveal how signaling-dependent p19INK4d unfolding contributes to the irreversibility of G1/S transition. PMID- 29531092 TI - Metastudies for robust tests of theory. AB - We describe and demonstrate an empirical strategy useful for discovering and replicating empirical effects in psychological science. The method involves the design of a metastudy, in which many independent experimental variables-that may be moderators of an empirical effect-are indiscriminately randomized. Radical randomization yields rich datasets that can be used to test the robustness of an empirical claim to some of the vagaries and idiosyncrasies of experimental protocols and enhances the generalizability of these claims. The strategy is made feasible by advances in hierarchical Bayesian modeling that allow for the pooling of information across unlike experiments and designs and is proposed here as a gold standard for replication research and exploratory research. The practical feasibility of the strategy is demonstrated with a replication of a study on subliminal priming. PMID- 29531093 TI - Correction for Hoffecker, The complexity of Neanderthal technology. PMID- 29531095 TI - Scientific progress despite irreproducibility: A seeming paradox. AB - It appears paradoxical that science is producing outstanding new results and theories at a rapid rate at the same time that researchers are identifying serious problems in the practice of science that cause many reports to be irreproducible and invalid. Certainly, the practice of science needs to be improved, and scientists are now pursuing this goal. However, in this perspective, we argue that this seeming paradox is not new, has always been part of the way science works, and likely will remain so. We first introduce the paradox. We then review a wide range of challenges that appear to make scientific success difficult. Next, we describe the factors that make science work-in the past, present, and presumably also in the future. We then suggest that remedies for the present practice of science need to be applied selectively so as not to slow progress and illustrate with a few examples. We conclude with arguments that communication of science needs to emphasize not just problems but the enormous successes and benefits that science has brought and is now bringing to all elements of modern society. PMID- 29531094 TI - Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. AB - For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation. PMID- 29531096 TI - Unique Gene Expression in Developing Ascending Vasa Recta: A Tale of Tie. PMID- 29531098 TI - Bariatric Surgery and Kidney Health. PMID- 29531097 TI - Gpr97 Exacerbates AKI by Mediating Sema3A Signaling. AB - Background G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. We investigated the role of Gpr97, a newly identified member of the adhesion GPCR family, in AKI.Methods AKI was induced by ischemia-reperfusion or cisplatin treatment in Gpr97-deficient mice. We assessed renal injury in these models and in patients with acute tubular necrosis by histologic examination, and we conducted microarray analysis and in vitro assays to determine the molecular mechanisms of Gpr97 function.Results Gpr97 was upregulated in the kidneys from mice with AKI and patients with biopsy-proven acute tubular necrosis compared with healthy controls. In AKI models, Gpr97-deficient mice had significantly less renal injury and inflammation than wild-type mice. Gpr97 deficiency also attenuated the AKI induced expression of semaphorin 3A (Sema3A), a potential early diagnostic biomarker of renal injury. In NRK-52E cells subjected to oxygen-glucose deprivation, siRNA-mediated knockdown of Gpr97 further increased the expression of survivin and phosphorylated STAT3 and reduced toll-like receptor 4 expression. Cotreatment with recombinant murine Sema3A protein counteracted these effects. Finally, additional in vivo and in vitro studies, including electrophoretic mobility shift assays and luciferase reporter assays, showed that Gpr97 deficiency attenuates ischemia-reperfusion-induced expression of the RNA-binding protein human antigen R, which post-transcriptionally regulates Sema3A expression.Conclusions Gpr97 is an important mediator of AKI, and pharmacologic targeting of Gpr97-mediated Sema3A signaling at multiple levels may provide a novel approach for the treatment of AKI. PMID- 29531099 TI - Thank you, Reviewers and E-letter Contributors! PMID- 29531100 TI - Use of Asthma APGAR Tools in Primary Care Practices: A Cluster-Randomized Controlled Trial. AB - PURPOSE: The purpose of this study was to assess patient and practice outcomes after introducing the Asthma APGAR (Activities, Persistent, triGGers, Asthma medications, Response to therapy) tools into primary care practices. METHODS: We used a pragmatic cluster-randomized controlled design in 18 US family medicine and pediatric practices to compare outcomes in patients with persistent asthma aged 5 to 45 years after introduction of the Asthma APGAR tools vs usual care. Patient outcomes included asthma control, quality of life, and emergency department (ED), urgent care, and inpatient hospital visits. The practice outcome was adherence to asthma guidelines. RESULTS: We enrolled 1,066 patients: 245 children, 174 adolescents, and 647 adults. Sixty-five percent (692 patients) completed both baseline and 12-month questionnaires, allowing analysis for patient-reported outcomes. Electronic health record data were available for 1,063 patients (99.7%) for practice outcomes. The proportion of patients reporting an asthma-related ED, urgent care, or hospital visit in the final 6 months of the study was lower in the APGAR practices vs usual care practices (10.6% vs 20.9%, P = .004). The percentage of patients with "in control" asthma increased more between baseline and 1 year in the APGAR group vs usual care group (13.5% vs 3.4%, P =.0001 vs P =.86) with a trend toward better control scores and asthma related quality of life in the former at 1 year (P <=.06 and P = .06, respectively). APGAR practices improved their adherence to 3 or more guideline elements compared with usual care practices (20.7% increase vs 1.9% decrease, P = .001). CONCLUSIONS: Introduction of the Asthma APGAR tools improves rates of asthma control; reduces asthma-related ED, urgent care, and hospital visits; and increases practices' adherence to asthma management guidelines. PMID- 29531101 TI - Treating Subthreshold Depression in Primary Care: A Randomized Controlled Trial of Behavioral Activation With Mindfulness. AB - PURPOSE: We undertook a randomized controlled trial to assess the efficacy of group-based behavioral activation with mindfulness (BAM) for treating subthreshold depression in primary care in Hong Kong. METHODS: We recruited adult patients aged 18 years or older with subthreshold depression from public primary care clinics and randomly assigned them to a BAM intervention group or a usual care group. The BAM group was provided with eight 2-hour weekly BAM sessions by trained allied health care workers. Patients in the usual care group received usual medical care with no additional psychological interventions. The primary outcome was depressive symptoms measured by the Beck Depression Inventory-II at 12 months. Secondary outcomes included incidence of major depressive disorder at 12 months. We assessed quality of life, activity and circumstances change, functional impairment, and anxiety at baseline, end of intervention, 5 months, and 12 months. RESULTS: We randomly allocated 115 patients to the BAM intervention and 116 patients to usual care. At 12 months, compared with usual care peers, BAM patients had a slightly more favorable change in levels of depressive symptoms on the Beck Depression Inventory-II (between-group mean difference in score = -3.85; 95% CI, -6.36 to -1.34; Cohen d = -0.46, 95% CI, 0.76 to -0.16). Incidence of major depressive disorder was lower with BAM (10.8% vs 26.8%, P = .01), whereas groups did not differ significantly on other secondary outcomes at 12 months. CONCLUSIONS: Group BAM appears to be efficacious for decreasing depressive symptoms and reducing the incidence of major depression among patients with subthreshold depression in primary care, although generalizability of our findings may be limited. PMID- 29531102 TI - Sustainability of a Primary Care-Driven eConsult Service. AB - PURPOSE: Excessive wait times for specialist appointments pose a serious barrier to patient care. To improve access to specialist care and reduce wait times, we launched the Champlain BASE (Building Access to Specialists through eConsultation) eConsult service in April 2011. The objective of this study is to report on the impact of our multiple specialty eConsult service during the first 5 years of use after implementation, with a focus on growth and sustainability. METHODS: We conducted a cross-sectional study of all eConsult cases submitted between April 1, 2011 and April 30, 2016, and measured impact with system utilization data and mandatory close-out surveys completed at the end of each eConsult. Impact indicators included time interval to obtain specialist advice, effect of specialist advice on the primary care clinician's course of action, and rate of avoidance of face-to-face visits. RESULTS: A total of 14,105 eConsult cases were directed to 56 different medical specialty groups, completed with a median response time of 21 hours, and 65% of all eConsults were resolved without a specialist visit. We observed rapid growth in the use of eConsult during the study period: 5 years after implementation the system was in use by 1,020 primary care clinicians, with more than 700 consultations taking place per month. CONCLUSIONS: This study presents the first in-depth look at the growth and sustainability of the multispecialty eConsult service. The results show the positive impact of an eConsult service and can inform other regions interested in implementing similar systems. PMID- 29531103 TI - Multimorbidity and Socioeconomic Deprivation in Primary Care Consultations. AB - PURPOSE: The influence of multimorbidity on the clinical encounter is poorly understood, especially in areas of high socioeconomic deprivation where burdensome multimorbidity is concentrated. The aim of the current study was to examine the effect of multimorbidity on general practice consultations, in areas of high and low deprivation. METHODS: We conducted secondary analyses of 659 video-recorded routine consultations involving 25 general practitioners (GPs) in deprived areas and 22 in affluent areas of Scotland. Patients rated the GP's empathy using the Consultation and Relational Empathy (CARE) measure immediately after the consultation. Videos were analyzed using the Measure of Patient Centered Communication. Multilevel, multi-regression analysis identified differences between the groups. RESULTS: In affluent areas, patients with multimorbidity received longer consultations than patients without multimorbidity (mean 12.8 minutes vs 9.3, respectively; P = .015), but this was not so in deprived areas (mean 9.9 minutes vs 10.0 respectively; P = .774). In affluent areas, patients with multimorbidity perceived their GP as more empathic (P = .009) than patients without multimorbidity; this difference was not found in deprived areas (P = .344). Video analysis showed that GPs in affluent areas were more attentive to the disease and illness experience in patients with multimorbidity (P < .031) compared with patients without multimorbidity. This was not the case in deprived areas (P = .727). CONCLUSIONS: In deprived areas, the greater need of patients with multimorbidity is not reflected in the longer consultation length, higher GP patient centeredness, and higher perceived GP empathy found in affluent areas. Action is required to redress this mismatch of need and service provision for patients with multimorbidity if health inequalities are to be narrowed rather than widened by primary care. PMID- 29531104 TI - A Core Outcome Set for Multimorbidity Research (COSmm). AB - PURPOSE: We aimed to develop a consensus-based set of core outcomes specifically for studies in multimorbidity. METHODS: We undertook a consensus study following the COS-STAR (Core Outcome Set-STAndards for Reporting) guidelines for the design and reporting of core outcome sets. A Delphi panel of experts completed a web based survey with 2 rounds. Panelists were presented with a range of outcomes that had been identified in previous workshops and a related systematic review. They indicated their level of agreement on whether each outcome should be included in the core set using a 5-point Likert scale, and outcomes reaching a prespecified consensus level were included. RESULTS: Of 30 individuals invited to be panelists, 26 from 13 countries agreed. All 26 completed both rounds of the survey. The Delphi panel reached consensus on 17 outcomes for inclusion in a core outcome set for multimorbidity (COSmm). The highest-ranked outcomes were health related quality of life, mental health outcomes, and mortality. Other outcomes were grouped into overarching themes of patient-reported impacts and behaviors (treatment burden, self-rated health, self-management behavior, self-efficacy, adherence); physical activity and function (activities of daily living, physical function, physical activity); consultation related (communication, shared decision making, prioritization); and health systems (health care use, costs, quality of health care). CONCLUSIONS: This consensus study involved a wide range of international experts who identified a large number of outcomes for multimorbidity intervention studies. Our results suggest that quality of life, mental health outcomes, and mortality should be regarded as essential core outcomes. Researchers should, however, also consider the full range of outcomes when designing studies to capture important domains in multimorbidity depending on individual study aims and interventions. PMID- 29531105 TI - Recent Patterns in Shared Decision Making for Prostate-Specific Antigen Testing in the United States. AB - PURPOSE: Previous studies report infrequent use of shared decision making for prostate-specific antigen (PSA) testing. It is unknown whether this pattern has changed recently considering increased emphasis on shared decision making in prostate cancer screening recommendations. Thus, the objective of this study is to examine recent changes in shared decision making. METHODS: We conducted a retrospective cross-sectional study among men aged 50 years and older in the United States using 2010 and 2015 National Health Interview Survey (NHIS) data (n = 9,598). Changes in receipt of shared decision making were expressed as adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). Analyses were stratified on PSA testing (recent [in the past year] or no testing). Elements of shared decision making assessed included the patient being informed about the advantages only, advantages and disadvantages, and full shared decision making (advantages, disadvantages, and uncertainties). RESULTS: Among men with recent PSA testing, 58.5% and 62.6% reported having received >=1 element of shared decision making in 2010 and 2015, respectively (P = .054, aPR = 1.04; 95% CI, 0.98-1.11). Between 2010 and 2015, being told only about the advantages of PSA testing significantly declined (aPR = 0.82; 95% CI, 0.71-0.96) and full shared decision making prevalence significantly increased (aPR = 1.51; 95% CI, 1.28 1.79) in recently tested men. Among men without prior PSA testing, 10% reported >=1 element of shared decision making, which did not change with time. CONCLUSION: Between 2010 and 2015, there was no increase in shared decision making among men with recent PSA testing though there was a shift away from only being told about the advantages of PSA testing towards full shared decision making. Many men receiving PSA testing did not receive shared decision making. PMID- 29531106 TI - The Relationship Between Oseltamivir and Suicide in Pediatric Patients. AB - PURPOSE: Studies examining the association between use of oseltamivir and neuropsychiatric events (including suicide) among children have had mixed findings and have been limited by small sample size, reliance on older data, and potential confounding. We undertook an analysis that addresses these limitations. METHODS: Using a national administrative claims database and a case-crossover design that minimized confounding, we analyzed data from 5 contemporary influenza seasons (2009-2013) for individuals aged 1 to 18 years and ascertained oseltamivir exposure from pharmacy dispensing. RESULTS: We identified 21,407 suicide-related events during this study period, 251 of which were in oseltamivir exposed children. In case-crossover analysis, we did not find any significant association with suicide either for oseltamivir exposure (odds ratio = 0.64; 95% CI, 0.39-1.00; P = .05) or for influenza diagnosis alone (odds ratio = 0.63; 95% CI, 0.34-1.08; P = .10). CONCLUSION: Our findings suggest that oseltamivir does not increase risk of suicide in the pediatric population. PMID- 29531107 TI - Digital Rectal Examination for Prostate Cancer Screening in Primary Care: A Systematic Review and Meta-Analysis. AB - PURPOSE: Although the digital rectal examination (DRE) is commonly performed to screen for prostate cancer, there is limited data to support its use in primary care. This review and meta-analysis aims to evaluate the diagnostic accuracy of DRE in screening for prostate cancer in primary care settings. METHODS: We searched MEDLINE, Embase, DARE (Database of Abstracts of Reviews of Effects), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) from their inception to June 2016. Six reviewers, in pairs, independently screened citations for eligibility and extracted data. Pooled estimates were calculated for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DRE in primary care settings using an inverse variance meta-analysis. We used QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) and GRADE (Grades of Recommendation Assessment, Development, and Evaluation) guidelines to assess study risk of bias and quality. RESULTS: Our search yielded 8,217 studies, of which 7 studies with 9,241 patients were included after the screening process. All patients analyzed underwent both DRE and biopsy. Pooled sensitivity of DRE performed by primary care clinicians was 0.51 (95% CI, 0.36-0.67; I2 = 98.4%) and pooled specificity was 0.59 (95% CI, 0.41-0.76; I2 = 99.4%). Pooled PPV was 0.41 (95% CI, 0.31-0.52; I2 = 97.2%), and pooled NPV was 0.64 (95% CI, 0.58-0.70; I2 = 95.0%). The quality of evidence as assessed with GRADE was very low. CONCLUSION: Given the considerable lack of evidence supporting its efficacy, we recommend against routine performance of DRE to screen for prostate cancer in the primary care setting. PMID- 29531108 TI - Moving From Problem-Oriented to Goal-Directed Health Records. AB - Electronic health records (EHRs) have been in place for decades; however, most existing systems were designed in the prevailing disease- and payment-focused care paradigm that often loses sight of the goals, needs, and values of patients and clinicians. The goal-directed health care model was proposed more than 20 years ago, but no design principles have been developed for corresponding electronic record systems. Newly designed EHRs are needed to facilitate health care that is anchored by patient life and health goals. We explore the limitations of current EHRs and propose a blueprint for a new EHR design that may facilitate goal-directed health care. To reflect patient goals as a thread through the care continuum, we propose 5 major system functions for goal-directed health records based on the 8 characteristics of primary health care defined by the Institute of Medicine. We also discuss how new EHR functions could support goal-directed health care and how payment and quality measurement systems will need to be transformed. It may be possible for patient life and health goals to drive health care that is reinforced by a corresponding health record design; however, synchronized shifts must occur in the models of providing, documenting, and paying for health care. PMID- 29531110 TI - You Will Have a New Life. AB - This narrative presents my personal reflections as a medical anthropology researcher, and my journey as a chronic patient suffering for 30 years from ulcerative colitis. My surgeon promised me "a new life" after recommending a total colectomy 20 years ago. Indeed, a new life did begin following surgery, but I find I must renegotiate the challenges and rewards of this new life nearly every day. PMID- 29531109 TI - A Narrative Approach to Healing Chronic Illness. AB - Many clinicians may feel poorly prepared to manage patient suffering resulting from the travails of chronic illness. This essay explores the thesis that chronically and terminally ill patients can be holistically healed by transcending the suffering occasioned by the degradations of their illnesses. Suffering is conveyed as a story and clinicians can encourage healing by co constructing patients' illness stories. By addressing the inevitable existential conflicts uncovered in patients' narratives and helping them edit their stories to promote acceptance and meaning, suffering can be transcended. This requires that clinicians be skilled in narrative medicine and open to engaging the patient's existential concerns. By helping patients transcend their suffering, clinicians claim their heritage as healers. PMID- 29531111 TI - From Transactional Tasks to Personalized Care: A New Vision of Physicians' Roles. AB - Changes in health care delivery have affected the work that physicians are expected to perform and, in turn, their satisfaction. There is a gap between the professional mission-what physicians want to do (eg, caring relationships with patients, using intellectual and technical skills to help people, autonomy in their daily work) and what physicians spend a substantial portion of their time and energy doing (eg, data entry and forced function work). We believe that steps can be taken to align the current and future practice of medicine with the professional mission that motivates physicians and creates satisfaction. These steps focus on shifting physicians' responsibilities away from transactional tasks and towards personalized aspects of care. By taking steps to close the gap between mission and daily work, physicians will again be able to find joy, purpose, and meaning in their profession and give back what patients and society need from 21st century physicians. PMID- 29531112 TI - When It's Time to Retire: Notes From the Afterlife. AB - At the end of the Second World War, the US birth rate peaked at nearly 27 births per 1,000 population-a rate unparalleled in the previous 3 decades, and one that would not be repeated. That Boomer generation is now retiring. How do those of us caught in the wave feel about stepping back? Who will step in to replace us? And how will we replace the loss of purpose and fulfillment that comes from a career in medicine? A lengthening life expectancy has challenged many of us to consider the "second act" to our adult life. This essay describes the emotional turbulence of ending one career and contemplating the next. PMID- 29531113 TI - Citizen Engagement in Primary Care. PMID- 29531114 TI - Ordering Labs as a Team. PMID- 29531122 TI - Differential Expression Profiling of Microspores During the Early Stages of Isolated Microspore Culture Using the Responsive Barley Cultivar Gobernadora. AB - In barley, it is possible to induce embryogenesis in the haploid and uninucleate microspore to obtain a diploid plant that is perfectly homozygous. To change developmental fates in this fashion, microspores need to engage in cellular de differentiation, interrupting the pollen formation, and restore totipotency prior to engaging in embryogenesis. In this work, we used the barley cultivar Gobernadora to characterize the transcriptome of microspores prior to (day 0) and immediately after (days 2 and 5) the application of a stress pretreatment. A deep RNA-seq analysis revealed that microspores at these three time points exhibit a transcriptome of ~14k genes, ~90% of which were shared. An expression analysis identified a total of 3,382 differentially expressed genes (DEGs); of these, 2,155 and 2,281 DEGs were respectively identified when contrasting expression at days 0 and 2 and at days 2 and 5. These define 8 expression profiles in which DEGs share a common up- or down-regulation at these time points. Up-regulation of numerous glutathione S-transferase and heat shock protein genes as well as down regulation of ribosomal subunit protein genes was observed between days 0 and 2. The transition from microspores to developing embryos (days 2 vs. 5) was marked by the induction of transcription factor genes known to play important roles in early embryogenesis, numerous genes involved in hormone biosynthesis and plant hormonal signal transduction in addition to genes involved in secondary metabolism. This work sheds light on transcriptional changes accompanying an important developmental shift and provides candidate biomarkers for embryogenesis in barley. PMID- 29531123 TI - Tight Regulation of Srs2 Helicase Activity Is Crucial for Proper Functioning of DNA Repair Mechanisms. AB - Proper DNA damage repair is one of the most vital and fundamental functions of every cell. Several different repair mechanisms exist to deal with various types of DNA damage, in various stages of the cell cycle and under different conditions. Homologous recombination is one of the most important repair mechanisms in all organisms. Srs2, a regulator of homologous recombination, is a DNA helicase involved in DNA repair, cell cycle progression and genome integrity. Srs2 can remove Rad51 from ssDNA, and is thought to inhibit unscheduled recombination. However, Srs2 has to be precisely regulated, as failure to do so is toxic and can lead to cell death. We noticed that a very slight elevation of the levels of Srs2 (by addition of a single extra copy of the SRS2 gene) leads to hyper-sensitivity of yeast cells to methyl methanesulfonate (MMS, a DNA damaging agent). This effect is seen in haploid, but not in diploid, cells. We analyzed the mechanism that controls haploid/diploid sensitivity and arrived to the conclusion that the sensitivity requires the activity of RAD59 and RDH54, whose expression in diploid cells is repressed. We carried out a mutational analysis of Srs2 to determine the regions of the protein required for the sensitization to genotoxins. Interestingly, Srs2 needs the HR machinery and its helicase activity for its toxicity, but does not need to dismantle Rad51. Our work underscores the tight regulation that is required on the levels of Srs2 activity, and the fact that Srs2 helicase activity plays a more central role in DNA repair than the ability of Srs2 to dismantle Rad51 filaments. PMID- 29531124 TI - Fast Ordered Sampling of DNA Sequence Variants. AB - Explosive growth in the amount of genomic data is matched by increasing power of consumer-grade computers. Even applications that require powerful servers can be quickly tested on desktop or laptop machines if we can generate representative samples from large data sets. I describe a fast and memory-efficient implementation of an on-line sampling method developed for tape drives 30 years ago. Focusing on genotype files, I test the performance of this technique on modern solid-state and spinning hard drives, and show that it performs well compared to a simple sampling scheme. I illustrate its utility by developing a method to quickly estimate genome-wide patterns of linkage disequilibrium (LD) decay with distance. I provide open-source software that samples loci from several variant format files, a separate program that performs LD decay estimates, and a C++ library that lets developers incorporate these methods into their own projects. PMID- 29531126 TI - To Screen or Not to Screen: Overreliance on Risk Without Protective Factors in Violence Research. PMID- 29531125 TI - Predicting Teen Dating Violence Perpetration. AB - OBJECTIVES: With our study we aimed to (1) understand what factors uniquely conferred risk for physical and sexual forms of teen dating violence (TDV) perpetration and (2) create a screening algorithm to quantify perpetration risk on the basis of these factors. METHODS: A total of 1031 diverse public high school students living in Southeast Texas participated in our study (56% female; 29% African American, 28% white, and 31% Hispanic). Self-report measures concerning TDV and associated risk factors were completed annually for 6 years. RESULTS: Results suggested that family violence (domestic violence exposure, maltreatment) together with deficits in conflict resolution incrementally improved our forecasts above and beyond lifetime history of physical TDV perpetration (net reclassification improvement = 0.44; 95% confidence interval [CI] = 0.30-0.59). Meanwhile, a violent dating history (TDV sexual perpetration, sexual victimization, and emotional perpetration) and acceptance of TDV incrementally improved our models for forecasting sexual forms of perpetration (net reclassification improvement = 0.41; 95% CI = 0.24-0.58). These models adequately discriminated between future perpetrators and nonoffenders (area under the curve statistic >0.70; 95% CI: 0.69-0.74). Overall, adolescents with positive test results on our algorithms were over twice as likely to perpetrate dating violence over the course of 6 years. CONCLUSIONS: Our study represents one of the first applications of reclassification analyses to psychosocial research in a pediatric population. The result is a theoretically informed, empirically based algorithm that can adequately estimate the likelihood of physical and sexual TDV perpetration during vulnerable developmental periods. These findings can immediately aid emerging preventive initiatives for this increasing public health concern. PMID- 29531128 TI - US opioid overdoses rise by 30% in one year. PMID- 29531127 TI - Teen Pregnancy Risk Factors Among Young Women of Diverse Sexual Orientations. AB - OBJECTIVES: Young women who are sexual minorities (eg, bisexual and lesbian) are approximately twice as likely as those who are heterosexual to have a teen pregnancy. Therefore, we hypothesized that risk factors for teen pregnancy would vary across sexual orientation groups and that other potential risk factors exist that are unique to sexual minorities. METHODS: We used multivariable log-binomial models gathered from 7120 young women in the longitudinal cohort known as the Growing Up Today Study to examine the following potential teen pregnancy risk factors: childhood maltreatment, bullying victimization and perpetration, and gender nonconformity. Among sexual minorities, we also examined the following: sexual minority developmental milestones, sexual orientation-related stress, sexual minority outness, and lesbian, gay, and bisexual social activity involvement. RESULTS: Childhood maltreatment and bullying were significant teen pregnancy risk factors among all participants. After adjusting for childhood maltreatment and bullying, the sexual orientation-related teen pregnancy disparities were attenuated; these risk factors explained 45% of the disparity. Among sexual minorities, reaching sexual minority developmental milestones earlier was also associated with an increased teen pregnancy risk. CONCLUSIONS: The higher teen pregnancy prevalence among sexual minorities compared with heterosexuals in this cohort was partially explained by childhood maltreatment and bullying, which may, in part, stem from sexual orientation-related discrimination. Teen pregnancy prevention efforts that are focused on risk factors more common among young women who are sexual minorities (eg, childhood maltreatment, bullying) can help to reduce the existing sexual orientation related teen pregnancy disparity. PMID- 29531129 TI - Survival among Lung Cancer Patients in the U.S. Military Health System: A Comparison with the SEER Population. AB - Background: The U.S. military health system (MHS) provides universal health care access to its beneficiaries. However, whether the universal access has translated into improved patient outcome is unknown. This study compared survival of non small cell lung cancer (NSCLC) patients in the MHS with that in the U.S. general population.Methods: The MHS data were obtained from The Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR), and the U.S. population data were drawn from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. The study subjects were NSCLC patients diagnosed between January 1, 1987, and December 31, 2012, in ACTUR and a sample of SEER patients who were matched to the ACTUR patients on age group, sex, race, and year of diagnosis group with a matching ratio of 1:4. Patients were followed through December 31, 2013.Results: A total of 16,257 NSCLC patients were identified from ACTUR and 65,028 matched patients from SEER. Compared with SEER patients, ACTUR patients had significantly better overall survival (log-rank P < 0.001). The better overall survival among the ACTUR patients remained after adjustment for potential confounders (HR = 0.78, 95% confidence interval, 0.76-0.81). The survival advantage of the ACTUR patients was present regardless of cancer stage, grade, age group, sex, or race.Conclusions: The MHS's universal care and lung cancer care programs may have translated into improved survival among NSCLC patients.Impact: This study supports improved survival outcome among NSCLC patients with universal care access. Cancer Epidemiol Biomarkers Prev; 27(6); 673 9. (c)2018 AACR. PMID- 29531130 TI - Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study. AB - Background: Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy.Methods: We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study.Results: Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival (n = 160; HR, 0.56; P = 0.03) and 5-year overall survival (HR, 0.53; P = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology.Conclusions: The association between high TLE3 expression and a favorable response to taxane containing chemotherapy regimens was validated in patients with nonserous ovarian cancer.Impact: TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. Cancer Epidemiol Biomarkers Prev; 27(6); 680-8. (c)2018 AACR. PMID- 29531131 TI - Potential Role for Regulatory B Cells as a Major Source of Interleukin-10 in Spleen from Plasmodium chabaudi-Infected Mice. AB - Interleukin-10 (IL-10)-producing regulatory B (Breg) cells were found to be induced in a variety of infectious diseases. However, its importance in the regulation of immune response to malaria is still unclear. Here, we investigated the dynamics, phenotype, and function of Breg cells using Plasmodium chabaudi chabaudi AS-infected C57BL/6 and BALB/c mice. BALB/c mice were more susceptible to infection and had a stronger IL-10 response in spleen than C57BL/6 mice. Analysis of the surface markers of IL-10-producing cells with flow cytometry showed that CD19+ B cells were one of the primary IL-10-producing populations in P. c. chabaudi AS-infected C57BL/6 and BALB/c mice, especially in the latter one. The Breg cells had a heterogeneous phenotype which shifted during infection. The well-established Breg subset, CD19+ CD5+ CD1dhi cells, accounted for less than 20% of IL-10-producing B cells in both strains during the course of infection. Most Breg cells were IgG+ and CD138- from day 0 to day 8 postinfection. Adoptive transfer of Breg cells to C57BL/6 mice infected with P. c. chabaudi AS led to a transient increase of parasitemia without an impact on survival rate. Our finding reveals that B cells play an active and important regulatory role in addition to mediating humoral immunity in immune response against malaria, which should be paid more attention in developing therapeutic or vaccine strategies against malaria involving stimulation of B cells. PMID- 29531132 TI - Serum Amyloid P and IgG Exhibit Differential Capabilities in the Activation of the Innate Immune System in Response to Bacillus anthracis Peptidoglycan. AB - We showed that human IgG supported the response by human innate immune cells to peptidoglycan (PGN) from Bacillus anthracis and PGN-induced complement activation. However, other serum constituents have been shown to interact with peptidoglycan, including the IgG-like soluble pattern recognition receptor serum amyloid P (SAP). Here, we compared the abilities of SAP and of IgG to support monocyte and complement responses to PGN. Utilizing in vitro methods, we demonstrate that SAP is superior to IgG in supporting monocyte production of cytokines in response to PGN. Like IgG, the response supported by SAP was enhanced by phagocytosis and signaling kinases, such as Syk, Src, and phosphatidylinositol 3-kinase, that are involved in various cellular processes, including Fc receptor signaling. Unlike IgG, SAP had no effect on the activation of complement in response to PGN. These data demonstrate an opsonophagocytic role for SAP in response to PGN that propagates a cellular response without propagating the formation of the terminal complement complex. PMID- 29531133 TI - Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. AB - Helicobacter pylori, a Gram-negative bacterium, is a well-known risk factor for gastric cancer. H. pylori vacuolating cytotoxin A (VacA) is a secreted pore forming toxin that induces a wide range of cellular responses. Like many other bacterial toxins, VacA has been hypothesized to utilize lipid rafts to gain entry into host cells. Here, we used giant plasma membrane vesicles (GPMVs) as a model system to understand the preferential partitioning of VacA into lipid rafts. We show that a wild-type (WT) toxin predominantly associates with the raft phase. Acid activation of VacA enhances binding of the toxin to GPMVs but is not required for raft partitioning. VacA mutant proteins with alterations at the amino terminus (resulting in impaired membrane channel formation) and a nonoligomerizing VacA mutant protein retain the ability to preferentially associate with lipid rafts. Consistent with these results, the isolated VacA p55 domain was capable of binding to lipid rafts. We conclude that the affinity of VacA for rafts is independent of its capacity to oligomerize or form membrane channels. PMID- 29531134 TI - Two Phytoplasmas Elicit Different Responses in the Insect Vector Euscelidius variegatus Kirschbaum. AB - Phytoplasmas are plant-pathogenic bacteria transmitted by hemipteran insects. The leafhopper Euscelidius variegatus is a natural vector of chrysanthemum yellows phytoplasma (CYp) and a laboratory vector of flavescence doree phytoplasma (FDp). The two phytoplasmas induce different effects on this species: CYp slightly improves whereas FDp negatively affects insect fitness. To investigate the molecular bases of these different responses, transcriptome sequencing (RNA-seq) analysis of E. variegatus infected with either CYp or FDp was performed. The sequencing provided the first de novo transcriptome assembly for a phytoplasma vector and a starting point for further analyses on differentially regulated genes, mainly related to immune system and energy metabolism. Insect phenoloxidase activity, immunocompetence, and body pigmentation were measured to investigate the immune response, while respiration and movement rates were quantified to confirm the effects on energy metabolism. The activation of the insect immune response upon infection with FDp, which is not naturally transmitted by E. variegatus, confirmed that this bacterium is mostly perceived as a potential pathogen. Conversely, the acquisition of CYp, which is naturally transmitted by E. variegatus, seems to increase the insect fitness by inducing a prompt response to stress. This long-term relationship is likely to improve survival and dispersal of the infected insect, thus enhancing the opportunity of phytoplasma transmission. PMID- 29531135 TI - Signaling by a Conserved Quorum Sensing Pathway Contributes to Growth Ex Vivo and Oropharyngeal Colonization of Human Pathogen Group A Streptococcus. AB - Bacterial virulence factor production is a highly coordinated process. The temporal pattern of bacterial gene expression varies in different host anatomic sites to overcome niche-specific challenges. The human pathogen group A streptococcus (GAS) produces a potent secreted protease, SpeB, that is crucial for pathogenesis. Recently, we discovered that a quorum sensing pathway comprised of a leaderless short peptide, SpeB-inducing peptide (SIP), and a cytosolic global regulator, RopB, controls speB expression in concert with bacterial population density. The SIP signaling pathway is active in vivo and contributes significantly to GAS invasive infections. In the current study, we investigated the role of the SIP signaling pathway in GAS-host interactions during oropharyngeal colonization. The SIP signaling pathway is functional during growth ex vivo in human saliva. SIP-mediated speB expression plays a crucial role in GAS colonization of the mouse oropharynx. GAS employs a distinct pattern of SpeB production during growth ex vivo in saliva that includes a transient burst of speB expression during early stages of growth coupled with sustained levels of secreted SpeB protein. SpeB production aids GAS survival by degrading LL37, an abundant human antimicrobial peptide. We found that SIP signaling occurs during growth in human blood ex vivo. Moreover, the SIP signaling pathway is critical for GAS survival in blood. SIP-dependent speB regulation is functional in strains of diverse emm types, indicating that SIP signaling is a conserved virulence regulatory mechanism. Our discoveries have implications for future translational studies. PMID- 29531136 TI - The Ethanolamine Permease EutH Promotes Vacuole Adaptation of Salmonella enterica and Listeria monocytogenes during Macrophage Infection. AB - Ethanolamine is a ubiquitous and essential molecule within a host. Significantly, bacterial pathogens exploit ethanolamine during infection to promote growth and regulate virulence. The ethanolamine permease EutH is dispensable for growth in vitro under standard conditions, whereas EutH is required for ethanolamine utilization at low pH. These findings suggested a model in which EutH facilitates diffusion of ethanolamine into the bacterial cell in acidic environments. To date, the ecological significance of this model has not been thoroughly investigated, and the importance of EutH to bacterial growth under physiologically relevant conditions is not known. During infection, immune cells internalize invading bacteria within an acidic, nutrient-depleted vacuole called the phagosome. Here, we investigated the hypothesis that EutH promotes bacterial survival following phagocytosis. Our findings indicate that EutH is important for survival and replication of the facultative intracellular pathogens Salmonella enterica serovar Typhimurium and Listeria monocytogenes during prolonged or transient exposure to the phagosome, respectively. Furthermore, in agreement with EutH being important in the acidic environment, neutralization of the vacuole abolished the requirement for EutH. Significantly, consistent with a role for EutH in promoting intramacrophage survival, EutH was not required during S Typhimurium local intestinal infection but specifically conferred an advantage upon dissemination to peripheral organs. These findings reveal a physiologically relevant and conserved role for EutH in spatiotemporal niche adaptation during infection. PMID- 29531137 TI - The adjuvant Bordetella Colonization Factor A attenuates alum-induced Th2 responses and enhances Bordetella pertussis clearance from mouse lungs. AB - The reemergence of pertussis or whooping cough in several countries highlights the need for better vaccines. Acellular pertussis vaccines (aPV) contain alum as the adjuvant and elicit Th2 biased immune responses that are less effective in protecting against infection than the reactogenic whole cell pertussis vaccines (wPV), which elicit primarily a Th1/Th17 response. An important goal for the field is to devise aPVs that will induce immune responses similar to wPV. We show that Bordetella Colonization Factor A (BcfA), an outer membrane protein from B. bronchiseptica, has strong adjuvant function and elicits cellular and humoral immune responses to heterologous and B. pertussis antigens. Addition of BcfA to a commercial aPV resulted in greater reduction of B. pertussis numbers from the lungs than elicited by aPV alone. More efficient pathogen clearance was accompanied by increased IL-17 and reduced IL-5, and an increased ratio of IgG2/IgG1 antibodies. Thus our results suggest that BcfA improves aPV induced responses by modifying the alum-induced Th2-biased aPV response towards Th1/Th17. A re-designed aPV containing BcfA may allow better control of pertussis reemergence by reshaping immune responses to resemble those elicited by wPV immunization. PMID- 29531138 TI - Anti-HMGB1 Neutralizing Antibody Attenuates Periodontal Inflammation and Bone Resorption in a Murine Periodontitis Model. AB - High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-1beta (IL-1beta) were secreted in response to tumor necrosis factor-alpha (TNF-alpha) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1beta were observed in the conditioned media from TNF-alpha-stimulated HGECs and THP-1 in vitro Simultaneous stimulation with TNF-alpha and anti-HMGB1 antibody significantly decreased TNF-alpha-induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1beta and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis. PMID- 29531140 TI - GP leaders pass vote of no confidence in GMC. PMID- 29531141 TI - Anthropogenic resource subsidies and host-parasite dynamics in wildlife. PMID- 29531139 TI - Altered Brain Dynamics in Patients With Type 1 Diabetes During Working Memory Processing. AB - It is now generally accepted that diabetes increases the risk for cognitive impairment, but the precise mechanisms are poorly understood. A critical problem in linking diabetes to cognitive impairment is that patients often have multiple comorbidities (e.g., obesity, hypertension) that have been independently linked to cognitive deficits. In the study reported here we focused on young adults with and without type 1 diabetes who were virtually free of such comorbidities. The two groups were matched on major health and demographic factors, and all participants completed a verbal working memory task during magnetoencephalographic brain imaging. We hypothesized that patients would have altered neural dynamics in verbal working memory processing and that these differences would directly relate to clinical disease measures. Accordingly, we found that patients had significantly stronger neural responses in the superior parietal cortices during memory encoding and significantly weaker activity in parietal-occipital regions during maintenance compared with control subjects. Moreover, disease duration and glycemic control were both significantly correlated with neural responses in various brain regions. In conclusion, young healthy adults with type 1 diabetes already have aberrant neural processing relative to their peers without diabetes, using compensatory responses to perform the task, and glucose management and duration may play a central role. PMID- 29531142 TI - Resource-driven changes to host population stability alter the evolution of virulence and transmission. AB - What drives the evolution of parasite life-history traits? Recent studies suggest that linking within- and between-host processes can provide key insight into both disease dynamics and parasite evolution. Still, it remains difficult to understand how to pinpoint the critical factors connecting these cross-scale feedbacks, particularly under non-equilibrium conditions; many natural host populations inherently fluctuate and parasites themselves can strongly alter the stability of host populations. Here, we develop a general model framework that mechanistically links resources to parasite evolution across a gradient of stable and unstable conditions. First, we dynamically link resources and between-host processes (host density, stability, transmission) to virulence evolution, using a 'non-nested' model. Then, we consider a 'nested' model where population-level processes (transmission and virulence) depend on resource-driven changes to individual-level (within-host) processes (energetics, immune function, parasite production). Contrary to 'non-nested' model predictions, the 'nested' model reveals complex effects of host population dynamics on parasite evolution, including regions of evolutionary bistability; evolution can push parasites towards strongly or weakly stabilizing strategies. This bistability results from dynamic feedbacks between resource-driven changes to host density, host immune function and parasite production. Together, these results highlight how cross scale feedbacks can provide key insights into the structuring role of parasites and parasite evolution.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531143 TI - Reviewing the effects of food provisioning on wildlife immunity. AB - While urban expansion increasingly encroaches on natural habitats, many wildlife species capitalize on anthropogenic food resources, which have the potential to both positively and negatively influence their responses to infection. Here we examine how food availability and key nutrients have been reported to shape innate and adaptive immunity in wildlife by drawing from field-based studies, as well as captive and food restriction studies with wildlife species. Examples of food provisioning and key nutrients enhancing immune function were seen across the three study type distinctions, as were cases of trace metals and pharmaceuticals impairing the immunity of wildlife species. More generally, food provisioning in field studies tended to increase innate and adaptive responses to certain immune challenges, whereas patterns were less clear in captive studies. Mild food restriction often enhanced, whereas severe food restriction frequently impaired immunity. However, to enable stronger conclusions we stress a need for further research, especially field studies, and highlight the importance of integrating nutritional manipulation, immune challenge, and functional outcomes. Despite current gaps in research on this topic, modern high throughput molecular approaches are increasingly feasible for wildlife studies and offer great opportunities to better understand human influences on wildlife health.This article is part of the theme issue 'Anthropogenic resource subsidies and host parasite dynamics in wildlife'. PMID- 29531145 TI - Feeder density enhances house finch disease transmission in experimental epidemics. AB - Anthropogenic food provisioning of wildlife can alter the frequency of contacts among hosts and between hosts and environmental sources of pathogens. Despite the popularity of garden bird feeding, few studies have addressed how feeders influence host contact rates and disease dynamics. We experimentally manipulated feeder density in replicate aviaries containing captive, pathogen-naive, groups of house finches (Haemorhous mexicanus) and continuously tracked behaviours at feeders using radio-frequency identification devices. We then inoculated one bird per group with Mycoplasma gallisepticum (Mg), a common bacterial pathogen for which feeders are fomites of transmission, and assessed effects of feeder density on house finch behaviour and pathogen transmission. We found that pathogen transmission was significantly higher in groups with the highest density of bird feeders, despite a significantly lower rate of intraspecific aggressive interactions relative to the low feeder density groups. Conversely, among naive group members that never showed signs of disease, we saw significantly higher concentrations of Mg-specific antibodies in low feeder density groups, suggesting that birds in low feeder density treatments had exposure to subclinical doses of Mg. We discuss ways in which the density of garden bird feeders could play an important role in mediating the intensity of Mg epidemics.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531144 TI - Livestock abundance predicts vampire bat demography, immune profiles and bacterial infection risk. AB - Human activities create novel food resources that can alter wildlife-pathogen interactions. If resources amplify or dampen, pathogen transmission probably depends on both host ecology and pathogen biology, but studies that measure responses to provisioning across both scales are rare. We tested these relationships with a 4-year study of 369 common vampire bats across 10 sites in Peru and Belize that differ in the abundance of livestock, an important anthropogenic food source. We quantified innate and adaptive immunity from bats and assessed infection with two common bacteria. We predicted that abundant livestock could reduce starvation and foraging effort, allowing for greater investments in immunity. Bats from high-livestock sites had higher microbicidal activity and proportions of neutrophils but lower immunoglobulin G and proportions of lymphocytes, suggesting more investment in innate relative to adaptive immunity and either greater chronic stress or pathogen exposure. This relationship was most pronounced in reproductive bats, which were also more common in high-livestock sites, suggesting feedbacks between demographic correlates of provisioning and immunity. Infection with both Bartonella and haemoplasmas were correlated with similar immune profiles, and both pathogens tended to be less prevalent in high-livestock sites, although effects were weaker for haemoplasmas. These differing responses to provisioning might therefore reflect distinct transmission processes. Predicting how provisioning alters host pathogen interactions requires considering how both within-host processes and transmission modes respond to resource shifts.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531146 TI - Health hazards to wild birds and risk factors associated with anthropogenic food provisioning. AB - Provision of supplementary food for wild birds at garden feeding stations is a common, large-scale and year-round practice in multiple countries including Great Britain (GB). While these additional dietary resources can benefit wildlife, there is a concomitant risk of disease transmission, particularly when birds repeatedly congregate in the same place at high densities and through interactions of species that would not normally associate in close proximity. Citizen science schemes recording garden birds are popular and can integrate disease surveillance with population monitoring, offering a unique opportunity to explore inter-relationships between supplementary feeding, disease epidemiology and population dynamics. Here, we present findings from a national surveillance programme in GB and note the dynamism of endemic and emerging diseases over a 25 year period, focusing on protozoal (finch trichomonosis), viral (Paridae pox) and bacterial (passerine salmonellosis) diseases with contrasting modes of transmission. We also examine the occurrence of mycotoxin contamination of food residues in bird feeders, which present both a direct and indirect (though immunosuppression) risk to wild bird health. Our results inform evidence-based mitigation strategies to minimize anthropogenically mediated health hazards, while maintaining the benefits of providing supplementary food for wild birds.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531147 TI - Human-nature interactions and the consequences and drivers of provisioning wildlife. AB - Many human populations are undergoing an extinction of experience, with a progressive decline in interactions with nature. This is a consequence both of a loss of opportunity for, and orientation towards, such experiences. The trend is of concern in part because interactions with nature can be good for human health and wellbeing. One potential means of redressing these losses is through the intentional provision of resources to increase wildlife populations in close proximity to people, thereby increasing the potential for positive human-nature experiences, and thence the array of benefits that can result. In this paper, we review the evidence that these resource subsidies have such a cascade of effects. In some Westernized countries, the scale of provision is extraordinarily high, and doubtless leads to both positive and negative impacts for wildlife. In turn, these impacts often lead to more frequent, reliable and closer human-nature interactions, with a greater variety of species. The consequences for human wellbeing remain poorly understood, although benefits documented in the context of human-nature interactions more broadly seem likely to apply. There are also some important feedback loops that need to be better characterized if resource provisioning is to contribute effectively towards averting the extinction of experience.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531148 TI - Winter feeding of elk in the Greater Yellowstone Ecosystem and its effects on disease dynamics. AB - Providing food to wildlife during periods when natural food is limited results in aggregations that may facilitate disease transmission. This is exemplified in western Wyoming where institutional feeding over the past century has aimed to mitigate wildlife-livestock conflict and minimize winter mortality of elk (Cervus canadensis). Here we review research across 23 winter feedgrounds where the most studied disease is brucellosis, caused by the bacterium Brucella abortus Traditional veterinary practices (vaccination, test-and-slaughter) have thus far been unable to control this disease in elk, which can spill over to cattle. Current disease-reduction efforts are being guided by ecological research on elk movement and density, reproduction, stress, co-infections and scavengers. Given the right tools, feedgrounds could provide opportunities for adaptive management of brucellosis through regular animal testing and population-level manipulations. Our analyses of several such manipulations highlight the value of a research management partnership guided by hypothesis testing, despite the constraints of the sociopolitical environment. However, brucellosis is now spreading in unfed elk herds, while other diseases (e.g. chronic wasting disease) are of increasing concern at feedgrounds. Therefore experimental closures of feedgrounds, reduced feeding and lower elk populations merit consideration.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531149 TI - Responses of migratory species and their pathogens to supplemental feeding. AB - Migratory animals undergo seasonal and often spectacular movements and perform crucial ecosystem services. In response to anthropogenic changes, including food subsidies, some migratory animals are now migrating shorter distances or halting migration altogether and forming resident populations. Recent studies suggest that shifts in migratory behaviour can alter the risk of infection for wildlife. Although migration is commonly assumed to enhance pathogen spread, for many species, migration has the opposite effect of lowering infection risk, if animals escape from habitats where pathogen stages have accumulated or if strenuous journeys cull infected hosts. Here, we summarize responses of migratory species to supplemental feeding and review modelling and empirical work that provides support for mechanisms through which resource-induced changes in migration can alter pathogen transmission. In particular, we focus on the well-studied example of monarch butterflies and their protozoan parasites in North America. We also identify areas for future research, including combining new technologies for tracking animal movements with pathogen surveillance and exploring potential evolutionary responses of hosts and pathogens to changing movement patterns. Given that many migratory animals harbour pathogens of conservation concern and zoonotic potential, studies that document ongoing shifts in migratory behaviour and infection risk are vitally needed.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531150 TI - Consequences of resource supplementation for disease risk in a partially migratory population. AB - Anthropogenic landscape features such as urban parks and gardens, landfills and farmlands can provide novel, seasonally reliable food sources that impact wildlife ecology and distributions. In historically migratory species, food subsidies can cause individuals to forgo migration and form partially migratory or entirely sedentary populations, eroding a crucial benefit of migration: pathogen avoidance through seasonal abandonment of transmission sites and mortality of infected individuals during migration. Since many migratory taxa are declining, and wildlife populations in urban areas can harbour zoonotic pathogens, understanding the mechanisms by which anthropogenic resource subsidies influence infection dynamics and the persistence of migration is important for wildlife conservation and public health. We developed a mathematical model for a partially migratory population and a vector-borne pathogen transmitted at a shared breeding ground, where food subsidies increase the nonbreeding survival of residents. We found that higher resident nonbreeding survival increased infection prevalence in residents and migrants, and lowered the fraction of the population that migrated. The persistence of migration may be especially threatened if residency permits emergence of more virulent pathogens, if resource subsidies reduce costs of infection for residents, and if infection reduces individual migratory propensity.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531151 TI - Optimal foraging in seasonal environments: implications for residency of Australian flying foxes in food-subsidized urban landscapes. AB - Bats provide important ecosystem services such as pollination of native forests; they are also a source of zoonotic pathogens for humans and domestic animals. Human-induced changes to native habitats may have created more opportunities for bats to reside in urban settings, thus decreasing pollination services to native forests and increasing opportunities for zoonotic transmission. In Australia, fruit bats (Pteropus spp. flying foxes) are increasingly inhabiting urban areas where they feed on anthropogenic food sources with nutritional characteristics and phenology that differ from native habitats. We use optimal foraging theory to investigate the relationship between bat residence time in a patch, the time it takes to search for a new patch (simulating loss of native habitat) and seasonal resource production. We show that it can be beneficial to reside in a patch, even when food productivity is low, as long as foraging intensity is low and the expected searching time is high. A small increase in the expected patch searching time greatly increases the residence time, suggesting nonlinear associations between patch residence and loss of seasonal native resources. We also found that sudden increases in resource consumption due to an influx of new bats has complex effects on patch departure times that again depend on expected searching times and seasonality. Our results suggest that the increased use of urban landscapes by bats may be a response to new spatial and temporal configurations of foraging opportunities. Given that bats are reservoir hosts of zoonotic diseases, our results provide a framework to study the effects of foraging ecology on disease dynamics.One contribution of 14 to a theme isssue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531152 TI - From wetland specialist to hand-fed generalist: shifts in diet and condition with provisioning for a recently urbanized wading bird. AB - Many wildlife species shift their diets to use novel resources in urban areas. The consequences of these shifts are not well known, and consumption of reliable but low quality-anthropogenic food may present important trade-offs for wildlife health. This may be especially true for carnivorous species such as the American white ibis (Eudocimus albus), a nomadic wading bird which has been increasingly observed in urban parks in South Florida, USA. We tested the effects of anthropogenic provisioning on consumer nutrition (i.e. dietary protein), body condition and ectoparasite burdens along an urban gradient using stable isotope analysis, scaled mass index values and GPS transmitter data. Ibises that assimilated more provisioned food were captured at more urban sites, used more urban habitat, had lower mass-length residuals, lower ectoparasite scores, assimilated less delta15N and had smaller dietary isotopic ellipses. Our results suggest that ibises in urban areas are heavily provisioned with anthropogenic food, which appears to offer a trade-off by providing low-quality, but easily accessible, calories that may not support high mass but may increase time available for anti-parasite behaviours such as preening. Understanding such trade offs is important for investigating the effects of provisioning on infection risk and the conservation of wildlife in human-modified habitats.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531155 TI - Quebec doctors reject pay rise in favour of investment in health system. PMID- 29531153 TI - Assessing the direct and indirect effects of food provisioning and nutrient enrichment on wildlife infectious disease dynamics. AB - Anthropogenic resource supplementation can shape wildlife disease directly by altering the traits and densities of hosts and parasites or indirectly by stimulating prey, competitor or predator species. We first assess the direct epidemiological consequences of supplementation, highlighting the similarities and differences between food provisioning and two widespread forms of nutrient input: agricultural fertilization and aquatic nutrient enrichment. We then review an aquatic disease system and a general model to assess whether predator and competitor species can enhance or overturn the direct effects of enrichment. All forms of supplementation can directly affect epidemics by increasing host population size or altering parasite production within hosts, but food provisioning is most likely to aggregate hosts and increase parasite transmission. However, if predators or competitors increase in response to supplementation, they could alter resource-fuelled outbreaks in focal hosts. We recommend identifying the traits of hosts, parasites or interacting species that best predict epidemiological responses to supplementation and evaluating the relative importance of these direct and indirect mechanisms. Theory and experiments should examine the timing of behavioural, physiological and demographic changes for realistic, variable scenarios of supplementation. A more integrative view of resource supplementation and wildlife disease could yield broadly applicable disease management strategies.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531154 TI - Food for contagion: synthesis and future directions for studying host-parasite responses to resource shifts in anthropogenic environments. AB - Human-provided resource subsidies for wildlife are diverse, common and have profound consequences for wildlife-pathogen interactions, as demonstrated by papers in this themed issue spanning empirical, theoretical and management perspectives from a range of study systems. Contributions cut across scales of organization, from the within-host dynamics of immune function, to population level impacts on parasite transmission, to landscape- and regional-scale patterns of infection. In this concluding paper, we identify common threads and key findings from author contributions, including the consequences of resource subsidies for (i) host immunity; (ii) animal aggregation and contact rates; (iii) host movement and landscape-level infection patterns; and (iv) interspecific contacts and cross-species transmission. Exciting avenues for future work include studies that integrate mechanistic modelling and empirical approaches to better explore cross-scale processes, and experimental manipulations of food resources to quantify host and pathogen responses. Work is also needed to examine evolutionary responses to provisioning, and ask how diet-altered changes to the host microbiome influence infection processes. Given the massive public health and conservation implications of anthropogenic resource shifts, we end by underscoring the need for practical recommendations to manage supplemental feeding practices, limit human-wildlife conflicts over shared food resources and reduce cross-species transmission risks, including to humans.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. PMID- 29531156 TI - Clinical diagnosis of Graves' or non-Graves' hyperthyroidism compared to TSH receptor antibody test. AB - BACKGROUND: TSH receptor antibody (TRAb) is considered the gold standard diagnostic test for the autoimmunity of Graves' disease (GD), which is commonly diagnosed clinically. AIM: To evaluate the true positive (sensitivity) and true negative (specificity) rates of clinical diagnosis of GD or non-GD hyperthyroidism compared to the TRAb test. SETTING: University teaching hospital in North West England. PARTICIPANTS: Patients in the Endocrinology service who had a TRAb measurement between December 2009 and October 2015. METHODS: Electronic patient records were studied retrospectively for a pre-TRAb clinical diagnosis of GD or non-GD hyperthyroidism. We examined descriptive statistics and binary classification tests; Fisher exact test was used to analyse contingency tables. RESULTS: We identified 316 patients with a mean age of 45 (range, 17-89) years; 247 (78%) were women. Compared to the TRAb result, clinical diagnosis had a sensitivity of 88%, specificity 66%, positive predictive value 72%, negative predictive value 84%, false negative rate 12%, false positive rate 34%, positive likelihood ratio 2.6 and negative likelihood ratio 0.2 (P < 0.0001). CONCLUSIONS: Clinicians were liable to both over- and under-diagnose GD. The TRAb test can help reduce the number of incorrect or unknown diagnoses in the initial clinical assessment of patients presenting with hyperthyroidism. PMID- 29531157 TI - Testicular adrenal rest tumors in boys with 21-hydroxylase deficiency, timely diagnosis and follow-up. AB - BACKGROUND: Testicular adrenal rest tumors (TARTs) are found in 30-94% of adult males with congenital adrenal hyperplasia (CAH). We sought to explore TART appearance through yearly ultrasound examination of testes in young boys with CAH, and its association with metabolic control and genetic mutations. METHODS: Twenty-five boys with 21-hydroxylase deficiency in the age group 4-18 years diagnosed during the period 2001-2016 were included in the study. ACTH, 17 hydroxyprogesterone, androstenedione and testosterone were measured at 4-month intervals. Growth and BMI were assessed at the time of evaluation. PCR/ACRS method was used for CYP21A2 gene analysis. Testicular ultrasound examination was performed yearly. RESULTS: TARTs were detected by ultrasound in 8 children at the age of 6-16 years (13.2 years average). Five had salt-wasting form, two had simple virilizing form and one had non-classic form of CAH. Significant differences in the17OHP and androstenedione levels were detected between the boys, adherent and non-adherent to therapy. Inadequate metabolic control was not different in boys with and without TART (11/17 and 5/8 respectively). No significant difference was detected in the distribution of genetic mutations or adherence to therapy between patients with and without TARTs. One patient had a mutation not reported thus far in TART and another developed leukemia. CONCLUSION: TART is not rare in young boys with CAH, irrespective of the specific mutation or metabolic control. Ultrasound screening helps timely diagnosis and adjustment of therapy. PMID- 29531158 TI - Salivary cortisol in the diagnosis of adrenal insufficiency: cost efficient and patient friendly. AB - Saliva as a diagnostic tool is patient friendly and offers analytical advantages. Hormonal analysis of saliva is not influenced by changes in concentrations of binding globulins as the free concentration of the hormones is measured. Analysis of salivary cortisol is common practice in the diagnostic work-up of hypercortisolism. We investigated the potential role of measuring salivary cortisol when adrenal insufficiency (AI) is suspected, to reduce the numbers of ACTH stimulation tests. Over a period of 6 years, patients undergoing an ACTH stimulation test (tetracosactide, 250 ug) in our hospital were included. Plasma cortisol (Elecsys, Cobas, Roche Diagnostics) and salivary cortisol and cortisone (LC-MS/MS) were determined at t = 0, 30 and 60 min after stimulation. Based on peak plasma cortisol levels, AI was ruled out in 113 patients and was established in 16 patients. Patients without AI displayed maximal salivary cortisol concentrations of 12.6-123.4 nmol/L (95th percentile) after stimulation, as opposed to 0.5-15.2 nmol/L in AI patients. At t = 0 min, a minimal salivary cortisol concentration of 1.0 nmol/L was observed in patients without AI, whereas AI patients had a maximum concentration of 5.9 nmol/L. Using these cut-off values, 34% of the initial patient group could be diagnosed without an ACTH stimulation test (28% >5.9 nmol/L, 6% <1.0 nmol/L). A novel diagnostic algorithm, including early morning salivary cortisol analysis can reduce the numbers of ACTH stimulation tests in patients suspected of AI. This patient-friendly method can thereby reduce total health care costs. PMID- 29531159 TI - Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis. AB - Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.Significance: CBP mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. Cancer Res; 78(11); 2825-38. (c)2018 AACR. PMID- 29531160 TI - RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca2+ Uptake and Promotes Colorectal Oncogenesis. AB - The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat colorectal cancer.Significance: RIPK1-mediated cell proliferation through MCU is a central mechanism underlying colorectal cancer progression and may prove to be an important therapeutic target for colorectal cancer treatment. Cancer Res; 78(11); 2876-85. (c)2018 AACR. PMID- 29531162 TI - Lnc-chop Promotes Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Tumor and Inflammatory Environments. AB - Myeloid-derived suppressor cells (MDSCs) are major regulators of immune responses in cancer. Both C/EBP homologous protein (CHOP) and C/EBPbeta play a critical role in regulating immunosuppressive function of MDSCs. In this study, we identified a novel long noncoding RNA termed as lnc-chop in MDSCs, which may interact with CHOP and the C/EBPbeta isoform liver-enriched inhibitory protein. The binding of lnc-chop with both CHOP and the C/EBPbeta isoform liver-enriched inhibitory protein promoted the activation of C/EBPbeta and upregulated the expression of arginase-1, NO synthase 2, NADPH oxidase 2, and cyclooxygenase-2, which are related to the immunosuppressive function of MDSCs in inflammatory and tumor environments. Additionally, lnc-chop also promoted the enrichment of H3K4me3 on the promoter region of arginase-1, NO synthase 2, NADPH oxidase 2, and cyclooxygenase-2. These findings suggest an important role of lnc-chop in controlling immunosuppressive function of MDSCs in the tumor environment. PMID- 29531161 TI - Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. AB - Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NFkappaB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for patients with GBM. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling and the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.Significance: These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM. Cancer Res; 78(11); 3002-13. (c)2018 AACR. PMID- 29531163 TI - Biotin Deficiency Induces Th1- and Th17-Mediated Proinflammatory Responses in Human CD4+ T Lymphocytes via Activation of the mTOR Signaling Pathway. AB - Biotin (vitamin B7) is essential for human health because of its involvement, as a cofactor, in a variety of critical cellular metabolic reactions. Previous studies have shown that biotin deficiency enhances inflammation, and certain chronic inflammatory diseases are associated with biotin deficiency; however, the mechanisms that mediate the association between biotin status and inflammation are not well understood. In this study, we examined the effect of biotin deficiency on human CD4+ T cell responses to determine their role in biotin deficiency-associated inflammation. Our investigations revealed that anti CD3/CD28-stimulated CD4+ T cells cultured in biotin-deficient medium secreted significantly enhanced levels of the proinflammatory cytokines IFN-gamma, TNF, and IL-17. Expression of the transcription factors T-bet and RORgammat was increased, whereas Foxp3 expression was decreased, in biotin-deficient CD4+ T cells. The percentage of T regulatory cells was also decreased under biotin deficient condition. A similar increase in T-bet, RORgammat, and proinflammatory cytokine levels, as well as a decrease in Foxp3, was observed in inguinal lymph nodes of mice fed a biotin-deficient diet relative to pair-fed controls. Furthermore, differentiation of CD4+ T cells toward Th1 and Th17 cells was also enhanced. In vitro and in vivo investigations indicated that the increased inflammatory response was due to enhanced activation of the mammalian target of rapamycin signaling pathway in biotin-deficient CD4+ T cells. In summary, these results demonstrate that biotin deficiency enhances the inflammatory responses in CD4+ T cells, which may contribute to inflammation associated with biotin deficiency. PMID- 29531164 TI - Dendritic Cell PD-L1 Limits Autoimmunity and Follicular T Cell Differentiation and Function. AB - The programmed death (PD)-1 coinhibitory receptor regulates the balance between T cell activation and tolerance. Although the PD-1 ligands, PD-L1 and PD-L2, are expressed on a variety of cell types, the cell type-specific functions of PD-1 ligands in inducing signals through PD-1 are unknown. In this study, we use PD-L1 conditional knockout mice to investigate the cell type-specific functions of PD L1. We demonstrate that PD-L1 expressed on dendritic cells (DCs), and to a lesser extent on B cells, attenuates the progression of experimental autoimmune encephalomyelitis and inhibits naive and effector T cells. PD-1 is highly expressed on effector populations, including T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells, which reside in germinal centers. We also show that DC PD-L1 is essential for limiting Tfh and Tfr cell differentiation. In addition, we find that PD-1 suppresses Tfh cell differentiation and help for Ig class switching, even in the presence of wild-type Tfr cells. Our work points to critical roles for PD-L1 expressed on DCs in mediating PD-1 functions. PMID- 29531165 TI - B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity. AB - B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production. PMID- 29531166 TI - Identification of MHC Class Ib Ligands for Stimulatory and Inhibitory Ly49 Receptors and Induction of Potent NK Cell Alloresponses in Rats. AB - Early studies indicate that rats may have a repertoire of MHC class Ib-reactive Ly49 stimulatory receptors capable of mounting memory-like NK cell alloresponses. In this article, we provide molecular and functional evidence for this assumption. Pairs of Ly49 receptors with sequence similarities in the lectin-like domains, but with opposing signaling functions, showed specificity for ligands with class Ia-like structural features encoded from the first telomeric MHC class Ib gene cluster, RT1-CE, which is syntenic with the H2-D/H2-L/H2-Q cluster in mice. The activating Ly49s4 receptor and its inhibitory counterparts, Ly49i4 and Ly49i3, reacted with all allelic variants of RT1-U, whereas Ly49s5 and Ly49i5 were specific for RT1-Eu NK cell cytolytic responses were predictably activated and inhibited, and potent in vivo NK alloresponses were induced by repeated MHC class Ib alloimmunizations. Additional Ly49-class Ib interactions, including RT1 Cl with the Ly49s4/Ly49i4/Ly49i3 group of receptors, were characterized using overexpressed receptor/ligand pairs, in vitro functional assays, and limited mutational analyses. Obvious, as well as subtle, Ly49-class Ib interactions led to ligand-induced receptor calibration and NK subset expansions in vivo. Together, these studies suggest that in vivo NK alloresponses are controlled by pleomorphic Ly49-class Ib interactions, some of which may not be easily detectable in vitro. PMID- 29531167 TI - Correction: Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity. PMID- 29531168 TI - Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy. AB - Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced ~50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various autoimmune and inflammatory human diseases. PMID- 29531169 TI - Discovery of Blood Transcriptional Endotypes in Women with Pelvic Inflammatory Disease. AB - Sexually transmitted infections with Chlamydia trachomatis and/or Neisseria gonorrhoeae and rates of pelvic inflammatory disease (PID) in women continue to rise, with reinfection being common because of poor adaptive immunity. Diagnosis remains imprecise, and pathogenesis data are derived primarily from monoinfection of mice with C. trachomatis or N. gonorrhoeae By comparing blood mRNA responses of women with C. trachomatis- and/or N. gonorrhoeae-induced PID and histologic endometritis with those from women with C. trachomatis and/or N. gonorrhoeae infection limited to their cervix and asymptomatic uninfected women determined via microarray, we discovered important pathogenic mechanisms in PID and response differences that provide a pathway to biomarker discovery. Women with N. gonorrhoeae- and/or C. trachomatis-induced PID exhibit overexpression of myeloid cell genes and suppression of protein synthesis, mitochondrial oxidative phosphorylation, and T cell-specific genes. Coinfected women exhibited the greatest activation of cell death pathways and suppression of responses essential for adaptive immunity. Women solely infected with C. trachomatis expressed elevated levels of type I and type II IFN genes, and enhanced type I IFN-induced chemokines in cervical secretions were associated with ascension of C. trachomatis to the endometrium. Blood microarrays reveal discrete pathobiological endotypes in women with PID that are driven by pathogen invasion of the upper genital tract. PMID- 29531171 TI - Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma. AB - Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We hypothesized that CD85j (LILRB1), an inhibitory immune checkpoint for B cell function, may play a role in MM pathogenesis. In this study, we report that patients with active MM had significantly lower levels of CD85j and its ligand S100A9. Decreased CD85j expression could also be detected in the premalignant condition MGUS, suggesting that loss of CD85j may be an early event promoting tumor immune escape. To gain insight into the molecular mechanisms underlying CD85j functions, we next enforced expression of CD85j in human myeloma cell lines by lentiviral transduction. Interestingly, gene expression profiling of CD85j-overexpressing cells revealed a set of downregulated genes with crucial functions in MM pathogenesis. Furthermore, in vitro functional assays demonstrated that CD85j overexpression increased susceptibility to T cell- and NK-mediated killing. Consistently, ligation of CD85j decreased the number of PCs from individuals with MGUS but not from patients with MM. In conclusion, downregulation of inhibitory immune checkpoints on malignant PCs may provide a novel mechanism of immune escape associated with myeloma pathogenesis. PMID- 29531170 TI - rIgG1 Fc Hexamer Inhibits Antibody-Mediated Autoimmune Disease via Effects on Complement and FcgammaRs. AB - Activation of Fc receptors and complement by immune complexes is a common important pathogenic trigger in many autoimmune diseases and so blockade of these innate immune pathways may be an attractive target for treatment of immune complex-mediated pathomechanisms. High-dose IVIG is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the Fc portion. Further, recent data indicate that recombinant multimerized Fc molecules exhibit potent anti inflammatory properties. In this study, we investigated the biochemical and biological properties of an rFc hexamer (termed Fc-MUTP-L309C) generated by fusion of the IgM MU-tailpiece to the C terminus of human IgG1 Fc. Fc-MUTP-L309C bound FcgammaRs with high avidity and inhibited FcgammaR-mediated effector functions (Ab-dependent cell-mediated cytotoxicity, phagocytosis, respiratory burst) in vitro. In addition, Fc-MUTP-L309C prevented full activation of the classical complement pathway by blocking C2 cleavage, avoiding generation of inflammatory downstream products (C5a or sC5b-9). In vivo, Fc-MUTP-L309C suppressed inflammatory arthritis in mice when given therapeutically at approximately a 10-fold lower dose than IVIG, which was associated with reduced inflammatory cytokine production and complement activation. Likewise, administration of Fc-MUTP-L309C restored platelet counts in a mouse model of immune thrombocytopenia. Our data demonstrate a potent anti-inflammatory effect of Fc-MUTP-L309C in vitro and in vivo, likely mediated by blockade of FcgammaRs and its unique inhibition of complement activation. PMID- 29531172 TI - Constitutively Bound EGFR-Mediated Tyrosine Phosphorylation of TLR9 Is Required for Its Ability To Signal. AB - Mammalian TLRs recognize microbial infection or cell death-associated danger signals and trigger the appropriate cellular response. These responses determine the strength and the outcome of the host-microbe interaction. TLRs are transmembrane proteins located on the plasma or the endosomal membrane. Their ectodomains recognize specific microbial or endogenous ligands, and the cytoplasmic domains interact with specific proteins to activate intracellular signaling pathways. TLR9, an endosomal TLR, is activated by endocytosed DNA. Activated TLR9 recruits the cytoplasmic adapter MyD88 and other signaling proteins to induce the synthesis of inflammatory cytokines and IFN. Uncontrolled activation of TLR9 leads to the undesired overproduction of inflammatory cytokines and consequent pathogenesis. Therefore, appropriate activation and the regulation of TLR9 signaling are critical. Tyrosine (Tyr) phosphorylation of TLR9 is essential for its activation; however, the role of specific Tyr kinases is not clear. In this article, we report that epidermal growth factor receptor (EGFR), a membrane-bound protein Tyr kinase, is essential for TLR9 signaling. Genetic ablation of EGFR or pharmacological inhibition of its kinase activity attenuates TLR9-mediated induction of genes in myeloid and nonmyeloid cell types. EGFR is constitutively bound to TLR9; upon ligand stimulation, it mediates TLR9 Tyr phosphorylation, which leads to the recruitment of MyD88, activation of the signaling kinases and transcription factors, and gene induction. In mice, TLR9 mediated liver injury and death are blocked by an EGFR inhibitor or deletion of the EGFR gene from myeloid cells, which are the major producers of inflammatory cytokines. PMID- 29531175 TI - Intensive Blood Pressure Targets for Diabetic and Other High-Risk Populations: A Pooled Individual Patient Data Analysis. AB - Optimal blood pressure (BP) targets for different populations, especially diabetics, remain uncertain after conflicting data on intensive management. We assessed whether a <120 mm Hg systolic target is beneficial and whether certain patient populations differ in response. Individual patient data of 14 094 patients from 2 randomized control trials was pooled. Seven thousand forty patients were assigned to an intensive target of <120 mm Hg and 7054 patients to a standard target of <140 mm Hg in an intention-to-treat analysis. The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, and cardiovascular mortality. Interactions between treatment and baseline characteristics were assessed. Secondary outcomes included nonfatal myocardial infarction, stroke, heart failure, cardiovascular mortality, and overall mortality. Intensive management significantly lowered primary outcome rate (hazard ratio, 0.83; 95% confidence interval, 0.74-0.92; P<0.001). No significant interaction was observed between treatment effect and diabetes mellitus status (P=0.16). Significantly reduced secondary outcomes included stroke (hazard ratio, 0.75; P=0.033) and heart failure (hazard ratio, 0.76; P=0.014). No significant interactions were observed between treatment effect and baseline age, sex, race, cardiovascular disease history, systolic BP, or diastolic BP (P values: 0.40, 0.95, 0.54, 0.18, 0.86, and 0.67, respectively). BP targets of <120 mm Hg improved cardiovascular outcomes. Diabetic patients responded similarly to this intervention, as did those with different age, sex, cardiovascular disease history, baseline BPs, and race. The intensive group had increased risk of intervention-related adverse outcomes (3.97% versus 1.53%; P<0.001). Clinicians should consider <120 mm Hg systolic targets for a variety of patients, including diabetics. PMID- 29531174 TI - Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background. AB - Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays an important role. In C57BL/6 mice, baseline diameters of isolated pressurized parenchymal arterioles were similar in adult (4-5 month) and old mice (22+/-1 month; ~15+/-1 um). Endothelium-dependent dilation was impaired in old mice compared with adults in a pathway-specific manner. Vasodilation to NS-309 (which activates small- and intermediate-conductance Ca2+ activated K+ channels in endothelial cells) was intact while endothelial nitric oxide synthase-mediated vasodilation was reduced by >=60%, depending on the concentration (P<0.05). A similar reduction was present in basilar arteries. Inhibiting both ROCK isoforms with Y-27632 restored the majority of endothelial function in old mice. Because genetic background is a determinant of vascular disease, we performed similar studies using FVB/N mice. Endothelial dysfunction was seen with aging in both FVB/N and C57BL/6 mice although the magnitude was increased ~2-fold in the latter strain (P<0.05). In both strains of mice, age-induced endothelial dysfunction was reversed by inhibition of ROCK2 with SLX-2119. Thus, aging impairs endothelial function in both cerebral arteries and parenchymal arterioles, predominantly via effects on endothelial nitric oxide synthase-dependent regulation of vascular tone. The magnitude of these changes was influenced by genetic background and mediated by ROCK2. PMID- 29531176 TI - Office Blood Pressure Measurement: The Weak Cornerstone of Hypertension Diagnosis. PMID- 29531173 TI - Blood Pressure Measurement in SPRINT (Systolic Blood Pressure Intervention Trial). AB - : Recent publications have stated that the blood pressure (BP) measurement technique used in SPRINT (Systolic Blood Pressure Intervention Trial) was unattended. However, the SPRINT protocol does not address the issue of attendance. A survey was conducted immediately after SPRINT closeout visits were completed to inquire whether BP measurements were usually attended or unattended by staff. There were 4082 participants at 38 sites that measured BP after leaving the participant alone the entire time (always alone), 2247 at 25 sites that had personnel in the room the entire time (never alone), 1746 at 19 sites that left the participant alone only during the rest period (alone for rest), and 570 at 6 sites that left the participant alone only during the BP readings (alone for BP measurement). Similar systolic and diastolic BPs within randomized groups were noted during follow-up at the majority of visits in all 4 measurement categories. In the always alone and never alone categories, the intensive group had a similarly reduced risk for the primary outcome compared with the standard group (hazard ratio, 0.62; 95% confidence interval, 0.51-0.76 and hazard ratio, 0.64; 95% confidence interval, 0.46-0.91, respectively; pairwise interaction P value, 0.88); risk was not significantly reduced for the intensive group in the smaller alone-for-rest and the alone-for-BP-measurement categories. Similar BP levels and cardiovascular disease risk reduction were observed in the intensive group in SPRINT participants whether the measurement technique used was primarily attended or unattended. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062. PMID- 29531177 TI - Sympathetic Nervous System Regulation in Human Normotensive and Hypertensive Pregnancies. PMID- 29531178 TI - Promoter Boundaries for the luxCDABE and betIBA-proXWV Operons in Vibrio harveyi Defined by the Method Rapid Arbitrary PCR Insertion Libraries (RAIL). AB - Experimental studies of transcriptional regulation in bacteria require the ability to precisely measure changes in gene expression, often accomplished through the use of reporter genes. However, the boundaries of promoter sequences required for transcription are often unknown, thus complicating the construction of reporters and genetic analysis of transcriptional regulation. Here, we analyze reporter libraries to define the promoter boundaries of the luxCDABE bioluminescence operon and the betIBA-proXWV osmotic stress operon in Vibrio harveyi We describe a new method called rapid arbitrary PCR insertion libraries (RAIL) that combines the power of arbitrary PCR and isothermal DNA assembly to rapidly clone promoter fragments of various lengths upstream of reporter genes to generate large libraries. To demonstrate the versatility and efficiency of RAIL, we analyzed the promoters driving expression of the luxCDABE and betIBA-proXWV operons and created libraries of DNA fragments from these loci fused to fluorescent reporters. Using flow cytometry sorting and deep sequencing, we identified the DNA regions necessary and sufficient for maximum gene expression for each promoter. These analyses uncovered previously unknown regulatory sequences and validated known transcription factor binding sites. We applied this high-throughput method to gfp, mCherry, and lacZ reporters and multiple promoters in V. harveyi We anticipate that the RAIL method will be easily applicable to other model systems for genetic, molecular, and cell biological applications.IMPORTANCE Gene reporter constructs have long been essential tools for studying gene regulation in bacteria, particularly following the recent advent of fluorescent gene reporters. We developed a new method that enables efficient construction of promoter fusions to reporter genes to study gene regulation. We demonstrate the versatility of this technique in the model bacterium Vibrio harveyi by constructing promoter libraries for three bacterial promoters using three reporter genes. These libraries can be used to determine the DNA sequences required for gene expression, revealing regulatory elements in promoters. This method is applicable to various model systems and reporter genes for assaying gene expression. PMID- 29531179 TI - RAIL: A new tool for defining bacterial promoter regions. AB - In this issue of the Journal of Bacteriology, Hustmyer and colleagues describe a new method for rapidly generating reporter libraries (Hustmyer citation). This RAIL technique (Rapid Arbitrary PCR Insertion Libraries) uses arbitrary PCR and isothermal DNA assembly to insert random fragments of promoter regions into reporter plasmids, resulting in libraries that can be screened to identify regions required for gene expression. This technique will likely be useful for a number of different genetic applications. PMID- 29531180 TI - Chemotaxis arrays in Vibrio species and their intracellular positioning by the ParC/ParP system. AB - Most motile bacteria are able to bias their movement towards more favorable environments or to escape from obnoxious substances by a process called chemotaxis. Chemotaxis depends on a chemosensory system that is able to sense specific environmental signals and generate a behavioral response. Typically, the signal is transmitted to the bacterial flagellum, ultimately regulating the swimming behavior of individual cells. Chemotaxis is mediated by proteins that assemble into large, highly ordered arrays. It is imperative for successful chemotactic behavior and cellular competitiveness that chemosensory arrays form and localize properly within the cell. Here we review how chemotaxis arrays form and localize in Vibrio cholerae and Vibrio parahaemolyticus We focus on how the ParC/ParP-system mediates cell cycle-dependent polar localization of chemotaxis arrays and thus ensures proper cell pole development and array inheritance upon cell division. PMID- 29531181 TI - The Origin of Chromosomal Replication Is Asymmetrically Positioned on the Mycobacterial Nucleoid, and the Timing of Its Firing Depends on HupB. AB - The bacterial chromosome undergoes dynamic changes in response to ongoing cellular processes and adaptation to environmental conditions. Among the many proteins involved in maintaining this dynamism, the most abundant is the nucleoid associated protein (NAP) HU. In mycobacteria, the HU homolog, HupB, possesses an additional C-terminal domain that resembles that of eukaryotic histones H1/H5. Recently, we demonstrated that the highly abundant HupB protein occupies the entirety of the Mycobacterium smegmatis chromosome and that the HupB-binding sites exhibit a bias from the origin (oriC) to the terminus (ter). In this study, we used HupB fused with enhanced green fluorescent protein (EGFP) to perform the first analysis of chromosome dynamics and to track the oriC and replication machinery directly on the chromosome during the mycobacterial cell cycle. We show that the chromosome is located in an off-center position that reflects the unequal division and growth of mycobacterial cells. Moreover, unlike the situation in E. coli, the sister oriC regions of M. smegmatis move asymmetrically along the mycobacterial nucleoid. Interestingly, in this slow-growing organism, the initiation of the next round of replication precedes the physical separation of sister chromosomes. Finally, we show that HupB is involved in the precise timing of replication initiation.IMPORTANCE Although our view of mycobacterial nucleoid organization has evolved considerably over time, we still know little about the dynamics of the mycobacterial nucleoid during the cell cycle. HupB is a highly abundant mycobacterial nucleoid-associated protein (NAP) with an indispensable histone-like tail. It was previously suggested as a potential target for antibiotic therapy against tuberculosis. Here, we fused HupB with enhanced green fluorescent protein (EGFP) to study the dynamics of the mycobacterial chromosome in real time and to monitor the replication process directly on the chromosome. Our results reveal that, unlike the situation in Escherichia coli, the nucleoid of an apically growing mycobacterium is positioned asymmetrically within the cell throughout the cell cycle. We show that HupB is involved in controlling the timing of replication initiation. Since tuberculosis remains a serious health problem, studies concerning mycobacterial cell biology are of great importance. PMID- 29531182 TI - NsrA, a predicted beta-barrel outer membrane protein involved in plant signal perception and the control of secondary infection in Sinorhizobium meliloti. AB - An ongoing signal exchange fine-tunes the symbiotic interaction between rhizobia and legumes, ensuring the establishment and maintenance of mutualism. In a recently identified regulatory loop, endosymbiotic S. meliloti exert a negative feedback on root infection in response to unknown plant cues. Upon signal perception, three bacterial Adenylate Cyclases (ACs) of the inner membrane, CyaD1, CyaD2 and CyaK, synthesize the second messenger cAMP that, together with the cAMP-dependent Clr transcriptional activator, activates the expression of genes involved in root infection control. The pathway that links signal perception at the surface of the cell to cytoplasmic cAMP production by ACs was so far unknown.Here we first show that CyaK is the cognate AC for the plant signal, called signal 1, previously evidenced in mature nodule and shoot extracts. Second, we show that inactivation of the gene immediately upstream of cyaK, nsrA (smb20775) that encodes a beta-barrel protein of the outer membrane, also abolished signal 1 perception ex planta whereas nsrA overexpression increased signal 1 responsiveness. Inactivation of the nsrA gene abolished all Clr-dependent gene expression in nodules and led to a marked hyperinfection phenotype on plants, similar to that of a triple cyaD1cyaD2cyaK mutant. We suggest that the NsrA protein acts as the (co)receptor for two signal molecules, signal 1 and a hypothetical signal 1' , in mature and young nodules that cooperate in controlling secondary infection in the S. meliloti/Medicago symbiosis. The predicted topology and domain composition of the NsrA protein hints at a mechanism of transmembrane signaling.Importance: Symbiotic interactions, especially mutualistic ones, rely on a continuous signal exchange between the symbionts. Here we report advances on a recently discovered signal transduction pathway that fine-tunes the symbiotic interaction between S. meliloti and its Medicago host plant. We have identified an outer membrane protein of S. meliloti, called NsrA, that transduces Medicago plant signals to Adenylate cyclases in the Inner membrane thereby triggering a cAMP-signaling cascade controlling infection.Besides their relevance for the rhizobium legume symbiosis, these findings shed light on the mechanisms of signal perception and transduction by adenylate cyclases and of transmembrane signaling in bacteria. PMID- 29531183 TI - Accurate translation is important for longevity. PMID- 29531184 TI - Rate and pattern of unintentional injuries among 9-12 grades schoolchildren in Yemen and their associated factors. AB - BACKGROUND: The burden and pattern of unintentional child injuries in Yemen are not yet studied. This study aimed to determine the rate of unintentional injuries and their associated factors and describe the pattern of these injuries among schoolchildren in Sana'a city, Yemen. METHODS: A cross-sectional school-based study was conducted among students in grades 9-12 in Sana'a Capital City. A total of 10 schools were selected using multistage sampling technique. A self administered questionnaire was used to collect the data. RESULTS: A total of 1140 students (558 girls and 582 boys) participated in the study. Of all students, 550 (48.2%) students reported unintentional injuries during the last 12-months. In the multivariate analysis, boys were more likely to be injured compared to girls (OR = 1.6) and being a child of divorced or widowed parents was significantly associated with increased odds of injury (OR = 1.7). Age of the household head <=45 years was associated with deceased odds of injuries (OR = 0.76). Fall was the leading cause of injury. More than half of girls (58.9%) and 30.9% of boys were injured at home. About two thirds (64.9%) of injuries affected the lower or upper extremities. One quarter of students (24.5%) received care for their injuries in outpatient clinics and 15.3% were hospitalized because of the injury. About 26.0% of injured students missed schools for one week or more. The vast majority of students (98.4%) recovered the injury while 1.6% of injuries resulted in disability. CONCLUSIONS: Schoolchildren in Yemen had a high rate of unintentional injuries being higher in boys and in children of divorced or widowed parents. These injuries should be recognized as a public health problem in Yemen and should be included in the Ministry of Education and Ministry of Health agenda. The reported injury mechanisms and activities posing injury risks should have implications for future interventions and awareness programs. PMID- 29531185 TI - Effect of single nucleotide polymorphisms on intramuscular fat content in Hungarian Simmental cattle. AB - OBJECTIVE: To estimate effect of single nucleotide polymorphisms on the intramuscular fat content (IMF) of Hungarian Simmental bulls. METHODS: Genotypes were determined on high-density Illumina Bovine DNA Chip. After slaughtering of animals, chemical percentage of intramuscular fat was determined from longissimus dorsi muscle. A multi-locus mixed-model was applied for statistical analyses. RESULTS: Analyses revealed four loci (rs43284251, rs109210955, rs41630030, and rs41642251) to be highly associated (-log10P>12) with IMF located on chromosome 1, 6, 13, and 17, respectively. The frequency of their minor alleles was 0.426, 0.221, 0.162, and 0.106. CONCLUSION: The loci above can be useful in selection programs and gives the possibility to assist selection by molecular tools. PMID- 29531186 TI - Prediction of random-regression coefficient for daily milk yield after 305 days in milk by using the regression-coefficient estimates from the first 305 days. AB - OBJECTIVE: Because lactation periods in dairy cows lengthen with increasing total milk production, it is important to predict individual productivities after 305 days in milk (DIM) to determine the optimal lactation period. We therefore examined whether the random regression (RR) coefficient from 306 to 450 DIM (M2) can be predicted from those during the first 305 DIM (M1) by using a RR model. METHODS: We analyzed test-day milk records from 85,690 Holstein cows in their first lactations and 131,727 cows in their later (second to fifth) lactations. Data in M1 and M2 were analyzed separately by using different single-trait RR animal models. We then performed a multiple regression analysis of the RR coefficients of M2 on those of M1 during the first and later lactations. RESULTS: The first-order Legendre polynomials were practical covariates of RR for the milk yields of M2. All RR coefficients for the additive genetic (AG) effect and the intercept for the permanent environmental (PE) effect of M2 had moderate to strong correlations with the intercept for the AG effect of M1. The coefficients of determination for multiple regression of the combined intercepts for the AG and PE effects of M2 on the coefficients for the AG effect of M1 were moderate to high. The daily milk yields of M2 predicted by using the RR coefficients for the AG effect of M1 were highly correlated with those obtained by using the coefficients of M2. CONCLUSION: Milk production after 305 DIM can be predicted by using the RR coefficient estimates of the AG effect during the first 305 DIM. PMID- 29531187 TI - Effects of epigallocatechin-3-gallate on bovine oocytes matured in vitro. AB - OBJECTIVE: Epigallocatechin-3-gallate (EGCG) is a major ingredient of catechin polyphenols and is considered one of the most promising bioactive compounds in green tea because of its strong antioxidant properties. However, the protective role of EGCG in bovine oocyte in vitro maturation (IVM) has not been investigated. Therefore, we aimed to study the effects of EGCG on IVM of bovine oocytes. METHODS: Bovine oocytes were treated with different concentrations of EGCG (0, 25, 50, 100, and 200 MUM), and the nuclear and cytoplasmic maturation, cumulus cell expansion, intracellular reactive oxygen species (ROS) levels, total antioxidant capacity, the early apoptosis and the developmental competence of in vitro fertilized embryos were measured. The mRNA abundances of antioxidant genes (nuclear factor erythriod-2 related factor 2 [NRF2], superoxide dismutase 1 [SOD1], catalase [CAT], and glutathione peroxidase 4 [GPX4]) in matured bovine oocytes were also quantified. RESULTS: Nuclear maturation which is characterized by first polar body extrusion, and cytoplasmic maturation characterized by peripheral and cortical distribution of cortical granules and homogeneous mitochondrial distribution were significantly improved in the 50 MUM EGCG-treated group compared with the control group. Adding 50 MUM EGCG to the maturation medium significantly increased the cumulus cell expansion index and upregulated the mRNA levels of cumulus cell expansion-related genes (hyaluronan synthase 2, tumor necrosis factor alpha induced protein 6, pentraxin 3, and prostaglandin 2). Both the intracellular ROS level and the early apoptotic rate of matured oocytes were significantly decreased in the 50 MUM EGCG group, and the total antioxidant ability was markedly enhanced. Additionally, both the cleavage and blastocyst rates were significantly higher in the 50 MUM EGCG-treated oocytes after in vitro fertilization than in the control oocytes. The mRNA abundance of NRF2, SOD1, CAT, and GPX4 were significantly increased in the 50 MUM EGCG-treated oocytes. CONCLUSION: In conclusion, 50 MUM EGCG can improve the bovine oocyte maturation, and the protective role of EGCG may be correlated with its antioxidative property. PMID- 29531188 TI - Expression and regulation of avian beta-defensin 8 protein in immune tissues and cell lines of chickens. AB - OBJECTIVE: Defensins are a large family of antimicrobial peptides and components of the innate immune system that invoke an immediate immune response against harmful pathogens. Defensins are classified into alpha-, beta-, and theta defensins. Avian species only possess beta-defensins (AvBDs), and approximately 14 AvBDs (AvBD1-AvBD14) have been identified in chickens to date. Although substantial information is available on the conservation and phylogenetics, limited information is available on the expression and regulation of AvBD8 in chicken immune tissues and cells. METHODS: We examined AvBD8 protein expression in immune tissues of White Leghorn chickens (WL) by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (RT-qPCR). In addition, we examined AvBD8 expression in chicken T-, B-, macrophage-, and fibroblast-cell lines and its regulation in these cells after lipopolysaccharide (LPS) treatment by immunocytochemistry and RT-qPCR. RESULTS: Our results showed that chicken AvBD8 protein was strongly expressed in the WL intestine and in macrophages. AvBD8 gene expression was highly upregulated in macrophages treated with different LPS concentrations compared with that in T- and B-cell lines in a time-independent manner. Moreover, chicken AvBD8 strongly interacted with other AvBDs and with other antimicrobial peptides as determined by bioinformatics. CONCLUSION: Our study provides the expression and regulation of chicken AvBD8 protein in immune tissues and cells, which play crucial role in the innate immunity. PMID- 29531189 TI - Feed intake, digestibility and energy partitioning in beef cattle fed diets with cassava pulp instead of rice straw. AB - OBJECTIVE: This study was conducted to assess the effects of replacing rice straw with different proportions of cassava pulp on growth performance, feed intake, digestibility, rumen microbial population, energy partitioning and efficiency of metabolizable energy utilization in beef cattle. METHODS: Eighteen yearling Thai native beef cattle (Bos indicus) with an average initial body weight (BW) of 98.3+/-12.8 kg were allocated to one of three dietary treatments and fed ad libitum for 149 days in a randomized complete block design. Three dietary treatments using different proportions of cassava pulp (100, 300, and 500 g/kg dry matter basis) instead of rice straw as a base in a fermented total mixed ration were applied. Animals were placed in a metabolic pen equipped with a ventilated head box respiration system to determine total digestibility and energy balance. RESULTS: The average daily weight gain, digestible intake and apparent digestibility of dry matter, organic matter and non-fiber carbohydrate, total protozoa, energy intake, energy retention and energy efficiency increased linearly (p<0.05) with an increasing proportion of cassava pulp in the diet, whereas the three main types of fibrolytic bacteria and energy excretion in the urine (p<0.05) decreased. The metabolizable energy requirement for the maintenance of yearling Thai native cattle, determined by a linear regression analysis, was 399 kJ/kg BW0.75, with an efficiency of metabolizable energy utilization for growth of 0.86. CONCLUSION: Our results demonstrated that increasing the proportion of cassava pulp up to 500 g/kg of dry matter as a base in a fermented total mixed ration is an effective strategy for improving productivity in zebu cattle. PMID- 29531190 TI - Screening for candidate genes related with histological microstructure, meat quality and carcass characteristic in pig based on RNA-seq data. AB - OBJECTIVE: The aim of the present study was to identify genetic variants based on RNA-seq data, obtained via transcriptome sequencing of muscle tissue of pigs differing in muscle histological structure, and to verify the variants' effect on histological microstructure and production traits in a larger pig population. METHODS: RNA-seq data was used to identify the panel of single nucleotide polymorphisms (SNPs) significantly related with percentage and diameter of each fiber type (I, IIA, IIB). Detected polymorphisms were mapped to quantitative trait loci (QTLs) regions. Next, the association study was performed on 944 animals representing five breeds (Landrace, Large White, Pietrain, Duroc, and native Pulawska breed) in order to evaluate the relationship of selected SNPs and histological characteristics, meat quality and carcasses traits. RESULTS: Mapping of detected genetic variants to QTL regions showed that chromosome 14 was the most overrepresented with the identification of four QTLs related to percentage of fiber types I and IIA. The association study performed on a 293 longissimus muscle samples confirmed a significant positive effect of transforming acidic coiled-coil-containing protein 2 (TACC2) polymorphisms on fiber diameter, while SNP within forkhead box O1 (FOXO1) locus was associated with decrease of diameter of fiber types IIA and IIB. Moreover, subsequent general linear model analysis showed significant relationship of FOXO1, delta 4-desaturase, sphingolipid 1 (DEGS1), and troponin T2 (TNNT2) genes with loin 'eye' area, FOXO1 with loin weight, as well as FOXO1 and TACC2 with lean meat percentage. Furthermore, the intramuscular fat content was positively associated (p<0.01) with occurrence of polymorphisms within DEGS1, TNNT2 genes and negatively with occurrence of TACC2 polymorphism. CONCLUSION: This study's results indicate that the SNP calling analysis based on RNA-seq data can be used to search candidate genes and establish the genetic basis of phenotypic traits. The presented results can be used for future studies evaluating the use of selected SNPs as genetic markers related to muscle histological profile and production traits in pig breeding. PMID- 29531191 TI - Effects of high-pressure processing on taste-related ATP breakdown compounds and aroma volatiles in grass-fed beef during vacuum aging. AB - Objective: This study aimed to observe whether high-pressure processing (HPP) affected aroma development and the degradation rate of umami taste-related ATP breakdown products, specifically inosinic acid in grass-fed beef during vacuum aging. METHODS: Strip loin (longissimus lumborum) cuts obtained from six grass fed Friesian Holstein steers (32 months old) on day 4 post slaughter were vacuum packed and subjected to pressurization at 300 and 500 MPa for 180 s at 15 degrees C+/-2 degrees C. The samples were then stored for 4 weeks at 5 degrees C+/-0.5 degrees C under vacuum and compared with the control (0.1 MPa). RESULTS: HPP increased the shear force value, promoted moisture loss and lipid oxidation, induced surface paleness, stabilized pH during aging, and reduced bacterial load and growth. The shear force value of 500 MPa-treated samples remained higher than the control after aging, while no significant differences were found between the control and 300 MPa-treated samples. Degradation of inosinic acid and inosine occurred during pressurization, resulting in an increase in hypoxanthine content. However, the degradation rate in HPP-treated samples during aging was slower; therefore, inosinic acid and inosine content remained higher than in control samples. No significant differences were found in hypoxanthine content at the end of aging. HPP intensified the levels of hexanal, octanal, 2-methylbutanal, 3 methylbutanal, benzaldehyde, and 2,5-dimethylpyrazine in cooked-aged beef samples. CONCLUSION: HPP induced aroma development and delayed the degradation of inosinic acid. However, it also reduced the postmortem tenderization rate. PMID- 29531192 TI - Microbiological safety of processed meat products formulated with low nitrite concentration - A review. AB - Nitrite plays a major role in inhibiting the growth of foodborne pathogens, including Clostridium botulinum (C. botulinum) that causes botulism, a life threatening disease. Nitrite serves as a color-fixing agent in processed meat products. However, N-nitroso compounds can be produced from nitrite, which are considered as carcinogens. Thus, consumers desire processed meat products that contain lower concentrations (below conventional concentrations of products) of nitrite or no nitrite at all, although the portion of nitrite intake by processed meat consumption in total nitrite intake is very low. However, lower nitrite levels might expose consumers to risk of botulism poisoning due to C. botulinum or illness caused by other foodborne pathogens. Hence, lower nitrite concentrations in combination with other factors such as low pH, high sodium chloride level, and others have been recommended to decrease the risk of food poisoning. In addition, natural compounds that can inhibit bacterial growth and function as color-fixing agents have been developed to replace nitrite in processed meat products. However, their antibotulinal effects have not been fully clarified. Therefore, to have processed meat products with lower nitrite concentrations, low pH, high sodium chloride concentration, and others should also be applied together. Before using natural compounds as replacement of nitrite, their antibotulinal activities should be examined. PMID- 29531193 TI - Extent of linkage disequilibrium and effective population size of the Landrace population in Korea. AB - Objective: The genetic diversity of the Landrace population, a representative maternal pig breed in Korea, is important for genetic improvement. Previously, the effective population size (Ne) has been used to infer the genetic diversity of a population of interest. In this study, we aimed to use single nucleotide polymorphism (SNP) data to characterize linkage disequilibrium (LD) and the Ne of the Korean Landrace population. METHODS: We genotyped 1,128 Landrace individuals from three representative Korean major grand-grand-parent (GGP) farms using the Illumina PorcineSNP60 version2 BeadChip, which covers >61,565 SNPs located across all autosomes and mitochondrial and sex chromosomes. We estimated the expected LD and current Ne, as well as ancestral Ne. RESULTS: In the Korean Landrace population, the mean LD (r2) of 3.698 million SNP pairs was 0.135+/-0.204. The mean r2 decreased slowly with as the distance between SNPs increased, and remained constant beyond 3 Mb. According to the r2 calculations, 8,085 of 3.698 million SNP pairs were in complete LD. The current Ne (+/-standard deviation) of the Korean Landrace population is approximately 92.27 [79.46; 105.07] individuals. The ancestral Ne exhibited a slow and steady decline from 186.61 to 92.27 over the past 100 generations. Additionally, we observed more a rapid Ne decrease from the past 20 to 10 generations ago, compared with other intervals. CONCLUSION: We have presented an overview of LD and the current and ancestral Ne values in the Korean Landrace population. The mean LD and current Ne for the Korean Landrace population confirm the genetic diversity and reflect the history of this pig population in Korea. PMID- 29531194 TI - Effects of xylanase supplementation to wheat-based diets on growth performance, nutrient digestibility and gut microbes in weanling pigs. AB - OBJECTIVE: This study was designed to investigate the effects of an Aspergillus sulphureus xylanase expressed in Pichia pastoris on the growth performance, nutrient digestibility and gut microbes in weanling pigs. METHODS: A total of 180 weanling pigs (initial body weights were 8.47+/-1.40 kg) were assigned randomly to 5 dietary treatments. Each treatment had 6 replicates with 6 pigs per replicate. The experimental diets were wheat based with supplementation of 0, 500, 1,000, 2,000, and 4,000 U xylanase/kg. The experiment lasted 28 days (early phase, d 0 to 14; late phase, d 15 to 28). RESULTS: In the early phase, compared to the control, average daily gain (ADG) was higher for pigs fed diets supplemented with xylanase and there was a quadratic response in ADG (p<0.05). In the entire phase, ADG was higher for the pigs fed 1,000 or 2,000 U/kg xylanase compared to the control (p<0.05). The gain to feed ratio was higher for pigs fed diets supplemented with 1,000 or 2,000 U/kg xylanase compared to the control (p<0.05). Increasing the amount of xylanase improved the apparent total tract digestibility of dry matter, crude protein, neutral detergent fiber, calcium, and phosphorus during both periods (p<0.05). Xylanase supplementation (2,000 U/kg) decreased the proportion of Lachnospiraceae (by 50%) in Firmicutes, but increased Prevotellaceae (by 175%) in Bacteroidetes and almost diminished Enterobacteriaceae (Escherichia-Shigella) in Proteobacteria. CONCLUSION: Xylanase supplementation increased growth performance and nutrient digestibility up to 2,000 U/kg. Supplementation of xylanase (2,000 U/kg) decreased the richness of gut bacteria but diminished the growth of harmful pathogenic bacteria, such as Escherichia-Shigella, in the colon. PMID- 29531195 TI - Quality of life and recurrence of disease in patients with eosinophilic and non eosinophilic 1 chronic rhinosinusitis with nasal polyposis. AB - OBJECTIVE: To assess the quality of life (QoL) and recurrence of disease in patients with eosinophilic (ECRSwNP) and non-eosinophilic chronic rhinosinusitis with nasal polyposis (non-ECRSwNP) post endoscopic sinus surgery (ESS). METHODOLOGY: A cross-sectional comparative study was carried out in the Otorhinolaryngology - HNS Department, Universiti Kebangsaan Malaysia Medical Center (UKMMC). Subjective assessments of nasal symptoms and quality of life (QoL) using SNOT-22 and Visual Analogue Scale (VAS) and objective endoscopic assessment was undertaken using a modified Hadley endoscopic examination. RESULTS: There was no significant statistical difference in the quality of life between the ECRSwNP and non-ECRSwNP groups as evidenced by the SNOT-22 score and the VAS comparison (p>0.05). However, there was a significant difference in terms of recurrence of disease with the presence of nasal polyps on endoscopic examination. (p = 0.016) CONCLUSION: In conclusion, we found that there is no significant difference in QoL between ECRSwNP and non- ECRSwNP. There is higher frequency of recurrence of nasal polyps amongst ECRSwNP. PMID- 29531196 TI - Test-retest reliability and responsiveness of a Malay tinnitus questionnaire. AB - INTRODUCTION: Tinnitus is a common complaint among patients with ear diseases and can be serious if not treated. Recently, a Malay tinnitus questionnaire, known as the "Borang Evaluasi Soal selidik Tinnitus" (BEST) had been developed and preliminarily validated among Malayspeaking population. The aims of the present study were to determine the test-retest reliability and responsiveness of the BEST questionnaire. METHOD: Forty-six Malay adults (aged 23-74 years) with tinnitus were enrolled. They were instructed to fill in the BEST questionnaire accordingly. After one week, 21 of them were asked to fill in the questionnaire again. The other 25 subjects underwent tinnitus intervention for three months and following this; the BEST was administered to them again. RESULTS: In the test retest reliability task, the intraclass correlation values obtained were acceptably high (0.70-0.90). After the intervention, significant differences in the BEST result were found in the mind domain, main domain and composite score (p<0.05) with moderate effect sizes (0.61- 0.70). CONCLUSION: The test-retest reliability of the BEST was found to be good. It also showed good responsiveness to intervention. The clinical usefulness of the BEST in assessing patients with tinnitus was further supported by the present study. PMID- 29531197 TI - Reliability of the ultrasound classification system of thyroid nodules in predicting malignancy. AB - AIM: This study aims to evaluate the reliability of the Ultrasound (U) Classification system in predicting thyroid malignancy by using pathology diagnosis as the reference standard. METHODS: It was a cross-sectional study carried out at Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Malaysia. Records of patients with focal thyroid nodules on ultrasound (US) for which US guided fine needle aspiration cytology (FNAC) was performed and pathology results were available, from January 2014 to May 2016 were selected for review. Correlation of the U Classification with pathology results was assessed. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, predictive value, negative predictive value and accuracy were calculated in a conservative and non-conservative method. The threshold for statistical performance was set at 0.05. Each sonographic feature was also compared with its pathology results. RESULTS: A total of 91 patients with 104 nodules were eligible. 12 nodules out of 104 (11.5%) were malignant. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, negative predictive value and accuracy were 100%, 91.3%, 11.5, 0.0, 60%, 100% and 92.3%, and 100%, 91.4%, 11.7%, 0.0, 78.6%, 100% and 93.5%, for the non-conservative and conservative method of calculations respectively. CONCLUSION: The U Classification is reliable in predicting thyroid malignancy. More evidence is nevertheless necessary for widespread adaptation and use. PMID- 29531198 TI - Adaption, translation and validation of the Diabetes Mellitus in the Offspring Questionnaire (DMOQ): The Malay version. AB - BACKGROUND: The Diabetes Mellitus in the Offspring Questionnaire (DMOQ) assesses the perceptions of Type 2 diabetes mellitus (T2DM) patients on the risk of their offspring developing T2DM and the possibility of intervention to reduce this risk. It has 34 items framed within seven domains. This study aimed to adapt, translate and validate the DMOQ from English into the Malay language. METHODS: This was a cross-sectional validation study among 159 T2DM patients attending a public primary care clinic in Selangor. The DMOQ English version underwent adaptation, translation, face validation and field testing to produce the Malay version. Psychometric analysis was performed using Exploratory Factor Analysis, internal consistency and testretest reliability. RESULTS: The DMOQ domains were conceptually equivalent between English and Malay language. A total of 13 items and two domains were removed during the validation process (three items during the content validation, three items due to poor factor loadings, five items as they loaded onto two domains which were not interpretable, one item as it did not fit conceptually into the factor it loaded onto and one openended question as it did not fit into the retained domains). Therefore, the final DMOQ Malay version consisted of 21- items within five domains. The Cronbach alpha was 0.714 and the intraclass-correlation coefficient was 0.868. CONCLUSION: The DMOQ Malay version is a valid and reliable tool which is consistent over time. It can be used to examine the perception of T2DM patients towards the risk of their offspring developing diabetes and possibility of intervention in Malay-speaking patients. PMID- 29531199 TI - Visual impairment and amblyopia in Malaysian pre-school children - The SEGPAEDS study. AB - INTRODUCTION: Little is known regarding the extent of visual impairment amongst pre-school children in Malaysia. OBJECTIVE: To determine the prevalence of visual impairment and amblyopia in Malaysian preschool children. METHODOLOGY: A cross sectional, population-based study was conducted on children aged four to six years from 51 participating kindergartens in the district of Segamat, Johor, Malaysia from 20 March 2016 to 6 April 2016. All subjects had initial eye screening consisting of LogMar visual acuity, orthoptics examination and Spot vision screener assessment. Subjects who failed the initial eye screening were invited for a formal eye assessment consisting of cycloplegic refraction and a comprehensive ocular examination. Definitions of visual impairment and amblyopia were based on the Multi-Ethnic Pediatric Eye Disease Study criteria. RESULTS: A total of 1287 children were recruited. Mean subject age was 5.03 (SD:0.77) and males represented 52.3% of subjects. Subjects by ethnicity were Malay (54.8%), Chinese (27.7%), Indian (15.6%) and Orang Asli (1.9%). Formal eye assessment was required for 221 subjects and 88.8% required ophthalmic intervention. Refractive error, representing 95.4% of diagnosed ocular disorders, comprised of astigmatism (84%), myopia (9%) and hypermetropia (6.9%). With-the-rule astigmatism was present in 93.4% of the subjects with astigmatism. Visual impairment was present in 12.5% of our subjects, with 61% having bilateral visual impairment. Of the subjects with visual impairment, 59.1% had moderate visual impairment. The prevalence of amblyopia was 7.53%, and 66% of the amblyopic subjects had bilateral amblyopia. CONCLUSION: Our study highlights an urgent need for initiation of preschool vision screening in Malaysia. PMID- 29531200 TI - Prevalence and predictors of poor sleep quality among secondary school students in Gombak District, Selangor. AB - INTRODUCTION: Poor sleep quality among adolescents is becoming a major worldwide concern and is widely recognized as a significant public health issue. OBJECTIVES: To determine the prevalence and predictors of poor sleep quality among secondary school students in Gombak District, Selangor. METHODS: A cross sectional study was conducted in Gombak District. The sample size was 1,092 based on two group comparison formula. Students were selected using sampling with probability to proportionate to size. Selfadministered pretested questionnaires were used to collect the data. The data were analysed using the Statistical Package for Social Sciences (SPSS) version 22. Chi-square or Fisher's exact test was performed to determine the association between individual categorical variables and sleep quality. Variables with p-value <0.25 were selected to be subjected into multivariate logistic regression to determine the predictors. RESULTS: The response rate was 93.0%. The prevalence of poor sleep quality was 24.0% (95% CI = 21.5, 26.6). Based on the analysis of simple logistic regression seven variables that were significantly associated with poor sleep quality were age, gender, marital status of parents, depression, anxiety, stress and academic performance found fit in the model. Multivariate logistic analysis showed that the significant predictors of poor sleep quality were age, marital status of parents, depression, anxiety, stress and academic performance. Factors that were not statistically significant were gender, religion, ethnicity, parent's educational level and family income. CONCLUSIONS: Prevalence of poor sleep quality among adolescents is high. The predictors of poor sleep quality are age, marital status of parents, depression, anxiety, stress and academic performance. PMID- 29531201 TI - Manchester - Fothergill procedure for treatment of recurrence procidentia in young nulliparous woman: A case report. AB - Procidentia is uncommon condition altering quality of life of young and nulliparous women. Its management poses significant dilemma and challenges as its associated body image, fertility and sexuality issues. Uterine preservation surgery described by Archibald Donald in 1888 known as Manchester -Fothergill procedure seems best option as alternative to vaginal hysterectomy. Despite its increasing popularity among surgeons and patients, robust clinical evidence is needed. We report a case of recurrent procidentia in a young nulliparous woman who had Manchester repair following vaginal sacrospinous hysteropexy. We concluded that Manchester repair is a useful and safe alternative for uterine preserving technique. PMID- 29531202 TI - Breast cancer with dermatomyositis as initial presentation. AB - Patients with breast cancer normally present with breast lump or abnormal mammogram. Dermatomyositis is rarely the first presentation. We present a case of a 63-year-old woman who had generalised dermatitis, progressive fatigue and muscle weakness. She was first diagnosed as dermatomyositis and subsequently breast cancer. Her rash and muscle weakness progressed drastically over a month. Tumescent mastectomy and axillary surgery was performed, which led to gradual regression of her dermatomyositis over six months. This case report emphasized in the benefit of early diagnosis and treatment of dermatomyositis and breast cancer. Pros and cons of tumescent mastectomy is discussed as well. PMID- 29531203 TI - Curative lung metastectomy and complete pathological response after neo-adjuvant GEMOX chemotherapy for relapse fibrolamellar hepatocellular carcinoma. AB - Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma. It is commonly reported in the younger population with no underlying chronic liver disease and free of viral Hepatitis B and C. Local recurrence and distant metastasis are common despite better prognosis compared to conventional hepatocellular carcinoma. Complete surgical resection is associated with higher median survival and is the mainstay treatment option for localized FL HCC. Multi-modality therapies such as TACE can be used to downstage upfront unresectable FL-HCC. Complete response with GEMOX chemotherapy has been reported in advanced metastatic FL-HCC and should be considered in upfront unresectable or metastatic disease. We present a case of biopsied proven relapse FL-HCC with oligo- left lung metastasis who successfully underwent a left lung lobectomy after neo-adjuvant GEMOX chemotherapy, and is disease free at 24 months follow up. PMID- 29531204 TI - Drainage of multiloculated tuberculous pleural effusion by medical thoracoscopy: When and why should it be considered? AB - Tuberculous pleural effusion (TBE) is a common encounter in our region. Up to 50% of patients with TBE will develop residual pleural thickening (RPT) which can lead to functional impairment. However, the need of drainage remains controversial. We report a case of end-stage renal failure patient who presented with right multiloculated tuberculous pleural effusion which was drained via a medical thoracoscope. Patient reports immediate relief of breathlessness post procedure and one month follow up shown significant improvement of RPT. We also discussed the current perspective on the rationale of TBE drainage and the role of medical thoracoscope in TBE management. PMID- 29531205 TI - Catching an ectopic caesarean scar pregnancy - Radiological perspective. AB - Caesarean scar implantation is one of the rarest form of ectopic pregnancies and most unwanted complication of caesarean scar. However, with the increasing numbers of caesarean section performed, caesarean scar pregnancy (CSP) may be on the rise. The diagnosis is often difficult, but establishing an accurate diagnosis of CSP in the early first trimester is utmost important to prevent its detrimental consequences of uterine rupture and fatal haemorrhage. Hence, we present a case to highlight the role of imaging in diagnosing and managing this condition to prevent its associated high morbidity and mortality. PMID- 29531206 TI - Acquired lung cysts in post primary tuberculosis: An uncommon radiological finding in a common disease. AB - Tuberculosis (TB) is still an endemic disease in Malaysia. Cystic lung disease in post primary tuberculosis is not common. It can occur before, during or after completion of anti-TB treatment. Clinical history and review of serial chest radiograph is paramount to make the diagnosis. This case report highlights an interesting case of a young female patient who developed extensive cystic lung disease during the course of anti-TB treatment and the importance of recognizing this unusual manifestation. PMID- 29531207 TI - Paediatric middle aortic syndrome with endovascular treatment in East Malaysia. AB - Middle-aortic syndrome is a surgically curable cause of childhood hypertension. Open surgery is traditionally offered but with the advance of medical technology, endovascular approached is available in many country. Failure to control BP in open surgery is as low as 4.1% compares to 13% in endovascular approaches. However, mortality is 4% in open surgery almost 2 times higher than 2.3% in endovascular approach. This article presents a case of 10 years old child treated successfully without complication with endovascular balloon dilatation, as a first case of such disease in East Malaysia. PMID- 29531208 TI - Unexplained ascites, a sign for neuroendocrine carcinoma. AB - Neuroendocrine neoplasm is an epithelial neoplasm with predominant neuroendocrine differentiation that can arise from many organs in the body. We reported a rare case of gastric neuroendocrine carcinoma which accounts for less than 1% of all gastric tumours that is associated with poor prognosis. The recognition of this rare tumour in early stage is challenging and high suspicious into it might bring to early detection and so forth might improve the prognostication. PMID- 29531209 TI - The importance of oral health to prevent aspiration pneumonia. AB - No abstract provided. PMID- 29531210 TI - Living Donor Liver Transplantation in Acute Liver Failure Patients with Grade IV Encephalopathy: Is Deep Hepatic Coma Still an Absolute Contraindication? A Successful Single-Center Experience. AB - BACKGROUND The prognosis of the patients of acute liver failure (ALF) with onset of hepatic coma is often dismal. ALF is a well-accepted indication for liver transplantation (LT) and has markedly improved the prognosis of these patients. However, its role in ALF patients with onset of hepatic coma has never been elucidated before. The aim of our study was to analyze the outcome in patients of ALF with hepatic coma who underwent LT. MATERIAL AND METHODS From January 2002 to December 2015, a total of 726 liver transplantations were done at China Medical University Hospital, Taiwan. The hospital database of 59 recipients that underwent LT for ALF was analyzed. Eleven ALF patients with the onset of hepatic coma (grade IV encephalopathy) requiring mechanical ventilatory support were retrospectively analyzed. The patients were sub-grouped in 2 groups depending on the timing of LT after the onset of hepatic coma: Group A had LT within 48 h of onset of coma (n=7) and Group B had LT after 48 h of onset of coma (n=4). RESULTS The study cohort (group A and B) comprised 8 males and 3 females, with an average age of 39.63+/-13.95 years (range, 13 to 63). Ten patients received living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) was done in 1 recipient. All the patients in group A had complete neurological recovery and were extubated within 48 h after LT, whereas extubation was delayed for various reasons for group B patients. At a mean follow up of 36 months (range, 20 to 76 months), the overall survival of all the recipients (group A and B) was 72%. Three-year survival for Group A (n=7) was 85% and for Group B (n=4) it was 50%. There were no acute rejection episodes. CONCLUSIONS LT is an acceptable modality of treatment for patients of ALF with new onset of hepatic coma. Neurological recovery is expected in all patients if LT can be done within 48 h of onset of hepatic coma without increasing the risk of morbidity. Due to shortage of deceased donor organs in Asia, LDLT can be used proactively, with a success rate comparable to that of non-ALF patients undergoing LT. PMID- 29531211 TI - Added Value of NeuroGam Software Analysis in Single Photon Emission Computed Tomography Localization Diagnosis of Epilepsy in Interictal Stage. AB - BACKGROUND This study aimed to investigate the added value of NeuroGam software analysis in the localization diagnosis of epileptogenic zone during interictal phase of seizures. MATERIAL AND METHODS The clinical data of 67 patients, clinically diagnosed as epilepsy, were analyzed retrospectively. Visual analysis and NeuroGam software analysis were used for independent analysis. The 2 methods were used to compare the efficacy indicator of the diagnosis of epileptogenic zone, and the receiver operating characteristic (ROC) curve evaluated the diagnostic efficacy. RESULTS Through the final clinical diagnostic comprehensive localization, among 67 epilepsy patients, the epileptogenic zone in 51 cases could be located distinctly, and those in 16 cases could not be located. Compared to the visual analysis, the NeuroGam software analysis was more sensitive in the location of epileptogenic zone (chi2=4.876, P=0.027). The area under the ROC curve (AUC) and 95% confidence interval (CI) of the NeuroGam software and visual analyses was 0.760 and 0.689, (0.613, 0.908) and (0.547, 0.832), respectively. However, the consistency of the 2 methods was poor (Kappa=0.367, P=0.001). Compared to visual analysis, the NeuroGam software analysis exerted more advantages in the localization diagnosis of the epileptogenic zone (P<0.001). CONCLUSIONS In the location diagnosis of brain perfusion, single photon emission computed tomography (SPECT) epileptogenic zone was used in interictal phase of seizures, and NeuroGam software analysis exerted a distinct added value for visual analysis. PMID- 29531212 TI - An Uncommon Cause of Contralateral Brachial Plexus Injury Following Jugular Venous Cannulation. AB - BACKGROUND The complication rate of central venous catheterization ranges from 4% to 35%. Brachial plexus injury can occur, mostly on the same side as the catheterization, without affecting the contralateral brachial plexus. CASE REPORT A 71-year-old woman received placement of a vein hemodialysis catheter via right internal jugular vein. Five days after the cannulation, she complained of contralateral burning pain and numbness at the ulnar side of her left forearm. On the next day, the pain increased and extended to her left shoulder girdle and whole left arm, despite use of analgesics. When she passively tilted her head to the right side, ear to shoulder, the pain increased in the left arm. We found the patient had a tight suture with which the jugular catheter was fixed. The patient persistently turned her head to the right and slightly flexed her neck to loosen the suture to avoid discomfort. We removed the suture and the central venous catheter. Her pain in the left shoulder and arm was diminished the next day. Three days later, the symptoms had all disappeared completely. CONCLUSIONS Central venous catheterization may cause contralateral brachial plexus injury, which may result from a tight suture with which the jugular catheter is fixed. PMID- 29531214 TI - LASP1 promotes nasopharyngeal carcinoma progression through negatively regulation of the tumor suppressor PTEN. AB - LIM and SH3 protein 1 (LASP1) enhances tumor growth and metastasis in various cancers, but its role in nasopharyngeal carcinoma (NPC) remains unclear. Herein, we investigated the role of LASP1 in NPC and explored the underlying mechanisms in NPC. Clinically, overexpression of LASP1 is associated with tumor metastasis and poor prognosis of NPC patients. Gain-of-function and loss-of-function assays showed that LASP1 promoted NPC cell proliferation, metastasis, and invasion in vitro and in vivo. Mechanistically, we observed clear co-localization between LASP1 and PTEN in NPC cells. LASP1 interacted with PTEN and decreased the expression of PTEN in NPC. The ubiquitination assay indicated that LASP1 overexpression increased PTEN ubiquitination. PTEN was known as a tumor suppressor by negatively regulating phosphoinositide 3-kinase/AKT signaling pathway. Rescue experiments showed that PTEN weakened LASP1-mediated cell proliferation, migration, and invasive abilities and decreased the phosphorylation of AKT in NPC cells. Our findings suggest that LASP1 has a crucial role in NPC progression via LASP1/PTEN/AKT axis, highlighting LASP1 as a therapeutic target for NPC. PMID- 29531213 TI - A systematic approach to the development of a safe live attenuated Zika vaccine. AB - Zika virus (ZIKV) is a flavivirus that can cause congenital disease and requires development of an effective long-term preventative strategy. A replicative ZIKV vaccine with properties similar to the yellow fever 17D (YF17D) live-attenuated vaccine (LAV) would be advantageous, as a single dose of YF17D produces lifelong immunity. However, a replicative ZIKV vaccine must also be safe from causing persistent organ infections. Here we report an approach to ZIKV LAV development. We identify a ZIKV variant that produces small plaques due to interferon (IFN) restricted viral propagation and displays attenuated infection of endothelial cells. We show that these properties collectively reduce the risk of organ infections and vertical transmission in a mouse model but remain sufficiently immunogenic to prevent wild-type ZIKV infection. Our findings suggest a strategy for the development of a safe but efficacious ZIKV LAV. PMID- 29531215 TI - Capture Hi-C identifies putative target genes at 33 breast cancer risk loci. AB - Genome-wide association studies (GWAS) have identified approximately 100 breast cancer risk loci. Translating these findings into a greater understanding of the mechanisms that influence disease risk requires identification of the genes or non-coding RNAs that mediate these associations. Here, we use Capture Hi-C (CHi C) to annotate 63 loci; we identify 110 putative target genes at 33 loci. To assess the support for these target genes in other data sources we test for associations between levels of expression and SNP genotype (eQTLs), disease specific survival (DSS), and compare them with somatically mutated cancer genes. 22 putative target genes are eQTLs, 32 are associated with DSS and 14 are somatically mutated in breast, or other, cancers. Identifying the target genes at GWAS risk loci will lead to a greater understanding of the mechanisms that influence breast cancer risk and prognosis. PMID- 29531216 TI - Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice. AB - Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP. PMID- 29531217 TI - Infrequent occurrence of TET1, TET3, and ASXL2 mutations in myelodysplastic/myeloproliferative neoplasms. PMID- 29531218 TI - An examination of multiple classes of rare variants in extended families with bipolar disorder. AB - Bipolar disorder (BD) is a complex psychiatric condition with high heritability, the genetic architecture of which likely comprises both common variants of small effect and rare variants of higher penetrance, the latter of which are largely unknown. Extended families with high density of illness provide an opportunity to map novel risk genes or consolidate evidence for existing candidates, by identifying genes carrying pathogenic rare variants. We performed whole-exome sequencing (WES) in 15 BD families (117 subjects, of whom 72 were affected), augmented with copy number variant (CNV) microarray data, to examine contributions of multiple classes of rare genetic variants within a familial context. Linkage analysis and haplotype reconstruction using WES-derived genotypes enabled exclusion of false-positive single-nucleotide variants (SNVs), CNV inheritance estimation, de novo variant identification and candidate gene prioritization. We found that rare predicted pathogenic variants shared among >=3 affected relatives were overrepresented in postsynaptic density (PSD) genes (P = 0.002), with no enrichment in unaffected relatives. Genome-wide burden of likely gene-disruptive variants was no different in affected vs. unaffected relatives (P = 0.24), but correlated significantly with age of onset (P = 0.017), suggesting that a high disruptive variant burden may expedite symptom onset. The number of de novo variants was no different in affected vs. unaffected offspring (P = 0.89). We observed heterogeneity within and between families, with the most likely genetic model involving alleles of modest effect and reduced penetrance: a possible exception being a truncating X-linked mutation in IRS4 within a family specific linkage peak. Genetic approaches combining WES, CNV and linkage analyses in extended families are promising strategies for gene discovery. PMID- 29531219 TI - TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A. AB - Transcription-blocking DNA lesions are removed by transcription-coupled nucleotide excision repair (TC-NER) to preserve cell viability. TC-NER is triggered by the stalling of RNA polymerase II at DNA lesions, leading to the recruitment of TC-NER-specific factors such as the CSA-DDB1-CUL4A-RBX1 cullin RING ubiquitin ligase complex (CRLCSA). Despite its vital role in TC-NER, little is known about the regulation of the CRLCSA complex during TC-NER. Using conventional and cross-linking immunoprecipitations coupled to mass spectrometry, we uncover a stable interaction between CSA and the TRiC chaperonin. TRiC's binding to CSA ensures its stability and DDB1-dependent assembly into the CRLCSA complex. Consequently, loss of TRiC leads to mislocalization and depletion of CSA, as well as impaired transcription recovery following UV damage, suggesting defects in TC-NER. Furthermore, Cockayne syndrome (CS)-causing mutations in CSA lead to increased TRiC binding and a failure to compose the CRLCSA complex. Thus, we uncover CSA as a TRiC substrate and reveal that TRiC regulates CSA-dependent TC-NER and the development of CS. PMID- 29531220 TI - Disentangling the role of floral sensory stimuli in pollination networks. AB - Despite progress in understanding pollination network structure, the functional roles of floral sensory stimuli (visual, olfactory) have never been addressed comprehensively in a community context, even though such traits are known to mediate plant-pollinator interactions. Here, we use a comprehensive dataset of floral traits and a novel dynamic data-pooling methodology to explore the impacts of floral sensory diversity on the structure of a pollination network in a Mediterranean scrubland. Our approach tracks transitions in the network behaviour of each plant species throughout its flowering period and, despite dynamism in visitor composition, reveals significant links to floral scent, and/or colour as perceived by pollinators. Having accounted for floral phenology, abundance and phylogeny, the persistent association between floral sensory traits and visitor guilds supports a deeper role for sensory bias and diffuse coevolution in structuring plant-pollinator networks. This knowledge of floral sensory diversity, by identifying the most influential phenotypes, could help prioritize efforts for plant-pollinator community restoration. PMID- 29531221 TI - Evidence for ephemeral middle Eocene to early Oligocene Greenland glacial ice and pan-Arctic sea ice. AB - Earth's modern climate is defined by the presence of ice at both poles, but that ice is now disappearing. Therefore understanding the origin and causes of polar ice stability is more critical than ever. Here we provide novel geochemical data that constrain past dynamics of glacial ice on Greenland and Arctic sea ice. Based on accurate source determinations of individual ice-rafted Fe-oxide grains, we find evidence for episodic glaciation of distinct source regions on Greenland as far-ranging as ~68 degrees N and ~80 degrees N synchronous with ice-rafting from circum-Arctic sources, beginning in the middle Eocene. Glacial intervals broadly coincide with reduced CO2, with a potential threshold for glacial ice stability near ~500 p.p.m.v. The middle Eocene represents the Cenozoic onset of a dynamic cryosphere, with ice in both hemispheres during transient glacials and substantial regional climate heterogeneity. A more stable cryosphere developed at the Eocene-Oligocene transition, and is now threatened by anthropogenic emissions. PMID- 29531222 TI - miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF betaRI signaling pathway. AB - High-risk human papillomavirus infection is essential for the malignant transformation of cervical cancer and can inhibit host miR-27a expression. We investigated the role and mechanism of miR-27a in cervical cancer progression. miR-27a is decreased in cervical cancer cell lines and miR-27a-agomir inhibited the cell proliferation, migration, and invasion properties of HeLa (adenocarcinoma) cells, but not in SiHa cells (squamous cell carcinoma). Luciferase assays revealed that miR-27a directly targets the 3'-UTR of transforming growth factor beta receptor I (TGF-betaRI) and downregulates TGF beta signaling. The co-transfection of a TGF-betaRI expression vector largely restored the inhibition of TGF-beta signaling, cell proliferation, migration, and invasion mediated by miR-27a-agomir. Also, miR-27a-agomir slows down the growth of subcutaneous HeLa xenografts and downregulates the TGF-betaRI expression and TGF-beta signaling in tumor in vivo. Tissue microarray analysis revealed a low miR-27a level in adenocarcinoma cells, but not in squamous cell carcinoma cells, which was negatively associated with TGF-betaRI expression. High TGF-betaRI correlated with deep stromal invasion and lymph node metastasis. These results suggest that miR-27a acts as a tumor suppressor in cervical cancer, especially in adenocarcinoma, by inhibiting TGF-betaRI signaling pathway. Thus, enhancing miR 27a expression and function may be a novel treatment strategy for cervical adenocarcinoma. PMID- 29531223 TI - Vesicular glutamate release from central axons contributes to myelin damage. AB - The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury. PMID- 29531224 TI - CoA synthase regulates mitotic fidelity via CBP-mediated acetylation. AB - The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here we present evidence that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a novel mechanism that ensures faithful mitosis. We found that COASY knockdown triggers prolonged mitosis and multinucleation. Acetylome analysis reveals that COASY inactivation leads to hyper-acetylation of proteins associated with mitosis, including CBP and an Aurora A kinase activator, TPX2. During early mitosis, a transient CBP-mediated TPX2 acetylation is associated with TPX2 accumulation and Aurora A activation. The recruitment of COASY inhibits CBP-mediated TPX2 acetylation, promoting TPX2 degradation for mitotic exit. Consistently, we detected a stage-specific COASY-CBP-TPX2 association during mitosis. Remarkably, pharmacological and genetic inactivation of CBP effectively rescued the mitotic defects caused by COASY knockdown. Together, our findings uncover a novel mitotic regulation wherein COASY and CBP coordinate an acetylation network to enforce productive mitosis. PMID- 29531225 TI - Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer. AB - Ovarian cancer (OC) is most lethal malignancy among all gynecological cancer. Large bodies of evidences suggest that mitochondrial-derived ROS play a critical role in the development and progression of OC. Paraoxonase 2 (PON2) is a membrane associated lactonase with anti-oxidant properties. PON2 deficiency aggravates mitochondrial ROS formation, systemic inflammation, and atherosclerosis. The role of PON2 in cancer development remains unknown. In this report, in human, we identified that PON2 expression is higher in early stages (but not in late stages) of OC when compared to normal tissue. Using a mouse xenograft model of OC, we demonstrate that overexpression of PON2 prevents tumor formation. Mechanistically, PON2 decreases OC cell proliferation by inhibiting insulin like growth factor-1 (IGF-1) expression and signaling. Intriguingly, PON2 reduces c Jun-mediated transcriptional activation of IGF-1 gene by decreasing mitochondrial superoxide generation. In addition, PON2 impairs insulin like growth factor-1 receptor (IGF-1R) signaling in OC cells by altering cholesterol homeostasis, which resulted in reduced caveolin-1/IGF-1R interaction and IGF-1R phosphorylation. Taken together, we report for the first time that PON2 acts as a tumor suppressor in the early stage of OC by reducing IGF-1 production and its signaling, indicating PON2 activation might be a fruitful strategy to inhibit early stage ovarian tumor. PMID- 29531226 TI - Gestational cytokine concentrations and neurocognitive development at 7 years. AB - Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1beta, IL-8, tumor necrosis factor alpha (TNF-alpha), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959-1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro inflammatory cytokine, TNF-alpha, in the 2nd and 3rd trimesters had lower IQ (B = -2.51, 99% CI: -4.84,-0.18), higher problem scores in visual-motor maturity (B = 0.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (B = -1.28, 99% CI: -2.49,-0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-alpha and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children. PMID- 29531227 TI - Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour associated peptide. AB - Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B*07:02, presenting a 13-amino acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B*07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition. PMID- 29531229 TI - Large anisotropy of ferroelectric and pyroelectric properties in heteroepitaxial oxide layers. AB - Epitaxial PbZr0.52Ti0.48O3 (PZT) layers were integrated on Si(001) with single PZT {001} orientation, mosaicity below 1 degrees and a majority of a-oriented ferroelectric domains (~65%). Ferroelectric and pyroelectric properties are determined along both the out-of-plane and in-plane directions through parallel plate capacitor and coplanar interdigital capacitor along the <100>PZT direction. A large anisotropy in these properties is observed. The in-plane remnant polarization (21.5 uC.cm-2) is almost twice larger than that measured along the out-of-plane direction (13.5 uC.cm-2), in agreement with the domain orientation. Oppositely, the in-plane pyroelectric coefficient (-285 uC.m-2.K-1) is much lower than that measured out-of-plane (-480 uC.m-2.K-1). The pyroelectric anisotropy is explicated in term of degree of structural freedom with temperature. In particular, the low in-plane pyroelectric coefficient is explained by a two dimensional clamping of the layers on the substrate which induces tensile stress (from thermal expansion), competing with the decreasing tetragonality of a domains (shortening of the polar c-axis lattice parameter). Temperature-dependent XRD measurements have revealed an increased fraction of a-domains with temperature, attesting the occurrence of a partial two-dimensional clamping. These observed properties are of critical importance for integrated pyroelectric devices. PMID- 29531228 TI - Understanding the prebiotic potential of different dietary fibers using an in vitro continuous adult fermentation model (PolyFermS). AB - Consumption of fermentable dietary fibers (DFs), which can induce growth and/or activity of specific beneficial populations, is suggested a promising strategy to modulate the gut microbiota and restore health in microbiota-linked diseases. Until today, inulin and fructo-oligosaccharides (FOS) are the best studied DFs, while little is known about the gut microbiota-modulating effects of beta-glucan, alpha-galactooligosaccharide (alpha-GOS) and xylo-oligosaccharide (XOS). Here, we used three continuous in vitro fermentation PolyFermS model to study the modulating effect of these DFs on two distinct human adult proximal colon microbiota, independently from the host. Supplementation of DFs, equivalent to a 9 g daily intake, induced a consistent metabolic response depending on the donor microbiota. Irrespective to the DF supplemented, the Bacteroidaceae Ruminococcaceae dominated microbiota produced more butyrate (up to 96%), while the Prevotellaceae-Ruminococcaceae dominated microbiota produced more propionate (up to 40%). Changes in abundance of specific bacterial taxa upon DF supplementation explained the observed changes in short-chain fatty acid profiles. Our data suggest that the metabolic profile of SCFA profile may be the most suitable and robust read-out to characterize microbiota-modulating effects of a DF and highlights importance to understand the inter-individual response to a prebiotic treatment for mechanistic understanding and human application. PMID- 29531230 TI - Electrochemical Evaluations of Fractal Microelectrodes for Energy Efficient Neurostimulation. AB - Advancements in microfabrication has enabled manufacturing of microscopic neurostimulation electrodes with smaller footprint than ever possible. The smaller electrodes can potentially reduce tissue damage and allow better spatial resolution for neural stimulation. Although electrodes of any shape can easily be fabricated, substantial effort have been focused on identification and characterization of new materials and surface morphology for efficient charge injection, while maintaining simple circular or rectangular Euclidean electrode geometries. In this work we provide a systematic electrochemical evaluation of charge injection capacities of serpentine and fractal-shaped platinum microelectrodes and compare their performance with traditional circular microelectrodes. Our findings indicate that the increase in electrode perimeter leads to an increase in maximum charge injection capacity. Furthermore, we found that the electrode geometry can have even more significant impact on electrode performance than having a larger perimeter for a given surface area. The fractal shaped microelectrodes, despite having smaller perimeter than other designs, demonstrated superior charge injection capacity. Our results suggest that electrode design can significantly affect both Faradaic and non-Faradaic electrochemical processes, which may be optimized to enable a more energy efficient design for neurostimulation. PMID- 29531231 TI - Genome-wide identification and expression analyses of genes involved in raffinose accumulation in sesame. AB - Sesame (Sesamum indicum L.) is an important oilseed crop. However, multiple abiotic stresses severely affect sesame growth and production. Raffinose family oligosaccharides (RFOs), such as raffinose and stachyose, play an important role in desiccation tolerance of plants and developing seeds. In the present study, three types of key enzymes, galactinol synthase (GolS), raffinose synthase (RafS) and stachyose synthase (StaS), responsible for the biosynthesis of RFOs were identified at the genome-wide scale in sesame. A total of 7 SiGolS and 15 SiRS genes were identified in the sesame genome. Transcriptome analyses showed that SiGolS and SiRS genes exhibited distinct expression profiles in different tissues and seed developmental stages. Comparative expression analyses under various abiotic stresses indicated that most of SiGolS and SiRS genes were significantly regulated by drought, osmotic, salt, and waterlogging stresses, but slightly affected by cold stress. The up-regulation of several SiGolS and SiRS genes by multiple abiotic stresses suggested their active implication in sesame abiotic stress responses. Taken together, these results shed light on the RFOs-mediated abiotic stress resistance in sesame and provide a useful framework for improving abiotic stress resistance of sesame through genetic engineering. PMID- 29531232 TI - Genetic analyses in a bonobo (Pan paniscus) with arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder that may lead to sudden death and can affect humans and other primates. In 2012, the alpha male bonobo of the Milwaukee County Zoo died suddenly and histologic evaluation found features of ARVC. This study sought to discover a possible genetic cause for ARVC in this individual. We sequenced our subject's DNA to search for deleterious variants in genes involved in cardiovascular disorders. Variants found were annotated according to the human genome, following currently available classification used for human diseases. Sequencing from the DNA of an unrelated unaffected bonobo was also used for prediction of pathogenicity. Twenty-four variants of uncertain clinical significance (VUSs) but no pathogenic variants were found in the proband studied. Further familial, functional, and bonobo population studies are needed to determine if any of the VUSs or a combination of the VUSs found may be associated with the clinical findings. Future genotype phenotype establishment will be beneficial for the appropriate care of the captive zoo bonobo population world-wide as well as conservation of the bobono species in its native habitat. PMID- 29531233 TI - One-pot synthesis of purple benzene-derived MnO2-carbon hybrids and synergistic enhancement for the removal of cationic dyes. AB - MnO2-carbon hybrid (MnO2-C-PBz) was simultaneously synthesized by a one-step solution plasma process (SPP) using a single precursor referred to as "purple benzene", which was derived from the K+(dicyclohexano-18-crown-6 ether) complex. To clarify the synergistic effects on the cationic dye removal, MnO2-free carbon and carbon-free MnO2 samples were concurrently investigated. The results of adsorption for cationic dyes (methylene blue (MB) and rhodamine B (Rh B)) and anionic dye (methyl orange (MO)) revealed remarkably high affinity for cationic dyes. In particular, MnO2-C-PBz exhibited the highest adsorption capacity for MB, i.e., ~3 times greater than that of the others. In addition, MnO2-C-PBz exhibited a rapid, high decolorization ability at C0 = 10 mg L-1 (within a few seconds, ~99%) and at C0 = 100 mg L-1 (within 30 min, ~81%), and the theoretical maximum monolayer adsorption capacity was 357.14 mg g-1 as calculated from the Langmuir adsorption isotherm equation. Furthermore, compared with carbon-free MnO2, MnO2-C PBz exhibited quite a good cyclic stability. We expect that our findings give rise to the understanding of the synergistic effects of MnO2-carbon hybrid, as well as role of each components for the cationic dye adsorption, and may open an innovative synthesis approach to inorganic-organic hybrid materials. PMID- 29531234 TI - Influence of fecal collection conditions and 16S rRNA gene sequencing at two centers on human gut microbiota analysis. AB - To optimise fecal sampling for reproducible analysis of the gut microbiome, we compared different methods of sample collection and sequencing of 16S rRNA genes at two centers. Samples collected from six individuals on three consecutive days were placed in commercial collection tubes (OMNIgeneGut OMR-200) or in sterile screw-top tubes in a home fridge or home freezer for 6-24 h, before transfer and storage at -80 degrees C. Replicate samples were shipped to centers in Australia and the USA for DNA extraction and sequencing by their respective PCR protocols, and analysed with the same bioinformatic pipeline. Variation in gut microbiome was dominated by differences between individuals. Minor differences in the abundance of taxa were found between collection-processing methods and day of collection, and between the two centers. We conclude that collection with storage and transport at 4 degrees C within 24 h is adequate for 16S rRNA analysis of the gut microbiome. Other factors including differences in PCR and sequencing methods account for relatively minor variation compared to differences between individuals. PMID- 29531235 TI - Swelling Inhibition of Liquid Crystalline Colloidal Montmorillonite and Beidellite Clays by DNA. AB - Exploring the interaction of nucleic acids with clay minerals is important to understand such issues as the persistence in soils of biomolecules and the appearance of genetic polymers in prebiotic environments. Colloidal dispersions of double stranded DNA and clay nanosheets may also provide interesting model systems to study the statistical physics of mixtures of semi-flexible rods and plates. Here, we show that adding very small amounts of DNA to liquid-crystalline montmorillonite and beidellite smectite clay suspensions strongly widens the isotropic/nematic phase coexistence region. Moreover, a spectroscopic study shows that, upon DNA addition, the first DNA molecules adsorb onto the clay particles. Remarkably, synchrotron small-angle X-ray scattering experiments reveal that the average distance between the clay sheets, in the nematic phase at coexistence, decreases with increasing DNA concentration and that the inhibition of swelling by DNA becomes almost independent of clay concentration. We interpret this DNA mediated attraction between clay nanosheets by bridging conformations of DNA strands (plates on a string structure). In addition to bridging, DNA chains can form "loops" between sections adsorbed on the same particle, giving rise to sheet repulsions due to protruding loops. This interpretation agrees with the observed inter-clay spacings being dependent only on the DNA concentration. PMID- 29531236 TI - A Prognostic Nomogram for Postoperative Bone Remodeling in Patients with ADDWoR. AB - This study aimed to establish an effective prognostic nomogram for predicting the probability of postoperative bone remodeling of patients with anterior disc displacement without reduction (ADDWoR). The nomogram was based on a retrospective study on patients underwent surgical approaches for ADDWoR at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University from January, 2007 to January, 2017. A multivariate logistic regression analysis was used to develop variables suitable for probability estimation model. The predictive accuracy and discriminative ability were determined by ROC (AUC-index) and calibration curve. Results were validated using bootstrap resampling with all statistical tests two-sided. 1110 patients were included in the analysis. The probability of postoperative bone remodeling in ADDWoR was 0.51. Six independent prognostic factors including age of onset, nocturnal bruxism, disc morphology, BMD, Wilkes' classification, and postoperative splint therapy were integrated to construct the nomogram. The probability estimation model showed good discrimination in both internal and external validation with AUC-index of 0.84. The calibration curves for probability of postoperative bone remodeling showed optimal agreement with actual observation. In conclusion, a nomogram was established to provide individual prediction of postoperative bone remodeling for patients with ADDWoR treated by arthroscopy surgery. PMID- 29531237 TI - Prevalence and correlates of hyperuricemia in the middle-aged and older adults in China. AB - Hyperuricemia, the physiological prerequisite for gout, is linked to the presence and severity of multiple comorbidities that affect longevity and well-being. By using the baseline data from the China Health and Retirement Longitudinal Study, a nationally representative survey, the prevalence of hyperuricemia in general middle-aged and older Chinese was estimated. The potential effects of health behaviours and comorbidities on hyperuricemia were also explored. In 2010, the prevalence of hyperuricemia among middle-aged and older Chinese was 6.4%. Hyperuricemia was more prevalent in males than in females (7.9% vs. 4.9%). The risk of hyperuricemia increased with advanced age in both sexes. In males, current drinking, obesity and dyslipidemia were positively associated with hyperuricemia, whereas singles males and males living in North China were with lower odds of having hyperuricemia. For females, being single, at a higher economic level, living in the Southwest China, smoking, obesity, diabetes, hypertension and dyslipidemia were all significant risk factors for hyperuricemia, but females living in North China and Northwest China were with a lower hyperuricemia prevalence than females in East China. Therefore, hyperuricemia in China was not as prevalent as in developed countries, its prevalence varied greatly according to demographic, socioeconomic, and geographic factors. PMID- 29531239 TI - Rational Modification of a Metallic Substrate for CVD Growth of Carbon Nanotubes. AB - Growth of high quality, dense carbon nanotube (CNT) arrays via catalytic chemical vapor deposition (CCVD) has been largely limited to catalysts supported on amorphous alumina or silica. To overcome the challenge of conducting CNT growth from catalysts supported on conductive substrates, we explored a two-step surface modification that involves ion beam bombardment to create surface porosity and deposition of a thin AlxOy barrier layer to make the surface basic. To test the efficacy of our approach on a non-oxide support, we focus on modification of 316 stainless steel (SS), a well-known inactive substrate for CNT growth. Our study reveals that ion beam bombardment of SS has the ability to reduce film thickness of the AlxOy barrier layer required to grow CNTs from Fe catalysts to [Formula: see text] 5 nm, which is within the threshold for the substrate to remain conductive. Additionally, catalysts supported on ion beam-damaged SS with the same AlxOy thickness show improved particle formation, catalyst stability, and CNT growth efficiency, as well as producing CNTs with higher quality and density. Under optimal reaction conditions, this modification approach can lead to CNT growth on other nontraditional substrates and potentially benefit applications that require CNTs be grown on a conductive substrate. PMID- 29531238 TI - Loss and gain of N-linked glycosylation sequons due to single-nucleotide variation in cancer. AB - Despite availability of sequence site-specific information resulting from years of sequencing and sequence feature curation, there have been few efforts to integrate and annotate this information. In this study, we update the number of human N-linked glycosylation sequons (NLGs), and we investigate cancer relatedness of glycosylation-impacting somatic nonsynonymous single-nucleotide variation (nsSNV) by mapping human NLGs to cancer variation data and reporting the expected loss or gain of glycosylation sequon. We find 75.8% of all human proteins have at least one NLG for a total of 59,341 unique NLGs (includes predicted and experimentally validated). Only 27.4% of all NLGs are experimentally validated sites on 4,412 glycoproteins. With respect to cancer, 8,895 somatic-only nsSNVs abolish NLGs in 5,204 proteins and 12,939 somatic-only nsSNVs create NLGs in 7,356 proteins in cancer samples. nsSNVs causing loss of 24 NLGs on 23 glycoproteins and nsSNVs creating 41 NLGs on 40 glycoproteins are identified in three or more cancers. Of all identified cancer somatic variants causing potential loss or gain of glycosylation, only 36 have previously known disease associations. Although this work is computational, it builds on existing genomics and glycobiology research to promote identification and rank potential cancer nsSNV biomarkers for experimental validation. PMID- 29531240 TI - Spatio-temporal dynamics of soil bacterial communities as a function of Amazon forest phenology. AB - Most tropical evergreen rain forests are characterised by varying degrees of precipitation seasonality that influence plant phenology and litterfall dynamics. Soil microbes are sensitive to soil water:air ratio and to nutrient availability. We studied if within-year seasonality in precipitation and litterfall-derived nutrient input resulted in predictable seasonal variation in soil bacterial diversity/microbial functional groups in an Amazonian forest. We characterised the spatio-temporal dynamics of microbial communities from the plot to the stand scales and related them to precipitation seasonality and spatial variability in soil characteristics. Community composition and functional diversity showed high spatial heterogeneity and was related to variability in soil chemistry at the stand level. Large species turnover characterised plot level changes over time, reflecting precipitation seasonality-related changes in soil nutrient and moisture regimes. The abundance of decomposers was highest during the rainy season, characterised also by anaerobic saprophytes and N2-fixers adapted to fluctuating redox conditions. In contrast, Beijerinckiaceae, likely derived from the phyllosphere, were found at higher abundances when litter inputs and accumulation were highest. We showed that in a mildly seasonal rain forest, the composition of soil microbial communities appears to be following canopy phenology patterns and the two are interlinked and drive soil nutrient availability. PMID- 29531241 TI - Latitudinal effects on phenology near the northern limit of figs in China. AB - The interaction between pollinating wasps and figs is an obligate plant-insect mutualism, and the ca. 750 Ficus species are mainly tropical. Climatic constraints may limit species distributions through their phenology and this seems particularly likely for figs, where phenological mismatches can cause local extinction of the short-lived pollinators. We therefore compared the phenologies of Ficus altissima, F. racemosa and F. semicordata in tropical Xishuangbanna (21 degrees 55'N) and subtropical Liuku (25 degrees 50'N), SW China, to understand what factors limit fig distributions near their northern limits. All species produced synchronous crops of syconia in Xishuangbanna but production in Liuku was continuous, which may help maintain pollinator populations. However, in general, we found decreased fitness at the northern site: slower syconium development, so fewer crops each year; fewer seeds per syconium (two species); and fewer pollinators and more non-pollinators per syconium, so less pollen is dispersed. This is most easily explained by colder winters, although low humidities may also contribute, and suggests the northern limit is set by temperature constraints on reproductive phenology. If so, the warming predicted for future decades is expected to enhance the fitness of northern populations of figs and, in the longer term, allow them to shift their range limits northwards. PMID- 29531243 TI - Experimental study and new three-dimensional kinetic modeling of foamy solution gas drive processes. AB - Foamy solution-gas drive processes in heavy oil reservoirs are very complex. The influence of some microscopic factors on this process is not fully understood due to limitations of traditional depletion tests. This study aims to investigate foamy solution-gas drive by experiments and simulations. First, the effects of the pressure depletion rate on critical gas saturation and foamy solution-gas drive processes were investigated by laboratory experiments. Second, a new three dimensional foamy oil model that captures many important characteristics of foamy solution-gas drive, such as non-equilibrium behavior, gas evolution kinetics, and the effect of viscous forces on gas mobility, was developed. Last, the effects of some important parameters on foamy solution-gas drive were systematically investigated,and a model application was conducted in a typical foamy oil reservoir. The results indicate that the new model is capble of simulating many of the unusual behaviors observed in foamy solution-gas drive on a laboratory and field scales. High oil recoveries were obtained with a high oil viscosity, high depletion rate, long sandpack, and low solution gas-oil ratio. Foamy solution-gas drive processes are sensitive to the depletion rate, length, and critical gas saturation. The oil viscosity, solution GOR and diffusion coefficient are not sensitive factors. PMID- 29531242 TI - Bipolar disorder in youth is associated with increased levels of vitamin D binding protein. AB - Genetic, dietary, and inflammatory factors contribute to the etiology of major mood disorders (MMD), thus impeding the identification of specific biomarkers to assist in diagnosis and treatment. We tested association of vitamin D and inflammatory markers in 36 adolescents with bipolar disorder (BD) and major depressive disorder (MDD) forms of MMD and without MMD (non-mood control). We also assessed the overall level of inflammation using a cell-based reporter assay for nuclear factor kappa-B (NFkappaB) activation and measuring antibodies to oxidized LDL. We found that these factors were similar between non-mood and MMD youth. To identify potential biomarkers, we developed a screening immunoprecipitation-sequencing approach based on inflammatory brain glia maturation factor beta (GMFbeta). We discovered that a homolog of GMFbeta in human plasma is vitamin D-binding protein (DBP) and validated this finding using immunoprecipitation with anti-DBP antibodies and mass spectrometry/sequencing analysis. We quantified DBP levels in participants by western blot. DBP levels in BD participants were significantly higher (136%) than in participants without MMD (100%). The increase in DBP levels in MDD participants (121.1%) was not statistically different from these groups. The DBP responds early to cellular damage by binding of structural proteins and activating inflammatory cells. A product of enzymatic cleavage of DBP has been described as macrophage-activating factor. Circulating DBP is comprised of heterogenous high and low molecular fractions that are only partially recognized by mono- and polyclonal ELISA and are not suitable for the quantitative comparison of DBP in non-mood and MDD participants. Our data suggest DBP as a marker candidate of BD warranting its validation in a larger cohort of adolescent and adult MMD patients. PMID- 29531244 TI - Improved water use efficiency and shorter life cycle of Nicotiana tabacum due to modification of guard and vascular companion cells. AB - Severe droughts are predicted for the twenty-first century, which contrast with the increased demand for plant materials. Thus, to sustain future generations, a great challenge is to improve crop yield and water use efficiency (WUE), which is the carbon gained per water lost. Here, expression of maize NADP-malic enzyme (NADP-ME) in the guard and vascular companion cells of Nicotiana tabacum results in enhanced WUE, earlier flowering and shorter life cycle. Transgenic lines exhibit reduced stomatal aperture than wild-type (WT). Nevertheless, an increased net CO2 fixation rate is observed, which results in less water consumption and more biomass production per water used. Transgenic lines export sugars to the phloem at higher rate than WT, which leads to higher sugars levels in phloem exudates and veins. Leaf quantitative proteomic profiling revealed drastic differences in proteins related to cell cycle, flowering, hormone signaling and carbon metabolism between transgenic lines and WT. We propose that the increased sugar export from leaves in the transgenic lines alleviates sugar negative feedback on photosynthesis and thus, stomatal closure takes place without a penalty in CO2 assimilation rate. This results in improved WUE and accelerated overall life cycle, key traits for plant productivity in the near future world. PMID- 29531245 TI - Using massively parallel shotgun sequencing of maternal plasmatic cell-free DNA for cytomegalovirus DNA detection during pregnancy: a proof of concept study. AB - Human cytomegalovirus (HCMV) primary infections of pregnant women can lead to congenital infections of the fetus that could have severe impacts on the health of the newborn. Recent studies have shown that 10-100 billion DNA fragments per milliliter of plasma are circulating cell-free. The study of this DNA has rapidly expanding applications to non-invasive prenatal testing (NIPT). In this study, we have shown that we can detect viral specific reads in the massively parallel shotgun sequencing (MPSS) NIPT data. We have also observed a strong correlation between the viral load of calibration samples and the number of reads aligned on the reference genome. Based on these observations we have constructed a statistical model able to quantify the viral load of patient samples. We propose to use this new method to detect and quantify circulating DNA virus like HCMV during pregnancy using the same sequencing results as NIPT data. This method could be used to improve the NIPT diagnosis. PMID- 29531246 TI - Efficient molecular evolution to generate enantioselective enzymes using a dual channel microfluidic droplet screening platform. AB - Directed evolution has long been a key strategy to generate enzymes with desired properties like high selectivity, but experimental barriers and analytical costs of screening enormous mutant libraries have limited such efforts. Here, we describe an ultrahigh-throughput dual-channel microfluidic droplet screening system that can be used to screen up to ~107 enzyme variants per day. As an example case, we use the system to engineer the enantioselectivity of an esterase to preferentially produce desired enantiomers of profens, an important class of anti-inflammatory drugs. Using two types of screening working modes over the course of five rounds of directed evolution, we identify (from among 5 million mutants) a variant with 700-fold improved enantioselectivity for the desired (S) profens. We thus demonstrate that this screening platform can be used to rapidly generate enzymes with desired enzymatic properties like enantiospecificity, chemospecificity, and regiospecificity. PMID- 29531247 TI - High-sensitivity assay for monitoring ESR1 mutations in circulating cell-free DNA of breast cancer patients receiving endocrine therapy. AB - Approximately 70% of breast cancers (BCs) express estrogen receptor alpha (ERalpha) and are treated with endocrine therapy. However, the effectiveness of this therapy is limited by innate or acquired resistance in approximately one third of patients. Activating mutations in the ESR1 gene that encodes ERalpha promote critical resistance mechanisms. Here, we developed a high sensitivity approach based on enhanced-ice-COLD-PCR for detecting ESR1 mutations. The method produced an enrichment up to 100-fold and allowed the unambiguous detection of ESR1 mutations even when they consisted of only 0.01% of the total ESR1 allelic fraction. After COLD-PCR enrichment, methods based on next-generation sequencing or droplet-digital PCR were employed to detect and quantify ESR1 mutations. We applied the method to detect ESR1 mutations in circulating free DNA from the plasma of 56 patients with metastatic ER-positive BC. Fifteen of these patients were found to have ESR1 mutations at codons 536-538. This study demonstrates the utility of the enhanced-ice-COLD-PCR approach for simplifying and improving the detection of ESR1 tumor mutations in liquid biopsies. Because of its high sensitivity, the approach may potentially be applicable to patients with non metastatic disease. PMID- 29531248 TI - Spatially explicit poisoning risk affects survival rates of an obligate scavenger. AB - Obligate scavengers such as vultures provide critical ecosystem services and their populations have undergone severe declines in Asia and Africa. Intentional poisoning is a major threat to vultures in Africa, yet the impact on vulture populations of where poisoned carcasses are positioned is not known. We used re sightings of 183 African white-backed vultures captured and tagged in two regions of South Africa, some 200 km apart, to estimate spatial differences in relative survival rates across life stages. Juvenile survival rates were similar in the two regions, whilst subadult and adult survival rates differed significantly. Using agent-based modelling, we show that this pattern of relative survival rates is consistent between regions that differ in intensity of poisoning, despite the proximity of the two regions. This may have important consequences for vulture conservation and the targeting of conservation efforts, particularly with regard to the efficacy of "vulture safe zones" around vulture breeding populations. PMID- 29531249 TI - Retinal S-opsin dominance in Ansell's mole-rats (Fukomys anselli) is a consequence of naturally low serum thyroxine. AB - Mammals usually possess a majority of medium-wavelength sensitive (M-) and a minority of short-wavelength sensitive (S-) opsins in the retina, enabling dichromatic vision. Unexpectedly, subterranean rodents from the genus Fukomys exhibit an S-opsin majority, which is exceptional among mammals, albeit with no apparent adaptive value. Because thyroid hormones (THs) are pivotal for M-opsin expression and metabolic rate regulation, we have, for the first time, manipulated TH levels in the Ansell's mole-rat (Fukomys anselli) using osmotic pumps. In Ansell's mole-rats, the TH thyroxine (T4) is naturally low, likely as an adaptation to the harsh subterranean ecological conditions by keeping resting metabolic rate (RMR) low. We measured gene expression levels in the eye, RMR, and body mass (BM) in TH-treated animals. T4 treatment increased both, S- and M-opsin expression, albeit M-opsin expression at a higher degree. However, this plasticity was only given in animals up to approximately 2.5 years. Mass-specific RMR was not affected following T4 treatment, although BM decreased. Furthermore, the T4 inactivation rate is naturally higher in F. anselli compared to laboratory rodents. This is the first experimental evidence that the S-opsin majority in Ansell's mole-rats is a side effect of low T4, which is downregulated to keep RMR low. PMID- 29531250 TI - Modelling indirect interactions during failure spreading in a project activity network. AB - Spreading broadly refers to the notion of an entity propagating throughout a networked system via its interacting components. Evidence of its ubiquity and severity can be seen in a range of phenomena, from disease epidemics to financial systemic risk. In order to understand the dynamics of these critical phenomena, computational models map the probability of propagation as a function of direct exposure, typically in the form of pairwise interactions between components. By doing so, the important role of indirect interactions remains unexplored. In response, we develop a simple model that accounts for the effect of both direct and subsequent exposure, which we deploy in the novel context of failure propagation within a real-world engineering project. We show that subsequent exposure has a significant effect in key aspects, including the: (a) final spreading event size, (b) propagation rate, and (c) spreading event structure. In addition, we demonstrate the existence of 'hidden influentials' in large-scale spreading events, and evaluate the role of direct and subsequent exposure in their emergence. Given the evidence of the importance of subsequent exposure, our findings offer new insight on particular aspects that need to be included when modelling network dynamics in general, and spreading processes specifically. PMID- 29531251 TI - Predicting 131I-avidity of metastases from differentiated thyroid cancer using 18F-FDG PET/CT in postoperative patients with elevated thyroglobulin. AB - The quantitative relationship between iodine and glucose metabolism in metastases from differentiated thyroid cancer (DTC) remains unknown. Aim of the prospective study was to establish the value of 18F-FDG PET/CT in predicting 131I-avidity of metastases from DTC before the first radioiodine therapy. A total of 121 postoperative DTC patients with elevated stimulated serum thyroglobulin (ssTg) who underwent 131I adjuvant therapy or therapy after 18F-FDG PET/CT scan were enrolled. The Receiver operating characteristic curve was established to create an optimal cut-off point and evaluate the value of SUVmax for predicting 131I avidity. In our study, the median SUVmax in 131I-nonavid metastatic target lesions was also significantly higher than that in 131I-avid metastatic target lesions (5.37 vs. 3.30; P = 0.000). At a cut-off value of 4.0 in SUVmax, the area under curve was 0.62 with the sensitivity, specificity, positive predictive value and negative predictive value of 75.3%, 56.7%, 76.1%, and 54.8%, respectively. These results suggest that 18F-FDG PET/CT may be of great value in identifying metastases in postoperative DTC patients with elevated ssTg before 131I administration, leading to an improved management of disease. 18F-FDG positive metastatic DTC with SUVmax of greater than 4.0 possesses higher probability of non-avidity to radioiodine. PMID- 29531252 TI - Nutritionally recommended food for semi- to strict vegetarian diets based on large-scale nutrient composition data. AB - Diet design for vegetarian health is challenging due to the limited food repertoire of vegetarians. This challenge can be partially overcome by quantitative, data-driven approaches that utilise massive nutritional information collected for many different foods. Based on large-scale data of foods' nutrient compositions, the recent concept of nutritional fitness helps quantify a nutrient balance within each food with regard to satisfying daily nutritional requirements. Nutritional fitness offers prioritisation of recommended foods using the foods' occurrence in nutritionally adequate food combinations. Here, we systematically identify nutritionally recommendable foods for semi- to strict vegetarian diets through the computation of nutritional fitness. Along with commonly recommendable foods across different diets, our analysis reveals favourable foods specific to each diet, such as immature lima beans for a vegan diet as an amino acid and choline source, and mushrooms for ovo-lacto vegetarian and vegan diets as a vitamin D source. Furthermore, we find that selenium and other essential micronutrients can be subject to deficiency in plant-based diets, and suggest nutritionally-desirable dietary patterns. We extend our analysis to two hypothetical scenarios of highly personalised, plant-based methionine restricted diets. Our nutrient-profiling approach may provide a useful guide for designing different types of personalised vegetarian diets. PMID- 29531253 TI - General Prediction of Peptide-MHC Binding Modes Using Incremental Docking: A Proof of Concept. AB - The class I major histocompatibility complex (MHC) is capable of binding peptides derived from intracellular proteins and displaying them at the cell surface. The recognition of these peptide-MHC (pMHC) complexes by T-cells is the cornerstone of cellular immunity, enabling the elimination of infected or tumoral cells. T cell-based immunotherapies against cancer, which leverage this mechanism, can greatly benefit from structural analyses of pMHC complexes. Several attempts have been made to use molecular docking for such analyses, but pMHC structure remains too challenging for even state-of-the-art docking tools. To overcome these limitations, we describe the use of an incremental meta-docking approach for structural prediction of pMHC complexes. Previous methods applied in this context used specific constraints to reduce the complexity of this prediction problem, at the expense of generality. Our strategy makes no assumption and can potentially be used to predict binding modes for any pMHC complex. Our method has been tested in a re-docking experiment, reproducing the binding modes of 25 pMHC complexes whose crystal structures are available. This study is a proof of concept that incremental docking strategies can lead to general geometry prediction of pMHC complexes, with potential applications for immunotherapy against cancer or infectious diseases. PMID- 29531254 TI - Cost-effective generation of precise label-free quantitative proteomes in high throughput by microLC and data-independent acquisition. AB - Quantitative proteomics is key for basic research, but needs improvements to satisfy an increasing demand for large sample series in diagnostics, academia and industry. A switch from nanoflowrate to microflowrate chromatography can improve throughput and reduce costs. However, concerns about undersampling and coverage have so far hampered its broad application. We used a QTOF mass spectrometer of the penultimate generation (TripleTOF5600), converted a nanoLC system into a microflow platform, and adapted a SWATH regime for large sample series by implementing retention time- and batch correction strategies. From 3 ug to 5 ug of unfractionated tryptic digests that are obtained from proteomics-typical amounts of starting material, microLC-SWATH-MS quantifies up to 4000 human or 1750 yeast proteins in an hour or less. In the acquisition of 750 yeast proteomes, retention times varied between 2% and 5%, and quantified the typical peptide with 5-8% signal variation in replicates, and below 20% in samples acquired over a five-months period. Providing precise quantities without being dependent on the latest hardware, our study demonstrates that the combination of microflow chromatography and data-independent acquisition strategies has the potential to overcome current bottlenecks in academia and industry, enabling the cost-effective generation of precise quantitative proteomes in large scale. PMID- 29531255 TI - Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field 23Na MRI study. AB - Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo 23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*short and T2*long and in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo 23Na-MRI signal, 23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo 23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo 23Na MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states. PMID- 29531256 TI - Transcriptional landscape of human endogenous retroviruses (HERVs) and other repetitive elements in psoriatic skin. AB - Human endogenous retrovirus (HERV) sequences make up at least 8% of the human genome. Transcripts originating from these loci as well as proteins encoded by them have been detected in various tissues. HERVs are believed to be implicated in autoimmune diseases, however the extent to which, has remained unclear. Differential expression studies have so far been limited to certain HERV subfamilies with conserved sequences. No studies have been published describing the genome-wide expression pattern of HERVs and repetitive elements in the context of psoriasis. In the present study, we analysed total RNA sequencing data from skin samples of 12 psoriasis patients and 12 healthy controls, which enabled us to describe the entire transcriptional landscape of repetitive elements. We report high levels of repetitive element expression in the skin of psoriasis patients as well as healthy controls. The majority of differentially expressed elements were downregulated in lesional and non-lesional skin, suggesting active HERV suppression in the pro-inflammatory environment of psoriatic skin. However, we also report upregulation of a small subset of HERVs previously described in the context of autoimmune diseases, such as members of the HERV-K and W families, with the potential to affect the immunopathogenesis of psoriasis. PMID- 29531257 TI - Author Correction: Single shot laser writing with sub-nanosecond and nanosecond bursts of femtosecond pulses. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531258 TI - Publisher Correction: QTL mapping and molecular characterization of the classical D locus controlling seed and flower color in Linum usitatissimum (flax). AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29531259 TI - Identification of a novel 2-oxindole fluorinated derivative as in vivo antitumor agent for prostate cancer acting via AMPK activation. AB - The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound 8c, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound 8c caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of alpha1 or alpha2 isoforms as well as in vitro assays using human recombinant alpha1beta1gamma1 or alpha2beta1gamma1 AMPK isoforms revealed that compound 8c exhibit preference for AMPKalpha1. Consistent with efficacy at the cellular level, compound 8c was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent in vivo antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen independent prostate cancer. PMID- 29531260 TI - Author Correction: The role of directional interactions in the designability of generalized heteropolymers. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531261 TI - Erosion of natural darkness in the geographic ranges of cacti. AB - Naturally dark nighttime environments are being widely eroded by the introduction of artificial light at night (ALAN). The biological impacts vary with the intensity and spectrum of ALAN, but have been documented from molecules to ecosystems. How globally severe these impacts are likely to be depends in large part on the relationship between the spatio-temporal distribution of ALAN and that of the geographic ranges of species. Here, we determine this relationship for the Cactaceae family. Using maps of the geographic ranges of cacti and nighttime stable light composite images for the period 1992 to 2012, we found that a high percentage of cactus species were experiencing ALAN within their ranges in 1992, and that this percentage had increased by 2012. For almost all cactus species (89.7%) the percentage of their geographic range that was lit increased from 1992-1996 to 2008-2012, often markedly. There was a significant negative relationship between the species richness of an area, and that of threatened species, and the level of ALAN. Cacti could be particularly sensitive to this widespread and ongoing intrusion of ALAN into their geographic ranges, especially when considering the potential for additive and synergistic interactions with the impacts of other anthropogenic pressures. PMID- 29531262 TI - Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein. AB - Vesicular stomatitis virus (VSV) is an oncolytic rhabdovirus and its glycoprotein G is widely used to pseudotype other viruses for gene therapy. Low-density lipoprotein receptor (LDL-R) serves as a major entry receptor for VSV. Here we report two crystal structures of VSV G in complex with two distinct cysteine-rich domains (CR2 and CR3) of LDL-R, showing that their binding sites on G are identical. We identify two basic residues on G, which are essential for its interaction with CR2 and CR3. Mutating these residues abolishes VSV infectivity even though VSV can use alternative receptors, indicating that all VSV receptors are members of the LDL-R family. Collectively, our data suggest that VSV G has specifically evolved to interact with receptor CR domains. These structural insights into the interaction between VSV G and host cell receptors provide a basis for the design of recombinant viruses with an altered tropism. PMID- 29531263 TI - IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics. AB - Phytochemicals of medicinal plants encompass a diverse chemical space for drug discovery. India is rich with a flora of indigenous medicinal plants that have been used for centuries in traditional Indian medicine to treat human maladies. A comprehensive online database on the phytochemistry of Indian medicinal plants will enable computational approaches towards natural product based drug discovery. In this direction, we present, IMPPAT, a manually curated database of 1742 Indian Medicinal Plants, 9596 Phytochemicals, And 1124 Therapeutic uses spanning 27074 plant-phytochemical associations and 11514 plant-therapeutic associations. Notably, the curation effort led to a non-redundant in silico library of 9596 phytochemicals with standard chemical identifiers and structure information. Using cheminformatic approaches, we have computed the physicochemical, ADMET (absorption, distribution, metabolism, excretion, toxicity) and drug-likeliness properties of the IMPPAT phytochemicals. We show that the stereochemical complexity and shape complexity of IMPPAT phytochemicals differ from libraries of commercial compounds or diversity-oriented synthesis compounds while being similar to other libraries of natural products. Within IMPPAT, we have filtered a subset of 960 potential druggable phytochemicals, of which majority have no significant similarity to existing FDA approved drugs, and thus, rendering them as good candidates for prospective drugs. IMPPAT database is openly accessible at: https://cb.imsc.res.in/imppat . PMID- 29531264 TI - Haplotype-based allele mining in the Japan-MAGIC rice population. AB - Multi-parent advanced generation inter-cross (MAGIC) lines have broader genetic variation than bi-parental recombinant inbred lines. Genome-wide association study (GWAS) using high number of DNA polymorphisms such as single-nucleotide polymorphisms (SNPs) is a popular tool for allele mining in MAGIC populations, in which the associations of phenotypes with SNPs are investigated; however, the effects of haplotypes from multiple founders on phenotypes are not considered. Here, we describe an improved method of allele mining using the newly developed Japan-MAGIC (JAM) population, which is derived from eight high-yielding rice cultivars in Japan. To obtain information on the haplotypes in the JAM lines, we predicted the haplotype blocks in the whole chromosomes using 16,345 SNPs identified via genotyping-by-sequencing analysis. Using haplotype-based GWAS, we clearly detected the loci controlling the glutinous endosperm and culm length traits. Information on the alleles of the eight founders, which was based on the effects of mutations revealed by the analysis of next-generation sequencing data, was used to narrow down the candidate genes and reveal the associations between alleles and phenotypes. The haplotype-based allele mining (HAM) proposed in this study is a promising approach to the detection of allelic variation in genes controlling agronomic traits in MAGIC populations. PMID- 29531266 TI - Author Correction: Cystatin D (CST5): An ultra-early inflammatory biomarker of traumatic brain injury. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29531265 TI - Modulation of blood-brain barrier function by a heteroduplex oligonucleotide in vivo. AB - The blood-brain barrier (BBB) is increasingly regarded as a dynamic interface that adapts to the needs of the brain, responds to physiological changes, and gets affected by and can even promote diseases. Modulation of BBB function at the molecular level in vivo is beneficial for a variety of basic and clinical studies. Here we show that our heteroduplex oligonucleotide (HDO), composed of an antisense oligonucleotide and its complementary RNA, conjugated to alpha tocopherol as a delivery ligand, efficiently reduced the expression of organic anion transporter 3 (OAT3) gene in brain microvascular endothelial cells in mice. This proof-of-concept study demonstrates that intravenous administration of chemically synthesized HDO can remarkably silence OAT3 at the mRNA and protein levels. We also demonstrated modulation of the efflux transport function of OAT3 at the BBB in vivo. HDO will serve as a novel platform technology to advance the biology and pathophysiology of the BBB in vivo, and will also open a new therapeutic field of gene silencing at the BBB for the treatment of various intractable neurological disorders. PMID- 29531267 TI - Traumatic cervical spinal cord injury: recovery of penetration/aspiration and functional feeding outcome. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: This prospective cohort study aims to evaluate the recovery of penetration/aspiration and functional feeding outcome in patients with acute TCSCI. SETTING: Tampere University Hospital, Tampere, Finland METHODS: Forty-six patients with TCSCI were enrolled. All the patients received speech therapeutic interventions based on their clinical needs and were examined with a videofluoroscopic swallowing study (VFSS) at enrollment. The incidence of VFSS-verified laryngeal penetration/aspiration according to Rosenbek's Penetration-Aspiration Scale (PAS) served as the primary outcome. The secondary outcome was the level of functional oral intake (as per the Functional Oral Intake Scale; FOIS). Based on the PAS results, the patients were divided into two groups: (i) penetrator/aspirators (PAS score >=3) and (ii) non penetrator/aspirators (PAS score <=2). Follow-up VFS studies were primarily conducted on the patients with penetration/aspiration in prior VFS studies. The follow-up VFS studies were scheduled on the basis of clinical demand. RESULTS: Of the 46 patients, 48% had penetration/aspiration in the first VFSS. The second VFSS was conducted on 20 patients, of whom 6 patients (30%) had penetration/aspiration. The third VFSS was conducted on 9 patients. Of these, only two (22%) patients were still penetrator/aspirators. The majority (n = 37, 88%) of the patients presented a total oral intake without restrictions at the time of the final follow-up. Only one patient (2%) was still tube-dependent with consistent oral intake. CONCLUSION: Swallowing physiology in patients with TCSCI improved during the first months after injury, and the number of penetrator/aspirators decreased progressively. PMID- 29531268 TI - A Multi-modality Approach Towards Elucidation of the Mechanism for Human Achilles Tendon Bending During Passive Ankle Rotation. AB - The in vitro unconstrained Achilles tendon is nearly straight, while in vivo experiments reveal that the proximal region of the Achilles tendon, adjacent to Kager's fat pad, bends ventrally during plantarflexion but remains nearly straight during dorsiflexion. Tendon bending is an important factor in determining the displacement of the foot compared to the shortening of the muscle fibers. The objective of this study was to elucidate the various mechanisms that could cause tendon bending, which currently remain unknown. Examination of Thiel embalmed cadavers, with preservation of native articular joint mobility, revealed that the Achilles tendon still bent ventrally even when its surrounding tissues, including the skin surface, Kager's fat pad, and distal portions of the soleus muscle were removed. Shear modulus and collagen fiber orientation were distributed homogeneously with respect to the longitudinal line of the tendon, minimizing their causative contributions to the bending. Given that tendon bending is not caused by either the nature of the deformations of the tissues surrounding the Achilles tendon or its physical properties, we conclude that it results from the geometric architecture of the Achilles tendon and its configuration with respect to the surrounding tissues. PMID- 29531269 TI - C9orf140, a novel Axin1-interacting protein, mediates the negative feedback loop of Wnt/beta-catenin signaling. AB - Wnt/beta-catenin signaling activity is maintained in homeostasis by an expanding list of molecular determinants. However, the molecular components and the regulatory mechanisms involved in its fine-tuning remain to be determined. Here, we identified C9orf140, a tumor-specific protein, as a novel Axin1-interacting protein by tandem-affinity purification and mass spectrometry. We further showed that C9orf140 is a negative regulator of Wnt/beta-catenin signaling in cultured cells as well as in zebrafish embryos. It functions upstream of beta-catenin, outcompetes PP2A for binding to Axin1, influences the balance between phosphorylation and de-phosphorylation of beta-catenin, and ultimately compromises Wnt3A-induced beta-catenin accumulation. Interestingly, Wnt-induced C9orf140 expression via beta-catenin. We propose that C9orf140 mediates a negative feedback loop of Wnt/beta-catenin signaling by interacting with Axin1. Our results advance the current understanding of the exquisite control of Wnt/beta-catenin signaling cascade, and provide evidence of the new role of C9orf140. PMID- 29531270 TI - Author Correction: The impact of the introduction of new recognition criteria for overwork-related cardiovascular and cerebrovascular diseases: a cross-country comparison. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531271 TI - The relation of blood pressure and carotid intima-media thickness with the glutathione cycle in a young bi-ethnic population: the African-PREDICT study. AB - Oxidative stress has been implicated in the development of hypertension, arterial stiffness and atherosclerosis. Optimal functioning of the enzymatic antioxidant system is central to prevent increased oxidative stress and its consequences. We aimed to investigate the relationships of ambulatory blood pressure and carotid intima-media thickness with enzyme activities of the glutathione cycle in 396 young, black and white South Africans of the African-PREDICT study. Ambulatory blood pressure and carotid intima-media thickness were measured and glutathione peroxidase and glutathione reductase activities were analyzed. Black participants had higher reactive oxygen species (men: p = 0.019; women: borderline p = 0.064) and total glutathione (both p < 0.001), but lower glutathione peroxidase activity and total antioxidant status (all p < 0.001). In black men, ambulatory pulse pressure was negatively associated with glutathione peroxidase activity (R2 = 0.19; beta = -0.25; p = 0.06). Black and white women displayed positive associations of ambulatory systolic blood pressure (black: R2 = 0.25; beta = 0.21; p = 0.048; white: R2 = 0.44; beta = 0.18; p = 0.016) with glutathione reductase activity, whereas white men displayed a positive association of ambulatory pulse pressure with glutathione reductase activity (R2 = 0.25; beta = 0.29; p = 0.01). The lower glutathione peroxidase activity and total antioxidant status, the higher reactive oxygen species, as well as the negative association between ambulatory pulse pressure and glutathione peroxidase activity in the black men suggest that oxidative stress may be associated with early vascular changes in this group. In the other three groups, the positive associations of blood pressure with glutathione reductase activity suggest a possible role for adequate glutathione reductase activity in preventing or delaying the development of hypertension. PMID- 29531272 TI - An innovative methodology for the non-destructive diagnosis of architectural elements of ancient historical buildings. AB - In the following we present a new non-invasive methodology aimed at the diagnosis of stone building materials used in historical buildings and architectural elements. This methodology consists of the integrated sequential application of in situ proximal sensing methodologies such as the 3D Terrestrial Laser Scanner for the 3D modelling of investigated objects together with laboratory and in situ non-invasive multi-techniques acoustic data, preceded by an accurate petrographical study of the investigated stone materials by optical and scanning electron microscopy. The increasing necessity to integrate different types of techniques in the safeguard of the Cultural Heritage is the result of the following two interdependent factors: 1) The diagnostic process on the building stone materials of monuments is increasingly focused on difficult targets in critical situations. In these cases, the diagnosis using only one type of non invasive technique may not be sufficient to investigate the conservation status of the stone materials of the superficial and inner parts of the studied structures 2) Recent technological and scientific developments in the field of non-invasive diagnostic techniques for different types of materials favors and supports the acquisition, processing and interpretation of huge multidisciplinary datasets. PMID- 29531273 TI - Plasticity in nodal root elongation through the hardpan triggered by rewatering during soil moisture fluctuation stress in rice. AB - Rainfed lowland (RFL) rice fields have hardpans and experience soil moisture fluctuations (SMF) stress, which influence root system development. Here, we clarify the expression and timing of the plasticity in nodal root elongation through the hardpan under SMF and its contribution to shoot growth using a shallow-rooting IR64 and its deep-rooting introgression line, YTH304. Under SMF, soil moisture content had negative relationship with soil penetration resistance, regardless of hardpan bulk densities. YTH304 had greater root system below the hardpan than IR64 in hardpan with 1.50 but not in 1.70 g cm-3 bulk density (BD). YTH304 had greater plasticity in nodal root elongation through the hardpan than IR64 under SMF, which was clearly expressed during rewatering. YTH304 also had greater soil water uptake below the hardpan during drought and greater shoot growth than IR64. The results imply that deep root system development during SMF was due to the plasticity in nodal root elongation through the hardpan expressed during rewatering rather than during drought periods. This is against the long standing belief that active root elongation through the hardpan happens during drought. This also implies a need to revisit current root screening methods to identify rice lines with good hardpan penetration ability. PMID- 29531274 TI - Passenger pigeon genomic diversity and extinction. PMID- 29531275 TI - Author Correction: Ringing phenomenon based measurement of weak mode-coupling strength in an optical microresonator. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531276 TI - Author Correction: DNA metabarcoding and morphological macroinvertebrate metrics reveal the same changes in boreal watersheds across an environmental gradient. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531277 TI - Author Correction: Use of pulmonary CT angiography with low tube voltage and low iodine-concentration contrast agent to diagnose pulmonary embolism. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531278 TI - Author Correction: Periodontal pathogenic bacteria, Aggregatibacter actinomycetemcomitans affect non-alcoholic fatty liver disease by altering gut microbiota and glucose metabolism. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531279 TI - Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population. AB - Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1 3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 * 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 * 10-6), the one at 3q13.2 (rs78125721, p = 4.77 * 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study. PMID- 29531280 TI - A smartphone app to reduce excessive alcohol consumption: Identifying the effectiveness of intervention components in a factorial randomised control trial. AB - Our aim was to evaluate intervention components of an alcohol reduction app: Drink Less. Excessive drinkers (AUDIT>=8) were recruited to test enhanced versus minimal (reduced functionality) versions of five app modules in a 25 factorial trial. Modules were: Self-monitoring and Feedback, Action Planning, Identity Change, Normative Feedback, and Cognitive Bias Re-training. Outcome measures were: change in weekly alcohol consumption (primary); full AUDIT score, app usage, app usability (secondary). Main effects and two-way interactions were assessed by ANOVA using intention-to-treat. A total of 672 study participants were included. There were no significant main effects of the intervention modules on change in weekly alcohol consumption or AUDIT score. There were two-way interactions between enhanced Normative Feedback and Cognitive Bias Re-training on weekly alcohol consumption (F = 4.68, p = 0.03) and between enhanced Self monitoring and Feedback and Action Planning on AUDIT score (F = 5.82, p = 0.02). Enhanced Self-monitoring and Feedback was used significantly more often and rated significantly more positively for helpfulness, satisfaction and recommendation to others than the minimal version. To conclude, in an evaluation of the Drink Less smartphone application, the combination of enhanced Normative Feedback and Cognitive Bias Re-training and enhanced Self-monitoring and Feedback and Action Planning yielded improvements in alcohol-related outcomes after 4-weeks. PMID- 29531281 TI - Author Correction: The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long term synaptic plasticity. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29531282 TI - Shelf Life Evaluation of Clinical Grade Chondrogenic Induced Aged Adult Stem Cells for Cartilage Regeneration. AB - The study objectives include, enhancing the proliferations of aged bone marrow stem cells (BMSCs) and adipose stem cells (ADSCs); and evaluating the shelf lives of clinical grade chondrogenically induced cells from both samples. ADSCs and BMSCs from 56 patients (76 +/- 8 yrs) were proliferated using basal medium (FD) and at (5, 10, 15, 20 and 25) ng/ml of basal fibroblast growth factor (bFGF). They were induced to chondrogenic lineage and stored for more than 120 hrs in FD, serum, Dulbecco's phosphate buffered saline (DPBS) and saline at 4 degrees C. In FD, cells stagnated and BMSCs' population doubling time (PDT) was 137 +/- 30 hrs, while ADSCs' was 129.7 +/- 40 hrs. bFGF caused PDT's decrease to 24.5 +/- 5.8 hrs in BMSCs and 22.0 +/- 6.5 hrs in ADSCs (p = 0.0001). Both cells were positive to stem cell markers before inductions and thereafter, expressed significantly high chondrogenic genes (p = 0.0001). On shelf life, both cells maintained viabilities and counts above 70% in FD and serum after 120 hrs. BMSCs' viabilities in DPBS fell below 70% after 96 hrs and saline after 72 hrs. ADSCs' viability fell below 70% in DPBS after 24 hrs and saline within 24 hrs. Concentrations between 20 ng/ml bFGF is ideal for aged adult cells' proliferation and delivery time of induced BMSCs and ADSCs can be 120 hrs in 4 degrees C serum. PMID- 29531283 TI - Interfacial Phenomenon and Nanostructural Enhancements in Palladium Loaded Lanthanum Hydroxide Nanorods for Heterogeneous Catalytic Applications. AB - Hydrogenation and cross-coupling reactions are of great importance for industrial applications and noble metal based catalysts are filling the void since the last few decades. However, the high cost of noble metals and poor recycling performance provides an opportunity for chemists to look for alternate options. Herein, we present the use of Lanthanum hydroxide as support for loading ultra low amount of Pd for hydrogenation and cross-coupling reactions. Lanthanum hydroxide having controlled morphologies comprises exposed crystallographic facets which interact with small sized Pd NPs and shows versatile and effective catalytic performance. The reduction of 4-NP over Pd/La(OH)3 was achieved within very short time (45s) with a rate constant of 60 * 10-3 s-1. The hydrogenation of styrene was also accomplished within 1 hour with much high TOF value (3260 h-1). Moreover, the Suzuki cross-couplings of iodobenzene and phenyl boronic acid into biphenyl completed within 35 min with a TOF value of 389 h-1. The strong interfacial electronic communication regulates electron density of catalytic sites and lowers energy for adsorption of reactant and subsequently conversion into products. Moreover, abundant hydroxyl groups on the surface of La(OH)3, large surface area, mono-dispersity and ultra-small size of Pd NPs also favors the efficient conversion of reactants. PMID- 29531284 TI - Natural turn measures predict recurrent falls in community-dwelling older adults: a longitudinal cohort study. AB - Although turning has been reported as one of the leading activities performed during a fall, and falls during turning result in 8-times more hip fractures than falls during linear gait, the quantity and quality of turns resulting in falls remain unknown since turns are rarely assessed during activities of daily living. 160 community-dwelling older adults were monitored for one week using smartphone technology. Turn measures and activity rates were quantified. Fall incidence within 12 months from continuous monitoring defined fall status, with 7/153 prospective fallers/non-fallers. Based on the analysis of 718,582 turns, prospective fallers turned less frequently, took longer to turn, and were less consistent in turn angle (p = 0.007, 0.025, and 0.038, respectively). Prospective fallers also walked slower and spent less time walking and turning and more time engaged in sedentary behavior (p = 0.043, 0.012, and 0.015, respectively). Individuals experiencing decline in the control of gait and/or turning may attempt to reduce their risk of falling by limiting their exposure and implementing cautionary movement strategies while turning. Since there was no difference in the overall active rate between prospective fallers and non fallers, impaired gait and turning ability, specifically, may attribute to elevated fall risk within this cohort. PMID- 29531285 TI - Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. AB - Advances in therapy in recent years have led investigators to challenge the dogma that multiple myeloma (MM) is incurable. We assessed overall (OS) and progression free survival (PFS) of young patients ( <= 50 years) with MM and compared outcomes with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma (HL). All patients <= 50 years with newly diagnosed MM (n = 212), FL (n = 168), DLBCL (n = 195), and HL (n = 233) between 1 January 2005 and 31 December 2015 were included. Observed vs. expected survival was summarized by standardized mortality ratios (SMR). Compared to the background US population, excess mortality risk was seen at diagnosis in all four cancers, SMR 19.5 (15.2 24.5) in MM, 4.2 (2.3-7.2) in FL, 13.0 (9.2-18.4) in DLBCL, and 5.2 (2.6-9.3) in HL. We reasoned that cure would most likely occur in the first 3 years after diagnosis and be reflected by an overall survival probability similar to the background population. From the 36-month landmark, excess mortality risk was seen in MM (SMR 20.7 [14.7-28.3]) and FL (SMR 3.8 [1.5-7.8]), but not with DLBCL (SMR 3.1 [0.8-8.0]) or HL (SMR 0.9 [0.0-5.1]). MM patients have 20-fold excess mortality risk compared to the background population at diagnosis and at 3 years after diagnosis, suggesting that MM remains an incurable cancer. PMID- 29531286 TI - Combined effects of elevated temperature and CO2 enhance threat from low temperature hazard to winter wheat growth in North China. AB - We examined the growth and yield of winter wheat (Triticum aestivum) in response to the predicted elevated CO2 concentration and temperature to determine the mechanism of the combined impacts in North China Plain. An elevated treatment (CO2: 600 MUmol mol-1, temperature: +2.5~3.0 degrees C, ECTI) and a control treatment (ambient CO2 and temperature, CK) were conducted in open-top chambers from October 2013 to June 2016. Post-winter growth stages of winter wheat largely advanced and shifted to a cooler period of nature season under combined impact of elevated CO2 and temperature during the entire growing season. The mean temperature and accumulated photosynthetic active radiations (PAR) over the post winter growing period in ECTI decreased by 0.8-1.5 degrees C and 10-13%, respectively compared with that in CK, negatively impacted winter wheat growth. As a result, winter wheat in ECTI suffered from low temperature hazards during critical period of floret development and anthesis and grain number per ear was reduced by 10-31% in the three years. Although 1000-kernel weight in ECTI increased by 8-9% mainly due to elevated CO2, increasing CO2 concentration from 400 to 600 MUmol mol-1 throughout the growth stage was not able to offset the adverse effect of warming on winter wheat growth and yield. PMID- 29531288 TI - Global delay in nascent strand DNA methylation. AB - Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced lag between the copying of genetic and epigenetic information in embryonic stem cells that is reconsolidated within hours to accomplish faithful mitotic transmission. Populations of arrested cells show a global reduction of lag-induced intermediate CpG methylation when compared to proliferating cells, whereas sites of transcription factor engagement appear cell-cycle invariant. Alternatively, the cancer cell line HCT116 preserves global epigenetic heterogeneity independently of cell-cycle arrest. Taken together, our data suggest that heterogeneous methylation largely reflects asynchronous proliferation, but is intrinsic to actively engaged cis-regulatory elements and cancer. PMID- 29531290 TI - Risk of incident chronic kidney disease is better reduced by bedtime than upon awakening ingestion of hypertension medications. AB - This trial investigated whether therapy with the entire daily dose of >=1 hypertension medications at bedtime exerts a greater reduction in the risk of incident chronic kidney disease (CKD) than therapy with all medications upon awakening. We conducted a prospective, open-label, blinded endpoint trial of 2078 hypertensive patients without CKD (1017 men/1061 women, 53.6 +/- 13.7 years of age) randomized to ingest all their prescribed hypertension medications upon awakening (n = 1041) or the entire daily dose of >=1 of those medications at bedtime (n = 1037). During a 5.9-year median follow-up, 368 participants developed CKD. Patients of the bedtime, compared with the morning, treatment group showed (i) significantly lower asleep blood pressure (BP) mean, greater sleep-time relative BP decline, and attenuated prevalence of non-dipping at the final evaluation (38 vs. 55%; P < 0.001); and (ii) a significantly lower hazard ratio of CKD, adjusted for the significant influential characteristics of age, serum creatinine, urinary albumin, type 2 diabetes, previous cardiovascular event, asleep systolic BP mean, and sleep-time relative systolic BP decline (0.27 (95% confidence interval: 0.21-0.36); event-rate 8.3 vs. 27.1% in the bedtime and morning-treatment groups; P < 0.001). Greater benefit was observed for bedtime than awakening treatment, with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In hypertensive patients without CKD, ingestion of >=1 BP-lowering medications at bedtime, mainly those modulating or blocking the effects of angiotensin II, compared with ingestion of all such medications upon awakening, resulted in improved ambulatory BP control (significant further decrease of asleep BP and enhanced sleep-time relative BP decline) and reduced risk of incident CKD. PMID- 29531289 TI - Microbial metagenome of urinary tract infection. AB - Urine culture and microscopy techniques are used to profile the bacterial species present in urinary tract infections. To gain insight into the urinary flora, we analyzed clinical laboratory features and the microbial metagenome of 121 clean catch urine samples. 16S rDNA gene signatures were successfully obtained for 116 participants, while metagenome sequencing data was successfully generated for samples from 49 participants. Although 16S rDNA sequencing was more sensitive, metagenome sequencing allowed for a more comprehensive and unbiased representation of the microbial flora, including eukarya and viral pathogens, and of bacterial virulence factors. Urine samples positive by metagenome sequencing contained a plethora of bacterial (median 41 genera/sample), eukarya (median 2 species/sample) and viral sequences (median 3 viruses/sample). Genomic analyses suggested cases of infection with potential pathogens that are often missed during routine urine culture due to species specific growth requirements. While conventional microbiological methods are inadequate to identify a large diversity of microbial species that are present in urine, genomic approaches appear to more comprehensively and quantitatively describe the urinary microbiome. PMID- 29531287 TI - Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2. AB - Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the 247DLIIKGISVHI257 segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs. These associations include seven distinct interfaces displaying five different symmetry classes of steric zippers. Additionally, we find that this segment can adopt three different backbone conformations that contribute to its polymorphic capabilities. The polymorphic nature of this segment illustrates at the molecular level how amyloid proteins can form diverse fibril structures. PMID- 29531291 TI - Arterial stiffness in end-stage renal disease-pathogenesis, clinical epidemiology, and therapeutic potentials. AB - Arterial stiffness is an important risk factor for cardiovascular morbidity and mortality in patients with end-stage renal disease (ESRD). Arterial stiffness aggravates cardiovascular risk via multiple pathways, such as augmentation of aortic systolic pressure, subendocardial hypoperfusion, and excess pulsatile energy transmission from macro- to microcirculation. Pathogenesis of the arteriosclerotic process in ESRD is complex and not yet fully understood. Several factors unique to ESRD, such as mineral metabolism disturbances, vascular calcifications, formation of advanced glycation end-products, and acute and chronic volume overload, are proposed to play a particular role in the progression of arteriosclerosis in ESRD. As these and other mechanistic pathways of arterial stiffening in ESRD are elucidated, there is hope that this knowledge will be translated into novel therapeutic interventions targeting arterial stiffness. In the meantime, blood pressure (BP) lowering via strict volume control and appropriate use of antihypertensive drugs is a fundamental step in reversing accelerated arterial stiffening and modifying the cardiovascular risk profile of ESRD patients. In this article, we review the pathogenesis, clinical epidemiology, and therapies targeting arterial stiffness in ESRD, discussing recent advances and high-priority goals of future research in these important areas. PMID- 29531292 TI - Label-free analysis of physiological hyaluronan size distribution with a solid state nanopore sensor. AB - Hyaluronan (or hyaluronic acid, HA) is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication. Both the abundance and size distribution of HA in biological fluids are recognized as robust indicators of various pathologies and disease progressions. However, such analyses remain challenging because conventional methods are not sufficiently sensitive, have limited dynamic range, and/or are only semi-quantitative. Here we demonstrate label-free detection and molecular weight discrimination of HA with a solid-state nanopore sensor. We first employ synthetic HA polymers to validate the measurement approach and then use the platform to determine the size distribution of as little as 10 ng of HA extracted directly from synovial fluid in an equine model of osteoarthritis. Our results establish a quantitative method for assessment of a significant molecular biomarker that bridges a gap in the current state of the art. PMID- 29531294 TI - Modulation of functional pendant chains within poly(ethylene glycol) hydrogels for refined control of protein release. AB - Hydrogels are highly attractive delivery vehicles for therapeutic proteins. Their innate biocompatibility, hydrophilicity and aqueous permeability allow stable encapsulation and release of proteins. The release rates also can be controlled simply by altering the crosslinking density of the polymeric network. However, the crosslinking density also influences the mechanical properties of hydrogels, generally opposite to the permeability. In addition, the release of larger proteins may be hindered below critically diminished porosity determined by the crosslinking density. Herein, the physical properties of the hydrogels are tuned by presenting functional pendant chains, independent of crosslinking density. Heterobifunctional poly(ethylene glycol) monomethacrylate (PEGMA) with various end functional groups is synthesized and copolymerized with PEG dimethacrylate (PEGDA) to engineer PEG hydrogels with pendant PEG chains. The pendant chains of the PEG hydrogels consisting of sulfonate, trimethylammonium chloride, and phenyl groups are utilized to provide negative charge, positive charge and hydrophobicity, respectively, to the hydrogels. The release rates of proteins with different isoelectric points are controlled in a wide range by the type and the density of functional pendant chains via electrostatic and hydrophobic interactions. PMID- 29531293 TI - Proteome-wide mapping of immune features onto Plasmodium protein three dimensional structures. AB - Humoral immune responses against the malaria parasite are an important component of a protective immune response. Antibodies are often directed towards conformational epitopes, and the native structure of the antigenic region is usually critical for antibody recognition. We examined the structural features of various Plasmodium antigens that may impact on epitope location, by performing a comprehensive analysis of known and modelled structures from P. falciparum. Examining the location of known polymorphisms over all available structures, we observed a strong propensity for polymorphic residues to be exposed on the surface and to occur in particular secondary structure segments such as hydrogen bonded turns. We also utilised established prediction algorithms for B-cell epitopes and MHC class II binding peptides, examining predicted epitopes in relation to known polymorphic sites within structured regions. Finally, we used the available structures to examine polymorphic hotspots and Tajima's D values using a spatial averaging approach. We identified a region of PfAMA1 involving both domains II and III under a high degree of balancing selection relative to the rest of the protein. In summary, we developed general methods for examining how sequence-based features relate to one another in three-dimensional space and applied these methods to key P. falciparum antigens. PMID- 29531295 TI - TryTransDB: A web-based resource for transport proteins in Trypanosomatidae. AB - TryTransDB is a web-based resource that stores transport protein data which can be retrieved using a standalone BLAST tool. We have attempted to create an integrated database that can be a one-stop shop for the researchers working with transport proteins of Trypanosomatidae family. TryTransDB (Trypanosomatidae Transport Protein Database) is a web based comprehensive resource that can fire a BLAST search against most of the transport protein sequences (protein and nucleotide) from Trypanosomatidae family organisms. This web resource further allows to compute a phylogenetic tree by performing multiple sequence alignment (MSA) using CLUSTALW suite embedded in it. Also, cross-linking to other databases helps in gathering more information for a certain transport protein in a single website. PMID- 29531296 TI - miR-129-5p targets Wnt5a to block PKC/ERK/NF-kappaB and JNK pathways in glioblastoma. AB - Therapeutic application of microRNAs (miRNAs) in Wnt-driven glioma has been valuable; however, their specific roles and mechanisms have not been completely investigated. Real-time quantitative PCR (RT-qPCR) was used to analyse the expression of microRNA-129-5p (miR-129-5p) in human glioma samples. Cell-Counting Kit 8 (CCK-8), flow cytometry, EdU, angiogenesis, Transwell invasion, wound healing, in vitro 3D migration and neurosphere formation assays were employed to assess the role of miR-129-5p in glioblastoma multiforme (GBM) cells. Moreover, we performed the luciferase reporter assay and the RNA-ChIP (chromatin immunoprecipitation) assay to confirm whether Wnt5a was a direct target of miR 129-5p. We also confirmed the correlation between the expression profile of miR 129-5p and Wnt5a in glioma patients from the Chinese Glioma Genome Atlas (CGGA) and investigated the overall survival of GBM patients using two data sets, namely, TCGA and GSE16011, according to their Wnt5a expression status. MiR-129-5p expression levels were downregulated and inversely correlated with Wnt5a expression levels in CGGA glioma patients. Restored expression of miR-129-5p blocked GBM cell proliferation, invasion, migration, angiogenesis, neurosphere formation and resistance to temozolomide. We reported that miR-129-5p directly targeted Wnt5a in glioma. Furthermore, we observed that overexpression of miR-129 5p inhibited the expression of Wnt5a, thus blocking the protein kinase C(PKC)/ERK/NF-kappaB and JNK pathways. Inhibiting Wnt5a rescued the effects of miR-129-5p loss and increased Wnt5a expression was associated with reduced overall survival of GBM patients. We also demonstrated the inhibitory effect of miR-129-5p on tumour growth in GBM using an in vivo model. The miR-129-5p/Wnt5a axis-mediated PKC/ERK/NF-kappaB and JNK pathways have therapeutic potential in GBM treatment. PMID- 29531297 TI - Memory shapes visual search strategies in large-scale environments. AB - Search is a central visual function. Most of what is known about search derives from experiments where subjects view 2D displays on computer monitors. In the natural world, however, search involves movement of the body in large-scale spatial contexts, and it is unclear how this might affect search strategies. In this experiment, we explore the nature of memory representations developed when searching in an immersive virtual environment. By manipulating target location, we demonstrate that search depends on episodic spatial memory as well as learnt spatial priors. Subjects rapidly learned the large-scale structure of the space, with shorter paths and less head rotation to find targets. These results suggest that spatial memory of the global structure allows a search strategy that involves efficient attention allocation based on the relevance of scene regions. Thus spatial memory may allow less energetically costly search strategies. PMID- 29531298 TI - Author Correction: Changes in regional heatwave characteristics as a function of increasing global temperature. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29531299 TI - Feasibility and patient acceptability of a novel artificial intelligence-based screening model for diabetic retinopathy at endocrinology outpatient services: a pilot study. AB - The purpose of this study is to evaluate the feasibility and patient acceptability of a novel artificial intelligence (AI)-based diabetic retinopathy (DR) screening model within endocrinology outpatient settings. Adults with diabetes were recruited from two urban endocrinology outpatient clinics and single-field, non-mydriatic fundus photographs were taken and graded for referable DR ( >= pre-proliferative DR). Each participant underwent; (1) automated screening model; where a deep learning algorithm (DLA) provided real time reporting of results; and (2) manual model where retinal images were transferred to a retinal grading centre and manual grading outcomes were distributed to the patient within 2 weeks of assessment. Participants completed a questionnaire on the day of examination and 1-month following assessment to determine overall satisfaction and the preferred model of care. In total, 96 participants were screened for DR and the mean assessment time for automated screening was 6.9 minutes. Ninety-six percent of participants reported that they were either satisfied or very satisfied with the automated screening model and 78% reported that they preferred the automated model over manual. The sensitivity and specificity of the DLA for correct referral was 92.3% and 93.7%, respectively. AI-based DR screening in endocrinology outpatient settings appears to be feasible and well accepted by patients. PMID- 29531301 TI - Explaining the discontinuation of a non-tobacco nicotine project at Philip Morris: obstacles to innovation. AB - This paper investigates the fate of the Capillary Aerosol Generator (CAG), a nicotine aerosol device resembling modern e-cigarettes, developed by Philip Morris (PM) in 1994. A debate has emerged as to why this product never made it to market. In Donovan et al. v. Philip Morris USA, Inc., the sides presented opposing views in their arguments. To explore the reasons for CAG abandonment, we searched the Truth Tobacco Industry Documents database for key terms including 'Capillary Aerosol,' 'Project LEAP' (the project under which the CAG was housed), and 'Tony Howell' (CAG inventor). The results show that regulatory, legal, and political concerns deterred CAG development. A lack of progress even after these concerns had abated seems to reveal a larger reluctance to innovate non-tobacco products-perhaps due to concerns about competing against tobacco cigarettes. We also explored additional explanations such as technological barriers and lack of consumer interest. PMID- 29531302 TI - Global oral health in the framework of the Global Charter for the Public's Health. AB - Oral diseases are a neglected epidemic affecting all ages globally and can substantially impact overall health and well-being. Even though most oral diseases are preventable and share major risk factors with other non-communicable diseases, integration of oral health into public health systems is still limited in both clinical and health policy perspectives. This Viewpoint aims to highlight oral health from a global health perspective, calling for all public health leaders to advocate for oral health of all. We strongly recommend oral health as an essential part of public health policy and oral health-related activities to be aligned with the Global Charter for the Public's Health Framework. PMID- 29531303 TI - The relationship between health policy and public health interventions: a case study of the DRIVE project to "end" the HIV epidemic among people who inject drugs in Haiphong, Vietnam. AB - We present a case study of the effects of health policies on the implementation and potential outcomes of a public health intervention, using the DRIVE project, that aims to 'end' the HIV epidemic among people who inject drugs in Haiphong, Vietnam. DRIVE's success depends on two policy transitions: (1) integration of donor-funded HIV outpatient clinics into public health clinics and expansion of social health insurance; (2) implementation of a "Renovation Plan" for substance use treatment. Interviews and focus group discussions with key informants and review of policy documents and clinic data reveal that both policy transitions are underway but face challenges. DRIVE promises to show how evolving policy affects health interventions and how advocacy based on project data can improve policy. Broad lessons include the importance of clear and consistent policies, vigorous enforcement, and adequate funding of promulgated policies. PMID- 29531304 TI - Road death trend in the United States: implied effects of prevention. AB - This study estimates road deaths prevented by U.S. vehicle safety regulations, state laws, and other efforts based on comparison of actual deaths to those predicted from temperature and precipitation effects on exposure, migration to warmer areas, population growth, median age of the population, and vehicle mix. Logistic regression of risk factors predictive of road deaths in 1961, prior to the adoption of federal vehicle safety regulations, state behavioral change laws, and other preventive efforts were used to predict deaths in subsequent years given the changing prevalence of the risk factors from 1962 to 2015. The included risk factors are strong predictors of road death risk. Without the preventive efforts, an additional 5.8 million road deaths would likely have occurred in the U.S. from the initiation of federal safety standards for new vehicles in 1968 through 2015. PMID- 29531305 TI - From mother to child: the effects of prenatal maternal passive smoking on academic outcomes in the United States. AB - This is the first study in the United States to examine the effect of prenatal maternal passive smoking on student learning outcomes. We use a national sample of children in combination with ordinary least squares regression and matching methods to examine this effect. We find evidence that prenatal maternal exposure to secondhand smoke leads to lower academic performance in language/literacy and mathematics in the later years of elementary school, particularly for mothers who did not actively smoke while pregnant. Our results provide persuasive empirical evidence in support of public policies that address prenatal maternal exposure to secondhand smoking. PMID- 29531306 TI - Visualization method for stress-field evolution during rapid crack propagation using 3D printing and photoelastic testing techniques. AB - Quantitative visualization and characterization of stress-field evolution during fracture rapid growth is critical for understanding the mechanisms that govern the deformation and failure of solids in various engineering applications. However, the direct capture and accurate characterization of a rapidly-changing stress field during crack propagation remains a challenge. We report an experimental method to quantitatively visualize and characterize rapid evolution of the stress-field during crack propagation in a transparent disc model containing a penetrating fusiform crack. Three-dimensional (3D) printing technology and a stress-sensitive photopolymer resin were adopted to produce the disc model and to alleviate the residual processing stress that usually blurs the dynamic stress field due to overlap. A photoelastic testing system that synchronized a high-speed digital camera and a pulsed laser with a nanosecond full width at half maximum (FWHM) was used to capture the rapid evolution of the stress field in the vicinity of crack tips. The results show that the proposed method is suitable to directly visualize and quantitatively characterize the stress-field evolution during crack rapid propagation. It is proved that the crack propagation velocity is strongly governed by the stress field around the crack tips. PMID- 29531307 TI - Mucosal-luminal interface proteomics reveals biomarkers of pediatric inflammatory bowel disease-associated colitis. AB - OBJECTIVE: Improved biomarkers are an unmet clinical need for suspected inflammatory bowel disease (IBD). Need is greatest for children, since current biomarkers suffers from low specificity, particularly in this population; thus, invasive testing methods, with the accompanying risk of complications, are necessary. Additionally, current biomarkers do not delineate disease extent assessment for ulcerative colitis (UC), a factor involved in therapeutic decisions. METHODS: Intestinal mucosal-luminal interface (MLI) aspirates from the ascending colon (AC) and descending colon (DC) were collected during diagnostic colonoscopy from treatment-naive children. The MLI proteomes of 18 non-IBD and 42 IBD patients were analyzed by liquid chromatography mass spectrometry. Analyses of proteomic data generated protein panels distinguishing IBD from non-IBD and pancolitis from non-pancolitis (UC disease extent). Select protein biomarkers were evaluated in stool samples by enzyme-linked immunosorbent assay (n = 24). RESULTS: A panel of four proteins discriminated active IBD from non-IBD (discovery cohort) with a sensitivity of 0.954 (95% confidence interval (CI): 0.772-0.999) and >0.999 (95% CI: 0.824-1.00) for the AC and DC, respectively, and a specificity of >0.999 (AC, 95% CI: 0.815-1.00; DC, 95% CI:0.692-1.00) for both the AC and DC. A separate panel of four proteins distinguished pancolitis from non-pancolitis in UC patients with sensitivity >0.999 (95% CI: 0.590-1.00) and specificity >0.999 (95% CI: 0.715-1.00). Catalase (p < 0.0001) and LTA4H (p = 0.0002) were elevated in IBD stool samples compared to non-IBD stool samples. CONCLUSION: This study identified panels of proteins that have significantly different expression levels and contribute to accurate IBD diagnosis and disease extent characterization in children with UC. Biomarkers identified from the MLI demonstrate transferable results in stool samples. PMID- 29531308 TI - Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. AB - Ageing of haematopoietic stem cells (HSCs) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation; yet, how ageing impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR, leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non cell autonomous, as ATM signalling and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantated into young recipients. These data indicate that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition. PMID- 29531309 TI - Daughter-cell-specific modulation of nuclear pore complexes controls cell cycle entry during asymmetric division. AB - The acquisition of cellular identity is coupled to changes in the nuclear periphery and nuclear pore complexes (NPCs). Whether and how these changes determine cell fate remain unclear. We have uncovered a mechanism that regulates NPC acetylation to direct cell fate after asymmetric division in budding yeast. The lysine deacetylase Hos3 associates specifically with daughter cell NPCs during mitosis to delay cell cycle entry (Start). Hos3-dependent deacetylation of nuclear basket and central channel nucleoporins establishes daughter-cell specific nuclear accumulation of the transcriptional repressor Whi5 during anaphase and perinuclear silencing of the G1/S cyclin gene CLN2 in the following G1 phase. Hos3-dependent coordination of both events restrains Start in daughter, but not in mother, cells. We propose that deacetylation modulates transport dependent and transport-independent functions of NPCs, leading to differential cell cycle progression in mother and daughter cells. Similar mechanisms might regulate NPC functions in specific cell types and/or cell cycle stages in multicellular organisms. PMID- 29531311 TI - Submarine groundwater discharge derived strontium from the Bengal Basin traced in Bay of Bengal water samples. AB - Evaluating the submarine groundwater discharge (SGD) derived strontium (Sr) flux from the Bengal Basin to the Bay of Bengal (BoB) and determining its isotopic composition is crucial for understanding the marine Sr isotopic evolution over time. Measurements of spatially and temporally distributed water samples collected from the BoB show radiogenic 87Sr/86Sr, high Sr, calcium (Ca) concentrations and high salinity in samples collected dominantly from 100-120 m depth, which can be explained only by the contribution of saline groundwater from the Bengal Basin. These results provide a direct evidence of the SGD-Sr flux to the BoB. This SGD-Sr flux is however, spatially heterogeneous and using conservative hydrological estimates of the SGD flux to the BoB, we suggest a SGD Sr flux of 13.5-40.5 * 105 mol/yr to the BoB. Mass balance calculations using Sr concentrations and 87Sr/86Sr suggest up to 7% contribution of SGD to the 100-120 m BoB water samples. The identification of SGD at 100-120 m depth also provides an explanation for the anomalous variations in barium (Ba) concentrations and the delta18O-salinity relationship in intermediate depths of the BoB. PMID- 29531310 TI - NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming. AB - Somatic cell reprogramming by exogenous factors requires cooperation with transcriptional co-activators and co-repressors to effectively remodel the epigenetic environment. How this interplay is regulated remains poorly understood. Here, we demonstrate that NCoR/SMRT co-repressors bind to pluripotency loci to create a barrier to reprogramming with the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC), and consequently, suppressing NCoR/SMRT significantly enhances reprogramming efficiency and kinetics. The core epigenetic subunit of the NCoR/SMRT complex, histone deacetylase 3 (HDAC3), contributes to the effects of NCoR/SMRT by inducing histone deacetylation at pluripotency loci. Among the Yamanaka factors, recruitment of NCoR/SMRT-HDAC3 to genomic loci is mostly facilitated by c-MYC. Hence, we describe how c-MYC is beneficial for the early phase of reprogramming but deleterious later. Overall, we uncover a role for NCoR/SMRT co-repressors in reprogramming and propose a dual function for c MYC in this process. PMID- 29531312 TI - Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. AB - The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets. PMID- 29531313 TI - CRISPR-Cas12a has both cis- and trans-cleavage activities on single-stranded DNA. PMID- 29531314 TI - Early- and Long-term Outcomes of Cardiovascular Surgery via Minimal Right Vertical Infra-axillary Thoracotomy: A 15-year Study of 1,126 Patients. AB - This study reviews our results and experience with cardiothoracic surgery via RVIAT over the past 15 years. This retrospective overview summarises our results, describing the early and late clinical outcomes of 1,126 patients, including 370 ASD closures, 488 VSD closures and 268 valve surgeries, at a single center between October 2001 and December 2015. The mean follow-up time was 52 +/- 35 months (range 8-120 months). The mean incision length was 6 +/- 2.22 cm (range 3.9-8.9 cm). No patient required conversion to median sternotomy. All patients were satisfied with the cosmetic results at the follow-up assessment. No chest deformity or asymmetrical development of the breast was observed. Although there was no severe morbidity and operative mortality, ten late deaths occurred, 8 of which were due to cardiac causes and the other 2 to non-cardiac causes. RVIAT offers encouraging short- and long-term patient survival results and is a safe and reproducible approach with excellent late results. RVIAT should be considered as an alternative to conventional median sternotomy. PMID- 29531315 TI - Author Correction: Identification of Genetically Important Individuals of the Rediscovered Floreana Galapagos Giant Tortoise (Chelonoidis elephantopus) Provides Founders for Species Restoration Program. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29531316 TI - Rapid, real time pathology review for ECOG/ACRIN 1412: a novel and successful paradigm for future lymphoma clinical trials in the precision medicine era. AB - ECOG/ACRIN 1412 (E1412) is a randomized, phase II open-label study of lenalidomide/RCHOP vs. RCHOP alone in adults with newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) and requires NanoString gene expression profiling (GEP) for cell-of-origin testing. Because of high ineligibility rate on retrospective expert central pathology review (ECPR), real-time (RT) ECPR was instituted to confirm diagnosis and ensure adequate tissue for GEP prior to study enrollment. Goal was notification of eligibility within 2 working days (WD). Initially, 208 patients were enrolled, 74 (35.6%) of whom were deemed ineligible by retrospective ECPR. After initiation of RT-ECPR, 219 patients were registered. Of these, 73 (33.3%) were ineligible and were declined enrollment; 47 (21.5% of total) had an ineligible diagnosis on RT-ECPR, and 26 (11.9% of total) had inadequate tissue. Because the 73 ineligible patients were never enrolled, no study slots were "lost" during this phase. Notification of eligibility occurred in an average of 1 WD (Range 0-4) with 97.3% within 2 WD. This novel RT-ECPR serves as a model for future lymphoma trials. Real-time ECPR can help to reduce costs and ensure that study slots accurately reflect the targeted population. In the precision-medicine era, rapid collection of relevant pathology/biomarker data is essential to trial success. PMID- 29531317 TI - Time-lapse observation of stepwise regression of Erk activity in zebrafish presomitic mesoderm. AB - During somite segmentation, clock genes oscillate within the posterior presomitic mesoderm (PSM). The temporal information ties up with the posteriorly moving FGF gradient, leading to the formation of a presumptive somite within the PSM. We previously investigated Erk activity downstream of FGF signaling by collecting stained zebrafish embryos, and discovered that the steep gradient of Erk activity was generated in the PSM, and the Erk activity border regularly shifted in a stepwise manner. However, since these interpretations come from static analyses, we needed to firmly confirm them by applying an analysis that has higher spatiotemporal resolutions. Here we developed a live imaging system for Erk activity in zebrafish embryos, using a Forster resonance energy transfer (FRET) based Erk biosensor. With this system, we firmly showed that Erk activity exhibits stepwise regression within the PSM. Although our static analyses could not detect the stepwise pattern of Erk activity in clock-deficient embryos, our system revealed that, in clock-deficient embryos, the stepwise regression of Erk activity occurs at an irregular timing, eventually leading to formation of irregularly-sized somites. Therefore, our system overcame the limitation of static analyses and revealed that clock-dependent spatiotemporal regulation of Erk is required for proper somitogenesis in zebrafish. PMID- 29531318 TI - Humans thrived in South Africa through the Toba eruption about 74,000 years ago. AB - Approximately 74 thousand years ago (ka), the Toba caldera erupted in Sumatra. Since the magnitude of this eruption was first established, its effects on climate, environment and humans have been debated. Here we describe the discovery of microscopic glass shards characteristic of the Youngest Toba Tuff-ashfall from the Toba eruption-in two archaeological sites on the south coast of South Africa, a region in which there is evidence for early human behavioural complexity. An independently derived dating model supports a date of approximately 74 ka for the sediments containing the Youngest Toba Tuff glass shards. By defining the input of shards at both sites, which are located nine kilometres apart, we are able to establish a close temporal correlation between them. Our high-resolution excavation and sampling technique enable exact comparisons between the input of Youngest Toba Tuff glass shards and the evidence for human occupation. Humans in this region thrived through the Toba event and the ensuing full glacial conditions, perhaps as a combined result of the uniquely rich resource base of the region and fully evolved modern human adaptation. PMID- 29531319 TI - A single population of red globular clusters around the massive compact galaxy NGC 1277. AB - Massive galaxies are thought to form in two phases: an initial collapse of gas and giant burst of central star formation, followed by the later accretion of material that builds up their stellar and dark-matter haloes. The systems of globular clusters within such galaxies are believed to form in a similar manner. The initial central burst forms metal-rich (spectrally red) clusters, whereas more metal-poor (spectrally blue) clusters are brought in by the later accretion of less-massive satellites. This formation process is thought to result in the multimodal optical colour distributions that are seen in the globular cluster systems of massive galaxies. Here we report optical observations of the massive relic-galaxy candidate NGC 1277-a nearby, un-evolved example of a high-redshift 'red nugget' galaxy. We find that the optical colour distribution of the cluster system of NGC 1277 is unimodal and entirely red. This finding is in strong contrast to other galaxies of similar and larger stellar mass, the cluster systems of which always exhibit (and are generally dominated by) blue clusters. We argue that the colour distribution of the cluster system of NGC 1277 indicates that the galaxy has undergone little (if any) mass accretion after its initial collapse, and use simulations of possible merger histories to show that the stellar mass due to accretion is probably at most ten per cent of the total stellar mass of the galaxy. These results confirm that NGC 1277 is a genuine relic galaxy and demonstrate that blue clusters constitute an accreted population in present-day massive galaxies. PMID- 29531320 TI - A Highly Potent and Broadly Neutralizing H1 Influenza-Specific Human Monoclonal Antibody. AB - Influenza's propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1. KPF1 has broad and potent neutralizing activity against H1 influenza viruses, and recognized 83% of all H1 isolates tested, including the pandemic 1918 H1. Prophylactically, KPF1 treatment resulted in 100% survival of mice from lethal challenge with multiple H1 influenza strains and when given as late as 72 h after challenge with A/California/04/2009 H1N1, resulted in 80% survival. KPF1 recognizes a novel epitope in the HA globular head, which includes a highly conserved amino acid, between the Ca and Cb antigenic sites. Although recent HA stalk-specific mAbs have broader reactivity, their potency is substantially limited, suggesting that cocktails of broadly reactive and highly potent HA globular head-specific mAbs, like KPF1, may have greater clinical feasibility for the treatment of influenza infections. PMID- 29531322 TI - From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation. AB - Multiple clinical studies have revealed a link between genomic instability and response to anti-PD-1/PD-L1 therapy in cancer management. A recent study has revealed an important role for the ATR/Chk1 DNA damage checkpoint in regulating PD-L1 expression, raising important clinical and translational questions for therapy selection and study design. PMID- 29531321 TI - Development of the social brain from age three to twelve years. AB - Human adults recruit distinct networks of brain regions to think about the bodies and minds of others. This study characterizes the development of these networks, and tests for relationships between neural development and behavioral changes in reasoning about others' minds ('theory of mind', ToM). A large sample of children (n = 122, 3-12 years), and adults (n = 33), watched a short movie while undergoing fMRI. The movie highlights the characters' bodily sensations (often pain) and mental states (beliefs, desires, emotions), and is a feasible experiment for young children. Here we report three main findings: (1) ToM and pain networks are functionally distinct by age 3 years, (2) functional specialization increases throughout childhood, and (3) functional maturity of each network is related to increasingly anti-correlated responses between the networks. Furthermore, the most studied milestone in ToM development, passing explicit false-belief tasks, does not correspond to discontinuities in the development of the social brain. PMID- 29531323 TI - Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression. AB - BACKGROUND: Zinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) and here we further characterised their prevalence, survival outcomes and transcriptome. METHODS: Bone marrow mononuclear cells from 274 BCR-ABL1-negative pre-B-ALL patients were immunophenotyped and transcriptome molecularly characterised. Transcriptomic data was analysed by principal component analysis and gene-set enrichment analysis to identify gene and pathway expression changes. RESULTS: We exclusively detect E1A associated protein p300 (EP300)-ZNF384 in 5.7% of BCR-ABL1-negative adolescent/young adult (AYA)/adult pre-B-ALL patients. EP300-ZNF384 patients do not appear to be a high-risk subgroup. Transcriptomic analysis revealed that EP300-ZNF384 samples have a distinct gene expression profile that results in the up-regulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) and cell adhesion pathways and down-regulation of cell cycle and DNA repair pathways. CONCLUSIONS: Importantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity. PMID- 29531324 TI - Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials. AB - BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs. METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials. RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615). CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents. PMID- 29531325 TI - A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours. AB - BACKGROUND: PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models. METHODS: This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion. RESULTS: Twenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)-hypertension (2), epistaxis (1)-occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNgamma, TNFalpha, IP-10 and MCP-1. CONCLUSION: PG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies. PMID- 29531326 TI - Influence of obesity-related risk factors in the aetiology of glioma. AB - BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity related factors as causes of glioma. PMID- 29531327 TI - Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study. AB - Lower performances in cognitive ability in individuals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort (N = 7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the association between cognitive performance and MDD status in a case-control, single-episode-recurrent MDD and control-recurrent MDD study design. Test scores on verbal declarative memory, executive functioning, vocabulary, and processing speed were examined. Cognitive performance measures showing a significant difference between groups were subsequently analysed for genetic associations. Those with recurrent MDD have lower processing speed versus controls and single-episode MDD (beta = -2.44, p = 3.6 * 10-04; beta = -2.86, p = 1.8 * 10-03, respectively). There were significantly higher vocabulary scores in MDD cases versus controls (beta = 0.79, p = 2.0 * 10-06), and for recurrent MDD versus controls (beta = 0.95, p = 5.8 * 10-05). Observed differences could not be linked to significant single-locus associations. Polygenic scores created from a processing speed meta-analysis GWAS explained 1% of variation in processing speed performance in the single-episode versus recurrent MDD study (p = 1.7 * 10-03) and 0.5% of variation in the control versus recurrent MDD study (p = 1.6 * 10-10). Individuals with recurrent MDD showed lower processing speed and executive function while showing higher vocabulary performance. Within MDD, persons with recurrent episodes show lower processing speed and executive function scores relative to individuals experiencing a single episode. PMID- 29531328 TI - Arabidopsis vegetative actin isoforms, AtACT2 and AtACT7, generate distinct filament arrays in living plant cells. AB - Flowering plants express multiple actin isoforms. Previous studies suggest that individual actin isoforms have specific functions; however, the subcellular localization of actin isoforms in plant cells remains obscure. Here, we transiently expressed and observed major Arabidopsis vegetative actin isoforms, AtACT2 and AtACT7, as fluorescent-fusion proteins. By optimizing the linker sequence between fluorescent protein and actin, we succeeded in observing filaments that contained these expressed actin isoforms fused with green fluorescent protein (GFP) in Arabidopsis protoplasts. Different colored fluorescent proteins fused with AtACT2 and AtACT7 and co-expressed in Nicotiana benthamiana mesophyll cells co-polymerized in a segregated manner along filaments. In epidermal cells, surprisingly, AtACT2 and AtACT7 tended to polymerize into different types of filaments. AtACT2 was incorporated into thinner filaments, whereas AtACT7 was incorporated into thick bundles. We conclude that different actin isoforms are capable of constructing unique filament arrays, depending on the cell type or tissue. Interestingly, staining patterns induced by two indirect actin filament probes, Lifeact and mTalin1, were different between filaments containing AtACT2 and those containing AtACT7. We suggest that filaments containing different actin isoforms bind specific actin binding proteins in vivo, since the two probes comprise actin-binding domains from different actin-binding proteins. PMID- 29531329 TI - Fat mass and obesity-associated (FTO) rs9939609 polymorphism modifies the relationship between body mass index and affective symptoms through the life course: a prospective birth cohort study. AB - Although bi-directional relationships between high body mass index (BMI) and affective symptoms have been found, no study has investigated the relationships across the life course. There has also been little exploration of whether the fat mass and obesity-associated (FTO) rs9939609 single-nucleotide polymorphism (SNP) is associated with affective symptoms and/or modifies the relationship between BMI and affective symptoms. In the MRC National Survey of Health and Development (NSHD), 4556 participants had at least one measure of BMI and affective symptoms between ages 11 and 60-64 years. A structural equation modelling framework was used with the BMI trajectory fitted as latent variables representing BMI at 11, and adolescent (11-20 years), early adulthood (20-36 years) and midlife (36-53 years) change in BMI. Higher levels of adolescent emotional problems were associated with greater increases in adult BMI and greater increases in early adulthood BMI were associated with higher subsequent levels of affective symptoms in women. The rs9939609 risk variant (A allele) from 2469 participants with DNA genotyping at age 53 years showed mostly protective effect modification of these relationship. Increases in adolescent and early adulthood BMI were generally not associated with, or were associated with lower levels, of affective symptoms in the FTO risk homozygote (AA) group, but positive associations were seen in the TT group. These results suggest bi-directional relationships between higher BMI and affective symptoms across the life course in women, and that the relationship could be ameliorated by rs9939609 risk variant. PMID- 29531330 TI - Current polarity-dependent manipulation of antiferromagnetic domains. AB - Antiferromagnets have several favourable properties as active elements in spintronic devices, including ultra-fast dynamics, zero stray fields and insensitivity to external magnetic fields 1 . Tetragonal CuMnAs is a testbed system in which the antiferromagnetic order parameter can be switched reversibly at ambient conditions using electrical currents 2 . In previous experiments, orthogonal in-plane current pulses were used to induce 90 degrees rotations of antiferromagnetic domains and demonstrate the operation of all-electrical memory bits in a multi-terminal geometry 3 . Here, we demonstrate that antiferromagnetic domain walls can be manipulated to realize stable and reproducible domain changes using only two electrical contacts. This is achieved by using the polarity of the current to switch the sign of the current-induced effective field acting on the antiferromagnetic sublattices. The resulting reversible domain and domain wall reconfigurations are imaged using X-ray magnetic linear dichroism microscopy, and can also be detected electrically. Switching by domain-wall motion can occur at much lower current densities than those needed for coherent domain switching. PMID- 29531331 TI - Kinesin expands and stabilizes the GDP-microtubule lattice. AB - Kinesin-1 is a nanoscale molecular motor that walks towards the fast-growing (plus) ends of microtubules, hauling molecular cargo to specific reaction sites in cells. Kinesin-driven transport is central to the self-organization of eukaryotic cells and shows great promise as a tool for nano-engineering 1 . Recent work hints that kinesin may also play a role in modulating the stability of its microtubule track, both in vitro2,3 and in vivo 4 , but the results are conflicting5-7 and the mechanisms are unclear. Here, we report a new dimension to the kinesin-microtubule interaction, whereby strong-binding state (adenosine triphosphate (ATP)-bound and apo) kinesin-1 motor domains inhibit the shrinkage of guanosine diphosphate (GDP) microtubules by up to two orders of magnitude and expand their lattice spacing by ~1.6%. Our data reveal an unexpected mechanism by which the mechanochemical cycles of kinesin and tubulin interlock, and so allow motile kinesins to influence the structure, stability and mechanics of their microtubule track. PMID- 29531332 TI - Selective control of multiple ferroelectric switching pathways using a trailing flexoelectric field. AB - Flexoelectricity is an electromechanical coupling between electrical polarization and a strain gradient 1 that enables mechanical manipulation of polarization without applying an electrical bias2,3. Recently, flexoelectricity was directly demonstrated by mechanically switching the out-of-plane polarization of a uniaxial system with a scanning probe microscope tip3,4. However, the successful application of flexoelectricity in low-symmetry multiaxial ferroelectrics and therefore active manipulation of multiple domains via flexoelectricity have not yet been achieved. Here, we demonstrate that the symmetry-breaking flexoelectricity offers a powerful route for the selective control of multiple domain switching pathways in multiaxial ferroelectric materials. Specifically, we use a trailing flexoelectric field that is created by the motion of a mechanically loaded scanning probe microscope tip. By controlling the SPM scan direction, we can deterministically select either stable 71 degrees ferroelastic switching or 180 degrees ferroelectric switching in a multiferroic magnetoelectric BiFeO3 thin film. Phase-field simulations reveal that the amplified in-plane trailing flexoelectric field is essential for this domain engineering. Moreover, we show that mechanically switched domains have a good retention property. This work opens a new avenue for the deterministic selection of nanoscale ferroelectric domains in low-symmetry materials for non-volatile magnetoelectric devices and multilevel data storage. PMID- 29531333 TI - Author Correction: Metabolic pathway and cell adaptation mechanisms revealed through genomic, proteomic and transcription analysis of a Sphingomonas haloaromaticamans strain degrading ortho-phenylphenol. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29531334 TI - Effect of high-frequency loading and parathyroid hormone administration on peri implant bone healing and osseointegration. AB - The objective of this study is to examine the effect of low-magnitude, high frequency (LMHF) loading, and anti-osteoporosis medications such as parathyroid hormone (PTH) and bisphosphonates on peri-implant bone healing in an osteoporosis model, and to assess their combined effects on these processes. Thirteen-week-old ovariectomized rats (n = 44) were divided into three groups: PTH, alendronate, and saline. After 3 weeks of drug administration, titanium implants were inserted into the tibiae. Each group was subdivided into two groups: with or without LMHF loading via whole-body vibration (50 Hz at 0.5 g, 15 min per day, 5 days per week). Rats were killed 4 weeks following implantation. Removal torque test, micro-CT analyses (relative gray (RG) value, water = 0, and implant = 100), and histomorphometric analyses (bone-to-implant contact (BIC) and peri-implant bone formation (bone volume/tissue volume (BV/TV))) were performed. Removal torque values and BIC were significantly differed by loading and drug administration (ANOVA). Post hoc analysis showed that PTH-treated groups were significantly higher than the other drug-treated groups. BV/TV was significantly enhanced by PTH administration. In cortical bone, RG values were significantly increased by loading. In trabecular bone, however, RG values were significantly increased by PTH administration. These findings suggest that LMHF loading and PTH can act locally and additively on the bone healing process, improving the condition of implant osseointegration. PMID- 29531335 TI - Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations. AB - Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF 1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants' associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study's data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations. PMID- 29531336 TI - Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets. AB - Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease. PMID- 29531338 TI - High-sensitivity optical to microwave comparison with dual-output Mach-Zehnder modulators. AB - We demonstrate the use of two dual-output Mach-Zehnder modulators (DO-MZMs) in a direct comparison between a femtosecond (fs) pulse train and a microwave signal. Through balanced detection, the amplitude-to-phase modulation (AM-PM) conversion effect is suppressed by more than 40 dB. A cross-spectrum technique enables us to achieve a high-sensitivity phase noise measurement (-186 dBc/Hz above 10-kHz offset), which corresponds to the thermal noise of a +9 dBm carrier. This method is applied to compare a 1-GHz fs monolithic laser to a 1-GHz microwave signal generated from photodetection of a free-running 500 MHz mode-locked laser. The measured phase noise is -160 dBc/Hz at 4-kHz, -167 dBc/Hz at 10-kHz, and -180 dBc/Hz at offset frequencies above 100-kHz. The measurement is limited by the free-running 500-MHz laser's noise, the flicker noise of the modified uni traveling carrier photodiode and the thermal noise floor, not by the method itself. This method also has the potential to achieve a similar noise floor even at higher carrier frequencies. PMID- 29531337 TI - Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis. AB - Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions. PMID- 29531340 TI - Author Correction: Insights into the functionality of endophytic actinobacteria with a focus on their biosynthetic potential and secondary metabolites production. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29531339 TI - T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. AB - The hallmark function of alphabeta T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen-presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses. PMID- 29531341 TI - Effects of Amphiphilic Chitosan on Stereocomplexation and Properties of Poly(lactic acid) Nano-biocomposite. AB - This article demonstrates an elegant approach for the fabrication of high heat stable PLA using an industrially viable technique i.e. melt extrusion, which is quite challenging due to the higher viscosity of poly(lactic acid) melt. scPLA has been fabricated by melt extrusion of PLLA/PDLA using nano-amphiphilic chitosan (modified chitosan, MCH) which has been synthesized by grafting chitosan with oligomeric PLA via insitu polycondensation of L-lactic acid that possibly increases the molecular surface area and transforms it into nano-amphiphilic morphology and in turn lead to the formation of stereocomplex crystallites. The effect of MCH loading on the structural, morphological, mechanical and thermal properties of PLLA/PDLA have been investigated. The modification of chitosan and formation of stereocomplexation in PLA has been confirmed by FTIR and XRD techniques, respectively. Heat treatment has also laid a significant effect on the stereocomplexation and the degree of crystallinity of stereocomplex crystallites has been increased to ~70% for 1.5 wt % MCH content with the absence of homocrystals. The heat deflection temperature is found to be more than 140 degrees C for the biocomposite with 1.5% MCH in comparison to ~70 degrees C for pristine scPLA. The biocomposites display significant improvement in UTS and Young's modulus. PMID- 29531342 TI - Influence of the Nitrogen Content on the Carbide Transformation of AISI M42 High Speed Steels during Annealing. AB - Attempts were made to elucidate the effect of nitrogen on primary eutectic carbides in as-cast and annealed AISI M42 high-speed steel. Particular emphasis was placed on the transformation of carbides during forging and annealing in steels with different nitrogen concentrations and the influence of final carbides on the impact toughness of the steel. Microstructural observation, electrolytic extraction method, X-ray diffraction analysis, automated inclusion analysis (INCASteel), and impact toughness measurement combined with fractographic observation were conducted on the specimens. Primary M2C carbides were found to be dominant precipitates in the as-cast ingot, with a certain amount of V(C,N). Nitrogen addition promoted the formation of fibrous M2C, whereas lamellar M2C predominated in M42 steel with a low nitrogen concentration (w[N]% = 0.006). Fibrous carbides M2C tend to decompose into more stable carbides M6C and MC during forging and annealing compared to lamellar M2C. Nitrogen alloying only affected the morphologies and dimensions of carbides, but did not change the types of carbides. These improvements in the dimensions and fractions of carbides naturally increased the impact toughness of annealed steel. Hence, it was suggested that the addition of nitrogen to AISI M42 high-speed steel was required to achieve homogeneous distribution of carbides and sufficient impact toughness. PMID- 29531344 TI - Addressing discrimination and diversity in ecology is not just about implicit bias. PMID- 29531343 TI - Artificial cationic oligosaccharides for heteroduplex oligonucleotide-type drugs. AB - Heteroduplex oligonucleotides (HDOs), composed of a DNA/LNA gapmer and its complementary RNA, are a novel, promising candidates for antisense drugs. We previously reported oligodiaminogalactoses (ODAGals), designed to bind to A-type nucleic acid duplexes such as DNA/RNA and RNA/RNA duplexes. In this paper, we report oligodiguanidinogalactoses (ODGGals) as novel A-type duplex binding molecules. We aimed to study in detail applicability of ODAGals and ODGGals for additives to HDOs as an antisense drug. The effect of ODAGal4 (ODAGal 4mer) and ODGGal3 (ODGGal 3mer) on an HDO were evaluated by UV melting analyses, RNA degradation study by ribonuclease A (RNase A), and ribonuclease H (RNase H). Cleavage of a 13mer HDO by RNase A, which is considered to be the main cause of RNA degradation in serum, was effectively inhibited by the addition of only one equivalent of ODAGal4 and ODGGal3. In contrast, RNase H activity, which involves the cleavage of target RNAs by an antisense mechanism, was only slightly affected by the presence of the cationic oligosaccharides. These results suggest that ODAGal4 and ODGGal3 are useful because they could both stabilize the HDO and maintain RNase H activity of the gapmer. PMID- 29531345 TI - The demographic history and mutational load of African hunter-gatherers and farmers. AB - Understanding how deleterious genetic variation is distributed across human populations is of key importance in evolutionary biology and medical genetics. However, the impact of population size changes and gene flow on the corresponding mutational load remains a controversial topic. Here, we report high-coverage exomes from 300 rainforest hunter-gatherers and farmers of central Africa, whose distinct subsistence strategies are expected to have impacted their demographic pasts. Detailed demographic inference indicates that hunter-gatherers and farmers recently experienced population collapses and expansions, respectively, accompanied by increased gene flow. We show that the distribution of deleterious alleles across these populations is compatible with a similar efficacy of selection to remove deleterious variants with additive effects, and predict with simulations that their present-day additive mutation load is almost identical. For recessive mutations, although an increased load is predicted for hunter gatherers, this increase has probably been partially counteracted by strong gene flow from expanding farmers. Collectively, our predicted and empirical observations suggest that the impact of the recent population decline of African hunter-gatherers on their mutation load has been modest and more restrained than would be expected under a fully recessive model of dominance. PMID- 29531346 TI - Explosive diversification of marine fishes at the Cretaceous-Palaeogene boundary. AB - The Cretaceous-Palaeogene (K-Pg) mass extinction is linked to the rapid emergence of ecologically divergent higher taxa (for example, families and orders) across terrestrial vertebrates, but its impact on the diversification of marine vertebrates is less clear. Spiny-rayed fishes (Acanthomorpha) provide an ideal system for exploring the effects of the K-Pg on fish diversification, yet despite decades of morphological and molecular phylogenetic efforts, resolution of both early diverging lineages and enormously diverse subclades remains problematic. Recent multilocus studies have provided the first resolved phylogenetic backbone for acanthomorphs and suggested novel relationships among major lineages. However, these new relationships and associated timescales have not been interrogated using phylogenomic approaches. Here, we use targeted enrichment of >1,000 ultraconserved elements in conjunction with a divergence time analysis to resolve relationships among 120 major acanthomorph lineages and provide a new timescale for acanthomorph radiation. Our results include a well-supported topology that strongly resolves relationships along the acanthomorph backbone and the recovery of several new relationships within six major percomorph subclades. Divergence time analyses also reveal that crown ages for five of these subclades, and for the bulk of the species diversity in the sixth, coincide with the K-Pg boundary, with divergences between anatomically and ecologically distinctive suprafamilial clades concentrated in the first 10 million years of the Cenozoic. PMID- 29531347 TI - The origin and expansion of Pama-Nyungan languages across Australia. AB - It remains a mystery how Pama-Nyungan, the world's largest hunter-gatherer language family, came to dominate the Australian continent. Some argue that social or technological advantages allowed rapid language replacement from the Gulf Plains region during the mid-Holocene. Others have proposed expansions from refugia linked to climatic changes after the last ice age or, more controversially, during the initial colonization of Australia. Here, we combine basic vocabulary data from 306 Pama-Nyungan languages with Bayesian phylogeographic methods to explicitly model the expansion of the family across Australia and test between these origin scenarios. We find strong and robust support for a Pama-Nyungan origin in the Gulf Plains region during the mid Holocene, implying rapid replacement of non-Pama-Nyungan languages. Concomitant changes in the archaeological record, together with a lack of strong genetic evidence for Holocene population expansion, suggests that Pama-Nyungan languages were carried as part of an expanding package of cultural innovations that probably facilitated the absorption and assimilation of existing hunter-gatherer groups. PMID- 29531348 TI - Structural model of human dUTPase in complex with a novel proteinaceous inhibitor. AB - Human deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), essential for DNA integrity, acts as a survival factor for tumor cells and is a target for cancer chemotherapy. Here we report that the Staphylococcal repressor protein StlSaPIBov1 (Stl) forms strong complex with human dUTPase. Functional analysis reveals that this interaction results in significant reduction of both dUTPase enzymatic activity and DNA binding capability of Stl. We conducted structural studies to understand the mechanism of this mutual inhibition. Small-angle X-ray scattering (SAXS) complemented with hydrogen-deuterium exchange mass spectrometry (HDX-MS) data allowed us to obtain 3D structural models comprising a trimeric dUTPase complexed with separate Stl monomers. These models thus reveal that upon dUTPase-Stl complex formation the functional homodimer of Stl repressor dissociates, which abolishes the DNA binding ability of the protein. Active site forming dUTPase segments were directly identified to be involved in the dUTPase Stl interaction by HDX-MS, explaining the loss of dUTPase activity upon complexation. Our results provide key novel structural insights that pave the way for further applications of the first potent proteinaceous inhibitor of human dUTPase. PMID- 29531349 TI - Insulin mediates de novo nuclear accumulation of the IGF-1/insulin Hybrid Receptor in corneal epithelial cells. AB - Insulin and insulin-like growth factor-1 (IGF-1) are present in human tears and likely play an important role in mediating ocular surface homeostasis. We previously characterized the IGF-1/insulin hybrid receptor (Hybrid-R) in corneal epithelial cells and found that it was activated by IGF-1 and not insulin; and reported the novel finding that it localized to the corneal epithelial cell nucleus. Since the corneal epithelium is an insulin insensitive tissue and does not require insulin for glucose uptake, this study investigated the function of insulin in corneal epithelial cells. We show that stress induced by growth factor deprivation triggers transcriptional upregulation and de novo nuclear accumulation of Hybrid-R through the homodimeric insulin receptor (INSR). This occurs independent of PI3K/Akt signaling. Nuclear accumulation of Hybrid-R was associated with partial cell cycle arrest and a corresponding reduction in mitochondrial respiration. Treatment with insulin, and not IGF-1, attenuated IGF 1R and INSR transcription and restored cell cycle and metabolic homeostasis. Together, these findings support that insulin mediates receptor homeostasis in corneal epithelial cells, favoring an IGF-1 mediated pathway. This may have important implications in diabetic corneal disease and wound healing. PMID- 29531350 TI - Spin-transfer torque generated in graphene based topological insulator heterostructures. AB - We studied the spin-transfer torque (STT) in graphene based normal metal/topological-insulator/ferromagnet heterostructures (N/TI/F), which is induced by the helical spin-polarized current in the quantum spin Hall insulator. We found that the STT is comparable in magnitude to the STT in ferromagnetic normal- ferromagnetic graphene junction, while not requiring additional ferromagnetic layer with fixed magnetization, which makes it advantageous for the manipulation of magnetic devices in spintronics. More interestingly, the STT is very robust in our proposed nanostructure, as it is immune to changes in the geometry due to an asymmetrically notch or the presence of random nanopores in the quantum spin Hall insulator. Our theoretical prediction suggests that graphene based quantum spin Hall insulator could be used for very efficient magnetization manipulation for magnetic materials. PMID- 29531351 TI - Psychophysical Laws and the Superorganism. AB - Through theoretical analysis, we show how a superorganism may react to stimulus variations according to psychophysical laws observed in humans and other animals. We investigate an empirically-motivated honeybee house-hunting model, which describes a value-sensitive decision process over potential nest-sites, at the level of the colony. In this study, we show how colony decision time increases with the number of available nests, in agreement with the Hick-Hyman law of psychophysics, and decreases with mean nest quality, in agreement with Pieron's law. We also show that colony error rate depends on mean nest quality, and difference in quality, in agreement with Weber's law. Psychophysical laws, particularly Weber's law, have been found in diverse species, including unicellular organisms. Our theoretical results predict that superorganisms may also exhibit such behaviour, suggesting that these laws arise from fundamental mechanisms of information processing and decision-making. Finally, we propose a combined psychophysical law which unifies Hick-Hyman's law and Pieron's law, traditionally studied independently; this unified law makes predictions that can be empirically tested. PMID- 29531352 TI - Simultaneous Multiparameter Cellular Energy Metabolism Profiling of Small Populations of Cells. AB - Functional and genomic heterogeneity of individual cells are central players in a broad spectrum of normal and disease states. Our knowledge about the role of cellular heterogeneity in tissue and organism function remains limited due to analytical challenges one encounters when performing single cell studies in the context of cell-cell interactions. Information based on bulk samples represents ensemble averages over populations of cells, while data generated from isolated single cells do not account for intercellular interactions. We describe a new technology and demonstrate two important advantages over existing technologies: first, it enables multiparameter energy metabolism profiling of small cell populations (<100 cells)-a sample size that is at least an order of magnitude smaller than other, commercially available technologies; second, it can perform simultaneous real-time measurements of oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and mitochondrial membrane potential (MMP)-a capability not offered by any other commercially available technology. Our results revealed substantial diversity in response kinetics of the three analytes in dysplastic human epithelial esophageal cells and suggest the existence of varying cellular energy metabolism profiles and their kinetics among small populations of cells. The technology represents a powerful analytical tool for multiparameter studies of cellular function. PMID- 29531353 TI - Transdifferentiation of pancreatic progenitor cells to hepatocyte-like cells is not serum-dependent when facilitated by extracellular matrix proteins. AB - The rising prevalence of chronic liver disease, coupled with a permanent shortage of organs for liver transplantation, has sparked enormous interest in alternative treatment strategies. Previous protocols to generate hepatocyte-like cells (HLCs) via pancreas-to-liver transdifferentiation have utilised fetal bovine serum, introducing unknown variables and severely limiting study reproducibility. Therefore, the main goal of this study was to develop a protocol for transdifferentiation of pancreatic progenitor cells to HLCs in a chemically defined, serum-free culture medium. The clonal pancreatic progenitor cell line AR42J-B13 was cultured in basal growth medium on uncoated plastic culture dishes in the absence or presence of Dexamethasone on uncoated, laminin- or fibronectin coated culture substrata, with or without serum supplementation. The hepatocytic differentiation potential was evaluated: (i) morphologically through bright-field and scanning electron microscopy, (ii) by assessing pancreatic and hepatic marker expression and (iii) by determining the function of HLCs through their ability to synthesise glycogen or take up and release indocyanine green. Here we demonstrate for the first time that transdifferentiation of pancreatic cells to HLCs is not dependent on serum. These results will assist in converting current differentiation protocols into procedures that are compliant with clinical use in future cell-based therapies to treat liver-related metabolic disorders. PMID- 29531355 TI - Dynamical Coordination of Hand Intrinsic Muscles for Precision Grip in Diabetes Mellitus. AB - This study investigated the effects of diabetes mellitus (DM) on dynamical coordination of hand intrinsic muscles during precision grip. Precision grip was tested using a custom designed apparatus with stable and unstable loads, during which the surface electromyographic (sEMG) signals of the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) were recorded simultaneously. Recurrence quantification analysis (RQA) was applied to quantify the dynamical structure of sEMG signals of the APB and FDI; and cross recurrence quantification analysis (CRQA) was used to assess the intermuscular coupling between the two intrinsic muscles. This study revealed that the DM altered the dynamical structure of muscle activation for the FDI and the dynamical intermuscular coordination between the APB and FDI during precision grip. A reinforced feedforward mechanism that compensates the loss of sensory feedbacks in DM may be responsible for the stronger intermuscular coupling between the APB and FDI muscles. Sensory deficits in DM remarkably decreased the capacity of online motor adjustment based on sensory feedback, rendering a lower adaptability to the uncertainty of environment. This study shed light on inherent dynamical properties underlying the intrinsic muscle activation and intermuscular coordination for precision grip and the effects of DM on hand sensorimotor function. PMID- 29531356 TI - Synthetic wavelength interferometry of an optical frequency comb for absolute distance measurement. AB - We present a synthetic-wavelength based heterodyne interferometer of optical frequency combs with wide consecutive measurement range for absolute distance measurement. The synthetic wavelength is derived from two wavelengths obtained by two band-pass filters. The interferometric phase of the synthetic wavelength is used as a marker for the pulse-to-pulse alignment, which greatly improves the accuracy of traditional peak finding method. The consecutive measurement range is enlarged by using long fiber to increase the path length difference of the reference and measurement arms. The length of the long fiber is stabilized according to the interferometric phase of a CW laser. The experimental results show the present system can realize an accuracy of 75 nm in 350 mm consecutive measurement range. PMID- 29531358 TI - Photo-induced Hall effect in metals. AB - The Hall effect in metals is too small to have practical applications. Instead, the same effect in semiconductors is the standard for magnetic field sensing. Yet, in semiconducting Hall-sensors, Joule heating severely compromises the linearity range. We here show that a Hall effect can be photo-induced in metals used for bias-free magnetic sensing. The system consists of a transparent metal that forms a Schottky contact to a semiconductor. Light reaching the interface results in the injection of charge from the space charge region. If a magnetic field is applied, a transverse, open-circuit voltage appears at the metal edges that is proportional to the field, as well as light intensity. The system shows sensitivities that are comparable to semiconducting Hall-sensors but no net current flows, therefore its performances are not affected by Joule heating. PMID- 29531357 TI - Antagonism of Two Plant-Growth Promoting Bacillus velezensis Isolates Against Ralstonia solanacearum and Fusarium oxysporum. AB - Plant growth promoting rhizobacteria (PGPR) provide an effective and environmentally sustainable method to protect crops against pathogens. The spore forming Bacilli are attractive PGPR due to their ease of storage and application. Here, we characterized two rhizosphere-associated Bacillus velezensis isolates (Y6 and F7) that possess strong antagonistic activity against Ralstonia solanacearum and Fusarium oxysporum under both laboratory and greenhouse conditions. We identified three lipopeptide (LP) compounds (surfactin, iturin and fengycin) as responsible for the antimicrobial activity of these two strains. We further dissected the contribution of LPs to various biological processes important for rhizosphere colonization. Although either iturin or fengycin is sufficient for antibacterial activity, cell motility and biofilm formation, only iturin plays a primary role in defense against the fungal pathogen F. oxysporum. Additionally, we found that LP production is significantly stimulated during interaction with R. solanacearum. These results demonstrate the different roles of LPs in the biology of B. velezensis and highlight the potential of these two isolates as biocontrol agents against phytopathogens. PMID- 29531359 TI - High-power sub-terahertz source with a record frequency stability at up to 1 Hz. AB - Many state-of-the-art fundamental and industrial projects need the use of terahertz radiation with high power and small linewidth. Gyrotrons as radiation sources provide the desired level of power in the sub-THz and THz frequency range, but have substantial free-running frequency fluctuations of the order of 10-4. Here, we demonstrate that the precise frequency stability of a high-power sub-THz gyrotron can be achieved by a phase-lock loop in the anode voltage control. The relative width of the frequency spectrum and the frequency stability obtained for a 0.263 THz/100 W gyrotron are 4 * 10-12 and 10-10, respectively, and these parameters are better than those demonstrated so far with high-power sources by almost three orders of magnitude. This approach confirms its potential for ultra-high precision spectroscopy, the development of sources with large scale radiating apertures, and other new projects. PMID- 29531360 TI - Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis. AB - Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1.5-A structure revealed a dimeric assembly with two calcium ions per monomer and with the active sites located at the distal ends of the protein dimer. Mutational analysis and computational methods uncovered key residues for an acid-catalyzed [3,3] sigmatropic rearrangement, as well as specific determinants that control the position of terminal electrophilic aromatic substitution, leading to a switch from hapalindole to fischerindole alkaloids. PMID- 29531361 TI - Neural mediators of changes of mind about perceptual decisions. AB - Changing one's mind on the basis of new evidence is a hallmark of cognitive flexibility. To revise our confidence in a previous decision, we should use new evidence to update beliefs about choice accuracy. How this process unfolds in the human brain, however, remains unknown. Here we manipulated whether additional sensory evidence supports or negates a previous motion direction discrimination judgment while recording markers of neural activity in the human brain using fMRI. A signature of post-decision evidence (change in log-odds correct) was selectively observed in the activity of posterior medial frontal cortex. In contrast, distinct activity profiles in anterior prefrontal cortex mediated the impact of post-decision evidence on subjective confidence, independently of changes in decision value. Together our findings reveal candidate neural mediators of post-decisional changes of mind in the human brain and indicate possible targets for ameliorating deficits in cognitive flexibility. PMID- 29531363 TI - Set in one's thoughts. PMID- 29531362 TI - Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. AB - Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of beta-catenin, a Shank3 binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations. PMID- 29531364 TI - Learning by neural reassociation. AB - Behavior is driven by coordinated activity across a population of neurons. Learning requires the brain to change the neural population activity produced to achieve a given behavioral goal. How does population activity reorganize during learning? We studied intracortical population activity in the primary motor cortex of rhesus macaques during short-term learning in a brain-computer interface (BCI) task. In a BCI, the mapping between neural activity and behavior is exactly known, enabling us to rigorously define hypotheses about neural reorganization during learning. We found that changes in population activity followed a suboptimal neural strategy of reassociation: animals relied on a fixed repertoire of activity patterns and associated those patterns with different movements after learning. These results indicate that the activity patterns that a neural population can generate are even more constrained than previously thought and might explain why it is often difficult to quickly learn to a high level of proficiency. PMID- 29531366 TI - Towards predicting the environmental metabolome from metagenomics with a mechanistic model. AB - The environmental metabolome and metabolic potential of microorganisms are dominant and essential factors shaping microbial community composition. Recent advances in genome annotation and systems biology now allow us to semiautomatically reconstruct genome-scale metabolic models (GSMMs) of microorganisms based on their genome sequence 1 . Next, growth of these models in a defined metabolic environment can be predicted in silico, mechanistically linking the metabolic fluxes of individual microbial populations to the community dynamics. A major advantage of GSMMs is that no training data is needed, besides information about the metabolic capacity of individual genes (genome annotation) and knowledge of the available environmental metabolites that allow the microorganism to grow. However, the composition of the environment is often not fully determined and remains difficult to measure 2 . We hypothesized that the relative abundance of different bacterial species, as measured by metagenomics, can be combined with GSMMs of individual bacteria to reveal the metabolic status of a given biome. Using a newly developed algorithm involving over 1,500 GSMMs of human-associated bacteria, we inferred distinct metabolomes for four human body sites that are consistent with experimental data. Together, we link the metagenome to the metabolome in a mechanistic framework towards predictive microbiome modelling. PMID- 29531365 TI - The TRiC chaperonin controls reovirus replication through outer-capsid folding. AB - Viruses are molecular machines sustained through a life cycle that requires replication within host cells. Throughout the infectious cycle, viral and cellular components interact to advance the multistep process required to produce progeny virions. Despite progress made in understanding the virus-host protein interactome, much remains to be discovered about the cellular factors that function during infection, especially those operating at terminal steps in replication. In an RNA interference screen, we identified the eukaryotic chaperonin T-complex protein-1 (TCP-1) ring complex (TRiC; also called CCT for chaperonin containing TCP-1) as a cellular factor required for late events in the replication of mammalian reovirus. We discovered that TRiC functions in reovirus replication through a mechanism that involves folding the viral sigma3 major outer-capsid protein into a form capable of assembling onto virus particles. TRiC also complexes with homologous capsid proteins of closely related viruses. Our data define a critical function for TRiC in the viral assembly process and raise the possibility that this mechanism is conserved in related non-enveloped viruses. These results also provide insight into TRiC protein substrates and establish a rationale for the development of small-molecule inhibitors of TRiC as potential antiviral therapeutics. PMID- 29531367 TI - Coccolithovirus facilitation of carbon export in the North Atlantic. AB - Marine phytoplankton account for approximately half of global primary productivity 1 , making their fate an important driver of the marine carbon cycle. Viruses are thought to recycle more than one-quarter of oceanic photosynthetically fixed organic carbon 2 , which can stimulate nutrient regeneration, primary production and upper ocean respiration 2 via lytic infection and the 'virus shunt'. Ultimately, this limits the trophic transfer of carbon and energy to both higher food webs and the deep ocean 2 . Using imagery taken by the Moderate Resolution Imaging Spectroradiometer (MODIS) onboard the Aqua satellite, along with a suite of diagnostic lipid- and gene-based molecular biomarkers, in situ optical sensors and sediment traps, we show that Coccolithovirus infections of mesoscale (~100 km) Emiliania huxleyi blooms in the North Atlantic are coupled with particle aggregation, high zooplankton grazing and greater downward vertical fluxes of both particulate organic and particulate inorganic carbon from the upper mixed layer. Our analyses captured blooms in different phases of infection (early, late and post) and revealed the highest export flux in 'early-infected blooms' with sinking particles being disproportionately enriched with infected cells and subsequently remineralized at depth in the mesopelagic. Our findings reveal viral infection as a previously unrecognized ecosystem process enhancing biological pump efficiency. PMID- 29531368 TI - Evolutionary selection growth of two-dimensional materials on polycrystalline substrates. AB - There is a demand for the manufacture of two-dimensional (2D) materials with high quality single crystals of large size. Usually, epitaxial growth is considered the method of choice 1 in preparing single-crystalline thin films, but it requires single-crystal substrates for deposition. Here we present a different approach and report the synthesis of single-crystal-like monolayer graphene films on polycrystalline substrates. The technological realization of the proposed method resembles the Czochralski process and is based on the evolutionary selection 2 approach, which is now realized in 2D geometry. The method relies on 'self-selection' of the fastest-growing domain orientation, which eventually overwhelms the slower-growing domains and yields a single-crystal continuous 2D film. Here we have used it to synthesize foot-long graphene films at rates up to 2.5 cm h-1 that possess the quality of a single crystal. We anticipate that the proposed approach could be readily adopted for the synthesis of other 2D materials and heterostructures. PMID- 29531369 TI - Organic-based magnon spintronics. AB - Magnonics concepts utilize spin-wave quanta (magnons) for information transmission, processing and storage. To convert information carried by magnons into an electric signal promises compatibility of magnonic devices with conventional electronic devices, that is, magnon spintronics 1 . Magnons in inorganic materials have been studied widely with respect to their generation2,3, transport4,5 and detection 6 . In contrast, resonant spin waves in the room temperature organic-based ferrimagnet vanadium tetracyanoethylene (V(TCNE) x (x ~ 2)), were detected only recently 7 . Herein we report room-temperature coherent magnon generation, transport and detection in films and devices based on V(TCNE) x using three different techniques, which include broadband ferromagnetic resonance (FMR), Brillouin light scattering (BLS) and spin pumping into a Pt adjacent layer. V(TCNE) x can be grown as neat films on a large variety of substrates, and it exhibits extremely low Gilbert damping comparable to that in yttrium iron garnet. Our studies establish an alternative use for organic-based magnets, which, because of their synthetic versatility, may substantially enrich the field of magnon spintronics. PMID- 29531370 TI - Electric-field switching of two-dimensional van der Waals magnets. AB - Controlling magnetism by purely electrical means is a key challenge to better information technology 1 . A variety of material systems, including ferromagnetic (FM) metals2-4, FM semiconductors 5 , multiferroics6-8 and magnetoelectric (ME) materials9,10, have been explored for the electric-field control of magnetism. The recent discovery of two-dimensional (2D) van der Waals magnets11,12 has opened a new door for the electrical control of magnetism at the nanometre scale through a van der Waals heterostructure device platform 13 . Here we demonstrate the control of magnetism in bilayer CrI3, an antiferromagnetic (AFM) semiconductor in its ground state 12 , by the application of small gate voltages in field-effect devices and the detection of magnetization using magnetic circular dichroism (MCD) microscopy. The applied electric field creates an interlayer potential difference, which results in a large linear ME effect, whose sign depends on the interlayer AFM order. We also achieve a complete and reversible electrical switching between the interlayer AFM and FM states in the vicinity of the interlayer spin-flip transition. The effect originates from the electric-field dependence of the interlayer exchange bias. PMID- 29531371 TI - Grown with the wind. PMID- 29531372 TI - Sticky when wet. PMID- 29531373 TI - Dynamic protein assembly by programmable DNA strand displacement. AB - Inspired by the remarkable ability of natural protein switches to sense and respond to a wide range of environmental queues, here we report a strategy to engineer synthetic protein switches by using DNA strand displacement to dynamically organize proteins with highly diverse and complex logic gate architectures. We show that DNA strand displacement can be used to dynamically control the spatial proximity and the corresponding fluorescence resonance energy transfer between two fluorescent proteins. Performing Boolean logic operations enabled the explicit control of protein proximity using multi-input, reversible and amplification architectures. We further demonstrate the power of this technology beyond sensing by achieving dynamic control of an enzyme cascade. Finally, we establish the utility of the approach as a synthetic computing platform that drives the dynamic reconstitution of a split enzyme for targeted prodrug activation based on the sensing of cancer-specific miRNAs. PMID- 29531374 TI - Hydroxide diffuses slower than hydronium in water because its solvated structure inhibits correlated proton transfer. AB - Proton transfer via hydronium and hydroxide ions in water is ubiquitous. It underlies acid-base chemistry, certain enzyme reactions, and even infection by the flu. Despite two centuries of investigation, the mechanism underlying why hydroxide diffuses slower than hydronium in water is still not well understood. Herein, we employ state-of-the-art density-functional-theory-based molecular dynamics-with corrections for non-local van der Waals interactions, and self interaction in the electronic ground state-to model water and hydrated water ions. At this level of theory, we show that structural diffusion of hydronium preserves the previously recognized concerted behaviour. However, by contrast, proton transfer via hydroxide is less temporally correlated, due to a stabilized hypercoordination solvation structure that discourages proton transfer. Specifically, the latter exhibits non-planar geometry, which agrees with neutron scattering results. Asymmetry in the temporal correlation of proton transfer leads to hydroxide diffusing slower than hydronium. PMID- 29531354 TI - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. AB - Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. PMID- 29531375 TI - Crystal phase-based epitaxial growth of hybrid noble metal nanostructures on 4H/fcc Au nanowires. AB - Crystal-phase engineering offers opportunities for the rational design and synthesis of noble metal nanomaterials with unusual crystal phases that normally do not exist in bulk materials. However, it remains a challenge to use these materials as seeds to construct heterometallic nanostructures with desired crystal phases and morphologies for promising applications such as catalysis. Here, we report a strategy for the synthesis of binary and ternary hybrid noble metal nanostructures. Our synthesized crystal-phase heterostructured 4H/fcc Au nanowires enable the epitaxial growth of Ru nanorods on the 4H phase and fcc-twin boundary in Au nanowires, resulting in hybrid Au-Ru nanowires. Moreover, the method can be extended to the epitaxial growth of Rh, Ru-Rh and Ru-Pt nanorods on the 4H/fcc Au nanowires to form unique hybrid nanowires. Importantly, the Au-Ru hybrid nanowires with tunable compositions exhibit excellent electrocatalytic performance towards the hydrogen evolution reaction in alkaline media. PMID- 29531377 TI - ? PMID- 29531376 TI - [Consensus document and recommendations for the prevention of cardiovascular disease in Italy - 2018]. AB - Cardiovascular prevention represents a cornerstone of modern strategies to reduce the burden of cardiovascular disease. It is of key importance to prevent cardiovascular diseases and associated events, not only to reduce morbidity and mortality, but also to increase the years of wellness in the aging population and to make the growing socio-economic burden imposed by cardiovascular events more sustainable.The current approach to prevention is based on an integrated use of effective lifestyle measures and, whenever appropriate, of antihypertensive and antidiabetic drugs, lipid-lowering agents and antiplatelet drugs.Given that population characteristics, in terms of ethnicity, demography and lifestyle habits, and healthcare system organizations differ among countries, international guidelines are not always applicable to specific countries and, often, are difficult to translate into daily clinical practice.In order to afford the specific features of Italy, 10 Scientific Societies and Research Institutions, mostly involved in preventive strategies, contributed to the present Italian consensus document, which includes brief, practical recommendations to support the preventive actions within the physician community and the general practice setting. PMID- 29531378 TI - [The REVEAL study]. PMID- 29531379 TI - [PCSK9 inhibitors: how to bridge the gap between scientific evidence and regulatory barriers?] PMID- 29531380 TI - [Nutraceuticals: a useful tool for cardiologists to improve lipid profile?] AB - Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Treatment strategies include both lifestyle modification and pharmacological therapy. Statins are among the most effective agents to achieve optimal LDL cholesterol levels, but, not infrequently, patients suffer from myalgia or other side effects. The proven or perceived intolerance to statins requires, therefore, alternative lipid-lowering strategies. In recent years, nutraceuticals have become extensively accepted, and a growing number of molecules with hypothetical cholesterol-lowering activity have been proposed, sometimes with no scientific evidence and/or no methodological accuracy, based only on the belief that these agents are "natural" and do not show side effects. Here, nutraceuticals with potential evidence-based hypolipidemic effect will be reviewed (red yeast rice, berberine, phytosterols) in order to discuss their role in lipid control, their potential risks and their future prospective in clinical cardiology. PMID- 29531381 TI - [Latest news and perspectives in cardiogenetics]. AB - In recent years, cardiogenetics is emerging as a major discipline for the study of many pathologies, with immediate clinical effects for patients who were previously managed by the cardiologist alone. Recent acquisitions have allowed significant improvements in terms of diagnostic characterization, prognostic stratification and guidance for treatment for both patients with genetic disease and their family members. At present, cardiogenetics has an important role for the clinical management of patients with cardiomyopathies and channelopathies. We present an updated review of the literature and a proposal of organizational model. PMID- 29531382 TI - [Temporal evolution of antithrombotic therapy use in patients with acute coronary syndromes undergoing percutaneous coronary intervention in Italy: comparison between the EYESHOT and SCOPE registries]. AB - BACKGROUND: Few data exist on temporal evolution of antithrombotic agent use in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) in Italy. We sought to compare data from the most recent prospective, multicenter, nationwide registries conducted in Italy, namely EYESHOT and SCOPE. METHODS: EYESHOT enrolled 2585 consecutive ACS patients, both ST-segment elevation myocardial infarction (STEMI) and non-ST elevation ACS (NSTE ACS), admitted to 203 Italian coronary care units over a 3-week period (2-22 Dec 2013 and 27 Jan-16 Feb 2014). Among patients enrolled in EYESHOT, 1755 (67.9%) underwent PCI (52.6% with STEMI and 47.4% with NSTE-ACS). In the SCOPE registry, a total of 1363 patients undergoing PCI were enrolled over 3 months (15 Feb-15 Apr 2016) in 39 Italian cath lab centers at medium to high PCI volume: 331 (24.3%) with a diagnosis of STEMI and 1032 (75.7%) with a diagnosis of NSTE-ACS. RESULTS: Over 2 years, the use of clopidogrel in the cath lab significantly decreased (from 11% to 8% in STEMI; p=0.06 and from 9% to 5% in NSTE-ACS; p=0.0002), while the administration of ticagrelor dramatically increased (from 14% to 37%; p<0.0001 in STEMI and from 7% to 44%; p<0.0001 in NSTE-ACS). At discharge, a significant decrease in the use of clopidogrel (from 32% to 21% in STEMI; p=0.02, and from 47% to 24% in NSTE-ACS; p<0.0001) and a concomitant increase in the novel P2Y12 receptor inhibitor prescription occurred, particularly among NSTE-ACS patients (from 8% to 14% for prasugrel; p=0.002 and from 43% to 58% for ticagrelor; p=0.03). CONCLUSIONS: From the present analysis on ACS patients undergoing PCI enrolled in EYESHOT and SCOPE registries, a significant increase in the use of novel P2Y12 receptor inhibitors was observed, both at the time of PCI and at discharge. PMID- 29531383 TI - [Kawasaki disease shock syndrome: a case report]. AB - Kawasaki disease is a systemic vasculitis that presents with stable vital signs. Although it is well known that Kawasaki disease can cause myocarditis, tachycardia and heart failure during the acute stage, Kawasaki disease shock syndrome (KDSS) has recently been described. It is characterized by hypotension, signs and symptoms of poor perfusion and a shock-like state. We report the case of a 7-year-old boy with KDSS who presented with persistent fever, conjunctival injection, laterocervical lymphadenitis, and echocardiography showing signs of myocardial dysfunction and shock. The patient's hemodynamic status markedly improved with immunoglobulin therapy. Early recognition of KDSS can be challenging; however, delay in diagnosis may increase the risk of coronary artery abnormalities and death. PMID- 29531384 TI - [Cardiac infection by Listeria monocytogenes]. AB - We report the case of a 56-year-old man showing numerous cardiovascular manifestations of Listeria infection (myo-pericarditis, coronary vasospasm, intracavitary vegetations/thrombus, sinoatrial blocks). Cardiac magnetic resonance and echocardiography images provided an unexpected picture of this infection, and were relevant for the appropriate clinical management. Transthoracic and transesophageal echocardiography were useful for assessing the presence of an endocavitary mass. Tissue characterization by cardiac magnetic resonance confirmed the presence of a thrombus and revealed signs of active inflammation in the myocardial wall, pericardium and vascular pedicle. PMID- 29531385 TI - [The Pacemaker and Implantable Cardioverter-Defibrillator Registry of the Italian Association of Arrhythmology and Cardiac Pacing - Annual report 2016]. AB - BACKGROUND: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2016 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers. METHODS: The registry collects prospectively national PM and ICD implantation activity on the basis of European cards. RESULTS: PM Registry: data about 23 496 PM implantations were collected (19 003 first implant and 4493 replacements). The number of collaborating centers was 204. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 39.8% of first PM implants, sick sinus syndrome in 22.1%, atrial fibrillation plus bradycardia in 14.1%, other in 24.0%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (22.18% of first implants). Use of single-chamber PMs was reported in 26.9% of first implants, of dual-chamber PMs in 65.0%, of PMs with cardiac resynchronization therapy (CRT) in 1.5%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 6.6%. ICD Registry: data about 20 350 ICD implantations were collected (14 763 first implants and 5587 replacements). The number of collaborating centers was 430. Median age of treated patients was 72 years (63 quartile I; 78 quartile III]. Primary prevention indication was reported in 79.0% of first implants, secondary prevention in 21.0% (cardiac arrest in 7.9%). A single-chamber ICD was used in 32.2% of first implants, dual-chamber in 31.1% and biventricular in 36.7%. CONCLUSIONS: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. PMID- 29531386 TI - ? PMID- 29531387 TI - [The new position paper on the organization of intensive cardiac care units released by the Acute Cardiovascular Care Association (ACCA) of the European Society of Cardiology]. PMID- 29531388 TI - Role of temperature and oxygen content on structural and electrical properties of LaBaCo2O5+delta thin films. AB - The role of temperature and the oxygen content in the structural transformation and electrical conductivity of epitaxial double perovskite LaBaCo2O5+delta (0<= delta <= 1) thin films was systematically investigated. Reciprocal space mapping and omega-2theta x-ray diffraction performed at different temperatures in vacuum indicate that oxygen vacancies in the films become ordered at high temperature in a reducing environment. The changes of the oxygen content and the degree of oxygen vacancy ordering in the films result in a strong in-plane anisotropic lattice deformation and a large thermal expansion coefficient along the c-axis direction. The electrical conductivity measurements reveal that these behaviors are related to the degree of oxygen vacancy formation and lattice deformation in the films. PMID- 29531389 TI - Individually grown cobalt nanowires as magnetic force microscopy probes. AB - AC electric fields were utilized in the growth of individual high-aspect ratio cobalt nanowires from simple salt solutions using the Directed Electrochemical Nanowire Assembly method. Nanowire diameters were tuned from the submicron scale to 40 nm by adjusting the AC voltage frequency and the growth solution concentration. The structural properties of the nanowires, including shape and crystallinity, were identified using electron microscopy. Hysteresis loops obtained along different directions of an individual nanowire using vibrating sample magnetometry showed that the magnetocrystalline anisotropy energy has the same order of magnitude as the shape anisotropy energy. Additionally, the saturation magnetization of an individual cobalt nanowire was estimated to be close to the bulk single crystal value. A small cobalt nanowire segment was grown from a conductive atomic force microscope cantilever tip that was utilized in magnetic force microscopy (MFM) imaging. The fabricated MFM tip provided moderate quality magnetic images of an iron-cobalt thin-film sample. PMID- 29531390 TI - International Hospital Pharmacy: Learning from Each Other. PMID- 29531391 TI - ? PMID- 29531392 TI - Interaction between Psychotropic Medications and Alcohol: Perceptions among Patients Attending an Adult Mental Health Day Hospital Program. AB - Background: Interaction between alcohol and certain medications can lead to adverse consequences. Individuals with mental health disorders are particularly vulnerable because of their psychotropic medications, which are typically taken over extended periods and which are known to have pharmacokinetic and pharmacodynamic interactions with alcohol. It is unknown what education these patients receive from their health care providers and how such interactions are managed. Objectives: To determine whether individuals with mental health disorders are aware of alcohol-drug interactions and if so, how they use such information. Methods: A questionnaire was developed to explore the perceptions of mental health patients concerning alcohol-drug interactions. The questionnaire included questions in 3 domains: knowledge of potential alcohol-drug interactions, consumption of alcohol while taking psychotropic medications, and source of advice regarding the interactions. Attendees of an adult mental health day hospital program were invited to participate. Results: A total of 131 participants answered the questionnaire between July 2014 and February 2015; 31 of the questionnaires were incomplete and were excluded from analysis. Of the 100 participants included in the analyses, 75 reported having received counselling from a health care provider about alcohol-drug interactions, and 49 of these reported following the advice provided. The most common advice reported by participants was to avoid alcohol consumption while taking medications. Serious adverse effects, such as worsening of a psychiatric condition, admission to hospital, and increased drowsiness, were reported by 23 participants. Sixty-nine participants considered physicians to be the best source of information about these interactions. Conclusions: Most participants reported that they had received information about strategies to avoid negative consequences from alcohol drug interactions. Nevertheless, consumption of alcohol occurred, and almost one quarter of participants reported a serious adverse effect related to consuming alcohol. These self-reported data indicate that patients do not necessarily follow the advice of their health care providers. Future studies should explore reasons for the gap between advice and action and how to minimize it. PMID- 29531393 TI - Meropenem Assessment before and after Implementation of a Small-Dose, Short Interval Standard Dosing Regimen. AB - Background: Small-dose, short-interval dosing for meropenem has been shown to yield pharmacokinetic and pharmacodynamic properties similar to those associated with traditional dosing of this drug. However, few studies have examined clinical outcomes in the general population. Objectives: To characterize differences in effects between a small-dose, short-interval dosing regimen for meropenem (500 mg every 6 h) and the traditional regimen (1000 mg every 8 h) on clinical outcomes and costs to the health care system. Methods: This retrospective cohort study included 194 patients who received the traditional meropenem dosage (July 2006 to August 2008) and 188 patients who received the small-dose, short-interval regimen (December 2008 and October 2009) at a large tertiary care hospital and a community hospital. The primary outcome (clinical success), the secondary outcomes (30-day in-hospital mortality, time to defervescence, duration of therapy, and length of stay), and drug costs were compared between cohorts. Results: The 2 cohorts did not differ significantly in terms of baseline characteristics. There was no statistically significant difference between the small-dose, short-interval regimen and the traditional dosing regimen in terms of the primary outcome: clinical success was achieved in 83.5% (162/194) and 80.8% (152/188) of the patients, respectively. Likewise, there was no statistically significant difference in any of the secondary outcomes. The average drug cost per patient per visit was $222.23 with small-dose, short-interval dosing and $355.90 with traditional dosing, a significant difference of more than $130 per patient per visit. Conclusion: The small-dose, short-interval meropenem dosing regimen resulted in clinical outcomes similar to those achieved with the traditional dosing regimen at significantly lower cost. PMID- 29531394 TI - Effectiveness of Injectable Ibuprofen Salts and Indomethacin to Treat Patent Ductus Arteriosus in Preterm Infants: Observational Cohort Study. AB - Background: There is no injectable ibuprofen product marketed to treat patent ductus arteriosus (PDA) in newborns in Canada. The authors' institution has used ibuprofen arginine in the past. In the absence of published evidence supporting use of this salt form of ibuprofen for neonatal PDA, a retrospective analysis was undertaken. Objective: To compare the effectiveness and adverse effects of ibuprofen arginine, ibuprofen tromethamine, and indomethacin in the treatment of PDA. Methods: This retrospective observational cohort study, for patients admitted between 2009 and 2015, included preterm infants with symptomatic PDA who received at least one dose of injectable indomethacin, ibuprofen tromethamine, or ibuprofen arginine. Three effectiveness end points were analyzed: closure after one course of treatment, repeat medical treatment, and surgical ligation. The secondary end points included acute kidney injury, necrotizing enterocolitis, chronic lung disease, and time to full enteral feeding. Results: A total of 179 infants were included. There were no differences among groups in terms of closure after one course of treatment (37/54 [69%] with indomethacin, 42/70 [60%] with ibuprofen tromethamine, and 28/55 [51%] with ibuprofen arginine; p = 0.21) or surgical ligation (10/54 [19%] with indomethacin, 13/70 [19%] with ibuprofen tromethamine, and 12/55 [22%] with ibuprofen arginine; p = 0.88). However, there was a difference regarding use of a repeat course of treatment, ibuprofen arginine having the highest rate (8/54 [15%] with indomethacin, 18/70 [26%] with ibuprofen tromethamine, and 20/55 [36%] with ibuprofen arginine; p = 0.04). After adjustment for gestational age, the association between ibuprofen arginine and increased use of a repeat course of treatment remained significant. The groups did not differ with respect to adverse effects. Conclusion: These results highlight the potential for differences in effectiveness among various salt forms of injectable ibuprofen and indomethacin. Because of the small sample size and retrospective methodology, confirmation of the present results through a larger prospective study is needed. PMID- 29531395 TI - Potential Negative Effects of Antimicrobial Allergy Labelling on Patient Care: A Systematic Review. AB - Background: Antimicrobial allergy labels, either self-reported or placed in a patient's medical record, are common, but in many cases they are not associated with a true immunoglobulin E-mediated allergic response. Objective: To assess the impact of antimicrobial allergy labels on antimicrobial prescribing, resource utilization, and clinical outcomes. Data Sources: The MEDLINE, Embase, CINAHL, and Scopus electronic databases were searched for the period 1990 to January 2016. Study Selection: Controlled studies with the objective of assessing antimicrobial prescribing, resource utilization, and/or clinical outcomes associated with antimicrobial allergy labels were included. Results: The search identified 560 unique citations, of which 7 articles met the inclusion criteria. One additional article identified by an expert in the field was also included. Four of the identified papers were limited to penicillin or other beta-lactam allergies. Six studies noted differences in antibiotic selection between patients with allergy labels and those without such labels. Broader-spectrum or second line agents (e.g., vancomycin, clindamycin, and fluoroquinolones) were more commonly prescribed for patients with penicillin allergy labels. Antibiotic therapy costs were significantly higher for patients with allergy labels than for those without. The impact of allergy labels on clinical outcomes was mixed. One study indicated a longer length of hospital stay, 2 studies reported higher readmission rates, and 1 study reported a higher rate of antibiotic-resistant organisms for patients with allergy labels. Conclusions: Most of the available literature is limited to penicillin or beta-lactam allergy. The growing body of knowledge supports the concept that beta-lactam allergy labels are not benign and that labelling in the absence of a true allergy has a negative effect on patient care. Allergy labelling appears to be associated with suboptimal antibiotic selection, greater treatment costs, prolonged length of stay, greater readmission rates, and higher prevalence of antibiotic-resistant organisms. There is an opportunity for antimicrobial stewardship programs to implement systematic allergy verification to optimize antimicrobial therapy and improve patient care. PMID- 29531396 TI - Rivaroxaban for a Patient with Class III Obesity: Case Report with Literature Review. PMID- 29531397 TI - Do the Benefits of Electronic Cigarettes Outweigh the Risks? PMID- 29531398 TI - Path to the Canadian Antidote Registry. PMID- 29531400 TI - Tribute to the Reviewers of the Canadian Journal of Hospital Pharmacy. PMID- 29531399 TI - Funding for Antimicrobial Stewardship Programs: A Customizable Business Case Template. PMID- 29531401 TI - cshp47. PMID- 29531402 TI - ? PMID- 29531403 TI - ? PMID- 29531404 TI - Becoming United through Core Values. PMID- 29531405 TI - Asian Women's Action for Resilience and Empowerment Intervention: Stage I Pilot Study. AB - This study describes the development and pilot test of Asian Women's Action for Resilience and Empowerment (AWARE), a culturally informed group psychotherapy intervention designed to reduce depressive symptoms, suicidality, substance use, and HIV and sexual risk behaviors among 1.5 and second generation Asian American (AA) women. To participate, AA women had to meet the criteria for posttraumatic stress disorder (PTSD) or have a history of exposure to interpersonal violence (IPV) as determined using the Clinician-Administered PTSD Scale (CAPS) and Traumatic Life Events Questionnaire (TLEQ). This article also presents the preliminary feasibility and acceptability of AWARE from its Stage I pilot study of nine Chinese, Korean, and Vietnamese American women. To foster holistic treatment, AWARE was developed based on original research findings from Stage 0 and integrated theoretical models including fractured identity theory, empowerment theory, cognitive behavioral therapy (CBT), mindfulness-based techniques, and the AIDS Risk Reduction Model (ARRM). The development of AWARE was an iterative process informed by participant feedback, which led to frequent intervention modifications for a future randomized controlled trial (RCT) in Stage II. A qualitative analysis of participant feedback informed the following modifications: further exploration of feelings, improvements in technology delivery, learning and practicing coping skills, more specific cultural tailoring related to sexual health, decreased number of sessions and increased time per session. Findings provide support for the acceptability and feasibility of AWARE as "culturally informed" for AA young women with IPV histories, high-risk behaviors, and mental health issues. PMID- 29531406 TI - Pattern-mixture models with incomplete informative cluster size: Application to a repeated pregnancy study. AB - The incomplete informative cluster size problem is motivated by the NICHD Consecutive Pregnancies Study, aiming to study the relationship between pregnancy outcomes and parity. These pregnancy outcomes are potentially associated with the number of births over a woman's lifetime, resulting in an incomplete informative cluster size (censored at the end of the study window). We develop a pattern mixture model for informative cluster size by treating the lifetime number of births as a latent variable. We compare this approach with a simple alternative method that approximates the pattern mixture model. We show that the latent variable approach possesses good statistical properties for estimating both the mean trajectory of birthweight and the proportion of gestational hypertension with increasing parity. PMID- 29531407 TI - Preparing for Local Labor: Curricular Stratification across Local Economies in the United States. AB - I investigate how the educational demands of local labor markets shape high school course offerings and student course taking. Using the Education Longitudinal Study of 2002 linked to the U.S. Census 2000, I focus on local economic variation in the share of jobs that do not demand a bachelor's degree. I find that schools in local labor markets with higher concentrations of subbaccalaureate jobs devote a larger share of their course offerings to career and technical education (CTE) courses and a smaller share to advanced college preparatory courses compared to schools in labor markets with lower concentrations of subbaccalaureate jobs, even net of school resources. Students in labor markets with higher concentrations of subbaccalaureate jobs take greater numbers of CTE courses, and higher-achieving students in these labor markets are less likely to take advanced math and Advanced Placement/International Baccalaureate courses. These course-taking disparities are largely due to school course offerings. This study shows how local economic inequalities shape high school curricular stratification, and suggests that school curricula linked to the educational demands of local jobs delimits the college preparation opportunities of high-achieving students. PMID- 29531409 TI - Global hearing health: future directions. PMID- 29531410 TI - Flexibilities provided by the Agreement on Trade-Related Aspects of Intellectual Property Rights. PMID- 29531412 TI - Healthy buildings, healthy people. AB - An Australian medical research centre and a Norwegian hospital have won acclaim for their healthy designs. Sima Barmania reports. PMID- 29531411 TI - Public health round-up. PMID- 29531413 TI - Carol Brayne: a life-course approach to prevent dementia. AB - More research is needed to understand dementia and to find the approaches to dementia that are effective. Carol Brayne talks to Tatum Anderson. PMID- 29531414 TI - Ward-based clinical pharmacists and hospital readmission: a non-randomized controlled trial in Sri Lanka. AB - Objective: To assess if a ward-based clinical pharmacy service resolving drug related problems improved medication appropriateness at discharge and prevented drug-related hospital readmissions. Method: Between March and September 2013, we recruited patients with noncommunicable diseases in a Sri Lankan tertiary-care hospital, for a non-randomized controlled clinical trial. The intervention group received usual care and clinical pharmacy service. The intervention pharmacist made prospective medication reviews, identified drug-related problems and discussed recommendations with the health-care team and patients. At discharge, the patients received oral and written medication information. The control group received usual care. We used the medication appropriateness index to assess appropriateness of prescribing at discharge. During a six-month follow-up period, a pharmacist interviewed patients to identify drug-related hospital readmissions. Results: Data from 361 patients in the intervention group and 354 patients in the control group were available for analysis. Resolutions of drug-related problems were higher in the intervention group than in the control group (57.6%; 592/1027, versus 13.2%; 161/1217; P < 0.001) and the medication was more appropriate in the intervention group. Mean score of medication appropriateness index per patient was 1.25 versus 4.3 in the control group (P < 0.001). Patients in the intervention group were less likely to be readmitted due to drug-related problems (44 patients of 311 versus 93 of 311 in the control group; P < 0.001). Conclusion: A ward-based clinical pharmacy service improved appropriate prescribing, reduced drug-related problems and readmissions for patients with noncommunicable diseases. Implementation of such a service could improve health care in Sri Lanka and similar settings. PMID- 29531415 TI - Lead poisoning outbreak among opium users in the Islamic Republic of Iran, 2016 2017. AB - Objective: To describe an outbreak of lead poisoning among opium users in the Islamic Republic of Iran and estimate the number of affected people in the country. Methods: We used data from the country's largest poison treatment centre to illustrate the epidemiology of an outbreak of lead poisoning in oral opium users. We describe the government's referral and treatment guidelines in response to the outbreak. Based on the number of individuals treated and previous studies on the prevalence of oral opium use we estimated the total number of people at risk of lead-contaminated opium nationwide. Findings: In February 2016, we noticed a steep increase in the numbers of oral opium users referred to our poison treatment centre with abdominal pain, anaemia and constipation. Numbers peaked in June 2016 but the outbreak was ongoing in August 2017. The mean blood lead level in a sample of 80 patients was 140.3 ug/dL (standard deviation: 122.6). Analysis of an illegal opium sample showed 3.55 mg lead in 1 g opium. Treatment was exposure reduction with opioid substitutes and laxatives, or chelation therapy if indicated. Over 7 months, 4294 poison cases were seen at main referral hospitals in Tehran out of an estimated 31 914 oral opium users in the city. We estimate more than 260 000 out of 773 800 users nationwide remain untreated and at risk of poisoning. Conclusion: Lead-contaminated opium and heroin that has transited through the Iranian markets is a global risk and highlights a need for better monitoring of illegal drug supplies. PMID- 29531416 TI - National policies on the management of latent tuberculosis infection: review of 98 countries. AB - Objective: To review policies on management of latent tuberculosis infection in countries with low and high burdens of tuberculosis. Methods: We divided countries reporting data to the World Health Organization (WHO) Global Tuberculosis Programme into low and high tuberculosis burden, based on WHO criteria. We identified national policy documents on management of latent tuberculosis through online searches, government websites, WHO country offices and personal communication with programme managers. We made a descriptive analysis with a focus on policy gaps and deviations from WHO policy recommendations. Findings: We obtained documents from 68 of 113 low-burden countries and 30 of 35 countries with the highest burdens of tuberculosis or human immunodeficiency virus (HIV)-associated tuberculosis. Screening and treatment of latent tuberculosis infection in people living with HIV was recommended in guidelines of 29 (96.7%) high-burden and 54 (79.7%) low-burden countries. Screening for children aged < 5 years with household tuberculosis contact was the policy of 25 (83.3%) high- and 28 (41.2%) low-burden countries. In most high-burden countries the recommendation was symptom screening alone before treatment, whereas in all low-burden countries it was testing before treatment. Some low-burden countries' policies did not comply with WHO recommendations: nine (13.2%) recommended tuberculosis preventive treatment for travellers to high-burden countries and 10 (14.7%) for patients undergoing abdominal surgery. Conclusion: Lack of solid evidence on certain aspects of management of latent tuberculosis infection results in national policies which vary considerably. This highlights a need to advance research and develop clear, implementable and evidence-based WHO policies. PMID- 29531417 TI - Medicine procurement and the use of flexibilities in the Agreement on Trade Related Aspects of Intellectual Property Rights, 2001-2016. AB - Millions of people, particularly in low- and middle-income countries, lack access to effective pharmaceuticals, often because they are unaffordable. The 2001 Ministerial Conference of the World Trade Organization (WTO) adopted the Doha Declaration on the TRIPS (Trade-Related Aspects of Intellectual Property Rights) Agreement and Public Health. The declaration recognized the implications of intellectual property rights for both new medicine development and the price of medicines. The declaration outlined measures, known as TRIPS flexibilities, that WTO Members can take to ensure access to medicines for all. These measures include compulsory licensing of medicines patents and the least-developed countries pharmaceutical transition measure. The aim of this study was to document the use of TRIPS flexibilities to access lower-priced generic medicines between 2001 and 2016. Overall, 176 instances of the possible use of TRIPS flexibilities by 89 countries were identified: 100 (56.8%) involved compulsory licences or public noncommercial use licences and 40 (22.7%) involved the least developed countries pharmaceutical transition measure. The remainder were: 1 case of parallel importation; 3 research exceptions; and 32 non-patent-related measures. Of the 176 instances, 152 (86.4%) were implemented. They covered products for treating 14 different diseases. However, 137 (77.8%) concerned medicines for human immunodeficiency virus infection and acquired immune deficiency syndrome or related diseases. The use of TRIPS flexibilities was found to be more frequent than is commonly assumed. Given the problems faced by countries today in procuring high-priced, patented medicines, the practical, legal pathway provided by TRIPS flexibilities for accessing lower-cost generic equivalents is increasingly important. PMID- 29531418 TI - Integrating tuberculosis and antimicrobial resistance control programmes. AB - Many low- and middle-income countries facing high levels of antimicrobial resistance, and the associated morbidity from ineffective treatment, also have a high burden of tuberculosis. Over recent decades many countries have developed effective laboratory and information systems for tuberculosis control. In this paper we describe how existing tuberculosis laboratory systems can be expanded to accommodate antimicrobial resistance functions. We show how such expansion in services may benefit tuberculosis case-finding and laboratory capacity through integration of laboratory services. We further summarize the synergies between high-level strategies on tuberculosis and antimicrobial resistance control. These provide a potential platform for the integration of programmes and illustrate how integration at the health-service delivery level for diagnostic services could occur in practice in a low- and middle-income setting. Many potential mutual benefits of integration exist, in terms of accelerated scale-up of diagnostic testing towards rational use of antimicrobial drugs as well as optimal use of resources and sharing of experience. Integration of vertical disease programmes with separate funding streams is not without challenges, however, and we also discuss barriers to integration and identify opportunities and incentives to overcome these. PMID- 29531419 TI - Fiscal policy to improve diets and prevent noncommunicable diseases: from recommendations to action. AB - The World Health Organization has recommended that Member States consider taxing energy-dense beverages and foods and/or subsidizing nutrient-rich foods to improve diets and prevent noncommunicable diseases. Numerous countries have either implemented taxes on energy-dense beverages and foods or are considering the implementation of such taxes. However, several major challenges to the implementation of fiscal policies to improve diets and prevent noncommunicable diseases remain. Some of these challenges relate to the cross-sectoral nature of the relevant interventions. For example, as health and economic policy-makers have different administrative concerns, performance indicators and priorities, they often consider different forms of evidence in their decision-making. In this paper, we describe the evidence base for diet-related interventions based on fiscal policies and consider the key questions that need to be asked by both health and economic policy-makers. From the health sector's perspective, there is most evidence for the impact of taxes and subsidies on diets, with less evidence on their impacts on body weight or health. We highlight the importance of scope, the role of industry, the use of revenue and regressive taxes in informing policy decisions. PMID- 29531420 TI - Knowledge integration in One Health policy formulation, implementation and evaluation. AB - The One Health concept covers the interrelationship between human, animal and environmental health and requires multistakeholder collaboration across many cultural, disciplinary, institutional and sectoral boundaries. Yet, the implementation of the One Health approach appears hampered by shortcomings in the global framework for health governance. Knowledge integration approaches, at all stages of policy development, could help to address these shortcomings. The identification of key objectives, the resolving of trade-offs and the creation of a common vision and a common direction can be supported by multicriteria analyses. Evidence-based decision-making and transformation of observations into narratives detailing how situations emerge and might unfold in the future can be achieved by systems thinking. Finally, transdisciplinary approaches can be used both to improve the effectiveness of existing systems and to develop novel networks for collective action. To strengthen One Health governance, we propose that knowledge integration becomes a key feature of all stages in the development of related policies. We suggest several ways in which such integration could be promoted. PMID- 29531421 TI - Beyond hypertension: integrated cardiovascular care as a path to comprehensive primary care. PMID- 29531422 TI - Leadership, action, learning and accountability to deliver quality care for women, newborns and children. PMID- 29531423 TI - Trajectories of Unintended Fertility. AB - Having an unintended birth is strongly associated with the likelihood of having later unintended births. We use detailed longitudinal data from the Add Health Study (N=8,300) to investigate whether a host of measured sociodemographic, personality, and psychosocial characteristics select women into this "trajectory" of unintended childbearing. While some measured characteristics and aspects of the unfolding life course are related to unintended childbearing, explicitly modeling these effects does not greatly attenuate the association of an unintended birth with a subsequent one. Next, we statistically control for unmeasured time invariant covariates that affect all birth intervals, and again find that the association of an unintended birth with subsequent ones remains strong. This persistent, strong association may be the direct result of experiencing an earlier unplanned birth. We propose several mechanisms that might explain this strong association. PMID- 29531424 TI - The Five Key Questions of Human Performance Modeling. AB - Via building computational (typically mathematical and computer simulation) models, human performance modeling (HPM) quantifies, predicts, and maximizes human performance, human-machine system productivity and safety. This paper describes and summarizes the five key questions of human performance modeling: 1) Why we build models of human performance; 2) What the expectations of a good human performance model are; 3) What the procedures and requirements in building and verifying a human performance model are; 4) How we integrate a human performance model with system design; and 5) What the possible future directions of human performance modeling research are. Recent and classic HPM findings are addressed in the five questions to provide new thinking in HPM's motivations, expectations, procedures, system integration and future directions. PMID- 29531425 TI - Cohabitation and Intimate Partner Violence during Emerging Adulthood: High Constraints and Low Commitment. AB - In recent years, a majority of young adults experience cohabitation. Nevertheless, cohabitation is a risk factor for intimate partner violence (IPV). Drawing on social exchange and commitment theory we analyzed young adults' IPV experiences using the recently collected (2011-2012) Toledo Adolescent Relationships Study data (n = 926). We found that sociodemographic characteristics, relationship commitment, quality, and constraints as well as prior experience with violence (in prior relationships and family of origin) were associated with IPV, but did not explain the association between cohabitation and IPV. We examined variation among individuals in cohabiting relationships to determine which cohabitors face the greatest risk of intimate partner violence. Serial cohabitors along with cohabitors who experienced both low commitment and high relational constraints experienced the greatest risk of IPV. These findings provided insights into the implications of cohabitation for the well-being of young adults. PMID- 29531426 TI - MARRIAGE AND DISSOLUTION AMONG WOMEN'S COHABITATIONS: VARIATIONS BY STEPFAMILY STATUS AND SHARED CHILDBEARING. AB - Cohabiting unions increasingly involve children, either born during the union and/or from prior relationships (i.e., stepchildren). Drawing from arguments about the institutionalization of cohabitation and stepfamilies as well as the family systems perspective, this paper examines dissolution and marriage risks among women's cohabiting unions by stepfamily status, configuration (which partner has children) and shared intended and unintended fertility using the 2006 2013 National Survey of Family Growth. A minority (32%) of 1st cohabitations, but the majority of 2nd (65%) and 3rd (75%) cohabitations, are stepfamilies. Stepfamily cohabitations are less likely to transition to marriage compared to non-stepfamily unions, especially among complex stepfamilies (both partners have children), but neither stepfamily status nor configuration affect dissolution. Shared intended and unintended births are associated with dissolution and marriage risks but largely only for non-stepfamily cohabitations, suggesting that shared childbearing is only indicative of the institutionalization for cohabitations that are not stepfamilies. PMID- 29531427 TI - Short-term Impacts of an Unconditional Cash Transfer Program on Child Schooling: Experimental Evidence from Malawi. AB - This study analyzes the impact of a positive income shock on child schooling outcomes using experimental data from an unconditional cash transfer program in Malawi. Since households receive the cash and parents are responsible for making spending decisions, we also examine the intervening pathways between cash transfers and child schooling. Data comes from a cluster-randomized study of Malawi's Social Cash Transfer Program (SCTP). After a baseline survey, households in village clusters were randomly assigned to treatment and control arms with treatment villages receiving transfers immediately and control villages assigned a later entry. We test for treatment impacts on a panel of school-aged children (6-17) using a differences-in-differences model. After a years' worth of transfers, we find the Malawi SCTP both improves enrollment rates and decreases dropouts. The main intervening pathway between the program and schooling is education expenditures, suggesting that the cash improves the demand for education by reducing financial constraints. PMID- 29531429 TI - Detect-Treat-Prevent-Build: Strategy for TB Elimination in India by 2025. PMID- 29531428 TI - Accurate, predictable, repeatable micro-assembly technology for polymer, microfluidic modules. AB - A method for the design, construction, and assembly of modular, polymer-based, microfluidic devices using simple micro-assembly technology was demonstrated to build an integrated fluidic system consisting of vertically stacked modules for carrying out multi-step molecular assays. As an example of the utility of the modular system, point mutation detection using the ligase detection reaction (LDR) following amplification by the polymerase chain reaction (PCR) was carried out. Fluid interconnects and standoffs ensured that temperatures in the vertically stacked reactors were within +/- 0.2 C degrees at the center of the temperature zones and +/- 1.1 C degrees overall. The vertical spacing between modules was confirmed using finite element models (ANSYS, Inc., Canonsburg, PA) to simulate the steady-state temperature distribution for the assembly. Passive alignment structures, including a hemispherical pin-in-hole, a hemispherical pin in-slot, and a plate-plate lap joint, were developed using screw theory to enable accurate exactly constrained assembly of the microfluidic reactors, cover sheets, and fluid interconnects to facilitate the modular approach. The mean mismatch between the centers of adjacent through holes was 64 +/- 7.7 MUm, significantly reducing the dead volume necessary to accommodate manufacturing variation. The microfluidic components were easily assembled by hand and the assembly of several different configurations of microfluidic modules for executing the assay was evaluated. Temperatures were measured in the desired range in each reactor. The biochemical performance was comparable to that obtained with benchtop instruments, but took less than 45 min to execute, half the time. PMID- 29531430 TI - How Multipurpose Health Workers Spend Time During Work? Results from a Time-and motion Study from Puducherry. AB - Background: A multipurpose health worker (MPHW) is the key functionary and the first contact person in a subcenter. This study explores the workload of MPHWs in the multifarious domains of their activities and also assesses their time utilization pattern. Methods: A time and motion study was conducted among 19 auxiliary nurse midwives (ANMs) and 10 HWs male (M) from six selected primary health centers of Puducherry. Participants self-reported their daily activities on a time measurement sheet for 6 days in a week. Data were entered in EpiData software and analyzed using Excel. Calculations are based on a total of 646 and 340 person-hours of observation by ANMs and HWs (M), respectively. Results: Time utilization pattern revealed that ANMs spent half of their time on maternal and child health activities. HWs (M) utilized 45% of their time for vector control programs and 11% for other programs. Documentation constituted nearly 16% and 10% time spent by ANMs and HWs (M), respectively. Other activities that constituted multipurpose workers' time utilization include traveling (8-10%), patient education (5-10%) and personal activities (6-12% ). The proportion of time spent in community activities was around 54% by HWs (M) and 32% by ANMs. Observations on self-reporting were comparable with that of participant observations. Conclusions: This study reflects the workload in different domains of MPHWs' activities and the "multipurpose" nature of their work, relevance of their job responsibilities in the context of national programs, and changing profile of their job. PMID- 29531431 TI - A Comparative Study of Health Status and Quality of Life of Elderly People Living in Old Age Homes and within Family Setup in Raigad District, Maharashtra. AB - Background: The traditional concept of family in India to provide support to the elderly is changing soon with disintegration of joint families. In this scenario the concept of old age homes (OAHs) is gaining momentum and the number of people seeking OAH care is rapidly increasing. However, not much is known about the quality of life (QOL) of Indian elderly staying in the OAH setup. Objectives: To assess and compare the Health status, Quality of Life and Depression in elderly people living in OAHs & within family using WHOQOL -OLD questionnaire & Geriatric Depression Scale. Methods: A cross sectional study was conducted in elderly aged above 60 years of age. After taking a written consent and matching for age and sex & socioeconomic status, 60 elderly from OAHs & 120 elderly living within family setup were selected randomly. The WHOQOL-OLD standard questionnaire & GDS were used to assess quality of life & depression in elderly. Result: The QOL of elderly in domains of autonomy, past present & future activities, social participation and intimacy was better in family setup (60.62, 70.62, 66.14 and 58.43) as compared to OAHs (51.35, 62.91, 59.47and 41.16) (p<0.05). There was statistically significant difference in mean geriatric depression scores of both the group (3.96 within family setup and 5.76 in OAH's). Conclusion: Quality of life of elderly within family setup was better as compared to elderly in OAHs. PMID- 29531432 TI - A Step toward Healthy Newborn: An Assessment of 2 Years' Admission Pattern and Treatment Outcomes of Neonates Admitted in Special Newborn Care Units of Gujarat. AB - Context: Facility Based Newborn Care (FBNC) is a key strategy to improve child survival, especially in newborn care where neonatal mortality rate (NMR) is stagnant in declining. Gujarat has achieved considerable amount of reduction in child deaths, but neonatal health requires attention. The study was aimed to assess the admission pattern of Special Newborn Care Units (SNCUs) which supports decision-making. Settings and Design: A cross-sectional descriptive analysis was done from secondary data of the SNCU reports on the aspects of admission patterns, morbidity, and mortality pattern. The reports had been analyzed on various critical variables. Results: In 2015-2016, Gujarat has operationalized forty SNCUs by saturating each district with at least one SNCU. The study found near proportions of (53%) inborn - (47%) outborn admission and 44% admission of female. Out of 69,662 admissions, 67% were discharged, 16% died, 10% leaving against medical advice, and 7% referred to higher centers. Major reasons for admission were respiratory distress syndrome (RDS) (22%) and infection (21%). Similar pattern in mortality found as final diagnosis of deaths was RDS (23%) and infection (21%). The proportion of neonatal deaths in outborn was high compared to inborn. Conclusion: Strengthening of FBNC is essential to address neonatal mortality. NMR is of prime focus because the health interventions needed to tackle NMR differ from those needed for infant mortality rate and under-five mortality rate. This accentuates the need for focused attention on facility- and community-based child health interventions along with quality maternal health services and robust referral mechanisms to all delivery points. PMID- 29531433 TI - Capacity Assessment of District Health System in India on Services for Prevention and Management of Infertility. AB - Background: Infertility is a neglected service component in the public health care system in India. Objectives: This study aims to assess the availability and practices on prevention and management services for infertility in the district health system. Methodology: A cross-sectional survey of selected health facilities and the staff from 12 district hospitals (DHs), 24 community health centers (CHCs), 48 primary health centers (PHCs), and 48 subcenters was conducted using qualitative and quantitative methods. Interviewed staff included 26 gynecologists; 91 medical officers; 91 auxiliary nurse midwife; 67 laboratory technicians; and 84 accredited social health activist workers. Results: The findings indicate that adequate staff was in place at more than 70% of health facilities, but none of the staff had received any in-service training on infertility management. Most of the DHs had basic infrastructural and diagnostic facilities. However, the majority of the CHCs and PHCs had inadequate physical and diagnostic facilities related to infertility management. Semen examination service was not available at 94% of PHCs and 79% of CHCs. Advanced laboratory services were available in <42% at DHs and 8% at CHCs. Diagnostic laparoscopy and hysteroscopy were available in 25% and 8% of DHs, respectively. Ovulation induction with clomiphene was practiced at 83% and with gonadotropins at 33% of DHs. Conclusion: The district health infrastructure in India has a potential to provide basic services for infertility. With some policy decisions, resource inputs and capacity strengthening, it is possible to provide advanced services for infertility in the district health system. PMID- 29531434 TI - Metabolic Syndrome among Adults of Surendranagar District of Saurashtra, Gujarat: A Cross-Sectional Study. AB - Background: The metabolic syndrome (MetS) is a complex disorder and a major health concern in developing countries. Data on MetS in Indian population show multiplicity. There are no published reports about the prevalence of MetS in population of Saurashtra region, Gujarat. The aim of this study is to assess the prevalence of MetS and its components in adult population of this region. Methods: This cross-sectional observational study was carried out among 473 participants who attended free health checkup camps. Demographics, personal details along with anthropometric, clinical, and biochemical data were recorded. The MetS was diagnosed as per the definition provided by Joint Interim Statement 2009. Results: The overall prevalence of MetS among studied population was found to be 41.01% (females 44.21% and males 37.91%). Abdominal obesity (66.38%), low high-density lipoprotein-cholesterol (64.69%), and high blood pressure (40.59%) appeared as the most prevalent components. MetS showed a significant association with age, body mass index, total cholesterol, habit of chewing tobacco, and history of hypertension and hyperglycemia. Conclusion: The high prevalence of MetS shows that population of Saurashtra is at an increased risk of cardiovascular disease (CVD) and diabetes. This highlights the need for extensive diabetes and CVD prevention and control program in this region. PMID- 29531435 TI - The Tolerability and Efficacy of Oral Isotonic Solution versus Plain Water in Dengue Patients: A Randomized Clinical Trial. AB - Background: Plasma leakage plays an important role in dengue infection, and this condition can lead to hemoconcentration, hypovolemia, and shock. Fluid replacement is the main treatment for dengue. There is a lack of evidence to support certain oral fluid therapy as a treatment for dengue patients. Objectives: The objective of this study is to evaluate tolerability and efficacy of oral isotonic solution (OIS) compared to plain water as a fluid replacement in dengue patients. Materials and Methods: A randomized, clinical trial with single blinded groups was conducted to compare tolerability and efficacy of OIS and plain water in dengue patients. We evaluated gastrointestinal disturbances (nausea, vomiting, and bloating), body temperature, mean arterial pressure (MAP), fluid balance, hematocrit, Na+, and K+ levels. Data were analyzed with SPSS 20.0, and figures were made with GraphPad Prism version 5.01. Results: Twenty four subjects were included and divided equally into two groups. Our results showed that there are no significant differences but indicate several noteworthy trends. The intervention group (OIS) experienced less nausea, less vomiting, had positive fluid balance and higher MAP, and became afebrile faster compared to the control group (plain water). Conclusion: Although not statistically significant, this study shows the trend that OIS is well-tolerated and effective for dengue patients compared to plain water. PMID- 29531436 TI - Dietary Diversity and Stunting among Infants and Young Children: A Cross sectional Study in Aligarh. AB - Context: Child undernutrition is a public health problem in a developing country like India. Dietary diversity is an important immediate determinant of undernutrition. Aims: The aim of this study is to find the prevalence of stunting among infants and young children aged 6-23 months and its association with dietary diversity. Settings and Design: This study was community-based cross sectional study. It was carried out in the registered families of the Urban Health Training Centre and Rural Health Training Centre, Department of Community Medicine, Jawaharlal Nehru Medical College, AMU, Aligarh. Methods: A total of 326 children aged 6-23 months were included in the study. Study tools were predesigned and pretested questionnaire, modified infant and young child feeding practices questionnaire, and infantometer. Systematic random sampling with probability proportionate to size technique was utilized to drawn necessary sample size. Statistical analysis: Wald's statistics, Z-scores, and bivariate and multivariate logistic regression (LR) (stepwise backward LR) were used. Results: The prevalence of stunting in study population was 45.7% (95% CI - 40.1%, 51.1%); moderate stunting was 33.7% (95% CI - 28.8%, 39%); and severe stunting was 12% (95% CI - 8.8%, 16%). The prevalence of stunting was significantly associated with dietary diversity (OR - 0.17, 95% CI - 0.10-0.29). Conclusions: The study concludes that dietary diversity is a significant predictor of stunting. Therefore, interventions aimed at improving dietary diversity should be taken to reduce the burden of stunting among infants and young children. PMID- 29531437 TI - Assessment of Perception and Effectiveness of Concept Mapping in Learning Epidemiology. AB - Background and Objectives: Current programs in medical education technology concentrate mainly upon "how-to-teach." The focus is needed on learner's memory retention too. An innovative strategy like concept mapping might be a way forward. The study was carried out to assess its effectiveness and to know students' perceptions. Materials and Methods: During community medicine classes, a student-group was sensitized on how to make and use concept maps out of taught contents. At the end of epidemiology exercises sessions, this group was given additional minutes to prepare concept maps, interact, and brainstorm followed by quick QA session. Others were taught same contents in conventional way. Performances of both groups were assessed in one immediate (term-ending) and one distant (preliminary) exam. Feedback was also taken from study group. Results: Study group consistently scored higher in both exams. Difference in scored mean marks was highly significant in term-ending-examination (P < 0.0001, t = 5.754, df = 121.9). Largely positive feedback was received on utility of concept maps in memorizing, confidence-boosting, and understanding subject. Felt need for innovations in conventional teaching-learning (T-L) was palpable. Conclusion: Time has come to start focusing on enhancing students' learning. Performance enhancing utility of concept maps is proven and should be integrated in regular T L. PMID- 29531438 TI - An Alternative Approach for Supportive Supervision and Skill Measurements of Health Workers for Integrated Management of Neonatal and Childhood Illnesses Program in 10 Districts of Haryana. AB - Context: "Integrated Management of Neonatal and Childhood Illnesses" (IMNCI) needs regular supportive supervision (SS). Aims: The aim of this study was to find suitable SS model for implementing IMNCI. Settings and Design: This was a prospective interventional study in 10 high-focus districts of Haryana. Subjects and Methods: Two methods of SS were used: (a) visit to subcenters and home visits (model 1) and (b) organization of IMNCI clinics/camps at primary health center (PHC) and community health center (CHC) (model 2). Skill scores were measured at different time points. Routine IMNCI data from study block and randomly selected control block of each district were retrieved for 4 months before and after the training and supervision. Statistical Analysis Used: Change in percentage mean skill score difference and percentage difference in median number of children were assessed in two areas. Results: Mean skill scores increased significantly from 2.1 (pretest) to 7.0 (posttest 1). Supportive supervisory visits sustained and improved skill scores. While model 2 of SS could positively involve health system officials, model 1 was not well received. Outcome indicator in terms of number of children assessed showed a significant improvement in intervention areas. Conclusions: SS in IMNCI clinics/camps at PHC/CHC level and innovative skill scoring method is a promising approach. PMID- 29531439 TI - An Analysis of Integrated Child Development Scheme Performance in Contributing to Alleviation of Malnutrition in Two Economically Resurgent States. AB - Background: Good economic growth is considered synonymous with good nutrition. In recent past, some states (like Bihar and Gujarat) have seen unprecedented economic growth. Despite this and introducing plethora of programs (including integrated child development scheme [ICDS]) to reduce malnutrition, one state might be performing well in reducing malnutrition whereas other with equally high economic growth rate might lag behind. Is mere economic growth good enough to alleviate malnutrition? Objectives: The aim of the article is to document a critical comparative analysis of malnutrition with special emphasis on ICDS (with respect to finances, infrastructure, training, performance) in the two economically resurgent states of Gujarat and Bihar. Material and Methods: An exploratory study using secondary data sources (for ICDS performance) to critically analyze malnutrition status in Bihar and Gujarat. Results: Gujarat, which was criticized for placing excessive emphasis on economic growth, has shown sharp improvement in combating malnutrition. Undernourished children declined from 73.04% in 2007 to 25.09% in 2013, with just 1.6% being severely malnourished. On the other hand, Bihar too exhibited an impressive economic growth but still languishes at bottom with malnutrition rate of 82%. Conclusion: A high economic growth does not have automatic immediate positive gains on malnutrition alleviation. PMID- 29531440 TI - Depression Effects on Hospital Cost of Heart Failure Patients in California: An Analysis by Ethnicity and Gender. AB - Background: Depression often interferes with self-management and treatment of medical conditions. This may result in serious medical complications and escalated health-care cost. Objectives: Study distribution of heart failure (HF) cases estimates the prevalence of depression and its effects on HF-related hospital costs by ethnicity and gender. Methods: Secondary data files of California Hospital Discharge System for he year 2010 were examined. For patients with a HF diagnosis, details regarding depression, demographics, comorbid conditions, and hospital costs were studied. Age-adjusted HF rates and depression were examined for whites, blacks, Hispanics, and Asians/Pacific Islanders (AP) by comparing HF patients with depression (HF+D) versus HF without depression (HFND). Results: HF cases (n = 62,685; average age: 73) included nearly an equal number of males and females. HF rates were higher (P < 0.001) among blacks compared to Hispanics, AP, and whites and higher among males than females. One-fifth of HF patients had depression, higher among females and whites compared to males and other ethnic groups. Further, HF hospital costs for blacks and AP were higher (P < 0.001) compared to other groups. The cost for HF+D was 22% higher compared to HFND, across all gender and ethnic groups, largely due to higher comorbidities, more admissions, and longer hospitalization. Conclusion: Depression, ethnicity, and gender are all associated with increased hospital costs of HF patients. The higher HF and HF+D costs among blacks, AP, and males reflect additional burden of comorbidities (hypertension and diabetes). Prospective studies to assess if selective screening and treating depression among HF patients can reduce hospital costs are warranted. PMID- 29531441 TI - Factors Affecting Compliance to Antihypertensive Treatment among Adults in a Tertiary Care Hospital in Mumbai. AB - Background: Compliance to antihypertensive therapy reduces the risk of complications. It is important to understand the factors affecting compliance in patients so that the goal of successful treatment is not jeopardized. Objectives: To determine the proportion of participants' compliant to treatment and various factors associated with compliance of antihypertensive treatment. Settings and Design: A cross-sectional study of 330 hypertensive patients on treatment attending the outpatient department of a tertiary care hospital in Mumbai. Subjects and Methods: It was conducted over 8 weeks using a validated, pretested questionnaire including information on the individual's sociodemographic profile, compliance to antihypertensive therapy and lifestyle advice assessed using a 4 point Likert scale. Statistical Analysis: Data were entered into MS Excel 2007 and analyzed using SPSS 20. Results: Participants' mean age was 55.2 +/- 12.6 years. 39.4% were compliant to their treatment. Common reasons for frequently skipping the dose - forgetfulness (41.2%) and discontinued the medication when feeling well (30.3%). Factors positively associated with compliance were gender and illiteracy. The proportion of noncompliance among smokers and alcoholics was statistically significant. Conclusion: Forgetfulness and subjective feeling of wellness were the prevalent reasons for noncompliance. Controlling habits such as smoking and alcohol may prove as key factors for compliance. PMID- 29531442 TI - Analysis of Medical Students Perception for Community Medicine as Career Option and Subject. PMID- 29531443 TI - Final Leprosy Push: Out of Society. PMID- 29531444 TI - Profile of Patients with Active Tuberculosis Admitted to a Respiratory Intensive Care Unit in a Tertiary Care Center of North India. AB - Background: There is a paucity of literature regarding outcome of critically ill patients with tuberculosis (TB) from India. Herein, we describe our experience of patients with active TB admitted to a Respiratory Intensive Care Unit (RICU) of a tertiary care hospital. Methods: This was a retrospective analysis of all the patients admitted with active TB. The baseline clinical, demographic, ICU parameters and mortality were recorded. A multivariate logistic regression analysis was performed to identify factors predicting mortality. Results: A total 3630 patients were admitted to the ICU during the study period; of these, 63 (1.7%) patients (mean [standard deviation (SD)] age 37.3 [19] years, 55.6% females) were admitted with active TB. Fifty-seven patients were mechanically ventilated (56, invasive and 1, noninvasive) for a mean (SD) duration of 7.5 (9.1) days. Respiratory failure was the most common indication for mechanical ventilation. TB-related acute respiratory distress syndrome was seen in 18 (28.6%) patients. There were 28 deaths (44.4%) during the study period. On a multivariate logistic regression analysis, a high baseline Acute Physiology and Chronic Health Evaluation II (APACHE II) score (odds ratio [OR] [95 confidence interval (CI)], 1.12 [1.02-1.23]) and delta Sequential Organ Failure Assessment (SOFA) (OR [95 CI], 1.39 [1.00-1.94]) were the independent predictors of mortality. Conclusion: TB was an uncommon cause of ICU admission even in a high TB burden country. Critically ill patients with TB had high mortality. A higher APACHE II score and delta SOFA were independent predictors of ICU mortality. PMID- 29531445 TI - Colistin versus Colistin Combined with Ampicillin-Sulbactam for Multiresistant Acinetobacter baumannii Ventilator-associated Pneumonia Treatment: An Open-label Prospective Study. AB - Background: Retrospective studies have reported good clinical success rates using colistin as monotherapy to treat Acinetobacter baumannii ventilator-associated pneumonia (VAP), comparable to that obtained with colistin combined with other antibiotics. However, inadequate penetration into the pulmonary parenchyma for colistin has been shown in animal models. Aim: The aim of the study was to study prospectively the outcome, measured as clinical response and survival, of intravenously administered colistin versus colistin combined with high-dose ampicillin-sulbactam in Intensive Care Unit (ICU) patients with multiresistant A. baumannii VAP. Methods and Subjects: This prospective, open-label, randomized study included consecutive patients who developed microbiologically documented VAP due to A. baumannii with carbapenem-resistant strains but susceptible to colistin and ampicillin-sulbactam. Seventy-four patients were screened, but finally, 39 participants were enrolled and finished the study Patients received colistin (Group A - 19 patients) or colistin and ampicillin/sulbactam (Group B - 20 patients). The clinical response of VAP was assessed on day 4th to 5th of treatment (early response). If therapy was considered unsuccessful after this period, ampicillin/sulbactam was added in Group A or changed therapy in B. Results: Early cure rates in Group A and B were 15.8% and 70%, respectively (P = 0.001). Multiple regression analysis revealed that combination treatment (odds ratio [OR]: 43.6, 95% confidence interval [CI]: 3.594-530.9) and Sequential Organ Failure Assessment score <8 (OR: 0.022, 95% CI: 0.001-0.43) were independently associated with favorable clinical response. APACHE II score <=15 (OR: 0.049, 95% CI: 0.003-0.0942) and an early favorable response to treatment (OR: 244.4, 95% CI: 2.151-27850.9) were associated with survival and discharge from ICU. Conclusion: Combination therapy with colistin and a high dose of ampicillin/sulbactam was associated with a more favorable clinical response to VAP due to carbapenem-resistant A. baumannii than colistin monotherapy. PMID- 29531446 TI - Diagnostic Value of Procalcitonin in Predicting Bacteremia in Intensive Care Unit. AB - Background and Aims: Several biomarkers are used in the diagnosis of bacteremia. Procalcitonin (PCT) is more specific than other biomarkers in differentiating bacterial and nonbacterial inflammation. It was aimed to evaluate the diagnostic and prognostic value of PCT in bacteremic patients in Intensive Care Unit (ICU). Materials and Methods: A total of 156 patients diagnosed with noninfectious systemic inflammatory response syndrome, sepsis, and severe sepsis/septic shock in ICU between December 2014 and July 2015 were evaluated in this prospective cohort study. Results: The study group consisted of 64 (41%) bacteremic patients and the control group consisted of 92 (59%) nonbacteremic patients. The overall mortality rate was 60.3%. Although PCT levels in the bacteremic group (11.9 +/- 21.5 ng/dL) were higher than nonbacteremic group (5.9 +/- 11.5 ng/dL), this difference was not significant (P = 0.168). The mean levels of PCT in bacteremic patients with Gram-negative bacteria were 16.3 +/- 27.6 ng/dL, whereas Gram positive bacteria were 7.3 +/- 10.7 ng/dL (P = 0.145). The mean PCT levels were significantly higher in nonsurvivors compared to survivors (10.1 +/- 18.0 vs. 5.7 +/- 13.7 ng/dL; P < 0.001). Conclusions: PCT may be an effective biomarker for diagnosing sepsis and predicting disease severity and mortality. There is a need for further well-designed studies to confirm the diagnostic and prognostic value of PCT in septic patients in critical care. PMID- 29531447 TI - Comparative Study between Noninvasive Continuous Positive Airway Pressure and Hot Humidified High-flow Nasal Cannulae as a Mode of Respiratory Support in Infants with Acute Bronchiolitis in Pediatric Intensive Care Unit of a Tertiary Care Hospital. AB - Background: Early initiation of appropriate noninvasive respiratory support is utmost important intervention to avoid mechanical ventilation in severe bronchiolitis. Aim: This study aims to compare noninvasive continuous positive airway pressure (nCPAP) and hot humidified high-flow nasal cannulae (HHHFNC) as modes of respiratory support in infants with severe bronchiolitis. Methods: Prospective, randomized, open-label pilot study done in a tertiary-care hospital Pediatric Intensive Care Unit (PICU). Participants: 31 infants (excluding neonates) clinically diagnosed with acute bronchiolitis having peripheral capillary oxygen saturation (SpO2) <92% (with room air oxygen); Respiratory Distress Assessment Index (RDAI) >=11. Intervention: nCPAP (n = 16) or HHHFNC (n = 15), initiated at enrollment. Primary outcome: Reduction of need of mechanical ventilation assessed by improvements in (i) SpO2% (ii) heart rate (HR); respiratory rate; (iii) partial pressure of carbon dioxide; (iv) partial pressure of oxygen; (v) COMFORT Score; (vi) RDAI from preintervention value. Secondary outcome: (i) total duration of noninvasive ventilation support; (ii) PICU length of stay; and (iii) incidence of nasal injury (NI). Results: Mean age was 3.41 +/- 1.11 months (95% confidence interval 2.58-4.23). Compared to nCPAP, HHHFNC was better tolerated as indicated by better normalization of HR (P < 0.001); better COMFORT Score (P < 0.003) and lower incidence of NI (46.66% vs. 75%; P = 0.21). Improvements in other outcome measures were comparable for both groups. For both methods, no major patient complications occurred. Conclusion: HHHFNC is an emerging alternative to nCPAP in the management of infants with acute bronchiolitis. PMID- 29531448 TI - Relationship of Serum Procalcitonin, C-reactive Protein, and Lactic Acid to Organ Failure and Outcome in Critically Ill Pediatric Population. AB - Objective: To evaluate the clinical and prognostic utility of procalcitonin (PCT), C-reactive protein (CRP), and lactic acid in children admitted to the Pediatric Intensive Care Unit (PICU) of a university teaching hospital. Materials and Methods: Medical records of children (1 month-16 years) tested for serum PCT at the time of admission in the PICU of our hospital from July 1, 2013, to January 15, 2015, were reviewed. Within 24 h of admission, the Pediatric Risk of Mortality Score, blood cultures, white blood cell count, neutrophil counts, serum CRP, plasma lactic acid, and PCT were noted. Patient outcome was assessed at hospital discharge, and the patients were divided into nonsurvivors and survivors. Results: A total of 167 children being admitted to the PICU were enrolled. The median age of the study population was 3 years (0-16 years), with 58.6% being males. Nonsurvivors had significantly higher lactic acid (4.7 mmol/L [2.07-7.6]; P < 0.05) than that of the survivors (2 mmol/L [1.3-3]; P < 0.05). In addition, nonsurvivors (94.4%; P < 0.05) had greater incidence of multiple organ dysfunction syndrome (MODS) than that of the survivors (38.05%; P < 0.05). Binary logistic regression showed age, MODS, and lactic acid to be associated with mortality. Conclusions: This study found that in comparison to PCT and CRP, high plasma lactic acid levels are associated with the development of all-cause MODS and worse outcome in critically ill children admitted in PICU. Prediction of prognosis based on the lactic acid alone may contribute to improve patient management, but further studies are required to endorse our findings. PMID- 29531449 TI - Serum Estradiol Level at Intensive Care Unit Admission and Mortality in Critically Ill Patients. AB - Context: It has been observed that sex hormones may play a role in inflammatory processes and mortality of critically ill patients. Aims: The aim was evaluated the relationship between serum estradiol level at Intensive Care Unit (ICU) admission and mortality of critically ill patients. Settings and Design: This study was a prospective cohort conducted in one mixed ICU. Subjects and Methods: In heterogeneous group of critically ill patients admitted to the ICU, we measured serum estradiol at admission time. Statistical Analysis Used: The discrimination to predict mortality of serum estradiol level was assessed by the receiver-operating curve (ROC) curve and its association with mortality by logistic regression analysis. Results: We included 131 patients, 57.3% of which were male. The serum estradiol level measured at ICU admission was significantly higher in nonsurvivors than in survivors: 116 versus 67.2 pg/mL, respectively (P < 0.0001). The area under the ROC of serum estradiol level to predict mortality was 0.74 (P < 0.0001). Serum estradiol level >=97.9 pg/mL had sensitivity of 60%, specificity of 90%, positive predictive value of 64%, negative predictive value of 88%, positive likelihood ratio of 6, and negative likelihood ratio of 0.44, for predicting mortality. In multivariate analysis, it had relative risk of 6.47 (P = 0.002) for ICU mortality. Conclusions: The serum estradiol level is elevated in critically ill patients, regardless of gender, especially in those who die. It has good discriminative capacity to predict mortality, and it is an independent risk factor for death in this group of patients. PMID- 29531450 TI - Immediate Effects of Acapella(r) on Dynamic Lung Compliance in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome: A Case Series. AB - Background and Aims: One potential complication of acute respiratory distress syndrome (ARDS) is reduced dynamic compliance, saturation for peripheral oxygenation (SpO2) and increased sputum in patients that are mechanically ventilated. Airway clearance technique is the treatment given for patients on mechanically ventilator with ARDS. The purpose of the case series is to know the immediate effects of Acapella(r) on dynamic lung compliance (Cdyn) in subject with ARDS. Subjects and Methods: Patients who are on ventilator for more than 48hrs were included in the study. Readings for Cdyn, SpO2 were noted at baseline, immediately post treatment, 10, 20, 30 and 60minutes. Pre and post treatment sputum volume was also noted. Results: Five patients were included with age range of 25 to 75 years. Clinical improvement was seen immediately after treatment in Cdyn and SpO2. There was not much change in sputum volume. Conclusion: Acapella(r) increased the dynamic compliance of lungs and sputum clearance in mechanically ventilated ARDS patients. PMID- 29531451 TI - Colistin-resistant Klebsiella pneumoniae in Surgical Polytrauma Intensive Care Unit of Level-1 Trauma Center: First Case Series from Trauma Patients in India. AB - Introduction: There have been isolated case reports and reports of outbreak of colistin-resistant Klebsiella from various parts of the world but only two from India and that too from oncology centers. We report cluster of colistin-resistant Klebsiella pneumonia bloodstream infection cases from our surgical trauma Intensive Care Unit. Methodology: The study was carried out in surgical ICU of Level-I trauma center. Retrospective analysis of all the five patients with CRK was done. Demographic data, antibiotic exposure throughout the hospital stay, hospital course, and clinical outcome were analyzed. Results: Out of 5 patients, 4 were young males (mean age of 23.5 years) without comorbidities and had undergone exploratory laparotomy following blunt trauma abdomen. 3 patients were chronic patients and had been on carbapenem and colistin 11-20 days before isolation whereas 2 patienst had isolation of CRK just within 7 days of admission. Out of the five patients, 3 patients survived and 2 had fatal outcome. Conclusions: CRK is an emerging and challenging pathogen in polytrauma victims. There was an outbreak of CRK in our ICU that could be contained with infection control measures. PMID- 29531452 TI - Scrub Typhus - A Major Cause of Pediatric Intensive Care Admission and Multiple Organ Dysfunction Syndrome: A Single-Center Experience from India. AB - Aim of the Study: Scrub typhus has been globally recognized as an emerging infectious disease contributing significantly to pyrexia of unknown origin (PUO) and a potential cause of multiorgan dysfunction syndrome (MODS). We studied the incidence of scrub typhus as a cause of pediatric intensive care unit (PICU) admission and MODS in our hospital and its clinical and laboratory characteristics to measure the incidence of MODS caused by scrub typhus. Materials and Methods: This study was done in a pediatric teaching hospital in Kolkata, India. Records of patients admitted with PUO from March 2012 to December 2015 were reviewed. Rathi-Goodman-Aghai scoring system was used to identify potential ST patients and confirmed by serological testing. Clinical characteristics, laboratory findings, and treatment response were noted of those needing PICU admissions. Results: Ninety-seven cases of scrub typhus have been identified during that period. PICU admission was needed in 30 of them (31%) which contributed 8.43% of total PICU admissions. Among these 30 patients, 16 (53%) developed MODS which contributed 18.29% of total MODS admitted in PICU. Septic shock was the most common manifestation in as many as 18 (60%) patients followed by encephalopathy in 13 (43%). Patients were treated with either doxycycline alone or in combination with azithromycin. Mean time to complete defervescence was 32 h after first dose of doxycycline. The outcome was excellent without a single mortality. Conclusion: Scrub typhus is an important cause of MODS in this part of the world, especially in fevers associated with features as identified and not responding to conventional antibiotics. PMID- 29531454 TI - The Fondaparinux Paradox: Fondaparinux-Related Heparin-induced Thrombocytopenia. AB - Fondaparinux, a pentasaccharide administered for heparin-induced thrombocytopenia (HIT), can lead to the occurrence of thrombocytopenia. This patient underwent aortic stent graft placement for Salmonella paratyphi A-infected abdominal aortic aneurysm. Fondaparinux was administered for anticoagulation that led to a dramatic decline in his platelet counts. Investigations revealed HIT profile, PF4/heparin by particle gel immunoassay to be positive. Fondaparinux, a prescribed anticoagulant for HIT can paradoxically predispose to thrombocytopenia. PMID- 29531453 TI - Extracorporeal Membrane Oxygenation in Drug Overdose: A Clinical Case Series. AB - Overdose of cardiovascular medications such as beta blockers and calcium channel blockers cause impaired cardiac contractility, vasoplegia, and/or rhythm disturbances. In addition to conventional management of limiting absorption, increasing elimination and hemodynamic support intravenous (IV) calcium infusion, hyperinsulinemia-euglycemia therapy, glucagon infusion, and IV lipid emulsion have been tried. Extracorporeal circulatory assist device support has been reported as a rescue therapy in overdose refractory to maximal medical therapy. We report three patients with cardiovascular medication overdose presenting with profound cardiovascular instability refractory to medical therapy. Venoarterial extracorporeal membrane oxygenation support (VA ECMO) was initiated to provide hemodynamic support. Despite the occurrence of device-associated complications, the outcome was good and all patients survived. VA ECMO may be considered in patients with severe refractory shock due to cardiotoxic medication overdose. PMID- 29531455 TI - Recurrent Metabolic Acidosis during High-dose Midazolam Therapy for Refractory Status Epilepticus. AB - High-dose continuous midazolam therapy has been used successfully for control of refractory status epilepticus. However, normal anion gap (AG) metabolic acidosis, a deleterious complication of this therapy is underrecognized. Even though previously reported in an isolated case report in a pediatric patient, we observed similar complication in an adult patient. Stereotyped normal AG metabolic acidosis along with hypotension developed on two occasions during high dose continuous midazolam hydrochloride infusion that reverted rapidly following cessation of the infusion. PMID- 29531456 TI - A Case of Lemierre's Syndrome in Intensive Care Unit. AB - We report a 21-year-old young male with Lemierre's syndrome presented as tonsillitis and Fusobacterium septicemia with respiratory failure and required intensive care. Lemierre's syndrome is the septic embolic complication of recent pharyngeal illness. Fusobacterium spp. accounts for the majority of cases. High index of suspicion is needed and prolonged antibiotic is advised. It is seldom seen in intensive care but should never be forgotten. PMID- 29531457 TI - Pulmonary Nocardiosis: Unusual Presentation in Intensive Care Unit. AB - Pulmonary nocardiosis is a rare disease, which mainly affects immunocompromised hosts such as uncontrolled diabetics; HIV patients; and patients on immunosuppressive therapies such as anticancer drugs, systemic steroids, and transplant recipients. The diagnosis is often missed and delayed, resulting in inappropriate treatment and thus higher mortality. We are reporting a case of pulmonary nocardiosis with acute presentation in an immune-competent host, who presented with community-acquired pneumonia to the Intensive Care Unit. Clinical expertise with multiple high-end and interventional investigations timely confirmed the case as pulmonary nocardiosis. Conservative management with medications led to her complete recovery. PMID- 29531458 TI - Cerebral Venous Thrombosis after Intravenous Immunoglobulin Therapy in Immune Thrombocytopenic Purpura. PMID- 29531459 TI - Allergic Angina Syndrome in Anesthesia and Diabetes. PMID- 29531460 TI - Quantitative and noninvasive assessment of chronic liver diseases using two dimensional shear wave elastography. AB - Two-dimensional shear wave elastography (2D-SWE) is a rapid, simple and novel noninvasive method that has been proposed for assessing hepatic fibrosis in patients with chronic liver diseases (CLDs) based on measurements of liver stiffness. 2D-SWE can be performed easily at the bedside or in an outpatient clinic and yields immediate results with good reproducibility. Furthermore, 2D SWE was an efficient method for evaluating liver fibrosis in small to moderately sized clinical trials. However, the quality criteria for the staging of liver fibrosis are not yet well defined. Liver fibrosis is the main pathological basis of liver stiffness and a key step in the progression from CLD to cirrhosis; thus, the management of CLD largely depends on the extent and progression of liver fibrosis. 2D-SWE appears to be an excellent tool for the early detection of cirrhosis and may have prognostic value in this context. Because 2D-SWE has high patient acceptance, it could be useful for monitoring fibrosis progression and regression in individual cases. However, multicenter data are needed to support its use. This study reviews the current status and future perspectives of 2D-SWE for assessments of liver fibrosis and discusses the technical advantages and limitations that impact its effective and rational clinical use. PMID- 29531461 TI - Can bacterial virulence factors predict antibiotic resistant Helicobacter pylori infection? AB - AIM: To evaluate the association between virulence factor status and antibiotic resistance in Helicobacter pylori (H. pylori)-infected patients in Ireland. METHODS: DNA was extracted from antral and corpus biopsies obtained from 165 H. pylori-infected patients. Genotyping for clarithromycin and fluoroquinolone mediating mutations was performed using the Genotype HelicoDR assay. cagA and vacA genotypes were investigated using PCR. RESULTS: Primary, secondary and overall resistance rates for clarithromycin were 50.5% (n = 53/105), 78.3% (n = 47/60) and 60.6% (n = 100/165), respectively. Primary, secondary and overall resistance rates for fluoroquinolones were 15.2% (n = 16/105) and 28.3% (n = 17/60) and 20% (n = 33/165), respectively. Resistance to both antibiotics was 12.4% (n = 13/105) in treatment-naive patients, 25% (n = 15/60) in those previously treated and 17% (n = 28/165) overall. A cagA-positive genotype was detected in 22.4% (n = 37/165) of patient samples. The dominant vacA genotype was S1/M2 at 44.8% (n = 74/165), followed by S2/M2 at 26.7% (n = 44/165), S1/M1 at 23.6% (n = 39/165) and S2/M1 at 4.8% (n = 8/165). Primary clarithromycin resistance was significantly lower in cagA-positive strains than in cagA-negative strains [32% (n = 8/25) vs 56.3% (n = 45/80) P = 0.03]. Similarly, in patients infected with more virulent H. pylori strains bearing the vacA s1 genotype, primary clarithromycin resistance was significantly lower than in those infected with less virulent strains bearing the vacA s2 genotype, [41% (n = 32/78) vs 77.8% (n = 21/27) P = 0.0001]. No statistically significant association was found between primary fluoroquinolone resistance and virulence factor status. CONCLUSION: Genotypic H. pylori clarithromycin resistance is high and cagA negative strains are dominant in our population. Less virulent (cagA-negative and vacA S2-containing) strains of H. pylori are associated with primary clarithromycin resistance. PMID- 29531462 TI - Dysregulation of PARP1 is involved in development of Barrett's esophagus. AB - AIM: To investigate the potential role of poly(ADP-ribose) polymerase 1 (PARP1) in the development of Barrett's esophagus (BE). METHODS: A BE mouse model was established to examine the esophageal morphological changes and molecular changes. Microarray analysis was performed to compare the gene expression profiles between BE patients and healthy controls. qPCR was used to examine the PARP1 expression in cell lines after treatment with H2O2 and bile acids (pH 4). Immunofluorescence staining, comet assay, and annexin V staining were used to evaluate the impact of PARP1 activity on cell survival and DNA damage response after oxidative stress. RESULTS: The gene expression profile in normal and BE esophageal epithelial cells showed that PARP1, the major poly(ADP-ribose) polymerase, was overexpressed in BE. In the mouse model of BE, positive staining for NF-kappaB, gammaH2AX, and poly(ADP-ribose) (PAR) was observed. H2O2 and bile acids (pH 4) increased the PARP1 mRNA expression level in normal esophageal epithelial cells. Using shRNA-PARP1 to suppress PARP1 activity decreased the cell viability after treatment with H2O2 and bile acids (pH 4), and increased the oxidative damage as demonstrated by an increase in the levels of H2O2, intracellular reactive oxygen species (ROS), oxidative DNA damage, double-strand breaks, and apoptosis (P < 0.01). CONCLUSION: The dysfunction of PARP1 in esophageal epithelial cells increases the levels of ROS and oxidative DNA damage, which could be common risk factors for BE and esophageal adenocarcinoma. PMID- 29531463 TI - Autophagy activation by Jiang Zhi Granule protects against metabolic stress induced hepatocyte injury. AB - AIM: To elucidate the potential role of autophagy and the protective effects of Jiang Zhi Granule (JZG) in metabolic stress-induced hepatocyte injury. METHODS: An in vitro and in vivo approach was used in this study. HepG2 cells were incubated in culture medium containing palmitate (PA; 0, 0.1, 0.2, 0.3, 0.4 or 0.5 mmol/L) and treated with or without JZG (100 MUg/mL) for 24 h or 48 h, and the progression of autophagy was visualized by stable fluorescence-expressing cell lines LC3 and p62. Western blot analyses were performed to examine the expression of LC3-II/LC3-I, p62, mTOR and PI3K, while mitochondrial integrity and oxidative stress were observed by fluorescence staining of JC-1 and reactive oxygen species. C57BL/6 mice were divided into three groups: control group (n = 10), high fat (HF) group (n = 13) and JZG group (n = 13); and, histological staining was carried out to detect inflammation and lipid content in the liver. RESULTS: The cell trauma induced by PA was aggravated in a dose- and time dependent manner, and hepatic function was improved by JZG. PA had dual effects on autophagy by activating autophagy induction and blocking autophagic flux. The PI3K-AKT-mTOR signaling pathway and the fusion of isolated hepatic autophagosomes and lysosomes were critically involved in this process. JZG activated autophagy progression by either induction of autophagosomes or co-localization of autophagosomes and lysosomes as well as degradation of autolysosomes to protect against PA-induced hepatocyte injury, and protected mitochondrial integrity against oxidative stress in PA-induced mitochondrial dysfunction. In addition, JZG ameliorated lipid droplets and inflammation induced by HF diet in vivo, leading to improved metabolic disorder and associated liver injury in a mouse model of non-alcoholic fatty liver disease (NAFLD). CONCLUSION: Metabolic stress induced hepatocyte injury exhibited dual effects on autophagy and JZG activated the entire process, resulting in beneficial effects in NAFLD. PMID- 29531464 TI - Long noncoding RNA RP4 functions as a competing endogenous RNA through miR-7-5p sponge activity in colorectal cancer. AB - AIM: To investigate the role of long noncoding RNA (lncRNA) RP4 in colorectal cancer. METHODS: Lentivirus-mediated lncRNA RP4 overexpression and knockdown were performed in the colorectal cancer cell line SW480. Cell proliferation, tumor growth, and early apoptosis were evaluated by a cell counting kit-8 assay, an in vivo xenograft tumor model, and annexin V/propidium iodide staining, respectively. Analysis of the lncRNA RP4 mechanism involved assessment of the association of its expression with miR-7-5p and the SH3GLB1 gene. Western blot analysis was also performed to assess the effect of lncRNA RP4 on the autophagy mediated cell death pathway and phosphatidylinositol-3-kinase (PI3K)/Akt signaling. RESULTS: Cell proliferation, tumor growth, and early apoptosis in SW480 cells were negatively regulated by lncRNA RP4. Functional experiments indicated that lncRNA RP4 directly upregulated SH3GLB1 expression by acting as a competing endogenous RNA (ceRNA) for miR-7-5p. This interaction led to activation of the autophagy-mediated cell death pathway and de-repression of PI3K and Akt phosphorylation in colorectal cancer cells in vivo. CONCLUSION: Our results demonstrated that lncRNA RP4 is a ceRNA that plays an important role in the pathogenesis of colorectal cancer, and could be a potential therapeutic target for colorectal cancer treatment. PMID- 29531465 TI - Quality indicators in pediatric colonoscopy in a low-volume center: Implications for training. AB - AIM: To study implications of measuring quality indicators on training and trainees' performance in pediatric colonoscopy in a low-volume training center. METHODS: We reviewed retrospectively the performance of pediatric colonoscopies in a training center in Malaysia over 5 years (January 2010-December 2015), benchmarked against five quality indicators: appropriateness of indications, bowel preparations, cecum and ileal examination rates, and complications. The European Society of Gastrointestinal Endoscopy guideline for pediatric endoscopy and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition training guidelines were used as benchmarks. RESULTS: Median (+/- SD) age of 121 children [males = 74 (61.2%)] who had 177 colonoscopies was 7.0 (+/- 4.6) years. On average, 30 colonoscopies were performed each year (range: 19-58). Except for investigations of abdominal pain (21/177, 17%), indications for colonoscopies were appropriate in the remaining 83%. Bowel preparation was good in 87%. One patient (0.6%) with severe Crohn's disease had bowel perforation. Cecum examination and ileal intubation rate was 95% and 68.1%. Ileal intubation rate was significantly higher in diagnosing or assessing inflammatory bowel disease (IBD) than non-IBD (72.9% vs 50.0% P = 0.016). Performance of four trainees was consistent throughout the study period. Average cecum and ileal examination rate among trainees were 97% and 77%. CONCLUSION: Benchmarking against established guidelines helps units with a low-volume of colonoscopies to identify area for further improvement. PMID- 29531466 TI - Prognostic value of lymph nodes count on survival of patients with distal cholangiocarcinomas. AB - AIM: To evaluate the prognostic value of the number of retrieved lymph nodes (LNs) and other prognostic factors for patients with distal cholangiocarcinomas, and to determine the optimal retrieved LNs cut-off number. METHODS: The Surveillance, Epidemiology and End Results database was used to screen for patients with distal cholangiocarcinoma. Patients with different numbers of retrieved LNs were divided into three groups by the X-tile program. X-tile from Yale University is a useful tool for outcome-based cut-point optimization. The Kaplan-Meier method and Cox regression analysis were utilized for survival analysis. RESULTS: A total of 449 patients with distal cholangiocarcinoma met the inclusion criteria. The Kaplan-Meier survival analysis for all patients and for N1 patients revealed no significant differences among patients with different retrieved LN counts in terms of overall and cancer-specific survival. In patients with node-negative distal cholangiocarcinoma, patients with four to nine retrieved LNs had a significantly better overall (P = 0.026) and cancer-specific survival (P = 0.039) than others. In the subsequent multivariate analysis, the number of retrieved LNs was evaluated to be independently associated with survival. Additionally, patients with four to nine retrieved LNs had a significantly lower overall mortality risk [hazard ratio (HR) = 0.39; 95% confidence interval (CI): 0.20-0.74] and cancer cause-specific mortality risk (HR = 0.32; 95%CI: 0.15-0.66) than other patients. Additionally, stratified survival analyses showed persistently better overall and cancer-specific survival when retrieving four to nine LNs in patients with any T stage of tumor, a tumor between 20 and 50 mm in diameter, or a poorly differentiated or undifferentiated tumor, and in patients who were <= 70-years-old. CONCLUSION: The number of retrieved LNs was an important independent prognostic factor for patients with node-negative distal cholangiocarcinoma. Additionally, patients with four to nine retrieved LNs had better overall and cancer-specific survival rates than others, but the reason and mechanism were unclear. This conclusion should be validated in future studies. PMID- 29531467 TI - Phenotypic and genotypic characterization of inflammatory bowel disease in children under six years of age in China. AB - AIM: To analyze clinical differences between monogenic and nonmonogenic very early-onset inflammatory bowel disease (VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS: A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing. RESULTS: A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn's disease (CD) or CD-like intestinal manifestations accounted for 72.2% of the VEO IBD cases. Nine patients (16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo (interquartile range (IQR): 4 to 78) and 43.5 mo (IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group (P = 0.001). However, there were no significant differences between weight-for-age and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency. CONCLUSION: A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort. PMID- 29531468 TI - Effect of polyglycolic acid sheet plus esophageal stent placement in preventing esophageal stricture after endoscopic submucosal dissection in patients with early-stage esophageal cancer: A randomized, controlled trial. AB - AIM: To assess the effect of polyglycolic acid (PGA) plus stent placement compared with stent placement alone in the prevention of post-endoscopic submucosal dissection (ESD) esophageal stricture in early-stage esophageal cancer (EC) patients. METHODS: Seventy EC patients undergoing ESD were enrolled in this randomized, controlled study. Patients were allocated randomly at a 1:1 ratio into two groups as follows: (1) PGA plus stent group (PGA sheet-coated stent placement was performed); and (2) Stent group (only stent placement was performed). This study was registered on http://www.chictr.org.cn (No. chictr-inr 16008709). RESULTS: The occurrence rate of esophageal stricture in the PGA plus stent group was 20.5% (n = 7), which was lower than that in the stent group (46.9%, n = 15) (P = 0.024). The mean value of esophageal stricture time was 59.6 +/- 16.1 d and 70.7 +/- 28.6 d in the PGA plus stent group and stent group (P = 0.174), respectively. Times of balloon dilatation in the PGA plus stent group were less than those in the stent group [4 (2-5) vs 6 (1-14), P = 0.007]. The length (P = 0.080) and diameter (P = 0.061) of esophageal strictures were numerically decreased in the PGA plus stent group, whereas no difference in location (P = 0.232) between the two groups was found. Multivariate logistic analysis suggested that PGA plus stent placement (P = 0.026) was an independent predictive factor for a lower risk of esophageal stricture, while location in the middle third (P = 0.034) and circumferential range = 1/1 (P = 0.028) could independently predict a higher risk of esophageal stricture in EC patients after ESD. CONCLUSION: PGA plus stent placement is more effective in preventing post ESD esophageal stricture compared with stent placement alone in EC patients with early-stage disease. PMID- 29531469 TI - Four cancer cases after esophageal atresia repair: Time to start screening the upper gastrointestinal tract. AB - Esophageal atresia (EA) is one of the most common congenital digestive malformations and requires surgical correction early in life. Dedicated centers have reported survival rates up to 95%. The most frequent comorbidities after EA repair are dysphagia (72%) and gastroesophageal reflux (GER) (67%). Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma. Several long-term follow-up studies found an increased risk of Barrett's esophagus and esophageal carcinoma in EA patients, both at a relatively young age. Given these findings, the recent ESPGHAN-NASPGHAN guideline recommends routine endoscopy in adults born with EA. We report a series of four EA patients who developed a carcinoma of the gastrointestinal tract: three esophageal carcinoma and one colorectal carcinoma in a colonic interposition. These cases emphasize the importance of lifelong screening of the upper gastrointestinal tract in EA patients. PMID- 29531470 TI - Sexual Scripts in Contemporary Mexican Cinema: A Quantitative Content Analysis. AB - While the literature on sexual scripts is substantive, with some scholarship examining the role of popular media in the production of dominant and divergent sexual practices and interactions, limited attention has been paid to the contemporary Mexican context. In this article, we share findings from a quantitative content analysis of popular Mexican films in order to explore how sexual behavior is portrayed and more specifically how relationship characteristics, condom use, and substance use interact with representations of sexual behavior. We find that more sexually explicit portrayals featured people engaged in heterosexual sexual interactions outside the context of marriage and also in age discordant relationships, where one partner was a minor. Few films featured safer sex practices or substance use in concert with sexual behavior. This research sheds light on how film as a powerful agent of socialization communicates sexual scripts in contemporary Mexican culture that may contribute to risky sexual behaviors among Mexican youth. PMID- 29531471 TI - Guest Editorial-Special Collection Topic: Statistical Systems Theory in Cancer Modeling, Diagnosis, and Therapy. AB - Cancer is a systems disease involving mutations and altered regulation. This supplement treats cancer research as it pertains to 3 systems issues of an inherently statistical nature: regulatory modeling and information processing, diagnostic classification, and therapeutic intervention and control. Topics of interest include (but are not limited to) multiscale modeling, gene/protein transcriptional regulation, dynamical systems, pharmacokinetic/pharmacodynamic modeling, compensatory regulation, feedback, apoptotic and proliferative control, copy number-expression interaction, integration of different feature types, error estimation, and reproducibility. We are especially interested in how the above issues relate to the extremely high-dimensional data sets and small- to moderate sized data sets typically involved in cancer research, for instance, their effect on statistical power, inference accuracy, and multiple comparisons. PMID- 29531472 TI - Predictors of Dropout From Inpatient Substance Use Treatment: A Prospective Cohort Study. AB - Introduction: Dropout from inpatient treatment for substance use disorder (SUD) is an ongoing challenge. The aim of this study was to identify demographic, substance use, and psychological factors that predict dropout from postdetoxification inpatient SUD treatment. Materials and methods: A total of 454 patients from 5 inpatient SUD centers in Central Norway were consecutively included in this naturalistic, prospective cohort study. Results: A total of 132 patients (28%) did not complete the planned treatment stay (dropped out). Cox regression analysis showed that higher levels of intrinsic motivation for changing personal substance use reduced the dropout risk (adjusted hazard ratio [adjHR]: 0.62, 95% confidence interval [CI]: 0.48-0.79). Higher levels of mental distress were associated with an increased risk for dropout (adjHR: 1.48, 95% CI: 1.11-1.97). Conclusions: The role of mental health and motivation in reducing dropout risk from inpatient SUD treatment should be targeted in future prospective intervention studies. PMID- 29531473 TI - Analysis of Trends and Factors in Breast Multiple Primary Malignant Neoplasms. AB - Background: The study aims to evaluate the current state and tendencies in multiple primary breast cancer incidence, behavior, and treatment in Ukraine. Methods: A total of 2032 patients who received special treatment at the Department of Breast Tumors and Reconstructive Surgery of the National Cancer Institute from 2008 to 2015 were included in the study. Among them, there were 195 patients with multiple primary malignant neoplasms: 54.9% patients with synchronous cancer and 45.1% patients with metachronous cancer. The average age of patients was 46.6 years, and the percentage of postmenopausal women was 63.1%. Among patients with synchronous cancer, there were 56.1% patients with only breast localizations and 43.9% with combination of breast and other localizations, and among patients with metachronous cancer, there were 46.6% patients with only breast localizations and 53.4% with combination of breast and other localizations. All the patients were evaluated in terms of aggressiveness of the disease, survival rates, as well as risk factors and treatment options. Results: A more aggressive course of breast cancer is observed in patients exposed to radiation from the Chernobyl accident under the age of 30 years (P < .01). The clinical course of disease in patients with synchronous cancer is worse and prognostically unfavorable compared with metachronous cancer (P < .01). The course of the disease in patients who underwent mastectomy is worse compared with patients who underwent breast-conserving surgery (P < .01). Plastic and reconstructive surgery in patients with synchronous cancer was proven to be reasonable in terms of increase in survival (P < .01). Conclusions: The patients with multiple primary breast cancer should have attentive management and treatment. Multidisciplinary team should concern all the risk factors and provide the most sufficient option of management. This is crucial to continue research in this oncological area. PMID- 29531474 TI - Wrapping Glial Morphogenesis and Signaling Control the Timing and Pattern of Neuronal Differentiation in the Drosophila Lamina. AB - Various regions of the developing brain coordinate their construction so that the correct types and numbers of cells are generated to build a functional network. We previously discovered that wrapping glia in the Drosophila visual system are essential for coordinating retinal and lamina development. We showed that wrapping glia, which ensheath photoreceptor axons, respond to an epidermal growth factor cue from photoreceptors by secreting insulins. Wrapping glial insulins activate the mitogen-activated protein kinase (MAPK) pathway downstream of insulin receptor in lamina precursors to induce neuronal differentiation. The signaling relay via wrapping glia introduces a delay that allows the lamina to assemble the correct stoichiometry and physical alignment of precursors before differentiating and imposes a stereotyped spatiotemporal pattern that is relevant for specifying the individual lamina neuron fates. Here, we further describe how wrapping glia morphogenesis correlates with the timing of lamina neuron differentiation by 2-photon live imaging. We also show that although MAPK activity in lamina precursors drives neuronal differentiation, the upstream receptor driving MAPK activation in lamina precursors and the ligand secreted by wrapping glia to trigger it differentially affect lamina neuron differentiation. These results highlight differences in MAPK signaling properties and confirm that communication between photoreceptors, wrapping glia, and lamina precursors must be precisely controlled to build a complex neural network. PMID- 29531475 TI - Using an Assessment Tool to Further Tobacco Control Accomplishment in Thailand. AB - Background: Because implementation of the Framework Convention on Tobacco Control (FCTC), a World Health Organization (WHO) treaty to reduce tobacco use, is an important goal of the 2015 United Nations Sustainable Development Goals (SDGs) and Thailand has sought to fully comply with all its articles, a multiperspective assessment was developed to ensure that any gaps in compliance with FCTC provisions were identified and addressed. Method: One assessment mechanism of this multicomponent assessment was the development by experts and use by stakeholders of a 3-tiered rating of all major provisions of the main articles of the FCTC. The results of the performance ratings on FCTC articles by a diverse group of stakeholders were used to spotlight areas of local and regional implementation and compliance with FCTC provisions. Results: Implementation ratings by stakeholders generally followed the chronology of WHO priorities as reflected in the development by WHO of guidelines for the various FCTC articles with highest ratings for articles 6, 8, 11, 12, 14, 15, and 16. However, only 5 articles (Articles 6, 11, 12, 15, and 16) reached level 2 (effectiveness) of the 3-level rating; articles 6, 8, 11, 13, and 14 are discussed because they are the WHO priority articles of the MPOWER tobacco control policy. Importantly, stakeholders cited problems with lack of completeness of present Thai law and processes for enforcement, as well as lack of public understanding regarding tobacco control strategies and provisions. Conclusions: Overall, the breadth and inclusiveness of the stakeholder approach devised for improving implementation by the Tobacco Control Research and Knowledge Management Center provided greater understanding about shortcomings of present policy and resource management which informed the Tobacco Products Control Act passed in 2017 and plans for advancing stronger Thai regulation by local and national government. PMID- 29531476 TI - Oviposition Strategies of Tachinid Parasitoids: Two Exorista Species as Case Studies. AB - Oviposition strategies and mechanisms of host selection in parasitoids may be crucial for the success of parasitization and parasitoid production. These aspects are far less known in tachinid parasitoids than in hymenopteran parasitoids. Depending on the species, parasitoid flies may adopt direct or indirect oviposition strategies. The 'direct type' females lay eggs on or, in relatively a few species, inside the host body. This review describes cues involved in host selection by tachinid parasitoids and their oviposition strategies and presents 2 case studies in more detail, focusing on Exorista larvarum and Exorista japonica. These 2 polyphagous parasitoids of Lepidoptera lay macrotype eggs directly on the host cuticle. Both species have been used as biological control agents in inoculative release against the gypsy moth Lymantria dispar in the Northern United States. Improved knowledge of the mechanisms involved in host selection and oviposition strategies may increase the possibility of eliciting oviposition by these tachinids on target lepidopterous hosts (and even artificial substrates), thus facilitating their rearing and ultimately making their exploitation as regulators of target insect pests more feasible and efficient. PMID- 29531477 TI - Do Bioflavonoids in Juniperus virginiana Heartwood Stimulate Oviposition in the Ladybird Coleomegilla maculata? AB - Maximizing the reproductive potential of ladybird beetles fed factitious foods or artificial diets, in lieu of natural prey, is a major challenge to cost-effective mass rearing for augmentative biological control. In this study, we tested the hypothesis that compounds in redcedar, Juniperus virginiana, stimulate oviposition in the ladybird Coleomegilla maculata. We also tested the prediction that several bioflavonoids, identified in heartwood fractions, elicited this behavioral response. Phenolic compounds were extracted from J. virginiana heartwood sawdust, separated into several fractions, then presented to adult beetles, in a powdered, pure form, in the laboratory. Females preferentially oviposited within 1 to 2 cm of fractions B, C, D, and E, but not A or the unfractionated extract, at the base of test cages. Chemical analysis identified bioflavonoids in heartwood fractions and subsequent bioassays using several identified in fractions C, D, and E confirmed that quercetin, taxifolin, and naringenin (to a lesser extent) stimulated oviposition. All tested fractions and bioflavonoids readily adhered to the chorion of freshly laid eggs but did not reduce egg hatch. This study demonstrates that several bioflavonoids stimulate oviposition by C. maculata and could be useful for mass rearing programs. PMID- 29531478 TI - Recurrent Pleural Effusion as a Result of Bilateral Renal Artery Stenosis. Does Renal Revascularization Help? AB - Renal artery stenosis (RAS) is the leading cause of secondary hypertension. Renal artery stenosis can result in various cardiopulmonary complications mostly through activation of neurohormonal pathways that result in fluid overload and systemic hypertension. We herein describe a 72-year-old man with recurrent rapidly accumulating transudative pleural effusion in a patient with severe bilateral RAS. Patient pleural effusion resolved following stent placement with revascularization of the left renal artery despite absence of improvement of renal function. Patient renal function continued to decline and ultimately treated with fixed hemodialysis. PMID- 29531479 TI - Intraoperative Functional Endoscopic Sinus Surgery Training: Efficient Teaching Techniques-A New Method. AB - Introduction: Functional endoscopic sinus surgery is a complex procedure used by otorhinolaryngologists to treat a host of nasal sinus pathologies. Due to the involved nasal anatomy and the nature of the procedure, teaching residents to use an endoscope is challenging. Simulation labs have been helpful but intraoperative instruction can still present difficulty in communication between resident and attending physicians during the teaching process. The purpose of this is to hypothesize a method of teaching intraoperatively that can be used supplemental to or independently of virtual reality teaching. Method: Literature review to determine current intraoperative verbal teaching methods used by surgeons was performed. Review was also performed on the effects of simulation techniques in preparing residents for the operating room. Although this was not a systematic review including statistical analysis, a gap was found in the literature on how residents can be efficiently taught intraoperatively to navigate an endoscope while maintaining patient safety. A novel and inexpensive method has been devised as a possible teaching method. Conclusions: Extensive literature is not available in intraoperative teaching techniques. It is therefore uncertain whether such a method has been used before. Further study, possibly in the form of surveys and intraoperative trials, must be done to determine the effectiveness of this mechanism. PMID- 29531480 TI - Prognostic Value and Changes of Auditory Brain Stem Response in Children With Bacterial Meningitis in Luanda, Angola. AB - Objective: To assess the role of single and repeated auditory brain stem response (ABR) in predicting mortality and severe neurological injury among children having bacterial meningitis (BM) in Luanda, Angola. Methods: The morphology of ABR traces of 221 children (aged 2 months to 12 years) from admission day was analyzed and compared with age-matched normative data. Absence and delay of traces were compared with mortality and mortality or severe neurological injury in subgroup analyses. Outcome was also evaluated with repeated ABR of 166 children based on presence or absence of responses at 80 dB nHL (normal hearing level) stimulation level. Results: Individually, the absence of typical ABR waveform did not signify poor outcome. At the group level, latencies and interpeak latencies (IPLs) were significantly prolonged among patients with BM in comparison with controls, and the prolongation correlated with higher mortality or severe neurological sequelae. Conclusions: We confirmed the effect of BM on neural conduction time in auditory pathway. However, ABR in similar settings seems not useful for individual prognostication, although at the group level, delayed latencies, IPLs, or both associated with poorer outcome. PMID- 29531481 TI - Further Delineation of the Clinical Phenotype of Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome Type 4. AB - Background: Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait. Methods: We investigated three Saudi families with CAMRQ4. Blood samples were collected from the affected patients, their parents, and healthy siblings. DNA was extracted from whole blood, and whole-exome sequencing was performed. Findings were confirmed by segregation analysis, which was performed on other family members. Results: Thus far, 17 patients have been affected by CAMRQ4. Genetic analysis of all patients, including our current patients, showed a mutation in the aminophospholipid transporter, class I, type 8A, member 2 gene (ATP8A2). A series of common phenotypical features have been reported in these patients, with few exceptions. Ataxia, mental retardation, and hypotonia were present in all patients, consanguinity in 90% and abnormal movements in 50%. Moreover, 40% achieved ambulation at least once in their lifetime, 40% had microcephaly, whereas 30% were mute. Magnetic resonance imaging (MRI) of the brain was normal in 60% of patients. Conclusions: We described the largest cohort of patients with CAMRQ4 syndrome and identified three novel mutations. CAMRQ4 syndrome should be suspected in patients presenting with ataxia, intellectual disability, hypotonia, microcephaly, choreoathetoid movements, ophthalmoplegia, and global developmental delay, even if brain MRI appears normal. PMID- 29531482 TI - Computed Tomography Perfusion Imaging for the Diagnosis of Hepatic Alveolar Echinococcosis. AB - Objective: Alveolar echinococcosis (AE) is a rare life-threatening parasitic infection. Computed tomography perfusion (CTP) imaging has the potential to provide both quantitative and qualitative information about the tissue perfusion characteristics. The purpose of this study was the examination of the characteristic features and feasibility of CTP in AE liver lesions. Material and Methods: CTP scanning was performed in 25 patients who had a total of 35 lesions identified as AE of the liver. Blood flow (BF), blood volume (BV), portal venous perfusion (PVP), arterial liver perfusion (ALP), and hepatic perfusion indexes (HPI) were computed for background liver parenchyma and each AE lesion. Results: Significant differences were detected between perfusion values of the AE lesions and background liver tissue. The BV, BF, ALP, and PVP values for all components of the AE liver lesions were significantly lower than the normal liver parenchyma (p<0.01). Conclusions: We suggest that perfusion imaging can be used in AE of the liver. Thus, the quantitative knowledge of perfusion parameters are obtained via CT perfusion imaging. PMID- 29531483 TI - Clinical Characteristics Based on the New Criteria of Acute Exacerbation in Patients with Idiopathic Pulmonary Fibrosis. AB - Objective: Idiopathic pulmonary fibrosis (IPF) is the most common parenchymal lung disease. Patients with IPF sometimes develop acute exacerbation (AE), which predicts a poor prognosis. To evaluate the predictors of 90-day mortality of AE in patients with IPF based on the new 2016 criteria. Materials and Methods: Sixty five patients with AE were studied retrospectively between January 2001 and December 2016 at Okinawa Chubu Hospital. Results: The mean age of the patients was 74 years, with 40 (61.5%) men and 25 (38.5%) women. Among our cohort, 37 were current or ex-smokers, with a mean exposure of 32.4 pack-years. The mean grade of the modified Medical Research Council breathlessness scale was 2.8, and the mean duration of dyspnea prior to admission was 6.5 days. Clubbed fingernails were present in 29% of patients. Triggered AE occurred in 12 (18%) of patients. Patients with triggered AE had more extensive ground-glass opacity and higher consolidation scores than the idiopathic AE group (7.3 vs. 4.2, p=0.01). The triggered group had shorter survival than the idiopathic group (1.4 vs. 11.4 months, p=0.094). Serum lactate dehydrogenase (LDH), DeltaLDH, and the ratio of partial pressure of oxygen to the fraction of inspiratory oxygen ratio were strong predictors of 90-day mortality. Hazard ratios were 1.003 (p=0.004), 1.004 (p=0.02), and 0.994 (p=0.010), respectively. Conclusion: Compared with idiopathic AE, triggered AE in patients with IPF had more extensive infiltration and tended toward shorter survival. Serial trends of serum LDH >2 weeks can help predict prognosis of AE in patients with IPF. PMID- 29531484 TI - Can Red Blood Cell Distribution Width be a Potential Marker in the Decision to Perform Tonsillectomy? AB - Objective: Tonsillectomy is one of the most common surgical procedures performed at ear, nose, and throat clinics. Chronic recurrent tonsillitis, obstructive tonsillitis, and halitosis are among the most common indications for surgery. Determining whether the infection is chronic and the patient's annual number of infections are important in estimating the necessity for surgery to be performed due to infectious causes. Red blood cell distribution width (RDW) is a numerical value present in normal complete blood count that provides information about erythrocytes and their dimensions. Studies in recent years have shown that RDW increases in chronic infections, hypoxia, and oxidative stress. This study investigated the changes in RDW in patients with chronic tonsillitis and the effect tonsillectomy has on this value by comparing RDW between patients scheduled for tonsillectomy and normal population and examining preoperative and postoperative changes in RDW. Materials and Methods: Sixty-three patients scheduled for tonsillectomy due to recurrent tonsillitis aged 4-14 years were included in the study. The control group consisted of 60 subjects comparable in terms of age and sex. Hemoglobin level and RDW were recorded by collecting 2 mlof blood before surgery and at 4 months postoperatively from all patients. Results: Preoperative RDW was significantly higher in the patient group than in the control group. Comparison of patients' preoperative and postoperative RDW revealed a significant decrease in RDW after surgery. Conclusion: As a biomarker showing chronic infection in patients with tonsillitis, RDW can provide support to the clinician in deciding on surgery. However, this has to be confirmed in further studies with greater participation. PMID- 29531485 TI - Surgical Management of Aortic Coarctation from Infant to Adult. AB - Objective: In the present study, we aimed to retrospectively investigate the early and late results of different surgical treatment techniques applied in different age groups with coarctation of the aorta (CoA). Materials and Methods: Between January 2007 and February 2017, 26 patients (12 males, 14 females; mean age: 12.2+/-12.4 years; range: 29 days-34 years) who underwent surgery with the diagnosis of CoA were evaluated. Overall, 11 of these patients (42.3%) were in the infantile period, whereas 15 patients (57.7%) aged between 6 and 34 years. Resection and end-to-end anastomosis were performed in 13 patients (50%). Bypass grafting was performed in six patients (23.1%), and patch plasty was performed in seven patients (26.9%). Results: A patient (3.8%) who was operated on during the infantile period died early, whereas another patient (3.8%) died 2 years after the surgery. Recoarctation was detected in two patients. A patient underwent balloon dilatation, whereas another patient underwent balloon dilatation and stenting. In patients who underwent re-section and end-to-end anastomosis based on postoperative echocardiography results during follow-up, a lower statistically significant gradient was observed compared with the preoperative period. Despite the decrease in the left ventricular systolic diameter (LVSD) and the increase in the ejection fraction (EF) the decrease in LVSD and increase in EF were not statistically significant. In patients who underwent patch plasty or graft interposition, the low values of the gradient and left ventricular diastolic diameter in the postoperative follow-up were statistically significant. However, the decrease in LVSD and increase in EF were not statistically significant. Conclusions: Our clinical experience suggests that repairing with resection and end-to-end anastomosis is a more appropriate treatment option during the infancy, whereas patch plasty or bypass grafting may be preferred in advanced ages. PMID- 29531486 TI - Eighteen Years' Retrospective Review of Colorectal Cancer Cases in Eastern Population. AB - Objective: We aimed to determine the demographic characteristics of colorectal cases and changes in cancer localization according to years in our region. Materials and Methods: In the present study, 752 patients diagnosed with colorectal cancer between January 1992 and December 2010 were included. Results: Of all the patients, 427 (56.8%) were males and 325 (43.2%) were females, with a male/female ratio of 1.3/1. The mean age was 56.2+/-14.9 years. The most commonly encountered complaint at the first application was rectal bleeding (38.4%). The most commonly encountered tumor localizations were in the rectum (55%) and sigmoid colon (18%). In general, tumors were observed to be localized in the right colon at 16.1% and in the left colon at 83.9%. When tumor localizations were compared in the first 10 years of the study with the second 10 years in the present study, it was observed that tumor numbers in the right colon were increased. Cases in our study were diagnosed as Stage IV according to the tumor, node, metastasis (TNM) classification, and liver metastasis was encountered most commonly. Conclusion: Although colorectal cancer cases have been most commonly encountered in the rectum, it has been recently determined that right colon tumor percentages were increased. It was defined that they were generally diagnosed at later stages. Therefore, colorectal cancer incidence may be decreased by the widespread use of endoscopic techniques in the determination of precancerous lesions. PMID- 29531487 TI - Evaluating Ossifications of the Nuchal Ligament with Cervical Computed Tomography. AB - Objective: The nuchal ligament (NL) extends from the external occipital protuberance and median nuchal line to the spinous process of the 7th cervical vertebrae. In this study, we evaluated the incidence, location level, and size of ossifications of the NL (ONL) in patients who underwent cervical computed tomography (CT) for various reasons. Materials and Methods: The present study included 481 patients (187 females and 294 males) who underwent cervical CT from February 2011 to November 2016 due to reasons such as trauma, cervical spondylosis, neck pain, and screening for metastasis. CT was performed using 2- or 8-slice scanners. Archive images of patients on picture archiving and communication system were retrospectively evaluated by two radiologists. The structures in bone density and form detected in NL were evaluated as nuchal ossification. ONL location levels, numbers, and dimensions were determined. The relationship between both sexes and age and the incidence of ONL was investigated. Results: ONL was detected in 44 patients (9.14%). The mean ages of patients with ONL and without ONL were 62.27+/-13.92 (23-86) and 41.78+/-20.76 (4 101) years, respectively. There was a statistically significant relationship between ONL and age (p<0.001). Thirty-six patients had one ONL, seven patients had two, and one patient had three. The most common ONL location was the C5 spinous process level (n=12) followed by the C6 spinous process level (n=8). The longest ONL in craniocaudal direction was 20.9 mm, and the shortest one was 3.1 mm. Conclusion: ONL is a smooth-contoured ovoid or round bone structure extending parallel to the longitudinal axis that can frequently be observed as one or multiple occurrences with different sizes on cervical CT images. PMID- 29531488 TI - Investigation of the Relationship between Anterior Knee Pain and Chondromalacia Patellae and Patellofemoral Malalignment. AB - Objective: The study aimed to investigate whether there is any association of anterior knee pain and knee function with chondromalacia stage and patellofemoral alignment in patients with anterior knee pain for over a month and with chondromalacia patellae (CMP) detected by magnetic resonance imaging (MRI). Materials and Methods: We reviewed the medical records of 38 patients who underwent a knee MRI examination and were diagnosed with chondromalacia based on the MRI. Knee MRI images were evaluated by a radiologist for chondromalacia staging. Patients were divided into two groups as early stage (stage 1-2) and advanced stage (stage 3-4) chondromalacia. Patients' demographical data (age, sex, and occupation), clinical features, physical examination findings and patellofemoral pain severity scale, kujala patellofemoral scoring system, and functional index questionnaire scores were obtained from their medical records. Trochlear sulcus angle, sulcus depth, lateral patellofemoral angle, patellar translation, and Insall-Salvati index were measured using the MRI images. Results: The mean patient age was higher in the advanced stage CMP group compared to the early stage CMP group (p=0.038). There was no statistically significant difference regarding other demographical data (p>0.05). MRI measurement parameters did not show difference between the groups (p>0.05). Patients in the advanced stage CMP group had higher patellofemoral pain severity score, lower kujala patellofemoral score, and lower functional index questionnaire score compared to the early stage CMP group. The differences were statistically significant (p=0.008, p=0.012, and p=0.026, respectively). Conclusion: As chondromalacia stage advances, the symptom severity worsens and knee functions decline; however, MRI measurements do not show difference between early and advanced stage CMP patients. PMID- 29531489 TI - Increased Iron Deficiency and Iron Deficiency Anemia in Children with Zinc Deficiency. AB - Objective: The aim of the present study is to determine the presence of iron (Fe) deficiency and Fe deficiency anemia in children with zinc (Zn) deficiency. Materials and Methods: This retrospective study comprised 560 patients aged 6 months to 16 years in whom Zn levels in hair samples were measured concurrently with serum levels of ferritin, Fe, Fe-binding capacity, and blood count analysis. For all patients, we retrospectively assessed serum ferritin, serum Fe, Fe binding capacity, transferrin saturation index, red blood cell count, hemoglobin levels, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and red cell distribution width (RDW). Patients were divided into two groups according to the level of the hair Zn level as Zn deficiency (hair Zn level <100 ug/g) and without Zn deficiency (hair Zn level >100 ug/g). Data were analyzed to determine whether there was a significant difference between any of these parameters and the presence of Fe deficiency and Fe deficiency anemia between patients with and without Zn deficiency. Results: A total of 238 patients had Zn levels <100 ug/g, and 322 patients had Zn levels >100 ug/g. The median ferritin level was 16.2 (9.8-24.9) ng/mL in the Zn deficient group and 18.7 (12-29.3) ng/mL in those without Zn deficiency group. The presence of Fe deficiency was higher in the Zn deficiency group (60.1%) than in the without Zn deficiency group (50%; p<0.05). The presence of Fe deficiency anemia was significantly higher in the Zn deficiency group (20.2%) than in the without Zn deficiency group (12.7%; p<0.05). There were very weak negative significant correlation between hair Zn and RDW level (r=-0.24; p<0.001) and weak positive correlation between hair Zn and MCV (r=0.31; p<0.001). Conclusion: Fe deficiency and Fe deficiency anemia increased in patients with zinc deficiency. PMID- 29531490 TI - Tibial Tuberosity-Trochlear Groove Distance Shows no Change in Patients with or Without Knee Osteoarthritis. AB - Objective: The primary aim of this study is to compare tibial tuberosity trochlear groove (TTTG) distance in patients with or without knee osteoarthritis. Additionally, the variability of tibial tubercle according to trochlear groove was evaluated. Materials and Methods: In this retrospective cohort study, TTTG distance was measured with two different methods on magnetic resonance (MR) images. TTTG distance was measured by the familiar method on 173 MR images, and by the novel method on 157 MR images of 175 patients totally. The patients were divided into two groups as group 1 (Kellgren Lawrence osteoarthritis grade <2) and group 2 (Kellgren Lawrence osteoarthritis grade >=2). TTTG values measured by both methods were compared between groups. The coefficient of variation for all patients in TTTG values were calculated. A p-value <0.05 was considered as significant. Results: The mean age, sex distributions, and side ratios were different between groups. There was no statistical difference in TTTG values between group 1 and 2. There was no statistically significant difference between the two measurement methods. The coefficient of variation for all patients in TTTG values were high (43.95% for familiar method and 44.64% for novel method). There was excellent interrater reliability for two measurement methods in both groups. Conclusion: The TTTG distance is similar in patients with/without knee osteoarthritis. The position of the tibial tubercle according to the trochlear groove is variable, so the tibial tubercle may not be a good reference point for rotational position of the tibial component in total knee arthroplasty. PMID- 29531491 TI - Surgical Management of Concurrent Partial Anomalous Pulmonary Venous Return and Lung Cancer of the Same Lobe. AB - Partial anomalous pulmonary venous return (PAPVR) is a rare congenital left-to right shunt where pulmonary veins drain into systemic circulation. This is a presentation of the case of a patient with concurrent PAPVR and adenocarcinoma of the same lobe. The pulmonary veins of right upper lobe drained into superior vena cava (SVC), whereas the middle and lower lobes veins drained into the left atrium as two distinct vessels. Surgeons should always perform a diligent search for anomalous vascular structure using computed tomographic (CT) angiography prior to surgery. In our case, surgical approach was "safe" because both pathologies developed in the same lobe. PMID- 29531492 TI - Nonfatal Systemic Air Embolism: A Grave Complication of Computed Tomography Guided Percutaneous Transthoracic Needle Biopsy. AB - Transthoracic computed tomography-guided core needle biopsy (TTNB) is a well established method for diagnosing focal pulmonary lesions. However, the dangers associated with this method as well as the significant number of complications caused by it cannot be ignored. Systemic air embolism is a rare but potentially fatal complication that can accompany transthoracic needle biopsies of pulmonary lesions. In this study, we report nonfatal systemic air embolism as a complication of a transthoracic needle core biopsy of a subpleural nodule in the right upper pulmonary lobe of a patient with hemoptysis. Although extremely rare, the complication may result in a transient myocardial ischemia, which is presented with a transient depression of the ST segment. PMID- 29531493 TI - Left Supraclavicular Swelling: Sclerosing Perineurioma. AB - A sclerosing perineurioma presents as a single asymptomatic papule or nodule located on the hands of adult patients; approximately 60 cases have been reported in medical literature since 1997. Histologically, it originates from the perineural cells of the peripheral nerves and presents epithelial membrane antigen (EMA) positivity and S100 protein negativity. Here, we present the case of a 58-year-old male admitted to our surgery unit complaining of left supraclavicular swelling of 1-cm in size, having no significant past medical history. A lymph node neck tumor was suspected, and the patient underwent surgery under local anesthesia in outpatient care. The intraoperative finding was a whitish mass, wooden-fibrous in consistency, strictly adhering to the skin and apparently fixed to the deep planes. Upon histological examination, a sclerosing perineurioma was diagnosed: neoplastic cells were immunoreactive for CD34, CD99, and EMA, and negative for S100 protein, smooth-muscle actin, pancytokeratin (AE1 AE3), CD31, neurofilaments, and beta-catenin. According to the benign biological tumor behavior, radical resection was considered an adequate treatment. Our case presents as peculiarity the unusual non-acral location (first reported as supraclavicular swelling) and the rare immunopositivity for CD34 and CD99. PMID- 29531494 TI - Concurrent Septal and Right Ventricular Aneurysms Detected on Second Trimester Ultrasound Scan: A Case Report. AB - Congenital aneurysms and diverticula of the heart are rare anomalies and their prenatal diagnosis is challenging. Fetuses with suspected cardiac aneurysms on ultrasound (US) screening should undergo targeted fetal echocardiography, postnatal imaging, and follow-ups. Herein, we describe the second trimester US scan and postnatal cardiac magnetic resonance imaging (MRI) findings of a baby girl with concurrent septal and right ventricular cardiac aneurysms. Other cardiac and extra-cardiac structures were normal. Upon consultation about the prognostic uncertainty of the situation, the family chose to continue the pregnancy. The rest of the pregnancy and birth was without any complications. Follow-up postnatal echocardiograms showed no progression regarding the size of the aneurysms. The baby is still on follow-up without any medication and is thriving. To the best of our knowledge, this case report is the first to show the prenatal diagnosis of two concurrent rare cardiac aneurysms. PMID- 29531495 TI - Pustulotic Arthro-Osteitis (Sonozaki Syndrome): A Case Report and Review of Literature. AB - Pustulotic arthro-osteitis (PAO) is a rare chronic inflammatory disease, which has now been classified as a seronegative spondyloarthritis. The sternoclavicular and sternocostal joints, pelvis, vertebra, hip, and long bones are affected. Skin findings of the disease are accepted as a variant of pustular psoriasis, but some authors have suggested that palmoplantar pustulosis (PPP) is a different entity. The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome should be considered in the differential diagnosis. PAO differs from SAPHO by the absence of hyperostosis and the difference in skin manifestations. Here, we aimed to present a 34-year-old female patient with a diagnosis of PAO with typical skin findings and joint involvement. PMID- 29531496 TI - Epiploic Appendagitis as a Rare Cause of Acute Abdomen in the Pediatric Population: Report of Three Cases. AB - Epiploic appendagitis, caused by inflammation of small adipose tissue on the colon wall, is a rare cause of acute abdominal pain in the pediatric population. It is nearly impossible to establish a specific diagnosis merely on the basis of clinical findings; thus, radiological evaluation is always necessary. In this report, we present the cases of three children with abdominal pain who were diagnosed with epiploic appendagitis. All cases were successfully treated with conservative management. PMID- 29531497 TI - Late Presentation of an Unruptured and Calcified Pseudoaneurysm of The Atrioventricular Groove. PMID- 29531498 TI - A Rare Cause and Complication of Acute Gastric Dilatation: Superior Mesenteric Artery Syndrome and Perforation. PMID- 29531499 TI - Unilateral Nasal Obstruction Caused by a Large Nasopharyngeal Cyst. PMID- 29531501 TI - Volume 49 - Reviewer List. PMID- 29531500 TI - Erratum. AB - [This corrects the article on p. 209 in vol. 48, PMID: 28149148.]. PMID- 29531502 TI - Using smartphone technology to deliver a virtual pedestrian environment: usability and validation. AB - Various programs effectively teach children to cross streets more safely, but all are labor- and cost-intensive. Recent developments in mobile phone technology offer opportunity to deliver virtual reality pedestrian environments to mobile smartphone platforms. Such an environment may offer a cost- and labor-effective strategy to teach children to cross streets safely. This study evaluated usability, feasibility, and validity of a smartphone-based virtual pedestrian environment. A total of 68 adults completed 12 virtual crossings within each of two virtual pedestrian environments, one delivered by smartphone and the other a semi-immersive kiosk virtual environment. Participants completed self-report measures of perceived realism and simulator sickness experienced in each virtual environment, plus self-reported demographic and personality characteristics. All participants followed system instructions and used the smartphone-based virtual environment without difficulty. No significant simulator sickness was reported or observed. Users rated the smartphone virtual environment as highly realistic. Convergent validity was detected, with many aspects of pedestrian behavior in the smartphone-based virtual environment matching behavior in the kiosk virtual environment. Anticipated correlations between personality and kiosk virtual reality pedestrian behavior emerged for the smartphone-based system. A smartphone based virtual environment can be usable and valid. Future research should develop and evaluate such a training system. PMID- 29531503 TI - An Instrumental Electrode Configuration for 3D Ultrasound Modulated Electrical Impedance Tomography. AB - Ultrasound modulated electrical impedance tomography (UMEIT) is a novel hybrid imaging technique, which utilizes coupling between electric and acoustic modalities. Based on the forward solver along different current directions, an instrumental electrode configuration is proposed for 3D UMEIT. The proposed electrode configuration can produce a similar longitudinal current, making the power density distribution on the x-y plane approximately consistent with the corresponding conductivity distribution. Then, this satisfying power density is adopted to reconstruct a higher-resolution conductivity distribution. Therefore, the proposed electrode configuration contributes to improving the image reconstruction quality of UMEIT. Also, to clearly demonstrate its meaning in theory, the forward solver results are analyzed from an electrical point of view. In addition, the nonlinear partial differential equation (PDE) relating the power density to the measured data is derived again with a more reasonable expression. Finally, simulation with realistic geometry model of human breast is done and feasibility verifying experiment is made. Both simulation and experimental results validate the feasibility of the proposed electrode configuration. PMID- 29531504 TI - Automated Whole-Body Bone Lesion Detection for Multiple Myeloma on 68Ga Pentixafor PET/CT Imaging Using Deep Learning Methods. AB - The identification of bone lesions is crucial in the diagnostic assessment of multiple myeloma (MM). 68Ga-Pentixafor PET/CT can capture the abnormal molecular expression of CXCR-4 in addition to anatomical changes. However, whole-body detection of dozens of lesions on hybrid imaging is tedious and error prone. It is even more difficult to identify lesions with a large heterogeneity. This study employed deep learning methods to automatically combine characteristics of PET and CT for whole-body MM bone lesion detection in a 3D manner. Two convolutional neural networks (CNNs), V-Net and W-Net, were adopted to segment and detect the lesions. The feasibility of deep learning for lesion detection on 68Ga-Pentixafor PET/CT was first verified on digital phantoms generated using realistic PET simulation methods. Then the proposed methods were evaluated on real 68Ga Pentixafor PET/CT scans of MM patients. The preliminary results showed that deep learning method can leverage multimodal information for spatial feature representation, and W-Net obtained the best result for segmentation and lesion detection. It also outperformed traditional machine learning methods such as random forest classifier (RF), k-Nearest Neighbors (k-NN), and support vector machine (SVM). The proof-of-concept study encourages further development of deep learning approach for MM lesion detection in population study. PMID- 29531505 TI - Spectral Unmixing Imaging for Differentiating Brown Adipose Tissue Mass and Its Activation. AB - Recent large-scale clinical analysis indicates that brown adipose tissue (BAT) mass levels inversely correlate with body-mass index (BMI), suggesting that BAT is associated with metabolic disorders such as obesity and diabetes. PET imaging with 18F-FDG is the most commonly used method for visualizing BAT. However, this method is not able to differentiate between BAT mass and BAT activation. This task, in fact, presents a tremendous challenge with no currently existing methods to separate BAT mass and BAT activation. Our previous results indicated that BAT could be successfully imaged in mice with near infrared fluorescent (NIRF) curcumin analogues. However, the results from conventional NIRF imaging could not reflect what portion of the NIRF signal from BAT activation contributed to the signal observed. To solve this problem, we used spectral unmixing to separate/unmix NIRF signal from oil droplets in BAT, which represents its mass and NIRF signal from blood, which represents BAT activation. In this report, results from our proof-of-concept investigation demonstrated that spectral unmixing could be used to separate NIRF signal from BAT mass and BAT activation. PMID- 29531506 TI - Brain Network Alterations in Alzheimer's Disease Identified by Early-Phase PIB PET. AB - The aim of this study was to identify the brain networks from early-phase 11C-PIB (perfusion PIB, pPIB) data and to compare the brain networks of patients with differentiating Alzheimer's disease (AD) with cognitively normal subjects (CN) and of mild cognitively impaired patients (MCI) with CN. Forty participants (14 CN, 12 MCI, and 14 AD) underwent 11C-PIB and 18F-FDG PET/CT scans. Parallel independent component analysis (pICA) was used to identify correlated brain networks from the 11C-pPIB and 18F-FDG data, and a two-sample t-test was used to evaluate group differences in the corrected brain networks between AD and CN, and between MCI and CN. Our study identified a brain network of perfusion (early phase 11C-PIB) that highly correlated with a glucose metabolism (18F-FDG) brain network and colocalized with the default mode network (DMN) in an AD-specific neurodegenerative cohort. Particularly, decreased 18F-FDG uptake correlated with a decreased regional cerebral blood flow in the frontal, parietal, and temporal regions of the DMN. The group comparisons revealed similar spatial patterns of the brain networks derived from the 11C-pPIB and 18F-FDG data. Our findings indicate that 11C-pPIB derived from the early-phase 11C-PIB could provide complementary information for 18F-FDG examination in AD. PMID- 29531509 TI - Ageing and transitions: looking back and looking forward. PMID- 29531508 TI - Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate-Dependent Manner. AB - A central question in radiation protection research is whether low-dose and low dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR. PMID- 29531510 TI - Socio-demographic correlates of physical activity among European older people. AB - From a public health perspective, identifying factors related to attaining the physical activity (PA) recommendations is important in order to identify subgroups for intervention programs. The aim of this study is to identify the socio-demographic correlates of attaining the recommended levels of PA in the older European population. Using data from the European Social Survey round 6, PA and socio-demographic characteristics were collected from 10,148 participants (4556 men, 5592 women), aged 65 years and over, from 28 countries in 2012. PA was accessed using the question "On how many of the last seven days did you walk quickly, do sports, or other PA for 30 min or longer?" and meeting PA guidelines was assessed using World Health Organization criteria. Overall, 59.7% of the participants attained the PA-recommended levels. The likelihood of attaining PA recommendations was higher among older people with higher education levels (p < 0.05; p < 0.01; p < 0.001). Men who lived in a town or small city (p < 0.05) and lived in a rural area (p < 0.001) were more likely to attain the PA recommendations. Women who lived with a partner were more likely to attain the PA recommendations (p < 0.001). Promotion of PA is critical to health among older people; therefore, intervention programs must consider these socio-demographic factors when planning an increase in PA. PMID- 29531511 TI - An analysis of factors related to disability-free life expectancy at 65 years of age across Japanese prefectures in 2010. AB - Compared to the large volume of research focused on mortality differentials within Japan, relatively little is known about regional variations in health expectancy, particularly among older people. This article has two interrelated objectives. The first objective is to estimate prefecture-specific disability free life expectancy (DFLE) at 65 years of age in 2010. DFLE at 65 by gender and prefecture was computed using the Sullivan method, which was applied to prefecture-specific life tables and prevalence of disability from Kokumin Seikatsu Kiso Chosa (Comprehensive Survey of Living Conditions) of 2010. The second objective is to investigate macro-level factors associated with DFLE at 65 across 47 Japanese prefectures. Our results indicate regional disparities in DFLE at older ages. Importantly, we note close relationships between a prefecture's wealth, labor, and welfare characteristics and DFLE at 65. Income per capita, the proportion of workers older than 65, and welfare expenditures are positively related to DFLE, whereas unemployment and long-term care insurance expenditures per-capita are inversely associated with DFLE for both genders. The proportion of older adults relying on public assistance is negatively related only to women's DFLE. These results suggest that narrowing socioeconomic disparities may contribute to the health of Japanese elders. Reducing regional health disparities therefore requires policy makers to take into account the broader socioeconomic conditions of each prefecture. PMID- 29531507 TI - Prospective of 68Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation. AB - During the last decade, the utilization of 68Ga for the development of imaging agents has increased considerably with the leading position in the oncology. The imaging of infection and inflammation is lagging despite strong unmet medical needs. This review presents the potential routes for the development of 68Ga based agents for the imaging and quantification of infection and inflammation in various diseases and connection of the diagnosis to the treatment for the individualized patient management. PMID- 29531512 TI - Gender, age and migration: an intersectional approach to inequalities in the labour market. AB - This paper analyses the interference of three socio-demographic characteristics: gender, age and migration status on the labour market outcomes from the perspective of intersectionality theory. Concretely, we investigate whether gender and migration differences in hourly wages are observable at younger ages and whether these differences increase with age. Further, we analyse whether gender and migration interact in such a way that women with migration background suffer lower wage growth in relation to their counterparts. Our analyses draw on data from the Socio-Economic Panel (German SOEP from 1991 to 2014), distinguishing between populations with and without a migration background. Random effects hourly wage regressions controlling for selection bias using Heckman procedure have been estimated in our analysis. The results show that there are large gender differences in hourly wage at younger ages, and these differences are maintained over the life course. Regarding migration status, no significant disadvantages in wages are observable at early stages. However, disadvantages of men and women with migration background increase with age, resulting in lower earnings for older workers with migration background. When we analyse the interaction between migration and gender, we observe no effect either at younger ages or over the entire lifespan, indicating that the gender disadvantage is no more pronounced for women with migration background than for women without such a background (and vice versa). PMID- 29531513 TI - The 2008-2009 Great Recession and employment outcomes among older workers. AB - This study examined whether economic changes related to the 2008-2009 Recession were associated with employment status and job quality indicators among older workers in Europe and Israel. Data were derived from 4917 respondents (16,090 observations both before and after the recession) from 13 countries who participated in the Survey of Health, Ageing and Retirement in Europe. Annual data on gross domestic product (GDP) per capita, life expectancy, and quarterly unemployment rates were assigned to employment assessments from 2004 to 2013. Using difference-in-differences models, we assessed the recession's implications on individual employment outcomes, while isolating cyclical variation within countries and individual changes over time. Among older workers, decreases in GDP were associated with an increase in the likelihood of being unemployed and a decrease in the likelihood of being retired. An increasing country-level unemployment rate had a significant effect on aspects of job quality: lower prospects for job advancement, lower job security, and higher job satisfaction. Economic recessions are thus negatively associated with employment outcomes for older workers. However, malleable policy-related factors such as longer tenure and improved general health can limit the negative employment and job quality outcomes following a recession. PMID- 29531514 TI - Assessing age stereotypes in the German population in 1996 and 2011: socio demographic correlates and shift over time. AB - The present study aimed to extend the knowledge regarding dimensionality, socio demographic correlates and shifts in age stereotypes over the past 15 years using a time-sequential design. In 1996 and 2011, we assessed age stereotypes in two independent samples of the German population aged >= 45 years (N = 970 in sample 1, N = 1545 in sample 2). Three scales with six items each were assessed. Two scales cover negative (i.e., rigidity/isolation, burden), and one scale covers positive age stereotypes (wisdom/experience). Dimensionality of the scale, associations with socio-demographic variables and whether the stereotypes have shifted were tested using confirmatory factor analyses, structural equation modeling and analyses of variances. Three dimensions were identified and replicated following an exploratory as well as a confirmatory approach. Age stereotypes did shift between 1996 and 2011 in the dimension burden (i.e., becoming more negative). Our results further underpin the finding that age stereotypes are multifaceted and suggest that dimensions do not change over time. Additionally, our data provide some evidence that societal age stereotypes partly change over time. PMID- 29531515 TI - Cognitive functioning is more closely related to real-life mobility than to laboratory-based mobility parameters. AB - Increasing evidence indicates that mobility depends on cognitive resources, but the exact relationships between various cognitive functions and different mobility parameters still need to be investigated. This study examines the hypothesis that cognitive functioning is more closely related to real-life mobility performance than to mobility capacity as measured with standardized laboratory tests. The final sample used for analysis consisted of 66 older adults (72.3 +/- 5.6 years). Cognition was assessed by measures of planning (HOTAP test), spatial working memory (Grid-Span test) and visuospatial attention (Attention Window test). Mobility capacity was assessed by an instrumented version of the Timed Up-and-Go test (iTUG). Mobility performance was assessed with smartphones which collected accelerometer and GPS data over one week to determine the spatial extent and temporal duration of real-life activities. Data analyses involved an exploratory factor analysis and correlation analyses. Mobility measures were reduced to four orthogonal factors: the factor 'real-life mobility' correlated significantly with most cognitive measures (between r = .229 and r = .396); factors representing 'sit-to-stand transition' and 'turn' correlated with fewer cognitive measures (between r = .271 and r = .315 and between r = .210 and r = .316, respectively), and the factor representing straight gait correlated with only one cognitive measure (r = .237). Among the cognitive functions tested, visuospatial attention was associated with most mobility measures, executive functions with fewer and spatial working memory with only one mobility measure. Capacity and real-life performance represent different aspects of mobility. Real-life mobility is more closely associated with cognition than mobility capacity, and in our data this association is most pronounced for visuospatial attention. The close link between real-life mobility and visuospatial attention should be considered by interventions targeting mobility in old age. PMID- 29531516 TI - Subjective remaining lifetime and concreteness of the future as differential predictors of preparation for age-related changes. AB - Demographic changes have been linked to the expectation of cuts in government provided social security services, emphasizing individual responsibility to prepare for old age and concomitant challenges and changes. Accordingly, the identification of psychological variables predicting preparation is a matter of theoretical as well as practical importance. We thus consider different aspects of a person's future time as theoretically prominent psychological predictors of preparation. The subjectively perceived quantity of remaining lifetime, the concreteness of future time, and preparation for life domains indicative of an active third age as well as of a more dependent fourth age were assessed in a longitudinal study in a core sample of N = 593 participants (30-80 years old at T1) at two measurement occasions 4 years apart. The quantity of subjective remaining lifetime predicted subsequent changes in preparation, but this effect was restricted to preparation for the fourth age. In contrast, a more open and concrete outlook on ones' personal future predicted changes in preparation for an active third age. Our findings highlight the importance of distinguishing between different aspects of future time-its quantity versus its relation to goals and action plans-when predicting specific facets of developmental self-regulation. PMID- 29531517 TI - Multidimensional social support is associated with healthcare utilization among older Mexican adults. AB - In this study, we aimed to estimate the association between social support and healthcare utilization among older Mexican adults. We conducted a prospective study with 4027 older adults aged 65-74 in rural areas in seven Mexican states. Data were collected at baseline (2007) and 14 months later (2009). Healthcare utilization was defined as number of visits to a physician for preventive or curative purposes in the last 6 months. Multidimensional social support was operationalized into two components: structural (living arrangements, marital status and network size) and functional (perceived availability of support; and perceived support across emotional, instrumental, economic and information domains). Mixed-effects regression models were used to estimate the probability of healthcare use and to examine the association between social support and the number of visits to a physician. Results showed that perceived availability of social support was associated with the probability of visits to a physician (OR 1.44; p < .01). Meanwhile, the following domains of functional component of social support were associated with the probability of visits to a physician: instrumental (OR 1.55; p < .01), economic (OR 1.19; p = .03) and informational (OR 1.39; p < .01); and also with the number of visits to a physician: instrumental (e beta = 1.27; p < .01), economic (e beta = 1.14; p = .01) and informational (e beta = 1.12; p < .10). Our findings suggest that a significant association exists between social support, measured from a multidimensional viewpoint, and healthcare utilization, in which greater social support was related to a greater extent of use of health services. PMID- 29531518 TI - Detection of maltreatment of people with dementia in Spain: usefulness of the Caregiver Abuse Screen (CASE). AB - The objective of our study is to validate the Caregiver Abuse Screen (CASE) as an instrument for detecting the maltreatment of people with dementia in Spain. In total, 326 informal caregivers of people with different types of dementia were interviewed in several cities in northwest Spain. The caregivers were selected from outpatient neurology clinics and associations of relatives of people with Alzheimer's disease and other dementias. A comprehensive sociodemographic questionnaire was administered to all participants, and several standardized scales were used to assess burden, anxiety, depression, social support and resilience. The "Psychological Aggression" and "Physical Assault" dimensions of the Revised Conflicts Tactics Scale were used as risk factors of caregivers' maltreatment for the construct validation. To establish the probability of maltreatment, a latent class analysis was carried out according to the item responses obtained from the CASE. The internal consistency (Cronbach's alpha) of the CASE was 0.71. The construct validity was explored through factorial analysis, and we found that two dimensions of CASE-i.e., interpersonal abuse and neglect/dependency-explained 62.5% of the variability. According to the latent class probabilities, 20.4% of participants were categorized as possible abusers and 21.4% as non-abusers. The optimal maltreatment cutoff point was six points on the CASE. The validation of the CASE provides us a brief and easy instrument for detecting possible cases of maltreatment of Spanish people with dementia. PMID- 29531519 TI - Validity of the EASYCare Standard 2010 assessment instrument for self-assessment of health, independence, and well-being of older people living at home in Poland. AB - EASYCare Standard 2010 is a brief instrument identifying concerns in health, functional independence, and well-being, from older persons' perspective. It has not previously been validated for self-assessment. Our aim was to determine whether self-assessment (EC1) can give comparable results to an evaluation performed by professionals (EC2), for older people living at home. The study included community-dwelling individuals (aged at least 60 years, n = 100; 67 females) without dementia (abbreviated mental test score [AMTS] above 6). It comprised two assessments (self and professional), including summarising indexes: Independence score [IS], Risk of breakdown in care [RBC], Risk of falls [RF], performed within a period between 1 and 2 weeks. Additionally, during EC1, reference tests of physical and mental function (Barthel Index: 96.3 +/- 6.5, Lawton scale: 6.7 +/- 2.0, geriatric depression scale: 3.0 +/- 2.7, AMTS: 10.2 +/ 1.0) were applied to test for concurrent validity. Cohen's kappa values (self assessment vs. professional assessment) across all EASYCare domains were high (0.89-0.95). Results of all summarising indexes derived from self-assessment correlated strongly with reference tests. No differences were found in IS and RBC between EC1 and EC2 (8.6 +/- 12.0 vs. 9.0 +/- 12.7 and 1.0 +/- 1.1 vs. 1.2 +/- 1.4). Results of RF were higher in EC2 (1.0 +/- 1.1 vs. 1.1 +/- 1.4; p = 0.005), due to a different response to the item "Do you feel safe outside your home?" We conclude that self-assessment with EASYCare Standard in older people without severe functional impairment living at home can deliver valid results, similar to those obtained through professional assessment, thus providing an efficient system for assessment of relatively independent individuals. PMID- 29531520 TI - European Journal of Ageing: Reviewers 2017. PMID- 29531521 TI - Arylation of Azaarylmethylamines with Aryl Chlorides and a NiBr2/NIXANTPHOS-based Catalyst. AB - A nickel-catalyzed coupling of azaarylmethylamines with aryl chlorides has been achieved. NIXANTPHOS together with low cost NiBr2 was successfully developed and optimized to exhibit high reactivity at 2.5 mol % loading. Under optimized reaction conditions, aryl(azaaryl)methylamine products were afforded in good to excellent yields (22 examples, up to 98% yield). PMID- 29531522 TI - Corrigendum: Clostridium chauvoei, an Evolutionary Dead-End Pathogen. AB - [This corrects the article on p. 1054 in vol. 8, PMID: 28649238.]. PMID- 29531523 TI - Corrigendum: Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study. AB - [This corrects the article on p. 386 in vol. 8, PMID: 28446908.]. PMID- 29531524 TI - Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling. AB - The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6 kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms. PMID- 29531525 TI - Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population Dynamics. AB - The perineuronal net (PNN) represents a lattice-like structure that is prominently expressed along the soma and proximal dendrites of parvalbumin- (PV-) positive interneurons in varied brain regions including the cortex and hippocampus. It is thus apposed to sites at which PV neurons receive synaptic input. Emerging evidence suggests that changes in PNN integrity may affect glutamatergic input to PV interneurons, a population that is critical for the expression of synchronous neuronal population discharges that occur with gamma oscillations and sharp-wave ripples. The present review is focused on the composition of PNNs, posttranslation modulation of PNN components by sulfation and proteolysis, PNN alterations in disease, and potential effects of PNN remodeling on neuronal plasticity at the single-cell and population level. PMID- 29531526 TI - Astrocytes and the Warning Signs of Intracerebral Hemorrhagic Stroke. AB - Two decades into the two thousands, intracerebral hemorrhagic stroke (ICH) continues to reap lives across the globe. In the US, nearly 12,000 people suffer from ICH every year. Half of them survive, but many are left with permanent physical and cognitive disabilities, the severity of which depends on the location and broadness of the brain region affected by the hemorrhage. The ongoing efforts to identify risk factors for hemorrhagic stroke have been instrumental for the development of new medical practices to prevent, aid the recovery and reduce the risk of recurring ICH. Recent efforts approach the study of ICH from a different angle, providing information on how we can limit brain damage by manipulating astrocyte receptors. These results provide a novel understanding of how astrocytes contribute to brain injury and recovery from small ICH. Here, we discuss current knowledge on the risk factors and molecular pathology of ICH and the functional properties of astrocytes and their role in ICH. Last, we discuss candidate astrocyte receptors that may prove to be valuable therapeutic targets to treat ICH. Together, these findings provide basic and clinical scientists useful information for the future development of strategies to improve the detection of small ICH, limit brain damage, and prevent the onset of more severe episodes of brain hemorrhage. PMID- 29531527 TI - Different Associations of Trunk and Lower-Body Fat Mass Distribution with Cardiometabolic Risk Factors between Healthy Middle-Aged Men and Women. AB - The aim of this study was to assess whether the gender-specific pattern of fat mass (FM) distribution is related to gender differences in cardiometabolic risk factors. 207 healthy middle-aged Japanese were included in the study. We measured FM in the total body, trunk, and lower-body with dual-energy X-ray absorptiometry (DXA). The percentage of trunk FM (TFM) and lower-body FM (LFM) is noted as %TFM and %LFM, respectively. Other measurements included glucose and insulin during oral glucose tolerance test (OGTT), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), and systemic oxidative stress marker. Arterial properties were indicated by cardio-ankle vascular index (CAVI) and intima-media thickness (IMT) of the common carotid artery. The results showed that %TFM is higher whereas %LFM is lower in men than in women and men have a more atherogenic cardiometabolic profile. In both genders, %TFM (%LFM) is related to an unfavorable (favorable) cardiometabolic profile. In particular, the relation between %LFM and OGTT derived insulin sensitivity index is stronger in women than in men. These findings suggested that in relatively healthy adults, android and gynoid pattern of FM distribution contributes to gender differences in cardiometabolic risk factors. PMID- 29531528 TI - Vitamin D and Male Sexual Function: A Transversal and Longitudinal Study. AB - Background: The effects of vitamin D on sexual function are very unclear. Therefore, we aimed at evaluating the possible association between vitamin D and sexual function and at assessing the influence of vitamin D administration on sexual function. Methods: We retrospectively studied 114 men by evaluating clinical, biochemical, and sexual parameters. A subsample (n = 41) was also studied longitudinally before and after vitamin D replacement therapy. Results: In the whole sample, after performing logistic regression models, higher levels of 25(OH) vitamin D were significantly associated with high values of total testosterone and of all the International Index of Erectile Function (IIEF) questionnaire parameters. On the other hand, higher levels of total testosterone were positively and significantly associated with high levels of erectile function and IIEF total score. After vitamin D replacement therapy, total and free testosterone increased and erectile function improved, whereas other sexual parameters did not change significantly. At logistic regression analysis, higher levels of vitamin D increase (Delta-) were significantly associated with high values of Delta-erectile function after adjustment for Delta-testosterone. Conclusions: Vitamin D is important for the wellness of male sexual function, and vitamin D administration improves sexual function. PMID- 29531529 TI - Pre- and Postoperative Body Composition and Metabolic Characteristics in Patients with Acromegaly: A Prospective Study. AB - Objective: To investigate the preoperative body composition, metabolic characteristics, and postoperative changes in patients with active acromegaly and analyze the effects of gender and age. Methods: We included 36 patients with untreated acromegaly and 37 patients with nonfunctional pituitary adenomas. Adipose tissue (AT), the visceral fat index (VFI), sclerotin, protein, skeletal muscle, total body water (TBW), intracellular water (ICW), and extracellular water (ECW) were measured using bioelectrical impedance analysis (BIA). Total energy expenditure (TEE) and basal metabolism (BM) were measured with a cardiopulmonary and metabolic analyzer (CMA). Tricep skinfold thickness (TST), bicep circumference, waistline, hipline, and calf circumference were measured with a skinfold caliper and tape. These indices were measured before surgery and 3 months and 1 year after surgery. Results: Overall, AT, VFI, and TST were lower, whereas sclerotin, protein, skeletal muscle, TBW, ICW, ECW, TEE, and BM were higher in acromegaly patients. Postoperatively, TST rose initially and then decreased, the waistline increased, and sclerotin, skeletal muscle, TEE, and BM decreased. Changes in these indices differed with gender and age in unique patterns. Conclusions: Body composition and metabolism in acromegaly patients changed after surgery, and gender and age influenced these changes. PMID- 29531530 TI - Gap Junctions Are Involved in the Rescue of CFTR-Dependent Chloride Efflux by Amniotic Mesenchymal Stem Cells in Coculture with Cystic Fibrosis CFBE41o- Cells. AB - We previously found that human amniotic mesenchymal stem cells (hAMSCs) in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE) on Transwell(r) filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ-) mediated intercellular communication (GJIC) in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio) were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43), a major component of GJs. Functional GJs in cocultures were inhibited when the expression of the Cx43 protein was downregulated. Transfection of cocultures with siRNA against Cx43 resulted in the absence of specific CFTR signal on the apical membrane and reduction in the mature form of CFTR (band C), and in parallel, the CFTR dependent chloride channel activity was significantly decreased. Cx43 downregulation determined also a decrease in transepithelial resistance and an increase in paracellular permeability as compared with control cocultures, implying that GJIC may regulate CFTR expression and function that in turn modulate airway epithelium tightness. These results indicate that GJIC is involved in the correction of CFTR chloride channel activity upon the acquisition of an epithelial phenotype by hAMSCs in coculture with CF cells. PMID- 29531531 TI - Inflammatory Stimuli Significantly Change the miRNA Profile of Human Adipose Derived Stem Cells. AB - Background: Human adipose-derived stem cells (hASCs) have been shown to have immunoregulatory properties in many studies. However, the mechanisms remain unknown. miRNAs are associated with many cellular processes, including immune responses. Thus, we hypothesized that miRNAs act as immunoregulators when hASCs are stimulated by inflammatory environments. Methods: A set of cytokines was used to stimulate the hASCs in the cytokine group, while no cytokines were used to stimulate the cells in the normal group. A microarray was used to obtain the miRNA expression profile of hASCs, and RT-PCR was used to validate the miRNAs that were differentially expressed between the two groups. Target genes were predicted using online databases, and KEGG analysis was performed to identify the pathways enriched by the target genes of all the differentially expressed miRNAs. Results: Five miRNAs were significantly upregulated, and 2 miRNAs were downregulated in the cytokine group compared with the normal group. We identified several immune-related pathways that are targeted individually or collectively by those miRNAs. Conclusion: Inflammatory stimuli changed the miRNA expression profile of hASCs. miRNAs may play a pivotal role in the immune response in hASCs and may be targets through which the immunoregulatory functions of hASCs can be enhanced. PMID- 29531532 TI - Link Protein N-Terminal Peptide as a Potential Stimulating Factor for Stem Cell Based Cartilage Regeneration. AB - Background: Link protein N-terminal peptide (LPP) in extracellular matrix (ECM) of cartilage could induce synthesis of proteoglycans and collagen type II in cartilaginous cells. Cartilage stem/progenitor cells (CSPCs), the endogenous stem cells in cartilage, are important in cartilage degeneration and regeneration. We hypothesized that LPP could be a stimulator for stem cell-based cartilage regeneration by affecting biological behaviors of CSPC. Methods: CSPCs were isolated from rat knee cartilage. We evaluated the promoting effect of LPP on proliferation, migration, and chondrogenic differentiation of CSPCs. The chondrogenic differentiation-related genes and proteins were quantitated. Three dimensional culture of CSPC was conducted in the presence of TGF-beta3 or LPP, and the harvested pellets were analyzed to assess the function of LPP on cartilage regeneration. Results: LPP stimulated the proliferation of CSPC and accelerated the site-directional migration. Higher expression of SOX9, collagen II, and aggrecan were demonstrated in CSPCs treated with LPP. The pellets treated with LPP showed more distinct characteristics of chondroid differentiation than those with TGF-beta3. Conclusion: LPP showed application prospect in cartilage regeneration medicine by stimulating proliferation, migration, and chondrogenic differentiation of cartilage stem/progenitor cells. PMID- 29531533 TI - Metabolic Heterogeneity Evidenced by MRS among Patient-Derived Glioblastoma Multiforme Stem-Like Cells Accounts for Cell Clustering and Different Responses to Drugs. AB - Clustering of patient-derived glioma stem-like cells (GSCs) through unsupervised analysis of metabolites detected by magnetic resonance spectroscopy (MRS) evidenced three subgroups, namely clusters 1a and 1b, with high intergroup similarity and neural fingerprints, and cluster 2, with a metabolism typical of commercial tumor lines. In addition, subclones generated by the same GSC line showed different metabolic phenotypes. Aerobic glycolysis prevailed in cluster 2 cells as demonstrated by higher lactate production compared to cluster 1 cells. Oligomycin, a mitochondrial ATPase inhibitor, induced high lactate extrusion only in cluster 1 cells, where it produced neutral lipid accumulation detected as mobile lipid signals by MRS and lipid droplets by confocal microscopy. These results indicate a relevant role of mitochondrial fatty acid oxidation for energy production in GSCs. On the other hand, further metabolic differences, likely accounting for different therapy responsiveness observed after etomoxir treatment, suggest that caution must be used in considering patient treatment with mitochondria FAO blockers. Metabolomics and metabolic profiling may contribute to discover new diagnostic or prognostic biomarkers to be used for personalized therapies. PMID- 29531534 TI - Derivation and Identification of Motor Neurons from Human Urine-Derived Induced Pluripotent Stem Cells. AB - Induced pluripotent stem cells (iPSCs) have provided new opportunities for motor neuron disease (MND) modeling, drug screening, and cellular therapeutic development. Among the various types of iPSCs, urine-derived iPSCs have become a promising source of stem cells because they can be safely and noninvasively isolated and easily reprogrammed. Here, for the first time, we differentiated urine-derived iPSCs (urine-iPSCs) into motor neurons (MNs) and compared the capacity of urine-iPSCs and cord-blood-derived iPSCs (B-iPSCs) to differentiate into MNs. With the use of small molecules, mature MNs were generated from urine iPSCs as early as 26 days in culture. Furthermore, in coculture with muscle cells, MNs projected long axons and formed neuromuscular junctions (NMJs). Immunofluorescence and PCR confirmed the expression levels of both MN and NMJ markers. The comparison of the ratios of positive labeling for MN markers between urine-iPSCs and B-iPSCs demonstrated that the differentiation potentials of these cells were not significantly different. The abovementioned results indicate that urine-iPSCs are a new, promising source of stem cells for MND modeling and further cellular therapeutic development. PMID- 29531535 TI - A Nonenzymatic and Automated Closed-Cycle Process for the Isolation of Mesenchymal Stromal Cells in Drug Delivery Applications. AB - The adipose tissue is a good source of mesenchymal stromal cells that requires minimally invasive isolation procedures. To ensure reproducibility, efficacy, and safety for clinical uses, these procedures have to be in compliant with good manufacturing practices. Techniques for harvesting and processing human adipose tissue have rapidly evolved in the last years, and Lipogems(r) represents an innovative approach to obtain microfragmented adipose tissue in a short time, without expansion and/or enzymatic treatment. The aim of this study was to assess the presence of mesenchymal stromal cells in the drain bag of the device by using a prototype Lipogems processor to wash the lipoaspirate in standardized condition. We found that, besides oil and blood residues, the drain bag contained single isolated cells easy to expand and with the typical characteristics of mesenchymal stromal cells that can be loaded with paclitaxel to use for drug delivery application. Our findings suggest the possibility to replace the drain bag with a "cell culture chamber" obtaining a new integrated device that, without enzymatic treatment, can isolate and expand mesenchymal stromal cells in one step with high good manufacturing practices compliance. This system could be used to obtain mesenchymal stromal cells for regenerative purposes and for drug delivery. PMID- 29531536 TI - Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice. AB - Cognitive deficits after traumatic brain injury (TBI) are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI) in adult mice and transplanted embryonic stem cell derived neural progenitor cells (NPC). Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation. PMID- 29531537 TI - Injected Human Muscle Precursor Cells Overexpressing PGC-1alpha Enhance Functional Muscle Regeneration after Trauma. AB - While many groups demonstrated new muscle tissue formation after muscle precursor cell (MPC) injection, the capacity of these cells to heal muscle damage, for example, sphincter in stress urinary incontinence, in long-term is still limited. Therefore, the first goal of our project was to optimize the functional regenerative potential of hMPC by genetic modification to overexpress human peroxisome proliferator-activated receptor gamma coactivator 1-alpha (hPGC 1alpha), key regulator of exercise-mediated adaptation. Moreover, we aimed at establishing a feasible methodology for noninvasive PET visualization of implanted cells and their microenvironment in muscle crush injury model. PGC 1alpha-bioengineered muscles showed enhanced marker expression for myogenesis (alpha-actinin, MyHC, and Desmin), vascularization (VEGF), neuronal (ACHE), and mitochondrial (COXIV) activity. Consistently, use of hPGC-1alpha_hMPCs produced significantly increased contractile force one to three weeks postinjury. PET imaging showed distinct differences in radiotracer signals ([18F]Fallypride and [11C]Raclopride (both targeting dopamine 2 receptors (D2R)) and [64Cu]NODAGA-RGD (targeting neovascularization)) between GFP_hMPCs and hD2R_hPGC-1alpha_hMPCs. After muscle harvesting, inflammation levels were in parallel to radiotracer uptake amount, with significantly lower uptake in hPGC-1alpha overexpressing samples. In summary, we facilitated early functional muscle tissue regeneration, introducing a novel approach to improve skeletal muscle regeneration. Besides successful tracking of hMPCs in muscle crush injuries, we showed that in high inflammation areas, the specificity of radioligands might be significantly reduced, addressing a possible bottleneck of neovascularization PET imaging. PMID- 29531538 TI - Influence of Genetically Modified Human Umbilical Cord Blood Mononuclear Cells on the Expression of Schwann Cell Molecular Determinants in Spinal Cord Injury. AB - Spinal cord injury (SCI) unavoidably results in death of not only neurons but also glial cells. In particular, the death of oligodendrocytes leads to impaired nerve impulse conduction in intact axons. However, after SCI, the Schwann cells (SCs) are capable of migrating towards an area of injury and participating in the formation of functional myelin. In addition to SCI, cell-based therapy can influence the migration of SCs and the expression of their molecular determinants. In a number of cases, it can be explained by the ability of implanted cells to secrete neurotrophic factors (NTFs). Genetically modified stem and progenitor cells overexpressing NTFs have recently attracted special attention of researchers and are most promising for the purposes of regenerative medicine. Therefore, we have studied the effect of genetically modified human umbilical cord blood mononuclear cells on the expression of SC molecular determinants in SCI. PMID- 29531540 TI - Environmental Stimulus on Stem Cell Behaviour. PMID- 29531539 TI - Improved Left Ventricular Aneurysm Repair with Cell- and Cytokine-Seeded Collagen Patches. AB - Background: Engineered heart tissues (EHTs) present a promising alternative to current materials for surgical ventricular restoration (SVR); however, the clinical application remains limited by inadequate vascularization postimplantation. Moreover, a suitable and economic animal model for primary screening is another important issue. Methods: Recently, we used 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride chemistry (EDC) to initiate a strengthened, cytokine-conjugated collagenous platform with a controlled degradation speed. In vitro, the biomaterial exhibited an enhanced mechanical strength maintaining a porous ultrastructure, and the constant release of cytokines promoted the proliferation of seeded human mesenchymal stem cells (hMSCs). In vivo, with the hMSC-seeded, cytokine-immobilized patch (MSCs + GF patch), we performed modified SVR for rats with left ventricular aneurysm postmyocardial infarction (MI). Overall, the rats that underwent modified SVR lost less blood and had lower mortality. After 4 weeks, the rats repaired with this cell-seeded, cytokine-immobilized patch presented preserved cardiac function, beneficial morphology, enhanced cell infiltration, and functional vessel formation compared with the cytokine-free (MSC patch), cell-free (GF patch), or blank controls (EDC patch). Furthermore, the degradable period of the collagen patch in vivo extended up to 3 months after EDC treatment. Conclusions: EDC may substantially modify collagen scaffold and provide a promising and practical biomaterial for SVR. PMID- 29531542 TI - External Dacryocystorhinostomy; Success Rate and Causes of Failure in Endoscopic and Pathologic Evaluations. AB - Background and Objectives: External dacryocystorhinostomy (DCR) is the method of choice to treat nasolacrimal duct (NLD) obstruction and the other approaches are compared with it, with a failure rate of 4% to 13%. The current study aimed to assess the causes of failure in external DCR by postoperative endoscopic and pathological evaluation. Methods: The current retrospective cross sectional study followed-up113 patients with external DCR and silicone intubation for three months. Silicone tubes were removed after the third months. Failure was confirmed based on the clinical findings and irrigation test. Paranasal sinus computed tomography (CT) scanning, and endoscopic and pathological evaluations were performed in the failed cases. Results: Totally, 113 patients underwent external DCR. The patients included 71 females and 42 males. The mean age of the patients was 55.91 years; ranged from 18 to 86. Epiphora was the most common complaint before surgery (90.3%). Clinically, epiphora continued in 17 cases (15%), of which 94.11% had at least one sinus CT abnormality and 82.35% had at least one endoscopic abnormality. The most common endoscopic findings were deviated septum (70.6%), scar tissue (52.94%), concha bullosa (46.9%), septal adhesion (47.05%), enlarged middle turbinate (41.2%), and sump syndrome (11.7%). The failure was significantly associated with the chronicity of the initial symptoms (P value=0.00). Pathologically, there were significant relationship amongst the failure rate, scar formation, and allergic rhinitis (P-values =0.00 and <0.05, respectively). Conclusion: Preoperative endonasal evaluation and consultation with an otolaryngologist can improve surgical outcomes and help to have a better conscious to intranasal abnormalities before external DCR surgery. PMID- 29531543 TI - The Diagnostic Value of TTF-1, P63, HMWK, CK7, and CD56 Immunostaining in the Classification of Lung Carcinoma. AB - Background & objective: The histologic distinction of small cell from non-small cell lung carcinoma and correct identification of all subtypes of lung carcinoma are very important in treatment management. The main method for histologic classification of lung tumors is based on morphology. However, in small bronchoscopic biopsies in particular, distinction is very difficult upon morphology alone. The current study aimed at evaluating the utility of a panel of antibodies, consisting of thyroid transcription factor (TTF-1), P63, high molecular weight keratin [HMWK (34betaE12)], cytokeratin (CK7), and cluster of differentiation (CD56) for accurate distinction of bronchogenic carcinomas. Methods: Bronchoscopic biopsies of 60 lung carcinoma cases including 20 small cell carcinomas, 20 adenocarcinomas, and 20 squamous cell carcinomas (SCCs) with typical morphologic features were selected. All these cases were immunohistochemically stained for TTF-1, P63, HMWK (34betaE12), CK7, and CD56. All immunostained slides were scored as either positive or negative. Results: The mean age of the patients was 60 years; ranged from 35 to 81. Sixteen patients were female and 44 were male. All adenocarcinomas were positive for CK7 and most of them (18/20; 90%) were positive for TTF-1. Most of small cell lung carcinomas were positive for TTF-1 (17/20; 85%), and CD56 (18/20; 90%). All squamous cell carcinomas (SCCs) were negative for TTF-1, but most of them were positive for HMWK (34betaE12) and P63. Conclusion: The obtained data showed that TTF-1, P63, CK7, CD56 and/or 34betaE12 represent a useful panel of antibodies to identify lung carcinoma subtypes in small bronchoscopic biopsies. PMID- 29531541 TI - Sitagliptin Accelerates Endothelial Regeneration after Vascular Injury Independent from GLP1 Receptor Signaling. AB - Introduction: DPP4 inhibitors (gliptins) are commonly used antidiabetic drugs for the treatment of type 2 diabetes. Gliptins also act in a glucose-independent manner and show vasoregenerative effects. We have shown that gliptins can remarkably accelerate vascular healing after vascular injury. However, the underlying mechanisms remain unclear. Here, we examined potential signaling pathways linking gliptins to enhanced endothelial regeneration. Methods and Results: We used wild-type and GLP1 receptor knockout (Glp1r-/-) mice to investigate the underlying mechanisms of gliptin-induced reendothelialization. The prototype DPP4 inhibitor sitagliptin accelerated endothelial healing in both animal models. Improved endothelial growth was associated with gliptin-mediated progenitor cell recruitment into the diseased vascular wall via the SDF1-CXCR4 axis independent of GLP1R-dependent signaling pathways. Furthermore, SDF1 showed direct proproliferative effects on endothelial cells. Excessive neointimal formation was not observed in gliptin- or placebo-treated Glp1r-/- mice. Conclusion: We identified the SDF1-CXCR4 axis as a crucial signaling pathway for endothelial regeneration after acute vascular injury. Furthermore, SDF1 can directly increase endothelial cell proliferation. Gliptin-mediated potentiation of endothelial regeneration was preserved in Glp1r-/- animals. Thus, gliptin mediated endothelial regeneration proceeds through SDF-1/CXCR4 in a GLP1R independent manner after acute vascular injury. PMID- 29531544 TI - The Core Needle and Surgical Biopsy Concordance to Detect Estrogen, Progesterone, and Her-2 Receptors in Breast Cancer: A Comparative Study. AB - Background &Objectives: Evaluation of estrogen receptor (ER), progesterone receptor (PR), and (human epidermal growth factor receptor-2) Her-2 on core needle biopsies (CNBs) is increasingly in use to diagnosis early breast cancer, but its concordance with surgical excision (SE) is not well documented. Methods: The study included 100 formalin fixed, paraffin-embedded specimens of invasive breast carcinoma archived in Pathology Department of Cancer Institute, Tehran, Iran, from 2011 to 2014. Immunohistochemistry was applied to detect ER, PR, and Her-2. Results: The current study findings indicated a significant correlation of 90% between CNB and SE specimens for ER expression. The correlation between CNB and SE specimens was estimated as 81% and 97.3% for PR and Her-2, respectively. Discussion: CNB can be performed confidently to determine ER and Her-2. For PR, results obtained from CNB should be considered. PMID- 29531545 TI - Differentiating and Categorizing of Liposarcoma and Synovial Sarcoma Neoplasms by Fluorescence in Situ Hybridization. AB - Background & Objective: Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumors of mesenchymal origin and various cytogenetic abnormalities ranging from distinct genomic rearrangements, such as chromosomal translocations and amplifications, to more intricate rearrangements involving multiple chromosomes. Fluorescence in situ hybridization (FISH) can be used to identify these chromosomal translocations and amplifications, and sub classify STS precisely. The current study aimed at investigating the usefulness of FISH, as a diagnostic ancillary aid, to detect cytogenetic abnormalities such as MDM2 (murine double minute 2) amplification and CHOP(C/EBP homologous protein) rearrangement in liposarcoma, as well as SYT (synaptotagmin) rearrangement in synovial sarcoma. Methods: The FISH technique was used to analyze 17 specimens of liposarcoma for MDM2 amplification and CHOP rearrangement, and 10 specimens of synovial sarcoma for SYT rearrangement. The subtypes of liposarcoma and synovial sarcomas were reclassified according to the FISH results and compared with those of the respective histological findings. Results: According to the FISH results in 17 liposarcoma cases, well-differentiated liposarcoma(WDLPS), dedifferentiated liposarcoma (DDLPS), and myxoidliposarcoma (MLPS)subtypes were 41%, 53%, and 6%, respectively. In different subtypes of liposarcoma, a total of 30% mismatches were observed between pathologic and cytogenetic results. According to the histological findings from FISH analysis, SYT rearrangement was found only in three out of 10 (30%) synovial sarcomas. Conclusion: The detection of cytogenetic abnormalities in patients with liposarcoma and synovial sarcoma by FISH technique provides an important objective tool to confirm sarcoma diagnosis and sub classification of specific sarcoma subtypes in such patients. PMID- 29531546 TI - High Expression of Sphingosine Kinase 1 in Estrogen and Progesterone Receptors Negative Breast Cancer. AB - Background & objective: Breast cancer is the leading cause of cancer related death in females. Sphingosine kinase 1 (SPHK1) and its product sphingosine-1 phosphate (S1P) are the essential key regulator molecules in breast cancer through their ability to promote cell proliferation, angiogenesis, cell proliferation, and lymphagiogenesis. SPHK1 is overexpressed in multiple types of cancer including breast cancer and is associated with resistance to treatment. The current study aimed at investigating the expression of SPHK1 in estrogen and progesterone receptors (ER, PR) negative in comparison to ER, and PR positive breast cancer and their normal controls, and also finding the relationship between SPHK1 expression and high body index (BMI) in the selected groups with breast cancer. Methods: A total of 120 human breast cancer tissue specimens were analyzed for SPHK1 expression using Quantitative Real-Time Polymerase Chain Reaction (q RT-PCR) assay. Detection of hormonal status of breast cancer tissue samples was conducted by immunohistochemical assay. Result: The current study findings showed that the level of SPHK1expression in the breast cancer tissue was significantly higher in patients with estrogen and progesterone negative receptors, compared to the ones without them (P-value< 0.05). The obtained data confirmed that the obesity in patients with ER negative was higher than the ones with positive receptors (BMI> 25). Conclusion: The current study showed that expression of SPHK1gene was higher in the patients with ER and PR negative breast cancer and high BMI, compared with other groups. PMID- 29531547 TI - Correlation of Vascularization and Inflammation with Severity of Oral Leukoplakia. AB - Background & objective: Changes in submucosal vascularization and inflammation, determined by immunohistochemistry staining, were shown to be correlated with the development of dysplasia and invasiveness of epithelial cells in premalignant and malignant lesions. This study evaluated changes in sections routinely stained with Hematoxylin and Eosin (H&E) in order to investigate vascular density and intensity of inflammatory cells infiltration during the progression of oral leukoplakia with mild dysplasia to Squamous Cell Carcinoma (SCC).The aim of the research was to determine whether changes in sub-mucosal vascularity and inflammatory infiltration of leukoplakia in routine H&E-stained sections could contribute to the assessment of severity of the lesion. Methods: In this cross sectional, comparative and descriptive study, vascular density and inflammation intensity of 125 available samples of H&E-stained sections, consisting of 35 cases of mild and moderate dysplasia, 38 severe dysplasia and carcinoma in situ, and 52 SCC, were investigated. To analyze the data, chi-square test, Mann-Whitney test, Kruskal-Wallis test, Tukey's post hoc test, and cumulative ordinal logistic regression were conducted. Results: There was a significantly higher vascular density in cases with severe dysplasia, in situ carcinoma, and SCC compared to those with mild to moderate dysplasia (P<0.0001). However, the difference in vascularity was not statically significant between severe dysplasia, carcinoma in situ, and SCC (P=0.78). Intensity of inflammatory cells infiltration in the underlying connective tissue was significantly different among the three groups (P<0.0001), and the highest intensity of inflammatory cells infiltration was seen in the SCC group. Conclusions: Increased submucosal vascularization and inflammatory cells infiltration can contribute further to predicting more aggressive epithelial dysplasia. PMID- 29531548 TI - Expression of Apoptosis Related and Proliferative Proteins in Malignant Lympho Proliferative Disorders. AB - Background & Objective: The current study aimed to perform an immunohistochemical analysis of patterns of apoptotic and cell proliferative related protein expression in different histological grades and immune phenotypes of malignant lymphomas and other lymphoproliferative disorders. Methods: This observational study was carried on 60lymph node biopsies of lymphoproliferative disorders. The biopsies were analyzed histologically and immunohistochemically. Results: A total of 60 lymph node biopsies were included in the study, of which 81.6% were of malignant lympho-proliferative lesions. The majority of the biopsies were B-cell (66%) and were grouped in the intermediate grade. Bax and BCL-2 protein expression was presented by percentage of immune positive neoplastic cells per 10fields and graded on a scale of 1 to4. A Bcl-2, Bax Protein Ratio (BBPR) was determined for each case by dividing the estimated Bcl-2 protein (percentage of Bcl-2 positive cells x Bcl-2 staining intensity) by the estimated Bax protein (percentage of Bax positive cells x Bax immunostaining intensity). The mean BBPR was found to be significantly higher in indolent lymphomas (2.64 +/- 1.3) as compared to aggressive lymphomas (0.47 +/- 0.9) (P<0.01). The expression of P53 and PCNA in 35 biopsies of Non Hodgkin Lymphomas (NHL) was found to increase from low to high grade tumors. Conclusions: A significant correlation was found between BBPR and predicted biological behavior of indolent and aggressive lymphomas. This indicates the important role of Bcl-2 and Bax in biological behavior of lymphomas. Furthermore, P53 and PCNA expression were found to increase from low to high-grade tumors suggesting their prognostic value in NHL. PMID- 29531549 TI - Basic Characteristics of Oligodendrogliomas at the Shohada-e Tajrish Hospital (2008 to 2014). AB - Background and Objectives: Gliomas are the most prevalent subgroup of primary brain tumors with a relatively high mortality. However, oligodendrogliomas have a better prognosis compared to other subtypes due to their sensitivity to chemotherapy. Considering the low incidence and the resulting lack of information about oligodendrogliomas, particularly in Iran, this study aimed at assessing their basic characteristics. Methods: In this descriptive retrospective study, patients with definite diagnosis of oligodendroglioma were identified by reviewing the archives of pathology reports at the department of pathology of Shohada-e Tajrish Hospital during years 2008 to 2014. Age, gender, location, and the grade of the tumor were extracted and entered to the SPSS statistical software for analysis. Results: A total of 182 patients, including 115 males (63.2%) and 67 females (36.8%), were included with a mean age of 38.5+/-13.36 years. Frontal lobe was involved in 53 patients (29.1%), parietal lobe in 31 (17.0%), temporal lobe in 22 (12.1%), frontoparietal area in 15 (8.2%), parieto occipital area in 11 (6.0%), temporoparietal and frontotemporal areas each in 9 subjects (4.9%), occipital lobe in 5 (2.7%), and the brainstem in 4 (2.2%). Furthermore, 108 cases (59.3%) had grade-2 and the remaining74 patients (40.7%) had grade-3 anaplastic oligodendrogliomas. The mean age of subjects with brainstem oligodendrogliomas was significantly lower than the other patients (p=0.025). Conclusion: Oligodendrogliomas commonly effects the frontal lobe, followed by the parietal and temporal lobes. The mean age of subjects with brainstem lesions was significantly lower than other patients. Age, gender or location of the tumor did not independently predict a higher grade lesion. PMID- 29531551 TI - Evaluation of Association Between the Serum Levels of MMP-9 and MMP-9/TIMPs With Soluble Forms of Selectins and Itching Induced by Sulfur Mustard. AB - Background & objective: Pruritus is the most frequent chronic dermal complication of sulfur mustard (SM), which negatively influences the quality of life. Exact pathophysiology of SM-induced itching is unknown. The current study aimed at evaluating the possible association between SM-induced itching and the serum levels of matrix metalloproteinase (MMP)-9 and their endogenous inhibitors, and serum levels of soluble forms of selectins (sL-, sP-, and sE-selectins) as adhesion molecules involved in the development of different inflammatory reactions. Methods: Serum levels of MMP-9, MMP-9/ tissue inhibitors of metalloproteinases (TIMPs), and selectins were measured by the enzyme-linked immunosorbent assay (ELISA), and compared between the groups (n=368) with and without itching, and matched control groups (n=126). Results: Serum levels of MMP 9 were significantly higher in the SM exposed group with itching, compared with that of the group without itching (medians: 894 and 624 pg/mL respectively; P value =0.034). There was no relationship between the serum levels of MMP-9/TIMP 1, MMP-9/TIMP-2, MMP-9/TIMP-4, and itching in the patients exposed to SM. Median serum levels of sE- and sL-selectins in the exposed group with itching were higher than those of the exposed group without itching. These differences were statistically insignificant (P-values =0.084 and 0.095, respectively). Conclusion: According to the results of the current study, the increased serum levels of MMP-9 and selectins 20 years after exposure may play role in the pathogenesis and persistence of SM-induced itching in the exposed individuals. PMID- 29531550 TI - Comparison of Interferon-Gamma (IFNG) +874 T/A Single Nucleotide Polymorphism in Hepatitis C Virus Infected Patients and Non-Infected Controls in Mashhad, Iran. PMID- 29531552 TI - Acute Myeloid Leukemia as the Main Cause of Pancytopenia in Iranian Population. AB - Background & objective: Pancytopenia is the reduction in the number of all 3 major cellular elements of blood and leads to anemia, leukopenia, and thrombocytopenia. A wide variety of etiologies result in pancytopenia including leukemia, aplastic anemia, and megaloblastic anemia. The current study identified the different etiologies of pancytopenia based on bone marrow examination in Iranian patients with pancytopenia. Methods: A total of 683 cases of pancytopenia with various etiologies were selected for this retrospective study. Bone marrow biopsy was performed with the standard technique using Jamshidi needle. The inclusion criteria for patients with pancytopenia were hemoglobin (Hb) <10 g/dL, total leukocyte count (TLC) <4 x 109/L, and platelet count <140 x 109/L. Results: In the present study acute leukemia was the first most common etiology detected in 235 (35.4%) patients in which acute myeloid leukemia (AML) comprised the majority of cases 142 (21.4%), followed by myelodysplastic syndrome (MDS) 100 (15%). In patients less than 20 years old, acute leukemia was also the commonest cause identified in 56 (57.7%) cases in which acute lymphoblastic leukemia (ALL) with 38.7% was the most common etiology; however in adults (>45 year old), AML accounted for the majority of cases 76 (53.5%). Conclusion: Since acute leukemia was the commonest etiology in both young and adults in which AML accounted for the majority of cases with pancytopenia in Iranian population, there was an urgent need to identify the underlying molecular or genetic mechanism of this malignancy for better further medical management and patients' survival. PMID- 29531553 TI - Duodenal Metastases From Renal Cell Carcinoma Presented With Melena: Review and Case Report. AB - Renal cell carcinoma (RCC) metastasis to duodenum is very rare and only a few case reports are available in the literature. We here reported a patient with solitary duodenal metastasis presented with melena six years after right nephrectomy. The patient underwent upper gastrointestinal endoscopy showing ulcerative mass at the second portion of duodenum and biopsy of this mass was consistent with metastatic RCC. Metastasis work up did not find any other site of malignancy, thus Whipple's operation (Pancreaticoduodenectomy) was performed. In conclusion metastasis from RCC should be considered in mind in patients with history of nephrectomy presenting with gastrointestinal symptoms and a complete evaluation, especially endoscopic examination followed by biopsy, is suggested. PMID- 29531554 TI - A Carcinoid Tumor in the Urinary Bladder with Uncommon Clinicopathological Presentation. AB - Background: Carcinoid tumors usually originate from the enterochromaffin cells located in gastrointestinal tract and bronchopulmonary system. They may rarely arise in the urinary bladder, where this can be eventually miscued as any other commoner bladder neoplasms. The current study was conducted to connote an uncommon clinicopathological presentation by a carcinoid tumor in the urinary bladder. Case: A 52-year-old male, who initially experienced obstructive urinary symptoms, underwent cystourethroscopy to remove a tumor in the urinary bladder. The tumor exhibited insular, trabecular, and organoid architecture on histology without any necrosis or mitosis, stained positively with chromogranin A, and thereby, confirmed the diagnosis of a pure carcinoid tumor. Conclusion: Carcinoid tumors rarely arise in the urinary bladder and other genitourinary organs. But, several other and relatively more common bladder neoplasms may often deceptively simulate it. This dilemma could be resolved easily with the application of proper immunohistochemistry (IHC) in neuroendocrine tumors. PMID- 29531555 TI - Immunohistochemical Expression of Nuclear beta-Catenin and STAT-6 in a Solitary Fibrous Tumor of the Soft Palate: A Case Report and Review of the Literature. AB - The solitary fibrous tumors (SFT) are rare tumors in the head and neck region and there have been only 5 cases reported in the literature in the soft palate. The current paper presents a unique case of a 62-year-old male with TFS arising in the soft palate. The tumor was highly cellular, composed of bland looking haphazardly arranged spindle cells. The signal transducer and activator of transcription (STAT)-6 and nuclear beta-catenin were reactive by immunohistochemistry (IHC). The current case highlights the importance of the STAT-6 and the beta-catenin as IHC markers to make a differential diagnosis with other entities. In summary, the paper presents the first reported case of a SFT of the soft palate in a male patient with nuclear expression of STAT-6 and beta catenin. PMID- 29531556 TI - CD99: A potential Diagnostic Marker for Differentiating Sub-ependymal Giant Cell Astrocytoma From Other Mimickers: A Report of Five Cases. AB - Background: Tuberous sclerosis (TSC) is inherited as an autosomal dominant disease, characterized by skin lesion and tubers in vital organs, especially brain in three categories including subependymal nodules, cortical tubers and subependymal giant cell astrocytoma. Subependymal giant cell astrocytoma (SEGA) is an indolent neoplasm which usually arises at the cauda thalamic groove near foramen monro, although it occurs usually in the clinical settings of TSC, a few number of SEGA has been reported without such history. Its morphology with special cytoarchitecture could be mistaken with other glial brain tumors with similar morphology. Therefore, investigating new markers for differentiating SEGA from other mimickers seems logical rather than other glioneural immunohistochemical markers introduced before. Case studies: We investigated CD99 expression in SEGA as an adjunctive marker for diagnostic purposes. Five reported cases of SEGA were studied and all of them showed CD99 expression besides usual glioneural markers. Conclusion: CD99 may be a useful adjunctive marker in differentiating SEGA from other mimickers. PMID- 29531557 TI - Benign Phyllodes Tumor With Cystic Squamous Metaplasia: A Cytohistological Correlation of a Rare Case. AB - Background: Phyllodes tumors (PTs) are uncommon biphasic fibroepithelial neoplasms of the breast occurring in elderly females with a peak incidence between 45 and 49 years. Depending on various histological criteria, they are subdivided into benign, borderline, and malignant forms. Metaplastic changes occur, but are quite infrequent and cystic squamous metaplasia is very rare among the observed metaplastic changes in PT. Case: The current paper presents the case of a 41-year-old female with a progressively enlarging swelling in the left breast. Subsequent histopathological examination revealed benign PT with cystic squamous metaplasia. The previously done fine needle aspiration smears were also reviewed, which showed important diagnostic clues to this rare entity, but were ignored due to the rarity of the lesion. Conclusion: The case was presented because of its unique cytological and histopathological morphology and also to determine the role of aspiration cytology to diagnose such a rare occurrence. PMID- 29531558 TI - Nosocomial Jejunal Mucormycosis - an Unusual Cause of Perforation Peritonitis. AB - Mucormycosis is a rare but highly invasive opportunistic fungal infection. Gastrointestinal disease although uncommon is highly fatal. We report a case of jejunal mucormycosis in a 24 year old undernourished female with preceding surgical intervention for acute intestinal obstruction of tubercular etiology. On 8th post-operative day, she developed oozing from suture line, prompting exploratory laparotomy, bowel resection, jejunostomy and ileal mucus fistula. Resected bowel showed one perforation and several areas of impending perforations. Characteristic broad, pauci-septate hyaline, empty looking hyphae with infrequent branching were found transmurally and showing angio-invasion. Local intestinal tissue trauma coupled with her sub-normal immune status permitted this unusual nosocomial infection. Histopathological demonstration of the fungus in surgical specimens remains cornerstone of diagnosis of mucormycosis in view of its non-specific symptoms, low isolation rates of mycological culture and lack of other rapid tests. PMID- 29531559 TI - Gorham's Disease of the Maxilla and Mandible With Distinctive Cone Beam Computerized Tomographic Features. AB - Gorham's disease is a rare and atypical disorder epitomized by progressive osteolysis of bone with eventual total disappearance of bone. The etiology is poorly understood with variable clinical presentation. Most times it is initially misdiagnosed as temporomandibular joint dysfunction, periodontal disease or odontogenic tumors clinically and radiographically in routine dental practice. Radiographic examination, such as Cone Beam Computerized Tomography (CBCT) play a vital role in diagnosing such disorder resulting in disappearance of the involved bone entirely, which is a definitive distinguishing feature of this condition. Regarding the rarity of the condition, the current study presents a case of Gorham's disease with distinctive clinical, radiological, and histological, features involving maxilla and mandible. PMID- 29531560 TI - Placental Mesenchymal Dysplasia With Normal Fetus: A Rare Case Report. AB - Placental mesenchymal dysplasia (PMD) is a rare benign placental abnormality. It is characterized by hydropic degeneration of stem villi, placentomegaly, and increased maternal serum alpha-fetoprotein (AFP). It can be associated with different congenital abnormalities, karyotype abnormalities, and feto-maternal morbidities. It is difficult to differentiate PMDfrom partial mole, complete mole with twin pregnancy in ultrasound, and in macroscopic examination. The current paper presentsa rare case of placental mesenchymal dysplasia in a young primigravida mother who delivered a normal fetus withnormal karyotype. PMID- 29531561 TI - Dark Chocolate Intake Acutely Enhances Neutrophil Count in Peripheral Venous Blood. AB - Beside the well-established impact on decreasing the risk of cardiovascular diseases (1), recent attention has been paid to the relationship between cocoa containing foods and the immune system (2), showing that dark chocolate consumption enhances the systemic defense against bacterial (3) and viral (4) infections. Hence, the current study aimed at investigating the acute effect of dark chocolate intake on peripheral blood leukocytes. PMID- 29531562 TI - Current Diagnostic Status of Pheochromocytomaand Future Perspective: A Mini Review. AB - Pheochromocytomas (PCCs) are rare neuroendocrine tumors. The current diagnostic tools are based on biochemistry and histopathology results, but heterogeneity of diagnostic markers, signs and symptoms of PCCs bring a lot of difficulties for these two current methods. Unfortunately, microscopic understanding of PCCs is not adequate for its confident prognosis and management. There are data linking specific genotypes of PCCs tumors to specific locations, typical biochemical phenotypes or future clinical behaviors. The detection of a germ-line mutation possibly can guide us to an early diagnosis, appropriate treatment, and regular surveillance with better prognosis for patients but also and their family members. Moreover, the latest discoveries in gene sequencing, circulating DNA (ctDNA) and circulating tumor cells (CTCs) will support the exact molecular pathogenesis of PCCs to provide an important basis for future PCCs managements. PMID- 29531563 TI - Lipid regulatory genes polymorphism in children with and without obesity and cardiometabolic risk factors: The CASPIAN-III study. AB - Background: Genetically, predisposed children are considered as at-risk individuals for cardiovascular disease. In this study, we aimed to compare the frequency of four-lipid regulatory polymorphism in obese and normal-weight children with and without cardiometabolic risk factors. Materials and Methods: In this nested case-control study, 600 samples of four groups of participants consisted of those with normal weight with and without cardiometabolic risk factors and obese with and without cardiometabolic risk factors. Allelic and genotypic frequencies of GCKR (rs780094), GCKR (rs1260333), MLXIPL (rs3812316), and FADS (rs174547) polymorphisms were compared in the four studied groups. Results: Data of 528 samples were complete and included in this study. The mean (standard deviation) age of participants was 15.01 (2.21) years. Frequency of tt allele (minor allele) of GCKR (rs1260333) polymorphism was significantly lower in normal weight metabolically healthy participants than metabolically unhealthy normal weight (MUHNW) and obese children with and without cardiometabolic risk factor (P = 0.01). Frequency of ga allele of GCKR (rs780094) polymorphism was significantly higher in normal weight children with cardiometabolic risk factor than in their obese counterparts with cardiometabolic risk factor (P = 0.04). Frequency of cg and gg alleles (minor type) of MLXIPL (rs3812316) polymorphism in normal weight metabolically healthy participants was significantly higher than MUHNW (P = 0.04) and metabolically healthy obese children (P = 0.04). Conclusion: The findings of our study indicated that the minor allele of GCKR (rs1260333) single nucleotide polymorphisms (SNPs) could have pathogenic effect for obesity and cardiometabolic risk factors. Ga allele of GCKR (rs780094) SNPs had a protective effect on obesity. Minor alleles of MLXIPL (rs3812316) could have a protective effect for obesity and cardiometabolic risk factors. PMID- 29531564 TI - Efficacy of combined endurance-resistance training versus endurance training in patients with heart failure after percutaneous coronary intervention: A randomized controlled trial. AB - Background: This study aimed to compare the effects of combined endurance resistance training (CT) versus endurance training (ET) on some cardiovascular markers in patients with heart failure after percutaneous coronary intervention (PCI). Materials and Methods: The study applied a randomized, controlled design in which 75 patients with heart failure who had undergone PCI were randomly assigned to one of three groups: ET, CT, and control. The ET group performed ET for 45 min, three times a week for 7 weeks. The CT group performed the same ET for 30 min followed by a resistance exercise protocol. The control group received usual care. Functional capacity, N-terminal pro-brain natriuretic peptide (NT-pro BNP), and high sensitivity C-reactive protein (hs-CRP) levels were measured. Results: After the intervention, functional capacity was improved (P < 0.001) and NT-pro BNP level was significantly reduced (P = 0.004 in the CT group, P = 0.002 in the ET group). Hs-CRP level was significantly reduced only in the ET group (P = 0.030). The control group showed no significant changes in any cardiovascular parameters (P >= 0.05). Changes in functional capacity (P < 0.001) in both training groups were significantly different from the control group. No significant differences were found between the ET and CT groups regarding changes in all outcomes after exercise training (P >= 0.05). Conclusion: Exercise training is safe and feasible in post-PCI patients, even in those with reduced ejection fraction. CT was as effective as ET in reducing NT-pro BNP level and improving functional capacity in heart failure patients after PCI. PMID- 29531565 TI - Evaluation of the predictive value of fetal Doppler ultrasound for neonatal outcome from the 36th week of pregnancy. AB - Background: Early prediction of adverse neonatal outcome would be possible by Doppler impedance indices of middle cerebral artery (MCA), umbilical artery (UmA), and descending aortal artery (AO) that result in decrease neonatal morbidity and mortality rate. The aim of the present study was a determination of optimal value for the ratio of MCA to descending aorta blood flow (MCA/AO) impedance indices and its comparison with the ratio of MCA to UmA (MCA/UmA) impedance indices and their relationship with neonatal outcome. Materials and Methods: This was a prospective cohort study on 212 pregnant women with gestational age 36 weeks or more, in three hospitals in Tehran, from April 2012 to April 2013. We investigated AO, MCA, and UmA impedance indices Doppler ultrasound every 2 weeks till delivery. The mother was monitored for adverse pregnancy outcome (hypertension [HTN], fetal growth retardation, and other maternal complications) then infant birth weight, cord blood of pH, and Neonatal Intensive Care Unit (NICU) admission during the first 24 h after delivery were assessed. Finally, we investigated relationships between Doppler indices and neonatal outcomes include neonatal body weight (NBW), cord blood of pH, and NICU admission. Results: MCA/AO resistance index (RI) and MCA/AO pulsatile index (PI) showed an area under the receiver operating characteristics curve (area under the curve) of 0.905 (95% confidence interval (CI): 0.850, 0.959) and 0.818 (95% CI: 0.679, 0.956), respectively. The cutoff values for pH (>=7.2 vs. <7.2) based on MCA/AO RI and MCA/AO PI indices were 0.951 (sensitivity, 80% and specificity, 86%) and 0.853 (sensitivity, 91% and specificity, 83%), respectively. The cutoff value for NBW (>=2500 vs. <2500 g) based on MCA/UmA PI index was 1.467 (sensitivity, 73% and specificity, 63%). The cutoff value of NICU admission of child based on MCA/AO PI index was 1.114 (sensitivity, 73% and specificity, 54%). Conclusion: In the end of third-trimester pregnancies with the assessment of MCA and AO artery Doppler ultrasonography, it is possible to prevent many cases of neonatal acidosis caused by prenatal asphyxia as well as inappropriate interventions which are applied on mother. If MCA/AO PI was <0.85, the fetus needs to be evaluated further because it is at risk for acidosis. PMID- 29531567 TI - Hidden cost of disability: What policy makers usually forget. PMID- 29531566 TI - Incidence of nonmelanoma skin cancer in renal transplant recipients: A systematic review and meta-analysis. AB - Background: Nonmelanoma skin cancer (NMSC) in renal transplant recipients is common and associated with significant morbidity and mortality. The aim of the present systematic review and meta-analysis was to estimate the incidence of NMSC among renal transplant recipients. Materials and Methods: We systematically searched PubMed, Medline, Scopus, and Web of Science databases for studies that assessed the incidence of NMSC in renal transplant recipients using a combination of relevant keywords. Two independent investigators included studies and extracted necessary information. Random effect meta-analysis was used to estimate pooled incidence of NMSC with 95% confidence intervals (CIs). Results: Twenty nine studies comprising 36,021 patients meet the criteria for the systematic review. The pooled incidence of NMSC in renal transplant recipients was 12.6% (95% CI: 12%-14%) with a majority of squamous cell carcinoma (SCC) 55% (95% CI: 47%-63%). The pooled estimate of the incidence rates of SCC and basal cell carcinoma was 2.7% (95% CI: 2%-3.4%) and 2.2% (95% CI: 1.5%-2.8%), respectively. Subgroup analysis per geographic location showed that pooled incidence of NMSC was 39.1% (95% CI: 26.3%-51.8%), 12.4% (95% CI: 8.8%-16%), and 1.2% (95% CI: 0.4% 2%) in Australia and New Zealand, Europe, and Middle East, respectively. Conclusion: The results of the current meta-analysis demonstrated that the incidence of NMSC in renal transplant recipients varies widely. Regarding the high incidence of NMSC among renal transplant recipients, awareness of associated risk factors and early diagnosis of the malignancy in the population is a major clinical need. PMID- 29531568 TI - The effect of saffron (Crocus sativus L.) hydroalcoholic extract on metabolic control in type 2 diabetes mellitus: A triple-blinded randomized clinical trial. AB - Background: Metabolic control is a major concern in preventing diabetic complications. Saffron as a natural source of antioxidants could play a role in alleviating diabetes insults. The aim of this study was to investigate effect of saffron hydroalcoholic extract on metabolic control in type 2 diabetes (T2D) mellitus. Materials and Methods: This randomized triple blind study was included 54 T2D patients which randomly received either saffron (Group 1) or placebo (Group 2) twice daily other than routine antidiabetic treatments for 8 weeks. Serum concentration of fasting blood sugar (FBS), 2-h plasma glucose, hemoglobin A1c (HbA1c), total cholesterol, triglyceride (TG), low-density lipoprotein, and high-density lipoprotein were measured as the markers of metabolic control. Anthropometric measures and blood pressure were also measured at the baseline, every 2 weeks during the intervention and the end of the study. Data analyzed using repeated measure analysis of variance test. Results: The baseline metabolic parameters were the same in two group (P > 0.01). FBS serum level significantly decreased within 8 weeks in the saffron group (128.84 +/- 31.86) as compared to the placebo (153.76 +/- 41.23), (P < 0.001). There was no statistical difference in other metabolic parameters such as serum lipids, blood pressure, and HbA1c (P > 0.01). Conclusion: Saffron hydroalcoholic extract may improve blood glucose control by reducing FBS in T2D patients. However, saffron extract has no significant effect on other aspects of diabetic control in diabetic patients. PMID- 29531569 TI - A comparison of pain control and complications using three different ways of anesthesia in patients undergoing transrectal ultrasound-guided prostate biopsy. AB - Background: We aim to compare the degree of pain control and complications in three types of anesthesia using periprostatic nerve block (PPNB) plus intrarectal local anesthesia (IRLA), low-dose spinal anesthesia, and intravenous (IV) sedation in patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy. Materials and Methods: In this clinical trial study, 106 patients were participated from December 2015 to December 2016 at Alzahra Hospital, Isfahan, Iran. Patients were randomly allocated into three groups to receive PPNB plus IRLA (n = 36), low-dose spinal anesthesia (n = 35) and IV sedation (n = 35) before TRUS-guided prostate biopsy. Pain scores were recorded using a 10 point visual analog scale right after the biopsy was done. Early and late complications were assessed using a questionnaire after the procedure and in follow-up of patients. Results: Overall, the pain score in the low-dose spinal anesthesia group was significantly lower than PPNB plus IRLA and IV sedation groups (P < 0.001). The differences in pain scores between PPNB plus IRLA group and IV sedation group were not significant (P = 0.30). Urinary retraction and fever were significantly more frequent in low-dose spinal anesthesia and IV sedation, retrospectively (P = 0.04, P = 0.03). No significant difference in late complications was found among the groups. Conclusion: This study demonstrates that low-dose spinal anesthesia is superior to PPNB plus IRLA and IV sedation in terms of pain controlling and was associated with higher tolerance of the examination and patient comfort. PMID- 29531570 TI - The effect of nitrous oxide in comparison to oxygen combined with fentanyl on the hospitalization time and pain reduction in renal colic patients at emergency department. AB - Background: Renal colic is a painful medical emergency, needs urgent intervention to reduce pain. Nonsteroidal anti-inflammatory drugs, opioids, and entonox are pain-relieving agents. This study was aimed to compare fentanyl + entonox (nitrous oxide + O2) versus fentanyl + oxygen. Materials and Methods: One hundred and twenty patients with acute renal colic presenting to the emergency department were enrolled. First, 50 MUg fentanyl was infused for all patients. Then, patients divided into two groups receiving masks of entonox and oxygen, respectively. Quantitative measurement of pain was performed by visual analog scale, before the intervention, after 3, 5, 10, and 30 min of that. If the pain was not relieved after 30 min, 50 MUg fentanyl was infused. If the pain was still continued, ketorolac and ketamine were used. Hospitalization duration and severity of pain at specified times were compared between patients in two groups. Results: The mean (standard deviation) time of hospitalization was 211 (59) and 236 (61) min in fentanyl + entonox and fentanyl + O2 groups, respectively (P = 0.024). The decrease in pain severity after 10 and 30 min in fentanyl + entonox group were significantly greater than fentanyl + O2 group (P = 0.002 and 0.001, respectively). Mean (standard error) of needed time for renal colic pain to get better was 11.27 (1.23) and 20.47 (1.71) min in fentanyl + entonox and fentanyl + O2 groups, respectively (P < 0.001). Proportion of patients relief from pain in fentanyl + entonox in the second, third, and fourth measurements were significantly more than fentanyl + O2 group (P = 0.036, P < 0.001, and P < 0.001, respectively). Conclusion: Entonox is more effective to decrease the duration of hospitalization and reduction of pain than O2 in renal colic patients. PMID- 29531571 TI - Classification of thyroid fine-needle aspiration cytology into Bethesda categories: An institutional experience and review of the literature. AB - Background: Fine-needle aspiration cytology (FNAC) of thyroid is the initial screening test for thyroid nodules. The Bethesda system classifies thyroid FNAC into six categories. Each category is linked to a malignancy risk and has a recommended clinical management. The aim of this study is to analyze the thyroid cytology smears by Bethesda system and to correlate the diagnosis of cytopathology with histopathology, whenever surgery was done. Materials and Methods: This study presents our experience with the Bethesda system in 681 thyroid FNAs from 632 patients in the period between January 2013 and December 2016. Results: Categories were as follows: 10.1% were Category I (nondiagnostic), 68.8% Category II (benign), 12.4% were Category III (atypia of undetermined significance), 2.9% were Category IV (suspicious for follicular neoplasm), 2.6% were Category V (suspicious for malignancy), and 4.1% were Category VI (malignant). Surgery was done on 126 nodules from 119 patients with an overall rate of malignancy of 27.8% (35/126 nodules). Conclusion: The Bethesda System for Reporting Thyroid Cytopathology proved to be an excellent reporting system. PMID- 29531572 TI - Cokeromyces recurvatus in a Papanicolaou test: An exceedingly rare finding that can be mistaken for Paracoccidioides brasiliensis. AB - Cokeromyces recurvatus is a zygomycetes yeast form that is very rarely detected in Papanicolaou (Pap) tests, in which it typically represents an innocuous colonizer. Its morphology closely resembles that of the better known Paracoccidioides brasiliensis, which can disseminate widely and cause clinically significant disease. We present a case of C. recurvatus detected in a cervical liquid-based preparation obtained from a 38-year old healthy woman. Careful cytomorphologic evaluation, in combination with culture and molecular techniques, was utilized to make a diagnosis and prevent the misdiagnosis of P. brasiliensis. PMID- 29531573 TI - Myoepithelioma of soft tissue and diagnostic pitfall in cytology. PMID- 29531574 TI - Fine-needle aspiration of bilateral small round blue cell tumors in neck in a 65 year-old man: Significance of a wider differential. PMID- 29531575 TI - Juxta-Vascular Pulmonary Nodule Segmentation in PET-CT Imaging Based on an LBF Active Contour Model with Information Entropy and Joint Vector. AB - The accurate segmentation of pulmonary nodules is an important preprocessing step in computer-aided diagnoses of lung cancers. However, the existing segmentation methods may cause the problem of edge leakage and cannot segment juxta-vascular pulmonary nodules accurately. To address this problem, a novel automatic segmentation method based on an LBF active contour model with information entropy and joint vector is proposed in this paper. Our method extracts the interest area of pulmonary nodules by a standard uptake value (SUV) in Positron Emission Tomography (PET) images, and automatic threshold iteration is used to construct an initial contour roughly. The SUV information entropy and the gray-value joint vector of Positron Emission Tomography-Computed Tomography (PET-CT) images are calculated to drive the evolution of contour curve. At the edge of pulmonary nodules, evolution will be stopped and accurate results of pulmonary nodule segmentation can be obtained. Experimental results show that our method can achieve 92.35% average dice similarity coefficient, 2.19 mm Hausdorff distance, and 3.33% false positive with the manual segmentation results. Compared with the existing methods, our proposed method that segments juxta-vascular pulmonary nodules in PET-CT images is more accurate and efficient. PMID- 29531576 TI - Quantitative Assessment of the Physiological Parameters Influencing QT Interval Response to Medication: Application of Computational Intelligence Tools. AB - Human heart electrophysiology is complex biological phenomenon, which is indirectly assessed by the measured ECG signal. ECG trace is further analyzed to derive interpretable surrogates including QT interval, QRS complex, PR interval, and T wave morphology. QT interval and its modification are the most commonly used surrogates of the drug triggered arrhythmia, but it is known that the QT interval itself is determined by other nondrug related parameters, physiological and pathological. In the current study, we used the computational intelligence algorithms to analyze correlations between various simulated physiological parameters and QT interval. Terfenadine given concomitantly with 8 enzymatic inhibitors was used as an example. The equation developed with the use of genetic programming technique leads to general reasoning about the changes in the prolonged QT. For small changes of the QT interval, the drug-related IKr and ICa currents inhibition potentials have major impact. The physiological parameters such as body surface area, potassium, sodium, and calcium ions concentrations are negligible. The influence of the physiological variables increases gradually with the more pronounced changes in QT. As the significant QT prolongation is associated with the drugs triggered arrhythmia risk, analysis of the role of physiological parameters influencing ECG seems to be advisable. PMID- 29531577 TI - Neural and Cognitive Factors Influencing the Emergence of Psychopathology: Insights From the Bucharest Early Intervention Project. AB - The adverse effects of institutionalized care and psychosocial deprivation have been documented for more than 100 years. Children who have been raised in institutions are at heightened risk of developing internalizing and externalizing disorders. Given the profound biological and psychological effects of institutional rearing, identifying neural and cognitive factors that influence the emergence of psychopathology in institutionalized children is of great interest. Using data from the Bucharest Early Intervention Project, a randomized control study on the effects of institutional care and a foster care intervention, this article examines two factors that appear to influence the emergence of psychopathology in children who have been institutionalized-neural indices of cognitive control and visual attention biases. PMID- 29531578 TI - Video capsule endoscopy in pediatric patients with Crohn's disease: a single center experience of 180 procedures. AB - Background: Video capsule endoscopy (VCE) is a noninvasive method enabling excellent visualization of the small bowel (SB) mucosa. The aim of this study was to examine the impact and safety of VCE performed in children and adolescents with suspected or established Crohn's disease (CD). Methods: A total of 180 VCE examinations in 169 consecutive patients conducted in 2003-14 in a single center were retrospectively analyzed. The median age was 13 years (range 3-17 years) and indications for VCE were suspected (125 cases, 69%) and established (55 cases, 31%) CD. VCE was performed with a PillCam SB (Given Imaging, Yokneam, Israel) VCE system with 8-12 h of registration without bowel preparation. Results: A total of 154 of 180 (86%) patients swallowed the capsule and 26 (14%) had the capsule endoscopically placed in the duodenum. Patency capsule examination was performed in 71 cases prior to VCE to exclude SB obstruction. VCE detected findings consistent with SB CD in 71 (40%) examinations and 17 (9%) procedures showed minor changes not diagnostic for CD. A total of 92 (51%) examinations displayed normal SB mucosa. The capsule did not reach the colon within the recording time in 30 (17%) procedures and were defined as incomplete examinations. A change in diagnosis or therapy was recommended in 56 (31%) patients based on VCE results. Capsule retention occurred in one patient. Conclusions: VCE is a safe method in children with suspected or established CD. VCE often leads to a definitive diagnosis and has a significant impact on the clinical management of pediatric patients with CD. PMID- 29531579 TI - Induction of Immune Responses by DNA Vaccines Formulated with Dendrimer and Poly (Methyl Methacrylate) (PMMA) Nano-Adjuvants in BALB/c Mice Infected with Leishmania major. AB - BACKGROUND: Leishmaniasis is a parasitic disease induced by a protozoan from the genus Leishmania. No effective vaccine has yet been developed against the disease. AIM: In this work, two nano-vaccines, TSA recombinant plasmid and dendrimer and poly (methyl methacrylate) (PMMA) nanoparticles (as adjuvants), were designed and tested for their immunogenicity in BALB/c mice. METHODS: After the plasmid construction and preparation of adjuvants, three intramuscular injections of the nano-vaccines (100 ug) and the recombinant TSA protein (20 ug) were subcutaneously performed. Eventually, the challenged animals were infected with the parasites (1*106 promastigotes). After the last injections of the nano vaccines, the responses of their antibody subclasses and cytokines were assessed via ELISA method before and after the challenge. RESULTS: This study revealed that the new nano-vaccines were strong and effective in inducing specific antibody and cellular responses and reducing the parasite burden in the spleen compared to the control groups of Leishmania major-infected BALB/c mice. CONCLUSION: Based on the results, we can suggest that the formulated vaccines are suitable candidates for further studies in the field of leishmaniasis control. PMID- 29531580 TI - Histopathological Pattern and Age Distribution, of Malignant Ovarian Tumor among Sudanese Ladies. AB - INTRODUCTION: Ovarian cancer is the cause of a high case-fatality ratio, and most of the cases are diagnosed in late stages. OBJECTIVES: To determine the histopathological types, age distribution, and ovarian tumour stages among diagnosed with ovarian cancer at Al - Amal Tower a multi-referral polyclinic of Radiology & Isotope Center Khartoum (RICK), Sudan. METHODS: All histopathology reports patients' case from January to June 2015 were reviewed. The cancers classified according to federation international of Obstetrics and Gynecology (FIGO). RESULTS: There were 127 cases of ovarian cancers. Surface epithelial cancers were the most common 77.7% (n = 98), followed by sex cord-stromal cancers 11.23% (n = 14), Germ cell tumor 1.6% (n = 2). Metastatic cancers were seen from colon and breast in 6.3% and 3.9 % of cases respectively. Few cases (14%) of ovarian cancers were reported before 40 years of age, after the age of 50 is a sharp increase in the incidence of a tumour. The mean age at presentation was 52.36 +/- 14.210 years, there is mean age of menarche 13.59 +/- 2.706 years. Very few patients used HRT (1.6%) or had been on ovulation induction treatment (8.7%). Most of patients 39 (30.7%) presented in stage IIIC, and stage 1V 32 (25.2%) indicating a poor prognosis. CONCLUSION: The incidence of different types of ovarian cancers in the present study is similar to worldwide incidence. The surface epithelial tumour is the commonest ovarian cancer, of which serous adenocarcinoma is the commonest and most of our patients present in late stages. PMID- 29531581 TI - Evaluation of Combined Use of Temocillin Disk and Mastdisks Inhibitor Combination Set Against Polymerase Chain Reaction for Detection of Carbapenem-Resistant Enterobacteriaceae. AB - AIM: To evaluate the diagnostic performance of MDI and temocillin disk (30 MUg) for detection of carbapenem-resistant Enterobacteriaceae in comparison to real time PCR. MATERIAL AND METHODS: Fifty specimens submitted to the Microbiology Laboratory of Ain Shams University Hospitals and showed resistance to carbapenem drugs through routine culture and susceptibility testing, were assessed by both temocillin disk (30 MUg) and MDI set to detect carbapenem-resistant Enterobacteriaceae. Results were compared to real-time PCR for detection of carbapenemase genes blaKPC, blaNDM, blaOXA-48-like, blaVIM, and blaIMP. RESULTS: Our work revealed that most of the CPE isolates were Klebsiella species (62%) followed by E. coli (24%), Serratia (10%) and Citrobacter (4%). Phenotypic detection of carbapenem-resistant classes revealed OXA - 48 in 96% of isolates, followed by MBLs (82%), and KPC (34%). All isolates were negative for AmpC. Detection of the genes by real-time PCR showed that the predominance was for the blaOXA-48 gene (96%) then blaVIM (94%) followed by blaNDM (54%), blaKPC (46%) and finally blaIMP (40%). Evaluation of the MDI set against PCR showed sensitivity (82.1%) and specificity (70%). The temocillin disk had 97.9% sensitivity and 50% specificity. The evaluation of Temocillin disk and MDI in combination for detection of carbapenem-resistant Enterobacteriaceae showed 99.7% sensitivity and 35% specificity. CONCLUSION: Adding Temocillin disk to Mastdisks ID inhibitor combination set provides a simple, easy, rapid and highly sensitive test that can be used for screening and classification of carbapenem-resistant Enterobacteriaceae. However, it still needs confirmation by molecular techniques. PMID- 29531582 TI - Value of SSTR2A and Claudin - 1 in Differentiating Meningioma from Schwannoma and Hemangiopericytoma. AB - BACKGROUND: The distinction between meningioma, schwannoma and solitary fibrous tumour/ hemangiopericytoma can be challenging in some cases. This study evaluates the expression of Somatostatin receptor 2A (SSTR2A) and Claudin-1 in these different tumours. MATERIAL AND METHODS: Thirty-five cases of meningioma, 10 cases of intracranial schwannoma and 10 cases of hemangiopericytoma were assessed. The immunohistochemical expression of SSTR2A and Claudin-1 was evaluated and scored according to the percentage of immunostained tumour cells (0: 1+, 2+ and 3). The intensity of staining was classified as weak, moderate and strong. RESULTS: Positivity for SSTR2A and Claudin-1 was encountered in 89% and 49% of meningiomas respectively. None of the schwannomas or hemangiopericytomas was positive for any of both markers. All grade I and II meningiomas were positive for SSTR2A, and only 20% of grade III showed positive staining (p < 0.05). Claudin-1 positivity was detected in 50%, 43% and 60% of grade I, II and III meningioma respectively, with significantly higher intensity in grade III (p < 0.05). CONCLUSION: SSTR2A is highly sensitive and specific for meningioma. Claudin-1 is highly specific for meningioma, with low sensitivity. The adjunctive use of both markers can be very helpful in the diagnosis of meningioma and its distinction from schwannoma and hemangiopericytoma. PMID- 29531584 TI - Ki-67 Expression as a Predictive Factor of Muscle Invasion in Bladder Cancer. AB - BACKGROUND: Bladder cancer is the 9th most frequent cancer worldwide. Ki-67 is immunohistochemistry marker that is predictive of cancer cell proliferation. The expression of Ki-67 is associated with poor prognosis in several types of malignancy, yet the value of Ki-67 as the prognostic factor in bladder cancer remains controversial. AIM: This study is aimed to investigate the association between Ki-67 expression with muscle-invasive bladder cancer (MIBC) and non muscle invasive bladder cancer (NMIBC). METHODS: This was a case-control study with a retrospective design. The study was conducted at the Department of Pathology, University of Sumatera Utara, Indonesia. Samples were paraffin blocks from patients diagnosed with bladder cancer and agreed to be put in the study. The samples were stained with Immunohistochemistry Staining (IHC), and then we quantitatively counted the number of the Ki-67 stained nucleus on a microscope. RESULTS: A total of 54 samples were obtained in this study. Samples consisted of 27 samples with NMIBC and 27 samples with MIBC. The cut-off point was 20%, we found 17 patients with MIBC and 14 patients with NMIBC presented with biomarker > 20%. Biomarker <= 20% was found in 10 patients with MIBC and 13 patients with NMIBC. On statistical analysis with Chi-Square test, no significant association found (p = 0.583) between KI-67 and muscle - invasiveness with OR of 1.579, 95% CI (0.533-4.678). CONCLUSION: There is no association between expression of Ki-67 and muscle invasiveness in bladder cancer. PMID- 29531583 TI - Preclinical Assessment of the Proliferation Capacity of Gingival and Periodontal Ligament Stem Cells from Diabetic Patients. AB - BACKGROUND: Stem cells have recently received great interest as potential therapeutics alternative for a variety of diseases. The oral and maxillofacial region, in particular, encompasses a variety of distinctive mesenchymal (MSC) populations and is characterized by a potent multilineage differentiation capacity. AIM: In this report, we aimed to investigate the effect of diabetes on the proliferation potential of stem cells isolated from controlled diabetic patients (type 2) and healthy individuals. SUBJECTS & METHODS: The proliferation rate of gingival and periodontal derived stem cells isolated from diabetic & healthy individuals were compared using MTT Assay. Expression levels of Survivin in isolated stem cells from all groups were measured by qRt - PCR. RESULTS: There was a significantly positive correlation between proliferation rate and expression of Survivin in all groups which sheds light on the importance of Survivin as a reliable indicator of proliferation. The expression of Survivin further confirmed the proliferation results from MTT Assay where the expression of stem cells from non - diabetic individuals was higher than diabetic patients. CONCLUSION: Taking together all the results, it could be concluded that PDLSC and GSC are promising candidates for autologous regenerative therapy due to their ease of accessibility in addition to their high proliferative rates. PMID- 29531585 TI - Prognostic Significance of Vascular Endothelial Growth Factor (VEGF) and Her-2 Protein in the Genesis of Cervical Carcinoma. AB - BACKGROUND: Angiogenesis plays a pivotal role in the progression of tumours through the formation of new blood vessels. Vascular endothelial growth factor (VEGF) is a chief factor responsible for inducing and regulating angiogenesis. Additionally, the human epidermal growth factor receptor family of receptors also plays an important role in the pathogenesis of tumours. AIM: This study aimed to examine the association between VEGF and Her-2 protein expression and its correlation with clinic-pathological characteristics; in particular, prognosis. METHODS: A total of 65 cases of cervical carcinoma and 10 samples of inflammatory lesions were evaluated for VEGF and Her-2 protein expression. RESULTS: Expression of VEGF and Her-2 was detected in 63.07% and 43.07% in cervical carcinoma cases respectively whereas control cases did not show any expression. The difference in the expression pattern of both markers comparing cancer and control cases was statistically significant (p < 0.05). However, no significant difference in the expression pattern of VEGF protein was observed among the different grades and stages of tumours (p > 0.05). Comparing different grades of a tumour, expression of Her-2 was detected in 31.8% of well-differentiated tumours, 36.0 % in moderately differentiated tumours and 66.66 % in poorly differentiated cancers. The expression of Her-2 was increased in high-grade tumours, and the difference of expression level between tumour grades was statistically significant (p < 0.05). The expression level of Her-2 protein was not correlated with the stage of a tumour (p > 0.05). CONCLUSION: The present study supports earlier findings that over-expression / up-regulation of VEGF and Her - 2 is linked with poor prognosis and may play a vital role in the development and progression of cervical cancer. PMID- 29531586 TI - Effect of a Histone Deacetylases Inhibitor of IL-18 and TNF-Alpha Secretion in Vitro. AB - BACKGROUND: Interleukin-18 (IL-18) and Tumor Necrosis Factor-alpha (TNF-alpha) are proinflammatory cytokines that increased the development of Th1 immune response, but have a different type of regulation of the gene expression. Whereas TNF-alpha has an inducible expression, IL-18 is translated as an inactive protein and required proteolytic cleavage by Casp-1 in inflammasome complexes. AIM: To investigate the effect of the histone deacetylases inhibitor Suberoylanilide Hydroxamic Acid (SAHA) on the gene expression and secretion of both cytokines, IL 18 and TNF-alpha, according to their contribution to the cancer development and anticancer immunity. METHODS: Isolated peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. Cytokine production was assessed by ELISA at 6 and 24h. RESULTS: IL-18 and TNF-alpha secretion was significantly increased at 6h and 24h in response to stimulation. TNF-alpha production from stimulated PBMC was downregulated by SAHA at 6 and 24h. Treatment with SAHA does not inhibit the secretion of IL-18 significantly either at 6 or 24h of stimulation. CONCLUSION: The inhibition of histone deacetylases by SAHA does not influence the inflammasome-dependent production of immunologically active IL-18. In contrast, the production of proinflammatory TNF-alpha in cultures was mediated by the activity of HDAC class I and class II enzymes. PMID- 29531587 TI - Association Study of the ATP - Binding Cassette Transporter A1 (ABCA1) Rs2230806 Genetic Variation with Lipid Profile and Coronary Artery Disease Risk in an Iranian Population. AB - BACKGROUND: ATP - binding cassette transporter A1 (ABCA1) plays essential roles in the biogenesis of high -density lipoprotein - cholesterol. Variations in the ABCA1 gene may influence the risk of coronary artery disease (CAD). AIM: Present study aimed to investigate the association of rs2230806 (R219K) polymorphism of ABCA1 gene with the development and severity of CAD in an Iranian population. MATERIALS AND METHODS: Our study population consisted of 100 patients with angiographically confirmed CAD and 100 controls. The genotyping of R219K mutation of ABCA1 gene was determined by PCR - RFLP method. Lipid profile was determined using routine colourimetric assays. Statistical analysis was done by SPSS - 16. RESULTS: The genotypic (P = 0.024) and allelic (P = 0.001) distribution of the ABCA1 R219K polymorphism were significantly different between the two groups. In a univariate analysis (with genotype RR as the reference), the RK genotype (OR = 0.46, 95%CI = 0.25-0.86, P = 0.020) and KK genotype (OR = 0.27, 95%CI = 0.11 - 0.66, P = 0.005) was significantly associated with a decreased risk of CAD. A multiple logistic regression analysis revealed that smoking (0.008), diabetes (P = 0.023), triglyceride (P = 0.001), HDL - cholesterol (P = 0.002) and ABCA1 KK genotype (P = 0.009) were significantly and independently associated with the risk of CAD. The association between different genotypes of R219K polymorphism with lipid profile was not significant in both groups (P > 0.05). The R219K polymorphism was significantly associated with severity of CAD (P < 0.05). CONCLUSION: The carriage of K allele of ABCA1 R219K polymorphism has a protective effect on CAD risk and correlates with a decreased severity of CAD. This protective effect seems to be mediated independently of plasma lipid levels. PMID- 29531588 TI - Polymerase Chain Reaction-Restriction Fragment Length Polymorphism as a Confirmatory Test for Onychomycosis. AB - BACKGROUND: Onychomycosis is a fungal infection of one or more units of the nail caused by dermatophytes, or mould and nondermatophytes yeast. Investigations are needed to establish the diagnosis of onychomycosis before starting treatment. Several investigations methods for diagnosing onychomycosis are microscopic examination with 20% KOH, fungal culture, histopathology examination with PAS staining (Periodic acid Schiff) and PCR (Polymerase Chain Reaction). Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) is a method after PCR amplification allowing more specific results. AIM: To determine the diagnostic value of PCR - RFLP in the diagnosis of onychomycosis using fungal culture as the gold standard and to find out the majority fungal species that cause onychomycosis. METHODS: This study is a diagnostic test for the diagnosis of onychomycosis by using culture as the gold standard. SUBJECTS: Thirty - five patients suspected of having onychomycosis from history and dermatological examination. RESULTS: PCR - RFLP in the diagnosis of onychomycosis has a sensitivity of 85.71%, specificity of 28.57%, positive predictive value (PPV) of 82.76% and negative predictive value (NPV) of 33.33%. The positive and negative likelihood ratios are 1.20 and 0.5 with an accuracy of 74.29%. CONCLUSIONS: PCR - RFLP may be considered for a faster and more accurate alternative examination in the diagnosis of onychomycosis. PMID- 29531589 TI - Total Antioxidant Capacity, Haematological and Coagulation Parameters after Orthodox Christian Fast. AB - BACKGROUND: Orthodox Christian believers fast abstaining from meat, eggs, dairy products or even fish and oil in certain days of the fasting period, three times a year. AIM: The present study aimed to investigate the impact of a 48-day fast before Easter in blood count parameters, coagulation and antioxidant status. MATERIAL AND METHODS: A total of 35 healthy volunteers, 19-66 years old, were included in the study. White blood cells (WBC), lymphocytes (Lymph), granulocytes (Gran), haemoglobin (Hb), hematocrit (Ht), red blood cells (RBC), mean erythrocyte volume (MCV), platelets (Plt), were measured. Blood coagulation parameters, such as PT, aPTT, fibrinogen concentration, factor VII activity were also determined, and INR (PTsample/PTcontrol) and aPTT ratio (aPTTsample/aPTTcontrol) were calculated. Total antioxidant capacity (TAC) was assayed. RESULTS: Levels of all parameters remained within normal. By the end of the fasting period, lymphocytes and TAC levels were significantly increased (p = 0.011), whereas all the other parameters, except fibrinogen, were significantly decreased. CONCLUSION: Orthodox Christian fast impairs all haematological and coagulation parameters and seems to be beneficial in the body antioxidant protection. PMID- 29531590 TI - Increasing Atherosclerosis in Streptozotocin-Induced Diabetes into Four Groups of Mice. AB - AIM: To study the protective effect of medicines on the formation of atherosclerosis in mice, it is needed to conduct the study in mice which is not genetically diabetic mice induced by streptozotocin (STZ) to produce hyperglycemia and atherosclerosis, compared with mice treated by yolk or its combination. MATERIAL AND METHODS: Fifty-six mice, Double Deutch Webster strain, male, receive 10 weeks, 20 - 30 gr bodyweight were divided into 4 groups (n = 14) i.e. control (do not received any agents), STZ (45 mg/kg/BW was injected intraperitoneally for 5 days), yolk (0.2 cc orally daily for 6 weeks), and combination of STZ and yolk (. STZ: 45 mg/kg/BW intraperitoneally add 0.2 cc yolk orally). All animals were executed in the 42nd day. Then, the aorta of the mice's heart tissue was histopathology examined. Blood glucose and cholesterol levels were determined every week. RESULTS: Hyperglycemia occurred in mice induced by STZ injection with the highest BGL (521.8 +/- 48.2 mg/dl; 188.4%) in the 4th-week observation; after that BGL decrease. We found that, except the control, all treatment groups with STZ, egg yolk, and combination underwent atherosclerosis. CONCLUSION: The present study was able to demonstrate the occurrence of atherosclerosis in mice treated by STZ accompanied with increasing blood glucose and cholesterol level. PMID- 29531591 TI - Mean Blood Pressure Difference among Adolescents Based on Dyssomnia Types. AB - BACKGROUND: Dyssomnia is the most frequent sleep disturbance and associated with increased blood pressure. There has been no study determining the difference in mean blood pressure based on dyssomnia types among adolescents. OBJECTIVE: To determine the difference in mean blood pressure among adolescents based on dyssomnia types. METHODS: Cross-sectional study was conducted in SMP Negeri 1 Muara Batang Gadis in April 2016. Samples were students having sleep disturbance based on Sleep Disturbance Scale for Children (SDSC) questionnaire. Stature and blood pressure data were collected along with demographic data and sleep disorder questionnaire. Analyses were done with Kruskal-Wallis test and logistic regression. P - value < 0.05 was considered significant. RESULTS: Seventy-six samples were obtained with mean age 13.9 (SD 1.14) years - old. Dyssomnia proportion and hypertension were 72/76 and 20/76 respectively. Mean systolic (SBP) and diastolic blood pressure (DBP) was 111.1 (SD 16.46) mmHg and 70.3 (SD 11.98) mmHg respectively. Mean SDSC score was 49.7 (SD 8.96), and the most frequent dyssomnia type was disorders of initiating and maintaining sleep. Age and sex were not the risk factors of hypertension in dyssomnia. There was a significant difference in mean SBP (P = 0.006) and DBP (P = 0.022) based on dyssomnia types. Combination dyssomnia type had the highest mean blood pressure among dyssomnia types. CONCLUSION: There is a significant difference in mean blood pressure among adolescents based on dyssomnia types. PMID- 29531592 TI - Electrocardiographic Parameters as Predictors of Response to Cardiac Resynchronization Therapy. AB - INTRODUCTION: Although strict selection criteria are used to select patients for cardiac resynchronisation therapy, up to 30% of patients do not have a positive clinical response. PATIENTS: A total of 102 consecutive patients who had biventricular pacemaker/defibrillator (CRT-P or CRT-D) implanted were enrolled in this prospective observational study. RESULTS: During the average follow-up period of 24.3 months 5 patients died and 17 (16.7%) patients were hospitalised with the symptoms of heart failure; 75 (73.5%) patients were responders based on the previously defined criteria. Responders in the group of LBBB patients kept the significant difference in a computed variable (S1 + R6) - (S6 + R1) and R6/S6 ratio. Responders in non-LBBB patients kept the significant difference only in the height of R waves in V6. The R6/S6 ratio tended to be higher, but it did not reach a statistical significance. CONCLUSION: None of the tested ECG parameters stands out as an independent predictor of response to cardiac resynchronisation therapy, but some of them were different in responder-compared to the non responder group. The amplitude of R wave in V6, higher R/S ratio in V6 and higher computed variable (S1 + R6) - (S6 + R1) may predict the likelihood of response to CRT therapy in both LBBB-patients and non-LBBB patients. PMID- 29531593 TI - CD33+ HLA-DR- Myeloid-Derived Suppressor Cells Are Increased in Frequency in the Peripheral Blood of Type1 Diabetes Patients with Predominance of CD14+ Subset. AB - INTRODUCTION: Type 1 Diabetes Mellitus (T1D) is an autoimmune disease that results from the destruction of insulin-producing beta cells of the pancreas by autoreactive T cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that can potently suppress T cell responses. AIM: To detect the presence of MDSCs in T1D and compare their percentage in T1D versus healthy individuals. METHOD: Thirty T1D patients were included in the study. Diabetic patients with nephropathy (n = 18) and diabetic patients without nephropathy (n = 12). A control group of healthy individuals (n = 30) were also included. CD33+ and HLA-DR- markers were used to identify MDSCs by flow cytometry. CD14 positive and negative MDSCs subsets were also identified. RESULTS: MDSCs was significantly increased in T1D than the control group and diabetic patient with nephropathy compared to diabetic patients without nephropathy. M-MDSCs (CD14+ CD33+ HLA-DR-) were the most abundant MDSCs subpopulation in all groups, however their percentage decrease in T1D than the control group. CONCLUSION: MDSCs are increased in the peripheral blood of T1D with a predominance of the CD14+ MDSCs subset. Future studies are needed to test the immune suppression function of MDSCs in T1D. PMID- 29531594 TI - Immunological Evaluation in Patients with Familial Mediterranean fever. AB - OBJECTIVE: This study aimed to investigate T & B lymphocyte subsets and Natural Killer (NK) cells patterns in children with FMF versus normal control subjects, to estimate the immunoglobulins IgG, IgM, and IgA levels, and to scrutinize the possible use of Neutrophil / Lymphocyte ratio (NLR) as a marker for subclinical inflammation in FMF patients. PATIENTS AND METHODS: A group of 42 patients with FMF attending the Genetics Clinic at National Research Centre were included in this study. They were 13 males and 19 females; their age ranged from 2 to 17 years old. Normal healthy subjects within the same age and sex range were included as a control group. Complete blood picture was done for all cases, and neutrophil/ lymphocyte ratio was calculated. Flow cytometer analysis was done for CD3, CD4, CD8, CD19 and CD16 using monoclonal antibodies. Immunoglobulins IgG, IgA and IgM were estimated in serum using nephelometry. RESULTS: Positive consanguinity was present in 20 patients (47.6%). Abdominal pain was the most common manifestation followed by fever, arthritis, and red rash. CD3, CD4 and CD8 were statistically increased in patients group as compared to normal control group, while CD16 was statistically decreased. CONCLUSION: The study suggests that quantitative measurement of CD expressions of CD3, CD4 and CD8 as well as NLR might be used as valuable markers for subclinical inflammation in FMF. PMID- 29531595 TI - Utility of Tissue Inhibitor Metalloproteinase-1 and Osteopontin as Prospective Biomarkers of Early Cardiovascular Complications in Type 2 Diabetes. AB - AIM: This work investigated associations between tissue inhibitor metalloproteinase-1 and diabetic cardiovascular diseases in type 2 diabetic patients; also it investigated the role of osteopontin in the diagnosis of type 2 cardiovascular diabetes complications. SUBJECTS AND METHODS: These were examined on eighty subjects, divided into three groups as follows: twenty volunteer healthy control subjects, thirty type 2 diabetes mellitus (DM) patients, and thirty cardiovascular, diabetic patients. Full clinical measurements were carried out, and the expression level of tissue inhibitor metalloproteinase-1 in blood samples was analysed by real-time PCR, using gene-specific primer pairs. Also osteopontin concentrations had been measured by the enzyme-linked immunosorbent assay. Data were tested statistically by parametric tests. RESULTS: The concentrations of osteopontin and the expression levels of tissue inhibitor metalloproteinase-1 were significantly increased in diabetic and cardiovascular diabetic groups compared to control group also they were significantly increased in the cardiovascular diabetic group compared to the diabetic group. CONCLUSION: Tissue inhibitor metalloproteinase-1 and osteopontin concentrations were significantly increased in diabetic patients with cardiovascular complications than other groups. PMID- 29531596 TI - Dynamic MRI Evaluation of the Gastric Fundus and Splenic Circulation to Assess the Gastric Breves Dissection during Laparoscopic Nissen Fundoplication. AB - AIM: We aimed to evaluate the possible effects of dissecting gastric breves (GB) during the Laparoscopic Nissen Fundoplication (LNF) on the gastric fundus and splenic circulation using dynamic Magnetic Resonance Imaging (MRI). METHODS: In total 14 patients with gastroesophageal reflux disease (GERD) that was diagnosed with esophagogastroduodenoscopy and 24 - hour PH monitorization and undergoing LNF surgery were included. All patients underwent LNF surgery between October 2006 and March 2010. All patients were evaluated regarding gastric fundus and splenic circulation one week before and 15 days after the surgery with dynamic MRI. Alteration of the signal intensity before and after surgery was used to assess gastric fundus and splenic circulation. RESULTS: We detected a significant decrease in DeMeester score before and after surgery (p < 0.001). There were no statistical differences between preoperative and postoperative dynamic MRI measurements of the spleen, anterior wall measurements, posterior wall measurements in different MRI phases (Bonferroni corrected p < 0.01). Postoperative measurements of anterior and posterior gastric wall measurements were comparable (Bonferroni corrected p < 0.0033). CONCLUSIONS: We did not detect any significant differences in the abovementioned tissues regarding perfusion. PMID- 29531597 TI - Comparative Clinical Efficacy between Electrodesiccation with Curettage and Application of 80% Phenol Solution in Treatment of Common Warts. AB - BACKGROUND: Common warts are skin diseases caused by human papillomavirus. Several treatment modalities available for common warts, two of them are electrodesiccation with curettage and application of 80% phenol solution. AIM: This study aims to compare clinical efficacy between these two modalities. MATERIAL AND METHODS: Open clinical trial was conducted at Dr Pirngadi General Hospital Medan and H. Adam Malik General Hospital Medan from February to June 2013 on 17 patients with multiple common warts. Both treatments began and applied simultaneously on the same day on each patient. RESULTS: Cure rate was higher in electrodesiccation with curettage (76.5%, 100%) compared to the application of 80% phenol solution (11.8%, 64.7%) on three weeks and six weeks of follow up. Statistical analysis showed a significant difference of common warts cure rate between electrodesiccation with curettage and application of 80% phenol solution after three weeks (p < 0.001) and six weeks (p = 0.018) of treatment. CONCLUSION: As a conclusion, electrodesiccation with curettage has higher cure rate than the application of 80% phenol solution on the treatment of common warts. Further study is needed to find out the best concentration and time interval for application of phenol solution to improve its clinical efficacy as an alternative treatment of choice for common warts. PMID- 29531598 TI - The Kapandji Technique of Closed Reduction Using Sommer - Pins in the Treatment of Completely Dislocated Fractures of the Distal Radius in Children. AB - BACKGROUND: The fractures of the distal radius are one of the most frequent cases in the pediatric population. The primary way of treating these fractures is conservative, with manual reduction and cast immobilisation. In patients where reduction and retention of the fracture cannot be achieved, a surgical approach is the treatment of choice. AIM: To evaluate the benefits of using the minimally invasive surgical treatment of closed reduction using Sommer - pins in the treatment of the fractures of the distal radius in the pediatric population with the method of the Kapandji technique. MATERIAL AND METHODS: In this study, we used cases treated from 2012 to 2017, of 48 completely dislocated fractures of the distal radius in patients ages 6 -14 yrs., where the use of non-surgical treatment proved ineffective. In the surgical treatment, we used one or two Sommer - pins to achieve a correct reduction and fixation. RESULTS: The post-op immobilisation lasted 4 - 7 weeks with an underarm cast. The patients were closely followed in the period of 6 months following the intervention. The anatomic reduction was easily achieved with this type of technique in every case. In the post-op period, there was no significant loss of reduction and another surgical procedure was not needed in any of the cases. CONCLUSION: With the use of the closed reduction Kapandji technique, an easy and good anatomical reduction is achieved with good post-op results in the treatment of completely dislocated fractures in the distal radius in children. PMID- 29531599 TI - Prevalence of Coxitis and its Correlation with Inflammatory Activity in Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterised by intra-articular and extra-articular manifestations but very rarely with coxitis. AIM: This study aimed to investigate the prevalence of coxitis, clinical changes, and its correlation with the parameters of inflammatory activity. METHODS: A cohort of 951 patients diagnosed with ACR/EULAR (American College of Rheumatology/European League against Rheumatism) 2010 criteria was enrolled in this prospective, observational and analytic research study. The CBC (Complete Blood Count), ESR (Erythrocyte sedimentation rate), CRP(C - reactive protein), Anti CCP (Antibodies to cyclic citrullinated peptides), X-ray examination of palms and pelvis, and the activity of the disease as measured by DAS - 28 (28 - joint disease activity score) were carried out in all subjects. Independent samples t-test was used to compare the group's characteristics, whereas Pearson correlation test was used to analyse the correlation between study variables. RESULTS: Of the total number of the subjects, 730 (76.8 %) were females, whereas 221 (23.2%) were males. The average age was 51.3, y/o while the most of them were between 40 - 49 y/o (32.6%). The prevalence of coxitis was 14.2%, mostly found in males (19.46%). The echosonografic prevalence of changes was 21.45%, while the radiological changes were 16.3%; in both cases, the changes were more expressed in males. The analysis showed that inflammatory parameters were significantly higher in patients with coxitis. CONCLUSION: Coxitis has high economic cost because it ends up with a mandatory need for a total hip joint prosthesis. Thus the results of this study can serve to plan and initiate early preventive measures. PMID- 29531600 TI - Prevalence of Depression Symptoms in Diabetes Mellitus. AB - BACKGROUND: Diabetes mellitus (DM) is one of the most prevalent diseases all over the world. Prevalence of DM in Turkey is 13.7%. Depression is another condition which has a high prevalence. All over the world, an estimated 300 million people of all ages suffer from depression. The relevance between depression and DM is a well - known condition. AIM: We aimed in this study to find out the prevalence of depression symptoms for DM in an attempt to better manage the disease. METHODS: We preferred the Beck Depression Index (BDI) to evaluate the depression symptoms. RESULTS: The number of patients introduced the study were 171 (101 (59.1%) female). As a results of BDI 67 (39.2%) patients evaluated as normal [29 (28.7%) female], 54 (31.6%) had poor symptoms [35 (34.7%) female], 46 (26.9%) had moderate symptoms [34 (33.7%) female] and lastly only 4(2.3%) had strong symptoms 3 (3.0%) female]. So 50 (29.2%) of patients had median plus strong symptoms. There were statistically significant association between HbA1c stages and depression (P = 0.018). CONCLUSION: Being a patient with DM is a strong indicator that the patient may have a depressive disorder. So the physician who takes care patients with DM should be alert about depression, and the simplest way to accomplish is BDI. PMID- 29531601 TI - Dynapenia and Sarcopenia as a Risk Factor for Disability in a Falls and Fractures Clinic in Older Persons. AB - BACKGROUND: The role of sarcopenia and dynapenia in disability in older persons from falls and bone health clinics remain unknown. AIM: This study aims to compare the association of sarcopenia and dynapenia with physical and instrumental disability in a population of older persons attending a falls and fractures clinic. METHODS: This is a cross-sectional study in Manizales, Andes Mountains, Colombia. A cohort of 534 subjects (mean age = 74, 75% female) Sarcopenia was measured according to the European Working Group on Sarcopenia in Older People (EWGSOP) including an index of skeletal mass, muscle strength, and gait speed. Dynapenia was defined as a handgrip force <= 30 kg for men and <= 20 kg for women. RESULTS: Dynapenia and sarcopenia were present in 84.6% and 71.2% respectively. Both were more prevalent in older subjects and women than men. While sarcopenia was associated with body mass index and hypertension, dynapenia was associated with hypothyroidism and visual impairment. After controlling for all covariates, sarcopenia was associated with low IADL and mobility disability. CONCLUSIONS: Sarcopenia was associated with mobility, ADL and IADL disability. Dynapenia was not associated with disability in this high - risk population. Systematic assessment of sarcopenia should be implemented in falls and fractures clinics to identify sarcopenia and develop interventions to prevent functional decline among elderly individuals. PMID- 29531602 TI - Survey about the Extubation Practice among Anaesthesiologists in Kosovo. AB - BACKGROUND: Tracheal extubations may be performed before or after awakening from anaesthesia. The advantage of extubation during anaesthesia may avoid all the unpleasant effects of fully awake extubation such as severe hypertension and tachycardia, malignant dysrhythmias, myocardial ischemia laryngospasm, and cough induced high intraocular and intracranial pressure. AIM: To show the current practice of performing extubations in Kosovo, as well as the advantage and disadvantage in performing this procedure in an awake patient or inpatient in light anaesthesia. MATERIAL: This study is conducted at the Regional Hospitals and the University Clinical Center of Kosovo during the year 2015. A questionnaire is given to the anesthesiologists to collect information about the techniques used for extubation, timing and management of extubation. RESULTS: Based on this survey results that 86% of an anesthesiologist (71) extubate the patients when they are completely awake, while 14% of them (12) prefer to extubate the patients under light anaesthesia. From all anesthesiologists involved in this study, forty of them reported problems during extubation. Complications were related to airway, and they are treated by oxygenation and jaw support, but in rare cases, reintubation were performed. CONCLUSION: Complications during extubation remain important risk factor while extubation during light anaesthesia can minimise some of them. PMID- 29531603 TI - Evaluation of Fast Glycaemia in Hypertonic Population that Suffer from Diabetes: The Importance of Self-Monitoring of Glycemic Level and the Effects of Interactions, with the Aim of Reducing the Levels of Fast Glycaemia in These Patients. AB - AIM: Identification of glycemic level tendency rates in a hypertonic population that suffers from diabetes mellitus in Health Centre Nr. 1, Tirana, evaluation of self-monitoring and the effects of interactions, with the aim of reducing the levels of fast glycaemia in these patients. MATERIAL AND METHODS: In the study participated 810 patients of Health Centre Nr 1 in Tirana that suffer from hypertension and diabetes mellitus type 1 and 2. The study was conducted through 10 months' period. The patients that owned glucometer passed through the process of calibration of the devices, the others that had no glucometer had been given one. All the patients had been instructed how to use the device properly. Informative and educative materials regarding hypertension and diabetes were given to them. A standardised table was used to collect all the data. Changes in therapy were done regarding the glycemic levels. RESULTS: The most of the patient shown an important improvement in glycemic rates during ten months of study. From 810 patients, 617 of them shown an improvement of the glycemic level data (median = 24 mg/dl; IQR: 14 - 50 mg/dl), and the other 193 patients have shown no improvement (n = 11) or aggravation (n = 182). The data showed that the patients that had no improvement during the study have diabetes type one (40%), they that have shown improvement has diabetes type 2 (33%) The difference between 2 those groups were insignificant (p = 0.075). The data of glycemic levels shown a significant decreased of 19% of basal glycemic levels (128 +/- 31 vs. 158 +/- 55 mg/dl: p < 0.05) at the end of the study, and decreased of glycemic levels was visible especially after the first month of the study, in both groups male and females. CONCLUSION: A total of 205 therapy changes like adding a new or two drugs or an increase of doses of the drugs, are done in some 181 patients that have diabetes, with a frequency of 1.1 changes in therapy per patient. PMID- 29531604 TI - Classification of Radiological Changes in Burst Fractures. AB - AIM: Burst fractures can occur with different radiological images after high energy. We aimed to simplify radiological staging of burst fractures. METHODS: Eighty patients whom exposed spinal trauma and had burst fracture were evaluated concerning age, sex, fracture segment, neurological deficit, secondary organ injury and radiological changes that occurred. RESULTS: We performed a new classification in burst fractures at radiological images. CONCLUSIONS: According to this classification system, secondary organ injury and neurological deficit can be an indicator of energy exposure. If energy is high, the clinical status will be worse. Thus, we can get an idea about the likelihood of neurological deficit and secondary organ injuries. This classification has simplified the radiological staging of burst fractures and is a classification that gives a very accurate idea about the neurological condition. PMID- 29531605 TI - Palatal Melanoma: "The Silent Killer". AB - Primary melanoma of the oral cavity is extremely uncommon tumour consisting approximately 0.2 - 8.0% of all melanoma cases and 0.5% of all oral malignancies. It has an aggressive behaviour and poor prognosis, with 5 - year - survival rate between 5 - 20%. The initial symptoms are often unnoticed, which lead to late diagnosis and worsening of the prognosis. Because of its infrequent occurrence, there is no well - defined classification and therapeutic protocol, in contrast to melanomas of another side. Early diagnosis and treatment are essentially linked to survival rate. We present a case of palatal melanoma in a 76 - year - old female patient, as we want to emphasise the importance of the early detection and accurate diagnosis of melanoma of oral cavity, to its influence of the therapeutic outcome. PMID- 29531606 TI - One Step Melanoma Surgery for Patient with Thick Primary Melanomas: "To Break the Rules, You Must First Master Them!" AB - BACKGROUND: We present to the attention of the medical, dermatological and oncosurgical community data that serves to indicate the indispensability of optimisation of the algorithm and recommendations for diagnosis and surgical treatment of cutaneous melanoma. These recommendations could be referred to different subgroups of patients in different clinical stages as well as to patients with different initial characterisation (histological morphology) of the primary tumours. One step surgery is not a myth, even more, it could prove to be one of the best solutions for some patient collectives with advanced stages of melanoma. CASE REPORT: We present a case of a 74 - year old patient with a congenital medium sized melanocytic nevus, located directly above the lateral part of the elbow joint. In one month and a half, an achromatic nodular formation evolves with a diameter of 2.7 x 2.3 cm, prominent over the skin level, painful by palpation and spontaneously bleeding. By the anamnestic, clinical and dermoscopic findings the patient was diagnosed with nodular melanoma associated with a congenital medium sized melanocytic nevus. A primary excision with a field of safety 0.5 cm in all directions was performed. After confirmation of the primary diagnosis (tumour thickness 8 mm with no ultrasonographic detection of enlarged lymph nodes), seven days later are - excision was performed with an additional field of surgical safety of 1.5 cm in all directions. CONCLUSIONS: In this case remains unclear the following question: For what reason a preoperative high - frequent ultrasonography (HFUS) is not recommended to be used as it will allow only one surgical excision with the elimination of a tumour with a safety field of 2cm in all directions? The enigma about the obstacles preventing such a rational optimisation of the current diagnostic and therapeutic algorithm in patients with melanomas remains unresolved. One step surgery for cutaneous melanoma is widely used in many countries although it continues to be considered as a matter of dispute for some experts. Once again, by a clinical case and the following analysis, we would like to focus the attention of the dermatosurgical community on this crucial and highly significant problem. Innovations are very often resulting from the simplicity of logic, which unfortunately is not always accepted appropriately. PMID- 29531607 TI - Successful Craniotomy for Advanced Basal Cell Carcinomas with Cranial Bone Invasion and Dura Mater Infiltration - Unique Presentation in a Bulgarian Patient. AB - BACKGROUND: Basal cell carcinomas (BCC) located in the sun-exposed regions are a serious therapeutic challenge. Therefore early diagnosis and adequate therapy should be of a high priority for every dermatologic surgeon. CASE PRESENTATION: We are presenting a patient with multiple BCCs, located on the area of the scalp, who had been treated several years ago with electrocautery and curettage after histopathological verification. However, the last few years the tumours have advanced, infiltrating firstly the tabula external and a year later the tabula interna of the cranium. A computed -tomography (CT) imaging and radiography of the skull were performed to reveal the definite tumour localisation, needed for planning an one - step surgical intervention. Both of the instrumental examinations confirmed the existence of osteolytic tumour lesions. Craniotomy with precise removal of the BCCs infiltrating the cranial bone in all of its thickness was performed. Partial resection of dura mater was also performed also because intraoperative findings established the involvement of the dura. Histopathological verification revealed bone and dural invasion with clean resection margins. The bone defect was recovered with hydroxyapatite cement. Reconstruction as the shape of the skull was carefully modified and adapted to its initial size and form. Layered closure of the skin and soft tissues were performed after the complete removal of the BCCs. The postoperative period had no serious complications. CONCLUSION: Precisely managed therapy of BCC is curative in most of the cases as it ensures good prognosis for the patient. PMID- 29531608 TI - Bullous Tinea Incognito in a Bulgarian Child: First Description in the Medical Literature! AB - For the first time in the world medical literature, we describe a rare form of cutaneous dermatophytosis - a bullous form of Tinea incognito, classified by clinical picture, histopathological findings and an isolated infectious agent from the microbiological culture. After a thorough review of Medline/PubMed's relevant literature, we could not find similar cases of patients with Tinea incognito who are clinically presented with bullous lesions at the same time. Local application of corticosteroids in infants with unknown lesions may lead to progression of the underlying disease and may cause some serious problems in differential diagnosis aspect, while the clinical expression remains completely masked. Exactly for this reason, right at the beginning of the clinical complaints, a skin biopsy should be obligatorily performed in parallel with microbiological swabs. If there is no improvement after the local corticosteroid application, then diagnosis revision and change of the strategy of clinical behaviour would be appropriate to be done. The systemic treatment that we performed with Fluconazole 50 mg in combination with the local antimycotic agent for a 2-week period led to complete remission. PMID- 29531609 TI - Oral Hygiene Index in Early Childhood Caries, Before and After Topical Fluoride Treatment. AB - BACKGROUND: Circular caries occurs in the earliest age of the children (1 - 1.5 year), immediately after the eruption of the deciduous teeth. During this period, children are too young to be able to properly implement oral hygiene. Consequently, it is at a negligible level, with plenty of soft plaque on the deciduous tooth surfaces. OBJECTIVE: The main objective of this clinical trial was to determine the correlation between oral hygiene shown with Oral Hygiene index, and the initial stages of circular caries (initial lesion and superficial form), before and after topical fluoride treatment. MATERIAL AND METHODS: For determination of the OHI - index we used the method of Green - Vermillion. It was determined two times in 117 patients, during the first visit and immediately before physiological replacement of deciduous teeth. Patients were two to three years old and diagnosed with initial stages of circular caries. Amino fluoride solution was applied once a week, during six months. RESULTS: We obtained statistically significant improvement of OHI - index at the end of the test, among treated subjects from both major groups. CONCLUSION: It can be concluded that the level of oral hygiene is correlated with the progression of changes in enamel. Topical fluoride treatment has a positive impact on reducing ECC. PMID- 29531610 TI - Evaluating the Amount of Tooth Movement and Root Resorption during Canine Retraction with Friction versus Frictionless Mechanics Using Cone Beam Computed Tomography. AB - BACKGROUND: The current study was carried out to compare the amount of tooth movement during canine retraction comparing two different retraction mechanics; friction mechanics represented by a NiTi closed coil spring versus frictionless mechanics represented by T - loop, and their effect on root resorption using Cone Beam Computed Tomography (CBCT). METHOD: Ten patients were selected in a split mouth study design that had a malocclusion that necessitates the extraction of maxillary first premolars and retraction of maxillary canines. The right maxillary canines were retracted using T - loops fabricated from 0.017 X 0.025 TMA wires. The left maxillary canines received NiTi coil spring with 150 gm of retraction force. Pre retraction and post retraction Cone Beam Computed Tomography were taken to evaluate the amount of tooth movement and root resorption using three-dimensional planes. RESULTS: T - loop side showed statistically significant higher mean anteroposterior measurement than NiTi coil spring side, indicating a lower amount of canine movement pre and post a canine retraction. Concerning the root resorption, there was no statistically significant change in the mean measurements of canine root length post retraction. CONCLUSION: The NiTi coil spring side showed more distal movement more than the T-loop side. Both retraction mechanics with controlled retraction force, do not cause root resorption. PMID- 29531611 TI - The Effect of Gaseous Ozone in Infected Root Canal. AB - OBJECTIVES: During the treatment of chronic apical periodontitis and pulp necrosis the main role is to irrigate the root canal. AIM: The aim of this in vivo study was to irrigate with 0.9% NaCl (Natrium Chloride), 2.5 % NaOCl (Sodium Hypochlorite Solution, Sigma Aldrich - Germany) and 2% CHX (Chlorhexidine Digluconate Solution, Sigma Aldrich - Spain) combined with Gaseous Ozone (Prozone WH, Austria). MATERIAL AND METHODS: This study was realised in the University Dentistry Clinical Centre of Kosovo (UDCCK), respectively in the Department of Endodontic and Dental Pathology, Dental Branch, Faculty of Medicine, Prishtina, Kosovo. The 40 subjects involved in this study belonged to both genders, in age between 15 -65 years. The sample selection was randomised. The retroalveolar radiography for each patient was taken in the suspected tooth. As a therapeutic plan the authors decided to disinfect the root canal with the irrigants, as follows: 2.5 % NaOCl, 2 % CHX and gaseous ozone. RESULTS: The statistical analyses were based on Kruskal - Vallis test, X - test, DF = 3, r < 0.01. In the isolated average number of the aerobe and anaerobe bacteria colonies, when gaseous ozone was used, there was the significant statistical difference. CONCLUSIONS: When gaseous ozone was combined with irrigants 0.9%, 2.5 % NaOCl and 2% CHX, it was concluded that the number of colonies of aerobic and anaerobic bacteria was reduced. PMID- 29531612 TI - Angulated Dental Implants in Posterior Maxilla FEA and Experimental Verification. AB - AIM: This study aimed to evaluate the effect of different implant angulations in posterior maxilla on stress distribution by finite element analysis and verify its results experimentally. METHODS: Two simplified models were prepared for an implant placed vertically and tilted 25 degrees piercing the maxillary sinus. Geometric models' components were prepared by Autodesk Inventor then assembled in ANSYS for finite element analysis. The results of finite element analysis were verified against experimental trials results which were statistically analysed using student t-test (level of significance p < 0.05). RESULTS: Implant - abutment complex absorbed the load energy in case of vertical implant better than the case of angulated one. That was reflected on cortical bone stress, while both cases showed stress levels within the physiological limits. Comparing results between FEA and experiment trials showed full agreement. CONCLUSION: It was found that the tilted implant by 25 degrees can be utilised in the posterior region maxilla for replacing maxillary first molar avoiding sinus penetration. The implant-bone interface and peri-implant bones received the highest Von Mises stress. Implant - bone interface with angulated implant received about 66% more stresses than the straight one. PMID- 29531613 TI - Knowledge and Preparedness of Dental Practitioners on Management of Medical Emergencies in Jazan Province. AB - Medical emergencies are one of the most stressful situations the staff in a dental practice might encounter. The duty of care toward the attending patients obligates suitable preparedness to provide the necessary care if such emergencies ensue. Unfortunately, we found that 22% of the investigated dental clinics had no emergency kit available. Only 38% of the interviewed dentists felt confident to perform CPR, and 18% had no confidence to manage any medical emergency. An MCQ test of 20 questions examining the dentists' knowledge in medical emergencies was distributed, and the level of knowledge was found to be suboptimal. The average score of the interviewed dentists was 10.87 out of 20. Experience and specialty training had a negligible effect on the level of knowledge. PMID- 29531614 TI - Brown Tumour in the Mandible and Skull Osteosclerosis Associated with Primary Hyperparathyroidism - A Case Report. AB - BACKGROUND: The hyperparathyroidism (HPT) is a condition in which the parathyroid hormone (PTH) levels in the blood are increased. HPT is categorised into primary, secondary and tertiary. A rare entity that occurs in the lower jaw in association with HPT is the so-called brown tumour, which an osteolytic lesion is predominantly occurring in the lower jaw. It is usually a manifestation of the late stage of the disease. Osteosclerotic changes in other bones are almost always associated with renal osteodystrophy in secondary HPT and are extremely rare in primary HPT. This article reports a rare case of a brown tumour in the mandible as the first sign of a severe primary HPT, associated with osteosclerotic changes on the skull. CASE REPORT: A brown tumour in the mandible was diagnosed in 60 - year old female patient with no previous history of systemic disease. The x - rays showed radiolucent osteolytic lesion in the frontal area of the mandible affecting the lamina dura of the frontal teeth, and skull osteosclerosis in the form of salt and pepper sign. The blood analyses revealed increased values of PTH, calcitonin and beta - cross-laps, indicating a primary HPT. The scintigraphy of the parathyroid glands showed a presence of adenoma in the left lower lobe. The tumour lesion was surgically removed together with the lower frontal teeth, and this was followed by total parathyroidectomy. The follow - up of one year did not reveal any signs of recurrence. CONCLUSION: It is critical to ensure that every osteolytic lesion in the maxillofacial region is examined thoroughly. Moreover, a proper and detailed systemic investigation should be performed. Patients should undergo regular check-ups to prevent late complications of HPT. PMID- 29531615 TI - Effectiveness of Acceptance and Commitment Therapy on Anxiety and Depression of Razi Psychiatric Center Staff. AB - AIM: Considering the key role of human resources as the main operator of organisations, the present research aimed to determine the effectiveness of acceptance and commitment therapy for anxiety and depression of Razi Psychiatric Center staff. MATERIALS AND METHODS: This research follows a quasi-experimental type with pre-test, post-test plans, and control group. Accordingly, 30 people were selected through volunteered sampling among Razi Psychiatric Center staff. Then, they were randomly placed into two groups of 15 (experimental and control) and evaluated using research tools. Research tools consisted of Beck Anxiety and Depression Inventories whose reliability and validity have been confirmed in several studies. Research data were analysed using the analysis of covariance (ANCOVA). Results: The statistical analysis confirmed the difference in the components of anxiety and depression in the experimental group, which had received acceptance and commitment therapy compared to the group that had not received any therapy in this regard (control group) (p < 0.05). CONCLUSION: Acceptance and commitment therapy reduces anxiety and depression. PMID- 29531616 TI - Stress Factors among Nurses at the Primary and Secondary Level of Public Sector Health Care: The Case of Slovenia. AB - BACKGROUND: Working in nursing is mentally and physically demanding and is one of the most stressful professions. AIM: To determine the basic causes of stress and examine the symptoms of stress among healthcare professionals at the primary and secondary level of health care. MATERIAL AND METHODS: The research was based on the descriptive and causal non-experimental method of empirical research. The independent samples t-test was used. RESULTS: The survey results have shown that those employed in nursing are exposed to stressful situations on a daily basis, most often involving psychological or physical violence in the workplace (M = 4.2), dealing with death (M = 3.9), lack of personnel (M = 3.9) and a high frequency of patients (M = 3.8). The following stress factors cause women greater stress than they do men: relationships among co-workers (t = 2.745; p = 0.006), psychological or physical violence in the workplace (t = 3.492; p = 0.001), and working with difficult patients (t = 2.427; p = 0.017). CONCLUSION: To manage risks, employees and employers must work together and establish a suitable safety and organisational culture, which would enable them to manage and reduce stress. PMID- 29531617 TI - Epidemiological Profile of Acute Viral Encephalitis in a Sample of Egyptian Children. AB - INTRODUCTION: Acute encephalitis syndrome (AES) is a considerable public health problem. AIM: This study was designed to describe the aetiology, demographic features, clinical picture, short-term outcome and risk factors of mortality of children with viral encephalitis in Egyptian children. METHODS: PCR detection of viruses in the CSF of pediatric patients admitted to the pediatric unit or ICU Cairo University Pediatric hospital presenting with encephalitis syndrome. RESULTS: Of the 96 patients included in the study, viral etiological agents were detected in 20 cases (20.8%), while 76 patients (79.2%) had no definite viral aetiology. The most abundant virus detected was Enterovirus (EV) in fourteen (14.5%), two (2.1%) were positive for human herpes simplex virus 6 (HSV-6), one (1.0%), human herpes simplex virus1 (HSV-1), one (1.0%) Epstein Barr virus (EBV), one (1.0%), cytomegalovirus (CMV) and one (1.0%) with varicella-zoster virus (VZV). On the short term outcome, 22 (22.9) patients died, and 74 (77.1%) survived. Severity outcome among survival was vegetative in three cases (4%) severe in 9 (12.16%), moderate in 14 (18.9%), mild in 29 (39.2%) and full recovery in 19 (25.6%). Mortality risk factors for younger age, the presence of apnea, the need for mechanical ventilation and the presence of abnormal CT findings were all significantly associated with fatal outcome (p < 0.05). CONCLUSION: Enterovirus was the most common cause of encephalitis among Egyptian children. Mortality was correlated with younger age and disease severity at admission. Sequelae were high among infected children. PMID- 29531618 TI - Female Genital Mutilation in Sudan. AB - BACKGROUND: Female genital mutilation or female circumcision (FGM) is a serious health problem in Sudan. This procedure is harmful to women and causes many complications during pregnancy and childbirth. OBJECTIVE: This study aims to determine the female genital mutilation (FGM) and its associated factors in Sudan. SUBJECTS AND METHODS: Data from Sudan Multiple Indicator Cluster Survey (MICS - UNICEF) was used in this research. The survey was carried out in 2014 and included women aged between 14 - 49 years. A logistic regression model was used to find an association between dependent and independent variables. RESULT: Total numbers of 21947 women were included in the survey and out of the 6249 (28.5 %) from urban and 15698 (71.5%) from rural areas. The prevalence of female circumcision was 89%. Women who had circumcised daughters were 32.1 %. The highest prevalence of FGM was reported from South Kordofan state with 7.8%, and lowest was in Red Sea state (7.6%). A significant association was observed between circumcised women and their marital status, daughter circumcision, and the level of education. CONCLUSION: The practice of female genital mutilation is spread all over the country. Poor women with low level of education are at high risk for this phenomenon. More efforts have to be provided to end this dangerous practice. PMID- 29531620 TI - Cover: August 1897. PMID- 29531619 TI - Follow-up in community pharmacy should be routine, not extraordinary. PMID- 29531621 TI - A change: December 1896. PMID- 29531622 TI - What others think of us: July 1897. PMID- 29531624 TI - Cross-Canada updates. PMID- 29531623 TI - Why you should mentor a pharmacy student. PMID- 29531625 TI - Clearing up potential misconceptions about the treatment of rheumatoid arthritis and the use of methotrexate in combination therapy. PMID- 29531626 TI - Pharmacy-initiated immunizations in the emergency department-HaliVax PIIE. PMID- 29531628 TI - Pharmacists' assessment and management of acute and chronic gout. PMID- 29531627 TI - A pharmacist checklist for direct oral anticoagulant management: Raising the bar. PMID- 29531629 TI - Guidance on opioid tapering in the context of chronic pain: Evidence, practical advice and frequently asked questions. PMID- 29531630 TI - Medical assistance in dying: Examining Canadian pharmacy perspectives using a mixed-methods approach. AB - Background: Canada legalized assisted dying with the passing of Bill C-14, Medical Assistance in Dying (MAiD), in June 2016. This legislation has implications for health care professionals participating in MAiD. This research aims to understand the effect that MAiD has on pharmacists and pharmacy technicians in Canada. Methods: We conducted a thematic document analysis of pharmacy guidelines, position statements and standards of practice from pharmacy regulatory authorities across Canada. In addition, the Ontario Pharmacists Association surveyed its members (including pharmacists, pharmacy technicians and pharmacy students) about their perceptions of MAiD. Results: Our thematic analysis of the reviewed documents resulted in 3 major themes: pharmacists' role in quality assurance, practice considerations when implementing MAiD and resources for pharmacy staff involved in MAiD. Survey responses illustrated that most (68%) pharmacy staff would dispense MAiD medications. Nonetheless, many respondents perceived that they lacked knowledge or comfort with different aspects of the MAiD process. Overall, 80% of participants reported a desire for professional development about MAiD. Conclusion: Despite the rapidly changing landscape surrounding medical assistance in dying within the past year, most pharmacy regulatory authorities have provided direction and resources to their pharmacists. Ontario pharmacists and pharmacy technicians are willing to dispense MAiD medications; however, additional support in the form of professional development may be necessary based on participants' desire for education coupled with their perceived lack of knowledge. Future research may focus on the efficacy of provincial guidelines in supporting pharmacists' participation in MAiD. PMID- 29531631 TI - A prototype for evidence-based pharmaceutical opinions to promote physician pharmacist communication around deprescribing. AB - Context: Interprofessional communication is an effective mechanism for reducing inappropriate prescriptions among older adults. Physicians' views about which elements are essential for pharmacists to include in an evidence-based pharmaceutical opinion for deprescribing remain unknown. Objective: To develop a prototype for an evidence-based pharmaceutical opinion that promotes physician pharmacist communication around deprescribing. Methods: A standardized template for an evidence-based pharmaceutical opinion was developed with input from a convenience sample of 32 primary care physicians and 61 primary care pharmacists, recruited from conferences and community settings in Montreal, Canada. Participants were asked to comment on the need for clarifying treatment goals, including personalized patient data and biomarkers, highlighting evidence about drug harms, listing the credibility and source of the recommendations, providing therapeutic alternatives and formalizing official documentation of decision making. The content and format of the prototype underwent revision by community physicians and pharmacists until consensus was reached on a final recommended template. Results: The majority of physicians (84%-97%) requested that the source of the deprescribing recommendations be cited, that alternative management options be provided and that the information be tailored to the patient. Sixteen percent of physicians expressed concern about the information in the opinions being too dense. Pharmacists also questioned the length of the opinion and asked that additional space be provided for the physician's response. A statement was added making the opinion a valid prescription upon receipt of a signature from physicians. Compared to a nonstandardized opinion, the majority of pharmacists believed the template was easier to use, more evidence based, more time efficient and more likely to lead to deprescribing. Conclusion: Physicians and pharmacists endorsed a standardized template that promotes interprofessional communication for deprescribing (available at https://www.deprescribingnetwork.ca/pharmaceutical-opinions). The outcome of the D-Prescribe trial will determine the effectiveness of these evidence-based pharmaceutical opinions on deprescribing processes and outcomes. Can Pharm J (Ott) 2018;151:xx-xx. PMID- 29531632 TI - Patient perspectives on the role of community pharmacists for antidepressant treatment: A qualitative study. AB - Objectives: Patients prescribed antidepressant drug treatment (ADT) for major depression report several needs in relation to their treatment, and a large proportion of these patients will end ADT prematurely. Community pharmacists may play an important role in monitoring ADT and supporting these patients. However, little is known about patient experiences of the services provided in community pharmacies. The objectives of this study were to 1) explore patients' experiences with the services community pharmacists provide for ADT and 2) identify potential avenues for improvement of pharmacists' services within the context of ADT. Methods: A qualitative descriptive exploratory study was conducted among individuals diagnosed with major depression who had initiated ADT at some point in the 12 months prior to their participation in the study. A total of 14 persons recruited in a local health centre and a community-based organization participated in individual interviews. A thematic analysis of the interview transcripts was conducted. Results: Pharmacists tend to concentrate their involvement in treatment at initiation and at the first refill when questions, uncertainties and side effects are major issues. Patients felt that the pharmacists' contributions consisted of providing information and reassurance; in these respects, their needs were met. Participants had few ideas as to what additional services pharmacists could implement to improve patients' experience with ADT. Patients' sole expectations were that pharmacists extend this information role to the whole length of the treatment and enhance the confidentiality of discussions in pharmacy. Conclusion: Pharmacists should provide counselling throughout the entire treatment rather than passively waiting for patients to ask their questions. However, facilitation of open discussions may not be achieved unless confidentiality at pharmacies is secured. PMID- 29531633 TI - Migration of magnetotactic bacteria in porous media. AB - Magnetotactic bacteria (MTB) migrate in complex porous sediments where fluid flow is ubiquitous. Here, we demonstrate that magnetotaxis enables MTB to migrate effectively through porous micromodels. Directed MTB can circumvent curved obstacles by traveling along the boundaries and pass flat obstacles by repeatedly switching between forward and backward runs. Magnetotaxis enables directed motion of MTB through heterogeneous porous media, overcoming tortuous flow fields with local velocities as high as 250 MUm s-1. Our findings bring new insights into the migration behaviour of MTB in their natural habitats and their potential in vivo applications as microbiorobots. PMID- 29531635 TI - Hydrodynamic mobility of confined polymeric particles, vesicles, and cancer cells in a square microchannel. AB - The transport of deformable objects, including polymer particles, vesicles, and cells, has been a subject of interest for several decades where the majority of experimental and theoretical studies have been focused on circular tubes. Due to advances in microfluidics, there is a need to study the transport of individual deformable particles in rectangular microchannels where corner flows can be important. In this study, we report measurements of hydrodynamic mobility of confined polymeric particles, vesicles, and cancer cells in a linear microchannel with a square cross-section. Our operating conditions are such that the mobility is measured as a function of geometric confinement over the range 0.3 < lambda < 1.5 and at specified particle Reynolds numbers that are within 0.1 < Rep < 2.5. The experimental mobility data of each of these systems is compared with the circular-tube theory of Hestroni, Haber, and Wacholder [J. Fluid Mech. 41, 689 705 (1970)] with modifications made for a square cross-section. For polymeric particles, we find that the mobility data agrees well over a large confinement range with the theory but under predicts for vesicles. The mobility of vesicles is higher in a square channel than in a circular tube, and does not depend significantly on membrane mechanical properties. The mobility of cancer cells is in good agreement with the theory up to lambda ~ 0.8, after which it deviates. Comparison of the mobility data of the three systems reveals that cancer cells have higher mobility than rigid particles but lower than vesicles, suggesting that the cell membrane frictional properties are in between a solid-like interface and a fluid bilayer. We explain further the differences in the mobility of the three systems by considering their shape deformation and surface flow on the interface. The results of this study may find potential applications in drug delivery and biomedical diagnostics. PMID- 29531636 TI - Asymmetric fluttering ferromagnetic bar-driven inertial micropump in microfluidics. AB - Even though microfluidics has been successfully used in minimizing complicated and onerous processes, the pumping and tubing systems used with it are yet undeveloped and need immediate development. The present study developed a fluttering bar-driven micropump, mounted on a polydimethylsiloxane microfluidic system. The pump consists of a rectangular ferromagnetic bar and a fan-shaped chamber with an inlet and outlet. Through various experiments, the net flow was examined as a function of chamber shape, inlet and outlet channel location, rotating center of the magnet, and rotational speed. Using high-speed camera and image analysis, the net flow was found to be generated by the fluid inertia associated with the varying reciprocating speeds of the bar inside the fan-shaped chamber. Depending on the locations of the inlet and outlet, the cycle time taken to circulate the loop was significantly reduced from 200 to 4 s. The flow rate of the micropump ranges from 48-225 MUl/min, which is proportional to the rotational speed of the magnet (150-3000 rpm). Using a fluttering bar-driven inertial micropump, the microfluidic system not only provides improved mixing, but also eliminates certain problems associated with external tubing and connection. PMID- 29531634 TI - Dielectrophoresis-based microfluidic platforms for cancer diagnostics. AB - The recent advancement of dielectrophoresis (DEP)-enabled microfluidic platforms is opening new opportunities for potential use in cancer disease diagnostics. DEP is advantageous because of its specificity, low cost, small sample volume requirement, and tuneable property for microfluidic platforms. These intrinsic advantages have made it especially suitable for developing microfluidic cancer diagnostic platforms. This review focuses on a comprehensive analysis of the recent developments of DEP enabled microfluidic platforms sorted according to the target cancer cell. Each study is critically analyzed, and the features of each platform, the performance, added functionality for clinical use, and the types of samples, used are discussed. We address the novelty of the techniques, strategies, and design configuration used in improving on existing technologies or previous studies. A summary of comparing the developmental extent of each study is made, and we conclude with a treatment of future trends and a brief summary. PMID- 29531637 TI - Motivations and Experiences Related to Women's First Same-sex Sexual Encounters. AB - Using women's self-identified sexual identity, the current study compares motivations for first same-sex sexual encounters as well as associated experiential outcomes. We also examine whether relations between sexual motivations and experiential outcomes differ as a function of women's sexual identity status. Participants were women (N=123), ages 18-to-29 (M=21.59, SD=3.33), who self-reported a history of same-sex sexual contact. Approximately 27% of women identified as exclusively heterosexual (i.e., EH), 35% as primarily heterosexual (i.e., 'mostly heterosexual' [MH]), and 38% as exclusively or primarily lesbian/ gay, or bisexual (i.e., LGB). Participants completed an online survey. MH and LGB women reported first same-sex sexual encounters that were more motivated by intimacy and exploration motives, relative to EH women. Compared to MH and LGB women, EH also engaged in fewer sexual activities with their first same-sex partner. Intimacy and exploration motives were related to positive experiential outcomes during first same-sex contact. Associations between motivations and experiential outcomes were not moderated by sexual identity. Findings contribute to understanding motivations and experiences related to women's first same-sex sexual encounters and show that not all women with a history of same-sex sexual contact subsequently identify with a minority sexual identity label. PMID- 29531638 TI - Spatiotemporal switching signals for cancer stem cell activation in pediatric origins of adulthood cancer: Towards a watch-and-wait lifetime strategy for cancer treatment. AB - Pediatric origin of cancer stem cell hypothesis holds great promise and potential in adult cancer treatment, however; the road to innovation is full of obstacles as there are plenty of questions left unanswered. First, the key question is to characterize the nature of such stem cells (concept). Second, the quantitative imaging of pediatric stem cells should be implemented (technology). Conceptually, pediatric stem cell origins of adult cancer are based on the notion that plasticity in early life developmental programming evolves local environments to cancer. Technologically, such imaging in children is lacking as all imaging is designed for adult patients. We postulate that the need for quantitative imaging to measure space-time changes of plasticity in early life developmental programming in children may trigger research and development of the imaging technology. Such quantitative imaging of pediatric origin of adulthood cancer will help develop a spatiotemporal monitoring system to determine cancer initiation and progression. Clinical validation of such speculative hypothesis that cancer originates in a pediatric environment-will help implement a wait-and watch strategy for cancer treatment. PMID- 29531639 TI - Mutation detection using plasma circulating tumor DNA (ctDNA) in a cohort of asymptomatic adults at increased risk for cancer. AB - PURPOSE: The primary purpose of this study was to clinically evaluate circulating tumor DNA (ctDNA) with a nine gene, 96 mutation panel among subjects at increased risk for cancer with no previous cancer diagnosis. SUBJECTS AND METHODS: DNA from 1059 asymptomatic subjects was analyzed for detection of low levels ctDNA using a blood plasma liquid biopsy assay. Subjects with detectable copies of ctDNA were asked to provide additional blood samples and relevant medical records throughout their one-year of participation. Subjects with a negative result were followed-up at one-year with a questionnaire. RESULTS: Mutations were detected in 58 subjects and not detected in 1001 subjects. Among the subjects who tested positive for one or more mutations, four were diagnosed with cancer, two of which through study triggered clinical follow-up. Two subjects who tested negative on the screen received an early cancer diagnosis over the course of the year. The sensitivity of the assay at a threshold of >=2 copies in this population was 66.67% and specificity was 94.87%. While the negative predictive value was 99.8%, the positive predictive value was only 6.9% in this cohort. Analysis of buffy coat DNA from eight positive subjects, including one who was diagnosed with cancer, revealed matching mutations suggesting that the ctDNA could have been derived from clonal hematopoiesis. CONCLUSION: The observed false positive rate of ctDNA on a 96-mutation assay in an asymptomatic high-risk population is much greater than the true positive rate, limiting its usefulness as a cancer screening tool in its current form. PMID- 29531640 TI - Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis. AB - AIM: To determine the scope of acute hypoglycemic effects for certain anti rheumatic medications in a large retrospective observational study. METHODS: Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti rheumatic drugs (DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics. RESULTS: Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events (-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events (+5.85 mg/dL, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events (-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (beta = -0.58, P = 0.01) and hydroxychloroquine (beta = -5.78, P = 0.01) use as predictors of lower post medication-initiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure (beta = 4.69, P = 0.03) was predictive for higher post initiation RBG values among all medication-initiation events. CONCLUSION: No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects. PMID- 29531641 TI - Results of Kidney Transplantation from Expanded Criteria Donors: A Single-Center Experience. AB - Background: Collection of kidneys from extended criteria donors (ECD) with diagnosed brain-death forms a part of the collection program that increases the number of transplantations. Objective: To compare the results of ECD with those of standard criteria donors (SCD). Methods: In a retrospective analysis in a group of 156 kidney donors, we identified ECD donors. We detected the basic parameters of the donors before kidney collection, and then evaluated the function of the graft, the survival of the graft, and the survival of the patients after 1, 3, and 5 years of transplantation. The results were then compared with the function of the graft from those of SCD donors. Results: The ECD donors were significantly (p<0.001) older than the SCD donors. They had a higher body mass index (p=0.006) and prevalence of hypertension (p<0.001) and diabetes mellitus (p=0.004) compared to SCD donors. The graft function within the first 6 months and the survival of recipients in the first year of transplantation were significantly worse in ECD than in SCD groups (p=0.01, and 0.023, respectively). No difference in the graft survival was observed between the two groups. Conclusion: The long-term function of the graft and survival of patients and grafts in recipients of kidneys from ECD donors are comparable to SCD donors. Exploitation of the given organs for transplantation is important due to the constantly increasing demand versus limited offer of organs. PMID- 29531642 TI - One-year Allograft and Patient Survival in Renal Transplant Recipients Receiving Antiplatelet Therapy at the Time of Transplantation. AB - Background: Antiplatelet therapy is common in patients on the waiting list for kidney transplantation. Objective: To evaluate the incidence of post-operative bleeding in patients with antiplatelet therapy undergoing kidney transplantation and analyze the impact on the outcome. Methods: We studied all patients with concomitant antiplatelet therapy undergoing kidney transplantation in our center from January 2007 to June 2012. Data were collected by chart review. Univariate and multivariate logistic regression and Cox proportional hazard model were used to identify risk factors for the long-term outcome. Results: Of 744 kidney transplant recipients during the study period, 161 received oral antiplatelet therapy and were included in the study. One-third of the patients demonstrated signs of bleeding, half of which requiring surgical treatment. Coronary artery disease, deceased donor kidney transplantation, and dual antiplatelet medication were independent risk factors for post-operative bleeding. One-year allograft survival was significantly better in the non-bleeding group (91.4% vs 75.9%, p=0.023). Multivariable analysis found that post-operative bleeding, recipient age, and biopsy-proven rejection were independent risk factors for graft survival. Recipient age and biopsy-proven rejection were also identified as independent risk factors for patient survival. Conclusion: This analysis indicated a high risk for post-operative bleeding in renal transplant patients under antiplatelet therapy. The associated negative effect on allograft survival underscored the need to reduce any risk factors for post-operative bleeding. PMID- 29531643 TI - Concurrent Umbilical Hernia Repair at the Time of Liver Transplantation: A Six Year Experience from a Single Institution. AB - Background: Umbilical hernias are common in patients with end-stage liver disease undergoing liver transplantation. Management of those persisting at the time of liver transplantation is important to define. Objective: To evaluate the long term results of patients undergoing simultaneous primary umbilical hernia repair (UHR) at the time of liver transplantation at a single institution. Methods: Retrospective chart review was performed on patients undergoing simultaneous UHR and liver transplantation from 2010 through 2016. 30-day morbidity and mortality outcomes and long-term hernia recurrence were investigated. Results: 59 patients had primary UHR at the time of liver transplantation. All hernias were reducible with no overlying skin breakdown or leakage of ascites. 30-day morbidity and mortality included 5 (8%) superficial surgical site infections, 1 (2%) deep surgical site infection, and 7 (12%) organ space infections. Unrelated to the UHR, 10 (17%) patients had an unplanned return to the operating room, 16 (27%) were readmitted within 30 days of their index operation, and 1 (2%) patient died. With a mean follow-up of 21.8 months, 7 (18%) patients experienced an umbilical hernia recurrence. Conclusion: Despite the high perioperative morbidity associated with the transplant procedure, concurrent primary UHR resulted in an acceptable long-term recurrence rate with minimal associated morbidity. PMID- 29531644 TI - Prevalence of CYP2C19 Genetic Polymorphism among Normal People and Patients with Hepatic Diseases. AB - Background: Patients with hepatic diseases are treated with numerous drugs metabolized by cytochrome P450. Objective: To evaluate the frequencies of CYP2C19 variant alleles (*2, *3, and *17), genotypes, and phenotypes, and the relationship between the frequency of these alleles and the underlying hepatic diseases among patients with advanced liver diseases who were candidates for liver transplantation. Methods: The Study was conducted on 120 patients suffering from various hepatic disorders, candidates for liver transplantation, and 52 healthy volunteers. DNA was extracted from blood samples and analyzed by TaqMan SNP genotyping assay. The CYP2C19 genotypes were classified into poor, extensive, intermediate, and ultra-rapid metabolizer phenotypes. Results: Viral hepatitis was the most common cause of liver disease among studied patients. The frequencies of CYP2C19 alleles *1, *17, and *2 were 66.7% (160/240), 20.8% (50/240) and 12.5% (30/240), respectively. Allele CYP2C19*3 was not found in the studied population. The most prevalent genotypes were CYP2C19 *1/*1 (47.5%) and *1/*17 (24.2%). The predicted CYP2C19 phenotypes were extensive metabolizer (47.5%), heterozygote extensive metabolizer (45.9%), ultra-rapid metabolizer (5%), and poor metabolizer (1.6%). There was no significant difference between the frequencies of CYP2C19 genotypes between healthy people and patients. The distribution of CYP2C19 genotype frequencies was not significantly associated with the underlying disease conditions (p=0.472). Conclusion: The distribution of CYP2C19 genotype frequencies in Iranian healthy people and patients with various hepatic diseases was not significantly different. This may allow the physicians to predict a tailoring dose regimens based on the individual's metabolic capacity, decrease the risk of harmful side effects of the drugs, and optimize the treatment. PMID- 29531645 TI - mRNA Expression of Interferon Regulatory Factors during Acute Rejection of Liver Transplants in Patients with Autoimmune Hepatitis. AB - Background: Interferon regulatory factors (IRFs) can play a critical role in the regulation of many facets of innate and adaptive immune responses through transcriptional activation of type I interferons, other proinflammatory cytokines, and chemokines. However, their roles in transplantation immunity still remain to be elucidated. Objective: To evaluate the time course of mRNA expression of all 9 members of IRFs family of transcription factors during liver allograft acute rejection. Methods: Blood samples of 19 patients with autoimmune hepatitis receiving liver transplants were collected on days 1, 3, 5, and 7 post transplantation. The patients were followed for 6 months after transplantation and divided into two groups of acute rejection (AR) (n=4) and non-acute rejection (non-AR) (n=15). Results: All of the studied transcription factors were down regulated in AR-group on days 3, 5, and 7 post-transplantation compared to non-AR group. The mean+/-SEM IRF5 on day 7 post-transplantation was significantly (p=0.005) lower in AR-group than in non-AR group (0.7+/-0.21 vs. 1.91+/-0.27, respectively); expression of other IRFs family members was not significantly different between the two groups on days 3, 5, and 7 post-transplantation. Conclusion: IRF5 may have an important role during the acute rejection of liver transplants. PMID- 29531647 TI - Delayed Hemorrhage in Kidney Transplantation: A Life-threatening Condition. AB - One of the most catastrophic complications of kidney transplantation is non traumatic delayed bleeding caused by arterial dissection and pseudoaneurysm, endangering the survival of the graft and the patient. Herein, we discuss the management of this condition in 3 cases. The patients included 2 men, 30 and 47 years old, and a 33-year-old woman, who developed a massive hemorrhage in the second week after kidney transplant. All our patients were diabetic for more than 5 years. Massive hemorrhage occurred in the second week without any trauma or precipitating factor. A combination of antibiotic therapy, surgery and interventional procedures was required and all three transplanted kidneys inevitably had to be removed. Although there were trivial signs of infection, considerable pus and infectious and necrotic tissue were drained during graft nephrectomy. A high index of suspicion is necessary for the timely diagnosis of arterial dissection and aneurysm. Aggressive treatment with arterial drug-eluting stents and surgical drainage are necessary in order to prevent potentially fatal complications. PMID- 29531646 TI - Acute Hepatic Allograft Rejection in Pediatric Recipients: Effective Factors. AB - Background: Acute cellular rejection (ACR), a reversible process, can affect the graft survival. Objective: To evaluate the relation between ACR and clinical factors in recipients of allograft liver transplantation. Methods: 47 recipients of liver were consecutively enrolled in a retrospective study. Their information were retrieved from their medical records and analyzed. Results: Of the 47 recipients, 38 (81%) experienced acute rejection during 24 months of the transplantation. None of the studied factors for occurring transplant rejection, i.e., blood groups, sex, age, familial history of disease, receiving drugs and blood products, type of donor, Child score, and Child class, was not found to be significant. Conclusion: During a limited follow-up period, we did not find any association between ACR and suspected risk factors. PMID- 29531648 TI - Living Donor Re-transplantation for Repeated Acute Liver Failure. AB - Emergency liver transplantation (LT) for acute liver failure (ALF) is a life saving treatment. Occurrence of this situation in the same patient twice is very rare. Herein, we describe a patient who underwent two emergency LTs for ALF, both from living donors. When she was 26 years old, she underwent a right lobe living donor LT (LDLT) from her sister for ALF due to use of herbal weight loss medications. The next 3 years were uneventful but another ALF developed during a terminal stage pregnancy (37th week). Despite medical treatment, her liver functions worsened, and the baby was delivered by caesarean section. The second time, her brother was the donor and she recovered after the emergency right lobe re-LDLT. Both patient and baby were well at the 2-month follow-up. As far as we know, there is no reported similar case, and we concluded that LDLT is a paramount treatment option for both primary and secondary ALFs. PMID- 29531649 TI - Association of the SOD2 Polymorphism (Val16Ala) and SOD Activity with Vaso occlusive Crisis and Acute Splenic Sequestration in Children with Sickle Cell Anemia. AB - The SOD2 polymorphism Val16Ala T->C influences the antioxidative response. This study investigated the association of the SOD2 polymorphism and superoxide dismutase (SOD) activity with the vaso-occlusive crisis (VOC) and acute splenic sequestration (ASS) in children with sickle cell anemia (SCA). One hundred ninety five children with SCA aged 1-9 years old were analyzed. The TC and CC genotypes were associated with lower SOD activity compared with the TT genotype (p=0.0321; p=0.0253, respectively). Furthermore, TC and CC were more frequent in patients with VOC or ASS (p=0.0285; p=0.0090, respectively). These results suggest that the SOD2 polymorphism associated with low SOD activity could be a susceptibility factor for the occurrence of VOC and ASS. PMID- 29531650 TI - Genomic Integration of HHV-6 Mimicking Viral Reactivation after Autologous Stem Cell Transplantation. AB - The monitoring of Human Herpesvirus 6 (HHV-6) after allogeneic stem cell transplantation has proven to be useful in preventing life-threatening complications; however, the pathogenic role of HHV-6 after autologous transplantation is not well-characterized, although viral reactivation might be responsible for significant complications even after this type of transplant. Here we report, for the first time to our knowledge, the case of a patient with chromosomally integrated HHV-6 (ciHHV-6), presenting with high titers of HHV-6 DNA copies after autologous transplantation, mimicking HHV-6 reactivation. The presence of viral DNA in the follicle bulb confirmed the ciHHV-6 and allowed for the discontinuation of the antiviral treatment. Due to the increasing awareness of HHV-6 potential pathogenicity and the fact that ciHHV-6 is expected in 1-2% of the population, such a case might be helpful in recognizing ci HHV-6, thus avoiding unnecessary and potentially toxic antiviral therapy once the viral genomic integration is confirmed. PMID- 29531651 TI - Elotuzumab for the Treatment of Relapsed or Refractory Multiple Myeloma, with Special Reference to its Modes of Action and SLAMF7 Signaling. AB - Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity. The ADCC is mediated through engagement between Fc portion of elotuzumab and FcgRIIIa/CD16 on NK cells. Enhanced NK cell cytotoxicity results from phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) that is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2. The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+ influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis in NK cells. Elotuzumab does not stimulate the proliferation of MM cells due to a lack of EAT-2. The inhibitory effects of elotuzumab on MM cell growth are not induced by the lack of CD45, even though SHP-2, SHP-1, SHIP-1, and Csk may be recruited to phosphorylated ITSM of SLAMF7. ELd improves PFS in patients with high-risk cytogenetics, i.e. t(4;14), del(17p), and 1q21 gain/amplification. Since the immune state is paralytic in advanced MM, the efficacy of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease. PMID- 29531652 TI - An Observational Study of the Effect of Hemoglobinopathy, Alpha Thalassemia and Hemoglobin E on P. Vivax Parasitemia. AB - Background: The protective effect of alpha-thalassemia, a common hematological disorder in Southeast Asia, against Plasmodium falciparum malaria has been well established. However, there is much less understanding of the effect of alpha thalassemia against P. vivax. Here, we aimed to investigate the proportion of alpha-thalassemia including the impact of alpha-thalassemia and HbE on the parasitemia of P. vivax in Southeast Asian malaria patients in Thailand. Methods: A total of 210 malaria patients, admitted to the Hospital for Tropical Diseases, Thailand during 2011-2012, consisting of 159 Myanmeses, 13 Karens, 26 Thais, 3 Mons, 3 Laotians, and 6 Cambodians were recruited. Plasmodium spp. and parasite densities were determined. Group of deletion mutation (--SEA, -alpha3.7, alpha4.2deletion) and substitution mutation (HbCS and HbE) were genotyped using multiplex gap-PCR and PCR-RFLP, respectively. Results: In our malaria patients, 17/210 homozygous and 74/210 heterozygous -alpha3.7 deletion were found. Only 3/210 heterozygous -alpha4.2 and 2/210 heterozygous--SEA deletion were detected. HbE is frequently found with 6/210 homozygotes and 35/210 heterozygotes. The most common thalassemia allele frequencies in Myanmar population were -alpha3.7 deletion (0.282), followed by HbE (0.101), HbCS (0.013), -alpha4.2 deletion (0.009), and --SEA deletion (0.003). Only density of P. vivax in alpha thalassemia trait patients (-alpha3.7/-alpha3.7, --SEA/alphaalpha, -alpha3.7/ alpha4.2) but not in silent alpha-thalassemia (-alpha3.7/alphaalpha, alpha4.2/alphaalpha, alphaalphaCS/alphaalpha) were significantly higher compared with non-alpha-thalassemia patients (p=0.027). HbE did not affect P. vivax parasitemia. The density of P. falciparum significantly increased in heterozygous HbE patients (p=0.046). Conclusions: Alpha-thalassemia trait is associated with high levels of P. vivax parasitemia in malaria patients in Southeast Asia. PMID- 29531653 TI - Characterization and Antimicrobial Susceptibility Profile of Bacteraemia Causing Pathogens Isolated from Febrile Children with and without Sickle Cell Disease in Kano, Nigeria. AB - Background and Objectives: Bacterial infection in sickle cell anaemic patients is a major cause of mortality and requires proper treatment with appropriate antibiotics. However, continue defiant of these infections causing pathogens to many antibiotics and inadequate screening methods in overburden health care facilities such as our in Kano, Nigeria necessitates the conduct of this study. A research was therefore conducted to isolate, characterize and test for antimicrobial susceptibility of bacteraemia-causing pathogens from febrile children with and without sickle cell disease in Kano, Nigeria. Method: A total of 225 venous blood samples from suspected sickle cell anaemic children attending three selected hospitals within Kano metropolis were collected and screened for sickle cell disease, followed by blood culture using automated blood culture system. The bacteria isolated from confirmed febrile SCD and non-SCD children were characterized using microscopic, biochemical and serological techniques. Their susceptibility to commonly used antibiotics was tested using disc diffusion method. Results: Of the 225 blood specimens screened, 68 (30.22%) were SCD positive, with the highest percentage (16%) among subjects within 1-2 years of age. A total of 11 genera of bacteria were isolated from both SCD and non SCD positive bloods, with Salmonella typhi having highest occurring rate in SCD positive children 27 (39.71%), followed by Streptococcus pneumoniae 10(14.71%), Salmonella Group B 9(13.24%), Staphylococcus aureus 4 (5.88%), and Escherichia coli 3 (4.41%). Majority of the isolates from SCD children 59 (86.76%) were highly susceptible to ciprofloxacin followed by cefuroxime 45 (66.18%), gentamicin 38 (55.88%), ceftriaxone 30 (44.12%), augmentin 39 (57.35%), ampicillin 25 (36.77%) and co-trimoxazole (22.06%). Conclusion: Bacteraemia in SCD confirmed children in the three hospitals are caused by a combination of 11 genera of bacteria. The lesser rate of bacteraemia was found in non-SCD children. Resistance to commonly used antibiotics is on increase, but treatment with ciprofloxacin and some 3rd generation cephalosporin are still promising. PMID- 29531655 TI - Parvovirus B19-triggered Acute Hemolytic Anemia and Thrombocytopenia in a Child with Evans Syndrome. AB - Background: Human parvovirus B19 (HPV-B19) is the etiologic agent of erythema infectiosum, of transient aplastic crises in individuals with underlying chronic hemolytic disorders, and of chronic pure red cell aplasia in immunocompromised individuals. Case report: We describe a 14-year-old girl with long-standing Evans syndrome, who presented with severe anemia, reticulocytopenia and thrombocytopenia. A bone marrow aspirate revealed severe erythroid hypoplasia along with the presence of giant pronormoblasts, while serological studies and real-time PCR of whole blood were positive for acute parvovirus B19 infection. The patient was initially managed with corticosteroids, but both cytopenias resolved only after administration of intravenous gamma globulin 0.8g/kg. Conclusion: Acute parvovirus B19 infection should be suspected in patients with immunologic diseases, who present reticulocytopenic hemolytic anemia and thrombocytopenia. In this setting, intravenous gamma globulin is effective for both cytopenias. PMID- 29531654 TI - Adult Sickle Cell Anaemia Patients in Bone Pain Crisis have Elevated Pro Inflammatory Cytokines. AB - Background and Objectives: Inflammatory markers that influence bone pain crisis (BPC) and other complications of sickle cell anaemia (SCA) are numerous and play various roles. This study determined the plasma levels of tumour necrosis factor (TNF) - alpha, interleukin - 8 (IL-8), and endothelin - 1 (ET-1) in adult SCA patients during BPC and in steady state. In addition, the plasma levels of these cytokines were correlated with the severity of BPC of the patients. Methods and Materials: Sixty adult SCA patients (30 during BPC and 30 during steady state) and 30 haemoglobin A controls were enrolled for this cross-sectional study. The severity of BPC was assessed clinically, and questionnaires were filled. Plasma levels of TNF- alpha, IL-8 and ET-1 were quantified by ELISA, and haematological parameters were determined using a 5-part auto-analyzer. Plasma levels were correlated with the severity of bone pain crisis. Results were considered statistically significant if p<0.05. Results: Plasma TNF-alpha, IL-8, and ET-1 were significantly elevated in the BPC group than in the steady state group and the controls. Plasma TNF-alpha, IL-8 and ET-1 were markedly higher in the severe BPC groups than the steady state and control groups, There was a positive correlation between TNF-alpha and ET-1 in the bone pain crisis group. Conclusion: Elevated levels of plasma TNF-alpha, IL-8, and ET-1 further establish the chronic inflammatory state in SCA and equally affirm their significant contribution, not only to pathogenesis but also to the severity of pain in SCA. PMID- 29531656 TI - Chemotherapy-Colchicine Interaction in a Child with Familial Mediterranean Fever and Hodgkin Lymphoma. AB - Familial Mediterranean fever (FMF) has been associated with hematological malignancies but has not been reported in association with Hodgkin lymphoma (HL). We hereby describe the first pediatric patient with FMF and stage IIA nodular sclerosis HL. She was treated with prednisone, doxorubicin, vincristine and etoposide (OEPA) being on therapy with colchicine. However, she suffered more than expected treatment-related toxicity attributed either to chemotherapy (severe neutropenia) or colchicine (Abdominal pains and diarrhoea). Colchicine had to be discontinued. In the absence of colchicine, she tolerated very well the second cycle of chemotherapy. Currently, she is in remission at 17 months after her HL diagnosis, and her FMF is under control with colchicine without any signs of toxicity. PMID- 29531658 TI - Clinical and Hematological Profile of Patients with Dengue Fever at a Tertiary Care Hospital - An Observational Study. AB - Background: Dengue is a major health issue with seasonal rise in dengue fever cases imposing an additional burden on hospitals, necessitating bolstering of services in the emergency department, laboratory with creation of additional dengue fever wards. Objectives: To study the clinical and hematological profile of dengue fever cases presenting to a hospital. Methods: Patients with fever and other signs of dengue with either positive NS1 antigen test or IgM or IgG antibody were included. Age, gender, clinical presentation, platelet count and hematocrit were noted and patients classified as dengue fever without warning signs (DF) or with warning signs (DFWS), and severe dengue (SD) with severe plasma leakage, severe bleeding or severe organ involvement. Duration of hospitalization, bleeding manifestations, requirement for platelet component support and mortality were recorded. Results: There were 443 adults and 57 children between 6 months to 77 year age. NS1 was positive in 115 patients (23%). Fever (99.8%) and severe body ache (97.4%) were the commonest presentation. DF was seen in 429 (85.8 %), DFWS in 55 (11%), SD with severe bleeding in 10 (2%) and SD with severe plasma leakage in 6 cases (1.2%). Outpatient department (OPD) treatment was needed in 412 (82%) and hospitalization in 88 (18%). Intravenous fluid resuscitation was needed in 16 (3.2%) patients. Thrombocytopenia was seen in 335 (67%) patients at presentation. Platelet transfusion was needed in 46 (9.2%). Packed red blood cell (PRBC) transfusion was given in 3 patients with DFWS and 10 of SD with severe bleeding. Death occurred in 3 patients of SD with severe plasma leak and 2 patients with SD and severe bleeding. Conclusions: Majority of DF cases can be managed on OPD basis. SD with severe bleeding or with severe plasma leakage carries high mortality. Hospitals can analyze annual data for resource allocation for capacity expansion. PMID- 29531657 TI - Outcome and Toxicity Patterns in Children and Adolescents with Non-Hodgkin Lymphoma: A Single Institution Experience. AB - Background: The incidence and biology of non-Hodgkin lymphoma (NHL) vary according to age. Some data suggest that the impact of age in pediatric and adolescent NHL patients depends on the histological subtype. Objectives: We aimed to analyze the impact of age at diagnosis on clinical characteristics and treatment-related toxicity in children and adolescents with NHL. Methods: Retrospective review of medical records of children and adolescents diagnosed with NHL at the Hospital for Sick Children, Toronto, between January 1995 and December 2008. Results: 164 children were diagnosed with NHL during the study period, with a median age at diagnosis of 10 years. With a median follow-up of 6.2 years, 5-year OS in patients aged <15 and 15-18 years was 89+/- 2% vs 82% +/- 6%, respectively (P = 0.30), and 5-year EFS was 84% +/- 3% vs. 77% +/- 7% (P= 0.37). In Burkitt's lymphoma (BL) and lymphoblastic lymphoma (LL) there was a trend towards better outcomes in children compared to adolescents, with EFS of 91% +/- 4% vs. 75% +/- 15%, respectively in BL (P= 0.17), and 82% +/- 7% vs. 51.4% +/- 2% respectively in LL (P= 0.16). Late effects occurred in 21 patients (12.8%). Conclusions: Children with NHL aged < 15 years tend to have better survival rates and similar long-term toxicity than adolescents aged 15-18 years. PMID- 29531660 TI - Safety and efficacy of nilotinib in routine clinical practice in patients with chronic myeloid leukemia in chronic or accelerated phase with resistance or intolerance to imatinib: results from the NOVEL study. AB - Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. Methods: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs. The primary objective was to collect the long-term safety data in patients treated with nilotinib 400 mg, twice daily for up to 2 years. Results: The study enrolled 85 patients with CML, including 76 in the chronic phase (CML-CP) and 9 in the accelerated phase (CML-AP). Overall, 1166 adverse events (AEs) were reported in 80 patients (94.1%), of which 70 AEs (6%) in 28 patients (32.9%) were serious and 336 AEs (28.8%) reported in 60 patients (70.6%) were drug-related. Common drug-related AEs were thrombocytopenia (21.2%), increased alanine aminotransferase (21.2%) and pruritus (17.7%). Of the 85 patients, 19 switched from imatinib due to intolerance - AEs were resolved in 16 of these 19 patients (84.2%). By 24 months, the cumulative rates of complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABL1IS ?0.01%) and MR4.5 (BCR-ABL1IS ?0.0032%) were 75.3, 56.8, 16.2 and 7.4%, respectively. Patients with CML-CP at baseline had higher overall survival (OS) and progression-free survival (PFS) than those with CML-AP. Conclusion: This is the first study that demonstrated that nilotinib is effective and well-tolerated in patients resistant or intolerant to imatinib in the real-world setting in Taiwan, reflecting effective management of CML by physicians under routine clinical practice in Taiwan. PMID- 29531661 TI - Mate choice decision rules: Trait synergisms and preference shifts. AB - An important and understudied question in sexual selection is how females evaluate information from multiple secondary sexual traits (SSTs), particularly when expression of traits is phenotypically uncorrelated. We performed mate choice experiments on zebra finches (Taeniopygia guttata castanotis Gould) to evaluate two hypotheses: preference shifts (obstacles to choice using one trait increase chooser reliance on others) and trait synergisms (choice based on the sum/product of two or more independently varying traits). The first experiment, which employed males raised on diets that impact SST expression, supported the trait synergism hypothesis: overall, male pairing success was best predicted by synergisms involving beak color and cheek patch size. Results did not support the preference shift hypothesis. Results of a follow-up experiment that included males reared on a single diet, and in which male beak color and cheek patch size were manipulated, were also consistent with the trait synergism hypothesis. Results have implications for understanding the long-term persistence of multiple SSTs in populations and for the measurement of repeatability and heritability of mate preferences. PMID- 29531659 TI - Light Chain Amyloidosis. AB - Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic light chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by the response to therapy. The specific treatment is chemotherapy targeting the underlying plasma cell clone. It needs to be risk-adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease. PMID- 29531662 TI - Functional and phylogenetic diversity determine woody productivity in a temperate forest. AB - Understanding the relationships between biodiversity and ecosystem productivity has become a central issue in ecology and conservation biology studies, particularly when these relationships are connected with global climate change and species extinction. However, which facets of biodiversity (i.e. taxonomic, functional, and phylogenetic diversity) account most for variations in productivity are still not understood very well. This is especially true with regard to temperate forest ecosystems. In this study, we used a dataset from a stem-mapped permanent forest plot in northeastern China exploring the relationships between biodiversity and productivity at different spatial scales (20 * 20 m; 40 * 40 m; and 60 * 60 m). The influence of specific environmental conditions (topographic conditions) and stand maturity (expressed by initial stand volume and biomass) were taken into account using the multivariate approach known as structural equation models. The variable "Biodiversity" includes taxonomic (Shannon), functional (FDis), and phylogenetic diversity (PD). Biodiversity-productivity relationships varied with the spatial scales. At the scale of 20 * 20 m, PD and FDis significantly affected forest biomass productivity, while Shannon had only indirect effects. At the 40 * 40 m and 60 * 60 m scales, biodiversity and productivity were weakly correlated. The initial stand volume and biomass were the most important drivers of forest productivity. The local environmental conditions significantly influenced the stand volume, biomass, biodiversity, and productivity. The results highlight the scale dependency of the relationships between forest biodiversity and productivity. The positive role of biodiversity in facilitating forest productivity was confirmed at the smaller scales. Our findings emphasize the fundamental role of environmental conditions in determining forest ecosystem performances. The results of this study provide a better understanding of the underlying ecological processes that influence specific forest biodiversity and productivity relationships. PMID- 29531663 TI - Multiple surveys employing a new sample-processing protocol reveal the genetic diversity of placozoans in Japan. AB - Placozoans, flat free-living marine invertebrates, possess an extremely simple bauplan lacking neurons and muscle cells and represent one of the earliest branching metazoan phyla. They are widely distributed from temperate to tropical oceans. Based on mitochondrial 16S rRNA sequences, 19 haplotypes forming seven distinct clades have been reported in placozoans to date. In Japan, placozoans have been found at nine locations, but 16S genotyping has been performed at only two of these locations. Here, we propose a new processing protocol, "ethanol treated substrate sampling," for collecting placozoans from natural environments. We also report the collection of placozoans from three new locations, the islands of Shikine-jima, Chichi-jima, and Haha-jima, and we present the distribution of the 16S haplotypes of placozoans in Japan. Multiple surveys conducted at multiple locations yielded five haplotypes that were not reported previously, revealing high genetic diversity in Japan, especially at Shimoda and Shikine-jima Island. The observed geographic distribution patterns were different among haplotypes; some were widely distributed, while others were sampled only from a single location. However, samplings conducted on different dates at the same sites yielded different haplotypes, suggesting that placozoans of a given haplotype do not inhabit the same site constantly throughout the year. Continued sampling efforts conducted during all seasons at multiple locations worldwide and the development of molecular markers within the haplotypes are needed to reveal the geographic distribution pattern and dispersal history of placozoans in greater detail. PMID- 29531664 TI - Effects of field experimental warming on wheat root distribution under conventional tillage and no-tillage systems. AB - Despite the obvious importance of roots to agro-ecosystem functioning, few studies have attempted to examine the effects of warming on root biomass and distribution, especially under different tillage systems. In this study, we performed a field warming experiment using infrared heaters on winter wheat, in long-term conventional tillage and no-tillage plots, to determine the responses of root biomass and distribution to warming. Soil monoliths were collected from three soil depths (0-10, 10-20, and 20-30 cm). Results showed that root biomass was noticeably increased under both till and no-till tillage systems (12.1% and 12.9% in 2011, and 9.9% and 14.5% in 2013, in the two tillage systems, respectively) in the 0-30 cm depth, associated with a similar increase in shoot biomass. However, warming-induced root biomass increases occurred in the deeper soil layers (i.e., 10-20 and 20-30 cm) in till, while the increase in no-till was focused in the surface layer (0-10 cm). Differences in the warming-induced increases in root biomass between till and no-till were positively correlated with the differences in soil total nitrogen (R2 = .863, p < .001) and soil bulk density (R2 = .853, p < .001). Knowledge of the distribution of wheat root in response to warming should help manage nutrient application and cycling of soil C N pools under anticipated climate change conditions. PMID- 29531665 TI - Life history changes in Trogoderma variabile and T. inclusum due to mating delay with implications for mating disruption as a management tactic. AB - Controlling postharvest pest species is a costly process with insecticide resistance and species-specific control requiring multiple tactics. Mating disruption (MD) can be used to both decrease a female's access to males and delay timing of mating and decreases overall mating success in a population and population growth rate. Development of new commercially available MD products requires an understanding of life history parameters associated with mating delay. These can provide information for targeting proportions of reproducing individuals using MD. After delaying mating for females of two closely related beetle species, Trogoderma variabile and T. inclusum, we surveyed survivorship, number of eggs laid, and number of progeny emerged. With increases in mating age, total number of eggs laid and total number of progeny emerged significantly declined over time. T. inclusum typically had greater numbers of eggs laid and progeny emerged compared to T. variabile as female age at mating increased, suggesting that T. inclusum may be more resistant to long-term delays in mating. Life span showed an increase as mating age increased but life span significantly decreased almost immediately following mating. Simulations depicting multiple distributions of mating within a population suggest that in a closed population, high levels of mating delay significantly reduced reproductive growth rates. Although reproductive growth rates were decreased with increased mating age, they are still large enough to maintain populations. This study highlights the differences in life history between two closely related species, suggesting that T. inclusum outperforms T. variabile over the course of a life span, but T. variabile has better reproductive capabilities early in life. MD may also be a viable component of a pest management system for these two species as it significantly decreased overall reproductive output and population growth. PMID- 29531666 TI - Living in two worlds: Evolutionary mechanisms act differently in the native and introduced ranges of an invasive plant. AB - Identifying the factors that influence spatial genetic structure among populations can provide insights into the evolution of invasive plants. In this study, we used the common reed (Phragmites australis), a grass native in Europe and invading North America, to examine the relative importance of geographic, environmental (represented by climate here), and human effects on population genetic structure and its changes during invasion. We collected samples of P. australis from both the invaded North American and native European ranges and used molecular markers to investigate the population genetic structure within and between ranges. We used path analysis to identify the contributions of each of the three factors-geographic, environmental, and human-related-to the formation of spatial genetic patterns. Genetic differentiation was observed between the introduced and native populations, and their genetic structure in the native and introduced ranges was different. There were strong effects of geography and environment on the genetic structure of populations in the native range, but the human-related factors manifested through colonization of anthropogenic habitats in the introduced range counteracted the effects of environment. The between range genetic differences among populations were mainly explained by the heterogeneous environment between the ranges, with the coefficient 2.6 times higher for the environment than that explained by the geographic distance. Human activities were the primary contributor to the genetic structure of the introduced populations. The significant environmental divergence between ranges and the strong contribution of human activities to the genetic structure in the introduced range suggest that invasive populations of P. australis have evolved to adapt to a different climate and to human-made habitats in North America. PMID- 29531667 TI - Ecological differentiation, speciation, and rarity: How do they match in Tephroseris longifolia agg. (Asteraceae)? AB - Tephroseris longifolia agg. is a complex group of outcrossing perennials distributed throughout Central Europe. Recent morphological study revealed six morphotypes corresponding to five previously distinguished subspecies, together with Alpine and Pannonian morphotypes of T. longifolia subsp. longifolia. The delimited morphotypes differ in relative DNA content, geographical range, and rarity. We compared ecological niches of the six morphotypes in order to assess the impact of ecological differentiation on the speciation processes within the T. longifolia agg. Further, we examined whether morphotypes with small range are more ecologically specialized than their widespread relatives. The distribution area of the aggregate includes the Alps, Apennines, Carpathians, and the Pannonian Basin. Ecological variables linked to climate, topography, soil, and vegetation were gathered from 135 circular plots recorded in 35 localities. Related variables were grouped to describe the partial ecological niches: climatic, topographic, pedological, biotic, and coenotic (based either on vascular plants or on bryophytes), each of them visualized as an envelope in the two-dimensional nonmetric multidimensional scaling ordination space. Each partial ecological niche for a given morphotype was characterized by its position (location of the envelope centroid), breadth (surface of the envelope), and overlaps with envelopes of the other morphotypes. Mantel statistics based on Spearman correlation coefficients were used to quantify differentiation of morphotypes in ecological parameters represented by the partial ecological niches. The significant niche differentiation was confirmed for climatic, topographic, pedological, and vascular plant-based coenotic niches. Ecological niche differentiation corresponded well to morphological and partially also to karyological differentiation. Narrowly distributed morphotypes occupied more specific habitats and had narrower ecological niches than their widespread relatives. Ecological differentiation could be considered an important driver in allopatric speciation within the T. longifolia agg. Our results demonstrate that quantification of ecological divergence is helpful in assessing evolutionary history of closely related taxa. PMID- 29531668 TI - Dynamical facilitation of the ideal free distribution in nonideal populations. AB - The ideal free distribution (IFD) requires that individuals can accurately perceive density-dependent habitat quality, while failure to discern quality differences below a given perception threshold results in distributions approaching spatial uniformity. Here, we investigate the role of population growth in restoring a nonideal population to the IFD. We place a simple model of discrete patch choice under limits to the resolution by which patch quality is perceived and include population growth driven by that underlying quality. Our model follows the population's distribution through both breeding and dispersal seasons when perception limits differ in their likely influence. We demonstrate that populations of perception limited movers can approximate an IFD provided sufficient population growth; however, the emergent IFD would be temporally inconstant and correspond to reproductive events. The time to emergence of the IFD during breeding is shorter under exponential growth than under logistic growth. The IFD during early colonization of a community persists longer when more patches are available to individuals. As the population matures and dispersal becomes increasingly random, there is an oscillation in the observance of IFD, with peaks most closely approximating the IFD occurring immediately after reproductive events, and higher reproductive rates producing distributions closer to the IFD. PMID- 29531669 TI - Postreproductive lifespans are rare in mammals. AB - A species has a post-reproductive stage if, like humans, a female entering the adult population can expect to live a substantial proportion of their life after their last reproductive event. However, it is conceptually and statistically challenging to distinguish these true post-reproductive stages from the usual processes of senescence, which can result in females occasionally surviving past their last reproductive event. Hence, despite considerable interest, the taxonomic prevalence of post-reproductive stages remains unclear and debated. In this study we use life tables constructed from published data on wild populations of mammals, and statistical measures of post-reproductive lifespans, to distinguish true post-reproductive stages from artefacts of senescence and demography in 52 species. We find post-reproductive stages are rare in mammals and are limited to humans and a few species of toothed whales. By resolving this long-standing debate, we hope to provide clarity for researchers in the field of evolutionary biology and a solid foundation for further studies investigating the evolution and adaptive significance of this unusual life history trait. PMID- 29531670 TI - Diet selectivity in a terrestrial forest invertebrate, the Auckland tree weta, across three habitat zones. AB - Insects are important but overlooked components of forest ecosystems in New Zealand. For many insect species, information on foraging patterns and trophic relationships is lacking. We examined diet composition and selectivity in a large bodied insect, the Auckland tree weta Hemideina thoracica, in three habitat zones in a lowland New Zealand forest. We asked whether H. thoracica selectively forage from available plant food sources, and whether these choices were lipid-rich compared to nonpreferred available plants. We also identified the proportion of invertebrates in their frass as a proxy for omnivory. From reconnaissance plot sampling, together with fecal fragment analysis, we report that more than 93% of individual tree weta had eaten invertebrates before capture. Additionally, weta in the highest elevation hillslope habitat zone consumed significantly fewer species of plants on average than weta on the low-elevation terrace habitat. Upper hillslope weta also had the highest average number of invertebrate fragments in their frass, significantly more than weta in the low-elevation terrace habitat zone. Weta showed high variability in the consumption of fruit and seeds across all habitat zones. Generally, we did not observe diet differences between the sexes (although it appears that male weta in the mid hillslope habitat ate fruits and seeds more voraciously than females), suggesting that the sexes have similar niche breadths and display similar degrees of omnivorous behavior. Extraction of leaf lipids demonstrated a range of lipid content values in available plants, and Ivlev's Electivity Index indicated that plant species which demonstrated high electivity tended to have higher concentrations of lipids in their leaves. Our findings indicate that H. thoracica forage omnivorously and selectively, and hence play multiple roles in native ecosystems and food webs. PMID- 29531671 TI - Microgeographic morphological variation across larval wood frog populations associated with environment despite gene flow. AB - Gene flow has historically been thought to constrain local adaptation; yet, recent research suggests that populations can diverge despite exchanging genes. Here I use a common garden experiment to assess the combined effects of gene flow and natural selection on morphological variation of 16 wood frog (Rana sylvatica) populations, a species known to experience divergent selection pressures in open- and closed-canopy ponds across relatively small geographic scales. Wood frog tadpoles from different ponds showed significant morphological variation associated with canopy type with a trade-off between tail length and body depth consistent with previous research. In contrast, neutral genetic differentiation of nine microsatellite loci as measured by Jost's D was not associated with canopy type, indicating no pattern of isolation by environment. Genetic structure analyses indicated some substructure across the 16 ponds (K = 4); however, three out of four assigned clusters included both open- and closed-canopy ponds. Together, these results suggest that morphological divergence among these wood frog populations is occurring despite gene flow and that selection within these environments is strong. Furthermore, morphological variation among ponds differed across two sampling periods during larval development, demonstrating the importance of evaluating phenotypic divergence over multiple time periods and at a time relevant to the processes being studied. PMID- 29531672 TI - Effects of vulture exclusion on carrion consumption by facultative scavengers. AB - Vultures provide an essential ecosystem service through removal of carrion, but globally, many populations are collapsing and several species are threatened with extinction. Widespread declines in vulture populations could increase the availability of carrion to other organisms, but the ways facultative scavengers might respond to this increase have not been thoroughly explored. We aimed to determine whether facultative scavengers increase carrion consumption in the absence of vulture competition and whether they are capable of functionally replacing vultures in the removal of carrion biomass from the landscape. We experimentally excluded 65 rabbit carcasses from vultures during daylight hours and placed an additional 65 carcasses that were accessible to vultures in forested habitat in South Carolina, USA during summer (June-August). We used motion-activated cameras to compare carrion use by facultative scavenging species between the experimental and control carcasses. Scavenging by facultative scavengers did not increase in the absence of competition with vultures. We found no difference in scavenger presence between control carcasses and those from which vultures were excluded. Eighty percent of carcasses from which vultures were excluded were not scavenged by vertebrates, compared to 5% of carcasses that were accessible to vultures. At the end of the 7-day trials, there was a 10.1 fold increase in the number of experimental carcasses that were not fully scavenged compared to controls. Facultative scavengers did not functionally replace vultures during summer in our study. This finding may have been influenced by the time of the year in which the study took place, the duration of the trials, and the spacing of carcass sites. Our results suggest that under the warm and humid conditions of our study, facultative scavengers would not compensate for loss of vultures. Carcasses would persist longer in the environment and consumption of carrion would likely shift from vertebrates to decomposers. Such changes could have substantial implications for disease transmission, nutrient cycling, and ecosystem functioning. PMID- 29531673 TI - Strong indication of an extinction-based saturation of the flora on the Pacific Robinson Crusoe Islands. AB - Oceanic islands are vulnerable ecosystems and their flora has been under pressure since the arrival of the first humans. Human activities and both deliberately and inadvertently introduced biota have had and continue to have a severe impact on island endemic plants. The number of alien plants has increased nearly linearly on many islands, perhaps resulting in extinction-based saturation of island floras. Here, we provide evidence for such a scenario in Alejandro Selkirk, Robinson Crusoe Islands (Archipelago Juan Fernandez, Chile). We compared species richness and species composition of historical vegetation samples from 1917 with recent ones from 2011. Changes in species' relative occurrence frequency were related to their taxonomic affiliation, dispersal mode, distribution status, and humidity and temperature preferences. While total species richness of vascular plants remained relatively similar, species composition changed significantly. Plants endemic to the Robinson Crusoe Islands declined, exotic species increased substantially within the period of ca. 100 years. Further, the relative occurrence frequency of plants with preferences for very warm and humid climate decreased, while the opposite was found for plants preferring drier and colder environments. Potential drivers responsible for this dramatic shift in the vegetation within only one century might have been the large goat population affecting especially small populations of endemic plants and climatic changes. Taking into account a substantial extinction debt, we expect further shifts in the vegetation of this small oceanic island toward alien plants. This would have significant negative consequences on global biodiversity, considering that island floras contribute substantially to global plant species richness due to their high proportion of endemics. PMID- 29531674 TI - Urbanization disrupts latitude-size rule in 17-year cicadas. AB - Many ectotherms show a decrease in body size with increasing latitude due to changes in climate, a pattern termed converse Bergmann's rule. Urban conditions particularly warmer temperatures and fragmented landscapes-may impose stresses on development that could disrupt these body size patterns. To test the impact of urbanization on development and latitudinal trends in body size, we launched a citizen science project to collect periodical cicadas (Magicicada septendecim) from across their latitudinal range during the 2013 emergence of Brood II. Periodical cicadas are long-lived insects whose distribution spans a broad latitudinal range covering both urban and rural habitats. We used a geometric morphometric approach to assess body size and developmental stress based on fluctuating asymmetry in wing shape. Body size of rural cicadas followed converse Bergmann's rule, but this pattern was disrupted in urban habitats. In the north, urban cicadas were larger than their rural counterparts, while southern populations showed little variation in body size between habitats. We detected no evidence of differences in developmental stress due to urbanization. To our knowledge, this is the first evidence that urbanization disrupts biogeographical trends in body size, and this pattern highlights how the effects of urbanization may differ over a species' range. PMID- 29531675 TI - Macroinvertebrate identity mediates the effects of litter quality and microbial conditioning on leaf litter recycling in temperate streams. AB - Plant litter decomposition is an essential ecosystem function that contributes to carbon and nutrient cycling in streams. Aquatic shredders, mainly macroinvertebrates, can affect this process in various ways; they consume leaf litter, breaking it down into fragments and creating suitable habitats or resources for other organisms through the production of fine particulate organic matter (FPOM). However, measures of litter-feeding traits across a wide range of aquatic macroinvertebrates are still rare. Here, we assessed the contributions of 11 species of freshwater macroinvertebrates to litter decomposition, by measuring consumption rate, FPOM production, and assimilation rate of highly decomposable (Alnus glutinosa) or poorly decomposable (Quercus robur) leaf litter types. In general, an increase in the quality of litter improved the litter consumption rate, and fungal conditioning of the leaf litter increased both the litter consumption rate and FPOM production. Macroinvertebrates specializing in leaf litter consumption also appeared to be the most sensitive to shifts in litter quality and the conditioning process. Contrary to expectations, the conditioning process did not increase the assimilation of low-quality litter. There was a strong correlation between the relative consumption rate (RCR) of the two litter types, and the relative FPOM production (RFP) was strongly correlated to the RCR. These findings suggest a consistent relationship between RCR and macroinvertebrate identity that is not affected by litter quality, and that the RFP could be inferred from the RCR. The varying responses of the macroinvertebrate feeding traits to litter quality and the conditioning process suggest that the replacement of a shredder invertebrate species by another species could have major consequences for the decomposition process and the detritus-based food web in streams. Further studies onto the importance of invertebrate identity and the effects of litter quality in a variety of freshwater ecosystems are needed to understand the whole ecosystem functioning and to predict its response to environmental changes. PMID- 29531676 TI - Basic description and some notes on the evolution of seven sympatric morphs of Dolly Varden Salvelinus malma from the Lake Kronotskoe Basin. AB - The study examines the basic morphological and ecological features of Dolly Varden from Lake Kronotskoe (Russia, Kamchatka). Seven valid morphs different in head proportions, feeding, timing, and place of spawning have been determined in this ecosystem. The basic morphometric characteristics clearly separate Lake Kronotskoe morphs from each other, as well as from its potential ancestor (Dolly Varden). According to CVA analysis, the most notable morphological characteristics determining the mouth position are the length of a lower jaw and rostrum. Furthermore, five of seven morphs inhabit different depth zones of the lake and feed on different food resources. Our data suggest that reproductive isolation may be maintained by temporal/spatial isolation for two morphs with lacustrine spawning, and by spatial isolation only for the rest of the morphs with riverine spawning. The sympatric diversity of the Lake Kronotskoe charrs is exceptionally wide, and there are no other examples for seven sympatric morphs of genus Salvelinus to coexist within a single ecosystem. This study puts forward a three-step hypothetical model of charr divergence in Lake Kronotskoe as a potential ground for future studies. PMID- 29531677 TI - Aquatic and terrestrial morphotypes of the aquatic invasive plant, Ludwigia grandiflora, show distinct morphological and metabolomic responses. AB - In the context of expansion of invasive species, survival of invasive plants is conditioned by their ability to adapt. In France, the water primrose Ludwigia grandiflora, an aquatic invasive species, invades yet wet meadows, leading to a depreciation of their fodder value. Understanding its potential adaption is necessary to its management, strong differences between both morphotypes were expected. So morphological and metabolic responses to terrestrial environment were analyzed for aquatic and terrestrial morphotypes. All morphological and biomass variables were greater in the terrestrial morphotype than the aquatic morphotype, independent of conditions. In terrestrial condition, both morphotypes showed a high production of sugars in root tissues, especially in the terrestrial morphotype and both morphotypes produced a low level of amino acids in shoot tissues. All results demonstrate that the terrestrial condition seems a stressful situation for both morphotypes, which activates glycolysis and fermentation pathways to improve their survival under hypoxic stress. But, only the terrestrial morphotype has been able to adjust its metabolism and maintain efficient growth. In the future, a differential transcriptomic analysis will be carried out to confirm this result. PMID- 29531678 TI - How do similarities in spatial distributions and interspecific associations affect the coexistence of Quercus species in the Baotianman National Nature Reserve, Henan, China. AB - Congeneric species often have similar ecological characteristics and use similar resources. These similarities may make it easier for them to co-occur in a similar habitat but may also lead to strong competitions that limit their coexistence. Hence, how do similarities in congeneric species affect their coexistence exactly? This study mainly used spatial point pattern analysis in two 1 hm2 plots in the Baotianman National Nature Reserve, Henan, China, to compare the similarities in spatial distributions and interspecific associations of Quercus species. Results revealed that Quercus species were all aggregated under the complete spatial randomness null model, and aggregations were weaker under the heterogeneous Poisson process null model in each plot. The interspecific associations of Quercus species to non-Quercus species were very similar in Plot 1. However, they can be either positive or negative in different plots between the co-occurring Quercus species. The spatial distributions of congeneric species, interspecific associations with non-Quercus species, neighborhood richness around species, and species diversity were all different between the two plots. We found that congeneric species did have some similarities, and the closely related congeneric species can positive or negative associate with each other in different plots. The co-occurring congeneric species may have different survival strategies in different habitats. On the one hand, competition among congenerics may lead to differentiation in resource utilization. On the other hand, their similar interspecific associations can strengthen their competitive ability and promote local exclusion to noncongeneric species to obtain more living space. Our results provide new knowledge for us to better understand the coexistence mechanisms of species. PMID- 29531679 TI - Genetic and epigenetic variations associated with adaptation to heterogeneous habitat conditions in a deciduous shrub. AB - Environmentally induced phenotypic plasticity is thought to play an important role in the adaption of plant populations to heterogeneous habitat conditions, and yet the importance of epigenetic variation as a mechanism of adaptive plasticity in natural plant populations still merits further research. In this study, we investigated populations of Vitex negundo var. heterophylla (Chinese chastetree) from adjacent habitat types at seven sampling sites. Using several functional traits, we detected a significant differentiation between habitat types. With amplified fragment length polymorphisms (AFLP) and methylation sensitive AFLP (MSAP), we found relatively high levels of genetic and epigenetic diversity but very low genetic and epigenetic differences between habitats within sites. Bayesian clustering showed a remarkable habitat-related differentiation and more genetic loci associated with the habitat type than epigenetic, suggesting that the adaptation to the habitat is genetically based. However, we did not find any significant correlation between genetic or epigenetic variation and habitat using simple and partial Mantel tests. Moreover, we found no correlation between genetic and ecologically relevant phenotypic variation and a significant correlation between epigenetic and phenotypic variation. Although we did not find any direct relationship between epigenetic variation and habitat environment, our findings suggest that epigenetic variation may complement genetic variation as a source of functional phenotypic diversity associated with adaptation to the heterogeneous habitat in natural plant populations. PMID- 29531680 TI - Depressed hydraulic redistribution of roots more by stem refilling than by nocturnal transpiration for Populus euphratica Oliv. in situ measurement. AB - During the night, plant water loss can occur either through the roots, as hydraulic redistribution (HR), or through the leaves via the stoma, as nocturnal transpiration (En), which was methodologically difficult to separate from stem refilling (Re). While HR and En have been reported across a range of species, ecosystem, and climate zone, there is little understanding on the interactions between En and/or Re and HR. As water movement at night occurs via gradients of water potential, it is expected that during periods of high atmospheric vapor pressure deficit (VPD), water loss via En will override water loss via HR. To test this hypothesis, sap flow in stems and roots of Populus euphratica Oliv. trees, growing in a riparian zone in a hyperarid climate, was measured once in a year. Nocturnal stem sap flow was separated into En and Re using the "forecasted refilling" method. Substantial nocturnal sap flow (38% of 24-hr flux on average) was observed and positively correlated with VPD; however, the strength of the correlation was lower (R2 = .55) than diurnal sap flow (Ed) (R2 = .72), suggesting that nocturnal stem sap flow was attributed to both water loss through the canopy and replenishment of water in stem tissues. Partitioning of nocturnal sap flow shows that Re constituted approximately 80%, and En ~20%, of nocturnal sap flow. The amount of root sap flow attributed to redistribution was negatively related to Ed (R2 = .69) and the amount of acropetally sap flow in stems, Re (R2 = .41) and En (R2 = .14). It was suggested that the magnitude of HR is more strongly depressed by Re that was recharge to the water loss via Ed than by En. It was consistent with whole-tree water balance theory, that the nighttime upward sap flow to xylem, stem refilling and transpiration, may depress hydraulic redistribution of roots. PMID- 29531681 TI - Diversifying selection drives parallel evolution of gill raker number and body size along the speciation continuum of European whitefish. AB - Adaptive radiation is the evolution of ecological and phenotypical diversity. It arises via ecological opportunity that promotes the exploration of underutilized or novel niches mediating specialization and reproductive isolation. The assumed precondition for rapid local adaptation is diversifying natural selection, but random genetic drift could also be a major driver of this process. We used 27 populations of European whitefish (Coregonus lavaretus) from nine lakes distributed in three neighboring subarctic watercourses in northern Fennoscandia as a model to test the importance of random drift versus diversifying natural selection for parallel evolution of adaptive phenotypic traits. We contrasted variation for two key adaptive phenotypic traits correlated with resource utilization of polymorphic fish; the number of gill rakers and the total length of fish, with the posterior distribution of neutral genetic differentiation from 13 microsatellite loci, to test whether the observed phenotypic divergence could be achieved by random genetic drift alone. Our results show that both traits have been under diversifying selection and that the evolution of these morphs has been driven by isolation through habitat adaptations. We conclude that diversifying selection acting on gill raker number and body size has played a significant role in the ongoing adaptive radiation of European whitefish morphs in this region. PMID- 29531682 TI - Geographic range velocity and its association with phylogeny and life history traits in North American woody plants. AB - The geographic ranges of taxa change in response to environmental conditions. Yet whether rates of range movement (biotic velocities) are phylogenetically conserved is not well known. Phylogenetic conservatism of biotic velocities could reflect similarities among related lineages in climatic tolerances and dispersal associated traits. We assess whether late Quaternary biotic velocities were phylogenetically conserved and whether they correlate with climatic tolerances and dispersal-associated traits. We used phylogenetic regression and nonparametric correlation to evaluate associations between biotic velocities, dispersal-associated traits, and climatic tolerances for 28 woody plant genera and subgenera in North America. The velocities with which woody plant taxa shifted their core geographic range limits were positively correlated from time step to time step between 16 and 7 ka. The strength of this correlation weakened after 7 ka as the pace of climate change slowed. Dispersal-associated traits and climatic tolerances were not associated with biotic velocities. Although the biotic velocities of some genera were consistently fast and others consistently slow, biotic velocities were not phylogenetically conserved. The rapid late Quaternary range shifts of plants lacking traits that facilitate frequent long distance dispersal has long been noted (i.e., Reid's Paradox). Our results are consistent with this paradox and show that it remains robust when phylogenetic information is taken into account. The lack of association between biotic velocities, dispersal-associated traits, and climatic tolerances may reflect several, nonmutually exclusive processes, including rare long-distance dispersal, biotic interactions, and cryptic refugia. Because late Quaternary biotic velocities were decoupled from dispersal-associated traits, trait data for genera and subgenera cannot be used to predict longer-term (millennial-scale) floristic responses to climate change. PMID- 29531683 TI - Phylogeography and taxonomic status of trout and salmon from the Ponto-Caspian drainages, with inferences on European Brown Trout evolution and taxonomy. AB - Current taxonomy of western Eurasian trout leaves a number of questions open; it is not clear to what extent some species are distinct genetically and morphologically. The purpose of this paper was to explore phylogeography and species boundaries in freshwater and anadromous trout from the drainages of the Black and the Caspian Seas (Ponto-Caspian). We studied morphology and mitochondrial phylogeny, combining samples from the western Caucasus within the potential range of five nominal species of trout that are thought to inhabit this region, and using the sequences available from GenBank. Our results suggest that the genetic diversity of trout in the Ponto-Caspian region is best explained with the fragmentation of catchments. (1) All trout species from Ponto-Caspian belong to the same mitochondrial clade, separated from the other trout since the Pleistocene; (2) the southeastern Black Sea area is the most likely place of diversification of this clade, which is closely related to the clades from Anatolia; (3) The species from the Black Sea and the Caspian Sea drainages are monophyletic; (4) except for the basal lineage of the Ponto-Caspian clade, Salmo rizeensis, all the lineages produce anadromous forms; (5) genetic diversification within the Ponto-Caspian clade is related to Pleistocene glacial waves; (6) the described morphological differences between the species are not fully diagnostic, and some earlier described differences depend on body size; the differences between freshwater and marine forms exceed those between the different lineages. We suggest a conservative taxonomic approach, using the names S. rizeensis and Salmo labrax for trout from the Black Sea basin and Salmo caspius and Salmo ciscaucasicus for the fish from the Caspian basin. PMID- 29531684 TI - Repurposing environmental DNA samples-detecting the western pearlshell (Margaritifera falcata) as a proof of concept. AB - Information on the distribution of multiple species in a common landscape is fundamental to effective conservation and management. However, distribution data are expensive to obtain and often limited to high-profile species in a system. A recently developed technique, environmental DNA (eDNA) sampling, has been shown to be more sensitive than traditional detection methods for many aquatic species. A second and perhaps underappreciated benefit of eDNA sampling is that a sample originally collected to determine the presence of one species can be re-analyzed to detect additional taxa without additional field effort. We developed an eDNA assay for the western pearlshell mussel (Margaritifera falcata) and evaluated its effectiveness by analyzing previously collected eDNA samples that were annotated with information including sample location and deposited in a central repository. The eDNA samples were initially collected to determine habitat occupancy by nonbenthic fish species at sites that were in the vicinity of locations recently occupied by western pearlshell. These repurposed eDNA samples produced results congruent with historical western pearlshell surveys and permitted a more precise delineation of the extent of local populations. That a sampling protocol designed to detect fish was also successful for detecting a freshwater mussel suggests that rapidly accumulating collections of eDNA samples can be repurposed to enhance the efficiency and cost-effectiveness of aquatic biodiversity monitoring. PMID- 29531685 TI - Simulated eutrophication and browning alters zooplankton nutritional quality and determines juvenile fish growth and survival. AB - The first few months of life is the most vulnerable period for fish and their optimal hatching time with zooplankton prey is favored by natural selection. Traditionally, however, prey abundance (i.e., zooplankton density) has been considered important, whereas prey nutritional composition has been largely neglected in natural settings. High-quality zooplankton, rich in both essential amino acids (EAAs) and fatty acids (FAs), are required as starting prey to initiate development and fast juvenile growth. Prey quality is dependent on environmental conditions, and, for example, eutrophication and browning are two major factors defining primary producer community structures that will directly determine the nutritional quality of the basal food sources (algae, bacteria, terrestrial matter) for zooplankton. We experimentally tested how eutrophication and browning affect the growth and survival of juvenile rainbow trout (Oncorhynchus mykiss) by changing the quality of basal resources. We fed the fish on herbivorous zooplankton (Daphnia) grown with foods of different nutritional quality (algae, bacteria, terrestrial matter), and used GC-MS, stable isotope labeling as well as bulk and compound-specific stable isotope analyses for detecting the effects of different diets on the nutritional status of fish. The content of EAAs and omega-3 (omega-3) polyunsaturated FAs (PUFAs) in basal foods and zooplankton decreased in both eutrophication and browning treatments. The decrease in omega-3 PUFA and especially docosahexaenoic acid (DHA) was reflected to fish juveniles, but they were able to compensate for low availability of EAAs in their food. Therefore, the reduced growth and survival of the juvenile fish was linked to the low availability of DHA. Fish showed very low ability to convert alpha-linolenic acid (ALA) to DHA. We conclude that eutrophication and browning decrease the availability of the originally phytoplankton-derived DHA for zooplankton and juvenile fish, suggesting bottom-up regulation of food web quality. PMID- 29531686 TI - Contrasting geographic structure in evolutionarily divergent Lake Tanganyika catfishes. AB - Geographic isolation is suggested to be among the most important processes in the generation of cichlid fish diversity in East Africa's Great Lakes, both through isolation by distance and fluctuating connectivity caused by changing lake levels. However, even broad scale phylogeographic patterns are currently unknown in many non-cichlid littoral taxa from these systems. To begin to address this, we generated restriction-site-associated DNA sequence (RADseq) data to investigate phylogeographic structure throughout Lake Tanganyika (LT) in two broadly sympatric rocky shore catfish species from independent evolutionary radiations with differing behaviors: the mouthbrooding claroteine, Lophiobagrus cyclurus, and the brood-parasite mochokid, Synodontis multipunctatus. Our results indicated contrasting patterns between these species, with strong lake-wide phylogeographic signal in L. cyclurus including a deep divergence between the northern and southern lake basins. Further structuring of these populations was observed across a heterogeneous habitat over much smaller distances. Strong population growth was observed in L. cyclurus sampled from shallow shorelines, suggesting population growth associated with the colonization of new habitats following lake-level rises. Conversely, S. multipunctatus, which occupies a broader depth range, showed little phylogeographic structure and lower rates of population growth. Our findings suggest that isolation by distance and/or habitat barriers may play a role in the divergence of non-cichlid fishes in LT, but this effect varies by species. PMID- 29531687 TI - The fitness effects of delayed switching to sex in a facultatively asexual insect. AB - Facultative reproductive strategies that incorporate both sexual and parthenogenetic reproduction should be optimal, yet are rarely observed in animals. Resolving this paradox requires an understanding of the economics of facultative asexuality. Recent work suggests that switching from parthenogenesis to sex can be costly and that females can resist mating to avoid switching. However, it remains unclear whether these costs and resistance behaviors are dependent on female age. We addressed these questions in the Cyclone Larry stick insect, Sipyloidea larryi, by pairing females with males (or with females as a control) in early life prior to the start of parthenogenetic reproduction, or in mid- or late life after a period of parthenogenetic oviposition. Young females were receptive to mating even though mating in early life caused reduced fecundity. Female resistance to mating increased with age, but reproductive switching in mid- or late life did not negatively affect female survival or offspring performance. Overall, mating enhanced female fitness because fertilized eggs had higher hatching success and resulted in more adult offspring than parthenogenetic eggs. However, female fecundity and offspring viability were also enhanced in females paired with other females, suggesting a socially mediated maternal effect. Our results provide little evidence that switching from parthenogenesis to sex at any age is costly for S. larryi females. However, age dependent effects of switching on some fitness components and female resistance behaviors suggest the possibility of context-dependent effects that may only be apparent in natural populations. PMID- 29531688 TI - A taxonomic, functional, and phylogenetic perspective on the community assembly of passerine birds along an elevational gradient in southwest China. AB - Integrating multiple facets of biodiversity to describe spatial and temporal distribution patterns is one way of revealing the mechanisms driving community assembly. We assessed the species, functional, and phylogenetic composition and structure of passerine bird communities along an elevational gradient both in wintering and breeding seasons in the Ailao Mountains, southwest China, in order to identify the dominant ecological processes structuring the communities and how these processes change with elevation and season. Our research confirms that the highest taxonomic diversity, and distinct community composition, was found in the moist evergreen broadleaf forest at high elevation in both seasons. Environmental filtering was the dominant force at high elevations with relatively cold and wet climatic conditions, while the observed value of mean pairwise functional and phylogenetic distances of low elevation was constantly higher than expectation in two seasons, suggested interspecific competition could play the key role at low elevations, perhaps because of relative rich resource result from complex vegetation structure and human-induced disturbance. Across all elevations, there was a trend of decreasing intensity of environmental filtering whereas increasing interspecific competition from wintering season to breeding season. This was likely due to the increased resource availability but reproduction-associated competition in the summer months. In general, there is a clear justification for conservation efforts to protect entire elevational gradients in the Ailao Mountains, given the distinct taxonomic, functional, and phylogenetic compositions and also elevational migration pattern in passerine bird communities. PMID- 29531689 TI - A hidden cost of migration? Innate immune function versus antioxidant defense. AB - Migration is energetically demanding and physiologically challenging. Migrating birds, for example, need to boost their antioxidant defenses to defeat the pro oxidants produced during high energetic activity. The enhanced antioxidant defense possibly withdraws limited resources (e.g., energy or micronutrients) from other physiological functions, such as immune defense. Such a trade-off might not occur outside the migration seasons or in resident individuals. Here, we investigate whether there is a negative relationship between innate immune function and antioxidant defense by sampling both migrating and resident blackbirds (Turdus merula) at the same location during the same period of the annual cycle. We show that in migrating blackbirds microbial killing capacity (BKA), an integrative measure of baseline innate immune function was negatively correlated with total nonenzymatic antioxidant capacity. In contrast, in resident conspecifics, sampled at the same time and location, these two physiological measures were not correlated. This suggests that migrating birds trade off innate immune function and antioxidant defense. Furthermore, and likely a consequence of this trade-off, in migrant blackbirds BKA was positively correlated with oxidative damage to lipids. In resident blackbirds BKA and degree of lipid oxidation were uncorrelated. The mechanism and currencies of the supposed trade off are currently unknown, but energetic investments or micronutrients are likely candidates. Future experimental studies could provide more conclusive evidence for this trade-off; yet, our results open up a new level of thinking about the physiological costs of migration. PMID- 29531690 TI - Life histories and ecotype conservation in an adaptive vertebrate: Genetic constitution of piscivorous brown trout covaries with habitat stability. AB - Ecotype variation in species exhibiting different life history strategies may reflect heritable adaptations to optimize reproductive success, and potential for speciation. Traditionally, ecotypes have, however, been defined by morphometrics and life history characteristics, which may be confounded with individual plasticity. Here, we use the widely distributed and polytypic freshwater fish species brown trout (Salmo trutta) as a model to study piscivorous life history and its genetic characteristics in environmentally contrasting habitats; a large lake ecosystem with one major large and stable tributary, and several small tributaries. Data from 550 fish and 13 polymorphic microsatellites (He = 0.67) indicated ecotype-specific genetic differentiation (theta = 0.0170, p < .0001) among Bayesian assigned small riverine resident and large, lake migrating brown trout (>35 cm), but only in the large tributary. In contrast, large trout did not constitute a distinct genetic group in small tributaries, or across riverine sites. Whereas life history data suggest a small, river resident and a large migratory piscivorous ecotype in all studied tributaries, genetic data indicated that a genetically distinct piscivorous ecotype is more likely to evolve in the large and relatively more stable river habitat. In the smaller tributaries, ecotypes apparently resulted from individual plasticity. Whether different life histories and ecotypes result from individual plasticity or define different genetic types, have important consequence for conservation strategies. PMID- 29531691 TI - Volatility in the effective size of a freshwater gastropod population. AB - Despite the utility of gastropod models for the study of evolutionary processes of great generality and importance, their effective population size has rarely been estimated in the field. Here, we report allele frequency variance at three allozyme-encoding loci monitored over 7 years in a population of the invasive freshwater pulmonate snail Physa acuta (Draparnaud 1805), estimating effective population size with both single-sample and two-sample approaches. Estimated Ne declined from effectively infinite in 2009 to approximately 40-50 in 2012 and then rose back to infinity in 2015, corresponding to a striking fluctuation in the apparent census size of the population. Such volatility in Ne may reflect cryptic population subdivision. PMID- 29531692 TI - Stable isotopes document the winter foraging ecology of king penguins and highlight connectivity between subantarctic and Antarctic ecosystems. AB - The poorly known winter foraging ecology of the king penguin, a major Southern Ocean consumer, was investigated at the subantarctic Crozet Islands where the largest global population breeds. Blood delta13C and delta15N values were used as proxies of the birds' foraging habitat and diet, respectively, and circulating prolactin levels helped in determining the birds' reproductive status. Plasma prolactin concentrations showed that king penguin adults of unknown breeding status (n = 52) that were present at the colony in winter were in fact breeders and failed breeders, but were not non -breeders. Circulating prolactin was neither related to delta13C nor delta15N values, thus suggesting that both breeders and failed breeders used the same foraging habitats and fed on the same prey. Plasma and blood cell isotopic values depicted four new relevant biological features on the feeding strategies of king penguins during the critical winter period: (1) 42% of the birds foraged in the distant Antarctic Zone, but 58% fed primarily in subantarctic waters (delta13C), (2) they preyed upon myctophids in both zones (delta15N), (3) individuals were consistent in their foraging strategies over the winter months (delta13C and delta15N), and (4) a higher proportion of females (77%-80%) than males (27%-31%) favored feeding in distant Antarctic waters (delta13C). This study highlights trophic connectivity between subantarctic and Antarctic ecosystems and hence the key role of energy export from Antarctic waters to sustain breeding populations of subantarctic predators, including during the Austral winter. PMID- 29531693 TI - Influence of northern limit range on genetic diversity and structure in a widespread North American tree, sugar maple (Acer saccharum Marshall). AB - Due to climate change, the ranges of many North American tree species are expected to shift northward. Sugar maple (Acer saccharum Marshall) reaches its northern continuous distributional limit in northeastern North America at the transition between boreal mixed-wood and temperate deciduous forests. We hypothesized that marginal fragmented northern populations from the boreal mixed wood would have a distinct pattern of genetic structure and diversity. We analyzed variation at 18 microsatellite loci from 23 populations distributed along three latitudinal transects (west, central, and east) that encompass the continuous-discontinuous species range. Each transect was divided into two zones, continuous (temperate deciduous) and discontinuous (boreal mixed wood), based on sugar maple stand abundance. Respective positive and negative relationships were found between the distance of each population to the northern limit (D_north), and allelic richness (AR) and population differentiation (FST). These relations were tested for each transect separately; the pattern (discontinuous-continuous) remained significant only for the western transect. structure analysis revealed the presence of four clusters. The most northern populations of each transect were assigned to a distinct group. Asymmetrical gene flow occurred from the southern into the four northernmost populations. Southern populations in Quebec may have originated from two different postglacial migration routes. No evidence was found to validate the hypothesis that northern populations were remnants of a larger population that had migrated further north of the species range after the retreat of the ice sheet. The northernmost sugar maple populations possibly originated from long-distance dispersal. PMID- 29531694 TI - Usnic acid, as a biotic factor, changes the ploidy level in mosses. AB - Lichens and mosses often share the same environmental conditions where they compete for substrate and other essential factors. Lichens use secondary metabolites as allelochemicals to repel surrounding plants and potential rivals. In mosses, endoreduplication leads to the occurrence of various ploidy levels in the same individual and has been suggested as an adaptation to abiotic stresses. Here, we show that also biotic factors such as usnic acid, an allelochemical produced by lichens, directly influenced the level of ploidy in mosses. Application of usnic acid changed the nuclei proportion and significantly enhanced the endoreduplication index in two moss species, Physcomitrella patens and Pohlia drummondii. These investigations add a new aspect on secondary metabolites of lichens which count as biotic factors and affect ploidy levels in mosses. PMID- 29531695 TI - Characterizing habitat suitability for a central-place forager in a dynamic marine environment. AB - Characterizing habitat suitability for a marine predator requires an understanding of the environmental heterogeneity and variability over the range in which a population moves during a particular life cycle. Female California sea lions (Zalophus californianus) are central-place foragers and are particularly constrained while provisioning their young. During this time, habitat selection is a function of prey availability and proximity to the rookery, which has important implications for reproductive and population success. We explore how lactating females may select habitat and respond to environmental variability over broad spatial and temporal scales within the California Current System. We combine near-real-time remotely sensed satellite oceanography, animal tracking data (n = 72) from November to February over multiple years (2003-2009) and Generalized Additive Mixed Models (GAMMs) to determine the probability of sea lion occurrence based on environmental covariates. Results indicate that sea lion presence is associated with cool (<14 degrees C), productive waters, shallow depths, increased eddy activity, and positive sea-level anomalies. Predictive habitat maps generated from these biophysical associations suggest winter foraging areas are spatially consistent in the nearshore and offshore environments, except during the 2004-2005 winter, which coincided with an El Nino event. Here, we show how a species distribution model can provide broadscale information on the distribution of female California sea lions during an important life history stage and its implications for population dynamics and spatial management. PMID- 29531696 TI - Untangling climate and water chemistry to predict changes in freshwater macrophyte distributions. AB - Forecasting changes in the distributions of macrophytes is essential to understanding how aquatic ecosystems will respond to climate and environmental changes. Previous work in aquatic ecosystems has used climate data at large scales and chemistry data at small scales; the consequence of using these different data types has not been evaluated. This study combines a survey of macrophyte diversity and water chemistry measurements at a large regional scale to demonstrate the feasibility and necessity of including ecological measurements, in addition to climate data, in species distribution models of aquatic macrophytes. A survey of 740 water bodies stratified across 327,000 square kilometers was conducted to document Characeae (green macroalgae) species occurrence and water chemistry data. Chemistry variables and climate data were used separately and in concert to develop species distribution models for ten species across the study area. The impacts of future environmental changes on species distributions were modeled using a range of global climate models (GCMs), representative concentration pathways (RCPs), and pollution scenarios. Models developed with chemistry variables generally gave the most accurate predictions of species distributions when compared with those using climate variables. Calcium and conductivity had the highest total relative contribution to models across all species. Habitat changes were most pronounced in scenarios with increased road salt and deicer influences, with two species predicted to increase in range by >50% and four species predicted to decrease in range by >50%. Species of Characeae have distinct habitat ranges that closely follow spatial patterns of water chemistry. Species distribution models built with climate data alone were insufficient to predict changes in distributions in the study area. The development and implementation of standardized, large-scale water chemistry databases will aid predictions of habitat changes for aquatic ecosystems. PMID- 29531697 TI - Spatial correlations between browsing on balsam fir by white-tailed deer and the nutritional value of neighboring winter forage. AB - Associational effects, that is, the influence of neighboring plants on herbivory suffered by a plant, are an outcome of forage selection. Although forage selection is a hierarchical process, few studies have investigated associational effects at multiple spatial scales. Because the nutritional quality of plants can be spatially structured, it might differently influence associational effects across multiple scales. Our objective was to determine the radius of influence of neighbor density and nutritional quality on balsam fir (Abies balsamea) herbivory by white-tailed deer (Odocoileus virginianus) in winter. We quantified browsing rates on fir and the density and quality of neighboring trees in a series of 10 year-old cutovers on Anticosti Island (Canada). We used cross-correlations to investigate relationships between browsing rates and the density and nutritional quality of neighboring trees at distances up to 1,000 m. Balsam fir and white spruce (Picea glauca) fiber content and dry matter in vitro true digestibility were correlated with fir browsing rate at the finest extra-patch scale (across distance of up to 50 m) and between cutover areas (300-400 m). These correlations suggest associational effects, that is, low nutritional quality of neighbors reduces the likelihood of fir herbivory (associational defense). Our results may indicate associational effects mediated by intraspecific variation in plant quality and suggest that these effects could occur at scales from tens to hundreds of meters. Understanding associational effects could inform strategies for restoration or conservation; for example, planting of fir among existing natural regeneration could be concentrated in areas of low nutritional quality. PMID- 29531698 TI - Oceanographic variation influences spatial genomic structure in the sea scallop, Placopecten magellanicus. AB - Environmental factors can influence diversity and population structure in marine species and accurate understanding of this influence can both improve fisheries management and help predict responses to environmental change. We used 7163 SNPs derived from restriction site-associated DNA sequencing genotyped in 245 individuals of the economically important sea scallop, Placopecten magellanicus, to evaluate the correlations between oceanographic variation and a previously identified latitudinal genomic cline. Sea scallops span a broad latitudinal area (>10 degrees), and we hypothesized that climatic variation significantly drives clinal trends in allele frequency. Using a large environmental dataset, including temperature, salinity, chlorophyll a, and nutrient concentrations, we identified a suite of SNPs (285-621, depending on analysis and environmental dataset) potentially under selection through correlations with environmental variation. Principal components analysis of different outlier SNPs and environmental datasets revealed similar northern and southern clusters, with significant associations between the first axes of each (R2adj = .66-.79). Multivariate redundancy analysis of outlier SNPs and the environmental principal components indicated that environmental factors explained more than 32% of the variance. Similarly, multiple linear regressions and random-forest analysis identified winter average and minimum ocean temperatures as significant parameters in the link between genetic and environmental variation. This work indicates that oceanographic variation is associated with the observed genomic cline in this species and that seasonal periods of extreme cold may restrict gene flow along a latitudinal gradient in this marine benthic bivalve. Incorporating this finding into management may improve accuracy of management strategies and future predictions. PMID- 29531699 TI - Nutritional geometry and fitness consequences in Drosophila suzukii, the Spotted Wing Drosophila. AB - Since its arrival to North America less than a decade ago, the invasive Spotted Wing Drosophila (Drosophila suzukii) has inflicted substantial economic losses on soft fruit agriculture due to its ability to oviposit into ripening fruits. More effective management approaches for this species are needed, but little is known about the factors that influence behavioral choices made by D. suzukii when selecting hosts, or the consequences that their offspring experience when developing in different environments. Using a nutritional geometry methodology, we found that the ratio of proteins-to-carbohydrates (P:C) present in media greatly influenced adult D. suzukii behavior and subsequent offspring development. Whereas adult flies showed a strong bias in their oviposition and association behaviors toward carbohydrate-rich foods, larval survival and eclosion rate were strongly dependent on protein availability. Here, we explore the preference-performance hypothesis (PPH), in which females are predicted to oviposit on medias that provide the greatest offspring benefits, in regard to its relevance in D. suzukii behavior and consequences for management. Our results provide valuable insight into the ecology and evolution of this species that may hopefully lead to more effective management strategies. PMID- 29531700 TI - Rapid sexual and genomic isolation in sympatric Drosophila without reproductive character displacement. AB - The rapid evolution of sexual isolation in sympatry has long been associated with reinforcement (i.e., selection to avoid maladaptive hybridization). However, there are many species pairs in sympatry that have evolved rapid sexual isolation without known costs to hybridization. A major unresolved question is what evolutionary processes are involved in driving rapid speciation in such cases. Here, we focus on one such system; the Drosophila athabasca species complex, which is composed of three partially sympatric and interfertile semispecies: WN, EA, and EB. To study speciation in this species complex, we assayed sexual and genomic isolation within and between these semispecies in both sympatric and allopatric populations. First, we found no evidence of reproductive character displacement (RCD) in sympatric zones compared to distant allopatry. Instead, semispecies were virtually completely sexually isolated from each other across their entire ranges. Moreover, using spatial approaches and coalescent demographic simulations, we detected either zero or only weak heterospecific gene flow in sympatry. In contrast, within each semispecies we found only random mating and little population genetic structure, except between highly geographically distant populations. Finally, we determined that speciation in this system is at least an order of magnitude older than previously assumed, with WN diverging first, around 200K years ago, and EA and EB diverging 100K years ago. In total, these results suggest that these semispecies should be given full species status and we adopt new nomenclature: WN-D. athabasca, EA-D. mahican, and EB-D. lenape. While the lack of RCD in sympatry and interfertility do not support reinforcement, we discuss what additional evidence is needed to further decipher the mechanisms that caused rapid speciation in this species complex. PMID- 29531701 TI - Direct effects of warming increase woody plant abundance in a subarctic wetland. AB - Both the direct effects of warming on a species' vital rates and indirect effects of warming caused by interactions with neighboring species can influence plant populations. Furthermore, herbivory mediates the effects of warming on plant community composition in many systems. Thus, determining the importance of direct and indirect effects of warming, while considering the role of herbivory, can help predict long-term plant community dynamics. We conducted a field experiment in the coastal wetlands of western Alaska to investigate how warming and herbivory influence the interactions and abundances of two common plant species, a sedge, Carex ramenskii, and a dwarf shrub, Salix ovalifolia. We used results from the experiment to model the equilibrium abundances of the species under different warming and grazing scenarios and to determine the contribution of direct and indirect effects to predict population changes. Consistent with the current composition of the landscape, model predictions suggest that Carex is more abundant than Salix under ambient temperatures with grazing (53% and 27% cover, respectively). However, with warming and grazing, Salix becomes more abundant than Carex (57% and 41% cover, respectively), reflecting both a negative response of Carex and a positive response of Salix to warming. While grazing reduced the cover of both species, herbivory did not prevent a shift in dominance from sedges to the dwarf shrub. Direct effects of climate change explained about 97% of the total predicted change in species cover, whereas indirect effects explained only 3% of the predicted change. Thus, indirect effects, mediated by interactions between Carex and Salix, were negligible, likely due to use of different niches and weak interspecific interactions. Results suggest that a 2 degrees C increase could cause a shift in dominance from sedges to woody plants on the coast of western Alaska over decadal timescales, and this shift was largely a result of the direct effects of warming. Models predict this shift with or without goose herbivory. Our results are consistent with other studies showing an increase in woody plant abundance in the Arctic and suggest that shifts in plant-plant interactions are not driving this change. PMID- 29531702 TI - Spatial patterns of the frog Oophaga pumilio in a plantation system are consistent with conspecific attraction. AB - The conspecific attraction hypothesis predicts that individuals are attracted to conspecifics because conspecifics may be cues to quality habitat and/or colonists may benefit from living in aggregations. Poison frogs (Dendrobatidae) are aposematic, territorial, and visually oriented-three characteristics which make dendrobatids an appropriate model to test for conspecific attraction. In this study, we tested this hypothesis using an extensive mark-recapture dataset of the strawberry poison frog (Oophaga pumilio) from La Selva Biological Station, Costa Rica. Data were collected from replicate populations in a relatively homogenous Theobroma cacao plantation, which provided a unique opportunity to test how conspecifics influence the spatial ecology of migrants in a controlled habitat with homogenous structure. We predicted that (1) individuals entering a population would aggregate with resident adults, (2) migrants would share sites with residents at a greater frequency than expected by chance, and (3) migrant home ranges would have shorter nearest-neighbor distances (NND) to residents than expected by chance. The results were consistent with these three predictions: Relative to random simulations, we observed significant aggregation, home-range overlap, and NND distribution functions in four, five, and six, respectively, of the six migrant-resident groups analyzed. Conspecific attraction may benefit migrant O. pumilio by providing cues to suitable home sites and/or increasing the potential for social interactions with conspecifics; if true, these benefits should outweigh the negative effects of other factors associated with aggregation. The observed aggregation between migrant and resident O. pumilio is consistent with conspecific attraction in dendrobatid frogs, and our study provides rare support from a field setting that conspecific attraction may be a relevant mechanism for models of anuran spatial ecology. PMID- 29531703 TI - Chloroplastic and nuclear diversity of wild beets at a large geographical scale: Insights into the evolutionary history of the Beta section. AB - Historical demographic processes and mating systems are believed to be major factors in the shaping of the intraspecies genetic diversity of plants. Among Caryophyllales, the Beta section of the genus Beta, within the Amaranthaceae/Chenopodiaceae alliance, is an interesting study model with species and subspecies (Beta macrocarpa, Beta patula, Beta vulgaris maritima and B.v. adanensis) differing in geographical distribution and mating system. In addition, one of the species, B. macrocarpa, mainly diploid, varies in its level of ploidy with a tetraploid cytotype described in the Canary Islands and in Portugal. In this study, we analyzed the nucleotide diversity of chloroplastic and nuclear sequences on a representative sampling of species and subspecies of the Beta section (except B. patula). Our objectives were (1) to assess their genetic relationships through phylogenetic and multivariate analyses, (2) relate their genetic diversity to their mating system, and (3) reconsider the ploidy status and the origin of the Canarian Beta macrocarpa. PMID- 29531704 TI - Adaptation to fluctuations in temperature by nine species of bacteria. AB - Rapid environmental fluctuations are ubiquitous in the wild, yet majority of experimental studies mostly consider effects of slow fluctuations on organism. To test the evolutionary consequences of fast fluctuations, we conducted nine independent experimental evolution experiments with bacteria. Experimental conditions were same for all species, and we allowed them to evolve either in fluctuating temperature alternating rapidly between 20 degrees C and 40 degrees C or at constant 30 degrees C temperature. After experimental evolution, we tested the performance of the clones in both rapid fluctuation and in constant environments (20 degrees C, 30 degrees C and 40 degrees C). Results from experiments on these nine species were combined meta-analytically. We found that overall the clones evolved in the fluctuating environment had evolved better efficiency in tolerating fluctuations (i.e., they had higher yield in fluctuating conditions) than the clones evolved in the constant environment. However, we did not find any evidence that fluctuation-adapted clones would have evolved better tolerance to any measured constant environments (20 degrees C, 30 degrees C, and 40 degrees C). Our results back up recent empirical findings reporting that it is hard to predict adaptations to fast fluctuations using tolerance curves. PMID- 29531705 TI - Studies of modern Italian dog populations reveal multiple patterns for domestic breed evolution. AB - Through thousands of years of breeding and strong human selection, the dog (Canis lupus familiaris) exists today within hundreds of closed populations throughout the world, each with defined phenotypes. A singular geographic region with broad diversity in dog breeds presents an interesting opportunity to observe potential mechanisms of breed formation. Italy claims 14 internationally recognized dog breeds, with numerous additional local varieties. To determine the relationship among Italian dog populations, we integrated genetic data from 263 dogs representing 23 closed dog populations from Italy, seven Apennine gray wolves, and an established dataset of 161 globally recognized dog breeds, applying multiple genetic methods to characterize the modes by which breeds are formed within a single geographic region. Our consideration of each of five genetic analyses reveals a series of development events that mirror historical modes of breed formation, but with variations unique to the codevelopment of early dog and human populations. Using 142,840 genome-wide SNPs and a dataset of 1,609 canines, representing 182 breeds and 16 wild canids, we identified breed development routes for the Italian breeds that included divergence from common populations for a specific purpose, admixture of regional stock with that from other regions, and isolated selection of local stock with specific attributes. PMID- 29531706 TI - The genomic and ecological context of hybridization affects the probability that symmetrical incompatibilities drive hybrid speciation. AB - Despite examples of homoploid hybrid species, theoretical work describing when, where, and how we expect homoploid hybrid speciation to occur remains relatively rare. Here, I explore the probability of homoploid hybrid speciation due to "symmetrical incompatibilities" under different selective and genetic scenarios. Through simulation, I test how genetic architecture and selection acting on traits that do not themselves generate incompatibilities interact to affect the probability that hybrids evolve symmetrical incompatibilities with their parent species. Unsurprisingly, selection against admixture at "adaptive" loci that are linked to loci that generate incompatibilities tends to reduce the probability of evolving symmetrical incompatibilities. By contrast, selection that favors admixed genotypes at adaptive loci can promote the evolution of symmetrical incompatibilities. The magnitude of these outcomes is affected by the strength of selection, aspects of genetic architecture such as linkage relationships and the linear arrangement of loci along a chromosome, and the amount of hybridization following the formation of a hybrid zone. These results highlight how understanding the nature of selection, aspects of the genetics of traits affecting fitness, and the strength of reproductive isolation between hybridizing taxa can all be used to inform when we expect to observe homoploid hybrid speciation due to symmetrical incompatibilities. PMID- 29531707 TI - Environmental consequences of deltamethrin residues in cattle feces in an African agricultural landscape. AB - Pyrethroid insecticides are widely used to control ectoparasites of livestock, particularly ticks and biting flies. Their use in African livestock systems is increasing, driven by the need to increase productivity and local food security. However, insecticide residues present in the dung after treatment are toxic to dung-inhabiting insects. In a semiarid agricultural habitat in Botswana, dung beetle adult mortality, brood ball production, and larval survival were compared between untreated cattle dung and cattle dung spiked with deltamethrin, to give concentrations of 0.01, 0.1, 0.5, or 1 ppm. Cattle dung-baited pitfall traps were used to measure repellent effects of deltamethrin in dung on Scarabaeidae. Dung decomposition rate was also examined. There was significantly increased mortality of adult dung beetles colonizing pats that contained deltamethrin compared to insecticide-free pats. Brood ball production was significantly reduced at concentrations of 1 ppm; larval survival was significantly reduced in dung containing 0.1 ppm deltamethrin and above. There was no difference in the number of Scarabaeidae attracted to dung containing any of the deltamethrin concentrations. Dung decomposition was significantly reduced even at the lowest concentration (0.01 ppm) compared to insecticide-free dung. The widespread use of deltamethrin in African agricultural ecosystems is a significant cause for concern; sustained use is likely to damage dung beetle populations and their provision of environmentally and economically important ecosystem services. Contaminated dung buried by paracoprid (tunneling) beetles may retain insecticidal effects, with impacts on developing larvae below ground. Lethal and sublethal effects on entire dung beetle (Scarabaeidae) communities could impair ecosystem function in agricultural landscapes. PMID- 29531708 TI - Hydrological and environmental variables outperform spatial factors in structuring species, trait composition, and beta diversity of pelagic algae. AB - There has been increasing interest in algae-based bioassessment, particularly, trait-based approaches are increasingly suggested. However, the main drivers, especially the contribution of hydrological variables, of species composition, trait composition, and beta diversity of algae communities are less studied. To link species and trait composition to multiple factors (i.e., hydrological variables, local environmental variables, and spatial factors) that potentially control species occurrence/abundance and to determine their relative roles in shaping species composition, trait composition, and beta diversities of pelagic algae communities, samples were collected from a German lowland catchment, where a well-proven ecohydrological modeling enabled to predict long-term discharges at each sampling site. Both trait and species composition showed significant correlations with hydrological, environmental, and spatial variables, and variation partitioning revealed that the hydrological and local environmental variables outperformed spatial variables. A higher variation of trait composition (57.0%) than species composition (37.5%) could be explained by abiotic factors. Mantel tests showed that both species and trait-based beta diversities were mostly related to hydrological and environmental heterogeneity with hydrological contributing more than environmental variables, while purely spatial impact was less important. Our findings revealed the relative importance of hydrological variables in shaping pelagic algae community and their spatial patterns of beta diversities, emphasizing the need to include hydrological variables in long-term biomonitoring campaigns and biodiversity conservation or restoration. A key implication for biodiversity conservation was that maintaining the instream flow regime and keeping various habitats among rivers are of vital importance. However, further investigations at multispatial and temporal scales are greatly needed. PMID- 29531710 TI - Factors influencing the natural regeneration of the pioneering shrub Calligonum mongolicum in sand dune stabilization plantations in arid deserts of northwest China. AB - Calligonum mongolicum is a successful pioneer shrub to combat desertification, which is widely used for vegetation restoration in the desert regions of northwest China. In order to reveal the limitations to natural regeneration of C. mongolicum by asexual and sexual reproduction, following the process of sand dune stabilization, we assessed clonal shoots, seedling emergence, soil seed bank density, and soil physical characteristics in mobile and stabilized sand dunes. Controlled field and pot experiments were also conducted to assess germination and seedling emergence in different dune soil types and seed burial depths. The population density of mature C. mongolicum was significantly different after sand dune stabilization. Juvenile density of C. mongolicm was much lower in stabilized sand dunes than mobile sand dune. There was no significant difference in soil seed bank density at three soil depths between mobile and stabilized sand dunes, while the emergence of seedlings in stabilized dunes was much lower than emergence in mobile dunes. There was no clonal propagation found in stabilized dunes, and very few C. mongolicum seedlings were established on stabilized sand dunes. Soil clay and silt content, air-filled porosity, and soil surface compaction were significantly changed from mobile sand dune to stabilized dunes. Seedling emergence of C. mongolicm was highly dependent on soil physical condition. These results indicated that changes in soil physical condition limited clonal propagation and seedling emergence of C. mongolicum in stabilized sand dunes. Seed bank density was not a limiting factor; however, poor seedling establishment limited C. mongolicum's further natural regeneration in stabilized sand dunes. Therefore, clonal propagation may be the most important mode for population expansion in mobile sand dunes. As a pioneer species C. mongolicum is well adapted to propagate in mobile sand dune conditions, it appears unlikely to survive naturally in stabilized sand dune plantations. PMID- 29531711 TI - Genotyping validates photo-identification by the head scale pattern in a large population of the European adder (Vipera berus). AB - Capture-mark-recapture procedures are a basic tool in population studies and require that individual animals are correctly identified throughout their lifetime. A method that has become more and more popular uses photographic records of natural markings, such as pigmentation pattern and scalation configuration. As with any other marking tool, the validity of the photographic identification technique should be evaluated thoroughly. Here, we report on a large-scale double-marking study in which European adders (Vipera berus) were identified by both microsatellite genetic markers and by the pattern of head scalation. Samples that were successfully genotyped for all nine loci yielded 624 unique genotypes, which matched on a one-to-one basis with the individual assignments based on the head scalation pattern. Thus, adders considered as different individuals by their genotypes were also identified as different individuals by their head scalation pattern, and vice versa. Overall, variation in the numbers, shape, and arrangement of the head scales enabled us to distinguish among 3200+ photographed individual snakes. Adders that were repeatedly sequenced genetically over intervals of 2-3 years showed no indication whatsoever for a change in the head scale pattern. Photographic records of 900+ adders that were recaptured over periods of up to 12 years showed a very detailed and precise match of the head scale characteristics. These natural marks are thus robust over time and do not change during an individual's lifetime. With very low frequency (0.3%), we detected small changes in scalation that were readily discernible and could be attributed to physical injury or infection. Our study provides a conclusive validation for the use of photo-identification by head scale patterns in the European adder. PMID- 29531709 TI - Chemical signaling and insect attraction is a conserved trait in yeasts. AB - Yeast volatiles attract insects, which apparently is of mutual benefit, for both yeasts and insects. However, it is unknown whether biosynthesis of metabolites that attract insects is a basic and general trait, or if it is specific for yeasts that live in close association with insects. Our goal was to study chemical insect attractants produced by yeasts that span more than 250 million years of evolutionary history and vastly differ in their metabolism and lifestyle. We bioassayed attraction of the vinegar fly Drosophila melanogaster to odors of phylogenetically and ecologically distinct yeasts grown under controlled conditions. Baker's yeast Saccharomyces cerevisiae, the insect-associated species Candida californica, Pichia kluyveri and Metschnikowia andauensis, wine yeast Dekkera bruxellensis, milk yeast Kluyveromyces lactis, the vertebrate pathogens Candida albicans and Candida glabrata, and oleophilic Yarrowia lipolytica were screened for fly attraction in a wind tunnel. Yeast headspace was chemically analyzed, and co-occurrence of insect attractants in yeasts and flowering plants was investigated through a database search. In yeasts with known genomes, we investigated the occurrence of genes involved in the synthesis of key aroma compounds. Flies were attracted to all nine yeasts studied. The behavioral response to baker's yeast was independent of its growth stage. In addition to Drosophila, we tested the basal hexapod Folsomia candida (Collembola) in a Y-tube assay to the most ancient yeast, Y. lipolytica, which proved that early yeast signals also function on clades older than neopteran insects. Behavioral and chemical data and a search for selected genes of volatile metabolites underline that biosynthesis of chemical signals is found throughout the yeast clade and has been conserved during the evolution of yeast lifestyles. Literature and database reviews corroborate that yeast signals mediate mutualistic interactions between insects and yeasts. Moreover, volatiles emitted by yeasts are commonly found also in flowers and attract many insect species. The collective evidence suggests that the release of volatile signals by yeasts is a widespread and phylogenetically ancient trait, and that insect-yeast communication evolved prior to the emergence of flowering plants. Co-occurrence of the same attractant signals in yeast and flowers suggests that yeast-insect communication may have contributed to the evolution of insect-mediated pollination in flowers. PMID- 29531712 TI - Florivory indirectly decreases the plant reproductive output through changes in pollinator attraction. AB - Species often interact indirectly with each other via their traits. There is increasing appreciation of trait-mediated indirect effects linking multiple interactions. Flowers interact with both pollinators and floral herbivores, and the flower-pollinator interaction may be modified by indirect effects of floral herbivores (i.e., florivores) on flower traits such as flower size attracting pollinators. To explore whether flower size affects the flower-pollinator interaction, we used Eurya japonica flowers. We examined whether artificial florivory decreased fruit and seed production, and also whether flower size affected florivory and the number of floral visitors. The petal removal treatment (i.e., artificial florivory) showed approximately 50% reduction in both fruit and seed set in natural pollination but not in artificial pollination. Furthermore, flower size increased the number of floral visitors, although it did not affect the frequency of florivory. Our results demonstrate that petal removal indirectly decreased 75% of female reproductive output via decreased flower visits by pollinators and that flower size mediated indirect interactions between florivory and floral visitors. PMID- 29531713 TI - Improved protocols to accelerate the assembly of DNA barcode reference libraries for freshwater zooplankton. AB - Currently, freshwater zooplankton sampling and identification methodologies have remained virtually unchanged since they were first established in the beginning of the XX century. One major contributing factor to this slow progress is the limited success of modern genetic methodologies, such as DNA barcoding, in several of the main groups. This study demonstrates improved protocols which enable the rapid assessment of most animal taxa inhabiting any freshwater system by combining the use of light traps, careful fixation at low temperatures using ethanol, and zooplankton-specific primers. We DNA-barcoded 2,136 specimens from a diverse array of taxonomic assemblages (rotifers, mollusks, mites, crustaceans, insects, and fishes) from several Canadian and Mexican lakes with an average sequence success rate of 85.3%. In total, 325 Barcode Index Numbers (BINs) were detected with only three BINs (two cladocerans and one copepod) shared between Canada and Mexico, suggesting a much narrower distribution range of freshwater zooplankton than previously thought. This study is the first to broadly explore the metazoan biodiversity of freshwater systems with DNA barcodes to construct a reference library that represents the first step for future programs which aim to monitor ecosystem health, track invasive species, or improve knowledge of the ecology and distribution of freshwater zooplankton. PMID- 29531715 TI - Anthropogenic food provisioning and immune phenotype: Association among supplemental food, body condition, and immunological parameters in urban environments. AB - Direct or indirect supplemental feeding of free-ranging animals occurs worldwide, resulting in significant impacts on population density or altered demographic processes. Another potential impact of increased energy intake from supplemental feeding is altered immunocompetence. As immune system maintenance is energetically costly, there may be trade-offs between immune responses and other energy-demanding physiological processes in individual animals. Although increased availability of food sources through supplemental feeding is expected to increase the overall immunocompetence of animals, empirical data verifying the association between supplemental feeding and different immune parameters are lacking. Understanding the potential influence of supplemental feeding on immune phenotypes is critical, as it may also impact host-pathogen dynamics in free ranging animals. Using urban stray cats as a study model, we tested for associations between the intensity of supplemental feeding due to cat caretaker activity (CCA); body condition; and immune phenotype (bacterial killing assay (BKA), immunoglobulin G (IgG) concentration, and leukocyte counts). Significantly higher bacterial killing ability was observed in cats from high CCA districts, whereas higher IgG concentration and eosinophil counts were observed in cats from low CCA districts. Other leukocyte counts and body condition indices showed no significant association with CCA. We observed varying patterns of different immune components in relation to supplemental feeding. Out data suggest that supplemental feeding influences immune phenotype, not only by means of energy provisioning, but also by potentially reducing exposure rates to parasite infections through stray cat behavioral changes. PMID- 29531714 TI - Comparative phylogeography of Aedes mosquitoes and the role of past climatic change for evolution within Africa. AB - The study of demographic processes involved in species diversification and evolution ultimately provides explanations for the complex distribution of biodiversity on earth, indicates regions important for the maintenance and generation of biodiversity, and identifies biological units important for conservation or medical consequence. African and forest biota have both received relatively little attention with regard to understanding their diversification, although one possible mechanism is that this has been driven by historical climate change. To investigate this, we implemented a standard population genetics approach along with Approximate Bayesian Computation, using sequence data from two exon-primed intron-crossing (EPIC) nuclear loci and mitochondrial cytochrome oxidase subunit I, to investigate the evolutionary history of five medically important and inherently forest dependent mosquito species of the genus Aedes. By testing different demographic hypotheses, we show that Aedes bromeliae and Aedes lilii fit the same model of lineage diversification, admixture, expansion, and recent population structure previously inferred for Aedes aegypti. In addition, analyses of population structure show that Aedes africanus has undergone lineage diversification and expansion while Aedes hansfordi has been impacted by population expansion within Uganda. This congruence in evolutionary history is likely to relate to historical climate-driven habitat change within Africa during the late Pleistocene and Holocene epoch. We find differences in the population structure of mosquitoes from Tanzania and Uganda compared to Benin and Uganda which could relate to differences in the historical connectivity of forests across the continent. Our findings emphasize the importance of recent climate change in the evolution of African forest biota. PMID- 29531717 TI - Occupational hypersensitivity pneumonitis in a koji brewer. AB - Koji is a fermenting agent used in many traditional Japanese foods, and Aspergillus oryzae is the most frequently used microorganism in koji production. Few cases of hypersensitivity pneumonitis due to A. oryzae have been reported. However, physicians should recognize the disease because of the increasing globalization of food production. PMID- 29531718 TI - Congenital central hypoventilation syndrome mimicking mitochondrial disease. AB - Later-onset congenital central hypoventilation syndrome (LO-CCHS) does not present only breathing problems but can be present as episodic multiple organs involvement. Our unique case demonstrated LO-CCHS should be considered in the differential diagnosis of mitochondrial diseases and having nontypical polysomnography result. PMID- 29531716 TI - Increased transgenerational epigenetic variation, but not predictable epigenetic variants, after environmental exposure in two apomictic dandelion lineages. AB - DNA methylation is one of the mechanisms underlying epigenetic modifications. DNA methylations can be environmentally induced and such induced modifications can at times be transmitted to successive generations. However, it remains speculative how common such environmentally induced transgenerational DNA methylation changes are and if they persist for more than one offspring generation. We exposed multiple accessions of two different apomictic dandelion lineages of the Taraxacum officinale group (Taraxacum alatum and T. hemicyclum) to drought and salicylic acid (SA) treatment. Using methylation-sensitive amplified fragment length polymorphism markers (MS-AFLPs) we screened anonymous methylation changes at CCGG restriction sites throughout the genome after stress treatments and assessed the heritability of induced changes for two subsequent unexposed offspring generations. Irrespective of the initial stress treatment, a clear buildup of heritable DNA methylation variation was observed across three generations, indicating a considerable background rate of heritable epimutations. Less evidence was detected for environmental effects. Drought stress showed some evidence for accession-specific methylation changes, but only in the exposed generation and not in their offspring. By contrast, SA treatment caused an increased rate of methylation change in offspring of treated plants. These changes were seemingly undirected resulting in increased transgenerational epigenetic variation between offspring individuals, but not in predictable epigenetic variants. While the functional consequences of these MS-AFLP-detected DNA methylation changes remain to be demonstrated, our study shows that (1) stress-induced transgenerational DNA methylation modification in dandelions is genotype and context-specific; and (2) inherited environmental DNA methylation effects are mostly undirected and not targeted to specific loci. PMID- 29531719 TI - Diffusion-weighted imaging characteristics of methotrexate-induced acute encephalopathy. AB - Methotrexate (MTX)-induced encephalopathy is a grave complication in patients with malignancies. The early diagnosis of acute encephalopathy was difficult by conventional computed tomography (CT), and T1- or T2-weighted magnet resonance (MR) imaging. We report that the diffusion-weighted (DW) imaging is useful for early detection of acute leukoencephalopathy. PMID- 29531720 TI - Multicentric castleman's disease resembling metastatic lung carcinoma. A case report. AB - A 67-year-old patient presented for persistent cough. Computed tomography showed right lower lung opacity associated with mediastinal adenopathy. On suspicion of metastatic pulmonary neoplasm, the patient was submitted to right lower lobectomy with lymphadenectomy. Postoperative histopathology led to the diagnosis of multicentric Castleman's disease. PMID- 29531721 TI - The histopathology and phenotypic variability in H syndrome. AB - Skin biopsy may be helpful in the diagnosis of H syndrome. A triad of dermal fibrosis, lymphocytic aggregates, and numerous CD68+, CD163+, S100-positive, and CD1a-negative dermal histiocytes is characteristic. PMID- 29531722 TI - A novel homozygous mutation in the mannose phosphate isomerase gene causing congenital disorder of glycation and hyperinsulinemic hypoglycemia in an infant. AB - We report a 4 years girl with congenital disorders of glycosylation (CDG) type Ib due to a novel homozygous mutation in MPI gene. She presented with diazoxide responsive hyperinsulinemic hypoglycemia. CDG should be considered in unexplained hypoglycemia particularly in consanguineous families. Diagnosis enables monitoring/prevention of disease comorbidities and early effective treatment. PMID- 29531723 TI - Virginal breast hypertrophy in a patient with Beckwith-Wiedemann syndrome. AB - Virginal breast hypertrophy is a multidisciplinary condition including surgical, pediatric, and endocrine/gynecological disciplines, and its successful diagnosis and management requires complex, team approach. PMID- 29531724 TI - Fatal cardiac arrhythmia caused by tumor lysis in a patient with diffuse large B cell lymphoma upon start of R-CHOP. AB - Tumor lysis syndrome is rare in diffuse large cell lymphoma, but it is important to recognize the risk in patients with massive tumor burden and reduced kidney function. Very intense vigilance can be necessary despite adequate prophylactic measures and certain drugs may exacerbate electrolyte derangements. PMID- 29531725 TI - Iatrogenic seeding of osteosarcoma in a tracheotomy tract - a case report. AB - Here, we describe the first reported case of osteosarcoma occurring postsurgically in a tracheotomy tract, highlighting the possibility of osteosarcoma seeding during head and neck surgery. Preventative measures such as performing the tracheostomy after the tumor resection while walling off the tracheostomy site from the operative field should be considered. PMID- 29531726 TI - Novel myophosphorylase mutation (p.Arg94Pro) with progressive exercise intolerance. AB - We present a 16-year-old girl with a unique clinical phenotype characterized by rapidly progressive exercise intolerance, transient exertional weakness, and progressive muscle cramps involving all limbs and bulbar muscles, following a first myoglobinuric episode at age 15 years, arising from homozygosity for a novel missense mutation (c.281G>C) in PYGM. PMID- 29531727 TI - Successful implantation of a Micra leadless pacemaker via collateral femoral vein and inferior vena cava filter. AB - This case details the successful implementation of a leadless pacemaker device in a patient with multiple venous occlusions and an IVC filter. As the incidence of IVC filters increases in patients with dysrhythmias, further investigations are required to determine the risk and safety of leadless pacemaker placement in this population. PMID- 29531728 TI - Indomethacin induced ductus arteriosus closure in midgestation fetus. AB - This article reports a rare but potentially serious complication of ductus arteriosus closure resulting from second-trimester indomethacin exposure. Serial echocardiograms are indicated to monitor for development of right heart dysfunction and to ensure delivery prior to the onset of right heart failure and hydrops fetalis. PMID- 29531729 TI - Severe pancytopenia and splenomegaly associated with felty's syndrome, both fully responsive solely to corticosteroids. AB - In severe cases of pancytopenia with subsequent infections due to long-term untreated Felty's syndrome, the initiation of immunosuppressive treatment with sole prednisone (1 mg/kg iv) should be considered, despite that, the low neutrocytes count would make one physician hesitant. A full resolution of whole blood count within 3 weeks and a 30% reduction in spleens sized was noted. PMID- 29531730 TI - Direct Factor X sequestration by systemic amyloid light-chain amyloidosis. AB - We present a lymphoplasmacytic lymphoma patient with Factor X (FX) deficiency. Despite the absence of FX inhibitor, the administration of fresh frozen plasma and anti-inhibitor coagulant complex did not increase the FX level. The autopsy showed that massive amyloid depositions to multiple organs and FX existed in union with amyloidosis. PMID- 29531731 TI - Intracranial subdural abscess with polymicrobial infections due to frontal sinusitis in an adolescent: life-threatening complication of a common disease. AB - Intracranial abscess is one of the most serious complications of frontal sinusitis, particularly among adolescents, even in the absence of odontogenic infection. Polymicrobial infections due to anaerobes are common. Because antibiotic therapy alone is usually ineffective, early endoscopic sinus surgery is the key for infection control and good clinical outcomes. PMID- 29531732 TI - Dystopic retrohepatic gallbladder and cholecysto-choledocho lithiasis: the rendez vous and indocyanine green fluorescence. AB - Laparoscopic cholecystectomy is a well-known procedure for the treatment of most gallbladder diseases. Sometimes, it could be very difficult, in the presence of aberrations regarding the cystic duct, the cystic artery, or the gallbladder itself. Fluorescence laparoscopy using indocyanine green could be very useful for all the situations of anatomy aberrations. PMID- 29531733 TI - A reminder of the place of morphology and the H-score in the diagnosis of hemophagocytic lymphohistiocytosis (HLH). AB - This case report reminds the reader of the place of hemophagocytosis and the H Score in the diagnosis of secondary hemophagocytic lymphohistiocytosis. PMID- 29531734 TI - Pseudo liposarcomatous plasma cells in a patient with liposarcoma and lymphoplasmacytic lymphoma. AB - First, patients may always develop a second severe illness, even a second cancer. Second, things are not always as they are expected to be. So, careful diagnosis is mandatory. Third, morphology is very important, but sometimes misleading. Always be aware of morphological variants! PMID- 29531735 TI - Portal vein thrombosis after cesarean section in a patient on prolonged bed rest due to threatened preterm labor. AB - Portal vein thrombosis is a rare but life-threatening complication during pregnancy and postpartum period. Color Doppler ultrasound is useful for prompt diagnosis. Although the risk of complications should be considered, successful pregnancy with comorbid portal vein thrombosis is possible with appropriate anticoagulation therapy and close monitoring. PMID- 29531736 TI - Prenatal sonography of placental abscess and prolonged antibiotic treatment for Serratia marcescens bacteremia. AB - Termination of pregnancy is indicated for Serratia marcescens bacteremia, a major cause of mortality. Our present case was highly challenging because the patient wished to continue with her pregnancy, and the ultrasonography showed features of a placental abscess. Although the outcomes were good after prolonged antibiotic treatment, this was an exceptional case. PMID- 29531737 TI - Fracture of a femoral hemodialysis catheter during placement in a man with metastatic cancer. AB - Central venous catheterization can be challenging in patients that had undergone repeated catheter placements. Ultrasound scan may overlook venous stenosis which is better visualized using venography. The use of venography should be considered to assess for venous stenosis or vascular anomalies in individuals with multiple catheterizations or in close proximity to cancer. PMID- 29531738 TI - Febrile neutropenia with bacterial paronychia. AB - The symptoms of infection can be minimal or absent in patients with febrile neutropenia at first. The focal site of infection, which may be the main cause of a fever or be a complication of neutropenia, can develop as neutrophils increase during the clinical course of febrile neutropenia. PMID- 29531739 TI - The role of multidetector CT angiography and 3D postprocessing imaging in the diagnosis and investigation of bronchopulmonary sequestration. AB - Congenital bronchopulmonary malformations are usually asymptomatic. Precise multimodality imaging plays an essential role in the identification of rare cardiothoracic entities, offering excellent imaging quality and the decisive diagnosis. PMID- 29531740 TI - Spoon nails: still seen in today's world. AB - Koilonychia is a nail abnormality characterized by thin, brittle, and spoon shaped nails. It is frequently observed in chronic iron deficiency secondary to malnutrition, chronic blood loss, or malabsorption. It may also be idiopathic or related to occupation and rare systemic disorders. Presence of koilonychia should prompt investigations for iron deficiency. PMID- 29531741 TI - CK 20-positive and CK 7-negative Merkel cell carcinoma of the cheek. AB - Merkel cell carcinomas (MCCs) are uncommon, highly malignant skin tumors that develop in sun-exposed areas of the skin. Most of the MCCs are CK 20-positive and CK 7-negative such as our case. About 80% of Merkel cell carcinoma is associated with Merkel cell polyomavirus. PMID- 29531742 TI - Mycoplasma pneumoniae-induced mucositis without rash in an 11-year-old boy. AB - Mycoplasma pneumoniae is a frequent cause of childhood pneumonia, and extrapulmonary manifestations may be noted at the time of infection. While M. pneumoniae has long been associated with Stevens-Johnson syndrome, a separate diagnostic entity, Mycoplasma pneumoniae-induced rash and mucositis (MIRM), has recently been proposed to better characterize the rash and severe mucositis that some patients exhibit. A subset of patients with MIRM will have mucositis without skin rash. Physicians should recognize this clinical entity and be familiar with treatment options for MIRM. PMID- 29531743 TI - Using domiciliary non-invasive ventilator data downloads to inform clinical decision-making to optimise ventilation delivery and patient compliance. AB - Introduction: Ventilation parameter data from patients receiving home mechanical ventilation can be collected via secure data cards and modem technology. This can then be reviewed by clinicians and ventilator prescriptions adjusted. Typically available measures include tidal volume (VT), leak, respiratory rate, minute ventilation, patient triggered breaths, achieved pressures and patient compliance. This study aimed to assess the potential impact of ventilator data downloads on management of patients requiring home non-invasive ventilation (NIV). Methods: A longitudinal within-group design with repeated measurements was used. Baseline ventilator data were downloaded, reviewed and adjustments made to optimise ventilation. Leak, VT and compliance data were collected for comparison at the first review and 3-7 weeks later. Ventilator data were monitored and amended remotely via a modem by a consultant physiotherapist between the first review and second appointment. Results: Analysis of data from 52 patients showed increased patient compliance (% days used >4 hours) from 90% to 96% (p=0.007), increased usage from 6.53 to 6.94 hours (p=0.211) and a change in VT(9.4 vs 8.7 mL/kg/ideal body weight, p=0.022). There was no change in leak following review of NIV prescriptions (mean (SD): 43 (23.4) L/min vs 45 (19.9)L/min, p=0.272). Conclusion: Ventilator data downloads, via early remote assessment, can help optimise patient ventilation through identification of modifiable factors, in particular interface leak and ventilator prescriptions. However, a prospective study is required to assess whether using ventilator data downloads provides value in terms of patient outcomes and cost-effectiveness. The presented data will help to inform the design of such a study. PMID- 29531744 TI - Is childhood wheeze and asthma in Latin America associated with poor hygiene and infection? A systematic review. AB - Introduction: High asthma prevalence in Latin-American cities is thought to be caused by poor hygiene and infections. This contradicts the widely accepted 'hygiene hypothesis' for asthma aetiology. Methods: Systematic review of observational studies evaluating the association between poor hygiene exposures or infections and asthma/wheeze among Latin-American children aged 4-16 years. MEDLINE, EMBASE, LILACS and CINAHL electronic databases were searched following a predefined strategy to 18 December 2017. We quantified outcomes measured and reported, assessed risk of bias and tabulated the results. Results: Forty-five studies included: 6 cohort, 30 cross-sectional and 9 case-control studies. 26 cross-sectional studies were school-based surveys (14 of over 3000 children), whereas 5 case-control studies were hospital/health centre-based. Exposures measured and reported varied substantially between studies, and current wheeze was the most common outcome reported. Data showed selective reporting based on statistical significance (P value <0.05): 17/45 studies did not clearly describe the number of exposures measured and 15/45 studies reported on less than 50% of the exposures measured. Most exposures studied did not show an association with wheeze or asthma, except for a generally increased risk associated with acute respiratory infections in early life. Contradictory associations were observed frequently between different studies. Conclusion: Selective reporting is common in observational studies exploring the association between environmental exposures and risk of wheeze/asthma. This, together with the use of different study outcomes (wheeze/asthma) associated with possibly distinct causal mechanisms, complicates inferences about the role of poor hygiene exposures and childhood infections in explaining asthma prevalence in Latin-American children. PMID- 29531745 TI - Symptom severity and its effect on health-related quality of life over time in patients with pulmonary hypertension: a multisite longitudinal cohort study. AB - Introduction: The aim of this cohort study was to examine health-related quality of life (HRQoL) and symptomatology in patients with pulmonary hypertension (PH) and explore factors that influence its evolution over time. Methods: A prospective longitudinal multisite cohort study. Participants were recruited from specialist UK PH centres and completed a questionnaire pack at baseline, 6, 12 and 18 months to assess HRQoL (emPHasis-10), dyspnoea, fatigue, sleep, anxiety and depression. Results: 185 patients entered the study at baseline and 126 (68%) completed month 18. At baseline, patients had significant impairment of HRQoL, anxiety, depression, dyspnoea and severe fatigue. No significant changes, apart from a reduction in the Hospital Anxiety and Depression Scale-Anxiety score (P=0.04), were observed over 18 months. Depression and dyspnoea were predictors of HRQoL (P=0.002 and P=0.03, respectively). Oxygen use was also associated with diminished HRQoL and increased symptom severity. Conclusion: Patients with PH experience high levels of symptom severity and the negative impact on HRQoL was unchanged over time. The use of oxygen therapy, in particular, was associated with a significant impact on HRQoL. Further study of factors impacting HRQoL and interventions that target a combination of physiological and psychosocial consequences of living with PH are needed. PMID- 29531746 TI - BTS guideline for the investigation and management of malignant pleural mesothelioma. AB - The full guideline for the investigation and management of malignant pleural mesothelioma is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline. PMID- 29531747 TI - Patterns and management of chronic obstructive pulmonary disease in urban and rural China: a community-based survey of 25 000 adults across 10 regions. AB - Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with COPD deaths in China accounting for one-third of all such deaths. However, there is limited available evidence on the management of COPD in China. Methods: A random sample of 25 011 participants in the China Kadoorie Biobank, aged 38-87 years, from 10 regions in China was surveyed in 2013 2014. Data were collected using interviewer-administered questionnaires on the diagnosis ('doctor-diagnosed' or 'symptoms-based') and management of COPD (including use of medication and other healthcare resources), awareness of diagnosis and severity of symptoms in COPD cases. Results: Overall, 6.3% of the study population were identified as COPD cases (doctor-diagnosed cases: 4.8% and symptom-based cases: 2.4%). The proportion having COPD was higher in men than in women (7.9% vs 5.3%) and varied by about threefold (3.7%-10.0%) across the 10 regions. Among those with COPD, 54% sought medical advice during the last 12 months, but <10% reported having received treatment for COPD. The rates of hospitalisation for COPD, use of oxygen therapy at home and influenza or pneumococcal vaccinations in the previous year were 15%, 3% and 4%, respectively. Of those with COPD, half had moderate or severe respiratory symptoms, and over 80% had limited understanding of their disease and need for treatment. Conclusion: Despite a high prevalence of COPD in China and its substantial impact on activities of daily living, knowledge about COPD and its management were limited. PMID- 29531748 TI - Randomised clinical trial of an early palliative care intervention (SUPPORT) for patients with idiopathic pulmonary fibrosis (IPF) and their caregivers: protocol and key design considerations. AB - Introduction: Idiopathic pulmonary fibrosis (IPF), a progressive life-limiting lung disease affects approximately 128 000 newly diagnosed individuals in the USA annually. IPF, a disease of ageing associated with intense medical and financial burden, is expected to grow in incidence globally. Median survival from diagnosis is 3.8 years, and many of these patients succumb to a rapid death within 6 months. Despite the fatal prognosis, we have found that patients and caregivers often fail to understand the poor prognosis as the disease relentlessly progresses. Based on feedback from patients and families living with IPF, we developed the S-Symptom Management, U-Understanding the Disease, P-Pulmonary Rehabilitation, P-Palliative Care, O-Oxygen Therapy, R-Research Considerations and T-Transplantation ('SUPPORT') intervention to increase knowledge of the disease, teach self-management strategies and facilitate preparedness with end of life (EOL) planning. Methods: This study is a randomised trial to test the efficacy of SUPPORT intervention compared with routine care in patients with IPF and their caregivers delivered after three clinical visits. We are recruiting a cohort of 64 new IPF patient/caregiver dyads (32 for each dyad). Results: The trial will evaluate whether the SUPPORT intervention decreases stress, improves symptom burden, quality of life, preparedness and advance care planning for patients and caregivers, quality of dying and death for caregivers if the patient dies during the course of the study, as well as assess the impact of primary palliative care on healthcare resource use near the EOL. Conclusion: By increasing knowledge of the disease, teaching self-management strategies and facilitating preparedness with EOL planning, we will address a critical gap in the care of patients with IPF. Trial registration number: NCT02929017; Pre results. PMID- 29531750 TI - Determining resolution of Angiostrongylus vasorum in dogs following anthelmintic treatment with an imidacloprid 10 per cent/moxidectin 2.5 per cent spot-on. AB - Objectives: To determine the time from treatment with a product containing imidacloprid 10 per cent/moxidectin 2.5 per cent spot-on (AdvocateTM), to dogs becoming negative for Angiostrongylus vasorum (A. vasorum). The authors hypothesised that most dogs would have resolution of A. vasorum within four weeks of treatment with AdvocateTM. Design: Prospective, non-randomised, prepost treatment study. Setting: Cases were enrolled from general practices along the southern coast of the United Kingdom. Participants: Nine dogs completed the study and were enrolled if A. vasorum had been diagnosed based on a positive commercially available, in-clinic, serological A. vasorum antigen test (Angio Detect(r)) or Baermann performed at an external laboratory or both. Interventions: The only treatment A. vasorum-positive dogs received was AdvocateTM which was applied at the time of diagnosis and reapplied if necessary at four-weekly intervals until dogs tested negative by Angio Detect. Primary outcome measures: Angio Detect(r) was performed and AdvocateTM was reapplied at four-weekly intervals until dogs tested negative by this method. Secondary outcome measures: Baermann was also performed at four-weekly intervals until dogs tested negative by this method. Results: Application of AdvocateTM was an effective treatment for A. vasorum infection in dogs and resulted in resolution of the infection, based on Angio Detect(r) testing and Baermann, within four weeks, in eight out of nine dogs. Post-treatment Angio Detect(r) testing was concordant with Baermann in seven of nine dogs. Conclusions: Application of AdvocateTM was an effective treatment for A. vasorum infection in dogs and resulted in resolution of the infection within four weeks in most dogs. Repeat Angio Detect(r) testing is recommended following treatment of A. vasorum to confirm resolution of the infection. PMID- 29531751 TI - Comparison of pain response after subcutaneous injection of two maropitant formulations to beagle dogs. AB - The antiemetic maropitant, with metacresol as preservative (Cerenia, Zoetis), has been associated with pain after subcutaneous injection in dogs and cats. Recently, a generic formulation containing benzyl alcohol was authorised (Prevomax, Le Vet). Benzyl alcohol is reported to have local anaesthetic properties and reduce injection pain. This study compared local pain after subcutaneous injection of the two maropitant formulations, administered at approximately 4 degrees C and 25 degrees C, to dogs. Thirty-two healthy beagle dogs were enrolled into a blinded, randomised, cross-over study. Dogs received subcutaneous injections of maropitant injection containing metacresol as preservative and maropitant injection containing benzyl alcohol as preservative, both at approximately 4 degrees C and 25 degrees C, with at least three days in between treatments. Injection pain was evaluated by two blinded observers using a visual analogue scale immediately after injection and a simple descriptive scale at two minutes after injection. In healthy beagle dogs, subcutaneous injection of maropitant with benzyl alcohol is significantly less painful than injection of maropitant with metacresol. PMID- 29531752 TI - A method for the production and expedient screening of CRISPR/Cas9-mediated non transgenic mutant plants. AB - Developing CRISPR/Cas9-mediated non-transgenic mutants in asexually propagated perennial crop plants is challenging but highly desirable. Here, we report a highly useful method using an Agrobacterium-mediated transient CRISPR/Cas9 gene expression system to create non-transgenic mutant plants without the need for sexual segregation. We have also developed a rapid, cost-effective, and high throughput mutant screening protocol based on Illumina sequencing followed by high-resolution melting (HRM) analysis. Using tetraploid tobacco as a model species and the phytoene desaturase (PDS) gene as a target, we successfully created and expediently identified mutant plants, which were verified as tetra allelic mutants. We produced pds mutant shoots at a rate of 47.5% from tobacco leaf explants, without the use of antibiotic selection. Among these pds plants, 17.2% were confirmed to be non-transgenic, for an overall non-transgenic mutation rate of 8.2%. Our method is reliable and effective in creating non-transgenic mutant plants without the need to segregate out transgenes through sexual reproduction. This method should be applicable to many economically important, heterozygous, perennial crop species that are more difficult to regenerate. PMID- 29531754 TI - Shared care versus hospital-based cardiac rehabilitation: a cost-utility analysis based on a randomised controlled trial. AB - Background: Changes in the organisation of chronic healthcare, an increased awareness of costs and challenges of low adherence in cardiac rehabilitation (CR) call for the exploration of more flexible CR programmes as alternatives to hospital-based CR (H-CR). A model of shared care cardiac rehabilitation (SC-CR) that included general practitioners and the municipality was developed. The aim of this study was to analyse the cost utility of SC-CR versus H-CR. Methods: The cost-utility analysis was based on a randomised controlled trial of 212 patients who were allocated to SC-CR or H-CR and followed up for 12 months. A societal cost perspective was applied that included the cost of intervention, informal time, healthcare and productivity loss. Costing was based on a microcosting approach for the intervention and on national administrative registries for the other cost categories. Quality-adjusted life years (QALYs) were based on the EuroQol 5-Dimensions measurements at baseline, after 4 months and after 12 months. Conventional cost-effectiveness methodology was employed to estimate the net benefit of SC-CR. Results: The average cost of SC-CR was 165.5 kDKK and H-CR 163 kDKK. Productivity loss comprised 74.1kDKK and 65.9 kDKK. SC-CR cost was an additional 2.5 kDKK (95% CI -38.1 to 43.1) ~ (0.33; -5.1 to 5.8 k?) and a QALY gain of 0.02 (95% CI -0.03 to 0.06). The probability that SC-CR would be cost effective was 59% for a threshold value of willingness to pay of 300 kDKK (k?40.3). Conclusion: CR after shared care model and H-CR are comparable and similar in socioeconomic terms. Trial registration number: NCT01522001; Results. PMID- 29531755 TI - How much does a heart valve implantation cost and what are the health care costs afterwards? AB - Objective: In the era of limited healthcare budgets, healthcare costs of heart valve implantations need to be considered to inform cost-effectiveness analyses. We aimed to provide age group-specific costs estimates of heart valve implantations, related complications and other healthcare utilisation following the intervention. Methods: We performed retrospective analyses of healthcare costs of patients who had undergone heart valve implantations in 2010-2013 and controls using claims data from Dutch health insurers. Heart valve implantations included surgical valve replacement and transcatheter valve implantation in all heart valve positions. Patients were divided in four age groups. Control groups were created by taking random samples of the Dutch population stratified by age, gender, socioeconomic status and comorbidities. We applied non-parametric bootstrapping to address uncertainty of the cost estimates. The association of patient and intervention characteristics with costs was determined by (multilevel) generalised linear models. Results: The baseline characteristics of 18 903 patients and 188 925 controls were comparable. The annual healthcare costs were substantially higher for surgical heart valve replacement patients than for controls, especially in the year of heart valve implantation. Factors associated with increased annual healthcare costs for patients were older age, female gender, comorbidities, low socioeconomic status and complications. Conclusions: We provided a comprehensive overview of age group-specific incidence of heart valve implantations, subsequent survival and complications as well as associated healthcare costs of all patients in the Netherlands. Our results provide real world costs estimates that can be used as a benchmark for costs of future innovative heart valve implantations. PMID- 29531756 TI - MicroRNA 8059 as a marker for the presence and extent of coronary artery calcification. AB - Objective: MicroRNAs (miRNAs) may serve as potential biomarkers in a variety of pathologies. The aim of this study was to determine whether miRNAs could serve as blood-based markers of isolated coronary artery calcification (CAC) defined as CAC in the absence of an underlying metabolic abnormality. Methods: 24 age matched and sex-matched patients who had been referred for elective CT coronary calcium score and angiography as part of investigation for cardiac chest pain were recruited. Peripheral venesection was performed and an Agatston calcium score was derived from the CT coronary angiogram using default software. RNA was extracted using the LeukoLOCK Total RNA Isolation System for Toray's microarray analysis and quantitative reverse transcription PCR (qRT-PCR). Results: The patients were well matched for age, sex and conventional risk factors for coronary artery disease. Microarray analysis identified lower expression of miRNA 138-2-3p, miRNA-1181, miRNA-6816-3p and miRNA-8059 in patients with coronary artery calcium score (CACS)=0 vs CACS>100. qRT-PCR confirmed significant downregulation of miRNA-8059 in patients with CACS>100 (CACS=0 vs CACS>100; P=0.03). Conclusion: miRNA-8059 may serve as a peripheral blood-based biomarker for the presence of CAC, as well as provide a platform for studying the pathophysiological basis of isolated CAC. Trial registration number: NCT01992848; Results. PMID- 29531757 TI - Troponin and BNP are markers for subsequent non-ischaemic congestive heart failure: the Caerphilly Prospective Study (CaPS). AB - Objective: To examine the long-term predictive value of 28 biomarkers for subsequent non-ischaemic congestive heart failure (CHF) and separately for other cardiovascular outcomes (myocardial infarction (MI) and stroke). Methods: The Caerphilly Prospective Study recruited 2171 men aged 55-69 years from the general population in 1989-1993; men were screened for evidence of cardiovascular disease (CVD) and followed for clinical cardiovascular events. Fasting blood samples were stored at -70 degrees C until assayed for novel biomarkers in 2010-2013. A competing risks proportional hazards regression analysis was used to estimate subhazard ratios (SHRs) for each biomarker for each cardiovascular outcome. Results: During follow-up (average 13 years), only new, initial events were evaluated in the whole cohort: 584 MIs, 313 strokes and 261 episodes of CHF (not associated with acute MI). In a subcohort of men who had no clinical history or evidence of CVD at baseline examination (n=1279) those in the top third of the distributions of troponin and B-type natriuretic peptide (BNP) showed a threefold increase in risk for subsequent CHF as a first event after adjustment for all conventional risk factors (SHRs 3.37, 95% CI 1.39 to 8.14 and 3.23, 95% CI 1.45 to 7.23), respectively, in contrast to moderate elevations in risk for acute MI (troponin SHR 1.63, 95% CI 1.10 to 2.41) and for stroke (BNP SHR 1.75 95% CI 1.06 to 2.88). Conclusion: Troponin and BNP could be considered as potentially useful screening tools to detect subjects without prior CVD at increased risk of developing CHF in subsequent years in addition to having lesser roles for predicting subsequent MI (troponin) or stroke (BNP). PMID- 29531758 TI - Direct oral anticoagulants versus warfarin: is new always better than the old? AB - About 1.4 British million people are at risk of strokes due to non-valvular atrial fibrillation (AF) necessitating long-term anticoagulation. The vitamin K antagonist, warfarin, has a long half-life and narrow therapeutic range necessitating regular monitoring and is a common cause of iatrogenic hospital admission. Direct-acting oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban are not required to have monitoring but are sensitive to changes in renal function and are associated with poorer adherence. There are good grounds to believe that DOACs are not always superior to warfarin in routine practice particularly with an older population. Much higher levels of therapeutic effectiveness can be achieved using a simple genotype guidance to identify those who are highly sensitive and by adoption of home monitoring. These adjustments could make warfarin the preferred drug for most people and would reduce the dramatic rise in health service expenditure. PMID- 29531759 TI - Associations between cardiac troponin, mortality and subsequent use of cardiovascular services: differences in sex and ethnicity. AB - Background: The impact of cardiac troponin (cTn) testing on the downstream use of cardiovascular services is not well understood. We conducted this large-scale single centre cohort study to investigate the patterns of testing that result from the use of cTn. Methods: We conducted this investigation using data collected between 1 January 2013 and 18 December 2015 from an academically affiliated tertiary care centre. Data from all hospitalised patients evaluated with cTn (Roche Elecsys cTn-T) assay were collected from our integrated data repository and divided into two cohorts: all cTn assays negative (<0.03 ug/L) versus at least one elevated (>=0.03 ug/L). The main outcomes were the frequency of use cardiovascular services and mortality. Results: Among 26 663 subjects, 18.6% had at least one elevated cTn assay; acute myocardial infarction was diagnosed in 3.9% overall. More men received cardiac catheterisation and cardiology consultation (OR 1.29, 95% CI 1.20 to 1.39 and OR 1.45, 95% CI 1.31 to 1.61) while African-American patients were less likely to have either catheterisation (OR 0.85, 95% CI 0.77 to 0.93) or consultation (OR 0.72, 95% CI 0.63 to 0.82) performed. Mortality was associated with detectable cTn (HR 2.05, P<0.0001). Conclusions: Among hospitalised patients evaluated with cTn, we observed patterns of underuse and overuse of cardiovascular services. These patterns may have further relevance when high-sensitivity cTn assays are available in the USA. Sex and race-based disparities in cardiovascular services persist. PMID- 29531760 TI - Variability of cardiovascular magnetic resonance (CMR) T1 mapping parameters in healthy volunteers during long-term follow-up. AB - Background: Myocardial T1 and extracellular volume (ECV) derived from cardiovascular MRIs are more and more widely accepted as important markers for diagnosis, risk prediction and monitoring of cardiac disease. Yet data regarding long-term stability of myocardial T1 mapping are lacking. The aim of this study was to investigate the long-term stability of native and postcontrast T1 mapping values in healthy volunteers. Methods: 18 strictly selected healthy volunteers (52+/-10 years, 12 men) were studied on a Philips Achieva 1.5 Tesla scanner. T1 relaxation times were measured before and 15 min after a bolus contrast injection of gadolinium diethylenetriamine penta-acetic acid (DTPA) (0.2 mmol/kg) using a single-breath-hold modified Look-Locker inversion recovery 3(3)3(3)5 sequence. ECV was calculated using native and postcontrast T1 times of myocardium and blood correcting for blood haematocrit. Exams were repeated 3.6+/-0.5 years later under the same conditions and using the same scan protocols. Results: Cardiac biomarkers (high-sensitivity troponin T and N terminal pro-brain natriuretic peptide) remained unchanged, as well as left ventricular mass, and global and longitudinal function. No significant change occurred regarding native T1 times (1017+/-24 ms vs 1015+/-21 ms; P=0.6), postcontrast T1 times (426+/-38 ms vs 413+/-20 ms; P=0.13) or ECV (22%+/-2% vs 23%+/-2%; P=0.3). Native T1 time and ECV appeared to be better reproducible than postcontrast T1, resulting in lower coefficients of variation (ECV: 3.5%, native T1: 1.3%, postcontrast T1: 6.4%) and smaller limits of agreement (ECV: 2%/-2%, native T1: 39 ms/-35 ms, postcontrast T1: 85 ms/-59 ms). Conclusions: During long-term follow-up, native T1 and ECV values are very robust markers, whereas postcontrast T1 results appear less stable. PMID- 29531761 TI - Clinically feasible stratification of 1-year to 3-year post-myocardial infarction risk. AB - Objective: Post-myocardial infarction (MI) care is crucial to preventing recurrent major adverse cardiovascular events (MACE), but can be complicated to personalise. A tool is needed that effectively stratifies risk of cardiovascular (CV) events 1-3 years after MI but is also clinically usable. Methods: Patients surviving >=1 year after an index MI with >=1 risk factor for recurrent MI (ie, age >=65 years, prior MI, multivessel coronary disease, diabetes, glomerular filtration rate <60 mL/min/1.73 m2) were studied. Cox regression derived sex specific Intermountain Major Adverse Cardiovascular Events (IMACE) risk scores for the composite of 1-year to 3-year MACE (CV death, MI or stroke). Derivation was performed in 70% of subjects (n=1342 women; 3047 men), with validation in the other 30% (n=576 women; 1290 men). Secondary validations were also performed. Results: In women, predictors of CV events were glucose, creatinine, haemoglobin, platelet count, red cell distribution width (RDW), age and B-type natriuretic peptide (BNP); among men, they were potassium, glucose, blood urea nitrogen, haematocrit, white blood cell count, RDW, mean platelet volume, age and BNP. In the primary validation, in women, IMACE ranged from 0 to 11 (maximum possible: 12) and had HR=1.44 per +1 score (95% CI 1.29 to 1.61; P<0.001); men had IMACE range 0-14 (maximum: 16) and HR=1.29 per +1 score (95% CI 1.20 to 1.38; P<0.001). IMACE >=5 in women (>=6 in men) showed strikingly higher MACE risk. Conclusions: Sex-specific risk scores strongly stratified 1-year to 3-year post-MI MACE risk. IMACE is an inexpensive, dynamic, electronically delivered tool for evaluating and better managing post-MI patient care. PMID- 29531762 TI - Repetitive squatting exercise as a diagnostic predictor in patients with dilated cardiomyopathy. AB - Objectives: Non-ischaemic dilated cardiomyopathy (DCM) is characterised by a highly variable disease progression. Stress echocardiography and cardiopulmonary exercise testing (CPET) are beneficial in risk assessment, but are labour intensive. Repetitive squatting and standing without weights is a simple exercise (EX). The aim of this study was to investigate the prognostic role of left ventricular (LV) contractile recruitment (CR) after a simple EX of repetitive squatting through three-dimensional (3D) echocardiography. Methods: Patients with DCM (LV ejection fraction (EF)<50%, n=68) and age-matched healthy volunteers (n=25) received a 3D echocardiographic evaluation of LV EF before and after 30 repetitions of squatting-standing EX. CR was defined by the change of LV EF (Delta>4%). Patients were followed up prospectively (2 years) for cardiac death and deteriorating heart failure. Results: During follow-up, 14 cardiac events occurred (21%) with six deaths and eight severe heart failure deteriorations. A poor CR after squatting EX differentiated DCM patients with cardiac events during follow-up as accurately as a reduced peak oxygen consumption (peak VO 2<20 mL/kg/min) (sensitivity: 0.97 and 0.95). Both had a significant incremental diagnostic value over clinical (age, dyspnoea and natriuretic peptide level) or resting echocardiographic parameters (E/E' ratio, LV EF and end-diastolic LV volume) to predict cardiac events (global chi2: 16.0 vs 5.3; 19.5 vs 6.1; P<0.01 for all). Conclusions: The presence of LV CR after EX of repetitive squatting without weights can stratify risk and predict cardiac events in patients with DCM as correct as CPET. PMID- 29531763 TI - Understanding haemorrhagic risk following thrombolytic therapy in patients with intermediate-risk and high-risk pulmonary embolism: a hypothesis paper. AB - While systemic intravenous thrombolysis decreases mortality in patients with high risk pulmonary embolism (PE), it clearly increases haemorrhagic risk. There are many contraindications to thrombolysis, and efforts should aim at selecting those patients who will benefit most, without suffering complications. The current review summarises the evidence for the use of thrombolytic therapy in PE. It clarifies the pathophysiological mechanisms in PE and acute cor pulmonale that increase the risk of bleeding following thrombolysis. It discusses future management challenges, namely tailored drug administration, new treatment monitoring techniques and catheter-directed thrombolysis. PMID- 29531764 TI - Rationale and design of the ranolazine PH-RV study: a multicentred randomised and placebo-controlled study of ranolazine to improve RV function in patients with non-group 2 pulmonary hypertension. AB - Introduction: A major determining factor on outcomes in patients with pulmonary arterial hypertension (PAH) is right ventricular (RV) function. Ranolazine, which is currently approved for chronic stable angina, has been shown to improve RV function in an animal model and has been shown to be safe in small human studies with PAH. We aim to study the effect of ranolazine on RV function using cardiovascular magnetic resonance (CMR) in patients with pulmonary hypertension (non-group 2 patients) and monitor the effect of ranolazine on metabolism using metabolic profiling and changes of microRNA. Methods and analysis: This study is a longitudinal, randomised, double-blind, placebo-controlled, multicentre proof of-concept study in 24 subjects with pulmonary hypertension and RV dysfunction treated with ranolazine over 6 months. Subjects who meet the protocol definition of RV dysfunction (CMR RV ejection fraction (EF) <45%) will be randomised to ranolazine or placebo with a ratio of 2:1. Enrolled subjects will be assessed for functional class, 6 min walk test and health outcome based on SF-36 tool. Peripheral blood will be obtained for N-terminal-pro brain natriuretic peptide, metabolic profiling, and microRNA at baseline and the conclusion of the treatment period. CMR will be performed at baseline and the conclusion of the treatment period. The primary outcome is change in RVEF. The exploratory outcomes include clinical, other CMR parameters, metabolic and microRNA changes. Ethics and dissemination: The trial protocol was approved by Institutional Review Boards. The trial findings will be disseminated in scientific journals and meetings. Trial registration numbers: NCT01839110 and NCT02829034; Pre-results. PMID- 29531765 TI - The prognostic value of sST2 and galectin-3 considering different aetiologies in non-ischaemic heart failure. AB - Objective: Several studies indicate a prognostic value of sST2 and galectin-3 in heart failure (HF). While previous studies focused on ischaemic cause of HF, we investigated the role of sST2 and galectin-3 in patients with non-ischaemic dilated cardiomyopathy (DCM). Methods: sST2 and galectin-3 serum concentrations were measured in 262 subjects with DCM. Survival rates were determined for all cause mortality (ACM) and cardiac mortality (CM). Results: In a univariate model, sST2 as a continuous variable was a predictor of ACM (HR 1.05; 95% CI 1.03 to 1.07, P<0.001) and CM (HR 1.03; 95% CI 1.00 to 1.06, P=0.040). In the subgroup of patients with inflammatory and/or viral DCM (DCMi?viral), the endpoints ACM (HR 1.10; 95% CI 1.05 to 1.17, P<0.001) and CM (HR 1.10; 95% CI 1.02 to 1.18, P=0.013) were significant. In the subgroup of patients with idiopathic DCM, the endpoint ACM (HR 1.04; 95% CI 1.01 to 1.07, P=0.019) was significant. In a multivariate model, the prognostic value of the sST2 main group remained intact for ACM (HR 1.04; 95% CI 1.02 to 1.07, P=0.003).Univariate and multivariate analysis of galectin-3 as continuous variable did not show any significant result. However, in a quartile model, intermediate values of galectin-3 were significantly associated with a lower event rate of ACM and CM. Conclusion: The study revealed that sST2 predicts ACM and CM in patients with non-ischaemic HF and could be useful especially in patients with inflammatory background. Our findings that intermediate levels of galectin-3 allow for better prognosis were new and different to other investigations. Trial registration number: NCT03090425; Results. PMID- 29531766 TI - Six-minute walk distance after coronary artery bypass grafting compared with medical therapy in ischaemic cardiomyopathy. AB - Background: In patients with ischaemic left ventricular dysfunction, coronary artery bypass surgery (CABG) may decrease mortality, but it is not known whether CABG improves functional capacity. Objective: To determine whether CABG compared with medical therapy alone (MED) increases 6 min walk distance in patients with ischaemic left ventricular dysfunction and coronary artery disease amenable to revascularisation. Methods: The Surgical Treatment in Ischemic Heart disease trial randomised 1212 patients with ischaemic left ventricular dysfunction to CABG or MED. A 6 min walk distance test was performed both at baseline and at least one follow-up assessment at 4, 12, 24 and/or 36 months in 409 patients randomised to CABG and 466 to MED. Change in 6 min walk distance between baseline and follow-up were compared by treatment allocation. Results: 6 min walk distance at baseline for CABG was mean 340+/-117 m and for MED 339+/-118 m. Change in walk distance from baseline was similar for CABG and MED groups at 4 months (mean +38 vs +28 m), 12 months (+47 vs +36 m), 24 months (+31 vs +34 m) and 36 months (-7 vs +7 m), P>0.10 for all. Change in walk distance between CABG and MED groups over all assessments was also similar after adjusting for covariates and imputation for missing values (+8 m, 95% CI -7 to 23 m, P=0.29). Results were consistent for subgroups defined by angina, New York Heart Association class >=3, left ventricular ejection fraction, baseline walk distance and geographic region. Conclusion: In patients with ischaemic left ventricular dysfunction CABG compared with MED alone is known to reduce mortality but is unlikely to result in a clinically significant improvement in functional capacity. Trial registration number: NCT00023595. PMID- 29531767 TI - Comprehensive update on the new indications for transcatheter aortic valve replacement in the latest 2017 European guidelines for the management of valvular heart disease. AB - New European guidelines on the management of valvular heart disease-supported by the European Society of Cardiology (ESC) and European Association of CardioThoracic Surgery (EACTS)-were recently published. Although these guidelines are very comprehensive, these typically are not very inviting to read. In this document, we aimed to distil all the information about transcatheter aortic valve replacement (TAVR) in the new 2017 ESC/EACTS guidelines to the essential and give additional comments on the position of TAVR in 2017. PMID- 29531768 TI - Mild cognitive impairment impacts health outcomes of patients with atrial fibrillation undergoing a disease management intervention. AB - Objective: Mild cognitive impairment (MCI) is prevalent in atrial fibrillation (AF) and has the potential to contribute to poor outcomes. We investigated the influence of MCI on survival and rehospitalisation in patients with chronic forms of AF undergoing a home-based, AF-specific disease management intervention (home based intervention (HBI)) or standard management (SM). Methods: The Montreal Cognitive Assessment tool was administered at baseline (a score of <26/30 indicated MCI) in patients with AF randomised to HBI versus SM. Post hoc analyses of mortality and rehospitalisations during a minimum 24-month follow-up were conducted in the overall cohort and in each study group separately. Results: Of 260 patients (mean age 72+/-11, 47% female), 65% demonstrated MCI on screening (34% in SM; 31% in HBI). Overall, the number of days spent alive and out-of hospital during follow-up (P=0.012) and all-cause rehospitalisation were influenced by MCI during follow-up (OR 3.16 (95% CI 1.46 to 6.84)) but MCI did not influence any outcomes in the SM group. However, survival was negatively influenced by MCI in the HBI group (P=0.036); those with MCI in this group were 5.6 times more likely to die during follow-up (OR 5.57 (95% CI 1.10 to 28.1)). Those with MCI in the HBI group also spent less days alive and out-of-hospital than those with no MCI (P=0.022). MCI was also identified as a significant independent correlate of shortest duration of event-free survival (OR 3.48 (95% CI 1.06 to 11.4)), all-cause rehospitalisation (OR 3.30 (95% CI 1.25 to 8.69)) and cardiovascular disease (CVD)-related rehospitalisation (OR 2.35 (95% CI 1.12 to 4.91)) in this group. Conclusions: The effectiveness of home-based, disease management for patients with chronic forms of AF is negatively affected by comorbid MCI. The benefit of adjunctive support for patients with MCI on CVD related health outcomes requires further investigation. PMID- 29531769 TI - Coronary artery bypass grafting in patients treated with thoracic radiation: a case-control study. AB - Background and aim: Thoracic radiation therapy (XRT) for cancer is associated with the development of significant coronary artery disease that may require coronary artery bypass grafting surgery (CABG). Contemporary acute surgical outcomes and long-term postoperative survival of patients with prior XRT have not been well characterised. Methods: This was a retrospective, single-centre study of patients with a history of thoracic XRT who required CABG and who were propensity matched against 141 controls who underwent CABG over the same time period. The objectives were to assess early CABG outcomes and long-term survival in patients with prior XRT. Results: Thirty-eight patients with a history of previous thoracic XRT underwent CABG from 1994 to 2013. The median time from XRT exposure to surgery was 7.9 years (IQR: 2.5-18.4 years). Perioperative adverse events were similar in the XRT group and controls; however, there was a trends lower utilisation of internal mammary artery (IMA) grafts in the XRT group (89%vs98%, P=0.13). After a median postoperative follow-up of 5.4 years (IQR 0.9 9.4 years), no difference in long-term all-cause mortality was observed. Conclusion: Patients with prior thoracic XRT who undergo CABG have similar long term all-cause mortality compared with controls. Isolated CABG after thoracic XRT is not associated with higher perioperative complications, but IMA graft use may be limited by prior XRT. PMID- 29531770 TI - Critical appraisal of cardiology guidelines on revascularisation: clinical practice. AB - Evidence-based medicine (EBM) provides clinicians with beneficial information. Nonetheless, study findings are often arbitrary, speculative or provisional. The current state of misleading evidence exists in all applications, including those for guideline recommendations. We conductedan appraisal of the American College of Cardiologyand European Society of Cardiology Guidelines for revascularisation of complex coronary anatomy to determine the veracity of the evidence that recommendations were based on. Study-specific critical appraisals were conducted by the authors on the 5-year Synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) and future revascularisation evaluation in patients with diabetes mellitus: optimal management of multivessel disease (FREEDOM) Trials. Each appraisal was performed according the standard EBM practices. A thorough design and analytic critique was performed for each study and the results presented and explained. The guideline recommendations were reviewed in terms of the veracity of the evidence cited. The relative difference in major adverse cardiac and cerebrovascular event (MAACE) rates between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are not the 30% level reported by the SYNTAX Trial but closer to 11% difference when study limitations are factored in. Similarly, the 30% effect size in MAACE rates between procedures from the FREEDOM Trial is closer to a non-significant 5% relative difference when limitations are adjusted for. Based on the actual findings of each study, outcomes from procedures by CABG or PCI for multivessel revascularisation are similar and contradict the conclusions of the study authors as well as the recommendations. These recommendations fail to inform current clinical practice. PMID- 29531771 TI - Progressive left ventricular dysfunction and long-term outcomes in patients with Duchenne muscular dystrophy receiving cardiopulmonary therapies. AB - Objective: To describe the natural history of cardiomyopathy in patients with Duchenne muscular dystrophy (DMD) who are receiving contemporary therapies. Methods: This is a single-institution retrospective cohort study of 57 patients aged >15 years with DMD. Serial digital echocardiograms were performed over a median follow-up of 8 years. Left ventricular dysfunction (LVD) was defined as shortening fraction (SF) <29% plus focal wall motion abnormalities. Therapies included ACE inhibitors, beta-blockers and assisted ventilation. Results: The SF declined progressively in 53/57 patients (93%). LVD occurred in 40 of 57 patients (70%), with variable age at onset (median 18 years, IQR 14-21.5 years). Rate of SF decline (-1.51%+/-1.16%/year) was variable and unrelated to genotype. However, survival was shorter for patients with LVD onset at age <18 years vs onset at >=18 years (death at 21.1+/-2.5 years vs 33.1+/-4.4 years; P<0.001). Death occurred in 27/57 (47%) patients at a median age of 26.3 years (IQR 20.6-31.5). Death was preceded by LVD in 22/27 patients (81%), 15 (68%) of whom developed class 4 heart failure (CHF). Time from CHF to death was brief (median 8.0 months). Conclusion: Despite contemporary therapies, SF declined progressively in almost all patients. Age at onset of LVD and age at death were variable and unrelated to genotype; however, survival was shortened for patients with LVD onset at age <18 years. Death was usually preceded by LVD. CHF was a sentinel event, with death occurring shortly thereafter. PMID- 29531772 TI - Remission and low disease activity in systemic lupus erythematosus: an achievable goal even with fewer steroids? Real-life data from a monocentric cohort. AB - Objectives: To evaluate what proportion of patients fulfil the DORIS definition of remission, the definition of lupus low disease activity state (LLDAS) and LLDAS with a glucocorticoid (GC) dosage <=5 (LLDAS5) in a longitudinal monocentric cohort of patients with SLE; to identify predictors of sustained remission and LLDAS attainment; to evaluate the effect of sustained remission and LLDAS on damage accrual over a period of 5 years and compare the two conditions in terms of clinical outcomes. Methods: Retrospective analysis of data prospectively collected from patients with SLE followed from 2012 to 2016. Results: 115 patients were included in this analysis. At baseline, 72% of patients were on LLDAS and almost all patients also fulfilled the LLDAS5 definition; 45% of patients were in remission on treatment, 12% were in remission off treatment, 26% were in complete remission on treatment, 2% were in complete remission off treatment. Disease activity at baseline was the strongest predictor of subsequent LLDAS and remission; the presence of joint and cutaneous manifestations was associated with a minor likelihood to achieve LLDAS or remission during follow-up.Patients in remission and LLDAS for the whole follow up period accrued significantly less organ damage; on the contrary, patients who maintained all kinds of remissions or LLDAS for less than 50% of the time did not show any differences in damage accrual with respect to the rest of the cohort. Conclusion: Remission and LLDAS, even with reduced GC use, are an achievable goal in clinical practice; sustained LLDAS and remission are both associated with reduced damage accrual. PMID- 29531773 TI - Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus. AB - Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with varied morbidity and mortality. We assessed clinical presentations, autoantibody specificities and therapeutic interventions in Native American (NA) patients with SLE. Methods: Patients with SLE meeting 1997 American College of Rheumatology classification criteria (n=3148) were enrolled between 1992 and 2010 in the multiethnic, cross-sectional Lupus Family Registry and Repository. Clinical, demographic and therapeutic information were extracted from medical records using a standardised form and formalised training. Autoantibodies were assessed by indirect immunofluorescence (antinuclear antibodies (ANA) and antidouble-stranded DNA), precipitin (ENA) and ELISA (IgG and IgM anticardiolipins). Results: NA patients met SLE classification at a younger age (29.89+/-12.3 years) than European Americans (EA; 32.02+/-12.87, P=0.0157) and a similar age to African-Americans (AAs) and Hispanics (HIS). More NA patients had concurrent rheumatic diseases or symptoms, such as Raynaud's phenomenon, interstitial lung disease, Sjogren's syndrome and systemic sclerosis. Compared with EAs, NAs were more likely to have high-titre ANA (>=1:3240; P<0.0001) and had more SLE-associated autoantibodies. Autoantibodies with unknown specificities were more common in NAs (41%) compared with other racial/ethnic groups in this collection (AA: 24%, P=0.0006; EA: 17%, P<0.0001; HIS: 23%, P=0.0050). Fewer NA patients used hydroxychloroquine (68%) compared with others (AA: 74%, P=0.0308; EA: 79%, P=0.0001, HIS: 77%, P=0.0173); this was influenced by lower hydroxychloroquine use in NA patients from Latin America (32%). NA patients had higher rates of methotrexate use (28%) compared with AA (18%, P=0.0006) and HIS patients (14%, P=0.0003), higher azathioprine use (38%) compared with EA patients (30%, P=0.0105) and higher mycophenolate mofetil use (26%) compared with EA (17%, P=0.0012) and HIS patients (11%, P<0.0001). Conclusions: NA patients are diagnosed with SLE earlier in life and present worse concurrent rheumatic disease symptoms than EA patients. NA patients also are more likely to have expanded autoantibody profiles and precipitins of unknown specificities. PMID- 29531774 TI - A novel PGAP3 mutation in a Croatian boy with brachytelephalangy and a thin corpus callosum. AB - Biallelic mutations in the post-GPI attachment to proteins 3 (PGAP3) gene cause hyperphosphatasia with mental retardation syndrome 4 (HPMRS4), which is characterized by elevated serum alkaline phosphatase, severe psychomotor developmental delay, seizures, and facial dysmorphism. To date, 15 PGAP3 mutations have been reported in humans. Here we report a novel homozygous PGAP3 mutation (c.314C>A, p.Pro105Gln) in a Croatian patient and fully describe the clinical features. PMID- 29531775 TI - An unclassified variant of CHD7 activates a cryptic splice site in a patient with CHARGE syndrome. AB - CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous CHD7 mutations. A de novo variant in a CHD7 splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an "unclassified variant" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing. PMID- 29531776 TI - MRI findings of neuronal ceroid lipofuscinosis in a cat. AB - Case summary: A 2-year-old male domestic shorthair cat presented to the University of Liverpool Small Animal Teaching Hospital with a 2 week history of altered mentation, blindness and focal epileptic seizures. MRI examination revealed generalised cerebral and cerebellar atrophy, diffuse T2-weighted hyperintensity of the white matter and meningeal thickening. Neuronal ceroid lipofuscinosis was confirmed on post-mortem examination. Relevance and novel information: This is the first report of the MRI findings of neuronal ceroid lipofuscinosis in a cat. PMID- 29531777 TI - Net growth rate of continuum heterogeneous biofilms with inhibition kinetics. AB - Biofilm systems can be modeled using a variety of analytical and numerical approaches, usually by making simplifying assumptions regarding biofilm heterogeneity and activity as well as effective diffusivity. Inhibition kinetics, albeit common in experimental systems, are rarely considered and analytical approaches are either lacking or consider effective diffusivity of the substrate and the biofilm density to remain constant. To address this obvious knowledge gap an analytical procedure to estimate the effectiveness factor (dimensionless substrate mass flux at the biofilm-fluid interface) was developed for a continuum heterogeneous biofilm with multiple limiting-substrate Monod kinetics to different types of inhibition kinetics. The simple perturbation technique, previously validated to quantify biofilm activity, was applied to systems where either the substrate or the inhibitor is the limiting component, and cases where the inhibitor is a reaction product or the substrate also acts as the inhibitor. Explicit analytical equations are presented for the effectiveness factor estimation and, therefore, the calculation of biomass growth rate or limiting substrate/inhibitor consumption rate, for a given biofilm thickness. The robustness of the new biofilm model was tested using kinetic parameters experimentally determined for the growth of Pseudomonas putida CCRC 14365 on phenol. Several additional cases have been analyzed, including examples where the effectiveness factor can reach values greater than unity, characteristic of systems with inhibition kinetics. Criteria to establish when the effectiveness factor can reach values greater than unity in each of the cases studied are also presented. PMID- 29531778 TI - Association between glucocorticoid therapy and incidence of diabetes mellitus in polymyalgia rheumatica and giant cell arteritis: a systematic review and meta analysis. AB - Background: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are almost always treated with glucocorticoids (GCs), but long-term GC use is associated with diabetes mellitus (DM). The absolute incidence of this complication in this patient group remains unclear. Objective: To quantify the absolute risk of GC-induced DM in PMR and GCA from published literature. Methods: We identified literature from inception to February 2017 reporting diabetes following exposure to oral GC in patients with PMR and/or GCA without pre existing diabetes. A random-effects meta-analysis was performed to summarise the findings. Results: 25 eligible publications were identified. In studies of patients with GCA, mean cumulative GC dose was almost 1.5 times higher than in studies of PMR (8.2 g vs 5.6 g), with slightly longer treatment duration and longer duration of follow-up (6.4 years vs 4.4 years). The incidence proportion (cumulative incidence) of patients who developed new-onset DM was 6% (95% CI 3% to 9%) for PMR and 13% (95% CI 9% to 17%) for GCA. Based on UK data on incidence rate of DM in the general population, the expected background incidence rate of DM over 4.4 years in patients with PMR and 6.4 years in patients with GCA (follow up duration) would be 4.8% and 7.0%, respectively. Heterogeneity between studies was high (I2=79.1%), as there were differences in study designs, patient population, geographical locations and treatment. Little information on predictors of DM was found. Conclusion: Our meta-analysis produced plausible estimates of DM incidence in patients with PMR and GCA, but there is insufficient published data to allow precise quantification of DM risk. PMID- 29531779 TI - Prevalence of axial spondyloarthritis in patients with acute anterior uveitis: a cross-sectional study utilising MRI. AB - Objective: Acute anterior uveitis (AAU) is the most common extra-articular manifestation of axial spondyloarthritis (axSpA). In this study, patients presenting with AAU were evaluated clinically and with MRI in order to estimate the prevalence of axSpA. Methods: Consecutive patients presenting to a university teaching hospital between February 2014 and March 2015 with AAU were invited to participate. Those with a history of chronic back pain (CBP) beginning <45 years were evaluated clinically and with MRI of thoracolumbar spine and sacroiliac joints. Results: Of 366 patients with AAU, 57 had a pre-existing diagnosis of axSpA; 77 others fulfilled the study eligibility criteria and 73 (95%) completed the study. Seventeen patients (23.3%) were diagnosed with axSpA by an experienced rheumatologist; of these, eight were human leucocyte antigen-B27 negative. Including those with a previous diagnosis, this equates to a minimum axSpA prevalence of 20.2%; one-quarter of patients were previously undiagnosed. Conclusion: This is the first study to actively search for the presence of axSpA in unselected patients presenting with AAU utilising MRI as an essential part of the assessment. There is a significant burden of undiagnosed axSpA in patients with AAU, but there does not appear to be a simple mechanism for screening. We recommend that ophthalmologists refer all patients with AAU with CBP, onset <45 years, to rheumatology for further evaluation. PMID- 29531780 TI - Long-term efficacy and predictors of remission following adalimumab treatment in peripheral spondyloarthritis: 3-year results from ABILITY-2. AB - Objectives: Describe efficacy and safety of 3 years of adalimumab treatment in patients with peripheral spondyloarthritis (pSpA) and identify predictors of remission. Methods: Patients with pSpA were randomised to adalimumab 40 mg every other week or placebo for 12 weeks; a 144-week open-label extension followed (NCT01064856). Remission was assessed by the Peripheral SpA Response Criteria (PSpARC) and Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS ID). Logistic regression analyses were performed to determine predictors of remission at 1 and 3 years and sustained remission (>=24 consecutive weeks). Results: In 165 patients, ASDAS ID was achieved by 47% at 1 year and 39% at 3 years; 36% and 33% achieved PSpARC remission, respectively. Sustained ASDAS ID and PSpARC remission were achieved by 52% (86/165) and 42% (70/165) of patients, respectively. Achieving ASDAS ID at week 12 significantly predicted 1 year (OR, 8.64 (95% CI 2.97 to 25.14)), 3 year (OR, 36.12 (95% CI 2.29 to 569.08)) and sustained ASDAS ID (OR, 8.01 (95% CI 2.47 to 25.97)); achieving PSpARC remission at week 12 consistently predicted 1 year (OR, 6.47 (95% CI 1.91 to 21.95)), 3 years (OR, 15.66 (95% CI 4.19 to 58.56)) and sustained PSpARC remission (OR, 20.27 (95% CI 5.37 to 76.46)). No baseline variables consistently predicted 1 year or 3-year remission or sustained remission. The safety profile of adalimumab was consistent with observations in other SpA disease indications. Conclusions: In patients with pSpA, early response to adalimumab, but not baseline demographics or disease characteristics, was a better predictor of long-term remission. PMID- 29531781 TI - Hospitalisation rates among patients with primary Sjogren's syndrome: a population-based study, 1995-2016. AB - Objective: To determine rates and primary discharge diagnoses of hospitalisation in a cohort of patients with incident primary Sjogren's syndrome (pSS) compared with the general population. Methods: This was a retrospective population-based cohort study focused on Olmsted County, Minnesota. The pSS cohort consisted of patients with incident pSS in the 1976-2015 period and was compared with a cohort of individuals without pSS matched 3:1 for age, sex and calendar year, randomly selected from the same population. Hospitalisations in 1995-2016 were examined. Discharge diagnoses were categorised using the Clinical Classifications Software for International Classification of Diseases, 9th revision, Clinical Modification. Results: A total of 385 hospitalisations occurred in the 160 patients with pSS during 1592 person-years of follow-up. Among 466 comparators, there were 899 hospitalisations during 4660 person-years of follow-up, resulting in a significantly higher rate of hospitalisations in patients with pSS (rate ratio (RR): 1.25, 95% CI: 1.11 to 1.41). Rates of hospitalisation were increased among patients with pSS for endocrine, nutritional and metabolic diseases and immunity disorders (RR 1.82, 95% CI 1.08 to 2.98), diseases of the musculoskeletal system and connective tissue (RR 1.49, 95% CI 1.05 to 2.05) and for injuries and poisoning (RR 1.46, 95% CI 1.01 to 2.06). While not significantly increased overall, hospitalisations for diseases of the circulatory system were significantly increased in patients with pSS aged >=75 years (RR 1.54, 95% CI 1.11 to 2.11). Conclusions: Patients with pSS experienced higher rates of hospitalisation than the general population. Hospitalisations for endocrine/metabolic disorders, diseases of the circulatory system, diseases of the musculoskeletal system and connective tissue disorders, and injuries were more common among patients with pSS than comparators. PMID- 29531782 TI - Physician global assessments for disease activity in rheumatoid arthritis are all over the map! AB - Introduction: Physician global assessments of disease activity (medical doctor (MD) globals) are important outcomes. MD globals may vary based on their age, gender, practice setting and experience (number of patients seen per year and years in practice). Methods: We determined the variability of MD globals, surveying rheumatologists from the Canadian Rheumatology Association using rheumatoid arthiritis (RA) cases rated by MD for disease activity from 0 to 10. Cases were developed to span the spectrum of disease activity. Kappa, intraclass correlation (ICC) coefficients and linear mixed models were used. Results: 109 responded to the survey (approximately 30% response). The range of MD globals for the same scenario was as high as 7.6 out of 10, indicating vast discrepancies between physicians. Some scenarios outlined changes in individual patients; however, physicians surveyed were often in disagreement as to how much the patient recovered or worsened but the direction was the same (ie, if better all agreed). When physician-related factors were analysed separately, MD global scores were significantly influenced by age and experience (ranked by a physician, number of patients seen per year and years in clinical practice) in linear mixed models. Multivariate analysis revealed borderline significance for two age categories (56-65 years, P=0.049; over 65 years, P=0.058) and those who have seen 600-800 patients per year (P=0.056). Conclusions: This emphasises the need to establish evaluation criteria in RA for disease. Perhaps, a catalogue of patient scenarios that range from 0 to 10 could be developed, standardised and agreed on to decrease the wide variability of ranking by rheumatologists. PMID- 29531783 TI - Atlas for the OMERACT thumb base osteoarthritis MRI scoring system (TOMS). AB - This paper presents an atlas for the Outcome Measures in Rheumatology Clinical Trials (OMERACT) thumb base osteoarthritis MRI scoring system (TOMS). The atlas includes reference images of each grade of each feature that is assessed in TOMS (synovitis grade 0-3, subchondral bone defects grade 0-3, osteophytes grade 0-3, cartilage assessment grade 0-3, subluxation and bone marrow lesions grade 0-3) in the first carpometacarpal and scapho-trapezio-trapezoid joint. The presented reference images can be used to guide scoring of thumb base MRIs in patients with hand osteoarthritis according to the OMERACT TOMS. PMID- 29531784 TI - Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study. AB - Objectives: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. Methods: Forty-one subjects were randomised into two cohorts of verinurad (2.5-20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid. Results: Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7-12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose dependent manner: least-squares means Emax was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmax by 19.0%-32.4% and area under the plasma concentration-time curve from time zero to the last measurable time point by 20.8%-39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes. Conclusion: Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration number: NCT02498652. PMID- 29531785 TI - Don't neglect nutrition in rheumatoid arthritis! PMID- 29531786 TI - MRI of psoriatic nail disease pre- and post-TNF inhibitor therapy shows persistent subclinical inflammation after 6 months despite good clinical response. PMID- 29531787 TI - Design and rationale of the Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA). AB - Objective: To evaluate the efficacy of etanercept and methotrexate as monotherapies and as combination therapy in subjects with active psoriatic arthritis (PsA). Methods: The Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA) is an ongoing, global, double-blind, 48-week, randomised, controlled study. Subjects are randomised (1:1:1) to etanercept monotherapy, methotrexate monotherapy or etanercept-methotrexate combination therapy. Endpoints include rates of ACR20 response and Minimal Disease Activity, measures to characterise extra-articular manifestations (dactylitis, enthesitis, nail disease) and safety. Conclusion: SEAM-PsA will characterise the effects of etanercept with and without background methotrexate and methotrexate alone on PsA manifestations, and provide information of practical importance to clinicians on the optimal treatment of PsA. PMID- 29531788 TI - Imaging in diagnosis, outcome prediction and monitoring of large vessel vasculitis: a systematic literature review and meta-analysis informing the EULAR recommendations. AB - Objectives: To perform a systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis (LVV) informing the European League Against Rheumatism recommendations for imaging in LVV. Methods: Systematic literature review (until 10 March 2017) of diagnostic and prognostic studies enrolling >20 patients and investigating ultrasound, MRI, CT or positron emission tomography (PET) in patients with suspected and/or established primary LVV. Meta-analyses were conducted, whenever possible, obtaining pooled estimates for sensitivity and specificity by fitting random effects models. Results: Forty-three studies were included (39 on giant cell arteritis (GCA), 4 on Takayasu arteritis (TAK)). Ultrasound ('halo' sign) at temporal arteries (8 studies, 605 patients) and MRI of cranial arteries (6 studies, 509 patients) yielded pooled sensitivities of 77% (95% CI 62% to 87%) and 73% (95% CI 57% to 85%), respectively, compared with a clinical diagnosis of GCA. Corresponding specificities were 96% (95% CI 85% to 99%) and 88% (95% CI 81% to 92%). Two studies (93 patients) investigating PET for GCA diagnosis reported sensitivities of 67%-77% and specificities of 66%-100% as compared with clinical diagnosis or temporal artery biopsy. In TAK, one study each evaluated the role of magnetic resonance angiography and CT angiography for diagnostic purposes revealing both a sensitivity and specificity of 100%. Studies on outcome prediction and monitoring disease activity/damage were limited and mainly descriptive. Conclusions: Ultrasound and MRI provide a high diagnostic value for cranial GCA. More data on the role of imaging for diagnosis of extracranial large vessel GCA and TAK, as well as for outcome prediction and monitoring in LVV are warranted. PMID- 29531789 TI - Knee joint synovitis: study of correlations and diagnostic performances of ultrasonography compared with histopathology. AB - Objectives: Ultrasonography (US) is a fast, available and low-cost imaging tool used for detecting knee synovitis. Our aims were to assess the relationship between US and histology findings in appraising levels of inflammation and vascularity in the knee joint in subjects with inflammatory arthropathies; to determine whether differences exist in the appraisal between varying knee compartments and to compare US performances compared with gold standard histology for knee synovitis detection. Methods: Subjects with actively inflamed knee joint having crystal arthropathies, rheumatoid arthritis, psoriatic arthritis or ostoearthritis were prospectively recruited from rheumatology clinics after giving their written consent between May and October 2015. Study was approved by the institutional ethics committee. The knee was divided into three compartments (medial, lateral, superior). Patients had a knee US followed by a knee arthroscopy with biopsies retrieval from each compartment. Biopsies were blindly scored for lining layer hyperplasia, inflammation, vascularity, CD68 and factor VIII staining. Correlation was determined using the Spearman's correlation test. Results: 26 patients with active arthritis in a knee joint and recent onset of disease were prospectively included. Strong correlations were observed between US synovitis grade and histological inflammation score (r=0.63; P=0.002), US Doppler grade and histological score for vascularity (r=0.68; P<0.001); US measured synovial thickness and lining layer hyperplasia (r=0.61; P=0.002). Moderate correlation was found between US synovitis grade and CD68 score (r=0.49; P=0.02). Conclusion: US findings correlate with histological inflammation and vascularity scores in actively inflamed knee joints. US accurately describes knee synovitis. PMID- 29531790 TI - Improving the peer review skills of young rheumatologists and researchers in rheumatology: the EMEUNET Peer Review Mentoring Program. AB - Although peer review plays a central role in the maintenance of high standards in scientific research, training of reviewing skills is not included in the common education programmes. The Emerging EULAR (European League Against Rheumatism) Network (EMEUNET) developed a programme to address this unmet need. The EMEUNET Peer Review Mentoring Program for Rheumatology Journals promotes a systematic training of reviewing skills by engaging mentees in a 'real world' peer review experience supervised by experienced mentors with support from rheumatology journals. This viewpoint provides an overview of this initiative and its outcomes, and discusses its potential limitations. Over 4 years, 18 mentors and 86 mentees have participated. Among the 33 participants who have completed the programme, 13 (39.3%) have become independent reviewers for Annals of the Rheumatic Diseases after the training. This programme has been recently evaluated by a survey and qualitative interviews, revealing a high interest in this initiative. The main strengths (involvement of a top journal and learning opportunities) and weaknesses of the programme (limited number of places and insufficient dissemination) were identified. Overall, this programme represents an innovative and successful approach to peer review training. Continuous evaluation and improvement are key to its functioning. The EMEUNET Peer Review Mentoring Program may be used as a reference for peer review training in areas outside rheumatology. PMID- 29531792 TI - DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins. AB - Cell-to-cell transmission of misfolded proteins propagates proteotoxic stress in multicellular organisms when transmitted polypeptides serve as a seeding template to cause protein misfolding in recipient cells, but how misfolded proteins are released from cells to initiate this process is unclear. Misfolding-associated protein secretion (MAPS) is an unconventional protein-disposing mechanism that specifically exports misfolded cytosolic proteins including various neurodegenerative disease-causing proteins. Here we establish the HSC70 co chaperone DNAJC5 as an essential mediator of MAPS. USP19, a previously uncovered MAPS regulator binds HSC70 and acts upstream of HSC70 and DNAJC5. We further show that as a membrane-associated protein localized preferentially to late endosomes and lysosomes, DNAJC5 can chaperone MAPS client proteins to the cell exterior. Intriguingly, upon secretion, misfolded proteins can be taken up through endocytosis and eventually degraded in the lysosome. Collectively, these findings suggest a transcellular protein quality control regulatory pathway in which a deubiquitinase-chaperone axis forms a "triaging hub", transferring aberrant polypeptides from stressed cells to healthy ones for disposal. PMID- 29531794 TI - Role of CT angiography in bilateral pulmonary sequestration: a case report. AB - Bilateral pulmonary sequestration (PS) is a very rare congenital malformation. We describe a case of bilateral intralobar pulmonary sequestration (ILS) in a newborn. Both sequestrations received arterial supply from separate branches of the descending aorta and venous drainage was into ipsilateral inferior pulmonary veins. Prenatal ultrasonography showed cystic changes in the lungs. Computed tomography angiography (CTA) with supplemental two-dimensional (2D) and three dimensional (3D) images was performed to clearly define the pathology and revealed bilateral intralobar pulmonary sequestration with aberrant blood supply. The child underwent successful video-assisted thoracoscopic surgical (VATS) lobectomy on the left side and thoracoscopic wedge resection on the right side. There were no complications. CTA with supplemental 2D and 3D images plays a vital role in revealing the exact pathology in congenital pulmonary malformations associated with anomalous vasculature. PMID- 29531791 TI - Evidence for a second ankylosing spondylitis-associated RUNX3 regulatory polymorphism. AB - Objectives: To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS). Methods: Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR. Results: We confirmed the independent association of AS with rs4265380, which was robust (P=4.7*10-6) to conditioning on another nearby AS-associated RUNX3 SNP (rs4648889). A RUNX3 haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95% CI 3.1 to 13.2, P=1.4*10-8). In a large UK cohort, rs4265380 is associated with leucocyte counts (including monocytes). RUNX3 expression is lower in AS peripheral blood mononuclear cells than healthy controls (P<0.002), independent of rs4265380 genotype. Enhancer function for this RUNX3 region was suggested by increased luciferase activity (approximately tenfold; P=0.005) for reporter constructs containing rs4265380. In monocytes, there was differential allelic binding of nuclear protein extracts to a 50 bp DNA probe containing rs4265380 that was strongly augmented by lipopolysaccharide activation. TF binding also included the histone modifier p300. There was enrichment for histone modifications associated with active enhancer elements (H3K27Ac and H3K79Me2) that may be allele dependent. Hi-C database interrogation showed chromosome interactions of RUNX3 bait with the nearby RP4-799D16.1 lincRNA. Conclusions: The association of AS with this RUNX3 regulatory region involves at least two SNPs apparently operating in different cell types. Monocytes may be potential therapeutic targets in AS. PMID- 29531793 TI - Matrix Stiffness Enhances VEGFR-2 Internalization, Signaling, and Proliferation in Endothelial Cells. AB - Vascular endothelial growth factor (VEGF) can mediate endothelial cell migration, proliferation, and angiogenesis. During cancer progression, VEGF production is often increased to stimulate the growth of new blood vessels to supply growing tumors with the additional oxygen and nutrients they require. Extracellular matrix stiffening also occurs during tumor progression, however, the crosstalk between tumor mechanics and VEGF signaling remains poorly understood. Here, we show that matrix stiffness heightens downstream endothelial cell response to VEGF by altering VEGF receptor-2 (VEGFR-2) internalization, and this effect is influenced by cell confluency. In sub-confluent endothelial monolayers, VEGFR-2 levels, but not VEGFR-2 phosphorylation, are influenced by matrix rigidity. Interestingly, more compliant matrices correlated with increased expression and clustering of VEGFR-2; however, stiffer matrices induced increased VEGFR-2 internalization. These effects are most likely due to actin-mediated contractility, as inhibiting ROCK on stiff substrates increased VEGFR-2 clustering and decreased internalization. Additionally, increasing matrix stiffness elevates ERK 1/2 phosphorylation, resulting in increased cell proliferation. Moreover, cells on stiff matrices generate more actin stress fibers than on compliant substrates, and the addition of VEGF stimulates an increase in fiber formation regardless of stiffness. In contrast, once endothelial cells reached confluency, stiffness-enhanced VEGF signaling was no longer observed. Together, these data show a complex effect of VEGF and matrix mechanics on VEGF-induced signaling, receptor dynamics, and cell proliferation that is mediated by cell confluency. PMID- 29531795 TI - Growth of the colon and rectum throughout gestation: evaluation with fetal MRI. AB - Background: Congenital abnormalities of the gastrointestinal tract are increasingly being evaluated by prenatal magnetic resonance imaging (MRI). However, there is a paucity of reports describing the normal quantitative development of the fetal colon and rectum on MRI. Purpose: To provide growth curves of the MRI estimated diameter of the fetal colon and rectum as a function of gestational age. Material and Methods: This is a retrospective review of 191 singleton fetal MRI studies at 25-39 weeks of gestation. Measurements included maximal diameter of the ascending, transverse, and descending colon on coronal and sagittal views, maximal diameter of the rectum on coronal and sagittal views, and maximal diameter of the rectum at the level of the bladder base on sagittal views. Median growth curves were built using a generalized additive model. Confidence regions were built for 10th, 25th, 75th, and 90th percentiles. Results: Smoothed growth curves for the median, and one and three quartiles for each of the five sections as a function of gestational age were calculated. All graphs had a slightly exponential curve. Conclusion: This study provides normal ranges of the prenatal colon and rectum as a function of gestational age. They may serve as reference values when interpreting fetal MRI. PMID- 29531796 TI - Two-stage corrective surgery for severe rigid cervical kyphotic deformity with unilateral vertebral artery occlusion after old blunt trauma: a case report. AB - Introduction: There are considerable risks for vertebral artery (VA) injury in case of corrective surgery for a severe and rigid cervical kyphotic deformity. This case report describes a rare case of surgical management for pre-existing traumatic rigid cervical kyphosis associated with unilateral VA occlusion. Case presentation: A 73-year-old male fell down and injured his neck. He was referred to our hospital 10 months after injury because his degree of head drop progressed gradually to a chin-on-chest position such that he could not look straight forward. On plain X-ray, the C2-7 angles in the neutral, flexion, and extension positions were 61 degrees , 71 degrees , and 50 degrees , respectively. CT revealed a collapse of the C5 vertebral body and bone fusion between C4 and C5 in the anterior vertebrae, and unilateral VA occlusion was confirmed by angiography. Two-stage surgery was planned to correct the kyphosis. In the first stage, anterior release of the C4/5 bone-spur fusion and dissection of the intervertebral disk were performed. After release, angiography confirmed neither occlusion nor rupture of the VA. In the second stage, anterior and posterior fixation was performed at correcting position while maintaining slight kyphosis in order to avoid excessive distortion of the VA. The postoperative C2-7 kyphosis angle improved to 16 degrees without any VA injury, and the patient could look forward easily. Discussion: The degree of correction as well as risk management of VAs should be considered carefully during corrective surgery for severe and rigid cervical kyphosis, especially with unilateral VA occlusion. PMID- 29531797 TI - Aspergillus spinal epidural abscess: case presentation and review of the literature. AB - Study design: In this review, we present a case of Aspergillus spinal epidural abscess (ASEA) and review the literature. Objectives: To provide further insight on a rare condition. Setting: A description of a patient with ASEA in a 58-year old woman that was successfully treated with conservative management is presented. Methods: Following case presentation, a literature search (MedLine and PubMed) and assessment of epidemiology, presentation, diagnosis, treatments, and outcomes is performed. Results: Review of the literature finds 26 reported cases. The infection occurs in males with a higher frequency (66.7%). The thoracic and lumbar regions are more likely afflicted (96.1%). Common symptoms are backache, neurological deficits, and fever. Most frequent comorbidities were malignancy, diabetes mellitus, and immunodeficiency. Complications were numerous and often catastrophic. Treatment entailed a combination of antibiotics and surgery. Overall, ASEA patients did poorly: death in majority (52%), minimal recovery in 22%, and others did attain full recovery (26%). Conclusions: Generally, this infection has high morbidity and mortality. Early identification is important to a successful outcome. Appropriate management with antifungals is central and proves to be effective as seen in the reported case though surgical intervention is usually a necessity as the literature suggests. From an epidemiological and public health perspective, particularly with recent outbreaks, understanding the treatment of this rare CNS infection becomes even more imperative. PMID- 29531798 TI - Fountain of youth of pancreatic cancer cells: the extracellular matrix. PMID- 29531799 TI - WAH-1/AIF regulates mitochondrial oxidative phosphorylation in the nematode Caenorhabditis elegans. AB - Impaired mitochondrial energy metabolism contributes to a wide range of pathologic conditions, including neurodegenerative diseases. Mitochondrial apoptosis-inducing factor (AIF) is required for the correct maintenance of mitochondrial electron transport chain. An emerging body of clinical evidence indicates that several mutations in the AIFM1 gene are causally linked to severe forms of mitochondrial disorders. Here we investigate the consequence of WAH 1/AIF deficiency in the survival of the nematode Caenorhabditis elegans. Moreover, we assess the survival of C. elegans strains expressing a disease associated WAH-1/AIF variant. We demonstrate that wah-1 downregulation compromises the function of the oxidative phosphorylation system and reduces C. elegans lifespan. Notably, the loss of respiratory subunits induces a nuclear encoded mitochondrial stress response independently of an evident increase of oxidative stress. Overall, our data pinpoint an evolutionarily conserved role of WAH-1/AIF in the maintenance of proper mitochondrial activity. PMID- 29531800 TI - IRE1alpha deficiency promotes tumor cell death and eIF2alpha degradation through PERK dipendent autophagy. AB - Sensors of endoplasmic reticulum (ER) stress function in a co-ordinated manner. In the present study we investigated the relationship between IRE1alpha and PERK pathways and survival of ER stressed U937 cells and BC3 cells. To this end, we investigated the effects of a subcytotoxic concentration of Tunicamycin in IRE1alpha-proficient and in IRE1alpha-deficient cells, by pharmacological inhibition with 4MU8 C or down-regulation by specific siRNA. We show that either type of IRE1alpha deficiency affects eIF2alpha expression and causes cell death increase. GSK2606414, a PERK inhibitor, and PERK specific siRNA prevent eIF2alpha down-regulation and restore cell survival. Degradation of this protein is due to autophagy, as it is prevented by bafilomycin and not by proteasome inhibition. Furthermore, activation of the autophagy flux is PERK dependent. Also the Cathepsin B inhibitor CA074 prevents eIF2alpha from degradation and reduces cell death. Altogether, these results show that IRE1alpha deficiency in ER stressed cells leads to an unexpected decrease of eIF2alpha, an important molecule for protein translation, through PERK dependent autophagy. Thus, IRE1/XBP1 inhibitors may represent a feasible strategy for tumor therapy, while PERK inhibitors may vanish the goal. PMID- 29531801 TI - Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis. AB - Alzheimer's disease (AD) is characterized by two neuropathological hallmarks: senile plaques, which are composed of amyloid-beta (Abeta) peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Abeta peptides are derived from sequential proteolytic cleavage of the amyloid precursor protein (APP). In this study, we identified a so far unknown mode of regulation of APP protein synthesis involving the MID1 protein complex: MID1 binds to and regulates the translation of APP mRNA. The underlying mode of action of MID1 involves the mTOR pathway. Thus, inhibition of the MID1 complex reduces the APP protein level in cultures of primary neurons. Based on this, we used one compound that we discovered previously to interfere with the MID1 complex, metformin, for in vivo experiments. Indeed, long-term treatment with metformin decreased APP protein expression levels and consequently Abeta in an AD mouse model. Importantly, we have initiated the metformin treatment late in life, at a time-point where mice were in an already progressed state of the disease, and could observe an improved behavioral phenotype. These findings together with our previous observation, showing that inhibition of the MID1 complex by metformin also decreases tau phosphorylation, make the MID1 complex a particularly interesting drug target for treating AD. PMID- 29531802 TI - Cross-talk between androgen receptor and nerve growth factor receptor in prostate cancer cells: implications for a new therapeutic approach. PMID- 29531803 TI - Glucose-6-phosphate dehydrogenase is critical for suppression of cardiac hypertrophy by H2S. AB - Hydrogen Sulfide (H2S), recently identified as the third endogenously produced gaseous messenger, is a promising therapeutic prospect for multiple cardio pathological states, including myocardial hypertrophy. The molecular niche of H2S in normal or diseased cardiac cells is, however, sparsely understood. Here, we show that beta-adrenergic receptor (beta-AR) overstimulation, known to produce hypertrophic effects in cardiomyocytes, rapidly decreased endogenous H2S levels. The preservation of intracellular H2S levels under these conditions strongly suppressed hypertrophic responses to adrenergic overstimulation, thus suggesting its intrinsic role in this process. Interestingly, unbiased global transcriptome sequencing analysis revealed an integrated metabolic circuitry, centrally linked by NADPH homeostasis, as the direct target of intracellular H2S augmentation. Within these gene networks, glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme (producing NADPH) in pentose phosphate pathway, emerged as the critical node regulating cellular effects of H2S. Utilizing both cellular and animal model systems, we show that H2S-induced elevated G6PD activity is critical for the suppression of cardiac hypertrophy in response to adrenergic overstimulation. We also describe experimental evidences suggesting multiple processes/pathways involved in regulation of G6PD activity, sustained over extended duration of time, in response to endogenous H2S augmentation. Our data, thus, revealed H2S as a critical endogenous regulator of cardiac metabolic circuitry, and also mechanistic basis for its anti-hypertrophic effects. PMID- 29531804 TI - Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies. AB - In vitro modeling of complex diseases is now a possibility with the use of patient-derived induced pluripotent stem (iPS) cells. Their stem cell properties, including self-renewal and their potential to virtually differentiate into any cell type, emphasize their importance as a translational tool for modeling disorders that so far have been limited by the unavailability of primary cell lines, animal models, or inaccessible human materials. Around 100 genes with germline mutations have been described to be responsible for cancer predisposition. Familial cancers are usually diagnosed earlier in life since these patients already carry the first transforming hit. Deriving iPS cells from patients suffering from familial cancers provides a valuable tool for understanding the mechanisms underlying pediatric cancer onset and progression since they require less mutation recurrence than adult cancers to develop. At the same time, some familial mutations are found in sporadic cases and are a valuable prognostic tool. Patient-derived iPS cells from germline malignancies can also create new tools in developing specific drugs with more personalized-therapy strategies. PMID- 29531805 TI - Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. AB - Human immunodeficiency virus-1 (HIV) infection of the central nervous system promotes neuronal injury that culminates in HIV-associated neurocognitive disorders. Viral proteins, including transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Tat transgenic mice or neurons exposed to Tat, which show neuronal loss, exhibit smaller mitochondria as compared to controls. To provide an experimental clue as to which mechanisms are used by Tat to promote changes in mitochondrial morphology, rat cortical neurons were exposed to Tat (100 nM) for various time points. Within 30 min, Tat caused a significant reduction in mitochondrial membrane potential, a process that is regulated by fusion and fission. To further assess whether Tat changes these processes, fission and fusion proteins dynamin-related protein 1 (Drp1) and mitofusin-2 (Mfn2), respectively, were measured. We found that Drp1 levels increased beginning at 2 h after Tat exposure while Mfn2 remained unchanged. Moreover, increased levels of an active form of Drp1 were found to be present following Tat exposure. Furthermore, Drp1 and calcineurin inhibitors prevented Tat-mediated effects on mitochondria size. These findings indicate that mitochondrial fission is likely the leading factor in Tat-mediated alterations to mitochondrial morphology. This disruption in mitochondria homeostasis may contribute to the instability of the organelle and ultimately neuronal cell death following Tat exposure. PMID- 29531806 TI - Quantitative peptidomics of endogenous peptides involved in TGF-beta1-induced epithelial mesenchymal transition of renal epithelial cells. AB - TGF-beta1 is a key fibrotic factor mediating epithelial mesenchymal transition (EMT) of epithelial cells through various signaling pathways. However, roles of proteolytic cleavage and endogenous peptide dynamics in TGF-beta1-induced EMT remain unknown. We therefore performed quantitative peptidomics of TGF-beta1 induced EMT in renal tubular epithelial cells. The acquired mesenchymal characteristics were confirmed, including morphological change (from cobblestone like to fibroblast-like), decreased epithelial marker (ZO-1), and increased mesenchymal marker (vimentin). Quantitative peptidomics using stable isotope labeling revealed significantly altered levels of 70 unique endogenous peptides (derived from internal and C-terminal parts of 39 unique precursor proteins) after EMT induction. Interestingly, the majority of these peptides were derived from non-short-lived proteins, and analysis of P1 position revealed predominance of hydrophobic residues, suggesting that these endogenous peptides were generated mainly from proteasome cleavage. This hypothesis was confirmed by treating the cells with MG132 (a proteasome inhibitor), which provided almost identical endogenous peptide pattern as of the TGF-beta1-treated cells. Moreover, validation assay showed marked reduction of proteasome peptidase activity in both TGF-beta1-treated and MG132-treated cells. This is the first peptidome dataset that provides several novel aspects of mechanisms for TGF-beta1-induced EMT. Our data also suggest that TGF-beta1 exerts inhibitory effect against proteasome activity during EMT induction. PMID- 29531807 TI - NF-kappaB inhibition by dimethylaminoparthenolide radiosensitizes non-small-cell lung carcinoma by blocking DNA double-strand break repair. AB - Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-kappaB pathway is a proposed mechanism of radiosensitization. Here we demonstrate that inhibition of the canonical NF-kappaB pathway by dimethylaminoparthenolide (DMAPT) radiosensitizes NSCLC by blocking DNA double strand break (DSB) repair. NF-kappaB inhibition results in significant impairment of both homologous recombination (HR) and non-homologous end joining (NHEJ), as well as reductions in ionizing radiation (IR)-induced DNA repair biomarkers. NF kappaB inhibition by DMAPT shows preclinical potential for further investigation as a NSCLC radiosensitizer. PMID- 29531808 TI - PLEKHN1 promotes apoptosis by enhancing Bax-Bak hetro-oligomerization through interaction with Bid in human colon cancer. AB - The anti-apoptotic nature of cancer cells often impedes the effects of anti cancer therapeutic agents. Multiple death signals influence mitochondria during apoptosis, and though many studies have attempted to elucidate these complicated pathways, Bax oligomerization, an important step in the process, remains controversial. Here we demonstrate that pleckstrin-homology N1 (PLEKHN1), also known as cardiolipin phosphatidic acid binding protein, plays pro-apoptotic roles during reactive oxygen species (ROS)-induced apoptosis. Human PLEKHN1 was expressed in several cancer cell lines of differing origin. Its expression was regulated by hypoxia, and it existed in the mitochondrial fraction. Genome editing of hPLEKHN1 in human colon cancer HT-29 cells revealed enhanced survival of knockout cells compared with that of parental cells in vitro and in vivo. Thapsigargin or hydrogen peroxide treatment activated multiple death signals including JNK, Bcl-2 family members, and caspases. PLEKHN1 was bound to Bid, a pro-apoptotic protein, and not to Bax, and PLEKHN1 could remove Bid from transient Bid-Bax complexes. Fluorescent time-lapse imaging revealed that PLEKHN1 aggregated with Bid during thapsigargin- or hydrogen peroxide-induced apoptosis prior to Bax aggregation. Inhibition of PLEKHN1 led to attenuation of Bax-Bak hetero-oligomerization and Bid translocation. The immunohistochemistry of cancer patient specimens showed that PLEKHN1 expression was absent from cancer region at the transition area of normal/cancer tissues. Collectively, the silencing of PLEKHN1 may be the key that cancer cells acquire the drug resistance. PMID- 29531809 TI - Na+/Ca2+ exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca2+ regulation during neuronal differentiation. AB - Nuclear envelope (NE) is a Ca2+-storing organelle controlling neuronal differentiation through nuclear Ca2+ concentrations ([Ca2+]n). However, how [Ca2+]n regulates this important function remains unknown. Here, we investigated the role of the nuclear form of the Na+/Ca2+ exchanger 1(nuNCX1) during the different stages of neuronal differentiation and the involvement of PTEN/PI3'K/Akt pathway. In neuronal cells, nuNCX1 was detected on the inner membrane of the NE where protein expression and activity of the exchanger increased during NGF-induced differentiation. nuNCX1 activation by Na+-free perfusion induced a time-dependent activation of nuclear-resident PI3K/Akt pathway in isolated nuclei. To discriminate the contribution of nuNCX1 from those of plasma membrane NCX, we generated a chimeric protein composed of the fluorophore EYFP, the exchanger inhibitory peptide, and the nuclear localization signal, named XIP-NLS. Fura-2 measurements on single nuclei and patch-clamp experiments in whole-cell configuration showed that XIP-NLS selectively inhibited nuNCX1. Once it reached the nuclear compartment, XIP-NLS increased the nucleoplasmic Ca2+ peak elicited by ATP and reduced Akt phosphorylation, GAP-43 and MAP-2 expression through nuclear-resident PTEN induction. Furthermore, in accordance with the prevention of the neuronal phenotype, XIP-NLS significantly reduced TTX-sensitive Na+ currents and membrane potential during neuronal differentiation. The selective inhibition of nuNCX1 by XIP-NLS increased the percentage of beta III tubulin-positive immature neurons in mature cultures of MAP-2-positive cortical neurons, thus unraveling a new function for nuNCX1 in regulating neuronal differentiation through [Ca2+]n-dependent PTEN/PI3K/Akt pathway. PMID- 29531810 TI - Lithium induces mesenchymal-epithelial differentiation during human kidney development by activation of the Wnt signalling system. AB - Kidney function is directly linked to the number of nephrons which are generated until 32-36 weeks gestation in humans. Failure to make nephrons during development leads to congenital renal malformations, whilst nephron loss in adulthood occurs in progressive renal disease. Therefore, an understanding of the molecular processes which underlie human nephron development may help design new treatments for renal disease. Mesenchyme to epithelial transition (MET) is critical for forming nephrons, and molecular pathways which control rodent MET have been identified. However, we do not know whether they are relevant in human kidney development. In this study, we isolated mesenchymal cell lines derived from human first trimester kidneys in monolayer culture and investigated their differentiation potential. We found that the mesenchymal cells could convert into osteogenic, but not adipogenic or endothelial lineages. Furthermore, addition of lithium chloride led to MET which was accompanied by increases in epithelial (CDH1) and tubular (ENPEP) markers and downregulation of renal progenitor (SIX2, EYA1, CD133) and mesenchymal markers (HGF, CD24). Prior to phenotypic changes, lithium chloride altered Wnt signalling with elevations in AXIN2, GSK3beta phosphorylation and beta-catenin. Collectively, these studies provide the first evidence that lithium-induced Wnt activation causes MET in human kidneys. Therapies targeting Wnts may be critical in the quest to regenerate nephrons for human renal diseases. PMID- 29531812 TI - Modulation of nuclear factor-kappa B activation by the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in breast cancer cells. AB - Stress responses are critical for estrogen (E2)-induced apoptosis in E2-deprived breast cancer cells. Nuclear factor-kappa B (NF-kappaB) is an important therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-kappaB to participate in stress-associated apoptosis in E2-deprived breast cancer cells is unknown. Here, we demonstrated that E2 differentially modulates NF-kappaB activity according to treatment time. E2 initially has significant potential to suppress NF-kappaB activation; it completely blocks tumor necrosis factor alpha (TNFalpha)-induced activation of NF-kappaB. We found that E2 preferentially and constantly enhances the expression of the adipogenic transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta), which is responsible for the suppression of NF-kappaB activation by E2 in MCF-7:5C cells. Interestingly, NF-kappaB p65 DNA-binding activity is increased when E2 is administered for 48 h, leading to the induction of TNFalpha and associated apoptosis. Blocking the nuclear translocation of NF kappaB can completely prevent the induction of TNFalpha and apoptosis induced by E2. Further examination revealed that protein kinase RNA-like endoplasmic reticulum kinase (PERK), a stress sensor of unfolded protein response (UPR), plays an essential role in the late activation of NF-kappaB by E2. This modulation between PERK and NF-kappaB is mainly mediated by a stress responsive transcription factor, transducer and activator of transcription 3 (STAT3), independently of the classic canonical IkappaBalpha signaling pathway. Thus, inhibition of PERK kinase activity completely blocks the DNA binding of both STAT3 and NF-kappaB, thereby preventing induction of NF-kappaB-dependent genes and E2-induced apoptosis. All of these findings suggest that PERK is a key regulator to convey stress signals from the endoplasmic reticulum to the nucleus and illustrate a crucial role for the novel PERK/STAT3/NF-kappaB/TNFalpha axis in E2-induced apoptosis in E2-deprived breast cancer cells. PMID- 29531811 TI - Single-cell analyses of human islet cells reveal de-differentiation signatures. AB - Human pancreatic islets containing insulin-secreting beta-cells are notoriously heterogeneous in cell composition. Since beta-cell failure is the root cause of diabetes, understanding this heterogeneity is of paramount importance. Recent reports have cataloged human islet transcriptome but not compared single beta cells in detail. Here, we scrutinized ex vivo human islet cells from healthy donors and show that they exhibit de-differentiation signatures. Using single cell gene expression and immunostaining analyses, we found healthy islet cells to contain polyhormonal transcripts, and INS+ cells to express decreased levels of beta-cell genes but high levels of progenitor markers. Rare cells that are doubly positive for progenitor markers/exocrine signatures, and endocrine/exocrine hormones were also present. We conclude that ex vivo human islet cells are plastic and can possibly de-/trans-differentiate across pancreatic cell fates, partly accounting for beta-cell functional decline once isolated. Therefore, stabilizing beta-cell identity upon isolation may improve its functionality. PMID- 29531813 TI - FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation. AB - Alcohol consumption is generally well tolerated by the liver but in some individuals it results in persistent inflammation and liver disease. The mechanisms that regulate alcohol-induced liver inflammation are poorly understood. The transcription factor FOXO3 has previously been shown to be involved in suppressing alcohol-induced liver injury. In this study we demonstrate that in response to alcohol, approximately 10% of mouse hepatic macrophages undergo FOXO3-dependent apoptosis. By 3 days of alcohol exposure total hepatic macrophage numbers declined by 30% but these were restored to normal after 10 days of continued exposure. Whole body or myeloid specific Foxo3 /- mice failed to show this apoptotic response. After 10 days of alcohol exposure, Foxo3-/- mice had an increased basal inflammatory phenotype and an increase in the proportion of pro-inflammatory CD11b+, Ly6C+ infiltrating macrophages (IMs) infiltrating. This led to marked sensitivity to LPS with a 5 fold ALT elevation and liver injury after LPS challenge in Foxo3-/- but not WT mice. Restoring the early macrophage apoptosis burst with a pulse of intravenous GdCl3 at day 2 had no effect on the day 10 phenotype of WT mice but it corrected the hyper-inflammatory phenotype in Foxo3-/- mice. In conclusion, FOXO3-dependent hepatic macrophage apoptosis in response to ethanol serves to promote differentiation of infiltrating macrophages thus limiting the magnitude of the inflammatory response to ethanol. PMID- 29531814 TI - 2-aminopurine suppresses the TGF-beta1-induced epithelial-mesenchymal transition and attenuates bleomycin-induced pulmonary fibrosis. AB - The epithelial-mesenchymal transition (EMT) is a multifunctional cell process involved in the pathogenesis of numerous conditions, including fibrosis and cancer. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by fibroblast accumulation and collagen deposition in the lungs. The fibroblasts involved in this process partially originate from lung epithelial cells via the EMT. Evidence suggests that the EMT contributes to progression, invasion, and metastasis of various types of cancer. We screened a series of 80 compounds for the ability to interfere with the EMT and potentially be applied as a therapeutic for IPF and/or lung cancer. We identified 2-aminopurine (2-AP), a fluorescent analog of guanosine and adenosine, as a candidate in this screen. Herein, we demonstrate that 2-AP can restore E-cadherin expression and inhibit fibronectin and vimentin expression in TGF-beta1-treated A549 lung cancer cells. Moreover, 2-AP can inhibit TGF-beta1-induced metastasis of A549 cells. This compound significantly attenuated bleomycin (BLM)-induced pulmonary inflammation, the EMT, and fibrosis. In addition, 2-AP treatment significantly decreased mortality in a mouse model of pulmonary fibrosis. Collectively, we determined that 2-AP could inhibit metastasis in vitro by suppressing the TGF-beta1-induced EMT and could attenuate BLM-induced pulmonary fibrosis in vivo. Results of this study suggest that 2-AP may have utility as a treatment for lung cancer and pulmonary fibrosis. PMID- 29531815 TI - Flubendazole inhibits glioma proliferation by G2/M cell cycle arrest and pro apoptosis. AB - Flubendazole, FDA-approved anthelmintic, has been widely used in treating testinal parasites. In the recent years, Flubendazole has been reported to exert anticancer activities. On the other hand, little was known about the effects of Flubendazole on gliomas. Here we demonstrated a novel effect of flubendazole on glioma cells. We found that Flubendazole inhibited cell proliferation and promoted cell apoptosis of glioma cell lines in vitro, and suppressed tumor growth in xenograft models by intraperitoneal injection. However, Flubendazole might have no influence on cell migration. Mechanism study reaveled that Flubendazole caused cell cycle arrest in G2/M phase, which partly account for the suppressed proliferation. Consistently, Flubendazole induced P53 expression and reduced Cyclin B1 and p-cdc2 expression in glioma cells. In addition, Flubendazole promoted cell apoptosis by regulating the classical apoptosis protein BCL-2 expression. These observations suggest that Flubendazole exerts anti-proliferation and pro-apoptosis effects in Glioma through affecting the cell cycle and intrinsic apoptotic signaling, and indicate a novel utilization of Flubendazole in the treatment of Glioma. PMID- 29531816 TI - Gomesin peptides prevent proliferation and lead to the cell death of devil facial tumour disease cells. AB - The Tasmanian devil faces extinction due to devil facial tumour disease (DFTD), a highly transmittable clonal form of cancer without available treatment. In this study, we report the cell-autonomous antiproliferative and cytotoxic activities exhibited by the spider peptide gomesin (AgGom) and gomesin-like homologue (HiGom) in DFTD cells. Mechanistically, both peptides caused a significant reduction at G0/G1 phase, in correlation with an augmented expression of the cell cycle inhibitory proteins p53, p27, p21, necrosis, exacerbated generation of reactive oxygen species and diminished mitochondrial membrane potential, all hallmarks of cellular stress. The screening of a novel panel of AgGom-analogues revealed that, unlike changes in the hydrophobicity and electrostatic surface, the cytotoxic potential of the gomesin analogues in DFTD cells lies on specific arginine substitutions in the eight and nine positions and alanine replacement in three, five and 12 positions. In conclusion, the evidence supports gomesin as a potential antiproliferative compound against DFTD disease. PMID- 29531817 TI - GCN2 controls the cellular checkpoint: potential target for regulating inflammation. PMID- 29531818 TI - Preserving self-renewal of porcine pluripotent stem cells in serum-free 3i culture condition and independent of LIF and b-FGF cytokines. AB - Derivation of bona fide porcine pluripotent stem cells is still a critical issue because porcine embryonic stem cells (ESCs) are not available yet, and most of the culture conditions to maintain porcine induced pluripotent stem cells (piPSCs) are based on conditions for mouse and human iPS cells. In this study, we generated a doxycycline-inducible porcine iPS cell line (DOX-iPSCs) and used it to screen the optimal culture condition to sustain the self-renewal of piPSCs. We found that LIF and b-FGF were required for porcine cell reprogramming, but were not essential cytokines for maintaining the self-renewal and pluripotency of piPSCs. A serum-free 3i medium, which includes three inhibitors CHIR99021, SB431542, and PD0325901, three cytokines BMP4, SCF, and IL-6, and human platelet lysates (PL), was made through serious selections. In 3i condition, the doxycycline-inducible iPSCs could be passaged for a long term without the addition of doxycycline, and the flattened morphology of intermediate state piPSCs could convert to the naive-like morphology with the increase in endogenous pluripotent gene expressions. Additionally, pPSC cell line isolated from 5.5 days blastocysts could be sustained in 3i medium and the expression of endogenous pluripotent genes OCT4, ESRRB, and STELLA was significantly increased. Our finding directed a new reprogramming strategy by using 3i condition to maintain and convert primed piPSCs into naive-like pluripotent state. A combination of traditional LIF/b-FGF conditions and 3i condition may help us to find out an appropriate reprogramming approach to generate the naive state of porcine iPSCs. PMID- 29531819 TI - Mechanism of inhibition of Shiga-toxigenic Escherichia coli SubAB cytotoxicity by steroids and diacylglycerol analogues. AB - Shiga toxigenic Escherichia coli (STEC) are responsible for a worldwide foodborne disease, which is characterized by severe bloody diarrhea and hemolytic uremic syndrome (HUS). Subtilase cytotoxin (SubAB) is a novel AB5 toxin, which is produced by Locus for Enterocyte Effacement (LEE)-negative STEC. Cleavage of the BiP protein by SubAB induces endoplasmic reticulum (ER) stress, followed by induction of cytotoxicity in vitro or lethal severe hemorrhagic inflammation in mice. Here we found that steroids and diacylglycerol (DAG) analogues (e.g., bryostatin 1, Ingenol-3-angelate) inhibited SubAB cytotoxicity. In addition, steroid-induced Bcl-xL expression was a key step in the inhibition of SubAB cytotoxicity. Bcl-xL knockdown increased SubAB-induced apoptosis in steroid treated HeLa cells, whereas SubAB-induced cytotoxicity was suppressed in Bcl-xL overexpressing cells. In contrast, DAG analogues suppressed SubAB activity independent of Bcl-xL expression at early time points. Addition of Shiga toxin 2 (Stx2) with SubAB to cells enhanced cytotoxicity even in the presence of steroids. In contrast, DAG analogues suppressed cytotoxicity seen in the presence of both toxins. Here, we show the mechanism by which steroids and DAG analogues protect cells against SubAB toxin produced by LEE-negative STEC. PMID- 29531820 TI - Warm blood cardioplegia versus cold crystalloid cardioplegia for myocardial protection during coronary artery bypass grafting surgery. AB - We retrospectively analyzed early results of coronary artery bypass grafting (CABG) surgery using two different types of cardioplegia for myocardial protection: antegrade intermittent warm blood or cold crystalloid cardioplegia. From January 2015 to October 2016, 330 consecutive patients underwent isolated on pump CABG. Cardiac arrest was obtained with use of warm blood cardioplegia (WBC group, n = 297) or cold crystalloid cardioplegia (CCC group, n = 33), according to the choice of the surgeon. Euroscore II and preoperative characteristics were similar in both groups, except for the creatinine clearance, slightly lower in WBC group (77.33 +/- 27.86 mL/min versus 88.77 +/- 51.02 mL/min) (P < 0.05). Complete revascularization was achieved in both groups. In-hospital mortality was 2.0% (n = 6) in WBC group, absent in CCC group. The required mean number of cardioplegia's doses per patient was higher in WBC group (2.3 +/- 0.8) versus CCC group (2.0 +/- 0.7) (P = 0.045), despite a lower number of distal coronary artery anastomoses (2.7 +/- 0.8 versus 3.2 +/- 0.9) (P = 0.0001). Cardiopulmonary and aortic cross-clamp times were similar in both groups. The incidence of perioperative myocardial infarction (WBC group 3.4% versus CCC group 3.0%) and low cardiac output syndrome (4.4% versus 3.0%) were similar in both groups. As compared with WBC group, in CCC group CK-MB/CK ratio >10% was lower during each time points of evaluation, with a statistical significant difference at time 0 (4% +/- 1.6% versus 5% +/- 2.5%) (P = 0.021). In presence of complete revascularization, despite the value of CK-MB/CK ratio >10% was less in the CCC group, clinical results were not affected by both types of cardioplegia adopted to myocardial protection. As compared with cold crystalloid, warm blood cardioplegia requires a shorter interval of administration to achieve better myocardial protection. PMID- 29531821 TI - #2714, a novel active inhibitor with potent G2/M phase arrest and antitumor efficacy in preclinical models. AB - Arresting cell cycle has been one of the most common approaches worldwide in cancer therapy. Specifically, arresting cells in the G2/M phase is a promising therapeutic approach in the battle against lung cancer. In the present study, we demonstrated the anticancer activities and possible mechanism of compound #2714, which can prompt G2/M phase arrest followed by cell apoptosis induction in Lewis lung carcinoma LL/2 cells. In vitro, #2714 significantly inhibited LL/2 cell viability in a concentration- and time-dependent manner while exhibiting few toxicities on non-cancer cells. The mechanism study showed that cell proliferation inhibition due to the treatment with #2714 correlated with G2/M phase arrest and was followed by LL/2 cell apoptosis. The characterized changes were associated with the downregulation of phosphorylated cell division cycle 25C (Cdc25C) and upregulation of p53. Apoptosis-associated activation of cleaved caspase-3 was also detected. Moreover, #2714 strongly attenuated LL/2 cell proliferation by disrupting the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). In vivo, intraperitoneal administration of #2714 (25-100 mg/kg/day) to mice bearing established tumors in xenograft models significantly prevented LL/2 tumor growth (58.1%) without detectable toxicity. Compound #2714 significantly increased apoptosis in LL/2 lung cancer cells in mice models, as observed via terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and the data from an immunohistochemical analysis showed that #2714 remarkably inhibited the proliferation and angiogenesis of lung cancer in vivo. Taken together, our data suggest that #2714 has a high potential anti-lung cancer efficacy with a pathway-specific mechanism of G2/M phase arrest and subsequent apoptosis induction both in vitro and in vivo; its potential to be an anticancer candidate warrants further investigation. PMID- 29531822 TI - GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion. AB - The modern understanding of the G protein-coupled receptor kinase 2 has grown towards the definition of a stress protein, for its ability to rapidly compartmentalize within the cell in response to acute stimulation. Also, mitochondria can be regulated by GRK2 localization. We show that Ionizing Radiation (IR) exposure acutely damages mitochondria regarding mass, morphology, and respiration, with recovery in a framework of hours. This phenomenon is actively regulated by GRK2, whose overexpression results to be protective, and reciprocally, deletion accelerates degenerative processes. The regulatory effects of the kinase involve a new interactome that includes binding HSP90 and binding and phosphorylation of the key molecules involved in the process of mitochondrial fusion and recovery: MFN-1 and 2. PMID- 29531823 TI - Sotetsuflavone suppresses invasion and metastasis in non-small-cell lung cancer A549 cells by reversing EMT via the TNF-alpha/NF-kappaB and PI3K/AKT signaling pathway. AB - Epithelial-mesenchymal transition (EMT) is associated with tumor invasion and metastasis, and offers insight into novel strategies for cancer treatment. Sotetsuflavone was isolated from Cycas revolute, which has excellent anticancer activity in the early stages. The present study aims to evaluate the anti metastatic potential of sotetsuflavone in vitro. Our data demonstrated that sotetsuflavone inhibits metastasis of A549 cells, and EMT. This inhibition was reflected in the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, and Snail. Mechanistically, our study demonstrated that HIF-1alpha played an important role in the anti-metastatic effect of sotetsuflavone in non small-cell lung cancer A549 cells. Sotetsuflavone not only mediated VEGF expression but also downregulated VEGF and upregulated angiostatin, and simultaneously affected the expression of MMPs and decreased MMP-9 and MMP-13 expression. More importantly, HIF-1alpha expression may be regulated by the inhibition of PI3K/AKT and TNF-alpha/NF-kappaB pathways. These results suggest that sotetsuflavone can reverse EMT, thereby inhibiting the migration and invasion of A549 cells. This process may be associated with both PI3K/AKT and TNF alpha/NF-kappaB pathways, and sotetsuflavone may be efficacious in the treatment of non-small-cell lung cancer. PMID- 29531824 TI - NR4A2 protects cardiomyocytes against myocardial infarction injury by promoting autophagy. AB - Myocardial infarction (MI), characterized by ischemia-induced cardiomyocyte apoptosis, is the leading cause of mortality worldwide. NR4A2, a member of the NR4A orphan nucleus receptor family, is upregulated in mouse hearts with MI injury. Furthermore, NR4A2 knockdown aggravates heart injury as evidenced by enlarged hearts and increased apoptosis. To elucidate the underlying mechanisms of NR4A2-regulated apoptosis, we used H9c2 cardiomyocytes deprived of serum and neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia to mimic ischemic conditions in vivo. As NR4A2 knockdown aggravates cardiomyocyte apoptosis, while NR4A2 overexpression ameliorates it, NR4A2 upregulation was considered an adaptive response to ischemia-induced cardiomyocyte apoptosis. By detecting changes in LC3 and using autophagy detection tools including Bafilomycin A1, 3MA and rapamycin, we found that NR4A2 knockdown promoted apoptosis through blocking autophagic flux. This apoptotic response was phenocopied by downregulation of NR4A2 after autophagic flux was impaired by Bafilomycin A1. Further study showed that NR4A2 binds to p53 directly and decreases its levels when it inhibits apoptosis; thus, p53/Bax is the downstream effector of NR4A2-mediated apoptosis, as previously reported. Changes in p53/Bax that were regulated by NR4A2 were also detected in injured hearts with NR4A2 knockdown. In addition, miR-212-3p is the upstream regulator of NR4A2, and it could downregulate the expression of NR4A2, as well as p53/Bax. The mechanism underlying the role of NR4A2 in apoptosis and autophagy was elucidated, and NR4A2 may be a therapeutic drug target for heart failure. PMID- 29531825 TI - Magnolol restores the activity of meropenem against NDM-1-producing Escherichia coli by inhibiting the activity of metallo-beta-lactamase. AB - The emergence of plasmid-mediated New Delhi metallo-beta-lactamase-1 (NDM-1) in carbapenem-resistant Gram-negative pathogens is an increasing clinical threat. Here we report the discovery of an NDM-1 inhibitor, magnolol, through enzyme inhibition screening. We showed that magnolol significantly inhibited NDM enzyme activity (IC50 = 6.47 ug/mL), and it restored the activity of meropenem against Escherichia coli ZC-YN3, an NDM-1-producing E. coli isolate, in in vitro antibacterial activity assays. Magnolol lacked direct antibacterial activity, but compared with meropenem alone, it reduced the MICs of meropenem against E. coli ZC-YN3 by 4-fold and killed almost all the bacteria within 3 h. Molecular modeling and a mutational analysis demonstrated that magnolol binds directly to the catalytic pocket (residues 110 to 200) of NDM-1, thereby blocking the binding of the substrate to NDM-1 and leading to its inactivation. Our results demonstrate that the combination of magnolol and meropenem may have the potential to treat infections caused by NDM-1-positive, carbapenem-resistant Gram-negative pathogens. PMID- 29531826 TI - BIX-01294 sensitizes renal cancer Caki cells to TRAIL-induced apoptosis through downregulation of survivin expression and upregulation of DR5 expression. AB - BIX-01294 (BIX), a G9a histone methyltransferase inhibitor, has been reported for its anti-proliferative and anticancer activities against various cancer cell lines. In this study, we investigated whether BIX could sensitize TRAIL-mediated apoptosis in various cancer cells. Combined treatment with BIX and TRAIL markedly induced apoptosis in human renal carcinoma (Caki, ACHN, and A498), breast carcinoma (MCF-7), and lung carcinoma (A549) cells. In contrast, BIX and TRAIL co treatment did not induce apoptosis in normal cells, specifically mouse kidney cell (TCMK-1) and human skin fibroblast (HSF). BIX downregulated protein expression levels of XIAP and survivin at the post-translational level. Overexpression of survivin markedly blocked combined BIX and TRAIL treatment induced apoptosis, but XIAP had no effect. Furthermore, BIX induced upregulation of DR5 expression at the transcriptional levels, and knockdown of DR5 expression using small interfering RNAs (siRNAs) markedly attenuated BIX and TRAIL-induced apoptosis. Interestingly, siRNA-mediated G9a histone methyltransferase knockdown also enhanced TRAIL-induced apoptosis in Caki cells. However, knockdown of G9a did not change expression levels of XIAP, survivin, and DR5. Therefore, BIX mediated TRAIL sensitization was independent of histone methyltransferase G9a activity. Taken together, these results suggest that BIX facilitates TRAIL mediated apoptosis via downregulation of survivin and upregulation of DR5 expression in renal carcinoma Caki cells. ? BIX facilitates TRAIL-mediated apoptosis in human renal carcinoma Caki cells. ? Downregulation of survivin contributes to BIX plus TRAIL-induced apoptosis. ? Upregulation of DR5 is involved in BIX plus TRAIL-mediated apoptosis. ? BIX-mediated TRAIL sensitization is independent of ROS production. PMID- 29531827 TI - Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages. AB - Mycobacterium fortuitum is a natural fish pathogen. It induces apoptosis in headkidney macrophages (HKM) of catfish, Clarias sp though the mechanism remains largely unknown. We observed M. fortuitum triggers calcium (Ca2+) insult in the sub-cellular compartments which elicits pro-apototic ER-stress factor CHOP. Alleviating ER-stress inhibited CHOP and attenuated HKM apoptosis implicating ER stress in the pathogenesis of M. fortuitum. ER-stress promoted calpain activation and silencing the protease inhibited caspase-12 activation. The study documents the primal role of calpain/caspase-12 axis on caspase-9 activation in M. fortuitum-pathogenesis. Mobilization of Ca2+ from ER to mitochondria led to increased mitochondrial Ca2+ (Ca2+)m load,, mitochondrial permeability transition (MPT) pore opening, altered mitochondrial membrane potential (DeltaPsim) and cytochrome c release eventually activating the caspase-9/-3 cascade. Ultra structural studies revealed close apposition of ER and mitochondria and pre treatment with (Ca2+)m-uniporter (MUP) blocker ruthenium red, reduced Ca2+ overload suggesting (Ca2+)m fluxes are MUP-driven and the ER-mitochondria tethering orchestrates the process. This is the first report implicating role of sub-cellular Ca2+ in the pathogenesis of M. fortuitum. We summarize, the dynamics of Ca2+ in sub-cellular compartments incites ER-stress and mitochondrial dysfunction, leading to activation of pro-apoptotic calpain/caspase-12/caspase-9 axis in M. fortuitum-infected HKM. PMID- 29531828 TI - Thrombospondin-1 protects against Abeta-induced mitochondrial fragmentation and dysfunction in hippocampal cells. AB - Alzheimer's disease (AD) is often characterized by the impairment of mitochondrial function caused by excessive mitochondrial fragmentation. Thrombospondin-1 (TSP-1), which is primarily secreted from astrocytes in the central nervous system (CNS), has been suggested to play a role in synaptogenesis, spine morphology, and synaptic density of neurons. In this study, we investigate the protective role of TSP-1 in the recovery of mitochondrial morphology and function in amyloid beta (Abeta)-treated mouse hippocampal neuroblastoma cells (HT22). We observe that TSP-1 inhibits Abeta-induced mitochondrial fission by maintaining phosphorylated-Drp1 (p-Drp1) levels, which results in reduced Drp1 translocation to the mitochondria. By using gabapentin, a drug that antagonizes the interaction between TSP-1 and its neuronal receptor alpha2delta1, we observe that alpha2delta1 acts as one of the target receptors for TSP-1, and blocks the reduction of the p-Drp1 to Drp1 ratio, in the presence of Abeta. Taken together, TSP-1 appears to contribute to maintaining the balance in mitochondrial dynamics and mitochondrial functions, which is crucial for neuronal cell viability. These data suggest that TSP-1 may be a potential therapeutic target for AD. PMID- 29531829 TI - The genomic tool-kit of the truffle Tuber melanosporum programmed cell death. AB - A survey of the truffle Tuber melanosporum genome has shown the presence of 67 programmed cell death (PCD)-related genes. The 67 genes are all expressed during fruit body (FB) development of T. melanosporum development; their expression has been detected by DNA microarrays and qPCR. A set of 14 PCD-related genes have been chosen, those with the highest identities to the homologs of other species, for a deeper investigation. That PCD occurs during T. melanosporum development has been demonstrated by the TUNEL reaction and transmission electron microscopy. The findings of this work, in addition to the discovery of PCD-related genes in the T. melanosporum genome and their expression during the differentiation and development of the FB, would suggest that one of the PCD subroutines, maybe autophagy, is involved in the FB ripening, i.e., sporogenesis. PMID- 29531830 TI - Multiscale analysis of a regenerative therapy for treatment of volumetric muscle loss injury. AB - Skeletal muscle possesses a remarkable capacity to regenerate when injured, but when confronted with major traumatic injury resulting in volumetric muscle loss (VML), the regenerative process consistently fails. The loss of muscle tissue and function from VML injury has prompted development of a suite of therapeutic approaches but these strategies have proceeded without a comprehensive understanding of the molecular landscape that drives the injury response. Herein, we administered a VML injury in an established rodent model and monitored the evolution of the healing phenomenology over multiple time points using muscle function testing, histology, and expression profiling by RNA sequencing. The injury response was then compared to a regenerative medicine treatment using orthotopic transplantation of autologous minced muscle grafts (~1 mm3 tissue fragments). A chronic inflammatory and fibrotic response was observed at all time points following VML. These results suggest that the pathological response to VML injury during the acute stage of the healing response overwhelms endogenous and therapeutic regenerative processes. Overall, the data presented delineate key molecular characteristics of the pathobiological response to VML injury that are critical effectors of effective regenerative treatment paradigms. PMID- 29531831 TI - Common medium versus advanced IVF medium for cryopreserved oocytes in heterologous cycles. AB - Granulocyte-macrophage colony-stimulation factor plays different crucial roles during embryo implantation and subsequent development. Here we aimed to evaluate the effects of embryo cell culture medium, with the inclusion of granulocyte macrophage colony-stimulation factor (GM-CSF), on embryo development and pregnancy rate. To this end, we took advantage of our retrospective observational study to correlate the outcomes from two different culture media. We included in this study 25 unselected patient from our IVF Center that underwent heterologous IVF cycle with crypreserved oocytes. We analyze the fertilization rate, pregnancy rate, and embryo quality at different day of transfer obtained from two different media composition. Our results show that the rate of fertilization and the pregnancy rate were increased using medium added with this particular type of cytokines (GM-CSF). PMID- 29531832 TI - Characterization of dysregulated lncRNA-mRNA network based on ceRNA hypothesis to reveal the occurrence and recurrence of myocardial infarction. AB - Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) play important roles in initiation and development of human diseases. However, the mechanism of ceRNA regulated by lncRNA in myocardial infarction (MI) remained unclear. In this study, we performed a multi-step computational method to construct dysregulated lncRNA-mRNA networks for MI occurrence (DLMN_MI_OC) and recurrence (DLMN_MI_Re) based on "ceRNA hypothesis". We systematically integrated lncRNA and mRNA expression profiles and miRNA-target regulatory interactions. The constructed DLMN_MI_OC and DLMN_MI_Re both exhibited biological network characteristics, and functional analysis demonstrated that the networks were specific for MI. Additionally, we identified some lncRNA-mRNA ceRNA modules involved in MI occurrence and recurrence. Finally, two new panel biomarkers defined by four lncRNAs (RP1 239B22.5, AC135048.13, RP11-4O1.2, RP11-285F7.2) from DLMN_MI_OC and three lncRNAs (RP11-363E7.4, CTA-29F11.1, RP5-894A10.6) from DLMN_MI_Re with high classification performance were, respectively, identified in distinguishing controls from patients, and patients with recurrent events from those without recurrent events. This study will provide us new insight into ceRNA-mediated regulatory mechanisms involved in MI occurrence and recurrence, and facilitate the discovery of candidate diagnostic and prognosis biomarkers for MI. PMID- 29531833 TI - Novel biomarker ZCCHC13 revealed by integrating DNA methylation and mRNA expression data in non-obstructive azoospermia. AB - The objective of this study was to identify genes regulated by methylation that were involved in spermatogenesis failure in non-obstructive azoospermia (NOA). Testis biopsies of patients with NOA and OA (with normal spermatogenesis) were evaluated by microarray analysis to examine DNA methylation and mRNA expression using our established integrative approach. Of the coordinately hypermethylated and down-regulated gene list, zinc-finger CCHC-type containing 13 (ZCCHC13) was present within the nuclei of germ cells of testicular tissues according immunohistochemistry, and there was decreased protein expression in men with NOA compared with OA controls. Mechanistic analyses indicated that ZCCHC13 increased c-MYC expression through the p-AKT and p-ERK pathways. To confirm the changes in ZCCHC13 expression in response to methylation, 5-aza-2'-deoxycitidine (5-Aza), a hypomethylating agent, was administered to mouse spermatogonia GC-1 cells. We demonstrated that 5-Aza enhanced protein and mRNA expression of ZCCHC13 epigenetically, which was accompanied by activation of p-AKT and p-ERK signaling. Our data, for the first time, demonstrate that ZCCHC13 is an important signaling molecule that positively regulates the AKT/MAPK/c-MYC pathway and that methylation aberrations of ZCCHC13 may cause defects in testis development in human disease, such as NOA. PMID- 29531834 TI - Bcl-2 regulates store-operated Ca2+ entry to modulate ER stress-induced apoptosis. AB - Ca2+ plays a significant role in linking the induction of apoptosis. The key anti apoptotic protein, Bcl-2, has been reported to regulate the movement of Ca2+ across the ER membrane, but the exact effect of Bcl-2 on Ca2+ levels remains controversial. Store-operated Ca2+ entry (SOCE), a major mode of Ca2+ uptake in non-excitable cells, is activated by depletion of Ca2+ in the ER. Depletion of Ca2+ in the ER causes translocation of the SOC channel activator, STIM1, to the plasma membrane. Thereafter, STIM1 binds to Orai1 or/and TRPC1 channels, forcing them to open and thereby allow Ca2+ entry. In addition, several anti-cancer drugs have been reported to induce apoptosis of cancer cells via the SOCE pathway. However, the detailed mechanism underlying the regulation of SOCE by Bcl-2 is not well understood. In this study, a three-amino acid mutation within the Bcl-2 BH1 domain was generated to verify the role of Bcl-2 in Ca2+ handling during ER stress. The subcellular localization of the Bcl-2 mutant (mt) is similar to that in the wild-type Bcl-2 (WT) in the ER and mitochondria. We found that mt enhanced thapsigargin and tunicamycin-induced apoptosis through ER stress-mediated apoptosis but not through the death receptor- and mitochondria-dependent apoptosis, while WT prevented thapsigargin- and tunicamycin-induced apoptosis. In addition, mt depleted Ca2+ in the ER lumen and also increased the expression of SOCE-related molecules. Therefore, a massive Ca2+ influx via SOCE contributed to caspase activation and apoptosis. Furthermore, inhibiting SOCE or chelating either extracellular or intracellular Ca2+ inhibited mt-mediated apoptosis. In brief, our results explored the critical role of Bcl-2 in Ca2+ homeostasis and the modulation of ER stress. PMID- 29531835 TI - SLC2A5 promotes lung adenocarcinoma cell growth and metastasis by enhancing fructose utilization. AB - The metabolism of cancer cells is highly plastic. Cancer cells can change their preference for nutrient uptake under nutrient stress. Fructose is one of the most common carbohydrates in diet and its metabolism is also involved in the development and progression of tumors. GLUT5, encoded by SLC2A5, is the specific fructose transporter in mammalian cells. In this study, we found that SLC2A5 is significantly upregulated in lung adenocarcinoma (LUAD) patients and overexpression of SLC2A5 is highly correlated with poor prognosis of LUAD patients. The expression of SLC2A5 determined fructose uptake and utilization efficacy in LUAD cells. GLUT5 is critical for the survival of LUAD cells in fructose-containing culture medium. Depletion of SLC2A5 undermined cell proliferation and invasion meanwhile increased cell apoptosis. Overexpression of SLC2A5 enhances cell proliferation, migration, invasion, and tumorigenic. Compared to glucose, fructose is prone to strengthen intracellular-free fatty acid accumulation and ATP production. Moreover, inhibition of GLUT5 by specific small chemical inhibitor sensitizes LUAD cells to paclitaxel treatment. Taken together, our results suggest that GLUT5 could be a potential target alone or combination with other treatment for lung cancer therapy. PMID- 29531836 TI - Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. AB - Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient specific cardiac regenerative medicine. PMID- 29531837 TI - Exploratory pooled analysis evaluating the effect of sequence of biological therapies on overall survival in patients with RAS wild-type metastatic colorectal carcinoma. AB - Background: The aim of this study was to evaluate the optimal sequence of targeted therapies (epidermal growth factor receptor inhibitors (EGFRi) and vascular endothelial growth factor inhibitors (VEGFi)), combined with chemotherapy, in patients with RAS wild-type (WT) metastatic colorectal carcinoma (mCRC). Exploratory analyses of overall survival (OS) for patients treated with either first-line panitumumab (EGFRi) and second-line VEGFi therapy, or first line bevacizumab (VEGFi) and second-line EGFRi, were conducted. Methods: Patients from PEAK (NCT00819780), PRIME (NCT00364013) and Study 181 (NCT00339183), with RAS WT or RAS WT/BRAF WT tumours, were included in the analyses. OS data were pooled for patients receiving first-line panitumumab (PEAK and PRIME) or first line bevacizumab (PEAK and 181), followed by second-line VEGFi or EGFRi, respectively. Results: Overall, 104 RAS WT patients were included (n=66 panitumumab->VEGFi, n=38 bevacizumab->EGFRi). At the time of final data analysis, 63.6% versus 92.1% of patients in the panitumumab->VEGFi versus bevacizumab >EGFRi arms had died; median OS was 36.8 versus 27.8 months, respectively (HR 0.65; 95% CI 0.42 to 1.03). The OS HR for patients with RAS WT/BRAF WT mCRC overall was 0.58 (95% CI 0.36 to 0.95) and was 0.56 (95% CI 0.30 to 1.04) in those with left-sided tumours. Conclusion: Although numbers are small, these exploratory analyses suggest a trend towards improved OS for first-line panitumumab plus chemotherapy followed by second-line VEGFi, compared with first line bevacizumab followed by second-line EGFRi in patients with RAS WT and RAS WT/BRAF WT mCRC. Large prospective randomised trials are needed to further evaluate the optimum sequence of EGFRi/VEGFi in mCRC. PMID- 29531838 TI - Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan. AB - Background: Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. Patients and methods: The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. Results: Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. Conclusion: Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully. PMID- 29531839 TI - Prognostic indices of inflammatory markers, cognitive function and fatigue for survival in patients with localised colorectal cancer. AB - Background: Inflammation promotes the development of malignancy, while a variety of systemic markers of inflammation predict for worse cancer outcomes including recurrence and survival. Here, we evaluate the prognostic impact of cytokine concentrations, full blood count (FBC) differential ratios, cognitive function and fatigue on survival in patients with localised colorectal cancer (CRC). Patients and methods: Data are from a prospective longitudinal study comparing cognitive function and fatigue in patients with CRC who did (n=173) and did not (n=116) receive adjuvant/neoadjuvant chemotherapy. Baseline blood results (prior to any chemotherapy) included cytokines and FBC from which neutrophil lymphocyte ratio, lymphocyte monocyte ratio, platelet lymphocyte ratio and platelet monocyte ratio were derived. Fatigue was measured with the Functional Assessment of Cancer Therapy-Fatigue subscale and cognitive function by a neuropsychological test battery. Kaplan-Meier methods were used to estimate disease-free survival (DFS) and overall survival (OS). Univariable and multivariable Cox regression analyses were performed to evaluate factors potentially prognostic of outcomes. Results: At a median follow-up of 91.2 months, 227 subjects (79%) are still alive, and 212 (73%) have no evidence of a recurrence. Five-year OS and DFS are 86% (95% CI 81% to 90%) and 77% (95% CI 71% to 82%), respectively. None of the cytokines (interleukin (IL-6), IL-1 and tumour necrosis factor) or differential ratios of blood components, fatigue or cognitive function was statistically related to DFS or OS. Patient educational status (P=0.018), stage of disease (P=0.032), alanine transaminase (P=0.003), lactate dehydrogenase (P=0.008) and carcinoembryonic antigen (P=0.002) were significant as prognostic covariates of OS in univariable analyses, with similar results for DFS. Conclusion: None of the a priori selected markers of inflammation, fatigue or cognitive function was associated with OS or DFS in this cohort of patients. Trial registration number: NCT00188331, Post results. PMID- 29531840 TI - Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations. AB - Background: The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events. Patients and methods: Progression-free survival (PFS) and OS were re evaluated at the final data cut-off point (March 2017) for the entire population (n=80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report. Conclusions: This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice. Trial registration number: UMIN C000002789, Post-results. PMID- 29531841 TI - Impact of clinical response to neoadjuvant endocrine therapy on patient outcomes: a follow-up study of JFMC34-0601 multicentre prospective neoadjuvant endocrine trial. AB - Background: Neoadjuvant endocrine therapy (NET) has been demonstrated to improve breast-conserving rate and is a widely accepted treatment option for postmenopausal patients with hormone receptor-positive breast cancer. There are few reports on the association of NET response and long-term outcomes. Objectives: To investigate the prognostic value of clinical response to NET. Methods: Long-term outcomes of NET were examined in 107 patients who participated in the multicentre prospective neoadjuvant exemestane study, JFMC34-0601. Patients were treated with 25 mg/day exemestane for 16 weeks followed by an 8 week extension depending on the treatment response. Results: Clinical response included partial response (PR) in 58 patients, stable disease in 41 patients and progressive disease (PD) in 8 patients. Clinical response was significantly associated with disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P<0.0001 for all). Especially, patients with PD showed markedly poor outcomes with median DFS=17.8 months (HR (vs PR): 7.7 (95% CI 1.6 to 33)) and median OS=37.7 months (HR (vs PR): 26.3 (95% CI 2.4 to 655)). Preoperative endocrine prognostic index (PEPI) were associated with DFS and marginally with OS (P=0.022 and 0.066, respectively). PEPI=0 indicated an excellent prognosis with 95% 5-year DFS (95% CI 73 to 99). In the multivariate analysis including T stage, nodal status and Ki67, clinical response was an independent prognostic factor for DFS, DDFS and OS (P=0.032, 0.0007 and 0.020, respectively), whereas PEPI was marginally associated with DFS and OS (P=0.079 and 0.068, respectively). Conclusions: Clinical response to NET showed an independent prognostic value. Patients with PD had markedly poor prognosis, indicating a need of additional therapy. PEPI=0 indicated an excellent prognosis. The integration of clinical response and PEPI would improve decision-making with regard to treatment options for endocrine-responsive breast cancer when these results are validated in a larger clinical trial. Trial registration number: UMIN C000000345. PMID- 29531842 TI - Contemporary outcomes from the use of regular imaging to detect relapse in high risk cutaneous melanoma. AB - Background: Agreement on the utility of imaging follow-up in patients with high risk melanoma is lacking. A UK consensus statement recommends a surveillance schedule of CT or positron-emission tomography-CT and MRI brain (every 6 months for 3 years, then annually in years 4 and 5) as well as clinical examination for high-risk resected Stages II and III cutaneous melanoma. Our aim was to assess patterns of relapse and whether imaging surveillance could be of clinical benefit. Patients and methods: A retrospective study of patients enrolled between July 2013 and June 2015 from three UK tertiary cancer centres followed-up according to this protocol was undertaken. We evaluated time-to-recurrence (TTR), recurrence-free survival (RFS), method of detection and characteristics of recurrence, treatment received and overall survival (OS). Results: A total of 173 patients were included. Most (79%) had treated Stages IIIB and IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median TTR was 10.1 months and median RFS was 21.2 months. The majority of recurrences (66%) were asymptomatic and detected by scheduled surveillance scan. Fifty-six (68%) patients recurred with Stage IV disease, with a median OS of 25.3 months; 26 (31.7%) patients had a locoregional recurrence, median OS not reached (P=0.016). Patients who underwent surgery at recurrence for either Stage III (27%) or IV (18%) disease did not reach their median OS. The median OS for the 33 patients (40%) who received systemic therapy was 12.9 months. Conclusion: Imaging appears to reliably detect subclinical disease and identify patients suitable for surgery, conferring favourable outcomes. The short median TTR provides rationale to intensify imaging schedule in the first year of surveillance. The poor OS of patients treated with systemic therapy probably reflects the relatively inferior treatment options during this time and requires further evaluation in the current era. PMID- 29531843 TI - Carboplatin dose based on actual renal function: no excess of acute haematotoxicity in adjuvant treatment in seminoma stage I. AB - Introduction: The practice of carboplatin dosing is not concordant among different centres and oncologists. Some clinical guidelines recommend capping of the carboplatin dose at, for example, creatinine-clearance (Crea-Cl) of 125 mL/min because of concerns of excessive toxicity. Clinical data to support such recommendations are lacking, especially in patients with seminoma. Methods: This is a retrospective analysis of acute haematotoxicity of patients with stage I seminoma treated with adjuvant carboplatin area under the curve (AUC) 7 in routine practice in two Swiss centres in 2005-2015, and a comparison of incidence and grade (according to Common Terminology Criteria for Adverse Events v4.0) of haematological adverse events (hAEs) in patients with Crea-Cl <125 mL/min vs >125 mL/min without dose capping. Results: 74 patients with 229 documented measurements were included (median 3/patient). A total of 151 hAEs occurred. Platelet nadir occurred earlier than median white cell/neutrophil count (median day 15 vs day 22; P<0.0001). The majority of hAEs were mild, with more than 80% being of grade 1. Only two (2.7%) clinically relevant hAEs necessitating subsequent interventions occurred (one patient received platelet transfusion, one patient with febrile neutropaenia). Haematological toxicities were not statistically different in patients dosed with Crea-Cl >125 mL/min versus those with Crea-Cl <125 mL/min. No hAEs other than grade 1 occurred before day 10 and after day 24. Conclusions: Toxicity after single-dose carboplatin AUC 7 is generally mild. No excess of toxicity occurs in patients with high Crea-Cl above 125 mL/min, and therefore dose capping is not routinely necessary. In addition, this study provides a rationale for efficient use of healthcare services without compromising patients' safety. PMID- 29531844 TI - Perceptions of the quality of generic medicines: implications for trust in public services within the local health system in Tumkur, India. AB - Introduction: Generic medicines are an important policy option to reduce out-of pocket expenditure on medicines. However, negative perceptions of their quality affect utilisation and raise issues of confidence and trust in medicines and health services. The aim of the study was to test the quality of generic and branded medicines and explain negative perceptions towards generic medicines. Methods: The study was part of a larger study on access to medicines. Information on various quality parameters was collected for branded medicines and branded and unbranded generic versions of the same medicines from government and private pharmacies in Karnataka in Southern India. To assess perceptions related to quality and drivers of preferred point of care (public vs private), focus group discussions were conducted with diabetes and hypertension patients, health workers and private pharmacists. The results of the quality tests were assessed and thematic analysis was conducted on the qualitative data to develop a conceptual framework to explain perceptions of medicine and care quality in the local health system. Results: The generic and branded variants of the medicines tested were of comparable quality. Contrary to the quality test results, patients' and health workers' perceptions of quality were largely in favour of branded medicines. Negative perceptions of medicine quality along with other drivers contribute towards choosing more expensive medicines in the private sector. Trust in the health system emerged as an underlying central theme that explained and drove choice of medicines and providers within the local health system. Conclusion: Negative perceptions of generic medicines and preferential promotion of branded medicines over generics by pharmaceutical companies could influence prescriber behaviour and affect trust in healthcare provided in public services. To succeed, access to medicines programmes need to systematically invest in information on quality of medicines and develop strategies to build trust in healthcare offered in government health services. PMID- 29531845 TI - Expression of RecA and cell-penetrating peptide (CPP) fusion protein in bacteria and in mammalian cells. AB - Genome editing is a powerful tool to modify a specific gene and to correct a disease-causing mutation. Recently developed new techniques, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9), significantly facilitate the progression in this field. However, mutations associated with the double strand DNA breaks (DSBs) introduced by these systems hampered their direct usage in clinic. In order to prevent the mutations caused by DSBs, we have designed a novel mean to induce homology-directed recombination (HDR) without DSBs, i.e., the fusion protein of RecA with cell-penetrating peptide (CPP). The involvement of RecA in these fusion proteins will play important roles in formation of the nucleoprotein filament with single strand DNA (ssDNA) in vitro and promoting HDR in vivo; whereas the involvement of CPP in these fusion proteins will mainly play a role in facilitating cellular intake/uptake of the nucleoprotein filaments. Our results indicated that certain amount of the fusion proteins expressed in bacteria is in soluble fraction, whereas majority of the fusion proteins expressed in baby hamster kidney (BHK) cells is in soluble fraction. Interestingly, expression of these fusion proteins in bacteria completely blocked cell growth, whereas expression of them in BHK cells significantly inhibited cell growth, implying that these fusion proteins may bind to ssDNA regions, such as ssDNA regions in DNA replication forks, and inhibit cell growth. These results suggest that we have functional RecA.CPP fusion proteins ready to test our novel idea of inducing HDR without DSB. PMID- 29531846 TI - Enabling Histopathological Annotations on Immunofluorescent Images through Virtualization of Hematoxylin and Eosin. AB - Context: Medical diagnosis and clinical decisions rely heavily on the histopathological evaluation of tissue samples, especially in oncology. Historically, classical histopathology has been the gold standard for tissue evaluation and assessment by pathologists. The most widely and commonly used dyes in histopathology are hematoxylin and eosin (H&E) as most malignancies diagnosis is largely based on this protocol. H&E staining has been used for more than a century to identify tissue characteristics and structures morphologies that are needed for tumor diagnosis. In many cases, as tissue is scarce in clinical studies, fluorescence imaging is necessary to allow staining of the same specimen with multiple biomarkers simultaneously. Since fluorescence imaging is a relatively new technology in the pathology landscape, histopathologists are not used to or trained in annotating or interpreting these images. Aims Settings and Design: To allow pathologists to annotate these images without the need for additional training, we designed an algorithm for the conversion of fluorescence images to brightfield H&E images. Subjects and Methods: In this algorithm, we use fluorescent nuclei staining to reproduce the hematoxylin information and natural tissue autofluorescence to reproduce the eosin information avoiding the necessity to specifically stain the proteins or intracellular structures with an additional fluorescence stain. Statistical Analysis Used: Our method is based on optimizing a transform function from fluorescence to H&E images using least mean square optimization. Results: It results in high quality virtual H&E digital images that can easily and efficiently be analyzed by pathologists. We validated our results with pathologists by making them annotate tumor in real and virtual H&E whole slide images and we obtained promising results. Conclusions: Hence, we provide a solution that enables pathologists to assess tissue and annotate specific structures based on multiplexed fluorescence images. PMID- 29531847 TI - A Review on the Applications of Crowdsourcing in Human Pathology. AB - The advent of the digital pathology has introduced new avenues of diagnostic medicine. Among them, crowdsourcing has attracted researchers' attention in the recent years, allowing them to engage thousands of untrained individuals in research and diagnosis. While there exist several articles in this regard, prior works have not collectively documented them. We, therefore, aim to review the applications of crowdsourcing in human pathology in a semi-systematic manner. We first, introduce a novel method to do a systematic search of the literature. Utilizing this method, we, then, collect hundreds of articles and screen them against a predefined set of criteria. Furthermore, we crowdsource part of the screening process, to examine another potential application of crowdsourcing. Finally, we review the selected articles and characterize the prior uses of crowdsourcing in pathology. PMID- 29531848 TI - Commentary: Whole-slide Images - Good Enough for Primary Diagnosis? PMID- 29531849 TI - Initial Assessments of E-Learning Modules in Cytotechnology Education. AB - Background: Nine E-learning modules (ELMs) were developed in our program using Articulate software. This study assessed our cytotechnology (CT) students' perceptions on the content of the ELMs, and the perceived influence of the ELMs on students' performance during clinical rotations. Subjects and Methods: All CT students watched nine ELMs before the related classroom lecture and group discussion. Following that, students completed nine preclinical rotation surveys. After their clinical rotations, students completed nine postclinical rotation surveys. Results: Statements on the content of the ELMs regarding the quality of the video and audio, duration, navigation, and the materials presented, received positive responses from the majority of the students. While there were a few disagreements and neutral responses, most of the students responded positively saying that the ELMs better prepared them for their role, as well as helped them to better perform their roles during the clinical rotation. The majority of the students recommended developing more EMLs for cytology courses in the future. Conclusions: This study has given hope that the ELMs have potential to enhance our online curriculum and benefit students, within the United States and internationally, who have no easy access to cytology clinical laboratories for hands-on training. PMID- 29531850 TI - Enantioselective C-H Arylation and Vinylation of Cyclobutyl Carboxylic Amides. AB - Chiral mono-N-protected aminomethyl oxazoline (MPAO) ligands are found to promote enantioselective C-H arylation and vinylation of the cyclobutyl carboxylic acid derivatives via Pd(II)/Pd(IV) redox catalysis. This ligand scaffold overcame two important limitations of the previous MPAHA (mono-N-protected alpha-amino-O methylhydroxamic acid) ligands-enabled asymmetric C-H activation/C-C coupling reactions of cyclic carboxylic amides through Pd(II)/Pd(0) catalysis: substrates containing alpha-hydrogen atoms are not compatible; vinylation has not been developed. Sequential C-H arylation and vinylation of cyclobutanes are also accomplished to construct three consecutive chiral centers on the crowded cyclobutane rings, rendering this reaction highly versatile for the preparation of chiral cyclobutanes. PMID- 29531851 TI - Surveillance nanotechnology for multi-organ cancer metastases. AB - The identification and molecular profiling of early metastases remains a major challenge in cancer diagnostics and therapy. Most in vivo imaging methods fail to detect small cancerous lesions, a problem that is compounded by the distinct physical and biological barriers associated with different metastatic niches. Here, we show that intravenously injected rare-earth-doped albumin-encapsulated nanoparticles emitting short-wave infrared light (SWIR) can detect targeted metastatic lesions in vivo, allowing for the longitudinal tracking of multi-organ metastases. In a murine model of basal human breast cancer, the nanoprobes enabled whole-body SWIR detection of adrenal gland microlesions and bone lesions that were undetectable via contrast-enhanced magnetic resonance imaging (CE-MRI) as early as, respectively, three weeks and five weeks post-inoculation. Whole body SWIR imaging of nanoprobes functionalized to differentially target distinct metastatic sites and administered to a biomimetic murine model of human breast cancer resolved multi-organ metastases that showed varied molecular profiles at the lungs, adrenal glands and bones. Real-time surveillance of lesions in multiple organs should facilitate pre-therapy and post-therapy monitoring in preclinical settings. PMID- 29531852 TI - Circulating microRNA profiles in different arterial territories of stable atherosclerotic disease: a systematic review. AB - AIMS: Atherosclerosis is associated with altered circulating microRNA profiles. It is yet unclear whether the expression of these potential biomarkers differs according to the location of atherosclerosis. We assessed whether atherosclerosis of different arterial territories, except the coronary, is associated with specific circulating microRNA profiles. METHODS: A systematic search in PubMed, Web of Science, Embase, and Cochrane Library was carried out using a retrieval strategy including MESH and non-MSH terms. Eligible studies have compared circulating microRNA profiles between individuals with and without stable atherosclerotic disease of large or medium size arteries. The review protocol was registered in PROSPERO database (reference CRD42017073846). RESULTS: Eighteen studies were selected for qualitative synthesis: ten focused on carotid, six on lower limbs, and two on renal arteries atherosclerosis, none reporting on other locations. A common microRNA profile to different atherosclerotic disease locations was identified, including deregulation of miR-21, miR-30, miR-126, and miR-221-3p. Specific microRNA profiles for each territory were also identified, with consistency across studies, such as deregulation of miR-21 and miR-29 in carotid atherosclerosis, and let 7e, miR-27b, miR-130a, and miR-210 in lower limbs atherosclerosis. The robustness of the results was very high for let 7e, miR-29, miR-30, considering both the adjustment of microRNA expression for baseline variables and the replication of results in different studies (miR-29 in carotid, let 7e in lower limbs, and miR-30 in carotid and lower limbs atherosclerosis). Globally, the deregulated microRNAs are associated with control of angiogenesis, endothelial cell function, inflammation, cholesterol metabolism, oxidative stress and extracellular matrix composition. CONCLUSIONS: A common microRNA profile to different atherosclerotic disease locations and specific microRNA profiles for each territory were identified. These findings may provide insights into pathophysiology and be useful for selecting potential biomarkers for clinical practice. To the best of our knowledge, no systematic data on this subject has been reported. PMID- 29531853 TI - Pattern of burn injury at north of Jordan. AB - To the best of our knowledge, pattern of burn injury was not reported yet at our region, our hospital considered the only tertiary referral center with the only burn unit at the region since 2001 till date, a retrospective analysis of our computerized filing system recorded 527 burn patients between 2001-2016, mean age was 26 years; 1.27:1 was the male to female ratio, 79 patients were found to have major burns, 46% of admissions were below 20 years' age, 92% was at domestic site of affection and 65% due to flame burn followed by scald burn in about 23%. The limbs were the most affected body site, majority of patients were below 15% TBSA and partial thickness, 77 patients found to have inhalational injury. Our mean hospital stay was 16 days and mortality was 8.2%. Mortality was associated with high TBSA affection, depth and flame type. This study shows the pattern of burn at north of Jordan, preventive measures by education and observation will reduce the incidence of burn and its sequel, non-flammable cook plates and stoves will probably help in decrease burn morbidity and mortality. PMID- 29531854 TI - The systemic immune response to pediatric thermal injury. AB - BACKGROUND: The immune response to critical injury, including thermal injury, can heavily influence the recovery and long term prognosis for patients suffering such insults. A growing body of evidence supports that a suppressed immunologic state following critical injury can lead to adverse outcomes for adult and pediatric patients. METHODS: A Pubmed literature search was conducted to review areas of the immune system that are impaired after thermal injury and identify key immune players that are potential targets for therapeutic intervention. The focus was pediatric thermal injury; however, where pediatric studies were lacking adult studies were used as reference. RESULTS: Changes in cytokine profiles and immune cell phenotypes have been observed following thermal injury. Treatment with immunomodulatory stimulants, including IL-7 and GM-CSF, lead to improved outcomes in critically ill patients and may also be useful tools to improve immune function in pediatric burn patients. CONCLUSIONS: The innate and adaptive branches of the systemic immune system are impaired following thermal injury in adult and pediatric patients. Immunomodulatory therapies currently being used in areas outside of thermal injury may be useful tools to help improve outcomes following pediatric thermal injury. PMID- 29531855 TI - Short-term hypoxia improves early cardiac progenitor cell function in vitro. AB - The use of cardiovascular progenitor cells (CPCs) to repair damaged myocardium has been the focus of intense research. Previous reports have shown that pretreatments, including hypoxia, improve cell function. However, the age dependent effects of short-term hypoxia on CPCs, and the role of signaling in these effects, are unknown. Cloned neonatal and adult CPCs expressing Isl1, c Kit, KDR, PDGFRA, and CXCR4, were preconditioned using hypoxia (1% O2 for six hours). Intracellular signaling pathway changes were modeled using Ingenuity Pathway Analysis (IPA), while qRT-PCR, flow cytometry, and immunoblotting were used to measure pathway activation. Cellular function, including survival, cell cycle, and invasion, were evaluated using a TUNEL assay, flow cytometry, and a Transwell(r) invasion assay, respectively. IPA predicted, and RT-PCR and flow cytometry confirmed, that the PI3K/AKT pathway was activated following short-term hypoxia. Heat shock protein (HSP) 40 expression increased significantly in both age groups, while HSP70 expression increased only in neonatal CPCs. Neonatal CPC invasion and survival improved after hypoxia pre-treatment, while no effect was observed in cell cycling and developmental status. Prostaglandin receptor expression was enhanced in neonatal cells. Prior to transplantation, hypoxic preconditioning enhances CPC function, including invasion ability and pro survival pathway activation. PMID- 29531856 TI - Human corneal endothelial cell transplantation using nanocomposite gel sheet in bullous keratopathy. AB - Transplantation of in vitro expanded human corneal endothelial precursors (HCEP) cells using a nanocomposite (D25-NC) gel sheet as supporting material in bovine's cornea has been earlier reported. Herein we report the transplantation of HCEP cells derived from a cadaver donor cornea to three patients using the NC gel sheet. In three patients with bullous keratopathy, one after cataract surgery, one after trauma and another in the corneal graft, earlier performed for congenital corneal dystrophy, not amenable to medical management HCEP cells isolated from a human cadaver donor cornea in vitro expanded using a thermoreversible gelation polymer (TGP) for 26 days were divided into three equal portions and 1.6 * 105 HCEP cells were injected on to the endothelium of the affected eye in each patient using the D25-NC gel sheet as a supporting material. The sheets were removed after three days. The bullae in the cornea disappeared by the 3rd-11th post-operative day in all the three patients. Visual acuity improved from Perception of light (PL)+/Projection of rays (PR)+ to Hand movements (HM)+ in one of the patients by post-operative day 3 which was maintained at 18 months follow-up. At 18 months follow-up, in another patient the visual acuity had improved from HM+ to 6/60 while in the third patient, visual acuity remained HM+ as it was prior to HCEP transplantation. There were no adverse effects during the follow-up in any of the patients. PMID- 29531857 TI - Adenoid cystic carcinoma: focus on heavy ion therapy and molecular imaging. AB - Surgery, radiation therapy and chemotherapy are the oldest modalities for cancer treatment. However, as part of a continuous research in medicine, in order to improve therapeutic precision and biological effectiveness, there is an increasing interest into the use of heavy particle (e.g. protons or heavy ions) in the treatment of solid tumors. However, the restricted availability of the technology has concentrated the expertise in highly specialized centers that take care and treat extreme cases and rare pathologies. One of the tumors that has mostly beneficiated from heavy ion therapy is represented by adenoid cystic carcinoma (ACC) of the head and neck. In the current review we will focus our attention on the role of heavy particle therapy in general, with particular interest on ACC. The article will also summarize recent clinical evidence comparing traditional radiotherapy with the new heavy particles. Moreover, molecular imaging features of this uncommon tumor with 18F-FDG and 11C-MET will be discussed and illustrated. PMID- 29531858 TI - Preparation and evaluation of a 68Ga-labeled RGD-containing octapeptide for noninvasive imaging of angiogenesis: biodistribution in non-human primate. AB - Monitoring general disease marker such as angiogenesis may contribute to the development of personalized medicine and improve therapy outcome. Readily availability of positron emitter based imaging agents providing quantification would expand clinical positron emission tomography (PET) applications. Generator produced 68Ga provides PET images of high resolution and the half-life time frame is compatible with the pharmacokinetics of small peptides comprising arginine glycine-aspartic acid (RGD) sequence specific to alphavbeta3 integrin receptors. The main objective of this study was to develop a method for 68Ga-labeling of RGD containing bicyclic octapeptide ([68Ga]Ga-DOTA-RGD) with high specific radioactivity and preclinically assess its imaging potential. DOTA-RGD was labeled using generator eluate preconcentration technique and microwave heating. The binding and organ distribution properties of [68Ga]Ga-DOTA-RGD were tested in vitro by autoradiography of frozen tumor sections, and in vivo in mice carrying a Lewis Lung carcinoma graft (LL2), and in non-human primate (NHP). Another peptide with aspartic acid-glycine-phenylalanine sequence was used as a negative control. The full 68Ga radioactivity eluted from two generators was quantitatively incorporated into 3-8 nanomoles of the peptide conjugates. The target binding specificity was confirmed by blocking experiments. The specific uptake in the LL2 mice model was observed in vivo and confirmed in the corresponding ex vivo biodistribution experiments. Increased accumulation of the radioactivity was detected in the wall of the uterus of the female NHP probably indicating neovascularization. [68Ga]Ga-DOTA-RGD demonstrated potential for the imaging of angiogenesis. PMID- 29531859 TI - Synthesis, radiolabelling, and evaluation of [11C]PB212 as a radioligand for imaging sigma-1 receptors using PET. AB - The Sigma-1 receptor (Sig-1R) has been described as a pluripotent modulator of distinct physiological functions and its involvement in various central and peripheral pathological disorders has been demonstrated. However, further investigations are required to understand the complex role of the Sig-1R as a molecular chaperon. A specific PET radioligand would provide a powerful tool in Sig-1R related studies. As part of our efforts to develop a Sig-1R PET radioligand that shows antagonistic properties, we investigated the suitability of 1-(4-(6-methoxynaphthalen-1-yl)butyl)-4-methylpiperidine (designated PB212) for imaging Sig-1R. PB212 is a Sig-1R antagonist and exhibits subnanomolar affinity (Ki = 0.030 nM) towards Sig-1R as well as good to excellent selectivity over Sig-2R. The radiolabelling of [11C]PB212 was accomplished by O-methylation of the phenolic precursor using [11C]MeI. In vitro autoradiography with [11C]PB212 on WT and Sig-1R KO mouse brain tissues revealed high non-specific binding, however using rat spleen tissues from CD1 mice and Wistar rats, high specific binding was observed. The spleen is known to have a high expression of Sig-1R. In vivo PET experiments in Wistar rats also showed high accumulation of [11C]PB212 in the spleen. Injection of Sig-1R binding compounds, haloperidol (1 mg/kg) or fluspidine (1 mg/kg) shortly before [11C]PB212 administration induced a drastic reduction of radiotracer accumulation, confirming the specificity of [11C]PB212 towards Sig-1R in the spleen. The results obtained herein indicate that although [11C]PB212 is not suitable for imaging Sig-1R in the brain, it is a promising candidate for the detection and quantification of Sig-1Rs in the periphery. PMID- 29531860 TI - Thalamic and basal ganglia metabolism on interictal 18F-FDG PET in temporal lobe epilepsy: an SUV-based analysis. AB - The aim of this study was to investigate thalamic and basal ganglia (BG) metabolism in temporal lobe epilepsy (TLE) on interictal 18F-FDG PET using standardized uptake value (SUV). Retrospective review of data was undertaken for patients who were surgically treated for medically intractable TLE. All patients underwent 18F-FDG PET, MRI brain and EEG as preoperative workup, and subsequently underwent temporal lobe resection. Postoperative outcomes were analyzed as without or with residual disabling seizures. SUVmax and SUVpeak values were calculated for thalamus and BG. Subgroup comparisons were performed with non parametric tests. Study sample consisted of 33 patients (58% female; mean age 44.7 years) and 33 age- and sex-matched controls. Mean SUVpeak for both right and left thalamus was significantly lower in TLE than controls (8.1 +/- 1.9 vs. 9.7 +/- 2.9 and 8.1 +/- 1.9 vs. 9.8 +/- 2.9, respectively, both p=0.035). Mean SUVpeak for thalamus on the epileptogenic side was overall significantly lower than the contralateral side (8.0 +/- 2.0 vs. 8.3 +/- 2.0, p=0.040). One (3%) patient with MRI- and EEG-congruent left TLE showed marked left thalamic hypometabolism as the only finding on PET. There was no evidence of basal ganglia hypometabolism. No correlation was noted between thalamic metabolic asymmetry and postoperative outcomes. Thalamic metabolism was significantly reduced in patients with TLE compared to controls, and on the epileptogenic compared to the contralateral side among patients. Thalamic hypometabolism can have value in seizure focus localization in patients without interictal temporal hypometabolism. PMID- 29531861 TI - Assessment of very early response evaluation with 18F-FDG-PET/CT predicts survival in erlotinib treated NSCLC patients-A comparison of methods. AB - : We evaluated whether changes in 18F-Fluoro-D-Glucose (18F-FDG)-uptake evaluated early during erlotinib treatment predict survival in non-small cell lung cancer (NSCLC) patients. Positron emission tomography (PET)/CT scans from 56 NSCLC patients before and after 7-10 days of erlotinib treatment were analyzed with four different methods: Visual evaluation and percentage change in lean body mass corrected standardized uptake values (SULs): SULpeak, SULmax and total lesion glycolysis (TLG). The semi-quantitative parameters abilities to predict progression free survival (PFS) and overall survival (OS) were compared and we found that percentage change in SULpeak, SULmax and TLG all correlated with PFS and OS with the strongest correlation found for TLG (R=0.51, P < 0.001). The highest area under the curve (AUC) for predicting OS was for TLG (0.70 (0.56 0.85)) with a sensitivity of 0.68 and a specificity of 079. All methods except visual evaluation, SULpeak at 15% and 30%, and TLG at 40% cut-off separates the survival curves for the response categories for PFS. For OS, visual evaluation and SULmax did not, whereas TLG at 4 different cut-off levels and SULpeak at the three lowest cut-off levels did. IN CONCLUSION: Early change in 18F-FDG-uptake during erlotinib correlated to both PFS and OS. TLG, as suggested by PERCIST 1.0, shows the strongest correlation to survival, whereas visual evaluation seems to be less sensitive at this very early time-point, but lower cut-off levels for discriminating between response categories seem to be relevant as we find that 20 25% change for both response and progression is optimal. PMID- 29531863 TI - Open letter to journal editors on: international consensus radiochemistry nomenclature guidelines. PMID- 29531862 TI - Diagnostic performance of PET/MR in the evaluation of active inflammation in Crohn disease. AB - This study investigates the performance of PET/MR versus each sub-modality alone in the assessment of active inflammation in patients with Crohn disease, when compared to surgery as standard of reference. Sensitivity for detecting active inflammation was 91.5% for PET, 80% for MR, and 88% for PET/MR. Specificity for active inflammation was 74% for PET, 87% for MR, and 93% for PET/MR. Diagnostic accuracy was 84% for PET, 83% for MR, and 91% for PET/MR. In conclusion, PET/MR is significantly more accurate than either sub-modality alone and more specific than PET alone in the detection of active inflammation in patients with Crohn disease. PMID- 29531864 TI - Posterior reversible encephalopathy syndrome (PRES) attributed to mycophenolate mofetil during the management of SLE: a case report and review. AB - Posterior reversible encephalopathy syndrome (PRES) is a rare clinical entity associated with systemic lupus erythematosus which characterized by seizure, headache, and altered mental status. The pathophysiology involves subcortical vasogenic edema secondary to hypertension and endothelial damage. PRES is reversible with withdrawal of the offending agent, strict blood pressure control, and treating the underlying disease. We report present here a patient with lupus nephritis who developed PRES following mycophenolate administration. PMID- 29531865 TI - The protective effects of crocin in the management of neurodegenerative diseases: a review. AB - Flavonoids have been used in traditional medicine to promote human health. Crocin has been proposed to be effective in the management of the various diseases including the neurodegenerative diseases. Antiepileptic and anti-Alzheimer effects of crocin have also been indicated. The efficacy of crocis in the treatment of cerebral ischemia and traumatic brain injury was also confirmed by using animal models. Crocin treatment increased dopamine levels in the brain of experimental model of Parkinson's disease. In addition, crocin modulates the opioid system to decrease the withdrawal syndrome. Thus, the present study highlighted the effects of crocin on the nervous system and the underling mechanisms. This review also indicated that crocins can be considered as an effective candidate in the management of nervous system diseases due to their antioxidant and anti-inflammation effects. PMID- 29531867 TI - A Meshfree Representation for Cardiac Medical Image Computing. AB - The prominent advantage of meshfree method, is the way to build the representation of computational domain, based on the nodal points without any explicit meshing connectivity. Therefore, meshfree method can conveniently process the numerical computation inside interested domains with large deformation or inhomogeneity. In this paper, we adopt the idea of meshfree representation into cardiac medical image analysis in order to overcome the difficulties caused by large deformation and inhomogeneous materials of the heart. In our implementation, as element-free Galerkin method can efficiently build a meshfree representation using its shape function with moving least square fitting, we apply this meshfree method to handle large deformation or inhomogeneity for solving cardiac segmentation and motion tracking problems. We evaluate the performance of meshfree representation on a synthetic heart data and an in-vivo cardiac MRI image sequence. Results showed that the error of our framework against the ground truth was 0.1189 +/- 0.0672 while the error of the traditional FEM was 0.1793 +/- 0.1166. The proposed framework has minimal consistency constraints, handling large deformation and material discontinuities are simple and efficient, and it provides a way to avoid the complicated meshing procedures while preserving the accuracy with a relatively small number of nodes. PMID- 29531868 TI - Colonic Granular Cell Tumor: An Endoscopic and Histopathologic Review with Case Illustration. AB - Granular cell tumors (GCTs) are rare and benign tumors that can occur at any anatomical site. GCTs are thought to originate from nerve cells, particularly Schwann cells. Their name derives from the fact that an accumulation of cytoplasmic lysosomes imparts the tumor with a granular appearance. They are most commonly observed in the oral cavity, skin and subcutaneous tissue, breast, and respiratory tract. Granular cell tumors rarely affect the gastrointestinal tract. We report a 58-year-old female with a past medical history of hypertension, mitral valve prolapse, and depression who presented for surveillance colonoscopy. A single firm sessile polypoid lesion, with overlying pale tan color mucosa, measuring approximately 1 to 1.5 cm, was found in the ascending colon. Biopsy of the nodule followed by histopathology was positive for S100 and CD68, but negative for AE1/AE3, CD117, smooth muscle actin, and desmin, consistent with the diagnosis of GCT. We review the clinicopathologic features of GCTs. PMID- 29531866 TI - Overexpression of ter94, Drosophila VCP, improves motor neuron degeneration induced by knockdown of TBPH, Drosophila TDP-43. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the motor neuron degeneration that eventually leads to complete paralysis and death within 2-5 years after disease onset. One of the major pathological hallmark of ALS is abnormal accumulation of inclusions containing TAR DNA-binding protein-43 (TDP-43). TDP-43 is normally found in the nucleus, but in ALS, it localizes in the cytoplasm as inclusions as well as in the nucleus. Loss of nuclear TDP-43 functions likely contributes to neurodegeneration. TBPH is the Drosophila ortholog of human TDP-43. In the present study, we confirmed that Drosophila models harboring TBPH knockdown develop locomotive deficits and degeneration of motoneurons (MNs) due to loss of its nuclear functions, recapitulating the human ALS phenotypes. We previously suggested that ter94, the Drosophila ortholog of human Valosin-containing protein (VCP), is a modulator of degeneration in MNs induced by knockdown of Caz, the Drosophila ortholog of human FUS. In this study, to determine the effects of VCP on TDP-43-assosiated ALS pathogenic processes, we examined genetic interactions between TBPH and ter94. Overexpression of ter94 suppressed the compound eye degeneration caused by TBPH knockdown and suppressed the morbid phenotypes caused by neuron-specific TBPH knockdown, such as locomotive dysfunction and degeneration of MN terminals. Further immunocytochemical analyses revealed that the suppression is caused by restoring the cytoplasmically mislocalized TBPH back to the nucleus. In consistent with these observations, a loss-of-function mutation of ter94 enhanced the compound eye degeneration caused by TBPH knockdown, and partially enhanced the locomotive dysfunction caused by TBPH knockdown. Our data demonstrated that expression levels of ter94 influenced the phenotypes caused by TBPH knockdown, and indicate that reagents that up-regulate the function of human VCP could modify MN degeneration in ALS caused by TDP-43 mislocalization. PMID- 29531869 TI - A Rare Case of Dermatofibrosarcoma Protuberans of the Thumb in an 80-year-old Woman. AB - Dermatofibrosarcoma protuberans (DFSP) has been described as a rare, locally invasive, malignant fibroblastic tumor with a high rate of recurrence that usually affects middle-aged patients. Herein, we describe a rare case of a pedunculated dermatofibrosarcoma protuberans of the right thumb in an 80-year-old woman treated with excision through the base of the pedicle. We also make a brief literature review concerning this tumor. PMID- 29531870 TI - Rosai-Dorfman Disease: Rare Presentation as Isolated Mediastinal and Hilar Lymphadenopathy. AB - Rosai-Dorfman disease (RDD) is a rare, benign, and predominantly nodal disease that most commonly presents as bilateral, painless cervical lymphadenopathy; although inguinal, axillary, mediastinal, and hilar lymphadenopathy has also been reported. Apart from nodal involvement, RDD has extranodal manifestations involving bone, soft tissue, and liver as well as constitutional symptoms of fever, night sweats, and weight loss, which make it reasonable to rule out the infectious, autoimmune, and malignant conditions as the differential diagnosis. We herein report a case of RDD affecting only the mediastinal and hilar region in an 83-year-old woman. PMID- 29531871 TI - Development of a Three-dimensional Surgical Navigation System with Magnetic Resonance Angiography and a Three-dimensional Printer for Robot-assisted Radical Prostatectomy. AB - We sought to develop a surgical navigation system using magnetic resonance angiography (MRA) and a three-dimensional (3D) printer for robot-assisted radical prostatectomy (RARP). Six patients with pathologically proven localized prostate cancer were prospectively enrolled in this study. Prostate magnetic resonance imaging (MRI), consisting of T2-weighted sampling perfection with application optimized contrasts using different flip-angle evolutions (SPACE) and true fast imaging with steady-state precession (true FISP), reconstructed by volume rendering, was followed by dynamic contrast-enhanced MRA performed with a volumetric interpolated breath-hold examination (VIBE) during intravenous bolus injection of gadobutrol. Images of arterial and venous phases were acquired over approximately 210 seconds. Selected images were sent to a workstation for generation of 3D volume-rendered images and standard triangulated language (STL) files for 3D print construction. The neurovascular bundles (NVBs) were found in sequence on non-contrast images. Accessory pudendal arteries (APAs) were found in all cases in the arterial phase of contrast enhancement but were ill-defined on non-contrast enhanced MRA. Dynamic contrast-enhanced MRA helped to detect APAs, suggesting that this 3D system using MRI will be useful in RARP. PMID- 29531872 TI - Community-acquired Pneumonia with Methicillin-resistant Staphylococcus Aureus in a Patient Admitted to the Intensive Care Unit: A Therapeutic Challenge. AB - Methicillin-resistant Staphylococcus aureus (MRSA) was previously considered a purely nosocomial pathogen. However, community-acquired MRSA has recently emerged as an important cause of severe necrotizing community-acquired pneumonia (CA MRSA) in previously healthy individuals. This new pathogen exhibits antibiotic resistance and is linked to extended hospital stay and higher mortality. CA-MRSA has presented new therapeutic challenges due to high vancomycin treatment failure and lack of specificity of clinical findings. There is emerging evidence that treatment with linezolid leads to better patient outcomes in patients with CA MRSA. Through this case, we aim to raise awareness about early institution of therapy for CA-MRSA whenever it is suspected, to improve patient outcomes. PMID- 29531873 TI - The Concomitant Use of Atorvastatin and Amlodipine Leading to Rhabdomyolysis. AB - A 65-year-old man, with a history of hypertension and hyperlipidemia, presented with intractable lower back pain, shortness of breath, and decreasing urine output at the emergency room and was admitted after he was found to have elevated creatinine kinase levels of greater than 160,000 U/L. We discontinued all his home medications, which included atorvastatin and amlodipine. We trended his creatine phosphokinase (CPK) level daily and noticed it decreasing significantly off these meds. We hydrated him with normal saline and monitored his kidney functions. By the time he was ready for discharge, his CPK levels were back to normal. This case report summarizes the drug-drug interactions of atorvastatin and amlodipine. PMID- 29531874 TI - Curated Collections for Educators: Five Key Papers on Evaluating Digital Scholarship. AB - Traditionally, scholarship that was recognized for promotion and tenure consisted of clinical research, bench research, and grant funding. Recent trends have allowed for differing approaches to scholarship, including digital publication. As increasing numbers of trainees and faculty turn to online educational resources, it is imperative to critically evaluate these resources. This article summarizes five key papers that address the appraisal of digital scholarship and describes their relevance to junior clinician educators and faculty developers. In May 2017, the Academic Life in Emergency Medicine Faculty Incubator program focused on the topic of digital scholarship, providing and discussing papers relevant to the topic. We augmented this list of papers with further suggestions by guest experts and by an open call via Twitter for other important papers. Through this process, we created a list of 38 papers in total on the topic of evaluating digital scholarship. In order to determine which of these papers best describe how to evaluate digital scholarship, the authorship group assessed the papers using a modified Delphi approach to build consensus. In this paper we present the five most highly rated papers from our process about evaluating digital scholarship. We summarize each paper and discuss its specific relevance to junior faculty members and to faculty developers. These papers provide a framework for assessing the quality of digital scholarship, so that junior faculty can recommend high-quality educational resources to their trainees. These papers help guide educators on how to produce high quality digital scholarship and maximize recognition and credit in respect to receiving promotion and tenure. PMID- 29531875 TI - The British Columbia Emergency Medicine Network: A Paradigm Shift in a Provincial System of Emergency Care. AB - As generalists, emergency practitioners face challenges in providing state-of-the art care owing to the broad spectrum of practice and the rapid rate of new knowledge generation. Networks have become increasingly prevalent in health care, and it was in this backdrop, and the resulting opportunity to advance evidence informed emergency care in the Canadian province of British Columbia (BC), that a new "Emergency Medicine Network" (EM Network) was launched in 2017. The EM Network consists of four programs, each led by a physician with expertise and a track record in the domain: (1) Clinical Resources; (2) Innovation; (3) Continuing Professional Development; and (4) Real-time Support. This paper provides an overview of the EM Network, including its background, purpose, programs, anticipated evolution, and impact on the BC health care system. PMID- 29531876 TI - A Rare Case of Adult Colonic Intussusception from Benign Etiology. AB - Defined as the tunneling of one bowel segment into an adjacent bowel segment, intussusception is typically observed in pediatric populations. Here, we present the case of a 78-year-old man who, in a series of unlikely events, developed colonic intussusception due to a benign lead point pathology. Intussusception of the colon is an uncommon occurrence in adults. However, adult colonic intussusception, observed in the absence of a malignant lead point pathology, represents a true clinical anomaly. PMID- 29531877 TI - A Suspected Vestibular Schwannoma with Uncharacteristic Growth Dynamic and Symptom Severity: A Case Report. AB - Vestibular schwannomas are mostly sporadic, neuroectodermal, benign tumors of the myelin-forming cells of the vestibulocochlear nerve. Typical initial symptoms of vestibular schwannomas often include unilateral hearing loss, tinnitus, vertigo, and headaches. As schwannomas characteristically show a slow growth rate and various symptoms, different therapeutic approaches are possible, ranging from a watchful waiting strategy to radiation therapy and neurosurgical tumor removal. In addition, these treatment options should be evaluated carefully and assigned individually to the patients' needs and symptoms while respecting the feasibility and possible outcome of the chosen treatment. We present a 69-year-old patient with an atypical, severe symptom constellation and tumor growth dynamic. The planned treatment of the schwannoma with radiosurgery revealed an unforeseen change of focus. Most notably, this case emphasizes the importance of a thorough radiological and patient-orientated assessment. PMID- 29531878 TI - Successful Retrieval of a Retained Rectal Foreign Body in the Emergency Department. AB - Rectal foreign bodies are a common presenting complaint in the emergency department. Anal eroticism is the major reason for the majority of cases of rectal foreign bodies. A high index of suspicion is required to accurately diagnose a rectal foreign body as patients are often embarrassed about their condition and may not present in a timely fashion to be evaluated or volunteer their history. Extraction techniques include transanal, endoscopic, and laparotomy with repair of complications. Here, we present the case of successful transanal manual removal of a retained dumbbell in the rectum of a middle-aged man. PMID- 29531879 TI - Clinical Tests Combined with Color Doppler Versus Color Doppler Alone in Identifying Incompetent Perforator Veins of the Lower Limb: A Prospective Analytical Study. AB - Background The color Doppler, a better investigation to identify the perforators objectively has replaced the clinical examination for the same. However, this has led to a significant number of negative explorations and cosmetic disfigurement. Objective To compare the efficacy of the clinical tests combined with the color Doppler versus color Doppler alone to identify the perforator incompetence during the surgery for primary varicose veins of the lower limb. Methods This was a prospective analytical study, including 61 lower limb varicose vein patients who belonged to the Clinical-Etiology-Anatomy-Pathophysiology (CEAP) class four-six, planned for the surgical treatment for perforator incompetence, excluding those requiring additional vascular or nonvascular procedure, recurrent varicose veins and those who had injection sclerotherapy prior to the surgery. The clinical tests, including Trendelenburg's test, multiple tourniquet tests and, the Fegan's tests were performed and incompetent perforators were marked on a template as 'C' to indicate the clinically positive perforator incompetence. The patients were then examined with the color Doppler ultrasound and the pathological incompetent perforators were marked as 'D'. The surgical management of the perforator incompetence was done by stab ligation. The incision was made in the color Doppler 'D' marked sites as it has been the standard protocol. The number of incompetent perforators identified during the surgical exploration were categorized as 'D' positive or 'C' and 'D' positive and were recorded in the specified proforma. Results It was found that the mean number of the perforator incompetence identified by the color Doppler alone was 8.2 whereas during the surgery, only a mean of six perforators was identified, leading to 20 unnecessary explorations per 10 patients (8.2 vs. 6; mean difference 2.229; P <0.001). The mean number of the perforator incompetence identified by the color Doppler combined with the clinical tests was 4.5 and during the surgery, a mean of four perforators was identified (4.5 vs. 4; mean difference 0.377; P <0.001). The color Doppler combined with the clinical examination lead to only four unnecessary explorations per 10 patients. Conclusion A combination of both the clinical tests and the color Doppler ultrasound has a higher accuracy in detecting perforator incompetence and can reduce the number of negative explorations by the rate of 16 unnecessary explorations per 10 patients. PMID- 29531880 TI - Internal Carotid Artery Dissection with Lidocaine Nerve Block Injection Trauma: A Rare Case Report. AB - Internal carotid artery dissection (ICAD) accounts for 25% of cerebrovascular accidents in young and middle-aged patients. Dissection occurs when the intimal wall of an artery is damaged as a result of trauma or defect. ICAD development after dental work is a relatively uncommon phenomenon. Our study highlights a rare presentation of ICAD that resulted from a direct lidocaine nerve block injection in a patient undergoing pulpotomy for a right maxillary second premolar tooth. We have described the case and reviewed the literature on this rare but potentially life-threatening phenomenon. PMID- 29531881 TI - Association of Hypertrophic Obstructive Cardiomyopathy with Rheumatoid Arthritis. AB - Our article refers to a 50-year-old woman with previously diagnosed rheumatoid arthritis (RA) who presented with symptoms of dyspnea on exertion and dizziness. An echocardiogram revealed a 17-mm asymmetric interventricular septum hypertrophy and systolic anterior motion of the anterior mitral valve leaflet. Association of hypertrophic obstructive cardiomyopathy (HCM) with connective tissue diseases has been well documented. For RA the human leukocyte antigen (HLA) system, particularly HLA-DR4, may possibly be a link between the two entities, as it is associated with both RA and HCM. Therefore, a patient with RA and suggestive history should be investigated for cardiac involvement. Further studies are needed to elucidate a more accurate association between the above diseases. PMID- 29531882 TI - Creating a Student-centered Learning Environment: Implementation of Problem-based Learning to Teach Microbiology to Undergraduate Medical Students. AB - Introduction Medical education involves training necessary to become a physician or a surgeon. This includes various levels of training like undergraduate, internship, and postgraduate training. Medical education can be quite complex, since it involves training in pre-clinical subjects (anatomy, physiology, biochemistry), the para-clinical subjects (microbiology, pathology, pharmacology, and forensic medicine), and a discrete group of clinical subjects that include general medicine, surgery, obstetrics and gynaecology, ear, nose and throat specialization, paediatrics, cardiology, pulmonology, dermatology, ophthalmology, and orthopaedics, and many other clinical specializations and super specialities (cardio-thoracic surgery, neurosurgery, etc.). Training medical students involves both classroom teaching and practical applications. Classroom teaching is usually confined to didactic lectures, where the teacher unilaterally disseminates the information. This kind of teaching was recently noted to be not very effective in producing better quality medical graduates. The present study aims to introduce problem-based learning (PBL) to teach microbiology to undergraduate medical students and evaluate their perception towards such type of learning. Methods A total of 159 students were included in the study. An informed and oral consent was obtained from each participant, and the study was approved by the institutional ethical committee. All the students included in the study were grouped into 14 groups of 11-13 students. Students were carefully grouped ensuring that each group had a good mix that included different levels of achievers. Students were given a detailed introduction to the exercise before they started it. A questionnaire that consisted of 11 points was given to the students and they were asked to give feedback (strongly disagree, disagree, agree to some extent, agree, strongly agree) both on the functioning of PBL and the tutor performance during PBL. Results The study included a total of 159 students. Among the study participants, 55 (35%) were male and 104 (65%) were female. There was a positive response towards PBL being instrumental in improving cognitive skills as evidenced by the results (females (59%) and males (29%)) (p=0.191). We found that 61% females and 30% males felt that PBL was the best learning technique, as compared to traditional teaching (p=0.241). Most students were happy with the number of students in a group (females (63%) and males (34%)), but a few students felt that there would have been an improvement in the learning process if the groups were smaller (<10 students) (p=0.239). A positive response was given by the students regarding the feedback encouragement provided by the tutor (females (43%) and males (27%)) (p=0.253). Tutor evaluation by the students revealed some interesting observations, which include an agreement by most students that the tutor had completely avoided traditional teaching (females (55%), males (32%)) during the PBL sessions (p=0.001). Conclusion Most students liked PBL as it encouraged group discussions and presentations, which helped in retaining information and improving cognitive skills. PMID- 29531883 TI - Early-Stage Incorporation Strategy for Regioselective Labeling of Peptides using the 2-Cyanobenzothiazole/ 1,2-Aminothiol Bioorthogonal Click Reaction. AB - Invited for this month's cover picture is the group of Dr. Yann Seimbille at the Life Sciences Division at TRIUMF (Canada). The cover picture shows how a simple and innovative methodology based on the bioorthogonal click reaction between 2 cyanobenzothiazole and 1,2-aminothiol has been elaborated to facilitate the labeling of peptide biovectors. Read the full text of their Communication at 10.1002/open.201700191. PMID- 29531884 TI - Virtual Issue: Chemosensors. AB - Chemosensors are compounds that incorporate a receptor unit and a reporter unit in a single molecule. A chemosensor transforms the action of binding to a specific analyte into a readable signal. Chemosensors have enabled the study of molecular interactions in a range of different media and interfaces. This offers a non-invasive approach to observe living biological samples in real time without the sample being destroyed. For example, fluorescence-based chemosensors are designed to have a high sensitivity and specificity, allowing them to interact selectively with a single target within a complex biological environment. As a result, such chemosensors can be used for fluorescence imaging, allowing for high spatial and temporal resolution of biological samples. Consequently, chemosensors have been used for a broad range of applications including clinical diagnostics and for the detection of environmental, agriculture, and industrial pollutants, making them critically important for public health and safety. PMID- 29531886 TI - Dihydroxyacetone: An Updated Insight into an Important Bioproduct. AB - Currently obtained from glycerol through microbial fermentation, the demand of 1,3-dihydroxyacetone (DHA) has significantly grown during the course of the last decade, driven by the consumer passion for a tan and increasing awareness of UV photodamage to the skin caused by prolonged exposure to the sun. We provide an updated bioeconomy perspective into a valued bioproduct (DHA), whose supply and production from glycerol, we argue in this study, will rapidly expand and diversify, with important global health benefits. PMID- 29531885 TI - Translational Chemistry Meets Gluten-Related Disorders. AB - Gluten-related disorders are a complex group of diseases that involve the activation of the immune system triggered by the ingestion of gluten. Among these, celiac disease, with a prevalence of 1 %, is the most investigated, but recently, a new pathology, named nonceliac gluten sensitivity, was reported with a general prevalence of 7 %. Finally, there other less-prevalent gluten-related diseases such as wheat allergy, gluten ataxia, and dermatitis herpetiformis (with an overall prevalence of less than 0.1 %). As mentioned, the common molecular trigger is gluten, a complex mixture of storage proteins present in wheat, barley, and a variety of oats that are not fully degraded by humans. The most studied protein related to disease is gliadin, present in wheat, which possesses in its sequence many pathological fragments. Despite a lot of effort to treat these disorders, the only effective method is a long-life gluten-free diet. This Review summarizes the actual knowledge of gluten-related disorders from a translational chemistry point of view. We discuss what is currently known from the literature about the interaction of gluten with the gut and the critical host responses it evokes and, finally, connect them to our current and novel molecular understanding of the supramolecular organization of gliadin and the 33-mer gliadin peptide fragment under physiological conditions. PMID- 29531887 TI - Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl 2'-Deoxy-5-oxopropynyluridines. AB - Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2'-deoxy-5-oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83-31 %). The synthetic outcomes were confirmed by X-ray structure determination of dicobalt hexacarbonyl 2'-deoxy-5-(4-hydroxybut-1-yn-1-yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2'-deoxy-5-alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80 MUm for the HeLa cell line and 18 to 30 MUm for the K562 cell line. Coordination of an acetyl-substituted cobalt nucleoside was expanded by using the 1,1-bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress. PMID- 29531888 TI - Sulfenamides as Building Blocks for Efficient Disulfide-Based Self-Healing Materials. A Quantum Chemical Study. AB - The theoretical self-healing capacity of new sulfenamide-based disulfides is estimated by using theoretical methods of quantum chemistry. Starting from previously studied aromatic disulfides, the influence of inserting a NH group between the disulfide and the phenyl ring (forming the sulfenamide), as well as the role of the phenyl ring in the self-healing process is analyzed. Three parameters are used in the evaluation of the self-healing capacity: i) the probability to generate sulfenyl radicals, which is the first step of the process; ii) the effect of the hydrogen bonding, which affects the mobility of the chains; and iii) the height of the exchange reaction barrier. The insertion of the NH group notably decreases the bond dissociation energy and, therefore, increases the probability to produce sulfenyl radicals and helps the approach of these radicals to neighboring disulfides, favoring the self-healing process. The role of the phenyl rings is clearly observed in the reaction barriers, where the pi-pi stacking interactions notably stabilize the transition states, resulting in larger rate constants. Nevertheless, this stabilization is somewhat reduced in the aromatic sulfenamides, owing to a less effective pi-pi interaction. Therefore, the sulfenamide-based aromatic disulfides may be considered as promising candidates for the design of efficient self-healing materials. PMID- 29531889 TI - Early-Stage Incorporation Strategy for Regioselective Labeling of Peptides using the 2-Cyanobenzothiazole/1,2-Aminothiol Bioorthogonal Click Reaction. AB - Herein, we describe a synthetic strategy for the regioselective labeling of peptides by using a bioorthogonal click reaction between 2-cyanobenzothiazole (CBT) and a 1,2-aminothiol moiety. This methodology allows for the facile and site-specific modification of peptides with various imaging agents, including fluorophores and radioisotope-containing prosthetic groups. We investigated the feasibility of an early-stage incorporation of dipeptide 1 into targeting vectors, such as c[RGDyK(C)] and HER2 pep, during solid-phase peptide synthesis. Then, the utility of the click reaction to label bioactive peptides with a CBT modified imaging agent (FITC-CBT, 9) was assessed. The ligation reaction was found to be highly selective and efficient under various conditions. The fluorescently labeled peptides 2 and 3 were obtained in respective yields of 88 and 82 % under optimized conditions. PMID- 29531890 TI - Boronate-Based Fluorescence Probes for the Detection of Hydrogen Peroxide. AB - In this work, we synthesized a series of boronate ester fluorescence probes (E) 4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane (STBPin), (E)-N,N dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)aniline (DSTBPin), (E)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)styryl)benzonitrile (CSTBPin), (E)-2-(4-(4-methoxystyryl)phenyl)-4,4,5,5 tetramethyl-1,3,2-dioxaborolane (MSTBPin), (E)-N,N-dimethyl-4-(4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)naphthalen-1-amine (NDSTBPin), and N,N dimethyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazol-5 yl)aniline (DAPOX-BPin) for the detection of hydrogen peroxide (H2O2). DSTBPin and MSTBPin displayed an "Off-On" fluorescence response towards H2O2, owing to the loss of the intramolecular charge transfer (ICT) excited state. Whereas, CSTBPin displayed a decrease in fluorescence intensity in the presence of H2O2 owing to the introduction of an ICT excited state. STBPin, on the other hand, produced a small fluorescence decrease, indicating the importance of an electron withdrawing or electron-donating group in these systems. Unfortunately, the longer wavelength probe, NDSTBPin, displayed a decrease in fluorescence intensity. Oxazole-based probe DAPOX-BPin produced a "turn-on" response. Regrettably, DAPOX-BPin required large concentrations of H2O2 (>3 mm) to produce noticeable changes in fluorescence intensity and, therefore, no change in fluorescence was observed in the cell imaging experiments. PMID- 29531891 TI - Dye Displacement Assay for Saccharides using Benzoxaborole Hydrogels. AB - Dye displacement assays are a simple but effective method to determine the concentration of target analytes. Previously, we have shown that phenylboronic acid pinacol ester hydrogels (borogels) can be used to develop a boronic acid Alizarin red S dye displacement assay for the determination of fructose (orange to red). In this work, benzoxaborole hydrogels (BOBgels) were developed, and these BOBgels demonstrated an enhanced apparent binding affinity towards monosaccharides, in particular towards glucose. PMID- 29531892 TI - Rapidly Expanding Lateral Ventricular Meningioma Presenting with Intraventricular Hemorrhage following Remote Whole Brain Radiation and Stereotactic Radiosurgery. AB - Intraventricular meningiomas are uncommon intracranial tumors and infrequently present with hemorrhage. With only 10 reported cases in the literature, it is exceedingly rare for meningiomas of the ventricular system to present with hemorrhage. To our knowledge, this is the first report of a patient presenting with an acute intraventricular hemorrhage in relation to a ventricular meningioma suspected to be radiation induced. In addition, we review the current literature on hemorrhagic intraventricular meningiomas and review the natural history of radiation-induced meningiomas. PMID- 29531894 TI - An innovative mesothelioma treatment based on miR-16 mimic loaded EGFR targeted minicells (TargomiRs). PMID- 29531893 TI - Applying Risk Prediction Models to Optimize Lung Cancer Screening: Current Knowledge, Challenges, and Future Directions. AB - Purpose of review: Risk prediction models may be useful for facilitating effective and high-quality decision-making at critical steps in the lung cancer screening process. This review provides a current overview of published lung cancer risk prediction models and their applications to lung cancer screening and highlights both challenges and strategies for improving their predictive performance and use in clinical practice. Recent findings: Since the 2011 publication of the National Lung Screening Trial results, numerous prediction models have been proposed to estimate the probability of developing or dying from lung cancer or the probability that a pulmonary nodule is malignant. Respective models appear to exhibit high discriminatory accuracy in identifying individuals at highest risk of lung cancer or differentiating malignant from benign pulmonary nodules. However, validation and critical comparison of the performance of these models in independent populations are limited. Little is also known about the extent to which risk prediction models are being applied in clinical practice and influencing decision-making processes and outcomes related to lung cancer screening. Summary: Current evidence is insufficient to determine which lung cancer risk prediction models are most clinically useful and how to best implement their use to optimize screening effectiveness and quality. To address these knowledge gaps, future research should be directed toward validating and enhancing existing risk prediction models for lung cancer and evaluating the application of model-based risk calculators and its corresponding impact on screening processes and outcomes. PMID- 29531895 TI - Treatment redirection from cure to palliation, then cure again?-a cautious, but urgent matter. PMID- 29531898 TI - PACIFIC trial: new perspectives for immunotherapy in lung cancer. PMID- 29531896 TI - Emerging resistance pathways in lung cancer: what has ROS-1 taught us? PMID- 29531899 TI - Can population data guide surveillance strategies for second primary lung cancers? PMID- 29531901 TI - Next-generation molecular therapy in lung cancer. PMID- 29531902 TI - Putting the brakes on CTLA-4 inhibition in lung cancer? PMID- 29531900 TI - Nivolumab as first-line treatment in non-small cell lung cancer patients-key factors: tumor mutation burden and PD-L1 >=50. PMID- 29531903 TI - Do EGFR tyrosine kinase inhibitors (TKIs) still have a role in EGFR wild-type pre treated advanced non-small cell lung cancer (NSCLC)?-the shifting paradigm of therapeutics. PMID- 29531897 TI - Targeting the metastatic niche through anti-angiogenic approaches in epidermal growth factor receptor mutant non-small cell lung cancer. PMID- 29531904 TI - Tumor heterogenicity: multiple needle biopsies from different lesion sites-key to successful targeted therapy and immunotherapy. PMID- 29531905 TI - Long-term CT surveillance after primary lung cancer treatment captures events in all risk groups. PMID- 29531906 TI - The risk of second primary lung cancer: an unsolved dilemma. PMID- 29531907 TI - Response to "An innovative mesothelioma treatment based on mir-16 mimic loaded EGFR targeted minicells (TargomiRs)". PMID- 29531908 TI - Prof. Lukas Bubendorf: the pros and cons of using cytology specimens in molecular testing. PMID- 29531909 TI - Prof. Nir Peled: CT first, biomarkers next. PMID- 29531910 TI - Dr. Lucio Crino: our greatest challenge is finding the right treatment for the right patients. PMID- 29531911 TI - Dr. David Ross Camidge: always be the first to see something. PMID- 29531912 TI - Dr. Jhingook Kim: surgeons are not merely technicians, but scientists. PMID- 29531913 TI - Dr. Vera Hirsh: improving patient's quality of life is necessary for cancer treatment. PMID- 29531914 TI - Dr. Ignacio Gil-Bazo: family support is my key to success! PMID- 29531915 TI - Professor Fred R. Hirsch, the IASLC CEO-showing you around the 18th World Conference on Lung Cancer (WCLC 2017). PMID- 29531916 TI - Professor David Ball: prophylactic cranial irradiation (PCI) benefits patients with SCLC. PMID- 29531917 TI - Professor Raymond U. Osarogiagbon: another major challenge over next decades-how to incorporate the cutting-edge diagnostics and biologic prognosticating ability into a traditionally anatomy-centered TNM staging system. PMID- 29531918 TI - Professor Fred R. Hirsch: together, our voices are much stronger than individually-a special interview about the 2017 Lung Cancer Awareness Month campaign. PMID- 29531919 TI - In silico Design, and In vitro Expression of a Fusion Protein Encoding Brucella abortus L7/L12 and SOmp2b Antigens. AB - Background: L7/L12 is a protective antigen conserved in main Brucella pathogens and is considered as potential vaccine candidate. Outer membrane protein 2b is an immunogen conserved in all Brucella pathogens. Materials and Methods: The purpose of the current study was to in silico design a L7/L12-SOmp2b fusion protein and in vitro production of the chimera. Two possible fusion forms, L7/L12-SOmp2b and SOmp2b-L7/L12, were subjected to in silico modeling and analysis. Cloning and expression of the fusion protein has been done in the pET28a vector and Escherichia coli Bl21 (DE3), respectively. Results: Analysis and validation of the fusion proteins three-dimensional models showed that both models are in the range of native proteins. However, L7/L12-SOmp2b structure was more valid than the SOmp2b-L7/L12 model and subjected to in vitro production. The major histocompatibility complex II (MHC-II) epitope mapping using Immune Epitope DataBase indicated that the model contained good MHC-II binders. The L7/L12-Omp2b coding sequence was cloned in pET28a vector. The fusion was successfully expressed in E. coli BL21 by induction with isopropyl-beta-d thiogalactopyranoside. The rL7/L12-SOmp2b was purified with Ni-NTA column. The yield of the purified rL7/L12-SOmp2b was estimated by Bradford method to be 240 MUg/ml of the culture. Western blot analysis revealed a specific reactivity with purified rL7/L12-SOmp2b produced in E. coli cells and showed the expression in the prokaryotic system. Conclusions: Our data indicates that L7/L12-SOmp2b fusion protein has a potential to induce both B- and T-cell-mediated immune responses and it can be evaluated as a new subunit vaccine candidate against brucellosis. PMID- 29531920 TI - Ultrasonography Predictive Factors of Response to Local Steroid Injection in Patients with Carpal Tunnel Syndrome. AB - Background: The aim of this study is to determine the predictive value of ultrasonography for results of local steroid injection in patients with carpal tunnel syndrome (CTS). Materials and Methods: This prospective cohort study was conducted during a 1-year period in outpatient clinics of rehabilitation and physical medicine including 35 patients with moderate and severe CTS who receive ultrasonography-guided local steroid injection. The Boston self-assessment questionnaire and electrodiagnosis parameters were recorded at baseline, 1 month, and 3 months after therapy. We also recorded the baseline ultrasonography parameters to determine the predictors of outcome. Results: The sensory severity score and functional status scale along with electrodiagnosis parameters decreased significantly at 1 month (P < 0.001) and remained unchanged after 3 months. Volar bulging was negatively associated with sensory nerve action potential latency (r = -0.392; P = 0.020). Cross-sectional area (CSA) of maximal swelling (MS; r = 0.409; P = 0.015), CSA at 2-cm of MS (r = 0.563; P < 0.001), and CSA at 12-cm of MS (r = 0.521; P = 0.001) correlated positively with compound muscle action potential (CMAP) amplitude while maximal swelling/12-cm MS ratio (r = -0.439; P = 0.008) and maximal swelling/2-cm MS ratio (r = -0.342; P = 0.045) correlated negatively. CSA at 12-cm of MS also correlated positively with CMAP amplitude nerve conduction velocity (r = 0.436; P = 0.010). Conclusion: Volar bulging, CSA of maximal swelling, CSA of MS at 2-cm, and CSA of MS at 12-cm are among the ultrasonographic predictors of response to local steroid injection in patients with CTS. PMID- 29531921 TI - Genetic Diversity of Drug-resistant Mycobacterium tuberculosis Isolates in Isfahan Province of Iran. AB - Background: Increasing drug resistance is an important factor in the complexity of tuberculosis (TB) control. The identification of disease transmission type, recurrence of a previous infection, or new transmission of the disease is the key factor in the control of TB. In this study, we aimed to identify the genetic diversity of drug-resistant Mycobacterium tuberculosis isolates in Isfahan province of Iran through the mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing method based on 24 loci. Materials and Methods: Of 300 isolates obtained from a variety of clinical specimens, 18 drug resistance M. tuberculosis clinical isolates (resistant to a single drug to more than one drug) were collected between 2013 and 2015 from regional TB reference laboratory in Isfahan. All drug-resistance M. tuberculosis isolates were typed by 24-locus MIRU-VNTR typing. Results: The highest percentage of isolates, 38.8%, belonged to the East-Asian lineage (lineage 2), while the lineages Indo-Oceanic (lineage 1), East-African-Indian (lineage 3), and Euro-American (lineage 4) represented 5.5%, 22.2%, and 33.3%, respectively. Among the 33.3% (6/18) Euro American strains, the Latin American- Mediterranean and Ural sub-lineage were 22.2% (4/18) and 11.1% (2/18), respectively. Conclusion: The results of this study show that the lineages of drug-resistant M. tuberculosis isolates in Isfahan province of Iran are similar to those reported in the Eastern Mediterranean region (indicative of the epidemiological relationship between the countries in the region). Continued molecular monitoring is important as it has been proposed that the genetics and evolutionary backgrounds of drug-resistant M. tuberculosis strains may have an impact on the transmissibility profile. PMID- 29531922 TI - Effect of Ganoderma lucidum Powder on Oxidative Stability, Microbial and Sensory Properties of Emulsion Type Sausage. AB - Background: Ganoderma lucidum from Ganodermataceae family is a kind of mushroom known to have various therapeutic properties such as lowering high blood sugar and high blood pressure, boosting the immune system as well as its antibacterial and antioxidant effects. Materials and Methods: this study investigated the oxidative stability, microbial and sensory properties of sausage at three different treatments; (i) 1% w/w Ganoderma lucidum powder (GLP) without nitrite as a food preservative (P), (ii) 0.5% w/w GLP with 80 ppm nitrite (N + P), and (iii) sausage with 120 ppm nitrate (N). Lipid oxidation was evaluated using peroxide value (PV) and thiobarbituric acid reactive species. Antimicrobial properties were assessed by total plate count (TPC), yeasts and molds, coliforms, Clostridium perfringens, and Staphylococcus aureus. Sensory assessment was evaluated by nine-point hedonic procedure. Results: Samples in N + P treatment showed lower PV than other treatments at the storage period with no significant difference in 2-thiobarbituric acid (TBA) between N and N + P. The P group showed the highest TBA value (P < 0.01). TPC remained below maximal permissible limit recommended by ISIRI during 30 days of storage in all sausage formulations (6.9798 log CFU). There was not found any coliforms bacteria, Clostridium perfringens, and S. aureus. The sensory evaluation indicated that there is no significant difference between samples in texture, taste, and smell. The color and overall acceptability of N group were higher and N + P group was closer to N group. Conclusion: The results suggest that G. lucidum powder might be considered as a potential natural preservative for meat products. PMID- 29531923 TI - The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats. AB - Background: Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin-Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats. Materials and Methods: Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples. Results: In female rats, the serum and kidney nitrite levels increased significantly by Ang II (P < 0.05) and decreased significantly (P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups (P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats (P < 0.05). Conclusion: Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors. PMID- 29531924 TI - The Effect of Pregabalin and Metformin on Subacute and Chronic Radiculopathy. AB - Background: Radicular pain is one of the most common forms of chronic pain in the world, which has challenges about effective medical therapy. The aim of this study was to evaluate the effect of pregabalin (PGB) and metformin (Met) on subacute and chronic radiculopathy. Materials and Methods: This double-blind prospective clinical trial was performed on 71 patients with subacute and chronic cervical and lumbosacral radiculopathy. Group A was treated with PGB 75 mg daily while Group B was treated with PGB 75 mg daily and Met 500 mg daily for 3 months. Finally, the pain score in both groups was evaluated based on visual analog scale (VAS) and numerical scale pain. Results: The results showed a significant reduction in VAS and pain severity in both groups but this reduction in the terms of VAS (47.79% vs. 46.48%, P = 0.125) and pain severity (47.1% vs. 39.2%, P = 0.264) was more in treated patients with PGB and Met as compared to PGB group while total pain experience (53.5% vs. 49.1%, P = 0.464) and interference with daily function (57.1% vs. 50.61%, P = 0.726) were more in patients treated with PGB alone. Conclusion: Our results showed that PGB and PGB + Met reduced pain intensity and interference with daily function while we did not observe significant differences between two groups. PGB alone would have the potentiality to become a simple and economic means to decrease radicular pain. PMID- 29531925 TI - The Comparison of Nasaleze and Mometasone Nasal Spray to Control the Symptoms of Allergic Rhinitis. AB - Background: Nasal corticosteroids are the main drug class for the treatment of allergic rhinitis, and their long-term continuous use can be problematic. The current study aimed to compare the use of Nasaleze and mometasone nasal spray in patients with allergic rhinitis. Materials and Methods: In this study, 64 patients were studied in two groups of 32 patients. Nasaleze was used for the first group and mometasone for the second group for 4 weeks. The severity of sneezing, runny nose, tearing, nasal congestion, itchy eyes, and scratchy throat were evaluated at the onset of the study, and also 14 and 28 days after treatment in the form of a single-blind study. Statistical analysis was performed using SPSS Software (SPSS Inc., Chicago, IL, USA, Version 20). Results: The severity of allergic rhinitis symptoms had a significant difference in both groups of Nasaleze and mometasone at three times. Furthermore, in the Nasaleze group, the intensity of tearing significantly reduced 14 and 28 days after treatment compared to the mometasone group. In addition, the mean pretreatment score of allergic had no significant difference in the two groups neither14 days nor 28 days after the treatment. Conclusion: The efficacy of Nasaleze nasal spray is very similar to that of mometasone nasal spray to control the symptoms of allergic rhinitis. Therefore, Nasaleze nasal spray can be a suitable alternative for nasal corticosteroids in children older than 18 months, pregnant and lactating women. PMID- 29531926 TI - Clinical Aspects of Microsatellite Instability Testing in Colorectal Cancer. AB - Microsatellite instability (MSI) is a molecular hallmark for some colorectal cancers (CRCs) in which short tandem repeats are prone to mutations along with DNA sequences. It is due to DNA-mismatch-repair system deficiency because of a germline/somatic mutation in mismatch-repair (MMR) genes. The germline mutations lead to Lynch syndrome (LS) while epigenetic gene silencing results in sporadic CRC tumors. We discuss in our paper the most important clinical aspects of MSI testing in CRCs. We reviewed the most reliable relevant studies and clinical trials according to their high-quality methods, particularly within two recent decades. MSI testing is used to classify CRC tumors as MSI-high (MSI-H), MSI-low, and microsatellite stable tumors. MSI-H or MMR deficient tumors have shown the best prognosis among all CRCs, so MSI testing is considered as a good prognostic marker. Moreover, it is used to identify LS among familial CRC patients. There is a diagnostic mutation in BRAF gene (V600E) by which sporadic CRCs could be distinguished from LS associated CRCs, due to its concordance with sporadic CRCs not LS. Although, some previous studies had demonstrated a predictive role for MSI testing in chemotherapy process, emerging some controversial findings in recent studies has not convinced many authors to recommend it as a routine examination to evaluate therapeutic response. Though emerging new molecular findings have opened novel windows to develop clinical management of CRC, MSI testing has remained as an excellent prognostic and diagnostic tool for CRC tumors. PMID- 29531927 TI - Comparison the Postoperation Results of Discectomy with Nucleoplasty in Single Cervical Disc Herniation. AB - Background: The standard treatment for cervical disc herniation is open discectomy surgery but some of techniques, such as nucleoplasty were applied by neurosurgeons in recent decade. The aim of this study was to compare the postoperation results of open discectomy and nucleoplasty methods in people suffering from single cervical disc herniation. Materials and Methods: In a clinical trial study that performed during 2012-2013, 70 patients who candidate for neck surgery were selected and randomly divided into two groups. The first group was operated with standard discectomia and the second group was operated with nucleoplasty method. All patients were followed neck pain, upper limb pain and common complications included discitis, infection and hematoma in 2 weak, 1, 2, 3, and 6 months after operation. All data were analyzed using SPSS software. Results: Cervical pain mean from before the operation to 6 months after operation had no significant difference between two groups, but radicular pain had significant difference in 2 and 3 months after operation (P < 0.05). It is notable that after operation it is not observed any discitis, infection and hematoma of operated place. Conclusion: Doing nucleoplasty surgery in patients suffering from single cervical disc herniation causes decrease in cervical and radicular pain, at least as the same as discectomy method. Since now it is possible in our country to apply this method and on the other hand, in this method, time of surgery, postoperation complications, hospital costs, and period of convalescence is low, it is preferred in patients suffering from cervical disc and its application is advised. PMID- 29531928 TI - Early Versus Delayed (Traditional) Postoperative Oral Feeding in Patients Undergoing Colorectal Anastomosis. AB - Background: A period of starvation after colorectal anastomosis to permit for resolution of the clinical evidence of ileus has been an unchallenged surgical dogma until recent years. We intended to determine the safety and feasibility of an unconventional postoperative oral intake protocol in patients experiencing colorectal anastomosis. Materials and Methods: Between 2013 and 2015, sixty consecutive patients underwent colorectal anastomosis and they were randomized into two groups. The early feeding group began fluids on the first postoperative day while the regular feeding group was managed in the traditional way - nothing by mouth until the complete resolution of ileus. Results: The majority of patients (93%) tolerated the early feeding. The times to first passage of flatus (2.66 +/- 0.71 days vs. 3.9 +/- 0.071 days) and stool (3.9 +/- 0.92 days vs. 5.4 +/- 0.77 days) were significantly quicker in early feeding group. Hospital stay was also significantly shorter in the early feeding group (4 +/- 0.64 days vs. 6.1 +/- 0.84 days). Anastomosis leakage and abscess formation were not seen in early feeding group. The patient's satisfaction (visual analog scale) in the early feeding group was higher than delayed feeding group (8.56 +/- 1.16 vs. 7.06 +/- 1.59, P < 0.001). Conclusions: Early oral feeding after colorectal surgeries is safe and tolerated by the majority of patients. PMID- 29531929 TI - Determination Relation of the Zinc Serum Level in Acute Leukemia Adult Patients with Mucositis and Neutropenic Prevalence before and after Treatment in Isfahan' Seyed-Al-Shohada Hospital, 2012-2013. AB - Background: Neutropenic fever and mucositis with 70% outbreak average is one of the major reasons of death in the acute leukemia adult patients. The aim of this study was to determine the relationship of serum zinc level with neutropenic fever and mucositis prevalence in acute leukemia adult patients and comparison of the effects of therapeutic intervention with the serum zinc correct level in the group of patients with zinc deficiency. Materials and Methods: From May 2012 to May 2013 in a double-blind, randomized, placebo-controlled study, on the basis of zinc serum level, 40 acute leukemia adult patients were divided into two groups of normal and deficiency zinc, and neutropenic fever and mucositis prevalence were taken into consideration in each and every group. The deficiency zinc patients were randomly allocated to zinc or control group in a blocked randomization schedule. The data analysis was performed by SPSS software 20 and with the aid of variance analysis statistical method, logistic regression, and X2 statistical test. Results: Serum zinc level was higher in acute leukemia adult patients without mucositis and neutropenic fever than others but was not statistically significant. There is a positive relation between receiving zinc with recovery; although the relationship has not become statistically significant. Conclusion: These data, although preliminary, suggest that zinc therapy could be a valid therapeutic adjuvant to improve the quality-of-life of acute leukemia adult patients. PMID- 29531930 TI - Emotional Intelligence: An Old Issue and a New Look in Clinical Teaching. AB - In this paper, a novel model of clinical teachers with social and emotional competency which is emphasized on the importance of clinical teacher's social and emotional competence is presented. In this model, we supposed that a teacher with social and emotional competence can manage her/his emotions and has the ability to personal development and well-being. Such teacher has the competency of empathy, communication with the patients, teamwork, and collaboration to provide successful patient-centered care and relationship-centered care. He/she will be success in clinical supervision, role modeling, and mentoring by providing appropriate relationship with students. This teacher can influence and build bonds that will be effective for clinical management and leadership. In addition, it will affect the hidden and informal curriculum with the awareness of the context. These factors establish an appropriate learning environment to achieve students' academic, professional, social, and emotional outcomes and create an appropriate health care environment that influences the successful care of patient and patient's satisfaction. We reviewed a broad body of research to support our proposed model and finally proposed agendas for future research. PMID- 29531931 TI - Thrombotic Thrombocytopenic Purpura in a Child with Diabetic Ketoacidosis. AB - Thrombotic thrombocytopenic purpura (TTP) secondary to diabetic ketoacidosis has been rarely reported and is considered as a rare complication. If left untreated, this condition could be life threatening with considerable morbidity and mortality. Herein, we report a 6-year-old girl with reduced consciousness and respiratory distress with a history of polydipsia and polyuria in the 2 weeks before hospitalization. The patient was initially diagnosed as diabetic ketoacidosis based on clinical and laboratory findings and treated accordingly. After treatment and during hospitalization although she had gained relative consciousness, she experienced seizure and reduced consciousness again. Considering laboratory and clinical findings and the patient's underlying conditions (thrombocytopenia, renal failure, and high lactate dehydrogenase), TTP was suspected although ADAMTS13 test could not be done. Treatment with plasmapheresis was initiated, and after 48 h, the patient was conscious, and laboratory indices became normal within a few days. The patient was discharged after full recovery. TTP should be considered as a rare complication of diabetic ketoacidosis in patients with thrombocytopenia, renal failure, and reduced consciousness and should be immediately treated. PMID- 29531932 TI - Depression in Main Caregivers of Dementia Patients: Prevalence and Predictors. AB - Background: The most common neurodegenerative disease is dementia. Family of dementia patients says that their lives have been changed extensively after happening of dementia to their patients. One of the problems of family and caregivers is depression of the caregiver. In this study, we aimed to find the prevalence of depression and factors can affect depression in the dementia caregivers. Materials and Methods: This study was cross-sectional study with convenient sampling method. Our society was 96 main caregivers of dementia patients in the year 2015 in Iran. We had two questionnaires, a demographic and Beck Depression Inventory (BDI). BDI Cronbach's alpha is 0.86 for psychiatric patients and 0.81 for nonpsychiatric persons, and Beck's scores are between 0 and 64. We used SPSS version 22 for statistical analysis. Results: According to Beck depression test, 69.8% (n = 67 out of 96) of all caregivers had scores in the range of depression. In bivariate analysis, we found higher dementia severity and lower support of other family members from the caregiver can predict higher depression in the caregiver. As well, in regression analysis using GLM model, we found higher age and lower educational level of the caregiver can predict higher depression in the caregiver. Moreover, regression analysis approved findings about severity and support of other family members in bivariate analysis. Conclusion: High-level depression is found in caregivers of dementia patients. It needs special attention from healthcare managers, clinicians and all of health care personnel who deals with dementia patients and their caregivers. PMID- 29531933 TI - The First Report on the Frequency of Asymptomatic Proteinuria in Iranian School aged Children. AB - Background: Proteinuria is a well-known indicator of renal dysfunction. In this study, we evaluated the frequency of proteinuria in a sample of healthy Iranian elementary school students using both dipsticks and urine albumin-to-creatinine ratio (UACR) methods. Materials and Methods: This cross-sectional study was performed on 478 school students aged 7-9 years who were selected by multistage random cluster sampling from Isfahan city, Iran. A clean midstream first-morning urine sample was obtained from each subject. Urine samples were examined by dipstick method, and accordingly, they were reported as negative; trace; 1+; 2+; 3+; and 4+. UACR was determined in samples with positive dipstick proteinuria (defined as trace or greater). Results: This study included 478 students (42.8% boys), with mean age of 7.0 +/- 0.4 years. Positive dipstick was detected in 124 (25.9%) cases. The frequency of positive dipstick proteinuria was significantly higher in the girls than boys (29.6% vs. 20.9%, respectively; P = 0.04). In cases with a positive dipstick, 10 (2.1%) cases had UACR 30-300 mg/g. The frequency of UACR of 30-300 mg/g was 1.4% and 2.5% in boys and girls, respectively. There was no significant difference in the frequency of UACR 30-300 mg/g in terms of gender (P = 0.4). None of the subjects had UACR above 300 mg/g. Conclusion: While the frequency of asymptomatic proteinuria varies widely across different studies, we found a higher rate of proteinuria in Iranian children. Cost-effectiveness analyses are needed to justify large screening program for detecting asymptomatic proteinuria, as a cardinal manifestation of kidney disease, in Iranian children. PMID- 29531934 TI - Cartilage Tissue Engineering Via Icariin and Adipose-derived Stem Cells in Fibrin Scaffold. AB - Background: Nowadays, cartilage tissue engineering is the best candidate for regeneration of cartilage defects. This study evaluates the function of herbal extracts icariin (ICA), the major pharmacological constituent of herba Epimedium, compared with transforming growth factor beta3 (TGFbeta3) to prove its potential effect for cartilage tissue engineering. Materials and Methods: ICA, TGFbeta3, and TGFbeta3 + ICA were added fibrin-cell constructions derived from adipose tissue stem cells. After 14 days, cell viability analyzed by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide assay and the expression of cartilage genes was evaluated with real-time polymerase chain reaction (RT-PCR). Results: The results showed ICA, TGFbeta3, and TGFbeta3 + ICA increased the rate of proliferation and viability of cells; but there were no significant differences between them (P > 0.05). Furthermore, quantitative RT-PCR analysis demonstrated that cooperation of ICA with TGFbeta3 showed a better effect in expression of cartilaginous specific genes and increased Sox9, type II collagen, and aggrecan expression significantly. Furthermore, the results of the expression of type I and X collagens revealed that TGFbeta3 increased the expression of them (P < 0.01); However, treatment with ICA + TGFbeta3 down regulated the expression of these genes significantly. Conclusion: The results indicated ICA could be a potential factor for chondrogenesis and in cooperation with TGFbeta3 could reduce its hypertrophic effects and it is a promising factor for cartilage tissue engineering. PMID- 29531935 TI - A Rare Missense Mutation and a Polymorphism with High Frequency in LDLR Gene among Iranian Patients with Familial Hypercholesterolemia. AB - Background: Familial hypercholesterolemia (FH) is a disorder that is inherited by autosomal dominant pattern. The main cause of FH disease is the occurrence of mutations in low-density lipoprotein receptor (LDLR) gene sequence, as well as apolipoprotein B and proprotein convertase subtilisin/kexin type 9 genes, located in the next ranks, respectively. Materials and Methods: Forty-five unrelated Iranian patients with FH were screened using a high-resolution melting (HRM) method for exon 9 along with intron/exon boundaries of LDLR gene. Samples with shift in resultant HRM curves were compared to normal ones, sequenced, and analyzed. Results: Our findings revealed a missense mutation c. 1246C>T and a known variant IVS9-30C>T (rs1003723) that was recognized in 71% of the patients (22%: homozygous and 49%: heterozygous genotypes). In silico analysis, predicted the pathological effect of the c. 1246C>T mutation in LDLR protein structure, but IVS9-30C>T variant had no predicted effect on splice site and branch point function. Conclusion: FH is a hereditary type of hypercholesterolemia that leads to premature cardiovascular disease and atherosclerosis, and early diagnosis is needed. We detected a rare missense mutation (1246C>T) and a common single nucleotide polymorphism (SNP) in the Iranian population. These reports could help in the genetic diagnosis and counseling of FH patients. PMID- 29531936 TI - Novel condylar repositioning method for 3D-printed models. AB - Background: Along with the advances in technology of three-dimensional (3D) printer, it became a possible to make more precise patient-specific 3D model in the various fields including oral and maxillofacial surgery. When creating 3D models of the mandible and maxilla, it is easier to make a single unit with a fused temporomandibular joint, though this results in poor operability of the model. However, while models created with a separate mandible and maxilla have operability, it can be difficult to fully restore the position of the condylar after simulation. The purpose of this study is to introduce and asses the novel condylar repositioning method in 3D model preoperational simulation. Methods: Our novel condylar repositioning method is simple to apply two irregularities in 3D models. Three oral surgeons measured and evaluated one linear distance and two angles in 3D models. Results: This study included two patients who underwent sagittal split ramus osteotomy (SSRO) and two benign tumor patients who underwent segmental mandibulectomy and immediate reconstruction. For each SSRO case, the mandibular condyles were designed to be convex and the glenoid cavities were designed to be concave. For the benign tumor cases, the margins on the resection side, including the joint portions, were designed to be convex, and the resection margin was designed to be concave. The distance from the mandibular ramus to the tip of the maxillary canine, the angle created by joining the inferior edge of the orbit to the tip of the maxillary canine and the ramus, the angle created by the lines from the base of the mentum to the endpoint of the condyle, and the angle between the most lateral point of the condyle and the most medial point of the condyle were measured before and after simulations. Near-complete matches were observed for all items measured before and after model simulations of surgery in all jaw deformity and reconstruction cases. Conclusions: We demonstrated that 3D models manufactured using our method can be applied to simulations and fully restore the position of the condyle without the need for special devices. PMID- 29531937 TI - Corrigendum: IRAK4 Deficiency in a Patient with Recurrent Pneumococcal Infections: Case Report and Review of the Literature. AB - [This corrects the article on p. 83 in vol. 5, PMID: 28503543.]. PMID- 29531938 TI - The impact of perioperative blood transfusions on short-term outcomes following hepatectomy. AB - Background: Bleeding and need for red blood cell transfusions (RBCT) remain a significant concern with hepatectomy. RBCT carry risk of transfusion-related immunomodulation that may impact post-operative recovery. This study soughs to assess the association between RBCT and post-hepatectomy morbidity. Methods: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry, we identified all adult patients undergoing elective hepatectomy over 2007-2012. Two exposure groups were created based on RBCT. Primary outcomes were 30-day major morbidity and mortality. Secondary outcomes included 30-day system-specific morbidity and length of stay (LOS). Relative risks (RR) with 95% confidence interval (95% CI) were computed using regression analyses. Sensitivity analyses were conducted to understand how missing data might have impacted the results. Results: A total of 12,180 patients were identified. Of those, 11,712 met inclusion criteria, 2,951 (25.2%) of whom received RBCT. Major morbidity occurred in 14.9% of patients and was strongly associated with RBCT (25.3% vs. 11.3%; P<0.001). Transfused patients had higher rates of 30-day mortality (5.6% vs. 1.0%; P<0.0001). After adjustment for baseline and clinical characteristics, RBCT was independently associated with increased major morbidity (RR 1.80; 95% CI: 1.61-1.99), mortality (RR 3.62; 95% CI: 2.68-4.89), and 1.29 times greater LOS (RR 1.29; 95% CI: 1.25-1.32). Results were robust to a number of sensitivity analyses for missing data. Conclusions: Perioperative RBCT for hepatectomy was independently associated with worse short term outcomes and prolonged LOS. These findings further the rationale to focus on minimizing RBCT for hepatectomy, when they can be avoided. PMID- 29531940 TI - The emerging role for robotics in cholecystectomy: the dawn of a new era? AB - Though laparoscopic cholecystectomy (LC) was highly criticized in its early stages, it quickly grew to become a new standard of care and has revolutionized the field of general surgery. Now emerging robotic technology is making its way into the minimally invasive arena. Robotic cholecystectomy (RC) is often disparaged as a costly technology that can lead to increased operative times with outcomes that are quite similar to LC. However, this perspective is skewed as many existing studies were performed in the early phase of learning for this procedure. RC can be performed in a cost-effective manner as the volume of robotic procedures increases. In addition, improved visualization and capability to perform fluorescence cholangiography can improve the safety profile of cholecystectomy to a level that has not yet been achieved with conventional laparoscopy. Advanced simulation technology for robotic surgery, and newer single site robotic platforms have the potential to further revolutionize this technology and lead to improved patient satisfaction. In this review, we will present current data, trends, and controversies in robotic-assisted cholecystectomy. PMID- 29531941 TI - Congenital membranous occlusion of the suprahepatic inferior vena cava in a pediatric liver transplant. AB - Congenital membranous occlusion of the inferior vena cava (IVC) in pediatric liver recipients may present with outflow occlusion and if unrecognized, result in graft loss. Prompt evaluation of outflow obstruction in the setting of unexplained inflow compromise is paramount. We report a case of successful IVC reconstruction in a patient with recurrent hepatic artery thrombosis (HAT). A 2 year-old child with history of two liver transplantations developed fevers, ascites, and abdominal tenderness one month after her second liver transplant. Hepatic duplex revealed decreased flow in the hepatic artery and IVC venogram revealed patent hepatic veins with occlusion of the suprahepatic IVC. We performed reconstruction of her suprahepatic IVC to intrapericardial IVC using an end-to-side technique after complete mobilization of the liver. Recovery was uneventful and the patient has been doing well for the last 5 years. PMID- 29531939 TI - Targeting gut microbiota in hepatocellular carcinoma: probiotics as a novel therapy. AB - Hepatocellular carcinoma (HCC), the most common primary liver cancer, is one of the dreaded complications of chronic liver disease. Recent experimental and clinical studies have revealed that the alteration of gut-liver axis plays a pivotal role in the onset of chronic liver diseases, including HCC. Altered gut microbiota and endotoxemia are increasingly recognized as critical components in promoting the progression of chronic liver diseases to HCC. Probiotics have been suggested as a novel, safe and cost-effective approach to prevent or treat HCC. Mechanisms by which probiotics exerts their anti-cancer effects include their ability to bind carcinogens, modulation of gut microbiota, improvement of intestinal barrier function, and immunomodulation. This review summarizes the literature findings of the changes in gut microbiota linked to HCC, and discusses the possible therapeutic implications of probiotics for HCC. PMID- 29531942 TI - Gut microbiota and surgical disease. PMID- 29531943 TI - Behavioral primary prevention of cardiovascular diseases. PMID- 29531944 TI - Enteric dysbiosis, gut barrier and liver disease. PMID- 29531945 TI - Astrocyte elevated gene-1 (AEG-1): a new potential therapeutic target for the treatment of nonalcoholic steatohepatitis (NASH). PMID- 29531946 TI - Single cell profiling reveals window for immunotherapy in liver cancers. PMID- 29531947 TI - A novel role for polymeric immunoglobulin receptor in tumour development: beyond mucosal immunity and into hepatic cancer cell transformation. PMID- 29531948 TI - Mirizzi syndrome: a new approach to an old problem. PMID- 29531949 TI - Radioembolization in the setting of liver transplantation: great expectations or hard times? PMID- 29531950 TI - The "Chinese Mode" of organ donation and transplantation: moving towards the center stage of the world. PMID- 29531951 TI - Response to Comment on: Early recovery pathway for hepatectomy: data-driven liver resection care and recovery. PMID- 29531952 TI - Laparoscopic liver resection in patients with liver cirrhosis-the path towards standard of care. PMID- 29531953 TI - Dr. Morris-Stiff: the diagnosis and management of pancreatic adenocarcinoma. PMID- 29531954 TI - Prof. Sung-Gyu Lee: future perspectives of living donor liver transplantation. PMID- 29531955 TI - Prof. Jamila Faivre: microbiology is a new field to me but it's interesting. PMID- 29531956 TI - RON tyrosine kinase mutations in brain metastases from lung cancer. AB - RON mutations might identify actionable targets in highly aggressive lung tumours http://ow.ly/RTUp30hSBX6. PMID- 29531958 TI - The annual prognostic ability of FACED and E-FACED scores to predict mortality in patients with bronchiectasis. AB - Both FACED and E-FACED scores have shown good short-term prognostic value for predicting mortality in bronchiectasis http://ow.ly/albl30i11bv. PMID- 29531957 TI - An algorithmic approach for the treatment of severe uncontrolled asthma. AB - A small subgroup of patients with asthma suffers from severe disease that is either partially controlled or uncontrolled despite intensive, guideline-based treatment. These patients have significantly impaired quality of life and although they constitute <5% of all asthma patients, they are responsible for more than half of asthma-related healthcare costs. Here, we review a definition for severe asthma and present all therapeutic options currently available for these severe asthma patients. Moreover, we suggest a specific algorithmic treatment approach for the management of severe, difficult-to-treat asthma based on specific phenotype characteristics and biomarkers. The diagnosis and management of severe asthma requires specialised experience, time and effort to comprehend the needs and expectations of each individual patient and incorporate those as well as his/her specific phenotype characteristics into the management planning. Although some new treatment options are currently available for these patients, there is still a need for further research into severe asthma and yet more treatment options. PMID- 29531959 TI - Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study. AB - Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participating centres will undergo an echocardiography- and biomarker-based pulmonary hypertension screening procedure as in the DETECT study. Standard right heart catheterisation will be provided to patients with intermediate or high echocardiographic probability of pulmonary hypertension. Those with low echocardiographic probability will rescreen within 1 year. The primary measure will be the diagnosis and types of pulmonary hypertension and prevalence of pulmonary hypertension in SLE patients. The secondary measures will be the predictors and prediction models for pulmonary hypertension in SLE patients. The estimated sample size is approximately 895 participants. The results of the SOPHIE study will be an important contribution to the literature of SLE-related pulmonary hypertension and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for screening of pulmonary hypertension in SLE patients. PMID- 29531960 TI - Lower Leg Chronic Exertional Compartment Syndrome in Patients 50 Years of Age and Older. AB - Background: Lower leg chronic exertional compartment syndrome (CECS) is usually diagnosed in young and athletic individuals. The presence of CECS in older patients has received little attention in the literature, and patient characteristics are unknown. Purpose: To determine the prevalence of CECS in older patients (>=50 years) and to assess whether older patients with CECS differ clinically from younger patients with CECS. Study Design: Cohort study; Level of evidence, 3. Methods: All individuals with exercise-induced lower leg pain who visited a referral center for CECS between January 2001 and December 2013 were eligible for analysis. Patients were included if history, physical examination, and dynamic intracompartmental pressure measurement indicated CECS. Characteristics of patients 50 years of age or older were compared with characteristics of patients younger than 50. Results: A total of 698 patients with CECS were included: 98 patients were aged 50 years or older and 600 patients were younger than 50 years. Older individuals more often reported a history of lower leg events or comorbidities (>=50 years, 45% vs <50 years, 25%; P < .01) and unilateral symptoms (>=50 years, 45% vs <50 years, 22%; P < .01). Most older patients (62%) did not participate in sport or only walked or hiked, whereas the same was true of only 7% of the younger population. Pain (>=50 years, 94%; <50 years, 96%) and tightness (>=50 years, 57%; <50 years, 62%) were the predominant symptoms of CECS in both groups. Type of CECS differed significantly (P < .01); the anterior muscle compartment was involved more frequently in older patients (>=50 years, 82% vs <50 years, 59%) and deep flexor muscle CECS was more often diagnosed in younger patients (>=50 years, 26% vs <50 years, 53%). Conclusion: In the present population, 1 in 7 patients diagnosed with lower leg CECS was 50 years of age or older. These individuals were less active and had more comorbidities than patients younger than 50 years. Older individuals predominantly have anterior CECS. Clinicians should consider CECS in older individuals with exercise-induced lower leg pain, particularly if it is unilateral. PMID- 29531961 TI - Ten-Year Incidence of Sport and Recreation Injuries Resulting in Major Trauma or Death in Victoria, Australia, 2005-2015. AB - Background: Sports injuries that result in major trauma or death are associated with significant health care burden and societal costs. An understanding of changes in injury trends, and their drivers, is needed to implement policy aimed at risk reduction and injury prevention. To date, population-level reporting has not been available regarding trends in serious sport and recreation injuries anywhere in Australia over such an extended period, nor have any studies of this length captured comprehensive, long-term data on all sports-related major trauma internationally. Purpose: To describe the incidence of sport and active recreation injuries resulting in major trauma or death over a 10-year period (July 2005 to June 2015) in the state of Victoria, Australia. Study Design: Descriptive epidemiological study. Methods: All sport and active recreation related major trauma cases and deaths in Victoria, Australia, over a 10-year period were extracted from the population-level Victorian State Trauma Registry and the National Coroners Information System. Poisson regression analysis was used to examine trends in the incidence of sport and active recreation-related major trauma and death. Results: The 10-year study period entailed 2847 nonfatal major trauma cases and 614 deaths (including 96 in-hospital deaths). The highest frequencies of major trauma cases and deaths were in cycling, motor sports, and equestrian activities. The participation-adjusted major trauma and death rate was 12.2 per 100,000 participants per year over the study period. An 8% increase was noted in the rate of nonfatal major trauma (incident rate ratio [IRR], 1.08; 95% CI, 1.06-1.10; P < .001) and a 7% decrease in the death rate (IRR, 0.93; 95% CI, 0.90-0.97; P < .001). Significant increases were found in the rates of major trauma (including deaths) in equestrian activities, motor sports, and cycling. Conclusion: The death rate from sport and active recreation decreased by more than half over the course of 10 years in Victoria, while the rate of nonfatal major trauma almost doubled. This increase is largely attributable to equestrian activities, motor sports, and cycling. Study findings highlight the need to prioritize investments in the prevention of trauma in these activities. PMID- 29531962 TI - Noninvasive detection of acute cerebral hypoxia and subsequent matrix metalloproteinase activity in a mouse model of cerebral ischemia using multispectral-optoacoustic-tomography. AB - Oxygen metabolism and matrix metalloproteinases (MMPs) play important roles in the pathophysiology of cerebral ischemia. Using multispectral optoacoustic tomography (MSOT) imaging, we visualized in vivo changes in cerebral tissue oxygenation during 1 h of transient middle cerebral artery occlusion (tMCAO) and at 48 h after reperfusion together with MMP activity using an MMP-activatable probe. The deoxyhemoglobin, oxyhemoglobin, and MMP signals were coregistered with structural magnetic resonance imaging data. The ipsi-/contralateral ratio of tissue oxygen saturation ([Formula: see text]) was significantly reduced during 1 h of tMCAO and recovered after 48 h of reperfusion in tMCAO compared with sham operated mice ([Formula: see text] to 10 per group). A higher ipsi-/contralateral MMP signal ratio was detected at 48 h after reperfusion in the lesioned brain regions of tMCAO compared with the sham-operated animal ([Formula: see text] to 6 per group). Ex vivo near-infrared fluorescence imaging of MMP signal in brain slices was used to validate in vivo MSOT measurements. In conclusion, noninvasive MSOT imaging can provide visualization of hemodynamic alterations and MMP activity in a mouse model of cerebral ischemia. PMID- 29531963 TI - Modulating the resting-state functional connectivity patterns of language processing areas in the human brain with anodal transcranial direct current stimulation applied over the Broca's area. AB - Cortical circuit reorganization induced by anodal transcranial direct current stimulation (tDCS) over the Broca's area of the dominant language hemisphere in 13 healthy adults was quantified by functional near-infrared spectroscopy (fNIRS). Transient cortical reorganization patterns in steady-state functional connectivity (seed-based and graph theory analysis) and temporal functional connectivity (sliding window correlation analysis) were recorded before, during, and after applying high current tDCS (1 mA, 8 min). fNIRS connectivity mapping showed that tDCS induced significantly ([Formula: see text]) increased functional connectivity between Broca's area and its neighboring cortical regions while it simultaneously decreased the connectivity to remote cortical regions. Furthermore, the anodal stimulation caused significant increases to the functional connectivity variability (FCV) of remote cortical regions related to language processing. In addition to the high current tDCS, low current tDCS (0.5 mA, 2 min 40 s) was also applied to test whether the transient effects of lower stimulation current could qualitatively predict cortical connectivity alterations induced by the higher currents. Interestingly, low current tDCS could qualitatively predict the increase in clustering coefficient and FCV but not the enhancement of local connectivity. Our findings indicate the possibility of combining future studies fNIRS with tDCS at lower currents to help guide therapeutic interventions. PMID- 29531964 TI - Overexpression of channelrhodopsin-2 interferes with the GABAb receptor-mediated depression of GABA release from the somatostatin-containing interneurons of the prefrontal cortex. AB - Region and cell-type restricted expression of light-activated ion channels is the indispensable tool to study properties of synapses in specific circuits and to monitor synaptic alterations by various stimuli including neuromodulators and behaviors, both ex vivo and in vivo. These analyses require the light-activated proteins or viral vectors for their delivery that do not interfere with the phenomenon under study. Here, we report a case of such interference in which the high-level expression of channelrhodopsin-2 introduced in the somatostatin positive GABAergic neurons of the dorsomedial prefrontal cortex by an adeno associated virus vector weakens the presynaptic GABAb receptor-mediated suppression of GABA release. PMID- 29531965 TI - Empirical estimation of intravoxel structure with persistent angular structure and Q-ball models of diffusion weighted MRI. AB - The diffusion tensor model is nonspecific in regions where micrometer structural patterns are inconsistent at the millimeter scale (i.e., brain regions with pathways that cross, bend, branch, fan, etc.). Numerous models have been proposed to represent crossing fibers and complex intravoxel structure from in vivo diffusion weighted magnetic resonance imaging (e.g., high angular resolution diffusion imaging-HARDI). Here, we present an empirical comparison of two HARDI approaches-persistent angular structure MRI (PAS-MRI) and Q-ball-using a newly acquired reproducibility dataset. Briefly, a single subject was scanned 11 times with 96 diffusion weighted directions and 10 reference volumes for each of two [Formula: see text] values (1000 and [Formula: see text] for a total of 2144 volumes). Empirical reproducibility of intravoxel fiber fractions (number/strength of peaks), angular orientation, and fractional anisotropy was compared with metrics from a traditional tensor analysis approach, focusing on [Formula: see text] values of 1000 and [Formula: see text]. PAS-MRI is shown to be more reproducible than Q-ball and offers advantages at low [Formula: see text] values. However, there are substantial and biologically meaningful differences between the intravoxel structures estimated both in terms of analysis method as well as by [Formula: see text] value. The two methods suggest a fundamentally different microarchitecture of the human brain; therefore, it is premature to perform meta-analysis or combine results across HARDI studies using a different analysis model or acquisition sequences. PMID- 29531966 TI - Lesion modeling, characterization, and visualization for image-guided cardiac ablation therapy monitoring. AB - In spite of significant efforts to improve image-guided ablation therapy, a large number of patients undergoing ablation therapy to treat cardiac arrhythmic conditions require repeat procedures. The delivery of insufficient thermal dose is a significant contributor to incomplete tissue ablation, in turn leading to the arrhythmia recurrence. Ongoing research efforts aim to better characterize and visualize RF delivery to monitor the induced tissue damage during therapy. Here, we propose a method that entails modeling and visualization of the lesions in real-time. The described image-based ablation model relies on classical heat transfer principles to estimate tissue temperature in response to the ablation parameters, tissue properties, and duration. The ablation lesion quality, geometry, and overall progression are quantified on a voxel-by-voxel basis according to each voxel's cumulative temperature and time exposure. The model was evaluated both numerically under different parameter conditions, as well as experimentally, using ex vivo bovine tissue samples undergoing ex vivo clinically relevant ablation protocols. The studies demonstrated less than 5 degrees C difference between the model-predicted and experimentally measured end-ablation temperatures. The model predicted lesion patterns were within 0.5 to 1 mm from the observed lesion patterns, suggesting sufficiently accurate modeling of the ablation lesions. Lastly, our proposed method enables therapy delivery feedback with no significant workflow latency. This study suggests that the proposed technique provides reasonably accurate and sufficiently fast visualizations of the delivered ablation lesions. PMID- 29531967 TI - Radiomic signature of infiltration in peritumoral edema predicts subsequent recurrence in glioblastoma: implications for personalized radiotherapy planning. AB - Standard surgical resection of glioblastoma, mainly guided by the enhancement on postcontrast T1-weighted magnetic resonance imaging (MRI), disregards infiltrating tumor within the peritumoral edema region (ED). Subsequent radiotherapy typically delivers uniform radiation to peritumoral FLAIR hyperintense regions, without attempting to target areas likely to be infiltrated more heavily. Noninvasive in vivo delineation of the areas of tumor infiltration and prediction of early recurrence in peritumoral ED could assist in targeted intensification of local therapies, thereby potentially delaying recurrence and prolonging survival. This paper presents a method for estimating peritumoral edema infiltration using radiomic signatures determined via machine learning methods, and tests it on 90 patients with de novo glioblastoma. The generalizability of the proposed predictive model was evaluated via cross validation in a discovery cohort ([Formula: see text]) and was subsequently evaluated in a replication cohort ([Formula: see text]). Spatial maps representing the likelihood of tumor infiltration and future early recurrence were compared with regions of recurrence on postresection follow-up studies with pathology confirmation. The cross-validated accuracy of our predictive infiltration model on the discovery and replication cohorts was 87.51% (odds ratio = 10.22, sensitivity = 80.65, and specificity = 87.63) and 89.54% (odds ratio = 13.66, sensitivity = 97.06, and specificity = 76.73), respectively. The radiomic signature of the recurrent tumor region revealed higher vascularity and cellularity when compared with the nonrecurrent region. The proposed model shows evidence that multiparametric pattern analysis from clinical MRI sequences can assist in in vivo estimation of the spatial extent and pattern of tumor recurrence in peritumoral edema, which may guide supratotal resection and/or intensification of postoperative radiation therapy. PMID- 29531968 TI - Development of a modular fluorescence overlay tissue imaging system for wide field intraoperative surgical guidance. AB - Fluorescence imaging is a well-established optical modality that has been used to localize and track fluorophores in vivo and has demonstrated great potential for surgical guidance. Despite the variety of fluorophores currently being researched, many existing intraoperative fluorescence imaging systems are specifically designed for a limited number of applications. We present a modular wide-field fluorescence overlay tissue imaging system for intraoperative surgical guidance that is comprised of commercially available standardized components. Its modular layout allows for the accommodation of a broad range of fluorophores, fields of view (FOV), and spatial resolutions while maintaining an integrated portable design for intraoperative use. Measurements are automatic and feature a real-time projection overlay technique that intuitively displays fluorescence maps directly onto a [Formula: see text] FOV from a working distance of 35 cm. At a 20-ms exposure time, [Formula: see text] samples of indocyanine green could be measured with high signal-to-noise ratio and was later tested in an in vivo mouse model before finally being demonstrated for intraoperative autofluorescence imaging of human soft tissue sarcoma margins. The system's modular design and ability to enable naked-eye visualization of wide-field fluorescence allow for the flexibility to adapt to numerous clinical applications and can potentially extend the adoption of fluorescence imaging for intraoperative use. PMID- 29531969 TI - Blood vessel segmentation in modern wide-field retinal images in the presence of additive Gaussian noise. AB - Retinal blood vessels indicate some serious health ramifications, such as cardiovascular disease and stroke. Thanks to modern imaging technology, high resolution images provide detailed information to help analyze retinal vascular features before symptoms associated with such conditions fully develop. Additionally, these retinal images can be used by ophthalmologists to facilitate diagnosis and the procedures of eye surgery. A fuzzy noise reduction algorithm was employed to enhance color images corrupted by Gaussian noise. The present paper proposes employing a contrast limited adaptive histogram equalization to enhance illumination and increase the contrast of retinal images captured from state-of-the-art cameras. Possessing directional properties, the multistructure elements method can lead to high-performance edge detection. Therefore, multistructure elements-based morphology operators are used to detect high quality image ridges. Following this detection, the irrelevant ridges, which are not part of the vessel tree, were removed by morphological operators by reconstruction, attempting also to keep the thin vessels preserved. A combined method of connected components analysis (CCA) in conjunction with a thresholding approach was further used to identify the ridges that correspond to vessels. The application of CCA can yield higher efficiency when it is locally applied rather than applied on the whole image. The significance of our work lies in the way in which several methods are effectively combined and the originality of the database employed, making this work unique in the literature. Computer simulation results in wide-field retinal images with up to a 200-deg field of view are a testimony of the efficacy of the proposed approach, with an accuracy of 0.9524. PMID- 29531970 TI - Quantifying the costs of interruption during diagnostic radiology interpretation using mobile eye-tracking glasses. AB - What are the costs and consequences of interruptions during diagnostic radiology? The cognitive psychology literature suggests that interruptions lead to an array of negative consequences that could hurt patient outcomes and lead to lower patient throughput. Meanwhile, observational studies have both noted a strikingly high rate of interruptions and rising number of interruptions faced by radiologists. There is some observational evidence that more interruptions could lead to worse patient outcomes: Balint et al. (2014) found that the shifts with more telephone calls received in the reading room were associated with more discrepant calls. The purpose of the current study was to use an experimental manipulation to precisely quantify the costs of two different types of interruption: telephone interruption and an interpersonal interruption. We found that the first telephone interruption led to a significant increase in time spent on the case, but there was no effect on diagnostic accuracy. Eye-tracking revealed that interruptions strongly influenced where the radiologists looked: they tended to spend more time looking at dictation screens and less on medical images immediately after interruption. Our results demonstrate that while radiologists' eye movements are reliably influenced by interruptions, the behavioral consequences were relatively mild, suggesting effective compensatory mechanisms. PMID- 29531972 TI - Editorial for the launch of Addictive Behaviors Reports. PMID- 29531971 TI - BCL-2 and BCL-XL expression are down-regulated in benign prostate hyperplasia nodules and not affected by finasteride and/or celecoxib. AB - The mechanisms involved in the development of benign prostatic hyperplasia (BPH) are poorly understood. One potential mechanism involved in BPH pathogenesis may involve altered expression of genes related to apoptosis and proliferation because reduced cell death and increased proliferation are thought to contribute to prostatic enlargement. This study examined the expression of B-cell lymphoma 2 (BCL-2) and B-cell lymphoma-extra large (BCL-XL), two important anti-apoptosis factors that are also capable of inhibiting cell proliferation via accelerated G1 arrest or delayed G1/S transition, using immunostaining in simple prostatectomy BPH specimens from patients naive to androgen manipulation. Since androgens and inflammation are thought to play important roles in BPH pathogenesis, we tested the effect of inhibiting 5a-reductase and/or COX-2 on the expression of BCL-2 and BCL-XL in BPH specimens from prostate cancer patients with BPH. These patients had no prior use of chronic NSAIDs and/or 5a-reductase inhibitors and were treated with celecoxib, finasteride, celecoxib plus finasteride or no treatment for 28 consecutive days prior to surgery. In all specimens, BCL-2 and BCL-XL staining was evident in both luminal and basal epithelial cells, with more intense staining in basal cells. Both luminal and basal cells exhibited decreased BCL-2 and BCL-XL staining in BPH nodules compared to the surrounding normal prostatic tissues. In prostate cancer patients with BPH, celecoxib and/or finasteride did not affect the expression of BCL-2 and BCL-XL in luminal or basal cells in BPH nodules and normal adjacent tissues. These results suggest that BCL 2 and BCL-XL may act as anti-proliferative factors in BPH pathogenesis, and the effect of celecoxib and/or finasteride on BPH is unlikely mediated through modulating BCL-2 and BCL-XL signaling. PMID- 29531973 TI - Desire thinking as a mediator of the relationship between novelty seeking and craving. AB - Background: The construct of craving has been shown to play a crucial role in the development and maintenance of addictive behaviors. Both novelty seeking and desire thinking have been identified, respectively, as important temperamental and cognitive predictors of craving. Aims: In the present study we aimed to explore the relative contribution of novelty seeking and desire thinking towards craving, hypothesizing a sequence of multiple mediating relationships starting from novelty seeking and moving onto imaginal prefiguration, verbal perseveration and craving in serial fashion. Method: A convenience sample of 270 individuals completed measures assessing novelty seeking, desire thinking, and craving relating to a chosen activity. Results: Findings showed that, controlling for age and gender, desire thinking components predicted craving over and above novelty seeking. The indirect effect from novelty seeking to craving, via desire thinking components, was significant thus supporting a multiple-mediational sequence. Finally, the relationship between imaginal prefiguration and craving was found to be partially mediated by verbal perseveration. Conclusions: The findings provide support for the conceptualization of desire thinking as an independent construct in predicting craving over and above novelty seeking. PMID- 29531974 TI - The relative contribution of metacognitions and attentional control to the severity of gambling in problem gamblers. AB - The present study explored the relationship between metacognitions, attentional control, and the severity of gambling in problem gamblers. One hundred and twenty six problem gamblers completed the Depression Anxiety Stress Scales 21, the Meta Cognitions Questionnaire 30, the Attentional Control Scale, and the Problem Gambling Severity Index. Results revealed that negative affect, four out of five metacognitions factors (positive beliefs about worry, negative beliefs about thoughts concerning danger and uncontrollability, cognitive confidence and beliefs about the need to control thoughts), and all attentional control factors (focusing, shifting and flexible control of thought) were correlated, in the predicted directions, with the severity of gambling. The same metacognitions were also found to be correlated, in the predicted directions, with attention focusing, however only negative beliefs about thoughts concerning danger and uncontrollability and cognitive confidence were found to be correlated with attention shifting and flexible control of thought. A hierarchical regression analysis showed that beliefs about the need to control thoughts were the only predictor of the severity of gambling controlling for negative affect. Overall these findings support the hypotheses and are consistent with the metacognitive model of psychological dysfunction. The implications of these findings are discussed. PMID- 29531975 TI - Do online assessed self-report and behavioral measures of impulsivity-related constructs predict onset of substance use in adolescents? AB - Introduction: To prospectively predict the onset of use of alcohol, cigarettes and marijuana among Dutch adolescents, using behavioral and self-report measures of impulsivity-related facets. Specifically, we investigated whether behavioral measures of impulsivity predicted the onset of substance use above and beyond self-report measures of impulsivity and sensation seeking in an online sample. Methods: Self-report and behavioral data from 284 adolescents (195 girls, mean age = 14.8 years, SD = 1.26) were collected at four time points over a period of two years, using an online survey system. Impulsivity-related facets were assessed at time point 1 with the Delay Discounting Task, the Balloon Analogue Risk Task and the Passive Avoidance Learning Task. We conducted logistic regression analysis to examine whether behavioral and self-report measures uniquely predicted onset of alcohol use, heavy episodic drinking, smoking and marijuana use. Results: Onset of cigarette smoking was associated with behavioral assessment of impulsive decision making, but not after controlling for self reported impulsivity and sensation seeking. Behavioral measures were sometimes associated with, but appeared not to prospectively predict, the onset of substance use in this online sample after controlling for self-report measures. Conclusions: Based on the present results, the added value of online behavioral assessment of impulsivity-related factors in the prediction of onset of substance use was not confirmed. We suggest that factors specific to each behavioral task underlie their lack of prediction and suggest that future research addresses limitations of current behavioral tasks to increase their validity in online testing. PMID- 29531976 TI - The impact of Internet-based specific activities on the perceptions of Internet addiction, quality of life, and excessive usage: A cross-sectional study. AB - Introduction: Recent research has examined the context in which preference for specific online activities arises, leading researchers to suggest that excessive Internet users are engaged in specific activities rather than 'generalized' Internet use. The present study aimed to partially replicate and expand these findings by addressing four research questions regarding (i) participants' preferred online activities, (i) possible expected changes in online behavior in light of hypothetical scenarios, (iii) perceived quality of life when access to Internet was not possible, and (iv) how participants with self-diagnosed Internet addiction relate to intensity and frequency of Internet use. Methods: A cross sectional design was adopted using convenience and snowball sampling to recruit participants. A total of 1057 Internet users with ages ranging from 16 to 70 years (Mage = 30 years, SD = 10.84) were recruited online via several English speaking online forums. Results: Most participants indicated that their preferred activities were (i) accessing general information and news, (ii) social networking, and (iii) using e-mail and/or online chatting. Participants also reported that there would be a significant decrease of their Internet use if access to their preferred activities was restricted. The study also found that 51% of the total sample perceived themselves as being addicted to the Internet, while 14.1% reported that without the Internet their life would be improved. Conclusions: The context in which the Internet is used appears to determine the intensity and the lengths that individuals will go to use this tool. The implications of these findings are further discussed. PMID- 29531977 TI - Satisfying needs through Social Networking Sites: A pathway towards problematic Internet use for socially anxious people? AB - Introduction: Following the theoretical frameworks of the dual-factor model of Facebook use and the Self Determination Theory, the present study hypothesizes that the satisfaction of unmet needs through Social Networking Sites (SNSs) may represent a pathway towards problematic use of Internet communicative services (GPIU) for socially anxious people. Methods: Four hundred undergraduate students (females = 51.8%; mean age = 22.45 + 2.09) completed three brief scales measuring the satisfaction via SNSs of the need to belong, the need for self-presentation and the need for assertiveness, the Generalized Problematic Internet Use Scale 2 and the Social Interaction Anxiety Scale. Structural equation modeling was performed separately for males and females. Results: A direct effect of social anxiety on GPIU was found among both genders. Socially anxious males and females tend to use SNSs for self-presentation purposes, as well as for the opportunity to be more assertive. The association between social anxiety and GPIU was partially mediated by the need for self-presentation only among males. Conclusions: The present results extend our understanding of the development of problematic use of Internet communicative services, based on the framework of the dual factor model of Facebook use and the Self Determination Theory. The fulfillment of an unmet need for self-presentation (i.e. the desire to create a positive impression of one's self in others) through SNSs could be one of the possible pathways to GPIU for socially anxious males. PMID- 29531978 TI - Cigarette smoking, problem-gambling severity, and health behaviors in high-school students. AB - Introduction: Smoking and gambling are two significant public health concerns. Little is known about the association of smoking and gambling in adolescents. The current study of high-school adolescents examined: (1) smoking behavior by problem-gambling severity and (2) health-related variables by problem-gambling severity and smoking status. Methods: Analyses utilized survey data from 1591 Connecticut high-school students. Adolescents were classified by problem-gambling severity (Low-Risk Gambling [LRG], At-Risk/Problem Gambling [ARPG]) and smoking status (current smoker, non-smoker). Analyses examined the smoking behavior of ARPG versus LRG adolescents as well as the smoking-by-problem-gambling-severity interactions for health and well-being measures (e.g., grades, substance use). Chi-square and logistic regression analyses were used; the latter controlled for gender, race/ethnicity, school grade, and family structure. Results: More adolescents with ARPG than LRG reported regular smoking, heavy smoking, early smoking onset, no smoking quit attempts, and parental approval of smoking. ARPG and LRG adolescents who smoked were more likely to report poor grades, lifetime use of marijuana and other drugs, current heavy alcohol use, current caffeine use, depression, and aggressive behaviors and less likely to report participation in extracurricular activities. The association between not participating in extracurricular activities and smoking was statistically stronger in the LRG compared to the ARPG groups. Post-hoc analyses implicated a range of extracurricular activities including team sports, school clubs, and church activities. Conclusions: Smoking was associated with poorer health-related behaviors in both ARPG and LRG groups. Interventions with adolescents may benefit from targeting both smoking and gambling. PMID- 29531979 TI - Prevalence and characteristics of addictive behaviors in a community sample: A latent class analysis. AB - While addictions to substances such as alcohol, tobacco, and other drugs have been extensively investigated, interest has been growing in potential non substance-related addictive behaviors (e.g., excessive gambling, buying or playing video games). In the current study, we sought to determine the prevalence and characteristics of a wide range of addictive behaviors in a general population sample and to identify reliable subgroups of individuals displaying addictive behaviors. Seven hundred seventy participants completed an online survey. The survey screened for the presence and characteristics of the main recognized substance and behavioral addictions (alcohol, tobacco, cannabis, other drugs, gambling, compulsive shopping, intensive exercise, Internet and mobile phone overuse, intensive work involvement, and overeating) in a three-month period. Key aspects of addiction were measured for each reported behavior, including negative outcomes, emotional triggers (positive and negative emotional contexts), search for stimulation or pleasure, loss of control, and cognitive salience. Latent class analysis allowed us to identify three theoretically and clinically relevant subgroups of individuals. The first class groups problematic users, i.e., addiction-prone individuals. The second class groups at-risk users who frequently engage in potentially addictive behaviors to regulate emotional states (especially overinvolvement in common behaviors such as eating, working, or buying). The third class groups individuals who are not prone to addictive behaviors. The existence of different groups in the population sheds new light on the distinction between problematic and non-problematic addiction-like behaviors. PMID- 29531980 TI - Culture and age influences upon gambling and problem gambling. AB - Objective: This study aimed to (i) examine the prevalence and types of gambling, (ii) establish prevalence of 'pathological' gambling, (iii) explore the correlates of gambling, and (iv) establish psychiatric and physical comorbidity in a sample of older adult gamblers (>= 60 years) in contrast to younger gamblers in a representative population sample in Singapore. Method: This paper reports the results of a secondary analysis of data from a representative community survey of 6616 participants, of which 2252 had engaged in gambling activities at least once in their lifetime. Results: 48.9% of older adults reported lifetime gambling. Older gamblers were more likely to be males, married or widowed (vs. never married), with pre-primary, primary and secondary education (vs. university), economically inactive (vs. employed) and had personal annual income of SGD $19,999 and below (vs. SGD $50,000 and above). Older gamblers had significantly higher rates of betting on horses, playing numbers or betting on lotteries, and playing Mahjong. After adjusting for demographic variables in multiple logistic regression analyses, gamblers aged 60 years and older had significantly lower odds of having pathological gambling than those in the younger age group (OR = 0.4). Older gamblers had significantly higher odds of having diabetes (OR = 3.2), hypertension (OR = 4.9), and any comorbid chronic physical condition assessed in this study. Conclusions: For the majority of older adults, gambling remains a recreational activity that is entertaining and a way of socialization. However, one must remain cognizant of the possible risks for some to develop disordered gambling. PMID- 29531981 TI - Categories of alcohol outcome expectancies and their relationships to alcohol related consequences. AB - Extensive research has generally supported a significant and positive relationship of positive outcome expectancies with the amount of alcohol consumed among young adult drinkers, a group generally considered at high risk. Researchers have also naturally been interested in the relationships between these beliefs about drinking and the negative consequences experienced among those who abuse alcohol. Interestingly, those studies found significant positive associations of the number of alcohol outcome expectancies with drinking related consequences, independent of the amount of alcohol being consumed, suggesting that some consequences may be a function of beliefs rather than chemical effects. In addition, there has been evidence that age related differences may exist in the experience of positive outcome expectancies and their associations with consumption. One area that has not been examined is how different categories of alcohol outcome expectancies may be associated with different types of consequences among young adults. Young adults between ages 18-30 were assessed for different categories of alcohol outcome expectancies as well as different types of alcohol consequences. Study hypotheses were partially supported in that specific categories of expectancies were significantly associated with different types of consequences in multiple regression models, but not in the pattern that was predicted from a review of the literature. Expectancies with themes of personal power were consistently found to be significantly and positively associated with various types of consequences after controlling for alcohol consumption. The paper discusses the clinical relevance of these findings with regard to young adult drinkers. PMID- 29531982 TI - Testing a frequency of exposure hypothesis in attentional bias for alcohol related stimuli amongst social drinkers. AB - Aims: To examine whether a group of social drinkers showed longer response latencies to alcohol-related stimuli than neutral stimuli and to test whether exposure to 1) an alcohol-related environment and 2) consumption related cues influenced the interference from alcohol-related stimuli. Methods: A 2 * 2 * 2 * 5 factorial design with Exposure Group (high, low) and Consumption Group (high, low) as between-participant factors and Word Type (alcohol, neutral) and Block (1 5) as within-participant factors was used. Forty-three undergraduate university students, 21 assigned to a high exposure group and 22 to a low exposure group, took part in the experiment. Exposure Group was defined according to whether or not participants currently worked in a bar or pub. Consumption Group was defined according to a median split on a quantity-frequency measure derived from two questions of the Alcohol Use Disorders Identification Test (AUDIT) questionnaire. A modified computerised Stroop colour naming test was used to measure response latencies. Results: Exposure and consumption factors interacted to produce greater interference from alcohol-related stimuli. In particular, the low consumption group showed interference from alcohol-related stimuli only in the high exposure condition. Exposure did not affect the magnitude of interference in the high consumption group. Conclusions: Attentional bias is dependent upon exposure to distinct types of alcohol-related cues. PMID- 29531983 TI - 'Neknomination': Predictors in a sample of UK university students. AB - Objectives: To identify prevalence and predictors of participation in the online drinking game 'neknomination' amongst university students. Method: A convenience sample of 145 university students participated in a study about drinking behaviours, completing a questionnaire about their participation in neknomination, the Alcohol Use Disorders Identification Test, and the Resistance to Peer Influence Scale. Results: Out of 145 students sampled, 54% took part in neknomination in the previous month. Mann-Whitney U tests revealed significantly higher scores on the Alcohol Use Disorders Identification Test, and significantly lower scores on the Resistance to Peer Influence Scale, for those who had participated in neknomination. A significant correlation was also shown between specific peer pressure to neknominate, and engagement in neknomination. A logistic regression analysis indicated that scores on the Alcohol Use Disorders Identification Test, but not the Resistance to Peer Influence Scale, predicted classification as an individual who participated in neknomination. Conclusions: We found that over half of respondents had participated in a neknomination game in the past month, with almost all male respondents having done so. Participation in neknomination was strongly associated with general hazardous drinking behaviour but not with resistance to peer influence. Further research is needed to understand the role of engagement with social media in drinking games and risky drinking. PMID- 29531984 TI - Systematic analysis of changes in cannabis use among participants in control conditions of randomised controlled trials. AB - Introduction: Cannabis remains the most used illegal substance across the globe, and negative outcomes and disorders are common. A spotlight therefore falls on reductions in cannabis use in people with cannabis use disorder. Current estimates of unassisted cessation or reduction in cannabis use rely on community surveys, and few studies focus on individuals with disorder. A key interest of services and researchers is to estimate effect size of reductions in consumption among treatment seekers who do not obtain treatment. Effects within waiting list or information-only control conditions of randomised controlled trials offer an opportunity to study this question. Method: This paper examines the extent of reductions in days of cannabis use in the control groups of randomised controlled trials on treatment of cannabis use disorders. A systematic literature search was performed to identify trials that reported days of cannabis use in the previous 30 (or equivalent). Results: Since all but one of the eight identified studies had delayed treatment controls, results could only be summarised across 2-4 months. Average weighted days of use in the previous 30 days fell from 24.5 to 19.9, and a meta-analysis using a random effects model showed an average reduction of 0.442 SD. However, every study had at least one significant methodological issue. Conclusions: While further high-quality data is needed to confirm the observed effects, these results provide a baseline from which researchers and practitioners can estimate the extent of change required to detect effects of cannabis treatments in services or treatment trials. PMID- 29531985 TI - Experimentally induced states of mind determine abstinent smokers' level of craving in reaction to smoking-cues. AB - Introduction: The present study aims to contribute to our knowledge on the causes of variations in experienced craving of (ex)smokers. The general idea is tested that when (ex)smokers are exposed to a smoking-cue, their level of craving is determined by the momentary state of mind through which the smoking-cue is interpreted. Methods: A cue-reactivity paradigm in temporary abstinent smokers is applied to trigger craving responses under different experimentally induced states of mind. Craving is assessed with a three-item self-report measure. In study 1 (N = 120) a self-affirmation procedure is applied right before abstinent smokers were exposed to their own smoking paraphernalia. In study 2 (N = 140) abstinent smokers received bogus feedback inducing a high or low self-efficacy and strong or weak positive outcome expectations. Results: Study 1 showed a significant interaction: When involvement was high, self-affirmation increased the level of craving but when involvement was low self-affirmation lowered craving. Study 2 also showed a significant interaction: Only when the positive outcome expectation of smoking were high, self-efficacy lowered the level of craving. All analyses were controlled for the number of cigarettes smoked a day and number of past quit attempts. Conclusions: The present studies provide experimental evidence that levels of craving can be determined by momentary states of mind. This theoretical perspective can be integrated in existing conditioning and social cognitive learning perspectives on craving and substance use. PMID- 29531986 TI - Self-control, future orientation, smoking, and the impact of Dutch tobacco control measures. AB - Introduction: The pronounced discrepancy between smokers' intentions to quit and their smoking behavior has led researchers to suggest that many smokers are time inconsistent, have self-control problems, and may benefit from external efforts to constrain their consumption. This study aims to test whether self-control and future orientation predict smoking levels and to identify if these traits modify how cigarette consumption responds to the introduction of tobacco control measures. Methods: A sample of Dutch adults (N = 1585) completed a measure of self-control and the Consideration of Future Consequences Scale (CFCS) in 2001 and indicated their tobacco consumption each year from 2001 to 2007. In 2004, a workplace smoking ban and substantial tax increase on tobacco was introduced in the Netherlands. To identify the potential impact of these tobacco control measures we examined whether participants smoked or were heavy smokers (20 + cigarettes per day) each year from 2001 to 2007. Results: Participants with high self-control and CFCS scores showed lower rates of smoking across the seven year period of the study. The 2004 smoking restrictions were linked with a subsequent decline in heavy smoking. This decline was moderated by self-control levels. Those with low self-control showed a large reduction in heavy smoking whereas those with high self-control did not. The effects were, however, temporary: many people with low self-control resumed heavy smoking 2-3 years after the introduction of the tobacco restrictions. Conclusions: The immediate costs which national tobacco control measures impose on smokers may assist smokers with poor self-control in reducing their cigarette consumption. PMID- 29531987 TI - Epidemiology of alcohol use in the general population of Togo. AB - Introduction: Alcohol use is responsible for a high level of mortality and morbidity throughout the world. The WHO global strategy recommends that the detrimental effects of alcohol use be reduced. Aims: The objective of this paper was to investigate, using data from the 2010 Togo STEPS survey, alcohol use and other health-related factors in the general population of Togo. Methods: This epidemiological investigation using the STEPwise approach was undertaken from December 1st, 2010, to January 23rd, 2011, throughout the five regions of Togo. Togo is a low-income country (World Bank) located in West Africa. The study involved 4800 people aged 15 to 64 who were representative of the population of Togo and who were selected using the one-stage cluster sampling method. Results: The sample was young and predominantly male. Approximately one-third of the respondents were alcohol abstainers, with the majority of these being women. Approximately the same proportion of current drinkers (daily consumption) by gender was observed. The reported daily average consumption of alcohol was 13 g of pure alcohol for men and 9 g for women. The mean number of heavy drinking days over the previous 30 days was higher for men (3 days), and this included 37.5% of the men who drink. Conclusion: We suggest a comparative analysis of the prevalence of harmful alcohol use in Togo and the WHO African region. PMID- 29531988 TI - Daily tobacco smoking, heavy alcohol use, and hashish use among adolescents in southern Sweden: A population-based multilevel study. AB - Introduction: The aim of this study was to investigate school contextual effects on daily tobacco smoking, heavy alcohol use and hashish use among adolescents, using multilevel analyses adjusting for individual-level factors. Methods: The 2012 public health survey among adolescents in Skane includes pupils in ninth grade in primary school (predominantly 15-16 years old) and second grade in secondary school (gymnasium) (predominantly 17-18 years old). Multilevel logistic regressions were performed. Results: The prevalence of all three behaviors was higher in the second grade in the gymnasium. Several sociodemographic, psychosocial and parental factors were associated with these behaviors. In the ninth grade, variance partition coefficients (VPCs) for tobacco smoking decreased from 10.2% in the empty model to 1.9% in the fully adjusted model, for heavy alcohol use from 6.5% to 6.3%, while VPCs for hashish increased from 9.9% to 11.0%. In the second grade, VPCs for daily tobacco smoking decreased from 13.6% in the empty model to 6.5% in the fully adjusted model, VPCs for heavy alcohol use decreased from 4.6% to 1.7%, and VPCs for hashish use increased from 7.3% to 8.3%. Conclusions: Daily tobacco smoking (in both grades) and heavy alcohol use in the second grade in the gymnasium may be preventable by actions directed against individual-level protective factors including social capital, social support and peer/parent behavior and attitude, while interventions directed at school contexts may be more important for alcohol use in the ninth grade and hashish use in both grades. PMID- 29531989 TI - Early developmental, temperamental and educational problems in 'substance use disorder' patients with and without ADHD. Does ADHD make a difference? AB - Introduction: The prevalence of ADHD among patients with substance use disorder (SUD) is substantial. This study addressed the following research questions: Are early developmental, temperamental and educational problems overrepresented among SUD patients with ADHD compared to SUD patients without ADHD? Do this comorbid group receive early help for their ADHD, and are there signs of self-medicating with illicit central stimulants? Method: An international, multi-centre cross sectional study was carried out involving seven European countries, with 1205 patients in treatment for SUD. The mean age was 40 years and 27% of the sample was female. All participants were interviewed with the Mini International Neuropsychiatric Interview Plus and the Conners' Adult ADHD Diagnostic Interview for DSM-IV. Results: SUD patients with ADHD (n = 196; 16.3% of the total sample) had a significantly slower infant development than SUD patients without ADHD (n = 1,009; 83.4%), had greater problems controlling their temperament, and had lower educational attainment. Only 24 (12%) of the current ADHD positive patients had been diagnosed and treated during childhood and/or adolescence. Finally, SUD patients with ADHD were more likely to have central stimulants or cannabis as their primary substance of abuse, whereas alcohol use was more likely to be the primary substance of abuse in SUD patients without ADHD. Conclusion: The results emphasize the importance of early identification of ADHD and targeted interventions in the health and school system, as well as in the addiction field. PMID- 29531990 TI - Development and validation of a short Italian UPPS-P Impulsive Behavior Scale. AB - Impulsivity is a multidimensional construct that plays a prominent role in the development, maintenance, and relapse of addictive disorders. The UPPS-P model of impulsivity, which distinguishes between five impulsivity components (positive urgency, negative urgency, lack of perseverance, lack of premeditation, sensation seeking), has been increasingly investigated during the last decade in relation to addictive and risky behaviors. Unfortunately, it currently lacks a validated scale that allows Italian researchers and clinicians to measure impulsivity based on the UPPS-P model. The current study fills this gap by testing the psychometric properties of a short 20-item Italian scale used to assess the five dimensions of the UPPS-P model in 188 volunteer participants from the community. Confirmatory factor analysis supported a model of five distinct, but interrelated, impulsivity components. The results indicated good internal consistency (Cronbach's alpha ranges from .73 to .84). Construct validity was evidenced by specific relations with measures of addictive behaviors and depressive symptoms. On the whole, this study demonstrated that the Italian short UPPS-P has good psychometric properties. PMID- 29531991 TI - The importance of analogue zeitgebers to reduce digital addictive tendencies in the 21st century. AB - Analogue zeitgebers such as wristwatches and alarm clocks are essential for structuring everyday life. Since the dawn of the digital revolution - particularly since the advent of the smartphone - mobile phones have increasingly replaced analogue zeitgebers as a means of telling time. This functionality may prove problematic, in that it may contribute to the overuse of digital media (e.g. when checking the time turns into extended use of other smartphone utilities, including Internet-based applications). Of N = 3084 participants, 45% reported wearing a wristwatch and 67% used an analogue alarm clock. We observed that participants who reported using analogue zeitgebers used their mobile /smartphone significantly less. Use of analogue zeitgebers may prove a practical tool for therapeutic and preventative interventions for problematic Internet use in an increasingly digital age. PMID- 29531992 TI - Foods and dietary profiles associated with 'food addiction' in young adults. AB - Background: It has been suggested that addictive behaviors related to consumption of specific foods could contribute to overeating and obesity. Although energy dense, hyper-palatable foods are hypothesized to be associated with addictive like eating behaviors, few studies have assessed this in humans. Objective: To evaluate in young adults whether intakes of specific foods are associated with 'food addiction', as assessed by the Yale Food Addiction Scale (YFAS), and to describe the associated nutrient intake profiles. Design: Australian adults aged 18-35 years were invited to complete an online cross-sectional survey including demographics, the YFAS and usual dietary intake. Participants were classified as food addicted (FAD) or non-addicted (NFA) according to the YFAS predefined scoring criteria. Results: A total 462 participants (86% female, 73% normal weight) completed the survey, with 14.7% (n = 68) classified as FAD. The FAD group had a higher proportion of females (p = .01) and higher body mass index (p < .001) compared to NFA. Higher YFAS symptom scores were associated with higher percentage energy intake (%E) from energy-dense, nutrient-poor foods including candy, take out and baked sweet products, as well as lower %E from nutrient-dense core foods including whole-grain products and breakfast cereals. These remained statistically significant when adjusted for age, sex and BMI category (p = .001). Conclusions: Statistically significant associations were identified between YFAS assessed food addiction and dietary intake, specifically intakes of energy-dense, nutrient-poor foods. However, the effect sizes were small limiting clinical applications. Further examination of the relationship between addictive-like eating and intake of specific foods in a nationally representative sample is warranted. PMID- 29531993 TI - The association between at-risk gambling and binge drinking in the general Swedish population. AB - While the association between problem gambling and alcohol use disorders has been studied previously, little is known about the association between risk gambling and risk drinking. This study aimed at examining the association between at-risk gambling and binge drinking in the general Swedish population and to test whether this association remained after controlling for demographic factors. The data was part of a larger ongoing survey in the general Swedish population. Respondents (N = 19 530) were recruited through random digit dialing and interviewed about their alcohol habits (binge drinking), at-risk gambling (the Lie/Bet questionnaire) and demographics (gender, age, education, residence size, marital status, labor market status, country of origin and smoking). There was an association between lifetime at-risk gambling and current (12 months) weekly binge drinking for both men (OR = 1.73; CI 95%: 1.27-2.35) and women (OR = 2.27; CI 95%: 1.05-4.90). After controlling for demographics this association no longer remained significant (OR = 1.38; CI 95%; .99-1.90 for men and OR = 1.99; CI 95%: .94-4.66 for women). Age and smoking had the largest impact on this association. At-risk gambling and binge drinking are associated behaviors. However, it seems as if this association may be confounded by demographic variables. We hypothesize that similarities in personality profiles and health aspects could account for an additional part of the association. PMID- 29531994 TI - Rasch model of the GAIN substance problem scale among inpatient and outpatient clients in the city of Sao Paulo, Brazil. AB - Introduction: This study used the Rasch model to evaluate the psychometric properties of the Portuguese version of the Substance Problem Scale (SPS) of the "Global Appraisal of Individual Needs - Initial" for use in Brazil. The SPS measures alcohol and drug problem severity within a DSM-IV-TR framework. The goal of the Rasch analysis was to assess scale dimensionality, item severity, and differential item functioning (DIF). Methods: Data was collected from 40 inpatients and 70 outpatients in Sao Paulo, Brazil. The Rasch model fit and DIF by gender and level of care were examined. Results: The SPS fit the Rasch model, with no items distorting the measure. Only three of the sixteen items performed differently between men and women and three performed differently by level of care. Conclusions: The results were compatible with those from Rasch analyses of the American English and Canadian English versions of the scale. The Portuguese version of the SPS is, thus, valid for use in Brazil, both with men and women in inpatient and outpatient programs. PMID- 29531995 TI - Gender differences in felt stigma and barriers to help-seeking for problem gambling. AB - Background: Men and women differ in their patterns of help-seeking for health and social problems. For people experiencing problem gambling, feelings of stigma may affect if and when they reach out for help. In this study we examine men's and women's perceptions of felt stigma in relation to help-seeking for problematic gambling. Methods: Using concept mapping, we engaged ten men and eighteen women in group activities. We asked men and women about their perceptions of the pleasurable aspects and negative consequences of gambling; they generated a list of four hundred and sixteen statements. These statements were parsed for duplication and for relevance to the study focal question and reduced to seventy three statements by the research team. We then asked participants to rate their perceptions of how much felt stigma (negative impact on one's own or family's reputation) interfered with help-seeking for gambling. We analyzed the data using a gender lens. Findings: Men and women felt that shame associated with gambling related financial difficulties was detrimental to help-seeking. For men, the addictive qualities of and emotional responses to gambling were perceived as stigma-related barriers to help-seeking. For women, being seduced by the 'bells and whistles' of the gambling venue, their denial of their addiction, their belief in luck and that the casino can be beat, and the shame of being dishonest were perceived as barriers to help-seeking. Conclusions: Efforts to engage people who face gambling problems need to consider gendered perceptions of what is viewed as stigmatizing. PMID- 29531996 TI - Age of first use of energy beverages predicts future maximal consumption among naval pilot and flight officer candidates. AB - Background: Energy drinks are popular beverages that can have adverse long-term health effects when consumed by children and adolescents. This study sought to determine if the age of first energy drink use in a U.S. military population is predictive of the maximum number of energy drinks consumed during a single day and/or single occasion (operationally defined as a couple of hours; e.g., a night out, during studying or sport session). Method: Student U.S. naval aviator and naval flight officers who reported past-year use of energy drinks (N = 239) were surveyed to determine various measures of energy drink consumption. Results: Age of first consumption was predictive of the maximum number of energy drinks consumed during a single occasion within the past year. Within this sample, the age range between 13 and 16 years appeared to be a critical period with results indicating that people who began consuming energy drinks during this period were 4.88 times more likely to consume high quantities (four or more) of energy drinks during a single occasion when compared to those who started consuming energy drinks between the ages of 20-23. Likewise, persons who began to consume energy drinks between the ages of 13-16 are 2.48 times more likely to consume high quantities of energy drinks during a single occasion than those who started between the ages of 17-19. There was no difference between 17 and 19 year olds and 20-23 year olds. Age of first use was not correlated to daily average intake or daily maximal intake of energy drinks. Conclusions: A lower age of first energy drink use suggests higher risk of single-occasion heavy episodic consumption in this military population. Researchers should further explore the relationship of early onset energy drink consumption and potential future health risks. PMID- 29531997 TI - Exercise addiction in CrossFit: Prevalence and psychometric properties of the Exercise Addiction Inventory. AB - Introduction: CrossFit is a mix of aerobic and anaerobic exercise regimes with the stated goal of improving fitness and physical performance. It is growing in popularity and has a strong community known to motivate and push the participants to maximal performance. The negative consequences of these extreme exercise patterns have rarely been described. The prevalence of injuries in CrossFit is high but exercise addiction and harmful exercise attitudes have not yet been assessed. The aim of this study was to measure the prevalence of exercise addiction in CrossFit and to evaluate the reliability and validity of the Exercise Addiction Inventory (EAI) in a CrossFit population. Methods: We invited crossfitters to participate in an online survey using Facebook groups. A total of 603 regular crossfitters completed the EAI and additional questions concerning exercise amounts and negative exercise attitudes and beliefs. We used principal component analyses and structural equation models to test the psychometric properties of the EAI and to describe the characteristics of the addicted crossfitters. Results: We found that 5% of the crossfitters were addicted to exercise and that young males had a higher risk. The EAI had good internal reliability (0.73) and construct validity. Thus we found significant positive associations between exercise addiction and the tendency to exercise in spite of injury, feelings of guilt when unable to exercise, passion turning into obsession and taking medication to be able to exercise. Conclusions: Exercise addiction is prevalent in CrossFit and needs further exploration. The EAI is recommended for research in CrossFit communities and applied settings. PMID- 29531998 TI - Heavy cannabis use and attentional avoidance of anxiety-related stimuli. AB - Objectives: Cannabis is now the most widely used illicit substance in the world. Previous research demonstrates that cannabis use is associated with dysfunctional affect regulation and anxiety. Anxiety is characterised by attentional biases in the presence of emotional information. This novel study therefore examined the attentional bias of cannabis users when presented with anxiety-related stimuli. The aim was to establish whether cannabis users respond to anxiety-related stimuli differently to control participants. Methods: A dot-probe paradigm was utilised using undergraduate students. Trials contained anxiety-related stimuli and neutral control stimuli. Eye-tracking was used to measure attention for the stimuli. Results: Results indicated that cannabis users demonstrated attentional avoidance behaviour when presented with anxiety-related stimuli. Conclusions: The findings suggest a difference in processing of emotional information in relation to neutral information between groups. It would appear that cannabis users avoid anxiety provoking stimuli. Such behaviour could potentially have motivational properties that could lead to exacerbating anxiety disorder-type behaviour. PMID- 29531999 TI - Which facets of impulsivity predict binge drinking? AB - Background: Impulsive binge drinking is a serious public health issue, and to reveal predisposing factors to this consumption pattern is, therefore, required. Impulsivity-related traits are important predictors of alcohol use and abuse. Nonetheless, previous research in binge drinking has been confounded by various definitions and cut-off scores, implying that existing studies contributed to limited comprehension on the specific role of different impulsivity facets. The current study thus disentangles the role of impulsivity facets in binge drinking by adopting a dimensional approach, considering the condition on a continuum, to avoid relying on debatable and non-definitive criteria. Methods: 162 students underwent assessment of alcohol consumption, including drinking patterns and impulsive traits, as captured in the UPPS-P framework (i.e., negative urgency, positive urgency, sensation seeking, lack of perseverance, lack of premeditation). Multiple regression analyses were utilized in order to investigate the predictive role of each impulsivity facet in binge drinking. Results: Binge drinking was associated with sensation seeking. However, when statistically controlling for gender, age and global alcohol consumption, this effect disappeared, and negative urgency remained the only impulsivity component that significantly predicted binge drinking. Conclusion: We found the severity of binge drinking to be associated with negative urgency, suggesting that the binge drinking pattern is displayed in reaction to negative emotional states, and can be conceptualized as a maladaptive and short-term emotional coping. The study calls for prevention and treatment interventions designed to improve self control, and more adaptive emotion regulation strategies. PMID- 29532000 TI - Traits associated with internet addiction in young adults: Potential risk factors. AB - The present study sought to determine whether certain personality traits associated with problematic substance use may also characterize young adults who report problematic internet use. An index of internet addiction as well as measures of traits previously linked to problematic substance use were administered to a sample of 86 young adults aged 18-30 years. Measures included the Internet Addiction Test (IAT), Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ), Depression Anxiety and Stress Scales (DASS-21), Toronto Alexithymia Scale (TAS-20), and the Fear of Intimacy Scale (FIS). Results indicated that IAT scores were significantly positively correlated with TAS-20, DASS-21, SPSRQ and FIS scores, as predicted. When age, gender and negative mood were controlled in a hierarchical regression, sensitivity to punishment (SP), sensitivity to reward (SR) and FIS significantly contributed to variance in IAT in the final model. SP partially mediated the relationship between TAS-20 and IAT, whereas no such mediation was indicated for SR or FIS. Present findings suggest that alexithymia and reward sensitivity may be important risk factors for internet addiction as for problematic substance use, whereas sensitivity to punishment may account for at least part of the association between alexithymia and problematic use of the internet. PMID- 29532001 TI - Sociodemographic predictors of latent class membership of problematic and disordered gamblers. AB - This paper reports a series of analyses examining the predictors of gambling subtypes identified from a latent class analysis of problem gambling assessment data, pooled from four health and gambling surveys conducted in Britain between 2007 and 2012. Previous analyses have indicated that gambling assessments have a consistent three class structure showing quantitative and potentially qualitative differences. Bringing this data together is useful for studying more severe problem gamblers, where the small number of respondents has been a chronic limitation of gambling prevalence research. Predictors were drawn from sociodemographic indicators and engagement with other legal addictive behaviours, namely smoking and alcohol consumption. The pooled data was entered into a multinomial logistic regression model in which class membership was regressed along a series of demographic variables and survey year, based on previous analyses of gambling prevalence data. The results identified multiple demographic differences (age, general health, SES, being single, membership of ethnic minority groups) between the non-problem and two classes endorsing some problem gambling indicators. Although these two groups tended to share a sociodemographic profile, the odds of being male, British Asian and a smoker increased between the three groups in line with problem gambling severity. Being widowed was also found to be associated with the most severe gambling class. A number of associations were also observed with other addictive behaviours. However these should be taken as indicative as these were limited subsamples of a single dataset. These findings identify specific groups in which gambling problems are more prevalent, and highlight the importance of the interaction between acute and determinant aspects of impulsivity, suggesting that a more complex account of impulsivity should be considered than is currently present in the gambling literature. PMID- 29532002 TI - "I cannot stand the boredom." Binge drinking expectancies in adolescence. AB - INTRODUCTION: The main aim of this study is to improve our knowledge on binge drinking behavior in adolescents. In particular, we tested a model of predictors of binge drinking focusing on boredom proneness; we also examined the predictive and mediating role of drinking expectancies on binge drinking. METHODS: A questionnaire designed to assess current drinking behavior, such as binge drinking, drinking expectancies and boredom proneness, was administered to 721 Italian adolescents (61% females) aged between 13 and 19 years (M = 15.98, SD = 1.61). RESULTS: Structural equation modeling confirmed the evidence on drinking expectancies as predicted by boredom proneness and as predictive of adolescents' binge drinking. Interestingly, disinhibition and relief from pain seem to play a more important mediating role between boredom and alcohol outcome. Conversely, no mediation was found for interpersonal and social confidence expectancies on binge drinking. CONCLUSIONS: In general, the results suggest that preventative interventions on alcohol misuse should focus on personality traits and underlying drinking expectancies. PMID- 29532003 TI - A test of the Social Identity Model of Cessation Maintenance: The content and role of social control. AB - Engagement with self-help groups is a predictor of positive outcomes for those attempting to control their addictive behaviours. In common with other groups, self-help groups have to manage non-normative ('deviant') behaviour to ensure the social values of the group remain preserved, and the group can fulfil its aims. These processes may protect group members from relapse. Drawing on the Social Identity Model of Cessation Maintenance, the current study asked a number (n = 44) of attendees of fellowship (AA/NA/CA) and of SMART groups to list behaviours they saw as normative and deviant, and rate a variety of responses to deviant behaviours. Costs of relapse to both the self and the group were also measured alongside self-efficacy regarding cessation and identity as both an active addict and as a member of a self-help group. Results suggest that social control responses to deviance grouped into education, punishment and avoidant type responses. More social control was perceived by highly identifying self-help group members. Educational responses were seen as used by groups more extensively than other responses. Punishment responses were mediated by the perceived costs an individual's relapse incurred on the rest of the group. These findings inform our understanding of what standards of normative and deviant behaviour self-help groups hold, and how they react to violations of such norms. They also have a number of implications for practitioners and facilitators in regard to using social identities as part of the treatment process. PMID- 29532004 TI - Implicit and explicit drinker identities interactively predict in-the-moment alcohol placebo consumption. AB - Introduction: Having an identity as a 'drinker' has been linked to increased alcohol-related harm, self-reported consumption and self-reported intention to engage in risky drinking behavior. These effects have been observed when identities have been measured using explicit measures (e.g. via questionnaires) and implicitly (e.g. using Implicit Association Tests [IATs] adapted to measure identity). Little research has used actual behavioral measures to measure alcohol consumption in-the-moment, nor compared the effects of implicit and explicit identities directly. Methods: Participants' (n = 40) implicit and explicit identities associated with being a drinker were measured. Attitudes towards one's own drinking were measured explicitly. Participants completed a Pouring Taste Preference Task [PTPT] involving the consumption and rating of non-alcoholic wine. This provided a behavioral measure of intention (pouring), a behavioral measure of consumption and a measure of the implementation of intention into behavior. Results: Results showed an interactive effect of implicit and explicit identities on attitudes and behavior. Explicit identities predicted attitudes towards drinking, but not behavior. Neither identity predicted the amount poured. Implicit identities predicted the amount consumed. A greater proportion of wine poured was predicted by higher implicit identities when explicit identities were absent. Conclusion: These results suggest that explicit identities may be associated more with those beliefs about drinking that one is aware of than behavioral intention. In addition, explicit identities may not predict behavioral enactment well. Implicit identity shows effects on actual behavior and not behavioral intention. Together this highlights the differential influence of reflective (explicit) and impulsive (implicit) identity in-the-moment behavior. PMID- 29532005 TI - Stricture at colorectal anastomosis: to dilate or to incise. PMID- 29532006 TI - Fibrotic submucosal scar after endoscopic submucosal dissection (ESD) or how to divert a negative adverse event into a positive endoscopic result. PMID- 29532007 TI - Biomarkers of aging associated with past treatments in breast cancer survivors: when therapy-induced pathways turn out to be potential therapeutic targets. PMID- 29532009 TI - A Conversation with Shreya Dave. PMID- 29532008 TI - Associations between genomic stratification of breast cancer and centrally reviewed tumour pathology in the METABRIC cohort. AB - The integration of genomic and transcriptomic profiles of 2000 breast tumours from the METABRIC [Molecular Taxonomy of Breast Cancer International Consortium] cohort revealed ten subtypes, termed integrative clusters (IntClust/s), characterised by distinct genomic drivers. Central histopathology (N = 1643) review was undertaken to explore the relationship between these ten molecular subtypes and traditional clinicopathological features. IntClust subtypes were significantly associated with histological type, tumour grade, receptor status, and lymphocytic infiltration (p < 0.0001). Lymph node status and Nottingham Prognostic Index [NPI] categories were also significantly associated with IntClust subtype. IntClust 3 was enriched for tubular and lobular carcinomas, the latter largely accounting for the association with CDH1 mutations in this cluster. Mucinous carcinomas were not present in IntClusts 5 or 10, but did not show an association with any of the remaining IntClusts. In contrast, medullary like cancers were associated with IntClust 10 (15/26). Hormone receptor-positive tumours were scattered across all IntClusts. IntClust 5 was dominated by HER2 positivity (127/151), including both hormone receptor-positive (60/72) and hormone receptor-negative tumours (67/77). Triple-negative tumours comprised the majority of IntClust 10 (132/159) and around a quarter of IntClust 4 (52/217). Whilst the ten IntClust subtypes of breast cancer show characteristic patterns of association with traditional clinicopathological variables, no IntClust can be adequately identified by these variables alone. Hence, the addition of genomic stratification has the potential to enhance the biological relevance of the current clinical evaluation and facilitate genome-guided therapeutic strategies. PMID- 29532010 TI - Safety Standards Aim to Rein in 3-D Printer Emissions. PMID- 29532011 TI - Gapping into Ultrahigh Surface-Enhanced Raman Scattering Amplification. PMID- 29532012 TI - Preventing Crossover in Redox Flow Batteries through Active Material Oligomerization. PMID- 29532013 TI - Toward the Systematic Control of the Exfoliation of Atomically Thin Layered Materials by Electrostatics. PMID- 29532014 TI - The Matter Simulation (R)evolution. AB - To date, the program for the development of methods and models for atomistic and continuum simulation directed toward chemicals and materials has reached an incredible degree of sophistication and maturity. Currently, one can witness an increasingly rapid emergence of advances in computing, artificial intelligence, and robotics. This drives us to consider the future of computer simulation of matter from the molecular to the human length and time scales in a radical way that deliberately dares to go beyond the foreseeable next steps in any given discipline. This perspective article presents a view on this future development that we believe is likely to become a reality during our lifetime. PMID- 29532015 TI - Walking Metals for Remote Functionalization. AB - The distant and selective activation of unreactive C-H and C-C bonds remains one of the biggest challenges in organic chemistry. In recent years, the development of remote functionalization has received growing interest as it allows for the activation of rather challenging C-H and C-C bonds distant from the initiation point by means of a "metal-walk". A "metal-walk" or "chain-walk" is defined by an iterative series of consecutive 1,2- or 1,3-hydride shifts of a metal complex along a single hydrocarbon chain. With this approach, simple building blocks or mixtures thereof can be transformed into complex scaffolds in a convergent and unified strategy. A variety of catalytic systems have been developed and refined over the past decade ranging from late-transition-metal complexes to more sustainable iron- and cobalt-based systems. As the possibilities of this field are slowly unfolding, this area of research will contribute considerably to provide solutions to yet unmet synthetic challenges. PMID- 29532016 TI - Conditional and Reversible Activation of Class A and B G Protein-Coupled Receptors Using Tethered Pharmacology. AB - Understanding the activation and internalization of G protein-coupled receptors (GPCRs) using conditional approaches is paramount to developing new therapeutic strategies. Here, we describe the design, synthesis, and testing of ExONatide, a benzylguanine-linked peptide agonist of the glucagon-like peptide-1 receptor (GLP 1R), a class B GPCR required for maintenance of glucose levels in humans. ExONatide covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged cAMP generation, Ca2+ rises, and intracellular retention of the receptor. These effects were readily switched OFF following cleavage of the introduced disulfide bridge using the cell-permeable reducing agent beta mercaptoethanol (BME). A similar approach could be extended to a class A GPCR using GhrelON, a benzylguanine-linked peptide agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), which is involved in food intake and growth. Thus, ExONatide and GhrelON allow SNAP-tag-directed activation of class A and B GPCRs involved in gut hormone signaling in a reversible manner. This tactic, termed reductively cleavable agONist (RECON), may be useful for understanding GLP 1R and GHS-R1a function both in vitro and in vivo, with applicability across GPCRs. PMID- 29532017 TI - Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple). AB - Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands. PMID- 29532018 TI - High-Performance Oligomeric Catholytes for Effective Macromolecular Separation in Nonaqueous Redox Flow Batteries. AB - Nonaqueous redox flow batteries (NRFBs) represent an attractive technology for energy storage from intermittent renewable sources. In these batteries, electrical energy is stored in and extracted from electrolyte solutions of redox active molecules (termed catholytes and anolytes) that are passed through an electrochemical flow cell. To avoid battery self-discharge, the anolyte and catholyte solutions must be separated by a membrane in the flow cell. This membrane prevents crossover of the redox active molecules, while simultaneously allowing facile transport of charge-balancing ions. A key unmet challenge for the field is the design of redox-active molecule/membrane pairs that enable effective electrolyte separation while maintaining optimal battery properties. Herein, we demonstrate the development of oligomeric catholytes based on tris(dialkylamino)cyclopropenium (CP) salts that are specifically tailored for pairing with size-exclusion membranes composed of polymers of intrinsic microporosity (PIMs). Systematic studies were conducted to evaluate the impact of oligomer size/structure on properties that are crucial for flow battery performance, including cycling stability, charge capacity, solubility, electron transfer kinetics, and crossover rates. These studies have led to the identification of a CP-derived tetramer in which these properties are all comparable, or significantly improved, relative to the monomeric counterpart. Finally, a proof-of-concept flow battery is demonstrated by pairing this tetrameric catholyte with a PIM membrane. After 6 days of cycling, no crossover is detected, demonstrating the promise of this approach. These studies provide a template for the future design of other redox-active oligomers for this application. PMID- 29532019 TI - PEGylation and Dimerization of Expressed Proteins under Near Equimolar Conditions with Potassium 2-Pyridyl Acyltrifluoroborates. AB - The covalent conjugation of large, functionalized molecules remains a frontier in synthetic chemistry, as it requires rapid, chemoselective reactions. The potassium acyltrifluoroborate (KAT)-hydroxylamine amide-forming ligation shows promise for conjugations of biomolecules under aqueous, acidic conditions, but the variants reported to date are not suited to ligations at micromolar concentrations. We now report that 2-pyridyl KATs display significantly enhanced ligation kinetics over their aryl counterparts. Following their facile, one-step incorporation onto the termini of polyethylene glycol (PEG) chains, we show that 2-pyridyl KATs can be applied to the construction of protein-polymer conjugates in excellent (>95%) yield. Four distinct expressed, folded proteins equipped with a hydroxylamine could be PEGylated with 2-20 kDa 2-pyridyl mPEG KATs in high yield and with near-equimolar amounts of coupling partners. Furthermore, the use of a bis 2-pyridyl PEG KAT enables the covalent homodimerization of proteins with good conversion. The 2-pyridyl KAT ligation offers an effective alternative to conventional protein-polymer conjugation by operating under aqueous acidic conditions well suited for the handling of folded proteins. PMID- 29532020 TI - Highly Viscous States Affect the Browning of Atmospheric Organic Particulate Matter. AB - Initially transparent organic particulate matter (PM) can become shades of light absorbing brown via atmospheric particle-phase chemical reactions. The production of nitrogen-containing compounds is one important pathway for browning. Semisolid or solid physical states of organic PM might, however, have sufficiently slow diffusion of reactant molecules to inhibit browning reactions. Herein, organic PM of secondary organic material (SOM) derived from toluene, a common SOM precursor in anthropogenically affected environments, was exposed to ammonia at different values of relative humidity (RH). The production of light-absorbing organonitrogen imines from ammonia exposure, detected by mass spectrometry and ultraviolet-visible spectrophotometry, was kinetically inhibited for RH < 20% for exposure times of 6 min to 24 h. By comparison, from 20% to 60% RH organonitrogen production took place, implying ammonia uptake and reaction. Correspondingly, the absorption index k across 280 to 320 nm increased from 0.012 to 0.02, indicative of PM browning. The k value across 380 to 420 nm increased from 0.001 to 0.004. The observed RH-dependent behavior of ammonia uptake and browning was well captured by a model that considered the diffusivities of both the large organic molecules that made up the PM and the small reactant molecules taken up from the gas phase into the PM. Within the model, large-molecule diffusivity was calculated based on observed SOM viscosity and evaporation. Small-molecule diffusivity was represented by the water diffusivity measured by a quartz-crystal microbalance. The model showed that the browning reaction rates at RH < 60% could be controlled by the low diffusivity of the large organic molecules from the interior region of the particle to the reactive surface region. The results of this study have implications for accurate modeling of atmospheric brown carbon production and associated influences on energy balance. PMID- 29532021 TI - Chemical Stabilization of Perovskite Solar Cells with Functional Fulleropyrrolidines. AB - While perovskite solar cells have invigorated the photovoltaic research community due to their excellent power conversion efficiencies (PCEs), these devices notably suffer from poor stability. To address this crucial issue, a solution processable organic chemical inhibition layer (OCIL) was integrated into perovskite solar cells, resulting in improved device stability and a maximum PCE of 16.3%. Photoenhanced self-doping of the fulleropyrrolidine mixture in the interlayers afforded devices that were advantageously insensitive to OCIL thickness, ranging from 4 to 190 nm. X-ray photoelectron spectroscopy (XPS) indicated that the fulleropyrrolidine mixture improved device stability by stabilizing the metal electrode and trapping ionic defects (i.e., I-) that originate from the perovskite active layer. Moreover, degraded devices were rejuvenated by repeatedly peeling away and replacing the OCIL/Ag electrode, and this repeel and replace process resulted in further improvement to device stability with minimal variation of device efficiency. PMID- 29532022 TI - Metabolic Fingerprinting on a Plasmonic Gold Chip for Mass Spectrometry Based in Vitro Diagnostics. AB - Current metabolic analysis is far from ideal to engage clinics and needs rationally designed materials and device. Here we developed a novel plasmonic chip for clinical metabolic fingerprinting. We first constructed a series of chips with gold nanoshells on the surface through controlled particle synthesis, dip-coating, and gold sputtering for mass production. We integrated the optimized chip with microarrays for laboratory automation and micro-/nanoscaled experiments, which afforded direct high-performance metabolic fingerprinting by laser desorption/ionization mass spectrometry using 500 nL of various biofluids and exosomes. Further we for the first time demonstrated on-chip in vitro metabolic diagnosis of early stage lung cancer patients using serum and exosomes. This work initiates a new bionanotechnology based platform for advanced metabolic analysis toward large-scale diagnostic use. PMID- 29532023 TI - Discovery of Shoot Branching Regulator Targeting Strigolactone Receptor DWARF14. AB - DWARF14 (D14) is a strigolactone receptor that plays a central role in suppression of shoot branching, and hence is a potential target to increase crop productions and biomass. Recently, we reported a fluorescence turn-on probe, Yoshimulactone Green (YLG), which generates a strong fluorescence upon the hydrolysis by D14-type strigolactone receptors. Herein, we applied a YLG-based in vitro assay to a high-throughput chemical screening and identified a novel small molecule DL1 as a potent inhibitor of D14. DL1 competes with endogenous strigolactones, thereby increasing the number of shoot branching in a model plant Arabidopsis as well as in rice. Thus, DL1 is expected to be useful not only as a tool to understand the biological roles of D14 receptors in plant growth and development, but also as a potent agrochemical to improve the crop yield. PMID- 29532024 TI - Cutting Materials in Half: A Graph Theory Approach for Generating Crystal Surfaces and Its Prediction of 2D Zeolites. AB - Scientific interest in two-dimensional (2D) materials, ranging from graphene and other single layer materials to atomically thin crystals, is quickly increasing for a large variety of technological applications. While in silico design approaches have made a large impact in the study of 3D crystals, algorithms designed to discover atomically thin 2D materials from their parent 3D materials are by comparison more sparse. We hypothesize that determining how to cut a 3D material in half (i.e., which Miller surface is formed) by severing a minimal number of bonds or a minimal amount of total bond energy per unit area can yield insight into preferred crystal faces. We answer this question by implementing a graph theory technique to mathematically formalize the enumeration of minimum cut surfaces of crystals. While the algorithm is generally applicable to different classes of materials, we focus on zeolitic materials due to their diverse structural topology and because 2D zeolites have promising catalytic and separation performance compared to their 3D counterparts. We report here a simple descriptor based only on structural information that predicts whether a zeolite is likely to be synthesizable in the 2D form and correctly identifies the expressed surface in known layered 2D zeolites. The discovery of this descriptor allows us to highlight other zeolites that may also be synthesized in the 2D form that have not been experimentally realized yet. Finally, our method is general since the mathematical formalism can be applied to find the minimum cut surfaces of other crystallographic materials such as metal-organic frameworks, covalent organic frameworks, zeolitic-imidazolate frameworks, metal oxides, etc. PMID- 29532025 TI - Ube2V2 Is a Rosetta Stone Bridging Redox and Ubiquitin Codes, Coordinating DNA Damage Responses. AB - Posttranslational modifications (PTMs) are the lingua franca of cellular communication. Most PTMs are enzyme-orchestrated. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. Herein, we designed "G-REX"-a technique that allows controlled release of reactive electrophiles in vivo. Mitigating toxicity/off-target effects associated with uncontrolled bolus exposure, G-REX tagged first-responding innate cysteines that bind electrophiles under true kcat/Km conditions. G-REX identified two allosteric ubiquitin conjugating proteins-Ube2V1/Ube2V2-sharing a novel privileged-sensor-cysteine. This non-enzyme-catalyzed-PTM triggered responses specific to each protein. Thus, G-REX is an unbiased method to identify novel functional cysteines. Contrasting conventional active-site/off-active-site cysteine-modifications that regulate target activity, modification of Ube2V2 allosterically hyperactivated its enzymatically active binding-partner Ube2N, promoting K63-linked client ubiquitination and stimulating H2AX-dependent DNA damage response. This work establishes Ube2V2 as a Rosetta-stone bridging redox and ubiquitin codes to guard genome integrity. PMID- 29532026 TI - An Aqueous Inorganic Polymer Binder for High Performance Lithium-Sulfur Batteries with Flame-Retardant Properties. AB - Lithium-sulfur (Li-S) batteries are regarded as promising next-generation high energy density storage devices for both portable electronics and electric vehicles due to their high energy density, low cost, and environmental friendliness. However, there remain some issues yet to be fully addressed with the main challenges stemming from the ionically insulating nature of sulfur and the dissolution of polysulfides in electrolyte with subsequent parasitic reactions leading to low sulfur utilization and poor cycle life. The high flammability of sulfur is another serious safety concern which has hindered its further application. Herein, an aqueous inorganic polymer, ammonium polyphosphate (APP), has been developed as a novel multifunctional binder to address the above issues. The strong binding affinity of the main chain of APP with lithium polysulfides blocks diffusion of polysulfide anions and inhibits their shuttling effect. The coupling of APP with Li ion facilitates ion transfer and promotes the kinetics of the cathode reaction. Moreover, APP can serve as a flame retardant, thus significantly reducing the flammability of the sulfur cathode. In addition, the aqueous characteristic of the binder avoids the use of toxic organic solvents, thus significantly improving safety. As a result, a high rate capacity of 520 mAh g-1 at 4 C and excellent cycling stability of ~0.038% capacity decay per cycle at 0.5 C for 400 cycles are achieved based on this binder. This work offers a feasible and effective strategy for employing APP as an efficient multifunctional binder toward building next-generation high energy density Li-S batteries. PMID- 29532027 TI - Automatic Chemical Design Using a Data-Driven Continuous Representation of Molecules. AB - We report a method to convert discrete representations of molecules to and from a multidimensional continuous representation. This model allows us to generate new molecules for efficient exploration and optimization through open-ended spaces of chemical compounds. A deep neural network was trained on hundreds of thousands of existing chemical structures to construct three coupled functions: an encoder, a decoder, and a predictor. The encoder converts the discrete representation of a molecule into a real-valued continuous vector, and the decoder converts these continuous vectors back to discrete molecular representations. The predictor estimates chemical properties from the latent continuous vector representation of the molecule. Continuous representations of molecules allow us to automatically generate novel chemical structures by performing simple operations in the latent space, such as decoding random vectors, perturbing known chemical structures, or interpolating between molecules. Continuous representations also allow the use of powerful gradient-based optimization to efficiently guide the search for optimized functional compounds. We demonstrate our method in the domain of drug like molecules and also in a set of molecules with fewer that nine heavy atoms. PMID- 29532028 TI - Dealloyed Intra-Nanogap Particles with Highly Robust, Quantifiable Surface Enhanced Raman Scattering Signals for Biosensing and Bioimaging Applications. AB - Uniformly controlling a large number of metal nanostructures with a plasmonically enhanced signal to generate quantitative optical signals and the widespread use of these structures for surface-enhanced Raman scattering (SERS)-based biosensing and bioimaging applications are of paramount importance but are extremely challenging. Here, we report a highly controllable, facile selective interdiffusive dealloying chemistry for synthesizing the dealloyed intra-nanogap particles (DIPs) with a ~2 nm intragap in a high yield (~95%) without the need for an interlayer. The SERS signals from DIPs are highly quantitative and polarization-independent with polarized laser sources. Remarkably, all the analyzed particles displayed the SERS enhancement factors (EFs) of >=1.1 * 108 with a very narrow distribution of EFs. Finally, we show that DIPs can be used as ultrasensitive SERS-based DNA detection probes for detecting 10 aM to 1 pM target concentrations and highly robust, quantitative real-time cell imaging probes for long-term imaging with low laser power and short exposure time. PMID- 29532029 TI - Nanoscale Probing of Interaction in Atomically Thin Layered Materials. AB - We combine conductive atomic force microscopy (CAFM) and molecular dynamics (MD) simulations to reveal the interaction of atomically thin layered materials (ATLMs) down to nanoscale lateral dimension. The setup also allows quantifying, for the first time, the effect of layer number and electric field on the dielectric constant of ATLMs with few-layer down to monolayer thickness. Our CAFM assisted electrostatic technique shows that high-quality mono- and bilayer graphene is reliably produced at significant yields only by the shear type of bond breaking between layers, whereas the normal type of bond breaking exhibits a very stochastic process mainly due to the coexistence of local delamination and interlayer twist. Our dielectric constant measurements also reveal a very weak dependence on the layer number and the electric field (up to our experimental limit of 0.1 V/A), which is in contrast with theoretical reports. Owing to unexpectedly large variations in the screening ability of pristine monolayer graphene under ambient conditions, we further demonstrate that the effective dielectric constant of monolayer graphene can be engineered to provide a broad spectrum of dielectric responses (3.5-17) through oxidation and thermal annealing, thus confirming its much higher chemical reactivity than bilayer and few layers. PMID- 29532030 TI - A "Tug of War" Maintains a Dynamic Protein-Membrane Complex: Molecular Dynamics Simulations of C-Raf RBD-CRD Bound to K-Ras4B at an Anionic Membrane. AB - Association of Raf kinase with activated Ras triggers downstream signaling cascades toward regulating transcription in the cells' nucleus. Dysregulation of Ras-Raf signaling stimulates cancers. We investigate the C-Raf RBD and CRD regions when bound to oncogenic K-Ras4B at the membrane. All-atom molecular dynamics simulations suggest that the membrane plays an integral role in regulating the configurational ensemble of the complex. Remarkably, the complex samples a few states dynamically, reflecting a competition between C-Raf CRD- and K-Ras4B- membrane interactions. This competition arises because the interaction between the RBD and K-Ras is strong while the linker between the RBD and CRD is short. Such a mechanism maintains a modest binding for the overall complex at the membrane and is expected to facilitate fast signaling processes. Competition of protein-membrane contacts is likely a common mechanism for other multiprotein complexes, if not multidomain proteins at membranes. PMID- 29532031 TI - Fragile skin microbiomes in megacities are assembled by a predominantly niche based process. AB - Given the higher incidence of skin diseases in more urbanized populations and its association with the skin microbiome, we questioned how the skin microbiome differed depending on the degree of urbanization. Skin microbiomes of 231 healthy subjects in five large cities in China varied mainly with environment and socioeconomic status of the cities in question. The differences among microbiomes could be explained by the predominantly niche-based assembly of microbial communities, which was supported by a dominance test, beta-null deviation, and edge-length abundance distribution. Networks among microbes in larger cities were more fragile, which may contribute to the higher incidence of skin diseases in more urbanized environments. These results suggest that microbial ecological theory can provide a framework for understanding crucial health-associated features of the human microbiome. PMID- 29532032 TI - Hallmarks of science missing from North American wildlife management. AB - Resource management agencies commonly defend controversial policy by claiming adherence to science-based approaches. For example, proponents and practitioners of the "North American Model of Wildlife Conservation," which guides hunting policy across much of the United States and Canada, assert that science plays a central role in shaping policy. However, what that means is rarely defined. We propose a framework that identifies four fundamental hallmarks of science relevant to natural resource management (measurable objectives, evidence, transparency, and independent review) and test for their presence in hunt management plans created by 62 U.S. state and Canadian provincial and territorial agencies across 667 management systems (species-jurisdictions). We found that most (60%) systems contained fewer than half of the indicator criteria assessed, with more criteria detected in systems that were peer-reviewed, that pertained to "big game," and in jurisdictions at increasing latitudes. These results raise doubt about the purported scientific basis of hunt management across the United States and Canada. Our framework provides guidance for adopting a science-based approach to safeguard not only wildlife but also agencies from potential social, legal, and political conflict. PMID- 29532033 TI - Shark baselines and the conservation role of remote coral reef ecosystems. AB - Scientific monitoring has recorded only a recent fraction of the oceans' alteration history. This biases our understanding of marine ecosystems. Remote coral reef ecosystems are often considered pristine because of high shark abundance. However, given the long history and global nature of fishing, sharks' vulnerability, and the ecological consequences of shark declines, these states may not be natural. In the Chagos archipelago, one of the remotest coral reef systems on the planet, protected by a very large marine reserve, we integrated disparate fisheries and scientific survey data to reconstruct baselines and long term population trajectories of two dominant sharks. In 2012, we estimated 571,310 gray reef and 31,693 silvertip sharks, about 79 and 7% of their baseline levels. These species were exploited longer and more intensively than previously thought and responded to fishing and protection with variable and compensatory population trajectories. Our approach highlights the value of integrative and historical analyses to evaluate large marine ecosystems currently considered pristine. PMID- 29532034 TI - Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. AB - Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels. PMID- 29532036 TI - Intramedullary Screws versus Kirschner Wires for Metacarpal Fixation, Functional, and Patient-Related Outcomes. AB - Purpose The purpose of our study is to compare the intramedullary fixation of metacarpal fractures with cannulated headless screws and antegrade Kirschner wires in terms of final total active motion, grip strength, patient-related outcomes, need for casting, and return to work times. Methods The authors performed a retrospective review of the hospital records. Thirty fractures were included in the study, 19 in the screw fixation group, and 11 in the Kirschner wire group. Grip strength, and total active motion, was measured at the latest follow-up for both the injured and contralateral hand. Pain was measured on the visual analog scale. Patients were requested to fill a Quick disabilities of the arm and hand score (DASH) questionnaire at the latest follow-up. Satisfaction was measured on a scale from 0 to 10. The time to return to work was quantified from the accident to the point when the patient was back to active duty. Postoperative casting time was also quantified. Results The authors did not find any differences between the two groups in total active motion, grip strength, pain, satisfaction, or Quick DASH scores. We did find a difference in the return to work and casting times; these appeared to be shorter in the screw group. Conclusion Due to the small number of cases, we have been unable to clearly conclude that there were any benefits in the application of one particular technique when compared with the other. PMID- 29532037 TI - Comminuted Fracture of the Body of the Trapezium and Thumb Carpometacarpal Dislocation: A Particular Pattern. AB - Trapezium fractures are uncommon injuries. Our case is that of a thumb carpometacarpal joint dislocation associated to a partly comminuted fracture of the body of the trapezium. To the best of the authors' knowledge, this particular variation has not been previously reported in the indexed literature. PMID- 29532035 TI - Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. AB - Binding of programmed death ligand-1 (PD-L1) to programmed cell death protein-1 (PD1) leads to cancer immune evasion via inhibition of T cell function. One of the defining characteristics of glioblastoma, a universally fatal brain cancer, is its profound local and systemic immunosuppression. Glioblastoma has also been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that glioblastoma EVs may be important mediators of immunosuppression and that PD-L1 could play a role. We show that glioblastoma EVs block T cell activation and proliferation in response to T cell receptor stimulation. PD-L1 was expressed on the surface of some, but not of all, glioblastoma-derived EVs, with the potential to directly bind to PD1. An anti-PD1 receptor blocking antibody significantly reversed the EV-mediated blockade of T cell activation but only when PD-L1 was present on EVs. When glioblastoma PD-L1 was up-regulated by IFN-gamma, EVs also showed some PD-L1-dependent inhibition of T cell activation. PD-L1 expression correlated with the mesenchymal transcriptome profile and was anatomically localized in the perinecrotic and pseudopalisading niche of human glioblastoma specimens. PD-L1 DNA was present in circulating EVs from glioblastoma patients where it correlated with tumor volumes of up to 60 cm3. These results suggest that PD-L1 on EVs may be another mechanism for glioblastoma to suppress antitumor immunity and support the potential of EVs as biomarkers in tumor patients. PMID- 29532038 TI - Improving Medication Safety and Cardiovascular Risk Factor Control to Mitigate Disparities in African-American Kidney Transplant Recipients: Design and Methods. AB - There is a lack of data analyzing the influence of cardiovascular disease (CVD) risk factor control on graft survival disparities in African-American kidney transplant recipients. Studies in the general population indicate that CVD risk factor control is poor in African-Americans, leading to higher rates of renal failure and major acute cardiovascular events. However, with the exception of hypertension, there is no data demonstrating similar results within transplant recipients. Recent analyses conducted by our investigator group indicate that CVD risk factors, especially diabetes, are poorly controlled in African-American recipients, which likely impacts graft loss. This study protocol describes a prospective interventional clinical trial with the goal of demonstrating improved medication safety and CVD risk factor control in adult solitary kidney transplant recipients at least one-year post-transplant with a functioning graft. This is a prospective, interventional, 6-month, pharmacist-led and technology enabled study in adult kidney transplant recipients with the goal of improving CVD risk factor outcomes by improving medication safety and patient self-efficacy. This papers describes the issues related to racial disparities in transplant, the details of this intervention and how we expect this intervention to improve CVD risk factor control in kidney transplant recipients, particularly within African-Americans. PMID- 29532039 TI - Structural Sensitivity in HIV Modeling: A Case Study of Vaccination. AB - Structural assumptions in infectious disease models, such as the choice of network or compartmental model type or the inclusion of different types of heterogeneity across individuals, might affect model predictions as much as or more than the choice of input parameters. We explore the potential implications of structural assumptions on HIV model predictions and policy conclusions. We illustrate the value of inference robustness assessment through a case study of the effects of a hypothetical HIV vaccine in multiple population subgroups over eight related transmission models, which we sequentially modify to vary over two dimensions: parameter complexity (e.g., the inclusion of age and HCV comorbidity) and contact/simulation complexity (e.g., aggregated compartmental vs. individual/disaggregated compartmental vs. network models). We find that estimates of HIV incidence reductions from network models and individual compartmental models vary, but those differences are overwhelmed by the differences in HIV incidence between such models and the aggregated compartmental models (which aggregate groups of individuals into compartments). Complexities such as age structure appear to buffer the effects of aggregation and increase the threshold of net vaccine effectiveness at which aggregated models begin to overestimate reductions. The differences introduced by parameter complexity in estimated incidence reduction also translate into substantial differences in cost effectiveness estimates. Parameter complexity does not appear to play a consistent role in differentiating the projections of network models. PMID- 29532040 TI - Environmental Agents, Oxidative Stress and Autoimmunity. AB - Oxidative stress (OS) plays an important role in the pathogenesis of a variety of autoimmune diseases (ADs) and many environmental agents participate in this process. Environmental agents, including trichloroethylene (TCE), silica, pristane, mercury, and smoke, are known to induce an autoimmune response, potentially through OS-mediated mechanisms. Here, we focus on unraveling the targets and signaling pathways that have been mechanistically linked with OS, as a result of exposure to these and numerous other environmental agents, and their impact on the immune system in triggering ADs. Antioxidants and molecular targets impeding autoimmunity by targeting specific signaling pathways are also reviewed. The review not only provides an overview of the current knowledge and evidence showing strong associations between environmental exposures, OS, and ADs, but also plausible mechanisms by which OS causes autoimmunity/ADs. We also discuss areas that require additional approaches, such as unraveling specific events/mechanisms leading to such devastating diseases and measures to prevent or attenuate such diseases. PMID- 29532041 TI - Progress and Remaining Challenges in the Application of High Frequency Oscillations as Biomarkers of Epileptic Brain. AB - High-frequency oscillations (HFOs: 100 - 600 Hz) have been widely proposed as biomarkers of epileptic brain tissue. In addition, HFOs over a broader range of frequencies spanning 30 - 2000 Hz are potential biomarkers of both physiological and pathological brain processes. The majority of the results from humans with focal epilepsy have focused on HFOs recorded directly from the brain with intracranial EEG (iEEG) in the high gamma (65 - 100 Hz), ripple (100 - 250 Hz), and fast ripple (250 - 600 Hz) frequency ranges. These results are supplemented by reports of HFOs recorded with iEEG in the low gamma (30 - 65Hz) and very high frequency (500 - 2000 Hz) ranges. Visual detection of HFOs is laborious and limited by poor inter-rater agreement; and the need for accurate, reproducible automated HFOs detection is well recognized. In particular, the clinical translation of HFOs as a biomarker of the epileptogenic brain has been limited by the ability to reliably detect and accurately classify HFOs as physiological or pathological. Despite these challenges, there has been significant progress in the field, which is the subject of this review. Furthermore, we provide data and corresponding analytic code in an effort to promote reproducible research and accelerate clinical translation. PMID- 29532047 TI - JAMA Neurology-The Year in Review, 2017. PMID- 29532048 TI - JAMA Internal Medicine-The Year in Review, 2017. PMID- 29532049 TI - Italy's New Advance Directive Law: When in Rome.... PMID- 29532042 TI - Physiology of Cardiac Development: From Genetics to Signaling to Therapeutic Strategies. AB - The heart is one of the first organs to form and function during embryonic development. It is comprised of multiple cell lineages, each integral for proper cardiac development, and include cardiomyocytes, endothelial cells, epicardial cells and neural crest cells. The molecular mechanisms regulating cardiac development and morphogenesis are dependent on signaling crosstalk between multiple lineages through paracrine interactions, cell-ECM interactions, and cell cell interactions, which together, help facilitate survival, growth, proliferation, differentiation and migration of cardiac tissue. Aberrant regulation of any of these processes can induce developmental disorders and pathological phenotypes. Here, we will discuss each of these processes, the genetic factors that contribute to each step of cardiac development, as well as the current and future therapeutic targets and mechanisms of heart development and disease. Understanding the complex interactions that regulate cardiac development, proliferation and differentiation is not only vital to understanding the causes of congenital heart defects, but to also finding new therapeutics that can treat both pediatric and adult cardiac disease in the near future. PMID- 29532051 TI - Unnecessary Repeat Enzyme Testing in Acute Pancreatitis: A Teachable Moment. PMID- 29532052 TI - Considerations in Assessing Disability Trajectories Before and After Stroke and Myocardial Infarction. PMID- 29532050 TI - Prevalence of Invalid Performance on Baseline Testing for Sport-Related Concussion by Age and Validity Indicator. AB - Importance: Estimated base rates of invalid performance on baseline testing (base rates of failure) for the management of sport-related concussion range from 6.1% to 40.0%, depending on the validity indicator used. The instability of this key measure represents a challenge in the clinical interpretation of test results that could undermine the utility of baseline testing. Objectives: To determine the prevalence of invalid performance on baseline testing and to assess whether the prevalence varies as a function of age and validity indicator. Design, Setting, and Participants: This retrospective, cross-sectional study included data collected between January 1, 2012, and December 31, 2016, from a clinical referral center in the Midwestern United States. Participants included 7897 consecutively tested, equivalently proportioned male and female athletes aged 10 to 21 years, who completed baseline neurocognitive testing for the purpose of concussion management. Interventions: Baseline assessment was conducted with the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT), a computerized neurocognitive test designed for assessment of concussion. Main Outcomes and Measures: Base rates of failure on published ImPACT validity indicators were compared within and across age groups. Hypotheses were developed after data collection but prior to analyses. Results: Of the 7897 study participants, 4086 (51.7%) were male, mean (SD) age was 14.71 (1.78) years, 7820 (99.0%) were primarily English speaking, and the mean (SD) educational level was 8.79 (1.68) years. The base rate of failure ranged from 6.4% to 47.6% across individual indicators. Most of the sample (55.7%) failed at least 1 of 4 validity indicators. The base rate of failure varied considerably across age groups (117 of 140 [83.6%] for those aged 10 years to 14 of 48 [29.2%] for those aged 21 years), representing a risk ratio of 2.86 (95% CI, 2.60-3.16; P < .001). Conclusions and Relevance: The results for base rate of failure were surprisingly high overall and varied widely depending on the specific validity indicator and the age of the examinee. The strong age association, with 3 of 4 participants aged 10 to 12 years failing validity indicators, suggests that the clinical interpretation and utility of baseline testing in this age group is questionable. These findings underscore the need for close scrutiny of performance validity indicators on baseline testing across age groups. PMID- 29532053 TI - An HIV Behavioral Intervention Gets It Right-and Shows We Must Do Even Better. PMID- 29532055 TI - The Dependent Coverage Provision Is Good for Mothers, Good for Children, and Good for Taxpayers. PMID- 29532054 TI - Effect of a Digital Health Intervention on Receipt of Colorectal Cancer Screening in Vulnerable Patients: A Randomized Controlled Trial. AB - Background: Screening for colorectal cancer (CRC) reduces mortality, yet more than one third of age-eligible Americans are unscreened. Objective: To examine the effect of a digital health intervention, Mobile Patient Technology for Health CRC (mPATH-CRC), on rates of CRC screening. Design: Randomized clinical trial. (ClinicalTrials.gov: NCT02088333). Setting: 6 community-based primary care practices. Participants: 450 patients (223 in the mPATH-CRC group and 227 in usual care) scheduled for a primary care visit and due for routine CRC screening. Intervention: An iPad application that displays a CRC screening decision aid, lets patients order their own screening tests, and sends automated follow-up electronic messages to support patients. Measurements: The primary outcome was chart-verified completion of CRC screening within 24 weeks. Secondary outcomes were ability to state a screening preference, intention to receive screening, screening discussions, and orders for screening tests. All outcome assessors were blinded to randomization. Results: Baseline characteristics were similar between groups; 37% of participants had limited health literacy, and 53% had annual incomes less than $20 000. Screening was completed by 30% of mPATH-CRC participants and 15% of those receiving usual care (logistic regression odds ratio, 2.5 [95% CI, 1.6 to 4.0]). Compared with usual care, more mPATH-CRC participants could state a screening preference, planned to be screened within 6 months, discussed screening with their provider, and had a screening test ordered. Half of mPATH-CRC participants (53%; 118 of 223) "self-ordered" a test via the program. Limitation: Participants were English speakers in a single health care system. Conclusion: A digital health intervention that allows patients to self-order tests can increase CRC screening. Future research should identify methods for implementing similar interventions in clinical care. Primary Funding Source: National Cancer Institute. PMID- 29532056 TI - Association of Hospital Performance Based on 30-Day Risk-Standardized Mortality Rate With Long-term Survival After Heart Failure Hospitalization: An Analysis of the Get With The Guidelines-Heart Failure Registry. AB - Importance: Among patients hospitalized with heart failure (HF), the long-term clinical implications of hospitalization at hospitals based on 30-day risk standardized mortality rates (RSMRs) is not known. Objective: To evaluate the association of hospital-specific 30-day RSMR with long-term survival among patients hospitalized with HF in the American Heart Association Get With The Guidelines-HF registry. Design, Setting, and Participants: The longitudinal observational study included 106 304 patients with HF who were admitted to 317 centers participating in the Get With The Guidelines-HF registry from January 1, 2005, to December 31, 2013, and had Medicare-linked follow-up data. Hospital specific 30-day RSMR was calculated using a hierarchical logistic regression model. In the model, 30-day mortality rate was a binary outcome, patient baseline characteristics were included as covariates, and the hospitals were treated as random effects. The association of 30-day RSMR-based hospital groups (low to high 30-day RSMR: quartile 1 [Q1] to Q4) with long-term (1-year, 3-year, and 5-year) mortality was assessed using adjusted Cox models. Data analysis took place from June 29, 2017, to February 19, 2018. Exposures: Thirty-day RSMR for participating hospitals. Main Outcomes and Measures: One-year, 3-year, and 5-year mortality rates. Results: Of the 106 304 patients included in the analysis, 57 552 (54.1%) were women and 84 595 (79.6%) were white, and the median (interquartile range) age was 81 (74-87) years. The 30-day RSMR ranged from 8.6% (Q1) to 10.7% (Q4). Hospitals in the low 30-day RSMR group had greater availability of advanced HF therapies, cardiac surgery, and percutaneous coronary interventions. In the primary landmarked analyses among 30-day survivors, there was a graded inverse association between 30-day RSMR and long-term mortality (Q1 vs Q4: 5-year mortality, 73.7% vs 76.8%). In adjusted analysis, patients admitted to hospitals in the high 30-day RSMR group had 14% (95% CI, 10-18) higher relative hazards of 5-year mortality compared with those admitted to hospitals in the low 30-day RSMR group. Similar findings were observed in analyses of survival from admission, with 22% (95% CI, 18-26) higher relative hazards of 5-year mortality for patients admitted to Q4 vs Q1 hospitals. Conclusions and Relevance: Lower hospital-level 30-day RSMR is associated with greater 1-year, 3-year, and 5-year survival for patients with HF. These differences in 30-day survival continued to accrue beyond 30 days and persisted long term, suggesting that 30-day RSMR may be a useful HF performance metric to incentivize quality care and improve long-term outcomes. PMID- 29532058 TI - Results Reporting for Trials With the Same Sponsor, Drug, and Condition in ClinicalTrials.gov and Peer-Reviewed Publications. PMID- 29532057 TI - Association of Excessive Daytime Sleepiness With Longitudinal beta-Amyloid Accumulation in Elderly Persons Without Dementia. AB - Importance: Aging is associated with excessive daytime sleepiness (EDS), which has been linked to cognitive decline in the elderly. However, whether EDS is associated with the pathologic processes of Alzheimer disease remains unclear. Objective: To investigate whether EDS at baseline is associated with a longitudinal increase in regional beta-amyloid (Abeta) accumulation in a cohort of elderly individuals without dementia. Design, Setting, and Participants: This prospective analysis included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota. Of 2900 participants, 2172 (74.9%) agreed to undergo carbon 11-labeled Pittsburgh compound B positron emission tomography (PiB-PET). We included 283 participants 70 years or older without dementia who completed surveys assessing sleepiness at baseline and had at least 2 consecutive PiB-PET scans from January 1, 2009, through July 31, 2016, after excluding 45 (13.7%) who had a comorbid neurologic disorder. Main Outcomes and Measures: Excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score of at least 10. The difference in Abeta levels between the 2 consecutive scans (DeltaPiB) in Abeta-susceptible regions (prefrontal, anterior cingulate, posterior cingulate-precuneus, and parietal) was determined. Multiple linear regression models were fit to explore associations between baseline EDS and DeltaPiB while adjusting for baseline age, sex, presence of the apolipoprotein E epsilon4 allele, educational level, baseline PiB uptake, global PiB positivity (standardized uptake value ratio >=1.4), physical activity, cardiovascular comorbidities (obesity, hypertension, hyperlipidemia, and diabetes), reduced sleep duration, respiratory symptoms during sleep, depression, and interval between scans. Results: Of the initial 283 participants, mean (SD) age was 77.1 (4.8) years; 204 (72.1%) were men and 79 (27.9%) were women. Sixty three participants (22.3%) had EDS. Baseline EDS was significantly associated with increased regional Abeta accumulation in the anterior cingulate (B coefficient = 0.031; 95% CI, 0.001-0.061; P = .04), posterior cingulate-precuneus (B coefficient = 0.038; 95% CI, 0.006-0.069; P = .02), and parietal (B coefficient = 0.033; 95% CI, 0.001-0.065; P = .04) regions. Association of EDS with longitudinal Abeta accumulation was stronger in participants with baseline global PiB positivity in the anterior cingulate (B coefficient = 0.065; 95% CI, 0.010-0.118; P = .02) and cingulate-precuneus (B coefficient = 0.068; 95% CI, 0.009-0.126; P = .02) regions. Conclusions and Relevance: Baseline EDS was associated with increased longitudinal Abeta accumulation in elderly persons without dementia, suggesting that those with EDS may be more vulnerable to pathologic changes associated with Alzheimer disease. Further work is needed to elucidate whether EDS is a clinical marker of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers. Early identification of patients with EDS and treatment of underlying sleep disorders could reduce Abeta accumulation in this vulnerable group. PMID- 29532060 TI - Progressive Multifocal Leukoencephalopathy Lesions and JC Virus: The Limits and Value of Imaging. PMID- 29532059 TI - Effectiveness of a Peer Navigation Intervention to Sustain Viral Suppression Among HIV-Positive Men and Transgender Women Released From Jail: The LINK LA Randomized Clinical Trial. AB - Importance: Diagnosis of human immunodeficiency virus (HIV) infection, linkage and retention in care, and adherence to antiretroviral therapy are steps in the care continuum enabling consistent viral suppression for people living with HIV, extending longevity and preventing further transmission. While incarcerated, people living with HIV receive antiretroviral therapy and achieve viral suppression more consistently than after they are released. No interventions have shown sustained viral suppression after jail release. Objective: To test the effect on viral suppression in released inmates of the manualized LINK LA (Linking Inmates to Care in Los Angeles) peer navigation intervention compared with standard transitional case management controls. Design, Setting, and Participants: Randomized clinical trial conducted from December 2012 through October 2016 with people living with HIV being released from Los Angeles (LA) County Jail. All participants were (1) 18 years or older; (2) either men or transgender women diagnosed with HIV; (3) English speaking; (4) selected for the transitional case management program prior to enrollment; (5) residing in LA County; and (6) eligible for antiretroviral therapy. Main Outcomes and Measures: Change in HIV viral suppression (<75 copies/mL) over a 12-month period. Interventions: During the 12-session, 24-week LINK LA Peer Navigation intervention, trained peer navigators counseled participants on goal setting and problem solving around barriers to HIV care and adherence, starting while the participants were still in jail. After their release, they continued counseling while they accompanied participants to 2 HIV care visits, then facilitated communication with clinicians during visits. Results: Of 356 participants randomized, 151 (42%) were black; 110 (31%) were Latino; 303 (85%) were men; 53 (15%) were transgender women; and the mean (SD) age was 39.5 (10.4) years. At 12 months, viral suppression was achieved by 62 (49.6%) of 125 participants in the peer navigation (intervention) arm compared with 45 (36.0%) of 125 in the transitional case management (control) arm, for an unadjusted treatment difference of 13.6% (95% CI, 1.34%-25.9%; P = .03). In the repeated measures, random effects, logistic model the adjusted probability of viral suppression declined from 52% at baseline to 30% among controls, while those in the peer navigation arm maintained viral suppression at 49% from baseline to 12 months, for a difference-in-difference of 22% (95% CI, 0.03-0.41; P = .02). Conclusions and Relevance: The LINK LA peer navigation intervention was successful at preventing declines in viral suppression, typically seen after release from incarceration, compared with standard transitional case management. Future research should examine ways to strengthen the intervention to increase viral suppression above baseline levels. Trial Registration: clinicaltrials.gov Identifier: NCT01406626. PMID- 29532062 TI - Considerations in Assessing Disability Trajectories Before and After Stroke and Myocardial Infarction-Reply. PMID- 29532061 TI - Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab Treated Patients With Multiple Sclerosis. AB - Importance: The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. Objective: To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. Design, Setting and Participants: This was a retrospective, cross sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. Main Outcomes and Measures: Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. Results: Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman rho, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms. Conclusions and Relevance: Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance. PMID- 29532063 TI - Big Data and Machine Learning in Health Care. PMID- 29532064 TI - Medical Overuse in Pediatric End-of-Life Care. PMID- 29532065 TI - Medical Overuse in Pediatric End-of-Life Care-Reply. PMID- 29532066 TI - Adolescent Sexting Research: The Challenges Ahead. PMID- 29532068 TI - Considerations in Assessing Disability Trajectories Before and After Stroke and Myocardial Infarction. PMID- 29532067 TI - Association of Mental Health Conditions and Treatments With Long-term Opioid Analgesic Receipt Among Adolescents. AB - Importance: Adults with mental health conditions are more likely than those without to receive long-term opioid therapy. Less is known about opioid therapy among adolescents, especially those with mental health conditions. Objective: To examine associations between preexisting mental health conditions and treatments and initiation of any opioid and long-term opioid therapy among adolescents. Design, Setting, and Participants: A cohort of 1 224 520 incident opioid recipients without cancer diagnoses aged 14 to 18 years at first receipt was extracted from nationwide commercial health care claims data from January 1, 2003, to December 31, 2014. Analysis was conducted from August 19, 2016, to November 16, 2017. Associations between preexisting mental health conditions and treatments and any opioid receipt were examined by comparing recipients with nonrecipients matched on sex, calendar year and years of age of first enrollment, and months of enrollment (prior to the index month for recipients, ever for nonrecipients). Associations between preexisting mental health conditions and treatments and subsequent long-term opioid therapy were examined among recipients with at least 6 months' follow-up using Cox proportional hazards regressions adjusted for demographics. Exposures: Mental health condition diagnoses and treatments recorded in inpatient, outpatient, and filled-prescription claims prior to opioid receipt. Main Outcomes and Measures: Opioid receipt, defined as any opioid analgesic prescription claim, and long-term opioid therapy, defined as more than 90 days' supply within a 6-month window having no gaps in supply of more than 32 days. Results: Of the 1 224 520 new opioid recipients included, the median age at first receipt was 17 years (interquartile range, 16-18 years), and 51.1% were female. Median follow-up after first receipt was 625 days (interquartile range, 255-1268 days). Adolescents with anxiety, mood, neurodevelopmental, sleep, and nonopioid substance use disorders and most mental health treatments were significantly more likely to receive any opioid (odds ratios from 1.13 [95% CI, 1.10-1.16] for nonopioid substance use disorders to 1.69 [95% CI, 1.58-1.81] for nonbenzodiazepine hypnotics). Among the 1 000 453 opioid recipients (81.7%) who had at least 6 months' follow-up, the cumulative incidence of long-term opioid therapy was 3.0 (95% CI, 2.8-3.1) per 1000 recipients within 3 years after first opioid receipt. All preexisting mental health conditions and treatments were strongly associated with higher rates of long-term opioid therapy (adjusted hazard ratios from 1.73 [95% CI 1.54-1.95] for attention-deficit/hyperactivity disorder to 8.90 [95% CI, 5.85-13.54] for opioid use disorder). Conclusions and Relevance: Commercially insured adolescents with many types of preexisting mental health conditions and treatments were modestly more likely to receive any opioid and were substantially more likely to subsequently transition to long-term opioid therapy relative to those without, although overall rates of long-term opioid therapy were low. PMID- 29532069 TI - Institutional Research Misconduct Reports Need More Credibility. PMID- 29532070 TI - Fatal Firearm Incidents Before and After Australia's 1996 National Firearms Agreement Banning Semiautomatic Rifles. PMID- 29532071 TI - From the Mouths of Babes: Preschool Racism. PMID- 29532072 TI - JAMA Pediatrics-The Year in Review, 2017. PMID- 29532073 TI - Bronchial Thermoplasty for Severe Asthmatic Cough. PMID- 29532074 TI - Association of Psychiatric Comorbidity With Opioid Prescriptions and Long-term Opioid Therapy Among US Adolescents. PMID- 29532076 TI - Engaging Survivors of Human Trafficking: Complex Health Care Needs and Scarce Resources. AB - Human trafficking, also known as modern-day slavery, is an egregious human rights violation associated with wide-ranging medical and mental health consequences. Because of the extensive health problems related to trafficking, health care providers play a critical role in identifying survivors and engaging them in ongoing care. Although guidelines for recognizing affected patients and a framework for developing response protocols in health care settings have been described, survivors' ongoing engagement in health care services is very challenging. High rates of disengagement, lost contact, premature termination, and attrition are common outcomes. For interventions to be effective in this marginalized population, challenges in engaging survivors in long-term therapeutic primary and mental health care must be better understood and overcome. This article uses the socioecological model of public health to identify barriers to engagement; offers evidence- and practice-based recommendations for overcoming these barriers; and proposes an interdisciplinary call to action for developing more flexible, adaptable models of care. PMID- 29532075 TI - Effect of Protein Intake on Lean Body Mass in Functionally Limited Older Men: A Randomized Clinical Trial. AB - Importance: The Institute of Medicine set the recommended dietary allowance (RDA) for protein at 0.8 g/kg/d for the entire adult population. It remains controversial whether protein intake greater than the RDA is needed to maintain protein anabolism in older adults. Objective: To investigate whether increasing protein intake to 1.3 g/kg/d in older adults with physical function limitations and usual protein intake within the RDA improves lean body mass (LBM), muscle performance, physical function, fatigue, and well-being and augments LBM response to a muscle anabolic drug. Design, Setting, and Participants: This randomized clinical trial with a 2 * 2 factorial design was conducted in a research center. A modified intent-to-treat analytic strategy was used. Participants were 92 functionally limited men 65 years or older with usual protein intake less thanor equal to 0.83 g/kg/d within the RDA. The first participant was randomized on September 21, 2011, and the last participant completed the study on January 19, 2017. Interventions: Participants were randomized for 6 months to controlled diets with 0.8 g/kg/d of protein plus placebo, 1.3 g/kg/d of protein plus placebo, 0.8 g/kg/d of protein plus testosterone enanthate (100 mg weekly), or 1.3 g/kg/d of protein plus testosterone. Prespecified energy and protein contents were provided through custom-prepared meals and supplements. Main Outcomes and Measures: The primary outcome was change in LBM. Secondary outcomes were muscle strength, power, physical function, health-related quality of life, fatigue, affect balance, and well-being. Results: Among 92 men (mean [SD] age, 73.0 [5.8] years), the 4 study groups did not differ in baseline characteristics. Changes from baseline in LBM (0.31 kg; 95% CI, -0.46 to 1.08 kg; P = .43) and appendicular (0.04 kg; 95% CI, -0.48 to 0.55 kg; P = .89) and trunk (0.24 kg; 95% CI, -0.17 to 0.66 kg; P = .24) lean mass, as well as muscle strength and power, walking speed and stair-climbing power, health-related quality of life, fatigue, and well-being, did not differ between men assigned to 0.8 vs 1.3 g/kg/d of protein regardless of whether they received testosterone or placebo. Fat mass decreased in participants given higher protein but did not change in those given the RDA: between-group differences were significant (difference, -1.12 kg; 95% CI, -2.04 to -0.21; P = .02). Conclusions and Relevance: Protein intake exceeding the RDA did not increase LBM, muscle performance, physical function, or well being measures or augment anabolic response to testosterone in older men with physical function limitations whose usual protein intakes were within the RDA. The RDA for protein is sufficient to maintain LBM, and protein intake exceeding the RDA does not promote LBM accretion or augment anabolic response to testosterone. Trial Registration: clinicaltrials.gov Identifier: NCT01275365. PMID- 29532078 TI - Comparison of Surgical and Medical Therapy for Type 2 Diabetes in Severely Obese Adolescents. AB - Importance: Because of the substantial increase in the occurrence of type 2 diabetes in the pediatric population and the medical complications of this condition, therapies are urgently needed that will achieve better glycemic control than standard medical management. Objective: To compare glycemic control in cohorts of severely obese adolescents with type 2 diabetes undergoing medical and surgical interventions. Design, Setting, and Participants: A secondary analysis of data collected by the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) consortia was performed. Teen-LABS enrolled 242 adolescents (<=19 years of age) from March 1, 2007, through December 31, 2011. TODAY randomized 699 participants (aged 10-17 years) from July 24, 2004, through February 25, 2009. Data analysis was performed from July 6, 2015, to June 24, 2017. Anthropometric, clinical, and laboratory data from adolescents with severe obesity and type 2 diabetes who underwent treatment with metabolic or bariatric surgery in the Teen LABS study or medical therapy in the TODAY study were compared. Interventions: Teen-LABS participants underwent a primary bariatric surgical procedure; TODAY participants were randomized to receive metformin therapy alone or in combination with rosiglitazone or an intensive lifestyle intervention; insulin therapy was given in cases of progression of disease. Main Outcomes and Measures: Glycemic control, body mass index, prevalence of elevated blood pressure, dyslipidemia, abnormal kidney function, and clinical adverse events were measured. Results: Data from 30 participants from Teen-LABS (mean [SD] age at baseline, 16.9 [1.3] years; 21 [70%] female; 18 [66%] white) and 63 from TODAY (mean [SD] age at baseline, 15.3 [1.3] years; 28 [44%] female; 45 [71%] white) were analyzed. During 2 years, mean hemoglobin A1c concentration decreased from 6.8% (95% CI, 6.4%-7.3%) to 5.5% (95% CI, 4.7% -6.3%) in Teen-LABS and increased from 6.4% (95% CI, 6.1%-6.7%) to 7.8% (95% CI, 7.2%-8.3%) in TODAY. Compared with baseline, the body mass index decreased by 29% (95% CI, 24%-34%) in Teen-LABS and increased by 3.7% (95% CI, 0.8%-6.7%) in TODAY. Twenty-three percent of Teen-LABS participants required a subsequent operation during the 2-year follow-up. Conclusions and Relevance: Compared with medical therapy, surgical treatment of severely obese adolescents with type 2 diabetes was associated with better glycemic control, reduced weight, and improvement of other comorbidities. These data support the need for a well-designed, prospective controlled study to define the role of surgery for adolescents with type 2 diabetes, including health and surgical outcomes. PMID- 29532082 TI - A Health App to Promote Colorectal Cancer Screening. PMID- 29532079 TI - Does Using an iPad Make an Intervention Innovative? PMID- 29532083 TI - Waking Up to the Importance of Sleep in the Pathogenesis of Alzheimer Disease. PMID- 29532084 TI - Human Trafficking: A Health and Human Rights Agenda. PMID- 29532085 TI - Colonoscopy and Colorectal Cancer Mortality in the Veterans Affairs Health Care System: A Case-Control Study. AB - Background: Colonoscopy is widely used in the Veterans Affairs (VA) health care system for colorectal cancer (CRC) prevention, but its effect on CRC mortality is unknown. Objective: To determine whether colonoscopy is associated with decreased CRC mortality in veterans and whether its effect differs by anatomical location of CRC. Design: Case-control study. Setting: VA-Medicare administrative data. Participants: Case patients were veterans aged 52 years or older who were diagnosed with CRC between 2002 and 2008 and died of the disease by the end of 2010. Case patients were matched to 4 control patients without prior CRC on the basis of age, sex, and facility. Conditional logistic regression was performed to calculate odds ratios (ORs) for exposure to colonoscopy, with adjustment for race, Charlson Comorbidity Index score, selected chronic conditions, nonsteroidal anti-inflammatory drug use, and family history of CRC. Measurements: Exposure to colonoscopy was determined from 1997 to 6 months before CRC diagnosis in case patients and to a corresponding date in control patients. Subgroup analysis was performed for patients who had undergone screening colonoscopy. Results: A total of 4964 case patients and 19 856 control patients were identified. Case patients were significantly less likely to have undergone any colonoscopy (OR, 0.39 [95% CI, 0.35 to 0.43]). Colonoscopy was associated with reduced mortality for left sided cancer (OR, 0.28 [CI, 0.24 to 0.32]) and right-sided cancer (OR, 0.54 [CI, 0.47 to 0.63]). The results were similar for patients who had undergone screening colonoscopy (overall OR, 0.30 [CI, 0.24 to 0.38]). Sensitivity analyses that varied the interval between CRC diagnosis and colonoscopy exposure did not affect the primary findings. Limitation: Unmeasured confounding. Conclusion: In this study using national VA-Medicare data, colonoscopy was associated with significant reductions in CRC mortality among veterans and was associated with greater benefit for left-sided cancer than right-sided cancer. Primary Funding Source: U.S. Department of Veterans Affairs. PMID- 29532087 TI - The Changing Landscape of Pediatric Migraine Therapy: A Review. AB - Importance: Migraine is a disabling and prevalent condition that affects the pediatric and adolescent population. This review describes current acute and preventive migraine pharmacologic therapies for the pediatric and adolescent population. Observations: Multiple pharmacotherapies that have been used in the treatment of acute headache and prevention in pediatric migraine are reviewed. There have been recent advances in the management of migraines among pediatric and adolescent patients, including US Food and Drug Administration approval of triptans for acute management in children as young as 6 years, and the first prospective, randomized, double-blind, placebo-controlled comparative study of preventive pharmacotherapy in pediatric migraine. A major challenge of evidence based research in pediatric and adolescent migraine is the significant placebo effect. Conclusions and Relevance: Although progress is being made in the management of migraines among pediatric and adolescent patients, there remains much work to be done. PMID- 29532089 TI - Speak Therapy. PMID- 29532090 TI - Traumatic Brain Injury News Reports and Participation in High School Tackle Football. PMID- 29532091 TI - Influence of tooth position on wind instrumentalists' performance and embouchure comfort : A systematic review. AB - PURPOSE: To systematically search the scientific literature concerning the influence of tooth position on wind instrumentalists' performance and embouchure comfort. METHODS: The PubMed, Cochrane, and Embase databases were searched up to November 2017. The main orthodontic journals were searched for papers older than the inception date of PubMed. Grey literature was sought via Google Scholar. Eligible studies were critically appraised and analysed. RESULTS: The searches retrieved 54 papers. Only two met the inclusion criteria. Searching the orthodontic journals and Google Scholar resulted in two additional eligible studies. All four studies had a cross-sectional design. The sample sizes ranged from 20-100 participants, varying from children to professional musicians. Because of a large heterogeneity in outcome variables, no meta-analysis could be performed. Descriptive analysis shows that there are indications that tooth irregularities have a negative influence on embouchure comfort and performance of a wind instrument player. A large overjet may impede the embouchure of brass musicians and may have a negative influence on trumpet player performance. A wide jaw form seems more beneficial to trumpet player performance than a small jaw form. Furthermore, players of all types of wind instruments can experience embouchure difficulties from extreme spacing or an open bite. CONCLUSION: Tooth position can influence musical performance and embouchure comfort of wind instrumentalists. A Class I relationship without malocclusion seems appropriate for every type of wind instrument. The more extreme the malocclusion, the greater the interference with wind instrumentalists' performance and embouchure comfort. Evidence however is limited. PMID- 29532092 TI - [Nationwide implementation of a hospital resource register for daily trauma care, mass casualties and disasters : Position paper of the German Trauma Society and the Federation of German Medical Directors of Emergency Medical Services]. AB - The introduction of requirements for a minimum intake capacity of trauma patients by the German Trauma Society (DGU) into the so-called white book of treatment of seriously injured patients, is helpful for a sufficient preparation for threats and for dealing with mass casualties for trauma centers as well as for the emergency medical services (EMS). In the hospital information database provided by the Federation of German Medical Directors of Emergency Medical Services, more than 1300 hospitals are currently listed. This information supports the allocation of trauma patients from the field to the appropriate trauma center. Currently, without any coordination requirements, the current 626 trauma centers in Germany are able to immediately handle 6260 patients. This number could be doubled by activating the local hospital action plan, where a priority plan is set up. Additionally, the implementation of a nationwide flexible standardized communication structure between the dispatch center of the ambulance service and the hospitals, would improve daily care as well as the management of threats and mass casualties. It is the obligation of the local medical director of the EMS, to maintain and update the hospital database. Providing the information in the database with the hospital resources and the flexible standard communication structure, is appropriate to improve the daily collaboration and the preparation for mass casualties. PMID- 29532093 TI - There's more to medicine than machines. PMID- 29532094 TI - Have we averted deaths using venoarterial ECMO? PMID- 29532095 TI - Target blood pressure for septic and vasodilatory shock: what is optimal? PMID- 29532096 TI - The relaunch of IJPH's knowledge synthesis, translation, and exchange section. PMID- 29532097 TI - [Once-a-week versus once-every-three-weeks cisplatin application in combined chemoradiotherapy for locally advanced head and neck cancer?] PMID- 29532098 TI - Cancer patients' wish for psychological support during outpatient radiation therapy : Findings from a psychooncological monitoring program in clinical routine. AB - BACKGROUND: Cancer patients frequently suffer from physical and psychosocial impairments due to their disease and its treatment. Psychooncology (PO) can help to cope with stress resulting from outpatient radiotherapy (RT) treatment. There are currently few data regarding patients' wishes for PO support. The aim of this study was to investigate the number of patients with a wish for PO, treatment paths, and predictors of the wish for PO among cancer patients at the beginning of RT. METHODS: The results of routine psychological stress screening (Hornheide screening instrument; cut-off >= 4) of 944 cancer patients between 2015 and 2017 were analyzed in a retrospective cross-sectional study. Predictors for a wish for PO support were identified by stepwise binary logistic regression, in which sociodemographic and treatment data were included in addition to the screening items. RESULTS: Around 20% of patients had above-average stress levels and 13% expressed a wish for PO support (participation rate was approximately 55%). Low emotional wellbeing (OR = 11.3) and lack of social support (OR = 9.4) were strong predictors for this treatment wish. Among patients with pancreatic cancer, head and neck tumors, and hematologic disease, there was a substantial difference between the degree of psychological stress and the wish for treatment. Patients with urological (23.5%) and lung tumors (20.9%) most frequently expressed a wish for PO support. CONCLUSION: Patient-reported psychosocial problems were better predictors of a wish for PO support than sociodemographic or clinical data. Stress screening should thus be implemented in clinical routine. PMID- 29532099 TI - [ADRENAL and the controversy surrounding hydrocortisone in septic shock : Do we know more now?] PMID- 29532100 TI - Multi-finger synergies and the muscular apparatus of the hand. AB - We explored whether the synergic control of the hand during multi-finger force production tasks depends on the hand muscles involved. Healthy subjects performed accurate force production tasks and targeted force pulses while pressing against loops positioned at the level of fingertips, middle phalanges, and proximal phalanges. This varied the involvement of the extrinsic and intrinsic finger flexors. The framework of the uncontrolled manifold (UCM) hypothesis was used to analyze the structure of inter-trial variance, motor equivalence, and anticipatory synergy adjustments prior to the force pulse in the spaces of finger forces and finger modes (hypothetical finger-specific control signals). Subjects showed larger maximal force magnitudes at the proximal site of force production. There were synergies stabilizing total force during steady-state phases across all three sites of force production; no differences were seen across the sites in indices of structure of variance, motor equivalence, or anticipatory synergy adjustments. Indices of variance, which did not affect the task (within the UCM), correlated with motor equivalent motion between the steady states prior to and after the force pulse; in contrast, variance affecting task performance did not correlate with non-motor equivalent motion. The observations are discussed within the framework of hierarchical control with referent coordinates for salient effectors at each level. The findings suggest that multi-finger synergies are defined at the level of abundant transformation between the low-dimensional hand level and higher dimensional finger level while being relatively immune to transformations between the finger level and muscle level. The results also support the scheme of control with two classes of neural variables that define referent coordinates and gains in back-coupling loops between hierarchical control levels. PMID- 29532102 TI - Is it time to change our vision of tumor metabolism prior to immunotherapy? PMID- 29532101 TI - Diagnostic performance and impact on patient management of 68Ga-DOTA-TOC PET/CT for detecting osteomalacia-associated tumours. AB - PURPOSE: Oncogenic osteomalacia is an endocrine disorder induced by small benign tumours (TIO) producing excessive fibroblast growth factor-23 (FGF23). The only way of curing oncogenic osteomalacia is surgical resection of the culprit TIO, which is extremely difficult to detect using conventional imaging modalities due to its small size and variable location in the body. Since TIO frequently overexpress somatostatin receptors, a clinical utility of SPECT or PET with radiolabelled somatostatin analogues has been reported. Among them, 68Ga-DOTA-TOC has recently been granted a marketing authorization, facilitating its routine application. We report here the results of the first series evaluating the diagnostic performance of 68Ga-DOTA-TOC PET/CT in detecting TIO and its impact on patient management. METHODS: 68Ga-DOTA-TOC PET/CT and clinical and imaging data from 15 patients with clinical and biochemical signs of oncogenic osteomalacia were retrospectively reviewed. The 68Ga-DOTA-TOC PET/CT findings were compared with the results of post-surgical pathology and clinical and biochemical follow up. RESULTS: 68Ga-DOTA-TOC PET/CT resulted in the detection of one focus suspicious for TIO in nine of 15 patients (60%), and a tumour was surgically removed in eight. Post-operative pathology confirmed a TIO in those eight patients whose symptoms diminished promptly and biochemical anomalies resolved. 68Ga-DOTA-TOC PET/CT sensitivity, specificity and accuracy were 73%, 67% and 71%, respectively. 68Ga-DOTA-TOC PET/CT findings affected patient management in 67% of cases. In particular, 68Ga-DOTA-TOC PET/CT was able to detect the TIO with a negative or a false-positive result of a previous 111In-pentetreotide SPECT/CT in 5/8 patients (63%) or a previous FDG PET/CT in 7/11 patients (64%). No close relationship was found between the positivity of 68Ga-DOTA-TOC PET/CT and the serum level of a biochemical marker. However, a true-positive result of 68Ga-DOTA TOC PET/CT was obtained in only one patient with a non-elevated serum level of FGF23. CONCLUSION: 68Ga-DOTA-TOC PET/CT is an accurate imaging modality in the detection of TIO; in particular, it is worthwhile after failure of somatostatin receptor SPECT(/CT) or FDG PET/CT. PMID- 29532103 TI - Integrated network analysis reveals the importance of microbial interactions for maize growth. AB - Microbes play a critical role in soil global biogeochemical circulation and microbe-microbe interactions have also evoked enormous interests in recent years. Utilization of green manures can stimulate microbial activity and affect microbial composition and diversity. However, few studies focus on the microbial interactions or detect the key functional members in communities. With the advances of metagenomic technologies, network analysis has been used as a powerful tool to detect robust interactions between microbial members. Here, random matrix theory-based network analysis was used to investigate the microbial networks in response to four different green manure fertilization regimes (Vicia villosa, common vetch, milk vetch, and radish) over two growth cycles from October 2012 to September 2014. The results showed that the topological properties of microbial networks were dramatically altered by green manure fertilization. Microbial network under milk vetch amendment showed substantially more intense complexity and interactions than other fertilization systems, indicating that milk vetch provided a favorable condition for microbial interactions and niche sharing. The shift of microbial interactions could be attributed to the changes in some major soil traits and the interactions might be correlated to plant growth and production. With the stimuli of green manures, positive interactions predominated the network eventually and the network complexity was in consistency with maize productivity, which suggested that the complex soil microbial networks might benefit to plants rather than simple ones, because complex networks would hold strong the ability to cope with environment changes or suppress soil-borne pathogen infection on plants. In addition, network analyses discerned some putative keystone taxa and seven of them had directly positive interactions with maize yield, which suggested their important roles in maintaining environmental functions and in improving plant growth. PMID- 29532105 TI - Reply to Commentaries on: Management of Tuberous Breast Deformities-Review of Long-Term Outcomes and Patient Satisfaction with Breast-Q. PMID- 29532104 TI - Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin alphavbeta6 inhibitor, in healthy participants. AB - PURPOSE: Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the alphavbeta6 integrin for the treatment of IPF. The phase 1 first time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants. METHODS: Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1-3000 mcg given by nebulisation. RESULTS: A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100-3000 mcg). Dose normalised geometric mean Cmax increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety. CONCLUSIONS: In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300-3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF. PMID- 29532106 TI - Elimination of Aesthetic Deformations of the Midface Area Our Experience. AB - INTRODUCTION: The aesthetic manifestations of the aging process in the cheekbone, cheek and infraorbital areas are especially concerning for patients, so rejuvenating interventions in these areas are most in demand. OBJECTIVE: To introduce the experience of our clinic for aesthetic manipulation using Aptos (anti-ptosis) thread lifting methods in the midface area. METHODS: Among the surgical interventions that we used were Aptos thread lifting methods both in combination with lower blepharoplasty, and without it. At the same time, special attention was paid to the individual approach, trying to minimize invasiveness and, most importantly, trying to achieve the effect of moving subcutaneous soft tissues to a new, more advantageous position from an aesthetic point of view, with their fixation to dense structures. RESULTS: The results of application of the presented methods to lift the cheek-zygomatic and infraorbital regions using Aptos methods were studied. In the overwhelming majority of cases, the results satisfied both surgeons and patients. CONCLUSIONS: Aptos methods for lifting the midface soft tissues, which we used, are quite effective for rejuvenating the aging face. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29532107 TI - Maturation of the QT Variability Index is Impaired in Preterm Infants. AB - Reduced heart rate (HR) variability in preterm infants compared with full-term infants suggests that autonomic cardiac control is developmentally delayed. However, the association between developmental changes in myocardial repolarization and gestational age remains unknown. This study investigated the association between the myocardial repolarization lability index, namely the QT variability index (QTVI) = log10 [(QTv/QTm2)/(HRv/HRm2)], and the perinatal profile of healthy 1-month-old infants. We included 209 infants (143 boys and 87 girls; mean gestational weeks at birth, 38.6 +/- 1.7) who were born in university hospitals between 2014 and 2015 without apparent cardiac disease. We compared the ECG variability indices in 28 infants born before 37 gestational weeks (mean gestational weeks at birth, 35.6 +/- 1.1 as preterm) and 181 infants born at the average number of gestational weeks (mean gestational weeks at birth, 38.8 +/- 1.1 as controls). There was a negative correlation between the QTVI and gestational weeks (r = - 0.460, p = 0.035). QTVI values in preterm infants were larger than those in the controls (0.01 +/- 0.50 vs. -0.26 +/- 0.48, p = 0.023). In conclusion, the QTVI is negatively correlated with gestational age. The QTVI can serve as an index of the maturity of the cardiac autonomic nervous system and myocardial depolarization. PMID- 29532108 TI - [Dependency of APHAB score in the ECu subscale on age, gender and subjective hearing loss : Hearing aid fitting in two subjective hearing loss groups]. AB - OBJECTIVE: The Abbreviated Profile of Hearing Aid Benefit (APHAB) determines subjective impairment by hearing loss in four situations before and after hearing aid fitting. The first part (APHABu) of the questionnaire can be used independently of hearing aid fitting. Previous research has demonstrated that the answers in the ECu subscale for hearing under easy conditions are concentrated in two groups: one with subjectively better, one with subjectively worse hearing. This study aimed to investigate in a large collective whether there are differences between these two groups in terms of age, gender, and individual hearing loss. PATIENTS AND METHODS: The data of 1755 patients were analyzed, whose APHAB answers and pure-tone thresholds had been collected during hearing aid fitting. Group 1 had an average ECu score <=37.5%; in group 2 it was >=67.5%. The individual hearing losses was determined. Statistical analysis was performed using Mann-Whitney U, chi2, Spearman, and Pearson tests. RESULTS: The 616 members of group 1 were significantly younger (68.7 vs. 73.0 years) and comprised more females (53.9 vs. 46.1%) than the 1139 members of group 2. Hearing was frequency specific in group 1, and hearing loss as classified using standard audiograms and according to the three-frequency table was significantly lower in group 1 than in group 2, CONCLUSION: The distribution with two maximums in the ECu subscale can be explained by individual differences in terms of age and hearing loss, in part also by gender. The lower absolute number of patients in group 1 could be explained by the still relatively late fitting of hearing aids in general. PMID- 29532110 TI - Glycoengineering of Mammalian Expression Systems on a Cellular Level. AB - Mammalian expression systems such as Chinese hamster ovary (CHO), mouse myeloma (NS0), and human embryonic kidney (HEK) cells serve a critical role in the biotechnology industry as the production host of choice for recombinant protein therapeutics. Most of the recombinant biologics are glycoproteins that contain complex oligosaccharide or glycan attachments representing a principal component of product quality. Both N-glycans and O-glycans are present in these mammalian cells, but the engineering of N-linked glycosylation is of critical interest in industry and many efforts have been directed to improve this pathway. This is because altering the N-glycan composition can change the product quality of recombinant biotherapeutics in mammalian hosts. In addition, sialylation and fucosylation represent components of the glycosylation pathway that affect circulatory half-life and antibody-dependent cellular cytotoxicity, respectively. In this chapter, we first offer an overview of the glycosylation, sialylation, and fucosylation networks in mammalian cells, specifically CHO cells, which are extensively used in antibody production. Next, genetic engineering technologies used in CHO cells to modulate glycosylation pathways are described. We provide examples of their use in CHO cell engineering approaches to highlight these technologies further. Specifically, we describe efforts to overexpress glycosyltransferases and sialyltransfereases, and efforts to decrease sialidase cleavage and fucosylation. Finally, this chapter covers new strategies and future directions of CHO cell glycoengineering, such as the application of glycoproteomics, glycomics, and the integration of 'omics' approaches to identify, quantify, and characterize the glycosylated proteins in CHO cells. Graphical Abstract. PMID- 29532109 TI - Characteristics of slow progression to diabetes in multiple islet autoantibody positive individuals from five longitudinal cohorts: the SNAIL study. AB - AIMS/HYPOTHESIS: Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. METHODS: Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using the chi2 test. RESULTS: In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. CONCLUSION: No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes. PMID- 29532111 TI - Sigmoid sinus dehiscence and suspected idiopathic intracranial hypertension in pulsatile tinnitus? PMID- 29532112 TI - Implant and limb survival after resection of primary bone tumors of the lower extremities and reconstruction with mega-prostheses fifty patients followed for a mean of forteen years. AB - PURPOSE: Previous studies reported variable outcome and failure rates after mega prosthetic reconstructions in the lower extremities. The purpose of this study was to make a long-term single-center evaluation of patients treated with limb sparing surgery and reconstruction with mega-prostheses in the lower extremities. METHODS: We identified 50 patients (osteosarcoma (n = 30), chondrosarcoma (n = 9), osteoclastoma (n = 6), Ewing sarcoma (n = 4), angiosarcoma (n = 1)), who underwent limb-sparing reconstruction of the lower extremities (proximal femur (n = 9), distal femur (n = 29), proximal tibia (n = 9), and the entire femur (n = 3)) between 1985 and 2005. Surviving patients not lost to follow-up were evaluated using the MSTS score. Causes of failure were classified according to the Henderson classification. Kaplan-Meier survival analysis was used for evaluation of patient, prosthesis, and limb survival. RESULTS: Twenty-eight patients were alive at follow-up. Fifty-four percent had revision surgery (n = 27). The ten year patient survival was 60% (95%CI 46-74%); the ten year implant survival was 24% (95%CI 9-41%), and the ten year limb survival rate was 83% (95%CI 65-96%). Type 1 failure occurred in 9%, type 2 in 16%, type 3 in 28%, type 4 in 18%, and type 5 in 3%. Mean MSTS score was 21 (range, 6-30), representing a median score of 71%. CONCLUSIONS: Our long-term results with mega-prostheses justify the use of limb-salvage surgery and prosthetic reconstruction. Our results are fully comparable with other findings, with regard to limb and prosthesis survival, but also with regard to functional outcome. PMID- 29532113 TI - Anterior cruciate ligament reconstruction in patients older than fifty years: a comparison with a younger age group. AB - PURPOSE: To evaluate functional and radiological results in patients older than 50 years who underwent an anatomic anterior cruciate ligament (ACL) reconstruction with semitendinosus and gracilis tendons and to compare these results with those of patients younger than 40 years. METHODS: Thirty-six patients over the age of 50 years with a diagnosis of ACL complete lesion and 36 consecutive patients under 40 years were included in this prospective study. Follow-up included clinical evaluation using Lysholm, IKDC, and Tegner scores and a KT-1000 arthrometric evaluation. Bilateral weight-bearing radiographs were obtained before surgery and at final follow-up of five years to evaluate the degree of osteoarthritis. All patients were evaluated at a one year follow-up (T1) (range 13-17 months) and at final follow-up (T2) (range 60-72 months). RESULTS: No statistically significant difference was found between the two groups at the subjective and objective evaluations. At a KT-1000 arthrometric evaluation, the mean side to side maximum manual difference was 1.6 mm in the over 50 (group I) and 2.7 mm in the under 40 (group II) (p = 0.009). At 30 lb, the mean side to side difference was 1.7 mm in the over 50 group and 2.6 mm in the under 40 group (p = 0.040). No statistically significant increase in the degree of osteoarthritis was found at follow-up in the over 50 group. CONCLUSIONS: The results of this study seems to confirm that ACL reconstruction in patients older than 50 years is a safe procedure with good to excellent subjective, objective, and radiological outcomes that are comparable to those for younger patients. PMID- 29532114 TI - Peri-operative complications of lumbar spine surgery in patients over eighty five years of age: a retrospective cohort study. AB - PURPOSE: To compare peri-operative complication rates in >= 85-year-old patients who underwent decompression surgery with or without instrumented fusion for degenerative disorders. METHODS: This study involved 907 patients who underwent lumbar spine surgery for degenerative disorders between January 2006 and June 2012. Of these, 33 patients (3.6% of the entire population) were over 85 years of age (85-94 years). Decompression-alone and instrumentation groups were compared in terms of comorbidities, American Society of Anesthesiologists (ASA)-physical status (PS) class, peri-operative complications, and Japanese Orthopedic Association (JOA) scores. RESULTS: Thirty-three >= 85-year-old patients underwent surgery. All were ASA-PS class 2 (94%) or 3. The decompression-alone (n = 19) and instrumentation (n = 14) groups did not differ in comorbidity (95 vs. 100%, P = 0.383) or ASA-PS class (P = 0.561). Both exhibited improved JOA scores (decompression-alone: 13.4/29 to 22.7/29; instrumentation: 8.6/29 to 17.9/29; P = 0.9068) and had similar peri-operative complication rates (21.0 vs. 28.5%, P = 0.374). CONCLUSIONS: Although instrumentation is considered more invasive than decompression, we detected no statistically significant differences in peri operative complication rates between these two types of surgery in >= 85-year-old patients. Surgeons should perform instrumentation even in the patients over 85 years with ASA class 3 or less. PMID- 29532115 TI - [Inflammatory changes of the foot]. AB - BACKGROUND: Inflammatory changes of the foot are comparatively rare and can be a challenge for radiologists with respect to the differential diagnosis, especially in cases with pre-existing degenerative changes of the foot skeleton. Comprehensive anamnesis and the use of contrast-enhanced MRI diagnostics are therefore often essential for diagnosis. OBJECTIVES: This review provides a cursory overview of the morphological characteristics of inflammatory changes of the foot and their differential diagnoses with a focus on osteomyelitis, joint infections, rheumatological diseases and tenosynovitis. PMID- 29532116 TI - An NB-LRR gene, TYNBS1, is responsible for resistance mediated by the Ty-2 Begomovirus resistance locus of tomato. AB - KEY MESSAGE: An NB-LRR gene, TYNBS1, was isolated from Begomovirus-resistance locus Ty-2. Transgenic plant analysis revealed that TYNBS1 is a functional resistance gene. TYNBS1 is considered to be synonymous with Ty-2. Tomato yellow leaf curl disease caused by Tomato yellow leaf curl virus (TYLCV) is a serious threat to tomato (Solanum lycopersicum L.) production worldwide. A Begomovirus resistance gene, Ty-2, was introduced into cultivated tomato from Solanum habrochaites by interspecific crossing. To identify the Ty-2 gene, we performed genetic analysis. Identification of recombinant line 3701 confirmed the occurrence of a chromosome inversion in the Ty-2 region of the resistant haplotype. Genetic analysis revealed that the Ty-2 gene is linked to an introgression encompassing two markers, SL11_25_54277 and repeat A (approximately 200 kb). Genomic sequences of the upper and lower border of the inversion section of susceptible and resistant haplotypes were determined. Two nucleotide-binding domain and leucine-rich repeat-containing (NB-LRR) genes, TYNBS1 and TYNBS2, were identified around the upper and lower ends of the inversion section, respectively. TYNBS1 strictly co-segregated with TYLCV resistance, whereas TYNBS2 did not. Genetic introduction of genomic fragments containing the TYNBS1 gene into susceptible tomato plants conferred TYLCV resistance. These results demonstrate that TYNBS1 is a functional resistance gene for TYLCV, and is synonymous with the Ty-2 gene. PMID- 29532117 TI - Commentary on "Comparison of adjustable continence therapy periurethral balloons and artificial urinary sphincter in female patients with stress urinary incontinence due to intrinsic sphincter deficiency". PMID- 29532118 TI - Response to comment by Petros: anatomy and cure of descending perineum syndrome. PMID- 29532119 TI - Reply to Wael Agur letter to the editor re: Gamal Ghoniem and Diaa Rizk, "Renaissance of the autologous pubovaginal sling" International Urogynecology Journal, 29 (2) 177-178. PMID- 29532120 TI - Re: Renaissance of the autologous pubovaginal sling. PMID- 29532121 TI - Impact of subsequent pregnancies on pelvic floor functional anatomy. AB - INTRODUCTION AND HYPOTHESIS: Vaginal childbirth clearly has an effect on pelvic floor anatomy, and pregnancy itself also likely plays a role. This study investigated the effects of consecutive pregnancies by comparing pelvic organ support and function in urogynecological patients delivered by cesarean section (CS) only. METHODS: This was a retrospective study using 161 archived data sets of urogynecological patients delivered exclusively by CS presenting with symptoms of pelvic floor dysfunction between 2007 and 2015. Patients had undergone an interview, clinical examination using the Pelvic Organ Prolapse Quantification (POP-Q) system, and 3D/4D translabial ultrasound (TLUS) using Voluson systems. Measures of functional pelvic floor anatomy were obtained from stored ultrasound (US) volumes at a later date, using proprietary software, and blinded against all other data. RESULTS: One hundred and sixty-one women delivered exclusively by CS were seen in a urogynecological clinic. Volume data analysis was possible in 151 patients. Mean age was 52 (26-82) years, with a mean body mass index (BMI) of 29.5 (18.4-48.7) kg/m2. Forty-three (28.5%) women had one CS, 67 (44.4%) had two, and 41 (27.1%) had three or more. On multivariate analysis, adjusting for age, BMI, history of hysterectomy, and incontinence or prolapse surgery, there were no significant differences between groups. CONCLUSIONS: On comparing women with one, two, or three or more CS, we found no significant differences in any measured sonographic parameters of pelvic organ descent and pelvic floor muscle function. This implies that subsequent pregnancies after the first are unlikely to exert significant additional effects on pelvic floor functional anatomy. PMID- 29532122 TI - Can maximal voluntary pelvic floor muscle contraction reduce vaginal resting pressure and resting EMG activity? AB - INTRODUCTION AND HYPOTHESIS: The purpose of the present study was to assess whether attempts at a maximal voluntary pelvic floor muscle (PFM) contraction can reduce vaginal resting pressure (VRP) and surface EMG activity in women with and without provoked vestibulodynia (PVD). METHOD: An assessor blinded comparison study included 35 women with and 35 women without PVD. VRP and PFM strength were measured with a high precision pressure transducer connected to a vaginal balloon (Camtech AS, Sandvika Norway). PFM activity was measured before and after three MVCs with surface EMG (NeuroTrac ETSTM; Verity Medical, Romsey, UK). Paired sample t test was used to analyze differences within groups and independent sample t test to analyze differences between groups. p value was set at <0.05. RESULTS: Mean age of the participants was 24.3 years (SD 4.7) and mean BMI was 22.0 kg/m2 (SD 2.6). There were no significant differences between the groups in any background variables. PFM contraction led to a statistically significant reduction of VRP in both the PVD (p = 0.001) and the control group (p = 0.027). Surface EMG activity was significantly reduced in the PVD group only (p = 0.001). DISCUSSION: Young, nulliparous women with PVD had significantly lower vaginal resting pressure and sEMG activity after three maximum contractions of the PFM. The results indicate that attempts at voluntary maximal contractions may be investigated as a method of reducing PFM hypertonicity. PMID- 29532123 TI - Collagen XVIII and LOXL-4 polymorphisms in women with and without advanced pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: We verified the presence of single nucleotide polymorphisms (SNP) rs2236479 of the collagen 18 (COL18A1) and rs2862296 of the lysyl oxidase-like 4 (LOXL-4) genes and the association with pelvic organ prolapse (POP) in Brazilian women and determined risk factors for POP development. METHODS: We assessed 532 postmenopausal women divided into POP (stages III and IV) and control (stages 0 and I) groups by examination and peripheral blood sample collection. DNA sequences of interest were analyzed by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). We used logistic regression models for the analyses, with p < 0.005 for significance. RESULTS: The frequency of homozygous polymorphic alleles (AA) in COL18A1 and (GG) in LOXL-4 were similar in both groups (17.5% and 15.4% for COL18A1 and 18.9% and 20.6% for LOXL-4, respectively). There were no associations between those polymorphisms or other genotypes and POP. Multiple logistic regression analysis identified age [odds ratio (OR) = 1.10, confidence interval (CI) 95% = 1.07; 1.14), number of vaginal births (OR = 1.66, CI 95% = 1.36; 2.03), and family history (OR = 2.55 CI 95% = 1.43; 4.55) as independent risk factors for POP. CONCLUSION: Our study suggests lack of association between DNA polymorphisms rs2236479 of COL18A1 and rs2862296 of LOXL-4 with advanced POP in this population. PMID- 29532124 TI - The use of synthetic mesh for vaginal prolapse in the UK: a review of cases submitted to the British Society of Urogynaecology database. AB - INTRODUCTION AND HYPOTHESIS: The use of mesh for vaginal prolapse gained popularity during the 1990s. More recently, concerns have been raised regarding the safety of mesh procedures. Mesh can be inserted vaginally, laparoscopically or via an open abdominal route, but there are few data comparing the outcomes. Most previous published data relate to small numbers of procedures. METHODS: This was a review of data submitted to the British Society of Urogynaecology (BSUG) database of all cases reporting the use of mesh placed vaginally or abdominally (open or laparoscopic) between January 2006 and December 2016. The primary outcome was based on the reported patient global impression of improvement (PGI I). RESULTS: A total of 6,709 cases of mesh prolapse repair were entered during the study period. Women in the laparoscopic group had a lower BMI and were younger. Significantly more patients in the open group (96.4%) described themselves as very much better or much better compared with the laparoscopic group (91%) and the vaginal mesh group (90.7%; p < 0.001). Only 0.5% of patients reported that they were worse or very much worse. CONCLUSIONS: This dataset suggests that the effectiveness of mesh repair might be good regardless of the route of insertion. The improvement in PGI-I seems to be greatest with open sacrocolpopexy. PMID- 29532125 TI - Rectocele plication: description of a novel surgical technique and review of clinical results. AB - INTRODUCTION AND HYPOTHESIS: A rectocele is the bulging of the anterior rectal wall into the posterior vaginal compartment. The route of surgical repair can be transvaginal, transrectal or abdominal. The aim of this retrospective study is to describe a novel transvaginal surgical procedure and investigate the associated subjective and objective clinical outcomes. METHODS: Database records were retrieved for all women who underwent a rectocele plication for the period from January 2010 until December 2015 in a referral urogynecology unit with a minimum follow-up period of 12 months. This transvaginal technique entails a plication of the anterior rectal wall by suturing of the rectal muscularis layer. Clinical findings and quality of life (QOL) metrics were evaluated and reported on. RESULTS: One hundred thirty-nine women met the initial inclusion criteria with full data available for 123. The presenting symptoms included a vaginal bulge in 73 (52.5%), overactive bladder (OAB) in 73 (52.5%), obstructed defecation (OD) in 49 (35.3%) and anal incontinence (AI) in 35 (25.2%). The majority of women (n = 72, 51.8%) had stage 3-4 posterior prolapse. The mean follow-up period was 27 +/- 15 months. The postoperative symptoms were significantly improved for all, except AI (p = 0.43). There was a significant improvement in posterior prolapse (p < 0.001) with the majority of women noted to have a stage 0 or 1 (n = 109; 88.6%) posterior prolapse at follow-up. CONCLUSIONS: The rectocele plication is a novel surgical technique with good subjective and objective clinical outcomes in the medium term. PMID- 29532126 TI - The Manchester procedure: anatomical, subjective and sexual outcomes. AB - INTRODUCTION AND HYPOTHESIS: Classical native-tissue techniques for pelvic organ prolapse (POP) repairs, such as the Manchester procedure (MP), have been revitalized because of vaginal mesh complications. However, there are conflicting opinions regarding sufficient apical (mid-compartment) support by the MP and concerns about the risk of dyspareunia. The aims of this study were therefore to investigate anatomical and patient-reported outcomes 1 year after MP. METHODS: Prospective cohort study of 153 females undergoing an MP for anterior compartment POP between October 2014 and June 2016. Pre- and 1-year postoperative evaluations included POP-Q measurements and the questionnaires Pelvic Floor Distress Inventory Short Form 20 (PFDI-20) and POP/Urinary Incontinence Sexual Questionnaire (PISQ-12). RESULTS: At 1 year, 97% (148/153) attended the follow up. Significant anatomical improvements (p < 0.01) were obtained in all compartments. Mean Ba was -1.1 (+/- 1.4), mean C -5.9 (+/- 1.7) and mean D -7.0 (+/- 1.2) at follow-up. Point C <= -5 was present in 81.1%. POP-Q stage 0-1 was obtained in 99.3% in the mid-compartment (C < -1), but only in 48.6% in the anterior compartment (Ba < -1). A significant reduction in symptom scores was obtained for PFDI-20 (p < 0.01) and PISQ-12 (p = 0.01). No significant changes were seen in dyspareunia rates (q.5, PISQ-12), but 5.6% reported de novo dyspareunia. Concerning POP symptoms, 96.0% reported being cured or significantly improved. CONCLUSIONS: The Manchester procedure provides adequate apical support, albeit inferior anatomical anterior compartment results, and 96.0% reported being subjectively cured or substantially better at 1-year follow-up, with no significant change in dyspareunia. PMID- 29532127 TI - Commentary on: Influence of body mass index on short-term subjective improvement and risk of reoperation after mid-urethral sling surgery. PMID- 29532128 TI - Method and reliability of measuring midurethral area and echogenicity, and changes during and after pregnancy. AB - INTRODUCTION AND HYPOTHESIS: Internal closure of the urethral sphincter is one of the mechanisms in maintaining continence. Little is known about changes in the urethral sphincter during pregnancy. We designed this study to develop a reliable method to measure the area and mean echogenicity of the midurethra during and after pregnancy and to assess changes over time. METHODS: Two observers independently segmented the urethra as follows: in the sagittal plane, the urethra was positioned vertically, the marker was placed in the middle section of the lumen of the urethra, and eight tomographic US images of 2.5 -mm slices were obtained. The central image was selected, and area and mean echogenicity were calculated automatically. Intra- and interobserver reliability were determined by intraclass correlation coefficients (ICC) and their 95% confidence intervals (CI). Two hundred and eighty women underwent TPUS at 12 weeks and 36 weeks of gestation and 6 months postpartum, and 3D/4D transperineal ultrasound (TPUS) images of 40 pregnant nulliparous women were used for the reliability study. Paired t tests were used to assess changes in echogenicity and area. RESULTS: The ICC for measuring the area was substantial, at 0.77 and for measuring mean echogenicity was almost perfect, at 0.86. In the total study group (n = 280), midurethral area and mean echogenicity were significantly lower 6 months after delivery compared with 12 and 36 weeks of gestation. CONCLUSIONS: Our protocol for measuring area and mean echogenicity of the midurethra is reliable. This study indicates that structural changes in the midurethraoccur during pregnancy. PMID- 29532129 TI - Morbidity rate and medical utilization in interstitial cystitis/painful bladder syndrome. AB - INTRODUCTION AND HYPOTHESIS: The objective was to calculate the morbidity rate and medical utilization of interstitial cystitis/painful bladder syndrome (IC/PBS) over 12 years using a nationwide database of Taiwan. METHODS: This was a cohort study of the Longitudinal Health Insurance Database 2010 with new diagnoses of IC/PBS from 2002 through 2013. The morbidity rate was adjusted for age, sex, and calendar date using density methods. Moreover, medical utilization during the study period was measured. RESULTS: It was observed that the incidence of IC/PBS was 21.8/100,000 in 2002 and 21.1/100,000 in 2013. The prevalence of IC/PBS was 21.8/100,000 in 2002 and 40.2/100,000 in 2013. In 2003, the incidence and prevalence of women was 28.6/100,000 and 63.5/100,000 respectively. The incidence and prevalence of men was 12.3/100,000 and 19.4/100,000 respectively. In 2002, the incidence was 45.5/100,000, 32.4/100,000, and 9/100,000 in the age groups above 65, 40-65, and under 40 years respectively. The prevalence in 2003 was 86.3/100,000, 63.1/100,000, and 16.4/100,000 in age groups above 65, 40-65, and under 40 years respectively. This pattern was similar until 2013. The mean outpatient and inpatient visit time was 4.8 and 1.8 times per year respectively. The mean surgical fee (US$ 246.6 +/- 304.5) was 23.6% of the total fee. CONCLUSIONS: The morbidity rate of IC/PBS showed a higher incidence and prevalence in women and older patients. A new drug for the treatment of IC/PBS may be a factor of the peak in the morbidity rate. The increase in medical utilization could be explained by the awareness of physicians and patients seeking medical help. PMID- 29532130 TI - Depression and risk of fracture and bone loss: an updated meta-analysis of prospective studies. AB - : This meta-analysis pooled results from 23 qualifying individual cohort studies and found that depression was significantly associated with an increased risk of fractures and bone loss. INTRODUCTION: The association between depression and risk of fracture remains controversial. We conducted a comprehensive meta analysis to examine the effect of depression on the risk of osteoporotic fractures and bone loss. METHODS: We searched databases and reviewed citations in relevant articles for eligible cohort studies. Two investigators independently conducted study selection, appraisal, and data abstraction through the use of a standardized protocol. Random effect models were used for meta-analysis. Cochrane Q and I2 statistics were used to assess heterogeneity. Funnel plots and rank correlation tests were used to evaluate publication bias. RESULTS: Twenty-three studies were included for meta-analysis. In studies that reported hazard ratio (HR) as the outcome (nine studies [n = 309,862]), depression was associated with 26% increase in fracture risk (HR = 1.26, 95% CI, 1.10-1.43, p < 0.001). Studies that reported risk ratio (RR) as the outcome (seven studies [n = 64,975]) suggested that depression was associated with 39% increase in fracture risk (RR = 1.39, 95% CI, 1.19-1.62, p < 0.001). Among studies that reported hip bone mineral density (BMD) as an outcome (eight studies [n = 15,442]), depression was associated with a reduced mean annual bone loss rate of 0.35% (0.18-0.53%, p < 0.001). The increased risk of fracture and bone loss associated with depression was consistent in all meta-analysis having modified inclusion criteria and in different subgroup analyses as well. Significant heterogeneity was observed in the meta-analysis; however, no significant publication bias was detected. CONCLUSION: Depression is associated with a significant increased risk in fracture and bone loss. Effective prevention may decrease such risk. PMID- 29532131 TI - The relationship between objectively assessed physical activity and bone health in older adults differs by sex and is mediated by lean mass. AB - : Relationships between objectively assessed free-living physical activity (PA) and changes in bone health over time are poorly understood in older adults. This study suggests these relationships are sex-specific and that body composition may influence the mechanical loading benefits of PA. INTRODUCTION: To investigate associations of objectively assessed PA and bone health in community-dwelling older adults. METHODS: This secondary analysis of a subset of the Tasmanian Older Adult Cohort study included participants with PA assessed utilising ActiGraph GT1M accelerometers over 7 days (N = 209 participants, 53% female; mean +/- SD age 64.5 +/- 7.2 years). Steps/day and PA intensity were estimated via established thresholds. Bone mineral content (BMC) was acquired at the total hip, lumbar spine, legs and whole body by DXA at baseline and approximately 2.2 years later. Relationships between PA and BMC were assessed by multivariable linear regression analyses adjusted for age, smoking status, height and total lean mass. RESULTS: Men with above-median total hip BMC completed significantly less steps per day, but there was no significant difference in PA intensity compared with those with below-median BMC. There were no significant differences in PA in women stratified by median BMC. In women, steps/day were positively associated with leg BMC (B = 0.178; P = 0.017), and sedentary behaviour was negatively associated with leg BMC (- 0.165; 0.016) at baseline. After adjustment for confounders including lean mass and height, higher sedentary behaviour at baseline was associated with declines in femoral neck BMC (- 0.286; 0.011) but also with increases in pelvic BMC (0.246; 0.030) in men and increases in total hip BMC (0.215; 0.032) in women, over 2.2 years. No other significant longitudinal associations were observed after adjustment for body composition. CONCLUSIONS: Associations of accelerometer-determined sedentary behaviour and PA with bone health in older adults differ by sex and anatomical site and are mediated by body composition. PMID- 29532132 TI - Optimization of Field and Laboratory Sample Processing for Characterization of Metallic Residues at Military Training Ranges. AB - Military ranges are unlike many waste sites because the contaminants, both energetics and metals, are heterogeneously distributed in soil during explosive detonation or ballistic impact and cannot be readily characterized using conventional grab sampling. The Incremental Sampling Methodology (ISM) has been successful for characterization of energetic contamination in soils, but no published ISM processing studies for soils with small arms range metals such as Pb, Cu, Sb, and Zn exists. This study evaluated several ISM sample-processing steps: (1) field splitting to reduce the sample mass shipped to the analytical laboratory, (2) necessity of milling, and (3) processing a larger subsample mass for digestion in lieu of milling. Cone-and-quartering and rotary sectorial splitting techniques yielded poor precision and positively skewed distributions. Hence, an increase in digestion mass from 2 to 10 g was evaluated with milled and unmilled samples. Unmilled samples yielded results with the largest variability regardless of aliquot mass. PMID- 29532133 TI - [Uncertain, reddish plaque on the left sole of the foot]. PMID- 29532134 TI - [Clarification of terms for wound treatment : Recommendations of the Initiative Chronische Wunde (ICW) e. V.] PMID- 29532135 TI - [Octenidine dihydrochloride : The antiseptic that does not like every base formulation]. PMID- 29532136 TI - [Survey on the diagnostics and therapy of patients with lymphedema and lipedema]. AB - BACKGROUND: Implementation of guideline recommendations for the diagnosis and therapy of lipedema and lymphedema seems to be problematic in daily routine. Systematic data for Germany are missing. The aim of the study was data collection regarding diagnosis and therapy of lymphologic diseases in an outpatient setting. METHODS: Monocentric, prospective survey of patients from a lymphologic outpatient clinic using a standardized questionnaire focusing on diagnostics and therapy at the initial diagnosis. RESULTS: In all, 72 patients (83.3% women) with lymphedema (n = 26), lipedema (n = 14) or lipolymphedema (n = 32) were included; 44.4% had symptoms more than 5 years before the initial diagnosis. Main symptoms were swelling of the leg and foot (especially lymphedema) and feeling of heaviness (especially lipedema). In 75%, the initial diagnosis was made by a medical specialist. The basic diagnostics recommended by the guidelines-medical history (73.6%) and clinical examination (84.7%)-were done in most of the patients. After the initial diagnosis, 46% of the patients had decongestion therapy of different intensity and quality. A total of 58.3% of the patients were directly provided a prescription for a medical stocking. Only a few patients received instructions for breathing exercises (22.2%), self-performed lymphatic drainage (6.9%) or muscle exercises (8.3%). DISCUSSION: There are still deficits in the diagnosis and especially in the therapy of patients with lymphologic diseases in an outpatient setting. Further education and training are necessary for physicians, physiotherapists, medical supply businesses, and patients. PMID- 29532137 TI - Interaction studies of a protein and carbohydrate system using an integrated approach: a case study of the miniagrin-heparin system. AB - The major challenges in biophysical characterization of human protein carbohydrate interactions are obtaining monodispersed preparations of human proteins that are often post-translationally modified and lack of detection of carbohydrates by traditional detection systems. Light scattering (dynamic and static) techniques offer detection of biomolecules and their complexes based on their size and shape, and do not rely on chromophore groups (such as aromatic amino acid sidechains). In this study, we utilized dynamic light scattering, analytical ultracentrifugation and small-angle X-ray scattering techniques to investigate the solution properties of a complex resulting from the interaction between a 15 kDa heparin preparation and miniagrin, a miniaturized version of agrin. Results from dynamic light scattering, sedimentation equilibrium, and sedimentation velocity experiments signify the formation of a monodisperse complex with 1:1 stoichiometry, and low-resolution structures derived from the small-angle X-ray scattering measurements implicate an extended conformation for a side-by-side miniagrin-heparin complex. PMID- 29532138 TI - Focus on high energy pelvic trauma. PMID- 29532139 TI - The Impact of the Implementation of the Enhanced Recovery After Surgery (ERAS(r)) Program in an Entire Health System: A Natural Experiment in Alberta, Canada. AB - BACKGROUND: The Enhanced Recovery After Surgery (ERAS) program has been shown to reduce length of stay (LOS) in colorectal surgical patients in randomized trials. The impact outside of trial settings, or in subgroups of patients excluded from trials such as individuals with diabetes, is uncertain. We conducted this study to evaluate the impact of ERAS implementation in Alberta, Canada. METHODS: This is a retrospective cohort study and interrupted time series analysis using linked administrative data to examine LOS and postoperative outcomes in the 12 months pre- and post-implementation of ERAS in 2013 for all adults undergoing elective colorectal surgery. RESULTS: Of 2714 patients (mean age 60.4 years, 55% men) with similar demographics and comorbidity profiles in the pre/post-ERAS time periods, LOS was significantly shorter post-ERAS (8.5 vs. 9.5 days, p = 0.01; - 0.84 days [95% CI - 0.04 to - 1.64 days] after adjustment for age, sex, Charlson comorbidity score, procedure type, surgical approach, and hospital). However, interrupted time series demonstrated no significant level change (p = 0.30) or change in slope (p = 0.63) with ERAS implementation, consistent with continuation of an underlying secular trend of reductions in LOS over time. There were no significant differences (in multivariate analysis or ITS) in risk of 30-day death/readmission (14.3% post vs. 13.5% pre-ERAS, aOR 1.12, 95% CI 0.89-1.40), 30 day death/ED visit (27.2% post vs. 30.0% pre, aOR 0.93, 95% CI 0.78-1.10), or 30 day death/readmission/ED visit (27.8% post vs. 30.6% pre, aOR 0.93, 95% CI 0.78 1.10). The 428 patients with diabetes had longer LOS but exhibited no significant difference post- versus pre-ERAS (10.7 vs. 11.6 days, p = 0.53; p = 0.56 for level change and p = 0.66 for slope change on ITS). CONCLUSION: Although there was a secular trend toward decreasing LOS over time in Alberta, ERAS implementation was not associated with statistically significant changes in LOS or postoperative outcomes for all colorectal surgery patients or for those with diabetes. Our study highlights the importance of evaluating system changes (for both uptake and outcomes) rather than assuming trial benefits will translate directly into practice. Interventions to improve LOS and postoperative outcomes for patients with diabetes undergoing colorectal surgery are still needed even in the ERAS era. PMID- 29532140 TI - A Prospective Comparative Study on Improvement of Hyperthyroid Cardiovascular Dysfunction in Patients Undergoing Total Thyroidectomy Versus Medical Management. AB - INTRODUCTION: Cardiovascular dysfunction (CVD) is a well-recognized complication in patients with hyperthyroidism and is the major cause of mortality. Very few studies have compared the outcome of CVD following different treatment modalities. In this study we intended to compare treatment modalities (antithyroid drugs vs surgery) for reversal of CVD. MATERIALS AND METHODS: Patients with newly detected hyperthyroidism were grouped into, Group I [n = 123, age <60 years, undergoing total thyroidectomy], Group II [n = 42, age <60 years, treated with antithyroid medications] were evaluated with 2D echocardiography, serum N terminal pro brain natriuretic peptide (NT-pro-BNP) at the time of diagnosis (Point A), after achieving euthyroidism (Point B) with antithyroid drugs and 6 months after surgery/continuation of antithyroid medications (Point C). Forty patients (Group III), age < 60 years, undergoing total thyroidectomy for nontoxic benign thyroid nodules served as controls. RESULTS: All groups were age and sex matched. At Point A, CVD was evident in 80/123 (65%) in Group I and 28/42 (66.7%) in Group II. At Point B improvement in CVD occurred in 84/123 (68.3%) in Group and 29/42 (69.04%) in Group II. At Point C dramatic improvement in CVD occurred in 118/123 (95.9%) in Group I, whereas only 33/42 (78.5%) improved in Group II. CVD were comparable between Groups I and II at Point A and Point B (p > 0.05). At Point C there was a significant decrease in all the diastolic dysfunction parameters in Group I, whereas the same was not observed in Group II patients. Systolic dysfunction between Groups II and II had no statistical significance at Point C. CONCLUSION: Total thyroidectomy seems to be the definitive treatment of choice for hyperthyroid cardiac dysfunction with diastolic dysfunction completely reversing at 6 months after TT. PMID- 29532141 TI - Preoperative Smoking Cessation is Integral to the Prevention of Postoperative Morbidities in Minimally Invasive Esophagectomy. AB - BACKGROUND: Preoperative smoking cessation is considered integral to decreasing postoperative morbidities after esophagectomy. To our knowledge, the association of the duration of smoking cessation with the occurrence of postoperative morbidity has never been investigated in minimally invasive esophagectomy (MIE). METHODS: A total of 198 consecutive MIEs for esophageal cancer between June 2011 and December 2017 were eligible for the study. According to the length of smoking cessation, patients were separated into three groups: <= 30, 31-90, and >= 91 days. Incidence of postoperative morbidities was retrospectively analyzed among the groups. RESULTS: In patients with smoking cessation <= 30 days, morbidities of Clavien-Dindo classification (CDc) >= II, severe morbidities of CDc >= IIIb, pneumonia, and any pulmonary morbidities were frequently observed. Morbidities of CDc >= II, pneumonia, and any pulmonary morbidities increased as the length of cessation became shorter. Smoking cessation <= 30 days was a significant risk factor for severe morbidity (hazard ratio [HR] 4.89, 95% confidence interval [CI] 1.993-12.011; P < 0.001). Smoking cessation <= 90 days (HR 3.98, 95% CI 1.442 10.971; P = 0.008), past smoking (per 100 increase in Brinkman index), and cardiovascular comorbidity were significant risk factors for pneumonia. Smoking cessation <= 30 days (HR 3.13, 95% CI 1.351-7.252; P = 0.008) and past smoking were significant risk factors for any pulmonary morbidity. CONCLUSIONS: Preoperative smoking cessation is considerably important to prevent postoperative morbidities, even in MIE. At least, preoperative cessation >= 31 days is preferable to decrease considerable morbidities after MIE. PMID- 29532142 TI - Medial Approach for the Resection of Goiters with Suprahyoid, Retropharyngeal, or Substernal Extension. AB - BACKGROUND: Resection of massive goiters with suprahyoid, retropharyngeal, and substernal extension may not be amenable to standard approaches. This study evaluates a surgical approach allowing resection of massive goiters with minimal substernal and deep neck dissection. METHODS: Cases of thyroidectomy for goiters with substernal, retropharyngeal, or suprahyoid extension at a single institution from 2006 to 2017 were reviewed. The technique involves initial complete division of the medial thyroid tracheal attachments after identification of the RLN medial inferiorly or superiorly. Deep components are then delivered into the superficial paratracheal region of the neck. RESULTS: Sixty patients were included, 46 of which had substernal and 14 had only suprahyoid or retropharyngeal extension. Mean substernal extension was 3.7 cm (range 1.5-7.5 cm). The medial approach was successful in identifying the RLN in 70 (83%) of 84 goiter sides (71% medial inferiorly and 29% superiorly). Standard inferior/lateral approaches were used in 12 (14%) nerves or not found until after goiter removal in 2 (2.5%). No patients required sternotomy or tracheotomy. Complications included postoperative seroma/hematoma (n = 9, 15%) with one re-exploration, transient RLN injury (n = 4, 4% of all lobectomies), transient hypocalcemia (n = 6, 16% of total thyroidectomies), permanent hypocalcemia (n = 2, 5% of total thyroidectomies), and permanent RLN paralysis (n = 1, 1% of all lobectomies). CONCLUSION: Large suprahyoid, retropharyngeal, and substernal goiters were resected transcervically with low morbidity. Early complete division of Berry's ligament after medial inferior RLN identification was achieved in a high proportion of patients, facilitating goiter delivery with minimal mediastinal and deep neck dissection. PMID- 29532144 TI - ? PMID- 29532143 TI - Primary Hyperparathyroidism is Underdiagnosed and Suboptimally Treated in the Clinical Setting. AB - PURPOSE: To evaluate whether patients presenting with laboratory results consistent with primary hyperparathyroidism (pHPT) are managed in accordance with guidelines. METHODS: The laboratory database at a hospital in Sweden, serving 127,000 inhabitants, was searched for patients with biochemically determined pHPT. During 2014, a total of 365 patients with biochemical laboratory tests consistent with pHPT were identified. Patients with possible differential diagnoses or other reasons for not being investigated according to international guidelines were excluded after scrutinizing records, after new blood tests, and clinical assessments by endocrine surgeons. RESULTS: Altogether, 92 patients had been referred to specialists and 82 had not. The latter group had lower serum calcium (median 2.54 mmol/L) and PTH (5.7 pmol/L). Out of these 82 cases, 9 patients were diagnosed with pHPT or had some sort of long-term follow-up planned as outpatients. CONCLUSION: Primary hyperparathyroidism is overlooked and underdiagnosed in a number of patients in the clinical setting. It is important to provide local guidelines for the management of patients presenting with mild pHPT to ensure that these patients receive proper evaluation and follow-up according to current research. PMID- 29532145 TI - Combined effect of whole-body vibration and ambient lighting on human discomfort, heart rate, and reaction time. AB - PURPOSE: This study aimed to investigate the effect of whole-body vibration and ambient lighting, as well as their combined effect on human discomfort, heart rate, and reaction time in laboratory conditions. METHODS: 44 men were recruited with an average age of 25.4 +/- 1.9 years. Each participant was subjected to 12 experimental steps, each step lasting five minutes for four different vibration accelerations in X, Y, and Z axes at a fixed frequency; three different lighting intensities of 50, 500, and 1000 lx were also considered. At each step, a visual computerized reaction test was taken from subjects and their heart rate recorded by pulse oximeter. In addition, the discomfort rate of subjects was measured using Borg scale. RESULTS: Increasing vibration acceleration significantly increased the discomfort rate and heart beat but not the reaction time. Lack of lighting caused more discomfort in the subjects, but there was no significant correlation between lighting intensity with heart rate and reaction time. The results also showed that the combined effect of vibration and lighting had no significant effect on any of the discomfort, heart rate, and reaction time variables. CONCLUSIONS: Whole-body vibration is an important factor in the development of human subjective and physiological reactions compared to lighting. Therefore, consideration of the level of vibration to which an individual is exposed in workplaces subject to vibration plays an important role in reducing the level of human discomfort, but its interaction with ambient lighting does not have a significant effect on human subjective and physiological responses. PMID- 29532146 TI - Comment to the letter of Dr. Yeon-Suk Kim et al. PMID- 29532147 TI - Comment to the letter by Drs. Safiri and Ashrafi-Asgarabad. PMID- 29532148 TI - Correction to: Nuclear, chloroplast, and mitochondrial data of a US cannabis DNA database. AB - The original version of this article contained a mistake. In page 10 of the original article, the significant level (p > 0.01) is incorrect. The correct significant level is (p < 0.01). The original article has been corrected. PMID- 29532149 TI - 17 Y-STR haplotype diversity in Sao Paulo state (southeast of Brazil). AB - A sample of 158 Brazilian males from Sao Paulo (SP), Brazilian southeast, was typed for 17 Y-STR loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, YGATA_H4.1, and DYS385ab). A total of 158 haplotypes were identified, of which all were unique. The haplotype diversity and discrimination capacity were calculated in 1.0 and the genetic diversity was 67.4%. Pairwise haplotype distances showed that the Sao Paulo population is not significantly different from Rio de Janeiro and Portugal, but is different from African and Native American. PMID- 29532151 TI - Linguistic and motor representations of everyday complex actions: an fNIRS investigation. AB - The present work aimed at exploring functional correlates of motor and linguistic representations of everyday actions, with a specific interest in potential sensorimotor activation effects induced by the use of related action sentences. While it is indeed known that observing simple motor acts (e.g., precision grasping) and listening to the sound of specific actions (e.g., walking) activate sensorimotor structures, less is known when we move to more complex behaviors and more abstract linguistic representations (e.g., verbal descriptions). Again, the potential of linguistic representations to facilitate the activation of specific sensorimotor structures during action execution or observation is yet unexplored. We then aimed at investigating hemodynamic activation patterns (via functional near-infrared spectroscopy, fNIRS) within the sensorimotor network during different tasks based on everyday activities. Twenty volunteers were asked to execute (EXE), observe (OBS), or listen (LIS) to brief verbal descriptions of transitive actions, to observe them while listening to their description (OBS LIS), or to execute them while listening to their description (EXE-LIS). Analyses highlighted that, in the left hemisphere, hemodynamic responses were the lowest during observation of complex actions and observation coupled with listening, greater during simple listening to verbal description of actions, and maximal when participants actually executed complex actions or executed them while listening to their verbal descriptions. The present results suggest that processing verbal descriptions of actions might keep the sensorimotor network more active than simply observing them. Such first pieces of evidence hint at potential implications for novel procedures for rehabilitation of movement and action deficits. PMID- 29532150 TI - The Bacterial Population of Neutral Mine Drainage Water of Elizabeth's Shaft (Slovinky, Slovakia). AB - Although neutral mine drainage is the less frequent subject of the interest than acid mine drainage, it can have adverse environmental effects caused mainly by precipitation of dissolved Fe. The aim of the study was to characterize the composition of bacterial population in environment with high concentration of iron and sulfur compounds represented by neutral mine drainage water of Elizabeth's shaft, Slovinky (Slovakia). Direct microscopic observations, cultivation methods, and 454 pyrosequencing of the 16S rRNA gene amplicons were used to examine the bacterial population. Microscopic observations identified iron-oxidizing Proteobacteria of the genera Gallionella and Leptothrix which occurrence was not changed during the years 2008-2014. Using 454 pyrosequencing, there were identified members of 204 bacterial genera that belonged to 25 phyla. Proteobacteria (69.55%), followed by Chloroflexi (10.31%) and Actinobacteria (4.24%) dominated the bacterial community. Genera Azotobacter (24.52%) and Pseudomonas (14.15%), followed by iron-oxidizing Proteobacteria Dechloromonas (11%) and Methyloversatilis (8.53%) were most abundant within bacterial community. Typical sulfur bacteria were detected with lower frequency, e.g., Desulfobacteraceae (0.25%), Desulfovibrionaceae (0.16%), or Desulfobulbaceae (0.11%). Our data indicate that the composition of bacterial community of the Elizabeth's shaft drainage water reflects observed neutral pH, high level of iron and sulfur ions in this aquatic habitat. PMID- 29532152 TI - Non-prosthetic peri-implant fractures: classification, management and outcomes. AB - INTRODUCTION: Non-prosthetic peri-implant fractures (NPPIFs) are an under reported entity. Management is challenging because of alterations in anatomy, the presence of orthopaedic implants and phenomena such as stress shielding, disuse osteopenia and fracture remodeling. The aims of this paper were to review patterns of injury, management and outcomes and to propose a classification system to aid further research. MATERIALS AND METHODS: This study is a multi centered retrospective case series. Patients were identified from the orthopaedic department trauma databases of public hospitals in Singapore and individual surgeon case series of members of the Singapore Orthopaedic Research Collaborative (SORCE) group. RESULTS: We collected a series of 60 NPPIFs in 53 patients. 38 fractures involved the femur, 12 the radius/ulna, 5 humeri, 3 tibia/fibula and 1 clavicle. 39 patients had fractures around plates and screws, 12 around nails, and 3 around screws. Fractures were managed with a variety of surgical techniques. Six patients had surgical complications with refracture in four and non-union in two cases. Two patients had multiple refractures (total 12 additional fractures). All surgical complications required further surgery. Three patients had deep vein thrombosis and one patient died of post-operative pneumonia. Fractures were classified according to the initial implant (plate or nail), the position of the new fracture relative to the original implant (at the tip or distant) and the status of the original fracture (healed, not healed or failing). Surgical strategies for common subtypes were reviewed. CONCLUSIONS: This study represents the largest series in the literature. NPPIFs are a challenging clinical problem with a high rate of post-operative complications. They are distinct from peri-prosthetic fractures and should be understood as a separate entity. We, therefore, propose a novel classification system. Further research is needed to determine the optimal treatment for the various subtypes. LEVEL OF EVIDENCE: Therapeutic Level IV-case series. PMID- 29532153 TI - Antitumor activity of the microtubule inhibitor MBRI-001 against human hepatocellular carcinoma as monotherapy or in combination with sorafenib. AB - PURPOSE: MBRI-001 is a novel synthetic derivative of plinabulin. In this study, our purpose is to investigate the inhibition effects of MBRI-001 on human hepatocellular carcinoma as monotherapy or in combination with sorafenib. METHODS: HCCLM3 and Bel-7402 cell lines were used for activity evaluation in vitro. The anti-proliferative activity of MBRI-001 was assessed by MTT assay. The morphological change of microtubules was determined by immunofluorescence assay. The cell cycle was measured by flow cytometer. The expression of cyclin B1 (CCNB1) was analyzed by RT-qPCR and western blotting assays. The antitumor activities in vivo were evaluated with human HCC xenograft mice model. RESULTS: Our data demonstrated that MBRI-001 had better anti-proliferative activities than that of plinabulin against HCCLM3 and Bel-7402 cell lines. MBRI-001 inhibited the formation of microtubules and induced G2/M arrest with the downregulation of CCNB1. In vivo orthotopic mice model demonstrated that MBRI-001 significantly inhibited the growth of HCCLM3 with the apoptosis and necrosis observed in tumor. The combination treatment of MBRI-001 with sorafenib in subcutaneous mice model exhibited a higher antitumor inhibition rate at 72.0%, in comparison with MBRI 001 or sorafenib as monotherapy at 40.7% or 47.7%, respectively. CONCLUSION: MBRI 001 had better inhibition effects on microtubules and human hepatocellular carcinoma than that of plinabulin. The combination treatment of MBRI-001 and sorafenib exhibited a higher antitumor effect, which could provide a new strategy to treat HCC in the future. PMID- 29532154 TI - [Headache, abdominal pain, and back pain in children and adolescents in Thuringia : Representative results of a regional module study in KiGGS wave 1]. AB - Recurring pain in children and adolescents can have a negative impact on health and well-being. This study investigates recurring headache, abdominal pain, and back pain in children and adolescents in Thuringia. Data is based on a representative sub-sample from the federal state module Thuringia (2010-2012, n = 4096, 3-17 years), carried out in KiGGS wave 1 (first follow-up interview of the "German Health Interview and Examination Survey for Children and Adolescents"). The 3-month prevalence of recurrent headache, abdominal pain, and back pain is reported according to socio-demographic factors and is compared with the prevalence for the whole of Germany. In addition, possible associated factors of recurring headache, abdominal pain, and back pain in the previous 3 months are analyzed. Results for Thuringia show that 3- to 10-year-old children were most frequently affected by recurrent abdominal pain (girls: 24.1%; boys: 16.7%), while 11- to 17-year-old adolescents were most frequently affected by recurrent headaches (girls: 36.8%; boys: 20.6%). There were isolated socio-economic differences in the 3-month prevalences of recurrent headache and back pain to the detriment of the low status group. Compared to peers in the whole of Germany, girls and boys in Thuringia did not report headache, abdominal pain, and back pain in the previous 3 months more frequently. The investigated associated factors-fair to very poor self-rated health, emotional problems such as anxiety and depressive symptoms, chronic diseases and other health complaints, migraine, use of a general medical practice, as well as practices for orthopedics and neurology, and in-patient treatment at a hospital-were positively related to the 3-month prevalence of recurrent headache, abdominal pain, and back pain. Overall, the results confirm that recurring pain is a common phenomenon in childhood and adolescents and, therefore, underline the public health relevance of pain in this young age group. PMID- 29532156 TI - Beta-blockers do not protect against cardiac toxicity of hyperkalemia : Response to the article by Legrand et al. 'Association between hypo- and hyperkalemia and outcome in acute heart failure patients: the role of medications' [1]. PMID- 29532155 TI - Combined use of lung ultrasound, B-type natriuretic peptide, and echocardiography for outcome prediction in patients with acute HFrEF and HFpEF. AB - BACKGROUND: Lung ultrasound (LUS) can be used to assess pulmonary congestion by imaging B-lines ('comets') for patients with acute heart failure (AHF). OBJECTIVES: Investigate relationship of B-lines, plasma concentrations of B-type natriuretic peptide (BNP), and echocardiographic left ventricular (LV) function measured at admission and discharge and their relationship to prognosis for AHF with preserved (HFpEF) or reduced (HFrEF) LV ejection fraction. METHODS: Patients with AHF had the above tests done at admission and discharge. The primary outcome was re-hospitalization for heart failure or death at 6 months. RESULTS: Of 162 patients enrolled, 95 had HFrEF and 67 had HFpEF, median age was 80 [77-85] years, and 85 (52%) were women. The number of B-lines at admission (median 31 [27 36]) correlated with respiratory rate (r = 0.75; p < 0.001), BNP (r = 0.43; p < 0.001), clinical congestion score (r = 0.25; p = 0.001), and systolic pulmonary artery pressure (r = 0.42; p < 0.001). At discharge, B-lines were also correlated with BNP (r = 0.69; p < 0.001) and congestion score (r = 0.57; p < 0.001). B-line count at discharge predicted outcome (AUC 0.83 [0.77-0.90]; univariate HR 1.12 [1.09-1.16]; p < 0.001; multivariable HR 1.16 [1.11-1.21]; p < 0.001). Results were similar for HFpEF and HFrEF. CONCLUSIONS: LUS appears a useful method to assess severity and monitor the resolution of lung congestion. At hospital admission, B-lines are strongly related to respiratory rate, which may be a key component of the sensation of dyspnea. Measurement of lung congestion at discharge provides prognostic information for patients with either HFpEF or HFrEF. PMID- 29532157 TI - Successful localization and ablation of a Mahaim potential using a high resolution mapping catheter after a failed conventional ablation attempt. PMID- 29532158 TI - Tryptase as a polyfunctional component of mast cells. AB - Mast cells are haematopoietic cells that arise from pluripotent precursors of the bone marrow. They play immunomodulatory roles in both health and disease. When appropriately activated, mast cells undergo degranulation, and preformed granule compounds are rapidly released into the surroundings. In many cases, the effects that mast cells have on various inflammatory settings are closely associated with the enzymatic characteristics of tryptase, the main granule compound of mast cells. Tryptase degranulation is often linked with the development of an immune response, allergy, inflammation, and remodelling of tissue architecture. Tryptase also represents an informative diagnostic marker of certain diseases and a prospective target for pharmacotherapy. In this review, we discuss the current knowledge about mast cell tryptase as one of the mast cell secretome proteases. The main points of the reviewed publications are highlighted with our microscopic images of mast cell tryptases visualized using immunohistochemical staining. PMID- 29532159 TI - Expression of serine peptidase inhibitor Kunitz type 1 in differentiated thyroid cancer. AB - SPINT1, also known as HAI-1, is a Kunitz-type serine protease inhibitor that inhibits multiple proteases including hepatocyte growth factor (HGF) activator and matriptase. SPINT1 has been shown to modulate HGF/MET activation in certain cancer types. In the present study, we analyzed microarray datasets and found that SPINT1 was consistently upregulated in differentiated thyroid cancer. SPINT1 protein expression was investigated using tissue microarrays and independent samples of our 143 patients. Strong SPINT1 expression was observed in 61-68% of papillary thyroid cancer and 41-50% of follicular thyroid cancer. The overexpression diminished in anaplastic thyroid cancer. The SPINT1 expression in normal thyroid tissues and benign thyroid lesions was low. Furthermore, we noted that the SPINT1 expression was associated with extrathyroidal invasion, lymphovascular invasion, lymph node metastasis, advanced TNM stage, and a higher risk of recurrence in differentiated thyroid cancer. The results were in accordance with our analysis of The Cancer Genome Atlas data. In conclusion, an overexpression of SPINT1 appears to be associated with an invasive phenotype in differentiated thyroid cancer. PMID- 29532160 TI - Treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: the role of corticosteroids. AB - We aimed to evaluate the treatments, particularly the role of corticosteroids, in patients with late-onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). One hundred and sixty-three consecutive patients who underwent non-T-cell-depleted allo-HSCT and met the criterion of LOHC after allo-HSCT were enrolled in this study. The median time from allo-HSCT to the occurrence of LOHC was 29 (range, 4-155) days. Pathogens identified in blood and/or urine samples from 143 patients were mostly viruses. All of the patients with LOHC received intravenous fluid hydration, alkalization, and forced diuresis, of which 2 patients achieved complete remission (CR) after these treatments. The remaining 161 patients received anti-infection therapies and 71 achieved CR after the therapies. Corticosteroids were additionally applied to 83 out of 90 patients who did not achieve CR after anti-infection therapies, and 88.0% (n = 73) of them showed a grade 3 to 4 LOHC at the beginning of corticosteroid therapy. Thirty-five patients showed an immediate response (CR or downgraded at least one grade) within 1 week after the beginning of the corticosteroid therapy. Sixty-four patients (77.1%) achieved CR after corticosteroid therapy, and the median period from the beginning of corticosteroid therapy to CR was 17 days. Thus, we observed that viruses were the most common pathogens in LOHC after allo-HSCT and that anti-infection therapies were critical. For patients not showing a satisfactory response to anti-infection therapies, additional corticosteroid therapy may help to achieve CR. PMID- 29532161 TI - Higher Sclerostin/SOST expression is associated with lower percentage of circulatory blasts and better prognosis in patients with myelofibrosis. PMID- 29532162 TI - Eculizumab treatment for ischemic enteritis accompanied with paroxysmal nocturnal hemoglobinuria: a case report and literature review. PMID- 29532164 TI - Long-term unprocessed and processed red meat consumption and risk of chronic obstructive pulmonary disease: a prospective cohort study of women. AB - PURPOSE: Limited studies have examined red meat consumption in relation to risk of chronic obstructive pulmonary disease (COPD), and none have examined the impact of long-term diet on COPD risk. We sought to investigate the association between long-term red meat consumption and risk of COPD. METHODS: The population based prospective Swedish Mammography Cohort included 34,053 women, aged 48-83 years, followed for the current analyses from 2002 to 2014. Unprocessed and processed red meat consumption was assessed with a self-administered questionnaire in 1987 and 1997. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a mean follow-up of 11.6 years (2002-2014; 393,831 person-years), 1488 COPD cases were ascertained via linkage to the Swedish health registers. A positive association between long-term processed red meat (average from 1987 to 1997) and risk of COPD was observed. In contrast, no association was observed with unprocessed red meat with corresponding HRs of 1.36 (95% CI 1.03-1.79) for processed and 0.87 (95% CI 0.74-1.02) for unprocessed red meat among women who consumed >= 50 g/day compared to < 25 g/day. The observed association with processed meat was confined to ex-smokers (P for interaction = 0.30); women consuming of >= 50 g/day of processed meat had a 2.3-fold (95% CI 1.24-4.12) higher risk of COPD than those consuming < 25 g/day. No similar associations were observed among current or never smokers. CONCLUSION: In this prospective cohort of women with moderate red meat consumption, long-term processed red meat consumption was associated with an increased risk of COPD particularly among ex smokers. PMID- 29532163 TI - Isoprenoid-derived plant signaling molecules: biosynthesis and biological importance. AB - MAIN CONCLUSION: The present review summarizes current knowledge of the biosynthesis and biological importance of isoprenoid-derived plant signaling compounds. Cellular organisms use chemical signals for intercellular communication to coordinate their growth, development, and responses to environmental cues. The skeletons of majority of plant signaling molecules, mediators of plant intercellular 'broadcasting', are built from C5 units of isoprene and therefore belong to a huge and diverse group of natural substances called isoprenoids (terpenoids). They fill many important roles in nature. This review summarizes current knowledge of the biosynthesis and biological importance of a group of isoprenoid-derived plant signaling compounds. PMID- 29532165 TI - Prevalence of Myositis-Specific Antibodies in Idiopathic Interstitial Pneumonias. AB - Although included in the serological domain of the 'interstitial pneumonia with auto-immune features' (IPAF) research statement, the search for myositis-specific antibodies (MSA) is not incorporated in routine clinical practice. The objective of the study was to evaluate MSA prevalence in an idiopathic interstitial pneumonia (IIP) cohort (n = 68) with suggestive morphological interstitial lung disease patterns. Twelve of 68 patients (17.6%) carried MSA, whereof only two were anti-nuclear antibody-positive. Besides female gender, no demographic or pulmonary function parameter was predictive for MSA positivity. MSA were present in 32.4% of IPAF patients (n = 37), being essential for IPAF diagnosis in four of them (10.8%). PMID- 29532166 TI - International survey on the management of Chiari 1 malformation and syringomyelia: evolving worldwide opinions. AB - INTRODUCTION: In 2003, pediatric neurosurgeons were surveyed under the auspices of the education committee of the International Society for Pediatric Neurosurgery (ISPN) to determine prevailing opinions regarding the management of Chiari I malformation (C1M) with and without associated syringomyelia. In the ensuing years, there has been further information from multiple C1M studies, with regards to indications, success rates of different surgical interventions, and complications. The purpose of this study was to re-evaluate current opinions and practices in pediatric C1M. MATERIALS AND METHODS: Pediatric neurosurgeons worldwide were surveyed, using an e-mail list provided by the ISPN communication committee chairperson. Respondents were given scenarios similar to the 2003 C1M survey in order to determine opinions regarding whether to surgically intervene, and if so, with which operations. RESULTS: Of 300 surveys electronically distributed, 122 responses were received (40.6% response rate)-an improvement over the 30.8% response rate in 2003. Pediatric neurosurgeons from 34 different countries responded. There was broad consensus that non-operative management is appropriate in asymptomatic C1M (> 90%) as well as asymptomatic C1M with a small syrinx (> 65%). With a large syrinx, a majority (almost 80%) recommended surgical intervention. Scoliotic patients with CIM were generally offered surgery only when there was a large syrinx. There has been a shift in the surgical management over the past decade, with a bone-only decompression now being offered more commonly. There remains, however, great variability in the operation offered. CONCLUSION: This survey, with a relatively strong response rate, and with broad geographic representation, summarizes current worldwide expert opinion regarding management of pediatric C1M. Asymptomatic C1M and C1M with a small syrinx are generally managed non-operatively. When an operation is indicated, there has been a shift towards less invasive surgical approaches. PMID- 29532167 TI - Dandy-Walker malformation and syringomyelia: a rare association. AB - PURPOSE: Dandy-Walker malformation is a rare condition due to imperforation of the Blake's pouch during intrauterine brain development, usually leading to early severe hydrocephalus. The association with holocord syringomyelia is rare, and from the Gardner's first report in 1957, only 23 cases have been described, mostly from autopsy series and pre-MRI period. Besides a worsening of clinical picture, its occurrence generates some concern about the best surgical treatment that varies widely among the literature reports. METHODS: An 11-year-old girl with Dandy-Walker malformation presented with a holocord syrinx due to the herniation of the lower pole of the posterior fossa cyst through the foramen magnum. RESULTS: After an unsuccessful shunt revision, she underwent a cystoperitoneal shunt with regression of the syrinx and of neurological symptoms at the 12-month follow-up. CONCLUSIONS: Previous literature about pathogenesis, treatment, and follow-up is discussed and summarized. PMID- 29532168 TI - Common trunk of the posterior intercostal arteries from the thoracic aorta: anatomical variation, frequency, and importance in individuals. AB - PURPOSE: A common trunk of the posterior intercostal arteries originating from the descending thoracic aorta is normally an anatomical variation. A search through the literature disclosed the frequencies of common trunks variations among population, but no information relates to particular topic of simultaneous multiple common trunks of the PIA present in individuals. METHODS: A total of 396 intercostal spaces were dissected in 44 cadavers from the vertebral body to the mid-axillary line to observe a common trunk of the paired posterior intercostal artery at the level from T2 to T11 intercostal space. RESULTS: In 31 cadavers (70%), a common trunk of posterior intercostal arteries arising from descending thoracic aorta was visualed and 22 of those (71%) had two or more common trunks simultaneously present. CONCLUSIONS: It is important to recognize this anatomical variation when the number of origins of the posterior intercostal arteries from the thoracic aorta due to the multiple common trunk present can be reduced, as their origins and vascular territories are involved in primary diseases of the thoracic aorta, like atherosclerosis, aneurysm, or dissection that lead to serious complications. For example, in thoracoabdominal aneurysm repair, reimplantation of the posterior intercostal arteries is recommended to avoid potential ischemic injury to the supplying areas, especially to the spinal cord. PMID- 29532169 TI - On the accuracy of cochlear duct length measurement in computed tomographic images. AB - PURPOSE: Patient specific selection of cochlear implants would benefit from pre operative knowledge of cochlear length. Several methods for its measurement or estimation have been described in literature. This study focused on the achievable accuracy in clinically available imaging. METHODS: Five simplified cochlea models milled into porcine bone were scanned in water using clinical cone beam computed tomography. Due to their well-known dimensions these phantoms served as gold standard for the length measurements. Each phantom was measured ten times using the custom software Comet. In addition, cochleae in ten image datasets taken indiscriminately from clinical routine were measured ten times each to test the precision under realistic conditions. The results were also compared to estimations based on the diameter of the basal turn (A value) as described in literature. RESULTS: Measurement accuracy of the phantoms' lengths was high (average error: - 0.2 mm; standard deviation: 0.3 mm). The pooled standard deviation for the measurements in clinical datasets was 0.6 mm. Errors resulted mainly from problems locating the helicotrema. The estimations differed on average - 1.7 to + 0.4 mm from the manual measurements and had standard deviations between 0.5 and 0.6 mm depending on the algorithm. CONCLUSIONS: The program Comet was successfully used to accurately measure the length of the cochlea models in clinically available imaging. The lower image quality of patient scans reduced the precision of the measurement. Estimations using the A value are a quicker alternative for averagely sized cochleae in cases where the lack of accuracy is tolerable. PMID- 29532170 TI - Inverted internal limiting membrane flap technique for large macular holes: a systematic review and single-arm meta-analysis. AB - PURPOSE: The aim of this systematic review was to determine the anatomical outcome-macular hole (MH) closure rate-and functional outcome-visual acuity (VA) improvement rate-of the inverted internal limiting membrane (ILM) flap technique for large MH. METHODS: We searched for articles on large MH (> 400 MUm) treated with inverted ILM flap technique in databases as of December 1, 2017. And single arm meta-analysis was performed for the primary outcome of MH closure rate and the secondary outcome of VA improvement rate. In addition, we searched and pooled studies treating large MH with indocyanine green (ICG)-assisted ILM peeling as the reference. R software (version 2.15.2) was used for analysis. RESULTS: This review includes eight studies that used inverted ILM flap technique to treat large MH (> 400 MUm). Based on the single-arm meta-analysis performed in R 2.15.2, the pooled MH closure rate and VA improvement rate following inverted ILM flap technique were 95% (95% CI, 88 to 98%) and 75% (95% CI, 62 to 85%), respectively, in fixed-effect models. There was no substantial methodological heterogeneity. In addition, we selected four studies on large MH treated with ICG assisted ILM peeling as the reference. The fixed-model pooled MH closure rate and VA improvement rate were 87% (95% CI, 79 to 92%) and 57% (95% CI, 46 to 68%), respectively. CONCLUSIONS: Inverted ILM flap technique should be an effective and safe method for treating large MH, with high closure rates and good VA improvement. However, further studies in large randomized controlled trials on minimizing surgical complications and understanding the mechanism of this technique are necessary. PMID- 29532172 TI - Society for Neuroscience 2017 Satellite Symposium on Feeding and Swallowing: From Neural Mechanisms to Rehabilitation. PMID- 29532171 TI - A quality of life survey in patients with long-term silicone oil or phthisis bulbi. AB - AIM: The aim of this study is to determine whether there is any difference in the quality of life of patients with a blind eye with long-term silicone oil compared to without. METHOD: Patients with either long-term silicone oil in situ (N = 17), defined as a period greater than 6 months duration with no plan for future removal, or those with a phthisical, non oil-filled eye were identified (N = 13). Two validated questionnaires (NEI VFQ-25 and the FACE-Q) that cover indicators for visual function, pain and cosmesis were sent to all patients in the two cohorts. RESULTS: There was no significant difference found in quality of life outcomes between the two groups in terms of visual function, pain or cosmesis. CONCLUSION: The results of this study support a holistic approach to the consent process before vitreoretinal surgery. Patients that may need to undergo multiple vitreoretinal procedures, where the endstage result is a long-term silicone oil fill, should be informed that their functional outcome may be similar to having no surgical intervention. PMID- 29532173 TI - Soil erodibility mapping using the RUSLE model to prioritize erosion control in the Wadi Sahouat basin, North-West of Algeria. AB - Soil losses must be quantified over watersheds in order to set up protection measures against erosion. The main objective of this paper is to quantify and to map soil losses in the Wadi Sahouat basin (2140 km2) in the north-west of Algeria, using the Revised Universal Soil Loss Equation (RUSLE) model assisted by a Geographic Information System (GIS) and remote sensing. The Model Builder of the GIS allowed the automation of the different operations for establishing thematic layers of the model parameters: the erosivity factor (R), the erodibility factor (K), the topographic factor (LS), the crop management factor (C), and the conservation support practice factor (P). The average annual soil loss rate in the Wadi Sahouat basin ranges from 0 to 255 t ha-1 year-1, maximum values being observed over steep slopes of more than 25% and between 600 and 1000 m elevations. 3.4% of the basin is classified as highly susceptible to erosion, 4.9% with a medium risk, and 91.6% at a low risk. Google Earth reveals a clear conformity with the degree of zones to erosion sensitivity. Based on the soil loss map, 32 sub-basins were classified into three categories by priority of intervention: high, moderate, and low. This priority is available to sustain a management plan against sediment filling of the Ouizert dam at the basin outlet. The method enhancing the RUSLE model and confrontation with Google Earth can be easily adapted to other watersheds. PMID- 29532174 TI - Blood-to-Retina Transport of Fluorescence-Labeled Verapamil at the Blood-Retinal Barrier. AB - PURPOSE: To investigate the blood-to-retina verapamil transport at the blood retinal barrier (BRB). METHODS: EverFluor FL Verapamil (EFV) was adopted as the fluorescent probe of verapamil, and its transport across the BRB was investigated with common carotid artery infusion in rats. EFV transport at the inner and outer BRB was investigated with TR-iBRB2 cells and RPE-J cells, respectively. RESULTS: The signal of EFV was detected in the retinal tissue during the weak signal of cell impermeable compound. In TR-iBRB2 cells, the localization of EFV differed from that of LysoTracker(r) Red, a lysosomotropic agent, and was not altered by acute treatment with NH4Cl. In RPE-J cells, the punctate distribution of EFV was partially observed, and this was reduced by acute treatment with NH4Cl. EFV uptake by TR-iBRB2 cells was temperature-dependent and membrane potential- and pH independent, and was significantly reduced by NH4Cl treatment during no significant effect obtained by different extracellular pH and V-ATPase inhibitor. The EFV uptake by TR-iBRB2 cells was inhibited by cationic drugs, and inhibited by verapamil in a concentration-dependent manner with an IC50 of 98.0 MUM. CONCLUSIONS: Our findings provide visual evidence to support the significance of carrier-mediated transport in the blood-to-retina verapamil transport at the BRB. PMID- 29532175 TI - The vitamin D receptor expression in skeletal muscle of women with distal radius fracture. AB - : We evaluated the vitamin D receptor (VDR) expression in the forearm flexor muscle of women with distal radius fracture. High VDR expression was associated with low appendicular lean mass index. INTRODUCTION: We aimed to evaluate the relationship between the VDR expression in the muscle cell and the muscle mass in women with a distal radius fracture (DRF). METHODS: We prospectively recruited 45 women over 50 years of age (mean age, 66 years) with DRF and acquired biopsy of the forearm flexor muscle. The muscle cross-sectional area (CSA) and VDR expression were measured using immunohistochemistry staining. The clinical parameters including grip strength, gait speed, body mass index (BMI), bone mineral density (BMD), and serum vitamin D levels were compared between patients grouped by appendicular lean mass index and were correlated with the VDR expression. RESULTS: Twelve patients (27%) showed a decreased appendicular lean mass index, less than the cut-off value of 5.4 kg/m2 which was suggested by the Asian Working Group for Sarcopenia. Patients with a low appendicular lean mass index had significantly lower muscle CSA (p = 0.037), but a higher VDR expression (p = 0.045) than those with higher indices. VDR expression was negatively correlated with BMI (r = - 0.417, p = 0.004) and appendicular lean mass index (r = - 0.316, p = 0.044). CONCLUSIONS: DRF patients with low appendicular lean mass index presented high VDR expression and low CSA in forearm muscle cells. This suggests that the VDR expression might be upregulated in the attempt to compensate for the decreasing muscle mass. Further studies are necessary to explore the role of VDR in the progression of sarcopenia. PMID- 29532176 TI - A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion. AB - PURPOSE: The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. METHODS: Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non linear mixed effect approach and using NONMEM software. A detailed sub-model was implemented for kidneys to handle the complex disposition of CMS and colistin within this organ. RESULTS: The WB-PBPK model well captured the kinetic profiles of CMS and colistin in plasma. In kidneys, an accumulation and slow elimination of colistin were observed and well described by the model. Kidneys seemed to have a major role in the elimination processes, through tubular secretion of CMS and intracellular degradation of colistin. Lastly, to illustrate the usefulness of the PBPK model, an estimation of the withdrawal periods after veterinary use of CMS in pigs was made. CONCLUSIONS: The WB-PBPK model gives an insight into the renal distribution and elimination of CMS and colistin in pigs; it may be further developed to explore the colistin induced-nephrotoxicity in humans. PMID- 29532177 TI - Occurrence and risk assessment of persistent organic pollutants in a branch of the Grand Canal in Hangzhou, China. AB - The Grand Canal is one of the most important waterways and sources of drinking water in China. The security of this water environment has a strong influence on national economic development and public health. However, data on the pollution status and potential risks due to persistent organic pollutants (POPs) in this area is insufficient. In this study, we selected a branch of the Grand Canal in Hangzhou as the study subject from which 16 surface water samples were collected in the summer of 2016. The concentrations of organochlorine pesticides (OCPs) (including 4 hexachlorocyclohexanes (HCHs) and 6 dichlorodiphenyltrichloroethanes (DDTs)), 12 polycyclic aromatic hydrocarbons (PAHs), and 35 polychlorinated biphenyls (PCBs) in the water samples were determined by gas chromatography-mass spectrometry (GC-MS). Non-carcinogenic risk, carcinogenic risk, and cytotoxicity experiments were conducted to evaluate the potential health risks due to these POPs. Additionally, the toxicological data for the Danio rerio aquatic organism from the US EPA were employed for comparison with the residue from POPs in this area. The results showed that the total concentrations of HCHs, DDTs, PCBs, and PAHs were 29.937, 60.2, 8.30, and 1670.2 ng/L, respectively. Some pollutants (including acenaphthene and acenaphthylene, hepta-PCBs and tetra-PCBs, octa-PCBs and hexa-PCBs, beta-HCH and alpha-HCH, and delta-HCH and gamma-HCH) showed a correlation, which indicated they might have a similar origin. There were no non carcinogenic risks or ecological risks for adults, children, and aquatic organisms, but a relatively low carcinogenic risk for adults presented at certain sites. The data provided here will be helpful in fully understanding the pollution status of the surface water in this branch of the Grand Canal and the potential risks from this water. Graphical abstract ?. PMID- 29532178 TI - Use of Psychophysiological Portable Devices to Analyse Stress Response in Different Experienced Soldiers. AB - Previous studies have shown that actuate stress have a negative effect on working memory, visio-spatial ability and symptoms of disassociation. We conducted the present research with the aim of to analyse the effect of experience and training in psychophysiological response, attention and memory of soldiers in combat. Variables of blood lactate, blood glucose, blood oxygen saturation, body temperature, heart rate, lower body muscular strength manifestation, autonomic modulation, cortical arousal, cognitive and somatic anxiety, and memory by a post mission questionnaire were analysed before and after a combat simulation in 49 soldiers of Spanish Army. Combat simulation produced a significant increase (p < 0.05) in blood lactate, blood glucose, blood oxygen saturation, rated perceived exertion, heart rate, cognitive and somatic anxiety. Significant increase in low frequency domain and significant decrease in high frequency domain of the heart rate variability was found in experienced and highly trained soldiers. The percentage of correct response in the post mission questionnaire indicated that elements better remembered were those related with soldier integrity and considered as a possible life threat, Significant differences in the post mission questionnaire by experience and training was also found. Correlation analysis showed that higher psychophysiological activation correlated positively with cognitive impairment and lower memory. As a conclusion, higher experienced soldiers presented higher physiological activation as well as cognitive and memory impairment than lower experienced soldier after a combat simulation and memory function was modulated by the stimulus nature. PMID- 29532179 TI - Selective Ligands and Drug Discovery Targeting the Voltage-Gated Sodium Channel Nav1.7. AB - The voltage-gated sodium (Nav) channel Nav1.7 has been the focus of intense investigation in recent years. Human genetics studies of individuals with gain-of function and loss-of-function mutations in the Nav1.7 channel have implicated Nav1.7 as playing a critical role in pain. Therefore, selective inhibition of Nav1.7 represents a potentially new analgesic strategy that is expected to be devoid of the significant liabilities associated with available treatment options. Although the identification and development of selective Nav channel modulators have historically been challenging, a number of recent publications has demonstrated progression of increasingly subtype-selective small molecules and peptides toward potential use in preclinical or clinical studies. In this respect, we focus on three binding sites that appear to offer the highest potential for the discovery and optimization of Nav1.7-selective inhibitors: the extracellular vestibule of the pore, the extracellular loops of voltage-sensor domain II (VSD2), and the extracellular loops of voltage-sensor domain IV (VSD4). Notably, these three receptor sites on Nav1.7 can all be defined as extracellular druggable sites, suggesting that non-small molecule formats are potential therapeutic options. In this chapter, we will review specific considerations and challenges underlying the identification and optimization of selective, potential therapeutics targeting Nav1.7 for chronic pain indications. PMID- 29532182 TI - Hyperkyphotic measures using distance from the wall: validity, reliability, and distance from the wall to indicate the risk for thoracic hyperkyphosis and vertebral fracture. AB - : C7WD is a practical, valid, and reliable measure that could clearly indicate a risk of hyperkyphosis and vertebral fracture in the elderly. The findings might be particularly of use in regions difficult to access radiology or for the determination of those who need further invasive radiologic examination and therapy. PURPOSE: To investigate psychometric properties of the 7th cervical vertebra wall distance (C7WD) to determine the risk of thoracic hyperkyphosis and spinal fracture, as compared to a standard radiologic Cobb's method. METHODS: Community-dwelling elderly (n = 104), aged at least 60 years with occiput-wall distance > 0 cm, were assessed for their C7WD using rulers and a specially developed tool for an accurate perpendicular distance from C7 to the wall: infrared-gun kyphosis wall distance tool (IG-KypDisT). The first 15 participants were also involved in the reliability tests by a healthcare professional, village health volunteer, and caregiver. Within 7 days, all participants were at a hospital to complete a lateral plain radiograph (Cobb's method). RESULTS: Outcomes of C7WD had excellent correlation to the Cobb angles (r = 0.87 for rulers and r = 0.92 for IG-KypDisT), with excellent reliability when used by all three raters (ICC3,3 = 0.85-0.99). The C7WD of at least 7.5 and 9.5 cm had the best diagnostic properties to determine the risk of thoracic hyperkyphosis and vertebral fracture, respectively. CONCLUSION: C7WD is valid and reliable with good diagnostic properties for thoracic hyperkyphosis and vertebral fracture. The findings confirm the use of C7WD using traditional ruler-based method as a practical tool to screen and monitor severity of thoracic hyperkyphosis in clinics and communities. In addition, the measurement using the IG-KypDisT provided accurate data that can be saved for further analysis; it is therefore suggested for research settings. The findings would promote the standardization of hyperkyphosis measurements in various settings. PMID- 29532181 TI - The presynaptic machinery at the synapse of C. elegans. AB - Synapses are specialized contact sites that mediate information flow between neurons and their targets. Important physical interactions across the synapse are mediated by synaptic adhesion molecules. These adhesions regulate formation of synapses during development and play a role during mature synaptic function. Importantly, genes regulating synaptogenesis and axon regeneration are conserved across the animal phyla. Genetic screens in the nematode Caenorhabditis elegans have identified a number of molecules required for synapse patterning and assembly. C. elegans is able to survive even with its neuronal function severely compromised. This is in comparison with Drosophila and mice where increased complexity makes them less tolerant to impaired function. Although this fact may reflect differences in the function of the homologous proteins in the synapses between these organisms, the most likely interpretation is that many of these components are equally important, but not absolutely essential, for synaptic transmission to support the relatively undemanding life style of laboratory maintained C. elegans. Here, we review research on the major group of synaptic proteins, involved in the presynaptic machinery in C. elegans, showing a strong conservation between higher organisms and highlight how C. elegans can be used as an informative tool for dissecting synaptic components, based on a simple nervous system organization. PMID- 29532180 TI - Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action. AB - Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new. PMID- 29532183 TI - Effect of fairy ring bacteria on the growth of Tricholoma matsutake in vitro culture. AB - Tricholoma matsutake (pine mushroom) (Basidiomycota, Agaricales) is a valuable edible fungal species that cannot be cultivated artificially. As an ectomycorrhizal fungus, T. matsutake interacts with trees belonging to the Pinaceae and Fagaceae, and forms fairy rings around host trees that are arc shaped areas with dense hyphae of T. matsutake in the soil. Because the fairy rings maintain their dense hyphae for several years and form fruiting bodies, the characteristics of the fairy ring may be important in understanding the ecology of T. matsutake. Recent studies have shown that diverse bacteria co-exist in the fairy ring, and suggest that the fairy ring bacteria may influence on the growth of T. matsutake. However, the effect of the fairy ring bacteria on the growth of T. matsutake is largely unknown. In this study, we isolated fairy ring bacteria and investigated their effect on the growth of T. matsutake in co-culture experiments. In addition, the relationship between bacterial effects and nutrient conditions was tested using different media with varying glucose concentrations. A total of 237 bacteria (28 species) were isolated from fairy rings of four different T. matsutake producing areas: Proteobacteria (17 species), Firmicutes (7 species), and Actinobacteria (4 species). Burkholderiaceae (Burkholderia and Paraburkholderia) was most abundant in the fairy ring bacteria communities. Most bacteria showed a negative effect on the growth of T. matsutake when it grew on glucose rich medium (20 g/L). In glucose deficient medium (2 g/L), however, some bacteria promoted the growth of T. matsutake. In addition, the mode of interaction between bacteria and T. matsutake is different, depending on the glucose concentration. PMID- 29532184 TI - The effect of pacifier sucking on orofacial structures: a systematic literature review. AB - BACKGROUND: Non-nutritive sucking habits may adversely affect the orofacial complex. This systematic literature review aimed to find scientific evidence on the effect of pacifier sucking on orofacial structures. METHODS: A search on MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases was conducted to find all pertinent articles published from inception until February 2018, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of the studies was evaluated using the risk of bias judgements in non-randomized studies of interventions (ROBINS-I). RESULTS: Among the 2288 articles found, 17 articles met the selection criteria: seven prospective cohort studies, nine cross sectional studies, and one randomized clinical trial. Using ROBINS-I, 12 studies were evaluated to have a serious overall risk of bias and five, a moderate one. These studies claimed a strong association between a pacifier sucking habit and the presence of an anterior open bite and posterior crossbite. Functional/orthodontic pacifiers were shown to cause significantly less open bites than the conventional ones. CONCLUSIONS: High level of evidence of the effect of sucking habits on orofacial structures is missing. The available studies show severe or moderate risk of bias; hence, the findings in the literature need to be very carefully evaluated. There is moderate evidence that the use of pacifier is associated with anterior open bite and posterior crossbite, thus affecting the harmonious development of orofacial structures. Functional/orthodontic pacifiers reduce the prevalence of open bite when compared to the conventional ones, but evidence is needed concerning the effects on posterior crossbite. Well-designed randomized controlled trials are needed to further analyze the effects of functional/orthodontic and conventional pacifiers on orofacial structures. PMID- 29532185 TI - Polypoid pulmonary arteriovenous malformation causing hemothorax treated with thoracoscopic wedge resection. AB - BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) can be associated with life-threatening complications such as paradoxical embolization, cerebral abscess, and hemothorax. Therefore, all adults with PAVMs should be offered treatment. Percutaneous transcatheter embolization is the first-line treatment, but 5-25% of cases require further treatment due to persistence after embolization. Recently, the role of minimally invasive thoracic surgery as a definitive treatment has been evaluated. We describe a case of a small peripheral PAVM causing hemothorax, which was safely treated with video-assisted thoracoscopic surgery (VATS). In our case, the PAVM appeared to protrude into the pleural cavity on chest computed tomography (CT), perhaps explaining why it led to a hemothorax. CASE PRESENTATION: A 64-year-old man with a history of a brain abscess, for which he underwent surgery 6 months previously, developed a left sided hemothorax. He had experienced recurrent epistaxis and received anticoagulation therapy for chronic atrial fibrillation. Chest CT after drainage revealed a solitary 15-mm nodule in the periphery of the left lower lobe, and identification of a feeding artery and draining vein on three-dimensional CT suggested that the node was a PAVM. The PAVM was adjacent to the diaphragm and multi-detector CT (MDCT) and three-dimensional CT (3DCT) showed that the nodule slightly displaced the diaphragm and protruded into the pleural cavity. After discussion in a multidisciplinary conference, it was decided that surgical treatment would be preferable to catheter embolization. The patient underwent VATS with three ports, the largest of which was 15 mm. The PAVM protruded from the peripheral lung like a polyp, and wedge resection was performed after simple adhesiolysis. There were no complications, and the patient is asymptomatic after 1-year of follow-up. CONCLUSIONS: As in the present case, PAVMs protruding into the pleural cavity can cause hemothorax, and surgical wedge resection of the involved lung as a definitive treatment is feasible and possibly safer than catheter embolization, particularly if the PAVM is localized close to the visceral pleura. Protrusion into the pleural cavity (polypoid appearance) was detected using MDCT and 3DCT preoperatively. PMID- 29532186 TI - Improving performance in the ED through laboratory information exchange systems. AB - BACKGROUND: The accessibility of laboratory test results is crucial to the performance of emergency departments and to the safety of patients. This study aims to develop a better understanding of which laboratory information exchange (LIE) systems emergency care physicians (ECPs) are using to consult their patients' laboratory test results and which benefits they derive from such use. METHODS: A survey of 163 (36%) ECPs in Quebec was conducted in collaboration with the Quebec's Department of Health and Social Services. Descriptive statistics, chi-square tests, cluster analyses, and ANOVAs were conducted. RESULTS: The great majority of respondents indicated that they use several LIE systems including interoperable electronic health record (iEHR) systems, laboratory results viewers (LRVs), and emergency department information systems (EDIS) to consult their patients' laboratory results. Three distinct profiles of LIE users were observed. The extent of LIE usage was found to be primarily determined by the functional design differences between LIE systems available in the EDs. Our findings also indicate that the more widespread LIE usage, the higher the perceived benefits. More specifically, physicians who make extensive use of iEHR systems and LRVs obtain the widest range of benefits in terms of efficiency, quality, and safety of emergency care. CONCLUSIONS: Extensive use of LIE systems allows ECPs to better determine and monitor the health status of their patients, verify their diagnostic assumptions, and apply evidence-based practices in laboratory medicine. But for such benefits to be possible, ECPs must be provided with LIE systems that produce accurate, up-to-date, complete, and easy-to-interpret information. PMID- 29532187 TI - Heat stress induces spikelet sterility in rice at anthesis through inhibition of pollen tube elongation interfering with auxin homeostasis in pollinated pistils. AB - BACKGROUND: Pollen tube elongation in the pistil is a key step for pollination success in plants, and auxins play an important role in this process. However, the function of auxins in pollen tube elongation in the pistil of rice under heat stress has seldom been previously reported. RESULTS: Two rice genotypes differing in heat tolerance were subjected to heat stress of 40 degrees C for 2 h after flowering. A sharp decrease in spikelet fertility was found in the Nipponbare (NPB) and its mutant High temperature susceptible (HTS) under heat stress, but the stress-induced spikelet sterility was reversed by 1-naphthaleneacetic acid (NAA), especially the HTS. Under heat stress, the pollen tubes of NPB were visible in ovule, while those of HTS were invisible. However, we found the pollen tubes in ovule when sprayed with NAA. During this process, a significant increase in indole-3-acetic acid (IAA) and reactive oxygen species (ROS) levels was found in the pistil of heat-stressed NPB, while in heat-stressed HTS they were obviously decreased. Additionally, the peroxidase (POD) activity in pistil of NPB was significantly decreased by heat stress, whereas there was no difference between the heat-stressed and non-heat-stressed pistils of HTS. CONCLUSION: It was concluded that the enhancement of heat tolerance in plants by NAA was achieved through the increase of the levels of auxins, which prevented the inhibition of pollen tube elongation in pistil, and the crosstalk between auxins and ROS, which might be involved in this process. In addition, POD might be a negative mediator in pollen tube elongation under heat stress due to its ability to scavenge ROS and degrade auxin. PMID- 29532188 TI - Balanced trafficking between the ER and the Golgi apparatus increases protein secretion in yeast. AB - The yeast Saccharomyces cerevisiae is widely used as a cell factory to produce recombinant proteins. However, S. cerevisiae naturally secretes only a few proteins, such as invertase and the mating alpha factor, and its secretory capacity is limited. It has been reported that engineering protein anterograde trafficking from the endoplasmic reticulum to the Golgi apparatus by the moderate overexpression of SEC16 could increase recombinant protein secretion in S. cerevisiae. In this study, the retrograde trafficking in a strain with moderate overexpression of SEC16 was engineered by overexpression of ADP-ribosylation factor GTP activating proteins, Gcs1p and Glo3p, which are involved in the process of COPI-coated vesicle formation. Engineering the retrograde trafficking increased the secretion of alpha-amylase but did not induce production of reactive oxygen species. An expanded ER membrane was detected in both the GCS1 and GLO3 overexpression strains. Physiological characterizations during batch fermentation showed that GLO3 overexpression had better effect on recombinant protein secretion than GCS1 overexpression. Additionally, the GLO3 overexpression strain had higher secretion of two other recombinant proteins, endoglucanase I from Trichoderma reesei and glucan-1,4-alpha-glucosidase from Rhizopus oryzae, indicating overexpression of GLO3 in a SEC16 moderate overexpression strain might be a general strategy for improving production of secreted proteins by yeast. PMID- 29532189 TI - Extracorporeal membrane oxygenation line-associated complications: in vitro testing of cyanoacrylate tissue adhesive and securement devices to prevent infection and dislodgement. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) delivers cardiac and/or respiratory support to critically ill patients who have failed conventional medical therapies. If the large-bore cannulas used to deliver ECMO become infected or dislodged, the patient consequences can be catastrophic. ECMO cannula related infection has been reported to be double the rate of other vascular devices (7.1 vs 3.4 episodes/1000 ECMO days respectively). The aim of this study was to assess the ability of cyanoacrylate tissue adhesive (TA) to inhibit bacterial growth at the ECMO cannulation site, and the effectiveness of TA and securement devices in securing ECMO cannulas and tubing. METHODS: This in vitro study tested the (1) antimicrobial qualities of TA against standard transparent dressing with ECMO cannula; (2) chemical compatibility between cannula, TA and removal agent; (3) pull-out strength of transparent dressing and TA at the cannula insertion site; and (4) pull-out strength of adhesive bandage and commercial sutureless securement devices (SSDs) on circuit tubing. Fisher's exact test was used to evaluate differences in bacterial growth observed between the transparent dressing and TA groups. Data from mechanical testing were analysed using one-way ANOVA, followed by Tukey's multiple comparison test or t test as appropriate. Statistical significance was defined as p < 0.05. RESULTS: No bacterial growth occurred under TA-covered cannulas compared with transparent dressing-covered cannulas (p = 0.002). Compared to plates lacking TA or transparent dressing, growth was observed at the insertion point and under the dressing in the transparent dressing group; however, no growth was observed in the TA group (p = 0.019). TA did not weaken the cannulas; however, the TA removal agent did after 60 min of exposure, compared with control (p < 0.01). Compared with transparent dressing, TA increased the pull-out force required for cannula dislodgement from the insertion point (p < 0.0001). SSDs significantly increased the force required to remove the tubing from the fixation points compared with adhesive bandage (p < 0.01). CONCLUSIONS: Our findings suggest that the combined use of TA at the cannula insertion site with a commercial device for tubing securement could provide an effective bedside strategy to prevent or minimise infection and line dislodgement. PMID- 29532190 TI - Effect of Pulse Rate on Loudness Discrimination in Cochlear Implant Users. AB - Stimulation pulse rate affects current amplitude discrimination by cochlear implant (CI) users, indicated by the evidence that the JND (just noticeable difference) in current amplitude delivered by a CI electrode becomes larger at higher pulse rates. However, it is not clearly understood whether pulse rate would affect discrimination of speech intensities presented acoustically to CI processors, or what the size of this effect might be. Intensity discrimination depends on two factors: the growth of loudness with increasing sound intensity and the loudness JND (or the just noticeable loudness increment). This study evaluated the hypothesis that stimulation pulse rate affects loudness JND. This was done by measuring current amplitude JNDs in an experiment design based on signal detection theory according to which loudness discrimination is related to internal noise (which is manifested by variability in loudness percept in response to repetitions of the same physical stimulus). Current amplitude JNDs were measured for equally loud pulse trains of 500 and 3000 pps (pulses per second) by increasing the current amplitude of the target pulse train until it was perceived just louder than a same-rate or different-rate reference pulse train. The JND measures were obtained at two presentation levels. At the louder level, the current amplitude JNDs were affected by the rate of the reference pulse train in a way that was consistent with greater noise or variability in loudness perception for the higher pulse rate. The results suggest that increasing pulse rate from 500 to 3000 pps can increase loudness JND by 60 % at the upper portion of the dynamic range. This is equivalent to a 38 % reduction in the number of discriminable steps for acoustic and speech intensities. PMID- 29532191 TI - Analysis of hard protein corona composition on selective iron oxide nanoparticles by MALDI-TOF mass spectrometry: identification and amplification of a hidden mastitis biomarker in milk proteome. AB - Surface active maghemite nanoparticles (SAMNs) are able to recognize and bind selected proteins in complex biological systems, forming a hard protein corona. Upon a 5-min incubation in bovine whey from mastitis-affected cows, a significant enrichment of a single peptide characterized by a molecular weight at 4338 Da originated from the proteolysis of aS1-casein was observed. Notably, among the large number of macromolecules in bovine milk, the detection of this specific peptide can hardly be accomplished by conventional analytical techniques. The selective formation of a stable binding between the peptide and SAMNs is due to the stability gained by adsorption-induced surface restructuration of the nanomaterial. We attributed the surface recognition properties of SAMNs to the chelation of iron(III) sites on their surface by sterically compatible carboxylic groups of the peptide. The specific peptide recognition by SAMNs allows its easy determination by MALDI-TOF mass spectrometry, and a threshold value of its normalized peak intensity was identified by a logistic regression approach and suggested for the rapid diagnosis of the pathology. Thus, the present report proposes the analysis of hard protein corona on nanomaterials as a perspective for developing fast analytical procedures for the diagnosis of mastitis in cows. Moreover, the huge simplification of proteome complexity by exploiting the selectivity derived by the peculiar SAMN surface topography, due to the iron(III) distribution pattern, could be of general interest, leading to competitive applications in food science and in biomedicine, allowing the rapid determination of hidden biomarkers by a cutting edge diagnostic strategy. Graphical abstract The topography of iron(III) sites on surface active maghemite nanoparticles (SAMNs) allows the recognition of sterically compatible carboxylic groups on proteins and peptides in complex biological matrixes. The analysis of hard protein corona on SAMNs led to the determination of a biomarker for cow mastitis in milk by MALDI-TOF mass spectrometry. PMID- 29532192 TI - Probing the application range and selectivity of a differential mobility spectrometry-mass spectrometry platform for metabolomics. AB - Metabolomics applications of differential mobility spectrometry (DMS)-mass spectrometry (MS) have largely concentrated on targeted assays and the removal of isobaric or chemical interferences from the signals of a small number of analytes. In the work reported here, we systematically investigated the application range of a DMS-MS method for metabolomics using more than 800 authentic metabolite standards as the test set. The coverage achieved with the DMS-MS platform was comparable to that achieved with chromatographic methods. High orthogonality was observed between hydrophilic interaction liquid chromatography and the 2-propanol-mediated DMS separation, and previously observed similarities were confirmed for the DMS platform and reversed-phase liquid chromatography. We describe the chemical selectivity observed for selected subsets of the metabolite test set, such as lipids, amino acids, nucleotides, and organic acids. Furthermore, we rationalize the behavior and separation of isomeric aromatic acids, bile acids, and other metabolites. Graphical abstract Differential mobility spectrometry-mass spectrometry (DMS-MS) facilitates rapid separation of metabolites of similar mass-to-charge ratio by distributing them across the compensation voltage range on the basis of their different molecular structures. PMID- 29532193 TI - Variations of L- and D-amino acid levels in the brain of wild-type and mutant mice lacking D-amino acid oxidase activity. AB - D-amino acids are now recognized to be widely present in organisms and play essential roles in biological processes. Some D-amino acids are metabolized by D amino acid oxidase (DAO), while D-Asp and D-Glu are metabolized by D-aspartate oxidase (DDO). In this study, levels of 22 amino acids and the enantiomeric compositions of the 19 chiral proteogenic entities have been determined in the whole brain of wild-type ddY mice (ddY/DAO+/+), mutant mice lacking DAO activity (ddY/DAO-/-), and the heterozygous mice (ddY/DAO+/-) using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). No significant differences were observed for L-amino acid levels among the three strains except for L-Trp which was markedly elevated in the DAO+/- and DAO-/- mice. The question arises as to whether this is an unknown effect of DAO inactivity. The three highest levels of L-amino acids were L-Glu, L-Asp, and L-Gln in all the three strains. The lowest L-amino acid level was L-Cys in ddY/DAO+/- and ddY/DAO-/- mice, while L-Trp showed the lowest level in ddY/DAO+/+mice. The highest concentration of D-amino acid was found to be D-Ser, which also had the highest % D value (~ 25%). D-Glu had the lowest % D value (~ 0.01%) in all the three strains. Significant differences of D-Leu, D-Ala, D-Ser, D-Arg, and D-Ile were observed in ddY/DAO+/- and ddY/DAO-/- mice compared to ddY/DAO+/+ mice. This work provides the most complete baseline analysis of L- and D-amino acids in the brains of ddY/DAO+/+, ddY/DAO+/-, and ddY/DAO-/- mice yet reported. It also provides the most effective and efficient analytical approach for measuring these analytes in biological samples. This study provides fundamental information on the role of DAO in the brain and may be relevant for future development involving novel drugs for DAO regulation. PMID- 29532194 TI - Combination of in situ metathesis reaction with a novel "magnetic effervescent tablet-assisted ionic liquid dispersive microextraction" for the determination of endogenous steroids in human fluids. AB - Herein, a novel magnetic effervescence tablet-assisted microextraction coupled to in situ metathesis reaction of ionic liquid (IS-META-ILDM) is presented for the determination of four endogenous steroids in human urine, pregnant women's blood, and fetal umbilical cord blood. The magnetic effervescent tablets, which were composed of Fe3O4 nanoparticles, sodium carbonate (alkaline source), and tartaric acid (acidic source), were used to disperse the extractant and for convenient magnetic separation. After the effervescent reaction, in situ reaction between NH4PF6 and [C6MIM]BF4 was adopted to change hydrophilic ionic liquid to hydrophobic liquid, which could be separated from the aqueous phase. The newly developed method has three obvious advantages: (1) combination of effervescent dispersion and magnetic nanoparticles' retrieval is cost-effective and the dispersion and collection of the extractant can be completed almost simultaneously; (2) as compared to temperature-controlled ionic liquid dispersive microextraction and cold-induced solidified microextraction, this method avoids a heating and cooling process which significantly reduces the extraction time and energy cost; and (3) the combination of adsorption by magnetic nanoparticles with extraction by in situ metathesis reaction easily produces high recoveries for target analytes. The optimized composition of effervescent tablet and experimental parameters are as follows: 0.64 g mixture of sodium carbonate and tartaric acid, 7 mg of Fe3O4 (20 nm) as magnetic sorbents, 40 MUL of [C6MIM]BF4 as the extraction solvent, 0.15 g NH4PF6, and 300 MUL of elution solvent. Under the optimized conditions, the newly developed method provided high extraction recoveries (90.0-118.5%) and low LODs (0.14-0.17 MUg L-1) in urine and blood samples. In total, this IS-META-ILDM method provided high extraction efficiency, fast and convenient separation, and underutilization of any organic solvent, and thus it has great potential for the determination of trace endogenous steroids in complex human fluids. Graphical abstract The newly developed method has three obvious advantages: combination of effervescent dispersion and magnetic nanoparticles' retrieval is cost-effective and the dispersion and collection of the extractant can be completed almost simultaneously. It avoids a heating and cooling process which significantly reduces the extraction time and energy cost and easily produces high recoveries for target analytes. PMID- 29532195 TI - The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. This contribution deals with the questions, from which sites CGRP is released, where it is drained and where it acts to cause its headache proliferating effects in the trigeminovascular system. RESULTS: The available literature suggests that the bulk of CGRP is released from trigeminal afferents both in meningeal tissues and at the first synapse in the spinal trigeminal nucleus. CGRP may be drained off into three different compartments, the venous blood plasma, the cerebrospinal fluid and possibly the glymphatic system. CGRP receptors in peripheral tissues are located on arterial vessel walls, mononuclear immune cells and possibly Schwann cells; within the trigeminal ganglion they are located on neurons and glial cells; in the spinal trigeminal nucleus they can be found on central terminals of trigeminal afferents. All these structures are potential signalling sites for CGRP, where CGRP mediates arterial vasodilatation but not direct activation of trigeminal afferents. In the spinal trigeminal nucleus a facilitating effect on synaptic transmission seems likely. In the trigeminal ganglion CGRP is thought to initiate long-term changes including cross signalling between neurons and glial cells based on gene expression. In this way, CGRP may upregulate the production of receptor proteins and pro-nociceptive molecules. CONCLUSIONS: CGRP and other big molecules cannot easily pass the blood brain barrier. These molecules may act in the trigeminal ganglion to influence the production of pronociceptive substances and receptors, which are transported along the central terminals into the spinal trigeminal nucleus. In this way peripherally acting therapeutics can have a central antinociceptive effect. PMID- 29532196 TI - Effect of GaAlAs low-level laser therapy on mouth opening after orthognathic surgery. AB - To evaluate low-level laser therapy (LLLT) as an adjunct to enhance postoperative mouth opening after orthognathic surgery. Prospective clinical trial of 82 patients allocated into an intervention group (laser, LG) and a control group (no laser, CG) and subgroups according to the procedure type : (1) surgically assisted rapid maxillary expansion (SARME); (2) maxillary surgery; (3) mandibular surgery; or (4) bimaxillary surgery. LG patients received LLLT immediately after surgery and every 24 h thereafter for 3 days, using a gallium-aluminum-arsenide (GaAlAs) diode laser (780 nm, 28 spots, 14 on each side of the face, output power 2 J/spot). Maximum mouth opening was measured using digital calipers at five time points: preoperative baseline and postoperative days 2, 7, 14, and 21. ANOVA was used to evaluate difference in mouth opening across groups. Significance was accepted at P <= 0.05. Final average mouth opening differed between women (GL1 = 94.24%, GC1 = 89.54%, GL2 = 69.39%; GC2 = 68.46%; GL3 = 65.11%; GC3 = 58.64%; GL4 = 61.85%; GC4 = 57.11%) and men (GL1 = 86.92%, GC1 = 102.44%, GL2 = 77.56%; GC2 = 81.65%; GL3 = 80.29%; GC3 = 67.63%; GL4 = 66.93%; GC4 = 55.31%). There were no significant differences between the SARME and isolated maxillary/mandibular surgery groups. In the bimaxillary groups, average mouth opening was increased in all patients who received LLLT, significantly so in male patients. LLLT with a GaAlAs diode laser (780 nm) did not affect postoperative mouth opening after SARME, isolated maxillary surgery, or isolated mandibular surgery. However, it improved mouth opening in men who had undergone bimaxillary orthognathic surgery. PMID- 29532197 TI - Keeping pace with the ebbs and flows in daily nursing home operations. AB - Nursing homes are challenged to develop staffing strategies that enable them to efficiently meet the healthcare demand of their residents. In this study, we investigate how demand for care and support fluctuates over time and during the course of a day, using demand data from three independent nursing home departments of a single Dutch nursing home. This demand data is used as input for an optimization model that provides optimal staffing patterns across the day. For the optimization we use a Lindley-type equation and techniques from stochastic optimization to formulate a Mixed-Integer Linear Programming (MILP) model. The impact of both the current and proposed staffing patterns, in terms of waiting time and service level, are investigated. The results show substantial improvements for all three departments both in terms of average waiting time as well as in 15 minutes service level. Especially waiting during rush hours is significantly reduced, whereas there is only a slight increase in waiting time during non-rush hours. PMID- 29532198 TI - Quantification of gait in children with mitochondrial disease. AB - Mitochondrial disorders are multisystem conditions that can potentially affect gait in many ways. The aim of this study was to select the optimal protocol to quantify the spatiotemporal parameters of gait in ambulatory children with mitochondrial disorders based on feasibility, test-retest reliability, and the difference between patients and controls. Gait at self-selected pace was quantified in ambulatory children with a genetically confirmed primary mitochondrial disease using the GAITRite electronic walkway. Three protocols were tested: pre-exercise, post-exercise (after a 3-min walking test), and recovery. In 14 ambulatory patients, we showed good to perfect reliability for velocity, cadence, step length, step time, step time variability, and step width in the recovery condition. The difference between patients and 70 individually age- and gender matched healthy controls only became apparent in the post-exercise protocol. In conclusion, measuring spatiotemporal parameters of gait using the GAITRite in ambulatory children with mitochondrial disease is feasible and reliable for most of the parameters measured. When using gait analysis in future studies in children with mitochondrial disease, we advise i) to use an exercise test prior to the gait analysis, ii) to let children practice the test before the actual data collection, and iii) not to use symmetry parameters. PMID- 29532199 TI - Temporal relationship between daily pain and actigraphy sleep patterns in pediatric sickle cell disease. AB - Limited research is available on the relationship between objective sleep patterns and pain in children with SCD. Research in other chronic pain populations suggests that the effect of sleep disruption on pain may be stronger than the effect of pain on sleep that night. To examine the bi-directional relationship between objective sleep patterns and daily pain in a pediatric SCD sample. Participants were 30 African American children with SCD 8-18 years (13 +/ 2.8 years; 66.7% female) with frequent pain. Children and parents completed questionnaires to assess pain, medications, and depression/anxiety. Over a 14-day period, children completed a pain diary and ambulatory actigraphy monitoring to assess nighttime sleep (duration, efficiency and WASO). Greater pain severity was associated with worse sleep efficiency and greater WASO that night, controlling for age, sex, opioid medication, and depression/anxiety symptoms. Worse sleep efficiency was associated with the occurrence of pain and more severe pain the next day. There was no relationship between WASO and pain. Similarly, sleep duration did not influence pain. Results lend support for a bi-directional relationship between sleep parameters and daily pain in pediatric SCD, and identify sleep as a potential target for future research and intervention. PMID- 29532201 TI - Induction immunosuppressive therapy in cardiac transplantation: a systematic review and meta-analysis. AB - Approximately 50% of heart transplant programs currently employ a strategy of induction therapy (IT) with either interleukin-2 receptor antagonists (IL2RA) or polyclonal anti-thymocyte antibodies (ATG) during the early postoperative period. However, the overall utility of such therapy is uncertain and data comparing induction protocols are limited. The authors searched PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov through January 2018 for randomized controlled trials (RCTs) or observational controlled studies of IT vs no IT and IL2RA vs ATG. Inverse variance fixed effects models with odds ratio (OR) as the effect measure were used for primary analyses. Main outcomes include moderate and severe rejection, all-cause mortality, infection, and cancer. The authors' search retrieved 2449 studies, of which 11 met criteria for inclusion (8 RCTs and 3 observational case-control studies). Quality of evidence for RCTs was moderate to high. Overall, patients receiving IT had similar risk of moderate-to-severe rejection, all-cause death, infection, and cancer with patients who did not receive IT. The use of IL2RA was associated with significantly higher risk of moderate-to-severe rejection than ATG (OR 3.4; 95% CI 1.4 to 8.1), but similar risk of death, infections, and cancer. The use of IT was not associated with any benefits or harms compared with no IT. Moderate-to severe rejection may be reduced by ATG compared with IL2RA. PMID- 29532200 TI - Oocyte cryopreservation for women with GATA2 deficiency. AB - PURPOSE: To describe controlled ovarian stimulation (COS) in a population of women with GATA2 deficiency, a genetic bone marrow failure syndrome, prior to allogeneic hematopoietic stem cell transplant METHODS: This is a retrospective case series of nine women with GATA2 deficiency who underwent oocyte preservation at a research institution. Main outcomes measured include baseline fertility characteristics ((antimullerian hormone (AMH) and day 3 follicle-stimulating hormone (FSH) and estradiol (E2)) and total doses of FSH and human menopausal gonadotropins (HMG), E2 on day of trigger, and total number of metaphase II oocytes retrieved. RESULTS: The mean age was 24 years [16-32], mean AMH was 5.2 ng/mL [0.7-10], and day 3 mean FSH was 5.1 U/L [0.7-8.1], and E2 was 31.5 pg/mL [< 5-45]. The mean dose of FSH was 1774 IU [675-4035], and HMG was 1412 IU [375 2925] with a mean E2 of 2267 pg/mL [60.7-4030] on day of trigger. The mean total of metaphase II oocytes was 7.7 [0-15]. One patient was diagnosed with a deep vein thrombosis (DVT) with pulmonary embolism (PE) during COS. CONCLUSION: This study is the first to analyze the outcomes of COS in women with GATA2 deficiency. The response to ovarian stimulation suggests that oocyte cryopreservation should be considered prior to gonadotoxic therapy. However, due to the risk of potentially life-threatening complications, it is prudent that patients are properly counseled of the risks and are evaluated by a multi-disciplinary medical team prior to COS. PMID- 29532202 TI - A systematic review and meta-analysis of outpatient treatment for acute diverticulitis. AB - BACKGROUND: The shift from routine antibiotics towards omitting antibiotics for uncomplicated acute diverticulitis opens up the possibility for outpatient instead of inpatient treatment, potentially reducing the burden of one of the most common gastrointestinal diseases in the Western world. PURPOSE: Assessing the safety and cost savings of outpatient treatment in acute colonic diverticulitis. METHODS: PubMed and EMBASE were searched for studies on outpatient treatment of colonic diverticulitis, confirmed with computed tomography or ultrasound. Outcomes were readmission rate, need for emergency surgery or percutaneous abscess drainage, and healthcare costs. RESULTS: A total of 19 studies with 2303 outpatient treated patients were included. These studies predominantly excluded patients with comorbidity or immunosuppression, inability to tolerate oral intake, or lack of an adequate social network. The pooled incidence rate of readmission for outpatient treatment was 7% (95%CI 6-9%, I2 48%). Only 0.2% (2/1288) of patients underwent emergency surgery, and 0.2% (2/1082) of patients underwent percutaneous abscess drainage. Only two studies compared readmission rates outpatients that had similar characteristics as a control group of inpatients; 4.5% (3/66) and 6.3% (2/32) readmissions in outpatient groups versus 6.1% (4/66) and 0.0% (0/44) readmissions in inpatient groups (p = 0.619 and p = 0.174, respectively). Average healthcare cost savings for outpatient compared with inpatient treatment ranged between 42 and 82%. CONCLUSION: Outpatient treatment of uncomplicated diverticulitis resulted in low readmission rates and very low rates of complications. Furthermore, healthcare cost savings were substantial. Therefore, outpatient treatment of uncomplicated diverticulitis seems to be a safe option for most patients. PMID- 29532203 TI - Perforated diverticulitis: is the right and left difference present here too? AB - BACKGROUND: It is unclear if location of disease matters in perforated diverticulitis. Management guidelines for perforated diverticulitis currently do not make a distinction between right perforated diverticulitis (RPD) and left perforated diverticulitis (LPD). We aim to compare disease presentation and management outcomes between RPD and LPD. METHODS: This was a 10-year retrospective comparative cohort study of 99 patients with acute perforated diverticulitis between 2004 and 2013 in a single institution. Patients were divided into RPD and LPD groups based on location of disease and compared. Disease presentation was compared using modified Hinchey classification. Management outcomes assessed were failure of therapy, length of stay, mortality, surgical complications, and disease recurrence. Univariate analysis was performed using Student's t test and chi2 test where appropriate. RESULTS: RPD patients were younger (45.7 +/- 16.1 versus 58.3 +/- 14.7 years) and presented with lower modified Hinchey stage and no Hinchey IV diverticulitis when compared to LPD (14.3% Hinchey III versus 44.0% Hinchey III or IV). Conservative management of Hinchey I and II RPD and LPD was similarly successful (96.1 versus 96.5%), although RPD patients had shorter inpatient stay (4.6 +/- 2.2 versus 6.3 +/- 3.8 days) and less disease recurrence (3.1 versus 17.9%). Ten (20.4%) Hinchey I and II RPD patients were initially misdiagnosed with appendicitis and underwent surgery. CONCLUSION: LPD is a more aggressive disease presenting with greater clinical severity in older patients and is associated with frequent disease recurrence when treated conservatively. Misdiagnosis of RPD as appendicitis is common and may lead to unnecessary surgery. PMID- 29532204 TI - Non-visible colovesical fistula located by cystoscopy and successfully managed with the novel Padlock(r) device for endoscopic closure. AB - INTRODUCTION: The development of novel mechanical endoscopic closure systems allows now the management of some gastrointestinal fistula types in a minimally invasive way. However, the correct location of the fistulous tract is essential to achieve successful endoscopic closure. CASE REPORT: A 69-year-old woman with high risk for surgery presented with recurrent cystitis, pneumaturia, and enteruria 2 months after medical-treated diverticulitis. Computerized tomography demonstrated colovesical fistula but colonoscopy could not locate the fistulous opening. A cystoscopy was performed and the fistulous tract was shown using a guidewire. Then, a novel over-the-scope clip device Padlock(r) system was released in the sigmoid colon, with successful endoscopic closure through this not previously described collaborative approach between urologists, surgeons, and gastroenterologists. PMID- 29532205 TI - Improved perioperative care is associated with improved long-term survival in colorectal cancer. AB - PURPOSE: To compare perioperative colorectal cancer care and survival in patient cohorts operated in 2005 and in 2010 in Lithuania. METHODS: Comparative observational cohort study was performed. The study was conducted in the three Lithuanian cancer hospitals. Patients, who underwent curative surgery for colorectal cancer in 2005 and 2010, were included. Demographic characteristics, distribution of the tumors, preoperative diagnostics and staging, surgical treatment, the quality of pathological examination, morbidity, and mortality were analyzed. One- and 5-year overall survival data were compared between the groups. RESULTS: Colorectal cancer diagnostics and treatment improved from 2005 to 2010 significantly. The disease was identified as stage III-IV for 45 vs. 48% of the patients; however, computed tomography staging scan was performed only for 5.9 vs. 17.8% in 2005 and 2010, respectively. Laparoscopic operations were performed 1.5 vs. 10.5% and abdominoperineal resections-42.7 vs. 31.7% in 2005 and 2010, respectively. The number of harvested lymph nodes was mentioned in 55.8 vs. 97.7% of the cases, whereas more than 12 lymph nodes were examined in 18 vs. 66.6% of cases after histological examination. The overall 5-year survival was 52.1 vs. 63.1% (p < 0.0001), while the 5-year survival of the patients with stage IV of disease was 4.2 vs. 17.8% in 2005 and 2010, respectively. CONCLUSION: Preoperative investigation, surgical treatment, pathological examination, and postoperative course are associated with improved overall survival in colorectal cancer patients, undergoing curative surgery in the resource-limited settings. PMID- 29532206 TI - Metachronous colorectal cancer risk in Lynch syndrome patients-should the endoscopic surveillance be more intensive? AB - PURPOSE: Regular follow-up for patients with Lynch syndrome (LS) is vital due to the increased risk of colorectal (50-80%), endometrial (40-60%), and other cancers. However, there is an ongoing debate concerning the best interval between colonoscopies. Currently, no specific endoscopic follow-up has been decided for LS patients who already have an index colorectal cancer (CRC). The aim of this study was to evaluate the risk of metachronous cancers (MC) after primary CRC in a LS population and to determinate if endoscopic surveillance should be more intensive. METHODS: A prospective cohort of patients with a confirmed diagnosis of hereditary CRC since 2009 was included. Patients with LS and a primary CRC were the cohort of choice. RESULTS: One hundred twenty-one patients were included with a median age of 44 years(16-70). At least one MC occurred in 39 patients (32.2%), with a median interval of 67 months (6-300) from index cancer. Fifteen (38.5%) developed two or more MCs during follow-up, with a median number of two (2-6) tumors occurring. Metachronous CRC were diagnosed after a median interval of 24 (6-57) months since last colonoscopy and were more commonly seen in MSH2 mutation carriers (58 vs. 35%, p = 0.001). After a median follow-up of 52.9 (3 72) months, no cancer-related deaths were recorded. CONCLUSION: Patients with LS have an increased risk of MC, especially CRCs. With a median time period of 24 months between colonoscopy and metachronous CRC, the interval between surveillance colonoscopies following primary CRC should not exceed 18 months, especially in patients with MSH2 mutation. PMID- 29532207 TI - Recurrence rate of lateral margin-positive cases after en bloc endoscopic submucosal dissection of colorectal neoplasia. AB - PURPOSE: We aimed to evaluate the recurrence rate of colorectal neoplasia showing histologic lateral margin involvement after en bloc endoscopic submucosal dissection (ESD). METHODS: We reviewed 527 colorectal lesions that were removed by en bloc ESD from 2005 to 2013 and followed by endoscopy. Based on the postprocedural pathologic reports, the lesions were categorized as follows: lesions with clear deep and positive lateral margins (n = 63) and lesions with R0 resection (n = 299). RESULTS: The tumor size was 45.7 +/- 21.1 mm in the lateral margin-positive group and 30.6 +/- 15.1 in the R0 group (P < 0.001). Procedure time was longer in the lateral margin-positive group than in the R0 group (94.3 +/- 75.1 vs. 54.1 +/- 48.9 min; P < 0.001). Lateral margin positivity was associated with ESD time >= 120 min in the multivariate analysis. Compared with 0 I morphology, LST-G was significantly associated with the lateral margin positivity. The volume of ESD experience in endoscopists may also be associated with the lateral margin positivity. Histologic reassessment of the specimen suggested that 32.2% of lateral margin-positive cases based on the initial pathology report were false-positive lateral margin involvement. The 5-year cumulative recurrence rate was 0.6% in the R0 group and 5% in the margin-positive group (P = 0.198). CONCLUSIONS: The local recurrence rate was not higher in lateral margin-positive cases than in R0 resection cases if the colorectal epithelial neoplasia was removed in an en bloc manner using ESD. Meticulous pathologic interpretation may reduce unnecessarily frequent surveillance after en bloc ESD. PMID- 29532208 TI - The fate of preserved sphincter in rectal cancer patients. AB - PURPOSE: Sphincter-saving surgery is widely accepted operative modality to treat rectal cancer. It often requires temporary diverting stoma to avoid the complications of anastomotic failure. This study investigates the cumulative failure rate in sphincter preservation for rectal cancer and the risk factors associated with the permanent stoma. METHODS: A retrospective study on 358 patients diagnosed with primary rectal cancer from 2009 to 2013 was conducted at a single institute. Three hundred and thirty-one out of 358 patients with rectal cancer located within 12 cm from the anal verge, who underwent sphincter preserving surgery, were included in this study. The cumulative rate for permanent stoma was calculated. Univariate and multivariate analysis were performed, comparing the patients with stoma to the ones without. RESULTS: Temporary diverting stoma was created in 223 (82%) patients. After median follow up of 42 months, 18 patients (6.6%) persistently used temporary stoma or required re-creation of stoma. Univariate analysis revealed that BMI, tumor location below 4 cm from the anal verge, coloanal anastomosis, anastomotic leakage, and local recurrence were significantly associated with persistent use or re-formation of stoma. Multivariate analysis showed that anastomotic leakage (OR 50.3; 95% CI, 10.1-250.1; p < 0.0001) and local recurrence (OR 11.3; 95% CI, 1.61-78.5; p = 0.015) were the independent risk factors. CONCLUSION: Patients with anastomotic leakage and local recurrence are at high risk for permanent stoma. Not only should patients be fully informed of possible failure in sphincter preservation preoperatively, but also patient-oriented decision should be made on patient tailored surgical plan. PMID- 29532209 TI - Long-term outcomes after stenting as a bridge to surgery in patients with obstructing left-sided colorectal cancer. AB - PURPOSE: Self-expandable metallic stents (SEMS) may be used in acute, obstructing, left-sided colorectal cancer (CRC) to avoid high-risk emergency surgery. However, the data regarding the long-term effects of SEMS as a bridge to surgery are limited and contradictory. Our aim is to analyze the long-term oncological outcomes of SEMS compared with surgery. METHODS: Between January 2006 and November 2013, a total of 855 patients with stage III CRC were regularly followed at the CRC clinic of Severance Hospital, Seoul, Korea. We retrospectively evaluated their 5-year disease-free survival (DFS), 5-year overall survival (OS), and 5-year cancer-specific survival (CSS). RESULTS: There were 94 patients in the SEMS group, 17 in the emergent-surgery group, and 744 in the elective-surgery group. In the short term, the rate of permanent stoma formation was significantly higher in the emergent-surgery group than in the SEMS group (p = 0.030), although the median hospital stay and overall complication rate were comparable. During the long-term follow-up period, oncological outcomes including 5-year DFS (70.2 vs 52.9%; p = 0.210), OS (70.2 vs 52.9%; p = 0.148), and CSS (79.8 vs 70.6%; p = 0.342) were not different between the SEMS group and the emergent-surgery group. Multivariate analysis showed emergent operation to be a significant risk factor of DFS (hazard ratio [HR], 3.117; 95% confidence interval [CI], 1.498-6.489; p = 0.002). CONCLUSIONS: Preoperative SEMS insertion does not adversely affect long-term oncological outcomes or patient survival. PMID- 29532211 TI - Correction to: Anal canal squamous cell cancer: are surgical alternatives to chemoradiation just as effective? AB - One of the author's middle name of this article was incorrectly published as "Emmanouil E. Pappou." This is now presented correctly in this article as "Emmanouil P. Pappou." PMID- 29532212 TI - Predicting methotrexate resistance in rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is an incurable, systemic autoimmune disease that decreases quality of life and can lead to severe disability. While there are many medications available to treat RA, the first-line of therapy is low-dose methotrexate (MTX), a small molecule disease-modifying anti-rheumatic drug (DMARD). MTX is the recommended therapy due to its affordability and efficacy in reducing symptoms in most RA patients. Unfortunately, there is great person-to person variability in the physiological response to MTX, with up to 50% of patients showing little response to the medication. Thus, many RA patients initially placed on MTX do not experience an adequate reduction of symptoms, and could have benefited more in both the short and long terms if initially prescribed a different drug that was more effective for them. To combat this problem and better guide treatment decisions, many research groups have attempted to develop predictive tools for MTX response. Currently, there is no reliable, clinical-grade method to predict an individual's response to MTX treatment. In this review, we describe progress made in the area of MTX non-response/resistance in RA patients. We specifically focus on application of the following elements as predictive markers: proteins related to MTX transport and function, intracellular MTX concentration, immune cell frequencies, cytokines, and clinical factors. PMID- 29532214 TI - Development and Feasibility of a Community-Based, Culturally Flexible Colorectal Cancer Prevention Program. AB - Comprehensive cancer centers are an important community resource for cancer prevention education in their catchment areas. Colorectal cancer remains one of the most commonly diagnosed cancers in the United States, making prevention a priority. Colorectal cancer prevention targets include lifestyle modifications that are influenced by cultural norms, such as diet change, physical activity and screening behavior. Cancer centers must tailor prevention efforts to multiethnic catchment areas. This paper describes the development and feasibility of a comprehensive cancer center's approach to community-based colorectal cancer prevention in Houston, Texas, specifically targeting Hispanic and Asian populations. Sites were recruited through a city-wide network of partnerships between the community relations department in the hospital and community organizations. The program consisted of three workshop-style classes per community site. Each class had a similar overall structure, but cultural and site specific adaptations were made for each group. A total of 33 classes were taught at nine distinct community sites to 1054 participants over 9 months. This program structure may be adapted for the future dissemination of other cancer prevention tools to communities in the area. PMID- 29532213 TI - Treatment of inflammatory bowel disease via green tea polyphenols: possible application and protective approaches. AB - Inflammatory bowel disease (IBD) is a collection of inflammatory conditions of colon and small intestine which affect millions of individuals worldwide and the prevalence amount is on the rise. The organ failure as well as loss of tissue function is because of the inflammatory reaction which is the major contributor of tissue healing leading to lifelong debilitation. To stop the tough consequences of inflammation every patient pursues alternative therapy to relieve symptoms. Green tea polyphenols (GTPs) play significant roles in down regulating signaling pathways because GTPs exert effective antioxidant properties and regulate Toll-like receptor 4 (TLR4) expression via certain receptor, inhibited endotoxin-mediated tumor necrosis factor alpha (TNF-alpha) production by blocking transcription nuclear factor-kappa B (NF-kB) activation and upstream of mediated I kappa B kinase complex pathway activities, as well as intrusion with the flow of cytokines and synthesis of cyclooxygenase-2 (COX-2). This article highlights the green approach regarding the defensive effects of GTP review-related studies concerning the contrary effects and the key therapeutic targets application of GTPs in biomedical field to treat inflammatory bowel disease (IBD) and its complications. . PMID- 29532215 TI - Tobacco Control Policy Adoption Dynamics: A Case Study of Missouri Communities. AB - Tobacco control policies reduce the health and economic burden caused by tobacco. With over half of the United States communities lacking adequate protective policies, an examination of policy adoption factors can provide insights to facilitate policy adoption. A case study approach examines the rate of adoption, prominent media frames, policy leaders' perceptions and coalition activities for smokefree and Tobacco 21 policies adopted in Missouri. Findings show compared to smokefree policy, Tobacco 21 requires a considerably shorter timeframe and fewer resources for adoption. Tobacco 21 coalitions target a small group of stakeholders compared to smokefree coalitions' emphasis on broad community engagement. Both policies are formally opposed, but elected officials perceive less political risk supporting Tobacco 21. As a new tobacco control policy tool, Tobacco 21 has relative advantage that should be considered by community health advocates. PMID- 29532216 TI - Early isolated optic neuropathy caused by cyclosporine. AB - PURPOSE: To examine, for the first time, whether cyclosporine intake has an early isolated effect on the optic nerve. MATERIALS AND METHODS: This observational case series consisted of 192 eyes of 98 patients treated with cyclosporine. Patient age and duration and dosage of cyclosporine were recorded, and visual acuity, optic nerve function, visual fields, and visual evoked potential (VEP) were tested. Fundus examination was also performed. Patients with glaucoma, vascular retinopathies, and deep amblyopia were excluded. RESULTS: Mean patient age was 46 years, average duration of treatment was 6 years, and median dosage of cyclosporine was 200 mg daily. VEP was tested in 73 patients (142 eyes) and yielded a delayed P100 wave in 9 (12.32%) (14 eyes). Among these 9 patients, abnormal findings were also noted on the Ishihara colour test in 42.86% of the eyes, and on the visual field test in 64.3% of the eyes. Abnormal VEP showed a significant correlation (p < 0.05) with older age (> 46 years) and a non significant correlation with longer duration of treatment. Higher abnormal VEP potential was not correlated with higher cyclosporine dose, and there was no correlation between abnormal VEP and blood level of cyclosporine. CONCLUSION: Optic neuropathy was significantly associated with older age in cyclosporine treated patients. A correlation between optic neuropathy with longer duration of cyclosporine treatment was noted but was not statistically significant. We suggest that tests of optic nerve function, including VEP, be a part of the follow-up of patients receiving cyclosporine. PMID- 29532217 TI - Z-LASIK and Trans-PRK for correction of high-grade myopia: safety, efficacy, predictability and clinical outcomes. AB - PURPOSE: The aim of the study was to examine the outcomes of transepithelial photorefractive keratectomy (Trans-PRK) and Femtosecond Laser-assisted in situ keratomileusis (Z-LASIK) for the correction of high myopia. METHODS: A retrospective cohort study design was used. The study group included 792 eyes with high-grade myopia (- 6.0 diopters or higher) or high-grade myopia with astigmatism that were treated with Z-LASIK or Trans-PRK in 2013 through 2014 in an optical outpatient clinic of a large private medical service. The Trans-PRK group comprised of 674 eyes with a spherical equivalent (SE) of - 7.87 +/- 1.46 and the Z-LASIK group comprised of 118 eyes with a SE of - 7.19 +/- 0.81 (P < 0.001). RESULTS: The mean postoperative SE in the Trans-PRK group was - 0.06 and 0.02 in the Z-LASIK group (P = 0.545). Efficacy index values were 0.92 in the Trans-PRK group and 0.95 in the Z-LASIK group (P = 0.083), and corresponding safety index values were 0.95 and 0.97 (P = 0.056). An UCVA of 20/40 or better was achieved in 94.20% of eyes in the Trans-PRK group, and 98.31% in the Z-LASIK group (P = 0.063). The majority of eyes in both the Trans-PRK and Z-LASIK groups were within +/- 0.5D of attempted correction: 59.35 and 64.71%, respectively (P = 0.271). CONCLUSIONS: Both Trans-PRK and Z-LASIK demonstrated excellent efficacy, safety and predictability profiles, with results comparable and in some cases superior to the current literature. Results of Z-LASIK were slightly better than those of Trans-PRK, though the preoperative SE of the latter was higher. PMID- 29532218 TI - Acanthamoeba of three morphological groups and distinct genotypes exhibit variable and weakly inter-related physiological properties. AB - Free-living amoeba of the genus Acanthamoeba can eventually act as parasites, causing infections in humans. Some physiological characteristics of Acanthamoeba have been related to the grade of pathogenicity, allowing inferences about the pathogenic potential. The main goal of this study was to characterize isolates of Acanthamoeba obtained in Brazil and evaluate properties associated with their pathogenicity. A total of 39 isolates obtained from keratitis cases (n = 16) and environmental sources (n = 23) were classified into morphological groups and genotyped by sequencing the 18S rDNA fragments ASA.S1 and GTSA.B1. Samples were also tested regarding their thermo-tolerance, osmo-tolerance, and cytopathogenicity in MDCK cells. Isolates were identified and classified as follows: group I (T17, T18); group II (T1, T3, T4, T11); and group III (T5, T15), with the predominance of genotype T4 (22/39). Clinical isolates were genotyped as T3 (1/16), T4 (14/16) and T5 (1/16). The majority of isolates (38/39) were able to grow at 37 degrees C, but tolerance to 40 degrees C was more frequent among environmental samples. The tolerance to 1 M mannitol was infrequent (4/39), with three of these corresponding to clinical samples. The variable ability to cause cytopathic effects was observed among isolates of distinct genotypes and origins. This study identified, for the first time, T1 and T18 in Brazil. It also indicated a weak association between the clinical origin of the isolates and tolerance to high temperatures, high osmolarity, and cytopathogenicity, demonstrating that some in vitro parameters do not necessarily reflect a higher propensity of Acanthamoeba to cause a disease. PMID- 29532219 TI - The first report of Cryptosporidium spp. in Microtus fuscus (Qinghai vole) and Ochotona curzoniae (wild plateau pika) in the Qinghai-Tibetan Plateau area, China. AB - Cryptosporidium is one of the most important genera of intestinal zoonotic pathogens, which can infect various hosts and cause diarrhoea. There is little available information about the molecular characterisation and epidemiological prevalence of Cryptosporidium spp. in Microtus fuscus (Qinghai vole) and Ochotona curzoniae (wild plateau pika) in the Qinghai-Tibetan Plateau area of Qinghai Province, Northwest China. Therefore, the aim of this study was to determine Cryptosporidium species/genotypes and epidemiological prevalence in these mammals by detecting the SSU rRNA gene by PCR amplification. The Cryptosporidium spp. infection rate was 8.9% (8/90) in Qinghai voles and 6.25% (4/64) in wild plateau pikas. Positive samples were successfully sequenced, and the following Cryptosporidium species were found: C. parvum, C. ubiquitum, C. canis and a novel genotype in Qinghai voles and C. parvum and a novel genotype in wild plateau pikas. This is the first report of Cryptosporidium infections in M. fuscus and wild O. curzoniae in Northwest China. The results suggest the possibility of Cryptosporidium species transmission among these two hosts, the environment, other animals and humans and provide useful molecular epidemiological data for the prevention and control of Cryptosporidium infections in wild animals and the surrounding environments. The results of the present study indicate the existence of Cryptosporidium species infections that have potential public health significance. This is the first report of Cryptosporidium multi-species infections in these animal hosts. PMID- 29532220 TI - Anti-amoebic activity of acyclic and cyclic-samarium complexes on Acanthamoeba. AB - This work investigated the anti-amoebic activity of two samarium (Sm) complexes, the acyclic complex [bis(picrato)(pentaethylene glycol)samarium(III)] picrate referred to as [Sm(Pic)2(EO5)](Pic)-and the cyclic complex [bis(picrato)(18-crown 6)samarium(III)] picrate-referred to as [Sm(Pic)2(18C6)](Pic). Both Sm complexes caused morphological transformation of the protozoa Acanthamoeba from its native trophozoite form carrying a spine-like structure called acanthopodia, to round shaped cells with loss of the acanthopodia structure, a trademark response to environmental stress. Further investigation, however, revealed that the two forms of the Sm complexes exerted unique cytotoxicity characteristics. Firstly, the IC50 of the acyclic complex (0.7 MUg/mL) was ~ 10-fold lower than IC50 of the cyclic Sm complex (6.5 MUg/mL). Secondly, treatment of the Acanthamoeba with the acyclic complex caused apoptosis of the treated cells, while the treatment with the cyclic complex caused necrosis evident by the leakage of the cell membrane. Both treatments induced DNA damage in Acanthamoeba. Finally, a molecular docking simulation revealed the potential capability of the acyclic complex to form hydrogen bonds with profilin-a membrane protein present in eukaryotes, including Acanthamoeba, that plays important roles in the formation and degradation of actin cytoskeleton. Not found for the cyclic complex, such potential interactions could be the underlying reason, at least in part, for the much higher cytotoxicity of the acyclic complex and also possibly, for the observed differences in the cytotoxicity traits. Nonetheless, with IC50 values of < 10 MUg/mL, both the acyclic and cyclic Sm complexes feature a promising potential as cytotoxic agents to fight amoebic infections. PMID- 29532221 TI - Pelvic floor ultrasound in the diagnosis of sling complications. AB - PURPOSE: The mid-urethral synthetic sling (MUS) procedure has become the standard of care for treatment of female stress urinary incontinence. However, a small number of patients will have complications following MUS including failure, obstructive voiding, sling erosion, or chronic pain. This paper discusses the role of 2D and 3D ultrasound imaging in the evaluation of the female patient with complications following placement of a synthetic mid-urethral sling. RESULTS: The MUS is easily visualized as an echogenic structure on ultrasound and can be imaged by transperineal, transvaginal and introital approaches. Ultrasound allows dynamic assessment of the sling and can assist in the diagnosis of sling failure, obstruction, erosion and mesh related pain. CONCLUSIONS: Pelvic floor ultrasound has an emerging role in the assessment of complications following MUS surgery. 3D ultrasound can assist the clinician in assessment of the complex patient with multiple slings or meshes in situ. PMID- 29532223 TI - Scientific Session of the 16th World Congress of Endoscopic Surgery, Jointly Hosted by Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) & Canadian Association of General Surgeons (CAGS), Seattle, Washington, USA, 11-14 April 2018: Podium Abstracts. PMID- 29532222 TI - Comparison of functional outcomes of robotic and open partial nephrectomy in patients with pre-existing chronic kidney disease: a multicenter study. AB - BACKGROUND: We compared renal functional outcomes of robotic (RPN) and open partial nephrectomy (OPN) in patients with chronic kidney disease (CKD), a definite indication for nephron-sparing surgery. METHODS: A multicenter retrospective analysis of OPN and RPN in patients with baseline >= CKD Stage III [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2] was performed. Primary outcome was change in eGFR (DeltaeGFR, mL/min/1.73 m2) between preoperative and last follow-up with respect to RENAL nephrometry score group [simple (4-6), intermediate (7-9), complex (10-12)]. Secondary outcomes included eGFR decline > 50%. RESULTS: 728 patients (426 OPN, 302 RPN, mean follow-up 33.3 months) were analyzed. Similar RENAL score distribution (p = 0.148) was noted between groups. RPN had lower median estimated blood loss (p < 0.001), and hospital stay (3 vs. 5 days, p < 0.001). Median ischemia time (OPN 23.7 vs. RPN 21.5 min, p = 0.089), positive margin (p = 0.256), transfusion (p = 0.166), and 30-day complications (p = 0.208) were similar. For OPN vs. RPN, mean DeltaeGFR demonstrated no significant difference for simple (0.5 vs. 0.3, p = 0.328), intermediate (2.1 vs. 2.1, p = 0.384), and complex (4.9 vs. 6.1, p = 0.108). Cox regression analysis demonstrated that decreasing preoperative eGFR (OR 1.10, p = 0.001) and complex RENAL score (OR 5.61, p = 0.03) were independent predictors for eGFR decline > 50%. Kaplan-Meier analysis demonstrated 5-year freedom from eGFR decline > 50% of 88.6% for OPN and 88.3% for RPN (p = 0.724). CONCLUSIONS: RPN and OPN demonstrated similar renal functional outcomes when stratified by tumor complexity group. Increasing tumor age and tumor complexity were primary drivers associated with functional decline. RPN provides similar renal functional outcomes to OPN in appropriately selected patients. PMID- 29532224 TI - Diagnostic and therapeutic single-operator cholangiopancreatoscopy with SpyGlassDSTM: results of a multicenter retrospective cohort study. AB - BACKGROUND AND AIMS: The aim of the study was to evaluate the usefulness and diagnostic and therapeutic outcome of the single-operator cholangiopancreatoscopy (SOC) with SpyGlassDSTM. METHODS: In a retrospective multicenter study between November 2015 and January 2017, SpyGlassDSTM procedures were analyzed in participating centers. Indications, accuracy of SOC-guided biopsies, management of large bile duct stones, and complications were analyzed. Follow-up was 4 months. RESULTS: Two hundred and six patients out of 250 examinations were evaluated. Indications were biliary stones (n = 132), bile duct stenosis (n = 93), stones and stenosis combined (n = 24), and bile duct leakage (n = 1). Of the 117 cases which were suspicious of malignancy, in 99 cases the lesion could be stratified into benign (n = 55) or malignant (n = 44) indicating a sensitivity of 95.5% and a specificity of 94.5% for the indication tumor. SOC-guided biopsies revealed a sensitivity of 57.7% with a specificity of 100%. In 107 examinations, biliary stones were visualized and could be completely removed in 91.1% with a need of three procedures (range 1-6) to achieve final stone clearance. In 75 cases, lithotripsy was performed and was successful in 71 cases (95%). Four out of 45 patients (8.9%) underwent cholecystectomy with surgical bile duct revision as a final therapy. Adverse Event (AE) occurred in 33/250 patients (13.2%) and Serious Adverse Event (SAE) occurred in 1/250 patients (0.4%). Cholangitis was 1% (n = 102) after peri-interventional administration of antibiotics and 12.8% (n = 148) without antibiotic prophylaxis (p < 0.001). CONCLUSIONS: SOC with SpyGlassDSTM became a new standard for the diagnosis of indefinite biliary lesions and therapy of large bile duct stones. The diagnostic yield of SOC-guided biopsies facilitated a definite diagnosis in most cases and should be improved by standardized biopsy protocols. SOC-guided interventions allowed removal of large biliary stones by SOC-guided lithotripsy. The complication rate of 13.2% can be considerably reduced by use of a single-shot antibiotic treatment. PMID- 29532225 TI - A molecular dynamics approach to explore the structural characterization of cataract causing mutation R58H on human gammaD crystallin. AB - The crystallins are a family of monomeric proteins present in the mammalian lens and mutations in these proteins cause various forms of cataracts. The aim of our current study is to emphasize the structural characterization of aggregation propensity of mutation R58H on gammaD crystallin using molecular dynamics (MD) approach. MD result revealed that difference in the sequence level display a wide variation in the backbone atomic position, and thus exhibits rigid conformational dynamics. Changes in the flexibility of residues favoured to increase the number of intra-molecular hydrogen bonds in mutant R58H. Moreover, notable changes in the hydrogen bonding interaction resulted to cause the misfolding of mutant R58H by introducing alpha-helix. Principal component analysis (PCA) result suggested that mutant R58H showed unusual conformational dynamics along the two principal components when compared to the wild-type (WT)-gammaD crystallin. In a nutshell, the increased surface hydrophobicity could be the cause of self-aggregation of mutant R58H leading to aculeiform cataract. PMID- 29532226 TI - A novel matrine derivative WM622 inhibits hepatocellular carcinoma by inhibiting PI3K/AKT signaling pathways. AB - Hepatocellular carcinoma (HCC) is among the most common lethal cancers of the digestive system with poor prognosis rates and ineffective therapeutic options. Matrine, a traditional Chinese medicine found in the roots of sophora species, has been used in the clinical treatment of liver fibrosis, chronic hepatitis B and other diseases. We have synthesized a matrine derivatives named WM622 (C26H35ON3S2) with a significant inhibitory effect on transplanted tumors in vivo. The half inhibitory concentration (IC50) of WM622 is 34 uM, which is much lower than matrine. WM622 inhibited the proliferation and promoted apoptosis of hepatocellular carcinoma cells significantly, and the cell cycle was blocked in G0/G1 phase. The protein phosphorylation levels of EGFR, AKT, PI3K and GSK3beta (p-EGFR, p-AKT, p-PI3K, and p-GSK3beta) were also decreased by WM622 treatment dose dependently. In tumor-bearing mice, WM622 could reduce the tumor volumes. In conclusion, the study demonstrated that WM622 could inhibit the proliferation of the hepatocellular carcinoma both in vivo and in vitro by inducing apoptosis, blocking cell cycle in G0/G1 phase and inhibiting the PI3K/AKT signal pathways. PMID- 29532227 TI - Predictors of recurrence and survival of pathological T1N0M0 invasive adenocarcinoma following lobectomy. AB - BACKGROUND: This retrospective research was designed to investigate the relationship between pT1N0M0 invasive adenocarcinoma (IADC) harboring solid (SOL) and/or micropapillary (MIP) components and its prognosis following lobectomy. METHODS: Clinical data of pT1N0M0 IADC patients were retrospectively collected from Shanghai Chest Hospital. Survival curves were plotted by Kaplan-Meier methods. Multivariable cox regressions were conducted to discover the independent risk factors of recurrence-free survival (RFS) and overall survival (OS), through which nomograms were performed to visualize the risk of recurrences and outcomes in personalized information. RESULTS: Totally, 1965 patients were enrolled, including 248 harboring SOL/MIP and 1717 not. IADC demonstrated worse 5-year RFS (81.9 vs. 92.2%, p < 0.001) and OS (85.7 vs. 94.4%, p < 0.001) when harboring SOL and/or MIP components. And this status became an independent factor associated with poorer RFS (HR 2.445, 95% CI 1.565-3.821, p < 0.001) and OS (HR 2.139, 95% CI 1.180-3.878, p = 0.012) instead of novel classification of IADC predominant patterns. No difference existed between SOL/MIP predominant and minor patterns. In addition, age > 60, smoking, post-chemotherapy and T1b were all indicating poorer RFS and smoking was also related with worse OS. The c-indexes of nomograms were 0.723 for RFS (95% CI, 0.662-0.784) and 0.703 for OS (95% CI, 0.629-0.777) respectively. CONCLUSIONS: Once the pT1N0M0 IADC harboring SOL/MIP, it strongly indicated the worse clinical recurrence and survival outcome, no matter whether the SOL and/or MIP was predominant. Smoking was correlated with worse prognosis for those patients. Age > 60 and stage T1b also indicated poorer RFS. Whether post-chemotherapy was harmful to pT1N0M0 IADC patients needed further research. PMID- 29532228 TI - High MLL2 expression predicts poor prognosis and promotes tumor progression by inducing EMT in esophageal squamous cell carcinoma. AB - BACKGROUND: MLL2 has been identified as one of the most frequently mutated genes in a variety of cancers including esophageal squamous cell carcinoma (ESCC). However, its clinical significance and prognostic value in ESCC has not been elucidated. In the present study, we aimed to investigate the expression and role of MLL2 in ESCC. METHODS: Immunohistochemistry (IHC) and qRT-PCR were used to examine the expression profile of MLL2. Kaplan-Meier survival analysis and univariate and multivariate Cox analyses were used to investigate the clinical and prognostic significance of MLL2 expression in Kazakh ESCC patients. Furthermore, to evaluate the biological function of MLL2 in ESCC, we applied the latest gene editing technique CRISPR/Cas9 to knockout MLL2 in ESCC cell line Eca109. MTT, colony formation, flow cytometry, scratch wound-healing and transwell migration assays were performed to investigate the effect of MLL2 on ESCC cell proliferation and migration. The correlation between MLL2 and epithelial-mesenchymal transition (EMT) was investigated by Western blot assay in vitro and IHC in ESCC tissue, respectively. RESULTS: Both mRNA and protein expression levels of MLL2 were significantly overexpressed in ESCC patients. High expression of MLL2 was significantly correlated with TNM stage (P = 0.037), tumor differentiation (P = 0.032) and tumor size (P = 0.035). Kaplan-Meier survival analysis showed that patients with low MLL2 expression had a better overall survival than those with high MLL2 expression. Multivariate Cox analysis revealed that lymph node metastasis and tumor differentiation were independent prognostic factors. Knockout of MLL2 in Eca109 inhibited cell proliferation and migration ability, induced cell cycle arrest at G1 stage, but it had no significant effect on apoptosis. In addition, knockout of MLL2 could inhibit EMT by up-regulation of E-Cadherin and Smad7 as well as down-regulation of Vimentin and p-Smad2/3 in ESCC cells. In cancer tissues, the expression of E-Cadherin was negatively correlated with MLL2 expression while Vimentin expression was positively correlated with MLL2 expression. CONCLUSION: Our results indicate that overexpression of MLL2 predicts poor clinical outcomes and facilitates ESCC tumor progression, and it may exert oncogenic role via activation of EMT. MLL2 may be used as a novel prognostic factor and therapeutic target for ESCC patients. PMID- 29532229 TI - County socioeconomic characteristics and pediatric renal transplantation outcomes. AB - BACKGROUND: Existing risk adjustment models for solid organ transplantation omit socioeconomic status (SES). With limited data available on transplant candidates' SES, linkage of transplant outcomes data to geographic SES measures has been proposed. We investigate the utility of county SES for understanding differences in pediatric kidney transplantation (KTx) outcomes. METHODS: We identified patients < 18 years of age receiving first-time KTx using United Network for Organ Sharing registry data in two eras: 2006-2010 and 2011-2015, corresponding to periods of county SES data collection. In each era, counties were ranked by 1 year rates of survival with intact graft, and by county SES score. We used Spearman correlation (rho) to evaluate the association between county rankings on SES and transplant outcomes in each era and consistency between these measures across eras. We also evaluated the utility of county SES for improving prediction of individual KTx outcomes. RESULTS: The analysis included 2972 children and 108 counties. County SES and transplant outcomes were not correlated in either 2006 2010 (rho = 0.06; p = 0.525) or 2011-2015 (rho = 0.162, p = 0.093). County SES rankings were strongly correlated between eras (rho = 0.99, p < 0.001), whereas county rankings of transplant outcomes were not correlated between eras (rho = 0.16, p = 0.097). Including county SES quintile in individual-level models of transplant outcomes did not improve model predictive utility. CONCLUSIONS: Pediatric kidney transplant outcomes are unstable from period to period at the county level and are not correlated with county-level SES. Appropriate adjustment for SES disparities in transplant outcomes could require further collection of detailed individual SES data. PMID- 29532230 TI - Hypouricemia and hyperuricosuria in a pubescent girl: Questions. PMID- 29532231 TI - Nephrotic syndrome associated with severe hypertriglyceridemia in a pediatric patient: Questions. PMID- 29532232 TI - Hypouricemia and hyperuricosuria in a pubescent girl: Answers. PMID- 29532233 TI - Nephrotic syndrome associated with severe hypertriglyceridemia in a pediatric patient: Answers. PMID- 29532234 TI - Pulmonary hypertension in an adolescent with end-stage-renal disease-a diagnostic challenge: Questions. PMID- 29532235 TI - Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders. AB - BACKGROUND: Distinguishing between urinary tract infection (UTI) and colonization (UTC) in patients with neurogenic bladders who require clean intermittent catheterization (CIC) is difficult. Urinary neutrophil gelatinase-associated lipocalin concentrations (uNGAL) are increased in UTIs. Our objective was to determine the predictive accuracy of uNGAL for UTI in CIC-dependent children. METHODS: Cross-sectional study of CIC-dependent patients from August, 2015 to November, 2016. UTI was defined as (1) growth of >= 50,000 cfu/mL of a uropathogen, (2) > 10 urinary white blood cells/hpf, and (3) >= 2 of the following: temperature > 38 degrees C, abdominal pain, back pain, worsened incontinence, pain with catheterization, or malodorous/cloudy urine. Positive urine cultures that did not meet these criteria were grouped as UTC, and negative cultures were grouped as no growth. RESULTS: Two hundred one patients were included (no growth = 100, UTC = 77, UTI = 24). Median (interquartile range) uNGAL was higher in the UTI group (UTI 1361 (931, 2516) MUg/g creatinine, UTC 246 (106, 548) MUg/g creatinine, no growth 36 (11, 179) MUg/g creatinine, p < 0.01 for all comparisons). The area under the ROC curve for uNGAL for UTI versus no UTI was 0.89, 95% CI (0.80-0.98). CONCLUSION: uNGAL is elevated in CIC-dependent children with UTI compared to those with negative cultures and those with UTC. PMID- 29532236 TI - Pulmonary hypertension in an adolescent with end-stage-renal disease-a diagnostic challenge: Answers. PMID- 29532237 TI - Extraction of large-scale structural covariance networks from grey matter volume for Parkinson's disease classification. AB - OBJECTIVES: To identify disease-related spatial covariance patterns of grey matter volume as an aid in the classification of Parkinson's disease (PD). METHODS: Seventy structural covariance networks (SCNs) based on grey matter volume covariance patterns were defined using independent component analysis with T1-weighted structural MRI scans (discovery sample, 70 PD patients and 70 healthy controls). An image-based classifier was constructed from SCNs using a multiple logistic regression analysis with a leave-one-out cross-validation-based feature selection scheme. A validation sample (26 PD patients and 26 healthy controls) was further collected to evaluate the generalization ability of the constructed classifier. RESULTS: In the discovery sample, 13 SCNs, including the cerebellum, anterior temporal poles, parahippocampal gyrus, parietal operculum, occipital lobes, supramarginal gyri, superior parietal lobes, paracingulate gyri and precentral gyri, had higher classification performance for PD. In the validation sample, the classifier had moderate generalization ability, with a mean sensitivity of 81%, specificity of 69% and overall accuracy of 75%. Furthermore, certain individual SCNs were also associated with disease severity. CONCLUSIONS: Although not applicable for routine care at present, our results provide empirical evidence that disease-specific, large-scale structural networks can provide a foundation for the further improvement of diagnostic MRI in movement disorders. KEY POINTS: * Disease-specific, large-scale SCNs can be identified from structural MRI. * A new network-based framework for PD classification is proposed. * An SCN-based classifier had moderate generalization ability in PD classification. * The selected SCNs provide valuable functional information regarding PD patients. PMID- 29532238 TI - Is the brain spared in Crimean-Congo haemorrhagic fever? An MR-SWI study to reveal CNS involvement. AB - OBJECTIVES: The aim of this prospective study is to investigate the central nervous system involvement in Crimean-Congo haemorrhagic fever (CCHF) with magnetic resonance imaging (MRI) in conjunction with clinical and laboratory findings. METHODS: Between July 2015 and August 2016, 36 patients with CCHF were undergone brain MRI including SWI. Two MRIs, one at the time of admission and the second in the convalescent period, were performed for each patient in order to see if there is any sign of central nervous system (CNS) involvement, especially in terms of intracranial haemorrhage or viral encephalitis. Clinical severity scoring was also done and laboratory findings were noted in order to correlate with clinical and imaging findings. RESULTS: None of the 36 patients showed any MRI findings of an acute intracranial event during the course of the disease. There was a significant difference between mild cases and moderate cases in terms of some laboratory parameters (p < 0.05). CONCLUSIONS: Although CCHF is a highly lethal disease which involves multiple organs and systems, CNS involvement seems to be extremely rare in mild and moderate cases. KEY POINTS: * MRI is the imaging method of choice to diagnose microbleeds and encephalitis * Although CCHF causes multisystem bleeding, intracranial haemorrhage seems to be very rare * CNS complications are uncommon, even in the setting of suggestive symptoms * Death usually results from extracranial bleeding and multiorgan failure * Severity scoring is associated with some laboratory abnormalities in CCHF. PMID- 29532239 TI - Imaging complex ventral hernias, their surgical repair, and their complications. AB - : Complex ventral hernia (CVH) describes large, anterior, ventral hernias. The incidence of CVH is rising rapidly due to increasing laparotomy rates in ever older, obese and co-morbid patients. Surgeons with a specific interest in CVH repair are now frequently referring these patients for imaging, normally computed tomography scanning. This review describes what information is required from preoperative imaging and the surgical options and techniques used for CVH repair, so that radiologists understand the postoperative appearances specific to CVH and are aware of the common complications following surgery. KEY POINTS: * Complex ventral hernia (CVH) describes large abdominal wall hernias (e.g. width >=10cm). * CVH patients are being referred increasingly for preoperative and postoperative imaging. * Imaging is pivotal to characterise preoperative morphology and quantify loss of domain. * Postoperative imaging appearances are contingent on the surgical methods used for CVH repair. * Postoperative complications are depicted easily by imaging. PMID- 29532240 TI - Direct localisation of the human pedunculopontine nucleus using MRI: a coordinate and fibre-tracking study. AB - OBJECTIVES: To image the pedunculopontine tegmental nucleus (PPN), a deep brain stimulation (DBS) target for Parkinson disease, using MRI with validated results. METHODS: This study used the MP2RAGE sequence with high resolution and enhanced grey-white matter contrast on a 7-T ultra-high-field MRI system to image the PPN as well as a diffusion spectrum imaging method on a 3-T MRI system to reconstruct the main fibre systems surrounding the PPN. The coordinates of the rostral and caudal PPN poles of both sides were measured in relation to the third and fourth ventricular landmarks on the 7-T image. RESULTS: The boundary of the PPN was delineated, and showed morphology consistent with previous histological works. The main fibres around the PPN were reconstructed. The pole coordinate results combined with the fibre spatial relationships validate the imaging results. CONCLUSIONS: A practical protocol is provided to directly localise the PPN using MRI; the position and morphology of the PPN can be obtained and validated by locating its poles relative to two ventricular landmarks and by inspecting its spatial relationship with the surrounding fibre systems. This technique can be potentially used in clinics to define the boundary of the PPN before DBS surgery for treatment of Parkinson disease in a more precise and reliable manner. KEY POINTS: * Combined information helps localise the PPN as a DBS target for PD patients * Scan the PPN at 7 T and measure its coordinates against different ventricular landmarks * Reconstruct the main fibres around the PPN using diffusion spectrum imaging. PMID- 29532241 TI - Gd-EOB-DTPA-enhanced T1 relaxometry for assessment of liver function determined by real-time 13C-methacetin breath test. AB - OBJECTIVES: To determine whether liver function as determined by intravenous administration of 13C-methacetin and continuous real-time breath analysis can be estimated quantitatively from gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) relaxometry. METHODS: Sixty-six patients underwent a 13C methacetin breath test (13C-MBT) for evaluation of liver function and Gd-EOB-DTPA enhanced T1-relaxometry at 3 T. A transverse 3D VIBE sequence with an inline T1 calculation based on variable flip angles was acquired prior to (T1 pre) and 20 min post-Gd-EOB-DTPA (T1 post) administration. The reduction rate of T1 relaxation time (rrT1) and T1 relaxation velocity index (?R1) between pre- and post-contrast images was evaluated. 13C-MBT values were correlated with T1post, ?R1 and rrT1, providing an MRI-based estimated 13C-MBT value. The interobserver reliability was assessed by determining the intraclass correlation coefficient (ICC). RESULTS: Stratified by three different categories of 13C-MBT readouts, there was a constant increase of T1 post with increasing progression of diminished liver function (p <= 0.030) and a constant significant decrease of ?R1 (p <= 0.025) and rrT1 (p < 0.018) with progression of liver damage as assessed by 13C-methacetin breath analysis. ICC for all T1 relaxation values and indices was excellent (> 0.88). A simple regression model showed a log-linear correlation of 13C-MBT values with T1post (r = 0.57; p < 0.001), ?R1 (r = 0.59; p < 0.001) and rrT1 (r = 0.70; p < 0.001). CONCLUSION: Liver function as determined using real time 13C-methacetin breath analysis can be estimated quantitatively from Gd-EOB DTPA-enhanced MR relaxometry. KEY POINTS: * Gd-EOB-DTPA-enhanced T1 relaxometry quantifies liver function * Gd-EOB-DTPA-enhanced MR relaxometry may provide parameters for assessing liver function before surgery * Gd-EOB-DTPA-enhanced MR relaxometry may be useful for monitoring liver disease progression * Gd-EOB-DTPA enhanced MR relaxometry has the potential to become a novel liver function index. PMID- 29532242 TI - Vertebral metastases from neuroendocrine tumours: How to avoid false positives on 68Ga-DOTA-TOC PET using CT pattern analysis? AB - OBJECTIVES: To develop criteria to improve discrimination between vertebral metastases from neuroendocrine tumours (NETs) and benign bone lesions on PET combined with CT using DOTA-D-Phe1-Tyr3-octreotide labelled with gallium-68 (68Ga DOTA-TOC). METHODS: In 535 NET patients, 68Ga-DOTA-TOC PET/CT examinations were reviewed retrospectively for vertebral CT lesions and/or PET foci. For each vertebral PET abnormality, appearance on CT, biological volume (BV), standardized uptake value (SUVmax) and ratios to those of reference organs were determined. All vertebral abnormalities were characterized as a metastasis, a typical vertebral haemangioma (VH) or other benign lesion. RESULTS: In 79 patients (14.8 %), we found 107 metastases, 34 VHs and 31 other benign lesions in the spine. The optimal cut-off values to differentiate metastases from benign lesions were BV >=0.72 cm3, SUVmax >=2, SUVmax ratio to a reference vertebra >=2.1, to liver >=0.28 and to spleen >=0.14. They corresponded to lesion-based 68Ga-DOTA-TOC PET/CT sensitivity of 87 %, 98 %, 97 %, 99 % and 94 %, and specificity of 55 %, 100 %, 90 %, 97 %, 100 %, respectively. CONCLUSIONS: The high sensitivity of 68Ga DOTA-TOC-PET/CT in detecting NET vertebral metastases was confirmed; this study showed that specificity could be improved by combining CT features and quantifying 68Ga-DOTA-TOC uptake. KEY POINTS: * Bone metastases in neuroendocrine tumours correlate with prognosis. * Benign bone lesions may mimic metastases on 68 Ga-DOTA-TOC PET/CT imaging. * The specific polka-dot CT pattern may be missing in some vertebral haemangiomas. * Lesion atypical for haemangiomas can be better characterized by quantifying 68 Ga-DOTA-TOC uptake. PMID- 29532243 TI - Healthy Bones Study: can a prescription coupled with education improve bone health for patients receiving androgen deprivation therapy?-a before/after study. AB - PURPOSE: To evaluate the ability of a multimodal patient education initiative to improve adherence to healthy bone behaviors (HBBs) in men with prostate cancer receiving androgen deprivation therapy (ADT). METHODS: This was a pilot prospective, single-site, before-and-after clinical trial. The control arm (n = 51) received routine care. The intervention arm (n = 52) received multimodal HBB education which included a healthy bones prescription (BoneRx), focused face-to face education with an oncology nurse or physician, and customized educational materials. The primary endpoints were feasibility of study methods and self reported adherence to HBBs (vitamin D intake >= 1000 IU/day, calcium intake 1000 1500 mg/day, and exercise >= 150 min/week) at 3-month follow-up. Secondary endpoints included receipt of bone mineral density (BMD) testing. RESULTS: Patients were satisfied with the study intervention, found educational materials easy to understand, and felt that it increased their knowledge about osteoporosis. Although the intervention appeared to be associated with trends toward improved levels of vitamin D intake (adjusted odds ratio [OR] 1.8, 95% confidence interval [CI] 0.74-4.5), calcium intake (OR 1.5, 95% CI 0.63-3.4), and exercise (OR 1.7, 0.75-3.9) as compared to the control arm, none of these were statistically significant. Patients who received the study intervention were more likely to receive BMD testing (OR 3.3, 95% CI 1.3-8.8). CONCLUSIONS: Although a brief, tailored educational intervention was feasible to implement and improve BMD test utilization, it did not increase HBB participation. Larger, well designed trials are needed to clarify the effect of patient education interventions on HBB adherence. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01973673 ). PMID- 29532244 TI - TOXICAN: a guide for grading dermatological adverse events of cancer treatments. AB - PURPOSE: The dermatological toxicity of cancer treatments is frequent and sometimes debilitating. Its reference classification, the NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events), is sometimes difficult to use and does not include yet the newest toxicities. Our objective was to create a guide, TOXICAN, based on the CTCAE, which is easy to use in everyday practice and which facilitates the recognition and grading of these dermatological toxicities. METHODS: This guide was developed by a working group ("GESTIM") comprising oncodermatologists, allergists, pathologists, and researchers from Nantes University Hospital. It was based on the dermatological toxicities found in the CTCAE and adapted to daily practice. These toxicities were grouped into categories and associated with photographs of typical cases to aid recognition. A simplified grading scale derived from the CTCAE was also created. This booklet was validated by means of user evaluation, and then the Delphi consensus method. RESULTS: We selected 32 dermatological toxicities, including 12 created by our group, sorted into 7 categories: skin rash, dry skin/pruritus, hyperkeratotic papules, palmoplantar changes, hair and nail changes, mucosal changes, and others. Our simplified grading scale only differed from the CTCAE for one item, urticaria. Three items were modified after evaluation by the user group and 11 after application of the Delphi method. CONCLUSION: The objective of our practical guide is to facilitate the use of the CTCAE for recognizing and grading dermatological toxicity of cancer treatments in order to provide optimal guidance for therapeutic adaptations. Its impact on clinical practice remains to be evaluated. PMID- 29532245 TI - A systematic review of the measurement properties of the Body Image Scale (BIS) in cancer patients. AB - INTRODUCTION: Body image is acknowledged as an important aspect of health-related quality of life in cancer patients. The Body Image Scale (BIS) is a patient reported outcome measure (PROM) to evaluate body image in cancer patients. The aim of this study was to systematically review measurement properties of the BIS among cancer patients. METHODS: A search in Embase, MEDLINE, PsycINFO, and Web of Science was performed to identify studies that investigated measurement properties of the BIS (Prospero ID 42017057237). Study quality was assessed (excellent, good, fair, poor), and data were extracted and analyzed according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology on structural validity, internal consistency, reliability, measurement error, hypothesis testing for construct validity, and responsiveness. Evidence was categorized into sufficient, insufficient, inconsistent, or indeterminate. RESULTS: Nine studies were included. Evidence was sufficient for structural validity (one factor solution), internal consistency (alpha = 0.86 0.96), and reliability (r > 0.70); indeterminate for measurement error (information on minimal important change lacked) and responsiveness (increasing body image disturbance in only one study); and inconsistent for hypothesis testing (conflicting results). Quality of the evidence was moderate to low. No studies reported on cross-cultural validity. CONCLUSION: The BIS is a PROM with good structural validity, internal consistency, and test-retest reliability, but good quality studies on the other measurement properties are needed to optimize evidence. It is recommended to include a wider variety of cancer diagnoses and treatment modalities in these future studies. PMID- 29532246 TI - Sestrin family of genes and their role in cancer-related fatigue. PMID- 29532247 TI - Ameliorative Effects of Selenium in ZnO NP-Induced Oxidative Stress and Hematological Alterations in Catla catla. AB - Various applications of zinc oxide nanoparticles (ZnO NPs) can increase pollution in aquatic environments. Consequently, pollution can cause toxicity in fish as indicated by oxidative stress, hematotoxicity, and changes in gill and liver histology. Selenium is known for its antioxidant potential in scavenging the free radicals generated during ZnO NP-induced oxidative stress. This study tested the ameliorative role of selenium against ZnO NP-induced toxicity in freshwater fish Catla catla. Four groups of replicated fish, representing control, selenium treated, ZnO NP-treated, and ZnO NPs+selenium-treated, were used in this study. The ZnO NPs (40 mg l-1) were given to fish in water whereas selenium (50 MUg kg 1) was given as sodium selenite in feed. After 28 days of exposure, the fish specimens were processed to collect samples of blood, gills, and liver. The results demonstrated that the consumption of selenium containing feeds protected the C. catla from ZnO NP-induced toxicity and oxidative stress. The use of selenium containing feeds appeared to have reduced the contents of glutathione S transferase (GST) and glutathione reduced (GSH), and increased the level of catalase (CAT) and superoxide dismutase (SOD). Furthermore, the consumption of selenium in feeds improved the hematological parameters in ZnO NP-treated fish. This study suggests that dietary selenium might be able to ameliorate ZnO NP induced toxicity in fish. PMID- 29532248 TI - The safety and effectiveness profile of eldecalcitol in a prospective, post marketing observational study in Japanese male patients with osteoporosis. AB - We conducted a post-marketing observational study to investigate the safety and effectiveness of eldecalcitol for the treatment of osteoporosis in a Japanese clinical setting. The observation period was 12 months for women and 36 months for men. The final results for the female patients have already been published. In this article, the final results for the male patients are reported. A total of 470 male osteoporosis patients were enrolled. The safety analysis set included 431 patients (mean age, 76.8 years; mean +/- SD follow-up period, 631.0 +/- 450.3 days), and 175 patients continued treatment throughout the 3-year observational period. Adverse drug reactions (ADRs) were reported in 28 patients (6.49%); the most common ADRs were hypercalcemia (1.16%) and renal impairment (1.16%). Serious ADRs were reported in 5 patients (1.16%). Mean serum calcium was within the normal range throughout the observation period. The cumulative incidence of new vertebral and nonvertebral fractures at 36 months, estimated by Kaplan-Meier analysis, was 10.23 and 4.06%, respectively. At the last observation, mean lumbar spine bone mineral density was 3.49% higher (P < 0.0001) than at baseline, and levels of the bone turnover markers BAP and TRACP-5b were reduced (-14.64%; P = 0.0009, and - 29.51%; P < 0.0001, respectively). In conclusion, the safety and effectiveness of eldecalcitol for the treatment of Japanese male osteoporosis patients was confirmed in clinical practice. Careful monitoring of serum calcium and estimated glomerular filtration rate, both before and during treatment, is necessary to minimize the risk of hypercalcemia and renal impairment while maximizing the effectiveness of eldecalcitol. PMID- 29532249 TI - DNA double-strand breaks promote endoreduplication in radish cotyledon. AB - KEY MESSAGE: DSBs differently affect endoreduplication and organ size in radish cotyledons and hypocotyls in different light conditions, suggesting that DSBs mediated endoreduplication varies based on different developmental and environmental cues. Endoreduplication induced by DNA double strand breaks (DSBs) in Arabidopsis thaliana roots and cultured cells has been reported in recent years. In this study, we investigated whether DSBs-mediated endoreduplication also occurs in other tissues, such as cotyledons and hypocotyls of radish (Raphanus sativus var. longipinnatus) plants. To induce DSBs, UV irradiation and Zeocin treatment were applied to in vitro-cultured radish seedlings, and ploidy distribution of the treated tissues was analyzed by flow cytometry. Consequently, frequencies of the higher ploidy (8C) cells and cycle values in the cotyledon tissues increased with increasing doses of UV irradiation and concentrations of Zeocin, irrespective of light conditions. UV-stimulated endoreduplication was also observed in four Brassica species. In hypocotyls, UV treatments decreased the frequencies of higher ploidy (32C) cells and cycle values in dark-grown seedlings, whereas Zeocin treatments increased the frequencies of higher ploidy (16C and 32C) cells and cycle values in light- and dark-grown seedlings. Among the treatments, organ sizes did not simply correlate with cycle values. The effects of treatments on endoreduplication and organ size differed based on organ and light conditions, indicating that DSBs-mediated endoreduplication may involve a multifaceted response to different developmental and environmental cues. PMID- 29532250 TI - Sensitive mutant detection by concentrating mutant DNA with allele-specific capture and its application to analysis of contaminated grains in rice. AB - KEY MESSAGE: We developed a method for detection of mutants in a large number of plants, and found this method to be applicable to detection of a mutant allele at a concentration of 1/1000. Many techniques for SNP analysis have been developed, but most of these techniques are not so sensitive to be used for detection of mutants in a large number of plants. Although some highly sensitive methods of SNP analysis have been reported, they are costly. In the present study, a method for concentrating mutant DNA was examined for sensitive detection of an SNP allele in a bulked DNA sample. PCR products of mutant alleles were captured by biotin-labeled oligonucleotide conjugated with streptavidin-coated magnetic beads. By repeated captures of each strand and combining both strands, mutant alleles with a concentration of 1/1000 in wild-type alleles were detectable by CAPS or dCAPS analysis. Indirect capture of a mutant allele was possible, but efficiency was slightly lower than that of the direct capture. The developed method was applied to detection of contamination of rice grains by grains of a different cultivar. Possible applications of this method are discussed. PMID- 29532251 TI - The wheat multidomain cystatin TaMDC1 displays antifungal, antibacterial, and insecticidal activities in planta. AB - KEY MESSAGE: Expression of the TaMDC1 in transgenic tomato plants confer resistance to bacterial and fungal pathogens, as well as an insect pest and thus prove in planta function of the wheat cystatin. Cystatins are the polypeptides with cysteine proteinase inhibitory activities. Plant cystatins or phytocystatins are known to contribute to plant resistance against insect pests. Recently, increasing data proved that some of the phytocystatins also have antifungal activities in vitro. Here, we functionally characterized a wheat multidomain cystatin, TaMDC1, using in planta assays. Expression of TaMDC1 in wheat seedlings is up-regulated in response to methyl jasmonate and salicylic acid, indicating that TaMDC1 is involved in biotic stress responses mediated by these plant hormones. The TaMDC1 cDNA was integrated in tomato genome and expressed under cauliflower mosaic virus 35S promoter. Four transgenic plants that show high level of the transgene expression were selected by RNA gel blot and immunoblot analysis and utilized to assess biotic stress resistance against the bacterial pathogen Pseudomonas syringae, the fungal pathogens Botrytis cinerea and Alternaria alternata, and the insect pest Colorado potato beetle (CPB, Leptinotarsa decemlineata). Detached leaf inoculation assays revealed that the tomato plants expressing TaMDC1 showed high levels of resistance against P. syringae and A. alternata, and elevated tolerance against B. cinerea. Sustenance of L. decemlineata larvae to the transgenic plants demonstrated inhibition of CPB larvae growth. Inhibitory activity of TaMDC1 against selected pathogens was also demonstrated by in vitro assays with total protein extracted from transgenic tomato plants. Taken together, the presented data suggest that TaMDC1 is involved in a broad spectrum biotic stress resistance in planta. PMID- 29532252 TI - A Nondestructive Method to Identify POP Contamination Sources in Omnivorous Seabirds. AB - Persistent organic pollutants (POPs) are present in almost all environments due to their high bioaccumulation potential. Especially species that adapted to human activities, like gulls, might be exposed to harmful concentrations of these chemicals. The nature and degree of the exposure to POPs greatly vary between individual gulls, due to their diverse foraging behavior and specialization in certain foraging tactics. Therefore, in order clarify the effect of POP contaminated areas on gull populations, it is important to identify the sources of POP contamination in individual gulls. Conventional sampling methods applied when studying POP contamination are destructive and ethically undesired. The aim of this literature review was to evaluate the potential of using feathers as a nondestructive method to determine sources of POP contamination in individual gulls. The reviewed data showed that high concentrations of PCBs and PBDEs in feathers together with a large proportion of less bioaccumulative congeners may indicate that the contamination originates from landfills. Low PCB and PBDE concentrations in feathers and a large proportion of more bioaccumulative congeners could indicate that the contamination originates from marine prey. We propose a nondestructive approach to identify the source of contamination in individual gulls based on individual contamination levels and PCB and PBDE congener profiles in feathers. Despite some uncertainties that might be reduced by future research, we conclude that especially when integrated with other methods like GPS tracking and the analysis of stable isotopic signatures, identifying the source of POP contamination based on congener profiles in feathers could become a powerful nondestructive method. PMID- 29532254 TI - Thermal comfort of pedestrians in an urban street canyon is affected by increasing albedo of building walls. AB - Numerical simulations based on the ENVI-met model were carried out for an E-W street canyon in the city of Stuttgart (Southwest Germany) to analyse the effect of increased albedo of building walls on outdoor human thermal comfort. It was quantified by air temperature (Ta), mean radiant temperature (Tmrt) and physiologically equivalent temperature (PET). The simulations were conducted on 4 August 2003 as a heat wave day that represents a typical scenario for future summer weather in Central Europe. The simulation results presented for 13 CET and averaged over the period 10-16 CET are focused on pedestrians on both sidewalks. For the initial situation, i.e. albedo of 0.2, human heat stress indicated by mean PET is by 26% lower on the N-facing than on the S-facing sidewalk, while this reduction amounts to 42% for mean Tmrt. Mean Ta does not show any spatial differentiation. The systematic albedo increment by 0.2 from 0.2 to 0.8 leads to a linear increase of outdoor human heat stress in terms of Tmrt and PET. For both variables, this increase is more pronounced on the N-facing than on the S-facing sidewalk. Mean relative Ta shows the tendency of a minimal increase with rising albedo. The results were achieved for the usual standardised human biometeorological reference person. Its substitution by two other types of male and female pedestrians, respectively, which are statistically characteristic of human conditions in Germany, does not reveal any significant change in the results. PMID- 29532255 TI - The functional dependence of canopy conductance on water vapor pressure deficit revisited. AB - Current research seeking to relate between ambient water vapor deficit (D) and foliage conductance (gF) derives a canopy conductance (gW) from measured transpiration by inverting the coupled transpiration model to yield gW = m - n ln(D) where m and n are fitting parameters. In contrast, this paper demonstrates that the relation between coupled gW and D is gW = AP/D + B, where P is the barometric pressure, A is the radiative term, and B is the convective term coefficient of the Penman-Monteith equation. A and B are functions of gF and of meteorological parameters but are mathematically independent of D. Keeping A and B constant implies constancy of gF. With these premises, the derived gW is a hyperbolic function of D resembling the logarithmic expression, in contradiction with the pre-set constancy of gF. Calculations with random inputs that ensure independence between gF and D reproduce published experimental scatter plots that display a dependence between gW and D in contradiction with the premises. For this reason, the dependence of gW on D is a computational artifact unrelated to any real effect of ambient humidity on stomatal aperture and closure. Data collected in a maize field confirm the inadequacy of the logarithmic function to quantify the relation between canopy conductance and vapor pressure deficit. PMID- 29532256 TI - Operational forecasting of human-biometeorological conditions. AB - This paper presents the development of an operational forecasting service focusing on human-biometeorological conditions. The service is based on the coupling of numerical weather prediction models with an advanced human biometeorological model. Human thermal perception and stress forecasts are issued on a daily basis for Greece, in both point and gridded format. A user-friendly presentation approach is adopted for communicating the forecasts to the public via the worldwide web. The development of the presented service highlights the feasibility of replacing standard meteorological parameters and/or indices used in operational weather forecasting activities for assessing the thermal environment. This is of particular significance for providing effective, human biometeorology-oriented, warnings for both heat waves and cold outbreaks. PMID- 29532258 TI - Prevalence of and risk factors for recurrence of chronic subdural hematoma. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a common disease in neurosurgical practice with substantial recurrence rate. We aimed to estimate recurrence rate of CSDH and to identify risk factors for CSDH recurrence. METHODS: We retrospectively studied consecutive cases with CSDH and performed surgical therapy in our hospital. Univariate and multivariate logistic regression analyses were performed to identify factors associated with recurrence of CSDH. RESULTS: A total of 226 patients with CSDH were included; 34 patients recurred after surgery with a recurrence rate of 15.0%. Univariate analysis showed that the recurrence group had more patients with homogenous hyper-dense hematoma (20.6 vs 6.3%, p = 0.035) and shorter duration of subdural drainage post-surgery (1.2 +/- 1.4 vs 1.5 +/- 0.9, p = 0.022) than the non-recurrence group. Logistic regression analysis revealed that duration of subdural drainage (OR = 0.66, p = 0.05) and hyper-dense of hematoma (OR = 4.94, p = 0.012) were independent predictors for CSDH recurrence. CONCLUSIONS: Homogenous hyper-dense of hematoma and duration of subdural drainage post-surgery were independent predictors for CSDH recurrence; longer duration of postoperative subdural drainage was associated with lower risk of recurrence. PMID- 29532257 TI - Climate change: potential implications for Ireland's biodiversity. AB - A national biodiversity and climate change adaptation plan is being developed for Ireland by the Department of Communications, Climate Action, and Environment. In order to inform such a plan, it was necessary to review and synthesize some of the recent literature pertaining to the impact of climate change on biodiversity in Ireland. Published research on this topic fell within three broad categories: (i) changes in the timing of life-cycle events (phenology) of plants, birds, and insects; (ii) changes in the geographic range of some bird species; and (iii) changes in the suitable climatic zones of key habitats and species. The synthesis revealed evidence of (i) a trend towards earlier spring activity of plants, birds, and insects which may result in a change in ecosystem function; (ii) an increase in the number of bird species; and (iii) both increases and decreases in the suitable climatic area of key habitats and species, all of which are expected to impact Ireland's future biodiversity. This process identified data gaps and limitations in available information both of which could be used to inform a focused research strategy. In addition, it raises awareness of the potential implications of climate change for biodiversity in Ireland and elsewhere and demonstrates the need for biodiversity conservation plans to factor climate change into future designs. PMID- 29532259 TI - Intradural disc herniation: how I do it. AB - BACKGROUND: Intradural disc herniation is a rare phenomenon in spine surgery. Diagnosis is difficult despite current neuroradiologic imaging techniques. METHOD: We present a case of a 59-year-old man with lumbar and radicular pain and a recurrent lumbar herniation. A laminectomy was performed after no clear disc herniation in the epidural space was found and an intradural mass was palpable. A durotomy showed an intradural disc fragment that was removed, followed by an arthrodesis. CONCLUSION: Only intraoperative findings lead to a definitive diagnosis for intradural herniation. A durotomy needs to be performed. In this case, an arthrodesis was necessary to avoid complications of segmental instability. PMID- 29532253 TI - Transcriptional and Epigenetic Control of Mammalian Olfactory Epithelium Development. AB - The postnatal mammalian olfactory epithelium (OE) represents a major aspect of the peripheral olfactory system. It is a pseudostratified tissue that originates from the olfactory placode and is composed of diverse cells, some of which are specialized receptor neurons capable of transducing odorant stimuli to afford the perception of smell (olfaction). The OE is known to offer a tractable miniature model for studying the systematic generation of neurons and glia that typify neural tissue development. During OE development, stem/progenitor cells that will become olfactory sensory neurons and/or non-neuronal cell types display fine spatiotemporal expression of neuronal and non-neuronal genes that ensures their proper proliferation, differentiation, survival, and regeneration. Many factors, including transcription and epigenetic factors, have been identified as key regulators of the expression of such requisite genes to permit normal OE morphogenesis. Typically, specific interactive regulatory networks established between transcription and epigenetic factors/cofactors orchestrate histogenesis in the embryonic and adult OE. Hence, investigation of these regulatory networks critical for OE development promises to disclose strategies that may be employed in manipulating the stepwise transition of olfactory precursor cells to become fully differentiated and functional neuronal and non-neuronal cell types. Such strategies potentially offer formidable means of replacing injured or degenerated neural cells as therapeutics for nervous system perturbations. This review recapitulates the developmental cellular diversity of the olfactory neuroepithelium and discusses findings on how the precise and cooperative molecular control by transcriptional and epigenetic machinery is indispensable for OE ontogeny. PMID- 29532260 TI - Intraventricular urokinase to treat a blocked ventriculoperitoneal shunt in a glioblastoma patient with leptomeningeal spread. AB - Leptomeningeal spread and hydrocephalus are increasingly recognized as late disease complications of glioblastoma with almost a quarter of patients requiring early cerebrospinal fluid shunting. The neurosurgeon is challenged with maintaining shunt patency when tumor disease progression is rapid and adjuvant oncologic therapy has yet to be initiated. We describe our experience in treating a young female with diffuse glioblastoma leptomeningeal spread and communicating hydrocephalus who had several episodes of shunt obstruction due to intraluminal tumor cell-fibrin deposits. Regular intraventricular instillations of urokinase fibrinolytic therapy not only re-established shunt patency but also contributed to the resolution of her hydrocephalus. PMID- 29532261 TI - A comparison of the clinical outcomes of esophagectomy and chemoradiotherapy after noncurative endoscopic submucosal dissection for esophageal squamous cell carcinoma. AB - PURPOSE: Endoscopic submucosal dissection (ESD) is widely used to treat esophageal cancer, but some patients require additional treatment due to the possibility of lymph node metastasis. The aim of this study was to elucidate the clinical outcomes of these additional treatments. METHODS: The study included 59 patients who developed superficial esophageal squamous cell carcinoma after noncurative ESD treated between 2005 and 2016, of whom 28 underwent esophagectomy and 31 received chemoradiotherapy (CRT). RESULTS: The median follow-up periods were 45 months in the esophagectomy group and 41 months in the CRT group. The overall survival did not differ significantly between the groups (P = 0.46). However, there were no recurrences in the esophagectomy group, and the disease specific survival rate was significantly higher in this group (P = 0.042). Among the patients at high risk for recurrence due to massive tumor invasion (>= SM2) with lymphovascular invasion (esophagectomy group, six patients; CRT group, ten patients), none in the esophagectomy group had recurrence, whereas four in the CRT group died of esophageal cancer (P = 0.031). CONCLUSION: The overall survival did not differ significantly between the groups. However, compared with CRT, esophagectomy provided more favorable disease control for patients with massive tumor invasion (>= SM2) with lymphovascular invasion. PMID- 29532262 TI - Intersection as key locations for bearded capuchin monkeys (Sapajus libidinosus) traveling within a route network. AB - There is evidence that wild animals are able to recall key locations and associate them with navigational routes. Studies in primate navigation suggest most species navigate through the route network system, using intersections among routes as locations of decision-making. Recent approaches presume that points of directional change may be key locations where animals decide where to go next. Over four consecutive years, we observed how a wild group of bearded capuchin monkeys used a route network system and Change Point locations (CPs) in the Brazilian ecotone of Cerrado-Caatinga. We built 200 daily routes of one wild bearded capuchin group. We used ArcGIS, the Change Point Test, Spatial Analysis in Macroecology (SAM), and statistical models to test the hypothesis that wild bearded capuchins use CPs located along routes in a different fashion than they use the CPs located at intersections of routes. A logistic regression model was used to determine the landscape variables affecting capuchins' directional changes at intersections or along routes. CPs at intersections were important points of travel path changes, whereas CPs along routes represented a zig-zag movement along the routes following the landscape features. CPs at intersections were associated with steeper terrains and shorter distances from important resources, along with better visibility of the home range. Our results support the hypothesis that intersections among routes in the route network system are located at points where monkeys have the best visibility available to make decisions on where to visit next. PMID- 29532263 TI - Adding a speed-accuracy trade-off to discrete-state models: A comment on Heck and Erdfelder (2016). AB - Heck and Erdfelder (2016) developed a model that extends discrete-state multinomial processing tree models to response time (RT) data. Their model is an important advance, but it does not have a mechanism to produce the speed-accuracy trade-off, the bedrock empirical observation that rushed decisions are less accurate. I present a similar model, the "discrete-race" model, with a simple mechanism for the speed-accuracy trade-off. In the model, information that supports detection of the stimulus type is available for some proportion of items and unavailable for others. Both the amount of time needed for detection to succeed and the amount of time that the decision maker waits before guessing are variable from trial to trial. Responses are based on detection when it is available and has a finishing time before the guess time for that trial. In other words, the decision maker sometimes loses opportunities to respond correctly on the basis of detection by first making a guess. These lost opportunities are more common when the guess-time distribution tends to have low wait times, which decreases accuracy. I report simulations showing that the model can accurately recover parameter values and is strongly constrained by the speed-accuracy trade offs across conditions with different levels of response caution. PMID- 29532264 TI - Propofol Attenuates Airway Inflammation in a Mast Cell-Dependent Mouse Model of Allergic Asthma by Inhibiting the Toll-like Receptor 4/Reactive Oxygen Species/Nuclear Factor kappaB Signaling Pathway. AB - Propofol, an intravenous anesthetic agent widely used in clinical practice, is the preferred anesthetic for asthmatic patients. This study was designed to determine the protective effect and underlying mechanisms of propofol on airway inflammation in a mast cell-dependent mouse model of allergic asthma. Mice were sensitized by ovalbumin (OVA) without alum and challenged with OVA three times. Propofol was given intraperitoneally 0.5 h prior to OVA challenge. The inflammatory cell count and production of cytokines in the bronchoalveolar lavage fluid (BALF) were detected. The changes of lung histology and key molecules of the toll-like receptor 4 (TLR4)/reactive oxygen species (ROS)/NF-kappaB signaling pathway were also measured. The results showed that propofol significantly decreased the number of eosinophils and the levels of IL-4, IL-5, IL-6, IL-13, and TNF-alpha in BALF. Furthermore, propofol significantly attenuated airway inflammation, as characterized by fewer infiltrating inflammatory cells and decreased mucus production and goblet cell hyperplasia. Meanwhile, the expression of TLR4, and its downstream signaling adaptor molecules--myeloid differentiation factor 88 (MyD88) and NF-kappaB, were inhibited by propofol. The hydrogen peroxide and methane dicarboxylic aldehyde levels were decreased by propofol, and the superoxide dismutase activity was increased in propofol treatment group. These findings indicate that propofol may attenuate airway inflammation by inhibiting the TLR4/MyD88/ROS/NF-kappaB signaling pathway in a mast cell dependent mouse model of allergic asthma. PMID- 29532265 TI - Downregulation of Aquaporins (AQP1 and AQP5) and Na,K-ATPase in Porcine Reproductive and Respiratory Syndrome Virus-Infected Pig Lungs. AB - Aquaporins (AQPs) and Na,K-ATPase control water transport across the air space capillary barrier in the distal lung and play an important role in the formation and resolution of lung edema. Porcine reproductive and respiratory syndrome virus (PRRSV) infection usually causes pulmonary inflammation and edema in the infected pig lungs. To investigate the possibility that PRRSV infection may cause altered expression of AQPs and Na,K-ATPase messenger RNA (mRNA) levels and protein expression of AQP1, AQP5, and Na,K-ATPase in the PRRSV-infected pig lungs were detected. Quantitative real-time PCR (qRT-PCR) analysis showed markedly decreased mRNA levels of AQP1 and AQP5 and Na,K-ATPase in the PRRSV-infected pig lungs compared to those of uninfected pig lungs. Western blot studies also revealed significantly reduced levels of AQP1, AQP5, and Na,K-ATPase proteins in the PRRSV infected pig lungs. In addition, immunohistochemical (IHC) analysis showed decreased protein expression of AQP1 and AQP5 in the endothelial cells of the capillaries and venules and secretory cells of terminal bronchiole and the alveolar type I cells, respectively. The expression of Na,K-ATPase in the basolateral membrane of alveolar type II cells presented great reduction in the PRRSV-infected pig lungs. To further understand the reduction of these proteins, the ubiquitination of AQP1 and Na,K-ATPase was examined in uninfected and PRRSV infected pig lungs. The results showed that there is no difference of ubiquitination for these proteins. Thus, our results suggest that PRRSV infection may induce downregulation of these proteins and cause impairment of edema resolution by failed water clearance in the infected pig lungs. PMID- 29532267 TI - Severe ischemic cytomegalovirus proctocolitis with multiple perforation. AB - Cytomegalovirus (CMV) typically causes gastrointestinal infections in immunocompetent patients. Colonic perforations secondary to CMV are exceeding rare. We describe a 88-year-old male presenting with a week-long history of intractable abdominal discomfort, bloating, nausea and diarrhea. Flexible sigmoidoscopy revealed significant ulceration with yellowish slough. Emergency surgery was performed subsequently in view of multiple perforations in the rectosigmoid junction. CMV gastrointestinal infections demonstrated an ischemic process secondary to vasculitis, which accelerated the pathway to colonic perforation. CMV gastrointestinal infection should be considered as a differential diagnosis in patients with colonoscopy findings similar to ischemic colitis and Clostridium difficile infections. PMID- 29532266 TI - Ibrutinib Exacerbates Bleomycin-Induced Pulmonary Fibrosis via Promoting Inflammation. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with high mortality rate. The etiology is unknown and treatment choices are limited. Thus, there is great interest to investigate novel agents for IPF therapy. Ibrutinib, BTK, and ITK irreversible inhibitor is a FDA-approved small molecule for the clinical therapy of B cell lymphoma. Its role in pulmonary fibrosis remains unknown. In this study, we investigated the anti-fibrotic activity of ibrutinib. Strikingly, ibrutinib did not inhibit but exacerbated bleomycin-induced pulmonary fibrosis by increased epithelial cell apoptosis, and inflammation in the lung. The upregulated TGF-beta and EMT transformation also contributes to enhanced myofibroblast differentiation and ECM deposition. Our findings reveal the detrimental effects of ibrutinib against bleomycin-mediated fibrosis and added to the understanding of IPF pathogenesis. PMID- 29532269 TI - Correction to: Antecedents of Emotional Distress and Sexual Dissatisfaction in Circumcised Men: Previous Findings and Future Directions-Comment on Bossio and Pukall (2017). AB - The term "body eudysmorphia" in the 6th paragraph of this Letter to the Editor incorrectly read "body dysmorphia" in the letter as originally published. The original article has been corrected. PMID- 29532268 TI - Monoclonal gammopathy in rheumatic diseases. AB - To analyze the clinical spectrum, laboratory characteristics, and outcomes of monoclonal gammopathy (MG) in patients with rheumatic diseases. Screening for the presence of MG was performed in 872 inpatients with rheumatic diseases from January 2010 to July 2017. A total of 41 patients were enrolled. Their clinical and biological features in addition to outcomes were described. For each patient with primary Sjogren syndrome (pSS), 2 age- and sex-matched pSS patients without MG were selected as controls. Risk factors for the presence of MG and malignant hematological neoplasias were assessed. MG was observed in patients with SS, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, primary biliary cirrhosis, polymyositis, hypomyopathic dermatomyositis, psoriatic arthritis, ANCA-associated vasculitis, polyarteritis nodosa, and polymyalgia rheumatic, with SS the most frequent type. Serum M protein was detected in 37 patients. The monoclonal bands identified in serum were 16 IgG (5 kappa, 11 lambda), 11 IgA (6 kappa, 5 lambda), 6 IgM (5 kappa, 1 lambda), and 4 free lambda chains. M components were observed in urine in the other 4 patients. High ESR, albumin/globulin inversion, rheumatoid factor positivity, hypergammaglobulinemia, and hypocomplementemia were common features, presented in more than half of the 41 patients. Patients with pSS, when complicated with MG, showed a higher rate of abnormal urine NAG (71.4 vs 15.8%, P = 0.025), higher levels of ESR [55.0 (53.5) mm/h vs 21.0 (31.8) mm/h, P = 0.001], ESSDAI [26.0 (25.0) vs 12.0 (9.0), P = 0.006], and ClinESSDAI scores [24.0 (25.0) vs 10.5 (10.0), P = 0.011]. Multivariate analysis revealed that the disease activity, assessed by either ESSDAI [adjusted OR 1.127 (95%CI 1.015-1.251), P = 0.025] or ClinESSDAI [adjusted OR 1.121 (95%CI 1.011-1.242), P = 0.030], was the only independent risk factor for the presence of MG. During the follow-up, 2 patients had transient serum M protein, 2 had isotype switch, 1 progressed to multiple myeloma (MM), and another 2 experienced renal injuries attributed by monoclonal or polyclonal plasma cell interstitial infiltration. Seven (17.1%) of the 41 MG patients presented hematological neoplasias, 4 with MM, 2 with smoldering multiple myeloma, and 1 with B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. The presence of light-chain MG was associated with the development of MM [OR 17.5 (95%CI 1.551-197.435), P = 0.041], but not with an increased risk of lymphoma or SMM. MG was observed in patients with various rheumatic disorders, with SS being the most common type. The presence of MG might be associated with higher disease activity. The development of hematological neoplasias including MM and lymphoma was seen in this setting. Therefore, we recommend the screening for MG and close monitoring for potential malignant transformation in patients with rheumatic diseases as needed. PMID- 29532270 TI - The Crisis in Content Validity Among Existing Measures of Transphobia. PMID- 29532271 TI - "Frotteuristic Disorder": Etymological and Historical Note. PMID- 29532272 TI - Publisher Correction to: Effect of glaucoma implant surgery on intraocular pressure reduction, flare count, anterior chamber depth, and corneal endothelium in primary open-angle glaucoma. AB - The publisher regrets that the original version. PMID- 29532273 TI - Detection of increase in corneal irregularity due to pterygium using Fourier series harmonic analyses with multiple diameters. AB - PURPOSE: To determine steep increase of corneal irregularity induced by advancement of pterygium. METHODS: A total of 456 eyes from 456 consecutive patients with primary pterygia were examined for corneal topography and advancement of pterygium with respect to the corneal diameter. Corneal irregularity induced by the pterygium advancement was evaluated by Fourier harmonic analyses of the topographic data that were modified for a series of analysis diameters from 1 mm to 6 mm. Incidences of steep increases in the asymmetry or higher-order irregularity components (inflection points) were determined by using segmented regression analysis for each analysis diameter. RESULTS: The pterygium advancement ranged from 2% to 57%, with a mean of 22.0%. Both components showed steep increases from the inflection points. The inflection points in the higher-order irregularity component altered with the analysis diameter (14.0%-30.6%), while there was no alternation in the asymmetry components (35.5%-36.8%). For the former component, the values at the inflection points were obtained in a range of 0.16 to 0.25 D. CONCLUSION: The Fourier harmonic analyses for a series of analysis diameters revealed that the higher order irregularity component increased with the pterygium advancement. The analysis results confirmed the precedence of corneal irregularity due to pterygium advancement. PMID- 29532274 TI - Preventing the risk of coronary injury in posteroseptal accessory pathway ablation in children: different strategies and advantages of fluoroscopy integrated 3D-mapping system (CARTO-UNIVUTM). AB - PURPOSE: To evaluate various strategies in order to minimize the risk of coronary injury during posteroseptal accessory pathways ablation in children. METHODS: We retrospectively reviewed 68 posteroseptal accessory pathways ablation procedures (20 decremental and 48 typical accessory pathways) performed in 62 pediatric patients at our institution between July 2009 and December 2016. Only posteroseptal accessory pathways targeted near or within the coronary sinus were included and ablation was mostly performed using irrigated tip radiofrequency. RESULTS: Median patient age was 11 years with a median body weight of 39 kg. Thirty patients underwent a coronary angiogram, 21 were coupled to the 3D navigation system CARTO-UNIVUTM. The coronary angiogram showed a distance of less than 5 mm between the coronary artery and the ablation site in 40% of our cases; 3 patients had a coronary injury related to RF ablation, 6 patients were switched for cryoablation, 3 patients received limited RF energy (20 W). There were no demographic data predicting the proximity of the coronary artery to the ablation site. CONCLUSION: Ablation of posteroseptal accessory pathways specifically in children carries a risk of coronary artery injury which is probably underestimated. The use of merged 3D images and coronary angiograms, the reduction of RF energy or the switch to cryoablation are possible alternatives to limit the risk of coronary injury. PMID- 29532275 TI - Permanent-temporary pacemakers in the management of patients with conduction abnormalities after transcatheter aortic valve replacement. AB - BACKGROUND: Damage to the cardiac conduction system requiring permanent pacemaker (PPM) implantation is a known adverse outcome of transcatheter aortic valve replacement (TAVR). A permanent-temporary pacemaker (PTPM) is a device that involves an active-fixation lead attached to an external pulse generator taped to the skin. We reviewed the utility of PTPMs as a temporary bridge measure after TAVR in patients with conduction abnormalities that do not meet conventional criteria for PPM placement. METHODS: Between January 01, 2013 and December 31, 2015, we analyzed 67 patients who received PTPM after TAVR. Baseline demographics, comorbidities, type and size of the valve, pre-TAVR electrocardiograms (ECGs), post-TAVR ECGs at 1 day, 1 month, and 6 months, and pacemaker interrogation results were reviewed for each patient if available. RESULTS: The mean age of patients was 80.5 +/- 9.1 years. PTPM were placed for 2.3 +/- 2.4 days. Among these patients, 44.8% (n = 30) received a PPM prior to discharge. Male gender (OR 2.84, 95% CI 1.05-7.69, p = 0.05) and an increase in QRS duration post-TAVR (p = 0.01) were associated with PPM placement. Pacemaker interrogation data of 11 patients with PPM revealed that 27% (n = 3) had < 1% V pacing requirements and < 10% A-pacing requirements. CONCLUSIONS: In post-TAVR patients who develop conduction abnormalities that do not meet conventional PPM implantation indications, PTPM safely provides a time period for further assessment and may prevent unnecessary PPM implantation. Male gender and an increase in QRS duration post-TAVR are associated with PPM implantation. Additionally, some patients may recover from their conduction disturbances and demonstrate low pacemaker utilization. PMID- 29532276 TI - Distance between the left atrium and the vertebral body is predictive of esophageal movement in serial MR imaging. AB - PURPOSE: MRI or CT imaging can be used to identify the esophageal location prior to left atrial ablation, but the esophagus may move making the location unreliable when ablating to minimize esophageal injury. The aim of this study was to evaluate esophageal position and movement based on serial MRI imaging with the goal of identifying imaging and clinical characteristics that can predict the esophageal movement. METHODS: Fifty patients undergoing 190 MRI scans were analyzed. The relative position of the esophagus in each MRI along with clinical and imaging characteristics was quantified, including the gap between the left atrium (LA) and the vertebral body (GAP), an anatomic space in which the esophagus can move. RESULTS: A mean of 3.8 MRIs was analyzed per patient. Sixteen patients (32.0%) experienced significant lateral esophageal movement of more than 10 mm. In the significant movement group, body mass index (BMI) was higher (33.0 +/- 6.5 vs 28.8 +/- 5.3, p = 0.02) and the GAP was significantly larger (7.1 +/- 2.5 vs 4.8 +/- 5.1 mm, p = 0.04). Multivariate logistic regression analysis revealed that the GAP <= 4.5 mm was the only independent predictor of the esophagus not moving (odds ratio = 9.25, 95% confidence interval = 1.72 to 49.67, p = 0.0095). CONCLUSIONS: A GAP of less than 4.5 mm between the LA and the vertebral body is associated with lack of esophageal movement (< 10 mm). This suggests that the measurement of GAP < 4.5 mm may be used to predict the esophageal location in patients undergoing atrial ablation. PMID- 29532277 TI - Indexing Versus Journal Ethics. AB - There is a profit if a journal managed to get indexed in a well-recognized database. The encouraging of being an indexed journal might cause an unethical management approaches in some unprofessional journals. This commentary discusses some of the unethical activities which may be done before submission for indexing. PMID- 29532278 TI - Fast Review Process in Established Journals is Not a Flaw. PMID- 29532279 TI - Alienation from the Objectives of the Patent System: How to Remedy the Situation of Biotechnology Patent. AB - Some fundamental biotechnologies hold unprecedented potential to eradicate many incurable diseases. However, in absence of regulations, the power of patent makes the future use of some important biotechnology in few institution's hands. The excessive patents restrict researcher access to the fundamental technologies. It generates concerns and complaints of deteriorating the public health and social welfare. Furthermore, intellectual curiosities, funding, respect among colleagues etc., rather than patents, are the real motivations driving a major ground breaking discoveries in biotechnology. These phenomena reveal that some biotechnology patents are alienated from the purpose of patent system. Therefore, it is necessary to take some approaches to stop over-patenting these fundamental biotechnology inventions. This article proposes a model regulatory framework for controlling biotechnology patent alienating from the purpose of patent system. PMID- 29532280 TI - Empowering Engineering Students in Ethical Risk Management: An Experimental Study. AB - The complexity of industrial reality, the plurality of legitimate perspectives on risks and the role of emotions in decision-making raise important ethical issues in risk management that are usually overlooked in engineering. Using a questionnaire answered by 200 engineering students from a major engineering school in Canada, the purpose of this study was to assess how their training has influenced their perceptions toward these issues. While our results challenge the stereotypical portrait of the engineer, they also suggest that the current engineering education might fail to empower engineers to engage in ethical risk management. We therefore propose an active-learning method to help in this matter. Carried out through workshops with 34 students in chemical engineering, the effectiveness of this method has been evaluated using group interviews and questionnaires. Our results suggest that such an approach is effective, at least in the short run, to motivate students to engage in ethical risk management and to trigger reflectivity on what it means to be an engineer today. PMID- 29532282 TI - The role of income in brain tumor patients: a descriptive register-based study : No correlation between patients' income and development of brain cancer. AB - Socioeconomic status (SES) and its association with cancer in general have been thoroughly studied in the last decades. Several studies have shown associations between SES and many types of cancer such as lung cancer, breast cancer, and prostate cancer. For gliomas, no clear occupational or exposure risk factors have been identified, although some possible risk factors such as use of cellular telephone are still controversial. The aim in the present study is to analyze whether there is an association between SES and development of brain cancer. Data from 1999 through 2013 were collected from the Swedish Cancer Registry and from the National Statistics of Sweden. Age-standardized incidence rates for people with different income were calculated using linear regression model. A total of 11,892 patients were included, of which 5675 were meningiomas, 1216 low-grade gliomas, and 5001 high-grade gliomas. No clear trend between increasing incidence rates and higher income was seen in neither of the investigated brain tumor histologies. In conclusion, the results should be interpreted with caution, but there does not seem to be a correlation in this material between increased income and development of brain cancer. PMID- 29532283 TI - Zika virus infection and autonomic symptoms. PMID- 29532281 TI - Role of the Immune System in Diabetic Kidney Disease. AB - PURPOSE OF REVIEW: The purpose of this review is to examine the proposed role of immune modulation in the development and progression of diabetic kidney disease (DKD). RECENT FINDINGS: Diabetic kidney disease has not historically been considered an immune-mediated disease; however, increasing evidence is emerging in support of an immune role in its pathophysiology. Both systemic and local renal inflammation have been associated with DKD. Infiltration of immune cells, predominantly macrophages, into the kidney has been reported in a number of both experimental and clinical studies. In addition, increased levels of circulating pro-inflammatory cytokines have been linked to disease progression. Consequently, a variety of therapeutic strategies involving modulation of the immune response are currently being investigated in diabetic kidney disease. Although no current therapies for DKD are directly based on immune modulation many of the therapies in clinical use have anti-inflammatory effects along with their primary actions. Macrophages emerge as the most likely beneficial immune cell target and compounds which reduce macrophage infiltration to the kidney have shown potential in both animal models and clinical trials. PMID- 29532284 TI - Genetic diversity of Haemaphysalis qinghaiensis (Acari: Ixodidae) in western China. AB - Haemaphysalis qinghaiensis as an endemic species in China mainly infests domestic animals and causes great harm to animals and humans in Northwestern plateau. However, there is no information about genetic diversity within the recently established populations of this tick species. Therefore, the present study analyzed the fragments of mitochondrial 16S rDNA, COI and the nuclear gene ITS1 of 56 H. qinghaiensis ticks across four regions of China which are main endemic areas of this species. Analysis showed 98.1-100% (16S rDNA), 97.9-100% (COI), 99.7-100% (ITS1) identity within individuals. For these sequences, 9, 15 and 8 haplotypes were found for 16S rDNA, COI and ITS1, respectively. Ticks from Yongjing were the most variable group, followed by Lintan, Huangyuan, and Tianzhu. Based on parallel analysis of the mitochondrial and nuclear genetic diversity of H. qinghaiensis, our results indicated that mitochondrial markers (especially COI) were much more useful than nuclear ITS for intraspecific genetic variability analysis. PMID- 29532285 TI - "To Name or Not to Name: That is the Question": The Role of Response Inhibition in Reading. AB - Reading is a complex process that includes the integration of information about letters (graphemes) and sounds (phonemes). In many circumstances, such as noisy environments, response inhibition is an additional factor that plays a marked role in successful oral reading. Response inhibition can take the form of task relevant inhibition (i.e., foils in a go/no-go task) and task irrelevant inhibition (i.e., distractor information). Here we investigated task relevant inhibition by having participants (N = 30) take part in two tasks: go/no-go naming with nonwords foils (GNG-NW) and go/no-go naming with pseudohomophones foils (GNG-PH). Also, we investigated the addition of task irrelevant inhibition by having participants (N = 28) take part in two tasks: GNG-NW + information masking and GNG-PH + information masking. We provide evidence that during a task relevant inhibition task, sub-word sound level information can be successfully inhibited, as evidenced by comparable response times for regular words and exception words, provided the foils do not contain familiar sound-based information (GNG-NW). In contrast, regular words were read aloud faster than exception words in a GNG-PH task, indicating that sub-word level interference occurs when the foils contain familiar sound-based information. The addition of task irrelevant inhibition (i.e., information masking at the phoneme level), served to increase response time overall, but did not impact the pattern of response times between regular words and exception words. Together these findings provide useful information regarding the role of response inhibition in word recognition and may be useful in computational models of word recognition and future work may benefit from accounting for the effects outlined in this paper. PMID- 29532286 TI - Serum anti-JCV antibody indexes in Japanese patients with multiple sclerosis: elevations along with fingolimod treatment duration. AB - BACKGROUND: The risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis (MS) patients is related to serum anti-JCV antibody (JCVAb) index. However, the correlation of JCVAb index with other disease-modifying treatments (DMTs) is not well understood. OBJECTIVE: In this study, we investigated the JCVAb seropositivity rate/JCVAb indexes and its correlation with clinical profiles in Japanese MS patients, and the relationship between JCVAb indexes and DMTs. METHODS: JCVAb indexes were measured in 149 serum samples from 105 patients with MS. JCVAb indexes and seropositivity, and their correlation with age, sex, disease duration, Kurtzke expanded disability status scale and the duration of the DMTs were evaluated in each patient. RESULTS: JCVAb was positive in 73 of 105 MS patients. Within 40 fingolimod-treated patients, 27 were positive for JCVAb and JCVAb indexes were positively correlated with the duration of fingolimod treatment. No significant relation was found between JCVAb indexes and the duration of treatment for the other disease-modifying drugs. CONCLUSION: JCVAb seropositivity was comparatively high in Japanese MS patients. Fingolimod treatment is likely to increase serum JCVAb index, possibly leading to the development of PML. Therefore, it is advised that JCVAb index should be serially monitored during fingolimod treatment to decrease PML risk. PMID- 29532287 TI - Meniere's disease: combined pharmacotherapy with betahistine and the MAO-B inhibitor selegiline-an observational study. AB - OBJECTIVES: Since oral betahistine has a very high first-pass effect (ca. 99%), metabolized by monoamine oxidases (MAO), the benefits of a high-dosage betahistine monotherapy were compared with those of a lower dosage of betahistine in combination with the MAO-B inhibitor (MAO-B) selegiline on the frequency of acute attacks of vertigo in patients with Meniere's disease (MD). METHODS: Thirteen adults aged 40-75 years (mean 58.9 years; six females) had initially been treated with a high dosage of betahistine dihydrochloride for at least 1 year. Under this therapy, all of them had <= 1 attack for >= 3 months prior to the combination pharmacotherapy. Subsequently, they received 5 mg/day selegiline and the dosage of betahistine was reduced to about one tenth and then individually adjusted to the dosage needed to achieve the same treatment response (<= 1 per 3 months, observational period of at least 6 months). RESULTS: The initial dosage for the long-term "titration" of the attacks of vertigo was 9-80 24-mg tablets/day (mean 37.3), i.e. 216-1920 mg/day (mean 895.4 mg/day). After the combination with selegiline, the dosage needed to achieve the same benefit for >= 3 months was 3-36 24-mg tablets (mean 8.5), i.e., 72-864 mg/day [mean 204.9 mg/day, p < 0.001 (paired t test)]. One patient transiently stopped the treatment with selegiline, another one reduced the dosage to 2.5 mg/day and the attacks re-occurred after 2-4 weeks. Six out of 13 patients reported transient fullness of the head during the combined treatment; in 2 of them this went away when they switched to 2.5 mg bid. In the longer term (> 9 months), one patient had to increase the selegiline dosage to 5 mg bd, one patient stopped the treatment with selegiline. CONCLUSIONS: The achievement of the same clinical effect with a significantly lower (about 1/5) dosage of betahistine can be explained by the inhibition of the MAO-B by selegiline leading to higher serum concentrations of betahistine. This approach is in line with recent developments to bypass the first-pass effect of betahistine by transbuccal or intranasal application. Despite the substantial methodological limitations of such an observational study, this combined pharmacotherapy could be an alternative to a high-dosage monotherapy with betahistine of MD. PMID- 29532288 TI - Dizziness and vertigo syndromes viewed with a historical eye. AB - Seasickness, fear of heights, and adverse effects of alcohol were the major areas where descriptions of vertigo and dizziness were found in Roman, Greek, and Chinese texts from about 730 BC-600 AD. A few detailed accounts were suggestive of specific vestibular disorders such as Meniere's attacks (Huangdi Neijing, the Yellow Thearch's Classic of Internal Medicine) or vestibular migraine (Aretaeus of Cappadocia). Further, the etymological and metaphorical meanings of the terms and their symptoms provide fascinating historical insights, e.g. Vespasian's feelings of dizzy exultations when becoming Emperor (69 AD) after Nero's suicide or the figurative meaning of German "Schwindel" (vertigo) derived from English "swindle" to express "financial fraud" in the Eighteenth century. The growth of knowledge of the vestibular system and its functions began primarily in the Nineteenth century. Erasmus Darwin, however, was ahead of his times. His work Zoonomia, or The Laws of Organic Life in 1794 described new dizziness syndromes and concepts of sensorimotor control including the mechanism of fear of heights as well as made early observations on positional alcohol vertigo. The latter is beautifully illustrated by the German poet and cartoonist Wilhelm Busch (1832 1908) who also documented the alleviating effect of the "morning after drink". The mechanism underlying positional alcohol vertigo, i.e., the differential gravities of alcohol and endolymph, was discovered later in the Nineteenth century. The first textbook on neurology (Lehrbuch der Nervenkrankheiten des Menschen, 1840) by Moritz Romberg contained general descriptions of signs and symptoms of various conditions having the key symptom of vertigo, but no definition of vestibular disorders. Our current knowledge of vestibular function and disorders dates back to the seminal work of a group of Nineteenth century scientists, e.g., Jan Evangelista Purkinje, Ernst Mach, Josef Breuer, Hermann Helmholtz, and Alexander Crum-Brown. PMID- 29532289 TI - Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab. AB - INTRODUCTION: At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. MATERIALS AND METHODS: In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P selectin expression and fibrinogen binding, platelet-EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC-MS/MS and ELISA. RESULTS: In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 MUM sunitinib: 71.3%, p < 0.001; 25 MUM sorafenib: 55.8%, p = 0.042). Sorafenib and sunitinib significantly inhibited P-selectin expression on platelets. Exposure to both TKIs resulted in a reduced tyrosine phosphorylation of c-Src. Ex vivo, within 24 h sunitinib impaired platelet aggregation (83.0%, p = 0.001, N = 8). Plasma concentrations of sunitinib, VEGF, and platelet/EC activation markers were not correlated with disturbed aggregation. In contrast, bevacizumab only significantly impaired platelet aggregation in vitro at high concentrations, but not ex vivo. CONCLUSION: Sunitinib significantly inhibits platelet aggregation in patients already after 24 h of first administration, whereas bevacizumab had no effect on aggregation. These findings may explain the clinically observed bleedings during treatment with antiangiogenic TKIs. PMID- 29532291 TI - The effect of CYP1A2 genotype on the ergogenic properties of caffeine during resistance exercise: a randomized, double-blind, placebo-controlled, crossover study. AB - AIM: The purpose of this study was to examine the effect of CYP1A2 -163C>A polymorphism on the ergogenic effects of caffeine supplementation during a resistance exercise (RE) session. METHODS: In a randomized, double-blind, placebo (PL)-controlled, crossover study, 30 resistance-trained men took part in two RE sessions (three sets to failure at 85% of one repetition maximum, 2-min rest between sets), including bench press (BP), leg press (LP), seated cable row, and shoulder press (SP) following caffeine (CAF) (6 mg kg-1) or PL (6 mg kg-1 of maltodextrin) ingestion 1 h prior to the trial. The number of repetitions was recorded after each set, along with calculation of total number of repetitions for each exercise. Genomic DNA was isolated from the whole blood samples for analyzing the CYP1A2 -163C>A polymorphism through amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Subjects were classified as either AA (n = 14) or AC/CC genotypes (n = 16). RESULTS: The two-way ANOVA with repeated measures revealed differences between AAs and AC/CCs under CAF conditions for repetitions performed in sets 1, 2, and 3 of BP (F(1, 28) = 14.84, P = 0.001, n2 = 0.34), LP (F(1, 28) = 8.92, P = 0.006, n2 = 0.24), SR (F(1, 28) = 17.38, P = 0.0001, n2 = 0.38), and SP (F(1, 28) = 3.76, P = 0.063, n2 = 0.11). CAF also increased the total number of repetitions performed for all three sets in AAs versus AC/CCs for BP (F(1, 28) = 8.72, P = 0.006, n2 = 0.23), LP (F(1, 28) = 4.67, P = 0.03, n2 = 0.14), SR (F(1, 28) = 5.54, P = 0.02, n2 = 0.16), and SP (F(1, 28) = 3.89, P = 0.058, n2 = 0.12) in athletes who were homozygous carriers of the A allele, compared to the C allele carriers. Therefore, AA homozygotes were able to carry out a greater total volume of RE work under CAF but not PL conditions, compared to the C allele carriers. CONCLUSION: In conclusion, acute ingestion of CAF significantly enhanced RE performance in resistance-trained men who were homozygous for the A allele, but not for C allele carriers. Further studies are needed to replicate the potential role of the CYP1A2 -163C>A polymorphism on the ergogenic effects of CAF in other modes of exercise and in other populations. PMID- 29532290 TI - Analysis of physiological and miRNA responses to Pi deficiency in alfalfa (Medicago sativa L.). AB - KEY MESSAGE: The induction of miR399 and miR398 and the inhibition of miR156, miR159, miR160, miR171, miR2111, and miR2643 were observed under Pi deficiency in alfalfa. The miRNA-mediated genes involved in basic metabolic process, root and shoot development, stress response and Pi uptake. Inorganic phosphate (Pi) deficiency is known to be a limiting factor in plant development and growth. However, the underlying miRNAs associated with the Pi deficiency-responsive mechanism in alfalfa are unclear. To elucidate the molecular mechanism at the miRNA level, we constructed four small RNA (sRNA) libraries from the roots and shoots of alfalfa grown under normal or Pi-deficient conditions. In the present study, alfalfa plants showed reductions in biomass, photosynthesis, and Pi content and increases in their root-to-shoot ratio and citric, malic, and succinic acid contents under Pi limitation. Sequencing results identified 47 and 44 differentially expressed miRNAs in the roots and shoots, respectively. Furthermore, 909 potential target genes were predicted, and some targets were validated by RLM-RACE assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed prominent enrichment in signal transducer activity, binding and basic metabolic pathways for carbohydrates, fatty acids and amino acids; cellular response to hormone stimulus and response to auxin pathways were also enriched. qPCR results verified that the differentially expressed miRNA profile was consistent with sequencing results, and putative target genes exhibited opposite expression patterns. In this study, the miRNAs associated with the response to Pi limitation in alfalfa were identified. In addition, there was an enrichment of miRNA-targeted genes involved in biological regulatory processes such as basic metabolic pathways, root and shoot development, stress response, Pi transportation and citric acid secretion. PMID- 29532293 TI - Prejudice in Perceptions of Physicians?: The Influence of Race and Gender on Evaluations of Medical Errors. PMID- 29532294 TI - Suffering Begets Suffering, and the Future of Primary Care. PMID- 29532292 TI - Antibiotic use for acute respiratory tract infections (ARTI) in primary care; what factors affect prescribing and why is it important? A narrative review. AB - BACKGROUND: Antimicrobial resistance is an emerging global threat to health and is associated with increased consumption of antibiotics. Seventy-four per cent of antibiotic prescribing takes place in primary care. Much of this is for inappropriate treatment of acute respiratory tract infections. AIMS: To review the published literature pertaining to antibiotic prescribing in order to identify and understand the factors that affect primary care providers' prescribing decisions. METHODS: Six online databases were searched for relevant paper using agreed criteria. One hundred ninety-five papers were retrieved, and 139 were included in this review. RESULTS: Primary care providers are highly influenced to prescribe by patient expectation for antibiotics, clinical uncertainty and workload induced time pressures. Strategies proven to reduce such inappropriate prescribing include appropriately aimed multifaceted educational interventions for primary care providers, mass media educational campaigns aimed at healthcare professionals and the public, use of good communication skills in the consultation, use of delayed prescriptions especially when accompanied by written information, point of care testing and, probably, longer less pressurised consultations. Delayed prescriptions also facilitate focused personalised patient education. CONCLUSION: There is an emerging consensus in the literature regarding strategies proven to reduce antibiotic consumption for acute respiratory tract infections. The widespread adoption of these strategies in primary care is imperative. PMID- 29532295 TI - Capsule Commentary on Cutrona et al., Improving Rates of Outpatient Influenza Vaccination Through EHR Portal Messages and Interactive Automated Calls: a Randomized Controlled Trial. PMID- 29532296 TI - How to Deliver Care Management: Guidance from an Analysis of Communication Patterns in Primary Care. PMID- 29532298 TI - The Comb Sign in Crohn's Ileocolitis. PMID- 29532297 TI - The Impact of Automated Notification on Follow-up of Actionable Tests Pending at Discharge: a Cluster-Randomized Controlled Trial. AB - BACKGROUND: Follow-up of tests pending at discharge (TPADs) is poor. We previously demonstrated a twofold increase in awareness of any TPAD by attendings and primary care physicians (PCPs) using an automated email intervention OBJECTIVE: To determine whether automated notification improves documented follow up for actionable TPADs DESIGN: Cluster-randomized controlled trial SUBJECTS: Attendings and PCPs caring for adult patients discharged from general medicine and cardiology services with at least one actionable TPAD between June 2011 and May 2012 INTERVENTION: An automated system that notifies discharging attendings and network PCPs of finalized TPADs by email MAIN MEASURES: The primary outcome was the proportion of actionable TPADs with documented action determined by independent physician review of the electronic health record (EHR). Secondary outcomes included documented acknowledgment, 30-day readmissions, and adjusted median days to documented follow-up. KEY RESULTS: Of the 3378 TPADs sampled, 253 (7.5%) were determined to be actionable by physician review. Of these, 150 (123 patients discharged by 53 attendings) and 103 (90 patients discharged by 44 attendings) were assigned to intervention and usual care groups, respectively, and underwent chart review. The proportion of actionable TPADs with documented action was 60.7 vs. 56.3% (p = 0.82) in the intervention vs. usual care groups, similar for documented acknowledgment. The proportion of patients with actionable TPADs readmitted within 30 days was 22.8 vs. 31.1% in the intervention vs. usual care groups (p = 0.24). The adjusted median days [95% CI] to documented action was 9 [6.2, 11.8] vs. 14 [10.2, 17.8] (p = 0.04) in the intervention vs. usual care groups, similar for documented acknowledgment. In sub-group analysis, the intervention had greater impact on documented action for patients with network PCPs compared with usual care (70 vs. 50%, p = 0.03). CONCLUSIONS: Automated notification of actionable TPADs shortened time to action but did not significantly improve documented follow-up, except for network-affiliated patients. The high proportion of actionable TPADs without any documented follow up (~ 40%) represents an ongoing safety concern. CLINICAL TRIALS IDENTIFIER: NCT01153451. PMID- 29532299 TI - Closing the Referral Loop: an Analysis of Primary Care Referrals to Specialists in a Large Health System. AB - PURPOSE: Ideally, a referral from a primary care physician (PCP) to a specialist results in a completed specialty appointment with results available to the PCP. This is defined as "closing the referral loop." As health systems grow more complex, regulatory bodies increase vigilance, and reimbursement shifts towards value, closing the referral loop becomes a patient safety, regulatory, and financial imperative. OBJECTIVE/DESIGN: To assess the ability of a large health system to close the referral loop, we used electronic medical record (EMR) generated data to analyze referrals from a large primary care network to 20 high volume specialties between July 1, 2015 and June 30, 2016. MAIN MEASURES: The primary metric was documented specialist appointment completion rate. Explanatory analyses included documented appointment scheduling rate, individual clinic differences, appointment wait times, and geographic distance to appointments. KEY RESULTS: Of the 103,737 analyzed referral scheduling attempts, only 36,072 (34.8%) resulted in documented complete appointments. Low documented appointment scheduling rates (38.9% of scheduling attempts lacked appointment dates), individual clinic differences in closing the referral loop, and significant differences in wait times and distances to specialists between complete and incomplete appointments drove this gap. Other notable findings include high variation in wait times among specialties and correlation between high wait times and low documented appointment completion rates. CONCLUSIONS: The rate of closing the referral loop in this health system is low. Low appointment scheduling rates, individual clinic differences, and patient access issues of wait times and geographic proximity explain much of the gap. This problem is likely common among large health systems with complex provider networks and referral scheduling. Strategies that improve scheduling, decrease variation among clinics, and improve patient access will likely improve rates of closing the referral loop. More research is necessary to determine the impact of these changes and other potential driving factors. PMID- 29532300 TI - It's Not Just About How Much You're Paid. PMID- 29532301 TI - Medical Schools Should Admit More Guitar Players. PMID- 29532302 TI - A Case of Disseminated Histoplasmosis in a Patient with Rheumatoid Arthritis on Abatacept. AB - Biologic agents are effective treatments for rheumatoid arthritis but are associated with important risks, including severe infections. Tumor Necrosis Factor (TNF) alpha inhibitors are known to increase the risk of systemic fungal infections such as disseminated histoplasmosis. Abatacept is a biologic agent with a mechanism different from that of TNFalpha inhibitors: It suppresses cellular immunity by competing for the costimulatory signal on antigen-presenting cells. The risk of disseminated histoplasmosis for patients on abatacept is not known. We report a case of abatacept-associated disseminated histoplasmosis and review the known infectious complications of abatacept. While the safety of resuming biologic agents following treatment for disseminated histoplasmosis is also not known, abatacept is recommended over TNFalpha inhibitors for rheumatoid arthritis patients with a prior serious infection. We discuss the evidence supporting this recommendation and discuss alternative treatments for rheumatoid arthritis patients with a history of a serious infection. PMID- 29532303 TI - Non-response to Communication Technology Outreach for Beta-agonist Overuse in a Pragmatic Randomized Trial of Patients with Asthma. PMID- 29532304 TI - The Role of Hopelessness in the Health of Low-Class Rural Chinese Residents. AB - It is well known that health inequality has been happening between rural and urban Chinese populations, however, the health differences among rural Chinese residents remain unclear. This study aims to assess the physical and mental health of rural Chinese residents in different social classes, and then to examine the mediating role of hopelessness between social class and health related quality of life (HRQOL). A stratified multi-stage sampling was used to recruit 2003 rural residents responding to the 12-item Short Form Health Survey (SF-12). The results showed that lower-class rural Chinese residents reported lower physical and mental health as well as a higher level of hopelessness. Furthermore, hopelessness could fully mediate the association between social class and physical and mental health. These findings will generate significant implications for identifying those at particular risk for lower quality of life and designing social work intervention programs in rural China's context. PMID- 29532305 TI - Effect of emergency physician burnout on patient waiting times. PMID- 29532307 TI - Implementation and evaluation of structured nephrology morbidity and mortality conferences: a quality education report. AB - BACKGROUND: Morbidity and Mortality Conferences (M&MCs) have for generations been part of the education of physicians, yet their effectiveness remains questionable. The Ottawa M&M Model (OM3) was developed to provide a structured approach to M&MCs in order to maximize the quality improvement impact of such rounds. STUDY DESIGN: We conducted a retrospective assessment of the impact of implementing nephrology-specific M&MCs using the OM3. SETTING AND PARTICIPANTS: All physicians, residents and fellows from the division of nephrology at a large academic medical center were invited to participate. QUALITY IMPROVEMENT PLAN: Structured M&MCs were implemented to identify preventable errors and generate actions to improve quality of care and patient safety. OUTCOMES: Number and nature of cases reviewed, number and nature of recommendations generated through identification of preventable health system and/or cognitive factors. MEASUREMENTS: Morbidity and/or mortality in each case were identified. A determination of the underlying factors and preventability of these events was made. A qualitative review of resulting recommendations was performed. RESULTS: Over the course of sixteen 1-h long conferences, 52 cases were presented. For all cases presented, discussion, action items and information dissemination followed the OM3. As a result of the M&MCs, 29 recommendations (emanating from 27 cases) lead to improve care delivery. LIMITATIONS: Limitations of this study include its retrospective nature and single-center design. CONCLUSIONS: The implementation of regularly scheduled M&MCs at an academic nephrology program, using a structured model, identified preventable health-systems issues and cognitive errors. Approximately one-half of the cases reviewed generated actions for health care delivery improvement. PMID- 29532306 TI - Calcimimetics versus parathyroidectomy: What is preferable? AB - Secondary hyperparathyroidism (SHPT) is common among patients with end-stage renal disease (ESRD). SHPT is associated with high-turnover bone disease, interstitial and vascular calcifications, cardiovascular morbidity and mortality. The pharmacological management of SHPT has progressed in recent years. The introduction of targeted therapies, such as selective vitamin D receptors activators and calcium-sensing receptor modulators, offers an increased opportunity to adequately control elevated parathyroid hormone (PTH), especially in patients with chronic kidney disease under dialysis treatment. Calcimimetic medications such as cinacalcet negatively feedback on the parathyroid glands and do not have the consequences of calcium augmentation. However, there are no randomised, prospective data that demonstrate improved quality of life, improvement in anemia, reduction in phosphate binders, reduction in use of vitamin D analogs, or reduction in mortality. Literature supports cinacalcet therapy to improve patient outcomes, especially with regard to vascular calcifications and presumably the very lethal condition of calciphylaxis. However, cinacalcet is administered orally and has been associated with gastrointestinal intolerance along with hypocalcemia. In addition, poor adherence has been observed among dialysis patients self-administering oral cinacalcet. On the other hand, successful surgical parathyroidectomy (sPTX) can yield a dramatic reduction in PTH level and clinical symptoms. The advanced pharmacological treatments of SHPT often obviate parathyroidectomy; however, some researchers have reported that sPTX may be more cost-effective than cinacalcet in some patients with ESRD and suffering uncontrolled SHPT. PMID- 29532308 TI - Disparities in early mortality among chronic kidney disease patients who transition to peritoneal dialysis and hemodialysis with and without catheters. AB - PURPOSE: The early period after chronic kidney disease (CKD) patients transition to end-stage renal disease (ESRD) represents the highest mortality risk but is variable among different patient populations and clinical circumstances. We compared early mortality outcomes among a diverse CKD population that transitioned to ESRD. METHODS: A retrospective cohort study (1/1/2002 through 12/31/2013) of CKD patients (age >= 18 years) who transitioned to peritoneal dialysis (PD), hemodialysis (HD) with arteriovenous fistula/grafts, and HD with catheters was performed. Multivariable Cox regression modeling was used to estimate 6-month all-cause mortality hazard ratios (HR) among the three treatment groups after adjustment for patient and clinical characteristics. RESULTS: Among 5373 ESRD patients (62.7 years, 41.3% females, 37.5% Hispanics, 13.3% PD, 34.9% HD with fistula/graft, 51.8% HD with catheter), 551 (10.3%) died at 6 months. Mortality rates were highest immediately after transition (299 deaths per 1000 person-years in first month). Compared to PD patients, the 6-month mortality HR (95% CI) was 1.87 (1.06-3.30) in HD with fistula/graft patients and 3.77 (2.17 6.57) in HD with catheter patients. Inpatient transition (HR 1.32), acute kidney injury (HR 2.06), and an eGFR >= 15 vs 5-9 (HR 1.68) at transition were also associated with higher early mortality risk. CONCLUSION: Among a diverse CKD population who transitioned to ESRD, we observed considerable differences in early mortality risk among PD, HD with fistula/graft, and HD with catheter patients. The identification of patient-specific and clinical environmental factors related to high early mortality may provide insights for managing advanced stages of CKD and shared decision making. PMID- 29532309 TI - Does sex matter? A matched pairs analysis of neuromodulation outcomes in women and men. AB - AIMS: To evaluate whether baseline symptoms and outcomes are influenced by gender in a matched cohort undergoing neuromodulation. METHODS: Patients in our prospective neuromodulation database that had a tined lead placed were reviewed. Those that had implantable pulse generator (IPG) placed were matched on age and urologic diagnosis. History, voiding diaries, satisfaction, Interstitial Cystitis Symptom/Problem Index (ICSIPI), and overactive bladder symptom severity (OABq ss)/health-related quality of life (HRQOL) preimplant and over 3 years were evaluated using descriptive statistics, repeated measures, and matched pair GEE or mixed analyses. RESULTS: Of 590 patients in the database, more women than men received an IPG (450/488; 92.2 vs. 84/102; 82.4%; p = 0.0011). Eighty matched pairs (n = 160; 81% >= 50 years old; 56.25% had urgency/frequency with urge incontinence-UI) were identified and evaluated. On voiding diaries, volume/void was greater in women only at baseline (p = 0.040); both groups improved over time (p < 0.0001). Urinary frequency improved in both women and men (p = 0.0010; p = 0.0025). Over 3 years, UI episodes/day improved only in men (p = 0.017) and UI severity improved only in women (p < 0.0001). ICSIPI, OABq ss, and HRQOL scores improved similarly in both groups (p < 0.0001 for all measures in both groups), and although more women were satisfied at 3 months (p = 0.027), groups did not differ at other time points. CONCLUSIONS: More women undergo neuromodulation and have initial success and subsequent IPG implantation. UI episodes improved only in men, and UI severity improved only in women. Both women and men experienced similar levels of symptom improvement on other measures. PMID- 29532310 TI - Spontaneous correction of misplaced peripherally inserted central catheters. AB - The purpose of the present study was to examine a new protocol involving the spontaneous correction of the misplaced tip of a peripherally inserted central catheter (PICC). Patients with PICCs misplaced in the jugular or contralateral subclavian veins were recruited. All patients underwent chest X-ray (CXR) after 3 days. In addition, those whose PICC tip still was misplaced and received another CXR after 4 days. The functions of the catheters, the subjective feelings of the patients, and local symptoms of the neck and upper anterior chest wall were recorded. Among 866 patients who had PICCs, we observed 22 PICC tips misplaced in the jugular, 3 tips misplaced in the contralateral subclavian vein, and 7 tips misplaced in other locations, which was confirmed by CXR. A total of 22 PICC tips automatically returned to the superior vena cava, which included all 3 tips in the contralateral subclavian vein and 19 tips in the jugular vein. All catheters functioned normally, and the patients had no complaints. In addition, we observed no local symptoms of the neck and upper anterior chest wall. For patients experiencing a PICC misplaced in the jugular and contralateral subclavian veins, there is no need to manually replace. In addition, the function of the catheter can remain normal. PMID- 29532312 TI - Liver Metastatic Melanoma: a Unique Case with Normal Alkaline Phosphatase and Melanuria. PMID- 29532311 TI - Intraparenchymal epidermoid cyst: proper surgical management may lead to satisfactory outcome. AB - Intraparenchymal epidermoid cysts (IECs) are rare lesions, thus the preoperative diagnosis and proper surgical management are still a challenge. We searched the database at our institution and performed a search of English literature in PubMed and Google Scholar. Keywords used were as follows: "intraparenchymal"; "intracerebral"; "intraaxial"; "epidermoid cyst"; "brainstem"; "cholesteatoma"; "pearly tumor". Only cases that were true intraparenchymally located and contained adequate clinical information were included. Six cases of IECs were recorded at our institution. Total removal was achieved in all the six patients with good outcomes. 29 cases meeting the above criteria were found in the literature. Including ours, a total of 35 patients were analyzed. Females were more frequently affected (F/M ratio, 1.9:1). Most of them were located in the brainstem (42.9%) and temporal lobe (22.9%). While in children, all were located in the brainstem. 45.2% showed subtle peripheral enhancement on Magnetic Resonance Imaging (MRI), and all appeared hyperintense on Diffusion Weighted Imaging (DWI). In the subgroup of cerebral lobes and cerebellums, total resection was achieved in 89.5%, and they all showed good outcomes. While in the subgroup of brainstem, 46.7% (seven cases) underwent total resection and 50% (three cases) of them died postoperatively. MRI with DWI is helpful in the preoperative diagnosis. Total resection should be achieved for the IECs located in cerebral lobes and cerebellums, while subtotal resection is a wise and safe strategy for the IECs located in the brainstem. PMID- 29532313 TI - The phylogenetic position of Choerodonicola Cribb, 2005 (Digenea: Opecoelidae) with a partial life-cycle for a new species from the blue-barred parrotfish Scarus ghobban Forsskal (Scaridae) in Moreton Bay, Australia. AB - Choerodonicola Cribb, 2005 is a minor genus of opecoelid trematodes defined for species with exceptionally small eggs but otherwise generalised morphology. Four species are currently recognised, all from fishes collected in Japanese waters but each from different perciform families: a labrid, a scarid, a sparid and pinguipeds. We report on a new species, Choerodonicola arothokoros n. sp., from the blue-barred parrotfish Scarus ghobban Forsskal (Scaridae) collected in subtropical waters of Moreton Bay, south-east Queensland, Australia. Using genetic sequence data for the ITS2 rDNA marker, we matched adult C. arothokoros to intramollsucan stages discovered in an intertidal gastropod Herpetopoma atratum (Gmelin) (Vetigastropoda: Chilodontidae) collected in close proximity to the fish hosts. Notably, the cercariae lack a penetration stylet and are among the smallest known in the Opecoelidae. We provide the first assessment of the phylogenetic position of Choerodonicola based on sequence data generated for the phylogenetically informative 18S and 28S rRNA coding regions, for C. arothokoros and also C. renko Machida, 2014, which we recollected from the yellowback seabream Dentex hypselosomus Bleeker from the fish market in Minabe, Wakayama Prefecture, Japan. In our analyses, species of Choerodonicola resolved to neither of the major marine Plagioporinae (sensu lato) clades, clustering instead with Trilobovarium parvvatis Martin, Cutmore & Cribb, 2017, Podocotyloides parupenei (Manter, 1963) Pritchard, 1966 and Macvicaria magellanica Laskowski, Jezewski & Zdzitowiecki, 2013. This clade is phylogenetically distinctive such that it has the potential to be recognised as a new opecoelid subfamily, but further investigation is required to establish the bounds for such a grouping and to determine the morphological and/or life-history patterns reflected by the phylogeny. Finally, we propose C. interruptus (Manter 1954) n. comb. for a species previously recognised in Plagioporus Stafford, 1904 and known only from Pseudolabrus miles (Schneider & Forster), a labrid endemic to New Zealand. PMID- 29532314 TI - Development of A Textile Capacitive Proximity Sensor and Gait Monitoring System for Smart Healthcare. AB - Gait is not only one of the most important functions and activities in daily life but is also a parameter to monitor one's health status. We propose a single channel capacitive proximity pressure sensor (TCPS) and gait monitoring system for smart healthcare. Insole-type TCPS (270 mm in length) was designed consisting of three layers including two shield layers and a sensor layer. Analyzing the step count and stride time are the basic indicators in gait analysis, thus they were selected as evaluation indicators. A total of 12 subjects participated in the experiment to evaluate the resolution of our TCPS. To evaluate the accuracy of TCPS, step count and its error rates were simultaneously detected by naked eye, ZIKTO Walk (ZIKTO Co., Korea), and HJ-203-K pedometer (Omron Co., Japan) as reference. Results showed that the error rate of 1.77% in TCPS was lower than those of other devices and correlation coefficient was 0.958 (p-value = 0.000). ZIKTO Walk and pedometer do not provide information on stride time, therefore it was detected by F-scan (Tekscan, USA) to evaluate the performance of TCPS. As a result, error rate of stride time measured by TCPS was found to be 1% and the correlation coefficient was 0.685 (p-value = 0.000). According to these results, our proposed system may be helpful in development of gait monitoring and measurement system as smart healthcare. PMID- 29532315 TI - Contrasting Views of the Post-bariatric Surgery Experience between Patients and their Practitioners: a Qualitative Study. AB - BACKGROUND: The superiority of obesity surgery for improving medical and weight outcomes in severely obese patients when compared to other weight loss interventions remains undisputed. However, knowledge about the psychological impact of the procedure on patients' lives is limited. Systematic reviews indicate persisting psychological distress after surgery compared to control groups especially longer term, suggesting the need for postoperative psychological support and assessment. Research literature also infers limited knowledge regarding the postoperative patient experience of obesity surgery. This may form a barrier in health practitioners' understanding of these patients' ongoing needs. METHODS: Ten patients who had obesity surgery two or more years ago and eight obesity surgery practitioners were recruited within hospital settings and individually interviewed by the researcher to capture their accounts of the postoperative experience. Concordance between the two groups was explored to gauge awareness of patients' subsequent health needs. RESULTS: Thematic analysis of transcribed interviews elicited a key finding around 'post-surgical cliffs in patient care' within a heavily structured service. Participants reported some unmet needs, namely, psychological aftercare to facilitate adjustment following drastic weight loss and excess skin, acceptance of their non obese self and perceived stigma. The impact of contrasting views of success between patients and practitioners on postoperative care within the service context was highlighted. CONCLUSIONS: Obesity surgery is a great weight loss catalyst for severe obesity. However, lack of psychological aftercare may threaten early gains in health outcomes over the longer term. More qualitative and quantitative studies are needed to validate current study results. PMID- 29532316 TI - Modifications of Resting Energy Expenditure After Sleeve Gastrectomy. AB - OBJECTIVES: Resting energy expenditure (REE) declines more than what is expected according to body composition changes after caloric restriction. This metabolic adaptation is considered one of the factors favoring weight regain. The aim of this study is to evaluate the changes of REE and calculate the degree of metabolic adaptation occurring after laparoscopic sleeve gastrectomy (LSG). METHODS: REE (by indirect calorimetry) and body composition (fat-free mass or FFM, fat mass or FM by bioelectrical impedance analysis) were determined before and after 12 months in 154 patients with obesity treated with laparoscopic sleeve gastrectomy (LSG). RESULTS: Weight loss was 29.8 +/- 10.6%, with corresponding relative reductions in FM (44.5 +/- 22.8%), FFM (13.7 +/- 9.9%), and REE (27.3 +/ 12.9%). A predictive equation for REE was computed by using the baseline FFM and FM values to account for body composition changes. A predicted post-weight loss REE was calculated by using this equation and entering post-weight loss body composition values. Observed post-surgery REE was significantly lower than predicted one (1410 +/- 312 vs 1611 +/- 340 kcal/day, P < 0.001) and metabolic adaptation, calculated as the difference between observed and predicted post weight loss REE, was - 199 +/- 238 kcal/day. The post-surgery level of metabolic adaptation was inversely related to postoperative percent weight loss (r = - 0.170; P < 0.05) and FM loss (r = - 0.245; P < 0.01). CONCLUSIONS: A significant reduction of resting energy expenditure and a significant degree of metabolic adaptation both occur after sleeve gastrectomy. A greater metabolic adaptation could be partly responsible for a lower weight loss after surgery. PMID- 29532317 TI - Validation of the Alterable Weight Loss Metric in Morbidly Obese Patients Undergoing Gastric Bypass in Korea. AB - BACKGROUND: Percentage of excess weight loss (%EWL) is the most common metric used after bariatric surgery. However, there has been consistent argument against its use since it varies significantly by initial body mass index (BMI). This study aimed to validate the newly suggested percentage of alterable weight loss (%AWL) metric in Korean patients. METHODS: A retrospective review of the prospectively established database at Soonchunhyang University Seoul Hospital identified 165 patients who underwent primary laparoscopic Roux-en-Y gastric bypass (RYGB) and had at least 2-year follow-up weight loss results after surgery. Patients were classified into subgroups based on initial BMI, and their weight loss results expressed as BMI, %EWL, %AWL, and percentage of total weight loss (%TWL) were compared in terms of nadir weight and weight loss trajectory. RESULTS: The study cohort included 27 male (16.4%) and 138 female (83.6%) patients with a mean baseline BMI of 38.1 +/- 5.4. Nadir weight was achieved at mean 24.1 +/- 10.6 months postoperatively. Female patients required significantly longer to achieve nadir weight than male patients (16.2 vs. 22.4 months, p = 0.001), and they achieved less weight loss expressed as nadir BMI, %EWL, and %AWL. Of these metrics, only %AWL was not significantly influenced by preoperative BMI and showed the least variation (25.2%) for reporting weight loss. CONCLUSION: The AWL metric can report weight loss regardless of baseline BMI in Korean patients undergoing RYGB; however, it must be validated in a larger population involving multiple centers from the Asia-Pacific area before being used clinically. PMID- 29532318 TI - Impact of orthodontic treatment on adolescents' quality of life: a longitudinal evaluation of treated and untreated individuals. AB - PURPOSE: To assess the impact of fixed appliance therapy on the quality of life of a cohort of Brazilian adolescents. METHODS: The treatment group was composed of individuals who started orthodontic treatment. The control group was composed of individuals not selected for immediate treatment. Adolescents answered the Brazilian short form of the Child Perceptions Questionnaire (CPQ11-14). Higher scores indicate a greater negative impact on quality of life. Adolescents in the treatment group completed four sets of interviews: prior to appliances' bonding (T1), 1 month (T2), 6 months (T3) and 12 months (T4) after appliances' placement. Adolescents in the control group were assigned to a comparable schedule. Statistics included inter-group comparisons, Friedman and Wilcoxon tests, and mixed-effects models. RESULTS: In the treatment group, the functional limitation score was higher at T1 (p = 0.004) and T2 (p = 0.007) compared to T4. The emotional well-being score was higher at T1 compared to T2 (p < 0.001), T3 (p < 0.001) and T4 (p < 0.001). The overall CPQ11-14 score was higher at T1 compared to T2 (p = 0.005), T3 (p < 0.001) and T4 (p < 0.001). The overall CPQ11-14 score was also higher at T2 compared to T3 (p = 0.001). No significant change was found in the control group. In the mixed-effects models, the interaction between group (treatment) and time was significant for functional limitations (p < 0.001), emotional well-being (p < 0.001), social well-being (p = 0.004) and the overall CPQ11-14 score (p < 0.001). CONCLUSION: Quality of life improved among adolescents undergoing orthodontic treatment. Orthodontists should inform patients what they might expect regarding the physical and the psychosocial repercussions of appliance therapy. PMID- 29532319 TI - Influence of sense of coherence on oral health-related quality of life: a systematic review. AB - PURPOSE: The aim of the present study was to perform a systematic review of the literature for scientific evidence regarding the association between a sense of coherence (SOC) and oral health-related of quality of life (OHRQoL). METHODS: Electronic searches were performed in five databases. Manual searches were also performed. To be included, studies needed to address the relationship between SOC and OHRQoL. The risk of bias was evaluated using the Newcastle-Ottawa scales for cross-sectional and cohort studies and the Physiotherapy Evidence Database scale for clinical trials. RESULTS: Seven cross-sectional studies, four cohort studies, and one clinical trial were included in the present review. Two independent reviewers selected the studies, extracted that data, and performed the evaluations of methodological quality based on the standardized scales. The majority of authors found a significant association between a weak SOC and greater impact on OHRQoL, but some methodological flaws were found in the execution of the studies. CONCLUSION: Based on the analysis of the studies included in the present systematic review, there is scientific evidence that a sense of coherence exerts an influence on oral health-related quality of life, but further population-based studies are needed to confirm such evidence. PMID- 29532320 TI - Collaboration, campaigns and champions for appropriate imaging: feedback from the Zagreb workshop. AB - : Leading radiologists and representatives from national radiation protection regulatory authorities and health ministries from 19 countries of the European region worked together with five experts at the workshop on justification and appropriate use of imaging in Zagreb, Croatia, from 26 to 28 October 2017 jointly organised by the IAEA and the European Society of Radiology. The workshop served as a forum to exchange information on challenges and solutions for improving justification and the appropriate use of diagnostic imaging. Common barriers to improving the use of imaging referral guidelines were discussed and the need for increased collaboration identified. Examples of good practices were presented, including use of Clinical Decision Support (CDS) systems to facilitate rapid and good justification decisions. The workshop identified some of the needs of European countries for achieving more appropriate imaging proposing wider use of collaboration, campaigns and champions. MAIN MESSAGES: * Drivers for appropriate imaging in Europe are similar to those elsewhere globally. * Implementing imaging referral guidelines is the main barrier to more appropriate imaging. * Clinical Decision Support systems (CDS) facilitates good referral practice and justification decisions. * Collaboration, campaigns and champions may improve awareness, appropriateness and audit. PMID- 29532321 TI - Effect of short-chain fatty acids on the expression of genes involved in short chain fatty acid transporters and inflammatory response in goat jejunum epithelial cells. AB - Short-chain fatty acids (SCFAs) produced by microbial fermentation of dietary fibers are utilized by intestinal epithelial cells to provide an energy source for the ruminant. Although the regulation of mRNA expression and inflammatory response involved in SCFAs is established in other animals and tissues, the underlying mechanisms of the inflammatory response by SCFAs in goat jejunum epithelial cells (GJECs) have not been understood. Therefore, the objective of the study is to investigate the underlying mechanisms of the effects of SCFAs on SCFA transporters and inflammatory response in GJECs. These results showed that the acetate, butyrate, and SCFA concentration were markedly reduced in GJECs (p < 0.01). In addition, the propionate concentration was significantly decreased in GJECs (p < 0.05). The mRNA abundance of monocarboxylate transporter 1 (MCT1), MCT4, NHE1, and putative anion transporter 1 (PAT1) was elevated (p < 0.05) by 20 mM SCFAs at pH 7.4 compared with exposure to the pH group. The anion exchanger 2 (AE2) was increased (p < 0.05) by 20 mM SCFAs at pH 6.2. The mRNA abundance of vH+ ATPase B subunit (vH+ ATPase) was attenuated by SCFAs. For inflammatory responses, IL-1beta and TNF-alpha were increased with SCFAs (p < 0.05). In addition, IkappaBalpha involved in NF-kappaB signaling pathways was disrupted by SCFAs. Consistently, p-p65 signaling molecule was enhanced by adding SCFAs. However, IL-6 was attenuated by adding SCFAs (p < 0.05). Furthermore, p-ErK1/2 mitogen-activated protein kinase (MAPK) signaling pathway was downregulated by adding SCFAs. In conclusion, these novel findings demonstrated that mRNA abundance involved in SCFA absorption is probably associated to SCFAs and pH value, and mechanism of the inflammatory response by SCFAs may be involved in NF kappaB and p-ErK1/2 MAPK signaling pathways in GJECs. These pathways may mediate protective inflammation response in GJECs. PMID- 29532322 TI - Commissioning and validation of fluence-based 3D VMAT dose reconstruction system using new transmission detector. AB - In this study, we evaluated the basic performance of the three-dimensional dose verification system COMPASS (IBA Dosimetry). This system is capable of reconstructing 3D dose distributions on the patient anatomy based on the fluence measured using a new transmission detector (Dolphin, IBA Dosimetry) during treatment. The stability of the absolute dose and geometric calibrations of the COMPASS system with the Dolphin detector were investigated for fundamental validation. Furthermore, multileaf collimator (MLC) test patterns and a complicated volumetric modulated arc therapy (VMAT) plan were used to evaluate the accuracy of the reconstructed dose distributions determined by the COMPASS. The results from the COMPASS were compared with those of a Monte Carlo simulation (MC), EDR2 film measurement, and a treatment planning system (TPS). The maximum errors for the absolute dose and geometrical position were - 0.28% and 1.0 mm for 3 months, respectively. The Dolphin detector, which consists of ionization chamber detectors, was firmly mounted on the linear accelerator and was very stable. For the MLC test patterns, the TPS showed a > 5% difference at small fields, while the COMPASS showed good agreement with the MC simulation at small fields. However, the COMPASS produced a large error for complex small fields. For a clinical VMAT plan, COMPASS was more accurate than TPS. COMPASS showed real delivered-dose distributions because it uses the measured fluence, a high resolution detector, and accurate beam modeling. We confirm here that the accuracy and detectability of the delivered dose of the COMPASS system are sufficient for clinical practice. PMID- 29532323 TI - Outcome of transarterial chemoembolization in Egyptian patients with hepatocellular carcinoma and branch portal vein thrombosis. AB - BACKGROUND/AIM: Portal vein tumor thrombosis (PVTT) is a common complication in hepatocellular carcinoma (HCC) and it was considered a relative contraindication for transarterial chemoembolization (TACE) by many centers. This study aimed to assess the outcomes after TACE in patients with branch PVT regarding Child classification, radiological response, and 1-year survival. METHODS: Thirty HCC patients (24 male, 6 females) Child A cirrhotics with branch PVT underwent TACE. Follow up was done at 1, 3, 6, and 12 months after first TACE. All patients underwent laboratory investigations including liver function tests to assess deterioration in liver functions and triphasic spiral computed tomography to assess radiological response according to modified response evaluation criteria in solid tumors (mRECIST) criteria, and survival analysis was recorded. RESULTS: TACE succeeded to achieve disease control in 93.3%, 86.3%, 57.7%, and 44.4% of patients after 1, 3, 6, and 12 months, respectively. Post-TACE liver decompensation occurred in the form of ascites in 30%, jaundice in 10%, and hepatic encephalopathy in 3.3% within 1 month of TACE. One month survival after TACE was 100%, 3 months was 96.6%, 6 months was 86.6%, and 1-year survival was 60%. Mean overall survival of the included patients was 17 months (SE = 1.59). CONCLUSION: TACE seems an alternative option for patients with unrespectable HCC with portal vein thrombosis in patients with good liver function tests. PMID- 29532324 TI - Characterization of an in vitro model system to explore control of tumor invasion of EMT6 and 4THM breast tumors by CD200:CD200R interactions. AB - BACKGROUND AND PURPOSE: In BALB/c mice with transplantable breast tumors, we showed that CD200R1KO mice were cured of local and metastatic growth of EMT6 cells following surgical resection of localized tumor and immunization with irradiated cells along with CpG as adjuvant. On the other hand, wild-type (WT) animals treated in the same fashion develop pulmonary and liver metastases within 20 days of surgery. To develop an in vitro system which would mimic the in vivo model and allow exploration of factors controlling tumor invasion as a precursor to in vivo metastasis, we have developed and characterized a two-phase culture system. METHODS: Bone marrow mesenchymal stromal cells (BMMSCs) from WT, CD200KO or CD200R1KO mice were admixed with T lymphocytes from tumor-immunized mice and cultured in collagen gels. Tumor cells were subsequently seeded in fresh medium above this gel 1d later. We then investigated the regulation of tumor invasion from the liquid to the gel layer. Tumor cells were measured in the gel layer following collagenase digestion and cultured at limiting dilution-an aliquot of the digest was also analyzed for cytokine levels in ELISA. RESULTS: BMMSCs from WT, CD200KO and CD200R1KO mice all augmented seeding/growth of EMT6 and 4THM tumor cells into the collagen matrix. Inclusion of IL-6 and IL-17 in the gel matrix was associated with increased invasion of tumor cells into this layer. Inclusion of DLN cells from EMT6 immune or 4THM immune mice further modified tumor invasion, with increased tumor numbers seen using stromal elements from CD200 and CD200R1KO mice and DLN from 4THM immune, while CD200R1KO-derived DLN of EMT6 immune mice attenuated tumor invasion, despite inclusion of IL-6/IL-17 in the gel layer. CONCLUSION: Multiple factors can regulate tumor invasion, including micro-environmental stromal elements, IL-6/IL-17, and signals from tumor-derived DLN cells. PMID- 29532325 TI - Apathy - Forme Fruste of Autoimmune Encephalitis. PMID- 29532326 TI - Comprehensive Proteoform Characterization of Plasma Complement Component C8alphabetagamma by Hybrid Mass Spectrometry Approaches. AB - The human complement hetero-trimeric C8alphabetagamma (C8) protein assembly (~ 150 kDa) is an important component of the membrane attack complex (MAC). C8 initiates membrane penetration and coordinates MAC pore formation. Here, we charted in detail the structural micro-heterogeneity within C8, purified from human plasma, combining high-resolution native mass spectrometry and (glyco)peptide-centric proteomics. The intact C8 proteoform profile revealed at least ~ 20 co-occurring MS signals. Additionally, we employed ion exchange chromatography to separate purified C8 into four distinct fractions. Their native MS analysis revealed even more detailed structural micro-heterogeneity on C8. Subsequent peptide-centric analysis, by proteolytic digestion of C8 and LC-MS/MS, provided site-specific quantitative profiles of different types of C8 glycosylation. Combining all this data provides a detailed specification of co occurring C8 proteoforms, including experimental evidence on N-glycosylation, C mannosylation, and O-glycosylation. In addition to the known N-glycosylation sites, two more N-glycosylation sites were detected on C8. Additionally, we elucidated the stoichiometry of all C-mannosylation sites in all the thrombospondin-like (TSP) domains of C8alpha and C8beta. Lastly, our data contain the first experimental evidence of O-linked glycans located on C8gamma. Albeit low abundant, these O-glycans are the first PTMs ever detected on this subunit. By placing the observed PTMs in structural models of free C8 and C8 embedded in the MAC, it may be speculated that some of the newly identified modifications may play a role in the MAC formation. Graphical Abstract ?. PMID- 29532327 TI - Electrospray Ionization with High-Resolution Mass Spectrometry as a Tool for Lignomics: Lignin Mass Spectrum Deconvolution. AB - The capability to characterize lignin, lignocellulose, and their degradation products is essential for the development of new renewable feedstocks. Electrospray ionization high-resolution time-of-flight mass spectrometry (ESI-HR TOF-MS) method was developed expanding the lignomics toolkit while targeting the simultaneous detection of low and high molecular weight (MW) lignin species. The effect of a broad range of electrolytes and various ionization conditions on ion formation and ionization effectiveness was studied using a suite of mono-, di-, and triarene lignin model compounds as well as kraft alkali lignin. Contrary to the previous studies, the positive ionization mode was found to be more effective for methoxy-substituted arenes and polyphenols, i.e., species of a broadly varied MW structurally similar to the native lignin. For the first time, we report an effective formation of multiply charged species of lignin with the subsequent mass spectrum deconvolution in the presence of 100 mmol L-1 formic acid in the positive ESI mode. The developed method enabled the detection of lignin species with an MW between 150 and 9000 Da or higher, depending on the mass analyzer. The obtained M n and Mw values of 1500 and 2500 Da, respectively, were in good agreement with those determined by gel permeation chromatography. Furthermore, the deconvoluted ESI mass spectrum was similar to that obtained with matrix assisted laser desorption/ionization (MALDI)-HR TOF-MS, yet featuring a higher signal-to-noise ratio. The formation of multiply charged species was confirmed with ion mobility ESI-HR Q-TOF-MS. Graphical Abstract ?. PMID- 29532329 TI - Long-Term Costs and Health Consequences of Issuing Shorter Duration Prescriptions for Patients with Chronic Health Conditions in the English NHS. AB - BACKGROUND: The National Health Service (NHS) in England spends over L9 billion on prescription medicines dispensed in primary care, of which over two-thirds is accounted for by repeat prescriptions. Recently, GPs in England have been urged to limit the duration of repeat prescriptions, where clinically appropriate, to 28 days to reduce wastage and hence contain costs. However, shorter prescriptions will increase transaction costs and thus may not be cost saving. Furthermore, there is evidence to suggest that shorter prescriptions are associated with lower adherence, which would be expected to lead to lower clinical benefit. The objective of this study is to estimate the cost-effectiveness of 3-month versus 28-day repeat prescriptions from the perspective of the NHS. METHODS: We adapted three previously developed UK policy-relevant models, incorporating transaction (dispensing fees, prescriber time) and drug wastage costs associated with 3-month and 28-day prescriptions in three case studies: antihypertensive medications for prevention of cardiovascular events; drugs to improve glycaemic control in patients with type 2 diabetes; and treatments for depression. RESULTS: In all cases, 3-month prescriptions were associated with lower costs and higher QALYs than 28-day prescriptions. This is driven by assumptions that higher adherence leads to improved disease control, lower costs and improved QALYs. CONCLUSION: Longer repeat prescriptions may be cost-effective compared with shorter ones. However, the quality of the evidence base on which this modelling is based is poor. Any policy rollout should be within the context of a trial such as a stepped-wedge cluster design. PMID- 29532328 TI - The neuroscience of perceptual categorization in pigeons: A mechanistic hypothesis. AB - We are surrounded by an endless variation of objects. The ability to categorize these objects represents a core cognitive competence of humans and possibly all vertebrates. Research on category learning in nonhuman animals started with the seminal studies of Richard Herrnstein on the category "human" in pigeons. Since then, we have learned that pigeons are able to categorize a large number of stimulus sets, ranging from Cubist paintings to English orthography. Strangely, this prolific field has largely neglected to also study the avian neurobiology of categorization. Here, we present a hypothesis that combines experimental results and theories from categorization research in pigeons with neurobiological insights on visual processing and dopamine-mediated learning in primates. We conclude that in both fields, similar conclusions on the mechanisms of perceptual categorization have been drawn, despite very little cross-reference or communication between these two areas to date. We hypothesize that perceptual categorization is a two-component process in which stimulus features are first rapidly extracted in a feed-forward process, thereby enabling a fast subdivision along multiple category borders. In primates this seems to happen in the inferotemporal cortex, while pigeons may primarily use a cluster of associative visual forebrain areas. The second process rests on dopaminergic error-prediction learning that enables prefrontal areas to connect top down the relevant visual category dimension to the appropriate action dimension. PMID- 29532330 TI - Left Ventricular Assist Devices - A State of the Art Review. AB - Cardiovascular diseases are the leading cause of mortality rates throughout the world. Next to an insufficient number of healthy donors, this has led to increasing numbers of patients on heart transplant waiting lists with prolonged waiting times. Innovative technological advancements have led to the production of ventricular assist devices that play an increasingly important role in end stage heart failure therapy. This review is intended to provide an overview of current implantable left ventricular assist devices, different design concepts and implantation techniques. Challenges such as infections and thromboembolic events that may occur during LVAD implantations have also been discussed. PMID- 29532331 TI - Athlete's Heart and Left Heart Disease. AB - Physical activity comprises all muscular activities that require energy expenditure. Regular sequence of structured and organized exercise with the specific purpose of improving wellness and athletic performance is defined as a sports activity.Exercise can be performed at various levels of intensity and duration. According to the social context and pathways, it can be recreational, occupational, and competitive. Therefore, the training burden varies inherently and the heart adaptation is challenging.Although a general agreement on the fact that sports practice leads to metabolic, functional and physical benefits, there is evidence that some athletes may be subjected to adverse outcomes. Sudden cardiac death can occur in apparently healthy individuals with unrecognized cardiovascular disease.Thus, panels of experts in sports medicine have promoted important pre-participation screening programmes aimed at determining sports eligibility and differentiating between physiological remodeling and cardiac disease.In this review, the most important pathophysiological and diagnostic issues are discussed. PMID- 29532332 TI - Experimental Assessment of Flow Fields Associated with Heart Valve Prostheses Using Particle Image Velocimetry (PIV): Recommendations for Best Practices. AB - Experimental flow field characterization is a critical component of the assessment of the hemolytic and thrombogenic potential of heart valve substitutes, thus it is important to identify best practices for these experimental techniques. This paper presents a brief review of commonly used flow assessment techniques such as Particle image velocimetry (PIV), Laser doppler velocimetry, and Phase contrast magnetic resonance imaging and a comparison of these methodologies. In particular, recommendations for setting up planar PIV experiments such as recommended imaging instrumentation, acquisition and data processing are discussed in the context of heart valve flows. Multiple metrics such as residence time, local velocity and shear stress that have been identified in the literature as being relevant to hemolysis and thrombosis in heart valves are discussed. Additionally, a framework for uncertainty analysis and data reporting for PIV studies of heart valves is presented in this paper. It is anticipated that this paper will provide useful information for heart valve device manufacturers and researchers to assess heart valve flow fields for the potential for hemolysis and thrombosis. PMID- 29532333 TI - Design and Biological Evaluation of Antifouling Dihydrostilbene Oxime Hybrids. AB - By combining the recently reported repelling natural dihydrostilbene scaffold with an oxime moiety found in many marine antifoulants, a library of nine antifouling hybrid compounds was developed and biologically evaluated. The prepared compounds were shown to display a low antifouling effect against marine bacteria but a high potency against the attachment and growth of microalgae down to MIC values of 0.01 MUg/mL for the most potent hybrid. The mode of action can be characterized as repelling via a reversible non-toxic biostatic mechanism. Barnacle cyprid larval settlement was also inhibited at low MUg/mL concentrations with low levels or no toxicity observed. Several of the prepared compounds performed better than many reported antifouling marine natural products. While several of the prepared compounds are highly active as antifoulants, no apparent synergy is observed by incorporating the oxime functionality into the dihydrostilbene scaffold. This observation is discussed in light of recently reported literature data on related marine natural antifoulants and antifouling hybrids as a potentially general strategy for generation of improved antifoulants. PMID- 29532334 TI - Development of SNP Panels as a New Tool to Assess the Genetic Diversity, Population Structure, and Parentage Analysis of the Eastern Oyster (Crassostrea virginica). AB - Culture of the eastern oyster (Crassostrea virginica) is rapidly expanding. Combined with their continuing role as an environmental sentinel species and ecological model, this trend necessitates improved molecular tools for breeding and selection, as well as population assessment and genetic conservation. Here, we describe the development and validation of two panels of 58 single nucleotide polymorphism markers (SNPs) for the species. Population analyses revealed three distinct populations, based on FST values and STRUCTURE, among wild oysters sampled from Delaware Bay (1), northwest Florida (2), Alabama (2), Louisiana (2), and the Texas Gulf Coast (3), consistent with previous microsatellite and mtDNA analyses. In addition, utilizing the developed panels for parentage assignment in cultured oysters (Rutgers, New Jersey) resulted in a highly accurate identification of parent pairs (99.37%). The SNP markers could, furthermore, clearly discriminate between hatchery stocks and wild-sourced individuals. The developed SNP panels may serve as an important tool for more rapid and affordable genetic analyses in eastern oyster. PMID- 29532335 TI - Peptides from Fish By-product Protein Hydrolysates and Its Functional Properties: an Overview. AB - The inadequate management of fish processing waste or by-products is one of the major problems that fish industry has to face nowadays. The mismanagement of this raw material leads to economic loss and environmental problems. The demand for the use of these by-products has led to the development of several processes in order to recover biomolecules from fish by-products. An efficient way to add value to fish waste protein is protein hydrolysis. Protein hydrolysates improve the functional properties and allow the release of peptides of different sizes with several bioactivities such as antioxidant, antimicrobial, antihypertensive, anti-inflammatory, or antihyperglycemic among others. This paper reviews different methods for the production of protein hydrolysates as well as current research about several fish by-products protein hydrolysates bioactive properties, aiming the dual objective: adding value to these underutilized by products and minimizing their negative impact on the environment. PMID- 29532336 TI - Identification of 4-Deoxy-L-Etychro-Hexoseulose Uronic Acid Reductases in an Alginolytic Bacterium Vibrio splendidus and their Uses for L-Lactate Production in an Escherichia coli Cell-Free System. AB - 4-Deoxy-L-erythro-hexoseulose uronic acid (DEH) reductase is a key enzyme in alginate utilizing metabolism, but the number of characterized DEH reductase is quite limited. In this study, novel two DEH reductases, VsRed-1 and VsRed-2, were identified in marine bacterium Vibrio splendidus, and the recombinant enzymes were expressed in an Escherichia coli system and purified by Ni-NTA chromatography. The optimal pH and temperature of the recombinant VsRed-1 and VsRed-2 were pH 7.5, 30 degrees C, and pH 7.0, 35 degrees C, respectively. The specific activities of VsRed-1 (776 U/mg for NADH) and VsRed-2 (176 U/mg for NADPH) were the highest among the DEH reductases reported so far. We also demonstrated that DEH could be converted to L-lactate with a yield of 76.7 and 81.9% in E. coli cell-free system containing VsRed-1 and VsRed-2 enzymes, respectively, indicating that two DEH reductases can be employed for production of biofuels and bio-chemicals from brown macroalgae biomass. PMID- 29532337 TI - Sequence and functional characterization of MIRNA164 promoters from Brassica shows copy number dependent regulatory diversification among homeologs. AB - The impact of polyploidy on functional diversification of cis-regulatory elements is poorly understood. This is primarily on account of lack of well-defined structure of cis-elements and a universal regulatory code. To the best of our knowledge, this is the first report on characterization of sequence and functional diversification of paralogous and homeologous promoter elements associated with MIR164 from Brassica. The availability of whole genome sequence allowed us to identify and isolate a total of 42 homologous copies of MIR164 from diploid species-Brassica rapa (A-genome), Brassica nigra (B-genome), Brassica oleracea (C-genome), and allopolyploids-Brassica juncea (AB-genome), Brassica carinata (BC-genome) and Brassica napus (AC-genome). Additionally, we retrieved homologous sequences based on comparative genomics from Arabidopsis lyrata, Capsella rubella, and Thellungiella halophila, spanning ca. 45 million years of evolutionary history of Brassicaceae. Sequence comparison across Brassicaceae revealed lineage-, karyotype, species-, and sub-genome specific changes providing a snapshot of evolutionary dynamics of miRNA promoters in polyploids. Tree topology of cis-elements associated with MIR164 was found to re-capitulate the species and family evolutionary history. Phylogenetic shadowing identified transcription factor binding sites (TFBS) conserved across Brassicaceae, of which, some are already known as regulators of MIR164 expression. Some of the TFBS were found to be distributed in a sub-genome specific (e.g., SOX specific to promoter of MIR164c from MF2 sub-genome), lineage-specific (YABBY binding motif, specific to C. rubella in MIR164b), or species-specific (e.g., VOZ in A. thaliana MIR164a) manner which might contribute towards genetic and adaptive variation. Reporter activity driven by promoters associated with MIR164 paralogs and homeologs was majorly in agreement with known role of miR164 in leaf shaping, regulation of lateral root development and senescence, and one previously un described novel role in trichome. The impact of polyploidy was most profound when reporter activity across three MIR164c homeologs were compared that revealed negligible overlap, whereas reporter activity among two homeologs of MIR164a displays significant overlap. A copy number dependent cis-regulatory divergence thus exists in MIR164 genes in Brassica juncea. The full extent of regulatory diversification towards adaptive strategies will only be known when future endeavors analyze the promoter function under duress of stress and hormonal regimes. PMID- 29532339 TI - Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer. AB - PURPOSE: Basal-like breast cancers are aggressive and often metastasize to vital organs. Treatment is largely limited to chemotherapy. This study aims to characterize the efficacy of cancer therapeutics in vitro and in vivo within the primary tumor and metastatic setting, using patient-derived xenograft (PDX) models. METHODS: We employed two basal-like, triple-negative PDX models, WHIM2 and WHIM30. PDX cells, obtained from mammary tumors grown in mice, were treated with twelve cancer therapeutics to evaluate their cytotoxicity in vitro. Four of the effective drugs-carboplatin, cyclophosphamide, bortezomib, and dacarbazine were tested in vivo for their efficacy in treating mammary tumors, and metastases generated by intracardiac injection of tumor cells. RESULTS: RNA sequencing showed that global gene expression of PDX cells grown in the mammary gland was similar to those tested in culture. In vitro, carboplatin was cytotoxic to WHIM30 but not WHIM2, whereas bortezomib, dacarbazine, and cyclophosphamide were cytotoxic to both lines. Yet, these drugs were ineffective in treating both primary and metastatic WHIM2 tumors in vivo. Carboplatin and cyclophosphamide were effective in treating WHIM30 mammary tumors and reducing metastatic burden in the brain, liver, and lungs. WHIM2 and WHIM30 metastases showed distinct patterns of cytokeratin and vimentin expression, regardless of treatment, suggesting that different tumor cell subpopulations may preferentially seed in different organs. CONCLUSIONS: This study highlights the utility of PDX models for studying the efficacy of therapeutics in reducing metastatic burden in specific organs. The differential treatment responses between two PDX models of the same intrinsic subtype, in both the primary and metastatic setting, recapitulates the challenges faced in treating cancer patients and highlights the need for combination therapies and predictive biomarkers. PMID- 29532338 TI - Transcriptomics analysis revealing candidate networks and genes for the body size sexual dimorphism of Chinese tongue sole (Cynoglossus semilaevis). AB - The Chinese tongue sole (Cynoglossus semilaevis) is a typical female heterogamete species that exhibits female-biased sexual size dimorphism, which has severely hindered the sustainable development of the species in aquaculture. In the present study, four important somatotropic and reproductive tissues including brain, pituitary, liver, and gonad from 15 females and 15 males were used for transcriptome analysis via RNA-seq. A mean of 37,533,991 high-quality clean reads was obtained from each library and 806, 1482, 818, and 14,695 differentially expressed genes in female and male were identified from the brain, pituitary, liver, and gonad, respectively (fold change >= 2 and q < 0.05). Enrichment analyses of GO terms and KEGG pathways showed that nucleic acid-binding transcription factor activity, G-protein-coupled receptor activity, MAPK signaling pathway, steroid biosynthesis, and neuroactive ligand-receptor interaction may be involved in the sexual growth differences. Furthermore, via weighted gene co-expression network analyses, two modules (yellowgreen and salmon4) were identified to be significantly positive-correlated with female biased sexual size dimorphism. An illustrated network map drawn by these two modules enabled the identification of a series of hub genes, including nipped-B like protein A (nipbla), transcriptional activator protein Pur-beta-like (purb), and BDNF/NT-3 growth factors receptor (ntrk2). Detailed functional investigation of these networks and hub genes will further improve our understanding of the underlying molecular mechanism of sexual size dimorphism in fish. PMID- 29532340 TI - Radial scar on image-guided breast biopsy: is surgical excision necessary? AB - PURPOSE: Radial scar's stellate appearance may mimic carcinoma mammographically and histologically. Management of radial scar (RS) found on breast core needle biopsies (CNB) ranges from excision to clinical observation due to the variation in reported upgrades to malignancy at surgical excision. We examined the upgrade rate in patients with RS detected on CNB at our institution and reviewed the current literature. METHODS: A retrospective study was conducted of all cases with RS diagnosed on CNB between December 2006 and March 2017 at our institution. Inclusion criteria were patients with "pure" RS and RS associated with high-risk lesions (HRL). Upgrade was defined as invasive or non-invasive cancer in the excisional biopsy. RESULTS: 157 cases were identified with RS on CNB, and 122 cases met inclusion criteria. Of these 122 cases, 91 (75%) had pure RS on CNB while 31 (25%) had associated atypia or HRL. 81 (66%) of patients proceeded to excisional biopsy and 41 (34%) did not. Two patients (1.6% of total) were found to have a low-grade invasive ductal carcinoma (0.6 and 0.8 cm) upon surgical excision. None of the remaining 120 patients developed an ipsilateral breast cancer with a mean of 32.3-month follow-up. CONCLUSIONS: We found a very low upgrade rate to breast cancer when RS was found on CNB with or without associated HRL. Our results are consistent with other reported series. Our data do not support surgical excision for RS but rather close clinical follow-up for patients with RS on CNB. PMID- 29532341 TI - Correction to: Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning. AB - The original article has been corrected. Table 4 in PDF version of this article has been corrected since the original publication of the article because the first column of numbers (under the heading "Female") in the original PDF version was typeset poorly. PMID- 29532343 TI - The New American Joint Commission on Cancer Staging System for Soft Tissue Sarcomas: Splitting versus Lumping. PMID- 29532342 TI - Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study. AB - BACKGROUND: Western multicenter studies on distal pancreatectomy with celiac axis resection (DP-CAR), also known as the Appleby procedure, for locally advanced pancreatic cancer are lacking. We aimed to study overall survival, morbidity, mortality and the impact of preoperative hepatic artery embolization (PHAE). METHODS: Retrospective cohort study within the European-African Hepato-Pancreato Biliary-Association, on DP-CAR between 1-1-2000 and 6-1-2016. Primary endpoint was overall survival. Secondary endpoints were radicality (R0-resection), 90-day mortality, major morbidity, and pancreatic fistulae (grade B/C). RESULTS: We included 68 patients from 20 hospitals in 12 countries. Postoperatively, 53% of patients had R0-resection, 25% major morbidity, 21% an ISGPS grade B/C pancreatic fistula, and 16% mortality. In total, 82% received (neo-)adjuvant chemotherapy and median overall survival in 62 patients with pancreatic ductal adenocarcinoma patients was 18 months (CI 10-37). We observed no impact of PHAE on ischemic complications. CONCLUSIONS: DP-CAR combined with chemotherapy for locally advanced pancreatic cancer is associated with acceptable overall survival. The 90 day mortality is too high and should be reduced. Future studies should investigate to what extent increasing surgical volume or better patient selection can improve outcomes. PMID- 29532344 TI - The Negative Impact of Body Mass Index on the Tumor Microenvironment in Colon Cancer: Results of a Prospective Trial. AB - BACKGROUND: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. METHODS: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. RESULTS: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+ T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+ (p = 0.008) and FOXP3+ (p = 0.005) T cells. Multivariable analysis linked CD4+ (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+ (HR 0.67; 95% CI 0.50-0.89), and number of tumor positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. CONCLUSIONS: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile. PMID- 29532345 TI - Predictor variables of abnormal imaging findings of syncope in the emergency department. AB - BACKGROUND: This study aimed to describe the pathological findings and to analyze clinical predictors of abnormal imaging findings in patients presenting to the emergency department (ED) with syncope. METHODS: The database was retrospectively reviewed for all patients who underwent cranial computed tomography (CT) or magnetic resonance imaging (MRI), having the symptom of syncope. Patients were included only if they were from the emergency department and excluded if were under 18 years of age, had known recent intracranial pathology, known brain tumor, or having a history of trauma. The primary outcome was assumed as abnormal head CT or MRI including intracranial hemorrhage, acute or subacute stroke, and newly diagnosed brain mass. Univariate and multivariate logistic regression analysis was utilized to determine the association between clinical variables and any significant pathology in either CT or MR scan. RESULTS: Total of 1230 syncope (717 men and 513 women; range, 18-92 years; mean, 54.5 years) as presenting symptoms were identified in patients receiving either cranial CT or MR scan in the ED. Abnormal findings related to the syncope were observed in 47 (3.8%) patients. The following predictor variables were found to be significantly correlated with acutely abnormal head CT and MRI: a focal neurologic deficit, history of malignancy, hypertension, and age greater than 60 years. CONCLUSIONS: Our data offer that the identification of predictor variables has a potential to decrease the routine use of head CT and MRI in patients admitting to the ED with syncope. PMID- 29532346 TI - It's all about relationships : A qualitative study of family physicians' teaching experiences in rural longitudinal clerkships. AB - INTRODUCTION: The relationship between preceptor and trainee is becoming recognized as a critical component of teaching, in particular in the negotiation of feedback and in the formation of professional identity. This paper elaborates on the nature of the relationships between preceptor and student that evolve in the context of rural longitudinal integrated clerkships (LICs). METHODS: We drew on constructivist grounded theory for the research approach. We interviewed nine LIC family practice preceptors from three sites at one educational institution. We adapted the interview framework based on early findings. We analyzed the data through a constant comparative process. We then drew on concepts of relationship based learning as sensitizing concepts in a secondary analysis. RESULTS: We constructed three themes from the data. First, preceptors developed trusting professional and personal relationships with students over time. These relationships expanded to include friendship, advocacy, and ongoing contact beyond the clerkship year. Second, preceptors' approach to teaching was anchored in the relationship with an understanding of the individual student. Third, preceptors set learning goals collaboratively with their students, based not only on program objectives, but also with the student as a future physician in mind. DISCUSSION: Our findings suggest that rural family medicine preceptors developed engaged and trusting relationships with their students over time. These relationships imbued all activities of teaching and learning with an individual and personal focus. This orientation may be a key factor in supporting the learning outcomes demonstrated for students studying in rural LICs. PMID- 29532347 TI - Prediction of Apoptosis Protein's Subcellular Localization by Fusing Two Different Descriptors Based on Evolutionary Information. AB - The apoptosis protein has a central role in the development and the homeostasis of an organism. Obtaining information about the subcellular localization of apoptosis protein is very helpful to understand the apoptosis mechanism and the function of this protein. Prediction of apoptosis protein's subcellular localization is a challenging task, and currently the existing feature extraction methods mainly rely on the protein's primary sequence. In this paper we develop a feature extraction model based on two different descriptors of evolutionary information, which contains the 192 frequencies of triplet codons (FTC) in the RNA sequence derived from the protein's primary sequence and the 190 features from a detrended forward moving-average cross-correlation analysis (DFMCA) based on a position-specific scoring matrix (PSSM) generated by the PSI-BLAST program. Hence, this model is called FTC-DFMCA-PSSM. A 382-dimensional (382D) feature vector is constructed on the ZD98, ZW225 and CL317 datasets. Then a support vector machine is adopted as classifier, and the jackknife cross-validation test method is used for evaluating the accuracy. The overall prediction accuracies are further improved by an objective and rigorous jackknife test. Our model not only broadens the source of the feature information, but also provides a more accurate and reliable automated calculation method for the prediction of apoptosis protein's subcellular localization. PMID- 29532348 TI - Wesley Bourne: leader extraordinaire of Canadian anesthesiology. PMID- 29532349 TI - The Williams Airway Intubator. PMID- 29532350 TI - Metabolic Brain Network Analysis of Hypothyroidism Symptom Based on [18F]FDG-PET of Rats. AB - PURPOSE: Recent researches have demonstrated the value of using 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) imaging to reveal the hypothyroidism-related damages in local brain regions. However, the influence of hypothyroidism on the entire brain network is barely studied. This study focuses on the application of graph theory on analyzing functional brain networks of the hypothyroidism symptom. PROCEDURES: For both the hypothyroidism and the control groups of Wistar rats, the functional brain networks were constructed by thresholding the glucose metabolism correlation matrices of 58 brain regions. The network topological properties (including the small-world properties and the nodal centralities) were calculated and compared between the two groups. RESULTS: We found that the rat brains, like human brains, have typical properties of the small-world network in both the hypothyroidism and the control groups. However, the hypothyroidism group demonstrated lower global efficiency and decreased local cliquishness of the brain network, indicating hypothyroidism-related impairment to the brain network. The hypothyroidism group also has decreased nodal centrality in the left posterior hippocampus, the right hypothalamus, pituitary, pons, and medulla. This observation accorded with the hypothyroidism-related functional disorder of hypothalamus-pituitary-thyroid (HPT) feedback regulation mechanism. CONCLUSION: Our research quantitatively confirms that hypothyroidism hampers brain cognitive function by causing impairment to the brain network of glucose metabolism. This study reveals the feasibility and validity of applying graph theory method to preclinical [18F]FDG PET images and facilitates future study on human subjects. PMID- 29532351 TI - Bioluminescence Imaging for Monitoring miR-200c Expression in Breast Cancer Cells and its Effects on Epithelial-Mesenchymal Transition Progress in Living Animals. AB - PURPOSE: Dysregulation of microRNAs (miRNAs) are not only involved in the formation of malignant tumors but also in the processes of differentiation and aggressiveness. However, current methods for detecting miRNA expression have major disadvantages, such as being invasive and non-reproducible. The epithelial mesenchymal transition (EMT) has been implicated as a pivotal event in the metastasis, stemness, and chemoresistance of malignant tumors. PROCEDURES: In our study, we constructed a new reporter gene, Luc2/tdT_miR200c_3TS, to examine the in vitro and in vivo expression of miR-200c, an EMT-associated miRNA. Quantitative real-time PCR was used to measure the expression levels of miR-200c and EMT-related mRNA, and luciferase assay and bioluminescence imaging were used to measure the luciferase activities in vitro and in vivo, respectively. RESULTS: We found that the expression level of miR-200c was negatively associated with cell migration and invasion. Luciferase activities were regulated by the differential expression levels of miR-200c and EMT process. CONCLUSIONS: Our results demonstrate that Luc2/tdT_miR200c_3TS may be a useful tool for monitoring the expression level of miR-200c at both the cellular level and in living animals, thereby providing a potential high-throughput approach for anticancer drug screening. PMID- 29532352 TI - Light-driven quinone reduction in heliobacterial membranes. AB - Photosynthetic reaction centers (RCs) evolved > 3 billion years ago and have diverged into Type II RCs reducing quinones and Type I RCs reducing soluble acceptors via iron-sulfur clusters. Photosystem I (PSI), the exemplar Type I RC, uses modified menaquinones as intermediate electron transfer cofactors, but it has been controversial if the Type I RC of heliobacteria (HbRC) uses its two bound menaquinones in the same way. The sequence of the quinone-binding site in PSI is not conserved in the HbRC, and the recently solved crystal structure of the HbRC does not reveal a quinone in the analogous site. We found that illumination of heliobacterial membranes resulted in reduction of menaquinone to menaquinol, suggesting that the HbRC can perform a function thought restricted to Type II RCs. Experiments on membranes and live cells are consistent with the hypothesis that the HbRC preferentially reduces soluble electron acceptors (e.g., ferredoxins) in low light, but switches to reducing lipophilic quinones in high light, when the soluble acceptor pool becomes full. Thus, the HbRC may represent a functional evolutionary intermediate between PSI and the Type II RCs. PMID- 29532353 TI - Evidence of Validity of the Autism Mental Status Examination (AMSE) in a Brazilian Sample. AB - This study investigated the psychometric properties of the Autism Mental Status Examination (AMSE) in a Brazilian sample of children and adolescents with autism spectrum disorder (ASD). A sample of 260 children and adolescents, comprising 56 (21.5%) females and 204 (78.5%) males, was assessed. The participants were submitted to both the childhood autism rating scale (CARS-BR) and the AMSE. The CARS-BR was used to estimate ASD severity and the cutoff point on the AMSE. Spearman's correlation test was employed to determine the correlation between the AMSE and CARS-BR scales. The cutoff values were calculated using the ROC (receiver operating characteristic) curve, identifying the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The homogeneity of the items of the AMSE was determined using Cronbach's alpha. The AMSE exhibited good internal consistency (0.74), sensitivity (0.91) and specificity (0.98); and high correlation with the CARS-BR (rho = 0.91, p < 0.01). Preliminary results showed that the AMSE is a tool with good psychometric properties for ASD screening. PMID- 29532354 TI - Understanding the Linguistic Needs of Diverse Individuals with Autism Spectrum Disorder: Some Comments on the Research Literature and Suggestions for Clinicians. AB - The practice of advising bilingual parents of children with autism spectrum disorder (ASD) to speak in a single language, often the majority language of the region, with their child with ASD seems to be common. Such advice, however, is not grounded on empirical evidence but appears to be based more on logical arguments and assumptions. In this commentary, fears surrounding dual language exposure and empirical evidence supporting bilingualism in children with ASD are discussed. Suggestions for future research and three key steps that clinicians can consider taking to better address the needs of diverse learners are provided. PMID- 29532355 TI - Composite carbohydrate interpenetrating polyelectrolyte nano-complexes (IPNC) as a controlled oral delivery system of citalopram HCl for pediatric use: in vitro/in-vivo evaluation and histopathological examination. AB - Citalopram HCl (CH) is one of the few drugs which can be used safely in childhood psychiatric disorders. This study was focused on the preparation of interpenetrating polyelectrolytes nano-complexes (IPNC) to transform the hydrophilic carbohydrate polymers into an insoluble form. The IPNCs were loaded with CH to sustain its effect. The IPNC2 (composed of chitosan:pectin in a 3:1 ratio) showed the most extended drug release pattern (P < 0.05) and followed a Higuchi-order kinetics model. It was characterized using SEM, X-rays diffractometry, and FTIR. In-vivo studies were performed using immature rats with induced depression, and were based on the investigation of behavioral, biochemical, and histopathological changes at different time intervals up to 24 h. Rats treated with IPNC2 showed a significant more rapid onset of action and more extended effect in the behavioral tests, in addition to a significantly higher serotonin brain level up to 24 h, compared to rats treated with the market product (P < 0.05). The histopathological examination showed a profound amelioration of the cerebral cortex features of the depressed rats after IPNC2 administration. This study proves the higher efficacy and more extended effect of the new polyelectrolytes nano-complexes compared to the market product. PMID- 29532356 TI - Covalently mucoadhesive amphiphilic prodrug of 5-fluorouracil for enhanced permeation and improved oral absorption. AB - 5-Fluorouracil (5-FU) is one of the important antitumor drugs and is widely used to treat various types of cancers. However, its administration is limited to intravenous route due to poor oral bioavailability. Herein, we hypothesized that the maleimide group-containing 5-FU prodrug (EMC-5-FU) could improve the intestinal mucoadhesion because the maleimide end group can covalently target thiol residues of mucin glycoprotein covering the intestinal enterocytes. In vitro bioadhesion results showed that EMC-5-FU exhibited good affinity to the cysteine-rich subdomains of mucin and NMR studies successfully verified the covalent attachment of EMC-5-FU to mucin. The intestinal perfusion study indicated that the intestinal bioadhesion and membrane permeability are greatly enhanced for EMC-5-FU, in comparison with 5-FU. Mucoadhesion investigations on rat intestine intuitively confirmed increased intestinal retention of 5-FU through maleimide-mediated mucoadhesion. Moreover, AUC0-24h of the total 5-FU level for EMC-5-FU solution was 2.65-fold higher compared with 5-FU solution. Our study further suggested that the amphiphilic prodrug EMC-5-FU with good mucoadhesion is a promising delivery strategy form to overcome multiple barriers of oral absorption. PMID- 29532358 TI - Submucosal Hematoma of the Sigmoid Colon as a Complication of Anticoagulation Treatment. AB - BACKGROUND: Anticoagulation therapy after coronary stent implantation is necessary and crucial for patients with severe coronary heart disease. Submucosal bleeding of the colon is an infrequent complication of anticoagulants. METHODS: TWe present the case of a 70-year-old woman with spontaneous submucosal hematoma and active bleeding of her sigmoid colon due to anticoagulants after intracoronary stenting. RESULTS: This patient underwent a timely surgical operation. Treated by our experienced multidisciplinary team, her recovery was smooth without any other major complications. CONCLUSIONS: Surgical intervention is an appropriate therapy for patients with intractable bleeding. PMID- 29532357 TI - Novel approach for a PTX/VEGF dual drug delivery system in cardiovascular applications-an innovative bulk and surface drug immobilization. AB - The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS3). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system. PMID- 29532359 TI - Feasibility and Safety of Endoscopic Ultrasound-Guided Biliary Drainage (EUS-BD) for Malignant Biliary Obstruction Associated with Ascites: Results of a Pilot Study. AB - BACKGROUND: It has been suggested that EUS-BD may be a feasible and safer alternative to percutaneous transhepatic biliary drainage (PTBD) after failed ERCP in patients with ascites. To date, no study has specifically evaluated the performance of EUS-BD in this context. METHODS: Retrospective analysis was done for patients with and without ascites who underwent EUS-BD for malignant biliary obstruction after failed ERCP between July 2010 and September 2014. Complications and technical and clinical successes between the two groups were compared. RESULTS: A total of 31 patients were included: 20 patients without ascites (group 1) and 11 with ascites (group 2). Nineteen patients underwent EUS hepaticogastrostomy (six in group 2), and 12 underwent EUS-choledochoduodenostomy (five in group 2). Technical success was achieved in all patients. Clinical success was observed in 95% (n = 19) in group 1 and 64% (n = 7) in group 2 (p = 0.042). In three out of four patients without clinical success in group 2, the follow-up period was not long enough to observe the clinical response because of early death within the 2 weeks after EUS-BD secondary to disease progression or preprocedural unresponsive sepsis. No significant differences were observed between groups 1 and 2 either in the overall rates of procedural-related complications (20 and 9%, respectively, p = 0.63) or in the rates of major complications (15 vs 9%, respectively, p = 0.639). Stent migration occurred in one patient in each group, intra- or post-procedural bleeding occurred in two patients in group 1, which was conservatively managed, and one patient in group 1 presented biliary leakage. Stent patency and the number of re-interventions were not significantly different. CONCLUSIONS: EUS-BD is technically feasible in patients with ascites. Our results suggest that EUS-BD may be a clinically effective and safe alternative after failed ERCP in patients with ascites. PMID- 29532360 TI - The Additional Value of Laparoscopic Ultrasound to Staging Laparoscopy in Patients with Suspected Pancreatic Head Cancer. AB - BACKGROUND: This study aimed to evaluate the additional value of laparoscopic ultrasound (LUS) to staging laparoscopy (SL) for detecting occult liver metastases in patients with potentially resectable pancreatic head cancer. METHODS: A retrospective cohort study was performed including all patients who underwent SL and LUS between 2005 and 2016. LUS was performed during SL to detect liver metastases not found by preoperative imaging or visual inspection of the liver. RESULTS: Out of 197 patients, visual inspection during SL detected distant metastases in 29 (14.7%) patients. LUS was performed in 127 patients, revealing 3 additional liver metastases. The proportion of patients with unresectable disease after SL and negative LUS was 32.3%, which was similar to 36.6% of patients with unresectable disease after SL without LUS (difference 4.3%; 95% CI - 13-23%; P = 0.61). Sensitivity, specificity, and positive and negative predictive values of LUS to detect liver metastases were 30, 100, 100, and 94%, respectively. The proportion of patients with distant metastases diagnosed at SL significantly increased over time (P = 0.031). CONCLUSION: The routine use of LUS during SL for patients with potentially resectable pancreatic head cancer cannot be recommended. Imaging should be repeated when significant delay occurs between index CT and the scheduled surgery. PMID- 29532361 TI - Preoperative Imaging with 18F-FDOPA PET/CT for Small Bowel Neuroendocrine Tumors. PMID- 29532362 TI - Pure Laparoscopic Right Hepatectomy Using Modified Liver Hanging Maneuver: Technical Evolution from Caudal Approach Toward Ventral Approach. AB - BACKGROUND: The liver hanging maneuver during right hepatectomy is a useful technique for parenchymal transection. The laparoscopic caudal approach is totally different from the laparoscopic ventral approach because of the direction of parenchymal transection. There are differences in the application and effectiveness of liver hanging maneuver between two approaches. This study evaluated the surgical techniques and outcomes of the ventral approach comparison with the caudal approach in laparoscopic right hemihepatectomy using liver hanging maneuver. METHODS: From February 2013 to February 2018, 16 patients underwent laparoscopic right hepatectomy using liver hanging maneuver. The caudal approach was used in 10 patients and the ventral approach in six. We adopted a different avascular plane located between the right adrenal gland and the vena cava for the hanging tape placement. In the caudal approach, the liver parenchyma were transected from the caudal to cranial side, pulling the hanging tape caudally. In the ventral approach, the parenchyma were transected from the ventral to the dorsal side, pulling the hanging tape superiorly. RESULTS: The clinical data and patient characteristics of both groups were similar. The median operation time was comparable between the two groups (275 vs. 278 min, p = 0.958). The median blood loss was significantly lower using the ventral approach group than the caudal approach group (375 vs. 190 ml, p = 0.016). The difference in median postoperative hospital stay was not statistically significant (9 vs. 8 days, p = 0.713). CONCLUSION: This ventral approach with liver hanging maneuver is a feasible and useful technique for laparoscopic right hemihepatectomy. PMID- 29532363 TI - Commentary on "Standards of Evidence for Conducting and Reporting Economic Evaluations in Prevention Science". AB - The current paper is a commentary on the Standards of Evidence for Conducting and Reporting Economic Evaluations in Prevention Science (Crowley et al. 2018). Although the standards got a lot right, some important issues were not addressed or could be explored further. Measuring rather than modeling is encouraged whenever possible. That also is in keeping with the approach taken by many prevention researchers. Pre-program planning for collection of data on resources used by individual participants (i.e., costs) is recommended, along with devotion of evaluation resources to cost assessment throughout program implementation. A "cost study" should never be an afterthought tacked on as a later aim in a research proposal. Needing inclusion or enhancement in the standards, however, are several key concepts, starting with the often-confused distinction between costs and outcomes. The importance of collecting data on individual-level variability in resource use, i.e., costs, needs to be distinguished from simplistic disaggregation-by-division of program cost totals down to individuals. In some passages of the standards, the uniqueness of individual participants seems dismissed as error variance rather than considered a primary phenomenon for study and understanding. Standards for formatting reports of economic evaluations could themselves be more evidence-based. Missing too is an explicit call for inclusion of the standards' recommendations in peer review of prevention research proposals, and in funding of prevention research. Finally, we can be confident that the better outcomes the standards promise will come at additional costs to prevention researchers. This commentary concludes by considering whether the standards themselves are cost-beneficial. PMID- 29532364 TI - Principles of Precision Prevention Science for Improving Recruitment and Retention of Participants. AB - Precision medicine and precision public health focus on identifying and providing the right intervention to the right population at the right time. Expanding on the concept, precision prevention science could allow the field to examine prevention programs to identify ways to make them more efficient and effective at scale, including addressing issues related to engagement and retention of participants. Research to date on engagement and retention has often focused on demographics and risk factors. The current paper proposes using McCurdy and Daro (Family Relations, 50, 113-121, 2001) model that posits a complex mixture of individual, provider, program, and community-level factors synergistically affect enrollment, engagement, and retention. The paper concludes recommending the use of research-practice partnerships and innovative, rapid cycle methods to design and improve prevention programs related to participant engagement and retention at scale. PMID- 29532365 TI - Inappropriate shock caused by P wave oversensing in an entirely subcutaneous ICD. PMID- 29532366 TI - Atrial fibrillation mimicking ventricular fibrillation confuses an automated external defibrillator. PMID- 29532367 TI - A spatiotemporal analysis of invasive cervical cancer incidence in the state of Maryland between 2003 and 2012. AB - PURPOSE: Invasive cervical cancer (ICC) rates have tremendously declined in the United States, yet new cases consistently occur in Maryland and throughout the United States. We hypothesized that although rates have generally declined, this decline is uneven across counties and over time. METHODS: Space-time cluster detection analysis was conducted to evaluate clusters of ICC incidence at the county level within Maryland between 2003 and 2012. RESULTS: The most likely cluster was a cluster of low incidence, which included 6 counties in eastern Maryland for the period 2009-2012. A secondary cluster of low rates, comprising 2 metropolitan counties in northern Maryland, was observed for the period 2009 2012. Two of the three clusters of high ICC rates occurred in 2009-2012 in the large metropolitan area of Baltimore City and another cluster in Frederick County, in rural western Maryland. The third cluster of high rates was observed 2005-2008, in western Maryland. CONCLUSION: In recent periods, some Maryland counties have experienced anomalously high or low ICC incidence. Clusters of high incidence are not explained by differences in screening rates and may be due to failures in follow-up care for cervical abnormalities that need to be investigated. Clusters of low incidence may represent areas of successful ICC control. PMID- 29532368 TI - Valproic Acid Promotes Survival of Facial Motor Neurons in Adult Rats After Facial Nerve Transection: a Pilot Study. AB - Valproic acid (VPA), a medication primarily used to treat epilepsy and bipolar disorder, has been applied to the repair of central and peripheral nervous system injury. The present study investigated the effect of VPA on functional recovery, survival of facial motor neurons (FMNs), and expression of proteins in rats after facial nerve trunk transection by functional measurement, Nissl staining, TUNEL, immunofluorescence, and Western blot. Following facial nerve injury, all rats in group VPA showed a better functional recovery, which was significant at the given time, compared with group NS. The Nissl staining results demonstrated that the number of FMNs survival in group VPA was higher than that in group normal saline (NS). TUNEL staining showed that axonal injury of facial nerve could lead to neuronal apoptosis of FMNs. But treatment of VPA significantly reduced cell apoptosis by decreasing the expression of Bax protein and increased neuronal survival by upregulating the level of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) expression in injured FMNs compared with group NS. Overall, our findings suggest that VPA may advance functional recovery, reduce lesion-induced apoptosis, and promote neuron survival after facial nerve transection in rats. This study provides an experimental evidence for better understanding the mechanism of injury and repair of peripheral facial paralysis. PMID- 29532369 TI - Muscarinic Acetylcholine Receptors Inhibit Fyn Activity in the Rat Striatum In Vivo. AB - The Src family kinase (SFK) is a subfamily of non-receptor tyrosine kinases. SFK members, Src and especially Fyn, are expressed in the striatum. These SFK members are involved in the regulation of neuronal and synaptic activities and are linked to the pathogenesis of a variety of neuropsychiatric and neurodegenerative disorders. Given the fact that muscarinic acetylcholine (mACh) receptors are highly expressed in striatal neurons and are critical for the regulation of striatal function, we investigated the role of mACh receptors in the regulation of SFKs in the adult rat striatum in vivo. We found that pharmacological blockade of mACh receptors by systemic administration of the mACh antagonist scopolamine induced a marked increase in phosphorylation of SFKs in the striatum of male and female rats. This scopolamine-induced increase in SFK phosphorylation occurred in the two subdivisions of the striatum (caudate putamen and nucleus accumbens) and was time-dependent and reversible. Another mACh antagonist atropine was also effective in stimulating SFK phosphorylation. Coadministration of subthreshold doses of scopolamine and a dopamine D1 receptor agonist SKF81297 enhanced striatal SFK phosphorylation. Between Fyn and Src proteins immunoprecipitated from striatal tissue, scopolamine selectively increased phosphorylation of Fyn. The increase in Fyn phosphorylation was accompanied by an increase in Fyn kinase activity in response to scopolamine. These results reveal a significant role of mACh receptors in the regulation of SFKs (mainly Fyn) in striatal neurons. Under normal conditions, endogenous mACh receptors appear to exert an inhibitory effect on Fyn activity. PMID- 29532370 TI - Bacterial community changes in response to oil contamination and perennial crop cultivation. AB - We investigated bacterial community dynamics in response to used motor oil contamination and perennial crop cultivation by 16S rRNA gene amplicon sequencing in a 4-year field study. Actinobacteria, Proteobacteria, Chloroflexi, Acidobacteria, and Gemmatimonadetes were the major bacterial phyla, and Rhodococcus was the most abundant genus. Initially, oil contamination decreased the overall bacterial diversity. Actinobacteria, Betaproteobacteria, and Gammaproteobacteria were sensitive to oil contamination, exhibiting clear succession with time. However, bacterial communities changed over time, regardless of oil contamination and crop cultivation. The abundance difference of most OTUs between oil-contaminated and non-contaminated plots remained the same in later sampling years after the initial abundance difference induced by oil spike. The abundances of three oil-favored actinobacteria (Lysinimonas, Microbacteriaceae, and Marmoricola) and one betaproteobacterium (Aquabacterium) changed in different manner over time in oil-contaminated and non-contaminated soil. We propose that these taxa are potential bio-indicators for monitoring recovery from motor oil contamination in boreal soil. The effect of crop cultivation on bacterial communities became significant only after the crops achieved stable growth, likely associated with plant material decomposition by Bacteroidetes, Armatimonadetes and Fibrobacteres. PMID- 29532371 TI - As(V) and Sb(V) co-adsorption onto ferrihydrite: synergistic effect of Sb(V) on As(V) under competitive conditions. AB - Competitive adsorption of As(V) and Sb(V) at environmentally relevant concentrations onto ferrihydrite was investigated. Batch experiments and XPS analyses confirmed that in a binary system, the presence of Sb(V) exhibited a slight synergistic effect on As(V) adsorption. XPS analyses showed that As(V) and Sb(V) adsorption led to obvious diminishment of Fe-O-Fe and Fe-O-H bonds respectively. At pH of 9, a more significant decrease of Fe-O-Fe was observed in the binary system than that in a single system, indicating that As(V) displayed an even stronger interaction with lattice oxygen atoms under competitive conditions. Basically, ionic strength demonstrated a negligible or positive influence on As(V) and Sb(V) adsorption in binary system. Study of adsorption sequence also indicated that the presence of Sb(V) showed a promotion effect on As(V) adsorption at neutral pHs. Considering that co-contamination of As and Sb in waters has been of great concern throughout the world, our findings contributed to a better understanding of their distribution, mobility, and fate in environment. PMID- 29532372 TI - Persistence of TBT and copper in excess on leisure boat hulls around the Baltic Sea. AB - A handheld XRF-analyzer specially calibrated for measurements of metals on plastic boat hulls has been used on leisure boats in Denmark (DK), Finland (FI), and Germany (DE). The results on tin and copper are presented as MUg metal/cm2. Tin is a proxy for the occurrence of organotin compounds on the boat. Two or three sites were visited in each country and between 25 and 90 boats were measured at each site. Every boat was measured at six to eight places, and the results are presented both as mean and median values. Linear regression of mean to median values of the 377 data pairs shows high relationship with R2 = 0.9566 for tin and R2 of 0.9724 for copper and thus both ways of calculation may be used. However, for regulative use, it is suggested that all individual measurements on each boat should be presented and used for decisions of removal or sealing of boat hulls. The results are compared with published data from different parts of Sweden, i.e., boats in fresh water, brackish water, and salt water. The results show that tin with mean values > 50 MUg Sn/cm2 is still found on 42, 24, and 23% of the boats in DK, FI, and DE, respectively. The corresponding percentages based on median values are 38, 22, and 18% for DK, FI, and DE, respectively. The variation among boats is high with a maximum mean value of 2000 MUg Sn/cm2. As comparison, one layer of an old TBT antifouling paint Hempels Hard racing superior, corresponds to 300 MUg Sn/cm2. The percentage of boats with tin > 400 MUg Sn/cm2 content based on mean values was 10% in DK, 5% in FI, and 1% in DE. The corresponding median values were 9, 6, and 1% for DK, FI, and DE. Copper, > 100 MUg Cu/cm2, was detected on all measured boats in DK and in DE and on all but 3% of the FI boats. One layer of Hempels MilleXtra corresponds to 4000 MUg Cu/cm2. The recommendation on the can is to apply two layers. The proportion of boats with higher mean copper values than 8000 MUg Cu/cm2 was 51, 56, and 61 for boats in DK, FI, and DE, respectively. The proportion based on median values > 8000 MUg Cu/cm2 was 50, 54, and 61% for DK, FI, and DE. The conclusion is that many leisure boats around the Baltic Sea still display or possess antifouling paints containing organotin compounds and that more than half of the boats have more copper than needed for one boat season according to the paint producers. Much of these known toxic compounds will probably be released into the environment and harm the biota. The calibrated XRF-method, intended for area measurements on boat hulls, is an easy and cheap way to detect boats with organotin compounds and high copper content. We recommend environmental authorities to use this method for identification of such boats and to use the results for requesting measures to minimize further leakage to the environment. PMID- 29532373 TI - Effect of dietary phytogenics (herbal mixture) supplementation on growth performance, nutrient utilization, antioxidative properties, and immune response in broilers. AB - This experiment was conducted to study that effect of a phytogenics (herbal mixture) supplementation as alternative to antibiotics on the growth performance and immune response in broilers. Three thousand broiler male chicks at 1 day of age were housed in floor pens and divided into five experimental groups with five replicates of 120 birds each. The first group was fed the basal diet without any additive in feed or water; the second group was fed the basal diet, and the drinking water was supplemented with mixture of antibiotics (Doxycycline 1 g/5 L + Colistine sulfate 1 g/5 L) for the first 10 days of life. The other three treatments of chickens were fed the control diet supplemented with herbal mixture at a level of 0.5, 1.0, and 1.5 kg/ton, respectively. Dietary herb mixture supplementation improved growth performance significantly in comparison with control group. In addition, herb mixture supplementation reduced plasma total cholesterol and triglycerides concentrations, whereas, high density lipoprotein HDL-cholesterol and glutathione peroxidase (GPX) were increased significantly. Furthermore, herb mixture supplementation increased plasma levels of total protein and antibodies titers for Newcastle disease virus before and after the infection. It could be concluded that dietary herb mixture supplementation had positive effects on growth performance, antioxidative properties, and humoral immunity in broiler chickens. PMID- 29532374 TI - A dual-permeability hydro-biodegradation model for leachate recirculation and settlement in bioreactor landfills. AB - A dual-permeability hydro-biodegradation model is developed to describe the leachate flow in municipal solid waste (MSW) and predict the long-term settlement induced by biodegradation in bioreactor landfills. The model is verified against Hydrus-1D and a recirculation experiment conducted in a full-scale landfill. Preferential flow and mass transfer between fissure and matrix can be reasonably modeled by the proposed model. A higher recirculation flow rate can speed up the stabilization process of landfill. However, too much recirculation leachate is not economical and environmental friendly. A stabilization speed index and a leachate utilization index are adopted to evaluate the stabilization speed of bioreactor landfill and utilization rate of leachate, respectively, and the optimal recirculation flow rate is estimated. A flow rate of q = 5 * 10-5-5 * 10 4 m/h (equivalent to recirculation intensity of Q = 15-150 L/tonwaste/year) is recommended for recirculation, which has been verified by the field data in numerous bioreactor landfills. PMID- 29532375 TI - Comparison of nickel adsorption on biochars produced from mixed softwood and Miscanthus straw. AB - In order to understand the influence of feedstock type on biochar adsorption of heavy metals, the adsorption characteristics of nickel (Ni2+), copper (Cu2+) and lead (Pb2+) onto biochars derived from mixed softwood and Miscanthus straw were compared. The biochars were produced from mixed softwood pellets (SWP) and Miscanthus straw pellets (MSP), at both 550 and 700 degrees C for each material, using a standardised production procedure recommended by the UK Biochar Research Centre. Kinetics analyses show that the adsorption of Ni2+ to all four biochars reached equilibrium within 5 min. The degree of Ni2+ removal for all four biochars remained nearly constant within initial pH values of 3-8, because the equilibrium pH values within this range were similar due to the buffering effect of the biochars. A sharp increase of Ni2+ removal percentage for all biochars at initial solution pH 8-10 was observed as the equilibrium pH also increased. MSP derived biochars generally had higher maximum adsorption capacities (Qmax) for the three tested metals as compared with those from SWP, which was likely due to their higher degree of carbonisation during production. This study shows that feedstock type is a primary factor affecting the adsorption capacities of the tested biochars for heavy metals. PMID- 29532376 TI - Comparative study on the toxic effects of some heavy metals on the Nile Tilapia, Oreochromis niloticus, in the Middle Delta, Egypt. AB - Heavy metals are the most dangerous hazards affecting aquatic biota in Egypt specially the Nile Tilapia, Oreochromis niloticus, which is an important species in commercial fisheries. Some areas were not fully studied to screen the hazards that may affect this economic fish. Therefore, the present study aimed to evaluate the potential hazards of heavy metals on O. niloticus in Al-Gharbiya Governorate in the Middle delta of Egypt. Water and fish samples were collected from Al-Qased canal, Kafr El-Zayaat Nile, El-Maash canal in Al-Gharbiya Governorate plus a reference site which is a fish farm at the Faculty of Agriculture, Damietta University, Damitta Governorate, Egypt. The results showed a significant increase (p < 0.05) in the lead, zinc, magnesium, manganese, and copper levels while showed a significant decrease (p < 0.05) in the iron level in the water from all the investigated areas. Cadmium level was significantly high (p < 0.05) in Kafr El-Zayaat Nile and EL-Maash canal only. These metals were also accumulated in the fish livers and gills. Consequently, ALT and AST activities and creatinine level were significantly (p < 0.05) high in all the investigated areas. Histopathological examination revealed cytoplasmic and nuclear degeneration in the hepatocytes in all the investigated areas. Renal glomeruli and Bowman's capsule were not completely intact in Al-Qased and El-Maash canals while conspicuous shrinkage of the glomeruli was determined in Kafr El-Zayaat Nile. Furthermore, slight damage in the secondary lamellae was detected in the gill from Al-Qased canal while in the other areas appeared vacuolated or destructed. Finally, spleen sections of fish from different sites showed the absence of melanin pigments and some vacuoles. In conclusion, the Nile Tilapia, Oreochromis niloticus, is affected by the toxic effects of the heavy metals in Al Gharbiya Governorate in Egypt and this gives an alarm and should be taken into consideration. PMID- 29532377 TI - The use of probiotics as eco-friendly alternatives for antibiotics in poultry nutrition. AB - Antibiotics as growth promoters in poultry have been used for long time for improving feed efficiency and performance. Due to their various side-effects such as antibiotic resistance, destruction of beneficial bacteria in the gut, and dysbiosis, it is required to think about some alternatives. Probiotics are one of the options in this regard for improving poultry production. Probiotics are defined as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host." They are available in various forms for use as feed additives. Probiotics as feed additives aid in proper digestion of feed hence make the nutrients available for faster growth. Immunity can also be improved by addition of probiotics to poultry diets. Moreover, probiotics aid in improving meat and egg quality traits. Various infectious diseases of poultry can be countered by use of probiotics in their feed. A proper selection of probiotic strains is required for gaining optimal effects. This review focuses on the mechanisms of action of probiotics and their importance in poultry feed supplementation for enhancing production and safeguarding health of poultry. PMID- 29532378 TI - Performance and efficiency of removal of pharmaceutical compounds from hospital wastewater by lab-scale biological treatment system. AB - The fate of pharmaceuticals after discharged from hospital into wastewater was clarified experimentally by using a new lab-scale conventional activated sludge (CAS) treatment reactor. The 43 target compounds belong to nine therapeutic classes (antivirals, antibacterials, anticancer drugs, psychotropics, antihypertensives, analgesic-antipyretics, contrast media, herbal medicines, and phytoestrogens) were selected with inclusion of 16 newly estimated compounds. The efficiency of the present reactor was estimated by comparing the reaction rate constant of the solid-water partition coefficients (log Kd) between liquid and solid samples and half-life during 48-h experiment obtained by using hospital effluents with those obtained by using STP wastewater. The results that no significant difference in removal efficiency was observed between both water samples (P > 0.05) indicate high reliability of the present lab-scale reactor. The actual rates of removal when hospital effluent was applied varied widely (mean, 59 +/- 40%) independent of type of the pharmaceuticals. More than 90% of 17 compounds were removed after 8 h of treatment. However, the values for psychotropics (mean, 19 +/- 26%) and contrast media (mean, 24 +/- 17%) were generally low, indicating high stability. The log Kd values ranged from 1.3 to 4.8. Notably, clarithromycin, acridine, and glycitein could be removed in both liquid and solid phases. The dominant removal mechanisms were found to be different for individual pharmaceutical. These results suggest the effectiveness of introduction of the lab-scale biological treatment system for development of a new solution for discharge of pharmaceuticals from hospital. PMID- 29532379 TI - Effect of composition and microstructure of humic acid on 3,3',4,4' tetrachlorobiphenyl sorption. AB - The fate and transport of polychlorinated biphenyls (PCBs), a class of persistent organic compounds, in soils was markedly affected by their sorption/desorption on soil organic matters (SOM) due to high hydrophobicity of PCBs. Humic acid (HA), an important fraction of SOM, has no steady composition and microstructure from different origins, resulting in their diverse sorption capacity. Therefore, the effect of composition and microstructure of HA on sorption of 3,3',4,4' tetrachlorobiphenyl (PCB77) was investigated in this study. The primary sorption mechanism of PCB77 on HAs was also demonstrated by using Fourier transform infrared (FTIR) and solid-state carbon-13 nuclear magnetic resonance (13C-NMR) spectroscopy analysis. Elemental content analysis of three HAs showed that the content of unsaturated C (the total of aromatic, carboxylic, and carbonyl carbon) followed an order of YHA>SHA>AHA. Furthermore, YHA and SHA had remarkably rough and complicated particle surfaces but AHA had relatively smooth surface and the well-proportioned and interspersed particle sizes. The results of the sorption experiment showed that the sorption capacity of PCB77 on HAs followed a similar order of YHA>SHA>AHA, indicating the content of unsaturated C of HAs controlled the sorption of PCB77 on HAs. Sorption of PCB77 on either AHA or SHA did not change with increasing ionic strength of background solution, implying that there was no H-bond or electrostatic interaction between PCB77 and HAs. The result of FTIR and 13C-NMR spectra showed the primarily possible mechanism was pi-pi conjugative interaction and hydrophobic binding between PCB77 and HAs. PMID- 29532380 TI - Potential harmful elements in coal dust and human health risk assessment near the mining areas in Cherat, Pakistan. AB - This study was aimed to investigate the potential harmful element (PHE) concentrations in coal dust and evaluate the human risk assessment and health effects near coal mining areas. For this purpose, dust samples were collected near various coal mines in Cherat, Pakistan, and analyzed for the PHE concentrations. Determined PHE concentrations were evaluated for the health risk assessment. Results revealed that ingestion was the major pathway as compared to others for PHE exposure. Individual chronic daily intake (CDI) of PHEs was higher than their respective permissible exposure limits set for oral exposure routes by the Agency for Toxic Substances and Disease Registry (ATSDR). Chronic risk or health index (HI) values were observed < 1 for all PHEs and in the order of Pb > Cr > Cd > Ni > Cu > Co > Zn. Higher HI values of Pb, Cr, and Cd could attribute to various chronic health problems as observed during the medical examination survey of this study. Cancer risk (CR) values for this study were observed within the US Environmental Protection Agency (EPA) limits. However, if current practices continued, the PHEs will cross these limits in a near future. Therefore, this study strongly recommends the provision of safety measures, rules, and regulation to avoid health hazards in the future. PMID- 29532381 TI - Effect of compression ratio, nozzle opening pressure, engine load, and butanol addition on nanoparticle emissions from a non-road diesel engine. AB - Currently, diesel engines are more preferred over gasoline engines due to their higher torque output and fuel economy. However, diesel engines confront major challenge of meeting the future stringent emission norms (especially soot particle emissions) while maintaining the same fuel economy. In this study, nanosize range soot particle emission characteristics of a stationary (non-road) diesel engine have been experimentally investigated. Experiments are conducted at a constant speed of 1500 rpm for three compression ratios and nozzle opening pressures at different engine loads. In-cylinder pressure history for 2000 consecutive engine cycles is recorded and averaged data is used for analysis of combustion characteristics. An electrical mobility-based fast particle sizer is used for analyzing particle size and mass distributions of engine exhaust particles at different test conditions. Soot particle distribution from 5 to 1000 nm was recorded. Results show that total particle concentration decreases with an increase in engine operating loads. Moreover, the addition of butanol in the diesel fuel leads to the reduction in soot particle concentration. Regression analysis was also conducted to derive a correlation between combustion parameters and particle number emissions for different compression ratios. Regression analysis shows a strong correlation between cylinder pressure-based combustion parameters and particle number emission. PMID- 29532382 TI - Modeling the emissions of a dual fuel engine coupled with a biomass gasifier supplementing the Wiebe function. AB - There is a growing market demand for small-scale biomass gasifiers that is driven by the economic incentives and the legislative framework. Small-scale gasifiers produce a gaseous fuel, commonly referred to as producer gas, with relatively low heating value. Thus, the most common energy conversion systems that are coupled with small-scale gasifiers are internal combustion engines. In order to increase the electrical efficiency, the operators choose dual fuel engines and mix the producer gas with diesel. The Wiebe function has been a valuable tool for assessing the efficiency of dual fuel internal combustion engines. This study introduces a thermodynamic model that works in parallel with the Wiebe function and calculates the emissions of the engines. This "vis-a-vis" approach takes into consideration the actual conditions inside the cylinders-as they are returned by the Wiebe function-and calculates the final thermodynamic equilibrium of the flue gases mixture. This approach aims to enhance the operation of the dual fuel internal combustion engines by identifying the optimal operating conditions and at the same time-advance pollution control and minimize the environmental impact. PMID- 29532383 TI - Studies on mercury occurrence in inorganic constituents of Polish coking coals. AB - During the cokemaking process, a significant amount of mercury occurring in a coal blend is released to the atmosphere. One of the ways of reducing this emission is to reduce mercury content in a coal blend. This could be obtained through the coal washing process. The optimization of this process requires the knowledge of mercury occurrence in coal, especially in its inorganic constituents. A qualitative analysis of mercury occurrence in the inorganic constituents of Polish coking coals was performed using an electron probe microanalyzer (EPMA). For that purpose, selected samples of rejects and middling products derived from the washing process in dense media separators and jig concentrators were examined. The obtained results have confirmed a strong connection between mercury occurrence and the presence of sulfides (pyrite, marcasite, and chalcopyrite) in Polish coking coals. Significant amounts of mercury were also noticed for barite, siderite, and aluminosilicates. The highest value of mercury content, at the level of 0.100%, was obtained for marcasite. For the analyzed coals, the effectiveness of mercury removal in the washing process was determined by the forms of pyrite occurring in coal. The highest values of effectiveness of mercury removal were obtained in the case of coals for which the large framboidal pyrite aggregates with chalcopyrite overgrowths were noticed. It was also found that middling products were characterized by the occurrence of the Hg-rich overgrowths of pyrite on organic matter. To achieve a significant reduction in mercury content in clean coal, it is necessary to develop an effective method of removing this form of pyrite from hard coal. PMID- 29532384 TI - Characterization of phosphate rock and phosphogypsum from Gabes phosphate fertilizer factories (SE Tunisia): high mining potential and implications for environmental protection. AB - Since the establishment of the coastal industrial complex in Gabes city (Gulf of Gabes, SE Tunisia), hundred million tons of untreated phosphogypsum have been discharged in the open sea causing serious environmental problems. To better understand the dynamic and behavior of phosphate/phosphogypsum contaminants from raw ores to marine environment, a chemical, organic, mineralogical, and morphological characterization of phosphate rock and phosphogypsum was conducted using several sophisticated techniques. The chemical analysis showed that phosphate and phosphogypsum contain high loads of trace elements and that the transfer factors of pollutants varied from 5.83% (U) to 140% (Hg). Estimated annual flows of phosphogypsum contaminants into the marine environment ranged between 0.05 (Re) and 87,249.60 (F) tons. The phosphate rock was found to be formed by carbonate fluorapatite, calcite, dolomite, natural gypsum, quartz, calcite-Mg, apatite, pyrite, fluorite, and sphalerite-Cd and phosphogypsum by synthetic gypsum and sphalerite-Cd. The phosphate was found to be richer in organic compounds compared to phosphogypsum. Based on this work, the Tunisian phosphogypsum has a high mining potential and encourages the development of an economically beneficial and environmentally friendly phosphogypsum-treating industry. PMID- 29532385 TI - Toxic effect and mechanism of four ionic liquids on seedling taproots of Arabidopsis thaliana. AB - Arabidopsis thaliana was selected as model organisms to investigate the toxic effect and mechanism of four kinds of imidazolium and pyridinium ionic liquids (ILs) on plant seedling taproots. After exposure to ILs, the growth of seedling taproots was significantly inhibited in a dose-dependent manner. The toxicity of ILs on seedling taproots was [Bmim][BF4] > [Bmpy][BF4] > [Bmim][Br] > [Bmpy][Br]. The reduction of seedling root cell vitality, aggravation of seedling root cell death, and repression of gravitropic growth responses were observed. The amounts of H2O2 and ROS in seedlings were enhanced with increasing concentrations of ILs. Moreover, the expression levels of cdc2a and pcna1 genes were decreased after exposure to ILs. Our results suggest that ILs can induce the overproduction of ROS in A. thaliana seedling taproots and thus cause oxidative damage to seedling taproots. Meanwhile, ILs alter the expression patterns of two cell cycle-related genes and hence cause the seedling taproot growth inhibition. This work provides an integrated understanding of the toxic effect and mechanism of ILs on A. thaliana seedlings at the molecular and physiological level and also provides theoretical basis and reference for the environmental safety evaluation of ILs, prior to their widespread use and release. Graphical abstract ?. PMID- 29532386 TI - Review of the Ethical Issues of a Biomarker-Based Diagnoses in the Early Stage of Alzheimer's Disease. AB - BACKGROUND: Today, many healthcare or dementia organizations, clinicians, and companies emphasize the importance of detection of Alzheimer's disease in an early phase. This idea has gained considerable momentum due to the development of biomarkers, the recent FDA and EMA approval of three amyloid tracers, and the failure of a number of recent therapeutic trials conducted in the early dementia phase. On the one hand, an early etiological diagnosis can lead to early and more efficacious intervention. On the other hand, it is questioned how early an etiological diagnosis is beneficial to the patient. Here we consider ethical issues related to the process of biomarker testing and the impact on the diagnostic disclosure to patients with mild cognitive impairment due to prodromal Alzheimer's disease. METHODS: A systematic review of the theoretical bioethics literature was performed by using electronic databases. The review was limited to articles published in English between 2003 and 2016. RESULTS: A total of twenty articles were included in our effort to make an analysis of the ethical challenges. One of the biggest challenges was the uncertainty and the predictive value of the biomarker-based diagnosis where patients can be amyloid positive without full certainty whether or when they will develop symptomatic decline due to Alzheimer's disease. Another challenge was the tension between the right to know versus the wish not to know, the limited efficacy of currently available treatment options, and the opportunities and consequences after receiving such an early diagnosis. CONCLUSION: Based on the results and the additional comments in the discussion, several unanswered questions emerged. Therefore, careful consideration of all these ethical issues is required before the disclosure of a biomarker-based diagnosis to the patient with mild cognitive impairment due to Alzheimer's disease. PMID- 29532387 TI - Moving Forward on Consent Practices in Australia. AB - Allowing persons to make an informed choice about their participation in research is a pre-eminent ethical and legal requirement. Almost universally, this requirement has been addressed through the provision of written patient information sheets and consent forms. Researchers and others have raised concerns about the extent to which such forms-particularly given their frequent lengthiness and complexity-provide participants with the tools and knowledge necessary for autonomous decision-making. Concerns are especially pronounced for certain participant groups, such as persons with low literacy and Indigenous persons. Multimedia strategies have the potential to usefully supplement current consent practices in Australia; however, information is needed about the need for supplementary consent practices, along with drivers for and barriers against adoption. This study initiates the required evidence base through an audit of informed consent practices for medical research in the Australian state of Tasmania to assess the need for, and current uptake of, supplementary consent strategies. Drivers for and barriers against adoption of multimedia consent practices were explored in detail through interviews with key stakeholders, including researchers, HREC chairs and members, and research participants, including Indigenous participants. PMID- 29532389 TI - ? PMID- 29532390 TI - ? PMID- 29532391 TI - ? PMID- 29532392 TI - ? PMID- 29532393 TI - ? PMID- 29532388 TI - Mosquito-Associated Viruses in China. AB - Mosquitoes are classified into approximately 3500 species and further grouped into 41 genera. Epidemiologically, they are considered to be among the most important disease vectors in the world and they can harbor a wide variety of viruses. Several mosquito viruses are considered to be of significant medical importance and can cause serious public health issues throughout the world. Such viruses are Japanese encephalitis virus (JEV), dengue virus (DENV), chikungunya virus (CHIKV), and Zika virus (ZIKV). Others are the newly recognized mosquito viruses such as Banna virus (BAV) and Yunnan orbivirus (YNOV) with unclear medical significance. The remaining mosquito viruses are those that naturally infect mosquitoes but do not appear to infect humans or other vertebrates. With the continuous development and improvement of mosquito and mosquito-associated virus surveillance systems in China, many novel mosquito-associated viruses have been discovered in recent years. This review aims to systematically outline the history, characteristics, distribution, and/or current epidemic status of mosquito-associated viruses in China. PMID- 29532394 TI - ? PMID- 29532395 TI - ? PMID- 29532396 TI - ? PMID- 29532397 TI - ? PMID- 29532398 TI - ? PMID- 29532399 TI - ? PMID- 29532400 TI - No evidence for unethical amnesia for imagined actions: A failed replication and extension. AB - In a recent study, Kouchaki and Gino (2016) suggest that memory for unethical actions is impaired, regardless of whether such actions are real or imagined. However, as we argue in the current study, their claim that people develop "unethical amnesia" confuses two distinct and dissociable memory deficits: one affecting the phenomenology of remembering and another affecting memory accuracy. To further investigate whether unethical amnesia affects memory accuracy, we conducted three studies exploring unethical amnesia for imagined ethical violations. The first study (N = 228) attempts to directly replicate the only study from Kouchaki and Gino (2016) that includes a measure of memory accuracy. The second study (N = 232) attempts again to replicate these accuracy effects from Kouchaki and Gino (2016), while including several additional variables meant to potentially help in finding the effect. The third study (N = 228) is an attempted conceptual replication using the same paradigm as Kouchaki and Gino (2016), but with a new vignette describing a different moral violation. We did not find an unethical amnesia effect involving memory accuracy in any of our three studies. These results cast doubt upon the claim that memory accuracy is impaired for imagined unethical actions. Suggestions for further ways to study memory for moral and immoral actions are discussed. PMID- 29532401 TI - Hunting with lead ammunition is not sustainable: European perspectives. AB - Much evidence demonstrates the adverse effects of lead ammunition on wildlife, their habitats and human health, and confirms that the use of such ammunition has no place within sustainable hunting. We identify the provisions that define sustainable hunting according to European law and international treaties, together with their guidance documents. We accept the substantial evidence for lead's actual and potential effects on wildlife, habitats and health as persuasive and assess how these effects relate to stated provisions for sustainability and hunting. We evaluate how continued use of lead ammunition negatively affects international efforts to halt loss of biodiversity, sustain wildlife populations and conserve their habitats. We highlight the indiscriminate and avoidable health and welfare impacts for large numbers of exposed wild animals as ethically unsustainable. In societal terms, continued use of lead ammunition undermines public perceptions of hunting. Given the existence of acceptable, non-toxic alternatives for lead ammunition, we conclude that hunting with lead ammunition cannot be justified under established principles of public/international policy and is not sustainable. Changing from lead ammunition to non-toxic alternatives will bring significant nature conservation and human health gains, and from the hunter's perspective will enhance societal acceptance of hunting. Change will create opportunities for improved constructive dialogue between hunting stakeholders and others engaged with enhancing biodiversity and nature conservation objectives. PMID- 29532402 TI - High overlap between traditional ecological knowledge and forest conservation found in the Bolivian Amazon. AB - It has been suggested that traditional ecological knowledge (TEK) may play a key role in forest conservation. However, empirical studies assessing to what extent TEK is associated with forest conservation compared with other variables are rare. Furthermore, to our knowledge, the spatial overlap of TEK and forest conservation has not been evaluated at fine scales. In this paper, we address both issues through a case study with Tsimane' Amerindians in the Bolivian Amazon. We sampled 624 households across 59 villages to estimate TEK and used remote sensing data to assess forest conservation. We ran statistical and spatial analyses to evaluate whether TEK was associated and spatially overlapped with forest conservation at the village level. We find that Tsimane' TEK is significantly and positively associated with forest conservation although acculturation variables bear stronger and negative associations with forest conservation. We also find a very significant spatial overlap between levels of Tsimane' TEK and forest conservation. We discuss the potential reasons underpinning our results, which provide insights that may be useful for informing policies in the realms of development, conservation, and climate. We posit that the protection of indigenous cultural systems is vital and urgent to create more effective policies in such realms. PMID- 29532403 TI - Automated Item Generation with Recurrent Neural Networks. AB - Utilizing technology for automated item generation is not a new idea. However, test items used in commercial testing programs or in research are still predominantly written by humans, in most cases by content experts or professional item writers. Human experts are a limited resource and testing agencies incur high costs in the process of continuous renewal of item banks to sustain testing programs. Using algorithms instead holds the promise of providing unlimited resources for this crucial part of assessment development. The approach presented here deviates in several ways from previous attempts to solve this problem. In the past, automatic item generation relied either on generating clones of narrowly defined item types such as those found in language free intelligence tests (e.g., Raven's progressive matrices) or on an extensive analysis of task components and derivation of schemata to produce items with pre-specified variability that are hoped to have predictable levels of difficulty. It is somewhat unlikely that researchers utilizing these previous approaches would look at the proposed approach with favor; however, recent applications of machine learning show success in solving tasks that seemed impossible for machines not too long ago. The proposed approach uses deep learning to implement probabilistic language models, not unlike what Google brain and Amazon Alexa use for language processing and generation. PMID- 29532404 TI - Missing Data Mechanisms and Homogeneity of Means and Variances-Covariances. AB - Unless data are missing completely at random (MCAR), proper methodology is crucial for the analysis of incomplete data. Consequently, methods for effectively testing the MCAR mechanism become important, and procedures were developed via testing the homogeneity of means and variances-covariances across the observed patterns (e.g., Kim & Bentler in Psychometrika 67:609-624, 2002; Little in J Am Stat Assoc 83:1198-1202, 1988). The current article shows that the population counterparts of the sample means and covariances of a given pattern of the observed data depend on the underlying structure that generates the data, and the normal-distribution-based maximum likelihood estimates for different patterns of the observed sample can converge to the same values even when data are missing at random or missing not at random, although the values may not equal those of the underlying population distribution. The results imply that statistics developed for testing the homogeneity of means and covariances cannot be safely used for testing the MCAR mechanism even when the population distribution is multivariate normal. PMID- 29532405 TI - Robust Measurement via A Fused Latent and Graphical Item Response Theory Model. AB - Item response theory (IRT) plays an important role in psychological and educational measurement. Unlike the classical testing theory, IRT models aggregate the item level information, yielding more accurate measurements. Most IRT models assume local independence, an assumption not likely to be satisfied in practice, especially when the number of items is large. Results in the literature and simulation studies in this paper reveal that misspecifying the local independence assumption may result in inaccurate measurements and differential item functioning. To provide more robust measurements, we propose an integrated approach by adding a graphical component to a multidimensional IRT model that can offset the effect of unknown local dependence. The new model contains a confirmatory latent variable component, which measures the targeted latent traits, and a graphical component, which captures the local dependence. An efficient proximal algorithm is proposed for the parameter estimation and structure learning of the local dependence. This approach can substantially improve the measurement, given no prior information on the local dependence structure. The model can be applied to measure both a unidimensional latent trait and multidimensional latent traits. PMID- 29532406 TI - MicroRNA 196B Regulates HOXA5, HOXB6 and GLTP Expression Levels in Colorectal Cancer Cells. AB - MiRNAs are non-coding RNAs that play important roles in the pathogenesis of human diseases by regulating target gene expression in specific cells or tissues. Previously we identified colorectal cancer (CRC) associated MIR196B, which was specifically up-regulated in CRC cells and tissue. We also identified 18 putative MIR196B target genes by comparing the mRNAs down-regulated in MIR196B overexpressed cells with MIR196B target genes predicted by public bioinformatics tools. In this study, we verified the association between MIR196B and three genes, HOXA5, HOXB6 and GLTP. HOXA5, HOXB6 and GLTP transcripts were directly down-regulated by MIR196B. The mRNA and proteins levels of HOXA5, HOXB6 and GLTP were also down-regulated in CRC cells by the up-regulated MIR196B. GLTP protein expression was decreased in CRC tissues compared to adjacent non-tumor tissues. These results suggest that HOXA5, HOXB6, and GLTP were direct target genes of MIR196B in CRC cells, and that the up-regulated MIR196B in CRC tissue regulates the expression levels of HOXA5, HOXB6, and GLTP during colorectal carcinogenesis. PMID- 29532407 TI - Mutational Analysis of the Mitochondrial DNA Displacement-Loop Region in Human Retinoblastoma with Patient Outcome. AB - Alteration in mitochondrial DNA plays an important role in the development and progression of cancer. The Displacement Loop (D-loop) region of mitochondrial DNA (mtDNA) is the regulatory region for its replication and transcription. Therefore, we aimed to characterize mutations in the D-loop region of mitochondrial DNA along with the morphological changes and analyzed their impact on survival in retinoblastoma patients. mtDNA D-loop region was amplified by Nested-Polymerase Chain Reaction (Nested-PCR) and mutations were analyzed in 60 tumor samples from retinoblastoma patients by DNA sequencing. Transmission electron microscopy was performed on 5 retinoblastoma specimens. Mutations were correlated with clinical, histopathological parameters and patient survival. D loop mutations were found in total of 52/60 (86.6%) patients. The most common mutations were T to C and C to T followed by A to G. There were 5.81% mutations which were not previously reported in the MITOMAP database. A73G (83.33%) were the most frequent mutations found in our cases and it was statistically significant with poor tumor differentiation and age. In addition, this study was further analyzed for morphological changes in retinoblastoma that had disorganized, swollen and less numbers of mitochondria on electron microscopy. This is the first study showing high frequency of mtDNA mutation which might be due to abnormal morphology of mitochondria in retinoblastoma. Our results indicate that pathogenic mtDNA D-loop mutations may be involved in tumorigenesis of retinoblastoma tumor. PMID- 29532408 TI - Inactivating Frameshift Mutations of HACD4 and TCP10L Tumor Suppressor Genes in Colorectal and Gastric Cancers. PMID- 29532409 TI - Protein Expression Analysis in Uterine Cervical Cancer for Potential Targets in Treatment. AB - Specific markers in lesions of the human uterine cervix cancer (UCC) are still needed for prognostic, diagnostic and/or therapeutic purposes. In this study we evaluated key molecules at protein level between normal epithelium, cervical intraepithelial neoplasia (CIN1-3) and invasive cancer of a group of molecules previously reported at mRNA level. For that purpose, human formalin-fixed paraffin embedded tissue microarrays (TMAs) were constructed containing 205 Mexican tissue core specimens. Immunohistochemistry and quantitative analysis of histological staining was performed against twenty-two distinct proteins for each core and the processing platform ImageJ. In the progression of the disease we found key statistical differences for the proteins SEL1, Notch3 and SOCS3. High expressions of SEL1L, Notch3 and SOCS3 have potential value to increase the prognostic of UCC in combination with markers such as p16INK4a. This study identified key drivers in cervical carcinogenesis that should be evaluated for the development of UCC therapies. PMID- 29532410 TI - Intratumoral Heterogeneity for Inactivating Frameshift Mutation of CYB5R2 Gene in Colorectal Cancers. PMID- 29532412 TI - Comparative study of selective in vitro and in silico BACE1 inhibitory potential of glycyrrhizin together with its metabolites, 18alpha- and 18beta-glycyrrhetinic acid, isolated from Hizikia fusiformis. AB - Hizikia fusiformis (Harvey) Okamura is a brown seaweed widely used in Korea and Japan, and it contains different therapeutically active constituents. In the present study, we investigated the activities of glycyrrhizin isolated from H. fusiformis, including its metabolites, 18alpha- and 18beta-glycyrrhetinic acid against Alzheimer's disease (AD) via acetyl and butyrylcholinesterase and beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition. Among these three compounds, 18beta-glycyrrhetinic acid (IC50 = 8.93 +/- 0.69 uM) demonstrated two fold potent activity against BACE1 compared to the positive control, quercetin (IC50 = 20.18 +/- 0.79 uM). Additionally, glycyrrhizin with an IC50 value of 20.12 +/- 1.87 uM showed similarity to quercetin, while 18alpha glycyrrhetinic acid showed moderate activity (IC50 = 104.35 +/- 2.84 uM). A kinetic study revealed that glycyrrhizin and 18beta-glycyrrhetinic acid were non competitive and competitive inhibitiors of BACE1, demonstrated via K i values of 16.92 and 10.91 uM, respectively. Molecular docking simulation studies evidently revealed strong binding energy of these compounds for BACE1, indicating their high affinity and capacity for tighter binding to the active site of the enzyme. These data suggest that glycyrrhizin isolated from the edible seaweed, H. fusiformis and its metabolite, 18beta-glycyrrhetinic acid demonstrated selective inhibitory activity against BACE1 to alleviate AD. PMID- 29532413 TI - Anti-neuroinflammatory effects of tryptanthrin from Polygonum tinctorium Lour. in lipopolysaccharide-stimulated BV2 microglial cells. AB - This study was conducted to isolate the anti-neuroinflammatory component(s) in the 80% EtOH extract of P. tinctoria, and to investigate underlying molecular mechanism of the anti-neuroinflammatory component(s) in LPS-induced BV2 microglial cells. To isolate the active component(s) in the extract, various chromatographic methods were employed, and the structures of the isolated secondary metabolites were determined mainly by analysis of spectroscopic data such as NMR and MS data. Tryptanthrin (1), isolated from P. tinctoria extract, significantly inhibited the protein expression of iNOS and COX-2, and reduced the levels of their products (NO and PGE2) in LPS-stimulated BV2 microglial cells. Tryptanthrin (1) also downregulated the production of pro-inflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta. These anti-neuroinflammatory effects of tryptanthrin (1) was elucidated to be correlated with inactivating NF-kappaB pathway by interrupting the phosphorylation and degradation of the inhibitor of kappaB-alpha protein, and inhibiting the DNA binding activity of NF-kappaB. In addition, tryptanthrin (1) suppressed the activation of p38 MAPK pathway. Furthermore, tryptanthrin (1) inhibited the TLR4 and MyD88 protein expression in LPS-stimulated BV2 microglial cells. Taken together, it was suggested that tryptanthrin (1) have anti-neuroinflammatory effect by regulating TLR4-MyD88 mediated several inflammatory pathways including p38 and NF-kappaB pathways in LPS-induced BV2 microglial cells. PMID- 29532411 TI - Kleine-Levin syndrome: clues to aetiology. AB - Kleine-Levin syndrome (KLS) is the commonest recurrent sleep disorder, with a prevalence of 1-2 per million population. Clear diagnostic criteria are now defined, but effective treatment remains elusive. The significant body of published literature allows consideration of possible aetiological mechanisms, an understanding of which could guide the development of therapeutic strategies. Functional imaging studies have been inconclusive; although diencephalic abnormalities are a common finding, no consistent pattern has emerged, and these studies have not revealed the mechanism(s) underlying the development of the abnormalities detected. An autoimmune aetiology is consistent with the available data. In this review, we argue that, in order to further our understanding of KLS, there needs to be a co-ordinated international effort to standardise approaches to functional imaging studies, genetic analyses that specifically address the possibility of an autoimmune aetiology, and clinical trials of immunosuppressive therapies. PMID- 29532414 TI - Direct-acting oral anticoagulant drug level monitoring in clinical patient management. AB - The role of drug-level monitoring among patients using direct-acting oral anticoagulant (DOAC) is unclear. We aimed to investigate its 'real-life' utilization and effect on clinical management. A review of records of patients who underwent DOAC level testing during 2013-2017. Overall, 212 patients (median age 77 years) underwent 292 DOAC measurements [apixaban (n = 147), rivaroxaban (n = 102), dabigatran (n = 43)]. Monitoring volume increased by 460% during study period. DOAC level testing was performed during routine follow-up in 51 (17.5%) cases, whereas the remaining 241 (82.5%) measurements were performed due to selected clinical circumstances, most commonly: bleeding (n = 60), perioperative status (n = 45), breakthrough thrombosis (n = 37) and renal failure (n = 35). Drug levels were within the expected range in 210 (71.9%), above the expected range in 62 (21.2%) and lower than expected range in 20 (6.8%). In multivariate analysis, older age (P = 0.005), lower glomerular filtration rate (P = 0.001) and lower body mass index (P = 0.006) were associated with DOAC levels above the expected range. Clinical decisions were affected by DOAC monitoring following most (140/241, 58.1%) measurements for which we identified an indication for testing; yet only rarely when monitoring was performed during routine follow-up (7.8%, 4/51) (P < 0.0001). While no benefit of routine DOAC monitoring was observed, drug level measurement has an important role in the management of patients in selected circumstances. Age, body weight and creatinine clearance were found to be significant predictors of drug levels. Future studies are warranted to establish associations between drug levels and outcomes, and better delineate the role of DOAC monitoring. PMID- 29532415 TI - In-vitro GIT Tolerance of Microencapsulated Bifidobacterium bifidum ATCC 35914 Using Polysaccharide-Protein Matrix. AB - Longevity of probiotic is the main concern for getting maximum benefits when added in food product. Bifidobacterium, a probiotic, tends to lose its viability during gastrointestinal track (GIT) transit and storage of food. Their viability can be enhanced through microencapsulation technology. In this study, Bifidobacterium bifidum (B. bifidum) ATCC 35914 was encapsulated by using two experimental plans. In the first plan, chitosan (CH) at 0.6, 0.8, and 1.0% and sodium alginate (SA) at 4, 5, and 6% were used. Based on encapsulation efficiency, 6% sodium alginate and 0.8% chitosan were selected for single coating of the bacteria, and the resulting micro beads were double coated with different concentrations (5, 7.5, and 10%) of whey protein concentrate (WPC) in the second plan. Encapsulation efficiency and GIT tolerance were determined by incubating the micro beads in simulated gastrointestinal juices (SIJ) at variable pH and exposure times, and their release (liberation of bacterial cells) profile was also observed in SIJ. The microencapsulated bacterial cells showed significantly (P < 0.01) higher viability as compared to the unencapsulated (free) cells during GIT assay. The double-coated micro beads SA 6%-WPC 5% and CH 0.8%-WPC 5% were proven to have the higher survival at pH 3.0 after 90 min of incubation time and at pH 7.0 after 3-h exposure in comparison to free cells in simulated conditions of the stomach and intestine, respectively. Moreover, double coating with whey protein concentrate played a significant role in the targeted (106-9 CFU/mL) delivery under simulated intestinal conditions. PMID- 29532416 TI - The Effects of Synbiotic Supplementation on Metabolic Status in Women With Polycystic Ovary Syndrome: a Randomized Double-Blind Clinical Trial. AB - : Data on the effects of synbiotic supplementation on glycemic control, lipid profiles, and atherogenic index of plasma (AIP) of women with polycystic ovary syndrome (PCOS) are limited. The purpose of this study was to assess the effects of synbiotic supplementation on glycemic control and lipid profiles in women with PCOS. A prospective, randomized, double-blind, placebo-controlled trial was done at the Naghavi Hospital affiliated to Kashan University of Medical Sciences, Kashan, Iran, between April 2017 and June 2017. Sixty women with PCOS were randomized to intake synbiotic capsule containing Lactobacillus acidophilus strain T16 (IBRC-M10785), Lactobacillus casei strain T2 (IBRC-M10783), and Bifidobacterium bifidum strain T1 (IBRC-M10771) (2 * 109 CFU/g each) plus 800 mg inulin (n = 30) or placebo (n = 30) for 12 weeks. Fasting blood samples were taken at baseline and after the 12-week intervention to determine related variables. Compared with the placebo, synbiotic supplementation resulted in a significant reduction in serum insulin concentrations (- 2.8 +/- 4.1 vs. + 1.8 +/ 6.4 MUIU/mL, P = 0.002) and homeostasis model of assessment-insulin resistance ( 0.7 +/- 1.0 vs. + 0.4 +/- 1.5, P = 0.002), and a significant elevation in the quantitative insulin sensitivity check index (+ 0.01 +/- 0.01 vs. - 0.01 +/- 0.03, P < 0.001). In addition, significant decreases in serum triglycerides (- 16.2 +/- 31.4 vs. + 5.8 +/- 23.1 mg/dL, P = 0.003), VLDL-cholesterol concentrations (- 3.3 +/- 6.3 vs. + 1.1 +/- 4.6 mg/dL, P = 0.003), and AIP (- 0.05 +/- 0.08 vs. - 0.003 +/- 0.10 mg/dL, P = 0.03) were seen following the supplementation of synbiotic compared with the placebo. Overall, we found that synbiotic supplementation to women with PCOS for 12 weeks had beneficial effects on markers of insulin resistance, triglycerides, VLDL-cholesterol concentrations, and AIP, but did not influence other lipid profiles. TRIAL REGISTRATION: www.irct.ir : IRCT201604015623N71. PMID- 29532417 TI - Simulating the ion permeation and ion selection for a eukaryotic voltage-gated sodium channel NaVPaS. PMID- 29532418 TI - The Psychophysiological Determinants of Pacing Behaviour and Performance During Prolonged Endurance Exercise: A Performance Level and Competition Outcome Comparison. AB - INTRODUCTION: A three-dimensional framework of centrally regulated and goal directed exercise behaviour emphasised the integration of distinct sensory discriminatory, affective-motivational and cognitive-evaluative dimensions that underpin perceived fatigability. This study aimed to capture the complex interdependencies and temporal dynamics in these processes, their interrelations with observed pacing behaviour, performance and biochemical variables as well as their performance level- and competition outcome-dependent variances. METHODS: Twenty-three cyclists of distinct performance level categories engaged in individual and head-to-head competition time trials against a performance-matched opponent. Sensory, affective and cognitive processes were respectively assessed with the constructs perceived physical strain and perceived mental strain, valence and felt arousal underpinning core affect and action crisis characterised by a shift from an implemental to a deliberative mindset. RESULTS: Performance level- and competition outcome-dependent variances and differential temporal dynamics in constructs were associated with alterations in pacing behaviour, performance and physiological disturbance. Perceived physical and mental strain were primarily associated with observed pacing behaviour as necessary to align planned behaviour with current physiological state. Valence and arousal were primarily associated with differential responses in performance regulation. The mindset shift associated with an action crisis was primarily associated with non adaptive, psycho-neuro-endocrinological distress response. CONCLUSION: The proposed constructs are interdependent in a nonlinear dynamic fashion, context dependent, constraint based, distinguishable by well-trained cyclists and interrelated with observed pacing behaviour, performance and physiological disturbance. The proposed framework provides a more comprehensive alternative to the Gestalt concept of perceived exertion and more completely accounts for centrally regulated and goal-directed exercise behaviour. PMID- 29532419 TI - Validation of the Italian Yale Food Addiction Scale in postgraduate university students. AB - PURPOSE: This study was aimed to examine the structural and construct validity of the Italian version of the Yale Food Addiction Scale in a multisite sample of postgraduate students. METHODS: Two hundred and fifty-six subjects (78.1% females) aged from 18 to 53 years (mean = 23.93, SD = 4.96) and attending different postgraduate university programs at multiple Italian universities completed the Italian YFAS, the Italian Binge Eating Scale (BES), the Italian Eating Attitudes Test-26 and the Italian Dutch Eating Behavior Questionnaire (DEBQ) online through Qualtrics. RESULTS: Confirmatory Factor Analysis showed that the single-factor model of the Italian YFAS including all original items had adequate fit indexes (chi2252 = 454.183; p < 0.001; normed chi2 = 1.802; RMSEA = 0.056; 90% CI 0.048-0.076; CFI = 0.761; WRMR = 1.592). However, item analysis revealed that item#25 had zero variance (all subjects were assigned the same score after item dichotomization) and item#24 had a low factor loading, and were thus removed. Furthermore, item#10 and item#11 showed to be almost perfectly correlated (r = 0.998) and were thus parceled. The resulting 19-item single factor model revealed a better fit to the data (chi2152 = 235.69; p < 0.001; normed chi2 = 1.556; RMSEA = 0.046; 90% CI 0.034-0.058; CFI = 0.858; WRMR = 1.236) and its internal consistency was acceptable (KR-20 = 0.72). Also, a single factor model including the seven diagnostic symptoms was tested and showed adequate fit values (chi220 = 41.911; p < 0.003; normed chi2 = 2.09; RMSEA = 0.065; 90% CI 0.037-0.093; CFI = 0.946; WRMR = 1.132). Statistically significant and small-to-high correlations were found with all convergent measures, in particular with the BES. CONCLUSION: The Italian 19-item YFAS resulted to be a valid and reliable tool for the assessment of food addiction in postgraduate students. LEVEL OF EVIDENCE: Level V, descriptive study. PMID- 29532420 TI - Detection of Streptococcus pyogenes virulence genes in Streptococcus dysgalactiae subsp. equisimilis from Vellore, India. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE), belonging to the group C and G streptococci, are human pathogens reported to cause clinical manifestations similar to infections caused by Streptococcus pyogenes. To scrutinize the distribution of gene coding for S. pyogenes virulence factors in SDSE, 255 isolates were collected from humans infected with SDSE in Vellore, a region in southern India, with high incidence of SDSE infections. Initial evaluation indicated SDSE isolates comprising of 82.35% group G and 17.64% group C. A multiplex PCR system was used to detect 21 gene encoding virulence-associated factors of S. pyogenes, like superantigens, DNases, proteinases, and other immune modulatory toxins. As validated by DNA sequencing of the PCR products, sequences homologous to speC, speG, speH, speI, speL, ssa and smeZ of the family of superantigen coding genes and for DNases like sdaD and sdc were detected in the SDSE collection. Furthermore, there was high abundance (48.12% in group G and 86.6% in group C SDSE) of scpA, the gene coding for C5a peptidase in these isolates. Higher abundance of S. pyogenes virulence factor genes was observed in SDSE of Lancefield group C as compared to group G, even though the incidence rates in former were lower. This study not only substantiates detection of S. pyogenes virulence factor genes in whole genome sequenced SDSE but also makes significant contribution towards the understanding of SDSE and its increasing virulence potential. PMID- 29532421 TI - Unusual oral mucosal microbiota after hematopoietic cell transplantation with glycopeptide antibiotics: potential association with pathophysiology of oral mucositis. AB - Severe oral mucositis occurs frequently in patients receiving hematopoietic stem cell transplantation (HCT). Oral mucosal bacteria can be associated with progression of oral mucositis, and systemic infection may occur via ulcerative oral mucositis. However, little information is available regarding the oral microbiota after HCT. Here, PCR-denaturing gradient gel electrophoresis (DGGE) was performed to characterize the oral mucosal microbiota, which can be affected by antibiotics, before and after HCT. Sixty reduced-intensity HCT patients were enrolled. Three patients with the least antibiotic use (quinolone prophylaxis and/or beta-lactam monotherapy group) and three patients with the most antibiotic use (beta-lactam-glycopeptide combination therapy group) were selected. Bacterial DNA samples obtained from the oral mucosa before and after HCT were subjected to PCR-DGGE. The trajectory of oral mucositis was evaluated. The oral mucosal microbiota in the beta-lactam-glycopeptide combination therapy group was different from that in the quinolone prophylaxis and/or beta-lactam monotherapy group, and Staphylococcus spp. and Enterococcus spp. were identified. Lautropia mirabilis was dominant in one patient. Ulcerative oral mucositis was observed only in the beta-lactam-glycopeptide combination therapy group. In conclusion, especially with the use of strong antibiotics, such as glycopeptides, the oral mucosal microbiota differed completely from that under normal conditions and consisted of Staphylococcus spp., Enterococcus spp., and unexpectedly L. mirabilis. The normal oral microbiota consists not only of bacteria, but these unexpected bacteria could be involved in the pathophysiology as well as systemic infection via oral mucositis. Our results can be used as the basis for future studies in larger patient populations. PMID- 29532422 TI - Anatomical variations of the torcular Herophili: macroscopic study and clinical aspects. AB - The anatomical variations of the confluence of sinuses were examined, focusing on the continuity of the superior sagittal sinus (SSS) and the transverse sinuses (TSs). In the 142 specimens studied, there were 72 symmetric cases (50.7%) and 70 asymmetric cases (49.3%). The symmetric group (no dominant type) was categorized into 34 cases of bifurcation (23.9%) and 38 cases of confluence (26.8%). The asymmetric group was categorized into 54 cases of the right-dominant type (38.0%) and 16 cases of the left-dominant type (11.3%). The right-dominant type was further categorized into 38 partially-communicating (26.8%) and 16 non communicating types (11.3%). The left-dominant type was categorized into 11 partially-communicating (7.7%) and 5 non-communicating types (3.5%). In summary, the SSS asymmetrically drained into one TS in about half of the cases studied. The right-dominant type was about three to four times as common as the left dominant type. The draining pattern shown by the asymmetric group could provoke intracranial hypertension due to unilateral jugular vein obstruction. In order to avoid this risk in cases of neck dissection, jugular vein catheterization, or hypercoagulopathy, preoperative evaluations of the dural sinus variations via MR venography, three-dimensional CT, or plain X-ray of the skull are recommended. PMID- 29532423 TI - Body composition and metabolic changes during a 520-day mission simulation to Mars. AB - PURPOSE: The "Mars-500 project" allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. METHODS: The "Mars-500 project" consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27-38 years). RESULTS: During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period (- 9.2 and - 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved (- 47%) 60 days after hatch closure, remaining at this nadir (- 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. CONCLUSIONS: Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement. PMID- 29532424 TI - Topical Niosome Gel Containing an Anthocyanin Complex: a Potential Oral Wound Healing in Rats. AB - Anthocyanins from dietary sources showing potential benefits as anti-inflammatory in oral lesions were developed as an anthocyanin complex (AC), comprised of extracts of Zea mays (CC) and Clitoria ternatea (CT), and formulated into a niosome gel to prove its topical oral wound healing in vitro and in vivo investigations. The AC formed nano-sized clusters of crystalline-like aggregates, occurring through both intra- and inter-molecular interactions, resulting in delivery depots of anthocyanins, following encapsulation in niosomes and incorporation into a mucoadhesive gel. In vitro permeation of anthocyanins was improved by complexation and further enhanced by encapsulation in niosomes. Collagen production in human gingival fibroblasts was promoted by AC and AC niosomes, but not CC or CT. The in vivo wound healing properties of AC gel (1 and 10%), AC niosome gel (1 and 10%), fluocinolone acetonide gel, and placebo gel were investigated for incisional wounds in the buccal cavities of Wistar rats. AC gel and AC niosome gel both reduced wound sizes after 3 days. AC niosome gel (10%) gave the highest reduction in wound sizes after day 3 (compared to fluocinolone acetonide gel, p < 0.05), and resulted in 100% wound healing by day 5. Histological observations of cross-sectioned wound tissues revealed the adverse effects of fluocinolone gel and wound healing potential of AC niosome gel. Topical application of AC niosome gel exhibited an anti-inflammatory effect and promoted oral wound closure in rats, possibly due to the improved mucosal permeability and presence of delivery depots of AC in the niosome gel. PMID- 29532425 TI - Biowaiver or Bioequivalence: Ambiguity in Sildenafil Citrate BCS Classification. AB - The aim of the present study is to contribute to the scientific characterization of sildenafil citrate according to the Biopharmaceutics Classification System, following the World Health Organization (WHO) guidelines for biowaivers. The solubility and intestinal permeability data of sildenafil citrate were collected from literature; however, the experimental solubility studies are inconclusive and its "high permeability" suggests an API in the borderline of BCS Class I and Class II. The pH-solubility profile was determined using the saturation shake flask method over the pH range of 1.2-6.8 at a temperature of 37 degrees C in aqueous media. The intestinal permeability was determined in rat by a closed-loop in situ perfusion method (the Doluisio technique). The solubility of sildenafil citrate is pH-dependent and at pH 6.8 the dose/solubility ratio obtained does not meet the WHO criteria for "high solubility." The high permeability values obtained by in situ intestinal perfusion in rat reinforce the published permeability data for sildenafil citrate. The experimental results obtained and the data available in the literature suggest that sildenafil citrate is clearly a Class II of BCS, according to the current biopharmaceutics classification system and WHO guidance. PMID- 29532426 TI - Lyotropic Liquid Crystalline Nanoparticles of Amphotericin B: Implication of Phytantriol and Glyceryl Monooleate on Bioavailability Enhancement. AB - Implication of different dietary specific lipids such as phytantriol (PT) and glyceryl monooleate (GMO) on enhancing the oral bioavailability of amphotericin B (AmB) was examined. Liquid crystalline nanoparticles (LCNPs) were prepared using hydrotrope method, followed by in vitro characterization, Caco-2 cell monolayer uptake, and in vivo pharmacokinetic and toxicity evaluation. Optimized AmB-LCNPs displayed small particle size (< 210 nm) with a narrow distribution (~ 0.2), sustained drug release and high gastrointestinal stability, and reduced hemolytic toxicity. PLCNPs presented slower release, i.e., ~ 80% as compared to ~ 90% release in case of GLCNPs after 120 h. Significantly higher uptake in Caco-2 monolayer substantiated the role of LCNPs in increasing the intestinal permeability followed by increased drug titer in plasma. Pharmacokinetic studies demonstrated potential of PT in enhancing the bioavailability (approximately sixfold) w.r.t. of its native counterpart with reduced nephrotoxicity as presented by reduced nephrotoxicity biomarkers and histology studies. These studies established usefulness of PLCNPs over GLCNPs and plain drug. It can be concluded that acid-resistant lipid, PT, can be utilized efficiently as an alternate lipid for the preparation of LCNPs to enhance bioavailability and to reduce nephrotoxicity of the drug as compared to other frequently used lipid, i.e., GMO. PMID- 29532427 TI - Development of Domperidone Solid Lipid Nanoparticles: In Vitro and In Vivo Characterization. AB - Domperidone (DOP) is extensively applied orally in the management of nausea and vomiting. Upon oral administration, its bioavailability is very poor due to its poor solubility in alkaline media. Therefore, the aim of this work was to investigate DOP-loaded solid lipid nanoparticles (DOP-SLNs) in order to sustain its release pattern and to enhance oral bioavailability. DOP-SLNs were prepared using four different lipids. Prepared DOP-SLNs were characterized for "polydispersity index (PDI), particle size, zeta potential, % entrapment efficiency (% EE), and drug release behavior." Differential scanning calorimetry (DSC) study was carried out to illustrate the physical form of DOP and excipients. The morphology of DOP-SLNs was confirmed by scanning electron microscopy (SEM). Pharmacokinetic study on optimized DOP-SLN in comparison to tablet was performed in rats. The "particle size, PDI, zeta potential, and % EE" of optimized formulation (F5) were recorded as 201.4 nm, 0.071, - 6.2 mV, and 66.3%, respectively. DSC thermograms suggested amorphous state of DOP in various SLNs. Surface morphology of SLNs using SEM suggested spherical shape of the nanoparticles within nanometer size range. In vitro release studies confirmed that all SLN formulations possessed a sustained release over a period of 12 h (51.3% from optimized formulation) in comparison with immediate release from conventional tablets (100% after 90 min). Pharmacokinetic study showed significant enhancement in oral absorption of DOP from optimized SLN in comparison with DOP tablet. The enhancement in relative bioavailability of DOP from optimized SLN was 2.62-fold in comparison with DOP tablet. PMID- 29532428 TI - TRPC1 Deficiency Impairs the Endothelial Progenitor Cell Function via Inhibition of Calmodulin/eNOS Pathway. AB - Endothelial progenitor cells (EPCs) promote angiogenesis and play a pivotal role in endothelial repair and re-endothelialization after vascular injury. Transient receptor potential-canonical1 (TRPC1) has been recently implied to play important roles on EPC function. Here, we studied the role of TRPC1 in regulating EPC function in vivo and in vitro. EPCs were cultured from TRPC1-knockout mice and their controls. In vitro, TRPC1 knockout reduced EPC functional activities, including migration and tube formation. Additionally, calmodulin (CaM)/endothelial nitric oxide synthase (eNOS) signaling activity were downregulated after TRPC1 knockout. Administration of CaM or eNOS inhibitor ameliorated TRPC1 knockout-reduced EPC migration and tube formation. In vivo Matrigel plug assay confirmed that TRPC1 knockout decreased formation of functional blood vessels of EPCs compared with wild-type EPCs. Taken together, these data suggest that TRPC1 is a critical regulator of angiogenesis. PMID- 29532429 TI - A new computational model for the prediction of toxicity of phosphonate derivatives using QSPR. AB - Structural and electronic properties of a series of 25 phosphonate derivatives were analyzed applying density functional theory, with the exchange-correlation functional PBEPBE in combination with the 6-311++G** basis set for all atoms. The chemical reactivity of these derivatives has been interpreted using quantum descriptors such as frontier molecular orbitals (HOMO, LUMO), Hirshfeld charges, molecular electrostatic potential, and the dual descriptor [[Formula: see text]]. These descriptors are directly related to experimental median lethal dose ([Formula: see text], expressed as its decimal logarithm [[Formula: see text]([Formula: see text]] through a multiple linear regression equation. The proposed model predicts the toxicity of phosphonates in function of the volume (V), the load of the most electronegative atom of the molecule (q), and the eigenvalue of the molecular orbital HOMO ([Formula: see text]. The obtained values in the internal validation of the model are: [Formula: see text]%, [Formula: see text]%, [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]%. The toxicity of nine phosphonate derivatives used as test molecules was adequately predicted by the model. The theoretical results indicate that the oxygen atom of the O=P group plays an important role in the interaction mechanism between the phosphonate and the acetylcholinesterase enzyme, inhibiting the removal of the proton of the ser-200 residue by the his-440 residue. PMID- 29532431 TI - Psychiatric Agnosticism and the Pedagogical Problem of Learning Psychiatry as a Medical Student. PMID- 29532430 TI - Complete evaluation of pituitary tumours in a single tertiary care institution. AB - INTRODUCTION: We retrospectively evaluated all patients with pituitary tumours treated in our department from 1/1/1997 to 01/11/2014. PATIENTS AND METHODS: Two hundred and fifteen patients (124 females, 91 males, mean age 50.9 years) were treated because of pituitary tumours. All patients underwent basal hormonal analysis and when required dynamic testing in order to check for hormonal activity. Pituitary masses were divided into groups concerning their hormonal status and were further classified according to gender, age at diagnosis, tumour size, and the development of postoperative pituitary insufficiency when neurosurgical intervention was conducted. RESULTS: One hundred and twenty-one patients had hormonally inactive tumours (non-functional adenomas; 56.3%), 57 prolactinomas (26.5%), 17 growth hormone secreting adenomas (7.9%), 16 Cushing's disease (7.4%), and 4 craniopharyngiomas (1.9%). Tumours with maximum size <1 cm (microadenomas) were detected in 62 patients (28.8%) and >=1 cm (macroadenomas) in 153 (71.2%) of all cases (rate 1:2.5). Ninty eight patients (45.6%) had surgery (87 transsphenoidal and 11 transcranial), of this group 34 with hormonally active tumours (37.8% of the 90 patients of this subcohort). Indications for surgery were an increased risk or manifestation of chiasma syndrome and clinical symptoms due to hormonal hypersecretion. Complete [32 cases (32.6%)] or partial [33 cases (33.7%)] postoperative insufficiency in minimum one pituitary axis was present in 65/98 (66.3%) of the operated patients. CONCLUSIONS: Pituitary adenoma prevalence is rising due to widely available imaging procedures. The majority of the tumours in our cohort were macroadenomas and hormonally inactive. Tumour extirpation via the transsphenoidal or transcranial route resulted in functional pituitary impairment of variable extent in 2/3 of the patients. PMID- 29532432 TI - The Ranting of Mr. Schafer: Finding Meaning in Life. PMID- 29532433 TI - Using Group Psychotherapy Skills for Small Group Teaching. PMID- 29532434 TI - A rare cause of chronic ataxia in childhood: ganglioneuroma. PMID- 29532435 TI - Calcineurin inhibitors and nephrotoxicity in children. AB - BACKGROUND: Calcineurin inhibitors (CNIs) are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders, such as steroid-resistant nephrotic syndrome, steroid-dependent nephrotic syndrome, and frequent relapse nephrotic syndrome. Although CNIs remain the most effective available immunosuppressant agent, there is clinical concern regarding possible long-term nephrotoxicity. This concern is especially significant in children who have a longer life expectancy and greater growth rate. DATA SOURCES: In this review, we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity. PubMed, Elsevier, and Tompson ISI Web of Knowledge were searched for identifying relevant papers. RESULTS: Clinical research supports the presence of CNI-related nephrotoxicity. However, some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity, especially because the pathological lesions typically associated with long-term CNI use are nonspecific. Many researchers have focused on early markers of CNI nephrotoxicity, and the methods that may help prevent and manage nephrotoxicity. CONCLUSIONS: Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy, and developing alternative treatments. CNI-mediated nephrotoxicity should always be taken seriously in clinic. PMID- 29532436 TI - Serial evaluation of myocardial function using the myocardial performance index in Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is known as systemic vasculitis, and more than half of the patients with KD have myocarditis, which can induce ventricular dysfunction. In this study, we evaluate left ventricular (LV) dysfunction in patients with KD based on the myocardial performance index (MPI) using pulse Doppler (PD) and tissue Doppler imaging (TDI), from the acute to convalescent phases. METHODS: We retrospectively studied 89 children diagnosed with KD from January 2010 to August 2012. We assessed the presence of coronary artery lesions (CALs) and the LV ejection fraction, PD-MPI, and TDI-MPI at diagnosis, and 2, 14, and 56 days after intravenous immunoglobulin (IVIG) treatment. We enrolled 70 healthy children as a control group. RESULTS: The ejection fraction in patients with KD at diagnosis (67.3 +/- 0.9%) was lower than that in the control group (69.8 +/- 0.8%, P = 0.035), and the LV TDI-MPIs for patients with KD at diagnosis (0.49 +/- 0.01) and 2 days after IVIG treatment (0.48 +/- 0.01) were higher than those in the control group (0.45 +/- 0.01, P = 0.002, P = 0.033, respectively). No significant differences were found in the LV dysfunction between the patients with complete and incomplete KD. Septal TDI-MPIs in patients with KD with CAL at diagnosis (0.52 +/- 0.02) were higher than those in patients with KD without CAL (0.47 +/- 0.01, P = 0.019). CONCLUSIONS: Transient LV dysfunction occurred in patients with complete and incomplete KD in the acute stage. In patients with KD with CAL at diagnosis, the LV dysfunction was more prominent. The PD-MPI and TDI MPI are useful parameters for assessing LV function in patients with KD. PMID- 29532438 TI - Ferric Carboxymaltose: A Review in Iron Deficiency. AB - Intravenous ferric carboxymaltose (Ferinject(r); Injectafer(r)) is a colloidal solution of nanoparticles which consist of a polynuclear iron (III) (oxyhydr)oxide core stabilized by carboxymaltose and may be given as a single high-dose, 15-min infusion. This article reviews the clinical use of ferric carboxymaltose in various patient populations with iron deficiency (ID) [+/- anaemia] and briefly summarizes its pharmacological properties. Based on extensive experience in the clinical trial and real-world settings, ferric carboxymaltose is an effective and generally well tolerated treatment for rapidly replenishing iron stores and correcting anaemia in patients with ID (+/- anaemia) of various aetiologies, including patients with chronic heart failure (CHF), chronic kidney disease, inflammatory bowel disease or perioperative anaemia, and women with ID during pregnancy, postpartum or associated with heavy uterine bleeding. As it may be given as a single high-dose infusion, ferric carboxymaltose has the potential to provide cost savings from a healthpayer perspective. Thus, ferric carboxymaltose remains an important option for the treatment of ID in adults and, where approved, children aged >= 14 years, when oral iron preparations are ineffective or cannot be used. PMID- 29532437 TI - "I Love Fruit But I Can't Afford It": Using Participatory Action Research to Develop Community-Based Initiatives to Mitigate Challenges to Chronic Disease Management in an African American Community Living in Public Housing. AB - As chronic conditions are on the rise in the USA, management initiatives outside of the inpatient setting should be explored to reduce associated cost and access disparities. Chronic conditions disproportionately affect African American public housing residents due to the effects of historical marginalization on the manifestation of economic and social problems exacerbating health disparities and outcomes. Informed by participatory research action tenets, this study focused on identifying the challenges to management of chronic conditions and developing community-envisioned initiatives to address these challenges in a predominantly African American public housing community. Two focus groups were conducted with former and current public housing residents and were analyzed using inductive content analysis. Physical activity, the cost associated with healthy eating, and lack of information were noted as challenges to chronic disease management. Initiatives discussed were the formation of a walking partner's program to promote physical activity, a shopper's club to exchange coupons and learn how to prepare healthy meals, and a natural remedy's book to share information intergenerationally about management tactics. Challenges identified existed predominantly on the individual and the system level, while the initiatives generated target engaging interpersonal and community relationships. These community-envisioned approaches should be explored to facilitate chronic disease management in public housing neighborhoods. PMID- 29532439 TI - OnabotulinumtoxinA: A Review in the Prevention of Chronic Migraine. AB - An intramuscular formulation of onabotulinumtoxinA (onabotA; Botox(r)) is currently the only therapy specifically approved for the prevention of headaches in adults with chronic migraine (CM) in the EU and North America. This article provides a narrative review of relevant data on the drug in this indication from an EU perspective. OnabotA was originally approved on the basis of pooled data from two phase III studies (PREEMPT 1 and 2). In these pivotal studies, injection of up to five cycles of onabotA (155-195 U/cycle) at 12-week intervals was generally well tolerated and effective in producing statistically significant and clinically meaningful improvements in headache symptoms, acute headache pain medication usage, headache impact and health-related quality of life in adults with CM, of whom approximately two-thirds were acute medication overusers and approximately one-third had failed to respond to >= 3 prior oral prophylactic therapies. More recently, the efficacy and tolerability of onabotA over a period of 1 year in the PREEMPT programme has been substantiated and extended by the results of a long-term phase IV study (COMPEL), in which patients received up to nine treatment cycles over a period of 2 years, and by findings from several real world clinical practice studies from Europe, including the prospective multinational REPOSE and CM-PASS studies. In conclusion, the totality of evidence from clinical trials and real-world studies indicates that onabotA is an effective and generally well tolerated option for the prevention of CM that may be particularly useful for patients who have previously failed to respond to or are intolerant of commonly prescribed oral prophylactics. PMID- 29532440 TI - Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson's Disease. AB - BACKGROUND: Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. OBJECTIVE: In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. PATIENTS AND METHODS: The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. RESULTS: At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was - 17.7 (standard error [SE] 1.3) vs. - 7.6 (1.3) points, respectively (- 10.1 points, 95% confidence interval [CI] - 13.8, - 6.5; p < 0.0001). The relative treatment difference between groups was 27.3% (p < 0.0001). At 12 weeks, the LS mean change in OFF time was - 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of - 1.00 h/day (95% CI - 1.57, - 0.44; p = 0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS 5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. CONCLUSIONS: These analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766. PMID- 29532442 TI - Vernet syndrome resulting from varicella zoster virus infection-a very rare clinical presentation of a common viral infection. AB - Vernet syndrome is a unilateral palsy of glossopharyngeal, vagus, and accessory nerves. Varicella zoster virus (VZV) infection has rarely been described as a possible cause. A 76-year-old man presented with 1-week-long symptoms of dysphonia, dysphagia, and weakness of the right shoulder elevation, accompanied by a mild right temporal parietal headache with radiation to the ipsilateral ear. Physical examination showed signs compatible with a right XI, X, and XI cranial nerves involvement and also several vesicular lesions in the right ear's concha. He had a personal history of poliomyelitis and chickenpox. Laringoscopy demonstrated right vocal cord palsy. Brain MRI showed thickening and enhancement of right lower cranial nerves and an enhancing nodular lesion in the ipsilateral jugular foramen, in T1 weighted images with gadolinium. Cerebrospinal fluid (CSF) analysis disclosed a mild lymphocytic pleocytosis and absence of VZV-DNA by PCR analysis. Serum VZV IgM and IgG antibodies were positive. The patient had a noticeable clinical improvement after initiation of acyclovir and prednisolone therapy. The presentation of a VZV infection with isolated IX, X, and XI cranial nerves palsy is extremely rare. In our case, the diagnosis of Vernet syndrome as a result of VZV infection was made essentially from clinical findings and supported by analytical and imaging data. PMID- 29532441 TI - Self-complementary circular codes in coding theory. AB - Self-complementary circular codes are involved in pairing genetic processes. A maximal [Formula: see text] self-complementary circular code X of trinucleotides was identified in genes of bacteria, archaea, eukaryotes, plasmids and viruses (Michel in Life 7(20):1-16 2017, J Theor Biol 380:156-177, 2015; Arques and Michel in J Theor Biol 182:45-58 1996). In this paper, self-complementary circular codes are investigated using the graph theory approach recently formulated in Fimmel et al. (Philos Trans R Soc A 374:20150058, 2016). A directed graph [Formula: see text] associated with any code X mirrors the properties of the code. In the present paper, we demonstrate a necessary condition for the self complementarity of an arbitrary code X in terms of the graph theory. The same condition has been proven to be sufficient for codes which are circular and of large size [Formula: see text] trinucleotides, in particular for maximal circular codes ([Formula: see text] trinucleotides). For codes of small-size [Formula: see text] trinucleotides, some very rare counterexamples have been constructed. Furthermore, the length and the structure of the longest paths in the graphs associated with the self-complementary circular codes are investigated. It has been proven that the longest paths in such graphs determine the reading frame for the self-complementary circular codes. By applying this result, the reading frame in any arbitrary sequence of trinucleotides is retrieved after at most 15 nucleotides, i.e., 5 consecutive trinucleotides, from the circular code X identified in genes. Thus, an X motif of a length of at least 15 nucleotides in an arbitrary sequence of trinucleotides (not necessarily all of them belonging to X) uniquely defines the reading (correct) frame, an important criterion for analyzing the X motifs in genes in the future. PMID- 29532443 TI - HTLV-1 myelopathy after renal transplant and antiviral prophylaxis: the need for screening. AB - The human T-lymphotropic virus type 1 (HTLV-1) is a RNA retrovirus that infects a minimum of 5-10 million people worldwide. Transmission by cell-containing blood products and solid organ transplantation has been reported. Clinical disease occurs in about 5-10% of infected individuals and consists mainly in adult T cell leukemia and HTLV-1-associated myelopathy (HAM). We present a 54-year-old woman who underwent kidney transplant from cadaveric donor in March 2015. Donor also underwent cornea extraction for another recipient (corneal transplant protocol includes HTLV-1/2 serology). Twenty-four hours after completion of kidney transplant donor, HTLV-1 serology was revealed positive. Following experts' recommendations, once donor seropositivity was demonstrated, antiviral prophylaxis including zidovudine and raltegravir was initially given to our patient, in spite of which the patient developed HAM. Once the diagnosis of HAM was established, antiretroviral therapy was restarted, and intravenous pulses of methylprednisolone were periodically administered with transient initial improvement. Later on, the patient experienced neurological deterioration becoming wheelchair dependent. Since the occurrence of this case, HTLV-1 screening has become mandatory for solid organ transplantation in the Spanish province of Navarra, and the same should happen worldwide. PMID- 29532444 TI - Metabolic Enhancer Piracetam Attenuates the Translocation of Mitochondrion Specific Proteins of Caspase-Independent Pathway, Poly [ADP-Ribose] Polymerase 1 Up-regulation and Oxidative DNA Fragmentation. AB - Piracetam, a nootropic drug, has been clinically used for decades; however, its mechanism of action still remains enigmatic. The present study was undertaken to evaluate the role of mitochondrion-specific factors of caspase-independent pathway like apoptotic-inducing factor (AIF) and endonuclease-G (endo-G) in piracetam-induced neuroprotection. N2A cells treated with lipopolysaccharide (LPS) exhibited significant cytotoxicity, impaired mitochondrial activity, and reactive oxygen species generation which was significantly attenuated with piracetam co-treatment. Cells co-treated with LPS and piracetam exhibited significant uptake of piracetam in comparison to only piracetam-treated cells as estimated by liquid chromatography-mass spectrometry (LC-MSMS). LPS treatment caused significant translocation of AIF and endonuclease-G in neuronal N2A cells which were significantly attenuated with piracetam co-treatment. Significant over expression of proinflammatory cytokines was also observed after treatment of LPS to cells which was inhibited with piracetam co-treatment demonstrating its anti inflammatory property. LPS-treated cells exhibited significant oxidative DNA fragmentation and poly [ADP-ribose] polymerase-1 (PARP-1) up-regulation in nucleus, both of which were attenuated with piracetam treatment. Antioxidant melatonin but not z-VAD offered the inhibited LPS-induced DNA fragmentation indicating the involvement of oxidative DNA fragmentation. Further, we did not observe the altered caspase-3 level after LPS treatment initially while at a later time point, significantly augmented level of caspase-3 was observed which was not inhibited with piracetam treatment. In total, our findings indicate the interference of piracetam in mitochondrion-mediated caspase-independent pathway, as well as its anti-inflammatory and antioxidative properties. Graphical Abstract Graphical abstract indicating the novel interference of metabolic enhancer piracetam (P) in neuronal death mechanisms. PMID- 29532446 TI - A consumer-grade LCD monitor for precise visual stimulation. AB - Because they were used for decades to present visual stimuli in psychophysical and psychophysiological studies, cathode ray tubes (CRTs) used to be the gold standard for stimulus presentation in vision research. Recently, as CRTs have become increasingly rare in the market, researchers have started using various types of liquid-crystal display (LCD) monitors as a replacement for CRTs. However, LCDs are typically not cost-effective when used in vision research and often cannot reach the full capacity of a high refresh rate. In this study we measured the temporal and spatial characteristics of a consumer-grade LCD, and the results suggested that a consumer-grade LCD can successfully meet all the technical demands in vision research. The tested LCD, working in a flash style like that of CRTs, demonstrated perfect consistency for initial latencies across locations, yet showed poor spatial uniformity and sluggishness in reaching the requested luminance within the first frame. After these drawbacks were addressed through software corrections, the candidate monitor showed performance comparable or superior to that of CRTs in terms of both spatial and temporal homogeneity. The proposed solution can be used as a replacement for CRTs in vision research. PMID- 29532445 TI - Combinatorial Preconditioning of Rat Brain Cultures with Subprotective Ethanol and Resveratrol Concentrations Promotes Synergistic Neuroprotection. AB - Preconditioning brain cultures with moderate concentrations of ethanol (EtOH) or trans-resveratrol (RES), key red wine constituents, can prevent amyloid-beta (Abeta) neurotoxicity. Past studies have indicated that moderate EtOH activates synaptic N-methyl-D-aspartate receptors (NMDAR) that, in part, signal via protein kinase C (PKC) to increase protective antioxidant proteins such as peroxiredoxin 2 (Prx2). RES preconditioning also is reported to involve NMDAR and PKC. However, although moderate, the EtOH and RES concentrations used have been noticeably above circulating levels from two glasses of wine, a daily intake linked to reduced risk of cognitive decline among older social drinkers. Given their mechanistic parallels, we speculated that subprotective EtOH and RES concentrations in a combinatorial preconditioning paradigm might elicit synergistic neuroprotection. To examine this notion, rat cerebellar cultures were pretreated with 10 mM EtOH (circulating concentration after ~ 2 drinks), 5 MUM RES, EtOH + RES combinatorially, or media alone (controls). After 3 days, media were removed, and fresh media aliquots containing Abeta25-35 (25 MUM) were added. Assessing apoptosis 24 h later with Hoescht 33342, neurodegeneration did not differ from controls in cultures separately preconditioned with 10 mM EtOH or 5 MUM RES. However, apoptosis was prevented in combinatorially preconditioned cultures. Also, immunoblotting revealed elevated Prx2 levels due to combinatorial pretreatment that correlated with subsequent neuroprotection, whereas Prx2 was unchanged in separately pretreated cultures. Although the protective mechanisms require clarification, synergistically upregulated NMDAR-PKC-Prx2 (and other antioxidant proteins) is a reasonable component. These findings imply that EtOH + RES antioxidant synergy could be involved in neurobenefits attributed to low moderate wine consumption. PMID- 29532447 TI - Passalidae (Coleoptera: Scarabaeoidea) of the Biogeographical Province of Choco and the West Andean Region of Colombia, with the Description of Two New Species. AB - We present a synopsis of the Passalidae of the Choco biogeographical province and the western slopes of the Western Andean range of Colombia as a result of field collections, examination of entomological collections, and review of the literature. We record a total of 41 species, provide an identification key, and, for the 39 species for which we were able to examine specimens, include a diagnosis and collecting data. Two new species of Passalus (Pertinax) are described and illustrated. The species of this region compose 42% of the passalid species known for Colombia. The richness of species and the high degree of endemism (34%) indicate the faunistic importance of this area, which is closely related to the fauna of lowland Central America. PMID- 29532448 TI - A Transpatellar Approach to Treat Distal Femoral Type C3 Fractures Combined with Patellar Fractures. AB - We report our surgical method used to treat type C distal femur fractures accompanied by patella fractures whereby we approach the articular surface of the femur through the already-fractured patella. We treated 10 patients with type C3 distal femur and patella fractures between May 2013 and April 2015. Because the patella was fractured in all cases, we could approach the articular surface of the distal femur through the transverse gap between the retracted patellar fracture fragments, "transpatellar approach." Any surgical complications were recorded. Knee function was evaluated using the Bostman system. The average age of the 10 patients (8 males) was 42.9 years (range, 22.0-58.0 years). All distal femur fractures were type C3, combined with patella fractures. Bony union of the distal femur and patella was achieved in all but one patient, who required an additional bone graft (without any change in the implant). Overall, three patients (30%) reported excellent results and seven (70%) reported good results, based on the Bostman system. A midline anterior approach through a patella fracture adequately exposes the entire joint surface of the distal femur, except the posterior surface. This approach is useful when treating a type C distal femur fracture accompanied by a patella fracture. The level of evidence is IV. PMID- 29532449 TI - Polyethylene on Cement Spacers: An Economic Approach to an Effective Infection Eradication in a Two-Stage Knee Revision Articulating Spacers. AB - Although two-stage revision surgery is generally considered as the gold standard treatment for periprosthetic joint infection (PJI) after total knee arthroplasty, the procedure is limited by the costs of commercially preformed spacers used for treatment. In this work, we aim to report a modified approach by which the cost of the spacer could be significantly reduced without compromising eradication of infection. Between 2010 and 2016, we performed a total of 11 two-stage revision arthroplasties using a surgically handmade spacer with a new polyethylene insert. Patients were aged 59 to 80 years old (mean 69.9 years), with a range of motion (ROM) between 20 degrees and 65 degrees on the affected knee (mean 46.4 degrees ) before the first-stage revision surgery. During the perioperative and postoperative period, functional and clinical evaluation of the patients were performed, including the determination of their articular ROM, Knee Society Knee Scores (KSKS), and Knee Society Function Scores (KSFS). All patients were followed up for an average of 2 years, ranging from 1 to 4 years. After the second-stage revision surgery, the mean ROM was increased by 46.8 degrees (46.4 degrees -93.2 degrees ) after the second-stage revision. KSKS and KSFS scores were recorded to increase by an average of 44.5 degrees (range 40.4 degrees 84.9 degrees ) and 46.9 degrees (range 38.5 degrees -85.4 degrees ), respectively. All 11 patients underwent a successful two-stage revision surgery, and no evidence of postsurgical infection was found during patient follow-up examination. Our results show that this personalized handmade antibiotic-loaded articulating spacer is cost-effective and efficacious. PMID- 29532450 TI - Associations of Measured Protein and Energy Intakes with Growth and Adiposity in Human Milk-Fed Preterm Infants at Term Postmenstrual Age: A Cohort Study. AB - OBJECTIVE: To determine the associations of measured protein, energy, and protein-to-energy (PER) intakes with body composition in human milk (HM)-fed preterm infants. STUDY DESIGN: Neonates born at < 33 gestational weeks were eligible. Standard fortification method with modular supplements was used and the HM composition was measured. The weight gain velocity was calculated, and body composition was assessed by air displacement plethysmography at 40 weeks' postmenstrual age (PMA). The fat mass percentage and fat mass index were used as indicators of adiposity, with convenience cut-offs <= -1 and >= + 1 z-scores for low and high adiposity, respectively. RESULTS: Thirty-three infants were included (median [interquartile range] gestational age: 30 [28-31] weeks; birth weight: 1.175 [1.010-1.408] g); 36.4 and 84.8% did not receive the minimum recommended protein and energy intakes, respectively. Weight gain velocity showed positive weak-to-moderate correlations with nutrient intakes. Overall, no correlations between nutrient intakes and body composition were found. Infants with lower adiposity received lower energy, protein, and PER intakes, while those with higher adiposity received lower energy intake but higher PER intake. CONCLUSION: Overall, no correlations of nutrient intakes with body composition were found; however, differences in nutrient intakes were found between infants with lower and higher adiposity at term PMA. PMID- 29532451 TI - Postpartum Thromboembolism Prophylaxis during Delivery Hospitalizations. AB - OBJECTIVE: This article evaluates trends in venous thromboembolism (VTE) prophylaxis during delivery hospitalizations in the United States. METHODS: We utilized an administrative database to determine if women hospitalized for vaginal or cesarean delivery received pharmacologic VTE prophylaxis, mechanical VTE prophylaxis, or both from January 2011 through March 2015. Mechanical prophylaxis included sequential compression devices, graduated compression stockings, and other pneumatic devices. Pharmacologic prophylaxis included unfractionated heparin, low molecular weight heparin, or fondaparinux. Probability of use of thromboprophylaxis for individual hospitals was estimated in an adjusted model. RESULTS: A total of 956,428 women who underwent cesarean and 1,914,142 women who underwent vaginal delivery were included in the analysis. Cesarean VTE prophylaxis declined between 2011 (50.3%) and 2015 (47.7%; p < 0.01). Of women undergoing vaginal delivery, 2.9% received prophylaxis. Delivery hospital was an important determinant of cesarean prophylaxis: in the adjusted model, one-third of hospitals used prophylaxis for less than 20% of deliveries, one-third of hospitals used prophylaxis for 20 to 80% of deliveries, and the final third of hospitals used prophylaxis in greater than 80% of deliveries. CONCLUSION: While many hospitals appear to be following best clinical practices, some do not provide routine cesarean VTE prophylaxis. Minimizing care quality variation may improve maternal safety. PMID- 29532452 TI - Hepcidin, an Iron Regulatory Hormone of Innate Immunity, is Differentially Expressed in Premature Fetuses with Early-Onset Neonatal Sepsis. AB - OBJECTIVE: Hepcidin, a mediator of innate immunity, binds the iron exporter ferroportin, leading to functional hypoferremia through intracellular iron sequestration. We explored hepcidin-ferroportin interactions in neonates clinically diagnosed with early-onset neonatal sepsis (EONS). STUDY DESIGN: Hepcidin and interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay (ELISA) in 92 paired cord blood-maternal blood samples in the following groups: "Yes" EONS (n = 41, gestational age [GA] 29 +/- 1 weeks) and "No" EONS (n = 51, GA 26 +/- 1 weeks). Placental hepcidin and ferroportin expression were evaluated by immunohistochemistry and real-time-polymerase chain reaction (RT PCR). Liver hepcidin and ferroportin expression patterns were ascertained in autopsy specimens of neonates (n = 8) who died secondary to culture-proven sepsis. RESULTS: Cord blood hepcidin was significantly elevated (GA corrected, p = 0.018) and was positively correlated with IL-6 (r = 0.379, p = 0.001) in EONS. Hepcidin localized at syncytiotrophoblast and fetal vascular endothelium. Placental ferroportin, but not hepcidin mRNA correlated with cord blood hepcidin levels (r = 0.46, p = 0.039) and funisitis severity (r = 0.50, p = 0.018). Newborns who died from sepsis (n = 4) had higher hepatic hepcidin and iron sequestration, but lower ferroportin staining than those who died of nonsepsis causes (n = 4). CONCLUSION: Premature fetuses with EONS have elevated circulating hepcidin, likely related to lower placenta and liver ferroportin expression. Fetal hepcidin-ferroportin interaction appears to play a role in EONS pathophysiology independent of maternal response to intrauterine inflammation. PMID- 29532453 TI - The Association of Metabolic Dysfunction with Breastfeeding Outcomes in Gestational Diabetes. AB - OBJECTIVE: To evaluate the relationship between prenatal metabolic markers and breastfeeding outcomes in women with gestational diabetes mellitus (GDM). STUDY DESIGN: Secondary analysis of a cluster-randomized trial of a lifestyle intervention to improve metabolic health among women with GDM. Women were enrolled between 22 and 36 weeks' gestation and followed through 10 months postpartum. Metabolic markers were measured at enrollment. Women reported when they stopped breastfeeding, whether they breastfed as long as desired, and when they introduced formula. We evaluated the association of tertiles of metabolic markers with undesired weaning and time to breastfeeding cessation using Cox proportional hazards models and Mantel-Haenszel chi-square tests, respectively. RESULTS: Eighty-two women were eligible for analysis. There was a statistically significant difference in time to breastfeeding cessation among tertiles of fasting glucose, hemoglobin A1c (A1c), body mass index (BMI), and skinfolds (all p < 0.05). Women with higher fasting glucose, BMI, or skinfolds were also more likely to report undesired weaning; women with higher fasting glucose introduced formula earlier. CONCLUSION: Higher fasting glucose, A1c, BMI, and subscapular skinfolds were associated with earlier breastfeeding cessation in women with GDM. These markers may identify mothers in need of enhanced postpartum support to achieve their breastfeeding goals. PMID- 29532454 TI - Impact of Short Bowel Syndrome on Quality of Life and Family: The Patient's Perspective. AB - BACKGROUND: Short bowel syndrome (SBS) has an impact on children and their families not only physically, but also emotionally, mentally, and socially. This study aimed to evaluate quality of life and family impact in patients with SBS, using the Pediatric Quality of Life Inventory (PedsQL) measurement model. MATERIALS AND METHODS: PedsQL questionnaires were administered to patients with SBS followed at the Pediatric Surgery of Royal Manchester Children's Hospital. The scores were compared between two groups differing in age (children <5 y vs. >5 y) and with known-groups from literature published by Varni et al. RESULTS: Forty-three patients were sent the questionnaires, and 30 (70%, 17 < 5 and 13 > 5) responded. Family Impact Module failed to distinguish between families of children younger and older than 5 years of age. In contrast, it distinguished between families with SBS children and the ones with children in a long-term care facility. Healthcare satisfaction was worse in families of children over 5 years regarding information received, inclusion of the family, and communication. When compared with normal population, SBS children scored worse on Generic Core Scales for all domains except for emotional functioning. CONCLUSION: Although advances have been made on the treatment of children with SBS, and improvements have been reached on home PN, this condition is still significantly affecting the quality of life of children and their families. The future quality control of medical care must have greater focus on psychosocial and emotional functioning, aiming for the best possible quality of life. PMID- 29532455 TI - A Study of Coagulation Changes at Early Stage after Total Knee Arthroplasty. AB - Coagulation changes after total knee arthroplasty (TKA) can provide evidence for optimization of timing of perioperative anticoagulation medicine. To evaluate the changes, 50 patients with knee osteoarthritis or rheumatoid arthritis were recruited for the study and underwent thrombelastography tests pre-, 6 hours, 12 hours, and 24 hours after TKA surgery and Doppler ultrasound examination 20 to 24 hours after surgery. The results have shown prolonged clotting time (R value) at 6 and 12 hours, while shortened at 24 hours. Similar results have been found in combined clotting and coagulation time (R + K value). However, other parameters, such as coagulation time (K value), coagulation speed (alpha angle), maximum amplitude (MA), and coagulation index (CI), have not significantly changed except that CI has increased significantly at 24 hours. Further Doppler ultrasound examination did not detect any deep venous thrombosis in all patients. The data showed that coagulation time after TKA within 12 hours, especially within the 6 hour time period, after surgery was significantly higher, while at 24 hours it became lower than the preoperation time. The results suggested that anticoagulation medicine is not necessary during the first 6 to 12 hours, but is required between 12 and 24 hours after surgery to reduce the risk of thrombosis. PMID- 29532456 TI - Association of HSP22 with mTOR in osteoblasts: regulation of TNF-alpha-stimulated IL-6 synthesis. AB - Heat shock protein 22 (HSP22) is ubiquitously expressed in various types of cells including in osteoblasts. We previously reported that tumor necrosis factor (TNF) alpha stimulates interleukin (IL)-6 synthesis via p44/p42 MAPK in osteoblast-like MC3T3-E1 cells and that mTOR/p70 S6 kinase (p70 S6K) negatively regulates the IL 6 synthesis. In this study, we investigated the involvement of HSP22 in TNF-alpha stimulated-IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. HSP22 knockdown reduces TNF-alpha-stimulated release of IL-6. In addition, HSP22 knockdown strengthens TNF-alpha-induced phosphorylation of p70 S6K but suppresses that of p44/p42 MAPK. HSP22 coimmunoprecipitates with mTOR. HSP22 knockdown increases the basal levels of phosphorylated mTOR. These results strongly suggest that HSP22 interacts with mTOR and regulates TNF-alpha-induced IL-6 synthesis in osteoblasts. PMID- 29532458 TI - Brain-derived neurotrophic factor (BDNF) in children with ASD and their parents: a 3-year follow-up. AB - OBJECTIVE: Several lines of evidence point to a probable relationship between brain-derived neurotrophic factor (BDNF) and autism spectrum disorder (ASD), but studies have yielded inconsistent findings on the BDNF serum level in ASD. The study aimed to assess those levels in children with ASD and their families. METHOD: BDNF serum levels were measured in 45 ASD children without intellectual disability (ID) and allergies, age 30-42 months and age-matched normal controls. BDNF serum levels in the parents of the ASD subjects were compared to normal controls. BDNF serum levels in the ASD subjects were followed up for 3 years and correlated with adaptive functioning changes. RESULTS: BDNF serum levels were measured to be lower in children with ASD and independent of all the major baseline characteristics of the subjects. Having a child with ASD raises the BDNF levels in parents comparing to controls. Prospectively, no correlation between the change of BDNF variables in time and the change of the Vineland scores was found. CONCLUSIONS: Our results contradict those from recent published meta analyses with the age, the presence of ID and allergies being possible contributing factors. The parents' data indeed point to a role of BDNF in the pathophysiology of ASD. PMID- 29532457 TI - Heat shock protein-27 and sex-selective regulation of muscarinic and proteinase activated receptor 2-mediated vasodilatation: differential sensitivity to endothelial NOS inhibition. AB - BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2). EXPERIMENTAL APPROACH: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. KEY RESULTS: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1. CONCLUSIONS AND IMPLICATIONS: HSPB1 can regulate intact vascular endothelial function to affect NO-mediated vascular relaxation, especially in females. PMID- 29532459 TI - Sociodemographic risk, parenting, and inhibitory control in early childhood: the role of respiratory sinus arrhythmia. AB - BACKGROUND: Deficits of inhibitory control in early childhood are linked to externalizing behaviors and attention problems. While environmental factors and physiological processes are associated with its etiology, few studies have examined how these factors jointly predict inhibitory control. This study examined whether respiratory sinus arrhythmia (RSA) functioned as a mediator or moderator of both cumulative sociodemographic risk and parenting behaviors on inhibitory control during early childhood. METHODS: The sample included 206 children and their biological mothers. At 24, 30, and 36 months of child age dyads participated in a series of laboratory visits in which sociodemographic, parenting, and baseline RSA (RSAB) data were collected. Inhibitory control was assessed at 36 months using a gift-wrap delay task. RESULTS: A series of structural equation models yielded no evidence that RSAB mediated the relations of risk or parenting and inhibitory control. RSAB moderated the effects of risk, such that high-risk children with low RSAB performed more poorly on tasks of inhibitory control, while high-risk children with high RSAB did not. CONCLUSIONS: These results suggest that higher levels of RSAB may mitigate the influence of environmental risk on the development of inhibitory control early childhood. PMID- 29532460 TI - Hormonal and reproductive factors and risk of upper gastrointestinal cancers in men: A prospective cohort study within the UK Biobank. AB - Incidence of upper gastrointestinal cancers of the oesophagus and stomach show a strong unexplained male predominance. Hormonal and reproductive factors have been associated with upper gastrointestinal cancers in women but there is little available data on men. To investigate this, we included 219,425 men enrolled in the UK Biobank in 2006-2010. Baseline assessments provided information on hormonal and reproductive factors (specifically hair baldness, number of children fathered, relative age at first facial hair and relative age voice broke) and incident oesophageal or gastric cancers were identified through linkage to U.K. cancer registries. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During 8 years of follow-up, 309 oesophageal 210 gastric cancers occurred. There was some evidence that male pattern baldness, was associated with gastric cancer risk (adjusted HR 1.35, 95% CI 0.97, 1.88), particularly for frontal male pattern baldness (adjusted HR 1.52, 95% CI 1.02, 2.28). There was little evidence of association between other hormonal and reproductive factors and risk of oesophageal or gastric cancer, overall or by histological subtype. In the first study of a range of male hormonal and reproductive factors and gastric cancer, there was a suggestion that male pattern baldness, often used as a proxy of sex hormone levels, may be associated with gastric cancer. Future prospective studies that directly test circulating sex steroid hormone levels in relation to upper gastrointestinal cancer risk are warranted. PMID- 29532461 TI - HpBase: A genome database of a sea urchin, Hemicentrotus pulcherrimus. AB - To understand the mystery of life, it is important to accumulate genomic information for various organisms because the whole genome encodes the commands for all the genes. Since the genome of Strongylocentrotus purpratus was sequenced in 2006 as the first sequenced genome in echinoderms, the genomic resources of other North American sea urchins have gradually been accumulated, but no sea urchin genomes are available in other areas, where many scientists have used the local species and reported important results. In this manuscript, we report a draft genome of the sea urchin Hemincentrotus pulcherrimus because this species has a long history as the target of developmental and cell biology in East Asia. The genome of H. pulcherrimus was assembled into 16,251 scaffold sequences with an N50 length of 143 kbp, and approximately 25,000 genes were identified in the genome. The size of the genome and the sequencing coverage were estimated to be approximately 800 Mbp and 100*, respectively. To provide these data and information of annotation, we constructed a database, HpBase (http://cell innovation.nig.ac.jp/Hpul/). In HpBase, gene searches, genome browsing, and blast searches are available. In addition, HpBase includes the "recipes" for experiments from each lab using H. pulcherrimus. These recipes will continue to be updated according to the circumstances of individual scientists and can be powerful tools for experimental biologists and for the community. HpBase is a suitable dataset for evolutionary, developmental, and cell biologists to compare H. pulcherrimus genomic information with that of other species and to isolate gene information. PMID- 29532464 TI - Courses and Conferences. PMID- 29532463 TI - Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea. AB - BACKGROUND: Rosacea is a common facial skin disorder mainly affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as an important factor. The Demodex mite population in the skin of rosacea patients is significantly higher than in patients with normal skin, suggesting that they may be of aetiological importance in this disorder. OBJECTIVES: To determine the potential of Demodex mites to interact with the host immune system. METHODS: Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalized SZ95 sebocyte line. Time- and mite dose-dependent experiments were performed. Direct effects of Demodex and effects of the medium in which Demodex had been cultured were evaluated on the Toll-like receptor (TLR) signalling pathway on both a gene and protein expression level. RESULTS: Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards downmodulation of genes in this pathway was observed. A subsequent switch to positive gene upregulation was recorded after 48 h of coculture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not. CONCLUSIONS: Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalized human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced interleukin-8 secretion by these cells. PMID- 29532465 TI - Voluntary Stopping Eating and Drinking. AB - Voluntary stopping of eating and drinking (VSED) is a deliberate, self-initiated attempt to hasten death in the setting of suffering refractory to optimal palliative interventions or prolonged dying that a person finds intolerable. Individuals who consider VSED tend to be older, have a serious but not always imminently terminal illness, place a high value on independence, and have significant illness burden. VSED can theoretically be performed independent of clinician assistance and therefore avoids many of the ethical and legal concerns associated with physician-assisted dying or other palliative measures of last resort, However, VSED is an intense process fraught with new sources of somatic and emotional suffering for individuals and their caregivers, so VSED is best supervised by an experienced, well-informed clinician who can provide appropriate pre-intervention assessment, anticipatory guidance, medical treatment of symptoms, and emotional support. Before initiation of VSED, clinicians should carefully screen for inadequately treated psychiatric conditions, unaddressed symptoms, existential suffering, and evidence of coercion-consultation from palliative medicine, psychiatry, or ethics is often indicated. The most common symptoms encountered after starting VSED are extreme thirst, hunger, dysuria, progressive disability, delirium, and somnolence. Although physiologically similar to cessation of artificial nutrition and hydration, the onset and management of symptoms is often different. We propose an organized system for evaluating individual appropriateness for VSED, anticipatory guidance, and management of symptoms associated with VSED. A brief review of ethical and legal considerations follows. PMID- 29532462 TI - Murine neutrophils treated with alphaB-crystallin reduce IL-12p40 production by dendritic cells. AB - Neutrophils are essential in the fight against invading pathogens. They utilize antimicrobial effector mechanisms, such as phagocytosis, release of proteases and other antimicrobial products, robust oxidative bursts and neutrophil extracellular traps to combat infections. Neutrophils also modulate immune responses through the production of eicosanoids, cytokines and chemokines, as well as via direct communication with other immune cells. This system of high intensity offense against pathogens is exquisitely balanced through regulation to limit damage to host tissue. Unfortunately, the control of neutrophils is not failproof. In cases of sterile injury, autoimmunity and even during an infection, neutrophils can cause tissue destruction and become detrimental to the host. For that reason, there is a need to find means to regulate the aberrant activation of these cells. We found that alphaB-crystallin (alphaBC), a heat-shock protein known to have anti-inflammatory abilities, affects certain properties of mouse neutrophils that subsequently influence the pro-inflammatory state of antigen presenting cells (APCs). More specifically, alphaBC mediated small but significant increases in the levels of IL-10 and matrix metalloproteinase 8, and altered hydrogen peroxide secretion by stimulated neutrophils. Further, the heat shock protein influenced the communication between neutrophils and dendritic cells by decreasing the production of pro-inflammatory cytokines, specifically IL 12p40, by the APCs. alphaBC could thus contribute to dampening neutrophil inflammatory responses by impacting the effect of neutrophils on other immune cells. PMID- 29532466 TI - Academic Detailing with Provider Audit and Feedback Improve Prescribing Quality for Older Veterans. AB - Suboptimal prescribing persists as a driver of poor quality care of older veterans and is associated with risk of hospitalization and emergency department visits. We adapted a successful medication management model, Integrated Management and Polypharmacy Review of Vulnerable Elders (IMPROVE), from an urban geriatric specialty clinic to rural community-based clinics that deliver primary care. The goals were to promote prescribing quality and safety for older adults, including reduced prescribing of potentially inappropriate medications (PIMs). We augmented the original model, which involved a pharmacist-led, one-on-one medication review with high-risk older veterans, to provide rural primary care providers (PCPs) and pharmacists with educational outreach through academic detailing and tools to support safe geriatric prescribing practices, as well as individual audit and feedback on prescribing practice and confidential peer benchmarking. Twenty PCPs and 4 pharmacists at 4 rural Georgia community-based outpatient clinics participated. More than 7,000 older veterans were seen in more than 20,000 PCP encounters during the 14-month intervention period. Implementation of the IMPROVE intervention reduced PIM prescribing incidence from 9.6 new medications per 100 encounters during baseline to 8.7 after the intervention (P = .009). IMPROVE reduced PIM prevalence (proportion of encounters involving veterans who were taking at least 1 PIM) from 22.6% to 16.7% (P < .001). These approaches were effective in reducing PIMs prescribed to older veterans in a rural setting and constitute a feasible model for disseminating geriatric best practices to the primary care setting. PMID- 29532467 TI - Epithelial oestrogen receptor alpha is dispensable for the development of oestrogen-induced cervical neoplastic diseases. AB - Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E2 mainly functions through oestrogen receptor alpha (ERalpha). However, the role of ERalpha in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERalpha-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E2 induced cervical epithelial cell proliferation in epithelial ERalpha-deficient mice. We also found that E2 promoted the development of CIN and CxCa in epithelial ERalpha-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ERalpha. In addition, proliferation indices were similar between ERalpha- and ERalpha+ CxCa. These results indicate that epithelial ERalpha is not necessary for E2 -induced CIN and CxCa. Taking these findings together, we conclude that stromal ERalpha rather than epithelial ERalpha mediates oncogenic E2 signalling in CxCa. Our results support stromal ERalpha signalling as a therapeutic target for the disease. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29532468 TI - THAM administration reduces pulmonary carbon dioxide elimination in hypercapnia - an experimental porcine study. AB - BACKGROUND: In a previous study, we found a rebound of arterial carbon dioxide tension (PaCO2 ) after stopping THAM buffer administration. We hypothesized that this was due to reduced pulmonary CO2 elimination during THAM administration. The aim of this study was to investigate this hypothesis in an experimental porcine hypercapnic model. METHODS: In seven, initially normoventilated, anesthetized pigs (22-27 kg) minute ventilation was reduced by 66% for 7 h. Two hours after commencing hypoventilation, THAM was infused IV for 3 h in a dose targeting a pH of 7.35 followed by a 2 h observation period. Acid-base status, blood-gas content and exhaled CO2 were measured. RESULTS: THAM raised pH (7.07 +/- 0.04 to 7.41 +/- 0.04, P < 0.05) and lowered PaCO2 (15.2 +/- 1.4 to 12.2 +/- 1.1 kPa, P < 0.05). After the infusion, pH decreased and PaCO2 increased again. At the end of the observation period, pH and PaCO2 were 7.24 +/- 0.03 and 16.6 +/- 1.2 kPa, respectively (P < 0.05). Pulmonary CO2 excretion decreased from 109 +/- 12 to 74 +/- 12 ml/min (P < 0.05) during the THAM infusion but returned at the end of the observation period to 111 +/- 15 ml/min (P < 0.05). The estimated reduction of pulmonary CO2 elimination during the infusion was 5800 ml. CONCLUSIONS: In this respiratory acidosis model, THAM reduced PaCO2 , but seemed not to increase the total CO2 elimination due to decreased pulmonary CO2 excretion, suggesting only cautious use of THAM in hypercapnic acidosis. PMID- 29532469 TI - Intraspecific interactions between algae with different nutritional histories. AB - The diatom Phaeodactylum tricornutum was cultured in five different growth regimes to obtain cells with different composition. Pairs of populations subjected to different treatments were then mixed in a communal culture regime that differed from those of origin. After 6 h, the ratio between the two populations was verified by flow cytometry. Alterations in this ratio were found when cells previously grown at 1 mM NH4+ were mixed with GeO2 - and 0.5 mM NH4+ grown cells. The nutritional background may thus make cells differently suited to new environmental conditions and afford advantages in terms of reproductive potential. Competitive interactions between populations may result from the differences in the expressed proteome and/or in the availability of tools for regulatory responses. This may have relevance to the persistence of phenotypically neutral variants present in the population best suited to the new condition, after the interaction of the conspecifics with different nutritional histories. PMID- 29532470 TI - Glucantime reduces mechanical hyperalgesia in cutaneous leishmaniasis and complete Freund's adjuvant models of chronic inflammatory pain. AB - OBJECTIVES: To evaluate the analgesic effect of Glucantime (antimoniate N methylglucamine) in Leishmania amazonensis infection and complete Freund's adjuvant (CFA), chronic paw inflammation model, in BALB/c mice. METHODS: Two models of chronic inflammatory pain in BALB/c mice paw were used: infection with L. amazonensis and CFA stimulation. Both animals models received daily treatment with Glucantime (10 mg/kg, i.p.) and during the treatment was measured the mechanical hyperalgesia with electronic version of von Frey filaments. After the treatment, the paw skin sample was collected for analysis of myeloperoxidase (MPO) and N-acetyl-beta-glucosaminidase (NAG) activity, and IL-1beta, TNF-alpha, IL-6, IFN-gamma and IL-10 cytokines production by ELISA. KEY FINDINGS: Leishmania amazonensis-induced chronic inflammation with significant increase in mechanical hyperalgesia, MPO and NAG activity, and IL-1beta, TNF-alpha and IL-6 production in the paw skin. Glucantime (10 mg/kg, i.p.) inhibited L. amazonensis-induced mechanical hyperalgesia and IL-1beta and IL-6 cytokines productions. In chronic inflammatory model induced by CFA, Glucantime treatment during 7 days inhibited CFA-induced mechanical hyperalgesia, MPO and NAG activity, and IL-1beta, TNF alpha, IL-6 and IFN-gamma production as well as increased IL-10 production. CONCLUSIONS: Our data demonstrated that Glucantime reduced the chronic inflammatory pain induced by L. amazonensis and CFA stimuli by inhibiting the hyperalgesic cytokines production. PMID- 29532471 TI - Development of an enteric nanoparticle of marine sulfated polysaccharide propylene glycol alginate sodium sulfate for oral administration: formulation design, pharmacokinetics and efficacy. AB - OBJECTIVES: Propylene glycol alginate sodium sulfate (PSS) is poorly absorbed by oral administration due to its large molecular weight and slightly degradability in stomach acidic environment. Here, a novel enteric-coated nano formulation of PSS (enteric PSS-NP) was prepared to improve its bioavailability and efficacy. METHODS: The enteric PSS-NP was prepared by double (W1 /O/W2 ) emulsion and solvent evaporation method. The drug release characteristics in vitro were studied in artificial gastrointestinal fluid. And the pharmacokinetics and efficacy of enteric PSS-NP were separately investigated in normal rats and type 2 diabetic db/db mice. KEY FINDINGS: The enteric PSS-NP were in spherical shape and exhibited negative zeta potential. The releasing characteristics of enteric PSS NP in vitro showed that it possessed a strong pH-sensitive release character. Single-dose (50 mg/kg) oral pharmacokinetic study in rat plasma showed that enteric PSS-NP could improve the relative bioavailability significantly compared with PSS solution. Furthermore, the efficacy of enteric PSS-NP in vivo was better than that of PSS solution at equivalent doses. CONCLUSIONS: The study showed that enteric-coated formulation of PSS had the intestinal-targeted absorption and improved pharmacodynamics, which indicated that enteric PSS-NP could be developed into a new formulation product in the future. PMID- 29532472 TI - Unravelling growth trajectories from complicated otoliths - the case of Brazilian codling Urophycis brasiliensis. AB - Uncertainty regarding the age determination of the Brazilian codling Urophycis brasiliensis has hampered its stock assessment. Transverse sections of otoliths displayed up to seven (in males) and 12 (in females) alternate opaque and translucent bands that could not be conclusively validated as annuli, resulting in unrealistically high ages of first maturity (A50 ) (A50male = 4.5 years and A50female = 6 years). Therefore, growth was described by the von Bertalanffy (VB) model using an alternative approach that combined microstructure data (daily growth increments) and a fixed asymptotic total length (Linfinity ). This approach was supported by applying it to two other co-occurring species, the whitemouth croaker Micropogonias furnieri and the king weakfish Macrodon atricauda, for which daily and annual ring formation has previously been validated. The sensitivity to realistic errors associated with the choice of the Linfinity and the daily increment readings was shown to be low. The results show that U. brasiliensis has a fast growth rate (Kmale = 1.19 year-1 , Kfemale = 0.71 year-1 ) and early maturation (A50male = 1.1-1.5 years, A50female = 1.6 1.8 years); typical life-history traits for a sub-tropical coastal gadiform. This novel study offers an alternative approach for age and growth reconstruction for species with complex patterns of opaque and translucent bands provided that daily growth increments in the yearlings can be counted and Linfinity reliably estimated. PMID- 29532473 TI - Derivation of the clonal-cell lines from Siberian sturgeon (Acipenser baerii) head-kidney cell lines and its applicability to foreign gene expression and virus culture. AB - This study was conducted to establish and characterize the clonal-cell lines from Siberian sturgeon Acipenser baerii head-kidney tissues and to evaluate its applicability as a research tool. From the culture of A. baerii head-kidney derived cells, 10 cell lines were established first and then eight clonal-cell lines were derived from clonal growth and colony expansion of two cell lines that showed significant high colony-forming ability. All eight clonal-cell lines were morphologically similar and grew stably under monolayer culture but their growth rates were significantly different. They possessed diploid DNA contents, expressed epithelial cell-related genes and showed strong anchorage dependency to substrates. When a clonal-cell line was transfected separately with three plasmid vectors including fluorescent reporter genes driven by cytomegalovirus, marine medaka Oryzias dancena beta-actin or A. baerii beta-actin promoter, the cell lines expressed fluorescent signals regardless of promoter types. The cells harbouring foreign genes could be expanded to stable cell lines under drug selection and then they additionally could form the extensively proliferating colonies at low-density culture. Finally, the clonal-cell lines showed the susceptibility to viral haemorrhagic septicaemia virus (VHSV). Collectively, the clonal-cell lines from A. baerii head kidney were established and these cell lines will be able to provide an excellent in vitro system for various biological studies in this fish species. PMID- 29532474 TI - Effects of water deficit on breadmaking quality and storage protein compositions in bread wheat (Triticum aestivum L.). AB - BACKGROUND: Water deficiency affects grain proteome dynamics and storage protein compositions, resulting in changes in gluten viscoelasticity. In this study, the effects of field water deficit on wheat breadmaking quality and grain storage proteins were investigated. RESULTS: Water deficiency produced a shorter grain filling period, a decrease in grain number, grain weight and grain yield, a reduced starch granule size and increased protein content and glutenin macropolymer contents, resulting in superior dough properties and breadmaking quality. Reverse phase ultra-performance liquid chromatography analysis showed that the total gliadin and glutenin content and the accumulation of individual components were significantly increased by water deficiency. Two-dimensional gel electrophoresis detected 144 individual storage protein spots with significant accumulation changes in developing grains under water deficit. Comparative proteomic analysis revealed that water deficiency resulted in significant upregulation of 12 gliadins, 12 high-molecular-weight glutenin subunits and 46 low-molecular-weight glutenin subunits. Quantitative real-time polymerase chain reaction analysis revealed that the expression of storage protein biosynthesis related transcription factors Dof and Spa was upregulated by water deficiency. CONCLUSION: The present results illustrated that water deficiency leads to increased accumulation of storage protein components and upregulated expression of Dof and Spa, resulting in an improvement in glutenin strength and breadmaking quality. (c) 2018 Society of Chemical Industry. PMID- 29532475 TI - Intracranial pressure in patients with papilloedema. AB - OBJECTIVES: Papilloedema is a clinical manifestation of chronically raised intracranial pressure (ICP), often seen in idiopathic intracranial hypertension (IIH). However, the extent of intracranial hypertension required to produce papilloedema is not known. We compare ICP values in IIH patients who developed papilloedema and those who did not. We aim to identify a pathological ICP threshold predictive of the development of papilloedema in IIH patients. MATERIALS AND METHODS: Single-centre cohort of IIH patients (2006-2016) who underwent 24-hour ICP monitoring (ICPM) and ophthalmology assessments, prior to intervention. Papilloedema was graded according to the Frisen scale. An unpaired t-test compared 24-hour ICPM between papilloedema and no-papilloedema groups. Fisher's exact test was used to determine predictive value of ICP. RESULTS: Thirty-six patients with IIH (35 F: 1M), mean age 32.5 +/- 9.49 years (mean +/- SD) were included. Patients with papilloedema had a mean median 24-hour ICP of 10.4 +/- 5.32 mm Hg (n = 25), significantly higher than the group without papilloedema 6.31 +/- 3.30 mm Hg (n = 11) (P < .05). The papilloedema group were exposed to higher pressures (10 mm Hg) for 30 minutes or more. Using 24-hour median ICP of 10 mm Hg as a minimum cut-off predictive value gives a specificity = 91%, sensitivity = 48%, PPV = 92% and NPV = 44% of detecting papilloedema. CONCLUSIONS: A 24-hour ICP of 10 mmHg or more is a good predictor for papilloedema and reflects a pathological threshold. The range varied widely suggesting papilloedema can occur at even lower pressures. These results are consistent with emerging evidence suggest that pathologically "high" 24 hours ICP is lower than previously quoted. PMID- 29532476 TI - Effect of resistance training and protein intake pattern on myofibrillar protein synthesis and proteome kinetics in older men in energy restriction. AB - KEY POINTS: Strategies to enhance the loss of fat while preserving muscle mass during energy restriction are of great importance to prevent sarcopenia in overweight older adults. We show for the first time that the integrated rate of synthesis of numerous individual contractile, cytosolic and mitochondrial skeletal muscle proteins was increased by resistance training (RT) and unaffected by dietary protein intake pattern during energy restriction in free-living, obese older men. We observed a correlation between the synthetic rates of skeletal muscle-derived proteins obtained in serum (creatine kinase M-type, carbonic anhydrase 3) and the synthetic rates of proteins obtained via muscle sampling; and that the synthesis rates of these proteins in serum revealed the stimulatory effects of RT. These results have ramifications for understanding the influence of RT on skeletal muscle and are consistent with the role of RT in maintaining muscle protein synthesis and potentially supporting muscle mass preservation during weight loss. ABSTRACT: We determined how the pattern of protein intake and resistance training (RT) influenced longer-term (2 weeks) integrated myofibrillar protein synthesis (MyoPS) during energy restriction (ER). MyoPS and proteome kinetics were measured during 2 weeks of ER alone and 2 weeks of ER plus RT (ER + RT) in overweight/obese older men. Participants were randomized to consume dietary protein in a balanced (BAL: 25% daily protein per meal * 4 meals) or skewed (SKEW: 7:17:72:4% daily protein per meal) pattern (n = 10 per group). Participants ingested deuterated water during the consecutive 2-week periods, and skeletal muscle biopsies and serum were obtained at the beginning and conclusion of ER and ER + RT. Bulk MyoPS (i.e. synthesis of the myofibrillar protein sub fraction) and the synthetic rates of numerous individual skeletal muscle proteins were quantified. Bulk MyoPS was not affected by protein distribution during ER or ER + RT (ER: BAL = 1.24 +/- 0.31%/day, SKEW = 1.26 +/- 0.37%/day; ER + RT: BAL = 1.64 +/- 0.48%/day, SKEW = 1.52 +/- 0.66%/day) but was ~26% higher during ER + RT than during ER (P = 0.023). The synthetic rates of 175 of 190 contractile, cytosolic and mitochondrial skeletal muscle proteins, as well as synthesis of muscle-derived proteins measured in serum, creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3), were higher during ER + RT than during ER (P < 0.05). In addition, the synthetic rates of CK-M and CA-3 measured in serum correlated with the synthetic rates of proteins obtained via muscle sampling (P < 0.05). This study provides novel data on the skeletal muscle adaptations to RT and dietary protein distribution. PMID- 29532477 TI - Trends in Opioid Use and Prescribing in Medicare, 2006-2012. AB - OBJECTIVE: To determine characteristics and trends in opioid use, questionable use, and prescribing in Medicare. STUDY SETTING: Opioid prescriptions filled through Medicare Part D for beneficiaries with full-year, fee-for-service Medicare coverage during 2006 to 2012. STUDY DESIGN: Retrospective analysis of a 20 percent sample of Medicare claims data. Estimates are adjusted using multivariable regression analysis. DATA COLLECTION: Opioid use, opioid abuse, questionable opioid use, and opioid prescribing by specialty. PRINCIPAL FINDINGS: Opioid use in Medicare was stable from 2006 to 2012 on average. More than 1 in 3 beneficiaries filled an opioid prescription annually; about 1 in 10 were chronic opioid users. The distribution of opioid users shifted in favor of diagnoses often associated with chronic pain. Opioid users were increasingly likely to abuse opioids or display patterns of questionable use from 2006 to 2010, with a slowdown in later years. Average outcomes mask significant variation as the distribution of opioid use widened over the analysis period. Prescribing quantity and intensity varied by specialty. The largest quantity increases were among nurse practitioners and physician assistants. CONCLUSIONS: Opioid utilization and prescribing are increasingly heterogeneous from 2006 to 2012. Future research should focus on explaining differential trends in utilization and prescribing. PMID- 29532478 TI - Impact of a New York City Supportive Housing Program on Housing Stability and Preventable Health Care among Homeless Families. AB - OBJECTIVE: To assess the impact of a New York City supportive housing program on housing stability and preventable emergency department (ED) visits/hospitalizations among heads of homeless families with mental and physical health conditions or substance use disorders. DATA SOURCES: Multiple administrative data from New York City and New York State for 966 heads of families eligible for the program during 2007-12. STUDY DESIGN: We captured housing events and health care service utilization during 2 years prior to the first program eligibility date (baseline) and 2 years postbaseline. We performed sequence analysis to measure housing stability and compared housing stability and preventable ED visits and hospitalizations between program participants (treatment group) and eligible applicants not placed in the program (comparison group) via marginal structural modeling. DATA COLLECTION/EXTRACTION METHODS: We matched electronically collected data. PRINCIPAL FINDINGS: Eighty-seven percent of supportive housing tenants experienced housing stability in 2 years postbaseline. Compared with unstably housed heads of families in the comparison group, those in the treatment group were 0.60 times as likely to make preventable ED visits postbaseline (95% CI = 0.38, 0.96). CONCLUSIONS: Supportive housing placement was associated with improved housing stability and reduced preventable health care visits among homeless families. PMID- 29532479 TI - Classification images for localization performance in ramp-spectrum noise. AB - PURPOSE: This study investigates forced localization of targets in simulated images with statistical properties similar to trans-axial sections of x-ray computed tomography (CT) volumes. A total of 24 imaging conditions are considered, comprising two target sizes, three levels of background variability, and four levels of frequency apodization. The goal of the study is to better understand how human observers perform forced-localization tasks in images with CT-like statistical properties. METHODS: The transfer properties of CT systems are modeled by a shift-invariant transfer function in addition to apodization filters that modulate high spatial frequencies. The images contain noise that is the combination of a ramp-spectrum component, simulating the effect of acquisition noise in CT, and a power-law component, simulating the effect of normal anatomy in the background, which are modulated by the apodization filter as well. Observer performance is characterized using two psychophysical techniques: efficiency analysis and classification image analysis. Observer efficiency quantifies how much diagnostic information is being used by observers to perform a task, and classification images show how that information is being accessed in the form of a perceptual filter. RESULTS: Psychophysical studies from five subjects form the basis of the results. Observer efficiency ranges from 29% to 77% across the different conditions. The lowest efficiency is observed in conditions with uniform backgrounds, where significant effects of apodization are found. The classification images, estimated using smoothing windows, suggest that human observers use center-surround filters to perform the task, and these are subjected to a number of subsequent analyses. When implemented as a scanning linear filter, the classification images appear to capture most of the observer variability in efficiency (r2 = 0.86). The frequency spectra of the classification images show that frequency weights generally appear bandpass in nature, with peak frequency and bandwidth that vary with statistical properties of the images. CONCLUSIONS: In these experiments, the classification images appear to capture important features of human-observer performance. Frequency apodization only appears to have a significant effect on performance in the absence of anatomical variability, where the observers appear to underweight low spatial frequencies that have relatively little noise. Frequency weights derived from the classification images generally have a bandpass structure, with adaptation to different conditions seen in the peak frequency and bandwidth. The classification image spectra show relatively modest changes in response to different levels of apodization, with some evidence that observers are attempting to rebalance the apodized spectrum presented to them. PMID- 29532480 TI - Low-dose cone-beam CT via raw counts domain low-signal correction schemes: Performance assessment and task-based parameter optimization (Part II. Task-based parameter optimization). AB - PURPOSE: Different low-signal correction (LSC) methods have been shown to efficiently reduce noise streaks and noise level in CT to provide acceptable images at low-radiation dose levels. These methods usually result in CT images with highly shift-variant and anisotropic spatial resolution and noise, which makes the parameter optimization process highly nontrivial. The purpose of this work was to develop a local task-based parameter optimization framework for LSC methods. METHODS: Two well-known LSC methods, the adaptive trimmed mean (ATM) filter and the anisotropic diffusion (AD) filter, were used as examples to demonstrate how to use the task-based framework to optimize filter parameter selection. Two parameters, denoted by the set P, for each LSC method were included in the optimization problem. For the ATM filter, these parameters are the low- and high-signal threshold levels pl and ph ; for the AD filter, the parameters are the exponents delta and gamma in the brightness gradient function. The detectability index d' under the non-prewhitening (NPW) mathematical observer model was selected as the metric for parameter optimization. The optimization problem was formulated as an unconstrained optimization problem that consisted of maximizing an objective function d'(P), where i and j correspond to the i-th imaging task and j-th spatial location, respectively. Since there is no explicit mathematical function to describe the dependence of d' on the set of parameters P for each LSC method, the optimization problem was solved via an experimentally measured d' map over a densely sampled parameter space. In this work, three high contrast-high-frequency discrimination imaging tasks were defined to explore the parameter space of each of the LSC methods: a vertical bar pattern (task I), a horizontal bar pattern (task II), and a multidirectional feature (task III). Two spatial locations were considered for the analysis, a posterior region-of interest (ROI) located within the noise streaks region and an anterior ROI, located further from the noise streaks region. Optimal results derived from the task-based detectability index metric were compared to other operating points in the parameter space with different noise and spatial resolution trade-offs. RESULTS: The optimal operating points determined through the d' metric depended on the interplay between the major spatial frequency components of each imaging task and the highly shift-variant and anisotropic noise and spatial resolution properties associated with each operating point in the LSC parameter space. This interplay influenced imaging performance the most when the major spatial frequency component of a given imaging task coincided with the direction of spatial resolution loss or with the dominant noise spatial frequency component; this was the case of imaging task II. The performance of imaging tasks I and III was influenced by this interplay in a smaller scale than imaging task II, since the major frequency component of task I was perpendicular to imaging task II, and because imaging task III did not have strong directional dependence. For both LSC methods, there was a strong dependence of the overall d' magnitude and shape of the contours on the spatial location within the phantom, particularly for imaging tasks II and III. The d' value obtained at the optimal operating point for each spatial location and imaging task was similar when comparing the LSC methods studied in this work. CONCLUSIONS: A local task-based detectability framework to optimize the selection of parameters for LSC methods was developed. The framework takes into account the potential shift-variant and anisotropic spatial resolution and noise properties to maximize the imaging performance of the CT system. Optimal parameters for a given LSC method depend strongly on the spatial location within the image object. PMID- 29532481 TI - Introduction to the Virtual Issue Alcohol and Epigenetic Regulation: Do the Products of Alcohol Metabolism Drive Epigenetic Control of Gene Expression in Alcohol-Related Disorders? PMID- 29532483 TI - Low-dose cone-beam CT via raw counts domain low-signal correction schemes: Performance assessment and task-based parameter optimization (Part I: Assessment of spatial resolution and noise performance). AB - PURPOSE: Low-signal correction (LSC) in the raw counts domain has been shown to effectively reduce noise streaks in CT because the data inconsistency associated with photon-starved regions may be mitigated prior to the log transformation step. However, a systematic study of the performance of these raw data correction methods is still missing in literature. The purpose of this work was to provide such a systematic study for two well-known low-signal correction schemes using either the adaptive trimmed mean (ATM) filter or the anisotropic diffusion (AD) filter in the raw counts domain. METHODS: Image data were acquired experimentally using an anthropomorphic chest phantom and a benchtop cone-beam CT (CBCT) imaging system. Phantom scans were repeated 50 times at a reduced dose level of 0.5 mGy and a reference level of 1.9 mGy. The measured raw counts at 0.5 mGy underwent LSC using the ATM and AD filters. Two relevant parameters were identified for each filter and approximately one hundred operating points in each parameter space were analyzed. Following LSC and log transformation, FDK reconstruction was performed for each case. Noise and spatial resolution properties were assessed across the parameter spaces that define each LSC filter; the results were summarized through 2D contour maps to better understand the trade-offs between these competing image quality features. 2D noise power spectrum (NPS) and modulation transfer function (MTF) were measured locally at two spatial locations in the field-of-view (FOV): a posterior region contaminated by noise streaks and an anterior region away from noise streaks. An isotropy score metric was introduced to characterize the directional dependence of the NPS and MTF (viz., epsilonNPS and epsilonMTF , respectively), with a range from 0 for highly anisotropic to 1 for perfectly isotropic. The noise magnitude and coarseness were also measured. RESULTS: (a) Both the ATM and AD LSC methods were successful in reducing noise streaks, but their noise and spatial resolution properties were found to be highly anisotropic and shift-variant. (b) NPS isotropy scores in the posterior region were generally improved from epsilonNPS = 0.09 for the images without LSC to the range epsilonNPS = (0.11, 0.67) for ATM and epsilonNPS = (0.06, 0.67) for AD, depending on the filter parameters used. (c) The noise magnitude was reduced across the parameter space of either LSC filter whenever a change along the axis of the controlling parameter led to stronger raw data filtration. Changes in noise magnitude were inversely related to changes in spatial resolution along the direction perpendicular to the streaks. No correlation was found, however, between the contour maps of noise magnitude and the NPS isotropy. (d) Both filters influenced the noise coarseness anisotropically, with coarser noise occurring along directions perpendicular to the noise streaks. The anisotropic noise coarseness was intrinsically and directly related to resolution losses in a given direction: coarseness plots mimic the topography of the 2D MTF, i.e., the coarser the noise, the lower the resolution. CONCLUSIONS: Both AD and ATM LSC schemes enable low-dose CBCT imaging. However, it was found that noise magnitude and overall spatial resolution vary considerably across the parameter space for each filter, and more importantly these image quality features are highly anisotropic and shift variant. PMID- 29532484 TI - Removal of irrelevant information from working memory: sometimes fast, sometimes slow, and sometimes not at all. AB - To function properly, working memory must be rapidly updated. Updating requires the removal of information no longer relevant. I present six experiments designed to explore the boundary conditions and the time course of removal. A condition in which three out of six memory items can be removed was compared to two baseline conditions in which either three or six items were encoded and maintained in working memory. The time for removal was varied. In experiment 1, in the removal condition, a distinct subset of three words was cued to be irrelevant after encoding all six words. With longer removal time, response times in the removal condition approximated those in the set-size 3 baseline, but accuracies stayed at the set-size 6 level. In experiment 2, in which a random subset of three words was cued as irrelevant, there was no evidence for removal. Experiments 3 and 4 showed that when each item is cued as relevant or irrelevant after its encoding, irrelevant items can be removed rapidly and completely. Experiments 5 and 6 showed that complete removal was no longer possible when words had to be processed before being cued as irrelevant. The pattern of findings can be explained by distinguishing two forms of removal: deactivation removes working memory contents from the set of competitors for retrieval; unbinding contents from their contexts removes them from working memory entirely, so that they also cease to compete for limited capacity. PMID- 29532482 TI - How does temperature affect splicing events? Isoform switching of splicing factors regulates splicing of LATE ELONGATED HYPOCOTYL (LHY). AB - One of the ways in which plants can respond to temperature is via alternative splicing (AS). Previous work showed that temperature changes affected the splicing of several circadian clock gene transcripts. Here, we investigated the role of RNA-binding splicing factors (SFs) in temperature-sensitive AS of the clock gene LATE ELONGATED HYPOCOTYL (LHY). We characterized, in wild type plants, temperature-associated isoform switching and expression patterns for SF transcripts from a high-resolution temperature and time series RNA-seq experiment. In addition, we employed quantitative RT-PCR of SF mutant plants to explore the role of the SFs in cooling-associated AS of LHY. We show that the splicing and expression of several SFs responds sufficiently, rapidly, and sensitively to temperature changes to contribute to the splicing of the 5'UTR of LHY. Moreover, the choice of splice site in LHY was altered in some SF mutants. The splicing of the 5'UTR region of LHY has characteristics of a molecular thermostat, where the ratio of transcript isoforms is sensitive to temperature changes as modest as 2 degrees C and is scalable over a wide dynamic range of temperature. Our work provides novel insight into SF-mediated coupling of the perception of temperature to post-transcriptional regulation of the clock. PMID- 29532485 TI - Facilitators and barriers for RhD-immunized women to become and remain anti-D donors. AB - BACKGROUND: The successful introduction of prophylaxis with anti-RhD immunoglobulin has resulted in a significant decline of pregnancy-related RhD immunizations but also has decreased the availability of naturally immunized women as (new) anti-D donors. An influx of new donors is necessary to maintain a sufficient pool of anti-D donors. We investigated motivators, barriers, and predictors for anti-D donorship in RhD-immunized women. STUDY DESIGN AND METHODS: A mixed-methods design was applied, including focus group discussions and questionnaires. Two focus groups (including 11 women) served as input for the questionnaire. RESULTS: In total, 47.6% of 750 anti-D donors and potential donors completed the questionnaire (50.4% donors; 38% nondonors; 11.6% former donors). Almost 70% of the nondonors would have become donors if they had known about the possibility. Travel time investment was reported as a disadvantage; one-half of donors mentioned no disadvantages. Motivators for anti-D donorship were "doing something in return" (31.2%) and "preventing others having a sick child or losing a child" (33.9%). In multivariable analysis, living single (odds ratio, 5.8; p = 0.02) and living partnered without resident children (odds ratio, 7.9; p = 0.03), compared with living partnered with children, were predictors for anti-D donorship. Not being registered as an organ donor (odds ratio, 0.25; p < 0.001) predicted that the individual would not be an anti-D donor. CONCLUSION: The main barrier for anti-D donorship was a lack of knowledge. Positive predictors of anti D donorship were living without resident children, altruism, and being registered as an organ donor. A blood bank should develop targeted recruitment strategies with a focus on spreading knowledge about anti-D donorship among RhD-immunized women. PMID- 29532486 TI - Glyoxalase 1 (GLO1) Inhibition or Genetic Overexpression Does Not Alter Ethanol's Locomotor Effects: Implications for GLO1 as a Therapeutic Target in Alcohol Use Disorders. AB - BACKGROUND: Glyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol (EtOH) drinking. This study assessed whether inhibition of GLO1, or genetic overexpression of Glo1, would also alter the locomotor effects of EtOH, which might explain reduced EtOH consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control. METHODS: Male C57BL/6J mice were pretreated with either the GLO1 inhibitor S bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether locomotor response to a range of EtOH doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of EtOH doses in FVB/NJ wild-type and transgenic Glo1 overexpressing mice (Experiment 3). Anxiety-like behavior (time spent in the center of the open field) was assessed in all 3 experiments. RESULTS: The EtOH dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low EtOH doses and potentiated locomotor sedation at higher EtOH doses. No drug or genotype differences were seen in anxiety-like behavior after EtOH treatment. CONCLUSIONS: The dose of pBBG used in this study is within the effective range shown previously to reduce EtOH drinking. Glo1 overexpression has been previously shown to increase EtOH drinking. However, neither manipulation altered the dose-response curve for EtOH's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of EtOH. The present data demonstrate that reduced EtOH drinking caused by GLO1 inhibition is not due to potentiation of EtOH's stimulant or depressant effects. PMID- 29532487 TI - Familial Risk for Alcohol Dependence and Brain Morphology: The Role of Cortical Thickness Across the Lifespan. PMID- 29532488 TI - Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. AB - BACKGROUND: Allogeneic natural killer (NK) cell adoptive immunotherapy is a growing therapeutic option for patients. Clinical-scale production of NK cells using immunomagnetic selection complies with current good manufacturing practices (cGMPs) and allows for closed-system, automated purification. We report our experience with CD3/CD19 cell-depleted (CD3/CD19dep ) NK cell production and compare to previous methods of CD3 cell depletion and CD3 cell depletion/CD56 cell enrichment. STUDY DESIGN AND METHODS: Nonmobilized mononuclear cells collected by apheresis were incubated with anti-CD3/anti-CD19 microbeads and depleted in an automated cell selection system (CliniMACS, Miltenyi). The NK cell enriched products were incubated overnight in interleukin (IL)-2 or IL-15, washed, and resuspended prior to lot release testing and infusion. RESULTS: Since 2010, 94 freshly infusible CD3/CD19dep NK cell products were manufactured in support of eight clinical trials. Sixty-six products were incubated in IL-2 and 28 products in IL-15. Processing resulted in a mean NK cell recovery of 74% and viability of 95.8%; NK cells, T cells, B cells, and monocytes accounted for 47%, 0.2%, 0.08%, and 49% of the final products, respectively. Seven products required dose adjustments to meet lot release. The specification for purity changed throughout the evolution of manufacturing. IL-2 or IL-15 activation enhanced in vitro cytotoxicity compared to preactivated cells. There was no difference in final product composition or cytotoxicity between cytokine cohorts. CONCLUSION: Clinical-scale/cGMP production of NK cells using CD3/CD19 cell-depletion effectively minimized T-cell and B-cell contamination in a single manipulation without compromise to NK-cell recovery. Cytokine activation increased in vitro cytotoxicity compared to column-depleted, preactivated NK cells. PMID- 29532489 TI - Positioning accuracy and daily dose assessment for prostate cancer treatment using in-room CT image guidance at a proton therapy facility. AB - PURPOSE: To evaluate the effectiveness of CT image-guided proton radiotherapy for prostate cancer by analyzing the positioning uncertainty and assessing daily dose change due to anatomical variations. MATERIALS AND METHODS: Patients with prostate cancer were treated by opposed lateral proton beams based on a passive scattering method using an in-room CT image-guided system. The system employs a single couch for both CT scanning and beam delivery. The patient was positioned by matching the boundary between the prostate and the rectum's anterior region identified in the CT images to the corresponding boundary in the simulator images after bone matching. We acquired orthogonal kV x-ray images after couch movement and confirmed the body position by referring to the bony structure prior to treatment. In offline analyses, we contoured the targeted anatomical structures on 375 sets of daily in-room CT images for 10 patients. The uncertainty of the image-matching procedure was evaluated using the prostate contours and actual couch corrections. We also performed dose calculations using the same set of CT images, and evaluated daily change of dose-volume histograms (DVHs) to compare the effectiveness of the treatment using prostate matching to the bone-matching procedure. RESULTS: The isocenter shifts by prostate matching after bone matching were 0.5 +/- 1.8 and -0.8 +/- 2.6 mm along the superior-inferior (SI) and anterior-posterior (AP) directions, respectively. The body movement errors (sigma) after couch movement were 0.7, 0.5, and 0.3 mm along the lateral, SI and AP direction, respectively, for 30 patients. The estimated errors (sigma) in the prostate matching were 1.0 and 1.3 mm, and, in conjunction with the movement errors, the total positioning uncertainty was estimated to be 1.0 and 1.4 mm along the SI and AP directions, respectively. Daily DVH analyses showed that in the prostate matching, 98.7% and 86.1% of the total 375 irradiations maintained a dose condition of V95% > 95% for the prostate and a dose constraint of V77% < 18% for the rectum, whereas 90.4% and 66.1% of the total irradiations did so when bone matching was used. The dose constraint of the rectum and dose coverage of the prostate were better maintained by prostate matching than bone matching (P < 0.001). The daily variation in the dose to the seminal vesicles (SVs) was large, and only 40% of the total irradiations maintained the initial planned values of V95% for high-risk treatment. Nevertheless, the deviations from the original value were -4 +/- 7% and -5 +/- 11% in the prostate and bone matching, respectively, and a better dose coverage of the SV was achieved by the prostate matching. CONCLUSION: The correction of repositioning along the AP and SI direction from conventional bone matching in CT image-guided proton therapy was found to be effective to maintain the dose constraint of the rectum and the dose coverage of the prostate. This work indicated that prostate cancer treatment by prostate matching using CT image guidance may be effective to reduce the rectal complications and achieve better tumor control of the prostate. However, an adaptive approach is desirable to maintain better dose coverage of the SVs. PMID- 29532490 TI - A pencil beam algorithm for magnetic resonance image-guided proton therapy. AB - PURPOSE: The feasibility of magnetic resonance image (MRI)-based proton therapy is based, among several other factors, on the implementation of appropriate extensions on current dose calculation methods. This work aims to develop a pencil beam algorithm (PBA) for dose calculation of proton beams within magnetic field regions of up to 3 T. METHODS: Monte Carlo (MC) simulations using the GATE 7.1/GEANT4.9.4p02 toolkit were performed to generate calibration and benchmarking data for the PBA. Dose distributions from proton beams in the clinical required energy range 60-250 MeV impinging on a 400 * 400 * 400 mm3 water phantom and transverse magnetic fields ranging from 0 to 3 T were considered. Energy depositions in homogeneous and heterogeneous phantoms filled with water, adipose, bone, and air were evaluated for proton energies of 80, 150, and 240 MeV, combining a trajectory calculation method and look-up tables (LUT). A novel parametrization model, using independent tailed Gauss fitting functions, was employed to describe the nonsymmetric shape of lateral beam profiles. Integrated depth-dose curves (IDD), lateral dose profiles, and two-dimensional dose distributions calculated with the PBA were compared with results from MC simulations to assess the performance of the algorithm. A gamma index criterion of 2%/2 mm was used for analysis. RESULTS: A close to perfect agreement was observed for PB-based dose calculations in water in magnetic fields of 0.5, 1.5, and 3 T. IDD functions showed differences between the PBA and MC of less than 0.1% before the Bragg peak, and deviations of 2-8% in the distal energy falloff region. Gamma index pass rates higher than 99% and mean values lower than 0.1 were encountered for all analyzed configurations. For homogeneous phantoms, only the full bone configuration offered deviations in the Bragg peak position of up to 1.7% and overestimations of the lateral beam spot width for high-energy protons and magnetic field intensities. An excellent agreement between PBA and MC dose calculation was also achieved using slab-like and lateral heterogeneous phantoms, with gamma index passing rates above 98% and mean values between 0.1 and 0.2. As expected, agreement reduced for high-energy protons and high intensity magnetic fields, although results remained good enough to be considered for future implementation in clinical practice. CONCLUSIONS: The proposed pencil beam algorithm for protons can accurately account for dose distortion effects induced by external magnetic fields. The application of an analytical model for dose estimation and corrections reduces the calculation times considerably, making the presented PBA a suitable candidate for integration in a treatment planning system. PMID- 29532491 TI - Association between transthoracic impedance and electrical cardioversion success with biphasic defibrillators: An analysis of 1055 shocks for atrial fibrillation and flutter. AB - BACKGROUND: The relevance of transthoracic impedance (TTI) to electrical cardioversion (ECV) success for atrial tachyarrhythmias when using biphasic waveform defibrillators is unknown. HYPOTHESIS: TTI is predictive of ECV success with contemporary defibrillators. METHODS: De-identified data stored in biphasic defibrillator memory cards from ECV attempts for atrial fibrillation (AF) or atrial flutter (AFL) over a 2-year period at our center were evaluated. ECV success, defined as arrhythmia termination and >= 1 sinus beat, was adjudicated by 2 blinded cardiac electrophysiologists. The association between TTI and ECV success was assessed via Cochrane-Armitage trend and Spearman rank correlation tests, as well as simple and multivariable logistic regression. The influence of TTI on the number of shocks and on cumulative energy delivered per patient was also examined. RESULTS: 703 patients (593 with AF, 110 with AFL) receiving 1055 shocks were included. Last shock success was achieved in 88.0% and 98.2% of patients with AF and AFL, respectively. In patients with AF, TTI was positively associated with last shock failure (Ptrend =0.019), the need for multiple shocks (Ptrend <0.001), and cumulative energy delivered (rho = 0.348; P < 0.001). After adjusting for first shock energy, 10-Omega increments in TTI were associated with odds ratios of 1.36 (95% CI: 1.24-1.49) and 1.22 (95% CI: 1.09-1.37) for first and last shock failure, respectively (P < 0.001 for both). CONCLUSIONS: Although contemporary defibrillators are designed to compensate for TTI, this variable continues to be associated with ECV failure in patients with AF. Strategies to lower TTI during ECV for AF may improve procedural success. PMID- 29532492 TI - Can we predict the structure and stability of molecular crystals under increased pressure? First-principles study of glycine phase transitions. AB - The aim of this study was to determine whether the periodic density functional theory (DFT) calculations can be used for accurate prediction of the influence of the increased pressure on crystal structure and stability of molecular solids. To achieve this goal a series of geometry optimization and thermodynamic parameters calculations were performed for gamma-glycine and delta-glycine structures at different pressure values using CASTEP program. In order to perform most accurate geometry optimization various exchange-correlation functionals defined within generalized gradient approximation (GGA): PBE, PW91, RPBE, WC, PBESOL as well as defined within local density approximation (LDA), i.e. CAPZ, were tested. Geometry optimization was carried out using different dispersion correction methods (i.e. Grimme, TS, OBS) or without them. The linear response density functional perturbation theory (DFPT) was used to obtain the phonon dispersion curves and phonon density of states from which thermodynamic parameters, such as: free energy (DeltaG), enthalpy (DeltaH) and entropy (DeltaS) were evaluated. The results of the geometry optimization depend strongly on the choice of the DFT functional. Calculated differences between the free energy of the studied polymorphic forms at the studied pressure values were consistent with experimental observations on their stability. The computations of thermodynamic properties not only confirmed the order of stability of two studied forms, but also enabled to predict the pressure at which this order is reversed. The results obtained in this study have proven that the plane-wave basis set first principles calculations under periodic conditions is suitable for accurate prediction of crystal structure and stability. (c) 2018 Wiley Periodicals, Inc. PMID- 29532493 TI - Image-guided radiotherapy quality control: Statistical process control using image similarity metrics. AB - PURPOSE: The purpose of this study was to demonstrate an objective quality control framework for the image review process. METHODS AND MATERIALS: A total of 927 cone-beam computed tomography (CBCT) registrations were retrospectively analyzed for 33 bilateral head and neck cancer patients who received definitive radiotherapy. Two registration tracking volumes (RTVs) - cervical spine (C-spine) and mandible - were defined, within which a similarity metric was calculated and used as a registration quality tracking metric over the course of treatment. First, sensitivity to large misregistrations was analyzed for normalized cross correlation (NCC) and mutual information (MI) in the context of statistical analysis. The distribution of metrics was obtained for displacements that varied according to a normal distribution with standard deviation of sigma = 2 mm, and the detectability of displacements greater than 5 mm was investigated. Then, similarity metric control charts were created using a statistical process control (SPC) framework to objectively monitor the image registration and review process. Patient-specific control charts were created using NCC values from the first five fractions to set a patient-specific process capability limit. Population control charts were created using the average of the first five NCC values for all patients in the study. For each patient, the similarity metrics were calculated as a function of unidirectional translation, referred to as the effective displacement. Patient-specific action limits corresponding to 5 mm effective displacements were defined. Furthermore, effective displacements of the ten registrations with the lowest similarity metrics were compared with a three dimensional (3DoF) couch displacement required to align the anatomical landmarks. RESULTS: Normalized cross-correlation identified suboptimal registrations more effectively than MI within the framework of SPC. Deviations greater than 5 mm were detected at 2.8sigma and 2.1sigma from the mean for NCC and MI, respectively. Patient-specific control charts using NCC evaluated daily variation and identified statistically significant deviations. This study also showed that subjective evaluations of the images were not always consistent. Population control charts identified a patient whose tracking metrics were significantly lower than those of other patients. The patient-specific action limits identified registrations that warranted immediate evaluation by an expert. When effective displacements in the anterior-posterior direction were compared to 3DoF couch displacements, the agreement was +/-1 mm for seven of 10 patients for both C spine and mandible RTVs. CONCLUSIONS: Qualitative review alone of IGRT images can result in inconsistent feedback to the IGRT process. Registration tracking using NCC objectively identifies statistically significant deviations. When used in conjunction with the current image review process, this tool can assist in improving the safety and consistency of the IGRT process. PMID- 29532494 TI - Tomographic and anatomical study of the orbit and nasolacrimal duct in capybaras (Hydrochoerus hydrochaeris-Linnaeus, 1766). AB - The objective of this study was to describe the reference values of cranial measurements of capybaras, correlating the ocular orbit with the nasolacrimal duct. The documentation of its results can contribute to standardizing characteristics of anatomical normality and favouring the correct diagnosis and treatment of changes. The capybara carcasses, maintained by freezing, were distributed in two groups (G) designated GA (n = 12) adult animals (A) and GY (n = 13) for young animals (Y). All subjects underwent dacryocystography examination by computed tomography (CT) and cranial measurements. Descriptive analyses of cranial and nasolacrimal duct measurements and statistical analysis of the Pearson correlation with the variable weight were performed. In GA, there was no correlation between the nasolacrimal and cranial duct measurements. However, in the GY, a correlation was verified with facial length (r = .6233), facial width (r = .5771), cranial height (r = .6981), cranial length (r = .7116), total right length (r = .7517) and left length (r = .7999). Thus, in the young animals, cranial length measurements were strongly correlated with nasolacrimal duct lengths. However, this biological behaviour was not observed in adults, demonstrating stability in development. The capybara's ocular orbit was found to be circular and incomplete, with developed zygomatic process of the maxilla. CT dacryocystography is indicated to evaluate the nasolacrimal canal pathway in capybaras, emphasizing the importance of normal anatomical study to aid in treating animals affected by diseases. PMID- 29532495 TI - Clinical predictors and outcomes of patients with pericardial effusion in chronic kidney disease. AB - BACKGROUND: Pericardial effusion is common in hospitalized patients with chronic kidney disease (CKD). We sought to identify predictors and prognostic impact of pericardial effusion in CKD patients. HYPOTHESIS: Clinical and biochemical parameters can predict pericardial effusion in CKD patients. METHODS: In a retrospective nested case-control design, we analyzed hospitalized adult patients with CKD stage 4, 5, or end-stage renal disease diagnosed with pericardial effusion. Controls were same-stage CKD patients without effusion. RESULTS: Among 84 cases and 61 controls, 44% and 34% were on dialysis, respectively. The mean creatinine was higher among cases versus controls (8.4+/-6.0 vs. 6.0+/-3.4 mg/dL, P = 0.002). Effusion was moderate to large in 46% of cases. Independent predictors of any pericardial effusion were serum potassium (OR: 1.95 per 1-mEq/L increment, 95% CI: 1.21-3.13, P = 0.006), serum corrected calcium (OR: 1.33 per 1 mg/dL decrement, 95% CI: 1.11-1.67, P = 0.015), and admission heart rate (OR: 1.29 per 10-bpm increment, 95% CI: 1.03-1.62, P = 0.027). Corrected calcium level was an independent predictor of moderate to large pericardial effusion (OR: 1.38 per 1-mg/dL decrement, 95% CI: 1.04-1.82, P = 0.023). Corrected calcium <8.0 mg/dL demonstrated 95% specificity for moderate to large effusion. Patients with effusion had no significant difference in the composite endpoint of mortality or cardiovascular rehospitalization (P = 0.408). CONCLUSIONS: In hospitalized CKD patients, hypocalcemia may be useful in identifying those with moderate to large pericardial effusion. In this population, pericardial effusion does not seem to be associated with adverse outcomes. PMID- 29532496 TI - Fast and flexible gpu accelerated binding free energy calculations within the amber molecular dynamics package. AB - Alchemical free energy (AFE) calculations based on molecular dynamics (MD) simulations are key tools in both improving our understanding of a wide variety of biological processes and accelerating the design and optimization of therapeutics for numerous diseases. Computing power and theory have, however, long been insufficient to enable AFE calculations to be routinely applied in early stage drug discovery. One of the major difficulties in performing AFE calculations is the length of time required for calculations to converge to an ensemble average. CPU implementations of MD-based free energy algorithms can effectively only reach tens of nanoseconds per day for systems on the order of 50,000 atoms, even running on massively parallel supercomputers. Therefore, converged free energy calculations on large numbers of potential lead compounds are often untenable, preventing researchers from gaining crucial insight into molecular recognition, potential druggability and other crucial areas of interest. Graphics Processing Units (GPUs) can help address this. We present here a seamless GPU implementation, within the PMEMD module of the AMBER molecular dynamics package, of thermodynamic integration (TI) capable of reaching speeds of >140 ns/day for a 44,907-atom system, with accuracy equivalent to the existing CPU implementation in AMBER. The implementation described here is currently part of the AMBER 18 beta code and will be an integral part of the upcoming version 18 release of AMBER. (c) 2018 Wiley Periodicals, Inc. PMID- 29532497 TI - The Ugandan version of the Pediatric Evaluation of Disability Inventory (PEDI UG). Part II: Psychometric properties. AB - BACKGROUND: The Pediatric Evaluation of Disability Inventory (PEDI) has been recommended as a gold standard in paediatric rehabilitation. A Ugandan version of PEDI (PEDI-UG) has been developed by culturally adapting and translating the original PEDI. The aim of this study was to investigate the psychometric properties of the PEDI-UG in Ugandan children by testing the instrument's rating scale functioning, internal structure, and test-retest reliability. METHODS: Two hundred forty-nine Ugandan children (125 girls) aged 6 months to 7.5 years (Mean = 3.4, SD = 1.9) with typical development were tested using the PEDI-UG. Forty nine children were tested twice to assess test-retest reliability. Validity was investigated by Rasch analysis and reliability by intraclass correlation coefficient. RESULTS: The PEDI-UG domains showed good unidimensionality based on principal component analysis of residuals. Most activities (95%) showed acceptable fit to the Rasch model. Six misfit items were deleted from the Functional Skills scales and one from the Caregiver Assistance scales. The category steps on the Caregiver Assistance scales' rating scale were reversed but functioned well when changed from a 6-point to 4-point rating scale. The reliability was excellent; intraclass correlation coefficient was 0.87-0.92 for the domains of the Functional Skills scales and 0.86-0.88 for the domains of the Caregiver Assistance scales. CONCLUSION: The PEDI-UG has good to excellent psychometric properties and provides a valid measure of the functional performance of typically developing children from the age of 6 months to 7.5 years in Uganda. Further analysis of all items, including misfit and deleted items, in children with functional disability is recommended. PMID- 29532498 TI - Posttraumatic stress disorder and mortality in VA patients with implantable cardioverter-defibrillators. AB - BACKGROUND: The association between posttraumatic stress disorder (PTSD) and mortality in patients undergoing implantable cardioverter-defibrillator (ICD) placement has not been evaluated in US veterans. HYPOTHESIS: PTSD in veterans with ICD is associated with increased mortality. METHODS: We studied a retrospective cohort of 25 678 veterans who underwent ICD implantation between September 30, 2002, and December 31, 2011. Of these subjects, 3280 carried the diagnosis of PTSD prior to ICD implantation. Primary outcome was all-cause mortality between date of ICD implantation and end of follow-up (September 30, 2013). We used Cox proportional hazard models to compute multivariable adjusted hazard ratios with corresponding 95% confidence intervals for the relation between PTSD diagnosis and death following ICD placement. RESULTS: During a mean follow-up of 4.21 +/- 2.62 years, 11 015 deaths were reported. The crude incidence rate of death was 87.8 and 103.9/1000 person-years for people with and without PTSD, respectively. We did not find an association between presence of PTSD before or after ICD implantation and incident death when adjusted for multiple risk factors (hazard ratio: 1.003, 95% confidence interval: 0.948 1.061). In secondary analysis, no statistically significant association was found. CONCLUSIONS: In this retrospective cohort study among more than 25 000 veterans undergoing ICD implantation, almost 13% had a diagnosis of PTSD. Subjects with PTSD were significantly younger, yet they had a higher incidence of coronary heart disease, major cardiac comorbidities, cancer, and mental health conditions. We found no association between presence of PTSD before or after ICD implantation and incident death when adjusting for all covariates. PMID- 29532499 TI - Influence of radiographic techniques on the measurement of femoral anteversion angles and a conformation score of pelvic limbs in Labrador retrievers. AB - OBJECTIVE: To determine repeatability of and correlation between 2 radiographic measurements of femoral anteversion angles (FAA) and to determine their influence on a score derived from tibial plateau angle (TPA) and FAA to predict the risk of cranial cruciate ligament disease (CCLD). STUDY DESIGN: Prospective clinical study. ANIMALS: Forty-eight Labrador retrievers with or without CCLD. METHODS: FAA and CCLD scores were calculated for each limb from extended pelvic radiographs (t-FAA) or angled (a-FAA) projections of the femur by 3 investigators. One investigator repeated measurements twice. Data were analyzed for repeatability, correlation between t-FAA and a-FAA, and their influence on CCLD scores. RESULTS: FAA correlated most strongly with the distance between the femoral head and the femoral axis on mediolateral radiographs, a measurement with excellent repeatability. t-FAA and a-FAA correlated with each other (r > 0.79, P < .0001), although t-FAA were about 1 degrees greater than a-FAA (P = .01). Intrainvestigator and interinvestigator repeatability of the CCLD score was fair when derived from t-FAA and good to excellent when derived from a-FAA. CCLD scores differed between radiographic techniques but led to different predictions in only 9 (10%) limbs, all with lower TPA and CCLD scores than the rest of the population. CONCLUSION: a-FAA correlated strongly with t-FAA and improved the repeatability of CCLD scores within and between investigators. CLINICAL SIGNIFICANCE: A craniocaudal angled beam projection of the femur is a suitable alternative to a ventrodorsal pelvic radiograph when measuring FAA and may improve the repeatability and positive predictive value of CCLD scores. PMID- 29532500 TI - POLARIS: Polygenic LD-adjusted risk score approach for set-based analysis of GWAS data. AB - Polygenic risk scores (PRSs) are a method to summarize the additive trait variance captured by a set of SNPs, and can increase the power of set-based analyses by leveraging public genome-wide association study (GWAS) datasets. PRS aims to assess the genetic liability to some phenotype on the basis of polygenic risk for the same or different phenotype estimated from independent data. We propose the application of PRSs as a set-based method with an additional component of adjustment for linkage disequilibrium (LD), with potential extension of the PRS approach to analyze biologically meaningful SNP sets. We call this method POLARIS: POlygenic Ld-Adjusted RIsk Score. POLARIS identifies the LD structure of SNPs using spectral decomposition of the SNP correlation matrix and replaces the individuals' SNP allele counts with LD-adjusted dosages. Using a raw genotype dataset together with SNP effect sizes from a second independent dataset, POLARIS can be used for set-based analysis. MAGMA is an alternative set based approach employing principal component analysis to account for LD between markers in a raw genotype dataset. We used simulations, both with simple constructed and real LD-structure, to compare the power of these methods. POLARIS shows more power than MAGMA applied to the raw genotype dataset only, but less or comparable power to combined analysis of both datasets. POLARIS has the advantages that it produces a risk score per person per set using all available SNPs, and aims to increase power by leveraging the effect sizes from the discovery set in a self-contained test of association in the test dataset. PMID- 29532501 TI - Tributyltin stimulates synthesis of interferon gamma and tumor necrosis factor alpha in human lymphocytes. AB - Tributyltin (TBT) is found in human blood and other tissues and thus is of considerable concern as to its effects on human health. Previous studies have demonstrated that TBT has detrimental effects on immune function. Recently, we found that exposures to TBT caused increased secretion of two important proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma). Elevation of either of these cytokines has the potential to cause chronic inflammation, which is an important factor in a number of diseases including cancer. The current study examined the mechanism of TBT-induced elevations of TNFalpha and IFNgamma secretion and found that the p38 mitogen activated protein kinase pathway was essential to the ability of TBT to stimulate secretion. Additionally, this study demonstrated that increased secretion of these cytokines was due to TBT-induced increases in their overall synthesis, rather than simply being due to an increase in the release of already formed proteins. The TBT-induced increases in synthesis were evident within 6 hours of exposure. The p38 mitogen-activated protein kinase pathway is also necessary for the TBT-induced increases in both TNFalpha and IFNgamma synthesis. The role of increased transcription of TNFalpha and IFNgamma mRNA in response to TBT exposures as a possible explanation for the increased synthesis of these cytokines was also examined. It was found that increased mRNA levels did not appear to explain fully the increases in either TNFalpha or IFNgamma synthesis. Thus, TBT is able to increase secretion of two important proinflammatory cytokines by increasing their synthesis. PMID- 29532502 TI - Administering atropine and ketamine before less invasive surfactant administration resulted in low pain scores in a prospective study of premature neonates. AB - AIM: Less invasive surfactant administration (LISA) can avoid tracheal intubation for neonatal respiratory distress syndrome, but can be painful because it requires laryngoscopy. The aim of this study was to assess the efficacy and tolerance of intravenous atropine plus ketamine administration before LISA. METHODS: We conducted a prospective observational study of all premature infants hospitalised in our French neonatal intensive care unit treated with LISA between March 2015 and March 2016. Ketamine was titrated by 0.5 mg/kg increments. The technical conditions, pain scores, emergent intubations and vital signs were collected and analysed. RESULTS: Values are reported as medians (interquartile ranges). We included 29 patients with a gestational age of 29.6 (28.6-30.9) weeks and birth weight of 1290 (945-1600) grams. Technical conditions were satisfying for 24 infants (83%). The Faceless Acute Neonatal Pain Scale score was 2 (2-4); seven infants (24%) required tracheal intubation before LISA could be performed; 17 (59%) had a pulse oxymetry value under 80% that lasted more than 60 seconds. Heart rate and mean arterial blood pressure transiently increased. CONCLUSION: Atropine plus ketamine before LISA resulted in low pain scores and stable haemodynamic parameters, but prolonged desaturations or apnoea leading to tracheal intubation were frequently observed. PMID- 29532503 TI - Identification of risk for neonatal haemolysis. AB - AIM: To identify neonates at risk of haemolytic hyperbilirubinaemia through near concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. METHODS: Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated. RESULTS: For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and >=75th percentile, respectively. TB/TcB (5.79 +/- 1.84 vs 9.14 +/ 2.25 mg/dL) and ETCOc (1.61 +/- 0.45 vs 2.02 +/- 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB >=75th percentile had ETCOc >= 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and >=75th percentile, respectively. TB/TcB (5.28 +/- 1.97 vs 9.53 +/- 2.78 mg/dL), ETCOc (1.72 +/- 0.48 vs 2.38 +/- 1.89 ppm, p = 0.05) and TB ROR (0.011 +/- 0.440 vs 0.172 +/- 0.471 mg/dL/h) were different between the groups. CONCLUSION: The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders. PMID- 29532504 TI - Clinical Simulation Learning for Small-Bowel Feeding Tube Insertion. AB - Clinical simulation training provides a realistic environment for students and healthcare professionals to strengthen and broaden skills and abilities. This type of learning experience creates a controlled environment in which learners may attain new skills or further develop skills that positively impact patient outcomes. Although few studies exist regarding the use of clinical simulation training and nutrition support practitioners, preliminary data following a small bowel feeding tube (SBFT) insertion workshop for intensive care unit registered nurses and registered dietitian nutritionists showed potential use in this realm. The purpose of this paper is to provide a basic overview of clinical simulation learning, review literature related to clinical simulation in healthcare, and discuss the recent implementation of a SBFT insertion workshop incorporating clinical simulation learning. PMID- 29532505 TI - Venovenous Extracorporeal Membrane Oxygenation in an Adult Patient With Prader Willi Syndrome: A Nutrition Case Report. AB - Prader-Willi Syndrome (PWS) is a genetic condition that results in a constellation of symptoms and typically results in hyperphagia and obesity in adulthood. Critically ill adults with PWS present a unique challenge to the nutrition professional, particularly when they require support modalities such as extracorporeal membrane oxygenation (ECMO). The purpose of this case study is to review the nutrition care of a critically ill adult patient with PWS who required venovenous ECMO. The patient was successfully managed with a hypocaloric, high protein approach, which did not result in the diagnosis of malnutrition during his hospitalization. The patient was ultimately transitioned off extracorporeal life support and discharged to a rehabilitation facility. PMID- 29532506 TI - Detection of gastro-oesophageal reflux in the neonatal unit. AB - AIM: To determine whether a pH probe or multichannel intraluminal impedance (MII) more frequently detected gastro-oesophageal reflux and test the hypothesis that acid reflux was associated with lower baseline impedance. METHODS: A prospective study of infants in whom reflux was suspected and evaluated using combined pH and multichannel impedance. Studies were considered abnormal if the acid index was >10% or there were >79MII reflux events in 24 hours. The acid index was the percentage of total study time with a pH=11, was found in 392/549 (71%) with completed scores, but only 40 of 649 (6%) assessed for dehydration were more than 5% dehydrated. None had sodium <130 mmol/L. Glucose of 3.0-3.3 mmol/L was detected in 52/578 (9%) and <3.0 mmol/L in 33/578 (6%). Hypoglycaemia, elevated urea, low bicarbonate and negative base excess were associated with disease severity. The duration of vomiting and the rotavirus infection were associated with hypoglycaemia. Elevated urea, low bicarbonate and negative base excess had high specificities, but low sensitivities. CONCLUSION: Hypoglycaemia was common in acute gastroenteritis, but major electrolyte disturbances were infrequent. PMID- 29532512 TI - Late adulthood mortality among African-American and white American people with Type 1 diabetes according to age at diabetes diagnosis. AB - AIMS: To estimate the overall and cause-specific mortality in a population of African-Americans and white Americans with a low socio-economic status who had young-onset insulin-treated diabetes and had survived beyond the age of 40 years, and to examine whether any excess risk varied according to age at diabetes onset. METHODS: Using the Southern Community Cohort Study, we conducted a mortality follow-up of a cohort of mostly low-income participants aged 40-79 years (mean 50 years) at cohort entry with insulin-treated diabetes diagnosed before age 30 years (n=475) and without diabetes (n=62 266). Childhood onset was defined as diabetes diagnosed before age 20 years (n=162), while young-adulthood onset was defined as diabetes diagnosed between ages 20 and 29 years (n=313). Cause specific mortality was based on both underlying and contributing causes of death, obtained from death certificates. Multivariable Cox analysis was performed. RESULTS: During follow-up (mean 9.5 years), 38.7% of those with and 12.9% of those without diabetes died. Compared with those without diabetes, increases in mortality rate were generally similar among those with childhood- and young adulthood-onset diabetes for deaths from: all causes (childhood: hazard ratio 4.3, CI 3.3-5.5; young adulthood: hazard ratio 4.9, CI 4.0-5.8); ischaemic heart disease (childhood: hazard ratio 5.7, CI 3.5-9.4; young adulthood: hazard ratio 7.9, CI 5.6-11.0); heart failure (childhood: hazard ratio 7.3, CI 4.2-12.7; young adulthood: hazard ratio 5.4, CI 3.3-8.9); sepsis (childhood: hazard ratio 10.3, CI 6.1-17.3; young adulthood: hazard ratio 8.8, CI 5.7-13.5); renal failure (childhood: hazard ratio 15.1, CI 8.6-26.5; young adulthood: hazard ratio 18.2, CI 12.3-27.1); respiratory disorders (childhood: hazard ratio 3.9, CI 2.3-6.7; young adulthood: hazard ratio 5.3, CI 3.7-7.7); suicide/homicide/accidents (childhood: hazard ratio 2.3, CI 0.72-7.0; young adulthood: hazard ratio 5.8, CI 3.4-10.2); and cancer (childhood: hazard ratio 2.1, CI 0.98-4.4; young adulthood: hazard ratio 1.2, CI 0.55-2.5). CONCLUSIONS: We observed high excess long-term mortality for all-cause, renal failure, ischemic heart disease and heart failure mortality in African-American and white American people with early-onset insulin treated diabetes. PMID- 29532513 TI - Historical perspective on folic acid and challenges in estimating global prevalence of neural tube defects. AB - Neural tube defects (NTD) are major congenital malformations affecting births worldwide. NTD are associated with life-long disability, significant medical care costs, and child mortality. Their prevalence varies worldwide. We conducted a review of published literature and surveillance systems to examine challenges in estimating an overall global prevalence estimate for NTD. Our review showed that most low- and middle-income countries do not track NTD and indicate a high prevalence of these malformations where data are available. Challenges in global NTD prevalence estimation include (1) quality of surveillance methods, (2) existing risk factors (including geographic or socioeconomic factors, availability and use of folic acid, and racial-ethnic and genetic factors), and (3) limitations in education and access to care. We recommend population-based surveillance systems tracking all pregnancy outcomes and major risk factors. Countries should invest in sustainable, multisource surveillance systems, in parallel to folic acid interventions, for gaining a more accurate knowledge of global prevalence of NTD than we currently have. Such efforts will assist in both global prevention of NTD and periodic evaluation of folic acid interventions for NTD reduction. Global NTD prevalence data can drive political will and accelerate the implementation and evaluation of NTD prevention programs. PMID- 29532514 TI - Improving maternal folate status to prevent infant neural tube defects: working group conclusions and a framework for action. AB - As infectious disease control programs achieve increasing success, further reductions in child mortality in low- and middle-income countries (LMICs) will require focused prevention strategies for birth defects and other noninfectious diseases. Neural tube defects (NTDs) can cause early death or lifelong disability. Preventing NTDs provides a feasible, significant opportunity to decrease the toll of birth defects and contribute to further reducing child mortality globally. The Micronutrient Forum convened a technical consultation on Folate Status in Women and Neural Tube Defects Prevention to develop a roadmap to inform and prioritize investments in NTD prevention in LMICs; help guide implementation efforts in terms of the feasibility of interventions and the potential for acceleration; and identify research and knowledge gaps. Here, we describe the impetus for and approach to the consultation and present the conclusions and a framework for developing a roadmap for action to accelerate NTD prevention in LMICs. The framework (1) provides options for action on folate status assessment; (2) outlines a way forward to develop and implement a time bound global action plan for NTD prevention; and (3) identifies common impediments to NTD prevention, broad strategies to overcome or minimize these impediments, and basic building blocks necessary to accelerate action. PMID- 29532515 TI - Triple surveillance: a proposal for an integrated strategy to support and accelerate birth defect prevention. AB - Preventing neural tube defects (NTDs) easily qualifies as a high-value opportunity to improve childhood survival and health: the unmet need is significant (major preventable burden), the intervention is transformative (providing sufficient folic acid), and delivery strategies (e.g., fortification) are effective in low-resource countries. Yet, NTD prevention is lagging. Can public health surveillance help fix this problem? Critics contend that surveillance is largely unnecessary, that limited resources are best spent on interventions, and that surveillance is unrealistic in developing countries. The counterargument is twofold: (1) in the absence of surveillance, interventions will provide fewer benefits and cost more and (2) effective surveillance is likely possible nearly everywhere, with appropriate strategies. As a base strategy, we propose "triple surveillance:" integrating surveillance of cause (folate insufficiency), of disease occurrence (NTD prevalence), and of health outcomes (morbidity, mortality, and disability). For better sustainability and usefulness, it is crucial to refocus and streamline surveillance activities (no recreational data collection), weave surveillance into clinical care (integrate in clinical workflow), and, later, work on including additional risk factors and pediatric outcomes (increase benefits at low marginal cost). By doing so, surveillance becomes not a roadblock but a preferential path to prevention and better care. PMID- 29532516 TI - Effects of levocetirizine and diphenhydramine on regional glucose metabolic changes and hemodynamic responses in the human prefrontal cortex during cognitive tasks. AB - OBJECTIVE: Antihistamines often have sedative side effects. This was the first study to measure regional cerebral glucose (energy) consumption and hemodynamic responses in young adults during cognitive tests after antihistamine administration. METHODS: In this double-blind, placebo-controlled, three-way crossover study, 18 healthy young Japanese men received single doses of levocetirizine 5 mg and diphenhydramine 50 mg at intervals of at least six days. Subjective feeling, task performances, and brain activity were evaluated during three cognitive tests (word fluency, two-back, and Stroop). Regional cerebral glucose consumption changes were measured using positron emission tomography with [18 F]fluorodeoxyglucose. Regional hemodynamic responses were measured using near infrared spectroscopy. RESULTS: Energy consumption in prefrontal regions was significantly increased after antihistamine administration, especially diphenhydramine, whereas prefrontal hemodynamic responses, evaluated with oxygenated hemoglobin levels, were significantly lower with diphenhydramine treatment. Stroop test accuracy was significantly impaired by diphenhydramine, but not by levocetirizine. There was no significant difference in subjective sleepiness. CONCLUSIONS: Physiological "coupling" between metabolism and perfusion in the healthy human brain may not be maintained under pharmacological influence due to antihistamines. This uncoupling may be caused by a combination of increased energy demands in the prefrontal regions and suppression of vascular permeability in brain capillaries after antihistamine treatment. Further research is needed to validate this hypothesis. PMID- 29532517 TI - Insights into Roseburia intestinalis which alleviates experimental colitis pathology by inducing anti-inflammatory responses. AB - BACKGROUND AND AIM: The study aims to elucidate the anti-inflammatory effect and mechanism of Roseburia intestinalis (R. intestinalis) in Crohn's disease (CD). METHODS: 16S-rRNA genome sequencing technique is used to detect the characteristics of intestinal microbiota in untreated CD patients and healthy controls. Then the study investigates the effects of R. intestinalis on disease activity index score, intestinal pathology, the differentiation of Treg cells, and the expressions of Thymic stromal lymphopoietin (TSLP), TGF-beta and IL-10 by using TNBS colitis models. At the cellular level, the study uses LPS to stimulate Caco-2 cells to conduct inflammation models and then co-culture with R. intestinalis and detect changes of TSLP and TGF-beta. The study then uses R. intestinalis to stimulate peripheral blood mononuclear cells, and the change of Treg cells was detected. RESULTS: Genome sequencing of fecal samples from untreated CD patients (n = 10) revealed decreases in the abundance and diversity of intestinal microbiota, including R. intestinalis. Moreover, R. intestinalis reduced disease activity index scores, colon shortening, intestinal mucosal epithelial injury, and mucosal lymphocyte infiltration in a colitis mice model. It suppressed intestinal inflammation by increasing Treg cell numbers and expression of the anti-inflammatory cytokines TSLP, TGF-beta, and interleukin-10 (P < 0.05). R. intestinalis also increased secretion of TSLP and TGF-beta in lipopolysaccharide-treated Caco-2 cells. CONCLUSION: These findings suggest that R. intestinalis suppresses CD pathogenesis by inducing anti-inflammatory responses. PMID- 29532518 TI - Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia - A Swedish nationwide cohort study. AB - OBJECTIVES: Antithymocyte globulin (ATG)-based immunosuppression remains a cornerstone in aplastic anaemia (AA) treatment. However, most ATG studies are not population-based and knowledge about real-world results concerning response and outcome could offer important information for treating physicians. METHODS: We have recently performed a nationwide retrospective cohort study on all AA patients diagnosed in Sweden in 2000-2011 and now present treatment and outcome data on patients receiving first-line ATG. In total, 158 patients showed a 47.0% response rate which was similar in all age groups (range 41.5%-51.7%) with no difference regarding ATG formulation. The response was significantly associated with severity grade-especially at time of treatment initiation: very severe (VSAA) 22.7%; severe (SAA) 54.5% (P < .001); and non-severe 88.5% (P < .001). A logistic regression-based predictive model indicated that VSAA patients with an absolute reticulocyte count <25 * 109 /L had only a 19% probability of response. In a multivariable analysis, age and VSAA at the time of treatment were the independent factors for inferior survival. CONCLUSIONS: Real-world VSAA patients respond poorly to ATG which indicates the need for a different treatment approach. Our findings suggest that age alone should not be a discriminating factor for administering ATG treatment. PMID- 29532519 TI - Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure. AB - Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase-4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti-hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure. PMID- 29532520 TI - Clinicopathological characteristics of de novo and secondary myeloid sarcoma: A monocentric retrospective study. AB - OBJECTIVE: Diagnosing myeloid sarcoma remains challenging, and we aimed to provide clinicopathological features to facilitate diagnosis. METHOD: Clinicopathological data from 41 patients with de novo and 31 with secondary myeloid sarcoma were reviewed. RESULTS: Most de novo cases presented with isolated myeloid sarcoma (n = 19) or myeloid sarcoma with concurrent acute myeloid leukemia (n = 15). Most secondary cases presented after acute myeloid leukemia (n = 11), myeloproliferative neoplasm (n = 9), or myelodysplastic syndrome (n = 8). Most frequent localizations were skin and lymph nodes. Immunohistochemistry showed immature and/or aberrant antigenic expression in 29% of de novo and 39% of secondary cases. Most genetic abnormalities were RUNX1 RUNX1T1 (n = 4), CBFB-MYH11 (n = 2), KMT2A-MLLT3 (n = 2), and JAK2 V617F (n = 2) mutations in de novo myeloid sarcoma, and BCR-ABL1 (n = 5) and KMT2A rearrangements (n = 2) in secondary cases. A complex karyotype was seen in 17% of de novo and 39% of secondary cases. Most prevalent treatment was induction chemotherapy followed by consolidation chemotherapy (n = 10) or allogeneic stem cell transplantation (n = 9) for de novo and radiotherapy (n = 11) for secondary cases. CONCLUSION: De novo myeloid sarcoma mostly presented isolated. Lesions were often localized at skin and lymph nodes. Genetic aberrations frequently involved core-binding factor rearrangements in de novo cases and a complex karyotype in secondary cases. PMID- 29532521 TI - Consensus guidelines for the uniform reporting of study ethics in anatomical research within the framework of the anatomical quality assurance (AQUA) checklist. AB - Unambiguous reporting of a study's compliance with ethical guidelines in anatomical research is imperative. As such, clear, universal, and uniform reporting guidelines for study ethics are essential. In 2016, the International Evidence-Based Anatomy Working group in collaboration with international partners established reporting guidelines for anatomical studies, the Anatomical Quality Assurance (AQUA) Checklist. In this elaboration of the AQUA Checklist, consensus guidelines for reporting study ethics in anatomical studies are provided with in the framework of the AQUA Checklist. The new guidelines are aimed to be applicable to research across the spectrum of the anatomical sciences, including studies on both living and deceased donors. The authors hope the established guidelines will improve ethical compliance and reporting in anatomical research. Clin. Anat. 31:521-524, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29532522 TI - Low prevalence of diabetes distress following total pancreatectomy with islet autotransplantation. AB - Diabetes distress (DD), or psychological fatigue associated with diabetes management, is common in type 1 and 2 diabetes mellitus and is associated with poor glycemic control. Diabetes distress has never been evaluated in patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We analyzed DD after TPIAT in 260 patients (average age 34.3 [standard deviation 15], 75.5% F) undergoing TPIAT between 2006 and 2014. Each patient completed 1 or more diabetes distress scale (DDS) questionnaires from 1 to 7 years post-TPIAT (631 total). We examined changes in DD over 7 years and also patient characteristics associated with DD 1 year post-TPIAT (n = 189). One year after TPIAT, 151 of 189 (80%) reported no or low distress (DD<2). Diabetes distress increased over time by an average of 0.084 (SE 0.017) points per year, an average 0.59 point increase from years 1 to 7 (P < .0001). Insulin-dependent patients had significantly greater DD 1 year post-TPIAT compared to insulin independent patients (P < .0001). Higher DD was associated with poorer glycemic control as indicated by HbA1c (P < .0001). Prevalence of DD is low but increases over time after TPIAT. Insulin dependence and poorer glycemic control are associated with higher levels of DD. PMID- 29532523 TI - Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma. AB - Epithelioid glioblastoma (eGBM) is a rare variant of GBM which was adopted in the 2016 WHO classification. eGBM and pleomorphic xanthoastrocytoma (PXA) sometimes show overlapping features histologically and genetically, such as epithelioid pattern and a highly frequent V600E mutation in the gene for vRAF murine sarcoma viral oncogene homolog B1 (BRAF), respectively. Accurate diagnosis of these rare tumors is challenging according to the new criteria in the revised 2016 WHO classification. It is an urgent task to elucidate the biological properties of the tumors and to select appropriate treatment. Twenty consecutive cases diagnosed as PXA or eGBM histologically were investigated. Twelve of the 20 cases were PXAs and eight were eGBMs. Morphologically, mitotic activity, necrosis and degenerative changes such as intracellular lipid accumulation, eosinophilic granular bodies and reticulin fiber deposits were scored. Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), alpha-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA. Of the 20 cases tested, Sanger technique showed no mutation in IDH1/2. BRAF mutation at T1799 > A (V600E) was detected in 4/12 (33.3%) PXA and 4/8 (50.0%) eGBM, while TERT-p mutation was detected at C228 > T in 2/12 (16.7%) PXA and at C250 > T in 1/8 (12.5%) eGBM. Retained nuclear ATRX was observed in 12/12 (100%) PXA and 6/7 (85.7%) eGBM while p53 mutation was observed in 2/10 (20%) PXA and 7/7 (100%) eGBM. All tumors retained INI1 expression in their nuclei. None of the tumors harbored H3F3A mutation. One PXA without BRAF mutation acquired TERT-p mutation at recurrence and one eGBM harbored both BRAF and TERT-p mutation. Molecular biological similarity between eGBM and PXA was suggested in our series, while degenerative changes reflected the features of PXA. It was speculated that the common genetic alterations for development and progression of eGBM and PXA might include BRAF and TERT-p mutations. PMID- 29532524 TI - Heterogeneous Pyrophosphate-Linked DNA-Oligonucleotides: Aversion to DNA but Affinity for RNA. AB - Pyrophosphate linkages are important in extant biology and are hypothesized to have played a role in prebiotic chemistry and in the origination of oligonucleotides. Inspired by pyrophosphate as backbones of primordial oligomers, DNA oligomers with varying amounts of pyrophosphate inserts (ppDNA) were synthesized and investigated for their base-pairing properties. As expected, pyrophosphate inserts into the backbone compromised the thermal stability of ppDNA-DNA duplexes. In contrast, the ppDNA-RNA duplex exhibited, remarkably, duplex stability, even with accumulation of pyrophosphate linkages. This seems to be a consequence of an increase in the diameter of the double-helix with eight bond-repeat units, and higher inclination of the base-pair axis with respect to the backbone in RNA (A-form), compared with that in DNA (B-form). These results suggest that pyrophosphate-linked oligonucleotides could harbor functional capabilities with implications for their roles in the origins of life and chemical biology. PMID- 29532525 TI - Effect of socket grafting with deproteinized bone mineral: An RCT on dimensional alterations after 6 months. AB - OBJECTIVE: To examine if (i) characteristics of the fresh extraction socket site influenced subsequent dimensional alterations and (ii) placement of deproteinized bovine mineral in the socket affected volumetric change during healing. MATERIALS AND METHODS: Twenty seven subjects and 28 extraction sites were included. Immediately after the removal of the tooth and after 6 months of healing, stone and virtual models of the jaw were produced. A cone beam computerized tomography scan was obtained immediately after extraction and the thickness of the buccal bone wall at the extraction site was measured. Extraction sites were randomly assigned to test or control group. In the test group, extraction sockets were filled with deproteinized bone mineral and covered with a collagen membrane. In the control group, only a collagen membrane was placed. RESULTS: The thickness of the buccal bone wall at the extraction site influenced the amount of volume reduction that occurred. Socket grafting influenced the degree of ridge diminution only at sites where the buccal bone wall was thin (<= 1 mm). CONCLUSION: A graft comprised of collagen-enriched deproteinized bovine bone mineral, placed to fill extraction sockets failed to influence the overall diminution of the ridge that occurred during healing. The thickness of the buccal bone wall apparently had a significant influence on volumetric alterations of the edentulous ridge following tooth extraction. PMID- 29532526 TI - Myricetin suppresses breast cancer metastasis through down-regulating the activity of matrix metalloproteinase (MMP)-2/9. AB - Tumour metastasis is the major cause of breast cancer mortality. Myricetin, a natural polyphenol, is found in teas, wines, and berries. The pharmacodynamic action and molecular mechanism of myricetin on breast cancer metastasis remain unknown. Here, we investigated the effect of myricetin on MDA-Mb-231Br cell viability, migration, invasion, and 4T1 mouse lung metastasis mouse models. MMP 2/9 protein expression and ST6GALNAC5 expression were analysed using western blot assays and quantitative real-time polymerase chain reaction, respectively. Cell migration and invasion were detected by wound-healing and Boyden transwell assays. The antimetastatic effect in vivo was evaluated by lung metastasis model. Myricetin significantly decreased the activities of MMP-2/9 and mRNA levels of ST6GALNAC5. In addition, the migration, invasion, and adhesion were effectively inhibited in a concentration-dependent manner. On the other hand, mice treated with myricetin exhibited smaller tumour nodules compared with the vehicle mice, with only 17.78 +/- 15.41% after treatment with 50 mg/kg myricetin. In conclusion, myricetin could significantly block invasion of MDA-Mb-231Br cells through suppressing the protein expression of MMP-2/9 and the expression of ST6GALNAC5, as well as lung metastasis in a mouse model, which suggests that myricetin should be developed as a potential therapeutic candidate for breast cancer. PMID- 29532528 TI - 2D and 3D Coordination Networks of Polynuclear Bismuth Oxido/Hydroxido Sulfonato Clusters from Low Temperature Solid-State Metathesis Reactions. AB - Solid-state metathesis (SSM) reactions between Bi(NO3 )3 ?5 H2 O and potassium benzene-1,2-disulfonate (=1,2-BDSK2 ), sodium benzene-1,3-disulfonate (=1,3 BDSNa2 ) allows access to the first 2D, {[Bi6 O4 (OH)4 (1-2BDS)2 (NO3 )2 ?4 H2 O]?11 H2 O}infinity and {[Bi22 O24 (OH)6 (1,3-BDS)6 ?12 DMSO]?3 DMSO?4 H2 O}infinity , and 3D, {[Bi6 O4 (OH)4 (1,3-BDS)3 ?4 H2 O]?6 H2 O}infinity , polymeric networks of sulfonato encapsulated polynuclear bismuth oxido/hydroxido clusters. PMID- 29532527 TI - Incidence of arrhythmias and impact of permanent pacemaker implantation in hospitalizations with transcatheter aortic valve replacement. AB - BACKGROUND: This study sought to analyze in-hospital outcomes associated with preexisting and newly implanted permanent pacemaker (PPM) in patients who underwent transcatheter aortic valve replacement (TAVR). PPM implantation following the development of conduction abnormalities is a common adverse event following TAVR. Furthermore, PPM implantation rates are higher in TAVR hospitalizations compared with the surgical alternative, thus we have analyzed the predictors of pacing post-TAVR. HYPOTHESIS: We hypothesize that incidence of arrhythmias are high post-TAVR and have worse adverse outcomes after receiving PPM. METHODS: The study population was identified from the National Inpatient Sample database between 2012 and 2014. TAVR population was identified using ICD-9 CM procedure codes 35.05 and 35.06. Hospitalizations were divided into 3 group: (1) with preexisting PPM, (2) with newly implanted PPM, and (3) without any PPM. RESULTS: Overall, 0.8% of hospitalizations presented with preexisting PPM and 23.7% of hospitalizations received new PPM. The overall incidence of atrial fibrillation was 44.5%, left bundle branch block 8.9%, complete atrioventricular block 9.5%, and right bundle branch block 2.7%. In-hospital mortality was higher in hospitalizations receiving PPM compared with those without (4.9% vs 4.0%; P = 0.05). Length of stay and cost were higher in the group receiving new PPM. Female sex, atrial fibrillation, left bundle branch block, and second-degree and complete atrioventricular block were significant predictors for receiving PPM after TAVR. CONCLUSIONS: A risk stratification for hospitalizations with conduction disorders is necessary to avoid longer hospital stays, added costs, and mortality. Further research is warranted to investigate additional predictors for PPM after TAVR. PMID- 29532529 TI - Diagnostic accuracy of first-trimester ultrasound in detecting abnormally invasive placenta in high-risk women with placenta previa. AB - OBJECTIVE: To ascertain the diagnostic accuracy of ultrasound in detecting abnormally invasive placenta (AIP) during the first trimester of pregnancy (11-14 weeks' gestation) in women at risk for this condition. METHODS: This was a retrospective analysis of data collected prospectively from women at risk for AIP based upon the presence of at least one prior Cesarean section (CS) and/or uterine surgery and placenta previa, who had ultrasound assessment for AIP at the time of the 11-14-week scan. The ultrasound signs explored in the present study were: loss of the clear zone, placental lacunae, bladder wall interruption and uterovesical hypervascularity. The potential of ultrasound and different ultrasound signs to predict the different types of AIP was assessed by computing summary estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and positive (LR+) and negative (LR-) likelihood ratios. RESULTS: One hundred and eighty-eight women with placenta previa and at least one previous CS or uterine surgery were included in the study. All the explored ultrasound signs were associated significantly with the occurrence of AIP. Overall, when at least one ultrasound sign was used to make the diagnosis, ultrasound had a sensitivity of 84.3% (95% CI, 74.7-91.4%), specificity of 61.9% (95% CI, 51.9-71.2%), DOR of 8.6 (95% CI, 4.1-19.3), LR+ of 2.2 (95% CI, 1.7-2.9) and LR- of 0.3 (95% CI, 0.1-0.4) in detecting AIP. Using two ultrasound signs to label a case as positive increased the diagnostic accuracy in terms of specificity, although it did not affect sensitivity. Among the different ultrasound signs, loss of the clear zone had a sensitivity of 84.3% (95% CI, 74.7-91.4%) and a specificity of 81.9% (95% CI, 73.2-88.7%) in detecting AIP, while sensitivities for placental lacunae and bladder wall interruption were 78.3% (95% CI, 67.9-86.6%) and 75.9% (95% CI, 65.3 84.6%), respectively, and specificities were 81.0% (95% CI, 72.1-88.0%) and 99.1% (95% CI, 94.8-100.0%), respectively. The optimal combination of sensitivity and specificity was achieved when at least two imaging signs of AIP were used in the diagnostic algorithm. CONCLUSIONS: AIP can be detected from the first trimester of pregnancy in women at risk for this condition, and ultrasound performed between 11 and 14 weeks' gestation has an overall good diagnostic accuracy for detecting all types of AIP. However, these findings are applicable only to women with placenta previa and prior uterine scar. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29532530 TI - Two- and three-dimensional transperineal ultrasound as a complementary tool for the management of vaginal hematomas. AB - Vaginal hematoma is an uncommon complication of vaginal delivery, with potential serious consequences (1) . Its optimal management remains unclear. Caudal extension and maternal hemodynamic condition are the main determinants of the outcome. A high index of suspicion, appropriate and timely diagnosis management are fundamental. We present a case of a woman in which transperineal ultrasound was helpful in the diagnosis and management of a vaginal hematoma. PMID- 29532531 TI - Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic inflammation in metabolic tissues. AB - BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of insulin resistance (IR); however, the specific mechanisms mediating this association are currently unknown. OBJECTIVE: To investigate whether the inflammatory activity associated with RA accounts for the observed defective glucose metabolism and lipid metabolism in these patients. METHODS: We followed two main strategies: (i) extensive metabolic profiling of a RA cohort of 100 patients and 50 healthy control subjects and (ii) mechanistic studies carried out in both a collagen induced arthritis mouse model and 3T3-L1 adipocytes treated with conditioned serum from RA patients. RESULTS: Following the exclusion of obese and diabetic subjects, data from RA patients demonstrated a strong link between the degree of systemic inflammation and the development of IR. These results were strengthened by the observation that induction of arthritis in mice resulted in a global inflammatory state characterized by defective carbohydrate and lipid metabolism in different tissues. Adipose tissue was most susceptible to the RA-induced metabolic alterations. These metabolic effects were confirmed in adipocytes treated with serum from RA patients. CONCLUSIONS: Our results show that the metabolic disturbances associated with RA depend on the degree of inflammation and identify inflammation of adipose tissue as the initial target leading to IR and the associated molecular disorders of carbohydrate and lipid homeostasis. Thus, we anticipate that therapeutic strategies based on tighter control of inflammation and flares could provide promising approaches to normalize and/or prevent metabolic alterations associated with RA. PMID- 29532532 TI - Induction of keratinocyte migration by ECa 233 is mediated through FAK/Akt, ERK, and p38 MAPK signaling. AB - Centella asiatica is widely considered the most important medicinal plant for treating and relieving skin diseases. Recently developed standardized extract of Centella asiatica ECa 233 has demonstrated positive effects on wound healing of incision and burn wound in rats. However, knowledge associated with wound healing mechanism of ECa 233 was scare. Therefore, this study aimed to investigate the effect and underlying molecular mechanisms of ECa 233 on the migration of a human keratinocyte cell line (HaCaT) using scratch wound healing assay. Formation of filopodia, a key protein in cell migration as well as signaling pathways possibly involved were subsequently assessed. It was found that HaCaT cell migration was significantly enhanced by ECa 233 in a concentration- and time-dependent manner. The filopodia formations were accordingly increased in exposure to ECa 233 at concentrations of 0.1-100 MUg/ml. Furthermore, ECa 233 was found to significantly upregulate the expression of Rac1 and RhoA and to induce phosphorylation of FAK and Akt as well as ERK and p38 MAPK. Taken all together, it is suggestive that ECa 233 induces cell migration and subsequently promotes wound healing activity, through the activation of FAK, Akt, and MAPK signaling pathways thereby supporting the role of ECa 233 to be further developed for the clinical treatment of wound. PMID- 29532533 TI - Traditionally vs sonographically coached pushing in second stage of labor: a pilot randomized controlled trial. AB - OBJECTIVE: To investigate the usefulness of visual biofeedback using transperineal ultrasound to improve coached pushing during the active second stage of labor in nulliparous women. METHODS: This was a randomized controlled trial of low-risk nulliparous women in the active second stage of labor. Patients were allocated to either coached pushing aided by visual demonstration on transperineal ultrasound of the progress of the fetal head (sonographic coaching) or traditional coaching. Patients in both groups were coached by an obstetrician for the first 20 min of the active second stage of labor and, subsequently, the labor was supervised by a midwife. Primary outcomes were duration of the active second stage and increase in the angle of progression at the end of the coaching process. Secondary outcomes included the incidence of operative delivery and complications of labor. RESULTS: Forty women were recruited into the study. Those who received sonographic coaching had a shorter active phase of the second stage (30 min (interquartile range (IQR), 24-42 min) vs 45 min (IQR, 39-55 min); P = 0.01) and a greater increase in the angle of progression (13.5 degrees (IQR, 9 20 degrees ) vs 5 degrees (IQR, 3-9.5 degrees ); P = 0.01) in the first 20 min of the active second stage of labor than did those who had traditional coaching. No differences were found in the secondary outcomes between the two groups. CONCLUSION: Our preliminary data suggest that transperineal ultrasound may be a useful adjunct to coached pushing during the active second stage of labor. Further studies are required to confirm these findings and better define the benefits of this approach. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29532534 TI - BMI change during puberty and the risk of heart failure. AB - AIM: Hospitalization for heart failure amongst younger men has increased. The reason for this is unknown but it coincides with the obesity epidemic. The aim of this study was to evaluate the association between childhood BMI (Body Mass Index) and BMI change during puberty for risk of adult heart failure in men. METHODS: Using the BMI Epidemiology Study (BEST), a population-based study in Gothenburg, Sweden, we collected information on childhood BMI at age 8 years and BMI change during puberty (BMI at age 20 - BMI at 8) for men born 1945-1961, followed until December 2013 (n = 37 670). BMI was collected from paediatric growth charts and mandatory military conscription tests. Information on heart failure was retrieved from high-quality national registers (342 first hospitalizations for heart failure). RESULTS: BMI change during puberty was independently of childhood BMI associated with risk of heart failure in a nonlinear J-shaped manner. Subjects in the upper quartile of BMI change during puberty (Q4) had more than twofold increased risk of heart failure compared with subjects in Q1 [HR (Hazard Ratio) = 2.29, 95% CI (Confidence Interval) 1.68 3.12]. Childhood BMI was not independently associated with risk of heart failure. Boys developing overweight during puberty (HR 3.14; 95% CI 2.25-4.38) but not boys with childhood overweight that normalized during puberty (HR 1.12, 95% CI 0.63-2.00) had increased risk of heart failure compared with boys without childhood or young adult overweight. CONCLUSION: BMI change during puberty is a novel risk factor for adult heart failure in men. PMID- 29532535 TI - Screening and diagnostic clinical algorithm for paroxysmal nocturnal hemoglobinuria: Expert consensus. AB - OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is a severe, life threatening disorder for which early diagnosis is essential. However, given the rarity of the disease and non-specificity of symptoms, correct diagnosis may be delayed or missed. While various hematologic guidelines note common signs and symptoms associated with PNH, international expert consensus based on real-world clinical experience and an actionable algorithm for non-specialists to facilitate screening and diagnosis are lacking. The objective of the study is to develop a clinically relevant, consensus-driven screening and diagnostic algorithm on PNH for non-specialist clinicians. METHODS: An expert advisory committee of PNH experts from North America, Europe, and Japan was convened, and a modified Delphi methodology was employed to develop an algorithm to assist non-specialist clinicians in identifying signs/symptoms of PNH and conducting appropriate differential diagnosis. Twelve globally representative Delphi panelists with clinical expertise in PNH were identified and recruited. Panelists provided their differential diagnosis for 5 blinded case studies via 2 rounds of online questionnaires. Responses mentioned by >50% of panelists in the first round were included in the second-round questionnaire, at which point consensus was attained if >80% of panelists agreed on an approach. RESULTS: Consensus was reached for 95% of screening and diagnostic decision points and 90% of tests required at decision points. CONCLUSION: These results facilitated development of a consensus based, clinically relevant algorithm, providing non-specialist clinicians with actionable guidance on PNH screening and diagnosis. PMID- 29532536 TI - Periprocedural management of anticoagulation for atrial fibrillation catheter ablation in direct oral anticoagulant-treated patients. AB - BACKGROUND: Guidelines recommend performing atrial fibrillation (AF) catheter ablation without interruption of a direct oral anticoagulants (DOACs) and to administer unfractionated heparin (UFH) for an activated clotting time (ACT) >=300 seconds, by analogy with vitamin K antagonist (VKA). Nevertheless, pharmacological differences between DOACs and VKA, especially regarding ACT sensitivity and UFH response, prevent extrapolation from VKA to DOACs. HYPOTHESIS: The level of anticoagulation at the time of the procedure in uninterrupted DOAC-treated patients is unpredictable and would complicate intraprocedural UFH administration and monitoring. METHODS: This prospective study included interrupted DOAC-treated patients requiring AF ablation. Preprocedural DOAC concentration ([DOAC]), intraprocedural UFH administration, and ACT values were recorded. A cohort of DOAC-treated patients requiring flutter catheter ablation was considered to illustrate [DOAC] without DOAC interruption. RESULTS: Forty-eight patients underwent AF and 14 patients underwent flutter ablation, respectively. In uninterrupted DOAC-treated patients, [DOAC] ranged from <=30 to 466 ng/mL. When DOAC were interrupted, from 54 to 218 hours, [DOAC] were minimal (maximum: 36 ng/mL), preventing DOAC-ACT interference. Anyway, ACT values were poorly correlated with UFH doses (R 2 = 0.2256). CONCLUSIONS: Our data showed that uninterrupted DOAC therapy resulted in an unpredictable and highly variable initial level of anticoagulation before catheter ablation. Moreover, even with DOAC interruption preventing interference between DOAC, UFH, and ACT, intraprocedural UFH monitoring was complex. Altogether, our exploratory results call into question the appropriateness of transposing UFH dose protocols, as well as the relevance of ACT monitoring in uninterrupted DOAC-treated patients. PMID- 29532537 TI - Magnetic resonance imaging can be useful for advanced diagnostic of the lower uterine segment in patients after previous cesarean section. AB - One of the main concerns in planning a vaginal birth after previous cesarean section is the risk for uterine rupture which is considered to be associated with the wall thickness in the scar area. Assuming the uterine scar to be located within the lower uterine segment (LUS), ultrasound diagnostic with LUS thickness measurement is widely used for prenatal risk assessment. Although intensively investigated there is a strong inhomogeneity of study results and reliable examination protocols and reference values are still missing 1,2 . PMID- 29532538 TI - Estimates of costs for modelling return on investment from smoking cessation interventions. AB - BACKGROUND AND AIMS: Modelling return on investment (ROI) from smoking cessation interventions requires estimates of their costs and benefits. This paper describes a standardized method developed to source both economic costs of tobacco smoking and costs of implementing cessation interventions for a Europe wide ROI model [European study on Quantifying Utility of Investment in Protection from Tobacco model (EQUIPTMOD)]. DESIGN: Focused search of administrative and published data. A standardized checklist was developed in order to ensure consistency in methods of data collection. SETTING AND PARTICIPANTS: Adult population (15+ years) in Hungary, Netherlands, Germany, Spain and England. For passive smoking-related costs, child population (0-15 years) was also included. MEASUREMENTS: Costs of treating smoking-attributable diseases; productivity losses due to smoking-attributable absenteeism; and costs of implementing smoking cessation interventions. FINDINGS: Annual costs (per case) of treating smoking attributable lung cancer were between ?5074 (Hungary) and ?52 106 (Germany); coronary heart disease between ?1521 (Spain) and ?3955 (Netherlands); chronic obstructive pulmonary disease between ?1280 (England) and ?4199 (Spain); stroke between ?1829 (Hungary) and ?14 880 (Netherlands). Costs (per recipient) of smoking cessation medications were estimated to be: for standard duration of varenicline between ?225 (England) and ?465 (Hungary); for bupropion between ?25 (Hungary) and ?220 (Germany). Costs (per recipient) of providing behavioural support were also wide-ranging: one-to-one behavioural support between ?34 (Hungary) and ?474 (Netherlands); and group-based behavioural support between ?12 (Hungary) and ?257 (Germany). The costs (per recipient) of delivering brief physician advice were: ?24 (England); ?9 (Germany); ?4 (Hungary); ?33 (Netherlands); and ?27 (Spain). CONCLUSIONS: Costs of treating smoking attributable diseases as well as the costs of implementing smoking cessation interventions vary substantially across Hungary, Netherlands, Germany, Spain and England. Estimates for the costs of these diseases and interventions can contribute to return on investment estimates in support of national or regional policy decisions. PMID- 29532539 TI - Cotransplantation of haploidentical hematopoietic stem cells and allogeneic bone marrow-derived mesenchymal stromal cells as a first-line treatment in very severe aplastic anemia patients with refractory infections. AB - OBJECTIVES: In patients with very severe aplastic anemia (VSAA), neutropenia is prolonged and persistent, resulting in refractory overwhelming infections. Hematopoiesis recovery is urgently needed. METHODS: Six patients with de novo VSAA lacking HLA-identical sibling donors and those who experienced refractory infections underwent haploidentical related donor (HRD) hematopoietic stem cell transplantation (HSCT) as a first-line therapy. The conditioning regimen consisted of busulfan, cyclophosphamide, and rabbit antithymocyte globulin. Culture-expanded allogeneic bone marrow-derived mesenchymal stromal cells were infused on day 0 and day +14. RESULTS: From diagnosis to HSCT, 6 patients experienced a total of 28 episodes of persistent fever, and the median number was 4 (range, 3-7). All cases developed major bacterial infections and invasive pulmonary fungal infection pre-HSCT. The median time from diagnosis to HSCT was 2 months (range, 1-3.5 months). All patients achieved sustained, full donor chimerism, and the median time of myeloid recovery and platelet engraftment was 13 days (range, 9-19 days) and 15.5 days (range, 10-23 days), respectively. One patient died of aGVHD, and 5 patients are alive after a median follow-up of 21 months (range 17-40.5). CONCLUSIONS: Upfront HRD-HSCT may be a safe and promising choice for patients with VSAA in critical situations without suitably matched donors. PMID- 29532540 TI - The relationship between physical ill-health and mental ill-health in adults with intellectual disabilities. AB - BACKGROUND: People with intellectual disabilities face a much greater burden and earlier onset of physical and mental ill-health than the general adult population. Physical-mental comorbidity has been shown to result in poorer outcomes in the general population, but little is known about this relationship in adults with intellectual disabilities. AIMS: To identify whether physical ill health is associated with mental ill-health in adults with intellectual disabilities and whether the extent of physical multi-morbidity can predict the likelihood of mental ill-health. To identify any associations between types of physical ill-health and mental ill-health. METHOD: A total of 1023 adults with intellectual disabilities underwent comprehensive health assessments. Binary logistic regressions were undertaken to establish any association between the independent variables: total number of physical health conditions, physical conditions by International Classification of Disease-10 chapter and specific physical health conditions; and the dependent variables: problem behaviours, mental disorders of any type. All regressions were adjusted for age, gender, level of intellectual disabilities, living arrangements, neighbourhood deprivation and Down syndrome. RESULTS: The extent of physical multi-morbidity was not associated with mental ill-health in adults with intellectual disabilities as only 0.8% of the sample had no physical conditions. Endocrine disease increased the risk of problem behaviours [odds ratio (OR): 1.22, 95% confidence interval (CI): 1.02-1.47], respiratory disease reduced the risk of problem behaviours (OR: 0.73, 95% CI: 0.54-0.99) and mental ill-health of any type (OR: 0.73, 95% CI: 0.58-0.92), and musculoskeletal disease reduced the risk of mental ill-health of any type (OR: 0.84, 95% CI: 0.73-0.98). Ischaemic heart disease increased the risk of problem behaviours approximately threefold (OR: 3.29, 95% CI: 1.02-10.60). CONCLUSIONS: The extent of physical multi-morbidity in the population with intellectual disabilities is overwhelming, such that associations are not found with mental ill-health. Mental health interventions and preventative measures are essential for the entire population with intellectual disabilities and should not be focussed on subgroups based on overall health burden. PMID- 29532541 TI - A screening algorithm for early detection of major depressive disorder in head and neck cancer patients post-treatment: Longitudinal study. AB - OBJECTIVE: The primary purpose of this study was to identify predictors of Major Depressive Disorder in head and neck cancer (HNC) patients in the immediate post treatment period (ie, at 3 months post-diagnosis), with a focus on previously unexamined historical and contextual factors. METHODS: Prospective longitudinal study of 223 consecutive adults (72% participation) newly diagnosed with a first occurrence of primary HNC, including validated psychometric measures, Structured Clinical Interviews for DSM Disorders, and medical chart reviews. RESULTS: The 3 month period prevalence of Major Depressive Disorder was 20.4%; with point prevalences of 6.8% upon HNC diagnosis, 14.2% at 3 months, and 22.6% lifetime. Patients most susceptible to developing Major Depressive Disorder in the immediate post-treatment period: were diagnosed with advanced-stage cancer rather than early-stage cancer (O.R. = 4.94, P = 0.04), received surgery only (O.R. = 8.73, P = 0.04), presented a lifetime history of Anxiety Disorder on SCID-I (O.R. = 6.62; P = 0.01), and indicated higher pre-treatment levels of anxiety on the HADS (O.R. = 0.45, P = 0.05). CONCLUSIONS: Our results outline the predominant role of anxiety upon diagnosis as a precursor to post-treatment Major Depressive Disorder, suggesting the need for identification and prophylactic treatment of anxiety upon diagnosis in head and neck cancer patients. Further investigation into pathways by which pre-treatment anxiety predisposes to post-treatment Major Depressive Disorder in this population is warranted. PMID- 29532542 TI - Amorphous calcium phosphate (ACP) in tissue repair process. AB - Synthetic biomaterials submitted to new structural technologies have become ideal for the recovery of traumatized bone tissues and some bone substitutes such as bioactive glass, beta-Tricalcium phosphate (beta-TCP) and amorphous calcium phosphate (ACP) are being used in areas of tissue defects. For this study, ACP was produced in the form of fibers and then submitted to cytotoxicity testing. A sample of ACP was inserted into the mandibular region of a patient with a lost implant so after removal and curettage, the remaining bone site was filled with the ACP biomaterial. Preliminary cytotoxicity test was negative. After 15 weeks of healing, a titanium implant was inserted at the site. Clinical and radiographic follow-up was conducted for 12 months and sequential radiographic analyses revealed tissue formation resembling spongy bone. Images under immunohistochemistry demonstrated efficient deposition and osteoconduction of the newly deposited tissue. Residual portion of the CaO:P2 O5 outer layers served as a substrate for osteoid matrix deposition, aiding growth, and the results of fiber absorption favored maturation of the new bone tissue. PMID- 29532543 TI - Evaluation of the US Food and Drug Administration sentinel analysis tools in confirming previously observed drug-outcome associations: The case of clindamycin and Clostridium difficile infection. AB - PURPOSE: The Food and Drug Administration's Sentinel System developed parameterized, reusable analytic programs for evaluation of medical product safety. Research on outpatient antibiotic exposures, and Clostridium difficile infection (CDI) with non-user reference groups led us to expect a higher rate of CDI among outpatient clindamycin users vs penicillin users. We evaluated the ability of the Cohort Identification and Descriptive Analysis and Propensity Score Matching tools to identify a higher rate of CDI among clindamycin users. METHODS: We matched new users of outpatient dispensings of oral clindamycin or penicillin from 13 Data Partners 1:1 on propensity score and followed them for up to 60 days for development of CDI. We used Cox proportional hazards regression stratified by Data Partner and matched pair to compare CDI incidence. RESULTS: Propensity score models at 3 Data Partners had convergence warnings and a limited range of predicted values. We excluded these Data Partners despite adequate covariate balance after matching. From the 10 Data Partners where these models converged without warnings, we identified 807 919 new clindamycin users and 8 815 441 new penicillin users eligible for the analysis. The stratified analysis of 807 769 matched pairs included 840 events among clindamycin users and 290 among penicillin users (hazard ratio 2.90, 95% confidence interval 2.53, 3.31). CONCLUSIONS: This evaluation produced an expected result and identified several potential enhancements to the Propensity Score Matching tool. This study has important limitations. CDI risk may have been related to factors other than the inherent properties of the drugs, such as duration of use or subsequent exposures. PMID- 29532544 TI - Validation of endotoxin-core antibodies in dried blood spots as a measure of environmental enteropathy and intestinal permeability. AB - OBJECTIVE: To validate a method for measuring endotoxin-core antibodies (EndoCAb) from dried blood spots (DBS)-drops of capillary whole blood collected and dried on filter paper-as an indicator of environmental enteropathy (EE) in infancy and early childhood. METHODS: A commercially available enzyme immunoassay kit was adapted for use with DBS, with optimized steps for sample elution. Technical validation included analysis of linearity/recovery, precision and reliability, lower limit of detection, and correspondence between matched plasma and DBS samples. Validation in a field-based setting was implemented with samples from Peruvian infants (n = 82; age = 2-33 months) collected at two time points six months apart. RESULTS: A high correspondence between plasma and DBS levels of EndoCAb was observed (R2 = 0.93, P < .001). The lower limit of detection was found to be 0.01 GMU/mL. Interassay coefficient of variation (CV) was 10.9% and 8.06% for low and high controls, respectively. Mean intra-assay CVs were 3.22% and 1.83%, respectively. In a sample of Peruvian infants, EndoCAb levels increased with age as expected (P < .001). Age explained nearly 34.6% of the variance in EndoCAb across the sample. CONCLUSION: These findings demonstrate the validity and feasibility of measuring EndoCAb in remote field settings using minimally invasive DBS sampling. PMID- 29532545 TI - An Asparagus polysaccharide fraction inhibits MDSCs by inducing apoptosis through toll-like receptor 4. AB - Despite decades of research, malignant tumors are extremely difficult to eliminate with conventional methods. Although surgical resection potentially eradicates the problem, only a few cases are suitable for operation, and other approaches often involve harmful consequences. Revolutionary methods are desperately needed to improve patient outcomes and diminish harmful side effects. Myeloid-derived suppressor cells (MDSCs), downregulators of the innate and adaptive immune systems, have been widely studied over the past 2 decades. MDSCs inhibit the antitumor immune response by suppressing T cell proliferation, cytokine production, and tumor cell killing. With MDSCs becoming novel targets in cancer therapy, our research has focused on the anti-MDSC function of Asparagus polysaccharide (AP), extracted from asparagus, a traditional Chinese herb. In this study, we have used MDSCs isolated from the spleen of mice with colon cancer as an in vitro model to assess the efficacy of AP. Treatment of MDSCs with AP significantly decreased cell proliferation and induced apoptotic cell death through a toll-like receptor 4 dependent way. Subsequent studies showed that the AP treatment enhanced the expression of Bax and Caspase-9 and inhibited the expression of Bcl-2, suggesting that AP induced apoptosis in the MDSCs via the intrinsic pathway. Altogether, the results showed that AP exhibited a significant anti-MDSC activity and attenuated suppression of the antitumor immune response, thereby indicating its potential use in cancer therapy. PMID- 29532546 TI - Adjuvant continuous metronomic adriamycin + cyclophosphamide followed by weekly nab-paclitaxel for high-risk early-stage breast cancer. AB - Many studies have sought to optimize the dosing schedule of adjuvant chemotherapy in early-stage breast cancer. Here, we assessed the use of continuous metronomic weekly doxorubicin plus daily oral cyclophosphamide (AC) with continuous G-CSF growth factor support for 12 weeks followed by weekly nab-paclitaxel (nP) for 12 weeks. A nonrandomized phase II clinical trial was designed to assess (1) DFS at 2 years, (2) dose delivered, (3) use of nP in the adjuvant setting, and (4) toxicities. The dosing of A was 24 mg/m2 IV weekly and C was 60 mg/m2 oral daily (with scheduled filgrastim 5mcg/kg 6 days/week); nP, 100 mg/m2 IV weekly. For patients with HER2 + disease, trastuzumab was started during the nP portion of therapy and continued for 12 months. Sixty patients enrolled with a median follow up of 6 years. Node-positive disease was present in 58% of patients. Receptor categories included hormone receptor positive/HER2 negative (n = 25; 42%); triple negative (n = 19; 32%); or HER2 positive (n = 16; 27%). DFS at 2 years was 93%. Mean dose delivered was greater than 90% for metronomic AC and 88% for nP. Treatment was well tolerated with a 2% incidence of febrile neutropenia. Continuous metronomic AC followed by nP was well tolerated in our patients with comparable DFS to historical controls. PMID- 29532547 TI - Vitamin D deficiency can impair respiratory health. PMID- 29532548 TI - Mediators of medication adherence and glycaemic control and their implications for direct outpatient medical costs: a cross-sectional study. AB - AIMS: To investigate the effects of diabetes-related distress and perception of hyperglycaemia on self-reported medication adherence and glycaemic control, as measured by HbA1c , and to compare the cost outcomes in patients with sub optimally vs uncontrolled Type 2 diabetes mellitus. METHODS: We conducted a retrospective cross-sectional study that involved the review of a chronic disease database in Singapore. Data on clinical characteristics, diabetes-related distress, perception of hyperglycaemia, self-reported medication adherence and costs were obtained from the database. Mediation analyses were conducted using a linear regression-based approach. A final path model was built to illustrate the sequential mediating effects of diabetes-related distress and perception on the association of medication adherence and HbA1c concentration. RESULTS: Diabetes related distress and perception of hyperglycaemia were significantly associated with medication adherence and HbA1c concentration. Mediation analyses showed a significant indirect effect of diabetes-related distress and perception of hyperglycaemia on medication adherence and HbA1c concentration. People with uncontrolled diabetes were found to incur significantly higher total direct medical costs than those with sub-optimally controlled diabetes (P = 0.034), with medication cost as the main cost driver (66.6%). CONCLUSIONS: Identifying the influence of the sequential mediating effects of distress and perception was important in understanding the pathway between medication adherence and glycaemic control. This suggests the importance of a team-based approach to address these mediators and thus improve glycaemic control. Poor glycaemic control was also found to be associated with higher direct medical costs. PMID- 29532549 TI - A novel role for cilia-dependent sonic hedgehog signaling during submandibular gland development. AB - BACKGROUND: Submandibular glands (SMGs) are specialized epithelial structures which generate saliva necessary for mastication and digestion. Loss of SMGs can lead to inflammation, oral lesions, fungal infections, problems with chewing/swallowing, and tooth decay. Understanding the development of the SMG is important for developing therapeutic options for patients with impaired SMG function. Recent studies have suggested Sonic hedgehog (Shh) signaling in the epithelium plays an integral role in SMG development; however, the mechanism by which Shh influences gland development remains nebulous. RESULTS: Using the Kif3af/f ;Wnt1-Cre ciliopathic mouse model to prevent Shh signal transduction by means of the loss of primary cilia in neural crest cells, we report that mesenchymal Shh activity is necessary for gland development. Furthermore, using a variety of murine transgenic lines with aberrant mesenchymal Shh signal transduction, we determine that loss of Shh activity, by means of loss of the Gli activator, rather than gain of Gli repressor, is sufficient to cause the SMG aplasia. Finally, we determine that loss of the SMG correlates with reduced Neuregulin1 (Nrg1) expression and lack of innervation of the SMG epithelium. CONCLUSIONS: Together, these data suggest a novel mechanistic role for mesenchymal Shh signaling during SMG development. Developmental Dynamics 247:818 831, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29532550 TI - Fibroblast-matrix interplay: Nintedanib and pirfenidone modulate the effect of IPF fibroblast-conditioned matrix on normal fibroblast phenotype. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Activated fibroblasts are the key effector cells in fibrosis, producing excessive amounts of collagen and extracellular matrix (ECM) proteins. Whether the ECM conditioned by IPF fibroblasts determines the phenotype of naive fibroblasts is difficult to explore. METHODS: IPF-derived primary fibroblasts were cultured on Matrigel and then cleared using ammonium hydroxide, creating an IPF-conditioned matrix (CM). Normal fibroblast CM served as control. Normal fibroblasts were cultured on both types of CM, and cell count, cell distribution and markers of myofibroblast differentiation; transforming growth factor beta (TGFbeta) signalling; and ECM expression were assessed. The effects of the anti-fibrotic drugs nintedanib and pirfenidone at physiologically relevant concentrations were also explored. RESULTS: Normal fibroblasts cultured on IPF-CM arranged in large aggregates as a result of increased proliferation and migration. Moreover, increased levels of pSmad3, pSTAT3 (phospho signal transducer and activator of transcription 3), alpha smooth muscle actin (alphaSMA) and Collagen1a were found, suggesting a differentiation towards a myofibroblast-like phenotype. SB505124 (10 MUmol/L) partially reversed these alterations, suggesting a TGFbeta contribution. Furthermore, nintedanib at 100 nmol/L and, to a lesser extent, pirfenidone at 100 MUmol/L prevented the IPF-CM induced fibroblast phenotype alterations, suggesting an attenuation of the ECM fibroblast interplay. CONCLUSION: IPF fibroblasts alter the ECM, thus creating a CM that further propagates an IPF-like phenotype in normal fibroblasts. This assay demonstrated differences in drug activities for approved IPF drugs at clinically relevant concentrations. Thus, the matrix-fibroblast phenotype interplay might be a relevant assay to explore drug candidates for IPF treatment. PMID- 29532551 TI - Comparison between incremental and thrice-Weekly hemodialysis: a systematic review and meta-analysis. AB - BACKGROUND: Incremental hemodialysis (HD) regimen has recently gained attention. However, its efficacy and safety, compared with conventional thrice-weekly HD, are controversial and previous research results are not convincing. We sought to conduct a meta-analysis to evaluate the benefits and limitations of incremental HD regimen in patients with end-stage renal disease. METHODS: We searched PubMed, Embase, and the Cochrane Central Register databases for controlled trials published until January 2017. Outcomes of interest included baseline patient characteristics, mortality risk, renal function, urine volume, laboratory values, and hospitalization rate. RESULTS: Overall, 16 studies (N = 252,330), including 15 observational studies and 1 cross-sectional study, were included. Incremental HD reduced mortality risk, compared with conventional HD (risk ratio [RR], 0.797; 95% confidence interval [CI], 0.731-0.870; P <0.001; I2 =0%). Renal function (standardized mean difference [SMD]=0.677, 95% CI: 0.035 to 1.318, P =0.039; I2 =92.7%) and urine volume (weighted mean difference[WMD] =333.37, 95% CI: 86.81 to 579.93, P=0.008; I2 =92.7%) were also better preserved in patients on incremental HD. Other clinical outcomes, including serum levels of calcium, phosphate, albumin, hemoglobin, and hospitalization rate, were similar between groups. CONCLUSIONS: An incremental therapeutic approach as a beginning HD regimen is associated with lower mortality and better preservation of greater residual renal function. PMID- 29532552 TI - The ongoing evolution of laser desorption/ionization mass spectrometry: Some observations on current trends and future directions. AB - The practice of laser desorption/ionization (LDI) mass spectrometry continues to evolve. In the most commonly adopted manifestation of LDI, matrix assisted LDI, attention continues to be directed towards novel sample application strategies and modifications to the sample plate. Specifically, researchers continue to explore adaptations to the conventional, stainless steel sample plate that is the centerpiece of conventional LDI. Numerous variants of LDI-MS have been reported based on modifications of the plate surface, but none of these is widely adopted, either by end-users or by instrument manufacturers. Further, at this time, advances in surface engineering have had only modest impact on day-to-day operation. In this article, we review and discuss some of the numerous, but scattered reports on novel LDI strategies with an emphasis on modified sample support substrates and plates. We discuss and highlight innovations that have the potential to markedly enhance the utility of LDI-MS. PMID- 29532553 TI - Caring for a patient with delirium in an acute hospital: The lived experience of cardiology, elderly care, renal, and respiratory nurses. AB - AIMS: To explore the lived experience of caring for a patient during an acute episode of delirium by nurses working in cardiology, elderly care, renal, or respiratory specialities. BACKGROUND: A missed or delayed diagnosis of delirium in an acute hospital setting adversely impacts on patient outcomes. Nurses are the best placed health care professionals to identify a change in patient's cognitive status but struggle to do so. DESIGN: Inductive interpretative phenomenology. METHODS: Semi-structured interviews with nurses working in an acute hospital in England between November 2016 and March 2017 (n = 23). Interviews were transcribed verbatim and analysed using thematic analysis. FINDINGS: Three themes were identified: (i) "sometimes delirium is confusing", difficultly in differentiating between delirium and dementia; (ii) "everyone in the ward was looking after him", a need for collaborative working to provide harm free care; and (iii) "he was aggressive with us, but after treatment he was a gentleman", acceptance and tolerance of aggression. CONCLUSION: The need for education across specialities, with a combination of classroom and simulation teaching. Alongside, the development of structures to support the development of nursing teamwork and reporting of near miss incidents that occur with patients during an episode of delirium. PMID- 29532554 TI - Management of patients with severe Epstein syndrome: A review of four patients who received living-donor renal transplantation. AB - AIM: Epstein syndrome is a hereditary disease characterised by macrothrombocytopaenia and progressive nephritis. The abnormality of the MYH9 gene has a strong relationship to the severity of the disease. Severe Epstein syndrome progresses to end-stage renal disease rapidly after adolescence. There is no established therapy. We sought to clarify appropriate management of Epstein syndrome nephropathy. METHODS: Epstein syndrome patients who underwent renal transplantation at our institution between March 2009 and March 2017 were enrolled. Epstein syndrome was diagnosed based on clinical features and genetic testing. Patient medical records were reviewed retrospectively. RESULTS: Four male patients with Epstein syndrome, all with severe MYH9 gene mutations (p.R702C in three and p.S96L in one), were enrolled. Despite treatment with renin angiotensin system blockers, nephropathy was refractory and progressed rapidly, and the patients required dialysis or renal transplantation after adolescence. Early preparation for treatment based on early and accurate diagnosis of Epstein syndrome enabled two patients to undergo pre-emptive renal transplantation. For these patients, we kept the platelet count above 100*109 /L until day 7 after renal transplantation with platelet transfusions for macrothrombocytopaenia, and no postoperative bleeding episodes occurred. CONCLUSION: Epstein syndrome nephropathy due to a severe MYH9 gene mutation can be refractory and progress rapidly; therefore, early and accurate diagnosis is important for safer therapeutic options including pre-emptive renal transplantation. By keeping the platelet count above 100*109 /L during the perioperative period, renal transplantation can be a safe treatment option for severe Epstein syndrome nephropathy. PMID- 29532555 TI - Economic evaluations of occupational therapy approaches for people with cognitive and/or functional decline: A systematic review. AB - With the ageing of the world's population comes significant implications for nearly all sectors of society, including health and aged care spending. Health and aged care systems need to respond to the increasing need for services for older people. Occupational therapy is concerned with maintaining a person's functional independence and well-being from preventative and treatment perspectives. The aim of this systematic review was to identify the costs and outcomes of occupational therapy for people with cognitive and/or functional decline. The searches for this review were conducted on 23 September 2016 and updated on 20 April 2017. Full economic evaluation studies, partial economic evaluations, randomised trials reporting estimates of resource use or costs associated with intervention(s) and comparator(s) and studies with pre- and post intervention cost comparators were included. Thirteen studies met the inclusion criteria. The type and duration of occupational therapy intervention in the included studies varied, ranging from one-off assessments through to systematic multicomponent programmes. Results suggested that structured occupational therapy interventions which comprised of multiple consultations and engaged caregivers delivered better functional and economic outcomes. PMID- 29532556 TI - Incorporating BIRD-based homodecoupling in the dual-optimized, inverted 1 JCC 1,n ADEQUATE experiment. AB - 1,n-ADEQUATE is a powerful NMR technique for elucidating the structure of proton deficient small molecules that can help establish the carbon skeleton of a given molecule by providing long-range three-bond 13 C?13 C correlations. Care must be taken when using the experiment to identify the simultaneous presence of one-bond 13 C?13 C correlations that are not filtered out, unlike the HMBC experiment that has a low-pass J-filter to filter 1 JCH responses out. Dual-optimized, inverted 1 JCC 1,n-ADEQUATE is an improved variant of the experiment that affords broadband inversion of direct responses, obviating the need to take additional steps to identify these correlations. Even though ADEQUATE experiments can now be acquired in a reasonable amount of experimental time if a cryogenic probe is available, low sensitivity is still the main impediment limiting the application of this elegant experiment. Here, we wish to report a further refinement that incorporates real-time bilinear rotation decoupling-based homodecoupling methodology into the dual-optimized, inverted 1 JCC 1,n-ADEQUATE pulse sequence. Improved sensitivity and resolution are achieved by collapsing homonuclear proton proton couplings from the observed multiplets for most spin systems. The application of the method is illustrated with several model compounds. PMID- 29532557 TI - A prolonged response to platinum-based therapy in a patient with metastatic urothelial carcinoma harboring a single rearranged and truncated NF2 gene. AB - Tumor genome sequencing has become an invaluable resource in determining targets for new therapies. In this report, we describe the case of a patient with metastatic urothelial carcinoma with sarcomatoid features. Sarcomatoid differentiation is a rare histologic subtype that confers a more aggressive course. The first-line treatment for patients with urothelial carcinoma is platinum-based chemotherapy. Next generation tumor sequencing performed using the FoundationOne assay revealed loss of one NF2 allele and an unbalanced der(22)t(10;22)(p11.22;q12.2) chromosomal rearrangement involving the other NF2 allele, resulting in truncation and predicted loss of function. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of one NF2 signal. NF2 mutations have been found in a variety of cancers and result in activation of the mTOR pathway. As such, the use of mTOR inhibitors, such as everolimus are thought to be particularly effective in the case of NF2 loss. Our patient had a dramatic response to first-line chemotherapy, but unfortunately experienced subsequent progression of his cancer and could not tolerate everolimus. Although our patient's tumor demonstrated unique acquired genetic features including both loss of heterozygosity and truncation of the NF2 locus, he still achieved a meaningful response to platinum-based chemotherapy. PMID- 29532559 TI - Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort. AB - BACKGROUND: Utilization of general anesthesia in children has important policy, economic, and healthcare delivery implications, yet there is little information regarding the epidemiology of these procedures in the United States. AIMS: The primary objective of this study was to describe in a geographically defined population the incidence of procedures requiring general anesthesia up to the child's third birthday, and the patient characteristics associated with receiving these procedures. A secondary objective was to determine the proportion of children in the population who meet the risk criteria promulgated by the Food and Drug Administration (FDA). METHODS: A retrospective cohort of children born from 1994 to 2007 in Olmsted County, MN was established. Birth certificate information and receipt of general anesthesia before age 3 were collected. Proportional hazard regressions were performed to evaluate the association between characteristics of children and incidence of general anesthesia. RESULTS: Among the 20 922 children in the cohort, 3120 (14.9%) underwent at least 1 general anesthesia before age 3. In multivariate regression, factors independently associated with receiving at least 1 procedure included prematurity, male sex, lower birth weight, cesarean delivery, a non-Hispanic mother, and a White mother, controlling for multiple gestation, number of children previously born, age, education, and marital status of the mother. Seven hundred and twenty-three children (3.5%) had at least 1 subsequent procedure. Estimated gestational age <32 weeks and low birth weight were independently associated with receiving repeated anesthesia. Eight hundred and twenty children (3.9%) had a single prolonged exposure above 3 hours, multiple exposures prior to age 3, or both. CONCLUSION: Approximately 1 in 7 children were exposed to at least 1 episode of general anesthesia before age 3, and approximately 1 in 4 children who received general anesthesia fall within the high-risk category as defined by the recent FDA warning. The apparent disparities in surgical utilization related to race and ethnicity in this study population deserve further exploration. PMID- 29532558 TI - Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations. AB - Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations. PMID- 29532560 TI - Comparison of Awake vs. Asleep Surgery for Subthalamic Deep Brain Stimulation in Parkinson's Disease. AB - BACKGROUND: Deep brain stimulation (DBS) surgery for Parkinson's disease (PD) is usually performed as awake surgery allowing sufficient intraoperative testing. Recently, outcomes after asleep surgery have been assumed comparable. However, direct comparisons between awake and asleep surgery are scarce. OBJECTIVE: To investigate the difference between awake and asleep surgery comparing motor and nonmotor outcome after subthalamic nucleus (STN)-DBS in a large single center PD population. METHODS: Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively. RESULTS: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems "freezing" and "speech" were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups. CONCLUSIONS: Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery. PMID- 29532561 TI - 'Good enough' is 'not enough' when managing indigenous adults with bronchiectasis in Australia and New Zealand. PMID- 29532562 TI - Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF-1alpha-induced pro-angiogenic factor. AB - Substantial data from preclinical studies have revealed the biphasic effects of statins on cardiovascular angiogenesis. Although some have reported the anti angiogenic potential of statins in malignant tumors, the underlying mechanism remains poorly understood. The aim of this study is to elucidate the mechanism by which simvastatin, a member of the statin family, inhibits tumor angiogenesis. Simvastatin significantly suppressed tumor cell-conditioned medium-induced angiogenic promotion in vitro, and resulted in dose-dependent anti-angiogenesis in vivo. Further genetic silencing of hypoxia-inducible factor-1alpha (HIF 1alpha) reduced vascular endothelial growth factor and fibroblast growth factor-2 expressions in 4T1 cells and correspondingly ameliorated HUVEC proliferation facilitated by tumor cell-conditioned medium. Additionally, simvastatin induced angiogenic inhibition through a mechanism of post-transcriptional downregulation of HIF-1alpha by increasing the phosphorylation level of AMP kinase. These results were further validated by the fact that 5-aminoimidazole-4-carboxamide ribonucleotide reduced HIF-1alpha protein levels and ameliorated the angiogenic ability of endothelial cells in vitro and in vivo. Critically, inhibition of AMPK phosphorylation by compound C almost completely abrogated simvastatin-induced anti-angiogenesis, which was accompanied by the reduction of protein levels of HIF-1alpha and its downstream pro-angiogenic factors. These findings reveal the mechanism by which simvastatin induces tumor anti-angiogenesis, and therefore identifies the target that explains the beneficial effects of statins on malignant tumors. PMID- 29532563 TI - External beam radiation therapy combined with airway stenting leads to better survival in patients with malignant airway obstruction. AB - BACKGROUND AND OBJECTIVE: Malignant airway obstruction (MAO), a common complication of patients with advanced lung cancer, causes debilitating dyspnoea and poor quality of life. Two common interventions used in the treatment of MAO include bronchoscopy with airway stenting and external beam radiotherapy (EBRT). Data are limited regarding their clinical effectiveness and overall effect on survival. METHODS: A retrospective chart review of patients treated with airway stenting and/or EBRT at the Johns Hopkins Hospital for MAO between July 2010 and January 2017 was reviewed. Demographics, performance status, cancer histology, therapeutic intervention and date of death were recorded. Survival was calculated using cox regression analysis. RESULTS: Of the 606 patients who were treated for MAO, 237 were identified as having MAO and included in the study. Sixty-eight patients underwent rigid bronchoscopy and stenting, 102 EBRT and 67 a combined approach. Patients who underwent stenting hand an increased hazard ratio (HR) of death in comparison to those who received combination therapy (HR: 2.12, 95% CI: 1.02, 4.39), while there was a trend towards significance in the EBRT alone group in comparison to the combination therapy group (HR: 1.62, 95% CI: 0.93, 2.83). CONCLUSION: In this retrospective analysis, combination therapy with stenting and EBRT led to better survival in comparison to stenting or EBRT alone. Prospective cohort trials are needed to confirm these results. PMID- 29532564 TI - ETV5 regulates ductal morphogenesis with Sox9 and is critical for regeneration from pancreatitis. AB - BACKGROUND: The plasticity of pancreatic acinar cells to undergo acinar to ductal metaplasia (ADM) has been demonstrated to contribute to the regeneration of the pancreas in response to injury. Sox9 is critical for ductal cell fate and important in the formation of ADM, most likely in concert with a complex hierarchy of, as yet, not fully elucidated transcription factors. RESULTS: By using a mouse model of acute pancreatitis and three dimensional organoid culture of primary pancreatic ductal cells, we herein characterize the Ets-transcription factor Etv5 as a pivotal regulator of ductal cell identity and ADM that acts upstream of Sox9 and is essential for Sox9 expression in ADM. Loss of Etv5 is associated with increased severity of acute pancreatitis and impaired ADM formation leading to delayed tissue regeneration and recovery in response to injury. CONCLUSIONS: Our data provide new insights in the regulation of ADM with implications in our understanding of pancreatic homeostasis, pancreatitis and epithelial plasticity. Developmental Dynamics 247:854-866, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29532566 TI - Application of functional magnetic resonance imaging in psychiatric clinical evaluation: Controversies and avenues. AB - RATIONALE, AIMS, AND OBJECTIVES: In this study, we have attempted to replicate the findings of altered emotional processing in depressed patients compared with healthy controls by means of functional magnetic resonance imaging during passive viewing of positive, negative, and neutral pictures from the International Affective Pictures System. METHODS: Nineteen medicated depressed patients and 19 sex and age-matched healthy controls underwent functional magnetic resonance imaging during presentation of affective pictures in a block design. The differences between the blood oxygen level dependent signal elicited in the tree conditions were compared. Within-group and between-group analyses were performed with stringent criteria for statistical inference (P < .05 with family-wise error correction). RESULTS: In medicated depressed patients, positive pictures compared with neutral pictures activated predominantly the posterior cingulate cortex and precuneus, as well as occipital and middle temporal areas mainly on the left side, while in healthy controls, only the occipito-temporal areas demonstrated significant activation. The negative pictures elicited stronger activation of occipital and temporal regions in both groups and of inferior frontal gyrus only in control subjects. The difference between the groups did not reach statistical significance. Positive correlation was demonstrated between activation levels of clusters located in left precuneus/posterior cingulate cortex and left inferior/middle occipital gyrus and Montgomery-Asberg Depression Rating Scale scores in patients while viewing positive compared with neutral pictures. CONCLUSIONS: Although the within-group analysis demonstrated significant activations in both groups with apparent discrepancies, the between-group analysis did not reach statistical significance under the stringent criteria for statistical inference. These results are further contextualized in the critical debate on the methodological issues of clinical evaluation in psychiatry, more specifically the validity and consistency of the applied methods and the limitations existing in the attempts to provide sound cross-disciplinary validation of the diagnostic tools by means of neuroscience. PMID- 29532565 TI - Established gastric cancer cell lines transplantable into C57BL/6 mice show fibroblast growth factor receptor 4 promotion of tumor growth. AB - Previously no mouse gastric cancer cell lines have been available for transplantation into C57BL/6 mice. However, a gastric cancer model in immunocompetent mice would be useful for analyzing putative therapies. N-Methyl-N nitrosourea (MNU) was given in drinking water to C57BL/6 mice and p53 heterozygous knockout mice. Only 1 tumor from a p53 knockout mouse could be cultured and the cells s.c. transplanted into a C57BL/6 mouse. We cultured this s.c. tumor, and subcloned it. mRNA expression in the most aggressive YTN16 subline was compared to the less aggressive YTN2 subline by microarray analysis, and fibroblast growth factor receptor 4 (FGFR4) in YTN16 cells was knocked out with a CRISPR/Cas9 system and inhibited by an FGFR4 selective inhibitor, BLU9931. These transplanted cell lines formed s.c. tumors in C57BL/6 mice. Four cell lines (YTN2, YTN3, YTN5, YTN16) were subcloned and established. Their in vitro growth rates were similar. However, s.c. tumor establishment rates, metastatic rates, and peritoneal dissemination rates of YTN2 and YTN3 were lower than for YTN5 and YTN16. YTN16 established 8/8 s.c. tumors, 7/8 with lung metastases, 3/8 with lymph node metastases and 5/5 with peritoneal dissemination. FGFR4 expression by YTN16 was 121-fold higher than YTN2. FGFR4-deleted YTN16 cells failed to form s.c. tumors and showed lower rates of peritoneal dissemination. BLU9931 significantly inhibited the growth of peritoneal dissemination of YTN16. These studies present the first transplantable mouse gastric cancer lines. Our results further indicate that FGFR4 is an important growth signal receptor in gastric cancer cells with high FGFR4 expression. PMID- 29532567 TI - Variations in practice patterns and resource utilization in patients treated for chronic obstructive pulmonary disease. AB - RATIONALE, AIMS, AND OBJECTIVES: Several studies have looked at patient-related variables influencing hospital length of stay (LOS) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, there has been increasing recognition that physician-related factors also play a significant role. This study aims to evaluate differences in practice patterns between teaching and nonteaching services and their effect on LOS in a large community hospital. METHODS: A retrospective study of 354 patients admitted to Florida Hospital, Orlando, with AECOPD between January 2009 and December 2011. Patients who presented with acute respiratory failure requiring mechanical ventilation were excluded. Practice patterns of interest were use of oral versus intravenous systemic steroids, use of oral versus intravenous antibiotics, and utilization of consultations. RESULTS: Length of stay was significantly lower in the teaching compared with the nonteaching group (2.80 vs. 5.04 days, P < .001). There was significantly greater use of oral steroids (85% vs. 8.9%, P < .001), greater use of oral antibiotics (72% vs. 33%, P < .001), and lower utilization of consults (0.3 vs. 1.4 consults per patient, P < .001) in the teaching compared with the nonteaching group. The teaching service was independently associated with decreased LOS in a multivariable regression model. However, after adjustment for the difference in practice patterns between the 2 groups, the teaching service was no longer associated with decreased LOS. Of the practice patterns, only utilization of consults was independently associated with increased LOS. CONCLUSIONS: The teaching service had decreased LOS compared with the nonteaching service in patients hospitalized for AECOPD. The observed difference was completely explained by differences in practice patterns between the 2 groups. The study identifies an opportunity for more efficient and cost-effective care of AECOPD patients through streamlining of consultations, use of oral steroids in lieu of IV steroids, and antibiotic stewardship. PMID- 29532568 TI - Adaptation in temporally variable environments: stickleback armor in periodically breaching bar-built estuaries. AB - The evolutionary consequences of temporal variation in selection remain hotly debated. We explored these consequences by studying threespine stickleback in a set of bar-built estuaries along the central California coast. In most years, heavy rains induce water flow strong enough to break through isolating sand bars, connecting streams to the ocean. New sand bars typically re-form within a few weeks or months, thereby re-isolating populations within the estuaries. These breaching events cause severe and often extremely rapid changes in abiotic and biotic conditions, including shifts in predator abundance. We investigated whether this strong temporal environmental variation can maintain within population variation while eroding adaptive divergence among populations that would be caused by spatial variation in selection. We used neutral genetic markers to explore population structure and then analysed how stickleback armor traits, the associated genes Eda and Pitx1 and elemental composition (%P) varies within and among populations. Despite strong gene flow, we detected evidence for divergence in stickleback defensive traits and Eda genotypes associated with predation regime. However, this among-population variation was lower than that observed among other stickleback populations exposed to divergent predator regimes. In addition, within-population variation was very high as compared to populations from environmentally stable locations. Elemental composition was strongly associated with armor traits, Eda genotype and the presence of predators, thus suggesting that spatiotemporal variation in armor traits generates corresponding variation in elemental phenotypes. We conclude that gene flow, and especially temporal environmental variation, can maintain high levels of within-population variation while reducing, but not eliminating, among population variation driven by spatial environmental variation. PMID- 29532569 TI - Gazelletta kashiwaensis sp. nov. (Medusettidae, Phaeodaria, Cercozoa), Its Morphology, Phylogeny, Distribution, and Feeding Behavior. AB - A phaeodarian morphotype, characterized by the feet surrounded with forked pedal spines with anchor-like structures, was collected in the subtropical North Pacific. Considering the morphological and phylogenetic uniqueness, this morphotype is described as Gazelletta kashiwaensis sp. nov. The distribution of this new species is possibly affected by the Kuroshio Current. The feeding behavior of living phaeodarians was first filmed: the present new species floated in the water column stretching "protoplasmic webs" and collected diatoms by repeating the expansion and retraction of "pseudopodium-like tentacles". PMID- 29532570 TI - Increasing mortality associated with the more recent epidemic wave of hepatitis C virus infection in Northern Italy. PMID- 29532571 TI - Sirolimus as an alternative treatment in patients with granulomatous-lymphocytic lung disease and humoral immunodeficiency with impaired regulatory T cells. AB - BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated. PMID- 29532572 TI - Drug safety and big clinical data: Detection of drug-induced anaphylactic shock events. AB - RATIONALE, AIMS, AND OBJECTIVES: The spontaneous reporting system currently used in pharmacovigilance is not sufficiently exhaustive to detect all adverse drug reactions (ADRs). With the widespread use of electronic health records, biomedical data collected during the clinical care process can be reused and analysed to better detect ADRs. The aim of this study was to assess whether querying a Clinical Data Warehouse (CDW) could increase the detection of drug induced anaphylaxis. METHODS: All known cases of drug-induced anaphylaxis that occurred or required hospitalization at Rennes Academic Hospital in 2011 (n = 19) were retrieved from the French pharmacovigilance database, which contains all reported ADR events. Then, from the Rennes Academic Hospital CDW, a training set (all patients hospitalized in 2011) and a test set (all patients hospitalized in 2012) were extracted. The training set was used to define an optimized query, by building a set of keywords (based on the known cases) and exclusion criteria to search structured and unstructured data within the CDW in order to identify at least all known cases of drug-induced anaphylaxis for 2011. Then, the real performance of the optimized query was tested in the test set. RESULTS: Using the optimized query, 59 cases of drug-induced anaphylaxis were identified among the 253 patient records extracted from the test set as possible anaphylaxis cases. Specifically, the optimal query identified 41 drug-induced anaphylaxis cases that were not detected by searching the French pharmacovigilance database but missed 7 cases detected only by spontaneous reporting. DISCUSSION: We proposed an information retrieval-based method for detecting drug-induced anaphylaxis, by querying structured and unstructured data in a CDW. CDW queries are less specific than spontaneous reporting and Diagnosis-related Groups queries, although their sensitivity is much higher. CDW queries can facilitate monitoring by pharmacovigilance experts. Our method could be easily incorporated in the routine practice. PMID- 29532573 TI - An Extra-Large-Pore Zeolite with 24*8*8-Ring Channels Using a Structure-Directing Agent Derived from Traditional Chinese Medicine. AB - Extra-large-pore zeolites have attracted much interest because of their important applications for processing larger molecules. Although great progress has been made in academic science and industry, it is challenging to synthesize these materials. A new extra-large-pore zeolite SYSU-3 (Sun Yat-sen University no. 3) has been synthesized by using a novel sophoridine derivative as an organic structure-directing agent (OSDA). The framework structure was solved and refined using continuous rotation electron diffraction (cRED) data from nanosized crystals. SYSU-3 exhibits a new zeolite framework topology, which has the first 24*8*8-ring extra-large-pore system and a framework density (FD) as low as 11.4 T/1000 A3 . The unique skeleton of the OSDA plays an essential role in the formation of the distinctive zeolite structure. This work provides a new perspective for developing new zeolitic materials by using alkaloids as cost effective OSDAs. PMID- 29532574 TI - Transient and Persistent Room-Temperature Mechanoluminescence from a White-Light Emitting AIEgen with Tricolor Emission Switching Triggered by Light. AB - Persistent luminescence from purely organic materials is basically triggered by light and electricity, which largely confines its practical applications. A purely organic AIEgen exhibits not only persistent photoluminescence, but also transient and persistent room-temperature mechanoluminescence. By simply turning on and off a UV lamp, tricolor emission switching between blue, white, and yellow was achieved. The data from single-crystal structure analysis and theoretical calculation suggest that mechanism of the observed persistent mechanoluminescence (pML) is correlated with the strong spin-orbit coupling of the bromine atom, as well as the formation of H-aggregates and restriction of intramolecular motions in noncentrosymmetric crystal structure. These results outline a fundamental principle for the development of new pML materials, providing an important step forward in expanding the application scope of persistent luminescence. PMID- 29532575 TI - Synthesis of Crystalline Porous Organic Salts with High Proton Conductivity. AB - Self-assembled crystalline porous organic salts (CPOSs) formed by an acid-base combination and with one-dimensional polar channels containing water molecules have been synthesized. The water content in the channels of the porous salts plays an important role in the proton conduction performance of the materials. The porous salts described in this study feature high proton conductivity at ambient conditions and can reach as high as 2.2*10-2 S cm-1 at 333 K and under high humid conditions. This is among the best conductivity values reported to date for porous materials, for example, metal-organic frameworks and hydrogen bonded organic frameworks. These materials exhibiting permanent porosity represent a group of porous materials and may find interesting applications in proton-exchange membrane fuel cells. PMID- 29532576 TI - Mylohyoid motor evoked potentials can effectively predict persistent dysphagia 3 months poststroke. AB - BACKGROUND: The purpose of this study was to investigate the association between mylohyoid motor-evoked potentials (MH-MEP) and swallowing function and determine the value of MH-MEP for predicting aspiration 3 months poststroke. METHODS: Subacute patients within a month of their first stroke were enrolled up for 2 consecutive years. Videofluoroscopic swallowing studies (VFSS) were performed twice. Patients were evaluated during VFSS using the penetration aspiration scale (PAS) and videofluoroscopic dysphagia scale (VDS). MH-MEP was recorded in the mylohyoid muscles. The active electrode was positioned submentally, 2 cm lateral to midline. Magnetic stimulation was performed on the contralateral motor cortex, 2-4 cm anterior and 4-6 cm lateral to the cranial vertex. The resting motor threshold (rMT), latency, and amplitude stimulation at 120% (amp120) and 150% (amp150) of the rMT were assessed. The ratio of each parameter was also estimated. The relationship between MH-MEP and VFSS findings was analyzed. KEY RESULTS: Sixty-eight patients completed the study. On VFSS at 3 months poststroke, 24 (35.3%) patients showed aspiration. The rMT, rMT ratio, amp120 and amp120 ratio were significantly correlated with the PAS and VDS (P < .05). The rMT ratio (OR = 1.208, P = .001) and amp120 ratio (OR = 0.821, P = .002) were independent predictors of aspiration at 3 months. The optimal cut-off value of the rMT ratio was 126.1 (AUC = 0.94, sensitivity = 0.92, specificity = 0.89); that of the amp120 ratio was 66.5 (AUC = 0.89, sensitivity = 0.88, specificity = 0.86). CONCLUSIONS AND INFERENCES: MH-MEP was well-correlated with dysphagia severity assessed by VFSS. The rMT ratio and amplitude ratio of MH-MEP can effectively predict persistent dysphagia 3 months poststroke. PMID- 29532577 TI - A High-Voltage Molecular-Engineered Organic Sensitizer-Iron Redox Shuttle Pair: 1.4 V DSSC and 3.3 V SSM-DSSC Devices. AB - The development of high voltage solar cells is an attractive way to use sunlight for solar-to-fuel devices, multijunction solar-to-electric systems, and to power limited-area consumer electronics. By designing a low-oxidation-potential organic dye (RR9)/redox shuttle (Fe(bpy)33+/2+ ) pair for dye-sensitized solar-cell (DSSC) devices, the highest single device photovoltage (1.42 V) has been realized for a DSSC not relying on doped TiO2 . Additionally, Fe(bpy)33+/2+ offers a robust, readily tunable ligand platform for redox potential tuning. RR9 can be regenerated with a low driving force (190 mV), and by utilizing the RR9/Fe(bpy)33+/2+ redox shuttle pair in a subcell for a sequential series multijunction (SSM)-DSSC system, one of the highest known three subcell photovoltage was attained for any solar-cell technology (3.34 V, >1.0 V per subcell). PMID- 29532578 TI - Assembly of Tetrahydropyran Derivatives from Aldehydes, Allylboronates, and Syngas by Asymmetric Relay Catalytic Cascade Reaction. AB - An efficient synthesis of highly enantio-enriched tetrahydropyrans from readily available aldehydes, allylboronates, and syngas has been established by multiply relay catalysis of rhodium and chiral phosphoric acid. The cascade reaction integrates the asymmetric allylboration of aldehydes and alkene hydroformylation, providing a structurally diverse range of products with different workup procedures. The concise synthesis of key chiral building blocks to access herboxidiene and leucascandrolide A demonstrates the high synthetic utility of this method. The cascade reaction employing alkenes to replace aldehydes was also successful. PMID- 29532579 TI - Editorial comments on this issue of the Journal. PMID- 29532580 TI - Mother-to-child transmission of hepatitis B: Examining viral cut-offs, maternal HBsAg serology and infant testing. AB - BACKGROUND & AIMS: Antipartum antiviral therapy in the setting of high viral load is recommended to prevent mother-to-child transmission of hepatitis B although recommended viral load cut-offs vary. Quantitative HBsAg has been proposed as an alternative screening strategy to identify high viral load in this setting. Guidelines suggest testing all infants for vaccine response and infection. We set out to re-examine viral load cut-offs; the predictive value of quantitative HBsAg and the need for follow-up infant testing in our cohort. METHODS: A retrospective cohort study of 469 HBsAg positive mother-baby pairs from 2 tertiary hospitals in Sydney was performed. Antiviral therapy (lamivudine or tenofovir disoproxil fumarate) was offered to women with viral load >=6 log10 IU/mL (high) from 32 weeks gestation. Transmission and vaccine response was analysed according to viral load. The utility of quantitative HBsAg in identifying high viral load was examined. RESULTS: Mother-to-child transmission only occurred in setting of high viral load, in 0.85% (1/117) of those who received antiviral therapy and in 8.66% (2/23) of those who chose not to. Quantitative HBsAg did not accurately identify high-risk mothers HBV DNA >=6 log10 IU/mL. Successful infant vaccine response was 98.7% overall, and 99.4% when viral load was <6 log10 IU/mL. CONCLUSION: Antiviral therapy initiated at 32 weeks when maternal viral load is >=6 log10 IU/mL almost completely abrogates transmission. Quantitative HBsAg does not reliably predict high viral load. When maternal viral load is <6 log10 IU/mL, high vaccine efficacy and zero transmission suggests testing infants is of little value. PMID- 29532581 TI - Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway. AB - The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 * 10-9 ), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-kappaB transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 * 10-9 ), and on 11p15 (P = 6.6 * 10-8 ) in an intron of AP2A2, and P = 4.2 * 10-7 for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 * 10-8 ) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction. PMID- 29532582 TI - Cultural animation in health research: An innovative methodology for patient and public involvement and engagement. AB - BACKGROUND: A significant challenge in Patient and Public Involvement and Engagement (PPIE) in health research is to include a wide range of opinions and experiences, including from those who repeatedly find themselves at the margins of society. OBJECTIVE: To contribute to the debate around PPIE by introducing a bottom-up methodology: cultural animation (CA). Cultural Animation is an arts based methodology of knowledge co-production and community engagement which employs a variety of creative and participatory exercises to help build trusting relationships between diverse participants (expert and non-experts) and democratize the process of research. DESIGN: Three CA full-day workshops for the research project "A Picture of Health." PARTICIPANTS: Each workshop was attended by 20-25 participants including 4 academics, 5 retired health professionals who volunteered in the local community and 15 community members. Participants ranged in age from 25 to 75 years, and 80% of the participants were women over the age of 60. RESULTS: The CA workshops unearthed a diversity of hidden assets, increased human connectivity, led to rethinking of and co-creating new health indicators and enabled participants to think of community health in a positive way and to consider what can be developed. DISCUSSION: Cultural animation encourages participants to imagine and create ideal pictures of health by experimenting with new ways of working together. CONCLUSION: We conclude by highlighting the main advantages to PPIE as follows: CA provides a route to co produce research agendas, empowers the public to engage actively with health professionals and make a positive contribution to their community. PMID- 29532583 TI - Synthesis of (bis)Silicon Complexes of [38], [37], and [36]Octaphyrins: Aromaticity Switch and Stable Radical Cation. AB - Silicon complexation of a [38]octaphyrin (1) was accomplished by reaction with an excess amount of MeSiCl3 in the presence of N,N-diisopropylethylamine, thus giving an aromatic [38]octaphyrin bis(silicon) complex 2. This complex was interconvertible with an antiaromatic [36]octaphyrin congener (3) by oxidation with MnO2 and reduction with NaBH4 . Curiously, mild oxidation of 2 with ferrocenium hexafluorophosphate afforded a [37]octaphyrin bis(silicon) complex 4 as an stable radical cation that can be stored under ambient conditions in the solid state. Owing to the two NNNCC-five-coordinated Si atoms bearing trigonal bipyramidal geometry, these octaphyrin bis(silicon) complexes take on similar and rigid figure-of-eight structures with different consecutive numbers of conjugated pi-electrons (38, 37, and 36), and are all stable. PMID- 29532584 TI - The 3 faces of clinical reasoning: Epistemological explorations of disparate error reduction strategies. AB - There is general consensus that clinical reasoning involves 2 stages: a rapid stage where 1 or more diagnostic hypotheses are advanced and a slower stage where these hypotheses are tested or confirmed. The rapid hypothesis generation stage is considered inaccessible for analysis or observation. Consequently, recent research on clinical reasoning has focused specifically on improving the accuracy of the slower, hypothesis confirmation stage. Three perspectives have developed in this line of research, and each proposes different error reduction strategies for clinical reasoning. This paper considers these 3 perspectives and examines the underlying assumptions. Additionally, this paper reviews the evidence, or lack of, behind each class of error reduction strategies. The first perspective takes an epidemiological stance, appealing to the benefits of incorporating population data and evidence-based medicine in every day clinical reasoning. The second builds on the heuristic and bias research programme, appealing to a special class of dual process reasoning models that theorizes a rapid error prone cognitive process for problem solving with a slower more logical cognitive process capable of correcting those errors. Finally, the third perspective borrows from an exemplar model of categorization that explicitly relates clinical knowledge and experience to diagnostic accuracy. PMID- 29532585 TI - A Conductive Self-Healing Double Network Hydrogel with Toughness and Force Sensitivity. AB - Mechanically tough and electrically conductive self-healing hydrogels may have broad applications in wearable electronics, health-monitoring systems, and smart robotics in the following years. Herein, a new design strategy is proposed to synthesize a dual physical cross-linked polyethylene glycol/poly(acrylic acid) (PEG/PAA) double network hydrogel, consisting of ferric ion cross-linked linear chain extensions of PEG (2,6-pyridinedicarbonyl moieties incorporated into the PEG backbone, PEG-H2 pdca) as the first physical network and a PAA-Fe3+ gel as the second physical network. Metal-ion coordination and the double network structure enable the double network hydrogel to withstand up to 0.4 MPa tensile stress and 1560 % elongation at breakage; the healing efficiency reaches 96.8 % in 12 h. In addition, due to dynamic ion transfer in the network, the resulting hydrogels exhibit controllable conductivity (0.0026-0.0061 S cm-1 ) and stretching sensitivity. These functional self-healing hydrogels have potential applications in electronic skin. It is envisioned that this strategy can also be employed to prepare other high-performance, multifunctional polymers. PMID- 29532586 TI - Resonance frequency analysis: Comparing two clinical instruments. AB - BACKGROUND: Numerous studies indicate implants placed immediately after extraction or with minimally invasive procedures have excellent long-term success and survival rates. There is general agreement that implants must be stable after implant placement. This study evaluated implant stability changes from the time of implant placement to second stage (prior to restoration). Resonance frequency analysis (RFA) was determined for two commercially available units (Osstell, Osstell USA, Columbia, MD and Penguin, Penguin Integration Diagnostics, Sweden). The unit of measurement was the implant stability quotient (ISQ). MATERIALS AND METHODS: Prior to treatment patients were given medical and dental evaluations. Periapical and panogram radiographs were taken Computerized tomography images were taken for sites where adequate bone volume or quality were uncertain. Thirty patients were enrolled in this study (13 females, 17 males, mean age 73.4 years, (maximum age 90, minimum 47 year total of 38 implants were placed. One implant was lost. Computerized implant planning (Nobel Clinician) Nobel Biocar United States (Nobel Biocare, Yorba Linda, CA) was performed for all patients. Implants were placed utilizing a surgical guide. Using Resonance Frequency anal this study compared two RFA systems for determining implant stability (ISQ; Osstell and Penguin). Measurement pegs were screwed into the implants, and RFA measurements were taken at mesial, distal, lingual, and buccal implant surfaces. Stability measurements were taken at implant placement and at second stage. Clinical data and RFA measurements were recorded on data sheets. The average interval between first and second stages was 144.1 days (range 21.3) RESULTS: Average interval between implant placement and second stage was 141.1 days. One implant was lost prior to second stage. The results are based on 30 patients with 38 implants. At second stage, the RFA measures were slightly higher than first stage with a mean increase of 1.15, SE = 0.3, P-.067. The Penguin RFA values were marginally higher than Osstell (mean increase 1.10, SE = 0.64, P < .08). CONCLUSIONS: RFA values between implant placement and second stage differed slightly between implant placement and second stage (P < 0.10). These differences were not clinically or statistically significant. At second stage, Penguin RFA values were slightly higher when compared with the Osstell device (P < 0.67). Bone quality appears to be an important factor when determining RFA readings. Type I bone had significantly higher readings when compared with other less dense bone types (P < .029) Resonance frequency evaluation data were similar for both instruments, indicating their reliability in determining implant stability. Neither instrument predicted implant failure. While subjective, Penguin was less cumbersome to utilize and the window revealing the readings was very easier to read. Further, the pegs are magnetized making insertion easy. PMID- 29532587 TI - An audit of the utilization of physiotherapy assistants in the musculoskeletal outpatients setting within a primary care physiotherapy service. AB - BACKGROUND: Physiotherapy assistants account for approximately 20% of the physiotherapy workforce across a community health service in North Staffordshire. Although their job descriptions state that the post is primarily clinical, their role depends heavily on the qualified physiotherapists and how they utilize their clinical skills. METHODS: An audit of the physiotherapy assistants' tasks was carried out to reveal whether the physiotherapy assistants' time spent on clinical tasks complied with their job descriptions. Using the audit improvement cycle, pathway mapping of specific anatomical areas was performed to identify which parts of treatment can be carried out by physiotherapy assistants, clarify the physiotherapy assistants' clinical role and standardize treatments. A competences and training needs analysis was completed and physiotherapy assistants were trained before the pathways were implemented. Finally, the physiotherapy assistants' practice was re-audited and job satisfaction questionnaires were redistributed after the pathways were implemented. RESULTS: The results showed that, following the implementation of the pathways, the amount of working time that physiotherapy assistants spent treating patients increased from 9% to 16%. Their job satisfaction changed from 11% prior to the implementation of the pathways to 100% post-implementation. CONCLUSIONS: Using defined pathways in the treatment of musculoskeletal conditions of the peripheral joints provides the framework to standardize delegation of clinical tasks from qualified physiotherapists to physiotherapy assistants. However, the utilization of such pathways needs to be examined further, to clarify the clinical and cost effectiveness of delegating clinical work to physiotherapy assistants, and also the perceptions of qualified physiotherapists. PMID- 29532588 TI - Intrauterine adhesions following an induced termination of pregnancy: a nationwide cohort study. AB - OBJECTIVE: Intrauterine adhesions (IUAs) are a problematic complication after termination of pregnancy, but their incidence is unknown. Our objective was to assess the incidence of IUAs following induced termination of pregnancy and the risk factors for IUAs. DESIGN: Retrospective cohort study. SETTING: A nationwide registry study. SAMPLE: All women undergoing induced termination of pregnancy (n = 80 015) in Finland between 2000 and 2008. METHODS: The data were retrieved from the Finnish Abortion Registry and the Hospital Discharge Registry. The diagnosis of IUAs or complications was based on the diagnostic codes (International Statistical Classification of Diseases and Related Health Problems 10th Revision, ICD-10) and operative codes according to the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures (NCSP). IUAs were defined as ICD 10 code N85.6 or operative code LCG02. A subanalysis of IUA cases and five matched controls was performed. MAIN OUTCOME MEASURES: The incidence of and risk factors for IUAs. RESULTS: A total of 12 (1.5 per 10 000) IUA diagnoses were identified from 79 960 eligible induced terminations of pregnancy. The rate of IUAs was 1.5 and 2.0 cases per 10 000 terminations of pregnancy following medically and surgically induced termination of pregnancy, respectively (P = 0.19). In a subgroup analysis of IUA cases and five matched controls, surgical treatment of the remaining products of conception following termination of pregnancy significantly increased the risk of IUAs (odds ratio, OR 5.50; 95% confidence interval, 95% CI 1.46-20.79; P = 0.012). CONCLUSION: IUAs that require further treatment are rare after an induced termination of pregnancy. Surgical evacuation following medical or surgical termination of pregnancy was a risk factor for the diagnosis of IUAs. These results suggest that trauma to a recently pregnant uterus is an important risk factor for IUAs. TWEETABLE ABSTRACT: IUA is rare after induced termination of pregnancy (iTOP), but surgical evacuation is a risk factor for IUAs. PMID- 29532589 TI - HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg-positive patients treated with nucleos(t)ide analogues. AB - HBeAg seroconversion marks an important spontaneous change and treatment end point for HBeAg-positive patients and is a pre-requisite for HBsAg loss or functional cure. In this retrospective analysis, we aimed to identify predictors of seroconversion using serum quantitative HBsAg and HBcrAg, in HBeAg-positive patients treated with nucleos(t)ide analogues (NA). Data and samples from 118 HBeAg-positive adults (genotypes A-G) started on NA between Jan 2005 and Sept 2016 were retrospectively analysed at several time-points. The predictive power of on-treatment levels of HBsAg and HBcrAg was determined using receiver operating curve (ROC) analysis and cut-off values determined by maximized Youden's index. About 36.4% of patients achieved HBeAg seroconversion after a median of 39 months' treatment. On treatment kinetics of HBV DNA, HBsAg and HBcrAg differed between HBeAg seroconverters and nonseroconverters. A combination of HBsAg and HBcrAg had the greatest predictive value for HBeAg seroconversion: at 6 months, HBsAg of 3.9 log10 IU/mL and HBcrAg of 5.7 log10 U/mL had a sensitivity of 71.4%, specificity of 79.5%, positive predictive value (PPV) of 65.2% and negative predictive value (NPV) of 83.8%, with AUROC of 0.769 (0.668, 0.869; 95%CI), and at 12 months, HBsAg 3.8 log10 IU/mL and HBcrAg 5.5 log10 U/mL had a sensitivity of 73.7%, specificity of 79.5%, PPV of 63.6% and NPV of 86.1%, with AUROC 0.807 (0.713, 0.901; 95% CI). In conclusion, our results may be used to identify patients who are unlikely to achieve treatment end-points, which will be important as the future management of chronic hepatitis B looks to therapies that offer functional cure. PMID- 29532590 TI - Generation of Elf5-Cre knockin mouse strain for trophoblast-specific gene manipulation. AB - Placental development is a complex and highly controlled process during which trophoblast stem cells differentiate to various trophoblast subtypes. The early embryonic death of systemic gene knockout models hampers the investigation of these genes that might play important roles during placentation. A trophoblast specific Cre mouse model would be of great help for dissecting out the potential roles of these genes during placental development. For this purpose, we generate a transgenic mouse with the Cre recombinase inserted into the endogenous locus of Elf5 gene that is expressed specifically in placental trophoblast cells. To analyze the specificity and efficiency of Cre recombinase activity in Elf5-Cre mice, we mated Elf5-Cre mice with Rosa26mT/mG reporter mice, and found that Elf5 Cre transgene is expressed specifically in the trophoectoderm as early as embryonic day 4.5 (E4.5). By E12.5, the activity of Elf5-Cre transgene was detected exclusively in all derivatives of trophoblast lineages, including spongiotrophoblast, giant cells, and labyrinth trophoblasts. In addition, Elf5 Cre transgene was also active during spermatogenesis, from spermatids to mature sperms, which is consistent with the endogenous Elf5 expression in testis. Collectively, our results provide a unique tool to delete specific genes selectively and efficiently in trophoblast lineage during placentation. PMID- 29532591 TI - Un-precipitated acute kidney injury is uncommon among stable patients with cirrhosis and ascites. AB - BACKGROUND & AIMS: Acute episodes of renal dysfunction or acute kidney injury (AKI) in cirrhotic patients with ascites are mostly precipitated by an acute event. The prevalence of un-precipitated AKI in stable ascitic cirrhotic patients is unknown. The aims of this study were to determine (i) the prevalence of un precipitated AKI in stable cirrhotics with ascites and (ii) any predictive factors for its development. METHODS: A total of 1115 stable cirrhotic patients with mild liver and renal dysfunction but varying degrees of ascites severity from 3 previous satavaptan vs placebo randomized controlled trials (Group A, ascites requiring diuretics but not paracentesis; Group B, ascites requiring frequent paracentesis; Group C, refractory ascites) were included. AKI was diagnosed when there was either an increase of >=0.3 mg/dL in <=48 hours or a 50% increase in serum creatinine, and staged according to the fold increase of the serum creatinine. Two serum creatinine levels measured maximally 7 days apart at screening and at randomization of the satavaptan studies with no acute intervening events were used. RESULTS: The prevalence of un-precipitated AKI was 1.8% overall, with the prevalence rising with increasing severity of ascites. Ninety-five per cent of cases were stage 1, with 15% progression rate, 3 reaching the severity of type 1 acute hepatorenal syndrome. Ascites severity was the most powerful predictor for un-precipitated AKI development, which did not predict overall mortality. CONCLUSIONS: Increased prevalence of AKI with more severe ascites despite minimal baseline liver and renal dysfunction suggests that frequent monitoring of renal function in these patients is mandatory. PMID- 29532592 TI - A Novel Anisotropic Hydrogel with Integrated Self-Deformation and Controllable Shape Memory Effect. AB - Although shape memory polymers have been highlighted widely and developed rapidly, it is still a challenging task to realize complex temporary shapes automatically in practical applications. Herein, a novel shape memory hydrogel with the ability of self-deformation is presented. Through constructing an anisotropic poly(acrylic acid)-polyacrylamide (PAAc-PAAm) structure, the obtained hydrogel exhibits stable self-deformation behavior in response to pH stimulus, and the shapes that formed automatically can be fixed by the coordination between carboxylic groups and Fe3+ ; therefore, self-deformation and shape memory behaviors are integrated in one system. Moreover, the magnitude of auto deformation and shape memory could be adjusted with the concentration of corresponding ions, leading to programmable shape memory and shape recovery processes. PMID- 29532593 TI - Case Series: Intrathecal Baclofen Therapy in Stiff-Person Syndrome. AB - OBJECTIVES: Stiff-person syndrome (SPS) is associated with axial rigidity superimposed on sustained muscle spasms. These symptoms commonly interfere with the performance of activities of daily living including ambulation. This retrospective case series evaluates the outcomes of screening tests and chronic infusion of intrathecal baclofen (ITB) in patients diagnosed with SPS treated in our spasticity clinic. MATERIALS AND METHODS: Patients were identified from an institutional review board-approved clinical registry of ITB therapy. Data from clinical encounters were extracted from the registry and from the patients' electronic medical record. All patients with medically refractory spasticity related to SPS screened with an ITB injection were included. In addition to pertinent demographic and clinical information, data from validated outcome measures routinely used in the clinic were collected: pain Numeric Rating Scale, Spasm Frequency Scale, lower extremity Modified Ashworth Scale (MAS), and Timed 25 Foot Walk. Outcomes data for chronic ITB infusion were assessed at early (<6 months) and late follow-up (6-12 months) visits after surgery. RESULTS: Nine patients were included, and seven received chronic ITB infusion. MAS scores were improved at early and late follow-up, and five patients experienced a reduction in pain scores. Walking performance remained stable in previously ambulatory patients. Four patients experienced complications related to ITB implantation, which resolved with medical or surgical treatment. CONCLUSION: Consistent with other case series, our results suggest that ITB is an effective therapy for medically intractable spasticity due to SPS, and symptom reduction can be achieved without compromising ambulation. PMID- 29532594 TI - Explorative study on mucosal and major salivary secretion rates, caries and plaque microflora in head and neck cancer patients. AB - OBJECTIVE: To analyse mucosal and major salivary secretion rates, caries and plaque microflora in connection with treatment for cancer in the head and neck region. METHODS: Thirty-three patients were included and the number of teeth, filled surfaces and caries lesions registered. The labial and buccal gland secretion and stimulated whole salivary secretion rates were determined. Supragingival plaque microflora was analysed using cultivation technique. Data were collected pretreatment, during treatment and 6 months, 1 year and 2 years post-treatment. RESULTS: Two years post-treatment, 36% had new caries lesions, which had been restored. The labial secretion was comparable with pretreatment, while the buccal secretion was lower (P < .001). The stimulated secretion rate was lower compared with pretreatment (P < .001) and was <=0.7 mL/minute for 50%. Growth of lactobacilli increased during treatment (P < .001) and remained increased (P < .001), while growth of mutans streptococci was decreased (P < .01) 2 years post-treatment. Growth of Candida increased over time and was higher 2 years post-treatment compared with pretreatment (P < .001) while growth of Prevotella was lower (P < .01). CONCLUSIONS: Two years post-treatment, the stimulated salivary secretion rate was substantially decreased, acid-tolerant lactobacilli and Candida increased, acid-sensitive microorganisms decreased, and the caries prevalence was low. PMID- 29532595 TI - Factor Xa and VIIa inhibition by tissue factor pathway inhibitor is prevented by a monoclonal antibody to its Kunitz-1 domain. AB - : Essentials Activated FVII (FVIIa) and FX (FXa) are inhibited by tissue factor pathway inhibitor (TFPI). A monoclonal antibody, mAb2F22, was raised against the N-terminal fragment of TFPI (1-79). mAb2F22 bound exclusively to the K1 domain of TFPI (KD ~1 nm) and not to the K2 domain. mAb2F22 interfered with inhibition of both FVIIa and FXa activities and restored clot formation. SUMMARY: Background Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI). TFPI contains three Kunitz-type protease inhibitor domains (K1-K3), of which K1 and K2 block the active sites of FVIIa and FXa, respectively. Objective To produce a monoclonal antibody (mAb) directed towards K1, to characterize the binding epitope, and to study its effect on TFPI inhibition. Methods A monoclonal antibody, mAb2F22, was raised against the N terminal TFPI(1-79) fragment. Binding data were obtained by surface plasmon resonance analysis. The Fab-fragment of mAb2F22, Fab2F22, was expressed and the structure of its complex with TFPI(1-79) determined by X-ray crystallography. Effects of mAb2F22 on TFPI inhibition were measured in buffer- and plasma-based systems. Results mAb2F22 bound exclusively to K1 of TFPI (KD ~1 nm) and not to K2. The crystal structure of Fab2F22/TFPI (1-79) mapped an epitope on K1 including seven residues upstream of the domain. TFPI inhibition of TF/FVIIa amidolytic activity was neutralized by mAb2F22, although the binding epitope on K1 did not include the P1 residue. Binding of mAb2F22 to K1 blocked TFPI inhibition of the FXa amidolytic activity and normalized hemostasis in hemophilia human A-like plasma and whole blood. Conclusion mAb2F22 blocked TFPI inhibition of both FVIIa and FXa activities and mapped a FXa exosite for binding to K1. It reversed TFPI feedback inhibition of TF/FVIIa-induced coagulation and restored clot formation in FVIII-neutralized human plasma and blood. PMID- 29532596 TI - High birthweight is associated with increased prevalence of dental caries in Japanese children. AB - OBJECTIVE: We determined the prevalence of dental caries in 3-year-old Japanese children in a cross-sectional study and analysed its associations with birthweight, gestational age and birthweight for gestational age among the study subjects. METHODS: Study subjects were 6327 children. Their parents or guardians completed our study questionnaire with information on birth conditions and oral examinations taken from their Maternal and Child Health Handbooks, as documented by medical personnel at the hospital, clinic or public health centre. Children with one or more primary teeth that had either decayed or been filled were categorized as having caries. RESULTS: The prevalence of dental caries was 14.7%. We found a significant association between high birthweight (>=4000 g) and a higher prevalence of caries, compared with normal birthweight (2500-3999 g). Low birthweight (<2500 g) was not associated with dental caries prevalence. In addition, no measurable associations between gestational age or birthweight for gestational age and caries prevalence were observed. CONCLUSIONS: Our findings indicate that high birthweight might increase the likelihood of dental caries in children. PMID- 29532597 TI - Effects of ultrasonic instrumentation on enamel surfaces with various defects. AB - OBJECTIVE: The aim of this study was to analyse the enamel damage caused by ultrasonic scaling of teeth with various enamel conditions that are difficult to identify by visual inspection, such as enamel cracks, early caries and resin restorations. METHODS: In total, 120 tooth surfaces were divided into 4 experimental groups using a quantitative light-induced fluorescence-digital system: sound enamel group, enamel cracks group, early caries group and resin restoration group. A skilled dental hygienist performed ultrasonic scaling under a standardized set of conditions: a <= 15 degrees angle between the scaler tip and tooth surface and 40-80 g of lateral pressure at the rate of 12 times/10 s. Following scaling, the depth of enamel damage was measured using a surface profilometer and observed using scanning electron microscopy (SEM). RESULTS: The damage depth was the greatest in the enamel cracks group (37.63 +/- 34.42 MUm), followed by the early caries group (26.81 +/- 8.67 MUm), resin restoration group (19.63 +/- 6.73 MUm) and the sound enamel group (17.00 +/- 5.66 MUm). The damage depth was significantly deeper in the enamel cracks and early caries groups than in the sound enamel group (P < .05). SEM clearly revealed enamel loss in the enamel cracks, early caries and resin restoration groups. CONCLUSIONS: The results of this study suggest that ultrasonic scaling can cause further damage to teeth with enamel cracks, early caries and resin restorations. Therefore, accurate identification of tooth conditions and calculus before the initiation of ultrasonic scaling is necessary to minimize damage. PMID- 29532598 TI - The man who lost his body: Suboptimal multisensory integration yields body awareness problems after a right temporoparietal brain tumour. AB - Reports on patients who lack ownership over their entire body are extremely rare. Here, we present patient SA who suffered from complete body disownership after a tumour resection in the right temporoparietal cortex. Neuropsychological assessment disclosed selective bilateral ownership problems, despite intact primary visual and somatosensory senses. SA's disownership seems to stem from a suboptimal multimodal integration, as shown by the rubber hand illusion and the beneficial effect during and after simple exercises aiming at multisensory recalibration. PMID- 29532599 TI - Hydrogen-Bonded Polymer-Small Molecule Complexes with Tunable Mechanical Properties. AB - A novel type of polymeric material with tunable mechanical properties is fabricated from polymers and small molecules that can form hydrogen-bonded intermolecular complexes (IMCs). In this work, poly(vinyl alcohol) (PVA)-glycerol hydrogels are first prepared, and then they are dried to form IMCs. The tensile strengths and moduli of IMCs decrease dramatically with increasing glycerol content, while the elongations increase gradually. The mechanical properties are comparable with or even superior to those of common engineering plastics and rubbers. The IMCs with high glycerol content also show excellent flexibility and cold-resistance at subzero temperatures. Cyclic tensile and stress relaxation tests prove that there is an effective energy dissipation mechanism in IMCs and dynamic mechanical analysis confirms their physical crosslinking nature. FTIR and NMR characterizations prove the existence of hydrogen bonding between glycerol and PVA chains, which suppresses the crystallization of PVA from X-ray diffraction measurement. These PVA-glycerol IMCs may find potential applications in barrier films, biomedical packaging, etc., in the future. PMID- 29532600 TI - An Optimized Protocol of Protargol Staining for Ciliated Protozoa. AB - Protargol staining is a crucial method to reveal the infraciliature of ciliates, which is the most important morphological character for species identification. In the present study, Wilbert's protocol of protargol staining was emended mainly toward the highly happened improper bleaching. Through reciprocal treatments, both insufficient and excessive bleachings were much eliminated from the protargol protocol and the tests performed with four different species of ciliates established that the stainings were considerably improved and more reliable with optimized bleaching. Compared to the original protocol, the optimized method was proved to be more suitable for the groups difficult to stain, and it is also friendlier for the beginners and researchers in related fields. PMID- 29532601 TI - Alpine glacial relict species losing out to climate change: The case of the fragmented mountain hare population (Lepus timidus) in the Alps. AB - Alpine and Arctic species are considered to be particularly vulnerable to climate change, which is expected to cause habitat loss, fragmentation and-ultimately extinction of cold-adapted species. However, the impact of climate change on glacial relict populations is not well understood, and specific recommendations for adaptive conservation management are lacking. We focused on the mountain hare (Lepus timidus) as a model species and modelled species distribution in combination with patch and landscape-based connectivity metrics. They were derived from graph-theory models to quantify changes in species distribution and to estimate the current and future importance of habitat patches for overall population connectivity. Models were calibrated based on 1,046 locations of species presence distributed across three biogeographic regions in the Swiss Alps and extrapolated according to two IPCC scenarios of climate change (RCP 4.5 & 8.5), each represented by three downscaled global climate models. The models predicted an average habitat loss of 35% (22%-55%) by 2100, mainly due to an increase in temperature during the reproductive season. An increase in habitat fragmentation was reflected in a 43% decrease in patch size, a 17% increase in the number of habitat patches and a 34% increase in inter-patch distance. However, the predicted changes in habitat availability and connectivity varied considerably between biogeographic regions: Whereas the greatest habitat losses with an increase in inter-patch distance were predicted at the southern and northern edges of the species' Alpine distribution, the greatest increase in patch number and decrease in patch size is expected in the central Swiss Alps. Finally, both the number of isolated habitat patches and the number of patches crucial for maintaining the habitat network increased under the different variants of climate change. Focusing conservation action on the central Swiss Alps may help mitigate the predicted effects of climate change on population connectivity. PMID- 29532602 TI - Pantoprazole-induced autoimmune chronic hepatitis. AB - BACKGROUND: Although very rare, pantoprazole can result in acute hepatitis. It has yet to be reported, however, that it can also cause chronic autoimmune hepatitis. AIM, METHOD AND RESULTS: We report the case of a patient in whom pantoprazole administration for 2 months was followed by acute liver injury with severe jaundice and features of autoimmunity. A liver biopsy revealed acute hepatocellular lesions associated with cholestasis, acute cholangitis and polymorphous inflammatory infiltration suggestive of drug-induced liver injury. The jaundice disappeared following discontinuation of the pantoprazole. There was, however, chronic autoimmune liver injury, with the occurrence of extensive liver fibrosis within a few months. This led to the administration of immunosuppressive agents, which led to progressive and complete recovery associated with the disappearance of autoantibodies. CONCLUSION: This observation further supports the notion that pantoprazole can induce acute hepatocellular hepatitis, and it strongly suggests that it may trigger acute cholangitis and autoimmune liver injury. This case also helps document that some drugs can induce chronic autoimmune hepatitis that can resolve with immunosuppressive treatment. PMID- 29532603 TI - Electrochemical and biological characterization HA/Al2 O3 -YSZ nano-composite coatings using electrophoretic process. AB - In this research work, hydroxyapatite/alumina/YSZ bio nanocomposite coatings on titanium substrate were created by electrophoretic deposition (EPD) and reaction bonding process. By using the EPD process, uniform green form coatings containing HA, yttria-stabilized zirconia (YSZ), and aluminum particles were produced on titanium. After oxidation of aluminum at 660 degrees C and sintering at 850 degrees C, a dense and adherent HA/Al2 O3 /YSZ coating was produced. Scanning electron microscopy, X-ray diffractometric and mechanical tests were employed to investigate the morphologies, compositions, hardness, toughness and bonding strength of the coatings. The corrosion studies and cell culturing experiment were carried out and the results show that the HA/YSZ/Al2 O3 coatings are more bioactive and more resistance to corrosion than HA coatings. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1916-1922, 2018. PMID- 29532605 TI - Hepatitis B virus and risk of non-Hodgkin lymphoma: An updated meta-analysis of 58 studies. AB - Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV-infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20 2.83) regardless of the study design (case-control studies: sOR: 2.47; 95% CI: 2.16-2.82; cohort studies: sOR: 2.64; 95% CI: 1.78-3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta-regression: P < .05). Overall, B-cell NHL (sOR: 2.46; 95% CI: 1.97-3.07) presented a stronger association with HBV infection than T-cell NHL (sOR: 1.67; 95% CI: 1.34-2.10). Within the B-cell NHL subtypes, HBV infection was significantly associated with diffuse large B-cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48-2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11-2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta-analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV-induced NHL are warranted. PMID- 29532604 TI - The Role of Non-Coding RNAs and Isothiocyanates in Cancer. AB - Cancer is the second leading cause of mortalities in the United States, only exceeded by heart disease. Current cancer treatments include chemotherapy, surgery, and/or radiation. Due to the often harsh effects of current cancer therapies, investigators are focusing their efforts on cancer prevention mediated by dietary phytochemicals. Since the discovery that cancer can be initiated by and progressed through both genetic and epigenetic pathways, there has been a significant surge in studies on epigenetic effects mediated by nutritive compounds. Isothiocyanates, naturally occurring molecules found in cruciferous vegetables, have been documented to exhibit many anticarcinogenic activities. Although isothiocyanates have been extensively documented as key players in epigenetic processes such as DNA methylation and histone modifications, their effects on non-coding RNAs is understudied. Non-coding RNAs are molecules that target mRNA production and repress protein translation and are known to be dysregulated in various human malignancies. Studies have used non-coding RNAs as novel targets for exploration in cancer therapy. This review focuses on the exploration of isothiocyanates and their effect on non-coding RNAs in cancer prevention and therapy. PMID- 29532606 TI - Quality of life and sexual well-being in patients with a Fontan circulation: An explorative pilot study with a mixed method design. AB - OBJECTIVE: To get an impression of the quality of life (QOL) and sexual well being in the Fontan population, and to generate hypotheses for future research. METHODS: For this cross-sectional pilot study, questionnaires regarding health related QOL, sexual function and fertility/pregnancy were completed by 21 patients with a Fontan circulation >16 years old, followed at the University Medical Center Groningen, the Netherlands. Semi-structured qualitative interviews were conducted in 8 patients. RESULTS: Fontan patients scored significantly lower on general health than their healthy peers (t(19)=-3.0, P = .008), whereas their scores on other QOL domains and sexual well-being were comparable to normal values. During childhood, most patients experienced physical limitations and the feeling of being an outsider, and frequently faced bullying. Regarding sexual well-being, large interindividual differences were noted. Four interviewed patients (25-30 years) reported a good sexual well-being, whereas the other interviewed patients (33-47 years) reported erectile dysfunction, low self-esteem and avoidance of sexual intercourse. Both the QOL domains mental health and role restrictions due to emotional problems were associated with female avoidance (P = .083, respectively, P = .089) and dyspareunia (P = ns respectively P = .094). In males, role restrictions due to physical problems and health change were related to sexual dissatisfaction (P = .056) respectively nonsensuality (P = .025). CONCLUSIONS: Overall, Fontan patients have a relatively preserved quality of life and sexual wellbeing but face more social isolation and bullying during childhood/adolescence than their healthy peers. Sexual problems were mainly associated with physical limitations in males and with psychosocial limitations in females. Finally, sexual dysfunction was more common in older Fontan patients, and future research has to clarify whether progressive attrition of the Fontan circulation affects the patients' QOL and sexual well-being. PMID- 29532608 TI - Genetic constraints on wing pattern variation in Lycaeides butterflies: A case study on mapping complex, multifaceted traits in structured populations. AB - Patterns of phenotypic variation within and among species can be shaped and constrained by trait genetic architecture. This is particularly true for complex traits, such as butterfly wing patterns, that consist of multiple elements. Understanding the genetics of complex trait variation across species boundaries is difficult, as it necessitates mapping in structured populations and can involve many loci with small or variable phenotypic effects. Here, we investigate the genetic architecture of complex wing pattern variation in Lycaeides butterflies as a case study of mapping multivariate traits in wild populations that include multiple nominal species or groups. We identify conserved modules of integrated wing pattern elements within populations and species. We show that trait covariances within modules have a genetic basis and thus represent genetic constraints that can channel evolution. Consistent with this, we find evidence that evolutionary changes in wing patterns among populations and species occur in the directions of genetic covariances within these groups. Thus, we show that genetic constraints affect patterns of biological diversity (wing pattern) in Lycaeides, and we provide an analytical template for similar work in other systems. PMID- 29532609 TI - Cascading effects of combining synthetic herbivore-induced plant volatiles with companion plants to manipulate natural enemies in an agro-ecosystem. AB - BACKGROUND: Whether tactics to manipulate natural enemies in agro-ecosystems enhance their ecosystem function and services remains debatable. We conducted field experiments in 2015-2016 to test the hypothesis that attraction of natural enemies to herbivore-induced plant volatiles (HIPVs), alone or in combination with companion plants, increases crop productivity. Our treatments consisted of bean plants alone or baited with methyl salicylate (MeSA; an HIPV), or combined with coriander (a companion plant), or with both MeSA and coriander. Numbers of arthropods were visually sampled in each treatment. Sentinel aphids were used to measure ecosystem function (i.e. predation). Plant damage and biomass, and the number and weight of pods and seeds, were measured as a proxy for ecosystem services. RESULTS: MeSA and coriander, when alone or combined, increased the abundance of insect predators from six families, reduced herbivore (e.g. spider mite and thrips) populations, and increased aphid predation. MeSA and coriander also reduced damage by spider mites. MeSA with or without coriander did not, however, increase crop biomass or any yield parameters. CONCLUSIONS: MeSA alone or combined with coriander attracted different predator communities, altered pest communities, and reduced damage; however, these results did not cascade down to improve crop productivity. (c) 2018 Society of Chemical Industry. PMID- 29532610 TI - Utility of preoperative 3-D simulation of laparoscopic lateral pelvic lymph node dissection for advanced rectal cancer: Surgical outcomes of 10 initial cases. AB - INTRODUCTION: Laparoscopic lateral pelvic lymph node dissection (LPLD) is technically challenging because of the complicated anatomy of the pelvic wall. To overcome this difficulty, we introduced preoperative 3-D simulation. The aim of the study is to investigate the usefulness of preoperative 3-D simulation for the safe conduct of laparoscopic LPLD for rectal cancer. METHODS: After undergoing colonoscopy, patients were brought to the radiology suite where multi-detector row CT was performed. Three-dimensional images were constructed at a workstation and showed branches of the iliac artery and vein, ureter, urinary bladder, and enlarged lymph nodes. All members of the surgical team participated in preoperative simulation using the 3-D images. RESULTS: A total of 10 patients with advanced lower rectal cancer and enlarged lateral pelvic lymph nodes underwent laparoscopic unilateral LPLD after total mesorectal excision, tumor specific mesorectal excision, or total proctocolectomy. Four of the 10 patients (40%) had variations in pelvic vascular anatomy. The median operative time for unilateral LPLD was 91 min (range, 66-142 min) and gradually declined, suggesting a good learning curve. The median number of lateral pelvic lymph nodes harvested was nine (range, 3-16). The median estimated blood loss was 13 mL (range, 10-160 mL). No conversion to open surgery or intraoperative complications occurred. No patient had major postoperative complications. CONCLUSION: Preoperative 3-D simulation may be useful for the safe conduct of laparoscopic LPLD, especially for surgeons with limited prior experience. PMID- 29532607 TI - Hippo-yap signaling in ocular development and disease. AB - The Hippo-Yes associated protein (Yap) pathway plays an important role in organ size control by regulating cell proliferation, apoptosis, and stem cell renewal. Hippo-Yap signaling also functions at the level of cellular development in a variety of organs through its effects on cell cycle control, cell survival, cell polarity, and cell fate. Because of its important roles in normal development and homeostasis, abnormal regulation of this pathway has been shown to lead to pathological outcomes such as tissue overgrowth, tumor formation, and abnormal organogenesis, including ocular-specific disorders. In this review, we summarize how normal and perturbed control of Yap signaling is implicated in ocular development and disease Developmental Dynamics 247:794-806, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29532611 TI - The impacts of pretreatment circulating eosinophils and basophils on prognosis of stage I-III colorectal cancer. AB - AIM: The effects of circulating eosinophils and basophils on cancer survival are unclear. Here, we aimed to explore the impacts of eosinophils and basophils on prognosis of stage I-III colorectal cancer (CRC) patients. METHODS: From February 2003 to March 2013, 569 stage I-III CRC patients were enrolled in this retrospective study. The associations between pretreatment circulating eosinophils, basophils and CRC overall survival (OS), disease-free survival (DFS) were investigated. Moreover, the prognostic value of combined eosinophils/basophils and neutrophil to lymphocyte ratio (NLR)/platelet to lymphocyte ratio (PLR) was investigated. RESULTS: Kaplan-Meier methods showed the associations of eosinophils < 0.095 * 109 /L and shorter OS (P < 0.0001), eosinophils < 0.055 * 109 /L and shorter DFS (P < 0.0001), basophils < 0.015 * 109 /L and shorter OS (P = 0.001), basophils < 0.015 * 109 /L and shorter DFS (P = 0.005). Cox regression model showed that eosinophils < 0.095 * 109 /L (hazard ratio [HR], 1.723; 95% confidence intervals [CI] = 1.177-2.523) and basophils < 0.015 * 109 /L (HR, 1.714; 95% CI = 1.152-2.548) were independent prognostic factors for OS, and eosinophils < 0.055 * 109 /L (HR, 2.309; 95% CI = 1.587 3.361) and basophils < 0.015 * 109 /L (HR, 1.397; 95% CI = 1.003-1.945) were independent prognostic factors for DFS, respectively. The combined eosinophil-PLR (HR, 2.611; 95% CI = 1.328-5.130) and basophil-PLR (HR, 2.520; 95% CI = 1.240 5.123) were the independent prognostic factors for OS. The combined eosinophil NLR (HR, 2.770; 95% CI = 1.528-5.019) and eosinophil-PLR (HR, 4.788; 95% CI = 2.458-9.329) were the independent prognostic factors for DFS. CONCLUSION: Pretreatment circulating eosinophils < 0.095 * 109 /L/0.055 * 109 /L and circulating basophils < 0.015 * 109 /L have significant impacts on prognosis of stage I-III CRC patients. PMID- 29532612 TI - Interfacial Materials for Anti-Icing: Beyond Superhydrophobic Surfaces. AB - The design and fabrication of interfacial materials for anti-icing is of great importance, since undesired ice accumulation leads to serious economic, energy, and safety issues. Substantial progress on interfacial materials for the passive removal of ice has been achieved in the past three years. The present focus review critically summarizes and analyzes recent breakthroughs in interfacial materials for anti-icing. In particular, we focus on the effect of surface textures on the timely removal of water droplets, the microscopic mechanism of ice formation, and the effect of an interfacial layer's properties on easy shedding of formed ice with a view towards designing high-performance and durable interfacial materials for anti-icing beyond superhydrophobic materials. PMID- 29532613 TI - Cost-containment in hypofractionated radiation therapy: a literature review. AB - Recent technological advances in radiation therapy have allowed for greater accuracy in planning and treatment delivery. The development of hypofractionated radiation treatment regimens is an example, and has the potential to decrease the cost per episode of care, relative to conventional treatments. Our aim was to analyse published literature on the cost-effectiveness and budgetary implications of hypofractionated radiation therapy. As such, this article will quantify the projected health care cost savings and address the optimal means of treatment delivery, associated patient outcomes, and implications arising from an increased use of hypofractionated regimens. PMID- 29532614 TI - Catching TFSI: A Computational-Experimental Approach to beta-Cyclodextrin-Based Host-Guest Systems as electrolytes for Li-Ion Batteries. AB - Cyclodextrins (CDs) are pyranoside-based macromolecules with a hydrophobic cavity to encapsulate small molecules. They are used as molecular vehicles, for instance in pharmaceutical drug delivery or as solubility enhancer of monomers for their polymerization in aqueous solution. In this context, it was discovered about 10 years ago that the bis(trifluoromethylsulonyl)imide (TFSI) anion forms host-guest complexes with betaCD in aqueous media. This sparked interest in using the TFSI anion in lithium-based battery electrolytes open for its encapsulation by betaCD as an attractive approach to increase the contribution of the cation to the total ion conductivity. By using semi-empirical quantum mechanical (SQM) methods and the conductor-like screening model for a real solvent (COSMO-RS), a randomly methylated betaCD (RMbetaCD) is here identified as a suitable host for TFSI when using organic solvents often used in battery technology. By combining molecular dynamics (MD) simulations with different NMR and FTIR experiments, the formation of the corresponding RMbetaCD-TFSI complex was investigated. Finally, the effects of the addition RMbetaCD to a set of electrolytes on the ion conductivity are measured and explained using three distinct scenarios. PMID- 29532615 TI - Expression profiles of host immune response-related genes against HEV genotype 3 and genotype 1 infections in rhesus macaques. AB - Hepatitis E virus (HEV) genotype (gt) 3 infection is food-borne causing sporadic infections in older individuals and gt1 infection is waterborne, often causing epidemics affecting primarily young adults. Although HEV infection causes self limited disease, gt3 induces chronic infection in immunocompromised individuals. Hepatic host gene expression against gt3 infection remains unknown. Host gene expression profiles for HEV gt1 (n = 3) and gt3 (n = 7) infections were analysed in the livers of experimentally infected rhesus macaques. HEV RNA was detected from 2 to 24 days after inoculation (DAI) in stool and serum, elevated alanine aminotransferase (ALT) activity was detected from 7 to 31 DAI, and anti-HEV antibody became detectable between 12 and 42 DAI. All 10 animals cleared the infection between 34 and 68 DAI. We found that 24%, 48% and 41% of hepatic immune response genes against gt3 infection were upregulated during the early, peak and decline phases of HEV RNA replication. For gt1 infection, 25% of hepatic immune response-related genes were downregulated during early viremia, but 6%, 34% and 37% of genes were upregulated at the early, peak and during decline of HEV RNA replication, respectively. Our study demonstrated distinct differences in the expression profiles of host immune response-related genes of HEV gt3 and gt1 infections in experimentally infected rhesus macaques. PMID- 29532616 TI - Corrigendum: Asymmetric [4+2] Annulation of C1 Ammonium Enolates with Copper Allenylidenes. PMID- 29532617 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 13/2018. PMID- 29532618 TI - Clinical values of Ku80 upregulation in superficial esophageal squamous cell carcinoma. AB - Ku80 is an important DNA repair protein. Here, this study sought to investigate clinical impacts of Ku80 expression for patients with superficial esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis of Ku80 expression was carried out in normal esophageal mucosa, squamous epithelial dysplasia, carcinoma in situ, and superficial ESCC. Its relationships with clinicopathological features and survival of superficial ESCC patients were further clarified. Lentivirus-mediated RNA interference was used to silence Ku80 gene in ECA109 and KYSE150 cells. Both quantitative real-time PCR and Western blot were employed to evaluate Ku80 levels. CCK-8 assay, clone formation assay, flow cytometry, and tumorigenesis experiment were performed to evaluate the malignant phenotype of ECA109 and KYSE150 cells. Increased Ku80 expression was observed in dysplastic esophageal mucosa and carcinoma in situ compared to normal esophageal mucosa (P < 0.001, P < 0.001). Ku80 expression was further increased in superficial ESCC in comparison with dysplastic esophageal mucosa and carcinoma in situ (P < 0.001, P = 0.034). In superficial ESCC, Ku80 overexpression was related to tumor differentiation (P = 0.017), T status (P = 0.011), nodal involvement (P = 0.005), TNM stage (P = 0.004), and postoperative recurrence (P = 0.008). Cox proportional hazards regression showed tumor differentiation, T status, nodal involvement, TNM stage, and Ku80 expression were both independent predictors of patients' overall survival and disease-free survival. Ku80 shRNA effectively reduced Ku80 expression, which significantly inhibited proliferation, clone formation, and induced apoptosis in ECA109 and KYSE150 cells. The tumor growth of xenografts was significantly reduced by Ku80 silencing in ECA109 and KYSE150 cells. Ku80 overexpression associates with unfavorable prognosis of superficial ESCC patients, and silencing of Ku80 could inhibit the malignant behavior of ESCC cells. We provide evidence that Ku80 has unrecognized roles in carcinogenesis and development of ESCC. PMID- 29532620 TI - Strategy of landing behavior of the tree frog Hyla japonica. AB - Toads on the ground control landing behavior by a simple strategy in which they extend their elbows at roughly the same time after take-off and continue extending them at the same velocity until they land. However, this simple strategy does not work well in much more complicated arboreal habitat. We analyzed properties of jumping and timing of forelimb extension of the tree frog, Hyla japonica, to demonstrate how the arboreal species land safely. The results showed that distance, duration, and velocity of jump were not affected by explicit optic flow information, whereas the all three parameters decreased significantly in the blindfolded animals. This suggests that the frogs do not use optic flow information during flight but need visual information to plan a jump to reach the destination appropriately. Many animals generate prelanding behavior when time-to-contact reaches a threshold value. However, the results showed that a significant positive correlation was found between jump duration and time-to contact both in normal and blindfolded animals. The slopes and the intercepts of the linear regression lines were about 0.8 and about 50 msec, respectively, in both cases. These suggest that, without any visual inputs, the animal can make the decision for prelanding forelimb extension at 20% of jump duration and start extending the forelimb after a motor delay of about 50 msec as in the normal condition. This strategy enables the tree frog to always maintain 80% of the jump duration to prepare for landing in their complex habitat. PMID- 29532619 TI - Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review. AB - It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients. PMID- 29532621 TI - Comparison between the efficacy of microneedling combined with 5-fluorouracil vs microneedling with tacrolimus in the treatment of vitiligo. AB - BACKGROUND: Several treatment modalities had been used for the treatment of vitiligo, but the optimal treatment has not yet been identified. OBJECTIVES: To study the efficacy of microneedling with 5-flurouracil vs its efficacy with tacrolimus in the treatment of vitiligo. PATIENTS AND METHODS: Twenty-five patients with vitiligo were subjected to microneedling of 2 patches of vitiligo with dermapen, then application of 5-fluorouracil to 1 patch and tacrolimus on the other patch. This procedure was repeated every 2 weeks for every patient for maximum 6 months (12 sessions). The patients were followed up for 3 months after the last session. RESULTS: The overall repigmentation was significantly higher in 5-fluorouracil-treated patches compared with tacrolimus. Excellent improvement occurred in 48% of 5- flurouracil-treated patches while only in 16% of tacrolimus treated patches. In the acral parts, 40% of the patches treated with 5 fluorouracil achieved excellent improvement (repigmentation >75%), while no patch in the acral parts achieved excellent improvement with tacrolimus. However, there was significant difference between the 2 drugs,regarding inflammation, ulceration, and hyperpigmentation which occurred with 5-fluorouracil. CONCLUSION: Microneedling combined with 5-fluorouracil or tacrolimus is safe and effective treatment of vitiligo. However, 5-fluorouracil achieved a greater percentage of repigmentation than tacrolimus particularly in the acral parts. PMID- 29532623 TI - Dithionated Nucleobases as Effective Photodynamic Agents against Human Epidermoid Carcinoma Cells. AB - Sulfur-substituted nucleobases (i.e., thiobases) are a prospective class of compounds for clinical and cosmetic topical phototherapies. Recent investigations of several thiobases have revealed the ultrafast and efficient population of reactive triplet states upon ultraviolet-A (UVA) irradiation and the subsequent generation of singlet oxygen in high yield. In this contribution, we examine the photosensitizing activities of three of the most promising thiobase derivatives discovered to date: 2,4-dithiothymine, 2,4-dithiouracil, and 2,6-dithiopurine. These derivatives are shown to decrease the proliferation of human epidermoid carcinoma cells by up to 63 % in vitro, only upon activation with a low dose of UVA radiation (5 J cm-2 ). The generation of reactive oxygen species plays a minor role in the mode of action, suggesting these dithiobases may be effective within oxygen-deficient environments. Importantly, the photosensitized activity correlates with the magnitude of the triplet lifetime, which should guide the molecular design of next-generation photodynamic agents. PMID- 29532622 TI - Long non-coding RNA linc01433 promotes migration and invasion in non-small cell lung cancer. AB - BACKGROUND: For many years, lung cancer has been the most common and deadly cancer worldwide. Early diagnosis of non-small cell lung cancer (NSCLC) in particular is very difficult because the symptoms are often ignored. The five year survival rate is very low despite great improvements to therapy. Thus, there is an urgent need to identify prognostic biomarkers and target molecules for the clinical diagnosis and individualized treatment of NSCLC. METHODS: We performed quantitative real-time PCR to determine the expression levels of the long non coding RNA (lncRNA) linc01433 in NSCLC and normal matched lung tissue. Subsequently, we established cell lines with overexpression or knockdown of linc01433 to evaluate the effects on proliferation and metastasis in vitro. Epithelial-to-mesenchymal transition was examined using Western blot. RESULTS: Linc01433 was significantly overexpressed in NSCLC tissues compared to normal lung tissues. In addition, linc01433 levels were associated with smoking history. Linc01433 overexpression in lung cancer cells increased proliferation, migration, and invasion abilities, as well as epithelial-to-mesenchymal transition. CONCLUSIONS: Linc01433 is a cancer-related lncRNA that may have an oncogene-like effect in NSCLC. PMID- 29532624 TI - Inhibitory effect of Spirogyra spp. algal extracts against herpes simplex virus type 1 and 2 infection. AB - AIMS: To determine the antiviral activities of Spirogyra spp. algal extracts against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). METHODS AND RESULTS: Spirogyra spp. was extracted using water, ethanol and methanol. Aqueous extract of Spirogyra spp. had the lowest toxicity on Vero cells with the 50% cytotoxicity concentration (CC50 ) of 4363.30 MUg ml-1 . As for potent inhibitory effect, the ethanolic extract presented the highest inhibition of viral infection on HSV-1 in the treatment during viral attachment on Vero cells with 50% inhibitory concentration (IC50 ) and selective index (SI) values of 164.20 and 2.17 MUg ml-1 . However, the methanolic extract showed the highest inhibition of HSV-2 when treated during viral attachment with IC50 and SI values of 75.03 and 3.34 MUg ml-1 . The methanolic extract of Spirogyra spp. also demonstrated significant virucidal effects on viral particles. Therefore, anti-HSV activity at various stages of the viral multiplication cycle was shown. The main active compounds in the active fractions of Spirogyra spp. ethanolic extract against HSV were found to be alkaloids, essential oils and terpenoids. CONCLUSIONS: The highest anti-HSV activity was obtained from the ethanolic extract of Spirogyra spp. The extract inhibited the HSV viral particles and the inhibition was during the viral attachment and the viral multiplication. SIGNIFICANCE AND IMPACT OF THE STUDY: Anti-HSV activity of extract of freshwater green macroalga Spirogyra spp. in Thailand was demonstrated. Therefore, anti-HSV product containing the Spirogyra spp. extract should be developed for treatment of HSV infection. PMID- 29532625 TI - Common Language Description of the Term Rheumatic and Musculoskeletal Diseases (RMDs) for Use in Communication With the Lay Public, Healthcare Providers, and Other Stakeholders Endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). AB - A European League Against Rheumatism-American College of Rheumatology working group consisting of practicing and academic rheumatologists, a rheumatology researcher, and a patient representative created a succinct general statement describing rheumatic and musculoskeletal diseases (RMDs) in adults and children in language that can be used in conversations with the lay public, media, healthcare providers, and other stakeholders. Based on the literature review, several elements were deemed important for inclusion in the description of RMDs. First, RMDs encompass many different diseases that can affect individuals at any age, including children. Second, there are various pathophysiological pathways underlying different RMDs. Third, the impact of RMDs on individuals and society should be emphasized. The working group agreed that the language should be comprehensible to the lay public. Thus, the following description of RMDs has been developed: "Rheumatic and musculoskeletal diseases (RMDs) are a diverse group of diseases that commonly affect the joints, but can affect any organ of the body. There are more than 200 different RMDs, affecting both children and adults. They are usually caused by problems of the immune system, inflammation, infections, or gradual deterioration of joints, muscles, and bones. Many of these diseases are long term and worsen over time. They are typically painful and limit function. In severe cases, RMDs can result in significant disability, having a major impact on both quality of life and life expectancy." This description can be used by rheumatology groups, researchers, and those who work in advocacy and education related to RMDs. PMID- 29532627 TI - The "Blue Whale Challenge"?: The first report on a consultation from a health care setting for carrying out "tasks" accessed through a mobile phone application. PMID- 29532626 TI - Children's academic attainment is linked to the global organization of the white matter connectome. AB - Literacy and numeracy are important skills that are typically learned during childhood, a time that coincides with considerable shifts in large-scale brain organization. However, most studies emphasize focal brain contributions to literacy and numeracy development by employing case-control designs and voxel-by voxel statistical comparisons. This approach has been valuable, but may underestimate the contribution of overall brain network organization. The current study includes children (N = 133 children; 86 male; mean age = 9.42, SD = 1.715; age range = 5.92-13.75y) with a broad range of abilities, and uses whole-brain structural connectomics based on diffusion-weighted MRI data. The results indicate that academic attainment is associated with differences in structural brain organization, something not seen when focusing on the integrity of specific regions. Furthermore, simulated disruption of highly-connected brain regions known as hubs suggests that the role of these regions for maintaining the architecture of the network may be more important than specific aspects of processing. Our findings indicate that distributed brain systems contribute to the etiology of difficulties with academic learning, which cannot be captured using a more traditional voxel-wise statistical approach. PMID- 29532628 TI - Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants. AB - : Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state. SUMMARY: Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2 DS2 -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2 DS2 -VASc score. Larger studies are warranted to confirm these preliminary observations. PMID- 29532629 TI - Countries with an immediate potential for primary prevention of spina bifida and anencephaly: Mandatory fortification of wheat flour with folic acid. AB - OBJECTIVES: Mandatory fortification of flour with folic acid has been proven to be a highly effective way to prevent spina bifida and anencephaly. Yet, over 100 countries worldwide do not implement this intervention. Our objectives were to identify countries with an immediate potential for mandatory fortification of wheat flour with folic acid and to estimate the number of preventable cases of spina bifida and anencephaly that would be averted each year through the intervention. METHODS: We examined folic acid fortification characteristics in countries as of September 2017. Country selection criteria included current fortification status, existing industrial capacity for flour production, fortification coverage, and daily grams of per capita wheat flour available for human consumption. We estimated the country-specific number of preventable cases of spina bifida and anencephaly by calculating the difference between the observed prevalence (prefortification) and expected prevalence that can be achieved postfortification (0.5 per 1,000 live births). RESULTS: We identified 71 countries with an immediate potential for mandatory fortification of 145 million metric tons of wheat flour with folic acid. Fortification in identified countries would avert approximately 57,000 live births associated with folic acid preventable spina bifida and anencephaly annually and increase global prevention from the current rate of 13% to a new rate of 34%. CONCLUSIONS: Fortification can be achieved immediately in many countries with existing industrial milling infrastructure. Effective fortification interventions can accelerate global primary prevention efforts of folic acid-preventable spina bifida and anencephaly, especially in developing countries with a high prevalence of neural tube defects and associated morbidity and mortality. PMID- 29532632 TI - Differential antioxidant enzyme activity in rapid-response glyphosate-resistant Ambrosia trifida. AB - BACKGROUND: The giant ragweed (Ambrosia trifida L.) rapid-response (RR) biotype exhibits a sacrificial form of glyphosate resistance whereby an oxidative burst in mature leaves results in foliage loss, while juvenile leaves remain uninjured. This work investigated the safening capacity of antioxidant enzymes in RR juvenile leaves following glyphosate treatment and examined cross tolerance to paraquat. RESULTS: Basal antioxidant enzyme activities were similar between glyphosate-susceptible (GS) and RR biotypes. Lipid peroxidation was first detected in RR mature leaves at 8 h after treatment (HAT) and by 32 HAT was 5.3 and 21.1 times greater than that in RR juvenile leaves and GS leaves, respectively. Preceding lipid peroxidation in the RR biotype at 2 and 4 HAT, the only increase in enzymatic activity was observed in ascorbate-glutathione cycle enzymes in RR juvenile leaves, particularly ascorbate peroxidase, dehydroascorbate reductase, and glutathione reductase. Sensitivity to paraquat was similar between biotypes. CONCLUSION: The RR biotype is not inherently more tolerant to oxidative stress. The difference in tissue damage between RR juvenile and mature leaves following glyphosate treatment is attributable at least partially to the transient increase in antioxidant enzyme expression in juvenile leaves (0-8 HAT), but may also be attributable to lower overall RR induction in juvenile leaves compared with mature leaves. (c) 2018 Society of Chemical Industry. PMID- 29532631 TI - Roux-en-Y gastric bypass compared with equivalent diet restriction: Mechanistic insights into diabetes remission. AB - AIMS: To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux-en-Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri-operative dietary restrictions, which may also alter glucose metabolism. MATERIALS AND METHODS: In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10-day inpatient supervised dietary intervention equivalent to the peri-operative diet (diet-only period), followed by, after a re-equilibration (washout) period, an identical period of pair-matched diet in conjunction with RYGB (diet and RYGB period). We conducted extensive metabolic assessments during a 6-hour mixed-meal challenge test, with stable isotope glucose tracer infusion performed before and after each intervention. RESULTS: Similar improvements in glucose levels, beta-cell function, insulin sensitivity and post-meal hepatic insulin resistance were observed with both interventions. Both interventions led to significant reductions in fasting and postprandial acyl ghrelin. The diet-only intervention induced greater improvements in basal hepatic glucose output and post-meal gastric inhibitory polypeptide (GIP) secretion. The diet and RYGB intervention induced significantly greater increases in post-meal glucagon-like peptide-1 (GLP 1), peptide YY (PYY) and glucagon levels. CONCLUSIONS: Strict peri-operative dietary restriction is a main contributor to the rapid improvement in glucose metabolism after RYGB. The RYGB-induced changes in the incretin hormones GLP-1 and PYY probably play a major role in long-term compliance with such major dietary restrictions through central and peripheral mechanisms. PMID- 29532633 TI - Behavioral intention to prevent cervical cancer and related factors among female high school students in Japan. AB - AIM: This study aimed to examine female high school students' behavioral intention to prevent cervical cancer and related factors. METHODS: The participants were 2158 female high school students at 16 high schools in A prefecture in the Tohoku region in Japan. A self-administered questionnaire was carried out that was developed based on a conceptual framework comprising the Health Belief Model and Theory of Reasoned Action. RESULTS: The responses were obtained from 2072 students (96.0%). Of these, the answers of 2028 respondents were analyzed after excluding those participants who did not complete the behavioral intention item (effective response rate: 97.0%). A factor analysis and covariance structure analysis yielded a model with strong goodness-of-fit that explained the behavioral intentions based on an "Awareness of the importance and effectiveness of cervical cancer screening," "Obstacles to cervical cancer prevention behavior," "Subjective norms for adopting cervical cancer prevention behavior," and "The behavior of someone close that encourages cervical cancer prevention behavior." CONCLUSION: The statistical analysis yielded a model with strong goodness-of-fit that explained female high school students' behavioral intentions, which were related to four factors, including "the awareness of the importance and effectiveness of cervical cancer screening." PMID- 29532634 TI - Meta-analysis and publication bias: How well does the FAT-PET-PEESE procedure work? AB - This paper studies the performance of the FAT-PET-PEESE (FPP) procedure, a commonly employed approach for addressing publication bias in the economics and business meta-analysis literature. The FPP procedure is generally used for 3 purposes: (1) to test whether a sample of estimates suffers from publication bias, (2) to test whether the estimates indicate that the effect of interest is statistically different from zero, and (3) to obtain an estimate of the mean true effect. Our findings indicate that the FPP procedure performs well in the basic but unrealistic environment of fixed effects, where all estimates are assumed to derive from a single population value and sampling error is the only reason for why studies produce different estimates. However, when we study its performance in more realistic data environments, where there is heterogeneity in the population effects across and within studies, the FPP procedure becomes unreliable for the first 2 purposes and is less efficient than other estimators when estimating overall mean effect. Further, hypothesis tests about the mean true effect are frequently unreliable. We corroborate our findings by recreating the simulation framework of Stanley and Doucouliagos (2017) and repeat our tests using their framework. PMID- 29532635 TI - Bioavailability of Isothiocyanates From Broccoli Sprouts in Protein, Lipid, and Fiber Gels. AB - SCOPE: Optimization of bioavailability of dietary bioactive health-beneficial compounds is as important as increasing their concentration in foods. The aim of this study is to explore the change in bioavailability of isothiocyanates (ITCs) in broccoli sprouts incorporated in protein, fiber, and lipid gels. METHODS AND RESULTS: Five participants took part in a cross-over study and collected timed urine samples up to 24 h after consumption of proteins, dietary fibers, and lipid gels containing broccoli sprouts powder. Sulforaphane and iberin metabolites were determined in the urine samples. Samples in which sulforaphane and iberin were preformed by myrosinase led to a higher bioavailability of those compounds. Compared to the control broccoli sprout, incorporation of sprouts in gels led to lower bioavailability for preformed sulforaphane and iberin (although for sulforaphane the lower bioavailability was not significantly different) whereas for the gels rich in their precursors, glucoraphanin and glucoiberin, the opposite trend was observed (although not significantly different). CONCLUSION: This explorative study suggests that ITCs bioavailability can be modulated by food structure and composition and further and deeper investigations are needed to develop food products that lead to an optimized ITCs bioavailability. PMID- 29532636 TI - Human noroviruses in the faeces of wild birds and rodents-new potential transmission routes. AB - Human noroviruses (HuNoVs) are one of the leading global causes of diarrhoeal diseases and are transmitted mainly from person to person but also through contaminated food, water and fomites. The possible zoonotic nature of NoVs has occasionally been discussed, although the viruses are generally considered to be host-species-specific. We investigated whether wild birds and rodents could serve as carriers of HuNoVs, thereby transmitting the virus to humans directly or indirectly by contaminating foods. All samples, 115 avian and 100 rat faeces collected in springs 2009-2013 from dump sites, and 85 faeces from yellow-necked mice trapped in late autumn 2008 and 2009 after the rodents entered human settlements due to the first night frosts, were screened for HuNoV using real time reverse transcription PCR. HuNoVs were detected in 31 (27%) faecal samples of wild birds, in two (2%) faecal samples of rats and in no samples of mice. Most (25) of the positive bird samples and both rat samples contained genogroup II, and six positive bird samples contained genogroup I HuNoV. The avian species shedding faeces containing HuNoVs were identified as gulls and crows using DNA barcoding. Our results show that wildlife, birds and rats in particular, is capable of spreading HuNoVs in the environment. PMID- 29532637 TI - Re: Acute calculus cholecystitis: commentary on Tokyo Guidelines 2018. PMID- 29532639 TI - Acute calculus cholecystitis: commentary on Tokyo Guidelines 2018. PMID- 29532638 TI - Differential diagnosis of cholangiocarcinoma and IgG4-related sclerosing cholangitis by fluorescence in situ hybridization using transpapillary forceps biopsy specimens. AB - BACKGROUND: Fluorescence in situ hybridization (FISH) of cytology specimens has been used to diagnose biliary strictures. However, the usefulness of FISH for differentiating between cholangiocarcinoma (CCA) and IgG4-related sclerosing cholangitis (IgG4-SC) has not been evaluated in forceps biopsy specimens. METHODS: We retrospectively reviewed 74 specimens obtained by transpapillary forceps biopsy between 2008 and 2015 from 49 consecutive patients with CCA and 25 with IgG4-SC. Specimens were considered positive for malignancy by FISH with UroVysion(r) if at least five cells exhibited polysomy (a gain of two or more in chromosomes 3, 7, or 17). RESULTS: A total of 27 (55.1%) patients with CCA, but none of the patients with IgG4-SC, were positive for malignancy by FISH. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FISH for the diagnosis of CCA were 55.1%, 100%, 100%, 53.2%, and 70.3%, respectively. The complementary use of FISH increased the sensitivity of hematoxylin-and-eosin (H&E) staining from 69.4% to 77.6%; the specificity was not reduced when either H&E or FISH was positive. CONCLUSIONS: The use of FISH in the analysis of forceps biopsy specimens might be one option to differentiate CCA from IgG4-SC. PMID- 29532640 TI - Impaired cerebrospinal fluid dynamics along the entire optic nerve in normal tension glaucoma. AB - PURPOSE: To investigate the cerebrospinal fluid (CSF) dynamics along the entire optic nerve (ON) in patients with normal-tension glaucoma (NTG). METHODS: Retrospective analysis of computed tomographic (CT) cisternographies in Caucasian patients with NTG. Fifty-six patients (99 of 112 eyes) fulfilled the diagnostic criteria of NTG and underwent CT-cisternography. Twelve subjects without NTG (24 eyes) served as controls. Contrast-loaded cerebrospinal fluid (CLCSF) density measurements in Hounsfield units (HU) were performed at four defined regions along the ON and in the basal cistern. RESULTS: In NTG patients, the mean density CLCSF in the bulbar segment measured 76 +/- 49 HU right and 88 +/- 74 HU left, in the mid-orbital segment 117 +/- 92 HU right and 119 +/- 73 HU left, in the intracanalicular ON portion 209 +/- 88 HU right and 216 +/- 101 HU left, in the intracranial ON portion 290 +/- 106 HU right and 286 +/- 118 HU left and in the basal cistern 517 +/- 213 HU. The distribution of CLCSF along the ON showed a statistically significant reduction in the intraorbital ON segments in NTG patients compared to controls without NTG with the far largest difference within the retrobulbar segment (-150 HU right and -117 HU left; right: p < 0.001, left: p < 0.001). CONCLUSION: This study demonstrates a gradual reduction in CLCSF towards the retrobulbar segment in NTG, while in controls without NTG, no reduction in CLCSF was measured within the orbital segments. Impaired CSF dynamics along the ON may contribute to the pathophysiology of NTG. PMID- 29532641 TI - Real time patient dosimetry in the cath lab: Can you see what they get? AB - Real time radiation dose monitoring in the cath lab may provide immediate feedback for potential dose reduction during PCI. Radiation dose monitoring to predict potential tissue injury utilizes equipment measured air Kerma at the interventional reference point (IRP) with then calculated specific tissue peak skin dose. The role of the cath lab Quality Committee is not only to assess individual high dose radiation cases but also to create processes and assess new technologies to assure radiation dose is best utilized in all cases. PMID- 29532642 TI - Carotid stenting with double layered stents: Double trouble or double benefit? AB - The use of double layer (covered) stents during carotid artery stenting (CAS) appears to be safe; attenuation of plaque prolapse and distal embolization is reasonable but unproven. Double layer stents are commercially available in Europe but not in the United States; similar benefits might be obtained by implanting two self-expanding stents, to decrease the effective free cell area. Embolic protection devices (EPDs) are recommended in all CAS patients; the use of double layer stents does not eliminate the need for EPDs. PMID- 29532643 TI - X-ray canary in the cath lab: Posterior cataracts. AB - Cataract formation in the posterior subcapsular region of the lens is a lesion highly specific to both high-dose acute radiation exposure and chronic low-dose exposure. Low-dose radiation may not manifest lens changes for several decades after initial exposure. Cardiac catheterization team members need to be educated on, and protected from, this form of radiation injury as its long latency period between exposure and physical damage may acutely reduce the sense of hazard amongst healthcare radiation workers. PMID- 29532644 TI - Long-term survival prospects of patients undergoing percutaneous coronary intervention: Envisioning the future. AB - Implicit and largely intuitive survival predictions guide current clinical decision making after percutaneous coronary intervention (PCI). A model based on nine simple factors known after diagnostic catheterization but prior to PCI provides accurate prediction of five-year survival probability after PCI. Future prediction models and methods incorporating age and gender adjusted risk of death, cause of death (competing risks), and low prevalence but impactful comorbidities automatically implemented in electronic health records have the potential to further inform clinical decision-making and target therapies. PMID- 29532645 TI - Coronary chronic total occlusions: How to dilate the tough ones. AB - Several chronic total occlusions (CTOs) may be undilatable despite successful wire passage; several techniques can be used for lesion preparation, such as high pressure balloon inflations, rotational atherectomy laser, cutting balloon, and scoring balloons. Presence of moderate to severe calcification and lesion length over 40 mm in association with comorbidities, such as diabetes mellitus and reduced ejection fraction, may contribute to making a CTO lesion undilatable. Still, appropriate therapy selection for a patient with CTO should be individualized and procedure safety attended to. PMID- 29532646 TI - Evaluation of the diagnostic utility of individual parameters in the disseminated intravascular coagulation (DIC) panel for use in underresourced settings. PMID- 29532647 TI - Blindness and Visual Impairment Profile and Rapid Assessment of Avoidable Blindness in South East Asia: Analysis of New Data. 2017 APAO Holmes Lecture. AB - PURPOSE: The International Agency for Prevention of Blindness (IAPB) South East Asia region (SEAR) that consists of 11 countries contains 26% of the world's population (1,761,000,000). In this region 12 million are blind and 78.5 million are visually impaired. This amounts to 30% of global blindness and 32% of global visual impairment. DESIGN: Rapid assessment of avoidable blindness (RAAB) survey analysis. METHODS: RAAB, either a repeat or a first time survey, was completed in 8 countries in this decade (2010 onwards). These include Bangladesh, Bhutan, India, Indonesia, Maldives, Sri Lanka, Thailand, and Timor Leste. RESULTS: Cataract is the principal cause of blindness and severe visual impairment in all countries. Refractive error is the principal cause of moderate visual impairment in 4 countries: Bangladesh, India, Maldives, and Sri Lanka; cataract continues to be the principal cause of moderate visual impairment in 4 other countries: Bhutan, Indonesia, Thailand, and Timor Leste. Outcome of cataract surgery is suboptimal in the Maldives and Timor Leste. CONCLUSIONS: Rigorous focus is necessary to improve cataract surgery outcomes and correction of refractive error without neglecting the quality of care. At the same time allowances must be made for care of the emerging causes of visual impairment and blindness such as glaucoma and posterior segment disorders, particularly diabetic retinopathy. PMID- 29532648 TI - The role of postural control in the association between aerobic capacity and walking capacity in chronic stroke: a cross-sectional analysis. AB - BACKGROUND: Reports on the association between aerobic capacity and walking capacity in people after stroke show disparate results. AIM: To determine (1) if the predictive validity of peak oxygen uptake (VO2peak) for walking capacity post stroke is different from that of maximal oxygen uptake (VO2max) and (2) if postural control, hemiplegic lower extremity muscle strength, age and gender distort the association between aerobic capacity and walking capacity. DESIGN: Cross-sectional study. SETTING: General community in Utrecht, the Netherlands. POPULATION: Community-dwelling people more than three months after stroke. METHODS: Measurement of aerobic capacity were performed with cardiopulmonary exercise testing (CPET) and differentiated between the achievement of VO2peak or VO2max. Measurement of walking capacity with the Six Minute Walk Test (6MWT), postural control with the Performance Oriented Mobility Assessment (POMA) and hemiplegic lower extremity muscle strength with the Motricity Index (MI-LE). RESULTS: Fifty-one out of 62 eligible participants, aged 64.7 (+/-12.5) years were included. Analysis of covariance (ANCOVA) showed a nonsignificant difference between the predictive validities of VO2max (N = 22, beta = 0.56; 95%CI 0.12 - 0.97) and VO2peak (N = 29, beta = 0.72; 95%CI 0.38 - 0.92). Multiple regression analysis of the pooled sample showed a significant decrease in the beta value of VO2peak (21.6%) for the 6MWT when adding the POMA as a covariate in the association model. VO2peak remained significantly related to 6MWT after correcting for the POMA (beta = 0.56 (95%CI 0.39 - 0.75)) CONCLUSIONS: The results suggest similar predictive validity of aerobic capacity for walking capacity in participants achieving VO2max compared to those only achieving VO2peak. Postural control confounds the association between aerobic capacity and walking capacity. Aerobic capacity remains a valid predictor of walking capacity. CLINICAL REHABILITATION IMPACT: Aerobic capacity is an important factor associated with walking capacity after stroke. However, to understand this relationship, postural control needs to be measured. Both aerobic capacity and postural control may need to be addressed during interventions aiming to improve walking capacity after stroke. PMID- 29532649 TI - Contralateral effect of short-duration unilateral neuromuscular electrical stimulation and focal vibration in healthy subjects. AB - BACKGROUND: The "contralateral effect" phenomenon refers to the strength gain in the opposite, untrained homonymous muscle following unilateral training. Previous studies showed that neuromuscular electrical stimulation (NMES) of the right quadriceps facilitated maximal voluntary strength and efferent neural drive of the left knee extensors, while no previous study investigated the contralateral effect elicited by focal muscle vibration. AIM: To investigate whether quadriceps NMES and focal vibration, when applied unilaterally, have the same potential to enhance the contralateral muscle strength and the associated neural drive. DESIGN: Randomised controlled experimental study. SETTING: University laboratory. POPULATION: Healthy subjects. METHODS: Subjects completed several maximal voluntary contractions (MVCs) of the left quadriceps (tested muscle) while the right quadriceps (treated muscle) received no conditioning stimulation (control condition), NMES or focal vibration. Paired supramaximal stimuli were delivered to the left quadriceps during and immediately after the MVCs to assess voluntary activation. The EMG activity of vastus lateralis, vastus medialis, and rectus femoris muscles of the left quadriceps was also concomitantly recorded. RESULTS: MVC torque and voluntary activation of the left quadriceps increased during contralateral NMES and vibration. A remarkable inter-individual variability was observed in the contralateral effect of NMES and vibration. In fact, MVC and voluntary activation increases were particularly evident in subjects "responders" to both treatments (who showed NMES-elicited increases in MVC and voluntary activation of 22.5% and 15.8%, respectively, and vibration-elicited increases of 13.1% and 10.7%, respectively). Moreover, we found that the increases in voluntary activation and EMG activity elicited by NMES were higher than those elicited by focal vibration. We also found that voluntary activation increases were higher in subjects presenting lower baseline levels of voluntary activation. CONCLUSIONS: The short-duration unilateral application of quadriceps NMES and focal vibration increased MVC torque and efferent neural drive of the contralateral homologous muscle in healthy subjects. CLINICAL REHABILITATION IMPACT: As the two physical therapy modalities can be useful to maximize motor unit recruitment contralaterally to the side of application, they could be incorporated in rehabilitation protocols when unilateral voluntary contractions are uncomfortable, painful or not feasible. PMID- 29532650 TI - Late open conversion after endovascular abdominal aortic repair: a 20 year experience. AB - BACKGROUND: With the increasing use of endovascular aortic repair, secondary interventions after aortic stent grafting remain a concern. We retrospectively reviewed open conversion cases with complications following endovascular abdominal aortic repair (EVAR). METHODS: EVAR due to infra-renal abdominal aortic aneurysm (AAA) was performed in 566 patients between January 1994 and May 2015. A retrospective review of EVAR requiring late open conversion (>1 month after implant) was conducted. Patient demographics, reasons for conversion, operative techniques, operative outcomes, and late survival were reviewed. RESULTS: Thirty of these patients (5.3%) required late conversion to open repair. The median interval to open conversion after EVAR was 48.6 months (range, 2-190 months). Indications of open conversion included type I endoleak (n=10), stent fracture (n=4), type V endoleak (n=4), stent graft infection (n=4), stent limb obstruction (n=3), stent migration (n=3), and type II endoleak (n=2). Twenty-four operations were elective, and six operations (20%) were emergent due to aneurysm rupture. Compete endograft removal was performed in 14 patients (46.6%) and 16 endografts were partially left in situ. The hospital mortality rate was 10% (3/30) overall, 33.3 % in the emergency group and 0% the elective group (p = 0.03). Overall survival rate at a mean follow-up of 35 months was 80.7%, with a tendency towards lower survival rate after emergency compared with elective open conversion (89.3% vs. 44.4%; p=0.06). CONCLUSIONS: Open conversion due to late complications after EVAR seems to be a lifesaving procedure with acceptable initial and mid-term outcomes. Elective conversion has better outcomes compared to those in an emergency setting. Therefore, lifelong surveillance is warranted, and an early decision for open conversion, if indicated, is necessary to achieve the best outcomes. PMID- 29532651 TI - An innovative arch-first surgical procedure under moderate hypothermia for acute type A aortic dissection. AB - BACKGROUND: We hypothesized that the arch-first procedure without extra devices under moderate-to-mild systemic hypothermia during acute type A aortic dissection is safe and efficient and will improve patient outcome compared with the standard total arch replacement technique. METHODS: From December 2014 to February 2017, 89 patients were enrolled in this study, 52 of whom underwent conventional deep hypothermic circulatory arrest (DHCA, 24.2 +/- 0.71 degrees C) using the antegrade cerebral perfusion surgical procedure (Group A) and 37 of whom underwent the "arch-first" technique with moderate (27.4 +/- 1.1 degrees C) systemic hypothermia during antegrade cerebral perfusion (Group B). The clinical data, surgical and postoperative data, complications, and mortality of the two groups were analyzed. RESULTS: The cardiopulmonary bypass (171.3 +/- 40.0 min) and awakening time (7.0 h) was significantly decreased in Group B. Two patients died 30 d after surgery (5.4%, 2/37) in Group B. The incidence of transient neurologic deficit (2.7%) and distal organ complications (5.4%) was lower in Group B. CONCLUSIONS: In patients with acute type A aortic dissection involving the arch, the innovative arch-first surgical procedure could provide feasible and safe treatment outcomes, which brings us closer to the goal of performing surgery with moderate-to-mild systemic hypothermia with better cerebral, distal organ, and survival outcomes. PMID- 29532652 TI - The von Willebrand factor ratio discriminates between more and less perioperative bleeding in patients with aortic valve stenosis. PMID- 29532653 TI - A different angle in through-and-through body wires in difficult aortic arch stentgraft placement. PMID- 29532654 TI - Moderate ischemic mitral regurgitation: coronary artery bypass grafting with versus without simultaneous treatment of the mitral valve. AB - BACKGROUND: Ischemic mitral regurgitation (IMR) is a frequent complication of coronary artery heart disease and is associated with increased mortality. Controversies exists whether patients with moderate IMR may benefit from a combined procedure with coronary artery bypass grafting (CABG) and treatment of mitral regurgitation. METHODS: 451 patients with moderate IMR (grade 2) receiving either CABG alone (CABG only) or additional mitral valve repair or replacement (CABG+MV) were included in this observational single-centre study. Patients were matched according to the number of bypass grafts, preoperative NYHA functional class and age. In total, 42 patients (21 CABG only, 21 CABG+MV) were analysed. RESULTS: The mean follow-up was 4.3+/-1.9 years. CABG alone reduced the IMR grade to 1.2+/-0.5, whereas the combined procedure resulted in a decrease to 0.6+/-0.7 (P=0.039). NYHA functional class was reduced from grade 2.8+/-0.6 to 1.6+/-0.5 (CABG only) and 2.0+/-1.1 (CABG+MV, P=0.55). Three- and five-year survival rates were 71% and 53% in the CABG only group compared to 60% both after 3 and 5 years in the CABG+MV group (P=0.89). CONCLUSIONS: In this observational study, combined CABG and surgical treatment of moderate IMR was associated with a more effective reduction of IMR than CABG alone. No statistically significant differences in survival or NYHA functional class were observed. Further studies will need to investigate the value of additional mitral valve surgery in moderate IMR. PMID- 29532656 TI - CNT@rGO@MoCuSe Composite as an Efficient Counter Electrode for Quantum Dot Sensitized Solar Cells. AB - This paper reports an efficient and simple strategy for the synthesis of molybdenum copper selenide (MoCuSe) nanoparticles decorated with a combination of a carbon nanotube (CNT) network and reduced graphene oxide (rGO) nanosheets to form an integrated hybrid architecture (CNT@rGO@MoCuSe) using a two-step hydrothermal approach. The synthesized hybrid CNT@rGO@MoCuSe material onto the Ni foam substrate is applied successfully as an effective counter electrode (CE) in quantum dot-sensitized solar cells (QDSSCs). A highly conductive CNT@rGO network grown on electrochemically active MoCuSe particles provides a large surface area and exhibits a rapid electron transport rate at the interface of CE/electrolyte. As a result, the QDSSC with the designed CNT@rGO@MoCuSe CE shows a higher power conversion efficiency of 8.28% under 1 sun (100 mW cm-2) irradiation, which is almost double the efficiency of 4.04% for the QDSSC with the MoCuSe CE. Furthermore, the QDSSC based on the CNT@rGO@MoCuSe CE delivers superior stability at a working state for over 100 h. Therefore, CNT@rGO@MoCuSe is very promising as a stable and efficient CE for QDSSCs and offers new opportunities for the development of hybrid, effective, and robust materials for energy-related fields. PMID- 29532655 TI - Antimicrobial susceptibility trends and evolution of isolates with extended spectrum beta-lactamases among Gram-negative organisms recovered during the SMART study in Spain (2011-2015). AB - OBJECTIVE: The SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study monitors antimicrobial susceptibility and extended spectrum beta-lactamases (ESBLs) in Gram-negative bacilli recovered from intra-abdominal infections (IAI). METHODS: Antimicrobial susceptibility of 5,343 isolates from IAI recovered in 11 centres during the 2011-2015 SMART-Spain program was analysed by standard microdilution (EUCAST criteria) and compared with that from 2002 2010. ESBLs were phenotypically detected. RESULTS: Escherichia coli, the most common isolate, significantly decreased in community acquired IAI (60.9% 2002 2010 vs. 56.1% 2011-2015, P=0.0003). It was followed in prevalence by Klebsiella pneumoniae that increased both in the community (8.9% vs. 10.8%, P=0.016) and nosocomial (9.2% vs. 10.8%, P=0.029) IAI and P. aeruginosa, which significantly increased in community acquired IAI (5.6% vs. 8.0%, P=0.0003). ESBLs were more prevalent in K. pneumoniae (16.3%) than in E. coli (9.5%) of nosocomial origin and were more frequently isolated from elderly patients (>60 years). Considering all Enterobacteriaceae, ertapenem (92.3-100%) and amikacin (95.5%-100%) were the most active antimicrobials. Ertapenem activity, unlike amoxicillin-clavulanate or piperacillin-tazobactam, remained virtually unchanged in ESBL (100%) and non-ESBL (98.8%) E. coli producers. Its activity decreased in ESBL-K. pneumoniae (74.7%) but was higher than that of amoxicillin-clavulanate (14.0%) and piperacillin tazobactam (24.0%). Interestingly, ertapenem susceptibility was maintained in >60% of ESBL isolates that were resistant to amoxicillin-clavulanate, piperacillin-tazobactam or fluoroquinolones. CONCLUSIONS: SMART-Spain results support current guidelines which include ertapenem as empiric treatment in mild moderate community-acquired IAI, particularly with ESBL producers. These recommendations will need to be updated with the recently introduction of new antimicrobials. PMID- 29532657 TI - Colorimetric Detection of Carcinogenic Aromatic Amine Using Layer-by-Layer Graphene Oxide/Cytochrome c Composite. AB - Graphene and its derivatives were found to be efficient modulators of enzymes in various systems. However, the modulating mechanism was not well discussed for long time. Inspired by the artificial enzyme-enhancing property of graphene oxide (GO) toward cytochrome c (cyt. c), we have successfully fabricated a protein/GO hybrid structure via a layer-by-layer (LbL) strategy. The obtained LbL assemblies showed great enhancement in peroxidase activity of cyt. c, as well as excellent stability, resistance to extreme environment change, and also possibility for recycling by simple centrifugation without any obvious activity loss. The LbL cyt. c/GO hybrids were expanded to a colorimetric sensing system for the detection of carcinogenic aromatic amines. The probe showed high sensitivity and selectivity for aromatic amines over various competing soluble aromatic compounds and could be determined by the naked eye or portable devices. The working mechanism was well studied through kinetic evaluation, experimental characterization, and molecular dynamics simulations. This work does not only introduce a new graphene/protein hybrid material or a rapid and sensitive visualization of carcinogenic aromatic amines, but also spread the practical application of biomolecule-graphene interface strategy and further give a better understanding of the interaction of graphene and protein. PMID- 29532658 TI - Predicting the Band Gaps of Inorganic Solids by Machine Learning. AB - A machine-learning model is developed that can accurately predict the band gap of inorganic solids based only on composition. This method uses support vector classification to first separate metals from nonmetals, followed by quantitatively predicting the band gap of the nonmetals using support vector regression. The superb accuracy of the regression model is obtained by using a training set composed entirely of experimentally measured band gaps and utilizing only compositional descriptors. In fact, because of the unique training set of experimental data, the machine learning predicted band gaps are significantly closer to the experimentally reported values than DFT (PBE-level) calculated band gaps. Not only does this resulting tool provide the ability to accurately predict the band gap for any composition but also the versatility and speed of the prediction based only on composition will make this a great resource to screen inorganic phase space and direct the development of functional inorganic materials. PMID- 29532659 TI - Magnetically Induced Ring-Current Strengths in Mobius Twisted Annulenes. AB - The topology of twisted molecular rings is characterized by the linking number, which is equal to the sum of the twist-a local property of the molecular frame and the writhe-a global parameter, which represents the bending of the molecular ring. In this work, we investigate a number of cyclic all- trans C40H40 annulenes with varying twisting numbers for a given linking number and their dications. The aromatic character is assessed by calculating ring-current strength susceptibilities using the gauge-including magnetically induced currents (GIMIC) method, which makes it possible to conduct a systematic study of the relation between the topology and aromaticity of twisted molecules. We found that the aromatic properties of the investigated Mobius twisted molecules are not only dependent on the linking number as previously suggested but also depend strongly on the partitioning of the linking number into the twist and writhe contributions. PMID- 29532660 TI - Fire Alarm Wallpaper Based on Fire-Resistant Hydroxyapatite Nanowire Inorganic Paper and Graphene Oxide Thermosensitive Sensor. AB - Wallpaper with multiple functions, such as fire resistance and an automatic alarm in fire disasters, will be attractive for the interior decoration of houses. Herein, we report a smart fire alarm wallpaper prepared using fire-resistant inorganic paper based on ultralong hydroxyapatite nanowires (HNs) and graphene oxide (GO) thermosensitive sensors. At room temperature, the GO thermosensitive sensor is in a state of electrical insulation; however, it becomes electrically conductive at high temperatures. In a fire disaster, high temperature will rapidly remove the oxygen-containing groups of GO, leading to the transformation process of GO from an electrically insulated state into an electrically conductive one. In this way, the alarm lamp and alarm buzzer connected with the GO thermosensitive sensor will send out the alerts to people immediately for taking emergency actions. After the surface modification with polydopamine of GO (PGO), the sensitivity and flame retardancy of the GO thermosensitive sensor are further improved, resulting in a low responsive temperature (126.9 degrees C), fast response (2 s), and sustained working time in the flame (at least 5 min). Compared with combustible commercial wallpaper, the smart fire alarm wallpaper based on HNs and GO (or PGO) is superior owing to excellent nonflammability and high-temperature resistance of HNs, which can protect the GO (or PGO) thermosensitive sensor from the flames. The smart fire alarm wallpaper can be processed into various shapes, dyed with different colors, and printed with the commercial printer and thus has promising applications in high-safety interior decoration of houses. PMID- 29532662 TI - Daunorubicin and Cytarabine Liposome in Newly Diagnosed Therapy-Related Acute Myeloid Leukemia (AML) or AML With Myelodysplasia-Related Changes. AB - OBJECTIVE: To evaluate the efficacy and safety of daunorubicin and cytarabine liposome in older adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). DATA SOURCE: A literature search of PubMed and MEDLINE (January 2017 to January 2018) was performed using the terms CPX-351, Vyxeos, daunorubicin and cytarabine liposome, and acute myeloid leukemia. STUDY SELECTION/DATA EXTRACTION: Phase I, II, and III clinical trials evaluating the efficacy and safety of daunorubicin and cytarabine liposome were reviewed with a specific focus on its use in older patients with newly diagnosed AML. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. DATA SYNTHESIS: The phase II trial demonstrated that daunorubicin and cytarabine liposome improved response rates (RR), but there was no difference in event-free survival and overall survival in the overall patient population. However, clinical benefit was most pronounced in secondary AML with an increased RR and survival. The phase III trial illustrated that daunorubicin and cytarabine liposome improved survival and RR with tolerable toxicity compared with standard 7 plus 3 (daunorubicin and cytarabine) in patients 60 to 75 years of age with t-AML or AML-MRC. More patients proceeded to a stem cell transplant, and 30-day and 60-day mortality was lower with daunorubicin and cytarabine liposome. Grade 3 to 5 toxicities were similar between the 2 groups, except daunorubicin and cytarabine liposome had prolonged cytopenia and a higher risk of hemorrhage. CONCLUSIONS: Daunorubicin and cytarabine liposome improves RR and survival, with tolerable toxicity in older patients with t-AML or AML-MRC. PMID- 29532666 TI - The Internet and HIV/STD prevention. PMID- 29532669 TI - ICRP Publication 139: Occupational Radiological Protection in Interventional Procedures. AB - Abstract: In recent publications, such as Publications 117 and 120, the Commission provided practical advice for physicians and other healthcare personnel on measures to protect their patients and themselves during interventional procedures. These measures can only be effective if they are encompassed by a framework of radiological protection elements, and by the availability of professionals with responsibilities in radiological protection. This framework includes a radiological protection programme with a strategy for exposure monitoring, protective garments, education and training, and quality assurance of the programme implementation. Professionals with responsibilities in occupational radiological protection for interventional procedures include: medical physicists; radiological protection specialists; personnel working in dosimetry services; clinical applications support personnel from the suppliers and maintenance companies; staff engaged in training, standardisation of equipment, and procedures; staff responsible for occupational health; hospital administrators responsible for providing financial support; and professional bodies and regulators. This publication addresses these elements and these audiences, and provides advice on specific issues, such as assessment of effective dose from dosimeter readings when an apron is worn, estimation of exposure of the lens of the eye (with and without protective eyewear), extremity monitoring, selection and testing of protective garments, and auditing the interventional procedures when occupational doses are unusually high or low (the latter meaning that the dosimeter may not have been worn). PMID- 29532675 TI - Answering your Questions about AIDS. PMID- 29532681 TI - Dedifferentiated Liposarcoma With Rhabdomyosarcomatous Differentiation Producing HCG: A Case Report of a Diagnostic Pitfall. AB - We report a first case of paraneoplastic human chorionic gonadotropin (HCG) production in a dedifferentiated liposarcoma with rhabdosarcomatous differentiation in an 83-year-old man with a retroperitoneal mass, unilateral scrotal enlargement, and a serum HCG level of 843 IU/L. Core biopsy of the retroperitoneal mass revealed rhabdomyosarcoma. Orchiectomy revealed a paratesticular dedifferentiated liposarcoma with rhabdosarcomatous differentiation. Fluorescence in situ hybridization analysis performed on both the retroperitoneal and paratesticular masses revealed amplification of MDM2. The retroperitoneal tumor was interpreted as metastatic dedifferentiated liposarcoma with the dedifferentiated component represented by rhabdomyosarcoma. HCG production is a common feature of testicular germ cell tumors, less common in carcinomas, and extremely rare in sarcomas. Accordingly, sarcomas secreting HCG are a potential diagnostic pitfall, and raise the differential diagnosis of germ cell tumors and a variety of carcinomas. HCG production by carcinomas is a known poor prognostic finding, however the significance of its production in sarcomas is unknown. PMID- 29532682 TI - Low density, good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement. AB - BACKGROUND: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency. METHODS: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations. RESULTS: The optimal formulation of CRBC (R4) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R4 was c.a. 5% which was far lower than spray-dried raffinose (R0, c.a. 65%). R4 exhibited a high fine particle fraction value of 70.56 +/- 0.61% and it was 3.75-fold against R0. The pulmonary and plasmatic bioavailability of R4 were significantly higher than R0 (p < 0.05). CONCLUSION: CRBC with anti hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI. PMID- 29532683 TI - Eimeria spp. in captive-reared corncrakes (Crex crex): results of a GeneScan assay consistent with high prevalence of infection and extra-intestinal life stages. AB - Eimeria crecis and Eimeria nenei have been detected in association with enteric disease ("coccidiosis") in the corncrake (Crex crex: Family Rallidae, Order Gruiformes). Both parasite species are common in apparently healthy free-living corncrakes, but captive-bred juvenile birds reared for reintroduction appeared particularly susceptible to clinical coccidiosis. We investigated the occurrence and relative pathogenicity of these Eimeria species in this juvenile corncrake population and developed a diagnostic species-specific polymerase chain reaction (PCR) for their identification. PCR amplification and sequencing of 18S rDNA were performed on genomic DNA extracted from samples of corncrake intestine, liver and spleen. Sequences generated were used to design a GeneScan diagnostic PCR assay targeting a species-specific TTA indel located within the 18S rDNA - the results suggested this assay was more sensitive than the 18S rDNA/amplicon sequencing approach. Eimeria sp. DNA (consistent with Eimeria sp. infection) was detected at a high prevalence and E. crecis was the predominant species. Each Eimeria species was detected in cases with and without histological evidence of coccidiosis: parasite detection was not statistically associated with disease. In addition to intestinal tissue, liver and spleen samples were positive for Eimeria sp. DNA. Its detection in tissues other than intestine is unusual and a novel finding in corncrakes, although extra-intestinal infection occurs with closely related Eimeria species in cranes (Family Gruidae, Order Gruiformes). Eimeria sp. infection of corncrakes appears typically to be chronic, and to exhibit extra intestinal spread: as in cranes, these characteristics may be adaptations to the host's migratory nature. PMID- 29532684 TI - Routine Hematoxylin and Eosin Stain Is Specific for the Diagnosis of Cytomegalovirus Infection in Gastrointestinal Biopsy Specimens. AB - BACKGROUND: Gastrointestinal cytomegalovirus (CMV) infection is a serious complication in immunocompromised patients; clinicians often expect expedited results for biopsy specimens. Our goal is to determine the accuracy of identification of CMV on hematoxylin and eosin (H&E) stain. METHODS AND RESULTS: A total of 361 biopsy specimens from 273 patients with suspicion for CMV infection were retrieved. CMV was detected by immunohistochemistry (IHC) in 37 specimens acquired from 33 individual patients (average age = 54 years). Among the CMV-positive patients, 29 (88%) were reported to be immunosuppressed. Colon was the most common affected location. Of 37 CMV-positive specimens by IHC, 28 were positive by H&E (76%), 6 were negative (16%), and 3 were suspicious (8%). Of the 29 positive specimens on H&E, 28 were confirmed by IHC (97%) and 1 was indeterminate (3%). The sensitivity and specificity of H&E were 84% and 94%, respectively; the positive predictive value was 97%, and the negative predictive value was 93% ( P < .00001). CONCLUSION: Our results show that a preliminary diagnosis of CMV infection, based on H&E stains, can be reported with high specificity and low risk for false-positive results. Suspicious cases should be deferred pending the result of IHC stains. PMID- 29532686 TI - Blood pressure responses of defensive hostile women when facing a real stress task. AB - OBJECTIVE: This study investigated the importance of the combination of the hostility and defensiveness variables as psychosocial factors that predict the risk of cardiovascular dysfunction. We examined the impact of a stressful situation on blood pressure responses, using a continuous psychophysiological assessment approach. DESIGN: We measured the evolution of these responses over three experimental phases (adaptation, task and recovery), also considering a minute-by-minute analysis within each phase. MAIN OUTCOME MEASURES: We used the Cook-Medley Hostility Scale and the Social Desirability Questionnaire to form four groups (high hostility and high defensiveness, high hostility and low defensiveness, low hostility and high defensiveness, and low hostility and low defensiveness). RESULTS: We expected the group of hostile defensive women to record higher activation (task phase: an academic exam) and slower habituation (recovery phase) compared to the other groups. The results confirmed our hypothesis, as the profile of the hostile defensive individuals was one of constant or sensitization during the task phase, while during the recovery phase those individuals underwent a slow recovery. CONCLUSION: Therefore, it can be indicated that the low hostility and low defensive group is the most adaptive, as recorded very little activation in response, and rapid recovery. PMID- 29532687 TI - Delivery of vinblastine-containing niosomes results in potent in vitro/in vivo cytotoxicity on tumor cells. AB - Vinblastine (VB), as a chemotherapeutic agent, is widely used in treatment of different types of cancer. However, its clinical application is limited due to its low water solubility, side effects, and multidrug resistance. The aim of this study was to increase the therapeutic efficacy of VB using drug delivery systems. For this purpose, a PEGylated niosomal formulation of vinblastine (Pn-VB) was prepared by thin film hydration method and physicochemically characterized. Drug release pattern was performed by dialysis diffusion method. The cytotoxicity of Pn-VB was investigated against murine lung cancer TC-1 cells using MTT assay and its tumor inhibitory effect was evaluated in lung tumor-bearing C57BL/6 mice. Mean particle size, zeta potential, entrapment, and loading efficiency of niosomes were obtained to be about 234.3 +/- 11.4 nm, -34.6 +/- 4.2 mV, 99.92 +/- 1.6%, and 2.673 +/- 0.30%, respectively. While, the mean particle size and zeta potential for non-PEGylated niosomes were obtained about 212.4 nm and -31.4 mV, respectively. The in vitro release pattern of drug from niosomes showed a sustained release behavior. Pn-VB indicated a significant increase in toxicity against TC-l cells as compared to free VB. In animal model, Pn-VB exhibited stronger tumor inhibitory effect and longer life time in comparison to free VB. In conclusion, Pn-VB showed appropriate stability, high-entrapment efficacy, lower releasing rate, and stronger cytotoxic activity against lung cancer TC-1 cells as compared to free drug. Thus, the Pn-VB could be a promising formulation for delivery of vinblastine to tumor cells with enhanced drug bioavailability and therapeutic efficacy. PMID- 29532689 TI - Protective effect of neferine against UV-B-mediated oxidative damage in human epidermal keratinocytes. AB - BACKGROUND: Studies have shown that skin exposure to ultraviolet radiation (UVR) results in the formation of reactive oxygen species (ROS), thus altering the cellular function. The human epidermal skin layer is mainly composed of keratinocytes, which is damaged by UV-B radiation-induced intracellular oxidative stress. Neferine is an alkaloid extract from lotus seed embryos and is known to promote antioxidant activity. OBJECTIVE: In this study for the first time, we investigated the photoprotective action of neferine, against UV-B-produced oxidative damage in human epidermal keratinocytes (HEKs). METHODS: We established an in Vitro study model using HEKs. Cellular viability was determined by MMT assay kits. The intracellular oxidative stress was measured using ROS and malondialdehyde (MDA) assay kits. Endogenous antioxidants were measured by superoxide dismutase (SOD) and glutathione peroxidase (GPx) assay kits. Photoprotective nature of neferine was further evaluated by analyzing the morphological and ultrastructural alterations in keratinocytes. RESULTS: Neferine inhibit the UV-B-mediated increase in ROS and MDA levels in pretreated keratinocytes. The antioxidants, SOD and GPx activities were significantly high in neferine pretreated UV-B groups. Mitochondrial and endoplasmic reticulum damage were less evident in neferine-pretreated UV-B groups as compared with the control group, which might be associated with reduced oxidative stress and lipid peroxidation. CONCLUSION: Taken together, our results suggest that neferine can prevent UV-B-induced oxidative damage and may thus be a potential agent for prevention and treatment of skin damage and photoaging. PMID- 29532688 TI - The hop-derived compounds xanthohumol, isoxanthohumol and 8-prenylnaringenin are tight-binding inhibitors of human aldo-keto reductases 1B1 and 1B10. AB - Xanthohumol (XN), a prenylated chalcone unique to hops (Humulus lupulus) and two derived prenylflavanones, isoxanthohumol (IX) and 8-prenylnaringenin (8-PN) gained increasing attention as potential anti-diabetic and cancer preventive compounds. Two enzymes of the aldo-keto reductase (AKR) superfamily are notable pharmacological targets in cancer therapy (AKR1B10) and in the treatment of diabetic complications (AKR1B1). Our results show that XN, IX and 8-PN are potent uncompetitive, tight-binding inhibitors of human aldose reductase AKR1B1 (Ki = 15.08 MUM, 0.34 MUM, 0.71 MUM) and of human AKR1B10 (Ki = 20.11 MUM, 2.25 MUM, 1.95 MUM). The activity of the related enzyme AKR1A1 was left unaffected by all three compounds. This is the first time these three substances have been tested on AKRs. The results of this study may provide a basis for further quantitative structure?activity relationship models and promising scaffolds for future anti diabetic or carcinopreventive drugs. PMID- 29532690 TI - Diagnostic Accuracy of Combined Acetylcholinesterase Histochemistry and Calretinin Immunohistochemistry of Rectal Biopsy Specimens in Hirschsprung's Disease. AB - BACKGROUND: Acetylcholinesterase (AchE) histochemistry has been established as an accurate diagnostic tool for Hirschsprung's disease (HD). In addition, calretinin immunohistochemistry is also reported as a reliable and adjunctive method to diagnose HD. We investigated the diagnostic value of combined AchE histochemistry and calretinin immunohistochemistry in rectal suction biopsies from HD and non-HD patients. METHODS: We retrospectively reviewed 99 rectal suction biopsy specimens including 4 repeat biopsies from 95 patients (34 HD and 61 non-HD). Each specimen was evaluated with hematoxylin-eosin, AchE histochemistry, and calretinin immunohistochemistry. RESULTS: Of 95 patients, only 21 (22.1%) showed some ganglion cells. All 61 non-HD cases revealed no abnormal AchE-positive fibers. Of 34 HD patients, 32 exhibited abnormal AchE fibers, but 2 showed no stained fibers. None of the tissues from the HD patients exhibited calretinin immunoreactivity. Test sensitivity and specificity of AchE histochemistry alone were 93.5% and 100.0%, respectively, while calretinin immunohistochemistry were 100.0% and 85.2%, respectively. CONCLUSIONS: AchE histochemistry is a good diagnostic method for HD, if feasible, and a combination of AchE histochemistry and calretinin immunohistochemistry will help increase the accuracy of the diagnosis of HD. PMID- 29532691 TI - Food Insecurity and Violence in the Home: Investigating Exposure to Violence and Victimization Among Preschool-Aged Children. AB - Children experiencing or witnessing violence in the home are at risk of a number of cognitive, social, and behavioral challenges as they age. A handful of recent studies have suggested that food insecurity may be one factor associated with violence against children in the home. The present study uses data from the Early Childhood Longitudinal Study-Birth Cohort to explore the link between household food insecurity during the first three waves of data collection (i.e., the first few years of life) and witnessing or being the victim of violence in the home among very young children (~ age 4). The results suggest that the predicted probability of early childhood exposure to violence and/or victimization in the home is nearly 6 times greater in persistently food-insecure households (i.e., households that are food insecure across all three waves) relative to food secure households. Limitations and avenues for future research are noted. PMID- 29532692 TI - Predictors of School Garden Integration: Factors Critical to Gardening Success in New York City. AB - The purpose of this study was to determine the level of integration of school gardens and identify factors that predict integration. 211 New York City schools completed a survey that collected demographic information and utilized the School Garden Integration Scale. A mean garden integration score was calculated, and multiple regression analysis was conducted to determine independent predictors of integration and assess relationships between individual integration characteristics and budget. The average integration score was 34.1 (of 57 points) and ranged from 8 to 53. Operating budget had significant influence on integration score, controlling for all other factors ( p < .0001). Partner organizations, evaluation/feedback, planning the physical space, and characteristics of the physical space were positively and significantly related to budget. The results of this study indicate that any garden can become well integrated, as budget is a modifiable factor. When adequate funding is secured, a well-integrated garden may be established with proper planning and sound implementation. PMID- 29532693 TI - A systematic review and meta-analysis of the efficacy and safety of the interleukin (IL)-12/23 and IL-17 inhibitors ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab and tildrakizumab for the treatment of moderate to severe plaque psoriasis. AB - OBJECTIVE: To systematically analyze the efficacy and safety of interleukin (IL) 12/23, IL-17, and selective IL-23 inhibitors in moderate to severe plaque psoriasis. METHODS AND RESULTS: Twenty-four randomized placebo-controlled trials were included. Compared to placebo, risk ratios (RR) of achieving PASI-75 and PGA/IGA 0/1 respectively were 20.20 (95% CI 13.82-29.54, p < .00001) and 14.55 (10.42-20.31, p < .00001) for ustekinumab 90 mg, 13.75 (8.49-22.28, p < .00001) and 9.81 (5.70-16.89, p < .00001) for ustekinumab 45 mg, 17.65 (12.38-25.17, p < .00001) and 26.13 (16.05-42.53, p < .00001) for secukinumab 300 mg, 15.36 (10.76 21.94, p < .00001) and 20.91 (12.82-34.13, p < .00001) for secukinumab 150 mg, 18.22 (10.63-31.23, p < .000001) and 18.82 (10.36-34.16, p < .00001) for ixekizumab 80 mg every 4 weeks, 19.83 (11.07-35.52, p < .00001) and 20.41 (11.01 37.81, p < .00001) for ixekizumab 80 mg every 2 weeks, 14.79 (9.86-22.16, p < .00001) and 21.93 (15.52-31.01, p < .00001) for brodalumab 210 mg, 11.55 (7.77 17.18, p < .00001) and 16.59 (11.72-23.49, p < .00001) for brodalumab 140 mg, 12.40 (8.87-17.34, p < .00001) and 10.84 (7.91-14.85, p < .00001) for guselkumab 100 mg, 11.45 (7.45-17.58, p < .00001) and 10.97 (6.44-18.69, p < .00001) for tildrakizumab 200 mg, 11.02 (7.17-16.93, p < .00001) and 10.03 (6.45-15.59, p < .00001) for tildrakizumab 100 mg. Similar outcomes were seen for PASI-90. Safety was satisfactory for each therapy at any dose, but a slightly increased risk of withdrawal due to toxicity was observed in individuals receiving ixekizumab compared to placebo. CONCLUSION: Ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab were highly efficacious and generally well-tolerated when used as treatments for moderate to severe plaque psoriasis. PMID- 29532695 TI - A Rare Mammary Serendipity: Mucinous Metaplasia of the Breast. PMID- 29532694 TI - Implementation of HbA1c Point of Care Testing in 3 German Medical Practices: Impact on Workflow and Physician, Staff, and Patient Satisfaction. AB - BACKGROUND: Medical practices face challenges of time and cost pressures with scarce resources. Point-of-care testing (POCT) has the potential to accelerate processes compared to central laboratory testing and can increase satisfaction of physicians, staff members, and patients. The objective of this study was to evaluate the effects of introducing HbA1c POCT in practices specialized in diabetes. METHOD: Three German practices that manage 400, 550, and 950 diabetes patients per year participated in this evaluation. The workflow and required time before and after POCT implementation (device: Alere Afinion AS100 Analyzer) was evaluated in each practice. Physician (n = 5), staff (n = 9), and patient (n = 298) satisfaction was assessed with questionnaires and interviews. RESULTS: After POCT implementation the number of required visits scheduled was reduced by 80% (88% vs 17.6%, P < .0001), the number of venous blood collections by 75% (91% vs 23%, P < .0001). Of patients, 82% (vs 13% prior to POCT implementation) were able to discuss their HbA1c values with treating physicians immediately during their first visit ( P < .0001). In two of the practices the POCT process resulted in significant time savings of approximately 20 and 22 working days per 1000 patients per year (95% CI 2-46; 95% CI 10-44). All physicians indicated that POCT HbA1c implementation improved the practice workflow and all experienced a relief of burden for the office and the patients. All staff members indicated that they found the POCT measurement easy to perform and experienced a relief of burden. The majority (61.3%) of patients found the capillary blood collection more pleasant and 83% saw an advantage in the immediate availability of HbA1c results. CONCLUSIONS: The implementation of HbA1c POCT leads to an improved practice workflow and increases satisfaction of physicians, staff members and patients. PMID- 29532696 TI - Kaposi Sarcoma With Coexisting Intravascular Lymphoma. PMID- 29532701 TI - Weight-Bearing Cone-Beam CT Scan Assessment of Stability of Supination External Rotation Ankle Fractures in a Cadaver Model. AB - BACKGROUND: The utility of computed tomography (CT) for measuring medial clear space (MCS) for determination of the stability of supination external rotation (SER) ankle fractures and in comparison to standard radiographs is unknown. We compared MCS on gravity stress (GS) radiographs to GS and weight bearing (WB) cone-beam CT (CBCT). METHODS: An AO SER 44B3.1 ankle fracture was simulated in 10 human cadavers, also serving as controls. MCS was measured on GS radiographs, GS CBCT, and a simulated WB CBCT scan. Specimens were stable if MCS was <5 mm and unstable if MCS was >=5 mm. Paired t tests were used to compare MCS from each imaging modality for controls versus SER injuries and stable versus unstable specimens. RESULTS: Compared with controls assessed by GS radiographs, MCS was greater for an SER injury when assessed by GS radiograph and GS CBCT scan within the stable group. Compared with controls assessed by GS radiographs, MCS was greater for SER injuries when assessed by GS radiograph, GS CBCT scan, and WB CBCT within the unstable group. MCS was reduced for stable versus unstable SER injuries assessed by WB CBCT. CONCLUSION: In a cadaveric model of SER ankle fracture, the medial clear space was statistically significantly greater for the experimental condition when assessed by gravity stress radiograph and gravity stress CBCT scan. Under weight-bearing conditions, the cone-beam CT scanner distinguished between stable and unstable ankles in the experimental condition. CLINICAL RELEVANCE: This study suggests that a WB cone-beam CT scan may be able to distinguish between stable and unstable SER ankle fractures and influence operative decision making. PMID- 29532702 TI - A unique cytoskeleton-associated protein in Cryptococcus neoformans. PMID- 29532703 TI - Protein-losing enteropathy may be an important characteristic manifestation in Sjogren's syndrome. PMID- 29532697 TI - FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity. AB - INTRODUCTION: Regulatory T cells (Treg) characterized by expression of FOXP3 and strong immunosuppressive activity play a key role in regulating homeostasis in health and disease. Areas covered: Human Treg are highly diverse phenotypically and functionally. In the tumor microenvironment (TME), Treg are reprogrammed by the tumor, acquiring an activated phenotype and enhanced suppressor functions. No unique phenotypic markers for Treg accumulating in human tumors exist. Treg are heterogeneous and use numerous mechanisms to mediate suppression, which either silences anti-tumor immune surveillance or prevents tissue damage by activated T cells. Treg plasticity in the TME endows them with dual functionality. Treg frequency in tumors associates either with poor or improved survival. Treg responses to immune checkpoint inhibition (ICI) differ from the restorative effects ICIs induce in other immune cells. Therapies used to silence Treg, including ICIs, are only partly successful. Treg persistence and resistance to depletion are critical for maintaining homeostasis. Expert opinion: Treg emerge as a heterogeneous subset of immunosuppressive T cells, which usually, but not always, favor tumor progression. Treg are also engaged in non-immune activities that benefit the host. Therapeutic silencing of Treg in cancer requires a deeper understanding of Treg activities in human health and disease. PMID- 29532704 TI - Low body mass index and lymphocytopenia associate with Mycobacterium avium complex pulmonary disease in patients with rheumatoid arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) are at an increased risk of Mycobacterium avium complex pulmonary disease (MAC-PD). We aimed to identify factors associated with MAC-PD in RA patients, and investigate their clinical significance for diagnosis of this disease. METHODS: We examined 396 patients with RA for the presence of MAC-PD, using the criteria of the American Thoracic Society and conducted three years of follow-up on these patients. Multivariate logistic analyses were employed for selecting factors associated with MAC-PD. We developed a point system based on these factors which we call MAC-PD score to improve diagnosis of MAC-PD. RESULTS: During this study, 14 out of 396 patients were newly diagnosed with MAC-PD. Multivariate analyses revealed body mass index (BMI) <18.0 kg/m2 and lymphocyte count <1500/MUl were associated with MAC-PD in RA patients. Points were assigned to them and totalled to provide the MAC-PD score. Among 20 patients with high-resolution computer tomography images consistent with MAC-PD, the scores were significantly higher in 14 patients with MAC-PD than those in six patients without MAC-PD. CONCLUSION: Using these data, in the forms of the MAC-PD score, could help to identify patients who should be considered for bronchoscopy more selectively. PMID- 29532705 TI - Palliative sedation: The end of heated debate? PMID- 29532706 TI - Notice of Redundant Publication. PMID- 29532708 TI - 'Opening the door' on domestic violence and abuse - the crucial role of medical professionals. PMID- 29532707 TI - Real-world implications of apathy among older adults: Independent associations with activities of daily living and quality of life. AB - OBJECTIVES: Apathy is common in older adults and has been linked to adverse health outcomes. The current study examined whether apathy contributes to problems managing activities of daily living (ADLs) and lower quality of life (QoL) in older adults. METHOD: Participants included 83 community-dwelling older adults. Apathy was assessed using a composite of the self and family-rating scales from the Frontal Systems Behavioral Scale (FrSBe). A knowledgeable informant completed the Activities of Daily Living Questionnaire (ADLQ), and participants completed the World Health Organization Quality of Life (WHOQol) scale. RESULTS: Nominal logistic regressions controlling for age, anxiety and depression symptoms, chronic medical conditions, and global cognition revealed that higher levels of apathy were significantly associated with a wide range of mild ADL problems. In parallel, a multiple linear regression indicated that greater apathy was significantly associated with lower QoL independent of ADL problems, anxious and depressive symptomology, chronic medical conditions, global cognition and age. DISCUSSION: Findings suggest that apathy confers an increased risk of problems in the independent management of daily activities and poorer well-being among community-dwelling older adults. Neurobehavioral and pharmacological interventions to improve apathy may have beneficial effects on the daily lives of older adults. PMID- 29532709 TI - Thoracic intervention and surgery to cure lung cancer: image-guided thermal ablation in primary lung cancer. PMID- 29532710 TI - Myositis-specific autoantibodies in Japanese patients with juvenile idiopathic inflammatory myopathies. AB - OBJECTIVES: The aim of our study is to clarify the association of myositis specific autoantibodies (MSAs) with clinical and laboratory features in Japanese patients with juvenile idiopathic inflammatory myopathies (JIIMs). METHODS: We retrospectively analyzed the frequency of MSAs and their association with clinical or laboratory findings in 25 Japanese patients with JIIMs in Hokkaido district. RESULTS: Eighteen of the 25 patients (72%) were positive for MSAs; seven with anti-melanoma differentiation associated gene (MDA) 5 (28%), five with anti-transcriptional intermediary factor (TIF)-1gamma (20%), four with anti MJ/nuclear matrix protein (NXP)-2 (16%), two with anti-Jo-1 (8%), one with anti- HMG-CoA reductase, one with anti-signal recognition peptide (SRP) antibodies (4% each), including co-existence and transition of MSAs in one patient each. Anti MDA5 antibodies were related to interstitial lung disease (ILD) and arthritis but not to amyopathic juvenile dermatomyositis. Drug-free remission was achieved, once ILD was overcome in this group. Anti-TIF-1gamma antibodies were associated with typical rashes and mild myositis. Anti-MJ/NXP2 and anti-SRP antibodies were associated with severe muscle weakness. No patient was complicated with malignancy. CONCLUSION: Anti-MDA5 antibodies are prevalent and closely associated with ILD in our series compared with other countries. There was no apparent difference in clinical features associated with other MSAs among races. PMID- 29532711 TI - An Analysis of Individual Differences in Recognizing Monosyllabic Words Under the Speech Intelligibility Index Framework. AB - Individual differences in the recognition of monosyllabic words, either in isolation (NU6 test) or in sentence context (SPIN test), were investigated under the theoretical framework of the speech intelligibility index (SII). An adaptive psychophysical procedure, namely the quick-band-importance-function procedure, was developed to enable the fitting of the SII model to individual listeners. Using this procedure, the band importance function (i.e., the relative weights of speech information across the spectrum) and the link function relating the SII to recognition scores can be simultaneously estimated while requiring only 200 to 300 trials of testing. Octave-frequency band importance functions and link functions were estimated separately for NU6 and SPIN materials from 30 normal hearing listeners who were naive to speech recognition experiments. For each type of speech material, considerable individual differences in the spectral weights were observed in some but not all frequency regions. At frequencies where the greatest intersubject variability was found, the spectral weights were correlated between the two speech materials, suggesting that the variability in spectral weights reflected listener-originated factors. PMID- 29532712 TI - Hydatid disease: MR imaging of calvarium and superior sagittal sinus involvement. AB - Extra-axial hydatid disease (HD) is rare and may create a diagnostic challenge. Herein, we report an extremely rare case of calvarial HD with superior sagittal sinus invasion and an extension to the scalp with unusual magnetic resonance imaging findings simulating osteomyelitis and abscess. Recognition of detached endocystic membranes was the most important clue for the correct diagnosis. HD should be included in the differential diagnosis for a patient having a destructive skull lesion with peripheral enhancing extra-axial soft tissue component. Preoperative correct imaging diagnosis is crucial to improving patient management. PMID- 29532713 TI - Systematically excluded: Young women's experiences of accessing child support grants in South Africa. AB - Unconditional cash transfers have risen in prominence for their potential to improve the health of the world's most marginalised and bring them into a relationship with the state. Typically, challenges to accessing grants are described in terms of technical issues such as access to documents and distance to offices. This paper explores the challenges of 30 young, poor, black South African women in accessing the Child Support Grant (CSG), an unconditional cash transfer provided by the South African government. Data suggest that while there were 'technical' issues, young women were systematically excluded from accessing the CSG in two ways. First, women were symbolically marginalised by state officials, who humiliated them, forcing women to sit quietly and acquiesce to state power to access the CSG. Second, there were large distances for women to travel to access state services, despite these being geared to serve the poor. Rather than promoting the active citizenship of the poorest in South Africa, accessing the CSG reinforced marginalisation. Transforming this will not be achieved through technical solutions, rather the barriers to access need to be recognised as political. PMID- 29532714 TI - Turning on virulence: Mechanisms that underpin the morphologic transition and pathogenicity of Blastomyces. AB - This review article focuses on the mechanisms underlying temperature adaptation and virulence of the etiologic agents of blastomycosis, Blastomyces dermatitidis, Blastomyces gilchristii, and Blastomyces percursus. In response to temperature, Blastomyces undergoes a reversible morphologic switch between hyphae and yeast known as the phase transition. The conversion to yeast for Blastomyces and related thermally dimorphic fungi is essential for virulence. In the yeast phase, Blastomyces upregulates the essential virulence factor, BAD1, which promotes attachment to host cells, impairs activation of immune cells, and blunts cytokine release. Blastomyces yeast also secrete dipeptidyl-peptidase IVA (DPPIVA), a serine protease that blunts the action of cytokines released from host immune cells. In vivo transcriptional profiling of Blastomyces yeast has uncovered genes such as PRA1 and ZRT1 involved in zinc scavenging that contribute to virulence during murine pulmonary infection. The discovery and characterization of genes important for virulence has led to advances at the bedside regarding novel diagnostics, vaccine development, and new targets for drug discovery. PMID- 29532716 TI - Corrigendum. PMID- 29532715 TI - Importin alpha5 negatively regulates importin beta1-mediated nuclear import of Newcastle disease virus matrix protein and viral replication and pathogenicity in chicken fibroblasts. AB - The matrix (M) protein of Newcastle disease virus (NDV) is demonstrated to localize in the nucleus via intrinsic nuclear localization signal (NLS), but cellular proteins involved in the nuclear import of NDV M protein and the role of M's nuclear localization in the replication and pathogenicity of NDV remain unclear. In this study, importin beta1 was screened to interact with NDV M protein by yeast two-hybrid screening. This interaction was subsequently confirmed by co-immunoprecipitation and pull-down assays. In vitro binding studies indicated that the NLS region of M protein and the amino acids 336-433 of importin beta1 that belonged to the RanGTP binding region were important for binding. Importantly, a recombinant virus with M/NLS mutation resulted in a pathotype change of NDV and attenuated viral replication and pathogenicity in chicken fibroblasts and SPF chickens. In agreement with the binding data, nuclear import of NDV M protein in digitonin-permeabilized HeLa cells required both importin beta1 and RanGTP. Interestingly, importin alpha5 was verified to interact with M protein through binding importin beta1. However, importin beta1 or importin alpha5 depletion by siRNA resulted in different results, which showed the obviously cytoplasmic or nuclear accumulation of M protein and the remarkably decreased or increased replication ability and pathogenicity of NDV in chicken fibroblasts, respectively. Our findings therefore demonstrate for the first time the nuclear import mechanism of NDV M protein and the negative regulation role of importin alpha5 in importin beta1-mediated nuclear import of M protein and the replication and pathogenicity of a paramyxovirus. PMID- 29532718 TI - Prades J-M et al. Randomized phase III trial comparing induction chemotherapy followed by radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3Mo pyriform sinus carcinoma. Acta Oto-Laryngol 2010; 130: 150 155. PMID- 29532719 TI - Georg von Bekesy - uber die mechanisch-akustischen Vorgange beim Horen. Acta Oto Laryngol 1939; 27: 281-296. PMID- 29532720 TI - Koskinen et al. Long-term follow-up after ESS and balloon sinoplasty: comparison of symptom reduction and patient satisfaction. Acta Oto-Laryngol 2016; 136: 532 536. PMID- 29532721 TI - Wan Du et al. - Prevalence of GJB2 mutations in the Silk Road region of China and a report of three novel variants. Acta Oto-Laryngol 2014; 134: 373-381. PMID- 29532722 TI - Usami S-I et al. - Hearing preservation and clinical outcome of 32 consecutive electric acoustic stimulation (EAS) surgeries. Acta Oto-Laryngol 2014; 134: 717 727. PMID- 29532717 TI - Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response. AB - Pseudomonas aeruginosa, a re-emerging, opportunistic human pathogen, encodes a variety of virulence determinants. Pyoverdine, a siderophore produced by this bacterium, is essential for pathogenesis in mammalian infections. This observation is generally attributed to its roles in acquiring iron and/or regulating other virulence factors. Here we report that pyoverdine translocates into the host, where it binds and extracts iron. Pyoverdine-mediated iron extraction damages host mitochondria, disrupting their function and triggering mitochondrial turnover via autophagy. The host detects this damage via a conserved mitochondrial surveillance pathway mediated by the ESRE network. Our findings illuminate the pathogenic mechanisms of pyoverdine and highlight the importance of this bacterial product in host-pathogen interactions. PMID- 29532724 TI - Schmiegelow E - Contribution to the pathology of the tuberculosis of the bronchial glands. Acta Oto-Laryngol 1918; 1: 1-37. PMID- 29532723 TI - Tjellstrom A et al. - Analysis of the mechanical impedance of bone-anchored hearing aids. Acta Oto-Laryngol 1980; 89: 85-92. PMID- 29532725 TI - F House & W E Hitselberger. The middle fossa approach for removal of small acoustic tumors. Acta Oto-Laryngol 1969; 67: 413-427. PMID- 29532726 TI - H Engstrom & J Wersall. Structure of the Organ of Corti: Outer Hair Cells. Acta Oto-Laryngol 2953; 43: 1-10. PMID- 29532727 TI - Acta Oto-Laryngologica. PMID- 29532729 TI - Thomsen J et al. - The non-specific effect of endolymphatic sac surgery in treatment of Meniere's disease: A prospective, randomized controlled study comparing "classic" endolymphatic sac surgery with the insertion of a ventilating tube in tympanic membrane. Acta Oto-Laryngol 1998: 118: 769-773. PMID- 29532728 TI - Preface. PMID- 29532731 TI - Zenner H-P - Motility of outer hair cells as an active, actin-mediated process. Acta Oto-Laryngol 1988; 105: 39-44. PMID- 29532730 TI - R Barany. Die Beeinflussung des Ohrensausens durch intravenos injizierte Lokalanasthetica. Vorlaufige Mitteilung. Acta Oto-Laryngol 1936; 23: 201-203. PMID- 29532732 TI - Wittmaack K - Die Funktionelle Bedeutung des Cortischen Organs und der marklosen Nervenendigungen fur den Horakt. Acta Oto-Laryngol 1928; 12: 1-10. PMID- 29532733 TI - Has development assistance for health facilitated the rise of more peaceful societies in sub-Saharan Africa? AB - Growing evidence suggests that health aid can serve humanitarian and diplomatic ends. This study utilised the Fragile States Index (FSI) for the 47 nations of the World Health Organizations' Africa region for the years 2005-2014 and data on health and non-health development aid spending from the United States (US) for those same years. Absolute amounts of health and non-health aid flows from the US were used as predictors of state fragility. We used time-lagged, fixed-effects multivariable regression modelling with change in FSI as the outcome of interest. The highest quartile of US health aid per capita spending (>=$4.00 per capita) was associated with a large and immediate decline in level of state fragility (b = -7.57; 95% CI, -14.6 to -0.51, P = 0.04). A dose-response effect was observed in the primary analysis, with increasing levels of spending associated with greater declines in fragility. Health per-capita expenditures were correlated with improved fragility scores across all lagged intervals and spending quartiles. The association of US health aid with immediate improvements in metrics of state stability across sub-Saharan Africa is a novel finding. This effect is possibly explained by our observations that relative to non-health aid, US health expenditures were larger and more targeted. PMID- 29532734 TI - Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T). AB - OBJECTIVE: To evaluate the efficacy and safety of sirukumab, a human anti interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. METHODS: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. CONCLUSION: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed. PMID- 29532735 TI - 'In the North you can't be openly gay': Contextualising sexual practices among sexually and gender diverse persons in Northern Canada. AB - Scant research has addressed health and well-being among lesbian, gay, bisexual, transgender, and queer (LGBTQ) persons in the Arctic. The Northwest Territories (NWT) has among Canada's highest rates of sexually transmitted infections (STIs). LGBTQ persons in NWT are at the nexus of LGBTQ and Arctic health disparities. Yet little is known of their sexual health needs. This qualitative study explored the sexual health needs of LGBTQ persons in the NWT. We conducted semi-structured, in depth interviews with 51 participants, including 16 LGBTQ youth aged 15-24, 21 LGBTQ adults aged 25 and above, and 14 key informants who worked with LGBTQ persons. Social-ecological approaches to understanding sexual health guided this study. Participants discussed how structural contexts such as heteronormativity in sexual health education and a lack of access to safer sex tools constrained their ability to practice safer sex. Social contexts of intersectional stigma resulted in shame, concealing identities, and fear of accessing safer sex materials. Myriad factors influenced partner communication about safer sex practices, including honesty, consent, and relationship power. Findings suggest the need for comprehensive sexuality education and interventions that address syndemics of substance use, stigma, and low self-esteem to advance sexual health among LGBTQ persons in Northern Canada. PMID- 29532736 TI - Minocycline-associated polyarteritis nodosa and self-limiting hepatitis: a reminder of a potentially re-emerging culprit in drug-induced autoimmune syndromes. PMID- 29532737 TI - The Venom of Ornithoctonus huwena affect the electrophysiological stability of neonatal rat ventricular myocytes by inhibiting sodium, potassium and calcium current. AB - Spider venoms are known to contain various toxins that are used as an effective means to capture their prey or to defend themselves against predators. An investigation of the properties of Ornithoctonus huwena (O.huwena) crude venom found that the venom can block neuromuscular transmission of isolated mouse phrenic nerve-diaphragm and sciatic nerve-sartorius preparations. However, little is known about its electrophysiological effects on cardiac myocytes. In this study, electrophysiological activities of ventricular myocytes were detected by 100 MUg/mL venom of O.huwena, and whole cell patch-clamp technique was used to study the acute effects of the venom on action potential (AP), sodium current (INa), potassium currents (IKr, IKs, Ito1 and IK1) and L-type calcium current (ICaL). The results indicated that the venom prolongs APD90 in a frequency dependent manner in isolated neonatal rat ventricular myocytes. 100 MUg/mL venom inhibited 72.3 +/- 3.6% INa current, 58.3 +/- 4.2% summit current and 54 +/- 6.1% the end current of IKr, and 65 +/- 3.3% ICaL current, yet, didn't have obvious effect on IKs, Ito1 and IK1 currents. In conclusion, the O.huwena venom represented a multifaceted pharmacological profile. It contains abundant of cardiac channel antagonists and might be valuable tools for investigation of both channels and anti- arrhythmic therapy development. PMID- 29532739 TI - Online interviewing with interpreters in humanitarian contexts. AB - PURPOSE: Recognising that one way to address the logistical and safety considerations of research conducted in humanitarian emergencies is to use internet communication technologies to facilitate interviews online, this article explores some practical and methodological considerations inherent to qualitative online interviewing. METHOD: Reflections from a case study of a multi-site research project conducted in post-conflict countries are presented. Synchronous online cross-language qualitative interviews were conducted in one country. Although only a small proportion of interviews were conducted online (six out of 35), it remains important to critically consider the impact upon data produced in this way. RESULTS: A range of practical and methodological considerations are discussed, illustrated with examples. Results suggest that whilst online interviewing has methodological and ethical potential and versatility, there are inherent practical challenges in settings with poor internet and electricity infrastructure. Notable methodological limitations include barriers to building rapport due to partial visual and non-visual cues, and difficulties interpreting pauses or silences. CONCLUSIONS: Drawing upon experiences in this case study, strategies for managing the practical and methodological limitations of online interviewing are suggested, alongside recommendations for supporting future research practice. These are intended to act as a springboard for further reflection, and operate alongside other conceptual frameworks for online interviewing. PMID- 29532738 TI - Prolonged Exposure of CBA/Ca Mice to Moderately Loud Noise Can Cause Cochlear Synaptopathy but Not Tinnitus or Hyperacusis as Assessed With the Acoustic Startle Reflex. AB - Hearing loss changes the auditory brain, sometimes maladaptively. When deprived of cochlear input, central auditory neurons become more active spontaneously and begin to respond more strongly and synchronously to better preserved sound frequencies. This spontaneous and sound-evoked central hyperactivity has been postulated to trigger tinnitus and hyperacusis, respectively. Localized hyperactivity has also been observed after long-term exposure to noise levels that do not damage the cochlea. Adult animals exposed to bands of nondamaging noise exhibited suppressed spontaneous and sound-evoked activity in the area of primary auditory cortex (A1) stimulated by the exposure band but had increased spontaneous and evoked activity in neighboring A1 areas. We hypothesized that the cortically suppressed frequencies should for some time after exposure be perceived as less loud than before (hypoacusis), whereas the hyperactivity outside of the exposure band might lead to frequency-specific hyperacusis or tinnitus. To investigate this, adult CBA/Ca mice were exposed for >2 months to 8 to 16 kHz noise at 70 or 75 dB sound pressure level and tested for hypo /hyperacusis and tinnitus using tone and gap prepulse inhibition of the acoustic startle reflex. Auditory brainstem responses and distortion product otoacoustic emissions showed evidence of cochlear synaptopathy after exposure at 75 but not 70 dB, putting a lower bound on damaging noise levels for CBA/Ca mice. Contrary to hypothesis, neither exposure significantly shifted startle results from baseline. These negative findings nevertheless have implications for startle test methodology and for the putative role of central hyperactivity in hyperacusis and tinnitus. PMID- 29532740 TI - Adaptive Processes in Hearing. AB - Our auditory environment is constantly changing and evolving over time, requiring us to rapidly adapt to a complex dynamic sensory input. This adaptive ability of our auditory system can be observed at different levels, from individual cell responses to complex neural mechanisms and behavior, and is essential to achieve successful speech communication, correct orientation in our full environment, and eventually survival. These adaptive processes may differ in individuals with hearing loss, whose auditory system may cope via "readapting" itself over a longer time scale to the changes in sensory input induced by hearing impairment and the compensation provided by hearing devices. These devices themselves are now able to adapt to the listener's individual environment, attentional state, and behavior. These topics related to auditory adaptation, in the broad sense of the term, were central to the 6th International Symposium on Auditory and Audiological Research held in Nyborg, Denmark, in August 2017. The symposium addressed adaptive processes in hearing from different angles, together with a wide variety of other auditory and audiological topics. The papers in this special issue result from some of the contributions presented at the symposium. PMID- 29532741 TI - Short-Term Radiographic Outcome After Distal Chevron Osteotomy for Hallux Valgus Using Intramedullary Plates With an Amended Algorithm for the Surgical Management of Hallux Valgus. AB - : Distal Chevron osteotomy is a well-established surgical procedure for mild to moderate hallux valgus deformity. Many methods have been described for fixation of osteotomy site; secure fixation, enabling large displacement of the metatarsal head, is one of the essentials of this procedure. The purpose of the present study was to evaluate the short-term radiographic outcome of a distal Chevron osteotomy using an intramedullary plate for the correction of hallux valgus deformity. The present study evaluated 37 patients (40 feet) who underwent distal Chevron osteotomy using an intramedullary plate by periodic radiographs obtained preoperatively and at 4 weeks, 8 weeks, 3 months, and 6 months postoperatively. Correction of the hallux valgus angle averaged 17.8 degrees , intermetatarsal angle 7.4 degrees , distal metatarsal articular angle 2.7 degrees , and sesamoid position 1.4 stages at 3 months postoperatively. The average lateral shift of the capital fragment was 6.5 mm. All patients achieved bone union, and there were no cases of dislocation, displacement, or avascular necrosis of the metatarsal head fragment. In conclusion, a distal Chevron osteotomy using an intramedullary plate was a favorable method for the correction of mild to moderate hallux valgus deformity. LEVELS OF EVIDENCE: Level IV: Case series. PMID- 29532742 TI - The Ability of Fluorescence Angiography to Detect Local Ischemia in Patients With Heel Ulceration. AB - : Heel ulcerations are a significant burden of care in both hospital and long term care settings. The presence of peripheral arterial disease as a contributing factor to delayed healing is often not recognized, resulting in prolonged healing and high patient morbidity and mortality. Formal vascular evaluation and intervention is often not performed as these patients can have palpable pedal pulses while having localized ischemia of the heel. As routine noninvasive vascular studies can be affected by medial calcinosis and collateralization and do not specifically assess tissue perfusion to the heel, a false sense of security of adequate perfusion for healing can result. Indocyanine green fluorescence angiography (ICGFA) allows for real-time visualization and objective assessment of site specific tissue perfusion not limited by the factors that can make routine noninvasive vascular studies unreliable or unobtainable. A retrospective medical record review of a subset of patients with chronic heel ulceration from a prospective institutional review board-approved study in which serial ICGFA was performed during their treatment course was performed. ICGFA was able to identify local heel ischemia and expedite vascular intervention. ICGFA should be considered as an additional vascular study in patients presenting with chronic, nonhealing heel ulcerations. LEVELS OF EVIDENCE: Level IV: Diagnostic, Case series. PMID- 29532743 TI - Calcaneal Osteotomy Safe Zone to Prevent Neurological Damage: Fact or Fiction? AB - BACKGROUND: Calcaneal osteotomy is a commonly used surgical option for the correction of hindfoot malalignment. A previous cadaveric study described a neurological "safe zone" for calcaneal osteotomy. We performed a retrospective chart review to evaluate the presence of neurological injuries following calcaneal osteotomies and the location of the osteotomy in relation to the reported safe zone. METHODS: In this retrospective study, we reviewed charts of patients who underwent calcaneal osteotomy at our institution from 2011 to 2015. All immediate postoperative radiographs were examined and the shortest distance between the calcaneal osteotomy line and a reference line connecting the posterior superior apex of the calcaneal tuberosity to the origin of the plantar fascia was measured. If the osteotomy line was positioned within an area 11.2 mm anterior to the reference line, it was considered to be inside the neurological safe zone. We correlated the positioning of the osteotomy with the presence of postoperative neurological complications. RESULTS: We identified 179 calcaneal osteotomy cases. Of the 174 (97.2%) nerve injury-free cases, 62.6% (109/174) were performed inside the defined "safe zone" while 37.4% (65/174) outside. A total of 5 (2.8%) nerve complications were identified: 3 (60%) were inside the safe zone and 2 (40%) outside the safe zone. Osteotomies outside the safe zone had a 1.114 relative risk of nerve injury with a 95% CI of 0.191 to 6.500 and showed no statistically significant difference ( P = .9042). CONCLUSION: Our findings suggest that the clinical "safe zone" in calcaneal osteotomies may not actually exist, likely because of wide anatomical variation of the implicated nerves, as described in prior studies. Patients should be properly counseled preoperatively on the low, but seemingly fixed, risk of nerve injury before undergoing calcaneal osteotomy. LEVELS OF EVIDENCE: Level III: Retrospective comparative study. PMID- 29532744 TI - Associations between maternal clinical features and fetal outcomes in pregnancies of mothers with connective tissue diseases. AB - OBJECTIVES: The purpose of this study is to clarify associations between maternal clinical features and adverse pregnancy outcomes (APOs) in mothers with connective tissue diseases (CTDs). METHODS: We retrospectively examined maternal clinical features including backgrounds, autoantibodies, CTD flare-ups, and therapies during pregnancies as well as fetal outcomes in 90 pregnancies (66 mothers) at our hospital from January 2006 to September 2016. RESULTS: Underlying CTDs were SLE (N = 41), MCTD (N = 10), RA (N = 15), SS (N = 10), and others (N = 14). Anti-SS-A antibody was detected in 60.3%, lupus anticoagulant (LAC) was in 11.4%, and anti-cardiolipin-beta2glycoprotein1 antibody was in 18.5%. Flare-ups of CTDs occurred in 20 pregnancies (22.2%). Corticosteroids (CS) was administered in 73 pregnancies, immunosuppressants in four, and biologics in one. Among the 85 pregnancies other than five early abortions within 12 weeks of gestational age, 33 cases had APOs while the remaining 52 cases were normal. Although disease duration, MCTD, high dose of CS, flare-ups of CTDs, and positive LAC significantly correlated with APOs by univariate analysis, only MCTD was a significant independent predictor for APOs by multivariate analysis. CONCLUSION: Disease duration, MCTD, high dose of CS, flare-ups of CTDs, and LAC might be possible predictive risk factors for APOs in pregnancies with CTDs. Of these, MCTD was a significant independent risk factor. PMID- 29532745 TI - Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis. AB - BACKGROUND: The course of multiple sclerosis (MS) shows substantial inter individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. OBJECTIVE: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. METHODS: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (E2) and rs429358 (E4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. RESULTS: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. CONCLUSIONS: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients' counseling upon initial diagnosis of MS. PMID- 29532747 TI - Temporomandibular disorders and mandibular vertical asymmetry. AB - Objective To analyze the association between mandibular vertical asymmetry and the presence of TMD in adult patients. Methods This case-control study recruited patients from the orthodontic clinic at FEBUAP. Patients were classified on the basis of diagnostic criteria for temporomandibular disorders (DC/TMD). Panoramic radiographs were measured to determine mandibular vertical asymmetry indices according to criteria described by Kjellberg and Habets. Both methods (DC/TMD and index criteria) were standardized a priori. Results A total of 56 patients were analyzed, of whom 25 (44.6%) met the inclusion criteria and were divided into two groups (TMD group, n = 15; non-TMD group, n = 10). The highest asymmetry index was observed in the condylar neck, followed by the total condylar asymmetry index, but without significant differences between groups (p > .05). Conclusion There is no association (p > .05) between temporomandibular disorders and mandibular vertical asymmetry. PMID- 29532746 TI - Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network. AB - BACKGROUND: Recent studies have reported that mesenchymal stem cells (MSCs) exert therapeutic effects on the treatment of diabetic nephropathy (DN), but the underlying mechanisms remain unclear. METHODS: A dataset GSE65561 was obtained from Gene Expression Omnibus (GEO) database, which contained four healthy control samples (group 1), four healthy controls samples co-cultured with MSCs (group 2), five DN samples (group 3) and five DN samples co-cultured with MSCs (group 4). The differentially expressed genes (DEGs) between group 3 vs. group 1 and group 4 vs. group 2 were constructed using Linear Models for Microarray (LIMMA) package package. Then, DAVID was used to analyze the functional enrichment of DEGs. Based on STRING database the protein-protein interaction (PPI) network was visualized by the Cytoscape plug-in CytoNCA. Besides, the hub miRNAs and transcription factors (TFs) regulating DEGs were predicted using Webgestalt. RESULTS: Totally, 303 up-regulated and 88 down-regulated DEGs were shared in group 3 vs. group 1 and group 4 vs. group 2. Besides, the up-regulated DEGs were mainly enriched in 'translation' and 'translational elongation', while the down-regulated genes were only enriched in 'protein kinase activity'. RPS27A and RPLP0 had a higher degree in the PPI network and they were regulated by EIF3M. In addition, ETF1 was predicted to be an important gene, which was regulated by miR-150, miR-134 and EIF2S1. CONCLUSIONS: RPS27A, RPLP0 and ETF1 may be potential targets for MSCs on the treatment of DN. Highlights RPS27A and RPLP0 may be important genes in the treatment of MSCs for DN. TF EIF3M may play a key role in the treatment of MSCs for DN. MiR-150 and miR-134 may be essential microRNAs in the treatment of MSCs for DN. PMID- 29532748 TI - A2A Adenosine Receptor Agonists and their Potential Therapeutic Applications. An Update. AB - BACKGROUND: Adenosine is an endogenous purine nucleoside, which mediates a variety of important biological processes and diseases, such as vasodilation, inflammation, cancer, wound healing, ischemia reperfusion injury, Parkinson disease, infectious diseases, and other CNS disorders. Particularly important are the A2A receptors that have been expressed in the lung, liver, heart, cardiovascular tissues, leukocytes, neutrophils, and endothelial cells. This review provides an update of the latest A2A receptor agonists developed in the period 2005-2017, their selectivity regarding other adenosine receptors and their potential therapeutic applications. METHODS: I have conducted an extensive search from the most common bibliographic databases for critically review the most recent works on the A2A receptor agonists and their therapeutic applications in inflammation, asthma and chronic obstructive pulmonary disease, myocardial perfusion imaging, sepsis, rheumatoid arthritis, and wound healing, among others. RESULTS: In the last decade, a great deal of effort has been devoted to develop adenosine receptor agonists and antagonists for treatment of a number of diseases. Thus, for A2A receptor agonists more than 130 papers and reviews have been found, many of them highlighting the usefulness of these compounds in the field. CONCLUSIONS: Although so far many of the A2A receptor agonists have failed in clinical trials due to their side effects, some of them have been approved for protection against cardiac ischemia-reperfusion injury and anemia. The recently reported crystal structure of the human A2A receptor in complex with the agonist UK-432097 is a fundamental keystone for the development of new and selective A2A ligands with new therapeutic applications. PMID- 29532749 TI - Nanotechnological Advances for Cutaneous Release of Tretinoin: An Approach to Minimize Side Effects and Improve Therapeutic Efficacy. AB - BACKGROUND: The clinical efficacy of the topical tretinoin is widely studied and has been well established for many therapeutic interventions, among some, photoaging, acne, and melasma. However, the side effects, mainly cutaneous irritation, erythema, xerosis and peeling, remain major obstacle to the patient compliance. Besides, the insight regarding the drug delivery profile is essential to understand the therapeutic action of the drug. METHODS: Through bibliographic research in databases we highlight further advances and an update on tretinoin delivery systems such as liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, cyclodextrins, nanostructured polymers and other technological systems that reduce its side effects and improve the permeation profile to potentiate efficacy and drug safety on the skin. RESULTS: Pharmaceutical preparations were developed and evaluated for permeability in in vitro models using pig ear, snake, mouse and human skin, and potential for irritation was also verified using release systems for tretinoin and compared to available commercial formulations. Overall results indicated the composition, charge and size of the system influences the tretinoin delivery, modulating the type of release and its retention. Small unilamellar vesicles promoted greater cutaneous delivery of tretinoin. Negative charge, for both liposomes and niosomes, can improve pig skin hydration as well as the tretinoin retention. The quantity of solid lipids and the type of oil used in the composition of solid lipid nanoparticles and nanostructured lipid carriers affected percutaneous drug delivery. CONCLUSION: As evident from the literature, the tretinoin technological delivery systems consist an innovative and potential management for increasing the patient compliance presenting safety and efficacy. PMID- 29532750 TI - IAP Proteins Antagonist: An Introduction and Chemistry of Smac Mimetics under Clinical Development. AB - BACKGROUND: Smac mimetics (also known as IAP antagonist) are a new class of targeted drugs having a goal to suppress the IAPs, reestablishing the apoptotic pathways and inducing cancer cell death. Therefore, development of Smac mimetics was considered an attractive strategy for the development of new anticancer drugs. Lots of reviews have come in yesteryears which mainly discussed the biology of IAPs and their role in cancer development. None of these reviews focused on the chemical synthesis of Smac mimetics. METHODS: Literature study was done by using standard bibliographic search engines like scifinder, pubmed etc. The characteristic features of screened articles were described in the review. RESULTS: The review gives an introduction of IAP proteins and Smac mimetics. Readers will gain an overview of the development of Smac mimetics with representative examples of both monovalent and bivalent Smac mimetics as anticancer agents and an understanding of their structure-activity relationships. Chemical synthesis of biologically important Smac mimetics was discussed briefly in this review. CONCLUSION: Small molecules that mimic Smac are continuously progressing towards clinical development. Smac mimetics are generally well tolerated and have demonstrated rapid suppression of their target (the IAPs), activation of apoptosis and anti-tumor activity. Continuous research has been done to generate even more insight into the function of IAP proteins to significantly enhance the therapeutical potential of Smac mimetics. PMID- 29532751 TI - Ischemic stroke and kynurenines: medicinal chemistry aspects. AB - Ischemic stroke is one of the leading causes of mortality and permanent disability in developed countries. Stroke induces massive glutamate release, which in turn causes N-Methyl-D-aspartate (NMDA) receptor over-excitation and thus calcium overload in neurons leading to cell death via apoptotic cascades. The kynurenine pathway is a complex enzymatic cascade of tryptophan catabolism, generating various neuroactive metabolites. One metabolite, kynurenic acid (KYNA), is a potent endogenous NMDA glutamate receptor antagonist, making it a possible therapeutic tool to decrease excitotoxicity and neuroinflammation. Recently, clinical investigations have shown that during the acute phase of ischemic stroke, kynurenine pathway is activated and peripheral levels of metabolites correlated with worse outcome. In this review we set out to summarize the current literature on the connection of the kynurenine pathway and ischemic stroke and set a course for future investigations and potential drug development. PMID- 29532752 TI - HDL dysfunction caused by mutations in apoA-I and other genes that are critical for HDL biogenesis and remodeling. AB - The "HDL hypothesis" supporting that an elevation in HDL cholesterol (HDL-C) levels by drugs or by life style changes should be paralleled by a decrease in the risk for Cardiovascular Disease (CVD) has been challenged by recent epidemiological and clinical studies using HDL-raising drugs. HDL components such as proteins, lipids or small RNA molecules, but not cholesterol itself, possess various atheroprotective functions in different cell types and accumulating evidence supports the new hypothesis that HDL functionality is more important than HDL-C levels for CVD risk prediction. Thus, the detailed characterization of changes in HDL composition and functions in various pathogenic conditions is critically important in order to identify new biomarkers for diagnosis, prognosis and therapy monitoring of CVD. Here we provide an overview of how HDL composition, size and functionality are affected in patients with monogenic disorders of HDL metabolism due to mutations in genes that participate in the biogenesis and the remodeling of HDL. We also review the findings from various mouse models with genetic disturbances in the HDL biogenesis pathway that have been generated for the validation of the data obtained in human patients and how these models could be utilized for the evaluation of novel therapeutic strategies such as the use of adenovirus-mediated gene transfer technology that aim to correct HDL abnormalities. PMID- 29532753 TI - Neurotrophic Factors in Parkinson's Disease: What Have we Learned from Pre Clinical and Clinical Studies? AB - BACKGROUND: Parkinson's Disease (PD) is a chronic, progressive condition, being the second most common neurodegenerative disorder worldwide. The classical features include: bradykinesia, resting tremor, rigidity and festination. These neurological alterations are probably due to the death of dopaminergic neurons in the Substantia Nigra pars compacta and consequent reduction of dopamine input into the striatum. The decrease of dopamine levels may also be involved in the emergence of non-motor symptoms, including cognitive impairment, anxiety and depression symptoms. Neurotrophic Factors (NF) are proteins that modulate neuronal function, development, and survival. It has been reported that NF might exert a protective role in PD. OBJECTIVE: We aim to discuss the emerging evidence from pre-clinical and clinical studies regarding the role of NF in PD as well as their potential as promising therapeutic strategies. METHODS: We carried out an extensive literature search in PubMed central. RESULTS: Pre-clinical studies using NF to treat PD are divergent probably due to several methodological differences, thus precluding any conclusion. Clinical studies findings obtained with the administration of NF in patients with PD were even more disappointed. On the other hand, pre-clinical and clinical studies generally support that physical activity is a low-cost, non-pharmacologic strategy with good results to treat PD. CONCLUSION: The use of NF as a treatment for PD is still a promise not incorporated in clinical practice. Methods to deliver NFs, doses and compounds administered, side effects, population characteristics and duration of disease may probably contribute to the unsuccessful results. PMID- 29532754 TI - The Fungal Metabolites with Potential Antiplasmodial Activity. AB - Malaria caused by Plasmodium parasites is amongst many prevalent public health concerns in several tropical regions of the world. Nowadays, the parasite resistance patterns to most currently used drugs in therapy and insecticides have created an urgent need for new chemical entities exhibiting new modes of action and management strategies. Fungus has been proven to be an excellent source of biologically active compounds, which have been screened for antiplasmodial activity as potential sources of new antimalarial drugs. This review summarizes the current 255 natural products from fungus, which may possess antimalarial activity and can be classified as sesquiterpenes, diterpenes, sesterterpenes, alkaloids, peptides depsipeptides, xanthones, anthraquinones, anthrones, bioxanthracenes, bixanthones, preussomerins, depsidones, phenols, trichothecenes, azaphliones, macrolides, and steroids. However, the treatments available for malaria are limited. Thus, the identification of novel antimicrobial agents should be continued, and all possible strategies should be explored. Carrying forward the antimalarial screening in exited terrestrial and marine natural products library, and finding the new natural products in new resources, particularly those living in marine environments, are still important approaches to find new antimalarial agents. Unusual marine environments are associated with chemical diversity, leading to a resource of novel active substances for the development of bioactive products. Finding new antimalarial natural products in marine fungus, particularly those living in deep-sea and special marine environments, is an important approach to identify novel active agents. PMID- 29532755 TI - Homocysteine and Hyperhomocysteinaemia. AB - Homocysteine (Hcy) is thiol group containing the amino acid, which naturally occurs in all humans. Hcy is degraded in the body through two metabolic pathways, while a minor part is excreted through kidneys. The chemical reactions that are necessary for degradation of Hcy require the presence of the folic acid, vitamins B6 and B12. Consequently, the level of the total Hcy in the serum is influenced by the presence or absence of these vitamins. An elevated level of the Hcy, hyperhomocysteinemia (HHcy) and homocystinuria are connected with occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer's disease, pregnancy problems, and others. Elevated Hcy levels are connected with various pathologies both in adult and child population. Causes of HHcy include genetic mutations and enzyme deficiencies in 5, 10 methylenetetrahydrofolate reductase (MTHFR) methionine synthase (MS), and cystathionine beta-synthase(CbetaS). HHcy can be caused by deficiencies in the folate, vitamin B12 and to a lesser extent deficiency in the B6 vitamin what influences methionine metabolism. Additionally, HHcy can be caused by the rich diet and renal impairment. This review presents literature data from recent research related to Hcy metabolism and the etiology of the Hcy blood level disorder. In addition, we also described various pathological mechanisms induced by hereditary disturbances or nutritional influences and their association with HHcy induced pathology in adults and children and treatment of these metabolic disorders. PMID- 29532756 TI - Docking of Natural Products against Neurodegenerative Diseases: General Concepts. AB - BACKGROUND: Since antiquity, humanity has used medicinal plant preparations to cure its ills, and, as research has progressed, new technologies have enabled more investigations on natural compounds which originate from plants, fungi, and marine species. The health benefits that these natural products provide have become a motive for treatment studies of various diseases. OBJECTIVE: Among them, the neurodegenerative diseases like Alzheimer's and Parkinson's, a major age related neurodegenerative disorder. Studies with natural products for neurodegenerative diseases (particularly through molecular docking) search for, and then focus on those ligands which offer effective inhibition of the enzymes monoamine oxidase and acetylcholinesterase. METHOD: This review introduces the main concepts involved in docking studies with natural products: and also in our group, which has conducted a docking study of natural products isolated from Tetrapterys mucronata for inhibition of acetylcholinesterase. RESULTS: We observed that compounds 4 and 5 formed more interactions than the theoretical ligand, but that ligands with greater activity also interacted with residues HIS 381 and GLN 527. CONCLUSION: We have reported on our docking study performed with AChE and alkaloids isolated from the plant Tetrapterys mucronata. Our docking results corroborate the experiments conducted, and emphasize the positive contribution that these theoretical studies involving natural products bring to the fight against neurodegenerative diseases. PMID- 29532757 TI - Targeting the Microcirculation by Indole-3-carbinol and Its Main Derivate 3,3,' diindolylmethane: Effects on Angiogenesis, Thrombosis and Inflammation. AB - The pharmacological targeting of microcirculatory dysregulations is a therapeutic strategy for the treatment of numerous pathological conditions, such as cancer, thrombosis and inflammation. A promising candidate for this purpose is indole-3 carbinol (I3C), a phytochemical compound of cruciferous vegetables, and its main derivate 3,3,'-diindolylmethane (DIM). As summarized in this review, I3C and DIM affect multiple molecular and cellular processes within the microcirculation due to their pleiotropic action profile. These include angiogenesis, leukocyte endothelial cell interaction, cytokine and reactive oxygen species (ROS) production, thrombus formation and microvascular leakage. Hence, I3C may serve as a lead compound for the future chemical synthesis of novel drugs that exert comparable beneficial effects while exhibiting an improved bioavailability. PMID- 29532758 TI - Platelet-derived exosomes affect the proliferation and migration of human umbilical vein endothelial cells via miR-126. AB - BACKGROUND: Intraplaque angiogenesis, the process of generating new blood vessels mediated by endothelial cells, contributes to plaque growth, intraplaque hemorrhage, and thromboembolic events. Platelet-derived exosomes (PLT-EXOs) affect angiogenesis in multiple ways. The ability of miR-126, one of the best characterized miRNAs that regulates angiogenesis, carried by PLT-EXOs to influence angiogenesis via the regulation of the proliferation and migration of endothelial cells is unknown. In this study, we aimed to investigate the effects of PLT-EXOs on angiogenesis by human umbilical vein endothelial cells (HUVECs). METHODS: We evaluated the levels of miR-126 and angiogenic factors in PLT-EXOs from acute coronary syndrome (ACS) patients and healthy donors by real-time polymerase chain reaction (PCR) and western blotting. We incubated HUVECs with PLT-EXOs and measured cell proliferation and migration with the Cell Counting Kit 8 assay and scratch assay, respectively. We also investigated the expression of miR-126 and angiogenic factors in HUVECs after exposure to PLT-EXOs by western blotting and real-time PCR. RESULTS: PLT-EXOs from ACS patients contained higher levels of miR-126 and angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor beta 1 (TGF-beta1), than those from healthy donors (p<0.05). Moreover, the levels of exosomal miR-126 and angiogenic factors were increased after stimulation with thrombin (p<0.01). HUVEC proliferation and migration were promoted by treatment with activated PLT-EXOs (p<0.01); they were accompanied by the over-expression of miR-126 and angiogenic factors, including VEGF, bFGF, and TGF-beta1 (p<0.01). CONCLUSIONS: Activated PLT-EXOs promoted the proliferation and migration of HUVECs, and the over-expression of miR-126 and angiogenic factors, thereby elucidating potential new therapeutic targets for intraplaque angiogenesis. PMID- 29532759 TI - Amlodipine (150 mg) Poisoning: A Case Study. AB - BACKGROUND: Treatments of patients with amlodipine (a calcium channel blocker, CCB) overdose/poisoning remain challenging and death is certain if not intervened timely. Furthermore, for the society, the availability and common use of this drug can drive more vulnerable groups, especially children, towards an accidental/suicidal poisoning. CASE REPORT: Herein, we describe the case of an 18 year-old-adolescent girl who took 150 mg of amlodipine with the suicidal intentions and was admitted in our hospital approximately 4-hours after the ingestion. She developed circulatory failure and tachypnea. Decontamination, calcium, glucagon, and dual vasopressors were started, however, persistent hypotension led to the initiation of hyperinsulinemiceuglycemia therapy. She recovered fully and discharged without any complications in few days. This case educates not only about the successful use of variant drugs in the management of CCB overdose/poisoning, but also calls for the attention of the society for a safe storage of often used drugs, especially away from the children/adolescents. PMID- 29532760 TI - Efficacy and Safety of Autologous Cell-based Therapy in Patients with No-option Critical Limb Ischaemia: A Meta-Analysis. AB - BACKGROUND: Revascularisation therapy is the current gold standard of care for critical limb ischemia (CLI), although a significant proportion of patients with CLI either are not fit for or do not respond well to this procedure. Recently, novel angiogenic therapies such as the use of autologous cellbased therapy (CBT) have been examined, but the results of individual trials were inconsistent. OBJECTIVE: To pool all published studies that compared the safety and efficacy of autologous CBT derived from different sources and phenotypes with non cell-based therapy (NCT) in CLI patients. METHODS: We searched Medline, Embase, Cochrane Library and ClinicalTrials.gov from 1974-2017. Sixteen randomised clinical trials (RCTs) involving 775 patients receiving the following interventions: mobilised peripheral blood stem cells(m-PBSC), bone marrow mononuclear cells(BM-MNC), bone marrow mesenchymal stem cells(BM-MSC), cultured BM-MNC(Ixmyelocel-T), cultured PB cells(VesCell) and CD34+ cells were included in the meta-analysis. RESULTS: High quality evidence (QoE) showed similar all-cause mortality rates between CBT and NCT. AR reduction by approximately 60% were observed in patients receiving CBT compared to NCT (moderate QoE). CBT patients experienced improvement in ulcer healing, ABI, TcO2, pain free walking capacity and collateral vessel formation (moderate QoE). Low-to-moderate QoE showed that compared to NCT, intramuscular BM MNC and m-PBSC may reduce amputation rate, rest pain, and improve ulcer healing and ankle-brachial pressure index, while intramuscular BM-MSC appeared to improve rest pain, ulcer healing and pain-free walking distance but not AR. Efficacy of other types of CBT could not be confirmed due to limited data. Cell harvesting and implantation appeared safe and well-tolerated with similar rates of adverse events between groups. CONCLUSION: Implantation of autologous CBT may be an effective therapeutic strategy for no-option CLI patients. BM-MNC and m-PSBC appear more effective than NCT in improving AR and other limb perfusion parameters. BM-MSC may be beneficial in improving perfusion parameters but not AR, however, this observation needs to be confirmed in a larger population of patients. Generally, treatment using various sources and phenotypes of cell products appeared safe and well tolerated. Large-size RCTs with long follow-up are warranted to determine the superiority and durability of angiogenic potential of a particular CBT and the optimal treatment regimen for CLI. PMID- 29532761 TI - Novel hybrid compound 4-[(E)-2-phenylethenesulfonamido]-N-hydroxybutanamide with antimetastatic and cytotoxic action: synthesis and anticancer screening. AB - BACKGROUND: One of the most promising strategies to develop multi-targeted anticancer therapeutics is to introduce to the structure of a potential drug two or more pharmacophores (functional groups or structural fragments), which have antiproliferative, proapoptotic or antimetastatic properties acting via different mechanisms. OBJECTIVE: To design, synthesize and perform screening of a novel hybrid anticancer compound. METHOD: A novel hybrid compound 4-[(E)-2 phenylethenesulfonamido]-N-hydroxybutanamide, combining butanehydroxamate and styrenesulfonamide moieties, was designed, synthesized and investigated as a potent antimetastatic and antiproliferative agent. The structure and purity of the synthesized compound were confirmed by 1H NMR, 13C NMR, LC/MS spectroscopy and elemental analysis. The compound was screened for the anticancer activity in vitro against HeLa and in vivo against Lewis lung carcinoma tumor, using an antitumor metalloenzyme inhibitor GM6001 (Ilomastat, Galardin) and Pifithrin-MU as control anticancer agents. RESULTS: It was found that the application of our compound resulted in a high fraction of apoptotic cells in the cell population, along with disruption in the cell cycle profile manifested as arrest of proliferative phases. Furthermore, changes of the morphological properties (i.e., an enhancement of adhesive properties and reduction of the nuclear-to-cytoplasm ratio) were found. The screening in vivo revealed that the compound significantly inhibited the metastasizing process that was manifested by a reduction in the number and volume of metastases. CONCLUSIONS: The obtained results demonstrate that our compound can serve as a base for further structure optimization in order to design new high-effective antimetastatic and antitumor agents. PMID- 29532762 TI - Heterocyclic compounds: 2-Pyrazolines are biological active as well as fluorescence agents, an Overview. AB - Nitrogen containing five membered heterocyclics play vital role in pharmaceuticals as well as medicinal chemistry. Pyrazolines play a significant role among other heterocycles because of their therapeutic and pharmacological properties. 2-Pyrazolines displayed a wide variety of biological activities such as anticancer, antiepileptic, anti-aids, antimalarial, insecticidal and antitubercular etc. and they are used as pesticides, herbicides, fungicides and also used in agrochemical research and analytical chemistry. 2-Pyrazolines are well known brightening agents used in chemosensor. They have excellent fluorescent properties and are widely used in synthetic fibers, dyes, photography and hole transporting materials. A number of preparation methods of pyrazolines have also been investigated by several research groups. In this review, most of the synthesized and reported nitrogen containing five membered herocycles including 2-pyrazolines, their pharmaceutical evaluation and structure reactivity are discussed. PMID- 29532763 TI - Co-delivery of Doxorubicin and D-alpha-Tocopherol polyethylene glycol 1000 succinate by Magnetic Nanoparticles. AB - BACKGROUND: Although conventional chemotherapy is the most common method for cancer treatment, it has several side effects such as neuropathy, alopecia and cardiotoxicity. Since the drugs are given to body systemically, normal cells are also affected, just like cancer cells. However, in recent years, targeted drug delivery has been developed to overcome these drawbacks. OBJECTIVE: The aim in this study was targeted co-delivery of doxorubicin (Dox) which is an anticancer agent and D-alpha-Tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) to breast cancer cells. For this purpose, magnetic nanoparticles (MNPs) were synthesized and coated with oleic acid (OA). Coated nanoparticles were encapsulated in poly(lactic-co-glycolic acid (PLGA) and TPGS polymers and loaded with Dox. The nanoparticles (NPs) were characterized by fouirer transform infrared (FTIR) spectroscopy, zeta-potential analysis, dynamic light scattering (DLS) analysis, thermal gravimetric analysis (TGA) and scanning electron microscope (SEM) analysis. RESULTS: The results showed that NPs were spherical, superparamagnetic and in the desired range for use in drug targeting. The targetability of NPs was confirmed. Moreover, TPGS and Dox loading was shown by TGA and FTIR analyses. NPs were internalized by cells and the cytotoxic effect of drug loaded NPs on sensitive (MCF-7) and drug-resistant (MCF-7/Dox) cells were examined. It was seen that the presence of TPGS increased cytotoxicity significantly. TPGS also enhanced drug loading efficiency, release rate, cellular internalization. In MCF-7/Dox cells, the drug resistance seems to be decreased when Dox is loaded onto TPGS containing NPs. CONCLUSION: This magnetic PLGA nanoparticle system is important for new generation targeted chemotherapy and could be used for breast cancer treatment after in vivo tests. PMID- 29532764 TI - Entresto, a New Panacea for Heart Failure? AB - Heart Failure (HF) is one of the main healthcare burdens in the United States and in the world. Many drugs are approved and used in practice for management of this condition; including beta blockers, diuretics, aldosterone antagonists, Angiotensin Converting Enzyme Inhibitors (ACEI's), and Angiotensin Receptor Blockers (ARBs). Recently, the Food and Drug Administration (FDA) approved a drug with brand name Entresto (Sacubitril/Valsartan or LCZ696), an angiotensin receptor neprilysin inhibitor for the use in Heart Failure with Reduced Ejection Fraction (HFrEF) patients instead of ACEI's and ARBs. The drug works through angiotensin receptor blockage via valsartan as well as neprilysin inhibition with sacubitril. This represented a new milestone in managing heart failure patients and provided yet another therapy in our armamentarium. This article reviews the stages that led to the development of this drug, the failure of its preceding agents, the lessons we have learnt, and the current trials of Entresto for new indications. PMID- 29532765 TI - Starch synthase IIIa and starch branching enzyme IIb-deficient mutant rice line ameliorates pancreatic insulin secretion in rats: screening and evaluating mutant rice lines with antidiabetic functionalities. AB - Diabetes mellitus is a metabolic disease spreading worldwide that has been reported to worsen the development and progression of other diseases (cancer, vascular diseases and dementia). To establish functional rice lines with anti postprandial hyperglycaemic effects, we developed mutant rice lines, which lack one or two gene(s) related to starch synthesis, and evaluated their effects. Powder of mutant rice lines or other grains was loaded to rats fasted overnight (oral grain powder loading test). Incremental area under time-concentration curves (iAUC) were calculated with monitored blood glucose levels. Rice lines with anti-postprandial hyperglycaemic effects were separated by cluster analysis with calculated iAUC. A double mutant rice #4019 (starch synthase IIIa (ss3a)/branching enzyme IIb (be2b)), one of the screened mutant rice lines, was fed to Goto-Kakizaki (GK) rats, an animal model for type 2 diabetes, for 5 weeks. Plasma levels of C-peptide, a marker of pancreatic insulin secretion, were measured with ELISA. For in vitro study, a rat pancreatic cell line was cultured with a medium containing rat serum which was sampled from rats fed #4019 diet for 2 d. After 24-h of incubation, an insulin secretion test was performed. Through the oral rice powder loading test, seven rice lines were identified as antidiabetic rice lines. The intake of #4019 diet increased plasma C-peptide levels of GK rats. This result was also observed in vitro. In rat serum added to cell medium, ornithine was significantly increased by the intake of #4019. In conclusion, the mutant rice #4019 promoted pancreatic insulin secretion via elevation of serum ornithine levels. PMID- 29532766 TI - Evaluation of measles and rubella integrated surveillance system in Apulia region, Italy, 3 years after its introduction. AB - This study aimed at evaluating the integrated measles and rubella surveillance system (IMRSS) in Apulia region, Italy, from its introduction in 2013 to 30 June 2016. Measles and rubella case reports were extracted from IMRSS. We estimated system sensitivity at the level of case reporting, using the capture-recapture method for three data sources. Data quality was described as the completeness of variables and timeliness of notification as the median-time interval from symptoms onset to initial alert. The proportion of suspected cases with laboratory investigation, the rate of discarded cases and the origin of infection were also computed. A total of 127 measles and four rubella suspected cases were reported to IMRSS and 82 were laboratory confirmed. Focusing our analysis on measles, IMRSS sensitivity was 82% (95% CI: 75-87). Completeness was >98% for mandatory variables and 57% for 'genotyping'. The median-time interval from symptoms onset to initial alert was 4.5 days, with a timeliness of notification of 33% (41 cases reported ?48 h). The proportion of laboratory investigation was 87%. The rate of discarded cases was 0.1 per 100 000 inhabitants per year. The origin of infection was identified for 85% of cases. It is concluded that IMRSS provides good quality data and has good sensitivity; still efforts should be made to improve the completeness of laboratory-related variables, timeliness and to increase the rate of discarded cases. PMID- 29532767 TI - Analytical Performance of a Loop-Mediated Isothermal Amplification Assay for Leishmania DNA Detection in Sandflies and Direct Smears of Patients with Cutaneous Leishmaniasis. AB - Loop-mediated isothermal amplification (LAMP) is ideal for the detection of Leishmania DNA as it is a quick and easy-to-perform test that does not require complex or sophisticated equipment or infrastructure. However, the application of this technique in the detection of Leishmania DNA has not been comprehensively analyzed to date (analytical validation). Our objective was to evaluate the sensitivity and analytical specificity (anticipated reportable range [ARR], the limit of detection [LoD], and accuracy) of LAMP targeting the 18S rRNA gene in the diagnosis of six New World Leishmania species. We then applied the validated LAMP assay across 50 samples of sandflies and 50 direct smears from a recent outbreak of cutaneous leishmaniasis in Colombia to determine its diagnostic performance. The LAMP assay exclusively amplified the DNA of Leishmania spp., and an ARR of between 1 * 104 and 1 * 10-2 equivalent parasites/mL was determined. An LoD of 1 * 10-2 equivalent parasites/mL was established and there was no statistically significant variation in terms of accuracy. Finally, a sensitivity of 100% in direct smears and sandflies samples was calculated and a specificity of 90.9% for direct smears using microscopy as reference and 96.8% for sandflies using real-time polymerase chain reaction as reference were determined. To our knowledge, this is the first attempt to analytically validate a LAMP test to detect Leishmania DNA, which showed good diagnostic potential from sandflies and direct smear samples. PMID- 29532768 TI - Impact of Four Years of Annual Mass Drug Administration on Prevalence and Intensity of Schistosomiasis among Primary and High School Children in Western Kenya: A Repeated Cross-Sectional Study. AB - Schistosomiasis remains a major public health problem in Kenya. The World Health Organization recommends preventive chemotherapy with praziquantel (PZQ) to control morbidity due to schistosomiasis. Morbidity is considered linked to intensity of infection, which along with prevalence is used to determine the frequency of mass drug administration (MDA) to school-age children. We determined the impact of annual school-based MDA on children across all primary and high school years using a repeated cross-sectional study design in five schools near Lake Victoria in western Kenya, an area endemic for Schistosoma mansoni. At baseline and for the following four consecutive years, between 897 and 1,440 school children in Grades 1-12 were enrolled and evaluated by Kato-Katz for S. mansoni and soil-transmitted helminths (STH), followed by annual MDA with PZQ and albendazole. Four annual rounds of MDA with PZQ were associated with reduced S. mansoni prevalence in all school children (44.7-14.0%; P < 0.001) and mean intensity of infection by 91% (90.4 to 8.1 eggs per gram [epg] of stool; P < 0.001). Prevalence of high-intensity infection (>= 400 epg) decreased from 6.8% at baseline to 0.3% by the end of the study. Soil-transmitted helminth infections, already low at baseline, also decreased significantly over the years. In this high prevalence area, annual school-based MDA with high coverage across all Grades (1-12) resulted in rapid and progressive declines in overall prevalence and intensity of infection. This decrease was dramatic in regard to heavy infections in older school-attending children. PMID- 29532769 TI - Natural Infection of Phlebotomus sergenti by Leishmania tropica in Libya. AB - Cutaneous Leishmaniasis (CL) is a public health concern caused by Leishmania (L.) major and L.tropica in Libya. Information on sandfly vectors, as well as their associated Leishmania species, is of paramount importance because vector dispersion is one of the major factors responsible for pathogen dissemination. A number of 515 sandflies (275 males and 240 females) were collected during June November 2012 using the Centers for Disease Control miniature light traps from Al Rabta, northwest of Libya. Two hundred and forty unfed females were identified; Phlebotomus (Ph.) papatasi (N = 97), Ph. sergenti (N = 27), Ph. longicuspis (N = 32), Sergentomyia (Se.) minuta (N = 38), and Se. fallax (N = 46). These flies were screened for Leishmania DNA using the polymerase chain reaction-restriction fragment length polymorphism analysis of the internal transcribed spacer 1 and sequencing. Two Ph. sergenti were found positive to L. tropica DNA. This finding should be considered for any further vector surveillance and epidemiological studies of CL in endemic areas across Libya. PMID- 29532770 TI - Water, Sanitation, and Hygiene Practices Associated with Nutritional Status of Under-Five Children in Semi-Pastoral Communities Tanzania. AB - Undernutrition among under-five children is a public health concern in developing countries and has been linked with poor water, sanitation, and hygiene (WASH) practices. This study aimed at assessing WASH practices and its association with nutritional status of under-five children in semi-pastoral communities of Arusha. The study was cross-sectional in design. Mother-child pairs from 310 households in four villages of Monduli and Longido were involved. Weight and height of children were measured using weighing scale and length/height board, respectively. Children's age was recorded using clinic cards. Hemoglobin level of each child was tested using Hemo Cue(r) Hb 201 + photometer (HemoCue AB, Angelholm, Sweden) machine. Structured questionnaire was used to gather information on WASH, child morbidity, demographic, and sociocultural characteristics. Prevalence of stunted, underweight, wasted, anemia, and diarrhea were 31.6%, 15.5%, 4.5% 61.2%, and 15.5%, respectively. Children with diarrhea 2 weeks preceding the survey (P = 0.004), children using surface water for domestic purposes (P < 0.001), and those with uneducated mothers (P = 0.001) had increased risk of being stunted and underweight. Children introduced to complementary foods before 6 months of age (P = 0.02) or belonging to polygamous families (P = 0.03) had increased risk of being stunted. Consumption of cow's milk that is not boiled (P = 0.05) or being a boy (P = 0.03) was associated with underweight. Prevalence of undernutrition among under-five children in the population under study was alarming and it could be associated with poor WASH practices and other sociocultural factors. This study underlines the importance of incorporating WASH strategies in formulation of interventions targeting on promotion of nutrition and disease prevention in pastoral communities. PMID- 29532771 TI - Leptospirosis Outbreak After the 2014 Major Flooding Event in Kelantan, Malaysia: A Spatial-Temporal Analysis. AB - Severe floods increase the risk of leptospirosis outbreaks in endemic areas. This study determines the spatial-temporal distribution of leptospirosis in relation to environmental factors after a major flooding event in Kelantan, Malaysia. We conducted an observational ecological study involving incident leptospirosis cases, from the 3 months before, during, and three months after flood, in reference to the severe 2014 Kelantan flooding event. Geographical information system was used to determine the spatial distribution while climatic factors that influenced the cases were also analyzed. A total of 1,229 leptospirosis cases were notified within the three study periods where incidence doubled in the postflood period. Twelve of 66 subdistricts recorded incidence rates of over 100 per 100,000 population in the postflood period, in comparison with only four subdistricts in the preflooding period. Average nearest neighborhood analysis indicated that the cases were more clustered in the postflood period as compared with the preflood period, with observed mean distance of 1,139 meters and 1,666 meters, respectively (both at P < 0.01). Global Moran's I was higher in the postflood period (0.19; P < 0.01) as compared with the preflood period (0.06; P < 0.01). Geographic weighted regression showed that living close to water bodies increased the risk of contracting the disease. Postflooding hotspots were concentrated in areas where garbage cleanup occurred and the incidence was significantly associated with temperature, humidity, rainfall, and river levels. Postflooding leptospirosis outbreak was associated with several factors. Understanding the spatial distribution and associated factors of leptospirosis can help improve future disease outbreak management after the floods. PMID- 29532773 TI - Challenges and Opportunities in Disease Forecasting in Outbreak Settings: A Case Study of Measles in Lola Prefecture, Guinea. AB - We report on and evaluate the process and findings of a real-time modeling exercise in response to an outbreak of measles in Lola prefecture, Guinea, in early 2015 in the wake of the Ebola crisis. Multiple statistical methods for the estimation of the size of the susceptible (i.e., unvaccinated) population were applied to weekly reported measles case data on seven subprefectures throughout Lola. Stochastic compartmental models were used to project future measles incidence in each subprefecture in both an initial and a follow-up iteration of forecasting. Measles susceptibility among 1- to 5-year-olds was estimated to be between 24% and 43% at the beginning of the outbreak. Based on this high baseline susceptibility, initial projections forecasted a large outbreak occurring over approximately 10 weeks and infecting 40 children per 1,000. Subsequent forecasts based on updated data mitigated this initial projection, but still predicted a significant outbreak. A catch-up vaccination campaign took place at the same time as this second forecast and measles cases quickly receded. Of note, case reports used to fit models changed significantly between forecast rounds. Model-based projections of both current population risk and future incidence can help in setting priorities and planning during an outbreak response. A swiftly changing situation on the ground, coupled with data uncertainties and the need to adjust standard analytical approaches to deal with sparse data, presents significant challenges. Appropriate presentation of results as planning scenarios, as well as presentations of uncertainty and two-way communication, is essential to the effective use of modeling studies in outbreak response. PMID- 29532772 TI - Detection of Histoplasma capsulatum in Organic Fertilizers by Hc100 Nested Polymerase Chain Reaction and Its Correlation with the Physicochemical and Microbiological Characteristics of the Samples. AB - Histoplasma capsulatum is the causative agent of histoplasmosis and this fungus inhabits soils rich in phosphorus and nitrogen that are enriched with bird and bat manure. The replacement of organic matter in agroecosystems is necessary in the tropics, and the use of organic fertilizers has increased. Cases and outbreaks due to the presence of the fungus in these components have been reported. The Instituto Colombiano Agropecuario resolution 150 of 2003 contains the parameters set by the Colombian Technical Standard (NTC 5167) on the physicochemical and microbiological features of fertilizers, but it does not regulate the search for H. capsulatum. The aim of this study was to demonstrate H. capsulatum presence in organic fertilizers by nested polymerase chain reaction (PCR). A total of 239 samples were collected: 201 (84.1%) corresponded to organic fertilizers, 30 (12.5%) to bird excrement, and 8 (3.4%) to cave soils. The Hc100 nested PCR had a detection limit of 0.1 pg/uL and a specificity of 100%. A total of 25 (10.5%) samples were positive and validated by sequencing. Seven of the positive samples represented locations where H. capsulatum was previously detected, suggesting the persistence of the fungus. No significant correlations were detected between the physicochemical and microbiological parameters with the presence of H. capsulatum by nested PCR, indicating the fungus existence in organic fertilizers that complied with the NTC 5167. The Hc100 nested PCR targeting H. capsulatum standardized in this work will improve the evaluation of organic fertilizers and ensure the prevention of outbreaks and cases due to manufacturing, marketing, and use of fertilizers contaminated with H. capsulatum. PMID- 29532774 TI - Role of Family with Sequence Similarity 3A in High Glucose-induced Oxidative Damage of Human Umbilical Vein Endothelial Cells. AB - Objective To investigate the role of family with sequence similarity 3A(Fam3A) in high glucose-induced damage of human umbilical vein endothelial cells (HUVECs). Methods HUVECs were divided into control group and high glucose group, which were cultured in endothelial cell medium (ECM) containing 5.5 mmol/L of glucose and ECM containing 33.3 mmol/L of glucose, respectively. Real-time quantitative polymerase chain reaction was used to detect the mRNA expression of Fam3A, whereas the protein expression of Fam3A was detected by enzyme-linked immunosorbent assay. HUVECs in control group and high glucose group were transfected with siNT and siFam3A, respectively, and the levels of reactive oxygen species(ROS), ATP, mitochondrial oxygen consumption rate(OCR), and P-p38 protein were detected.Results After HUVECs had been cultured for 24h, the relative mRNA expression of Fam3A between high glucose group and control group was 2.52+/-0.19 (t=13.296,P=0.000). The Fam3A protein level was (173.82+/ 33.28)pg/ml in the high glucose group, which was significantly higher than that [(39.45+/-33.78)pg/ml] in the control group (t=4.907,P=0.006). The intracellular ROS content in siNT-high glucose group was (8217+/-794)RFU, which was significantly higher than that [(3982+/-398)RFU] in siNT control group (t=15.109,P=0.002). The intracellular ROS content of siFam3A high glucose group was (11 910+/-1 001)RFU, significantly higher than that [(4171+/-402)RFU] of siFam3A control group (t=9.705,P=0.010) and than that of siNT high glucose group (t=4.026,P=0.048). The relative amounts of ATP synthesis in siNT high glucose group, siFam3A control group and siFam3A high glucose group were (61.2+/-5.6)%, (94.6+/-8.4)%, and (29.7+/-2.7)% of the siNT control group respectively; thus, it was significantly lower in siNT high glucose group than in siNT control group (t=12.001,P=0.007) and was also significantly lower in siFam3A high glucose group than in siFam3A control group (t=20.742,P=0.002) and in siNT high glucose group(t=18.814,P=0.003). The mitochondrial OCR was (0.57+/-0.05)pMO2/(MUg protein.min) in siNT high glucose group, significantly lower than that [(1.12+/ 0.09)pMO2/(MUg protein.min)] of siNT control group (t=6.804,P=0.021). The mitochondrial OCR of siFam3A high glucose group was (0.31+/-0.03)pMO2/(MUg protein.min), significantly lower than that [(1.01+/-0.09)pMO2/(MUg protein.min)] of siFam3A control group (t=19.876,P=0.003), which was significantly lower than that of siNT high glucose group (t=21.444,P=0.002). The relative expression of P p38 in siNT high glucose group, siFam3A control group, and siFam3A high glucose group was 2.239+/-0.353, 0.816+/-0.120, and 1.160+/-0.185, respectively; thus, it was significantly higher in the siNT high glucose group than in siNT control group (t=6.075,P=0.026); in addition, it was significantly higher in the siFam3A high glucose group than in siFam3A control group (t=6.242,P=0.024) and significantly lower than in siNT high glucose group (t=9.686,P=0.010). Conclusions High glucose can induce high expression of Fam3A in HUVECs. Knockdown of Fam3A gene expression can exacerbate the decrease of ATP synthesis and mitochondrial OCR caused by high glucose and promote the generation of ROS in high glucose. Fam3A may regulate high glucose-induced ROS production in HUVECs via the p38 MAPK signaling pathway. PMID- 29532775 TI - Effect of Different Doses of Radiation on Intestinal Injury in NOD/SCID Mice. AB - Objective To study the effect of different doses of radiation on intestinal injury,with an attempt to find the optimal radiation dose for establishing intestinal injury models in NOD/SCID mice. Methods Forty healthy male SPF-grade NOD/SCID mice were divided randomly into four groups:blank control group and 4-,5 ,6-Gy irradiatio groups,with 10 mice in each group. The irradiation rate was 1 Gy/min. The general conditions,body weight,intestinal bacterial translocation,and histopathologic changes were observed and compared. Results The survival rate was 60%,50%,and 30% in the 4-,5-,and 6-Gy groups 15 days after irradiation,and the intestinal bacterial translocation rate was 20%,50%,and 70%,respectively. The body weights in 5-Gy group (P=0.015) and 6-Gy group (P=0.011) were significantly higher than that in blank control group. The length of small intestinal villi decreased in the 4-Gy group. In the 5-Gy group,the structure of intestinal mucosa villi became wide,flat,and inverted,along with the shedding of epithelial cells,the atrophy of glands,and the damage of recess structures. In the 6-Gy group,the structure of intestinal mucosal villi was damaged,the villi were ruptured and smashed,and the recess structures were missing;meanwhile,there was a large amount of inflammatory cell infiltration between tissues,along with visible spotty bleeding and necrosis. The length of small intestine villi in the blank control group and 4-,5-,and 6-Gy groups were (361.77+/-22.77),(291.68+/ 32.45),(248.03+/-51.09),and (195.90+/-26.39) MUm,respectively. In particular,it was significantly shorter in 4-Gy group (P=0.005),5-Gy group (P<0.001),and 6-Gy (P<0.001) than in the blank control group,was significantly shorter in the 5-Gy group (P=0.041) and 6-Gy group (P=0.001) than in the 4-Gy group,and significantly shorter in 6-Gy group than in the 5-Gy group (P=0.020). Conclusion 5-Gy irradiation in mice models can decrease body weight,cause the damage of intestinal mucosa and the shedding of inflammatory cells,with stable survival rate and bacterial translocation rate. PMID- 29532777 TI - Effect of Adequate Anticoagulantion Therapy on the Outcome of Spontaneous Isolated Dissection of Superior Mesenteric Artery. AB - Objective To investigate the optimal treatment strategy of spontaneous isolated dissection of superior mesenteric artery (SIDSMA) and the effect of anticoagulation therapy on the prognosis of SIDSMA. Methods The clinical data of 29 patients presented with acute or subacute mesenteric ischemia (a history of less than 14 days) due to SIDSMA admitted to the Department of Vascular Surgery of Peking Union Medical College Hospital from January 1st 2003 to December 31th 2016 were retrospectively analyzed. Results In this study,28 cases were male and the remaining one was female,with an average age of (49.1+/-7.6) years. The emergency endovascular treatment were performed on 4 cases with severe mesenteric intestinal ischemia,and the symptoms were relieved postoperatively. The remaining 25 cases were treated with conservative treatment. Among 13 cases who were received adequate anticoagulantion therapy,symptoms were relieved or disappeared in 9 cases (69.2%),whereas conservative treatment was ineffective in 4 cases (30.8%),for whom surgical intervention were performed. Among 12 cases who received conservative treatment without sufficient anticoagulation,the abdominal pain was relieved in only 2 cases (16.7%) and the remaining 10 cases (83.3%) were converted to surgical intervention. The success rate of conservative treatment for patients with adequate anticoagulant therapy was significantly higher than that of patients who had not received adequate anticoagulant therapy (P=0.015). Conclusions Adequate anticoagulation therapy has good therapeutic effect in most SIDSMA cases with acute or subacute mesenteric ischemia. For patients with severe mesenteric ischemia or those fail to respond to initial conservative treatment,endovascular treatment may be a more reasonable option. PMID- 29532776 TI - Predictors of Short-term Outcomes of Patients with Peritoneal Dialysis-associated Peritonitis. AB - Objective To investigate the risk factors predicting the short-term outcomes of patients with peritoneal dialysis(PD)-associated peritonitis (PDAP). Methods In this retrospective cohort study,the clinical data at baseline and 0-3 months before peritonitis onset (peritonitis-free period) were collected from end-stage renal disease patients who started PD and suffered from PDAP between January 1,2004 and March 31,2017 in Peking Union Medical College Hospital. After 4 weeks of follow-up,these patients were divided into two groups according to the clinical outcomes,namely poor outcome group and good outcome group. Characteristics at baseline and before peritonitis were compared. Risk factors associated with short-term outcomes were also analyzed. Results Totally 162 PDAP patients were enrolled,among whom 55 (34.0%) experienced adverse outcomes and 107 (66.0%) had good outcome. At baseline,the proportion of clinical atherosclerotic vascular disease was significantly higher in poor outcome group than in good outcome group (49.1% vs. 31.8%;chi2=4.639,P=0.031),whereas indicators were comparable (all P>0.05). During the peritonitis-free period,significantly higher level of high-sensitivity C-reactive protein (hsCRP) [9.3(2.2,16.3)mg/dl vs. 3.6(1.4,9.5)mg/dl,Z=-2.879,P=0.004],higher proportion of low transport type of peritoneum function (8.7% vs. 1.0%;Z=4.879,P=0.027),and lower creatinine clearance rate [56.7 (45.7,71.1) ml/(min.w.1.73 m2)vs. 61.4 (54.5,76.4) ml/(min.w.1.73 m2);Z=-2.084,P=0.037] were observed in poor outcome group. Univariate Logistic regression analysis showed the combination of clinical atherosclerotic vascular disease (OR=2.070,95%CI:1.062-4.034,P=0.033) and higher hsCRP before peritonitis (OR=1.032,95%CI:1.001-1.059,P=0.015) were the risk factors of short-term poor outcome in PDAP patients. Multivariate Logistic regression analysis showed that,after the gender,age at peritonitis,PD duration,diabetes,and serum albumin before peritonitis were adjusted,higher hsCRP before peritonitis (OR=1.026,95%CI:1.000-1.052,P=0.046) and comorbidity of clinical atherosclerotic vascular disease (OR=2.105,95% CI:1.014-4.367,P=0.046) were the independent risk factors for the poor outcomes in PDAP patients. Conclusion Higher pre-peritonitis hsCRP and comorbidity of clinical atherosclerotic vascular disease at baseline may predict poor short-term outcomes in PDAP patients. PMID- 29532778 TI - Correlation between the Incidence of Allergic Rhinitis and the Environmental Air Quality in Zibo Area. AB - Objective To investigate the correlation between the incidence of allergic rhinitis (AR) and the air quality in Zibo area. Methods The number of AR cases in the outpatient departments of eight hospitals in five districts and three counties of Zibo city from January 2014 to December 2016 and the monthly change of the air pollution index (API) in Zibo area provided by Zibo Environment Protection Bureau during the same period were analyzed.Results The highest AR visit rates were recorded in April,May,and December,and the API was the highest in November,December,and January. The average AR visit rate in 2014,2015 and 2016 was 0.180+/-0.059,0.230+/-0.085,and 0.220+/-0.059 (F=2.251,P=0.123),and the average API was 113.26+/-20.152,126.81+/-30.688,and 112.58+/-22.934 (F=1.237,P=0.303). Pearson correlation analysis showed that the AR visit rate was positively correlated with the API (r=0.467,P=0.004). Conclusion The diagnostic rate of AR in Zibo area is positively correlated with the severity of air pollution. PMID- 29532779 TI - Role of Statins in Treatment and Prevention of Community-acquired Pneumonia:A Meta-analysis. AB - Objective To systemically evaluate the the role of statins in prevention and treatment of community-acquired pneumonia (CAP). Methods A computer-based searching was conducted in PubMed,EMbase,Cochrane Library,Wanfang,and CNKI database up to October 2016. Totally 21 eligible articles were retrieved. According to the Cochrane Handbook 5.0 or Newcastle-Ottawa Scale (NOS) quality evaluation criteria,two independent reviewers carried out literature screening,data retraction,and quality evaluation. Meta-analysis was conducted with RevMan 5.3 software. Results A total 1 007 765 CAP patients from 12 studies were divided into two groups:statin group (n=118 096) and non-statin group (n=889 669). Meta-analysis suggested that statin use was associated with decreased mortality of CAP (OR=0.67,95%CI:0.57-0.79). We further divided the studies into North America group and Europe group and found the heterogenicity of North America group was lower than that of Europe group,and the Meta-analysis of both group supported the association of statin use with decreased CAP mortality (OR=0.66,95%CI:0.62-0.67;OR=0.71,95%CI:0.55-0.92). To identify the effect of statin use on mechanical ventilation,we included three articles (n=123 645) for further analysis (statin group,n=23 796;non-statin group,n=99 849),and Meta analysis suggested that statin use was associated with decreased requirement for mechanical ventilation (OR=0.74,95%CI:0.70-0.78). Four articles (n=127 060) were enrolled (statin group,n=24 121 and non-statin group,n=102 939) to analyze the effect of statin use on ICU admission,and Meta-analysis suggested that statin use was associated with decreased requirement for ICU admission (OR=0.85,95%CI:0.82 0.88). Eleven articles (n=2 124 849) (statin group,n=306 108;non-statin group,n=1 818 741) to evaluate the effect of statin use on risk of CAP,and Meta-analysis suggested that long-term use of statins decreased the risk of CAP,although there was no statistical difference (OR=0.85,95%CI:0.85-1.07); the above studies were divided into case-control studies and cohort studies,and the case-control studies revealed statins increased the risk of CAP (OR=1.12,95%CI:1.03-1.21),while the cohort studies supported the association of statin use with decreased CAP risk (OR=0.46,95%CI:0.44-0.49). Conclusions Statin use may decrease the CAP mortality and the requirement for mechanical ventilation or ICU admission. However,whether statin use can reduce the risk of pneumonia remains unclear. PMID- 29532780 TI - Efficacy and Safety of Tacrolimus versus Cyclosporine A for Idiopathic Membranous Nephropathy:A Network Meta-analysis. AB - Objective To compare the efficacy and safety of tacrolimus with those of cyclosporine in treating idiopathic membranous nephropathy (IMN) via network meta analysis. Methods Databases including PubMed,Embase,CENTRAL (Cochrane),Wanfang Database,CNKI,and VIP citation database were searched for relevant studies according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Package Meta 4.5.0 and Gemtc 0.8.1 in R 3.3.1 were used to analyze the included studies. Results In this network meta-analysis,the complete remission rate (RR=0.98,95% CI:0.70-1.40)and the total remission rate (RR=1.00,95% CI:0.90-1.20)of idiopathic membranous nephropathy did not differ significantly between IMN patients treated with cyclosporine A or tacrolimusand,nor did the incidences of hepatic dysfunction(RR=1.40,95% CI:0.52 4.00),infection(RR=0.75,95% CI:0.18-3.10),or gastrointestinal syndrome(RR=2.1,95% CI:0.36-28.00). Conclusion Cyclosporine A seems to have similar effectiveness and safety to tacrolimus in treating IMN. PMID- 29532781 TI - Value of Internal Carotid Artery Stenosis in the Differential Diagnosis between Invasive Pituitary Adenoma and Invasive Meningioma. AB - Objective To assess the value of internal carotid artery stenosis in differentiating invasive pituitary adenoma (IPA) from invasive meningiomas (IM). Methods The clinical and imaging data of 28 IPA patients and 15 IM patients who were treated in our center from January 2012 to December 2016 were retrospectively analyzed. The magnetic resonance imaging (MRI) features were analyzed. The narrowest diameter (Dstenosis) and area (Astenosis) of internal carotid artery around the tumor were measured by computed tomography angiography (CTA),followed by the calculation of the stenosis score (%stenosis). The diagnostic validity of the measured indicators were calculated by receiver operating characteristic (ROC) curve. Results The median Ki-67 was 3% (2%-5%) in IPA group,which was significantly higher than that in IM group (1%,1%-2%) (Z= 3.983,P=0.000). The tumor texture showed significant differences between these two groups (P=0.001). While there was no significant difference in the average diameter [(39.63+/-13.15)mm in IPA group vs. (37.09+/-16.13)mm in IM group (t=0.518,P=0.607)],the shape (P=0.010),T1WI (P=0.001),signal (P=0.000),post gadolinium enhancement (P=0.000),separation from normal pituitary (P=0.001),dural tail sign (P=0.000),and skull (P=0.001) showed significant differences. ROC analysis showed that the AUC of Dstenosis was 0.725 (P=0.006),the cut-off was 3.45 mm,the sensitivity was 62.50%,and the specificity was 76.47%;the AUC of Astenosis was 0.737 (P=0.003),the cut-off level was 11.00 mm2,the sensitivity was 75.00%,and the specificity was 64.71%;finally,the AUC of %stenosis was 0.711 (P=0.013),the cut-off level was 0.306,the sensitivity was 43.75%,and the specificity was 97.06%. Conclusions In addition to the common imaging features,the internal carotid artery stenosis is a valuable tool for differentiating IPA from IM. Three indicators including Dstenosis,Astenosis,and %stenosis have moderate diagnostic validity. PMID- 29532782 TI - Diagnostic Value of Elastography for Thyroid Nodules in Hashimoto's Thyroiditis. AB - Objective To evaluate the diagnostic performance of elastography in the diagnosis of thyroid nodules in the context of Hashimoto's thyroiditis(HT). Methods The study evaluated 43 thyroid nodules by conventional ultrasound (CU) and elastography in 38 patients co-existed with HT who were referred for operation. The patients underwent CU and elastography before operation. The sensitivity,specificity,positive and negative predictive values,and accuracy for CU,elastography,and combination of these two techniques were assessed by using histopathological results as the gold standard. Results Among these 43 thyroid nodules,pathology confirmed 29 (67.4%) malignant nodules and 14 (32.6%) benign ones. There were statistically significant differences between malignant and benign groups in features such as solid shape (96.6% vs. 64.0%;OR:15.6,95%CI:1.600-151.262,P=0.004),irregularity (90.0% vs. 42.9%;OR:11.6,95%CI:2.341-57.032,P=0.001),taller than wide shape (72.0% vs. 21.4%;OR:9.6,95% CI:2.117-43.753,P=0.002),microcalcification (69% vs. 28.6%;OR:5.6,95% CI:1.368-22.556,P=0.012) and irregular blood flow (90.0% vs. 28.6%;OR:17.3,95%CI:3.186-94.290,P=0.000). The diagnostic performance of elastography and CU was as follows:sensitivity (86.2 % vs.96.6%),specificity (71.4% vs.42.9%),positive predictive value (86.2% vs.77.8%),negative predictive value (71.4% vs.85.7%),and accuracy (81.4% vs.79.0%). The combination of these two techniques had a sensitivity of 93.1%,a specificity of 71.4%,a positive predictive value of 87.1%,a negative predictive value of 83.3%,and an accuracy of 86.0%. Conclusions Elastography has a higher specificity in the diagnosis of thyroid nodules in HT,while its sensitivity is slightly lower than that of CU. Combination of these two techniques can increase the specificity and accuracy. PMID- 29532783 TI - Ultrasound-guided Radiofrequency Ablation for Cervical Lymph Nodes Metastasis from Papillary Thyroid Carcinoma. AB - Objective To assess the effectiveness and safety of ultrasound-guided percutaneous radiofrequency ablation (RFA) for nonsurgical treatment of metastatic lymph nodes (LNs) in the neck from papillary thyroid carcinoma (PTC). Methods Totally 45 PTC patients who had been treated with total thyroidectomy and radioiodine therapy were enrolled in this retrospective study. A total of 71 metastatic LNs in the neck from PTC were confirmed by percutaneous biopsy. Follow up consisted of conventional ultrasound,contrast-enhanced ultrasound,and thyroglobulin (Tg) measurement 1,3 and 6 months after RFA and then every 6 months. Results All 45 patients were successfully treated,without immediate or later major complications occurred. During the follow-up [(23+/-5) months;range:12-30 months)],there was no evidence of recurrence at ablated sites. The mean volume reduction ratio (VRR) was significantly reduced during the follow up. Significant differences in the VRR were found between every two follow-up visits (P<0.001). Furthermore,46 metastatic LNs (64.8%) completely disappeared and 25 metastatic lymph nodes (35.2%) remained as small scar-like lesions at the last follow-up visit. After RFA,mean serum Tg level decreased from (11.3+/ 6.3)ng/ml (range:0.8-19.4 ng/ml) to (1.3+/-0.9)ng/ml (range:0.2-3.9 ng/ml) at the last follow-up visit (P<0.001). Conclusion Ultrasound-guided percutaneous RFA is a safe and effective therapy for patients with cervical LNs metastasis from PTC. PMID- 29532785 TI - Radiation characterisation and dosimetric measurements of a femtosecond pulsed laser ablation system. AB - This work describes the radiation characterisation and dosimetric measurements performed on the low-energy micromachining station of the femtosecond STELA (Santiago TErawatt LAser) at the University of Santiago de Compostela (Spain). For this aim, ionisation chambers, solid state detectors, and radiochromic films were used. The results show the emission of pulsed x-ray produced by laser accelerated electrons from the ablated material exhibiting both bremsstrahlung and characteristic radiation. Although this radiation was produced unintentionally, a high superficial dose rate can be achieved. This radiation can be successfully stopped using small shielding to protect personnel from its effects. Based on the results of this work, the yearly dose equivalent after installing the shielding was negligible. PMID- 29532784 TI - A pragmatic randomised controlled trial and economic evaluation of family therapy versus treatment as usual for young people seen after second or subsequent episodes of self-harm: the Self-Harm Intervention - Family Therapy (SHIFT) trial. AB - BACKGROUND: Self-harm in adolescents is common and repetition rates high. There is limited evidence of the effectiveness of interventions to reduce self-harm. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of family therapy (FT) compared with treatment as usual (TAU). DESIGN: A pragmatic, multicentre, individually randomised controlled trial of FT compared with TAU. Participants and therapists were aware of treatment allocation; researchers were blind to allocation. SETTING: Child and Adolescent Mental Health Services (CAMHS) across three English regions. PARTICIPANTS: Young people aged 11-17 years who had self-harmed at least twice presenting to CAMHS following self-harm. INTERVENTIONS: Eight hundred and thirty-two participants were randomised to manualised FT delivered by trained and supervised family therapists (n = 415) or to usual care offered by local CAMHS following self-harm (n = 417). MAIN OUTCOME MEASURES: Rates of repetition of self-harm leading to hospital attendance 18 months after randomisation. RESULTS: Out of 832 young people, 212 (26.6%) experienced a primary outcome event: 118 out of 415 (28.4%) randomised to FT and 103 out of 417 (24.7%) randomised to TAU. There was no evidence of a statistically significant difference in repetition rates between groups (the hazard ratio for FT compared with TAU was 1.14, 95% confidence interval 0.87 to 1.49; p = 0.3349). FT was not found to be cost-effective when compared with TAU in the base case and most sensitivity analyses. FT was dominated (less effective and more expensive) in the complete case. However, when young people's and caregivers' quality-adjusted life-year gains were combined, FT incurred higher costs and resulted in better health outcomes than TAU within the National Institute for Health and Care Excellence cost-effectiveness range. Significant interactions with treatment, indicating moderation, were detected for the unemotional subscale on the young person-reported Inventory of Callous Unemotional Traits (p = 0.0104) and the affective involvement subscale on the caregiver-reported McMaster Family Assessment Device (p = 0.0338). Caregivers and young people in the FT arm reported a range of significantly better outcomes on the Strengths and Difficulties Questionnaire. Self-reported suicidal ideation was significantly lower in the FT arm at 12 months but the same in both groups at 18 months. No significant unexpected adverse events or side effects were reported, with similar rates of expected adverse events across trial arms. CONCLUSIONS: For adolescents referred to CAMHS after self-harm, who have self-harmed at least once before, FT confers no benefits over TAU in reducing self-harm repetition rates. There is some evidence to support the effectiveness of FT in reducing self-harm when caregivers reported poor family functioning. When the young person themselves reported difficulty expressing emotion, FT did not seem as effective as TAU. There was no evidence that FT is cost-effective when only the health benefits to participants were considered but there was a suggestion that FT may be cost-effective if health benefits to caregivers are taken into account. FT had a significant, positive impact on general emotional and behavioural problems at 12 and 18 months. LIMITATIONS: There was significant loss to follow-up for secondary outcomes and health economic analyses; the primary outcome misses those who do not attend hospital following self-harm; and the numbers receiving formal FT in the TAU arm were higher than expected. FUTURE WORK: Evaluation of interventions targeted at subgroups of those who self-harm, longer-term follow-up and methods for evaluating health benefits for family groups rather than for individuals. TRIAL REGISTRATION: Current Controlled Trials ISRCTN59793150. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 12. See the NIHR Journals Library website for further project information. PMID- 29532786 TI - Reply to Comment on 'Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats'. PMID- 29532787 TI - Comment on 'Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats'. PMID- 29532788 TI - Inhibitory Effects of Plumbagin on Retinal Pigment Epithelial Cell Epithelial Mesenchymal Transition In Vitro and In Vivo. AB - BACKGROUND This study aimed to explore the effects of plumbagin (PLB) on epithelial-to-mesenchymal transition in retinal pigment epithelial (RPE) cells and in proliferative vitreoretinopathy (PVR) rabbit models. MATERIAL AND METHODS Rabbit RPE cells were exposed to various concentrations (0, 5, 15, and 25 uM) of PLB. Motility, migration, and invasion of PLB-treated cells were determined in vitro using Transwell chamber assays and scratch wound assays. The contractile ability was evaluated by cell contraction assay. Expression of matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT) markers were assessed by western blotting. Furthermore, PLB was injected in rabbit eyes along with RPE cells after gas compression of the vitreous. The presence of PVR was determined by indirect ophthalmoscopy on days 1, 7, 14, and 21 after injection. Also, optical coherence tomography (OCT), ultrasound images, electroretinograms (ERG), and histopathology were used to assess efficacy and toxicity. RESULTS PLB significantly inhibited the migration and invasion of RPE cells. The agent also markedly reduced cell contractive ability. Furthermore, PLB treatment resulted in the decreased expression of MMP-1, MMP2, alpha-SMA, and the protection of ZO-1. In addition, the PLB-treated eyes showed lower PVR grades than the untreated eyes in rabbit models. PLB exhibited a wide safety margin, indicating no evidence of causing retinal toxicity. CONCLUSIONS PLB effectively inhibited the EMT of rabbit RPE cells in vitro and in the experimental PVR models. The results open new avenues for the use of PLB in prevention and treatment of PVR. PMID- 29532789 TI - Dual role for atypical chemokine receptor 1 in myeloid cell hematopoiesis and distribution. PMID- 29532790 TI - miRNA-31 regulates the CD8 T cell response to type I IFNs during chronic infection. PMID- 29532792 TI - Author Correction: Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target. AB - This corrects the article DOI: 10.1038/ncomms15987. PMID- 29532794 TI - Comorbidities: Cardiovascular disease and breast cancer. PMID- 29532793 TI - Author Correction: Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis. AB - This corrects the article DOI: 10.1038/ncomms7793. PMID- 29532795 TI - Risk factors: Mental stress puts women's hearts at risk. PMID- 29532791 TI - Mechanisms of ketamine action as an antidepressant. AB - Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine's widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine's antidepressant actions but lack its undesirable effects. Here we review hypotheses for the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid receptor activation. We also discuss links between ketamine's antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine's (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine's action are not mutually exclusive and may act in a complementary manner to exert acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine's antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression. PMID- 29532796 TI - Heart failure: Clonal haematopoiesis, IL-1beta, and the NLRP3 inflammasome in HF. PMID- 29532797 TI - Immunotherapy: Immune-modified response criteria - an iterative learning process? PMID- 29532798 TI - Targeted therapy: Larotrectinib effective against TRK-fusion-positive cancers. PMID- 29532799 TI - Melanoma: Time for adjuvant vemurafenib? PMID- 29532800 TI - Post-translational mutagenesis for installation of natural and unnatural amino acid side chains into recombinant proteins. AB - Methods for installing natural and unnatural amino acids and their modifications into proteins in a benign and precise manner are highly sought-after in protein science. Here we describe a protocol for 'post-translational mutagenesis' that enables the programmed installation of protein side chains through the use of rapid, mild and operationally simple free-radical chemistry performed on recombinantly expressed and purified proteins. By introduction of protein dehydroalanine (Dha) residues (in this instance, from a unique cysteine residue introduced by site-directed mutagenesis) as free-radical trapping 'tags' for downstream modification, exquisite control over the site of subsequent modification is achieved. Using readily available alkyl halide precursors and simple borohydride salts, alkyl radicals can be generated in aqueous solution. These alkyl radicals react rapidly with protein-bound Dha residues to yield functionalized protein products with new carbon-carbon bonds. Once the Dha is installed, the introduction of the desired functionality is limited only by the requirement for polarity matching of the generated radical with the Dha 'acceptor', the solubility of the alkyl halide precursors in aqueous solution and the kinetics of the reaction itself. For example, methylated derivatives of lysine, arginine and glutamine are readily accessible. Furthermore, as the side chains are constructed chemically, many unnatural modifications can also be directly introduced as part of the side chain, including isotope reporters (19F, 13C) that can be used in biophysical experiments such as protein NMR. From a suitable cysteine mutant of the target protein, the entire procedure for this chemical post-translational mutation takes 2 d and is readily performed by nonchemists. PMID- 29532802 TI - In situ cultivation of previously uncultivable microorganisms using the ichip. AB - Most microbial species remain uncultivated, and modifying artificial nutrient media brings only an incremental increase in cultivability. We reasoned that an alternative way to cultivate species with unknown requirements is to use naturally occurring combinations of growth factors. To achieve this, we moved cultivation into the microbes' natural habitat by placing cells taken from varying environmental samples into diffusion chambers, which are then returned to nature for incubation. By miniaturizing the chambers and placing only one to several cells into each chamber, we can grow and isolate microorganisms in axenic culture in one step. We call this cultivation platform the 'isolation chip', or 'ichip'. This platform has been shown to increase microbial recovery from 5- to 300-fold, depending on the study. Furthermore, it provides access to a unique set of microbes that are inaccessible by standard cultivation. Here we provide a simple protocol for building and applying ichips for environmental cultivation of soil bacteria as an example; the protocol consists of (i) preparing the ichip; (ii) collecting an environmental sample; (iii) serially diluting cells and loading them into the ichip; (iv) returning the ichip to the environment for incubation; (v) retrieving the ichip and harvesting grown material; and (vi) domestication of the ichip-derived colonies for growth in the laboratory. The ichip's full assembly and deployment is a relatively simple procedure that, with experience, takes ~2-3 h. After in situ incubation, retrieval of the ichip and processing of its contents will take ~1-4 h, depending on which specific procedures are used. PMID- 29532801 TI - Rapid immunopurification of mitochondria for metabolite profiling and absolute quantification of matrix metabolites. AB - Mitochondria carry out numerous metabolic reactions that are critical to cellular homeostasis. Here we present a protocol for interrogating mitochondrial metabolites and measuring their matrix concentrations. Our workflow uses high affinity magnetic immunocapture to rapidly purify HA-tagged mitochondria from homogenized mammalian cells in ~12 min. These mitochondria are extracted with methanol and water. Liquid chromatography and mass spectrometry (LC/MS) is used to determine the identities and mole quantities of mitochondrial metabolites using authentic metabolite standards and isotopically labeled internal standards, whereas the corresponding mitochondrial matrix volume is determined via immunoblotting, confocal microscopy of intact cells, and volumetric analysis. Once all values have been obtained, the matrix volume is combined with the aforementioned mole quantities to calculate the matrix concentrations of mitochondrial metabolites. With shortened isolation times and improved mitochondrial purity when compared with alternative methods, this LC/MS compatible workflow allows for robust profiling of mitochondrial metabolites and serves as a strategy generalizable to the study of other mammalian organelles. Once all the necessary reagents have been prepared, quantifying the matrix concentrations of mitochondrial metabolites can be accomplished within a week. PMID- 29532803 TI - Development: MAZ mediates urogenital development. PMID- 29532804 TI - Prostate cancer: Enhancing VTP. PMID- 29532806 TI - Reproductive medicine: Walk, don't run: a case study of frozen embryo transfers. PMID- 29532807 TI - Acute management of croup in the emergency department. AB - Croup is one of the most common causes of upper airway obstruction in young children. It is characterized by sudden onset of barky cough, hoarse voice, inspiratory stridor and respiratory distress caused by upper airway inflammation secondary to a viral infection. Published guidelines for the diagnosis and treatment of croup advise using steroids as the mainstay treatment for all children who present to emergency department (ED) with croup symptoms. Dexamethasone, given orally as a single dose at 0.6 mg/kg, is highly efficacious in treating croup symptoms. Despite the evidence supporting the use of steroids as the cornerstone of croup treatment, there is significant practice variation among physicians treating croup in the ED. This practice point discusses evidence based management of typical croup in the ED. PMID- 29532808 TI - Comment on: Early recovery pathway for hepatectomy: data-driven liver resection care and recovery. PMID- 29532809 TI - Editorial on PanCan study. PMID- 29532805 TI - Sexual dysfunction and male infertility. AB - Infertility affects up to 12% of all men, and sexual dysfunction occurs frequently in men of reproductive age, causing infertility in some instances. In infertile men, hypoactive sexual desire and lack of sexual satisfaction are the most prevalent types of sexual dysfunction, ranging from 8.9% to 68.7%. Erectile dysfunction and/or premature ejaculation, evaluated with validated tools, have a prevalence of one in six infertile men, and orgasmic dysfunction has a prevalence of one in ten infertile men. In addition, infertile men can experience a heavy psychological burden. Infertility and its associated psychological concerns can underlie sexual dysfunction. Furthermore, general health perturbations can lead to male infertility and/or sexual dysfunction. Erectile dysfunction and male infertility are considered proxies for general health, the former underlying cardiovascular disorders and the latter cancerous and noncancerous conditions. The concept that erectile dysfunction in infertile men might be an early marker of poor general health is emerging. Finally, medications used for general health problems can cause sperm abnormalities and sexual dysfunction. The treatment of some causes of male infertility might improve semen quality and reverse infertility-related sexual dysfunction. In infertile men, an investigation of sexual, general, and psychological health status is advisable to improve reproductive problems and general health. PMID- 29532810 TI - Hepatocellular carcinoma: one world, one cancer-different guidelines? PMID- 29532812 TI - Corrigendum. AB - [This corrects the article DOI: 10.2471/BLT.17.200139.]. PMID- 29532813 TI - Ethical dilemmas of dental implantology: Ready for aftercare? AB - Dental implantology is one of the most attractive and dynamic fields of work within clinical dentistry. It provides many patients with new and improved opportunities for stable (implant-supported) rehabilitation and also offers dentists a field that is interesting in both technical and economic terms. Adverse clinical outcomes are, however, often the subject of discussion. These relate both to prosthetic failure and to biologic complications and side effects, namely persistent infections surrounding implants. A further point of discussion relates to the question as to how far the triumphant march of implantology is accompanied by a reduction in the willingness to retain teeth. It thus appears all the more important to ask some questions regarding the normative overall conditions of responsible implantologic care on the basis of the present state of research and currently available studies. In line with this, this paper deals with both existing preconceptions and ethically relevant parameters of responsible implantology. These function simultaneously as concrete clinical ethical guidelines for dentists practicing implantology. PMID- 29532811 TI - Advancing methods for research on household water insecurity: Studying entitlements and capabilities, socio-cultural dynamics, and political processes, institutions and governance. AB - Household water insecurity has serious implications for the health, livelihoods and wellbeing of people around the world. Existing methods to assess the state of household water insecurity focus largely on water quality, quantity or adequacy, source or reliability, and affordability. These methods have significant advantages in terms of their simplicity and comparability, but are widely recognized to oversimplify and underestimate the global burden of household water insecurity. In contrast, a broader definition of household water insecurity should include entitlements and human capabilities, sociocultural dynamics, and political institutions and processes. This paper proposes a mix of qualitative and quantitative methods that can be widely adopted across cultural, geographic, and demographic contexts to assess hard-to-measure dimensions of household water insecurity. In doing so, it critically evaluates existing methods for assessing household water insecurity and suggests ways in which methodological innovations advance a broader definition of household water insecurity. PMID- 29532814 TI - Local anesthetic-induced myotoxicity as a cause of severe trismus after inferior alveolar nerve block. AB - A case of a 60-year-old man with severe trismus after inferior alveolar nerve block is presented. MRI scans as well as histologic examination revealed muscle fibrosis and degeneration of the medial part of the left temporal muscle due to myotoxicity of a local anesthetic agent. PMID- 29532815 TI - Cone beam computed tomography review and classification of mesiodens: Report of a case in the nasal fossa and nasal septum. AB - Supernumerary teeth are an uncommon occurrence that have the ability to arise anywhere in the dental arch. Mesiodens is a specific type of supernumerary tooth that occurs in the vicinity of the maxillary central incisors. Mesiodens are the most common among all supernumerary teeth, almost always impacted, and may also be seen in various positions based on the eruption status. The formation of mesiodens is a much-debated topic and many theories have been proposed. The reports also include its common radiographic findings and a pertinent literature review. This study reports a case of an impacted, inverted mesiodens incidentally discovered on a preimplant examination of maxilla. This article demonstrates the scope of eruption of an impacted and inverted mesiodens. Various methods of treatment plan are discussed and a new classification system of mesiodens is proposed. PMID- 29532816 TI - Editorial: The American Society of Anesthesiologists (ASA) physical status classification system and its utilization for dental patient evaluation. PMID- 29532817 TI - Factors affecting ultrasonic removal of separated endodontic instruments: A retrospective clinical study. AB - OBJECTIVE: The goal was to investigate the clinical value of two-dimensional radiographs and different radiographic measurement techniques before instrument removal with a microsonic technique. The aim was to find an easy-to-use technique for predicting the success of removal and case evaluation. Additionally the quality of root canal filling after instrument removal was assessed. METHOD AND MATERIALS: This retrospective study analyzed patients' records and preoperative and postoperative periapical radiographs made using the paralleling technique. On preoperative radiographs, canal access angle and Schneider and Weine angle of root canal curvature were measured and compared. The Schafer method was used for measuring the radius of curvature. In cases of successful removal taper, homogeneity and length of obturation were evaluated on postoperative radiographs. RESULTS: A total of 123 cases of instrument removal were investigated. In total, 97 fragments (78.9%) were removed successfully. Statistical analysis was performed with Pearson's chi-square and Fisher's exact test (alpha < .05). The site of fragment relative to canal curvature, canal access angle, and Schneider angle significantly influenced the success of removal. The highest chance of removal failure was associated with > 20 degrees of canal access angle and > 40 degrees of Schneider angle. Only 26.3% of obturations met all technical standards. Altered taper could be identified in 64.2% and was always associated with ledge formation. CONCLUSION: Microsonic removal is a successful method to retrieve separated instruments. The use of only one radiographic measurement technique is not sufficient to precisely evaluate root canal anatomy, case difficulty, and chance of successful removal before instrument removal on a periapical radiograph. Postoperative root canal fillings are mainly substandard. PMID- 29532818 TI - Age assessment in orthodontics and general dentistry. AB - In dentistry, methods for determining age and the degree of dental and skeletal development play an important role, in particular in the assessment of developmental disorders of the dentition as well as in the planning of orthodontic interventions. Dentistry is also important in the field of forensics due to the possibility of age determination based on the dentition. In addition to anthropometric and morphologic methods, numerous biochemical, histologic, radiologic, and radiation-free imaging methods exist to determine the chronologic, but also dental and skeletal age of a person or a patient. This article aims to provide an overview of the currently available methods for age determination in dentistry, both for forensic and diagnostic-therapeutic purposes, and to critically assess their indication and value based on the available evidence. PMID- 29532819 TI - Site-specific electronic structure of imidazole and imidazolium in aqueous solutions. AB - The occupied and unoccupied electronic structure of imidazole (C3N2H4) and imidazolium (C3N2H5+) in aqueous solutions is studied by X-ray emission spectroscopy (XES) and resonant inelastic soft X-ray scattering (RIXS). Both systems show distinct RIXS fingerprints with strong resonant effects. A comparison with calculated X-ray emission spectra of isolated imidazole and imidazolium suggests only a small influence of hydrogen bonding in the aqueous solution on the electronic structure of imidazole and imidazolium, and allows the attribution of specific spectral features to the non-equivalent nitrogen and carbon atoms in the molecules. In the case of nitrogen, this can also be achieved by site-selective resonant excitation. Furthermore, we find spectator shifts and symmetry selectivity in the RIXS spectra, as well as indications for rapid proton dynamics on the femtosecond timescale of the RIXS process, and derive the HOMO LUMO gaps for the two molecules in aqueous solution. PMID- 29532820 TI - Multi-channel dynamics in high harmonic generation of aligned CO2: ab initio analysis with time-dependent B-spline algebraic diagrammatic construction. AB - Here we present a fully ab initio study of the high-order harmonic generation (HHG) spectrum of aligned CO2 molecules. The calculations have been performed by using the molecular time-dependent (TD) B-spline algebraic diagrammatic construction (ADC) method. We quantitatively study how the sub-cycle laser-driven multi-channel dynamics, as reflected in the position of the dynamical minimum in the HHG spectrum, is affected by the full inclusion of both correlation-driven and laser-driven dipole interchannel couplings. We calculate channel-resolved spectral intensities as well as the phase differences between contributions of the different ionization-recombination channels to the total HHG spectrum. Our results show that electron correlation effectively controls the relative contributions of the different channels to the total HHG spectrum, leading to the opening of the new ones (12Piu, 12Sigma), previously disregarded for the aligned molecular setup. We conclude that inclusion of many-electron effects into the theoretical interpretation of molecular HHG spectra is essential in order to correctly extract ultrafast electron dynamics using HHG spectroscopy. PMID- 29532821 TI - MoS2 nanohybrid as a fluorescence sensor for highly selective detection of dopamine. AB - Fluorescence sensors for biologically active molecules are catching attention due to their good performance and simplicity. Herein, we report a fluorescence sensor for the selective and sensitive detection of dopamine (DA) in aqueous samples. MoS2 nanohybrid material composed of MoS2 quantum dots dispersed over MoS2 nanosheets (MoS2 QDNS) in alkaline medium was employed as the fluorescent probe. In the presence of DA, the photoluminescence intensity of MoS2 QDNS was quenched linearly with increasing concentration of the former. The quenching mechanism was found to operate via Forster resonance energy transfer (FRET), and the inner filter effect (IFE). The QDNS sensor demonstrates high selectivity towards DA, especially in the presence of ascorbic acid and uric acid, which are the most potential interference for DA in biological systems. The sensitivity of the system was as low as 0.9 nM and demonstrated two linear ranges from 2.5 nM to 5.0 MUM and from 5.0 MUM to 10.4 MUM. The sensor demonstrated a remarkable ability in the analysis of real blood samples and showed excellent potential for visual detection. PMID- 29532822 TI - Sensing and capture of toxic and hazardous gases and vapors by metal-organic frameworks. AB - Toxic and hazardous chemical species are ubiquitous, predominantly emitted by anthropogenic activities, and pose serious risks to human health and the environment. Thus, the sensing and subsequent capture of these chemicals, especially in the gas or vapor phase, are of extreme importance. To this end, metal-organic frameworks have attracted significant interest, as their high porosity and wide tunability make them ideal for both applications. These tailorable framework materials are particularly promising for the specific sensing and capture of targeted chemicals, as they can be designed to fit a diverse range of required conditions. This review will discuss the advantages of metal-organic frameworks in the sensing and capture of harmful gases and vapors, as well as principles and strategies guiding the design of these materials. Recent progress in the luminescent detection of aromatic and aliphatic volatile organic compounds, toxic gases, and chemical warfare agents will be summarized, and the adsorptive removal of fluorocarbons/chlorofluorocarbons, volatile radioactive species, toxic industrial gases and chemical warfare agents will be discussed. PMID- 29532823 TI - Comprehensive reaction mechanisms at and near the Ni-Fe active sites of [NiFe] hydrogenases. AB - [NiFe] hydrogenase (H2ase) catalyzes the oxidation of dihydrogen to two protons and two electrons and/or its reverse reaction. For this simple reaction, the enzyme has developed a sophisticated but intricate mechanism with heterolytic cleavage of dihydrogen (or a combination of a hydride and a proton), where its Ni Fe active site exhibits various redox states. Recently, thermodynamic parameters of the acid-base equilibrium for activation-inactivation, a new intermediate in the catalytic reaction, and new crystal structures of [NiFe] H2ases have been reported, providing significant insights into the activation-inactivation and catalytic reaction mechanisms of [NiFe] H2ases. This Perspective provides an overview of the reaction mechanisms of [NiFe] H2ases based on these new findings. PMID- 29532824 TI - Dual-mode holographic microscopy imaging platform. AB - We report on a novel layout capable of dual-mode imaging in real time with different magnifications and resolution capabilities in lensless microscopy. The concept is based on wavelength multiplexing for providing two illuminations with different wavefront curvatures: one is collimated, allowing a large field of view (FOV) with a poor resolution limit, and the other is divergent, to achieve a better resolution limit (micron range) over a small FOV. Moreover, our recently reported concept of MISHELF microscopy [M. Sanz, J. A. Picazo-Bueno, L. Granero, J. Garcia and V. Mico, Sci. Rep., 2017, 7, 43291] is applied to the divergent illumination case, improving the image quality by noise averaging and twin image minimization. The performance of this novel dual-mode lensless microscopy imaging platform is validated through experiments using both static amplitude (resolution test targets) and dynamic complex (flowing microbeads and live sperm cells) samples. The proposed imaging platform represents the background technology for a new generation of lensless microscopes with improved performance and capabilities. PMID- 29532825 TI - The near-UV absorber OSSO and its isomers. AB - Disulfur dioxide, OSSO, has been proposed as the enigmatic "near-UV absorber" in the yellowish atmosphere of Venus. However, the fundamentally important spectroscopic properties and photochemistry of OSSO are scarcely documented. By either condensing gaseous SO or 266 laser photolysis of an S2O2 complex in Ar or N2 at 15 K, syn-OSSO, anti-OSSO, and cyclic OS([double bond, length as m-dash]O)S were identified by IR and UV/Vis spectroscopy for the first time. The observed absorptions (lambdamax) for OSSO at 517 and 390 nm coincide with the near-UV absorption (320-400 nm) found in the Venus clouds by photometric measurements with the Pioneer Venus orbiter. Subsequent UV light irradiation (365 nm) depletes syn-OSSO and anti-OSSO and yields a fourth isomer, syn-OSOS, with concomitant dissociation into SO2 and elemental sulfur. PMID- 29532826 TI - Complementary effects of cereal and pulse polyphenols and dietary fiber on chronic inflammation and gut health. AB - Cereal grains and grain pulses are primary staples often consumed together, and contribute a major portion of daily human calorie and protein intake globally. Protective effects of consuming whole grain cereals and grain pulses against various inflammation-related chronic diseases are well documented. However, potential benefits of combined intake of whole cereals and pulses beyond their complementary amino acid nutrition is rarely considered in literature. There is ample evidence that key bioactive components of whole grain cereals and pulses are structurally different and thus may be optimized to provide synergistic/complementary health benefits. Among the most important whole grain bioactive components are polyphenols and dietary fiber, not only because of their demonstrated biological function, but also their major impact on consumer choice of whole grain/pulse products. This review highlights the distinct structural differences between key cereal grain and pulse polyphenols and non-starch polysaccharides (dietary fiber), and the evidence on specific synergistic/complementary benefits of combining the bioactive components from the two commodities. Interactive effects of the polyphenols and fiber on gut microbiota and associated benefits to colon health, and against systemic inflammation, are discussed. Processing technologies that can be used to further enhance the interactive benefits of combined cereal-pulse bioactive compounds are highlighted. PMID- 29532830 TI - The molecular mechanism of the inhibition effects of PVCaps on the growth of sI hydrate: an unstable adsorption mechanism. AB - The inhibition properties of kinetic hydrate inhibitor (KHI) molecules on the dynamic growth of a hydrate/water interface are investigated by using molecular dynamics simulations. The shape of the hydrate interface is transformed from laminar to funnel by PVCaps. Results indicate that the inhibition effects not only depend on the adsorption capacity which was believed to determine inhibition, but also on the fact that PVCaps must have some non-binding-hydrate sites that don't tend to combine with hydrate. By observing the time evolution of the distance between each component of PVCaps and hydrate, the heterocyclic ring of PVCaps mainly contributes to adsorption and can preferentially adjust itself to come into contact with a hydrate semi-large-cage. The distance between the amide of PVCaps and hydrate is about 4 A and exceeds the range of a general hydrogen bond (3.5 A), which proves that the non-binding-hydrate sites of PVCaps exist. On the other hand, the amide of PVCaps is at the intersection of the solid liquid interface but has no adsorption affinity for hydrate, so this adsorption pattern indicates that the PVCaps at the hydrate interface are not stable. Due to this unstable adsorption, a repeated hydrate destruction phenomenon was revealed by the identification algorithm of hydrate and the calculation of the local number density of methane. The statistical evolution of water rings further proved the existence of non-binding-hydrate sites in PVCaps and the inhibition mechanism to destroy the hydrate cages by PVCaps. This unstable adsorption mechanism may shed light on the development of novel efficient KHIs. PMID- 29532835 TI - Platinum microelectrodes on gadolinia doped ceria single crystals - bulk properties and electrode kinetics. AB - To better understand the electrode kinetics of oxygen reduction and oxidation of gadolinia doped ceria (GDC), the electrochemical properties of platinum electrodes on GDC single crystals and polycrystalline samples were investigated with geometrically well-defined microelectrodes. For comparison measurements were also performed on polycrystalline samples using platinum interdigital electrodes in order to access the effect of the electrode geometry on the electrochemical properties. The transport properties were characterised using impedance spectroscopy, allowing to separate the transport processes of the electrode and the electrolyte. Evaluation of the temperature dependence shows activation energies of 0.77 eV for bulk transport and 1.03 eV for the electrode exchange. Oxygen partial pressure dependent measurements in a reducing atmosphere reveal a strong increase in activation energy due to electronic defect formation. A distinct chemical capacitance is observed in the electrode impedance for all sample types independent of the electrode geometry. While this chemical capacitance is only visible in the electrolyte contribution for the samples measured with interdigital electrodes, for the samples investigated with microelectrodes no chemical capacitance is observed in the electrolyte contribution of the impedance. As the chemical capacitance is related to stoichiometry changes in the electrolyte materials, the results confirm the non uniform potential distribution occurring at a microelectrode, which results in a vanishing lateral potential gradient and therefore in a negligible stoichiometry gradient inside the electrolyte at a distance from the microelectrode. PMID- 29532836 TI - Electrically excited hot-electron dominated fluorescent emitters using individual Ga-doped ZnO microwires via metal quasiparticle film decoration. AB - The generation of hot electrons from metal nanostructures through plasmon decay provided a direct interfacial charge transfer mechanism, which no longer suffers from the barrier height restrictions observed for metal/semiconductor interfaces. Metal plasmon-mediated energy conversion with higher efficiency has been proposed as a promising alternative to construct novel optoelectronic devices, such as photodetectors, photovoltaic and photocatalytic devices, etc. However, the realization of the electrically-driven generation of hot electrons, and the application in light-emitting devices remain big challenges. Here, hybrid architectures comprising individual Ga-doped ZnO (ZnO:Ga) microwires via metal quasiparticle film decoration were fabricated. The hottest spots could be formed towards the center of the wires, and the quasiparticle films were converted into physically isolated nanoparticles by applying a bias onto the wires. Thus, the hot electrons became spatially localized towards the hottest regions, leading to a release of energy in the form of emitting photons. By adjusting the sputtering times and appropriate alloys, such as Au and Ag, wavelength-tunable emissions could be achieved. To exploit the EL emission characteristics, metal plasmons could be used as active elements to mediate the generation of hot electrons from metal nanostructures, which are located in the light-emitting regions, followed by injection into ZnO:Ga microwire-channels; thus, the production of plasmon decay-induced hot-electrons could function as an efficient approach to dominate emission wavelengths. Therefore, by introducing metal nanostructure decoration, individual ZnO:Ga microwires can be used to construct wavelength-tunable fluorescent emitters. The hybrid architectures of metal-ZnO micro/nanostructures offer a fantastic candidate to broaden the potential applications of semiconducting optoelectronic devices, such as photovoltaic devices, photodetectors, optoelectronic sensors, etc. PMID- 29532839 TI - A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation. AB - In vitro cardiac models able to mimic the fibrotic process are paramount to develop an effective anti-fibrosis therapy that can regulate fibroblast behaviour upon myocardial injury. In previously developed in vitro models, typical fibrosis features were induced by using scar-like stiffness substrates and/or potent morphogen supplementation in monolayer cultures. In our model, we aimed to mimic in vitro a fibrosis-like environment by applying cyclic stretching of cardiac fibroblasts embedded in three-dimensional fibrin-hydrogels alone. Using a microfluidic device capable of delivering controlled cyclic mechanical stretching (10% strain at 1 Hz), some of the main fibrosis hallmarks were successfully reproduced in 7 days. Cyclic strain indeed increased cell proliferation, extracellular matrix (ECM) deposition (e.g. type-I-collagen, fibronectin) and its stiffness, forming a scar-like tissue with superior quality compared to the supplementation of TGFbeta1 alone. Taken together, the observed findings resemble some of the key steps in the formation of a scar: (i) early fibroblast proliferation, (ii) later phenotype switch into myofibroblasts, (iii) ECM deposition and (iv) stiffening. This in vitro scar-on-a-chip model represents a big step forward to investigate the early mechanisms possibly leading later to fibrosis without any possible confounding supplementation of exogenous potent morphogens. PMID- 29532840 TI - Enhanced nucleation of germanium on graphene via dipole engineering. AB - The preparation of crystalline materials on incommensurate substrates has been a key topic of epitaxy. van der Waals (vdW) epitaxy on two-dimensional (2D) materials opened novel opportunities of epitaxial growth overcoming the materials compatibility issue. Therefore, vdW epitaxy has been considered as a promising approach for the preparation of building blocks of flexible devices and thin film based devices at the nano/microscale. However, an understanding of vdW epitaxy has not been thoroughly established. Especially, controlling nucleation during vdW epitaxy has not been achieved although nucleation in vdW epitaxy is suppressed due to the absence of surface dangling bonds on 2D materials. Here we show an enhancement of nucleation probability of germanium on graphene via introducing an out-of-plane dipole moment without any change in the chemical nature of graphene. A graphene/hexagonal boron nitride stack and transferred graphene on a polarized ferroelectric thin film were employed to demonstrate the significant enhancement of Ge nucleation on graphene. Theoretical calculations and chemical vapor deposition were employed to elucidate the effect of the out-of plane dipole moment on nucleation in vdW epitaxy. PMID- 29532841 TI - Impact of nuclearity and topology on the single molecule magnet behaviour of hexaazatrinaphtylene-based cobalt complexes. AB - A hexaazatrinaphtylene-based transition metal complex that exhibits single molecule magnet (SMM) behaviour is reported herein. Both monometallic (1) and bimetallic (2) CoII complexes with distorted octahedral geometries could be obtained through a straightforward change in synthetic conditions. Field induced SMM behaviour was exhibited by 1, with a D value of -60 cm-1 and Ueff = 17 K originating from the unquenched orbital angular momentum of the octahedral CoII (d7) centre. On the other hand, 2 exhibits weak antiferromagnetic interactions with a positive D value, thus preventing the observation of SMM behaviour. This investigation reveals the influence of both nuclearity and topology on the magnetic properties of HATN based complexes. PMID- 29532842 TI - Unified meso-pores and dense Cu2+ sites in porous coordination polymers for highly efficient gas storage and separation. AB - Unified meso-pores and dense open metal sites (OMS) in porous coordination polymers (PCPs) allow highly promising H2 and C2-hydrocarbon storage, as well as rapid and efficient C2H2/4 enrichment from CO2 mixtures. The positive function of the OMS, associated with guest thermodynamics, was well revealed by in situ infrared (IR) spectroscopy study. PMID- 29532843 TI - Two-dimensional Co-Ln networks bridged by phenyl pyrimidyl substituted nitronyl nitroxides: structural and magnetic properties. AB - Two-dimensional hetero-tri-spin 2p-3d-4f coordination polymers involving Co(ii) and Ln(iii) ions assembled with a polydentate paramagnetic nitronyl nitroxide ligand are reported. [Ln(hfac)3{Co(hfac)2}2(NITPhPyrim)2] (LnIII = Gd 1, Tb 2; hfac = hexafluoroacetylacetonate, NITPhPyrim = 2-[4-(5-pyrimidyl)phenyl]-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide) consists of a two-dimensional network in which the NITPhPyrim ligand is coordinated to the metal ions by means of its pyrimidine and aminoxyl (NO) groups. In the layer, the Tb center interacts with two NO groups from two different radical ligands, and each pyrimidine connects two Co(hfac)2 units through its two nitrogen atoms to form one-dimensional Co(ii) arrays. The magnetic behavior of the two compounds results from concomitant ferro and antiferromagnetic interactions between the spin carriers and the spin-orbit effect from Co(ii) as revealed by modeling performed for the Gd(iii) derivative. PMID- 29532844 TI - A reversible and highly selective two-photon fluorescent "on-off-on" probe for biological Cu2+ detection. AB - A two-photon active probe for physiological copper (Cu2+) detection is expected to play an important role in monitoring biological metabolism. Herein, a novel Schiff base derivative (E)-2,2'-((4-((4-(diethylamino)-2 hydroxybenzylidene)amino)phenyl)azanediyl)bis(ethan-1-ol) (L) with remarkable two photon activity was developed and synthetically investigated. L presents high selectivity and sensitivity for Cu2+ sensing in ethanol/HEPES buffer (v/v, 1 : 1), which is accompanied by the fluorescence switching "off" and subsequently "on" with the addition of EDTA. The mechanism for the detection of Cu2+ is further analyzed using 1H NMR titration, mass spectra and theoretical calculations. Furthermore, since the probe L possesses good photophysical properties, excellent biocompatibility and low cytotoxicity, it is successfully applied to track Cu2+ in the cellular endoplasmic reticulum by two-photon fluorescence imaging, showing its potential value for practical applications in biological systems. PMID- 29532845 TI - 3D depth profiling of the interaction between an AFM tip and fluid polymer solutions. AB - In the atomic force microscopy (AFM) investigation of soft polymers and liquids, the tip-sample interaction is dominated by long-range van der Waals forces, capillary forces and adhesion. Furthermore, the tip can indent several tens of nanometres into the surface, and it can pull off a polymer filament from the surface. Therefore, measuring the unperturbed shape of a polymeric fluid can be challenging. Here, we study the tip-sample interaction with polystyrene droplets swollen in chloroform vapour, where we can utilize the solvent vapour concentration to adjust the specimen's mechanical properties from a stiff solid to a fluid film. With the same AFM tip, we use two different AFM force spectroscopy methods to measure three-dimensional (3D) depth profiles of the tip sample interaction: force-distance (FD) curves and amplitude-phase-distance (APD) curves. The 3D depth profiles reconstructed from FD and APD measurements provide detailed insight into the tip-sample interaction mechanism for a fluid polymer solution. The fluid's intrinsic relaxation time, which we measure with an AFM based step-strain experiment, is essential for understanding the tip-sample interaction mechanism. Furthermore, measuring 3D depth profiles and using APD data to reconstruct the unperturbed surface comprise a versatile methodology for obtaining accurate dimensional measurements of fluid and gel-like objects on the nanometre scale. PMID- 29532846 TI - Versatile synthesis of chiral 6-oxoverdazyl radical ligands - new building blocks for multifunctional molecule-based magnets. AB - A versatile synthetic methodology to access the first family of chiral verdazyl N,N'-chelate ligands is described and exemplified by N,N'-dimethyl-, N,N'-di isopropyl- and N,N'-diphenyl oxoverdazyls bearing two isomers of the pinene pyridine functional group. Their physical properties were probed by X-band EPR spectroscopy, cyclic voltammetry and DFT calculations. Preliminary reactivity studies show they can act as N,N'-chelate ligands affording a chiral 1 : 1 complex (3b) with CuCl2, which was characterized by single-crystal X-ray diffraction. Variable temperature EPR studies on (3b) confirm the presence of antiferromagnetic interactions between the spins of the Cu(ii) ion and the verdazyl radical. PMID- 29532847 TI - In vivo and in vitro identification of Z-BOX C - a new bilirubin oxidation end product. AB - A new bilirubin oxidation end product (BOX) was isolated and characterized. The formation of the so-called Z-BOX C proceeds from bilirubin via propentdyopents as intermediates. This BOX was detected in pathological human bile samples using liquid chromatography/mass spectrometry and has potential relevance for liver dysfunction and cerebral vasospasms. PMID- 29532848 TI - C8-Guanine modifications: effect on Z-DNA formation and its role in cancer. AB - Base modifications are known to affect the structure and function of DNA. C8 guanine adducts from various carcinogenic compounds have been shown to be potent Z-DNA inducers. Hence, it has been hypothesized that Z-DNA plays a role in cancer and other genetic diseases. In this comprehensive review, Z-DNA and the effect of prevalent C8-guanine adducts on the B-Z transition are addressed. The discoveries of Z-DNA binding proteins including ADAR1, E3L, DLM1, and PKZ have suggested the relevance of Z-DNA in living systems. In addition, increasing evidence on the Z DNA connection to gene transcription and inhibition reveals potential biological functions of the left-handed DNA. Finally, C8-guanine adducts that promote Z-DNA formation can be used as a tool to explore the Z-DNA function and its role in carcinogenesis. PMID- 29532849 TI - Hot off the press. AB - A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as tundrenone from Methylobacter tundripaludum. PMID- 29532850 TI - Functions of chemokines in the perineural invasion of tumors (Review). AB - The perineural invasion (PNI) of malignant tumors is a form of tumor progression in which cancer cells encroach along nerves. PNI hinders curative resection. Residual tumor cells in or around nerves can bring about local recurrence, infiltration and metastasis. This behavior is usually associated with a poor clinical prognosis. Therefore, it is necessary to investigate novel ligand receptor crosstalk between nerves and tumor cells that promote the process of PNI. Chemokines are regarded as one of pivotal factors involved in the process of PNI. The present review collates information provided by previous studies with regard to the role of chemokines in PNI. The study presents a definition of PNI in cancer, generalizes the biological characteristics and the expression of chemokines and their receptors in cancer types associated with PNI, and discusses the underlying molecular mechanisms of chemokines, the reciprocal interactions between chemokines and other factors in PNI, and the interconnectivity of the microenvironment and chemokines. The aim of the review is to thoroughly illustrate the molecular cues of chemokines in cancer with PNI and to identify novel antitumor targets. PMID- 29532851 TI - MicroRNA-30e protects the heart against ischemia and reperfusion injury through autophagy and the Notch1/Hes1/Akt signaling pathway. AB - The aim of the present study was to determine the cardioprotective mechanisms by which micro (mi)RNA-30e protects the heart from myocardial ischemia/reperfusion injury (MI/R) and to explore the signaling pathways that may confer protection for the heart and be potential therapeutic targets. It was demonstrated that miRNA-30e expression was decreased in patients with MI/R. In H9C2 cells, silencing (si)miRNA-30e significantly inhibited cellular apoptosis, the expression of apoptosis regulator BAX (Bax) and caspase-3 activity. It also significantly increased the expression of microtubule-associated proteins 1A/1B light chain 3B, p62, Beclin-1, neurogenic locus notch homolog protein-1 (Notch1), Hes1 and phosphorylated-protein kinase B (p-Akt), and decreased the expression of inducible NO synthase (iNOS) and proteins associated with oxidative stress. The inhibition of autophagy following treatment with 3-methyladenine significantly reversed the effect of si-miRNA-30e on apoptosis, Bax, caspase-3, iNOS and oxidative stress in H9C2 cells. The promotion of Notch1 expression increased the effect of si-miRNA-30e on apoptosis, Bax, caspase-3, iNOS, Notch1, Hes1 and p-Akt protein expression and oxidative stress in H9C2 cells. Taken together, these results indicate that miRNA-30e protects the heart from MI/R via autophagy and the Notch1/Hes1/Akt signaling pathway. PMID- 29532852 TI - Inhibitory effects of bee venom on mast cell-mediated allergic inflammatory responses. AB - Although bee venom (BV) is a toxin that causes bee stings to be painful, it has been widely used clinically for the treatment of certain immune-associated diseases. BV has been used traditionally for the treatment of chronic inflammatory diseases. In this regard, the present study analyzed the effect of BV on the regulation of inflammatory mediator production by mast cells and their allergic inflammatory responses in an animal model. HMC-1 cells were treated with BV prior to stimulation with phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI). The production of allergy-associated pro-inflammatory mediators was examined, and the underlying mechanisms were investigated. Furthermore, to investigate whether BV exhibits anti-inflammatory effects associated with anti-allergic effects in vivo, a compound 48/80-induced anaphylaxis model was used. BV inhibited histamine release, mRNA expression and production of cytokines in the PMACI-stimulated HMC-1 cells. Furthermore, the inhibitory effects of BV on mitogen-activated protein kinase (MAPK), MAPK kinase, signal transducer and activator of transcription 3 (STAT3) and Akt were demonstrated. The present study also investigated the ability of BV to inhibit compound 48/80-induced systemic anaphylaxis in vivo. BV protected the mice against compound 48/80-induced anaphylactic-associated mortality. Furthermore, BV suppressed the mRNA expression levels of pro-inflammatory cytokines, and suppressed the activation of MAPK and STAT3 in this model. These results provide novel insights into the possible role of BV as a modulator for mast cell-mediated allergic inflammatory disorders. PMID- 29532853 TI - Anti-inflammatory effects of Passiflora foetida L. in LPS-stimulated RAW264.7 macrophages. AB - Passiflora foetida L. (Passifloraceae), a perennial climber in general, is used for treating many ailments in conventional medicine. In this study, the anti inflammatory effect of methanolic extracts of P. foetida L. (PFME) and the involvement of nuclear factor-kappaB (NF-kappaB) signalling in the regulation of inflammation were investigated. PFME prevented the production of prostaglandin E2 (PGE2) and the expression of inducible cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced macrophage cells. Additionally, PFME reduced the release of pro-inflammatory cytokines. Moreover, in LPS-induced RAW264.7 cells, the phosphorylation of MAPKs (ERK1/2, p38 and JNK) was suppressed by PFME. Furthermore, PFME inhibited the NF-kappaB activation induced by LPS, which was associated with nuclear p65 levels with the abrogation of IkappaBalpha degradation and subsequent decreases. These results indicated that the PFME inhibited the LPS-induced inflammatory and oxidative responses. Therefore, we propose that the PFME may be therapeutic for treating inflammatory diseases. PMID- 29532854 TI - FLVCR1 promotes the proliferation and tumorigenicity of synovial sarcoma through inhibiting apoptosis and autophagy. AB - Feline leukemia virus subgroup C receptor 1 (FLVCR1) has been reported to have a crucial role in variety of biological processes, including cell proliferation, cell death, apoptosis, oxidative stress response, cellular differentiation and metabolism. However, little is known about its role in synovial sarcoma (SS). In the current study, FLVCR1 expression was analyzed in two SS cell lines (SW982 and HS-SY-II), and in eight SS tissues and paired adjacent non-tumor tissues using reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Lentivirus-mediated short hairpin RNAs were used to knock down FLVCR1 expression in SW982 and HS-SY-II cells. The effects of FLVCR1 knockdown on the cell proliferation, clonogenicity, cell cycle and apoptosis in SS cells were evaluated by MTT, colony formation assay, flow cytometry analysis, western blotting and in vivo tumorigenesis in nude mice. In the current study, gene expression of FLVCR1 was upregulated in SS cell lines (SW982 and HS-SY-II) and SS tissues from patients. The protein levels of FLVCR1 in SS tissues were also significantly higher than in adjacent non-tumor tissues. Furthermore, suppressing the expression of FLVCR1 in SS cells using short hairpin RNA effectively attenuated cell proliferation, colony formation and impaired the cell cycle, and also significantly induced apoptosis and autophagy. In accordance with this, an in vivo tumorigenicity assay in mice demonstrated that suppression of FLVCR1 expression inhibited the growth of SS tumors implanted subcutaneously. Collectively, these results demonstrated that FLVCR1 may act as an oncoprotein, and have key roles in promoting proliferation and tumorigenicity of SS, and this may shed new light on finding novel therapeutic strategies against SS. PMID- 29532855 TI - Rhododendron album Blume extract inhibits TNF-alpha/IFN-gamma-induced chemokine production via blockade of NF-kappaB and JAK/STAT activation in human epidermal keratinocytes. AB - Rhododendron album Blume (RA) has traditionally been used as an herbal medicine and is considered to have anti-inflammatory properties. It is a well-known medicine for treatment of allergic or atopic diseases. In the present study, the biological effects of an RA methanol extract (RAME) on inflammation were investigated in tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN gamma)-stimulated human keratinocytes. The present study aimed to investigate the potential mechanisms by which RAME inhibited TNF-alpha/IFN-gamma-induced expression of chemokines [thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC)] and cytokines [interleukin (IL)-6 and IL-8] through the nuclear factor-kappaB (NF-kappaB) pathway in human keratinocytes. The effects of RAME treatment on cell viability were investigated in TNF-alpha/IFN gamma-stimulated HaCaT cells. The expression of TARC, MDC, IL-6 and IL-8 was assessed using reverse transcription-quantitative polymerase chain reaction analysis or ELISA, and its effect on the inhibitory mitogen-activated protein kinase pathway was also studied using western blot analysis. TNF-alpha/IFN-gamma induced the expression of IL-6, IL-8, TARC and MDC in a dose-dependent manner through NF-kappaB and Janus kinase/signal transducers and activators of transcription (JAK/STAT) activation. Notably, treatment with RAME significantly suppressed TNF-alpha/IFN-gamma-induced expression of IL-6, IL-8, TARC, and MDC. In addition, RAME treatment inhibited the activation of NF-kappaB and the JAK/STAT pathway in TNF-alpha/IFN-gamma-induced HaCaT cells. These results suggest that RAME decreases the production of chemokines and pro-inflammatory cytokines by suppressing the NF-kappaB and the JAK/STAT pathways. Consequently, RAME may potentially be used for treatment of atopic dermatitis. PMID- 29532856 TI - SIRT3 deficiency exacerbates p53/Parkin-mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts. AB - Mitochondrial dynamics have critical roles in aging, and their impairment represents a prominent risk factor for myocardial dysfunction. Mitochondrial deacetylase sirtuin (SIRT)3 contributes greatly to the prevention of redox stress and cell aging. The present study explored the role of SIRT3 on myocardium aging. Western blot analysis demonstrated that SIRT3 expression levels were significantly lower in the myocardia of aged mice compared with young mice. Immunoprecipitation and western blot assays indicated that the activity of mitochondrial manganese superoxide dismutase (MnSOD) and peroxisome proliferator activated receptor gamma coactivator (PGC)-1alpha was reduced in the aged heart. To further explore the association between SIRT3 and myocardial senescence, SIRT3 heart-specific knockout (SIRT3-/-) mice were used in the present study. The results revealed that obvious features of aging were present in the myocardium of SIRT3-/- mice, including mitochondrial protein dysfunction, enhanced oxidative stress, and energy metabolism dysfunction. SIRT3 deficiency impaired Parkin mediated mitophagy by increasing p53-Parkin binding and blocking the mitochondrial translocation of Parkin in cardiomyocytes. Injection of autophagy agonist CCCP significantly increased the mitochondrial Parkin level in young wild type hearts but not in aged hearts; the effect was less pronounced in SIRT3-/- hearts. These data suggest that CCCP-induced Parkin translocation was reduced in aged and SIRT3-/- hearts. CCCP-induced mitochondrial clearance, which could be rescued by autophagy antagonist bafilomycin-A1, was markedly weakened in aged and SIRT3-/- hearts vs. young hearts. SIRT3 deficiency exacerbated p53/Parkin mediated mitophagy inhibition and disrupted mitochondrial homeostasis, suggesting that loss of SIRT3 may increase the susceptibility of aged hearts to cardiac dysfunction. Therapeutic activation of SIRT3 and improved mitochondrial function may ameliorate the symptoms of cardiac aging. PMID- 29532858 TI - Hydrogen ameliorates oxidative stress via PI3K-Akt signaling pathway in UVB induced HaCaT cells. AB - Chronic ultraviolet (UV) exposure-induced oxidative stress is associated with the pathogenesis of skin damage. However, the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway is a critical factor in protecting cells against UVB induced injury through inhibiting oxidative stress. Furthermore, Nrf2 activation requires the involvement of the phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) pathway, which has a major role in survival of various cell types. Molecular hydrogen exerts protective effects on UV-induced injury, but the underlying mechanisms have remained elusive. The present study assessed the protective effects of hydrogen against oxidative stress-induced injury caused by UVB irradiation and investigated the molecular mechanisms. In vitro, UVB-induced HaCaT cells were collected for the detection of reactive oxygen species, 8-iso prostaglandin F2alpha, malondialdehyde via fluorescence spectrometry and ELISA; cell activity and cytotoxicity by MTT and lactate dehydrogenase assays, respectively. Additionally, the expression level of PI3K, Akt, Nrf2 and heme oxygenase-1 (HO-1) were investigated using western blot, etc. All of the results indicated that hydrogen decreased the levels of reactive oxygen species, 8-iso prostaglandin F2alpha and malondialdehyde, and promoted the UVB exposure-induced expression of PI3K, Akt, Nrf2 and heme oxygenase-1 in HaCaT cells. Of note, PI3K inhibition partially reversed the effects of hydrogen on UVB-induced HaCaT cells. Therefore, hydrogen effectively protects cells from UVB radiation-induced oxidative stress by inhibiting Nrf2/HO-1 activation through the PI3K/Akt signaling pathway. PMID- 29532857 TI - Cutaneous melanoma: From pathogenesis to therapy (Review). AB - In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma. The early steps of this transformation have taken place in research laboratories. The mitogen-activated protein kinase (MAPK) pathway, phosphoinositol-3-kinase (PI3K) pathway promote the development of melanoma through numerous genomic alterations on different components of these pathways. Moreover, melanoma cells deeply interact with the tumor microenvironment and the immune system. This knowledge has led to the identification of novel therapeutic targets and treatment strategies. In this review, the epidemiological features of cutaneous melanoma along with the biological mechanisms involved in its development and progression are summarized. The current state-of-the-art of advanced stage melanoma treatment strategies and the currently available evidence of the use of predictive and prognostic biomarkers are also discussed. PMID- 29532860 TI - Ciprofloxacin triggers the apoptosis of human triple-negative breast cancer MDA MB-231 cells via the p53/Bax/Bcl-2 signaling pathway. AB - Fluoroquinolone antibiotics induce cytotoxicity in various cancer cell lines and may therefore represent a potentially important source of novel anticancer agents. The aim of the present study was to examine the effect of ciprofloxacin on the viability, redox balance, apoptosis, expression of p53, Bax and Bcl-2, cell cycle distribution and DNA fragmentation of triple-negative MDA-MB-231 breast cancer cells. The results of the present study demonstrated that ciprofloxacin decreases cell viability in a dose- and time-dependent manner. The half maximal inhibitory concentration values of ciprofloxacin in MDA-MB-231 cells following treatment for 24, 48 and 72 h were 0.83, 0.14 and 0.03 umol/ml, respectively. Furthermore, it was demonstrated that ciprofloxacin altered the redox signaling pathway, as determined by intracellular glutathione depletion. The results of Annexin V/propidium iodide staining revealed that ciprofloxacin triggered the apoptosis of MDA-MB-231 cells. Furthermore, cipfloxacin treatment stimulated the loss of the mitochondrial transmembrane potential via the Bax/Bcl 2-dependent pathway, thus inducing apoptosis. Ciprofloxacin induced cell cycle arrest at the S-phase; therefore it was hypothesized that ciprofloxacin inhibits topoisomerase II. Oligonucleosomal DNA fragmentation and the elevation of p53 expression were observed in the present study, indicating that this late apoptotic event may be mediated by the p53-dependent pathway. Therefore, the results of the current study provide important molecular data concerning the cellular cascade, which may explain the cytotoxicity induced by ciprofloxacin in human triple-negative breast cancer cells, thus providing a novel insight into the therapeutic properties of this drug. PMID- 29532859 TI - PEDF improves cardiac function in rats subjected to myocardial ischemia/reperfusion injury by inhibiting ROS generation via PEDF-R. AB - The prevention and management of myocardial ischemia/reperfusion (MI/R) injury is an essential part of coronary heart disease surgery and is becoming a major clinical problem in the treatment of ischemic heart disease. Previous studies by our group have demonstrated that pigment epithelium-derived factor (PEDF) improves cardiac function in rats with acute myocardial infarction and reduces hypoxia-induced cell injury. However, the protective function and mechanisms underlying the effect of PEDF in MI/R injury remain to be fully understood. In the present study, the positive effect of PEDF in MI/R injury was confirmed by construction of the adult Sprague-Dawley rat MI/R model. PEDF reduced myocardial infarct size and downregulated cardiomyocyte apoptosis in the I/R myocardium in this model. In addition, PEDF improved cardiac function and increased cardiac functional reserve in rats subjected to MI/R Injury. To further study the protective effect of PEDF and the underlying mechanisms in MI/R injury, a H9c2 cardiomyocyte hypoxia/reoxygenation (H/R) model was constructed. PEDF was confirmed to decrease H/R-induced apoptosis in H9c2 cells, and this anti apoptotic function was abolished by pigment epithelium-derived factor-receptor (PEDF R) small interfering (si)RNA. Furthermore, administration of PEDF decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in H/R H9c2 cells. Compared with the H/R group, PEDF decreased mitochondrial ROS, increased the mitochondrial DNA copy number, reduced xanthine oxidase and NADPH oxidase activity, as well as RAC family small GTPase 1 protein expression. However, these effects of PEDF were markedly attenuated by PEDF-R siRNA. To the best of our knowledge, the present study is the first to identify the protective effect of PEDF in MI/R injury, and confirm that the antioxidative effect PEDF occurred via inhibition of ROS generation via PEDF-R under MI/R conditions. PMID- 29532861 TI - Tracking of transplanted human umbilical cord-derived mesenchymal stem cells labeled with fluorescent probe in a mouse model of acute lung injury. AB - The aim of the present study was topreliminarily visualize the distribution of humanumbilical cord-derivedmesenchymal stem cells (hUC-MSCs) in treating acute lung injury (ALI) using a targeted fluorescent technique. Anovel fluorescent molecule probe was first synthesized via the specific binding of antigen and antibody in vitro to label the hUC-MSCs. Two groups of mice, comprising a normal saline (NS)+MSC group and lipopolysaccharide (LPS)+MSC group, were subjected to optical imaging. At 4 h following ALI mouse model construction, the labeled hUC MSCs were transplanted into the mice in the NS+MSC group and LPS+MSC group by tail vein injection. The mice were sacrificed 30 min, 1 day, 3 days and 7 days following injection of the labeled hUC-MSCs, and the lungs, heart, spleen, kidneys and liver were removed. The excised lungs, heart, spleen, kidneys and liver were then detected on asmall animal fluorescent imager. The fluorescent results showed that the signal intensity in the lungs of the LPS+MSC group was significantly higher, compared with that of the NS+MSC group at 30 min (3.53+/ 0.06x10-4, vs. 1.95+/-0.05x10-4 scaled counts/sec), 1 day (36.20+/-0.77x10-4, vs. 23.45+/-0.43x10-4 scaled counts/sec), 3 days (11.83+/-0.26x10-4, vs. 5.39+/ 0.10x10-4 scaled counts/sec), and 7 days (3.14+/-0.04x10-4, vs. 0.00+/-0.00x10-4 scaled counts/sec; all P<0.05). The fluorescence intensity in the liver of the LPS+MSC group, vs. NS+MSC group was measured at 30 min (0.00+/-0.00x10-4, vs. 0.00+/-0.00x10-4 scaled counts/sec); 1 day (5.53+/-0.08x10-4, vs. 5.44+/-0.16x10 4 scaled counts/sec); 3 days (0.00+/-0.00x10-4, vs. 8.67+/-0.05x10-4 scaled counts/sec); 7 days (0.00+/-0.00x10-4, vs. 0.00+/-0.00x10-4 scaled counts/sec). The signal intensity of the heart, spleen and kidneys was minimal. In conclusion, the novel targeted fluorescence molecular probe was suitable for tracking the distribution processes of hUC-MSCs in treating ALI. PMID- 29532862 TI - High glucose induces the proliferation of prostatic cells via downregulating MRE11. AB - The aim of the present study was to investigate the candidate genes and pathways associated with benign prostatic hyperplasia (BPH) and diabetes. In vitro experiments were performed using normal prostatic epithelial RWPE-1 and HPr-1 cells. The cell lines were treated with a high-glucose solution and MTS and bromodeoxyuridine assays were used to assess cell viability. Transcriptome sequencing was used to screen the candidate genes. The expression of candidate genes was further verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. A meiotic recombination 11 (MRE11) overexpression vector was designed and transfected into RWPE-1 cells to verify the function of MRE11. A streptozotocin-induced diabetic rat model was established and rat MRE11 levels were determined by RT-qPCR and immunohistochemical staining. High concentrations of glucose resulted in RWPE-1 and HPr-1 cells with high viability. Transcriptome sequencing revealed that MRE11 was downregulated when RWPE-1 cells were exposed to high-glucose conditions. When MRE11 was overexpressed, cell viability decreased and cell apoptosis was induced under high-glucose conditions. Prostatic tissues from rats were collected and assessed; MRE11 expression was observed to be decreased, which was consistent with the in vitro cell experiments. BPH may be associated with diabetes, as MRE11 expression in prostatic cells was decreased when exposed to high-glucose conditions. Therefore, MRE11 may have potential as a biomarker for the early diagnosis of BPH and diabetes. PMID- 29532864 TI - Long non-coding RNA KCNQ1OT1 mediates the growth of hepatocellular carcinoma by functioning as a competing endogenous RNA of miR-504. AB - Accumulating evidence highlights the fact that long non-coding RNAs (lncRNAs) serve as critical factors in the growth of hepatocellular carcinoma (HCC). The dysregulation of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) has been reported in numerous human benign diseases. However, the role of KCNQ1OT1 in human HCC remains poorly understood. In this study, we demonstrated that the expression of KCNQ1OT1 was abnormally increased in HCC tissues. The ectopic high expression of KCNQ1OT1 was associated with liver cirrhosis, a larger tumor size, an advanced TNM stage, and a worse overall survival and tumor-free survival. For the first time, to the best of our knowledge, we report that KCNQ1OT1 knockdown results in a decreased cell viability and colony formation ability, and an increased rate of apoptosis in vitro. The results from our in vivo results demonstrated that KCNQ1OT1 silencing attenuated tumor growth by impairing cell proliferation. Additionally, we found that KCNQ1OT1 exerted its effects partly by relying on the microRNA-504 (miR-504)-mediated regulation of cyclin-dependent kinase 16 (CDK16), in addition to the regulation of the glycogen synthase kinase 3beta (GSK3beta)/beta-catenin/Bcl-2 signaling pathway. The present study revealed the functions and mechanisms of action of lncRNA KCNQ1OT1 regarding its role in promoting the growth of HCC. Thus, lncRNA KCNQ1OT1 may prove to be a potential therapeutic target for human HCC. PMID- 29532863 TI - Interfering RNA with multi-targets for efficient gene suppression in HCC cells. AB - RNA interference (RNAi) technology has been widely used in therapeutics development, especially multiple targeted RNAi strategy, which is a better method for multiple gene suppression. In the study, interfering RNAs (iRNAs) were designed for carrying two or three different siRNA sequences in different secondary structure formats (loop or cloverleaf). By using these types of iRNAs, co-inhibition of survivin and B-cell lymphoma-2 (Bcl-2) was investigated in hepatocellular carcinoma (HCC) cells, and we obtained promising gene silencing effects without showing undesirable interferon response. Furthermore, suppression effects on proliferation, invasion, and induced apoptosis in HCC cells were validated. The results suggest that long iRNAs with secondary structure may be a preferred strategy for multigenic disease therapy, especially for cancer and viral gene therapy and their iRNA drug development. PMID- 29532865 TI - CRISPR/Cas9-mediated ASXL1 mutations in U937 cells disrupt myeloid differentiation. AB - Additional sex combs-like 1 (ASXL1) is a well-known tumor suppressor gene and epigenetic modifier. ASXL1 mutations are frequent in myeloid malignances; these mutations are risk factors for the development of myelodysplasia and also appear as small clones during normal aging. ASXL1 appears to act as an epigenetic regulator of cell survival and myeloid differentiation; however, the molecular mechanisms underlying the malignant transformation of cells with ASXL1 mutations are not well defined. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) genome editing, heterozygous and homozygous ASXL1 mutations were introduced into human U937 leukemic cells. Comparable cell growth and cell cycle progression were observed between wild-type (WT) and ASXL1-mutated U937 cells. Drug-induced cytotoxicity, as measured by growth inhibition and apoptosis in the presence of the cell-cycle active agent 5-fluorouracil, was variable among the mutated clones but was not significantly different from WT cells. In addition, ASXL1-mutated cells exhibited defects in monocyte/macrophage differentiation. Transcriptome analysis revealed that ASXL1 mutations altered differentiation of U937 cells by disturbing genes involved in myeloid differentiation, including cytochrome B-245 beta chain and C type lectin domain family 5, member A. Dysregulation of numerous gene sets associated with cell death and survival were also observed in ASXL1-mutated cells. These data provide evidence regarding the underlying molecular mechanisms induced by mutated ASXL1 in leukemogenesis. PMID- 29532866 TI - Downregulation of the long non-coding RNA ZFAS1 is associated with cell proliferation, migration and invasion in breast cancer. AB - Long non-coding RNAs (lncRNAs) are non-coding RNAs that are >200 nucleotides in length. Recent studies have identified a number of lncRNAs with critical roles in various biological processes including tumorigenesis. Zinc finger antisense 1 (ZFAS1) is a lncRNA that has recently been reported to be involved in the progression of several human cancers. However, the biological function of ZFAS1 in breast cancer remains to be elucidated. In order to determine the effect of ZFAS1 in breast cancer cells, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to measure ZFAS1 expression in cells from breast cancer cell lines. In addition, gain-of-function experiments were performed in vitro to investigate the biological role of ZFAS1. The results revealed that ZFAS1 expression was significantly downregulated in breast cancer cell lines when compared with the levels in controls. In vitro experiments also demonstrated that ZFAS1 overexpression significantly suppressed cell proliferation by causing cell cycle arrest and inducing apoptosis in breast cancer cells. Further functional assays indicated that ZFAS1 overexpression inhibited cell migration and invasion by regulating epithelial-mesenchymal transition. These findings indicated that the lncRNA ZFAS1 may be a tumor suppressor in breast cancer, and thus, may serve as a potential therapeutic target for patients with breast cancer. PMID- 29532867 TI - H2A.Z regulates tumorigenesis, metastasis and sensitivity to cisplatin in intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is a fatal, malignant tumor of the liver; effective diagnostic biomarkers and therapeutic targets for ICC have not been identified yet. High expression of H2A histone family member Z (H2A.Z) is a high risk factor for poor prognosis in patients with breast cancer and primary hepatocellular cancer. However, the significance of H2A.Z and its expression in ICC remains unknown. The present study demonstrated that H2A.Z is overexpressed in ICC and expression of H2A.Z correlated with poor prognosis in patients with ICC. H2A.Z regulated cell proliferation in vitro and in vivo via H2A.Z/S-phase kinase-associated protein 2/p27/p21 signaling. Inhibition of H2A.Z reduced cell proliferation and induced apoptosis in ICC. In addition, downregulation of H2AZ reduced tumor metastasis by repressing epithelial-mesenchymal transition and enhanced the antitumor effects of cisplatin in the treatment of ICC. Overall, H2A.Z promoted cell proliferation and epithelial-mesenchymal transition in ICC, suggesting that H2A.Z may be a novel biomarker and therapeutic target for ICC. PMID- 29532868 TI - Secretome analysis of rat osteoblasts during icariin treatment induced osteogenesis. AB - Osteoporosis is a serious public health problem and icariin (ICA) is the active component of the Epimedium sagittatum, a traditional Chinese medicinal herb. The present study aimed to investigate the effects and underlying mechanisms of ICA as a potential therapy for osteoporosis. Calvaria osteoblasts were isolated from newborn rats and treated with ICA. Cell viability, apoptosis, alkaline phosphatase activity and calcium deposition were analyzed. Bioinformatics analyses were performed to identify differentially expressed proteins (DEPs) in response to ICA treatment. Western blot analysis was performed to validate the expression of DEPs. ICA administration promoted osteoblast viability, alkaline phosphatase activity, calcium deposition and inhibited osteoblast apoptosis. Secretome analysis of ICA-treated cells was performed using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A total of 56 DEPs were identified, including serpin family F member 1 (PEDF), protein disulfide isomerase family A, member 3 (PDIA3), nuclear protein, co-activator of histone transcription (NPAT), c-Myc and heat shock protein 70 (HSP70). These proteins were associated with signaling pathways, including Fas and p53. Bioinformatics and western blot analyses confirmed that the expression levels of the six DEPs were upregulated following ICA treatment. These genes may be directly or indirectly involved in ICA-mediated osteogenic differentiation and osteogenesis. It was demonstrated that ICA treatment promoted osteogenesis by modulating the expression of PEDF, PDIA3, NPAT and HSP70 through signaling pathways, including Fas and p53. PMID- 29532869 TI - Comparative characterization of SHED and DPSCs during extended cultivation in vitro. AB - Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are types of human dental tissue-derived mesenchymal stem cells (MSCs). These cells possess a capacity for self-renewal, multilineage differentiation potential and immunomodulatory functions. Previous studies have reported that DPSCs and SHED may be beneficial in regenerative treatments and immunotherapy. The substantial expansion of cells in vitro is a prerequisite to obtaining adequate cell numbers required for cell-based therapy. However, the regeneration and clinical potential of MSCs diminishes with long-term cell culture amplification. To assess the alterations in SHED and DPSCs characteristics that underlie cellular senescence and result from extended in vitro amplification, the biological properties of SHED and DPSCs at passages 4 (P4) and 20 (P20) were compared. The cells underwent senescence following serial expansion to P20, as determined by altered cell morphology, decreased proliferation and migration capacity, attenuated differentiation potential, elevated senescence-associated beta-galactosidase (SA-beta-gal)-positive rates and increased apoptosis. The phenotypic changes were also accompanied by a marked increase in the expression of p53, p21 and p16Ink4a. The present study also identified that senescent DPSCs exhibited an increased number of positive cells in SA-beta-gal staining and demonstrated varying expressions of p53, p21 and p16Ink4a in comparison with SHED, indicating the involvement of diverse pathways in cellular senescence during long-term sequential in vitro culture and passage. Furthermore, at early and late passages, SHED exhibited a higher proliferation rate and osteogenic differentiation capability when compared with DPSCs. In addition, both cell types maintained their characteristic immunophenotype during long-term cultivation, while the expression levels of CD73 were higher in SHED at P20. The present study concluded that notable alterations were exhibited in SHED and DPSCs during the process of extensive expansion in vitro and the results may provide guidance for the selection of safe and effective expanded SHED and DPSCs for regenerative medicine and therapy. PMID- 29532870 TI - Role of the EZH2/miR-200 axis in STAT3-mediated OSCC invasion. AB - Abnormal activation of signal transducer and activator of transcription 3 (STAT3) serves a pivotal role in oral squamous cell carcinoma (OSCC) tumor cell invasion into normal tissues or distant organs. However the downstream regulatory network of STAT3 signaling remains unclear. The present study aimed to investigate the potential mechanism underlying how STAT3 triggers enhancer of zeste homolog 2 (EZH2) expression and inhibits microRNA (miR)-200a/b/429 expression in SCC25 and SCC15 cells in vitro and in vivo. Western blotting and reverse transcription quantitative polymerase chain reaction were performed to detect expression, and numerous functional tests were conducted to explore cancer metastasis. The results indicated that when STAT3 signaling activity was attenuated by Stattic or enhanced with a STAT3 plasmid, the EZH2/miR-200 axis was markedly altered, thus resulting in modulation of the invasion and migration of OSCC cell lines. In addition, loss of function of EZH2 compromised the oncogenic role of STAT3 in both cell lines. F-actin morphology and the expression of epithelial-mesenchymal transition markers were also altered following disruption of the STAT3/EZH2/miR 200 axis. An orthotopic tumor model derived from SCC15 cells was used to confirm that targeting STAT3 or EZH2 suppressed OSCC invasion in vivo. In conclusion, the EZH2/miR-200 axis was revealed to mediate antitumor effects by targeting STAT3 signaling; these findings may provide a novel therapeutic strategy for the treatment of OSCC. PMID- 29532871 TI - Detection of epitopes in systemic lupus erythematosus using peptide microarray. AB - Systemic lupus erythematosus (SLE) is a common autoimmune disease, which features the secretion of antibodies directed against autoantigens in vivo. In the present study, a peptide microarray was developed to detect the epitopes recognized by autoantibodies in patients with SLE for an effective method of diagnosis. SLE associated epitopes in 14 autoantigens were predicted using the antigenic epitope prediction software DNA star. Peptides were synthesized based on the predicted antigenic epitopes and immobilized on a slide surface and developed into a peptide microarray. Using this peptide microarray the autoantibodies in 120 patients with SLE and 110 healthy subjects were detected. A total of 73 potential antigenic epitopes in 14 autoantigens were predicted and screened. The peptide microarray based on the 73 epitopes was used to detect the autoantibodies in patients with SLE. A total of 14 epitopes with potential diagnostic values were screened out. The sensitivity and specificity of the 14 epitopes for the diagnosis of SLE were 71.6 and 85.8%, respectively. An optimal set of epitopes for SLE diagnosis was obtained. As individual patients had a specific autoantibody spectrum it was possible to detect autoantibodies in SLE and perform the diagnosis of SLE using the peptide microarray. PMID- 29532872 TI - Isoquercetin ameliorates myocardial infarction through anti-inflammation and anti apoptosis factor and regulating TLR4-NF-kappaB signal pathway. AB - The aim of the present study was to investigate the protective mechanisms and identify the effects of isoquercetin on myocardial infarction in a rat model of acute myocardial infarction (AMI). Isoquercetin ameliorated myocardial infarct size, creatine kinase (CK), CK-MB and lactic dehydrogenase activity and inhibited inflammation, oxidative stress and heart cell apoptosis in a rat with AMI. Isoquercetin increased endothelial nitric oxide synthase, reduced inducible nitric oxide synthase levels and suppressed the Toll-like receptor 4-nuclear factor (TLR4-NF)-kappaB signaling pathway in a rat with AMI. Overall, isoquercetin ameliorated AMI through anti-inflammatory and anti-apoptotic factors, and regulation of the TLR4-NF-kappaB signaling pathway. Isoquercetin may therefore potentially exert a protective effect against AMI or other heart diseases. PMID- 29532873 TI - COMMD7 activates CXCL10 production by regulating NF-kappaB and the production of reactive oxygen species. AB - While >80% of the incidence occurs in sub-Saharan Africa and East Asia, cases of hepatocellular carcinoma (HCC) have been rapidly increasing in Western countries. Despite its global importance, HCC is relatively under-researched compared with other lethal cancer types, which is possibly due to the high complexity and heterogeneity of HCC. It has been reported previously that COMM domain-containing protein 7 (COMMD7) is upregulated in HCC and promotes HCC cell proliferation by triggering C-X-C motif chemokine 10 (CXCL10) production. However, the value of targeting CXCL10 signal transduction in treating COMMD7-positive tumors, or the molecular mechanisms underlying COMMD7-mediated CXCL10 expression, has not been completely addressed. In the present study, it was demonstrated that disruption of the CXCL10/C-X-C chemokine receptor type 3 axis reduces COMMD7-mediated HCC cell proliferation. Furthermore, COMMD7 modulates CXCL10 production by activating nuclear factor (NF)-kappaB. Additionally, it was demonstrated that intracellular reactive oxygen species (ROS) are required for NF-kappaB activation and CXCL10 production. In conclusion, COMMD7 activates CXCL10 production by regulating NF kappaB and the production of ROS. The present study highlighted the role of COMMD7 in the development of HCC, and provides novel options for anticancer drug design. PMID- 29532874 TI - Verification of the International Society of Urological Pathology recommendations in Japanese patients with clear cell renal cell carcinoma. AB - The aim of the present study was to evaluate the validity of potential prognostic parameters of clear cell renal cell carcinoma (ccRCC) recommended by the 2012 International Society of Urological Pathology (ISUP) Consensus Conference in the Japanese population. We reviewed 406 Japanese patients with localized or locally advanced ccRCC who underwent curative surgery during 2004-2014 at Tokai University Hospital (Isehara, Japan) and were followed up for >2 years after surgery. A single pathologist reviewed all the histological slides. Morphological subtype and pathological T stage were reassigned according to the 2016 World Health Organization and TNM classifications. Sarcomatoid differentiation (SD), rhabdoid differentiation (RD), tumor necrosis (TN) and microvascular invasion (MVI) were assessed according to the 2012 ISUP recommendations. Nuclear grade was reclassified according to both the Fuhrman and the ISUP grading systems. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed through univariate and multivariate analyses. According to the Fuhrman grading system (group Fuhrman), TN and MVI were independent risk factors for postoperative recurrence in the multivariate analysis using the Cox proportional hazards model. According to the ISUP grading system (group ISUP), TN and MVI were independent risk factors for postoperative recurrence. In group Fuhrman, age, Fuhrman grade and TN were independent risk factors for CSS. In group ISUP, age, ISUP grade, and TN were independent risk factors for CSS. Furthermore, the group that was upgraded from Fuhrman grade 2 to ISUP grade 3 exhibited poorer CSS compared with the group that was reclassified from Fuhrman grade 2 to ISUP grade 2 (non-upgraded). Regardless of the nuclear grade, TN remained an independent predictor of RFS and CSS. To the best of our knowledge, this is the first report to prove the correlation between the 2012 ISUP recommendations and clinical outcomes in a Japanese ccRCC cohort. TN and upgrading to ISUP grade 3 were found to be potentially useful independent indicators of postoperative prognosis. PMID- 29532875 TI - Store operated calcium channels are associated with diabetic cystopathy in streptozotocin-induced diabetic rats. AB - Store operated calcium channels (SOCCs) have been suggested to play a critical role in many diabetic complications. Diabetic cystopathy (DCP) is common in patients with diabetes, but the role of SOCCs in DCP is still unclear. The aim of the present study was to investigate the role of SOCCs in DCP with streptozocin (STZ)-induced diabetic rats. Specifically, the authors investigated whether SOCCs were altered in streptozocin (STZ)-induced diabetic rats and, if so, how this may contribute to the contraction of bladder detrusor strips and the intracellular Ca2+ concentration of bladder smooth muscle cells in diabetic rats. Cyclopiazonic acid (CPA, 10 uM) and SKF-96365 (10 uM) were used to activate and inhibit SOCCs respectively, to research the effects of SOCCs on the contraction of the bladder detrusor strips in normal and STZ-induced diabetic rats at the 4th, 8th and 12th week after the diabetic rat model was established. The changes of intracellular Ca2+ were also evaluated under confocal microscopy with pretreated Fluo-4AM. In addition, the expressions of Orai1 and STIM1 were detected by reverse transcription-quantitative polymerase chain reaction and western blotting at different time points. According to the results, the contractive frequency of diabetic bladder muscle strips was higher than that of controls in the 4th and 8th week. The increased fluorescence intensity was detected after using CPA and SKF-96365 in diabetic groups. The expressions of Orai1 and STIM1 changed in a time-dependent manner. PMID- 29532876 TI - Atorvastatin prevents glomerular extracellular matrix formation by interfering with the PKC signaling pathway. AB - Platelet-activating factor (PAF) promotes glomerular extracellular matrix (ECM) deposition, primarily through activation of the protein kinase C (PKC) pathway. The present study was designed to investigate whether atorvastatin, which mediates a protective effect against glomerular ECM deposition and diabetic neuropathy, may interfere with the PKC-transforming growth factor-beta1 (TGF beta1) pathway in a model of human mesangial cells (HMCs) exposed to a high glucose (HG) and lysophosphatidylcholine (LPC) environment. HMCs were divided into three treatment groups: Control, high glucose and lysophosphatidylcholine (HG+LPC), and HG+LPC+atorvastatin. Cells were cultured for 24 h. The levels of the ECM-associated molecules collagen IV (Col IV) and fibronectin (Fn) in the supernatant were detected using an ELISA kit. PKC-beta1, TGF-beta1 and PAF receptor gene expression was detected by reverse transcription-quantitative polymerase chain reaction. PKC-beta1 and TGF-beta1 protein expression was detected by western blotting, and the subcellular localization of PKC-beta1 was assessed using immunofluorescence. The results indicated that atorvastatin may reduce the secretion of ECM components (Fn and Col IV) in HMCs in a HG and LPC environment, by inhibiting the increase in PAF secretion and the activation of the PKC-TGF-beta1 signaling pathway. PMID- 29532877 TI - Upregulation of miR-614 promotes proliferation and inhibits apoptosis in ovarian cancer by suppressing PPP2R2A expression. AB - It has previously been demonstrated that microRNAs (miRNAs) have essential roles and participate in various biological processes by regulating their specific target genes. However, the precise role of miRNAs in ovarian cancer (OC) has not yet been elucidated. The present study demonstrated that miR-614 expression levels were significantly upregulated in OC tissues and cell lines, whereas decreased miR-614 demonstrated opposite effects. Furthermore, gain-of-function and loss-of-function experiments indicated that miR-614 overexpression promoted cell proliferation and suppressed cell apoptosis. Protein phosphatase 2 regulatory subunit B alpha, (PPP2R2A) was identified as a direct target of miR 614 using western blotting and luciferase reporter assays. Notably, silencing of PPP2R2A counter-acted the effect of miR-614 inhibitor in OC cell proliferation and cell apoptosis. Overall, the data suggested that miR-614 promoted cell proliferation and inhibited cell apoptosis of OC cells by targeting PPP2R2A, and may therefore act as a potential target for OC therapy in the future. PMID- 29532878 TI - Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation. AB - Osteosarcoma is the leading primary bone cancer in young adults and exhibits high chemoresistance rates. Therefore, characterization of both alternative treatment options and the underlying mechanisms is essential. Simvastatin, a cholesterol lowering drug, has among its pleiotropic effects anticancer potential. Characterizing this potential and the underlying mechanisms in osteosarcoma is the subject of the present study. Human osteosarcoma cells (SaOS-2 and U2OS) were treated with simvastatin (4-66 uM) for 48 or 72 h. The effects of downstream substrate mevalonate (MA) or substrates for isoprenylation farnesyl pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP) were evaluated using add-back experiments. Tumour growth using MTT assay, apoptosis, cell cycle and signalling cascades involved in simvastatin-induced manipulation were analysed. The results revealed that simvastatin dose-dependently inhibited cell growth. Simvastatin significantly induced apoptosis, increased the Bax/Bcl-2 ratio, and cleavage of caspase-3 and PARP protein. Simvastatin impaired cell cycle progression as shown by significantly increased percentages of cells in the G0/G1 phase and lower percentages of cells in the S phase. Gene expression levels of cell cycle regulating genes (TP53, CDKN1A and CDK1) were markedly altered. These effects were not completely abolished by FPP, but were reversed by MA and GGPP. JNK and c Jun phosphorylation was enhanced after simvastatin treatment, while those were abolished when either MA or GGPP were added. In conclusion, simvastatin acts primarily by reducing prenylation to induce apoptosis and reduce osteosarcoma cell growth. Particularly enhanced activation of c-Jun seems to play a pivotal role in osteosarcoma cell death. PMID- 29532879 TI - Pathway- and clinical-factor-based risk model predicts the prognosis of patients with gastric cancer. AB - Gastric cancer (GC) has a high incidence and mortality rate. If discovered late, GC tends to have a poor prognosis. Improvements in the prognostic accuracy of GC through combined analysis of multiple relevant genes and clinical factors may solve this problem. In the present study, GSE62254 (including 300 GC tissues), obtained from the Gene Expression Omnibus database, was used as a training set, and the mRNA-sequencing data of GC (including 384 GC tissues) downloaded from the Cancer Genome Atlas database served as a validation set. Based on the t-test and Wilcoxon test, the significantly differentially expressed genes (DEGs) were obtained by screening the intersecting DEGs. The prognosis-associated genes and clinical factors were identified using Cox regression analysis in the R survival package. The optimal prognosis-associated pathways were examined using the Cox proportional hazards (Cox-PH) model in the R penalized package. Finally, risk prediction models were constructed and validated using the Cox-PH model and the Kaplan-Meier method, respectively. There were a total of 382 significant DEGs, including 268 upregulated genes and 114 downregulated genes. A total of 50 prognosis-associated genes were identified, 16 optimal prognosis-associated pathways (including mitochondrial pathway and the tyrosine-protein kinase JAK signal transducer and activator of transcription signaling pathway, which involve caspase 7, phosphoinositide-3-kinase regulatory subunit 3, peroxisome proliferator-activated receptor gamma and collagen triple helix repeat containing 1) and four prognosis-associated clinical factors [including Pathologic_N, Pathologic_stage, mutL homolog 1 (MLH1) mutation and recurrence]. The pathway- and clinical-factor-based risk prediction model exhibited marked prognostic accuracy. The clinical-factor-based risk prediction model with improved P-values for prognosis prediction may be superior to the pathway-based risk prediction model in predicting the prognosis of GC patients. PMID- 29532880 TI - MicroRNA-214-5p/TGF-beta/Smad2 signaling alters adipogenic differentiation of bone marrow stem cells in postmenopausal osteoporosis. AB - Postmenopausal osteoporosis (OPM) is a common type of osteoporosis in females. It is a systemic, chronic bone disease that presents as microstructure degradation of osseous tissue, decreased bone mineral density and increased osteopsathyrosis caused by hypoovarianism and reduced estrogen levels in the body following menopause. In the present study, the role of microRNA (miR)-214-5p in the regulation of the expression of bone marrow stem cells (BMSCs) was investigated, and its molecular mechanism of osteogenic induction in vitro was assessed. When dexamethasone-induced adipogenic differentiation was performed, miR-214-5p expression was increased compared with the control group, as determined by RT qPCR. Furthermore, oil red O staining, RT-qPCR and western blot analysis demonstrated that overexpression of miR-214-5p promoted adipogenic differentiation, inhibited alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OC) and collagen alpha-1 (I) chain (COL1A1) mRNA expression, and suppressed transforming growth factor (TGF)-beta, phosphorylated (p)-Smad2 and collagen type IV alpha1 chain (COL4A1) protein expression in BMSCs. Additionally, downregulation of miR-214-5p increased the ALP, Runx2, OC and COL1 mRNA expression and increased TGF-beta, Smad2 and COL4A1 protein expression in BMSCs. Furthermore, a TGF-beta inhibitor was employed to inhibit TGF-beta expression in BMSCs following miR-214-5p downregulation, which led to reduced Smad2, TGF-beta and COL4A1 protein expression, and ALP, Runx2, OC and COL1 mRNA expression was also reduced, compared with the miR-214-5p downregulation only group. It was demonstrated that miR-214-5p may weaken osteogenic differentiation of BMSCs through regulating COL4A1. In conclusion, the results of the present study indicated that miR-214-5p may promote the adipogenic differentiation of BMSCs through regulation of the TGF-beta/Smad2/COL4A1 signaling pathway, and potentially may be used to develop a novel drug for postmenopausal osteoporosis. PMID- 29532881 TI - VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. AB - Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) are important treatments for a number of human malignancies, including colorectal cancers. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. The mechanism by which the cancer cells become resistant remains unclear. One potential mechanism is that VEGF/VEGF-R blockers directly act on tumor cells independently of anti-angiogenic effects. In this study, the direct effects of an anti-VEGF antibody (bevacizumab) and a VEGF-R tyrosine kinase inhibitor (sunitinib) on the evasive adaptation of colon cancer cells were compared. HCT116 and RKO human colon cancer cell lines were chronically exposed (3 months) to bevacizumab or sunitinib in vitro to establish bevacizumab- and sunitinib-adapted cells, respectively. Transwell migration and invasion assays, western blotting, reverse transcription-quantitative polymerase chain reaction, co-immunoprecipitation analysis, cell survival assays and ELISAs were conducted to analyze the adapted cells. Compared with the control vehicle-treated cells, the two cell models exhibited increased migration and invasion activities to different degrees and through different mechanisms. The bevacizumab-adapted cells, but not in the sunitinib-adapted cells, exhibited redundantly increased expression levels of VEGF/VEGF-R family members, including VEGF-A, placental growth factor, VEGF-C, VEGF-R1 and VEGF-R3. In addition, the phosphorylation levels of VEGF-R1 and VEGF-R3 were increased in the bevacizumab-adapted cells compared with the control cells. Thus, the inhibition of VEGF-R1 and VEGF-R3 decreased the evasive activities of the cells, suggesting that they remained dependent on redundant VEGF/VEGF-R signaling. By contrast, the sunitinib-adapted cells exhibited increased neuropilin-1 (NRP1) expression levels compared with the control cells. In the sunitinib-adapted cells, NRP1 interacted with phosphorylated cMet, and the cMet activation was dependent on NRP1. Thus, NRP1 or cMet blockade suppressed the evasive activation of the sunitinib-adapted cells. These results suggest that the sunitinib-adapted cells switched from a VEGF-R dependent pathway to an alternative NRP1/cMet-dependent one. The findings of the present study indicate that VEGF/VEGF-R inhibitors directly act on colon cancer cells and activate their evasive adaptation via different mechanisms. PMID- 29532882 TI - Placental expression of PAPPA, PAPPA-2 and PLAC-1 in pregnacies is associated with FGR. AB - Fetal growth restriction (FGR) is a gynecological disorder of varying etiology. In the present study, an expression analysis of pregnancy-associated plasma protein A (PAPPA), pregnancy-associated plasma protein A2 (PAPPA2) and placenta specific-1 (PLAC-1) was conducted in pregnancies with FGR and control pregnancies. Placental tissues were collected from pregnancies with FGR (n=16) and control pregnancies (n=16) and the expression of the genes of interest was examined by qPCR. The mean expression levels of PAPPA and PAPPA2 were significantly lower (P<0.001) in placental tissues from FGR pregnancies compared with tissues from healthy subjects, whereas the opposite pattern was observed for PLAC-1 (P<0.001). PAPPA and PLAC-1 expression in FGR and control subjects correlated with birth weight (P<0.001). The findings suggest a possible pathophysiological link between the development of FGR and the expression of PAPPA, PAPPA2 and PLAC-1. PMID- 29532884 TI - Protective effects of icariin on human vascular endothelial cells induced by oxidized low-density lipoprotein via modulating caspase-3 and Bcl-2. AB - Icariin belongs to the family of flavonoids that is extracted from Epimedium brevicornum Maxim, and exhibits antioxidative, antitumorigenic, antiosteoporotic, immunoregulatory and antiatherosclerotic properties. To understand the mechanisms underlying the antiatherosclerotic properties of icariin, the present study investigated the effects of icariin on human vascular endothelial cells (HUVECs) following treatment with oxidized low-density lipoprotein (ox-LDL). Thus, following pretreatment with icariin at four various concentrations (0, 10, 20 and 40 uM), HUVECs were stimulated with ox-LDL (100 ug/ml). The viability of cells was evaluated via an MTT assay and flow cytometry was performed to assess apoptosis. Additionally, the protein and mRNA expression levels of apoptosis regulator Bcl-2 (Bcl-2) and caspase-3 were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. The findings of the present study indicated that icariin prevented injury and apoptosis in HUVECs following ox-LDL treatment, in particular via the regulation of protein and mRNA expression levels of Bcl-2 and caspase-3. PMID- 29532883 TI - LncRNA BC032020 suppresses the survival of human pancreatic ductal adenocarcinoma cells by targeting ZNF451. AB - This study examined the effects of long non-coding RNA (lncRNA) BC032020 on the development of human pancreatic ductal adenocarcinoma (PDAC), and the potential molecular mechanisms responsible for these effects. The expression of BC032020 was assessed in 20 pairs of PDAC tumor tissues and adjacent normal tissues. The overexpression of BC032020 was enforced in the AsPC-1 and PANC-1 cells, and the effects on cell proliferation, cell cycle distribution, cell migration and apoptosis were determined. We also analyzed the functions of zinc finger protein 451 (ZNF451), which shares a gene sequence with two exons of BC032020 and a non coding region with another two exons, in PDAC cells. The AsPC-1 and PANC-1 cells that overexpressed BC032020 were used to establish a subcutaneous tumor xenograft model in order to examine the effects of BC032020 on tumor growth in vivo. The results revealed that the BC032020 levels in the PDAC tumor tissues were lower than those in the adjacent normal tissues, and ZNF451 expression inversely correlated with the BC032020 levels in the PDAC tumor tissues and cell lines. BC032020 overexpression led to a decrease in ZNF451 expression; it also suppressed the proliferation and migration of the AsPC-1 and PANC-1 cells, and induced G1 phase arrest and cell apoptosis. The results of in vivo experiments revealed that BC032020 suppressed tumor growth in a xenograft model by inhibiting ZNF451 expression. Taken together, the findings of this study indicate that BC032020 suppresses the survival of PDAC cells by inhibiting ZNF451 expression. PMID- 29532885 TI - Induction of Th1 chemokine secretion in dermal fibroblasts by vanadium pentoxide. AB - Vanadium is a soft, silvery-grey metal with a number of different oxidation states. The most common commercial form of vanadium is vanadium pentoxide (V2O5). All vanadium compounds are considered toxic. An increase in skin rashes has been observed in certain vanadium workers, including the development of atopic dermatitis. However, to the best of our knowledge, no prior in vivo or in vitro studies have evaluated the effect of vanadium exposure in human dermal fibroblasts. The present study evaluated the effect of V2O5 on proliferation and chemokine secretion in dermal fibroblasts. The results revealed that V2O5 had no significant effect on the viability or proliferation of fibroblasts, however it was able to induce the secretion of T-helper (Th)1 chemokines from dermal fibroblasts, synergistically increasing the effect of important Th1 cytokines, including interferon-gamma and tumor necrosis factor-alpha. Through these processes, V2O5 may lead to the induction and perpetuation of an inflammatory reaction in dermal tissue. The induction and perpetuation of inflammation in the dermis and the variety of involved candidate genes may be at the base of V2O5 induced effects following occupational and environmental exposures. Further studies are necessary to evaluate dermal integrity and manifestations in subjects who are occupationally exposed, or living in polluted areas. PMID- 29532886 TI - The inhibitory role of miR-485-5p in colorectal cancer proliferation and invasion via targeting of CD147. AB - Recently, miR-485-5p was identified as a tumor-suppressing microRNA in some human cancers. However, the expression and biological role of miR-485-5p in colorectal cancer (CRC) remain unclear. Herein, we found that the expression of miR-485-5p in CRC tissues and cell lines was much lower than that in the control, respectively. Moreover, the overexpression of miR-485-5p could inhibit the proliferation and invasion of CRC cell lines in vitro and in vivo. Furthermore, we determined that miR-485-5p could decrease the expression of CD147 by directly targeting CD147 3'UTR. In addition, the expression of CD147 was inversely correlated with the expression of miR-485-5p in CRC tissues. Collectively, our results revealed that miR-485-5p played a pivotal tumor-suppressing role in CRC through downregulation of cancer-associated gene CD147, and may provide a better understanding of the pathogenesis in CRC and a new bio-target for CRC therapy. PMID- 29532887 TI - Juglanin suppresses fibrosis and inflammation response caused by LPS in acute lung injury. AB - Acute lung injury in children is a complication showing devastating disorders linked to fibrosis progression and inflammation response. Fibrosis and inflammation response are two markers for acute lung injury. Juglanin is a natural product mainly isolated from green walnut husks of Juglans mandshurica, which isconsidered as the functional composition among a series of compounds. It exhibited effective role in various diseases by inhibiting inflammation response. In our study, the protective effects and anti-inflammatory activity of juglanin were investigated in mice and lung cells treated by lipopolysaccharide (LPS) to reveal the possible mechanism by which juglanin attenuates acute lung injury. The mice were separated into four groups. The mouse model was established with 15 mg/kg LPS injection. Juglanin dramatically reduced the inflammation of cell infiltration. Compared to mice only treated with LPS, LPS-treated mice in the presence of juglanin developed less lung fibrosis with lower levels of alpha smooth muscle-actin (alpha-SMA), collagen type I, collagen type III, and transforming growth factor-beta1 (TGF-beta1). Additionally, juglanin markedly downregulated inflammatory cytokine secretion and phosphorylated nuclear factor kappaB (NF-kappaB) expression via inhibiting IKKalpha/IkappaBalpha signaling pathway. Our results indicate that juglanin has a protective role in LPS triggered acute lung injury via suppression of fibrosis and inflammation response by NF-kappaB signaling pathways inactivation. Thus, juglanin may be a potential candidate as dietary supplement for acute lung injury for children in future. PMID- 29532888 TI - Anti-inflammatory effect of bee venom in an allergic chronic rhinosinusitis mouse model. AB - Bee venom (BV) has long been used as anti-inflammatory agent in traditional oriental medicine; however, the effect of BV on chronic rhinosinusitis (CRS) is not commonly studied. The aim of the present study was to determine the anti inflammatory effect of BV on an allergic CRS mouse model. An allergic CRS mouse model was established following the administration of ovalbumin with Staphylococcus aureus enterotoxin B (SEB) into the nose. A total of 0.5 or 5 ng/ml of BV were intranasally applied 3 times a week for 8 weeks. Histopathological alterations were observed using hematoxylin and eosin, and Periodic acid Schiff staining. The levels of inflammatory cell infiltration, interleukin (IL)-4, IL-10 and interferon (INF)-gamma in nasal lavage fluid (NLF) were measured. Nuclear factor (NF)-kappaB and activator protein (AP)-1 expressions were also determined by immunohistochemical staining. The group treated with BV had significantly decreased inflammatory cell infiltration and PAS-positive cells. The levels of INF-gamma, and neutrophil and eosinophil counts in NLF were significantly decreased, and the SEB-induced NF-kappaB and AP-1 expressions in mouse nasal mucosa were significantly suppressed by 0.5 and 5 ng/ml BV. Thus, BV exerted significant anti-inflammatory effects in an allergic CRS mouse model and may have potential value for the treatment of CRS. PMID- 29532889 TI - MicroRNA-130a regulates chondrocyte proliferation and alleviates osteoarthritis through PTEN/PI3K/Akt signaling pathway. AB - The function of microRNA-130a in development and progression of osteoarthritis was determined. In osteoarthritis patients, the serum levels of microRNA-130a were decreased, compared with normal group. Overexpression of microRNA-130a increased cell proliferation and decreased apoptosis of chondrocytes, and downregulation of microRNA-130a also decreased cell proliferation and induced apoptosis in chondrocytes. Downregulation of microRNA-130a promoted Bax and caspase-3/9 protein expression, increased inflammation divisors and suppressed the PTEN/PI3K/Akt signaling pathway. PTEN inhibitor, VO-Ohpic trihydrate increased the destructive effect of microRNA-130a on cell proliferation of chondrocytes. PI3K inhibitor, wortmannin also increased the destructive effect of microRNA-130a on osteoarthritis. In conclusion, microRNA-130a is an important regulator of osteoarthritis in chondrocytes through PTEN/PI3K/Akt signaling pathway. PMID- 29532890 TI - Long non-coding RNA TCF7 predicts the progression and facilitates the growth and metastasis of colorectal cancer. AB - Long non-coding RNA (lnc)TCF7 has been reported to promote the self-renewal of human cancer stem cells, and enhance the aggressiveness of human non-small cell lung cancer and hepatocellular carcinoma cells. However, the effect of lncTCF7 on colorectal cancer (CRC) tumorigenesis and progression is currently unclear. In the present study, reverse transcription-quantitative polymerase chain reaction results demonstrated that lncTCF7 expression was higher in CRC tissues compared with adjacent normal tissues and was significantly associated with tumor size, differentiation degree, tumor-node-metastasis grade, lymph node metastasis and invasion depth. In addition, lncTCF7 demonstrated a high sensitivity and specificity for diagnosing CRC, as determined by receiver operating characteristic curve analysis. Furthermore, lncTCF7 silencing in SW-620 and HT29 CRC cell lines inhibited the proliferation, cell cycle, migration and invasion of cells, as determined by Cell Counting Kit-8 assays, propidium iodide (PI) staining and flow cytometry, wound healing assays and Transwell invasion assays, respectively; however, Annexin V/PI double staining and flow cytometry indicated that lncTCF7 silencing did not significantly affect the apoptosis of CRC cells. These results indicate that lncTCF7 may predict the progression, and promote the growth and metastasis, of CRC, and may therefore be a novel diagnostic marker and therapeutic target for CRC treatment. PMID- 29532891 TI - Age-dependent changes in vesicular glutamate transporter 1 and 2 expression in the gerbil hippocampus. AB - Glutamate is a major excitatory neurotransmitter that is stored in vesicles located in the presynaptic terminal. Glutamate is transported into vesicles via the vesicular glutamate transporter (VGLUT). In the present study, the age associated changes of the major VGLUTs, VGLUT1 and VGLUT2, in the hippocampus were investigated, based on immunohistochemistry and western blot analysis at postnatal month 1 (PM1; adolescent), PM6, PM12 (adult group), PM18 and PM24 (the aged groups). VGLUT1 immunoreactivity was primarily detected in the mossy fibers, Schaffer collaterals and stratum lacunosum-moleculare. By contrast, VGLUT2 immunoreactivity was observed in the granule cell layer and the outer molecular layer of the dentate gyrus, stratum pyramidale, Schaffer collaterals and stratum lacunosum-moleculare in the hippocampal CA1-3 regions. VGLUT1 immunoreactivity and protein levels remained constant across all age groups. However, VGLUT2 immunoreactivity and protein levels decreased in the PM3 group when compared with the PM1 group. VGLUT2 immunoreactivity and protein levels were not altered in the PM12 group; however, they increased in the PM18 group. In addition, in the PM18 group, highly immunoreactive VGLUT2 cells were also identified in the stratum radiatum and oriens of the hippocampal CA1 region. In the PM24 group, VGLUT2 immunoreactivity and protein levels were significantly decreased and were the lowest levels observed amongst the different groups. These results suggested that VGLUT1 may be less susceptible to the aging process; however, the increase of VGLUT2 in the non-pyramidal cells in the PM18 group, and the consequent decrease in VGLUT2, may be closely linked to age-associated memory impairment in the hippocampus. PMID- 29532892 TI - Identification of key differentially expressed genes associated with non-small cell lung cancer by bioinformatics analyses. AB - Increasing evidence has indicated that the abnormal expressions of certain genes serve important roles in tumorigenesis, progression and metastasis. The aim of the present study was to explore the key differentially expressed genes (DEGs) between non-small cell lung cancer (NSCLC) and matched normal lung tissues by analyzing 4 different mRNA microarray datasets downloaded from the Gene Expression Omnibus (GEO) database. In improving the reliability of the bioinformatics analysis, the DEGs in each dataset that met the cut-off criteria (adjust P-value <0.05 and |log2fold-change (FC)|>1) were intersected with each other, from which 195 were identified (consisting of 57 upregulated and 138 downregulated DEGs). The GO analysis results revealed that the upregulated DEGs were significantly enriched in various biological processes (BP), including cell cycle, mitosis and cell proliferation while the downregulated DEGs were significantly enriched in angiogenesis and response to drug and cell adhesion. The hub genes, including CCNB1, CCNA2, CEP55, PBK and HMMR, were identified based on the protein-protein interaction (PPI) network. The Kaplan-Meier survival analysis indicated that the high expression level of each of these hub genes correlates with poorer overall survival in all patients with NSCLC, which indicates that they may serve important roles in the progression of NSCLC. In conclusion, the DEGs and hub genes identified in the present study may contribute to the comprehensive understanding of the molecular mechanisms of NSCLC and may be used as diagnostic and prognostic biomarkers as well as molecular targets for the treatment of NSCLC. PMID- 29532893 TI - Tree shrew neural stem cell transplantation promotes functional recovery of tree shrews with a hemi-sectioned spinal cord injury by upregulating nerve growth factor expression. AB - The aim of the present study was to determine the effect of implanted neural stem cells (NSCs) on the functional recovery of tree shrews (TSs) subjected to hemi sectioned spinal cord injury (hSCI), and to investigate the possible mechanism involved. NSCs (passage 2), derived from the hippocampus of TSs (embryonic day 20), were labeled with Hoechst 33342 and transplanted intraspinally into the hSC of TSs at thoracic level 10 in the acute (immediately after injury) and chronic (day 9 post-injury) stages. The Basso-Beattie-Bresnahan (BBB) score was recorded from days 1 to 16 post-injury, and the survival, migration, differentiation and neurotrophic factor (NTF) expression in vivo were detected. In vitro and in vivo, the expanded NSCs were able to differentiate into neurons and astrocytes, and secreted a variety of NTFs, including ciliary NTF, transforming growth factor beta1, glial cell line-derived NTF, nerve growth factor (NGF), brain-derived NTF and insulin-like growth factor. Following transplantation, the BBB score in the TSs with chronic-stage transplantation exhibited a statistically significant increase, while there was no significant difference in the acute group, compared with the control group. This corresponded with the marked upregulation of NGF indicated by reverse transcription-quantitative polymerase chain reaction. In conclusion, the transplantation of NSCs into the hSC in the chronic phase, but not the acute stage, of hSCI in non-human primate TSs is effective and associated with upregulated NGF expression. These findings may provide novel strategies for the treatment of SCI in clinical patients. PMID- 29532894 TI - Subcellular localization of aquaporin 3 in prostate cancer is regulated by RalA. AB - We previously found that in normal epithelia of the prostate, localization of AQP3 is limited to the cell membranes; however, the expression of AQP3 protein in cancer epithelia is distributed to the plasma. Yet, the detailed mechanism remains unclear. In the present study, PC-3 cell derivatives with stable knockdown of RAS like proto-oncogene A (RalA) and overexpression of E-cadherin were established. We found that overexpression of E-cadherin and knockdown of RaLA resulted in an increase in AQP3 in prostate cancer cell plasma membranes. In order to investigate the functions caused by of the AQP3 redistribution in prostate cancer cells, the growth function of AQP3 redistribution was detected with clonogenic, MTT and MTS assays. In regards to the effect on apoptosis, flow cytometric analysis and DNA Ladder TUNEL assay were utilized. The results showed that AQP3 redistribution in PC-3 cells significantly inhibited the proliferation of cells and enhanced cell apoptosis compared with these parameters in the control. Wound healing assay and Matrigel assays determined that knockout of RalA inhibited the motility and invasion capability of PC-3 cells. To investigate the molecular mechanism involved in AQP3 redistribution in PC-3 cells, the level of cAMP in PC-3 cells was examined, and the results showed that AQP3 distribution was regulated through cAMP/PKA/RalA signal pathways. In conclusion, these studies suggest a novel function of AQP3, and provide a creative view for RalA-directed therapies. PMID- 29532895 TI - Benzoxazole derivatives suppress lipopolysaccharide-induced mast cell activation. AB - Mast cells are central regulators of allergic inflammation that function by releasing various proallergic inflammatory mediators, including histamine, eicosanoids and proinflammatory cytokines. Occasionally, bacterial infections may initiate or worsen allergic inflammation. A number of studies have indicated that activation of lipoxygenase in mast cells positive regulates allergic inflammatory responses by generating leukotrienes and proinflammatory cytokines. In the present study, the effects of benzoxazole derivatives on the lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines, production of histamine and surface expression of co-stimulatory molecules on bone marrow-derived mast cells (BMMCs) were studied. The benzoxazole derivatives significantly reduced the expression of interleukin (IL)-1beta, IL-6, IL-13, tumor necrosis factor-alpha, perilipin (PLIN) 2, and PLIN3 in BMMCs treated with LPS. Furthermore, histamine production was suppressed in BMMCs treated with LPS, or treated with phorbol-12 myristate-13-acetate/ionomycin. Benzoxazole derivatives marginally affected the surface expression of cluster of differentiation (CD)80 and CD86 on BMMCs in the presence of LPS, although LPS alone did not increase the expression of those proteins. Therefore, benzoxazole derivatives inhibited the secretion of proinflammatory cytokines in mast cells and may be potential candidate anti allergic agents to suppress mast cell activation. PMID- 29532896 TI - Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress. AB - Pathogenic fungi, including Candida glabrata, develop strategies to grow and survive both in vitro and in vivo under azole stress. However, the mechanisms by which yeast cells counteract the inhibitory effects of azoles are not completely understood. In the current study, it was demonstrated that the expression of the ergosterol biosynthetic genes ERG2, ERG3, ERG4, ERG10, and ERG11 was significantly upregulated in C. glabrata following fluconazole treatment. Inhibiting ergosterol biosynthesis using fluconazole also increased the expression of the sterol influx transporter AUS1 and the sterol metabolism regulators SUT1 and UPC2 in fungal cells. The microarray study quantified 35 genes with elevated mRNA levels, including AUS1, TIR3, UPC2, and 8 ERG genes, in a C. glabrata mutant strain lacking ERG1, indicating that sterol importing activity is increased to compensate for defective sterol biosynthesis in cells. Bioinformatic analyses further revealed that those differentially expressed genes were involved in multiple cellular processes and biological functions, such as sterol biosynthesis, lipid localization, and sterol transport. Finally, to assess whether sterol uptake affects yeast susceptibility to azoles, we generated a C. glabrata aus1? mutant strain. It was shown that loss of Aus1p in C. glabrata sensitized the pathogen to azoles and enhanced the efficacy of drug exposure under low oxygen tension. In contrast, the presence of exogenous cholesterol or ergosterol in medium rendered the C. glabrata AUS1 wild-type strain highly resistant to fluconazole and voriconazole, suggesting that the sterol importing mechanism is augmented when ergosterol biosynthesis is suppressed in the cell, thus allowing C. glabrata to survive under azole pressure. On the basis of these results, it was concluded that sterol uptake and sterol biosynthesis may act coordinately and collaboratively to sustain growth and to mediate antifungal resistance in C. glabrata through dynamic gene expression in response to azole stress and environmental challenges. PMID- 29532897 TI - Identification of the key genes associated with neuropathic pain. AB - Neuropathic pain is a chronic pain state associated with multiple etiologies that results in considerable social and economic burden. The identification of key genes associated with neuropathic pain is important for the development of novel therapies. Therefore, the present study downloaded the gene expression profile GSE15041 from the Gene Expression Omnibus database. The unverified gene chip was removed and the microarray data was normalized following quality control. The limma package in R was used to screen the differentially expressed genes (DEGs), followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, a protein-protein interaction (PPI) network based on the identified DEGs was constructed to select hub proteins, and reverse transcription-quantitative polymerase chain reaction was performed to detect the expression of these proteins in a mouse model of neuropathic pain. In total, 86 common DEGs were identified. DEGs were significantly enriched in extracellular space and KEGG pathway enrichment analysis demonstrated that the DEGs were significantly enriched in inflammatory diseases and the mitogen activated protein kinase signaling pathway. The PPI network consisted of 27 nodes (proteins) and 47 PPI edges (interactions). Interleukin (IL)-6, transcription factor AP-1 (c-Jun) and urikinase-type plasminogen activator (Plau) were identified as hub proteins and key genes in neuropathic pain. The mRNA expression of these hub proteins was significantly increased in the neuropathic pain model, compared with the sham group. IL-6, c-Jun, and Plau may be involved in development of neuropathic pain and further research investigating the exact role of these key genes is required. PMID- 29532899 TI - Matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms promote increase and remodeling of the collagen III and V in posterior tibial tendinopathy. AB - Posterior tibial tendinopathy (PTT) can lead to acquired flatfoot in adults. Many patients develop PTT without any identifiable risk factors. Molecular changes in extracellular matrix (ECM) and matrix metalloproteinase (MMP) polymorphism may influence the risk of developing PTT. We aim to investigate the association between matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms with changes in collagen I, III and V in PTT. A case-control study with 22 patients and 5 controls was performed. The MMP-1 (2G/2G) and MMP-8 (T/T) genotypes were determined by PCR-restriction fragment length polymorphism. Tendon specimens were evaluated by a histologic semiquantitative score, immunofluorescence and histomorphometry for collagen I, III and V. Tendon specimens from PTT demonstrated marked distortion of the architecture with necrosis, large basophilic areas with disruption of the normal linear orientation of collagen bundles, infiltration of inflammatory cells, dystrophic calcification and ossification. Under immunofluorescence, PTT tendon specimens showed weak green fluorescence and diffuse distribution of collagen I fibers, but strong fluorescence of collagen III and V. The collagen I fibers were significantly decreased whereas an increase of collagen III and V were found in PTT compared to control groups. In addition, PTT group presented a significant association with MMP-1 and MMP-8 gene polymorphisms. Patients with PTT matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms presented an increase of the collagen III and V ratio, suggesting that the higher proportion in degenerated tendons could contribute to a decrease in the mechanical resistance of the tissue. Still, functional and association studies are needed to elucidate evident roles of MMPs in PTT. PMID- 29532898 TI - Identification of differentially expressed genes and biological pathways in bladder cancer. AB - The purpose of the present study was to identify key genes and investigate the related molecular mechanisms of bladder cancer (BC) progression. From the Gene Expression Omnibus database, the gene expression dataset GSE7476 was downloaded, which contained 43 BC samples and 12 normal bladder tissues. GSE7476 was analyzed to screen the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for the DEGs using the DAVID database, and a protein-protein interaction (PPI) network was then constructed using Cytoscape software. The results of the GO analysis showed that the upregulated DEGs were significantly enriched in cell division, nucleoplasm and protein binding, while the downregulated DEGs were significantly enriched in 'extracellular matrix organization', 'proteinaceous extracellular matrix' and 'heparin binding'. The results of the KEGG pathway analysis showed that the upregulated DEGs were significantly enriched in the 'cell cycle', whereas the downregulated DEGs were significantly enriched in 'complement and coagulation cascades'. JUN, cyclin-dependent kinase 1, FOS, PCNA, TOP2A, CCND1 and CDH1 were found to be hub genes in the PPI network. Sub-networks revealed that these gene were enriched in significant pathways, including the 'cell cycle' signaling pathway and 'PI3K-Akt signaling pathway'. In summary, the present study identified DEGs and key target genes in the progression of BC, providing potential molecular targets and diagnostic biomarkers for the treatment of BC. PMID- 29532900 TI - Functional expression of aryl-alcohol oxidase in Saccharomyces cerevisiae and Pichia pastoris by directed evolution. AB - Aryl-alcohol oxidase (AAO) plays a fundamental role in the fungal ligninolytic secretome, acting as a supplier of H2 O2 . Despite its highly selective mechanism of action, the presence of this flavooxidase in different biotechnological settings has hitherto been hampered by the lack of appropriate heterologous expression systems. We recently described the functional expression of the AAO from Pleurotus eryngii in Saccharomyces cerevisiae by fusing a chimeric signal peptide (prealphaproK) and applying structure-guided evolution. Here, we have obtained an AAO secretion variant that is readily expressed in S. cerevisiae and overproduced in Pichia pastoris. First, the functional expression of AAO in S. cerevisiae was enhanced through the in vivo shuffling of a panel of secretion variants, followed by the focused evolution of the prealphaproK peptide. The outcome of this evolutionary campaign-an expression variant that accumulated 4 mutations in the chimeric signal peptide, plus two mutations in the mature protein- showed 350-fold improved secretion (4.5 mg/L) and was stable. This secretion mutant was cloned into P. pastoris and fermented in a fed-batch bioreactor to enhance production to 25 mg/L. While both recombinant AAO from S. cerevisiae and P. pastoris were subjected to the same N-terminal processing and had a similar pH activity profile, they differed in their kinetic parameters and thermostability. The strong glycosylation observed in the evolved AAO from S. cerevisiae underpinned this effect, since when the mutant was produced in the glycosylation-deficient S. cerevisiae strain Deltakre2, its kinetic parameters and thermostability were comparable to its poorly glycosylated P. pastoris recombinant counterpart. PMID- 29532901 TI - Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles. AB - Controlling the charge profile of therapeutic protein is a critical challenge in the current quality-by-design (QbD) paradigm, throughout all phases of biologics process development (PD): cell line development, upstream cell culture, recovery process, downstream purification, and analytical characterization. Charge variant profiles may influence efficacy and/or lead to unintended side-effects. Thus, maintaining a consistent charge profile is of tremendous importance, and increasingly, researchers have focused efforts toward developing strategies to mitigate variability during cell culture and to improve separation and detection of charge variants. Current understanding of factors affecting charge variant formation during manufacturing remains inadequate, and sometimes, even substantial commitment of resources may still not fully achieve the desired or consistent profiles. As such, this review attempts to provide a comprehensive resource for the biologics community by summarizing the impact of charge variants and CQA management, analytical methods for charge variant detection, as well as strategies in downstream and upstream PD for controlling charge variant profiles. PMID- 29532902 TI - Development of N-acetylneuraminic acid responsive biosensors based on the transcriptional regulator NanR. AB - Transcriptional biosensors have various applications in metabolic engineering, including dynamic pathway control and high-throughput screening of combinatorial strain libraries. Previously, various biosensors have been created from naturally occurring transcription factors (TFs), largely relying on native sequences without the possibility to modularly optimize their response curve. The lack of design and engineering techniques thus greatly hinders the development of custom biosensors. In view of the intended application this is detrimental. In contrast, a bottom-up approach to design tailor-made biosensors was pursued here. Novel biosensors were created that respond to N-acetylneuraminic acid (Neu5Ac), an important sugar moiety with various biological functions, by employing native and engineered promoters that interact with the TF NanR. This bottom-up approach, whereby various tuned modules, e.g., the ribosome binding site (RBS) controlling NanR translation can be combined, enabled the reliable engineering of various response curve characteristics. The latter was validated by testing these biosensors in combination with various Neu5Ac-producing pathways, which allowed to produce up to 1.4 +/- 0.4 g/L extracellular Neu5Ac. In this way, the repertoire of biosensors was expanded with seven novel functional Neu5Ac responsive biosensors. PMID- 29532903 TI - Autoantibodies to thrombopoietin and the thrombopoietin receptor in patients with immune thrombocytopenia. AB - Autoantibodies to thrombopoietin (TPO, also termed THPO) or the TPO receptor (cMpl, also termed MPL) could play a pathological role in immune thrombocytopenia (ITP). In this study, we tested for autoantibodies against TPO, cMpl, or the TPO/cMpl complex in ITP and other thrombocytopenic disorders. Using an inhibition step with excess TPO in fluid-phase to improve binding specificity, the prevalence of anti-TPO autoantibodies was: active ITP: 9/32 (28%); remission ITP: 0/14 (0%); non-immune thrombocytopenias: 1/10 (10%); and healthy controls: 1/11 (9%). Similarly, using an inhibition step with excess cMpl, the prevalence of specific anti-cMpl autoantibodies was: active ITP: 7/32 (22%); remission ITP: 1/14 (7%); non-immune thrombocytopenias: 3/10 (30%); and healthy controls: 0/11 (0%). Two active ITP patients had autoantibodies against the TPO/cMpl complex, but not against TPO or cMpl alone. Anti-TPO or anti-cMpl autoantibodies were found in 44% of ITP patients, and in 40% of patients with other thrombocytopenic disorders. These autoantibodies did not correlate with ITP disease severity or number of ITP treatments received; however, in this cohort, 3 patients failed to respond to TPO receptor agonist medications, and of those, 2 had anti-TPO autoantibodies. This suggests that anti-TPO and anti-cMpl autoantibodies are associated with thrombocytopenia, and may be clinically relevant in a subset of ITP patients. PMID- 29532904 TI - What is the standard of care for primary mediastinal b-cell lymphoma; R-CHOP or DA-EPOCH-R? PMID- 29532905 TI - Twenty-year experience of paediatric thyroid surgery using intraoperative nerve monitoring. AB - BACKGROUND: There are few data on intermittent and continuous intraoperative nerve monitoring (IONM) during thyroidectomy in children. METHODS: All children aged 18 years or younger who had standard thyroid operations using intermittent or continuous IONM between January 1998 and December 2016 were included in the study. The impact of age and type of IONM on basal amplitude, latency and complications after thyroidectomy were assessed. RESULTS: A total of 504 children were included in the study. With continuous IONM, median basal amplitude and latency increased significantly with age, more on the left side (from 199 to 870 MUV, and from 3.88 to 5.75 ms) than on the right (from 340 to 778 MUV, and from 2.63 to 3.50 ms). Compared with intermittent IONM with needle electrode, continuous IONM with tube electrode resulted in an increase in median basal amplitude in children aged 13-18 years on both sides (from 675 to 778 MUV on the right and from 450 to 870 MUV on the left), and a decrease in median latency in all children older than 3 years: in children aged 4-6 years, from 4.20 to 3.00 ms on the right and from 6.10 to 4.63 ms on the left; in children aged 7-12 years, from 4.60 to 3.50 ms and from 6.00 to 5.25 ms respectively; and in children aged 13-18 years, from 4.60 to 3.50 ms and from 6.40 to 5.75 ms. Overall, wound infection, but not bleeding/haematoma or vocal fold palsy, affected younger children more: 3 per cent of children aged 3 years or less; 2 per cent of children aged 4-6 years; and 0 per cent of children aged over 6 years (P = 0.031). With continuous IONM, no wound infection, bleeding/haematoma or permanent vocal fold palsy was noted in any age group. CONCLUSION: Continuous IONM measures nerve electrophysiology more accurately than intermittent IONM during thyroidectomy in children. PMID- 29532906 TI - Detection of anti-platelet antibodies in immune thrombocytopenia by flow cytometry. PMID- 29532907 TI - The Effect of Hydraulic Gradient and Pattern of Conduit Systems on Tracing Tests: Bench-Scale Modeling. AB - Tracer breakthrough curves provide valuable information about the traced media, especially in inherently heterogeneous karst aquifers. In order to study the effect of variations in hydraulic gradient and conduit systems on breakthrough curves, a bench scale karst model was constructed. The bench scale karst model contains both matrix and a conduit. Eight tracing tests were conducted under a wide range of hydraulic gradients from 1 to greater than 5 for branchwork and network-conduit systems. Sampling points at varying distances from the injection point were utilized. Results demonstrate that mean tracer velocities, tracer mass recovery and linear rising slope of the breakthrough curves were directly controlled by hydraulic gradient. As hydraulic gradient increased, both one half the time for peak concentration and one fifth the time for peak concentration decreased. The results demonstrate the variations in one half the time for peak concentration and one fifth the time for peak concentration of the descending limb for different sampling points under differing hydraulic gradients are mainly controlled by the interactions of advection with dispersion. The results are discussed from three perspectives: different conduit systems, different hydraulic gradient conditions, and different sampling points. The research confirmed the undeniable role of hydrogeological setting (i.e., hydraulic gradient and conduit system) on the shape of the breakthrough curve. The extracted parameters (mobile fluid velocity, tracer-mass recovery, linear rising limb, one half the time for peak concentration, and one fifth the time for peak concentration) allow for differentiating hydrogeological settings and enhance interpretations the tracing tests in karst aquifers. PMID- 29532908 TI - Survival following liver transplantation for liver-only colorectal metastases compared with hepatocellular carcinoma. AB - BACKGROUND: Liver transplantation is considered the standard of care for patients with hepatocellular carcinoma (HCC) within the Milan criteria. Liver transplantation in patients with unresectable colorectal cancer with liver-only disease has been shown to be associated with a 5-year overall survival rate of 56 per cent, compared with 9 per cent in patients receiving standard palliative chemotherapy. The aim of the present study was to compare disease-free (DFS) and overall (OS) survival after liver transplantation in patients with HCC and those with colorectal metastases. METHODS: Data were collected from the SEcondary CAncer (SECA) study database and an institutional (national) database of patients undergoing liver transplantation for HCC; all liver-transplanted patients were included. Patients with colorectal metastases treated by liver transplantation were divided into high- and low-risk groups for mortality based on carcinoembryonic antigen levels, response to chemotherapy, largest lesion at time of transplantation and time from primary surgery to transplantation. RESULTS: Patients with colorectal metastases had a median of 8 lesions, compared with 1 in patients with HCC within the Milan criteria. DFS was shorter in both the high risk and the low-risk colorectal cancer groups compared with that in patients with HCC. The 5-year OS rate in the low-risk colorectal cancer group was 75 per cent, compared with 76 per cent in patients with HCC within the Milan criteria. The 5-year OS rate in patients with HCC beyond the Milan criteria was 56 per cent. CONCLUSION: The low-risk group of patients with colorectal cancer and unresectable liver-only disease had a 5-year OS rate following liver transplantation similar to that of patients with HCC with lesions within the Milan criteria. PMID- 29532909 TI - The relationship between negative symptoms and depression in schizophrenia: a systematic review. AB - OBJECTIVE: To provide an update on the evidence base for the nature of the relationship between negative symptoms and depressive features in people with schizophrenia, and propose new models that reflect their complex relationship. METHOD: A systematic review following PRISMA guidelines. A total of 2210 articles were identified from EMBASE, PsychInfo and MEDLINE, and further two articles were hand-searched from references. Twenty-seven met inclusion criteria and were included in the review. RESULTS: In schizophrenia, primary evidence suggests symptoms of low mood, suicidal ideation and pessimism have more specificity for depression whereas alogia and blunted affect may have more specificity as negative symptoms. Anhedonia, anergia and avolition may be common to both. CONCLUSION: It may be possible to further distinguish depressive features from negative symptoms in schizophrenia when detailed phenomenology is considered. However, in a proposed dimensional model, these two domains continue to share certain phenomena, highlighting their close relationship. PMID- 29532910 TI - Stochastic Modeling of Groundwater Extractions over a Data-Sparse Region of Australia. AB - Setting limit on groundwater extractions is important to ensure sustainable groundwater management. Lack of extraction data can affect interpretations of historical pressure changes, predictions of future impacts, accuracy of groundwater model calibration, and identification of sustainable management options. Yet, many groundwater extractions are unmetered. Therefore, there is a need for models that estimate extraction rates and quantify model outputs uncertainties arising due to a lack of data. This paper develops such a model within the Generalized Linear Modeling (GLM) framework, using a case study of stock and domestic (SD) extractions in the Surat Cumulative Management Area, a predominantly cattle farming region in eastern Australia. Various types of extraction observations were used, ranging from metering to analytically-derived estimates. GLMs were developed and applied to estimate the property-level extraction amounts, where observation types were weighted by perceived relative accuracy, and well usage status. The primary variables found to affect property level extraction rates were: yearly average temperature and rainfall, pasture, property area, and number of active wells; while variables most affecting well usage were well water electrical conductivity, spatial coordinates, and well age. Results were compared with analytical estimates of property-level extraction, illustrating uncertainties and potential biases across 20 hydrogeological units. Spatial patterns of mean extraction rates (and standard deviations) are presented. It is concluded that GLMs are well suited to the problem of extraction rate estimation and uncertainty analysis, and are ideal when model verification is supported by measurement of a random sample of properties. PMID- 29532911 TI - A Practical Modeling Framework for Non-Fickian Transport and Multi-Species Sequential First-Order Reaction. AB - Many studies indicate that small-scale heterogeneity and/or mobile-immobile mass exchange produce transient non-Fickian plume behavior that is not well captured by the use of the standard, deterministic advection-dispersion equation (ADE). An extended ADE modeling framework is presented here that is based on continuous time random walk theory. It can be used to characterize non-Fickian transport coupled with simultaneous sequential first-order reactions (e.g., biodegradation or radioactive decay) for multiple degrading contaminants such as chlorinated solvents, royal demolition explosive, pesticides, and radionuclides. To demonstrate this modeling framework, new transient analytical solutions are derived and are inverted in Laplace space. Closed-form, steady-state, multi species analytical solutions are also derived for non-Fickian transport in highly heterogeneous aquifers with linear sorption-desorption and matrix diffusion for use in spreadsheets. The solutions are general enough to allow different degradation rates for the mobile and immobile zones. The transient solutions for multi-species transport are applied to examine the effects of source remediation on the natural attenuation of downgradient plumes of both parent and degradation products in highly heterogeneous aquifers. Results for representative settings show that the use of the standard, deterministic ADE can over-estimate cleanup rates and under-predict the cleanup timeframe in comparison to the extended ADE analytical model. The modeling framework and calculations introduced here are also applied for a 30 year groundwater cleanup program at a site in Palm Bay, Florida. The simulated plume concentrations using the extended ADE exhibited agreement with observed long concentration tails of trichloroethene, cis 1,2 DCE, and VC that remained above cleanup goals. PMID- 29532912 TI - Prevalence and survival of smouldering Waldenstrom macroglobulinaemia in the United States. PMID- 29532913 TI - Low levels of von Willebrand markers associate with high serum IgM levels and improve with response to therapy, in patients with Waldenstrom macroglobulinaemia. PMID- 29532914 TI - Clonality and clonal evolution analysis of paediatric ALL based on B-cell receptor/T-cell receptor rearrangement. PMID- 29532915 TI - Patterns of Seismicity Associated with USGS Identified Areas of Potentially Induced Seismicity. AB - A systematic review across U.S. Geological Survey (USGS) identified potentially induced seismic locations was conducted to discover seismic distance patterns and trends over time away from injection disposal wells. Previous research indicates a 10 km (6 miles) average where the majority of induced seismicity is expected to occur within individual locations, with some areas reporting a larger radius of 35 km (22 miles) to over 70 km (43 miles). This research analyzed earthquake occurrences within nine USGS locations where specified wells were identified as contributors to induced seismicity to determine distance patterns from disposal wells or outward seismic migration over time using established principles of hydrogeology. Results indicate a radius of 31.6 km (20 miles) where 90% of felt earthquakes occur among locations, with the closest proximal felt seismic events, on average, occurring 3 km (1.9 miles) away from injection disposal wells. The results of this research found distance trends across multiple locations of potentially induced seismicity. PMID- 29532916 TI - When motor unit expansion in ageing muscle fails, atrophy ensues. PMID- 29532917 TI - The Test of Infant Motor Performance at 3 months predicts language, cognitive, and motor outcomes in infants born preterm at 2 years of age. AB - AIM: To determine the relationship between the Test of Infant Motor Performance (TIMP) at 3 months and cognitive, language, and motor outcomes on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 2 years of age in high-risk infants born preterm. METHOD: One hundred and six infants (47 females, 59 males) born at earlier than 31 weeks gestational age were prospectively tested with the TIMP at 10 to 15 weeks after term age and were assessed again with the Bayley-III at 2 years corrected age. Sensitivity and specificity were calculated for various cut points of the TIMP z-score and Bayley III composite scores of no more than 85. RESULTS: The TIMP z-scores at 10 to 15 weeks of age were significantly associated with all three subscales on the Bayley III at 2 years of age (p<0.001). Using a TIMP z-score cutoff of -0.5, specificity was relatively high for cognitive (87%), language (88%), and motor (89%) outcomes, but sensitivity was low (cognitive 41%, language 49%, motor 57%). INTERPRETATION: This study demonstrates that the TIMP is related to cognitive, language, and motor outcomes on the Bayley-III at 2 years of age in high-risk infants born preterm. WHAT THIS PAPER ADDS: The Test of Infant Motor Performance (TIMP) predicts Bayley Scales of Infant and Toddler Development, Third Edition outcomes at 2 years of age. The TIMP is relatively good at discriminating between children who will and will not have typical development. PMID- 29532918 TI - Low dose PD-1 inhibition in relapsed refractory Hodgkin lymphoma after allogeneic stem cell transplant with concomitant active GVHD. PMID- 29532919 TI - Impact of novel therapies for mantle cell lymphoma in the real world setting: a report from the UK's Haematological Malignancy Research Network (HMRN). AB - The treatment landscape for mantle cell lymphoma (MCL) has changed dramatically in recent years, with findings from clinical trials reporting improvements in survival. Data on the general patient population are, however, sparse; and it is unclear whether the effects observed in clinical trials have translated into the real-world setting. To investigate this, we examined first-line and relapsed/refractory (RR) disease management in 335 MCL patients diagnosed between 2004 and 2015 in an established population-based patient cohort, along with data on demographic, diagnostic and prognostic factors. Marked treatment and survival changes were observed; first-line rituximab immunotherapy, for example, increased from 32% to 86% over the 11-year period, and median survival increased from 2.0 years among those first treated in 2004-2011 to 3.5 years among those treated in 2012-2015. Outcomes for RR disease also improved, from 8 months in 2004-2011 to 16.8 months in 2012-2015, coinciding with the introduction of agents, such as bendamustine and ibrutinib. Encouragingly, improvements were seen across all ages; 1-year overall survival among patients over 70 years treated for RR disease almost doubled. Our analyses underscore the importance of monitoring the impact of treatment changes in the real-world setting. PMID- 29532920 TI - Adaptation in plant genomes: Bigger is different. PMID- 29532921 TI - Heterostyly promotes compatible pollination in buckwheats: Comparisons of intraflower, intraplant, and interplant pollen flow in distylous and homostylous Fagopyrum. AB - PREMISE OF THE STUDY: Heterostyly, the reciprocal positioning of stigmas and anthers in different floral morphs, has long been thought to promote intermorph pollination. However, extensive intramorph pollination occurs commonly in heterostylous species, leading to recurrent questions about the functional and evolutionary significance of heterostyly. METHODS: To identify the sources of stigmatic pollen (autogamous [intraflower], geitonogamous [intraplant], vs. interplant), we emasculated either one flower or entire plants in experimental populations of the two closely related buckwheat species, distylous Fagopyrum esculentum and homostylous F. tataricum. Differences in pollen size allowed unambiguous identification of pollen on stigmas. RESULTS: Only 2.4% of F. tataricum pollen and 1.5% of F. esculentum pollen arrived successfully on compatible stigmas of other plants. In the former (homostylous) species, 71.3% of the pollen load on stigmas was autogamous, 10.8% was geitonogamous, and 17.9% was interplant. In the latter (distylous) species, 37.45% of the pollen on stigmas was autogamous, 13.8% was geitonogamous, 17.0% was intramorph, and 31.75% was intermorph. The amount of incompatible pollen arriving on stigmas was greatly decreased by both one-flower and whole-plant emasculations, and thus, the proportion of compatible pollen deposited increased with one-flower emasculation and increased even more with whole-plant emasculation. CONCLUSIONS: Our quantification of pollen-donor sources in these two species indicated that heterostyly in Fagopyrum esculentum provided a nearly 2-fold fitness advantage (in terms of compatible pollination) over expected (random) pollen transfers between morphs. Because of reduced herkogamy, the homostylous F. tataricum was highly autogamous. PMID- 29532922 TI - Carbon dynamics in the deciduous broadleaf tree Erman's birch (Betula ermanii) at the subalpine treeline on Changbai Mountain, Northeast China. AB - PREMISE OF THE STUDY: The growth limitation hypothesis (GLH) and carbon limitation hypothesis (CLH) are two dominant explanations for treeline formation. The GLH proposes that low temperature drives the treeline through constraining C sinks more than C sources, and it predicts that non-structural carbohydrate (NSC) levels are static or increase with elevation. Although the GLH has received strong support globally for evergreen treelines, there is still no consensus for deciduous treelines, which experience great asynchrony between supply and demand throughout the year. METHODS: We investigated growth and the growing-season C dynamics in a common deciduous species, Erman's birch (Betula ermanii), along an elevational gradient from the closed forest to the treeline on Changbai Mountain, Northeast China. Samples were collected from developing organs (leaves and twigs) and main storage organs (stems and roots) for NSC analysis. KEY RESULTS: Tree growth decreased with increasing elevation, and NSC concentrations differed significantly among elevations, organs, and sampling times. In particular, NSC levels varied slightly during the growing season in leaves, peaked in the middle of the growing season in twigs and stems, and increased continuously throughout the growing season in roots. NSCs also tended to increase or vary slightly in developing organs but decreased significantly in mature organs with increasing elevation. CONCLUSIONS: The decrease in NSCs with elevation in main storage organs indicates support for the CLH, while the increasing or static trends in new developing organs indicate support for the GLH. Our results suggest that the growth limitation theory may be less applicable to deciduous species' growth than to that of evergreen species. PMID- 29532923 TI - Total duplication of the small single copy region in the angiosperm plastome: Rearrangement and inverted repeat instability in Asarum. AB - PREMISE OF THE STUDY: As more plastomes are assembled, it is evident that rearrangements, losses, intergenic spacer expansion and contraction, and syntenic breaks within otherwise functioning plastids are more common than was thought previously, and such changes have developed independently in disparate lineages. However, to date, the magnoliids remain characterized by their highly conserved plastid genomes (plastomes). METHODS: Illumina HiSeq and MiSeq platforms were used to sequence the plastomes of Saruma henryi and those of representative species from each of the six taxonomic sections of Asarum. Sequenced plastomes were compared in a phylogenetic context provided by maximum likelihood and parsimony inferences made using an additional 18 publicly available plastomes from early-diverging angiosperm lineages. KEY RESULTS: In contrast to previously published magnoliid plastomes and the newly sequenced Saruma henryi plastome published here, Asarum plastomes have undergone extensive disruption and contain extremely lengthy AT-repeat regions. The entirety of the small single copy region (SSC) of A. canadense and A. sieboldii var. sieboldii has been incorporated into the inverted repeat regions (IR), and the SSC of A. delavayi is only 14 bp long. All sampled Asarum plastomes share an inversion of a large portion of the large single copy region (LSC) such that trnE-UUC is adjacent to the LSC-IR boundary. CONCLUSIONS: Plastome divergence in Asarum appears to be consistent with trends seen in highly rearranged plastomes of the monocots and eudicots. We propose that plastome instability in Asarum is due to repetitive motifs that serve as recombinatory substrates and reduce genome stability. PMID- 29532925 TI - Herbarium specimens show patterns of fruiting phenology in native and invasive plant species across New England. AB - PREMISE OF THE STUDY: Patterns of fruiting phenology in temperate ecosystems are poorly understood, despite the ecological importance of fruiting for animal nutrition and seed dispersal. Herbarium specimens represent an under-utilized resource for investigating geographical and climatic factors affecting fruiting times within species, patterns in fruiting times among species, and differences between native and non-native invasive species. METHODS: We examined over 15,000 herbarium specimens, collected and housed across New England, and found 3159 specimens with ripe fruits, collected from 1849-2013. We examined patterns in fruiting phenology among 37 native and 18 invasive woody plant species common to New England. We compared fruiting dates between native and invasive species, and analyzed how fruiting phenology varies with temperature, space, and time. KEY RESULTS: Spring temperature and year explained a small but significant amount of the variation in fruiting dates. Accounting for the moderate phylogenetic signal in fruiting phenology, invasive species fruited 26 days later on average than native species, with significantly greater standard deviations. CONCLUSIONS: Herbarium specimens can be used to detect patterns in fruiting times among species. However, the amount of intraspecific variation in fruiting times explained by temporal, geographic, and climatic predictors is small, due to a combination of low temporal resolution of fruiting specimens and the protracted nature of fruiting. Later fruiting times in invasive species, combined with delays in autumn bird migrations in New England, may increase the likelihood that migratory birds will consume and disperse invasive seeds in New England later into the year. PMID- 29532926 TI - A new commelinid monocot seed fossil from the early Eocene previously identified as Solanaceae. AB - PREMISE OF THE STUDY: Fossils provide minimum age estimates for extant lineages. Here we critically evaluate Cantisolanum daturoides Reid & Chandler and two other early putative seed fossils of Solanaceae, an economically important plant family in the Asteridae. METHODS: Three earliest seed fossil taxa of Solanaceae from the London Clay Formation (Cantisolanum daturoides) and the Poole and Branksome Sand Formations (Solanum arnense Chandler and Solanispermum reniforme Chandler) were studied using x-ray microcomputed tomography (MCT) and scanning electron microscopy (SEM). KEY RESULTS: The MCT scans of Cantisolanum daturoides revealed a high level of pyrite preservation at the cellular level. Cantisolanum daturoides can be clearly excluded from Solanaceae and has more affinities to the commelinid monocots based on a straight longitudinal axis, a prominent single layer of relatively thin-walled cells in the testa, and a clearly differentiated micropyle surrounded by radially elongated and inwardly curved testal cells. While the MCT scans show no internal preservation in Solanum arnense and Solanispermum reniforme, SEM images show the presence of several characteristics that allow the placement of these taxa at the stem node of Solanaceae. CONCLUSIONS: Cantisolanum daturoides is likely a member of commelinid monocots and not Solanaceae as previously suggested. The earliest fossil record of Solanaceae is revised to consist of fruit fossil with inflated calyces from the early Eocene of Patagonia (52 Ma) and fossilized seeds from the early to mid Eocene of Europe (48-46 Ma). The new identity for Cantisolanum daturoides does not alter a late Cretaceous minimum age for commelinids. PMID- 29532927 TI - Editorial: The beginning of a new partnership. PMID- 29532928 TI - The fitness benefits of germinating later than neighbors. AB - PREMISE OF THE STUDY: Phenology, the seasonal timing of development, can alter biotic interactions. Emergence from dormant or quiescent stages often occurs earlier when neighbors are present, which may reduce the neighbors' competitive effects. Delayed emergence in response to neighbors also has been observed, but the potential benefits of such delays are unclear. Further, emergence time may respond to neighbors experienced by parents, which may predict future competition in offspring. METHODS: In the annual plant Arabidopsis thaliana (Brassicaceae), we quantified seed germination responses to neighbors in parental and offspring (seed) environments. To examine how observed changes in germination affect interactions with neighbors, we performed an outdoor experiment using neighbors of different sizes to represent different germination times. KEY RESULTS: Seeds were more likely to germinate if their parent had neighbors, but they were less likely to germinate if they themselves experienced a neighbor cue (canopy). As seeds lost dormancy over time, they gained the ability to germinate under a canopy, which suggests that they germinate later in the presence of neighbors. Neighbors of both sizes reduced growth, survival to reproduction, fecundity, and total fitness, but large neighbors increased seedling survival. Smaller neighbors provided no such benefit and had stronger negative effects. CONCLUSIONS: Delayed germination in response to neighbors can reduce negative interactions and promote positive ones if it occurs late enough to expose seedlings to larger neighbors. By altering relative phenologies and, in turn, the outcomes of biotic interactions, phenological responses to environmental change may influence species interactions and community dynamics. PMID- 29532929 TI - A quick glance at noteworthy articles in this month's issue. PMID- 29532930 TI - Greatly reduced phylogenetic structure in the cultivated potato clade (Solanum section Petota pro parte). AB - PREMISE OF THE STUDY: The species boundaries of wild and cultivated potatoes are controversial, with most of the taxonomic problems in the cultivated potato clade. We here provide the first in-depth phylogenetic study of the cultivated potato clade to explore possible causes of these problems. METHODS: We examined 131 diploid accessions, using 12 nuclear orthologs, producing an aligned data set of 14,072 DNA characters, 2171 of which are parsimony-informative. We analyzed the data to produce phylogenies and perform concordance analysis and goodness-of fit tests. KEY RESULTS: There is good phylogenetic structure in clades traditionally referred to as clade 1+2 (North and Central American diploid potatoes exclusive of Solanum verrucosum), clade 3, and a newly discovered basal clade, but drastically reduced phylogenetic structure in clade 4, the cultivated potato clade. The results highlight a clade of species in South America not shown before, 'neocardenasii', sister to clade 1+2, that possesses key morphological traits typical of diploids in Mexico and Central America. Goodness-of-fit tests suggest potential hybridization between some species of the cultivated potato clade. However, we do not have enough phylogenetic signal with the data at hand to explicitly estimate such hybridization events with species networks methods. CONCLUSIONS: We document the close relationships of many of the species in the cultivated potato clade, provide insight into the cause of their taxonomic problems, and support the recent reduction of species in this clade. The discovery of the neocardenasii clade forces a reevaluation of a hypothesis that section Petota originated in Mexico and Central America. PMID- 29532931 TI - A novel chloroplast gene reported for flagellate plants. AB - PREMISE OF THE STUDY: Gene space in plant plastid genomes is well characterized and annotated, yet we discovered an unrecognized open reading frame (ORF) in the fern lineage that is conserved across flagellate plants. METHODS: We initially detected a putative uncharacterized ORF by the existence of a highly conserved region between rps16 and matK in a series of matK alignments of leptosporangiate ferns. We mined available plastid genomes for this ORF, which we now refer to as ycf94, to infer evolutionary selection pressures and assist in functional prediction. To further examine the transcription of ycf94, we assembled the plastid genome and sequenced the transcriptome of the leptosporangiate fern Adiantum shastense Huiet & A.R. Sm. KEY RESULTS: The ycf94 predicted protein has a distinct transmembrane domain but with no sequence homology to other proteins with known function. The nonsynonymous/synonymous substitution rate ratio of ycf94 is on par with other fern plastid protein-encoding genes, and additional homologs can be found in a few lycophyte, moss, hornwort, and liverwort plastid genomes. Homologs of ycf94 were not found in seed plants. In addition, we report a high level of RNA editing for ycf94 transcripts-a hallmark of protein-coding genes in fern plastomes. CONCLUSIONS: The degree of sequence conservation, together with the presence of a distinct transmembrane domain and RNA-editing sites, suggests that ycf94 is a protein-coding gene of functional significance in ferns and, potentially, bryophytes and lycophytes. However, the origin and exact function of this gene require further investigation. PMID- 29532932 TI - Was the ancestral angiosperm flower whorled throughout? PMID- 29532933 TI - Intraspecific and interspecific adaptive latitudinal cline in Brassicaceae seed oil traits. AB - PREMISE OF THE STUDY: Nearly all seed plants rely on stored seed reserves before photosynthesis can commence. Natural selection for seed oil traits must have occurred over 319 million years of evolution since the first seed plant ancestor. Accounting for the biogeographic distribution of seed oil traits is fundamental to understanding the mechanisms of adaptive evolution in seed plants. However, the evolution of seed oils is poorly understood. We provide evidence of the adaptive nature of seed oil traits at the intraspecific and interspecific levels in Brassicaceae-an oilseed-rich and economically important plant family. METHODS: Univariate statistics, Pearson's correlation, multiple regression, generalized linear mixed model analysis, and phylogenetic autocorrelation tests on seed oil traits of 360 accessions of Arabidopsis thaliana and 216 Brassicaceae species helped provide evidence of the adaptive nature of seed oil traits. KEY RESULTS: At higher latitudes, both seed oil content and unsaturated fatty acids have selective advantages in Arabidopsis thaliana (intraspecific-level), while only unsaturated fatty acids have selective advantages across 216 Brassicaceae species (interspecific-level). The seed oil patterns fit within the theoretical framework of the gradient model. Seed oil content increases significantly from temperate to subtropical to tropical regions in Brassicaceae herbs. Absence of phylogenetic signals for seed oil traits and high seed oil content in four tribes of Brassicaceae were observed. CONCLUSIONS: Multiple seed oil traits are adaptive in nature and follow a gradient model. Consistent evolutionary patterns of seed oil traits were observed at the intraspecific and interspecific levels in Brassicaceae. Seed oil traits change with latitude and across biomes, suggesting selection. The absence of a phylogenetic signal for seed oil traits and the occurrence of high seed oil content in four Brassicaceae tribes provides evidence of the adaptive nature of seed oil traits in Brassicaceae. PMID- 29532934 TI - Small trees, big problems: Comparative leaf function under extreme edaphic stress. AB - PREMISE OF THE STUDY: The pygmy forest, a plant community of severely stunted conifers and ericaceous angiosperms, occurs on patches of highly acidic, nutrient poor soils along the coast of Northern California, USA. This system is an excellent opportunity to study the effect of severe nutrient deficiency on leaf physiology in a naturally-occurring ecosystem. In this study, we seek to understand the physiological mechanisms stunting the plants' growth and their implications for whole plant function. METHODS: We measured 14 traits pertaining to leaf photosynthetic function or physical structure on seven species. Samples were taken from the pygmy forest community and from conspecifics growing on higher-nutrient soils, where trees may grow over 30 m tall. KEY RESULTS: Pygmy plants of most species maintained similar area-based photosynthetic and stomatal conductance rates to conspecific controls, but had lower specific leaf area (leaf area divided by dry weight), lower percent nitrogen, and less leaf area relative to xylem growth. Sequoia sempervirens, a species rare in the pygmy forest, had a categorically different response from the more common plants and had remarkably low photosynthetic rates. CONCLUSIONS: Pygmy plants were not stunted by low photosynthetic rates on a leaf-area basis; instead, several species had restricted whole-plant photosynthesis due to low leaf area production. Pygmy plants of all species showed signs of greater carbon investment in their leaves and higher production of nonphotosynthetic leaf tissue, further contributing to slow growth rates. PMID- 29532935 TI - The Effects of Residual Air and Viscosity on the Rate of Heat Penetration of Retort Food Simulant in Pouch When Using Static and Oscillating Motions. AB - : The objectives of this work were to determine the effect of 3 levels of residual air and 2 different retort motions on the value of the average heating slope of the rate of heat penetration of 3 different viscosities of a food simulant in flexible retort pouches. Pouches were thermally processed in a water spray automated batch retort system using 2 different methods of motion: static and oscillating continuously at a speed of 10.5 rotations per min (RPM) with an angle of 15 degrees . Nine residual air and viscosity combinations were processed during each experimental run: low viscosity with no residual air (LV-NRA), medium viscosity with no residual air (MV-NRA), high viscosity with no residual air (HV NRA), low viscosity with medium residual air (LV-MRA), medium viscosity with medium residual air (MV-MRA), high viscosity with medium residual air (HV-MRA), low viscosity with high residual air (LV-HRA), medium viscosity with high residual air (MV-HRA), and high viscosity with high residual air (HV-HRA). As the amount of residual air in the pouches increased, the average heating slope value decreased in both static and oscillating motions. As the viscosity of the product increased the amount of residual air affected the average heating slope less in static and oscillating motions. Overall, the oscillating motion resulted in faster rates of heat penetration in all viscosities compared to static mode. The oscillating motion reduced processing times up to 27% compared to static mode. PRACTICAL APPLICATION: This research can be applied to food manufacturers that are retorting foods in pouches. Residual air in pouches has been studied previously; however, with the development of new retort motions, more research needs to be conducted about the effect of residual air in a pouch using the different motions. Food manufacturers can use this information to optimize their amount of residual air based on their product viscosity and retort motion. This could dramatically lower processing time which would save money and increase output as well as potentially increases product quality. This research is aimed at influencing food manufacturers, process authorities, and product developers. PMID- 29532936 TI - Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai Barrow syndrome. AB - Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow/facio-oculo-acustico-renal (DB/FOAR) syndrome or be on the phenotypic continuum between the 2 conditions. PMID- 29532937 TI - Holistic properties of foods: a changing paradigm in human nutrition. AB - Traditionally, the study of nutrition has been based on a reductionist approach, reducing a food to its constituent nutrients and then investigating the effects of these nutrients, either singly or together, on metabolism and metabolic outcomes. Nutrients are not consumed in isolation but, rather, are consumed in the form of foods. For this reason, the complex food matrix itself influences nutritional outcomes, which often cannot be fully explained on the basis of the effects of 'the sum of the nutrients' alone. Nutrient additivity effects, nutrient interactions, effects of food components other than the classical nutrients, effects of the food matrix for single foods and combinations of foods consumed as meals on the kinetics of nutrient digestion and subsequent metabolism and metabolic outcomes are discussed. A paradigm shift in human nutrition is needed, with more consideration being given to the holistic effects of specific foods and mixtures of foods constituting meals and diets. (c) 2018 Society of Chemical Industry. PMID- 29532938 TI - Prostaglandin E2 -EP3 receptor subtype gene deletion in mother and son impairs platelet aggregation. PMID- 29532939 TI - Diagnostic accuracy and clinical outcomes associated with prenatal diagnosis of fetal absent cavum septi pellucidi. AB - BACKGROUND: Absence of the cavum septi pellucidi (CSP) on prenatal imaging is historically associated with additional anomalies; however, recent cases of isolated absent CSP have also been identified. This study seeks to assess the accuracy of prenatal imaging in evaluating isolated absent CSP and to describe the spectrum of clinical outcomes. METHODS: This is a retrospective observational study of all prenatally diagnosed absent CSP cases between 2011 and 2016 at our institution. Cases with additional structural parenchymal abnormalities were excluded. Clinical outcomes were abstracted from available records. RESULTS: We identified 15 cases of prenatally diagnosed isolated absent CSP. All patients were initially diagnosed on ultrasound (US) and 11/15 patients had fetal magnetic resonance imaging (MRI) confirming the diagnosis. Prenatal US and MRI were concordant in all cases. Of the continuing pregnancies, 2 neonatal deaths occurred related to extreme prematurity. Two cases of septo-optic dysplasia were identified in our cohort. DISCUSSION: In this study, fetal MRI and US had a high degree of accuracy with concordant postnatal imaging. Our study is similar to other case series suggesting that a range of clinical outcomes is possible with isolated absent CSP, but long-term patient follow up is necessary. PMID- 29532940 TI - GIGANTEA-like genes control seasonal growth cessation in Populus. AB - Survival of trees growing in temperate zones requires cycling between active growth and dormancy. This involves growth cessation in the autumn triggered by a photoperiod shorter than the critical day length. Variations in GIGANTEA (GI) like genes have been associated with phenology in a range of different tree species, but characterization of the functions of these genes in the process is still lacking. We describe the identification of the Populus orthologs of GI and their critical role in short-day-induced growth cessation. Using ectopic expression and silencing, gene expression analysis, protein interaction and chromatin immunoprecipitation experiments, we show that PttGIs are likely to act in a complex with PttFKF1s (FLAVIN-BINDING, KELCH REPEAT, F-BOX 1) and PttCDFs (CYCLING DOF FACTOR) to control the expression of PttFT2, the key gene regulating short-day-induced growth cessation in Populus. In contrast to Arabidopsis, in which the GI-CONSTANS (CO)-FLOWERING LOCUS T (FT) regulon is a crucial day-length sensor for flowering time, our study suggests that, in Populus, PttCO-independent regulation of PttFT2 by PttGI is more important in the photoperiodic control of growth cessation and bud set. PMID- 29532941 TI - Collaborative songwriting for health sciences interprofessional service learning. PMID- 29532942 TI - Identification of causal effects with latent confounding and classical additive errors in treatment. AB - In this paper, we discuss the identifiability and estimation of causal effects of a continuous treatment on a binary response when the treatment is measured with errors and there exists a latent categorical confounder associated with both treatment and response. Under some widely used parametric models, we first discuss the identifiability of the causal effects and then propose an approach for estimation and inference. Our approach can eliminate the biases induced by latent confounding and measurement errors by using only a single instrumental variable. Based on the identification results, we give guidelines for determining the existence of a latent categorical confounder and for selecting the number of levels of the latent confounder. We apply the proposed approach to a data set from the Framingham Heart Study to evaluate the effect of the systolic blood pressure on the coronary heart disease. PMID- 29532943 TI - Inference from single occasion capture experiments using genetic markers. AB - Accurate estimation of the size of animal populations is an important task in ecological science. Recent advances in the field of molecular genetics researches allow the use of genetic data to estimate the size of a population from a single capture occasion rather than repeated occasions as in the usual capture-recapture experiments. Estimating the population size using genetic data also has sometimes led to estimates that differ markedly from each other and also from classical capture-recapture estimates. Here, we develop a closed form estimator that uses genetic information to estimate the size of a population consisting of mothers and daughters, focusing on estimating the number of mothers, using data from a single sample. We demonstrate the estimator is consistent and propose a parametric bootstrap to estimate the standard errors. The estimator is evaluated in a simulation study and applied to real data. We also consider maximum likelihood in this setting and discover problems that preclude its general use. PMID- 29532944 TI - Training residents for future careers in medical education. PMID- 29532945 TI - UPLC-HRMS-based untargeted metabolic profiling reveals changes in chickpea (Cicer arietinum) metabolome following long-term drought stress. AB - Genetic improvement for drought tolerance in chickpea requires a solid understanding of biochemical processes involved with different physiological mechanisms. The objective of this study is to demonstrate genetic variations in altered metabolic levels in chickpea varieties (tolerant and sensitive) grown under contrasting water regimes through ultrahigh-performance liquid chromatography/high-resolution mass spectrometry-based untargeted metabolomic profiling. Chickpea plants were exposed to drought stress at the 3-leaf stage for 25 days, and the leaves were harvested at 14 and 25 days after the imposition of drought stress. Stress produced significant reduction in chlorophyll content, Fv /Fm , relative water content, and shoot and root dry weight. Twenty known metabolites were identified as most important by 2 different methods including significant analysis of metabolites and partial least squares discriminant analysis. The most pronounced increase in accumulation due to drought stress was demonstrated for allantoin, l-proline, l-arginine, l-histidine, l-isoleucine, and tryptophan. Metabolites that showed a decreased level of accumulation under drought conditions were choline, phenylalanine, gamma-aminobutyric acid, alanine, phenylalanine, tyrosine, glucosamine, guanine, and aspartic acid. Aminoacyl-tRNA and plant secondary metabolite biosynthesis and amino acid metabolism or synthesis pathways were involved in producing genetic variation under drought conditions. Metabolic changes in light of drought conditions highlighted pools of metabolites that affect the metabolic and physiological adjustment in chickpea that reduced drought impacts. PMID- 29532946 TI - Peer observation of teaching for formative evaluation of faculty members. PMID- 29532947 TI - Teaching to undo structural racism. PMID- 29532948 TI - Mixtures of Berkson and classical covariate measurement error in the linear mixed model: Bias analysis and application to a study on ultrafine particles. AB - The ultrafine particle measurements in the Augsburger Umweltstudie, a panel study conducted in Augsburg, Germany, exhibit measurement error from various sources. Measurements of mobile devices show classical possibly individual-specific measurement error; Berkson-type error, which may also vary individually, occurs, if measurements of fixed monitoring stations are used. The combination of fixed site and individual exposure measurements results in a mixture of the two error types. We extended existing bias analysis approaches to linear mixed models with a complex error structure including individual-specific error components, autocorrelated errors, and a mixture of classical and Berkson error. Theoretical considerations and simulation results show, that autocorrelation may severely change the attenuation of the effect estimations. Furthermore, unbalanced designs and the inclusion of confounding variables influence the degree of attenuation. Bias correction with the method of moments using data with mixture measurement error partially yielded better results compared to the usage of incomplete data with classical error. Confidence intervals (CIs) based on the delta method achieved better coverage probabilities than those based on Bootstrap samples. Moreover, we present the application of these new methods to heart rate measurements within the Augsburger Umweltstudie: the corrected effect estimates were slightly higher than their naive equivalents. The substantial measurement error of ultrafine particle measurements has little impact on the results. The developed methodology is generally applicable to longitudinal data with measurement error. PMID- 29532949 TI - Travelling without a helmet: tourists' vulnerabilities and responses to disasters in Indonesia. AB - Tourists are particularly vulnerable when natural disasters occur in regions that they are visiting. It is assumed that they lack awareness and understanding of the actions that they need to take in such circumstances. This study examines the responses of tourists in times of disaster, building on empirical data collected through large-scale surveys conducted in Bali and Yogyakarta, Indonesia, in 2015. Both are important tourist destinations in the country that have suffered major disasters in recent years. The different types of responses to these events are framed using a grid/group analysis stemming from cultural theory. The study resulted in three key findings: (i) current disaster management planning largely follows a single rationale; (ii) tourists are not a homogeneous group, but rather a complex, diverse, and dynamic body of stakeholders; and (iii) the focus of disaster management planning should shift from a single rationale to a polyrational methodology. Disaster managers need to consider, therefore, these different aspects in the context of preparedness. PMID- 29532950 TI - Incorporating historical information in biosimilar trials: Challenges and a hybrid Bayesian-frequentist approach. AB - For the approval of biosimilars, it is, in most cases, necessary to conduct large Phase III clinical trials in patients to convince the regulatory authorities that the product is comparable in terms of efficacy and safety to the originator product. As the originator product has already been studied in several trials beforehand, it seems natural to include this historical information into the showing of equivalent efficacy. Since all studies for the regulatory approval of biosimilars are confirmatory studies, it is required that the statistical approach has reasonable frequentist properties, most importantly, that the Type I error rate is controlled-at least in all scenarios that are realistic in practice. However, it is well known that the incorporation of historical information can lead to an inflation of the Type I error rate in the case of a conflict between the distribution of the historical data and the distribution of the trial data. We illustrate this issue and confirm, using the Bayesian robustified meta-analytic-predictive (MAP) approach as an example, that simultaneously controlling the Type I error rate over the complete parameter space and gaining power in comparison to a standard frequentist approach that only considers the data in the new study, is not possible. We propose a hybrid Bayesian-frequentist approach for binary endpoints that controls the Type I error rate in the neighborhood of the center of the prior distribution, while improving the power. We study the properties of this approach in an extensive simulation study and provide a real-world example. PMID- 29532951 TI - Genetic and environmental factors contribute to variation in cell wall composition in mature desi chickpea (Cicer arietinum L.) cotyledons. AB - Chickpea (Cicer arietinum L.) is an important nutritionally rich legume crop that is consumed worldwide. Prior to cooking, desi chickpea seeds are most often dehulled and cleaved to release the split cotyledons, referred to as dhal. Compositional variation between desi genotypes has a significant impact on nutritional quality and downstream processing, and this has been investigated mainly in terms of starch and protein content. Studies in pulses such as bean and lupin have also implicated cell wall polysaccharides in cooking time variation, but the underlying relationship between desi chickpea cotyledon composition and cooking performance remains unclear. Here, we utilized a variety of chemical and immunohistological assays to examine details of polysaccharide composition, structure, abundance, and location within the desi chickpea cotyledon. Pectic polysaccharides were the most abundant cell wall components, and differences in monosaccharide and glycosidic linkage content suggest both environmental and genetic factors contribute to cotyledon composition. Genotype-specific differences were identified in arabinan structure, pectin methylesterification, and calcium-mediated pectin dimerization. These differences were replicated in distinct field sites and suggest a potentially important role for cell wall polysaccharides and their underlying regulatory machinery in the control of cooking time in chickpea. PMID- 29532952 TI - Blended learning: e-patients and patient perspectives in ophthalmology. PMID- 29532953 TI - Predictors of sustained research involvement among MD/PhD programme graduates. AB - CONTEXT: MD/PhD programmes provide structured paths for physician-scientist training. However, considerable proportions of graduates of these programmes do not pursue careers in research consistent with their training. OBJECTIVES: We sought to identify factors associated with sustained involvement in research after completion of all postgraduate training. METHODS: Anonymised data from a national survey of Canadian MD/PhD programme graduates who had completed all physician-scientist training (n = 70) were analysed. Multivariable logistic regression was used to measure the associations between characteristics of graduates and five indicators of sustained research involvement following postgraduate training: (i) protected research time in the current appointment; (ii) percentage of time dedicated to research; (iii) planned future involvement in research; (iv) role as a principal investigator on a recent funded project, and (v) receipt of funding from a federal granting agency since graduation. RESULTS: The majority of graduates were significantly involved in research on the basis of at least one outcome. Completion of a research fellowship, number of first-authored or co-authored manuscripts published during MD/PhD training, and duration of MD/PhD training were positively associated with continued research involvement. Completion of a Masters degree prior to MD/PhD training, female gender, debt greater than CAD$50 000 at completion of training, and pursuit of a clinical specialty other than internal medicine, paediatrics, neurology, pathology and the surgical specialties were negatively associated with sustained research involvement. CONCLUSIONS: Most MD/PhD programme graduates remain significantly involved in research, but this involvement often does not correspond to traditional physician-scientist roles, in which a majority of time is dedicated to research. To minimise loss of investment in physician-scientist training, MD/PhD programmes should prioritise research productivity during training and the pursuit of additional research training during residency, and policymakers should establish stable sources of funding to reduce debt among graduates. Our data suggest further study is warranted to identify interventions to reduce attrition among female MD/PhD programme graduates. PMID- 29532954 TI - Identification of putative cytochrome P450 monooxygenase genes from the small white butterfly, Pieris rapae (Lepidoptera: Pieridae), and their response to insecticides. AB - The small white butterfly, Pieris rapae (Lepidoptera: Pieridae), is an important pest on Brassicaceae plants, causing heavy crop loss each year. Cytochrome P450 monooxygenase (CYP) is a superfamily of enzymes involved in the detoxification of various xenobiotic compounds, including insecticides. However, little is known about the role of CYP genes in P. rapae. In this study, we identified 63 CYP genes in P. rapae, and analyzed their phylogenetic relationships, exon-intron structures and genomic locations. Moreover, our insecticide-response transcription profiling showed that LD5 doses of lambda-cyhalothrin, chlorantraniliprole, and abamectin significantly increased expression of five (CYP4M59, CYP6AE119, CYP6AE120, CYP6AE121, and CYP6BD18), three (CYP4AU1, CYP6AE120, and CYP6AW1), and five (CYP4L40, CYP4AU1, CYP6AE119, CYP6AW1, and CYP6BD19) CYP genes, respectively; and LD20 doses of the three pesticides significantly upregulated six (CYP4M59, CYP6AE119, CYP6AE120, CYP6AE121, CYP4AU1, and CYP6BD18), six (CYP4G168, CYP4L40, CYP4AU1, CYP6AE120, CYP6AW1, and CYP6BD19), and five (CYP4L40, CYP4AU1, CYP6AB108, CYP6AE119, and CYP6BD19) genes, respectively. When we used LD50 doses of the three insecticides, we reported significantly elevated expression levels of five (CYP4M59, CYP6AE119, CYP6AE120, CYP6BD17, and CYP6BD18), eight (CYP4G168, CYP4L40, CYP4AU1, CYP6AE120, CYP6AE121, CYP6AW1, CYP6BD18, and CYP6BD19), and six (CYP4L40, CYP4S34, CYP6AB108, CYP6AE119, CYP6AE120, and CYP6BD19) genes, respectively. Our expression analysis also revealed that five (CYP4G168, CYP4G169, CYP4S34, CYP6AW1, and CYP6CT3) and three (CYP4L40, CYP6AN33, and CYP6BD17) CYP genes were mainly expressed in the midgut and fat body, respectively, and one CYP gene (CYP6AE119) in the Malpighian tubules. This is the first large-scale report into the characterization of CYP genes in P. rapae. PMID- 29532955 TI - Electrophysiological changes in poststroke subjects with depressed mood: A quantitative EEG study. AB - BACKGROUND: We aimed to explore the electrophysiological changes in poststroke subjects with depressed mood. METHODS: Resting-state electroencephalogram (EEG) signals of 16 electrodes in 35 poststroke depressed, 24 poststroke nondepressed, and 35 age-matched healthy control subjects were analyzed by means of spectral power analysis, a quantitative EEG measurement of different frequency bands. The relationship among depressed mood, functional status, lesion side, and poststroke time was assessed by using variance and Spearman correlation analysis. Multiple analysis of variance was used to compare the differences among the 3 groups. Binary logistic regression analysis was used to establish a regression model to predict depressed mood in stroke subjects and to explore the association between depression and EEG band power. Receiver operating characteristic curves were used to estimate the ability of spectral power selected by binary logistic regression to indicate depressed mood in stroke subjects. RESULTS: We found that the hemisphere in which the lesion was located and the time since stroke onset had no effect on depressed mood. Only the patient's functional status was related to emotional symptoms. Quantitative EEG analysis revealed increased delta, theta, and beta2 power in stroke subjects with depressed mood, particularly in temporal regions. The theta and beta2 power in the right temporal area were shown to be highly sensitive to depressed mood, and these parameters showed good discriminatory ability for depressed subjects following stroke. CONCLUSION: Depressed mood after stroke is associated with functional status. Quantitative EEG parameters may be a useful tool in timely screening for depressed mood after stroke. PMID- 29532956 TI - Work-related stress in a humanitarian context: a qualitative investigation. AB - There is a paucity of research on the subjective stress-related experiences of humanitarian aid workers. Most evaluations of stress among these individuals focus on trauma and related conditions or adopt a quantitative approach. This interview-based study explored how 58 humanitarian aid workers employed by a United Nations-aligned organisation perceived the transactional stress process. The thematic analysis revealed eight main topics of interest: an emergency culture was found where most employees felt compelled to offer an immediate response to humanitarian needs; employees identified strongly with humanitarian goals and reported a high level of engagement; the rewards of humanitarian work were perceived as motivating and meaningful; constant change and urgent demands resulted in work overload; and managing work-life boundaries and receiving positive support from colleagues and managers helped to buffer perceived stress, work overload, and negative health outcomes. The practical implications of the results are discussed and suggestions made in the light of current research and stress theory. PMID- 29532957 TI - Imaging prostate cancer (PCa) with [99m Tc(CO)3 ]finasteride dithiocarbamate. AB - This investigation aimed to modify finasteride (1) to finasteride dithiocarbamate (2) for subsequent synthesis of the rhenium analogue (3) and [99m Tc]tricarbonyl complexes (4), to assess its prostate cancer (PCa) targeting potential in a rat model. To validate the identity of (4), reference (3) has been synthesized by using fac-[Net4 ]2 [ReBr3 (CO)3 ] precursor and characterized by 1 H-NMR, 13 C NMR, ESI-MS, and elemental analysis. The analogue (4) was synthesized by using fac-[99m Tc(H2 O)3 (CO)3 ]+ precursor, and its structure was confirmed by comparative HPLC by using (3) as a reference. Further, the suitability of (4) as a PCa imaging agent was investigated in vitro and in vivo. At room temperature, (4) had >=99% radiochemical purity and remained >=84% stable in serum. In preclinical studies, biodistribution of (4) in histopathologically established rat model showed adequately high in vivo uptake in the prostate attracting the possibility of using it for noninvasive imaging of PCa. PMID- 29532958 TI - Gender, households, and decision-making for wildfire safety. AB - This paper considers the impact of gendered norms on decision-making for wildfire preparation and response at the household level. Focusing on Australia, it provides a theoretical thematic analysis of data acquired in 107 interviews with residents of nine different localities. It builds on existing research on gender and disaster, as well as on decision-making and wildfires, and analyses the narratives that centre on 'split' households plans (where a male partner plans to stay and a female partner plans to evacuate) and disagreements within heterosexual couples as to an appropriate wildfire safety plan. The study finds that gender inequality and differences in gendered expectations are likely to create difficult conditions for negotiation between members of a heterosexual couple when there is disagreement over a plan and that this may contribute to risky decision-making practices and outcomes. The paper reiterates, therefore, the importance of taking into account the social construction of gender in wildfire research and policy. PMID- 29532959 TI - The Effects of Trauma Type and Executive Dysfunction on Symptom Expression of Polyvictimized Youth in Residential Care. AB - Risk for traumatic sequelae is conveyed directly by risk factors (i.e., exposure to trauma), and via the disruption of developmental competencies. Exposure to caregiver trauma is an especially salient risk factor, as its early and pervasive nature is likely to undermine multiple facets of development, most notably the emergence of cognitive controls (i.e., executive function [EF]). Deficits in EF have been observed among youth exposed to multiple types of trauma and are associated with a range of functional impairments, posttraumatic stress symptoms (PTSS), and behavioral disorders; they represent a mechanism by which the negative impact of caregiver trauma is conveyed. This study included 672 youth in residential placement, and examined the associations between both caregiver and noncaregiver trauma, measured by the Trauma History Profile (THP); executive dysfunction, measured by the Behavioral Inventory of Executive Function (BRIEF); PTSS, measured by the UCLA Posttraumatic Stress Disorder (PTSD) Reaction Index (PTSD-RI); and externalizing and internalizing problems, measured by the Child Behavior Checklist (CBCL). A structural equation model demonstrated direct associations between caregiver trauma and PTSS, beta = .15; noncaregiver trauma and externalizing problems, beta = .14; gender and PTSS, beta = .26, externalizing problems, beta = .12, and internalizing problems, beta = .26; and age and externalizing problems, beta = -.11. We observed indirect effects via deficits in EF between caregiver trauma and PTSS, beta = .04 and externalizing problems, beta = .19. Results indicate for screening for executive dysfunction among trauma-impacted youth is needed, as it represents a critical therapeutic target. PMID- 29532960 TI - Manipulation and Steering of Hyperbolic Surface Polaritons in Hexagonal Boron Nitride. AB - Hexagonal boron nitride (hBN) is a natural hyperbolic material that supports both volume-confined hyperbolic polaritons and sidewall-confined hyperbolic surface polaritons (HSPs). In this work, efficient excitation, control, and steering of HSPs are demonstrated in hBN through engineering the geometry and orientation of hBN sidewalls. By combining infrared nanoimaging and numerical simulations, the reflection, transmission, and scattering of HSPs are investigated at the hBN corners with various apex angles. It is also shown that the sidewall-confined nature of HSPs enables a high degree of control over their propagation by designing the geometry of hBN nanostructures. PMID- 29532961 TI - Impact of the Charlson comorbidity index and prognostic nutritional index on prognosis in patients with early gastric cancer after endoscopic submucosal dissection. AB - BACKGROUND AND AIM: With the aging of society, comorbidities or nutritional status are assessed prior to endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). However, it is uncertain which factors are important for predicting prognosis in EGC patients after ESD. Thus, we aimed to evaluate clinical outcomes of ESD for EGC, with respect to comorbidities or nutritional status. METHODS: We carried out a retrospective study involving 708 EGC in 585 patients who were enrolled between April 2007 and March 2012. They were classified into two groups; an elderly (>=80 years) and non-elderly (<80 years) group. Short- and long-term outcomes were evaluated between the groups. RESULTS: There were no significant differences regarding short-term outcomes. Overall survival (OS) rates in the elderly group were significantly lower than those in the non-elderly group (P = 0.001). OS rates in patients with a low (<=2) Charlson comorbidity index (CCI) were significantly higher than those in patients with a high (>=3) CCI, regardless of age. OS rates in patients with a high (>=47.7) prognostic nutritional index (PNI) were significantly higher than those in patients with a low (<47.7) PNI, regardless of age. In multivariate analysis, an Eastern Cooperative Oncology Group performance status (PS) >=2 (hazard ratio [HR], 95% confidence interval: 3.23, 1.54-6.75), CCI >=3 (HR 7.88, 4.50-13.80) and PNI <47.7 (HR 3.44, 2.00-5.90) were significantly associated with OS rate (P < 0.01). CONCLUSION: CCI and PNI can be prognostic indicators for non-elderly and elderly patients with EGC after ESD. PMID- 29532962 TI - Air-Stable and High-Performance Solution-Processed Organic Light-Emitting Devices Based on Hydrophobic Polymeric Ionic Liquid Carrier-Injection Layers. AB - A lot of research, mostly using electron-injection layers (EILs) composed of alkali-metal compounds has been reported with a view to increase the efficiency of solution-processed organic light-emitting devices (OLEDs). However, these materials have intractable properties, such as a strong affinity for moisture, which cause the degradation of OLEDs. Consequently, optimal EIL materials should exhibit high electron-injection efficiency as well as be stable in air. In this study, polymer light-emitting devices (PLEDs) based on the commonly used yellow fluorescence-emitting polymer F8BT, which utilize poly(diallyldimethylammonium) based polymeric ionic liquids, are experimentally and analytically investigated. As a result, the optimized PLED employing an EIL comprising poly(diallyldimethylammonium) bis(trifluoromethanesulfonyl)imide (poly(DDA)TFSI), which is expected to display good moisture resistance because of water repellency of fluorocarbon groups, exhibits excellent storage stability in air and electroluminescence performance with a low turn-on voltage of 2.01 V, maximum external quantum efficiency of 9.00%, current efficiency of 30.1 cd A-1 , and power efficiency of 32.4 lm W-1 . The devices with poly(DDA)TFSI show one of the highest efficiencies as compared to the reported standard PLEDs. Moreover, poly(DDA)TFSI is applied as a hole-injection layer (HIL). The optimized PLED using poly(DDA)TFSI as the HIL exhibits performances comparable to those of a device that uses a conventional poly(3,4-ethylenedioxy-thiophene):poly(4 styrenesulfonate) HIL. PMID- 29532963 TI - APTRA-Based Luminescent Lanthanide Complexes Displaying Enhanced Selectivity for Mg2. AB - A series of three europium(III) complexes has been created in which an APTRA moiety has been integrated into the sensitising chromophore (APTRA=o-aminophenol N,N,N-triacetate). The constitutionally isomeric complexes EuL1 and EuL2 feature the APTRA unit linked to a metal-bound pyridine ring through an alkynyl unit, differing according to the disposition of the APTRA substituents relative to the C=C unit (para-N and para-O). In EuL3 , the APTRA ring is directly bonded to the Eu-coordinated pyridine (para-O). The metal binding affinities for magnesium, calcium and zinc ions have been measured by using emission and excitation spectroscopy. The pyridylalkynylaryl systems, EuL1 and EuL2 , offer superior affinity and selectivity for Mg2+ . The Mg2+ affinities are surprisingly very different from prior studies on structurally related systems that incorporate organic fluorophores as reporters, as opposed to the macrocyclic Eu complex moiety. A much-reduced affinity for calcium and zinc-possibly arising from the lower donor ability of the aryl N or O atoms arising from extended conjugation means that magnesium ion concentrations can be measured directly in serum for the first time, by using such an approach. An apparent dissociation constant for magnesium binding of Kd =2.4 mm was calculated in the serum background. PMID- 29532964 TI - Two Discrete RuCp* (Cp*=Pentamethylcyclopentadienyl) Binding Modes of N-Confused Porphyrins: Peripheral pi Complex and Sitting Atop Ruthenocenophane Complex by Skeletal Transformation. AB - Complexation of a RuCp* cation with N-confused tetraarylporphyrins (NCPs) forms directly bound ruthenium(II) pentamethylcyclopentadienyl (Cp*) pi-complex on a specific meso-aryl group (e.g., phenyl) neighboring peripheral imino nitrogen of NCPs in high yields. In contrast, in the case of NCPs bearing bulky meso substituents (e.g., 3,5-di-tert-butylphenyl), new ruthenocenophane-like complex embedded on an N-confused calix[4]phyrin was formed through multiple C-H bond activation of methyl groups of Cp* ligand. The mechanistic insight into the formation of the ruthenocenophane was derived from DFT calculations. PMID- 29532965 TI - A High-Capacity O2-Type Li-Rich Cathode Material with a Single-Layer Li2 MnO3 Superstructure. AB - A high capacity cathode is the key to the realization of high-energy-density lithium-ion batteries. The anionic oxygen redox induced by activation of the Li2 MnO3 domain has previously afforded an O3-type layered Li-rich material used as the cathode for lithium-ion batteries with a notably high capacity of 250-300 mAh g-1 . However, its practical application in lithium-ion batteries has been limited due to electrodes made from this material suffering severe voltage fading and capacity decay during cycling. Here, it is shown that an O2-type Li-rich material with a single-layer Li2 MnO3 superstructure can deliver an extraordinary reversible capacity of 400 mAh g-1 (energy density: ~1360 Wh kg-1 ). The activation of a single-layer Li2 MnO3 enables stable anionic oxygen redox reactions and leads to a highly reversible charge-discharge cycle. Understanding the high performance will further the development of high-capacity cathode materials that utilize anionic oxygen redox processes. PMID- 29532966 TI - Cost-effectiveness of alternative smoking cessation scenarios in Spain: results from the EQUIPTMOD. AB - AIMS: To assess the cost-effectiveness of alternative smoking cessation scenarios from the perspective of the Spanish National Health Service (NHS). DESIGN: We used the European study on Quantifying Utility of Investment in Protection from Tobacco model (EQUIPTMOD), a Markov-based state transition economic model, to estimate the return on investment (ROI) of: (a) the current provision of smoking cessation services (brief physician advice and printed self-helped material + smoking ban and tobacco duty at current levels); and (b) four alternative scenarios to complement the current provision: coverage of proactive telephone calls; nicotine replacement therapy (mono and combo) [prescription nicotine replacement therapy (Rx NRT)]; varenicline (standard duration); or bupropion. A rate of 3% was used to discount life-time costs and benefits. SETTING: Spain. PARTICIPANTS: Adult smoking population (16+ years). MEASUREMENTS: Health-care costs associated with treatment of smoking attributable diseases (lung cancer, coronary heart disease, chronic obstructive pulmonary infection and stroke); intervention costs; quality-adjusted life years (QALYs). Costs and outcomes were summarized using various ROI estimates. FINDINGS: The cost of implementing the current provision of smoking cessation services is approximately ?61 million in the current year. This translates to 18 quitters per 1000 smokers and a life-time benefit-cost ratio of 5, compared with no such provision. All alternative scenarios were dominant (cost-saving: less expensive to run and generated more QALYs) from the life-time perspective, compared with the current provision. The life-time benefit-cost ratios were: 1.87 (proactive telephone calls); 1.17 (Rx NRT); 2.40 (varenicline-standard duration); and bupropion (2.18). The results remained robust in the sensitivity analysis. CONCLUSIONS: According to the EQUIPTMOD modelling tool it would be cost-effective for the Spanish authorities to expand the reach of existing GP brief interventions for smoking cessation, provide pro-active telephone support, and reimburse smoking cessation medication to smokers trying to stop. Such policies would more than pay for themselves in the long run. PMID- 29532967 TI - Anomalous-Diffusion-Assisted Brightness in White Cellulose Nanofibril Membranes. AB - The understanding of the interaction between light and complex, random structures is the key for designing and tailoring the optical appearance and performance of many materials that surround us, ranging from everyday consumer products, such as those for personal care, paints, and paper, to light diffusers used in the LED lamps and solar cells. Here, it is demonstrated that the light transport in membranes of pure cellulose nanofibrils (CNFs) can be controlled to achieve bright whiteness in structures only a few micrometers thick. This is in contrast to other materials, such as paper, which require hundreds of micrometers to achieve a comparable appearance. The diffusion of light in the CNF membranes is shown to become anomalous by tuning the porosity and morphological features. Considering also their strong mechanical properties and biocompatibility, such white coatings are proposed as a new application for cellulose nanofibrils. PMID- 29532969 TI - PSYCHE Pure Shift NMR Spectroscopy. AB - Broadband homodecoupling techniques in NMR, also known as "pure shift" methods, aim to enhance spectral resolution by suppressing the effects of homonuclear coupling interactions to turn multiplet signals into singlets. Such techniques typically work by selecting a subset of "active" nuclear spins to observe, and selectively inverting the remaining, "passive", spins to reverse the effects of coupling. Pure Shift Yielded by Chirp Excitation (PSYCHE) is one such method; it is relatively recent, but has already been successfully implemented in a range of different NMR experiments. Paradoxically, PSYCHE is one of the trickiest of pure shift NMR techniques to understand but one of the easiest to use. Here we offer some insights into theoretical and practical aspects of the method, and into the effects and importance of the experimental parameters. Some recent improvements that enhance the spectral purity of PSYCHE spectra will be presented, and some experimental frameworks, including examples in 1D and 2D NMR spectroscopy, for the implementation of PSYCHE will be introduced. PMID- 29532970 TI - Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus. AB - Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 +/- 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 +/- 21.7 mg/dL; control, 137.7 +/- 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo 1 H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 +/- 25.8 mg/dL; control, 142.3 +/- 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs. PMID- 29532971 TI - The Effects of Middle School Weight Climate on Youth With Higher Body Weight. AB - This study examines whether social-emotional difficulties associated with higher body weight vary across schools as a function of the school's weight climate. Weight climate, characterized by weight-policing, was assessed indirectly by examining how strongly self-reported weight predicts victim reputation within 26 ethnically diverse middle schools. Social-emotional indicators included self reported loneliness, school belonging, and self-esteem. In schools with stronger weight-policing at seventh grade, loneliness was intensified by eighth grade among both girls (n = 2,101) and boys (n = 1,985) with higher weight. Similar effects were found for low self-esteem among girls. Additionally, boys-regardless of their weight-reported lower sense of belonging in schools with stronger weight policing. The study offers a new method to estimate school weight climate, and the findings provide insights for interventions. PMID- 29532972 TI - Recent Trends in Metallopolymer Design: Redox-Controlled Surfaces, Porous Membranes, and Switchable Optical Materials Using Ferrocene-Containing Polymers. AB - Metallopolymers with metal functionalities are a unique class of functional materials. Their redox-mediated optoelectronic and catalytic switching capabilities, their outstanding structure formation and separation capabilities have been reported recently. Within this Minireview, the scope and limitations of intriguing ferrocene-containing systems will be discussed. In the first section recent advances in metallopolymer design will be given leading to a plethora of novel metallopolymer architectures. Discussed synthetic pathways comprise controlled and living polymerization protocols as well as surface immobilization strategies. In the following sections, we focus on recent advances and new applications for side-chain and main-chain ferrocene-containing polymers as (i) remote-switchable materials, (ii) smart surfaces, (iii) redox-responsive membranes, and some recent trends in (iv) photonic structures and (v) other optical applications. PMID- 29532973 TI - A High-Efficiency Organic Solar Cell Enabled by the Strong Intramolecular Electron Push-Pull Effect of the Nonfullerene Acceptor. AB - Besides broadening of the absorption spectrum, modulating molecular energy levels, and other well-studied properties, a stronger intramolecular electron push-pull effect also affords other advantages in nonfullerene acceptors. A strong push-pull effect improves the dipole moment of the wings in IT-4F over IT M and results in a lower miscibility than IT-M when blended with PBDB-TF. This feature leads to higher domain purity in the PBDB-TF:IT-4F blend and makes a contribution to the better photovoltaic performance. Moreover, the strong push pull effect also decreases the vibrational relaxation, which makes IT-4F more promising than IT-M in reducing the energetic loss of organic solar cells. Above all, a power conversion efficiency of 13.7% is recorded in PBDB-TF:IT-4F-based devices. PMID- 29532974 TI - The health implications of unconventional natural gas development in Pennsylvania. AB - We investigate the health impacts of unconventional natural gas development of Marcellus shale in Pennsylvania between 2001 and 2013 by merging well permit data from the Pennsylvania Department of Environmental Protection with a database of all inpatient hospital admissions. After comparing changes in hospitalization rates over time for air pollution-sensitive diseases in counties with unconventional gas wells to changes in hospitalization rates in nonwell counties, we find a significant association between shale gas development and hospitalizations for pneumonia among the elderly, which is consistent with higher levels of air pollution resulting from unconventional natural gas development. We note that the lack of any detectable impact of shale gas development on younger populations may be due to unobserved factors contemporaneous with drilling, such as migration. PMID- 29532975 TI - "Interdigital pilonidal sinus in a hairdresser" a case report. PMID- 29532977 TI - Placement of Baclofen Pump Catheter Tip for Upper Extremity Spasticity Management. PMID- 29532976 TI - Psychometric properties of the Spanish version of the family-centred practices scale for use with families of young children receiving early childhood intervention. AB - BACKGROUND: Early childhood intervention (ECI) centres in Spain recently initiated a process of change towards the adoption of family-centred practices (FCPs). Knowledge about the extent to which practitioners' use FCPs is needed. The psychometric properties of the Spanish version of the FCPs scale were examined. METHOD: A convenience sample of 105 families of children with developmental delays attending three different ECI centres in Spain completed the FCPs scale and provided information about the ECI centre characteristics and practices, caregiver self-efficacy beliefs, and family and child demographic information. RESULTS: The Spanish version of the FCP scale was found to be both reliable and valid. FCPs were correlated with self-efficacy beliefs, parents' involvement in their child's ECI program and family decision making. CONCLUSION: The FCP scale provides practitioners with useful information about their practices, but also has capacity-building consequences for families. The study is a first step for examining the use of FCPs in Spain. PMID- 29532978 TI - Barriers faced by adults with intellectual disabilities who experience sexual assault: A systematic review and meta-synthesis. AB - BACKGROUND: Sexual violence is associated with significant morbidity and mortality. The incidence of sexual violence against adults with intellectual disability is significantly higher than in the general population. The aim of this systematic review and qualitative meta-synthesis was to explore the barriers faced by adults with intellectual disability in reporting sexual assault from the perspective of different stakeholders. METHOD: A systematic literature search was conducted to identify relevant studies. A hermeneutic interpretive approach was employed to review and assess the methodological quality of the studies. Findings were meta-synthesized and juxtaposed to identify themes, concepts and interpretations. RESULTS: Thirteen studies were included. Three overarching themes emerged from an interpersonal, professional and social context, and within these domains, eight subthemes emerged as barriers to reporting sexual assault, including fear, communication, sexual knowledge and understanding, intellectual disability identification, lack of collaboration between service providers, presumption of capacity/credibility, lack of resources, myths and misconceptions. CONCLUSION: The research demonstrates that deficiencies in communication and collaboration among agencies, a lack of appropriate legislation and specific training needs and education programmes are significant barriers in the reporting of sexual assault by people with intellectual disability. These findings are not unique to adults with intellectual disability and have also been identified among people from the general population who experience sexual assault. However, adults with intellectual disability have additional barriers to overcome in order to access equal rights to healthcare, education and the legal system. PMID- 29532979 TI - Participatory monitoring to connect local and global priorities for forest restoration. AB - New global initiatives to restore forest landscapes present an unparalleled opportunity to reverse deforestation and forest degradation. Participatory monitoring could play a crucial role in providing accountability, generating local buy in, and catalyzing learning in monitoring systems that need scalability and adaptability to a range of local sites. We synthesized current knowledge from literature searches and interviews to provide lessons for the development of a scalable, multisite participatory monitoring system. Studies show that local people can collect accurate data on forest change, drivers of change, threats to reforestation, and biophysical and socioeconomic impacts that remote sensing cannot. They can do this at one-third the cost of professionals. Successful participatory monitoring systems collect information on a few simple indicators, respond to local priorities, provide appropriate incentives for participation, and catalyze learning and decision making based on frequent analyses and multilevel interactions with other stakeholders. Participatory monitoring could provide a framework for linking global, national, and local needs, aspirations, and capacities for forest restoration. PMID- 29532980 TI - The effect of splenectomy on the levels of PCV-13-induced memory B- and T cells. AB - AIM: Splenectomised patients are associated with lifelong risk of fatal overwhelming post-splenectomy infection (OPSI), which is mostly caused by Streptococcus pneumoniae. Today OPSI cases can still be reported even in patients with appropriate vaccination. In our study, the levels of vaccine-specific memory B- and T cells were compared between control and splenectomised patients to enlighten the underlying reason. MATERIALS AND METHODS: Five healthy and 14 post traumatic splenectomised individuals were vaccinated with 13-valent pneumococcal conjugate vaccine (PCV-13) followed by 23-valent pneumococcal polysaccharide vaccine (PPV-23). The levels of memory B- and T cells were compared by ELISPOT analysis. RESULTS: Splenectomised patients generated reduced levels of memory IgG B cells in response to PCV-13 vaccination, while the memory IFN-gamma T-cell levels were undetectable in asplenic patients. This was despite the detection of vaccine-induced memory T-cell levels in control patients, which were analysed simultaneously following the same experimental protocol. CONCLUSION: Our results suggest that spleen is important, but not essential, for survival and/or generation of memory IgG B cells. In contrast, it seems to be indispensable for PCV-13-specific memory TH 1-cell levels. Studies enhancing the levels of vaccine induced memory cells and further enlightening the immune responses in asplenic individuals are required to develop more effective vaccination strategies against OPSI. PMID- 29532981 TI - Effect of high amylose resistant starch (HAM-RS2) supplementation on biomarkers of inflammation and oxidative stress in hemodialysis patients: a randomized clinical trial. AB - INTRODUCTION: Systemic inflammation and oxidative stress play a central role in the pathogenesis of cardiovascular disease and numerous other complications of CKD. Recent studies demonstrated that consumption of a diet enriched with amylose (HAM-RS2), attenuates oxidative stress and inflammation, and improves intestinal microbiome in CKD rats. The present study was designed to explore the effect of dietary amylose supplementation in hemodialysis patients. METHODS: Forty-six stable hemodialysis patients were randomized to receive biscuits containing 20 g/day during the first four weeks and 25 g/day in the next four weeks of either HAM-RS2 or wheat-flour. Fasting predialysis blood samples obtained before, during and at the end of trial were processed for biomarkers of oxidative stress and inflammation. FINDINGS: There was no significant difference in baseline clinical or biochemical parameters between the two groups. Serum levels of TNF-alpha, IL 6, and malondialdehyde declined significantly (P < 0.05) in the HAM-RS2-treated group but remained unchanged in the placebo-treated group. No significant difference was observed in serum Interleukin-1beta (IL-1beta) and hs-CRP concentrations and total antioxidant activity between two groups. Serum urea and creatinine concentrations significantly declined and severity of constipation improved in HAM-RS2-treated patients (P < 0.05). HAM-RS2 consumption was well tolerated and did not cause discernible side effects. DISCUSSION: Administration of HAM-RS2 for eight weeks significantly reduced levels of inflammatory and oxidative markers in hemodialysis patients confirming the results observed in CKD animals. Long term trials are needed to explore the impact of HAM-RS2 supplementation on clinical outcomes in end stage renal disease population. PMID- 29532982 TI - Temperature-Dependent Atomic Models of Detergent Micelles Refined against Small Angle X-Ray Scattering Data. AB - Surfactants have found a wide range of industrial and scientific applications. In particular, detergent micelles are used as lipid membrane mimics to solubilize membrane proteins for functional and structural characterization. However, an atomic-level understanding of surfactants remains limited because many experiments provide only low-resolution structural information on surfactant aggregates. In this work, small-angle X-ray scattering is combined with molecular dynamics simulations to derive fully atomic models of two maltoside micelles at temperatures between 10 degrees C and 70 degrees C. The micelles take the shape of general tri-axial ellipsoids and decrease in size and aggregation number with increasing temperature. Density profiles of hydrophobic groups and water along the three principal axes reveal that the minor micelle axis closely mimics lipid membranes. The results suggest that coupling atomic simulations with low resolution data allows the structural characterization of surfactant aggregates. PMID- 29532983 TI - Intensive blood pressure lowering reduces adverse cardiovascular outcomes among patients with high-normal glucose: An analysis from the Systolic Blood Pressure Intervention Trial database. AB - The objective of this analysis is to determine the effect of intensive (<120 mm Hg) versus standard (<140 mm Hg) systolic blood pressure (SBP) targets on cardiovascular (CV) outcomes among SPRINT participants with low-normal or high normal fasting glucose (FG). We categorized the 5425 SPRINT participants with FG <100 mg/dL into 2 groups: <85 mg/dL (low-normal) and 85 to <100 mg/dL (high normal). Among participants with low-normal glucose, there was no significant difference in the primary outcome (PO) between the 2 treatment arms (adjusted hazard ratio, HR: 1.27 (95% confidence interval [CI] 0.68-2.37, P = .46). However, the intensive SBP target was associated with 27% lower risk for the PO compared with the standard SBP target in those with high-normal glucose (HR 0.73, 0.57-0.93, P = .01). Our results indicate that hypertensive patients with high normal FG may benefit from intensive SBP lowering, whereas benefits were inconclusive among those with low-normal FG. PMID- 29532984 TI - Blood pressure reduced to new guideline goals in patients with high-normal glucose further reduces cardiovascular events. PMID- 29532985 TI - The Interaction of Guest Molecules with Co-MOF-74: A Vis/NIR and Raman Approach. AB - Co-MOF-74 rod like crystals with a length of several hundred micrometers are synthesized by a solvothermal procedure and their interaction with different gases is evaluated for selective gas sensing. We show strongly anisotropic absorption behavior of the Co-MOF-74 crystals when illuminated with polarized light. The interactions of guests (CO2 , propane, propene, Ar, MeOH, H2 O) with Co-MOF-74, is studied by various spectroscopic techniques. Vis/NIR shows peak shifts of Co-MOF-74 depending on the interaction with the guest. In the visible and the NIR the maximum absorbance is shifted selectively corresponding to the intensity of the CoII -guest interaction. Even propene and propane could be distinguished at room temperature by their different interactions with Co-MOF-74. Raman spectroscopy was used to detect a modified vibrational behavior of Co-MOF 74 upon gas adsorption. We show that the adsorption of H2 O leads to a characteristic shift of the peak maxima in the Raman spectra. PMID- 29532986 TI - Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. PMID- 29532988 TI - Hubner's eyelid reconstruction using a free tarsomarginal autograft in eight dogs. A retrospective study. AB - OBJECTIVE: The aim of our work was to study the potential of tarsomarginal grafting technique, in canine. ANIMAL STUDIED: All dogs included in this study had tumors of the upper or lower eyelid. Furthermore, resection of the tumor necessitated excision of the eyelid margin comprising 1/4 and 2/3. PROCEDURE: Harvesting of the graft with the length of half the length of the tumor, including its free margins was performed via a full-thickness incision on the ipsilateral healthy eyelid. The cutaneous layer and all of the muscle fibers of the transplant were meticulously removed except a 3 mm strip along the free lid margin. A full-thickness tumor excision was then performed. The graft was sutured at the level of the defect to be reconstructed. A sliding H flap was generated. The resulting nourishing myocutaneous flap was then sutured along the free margin of the tarso-conjunctivo-marginal graft. The lateral edges of the advancement flap were sutured to the edges of the receiving sites. RESULTS: The average size of the reconstructed area was 17.8 mm. The resulting stretched lid fissure length after surgery was shortened over 7 to 11 mm. This technique for grafting was used to reconstruct an eyelid that had lost tissue measuring between 1/4 and 2/3 of its length. The few complications that were encountered were mainly the occurrence of keratitis or suture dehiscence. CONCLUSIONS: This tarsomarginal grafting technique has yielded encouraging results in dogs. This technique can fill large lid defects with a physiologic lid margin but is shortening the stretched lid fissure length. PMID- 29532989 TI - Let's discuss surgical performance anxiety. PMID- 29532987 TI - NDAMDA: Network distance analysis for MiRNA-disease association prediction. AB - In recent years, microRNAs (miRNAs) are attracting an increasing amount of researchers' attention, as accumulating studies show that miRNAs play important roles in various basic biological processes and that dysregulation of miRNAs is connected with diverse human diseases, particularly cancers. However, the experimental methods to identify associations between miRNAs and diseases remain costly and laborious. In this study, we developed a computational method named Network Distance Analysis for MiRNA-Disease Association prediction (NDAMDA) which could effectively predict potential miRNA-disease associations. The highlight of this method was the use of not only the direct network distance between 2 miRNAs (diseases) but also their respective mean network distances to all other miRNAs (diseases) in the network. The model's reliable performance was certified by the AUC of 0.8920 in global leave-one-out cross-validation (LOOCV), 0.8062 in local LOOCV and the average AUCs of 0.8935 +/- 0.0009 in fivefold cross-validation. Moreover, we applied NDAMDA to 3 different case studies to predict potential miRNAs related to breast neoplasms, lymphoma, oesophageal neoplasms, prostate neoplasms and hepatocellular carcinoma. Results showed that 86%, 72%, 86%, 86% and 84% of the top 50 predicted miRNAs were supported by experimental association evidence. Therefore, NDAMDA is a reliable method for predicting disease-related miRNAs. PMID- 29532990 TI - Thermoresponsive PEG-Coated Nanotubes as Chiral Selectors of Amino Acids and Peptides. AB - A series of nanotubes with a dense layer of short poly(ethylene glycol) (PEG) chains on the inner surface are prepared by means of a coassembly process using glycolipids and PEG derivatives. Dehydration of the PEG chains by heating increases the hydrophobicity of the nanotube channel and fluorescent-dye-labeled amino acids are extracted from bulk solution. Rehydration of the PEG chains by cooling results in back-extraction of the amino acids into the bulk solution. Because of the supramolecular chirality of the nanotubes, amino acid enantiomers can be separated in the back-extraction procedure, which is detectable with the naked eye as a change in fluorescence as the amino acids are released from the nanotubes. The efficiency and selectivity of the chiral separation are enhanced by tuning the chemical features and inner diameter of the nanotube channels. For example, compared with wide nanotube channels (8 nm), narrow nanotube channels (4 nm) provide more effective electrostatic attraction and hydrogen bond interaction environments for the transporting amino acids. Introduction of branched alkyl chains to the inner surface of the nanotubes enables chiral separation of peptides containing hydrophobic amino acids. The system described here provides a simple, quick, and on-site chiral separation in biological and medical fields. PMID- 29532991 TI - Vav1 is necessary for PU.1 mediated upmodulation of miR-29b in acute myeloid leukaemia-derived cells. AB - It has been recently demonstrated that high pre-treatment levels of miR-29b positively correlated with the response of patients with acute myeloid leukaemia (AML) to hypomethylating agents. Upmodulation of miR-29b by restoring its transcriptional machinery appears indeed a tool to improve therapeutic response in AML. In cells from acute promyelocytic leukaemia (APL), miR-29b is regulated by PU.1, in turn upmodulated by agonists currently used to treat APL. We explored here the ability of PU.1 to also regulate miR-29b in non-APL cells, in order to identify agonists that, upmodulating PU.1 may be beneficial in hypomethylating agents-based therapies. We found that PU.1 may regulate miR-29b in the non-APL Kasumi-1 cells, showing the t(8;21) chromosomal rearrangement, which is prevalent in AML and correlated with a relatively low survival. We demonstrated that the PU.1-mediated contribution of the 2 miR-29b precursors is cell-related and almost completely dependent on adequate levels of Vav1. Nuclear PU.1/Vav1 association accompanies the transcription of miR-29b but, at variance with the APL-derived NB4 cells, in which the protein is required for the association of PU.1 with both miRNA promoters, Vav1 is part of molecular complexes to the PU.1 consensus site in Kasumi-1. Our results add new information on the transcriptional machinery that regulates miR-29b expression in AML-derived cells and may help in identifying drugs useful in upmodulation of this miRNA in pre-treatment of patients with non-APL leukaemia who can take advantage from hypomethylating agent based therapies. PMID- 29532992 TI - Reference intervals and percentiles for carotid-femoral pulse wave velocity in a healthy population aged between 9 and 87 years. AB - There is little information regarding age-related reference intervals (RIs) of carotid-femoral pulse wave velocity (cfPWV) for large healthy populations in South America. The aims of this study were to determine cfPWV RIs and percentiles in a cohort of healthy children, adolescents, and adults and to generate year-to year percentile curves and body-height percentile curves for children and adolescents. cfPWV was measured in 1722 healthy participants with no cardiovascular risk factors (9-87 years, 60% men). First, RIs were evaluated for males and females through correlation and covariate analysis. Then, mean and standard deviation age-related equations were obtained for cfPWV using parametric regression methods based on fractional polynomials and age-specific (year-to year) percentile curves that were defined using the standard normal distribution. Age-specific first, 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, 97.5th, and 99th percentile curves were calculated. Finally, height-related cfPWV percentile curves for children and adolescents (<21 years) were established. After adjusting for age and blood pressure differences with respect to females, males showed higher cfPWV levels (6.60 vs 6.45 m/s; P < .01). Thus, specific RIs for males and females were reported. The study provides the largest database to date concerning cfPWV in healthy people from Argentina. Specific RIs and percentiles of cfPWV are now available according to age and sex. Specific percentiles of cfPWV according to body height were reported for people younger than 21 years. PMID- 29532993 TI - MicroRNA-30c suppresses the pro-fibrogenic effects of cardiac fibroblasts induced by TGF-beta1 and prevents atrial fibrosis by targeting TGFbetaRII. AB - Atrial fibrosis serves as an important contributor to atrial fibrillation (AF). Recent data have suggested that microRNA-30c (miR-30c) is involved in fibrotic remodelling and cancer development, but the specific role of miR-30c in atrial fibrosis remains unclear. The purpose of this study was to investigate the role of miR-30c in atrial fibrosis and its underlying mechanisms through in vivo and in vitro experiments. Our results indicate that miR-30c is significantly down regulated in the rat abdominal aortic constriction (AAC) model and in the cellular model of fibrosis induced by transforming growth factor-beta1 (TGF beta1). Overexpression of miR-30c in cardiac fibroblasts (CFs) markedly inhibits CF proliferation, differentiation, migration and collagen production, whereas decrease in miR-30c leads to the opposite results. Moreover, we identified TGFbetaRII as a target of miR-30c. Finally, transferring adeno-associated virus 9 (AAV9)-miR-30c into the inferior vena cava of rats attenuated fibrosis in the left atrium following AAC. These data indicate that miR-30c attenuates atrial fibrosis via inhibition of CF proliferation, differentiation, migration and collagen production by targeting TGFbetaRII, suggesting that miR-30c might be a novel potential therapeutic target for preventing atrial fibrosis. PMID- 29532994 TI - CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-kappaB signalling. AB - The purpose of this study was to figure out the effect of ciRS-7/miR-7/NF-kappaB axis on the development of non-small cell lung cancer (NSCLC). In response, the expressions of ciRS-7, miR-7 and NF-kappaB subunit (ie RELA) within NSCLC tissues and cell lines were determined with real-time polymerase chain reaction (RT-PCR) and Western blot. Moreover, the NSCLC cells were transfected with pcDNA3-ciRS-7 ir, pcDNA3-ciRS-7, miR-NC and miR-7 mimic. Furthermore, the targeted relationships between ciRS-7 and miR-7, as well as between miR-7 and RELA, were confirmed by luciferase reporter assay. The proliferation, migration and apoptosis of NSCLC cells were, successively, measured using CCK-8 assay, wound healing assay and flow cytometry test. Consequently, ciRS-7, miR-7, histopathological grade, lymph node metastasis and histopathological stage could independently predict the prognosis of patients with NSCLC (all P < .05). Moreover, remarkably up-regulated ciRS-7 and RELA expressions, as along with down regulated miR-7 expressions, were found within NSCLC tissues and cells in comparison with normal ones (P < .05). Besides, overexpressed ciRS-7 and underexpressed miR-7 were correlated with increased proliferation, migration and invasion, yet reduced apoptosis rate of NSCLC cells (P < .05). More than that, ciRS-7 specifically targeted miR-7 to reduce its expressions (P < .05). Ultimately, the NSCLC cells within miR-7 + RELA group were observed with superior proliferative, migratory and invasive capabilities than those within miR-7 group (P < .05), and RELA expression was also significantly modified by both ciRS-7 and miR-7 (P < .05). In conclusion, the ciRS-7/miR-7/NF-kB axis could exert pronounced impacts on the proliferation, migration, invasion and apoptosis of NSCLC cells. PMID- 29532995 TI - Timing of chemotherapy-induced neutropenia is a prognostic factor in patients with advanced gastric cancer undergoing first-line chemotherapy with oxaliplatin and capecitabine: a retrospective study. AB - Chemotherapy-induced neutropenia (CIN) has been shown to be associated with improved clinical outcomes in patients with various solid tumors. This study retrospectively assessed the association between timing of CIN and prognosis in 321 patients with advanced gastric cancer (AGC) who finished at least one cycle of chemotherapy with oxaliplatin and capecitabine (XELOX). Primary landmark analyses were restricted to 274 patients who received four cycles of chemotherapy and lived for more than 4 months. CIN was categorized as early-onset and non early-onset. The correlation between timing of CIN with survival was analyzed by the Kaplan-Meier method and a Cox proportional hazards model. Relative to patients with non-early-onset CIN, those with early-onset CIN had significantly longer times to disease progression (hazard ratio [HR] 0.574; 95% confidence interval [CI] 0.453-0.729, P < 0.001) and death (HR: 0.607; 95% CI: 0.478-0.770, P < 0.001), consistent with results from the landmark group. In conclusion, timing of CIN may be a potential prognostic biomarker in patients with AGC receiving first-line chemotherapy with XELOX. Early-onset CIN predicts better survival. PMID- 29532996 TI - National cancer database analysis of outcomes in pediatric glioblastoma. AB - Glioblastoma in children is an aggressive disease with no defined standard therapy. We evaluated hospital-based demographic and survival patterns obtained through the National Cancer Database to better characterize children with glioblastoma. Our study identified 1173 patients from 0 to 19 years of age between 1998 and 2011. Comparisons were made among demographics, clinical characteristics, treatment, and survival variables. Fifty-four percent of patients were over 10 years of age. Approximately 80% of patients underwent either partial or complete resection. Adjuvant therapy was used variably, and its use increased with patient age. Forty-eight percent of patients received the combination of surgery, radiation, and chemotherapy, and 4% did not receive any treatment. As expected, patients <=5 years of age had better 5-year survival than those ages 6-10 (P = 0.01) or 11-19 years (P = 0.0077). Other factors associated with poor survival included black race and central tumor location. Better outcomes were associated with treatment that included surgery, radiotherapy, and chemotherapy compared to any other treatment combinations. Radiotherapy had no impact on survival in the 0 to 10-year-old age group, but was associated with improved survival for patients 11-19 years. We report an extensive demographic and survival analysis of pediatric glioblastoma. The observed differences likely reflect variances in tumor biology and likelihood of treatment receipt. Improved survival was associated with the use of surgery, radiotherapy, and chemotherapy. Radiation therapy was not associated with survival in patients younger than 10 years of age. PMID- 29532997 TI - Ultrathin 2D Zirconium Metal-Organic Framework Nanosheets: Preparation and Application in Photocatalysis. AB - Synthesizing ultrathin 2D metal-organic framework nanosheets in high yields has received increasing research interest but remains a great challenge. In this work, ultrathin zirconium-porphyrinic metal-organic framework (MOF) nanosheets with thickness down to ~1.5 nm are synthesized through a pseudoassembly disassembly strategy. Owing to the their unique properties originating from their ultrathin thickness and highly exposed active sites, the as-prepared ultrathin nanosheets exhibit far superior photocatalysis performance compared to the corresponding bulk MOF. This work highlights new opportunities in designing ultrathin MOF nanosheets and paves the way to expand the potential applications of MOFs. PMID- 29532998 TI - YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFRL858R, T790M -mutant resistance in vitro and in vivo. AB - YL143 was identified as a novel wild-type sparing EGFRT790M inhibitor with good pharmacokinetic properties. It potently suppresses EGFRL858R/T790M with an 50% inhibitory concentration (IC50 ) value of 2.0 +/- 0.3 nmol/L, but is approximately 92-folds less potent against EGFRWT kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFRL858R/T790M mutation at 30 nmol/L. It also exhibits acceptable pharmacokinetics (PK) parameters with an oral bioavailability value of 25.0% after oral administration in rats and exhibits promising antitumor efficacy in a gefitinib-resistant human H1975 xenografted model after oral administration of 30 mg/kg/day. These data supported that YL143 could be a promising lead compound for overcoming clinical EGFRT790M resistance of patients with non-small-cell lung cancer (NSCLC). PMID- 29532999 TI - Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation. AB - Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In-silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin-3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin-3a inhibited cellular proliferation in ACC cell line NCI-H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin-3a induced cell apoptosis and G1 cell-cycle arrest in NCI-H295R cells. Nutlin-3a also decreased cellular migration and inhibited epithelial-to-mesenchymal transition (EMT) process in terms of EMT index. Nutlin-3a resulted in decreased beta-catenin level independent of p53 level in NCI-H295R but not SW13 cells. We also evaluated the effect of Nutlin-3a on hormonal secretion of NCI-H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin-3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin-3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta-Catenin signaling in ACC warrants further study. PMID- 29533000 TI - Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. AB - In the Asia-Pacific region, treatment options are limited for patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Rituximab is widely used in this setting when purine analog-based therapies are not appropriate. We evaluated the efficacy and safety of ibrutinib compared with rituximab in a randomized, open-label phase 3 study in predominantly Asian patients with relapsed/refractory CLL/SLL. Patients (N = 160) were randomly assigned 2:1 to receive 420 mg ibrutinib (n = 106) until disease progression (PD) or unacceptable toxicity or up to six cycles of rituximab (n = 54). The primary endpoint was investigator-assessed progression-free survival (PFS); key secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. Rituximab-treated patients could crossover to receive ibrutinib after confirmed PD. At data cutoff, median treatment duration was 16.4 months for ibrutinib and 4.6 months for rituximab. Ibrutinib significantly improved PFS (hazard ratio [HR] = 0.180, 95% confidence interval [CI]: 0.105-0.308). ORR was significantly higher (P < 0.0001) with ibrutinib (53.8%) than with rituximab (7.4%). At a median follow-up of 17.8 months, ibrutinib improved OS compared with rituximab (HR = 0.446; 95% CI: 0.221-0.900; P = 0.0206). Overall incidence of adverse events (AEs) was similar between treatments and was not exposure adjusted. With ibrutinib, most common AEs were diarrhea and platelet count decreased; with rituximab, most common AEs were neutrophil count decreased and platelet count decreased. Grade >=3 AEs were reported in 82.7% of ibrutinib treated patients and 59.6% of rituximab-treated patients. Ibrutinib improved PFS, ORR, and OS compared with rituximab and displayed a manageable safety profile in Asian patients with relapsed/refractory CLL/SLL. PMID- 29533001 TI - Comparison of survival between right-sided and left-sided colon cancer in different situations. AB - Mountain of studies has showed that right-sided colon cancer (RSCC) and left sided colon cancer (LSCC) have different clinical presentation and biologic features and should be considered as two distinct disease entities. The survival difference between RSCC and LSCC remains controversial. Using Surveillance, Epidemiology, and End Results (SEER) database, we identified colon adenocarcinoma patients from 2004 to 2013. The 5-year cause-specific survival (CSS) was our primary endpoint. All statistical analyses were performed using the Intercooled Stata 13.0. All statistical tests were two-sided. The study included 95,847 (58.72%) RSCC and 67,385 (41.28%) LSCC patients. RSCC patients were older, more often females, more Caucasian, more unmarried, more advanced T and N stage, larger tumor sizes, and more poorly differentiated tumor, while LSCC patients had more stage IV diseases. Location was an independent prognostic factor in the multivariable analysis. Compared with RSCC patients, the hazard ratio for LSCC was 0.87, 95% CI: 0.85-0.89 P < 0.001. There was no survival difference between RSCC and LSCC in the following situations: older than 68 years old, T3-4, N0, poorly differentiated, and undifferentiated diseases. We firstly reported that RSCC patients had a better prognosis than LSCC in mucinous adenocarcinoma/signet ring cell carcinoma patients. RSCC patients also had a better prognosis than LSCC in stage II disease. There is a need for further subdivisions when analyzing the survival difference between RSCC and LSCC patients. RSCC had lower mortality rate than LSCC in stage II disease and mucinous adenocarcinoma/signet ring cell carcinoma patients. PMID- 29533002 TI - Differences in clinicopathological characteristics and computed tomography findings between signet ring cell carcinoma and nonsignet ring cell carcinoma in early and advanced gastric cancer. AB - Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics. SRC's clinicopathological characteristics and prognosis are still controversial. Our study is to describe the clinicopathological features and multidetector computed tomography (MDCT) findings of patients with SRC of the stomach in comparison with nonsignet ring cell adenocarcinoma (NSRC). We retrospectively analyzed data from 241 patients who had undergone curative gastrectomy, including 62 SRC and 179 NSRC. Clinicopathological outcomes and MDCT findings were evaluated, and we investigated whether these variables were correlated with histopathological type. In early gastric carcinoma, patients with SRC were younger (50.2 vs. 60.2 years; P = 0.000) and more likely to be observed in the middle and lower third stomach (P = 0.010). Early SRC had a tendency to be confined to the mucosa (82.1%). There were significant differences in degree of enhancement between early SRC and NSRC on MDCT imaging (P < 0.001). In advanced gastric carcinoma, SRC was more likely to be stage T3-4 (100%). SRC patients had thicker tumors (P = 0.001) and a higher frequency of diffusely infiltrative gross appearance (P < 0.001). SRC was more likely to have high-degree contrast enhancement than were NSRC (P = 0.001). The maximal diameter of SRC tumor on MDCT imaging correlated with lymph node metastasis (sensitivity 93.9%, specificity 74.1%) and serosal invasion (sensitivity 89.5%, specificity 78.0%) of SRC. In conclusion, SRC differs significantly from NSRC in clinicopathological features at presentation. MDCT could help differentiate advanced gastric SRC from NSRC based on the thickened stomach wall, high-degree contrast enhancement, and a higher frequency of diffusely infiltrative gross appearance, particularly in combination. PMID- 29533003 TI - Cancer survival in Cixian of China, 2003-2013: a population-based study. AB - Cixian is one of the high-risk areas for upper gastrointestinal cancer in China and the world. From 2005, comprehensive population-based screening for upper gastrointestinal cancers has been conducted in Cixian. The aim of this study was to investigate population-based cancer survival from 2003 to 2013 and to explore the effect of screening on upper gastrointestinal cancer survival in Cixian. Observed survival was estimated using the life table method. The expected survival from the general population was calculated using all-cause mortality data from the population of Cixian with the EdererII method. Cixian cancer registry, with a total coverage of 6.88 million person years, recorded 19,628 cancer patients diagnosed during 2003-2013. In Cixian, from 2003 to 2013, there were 19,628 newly cancer cases and 13,984 cancer deaths, with an incidence rate of 285.37/100,000 and mortality rate of 203.31/100,000. The overall five-year relative cancer survival for patients diagnosed in Cixian in 2003-2013 was 22.53%. The relative survival for all cancers combined in Cixian had an overall upward trend from 2003 to 2013. Among upper gastrointestinal cancer in Cixian, the five-year relative survival for cardia gastric cancer was highest at 30.42%, followed by oesophageal cancer at 25.37% and noncardia gastric cancer at 18.93%. In 2013, the five-year relative survival for oesophageal cancer, cardia gastric cancer, and noncardia gastric cancer patients aged 45-69 years was 39.97% (95% CI: 34.52-45.43%), 51.74% (95% CI: 42.09-60.86%), and 37.43% (95% CI: 26.93 48.17%), respectively, the absolute values increasing 14.11%, 16.71%, and 14.92% compared with that in 2003. There is an increasing trend in overall survival for upper gastrointestinal cancer with early screening and treatment of cancer in Cixian. PMID- 29533004 TI - Comparison and validation of the prognostic value of preoperative systemic immune cells in hepatocellular carcinoma after curative hepatectomy. AB - In this study, we aimed to compare and validate the prognostic abilities of preoperative systemic immune cells in hepatocellular carcinoma (HCC) after curative hepatectomy. We developed two nomograms to predict the postoperative recurrence-free survival (RFS) and overall survival (OS) after comparisons of the systemic immune cell prognostic scores. The two nomograms were constructed based on 305 patients who underwent curative hepatectomy for HCC. The predictive accuracy and discriminative ability of the nomograms were compared with six commonly used staging systems for HCC. The results were validated using bootstrap resampling and an internal validation cohort of 142 patients and an external validation cohort of 169 patients. Necroinflammatory activity in peritumoral liver tissues in the primary cohort was evaluated by hematoxylin and eosin (H&E) staining. Neutrophil, monocyte, and lymphocyte ratio (NMLR) had a higher area under the receiver operating characteristic curves (AUROC) value at both RFS (AUC = 0.603) and OS (AUC = 0.726) compared to that of other systemic immune cell prognostic scores. The independent predictors of RFS or OS, including alpha fetoprotein (AFP), tumor size, tumor number, microvascular invasion, and NMLR, were incorporated into the two nomograms. In the primary cohort, the C-indexes of the RFS and OS nomograms were 0.705 and 0.797, respectively. The ROC analyses showed that the two nomograms had larger AUC values (0.664 for RFS and 0.821 for OS) than those of the American Joint Commission on Cancer seventh edition, Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, Japan Integrated Staging Score, Okuda stage, and the Vauthey's system. These results were verified by internal and external validations. The nomogram-predicted probability of RFS was associated with peritumoral necroinflammatory activity scores (r = 0.304, P < 0.001). The proposed nomograms had accurate prognostic prediction in patients with HCC after curative hepatectomy. PMID- 29533005 TI - Disparities in cancer survival and incidence by metropolitan versus rural residence in Utah. AB - Cancer disparities in rural and frontier communities are an important issue in Utah because much of Utah is sparsely populated. The aims of this study were to investigate whether there are differences in the cancer incidence and 5-year survival rates in Utah by metropolitan/rural residence and to investigate disparities in distributions of cancer risk factors. We used cancer registry records to identify patients diagnosed with a first primary cancer in Utah between 2004 and 2008. We estimated 5-year survival and incidence rates. The Cox proportional hazards model was used to estimate hazard ratios (HRs) for the risk of death. There were 32,498 (86.9%) patients with cancer who lived in metropolitan counties and 4906 (13.1%) patients with cancer who lived in rural counties at the time of cancer diagnosis. Patients with cancer from rural counties were more likely to be older, American Indian/Alaskan Native, non Hispanic, male, and diagnosed at higher stage. Rural residents had a five-year relative survival that was 5.2% lower than metropolitan residents and a 10% increase in risk of death (HR = 1.10, 95% CI = 1.03, 1.18) after adjustment for multiple factors. Overall, the cancer incidence rates in rural counties were lower by 11.9 per 100,000 per year (449.2 in rural counties vs. 461.1 in metropolitan counties). Cancer patients living in rural counties of Utah had different demographic characteristics as well as differences in incidence and survival rates. Further studies with individual-level data are necessary to investigate the reasons behind these differences in cancer incidence and survival to reduce disparities. PMID- 29533006 TI - Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease. AB - To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening. PMID- 29533007 TI - Oxaloacetate induces apoptosis in HepG2 cells via inhibition of glycolysis. AB - Most cancer cells perform glycolysis despite having sufficient oxygen. The specific metabolic pathways of cancer cells have become the focus of cancer treatment. Recently, accumulating evidence indicates oxidative phosphorylation (OXPHOS) and glycolysis can be regulated with each other. Thus, we suggest that the glycolysis of cancer cells is inhibited by restoring or improving OXPHOS in cancer cells. In our study, we found that oxaloacetate (OA) induced apoptosis in HepG2 cells in vivo and in vitro. Meanwhile, we found that OA induced a decrease in the energy metabolism of HepG2 cells. Further results showed that the expression and activity of glycolytic enzymes were decreased with OA treatment. Conversely, the expression and activity of enzymes involved in the TCA cycle and OXPHOS were increased with OA treatment. The results indicate that OA can inhibit glycolysis through enhancement of OXPHOS. In addition, OA-mediated suppression of HIF1alpha, p-Akt, and c-myc led to a decrease in glycolysis level. Therefore, OA has the potential to be a novel anticancer drug. PMID- 29533008 TI - Genomic complexity in pediatric synovial sarcomas (Synobio study): the European pediatric soft tissue sarcoma group (EpSSG) experience. AB - A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has emerged as independent prognostic factor associated with the risk of metastatic relapse in synovial sarcoma (SS). The aim was to assess GI in pediatric patients with SS, to determine its value as a prognostic factor. All pediatric/adolescent/young adults' (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Definition of GI was A2 /C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI1 group corresponds to cases with no copy number alterations (flat profile, GI = 0) and GI2 group cases with at least one or more copy number alterations (rearranged profile; GI >= 1). Samples were available from 61 patients. The median age of the cohort was 13 years (range: 4-24). Overall, 55.7% were GI1 group, and 44.3% GI2 . After a median follow-up of 62 months (range: 0.1 112), 10 tumor events occurred and five patients died. Respectively, for GI1 versus GI2 groups, five-year event-free survival (EFS) was 93.8 +/- 4.2% versus 64.9 +/- 10.1% (P < 0.006) and five-year Metastatic-Free Survival (MFS) 93.8 +/- 4.2% versus 72.9 +/- 9.5% (P < 0.04). In multivariate analysis, GI status as adjusted for IRS group, patient age, site, and tumor size remain independent prognostic for EFS with a relative risk (RR) of 6.4 [1.3-31.9] (P < 0.01) and RR for MFS is 4.8 [0.9-25.7] (P < 0.05). Genomic complexity evaluated through GI may explain the metastatic behavior of pediatric SS. PMID- 29533010 TI - Linking the fine-scale social environment to mating decisions: a future direction for the study of extra-pair paternity. AB - Variation in extra-pair paternity (EPP) among individuals of the same population could result from stochastic demography or from individual differences in mating strategies. Although the adaptive value of EPP has been widely studied, much less is known about the characteristics of the social environment that drive the observed patterns of EPP. Here, we demonstrate how concepts and well-developed tools for the study of social behaviour (such as social network analysis) can enhance the study of extra-pair mating decisions (focussing in particular on avian mating systems). We present several hypotheses that describe how characteristics of the social environment in which individuals are embedded might influence the levels of EPP in a socially monogamous population. We use a multi level social approach (Hinde, 1976) to achieve a detailed description of the social structure and social dynamics of individuals in a group. We propose that the pair-bond, the direct (local) social environment and the indirect (extended) social environment, can contribute in different ways to the variation observed in the patterns of EPP, at both the individual and the population level. A strength of this approach is that it integrates into the analysis (indirect) interactions with all potential mates in a population, thus extending the current framework to study extra-pair mating behaviour. We also encourage the application of social network methods such as temporal dynamic analysis to depict temporal changes in the patterns of interactions among individuals in a group, and to study how this affects mating behaviour. We argue that this new framework will contribute to a better understanding of the proximate mechanisms that drive variation in EPP within populations in socially monogamous species, and might ultimately provide insights into the evolution and maintenance of mating systems. PMID- 29533009 TI - Albumin-to-fibrinogen ratio as a promising biomarker to predict clinical outcome of non-small cell lung cancer individuals. AB - Chronic inflammation is one of the critical causes to promote the initiation and metastasis of solid malignancies including lung cancer (LC). Here, we aimed to investigate the prognostic roles of albumin (Alb)-to-fibrinogen (Fib) ratio (AFR), Fib and Alb in LC and to establish a novel effective nomogram combined with AFR. Four hundred twelve LC patients diagnosed between February 2005 and December 2014 were recruited in this prospective study. The prognostic roles of AFR, Fib, Alb, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) were identified by X-tile software, Kaplan-Meier curve, Cox regression model, and time-dependent ROC. Pretreatment high circulating Fib, low AFR, and Alb were significantly associated with increased risk of death for LC patients, especially for non-small cell lung cancer (NSCLC) patients in all stages. The area under curves (AUCs) of AFR, Fib, and NLR were higher than them within Alb and PLR for predicting the survival of NSCLC patients. Moreover, we found that clinical outcome of high AFR patient with chemo-radiotherapy was superior to low AFR patient; overall survival rate of stage II-III NSCLC patients undergoing chemo-radiotherapy was significantly lower than the surgical patients with treatment of adjuvant chemo-radiotherapy(P = 0.001) in low AFR subgroup. On the contrary, clinical outcome of the patients receiving chemo-radiotherapy was the same to the patients undergoing surgery and adjuvant chemo-radiotherapy (P = 0.405) in high AFR subgroup. In addition, c index of predicted nomogram including AFR (0.717) for NSCLC patients with treatment of chemo-radiotherapy was higher than that without AFR (0.707). Our findings demonstrated that circulating pretreatment AFR might be a potential biomarker to predict clinical efficacy of surgical resection and adjuvant chemo radiotherapy and be a prognostic biomarker for NSCLC individuals. PMID- 29533011 TI - Excessive risk of second primary cancers in young-onset colorectal cancer survivors. AB - With an increasing trend of patients with young-onset colorectal cancer (CRC), risks of second primary cancers (SPCs) among them become a concerning issue. We aimed to define the detailed risk and site-distributed patterns of SPCs in young CRC individuals (age <=50). A population-based cohort were identified from the Surveillance, Epidemiology, and End Results database between 1973 and 2013. Standardized incidence ratios (SIRs) and absolute excess risk (AER) were calculated to assess the risk for SPCs compared with the general population. A total of 44,106 patients, including 3245 (7.4%) the young and 40,861 (92.6%) the old, developed 50,679 secondary malignancies subsequently. With increased age, the risk of secondary cancers gradually decreased. A significant 44% excess risk of SPCs was observed in the young (SIR = 1.44, AER = 34.23), while a slightly increased risk was noted in the old (SIR = 1.02, AER = 4.29). For young survivors, the small intestine (SIR = 8.49), bile ducts (SIR = 3.77), corpus, and uterus (SIR = 2.45) were the most common sites of SPCs. Significantly, excess SIRs in the young were persisted regardless of other factors. For the young, secondary cancer-related deaths were responsible for 51.2% of overall deaths and secondary stomach, liver and bile, pancreas cancers were top three causes. An excessive risk of SPCs existed in young CRC survivors, and this trend was consistent among different subgroups. We hope our findings may inform future targeted screening strategies among young-onset CRC survivors. PMID- 29533012 TI - Polymorphism rs2682818 in miR-618 is associated with colorectal cancer susceptibility in a Han Chinese population. AB - MicroRNAs (miRNAs), endogenous small noncoding RNAs (ncRNAs), play crucial roles in cancer development. Many studies have demonstrated that miRNAs can serve as diagnostic and therapeutic biomarkers for malignancies. Additionally, single nucleotide polymorphisms (SNPs) located in miRNA functional regions have been reported to be involved in cancer susceptibility. In this study, we investigated the associations between SNPs located in miRNA functional regions and colorectal cancer (CRC) susceptibility. We systematically screened all candidate miRNAs and their SNPs and then evaluated the relationships between the SNPs and CRC susceptibility in a Han Chinese population including 878 patients with CRC and 884 controls. Genotyping was performed by TaqMan assay. After comprehensively screening the miRNAs and SNPs, we elected to evaluate the association between SNP rs2682818 in miR-618 and CRC susceptibility. We found that the AA and AC/AA genotypes of rs2682818 were associated with a decreased risk of CRC compared with the CC genotype (odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37-0.79 for AA vs. CC in codominant model; OR = 0.82, 95% CI = 0.68-0.99 for AC/AA vs. CC in dominant model). However, we obtained no statically significant results in our subgroup analyses. SNP rs2682818 in miR-618 has potential as a biomarker for individuals with high CRC susceptibility. Our findings need to be verified in studies including larger samples. Moreover, molecular functional studies of miR 681 must be performed to confirm its relationship with CRC. PMID- 29533013 TI - Promoting the Direct H2 O2 Generation Catalysis by Using Hollow Pd-Sn Intermetallic Nanoparticles. AB - Although direct hydrogen (H2 ) oxidation to hydrogen peroxide (H2 O2 ) is considered as a promising strategy for direct H2 O2 synthesis, the desirable conversion efficiency remains formidable challenge. Herein, highly active and selective direct H2 oxidation to H2 O2 is achieved by using hollow Pd-Sn intermetallic nanoparticles (NPs) as the catalysts. By tuning the catalytic solvents and catalyst supports, the efficiency of direct H2 oxidation to H2 O2 can be optimized well with the hollow Pd2 Sn NPs/P25 exhibiting H2 O2 selectivity up to 80.7% and productivity of 60.8 mol kgcat-1 h-1 . In situ diffuse reflectance infrared Fourier transform spectroscopy of CO adsorption results confirm the different surface atom arrangements between solid and hollow Pd-Sn NPs. X-ray photoelectron spectra results show that the higher efficiency of Pd2 Sn NPs/P25 is due to its higher content of metallic Pd and higher ratio of Snx+ , which benefit H2 O2 production and selectivity. PMID- 29533014 TI - Association between preoperative serum insulin levels and lymph node metastasis in endometrial cancer-a prospective cohort study. AB - Endometrial cancer is a common gynecological malignancy in developed countries. Insulin has been identified as a risk factor for endometrial cancer. However, whether insulin levels are related to the risk of lymph node metastasis (LNM) in endometrial cancer is unknown. We conducted a prospective cohort study in a regional hospital to examine the relationships between insulin levels and risk of LNM in premenopausal and postmenopausal women. A total of 668 patients were recruited. Of these, 206 were premenopausal (mean age: 42.01 +/- 10.17) and 462 were postmenopausal (mean age: 62.13 +/- 13.85). The incidence of LNM in both premenopausal and postmenopausal groups was comparable at 7% and 8%, respectively. In premenopausal women, multivariate logistic regression demonstrated that insulin levels (OR: 2.11, 95% CI: 1.48-2.85, P < 0.05) were significant predictors of LNM risk. In the same group, insulin levels remained significant predictors of LNM risk (cut-off: 10.48 MUIU/mL) when adjusted for body mass index (BMI) (OR: 3.51, 95% CI: 1.42-5.98; P < 0.05) or for waist-to-hip ratio (WHR) (OR: 1.87, 95% CI: 1.08-2.66; P < 0.05). Similarly, in postmenopausal women, multivariate logistic regression showed that insulin levels (OR: 1.99, 95% CI: 1.30-2.89; P < 0.05) also significantly predicted LNM risk. This relationship was maintained even after adjustment for BMI (cut-off: 7.40 MUIU/mL, OR: 1.99, 95% CI: 1.01-3.12, P < 0.05) or for WHR (cut-off: 10.15 MUIU/mL, OR: 1.61, 95% CI: 1.04-2.35; P < 0.05). Insulin levels are significantly associated with LNM risk in both premenopausal and postmenopausal women with endometrial cancer. Further prospective studies are needed to examine a potential causal relationship and determine whether its use can offer incremental value for risk stratification in this patient population. PMID- 29533015 TI - Physical activity across the lifespan and liver cancer incidence in the NIH-AARP Diet and Health Study cohort. AB - While liver cancer rates in the United States are increasing, 5-year survival is only 17.6%, underscoring the importance of prevention. Physical activity has been associated with lower risk of developing liver cancer, but most studies assess physical activity only at a single point in time, often in midlife. We utilized physical activity data from 296,661 men and women in the NIH-AARP Diet and Health Study cohort to test whether physical activity patterns over the life course could elucidate the importance of timing of physical activity on liver cancer risk. We used group modeling of longitudinal data to create physical activity trajectories using four time points across the life course from teenage years through middle age, identifying seven distinct trajectories. We then used Cox proportional hazards regression to assess the association between the physical activity trajectories and risk of hepatocellular carcinoma, the most common type of liver cancer. We found that, in adjusted analyses, compared to those with consistently low physical activity patterns, those who maintained activity levels over time had a 26-36% lower risk of liver cancer and those who increased physical activity over time had no associations with risk, while those who decreased activity over time had a nonsignificantly higher risk of liver cancer. Our results suggest that sustained physical activity is associated with lower risk of hepatocellular carcinoma, while increasing physical activity later in life may not yield the same benefit. Future research with larger sample sizes and more detailed data on dose and timing of physical activity may continue to yield insight into this association between physical activity and liver cancer risk. PMID- 29533017 TI - Traditional Chinese Medicine CFF-1 induced cell growth inhibition, autophagy, and apoptosis via inhibiting EGFR-related pathways in prostate cancer. AB - Traditional Chinese medicine (TCM) has a combined therapeutic result in cancer treatment by integrating holistic and local therapeutical effects, by which TCM can enhance the curative effect and reduce the side effect. In this study, we analyzed the effect of CFF-1 (alcohol extract from an anticancer compound Chinese medicine) on prostate cancer (PCa) cell lines and studied in detail the mechanism of cell death induced by CFF-1 in vitro and in vivo. From our data, we found for the first time that CFF-1 obviously arrested cell cycle in G1 phase, decreased cell viability and then increased nuclear rupture in a dose-dependent manner and finally resulted in apoptosis in prostate cancer cells. In molecular level, our data showed that CFF-1 induced inhibition of EGFR auto-phosphorylation and inactivation of EGFR. Disruption of EGFR activity in turn suppressed downstream PI3K/AKT and Raf/Erk signal pathways, resulted in the decrease of p-FOXO1 (Ser256) and regulated the expression of apoptosis-related and cycle-related genes. Moreover, CFF-1 markedly induced cell autophagy through inhibiting PI3K/AKT/mTOR pathway and then up-regulating Beclin-1 and LC-3II and down regulating phosphorylation of p70S6K. In vivo, CFF-1-treated group exhibited a significant decrease in tumor volume compared with the negative control group in subcutaneous xenograft tumor in nude mice via inhibiting EGFR-related signal pathways. Thus, bio-functions of Chinese medicine CFF-1 in inducing PCa cell growth inhibition, autophagy, and apoptosis suggested that CFF-1 had the clinical potential to treat patients with prostate cancer. PMID- 29533016 TI - A greater birthweight increases the risk of acute leukemias in Mexican children experience from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL). AB - In Mexico, due to the high rates of diabetes, overweight, and obesity, there has also been noted an increased newborn weight, which may be contributing to the elevated incidence rate of childhood acute leukemia (AL). We conducted a case control study in public hospitals of Mexico City aimed to know whether a greater weight at birth is associated with a higher risk of developing leukemia. We included incident cases with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 2010 and 2015. Controls were frequency-matched to the cases by age, sex, and health institution. Logistic regression analysis was performed adjusting risks by child's sex, overcrowding index, birth order, and mother's age at the time of pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals were calculated. A total of 1455 cases and 1455 controls were included. An evident association between ALL and child's birthweight >=2500 g was found (aOR 2.06; 95% CI: 1.59, 2.66) and also, in those with birthweight >=3500 g (aOR 1.19; 95% CI: 1.00, 1.41). In AML patients with birthweight >=2500 g and >=3500 g, an aOR of 1.77 (95% CI: 1.07, 2.94) and 1.42 (95% CI: 1.03-1.95) was observed, respectively. No association was noticed with either type of AL and a birthweight >=4000 g. To sum up, we found a moderate association between not having a low birthweight and an increased risk of acute leukemias. Birthweight >=3500 g was also a risk factor for both types of leukemia. This suggests that a greater birthweight may increase the risk of acute leukemias in Mexican children. PMID- 29533018 TI - Androgen receptor as a prognostic biomarker and therapeutic target in uterine leiomyosarcoma. AB - OBJECTIVE: To investigate the expression of androgen receptor (AR) and its correlation with disease status and survival outcome in uterine leiomyosarcoma with other hormone receptors. METHODS: The medical records and paraffin blocks of 42 patients were reviewed. The immunohistochemical expression of AR, estrogen receptor (ER), progesterone receptor (PR), gonadotropin releasing hormone (GnRH), and cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) were assessed using tissue microarray. RESULTS: In total, AR expression was observed in 11 patients (26.2%). International Federation of Gynecology and Obstetrics (FIGO) stage and AR were independent factors for disease-free survival (DFS) in multivariate regression analysis (odds ratio [OR]=5.8; 95% confidence interval [CI]=1.2-28.4 and OR=0.2; 95% CI=0.05-0.90; p=0.029 and 0.032, respectively). There were no deaths in the AR expression group, whereas the 5-year overall survival (OS) was 54.8% in the no expression group (p=0.014). Co-expression of ER and/or PR with AR was associated with significantly better 5-year DFS and OS than those with negative AR (72.7% vs. 28.6% and 100% vs. 64.3%; p=0.020 and 0.036, respectively). AR may be an independent prognostic marker regardless of ER/PR. CONCLUSION: AR can be a potential prognostic biomarker in uterine leiomyosarcoma. PMID- 29533019 TI - Prognostic factors for patients with early-stage uterine serous carcinoma without adjuvant therapy. AB - OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive type 2 endometrial cancer. Data on prognostic factors for patients with early-stage USC without adjuvant therapy are limited. This study aims to assess the baseline recurrence risk of early-stage USC patients without adjuvant treatment and to identify prognostic factors and patients who need adjuvant therapy. METHODS: Sixty-eight patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II USC between 1997 and 2016 were included. All the cases did not undergo adjuvant treatment as institutional practice. Clinicopathological features, recurrence patterns, and survival outcomes were analyzed to determine prognostic factors. RESULTS: FIGO stages IA, IB, and II were observed in 42, 7, and 19 cases, respectively. Median follow-up time was 60 months. Five-year disease-free survival (DFS) and overall survival (OS) rates for all cases were 73.9% and 78.0%, respectively. On multivariate analysis, cervical stromal involvement and positive pelvic cytology were significant predictors of DFS and OS, and >=1/2 myometrial invasion was also a significant predictor of OS. Of 68 patients, 38 patients had no cervical stromal invasion or positive pelvic cytology and showed 88.8% 5-year DFS and 93.6% 5-year OS. CONCLUSION: Cervical stromal invasion and positive pelvic cytology are prognostic factors for stage I-II USC. Patients with stage IA or IB USC showing negative pelvic cytology may have an extremely favorable prognosis and need not receive any adjuvant therapies. PMID- 29533020 TI - Insulin resistance and overweight prolonged fertility-sparing treatment duration in endometrial atypical hyperplasia patients. AB - OBJECTIVE: Our previous study showed that insulin resistance (IR) was related to endometrial hyperplasia as well as endometrial cancer. But the exact impact of IR on fertility-sparing treatment in endometrial hyperplasic disease is unclear. This study investigated how IR affects fertility-sparing treatment in endometrial atypical hyperplasia (EAH) patients. METHODS: The 151 EAH patients received fertility-sparing treatment were retrospectively investigated. All patients received high-dose progestin combined with hysteroscopy. Therapeutic effects were evaluated by hysteroscopy every 3 months during the treatment. RESULTS: The median age was 33.0 years old (range, 21-54 years old). Sixty-one patients (40.4%) were insulin resistant. Three patients were excluded from the analysis because they chose hysterectomy within 3 months after initiation of progestin treatment. The 141 out of 148 (95.3%) patients achieved complete response (CR). No difference was found in cumulative CR rate between those with or without IR (90.2% vs. 95.6%, p=0.320). IR significantly affected therapeutic duration to achieve CR (8.1+/-0.5 months with IR vs. 6.1+/-0.4 months without IR, p=0.004). Overweight (body mass index [BMI]>=25 kg/m2) was associated with higher risk of treatment failure (odds ratio=5.61; 95% confidence interval=1.11-28.35; p=0.040) and longer therapeutic duration to achieve CR (7.6+/-0.5 months vs. 6.3+/-0.4 months, p=0.019). EAH patients with both IR and overweight (IR+BMI+) had the longest therapeutic time compared with other patients (8.8+/-0.6 months vs. 5.6+/ 0.7, 6.3+/-0.4, and 6.4+/-0.8 months for IR-BMI+, IR-BMI-, and IR+BMI-, respectively, p=0.006). CONCLUSION: IR and overweight were associated with longer therapeutic duration in EAH patients receiving progestin-based fertility-sparing treatment. PMID- 29533021 TI - Retrospective analysis of sites of recurrence in stage I epithelial ovarian cancer. AB - OBJECTIVE: The aim of the study is to investigate recurrence of stage I epithelial ovarian cancer. METHODS: Six hundred two patients diagnosed with stage I epithelial ovarian cancer at 4 hospitals between 2000 and 2013 were retrospectively analyzed. Age, surgical procedure, substage, histologic type, adjuvant chemotherapy, recurrence, initial recurrence site (peritoneal dissemination [P], hematogenous recurrence [H], lymphogenous recurrence [L], and others [O]), and frequency of recurrence at each site were investigated retrospectively. RESULTS: Median age was 54 years and median follow-up was 60 months. The stage was IA in 180 cases (30%), IB in 8 (1%), IC1 in 247 (41%), IC2 in 63 (10%), and IC3 in 104 (17%). Systematic lymph node dissection including both pelvic and para-aortic lymph nodes was performed in 224 patients (37%), and 412 patients (68%) received adjuvant chemotherapy. Recurrence occurred in 70 patients (11.6%). The median time to recurrence was 18 months, and the stage was IA in 13 (19%), IB in 1 (1%), IC1 in 24 (34%), IC2 in 9 (13%), and IC3 in 23 (33%) cases. The numbers of recurrence at the P, H, L, and O sites, including overlapping cases, were 49 (70%), 18 (26%), 9 (13%), and 6 (9%), respectively, and recurrence by peritoneal dissemination in the pelvis occurred in 43 cases (61%). CONCLUSION: Recurrence of stage I epithelial ovarian cancer by peritoneal dissemination was frequent, especially in the pelvis. There is a need to elucidate the pathogenesis of peritoneal recurrence and to prepare a treatment strategy to prevent pelvic peritoneal recurrence. PMID- 29533022 TI - Endometrial cancer risk and survival by tumor MMR status. AB - OBJECTIVE: The risk of developing endometrial cancer (EC) and/or survival following a diagnosis of EC might differ by tumor DNA mismatch repair (MMR) status. We assessed the association between tumor MMR status (classified as MMR proficient, somatic MMR-deficient, germline MMR-deficient) and the risk of developing EC and survival following a diagnosis of EC. METHODS: We analyzed data from women who participated in the Australian National Endometrial Cancer Study (ANECS) conducted between 2005 and 2007. Risk analyses (698 cases/691 population controls) utilized sociodemographic and lifestyle information obtained from telephone interviews at recruitment. For survival analyses (728 cases), patients' clinical data was abstracted from medical records, and survival data were obtained via linkage with the Australian National Death Index. We used logistic regression analysis to evaluate the associations between tumor MMR status and EC risk, and proportional hazards models to perform survival analyses with adjustment of known prognostic factors. RESULTS: Established risk factors for EC did not differ significantly by tumor MMR status. In analyses including all EC subtypes, overall and EC-specific survival did not differ by tumor MMR status. Among women with the most common endometrioid subtype, EC-specific survival was worse for women with somatic MMR-deficient EC compared to women with MMR proficient EC (hazard ratio [HR]=2.18; 95% confidence interval [CI]=1.19-4.01). CONCLUSION: The risk of EC is not associated with MMR status. Accurate separation of germline from somatic causes of MMR deficiency suggests that patients with endometrioid subtype somatic MMR-deficient tumors have poorer EC-specific survival than those with MMR-proficient tumors, after accounting for other prognostic factors. PMID- 29533023 TI - A score system for complete cytoreduction in selected recurrent ovarian cancer patients undergoing secondary cytoreductive surgery: predictors- and nomogram based analyses. AB - OBJECTIVE: To test the applicability of the Arbeitsgemeinschaft Gynakologische Onkologie (AGO) and Memorial Sloan Kettering (MSK) criteria in predicting complete cytoreduction (CC) in patients undergoing secondary cytoreductive surgery (SCS) for recurrent ovarian cancer (ROC). METHODS: Data of consecutive patients undergoing SCS were reviewed. The Arbeitsgemeinschaft Gynakologische Onkologie OVARian cancer study group (AGO-OVAR) and MSK criteria were retrospectively applied. Nomograms, based on AGO criteria, MSK criteria and both AGO and MSK criteria were built in order to assess the probability to achieve CC at SCS. RESULTS: Overall, 194 patients met the inclusion criteria. CC was achieved in 161 (82.9%) patients. According to the AGO-OVAR criteria, we observed that CC was achieved in 87.0% of patients with positive AGO score. However, 45 out of 71 (63.4%) patients who did not fulfilled the AGO score had CC. Similarly, CC was achieved in 87.1%, 61.9% and 66.7% of patients for whom SCS was recommended, had to be considered and was not recommended, respectively. In order to evaluate the predictive value of the AGO-OVAR and MSK criteria we built 2 separate nomograms (c-index: 0.5900 and 0.5989, respectively) to test the probability to achieve CC at SCS. Additionally, we built a nomogram using both the aforementioned criteria (c-index: 0.5857). CONCLUSION: The AGO and MSK criteria help identifying patients deserving SCS. However, these criteria might be strict, thus prohibiting a beneficial treatment in patients who do not met these criteria. Further studies are needed to clarify factors predicting CC at SCS. PMID- 29533024 TI - Oncologic effectiveness of nerve-sparing radical hysterectomy in cervical cancer. AB - OBJECTIVE: Nerve-sparing radical hysterectomy (NSRH) was introduced with the aim to reduce pelvic dysfunctions related to conventional radical hysterectomy (RH). Here, we sought to assess the effectiveness and safety of NSRH in a relatively large number of the patients of cervical cancer (CC) patients undergoing either primary surgery or neoadjuvant chemotherapy (NACT) followed by surgery. METHODS: Outcomes of consecutive patients undergoing NSRH and of a historical cohort of patients undergoing conventional RH were retrospectively reviewed. RESULTS: This study included 325 (49.8%) and 327 (50.2%) undergoing NSRH and RH, respectively. Via a multivariable model, nodal status was the only factor predicting for DFS (hazard ratio [HR]=2.09; 95% confidence interval [CI]=1.17-3.73; p=0.01). A trend towards high risk of recurrence was observed for patients affected by locally advanced cervical cancer (LACC) undergoing NACT followed by surgery (HR=2.57; 95% CI=0.95-6.96; p=0.06). Type of surgical procedures (NSRH vs. RH) did not influence risk of recurrence (p=0.47). Similarly, we observed that the execution of NSRH rather than RH had not a detrimental effect on OS (HR=1.19; 95% CI=0.16 9.01; p=0.87). Via multivariable model, no factor directly correlated with OS. No difference in early complication rates was observed between the study groups. Conversely, a significant higher number of late complications was reported in RH versus NSRH groups (p=0.02). CONCLUSION: Our data suggested that NSRH upholds effectiveness of conventional RH, without increasing recurrence and complication rates but improving pelvic dysfunction rates. PMID- 29533025 TI - Outpatient cervical brachytherapy in the setting of ongoing antiplatelet therapy or oral anticoagulation. PMID- 29533026 TI - Gynecologic cancer in Brazil and the law of sixty days. PMID- 29533027 TI - Clinical and health policy experiences with HPV prevalence within the Hungarian organized cervical cancer screening program. PMID- 29533028 TI - Effect of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on relapse pattern in primary epithelial ovarian cancer: a propensity score based case-control study. AB - OBJECTIVE: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed as a treatment in ovarian cancer. A recently published RCT demonstrated that HIPEC prolongs disease-free survival (DFS) and overall survival (OS) in ovarian cancer. The aim of the study was to investigate oncologic results of cytoreductive surgery+HIPEC compared with cytoreductive surgery alone in advanced primary ovarian cancer with a particular attention to the pattern of recurrence. METHODS: This is a retrospective case control study with a propensity score (PS) matching of the patients. All the patients treated for primary advanced ovarian cancer who underwent interval surgery with or without HIPEC were collected; a PS was calculated in order to match cases to controls. RESULTS: Among 77 eligible patients 56 patients were included in the study. Preoperative patients' characteristics were homogeneous. No difference in morbidity and mortality after surgery were recorded. DFS was not different among the 2 groups (13.2 vs. 13.9 months, p=0.454) but OS was better in patients treated with HIPEC with no median reached vs. 35.5 months (p=0.048). Patients treated with cytoreductive surgery alone were more likely to have a peritoneal recurrence (43% vs. 14%). CONCLUSION: HIPEC seems to affect the relapse pattern with lesser peritoneal recurrence. This difference in relapse pattern seems to affect the OS with better results in patients treated with HIPEC. Further studies are needed to confirm these findings. PMID- 29533029 TI - [Thinking of the surgical treatment for cervical spondylotic myelopathy and the dredging Du meridian]. PMID- 29533030 TI - [A comparative study between on-endcaps and non-endcaps titanium mesh cage for the treatment of elderly cervical spondylotic myelopathy complicated with osteoporosis approach for anterior cervical spine surgery]. AB - OBJECTIVE: To compare radiographic results and clinical effects of titanium mesh cage with two endcaps(on-endcaps titanium mesh cage) and without endcaps(non endcaps titanium mesh cage) in anterior cervical corpectomy and fusion(ACCF) for elderly cervical spondylotic myelopathy. METHODS: The clinical data of 60 patients with cervical spondylotic myelopathy underwent ACCF from January 2011 to January 2016 were retrospectively analyzed. There were 26 males and 34 females, aged from 68 to 79 years old with a mean 75.8 years old. The patients were divided into two groups according to the different titanium mesh cage, using on endcaps titanium mesh cage(group A, 32 cases) or non-endcaps titanium mesh cage (group B, 28 cases). The nerve function was evaluated by JOA score system; the height of intervertebral fusion segments and fusion segmental lordosis angle (Cobb angle) were measured by cervical lateral X-ray films, the bone graft fusion rate of titanium mesh was evaluated by CT. RESULTS: All the patients were followed up from 1 to 2 years with an average of 1.5 years. The preoperative JOA scores of group A were 9.3+/-1.7, postoperative at 1 week, 3 months, 1 year were 14.2+/-1.8, 15.7+/-1.2, 15.4+/-1.5, respectively; and the preoperative JOA scores of group B were 9.1+/-1.8, postoperative at 1 week, 3 months, 1 year were 14.5+/ 1.3, 14.9+/-1.7, 15.2+/-1.6, respectively. The postoperative JOA scores between two groups were obviously improved than that of preoperative (P<0.05). There was no significant difference in JOA scores of 3 time-point after operation between two groups (P>0.05). In the group A, preoperative intervertebral height were(42.1+/-2.4) mm, postoperative at 1 week, 3 months, 1 year were (45.3+/-3.2) mm, (44.7+/-2.9) mm, (44.5+/-3.0) mm, respectively; preoperative Cobb angle of fusion segments were (5.3+/-1.2) degrees , postoperative at 1 week, 3 months, 1 year were (10.3+/-1.9) degrees , (10.1+/-1.7) degrees , (9.9+/-1.3) degrees , respectively. And in group B, preoperative intervertebral height were (43.4+/ 2.3)mm, postoperative at 1 week, 3 months, 1 year were (45.7+/-2.8) mm, (44.2+/ 2.7) mm, (41.5+/-2.1) mm, respectively; preoperative Cobb angle of fusion segments were (5.4+/-1.0) degrees , postoperative at 1 week, 3 months, 1 year were (11.2+/-1.8) degrees , (10.8+/-1.6) degrees , (7.2+/-1.4) degrees , respectively. The postoperative intervertebral height, Cobb angle of fusion segments between two groups were obviously improved than that of preoperative (P<0.05). There was no significant difference in intervertebral height and Cobb angle at 1 week, 3 months after operation between two groups(P>0.05). One year after operation, intervertebral height and Cobb angle in group A was better than that of group B(P<0.05). CONCLUSIONS: On-endcaps titanium mesh cage is superior to non-endcaps titanium mesh cage in the maintenance of cervical intervebral height and segmental lordosis angle postoperatively at elderly spondylotic myelopathy complicated with osteoporosis. The usage of on-endcaps titanium mesh cage can effectively reduce postoperative subsidence rate. PMID- 29533031 TI - [Change of 3D cervical range of motion after single-level anterior cervical corpectomy and fusion]. AB - OBJECTIVE: To study the change trend of cervical range of motion(ROM) after single-level anterior cervical corpectomy and fusion(ACCF) in treating cervical spondylotic myelopathy. METHODS: The clinical data of 23 patients with cervical spondylotic myelopathy was retrospectively analyzed from February 2015 to April 2016. There were 11 males and 12 females, with an average age of (54.6+/-13.3) years. All the patients were diagnosed as cervical spondylotic myelopathy by interrogation, physical examination and radiology, and were treated by ACCF. The Coda motion system was applied to assess the cervical range of motion pre-and post-operation. JOA and VAS scores were used to evaluate the clinical outcomes. RESULTS: The mean follow-up time was (9.4+/-1.6) months. Cervical ROM in all directions at 3 months postoperatively were significantly lower except for the left rotation(P<0.05). There was significant difference of cervical ROM in all directions between preoperative and 6 months postoperatively(P>0.05). The right lateral bending and the left rotation at 9 months postoperatively increased significantly(P<0.05). Postoperative extension at 6 months was significantly better than that of 3 months postoperatively(P<0.05). The extension, left and right lateral bending and left rotation at 9 months postoperatively were significantly better than of 6 months postoperatively(P<0.05). Postoperative JOA scores at each time points were significantly higher than that of preoperative(P<0.05) and VAS scores at each time points were significantly lower than that of preoperative(P<0.05). CONCLUSIONS: The change trend of three dimensional cervical ROM after single-level ACCF revealed that the ROM decreased in short term, and later increased and was better than the preoperative level. Meanwhile, the neurological function improved significantly. But the short-term and long-term change trend of ROM postoperatively and the change trend of ROM after multi-level ACCF need to be further studied. PMID- 29533032 TI - [Anterior corpectomy combined with intervertebral decompression and fusion for multilevel cervical spondylotic myelopathy]. AB - OBJECTIVE: To investigate the clinical outcomes of anterior corpectomy combined with anterior intervertebral decompression and fusion for multilevel cervical spondylotic myelopathy. METHODS: The clinical data of 28 patients with multilevel cervical spondylotic myelopathy who underwent surgery from October 2012 to June 2014 were retrospectively analyzed. There were 18 males and 10 females, aged from 45 to 77 years old with an average of (60.11+/-9.37) years. Three levels were involved in 27 cases, while four levels were involved in 1 case. The preoperative JOA score was 8.89+/-1.87; the fusion segments angles was (4.87+/-4.56) degrees ; and the cervical curvature was (11.68+/-1.25) degrees . Anterior hybrid decompression and fusion were performed in 28 patients. The fusion segments angles and the cervical curvature were assessed by X-rays at 1, 12 months after operation, respectively. JOA score was used to evaluate the clinical effect. RESULTS: The operative time was 163 min on average (ranged from 120 to 205 min), and intraoperative bleeding was 198 ml on average(ranged from 100 to 300 ml). Hoarseness occurred in 1 case and got recovery at 3 weeks after operation and choke cough occurred in 1 case, and got improvement at 1 week after operation. All the patients were regularly followed for 12-24 months with an average of(18.46+/-3.20) months. Graft bone obtained fusion at 12 months after operation and the position of internal fixation was good. The fusion segments angles, the cervical curvature and JOA scores were significantly improved at 1, 12 months after operation(P<0.05). The improvement rate of JOA score was(46.46+/-20.26)% at 12 months after operation, 12 cases got excellent results, 14 good and 2 fair. CONCLUSIONS: Anterior corpectomy combined with anterior intervertebral decompression and fusion is safe and effective and can get satisfactory effects for multilevel cervical spondylotic myelopathy. PMID- 29533033 TI - [Analysis of reason for postoperative axial pain caused by unilaterally open-door cervical laminoplasty]. AB - OBJECTIVE: To explore the reason of postoperative axial pain (PAP) complication caused by unilaterally open-door cervical laminoplasty with Centerpiece mini plate fixations for the treatment of multilevel cervical spondylotic myelopathy(CSM). METHODS: The clinical data of 79 patients with CSM who underwent unilaterally open-door cervical laminoplasty from January 2010 to December 2013 were retrospectively analyzed. There were 45 males and 34 females, aged from 48 to 75 years old with an average of (58.7+/-4.4) years, complicated with ossified posterior longitudinal ligament(OPLL) of 42 cases. Courses of disease were from 2.1 to 3.9 years with an average of (3.0+/-0.4) years. Decompression segment occurred in C3-C6 of 31 cases, C3-C7 of 9 cases, C4-C7 of 39 cases. The condition of PAP was record. Cervical curvature index, cervical lordosis angle, the rate of cervical instability, the motion of flexion and extension between PAP group and non-PAP group were compared preoperatively. Multivariate non-linear regression analysis was used to verify relationship between aforementioned parameters and incidence of PAP. JOA score of preoperative, postoperative 6 months and initial onset of PAP, the improvement rate of JOA score and Odom criteria at final follow up were used to evaluate curative efficacy. RESULTS: All the patients were followed up from 26 to 44 months with an average of (36+/-9) months. Among them, 12 patients occurred PAP who receive the conservative treatment. The rate of preoperative cervical instablility of PAP group were higher than that of non-PAP group(P<0.05). Preoperative cervical instability was the only independent risk factor in predicting occurrence of PAP. There were no significant differences in cervical curvature, cervical lordosis index, the motion of flexion and extension between PAP and non-PAP group before operation. There were no significant differences in the improvement of nerve function and clinical effect between PAP and non-PAP group after operation(P>0.05). CONCLUSIONS: Preoperative cervical instability is prone to inducing the respectively intervertebral motion disorder and imbalance of stress redistribution, which results in PAP after cervical unilateral laminoplasty. Correct treatment of preoperative cervical instability is a key factor to prevent the occurrence of PAP after cervical laminoplasty, which would not affect long-term nerve functional recovery pronouncedly. PMID- 29533034 TI - [Clinical study on spinal cord decompression combined with traditional Chinese medicine for the treatment of cervical spondylotic myelopathy]. AB - OBJECTIVE: To compare the clinical effect between spinal card decompression combined with traditional Chinese medicine and simple spinal card decompression for cervical spondylotic myelopathy. METHODS: From June 2012 to June 2015, 73 patients with cervical spondylotic myelopathy were treated, including 42 males and 31 females, aged from 29 to 73 years old with a mean of 50.9 years old. The patients were divided into the simple operation group (34 cases) and the operation combined with traditional Chinese medicine group(39 cases) according to the idea of themselves. The anterior discectomy or subtotal corpectomy with internal fixation or posterior simple open-door decompression with lateral mass screw fixation were performed in the patients. Among them, 39 cases were treated with traditional Chinese medicine after surgery. The Japanese orthopedic association (JOA) score of spinal cord function, the improvement rate of neural function, the neck dysfunction index (NDI) score and the governor vessel stasis syndrome score were compared between two groups preoperative and postoperative 1 week, 1 month and the final follow-up respectively. The internal fixation and the condition of spinal cord decompression were observed by CT, MRI and X-rays before and after operation. RESULTS: All the operations were successful, no injuries such as dura mater, spinal cord and nerve root were found. All the wounds were healed without infection except one patient had a superficial infection. It was solved after intermittent debridement and anti-infective therapy. Hematoma occurred in 1 case, complicated with spinal cord compression, caused incomplete paralysis, and promptly performed the re-operation to remove the hematoma without any obvious sequelae. All the patients were followed up from 12 to 24 months, (14.6+/-0.8) months for simple operation group and (13.5+/-0.7) months for operation combined with traditional Chinese medicine group, and there was no significant difference(P>0.05). The scores of JOA, NDI and the governor's vessel stasis syndrome in simple operation group were 8.31+/-3.15, 29.91+/-4.52, 6.58+/ 1.31 before operation, and 10.21+/-2.58, 18.67+/-4.31, 8.24+/-1.18 one week after operation, and 11.38+/-2.85, 16.11+/-3.18, 8.91+/-2.11 one month after operation, and 12.21+/-3.12, 14.61+/-3.28, 9.12+/-1.56 at final follow-up, respectively; and in operation combined with traditional Chinese medicine group were 8.29+/-3.47, 30.83+/-4.14, 6.38+/-1.81before operation, and 10.48+/-2.39, 17.59+/-5.14, 8.33+/ 1.57 one week after operation, and 12.14+/-3.12, 13.14+/-3.21, 9.55+/-2.49 one month after operation, and 13.85+/-3.34, 12.11+/-2.51, 10.33+/-1.95 at final follow-up, respectively. Postoperative JOA , NDI, and the governor vessel stasis syndrome score of two groups were significantly higher than preoperativee(P<0.05). There was no significant difference in JOA, NDI, and the governor vessel stasis syndrome score between two groups one week after operation (P>0.05). The above items in operation combined with traditional Chinese medicine group was better than that of simple operation group one month and final follow up after operation (P<0.05). The improvement rate of neural function in simple operation group was (67.59+/-10.78)%, and in operation combined traditional Chinese medicine group was (66.88+/-12.15)%, there was no significant difference between two groups(P>0.05). There were no complications such as internal fixation failure or re-dislocation of atlas by postoperative CT, MRI and X-rays examination. CONCLUSIONS: Spinal card decompression for the treatment of cervical spondylotic myelopathy can extend the spinal canal, relieve the compression of nerve, achieve the deoppilation of governor vessel, the regulation of qi and blood, the restore of Yangqi, combined with traditional Chinese medicine of activating blood removing stasis, warming yang and activating meridians, reinforcing liver benefiting kidney, which may obtain better clinical effect. PMID- 29533035 TI - [Comparison of clinical effects between anterior cervical discectomy combined with corpectomy and cervical posterior single open-door laminoplasty in treating three-segment cervical spondylotic myelopathy]. AB - OBJECTIVE: To compare the clinical effects between anterior cervical discectomy and fusion(ACDF) combined with anterior cervical corpectomy and fusion(ACCF) and cervical posterior single open-door laminoplasty with mini-titanium plate fixation in treating three-segment cervical spondylotic myelopathy. METHODS: The clinical data of 63 patients (39 males and 24 females) with three-segment cervical spondylotic myelopathy underwent surgical treatment from March 2014 to March 2016 were retrospectively analyzed. Among them, 43 cases were treated by ACDF combined with ACCF(anterior group), and 20 cases were treated by cervical posterior single open-door laminoplasty with mini-titanium plate fixation(posterior group). Operative time, intraoperative blood loss, postoperative complications were compared between two groups. And according to JOA score to evaluate the clinical effect. RESULTS: All the patients were follow up from 16 to 40 months with an average of 25.8 months. Operative time of anterior group and posterior group were (123.70+/-6.21) min and(118.70+/-5.41) min, respectively, there was no significant difference between two groups(P>0.05). Intraoperative blood loss of anterior group and posterior group were (85.23+/-7.51) ml and (107.18+/-9.41) ml, respectively, there was significant difference between two groups(P<0.05). In anterior group, axial symptoms occurred in 6 cases, dysphagia in 1 case, and no C5 nerve root palsy, hoarseness and choking cough were found, the incidence rate of complication was 16.3%(7/43); and in posterior group, axial symptoms occurred in 5 cases, C5 nerve root palsy in 1 case, and no dysphagia, hoarseness and choking cough were found, the incidence rate of complication was 30.0%(6/20); there was significant defference in incidence rate of complication between two group(P<0.05). At 1 week after operation and final follow-up, the JOA scores of anterior group were obviously better than that of posterior group(P<0.05). CONCLUSIONS: Above mintioned two surgical treatment for cervical spondylotic myelopathy can provide instantly stability, the method of ACDF combined with ACCF was obviously better that of the method of cervical posterior single open-door laminoplasty in intraoperative blood loss, the incidence rate of complications, clinical effect.Thus, for the treatment of three-segment cervical spondylotic myelopathy, the method of ACDF combined with ACCF would be firstly chosen. PMID- 29533036 TI - [Difference of spino-pelvic sagittal alignment between lumbar disc herniation and lumbar canal stenosis in adults]. AB - OBJECTIVE: To study the difference of spino-pelvic sagittal alignment between lumbar disc herniation(LDH) and lumbar canal stenosis(LCS) in adults. METHODS: The integrated imaging data of 88 patients with lumbar disc herniation (42 cases) or lumbar canal stenosis(46 cases) were searched from January 1, 2015 to September 10, 2016 in our hospital.Twenty-two cases were excluded because of age factor, 36 cases of LDH (LDH group) and 30 cases of LCS (LCS group) were internalized in the study. The spino-pelvic parameters were measured including pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), thoracic kyphosis (TK), thoracolumbar junction (TLJ), sagittal vertical axis (SVA), sagittal vertical axis location (SVA-Location), T1-spinopelvic inclination (T1-SPI), T9-spinopelvic inclination (T9-SPI). Independent sample t test was used in order to analyze the above data. RESULTS: Thoracic kyphosis (TK) in LDH group was smaller than that of LCS group (difference was about 6 degree), there was significant difference between two groups (P=0.031). And there were no significant differences in other parameters between two groups (P>0.05). CONCLUSIONS: The patients with lumbar disc herniation, the kyphosis of the thoracic spine is smaller, the truncus prones to the straight. The lumbar kyphosis is greater in patients with lumbar spinal stenosis, and the sagittal curvature of the lumbar spine is more obvious. PMID- 29533037 TI - [Clinical effects of high frequency repeated transcranial magnetic stimulation therapy on dyskinesia in patients with incomplete spinal cord injury:a Meta analysis]. AB - OBJECTIVE: To systematically evaluate the clinical effect of high frequency repeated transcranial magnetic stimulation(HF rTMS)therapy on dyskinesia in patients with incomplete spinal cord injury. METHODS: Randomized controlled trials(RCTs) about HF rTMS therapy on patients with motor incomplete spinal cord injury were searched electronically in PubMed, Google scholar, Cochrane library, Clinical trial, Medline, Web of science, CNKI, VIP, and Wanfang database before October 2016. Two reviewers independently screened the literatures according to the inclusion and exclusion criteria, as well as extracted the data and assessed the methodological quality. The observed outcomes included ASIA motor score, ASIA lower extremities motor score(LEMS), Modified Ashworth score (MAS), Ten-meter walking test (10MWT) and Walking index for SCI II(WISCI II), and the outcomes were analyzed using RevMan5.2 software provided by the Cochrane information management system. RESULTS: Five RCTs involved 103 patients were included, and 61 patients(experimental group) accepted real rTMS and physical rehabilitation care for SCI, 51 patients(control group) accepted only physical rehabilitation care. There were significant differences in ASIA motor score, LEMS and 10MWT between two groups after HF rTMS therapy (statistics were Z=2.96, P=0.003; Z=3.04, P=0.002; Z=2.16, P=0.03; respectively). When stimulating the leg motor cortex, there was significant difference in MAS between two groups(Z=2.79, P=0.005), and when stimulating the vertex, there was no significant difference(Z=0.09, P=0.93). There was no significant difference in WISCI IIscore after HF rTMS therapy between two groups(Z=0.90, P=0.37). CONCLUSIONS: HF rTMS can raise motor score in patients with incomplete spinal cord injury, improve the spasticity of the lower extremities, and increase the motor ability. PMID- 29533038 TI - [Arthroscopy-guided core decompression and bone grafting combined with selective arterial infusion for treatment of early stage avascular necrosis of femoral head]. AB - OBJECTIVE: To observe the clinical effects of arthroscopy-guided core decompression and bone grafting combined with selective arterial infusion for early stage avascular necrosis of femoral head. METHODS: From January 2010 to December 2014, 76 patients(76 hips) diagnosed as Ficat II stage avascular necrosis of femoral head were randomly divided into experimental group and control group. In the experimental group, there were 27 males and 8 females aged from 24 to 55 years old with an average of (43.96+/-6.81) years, treated with arthroscopic-guided core decompression and bone grafting combined with selective arterial infusion. Along the direction of the femoral neck, an 8 mm-diameter tunnel to necrotic areas was drilled, then curettage of necrotic bone was performed under arthroscope, and the iliac bone was grafted. In the control group, there were 29 males and 12 females aged from 26 to 56 years old with an average of (44.62+/-7.33) years, treated with percutaneous core decompression combined with selective arterial infusion. The preoperative and postoperative Harris scores were recorded and the changes of X-rays were analyzed. RESULTS: All the patients were followed up with an average of 30 months. Postoperative follow up at 12 months showed that there was significant difference in imaging outcome between two groups(P<0.05), the experimental group was better than that of control group. According to Harris hip score system, at the final follow-up, Harris score of the experimental group was 86.72+/-4.37 on average, 6 cases got excellent results, 24 good, 4 fair and 1 poor. Harris score of the control group was 78.62+/-5.62 on average, 2 cases got excellent results, 20 good, 15 fair and 4 poor. After Ridit analysis, there was significant difference in the effect between the two groups(P<0.05). By pairing sample t test, there was significant difference between the preoperative and postoperative Harris score in the both groups(P<0.05). Between the two groups, there was no significant difference in preoperative Harris score(P>0.05), but there was significant difference in postoperative Harris score(P<0.05). CONCLUSIONS: The two surgical procedures for early femoral head necrosis are effective. Using arthroscopic-guided core decompression method, the necrotic bone can be positioned and scraped more accurately, and can obtain better results. PMID- 29533039 TI - [Percutaneous pedicle screw fixation combined with limited-open decompression technique for thoracolumbar fractures with neurologic deficit]. AB - OBJECTIVE: To evaluate the clinical effects of percutaneous pedicle screw fixation combined with limited open decompression technique for the treatment of thoracolumbar fractures with neurologic deficit. METHODS: The clinical data of 76 patients with thoracolumbar fractures with neurologic deficit underwent percutaneous pedicle screw fixation combined with limited open decompression technique from June 2010 to June 2014 were retrospectively analyzed. There were 45 males and 31 femals, aged from 17 to 56 years with an average of 32.5 years old. According to the classification of Denis, 33 cases were type A, 26 cases were type B, 17 cases were type C. According to the criterion of American Spinal Injury Association(ASIA), 13 cases were grade A, 9 cases were grade B, 21 cases were grade C, 33 cases were grade D. The operative time, intraoperative blood loss, postoperative internal fixation lossening and breakage were recorded. The informations of the Cobb angle, the anterior height of injured vertebra, canal stenosis were observed before operation, 3 days after operation, and the final follow-up. The improvement of neurologic function were analyzed at final follow up. RESULTS: All the patients were followed up from 13 to 47 months with an average of 32.1 months. The mean operative time was 159 min (136 to 218 min) and the intraoperative blood loss was 225 ml(150 to 360 ml). The anterior height of injured vertebra was increased from (52.0+/-5.9)% before operation to (87.2+/ 1.8)% at 3 days after operation, and (86.1+/-1.5)% at final follow-up (F=45.27, P=0.000); the Cobb angle was decreased from (29.7+/-8.2) degrees before operation to (5.7+/-2.9) degrees at 3 days after operation, and (5.9+/-3.6) degrees at final follow-up (F=34.62, P=0.000); the canal stenosis was decreased from (37.5+/-7.2)% before operation to (12.3+/-3.3)% at 3 days after operation, and (11.9+/-3.1)% at final follow-up(F=37.02, P=0.000); there was no significant differences between postoperative 3 days and the final follow-up about the above parametres(P>0.05). According to ASIA criterion, the spinal cord function was classified as grade A in 13 cases, grade B in 0 cases, grade C in 10 cases, grade D in 21 cases and grade E in 32 cases at final follow-up. Internal fixation lossening and breakage occurred in 2 cases. CONCLUSIONS: Percutaneous pedicle screw fixation combined with limited open decompression technique can obtain satisfactory clinical effect for patients with thoracolumbar fractures with neurologic deficit, and have a good recovery of nerve function can be observed. PMID- 29533040 TI - [Effects of decompression combined with electro-acupuncture on rat with acute severe upper cervical spinal cord compression injury]. AB - OBJECTIVE: To explore the effect and underlying mechanism of decompression(DE)combined with Governor Vessel(GV)electro-acupuncture(EA) on rats with acute severe upper cervical spinal cord compression injury. METHODS: Thirty SPF rats were randomly divided into 5 groups(control group A, B and experiment group C, D, E), 6 rats in each group. The model of acute severe upper cervical spinal cord compression injury were made by forcing a balloon catheter put in atlas pillow clearance. The group A was blank one, the group B put balloon catheter in atlas pillow clearance without forcing, and the group C, D, E sustained compressed for 48 h. The group C received electric acupuncture intervention, selecting the Baihui and Dazhui point, having the continuous wave and frequency of 2 Hz, with the treatment time of 15 min and continuous treatment for 14 d; the group D received methylprednisolone intervention, injected by caudal vein; the group E did not received any intervention again. The arterial blood and injured spinal cord tissue of all the rats were obtained after 14 days' treatment, and BBB score was used to evaluate the change of each group hind limbs motor function, the contents of platelet activating factor(PAF) in injured spinal cord tissue and blood serum were assess by ELISA method; the Caspase-9 expression for each group after 14 days' treatment was assess by Western blot method. RESULTS: BBB scores were(21.000+/-0.000) points at the 6 time points, that was, 1 h, 48 h after forcing in control group, 24 h, 3 d, 7 d, 14 d after treating in experiment group; the score of experimental groups (group C, D, E) were always lower than control groups(group A, B); compared with group E, group C and D were significantly higher(P<0.05); and there was no significant difference between group C and group D(P>0.05). The results of PAF by ELISA method to measure:the concentration of serum PAF, there was no statistical difference among group A, B, D, E (P>0.05), group C was lower than the other groups (P<0.05); the concentration of tissue PAF, there was no significant difference between group A and group B(P>0.05), group D was significantly higher than that of group A, B, and C(P<0.05), group E was the highest one than that of the other groups(P<0.05). Western blot med tests showed that the Caspase-9 protein expression in group A and B was similar (P>0.05), group C was higher than that of group A and B(P<0.05), group D was higher than group A, B and C(P<0.05), group E was the highest than that of group A, B, C and D (P<0.05). CONCLUSIONS: Decompression and Governor Vessel electro-acupuncture on acute severe upper cervical spinal cord compression injury had a better effect compare with decompression and methylprednisolone or simple decompression only, its mechanism may be related to lower the PAF levels and downregulating Caspase-9 protein expression in spinal injury tissue. PMID- 29533041 TI - [Biomechanical study of the stability of subaxial cervical anterior transpedicular screw fixation for three-column injury]. AB - OBJECTIVE: To compare the stability of subaxial cervical anterior transpedicular screw(ATPS) fixation and three traditional fixations for three-column injury. METHODS: Six specimens of cervical spine were prepared. After measurememt of the range of motion(ROM) in intact state, the specimens were made into three-column injury models. The models were reconstructed with an anterior cervical cage, and stabilized by ATPS, anterior plate(AP), anterior plate + lateral mass screw(AP+LMS) and posterior transpedicular screw(PTPS). The ROM of the models in the four states were measured, and the results of data were compared after standardization. RESULTS: The normalized ROM of ATPS state in flexion-extension, lateral bending, axial rotation were(77.17+/-4.75)%, (82.00+/-2.61)%, (83.17+/ 2.23)%, which were significant small than those in intact state(P<0.05). The normalized ROM of AP state in flexion-extension, lateral bending, axial rotation were(119.67+/-7.42)%, (116.33+/-7.53)%, (112.67+/-5.99)% , which were significant larger than those in intact state(P<0.05). The normalized ROM of AP in all directions were significant larger than those of ATPS(P<0.05). There was no significant difference between normalized ROM of PTPS state and those of ATPS state in flexion-extension and lateral bending(P>0.05). The normalized ROM of PTPS state in axial rotation was(6.83+/-2.48)% and was significant larger than that of ATPS state(P=0.009). The normalized ROM of AP+LMS state in flexion extension was(68.50+/-2.43)%, which was significant smaller than that of ATPS state(P=0.003). There was no significant difference between the normalized ROM of AP+LMS state and those of ATPS state in lateral bending and axial rotation(P>0.05). CONCLUSIONS: Subaxial cervical three-column injury model reconstruction by ATPS can provide the adequate primary stability, of which biomechanics property is superior compared to AP and PTPS, and is similar to that of AP+LMS. It can be applied to the patients with no need to decompression and reduction through posterior approach. PMID- 29533042 TI - [Clinical analysis of repairing the defect of hand with reverse island skin flap of upper carpal cutaneous branches of ulnar artery]. AB - OBJECTIVE: To investigate the clinical effect of repairing soft tissue defect after hand wound using reverse island skin flap of upper carpal cutaneous branches of ulnar artery. METHODS: From June 2010 to November 2016, 12 patients with hand soft tissue defects were repaired by reverse island skin flap of upper carpal cutaneous branches of ulnar artery, including 9 males and 3 females with an average age of (35.2+/-9.4) years old ranging from 22 to 58 years. The defect area varied from 7.0 cm*3.0 cm to 12.0 cm*7.0 cm. Time interval from injury to operation ranged from 3 to 15 days with an average of (8.4+/-2.6) days. The flap was designed beforehand according to the size of the defect, sharply dissected the aponeurotic fascia from the proximal to the distal, abscised the communicating branch between the flap and the ulnar artery at the wrist epithelial branch, repairing the defect of flap with method of metastasis retrograde. The sensation, shape of the flap and hand function were observed, and the upper extremity function was evaluated according to the standard of hand surgery branch from Chinese Medical Association to assessment of functional recovery. RESULTS: The flaps in 10 patients obtained primary healing, the healed time was 14 to 18 days with an average of(15.0+/-1.5) days. Two patients occurred distal flap necrosis, and wound surface healed after change dressing and skingrafting cover. All patients were followed up from 3 to 15 months with an average of(7.0+/-3.8) months. According to the upper extremity functional evaluation standard by hand surgery branch of Chinese Medical Association, 2 cases got excellent results, 7 good, 2 fair and 1 poor. CONCLUSIONS: Reverse island skin flap of upper carpal cutaneous branches of ulnar artery for the treatment of soft tissue defect caused by hand wound has advantages of concealed donor area, no need sacrifice the main blood vessel, flap thin and no need repair it for thick and thin. PMID- 29533043 TI - [Diagnostic errors of ischiac osteochondroma as fracture:a case report]. PMID- 29533044 TI - [Chronic spontaneous lumbar spinal epidural hematoma: a case report]. PMID- 29533045 TI - [Mechanism of macrophage polarization on spinal cord injury]. AB - Spinal cord injury is a serious trauma of the spinal and nervous system, local tissue destruction and microcirculation disturbance can lead to a more serious spinal cord injury and extensive necrosis of neurons. Spinal cord injury often accompany with Inflammation reaction producing a variety of cytokines and bioactive substances, result in macrophage polarization. M1 macrophages polarization are induced by IFN-gamma, LPS, TNF-alpha and so on, it show the damage and proinflammatory effect. M2 macrophages polarization are caused by IL 4, IL-10, IL-13 and show the recovery and anti-inflammatory effect. However, clinical treatment after spinal cord injury is very limited, inhibition of proinflammatory and promotion of anti-inflammatory by regulating the M1 macrophages and M2 macrophages is a new direction for the treatment of spinal cord injury. The article will review different phenotype and function of macrophages after spinal cord injury. PMID- 29533046 TI - [Progress on clinical application of anterior cervical pedicle screw fixation for instable cervical spine disease]. AB - Instability of the cervical spine disease requires surgery to restore stability. In the past, surgical methods were divided into two kinds of anterior and posterior. But each has its own disadvantages:anterior vertebral screw has a higher failure rate, sometimes need a second operation; and posterior pedicle screw, lateral mass screw and facet joint screw may make greater trauma, lead to longer hospitalization. For general instable cervical spine disease, according to the location of the disease, only with the anterior or posterior approach can achieve a stable effect. However, it often fails to achieve the desired stability with only anterior or posterior approach for the three column injury of single segment, the disease need for multi-segment corpectomy and discectomy. Meanwhile, combined with the anterior and posterior have more obvious disadvantages:such as prolonged operation time, greater surgical injury, increased risk of infection and so on.In recent years, anterior transpedicular screw (ATPS) as a new technique was used for cervical spine fixation. Its laboratory and clinical studies have been conducted about biomechanical properties, morphological feasibility, pull-out strength, radiological features and new technology for inserting screws. Because of its strong stability, perfect mechanical properties and the satisfactory results of patients, which has been recognized by many scholars. Although this technique has been used in clinical practice, Its long term clinical effect needs to be further clarified. Even so, the innovative proposal will provide a new thread for the majority of doctors and colleagues in treating unstable cervical disease. PMID- 29533047 TI - Why Don't the Poor Save More? Evidence from Health Savings Experiments. AB - Using data from a field experiment in Kenya, we document that providing individuals with simple informal savings technologies can substantially increase investment in preventative health and reduce vulnerability to health shocks. Simply providing a safe place to keep money was sufficient to increase health savings by 66 percent. Adding an earmarking feature was only helpful when funds were put toward emergencies, or for individuals that are frequently taxed by friends and relatives. Group-based savings and credit schemes had very large effects. PMID- 29533048 TI - Early Life Health Interventions and Academic Achievement. AB - This paper studies the effect of improved early life health care on mortality and long-run academic achievement in school. We use the idea that medical treatments often follow rules of thumb for assigning care to patients, such as the classification of Very Low Birth Weight (VLBW ), which assigns infants special care at a specific birth weight cutoff. Using detailed administrative data on schooling and birth records from Chile and Norway, we establish that children who receive extra medical care at birth have lower mortality rates and higher test scores and grades in school. These gains are in the order of 0.15-0.22 standard deviations. PMID- 29533049 TI - Risk factors for bruxism AB - The aim of the present study was to summarize the risk factors for bruxism that were identified by a systematic search of the literature published between 2007 and 2016. Depending on the size of the odds ratios (ORs) and the lower limit of the 95% confidence intervals indicated by the reports, four risk categories were differentiated. Among others, emotional stress, consumption of tobacco, alcohol, or coffee, sleep apnea syndrome, and anxiety disorders were recognized as important factors among adults. In children and adolescents, apart from distress, behavioral abnormalities and sleep disturbances predominated.Knowledge of the identified risk factors may be useful when taking the medical history of bruxing patients. Although many of the described variables cannot be influenced by prophylactic or therapeutic means, we recommend the following patient-centered approach ("SMS therapy"): self-observation, muscle relaxation, stabilization (Michigan) splint. PMID- 29533050 TI - Abrasive effects of diamond dentifrices on dentine and enamel AB - This study was to analyse the abrasive wear of differently composed diamond dentifrices loaded with 2.4 MUm diamond particles on dentine and enamel surfaces in vitro. Bovine specimens were brushed with a diamond-loaded dentifrice (DD2; 2 g particles/kg), a diamond-loaded dentifrice (1.5 g/kg) containing 20% hydrated silica as extra abrasive (DD1.5+S), or a diamond-loaded dentifrice (3 g/kg) containing 20% hydrated silica abrasive (DD3+S). Values were compared to those obtained with Colgate Total (CT) and Elmex Sensitive plus (ES). Brushing was performed using a cross brushing machine (F = 2.5 N; 120 brushing strokes/min). Abrasive wear [MUm] of specimens (n = 12) was measured profilometrically and adjusted to 10,000 brushing strokes (10 kBS). Data were compared between groups using one-way ANOVA and post-hoc pairwise tests with Tukey correction, alpha = 0.05. Diamond dentifrices and ES showed no difference on dentine specimens: DD2 7.7 +/- 2.6 MUm/10 kBS; DD1.5+S 10.1 +/- 2.3 MUm/ 10 kBS; DD3+S 10.1 +/- 2.6 MUm/10 kBS; ES 7.4 +/- 1.1 MUm/10 kBS, while CT-brushed specimens exhibited significantly higher dentinal abrasion compared to all other groups: CT 31.0 +/- 7.7 MUm/ 10 kBS. Diamond loading significantly influenced enamel wear (mean +/- SD MUm/10 kBS): DD2 1.8 +/- 0.5 MUm/10 kBS. Conversely, addition of the silica abrasive reduced these values: DD1.5+S 1.1 +/- 0.3 MUm/10 kBS; DD3+S 1.6 +/- 0.3 MUm/10 kBS. CT and ES revealed similarly low values: CT 0.3 +/- 0.1 MUm/10 kBS; ES 0.2 +/- 0.1 MUm/10 kBS. These data suggest that abrasion caused by diamond particles in experimental toothpastes is differentially affected by diamond particle load, additional abrasives, and the type of hard tissue. PMID- 29533051 TI - Clinical follow-up evaluation of Dalbo(r)-Rotex(r) retention elements in the private practice AB - The aim of this retrospective study was to investigate the clinical outcome of Dalbo(r)-Rotex(r) retention elements in a private practice. The majority of the retention elements was fixed with self-adhesive composite cement, and in almost 40% the exposed root surface was additionally covered with composite. The success rate of 96.3% after 24 months in a total of 50 included patients (response rate 48.5%) demonstrated that a simple and cost-effective fixation of removable dentures using prefabricated, chair-side inserted retention elements is feasible. Maintenance care comprised single or repeated replacement and activation of the female part in 12.3% and 39.4% of the cases, respectively. Fractures were rare, occurring in 3.4% of the cases and more likely in patients with parafunctional habits. Frequent oral hygiene correlated with probing depths up to 3 mm at the maxi- mum, while the risk of greater probing depths associated with less frequent oral hygiene increased by a factor of 2.4. Patients' assessment of the parameters handling and wearing comfort, chewing ability and prosthesis retention was predominantly positive. Based on the findings of the study, covering of exposed dentin areas with composite resin and regular recall comprising professional cleaning, fluoride application and oral hygiene instruction are recommended. PMID- 29533052 TI - Histamine-release test in angioedema patients without urticaria - a retrospective cohort study of 404 patients. AB - Summary: A subset of patients with angioedema (AE) and urticaria has histamine releasing autoantibodies. The histamine release test (HR-test) has been used as a tool in chronic urticaria to define the autoimmune subgroup and may possibly guide the clinician to a more personalized therapy, like omalizumab and cyclosporine. The prevalence and value of positive histamine releasing autoantibodies in monosymptomatic AE is sparsely described in the literature. The purpose of this study was to report the prevalence of positive histamine releasing autoantibodies in a cohort of patients with recurrent AE and evaluate the usefulness of this test in AE patients. We performed a retrospective cohort study of 612 patients referred due to AE between 1995 and 2013. HR-test results were available in 404 patients. In the sub-group of patients with AE and urticaria, 17.3% had a positive HR-test but only 4.3% of patients with mono symptomatic AE had a positive HR-test. No statistically significant treatment benefits of antihistamines, corticosteroids or adrenaline were found comparing patients with angioedema +/- urticaria based on the result of the HR-test (negative / positive). Thus, the HR-test result cannot be used as predictor of the efficacy of anti-allergic treatment. PMID- 29533053 TI - Oral allergy syndrome amongst young Mexicans: prevalence and associated factors. AB - Summary: Background. Oral allergy syndrome (OAS) is the most common food allergy manifestation amongst adults. However, population studies aimed at estimating its prevalence and associated factors are scarce in Mexi-co. Objectives. To establish the prevalence of OAS in a sample of university students and to describe their clinical characteristics and its associated factors. Methods. From a sample group made up of 25,269 univer-sity students, the data corresponding to 1,200 students aged 18 to 25 was analyzed with a cross-sectional approach. A structured questionnaire was used to identify OAS, its symptoms and related foods, and the personal history of atopic diseases. The associations between variables were calculated through logistical regression analysis. Results. The prevalence of OAS was 3.4%, with a 95% confidence interval (95% CI) of 2.5 to 4.6. The main oral symptoms reported were lip pruritus, edema and the sensation of pharyngeal oppression. Among the extra-oral complaints were: reddish coloration of the skin, body pruritus, abdominal pain, and abdominal bloating. The foods that were most frequently associated with OAS were fruits (68.5%), vegetables (22.0%) and seafood (19.3%). Through multivariate analyses, allergy to pollen and latex were found to be associated with OAS, OR 3.29; 95%: CI 1.53 to 7.10 and OR 5.53; 95% CI: 1.08 to 28.2, respectively. Conclusions. Notably, the prevalence of OAS varies according to the geographic area. Personal histories of allergy to pollen or latex were the main factors linked to OAS. PMID- 29533054 TI - Reduction of the allergenicity of cow's milk alpha-lactalbumin under heat treatment and enzymatic hydrolysis in Moroccan population. AB - Summary: The aim of the present study is to evaluate the effect of heat-treatment and enzymatic hydrolysis on the allergenicity of cow's milk alpha-lactalbumin (alpha-LA) in a Moroccan population. A total of 557 patients were recruited from the University Hospital Complex and the Ibn El Khatib Hospital of Fez city. This population consented to realize a dosage of IgE levels to raw cow milk and then to alpha-LA native and treated with the studied treatments. The results revealed that 54.4% of the studied subjects presented positive values of serial IgE to raw cow milk. The effect of treatments on the allergenicity of alpha-LA showed that heat-treatment at 90 degrees C and pepsin hydrolysis at 37 degrees C, for 1 hour each, caused an important decrease in the IgE binding with an average of reduction of 59% and 74%, respectively. PMID- 29533055 TI - Effect of industrial processing on the IgE reactivity of three commonly consumed Mo-roccan fish species in Fez region. AB - Summary: Objectives. The aim of this work was to study the effect of industrial processing on the allergenicity of three commonly consumed Moroccan fish species in Fez region (sardine, common pandora, and shrimp). Methods. This work was conducted by a sera-bank obtained from 1248 patients recruited from Fez Hospitals. Their sera were analyzed for specific IgE binding to raw fish extracts. Among them, 60 patients with higher specific IgE levels were selected, and used to estimate the binding variation of IgE to these products under several processing (frying, cooking, canning, marinade, and fermentation) using ELISA analysis. Results. ELISA results demonstrated that all the studied processing cause a reduction in the immunoreactivity of human IgE to fish products, with a high action with marinade and fermentation compared to other processing. This alteration was also observed with rabbit IgG in all processed products, showing that the maximum reduction was marked in fermented sardine with 64.5%, in cooked common pandora with 58%, and in fermented shrimp with 69.2%. Conclusion. In conclusion, our study has shown that the allergenicity of the three studied fish could be reduced by different industrial processes with different degrees. PMID- 29533056 TI - Die ossare Dysplasie: ein radiologischer Zufallsbefund PMID- 29533057 TI - ? PMID- 29533058 TI - Limited Life Expectancy, Human Capital and Health Investments. PMID- 29533059 TI - The Effect of Education on Adult Mortality and Health: Evidence from Britain. AB - There is a strong, positive, and well-documented correlation between education and health outcomes. In this paper, we attempt to understand to what extent this relationship is causal. Our approach exploits two changes to British compulsory schooling laws that generated sharp across-cohort differences in educational attainment. Using regression discontinuity methods, we find the reforms did not affect health although the reforms impacted educational attainment and wages. Our results suggest caution as to the likely health returns to educational interventions focused on increasing educational attainment among those at risk of dropping out of high school, a target of recent health policy efforts. PMID- 29533060 TI - Multifunctional Efficiency: Extending the Concept of Atom Economy to Functional Nanomaterials. AB - Green chemistry, in particular, the principle of atom economy, has defined new criteria for the efficient and sustainable production of synthetic compounds. In complex nanomaterials, the number of embedded functional entities and the energy expenditure of the assembly process represent additional compound-associated parameters that can be evaluated from an economic viewpoint. In this Perspective, we extend the principle of atom economy to the study and characterization of multifunctionality in nanocarriers, which we define as "multifunctional efficiency". This concept focuses on the design of highly active nanomaterials by maximizing integrated functional building units while minimizing inactive components. Furthermore, synthetic strategies aim to minimize the number of steps and unique reagents required to make multifunctional nanocarriers. The ultimate goal is to synthesize a nanocarrier that is highly specialized but practical and simple to make. Owing to straightforward crystal engineering, metal-organic framework (MOF) nanoparticles are an excellent example to illustrate the idea behind this concept and have the potential to emerge as next-generation drug delivery systems. Here, we highlight examples showing how the combination of the properties of MOFs ( e.g., their organic-inorganic hybrid nature, high surface area, and biodegradability) and induced systematic modifications and functionalizations of the MOF's scaffold itself lead to a nanocarrier with high multifunctional efficiency. PMID- 29533061 TI - High Speed Ultraviolet Phototransistors Based on an Ambipolar Fullerene Derivative. AB - Combining high charge carrier mobility with ambipolar transport in light absorbing organic semiconductors is highly desirable as it leads to enhanced charge photogeneration, and hence improved performance, in various optoelectronic devices including solar cells and photodetectors. Here we report the development of [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM)-based ultraviolet (UV) phototransistors with balanced electron and hole transport characteristics. The latter is achieved by fine-tuning the source-drain electrode work function using a self-assembled monolayer. Opto/electrical characterization of as-prepared ambipolar PC61BM phototransistors reveals promising photoresponse, particularly in the UV-A region (315-400 nm), with a maximum photosensitivity and responsivity of 9 * 103 and 3 * 103 A/W, respectively. Finally, the temporal response of the PC61BM phototransistors is found to be high despite the long channel length (10 s of MUm) with typical switching times of <2 ms. PMID- 29533062 TI - Correction to Multifunctional Sensor Based on Porous Carbon Derived from Metal Organic Frameworks for Real Time Health Monitoring. PMID- 29533063 TI - Negative Photochromism Based on Molecular Diffusion between Hydrophilic and Hydrophobic Particles in the Solid State. AB - A colored hybrid based on a merocyanine adsorbed in a nanoporous-silica-composed dendritic fibrous silica was prepared by adsorption onto the nanoporous silica from a spiropyran solution during UV irradiation (photoinduced adsorption). The obtained red hybrid thus exhibited negative photochromism by visible-light irradiation. The hybrid was further combined with an organophilic clay by a solid state mixing without using solvent to achieve excellent reversibility of the color change, which was thought to be achieved by molecular diffusion through the two materials, where nanoporous silica and organophilic clay accommodated the colored (merocyanine) and colorless (photogenerated spiropyran) isomers, respectively. PMID- 29533064 TI - Ion-Hydrocarbon and/or Ion-Ion Interactions: Direct and Reverse Hofmeister Effects in a Synthetic Host. AB - A combination of 1H NMR spectroscopy, DLS, and turbidity measurements reveal that polarizable anions engender both the Hofmeister and reverse Hofmeister effects in positand 2. Host 2 possesses two principal and distinctly different binding sites: a "soft" nonpolar pocket and a "hard" crown of ammonium cations. NMR spectroscopy reveals that anion affinity to both sites is comparable, with each site showing characteristic selectivities. NMR spectroscopy also reveals that anions competitively bind to the pocket and induce the Hofmeister effect in host guest binding at very low concentrations (~2 mM). Furthermore, the suite of techniques utilized demonstrates that anion binding to both sites leads to charge attenuation, aggregation, and finally precipitation (the reverse Hofmeister effect). Anion-induced precipitation generally correlated with affinity, and comparisons between the free host and its adamantane carboxylate (Ada-CO2-) complex reveals that the reverse Hofmeister effect is attenuated by blocking anion binding/charge attenuation at the nonpolar pocket. PMID- 29533067 TI - Designing Smart Polymer Conjugates for Controlled Release of Payloads. AB - Incorporating labile bonds inside polymer backbone and side chains yields interesting polymer materials that are responsive to change of environmental stimuli. Drugs can be conjugated to various polymers through different conjugation linkages and spacers. One of the key factors influencing the release profile of conjugated drugs is the hydrolytic stability of the conjugated linkage. Generally, the hydrolysis of acid-labile linkages, including acetal, imine, hydrazone, and to some extent beta-thiopropionate, are relatively fast and the conjugated drug can be completely released in the range of several hours to a few days. The cleavage of ester linkages are usually slow, which is beneficial for continuous and prolonged release. Another key structural factor is the water solubility of polymer-drug conjugates. Generally, the release rate from highly water-soluble prodrugs is fast. In prodrugs with large hydrophobic segments, the hydrophobic drugs are usually located in the hydrophobic core of micelles and nanoparticles, which limits the access to the water, hence lowering significantly the hydrolysis rate. Finally, self-immolative polymers are also an intriguing new class of materials. New synthetic pathways are needed to overcome the fact that much of the small molecules produced upon degradation are not active molecules useful for biomedical applications. PMID- 29533068 TI - Polyoxometalate-Based Metal-Organic Frameworks for Selective Oxidation of Aryl Alkenes to Aldehydes. AB - Polyoxometalates (POMs) show considerable catalytic performance toward the selective oxidation of alkenes to aldehydes, which is commercially valuable for the production of pharmaceuticals, dyes, perfumes, and fine chemicals. However, the low specific surface area of POMs as heterogeneous catalysts and poor recyclability as homogeneous catalysts have hindered their wide application. Dispersing POMs into metal-organic frameworks (MOFs) for the construction of POM based MOFs (POMOFs) suggests a promising strategy to realize the homogeneity of heterogeneous catalysis. Herein, we report two new POMOFs with chemical formulas of [Co(BBTZ)2][H3BW12O40].10H2O (1) and [Co3(H2O)6(BBTZ)4][BW12O40].NO3.4H2O (2) (BBTZ = 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene) for the selective oxidation of alkenes to aldehydes. Compound 1 possesses a non-interpenetrated three dimensional (3D) cds-type open framework with a 3D channel system. Compound 2 displays a 3D polyrotaxane framework with one-dimensional channels along the [100] direction. In the selective oxidation of styrene into benzaldehyde, compound 1 can achieve a 100% conversion in 4 h with 96% selectivity toward benzaldehyde, which is superior to that of compound 2. A series of control experiments reveal that the co-role of [BW12O40]5- and Co2+ active center as well as a more open framework feature co-promote the catalytic property of the POMOFs in this case. This work may suggest a new option for the development of POMOF catalysts in the selective oxidation of alkenes. PMID- 29533069 TI - Domino Reaction of Pyrrolidinium Ylides: Michael Addition/[1,2]-Stevens Rearrangement. AB - A novel domino reaction featuring a Michael addition/[1,2]-Stevens rearrangement reaction of pyrrolidinium ylides with electrophilic alkenes is described. Ylides generated under mild conditions from 2-aryl- N-cyanomethyl- N-methylpyrrolidinium salts entered the Michael addition, followed by a [1,3]-hydrogen shift and finally the [1,2]-Stevens rearrangement to give 3-aryl-2-cyano-2-(2-EWG-ethyl)-1 methylpiperidines. PMID- 29533066 TI - Functionally Active Membrane Proteins Incorporated in Mesostructured Silica Films. AB - A versatile synthetic protocol is reported that allows high concentrations of functionally active membrane proteins to be incorporated in mesostructured silica materials. Judicious selections of solvent, surfactant, silica precursor species, and synthesis conditions enable membrane proteins to be stabilized in solution and during subsequent coassembly into silica-surfactant composites with nano- and mesoscale order. This was demonstrated by using a combination of nonionic ( n dodecyl-beta-d-maltoside or Pluronic P123), lipid-like (1,2-diheptanoyl- s n glycero-3-phosphocholine), and perfluoro-octanoate surfactants under mild acidic conditions to coassemble the light-responsive transmembrane protein proteorhodopsin at concentrations up to 15 wt % into the hydrophobic regions of worm-like mesostructured silica materials in films. Small-angle X-ray scattering, electron paramagnetic resonance spectroscopy, and transient UV-visible spectroscopy analyses established that proteorhodopsin molecules in mesostructured silica films exhibited native-like function, as well as enhanced thermal stability compared to surfactant or lipid environments. The light absorbance properties and light-activated conformational changes of proteorhodopsin guests in mesostructured silica films are consistent with those associated with the native H+-pumping mechanism of these biomolecules. The synthetic protocol is expected to be general, as demonstrated also for the incorporation of functionally active cytochrome c, a peripheral membrane protein enzyme involved in electron transport, into mesostructured silica-cationic surfactant films. PMID- 29533070 TI - Intramolecular [2 + 2] Cycloadditions of Alkyl(phenylthio)ketenes: Total Synthesis of (+)-Sphaerodiol. AB - Asymmetric total synthesis of (+)-sphaerodiol (2) has been achieved. A key step is an intramolecular [2 + 2] cycloaddition of alkyl(phenylthio)ketene for rapid assembly of the decalin ring. PMID- 29533071 TI - Stereospecific Decarboxylative Benzylation of Enolates: Development and Mechanistic Insight. AB - A palladium-catalyzed decarboxylative coupling of enol carbonates with diarylmethyl electrophiles that are derived from secondary benzylic alcohols has been developed. This method allows the generation of a variety of beta-diaryl ketones through an efficient and highly stereospecific coupling. In addition, detailed mechanistic insight into the coupling suggests that the reaction is a rare example of an intramolecular decarboxylative coupling that proceeds without crossover between reactants. PMID- 29533072 TI - Mollebenzylanols A and B, Highly Modified and Functionalized Diterpenoids with a 9-Benzyl-8,10-dioxatricyclo[5.2.1.01,5]decane Core from Rhododendron molle. AB - Two highly modified and functionalized diterpenoids, mollebenzylanols A (1) and B (2), and a known grayanane diterpenoid rhodojaponin III (3) were isolated from Rhododendron molle. Their structures were determined by spectroscopic data analysis, an electronic circular dichroism (ECD) exciton chirality method, ECD calculations, and X-ray diffraction analysis of the p-bromobenzoate ester of 1 (1a). Compounds 1 and 2 possess an unprecedented diterpene carbon skeleton featuring a unique 9-benzyl-8,10-dioxatricyclo[5.2.1.01,5]decane core, and their plausible biosynthetic pathways are proposed. Their PTP1B inhibitory activity and modes of action were investigated. PMID- 29533073 TI - Correction to "Copper-Catalyzed Direct Propargylation of Polyfluoroarenes with Secondary Propargyl Phosphates". PMID- 29533074 TI - Analytical Methods for the Determination of Rosuvastatin in Pharmaceutical Formulations and Biological Fluids: A Critical Review. AB - Rosuvastatin calcium (ROS), ( Figure 1 ) belongs to the "statins" group, which is the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. This drug is indicated for dyslipidemias treatment and can help to decrease the level of "bad cholesterol" and can consequently reduce the development of atherosclerosis and the risk of heart diseases. ROS was developed by Astra-Zeneca and it was approved in 2003 by the FDA in the United States. In 2015, under the trade name Crestor(r), it was the fourth largest selling drug in the United States with sales above $5 billion. This study presents a literature review of analytical methods for the quantification of ROS in pharmaceutical preparations and biological fluids. The major analytical methods described in this study for ROS were spectrophotometry, high-performance liquid chromatography (HPLC) coupled to ultraviolet (UV) detection, and tandem mass spectrometry (LC-MS/MS). PMID- 29533075 TI - Analysis of the Precursors, Simulants and Degradation Products of Chemical Warfare Agents. AB - Recent advances in analysis of precursors, simulants and degradation products of chemical warfare agents (CWA) are reviewed. Fast and reliable analysis of precursors, simulants and CWA degradation products is extremely important at a time, when more and more terrorist groups and radical non-state organizations use or plan to use chemical weapons to achieve their own psychological, political and military goals. The review covers the open source literature analysis after the time, when the chemical weapons convention had come into force (1997). The authors stated that during last 15 years increased number of laboratories are focused not only on trace analysis of CWA (mostly nerve and blister agents) in environmental and biological samples, but the growing number of research are devoted to instrumental analysis of precursors and degradation products of these substances. The identification of low-level concentration of CWA degradation products is often more important and difficult than the original CWA, because of lower level of concentration and a very large number of compounds present in environmental and biological samples. Many of them are hydrolysis products and are present in samples in the ionic form. For this reason, two or three instrumental methods are used to perform a reliable analysis of these substances. PMID- 29533076 TI - Are we missing dementia with Lewy bodies?: a case report. AB - OBJECTIVES: We aim to explore the importance of early diagnosis of dementia with Lewy bodies in order to facilitate effective psychiatric management. We present a case where delayed diagnosis stemming from an atypical presentation illustrates the complex issues involved in identifying and treating this type of dementia. CONCLUSIONS: We discuss the difficulty of diagnosis of this disorder in the absence of obvious memory dysfunction or parkinsonian symptoms. We use the case to draw attention to the limited availability of certain investigations and treatment options in Australia. PMID- 29533077 TI - Borderline personality disorder: does its clinical features show specificity to differing developmental risk factors? AB - OBJECTIVES: To determine if differing developmental factors show specificity to differing manifestations of borderline personality disorder (BPD). METHODS: A clinical sample of 73 females diagnosed with BPD undertook a psychiatrist interview and completed self-report questionnaires, including the semi-structured Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV) assessing for BPD status. A set of negative and potentially traumatic developmental factors were included in the assessment. RESULTS: Childhood sexual abuse, affirmed by 49% of the sample, showed specificity in being linked with DIPD-defined affective instability. DIPD-defined identity disturbance also showed specificity in being associated only with reporting significant non-sexual developmental trauma. DIPD defined anger and paranoia/dissociation showed minimal specificity and were associated with most antecedent developmental factors in adulthood. CONCLUSIONS: Differing manifestations of BPD are likely to be shaped by specific and non specific developmental events. Clarification of such links has the potential to shape more specific therapeutic interventions. PMID- 29533078 TI - Development of reliable techniques for the differential diagnosis of avian tumour viruses by immunohistochemistry and polymerase chain reaction from formalin-fixed paraffin-embedded tissue sections. AB - A variety of techniques have been developed as diagnostic tools for the differential diagnosis of tumours produced by Marek's disease virus from those induced by avian leukosis virus and reticuloendotheliosis virus. However, most current techniques are unreliable when used in formalin-fixed paraffin-embedded (FFPE) tissues, which often is the only sample type available for definitive diagnosis. A collection of tumours was generated by the inoculation of different strains of Marek's disease virus, reticuloendotheliosis virus or avian leukosis virus singularly or in combination. FFPE tissue sections from tumour and non tumour tissues were analysed by optimized immunohistochemistry (IHC) techniques and traditional as well as quantitative polymerase chain reaction (PCR) with newly designed primers ideal for DNA fragmented by fixation. IHC and PCR results were highly sensitive and specific in tissues from single-infected birds. Virus quantity was higher in tumours compared to non-tumour spleens from Marek's disease (MD) virus-infected birds. Thus, using FFPE sections alone may be sufficient for the diagnosis of MD by demonstration of high quantities of viral antigens or genome in tumour cells, along with the absence of other tumour viruses by traditional PCR, and if standard criteria are met based on clinical history and histology. IHC furthermore allowed detection of the specific cells that were infected with different viruses in tumours from birds that had been inoculated simultaneously with multiple viruses. Following validation with field samples, these new protocols can be applied for both diagnostic and research purposes to help accurately identify avian tumour viruses in routine FFPE tissue sections. PMID- 29533079 TI - Ice in the Outback: the epidemiology of amphetamine-type stimulant-related hospital admissions and presentations to the emergency department in Hedland, Western Australia. AB - OBJECTIVES: Despite research showing higher use of amphetamine-type stimulants (ATS) in rural areas, limited research has examined the epidemiology of ATS related presentations and admissions to remote regional centres. To determine the epidemiology of ATS-related (a) Emergency Department (ED) presentations and (b) inpatient admissions over a five-year period at the Hedland Health Campus (HHC) in remote Western Australia. METHODS: A retrospective review of medical records was conducted. Demographic data including gender, age and indigenous status were captured. RESULTS: Four hundred and eighty-two ATS-related hospital presentations were identified during the study period. The most common reason for ED presentation was mental and behavioural problems. Of those presenting, 66% were male and 69% identified as Aboriginal. ATS-related ED presentations increased seven-fold over the study period. Ninety-nine ATS-related inpatient admissions were identified during the study period. Psychotic disorder was the most common reason for admission. Males made up 75% of admissions and 53% identified as Aboriginal. CONCLUSIONS: This study showed a disproportionally high burden of ATS related harm among Aboriginal people. The number of ATS-related ED presentations and inpatient admissions increased significantly over the study period. PMID- 29533080 TI - Bioactive sesquiterpenoids and steroids from the resinous exudates of Commiphora myrrha. AB - Chemical investigation of the resinous exudates of Commiphora myrrha has led to the isolation of four sesquiterpenes (1a/1b, 2, and 3), including one pair of new sesquiterpene enantiomers (1a/1b), one new racemic mixture 2, and two steroids (4 and 5). Their structures were elucidated by spectroscopic analysis, and the absolute configurations of 1a/1b were determined by CD analysis. The antimigratory potential of compounds 1-5 were evaluated and compound 3 was found to inhibit human hepatocellular liver carcinoma HepG2 cell migration in dose dependent manner. PMID- 29533081 TI - Filial anxiety and sense of obligation among offspring of Holocaust survivors. AB - OBJECTIVES: Much is known about adult children caring for their aging parents, yet the potentially unique experience of offspring caring for traumatized parents is underexplored. Therefore, the current studies assessed filial anxiety and sense of obligation among offspring of Holocaust survivors (OHS) in caring for their parents. METHOD: In Study 1, we interviewed 10 OHS (mean age = 61.0) in order to extract themes of filial anxiety. Based on Study 1's data, a newly constructed scale of filial anxiety was administered in Study 2 to 59 adult offspring (mean age = 56.4): 28 OHS and 31 comparisons. Study 3 included 143 dyads of parents and offspring (mean age = 55.4 and 81.7, respectively): 86 Holocaust dyads and 57 comparison dyads. Parents reported posttraumatic stress disorder (PTSD) symptoms and offspring reported filial anxiety and sense of obligation. RESULTS: In Study 1, interviewees referred to concerns about parent experiencing decline alongside caregiving difficulties. In Study 2, OHS reported higher filial anxiety and sense of obligation relative to comparisons. This group difference was mediated by sense of obligation. In Study 3, OHS with parental PTSD reported higher filial anxiety and sense of obligation relative to comparisons. Once more, filial sense of obligation served as a mediator. In Studies 2-3, results remained significant after adjusting for offspring symptoms. CONCLUSION: Parental exposure to the Holocaust, and especially parental PTSD, related to higher filial obligation, which in turn was related to higher filial anxiety. These findings bear important implications for practitioners working with survivors' families. PMID- 29533083 TI - Social support predicts self-care confidence in patients with heart failure. AB - BACKGROUND: Self-care for patients with heart failure includes engaging in behaviours that maintain medical stability and manage problematic symptoms, as well as the confidence in one's ability to carry out such behaviours. Given the social context of self-care behaviours in heart failure, there has been increasing interest in social support as a predictor of self-care. AIM: The goal of the present study was to examine the role of social support in self-care across time for persons with heart failure. METHODS: Using data from an observational study of patients with chronic heart failure ( n = 280), we examined the role of three types of support - instrumental support, emotional support and assistance with self-care - in the longitudinal course of self-care maintenance, management and confidence. Self-report questionnaire data were collected at baseline and at three and six months later. RESULTS: We found that instrumental and emotional support predicted better self-care confidence on average and that self-care confidence improved at a faster rate for those with less instrumental support. Emotional support was positively associated with self care management and self-care confidence, and assistance with self-care was positively associated with self-care maintenance. CONCLUSION: These findings highlight the contribution of social support to self-care in heart failure and provide guidance for future family-based interventions to improve self-care. PMID- 29533084 TI - A systematic literature review on the association between loneliness and coping strategies. AB - Loneliness is an emerging and important public health concern associated with increased risk for health disorders and even mortality. Interventions targeting coping strategies might be effective in alleviating feelings of loneliness. However, the relationship between loneliness and coping strategies is not well understood. We systematically reviewed quantitative studies addressing the association between loneliness and coping. Studies were included if loneliness and coping styles were measured with a validated scale and the association between both was assessed quantitatively. We searched Medline, Embase, PsycINFO, Cochrane Library, and CINAHL databases in compliance with the predefined in- and exclusion criteria. Two independent reviewers performed the search, quality appraisal, and data extraction. Coping styles were subdivided according to problem-focused and emotion-focused coping strategies. We included twelve studies that measured the association between loneliness and coping. Half of the studies had low risk of bias (n = 6), in the remaining six the risk of bias was moderate (n = 1) or high (n = 5). All studies that showed a significant association between loneliness and coping consistently showed that problem-focused coping styles were associated with lower levels of loneliness, and emotion-focused coping styles with higher levels of loneliness. Our findings suggest that learning how to use problem-focused coping strategies could be an important aspect of interventions targeting loneliness. This should be further explored in randomized clinical trials. Trials should report changes is coping and changes in loneliness and also include multivariate models that investigate if changes in coping contributed to changes in loneliness. Furthermore, further research should explore the role of different subgroups (e.g. older people), and the role of different types of loneliness as these can affect the effectiveness of loneliness interventions. PMID- 29533085 TI - Anti-Leishmania and cytotoxic activities of perillaldehyde epoxide synthetic positional isomers. AB - Leishmaniasis belongs to a complex of zoonotic disease caused by protozoa of the genus Leishmania and is considered a major public health problem. Several essential oil chemical components have inhibitory effect against protozoa, including Leishmania donovani. Thus, the aim of this study was to evaluate for the first time the anti-Leishmania activity of two p-menthane monoterpene isomers (EPER-1: perillaldehyde 1,2-epoxide and EPER-2: perillaldehyde 8,9-epoxide) against L. donovani promastigotes as well as evaluating cytotoxic effect on mononuclear peripheral blood cells. Results of anti-Leishmania assay revealed that EPER-2 (IC50 = 3.8 MUg.mL-1) was 16-fold more potent than its isomer EPER-1 (IC50 = 64.6 MUg.mL-1). In contrast to PBMC cells, EPER-2 was not cytotoxic (IC50 > 400 MUg.mL-1) when compared to positive control. These data suggest that the disposition of epoxide group into the p-menthane skeleton affects the anti Leishmania activity, being that the presence of the exocyclic epoxide group considerably increased potency. Thus, it was possible to observe that the location of the epoxide group into the p-menthane skeleton resulted in different potencies. PMID- 29533086 TI - Isolation and identification of new anthraquinones from Rhamnus alaternus L and evaluation of their free radical scavenging activity. AB - From the butanolic and the ethyl acetate extracts of Rhamnus alaternus L root bark and leaves, three new anthraquinone glycosides, alaternosides A-C (1,4,6,8 tetrahydroxy-3 methyl anthraquinone 1-O-beta-D-glucopyranosyl-4,6-di-O-alpha-L rhamnopyranoside (1); 1,2,6,8 tetrahydroxy-3 methyl anthraquinone 8-O-beta-D glucopyranoside (2) and 1, 6 dihydroxy-3 methyl 6 [2'-Me (heptoxy)] anthraquinone (3)) were isolated and elucidated together with the two known anthraquinone glycosides, Physcion-8-O-rutinoside (4) and emodin-6-O-alpha-L-rhamnoside (5) as well as with the known kaempferol-7-methylether (6), beta-sitosterol (7) and beta sitosterol-3-O-glycoside (8). Their chemical structures were elucidated using spectroscopic methods (1D-, 2D-NMR and FAB-MS). Free radical scavenging activity of the isolated compounds was evaluated by their ability to scavenge DPPH. free radicals. Compounds (3), (4) and (6) showed the highest activity with IC50 values of 9.46, 27.68 and 2.35 MUg/mL, respectively. PMID- 29533087 TI - The gut microbiota and its potential role in obesity. AB - The human GI tract harbors a diverse and dynamic microbial community comprising bacteria, archaea, viruses and eukaryotic microbes, which varies in composition from individual to individual. A healthy microbiota metabolizes various indigestible dietary components of the host, maintains host immune homeostasis and nutrient intake, but, an imbalanced microbiota has been reported to be associated with many diseases, including obesity. Rodent studies have produced evidence in support of the causal role of the gut microbiota in the development of obesity, however, such causal relationship is lacking in humans. The objective of this review is to critically analyze the vast information available on the composition, function and alterations of the gut microbiota in obesity and explore the future prospects of this research area. PMID- 29533088 TI - Conscientiousness and adherence to the oral contraceptive pill: a cross-sectional analysis of the facets of conscientiousness. AB - We examine the association between a six-facet model of conscientiousness and adherence to the Oral Contraceptive Pill (OCP), to investigate if these 6 facets can account for variation in adherence to the OCP. Cross-sectional data were collected from an opportunity sample of 243 female participants who were current users of the OCP, via online survey. Data were analysed using correlation and standard regression. The 60-item Chernyshenko Conscientiousness Scale (CCS), the 10-item IPIP Conscientiousness (IPIP C) subscale and the 5-item OCP Medication Adherence Report Scale (MARS) were employed. Both the total CCS (rho = -0.26, p < 0.01) and the IPIP C scale (rho = -0.22, p < 0.01) were associated with MARS. All facets measured by the CCS had small to medium-sized statistically significant correlations (r > -0.18 and r < -0.23, p < 0.05) with OCP adherence with the exception of traditionalism. Within a multivariable model, the six facets accounted for 7.1% of variance (p < 0.01) in adherence to the OCP. No one facet made a significant unique contribution to the model. These findings replicate and extend previous links between conscientiousness and OCP adherence. Further research should be conducted to establish the reliability of these findings in a general population of OCP users. Future interventions should focus on the development of interventions which take conscientiousness into consideration. PMID- 29533089 TI - Using Network Analysis to Identify Central Symptoms of Adolescent Depression. AB - Experiencing depression symptoms, even at mild to moderate levels, is associated with maladaptive outcomes for adolescents. We used network analysis to evaluate which symptoms (and associations between symptoms) are most central to adolescent depression. Participants were part of a large, diverse community sample (N = 1,409) of adolescents between 13 and 19 years of age. Network analysis was used to identify the most central symptoms (nodes) and associations between symptoms (edges) assessed by the Children's Depression Inventory. We also evaluated these centrality indicators for network robustness using stability and accuracy tests, associated symptom centrality with mean levels of symptoms, and examined potential differences between the structure and connectivity of depression networks in boys and girls. The most central symptoms in the network were self hatred, loneliness, sadness, and pessimism. The strongest associations between symptoms were sadness-crying, anhedonia-school dislike, sadness-loneliness, school work difficulty-school performance decrement, self-hatred-negative body image, sleep disturbance-fatigue, and self-deprecation-self-blame. The network was robust to stability and accuracy tests. Notably, symptom centrality and mean levels of symptoms were not associated. Boys and girls' networks did not differ in levels of connectivity, though the link between body image and self-hatred was stronger in girls than boys. Self-hatred, loneliness, sadness, and pessimism were the most central symptoms in adolescent depression networks, suggesting that these symptoms (and associations between symptoms) should be prioritized in theoretical models of adolescent depression and could also serve as important treatment targets for adolescent depression interventions. PMID- 29533090 TI - Genomics and cure: understanding narratives of patients with Duchenne muscular dystrophy in Japan. AB - Globally, genomics research is expected to enhance the health of patients with intractable diseases such as Duchenne muscular dystrophy (DMD). But how do patients perceive medical and scientific attempts at creating drugs and finding cure, and why? Since the 1990s, a number of clinical trials for patients of DMD have been organized. Among them are a gene therapy and exon skipping, and they indicate the possibility of finding therapies for DMD patients. Since 2011, Japanese medical institutions have been participating in Global Clinical Trials so that Japanese DMD patients can have access to them once developed. Despite ongoing global clinical trials, however, field research shows that the DMD patients the author encountered were neither enthusiastic nor well informed about gene therapies developed in Japan or elsewhere. Why not? The author observed that the desire for a cure among DMD patients is not self-evident, but is framed by sociocultural conditions surrounding the patients, the local history of discrimination against genetic disorders, and the way care is organised. These factors further interplay with physical and mental conditions particular to DMD, affecting patients' desire for a cure. This paper discusses the perception of genomics research and the possibility of a cure of DMD patients the author encountered in Japan, indicating that such perceptions are a result of the deeply related interactions of the conditions in which patients live. Finally, the author suggests how commonly held views of patients and patients' desire for cure need to be nuanced in genomic medicine. Data in this paper were collected between April and July 2014, and between 1996 and 2005 in Japan. PMID- 29533091 TI - Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil. AB - Within the context of a globalising agenda for genetic research where 'global health' is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases 'rarenesss' has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the 'judicialisation' of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities. PMID- 29533092 TI - Inherited blood disorders, genetic risk and global public health: framing 'birth defects' as preventable in India. AB - This paper engages critically with the global assemblage framing sickle cell and thalassaemia disorders as a 'global health crisis'; and the promise of genomics, largely DNA-based carrier/pre-conceptual screening, prenatal diagnosis with a view to terminations, deployed in framing a solution to these historically racialised spectrum of diseases as essentially preventable. Sickle cell and thalassaemia are recessively inherited, potentially life-threatening haemoglobin disorders with significant variation of severity, often needing life-long treatment. I argue that the re-classification of inherited blood disorders (IBDs) under 'prevention and management of birth defects' by the WHO in 2010 can be read as an ethical moment within the 'globalising turn' of IBDs and the use of genomics in addressing structural inequalities underpinning health in low- and middle-income countries. Using an Indian case study, the paper aims at first examining the language of risk through which genes and IBDs are mapped onto pre existing populations (e.g. caste and tribe) as discrete, categories. Second, it discusses the likely social and ethical ramifications of classifying these recessive gene disorders as essentially preventable, despite cheaply available diagnostic tests and treatment options available in most countries in the South. PMID- 29533093 TI - The justification of studies in genetic epidemiology - political scaling in China Medical City. AB - Genetic epidemiology examines the role of genetic factors in determining health and disease in families and in populations to help addressing health problems in a responsible manner. This paper uses a case study of genetic epidemiology in Taizhou, China, to explore ways in which anthropology can contribute to the validation of studies in genetic epidemiology. It does so, first, by identifying potential overgeneralizations of data, often due to mismatching scale and, second, by examining it's embedding in political, historical and local contexts. The example of the longitudinal cohort study in Taizhou illustrates dimensions of such 'political scaling'. Political scaling is a notion used here to refer to the effects of scaling biases in relation to the justification of research in terms of relevance, reach and research ethics. The justification of a project on genetic epidemiology involves presenting a maximum of benefits and a minimum of burden for the population. To facilitate the delineation of political scaling, an analytical distinction between donating and benefiting communities was made using the notions of 'scaling of relevance', 'scaling of reach' and 'scaling of ethics'. Political scaling results at least partly from factors external to research. By situating political scaling in the context of historical, political and local discourses, anthropologists can play a complementary role in genetic epidemiology. PMID- 29533094 TI - City and cosmology: genetics, health, and urban living in Dubai. AB - In light of increasingly high rates of diabetes, heart disease, and obesity among citizens of the Arabian Gulf, popular health discourse in the region has emphasised the emergent Arab genome as the primary etiological basis of major health conditions. However, after many years of public dissemination of genomic knowledge in the region, and widespread acceptance of this knowledge among Gulf Arab citizens, the rates of chronic illness continue to increase. This paper briefly explores the clash between indigenous Islamic knowledge systems and biomedical knowledge systems imported into the United Arab Emirates. It presents vignettes collected from interviews and participant observation in Dubai as part of nearly four years of ethnographic research, completed as part of the author's doctoral work on 'Anxiety and Identity in Southeast Arabia'. Rather than radically informing health seeking behaviours among many UAE citizens, the emphasis on the 'Arab Genome' has instead reconfirmed the authority of Bedouin cosmological understandings of disease, reshaping the language that people use to engage with their bodies and their health. Local cosmology remains a powerful discursive element that often operates in contention, in sometimes powerfully subtle ways, with novel health initiative regimes. For many people in the region, genomic information, as it is often discussed and propagated in the UAE, shares an intimate relationship with ideas of fate and national identity, and sometimes serves to mitigate the increasingly uncertain terms of engagement that people share between the body, their health, and rapidly changing urban landscapes. PMID- 29533095 TI - Genomics and genetic medicine: pathways to global health? PMID- 29533096 TI - Chronic traumatic encephalopathy in sports: a historical and narrative review. AB - My objectives are to review: 1) a brief history of sport-related concussion (SRC) and chronic traumatic encephalopathy (CTE), 2) the evolution of CTE in American professional football, 3) the data regarding SRC/CTE as they relate to depression and suicide, 4) the data on the neurocognitive effects of subconcussion/repetitive head trauma (with emphases on heading the ball in soccer and early exposure to football), 5) the evidence related to SRC and neurodegenerative diseases, 6) the published studies of CTE, 7) the NINDS neuropathological criteria for CTE, 8) public beliefs about SRC/CTE, and 9) the scientific questions regarding CTE. PMID- 29533097 TI - Head and Neck Cancer Patients Do Not Meet Recommended Intakes of Micronutrients without Consuming Fortified Products. AB - This study assessed dietary and micronutrient intakes of head and neck cancer (HNC) patients at key points in the disease trajectory and evaluated the contribution of oral nutritional supplements (ONS) to micronutrient intake. HNC patients (n = 114) completed a three-day dietary record and a tool to assess Nutrition Impact Scores (NIS) at baseline, post-treatment, and follow-up. Foods were classified into food categories. Micronutrient, protein, and energy intakes were compared to European Society for Parenteral and Enteral Nutrition guidelines for cancer patients. The majority of patients did not meet recommended dietary intakes for vitamins D, E, C, folate, and magnesium at any study time point. Relative to baseline, the proportion of calories from milk, soup, and ONS significantly increased at post-treatment, while grain, meat, potato, baked dessert, and oil and sugar decreased (P < 0.03). At all study time points, patients categorized as high ONS consumers (>15% of total daily calories from ONS) had higher intakes of micronutrients (P < 0.003). They also had a higher NIS (P = 0.006) and experienced greater weight loss (P < 0.04) during the study, despite having similar energy intake to patients consuming <15% kcal from ONS. Fortification of usually consumed foods to improve micronutrient intake among cancer patients should be evaluated. PMID- 29533098 TI - Ferulic acid modification enhances the anti-oxidation activity of natural Hb in vitro. AB - During the development of artificial red blood cell (RBC) substitutes, oxidation side reaction is one of the major factors that hinder the application of haemoglobin (Hb)-based oxygen carriers (HBOCs). In order to avoid oxidation toxicity, we designed and prepared natural Hb conjugated with ferulic acid (FA) via simple chemical modification. In addition, the thiol groups on Hb surface were increased via the reaction of Hb with 2-iminothiolane (2-IT) and then modified with FA for the study of anti-oxidant ability. It was showed that Hb modified with FA (FA-Hb) had similar oxygen-binding capacity to natural Hb. Moreover, the anti-oxidant ability of FA-Hb in vitro in different systems was superior to natural Hb and in proportion to the degree of modification of FA. The results indicate that FA-Hb might have the potential to serve as a novel oxygen carrier with the capacity to reduce oxidative side reaction. PMID- 29533099 TI - Autonomic cardiac control response to walking and executive cognitive task in adolescents with acquired brain injury and typically developed controls. AB - INTRODUCTION: Adolescents with acquired brain injury (ABI) present a range of physical and cognitive as well as cardiac autonomic control system (CACS) dysfunctions. AIM: To examine the CACS response to an executive task, a physical task and a combined physical and executive task, in adolescents with ABI and typically developed (TD) controls. METHODS: Included were two groups: The first group consisted of 17 adolescents (11-18 years) with ABI, during the in-patient or out-patient rehabilitation period. All were independent walkers. The second group consisted of 18-year-olds age and gender-matched TD adolescents. A Polar RS800CX device was used to assess heart rate (HR) and heart rate variability (HRV). Walking velocity was assessed by average speed on the 6-Minute Walk Test, and executive cognitive function was assessed by the Behavior Rating Inventory of Executive Function (BRIEF) questionnaire. The physical task was walking for 5 minutes on a treadmill. The cognitive task was the Digit Span Backward test. The study included four stages divided into rest state with and without cognitive task and walking state with and without cognitive task. RESULTS: Adolescents with ABI presented higher HR and lower HRV measures at rest (p-value < 0.01). A significant 'group' and 'activity' interaction effect on HRV was found; change in the activity level had significantly smaller effects on HRV parameters in adolescents with ABI as compared to controls. An interaction effect of 'cognitive' and 'activity' on HR and HRV was noted, with no significant difference between groups; at rest, performing a cognitive task was associated with reduced HRV, while during walking HRV increased. CONCLUSIONS: While ABI was associated with a reduced HRV at rest and less adaptive cardiac autonomic system to activity, ABI adolescent's response to a cognitive demand during an activity task such as walking was similar to the response of TD adolescents. Accordingly, we may say that adding a cognitive task to a walking task can improve the CACS function of ABI adolescents. PMID- 29533100 TI - Successful outcome for patients with streptococcal prosthetic joint infections - a retrospective population-based study. AB - BACKGROUND/AIM: Streptococci cause approximately 10% of prosthetic joint infections (PJIs). The aim of this study was to identify the characteristics of patients with streptococcal PJIs and to describe the treatment and outcome of streptococcal PJIs in Skane county between 2011 and 2015. METHODS: Patients with streptococcal PJIs with positive cultures or PCRs on samples from joint aspirate and/or periprosthetic tissue between 2011 and 2015 in Skane county, were identified and medical records were studied. RESULTS: Eighty-three PJI episodes treated at seven hospitals were identified. The median age was 70 years (IQR: 64 78) and there were more men (61%) than women. Hip joints were the most common site of isolation (54%). The most frequently isolated pathogens were beta haemolytic streptococci of groups A, C and G (31%), group B (30%), and alpha haemolytic streptococci (23%). Overall failure rate was 11% (n = 9), and lack of comorbidity was significantly associated with a favourable outcome. The most common treatment strategy was debridement, antibiotic treatment and implant retention (DAIR) (n = 64; 77%) and the initial success rate using this strategy was 84% (n = 53). CONCLUSION: This study indicates an acceptable success rate for the patients treated with DAIR strategy, and a high overall success rate for episodes suffering streptococcal PJIs. PMID- 29533101 TI - Role of gold and silver nanoparticles in cancer nano-medicine. AB - Development of nanoparticles (NPs) as a part of cancer therapeutics has given rise to a new field of research - cancer nanomedicine. In comparison to traditional anti-cancer drugs, NPs provide a targeted approach which prevents undesirable effects. In this communication, we have reviewed the role of gold and silver NPs (AgNPs) in the cancer nanomedicine. The preparation of gold NPs (AuNPs) and AgNPs can be grouped into three categories - physical, chemical and biological. Among the three approaches, the biological approach is growing and receiving more attention due to its safe and effective production. In this review, we have discussed important methods for synthesis of gold and AgNPs followed by techniques employed in characterization of their physicochemical properties, such as UV-visible spectroscopy, electron microscopy (TEM and SEM) and size and surface analysis (DLS). The mechanism of formation of these NPs in an aqueous medium through various stages - reduction, nucleation and growth has also been reviewed briefly. Finally, we conclude our review with the application of these NPs as anti-cancer agents and numerous mechanisms by which they render cancer cell toxicity. PMID- 29533102 TI - Is recurrent respiratory infection associated with allergic respiratory disease? AB - OBJECTIVE: Respiratory infections cause high morbidity and mortality worldwide. This study aims to estimate the relationship between allergic respiratory diseases with the occurrence of recurrent respiratory infection (RRI) in children and adolescents. METHODS: The International Study of Asthma and Allergies in Childhood questionnaire and a questionnaire that provides data on the history of respiratory infections and the use of antibiotics were used to obtain data from patients. The relationship between the presence of asthma or allergic rhinitis and the occurrence of respiratory infections in childhood was analyzed. RESULTS: We interviewed the caregivers of 531 children aged 0 to 15 years. The average age of participants was 7.43 years, with females accounting for 52.2%. This study found significant relationship between: presence of asthma or allergic rhinitis with RRI, with prevalence ratio (PR) of 2.47 (1.51-4.02) and 1.61 (1.34-1.93), respectively; respiratory allergies with use of antibiotics for respiratory problems, with PR of 5.32 (2.17-13.0) for asthma and of 1.64 (1.29-2.09) for allergic rhinitis; asthma and allergic rhinitis with diseases of the lower respiratory airways, with PR of 7.82 (4.63-13.21) and 1.65 (1.38-1.96), respectively. In contrast, no relationship between upper respiratory airway diseases and asthma and allergic rhinitis was observed, with PR of 0.71 (0.35 1.48) and 1.30 (0.87-1.95), respectively. CONCLUSIONS: RRI is associated with previous atopic diseases, and these conditions should be considered when treating children. PMID- 29533103 TI - Treatment of chikungunya musculoskeletal disorders: a systematic review. AB - INTRODUCTION: Chikungunya virus is amongst the fastest expanding vector transmissible diseases in recent years and has been causing massive epidemics in Africa, Asia, Latin America and the Caribbean. Despite human infection by this virus being first described in the 1950s, there is a lack of adequate therapeutic evaluations to guide evidence-based recommendations. The current guidelines rely heavily in specialists' opinion and experience instead of using higher rated evidence. Areas covered: A systematic review of the literature was performed- not restricted to clinical trials - reporting the therapeutic response against this infection with the intent to gather the best evidence of the treatment options against musculoskeletal disorders following chikungunya fever. The 15 studies included in the analysis were categorized considering the initiation of treatment during the acute, subacute and chronic phase. Expert commentary: This review demonstrates the complexity of chikungunya fever and difficulty of therapeutic management. This review found no current evidence-based treatment recommendations for the musculoskeletal disorders following chikungunya fever. To provide an optimal treatment that prevents perpetuation or progression of chikungunya infection to a potentially destructive and permanent condition without causing more harm is an aim that must be pursued by researchers and health professionals working with this disease. PMID- 29533104 TI - Integrated curriculum and the change process in undergraduate medical education. AB - INTRODUCTION: This study is aimed at explaining the change process followed for the implementation of the new curriculum at Avalon University School of Medicine and its evaluation. BACKGROUND: Self-evaluation at Avalon University School of Medicine identified the need for a change in the curriculum. The main reasons for the change are isolated disciplines and overcrowded curriculum leading to less self-study time for students. The new curriculum is aimed to have an integrated curriculum and to avoid redundancies. The new curriculum is designed, implemented, and evaluation of the same is in place. Evaluation methods and materials: After implementation, quantitative (results from exams) and semi quantitative (self-administered questionnaire) evaluation methods are being used to evaluate the new curriculum. Feedback is also taken by having discussions with teachers and students to find out what they like and where modifications are needed. In this article, we are presenting the results of course evaluations (semi-quantitative methods) for two courses. The course evaluations were taken from the sample class size of 30 students. RESULTS AND DISCUSSION: The course evaluations demonstrated an improvement. The main reason for the improvement is due to collaborative efforts of the faculty members from different disciplines in teaching, assessments, and providing feedback to the students. CONCLUSIONS: The well-approached change process is required for the successful implementation of the new curriculum. The idea of ownership among all stakeholders is required for a well-managed change process. PMID- 29533105 TI - Evaluating outcomes of computer-based classroom testing: Student acceptance and impact on learning and exam performance. AB - Computer-based testing (CBT) has made progress in health sciences education. In 2015, the authors led implementation of a CBT system (ExamSoft) at a dental school in the U.S. Guided by the Technology Acceptance Model (TAM), the purposes of this study were to (a) examine dental students' acceptance of ExamSoft; (b) understand factors impacting acceptance; and (c) evaluate the impact of ExamSoft on students' learning and exam performance. Survey and focus group data revealed that ExamSoft was well accepted by students as a testing tool and acknowledged by most for its potential to support learning. Regression analyses showed that perceived ease of use and perceived usefulness of ExamSoft significantly predicted student acceptance. Prior CBT experience and computer skills did not significantly predict acceptance of ExamSoft. Students reported that ExamSoft promoted learning in the first program year, primarily through timely and rich feedback on examination performance. t-Tests yielded mixed results on whether students performed better on computerized or paper examinations. The study contributes to the literature on CBT and the application of the TAM model in health sciences education. Findings also suggest ways in which health sciences institutions can implement CBT to maximize its potential as an assessment and learning tool. PMID- 29533106 TI - Association of plasma neutrophil gelatinase-associated lipocalin with acute kidney injury and clinical outcome in cardiac arrest survivors depends on the time of measurement. AB - PURPOSE: The optimal timing for measurement of neutrophil gelatinase-associated lipocalin (NGAL) level to predict acute kidney injury (AKI) and prognosis in cardiac arrest (CA) survivors has not been elucidated. We aimed to compare the diagnostic and prognostic performance of NGAL levels after return of spontaneous circulation (ROSC) and at 48 h after CA. METHODS: We included 231 adult cardiac arrest survivors who underwent targeted temperature management between May 2013 and December 2016. The primary outcome was stage 2 and 3 AKI (high stage AKI), and the secondary outcomes were in-hospital mortality and neurologic outcome. Sixty-one (26.4%) developed high stage AKI, 50 (21.6%) died, and 152 (65.8%) had a poor neurologic outcome. RESULTS: NGAL level at 48 h (0.876; 95% confidence interval [CI], 0.826-0.916) had a higher area under receiver operating characteristic curve than NGAL level after ROSC (0.694; 95% CI, 0.631-0.753). Both NGAL levels were independently associated with high stage AKI. NGAL level at 48 h (1.001; 95% CI, 1.000-1.002) remained a significant predictor for in hospital mortality, while neither of the NGAL levels were independently associated with neurologic outcome. CONCLUSIONS: NGAL at 48 h after CA seems to be a robust predictor for high stage AKI and in-hospital mortality. PMID- 29533107 TI - Correction to: New cyclopentaquinoline hybrids with multifunctional capacities for the treatment of Alzheimer's disease. PMID- 29533109 TI - Low TT4 as a predictor of poor outcomes in severe encephalitis: a multivariate analysis of 94 patients. AB - BACKGROUND: To investigate the prognostic value of acute thyroid function in patients with severe encephalitis. METHODS: We retrospectively analyzed information from patients with severe encephalitis from June 2012 to June 2017. Using multivariate logistic regression analysis, we examined predictors of poor outcomes in these patients after 6 months. RESULTS: A total of 94 patients with severe encephalitis were included in the study. Univariate analysis showed that patients with good or poor outcomes had significantly different total thyroxine (TT4) (P = 0.012) and free triiodothyronine (FT3) (P = 0.049) levels, mechanical ventilation requirements (P < 0.001), pulmonary infection complications (P = 0.001), lengths of neurological intensive care unit (P = 0.003) and total hospital (P = 0.012) stay, and Acute Physiology and Chronic Health Evaluation (APACHE II) (P = 0.005) and Glasgow Coma Scale (GCS) (P = 0) scores. The results of multivariate analysis suggested the following factors to be associated with a poor outcome: a low TT4 level (OR 0.303, 95% CI 0.100-0.923) and a low GCS score (OR 0.683, 95% CI 0.506-0.923). CONCLUSIONS: Low TT4 has a predictive value for the adverse outcomes of severe encephalitis; further study is needed for verification. PMID- 29533110 TI - The Impact of Postoperative Enteral Immunonutrition on Postoperative Complications and Survival in Gastric Cancer Patients - Randomized Clinical Trial. AB - BACKGROUND: Immunomodulating enteral nutrition in the perioperative period may reduce postoperative complications in cancer patients. Little is known if this effect translates to the better survival. The aim of study was to assess the impact of postoperative immunomodulating enteral nutrition on postoperative complications and survival of gastric cancer patients. METHODS: A group of 98 gastric cancer patients was randomly assigned for postoperative immunomodulating enteral nutrition n = 44 (Reconvan, Fresenius Kabi, Bad Homburg, Germany), or standard enteral nutrition n = 54 (Peptisorb, Nutricia, Schipol, The Netherlands). Postoperative complications, mortality, 6-mo and 1-yr survival were analyzed. RESULTS: The overall postoperative morbidity did not differ between the groups. The rate of pulmonary complications (excluding pneumonia) was significantly lower in immunomodulation group (0% vs 9.3%, p = 0.044), as well as 60-day mortality (0% vs. 11.1%, p = 0.037). There was no difference in 6-mo and 1 yr survival between the groups. CONCLUSIONS: Postoperative immunomodulating enteral nutrition may reduce respiratory complications and postoperative mortality in comparison to standard enteral nutrition. Despite this effect, it did not improve 6-mo and 1-yr survival in immunomodulation group. Probably the beneficial effect of immunomodulating enteral nutrition is too weak to be significant in such a number of patients. PMID- 29533111 TI - Cyclopamine treatment disrupts extracellular matrix and alleviates solid stress to improve nanomedicine delivery for pancreatic cancer. AB - As one of the most intractable tumours, pancreatic ductal adenocarcinoma (PDA) has a dense extracellular matrix (ECM) which could increase solid stress within tumours to compress tumour vessels, reduce tumour perfusion and compromise nanomedicine delivery for PDA. Thus, alleviating solid stress represents a potential therapeutic target for PDA treatment. In this study, cyclopamine, a special inhibitor of the hedgehog signalling pathway which contributes a lot to ECM formation of PDA, was exploited to alleviate solid stress and improve nanomedicine delivery to PDA. Results demonstrated that cyclopamine successfully disrupted ECM and lowered solid stress within PDA, which increased functional tumour vessels and resulted in enhanced tumour perfusion as well as improved tumour nanomedicine delivery in PDA-bearing animal models. Therefore, solid stress within PDA represents a new therapeutic target for PDA treatment. PMID- 29533112 TI - A randomized, controlled multicenter study evaluating focused ultrasound treatment for fat reduction in the flanks. AB - INTRODUCTION: Energy-based cosmetic devices offer an in-office treatment option, with minimal downtime, to non-invasively remove unwanted fat. We evaluated focused, pulsed ultrasound treatment to randomized flanks, compared to corresponding non-treated contralateral flanks. MATERIAL AND METHODS: Subjects were enrolled at three sites for a series of focused ultrasound treatments to a single flank, with the contralateral flank remaining untreated throughout the study. Success criteria included measureable fat thickness reduction on ultrasound imaging in the treated areas at 16 weeks after the final treatment session, and correct identification of the post-treatment photo and treated flank in at least 80% of evaluated images, as assessed by two blinded evaluators. RESULTS: The post-treatment flank photo and treated flank side were correctly identified in 82% and 93% of cases, respectively. All study subjects demonstrated significant fat reduction in their treated area, as measured by ultrasound and skin caliper. Subjects expressed a high satisfaction from treatment outcomes. There were no complications with treatment. CONCLUSION: A series of three ultrasound treatments resulted in significant fat reduction in treated flanks. Although treatment results are more modest than with liposuction, non-invasive ultrasound treatment may provide an attractive alternative for patients seeking an in-office, nonsurgical procedure for fat reduction. PMID- 29533108 TI - CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing? AB - INTRODUCTION: The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients. PMID- 29533113 TI - Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. AB - BACKGROUND: Data on temozolomide (TEM) and irinotecan (IRI) activity in recurrent Ewing sarcoma (EWS), especially in adult patients, are limited. METHODS: Patients receiving TEM 100 mg/m2/day oral, and IRI 40 mg/m2/day intravenous, days 1-5, every 21 days, were included in this multi-institutional retrospective study. Disease control rate (DCR) [overall response rate (ORR) [complete response (CR) + partial response (PR)] + stable disease (SD)], 6-months progression-free survival (6-mos PFS) and 1-year overall survival (OS) were assessed. RESULTS: The median age of the 51 patients was 21 years (range 3-65 years): 34 patients (66%) were adults (>=18 years of age), 24 (48%) had ECOG 1 and 35 (69%) were presented with multiple site recurrence. TEMIRI was used at first relapse/progression in 13 (25%) patients, while the remainder received TEMIRI for second or greater relapse/progression. Fourteen (27%) patients had received prior myeloablative therapy with busulfan and melphalan. We observed five (10%) CR, 12 (24%) PR and 19 (37%) SD, with a DCR of 71%. 6-mos PFS was 49% (95% CI 35-63) and it was significantly influenced by ECOG (6-mos PFS 64% [95% CI 45-83] for ECOG 0, 34% [95% CI 14-54] for ECOG >=1; p = .006) and LDH (6-mos PFS 62% [95% CI 44-79] for normal LDH, 22% [95% CI 3-42] for high LDH; p = .02), with no difference according to line of treatment, age and metastatic pattern. One-year OS was 55% (95% CI 39-70), with RECIST response (p = .001) and ECOG (p = .0002) independently associated with outcome. Grade 3 and 4 toxicity included neutropenia in 12% of patients, thrombocytopenia in 4%, diarrhea in 4%. CONCLUSIONS: This series confirms the activity of TEMIRI in both adults and pediatric patients. This schedule offers a 71% DCR, independently of the line of chemotherapy. Predictive factors of response are ECOG and LDH. PMID- 29533114 TI - Red blood cell distribution width to platelet ratio levels in assessment of histologic severity in patients with primary biliary cholangitis. AB - We aimed to investigate the relationship between the histologic severity and red blood cell distribution width to platelet ratio (RPR) in patients with primary biliary cholangitis (PBC). One hundred and seven consecutive patients with liver biopsy-proven and as yet treatment-naive PBC were enrolled as the primary and validation cohort. The histologic stages were divided into early stage (Scheuer's stage 1 & 2) and late stage (Scheuer's stage 3 & 4). The overall patient demographics, clinical manifestations, hematological tests and biochemical profile were retrospectively collected from our database. Both groups were compared in terms of RPR, aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4) and AST/ALT ratio (AAR). Of the 77 patients in the primary cohort, a total of 24 (31.2%) had early stage PBC, whereas 53 (68.8%) represented late stage. Patients with late stage PBC showed significantly higher red blood cell distribution width (15.5 vs. 14.1%, p = .016), RPR (0.15 vs. 0.09, p < .001), direct bilirubin (32.4 vs. 12.9 MUmol/L, p = .041), FIB-4 (3.41 vs. 6.34, p = .001) and significantly lower platelet (132.8 vs. 185.8 * 109/L, p = .002). The area under the curve, cut-off value, sensitivity, specificity, positive predictive value, negative predictive value for determining late stage were 0.74, 0.14, 49.1%, 95.8%, 96.3% and 46.0%, respectively. Additionally, high RPR may also serve as a prognostic indicator for 18-month mortality. In conclusion, RPR can be used as a non-invasive and effective predictor of histologic severity in patients with PBC. PMID- 29533115 TI - Vitamin D Supplementation and Survival in Metastatic Colorectal Cancer. AB - BACKGROUND: Some studies have demonstrated that higher baseline plasma levels of 25-hydroxivitamin D [25(OH)D] are associated with a significant reduction in colorectal cancer (CRC) incidence. Patients with metastatic CRC (mCRC) tend to be vitamin D insufficient, but the effect of vitamin D on the survival of mCRC patients still remains uncertain. In this study, we evaluated the association between cholecalciferol 2,000 IU daily supplementation and survival of mCRC patients. METHODS: Seventy-two patients with mCRC were included. Seventy-one patients with 25(OH)D levels <75 nmol/l were randomized to receive standard chemotherapy or standard chemotherapy with cholecalciferol 2,000 IU daily. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). The follow-up period was 46 mo. RESULTS: All but one patient (98.6%) was vitamin D insufficient. There was no statistically significant difference in OS or PFS between those who received vitamin D supplements and controls. CONCLUSIONS: The majority of patients with mCRC are vitamin D insufficient at the time of diagnosis. In our study, adding 2,000 IU of cholecalciferol daily for 2 yr to standard chemotherapy did not show any benefit in OS or PFS. PMID- 29533116 TI - The comparative immunogenicity of biologic therapy and its clinical relevance in psoriatic arthritis: a systematic review of the literature. AB - INTRODUCTION: Biologic agents have demonstrated efficacy in treating patients with psoriatic arthritis (PsA). Biologic agents also have an intrinsic capacity to induce an immune response in patients that could result in unwanted adverse events and/or treatment failure. Areas covered: In this systematic literature review, the authors document the incidence of immune responses, primarily anti drug antibodies (ADA), to the biologic therapeutic agents currently in clinical practice for the treatment of PsA. The authors discuss the importance of these responses with respect to clinical practice. Expert opinion: Our evaluation of the published literature shows that the immune responses to the various biologic therapeutic agents currently being used to treat PsA are similar to those observed for these agents in other rheumatic diseases. Moreover, similar to observations in other rheumatic diseases, the incidence of ADA formation to biologic agents in patients with PsA is often decreased when patients are given concomitant treatment with disease-modifying anti-rheumatic drugs. These data strongly suggest that the immune response is a characteristic of the biologic agent. Using therapeutic drug monitoring may be an approach to assess the immune response to the agent and to mitigate the potential impact on efficacy and safety, and consequently optimize treatment. PMID- 29533117 TI - Potential nephrotoxicity of sofosbuvir-based treatment in patients infected with hepatitis C virus: a review on incidence, type and risk factors. AB - INTRODUCTION: There was no report of nephrotoxicity during clinical trials assessed sofosbuvir for treatment of hepatitis C (HCV) infection. This may be due to excluding patients with severe kidney dysfunction, as a main population at risk for drug-induced nephrotoxicity from these studies. There are some reports of acute kidney injury (AKI) possibly related to sofosbuvir-containing treatments from real-life experiences. Areas covered: Available data on epidemiology, type, and possible risk factors for nephrotoxicity of sofosbuvir-containing treatment are reviewed. Related articles were collected by searching Scopus, Pubmed, and Science direct. Search terms were 'sofosbuvir', 'nephrotoxicity', 'acute kidney injury', 'renal impairment', and "direct acting antiviral agents. Expert commentary: AKI may happen in 1-15% of patients who are treated with sofosbuvir containing regimens. Compared with patients with normal kidney function, higher incidences of AKI have been reported in patients with baseline moderate to severe kidney dysfunction. Median time to AKI is 9 weeks after starting sofosbuvir. Baseline renal impairment, presence of ascites, diabetes or concomitant use of nephrotoxic drugs are possible risk factors for sofosbuvir-induced AKI. AKI following sofosbuvir-containing treatment is characterized by histological feature of acute interstitial nephritis and may be reversible following drug discontinuation. Monitoring of kidney function is recommended in sofosbuvir treated patients. PMID- 29533118 TI - Are age-specific reference ranges for CYFRA 21-1 appropriate? PMID- 29533119 TI - Feedback: Form over function? PMID- 29533120 TI - Betel Quid Dependency and Associated Intrapersonal, Interpersonal, and Environmental Factors among Adolescents: A School-Based Cross-Sectional Survey. AB - BACKGROUND: Betel quid (BQ) is one of the fourth most commonly used substance globally. Though BQ is a psycho-active substance, yet little has been explored regarding dependency on it particularly among adolescents. OBJECTIVES: Therefore, in this study, we aimed to determine adolescents' dependency on BQ, along with their intrapersonal, interpersonal and environmental determinants of dependency. METHODS: This cross-sectional study focused on 2200 school-going adolescents of Karachi, Pakistan in 2016. Primary outcome was dependency on BQ among adolescents. Both univariate and multivariate regressions were used to estimate crude and adjusted odds ratios (after adjustments for all intrapersonal, interpersonal, and environmental factors) with 95% confidence level. RESULTS: Out of 2200 students, 874 (39.7%) were found to be BQ users amongst whom 69 (7.9%) were dependent on BQ. Comparing the groups with only areca nut users as reference category, betel quid with tobacco additives chewers were considerably dependent (OR = 14.08, 95% CI 3.64-54.16). The individuals who chewed >5 chews per day (OR = 1.87, 95% CI 1.08-3.29) and chronic users (>1year) (OR = 2.02, 95% CI 1.09 3.74) were more likely to be dependent. Older students (>12 years) (OR = 2.12, 95% CI 1.06-4.23), and who studied in government schools were significantly dependent (OR = 3.32, 95% CI 1.80-6.10) than those who studied in private schools. CONCLUSIONS: In conclusion, intrapersonal characteristics like more than 5 chews per day, chronic chewers of more than a year, BQ with tobacco chewers, older adolescents and children studying in government schools were significantly associated with BQ dependency. PMID- 29533121 TI - Extracellular vesicles mediate low dose ionizing radiation-induced immune and inflammatory responses in the blood. AB - PURPOSE: Radiation-induced bystander effects (RIBE) imply the involvement of complex signaling mechanisms, which can be mediated by extracellular vesicles (EVs). Using an in vivo model, we investigated EV-transmitted RIBE in blood plasma and radiation effects on plasma EV miRNA profiles. MATERIALS AND METHODS: C57Bl/6 mice were total-body irradiated with 0.1 and 2 Gy, bone marrow-derived EVs were isolated, and injected systemically into naive, 'bystander' animals. Proteome profiler antibody array membranes were used to detect alterations in plasma, both in directly irradiated and bystander mice. MiRNA profile of plasma EVs was determined by PCR array. RESULTS: M-CSF and pentraxin-3 levels were increased in the blood of directly irradiated and bystander mice both after low and high dose irradiations, CXCL16 and lipocalin-2 increased after 2 Gy in directly irradiated and bystander mice, CCL5 and CCL11 changed in bystander mice only. Substantial overlap was found in the cellular pathways regulated by those miRNAs whose level were altered in EVs isolated from the plasma of mice irradiated with 0.1 and 2 Gy. Several of these pathways have already been associated with bystander responses. CONCLUSION: Low and high dose effects overlapped both in EV-mediated alterations in signaling pathways leading to RIBE and in their systemic manifestations. PMID- 29533122 TI - Self-discrimination in vine tendrils of different plant families. AB - Previous study reported a novel type of self-discrimination in the tendrils of the vine Cayratia japonica (Vitaceae). However, whether self-discrimination in tendrils is common in vine plant species has not been elucidated. Here, we investigated whether tendrils of Momordica charantia var. pavel (Cucurbitaceae), Cucumis sativus (Cucurbitaceae) and Passiflora caerulea (Passifloraceae) can discriminate self and non-self plants. We also investigated whether the tendrils of M. charantia and C. sativus can discriminate differences in cultivars to determine the discrimination ability for genetic similarity. We found that tendrils of the M. charantia and P. caerulea were more likely to coil around non self plant than self plants, but not in C. sativus. Our findings support the common occurrence of self-discrimination in tendrils in different plant taxa, although some species lacked it. Furthermore, tendrils of M. charantia more rapidly coil around different cultivars than around same cultivars. The tendrils of M. charantia may can discriminate differences in cultivars. PMID- 29533123 TI - Protective effects of sulforaphane in experimental vascular cognitive impairment: Contribution of the Nrf2 pathway. AB - The major pathophysiological process of vascular cognitive impairment (VCI) is chronic cerebral ischemia, which causes disintegration of the blood-brain barrier (BBB), neuronal death, and white matter injury. This study aims to test whether sulforaphane (Sfn), a natural activator of nuclear factor erythroid 2-related factor 2 (Nrf2), reduces the chronic ischemic injury and cognitive dysfunction after VCI. Experimental VCI was induced in rats by permanent occlusion of both common carotid arteries for six weeks. This procedure caused notable neuronal death in the cortex and hippocampal CA1, myelin loss in the corpus callosum and hippocampal fimbria, accumulation of myelin debris in the corpus callosum, and remarkable cognitive impairment. Sfn treatment alleviated these ischemic injuries and the cognitive dysfunction. Sfn-mediated neuroprotection was associated with enhanced activation of Nrf2 and upregulation of heme oxygenase 1. Sfn also reduced neuronal and endothelial death and maintained the integrity of BBB after oxygen-glucose deprivation in vitro in an Nrf2 dependent manner. Furthermore, Nrf2 knockdown in endothelial cells decreased claudin-5 protein expression with downregulated claudin-5 promoter activity, suggesting that claudin-5 might be a target gene of Nrf2. Our results demonstrate that Sfn provides robust neuroprotection against chronic brain ischemic injury and may be a promising agent for VCI treatment. PMID- 29533124 TI - The modified polymethyl methacrylate-silicone keratoprosthesis in rabbit model. AB - PURPOSE: To evaluate the safety and effectiveness of a modified polymethyl methacrylate-silicone keratoprosthesis and its operation method in alkali-burned rabbit model. METHODS AND MATERIALS: The polymethyl methacrylate-silicone keratoprostheses were implanted into seven alkali-burned rabbit corneas by a special operation method using autologous graft as the keratoprosthesis (Kpro) carrier. The long-term postoperative outcomes were evaluated. RESULTS: During a postoperative study period of 16 months, except for one Kpro extruded at 3 months, all Kpros were in good position and were kept transparent without Kpro extrusion, keratolysis, infection, endophthalmitis, or retinal detachment. The postoperative complications included elevated intraocular pressure in two cases and temporary retroprosthetic membrane formation in two cases. CONCLUSION: The modified polymethyl methacrylate-silicone Kpro and its operation method is a relatively safe and effective choice for alkali-burned rabbit eyes. Elevated intraocular pressure is the main complication needing to be resolved. PMID- 29533125 TI - Bacterial growth, flow, and mixing shape human gut microbiota density and composition. AB - The human gut microbiota is highly dynamic, and host physiology and diet exert major influences on its composition. In our recent study, we integrated new quantitative measurements on bacterial growth physiology with a reanalysis of published data on human physiology to build a comprehensive modeling framework. This can generate predictions of how changes in different host factors influence microbiota composition. For instance, hydrodynamic forces in the colon, along with colonic water absorption that manifests as transit time, exert a major impact on microbiota density and composition. This can be mechanistically explained by their effect on colonic pH which directly affects microbiota competition for food. In this addendum, we describe the underlying analysis in more detail. In particular, we discuss the mixing dynamics of luminal content by wall contractions and its implications for bacterial growth and density, as well as the broader implications of our insights for the field of gut microbiota research. PMID- 29533126 TI - The role of zinc and nutritional immunity in Clostridium difficile infection. AB - Clostridium difficile in one of the most commonly reported nosocomial pathogens worldwide. Beyond antibiotic use, little is known about the host, microbiota, and environmental factors that contribute to susceptibility to and severity of C. difficile infection (CDI). We recently observed that in a mouse model of CDI, excess dietary zinc (Zn) alters the gut microbiota and decreases resistance to CDI. Moreover, we determined that high levels of Zn exacerbate C. difficile associated disease and calprotectin-mediated Zn limitation is an essential host response to infection. In this addendum, we discuss how these findings add to our understanding of CDI and consider the potential implications of excess metal intake on the microbiota and infection. PMID- 29533127 TI - ROS-Induced anthocyanin production provides feedback protection by scavenging ROS and maintaining photosynthetic capacity in Arabidopsis. AB - Anthocyanins are water-soluble pigments with antioxidant activities. In plants, multiple factors can trigger the accumulation of anthocyanins, including chemicals and environmental factors. Reactive oxygen species (ROS) are common by products produced under different biotic and abiotic conditions and cause oxidative stress when accumulated at a high level in plant cells. This in turn leads to the production of anthocyanins. However, the mechanisms of ROS-induced anthocyanin accumulation and the role of anthocyanins in the response of plants to different stresses are largely unknown. We have recently reported the cross regulation between ROS and anthocyanin production through analyzing ten Arabidopsis mutants covering the main anthocyanin regulatory and biosynthetic genes grown under different ROS-generating stresses. Here, we describe the general phenotypic response of anthocyanin mutants under normal and ROS generating stress conditions, showing the changing levels of anthocyanin accumulation and their sensitivity to stresses. In addition, we propose a model that describes a particular gene interaction that highlights how the cross regulation mechanisms between ROS and anthocyanin production are essential for plant resistance to various stresses through removing excessive ROS and maintaining photosynthetic capacity. PMID- 29533128 TI - O11 is multi-functional regulator in maize endosperm. AB - As a highly developed tissue, maize endosperm accumulates nutrients abundantly and supports embryo development. In a recent study, we constructed a regulatory network centered around Opaque11 (O11). This network unified cellular development, nutrient metabolism and stress responses during endosperm development. Here we discuss the evidences that O11 might have a regulatory role in cold stress response during seed development. Furthermore, we discuss the functional divergence between maize O11 and its Arabidopsis orthologue ZHOUPI, which might explain some of the differences in endosperm development between monocotyledonous and dicotyledonous seeds. PMID- 29533130 TI - Reply to the letter to the editor concerning the review Immunotherapy for pet allergies. PMID- 29533129 TI - Safety study of live, oral human rotavirus vaccine: A cohort study in United States health insurance plans. AB - As part of a regulatory commitment for post-licensure safety monitoring of live, oral human rotavirus vaccine (RV1), this study compared the incidence rates (IR) of intussusception, acute lower respiratory tract infection (LRTI) hospitalization, Kawasaki disease, convulsion, and mortality in RV1 recipients versus inactivated poliovirus vaccine (IPV) recipients in concurrent (cIPV) and recent historical (hIPV) comparison cohorts. Vaccine recipients were identified in 2 claims databases from August 2008 - June 2013 (RV1 and cIPV) and January 2004 - July 2008 (hIPV). Outcomes were identified in the 0-59 days following the first 2 vaccine doses. Intussusception, Kawasaki disease, and convulsion were confirmed via medical record review. Outcome IRs were estimated. Incidence rate ratios (IRRs) were obtained from Poisson regression models. A post-hoc self controlled case series (SCCS) analysis compared convulsion IRs in a 0-7 day post vaccination period to a 15-30 day post-vaccination period. We identified 57,931 RV1, 173,384 cIPV, and 159,344 hIPV recipients. No increased risks for intussusception, LRTI, Kawasaki disease, or mortality were observed. The convulsion IRRs were elevated following RV1 Dose 1 (cIPV: 2.07, 95% confidence interval [CI]: 1.27 - 3.38; hIPV: 2.05, 95% CI: 1.24 - 3.38), a finding which is inconclusive as it was observed in only one of the claims databases. The IRR following RV1 Dose 1 in the SCCS analysis lacked precision (2.40, 95% CI: 0.73 - 7.86). No increased convulsion risk was observed following RV1 Dose 2. Overall, this study supports the favorable safety profile of RV1. Continued monitoring for safety signals through routine surveillance is needed to ensure vaccine safety. PMID- 29533131 TI - The Hospice Patient's Right to Oral Care: Making Time for the Mouth. AB - The hospice philosophy embraces palliative care for the terminally ill, for whom quality of life is the central focus of comfort care management. Often, caregivers hesitate or simply do not elect to extend oral care for patients nearing the end of life, due to difficulties encountered in patient compliance, a sense of futility in doing so, staff time constraints in prioritizing care, underfunding, or a lack of education as to how and why such care should be delivered to the hospice patient. This article aims to show physiological and psychosocial reasons why the hospice patient has a need for properly and regularly implemented oral care and why dental professionals have an ethical responsibility to address the current void that exists in hospice-centered oral care. Varying viewpoints are discussed regarding the need for oral health monitoring and maintenance in both the capable patient with capacity and in the patient who lacks capacity and is totally dependent, yet who exhibits no particular signs of oral distress nor desire for hygiene measures. Consideration is given to family dynamics in such care. Oral care of the elderly patients and terminally ill is sorely lacking, and dental educators are challenged to cultivate in students a sense of professional duty toward caring for the vulnerable elderly patients. Dental professionals should create initiatives in developing, promoting, and implementing an appropriate standard of oral care for the hospice patient. PMID- 29533132 TI - Drought stress promotes xylem differentiation by modulating the interaction between cytokinin and jasmonic acid. AB - Drought stress provokes jasmonic acid (JA) signaling, which mediates plant stress responses; moreover, growing numbers of studies suggest that JA is involved in the modulation of root development under drought stress. Recently, we showed that JA promotes differentiation of xylem from procambial cells in Arabidopsis roots. Further molecular and genetic approaches revealed that the effect of JA on xylem development is caused by suppression of cytokinin responses, suggesting that JA antagonistically interacts with cytokinin to modulate xylem development. Here, we showed that, similar to JA, drought stress promotes xylem development. This suggests that the antagonistic interaction between JA and cytokinin is involved in drought-mediated xylem development, a hypothesis supported by the observation that drought stress increases JA responses and decreases cytokinin responses. Based on these findings, we propose that drought stress promotes xylem development, and the antagonistic interaction between JA and cytokinin is deeply involved in this process. PMID- 29533133 TI - Experimental studies on the biological effects of chronic low dose-rate radiation exposure in mice: overview of the studies at the Institute for Environmental Sciences. AB - This review summarizes the results of experiments conducted in the Institute for Environmental Sciences for the past 21 years, focusing on the biological effects of long-term low dose-rate radiation exposure on mice. Mice were chronically exposed to gamma rays at dose-rates of 0.05, 1 or 20 mGy/day for 400 days to total doses of 20, 400 or 8000 mGy, respectively. The dose rate 0.05 mGy/day is comparable to the dose limit for radiation workers. The parameters examined were lifespan, neoplasm incidence, antineoplasm immunity, body weight, chromosome aberration(s), gene mutation(s), alterations in mRNA and protein levels and trans generational effects. At 20 mGy/day, all biological endpoints were significantly altered except neoplasm incidence in the offspring of exposed males. Slight but statistically significant changes in lifespan, neoplasm incidences, chromosome abnormalities and gene expressions were observed at 1 mGy/day. Except for transient alterations in the mRNA levels of some genes and increased liver neoplasm incidence attributed to radiation exposure, the remaining biological endpoints were not influenced after exposure to 0.05 mGy/day. Results suggest that chronic low dose-rate exposure may induce small biological effects. PMID- 29533134 TI - The unique antibody suppresses HBV viremia and reduces hepatocarcinogenesis in HBV-transgenic mice. PMID- 29533135 TI - Silencing of a Unique Integrated Domain Nucleotide-Binding Leucine-Rich Repeat Gene in Wheat Abolishes Diuraphis noxia Resistance. AB - Plants respond in a similar manner to aphid feeding as to pathogen attack. Diuraphis noxia is a specialist aphid, feeding only on selected grasses that include wheat, barley, and oats. The wheat-Diuraphis noxia interaction is characterized by responses very similar to those seen in wheat-pathogen interactions with none of the underlying resistance pathways and genes characterized yet. From wheat harboring the Dn1 resistance gene, we have identified a nucleotide-binding leucine-rich repeat (NLR) gene containing two integrated domains (IDs). These are three C-terminus ankyrin repeat domains and an N-terminus WRKY domain. The NLR core of the gene can be traced through speciation events within the grass family, with a recent WRKY domain integration that is Triticum-specific. Virus-induced gene silencing of the gene in a resistant wheat line resulted in the abolishment of the resistance response and induced a highly susceptible phenotype. Silenced plants supported a higher number of aphids, similar to the susceptible near-isogenic line (NIL), and the intrinsic rate of increase of the aphids matched that of aphids feeding on the susceptible NIL. The presence of the gene is necessary for Dn1 resistance and we have named the gene Associated with Dn resistance 1 (Adnr1) to reflect this function. PMID- 29533136 TI - The use of the term 'radiosensitivity' through history of radiation: from clarity to confusion. AB - PURPOSES: The term 'radiosensitivity' appeared for the first time at the beginning of the 20th century, few years after the discovery of X-rays. Initially used by French and German radiologists, it illustrated the risk of radiation induced (RI) skin reactions. From the 1950s, 'radiosensitivity' was progressively found to describe other features of RI response such as RI cancers or cataracts. To date, such confusion may raise legal issues and complexify the message addressed to general public. Here, through an historical review, we aimed to better understand how this confusion appeared. METHODS: To support our historical review, a quantitative and qualitative wording analysis of the 'radiosensitivity' occurrences and its derived terms was performed with Google books, Pubmed, Web of ScienceTM databases, and in all the ICRP publications. CONCLUSIONS: While 'radiosensitivity' was historically related to RI adverse tissue events attributable to cell death, the first efforts to quantify the RI risk specific to each organ/tissue revealed some different semantic fields that are not necessarily compatible together (e.g. adverse tissue events for skin, cataracts for eyes, RI cancer for breast or thyroid). To avoid such confusion, we propose to keep the historical definition of 'radiosensitivity' to any clinical and cellular consequences of radiation attributable to cell death and to introduce the term 'radiosusceptibility' to describe the RI cancers or any feature that is attributable to cell transformation. PMID- 29533137 TI - Balance worsening associated with nabiximols in multiple sclerosis. AB - We performed a dual-task experiment to explore the effect of nabiximols on postural control in 22 patients with multiple sclerosis. They were assessed with static posturography and Stroop test in single- and dual-task conditions at treatment start and after 1, 3 and 12 months. At follow-up, we found more impaired postural control in single-task ( F = 3.07, p = 0.044) and dual-task ( F = 4.90, p = 0.005) conditions in patients who continued treatment (continuers, n = 11) compared with those who discontinued (quitters, n = 11). Continuers were more impaired at Stroop test only in dual-task condition ( F = 3.17, p = 0.038). Our findings suggest that nabiximols had a detrimental effect on postural control, especially in multi-tasking conditions. PMID- 29533138 TI - Addressing social and gender norms to improve uptake of maternal health services in Mali: a descriptive study of CARE's Project Hope for Mothers and Newborns (PEMN). AB - This study examines the design and implementation of a maternal mortality prevention intervention in central Mali. It uses Project Hope for Mothers and Newborns (PEMN) as a case study to examine the context around implementation, with special emphasis on the role of social, gender and power norms in meeting programme objectives. Interventions to strengthen the health system and workforce were coupled with a social norms change approach to catalyse the personal transformation of staff, community-level health workers and communities via critical reflection and dialogue on gender and social power norms related to maternal health. Processes of reflection among staff, health workers and the community, coupled with activities that challenged restrictive norms, provided a platform for critical thinking, communication and motivation for change. Rigorous and comprehensive monitoring and evaluation is needed to identify and understand unique pathways to transformative change. PMID- 29533139 TI - How Is Marijuana Vaping Portrayed on YouTube? Content, Features, Popularity and Retransmission of Vaping Marijuana YouTube Videos. AB - The purpose of the study is to investigate how vaping marijuana, a novel but emerging risky health behavior, is portrayed on YouTube, and how the content and features of these YouTube videos influence their popularity and retransmission. A content analysis of vaping marijuana YouTube videos published between July 2014 to June 2015 (n = 214) was conducted. Video genre, valence, promotional and warning arguments, emotional appeals, message sensation value, presence of misinformation and misleading information, and user-generated statistics, including number of views, comments, shares, likes and dislikes, were coded. The results showed that these videos were predominantly pro-marijuana-vaping, with the most frequent videos being user-sharing. The genre and message features influenced the popularity, evaluations, and retransmission of vaping marijuana YouTube videos. Theoretical and practical implications are discussed. PMID- 29533140 TI - Didymium azorellae, a new myxomycete from cushion plants of cold arid areas of South America. AB - A new species of Didymium (Myxomycetes), D. azorellae, isolated from plant debris in a moist chamber, collected during studies of cold arid areas of Argentina and Peru, is described. It can be distinguished by its small size, the tightly packed layer of lime crystals on the peridium, the very scant, or absent, capillitium, and the unique spore ornamentation, especially by scanning electron microscopy. The species developed on dead leaves of cushion plants growing in the extremely harsh environments of the central Andean puna at almost 5000 m elevation and the Andino-Patagonian steppe. Morphology was examined with scanning electron microscopy and light microscopy, and micrographs of relevant details are included here. In order to confirm the identity of the new species described in this paper, a molecular study was conducted based on partial sequences of both the 18S rRNA and the elongation factor 1-alpha gene. Phylogenetic analysis including two specimens from different countries of the newly described species, Didymium azorellae, strongly supports the grouping of these specimens as a separate clade from the rest of the analyzed species. PMID- 29533141 TI - Effect of Pomegranate Juice on Intestinal Recovery Following Methotrexate-Induced Intestinal Damage in a Rat Model. AB - BACKGROUND/AIMS: Several studies have demonstrated the antimicrobial, antihelminthic, and antioxidant potential of the active ingredients of pomegranate (PMG) extracts, suggesting their preventive and curative role in several gastrointestinal disorders. In the present study, the authors evaluated the effects of oral PMG supplementation on intestinal structural changes, enterocyte proliferation, and apoptosis during methotrexate (MTX)-induced intestinal damage in a rat. METHODS: Male rats were divided into 4 experimental groups: control rats; CONTR-PMG rats were treated with oral PMG given by gavage once a day 72 hours before and 72 hours following vehicle injection; MTX rats were treated with single dose of methotrexate; and MTX-PMG rats were treated with oral PMG following injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined 72 hours following MTX injection. Western blotting was used to determine phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase 3 protein levels. RESULTS: MTX-PMG rats demonstrated greater jejunal and ileal bowel and mucosal weights, greater jejunal and ileal mucosal DNA and protein levels, greater villus height in jejunum and ileum and crypt depth in ileum, compared with MTX animals. A significant decrease in enterocyte apoptosis in ileum of MTX-PMG rats (vs MTX) was associated with a decrease in caspase 3 protein expression as well as increased cell proliferation, which was correlated with elevated p-ERK protein levels. CONCLUSIONS: Treatment with oral PMG prevents mucosal injury and improves intestinal recovery following MTX injury in the rat. PMID- 29533142 TI - The Synergism in Hormonal and Cellular Changes in Male Mice on Long Term High Fat Exposure. AB - OBJECTIVE: To determine the hormonal changes that occur as a result of the long term intake of a very-high-fat diet (VHFD) that leads to simultaneous changes in the islets of Langerhans and adipocyte cell size. METHODS: Male mice were fed with a normal chow diet (ND, n = 15) and a VHFD (n = 30) for 2, 12, and 24 weeks. Body weight, food intake, caloric intake (fat [saturated and unsaturated], protein, and carbohydrate), hormone levels (leptin and insulin), and islet of Langerhans/adipocyte size were quantitatively recorded. RESULTS: In VHFD-fed animals, body weight showed a significant percent increase within the first 12 weeks and then plateaued with time. VHFD-fed animals consumed significantly less food than ND at all time periods, indicating that it was the quality of food and not the quantity that caused this increase in body weight. Male mice on VHFD showed a significant increase in leptin and insulin levels, along with accompanying growth in islet and adipocyte size within the first 12 weeks, which plateaued as the mice aged. The increases in the islet and adipocyte size in VHFD fed animals were similar to the analogous increases in hormonal levels (2 vs. 12 vs. 24 weeks). These results, therefore, suggest that in diet-induced obesity changes, shifts in hormonal levels works hand-in-hand with metabolic adjustments at the cellular level to combat the effect of fat. CONCLUSION: Thus, mechanisms like hormonal resistance, changes in adiposity, islet size, and caloric intake with prolonged exposure to high fat are probably defensive mechanisms employed to protect against diabetes. In order to understand these complicated and nuanced effects of high fat and to comprehend the underlying mechanism associated with it, it is important to focus on long-term studies that emphasize the synergy between cellular and hormonal changes, in addition to an analysis of individual components. PMID- 29533143 TI - Twenty-Seven-Year Follow-Up of Vietnam Air War USAF POWs and Matched Controls Not Captured: A Qualitative Study. AB - OBJECTIVE: To provide a follow up of a 1976 study of the impact of captivity on U.S. Air Force (USAF) POWs and USAF Controls matched for time in Southeast Asia, military rank and aircraft crew position. METHOD: Qualitative study of replies to open ended questions of positive and negative changes due to their captivity/combat experiences made by participants (POWs and Controls) who replied in both 1976 and in 2003. RESULTS: Both groups acknowledged positive and negative effects of the experiences in 1976. In 1976 and 2003 the POWs mainly reported negative effects on career and family domains but positive effects of individual development and growth. Controls reported mild negative effects on family in 1976, and benefits to their careers and sense of self in both 1976 and 2003. CONCLUSION: Captivity during the Vietnam War for USAF included two types of extreme duress which were the incarceration itself; and the repatriation experience which entailed re-assimilation despite loss of occupation and disrupted families. Despite these obstacles, POWs exhibited substantial resilience in achieving self-growth and how they regarded themselves psychologically in comparison to their matched control fellow aviators who while also suffering a lesser separation from family, tended to prosper in their careers and were proud of their accomplishments. Long term separation from work, family and friends and the inability to return to their families and careers with the effectiveness demanded by their ambition were a more devastating ongoing consequence of their captivity than the immediate suffering of their imprisonment. PMID- 29533144 TI - Application of a TiO2 nanocomposite in earplugs: a case study of noise reduction. AB - BACKGROUND: Use of hearing protection devices has become necessary when other control measures cannot reduce noise to a safe and standard level. In most countries, more effective hearing protection devices are in demand. OBJECTIVE: The aim of this study was to examine the effects of titanium dioxide (TiO2) nanoparticles on noise reduction efficiency in a polyvinyl chloride (PVC) earplug. METHODS: An S-60 type PVC polymer as the main matrix and TiO2 of 30-nm size were used. The PVC/TiO2 nanocomposite was mixed at a temperature of 160 degrees C and 40 rpm and the samples were prepared with 0, 0.2 and 0.5 wt% of TiO2 nanoparticle concentrations. RESULTS: Earplug samples with PVC/TiO2 (0.2, 0.5 wt%) nanoparticles, when compared with raw earplugs, showed almost equal noise attenuation at low frequencies (500-125 Hz). However, at high frequencies (2-8 kHz), the power of noise reduction for earplugs containing TiO2 nanoparticles was significantly increased. CONCLUSIONS: The results of the present study showed that samples containing nanoparticles of TiO2 had more noticeable noise reduction abilities at higher frequencies in comparison with samples without the nanoparticles. PMID- 29533145 TI - For data's sake: dilemmas in the measurement of gender minorities. AB - Gender-minority health disparity research is limited by binary gender measurement practices. This study seeks to broaden current discourse on gender identity measurement in the USA, including measurement adoption challenges and mitigation strategies, thereby allowing for better data collection to understand and address health disparities for people of all genders. Three data sources were used to triangulate findings: expert interviews with gender and sexuality research leaders; key-informant interviews with gender minorities in New Orleans, LA; and document analysis of relevant surveys, guides and commentaries. Ten key dilemmas were identified: 1) moving beyond binary gender construction; 2) conflation of gender, sex and sexual orientation; 3) emerging nature of gender-related language; 4) concerns about item sensitivity; 5) research fatigue among gender minorities; 6) design and analytical limitations; 7) categorical and procedural consistency; 8) pre-populated vs. open-field survey items; 9) potential misclassification; and 10) competing data collection needs. Researchers must continue working toward consensus concerning better practices is gender measurement and be explicit about their methodological choices. The existence of these dilemmas must not impede research on important health issues affecting gender minorities. PMID- 29533146 TI - Effect of the Shaping Healthy Choices Program, a Multicomponent, School-Based Nutrition Intervention, on Physical Activity Intensity. AB - OBJECTIVE: Physical activity has been shown to have a wide range of beneficial health effects, yet few youth meet the United States physical activity recommendation of 60 minutes of moderate-to-vigorous physical activity (MVPA) everyday. The objective of this study was to determine whether physical activity patterns improved in a subsample of fourth-graders participating in the multicomponent intervention, the Shaping Healthy Choices Program (SHCP). METHODS: At pre- and post-intervention assessments, youth at the control and intervention schools wore a Polar Active monitor on their nondominant wrist 24 h/d for at least 2 consecutive days. Multiple linear regression was used to evaluate change in physical activity by adjusting for covariates and other potential confounders, including ethnicity/race, household income, and sex. Statistical significance was set at p < 0.05. RESULTS: Mean minutes of MVPA significantly increased at the intervention school (22.3 + 37.8; p = 0.01) and at the control school (29.1 + 49.5; p = 0.01). There were no significant differences in the change in MVPA between the schools. Youth at the intervention school significantly decreased mean minutes in sedentary activity compared to the controls (p = 0.02). CONCLUSIONS: Youth who participated in the SHCP decreased time spent in sedentary activity and increased very vigorous physical activity from pre- to post intervention, while these changes were not observed at the control school. The overall small physical activity intensity pattern shift supports that physical activity is an important area to target within a multicomponent nutrition intervention aimed at preventing childhood obesity. PMID- 29533147 TI - Effects of processing and cooking on the reduction of dinotefuran concentration in Japanese rice samples. AB - Dinotefuran is an insecticide belonging to the neonicotinoid class, which is frequently used to control pests in paddy rice owing to its permeability and effectiveness against sucking insects. Since 2002, this insecticide has been commercially available in Japan, and has become controversial due to its high detection frequency in brown rice for primary consumption. In this study, the effects of processing and cooking on the reduction of dinotefuran residues in commercially available brown rice were investigated. Boiled rice is difficult to homogenise and extract with acetonitrile. Using pre-freezing and cryogenic milling with powdered dry ice, dinotefuran in boiled rice was extracted well. A measurement method comprising sample preparation (acetonitrile extraction, gel permeation chromatography, and SPE) and detection with anLC-MS/MS system was used. In 10 out of 25 commercial brown rice samples, dinotefuran was detected at a concentration of 0.04 MUg/g (mean), which was more than the limit of quantitation of 0.01 MUg/g. The dinotefuran levels were significantly less than the MRL of 2 MUg/g in Japan. Even after polishing, washing, and boiling, dinotefuran was detected in 10 brown rice samples, with mean residue levels of 74.7%, 60.8%, and 39.6%, respectively, of the original concentration in brown rice. Based on these data, the processing factor of dinotefuran in boiled rice has been estimated to be approximately 0.4. Dinotefuran residues were reduced in the boiled rice, but less so than other pesticides. Although the maximum daily intake of dinotefuran in boiled rice was 0.0065 mg/person/day, its percent ratio to the ADI of dinotefuran in Japan was less than 0.05%. These results suggest that the daily intake of dinotefuran from rice might not be a critical problem at present, in spite of its relatively high detection frequency in boiled rice. PMID- 29533148 TI - Anthropometric Evaluation and Functional Assessment of Patients with Pulmonary Hypertension and its Relationship with Pulmonary Circulation Parameters and Functional Performance. AB - OBJECTIVE: The objective of this study was to investigate the anthropometric and functional status in patients with pulmonary hypertension (PH) and its relationship with pulmonary circulation parameters and functional performance. METHODS: The study is cross-sectional with 34 subjects, who were evaluated in terms of anthropometric measurements, physical performance, pulmonary circulation, and regular physical activity. RESULTS: Subjects had a mean age of 47.0 +/- 14.5 years, mean IMC 28.5 +/- 7.7 kg/m2 among adults, and 27.65 +/- 2.68 kg/m2 among elderly, with high body fat and preserved muscle mass. The sample presented the parameters of pulmonary circulation expected for PH patients and adequate performance in the physical capacity test. By linear regression analysis there was observed a negative relationship between body fat and regular physical activity. CONCLUSION: The evaluated subjects had an excess of body weight and fat, with preserved muscle mass, which does not appear to interfere in the pulmonary circulation parameters. However, elevated body fat appears to impair regular their physical activity. PMID- 29533149 TI - Examining the Effects of a Service-Trained Facility Dog on Stress in Children Undergoing Forensic Interview for Allegations of Child Sexual Abuse. AB - Disclosure of child sexual abuse can be a stressful experience for the child. Gaining a better understanding of how best to serve the child, while preserving the quality of their disclosure, is an ever-evolving process. The data to answer this question come from 51 children aged 4-16 (M = 9.1, SD = 3.5), who were referred to a child advocacy center in Virginia for a forensic interview (FI) following allegations of sexual abuse. A repeated measures design was conducted to examine how the presence of a service-trained facility dog (e.g. animal assisted intervention (AAI) may serve as a mode of lowering stress levels in children during their FIs. Children were randomized to one of the two FI conditions: experimental condition (service-trained facility dog present-AAI) or control condition (service-trained facility dog not present- standard forensic interview). Stress biomarkers salivary cortisol, alpha-amylase, immunoglobulin A (IgA), heart rate, and blood pressure, and Immunoglobulin A were collected before and after the FI. Self-report data were also collected. Results supported a significant decrease in heart rate for those in the experimental condition (p = .0086) vs the control condition (p = .4986). Regression models revealed a significant decrease in systolic and diastolic blood pressure in the experimental condition (p = .03285) and (p = .04381), respectively. Statistically significant changes in alpha-amylase and IgA were also found in relation to disclosure and type of offense. The results of this study support the stress reducing effects of a service-trained facility dog for children undergoing FI for allegations of child sexual abuse. PMID- 29533150 TI - The Association Between Dietary Glycemic Index and Glycemic Load and a Body Shape and Fat Distribution Among Apparently Healthy Iranian Adults. AB - OBJECTIVE: The role of dietary glycemic index (GI) and glycemic load (GL) in the development of obesity has been debated globally. The relationship with body shape and fat distribution was examined in this cross-sectional association study among apparently healthy Iranian adults. METHODS AND MATERIALS: A study population of 265 (126 males and 139 females) aged 18-55 years participated in this cross-sectional study from the communities of Tehran based on cluster sampling. GI and GL were assessed by the 147-item food frequency questionnaire (FFQ) completed by a trained dietitian. Weight, height, waist circumference (WC), and hip circumference of the participants were measured, and body mass index (BMI), waist-to-hip ratio (WHR), and A Body Shape Index (ABSI) were further calculated. Fat mass and fat-free mass were also measured using a body composition analyzer, and fat mass index (FMI) and fat-free mass index (FFMI) were then calculated. Multivariate regression models were fitted to assess the association between GI/GL and fat distribution measures such as FMI, FFMI, WC, BMI, WHR, and ABSI, considering potential confounding factors such as sex, age, BMI, and physical activity. RESULTS: There was a statistically significant inverse association between GL and WC, BMI, and ABSI found in the adjusted model. GL was inversely associated with WC for both the adjusted model (p-trend = 0.027) and the crude model. Also, an inverse association was seen between GL and BMI (p trend = 0.019) in the adjusted model but a marginal association in the crude model. GL was also inversely associated with ABSI (p-trend = 0.089) in the highest tertile. CONCLUSION: Dietary GL but not GI is inversely associated with fat distribution measures such as WC, BMI, and ABSI in the study population. This result may suggest a beneficial role of higher-GL diets in the prevention of obesity. PMID- 29533151 TI - Comparison of Renal Function and Other Predictors in Lacto-Ovo Vegetarians and Omnivores With Chronic Kidney Disease. AB - Objective Vegetarian diets have been shown to increase the risk of certain nutritional deficiencies, such as iron. As a number of patients with chronic kidney disease (CKD) in Taiwan are lacto-ovo vegetarians, the aim of this study was to investigate the effects of different proportions and sources of protein in lacto-ovo vegetarian and omnivorous diets, as well as the influence of adequate dietary protein intake, on renal function and nutritional status of Taiwanese patients with stage 3 to stage 5 CKD. Methods This is a cross-sectional study. In total, 100 outpatients with stage 3 to stage 5 CKD were enrolled in this study, including 40 lacto-ovo vegetarians and 60 omnivores. Subjects were divided into the lacto-ovo vegetarian group and omnivorous group based on dietary protein patterns. The indicators of renal function included estimated glomerular filtration rate (eGFR), creatinine, and blood urea nitrogen (BUN). Albumin, hemoglobin (Hb), and red blood cell count (RBC) measurements served as nutritional indicators. The levels of dietary energy and protein, as well as protein sources (plant or animal), were also analyzed. Results The levels of serum phosphate and triglycerides were significantly lower in the lacto-ovo vegetarian group than in the omnivore group, suggesting that lacto-ovo vegetarian diets have both phosphate-lowering and lipid-lowering effects, which could reduce the development of hyperphosphatemia and dyslipidemia. However, since all groups consumed higher than the recommended amounts of protein diet intake, no significant differences were observed in other renal function indices between the two groups. Conclusion Although a larger cohort study is necessary, the findings of this study could help patients with CKD to make healthier food choices and be used to support future medical nutritional therapies. PMID- 29533152 TI - Collagen and Derived Peptides as Nutritional Supplements for Integumental Care. PMID- 29533153 TI - The Relationship Between Female Reproductive Functions and Vitamin D. AB - Nonclassical target organs recently defined for vitamin D, a major regulator of calcium phosphorus homeostasis and bone health, include reproductive ones. This compilation study focuses on the potential effects of vitamin D on female reproductive functions. Vitamin D receptor enzymes that metabolize vitamin D are expressed in both central and peripheral reproductive organs. Most studies suggest that vitamin D may be directly or indirectly related to gonadal functions. Vitamin D's effects on reproductive functions may be indirectly related to diseases such as polycystic ovary syndrome (PCOS), uterine leiomyomas, and endometriosis. In case of vitamin D deficiency during infertility treatment, vitamin D supplementation can be recommended especially for women who have PCOS, insulin resistance, or low anti-Mullerian hormone levels. Supplementation, however, should take into account possible toxic effects of high-dose vitamin D. To be able to recommend measuring vitamin D as a routine screening test and to better understand the effects of vitamin D and its supplementation on female reproductive functions, larger randomized controlled prospective studies are needed. PMID- 29533154 TI - Patient-Centered Care Transitions After Injury Hospitalization: A Comparative Effectiveness Trial. AB - OBJECTIVE: The investigation aimed to compare two approaches to the delivery of care for hospitalized injury survivors, a patient-centered care transition intervention versus enhanced usual care. METHOD: This pragmatic comparative effectiveness trial randomized 171 acutely injured trauma survivors with three or more early postinjury concerns and high levels of emotional distress to intervention (I; n = 85) and enhanced usual care control (C; n = 86) conditions. The care transition intervention components included care management that elicited and targeted improvement in patients' postinjury concerns, 24/7 study team cell phone accessibility, and stepped-up care. Posttraumatic concerns, symptomatic distress, functional status, and statewide emergency department (ED) service utilization were assessed at baseline and over the course of the 12 months after injury. Regression analyses assessed intervention and control group outcome differences over time. RESULTS: Over 80% patient follow-up was attained at each time point. Intervention patients demonstrated clinically and statistically significant reductions in the percentage of any severe postinjury concerns expressed when compared to controls longitudinally (Wald chi-square = 11.29, p = 0.01) and at the six-month study time point (C = 74%, I = 53%; Fisher's exact test, p = 0.02). Comparisons of ED utilization data yielded clinically significant cross-sectional differences (one or more three- to six month ED visits; C = 30.2%, I = 16.5%, [relative risk (95% confidence interval] C versus I = 2.00 (1.09, 3.70), p = 0.03) that did not achieve longitudinal statistical significance (F (3, 507) = 2.24, p = 0.08). The intervention did not significantly impact symptomatic or functional outcomes. CONCLUSIONS: Orchestrated investigative and policy efforts should continue to evaluate patient centered care transition interventions to inform American College of Surgeons' clinical guidelines for U.S. trauma care systems. PMID- 29533155 TI - Screening Children for Caries: An Ethical Dilemma in Nigeria. AB - Dental caries is the main oral health challenge for children in Nigeria. Concern about its negative impact makes screening for caries in children an attractive public health strategy. The ability to detect the preclinical phase of caries, the availability of screening tools with high accuracy, and the possibility of treatment before onset of clinical symptoms with significant cost and health benefits, makes it appropriate for screening. However in Nigeria, the poor availability of highly specific and sensitive screening tools, poor access to oral health care and concerns with pre-screening consent, raise the question of the appropriateness of conducting screening programmes for children. We argue that a number of structural challenges associated with poor uptake of oral health care services need to be addressed before screening for caries can be considered ethically appropriate. These include facilitating access of children to quality oral health care and a systematic national approach to oral health implementation. Failure to address challenges associated with dental service utilization by children in Nigeria increases the risk of screening programmes promoting inequitable access to oral health care services. PMID- 29533156 TI - Sex differences in wheelchair propulsion biomechanics and mechanical efficiency in novice young able-bodied adults. AB - An awareness of sex differences in gait can be beneficial for detecting the early stages of gait abnormalities that may lead to pathology. The same may be true for wheelchair propulsion. The aim of this study was to determine the effect of sex on wheelchair biomechanics and mechanical efficiency in novice young able-bodied wheelchair propulsion. Thirty men and 30 women received 12 min of familiarisation training. Subsequently, they performed two 10-m propulsion tests to evaluate comfortable speed (CS). Additionally, they performed a 4-min submaximal propulsion test on a treadmill at CS, 125% and 145% of CS. Propulsion kinetics (via Smartwheel) and oxygen uptake were continuously measured in all tests and were used to determine gross mechanical efficiency (GE), net efficiency (NE) and fraction of effective force (FEF). Ratings of perceived exertion (RPE) were assessed directly after each trial. Results indicated that CS for men was faster (0.98 +/- 0.24 m/s) compared to women (0.71 +/- 0.18 m/s). A lower GE was found in women compared to men. Push percentage, push angle and local RPE were different across the three speeds and between men and women. NE and FEF were not different between groups. Thus, even though their CS was lower, women demonstrated a higher locally perceived exertion than men. The results suggest sex differences in propulsion characteristics and GE. These insights may aid in optimising wheelchair propulsion through proper training and advice to prevent injuries and improve performance. This is relevant in stimulating an active lifestyle for those with a disability. PMID- 29533157 TI - Longitudinal Examination of Links Between Risk Factors for the Metabolic Syndrome and Both Age and Fasting Glucose Levels in Nondiabetic Subjects. AB - BACKGROUND: Previous evaluations in nondiabetic subjects revealed statistically significant correlations between fasting blood glucose (FBG) levels used as an estimate of insulin resistance and many components constituting the metabolic syndrome. Similar significant correlations were not found employing chronological age as the independent variable in the same nondiabetic individuals. OBJECTIVE: The major purpose here was to replicate as well as corroborate the previous cross sectional observations, emphasizing results obtained from data collected longitudinally. METHODS: Material was assessed from 99 nondiabetic volunteers who had undergone 2 separate baseline measurements carried out over a minimum of 5 and up to a maximum of 20 years. RESULTS: Findings from the starting baseline measurements mimicked many observations perceived in the earlier published cross sectional material. The following correlations with elements constituting the metabolic syndrome using FBG as an independent variable were once more statistically significantly positive: scale weight, fat mass, circulating levels of triglycerides and high-sensitivity C-reactive protein (hsCRP). High-density lipoprotein (HDL) cholesterol was once again appropriately significant in a negative direction. In contrast, the same correlations were generally nonsignificant when age replaced FBG as the independent variable. Examining the 2 data sets over the 5-20-year intervals, FBG increased statistically significantly over time. However, the average increase clinically was relatively minor: -92.1 mg/dL +/- 1.1 (SEM) vs 95.1 mg/dL +/- 1.1 (SEM), p < 0.007. When the actual changes (delta) in the dependent parameters were correlated with the individual passages of time (intervals in years), only downward changes in aspartate aminotransferase (AST) levels were statistically significant. Fat-free mass showed a trend downward, whereas fat mass, trunk fat, and triglycerides merely demonstrated trends upward. CONCLUSION: Current findings gathered over years are consistent with the original hypothesis that maintaining relatively low, stable circulating glucose levels during aging retards the development and intensity of many common manifestations of the metabolic syndrome. PMID- 29533158 TI - Distribution of POPs, pesticides and antibiotic residues in organic honeys from different production areas. AB - Demand for honey is increasing, especially if it is organic and if its nutritional properties are linked to untreated environments in order to guarantee quality for health. Sources of contamination of honey can be divided into environmental and apicultural. Therefore, the distribution of persistent organic pollutants, pesticides and antibiotic residues from geographical areas with different contamination sources (high anthropic impact, intensive farming, husbandry and low anthropic impact) was investigated in order to confirm the potential transfer of xenobiotics into the supply chain and to give beekeepers tools for the selection of areas dedicated to organic production. The presence of polychlorinated biphenyls, polybrominated diphenyl ether and polycyclic aromatic hydrocarbons was confirmed, not only in proximity to highly urbanised centres, where the concentrations were higher, but in all environment contexts, confirming their ubiquity. No antibiotics or neonicotinoids were detected in 95 organic honeys, demonstrating the absence of apicultural treatments and consequently the good quality of honey of different areas. These results are important due to the undefined regulatory European situation on honey antibiotic limits. PMID- 29533159 TI - Risk of Social Isolation among Older Patients: What Factors Affect the Availability of Family, Friends, and Neighbors upon Hospitalization? AB - OBJECTIVES: To examine the prevalence of social isolation among older patients admitted to a hospital, and the effects of sociodemographic and health-related factors on the availability of their family, friends, and neighbor networks. METHODS: Analyses are based on interviews with a sample of 2,449 older patients admitted to an urban academic medical center in the United States. A nine-item version of Lubben's Social Network Scale was developed and used to assess the availability of different social networks. RESULTS: About 47% of the sample was at risk of social isolation. The oldest old and non-White older adults showed greater risk. The availability of family networks was associated with age, sex, marital status, and prior hospitalization; friend networks with age, race, education, prior hospitalization, and functional limitations; neighbor networks with race, education, marital status, and functional limitations. CONCLUSIONS: The risk of social isolation and the availability of social support for hospitalized older adults varies by both patient and network characteristics. Health professionals should attend to this risk and the factors associated with such risk. CLINICAL IMPLICATIONS: By assessing the availability of various types and frequency of support among older patients, health professionals can better identify those who may need additional support after discharge. Such information should be used in discharge planning to help prevent unnecessary complications and potential readmission. PMID- 29533160 TI - Late activity rebound in non-active multiple sclerosis: A rare event. PMID- 29533161 TI - Polydeoxyribonucleotide injection in the patients with partial-thickness tear of supraspinatus tendon: a prospective and pilot study using ultrasound. AB - OBJECTIVE: Polydeoxyribonucleotide as adenosine receptor (A2A) agonist has been used in plastic surgery and dermatology related to its regenerative property. The aim of this pilot study is to evaluate the safety and efficacy of polydeoxynucleotide injection in patients with rotator cuff tears by a variety of outcomes including pain, disability, physical performance test, and ultrasonography (US). METHODS: Seventeen patients (9 men, 8 women, age: 57.9 +/- 9.1) with partial-thickness tear of supraspinatus tendon were evaluated in a prospective, open-label, and pre-and-post study. Seventeen patients underwent 3 times intra-lesional polydeoxynucleotide injection under ultrasound (US) guidance on weeks 0, 2 and 4. The safety and efficacy were assessed on weeks 0, 6 and 12. Main outcome measures included shoulder pain on Visual Analogue Scale (VAS) and DASH (disabilities of arm, hand, shoulder) score, range of motion in shoulder, shoulder strength and tear volume (cm3) by US. Adverse events were monitored. (CRIS: https://www.cris.nih.go.kr , KCT0000767). RESULTS: Active shoulder pain on VAS reduced from 5.53 to 3.53 (P = 0.016), and acting pain, one of DASH questionnaires, reduced from 3.35 to 2.00 (P < 0.001). However, resting shoulder pain on VAS and total DASH scores were not significantly different. Forward flexion and internal rotation in range of motion improved significantly (from 169.41 to 178.13 degrees [P = 0.004] and from 83.53 to 88.75 degrees [P = 0.014], respectively). The volume of torn lesion decreased during the study period, however it was not significant. There were no significant adverse events leading to hospitalization. CONCLUSIONS: Minimally invasive procedure through polydeoxynucleotide injection into torn area of supraspinatus tendon on US could be candidate for the safe and effective treatment on shoulder pain and limited range of motion in patients with rotator cuff tear. PMID- 29533162 TI - Going beyond social support: Fear of receiving compassion from others predicts depression symptoms in breast cancer patients. AB - BACKGROUND: Recent studies have highlighted the importance of being able to receive compassion and affiliative signals from others. The main aim of the present study was to explore whether social support and fear of receiving compassion from others are predictors of depression symptoms in a sample of breast cancer patients. METHODS: The sample included 86 female patients with non metastatic breast cancer. Participants were recruited at a Radiotherapy Service in central Portugal and completed validated self-report instruments. Multiple regression analysis were conducted to examine the predictive effects of clinical (cancer stage, comorbidities) and demographic variables (age, education), social support, and fear of receiving compassion from others on depressive symptoms. RESULTS: Fear of receiving compassion from others was the only significant predictor of the model, with a positive effect on depression symptomatology (beta = 0.44; p < 0.001). These results suggest that the amount of supportive social contacts and networks may not be as important as cancer patients' ability to receive compassion from others. CONCLUSIONS: This is the first study to focus on fear of receiving compassion from others in cancer patients and seems to be a significant contribution for the study of the social factors that may be associated with depression in breast cancer. Psychological screening interviews in breast cancer, besides assessing patients' level of depression and social support, ought to also evaluate the ability to receive empathy and emotional help and support from other people. PMID- 29533164 TI - Communities' perceptions of factors contributing to child sexual abuse vulnerability in Kenya: a qualitative study. AB - Child sexual abuse (CSA) is a major global health concern. Although it is prevalent in Kenya, scant literature on factors contributing to CSA vulnerability exists. Using qualitative data from 28 focus groups and ethnographic field notes, we explored and assessed community perceptions of factors contributing to CSA vulnerability in Homa Bay County, Western Kenya. Findings suggest that people living in these communities perceived CSA as being influenced by multiple factors: developmental stage, peer pressure, huge gender disparities exacerbated by negative social norms and cultural practices, the HIV epidemic and social media platforms that circulate sexualised images. From our findings, it was clear that participants also regarded poverty as exacerbating children's vulnerability to CSA. Minors from poor families engaged in transactional sex for survival and social status. Some community members perceived girls dressed in short skirts or tight clothing as warranting unwanted sexual advances. Although poverty and gender roles and relations were viewed as increasing vulnerability to CSA, blame was often placed on survivors' modes of dress or behaviour. There is a need for comprehensive education of the communities on CSA, its consequences and the rights of women and girls. PMID- 29533163 TI - Invasive Cronobacter species infection in infants and children admitted to a rural Kenyan hospital with a high prevalence of malnutrition. AB - For children with acute malnutrition, ready-to-use therapeutic foods (RUTF) are lifesaving treatments. In 2012, detailed testing detected Enterobacteriaceae including Cronobacter species at low levels in RUTF from all UNICEF-approved producers. Cronobacter in milk feeds has previously been associated with severe neonatal infections. Thus, given the susceptibility of severely malnourished children to invasive bacterial infections, concerns arose about the potential for Cronobacter infections from RUTF. This led to widespread production and supply problems in emergency feeding programmes. The KEMRI/Wellcome Trust Research Programme has conducted systematic surveillance for invasive bacterial infections among children admitted to Kilifi County Hospital, Kenya since 1998. 65,426 paediatric blood and cerebrospinal fluid cultures from 52,733 admissions resulted in 3953 with growth of a pathogenic organism. From the 60 Enterobacter and Cronobacter isolates, possible Cronobacter species were initially selected from their original API-20E biochemical profile, which was repeated and then confirmed using ID-32E. Only two isolates were consistent with Cronobacter species, neither case had received RUTF. Serious infection due to Cronobacter species does not have a significant burden in this population. This has important implications for the continued supply, manufacture and monitoring of emergency feeds for malnourished children. PMID- 29533165 TI - A Spatial Analysis of the Potato Cyst Nematode Globodera pallida in Idaho. AB - The potato cyst nematode Globodera pallida is a globally regulated and quarantine potato pest. It was detected for the first time in the United States in the state of Idaho in 2006. A spatial analysis was performed to (i) understand the spatial arrangement of fields infested with G. pallida in southern Idaho using spatial point pattern analysis, and (ii) evaluate the potential threat of G. pallida for entry to new areas using spatial interpolation techniques. Data point locations, cyst numbers and egg viability values for each infested field were collected by USDA-APHIS during 2006 to 2014. Results showed the presence of spatially clustered fields infested with G. pallida (P = 0.003). We determined that the spread of G. pallida grew in diameter from the original center of infestation toward the southwest as an ellipsoidal-shaped cluster. Based on the aggregated spatial pattern of distribution, we determined that G. pallida spread followed a contagion effect scenario, where nearby infested fields contributed to the infestation of new fields, probably through soil contaminated agricultural equipment or tubers. We determined that the presence of G. pallida in southern Idaho is unlikely to be associated with new introductions from outside the state of Idaho. The aggregation pattern of fields infested with G. pallida, with an average of 4,263 cysts/ha and egg viability of 25%, facilitates quarantine activities and confines the propagation of this pest to a small area, which in 2017 was estimated to be 1,233 ha. The tools and methods provided in this study facilitate comprehensive approaches to improve G. pallida control and eradication programs as well as to raise public awareness of the problems surrounding this economically important potato pest. PMID- 29533166 TI - Effort as Person-Focused Praise: "Hard Worker" Has Negative Effects for Adults After a Failure. AB - Although work with children demonstrates a benefit of process-focused praise relative to person-focused praise on post-failure motivation, few studies have examined this result in adults. We tested the effect of three types of praise on adults' post-failure outcomes: person-focused intelligence ("high intelligence"), person-focused effort ("hard worker"), and process-focused effort ("worked hard") in a sample of 156 adults recruited from Amazon's MTurk. Participants completed a set of easy visual pattern recognition problems and were told that they performed better than most adults and were given one of the three types of feedback. They then completed more difficult problems and were told that they had not performed well. Participants in the "hard worker" condition (compared to "worked hard") were more likely to endorse intelligence as a reason for failure. They also reported lower perceived success and less enjoyment than participants in other conditions. Participants in the "high intelligence" condition were more likely to attribute their failure to intelligence than participants in the "worked hard" condition. The results suggest that the benefit of process-focused praise typically found in children (worked hard compared to intelligent) was mostly not replicated in adults, and person-focused effort praise was detrimental in a non college student adult sample. PMID- 29533168 TI - "So we basically let them struggle": Student perceptions of challenges in intergenerational service-learning. AB - Service-learning is a widely used pedagogical practice that integrates community involvement and civic engagement into the classroom. Benefits of service-learning in gerontology include an increased sense of personal growth, greater knowledge of aging, and enhanced interest in aging-related careers. However, relatively little research has specifically explored the challenges associated with intergenerational service-learning. A focus group documented the experiences of 19 students who were required to participate in at least 20 hours of intergenerational service-learning for an introductory gerontology course. Because an administrative error prevented students from knowing about the service learning requirement until they were enrolled, these participants were well qualified to discuss the challenges and positive aspects of their experiences. In addition to confirming known benefits of service-learning, three major themes regarding challenges emerged: lack of communication, the need for guidance, and creating meaningful relationships. This study provides suggestions for further development of "best practice" guidelines unique to intergenerational service learning. PMID- 29533167 TI - Systematic Transcreation of Self-Help Smoking Cessation Materials for Hispanic/Latino Smokers: Improving Cultural Relevance and Acceptability. AB - Smoking-related illnesses are the leading causes of death among Hispanics/Latinos. Yet, there are few smoking cessation interventions targeted for this population. The goal of this study was to "transcreate" an existing, previously validated, English language self-help smoking cessation intervention, titled Forever Free(r): Stop Smoking for Good, for Spanish-speaking smokers. Rather than simply translating the materials, our transcreation process involved culturally adapting the intervention to enhance acceptability and receptivity of the information. We utilized a multiphase qualitative approach (focus groups and learner verification interviews) to develop a linguistically and culturally relevant intervention for the diverse sub-ethnic groups of Hispanic/Latino smokers. Focus group findings indicated a need to underscore several additional cultural characteristics and themes such as the need to address familism and unique stressors faced by immigrants and to provide information regarding nicotine replacement therapy. Learner verification findings indicated a need to further emphasize financial and social benefits of quitting smoking and to discuss how family and friends can support the quit attempt. These steps led to the development of a Spanish-language smoking cessation intervention titled, Libre del cigarillo, por mi familia y por mi: Guia para dejar de fumar, that is currently being tested in a national randomized controlled trial. PMID- 29533169 TI - How to conduct a qualitative meta-analysis: Tailoring methods to enhance methodological integrity. AB - : Although qualitative research has long been of interest in the field of psychology, meta-analyses of qualitative literatures (sometimes called meta syntheses) are still quite rare. Like quantitative meta-analyses, these methods function to aggregate findings and identify patterns across primary studies, but their aims, procedures, and methodological considerations may vary. OBJECTIVE: This paper explains the function of qualitative meta-analyses and their methodological development. Recommendations have broad relevance but are framed with an eye toward their use in psychotherapy research. Rather than arguing for the adoption of any single meta-method, this paper advocates for considering how procedures can best be selected and adapted to enhance a meta-study's methodological integrity. METHOD: Through the paper, recommendations are provided to help researchers identify procedures that can best serve their studies' specific goals. Meta-analysts are encouraged to consider the methodological integrity of their studies in relation to central research processes, including identifying a set of primary research studies, transforming primary findings into initial units of data for a meta-analysis, developing categories or themes, and communicating findings. CONCLUSION: The paper provides guidance for researchers who desire to tailor meta-analytic methods to meet their particular goals while enhancing the rigor of their research. PMID- 29533170 TI - Saccharomonospora piscinae sp. nov., a novel actinobacterium from fishpond sediment in Taiwan. AB - Strain 06168H-1T was isolated from a fishpond sediment sample collected from the southern area of Taiwan, and a polyphasic approach was used to determine its taxonomic position. The isolate grew between 20-40 degrees C and 0-8 % (w/v) NaCl. It produced branched and unfragmented substrate mycelia. Short spore chains (3-10 spores per chain) formed on branched aerial mycelia. The spore chains contained non-motile, smooth-surfaced, oval spores. Galactose, arabinose and ribose were the whole-cell sugars and meso-diaminopimelic acid was present in its peptidoglycan. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylcholine, hydroxyphosphati dylethanolamine and a ninhydrin-positive phosphoglycolipid. The predominant menaquinone was MK-9(H4) and minor components were MK-8(H4) and MK-9(H6). Mycolic acids were not detected. The major cellular fatty acids were iso-C16 : 0 and C17 : 1omega6c and C17 : 0omega8c. The DNA G+C content of the strain was 70.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed this strain clustered with the members of the genus Saccharomonospora and was closely related to Saccharomonospora xinjiangensis, Saccharomonospora azurea and Saccharomonosporacyanea. The levels of similarity between this strain and the closely related species were: Sxinjiangensis BCRC16887T, 98.34 %; S. azurea BCRC 16220T, 98.27 %; and S. cyanea BCRC 16886T, 97.99 %. Based on phylogenetic characteristics, strain 06168H-1T represents a novel species of the genus Saccharomonospora. We thus propose the name Saccharomonospora piscinae sp. nov. for this novel strain, with strain 06168H-1T (=BCRC 16893T=KCTC 19743T) as the type strain. PMID- 29533171 TI - Pseudodesulfovibrio hydrargyri sp. nov., a mercury-methylating bacterium isolated from a brackish sediment. AB - The strain BerOc1T was isolated from brackish sediments contaminated with hydrocarbons and heavy metals. This strain has been used as a model strain of sulfate-reducer to study the biomethylation of mercury. The cells are vibrio shaped, motile and not sporulated. Phylogeny and physiological traits placed this strain within the genus Pseudodesulfovibrio. Optimal growth was obtained at 30 degrees C, 1.5 % NaCl and pH 6.0-7.4. The estimated G+C content of the genomic DNA was 62.6 mol%. BerOc1T used lactate, pyruvate, fumarate, ethanol and hydrogen. Terminal electron acceptors used were sulfate, sulfite, thiosulfate and DMSO. Only pyruvate could be used without a terminal electron acceptor. The major fatty acids were C18 : 0, anteiso-C15 : 0, C16 : 0 and C18 : 1omega7. The name Pseudodesulfovibrio hydrargyri sp. nov. is proposed for the type strain BerOc1T (DSM 10384T=JCM 31820T). PMID- 29533172 TI - Field trials of blood culture identification FilmArray in regional Australian hospitals. AB - PURPOSE: In this field trial of rapid blood culture identification (BCID), we aimed to determine whether the improved speed and accuracy of specific BCID predicted in our earlier pilot study could be obtained in regional hospitals by deploying a multiplex PCR FilmArray (Biomerieux, France) capability in their laboratories. METHODS: We trained local hospital laboratory staff to operate the FilmArray equipment and act on the results. To do this, we integrated the multiplex PCR into the standard laboratory blood culture workflow and reporting procedure. RESULTS: Of 100 positive blood culture episodes, BCID FilmArray results were correct in all 42 significant monobacterial cultures, with a fully predictive identity in 38 (90.5 %) and a partial identity in another four (9.5 %). There was one major error; a false positive Pseudomonas aeruginosa. The minor errors were the detection of one methicillin-resistant Staphylococcus aureus, which proved to be a methicillin-sensitive S. aureus mixed with a methicillin resistant coagulase-negative staphylococcus, five false negative coagulase negative staphylococci and one false negative streptococcus species. We found that 41/49 (84 %) clinically significant mono- and polymicrobial culture results were fully predictive of culture-based identification to bacterial species level at a mean of 1.15 days after specimen collection. CONCLUSIONS: There was a reduction of 1.21 days in the time taken to produce a definitive BCID compared to the previous year, translating into earlier communication of more specific blood culture results to the treating physician. Reduced time to definitive blood culture results has a direct benefit for isolated Australian communities at great distances from specialist hospital services. PMID- 29533173 TI - Clostridium difficile shows no trade-off between toxin and spore production within the human host. AB - PURPOSE: This study aimed to describe the correlation between Clostridium difficile spore and toxin levels within the human host. In addition, we assessed whether overgrowth of Candida albicans modified this association. METHODOLOGY: We measured toxin, spore and Candida albicans levels among 200 successively collected stool samples that tested positive for C. difficile, and PCR ribotyped these C. difficile isolates. Analysis of variance and linear regression were used to test the association between spore and toxin levels. Kruskal-Wallis tests and t-tests were used to compare the association between spore or toxin levels and host, specimen, or pathogen characteristics. RESULTS: C. difficile toxin and spore levels were positively associated (P<0.001); this association did not vary significantly with C. albicans overgrowth [>=5 logs of C. albicans colony-forming units (c.f.u.) g-1]. However, ribotypes 027 and 078-126 were significantly associated with higher levels of toxin and spores, and C. albicans overgrowth. CONCLUSION: The strong positive association observed between in vivo levels of C. difficile toxin and spores suggests that patients with more severe C. difficile infections may have increased spore production, enhancing C. difficile transmission. Although, on average, spore levels were higher in toxin-positive samples than in toxin-negative/PCR-positive samples, spores were found in almost all toxin-negative samples. The ubiquity of spore production among toxin-negative and formed stool samples emphasizes the importance of following infection prevention and control measures for all C. difficile-positive patients during their entire hospital stay. PMID- 29533175 TI - Streptococcus penaeicida sp. nov., isolated from a diseased farmed Pacific white shrimp (Penaeus vannamei). AB - Strain CAIM 1838T, isolated from the hepatopancreas of a cultured diseased Pacific white shrimp (Penaeus vannamei), was subjected to characterization by a polyphasic taxonomic approach. On the basis of 16S rRNA gene sequence analysis, strain CAIM 1838T was most closely related to Streptococcus bovimastitidis 99.3 % and to other species of the Pyogenes clade of Streptococcus with lower similarity values. Average nucleotide identity values and the genome-to-genome distance of strain CAIM 1838T, as compared with the type strains, confirmed the separate species status with closely related species of the genus Streptococcus and were all below the thresholds to delimit a species, 93.1 and 49.4 %, respectively. The DNA G+C content was 38.1 mol%. Differential phylogenetic distinctiveness together with phenotypic properties obtained in this study revealed that strain CAIM 1838T could be differentiated from the closely related species. Based on these results it is proposed that strain CAIM 1838T represents a novel species in the genus Streptococcus, for which the name Streptococcus penaeicida sp. nov is proposed (type strain, CAIM 1838T=CECT 8596T,=DSM26545T), is proposed. PMID- 29533176 TI - Characterisation of Streptococcus pneumoniae isolates from invasive disease in adults following the introduction of PCV10 in Brazil. AB - PURPOSE: Invasive pneumococcal disease (IPD) in the elderly is an important public health issue due to the increased proportion of this population in many countries including Brazil. We aimed to characterise pneumococci isolates in adults >50 years with IPD, following the introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) as part of the National Childhood Immunisation Program for children <=2 years in March 2010. METHODOLOGY: Between 2013 and 2015, pneumococcal isolates were collected and serotypes were determined using multiplex PCR and/or Quellung reaction. Antimicrobial susceptibility was defined by E-test (bioMerieux); genetic diversity was determined using Multiple Locus Variable Number Tandem Repeat Analysis (MLVA) and, in selected isolates, Multi Locus Sequence Typing (MLST) was performed.Results/Key findings. Among 102 pneumococcal isolates, the most frequent serotypes were 19A, 13 of 102 (12.7 %) and 22F, 10 of 102 (9.8 %). Ninety-eight isolates were tested for antimicrobial susceptibility. Intermediate resistance to penicillin was present in 2/98 (2.0 %), ceftriaxone in 7/98 (7.1 %) and meropenem in 7/95 (7.4 %) of the isolates (non-meningitis breakpoint: 4 ug ml-1/2 ug ml-1/0.5 ug ml-1, respectively). Resistance to penicillin (meningitis breakpoint >=0.12 ug ml-1) was observed in 31/98 (31.6 %) of the isolates. Genetic analysis presented two relevant clonal groups, belonging to non-PCV10 serotypes: 19A (ST320, linked to non susceptibility) and 22F (ST6403). CONCLUSION: Our data suggest a predominance of non-PCV10 serotypes among IPD in the elderly population in circulating strains ca. 3 to 5 years after the introduction of PCV10 in Brazil. PMID- 29533174 TI - Neptunicella marina gen. nov., sp. nov., isolated from surface seawater. AB - A Gram-stain-negative, aerobic, short rod-shaped bacterium with a single polar flagellum, designated strain S27-2T, was isolated from surface seawater from the Indian Ocean. Growth was observed in 0-12.0 % (w/v) NaCl with an optimum of 0.5 2.0 % (w/v) NaCl, pH 6.0-9.0 with an optimum of pH 7.0, and growth temperature of 10-41 degrees C with an optimum of 25-37 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain S27-2T belonged to the family Alteromonadaceae and formed a distinct lineage with the type strain of Pseudobowmanella zhangzhouensis. Levels of 16S rRNA gene sequence similarity between strain S27-2T and members of related genera included in the trees ranged from 86.7 to 93.8 %. Strain S27-2T contained Q-8 as the predominant ubiquinone. The principal fatty acids (>10 %) were C16 : 0 (22.1 %), C16 : 1omega7c/omega6c (22.7 %) and C18 : 1omega7c/omega6c (20.1 %). The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unidentified phospholipid and two unknown lipids. The G+C content of strain S27 2T was 43.7 mol%. On the basis of the polyphasic taxonomic evidence presented in this study, strain S27-2T should be classified as a novel species in a new genus within the family Alteromonadaceae, for which the name Neptunicella marina gen. nov., sp. nov. is proposed, with the type strain S27-2T (= KCTC52335T=MCCC 1A02149T). PMID- 29533177 TI - Amycolatopsis silviterrae sp. nov., isolated from forest soil. AB - A novel actinobacterial strain, designated C12CA1T, was isolated from forest soil in the conservation area of Chulabhorn dam, Thailand, and its taxonomic position was determined by using a polyphasic approach. Strain C12CA1T contained meso-2,6 diaminopimelic acid in the cell-wall peptidoglycan, and arabinose and galactose as diagnostic sugars of the whole-cell hydrolysate. On the basis of morphological and chemotaxonomic characteristics, strain C12CA1T was classified in the genus Amycolatopsis. It contained MK-9(H4) as the predominant menaquinone, C16 : 0, iso C15 : 0 and iso-C16 : 0 as the major cellular fatty acids, and several phospholipids consisting of diphosphotidylglycerol, phosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, hydroxyphosphatidylethanolamine, phosphatidylinositol mannosides and an unidentified glucosamine-containing phospholipid. Based on 16S rRNA gene sequence and phylogenetic analyses, strain C12CA1T was closely related to Amycolatopsis vancoresmycina DSM 44592T (98.96 %) and Amycolatopsis pretoriensis JCM 12673T (98.82 %). The strain exhibited low DNA-DNA relatedness values with A. vancoresmycina DSM 44592T (6.9+/-0.2-11.6+/-1.9 %) and A. pretoriensis JCM 12673T (8.8+/-0.3-9.2+/-1.8 %). The DNA G+C content of strain C12CA1T was 69.8 mol%. Based on the results of polyphasic characterization, strain C12CA1T represents a novel species of the genus Amycolatopsis, for which the name Amycolatopsis silviterrae sp. nov. is proposed. The type strain is C12CA1T (=TBRC 1456T=NBRC 111116T). PMID- 29533178 TI - Method for identification of condition-associated public antigen receptor sequences. AB - Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) recognize antigens in the adaptive immune system. The development of immunoglobulin receptor repertoire sequencing methods makes it possible to perform repertoire-wide disease association studies of antigen receptor sequences. We developed a statistical framework for associating receptors to disease from only a small cohort of patients, with no need for a control cohort. Our method successfully identifies previously validated Cytomegalovirus and type one diabetes responsive TCR[Formula: see text] sequences . PMID- 29533179 TI - Adult-born neurons facilitate olfactory bulb pattern separation during task engagement. AB - The rodent olfactory bulb incorporates thousands of newly generated inhibitory neurons daily throughout adulthood, but the role of adult neurogenesis in olfactory processing is not fully understood. Here we adopted a genetic method to inducibly suppress adult neurogenesis and investigated its effect on behavior and bulbar activity. Mice without young adult-born neurons (ABNs) showed normal ability in discriminating very different odorants but were impaired in fine discrimination. Furthermore, two-photon calcium imaging of mitral cells (MCs) revealed that the ensemble odor representations of similar odorants were more ambiguous in the ablation animals. This increased ambiguity was primarily due to a decrease in MC suppressive responses. Intriguingly, these deficits in MC encoding were only observed during task engagement but not passive exposure. Our results indicate that young olfactory ABNs are essential for the enhancement of MC pattern separation in a task engagement-dependent manner, potentially functioning as a gateway for top-down modulation. PMID- 29533180 TI - Large, long range tensile forces drive convergence during Xenopus blastopore closure and body axis elongation. AB - Indirect evidence suggests that blastopore closure during gastrulation of anamniotes, including amphibians such as Xenopus laevis, depends on circumblastoporal convergence forces generated by the marginal zone (MZ), but direct evidence is lacking. We show that explanted MZs generate tensile convergence forces up to 1.5 MUN during gastrulation and over 4 MUN thereafter. These forces are generated by convergent thickening (CT) until the midgastrula and increasingly by convergent extension (CE) thereafter. Explants from ventralized embryos, which lack tissues expressing CE but close their blastopores, produce up to 2 MUN of tensile force, showing that CT alone generates forces sufficient to close the blastopore. Uniaxial tensile stress relaxation assays show stiffening of mesodermal and ectodermal tissues around the onset of neurulation, potentially enhancing long-range transmission of convergence forces. These results illuminate the mechanobiology of early vertebrate morphogenic mechanisms, aid interpretation of phenotypes, and give insight into the evolution of blastopore closure mechanisms. PMID- 29533181 TI - NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. AB - The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins. These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells. Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. Together, these findings identify NuRD and CAF-1 as mediators of DUX4 chromatin repression and suggest a mechanism for the amplification of DUX4 expression in FSHD muscle cells. PMID- 29533182 TI - Replication Study: Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. AB - As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Repass et al., 2016), that described how we intended to replicate an experiment from the paper 'Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma' (Castellarin et al., 2012). Here we report the results. When measuring Fusobacterium nucleatum DNA by qPCR in colorectal carcinoma (CRC), adjacent normal tissue, and separate matched control tissue, we did not detect a signal for F. nucleatum in most samples: 25% of CRCs, 15% of adjacent normal, and 0% of matched control tissue were positive based on quantitative PCR (qPCR) and confirmed by sequencing of the qPCR products. When only samples with detectable F. nucleatum in CRC and adjacent normal tissue were compared, the difference was not statistically significant, while the original study reported a statistically significant increase in F. nucleatum expression in CRC compared to adjacent normal tissue (Figure 2; Castellarin et al., 2012). Finally, we report a meta analysis of the result, which suggests F. nucleatum expression is increased in CRC, but is confounded by the inability to detect F. nucleatum in most samples. The difference in F. nucleatum expression between CRC and adjacent normal tissues was thus smaller than the original study, and not detected in most samples. PMID- 29533183 TI - Correction: Evolutionary transitions between beneficial and phytopathogenic Rhodococcus challenge disease management. PMID- 29533184 TI - Covert shift of attention modulates the value encoding in the orbitofrontal cortex. AB - During value-based decision making, we often evaluate the value of each option sequentially by shifting our attention, even when the options are presented simultaneously. The orbitofrontal cortex (OFC) has been suggested to encode value during value-based decision making. Yet it is not known how its activity is modulated by attention shifts. We investigated this question by employing a passive viewing task that allowed us to disentangle effects of attention, value, choice and eye movement. We found that the attention modulated OFC activity through a winner-take-all mechanism. When we attracted the monkeys' attention covertly, the OFC neuronal activity reflected the reward value of the newly attended cue. The shift of attention could be explained by a normalization model. Our results strongly argue for the hypothesis that the OFC neuronal activity represents the value of the attended item. They provide important insights toward understanding the OFC's role in value-based decision making. PMID- 29533185 TI - The who, where and how of fusobacteria and colon cancer. AB - The association between the bacterium Fusobacterium nucleatum and human colon cancer is more complicated than it first appeared. PMID- 29533187 TI - A theoretical approach to multiple scattering of surface waves by shallow cavities in a half-space. AB - The current theoretical work investigates multiple scattering of surface waves from shallow cavities at the surface of an elastic half-space. The multiple scattered field is shown to be equivalent to the field generated by the application of a distribution of tractions, obtained from the incident wave, on the surfaces of the cavities. Using a self-consistent method, an analytical approach is proposed to derive an explicit set of equations which approximate the multiple scattered field. Its far-field displacement amplitude is then calculated and verified by numerical calculation obtained by the boundary element method (BEM). The analytical and BEM results are graphically presented and show excellent agreement when the depths of cavities are small compared to the wavelength. The improvement of the proposed approach relative to a first order approximation is reported and its limitations are discussed based on the results of comparison. PMID- 29533186 TI - Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury. AB - Recovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored. PMID- 29533188 TI - Illuminating the invisible. PMID- 29533189 TI - Treatment of advanced hepatocellular carcinoma: beyond sorafenib. PMID- 29533190 TI - Patient Perspectives: call for papers. PMID- 29533191 TI - Paediatric NAFLD: more than just small adults. PMID- 29533192 TI - Screening strategies to prevent mother-to-child transmission of hepatitis B in sub-Saharan Africa. PMID- 29533193 TI - Role of hepatitis C virus core antigen assay in hepatitis C care in Africa. PMID- 29533194 TI - Authors' reply. PMID- 29533195 TI - Why do we offer palliative care so late to patients with liver disease? PMID- 29533199 TI - Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus. AB - Under normal physiological conditions, eosinophils are present throughout the gastrointestinal tract distal to the squamous oesophagus. Increases in their numbers signify primary and secondary eosinophilic conditions. The rare primary eosinophilic diseases eosinophilic gastroenteritis and eosinophilic colitis affect fewer than ten in 100 000 people, and are characterised by numerous mucosal eosinophils, distributed in sheets and sometimes extending from the mucosa into the submucosa. Pathogenesis of these diseases is poorly understood, but food allergies and intestinal dysbiosis have been implicated. Presentation ranges from vague abdominal symptoms and systemic complaints to, rarely, an acute abdomen with intestinal obstruction. Diagnosis is made from mucosal biopsy samples taken at endoscopy or from surgically resected specimens that demonstrate substantially increased numbers of eosinophils. Eosinophilia secondary to other conditions, such as pathogenic infections, must be excluded. Subtle eosinophilia has also been identified in the duodenum in functional dyspepsia and in the colon in spirochaetosis. Treatment of eosinophilic gastroenteritis and eosinophilic colitis is based on evidence from case reports and small case series, and first line therapy includes empirical food-elimination diets and single courses of steroids, whereas relapsing or refractory disease might respond to steroid sparing immunosuppressive agents and biological agents. The progression of disease in eosinophilic gastroenteritis and eosinophilic colitis is variable: a considerable number of patients have just one episode without relapse, whereas others have relapsing-remitting or chronic disease. Primary and secondary eosinophilia in the gastrointestinal tract is increasingly recognised as a clinical conundrum waiting to be solved. PMID- 29533200 TI - Effects of enteral nutrition on gastrointestinal function in patients who are critically ill. AB - Nutritional management is a cornerstone of therapy for patients who are critically ill. Data show that enteral nutrition is better than parenteral nutrition with regard to the morbidity of critcally ill patients, especially for infectious complications. These findings suggest that feeding patients enterally has other beneficial effects besides delivering nutrients. In the absence of enteral nutrition, the mucosal architecture changes distinctly, leading to an impairment in function of the gastrointestinal barrier. This impairment facilitates the migration of bacteria from the intestinal lumen into the submucosal tissue and triggers epithelial inflammation. Consequently, proinflammatory and anti-inflammatory factors are imbalanced, leading to further degradation of gastrointestinal mucosal resistance. The enteral stimulus is also important to maintain physiological interaction of commensal bacteria with enteric immune cells. The absence of enteral nutrition induces deregulation of receptors that modulate the immunological response to commensal bacteria and pathogens-an important factor that initiates intestinal inflammation. Additionally, without enteral nutrients, the gastrointestinal mucosa atrophies because epithelial cells absorb nutrients directly from the gastrointestinal tract to meet their nutritional requirements. All these negative effects of absent enteral nutrition can be explained by a distinct change in cellular signalling pathways. Studies show that the physiological stimulus of enteral nutrition is crucial to maintain gastrointestinal functions such as barrier, immunological, and resorptive function. Enteral nutrients are important to maintain intact gastrointestinal motility since the nutrients stimulate the secretion of motility-regulating gastrointestinal hormones. PMID- 29533201 TI - Migrated biliary stent. PMID- 29533202 TI - Use of optical motion capture for the analysis of normative upper body kinematics during functional upper limb tasks: A systematic review. AB - Quantifying three-dimensional upper body kinematics can be a valuable method for assessing upper limb function. Considering that kinematic model characteristics, performed tasks, and reported outcomes are not consistently standardized and exhibit significant variability across studies, the purpose of this review was to evaluate the literature investigating upper body kinematics in non-disabled individuals via optical motion capture. Specific objectives were to report on the kinematic model characteristics, performed functional tasks, and kinematic outcomes, and to assess whether kinematic protocols were assessed for validity and reliability. Five databases were searched. Studies using anatomical and/or cluster marker sets, along with optical motion capture, and presenting normative data on upper body kinematics were eligible for review. Information extracted included model characteristics, performed functional tasks, kinematic outcomes, and validity or reliability testing. 804 publication records were screened and 20 reviewed based on the selection criteria. Thirteen studies described their kinematic protocols adequately for reproducibility, and 8 studies followed International Society of Biomechanics standards for quantifying upper body kinematics. Six studies assessed their protocols for validity or reliability. While a substantial number of studies have adequately reported their protocols, more systematic work is needed to evaluate the validity and reliability of existing protocols. PMID- 29533203 TI - Comparison of autopsy findings and injury severity scores in deaths due to traumatic asphyxia (perthes syndrome). AB - : Traumatic asphyxia is a rare clinical syndrome usually caused by sudden and severe thoracic and/or thoracoabdominal compression. It presents with craniofacial cyanosis, petechiae, and subconjunctival haemorrhages. The present study employed a postmortem retrospective methodology to analyse autopsy findings and accompanying injuries in cases of death due to traumatic asphyxia. Four years of case files from a morgue department at a forensic medicine institute were searched and 53 cases of lethal traumatic asphyxia were found. These cases were then classified into groups and compared using the Injury Severity Score (ISS) and New Injury Severity Score (NISS) indices to measure trauma. RESULTS: The individuals had died due to occupational (n = 28; 52.8%), farm (n = 10; 18.9%), traffic (n = 9; 17.0%) or household (n = 6; 11.3%) accidents. At the external examination, conjunctival petechiae (60.4%) and petechiae on the face/neck (52.8%); at the autopsy, subpleural petechiae (58.5%) and petrous ridge hemorrgahe (without skull base fracture) (56.6%) were the most common findings. A finding of petrous ridge hemorrgahe was very common in the cases without any accompanying injuries (Group A in which mean Injury Severity Score was 0.83 +/- 0.98). Traumatic asphyxia is usually suspected from the given circumstances before an autosopy is performed. In cases without hospitalisation, any of the following signs may lead the physician to diagnose traumatic asphyxia as the cause of death: petechiae on the upper parts of the body and conjunctiva, petechiae on serous membranes (including subpleural regions), signs of petrous ridge haemorrhage without skull base fracture. PMID- 29533204 TI - Relationship between the tensile strengths and diameters of human umbilical cords. AB - Mothers of alleged infanticides might claim that umbilical cord broke during precipitate delivery causing injuries detected on baby at autopsy. There is paucity of evidence regarding this possibility. The objective of the study was to determine relationship between tensile strength and diameter or weight per unit length of cord. Diameters and weights per unit length of fresh umbilical cords were determined. Tensile strengths were measured by Hounsfield Testing Machine. Relationship between tensile strength versus cord diameter and weight per unit length were analyzed. Of 122 cords, average tensile strength, diameter and weight per centimeter were 50.4 N, 7.73 mm and 6.87 g respectively. The tensile strengths were directly proportional to diameter. There was no association between tensile strength and weight per centimeter. Measurement of the diameter of cord is important during autopsy to predict tensile strength and thereby to presume whether cord could have broken by the weight of the baby. PMID- 29533205 TI - Usefulness of liver function tests in postmortem samples. AB - Liver function tests have been investigated in the forensic setting in several biological fluids collected at autopsy. Nevertheless, the results of these investigations have provided diverging information on postmortem stability of liver function markers and postmortem reliability of liver function assessment. The first aim of this study was to determine gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, total proteins, and albumin in antemortem and postmortem serum samples in a series of cases that underwent forensic investigations and had both samples available. The second aim was to measure total bilirubin and gamma glutamyltransferase in cerebrospinal fluid. Preliminary results indicated that femoral (and cardiac) blood postmortem serum concentrations of bilirubin, total proteins, and albumin, as well as femoral blood postmortem serum concentrations of gamma-glutamyltransferase, can be considered to reliably reflect antemortem serum concentrations, thus suggesting that postmortem values could be used as surrogates for antemortem levels. Measurable bilirubin levels were demonstrable in cerebrospinal fluid samples in both preservative-free and sodium fluoride tubes, though with levels varying widely and unpredictably, irrespective of liver disease severity. PMID- 29533206 TI - Pre-offense alcohol intake in homicide offenders and victims: A forensic toxicological case-control study. AB - BACKGROUND AND AIM: Alcohol is associated with violent behavior, although little is known regarding to what extent alcohol increases homicide risk. We aimed to estimate risks of homicide offending and victimization conferred by the presence of ethanol in blood by using toxicological data from homicide victims and offenders and from controls who had died in vehicle-related accidents. METHODS: From nationwide governmental registries and databases, forensic-toxicological results were retrieved for victims (n = 200) and offenders (n = 105) of homicides committed during the years 2007-2009 and individuals killed in vehicle-related accidents (n = 1629) during the years 2006-2014. Ethanol levels in blood exceeding 0.01 g/100 ml were considered positive. RESULTS: Using logistic regression, we found that the presence of ethanol in blood conferred a significantly increased risk of homicide offending (age-adjusted odds ratio [aOR] = 3.6, 95% confidence interval [95% CI] = 2.3-5.6) and homicide victimization (aOR = 2.1, 95% CI = 1.4-3.0). After stratification by sex, risk estimates in females were about 3-fold greater than in males for both homicide offending ([aOR = 11.0, 95% CI = 2.4-49.8] versus [aOR = 3.1, 95% CI = 1.9-4.9]) and victimization ([aOR = 5.4, 95% CI = 2.4-12.2] versus [aOR = 1.7, 95% CI = 1.1 2.8]). Sensitivity analyses yielded similar estimates. CONCLUSIONS: The results of the present study are consistent with prior findings suggesting alcohol to be an important risk factor for homicide offending and victimization. Surprisingly, however, associations were more pronounced in females, although additional studies that control for potential confounders are warranted to facilitate speculations about causality. PMID- 29533207 TI - Lethal asphyxiation due to sadomasochistic sex training - How some sex partners avoid criminal responsibility even though their actions lead to someone's death. AB - INTRODUCTION: Erotic asphyxiation is a sexual phenomenon in which one partner reduces the other person's brain oxygen level through strangulation. This study analyzes deaths caused by sexually-motivated strangulation to cases of homicidal choking - summarizing criminal penalties for defendants, depending on the presence of drugs, or alcohol intoxication. METHODS: The mode of analysis involves three sources of data. First, a retrospective chart review of our clinics' two recent cases. Second, a meta-analysis of these materials in relationship to forensic reports obtained from prosecutor's office. Third, we examine the prevalence of death due to strangulation in erotic and non-erotic cases using central court database. Lastly, we provide the summary of interviews involving the country's only forensic unit, which investigates criminal cases involving voluntary and involuntary strangulation. RESULTS: In total, we analyzed 15 cases of sexual asphyxiation - 2 of our own; 5 reported in prosecutor's archives; 8 control cases ruled as a non-sexual homicide. The two of our clinical cases describe two victims of voluntary erotic asphyxiation, involving complex sexual environment in which a sexual partner accidentally strangulated the other one during sex. The first case describes a 30 years-old female, who required all of her past sexual partners to choke her with hands in order to reach orgasm. The second case is that of a 41 years-old homosexual male, who was still a novice to kinky play and succumbed to death as a result of being tied with a set of ropes around his neck and body. By combining findings from the analysis of our clinic's cases with 5 files obtained from prosecutor's office - we are able to compare results of these cases to controls (involving homicidal suffocation using the plastic bag). In our cases, the defendants who avoid serving prison time for strangulating in course of erotic play typically exhibit these characteristics - at the time of the killing, they were not under influence of drugs; the deceased had documented (based on witness interview, review of personal items, or medical documentation) long-standing paraphilic disorder. In controls, the likelihood of being convicted of voluntary manslaughter was lower for people who acted under the influence of drugs but higher for those under the influence of alcohol. CONCLUSIONS: These findings show that documented presence of paraphilic tendencies in the deceased might serve as grounds for not sentencing their sex partners for prison time if they acted to satisfy someone else's kinky needs. PMID- 29533208 TI - Rapid molecular identification of necrophagous diptera by means of variable length intron sequences in the wingless gene. AB - The arrival of arthropods at a corpse exhibits specific temporal patterns, and Diptera play a key role in the initial stages of the decomposition process. Thus, the correct species assignment of the insect larvae found on a decomposing body is an important step in forensic investigations. Here, we describe a molecular procedure to define the species at larval age found on a corpse more quickly and easily than current systems. Our method involves a unique PCR amplification of a DNA segment within the evolutionarily conserved wingless gene, involved in embryo development. The amplified DNA segment contains the fourth intron of wingless, which we found to be variable in length, from about 800 to 3000 bp, among species of necrophagous Diptera. The identification of the amplified segment size in species from Lucilia, Calliphora and Sarcophaga genera, allowed us to determine the species at larval age collected in the early stages of a decomposing body, with a simple PCR amplification and subsequent electrophoresis. This procedure may help in forensic investigations to estimate the minimum Post Mortem Interval (PMI-min) of a body colonized by these larvae, avoiding the use of time-consuming and/or more expensive procedures. PMID- 29533209 TI - GHB side effects: The need to clearly document drug dose and administration history. PMID- 29533211 TI - Degradation of bisphenol A and acute toxicity reduction by different thermo tolerant ascomycete strains isolated from arid soils. AB - Four different laccase-producing strains were isolated from arid soils and used for bisphenol A (BPA) degradation. These strains were identified as Chaetomium strumarium G5I, Thielavia arenaria CH9, Thielavia arenaria HJ22 and Thielavia arenaria SM1(III) by internal transcribed spacer 5.8 S rDNA analysis. Residual BPA was evaluated by HPLC analysis during 48 h of incubation. A complete removal of BPA was observed by the whole cell fungal cultures within different times, depending on each strain. C. strumarium G5I was the most efficient degrader, showing 100% of removal within 8 h of incubation. The degradation of BPA was accompanied by the production of laccase and dye decolorizing peroxidase (DyP) under degradation conditions. The presence of aminobenzotriazole (ABT) as an inhibitor of cytochrome P450s monooxygenases (CYP) demonstrated a slight decrease in BPA removal rate, suggesting the effective contribution of CYP in the conversion. The great involvement of laccase in BPA transformation together with cell-associated enzymes, such as CYP, was supported by the identification of hydroxylated metabolites by ultra-high performance liquid chromatography-mass spectroscopy (UHPLC-MS). The metabolic pathway of BPA transformation was proposed based on the detected metabolites. The acute toxicity of BPA and its products was investigated and showed a significant reduction, except for T. arenaria SM1(III) that did not caused reduction of toxicity (IC50 < 8%), possibly due to the presence of toxic metabolites. The results of the present study point out the potential application of the isolated ascomycetes in pollutant removal processes, especially C. strumarium G5I as an efficient degrader of BPA. PMID- 29533210 TI - Effects of TiO2, SiO2, Ag and CdTe/CdS quantum dots nanoparticles on toxicity of cadmium towards Chlamydomonas reinhardtii. AB - Nanoparticles (NPs) are inevitably released into the aquatic environment for being widely used and may affect the toxicity of other contaminants already present in the environment, such as trace metals. However, the effects of NPs on the ecotoxicity of cadmium (Cd), a common environmental trace metal pollutant, are not well explored. In this study, effects of four widely used NPs TiO2 (n TiO2), SiO2 (n-SiO2), Ag (n-Ag) and CdTe/CdS core/shell quantum dots (QD) on the toxicity of Cd to the freshwater algae Chlamydomonas reinhardtii were assessed respectively. Cd reduced the algae biomass, impaired the photosynthetic activities, and led to intracellular oxidative stress of algae. At non-toxic concentrations, both n-TiO2 (100 mg L-1) and n-SiO2 (400 mg L-1) attenuated the toxicity of Cd towards the algae for reducing the intracellular Cd contents, and the former was more pronounced. QD (0.5 mg L-1) increased the toxicity of Cd to algae, but n-Ag (0.2 mg L-1) had no significant influence on the Cd toxicity to algae. The microscopic observations on the ultrastructure of algae cells presented the same phenomena and n-TiO2, n-SiO2 aggregations were clearly observed outside the cell wall. Furthermore, the regulation of NPs to the Cd toxicity towards algae was related to the intracellular nitric oxide (NO), an important signaling molecule, rather than the phototaxis of algae. Above all, this study provided a basic understanding about the difference in joint toxicity of different kinds of NPs and Cd to aquatic organisms. PMID- 29533212 TI - Lindane dissipation in a biomixture: Effect of soil properties and bioaugmentation. AB - The biomixture is the major constituent of a biopurification system and one of the most important factors in its efficiency; hence the selection of the components is crucial to ensure the efficient pesticides removal. Besides, bioaugmentation is an interesting approach for the optimization of these systems. A mixed culture of the fungus Trametes versicolor SGNG1 and the actinobacteria Streptomyces sp. A2, A5, A11, and M7, was designed to inoculate the biomixtures, based on previously demonstrated ligninolytic and pesticide-degrading activities and the absence of antagonism among the strains. The presence of lindane and/or the inoculum in the biomixtures had no significant effect on the development of culturable microorganisms regardless the soil type. The consortium improved lindane dissipation achieving 81-87% of removal at 66 d of incubation in the different biomixtures, decreasing lindane half-life to an average of 24 d, i.e. 6 fold less than t1/2 of lindane in soils. However, after recontamination, only the bioaugmented biomixture of silty loam soil enhanced lindane dissipation and decreased the t1/2 compared to non-bioaugmented. The biomixture formulated with silty loam soil, sugarcane bagasse, and peat, inoculated with a fungal actinobacterial consortium, could be appropriate for the treatment of agroindustrial effluents contaminated with organochlorine pesticides in biopurification systems. PMID- 29533213 TI - Caged xanthones displaying protein tyrosine phosphatase 1B (PTP1B) inhibition from Cratoxylum cochinchinense. AB - Four new caged xanthones (1-4) and two known compounds (5, 6) were isolated from the roots of Cratoxylum cochinchinense, a polyphenol rich plant, collected in China. The structures of the isolated compounds (1-6) were characterized by obtaining their detailed spectroscopic data. In particular, compounds 1 and 6 were fully identified by X-ray crystallographic data. The isolated compounds (1 6) were evaluated against protein tyrosine phosphatase 1B (PTP1B), which plays an important role in diabetes, obesity, and cancer. Among these compounds, 3, 4, and 6 displayed significant inhibition with IC50 values of 76.3, 43.2, and 6.6 uM, respectively. A detailed kinetic study was conducted by determining Km, Vmax, and the ratio of Kik and Kiv, which revealed that all the compounds behaved as competitive inhibitors. PMID- 29533214 TI - Curcumin analogue 1,5-bis(4-hydroxy-3-((4-methylpiperazin-1 yl)methyl)phenyl)penta-1,4-dien-3-one mediates growth arrest and apoptosis by targeting the PI3K/AKT/mTOR and PKC-theta signaling pathways in human breast carcinoma cells. AB - Recent developments in the literature have demonstrated that curcumin exhibit antioxidant properties supporting its anti-inflammatory, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Despite the valuable findings of curcumin against different cancer cells, the clinical use of curcumin in cancer treatment is limited due to its extremely low aqueous solubility and instability, which lead to poor in vivo bioavailability and limited therapeutic effects. We therefore focused in the present study to evaluate the anti-tumor potential of curcumin analogues on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as their effects on non tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of curcumin analogue J1 in these cancer cell lines were determined to be 5 ng/ml and 10 ng/ml, in MDA-MB-231 and MCF-7 cells respectively. Interestingly, at these concentrations, the J1 did not affect the viability of non-tumorigenic normal breast epithelial cells MCF-10. Furthermore, we found that J1 strongly induced growth arrest of these cancer cells by modulating the mitochondrial membrane potentials without significant effect on normal MCF-10 cells using JC-1 staining and flow cytometry analysis. Using annexin-V/PI double staining assay followed by flow cytometry analysis, we found that J1 robustly enhanced the induction of apoptosis by increasing the activity of caspases in MDA-MB-231 and MCF-7 cancer cells. In addition, treatment of breast cancer cells with J1 revealed that, in contrast to the expression of cyclin B1, this curcumin analogue vigorously decreased the expression of cyclin A, CDK2 and cyclin E and subsequently sensitized tumor cells to cell cycle arrest. Most importantly, the phosphorylation of AKT, mTOR and PKC-theta in J1-treated cancer cells was markedly decreased and hence affecting the survival of these cancer cells. Most interestingly, J1-treated cancer cells exhibited a significant inhibition in the activation of RhoA followed by reduction in actin polymerization and cytoskeletal rearrangement in response to CXCL12. Our data reveal the therapeutic potential of the curcumin analogue J1 and the underlying mechanisms to fight breast cancer cells. PMID- 29533215 TI - Synthesis, molecular docking study and in vitro thymidine phosphorylase inhibitory potential of oxadiazole derivatives. AB - We have synthesized oxadiazole derivatives (1-16), characterized by 1H NMR, 13C NMR and HREI-MS and screened for thymidine phosphorylase inhibitory potential. All derivatives display varied degree of thymidine phosphorylase inhibition in the range of 1.10 +/- 0.05 to 49.60 +/- 1.30 MUM when compared with the standard inhibitor 7-Deazaxanthine having an IC50 value 38.68 +/- 1.12 MUM. Structure activity relationships (SAR) has been established for all compounds to explore the role of substitution and nature of functional group attached to the phenyl ring which applies imperious effect on thymidine phosphorylase activity. Molecular docking study was performed to understand the binding interaction of the most active derivatives with enzyme active site. PMID- 29533216 TI - Experimental and computational modeling of interaction of kolaviron-kolaflavanone with aldehyde dehydrogenase. AB - Aldehyde dehydrogenases (ALDHs) are a diverse family of enzymes that catalyze the NAD(P)+-dependent detoxification of toxic aldehyde compounds. ALDHs are also involved in non-enzymatic ligand binding to endobiotics and xenobiotics. Here, the enzyme crucial non-canonical and non-catalytic interaction with kolaflavanone, a component of kolaviron, and a major bioflavonoid isolated from Garcinia kola (Bitter kola) was characterized by various spectroscopic and in silico approaches under simulated physiological condition. Kolaflavanone quenched the intrinsic fluorescence of ALDH in a concentration dependent manner with an effective quenching constant (Ksv) of 1.14 * 103 L.mol-1 at 25 degrees C. The enzyme has one binding site for kolaflavanone with a binding constant (Ka) of 2.57 * 104 L.mol-1 and effective Forster resonance energy transfer (FRET) of 4.87 nm. The bonding process was enthalpically driven. The reaction was not spontaneous and was predominantly characterized by Van der Waals forces and hydrogen bond. The flavonoid bonding slightly perturbed the secondary and tertiary structures of ALDH that was 'tryptophan-gated'. The interaction was regulated by both diffusion and ionic strength. Molecular docking showed the binding of kolaflavanone was at the active site of ALDH and the participation of some amino acid residues in the complex formation with -9.6 kcal mol-1 binding energy. The profiles of atomic fluctuations indicated the rigidity of the ligand binding site during the simulation. With these, ALDH as a subtle nano-particle determinant of kolaviron bioavailability and efficacy is hereby proposed. PMID- 29533217 TI - Overlapping functional modules detection in PPI network with pair-wise constrained non-negative matrix tri-factorisation. AB - A large amount of available protein-protein interaction (PPI) data has been generated by high-throughput experimental techniques. Uncovering functional modules from PPI networks will help us better understand the underlying mechanisms of cellular functions. Numerous computational algorithms have been designed to identify functional modules automatically in the past decades. However, most community detection methods (non-overlapping or overlapping types) are unsupervised models, which cannot incorporate the well-known protein complexes as a priori. The authors propose a novel semi-supervised model named pairwise constrains nonnegative matrix tri-factorisation (PCNMTF), which takes full advantage of the well-known protein complexes to find overlapping functional modules based on protein module indicator matrix and module correlation matrix simultaneously from PPI networks. PCNMTF determinately models and learns the mixed module memberships of each protein by considering the correlation among modules simultaneously based on the non-negative matrix tri-factorisation. The experiment results on both synthetic and real-world biological networks demonstrate that PCNMTF gains more precise functional modules than that of state of-the-art methods. PMID- 29533218 TI - SMILE: a novel procedure for subcellular module identification with localisation expansion. AB - Computational clustering methods help identify functional modules in protein protein interaction (PPI) network, in which proteins participate in the same biological pathways or specific functions. Subcellular localisation is crucial for proteins to implement biological functions and each compartment accommodates specific portions of the protein interaction structure. However, the importance of protein subcellular localisation is often neglected in the studies of module identification. In this study, the authors propose a novel procedure, subcellular module identification with localisation expansion (SMILE), to identify super modules that consist of several subcellular modules performing specific biological functions among cell compartments. These super modules identified by SMILE are more functionally diverse and have been verified to be more associated with known protein complexes and biological pathways compared with the modules identified from the global PPI networks in both the compartmentalised PPI and InWeb_InBioMap datasets. The authors' results reveal that subcellular localisation is a principal feature of functional modules and offers important guidance in detecting biologically meaningful results. PMID- 29533219 TI - Robust adaptive Lyapunov-based control of hepatitis B infection. AB - A new robust adaptive controller is developed for the control of the hepatitis B virus (HBV) infection inside the body. The non-linear HBV model has three state variables: uninfected cells, infected cells and free viruses. A control law is designed for the antiviral therapy such that the volume of infected cells and the volume of free viruses are decreased to their desired values which are zero. One control input represents the efficiency of drug therapy in inhibiting viral production and the other control input represents the efficiency of drug therapy in blocking new infection. The proposed controller ensures the stability and robust performance in the presence of parametric and non-parametric uncertainties (and/or bounded disturbances). The global stability and tracking convergence of the process are investigated by employing the Lyapunov theorem. The performance of the proposed controller is evaluated using simulations by considering different levels of uncertainties. Based on the obtained results, the proposed strategy can achieve its desired objectives with different cases of uncertainties. PMID- 29533220 TI - Evaluation of an advanced model reference sliding mode control method for cardiac assist device using a numerical model. AB - In this study, the physiological control algorithm using sliding mode control method is implemented to track the reference input signal. The controller is developed using feed-forward part, reference model, and steady-state flow estimator. The proposed control method is evaluated using a dynamic heart-pump interaction model incorporating descriptions of the cardiovascular system - rotary blood pump. The immediate response of the controller to preload as well as afterload was studied. Stability and feasibility of the control system were demonstrated through the tests. The results showed that the present controller, which allows the left ventricular to automatically adjust to the right ventricular output, reduces the risk of suction. PMID- 29533221 TI - Adaptive non-linear control for cancer therapy through a Fokker-Planck observer. AB - In recent years, many efforts have been made to present optimal strategies for cancer therapy through the mathematical modelling of tumour-cell population dynamics and optimal control theory. In many cases, therapy effect is included in the drift term of the stochastic Gompertz model. By fitting the model with empirical data, the parameters of therapy function are estimated. The reported research works have not presented any algorithm to determine the optimal parameters of therapy function. In this study, a logarithmic therapy function is entered in the drift term of the Gompertz model. Using the proposed control algorithm, the therapy function parameters are predicted and adaptively adjusted. To control the growth of tumour-cell population, its moments must be manipulated. This study employs the probability density function (PDF) control approach because of its ability to control all the process moments. A Fokker-Planck-based non-linear stochastic observer will be used to determine the PDF of the process. A cost function based on the difference between a predefined desired PDF and PDF of tumour-cell population is defined. Using the proposed algorithm, the therapy function parameters are adjusted in such a manner that the cost function is minimised. The existence of an optimal therapy function is also proved. The numerical results are finally given to demonstrate the effectiveness of the proposed method. PMID- 29533222 TI - Tail-like regime and BCS-BEC crossover due to hybridization in a two-band superconductor. AB - Superconductivity in strongly correlated systems is a remarkable phenomenon that attracts huge interest. The study of this problem is relevant for materials such as the high T c oxides, pnictides and heavy fermions. These systems also have in common the existence of electrons of several orbitals that coexist at a common Fermi surface. In this paper we study the effect of pressure, chemical or applied on multi-band superconductivity. Pressure varies the atomic distances and consequently the overlap of the wave-functions in the crystal. This rearranges the electronic structure that we model including a pressure dependent hybridization between the bands. We consider the case of two-dimensional systems in a square lattice with inverted bands. We study the conditions for obtaining a pressure induced superconductor quantum critical point and show that hybridization, i.e. pressure can induce a Bardeen-Cooper-Schrieffer-Bose-Einstein condensation crossover in multi-band systems even for moderate interactions. We found a tail-like superconductor regime and briefly discuss the influence of the symmetry of the order parameter in the results. PMID- 29533223 TI - The piezoelectric gating effect in a thin bent membrane with a two-dimensional electron gas. AB - Thin suspended nanostructures with a two-dimensional electron gas can be used as nanoelectromechanical systems in which electron transport is piezoelectrically coupled to mechanical motion and vibrations. Apart from practical applications, these systems are interesting for studying electron transport under unusual conditions, namely, in the presence of additional mechanical degrees of freedom. In the present paper, we analyze the influence of the bending on the density of a gated two-dimensional electron gas contained in a suspended membrane using the Thomas-Fermi approach and the model of pure electrostatic screening. We show that a small bending is analogous to a small change in gate voltages. Our calculations demonstrate that the density change is most prominent near the edges of the conductive channel created by negatively biased gates. When moving away from these edges, the bending-induced density change rapidly decays. We propose several methods to increase the magnitude of the effect, with the largest benefit obtained from coverage of the conductive channel with an additional grounded gate. It is shown that, for a conductive channel under a bare surface, the largest effect can be achieved if the two-dimensional electron gas is placed near the middle of the membrane thickness, despite the bending-induced strain is zero there. PMID- 29533224 TI - Twisted bilayer graphene photoluminescence emission peaks at van Hove singularities. AB - We report on photoluminescence emission imaging by femtosecond laser excitation on twisted bilayer graphene samples. The emission images are obtained by tuning the excitation laser energies in the near infrared region. We demonstrate an increase of the photoluminescence emission at excitation energies that depends on the bilayer twist angle. The results show a peak for the light emission when the excitation is in resonance with transitions at the van Hove singularities in the electronic density of states. We measured the photoluminescence excitation peak position and width for samples with various twist angles showing resonances in the energy range of 1.2 to 1.7 eV. PMID- 29533225 TI - Recent developments in MrBUMP: better search-model preparation, graphical interaction with search models, and solution improvement and assessment. AB - Increasing sophistication in molecular-replacement (MR) software and the rapid expansion of the PDB in recent years have allowed the technique to become the dominant method for determining the phases of a target structure in macromolecular X-ray crystallography. In addition, improvements in bioinformatic techniques for finding suitable homologous structures for use as MR search models, combined with developments in refinement and model-building techniques, have pushed the applicability of MR to lower sequence identities and made weak MR solutions more amenable to refinement and improvement. MrBUMP is a CCP4 pipeline which automates all stages of the MR procedure. Its scope covers everything from the sourcing and preparation of suitable search models right through to rebuilding of the positioned search model. Recent improvements to the pipeline include the adoption of more sensitive bioinformatic tools for sourcing search models, enhanced model-preparation techniques including better ensembling of homologues, and the use of phase improvement and model building on the resulting solution. The pipeline has also been deployed as an online service through CCP4 online, which allows its users to exploit large bioinformatic databases and coarse-grained parallelism to speed up the determination of a possible solution. Finally, the molecular-graphics application CCP4mg has been combined with MrBUMP to provide an interactive visual aid to the user during the process of selecting and manipulating search models for use in MR. Here, these developments in MrBUMP are described with a case study to explore how some of the enhancements to the pipeline and to CCP4mg can help to solve a difficult case. PMID- 29533226 TI - Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE. AB - Molecular replacement (MR) is the predominant route to solution of the phase problem in macromolecular crystallography. Although routine in many cases, it becomes more effortful and often impossible when the available experimental structures typically used as search models are only distantly homologous to the target. Nevertheless, with current powerful MR software, relatively small core structures shared between the target and known structure, of 20-40% of the overall structure for example, can succeed as search models where they can be isolated. Manual sculpting of such small structural cores is rarely attempted and is dependent on the crystallographer's expertise and understanding of the protein family in question. Automated search-model editing has previously been performed on the basis of sequence alignment, in order to eliminate, for example, side chains or loops that are not present in the target, or on the basis of structural features (e.g. solvent accessibility) or crystallographic parameters (e.g. B factors). Here, based on recent work demonstrating a correlation between evolutionary conservation and protein rigidity/packing, novel automated ways to derive edited search models from a given distant homologue over a range of sizes are presented. A variety of structure-based metrics, many readily obtained from online webservers, can be fed to the MR pipeline AMPLE to produce search models that succeed with a set of test cases where expertly manually edited comparators, further processed in diverse ways with MrBUMP, fail. Further significant performance gains result when the structure-based distance geometry method CONCOORD is used to generate ensembles from the distant homologue. To our knowledge, this is the first such approach whereby a single structure is meaningfully transformed into an ensemble for the purposes of MR. Additional cases further demonstrate the advantages of the approach. CONCOORD is freely available and computationally inexpensive, so these novel methods offer readily available new routes to solve difficult MR cases. PMID- 29533227 TI - ARCIMBOLDO on coiled coils. AB - ARCIMBOLDO solves the phase problem by combining the location of small model fragments using Phaser with density modification and autotracing using SHELXE. Mainly helical structures constitute favourable cases, which can be solved using polyalanine helical fragments as search models. Nevertheless, the solution of coiled-coil structures is often complicated by their anisotropic diffraction and apparent translational noncrystallographic symmetry. Long, straight helices have internal translational symmetry and their alignment in preferential directions gives rise to systematic overlap of Patterson vectors. This situation has to be differentiated from the translational symmetry relating different monomers. ARCIMBOLDO_LITE has been run on single workstations on a test pool of 150 coiled coil structures with 15-635 amino acids per asymmetric unit and with diffraction data resolutions of between 0.9 and 3.0 A. The results have been used to identify and address specific issues when solving this class of structures using ARCIMBOLDO. Features from Phaser v.2.7 onwards are essential to correct anisotropy and produce translation solutions that will pass the packing filters. As the resolution becomes worse than 2.3 A, the helix direction may be reversed in the placed fragments. Differentiation between true solutions and pseudo solutions, in which helix fragments were correctly positioned but in a reverse orientation, was found to be problematic at resolutions worse than 2.3 A. Therefore, after every new fragment-placement round, complete or sparse combinations of helices in alternative directions are generated and evaluated. The final solution is once again probed by helix reversal, refinement and extension. To conclude, density modification and SHELXE autotracing incorporating helical constraints is also exploited to extend the resolution limit in the case of coiled coils and to enhance the identification of correct solutions. This study resulted in a specialized mode within ARCIMBOLDO for the solution of coiled coil structures, which overrides the resolution limit and can be invoked from the command line (keyword coiled_coil) or ARCIMBOLDO_LITE task interface in CCP4i. PMID- 29533228 TI - Fragon: rapid high-resolution structure determination from ideal protein fragments. AB - Correctly positioning ideal protein fragments by molecular replacement presents an attractive method for obtaining preliminary phases when no template structure for molecular replacement is available. This has been exploited in several existing pipelines. This paper presents a new pipeline, named Fragon, in which fragments (ideal alpha-helices or beta-strands) are placed using Phaser and the phases calculated from these coordinates are then improved by the density modification methods provided by ACORN. The reliable scoring algorithm provided by ACORN identifies success. In these cases, the resulting phases are usually of sufficient quality to enable automated model building of the entire structure. Fragon was evaluated against two test sets comprising mixed alpha/beta folds and all-beta folds at resolutions between 1.0 and 1.7 A. Success rates of 61% for the mixed alpha/beta test set and 30% for the all-beta test set were achieved. In almost 70% of successful runs, fragment placement and density modification took less than 30 min on relatively modest four-core desktop computers. In all successful runs the best set of phases enabled automated model building with ARP/wARP to complete the structure. PMID- 29533229 TI - Overview of refinement procedures within REFMAC5: utilizing data from different sources. AB - Refinement is a process that involves bringing into agreement the structural model, available prior knowledge and experimental data. To achieve this, the refinement procedure optimizes a posterior conditional probability distribution of model parameters, including atomic coordinates, atomic displacement parameters (B factors), scale factors, parameters of the solvent model and twin fractions in the case of twinned crystals, given observed data such as observed amplitudes or intensities of structure factors. A library of chemical restraints is typically used to ensure consistency between the model and the prior knowledge of stereochemistry. If the observation-to-parameter ratio is small, for example when diffraction data only extend to low resolution, the Bayesian framework implemented in REFMAC5 uses external restraints to inject additional information extracted from structures of homologous proteins, prior knowledge about secondary structure formation and even data obtained using different experimental methods, for example NMR. The refinement procedure also generates the 'best' weighted electron-density maps, which are useful for further model (re)building. Here, the refinement of macromolecular structures using REFMAC5 and related tools distributed as part of the CCP4 suite is discussed. PMID- 29533230 TI - Validation of ligands in macromolecular structures determined by X-ray crystallography. AB - Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) play a crucial role in structure-guided drug discovery and design, and also provide atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. The quality with which small-molecule ligands have been modelled in Protein Data Bank (PDB) entries has been, and continues to be, a matter of concern for many investigators. Correctly interpreting whether electron density found in a binding site is compatible with the soaked or co-crystallized ligand or represents water or buffer molecules is often far from trivial. The Worldwide PDB validation report (VR) provides a mechanism to highlight any major issues concerning the quality of the data and the model at the time of deposition and annotation, so the depositors can fix issues, resulting in improved data quality. The ligand-validation methods used in the generation of the current VRs are described in detail, including an examination of the metrics to assess both geometry and electron-density fit. It is found that the LLDF score currently used to identify ligand electron-density fit outliers can give misleading results and that better ligand-validation metrics are required. PMID- 29533231 TI - Worldwide Protein Data Bank validation information: usage and trends. AB - Realising the importance of assessing the quality of the biomolecular structures deposited in the Protein Data Bank (PDB), the Worldwide Protein Data Bank (wwPDB) partners established Validation Task Forces to obtain advice on the methods and standards to be used to validate structures determined by X-ray crystallography, nuclear magnetic resonance spectroscopy and three-dimensional electron cryo microscopy. The resulting wwPDB validation pipeline is an integral part of the wwPDB OneDep deposition, biocuration and validation system. The wwPDB Validation Service webserver (https://validate.wwpdb.org) can be used to perform checks prior to deposition. Here, it is shown how validation metrics can be combined to produce an overall score that allows the ranking of macromolecular structures and domains in search results. The ValTrendsDB database provides users with a convenient way to access and analyse validation information and other properties of X-ray crystal structures in the PDB, including investigating trends in and correlations between different structure properties and validation metrics. PMID- 29533232 TI - From crystal to structure with CCP4. PMID- 29533233 TI - CCP4i2: the new graphical user interface to the CCP4 program suite. AB - The CCP4 (Collaborative Computational Project, Number 4) software suite for macromolecular structure determination by X-ray crystallography groups brings together many programs and libraries that, by means of well established conventions, interoperate effectively without adhering to strict design guidelines. Because of this inherent flexibility, users are often presented with diverse, even divergent, choices for solving every type of problem. Recently, CCP4 introduced CCP4i2, a modern graphical interface designed to help structural biologists to navigate the process of structure determination, with an emphasis on pipelining and the streamlined presentation of results. In addition, CCP4i2 provides a framework for writing structure-solution scripts that can be built up incrementally to create increasingly automatic procedures. PMID- 29533234 TI - DIALS: implementation and evaluation of a new integration package. AB - The DIALS project is a collaboration between Diamond Light Source, Lawrence Berkeley National Laboratory and CCP4 to develop a new software suite for the analysis of crystallographic X-ray diffraction data, initially encompassing spot finding, indexing, refinement and integration. The design, core algorithms and structure of the software are introduced, alongside results from the analysis of data from biological and chemical crystallography experiments. PMID- 29533235 TI - Maximum-likelihood determination of anomalous substructures. AB - A fast Fourier transform (FFT) method is described for determining the substructure of anomalously scattering atoms in macromolecular crystals that allows successful structure determination by X-ray single-wavelength anomalous diffraction (SAD). This method is based on the maximum-likelihood SAD phasing function, which accounts for measurement errors and for correlations between the observed and calculated Bijvoet mates. Proof of principle is shown that this method can improve determination of the anomalously scattering substructure in challenging cases where the anomalous scattering from the substructure is weak but the substructure also constitutes a significant fraction of the real scattering. The method is deterministic and can be fast compared with existing multi-trial dual-space methods for SAD substructure determination. PMID- 29533236 TI - An introduction to experimental phasing of macromolecules illustrated by SHELX; new autotracing features. AB - For the purpose of this article, experimental phasing is understood to mean the determination of macromolecular structures by exploiting small intensity differences of Friedel opposites and possibly of reflections measured at different wavelengths or for heavy-atom derivatives, without the use of specific structural models. The SHELX programs provide a robust and efficient route for routine structure solution by the SAD, MAD and related methods, but involve a number of simplifying assumptions that may limit their applicability in borderline cases. The substructure atoms (i.e. those with significant anomalous scattering) are first located by direct methods, and the experimental data are then used to estimate phase shifts that are added to the substructure phases to obtain starting phases for the native reflections. These are then improved by density modification and, if the resolution of the data and the type of structure permit, polyalanine tracing. A number of extensions to the tracing algorithm are discussed; these are designed to improve its performance at low resolution. Given native data to 2.5 A resolution or better, a correlation coefficient greater than 25% between the structure factors calculated from such a trace and the native data is usually a good indication that the structure has been solved. PMID- 29533237 TI - Substructure determination using phase-retrieval techniques. AB - Thus far, the application of phase-retrieval methods in crystallography has mainly been aimed at variants of charge flipping or structure-factor flipping. In this work, the relaxed averaged alternating reflections (RAAR) algorithm is applied to determine anomalously scattering substructures from single-wavelength anomalous diffraction (SAD) data of macromolecules. The algorithm has been implemented in a new program, PRASA, and has been shown to significantly outperform charge flipping in determining anomalously scattering substructures on a test sample of 169 SAD data sets with resolutions up to 3.88 A. PMID- 29533238 TI - Macromolecular refinement by model morphing using non-atomic parameterizations. AB - Refinement is a critical step in the determination of a model which explains the crystallographic observations and thus best accounts for the missing phase components. The scattering density is usually described in terms of atomic parameters; however, in macromolecular crystallography the resolution of the data is generally insufficient to determine the values of these parameters for individual atoms. Stereochemical and geometric restraints are used to provide additional information, but produce interrelationships between parameters which slow convergence, resulting in longer refinement times. An alternative approach is proposed in which parameters are not attached to atoms, but to regions of the electron-density map. These parameters can move the density or change the local temperature factor to better explain the structure factors. Varying the size of the region which determines the parameters at a particular position in the map allows the method to be applied at different resolutions without the use of restraints. Potential applications include initial refinement of molecular replacement models with domain motions, and potentially the use of electron density from other sources such as electron cryo-microscopy (cryo-EM) as the refinement model. PMID- 29533239 TI - Model validation: local diagnosis, correction and when to quit. AB - Traditionally, validation was considered to be a final gatekeeping function, but refinement is smoother and results are better if model validation actively guides corrections throughout structure solution. This shifts emphasis from global to local measures: primarily geometry, conformations and sterics. A fit into the wrong local minimum conformation usually produces outliers in multiple measures. Moving to the right local minimum should be prioritized, rather than small shifts across arbitrary borderlines. Steric criteria work best with all explicit H atoms. 'Backrub' motions should be used for side chains and 'P-perp' diagnostics to correct ribose puckers. A 'water' may actually be an ion, a relic of misfitting or an unmodeled alternate. Beware of wishful thinking in modeling ligands. At high resolution, internally consistent alternate conformations should be modeled and geometry in poor density should not be downweighted. At low resolution, CaBLAM should be used to diagnose protein secondary structure and ERRASER to correct RNA backbone. All atoms should not be forced inside density, beware of sequence misalignment, and very rare conformations such as cis-non-Pro peptides should be avoided. Automation continues to improve, but the crystallographer still must look at each outlier, in the context of density, and correct most of them. For the valid few with unambiguous density and something that is holding them in place, a functional reason should be sought. The expectation is a few outliers, not zero. PMID- 29533240 TI - Distributed computing for macromolecular crystallography. AB - Modern crystallographic computing is characterized by the growing role of automated structure-solution pipelines, which represent complex expert systems utilizing a number of program components, decision makers and databases. They also require considerable computational resources and regular database maintenance, which is increasingly more difficult to provide at the level of individual desktop-based CCP4 setups. On the other hand, there is a significant growth in data processed in the field, which brings up the issue of centralized facilities for keeping both the data collected and structure-solution projects. The paradigm of distributed computing and data management offers a convenient approach to tackling these problems, which has become more attractive in recent years owing to the popularity of mobile devices such as tablets and ultra portable laptops. In this article, an overview is given of developments by CCP4 aimed at bringing distributed crystallographic computations to a wide crystallographic community. PMID- 29533242 TI - Strain Gauge Evaluation of Transfer Impression Techniques of Multiple Implant Supported Prosthesis. AB - PURPOSE: This in vitro study assessed the accuracy of multiple implant-level impression techniques (open tray and closed tray) for the fabrication of 3-unit implant prostheses with strain gauge (SG) analysis. MATERIALS AND METHODS: A polyurethane master model was designed to simulate a clinical situation. Two rigid custom trays were fabricated for the model. The impression material used was polysulfide. Transfer implant impressions were made using 2 techniques; ten tapered copings not splinted (custom closed tray) and ten square copings splinted with acrylic-resin (custom open tray). The improved stone models were allowed to set for 1 hour before being separated from the impression. The superstructures were sprued, invested, and cast with a cobalt-chromium alloy. Four SGs were bonded on the surface of each polyurethane block. RESULTS: A statistically significant difference was found between the 2 impression techniques tested (P = 0.000). This study found a significant average difference of 144.68 +/- 5.53 MUepsilon for open custom tray and 253.3 +/- 16.7 MUepsilon for closed custom tray. CONCLUSION: The custom open tray technique was the most accurate impression for multiple implants compared with closed custom tray. PMID- 29533243 TI - Use of Motivational Interviewing by Nurse Leaders: Coaching for Performance, Professional Development, and Career Goal Setting. AB - Motivational interviewing (MI) is a mentoring style used in various health care settings to guide patients toward health promotion and disease management. The aims of this project were (1) to identify evidence supporting the application of MI strategies and principles by nurse leaders to promote healthful leadership development among direct-report staff and (2) to report outcomes of an educational pilot project regarding MI use for new nurse leaders. Correlations between MI and the American Organization of Nurse Executives nurse executive competencies are reviewed and summarized. These competencies shape the roles, responsibilities, and skills required for nurse executives to function proficiently and successfully within health care organizations. Survey responses were gathered from new nurse supervisors and nurse managers following the MI educational session for nurse leaders. The results show acceptability for MI use in professional development of direct-report staff and in other aspects of nursing leadership roles. PMID- 29533244 TI - Thin Rigid Contact Lens Used in Vitreous-Retinal Surgery for Corneal Protection: A Randomized Controlled Trial. AB - PURPOSE: To design a rigid contact lens (CL) to be used in combination with a wide-angle viewing system and analyze its protection for corneal epithelial during vitreous-retinal surgery. METHODS: A thin and lightweight rigid CL was designed and constructed. The impact of the CL on the visualized fundus range was evaluated using a concrete eye model. Patients with severe proliferative diabetic retinopathy (PDR) were randomized to either the CL group, corneal protective agent (CPA) group, or balanced salt solution (BSS) group. All patients underwent phacoemulsification and a standard 23-gauge three-port vitrectomy. Surgery time and corneal fluorescein staining score (FSS) postoperatively were mainly measured. RESULTS: In the eye model, a larger area of fundus was visualized with the use of our CL under 128 D or 60 D Resight lens. The mean surgery time was 51.36+/-8.06 min, 50.89+/-8.26 min, and 55.46+/-9.14 in CL, CPA, and BSS group, respectively (F=2.325, P=0.105). In eight eyes in the BSS group, corneal epithelial layer was peeled off because the dryness of the cornea could not maintain a clear fundus image. The FSS in BSS group was markedly higher than that of CL and BSS group 1 day (P<0.001), 3 days (P<0.001), and 7 days (P=0.002) postoperatively. There was no statistical significance of the FSS between CL and CPA group at each follow-up endpoint. CONCLUSIONS: The CL that we designed can slightly enlarge the visible fundus range and efficiently protect corneal epithelium during vitrectomy for patients with PDR. PMID- 29533241 TI - Where is crystallography going? AB - Macromolecular crystallography (MX) has been a motor for biology for over half a century and this continues apace. A series of revolutions, including the production of recombinant proteins and cryo-crystallography, have meant that MX has repeatedly reinvented itself to dramatically increase its reach. Over the last 30 years synchrotron radiation has nucleated a succession of advances, ranging from detectors to optics and automation. These advances, in turn, open up opportunities. For instance, a further order of magnitude could perhaps be gained in signal to noise for general synchrotron experiments. In addition, X-ray free electron lasers offer to capture fragments of reciprocal space without radiation damage, and open up the subpicosecond regime of protein dynamics and activity. But electrons have recently stolen the limelight: so is X-ray crystallography in rude health, or will imaging methods, especially single-particle electron microscopy, render it obsolete for the most interesting biology, whilst electron diffraction enables structure determination from even the smallest crystals? We will lay out some information to help you decide. PMID- 29533246 TI - Classifications in Brief: Outerbridge Classification of Chondral Lesions. PMID- 29533245 TI - Intraocular Pressure Increases After Intraarticular Knee Injection With Triamcinolone but Not Hyaluronic Acid. AB - BACKGROUND: Intraarticular steroid injections are a common first-line therapy for severe osteoarthritis, which affects an estimated 27 million people in the United States. Although topical, oral, intranasal, and inhalational steroids are known to increase intraocular pressure in some patients, the effect of intraarticular steroid injections on intraocular pressure has not been investigated, to the best of our knowledge. If elevated intraocular pressure is sustained for long periods of time or is of sufficient magnitude acutely, permanent loss of the visual field can occur. QUESTIONS/PURPOSES: How does intraocular pressure change 1 week after an intraarticular knee injection either with triamcinolone acetonide or hyaluronic acid? METHODS: A nonrandomized, nonblinded prospective cohort study was conducted at an outpatient, ambulatory orthopaedic clinic. This study compared intraocular pressure elevation before and 1 week after intraarticular knee injection of triamcinolone acetonide versus hyaluronic acid for management of primary osteoarthritis of the knee. Patients self-selected to be injected in their knee with either triamcinolone acetonide or hyaluronic acid before being informed of the study. The primary endpoint was intraocular pressure elevation of >= 7 mm Hg 1 week after injection. This cutoff is determined as the minimum significant pressure change in the ophthalmology literature recognized as an intermediate responder to steroids. Intraocular pressure was measured using a handheld Tono-Pen(r) applanation device. This device is frequently used in intraocular pressure measurement in clinical and research settings; 10 sequential measurements are obtained and averaged with a confidence interval. Only measurements with a 95% confidence interval were used. Over a 6-month period, a total of 96 patients were approached to enroll in the study. Sixty-two patients out of 96 approached (65%) agreed. Thirty-one (50%) were injected with triamcinolone and 31 (50%) were injected with hyaluronic acid. Patients with osteoarthritis of the knee who were suitable candidates for either a steroid injection or hyaluronic acid injection were included in the study. Exclusion criteria included previous glaucoma surgery, previous corneal injury precluding use of a Tono-Pen, current acute or chronic steroid use, and diagnosis of glaucoma other than primary open-angle. Patients with elevated intraocular pressure at the 1-week timepoint were invited to return at 1 month for repeat measurement; however, only five of nine (55.6%) were able to do so. The mean age of the total population was 64.1 +/- 11.65 years. There were 46 (74%) women and 16 men. Patient in the hyaluronic acid injection group were younger than the triamcinolone group, 59.5 +/- 11.7 versus 68.7 +/- 9.7 years of age (p < 0.003). RESULTS: The mean intraocular pressure increased by 2.79 mm Hg 1 week after treatment with triamcinolone, but it did not change among those patients treated with hyaluronic acid (2.79 +/- 9.9 mm Hg versus -0.14 +/- 2.96 mm Hg; mean difference 2.93 mm Hg; 95% confidence interval, -0.71 to 6.57 mm Hg; p = 0.12). More patients who received triamcinolone injections developed an increase in intraocular pressure > 7 mm than did those who received hyaluronic acid (29% [nine of 29] versus 0% [zero of 31]; p = 0.002). Of the nine patients who developed elevated intraocular pressure after a triamcinolone injection, five returned for reevaluation 1 month later, and four of them had pressures that remained elevated > 7 mm Hg from baseline. CONCLUSIONS: There appears to be an associated intraocular pressure elevation found in patients who have undergone a triamcinolone injection of the knee. Further larger scale randomized investigations are warranted to determine the longevity of this pressure elevation as well as long-term clinical implications, including optic nerve damage and visual field loss. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29533247 TI - CORR Insights(r): Are Gait Parameters for Through-knee Amputees Different From Matched Transfemoral Amputees? PMID- 29533248 TI - Editorial: The Complexity of Reporting Race and Ethnicity in Orthopaedic Research. PMID- 29533250 TI - Styrene Exposure and Risk of Lymphohematopoietic Malignancies in 73,036 Reinforced Plastics Workers. AB - BACKGROUND: Styrene is an important industrial chemical that the general population is exposed to at low levels. Previous research has suggested increased occurrence of leukemia and lymphoma among reinforced plastics workers exposed at high levels of styrene. METHODS: We followed 73,036 workers of 456 small- and medium-sized Danish reinforced plastics companies from 1968 to 2011 and investigated the exposure-response relation between cumulative styrene exposure and incidence of lymphohematopoietic malignancies. We modeled styrene exposure from employment history, survey data, and historical styrene exposure measurements. We retrieved information on lymphohematopoietic malignancies from national cancer and patient registers. RESULTS: We identified 665 cases overall of 21 different lymphohematopoietic malignancies or combinations thereof, each with at least 20 cases, during 1,581,976 person-years of follow-up. Initial analyses suggested higher age, sex, and calendar year-adjusted incidence rate ratios (RRs) for acute myeloid leukemia, Hodgkin lymphoma, and T-cell lymphoma with higher estimates of cumulative styrene exposure. Accounting for time since exposure showed a trend by cumulative styrene exposure (P = 0.01) and a doubled risk (RR = 2.4; 95% CI, 1.2, 4.6) of acute myeloid leukemia following estimated high compared with estimated low cumulative exposure during the prior 15-29 years. We observed no increased risk following exposure during more recent years and less consistent risk patterns for Hodgkin lymphoma and T-cell lymphoma. CONCLUSIONS: This study, to our knowledge the largest epidemiologic study to date of occupational styrene exposure, suggests increased risk of acute myeloid leukemia following high styrene exposure with a latency period of about 15 years. PMID- 29533249 TI - A Variant of COL3A1 (rs3134646) Is Associated With Risk of Developing Diverticulosis in White Men. AB - BACKGROUND: Colonic diverticulosis is one of the most common gastroenterological disorders. Although diverticulosis is typically benign, many individuals develop diverticulitis or other aspects of diverticular disease. Diverticulosis is thought to stem from a complex interaction of environmental, dietary, and genetic factors; however, the contributing genetic factors remain unknown. OBJECTIVE: The aim of our present study was to determine the role of genetic variants within genes encoding for collagens of the connective tissue in diverticulosis. DESIGN: This was a transsectional genetic association study. SETTINGS: This study was conducted at three tertiary referral centers in Germany and Lithuania. PATIENTS: Single-nucleotide polymorphisms in COL3A1 (rs3134646, rs1800255) and COL1A1 (rs1800012) were genotyped in 422 patients with diverticulosis and 285 controls of white descent by using TaqMan assays. MAIN OUTCOME MEASURES: The association of colonoscopy-proven diverticulosis with genetic polymorphisms with herniations was assessed in multivariate models. RESULTS: The rs3134646, rs1800255, and rs1800012 variants were significantly associated with the risk of developing diverticulosis in the univariate model; however, these associations were not significant in the multivariate logistic regression analysis including additional nongenetic variables. When selectively analyzing sexes, the genotype AA (AA) in rs3134646 remained significantly associated with diverticulosis in men (OR, 1.82; 95% CI, 1.04-3.20; p = 0.04). LIMITATIONS: Because a candidate approach was used, additional relevant variants could be missed. Within our cohort of patients with diverticulosis, only a small proportion had diverticular disease and thus, we could not examine the variants in these subgroups. Functional studies, including the analysis of the involved collagens, are also warranted. CONCLUSIONS: Our study shows that a variant of COL3A1 (rs3134646) is associated with the risk of developing colonic diverticulosis in white men, whereas rs1800255 (COL3A1) and rs1800012 (COL1A1) were not associated with this condition after adjusting for confounding factors. Our data provide novel valuable insights in the genetic susceptibility to diverticulosis. See Video Abstract at http://links.lww.com/DCR/A504. PMID- 29533251 TI - Prevalence of Myocardial Fibrosis by Left Ventricular Assist Device Apical Core Biopsy and Correlation with Other Markers of Myocardial Recovery. AB - Myocardial fibrosis identified by apical core pathology at the time of left ventricular assist device (LVAD) implantation may add information regarding myocardial recovery potential. In this analysis, we report the prevalence of myocardial fibrosis by cardiomyopathy type and its association with other known markers of left ventricular recovery. Left ventricular assist device core pathology was reviewed on 332 patients who underwent LVAD implantation at a single institution between 2005 and 2016. Baseline clinical and echocardiographic characteristics were compared among patients with and without myocardial fibrosis by cardiomyopathy type. Among the 332 LVAD core specimens, myocardial fibrosis was present in 79%. Myocardial fibrosis was more common in ischemic than in nonischemic patients (90% vs. 66%; p < 0.001). Patients with fibrosis were older than those without (58 +/- 12 vs. 55 +/- 19; p < 0.05). Among the nonischemic cardiomyopathy cases, those with fibrosis were more likely to have an implantable cardioverter defibrillator (ICD) 81% and to be diabetic 81%. Fibrosis was not associated with left ventricular end-diastolic diameter (LVEDD), creatinine, or N terminal prohormone of brain natriuretic peptide (NT-pro BNP). Myocardial fibrosis by apical core biopsy correlated with several known markers of left ventricular recovery including cardiomyopathy type, age, and presence of an ICD. In nonischemic cardiomyopathy patients, the degree of myocardial fibrosis may add information regarding recovery potential. PMID- 29533252 TI - The Effects of a Motorized Aquatic Treadmill Exercise Program on Muscle Strength, Cardiorespiratory Fitness, and Clinical Function in Subacute Stroke Patients: A Randomized Controlled Pilot Trial. AB - OBJECTIVE: The aim of this study was to assess whether the effects of a motorized aquatic treadmill exercise program improve the isometric strength of the knee muscles, cardiorespiratory fitness, arterial stiffness, motor function, balance, functional outcomes, and quality of life in subacute stroke patients. DESIGN: Thirty-two patients were randomly assigned to 4-wk training sessions of either aquatic therapy (n = 19) or land-based aerobic exercise (n = 18). Isometric strength was measured using an isokinetic dynamometer. Cardiopulmonary fitness was evaluated using a symptom-limited exercise tolerance test and by measuring brachial ankle pulse wave velocity. Moreover, motor function (Fugl-Meyer Assessment [FMA] and FMA-lower limb [FMA-LL]), balance (Berg Balance Scale [BBS]), Activities of daily living (Korean version of the Modified Barthel Index [K-MBI]), and quality of life (EQ-5D index) were examined. RESULTS: There were no intergroup differences between demographic and clinical characteristics at baseline (P > 0.05). The results shows significant improvements in peak oxygen consumption (P = 0.02), maximal isometric strength of the bilateral knee extensors (P < 0.01) and paretic knee flexors (P = 0.01), FMA (P = 0.03), FMA-LL (P = 0.01), BBS (P = 0.01), K-MBI (P < 0.01), and EQ-5D index (P = 0.04) after treatment in the aquatic therapy group. However, only significant improvements in maximal isometric strength in the knee extensors (P = 0.03) and flexors (P = 0.04) were found within the aquatic therapy group and control group. CONCLUSIONS: Water-based aerobic exercise performed on a motorized aquatic treadmill had beneficial effect on isometric muscle strength in the lower limb. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Articulate the rationale for including walking on an aquatic treadmill in the rehabilitation of subacute stroke patients; (2) Describe the beneficial effects of a motorized aquatic treadmill exercise program in the rehabilitation of subacute stroke patients; and (3) Determine the appropriate indications for incorporating a motorized aquatic treadmill exercise program in the rehabilitation of subacute stroke patients.Level: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 29533253 TI - Complications of Cranioplasty. AB - Cranioplasty is a time-honoured surgical procedure to restore the calvarial form and function that is associated with a relatively high complication rate. The present article analyzed various complications and reviewed the complications based on study of the relevant research in the craniofacial literature. Complications were broadly divided into 2 groups, intraoperative and postoperative, for ease of understanding. The etiological factors, local and systemic condition of the patient, prevention, and management of various complications were widely discussed. The article also highlighted problems and complications associated with various reconstructive materials. Insights into various complications of cranioplasty enable surgeon to understand them better, minimize the chances of occurrence, and improve surgical outcome. In spite of reported high rate of complications, serious complications like meningitis, air embolism, and death are rare. PMID- 29533254 TI - Risk Factors for Titanium Mesh Implant Exposure Following Cranioplasty. AB - PURPOSE: Titanium mesh is used to reconstruct the neurocranium in cranioplasties. Though it is generally well-tolerated, erosion of the overlying soft tissue with exposure of the implant is a complication that adversely affects patient outcomes. The purpose of this study is to investigate potential risk factors for titanium mesh exposure. METHODS: This study comprises all consecutive patients who underwent titanium mesh cranioplasty between January 2000 and July 2016. A retrospective chart review was conducted to extract demographics, details of management, and outcome. Latest postoperative computed tomography scans were reviewed to document the thickness of soft tissue coverage over the implant and the presence of significant extradural dead space deep to it. RESULTS: Fifty patients were included. Implant exposure occurred in 7 (14%), while threatened exposure was observed in 1 additional patient, for a total complication count of 8 (16%).Four (50%) exposure and 3 (7.1%) nonexposure patients underwent preoperative radiotherapy (odds ratio [OR] = 19.67, P = 0.018). Similarly, 4 (50%) exposure and 5 (11.9%) nonexposure patients had a free flap tissue transfer for implant coverage (OR = 6.50, P = 0.046). Postoperative computed tomography scans revealed significant thinning of soft tissues over titanium mesh in 7 (87.5%) exposure and 15 (35.7%) nonexposure patients (OR = 10.71 P = 0.040). No significant association was found between transposition/rotation flap, postoperative radiotherapy, or the presence of significant extradural dead space, and exposure (P = 0.595, P = 0.999, P = 0.44). CONCLUSION: Preoperative radiotherapy, free flap coverage, and soft tissue atrophy resulted in greater odds of titanium mesh exposure. The findings of this study provide important considerations for reconstructive surgeons using titanium mesh for cranioplasty. PMID- 29533255 TI - Evaluation of the Efficacy of Different Concentrations of Dextrose Prolotherapy in Temporomandibular Joint Hypermobility Treatment. AB - PURPOSE: The aim of this study was to compare and evaluate the efficacy of different concentrations of dextrose prolotherapy for the treatment of temporomandibular joint (TMJ) hypermobility. PATIENTS AND METHODS: A prospective, randomized clinical trial including patients with subluxation or dislocation was performed. The study comprised 40 patients. Patients were randomly divided into 4 groups: control group, 10% dextrose, 20% dextrose, and 30% dextrose group. Patients in all groups received injections into 4 different areas of each TMJ in 4 sessions at monthly intervals. Visual analog scale of TMJ pain intensity, maximum mouth opening (MMO), joint sounds, and frequency of luxations were recorded preoperatively and postoperatively after 1 month of last injection. The collected data were then statistically analyzed. RESULTS: Each group showed postoperatively significant improvement in TMJ pain, significant decrease in both MMO and joint sound. Besides that, TMJ locking was not observed in any patient during the follow-up period. There were no statistically significant differences throughout the study intervals between the groups. CONCLUSION: It was concluded that there was no significant difference between control group and dextrose groups and there is no superiority of any concentration of dextrose over the others in TMJ prolotherapy, and all treatment procedures were efficient in improvement of clinical symptoms related to TMJ hypermobility. If dextrose is used as a proliferant, it can be said that 10% dextrose can be sufficient in TMJ hypermobility treatment. PMID- 29533256 TI - Use of Survey and Delphi Process to Understand Trauma Anesthesia Care Practices. AB - BACKGROUND: Few trauma guidelines evaluate and recommend anesthesiology practices and there are no trauma anesthesia-specific guidelines. There is no information on how anesthesiologists perceive clinical practice patterns. Our objective was to understand the perceptions of anesthesiologists regarding trauma anesthesia practices. METHODS: A survey assessing anesthesia management of trauma patients was distributed to 21,491 anesthesiologists. A subset of 10 of these questions was subsequently reviewed by a trauma anesthesiology focus group through a 3 round web-based Delphi process. A question was deemed to have respondent consensus if the response with the highest percentage of agreement was unchanged between rounds 1 and 2. RESULTS: A total of 2360 anesthesiologists (11% response rate) responded to the survey. Results demonstrated that the practitioners' answers conflicted with existing surgical trauma society recommendations (ie, when to transfuse component therapy), and several areas that lacked any guidelines, resulted in response variability among anesthesiologists where not 1 answer achieved >75% agreement (ie, intubation technique of choice for patients with uncleared cervical spine). Thirteen trauma anesthesiologists participated in round 1 (response rate 100%), and 12 responded in rounds 2 and 3 (response rate 92%) of the Delphi process. None of the questions received 100% agreement. Consensus was achieved on 9 of 10 statements pertaining to trauma anesthesia care. Consensus was not reached on the intubating technique in a hemodynamically unstable patient with an uncleared cervical spine with deficits. Delphi participant opinion conflicted with existing guidelines on 2 statements: the use of cricoid pressure, and when to begin blood component therapy. CONCLUSIONS: There are several important areas of trauma anesthesia practice where guidelines do not exist and several where existing guidelines are not endorsed by the majority of practitioners who completed our survey. The lack of consensus on trauma anesthesia management and the variation in survey responses demonstrate a need to develop evidence-based trauma anesthesia guidelines. PMID- 29533257 TI - Nil Per Os Consideration for Emergency Procedures: Cornerstone of Safety or an Obstacle to Patient Care? PMID- 29533258 TI - Patients at High Risk for Obstructive Sleep Apnea Are at Increased Risk for Atrial Fibrillation After Cardiac Surgery: A Cohort Analysis. AB - BACKGROUND: Patients with obstructive sleep apnea (OSA) experience intermittent hypoxia, hypercarbia, and sympathetic activation during sleep, which increases risk for paroxysmal atrial fibrillation and other cardiac arrhythmias. Whether patients with OSA experience increased episodes of atrial fibrillation after cardiac surgery is unclear. We examined whether patients at increased risk for OSA, assessed by the STOP-BANG (snoring, tired during the day, observed stop breathing during sleep, high blood pressure, body mass index more than 35 kg/m, age more than 50 years, neck circumference more than 40 cm, and male gender) questionnaire, had a higher incidence of new-onset postoperative atrial fibrillation after cardiac surgery. Because both postoperative atrial fibrillation and OSA increase resource utilization, we secondarily examined whether patients at increased OSA risk had longer duration of postoperative mechanical ventilation and intensive care unit (ICU) length of stay. METHODS: With institutional review board approval, this retrospective observational study evaluated adult patients who underwent elective cardiac surgery requiring cardiopulmonary bypass between 2014 and 2015 with preoperative assessment of OSA risk using the STOP-BANG questionnaire. Patients with a history of atrial fibrillation were excluded. The association between the STOP-BANG score and postoperative atrial fibrillation was examined using a multivariable logistic regression model. Secondarily, we estimated the association between the STOP-BANG score and duration of initial intubation using multivariable linear regression and ICU length of stay using Cox proportional hazards regression. We also descriptively summarized the percentage of patients requiring tracheal reintubation for mechanical ventilation. RESULTS: Of 4228 cardiac surgery patients, 1593 met inclusion and exclusion criteria. An increased STOP-BANG score was associated with higher odds of postoperative atrial fibrillation (odds ratio [95% confidence interval {CI}], 1.16 [1.09-1.23] per-point increase in the STOP BANG score; P < .001). The STOP-BANG score was not associated with ICU length of stay (estimated hazard ratio [97.5% CI], 0.99 [0.96-1.03] per-point increase in the STOP-BANG score; P = .99) or duration of initial intubation (ratio of geometric means [97.5% CI], 1.01 [1.00-1.04]; P = .03; significance criterion [Bonferroni correction] < 0.025). One percent of patients required reintubation. DISCUSSION: Increasing risk for OSA, assessed by STOP-BANG, was associated with higher odds of postoperative atrial fibrillation, but not prolonged duration of mechanical ventilation or ICU length of stay. PMID- 29533259 TI - Surveying the Literature: Synopsis of Recent Key Publications. PMID- 29533260 TI - The Effectiveness of Applying Soft Tissue Bonding Adhesive Composed of 2-Ethyl Cyanoacrylate to Epidural Catheter Fixations Using Film Dressings: An Open-Label, Randomized, Parallel-Group Comparative Study. AB - BACKGROUND: Insufficient fixation of an epidural catheter may result in migration of the catheter and eventual catheter failure. However, the best fixation method remains to be established. Aron Alpha A (2-ethyl cyanoacrylate) adhesive is approved for clinical use and can be used for surgical adhesion to both skin and blood vessels. We hypothesized that the addition of Aron Alpha A adhesive to film dressing would result in consistent and dependable catheter fixation. METHODS: In this study, 58 women who were scheduled for cesarean delivery under spinal and epidural anesthesia were recruited. Patients were randomly assigned to a control or treatment group. In the control group, the catheter was fixed solely by film dressing. In the treatment group, a small amount of Aron Alpha A was applied at 2 sites along the catheter. The fixation area was then covered by film dressing. The catheter insertion length was recorded after fixation (T0), immediately postoperatively (T1), on postoperative day 1 (T2), and when the catheter was removed (T3). The change in insertion length from T0 to T3 between the 2 groups was the primary outcome measure. The incidence of catheter failure was also recorded. For all comparisons, P < .05 was considered statistically significant. RESULTS: Initially, 58 women were enrolled; however, 3 patients were excluded. From the remaining 55 patients, 27 and 28 were assigned to the control and treatment groups, respectively, and were evaluated. The change in insertion length from T0 to T3 was significantly more in the control group compared with the treatment group (-1.9 +/- 2.2 vs 0 +/- 0 cm, respectively; P < .001). In the control group, 11 catheters (41%) failed; in the treatment group, all catheters provided effective analgesia throughout the study (P < .001). CONCLUSIONS: Epidural catheter fixation using film dressing combined with 2-ethyl cyanoacrylate adhesive application at 2 sites along the catheter resulted in secure fixation in patients receiving postoperative epidural analgesia for cesarean delivery. PMID- 29533261 TI - The Anesthesiologist-Informatician: A Survey of Physicians Board-Certified in Both Anesthesiology and Clinical Informatics. AB - All 36 physicians board-certified in both anesthesiology and clinical informatics as of January 1, 2016, were surveyed via e-mail, with 26 responding. Although most (25/26) generally expressed satisfaction with the clinical informatics boards, and view informatics expertise as important to anesthesiology, most (24/26) thought it unlikely or highly unlikely that substantial numbers of anesthesiology residents would pursue clinical informatics fellowships. Anesthesiologists wishing to qualify for the clinical informatics board examination under the practice pathway need to devote a substantive amount of worktime to informatics. There currently are options outside of formal fellowship training to acquire the knowledge to pass. PMID- 29533262 TI - Hypothermia During Cesarean Delivery. PMID- 29533263 TI - In Response. PMID- 29533265 TI - Interventions to Reduce Intraoperative Costs: A Systematic Review. AB - OBJECTIVE: The aim of this study was to systematically review the risks and benefits of interventions designed to reduce intraoperative costs. SUMMARY BACKGROUND DATA: Episode-based payments shift financial risk from insurers onto hospitals and providers. The operating room (OR) is a resource dense environment and there is growing interest in identifying ways to reduce intraoperative costs while maintaining patient safety. METHODS: We searched PubMed, Cochrane, and CINAHL for articles published between 2001 and March 2017 that assessed interventions designed to reduce intraoperative costs. We grouped interventions into 6 categories: standardization of instruments, switching to reusable instruments or removing instruments from trays, wound closure comparisons, cost feedback to surgeons, head-to-head instrument trials, and timely arrival of surgeon to the OR. RESULTS: Of 43 included studies, 12 were randomized trials and 31 were observational studies. Gross cost estimates ranged from -$413 (losses) to $3154 (savings) per operation, with only 2 studies reporting losses; however, studies had significant methodologic limitations related to cost data. Studies evaluating standardization and cost feedback were the most robust with estimated cost savings between $38 and $732/case, with no change in OR time, length of stay, or adverse events. CONCLUSIONS: Almost all studies assessing interventions to reduce intraoperative costs have demonstrated cost savings with no apparent increase in adverse effects. Methodologic limitations, especially related to cost data, weaken the reliability of these estimates for most intervention categories. However, hospitals seeking to reduce costs may be able to do so safely by standardizing operative instruments or providing cost feedback to surgeons. PMID- 29533264 TI - Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial. AB - BACKGROUND: Globally, >300 million patients have surgery annually, and <=20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were >=45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55 4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability. PMID- 29533266 TI - The Safety and Efficacy of Laparoscopic Common Bile Duct Exploration Combined with Cholecystectomy for the Management of Cholecysto-choledocholithiasis: An Up to-date Meta-analysis. AB - OBJECTIVE: The aim of this study was to compare the efficacy and safety of the laparoscopic common bile duct exploration (LCBDE) and laparoscopic cholecystectomy (LC) with preoperative endoscopic sphincterotomy (pre-EST) and LC for concomitant gallstones and common bile duct (CBD) stones. BACKGROUND: It remains controversial whether LCBDE+LC is better than pre-EST+LC for gallstones and CBD stones. METHODS: A specific search of online databases was performed from January 2006 to October 2017. Relative outcomes of perioperative safety and postoperative efficacy were synthesized. Single-arm meta-analysis and cumulative meta-analysis were also conducted. RESULTS: A total of 13 studies involving 1757 (872 vs 885) patients were included for analysis in our study. The CBD stones clearance rate [94.1% vs 90.1%; odds ratio (OR) 1.56, P = 0.012] was significantly higher in patients who underwent LCBDE+LC than pre-EST+LC, while perioperative complications (7.6% vs 12.0%; OR 0.67, P = 0.015), conversion to other procedure (4.1% vs 7.1%; OR 0.64, P = 0.025), retained stones rate (1.2% vs 7.9%; OR 0.34, P = 0.004), lithiasis recurrence rate (1.8% vs 5.6%, OR 0.32, P = 0.005), operative time [112.28 vs 132.03 minutes; weighted mean difference (WMD) 18.08, P = 0.002], length of hospital stay (4.94 vs 6.62 days; WMD -1.63, P = 0.023), and total charges [standardized mean difference (SMD) -2.76, P = 0.002] were significantly lower in LCBDE+LC. The mortality (0.6% vs 1.1%; OR 0.32, P = 0.117) was similar between the 2 groups. The cumulative meta-analyses indicated the effect sizes of CBD stones clearance rate, perioperative complications, and conversion to other procedure have already stabilized between 2 groups. CONCLUSION: The updated meta-analysis first confirms that LCBDE+LC is superior to pre-EST+LC both in perioperative safety and short- and long-term postoperative efficacy, which should be considered as optimal treatment choice for cholecysto choledocholithiasis. PMID- 29533267 TI - Emergency Computed Tomography Predicts Caustic Esophageal Stricture Formation. AB - BACKGROUND: Endoscopy is the best predictor of stricture formation after caustic ingestion. OBJECTIVE: Our aim was to compare the accuracy of emergency computed tomography (CT) and endoscopy in predicting risks of esophageal stricture. METHODS: We describe a CT classification of esophageal caustic injuries: Grade I show normal esophagus; Grade IIa display internal enhancement of the esophageal mucosa and enhancement of the outer wall conferring a "target" aspect; Grade IIb present as a fine rim of external esophageal wall enhancement. In 152 patients (56 males, median age 45) who underwent esophageal preservation after caustic ingestion we compared the accuracy of the CT and endoscopic (Zargar) classifications in predicting esophageal stricture. RESULTS: On endoscopy esophageal injuries were classified as grade 1 (n = 50; 33%), grade 2a (n = 11; 7%), grade 2b (n = 19; 13%), grade 3a (n = 14; 9%), and grade 3b (n = 58; 38%). On CT, 47 (31%) patients had grade I, 47 (31%) had grade IIa and 58 (38%) had grade IIb esophageal injuries. Fifty-six (37%) patients developed esophageal strictures. The risk of esophageal stricture formation was 0%, 17%, and 83%, for grade I, IIa, and IIb CT injuries and 0, 0, 28, 50, and 76% for endoscopic grade 1, 2a, 2b, and 3a and 3b injuries, respectively. ROC curve analysis at 120 days after ingestion showed that CT outperformed endoscopy in predicting stricture formation (AUC: 85.1 [95% CI, 74.9-95.3] vs 77.8 [95% CI, 66.5-89.0], P = 0.047) and did just as well as a combined CT-endoscopy algorithm (AUC: 85.8 [95% CI, 76.5-95.0] vs 85.1 [95% CI, 74.9-95.3], P = 0.73). CONCLUSION: Emergency CT outperforms endoscopy in predicting esophageal stricture formation after caustic ingestion. Emergency endoscopy evaluation after caustic ingestion is not indispensable. PMID- 29533268 TI - Perioperative Pain Management Strategies for Anterior Cruciate Ligament Reconstruction. PMID- 29533269 TI - Notice of Retraction and Replacement: "Autoimmune Progesterone Dermatitis Presenting as Stevens-Johnson Syndrome" (Drayer SM, Laufer LR, Farrell ME). PMID- 29533270 TI - The influence of formal and informal policies and practices on health care innovation implementation: A mixed-methods analysis. AB - BACKGROUND: The implementation science literature has contributed important insights regarding the influence of formal policies and practices on health care innovation implementation, whereas informal implementation policies and practices have garnered little attention. The broader literature suggests that informal implementation policies and practices could also influence innovation use. PURPOSE: We used the Organizational Theory of Innovation Implementation to further understand the role of formal and informal implementation policies and practices as determinants of implementation effectiveness. We examined their role within the context of initiatives to increase palliative care consultation in inpatient oncology. METHODS: We used a case study design in two organizational settings within one academic medical center: medical and gynecologic oncology. We completed semistructured interviews with medical (n = 12) and gynecologic (n = 10) oncology clinicians using questions based on organizational theory. Quantitative data assessed implementation effectiveness, defined as aggregated palliative care consult rates within oncology services from 2010 to 2016. Four palliative care clinicians were interviewed to gain additional implementation context insights. RESULTS: Medical oncology employed multiple formal policies and practices including training and clinician prompting to support palliative care consultation and a top-down approach, yet most clinicians were unaware of the policies and practices, contributing to a weak implementation climate. In contrast, gynecologic oncology employed one formal policy (written guideline of criteria for initiating a consult) but also relied on informal policies and practices, such as spontaneous feedback and communication; they adopted a bottom up approach, contributing to broader clinician awareness and strong implementation climate. Both services exhibited variable, increasing consult rates over time. PRACTICE IMPLICATIONS: Informal policies and practices may compensate or substitute for formal policies and practices under certain conditions (e.g., smaller health care organizations). Further research is needed to investigate the role of formal and informal policies and practices in shaping a strong and sustainable implementation climate and subsequent effective innovation implementation. PMID- 29533271 TI - Contextual factors that influence quality improvement implementation in primary care: The role of organizations, teams, and individuals. AB - BACKGROUND: Recent emphasis on value-based health care has highlighted the importance of quality improvement (QI) in primary care settings. QI efforts, which require providers and staff to work in cross-functional teams, may be implemented with varying levels of success, with implementation being affected by factors at the organizational, teamwork, and individual levels. PURPOSE: The purpose of our study was to (a) identify contextual factors (organizational, teamwork, and individual) that affect implementation effectiveness of QI interventions in primary care settings and (b) compare perspectives about these factors across roles (health care administrators, physician and nonphysician clinicians, and administrative staff). METHODS/APPROACH: We conducted semistructured interviews with 24 health care administrators, physician and nonphysician primary care providers, and administrative staff representing 10 primary care practices affiliated with one integrated delivery system. RESULTS: Participants across all roles identified similar organizational- and team-level factors that influence QI implementation including organizational capacity to take on new initiatives (e.g., time availability of physicians), technical capability for QI (e.g., data analysis skills), and team climate (e.g., how well staff work together). There was greater variation in terms of individual-level factors, particularly perceived meaning and purpose of QI. Perceptions about value of QI ranged from positive impacts on patient care and practice competitiveness to decreased efficiency and distractions from patient care, but differences did not appear attributable to role. CONCLUSIONS: Successful QI implementation requires effective collaboration within cross-functional teams. Additional research is needed to assess how best to employ implementation strategies that promote cross-understanding of QI among team members and, ultimately, effective implementation of QI programs. PRACTICE IMPLICATIONS: Health care managers in primary care settings should strive to create a strong teamwork climate, reinforced by opportunities for staff in various roles to discuss QI as a collective. PMID- 29533272 TI - Team functioning as a predictor of patient outcomes in early medical home implementation. AB - BACKGROUND: New models of patient-centered primary care such as the patient centered medical home (PCMH) depend on high levels of interdisciplinary primary care team functioning to achieve improved outcomes. A few studies have qualitatively assessed barriers and facilitators to optimal team functioning; however, we know of no prior study that assesses PCMH team functioning in relationship to patient health outcomes. PURPOSE: The aim of the study was to assess the relationships between primary care team functioning, patients' use of acute care, and mortality. METHODOLOGY/APPROACH: Retrospective longitudinal cohort analysis of patient outcomes measured at two time points (2012 and 2013) after PCMH implementation began in Veterans Health Administration practices. Multilevel models examined practice-level measures of team functioning in relationship to patient outcomes (all-cause and ambulatory care-sensitive condition-related hospitalizations, emergency department visits, and mortality). We controlled for practice-level factors likely to affect team functioning, including leadership support, provider and staff burnout, and staffing sufficiency, as well as for individual patient characteristics. We also tested the model among a subgroup of vulnerable patients (homeless, mentally ill, or with dementia). RESULTS: In adjusted analyses, higher team functioning was associated with lower mortality (OR = 0.92, p = .04) among all patients and with fewer all-cause admissions (incidence rate ratio [IRR] = 0.90, p < 0.01), ambulatory care-sensitive condition-related admissions (IRR = 0.91, p = .04), and emergency department visits (IRR = 0.91, p = .03) in the vulnerable patient subgroup. CONCLUSION: These early findings give support for the importance of team functioning within PCMH models for achieving improved patient outcomes. PRACTICE IMPLICATIONS: A focus on team functioning is important especially in the early implementation of team-based primary care models. PMID- 29533273 TI - Relationships between organizational and individual support, nurses' ethical competence, ethical safety, and work satisfaction. AB - BACKGROUND: Organizations and nurse leaders do not always effectively support nurses' ethical competence. More information is needed about nurses' perceptions of this support and relevant factors to improve it. PURPOSE: The aim of the study was to examine relationships between nurses' perceived organizational and individual support, ethical competence, ethical safety, and work satisfaction. METHODOLOGY: A cross-sectional questionnaire survey was conducted. Questionnaires were distributed to nurses (n = 298) working in specialized, primary, or private health care in Finland. Descriptive statistics, multifactor analysis of variance, and linear regression analysis were used to test the relationships. RESULTS: The nurses reported low organizational and individual support for their ethical competence, whereas perceptions of their ethical competence, ethical safety, and work satisfaction were moderate. There were statistically significant positive correlations between both perceived individual and organizational support, and ethical competence, nurses' work satisfaction, and nurses' ethical safety. CONCLUSIONS: Organizational and individual support for nurses' ethical competence should be strengthened, at least in Finland, by providing more ethics education and addressing ethical problems in multiprofessional discussions. Findings confirm that organizational level support for ethical competence improves nurses' work satisfaction. They also show that individual level support improves nurses' sense of ethical safety, and both organizational and individual support strengthen nurses' ethical competence. PRACTICE IMPLICATIONS: These findings should assist nurse leaders to implement effective support practices to strengthen nurses' ethical competence, ethical safety, and work satisfaction. PMID- 29533275 TI - 38th Symposium of the International Society of Dermatopathology. PMID- 29533274 TI - Livedoid Vasculopathy Presenting in a Patient With Sickle Cell Disease. AB - We report a case in which a 43-year-old African American male with medical history of sickle cell disease (SCD) presented with a nonhealing ulcer. Biopsy revealed features of livedoid vasculopathy. Previously, livedoid vasculopathy had only been described in a patient with sickle cell trait, but never in a patient with SCD. Livedoid vasculopathy most commonly affects the distal lower extremities and is characterized by irregular, punched-out, painful ulcers that heal with stellate white scars of atrophie blanche. Histologically, it reveals segmental hyalinizing vessels, focal thrombosis, and endothelial proliferation. The etiology is currently unclear, but it has been shown to be related to procoagulant states and a diagnosis of livedoid vasculopathy should prompt a thorough hypercoagulable workup, including testing for SCD in high-risk patients. PMID- 29533276 TI - Giant Pilomatricoma Arising as a Rapidly Growing Vascularized Tumor in a Child. AB - In this observation, we report an unusual presentation of a pilomatricoma in an 8 year-old girl who was initially referred to the department of vascular medicine for diagnosis and care of a suspected mixed lymphatic venous malformation. The lesion on her left shoulder presented as a giant bluish-purple red solitary mass, painful and rapidly growing, measuring 7 cm in anteroposterior diameter. This mass did not present the typical characteristics of a lymphatic venous malformation but exhibited warning signs of malignancy on clinical examination and imaging. The diagnosis of pilomatricoma was reached by fine-needle aspiration biopsy of the mass, showing mummified "ghost" squamous cells and a granulomatous inflammatory reaction stroma with scattered multinucleated giant cells and no sign of malignancy. Complete surgical excision associated with plastic surgery was curative. Diagnostic and management approach to skin lesion in childhood is subject of great concern for health care professionals, including dermatologists and vascular medicine specialists who may be confronted with this atypical presentation of one of the most common causes of superficial neck masses in children. PMID- 29533277 TI - Unusual Neuroendocrine Differentiation in a Small Round Cell Angiosarcoma: A Potential Histologic Mimicker of Superficial Ewing Sarcoma. AB - Neuroendocrine differentiation or aberrant expression of neuroendocrine markers is very uncommon in angiosarcomas (AS) and creates a challenging differential diagnosis with other superficial or soft tissue tumors. Herein, we report a new case of superficial AS presenting as a tumor lesion on the little finger of the right hand of a 52-year-old man. The tumor displayed CD56, chromogranin-A, and synaptophysin immunoreactivity. Tumor cells were positive for vascular markers (CD31, FLI1, ERG, D2-40, VE-cadherin, VEGR1,2, and 3), CD99, and EMA, but were negative for S100, CK (AE1/AE3), CK20, polyomavirus, and myogenic (desmin and myogenin) and melanocyte markers (melan-A and HMB45). Ki67 immunostains indicated high proliferative activity (>50%). The whole-body computed tomography did not reveal distant disease. The initial assessment considered several tumor subtypes as possible histological diagnoses, including Ewing sarcoma, Ewing-like sarcoma, Merkel cell carcinoma, and undifferentiated "small round cell sarcoma". Fluorescence in situ hybridization analysis was negative for EWSR1 translocation and molecular analysis failed to detect any EWSR1, CIC, SYT or BCOR rearrangement. As a follow-up investigation, we tested 17 cutaneous/superficial AS for neuroendocrine markers; however, only one of these showed focal CD56 and synaptophysin expression. In conclusion, the present findings indicate that neuroendocrine differentiation is a very infrequent feature in AS. We report an AS of the finger with an uncommon histological appearance and immunohistochemical profile: predominant round cell tumor proliferation and neuroendocrine differentiation. Pathologists should be aware of these potential histological and immunohistochemical pitfalls in AS. PMID- 29533278 TI - Rare Variant of Agminated Spitz Nevi on a Hypopigmented Background and Segmental Distribution: Case Report and Review of Literature. AB - Spitz nevus is a type of melanocytic nevus that can arise as a solitary lesion or as multiple lesions either disseminated or agminated (grouped) in different skin backgrounds (eg, grossly normal, hyperpigmented, or hypopigmented). Agminated Spitz nevi have been rarely reported and are even rarer in a background of hypopigmented skin. We present the case of a 2-month-old girl with multiple, grouped, dome-shaped, red papules arising on a hypopigmented patch with a segmental distribution. Biopsy of 2 lesions showed findings characteristic of Spitz nevus, confirming the diagnosis. We also review 4 other cases of agminated Spitz nevi arising on hypopigmented skin reported in the literature. PMID- 29533279 TI - Human Papillomavirus-Driven Squamous Lesions: High-Risk Genotype Found in Conjunctival Papillomas, Dysplasia, and Carcinoma. AB - BACKGROUND: Human papillomavirus (HPV) is a causative agent for intraepithelial squamous neoplasms, particularly on mucosal surfaces. HPV has a well-established association with squamous cell carcinoma (SCC) of the oropharynx and genital tract, and recent studies suggest a potential role in ocular and periocular squamous neoplasms. Multiple high-risk HPV genotypes are associated with histologically similar squamous neoplasms, and some HPV genotypes have been differentially associated with high- or low-grade lesions. METHODS: Squamous lesions were screened with immunohistochemical markers p16 and Ki-67 to compare expression in conjunctival papillomas (n = 21) to papillomas with high-grade dysplasia, SCC in situ, and invasive SCC (n = 40). Polymerase chain reaction was performed using the Roche COBAS HPV assay to identify the 14 most common high risk HPV genotypes. RESULTS: Compared with squamous papillomas, the lesions showing high-grade dysplasia or worse expressed p16 with greater intensity and in a greater percentage of the lesion. A trend toward mild Ki-67 expression in papillomas versus marked Ki-67 expression in high-grade squamous lesions was also observed. HPV-16 was present in 7 of the SCC in situ and invasive SCC lesions but none of the papillomas. CONCLUSIONS: HPV may have an important role in squamous lesions of the conjunctiva. In addition to positive polymerase chain reaction results, strong and diffuse p16 expression with marked Ki-67 is strongly suggestive of an HPV-driven lesion. PMID- 29533280 TI - Polymorphous Sweat Gland Carcinoma: An Immunohistochemical and Molecular Study. AB - Polymorphous sweat gland carcinoma is an uncommon low-grade malignant adnexal tumor with a marked predilection for the distal extremities. Histologically, the lesions are characterized by a cellular proliferation showing a combination of growth patterns, including trabecular, solid, tubular, cribriform, or adenoid cystic and pseudopapillary. The immunohistochemical and molecular profile of these tumors has not yet been properly addressed. We have studied 3 cases of polymorphous sweat gland carcinoma using a broad panel of immunohistochemical markers including cytokeratin AE1/AE3, CK5/6, MOC31, p40, p63, p16, chromogranin, synaptophysin, CD56, MIB-1, estrogen receptor, progesterone receptor, androgen receptor, BER-EP4, smooth muscle actin, epithelial membrane antigen, carcinoembryonic antigen, CD117, S100 protein, HBME-1, DOG1, vimentin, and mammaglobin. We also examined for the MYB-NFIB fusion by fluorescent in situ hybridization (ISH) and for human papilloma virus by ISH. Our studies show that cytokeratin AE1/AE3, CK5/6, p40, p63, p16, chromogranin, and CD56 stains were positive in all 3 cases. All 3 cases were negative for MYB-NFIB fusion by fluorescent ISH which rules out adenoid cystic carcinoma. DNA ISH studies for high-risk human papilloma virus were negative in all cases. MIB-1 proliferation index was very high (30%-70% nuclear positivity), supporting a malignant phenotype. The positivity for chromogranin and CD56 suggests partial neuroendocrine differentiation. The differential diagnosis includes metastases from internal malignancies, basal cell carcinoma, and other benign and malignant adnexal neoplasms such as adenoid cystic carcinoma, ductal eccrine carcinoma, and microcystic carcinoma. Positivity for p16 in combination with chromogranin and CD56 may be potentially good markers for differentiating this tumor from other adnexal tumors. PMID- 29533281 TI - A Case of a Malignant Cutaneous Mixed Tumor (Chondroid Syringoma) of the Scapula Treated With Staged Margin-Controlled Excision. AB - Cutaneous mixed tumor (chondroid syringoma) is the cutaneous counterpart of pleomorphic adenoma of salivary glands, comprised of both epithelial and mesenchymal components. Malignant transformation is exceptionally rare, with only a few cases reported. We report a case of a malignant cutaneous mixed tumor in an 86-year-old white man who presented with a pink indurated plaque on his left scapula. He had a history of nonmelanoma skin cancers, a stage IB malignant melanoma of a lower extremity and Gleason 4 + 3 prostate cancer treated with brachytherapy, external beam irradiation, and bicalutamide. A shave biopsy was performed and histologic examination revealed infiltrative single-unit atypical cells and small ducts in a superficially transected sclerotic dermis suggestive of a poorly differentiated adenocarcinoma. No epidermal connection was identified. Immunohistochemical studies revealed that the tumor was positive for CK7, CAM5.2, and mCEA and negative for CK20, epithelial membrane antigen, P63, prostate-specific antigen, prostatic specific acid phosphatase, and alpha methylacyl-coenzyme A racemase. A metastasis of the breast or upper digestive tract was favored, although a primary eccrine carcinoma was also considered. Imaging was performed and no other masses were identified. A slow Mohs excision was performed with negative margins. Microscopic examination revealed a biphasic neoplasm comprised of infiltrative epithelial strands and tubules consistent with an eccrine carcinoma in a hyalinized and chondromyxoid stroma within the dermis, arising from a well-circumscribed chondroid syringoma located in the deep dermis and subcutis. Areas of clear cell change, intracytoplasmic vacuolization, and mucin pools were noted. Multiple foci of perineural invasion were identified. Additional immunohistochemical studies revealed that the tumor was positive for S100 and negative for CK5/6, calponin, glial fibrillary acidic protein, GATA3, GCDFP-15, and mammoglobin. Based on the morphologic features and immunoprofile, this was diagnosed as a malignant cutaneous mixed tumor. This case highlights the importance of obtaining adequate tissue for histologic evaluation, as they can be confused with other skin neoplasms because of their clinically ambiguous presentations. Although rare, an accurate diagnosis is important given that long term follow-up is recommended because of the risk of local recurrence and both lymph node and distant metastases. PMID- 29533282 TI - Acute Effects of Walking on the Deformation of Femoral Articular Cartilage in Older Adults. AB - BACKGROUND AND PURPOSE: Although discomfort during walking is a common complaint in individuals with knee osteoarthritis (OA), how an acute bout of walking affects femoral cartilage remains unclear. Current literature has suggested that frontal plane knee malalignment (ie, varus and valgus) is associated with the initiation and/or progression of knee OA. However, the association between knee alignment and femoral cartilage deformation after an acute bout of loading has not yet been investigated. This study was aimed to compare the acute effects of walking on femoral cartilage deformation between older adults with and without knee OA. We also examined the association between frontal plane knee alignment and loading-induced femoral cartilage deformation. METHODS: Ten persons without OA (Kellgren Lawrence grading = 0 or 1; 5 females and 5 males; 55.0 [1.8] years of age; 78.8 [14.1] kg; 1.8 [0.2] m and 9 persons with OA (Kellgren Lawrence grading >=2; 4 females and 5 males; 55.6 [4.5] years of age; 97.4 [15.0] kg; 1.7 [0.1] m) participated. Each participant underwent magnetic resonance imaging before and immediately after 30 minutes of fast walking at 3 to 4 miles per hour. To obtain cartilage deformation postwalking, the medial and lateral femoral cartilage of the weight-bearing areas was segmented on participants' magnetic resonance imaging. Cartilage thickness was quantified by computing the average perpendicular distance between opposing voxels defining the edges of the femoral cartilage. Cartilage deformation of the medial and lateral femurs was defined as the percent changes in cartilage thickness after walking. Frontal plane knee alignment was obtained by measuring the angle between the long axes of femur and tibia. Independent t tests were used to compare cartilage deformation between the 2 groups. Pearson correlation coefficients were used to assess the association between cartilage deformation and knee alignment. RESULTS AND DISCUSSION: There was no significant difference in cartilage deformation between the OA and control groups in lateral (P= .69) or medial (P = .87) femur. A significant correlation was found between lateral femoral cartilage deformation and increased knee valgus alignment (r= 0.497; P = .03). No difference was found between medial femoral cartilage deformation and frontal plane knee alignment (r = 273; P = .26). CONCLUSIONS: This is the first study comparing the acute effects of walking on femoral cartilage deformation between older adults with and without knee OA. Although there was not a difference in walking-induced femoral cartilage deformation between the OA and control groups, knee valgus was related to lateral femoral cartilage deformation after walking. Our findings suggested that walking exercises may be used safely in older adults without knee malalignment. PMID- 29533283 TI - Involvement of Acute Care Physical Therapists in Care Transitions for Older Adults Following Acute Hospitalization: A Cross-sectional National Survey. AB - BACKGROUND AND PURPOSE: Recent evidence has suggested physical therapist involvement in care transitions after hospitalization is associated with reduced rates of hospital readmissions. However, little is known about how physical therapists participate in care transitions for older adults, the content of care communications, and the facilitators and barriers of implementing evidence-based care transition strategies into practice. Thus, the purpose of this article is to evaluate participation in care transition activities known to influence readmission risk among older adults, and understand perceptions of and barriers to participation in these activities. METHODS: We developed a survey questionnaire to quantify hospital-based physical therapist participation in care transitions and validated it using cognitive interviewing. It was introduced to a cross-sectional national sample of physical therapists who participate in the Academy of Acute Care Physical Therapy electronic discussion board using a SurveyMonkey tool. RESULTS AND DISCUSSION: More than 90% of respondents agreed they routinely recommended a discharge location and provided recommendations for durable medical equipment for patients at the time of hospital discharge. Respondents did not routinely initiate communication with therapists in other care settings, or follow up with patients to determine whether recommendations were followed. A majority of respondents agreed their facilities would not consider many key care transition activities to count as productive time.This survey provides a novel insight into how hospital-based physical therapists participate in care transitions. Communications between rehabilitation providers across care settings are infrequent, even those communications recommended to help reduce readmissions. However, administrative barriers were elucidated in this study that may help explain lack of therapist involvement. CONCLUSIONS: Physical therapists' communications across health care setting about older adults discharging from acute care hospitalization are infrequent, but may represent a meaningful intervention target for future studies. Future research is needed to evaluate best practices for hospital-based physical therapists during care transitions. PMID- 29533284 TI - POSTERIOR FUNDUS HEMORRHAGES: Frequency and Associated Factors: The Beijing Eye Study. AB - PURPOSE: To examine frequency and associations of retinal hemorrhages. METHODS: The population-based Beijing Eye Study included 3,468 individuals. Monoscopic fundus photographs were examined for hemorrhages. RESULTS: Retinal hemorrhages were detected in 515 eyes (429 individuals) (prevalence: 7.6%; 95% confidence interval [CI]: 7.0-8.0 per eye; 12.7%; 95% CI: 11.7-13.7 per person). Higher prevalence of retinal hemorrhages was correlated (multivariate analysis) with higher systolic blood pressure (P < 0.001; odds ratio: 1.02; 95% CI: 1.01-1.03), higher prevalence of diabetic retinopathy (P < 0.001; odds ratio: 121; 95% CI: 61 240), and higher prevalence of retinal vein occlusions (P < 0.001; odds ratio: 27; 95% CI: 17-42). Retinal hemorrhages were due to diabetic retinopathy (189 [36.7%] eyes), retinal vein occlusions (n = 65 [12.6%]), posterior vitreous detachment (n = 23 [4.5%]), glaucoma (n = 14 [2.7%]), exudative age-related macular degeneration (n = 8 [1.6%]), hypertensive retinopathy (n = 10 [1.9%]), and exudative myopic maculopathy (n = 1 [0.2%]). Retinal hemorrhages without evident ocular cause ("NOH") were detected in 204 (3.0%) eyes (or 39.6% of all retinal hemorrhages). Higher prevalence of NOHs was correlated with higher systolic blood pressure (P < 0.001; odds ratio: 1.02; 95% CI: 1.01-1.03) after adjusting for blood glucose concentration and prevalence of cortical cataract. CONCLUSION: In a population-based recruited cohort of individuals aged 50+ years, prevalence of any fundus hemorrhage was about 8% per eye and 13% per individual. Approximately 60% of the hemorrhages were due to ocular reasons, mainly diabetic retinopathy, retinal vein occlusions, and posterior vitreous detachment, whereas 40% of the bleedings were not evidently associated with ophthalmologic causes but strongly with elevated systolic blood pressure. PMID- 29533289 TI - Translational Research in Anesthesia: Animals Vs. Humans. PMID- 29533292 TI - Taking Pains with Aloe for More Than 35 Centuries: From Tightening Skin to Loosening Bowels. PMID- 29533291 TI - Dr. Brown Doubles Down: A With-and-without Trade Card for Laughing Gas Anesthesia. PMID- 29533294 TI - Dibucaine, Cinchocaine, or Nupercaine? CIBA's Trademarked Long-acting Amide Local Anesthetic. PMID- 29533293 TI - Monkeying Outside Central Park Zoo: Hasbrouck Advertises His Nitrous Oxide. PMID- 29533295 TI - Dr. C. H. Cannon's Armamentarium: "Local Anaesthetics...Gas or Either". PMID- 29533296 TI - Streams of Unconsciousness I: Amnesia Reflected in Lethe. PMID- 29533297 TI - Bispectral Index and Detection of Noxious Stimuli. PMID- 29533298 TI - In Reply. PMID- 29533299 TI - Left Uterine Tilt for Cesarean Delivery Significantly Improves Maternal Hemodynamics and Should Not Be Considered Outdated Dogma. PMID- 29533300 TI - Neonatal Outcome after Maternal Supine Position for Elective Cesarean Delivery under Spinal Anesthesia: Was the Umbilical Cord Blood Sampling Procedure Reliable? PMID- 29533301 TI - Left Lateral Table Tilt for Elective Cesarean Delivery under Spinal Anesthesia Should Not Be Abandoned. PMID- 29533302 TI - In Reply. PMID- 29533303 TI - Brief Report: Changes in Plasma RANKL-Osteoprotegerin in a Prospective, Randomized Clinical Trial of Initial Antiviral Therapy: A5260s. AB - BACKGROUND: The contributions of the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) axis to cardiovascular and bone disease in treated HIV-1 infection are not well defined. SETTING: Prospective, observational, longitudinal study. METHODS: In a subset analysis of a prospective randomized clinical trial, 234 HIV-1-infected antiretroviral therapy-naive participants received tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir and achieved plasma HIV-1 RNA <50 copies per milliliter by week 24 and thereafter. Associations between plasma RANKL, OPG, or RANKL/OPG ratio levels with total, hip, and spine bone mineral density (BMD) loss or progression of carotid artery intima-media thickness were assessed longitudinally over 96 weeks. RESULTS: Over 96 weeks, all treatment groups had similar and sustained declines in plasma RANKL, increases in plasma OPG, and subsequently, decreases in the RANKL/OPG ratio. There were no associations between plasma RANKL or RANKL/OPG ratio levels with total, hip, and spine BMD loss or progression of carotid artery intima-media thickness; however, plasma OPG in successfully treated HIV-infected patients (week 48 and 96) was associated with spine BMD loss. CONCLUSIONS: In virologically suppressed HIV-infected patients, the evolution of bone disease could be linked to plasma OPG levels; however, the role of plasma levels of RANKL and RANKL/OPG ratio in the prediction of morbidity in treated HIV-1 infection may be limited. PMID- 29533305 TI - Has the Proportion of Combat-Related Amputations That Develop Heterotopic Ossification Increased? AB - OBJECTIVES: To determine what proportion of residual limbs formed heterotopic ossification (HO) in amputations sustained by US service members, the injury profile of these amputations, and what effect the number of limb amputations sustained has on resource utilization. DESIGN: Retrospective review. SETTING: A tertiary military medical center. PATIENTS: Four-hundred seventy-one consecutive patients with 714 combat-related amputations were treated at our institution between September 2009 and August 2014. Four-hundred thirty-nine amputations had radiographic follow-up beyond 2 months of injury and met the criteria for study inclusion. MAIN OUTCOME MEASURE: Formation and grade of HO. RESULTS: HO was present in 399 of 439 (91%) residual limbs, including 211 of 216 (98%) transfemoral amputations. Dismounted improvised explosive device blast injury resulted in HO development in 346 of 372 (93%) residual limbs compared with 36 of 44 (82%) in mounted improvised explosive device blast injury [P = 0.014; odds ratio (OR) 2.96, 95% confidence interval (CI), 1.25-7.04]. As the number of amputations per patient increased, so too did blood product utilization [including packed red blood cells (P < 0.001), fresh frozen plasma (P < 0.001), and platelets (P < 0.001)]; the number of days on a ventilator (P < 0.001), in the intensive care unit (P < 0.001), and in the hospital (P = 0.007). CONCLUSIONS: HO prevalence in the traumatic amputations of war wounded has increased compared with earlier studies, which is temporally associated with higher rates of increasingly severe injuries due to dismounted blast. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29533304 TI - High Medication Possession Ratios Associated With Greater Risk of Virologic Failure Among Youth Compared With Adults in a Nigerian Cohort. AB - BACKGROUND: Medication possession ratio (MPR) is widely used as a measure of adherence to antiretroviral therapy (ART). Many adolescents and young adults (AYA) experience ART adherence challenges. Our objective was to determine whether the relationship between MPR and virologic failure (VF) is consistent between AYA and older adults in Nigeria. METHODS: We conducted a retrospective study of AYA (aged 15-25 years) and adults (aged >25 years) who initiated ART between January 2009 and December 2012 at 10 university-affiliated HIV clinics in Nigeria. We used multivariate generalized linear models to assess the relationship between age, MPR (ART doses dispensed)/(days since ART initiation), and risk of VF (HIV RNA >1000 copies/mL) in the 1st year on ART. RESULTS: The cohort included 1508 AYA and 11,376 older adults. VF was more common in AYA than older adults (30% vs. 24% P < 0.01). Overall, 74% of patients had optimal, 16% suboptimal, and 9% poor adherence (MPR >94%, 80%-94%, and <80%, respectively). AYA attended fewer pharmacy-only visits than older adults (5 vs. 6, P < 0.001). Higher MPR was associated with decreased rate of VF (80%-94%, accounting rate of return 0.57; >94% accounting rate of return 0.43, P < 0.001 vs. MPR <80%). Among those with optimal adherence by MPR, 26% of AYA had VF, a risk that was 20% higher than for older adults with optimal adherence (P < 0.001). CONCLUSIONS: In this Nigerian cohort, MPRs were high overall, and there was a strong association between low MPR and risk of VF. Nonetheless, 26% of AYA with high MPRs still had VF. Understanding the discrepancy between MPR and viral suppression in AYA is an important priority. PMID- 29533306 TI - Sarcopenia Is Predictive of 1-Year Mortality After Acetabular Fractures in Elderly Patients. AB - OBJECTIVES: To determine whether sarcopenia is an independent predictor of mortality in geriatric acetabular fractures. DESIGN: Retrospective cohort. SETTING: American College of Surgeons Level I trauma center. PATIENTS/PARTICIPANTS: One hundred and forty-six patients over the age 60 with acetabular fractures treated at our institution over a 12-year period. MAIN OUTCOME MEASUREMENTS: The primary outcome was 1-year mortality, collected using the Social Security Death Index. We used the psoas:lumbar vertebral index (PLVI), calculated using the cross-sectional area of the L4 vertebral body and the left and right psoas muscles, to assess for sarcopenia. RESULTS: Using a multivariate logistic regression model, we found that low PLVI was associated with increased 1 year mortality (P = 0.046) when controlling for age, gender, Charlson Comorbidity Index, Injury Severity Score (ISS), smoking status, and associated pelvic ring injury. Increasing age and ISS also showed a relationship with 1-year mortality in this cohort (P < 0.001, P < 0.001, respectively). We defined sarcopenia as those patients in the lowest quartile of PLVI. The mortality rate of this cohort was 32.4%, compared with 11.0% in patients without sarcopenia (odds ratio 4.04; 95% confidence interval 1.62-10.1). Age >75 years, ISS >14, and sarcopenia had 1 year mortality rates of 37.1%, 30.9%, and 32.4%, respectively. In patients with all 3 factors, the mortality rate was 90%. CONCLUSION: Sarcopenia is an independent risk factor for 1-year mortality in elderly patients with acetabular fractures. This study highlights the importance of objective measures to assess frailty in elderly patients who have sustained fractures about the hip and pelvis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29533308 TI - Is the Optic Nerve Head Structure Impacted by a Diagnostic Lumbar Puncture in Humans? PMID- 29533307 TI - Does Continuous Video-EEG in Patients With Altered Consciousness Improve Patient Outcome? Current Evidence and Randomized Controlled Trial Design. AB - Continuous video-EEG is recommended for patients with altered consciousness; as compared to routine EEG (lasting <30 minutes), it improves seizure detection, but is time- and resource-consuming. Although North American centers increasingly implement continuous video-EEG, most other (including European) hospitals have insufficient resources. Only one study suggested that continuous video-EEG could improve outcome in adults, and recent assessments challenge this view. This article reviews current evidence on the added value for continuous video-EEG in clinical terms and describes a design for a prospective study.In a multicenter randomized clinical trial (NCT03129438), adults with a Glasgow Coma Scale <=11 will be randomized 1:1 to continuous video-EEG (cEEG) for 30 to 48 hours or 2 routine EEG (rEEG), assessed through standardized American Clinical Neurophysiology Society (ACNS) guidelines. The primary outcome will be mortality at 6 months, assessed blindly. Secondary outcomes will explore functional status at 4 weeks and 6 months, intensive care unit (ICU) length of stay, infection rates, and hospitalization costs. Using a 2-sided approach with power of 0.8 and a error of 0.05, 2 * 174 patients are needed to detect an absolute survival difference of 14%, suggested by the single available study on the topic.This study should help clarifying whether cEEG has a significant impact on outcome and define its cost effectiveness. If the trial will result positive, it will encourage broader implementation of cEEG with consecutive substantial impact on health care and resource allocations. If not, it may offer a rationale to design a larger trial, and - at least for smaller centers - to avoid widespread implementation of cEEG, rationalizing personnel and device costs. PMID- 29533309 TI - alpha-Pyrrolidinopentiophenone ("Flakka") Catalyzing Catatonia: A Case Report and Literature Review. AB - : Synthetic cathinones are a class of novel psychoactive substances. alpha Pyrrolidinopentiophenone (alpha-PVP), or "Flakka", is one of these substances. Users often present acutely psychotic or agitated. We present the case of a 20 year-old male without prior psychiatric history who was brought to the hospital by his family because of increasingly bizarre and erratic behavior after reported ingestion of Flakka. What ensued was a prolonged course of psychosis and severe catatonia. Synthetic cathinones are thought to cause catatonia in approximately 1% of cases. Awareness of the possible presentations associated with alpha-PVP intoxication is increasingly important and should be further explored, as they can have important implications in setting expectations for care. Additionally, providers should have a low threshold for asking patients about bath salt ingestion. PMID- 29533311 TI - Nationwide Trend of Sepsis: A Comparison Among Octogenarians, Elderly, and Young Adults. AB - OBJECTIVE: We aimed to compare the sepsis incidence, mortality rates, and primary sites of infection among adult, elderly, and octogenarian patients with sepsis. DESIGN: Population-based cohort study. SETTING: The entire health insurance claims data of Taiwan, which enrolled 99.8% of the 23 million Taiwanese population. PATIENTS: Sepsis patients were identified by International Classification of Diseases, 9th Edition, Clinical Modification codes for both infection and organ dysfunction from January 1, 2002, to December 31, 2012. Patients were categorized into three age groups: 1) adults (18-64 yr); 2) elderly (65-84 yr); and 3) oldest old (>= 85 yr). The 30-day all-cause mortality was verified by a linked national death certificate database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 2002 to 2012, we identified 1,259,578 patients with sepsis, of which 417,328 (33.1%) were adults, 652,618 (51.8%) were elderly, and 189,632 (15.1%) were oldest old. We determined that the incidence of sepsis in the oldest old was 9,414 cases per 100,000 population on 2012, which was 31-fold greater than the adult incidence (303 cases per 100,000 population) and three-fold greater than the elderly incidence (2,908 cases per 100,000 population). Despite the increasing trend in incidence, the mortality decreased by 34% for adults, 24% for elderly, and 22% for oldest old. However, systemic fungal infection was disproportionately increased in oldest old patients (1.76% annual increase) and the elderly patients (1.00% annual increase). CONCLUSION: The incidence of sepsis is disproportionately increased in elderly and oldest old patients. Despite the increasing trend in incidence, the mortality rate in geriatric patients with sepsis has decreased. However, the increased incidence of fungal infections in the geriatric population warrants further attention. PMID- 29533310 TI - Phenotyping Cardiac Arrest: Bench and Bedside Characterization of Brain and Heart Injury Based on Etiology. AB - OBJECTIVES: Cardiac arrest etiology may be an important source of between-patient heterogeneity, but the impact of etiology on organ injury is unknown. We tested the hypothesis that asphyxial cardiac arrest results in greater neurologic injury than cardiac etiology cardiac arrest (ventricular fibrillation cardiac arrest), whereas ventricular fibrillation cardiac arrest results in greater cardiovascular dysfunction after return of spontaneous circulation. DESIGN: Prospective observational human and randomized animal study. SETTING: University laboratory and ICUs. PATIENTS: Five-hundred forty-three cardiac arrest patients admitted to ICU. SUBJECTS: Seventy-five male Sprague-Dawley rats. INTERVENTIONS: We examined neurologic and cardiovascular injury in Isoflurane-anesthetized rat cardiac arrest models matched by ischemic time. Hemodynamic and neurologic outcomes were assessed after 5 minutes no flow asphyxial cardiac arrest or ventricular fibrillation cardiac arrest. Comparison was made to injury patterns observed after human asphyxial cardiac arrest or ventricular fibrillation cardiac arrest. MEASUREMENTS AND MAIN RESULTS: In rats, cardiac output (20 +/- 10 vs 45 +/- 9 mL/min) and pH were lower and lactate higher (9.5 +/- 1.0 vs 6.4 +/- 1.3 mmol/L) after return of spontaneous circulation from ventricular fibrillation cardiac arrest versus asphyxial cardiac arrest (all p < 0.01). Asphyxial cardiac arrest resulted in greater early neurologic deficits, 7-day neuronal loss, and reduced freezing time (memory) after conditioned fear (all p < 0.05). Brain antioxidant reserves were more depleted following asphyxial cardiac arrest. In adjusted analyses, human ventricular fibrillation cardiac arrest was associated with greater cardiovascular injury based on peak troponin (7.8 ng/mL [0.8-57 ng/mL] vs 0.3 ng/mL [0.0-1.5 ng/mL]) and ejection fraction by echocardiography (20% vs 55%; all p < 0.0001), whereas asphyxial cardiac arrest was associated with worse early neurologic injury and poor functional outcome at hospital discharge (n = 46 [18%] vs 102 [44%]; p < 0.0001). Most ventricular fibrillation cardiac arrest deaths (54%) were the result of cardiovascular instability, whereas most asphyxial cardiac arrest deaths (75%) resulted from neurologic injury (p < 0.0001). CONCLUSIONS: In transcending rat and human studies, we find a consistent phenotype of heart and brain injury after cardiac arrest based on etiology: ventricular fibrillation cardiac arrest produces worse cardiovascular dysfunction, whereas asphyxial cardiac arrest produces worsened neurologic injury associated with greater oxidative stress. PMID- 29533314 TI - EDITORIAL. PMID- 29533312 TI - Routine Use of Radiostereometric Analysis in Elective Hip and Knee Arthroplasty Patients: Surgical Impact, Safety, and Bead Stability. AB - BACKGROUND: Radiostereometric analysis (RSA) accurately assesses arthroplasty implant performance and is routinely used for research purposes. Because of its efficacy in detecting implant failure in research subjects, we deployed the use of RSA beads for routine surveillance in all elective total hip and total knee arthroplasty patients. METHODS: We retrospectively compared 143 patients who received RSA beads intraoperatively with 343 patients who did not receive RSA beads. Using RSA images, we assessed bead stability at 6 weeks and 1 year postoperatively. RESULTS: There were no intraoperative complications in the RSA group and two in the control group. No differences were found between groups for the surgical time and the expected blood loss. At 6 weeks, 99.5% of beads were considered to be stable, with stability increasing to 99.7% of beads at 1 year. CONCLUSION: The routine use of RSA bead insertion is a safe procedure and may provide the ability to assess implant fixation in clinical practice. PMID- 29533315 TI - Howard P. Kern, FACHE, President and CEO, Sentara Healthcare. PMID- 29533316 TI - Why Focusing on Professional Burnout Is Not Enough. PMID- 29533317 TI - Strengthening Community Through Strategy: Building a Premier Academic Medical Destination. PMID- 29533318 TI - Patient Perceptions of Servicescape in Healthcare: A Systematic Review of the Literature. AB - EXECUTIVE SUMMARY: Many hospitals are competing for survival in their service areas. Because of intense competition within markets, hospitals are developing strategies to differentiate themselves. One way to do so is to create a physical infrastructure and service environment that generate a positive impact on patient perceptions. The purpose of this study is to review the literature on servicescape (i.e., a total impression of a service encounter developed through the use of human senses) and its effects on service quality and patient outcomes in healthcare settings. Servicescape studies have taken place in various healthcare settings (i.e., teaching hospitals, dental clinics, outpatient clinics) in 10 countries. Although servicescape in healthcare settings is a rarely researched topic at both the national and international levels, research indicates a significant positive association between servicescape and patient perceptions, patient satisfaction, and patient emotions. In light of the increasing emphasis in quality and value-based purchasing initiatives on patient experience and outcomes, more servicescape research in healthcare settings is needed. This systematic review underscores this need and enhances the knowledge base in this area. PMID- 29533319 TI - PRACTITIONER APPLICATION: Patient Perceptions of Servicescape in Healthcare: A Systematic Review of the Literature. PMID- 29533320 TI - Patient Perception of Medication Communications in the Hospital: The Role of the Pharmacist. AB - EXECUTIVE SUMMARY: The patient experience in the hospital has become an increasingly important measure of how well a healthcare system functions. Poor experiences as reported by patients have been associated with decreased compliance to medication instructions as well as increased recovery time from illness. While other studies have demonstrated the benefit of pharmacist counseling during patient discharge, the benefit of pharmacist intervention during the patient's hospital stay remains to be seen. This study was an institutional review board-approved pre-/post-analysis assessing patients' perception of medication communications during hospitalization in an academic teaching hospital. An attempt to counsel all patients newly admitted to the hospital was made by pharmacy personnel. Patients on general medical-surgical units participated in a brief, five-question survey prior to and following the pharmacy initiative. Overall, the patient satisfaction with medication communications increased significantly. Patients' increased satisfaction with communications about their medications was attributed to the expansion of patient counseling through the pharmacy department initiative. PMID- 29533321 TI - PRACTITIONER APPLICATION: Patient Perception of Medication Communications in the Hospital: The Role of the Pharmacist. PMID- 29533322 TI - Maximizing Operational Efficiency Using an In-House Ambulatory Surgery Model at an Academic Medical Center. AB - EXECUTIVE SUMMARY: Given the rising costs of healthcare delivery and reimbursement constraints, large academic medical centers (AMCs) must improve efficiency while delivering high-quality care. With standardized cases and high volumes, ambulatory surgery is a high-value target for efficiency improvement. Mining a data set of more than 7,500 cases consisting of the three highest-volume ambulatory procedures in orthopedics, otolaryngology-head and neck surgery, and urology, we analyzed process times and wait times involved in patient flow. We examined differences among delayed versus early versus on-time cases, as well as differences in scheduled start times, day of the week, and each individual operating room. Our analysis found statistically and clinically significant differences in registration and setup wait times when comparing delayed versus early versus on-time cases. We then developed recommendations to increase value added time. Using activity-based cost accounting, we created a model to quantify economic impact. Hospitals can adopt these methods to identify operational bottlenecks and employ our financial model to forecast changes in revenue. Application of this model can position AMCs for success in an increasingly competitive landscape. PMID- 29533323 TI - PRACTITIONER APPLICATION: Operational Efficiency Using an In-House Ambulatory Surgery Model at an Academic Medical Center. PMID- 29533324 TI - The Effectiveness of a Comprehensive Wellness Assessment on Medication Adherence in a Medicare Advantage Plan Diabetic Population. AB - EXECUTIVE SUMMARY: The issue of medication nonadherence has generated significant interest because of its complexity from both cost and outcomes perspectives. Of the 3.2 billion prescriptions written annually in the United States, estimates indicate that half are not taken as prescribed, especially among patients with asymptomatic chronic conditions. The objective of this study was to assess whether a comprehensive wellness assessment (CWA) program helps improve medication adherence for oral diabetic medications, statins, and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACE/ARBs) in a Medicare Advantage (MA) plan diabetic population. The Centers for Medicare & Medicaid Services includes these medications among its triple-weighted measures.The researchers used a retrospective panel study employing administrative claims data and member month-level enrollment data for members who were newly diagnosed with diabetes since 2010, allowing for up to 5 years of follow-up. The treatment variable of interest was whether the enrollee had undergone a CWA in the 12 months prior to the study. Results for the full sample show that a CWA visit in the prior 12 months is significantly associated with increased adherence to statin medication (incidence rate ratio [IRR]: 1.022, t test: 2.51) and oral diabetes medication (IRR: 1.032, t-test: 3.00), but it is not significantly associated with adherence to ACE/ARB medication (IRR: 1.009, t test: 1.09). Results vary considerably in subsamples stratified by dual Medicare and Medicaid eligibility status, presence of certain chronic conditions, and age. CWAs are most beneficial when targeted toward dual-eligible members or members younger than 65. On the basis of these findings, improving medication adherence by targeting CWA visits to certain MA member subcategories may be more cost effective than using CWAs for the full MA membership. PMID- 29533325 TI - PRACTITIONER APPLICATION: The Effectiveness of a Comprehensive Wellness Assessment on Medication Adherence in a Medicare Advantage Plan Diabetic Population. PMID- 29533326 TI - Depressive Symptoms, Exercise Capacity, and Clinical Outcomes After Lung Transplantation. AB - OBJECTIVE: Depressive symptoms are common among lung transplant recipients and have been associated with worse clinical outcomes. However, few studies have examined the association between depressive symptoms assessed at multiple time points or behavioral mechanisms by which posttransplant depressive symptoms may confer greater clinical risk. We therefore examined the associations between depressive symptoms, exercise capacity, chronic lung allograft dysfunction (CLAD), and mortality prospectively in a large sample of lung transplant recipients. METHODS: Between July 2009 and February 2016, 251 lung transplant recipients were assessed before transplantation and again approximately 3 weeks and 3 months after transplant. Depressive symptoms were assessed using the Centers for Epidemiologic Studies of Depression scale. Functional exercise capacity was assessed using the 6-minute walk test. Cox proportional hazards models were used to examine the associations between depressive symptoms, exercise capacity, CLAD, and mortality. RESULTS: During a median (range) follow up of 4.5 (0.1 to 6.3) years, 53 participants (21%) died. Greater depressive symptoms (hazard ratio [HR] = 1.39 [95% CI = 1.05 to 1.84], p = .021) and poorer exercise capacity (HR = 0.58 [95% CI = 0.38 to 0.90], p = .021) assessed 3 months after transplant were both independently associated with mortality. Although greater depressive symptoms were associated with lower exercise capacity (beta = 0.14, p = .039), exercise capacity did not mediate the association between depressive symptoms and mortality. In secondary analyses, depressive symptoms were independently predictive of CLAD (HR = 1.29 [95% CI = 1.01 to 1.65], p = .045) and the composite outcome of CLAD and mortality in a clustered event model (HR = 1.30 [1.09 to 1.56], p = .005). CONCLUSIONS: Depressive symptoms are associated with mortality and CLAD after lung transplantation, independent of exercise capacity. PMID- 29533327 TI - Interactions Between Stress and Sex in Microbial Responses Within the Microbiota Gut-Brain Axis in a Mouse Model. AB - OBJECTIVE: Animal models are frequently used to examine stress response, but experiments seldom include females. The connection between the microbiota-gut brain axis and behavioral stress response is investigated here using a mixed-sex mouse cohort. METHODS: CF-1 mice underwent alternating days of restraint and forced swim for 19 days (male n = 8, female n = 8) with matching numbers of control animals at which point the 16S rRNA genes of gut microbiota were sequenced. Mixed linear models accounting for stress status and sex with individuals nested in cage to control for cage effects evaluated these data. Murine behaviors in elevated plus-maze, open-field, and light/dark box were investigated. RESULTS: Community-level associations with sex, stress, and their interaction were significant. Males had higher microbial diversity than females (p = .025). Of the 638 operational taxonomic units detected in at least 25% of samples, 94 operational taxonomic units were significant: 31 (stress), 61 (sex), and 34 (sex-stress interaction). Twenty of the 39 behavioral measures were significant for stress, 3 for sex, and 6 for sex-stress. However, no significant associations between behavioral measures and specific microbes were detected. CONCLUSIONS: These data suggest sex influences stress response and the microbiota gut-brain axis and that studies of behavior and the microbiome therefore benefit from consideration of how sex differences drive behavior and microbial community structure. Host stress resilience and absence of associations between stress induced behaviors with specific microbes suggests that hypothalamic-pituitary adrenal axis activation represents a threshold for microbial influence on host behavior. Future studies are needed in examining the intersection of sex, stress response, and the microbiota-gut-brain axis. PMID- 29533328 TI - Can Fat-plug Myringoplasty Be a Good Alternative to Formal Myringoplasty? A Systematic Review and Meta-analysis. AB - OBJECTIVE: This study reviewed available literature to evaluate the success rate of fat myringoplasty compared with methods using other graft materials and suggests proper indications for this procedure. DATA SOURCES: Studies reporting the success rate of fat myringoplasty were systematically reviewed by searching the MEDLINE, PubMed, and Embase databases for studies published from database inception to 2017. STUDY SELECTION: The following terms were used for the literature search: ("Fat" OR "Adipose") and ("Myringoplasty" OR "Tympanoplasty"). DATA EXTRACTION: Eight case series reported the data of perforation size and audiologic results. The success rate varied according to the perforation size with a cutoff value of 3 to 5 mm in length or 30% of the total tympanic membrane area. The success rate in anterior perforation was lower than that in other sites, ranging from 76.7 and 85.2% to 84.5 and 91.7%, respectively. The meta analysis was performed on 10 articles. The overall success rate in fat myringoplasty and paper patch technique was not significantly different, while the success rate of fat myringoplasty was lower than that for the conventional myringoplasty technique using fascia or perichondrium (OR 0.63, 95% CI 0.49 0.80). Hyaluronic acid showed a significantly higher success rate than fat myringoplasty (90.1% versus 69.9%) (OR 0.20, 95% CI 0.09-0.46). CONCLUSIONS: The success rate of fat myringoplasty may be associated with the perforation site and size. The success rate of fat myringoplasty was equivalent to that of the paper patch but inferior to a conventional method using perichondrium or fascia. PMID- 29533329 TI - Right Ear Advantage of Speech Audiometry in Single-sided Deafness. AB - BACKGROUND: Postlingual single-sided deafness (SSD) is defined as normal hearing in one ear and severely impaired hearing in the other ear. A right ear advantage and dominance of the left hemisphere are well established findings in individuals with normal hearing and speech processing. Therefore, it seems plausible that a right ear advantage would exist in patients with SSD. METHODS: The audiometric database was searched to identify patients with SSD. Results from the German monosyllabic Freiburg word test and four-syllabic number test in quiet were evaluated. Results of right-sided SSD were compared with left-sided SSD. Statistical calculations were done with the Mann-Whitney U test. RESULTS: Four hundred and six patients with SSD were identified, 182 with right-sided and 224 with left-sided SSD. The two groups had similar pure-tone thresholds without significant differences. All test parameters of speech audiometry had better values for right ears (SSD left) when compared with left ears (SSD right). Statistically significant results (p < 0.05) were found for a weighted score (social index, 98.2 +/- 4% right and 97.5 +/- 4.7% left, p < 0.026), for word understanding at 60 dB SPL (95.2 +/- 8.7% right and 93.9 +/- 9.1% left, p < 0.035), and for the level at which 100% understanding was reached (61.5 +/- 10.1 dB SPL right and 63.8 +/- 11.1 dB SPL left, p < 0.022) on a performance-level function. CONCLUSION: A right ear advantage of speech audiometry was found in patients with SSD in this retrospective study of audiometric test results. PMID- 29533330 TI - Picosecond Infrared Laser (PIRL) Application in Stapes Surgery-First Experience in Human Temporal Bones. AB - OBJECTIVE: Using a contact-free laser technique for stapedotomy reduces the risk of mechanical damage of the stapes footplate. However, the risk of inner ear dysfunction due to thermal, acoustic, or direct damage has still not been solved. The objective of this study was to describe the first experiences in footplate perforation in cadaver tissue performed by the novel Picosecond-Infrared-Laser (PIRL), allowing a tissue preserving ablation. PATIENTS AND INTERVENTION: Three human cadaver stapes were perforated using a fiber-coupled PIRL. The results were compared with footplate perforations performed with clinically applied Er:YAG laser. Therefore, two different laser energies for the Er:YAG laser (30 and 60 mJ) were used for footplate perforation of three human cadaver stapes each. MAIN OUTCOME MEASURE: Comparisons were made using histology and environmental scanning electron microscopy (ESEM) analysis. RESULTS: The perforations performed by the PIRL (total energy: 640-1070 mJ) revealed a precise cutting edge with an intact trabecular bone structure and no considerable signs of coagulation. Using the Er:YAG-Laser with a pulse energy of 30 mJ (total energy: 450-600 mJ), a perforation only in the center of the ablation zone was possible, whereas with a pulse energy of 60 mJ (total energy: of 195-260 mJ) the whole ablation zone was perforated. For both energies, the cutting edge appeared irregular with trabecular structure of the bone only be conjecturable and signs of superficial carbonization. CONCLUSION: The microscopic results following stapes footplate perforation suggest a superiority of the PIRL in comparison to the Er:YAG laser regarding the precision and tissue preserving ablation. PMID- 29533331 TI - Bilateral Cochlear Implantation Versus Bimodal Hearing in Patients With Functional Residual Hearing: A Within-subjects Comparison of Audiologic Performance and Quality of Life. AB - OBJECTIVE: Evaluate performance and quality of life changes after sequential bilateral cochlear implantation in patients with preoperative residual hearing functioning in a bimodal hearing configuration. STUDY DESIGN: Retrospective analysis using within-subjects repeated measures design. SETTING: Tertiary otologic center. PATIENTS: Twenty-two adult patients with bilateral sensorineural hearing loss who used bimodal hearing before second cochlear implant (CI) meeting the following criteria: 1) preoperative residual hearing (<=80 dB HL at 250 Hz) in the ear to be implanted, 2) implantation with current CI technology (2013 2016), 3) consonant-nucleus-consonant (CNC) speech recognition testing in the bimodal condition preoperatively and bilateral CI condition postoperatively. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: CNC and AzBio sentence scores in quiet and noise (+5 SNR). Subjective measures of communication difficulty and sound quality were also administered. RESULTS: Twenty-two patients (mean 64 yr, 68% men) were included. At an average follow-up of 11.8 months, CNC scores in the bilateral CI condition (mean 63%, standard deviation [SD] = 22) were significantly better than preoperative bimodal scores with repeated measures analysis (mean 55%, SD = 22) (p = 0.03). AzBio scores in quiet were also higher with bilateral CI (mean 76%, SD = 24) compared with bimodal listening (mean 69%, SD = 29) (p = 0.0007). Global abbreviated profile of hearing aid benefit (APHAB) and overall speech, spatial, and qualities of hearing (SSQ) scores exhibited significant improvement following bilateral implantation (p = 0.006 for both analyses). CONCLUSIONS: For patients using a bimodal hearing configuration with substantial residual hearing in the non-CI ear, bilateral cochlear implantation yields improved audiologic performance and better subjective quality of life, irrespective of the ability to preserve acoustic hearing during the second sided implantation. PMID- 29533332 TI - Speech Perception in Quiet and Noise With an Off the Ear CI Processor Enabling Adaptive Microphone Directionality. AB - OBJECTIVE: To investigate the impact of the wearing position of an off-the-ear processor (OTE) on speech perception in quiet and noise. PATIENTS: The study group consisted of 16 adult subjects with bilateral severe-to-profound sensorineural hearing loss, 2 of them unilaterally, and 14 bilaterally provided with cochlear implants. MAIN OUTCOME MEASURES: Speech perception in quiet and noise was measured for frontal presentation with the recipients behind-the-ear processor CP810 or CP910 and the OTE processor Kanso (Cochlear Limited, Sydney, Australia). Additionally, speech performance in noise with the OTE for spatially separated signal and noise sources was assessed. RESULTS: The recipients showed monosyllabic word recognition scores in quiet between 65 and 95% and speech reception thresholds in noise between 2.4 and -5.5 dB SNR with the OTE. For frontal presentation of speech and noise, application of the adaptive directional microphone (Beam) yielded a slight median decrement of 0.6 dB for the speech reception threshold compared with standard directionality. However, huge median improvements, ranging from -3.7 to -11.6 dB, for the three tested conditions with spatially separated sources (S0NIL, S0NCL, S0N180) were observed. CONCLUSION: The beamforming algorithm in the investigated OTE processor provides similar benefits as described in previous studies for behind-the-ear processors in conditions with spatially separated speech and noise sources. Adaptive microphone directionality can be successfully implemented in an OTE processor. The OTE processor's potential to increase usability, comfort, and cosmetics might not be compromised by a deterioration of speech performance. PMID- 29533333 TI - Early Fitting in Cochlear Implantation: Benefits and Limits. AB - OBJECTIVE: Evaluation of a shortened delay time between surgical placement of the cochlear implant (CI) device and processor activation to less than 8 days (early CI fitting). Assessment of benefits and limits of early fitting in terms of medical, technical, audiological, and subjective outcome. STUDY DESIGN: Prospective. SETTING: Tertiary referral center. PATIENTS: Forty-one patients scheduled for cochlear implant surgery divided into early fit (EF, n = 21) and control group (CG, n = 19). MAIN OUTCOME MEASURES: Questionnaires were used to evaluate technical, medical, and subjective outcomes associated with early fitting. Additional, electrode impedance and speech recognition scores were measured. These data, collected preoperative, at first activation and after 3 months were compared with the CG with standard fitting. RESULTS: The medical and audiological status of the EF subjects allowed early fitting in nearly all patients (20/21). Evidence of pain, delayed wound healing, or other compromises was equal in both study groups. Speech recognition scores show comparable development over time for EF and CG. Average electrode impedance was significantly higher in the CG at first activation. CONCLUSIONS: Early fitting of the sound processor is feasible and did not compromise wound healing or generates additional pain. During the first month following surgery, reduction of wound swelling can be expected. Hence, regular inspection of magnet strength is recommended at follow-ups. Over all, early activation of their CI device was highly appreciated by nearly all patients. PMID- 29533334 TI - Application of Regenerative Treatment for Tympanic Membrane Perforation With Cholesteatoma, Tumor, or Severe Calcification. AB - OBJECTIVE: To apply regenerative treatment for tympanic membrane (TM) perforation to patients with severe calcification of the TM, cholesteatomas, or tumors localized to the tympanic cavity. STUDY DESIGN: Controlled clinical pilot study. SETTING: General hospitals. PATIENTS: Forty-five patients (age: 8-85; M = 19, F = 26) were selected from patients with or without TM perforation for the regenerative treatment. Twenty-five patients had cholesteatomas, 3 had tumors, and 17 had severe TM calcification. Patients were classified into three groups based on TM perforation size: less than 1/3 of the TM as Grade I (n = 5), 1/3 to 2/3 as Grade II (n = 19), and over 2/3 as Grade III (n = 21). Twenty patients who underwent standard tympanoplasty type I were selected as historical controls. MATERIALS AND METHODS: Materials for the TM repair included gelatin sponge with basic fibroblast growth factor and fibrin glue. After lesions were removed through the TM perforation, gelatin sponge immersed in basic fibroblast growth factor was placed over the perforation. Fibrin glue was then dripped onto the sponge. Treatment efficacy was evaluated 6 months posttreatment. RESULTS: Complete closure of the TM perforation was achieved in 91% (n = 41/45) of the patients in this regenerative treatment. Improvement in average hearing levels and air-bone gap were much better with this treatment than in the historical control group. CONCLUSION: This new regenerative therapy is useful not only for patients with simple TM perforations but also for those with cholesteatomas, tumors, or severe calcification without requiring conventional surgical procedures. This regenerative therapy is an easy, safe, cost-effective, and minimally-invasive treatment. PMID- 29533335 TI - Video Head Impulse Test (vHIT): The Role of Corrective Saccades in Identifying Patients With Vestibular Loss. AB - OBJECTIVE: 1) Characterize corrective saccades (CS) in normal controls, and 2) examine the sensitivity of the video head impulse test (vHIT) for identifying vestibular loss using both gain and CS. STUDY DESIGN: Prospective combined with retrospective review. SETTING: Tertiary referral center. PATIENTS: Seventy subjects with normal vestibular function served as controls (mean age, 44.1 yr; range, 10-78) and data from 49 patients with unilateral and bilateral vestibular loss was retrospectively reviewed (mean age, 50; range, 7-81). INTERVENTION: vHIT; individual horizontal head impulses were then analyzed in MATLAB. MAIN OUTCOME MEASURES: Horizontal vHIT gain, CS peak velocity, frequency, and latency. RESULTS: There was not an age effect for CS velocity or latency, and only a weak relationship between CS frequency and age in the control group. Gain and CS latency were the only parameters affected by impulse side, demonstrating higher gain and longer latency on the right. The group with vestibular loss had significantly lower mean vHIT gain, higher mean CS frequency, higher mean CS velocity, earlier CS latency, and smaller mean CS standard deviations of the latency compared with the control group.When all factors were analyzed separately by logistic regression, vHIT gain provided the best classification (83.8%), closely followed by CS frequency (83.1%). Using a two variable approach (both gain and CS frequency) yielded the best diagnostic accuracy (overall classification = 84.6%). CONCLUSIONS: Along with gain, incorporating CS frequency in interpreting vHIT improves diagnostic accuracy. A repeatable CS (>81.89%) and/or low gain (<0.78) indicate vestibular loss. PMID- 29533336 TI - Diagnoses of Dizziness- and Vertigo-related Disorders in ENT Practices in Germany. AB - AIM: The aim of this study was to analyze the prevalence of dizziness- and vertigo-related diagnoses in ear, nose, and throat (ENT) practices in Germany and the associated demographic characteristics based on data from a representative nationwide practice database. METHOD: The study sample included patients from 138 ENT practices in Germany who received dizziness- and vertigorelated diagnoses (ICD-10 code) between January 2012 and December 2015. Collected parameters included age, sex, insurance status, prescribed medication (anatomical therapeutic chemical [ATC] class), and referrals to other specialists and hospitals. RESULTS: A total of 107,458 patients were available for analysis. Most common diagnoses were "dizziness and giddiness" (67.7%), "benign paroxysmal vertigo" (10.2%) and "disorder of vestibular function, unspecified" (7.2%). Referrals and admissions were made in 12.8%, mostly to radiologists (7.7%), followed by neurologists (3.7%), and hospitals (1.4%). Most referrals were made for unspecific diagnoses and for "vestibular neuronitis." The rate of medical prescriptions was 37.3%, with the most common prescription being for antivertigo preparations. CONCLUSIONS: Dizziness- and vertigo-related disorders are frequently diagnosed in ENT practices in Germany. The majority of these diagnoses are unspecific and lead to an increased rate of referrals and hospital admissions. The medical prescription rate, especially of antivertigo preparations, was high, even among patients with benign paroxysmal positioning vertigo. This study reflects a mostly pragmatic approach to a complex diagnostic and therapeutic challenge in daily ENT practice as well as the limited ability of the ICD-10 system to classify the underlying etiology. PMID- 29533337 TI - A Relationship Between Blood Levels of Otolin-1 and Vitamin D. AB - OBJECTIVE: Low vitamin D levels have been associated with and could play a role in the pathogenesis of idiopathic benign paroxysmal positional vertigo (iBPPV). Since otoconia degeneration contributes to iBPPV and a lack of vitamin D may impact otoconia structure and integrity, we proposed a negative association between vitamin D levels and levels of a proposed circulatory biomarker for otolithic degeneration, otolin-1. STUDY DESIGN: Cross-sectional clinical study. SETTING: Clinical research center. PATIENTS: Seventy-nine men and women ranging in age from 22 to 95 years old without known vertigo. INTERVENTIONS: Diagnostic. MAIN OUTCOME MEASURES: Blood levels of 25-OH vitamin D and otolin-1. RESULTS: Previously, we had reported higher otolin-1 levels in older age groups. The majority of the subjects (83%) had vitamin D levels that were below 40 ng/ml. Vitamin D level was lowest in the young and increased with age before declining in subjects 70 years of age and older (p = 0.005). There was a negative correlation between vitamin D and otolin-1 levels of subjects over 70 (r = -0.36, p = 0.036). CONCLUSION: Our results demonstrate a relationship between vitamin D and otolin-1. The majority of our subjects had abnormally low vitamin D levels, but only those over 70 years of age showed a negative correlation with high otolin-1 levels. We postulate that a seasonal drop in vitamin D may not be sufficient for otoconia fragmentation and ultimately iBPPV, rather, chronically low vitamin D maybe required to induce otoconia degeneration. PMID- 29533338 TI - Radiosurgery of Glomus Tumors of Temporal Bone: a Meta-analysis. AB - OBJECTIVE: 1) Perform a meta-analysis of the available data on the outcomes of stereotactic radiosurgery (SRS) for the treatment of temporal bone glomus tumors (GT), and 2) evaluate the collective outcomes of SRS treatment with respect to tumor control. DATA SOURCES: A thorough literature search of the published English-language literature from 2011 to 2016 was performed in PubMed, Ovid, and Cochrane databases using the keywords ("Gamma Knife" or "CyberKnife" or "linear accelerator" or "radiosurgery") and ("glomus jugulare" or "jugular paraganglioma" or "glomus tympanicum"). STUDY SELECTION: Studies reporting outcomes of SRS for temporal bone GT were included. DATA EXTRACTION: Of 45 articles found, 15 studies met our inclusion and exclusion criteria and were selected for qualitative and quantitative analyses totaling 511 patients. DATA SYNTHESIS: Average margin dose, modality, isodose line, volume decrease, follow-up duration, and tumor control rate data were extracted and analyzed. CONCLUSION: Gamma Knife was the most commonly implemented radiosurgery modality and was used in eight studies. The mean marginal dose varied between 13.2 and 20 Gy. The pooled tumor control rate was 95.4% (95% CI: 93.6-97.2%) over a median follow-up duration ranging between 27.4 and 148 months. Clinical data on outcomes of SRS for the treatment of GTs are sparse and primarily limited to single institutional analyses, with considerable variation in tumor volume and follow-up duration. This meta-analysis provides an in-depth analysis of the available data in the literature and reviews the reported outcomes. Future studies on SRS for GT should include data on tumor growth before radiation as well as follow-up periods sufficiently long to identify true tumor control. PMID- 29533339 TI - Facial Nerve Trauma: A Call for Minimum Reporting Guidelines. PMID- 29533340 TI - Auricular Clyster, Otenchytes, and Pyoulcos: Precursors of the Ear Syringe. AB - OBJECTIVES/HYPOTHESIS: In Western medicine, the long history of the ear syringe dates back at least to the end of the 1st millennium BCE; but the corresponding Ancient Greek word surinx designates another tool. Other Greek and Latin words and phrases, in particular auricular clyster, otenchytes, and pyoulcos, were known as names of the ear syringe until modern times. The aim of this article is to study the Greek and Latin words and phrases referred to as names of the ear syringe up until modern times before syringe became the standard word. METHOD: Historical and philological review of ancient Greek and Latin medical literature dealing with the subject. RESULTS: Careful reading of ancient medical texts mentioning these tools shows a variety of shapes and uses: beside the piston driven syringe, the system of a bladder attached to a catheter remained in use throughout Antiquity; the otenchytes, being a piston-driven syringe, obviously was not used to squirt the liquid when the remedy put inside was warmed by a flame; the piston-driven pyoulcos is most likely of greater size, and never linked with ear care in Antiquity. CONCLUSION: Latin auricular clyster and Greek otenchytes and pyoulcos, in the few ancient texts in which they occur, designate tools of a large variety of shapes and uses, significantly different from Heron's description of piston-driven pyoulcos. PMID- 29533341 TI - IMPACT OF COCHLEAR IMPLANTATION ON COGNITIVE FUNCTIONS OF OLDER ADULTS: PILOT TEST RESULTS. PMID- 29533342 TI - RESPONSE TO WEAVER TS, SHAYMAN CS, HULLER TE. THE EFFECT OF HEARING AIDS AND COCHLEAR IMPLANTS ON BALANCE DURING GAIT. OTOL NEUROTOL 2017;38: 1327-1332. PMID- 29533343 TI - REPLY TO LETTER REGARDING "THE EFFECT OF HEARING AIDS AND COCHLEAR IMPLANTS ON BALANCE DURING GAIT". PMID- 29533344 TI - Tumor-to-background ratios of the maximum standardized uptake value could not indicate the prognosis of advanced high-grade serous ovarian cancer patients. AB - OBJECTIVE: Our study aimed to explore the prognostic influence of tumor-to background ratios (TBRs) of the maximum standardized uptake value (SUVmax) in advanced high-grade serous ovarian cancer (HGSC) patients. PATIENTS AND METHODS: We retrospectively investigated 51 advanced HGSC patients who underwent PET/CT before primary surgery at our hospital between January 2010 and June 2015. None of these patients received neoadjuvant chemotherapy. SUVmax of ovarian tumor (SUVmax-P) and background (SUVmax-B) were measured using a PET/CT workstation. TBR was calculated by SUVmax-P/SUVmax-B. Backgrounds included the liver, mediastinum, and muscle, and TBRs were noted as TBR-L, TBR-Me, and TBR-Mu, respectively. The chi-test was used to analyze the relationships between PET/CT parameters and several clinical features. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method and log-rank tests in univariate analyses. RESULTS: The median (range) follow-up duration was 27 (8-61) months. The median (range) PET/CT parameter values were as follows: SUVmax, 11.41 (3.24-24.14), TBR-L, 2.84 (2.08-11.93), TBL-Me, 2.09 (1.33-9.07), and TBR-Mu, 1.04 (0.56-14.02). The patients were categorized into low and high groups by the median values of these parameters above separately. A larger proportion of patients in the high TBR-Me group were chemoresistant compared with the low-value group (P=0.039). Neither the residual disease nor the ascites levels correlated with SUVmax or TBR values. There were no differences in progression-free survival and overall survival between the patients in the high and low TBR level groups. CONCLUSION: TBRs of SUVmax were not prognostic indicators for advanced HGSC patients. PMID- 29533345 TI - The value of whole-body contrast-enhanced 18F-FDG PET/CT imaging in the diagnosis and staging of patients with laryngeal carcinoma. AB - PURPOSE: This study aimed to determine whether intravenous contrast-enhanced dual phase fluorine-18--fluorodeoxyglucose (F-FDG) PET/CT scans provide additional diagnostic information compared with the MRI/CT in patients with laryngeal carcinoma during the initial staging. PATIENTS AND METHODS: Forty-five consecutive patients (44 men, one woman; mean age+/-SD, 67.0+/-9.0 years, range: 45-80 years) with carcinoma of the larynx who had MRI/CT and intravenous contrast enhanced PET/CT were enrolled. Each patient was scanned on the PET/CT system 1 h (early) and 2 h (delayed) after injection. The maximum standardized uptake values of the primary tumor, nodal, and distant metastatic lesions were measured using the dual-time-point method. Double-blinded F-FDG PET/CT and MRI/CT staging data were compared. The diagnostic accuracy of each modality was compared for primary tumors, nodal metastasis, and the tumor staging. RESULTS: For primary tumor detection, the sensitivity of PET/CT was higher (100%) than MRI/CT (93.3%). The accuracy for N status was 88.8% for PET/CT, being superior to MRI, which had an accuracy of 66.6%. The sensitivity and specificity for the detection of nodal metastasis were 100 and 84.6% for PET/CT compared with 100 and 50% for MRI/CT, respectively. As an initial TNM-staging method, the PET/CT had a diagnostic accuracy of 86.6% compared with 44.4% for MRI/CT. CONCLUSION: The results suggest that contrast-enhanced dual-phase PET/CT imaging contributes additional diagnostic information compared with the conventional methods for the initial evaluation of primary laryngeal tumors. F-FDG PET/CT has a good diagnostic performance for the detection of regional nodal and distant metastasis, and also synchronous tumors in patients with laryngeal carcinoma. PMID- 29533346 TI - Imaging approach in the evaluation of response to treatment of breast cancer. PMID- 29533347 TI - Superiority of 18F-NaF PET/CT for the detection of bone metastases. PMID- 29533348 TI - Re: "Mycobacterial Disease in Immunocompromised Children in a High Endemic Area". PMID- 29533349 TI - A Clear-cut Case of Acute Rheumatic Fever After Group G Streptococcal Pharyngitis in New Zealand. PMID- 29533350 TI - Amikacin Monotherapy for Treatment of Febrile Urinary Tract Infection Caused by Extended-Spectrum beta-Lactamase-producing Escherichia coli in Children. PMID- 29533351 TI - Useful References in Pediatric Cardiac Intensive Care: The 2017 Update. AB - OBJECTIVES: Pediatric cardiac intensive care continues to evolve, with rapid advances in knowledge and improvement in clinical outcomes. In the past, the Board of Directors of the Pediatric Cardiac Intensive Care Society created and subsequently updated a list of sentinel references focused on the care of critically ill children with congenital and acquired heart disease. The objective of this article is to provide clinicians with a compilation and brief summary of updated and useful references that have been published since 2012. DATA SELECTION: Pediatric Cardiac Intensive Care Society members were solicited via a survey sent out between March 20, 2017, and April 28, 2017, to provide important references that have impacted clinical care. The survey was sent to approximately 523 members. Responses were received from 45 members, of which some included multiple references. DATA EXTRACTION: Following review of the list of references, and removing editorials, references were compiled by the first and last author. The final list was submitted to members of the society's Research Briefs Committee, who ranked each publication. DATA SYNTHESIS: Rankings were compiled and the references with the highest scores included. Research Briefs Committee members ranked the articles from 1 to 3, with one being highly relevant and should be included and 3 being less important and should be excluded. Averages were computed, and the top articles included in this article. The first (K.C.U.) and last author (K.M.G.) reviewed and developed summaries of each article. CONCLUSIONS: This article contains a compilation of useful references for the critical care of children with congenital and acquired heart disease published in the last 5 years. In conjunction with the prior version of this update in 2012, this article may be used as an educational reference in pediatric cardiac intensive care. PMID- 29533352 TI - Variability in Antibiotic Use Across PICUs. AB - OBJECTIVES: To characterize and compare antibiotic prescribing across PICUs to evaluate the degree of variability. DESIGN: Retrospective analysis from 2010 through 2014 of the Pediatric Health Information System. SETTING: Forty-one freestanding children's hospital. SUBJECTS: Children aged 30 days to 18 years admitted to a PICU in children's hospitals contributing data to Pediatric Health Information System. INTERVENTIONS: To normalize for potential differences in disease severity and case mix across centers, a subanalysis was performed of children admitted with one of the 20 All Patient Refined-Diagnosis Related Groups and the seven All Patient Refined-Diagnosis Related Groups shared by all PICUs with the highest antibiotic use. RESULTS: The study included 3,101,201 hospital discharges from 41 institutions with 386,914 PICU patients. All antibiotic use declined during the study period. The median-adjusted antibiotic use among PICU patients was 1,043 days of therapy/1,000 patient-days (interquartile range, 977 1,147 days of therapy/1,000 patient-days) compared with 893 among non-ICU children (interquartile range, 805-968 days of therapy/1,000 patient-days). For PICU patients, the median adjusted use of broad-spectrum antibiotics was 176 days of therapy/1,000 patient-days (interquartile range, 152-217 days of therapy/1,000 patient-days) and was 302 days of therapy/1,000 patient-days (interquartile range, 220-351 days of therapy/1,000 patient-days) for antimethicillin-resistant Staphylococcus aureus agents, compared with 153 days of therapy/1,000 patient days (interquartile range, 130-182 days of therapy/1,000 patient-days) and 244 days of therapy/1,000 patient-days (interquartile range, 203-270 days of therapy/1,000 patient-days) for non-ICU children. After adjusting for potential confounders, significant institutional variability existed in antibiotic use in PICU patients, in the 20 All Patient Refined-Diagnosis Related Groups with the highest antibiotic usage and in the seven All Patient Refined-Diagnosis Related Groups shared by all 41 PICUs. CONCLUSIONS: The wide variation in antibiotic use observed across children's hospital PICUs suggests inappropriate antibiotic use. PMID- 29533353 TI - Cardiac Index Changes With Fluid Bolus Therapy in Children With Sepsis-An Observational Study. AB - OBJECTIVES: Fluid bolus therapy is the initial recommended treatment for acute circulatory failure in sepsis, yet it is unknown whether this has the intended effect of increasing cardiac index. We aimed to describe the effect of fluid bolus therapy on cardiac index in children with sepsis. DESIGN: A prospective observational cohort study. SETTING: The Emergency Department of The Royal Children's Hospital, Melbourne, VIC, Australia. PATIENTS: A convenience sample of children meeting international consensus criteria for sepsis with acute circulatory failure. INTERVENTION: Treating clinician decision to administer fluid bolus therapy. MEASUREMENTS AND MAIN RESULTS: Transthoracic echocardiography was recorded immediately before, 5 minutes after, and 60 minutes after fluid bolus therapy. Cardiac index was calculated by a pediatric cardiologist blinded to the timing of the echocardiogram. Cardiac index was calculated for 49 fluid boluses in 41 children. The median change in cardiac index 5 minutes after a fluid bolus therapy was +18.0% (interquartile range, 8.6 28.1%) and after 60 minutes was -6.0% (interquartile range, -15.2% to 3.0%) relative to baseline. Thirty-one of 49 fluid boluses (63%) resulted in an increase in cardiac index of greater than 10% at 5 minutes, and these participants were considered fluid responsive. This was sustained in four of 31 (14%) at 60 minutes. No association between change in cardiac index at 5 or 60 minutes and age, baseline mean arterial blood pressure, fluid bolus volume, and prior volume of fluid bolus therapy was found on linear regression. CONCLUSIONS: Fluid bolus therapy for pediatric sepsis is associated with a transient increase in cardiac index. Fluid responsiveness is variable and, when present, not sustained. The efficacy of fluid bolus therapy for achieving a sustained increase in cardiac index in children with sepsis is limited. PMID- 29533354 TI - A Multi-Institutional Simulation Boot Camp for Pediatric Cardiac Critical Care Nurse Practitioners. AB - OBJECTIVES: Assess the effect of a simulation "boot camp" on the ability of pediatric nurse practitioners to identify and treat a low cardiac output state in postoperative patients with congenital heart disease. Additionally, assess the pediatric nurse practitioners' confidence and satisfaction with simulation training. DESIGN: Prospective pre/post interventional pilot study. SETTING: University simulation center. SUBJECTS: Thirty acute care pediatric nurse practitioners from 13 academic medical centers in North America. INTERVENTIONS: We conducted an expert opinion survey to guide curriculum development. The curriculum included didactic sessions, case studies, and high-fidelity simulation, based on high-complexity cases, congenital heart disease benchmark procedures, and a mix of lesion-specific postoperative complications. To cover multiple, high-complexity cases, we implemented Rapid Cycle Deliberate Practice method of teaching for selected simulation scenarios using an expert driven checklist. MEASUREMENTS AND MAIN RESULTS: Knowledge was assessed with a pre /posttest format (maximum score, 100%). A paired-sample t test showed a statistically significant increase in the posttest scores (mean [SD], pre test, 36.8% [14.3%] vs post test, 56.0% [15.8%]; p < 0.001). Time to recognize and treat an acute deterioration was evaluated through the use of selected high fidelity simulation. Median time improved overall "time to task" across these scenarios. There was a significant increase in the proportion of clinically time sensitive tasks completed within 5 minutes (pre, 60% [30/50] vs post, 86% [43/50]; p = 0.003] Confidence and satisfaction were evaluated with a validated tool ("Student Satisfaction and Self-Confidence in Learning"). Using a five-point Likert scale, the participants reported a high level of satisfaction (4.7 +/- 0.30) and performance confidence (4.8 +/- 0.31) with the simulation experience. CONCLUSIONS: Although simulation boot camps have been used effectively for training physicians and educating critical care providers, this was a novel approach to educating pediatric nurse practitioners from multiple academic centers. The course improved overall knowledge, and the pediatric nurse practitioners reported satisfaction and confidence in the simulation experience. PMID- 29533357 TI - Predicting Bobsled Pushing Ability from Various Combine Testing Events. AB - The requisite combination of speed, power, and strength necessary for a bobsled push athlete coupled with the difficulty in directly measuring pushing ability makes selecting effective push crews challenging. Current practices by USA Bobsled and Skeleton (USABS) utilize field combine testing to assess and identify specifically selected performance variables in an attempt to best predict push performance abilities. Combine data consisting of 11 physical performance variables were collected from 75 subjects across two winter Olympic qualification years (2009 and 2013). These variables were sprints of 15-, 30-, and 60 m, a flying 30 m sprint, a standing broad jump, a shot toss, squat, power clean, body mass, and dry-land brake and side bobsled pushes. Discriminant Analysis (DA) in addition to Principle Component Analysis (PCA) was used to investigate two cases (Case 1: Olympians vs. non-Olympians; Case 2: National Team vs. non-National Team). Using these 11 variables, DA led to a classification rule that proved capable of identifying Olympians from non-Olympians and National Team members from non-National Team members with 9.33% and 14.67% misclassification rates, respectively. The PCA was used to find similar test variables within the combine that provided redundant or useless data. After eliminating the unnecessary variables, DA on the new combinations showed that 8 (Case 1) and 20 (Case 2) other combinations with fewer performance variables yielded misclassification rates as low as 6.67% and 13.33% respectively. Utilizing fewer performance variables can allow governing bodies in many other sports to create more appropriate combine testing that maximize accuracy, while minimizing irrelevant and redundant strategies. PMID- 29533356 TI - Mothers and Fathers Experience Stress of Congenital Heart Disease Differently: Recommendations for Pediatric Critical Care. AB - OBJECTIVE: To inform pediatric critical care practice by examining how mothers and fathers experience the stress of caring for a young child with congenital heart disease and use hospital and community supports. DESIGN: Qualitative study of mothers and fathers of young children with congenital heart disease. SETTING: Tertiary care pediatric hospital in the Mid-Atlantic region of the United States. SUBJECTS: Thirty-four parents (20 mothers, 14 fathers) from diverse backgrounds whose child previously underwent cardiac surgery during infancy. INTERVENTIONS: Subjects participated in semi-structured, individual interviews about their experiences and psychosocial needs at the time of congenital heart disease diagnosis, surgical admission, and discharge to home after surgery. Qualitative interview data were coded, and consistent themes related to emotional states, stressors, and supports were identified. MEASUREMENTS AND MAIN RESULTS: Fathers experience and respond to the stressors and demands of congenital heart disease in unique ways. Fathers often described stress from not being able to protect their child from congenital heart disease and the associated surgeries/pain and from difficulties balancing employment with support for their partner and care of their congenital heart disease child in the hospital. Fathers were more likely than mothers to discuss support from the work environment (coworkers/managers, flexible scheduling, helpful distraction) and were less likely to describe the use of hospital-based resources or congenital heart disease peer-to-peer supports. CONCLUSIONS: This study highlights the importance of understanding the paternal experience and tailoring interventions to the unique needs of both mothers and fathers. Opportunities for critical care practice change to promote the mental health of mothers and fathers following a diagnosis of congenital heart disease are discussed. PMID- 29533355 TI - Characterization of Pediatric In-Hospital Cardiopulmonary Resuscitation Quality Metrics Across an International Resuscitation Collaborative. AB - OBJECTIVES: Pediatric in-hospital cardiac arrest cardiopulmonary resuscitation quality metrics have been reported in few children less than 8 years. Our objective was to characterize chest compression fraction, rate, depth, and compliance with 2015 American Heart Association guidelines across multiple pediatric hospitals. DESIGN: Retrospective observational study of data from a multicenter resuscitation quality collaborative from October 2015 to April 2017. SETTING: Twelve pediatric hospitals across United States, Canada, and Europe. PATIENTS: In-hospital cardiac arrest patients (age < 18 yr) with quantitative cardiopulmonary resuscitation data recordings. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 112 events yielding 2,046 evaluable 60-second epochs of cardiopulmonary resuscitation (196,669 chest compression). Event cardiopulmonary resuscitation metric summaries (median [interquartile range]) by age: less than 1 year (38/112): chest compression fraction 0.88 (0.61-0.98), chest compression rate 119/min (110-129), and chest compression depth 2.3 cm (1.9 3.0 cm); for 1 to less than 8 years (42/112): chest compression fraction 0.94 (0.79-1.00), chest compression rate 117/min (110-124), and chest compression depth 3.8 cm (2.9-4.6 cm); for 8 to less than 18 years (32/112): chest compression fraction 0.94 (0.85-1.00), chest compression rate 117/min (110-123), chest compression depth 5.5 cm (4.0-6.5 cm). "Compliance" with guideline targets for 60-second chest compression "epochs" was predefined: chest compression fraction greater than 0.80, chest compression rate 100-120/min, and chest compression depth: greater than or equal to 3.4 cm in less than 1 year, greater than or equal to 4.4 cm in 1 to less than 8 years, and 4.5 to less than 6.6 cm in 8 to less than 18 years. Proportion of less than 1 year, 1 to less than 8 years, and 8 to less than 18 years events with greater than or equal to 60% of 60-second epochs meeting compliance (respectively): chest compression fraction was 53%, 81%, and 78%; chest compression rate was 32%, 50%, and 63%; chest compression depth was 13%, 19%, and 44%. For all events combined, total compliance (meeting all three guideline targets) was 10% (11/112). CONCLUSIONS: Across an international pediatric resuscitation collaborative, we characterized the landscape of pediatric in-hospital cardiac arrest chest compression quality metrics and found that they often do not meet 2015 American Heart Association guidelines. Guideline compliance for rate and depth in children less than 18 years is poor, with the greatest difficulty in achieving chest compression depth targets in younger children. PMID- 29533358 TI - Kinetic Analysis of Horizontal Plyometric Exercise Intensity. AB - Kossow, AJ, DeChiara, TG, Neahous, SM, and Ebben, WP. Kinetic analysis of horizontal plyometric exercise intensity. J Strength Cond Res 32(5): 1222-1229, 2018-Plyometric exercises are frequently performed as part of a strength and conditioning program. Most studies assessed the kinetics of plyometric exercises primarily performed in the vertical plane. The purpose of this study was to evaluate the multiplanar kinetic characteristics of a variety of plyometric exercises, which have a significant horizontal component. This study also sought to assess sex differences in the intensity progression of these exercises. Ten men and 10 women served as subjects. The subjects performed a variety of plyometric exercises including the double-leg hop, standing long jump, single-leg standing long jump, bounding, skipping, power skipping, cone hops, and 45.72-cm hurdle hops. Subjects also performed the countermovement jump for comparison. All plyometric exercises were evaluated using a force platform. Dependent variables included the landing rate of force development and landing ground reaction forces for each exercise in the vertical, frontal, and sagittal planes. A 2-way mixed analysis of variance with repeated-measures for plyometric exercise type demonstrated main effects for exercise type for all dependent variables (p <= 0.001). There was no significant interaction between plyometric exercise type and sex for any of the variable assessed. Bonferroni-adjusted pairwise comparisons identified a number of differences between the plyometric exercises for the dependent variables assessed (p <= 0.05). These findings should be used to guide practitioners in the progression of plyometric exercise intensity, and thus program design, for those who require significant horizontal power in their sport. PMID- 29533359 TI - Methodological Considerations on the Relationship Between the 1,500-M Rowing Ergometer Performance and Vertical Jump in National-Level Adolescent Rowers. AB - The purpose of the present study was to investigate whether three different approaches for evaluating squat jump performance were correlated to rowing ergometer performance in elite adolescent rowers. Fourteen young male competitive rowers (15.3 +/- 0.6 years), who took part in the French rowing national championships, performed a 1,500-m all-out rowing ergometer performance (P1500) and a squat jump (SJ) test. The performance in SJ was determined by calculating the jump height (HSJ in cm), a jump index (ISJ = HSJ . body mass . gravity, in J) and the mean power output (PSJ in W) from the Samozino et al.'s method. Furthermore, allometric modelling procedures were used to consider the importance of body mass (BM) in the assessment of HSJ, ISJ and PSJ, and their relationships with between P1500 and jump scores. P1500 was significantly correlated to HSJ (r2 = 0.29, P < 0.05), ISJ (r2 = 0.72, P < 0.0001) and PSJ (r2 = 0.86, P < 0.0001). Furthermore, BM explained at least 96% of the relationships between SJ and rowing performances. However, the similarity between both allometric exponents for PSJ and P1500 (1.15 and 1.04, respectively) indicates that BM could influence jump and rowing ergometer performances at the same rate, and that PSJ could be the best correlate of P1500. Therefore, the calculation of power seems to be more relevant than HSJ and ISJ to (i) evaluate jump performance, and (ii) infer the capacity of adolescent rowers to perform 1,500-m all-out rowing ergometer performance, irrespective of their body mass. This could help coaches to improve their training program and potentially identify talented young rowers. PMID- 29533360 TI - Sex Comparison of Knee Extensor Size, Strength and Fatigue Adaptation to Sprint Interval Training. AB - BACKGROUND: Regular sprint interval training (SIT) improves whole-body aerobic capacity and muscle oxidative potential, but very little is known about knee extensor anabolic or fatigue resistance adaptations, or whether effects are similar for males and females. The purpose of this study was to compare sex related differences in knee extensor size, torque-velocity relationship and fatigability adaptations to 12 weeks SIT. METHODS: Sixteen males and fifteen females (mean (SEM) age: 41 (+/-2.5) yrs) completed measurements of total body composition assessed by DXA, quadriceps muscle cross-sectional area (CSAQ) assessed by MRI, the knee extensor torque-velocity relationship (covering 0 - 240 degrees .sec) and fatigue resistance, which was measured as the decline in torque from the first to the last of 60 repeated concentric knee extensions performed at 180 degrees .sec. SIT consisted of 4 x 20 second sprints on a cycle ergometer set at an initial power output of 175% of power at VO2max, three times per week for 12 weeks. RESULTS: CSAQ increased by 5% (p=0.023) and fatigue resistance improved 4.8% (p=0.048), with no sex differences in these adaptations (sex comparisons: p=0.140 and p=0.282, respectively). Knee extensor isometric and concentric torque was unaffected by SIT in both males and females (p>0.05 for all velocities). CONCLUSIONS: 12 weeks SIT, totalling 4 minutes very intense cycling per week, significantly increased fatigue resistance and CSAQ similarly in males and females, but did not significantly increase torque in males or females. These results suggest that SIT is a time-effective training modality for males and females to increase leg muscle size and fatigue resistance. PMID- 29533361 TI - An investigation in to the positional running demands of elite Gaelic football players: how competition data can inform training practice. AB - PURPOSE: This study investigated the positional running demands of elite Gaelic football players during match-play and compared these demands with typical training activities used to prepare players for competition. METHODS: Global positioning system (GPS) data was obtained from thirty elite Gaelic football players (26.9 +/- 3.5 years, 182.8 +/- 6.1 cm, 84.6 +/- 8.1 kg) across a full season (13 competitive games and 78 training sessions). Only players who completed the full match and respective training sessions were included (n = 107 match files and n = 1,603 training files). Data was collected using 4-Hz GPS units (VX Sport, New Zealand). Mean high speed (>=17 km.h; m/min), mean speed (m/min), percentage at high speed (%) and mean sprint efforts (>=17 km.h; no./min) were recorded. Running variables were analysed across the 5 outfield positional lines in Gaelic football (full back [FB], half back [HB], midfield [MF], half forward [HF], full forward [FF]). RESULTS: For mean high speed running and mean speed, significant relationships (range r =.811 - .964 & r = .792 - .998 respectively) were found between competition and game-based training for players in the FB, HB, MF and FF lines (p<.05). Analyses of mean sprint efforts and percentage at high speed found positive correlations between competition and training activities across each of the positional lines. CONCLUSION: Appropriately designed training activities can ensure that the position-specific demands of elite Gaelic football competition are met using a game-based training approach. Collectively, these findings demonstrate the value of, and provide support for, the use of a game-based training approach as a method of preparing players for the physical demands of competition in elite Gaelic football. PMID- 29533362 TI - Antipsychotic-Induced Pisa Syndrome: A 2-Year Follow-up Study. AB - OBJECTIVES: Pisa syndrome is characterized by lateral trunk flexion. It is an uncommon adverse drug reaction in patients on antipsychotic medication. Although Pisa syndrome has been reported in patients on antipsychotic treatment, previous studies have not discussed the prognosis of patients with Pisa syndrome. We studied psychiatric patients with Pisa syndrome following antipsychotic treatment for a 2-year period. METHODS: From January 2012 to December 2014, 13 inpatients with Pisa syndrome following antipsychotic treatment were identified at our institution, from a prospectively collected database. These patients were studied for a 2-year period. RESULTS: The prevalence rate of Pisa syndrome during neuroleptic treatment was 0.45% in men and 0.37% in women, with a collective prevalence rate of 0.42%. The mean age of patients with Pisa syndrome was 47 years. Eight (61.5%) of the cases had a position with a tilt toward the right side. In 5 (38.5%) of the cases, a tilt toward the left side was observed. The average Cobb angle of the trunk was 17.3 (SD, 4.0) degrees. On presentation with Pisa syndrome within 3 months of medication modification, the pattern of trunk dystonia had a significantly shorter duration (P = .024) compared with that seen in the tardive-onset group. CONCLUSIONS: Pisa syndrome is an uncommon adverse event that can also be chronic or recurrent, especially in those with tardive onset. We should be aware of the risks in patients with the following predisposing factors: old age, chronic psychosis, long-term antipsychotic use, advanced drug-induced parkinsonism, and combined pharmacologic treatment. PMID- 29533363 TI - Treatment of Intermittent Explosive Disorder With Carbamazepine. PMID- 29533364 TI - Atomoxetine in the Treatment of Adolescent With Trichotillomania and Attention Deficit/Hyperactivity Disorder. PMID- 29533365 TI - Vaginal estrogen and mammogram results: case series and review of literature on treatment of genitourinary syndrome of menopause (GSM) in breast cancer survivors. AB - OBJECTIVE: To examine mammographic density before and after at least 1 year of vaginal estrogen use in a small cohort of healthy postmenopausal women and women with a personal history of breast cancer. METHODS: We extracted data via chart review of patients from a single practitioner's menopause specialty clinic in Baltimore, MD. Mammographic change was primarily determined via the Bi-RADS scoring system, including the Bi-RADS density score. In addition, we conduct a narrative review of the current literature on the usage of local estrogen therapy, and systemic and local alternatives in the treatment of genitourinary syndrome of menopause (GSM) in breast cancer survivors. RESULTS: Twenty healthy postmenopausal women and three breast cancer survivors fit our inclusion criteria. Amongst these two groups, we did not find an increase in mammographic density after at least 1 year and up to 18 years of local vaginal estrogen. Ospemifene use in one patient did not appear to be associated with any change in Bi-RADS score. Our narrative review found little data on the effects of vaginal estrogen therapy or newer alternative systemic therapies such as ospemifene on mammographic density. CONCLUSIONS: Low-dose vaginal estrogen use for 1 or more years in a small cohort of women with GSM did not appear to be associated with any changes in breast density or Bi-RADS breast cancer risk scores in the majority of study participants, including three breast cancer survivors. Larger long-term controlled clinical trials should be conducted to examine the effects of low-dose vaginal estrogen on mammographic density in women with and without a personal history of breast cancer. Furthermore, relative efficacy and risk of vaginal estrogen compared with other forms of treatment for GSM should also be studied in long-term trials. PMID- 29533366 TI - Effects of dietary and exercise intervention on weight loss and body composition in obese postmenopausal women: a systematic review and meta-analysis. AB - OBJECTIVE: This study examined the effects of dietary and exercise interventions on weight loss and body composition in overweight/obese peri- and postmenopausal women. METHODS: Medline, Central, Embase, and Google Scholar databases were searched for relevant trials conducted until December 31, 2016. Randomized controlled trials (RCTs) and prospective studies of overweight/obese peri- or postmenopausal women that examined the effects of dietary or exercise interventions, alone or combined, on weight loss were included. The primary outcome was percentage reduction in body weight. RESULTS: From 292 studies initially identified, 11 studies with 12 sets of participants were included. Both dietary and exercise intervention groups had significantly greater weight loss than control groups (diet vs control: difference in means = -6.55, 95% CI, -9.51 to -3.59, P < 0.001; exercise vs control: difference in means = -3.49, 95% CI, 6.96 to -0.02, P = 0.049). Combined dietary and exercise interventions resulted in greater weight loss than dietary interventions alone (diet plus exercise vs diet: difference in means = -1.22, 95% CI, -2.14 to -0.29, P = 0.010). Diet plus exercise resulted in greater fat loss (difference in means = -0.44, 95% CI, -0.67 to -0.20, P < 0.001) and greater lean mass loss (difference in means = -0.84, 95% CI, -1.13 to -0.55, P < 0.001) than diet alone. CONCLUSIONS: Dietary interventions reduced body weight and body composition profile parameters in peri and postmenopausal women more than exercise alone. The addition of exercise reinforced the effect of dietary interventions on changing body weight and composition. PMID- 29533368 TI - A randomized, double-blind, placebo-controlled trial of Chinese herbal medicine capsules for the treatment of premature ovarian insufficiency. AB - OBJECTIVE: This study was conducted to evaluate the treatment effectiveness of Chinese herbal medicine capsules containing the Yangyin Shugan formula (YYSG) in premature ovarian insufficiency (POI). METHODS: One-hundred forty-six women with POI participated in this stratified, randomized, double-blind, placebo-controlled clinical trial. Participants in two groups (n = 73 in each)-the YYSG group and control group-underwent treatment for 12 weeks. Outcome measures included the Chinese version Menopause-Specific Quality of Life questionnaire (CMS), serum levels of basal follicle-stimulating hormone (bFSH), basal estradiol, and anti Mullerian hormone (AMH), the antral follicle count (AFC), and ovarian peak systolic velocity (PSV; cm/s). RESULTS: Treatment with YYSG significantly reduced the total scores of the CMS at the end of the 12th week with statistical significance (P < 0.01); the vasomotor, psychosocial, physical, and sexual domains significantly improvement after treatment (P < 0.01). Compared with the baseline hormone levels, YYSG markedly decreased the bFSH level with statistical significance (P < 0.01) and improved the AMH level (P < 0.01). Furthermore, YYSG greatly improved the participants' AFC and ovarian PSV, compared with placebo (P < 0.01). There were no serious adverse events, and the safety indices of whole blood counts, renal function, and liver function were within the normal range, both before and after treatment. CONCLUSIONS: Treatment with YYSG was more effective than placebo for improving menopausal symptoms, basal hormone levels, and ovarian function in women with POI in Guangdong, China. PMID- 29533367 TI - Tissue selective estrogen complex (TSEC): a review. AB - OBJECTIVE: This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development. METHODS: This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors. RESULTS: SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety. CONCLUSIONS: Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms. PMID- 29533371 TI - Preface. PMID- 29533372 TI - Foreword. PMID- 29533369 TI - Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. AB - OBJECTIVE: Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect. METHODS: Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing >=7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time course analysis was completed. RESULTS: By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, -81.3 to -63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, -46.1 to -29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, -47.5 to -30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, -79.1 to -43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to -44%, -50%, and 70%, respectively by day 28, all P < 0.0001 compared with placebo). CONCLUSIONS: NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure. PMID- 29533373 TI - Practice of Otology During the First Quarter Century of the American Otological Society (1868-1893). AB - OBJECTIVE: To describe the practice of otology in America during the first quarter century of the American Otological Society (AOS). METHODS: Two sources were used to determine the most prevalent disease conditions cared for and surgical procedures undertaken during this era. All articles published in the AOS transactions between 1868 and 1893 were studied as were the otology textbooks published by 6 of the first 10 Presidents of the Society. RESULTS: The primary emphasis of late 19th century American otological scholarship was on chronic ear infection with numerous articles focusing on complications of otitis including frequent descriptions of fatalities. Much emphasis was placed upon the Eustachian tube with catheterization and insufflation a major part of otological practice. Due to limitations in technology, the overwhelming focus was on diseases of the ear canal and middle ear. Understanding of temporal bone anatomy was much superior to that of physiology. Erroneous speculations on the function of the middle and inner ear were common. Surgical interventions were largely limited to myringotomy and mastoidectomy, the latter of which was sometimes life saving during the preantibiotic era. CONCLUSION: The latter half of the 19th century saw the emergence of otology as a specialty in America and many emerging diagnostic and therapeutic advances were adopted. While capabilities were notably limited during this era, the efforts of a small band of pioneer otologists in the founder generation of the AOS contributed greatly to the progress of the emerging specialty. PMID- 29533374 TI - Assessment of Hearing During the Early Years of the American Otological Society. AB - OBJECTIVE: To describe the manner in which hearing was evaluated in American Otological Practice during the late 19th and early 20th centuries before introduction of the electric audiometer. METHODS: Primary sources were the Transactions of the American Otological Society and American textbooks, especially those authored by Presidents of the Society. RESULTS: In the era before electric audiometry multiple methods were used for evaluating the thresholds of different frequencies. Tuning forks were important for lower frequencies, whisper, and speech for mid-frequencies, and Galton's whistle and Konig's rod evaluated high frequencies. Hearing threshold was often recorded as in terms of duration of a sound, or distance from the source, rather than intensity. Hearing ability was often recorded a fraction, for example, with the distance a watch tick could be heard over the distance of a normal hearing individual. A variety of devices, such as Politzer's Acoumeter, attempted to deliver sound in a calibrated manner, thus enhancing the accuracy and reproducibility of test results. CONCLUSION: The early years of the American Otological Society were marked by a number of ingenious efforts to standardize hearing assessment despite the technical limitations. These efforts facilitated the development of the audiometer, and continue to influence clinical practice even today. PMID- 29533375 TI - History of Publications from the American Otological Society: A Celebration of the 150-Year History of the American Otological Society. AB - : The American Otological Society (AOS) has been on the forefront of advancing the science of auditory and vestibular physiology, and art of ear medicine since its founding in 1868. For 150 years, through its publications, the AOS has provided a critical forum to debate these advances, highlighting treatment successes and failures, and served a place to celebrate its history. This historical review provides an overview of the publications of the AOS since its founding: the Transactions of the annual meeting from 1868 through 2006, Treatises on Otosclerosis (1928-1935), the History of the Society from the 100 and 125th anniversary, and the sponsored Society journals-American Journal of Otology (1879-1883, 1979-2000) and Otology & Neurotology (2001-present). PMID- 29533376 TI - Evolution of Otology and Neurotology Education in the United States. AB - : A brief history of the evolution of Otology and Neurotology training in the United States is presented. The development of the Neurotology Fellowship accreditation process by the Accreditation Council on Graduate Education and the certification of neurotology fellows by the American Board of Otolaryngology is outlined. PMID- 29533377 TI - Women of the American Otological Society. AB - OBJECTIVE: To describe the history of women in the American Otological Society (AOS). METHODS: Biographies of the early women of the AOS were compiled through review of the AOS transactions, their published scholarship, newspaper articles, and memorials. Interviews were conducted with the only two women to have led the society and also with former colleagues and family members of pioneering AOS women members who are no longer with us. The evolving gender composition of the society over time was researched from AOS membership lists and compared with data on surgical workforce composition from multiple sources such as the Association of American Medical Colleges, Accreditation Council for Graduate Medical Education, American Medical Association, and the American Academy of Otolaryngology-Head and Neck Surgery. RESULTS: Although American women specialized in otology as far back as 1895, the first woman to be invited to join the AOS as Associate member in 1961 was Dorothy Wolff, PhD. The first female full member was otologic surgeon LaVonne Bergstrom, M.D., who was elected in 1977, 109 years after the foundation of the Society. As of 2017, only two women have served as AOS President. The first was Aina Julianna Gulya, M.D., who took office during the 133rd year in 2001. At the time of the sesquicentennial (2017), 7.5% of AOS members are women including three of eight who serve on the AOS Council. This compares with 15.8% of women among the otolaryngology workforce and a growing 10.9% representation among those who have earned subcertification in neurotology. CONCLUSION: Gender disparities remain in the AOS, but both participation and scholarly contributions by women in otology have grown substantially since the society's inception 150 years ago, and particularly in the 21st century. Increasing the presence of women in leadership provides role models and mentorship for the future. PMID- 29533379 TI - Perspectives From American Otological Society Past Presidents Since the 125th American Otological Society Anniversary Publication. PMID- 29533378 TI - Reflections on the Last 25 Years of the American Otological Society and Thoughts on its Future. AB - PURPOSE: To review contributions of the American Otological Society (AOS) over the most recent quarter century (1993-2018) and to comment on possible future evolution of the field during the quarter century to come. METHODS: Retrospective review of selected topics from the AOS transactions, distinguished lectureships over the past 25 years, and selective reflection by the authors. Speculation on potential advances of the next quarter century derived from emerging topics in the current literature and foreseeable trends in science and technology are also proffered for consideration (and possible future ridicule). RESULTS: Integration of multiple disciplines including bioengineering, medical imaging, genetics, molecular biology, physics, and evidence based medicine have substantially benefitted the practice of otology over the past quarter century. The impact of the contributions of members of the AOS in these developments cannot be over estimated. CONCLUSIONS: Further scientific advancement will certainly accelerate change in the practice of otologic surgery and medicine over the coming decade in ways that will be marvelous to behold. PMID- 29533380 TI - AMERICAN OTOLOGICAL SOCIETY (2017-2018 MEMBERSHIP ROSTER). PMID- 29533381 TI - AOS Member Photo - 150th Anniversary. PMID- 29533382 TI - AOS COUNCIL 2016-2017. PMID- 29533383 TI - PAST PRESIDENTS OF THE AMERICAN OTOLOGICAL SOCIETY. PMID- 29533384 TI - Reduced selective learning in patients with fibromyalgia vs healthy controls. AB - Impaired selective fear learning has been advanced as a core mechanism involved in excessive spreading of protective responses such as pain-related fear and avoidance leading to disability in chronic pain conditions. Using the litmus test for selective learning effects, the blocking procedure, we tested the hypothesis that patients with fibromyalgia (FM) show less selective threat learning than healthy controls (HCs). We introduce a novel selective learning task based around a clinical diary scenario. On a trial-by-trial basis, participants rated whether they expected certain situations (A, B, Z, and X) in the diary of a fictive FM patient would trigger pain in that patient. The procedure did not involve any experimental pain induction because the verbal outcomes "pain" or "no pain" were used. During the elemental acquisition phase, one situation was followed by "pain" (A+, eg, "Kim slept badly, and reports pain"), whereas another situation was followed by "no pain" (Z-, eg, "Kim was stressed, and reports no pain"). During the compound acquisition phase, another situation (X), referred to as the blocked stimulus, was presented in compound with a previously pain-eliciting situation and also paired with "pain" (AX+, eg, Kim slept badly" and "Kim has vacuumed," and reports pain). Simultaneously, a novel situation was introduced and also followed by "pain" (B+). Within-group comparisons showed blocking (ie, significant difference between B and X) in the HCs, but not in the patients with FM. This study is the first in directly assessing differences in selective learning between patients with FM and HCs using a blocking procedure. PMID- 29533385 TI - Burden of orofacial pain in a socially deprived and culturally diverse area of the United Kingdom. AB - Little is known about the burden and impact of orofacial pain in deprived areas, and whether it mediates the relationship between socioeconomic position and impacts on daily life. We analysed data from a representative sample of 2168 adults, aged 16 to 65 years, from the East London Oral Health Inequality study. Participants completed a validated questionnaire on demographics, socioeconomic position (area deprivation), orofacial pain (by anatomical site) in the past month, and impacts related to oral conditions on daily life. Negative binomial regression models with robust variance estimator were fitted. The prevalence of orofacial pain was high (30.2%). The most common subset of orofacial pain was intraoral pain (27.5%). The prevalence of pain related to temporomandibular disorders was 6.8%. The most common subsets of intraoral pain were tooth (20.4%) and gingival (11.4%) pain. Orofacial pain, its subsets (intraoral and temporomandibular disorder-related pain), and intraoral pain subsets (tooth and gingival pain) consistently showed associations with all dimensions of impacts on daily life that were highly statistically significant: functional limitation, psychological discomfort, disabilities, and handicap. Socioeconomic inequalities were present in orofacial pain and some dimensions of impacts on daily life. Orofacial pain did not mediate the relationship between area deprivation and impacts on daily life. Our study demonstrated a substantial burden and impact of orofacial pain in a socially deprived and culturally diverse area of the United Kingdom. To address this burden, interventions that lie within the remit of health services are needed to improve access to dental care for adults with orofacial pain. PMID- 29533386 TI - Sustained and repeated mouth opening leads to development of painful temporomandibular disorders involving macrophage/microglia activation in mice. AB - Temporomandibular disorder (TMD) is a set of heterogeneous musculoskeletal conditions involving the temporomandibular joint (TMJ) and/or the masticatory muscles. Up to 33% of the population has had at least 1 symptom of TMD with 5% to 10% of them requiring treatment. Common symptoms include limited jaw movement, joint sound, and pain in the orofacial area. Once TMD becomes chronic, it can be debilitating with comorbidities that greatly reduce one's overall quality of life. However, the underlying mechanism of TMD is unclear because of the multicausative nature of the disease. Here, we report a novel mouse model of TMD where a bite block was placed in between the upper and lower incisors such that the mouth was kept maximally open for 1.5 hours per day for 5 days. After sustained mouth opening, mice developed persistent orofacial mechanical allodynia and TMJ dysfunction. At the cellular level, we found masseter muscle dystrophy, and increased proteoglycan deposition and hypertrophic chondrocytes in the mandibular condyle. Increased F4/80 macrophages were also observed in the masseter muscles and the TMJ posterior synovium. We also found ATF3 neuronal injury and increased F4/80 macrophages in the trigeminal ganglia. Microglia activation was observed in the trigeminal subnucleus caudalis. Inhibiting macrophage and microglia activation with a colony stimulating factor-1 receptor inhibitor prevented the development of orofacial mechanical allodynia, but not TMJ dysfunction. This study suggests that mouth opening for an extended period during dental treatments or oral intubations may risk the development of chronic TMD and inflammation associated with macrophage and microglia in the tissue and trigeminal system contributes to the development of TMD pain. PMID- 29533387 TI - Dilute lidocaine suppresses ectopic neuropathic discharge in dorsal root ganglia without blocking axonal propagation: a new approach to selective pain control. AB - Ectopic impulse discharge (ectopia) generated in the soma of afferent neurons in dorsal root ganglia (DRG) after nerve injury is believed to be a major contributor to neuropathic pain. The DRG is thus a prime interventional target. The process of electrogenesis (impulse generation) in the DRG is far more sensitive to systemically administered Na channel blockers than the process of impulse propagation along sensory axons. It should therefore be possible to selectively suppress DRG ectopia with local application of membrane-stabilizing agents without blocking normal impulse traffic. Results from in vivo electrophysiological recordings in rats showed that epidural application of lidocaine to the DRG surface within the intervertebral foramen at 0.02% or 0.2% substantially suppresses electrogenesis in the DRG with only a modest blocking effect on impulse propagation through the foramen. Topically applied opiates and gamma aminobutyric acid, by contrast, blocked neither ongoing discharge nor spike through-conduction. This suggests that sustained intraforaminal delivery of dilute lidocaine, and by extension other membrane-stabilizing agents, is a potential new strategy for the control of chronic painful conditions in which ectopia in sensory ganglia is implicated as a key pain driver. Such conditions include postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, complex regional pain syndrome, and radicular low back pain. PMID- 29533389 TI - RAPIDLY PROGRESSIVE NEOVASCULAR GLAUCOMA FROM CYTOMEGALOVIRUS RETINITIS IN A NON HUMAN IMMUNODEFICIENCY VIRUS PATIENT. AB - PURPOSE: To describe a case of neovascular glaucoma from cytomegalovirus (CMV) retinitis in a human immunodeficiency virus-negative patient with immunosuppression after stem-cell transplant for multiple myeloma. METHODS: Retrospective case report. RESULTS: A 71-year-old man on monthly infusion of daratumumab for multiple myeloma after stem-cell transplant presenting with a 2 week history of floaters, photophobia, and blurry vision was found to have polymerase chain reaction-confirmed CMV retinitis associated with diffuse occlusive vasculitis. The patient was human immunodeficiency virus negative with a CD4 count of 450/mm. Despite immediate aggressive treatment, the patient developed neovascular glaucoma with poor visual outcome. CONCLUSION: Cytomegalovirus retinitis in human immunodeficiency virus-negative patients is becoming more prevalent with increasing use of systemic immunosuppression therapy for various reasons. Patients with non-human immunodeficiency virus related CMV retinitis can have severe ischemia atypical of the classic CMV retinitis and should be followed closely for neovascularization.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29533388 TI - The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes. AB - It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRbeta, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents. PMID- 29533390 TI - Human pluripotent stem cell derived HLC transcriptome data enables molecular dissection of hepatogenesis. AB - Induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) differentiated into hepatocyte-like cells (HLCs) provide a defined and renewable source of cells for drug screening, toxicology and regenerative medicine. We previously reprogrammed human fetal foreskin fibroblast cells (HFF1) into iPSCs employing an episomal plasmid-based integration-free approach, this iPSC-line and the hESC lines H1 and H9 were used to model hepatogenesis in vitro. Biochemical characterisation confirmed glycogen storage, ICG uptake and release, urea and bile acid production, as well as CYP3A4 activity. Microarray-based transcriptome analyses was carried out using RNA isolated from the undifferentiated pluripotent stem cells and subsequent differentiation stages- definitive endoderm (DE) hepatic endoderm (HE) and HLCs. K-means identified 100 distinct clusters, for example, POU5F1/OCT4 marking the undifferentiated stage, SOX17 the DE stage, HNF4alpha the HE stage, and ALB specific to HLCs, fetal liver and primary human hepatocytes (PHH). This data descriptor describes these datasets which should be useful for gaining new insights into the molecular basis of hepatogenesis and associated gene regulatory networks. PMID- 29533391 TI - A dataset on human navigation strategies in foreign networked systems. AB - Humans are involved in various real-life networked systems. The most obvious examples are social and collaboration networks but the language and the related mental lexicon they use, or the physical map of their territory can also be interpreted as networks. How do they find paths between endpoints in these networks? How do they obtain information about a foreign networked world they find themselves in, how they build mental model for it and how well they succeed in using it? Large, open datasets allowing the exploration of such questions are hard to find. Here we report a dataset collected by a smartphone application, in which players navigate between fixed length source and destination English words step-by-step by changing only one letter at a time. The paths reflect how the players master their navigation skills in such a foreign networked world. The dataset can be used in the study of human mental models for the world around us, or in a broader scope to investigate the navigation strategies in complex networked systems. PMID- 29533392 TI - GlobTherm, a global database on thermal tolerances for aquatic and terrestrial organisms. AB - How climate affects species distributions is a longstanding question receiving renewed interest owing to the need to predict the impacts of global warming on biodiversity. Is climate change forcing species to live near their critical thermal limits? Are these limits likely to change through natural selection? These and other important questions can be addressed with models relating geographical distributions of species with climate data, but inferences made with these models are highly contingent on non-climatic factors such as biotic interactions. Improved understanding of climate change effects on species will require extensive analysis of thermal physiological traits, but such data are both scarce and scattered. To overcome current limitations, we created the GlobTherm database. The database contains experimentally derived species' thermal tolerance data currently comprising over 2,000 species of terrestrial, freshwater, intertidal and marine multicellular algae, plants, fungi, and animals. The GlobTherm database will be maintained and curated by iDiv with the aim to keep expanding it, and enable further investigations on the effects of climate on the distribution of life on Earth. PMID- 29533393 TI - Tracking vegetation phenology across diverse North American biomes using PhenoCam imagery. AB - Vegetation phenology controls the seasonality of many ecosystem processes, as well as numerous biosphere-atmosphere feedbacks. Phenology is also highly sensitive to climate change and variability. Here we present a series of datasets, together consisting of almost 750 years of observations, characterizing vegetation phenology in diverse ecosystems across North America. Our data are derived from conventional, visible-wavelength, automated digital camera imagery collected through the PhenoCam network. For each archived image, we extracted RGB (red, green, blue) colour channel information, with means and other statistics calculated across a region-of-interest (ROI) delineating a specific vegetation type. From the high-frequency (typically, 30 min) imagery, we derived time series characterizing vegetation colour, including "canopy greenness", processed to 1- and 3-day intervals. For ecosystems with one or more annual cycles of vegetation activity, we provide estimates, with uncertainties, for the start of the "greenness rising" and end of the "greenness falling" stages. The database can be used for phenological model validation and development, evaluation of satellite remote sensing data products, benchmarking earth system models, and studies of climate change impacts on terrestrial ecosystems. PMID- 29533395 TI - Women's health and kidney disease. PMID- 29533394 TI - Global quantitative analysis of the human brain proteome in Alzheimer's and Parkinson's Disease. AB - Patients with Alzheimer's disease (AD) and Parkinson's disease (PD) often have overlap in clinical presentation and brain neuropathology suggesting that these two diseases share common underlying mechanisms. Currently, the molecular pathways linking AD and PD are incompletely understood. Utilizing Tandem Mass Tag (TMT) isobaric labeling and synchronous precursor selection-based MS3 (SPS-MS3) mass spectrometry, we performed an unbiased quantitative proteomic analysis of post-mortem human brain tissues (n=80) from four different groups defined as controls, AD, PD, and co-morbid AD/PD cases across two brain regions (frontal cortex and anterior cingulate gyrus). In total, we identified 11 840 protein groups representing 10 230 gene symbols, which map to ~65% of the protein coding genes in brain. The utility of including two reference standards in each TMT 10 plex assay to assess intra- and inter-batch variance is also described. Ultimately, this comprehensive human brain proteomic dataset serves as a valuable resource for various research endeavors including, but not limited to, the identification of disease-specific protein signatures and molecular pathways that are common in AD and PD. PMID- 29533396 TI - Diagnosis of Minimal Hepatic Encephalopathy: A Systematic Review of Point-of-Care Diagnostic Tests. AB - OBJECTIVES: Minimal hepatic encephalopathy (HE) is common, characterized by deficits in reaction time and executive function, and strongly associated with disability and mortality. Point-of-care diagnostics performed without specialized skills or equipment are now available, albeit with limited data regarding their generalizability. METHODS: We systematically reviewed MEDLINE, EMBASE, Cochrane Library, and Scopus for diagnostic studies of MHE using broad search terms including HE and minimal, covert, or the names of published diagnostic modalities. We included tests that provide results during clinical visits without requiring neuropsychologists to administer and/or special equipment. These include the Inhibitory Control Test (ICT, n=16), EncephalApp Stroop (n=3), an algorithm based on the Sickness Impact Profile (n=2), and the Animal Naming Test (ANT, n=1). RESULTS: The populations enrolled in the included study were highly selected, excluding patients with recent (6-months) alcohol or psychoactive medications use. Cutoffs for MHE for each test varied widely. For the ICT, the optimal cutoffs for MHE varied by 300%, whereas healthy control performance varied >400%. The optimal cutoffs for the EncephalApp also varied (by 50%). The gold standards for MHE varied substantially between studies, and clinical outcomes were never used to develop test cutoffs. Data comparing the performance of each modality are lacking. Longitudinal data are limited but suggest that good performance on the ICT, EncephalApp or ANT is associated with reduced risk of developing overt HE. CONCLUSION: The point-of-care tests for MHE are promising tools. However, additional longitudinal studies are needed in clinically representative populations of at-risk patients with cutoffs validated based on the development of clinical outcomes. PMID- 29533399 TI - Optimized polydopamine coating and DNA conjugation onto gold nanorods for single nanoparticle bioaffinity measurements. AB - Gold nanorods (NRs) have attracted a great deal of interest for a variety of biomedical and sensing applications. However, developing robust methods for biofunctionalizing NRs has continued to be challenging, especially for NR-DNA conjugates. This is due to the presence of cetyltrimethylammonium bromide (CTAB), which plays an essential role in controlling the anisotropic particle growth. In this article, we systematically explore the growth of a polydopamine (PDA) layer on a range of NR surfaces, comparing different polyelectrolyte and alkanethiol coatings as well as direct CTAB displacement. This revealed that the PDA layer thickness and growth rate is strongly dependent on the underlying nanorod functionalization chemistry and allowed us to establish a preferred route for the creation of stable, non-aggregated suspensions of PDA-coated NRs. The utility of this platform was then demonstrated by self-assembling packed monolayers of single-stranded DNA on the outer surface. Both the surface attachment and bioactivity of the resulting NR-DNA conjugates was then demonstrated by performing bulk solution and single nanoparticle imaging fluorescence measurements. PMID- 29533398 TI - Identification of Individuals with Functional Dyspepsia With a Simple, Minimally Invasive Test: A Single Center Cohort Study of the Oral Capsaicin Test. AB - OBJECTIVES: The diagnosis of functional dyspepsia (FD) is challenging due to the lack of reliable biological markers to support the diagnosis. We assessed the relevance of a previously validated simple test for chemical hypersensitivity in the setting of a gastrointestinal outpatient department. METHODS: A total of 224 outpatients who were referred for evaluation of gastrointestinal symptoms in the absence of alarm symptoms swallowed a capsule containing 0.75 mg capsaicin. Severity of symptoms before and after capsule ingestion was assessed by a graded questionnaire and the difference in aggregate symptom scores (delta) was calculated. RESULTS: Sensitivity of the test was between 0.51-0.59, specificity was 0.84-0.89 and positive predictive value for the diagnosis of FD 70-71%. FD patients had significantly higher median delta symptom scores (10.0; 25% quartile: 3.0; 75% quartile: 16.0) as compared to inflammatory bowel disease (2.5; 1.0/8.5)(P=0.003), peptic ulcer disease (0.0; -1.5/4.5) (P<0.001), irritable bowel syndrome (3.0;0.5/8.5)(P=0.001), and patients classified with "other disease" (2.5;0.0/5.0)(P<0.001). Patients with gastroesophageal reflux disease had significantly lower symptom scores if FD was not concomitantly diagnosed (2.0; 0.0/6.0) than if FD was present (10.0; 4.0/15.0). CONCLUSIONS: Hypersensitivity for capsaicin discriminates functional dyspepsia from patients with other GI disorders. The capsaicin test is a simple and non invasive method to detect a large subgroup of functional dyspepsia with chemical hypersensitivity. These findings might open new diagnostic options in functional dyspepsia and possibly new therapeutic options by targeting the specific capsaicin receptor TRPV1. PMID- 29533397 TI - Same-Day Single Dose of 2 Liter Polyethylene Glycol is Not Inferior to The Standard Bowel Preparation Regimen in Low-Risk Patients: A Randomized, Controlled Trial. AB - OBJECTIVES: Split dose of 4 l polyethylene glycol (PEG) is currently the standard regimen for bowel preparation (BP). However, it may be unnecessary for patients without high risks (e.g., old age, constipation, and diabetes, and so on) for inadequate BP. The study aimed to compare the efficacy of bowel cleansing between low-risk patients receiving same-day, single dose of low-volume (SSL) PEG vs. standard regimen. METHODS: This prospective, randomized, observer-blinded, non inferiority study enrolled low-risk patients in three centers. Patients undergoing colonoscopy were randomized (1:1) to the SSL or standard group. The primary outcome was adequate BP, defined by Boston Bowel Preparation Score (BBPS) >=6 and each segmental score >=2. Secondary outcomes included adverse events, cecal intubation rate, and patient willingness to repeat BP, and so on. RESULTS: Among 2,532 patients eligible for the study, 940 (37.1%) were at low risk and 792 (31.3%) at high risk for inadequate BP. The low-risk patients were randomly allocated to the SSL (n=470) or standard group (n=470). The baseline characteristics of the two groups were similar. Intention-to-treat analysis showed that adequate BP was achieved in 88.1% in the SSL group and 87.0% in the standard group (relative risk (RR) 1.10, 95% confidence interval (CI): 0.75-1.63, P=0.621). The overall BBPS was 7.3+/-1.2 and 7.3+/-1.3, respectively (P=0.948). No significant differences were found between the two groups with regards to the right, transverse, and left-segmental colon BBPS (all P>0.05). However, in terms of adverse events, patients in the SSL group reported less nausea (19.6% vs. 29.9%), vomiting (5.3% vs. 11.4%), and abdominal discomfort (2.2% vs. 6.0%) compared with those in the standard group. More patients in the SSL group were willing to repeat BP (94.0% vs. 89.5%, P=0.015). CONCLUSIONS: For low-risk patients, the SSL regimen was not inferior to the split dose of 4 l PEG for adequacy of BP. Single dose of low-volume regimen had significantly fewer adverse events. This simplified regimen may be preferable in the "easy-to prepare" population. PMID- 29533400 TI - Dissection of the effects that govern thioglucoside and thiomannoside reactivity. AB - Neighboring group effects were investigated in gluco- and manno-configured thioglycosides under NIS/TfOH activation. Donors possessing a 2-O-benzoyl group that are capable (1,2-trans) and incapable (1,2-cis) of exerting nucleophilic push were compared with donors possessing a participatory neutral 2-O-benzyl group. By using competition experiments between sets of glycosyl donors the direct effect of neighboring group participation and the electron withdrawing effect of the 2-O-benzoyl group could be separated. The study brings insight into how the stereochemistry of the 1 and 2 position and how the nature of the aglycon (Ph or Et) have a pronounced effect on glycosyl donor reactivity. PMID- 29533401 TI - Dynamic kinetic resolution of bis-aryl succinic anhydrides: enantioselective synthesis of densely functionalised gamma-butyrolactones. AB - The efficient Dynamic Kinetic Resolution (DKR) of disubstituted anhydrides has been shown to be possible for the first time. Using an ad hoc designed organocatalyst and an enantio- and diastereoselective cycloaddition process with aldehydes, stereochemically complex gamma-butyrolactone derivatives can be obtained - with control over three contiguous stereocentres, one of which is all carbon quaternary. PMID- 29533403 TI - Clathrate ice sL: a new crystalline phase of ice with ultralow density predicted by first-principles phase diagram computations. AB - In contrast to the rich knowledge of water and 17 experimentally confirmed crystalline phases of solid water under positive pressures, water under negative pressure has been poorly explored. In this study, a new crystalline phase of ice with ultralow density (0.6 g cm-3), named "clathrate ice sL", is constructed by nano water cage clusters, and it is predicted to be stable under a lower negative pressure than the experimentally confirmed sII phase by first-principles phase diagram computations, thereby extending the phase diagram of water to negative pressure regions below -5170 bar at 0 K and below -4761 bar at 300 K. In addition, according to our theoretical prediction, the optimal hydrogen storage mass density in the new clathrate ice sL is 7.7 wt% (larger than the 2017 DOE target of 5.5 wt%), which would set a new record of hydrogen storage capacity in clathrate hydrates. The finding of clathrate ice sL not only proposes a new type of crystalline ice under negative pressure but also explores the potential applications of the ultralow density ice phases while extending the water phase diagram and enriching the knowledge of people about water. PMID- 29533404 TI - Reaction kinetics of hydrogen atom abstraction from isopentanol by the H atom and HO2 radical. AB - Isopentanol is a potential next-generation biofuel for future applications to Homogeneous Charge Compression Ignition (HCCI) engine concepts. To provide insights into the combustion behavior of isopentanol, especially to its auto ignition behavior which is linked both to efficiency and pollutant formation in real combustion systems, detailed quantum chemical studies for crucial reactions are desired. H-Abstraction reaction rates from fuel molecules are key initiation steps for chain branching required for auto-ignition. In this study, rate constants are determined for the hydrogen atom abstraction reactions from isopentanol by the H atom and HO2 radical by implementing the CBS-QB3 composite method. For the treatment of the internal rotors, a Pitzer-Gwinn-like approximation is applied. On comparing the computed reaction energies, the highest exothermicity (DeltaE = -46 kJ mol-1) is depicted for Halpha abstraction by the H atom whereas the lowest endothermicity (DeltaE = 29 kJ mol-1) is shown for the abstraction of Halpha by the HO2 radical. The formation of hydrogen bonding is found to affect the kinetics of the H atom abstraction reactions by the HO2 radical. Further above 750 K, the calculated high pressure limit rate constants indicate that the total contribution from delta carbon sites (Cdelta) is predominant for hydrogen atom abstraction by the H atom and HO2 radical. PMID- 29533406 TI - Different effects of water molecules on CO oxidation with different reaction mechanisms. AB - The effects of water molecules (promotion/prohibition) on CO oxidation remain debated. Herein, using density functional theory calculations, we demonstrate that water molecules can facilitate the CO + O/O2 oxidation process, but prohibit the CO + OH oxidation process, which is consistent with the experimental finding that water molecules have two distinct effects on CO oxidation. For the CO + O/O2 oxidation mechanisms, we find that the reactants were pushed towards each other due to the steric effect of the water molecules, which decreases the reaction barriers and promotes the CO + O/O2 oxidation process. For the CO + OH oxidation mechanisms, water molecules increase the stability of the COOH* intermeditae by H bonds and van der Waals forces, which increase the barriers of the COOH* transformation process and the COOH*-tra dissociation process, and prohibit the CO + OH oxidation process. These results clarify the different effects of water molecules on CO oxidation and shed light on catalyst usage in the CO oxidation industry. PMID- 29533409 TI - On the generality of the superarmament of glycosyl donors. AB - It was established that 2-O-benzoyl-3,4,6-tri-O-benzyl protected beta-SEt, beta SPh and beta-SBox glucosyl donors are not superarmed when using the NIS/TfOH promoter system, but instead have a similar reactivity as their classically armed tetra-O-benzyl protected glucosyl counterparts. The beta-SBox 2-O-benzoyl-3,4,6 tri-O-benzyl glucosyl donor, however, was found to be superarmed under DMTST activation. Our studies have shown that the increased reactivity of the beta-SBox 2-O-benzoyl-3,4,6-tri-O-benzyl glucosyl donor with DMTST activation could be a unique case, and that the high reactivity of glucosyl donors with the 2-O-benzoyl 3,4,6-tri-O-benzyl protection pattern is not general as earlier suggested. PMID- 29533410 TI - Patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia for 50 years AB - We report on a patient with inherited macrothrombocytopenia, MYH9 related disease (MYH9-RD). The patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia (ITP) for nearly 50 years. Cases of misdiagnosed MYH9-RD and other hereditary thrombocytopenias have been described previously. Typical clinical features such as renal failure and/or progressive loss of hearing should give grounds to suspect hereditary thrombocytopenia. Initial laboratory diagnosis can start with a simple blood smear followed by immunohistochemistry and genotyping. Therapy with thrombopoietin receptor agonists may be beneficial in selected cases of MYH9-RD. ITP treatments including splenectomy are not indicated and may cause harm. PMID- 29533411 TI - ? PMID- 29533412 TI - ? PMID- 29533413 TI - ? PMID- 29533414 TI - ? PMID- 29533415 TI - ? PMID- 29533416 TI - Effectiveness of Reduced Radioiodine Activity for Thyroid Remnant Ablation after Total Thyroidectomy in Patients with Low to Intermediate Risk Differentiated Thyroid Carcinoma. AB - AIM: To compare the success rates of radioiodine therapy (RIT) for thyroid remnant ablation (TRA) after the administration of a high-standard activity (3700 MBq; 100 mCi) to a lower-activity regimen of 2000 MBq (54 mCi) I-131 in a cohort of differentiated thyroid carcinoma (DTC) patients (papillary, follicular, mixed, pT1a(m) - pT3, N0 - NX, R0). METHODS: 135 patients received approx. 2000 MBq I 131 (54 mCi) for thyroid remnant ablation after total thyroidectomy for DTC, 137 patients received approx. 3700 MBq (100 mCi) I-131. Ablation success was defined as thyroglobulin (TG) levels < 0.5 ng/ml after stimulation, negative I-131 whole body scan and inconspicuous results on neck ultrasonography approximately 6 months after initial RIT. RESULTS: In the follow-up 84.4 % of patients in the reduced-activity group and 87.6 % of the patients in the standard-activity group did not show any relevant residual I-131 uptake in the thyroid bed (p = 0.454). 90 % in the reduced-activity group and 91 % in the standard-activity group demonstrated a stimulated TG level < 0.5 ng/ml (p = 0.969). All patients were unre-markable in cervical ultrasonography. The success rate was comparable in both groups (81.5 % in the reduced-activity group vs. 83.9 % in the standard activity group, p = 0.592). No re-therapy was required in 85.2 % of the patients in the low-activity group as compared to 87.6 % of the patients in the standard activity group (p = 0.563). CONCLUSIONS: We could demonstrate that irrespective of the activity administered, the patients had comparable success rates with regard to TRA as defined by our criteria. We thus consider the use of a reduced activity regimen for TRA safe and feasible in the patient cohort examined in this study. PMID- 29533417 TI - Absorbed dose estimates from a single measurement one to three days after the administration of 177Lu-DOTATATE/-TOC. AB - AIM: To retrospectively analyze the accuracy of absorbed dose estimates from a single measurement of the activity concentrations in tumors and relevant organs one to three days after the administration of 177Lu-DOTA-TATE/TOC assuming tissue specific effective half-lives. METHODS: Activity kinetics in 54 kidneys, 30 neuroendocrine tumor lesions, 25 livers, and 27 spleens were deduced from series of planar images in 29 patients. After adaptation of mono- or bi-exponential fit functions to the measured data, it was analyzed for each fit function how precise the time integral can be estimated from fixed tissue-specific half-lives and a single measurement at 24, 48, or 72 h after the administration. RESULTS: For the kidneys, assuming a fixed tissue-specific half-life of 50 h, the deviations of the estimate from the actual integral were median (5 % percentile, 95 % percentile): -3 degrees % (-15 %>; +16 degrees %) for measurements after 24 h, +2 %> (-9 %>; +12 %>) for measurements after 48 h, and 0 % (-2 %; +12 %) for measurements after 72 h. The corresponding values for the other tissues, assuming fixed tissue-specific half-lives of 67 h for liver and spleen and 77 h for tumors, were +2 % (-25 %; +20 %) for measurements after 24 h, +2 degrees % (-16 %>; +17 %>) for measurements after 48 h, and +2 %> (-11 %>; +10 %>) for measurements after 72 h. CONCLUSIONS: Especially for the kidneys, which often represent the dose limiting organ, but also for liver, spleen, and neuroendocrine tumors, a meaningful absorbed dose estimate is possible from a single measurement after 2, more preferably 3 days after the administration of 177Lu-DOTA-TATE/-TOC assuming fixed tissue specific effective half-lives. PMID- 29533418 TI - Ewing sarcoma during follow-up. AB - AIM: To evaluate the performance of a prospectively defined follow-up imaging protocol that includes FDG-PET(/CT) to detect tumour recurrence in Ewing sarcoma (EwS) before becoming symptomatic. METHODS: Imaging results and clinical data during follow-up were retrospectively analysed from all patients treated successfully within the EURO E.W.I.N.G. 99 trial at the University Hospital Munster, Germany. All patients received follow-up imaging according to a comprehensive protocol that included regular X-ray, CT, MRI, bone scan and PET(/CT), albeit not all on the same day and with varying intervals for the different modalities. RESULTS: 80 of 105 patients underwent follow-up at our institution after complete remission. 30 patients had recurrent tumour during the follow-up period of 3.6 years on average. 19 recurrences (63%) were detected by scheduled imaging before the advent of clinical symptoms. The majority of these recurrences (8 out of 19; 42%) was detected first by PET/ CT (and confirmed with additional imaging thereafter), even though the total number of PET/CTs was comparatively low (138) and PET/CT was not systematically scheduled before other imaging techniques. Recurrences detected by bone scan were also detectable by PET. CONCLUSIONS: The implemented follow-up protocol was effective in the detection of EwS recurrence before the advent of symptoms. Most cases of those detected before onset of symptoms were detected by PET/CT first. This hybrid imaging modality should therefore be considered in the routine follow-up of EwS patients, as is standard in our hospital. In combination with PET, low-dose chest CT seems to be sufficient in the detection of small pulmonary nodules. PMID- 29533419 TI - The predictive ability of liver function indexes on 18F-FDG uptake in the liver. AB - AIM: The liver is an important reference organ for positron emission tomography/ computed tomography (PET-CT) examination using 18F-fluorodeoxyglucose (18F-FDG). However, 18F-FDG uptake by the liver is affected by many factors. We therefore investigated the effect of hepatic function on 18F-FDG uptake in the liver. METHODS: A retrospective analysis of data on the hepatic function and the mean liver standardized up-take value (SUV) of 18F-FDG uptake in the liver during PET CT examination of 500 (381 males, 119 females, aged 27-71) physical examinees. RESULTS: The mean liver SUV was 1.88 +/- 0.20. The correlation coefficient and partial correlation coefficient for age, the levels of conjugated bilirubin, globulin, AST and the mean liver SUV were statistically significant (r' = 0.119, 0.197, -0.089 and 0.151, all p < 0.05). Multiple linear regression analysis showed that age and the levels of conjugated bilirubin, globulin and aspartate amino-transferase (AST) were independent factors that influenced changes in the mean liver SUV (beta = 0.008, -0.025, -0.151 and 0.005, all p < 0.05). The globulin level had the biggest predictive ability (beta' = -0.151, p < 0.05). CONCLUSIONS: The uptake of 18F-FDG in the liver was influenced by some liver function indexes. The levels of conjugated bilirubin, globulin and AST were independent factors for predicting changes in the uptake of 18F-FDG in the liver. Liver function test results should be combined with an evaluation of the metabolic activity of the liver. PMID- 29533420 TI - ? PMID- 29533421 TI - [Imaging in clinic and research: contribution to individualized medicine?] PMID- 29533422 TI - [Selective intraarterial radiotherapy (SIRT) of malignant liver tumors]. AB - Die Leitlinie soll medizinisches Fachpersonal und onkologisch tatige Arzte bei der Auswahl geeigneter Patienten, der Planung, Vorbereitung und Durchfuhrung einer SIRT zur Behandlung primarer und sekundarer maligner Lebertumoren unterstutzen. Schwerpunkte sind personelle, technische und organisatorische Anforderungen an das Therapiezentrum einschliebetalich Strahlenschutz, d. h. insbesondere die Notwendigkeit einer interdisziplinaren Patientenselektion in Tumorboards und die Anforderungen an das Team, das die Therapie durchfuhrt und einen Medizinphysikexperten einbeziehen muss. Die Zielsetzung der Therapie, die erforderlichen Daten und Voruntersuchungen fur die Indikationsstellung und Therapieplanung und ihre Implikationen fur die Vermeidung von Komplikationen werden dargestellt, ebenso Anforderungen an die Aufklarung des Patienten. Die Nachsorge wird beschrieben und auf die Notwendigkeit einer interdisziplinaren Zusammenarbeit auch mit heimatnahen behandelnden Arzten hingewiesen. PMID- 29533423 TI - Radioiodine therapy of benign thyroid-disorders. AB - AIM: In radioiodine therapy (RIT) of benign thyroid-disorders empirical half lives (HLemp) may be used to calculate therapeutic dose. In this study the effective half-life (HLf as well as potential influence factors were retrospectively determined in order to better estimate HLemp. METHODS: Data from patients undergoing RIT from 01/09 to 04/14 were analysed (empirically estimated HLeff stratified by metabolic state and diagnosis). Inclusion criteria were: Benign thyroid-disorders, singular capsule administration and >= 6 dosimetry time points (i. e. > 72 h inpatient stay). The effects of metabolic state, previous thy- reostatic medication and sex on HLeff were assessed by non-parametric ANOVA. The effects of target-volume and patient-age were assessed by regression analysis and nonparametric correlation (Spearman). RESULTS: Data of 1,498 patients were analyzed: Graves' Disease (GD), n = 286; multinodular goiter/disseminated autonomy (AMG/DA), n = 751; autonomous thyroid nodules (ATN), n = 421; euthyroid goiter (EG), n = 40. Mean HLeff (days +/- SD) was 5.4 +/- 1.5 in GD, 6.6 +/- 1.2 in AMG/DA, 5.5 +/- 1.6 in ATN and 6.9 +/- 0.7 in EG. HLeff differed by metabolic state in GD, AMG/DA, and ATN, whereas neither thyreos- tatic medication nor sex were relevant. Moreover, target-volume (all diagnoses) and age (ATN and GD only) were associated with HLeft although the effect was small (R2 < 3.8%). CONCLUSION: When using standard HLeff for RIT, diagnosis and metabolic state should be considered for dose-calculations in RIT. Despite partial significance, the effects of target-volume and patient-age are small and a correction of HLeff, for these factors doesn't appear to be necessary in a routine setting. PMID- 29533424 TI - Impact of age and sex on the quality of life following radioactive iodine ablation in patients with thyroid cancer. AB - PURPOSE: We assessed patient discomfort and identified factors predictive of discomfort while receiving radioactive iodine (RAI) ablation. METHODS: Between August 2015 and April 2016, 52 patients with differentiated thyroid cancer were enrolled in this study. All patients received recombinant human thyroid stimulating hormone (rhTSH) aided RAI ablation using 3.7 GBq or 5.55 GBq of RAI. Discomfort during their stay for RAI ablation was evaluated using a symptom questionnaire. We analyzed the relationship between the patient's clinical data and the scores for the 15 items of the symptom questionnaire. We compared scores of questionnaires between male and female, under 45 years old and 45 and older, RAI activity of 3.7 GBq and 5.55 GBq. Also, scores of daily questionnaires were tested for differences. RESULTS: Most patients did not have severe discomfort, but some patients had mild discomfort during their stay for RAI ablation, despite using rhTSH. Important determinants of discomfort were sex and age. Female patients reported more symptoms of fatigue, facial edema, cold intolerance, and nausea. Older patients (45 and older) complained of insomnia more often. However, the dose of RAI ablation (3.7 GBq vs 5.55 GBq) did not affect the scores of questionnaires. CONCLUSIONS: Sex and age were important predictors of patient's discomfort during RAI ablation. Clinicians need to explain more about treatment and predicted discomforts to such patients before RAI ablation. PMID- 29533425 TI - Different patterns of dopaminergic and serotonergic dysfunction in manic, depressive and euthymic phases of bipolar disorder. AB - A variety of alterations in brain neurotransmitter systems has been proposed as the cause of bipolar disorder (BD). We conducted a PUBMED search, which provided a total of 45 in vivo investigations with PET and SPECT, in which binding to serotonin transporter (SERT), 5-HT1A receptor (R), 5-HT2AR, dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), D1R, D2R, muscarinic M2R and nicotinic beta2-nAChR as well as dopamine synthesis and/or dopamine release were assessed in BD patients in the manic (6 studies, 39 patients, 77 controls), depressive (15 studies, 248 patients, 488 controls) or eu- thymic condition (18 studies, 265 patients, 293 controls) and in mixed collectives of BD patients (6 studies, 55 patients, 80 controls). The retrospective analysis revealed a complex pattern of dysregulations within and between neurotransmitter systems, which is causally linked to the acute and euthymic states of BD. While increased mesencephalic, limbic and parietotemporoccipital serotonin and increased frontal dopamine underlie mania, the depressive state is characterized by decreased frontal and limbic serotonin, increased frontal and limbic acetylcholine and increased frontal dopamine. Also in euthymia, no normalization of receptor and transporter densities was observed. Alterations of regulation states of bindings sites, however, act together to achieve a normalization of mesencephalic, limbic and cortical serotonin. PMID- 29533426 TI - Military Prehospital Use of Low Titer Group O Whole Blood. AB - The military's use of whole-blood transfusions is not new but has recently received new emphasis by the Tactical Combat Casualty Care Committee. US Army units are implementing a systematic approach to obtain and use whole blood on the battlefield. This case report reviews the care of the first patient to receive low titer group O whole blood (LTOWB) transfusion, using a new protocol. PMID- 29533427 TI - Benefit of Critical Care Flight Paramedic-Trained Search and Rescue Corpsmen in Treatment of Severely Injured Aviators. AB - During routine aircraft start-up procedures at a US Naval Air Station, an aviation mishap occurred, resulting in the pilot suffering a traumatic brain injury and the copilot acquiring bilateral hemopneumothoraces, a ruptured diaphragm, and hepatic and splenic contusions. The care of both patients, including at point of injury and en route to the closest trauma center, is presented. This case demonstrates a benefit from advanced life-saving interventions and critical care skills beyond the required scope of practice of search and rescue medical technicians as dictated by relevant instructions. PMID- 29533428 TI - Challenges of Transport and Resuscitation of a Patient With Severe Acidosis and Hypothermia in Afghanistan. AB - We present the case of a patient with new-onset diabetes, severe acidosis, hypothermia, and shock who presented to a Role 1 Battalion Aid Station (BAS) in Afghanistan. The case is unique because the patient made a rapid and full recovery without needing hemodialysis. We review the literature to explain how such a rapid recovery is possible and propose that hypothermia in the setting of his severe acidosis was protective. PMID- 29533429 TI - The Shrail: A Comparison of a Novel Attachable Rail System With the Current Deployment Operating Table. AB - The current forward surgical team (FST) operating table is heavy and burdensome and hinders essential movement flexibility. A novel attachable rail system, the Shrail, has been developed to overcome these obstacles. The Shrail turns a North Atlantic Treaty Organization litter into a functional operating table. A local FST compared the assembly of the FST operating table with assembling the Shrail. Device weight, storage space, and assembly space were directly measured and compared. The mean assembly time required for the Shrail was significantly less compared with the operating table (23.36 versus 151.6 seconds; p <= .01). The Shrail weighs less (6.80kg versus 73.03kg) and requires less storage space (0.019m3 versus 0.323m3) compared with the current FST operating table. The Shrail provides an FST with a faster, lighter surgical table assembly. For these reasons, it is better suited for the demands of an FST and the implementation of prolonged field care. PMID- 29533430 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA): Introduction. PMID- 29533431 TI - Bringing Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Closer to the Point of Injury. AB - BACKGROUND: The management of noncompressible torso hemorrhage remains a significant issue at the point of injury. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been used in the hospital to control bleeding and bridge patients to definitive surgery. Smaller delivery systems and wirefree devices may be used more easily at the point of injury by nonphysician providers. We investigated whether independent duty military medical technicians (IDMTs) could learn and perform REBOA correctly and rapidly as assessed by simulation. METHODS: US Air Force IDMTs without prior endovascular experience were included. All participants received didactic instruction and evaluation of technical skills. Procedural times and pretest/posttest examinations were administered after completion of all trials. The Likert scale was used to subjectively assess confidence before and after instruction. RESULTS: Eleven IDMTs were enrolled. There was a significant decrease in procedural times from trials 1 to 6. Overall procedural time (+/- standard deviation) decreased from 147.7 +/- 27.4 seconds to 64 +/- 8.9 seconds (rho < .001). There was a mean improvement of 83.7 +/- 24.6 seconds from the first to sixth trial (rho < .001). All participants demonstrated correct placement of the sheath, measurement and placement of the catheter, and inflation of the balloon throughout all trials (100%). There was significant improvement in comprehension and knowledge between the pretest and posttest; average performance improved significantly from 36.4.6% +/- 12.3% to 71.1% +/- 8.5% (rho < .001). Subjectively, all 11 participants noted significant improvement in confidence from 1.2 to 4.1 out of 5 on the Likert scale (rho < .001). CONCLUSION: Technology for aortic occlusion has advanced to provide smaller, wirefree devices, making field deployment more feasible. IDMTs can learn the steps required for REBOA and perform the procedure accurately and rapidly, as assessed by simulation. Arterial access is a challenge in the ability to perform REBOA and should be a focus of further training to promote this procedure closer to the point of injury. PMID- 29533432 TI - Feasibility and Proposed Training Pathway for Austere Application of Resuscitative Balloon Occlusion of the Aorta. AB - BACKGROUND: Noncompressible junctional and truncal hemorrhage remains a significant cause of combat casualty death. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an effective treatment for many junctional and noncompressible hemorrhages. The current hospital standard for time of placement of REBOA is approximately 6 minutes. This study examined the training process and the ability of nonsurgical physicians to apply REBOA therapy in an austere field environment. METHODS: This was a skill acquisition and feasibility study. The participants for this experiment were two board-certified military emergency medicine physicians with no prior endovascular surgery exposure. Both providers attended two nationally recognized REBOA courses for training. A perfused cadaver model was developed for the study. Each provider then performed REBOA during different phases of prehospital care. Time points were recorded for each procedure. RESULTS: There were 28 REBOA catheter placement attempts in 14 perfused cadaver models in the nonhospital setting: eight placements in a field setting, eight placements in a static ambulance, four placements in a moving ambulance, and eight placements inflight on a UH-60 aircraft. No statistically significant differences with regard to balloon inflation time were found between the two providers, the side where the catheter was placed, or individual cadaver models. Successful placement was accomplished in 85.7% of the models. Percutaneous access was successful 53.6% of the time. The overall average time for REBOA placement was 543 seconds (i.e., approximately 9 minutes; median, 439 seconds; 95% confidence interval [CI], 429-657) and the average placement time for percutaneous catheters was 376 seconds (i.e., 6.3 minutes; 95% CI, 311-44 seconds) versus those requiring vascular cutdown (821 seconds; 95% CI, 655-986). Importantly, the time from the decision to convert to open cutdown until REBOA placement was 455 seconds (95% CI, 285-625). CONCLUSION: This study demonstrated that, with proper training, nonsurgical providers can properly place REBOA catheters in austere prehospital settings at speeds. PMID- 29533433 TI - Laboratory Model of a Collapsible Tube to Develop Bleeding Control Interventions. AB - BACKGROUND: To develop knowledge of mechanical control of bleeding in first aid, a laboratory model was set up to simulate flow through a blood vessel. A collapsible tube was used to mimic an artery in two experiments to determine (1) the extent of volumetric flow reduction caused by increases in the degree of compression of the vessel and (2) the extent of flow reduction caused by increases in the length of compression. METHODS: Water was used in vertical tubing. Gravity applied a pressure gradient of about 100mmHg to cause flow. A silicone tube (10mm-diameter lumen [the inner opening], 1mm-thick wall, 150mm length) was used. Tests of no compression of the external wall constituted the control group for both experiments. For all groups, flow volume was sampled over a period of time, and six samples were averaged. In both experiments, the study group consisted of tests with compression that was measured as the reduced area of the luminal cross section. In the first experiment, six groups with luminal area reductions of 0% (control), 74%, 81%, 91%, 94%, and 97% were tested. In the second experiment at 74% luminal area reduction, the three lengths of compression were 5mm, 20mm, and 70mm. The measured data were compared with calculated data by applying established mathematical equations. RESULTS: In the first experiment, flow decreased with decreasing area due to luminal compression, but the association was a parabolic curve such that 94% or greater reduction in luminal area was required to reduce flow by greater than 50%. A reduction in luminal area of 97% reduced flow by 95%. In the second experiment, mean flow rates were not significantly different among the three lengths of compression. Measured data and calculated data were in good agreement. CONCLUSIONS: Compared with an uncompressed vessel, volumetric flow of water through a single, unsupported collapsible tube in steady, nonpulsatile conditions with compression applied to its external wall to produce a reduction in luminal area of 97% reduced flow by 95%. Flow was affected by the degree of compression but not by the length of compression. PMID- 29533434 TI - The Myth of Hyperresilience Evolutionary Concept Analysis of Resilience in Special Operations Forces. AB - Despite many resilience studies and resilience-building initiatives in the military, resilience as a concept remains granularly unexamined, vague, and inconsistently interpreted throughout military-specific research literature. Specifically, studies of military suicide and related mental health constructs assert that Servicemembers in Special Operations Forces (SOF) possess higher levels of resilience without providing an empirical basis for these statements. To provide rigorous evidence for future studies of resilience in SOF, a concept analysis was performed via Rodgers' evolutionary method to contextualize resilience in the SOF community and provide accurate redefinitions on which theoretical and methodological frameworks can be constructed reliably. PMID- 29533435 TI - Intramuscular Tranexamic Acid in Tactical and Combat Settings. AB - BACKGROUND: Uncontrolled hemorrhage remains a leading cause of preventable death in tactical and combat settings. Alternate routes of delivery of tranexamic acid (TXA), an adjunct in the management of hemorrhagic shock, are being studied. A working group for the Committee for Tactical Emergency Casualty Care reviewed the available evidence on the potential role for intramuscular (IM) administration of TXA in nonhospital settings as soon as possible from the point of injury. METHODS: EMBASE and MEDLINE/PubMed databases were sequentially searched by medical librarians for evidence of TXA use in the following contexts and/or using the following keywords: prehospital, trauma, hemorrhagic shock, optimal timing, optimal dose, safe volume, incidence of venous thromboembolism (VTE), IM bioavailability. RESULTS: A total of 183 studies were reviewed. The strength of the available data was variable, generally weak in quality, and included laboratory research, case reports, retrospective observational reviews, and few prospective studies. Current volume and concentrations of available formulations of TXA make it, in theory, amenable to IM injection. Current bestpractice guidelines for large-volume injection (i.e., 5mL) support IM administration in four locations in the adult human body. One case series suggests complete bioavailability of IM TXA in healthy patients. Data are lacking on the efficacy and safety of IM TXA in hemorrhagic shock. CONCLUSION: There is currently insufficient evidence to support a strong recommendation for or against IM administration of TXA in the combat setting; however, there is an abundance of literature demonstrating efficacy and safety of TXA use in a broad range of patient populations. Balancing the available data and risk- benefit ratio, IM TXA should be considered a viable treatment option for tactical and combat applications. Additional studies should focus on the optimal dose and bioavailability of IM dosing of patients in hemorrhagic shock, with assessment of potential downstream sequelae. PMID- 29533436 TI - Successful Use of Ketamine as a Prehospital Analgesic by Pararescuemen During Operation Enduring Freedom. AB - Effective analgesia is a crucial part of the care and resuscitation of a traumatically injured patient. These secondary effects of pain may increase morbidity and mortality in the acutely injured patient. When ketamine is administered appropriately in the clinical setting, it can provide analgesia, anxiolysis, and amnesia for patients with less respiratory depression and hypotension than equivalent doses of opioid analgesics. PMID- 29533437 TI - Blood Lead Toxicity Analysis of Multipurpose Canines and Military Working Dogs. AB - Special Operations Forces and their accompanying tactical multipurpose canines (MPCs) who are involved in repeated live-fire exercises and military operations have the potential for increased blood lead levels and toxicity due to aerosolized and environmental lead debris. Clinical lead-toxicity symptoms can mimic other medical disorders, rendering accurate diagnosis more challenging. The objective of this study was to examine baseline lead levels of MPCs exposed to indoor firing ranges compared with those of nontactical military working dogs (MWDs) with limited or no exposure to the same environment. In the second part of the study, results of a commercially available, human-blood lead testing system were compared with those of a benchtop inductively coupled plasma-mass spectrometry (ICP-MS) analysis technique. Blood samples from 18 MPCs were tested during routine clinical blood draws, and six samples from a canine group with limited exposure to environmental lead (nontactical MWDs) were tested for comparison. There was a high correlation between results of the commercial blood testing system compared with ICP-MS when blood lead levels were higher than 4.0ug/dL. Both testing methods recorded higher blood lead levels in the MPC blood samples than in those of the nontactical MWDs, although none of the MPC samples tested contained lead levels approaching those at which symptoms of lead toxicity have previously been reported in animals (i.e., 35ug/dL). PMID- 29533438 TI - Ocular Injuries and Cultural Influences in Afghanistan During 5 Months of Operation Enduring Freedom. AB - In support of Operation Enduring Freedom, American, North American Treaty Organization (NATO) Coalition, and Afghan forces worked together in training exercises and counterinsurgency operations. While serving at the NATO Role 3 Multinational Medical Unit, Kandahar, Afghanistan, numerous patients with explosive blast injuries (Coalition and Afghan security forces, and insurgents) were treated. A disparity was noted between the ocular injury patterns of US and Coalition forces in comparison with their Afghan counterparts, which were overwhelmingly influenced by the use, or lack thereof, of eye protection. Computed tomography imaging coupled, with a correlative clinical examination, demonstrated the spectrum of ocular injuries that can result from an explosive blast. Patient examination was performed by Navy radiologists and an ophthalmologist. A cultural analysis by was performed to understand why eye protection was not used, even if available to Afghan forces, by the injured patients in hope of bridging the gap between Afghan cultural differences and proper operational risk management of combat forces. PMID- 29533439 TI - Lead Exposure in the Special Operations Shooter How to Prevent Cognitive Decline and Permanent Disability. AB - Lead toxicity is an important environmental disease and its effects on the human body can be devastating. Unique exposures to Special Operations Forces personnel may include use of firing ranges, use of automotive fuels, production of ammunition, and bodily retention of bullets. Toxicity may degrade physical and psychological fitness, and cause long-term negative health outcomes. Specific effects on fine motor movements, reaction times, and global function could negatively affect shooting skills and decision-making. Biologic monitoring and chelation treatment are poor solutions for protecting this population. Through primary prevention, Special Operations Forces personnel can be protected, in any environment, from the devastating effects of lead exposure. This article offers tools to physicians, environmental service officers, and Special Operations Medics for primary prevention of lead poisoning in the conventional and the austere or forward deployed environments. PMID- 29533440 TI - Routine Screening Laboratory Studies for Nonheat Stroke Field Heat Injuries Are Unnecessary: A Retrospective Review. AB - BACKGROUND: Heat injuries are common in the military training environment. Base policies often mandate that heat causalities require evaluation at a higher level of care, which comes at significant use of resources. Laboratory studies are often ordered routinely, but their utility is unclear at this time. METHODS: This project evaluated the use of screening laboratory studies for heat casualties brought to Bayne-Jones Army Community Hospital, Fort Polk, Louisiana. Casualties brought from the field directly to the emergency department (ED) were included. Abnormalities in laboratory study findings, admission/discharge rates, and length of stay were documented. RESULTS: From May through September 2014, 104 casualties were seen in the ED because of heat injury. Laboratory tests were ordered for 101 patients. Of these, 11 patients were admitted to the hospital because of laboratory, history, and/or physical examination abnormalities. Nine were discharged in less than 24 hours. The remaining two were discharged within 48 hours; both had documented altered mental status on arrival to the ED. Laboratory test abnormalities were seen in most of the patients and appeared to have no impact on the decision to admit. CONCLUSION: Routine laboratory studies appeared to have low clinical utility in this patient population. A more targeted approach based on the history and physical examination may reduce military resource use. PMID- 29533441 TI - Prehospital Care of Canine Gastric Dilatation and Volvulus. AB - The intent of the Operational K9 (OpK9) ongoing series is to provide the Special Operations Medical Association community with clinical concepts and scientific information on preventive and prehospital emergency care relevant to the OpK9. Often the only medical support immediately available for an injured or ill OpK9 in the field is their handler or the human Special Operations Combat Medic or civilian tactical medic attached to the team (e.g., Pararescueman, 18D, SWAT medic). The information is applicable to personnel operating within the US Special Operations Command as well as civilian Tactical Emergency Medical Services communities that may have the responsibility of supporting an OpK9. PMID- 29533442 TI - Spiritual Fitness: An Essential Component of Human Performance Optimization. AB - Spirituality is a key interweaving and interacting domain, and an integral component for maintaining Special Operations Forces readiness; however, it remains an under-researched and likely one of the most poorly understood domains of Preservation of the Force and Family and Total Force Fitness initiatives. Although there are numerous factors that contribute to spiritual performance or spiritual fitness, core values and value-directed living are essential. An initial step toward spiritual performance or fitness is developing core values and identity, followed by a second step toward spiritual performance or fitness, which is developing an increased awareness and deeper understanding of those values. This process of developing core values and identity, and building awareness can be enhanced through cognitive flexibility and agility (psychological performance domain). This article explains the importance of "spirituality" as a component of Special Operations Forces performance and describes approaches to enhancing performance through various spiritual activities, including mindfulness, meditation, and prayer. These three practices can be adapted and modified to be more vertical or more horizontal in their application. PMID- 29533443 TI - Giardiasis. PMID- 29533444 TI - Epidemiological Evidence and Possible Mechanisms for the Association Between Cigarette Smoking and Injuries (Part 1). AB - Surveys indicated that 24% of military personnel are current cigarette smokers. Smoking is well known to increase the risk of cancers, cardiovascular and respiratory diseases, reproductive problems, and other medical maladies, but one of the little known effects of smoking is that on injuries. There is considerable evidence from a variety of sources that (1) smoking increases overall injury risk, (2) the greater the amount of smoking, the higher is the injury risk, and (3) smoking is an independent injury risk factor. Smoking not only affects the overall injury risk but also impairs healing processes following fractures (e.g., longer healing times, more nonunions, more complications), ligament injury (e.g., lower subjective function scores, greater joint laxity, lower subsequent physical activity, more infections), and wounding (e.g., delayed healing, more complications, less satisfying cosmetic results). Smoking may elicit effects on fractures through low bone mineral density (BMD), lower dietary intake of calcium and vitamin D, altered calcium metabolism, and effects on osteogenesis and sex hormones. Effects on wound healing may be mediated through altered neutrophils and monocytes functions resulting in reduced ability to fight infections and remove damaged tissue, reduced gene expression of cytokines important for tissue healing, and altered fibroblast function leading to lower density and amount of new tissue formation. Limited data suggest smoking cessation has favorable effects on various aspects of bone health over periods of 1 to 30 years. Favorable effects on neutrophil and monocyte functions may occur as early as 4 weeks, but fibroblast function and collagen metabolism (important for wound remodeling) appear to take considerably longer and may be dependent on the amount of prior smoking. Part 2 of this series will use this information to explore the possibility of a causal relationship between smoking and injuries. PMID- 29533445 TI - Diagnosis and Treatment of Anaphylaxis During Law Enforcement Operations. PMID- 29533446 TI - Integrating Chemical Biological, Radiologic, and Nuclear (CBRN) Protocols Into TCCC Introduction of a Conceptual Model - TCCC + CBRN = (MARCHE)2. AB - The authors would like to introduce TCCC [Tactical Combat Casualty Care] + CBRN [chemical, biological, radiological, and nuclear] = (MARCHE)2 as a conceptual model to frame the response to CBRN events. This model is not intended to replace existing and well-established literature on CBRNE events but rather to serve as a response tool that is an adjunct to agent specific resources. PMID- 29533447 TI - Documentation in Prolonged Field Care. PMID- 29533448 TI - Prehospital Medicine and the Future Will ECMO Ever Play a Role? AB - Due to the hybrid warfare currently experienced by multiple NATO coalition and NATO partner nations, the tactical combat casualty care (TCCC) paradigm is greatly challenged. One of the major challenges to TCCC is the ad hoc extension phase in resource-poor environments, referred to as prolonged field care (PFC) and forward resuscitative care (FRC). The nuanced clinical skills with limited resources required by warfighters and auxiliary health care professionals to mitigate death on the battlefield and prevent morbidity and mortality in the PFC phase represent a balance that is still under review. The aim of our article is to describe the connection between extracorporeal membrane oxygenation (ECMO) or the extracorporeal life support (ECLS) treatment and its possible improvement in prehospital trauma care, at a Role 1 or 2 facility and, more provocatively, in the PFC phase of care in the future through innovative technology and how it connects with FRC. We report and describe here the primary components of ECMO/ECLS and present the main concept of a human extracorporeal circulation cocoon as a transitional living form for the cardiopulmonary stabilization of wounded combatants on the battlefield and their transportation to higher echelons of care and treatment facilities (to include damage control resuscitation [DCR] and damage control surgery [DCS]). As clinical governance, these matters would fall within the remit of the Committee on Surgical Combat Casualty Care (CoSCCC) and the Committee on Enroute Combat Casualty Care (CoERCCC), and it is within this framework that we propose this concept piece of ECMO in the prehospital space. We caution that this report is a proposed innovation to TCCC but also serves to push the envelope of the PFC and FRC paradigm. What we propose will not change the practice this year, but as ECMO technology progresses, it may change our practice within the next decade. We conclude with proposed novel future research to save life on the battlefield with ECMO as a major challenge and one worth the focus of further research. Medicine is controversial and constantly changing; for those who work in prehospital and battlefield medicine, change is the only constant on which we rely, and without provocative discussion that makes our systems and practice more robust, we will fail. PMID- 29533449 TI - Editorial Response. PMID- 29533451 TI - I Can't Breathe-A SIPe of Water. PMID- 29533450 TI - Patella Fracture in US Servicemember in an Austere Location. AB - OBJECTIVE: Review the management of a patient with acute patella fracture supported by telemedical consultation. Clinical Context: Regionally Aligned Forces (RAF) supporting US Army Africa/Southern European Task Force (USARAF/ SETAF) in Africa Command area of responsibility. Care was provided by a Role I facility on the compound. Organic Expertise: Three 68W combat medics; one Special Operations Combat Medic (SOCM). Closest Medical Support: Organic battalion physician assistant (PA) located in the United States; USARAF PA located in a European country; French Role II located in nearby West African country; telemedical consults via e-mail, phone, or videoteleconsultation. Earliest Evacuation: Estimated at 12 to 24 hours with appropriate clearances. PMID- 29533452 TI - You Never Know, Until You Know, and Then You Know: An Interview With COL (Ret) John F. Kragh Jr, MD. PMID- 29533453 TI - Medicine on the Edge of Darkness. AB - Austere care of the wounded is challenging for all Western medical professionals nurse, medic, or physician. There can be no doubt that working for the first time, either for a nongovernment organization or in the Special Forces, you will be taking care of wounded patients outside your training and experience. You must have the ability to adapt to and overcome lack of resources and equipment, and accept standards of treatment often very different and lower than that common in western hospitals. The International Committee of the Red Cross (ICRC) was asked to provide relief for the Pakistan Red Crescent in 1982 and set up the ICRC Hospital for Afghan War Wounded in Peshawar on the border to Afghanistan. This article relates how a western-trained young anesthetist on a ICRC surgical team experienced this, at the time, austere environment. PMID- 29533454 TI - Proceedings from the 2017 Mid-Year Meeting of the Committee for Tactical Emergency Casualty Care (C-TECC) and Committee Updates. PMID- 29533455 TI - Committee on Tactical Combat Casualty Care: Meeting Minutes. 6-7 September, 2017; San Antonio, TX. PMID- 29533456 TI - Effect of age on electrical nerve conduction in the somatosensory pathway and its correlation with somatometry and plasma concentrations of musculoskeletal enzymes in male rhesus monkeys (Macaca mulatta) held in captivity. AB - BACKGROUND: Somatosensory evoked potentials (SEPs) make it possible to obtain functional data on the activity of somatosensory pathway. OBJECTIVE: To evaluate the ontogeny of electrical nerve conduction in male rhesus monkeys using SEPs in correlation with the development of the musculoskeletal system based on somatometry and musculoskeletal enzymes. METHODS: Somatosensory evoked potentials of the medial and tibial nerves were performed, and somatometric measurements were obtained: total length, arm and forearm length, and thigh and calf length. Analysis of the musculoskeletal enzymes, lactic dehydrogenase, and creatininase was conducted using blood samples in 20 rhesus monkeys divided into 5 groups. RESULTS: Statistical analysis manifested a delay in the appearance of latencies as age increased. Also evident was a strong, direct relation between the lengths and the value of the latencies of the SEP, together with an inverse relation between the musculoskeletal enzymes. CONCLUSIONS: These findings contribute to standardizing this animal model in the neurophysiological sciences. PMID- 29533457 TI - Automatic deformable registration of histological slides to MUCT volume data. AB - Localizing a histological section in the three-dimensional dataset of a different imaging modality is a challenging 2D-3D registration problem. In the literature, several approaches have been proposed to solve this problem; however, they cannot be considered as fully automatic. Recently, we developed an automatic algorithm that could successfully find the position of a histological section in a micro computed tomography (MUCT) volume. For the majority of the datasets, the result of localization corresponded to the manual results. However, for some datasets, the matching MUCT slice was off the ground-truth position. Furthermore, elastic distortions, due to histological preparation, could not be accounted for in this framework. In the current study, we introduce two optimization frameworks based on normalized mutual information, which enabled us to accurately register histology slides to volume data. The rigid approach allocated 81 % of histological sections with a median position error of 8.4 MUm in jaw bone datasets, and the deformable approach improved registration by 33 MUm with respect to the median distance error for four histological slides in the cerebellum dataset. PMID- 29533458 TI - Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS: Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS: Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. (c) 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 29533459 TI - Head and neck squamous cell cancers in the United States are rare and the risk now is higher among white individuals compared with black individuals. AB - BACKGROUND: The increasing incidence of oropharyngeal squamous cell cancer (OPSCC) is well established. However, up-to-date incidence estimates and trends for head and neck squamous cell cancers (HNSCCs) overall, including major anatomic sites, and nonoropharyngeal (non-OP) HNSCCs by sex, race, and age in the United States are not well described. METHODS: A retrospective analysis of incident HNSCCs during 1992 through 2014 using the Surveillance, Epidemiology, and End Results database was performed to evaluate the incidence of HNSCCs overall, OPSCC, and non-OP HNSCC (those of the larynx, oral cavity, hypopharynx, nasopharynx, and nasal cavity). Incidence rates were calculated overall and by subgroups of interest, and incidence rate ratios were used to compare rates between groups. The incidence rates presented were per 100,000 population and were age adjusted to the 2000 US standard population (19 age groups; Census P25 1130). The annual percent change (APC) was modeled with and without joinpoints. RESULTS: The incidence of HNSCC overall declined (average APC [aAPC], -0.8; P<.001) despite significant increases in the incidence of OPSCCs, most notably between 2000 and 2014 (APC, 2.1; P<.001). Significant declines in incidence were observed for all non-OP HNSCC sites for both women and men (P<.001 each). Among women, the risk of OPSCC also significantly decreased (aAPC, -0.8; P = .002), whereas the risk among men was stable during 1992 through 2001 (APC, 0.4; P = .42) and then significantly increased from 2001 to 2014 (APC, 2.7; P<.001). Decreases in the risk of non-OP HNSCC were especially large for black women (aAPC, -2.6; P<.001) and men (aAPC, -3.0; P<.001). Although the incidence of HNSCC previously was highest among black individuals, since 2009 its incidence has been higher among white compared with black individuals. CONCLUSIONS: The incidence of HNSCC is declining, especially for non-OP HNSCC and among black individuals. Cancer 2018;124:2125-33. (c) 2018 American Cancer Society. PMID- 29533460 TI - What is told when the story is retold? Consistency of victimization reports in psychiatric patients. AB - The use of retrospective self-reports is a major methodological concern when ascertaining the occurrence of victimization experiences, with additional concerns when assessing psychiatric patients. The test for consistency can overcome some of these concerns, increasing the confidence in the information reported. Our aim was twofold: (1) to know the consistency of victimization reports; and (2) to test the role of changes on emotional distress in predicting report discrepancies, in a sample of 34 adult psychiatric patients. Participants were assessed twice, with a year interval. Sexual abuse was the experience that presented the higher level of consistency for childhood victimization, while assault with a weapon had the higher consistency level for adolescent and adult victimization. We found that increases on emotional distress predicted report discrepancies, and more specifically, increases in the report of victimization. Our results displayed acceptable consistency levels, suggesting some stability in the reporting of victimization over time. Considering that inconsistencies tended either to increases and decreases in the reporting of victimization, it would be important to consider the impact of such experiences when intervening with psychiatric patients. PMID- 29533461 TI - Exogenous trehalose enhanced the biocontrol efficacy of Hanseniaspora uvarum against grape berry rots caused by Aspergillus tubingensis and Penicillium commune. AB - BACKGROUND: Primarily, chemical pesticides are commonly used to control preharvest and postharvest diseases of fruits and vegetables. However, there is strong public concern regarding the human and environmental health problems that might emanate from the residues of these chemical pesticides. As a result, biocontrol is often preferred due to its safety for humans and animals. The microbial antagonists employed often encounter variable climatic conditions, which affect their efficacy. In this study, the biocontrol efficacy of Hanseniaspora uvarum enhanced with trehalose against Aspergillus tubingensis and Penicillium commune in grapes was investigated. RESULTS: H. uvarum Y3 pretreated with 2.0% w/v trehalose in nutrient yeast dextrose broth (NYDB) before used significantly inhibited the incidence of decay and lesion diameter without affecting the sensory qualities of the grapes stored at either 4 degrees C or 20 degrees C. There was also a significant (P < 0.05) increase in the population dynamics of H. uvarum that was pretreated with 2% trehalose compared to that of H. uvarum alone. The in vitro assay on spore germination revealed an inhibition of A. tubingensis and P. commune by 85.6% and 87.0% respectively. Scanning electron microscopy results showed that both untreated H. uvarum and H. uvarum pre-treated with the 2% w/v trehalose before use inhibited fungal mycelium and development of grape rot. CONCLUSION: The biocontrol efficacy of H. uvarum was enhanced against grape rot caused by A. tubingensis and P. commune. The findings indicate the potential applicability of trehalose in the enhancement of H. uvarum. (c) 2018 Society of Chemical Industry. PMID- 29533462 TI - High acclimation potential in floating Macrocystis pyrifera to abiotic conditions even under grazing pressure - a field study. AB - The persistence of floating seaweeds, which depends on abiotic conditions but also herbivory, had previously been mostly tested in outdoor mesocosm experiments. In order to investigate if the obtained mesocosm results of high seaweed persistence under natural environmental conditions and under grazing pressure can be extrapolated to field situations, we conducted in situ experiments. During two summers (2007 and 2008), Macrocystis pyrifera was tethered (for 14 d) to lines in the presence and absence of the amphipod Peramphithoe femorata at three sites (Iquique, Coquimbo, Calfuco). We hypothesized that grazing damage and seaweed persistence vary among sites due to different abiotic factors. By incubating the sporophytes in mesh bags, we were either able to isolate (grazing) or exclude (control) amphipods. To test for a mesh bag artifact, a set of sporophytes was incubated without mesh bags (natural). Mesh bags used to exclude herbivores influenced sporophyte growth and physiological performance. The chlorophyll a (Chl a) content depended largely on grazers and grazed sporophytes grew less than natural and control sporophytes within the two summers. A decrease in Chl a content was found for the sites with the highest prevailing irradiances and temperatures, suggesting an efficient acclimation to these sea surface conditions. Our field-based results of sporophyte acclimation ability even under grazing pressure widely align with previous mesocosm results. We conclude that M. pyrifera and other temperate floating seaweeds can function as long-distance dispersal vectors even with hitchhiking mesoherbivores. PMID- 29533464 TI - Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion. AB - In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29533463 TI - Parturition and the perinatal period: can mode of delivery impact on the future health of the neonate? AB - Caesarean section and instrumental delivery rates are increasing in many parts of the world for a range of cultural and medical reasons, with limited consideration as to how 'mode of delivery' may impact on childhood and long-term health. However, babies born particularly by pre-labour caesarean section appear to have a subtly different physiology from those born by normal vaginal delivery, with both acute and chronic complications such as respiratory and cardio-metabolic morbidities being apparent. It has been hypothesized that inherent mechanisms within the process of labour and vaginal delivery, far from being a passive mechanical process by which the fetus and placenta are expelled from the birth canal, may trigger certain protective developmental processes permissive for normal immunological and physiological development of the fetus postnatally. Traditionally the primary candidate mechanism has been the hormonal surges or stress response associated with labour and vaginal delivery, but there is increasing awareness that transfer of the maternal microbiome to the infant during parturition. Transgenerational transmission of disease traits through epigenetics are also likely to be important. Interventions such as probiotics, neonatal gut seeding and different approaches to clinical care have potential to influence parturition physiology and improve outcomes for infants. PMID- 29533465 TI - The Airway App: exploring the role of smartphone technology to capture emergency front-of-neck airway experiences internationally. AB - In this exploratory study we describe the utility of smartphone technology for anonymous retrospective observational data collection of emergency front-of-neck airway management. The medical community continues to debate the optimal technique for emergency front-of-neck airway management. Although individual clinicians infrequently perform this procedure, hundreds are performed annually worldwide. Ubiquitous smartphone technology and internet connectivity have created the opportunity to collect these data. We created the 'Airway App', a smartphone application to capture the experiences of healthcare providers involved in emergency front-of-neck airway procedures. In the first 18-month period, 104 emergency front-of-neck airway management reports were received; 99 (95%) were internally valid and unique from 21 countries. Eighty-one (82%) were performed by non-surgeons and 63 (64%) were 'cannot intubate, cannot oxygenate' emergencies. Overall first-attempt success varied by technique; 45 scalpel-bougie cricothyroidotomy (37 first-attempt success), 25 surgical cricothyroidotomy (15 first-attempt success), eight cannula cricothyroidotomy (five first-attempt success), six wire-guided cricothyroidotomy (three first-attempt success) and 15 tracheostomy reports (11 first-attempt success). The most commonly reported positive human factors were good communication, good teamwork and/or skilled personnel. The most commonly reported negative human factors were fixation on multiple tracheal intubation attempts, delay in initiating emergency front-of neck airway and/or the failure to plan for failure. Due to the anonymous nature of reporting, reports are open to recollection bias and spurious reporting. We conclude collection of data using a smartphone application is feasible and has the potential to expand our knowledge of emergency front-of-neck airway management. PMID- 29533466 TI - The advanced glycation end-product Nepsilon -carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention. AB - Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs), which characterizes all of the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumour-promoting role of receptor for advanced glycation end products (RAGE), the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE Nepsilon -carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration-dependent and time-dependent manner, and activated downstream tumourigenic signalling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in eight of 11 (72.7%) CML-treated versus one of 11 (9.1%) vehicle-treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms, and might be responsible for the additional risk conferred by diabetes and other conditions characterized by increased AGE accumulation. Finally, our data suggest that an AGE reduction strategy, instead of RAGE inhibition, might be suitable for the risk management and prevention of PaC. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29533467 TI - Depth in Cultural Socialization in Families with Children Adopted from China. AB - Parents raising children adopted from a different racial/ethnic group usually engage in cultural socialization-providing activities in adoptees' birth culture hoping to instill pride and help adoptees develop a positive identity. Adoptive parents engage in a wide variety of socialization activities, yet adult adoptees have reported not having deep enough exposure from their parents. The present study explored the depth of cultural socialization in transracial adoptive families. Informed by Pinderhughes' Ethnic-Racial Socialization model, this study developed a continuum examining the depth in cultural socialization with three indicators: (1) the depth of cultural activities, (2) parents' motivation for cultural socialization, and (3) parental cultural attitudes. Qualitative analyses of 41 White parents raising children adopted from China found that parents' motivation and acknowledgement of cultural differences reflected deep appreciation of adoptees' birth culture, however, activities they provided were not as deep. Activities that facilitated close relationships with people who shared adoptees' background in a natural context appeared to provide the deepest cultural connection. Despite limitations, the study demonstrated that the depth continuum was able to capture variations and nuances in cultural socialization. Suggestions for future research and recommendation for practice were also included. PMID- 29533468 TI - Bespoke intra-operative anaesthesia - the end of the formulaic approach? PMID- 29533469 TI - Health-Related Quality of Life in a Predictive Model for Mortality in Older Breast Cancer Survivors. AB - OBJECTIVES: To develop a predictive model and risk score for 10-year mortality using health-related quality of life (HRQOL) in a cohort of older women with early-stage breast cancer. DESIGN: Prospective cohort. SETTING: Community. PARTICIPANTS: U.S. women aged 65 and older diagnosed with Stage I to IIIA primary breast cancer (N=660). MEASUREMENTS: We used medical variables (age, comorbidity), HRQOL measures (10-item Physical Function Index and 5-item Mental Health Index from the Medical Outcomes Study (MOS) 36-item Short-Form Survey; 8 item Modified MOS Social Support Survey), and breast cancer variables (stage, surgery, chemotherapy, endocrine therapy) to develop a 10-year mortality risk score using penalized logistic regression models. We assessed model discriminative performance using the area under the receiver operating characteristic curve (AUC), calibration performance using the Hosmer-Lemeshow test, and overall model performance using Nagelkerke R2 (NR). RESULTS: Compared to a model including only age, comorbidity, and cancer stage and treatment variables, adding HRQOL variables improved discrimination (AUC 0.742 from 0.715) and overall performance (NR 0.221 from 0.190) with good calibration (p=0.96 from HL test). CONCLUSION: In a cohort of older women with early-stage breast cancer, HRQOL measures predict 10-year mortality independently of traditional breast cancer prognostic variables. These findings suggest that interventions aimed at improving physical function, mental health, and social support might improve both HRQOL and survival. PMID- 29533470 TI - Perioperative beta-blockers for preventing surgery-related mortality and morbidity. AB - BACKGROUND: Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. OBJECTIVES: The objective of this review was to systematically analyse the effects of perioperatively administered beta blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. SEARCH METHODS: We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, Embase , the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. SELECTION CRITERIA: We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. MAIN RESULTS: We included 88 randomized controlled trials with 19,161 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery.CARDIAC SURGERY (53 trials)We found no clear evidence of an effect of beta-blockers on the following outcomes.* All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality evidence.* Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality evidence.* Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality evidence.* Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality evidence.* Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality evidence.* Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality evidence.* Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality evidence.Beta-blockers significantly reduced the occurrence of the following endpoints.* Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality evidence.* Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB five, 6420 participants, high quality evidence.* On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality evidence).NON-CARDIAC SURGERY (35 trials)Beta-blockers significantly increased the occurrence of the following adverse events.* All-cause mortality: RR 1.25, 95% CI 1.00 to 1.57, 11,413 participants, low quality of evidence, number needed to treat for an additional harmful outcome (NNTH) 167.* Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 16, 10,947 participants, high quality evidence.* Bradycardia: RR 2.23, 95% CI 1.48 to 3.36, NNTH 21, 11,033 participants, moderate quality evidence.We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.* Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality evidence.Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta analysis to low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09, 95% CI 1.14 to 3.82, NNTH 265, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.* AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 76, 10,958 participants, high quality evidence.* Myocardial ischaemia: RR 0.51, 95% CI 0.34 to 0.77, NNTB nine, 978 participants, moderate quality evidence.* Supraventricular arrhythmias: RR 0.73, 95% CI 0.57 to 0.94, NNTB 112, 8744 participants, high quality evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.* Ventricular arrhythmias: RR 0.68, 95% CI 0.31 to 1.49, 476 participants, moderate quality evidence.* Congestive heart failure: RR 1.18, 95% CI 0.94 to 1.48, 9173 participants, moderate quality evidence.* Length of hospital stay: mean difference -0.45 days, 95% CI -1.75 to 0.84, 551 participants, low quality evidence. AUTHORS' CONCLUSIONS: According to our findings, perioperative application of beta-blockers still plays a pivotal role in cardiac surgery, as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear.In non-cardiac surgery, evidence shows an association of beta-blockers with increased all-cause mortality. Data from low risk of bias trials further suggests an increase in stroke rate with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke. PMID- 29533471 TI - Functional morphology of the cranio-mandibular complex of the Guira cuckoo (Aves). AB - The cranio-mandibular complex is an important structure involved in food capture and processing. Its morphology is related to the nature of the food item. Jaw muscles enable the motion of this complex and their study is essential for functional and evolutionary analysis. The present study compares available behavioral and dietary data obtained from the literature with novel results from functional morphological analyses of the cranio-mandibular complex of the Guira cuckoo (Guira guira) to understand its relationship with the zoophagous trophic habit of this species. The bite force was estimated based on muscle dissections, measurements of the physiological cross-sectional area, and biomechanical modeling of the skull. The results were compared with the available functional morphological data for other birds. The standardized bite force of G. guira is higher than predicted for exclusively zoophagous birds, but lower than for granivorous and/or omnivorous birds. Guira guira possesses the generalized jaw muscular system of neognathous birds, but some features can be related to its trophic habit. The external adductor muscles act mainly during food item processing and multiple aspects of this muscle group are interpreted to increase bite force, that is, their high values of muscle mass, their mechanical advantage (MA), and their perpendicular orientation when the beak is closed. The m. depressor mandibulae and the m. pterygoideus dorsalis et ventralis are interpreted to prioritize speed of action (low MA values), being most important during prey capture. The supposed ecological significance of these traits is the potential to widen the range of prey size that can be processed and the possibility of rapidly capturing agile prey through changes in the leverage of the muscles involved in opening and closing of the bill. This contributes to the trophic versatility of the species and its ability to thrive in different habitats, including urban areas. PMID- 29533472 TI - Dispersion interactions between neighboring Bi atoms in (BiH3 )2 and Te(BiR2 )2. AB - Triggered by the observation of a short Bi?Bi distance and a Bi?Te?Bi bond angle of only 86.6 degrees in the crystal structure of bis(diethylbismuthanyl)tellurane quantum chemical computations on interactions between neighboring Bi atoms in Te(BiR2 )2 molecules (R = H, Me, Et) and in (BiH3 )2 were undertaken. Bi?Bi distances atoms were found to significantly shorten upon inclusion of the d shells of the heavy metal atoms into the electron correlation treatment, and it was confirmed that interaction energies from spin component-scaled second-order Moller-Plesset theory (SCS-MP2) agree well with coupled-cluster singles and doubles theory including perturbative triples (CCSD(T)). Density functional theory-based symmetry-adapted perturbation theory (DFT-SAPT) was used to study the anisotropy of the interplay of dispersion attraction and steric repulsion between the Bi atoms. Finally, geometries and relative stabilities of syn-syn and syn-anti conformers of Te(BiR2 )2 (R = H, Me, Et) and interconversion barriers between them were computed. (c) 2018 Wiley Periodicals, Inc. PMID- 29533473 TI - Confirmatory factor analysis of the Eating Disorder Examination-Questionnaire: A comparison of five factor solutions across vegan and omnivore participants. AB - OBJECTIVE: The Eating Disorder Examination-Questionnaire (EDE-Q) is a valid and reliable measure of eating-related pathology, but its factor structure has proven difficult to replicate. Given differences in dietary patterns in vegans compared to omnivores, proper measurement of eating disorder symptoms is especially important in studies of animal product avoiders. METHOD: This study compared goodness-of-fit of five alternative models of the EDE-Q in vegans (i.e., individuals refraining from all animal products, n = 318) and omnivores (i.e., individuals not restricting intake of animal products, n = 200). Confirmatory factor analyses were used to compare fit indices of the original four-factor model of the EDE-Q, along with alternative three-, two-, full one-, and brief one factor models. RESULTS: No model provided adequate fit of the data in either sample of respondents. The fit of the brief one-factor model was the closest to acceptable in omnivores, but did not perform as well in vegans. Indicators of fit were comparable in vegans and omnivores across all other models. DISCUSSION: Our data confirm difficulties in replicating the proposed factor structure of the EDE Q, including in vegans. More research is needed to determine the suitability of the EDE-Q for quantifying eating behaviors, including in those abstaining from animal products. PMID- 29533474 TI - Evolution of hindlimb bone dimensions and muscle masses in house mice selectively bred for high voluntary wheel-running behavior. AB - We have used selective breeding with house mice to study coadaptation of morphology and physiology with the evolution of high daily levels of voluntary exercise. Here, we compared hindlimb bones and muscle masses from the 11th generation of four replicate High Runner (HR) lines of house mice bred for high levels of voluntary wheel running with four non-selected control (C) lines. Mass, length, diameter, and depth of the femur, tibia-fibula, and metatarsal bones, as well as masses of gastrocnemius and quadriceps muscles, were compared by analysis of covariance with body mass or body length as the covariate. Mice from HR lines had relatively wider distal femora and deeper proximal tibiae, suggesting larger knee surface areas, and larger femoral heads. Sex differences in bone dimensions were also evident, with males having thicker and shorter hindlimb bones when compared with females. Several interactions between sex, linetype, and/or body mass were observed, and analyses split by sex revealed several cases of sex specific responses to selection. A subset of the HR mice in two of the four HR lines expressed the mini-muscle phenotype, characterized mainly by an ~50% reduction in hindlimb muscle mass, caused by a Mendelian recessive mutation, and known to have been under positive selection in the HR lines. Mini-muscle individuals had elongated distal elements, lighter and thinner hindlimb bones, altered 3rd trochanter muscle insertion positions, and thicker tibia-fibula distal widths. Finally, several differences in levels of directional or fluctuating asymmetry in bone dimensions were observed between HR and C, mini- and normal-muscled mice, and the sexes. This study demonstrates that skeletal dimensions and muscle masses can evolve rapidly in response to directional selection on locomotor behavior. PMID- 29533475 TI - British Neuropathological Society and International Society of Forensic Radiology and Imaging expert consensus statement for post mortem neurological imaging. AB - AIMS: To develop an expert consensus statement regarding appropriate clinical and forensic post mortem neurological imaging. METHODS: An expert panel of clinicians were recruited from registered members of the British Neuropathological Society (BNS) and the International Society of Forensic Radiology and Imaging (ISFRI) with post mortem expertise. Following a focus group meeting, 16 core statements were incorporated into an online modified Delphi survey and each panellist was asked to score their level of agreement. Following the first iteration, two statements that failed to reach consensus were modified and re-rated. Consensus was predefined as 75% agreement across responders. RESULTS: Seventeen experts joined the panel and 12 (70.6%) attended the focus group meeting; 14 (82%) completed both iterations of the survey. Consensus was reached for need of adequate clinical history, multidisciplinary discussion, establishment of special interest groups to discuss cases, gathering further evidence to inform imaging choices, establishment of methods for quality assessment in reporting standards and adequate funding for imaging services. The panel agreed that pathologists should be responsible for neuroimaging referrals, collating results of ancillary tests, and producing the final post mortem report. Areas requiring further discussion include the impact of double reporting, indications for neuroimaging and utilities of three-dimensional printing. CONCLUSION: The BNS/ISFRI statement represents current views of an expert panel of health professionals engaged in post-mortem neuroimaging. We hope this provides a working guideline for less experienced operators, stimulates discussion and highlights the most pressing clinical and research questions. PMID- 29533476 TI - Differences in activated clotting time and initial heparin dosage during atrial fibrillation ablation for patients with edoxaban compared with warfarin. AB - BACKGROUND: Different target activated clotting times (ACTs) during atrial fibrillation (AF) ablation have been proposed. Moreover, relationships between initial bolus dose of heparin at the start of AF ablation in patients receiving edoxaban anticoagulation therapy and ACT are unclear. METHODS: Patients who received anticoagulation with uninterrupted warfarin (control; n = 120) or interrupted edoxaban (n = 120) on the morning of day of ablation were studied. An initial dose of 100 U/kg heparin was administered as a reliable control for warfarin. Initial heparin doses of 120, 130, 140, or 150 U/kg were randomly administered to the edoxaban group. RESULTS: Edoxaban group showed shorter baseline ACT before the procedure (130 +/- 16 seconds) than the warfarin group (152 +/- 26 seconds, P < 0.0001). In the warfarin group, 100 U/kg heparin showed 361 +/- 48 seconds 15-minute ACT. In the edoxaban group, an increase in initial dose induced prolongation of 15-minute ACT (i.e., 15-minute ACTs of 293 +/- 56, 306 +/- 39, 311 +/- 45, and 319 +/- 45 seconds for 120, 130, 140, and 150 U/kg initial doses, respectively). The total heparin required during the procedure was higher in the edoxaban group than in the warfarin group (109 +/- 37 vs. 77 +/- 21 U/kg/h, P < 0.0001). The 120-150 U/kg dose of heparin in edoxaban group did not cause thromboembolic or major bleeding complications. CONCLUSION: Edoxaban interrupted on the day of ablation showed a shorter baseline ACT than uninterrupted warfarin. Edoxaban required a higher initial heparin dose to achieve a similar 15-minute ACT to warfarin. These results are useful for determining the initial heparin dose required to achieve variable target ACTs. PMID- 29533477 TI - Anthropogenic fragmentation may not alter pre-existing patterns of genetic diversity and differentiation in perennial shrubs. AB - Many plant species have pollination and seed dispersal systems and evolutionary histories that have produced strong genetic structuring. These genetic patterns may be consistent with expectations following recent anthropogenic fragmentation, making it difficult to detect fragmentation effects if no prefragmentation genetic data are available. We used microsatellite markers to investigate whether severe habitat fragmentation may have affected the structure and diversity of populations of the endangered Australian bird-pollinated shrub Grevillea caleyi R.Br., by comparing current patterns of genetic structure and diversity with those of the closely related G. longifolia R.Br. that has a similar life history but has not experienced anthropogenic fragmentation. Grevillea caleyi and G. longifolia showed similar and substantial population subdivision at all spatial levels (global F'ST = 0.615 and 0.454; Sp = 0.039 and 0.066), marked isolation by distance and large heterozygous deficiencies. These characteristics suggest long-term effects of inbreeding in self-compatible species that have poor seed dispersal, limited connectivity via pollen flow and undergo population bottlenecks because of periodic fires. Highly structured allele size distributions, most notably in G. caleyi, imply historical processes of drift and mutation were important in isolated subpopulations. Genetic diversity did not vary with population size but was lower in more isolated populations for both species. Through this comparison, we reject the hypothesis that anthropogenic fragmentation has impacted substantially on the genetic composition or structure of G. caleyi populations. Our results suggest that highly self-compatible species with limited dispersal may be relatively resilient to the genetic changes predicted to follow habitat fragmentation. PMID- 29533478 TI - Phototherapy as a first-line treatment for early-stage mycosis fungoides: The results of a large retrospective analysis. AB - BACKGROUND: Phototherapy is one of the main treatments for mycosis fungoides (MF). In this study, we analyzed the efficacy and safety of phototherapy as a first-line treatment in patients with early-stage disease. METHODS: We analyzed treatment outcomes in a group of 227 early-stage patients. The chi-squared test, the parametric t test, and ANOVA test and the non-parametric tests of Mann Whitney and Kruskal-Wallis were applied for data analysis. RESULTS: 55.9% of patients treated with UVB-NB reached complete remission (CR), while analog rates after PUVA treatment were 74.5% (P = .015). Patients with patch-stage disease showed better response rates to PUVA compared to UVB-NB therapy (CRs 56.7% vs 91.3%, P < .001). Regarding the latter, long-lasting disease was proven as an independent negative prognostic factor for treatment outcome. Phototypes I and II were found to be favorable prognostic factors for patients treated with PUVA. Maintenance treatment did not alter final relapse rates but led to prolonged time to relapse compared to no-maintenance treated cases (19.5 months, vs 32.3, P < .002). CONCLUSION: Our analysis indicates that PUVA leads to better responses and longer relapse-free intervals both in patch- and plaque-stage disease. UVB-NB could be a valid therapeutic alternative for patients with recent disease presentation. PMID- 29533479 TI - Chemical regulation of body feather microbiota in a wild bird. AB - The microbiota has a broad range of impacts on host physiology and behaviour, pointing out the need to improve our comprehension of the drivers of host microbiota composition. Of particular interest is whether the microbiota is acquired passively, or whether and to what extent hosts themselves shape the acquisition and maintenance of their microbiota. In birds, the uropygial gland produces oily secretions used to coat feathers that have been suggested to act as an antimicrobial defence mechanism regulating body feather microbiota. However, our comprehension of this process is still limited. In this study, we for the first time coupled high-throughput sequencing of the microbiota of both body feathers and the direct environment (i.e., the nest) in great tits with chemical analyses of the composition of uropygial gland secretions to examine whether host chemicals have either specific effects on some bacteria or nonspecific broad spectrum effects on the body feather microbiota. Using a network approach investigating the patterns of co-occurrence or co-exclusions between chemicals and bacteria within the body feather microbiota, we found no evidence for specific promicrobial or antimicrobial effects of uropygial gland chemicals. However, we found that one group of chemicals was negatively correlated to bacterial richness on body feathers, and a higher production of these chemicals was associated with a poorer body feather bacterial richness compared to the nest microbiota. Our study provides evidence that chemicals produced by the host might function as a nonspecific broad-spectrum antimicrobial defence mechanism limiting colonization and/or maintenance of bacteria on body feathers, providing new insight about the drivers of the host's microbiota composition in wild organisms. PMID- 29533480 TI - Synthesis, Structures, and Optical Properties of Azahelicene Derivatives and Unexpected Formation of Azahepta[8]circulenes. AB - Polycyclic heteroaromatic compounds including pyrrole units are promising functional scaffolds owing to their electron-rich nature, bright fluorescence, and applicability to anion recognition at the pyrrolic hydrogen atom. We report herein the effective synthesis of pseudo-aza[5]helicene and aza[7]helicene derivatives, and unexpected formation of azahepta[8]circulenes by oxidative fusion reactions. By choosing reaction conditions and peripheral substituents attached at the terminal indole moieties, we obtained aza[7]helicenes 10 a-c and azahepta[8]circulenes 11 a,c selectively in moderate to good yields. Their solid state structures have been revealed by X-ray diffraction analysis. UV/Vis absorption, emission, and cyclic voltammetry of these compounds were studied in comparison with those of previously reported tetraaza[8]circulene (TA8C), a symmetric and planar molecule. Furthermore, the enantiomeric separation of dimethyl-substituted aza[7]helicene 10 b was achieved, and the racemization kinetics have been elucidated both theoretically and experimentally. This work illustrates a wealth of advantages of pyrrole incorporation into the polycyclic aromatic scaffolds in terms of synthetic aspects, structural variation, and optical tuning. PMID- 29533481 TI - Access to 3-Oxindoles from Allylic Alcohols and Indoles. AB - The site-selective and regioselective allylation of 2-substituted indoles was performed by using a ruthenium(IV) precatalyst containing a phosphine-sulfonate chelate. Mono-, di-, and triallylated indoles were selectively obtained depending on the reaction conditions with the formation of water as the only byproduct. The preparation of 3-oxindole derivatives was then successfully performed owing to air oxidation of the corresponding allylated indoles. Diallylated pseudoindoxyls were proven to be good synthons to perform cyclization through a ring-closing metathesis reaction to afford the corresponding tricyclic adducts. The photophysical properties of the 3-oxindoles were measured, and some of the compounds showed strong fluorescence in water. PMID- 29533482 TI - Decrease in artificial tanning by French teenagers: 2011-2016. AB - BACKGROUND: The major risk factor for skin cancers is exposure to solar and artificial ultraviolet radiation, in particular during childhood and adolescence. In France, a law was restricted for tanning-bed access to adults (>=18 years) since 1997. OBJECTIVE: To evaluate teenagers' artificial tanning behaviour in 2016 and to compare results with those obtained in a similar survey performed in 2011. METHODS: The SOLADO 2011 and 2016 surveys were conducted in a general school in Antony and a technical school in Fontenay-aux-Roses (Paris suburb). RESULTS: In 2016, 630 teenagers (mean age: 14.2 +/- 1.9 y: Males/Females: 301/329) completed the questionnaire, 1.3% of teenagers reported using tanning beds, 1.1% tanning pills and 8.9% tanning creams. Between 2011 and 2016, the use of tanning beds decreased from 1.4% to 0.7% in Antony (P = .26) and from 9.5% to 4.8% in Fontenay-aux-Roses (P = .01), and the use of tanning creams from 39.8% to 17.6% in Fontenay-aux-Rose (P = .0007). The incidence of sunburn decreased from 60.5% to 54.0% in Antony (P = .02) and from 55.4% to 42.4% in Fontenay-aux-Roses (P = .05). CONCLUSION: As compared to 2011, teenagers used artificial tanning methods less frequently in 2016. In particular, they used tanning beds less frequently, suggesting that the new stricter legislation has been effective. PMID- 29533483 TI - Cutaneous carcinogenic risk evaluation in 375 patients treated with narrowband UVB phototherapy: A 15-year experience from our Institute. AB - BACKGROUND: Narrowband-ultraviolet B (NB-UVB) is widely used for the treatment of several dermatological diseases. A cutaneous carcinogenic effect has been hypothesized, but not proved. METHODS: We retrospectively reviewed the data of patients treated with NB-UVB between January 1998 and December 2013 at the Dermatology Unit of our University Hospital, to evaluate the cutaneous carcinogenic risk of NB-UVB. RESULTS: In all, 375 patients were included, each receiving a mean follow-up of 6.9 years. Vitiligo and psoriasis were the most common diseases. In total, 19 non-melanoma skin cancers (NMSCs) were diagnosed in eight patients, after a mean latency of 5.2 years after the first radiation. No malignant melanoma (MM) was observed. The incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were 620.2/100 000 p/y and 116.3/100 000 p/y. NMSCs were more frequent in patients affected by psoriasis (P = .0232), with older age at the first radiation (mean = 68.8 years, P = .0001). CONCLUSION: Despite the small number of patients and limited follow-up, our data suggest that NB-UVB may trigger cutaneous carcinogenesis, mainly in patients at risk for NMSCs, increasing their personal risk for single and multiple neoplasms, usually superficial BCCs. MM risk does not seem to be enhanced. PMID- 29533484 TI - Cooperation and coexpression: How coexpression networks shift in response to multiple mutualists. AB - A mechanistic understanding of community ecology requires tackling the nonadditive effects of multispecies interactions, a challenge that necessitates integration of ecological and molecular complexity-namely moving beyond pairwise ecological interaction studies and the "gene at a time" approach to mechanism. Here, we investigate the consequences of multispecies mutualisms for the structure and function of genomewide differential coexpression networks for the first time, using the tractable and ecologically important interaction between legume Medicago truncatula, rhizobia and mycorrhizal fungi. First, we found that genes whose expression is affected nonadditively by multiple mutualists are more highly connected in gene networks than expected by chance and had 94% greater network centrality than genes showing additive effects, suggesting that nonadditive genes may be key players in the widespread transcriptomic responses to multispecies symbioses. Second, multispecies mutualisms substantially changed coexpression network structure of 18 modules of host plant genes and 22 modules of the fungal symbionts' genes, indicating that third-party mutualists can cause significant rewiring of plant and fungal molecular networks. Third, we found that 60% of the coexpressed gene sets that explained variation in plant performance had coexpression structures that were altered by interactive effects of rhizobia and fungi. Finally, an "across-symbiosis" approach identified sets of plant and mycorrhizal genes whose coexpression structure was unique to the multiple mutualist context and suggested coupled responses across the plant-mycorrhizal interaction to rhizobial mutualists. Taken together, these results show multispecies mutualisms have substantial effects on the molecular interactions in host plants, microbes and across symbiotic boundaries. PMID- 29533485 TI - Commentary on "increased oxidative protection by high active vitamin E content and partial radiation crosslinking of UHMWPE". PMID- 29533486 TI - Exposure to chorioamnionitis alters the monocyte transcriptional response to the neonatal pathogen Staphylococcus epidermidis. AB - Preterm infants are uniquely susceptible to late-onset sepsis that is frequently caused by the skin commensal Staphylococcus epidermidis. Innate immune responses, particularly from monocytes, are a key protective mechanism. Impaired cytokine production by preterm infant monocytes is well described, but few studies have comprehensively assessed the corresponding monocyte transcriptional response. Innate immune responses in preterm infants may be modulated by inflammation such as prenatal exposure to histologic chorioamnionitis which complicates 40-70% of preterm pregnancies. Chorioamnionitis alters the risk of late-onset sepsis, but its effect on monocyte function is largely unknown. Here, we aimed to determine the impact of exposure to chorioamnionitis on the proportions and phenotype of cord blood monocytes using flow cytometry, as well as their transcriptional response to live S. epidermidis. RNA-seq was performed on purified cord blood monocytes from very preterm infants (<32 weeks gestation, with and without chorioamnionitis-exposure) and term infants (37-40 weeks), pre- and postchallenge with live S. epidermidis. Preterm monocytes from infants without chorioamnionitis exposure did not exhibit an intrinsically deficient transcriptional response to S. epidermidis compared to term infants. In contrast, chorioamnionitis-exposure was associated with hypo-responsive transcriptional phenotype regarding a subset of genes involved in antigen presentation and adaptive immunity. Overall, our findings suggest that prenatal exposure to inflammation may alter the risk of sepsis in preterm infants partly by modulation of monocyte responses to pathogens. PMID- 29533487 TI - Solar urticaria in 145 patients: Assessment of action spectra and impact on quality of life in adults and children. AB - BACKGROUND: Solar urticaria (SU) is a rare chronic inducible urticaria triggered via uncharacterized chromophores. We detail responses of a large patient series to monochromator phototesting and broadband ultraviolet radiation (UVR); relationship to life quality is explored. METHODS: Retrospective review of all SU patients undergoing standardized diagnostic photoinvestigation at a specialist centre during 2000-2016. From 2011, patients completed dermatology life quality index (DLQI) questionnaires for the past week and year. RESULTS: In 145 patients (mean: 35.8, range: 3-69 years; 18 aged <18 years; 100 female), combined phototesting with broadband UVR and monochromator sources successfully provoked 74.5% patients, with 65.6% provoked by broadband UVR alone and 57.9% by monochromated radiation alone. The narrow wavebands most frequently eliciting wheal and flare response were between 370 and 400 nm, with 25% patients at 300 +/ 5 nm, 53.6% at 320 +/- 10 nm, 66.7% at 330 +/- 10 nm, 77.4% at 350 +/- 20 nm, 83.3% at 370 +/- 20 nm, 86.9% at 400 +/- 20 nm, 44% at 500 +/- 20 nm and 17.8% at 600 +/- 20 nm. In 62 patients, the DLQI revealed 56.1% had very to extremely large impact in the past week (all patients: mean score: 11.1, range: 0-29) rising to 69.8% for the past year (12.5, 0-30); adults and children were similarly affected. Patients with positive photoprovocation had higher DLQI score than those who were negative (DLQI for past week: mean: 12.6 +/- SEM 1.1 vs 4.6 +/- 1.4, P < .01). CONCLUSION: SU is predominantly provoked by longer UVA-shorter visible radiation, which penetrates window-glass and where sunscreens are less effective; impact on life quality is considerable. Photoprotective agents effective against this spectrum are needed. PMID- 29533488 TI - Catalytic C-C Bond Formation Using a Simple Nickel Precatalyst System: Base- and Activator-Free Direct C-Allylation by Alcohols and Amines. AB - A "totally catalytic" nickel(0)-mediated method for base-free direct alkylation of allyl alcohols and allyl amines is reported. The reaction is selective for monoallylation, uses an inexpensive NiII precatalyst system, and requires no activating reagents to be present. PMID- 29533489 TI - Sunburn at the seaside. AB - BACKGROUND/PURPOSE: The purpose of this paper is to estimate the contribution to our erythemal exposure at the coast of solar ultraviolet (UV) both reflected from, and transmitted into, the ocean. METHODS: The reflection of solar UV radiation from, and transmitted into, seawater was calculated using a numerical model under a number of atmospheric conditions to estimate erythemal exposure on the skin of supine/prone and ambulant people. RESULTS: The results were expressed as UV Indices. Even under the most extreme insolation with the sun directly overhead, where the ambient UV Index may be around 14, reflected UV from the ocean contributes an erythemal exposure to the skin equivalent to a UV Index of about 0.7. For typical ocean waters, with the sun high in the sky, the UV index within the water is about 7 at a depth of 2 m. CONCLUSION: Whilst our eyes often sense a high level of reflected sunlight from the ocean, especially when the sun is low in the sky, our skin does not share that experience. The reason people get sunburnt at the seaside has more to do with the absence of shade than with reflectance by the water surface or even beach sand. PMID- 29533490 TI - Effects of a protein-free oat plantlet extract on microinflammation and skin barrier function in atopic dermatitis patients. AB - Atopic dermatitis (AD) is a common, highly pruritic, chronic inflammatory skin disease. Dysfunction of the epidermal barrier is witnessed by an increased transepidermal water loss in lesional and non-lesional AD skin. The inflammation in lesional AD skin is well characterized. Non-lesional skin of AD patients shows histological signs of a subclinical inflammation and a pro-inflammatory cytokine milieu. This microinflammation is present even in seemingly healed skin and must be taken into account regarding treatment of AD. Emollients provide a safe and effective method of skin barrier improvement, because they provide the skin with a source of exogenous lipids, thus improving its barrier function. The use of emollients is recommended for all AD patients irrespective of overall disease severity. Patients with moderate to severe AD should combine the emollients with a proactive therapy regimen of topical calcineurin inhibitors or topical corticosteroids. Skin areas affected by active eczema in flare should receive daily anti-inflammatory therapy first before introducing emollients, to induce rapid relief of skin lesions and pruritus. The microinflammation persisting in seemingly healed AD lesions should be addressed by a proactive treatment approach, consisting of minimal anti-inflammatory therapy and liberal, daily use of emollients. An emollient containing an extract of Rhealba oat plantlet has shown anti-inflammatory and barrier repairing properties, and was clinically tested in studies targeting the microinflammation in AD. All emollients based on Rhealba oat plantlet extract are free of oat protein, as the Rhealba extract is derived from the aerial parts of the oat plantlet and is unrelated to oatmeal proteins. The Rhealba oat plantlet extract is produced in a specific process, allowing the extraction of high levels of active principles such as flavonoids and saponins, whilst being virtually free of oat proteins to minimize the risk for allergic reactions. PMID- 29533491 TI - A dose-finding study for hemoporfin in photodynamic therapy for port-wine stain: A multicenter randomized double-blind phase IIb trial. AB - BACKGROUND/PURPOSE: Previous studies have shown that hemoporfin-mediated photodynamic therapy (PDT) was a treatment for port-wine stain (PWS). Our current study aimed to identify optimal hemoporfin dose. METHODS: A prospective, multicenter, double-blind, randomized clinical trial was conducted. Patients were assigned into low- or high-dose hemoporfin (2.5 mg/kg and 5 mg/kg intravenously, respectively), or control (placebo) group, at a rate of 2:2:1. Treatment efficacy was evaluated at week 8. Then, patients in control group were randomly assigned into either high- or low-dose hemoporfin group. Treatment reactions and adverse events were analyzed at week 16. RESULTS: A total of 100 patients (40, 40, 20 in low-, high-dose hemoporfin, and control group, respectively) were enrolled. Compared to low dose (40%) and control group (15%), a higher proportion of patients in high-dose group (75%) had achieved skin lesion improvements. Treatment satisfactions were graded highest in high-dose group. Compared to low dose group (14.3%), high-dose group (46.0%) had more frequent skin hyperpigmentation, which disappeared 3-6 months after treatment. Other treatment reactions and adverse events were comparable between two groups. CONCLUSIONS: Photodynamic therapy with 5 mg/kg hemoporfin could be an effective and safe treatment for PWS. PMID- 29533492 TI - Synthesis and Identification of Aryl and Alkyl Gem-Dilithium Phosphido-Boranes: A Boost to the Chemistry of Phosphandiides. AB - The synthesis and identification of unprecedented gem-dianionic phosphorus compounds, that is, gem-dilithium phosphido-boranes Li2 [RP?BH3 ], with R=Ph or Cy, are reported in THF solution. These were obtained by double deprotonation of the corresponding primary phosphine-borane precursors RPH2 ?BH3 . Their in-depth structural study, based on multinuclear (1 H, 6 Li, 7 Li, 11 B, 13 C, 31 P) mono- and bi-dimensional NMR analyses, indicates a strong influence of the phosphorus substituent on the structure of the gem-dianionic phosphorus structure; a monomeric arrangement was obtained when R=phenyl, whereas a cyclic oligomer was observed for R=cyclohexyl. These compounds represent a new type of useful reagent, and their access paves the way for the concept of "RP synthons" (i.e., RP2- phosphandiides), likely to be the most flexible precursors of a variety of phosphorus targets. PMID- 29533493 TI - Multidisciplinary Approach for Full-Mouth Rehabilitation of an Adult Patient with Collapsed Occlusal Plane and Several Missing Teeth: A Clinical Report. AB - In the full-mouth rehabilitation of a patient with severely collapsed occlusion, a multidisciplinary approach including prosthodontics, orthodontics, endodontics, and surgery could provide better esthetic and functional results. Orthodontic treatment aiming for stable occlusion that meets the standard requirement of functional occlusion, enables the maintenance of occlusal function, and guarantees long-term stability on the basis of periodontal health was attempted. The essential element of this protocol is careful treatment planning based on the optimal sequence pursuing functional occlusion. PMID- 29533494 TI - Immune biomarkers and anti-HIV activity in the reproductive tract of sexually active and sexually inactive adolescent girls. AB - PROBLEM: Adolescent girls are disproportionately affected by the HIV/AIDS pandemic, accounting for 22% of all new HIV infections globally. Yet little is known regarding the immune microenvironment of the adolescent female reproductive tract, especially regarding differences among sexually active and inactive girls, a critical parameter to evaluate HIV susceptibility associated with young age and sexual debut. METHODS: Cervico-vaginal lavage (CVL) was collected from sexually active (10) and inactive (8) girls aged 11-19 years and analyzed by ELISA for inflammation-associated biomarkers IL-6, IL-8, TNF-alpha, MIP-3alpha, IL-1alpha, IL-1beta, matrix metalloproteinases (MMP) 1, 2, 7, 8, and 9, as well as anti-HIV mediators, Elafin, SLPI, human beta-defensin 2, and tissue inhibitor of matrix metalloproteinases (TIMP) 1 and 2. Cervical ectopy was analyzed using Volocity. Anti-HIV activity was determined by TZM-bl assay. Statistical analyses were performed using GraphPad Prism and R. RESULTS: Sexually inactive girls had significantly higher levels of TNF-alpha (P = .029) in CVL compared to sexually active girls. In contrast, sexually active girls showed a trend toward higher levels of IL-1alpha (P = .051) compared to the sexually inactive girls. Heat-map correlations between cervical ectopy and immune biomarkers were also distinct between the 2 populations with significant positive associations between % ectopy and inflammation-associated biomarkers IL-6, IL-1beta, IL-8, MIP-3alpha, MMP-8, and MMP-9 observed in the sexually inactive but not sexually active group. CONCLUSION: Higher pro-inflammatory biomarker TNF-alpha, as well as a distinct inflammation-associated immune clustering in sexually inactive girls, can potentially increase risk for infections including HIV upon sexual debut. Future studies with larger sample sizes are needed to characterize the immune parameters associated with sexual activity. PMID- 29533495 TI - Dental Shade Matching and Value Discernment Abilities of First-Year Dental Students. AB - PURPOSE: To determine if Farnsworth-Munsell 100 Hue Test, Perceptual Ability Test, gender, age, ethnicity, and time predict dental shade matching and value discernment in first-year dental students. MATERIALS AND METHODS: Farnsworth Munsell 100 Hue Test was administered to 95 first-year-dental students beneath a Judge II booth (color temperature of 6500 degrees K, and color rendering index of 90). Students also arranged 16 masked shade tabs from a Vita Classic shade guide by value (lightest to darkest) and matched together 16 pairs of masked shade tabs from two Vita Classic shade guides. Ethnicity, age, Perceptual Ability Test scores, gender, and time to complete the tests were recorded. Associations and correlations were investigated using chi-square, Tukey-Kramer HSD, standard least square, and multilinear regression (p < 0.05). RESULTS: Total error scores on the Farnsworth-Munsell 100 Hue Test ranged from 0 to 144. Forty-eight students exhibited superior color acuity, 45 average, and two poor. The mean number of correct answers for matching shade tabs together was 11.6, and 6.1 for arranging the shade tabs by value. Females performed statistically better than males on the Farnsworth-Munsell 100 Hue Test and shade tab matching. Better color discrimination identified by lower total error scores on the Farnsworth-Munsell 100 Hue Test was directly correlated to greater ability to match shade tabs together. Perceptual Ability Test scores had slight significance. As the scores increased there was slightly better performance on the Farnsworth-Munsell 100 Hue Test. Older participants performed better than younger subjects on the value test. No other correlations were significant for any of the tests. CONCLUSIONS: Females and individuals who performed better on the Farnsworth-Munsell 100 Hue Test have improved dental shade-matching ability. PMID- 29533496 TI - Blocking variant surface glycoprotein synthesis alters endoplasmic reticulum exit sites/Golgi homeostasis in Trypanosoma brucei. AB - The predominant secretory cargo of bloodstream form Trypanosoma brucei is variant surface glycoprotein (VSG), comprising ~10% total protein and forming a dense protective layer. Blocking VSG translation using Morpholino oligonucleotides triggered a precise pre-cytokinesis arrest. We investigated the effect of blocking VSG synthesis on the secretory pathway. The number of Golgi decreased, particularly in post-mitotic cells, from 3.5 +/- 0.6 to 2.0 +/- 0.04 per cell. Similarly, the number of endoplasmic reticulum exit sites (ERES) in post-mitotic cells dropped from 3.9 +/- 0.6 to 2.7 +/- 0.1 eight hours after blocking VSG synthesis. The secretory pathway was still functional in these stalled cells, as monitored using Cathepsin L. Rates of phospholipid and glycosylphosphatidylinositol-anchor biosynthesis remained relatively unaffected, except for the level of sphingomyelin which increased. However, both endoplasmic reticulum and Golgi morphology became distorted, with the Golgi cisternae becoming significantly dilated, particularly at the trans-face. Membrane accumulation in these structures is possibly caused by reduced budding of nascent vesicles due to the drastic reduction in the total amount of secretory cargo, that is, VSG. These data argue that the total flux of secretory cargo impacts upon the biogenesis and maintenance of secretory structures and organelles in T. brucei, including the ERES and Golgi. PMID- 29533497 TI - Spectrophotometric Evaluation of Anterior Maxillary Tooth Color Distribution According to Age and Gender. AB - PURPOSE: To determine the effects of age and gender on the color distribution of the right maxillary central, lateral incisors, and canine teeth. MATERIALS AND METHODS: The tooth color was measured using the VITA Easyshade V spectrophotometer with a total of 202 volunteers (89 men, 113 women). The age distribution in this study was between 15 and 70 years old (average: 31). A grey background color was used to prevent background reflection while performing the color measurements. RESULTS: According to the VITAPAN Classical shade guide, the tooth color distribution of the central and lateral incisors showed a maximum of A2, with a maximum of B3 for the canine teeth. When comparing the International Commission on Illumination L* , a* , and b* values (CIELab color space coordinates) of the teeth with subject gender, statistically significant differences were not found between gender and the L* and b* values (p > 0.05); however, a statistically significant difference was observed between gender and the a* values (p < 0.05). CONCLUSION: When the distribution ratio of tooth color was examined, different ratios were determined based on gender and age and between the maxillary central, lateral incisors, and canine teeth. A uniform tooth color should not be chosen for anterior restorations, and factors such as gender and age should be considered when making a color selection for patients. PMID- 29533498 TI - Eukaryotic initiation factor 5A and Ca2+ /calmodulin-dependent protein kinase 1D modulate trophoblast cell function. AB - PROBLEM: Trophoblast cells regulate embryo implantation and placental development. Eukaryotic initiation factor 5A (eIF5A) is an initiator of translation involved in cellular processes, such as migration, proliferation, and apoptosis. However, the function of eIF5A in trophoblast cells is unknown. METHOD OF STUDY: We inhibited eIF5A and Ca2+ /calmodulin-dependent protein kinase 1D (CAMK1D) expression in HTR8 cells using RNA interference. The effects of eIF5A and CAMK1D on HTR8 cells were investigated using real-time polymerase chain reaction, Western blotting, flow cytometry, cell transfection assays, cell migration assays, and terminal deoxynucleotidyl transferase dUTP nick-end labeling. RESULTS: eIF5A inhibition decreased CAMK1D expression, proliferation, migration, and invasion, but upregulated apoptosis, in HTR8 cells. CONCLUSION: Cross-talk between eIF5A and CAMK1D enhances proliferation, migration, and invasion, but inhibits apoptosis, in trophoblasts. PMID- 29533499 TI - Fracture Resistance of CAD/CAM-Fabricated Lithium Disilicate MOD Inlays and Onlays with Various Cavity Preparation Designs. AB - PURPOSE: To examine the fracture resistance of premolars restored with CAD/CAM lithium disilicate mesio-occlusal-distal (MOD) inlays and onlays of different cavity designs. MATERIALS AND METHODS: Two widths of occlusal isthmus (75%, 100% of intercuspal distance) and three designs of cuspal coverage (none, palatal, complete) were used for the preparation of MOD inlays and onlays in the extracted maxillary premolars. Sixty lithium disilicate restorations were milled and bonded into the cavities. After 24 hours of water storage, the specimens were loaded until fracture, and the fracture loads (N) were measured. Any evidence of cracks and fractures on the tested specimens were examined to classify failure patterns. RESULTS: Mean fracture load values for the tested groups were as follows: 664.4 +/- 214.7 N (group A), 659.3 +/- 391.2 N (B), 681.9 +/- 258.1 N (C), 938.1 +/- 862.0 N (D), 841.7 +/- 375.4 N (E), and 994.2 +/- 486.3 N (F). The width of occlusal isthmus did not significantly affect the fracture loads among all the groups. Within groups with identical isthmus width, the fracture loads showed no significant difference depending on the designs of cuspal coverage. The majority of specimens showed either type III or IV fracture mode. CONCLUSIONS: Within limitations of this study, the bonded restorations of premolars with CAD/CAM generated lithium disilicate were reliable, regardless of cavity preparation design. PMID- 29533500 TI - The burden of hepatitis C virus in Cameroon: Spatial epidemiology and historical perspective. AB - Cameroon is thought to have one of the highest prevalences of hepatitis C virus (HCV) infection in the world (4.9% among adults). A marked cohort effect exists in several communities where ~50% of the elderly are infected. Better assessment of HCV distribution is needed for planning treatment programmes. We tested for HCV antibodies 14 150 capillary blood samples collected during the 2011 Demographic and Health Survey, whose participants were representative of the Cameroonian population aged 15-49 (both genders) and 50-59 years (men only). Historical data on exposure to medical care were collected and factors associated with HCV assessed through logistic regression and geospatial analyses. To estimate prevalence in all persons aged >=15 years, we used data from the survey for the 15-59 years fraction and modelled a cohort effect for older individuals. The nationwide HCV prevalence was 0.81% for the 15-49 years group, and 2.51% for all individuals aged >=15 years. Only 0.2% of individuals aged 15-19 were seropositive. Among participants aged 15-44 years, HCV was associated with age, rural residence and, for males, with ritual circumcision. For those aged 45-59 years, HCV was associated with age and access to medical care in the late 1950s. Prevalence of HCV seropositivity in Cameroon is half of previous estimates. Nationwide surveys are essential to rationalize resources allocation. The high prevalence among older cohorts, a colonial legacy, has had little spillover into younger cohorts. HCV-free generations might be attainable in countries not plagued with intravenous drug abuse. PMID- 29533502 TI - The effect of cathepsin K inhibitor surface treatment on delayed tooth replantation in dogs. AB - BACKGROUND/AIM: Continuous research efforts have been focusing on promoting healing of delayed replantation of avulsed teeth. The aim of this in vivo study was to assess the effect of cathepsin K inhibitor surface treatment on delayed tooth replantation. MATERIALS AND METHODS: Thirty-four premolar roots of 4 beagle dogs were extracted, and conventional root canal treatment was performed. The canals were filled with gutta-percha and cement. All extracted teeth were air dried for 1 hour. Teeth were divided into 2 groups according to the root surface treatment prior to replantation: control (n = 13) and cathepsin K inhibitor (n = 21). Treated teeth were replanted in their original sockets and stabilized with a resin-wire splint for 1 week. After 12 weeks, the dogs were euthanized and micro computed tomography was performed. Tissues were then further processed as resin embedded specimens stained with hematoxylin and eosin. In each evaluation, data were analyzed using the Mann-Whitney U test (P < .05). RESULTS: In the micro computed tomography evaluation, inflammation scores of both groups were not statistically different (P > .05). In the histological evaluation, the mean proportions of inflammatory resorption and replacement resorption in the control group were similar to those in the cathepsin K inhibitor group (P > .05). CONCLUSIONS: Cathepsin K inhibitor did not demonstrate significant inhibitory effects on root resorption after delayed replantation in vivo. PMID- 29533501 TI - OMIP-046: Characterization of invariant T cell subset activation in humans. PMID- 29533503 TI - Model-free quantification and visualization of colocalization in fluorescence images. AB - The spatial association between fluorescently tagged biomolecules in situ provides valuable insight into their biological relationship. Within the limits of diffraction, such association can be measured using either Pearson's Correlation Coefficient (PCC) or Spearman's Rank Coefficient (SRC), which are designed to measure linear and monotonic correlations, respectively. However, the relationship between real biological signals is often more complex than these measures assume, rendering their results difficult to interpret. Here, we have adapted methods from the field of information theory to measure the association between two probes' concentrations based on their statistical dependence. Our approach is mathematically more general than PCC or SRC, making no assumptions about the type of relationship between the probes. We show that when applied to biological images, our measures provide more intuitive results that are also more robust to outliers and the presence of multiple relationships than PCC or SRC. We also devise a display technique to highlight regions in the input images where the probes' association is higher versus lower. We expect that our methods will allow biologists to more accurately and robustly quantify and visualize the association between two probes in a pair of fluorescence images. (c) 2018 International Society for Advancement of Cytometry. PMID- 29533504 TI - Evaluation of the McMahon Competence Assessment Instrument for Use with Midwifery Students During a Simulated Shoulder Dystocia. AB - INTRODUCTION: Intrapartum emergencies occur infrequently but require a prompt and competent response from the midwife to prevent morbidity and mortality of the woman, fetus, and newborn. Simulation provides the opportunity for student midwives to develop competence in a safe environment. The purpose of this study was to determine the inter-rater reliability of the McMahon Competence Assessment Instrument (MCAI) for use with student midwives during a simulated shoulder dystocia scenario. METHODS: A pilot study using a nonprobability convenience sample was used to evaluate the MCAI. Content validity indices were calculated for the individual items and the overall instrument using data from a panel of expert reviewers. Fourteen student midwives consented to be video recorded while participating in a simulated shoulder dystocia scenario. Three faculty raters used the MCAI to evaluate the student performance. These quantitative data were used to determine the inter-rater reliability of the MCAI. RESULTS: The intraclass correlation coefficient (ICC) was used to assess the inter-rater reliability of MCAI scores between 2 or more raters. The ICC was 0.86 (95% confidence interval, 0.60-0.96). Fleiss's kappa was calculated to determine the inter-rater reliability for individual items. Twenty-three of the 42 items corresponded to excellent strength of agreement. DISCUSSION: This study demonstrates a method to determine the inter-rater reliability of a competence assessment instrument to be used with student midwives. Data produced by this study were used to revise and improve the instrument. Additional research will further document the inter-rater reliability and can be used to determine changes in student competence. Valid and reliable methods of assessment will encourage the use of simulation to efficiently develop the competence of student midwives. PMID- 29533505 TI - Robot-assisted transvesical partial prostatectomy using a purpose-built single port robotic system. AB - OBJECTIVES: To evaluate the feasibility of robot-assisted single-port (SP) transvesical partial prostatectomy (TVPP) using a novel purpose-built SP surgical platform in a pre-clinical model. METHODS: The cadavers were placed in the lithotomy position. A 3-cm midline incision was made in the suprapubic area 4-cm from the symphisis pubis. After opening the Retzius space, an access mini device (GelPOINT; Applied Medical, Rancho Margarita, CA, USA) was introduced percutaneously directly into the bladder. The da Vinci SP1098 robotic platform (Intuitive Surgical, Sunnyvale, CA, USA) was docked to the GelPOINT by inserting a novel SP cannula through the GelSeal Cap. The surgical steps for en bloc anterior prostatectomy were performed in the following order: (i) antegrade dissection of the transition zone at the bladder neck; (ii) lateral excision of the peripheral zone; and (iii) urethrovesical anastomosis. Primary outcomes, such as intra-operative complications, rate of conversion to standard techniques and operating times, were recorded. RESULTS: The SP-TVPP procedure was technically completed in three male cadavers. All cases were completed successfully using the da Vinci SP1098 surgical system without conversion or the need for additional ports. There were no intra-operative complications. The mean total operating time was 49.3 min. CONCLUSION: Robot-assisted TVPP is feasible using a novel purpose built SP surgical platform in a cadaver model. Future clinical evaluation in humans is needed for assessment on patients with anterior localized prostate cancer. Prospective comparison with other surgical platforms and standard techniques is warranted. PMID- 29533506 TI - A field-applicable method for flow cytometric analysis of granulocyte activation: Cryopreservation of fixed granulocytes. AB - Upon activation granulocytes upregulate several adhesion molecules (CD11b) and granule proteins (CD35, CD66b) and shed surface l-selectin (CD62L). These changes in expression, as assessed by flow cytometry, can be used as markers for activation. Whereas these markers are usually studied in fresh blood samples, a new method is required when samples are collected at a field site with no direct access to a flow cytometer. Therefore, we developed and tested a field-applicable method in which fixed leukocytes were cryopreserved. Using this method, the intensity of granulocyte activation markers was compared to samples that were either stained fresh, or fixed prior to staining but not cryopreserved. In addition, the response to an in vitro stimulation with fMLF was determined. While we observed differences in marker intensities when comparing fresh and fixed granulocytes, similar intensities were found between fixed cells that had been cryopreserved and fixed cells that did not undergo cryopreservation. Although fixation using FACS lysing solution might lead to membrane permeabilization, activation markers, and the responsiveness to fMLF or eotaxin could still be clearly measured. This method will, therefore, enable future studies of granulocyte activation in settings with limited resources and will allow simultaneous analysis of samples collected at different time points. (c) 2018 International Society for Advancement of Cytometry. PMID- 29533507 TI - Antibiotic susceptibility of intestinal Escherichia coli in men undergoing transrectal prostate biopsies: a prospective, registered, multicentre study. AB - OBJECTIVES: To determine, in a prospective, multicentre setting, the prevalence of fluoroquinolone-resistant (FQ-R) and extended-spectrum beta-lactamase (ESBL) producing Escherichia coli (E. coli) strains in men undergoing transrectal ultrasonography-guided prostate biopsy (TRUS-Bx) in Finland; and to survey the associated risk factors for having the previously mentioned strains. PATIENTS AND METHODS: This is a substudy of the trial investigating the role of magnetic resonance imaging (MRI) in prostate cancer diagnosis (Improved Prostate Cancer Diagnosis - Combination of Magnetic Resonance Imaging Targeted Biopsies and Biomarkers Multi-institutional Study [multi-IMPROD], NCT02241122). In all, 359 patients from four study centres were recruited to this prospective study. After having signed the informed consent form, these men with suspicion of prostate cancer completed a detailed questionnaire on their medical, smoking, and travelling history, as well as their recent use of antibiotics. After the bi parametric MRI scan, TRUS-Bx was taken and a rectal swab sample was collected and cultured for determining the antimicrobial susceptibility profile of E. coli strains. The potential risk factors for having FQ-R or third-generation cephalosporin-resistant (3GC-R) E. coli strains were analysed using univariate and multivariate logistic regression analysis. RESULTS: The percentage of FQ-R and 3GC-R E. coli strains amongst the study population was 13% and 8%, respectively. Amongst patients having E. coli strains, the rate of FQ-R and 3GC-R strains was 14% and 8%, respectively. Of the 3GC-R E. coli strains, 62% proved to be ESBL-producers and 88% were also FQ-R. In multivariate analysis, international travel during the preceding year significantly increased the risk of having a FQ R E. coli strain (odds ratio [OR] 3.592, P = 0.001) and, unexpectedly, use of antibiotics during the previous year significantly decreased this risk (OR 0.442, P = 0.035). No significant risk factors for having 3GC-R E. coli were identified. CONCLUSION: The occurrence of intestinal FQ-R and/or 3GC-R (potentially ESBL producing) E. coli strains in men undergoing TRUS-Bx in Finland is notable. The finding is consistent with the global increase in antimicrobial resistance. International travel appears to be an indisputable risk factor for having intestinal FQ-R E. coli strains. The contemporary antimicrobial resistance situation should be taken into account in the care of post-TRUS-Bx infections. PMID- 29533508 TI - A guide to choosing fluorescent protein combinations for flow cytometric analysis based on spectral overlap. AB - The advent of facile genome engineering technologies has made the generation of knock-in gene-expression or fusion-protein reporters more tractable. Fluorescent protein labeling of specific genes combined with surface marker profiling can more specifically identify a cell population. However, the question of which fluorescent proteins to utilize to generate reporter constructs is made difficult by the number of candidate proteins and the lack of updated experimental data on newer fluorescent proteins. Compounding this problem, most fluorescent proteins are designed and tested for use in microscopy. To address this, we cloned and characterized the detection sensitivity, spectral overlap, and spillover spreading of 13 monomeric fluorescent proteins to determine utility in multicolor panels. We identified a group of five fluorescent proteins with high signal to noise ratio, minimal spectral overlap, and low spillover spreading making them compatible for multicolor experiments. Specifically, generating reporters with combinations of three of these proteins would allow efficient measurements even at low-level expression. Because the proteins are monomeric, they could function either as gene-expression or as fusion-protein reporters. Additionally, this approach can be generalized as new fluorescent proteins are developed to determine their usefulness in multicolor panels. (c) 2018 International Society for Advancement of Cytometry. PMID- 29533509 TI - Photo-biocatalytic One-Pot Cascades for the Enantioselective Synthesis of 1,3 Mercaptoalkanol Volatile Sulfur Compounds. AB - The synthesis of enantiomerically pure 1,3-mercaptoalkanol volatile sulfur compounds through a one-pot photo-biocatalytic cascade reaction is described. Two new KRED biocatalysts with opposite enantioselectivity were discovered and proved to be efficient on a wide range of substrates. The one-pot cascade reaction combining photocatalytic thio-Michael addition with biocatalytic ketoreduction in an aqueous medium provides a green and sustainable approach to enantiomerically pure 1,3-mercaptoalkanols in high yields with excellent enantioselectivity. PMID- 29533510 TI - Mild Friedel-Crafts Reactions inside a Hexameric Resorcinarene Capsule: C-Cl Bond Activation through Hydrogen Bonding to Bridging Water Molecules. AB - A novel catalytic feature of a hexameric resorcinarene capsule is highlighted. The self-assembled cage was exploited to promote the Friedel-Crafts benzylation of several arenes and heteroarenes with benzyl chloride under mild conditions. Calculations showed that there are catalytically relevant hydrogen-bonding interactions between the bridging water molecules of the capsule and benzyl chloride, which is fundamental for the activation of the C-Cl bond. The capsule controls the reaction outcome. Inside the inner cavity of the capsule, N methylpyrrole is preferentially benzylated in the unusual beta-position while mesitylene reacts faster than 1,3-dimethoxybenzene despite the greater pi nucleophilicity of the latter compound. PMID- 29533511 TI - Certified Nurse-Midwives' Knowledge, Attitudes, and Behaviors About Infant Safe Sleep. AB - INTRODUCTION: Little is known about the knowledge, attitudes, and behaviors of certified nurse-midwives related to sudden infant death syndrome and infant safe sleep. However, this population is an important and trusted source of information for pregnant women and may provide guidance on infant care. We explored these topics with certified nurse-midwives to identify potential barriers as well as enabling and reinforcing factors associated with providing infant safe sleep education in the prenatal health care environment. METHODS: Participants in this cross-sectional survey study were certified nurse-midwives who provide prenatal health care to women in Ohio. Surveys were mailed to all certified nurse-midwives listed with the licensing registry of the Ohio Board of Nursing (N = 333). RESULTS: A total of 153 eligible respondents completed the survey for a response rate of 55%. Most participants had at least some knowledge of the infant safe sleep recommendations from the American Academy of Pediatrics, and two-thirds had positive attitudes about providing infant safe sleep education in the prenatal environment. Many participants (61%) perceived that there were barriers to providing prenatal infant safe sleep education, but nearly all (94%) indicated that they were interested in providing this education to their patients. Positive attitudes about providing infant safe sleep education were predictive of whether they discussed this topic with their patients. DISCUSSION: Certified nurse midwives routinely provide guidance on infant care, and it is important that they are familiar with current evidence-based recommendations on infant safe sleep. They should be supported in their desire to provide infant safe sleep education to their prenatal patients. In addition, efforts should be made to improve attitudes and social norms related to providing infant safe sleep education in the prenatal environment. PMID- 29533512 TI - Clinical use of plasma lactate concentration. Part 1: Physiology, pathophysiology, and measurement. AB - OBJECTIVE: To review the current literature with respect to the physiology, pathophysiology, and measurement of lactate. DATA SOURCES: Data were sourced from veterinary and human clinical trials, retrospective studies, experimental studies, and review articles. Articles were retrieved without date restrictions and were sourced primarily via PubMed, Scopus, and CAB Abstracts as well as by manual selection. HUMAN AND VETERINARY DATA SYNTHESIS: Lactate is an important energy storage molecule, the production of which preserves cellular energy production and mitigates the acidosis from ATP hydrolysis. Although the most common cause of hyperlactatemia is inadequate tissue oxygen delivery, hyperlactatemia can, and does occur in the face of apparently adequate oxygen supply. At a cellular level, the pathogenesis of hyperlactatemia varies widely depending on the underlying cause. Microcirculatory dysfunction, mitochondrial dysfunction, and epinephrine-mediated stimulation of Na+ -K+ -ATPase pumps are likely important contributors to hyperlactatemia in critically ill patients. Ultimately, hyperlactatemia is a marker of altered cellular bioenergetics. CONCLUSION: The etiology of hyperlactatemia is complex and multifactorial. Understanding the relevant pathophysiology is helpful when characterizing hyperlactatemia in clinical patients. PMID- 29533517 TI - Clinical use of plasma lactate concentration. Part 2: Prognostic and diagnostic utility and the clinical management of hyperlactatemia. AB - OBJECTIVE: To review the current literature pertaining to the use of lactate as a prognostic indicator and therapeutic guide, the utility of measuring lactate concentrations in body fluids other than blood or plasma, and the clinical management of hyperlactatemia in dogs, cats, and horses. DATA SOURCES: Articles were retrieved without date restrictions primarily via PubMed, Scopus, and CAB Abstracts as well as by manual selection. HUMAN AND VETERINARY DATA SYNTHESIS: Increased plasma lactate concentrations are associated with increased morbidity and mortality. In populations with high mortality, hyperlactatemia is moderately predictive in identifying nonsurvivors. Importantly, eulactatemia predicts survival better than hyperlactatemia predicts death. Consecutive lactate measurements and calculated relative measures appear to outperform single measurements. The use of lactate as a therapeutic guide has shown promising results in people but is relatively uninvestigated in veterinary species. Increased lactate concentrations in body fluids other than blood should raise the index of suspicion for septic or malignant processes. Management of hyperlactatemia should target the underlying cause. CONCLUSION: Lactate is a valuable triage and risk stratification tool that can be used to separate patients into higher and lower risk categories. The utility of lactate concentration as a therapeutic target and the measurement of lactate in body fluids shows promise but requires further research. PMID- 29533521 TI - CYTO Innovation: An initiative for ISAC's cytometry product innovators. PMID- 29533522 TI - Repeat prostate-specific antigen (PSA) test before prostate biopsy: a 20% decrease in PSA values is associated with a reduced risk of cancer and particularly of high-grade cancer. AB - OBJECTIVES: To analyse the impact of repeating a prostate-specific antigen (PSA) level assessment on prostate biopsy decision in a cohort of men undergoing prostate biopsy. PATIENTS AND METHODS: From 2015 onwards, we consecutively enrolled, at a single institution in Italy, men undergoing 12-core transrectal ultrasonography-guided prostate needle biopsy. Indication for prostate biopsy was a PSA level of >=4 ng/mL. Demographic, clinical, and histopathological data were collected. The PSA level was tested at enrolment (PSA1 ) and 4 weeks later on the day before biopsy (PSA2 ). Variations in PSA level were defined as: stable PSA2 within a 10% variation, stable PSA2 within a 20% variation, PSA2 decreased by >=10%, PSA2 decreased by >=20%, PSA2 increased by >=10%, PSA2 increased by >=20%, and PSA2 <4 ng/mL. Percentages and multinomial logistic regression were used to analyse biopsy outcomes. High-grade cancer was defined as Grade group >=3. RESULTS: Overall, 331 patients were enrolled. Prostate cancer was diagnosed in 153/331 (46%) patients and of them 80/153 (52%) had high-grade disease. When compared to the rest of the population, patients with a stable PSA within 20% variation had a higher risk of prostate cancer (odds ratio [OR] 1.80, P < 0.05) and high grade disease (OR 2.56, P < 0.05), patients with a PSA2 decreased by >=20% had a lower risk of prostate cancer (OR 0.37, P < 0.05) and high grade disease (OR 0.13, P < 0.05), whilst patients with a PSA2 increased by >=10% had an increased risk of high-grade prostate cancer (OR 1.93, P < 0.05). When PSA returned to normal values (<4 ng/mL) both risks of prostate cancer and high-grade disease were reduced (OR 0.33 and 0.01, respectively, P = 0.001). CONCLUSION: In a cohort of Italian men undergoing prostate biopsy, a reduction of >=20% in PSA levels significantly reduced the risk of high-grade prostate cancer. Further multicentre studies should validate our present results. PMID- 29533523 TI - Prior Work and Educational Experience Are Not Associated With Successful Completion of a Master's-Level, Distance Education Midwifery Program. AB - INTRODUCTION: In order to increase and diversify the midwifery workforce, admissions criteria for midwifery education programs must not contain unnecessary barriers to entry. Once accepted, students need to successfully complete the program. Many admissions criteria commonly used in midwifery education programs in the United States are not evidence based and could be unnecessary barriers to education. The primary objective of this study was to identify factors known during the admission process that were related to successful completion or failure to complete a midwifery program educating both student nurse-midwives (SNMs) and student midwives (SMs); a secondary objective was to quantify reasons for program noncompletion. METHODS: This master's-level, distance education program educates a diverse group of both SNMs and SMs. A pilot, retrospective cohort study examined all students matriculating at the program from fall 2012 on and scheduled to graduate by summer 2016 (N = 58). Demographic information, admissions information, academic records, and advising notes were reviewed. Reasons for noncompletion were identified, and characteristics were compared between students who did and did not complete the program. RESULTS: Program completion was not significantly associated with students' status as nurses prior to admission, labor and delivery nursing experience, length of nursing experience, nursing degree held, presence of children at home, working while in school, or undergraduate grade point average. DISCUSSION: Being a nurse, years of nursing experience, type of nursing degree, or labor and delivery nursing experience were not associated with completion of this midwifery program. PMID- 29533524 TI - Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth-Generation by Prebiotic Methylations and Carbamoylations. AB - The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth. PMID- 29533525 TI - Effects of a Web-Based Antenatal Care System on Maternal Stress and Self-Efficacy During Pregnancy: A Study in Taiwan. AB - INTRODUCTION: Women may experience significant stress during pregnancy, and antenatal care and education provide a means to address this. E-health, the use of computer and information technology for health care, has been incorporated into antenatal care and education, but e-health has not been evaluated for its usefulness in addressing stress. The objective of this study was to investigate the effectiveness of a web-based antenatal care and education system on pregnancy related stress, general self-efficacy, and satisfaction with antenatal care. METHODS: A quasi-experimental design enrolled pregnant women at 16 to 24 weeks' gestation with a low-risk pregnancy. Women in the control group (n = 67) received routine antenatal care; women in the experimental group (n = 68) also received a web-based antenatal care and education program in the second trimester. Pregnancy stress and general self-efficacy were assessed at study entry and again at 36 to 38 weeks' gestation; satisfaction with care was assessed at the study endpoint. RESULTS: When the pretest scores were controlled, the women in the experimental group reported significantly lower pregnancy-related stress (F = 12.9, P < .001) and significantly higher self-efficacy (F = 17.61, P < .001) than did the women in the control group. Women in the experimental group reported lower pregnancy-related stress (t = 5.09, P < .001) and a higher general self-efficacy (t = -3.17, P = .001) at posttest compared to pretest. However, the women in the control group reported a lower general self-efficacy at posttest compared to pretest (t = 2.86, P = .006). Women in the experimental group reported significantly higher satisfaction levels with antenatal care than those in the control group. DISCUSSION: A web-based antenatal care and education system can improve pregnancy-related stress and general self-efficacy among pregnant women. Integrating health care with web-based or internet-based interventions may improve the quality of antenatal care. PMID- 29533527 TI - Hypertonic saline in viral wheezing. PMID- 29533528 TI - Structure of a bacterial ice binding protein with two faces of interaction with ice. AB - : Ice-binding proteins (IBPs) contribute to the survival of many living beings at subzero temperature by controlling the formation and growth of ice crystals. This work investigates the structural basis of the ice-binding properties of EfcIBP, obtained from Antarctic bacteria. EfcIBP is endowed with a unique combination of thermal hysteresis and ice recrystallization inhibition activity. The three dimensional structure, solved at 0.84 A resolution, shows that EfcIBP belongs to the IBP-1 fold family, and is organized in a right-handed beta-solenoid with a triangular cross-section that forms three protein surfaces, named A, B, and C faces. However, EfcIBP diverges from other IBP-1 fold proteins in relevant structural features including the lack of a 'capping' region on top of the beta solenoid, and in the sequence and organization of the regions exposed to ice that, in EfcIBP, reveal the presence of threonine-rich ice-binding motifs. Docking experiments and site-directed mutagenesis pinpoint that EfcIBP binds ice crystals not only via its B face, as common to other IBPs, but also via ice binding sites on the C face. DATABASE: Coordinates and structure factors have been deposited in the Protein Data Bank under accession number 6EIO. PMID- 29533529 TI - Dual Functionalization of alpha-Monoboryl Carbanions through Deoxygenative Enolization with Carboxylic Acids. AB - A dual functionalization of 1,1-diborylalkanes through deoxygenative enolization with carboxylic acids was developed. 1,1-Diborylalkanes were activated by MeLi to generate alpha-monoboryl carbanions. In situ IR spectroscopy indicated an interaction between carboxylic acid and 1,1-diborylalkane before addition of the activation reagent. Release of the active alpha-monoboryl carbanion from the masked form was necessary for its reaction with carboxylate to afford enolate species. Electrophilic trapping of enolate species with various electrophiles achieved dual functionalization of 1,1-diborylalkanes to afford a variety of alpha-mono, di-, and tri-substituted ketones. PMID- 29533530 TI - Determinants of Readiness for Adopting Healthy Lifestyle Behaviors Among Indigenous Adolescents with Type 2 Diabetes in Manitoba, Canada: A Cross Sectional Study. AB - OBJECTIVE: The aim of this study was to determine whether the readiness for adopting healthy lifestyle behaviors was associated with mental health and comorbid conditions in youth with T2D. METHODS: A cross-sectional comparison of various measures of mental health (distress, stress, resilience) and comorbid conditions (glycated hemoglobin, adiposity, hypertension) was conducted within a cohort of indigenous youth with T2D living in Canada, stratified according to their readiness to adopt healthy lifestyle behaviors based on Prochaska's transtheoretical model. RESULTS: Within the entire cohort (n = 162), only 14% were considered ready to adopt all healthy lifestyle behaviors. The readiness to adopt all lifestyle behaviors was associated with higher positive mental health (47 vs. 39 units; P < 0.05) and sense of mastery (40 vs. 37 units; P < 0.05), lower perceived stress (27 vs. 29 units; P < 0.05) and distress (8 vs. 10 units; P < 0.05), and better glycemic control (HbA1c: 8.4 +/- 2.6% vs. 9.7 +/- 2.8%; P < 0.05) compared with youth who were not ready to adopt all lifestyle behaviors. CONCLUSIONS: The readiness for adopting healthy lifestyle behaviors is low among adolescents with T2D. Being ready to adopt healthy lifestyle behaviors is associated with better mental health and glycemic control. PMID- 29533532 TI - Another nail in the coffin for learning styles? Disparities among undergraduate anatomy students' study strategies, class performance, and reported VARK learning styles. AB - The concept and existence of learning styles has been fraught with controversy, and recent studies have thrown their existence into doubt. Yet, many students still hold to the conventional wisdom that learning styles are legitimate, and may adapt their outside of class study strategies to match these learning styles. Thus, this study aims to assess if undergraduate anatomy students are more likely to utilize study strategies that align with their hypothetical learning styles (using the VARK analysis from Fleming and Mills, , Improve Acad. 11:137-155) and, if so, does this alignment correlate with their outcome in an anatomy course. Relatedly, this study examines whether students' VARK learning styles are correlated with course outcomes regardless of the students' study strategies, and whether any study strategies are correlated with course outcomes, regardless of student-specific VARK results. A total of 426 anatomy students from the 2015 and 2016 Fall semesters completed a study strategies survey and an online VARK questionnaire. Results demonstrated that most students did not report study strategies that correlated with their VARK assessment, and that student performance in anatomy was not correlated with their score in any VARK categories. Rather, some specific study strategies (irrespective of VARK results), such as use of the virtual microscope, were found to be positively correlated with final class grade. However, the alignment of these study strategies with VARK results had no correlation with anatomy course outcomes. Thus, this research provides further evidence that the conventional wisdom about learning styles should be rejected by educators and students alike. Anat Sci Educ. (c) 2018 American Association of Anatomists. PMID- 29533531 TI - Weight Change over the Course of Binge Eating Disorder Treatment: Relationship to Binge Episodes and Psychological Factors. AB - OBJECTIVE: Treatment for binge eating disorder (BED), a condition associated with both excess adiposity and psychological distress, has not typically produced significant weight loss despite reducing binge eating. Characterizing factors that promote or inhibit weight loss in individuals with co-occurring BED and obesity may help explain overall nonsignificant weight changes during treatment. METHODS: In this study, 189 adults with BED participated in a randomized clinical trial evaluating the efficacy of 5 months of cognitive behavioral therapy. Assessments included measured height and weight at baseline, midtreatment, end of treatment (EOT), and 6-month follow-up, the Eating Disorder Examination interview, and questionnaires. RESULTS: During treatment, there was a mean weight gain of 1.3 +/- 12.0 lb. Twenty-two percent of the sample lost >= 5 lb, and 25% of the sample gained >= 8 lb. Results showed that baseline objective binge eating episodes predicted weight over treatment. Changes in weight were significantly positively related to concurrent changes in shape concern, weight concern, and disinhibition, but not binge eating episodes. Changes in objective binge eating episodes from baseline to EOT were associated with changes in weight from EOT to follow-up. CONCLUSIONS: Further investigation of eating behavior during BED treatment to understand the energy balance contributions to weight change or stability is warranted. PMID- 29533533 TI - Placenta-Derived Decidua Stromal Cells for Treatment of Severe Acute Graft-Versus Host Disease. AB - Severe acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). The placenta protects the fetus from the mother's immune system. We evaluated placenta-derived decidua stromal cells (DSCs), which differ from bone marrow mesenchymal stromal cells (BM-MSCs), as a treatment for severe acute GVHD. DSCs were obtained from term placentas. The DSCs were given to 38 patients with severe acute GVHD; 25 were steroid refractory (SR). DSCs were thawed and infused in buffer supplemented with either 10% AB plasma (group 1, n = 17), or 5% albumin (group 2, n = 21). The viability of cells was higher when thawed in albumin rather than AB plasma (p < .001). Group 1 received a higher cell dose (p < .001), cells of lower passage number (p < .001), and fewer infusions (p = .002) than group 2. The GVHD response (no/partial/complete) was 7/5/5 in group 1 and 0/10/11 in group 2 (p = .01). One year survival in the two groups was 47% (95% confidence interval [CI] 23-68) and 76% (95% CI 51-89), respectively (p = .016). For the SR patients, 1-year survival was 73% (95% CI 37-90) in SR group 2 (n = 11), which was better than 31% (95% CI 11-54) in SR group 1 (n = 13; p = .02), 20% (95% CI 5-42) in BM-MSC treated (n = 15; p = .0015), and 3% (95% CI 0-14) in historic controls (n = 32; p < .001). DSCs are a promising new treatment for severe acute GVHD. Prospective randomized trials are needed for evaluation of efficacy. (Clinical trial NCT-02172937.) Stem Cells Translational Medicine 2018;7:325-332. PMID- 29533534 TI - Craniofacial structures' development in prenatal period: An MRI study. AB - INTRODUCTION: The development of skeletal structures (cranial base, upper and lower) and upper airways spaces (oropharyngeal and nasopharyngeal) of the skull has always been an issue of great interest in orthodontics. Foetal MRI images obtained as screening exam during pregnancy can help to understand the development of these structures using a sample cephalometric analysis. MATERIAL AND METHODS: A total of 28 MRI images in sagittal section of foetuses from 20th to 32th weeks of gestation were obtained to dispel doubts about the presence of skeletal malformations. Cephalometric measurements were performed on MRI T2 dependent images acquired with a 1.5 T scanner. The Software Osirix 5 permits to study sagittal and vertical dimensions of the skull analysing linear measurements, angles and areas of the skeletal structures. RESULTS: Vertical and sagittal dimension of cranial base, maxilla and mandible grow significantly (P < .01) between the second and third trimester of gestational period as well as nasopharyngeal and oropharyngeal spaces (P < .05). High correlation between the development of anterior cranial base and functional areas devoted to speech and swallow is demonstrated (r: .97). CONCLUSIONS: The development of craniofacial structures during foetal period seems to show a close correlation between skeletal features and functional spaces with a peak between the second and third trimester of gestation. MRI images result helpful for the clinician to detect with a sample cephalometric analysis anomalies of skeletal and functional structures during prenatal period. PMID- 29533536 TI - Mutation spectra and founder effect of TMC1 in patients with non-syndromic deafness in Xiamen area, China. AB - To analyze the spectrum and founder effect of TMC1 mutations in patients with non syndromic deafness in the Xiamen area. Sporadic pedigrees were detected by targeted next-generation sequencing, and 110 unrelated patients from Xiamen Special Education School were analyzed through Sanger sequencing for the TMC1 gene. In total, 53 SNPs were designed to analyze the haplotypes of the TMC1 c.2050G>C mutation. The probands of three families were found to be homozygous for TMC1 c.2050G>C, and their parents were all heterozygous for the TMC1 c.2050G>C mutation. In 110 unrelated patients from Xiamen Special Education School, four were found to carry compound heterozygotes of TMC1 c.2050G>C, which were compound heterozygotes of c.804G>A, c.1127T>C, c.1165C>T, and c.1396_1398delAAC, respectively. Three types of TMC1 polymorphisms (c.45C>T, c.1713C>T, c.2208+49C>T) and two heterozygotes of novel variants (c.1764-4C>A, c.2073G>A[p.K691K]) were found in the remaining 100 patients. In total, four novel variants were detected in this study. These mutations and variants were not detected in 100 normal samples. The haplotypes of the probands of families with TMC1 c.2050G>C were identical. There were unique hotspots and spectra of TMC1 mutations in the Xiamen deaf population. Haplotype analysis is useful to understand the founder effect of the hot spot mutation. PMID- 29533537 TI - The protective effect of niacinamide on CHO AA8 cell line against ultraviolet radiation in the context of main cytoskeletal proteins. AB - BACKGROUND: Niacinamide is a stable and water-soluble form of vitamin B3, a valuable and versatile cosmetic ingredient, which is well absorbed and tolerated by the skin. A large body of literature has reported on the antioxidant and cell repair properties of niacinamide. Therefore, it has been shown to be useful in the protection of the skin against ultraviolet B (UVB) radiation and free radicals. Despite numerous hypotheses on the mechanism of vitamin B3, its protective effects have not yet been fully elucidated. OBJECTIVES: The aim of the study was to determine the protective effects of niacinamide on CHO AA8 cell line against UVB radiation. We assessed the following factors: cell death, cell cycle phase distributions, reorganization of main cytoskeletal proteins, such as F actin, vimentin and beta-tubulin, and also alterations at the ultrastructural level. MATERIAL AND METHODS: The material used for our research was Chinese hamster ovary cell line (CHO AA8). We used 4 research groups: 1) control cells; 2) cells treated with niacinamide; 3) cells exposed to UV radiation; and 4) cells co-incubated with niacinamide and next exposed to ultraviolet. The cell death and cell cycle were evaluated by a Tali' based-image cytometer. A fluorescence microscope was used to assess the reorganization of cytoskeletal proteins, whereas a transmission electron microscope enabled the evaluation of the alterations at the ultrastructural level of cells. RESULTS: We showed that UV induced apoptosis and cell cycle distributions during treatment with niacinamide resulted in a non-statistical significance in cell survival and no significant changes in the morphology and cytoskeleton in comparison to the control group. In turn, a combination of both factors led to an increase in the population of live cells and a decreased level of apoptotic cells in comparison to UV-exposed cells. CONCLUSIONS: Our results confirmed the harmful effects of UV radiation on CHO AA8 cell line. Furthermore, niacinamide can protect cells against these factors, and the mechanism of action may be related to the stabilization of the cell cytoskeleton. PMID- 29533538 TI - Air-conducted and skull-tap cervical vestibular evoked myogenic potentials in determining nerve division involvement in vestibular schwannoma patients. AB - BACKGROUND: Air-conducted and skull-tap cervical vestibular evoked myogenic potentials (AC-cVEMP and Tap-cVEMP) have been shown to be very promising tools in clinical practice. They are noninvasive, easy to obtain and - importantly - they require little time and the cost of the instruments is low. OBJECTIVES: The aim of this study was to evaluate the usefulness of the combined use of ACand Tap cVEMPs as a diagnostic tool for advanced assessment of vestibular schwannoma in determining tumor origin, and to investigate whether the results are helpful for a surgeon as an additional source of information about the tumor before surgery. MATERIAL AND METHODS: ACand Tap-cVEMPs were acquired (with EMG-based biofeedback) from the sternocleidomastoid muscles (SCM) of 30 vestibular schwannoma patients just before surgery. The results were compared to the surgical information about nerve bundle involvement in the tumor and the size of the tumor obtained from magnetic resonance imaging (MRI). RESULTS: On the tumor side, abnormal corrected amplitude asymmetry ratios were detected in 73.33% of the patients, abnormalities in P1-latencies in 70% of the patients, and both in 90% of the patients. The cervical vestibular evoked myogenic potential (cVEMP) results indicated the affected nerve division to be the inferior in 23.33% of the patients, the superior in 20% of the patients, and both in 46.67% of the patients. No cVEMP abnormalities were found in 10% of cases. The combined results of both ACand Tap cVEMP were significantly compatible with the surgical information about the tumor origin. The number of abnormalities was significantly correlated with the tumor size. CONCLUSIONS: The information provided by the combined application of ACand Tap-cVEMPs might be useful for a surgeon in presurgical planning, providing more detailed information about the tumor and the affected nerve division in the internal auditory canal. It is not a diagnostic replacement for MRI in vestibular schwannoma patients; however, in our opinion, ACand Tap-cVEMPs may serve as additional sources of information about the tumor before the surgery. PMID- 29533535 TI - Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications. AB - Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron-specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end-products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3-kinase-protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon-like peptide-1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let-7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre-messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration. PMID- 29533539 TI - Cord blood lipid profile in healthy newborns: A prospective single-center study. AB - BACKGROUND: Atherosclerosis may originate during the fetal period, therefore it is reasonable to identify early risk markers of lifestyle diseases. OBJECTIVES: The aim of the study was to determine the relationship between fetal and maternal factors, and the neonatal cord blood lipid profile in term newborns. MATERIAL AND METHODS: In the study group, there were 206 healthy Polish newborns. Newborn characteristics included sex, gestational age at birth, Apgar score, and anthropometric data (weight and length at birth, neonatal ponderal index, head, chest and abdominal circumferences, placenta weight, and placental-fetal weight ratio). Cord blood samples were collected for total cholesterol (TC), high density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG). Information regarding selected maternal factors was collected. RESULTS: The cord blood concentration of TC (p = 0.0007), HDL (p = 0.001) and LDL (p = 0.003) was higher in girls than in boys. A significant positive correlation was found between TG and gestational age (p < 0.0001; r = 0.29). Significant negative correlations between maternal preconception BMI and TC (p = 0.03; r = -0.14), HDL (p = 0.04; r = -0.13) and LDL (p = 0.02; r = -0.15) were observed. CONCLUSIONS: In our study group, the influence of the newborns' gender, gestational age and mothers' preconception BMI on lipid concentration was observed. Further investigations are needed to determine markers in cord blood that may predict future metabolic disorders. PMID- 29533540 TI - A comparison of 2 cesarean section methods, modified Misgav-Ladach and Pfannenstiel-Kerr: A randomized controlled study. AB - BACKGROUND: The modified Misgav-Ladach method (MML) is a minimally invasive cesarean section procedure compared with the classic Pfannenstiel-Kerr (PK) method. OBJECTIVES: The aim of the study was to compare the MML method and the PK method in terms of intraoperative and short-term postoperative outcomes. MATERIAL AND METHODS: This prospective, randomized controlled trial involved 252 pregnant women scheduled for primary emergency or elective cesarean section between October, 2014 and July, 2015. The primary outcome measures were the duration of surgery, extraction time, Apgar score, blood loss, wound complications, and number of sutures used. Secondary outcome measures were the wound infection, time of bowel restitution, visual analogue scale (VAS) scores at 6 h and 24 h after the operation, limitations in movement, and analgesic requirements. At 6 weeks after surgery, the patients were evaluated regarding late complications. RESULTS: There was a significant reduction in total operating and extraction time in the MML group (p < 0.001). Limitations in movement were lower at 24 h after the MML operation, and less analgesic was required in the MML group. There was no difference between the 2 groups in terms of febrile morbidity or the duration of hospitalization. At 6 weeks after the operation, no complaints and no additional complications from the surgery were noted. CONCLUSIONS: The MML method is a minimally invasive cesarean section. In the future, as surgeons' experience increases, MML will likely be chosen more often than the classic PK method. PMID- 29533541 TI - beta2-microglobulin as a marker of systemic lupus erythematosus activity. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by alternating periods of activity and remission. A portion of the patients suffers from the chronically active form of the disease. The search for clinically useful markers of its activity is ongoing. At present, it is suggested that beta2-microglobulin (beta2M) may be useful in assessing SLE activity. OBJECTIVES: The objective of the paper was to investigate the relationship between serum beta2M concentration and SLE activity. MATERIAL AND METHODS: The study group consisted of 69 SLE patients (62 women and 7 men), aged 34.5 +/-11 years (19-69). Patients with kidney failure and infection were excluded from the study group. The concentration of beta2M was measured using an ELISA test. SLE activity was assessed with Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K), and by measuring the levels of C3 and C4 complement components, anti-double stranded DNA antibodies (anti-dsDNA antibodies) and beta2M. The relationship between beta2M and the clinical manifestation of SLE was also covered in the study. RESULTS: The study revealed a statistically significant correlation between beta2M concentration and SLEDAI-2K disease activity index (p < 0.05; r = 0.6), anti-dsDNA titer (p < 0.05; r = 0.3), and C4 component serum level (p < 0.05; r = -0.3). beta2M concentration was significantly higher in patients with arthritis and/or myositis (p = 0.005), vasculitis (p = 0.005), and hematological manifestations of SLE (p = 0.02). CONCLUSIONS: Periodical determination of beta2M concentration in SLE patients may prove helpful in assessing the disease activity. PMID- 29533542 TI - Exposure to hepatitis E virus, hepatitis A virus and Borrelia spp. infections in forest rangers from a single forest district in western Poland. AB - BACKGROUND: Hepatitis E virus (HEV) infection is an emerging problem in developed countries. At least 2 zoonotic genotypes of the virus (HEV-3 and HEV-4) infect human beings. There are some data suggesting that forest rangers (FRs) can be at a higher risk of contact with HEV. OBJECTIVES: The aim of this study was to assess the prevalence of HEV exposure markers in FRs from a single forest district in Greater Poland in relation to anti-HAV (hepatitis A virus) IgG, and anti-Borrelia spp. IgM and IgG antibodies. MATERIAL AND METHODS: In total, 138 participants (48 FRs and 90 blood donors - BDs) were tested for anti-HEV IgM and IgG (EUROIMMUN Medizinische Labordiagnostika AG, Luebeck, Germany) and 96 individuals (48 FRs and 48 BDs) were tested for anti-HAV IgG (ARCHITECT immunoassays, Abbott Laboratories, Wiesbaden, Germany); anti-Borrelia IgM and IgG (EUROIMMUN kits) were assessed in FRs only. RESULTS: Anti-HEV markers were detected in 3 participants (2.2%; IgM in 1 FR, IgG in 2 BDs), less frequently than anti-HAV (16 out of 96 individuals, about 17%; FRs 19% vs BDs 15%) or anti Borrelia antibodies (18 out of 48 individuals, 37.5%) (p < 0.0001 for both). Older study participants (>=45 years of age) were more frequently HAV seropositive (29% vs 4% of the younger individuals; p = 0.0012). CONCLUSIONS: We failed to unequivocally prove HEV exposure in FRs. The HAV seroprevalence in this study paralleled the situation in the general population. Exposure to Borrelia spp. in FRs was common. PMID- 29533543 TI - Immunomodulatory properties of human recombinant lactoferrin in mice: Implications for therapeutic use in humans. AB - BACKGROUND: Trauma and major surgery cause extensive immune hyporeactivity in patients. Thus, the preventive, preoperative application of immunoregulatory therapeutics may normalize this immune reactivity and decrease morbidity and mortality in these subjects. OBJECTIVES: The aim of this study was to investigate the immunomodulatory actions of recombinant human lactoferrin (rhLF) in mice, and to relate these effects to in vitro actions of rhLF on tumor necrosis factor alpha (TNF-alpha) production in lipopolysaccharide-stimulated whole blood cell cultures (LPS-stimulated WBCC) from patients admitted to intensive care units. MATERIAL AND METHODS: BALB/c and CBA mice were used. rhLF was tested for allergic response to ovalbumin (OVA), delayed-type hypersensitivity (DTH) to OVA, and carrageenan-induced inflammation in an air pouch. Blood samples from 30 patients diagnosed with severe sepsis/septic shock (Apache II 21 +/-1, mortality rate 40%) were collected on days 1, 3 and 5 of observation. The effects of rhLF on LPS induced TNF-alpha production were measured in WBCCs. RESULTS: Recombinant human lactoferrin reduced the parameters of OVA-induced inflammation and inhibited the elicitation phase of DTH and carrageenan-induced inflammation in mice. The majority of patients from whom whole blood cell cultures (WBCC) were established showed a strong hyporeactivity to LPS upon admission. rhLF exerted differential effects on the production of LPS-induced TNF-alpha in those cultures on days 1, 3 and 5 of observation. Cytokine production was upregulated only in patients with sustained anergy to LPS, and inhibited or unchanged in moderately reactive patients. CONCLUSIONS: Evidence for the potential preventive or therapeutic utility of rhLF in patients with impaired immune reactivity has been demonstrated. PMID- 29533544 TI - Severe infections caused by multidrug-resistant non-fermentative bacilli in southern Poland. AB - BACKGROUND: The impact of multidrug-resistant organisms (MDROs), including non fermentative bacilli (NFBs), is rising and underestimated, especially in intensive care units (ICUs). The growing prevalence of multidrug resistance (MDR) and extensive drug resistance (XDR) is challenging for clinicians, as the treatment options are limited. OBJECTIVES: The purpose of this study was to analyze the extent of the epidemiological problem of multidrugresistant, extensively drug-resistant and pandrug-resistant (PDR) non-fermentative bacilli isolated from pneumonia and bloodstream infections (BSIs) in patients hospitalized in southern Poland. MATERIAL AND METHODS: This study included 253 NFBs belonging to Acinetobacter sp. (ACI), Pseudomonas sp. (PAR), and Stenotrophomonas sp. (STM). The microorganisms were identified, and susceptibility testing was performed using a semi-automatic system. The different patterns of resistance were defined as MDR, XDR, or PDR strains. Epidemiological typing of A. baumannii from ICUs was performed by repetitive polymerase chain reaction (rep-PCR). RESULTS: More than half of the strains (57.7%) were isolated within ICUs. ACI-strains came significantly more often from ICU wards. The highest prevalence of ACI and PAR was found in pneumonia, whereas STM dominated in BSIs. ACIs were more frequently resistant than other pathogens to all studied antibiotics except colistin (n = 76; 58.9%), and they belonged to the XDR category. DiversiLab demonstrated the presence of 2 dominant clones in the ACI group, both classified as European Clone 2 (EUII). CONCLUSIONS: Our results indicate serious potential therapeutic problems related to high antibiotic resistance of ACI isolates. The stratification of drug resistance (MDR/XDR/PDR) may become an important tool for the assessment of public health epidemiology and microbiological hazards at the local, national, and international level. It allows clear presentation of the issues concerning the epidemiology of highly resistant bacilli, and the exchange of information between medical staff and local representatives of public health for the implementation of effective measures to reduce drug resistance. PMID- 29533545 TI - Fibulin-3 and other cartilage metabolism biomarkers in relationship to calprotectin (MRP8/14) and disease activity in rheumatoid arthritis patients treated with anti-TNF therapy. AB - BACKGROUND: Fibulin-3 (Fib-3) is a new potential biomarker of articular cartilage metabolism. OBJECTIVES: The aim of the study was to evaluate the effect of anti TNF therapy on serum fibulin-3, cartilage oligomeric matrix protein (COMP), procollagen II C-propeptide (PIICP), and urinary C-terminal telopeptide of type II collagen (CTX-II) levels in relation to calprotectin (MRP8/14) and disease activity in rheumatoid arthritis patients. MATERIAL AND METHODS: In the study, 35 female patients with rheumatoid arthritis (RA) were investigated. The concentration of fibulin-3, COMP, PIICP, MRP8/14, and urinary CTX-II in serum was measured before and after anti-TNF therapy. Ten healthy women were investigated as the controls. RESULTS: The concentration of fibulin-3 in RA patients before treatment did not differ significantly from the concentration of fibulin-3 in the control group. A significantly higher concentration of fibulin-3 was noted prior to treatment in the group of women with a worse response to the therapy (non responders) compared to the concentration of fibulin-3 in the healthy women. During the anti-TNF therapy, the serum fibulin-3 level decreased in patients. The fibulin-3 level correlated with CRP and ESR after anti-TNF treatment. Significant lowering of MRP8/14 was noted in the patients after anti-TNF therapy. No correlation between fibulin-3 and MRP8/14 was observed in the study group or in the control group. CONCLUSIONS: During the anti-TNF therapy, the serum fibulin-3 level decreased in RA patients. Serum MRP8/14 concentration also decreased. No correlation between fibulin-3 and MRP8/14 was observed in the study group before and after the treatment. We found a poor correlation between serum fibulin-3 and other cartilage metabolism biomarkers after anti-TNF therapy. PMID- 29533546 TI - Telocytes in the female reproductive system: An overview of up-to-date knowledge. AB - Telocytes are emerging cell population localized in the stroma of numerous organs, characterized by a distinctive morphology - small cell body with very long, slender prolongations, termed telopodes. Those cells can be found in the whole female reproductive system: in the vagina, uterus, oviducts and ovaries, mammary glands and also in the placenta. In our review, we aim at complete and transparent revision of the current knowledge of telocytes' localization and function, enriched by the analysis of the possible future direction of development of their clinical applications. The function of telocytes in the reproductive system has not been fully elucidated yet; however, many researchers point at their role in the regulation of local microenvironment, myogenic contractile mechanism, bioelectrical signaling, immunomodulation and regulation of blood flow. Additionally, previous research suggests that telocytes might act as sex hormone level sensors and are connected with pregnancy maintenance. As the morphology and number of those cells change under pathological conditions, such as pre-eclampsia, endometriosis and ovarian failure, there is a chance that they may contribute to therapy of abovementioned conditions. The impact of telocytes on stem cells and angiogenesis has been proven in many organs, and may be useful in regenerative medicine of the female reproductive system. A recently found connection between the proliferation rate of breast cancer cells and stromal cells like telocytes might be a step forward to the management of mammary gland neoplasms. PMID- 29533547 TI - Injectional anthrax in human: A new face of the old disease. AB - Unusual human behavior leads to the emergence of new forms of infectious diseases and new routes of infection. In recent years, a new form of anthrax, called injectional anthrax, emerged and was related to 2 human anthrax outbreaks in Europe. The infection was caused by heroin contaminated with anthrax spores. The new form of anthrax differs from the earlier known "natural" forms of the disease in symptoms, length of the incubation period and recommended treatment. Despite medical treatment, the mortality rate in injectional anthrax is about 35%. This article presents an overview of the forms of anthrax infection in humans, with focus on injectional anthrax syndrome, as well as actual recommendations for treatment, including antibiotic therapy, surgery and possibilities of administering anthrax antitoxin. As a source of contamination of heroin have not been identified and new cases of injectional anthrax might occur again in any country in the future. PMID- 29533549 TI - FINDING NEW VALUE IN TELEMEDICINE: Providers ramp up use to boost access to cost effective care. PMID- 29533548 TI - Gastrointestinal complications in patients with diabetes mellitus. AB - Diabetes mellitus is a systemic disease which affects patients of various age. Hyperglycemia induces damage of vascular endothelium, development of chronic inflammation, organic and functional lesions in several systems and organs. The principal gastroenterological complaints linked to the manifestation of the disease include abdominal pain, diarrhea, nausea, flatulence, and vomiting. However, complications in the alimentary system may manifest exclusively by difficulties in reaching normoglycemia and numerous persistent episodes of hypoglycemia. The most frequent complication of diabetes mellitus affecting the alimentary tract involves gastroparesis and disturbances in pancreatic function. Diabetes may also aggravate other coexisting diseases, such as gastroesophageal reflux or periodontitis. Subject-based references accentuate also a significantly more frequent manifestation together with diabetes of other autoimmune diseases, such as celiac disease or autoimmune gastritis. Also, a hepatic microangiopathy and increased incidence of certain tumors, linked to the manifestation of insulin resistance, may be regarded to represent complications of long-term diabetes. Rapid diagnosis and adequate treatment may significantly improve a patient's quality of life and influence the prolonged control of glycemia. Nevertheless, this requires a rigorous analysis of the signs and clinical condition of a patient as well as individualization of recommendations and therapy. PMID- 29533550 TI - ROUNDTABLE:RANSOMWARE What experts are doing to safeguard their institutions' data. PMID- 29533551 TI - GETTING ON THE SAME PAGE: Data exchange rises in importance for urgent care providers. PMID- 29533552 TI - TOO VULNERABLE TO ATTACK: Multitude of medical devices pose hacking threats for providers. PMID- 29533553 TI - BRINGING INFORMATION TOGETHER: Accountable care is forcing providers to manage more data. PMID- 29533554 TI - [Screening of Organisms Producing Inhibitors of 15-Lipoxygenase Among Micromycetes.] AB - The effects of extracts from the mycelium of Lecanicilium lecaniiNo.169, Beauveria fellina No.7 and Beauveria bassianaNo.15 on the activity of 15 lpoxygenase (15-LO) recovered from rat reticulocytes was investigated. The activity of 15-LO was determined by oxidation of linolic acid. The extract from the mycelium of the fungal complex was shown to inhibit 15-LO (IC50 of 12 mcg/ml). The inhibitory effect of the combined extract on 15-LO was due to the substances recovered from Lecanicilium lecanii No.169. The extract fractions responsible for the activity were determined and the compounds containing the fractions were identified. They proved to be 10 - 4-hydroxybenzoic acid and 4 hydroxybenzyl alcohol and genistein, a flavonoid from fraction 11. The possible role of the inhibitory effect of the compounds on 15-LO in the antiatherosclerotic activity of the fungal extract is discussed. PMID- 29533555 TI - [Effect of Sulfated Polysaccharides from Brown Alga Fucus evanescens and Their Enzymatic Transformation Product on Functional Activity of Innate Immunity Cells.] AB - The effect of sulfated polysaccharides (PS) from brown alga Fucus evanescens and their enzymatic transformation and low molecular weight product on the functional activity of the innate immunity cells, i.e. polymorphonuclear leukocytes of human peripheral blood (NF) was comparatively studied. The in vitro NF contact with PS resulted in significant changes in the functional activity of NF, evident from higher density of molecules CD69, CD14, CD11b on the cell membranes with simultaneous lowering of that of CD62L and increased phagocytic and bactericidal activity of NF. The low molecular weight product resulting from fucoidan transformation with fucoidanases showed a higher effect on the level of the molecules CD14, CD11b and CD62L expression vs. the high molecular weight PS. PMID- 29533556 TI - [Toxicological Evaluation of Intravenous Formulation of Rifapentine.] AB - Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD50 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application. PMID- 29533557 TI - [Antibiotic Resistance and Its Molecular Mechanisms in Carbapenem-Nonsusceptible Klebsiellapneumoniae Isolated in Pediatric ICUs in Moscow.] AB - Klebsiellapneumoniae is a significant pathogen associated with hospital infections. Its was isolated in intensive care units (ICU) at two pediatric hospitals in Moscow in 2012-2014 from 41% (387/935) of the patients. The rate of carbapenem-nonsusceptibility (Carba-NS) amounted to 25% for imipenem and 27% for meropenem. For further analyses, 67 isolates were selected, including 57 Carba-NS and 10 Carba-susceptible (Carba-S). Among the isolates, 100% was nonsusceptible to the III-IV generation cephalosporins, 50-84% was resistant to aminoglycosides. The rate of nonsusceptibility to ciprofloxacin and phosphomycin exceeded 90%. All the tested Carba-S Kpneumoniae isolates were susceptible to tigecycline, whereas 25% of the Carba-NS isolates was tigecycline-NS. The prevalence of the colistin NS isolates was the same in Carba-S (20%) and Carba-NS (26%) bacteria. The blamrx_ gene was carried by 100% of the Carba-S isolates, combining with the blaTEM gene in 60% of the isolates. In 89% of the Carba-NS isolates the OXA-48 carbapenemase was detected, which was combined with CTX-M and/or TEM in all but 1 isolate. Thus, over the last decade, the rate of Carba-NS among nosocomial Kpneuynoniae increased and the OXA-48 carbapenemase was shown to be dominating in the mechanism of Carba-NS in the pediatric ICUs in Moscow. PMID- 29533558 TI - [Antibiotic Resistance of Enterococci Isolated from Healthy Humans and Patients with Various Pathologies.] AB - High resistance of enterococci to the currently used antibacterials, such as tetracycline, ciprofloxacin and ampicillin was observed. Streptomycin, gentamicin and vancomycin showed the highest activity against the clinical isolates of Enterococcus spp. Streptomycin and gentamicin showed the highest activity against the intestinal enterococci. The PCR revealed the presence of the genetic determinants of resistance to aminoglycosides, glycopeptides and tetracycline in the isolates. The comparison of the results of the bacteriological and genetic tests provided detection of fecal and clinical isolates of Enterococcus spp. possessing the genes of resistance to aminoglycosides and glycopeptides, still without the finally developed significant clinical resistance to the above antibacterials. PMID- 29533559 TI - [Streptomycetes in the Light of the Concept of Multicellularity of Bacteria.] AB - The review concerns discussion of certain aspects of growth and development of streptomycetes, that have an adaptation meaning for their existence under natural conditions and reflect our perception of them as procaryotes which have a range of qualities typical of multicellular organisms. At present, the concept of multicellularity is the key idea in investigation of growth processes, differentiation and physiology of streptomycetes. Streptomyces olivocinereus is presented as an effective model that gives the unique opportunities for investigation of different aspects of biology of streptomycetes within laboratory environment as well as in natural environment in suli. S.olivocinereus produces luminescent antibiotic geliomycin (resistomycin). In this review we summarized the results of the many years of investigation of growth, differentiation and behavior of this streptomycete. The investigations were undertaken by a group of scientists of the Moscow State University. The results can be employed as arguments for the multicellular nature of streptomycetes. PMID- 29533560 TI - [Vaccinal Prevention of Lower Respiratory Tract Pneumococcal Disease in Adults Without Immunosuppression.] AB - Community-acquired pneumonia (CAP) remains one of the major healthcare problems globally. Pneumococcal disease is the leading cause of deaths among vaccine preventable diseases in children and adults. Plain polysaccharide vaccine PPSV-23 and conjugated pneumnococcal polysaccharide vaccine PCV-13 are widely used to prevent pneumococcal disease and CAP in adults without immunosuppression. The review concerns the results of trials and meta-analysis of PPSV-23 and PCV-13 effectiveness in invasive pneumococcal disease (IPD) and CAP prevention in immunocompetent adults. More and more expert immunization committees in different countries are taking into consideration uncertain effectiveness of PPSV-23 in CAP prevention in immunocompetent adults, and recommend the PCV-13 priority use for mass immunization campaigns in high-risk groups and elder population. Since the Russian Federation has started the PCV-13 vaccination campaign for early childhood only at the end of 2014, the anticipated serotype replacement should not be taken into consideration at the moment across all the age groups, and therefore the risk and age based approach to adult vaccination should be used with the PCV-13 priority. PMID- 29533561 TI - Adverse Selection and Inertia in Health Insurance Markets: When Nudging Hurts. AB - This paper investigates consumer inertia in health insurance markets, where adverse selection is a potential concern. We leverage a major change to insurance provision that occurred at a large firm to identify substantial inertia, and develop and estimate a choice model that also quantifies risk preferences and ex ante health risk. We use these estimates to study the impact of policies that nudge consumers toward better decisions by reducing inertia. When aggregated, these improved individual-level choices substantially exacerbate adverse selection in our setting, leading to an overall reduction in welfare that doubles the existing welfare loss from adverse selection. PMID- 29533562 TI - How Financial Incentives Induce Disability Insurance Recipients to Return to Work. AB - Using a local randomized experiment that arises from a sharp discontinuity in Disability Insurance (DI) policy in Norway, we provide transparent and credible identification of how financial incentives induce DI recipients to return to work. We find that many DI recipients have considerable capacity to work that can be effectively induced by providing financial work incentives. We further show that providing work incentives to DI recipients may both increase their disposable income and reduce program costs. Our findings also suggest that targeted policies may be the most effective in encouragingDI recipients to return to work. PMID- 29533563 TI - Physician Payment Reform and Hospital Referrals. PMID- 29533564 TI - Disability Insurance and Health Insurance Reform: Evidence from Massachusetts. PMID- 29533565 TI - The Accelerated Benefits Demonstration: Impacts on the Employment of Disability Insurance Beneficiaries. PMID- 29533566 TI - Micro-Loans, Insecticide-Treated Bednets, and Malaria: Evidence from a Randomized Controlled Trial in Orissa, India. AB - We describe findings from the first large-scale cluster randomized controlled trial in a developing country that evaluates the uptake of a health-protecting technology, insecticide-treated bednets (ITNs), through micro-consumer loans, as compared to free distribution and control conditions. Despite a relatively high price, 52 percent of sample households purchased ITNs, highlighting the role of liquidity constraints in explaining earlier low adoption rates. We find mixed evidence of improvements in malaria indices. We interpret the results and their implications within the debate about cost sharing, sustainability and liquidity constraints in public health initiatives in developing countries. PMID- 29533567 TI - How Does Risk Selection Respond to Risk Adjustment? New Evidence from the Medicare Advantage Program. AB - To combat adverse selection, governments increasingly base payments to health plans and providers on enrollees' scores from risk-adjustment formulae. In 2004, Medicare began to risk-adjust capitation payments to private Medicare Advantage (MA) plans to reduce selection-driven overpayments. But because the variance of medical costs increases with the predicted mean, incentivizing enrollment of individuals with higher scores can increase the scope for enrolling "overpriced" individuals with costs significantly below the formula's prediction. Indeed, after risk adjustment, MA plans enrolled individuals with higher scores but lower costs conditional on their score. We find no evidence that overpayments were on net reduced. PMID- 29533574 TI - Hospital Choices, Hospital Prices, and Financial Incentives to Physicians. AB - We estimate an insurer-specific preference function which rationalizes hospital referrals for privately insured births in California. The function is additively separable in: a hospital price paid by the insurer, the distance traveled, and plan- and severity-specific hospital fixed effects (capturing hospital quality). We use an inequality estimator that allows for errors in price and detailed hospital-severity interactions and obtain markedly different results than those from a logit. The estimates indicate that insurers with more capitated physicians are more responsive to price. Capitated plans send patients further to utilize similar quality, lower-priced hospitals; but the cost-quality trade-off does not vary with capitation rates. PMID- 29533575 TI - The Effects of Poor Neonatal Health on Children's Cognitive Development. AB - We make use of a new data resource--merged birth and school records for all children born in Florida from 1992 to 2002--to study the relationship between birth weight and cognitive development. Using singletons as well as twin and sibling fixed effects models, we find that the effects of early health on cognitive development are essentially constant through the school career; that these effects are similar across a wide range of family backgrounds; and that they are invariant to measures of school quality. We conclude that the effects of early health on adult outcomes are therefore set very early. PMID- 29533576 TI - [Voice Handicap Index - efficiency and correlation between physical, functional and emotional aspects and voice disorders]. AB - Voice disorders are a very common medical problem amongpeople whose occupation requires overusing their voice asa working tool. The lack of correct voice projection and phonationtraining courses is the reason why voice disorders are commonlyfound throughout society. In order to identify the reasonscausing voice disorders, the Voice Handicap Index (VHI) maybe used. As an instrument of iterative testing, the VHI allowsnot only self -assessment of someone's voice, but it is also a veryhelpful research tool during veri??ication of the effects of voicerehabilitation. PMID- 29533577 TI - Propranolol as an effective treatment for inoperable periocular haemangiomas in children. AB - Introduction: Infantile haemangiomas located in the periocularregion are a signi??icant clinical problem. When untreated, theycan lead to serious complications that can inhibit the properdevelopment of vision. As they are often inaccessible surgically,a noninvasive eye -saving therapy is required.The aim of the study was to assess the effectiveness of propranololtreatment for inoperable periocular haemangiomas (PH)in children. Material and methods: Seventeen children with haemangiomasof the upper and lower eyelid and internal eyelid angle werethoroughly examined. Lesions were seriously affecting movementof eyelids leading to ptosis in most of cases, but anisometricastigmatism and exophtalmia were also diagnosed. Patientswere carefully quali??ied for propranolol treatment and werere -evaluated when therapy was completed. Results: In all of the described cases brightening and softeningof the lesion were observed from the ??irst days of therapy.Ninety percent of patients showed signs of complete involution.In 5 cases a mild discolouration or skin enhancement persisted.All children presented signi??icant functional improvement. An86% reduction of astigmatism was found in cases that werediagnosed initially. Conclusions: In conclusion, early diagnosis and introduction ofpropranolol for PH reduce the risk of complications that posea threat to eye function. Measurement of astigmatism reductionmay be a useful tool to establish a proper moment to ceasethe therapy. Propranolol is the ??irst choice treatment option inPH based on its effectiveness, speed of action, and low rate ofside effects. PMID- 29533578 TI - Microbiota - a key to healing the gastrointestinal tract? AB - At present, it is already known that many gastrointestinal tractdiseases are caused by disorders of the intestinal ecosystem.The contribution of microbiota disorders to the developmentand sustaining of in??lammatory bowel diseases, irritable bowelsyndrome, necrotizing enterocolitis, constipation or bloatinghas been demonstrated in numerous scienti??ic studies. Anothermatter is bacterial imbalance in food allergy and atopic diseases.The effectiveness of probiotics and prebiotics in these diseaseshas been repeatedly con??irmed, which made researchers searchfor new diseases in which probiotics could be an ef??icient therapeuticsolution. Reports have also been published on microbiotadisturbances in children with a spectrum of autistic disorders,depression or metabolic syndrome, and in obese patients.New micro -organisms have been discovered, which in additionto Lactobacillus or Bi??idobacterium bacteria, may signi??icantlyin??luence the improvement of human health. Especially promisingare two bacterial species, Akkermansia muciniphila andFaecalibacterium prausnitzii, which seem to interact in continuityregeneration of the intestinal epithelium. A. muciniphila has theability to degrade mucin, while producing acetic acid, propionicacid and oligosaccharides. These products become the substratefor F. prausnitzii, one of the main producers of butyrate in theintestine. The anaerobic butyrate -producing bacterium helpsto inhibit in??lammation in the gastrointestinal tract, while preventingincreased intestinal permeability. Growth stimulationin bacteria (e.g. towards prebiotic therapy) may therefore proveto be a valuable nutritional option and an ef??icient way to restorethe intestinal epithelium. While A. muciniphila is extensivelystudied in the context of obesity and diabetes, F. prausnitzii maybecome an interesting marker for Crohn's disease activity.The aim of this paper is to present new and promising aspectsof intestinal microbiota restoration in the treatment of selecteddiseases. PMID- 29533579 TI - Long -term effects of optical defocus on eye growth and refractogenesis. AB - Introduction: The aim of this paper was to study the effect ofbinocular and alternating monocular myopic constant defocusprescribed in spectacle format on myopia onset and progressionin children. Material and methods: 129 children aged 5-12 years weredivided into 4 groups: 48 children aged 5-8 years (1st group)with emmetropia and risk factors of myopia development wereprescribed the continuous wearing of plus lenses to induce myopiaof 1.0 D. 46 children aged 7-11 years (2nd group) with lowmyopia from -0.75 to -2.25 D were prescribed 2 pairs of spectaclesfor alternating continuous wearing. One eye was correctedfor distance to obtain residual myopia in spectacles of about0.50 D, and the fellow eye was corrected to obtain residual orinduced myopia of about 1.50 D. The children changed spectaclesevery day. Control data were obtained from 15 children aged6-9 years (1st control group) with pseudomyopia with no correctionadministered, and 20 low myopic children aged 7-12 years(2nd control group) wearing conventional spectacle correction.Autorefractometry before and after cycloplegia and ultrasoundbiometry were performed. Results: A hyperopic shift caused by thinning of the crystallinelens and deepening of the anterior chamber in all patientsof the 1st group was observed after 1 month and persisted overthe follow -up period. Horizontal diameter (HD) increased morethan 3 times as much as the axial length (AL). No cases of myopiaonset were observed during the 9 -year follow -up period.36 (81.8%) children of the 2nd group had stable refraction overthe 4 year follow up, an insignificant increase in the AL and a significant increase in the HD were revealed. A 3-year follow -up revealed an increase in cycloplegic refraction in both control groups; the AL increased significantly, while the HD showed an insignificant increase. Conclusions: Permanent low myopic defocus of the image inbinocular spectacle format inhibits eye growth and refractionshift to myopia in children with low hyperopia, emmetropia andlow myopia. The method of alternating monolateral low myopicdefocus arrests the myopia progression in 81.8% of childrenwith low myopia for 4 years and 66% for 7 years. PMID- 29533580 TI - Beyond the Compositional Threshold of Nanoparticle-Based Materials. AB - The design of inorganic nanoparticles relies strongly on the knowledge from solid state chemistry not only for characterization techniques, but also and primarily for choosing the systems that will yield the desired properties. The range of inorganic solids reported and studied as nanoparticles is however strikingly narrow when compared to the solid-state chemistry portfolio of bulk materials. Efforts to enlarge the collection of inorganic particles are becoming increasingly important for three reasons. First, they can yield materials more performing than current ones for a range of fields including biomedicine, optics, catalysis, and energy. Second, looking outside the box of common compositions is a way to target original properties or to discover genuinely new behaviors. The third reason lies in the path followed to reach these novel nano-objects: exploration and setup of new synthetic approaches. Indeed, willingness to access original nanoparticles faces a synthetic challenge: how to reach nanoparticles of solids that originally belong to the realm of solid-state chemistry and its typical protocols at high temperature? To answer this question, alternative reaction pathways must be sought, which may in turn provide tracks for new, untargeted materials. The corresponding strategies require limiting particle growth by confinement at high temperatures or by decreasing the synthesis temperature. Both approaches, especially the latter, provide a nice playground to discover metastable solids never reported before. The aim of this Account is to raise attention to the topic of the design of new inorganic nanoparticles. To do so, we take the perspective of our own work in the field, by first describing synthetic challenges and how they are addressed by current protocols. We then use our achievements to highlight the possibilities offered by new nanomaterials and to introduce synthetic approaches that are not in the focus of recent literature but hold, in our opinion, great promise. We will span methods of low temperature "chimie douce" aqueous synthesis coupled to microwave heating, sol-gel chemistry and processing coupled to solid state reactions, and then molten salt synthesis. These protocols pave the way to metastable low valence oxyhydroxides, vanadates, perovskite oxides, boron carbon nitrides, and metal borides, all obtained at the nanoscale with structural and morphological features differing from "usual" nanomaterials. These nano-objects show original properties, from sensing, thermoelectricity, charge and spin transports, photoluminescence, and catalysis, which require advanced characterization of surface states. We then identify future trends of synthetic methodologies that will merit further attention in this burgeoning field, by emphasizing the importance of unveiling reaction mechanisms and coupling experiments with modeling. PMID- 29533581 TI - Sweet Switch: Sugar-Responsive Bioactive Surfaces Based on Dynamic Covalent Bonding. AB - Smart bioactive surfaces that can modulate interactions with biological systems are of great interest. In this work, a surface with switchable bioactivity in response to sugars has been developed. It is based on dynamic covalent bonding between phenylboronic acid (PBA) and secondary hydroxyls on the "wide" rim of beta-cyclodextrin (beta-CD). The system reported consists of gold surface modified with PBA-containing polymer brushes and a series of functional beta-CD derivatives conjugated to diverse bioactive ligands (CD-X). CD-X molecules are attached to the surface to give specified bioactivity such as capture of a specific protein or killing of attached bacteria. Subsequent treatment with cis diol containing biomolecules having high affinity for PBA (e.g. fructose) leads to the release of CD-X together with the captured proteins, killed bacteria, and so forth from the surface. The surface bioactivity is thereby "turned off". Effectively, this constitutes an on-off bioactivity switch in a mild and noninvasive way, which has the potential in the design of dynamic bioactive surfaces for biomedical applications. PMID- 29533582 TI - Porous Co-C Core-Shell Nanocomposites Derived from Co-MOF-74 with Enhanced Electromagnetic Wave Absorption Performance. AB - The combination of carbon materials and ferrite materials has recently attracted increased interest in microwave absorption applications. Herein, a novel composite with cobalt cores encapsulated in a porous carbon shell was synthesized via a facile sintering process with a cobaltic metal-organic framework (Co-MOF 74) as the precursor. Because of the magnetic loss caused by the Co cores and dielectric loss caused by the carbon shell with a unique porous structure, together with the interfacial polarization between two components, the ferromagnetic composite exhibited enhanced electromagnetic wave absorption performance compared to traditional ferrite materials. With the thermal decomposition temperature of 800 degrees C, the optimal reflection loss value achieved -62.12 dB at 11.85 GHz with thin thickness (2.4 mm), and the bandwidth ranged from 4.1 to 18 GHz with more than 90% of the microwave that could be absorbed. The achieved performance illustrates that the as-prepared porous Co-C core-shell composite shows considerable potential as an effective microwave absorber. PMID- 29533583 TI - Evolution of Active Sites in Pt-Based Nanoalloy Catalysts for the Oxidation of Carbonaceous Species by Combined in Situ Infrared Spectroscopy and Total X-ray Scattering. AB - We present results from combined in situ infrared spectroscopy and total X-ray scattering studies on the evolution of catalytically active sites in exemplary binary and ternary Pt-based nanoalloys during a sequence of CO oxidation reactivation-CO oxidation reactions. We find that when within a particular compositional range, the fresh nanoalloys may exhibit high catalytic activity for low-temperature CO oxidation. Using surface-specific atomic pair distribution functions (PDFs) extracted from the in situ total X-ray scattering data, we find that, regardless of their chemical composition and initial catalytic activity, the fresh nanoalloys suffer a significant surface structural disorder during CO oxidation. Upon reactivation in oxygen atmosphere, the surface of used nanoalloy catalysts both partially oxidizes and orders. Remarkably, it largely retains its structural state when the nanoalloys are reused as CO oxidation catalysts. The seemingly inverse structural changes of studied nanoalloy catalysts occurring under CO oxidation and reactivation conditions affect the active sites on their surface significantly. In particular, through different mechanisms, both appear to reduce the CO binding strength to the nanoalloy's surface and thus increase the catalytic stability of the nanoalloys. The findings provide clues for further optimization of nanoalloy catalysts for the oxidation of carbonaceous species through optimizing their composition, activation, and reactivation. Besides, the findings demonstrate the usefulness of combined in situ infrared spectroscopy and total X-ray scattering coupled to surface-specific atomic PDF analysis to the ongoing effort to produce advanced catalysts for environmentally and technologically important applications. PMID- 29533584 TI - [Sexual dimorphism and asymmetry of digit ratio (2D:4D) - pilot study]. AB - Introduction: Numerous studies have demonstrated sexualdimorphism in 2D:4D digit ratio. Shall be regarded that thevalue of the 2D:4D ratio is determined in fetal life by the actionof hormones. The aim of the study was to evaluate asymmetry and sexualdimorphism in 2D:4D digit ratio. Material and methods: The study was conducted on a group of115 women and 46 men, aged 19-25 years. Individuals, whichwere included in the study, are students of two universities inCracow - Academy of Physical Education and the JagiellonianUniversity. The measurement of the length the fingers II and IVboth hands was made in each person and the value of digit ratiowas calculated for all obtained data. Results: The women had the higher value of the index 2D:4Din both hands, compared with men covered by the survey. Inmales it was demonstrated higher average value of the lengthof the finger IV than the finger II. PMID- 29533585 TI - [Autoimmune/infl ammatory syndrome induced by adjuvants, ASIA]. AB - There have been many cases of the appearance of autoantibodiesand symptoms of disease after exposure to adjuvants, not onlyafter breast augmentation with silicone implants, but also asa very rare vaccination side effect, such as Gulf war syndrome ormacrophagic myofasciitis syndrome. Diseases whose symptomsdeveloped after such adjuvant exposure are called autoimmune/in??lammatory syndrome induced by adjuvants (ASIA). The groupof adjuvants includes not only silicone implants, silica, squalenand aluminium, but also ink components used for making tattoos.Analyzing the available reports on the in??luence of adjuvantson the development of autoimmune diseases, the conclusion isthat apart from long -term silicone exposure, the coexistenceof other factors such as genetic or environmental is also necessary.Metaanalyses clearly do not con??irm an increased risk ofdeveloping autoimmune disease after breast augmentation withsilicone implants, or tattooing, but it seems that among thesepatients there is a group that is more predestined to developdisease symptoms. In the general population the bene??its ofvaccination are obvious, and the risk of severe adverse eventsfollowing immunisation is incomparably lower than the riskof developing a speci??ic disease and its complications, also forpatients with diagnosed autoimmune diseases.Because of data heterogeneity in previous studies and dif??icultiesin diagnosing ASIA it seems necessary to conduct furtheranalyses of adjuvants' in??luence on autoimmune disease development,and to re??ine ASIA diagnostic criteria, which now allowtoo easy a diagnosis of this syndrome. PMID- 29533586 TI - [Functional limitations associated with lumbosacral spine pain in pregnant women]. AB - Introduction: Lower back pain affects most pregnant women.Pain is often associated with varying degrees of functional limitations,causing a problem for pregnant women in the performanceof many everyday activities.The aim of the study was to assess the extent to which lumbosacralspine pain caused limitations in the daily functioningof pregnant women, and the relationship between reportedrestrictions and analysed variables. Material and methods: The study was conducted in the city ofSzczecin in Poland among 81 pregnant women. Data were collectedusing a standardized Oswestry questionnaire survey (TheOswestry Lower Back Pain Disability Questionnaire). Resultswere analysed using the chi2 test of independence. The signi??icancelevel was adopted at p < 0.05. Results: The majority of women pregnant for the second time(n = 38) had mild disability. The relationship between the degreeof disability and the order of pregnancies was statistically signi??icant (chi2 = 40.457, p = 0.0000000085). Conclusions: The majority of pregnant women had minor functionallimitations due to pain in the lumbosacral spine region.The degree of functional limitations depends on the trimesterof pregnancy and the order of pregnancies. PMID- 29533587 TI - [Protection against oxidative stress in male reproductive system]. AB - Reactive oxygen species (ROS) play in the male reproductivesystem important physiological functions in cell signaling, spermatogenesisand sperm maturation in epididymis. The influenceof various factors, e.g. environmental, could be the reason foroxidative stress. This can lead to the exposure of cells to thetoxic effects of many oxidants such as O*-2, O3, H2O2, *OH. Thesource of ROS may be spermatozoa, which also, due to the compositionof the cytoplasmic membrane lipids and great amountof mitochondria are particularly susceptible to oxidative damage.Oxidative stress can damage their membranes, DNA, inhibitsperm motility and reduce their fertilization ability. This dualeffect of ROS confirms the unique role of antioxidant enzymes(such as SOD, CAT and GPX) and non-enzymatic (e.g. GSH, vitaminsA, E, C, transferrin) responsible for maintaining adequatelevels of ROS in the male reproductive system. PMID- 29533588 TI - [Fluorides in the human bones - selected issues]. AB - Long -term intake of ??luoride leads to skeletal ??luorosis. The toxicityof ??luoride, not only for the human body, but also the entireecosystem makes it necessary to constantly monitor their contentin the environment. Accordingly, there is a need to controlthe level of ??luorides (F-) in humans, particularly in bone tissue,which re??lects long -term accumulation of these compounds.The aim of the study was to determine the concentration of ??luoridein the human bones depending on biological factors and environmentalconditions on the basis of the published literature.Given the importance of bone tissue as the main reservoir of??luoride ions is an important issue to continue to monitor theconcentration of F- in this tissue, particularly for people living inthe polluted environment ??luorine compounds. There are numerousworks on concentrations of this element in human bones inworld literature which proves the great interest in the subject.It should be underlined the need for further study of this issuefor people living in different regions of Poland. PMID- 29533589 TI - [Kinesiotaping as an interdisciplinary therapeutic method]. AB - Introduction: Kinesiotaping (KT) is one of the newest methodscommonly used in many medical sciences: neurology, orthopaedicsand traumatology, oncology, gynaecology and obstetrics,and in paediatrics. Due to its special properties, KT canbe used depending on individual needs and problems duringrehabilitation. Aim: This article presents a systematic review of the clinicaleffectiveness of using KT in physiotherapy. Conclusions: KT method is widespread in different medicalsciences and is a good method supporting rehabilitation andpharmacological treatment. Due to its special properties it canbe used in children, adults, and also pregnant women. PMID- 29533590 TI - [The influence of grade 1 stress urinary incontinence on the physical activity of women depending on nutritional status as defined by the Body Mass Index]. AB - Introduction: Stress urinary incontinence (SUI) and obesityare problems recognized by the World Health Organization associal diseases. The International Continence Society has estimatedthat about 10-40% of women have problems with urinaryincontinence. Overweight states and obesity are among the biggesthealth problems in perimenopausal women.The aim of the study was to analyze the impact of SUI on thephysical activity (PA) of women in relation to their body weight. Material and methods: The study comprised 54 women aged41-67 years with SUI. Anthropometric measurements weretaken. Physical activity was examined by specially designedquestionnaires. The statistical significance was calculated inthe Statistica 12 software using normality tests, correlationcoefficient, nonparametric tests, and a post -hoc test. Results: The mean age of subjects was 55 +/-7 years. BodyMass Index (BMI) in subjects was normal (N1) - 11 (20.4%),or indicated the state of being overweight (N2) - 33 (59.2%)or obese (N3) - 11 (20.4%); 94% (51) patients had the androidbody type and 6% (3) had the gynoidal body type. PA before theonset of problems with SUI was assessed by patients as a sedentarylifestyle - 12 (22.2%), active - 23 (42.6%) or mixed - 19(35.2%). Subjects, when asked how strong the impact of SUIon their PA was, answered: minor 13 (24.1%), moderate - 14(25.9%), very strong - 27 (50%). No statistically signi??icantdifferences between PA and SUI were found in N1, N2 andN3 groups. Conclusions: Overweight patients reported the strongest impactof SUI on their PA, but the differences between the analysedgroups were not signi??icant. Most subjects had the android bodytype, which was assessed by means of WHR. PMID- 29533591 TI - [Quality and availability of care for people with mental disorders - assessment of health care providers]. AB - Introduction: The aim of this study was to identify the opinionsof mental health care providers on the quality of their services. Materials and methods: The study was based on the opinionsof mental health care providers. The study included facilities ofthe West Pomeranian province in Poland. A diagnostic surveywas chosen as the research method. The questionnaire -basedinterview was carried out in facilities located in Szczecin. Inother facilities the survey was carried out and the questionnairewas sent by post after prior calls. The study used a speciallydesigned questionnaire which was based on quality categoriesproposed by Maxwell. Results: In all categories of quality respondents most frequentlyindicated "high" and "average" scores. The "low" score was rarelyreported. The best rated category of quality is justice in accessto services. As many as 93.3% of respondents gave the highestrating to this category, and 6.7% rated it as average. The secondbest assessed category was the competence of personnel. Asmany as 80.0% of respondents representing health care centresrated personnel competence as high. The third top -ratedcategory of quality was the effectiveness of services, or the provisionof services in accordance with current knowledge andcurrent scienti??ic reports. As many as 76.7% of respondentsrated the effectiveness of their services as high. The lowest ratedcategory of quality was the adaptation of buildings to the needsof patients, and the safety of procedures. Conclusions: 1. Representatives of psychiatric care facilitieshighly rated the quality of services provided by their facility.2. Top rated quality categories were justice in access to services,personnel competence, and ef??iciency of the services. 3. Thelowest rated categories were the adaptation of facilities to theneeds of patients, and the safety of procedures. PMID- 29533592 TI - [Assessment of knowledge of women regarding sexual risk factors for cervical cancer]. AB - Introduction: In Poland, reproductive system cancers are animportant medical and social problem. Risky sexual behaviourssuch as early age of sexual initiation, or a large number of sexualpartners increase the risk of cervical cancer.The aim of this study was to assess the knowledge of womenabout sexual risk factors for cervical cancer. Materials and methods: The study included 200 women fromthe cities of Lublin and Radom, and the village of Jablonna.Respondents completed a diagnostic survey questionnaire speciallydeveloped for the purpose of this study. The results werestatistically analysed. Results: statistically signi??icant relationship was foundbetween the knowledge of respondents about early start ofsexual intercourse as a risk factor for cervical cancer and theirmarital status (p = 0.003), place of residence (p = 0.01) and typeof professional activity (p = 0.03). There was also a statisticallysigni??icant relationship between the knowledge of the surveyedwomen on a large number of sexual partners as a risk factor forcervical cancer and age (p = 0.002), marital status (p = 0.03),and the type of professional activity. Conclusions: Women know that the early age of sexual initiationand a large number of sexual partners is a risk factor forcervical cancer. On the other hand, they are not aware of theimpact of a large number of sexual partners of their currentpartner on the risk of cervical cancer. There is a need to educatewomen about the impact of risky sexual behaviour on thepotential development of cervical cancer. PMID- 29533593 TI - [Excessive left retroperitoneal abscess of an unknown aetiology perforating into the peritoneal cavity: a case report]. AB - Retroperitoneal abscesses present a relatively uncommon complicationof diseases of various abdominal organs, although most commonlythey are related to acute appendicitis of retrocoecal location.The paper presents the case of a healthy patient in whom anexcessive left retroperitoneal abscess developed, perforatedinto the peritoneal cavity, and almost perforated through theskin in XIIth intercostal space. The patient had no abdominalsymptoms or signs, but complained from slight pain in the leftlumbar area. The diagnosis was established based on abdominalcomputed tomography scanning and an operative treatmentby laparotomy. The evacuation and drainage of the abscess waseffective and the patient recovered. Bacteriological examinationof the pus from the abdominal cavity revealed single colonies ofanaerobic Fusobacterium species. The cause of the occurrenceof the abscess remained unknown. PMID- 29533594 TI - [Intracranial remote epidural haematoma as a complication after resection of an occipital lobe metastatic tumour from a testicular embryonal carcinoma - a case report]. AB - We present the case of a patient who suffered from intracranialepidural haematoma in the left fronto -temporo -parietal regionas a complication after left parieto occipital craniotomy anda resection of a metastatic lesion from a testicular embryonalcarcinoma to the left occipital lobe. We also discuss possiblecauses of this complication. PMID- 29533595 TI - Portable Nanofiber-Light Addressable Potentiometric Sensor for Rapid Escherichia coli Detection in Orange Juice. AB - The growing need to prevent pathogen outbreaks is irrefutable in the case of the food industry. Early detection in products, especially beverages, contaminated with bacterial strains is vital to avoid infected foods from reaching the consumer. If E. coli is pesent in such foods, it can cause infections. It can also be an indicator of the existence of other harmful coliforms. In this study, we have investigated the detection of Escherichia coli ( E. coli) in orange juice using a portable nanofiber-light addressable potentiometric sensor (NF-LAPS). We have chosen electrospun pH-sensitive poly(vinyl alcohol)/poly(acrylic acid) (PVA/PAA) hydrogel NFs as the sensitive layer. The successful detection of E. coli was reported with the NF-LAPS in less than 1 h. The limit of detection (LOD) measured in the sensor is found to be102 CFU/mL. We have confirmed the selectivity of the biosensor toward E. coli by examining the response of the NF LAPS against Salmonella typhimurium ( S. typhi), also commonly found in orange juice. Despite the complex nature of orange juice, the response of the biosensor is in no way affected while orange juice is tested as is. PMID- 29533596 TI - 20% Efficient Zn0.9Mg0.1O:Al/Zn0.8Mg0.2O/Cu(In,Ga)(S,Se)2 Solar Cell Prepared by All-Dry Process through a Combination of Heat-Light-Soaking and Light-Soaking Processes. AB - Development of Cd-free Cu(In,Ga)(S,Se)2 (CIGSSe)-based thin-film solar cells fabricated by an all-dry process is intriguing to minimize optical loss at a wavelength shorter than 520 nm owing to absorption of the CdS buffer layer and to be easily integrated into an in-line process for cost reduction. Cd-free CIGSSe solar cells are therefore prepared by the all-dry process with a structure of Zn0.9Mg0.1O:Al/Zn0.8Mg0.2O/CIGSSe/Mo/glass. It is demonstrated that Zn0.8Mg0.2O and Zn0.9Mg0.1O:Al are appropriate as buffer and transparent conductive oxide layers with large optical band gap energy values of 3.75 and 3.80 eV, respectively. The conversion efficiency (eta) of the Cd-free CIGSSe solar cell without K-treatment is consequently increased to 18.1%. To further increase the eta, the Cd-free CIGSSe solar cell with K-treatment is next fabricated and followed by posttreatment called the heat-light-soaking (HLS) + light-soaking (LS) process, including HLS at 110 degrees C followed by LS under AM 1.5G illumination. It is disclosed that the HLS + LS process gives rise to not only the enhancement of carrier density but also the decrease in the carrier recombination rate at the buffer/absorber interface. Ultimately, the eta of the Cd-free CIGSSe solar cell with K-treatment prepared by the all-dry process is enhanced to the level of 20.0%. PMID- 29533597 TI - Enhancement of Thermoelectric Performances in a Topological Crystal Insulator Pb0.7Sn0.3Se via Weak Perturbation of the Topological State and Chemical Potential Tuning by Chlorine Doping. AB - Topological insulators generally share commonalities with good thermoelectric (TE) materials because of their narrow band gaps and heavy constituent elements. Here, we propose that a topological crystalline insulator (TCI) could exhibit a high TE performance by breaking its crystalline symmetry and tuning the chemical potential by elemental doping. As a candidate material, we investigate the TE properties of the Cl-doped TCI Pb0.7Sn0.3Se. The infrared absorption spectra reveal that the band gap is increased from 0.055 eV for Pb0.7Sn0.3Se to 0.075 eV for Pb0.7Sn0.3Se0.99Cl0.01, confirming that the Cl doping can break the crystalline mirror symmetry of a TCI Pb0.7Sn0.3Se and thereby enlarge its bulk electronic band gap. The topological band inversion is confirmed by the extended X-ray absorption fine structure spectroscopy, which shows that the TCI state is weakened in a chlorine x = 0.05-doped compound. The small gap opening and partial linear band dispersion with massless and massive bands may have a high power factor (PF) for high electrical conductivity with an enhancement of the Seebeck coefficient. As a result, Pb0.7Sn0.3Se0.99Cl0.01 shows a considerably enhanced ZT of 0.64 at 823 K, which is about 1200% enhancement in ZT compared with that of the undoped Pb0.7Sn0.3Se. This work demonstrates that the optimal n-type Cl doping tunes the chemical potential together with breaking the state of the TCI, suppresses the bipolar conduction at high temperatures, and thereby enables the Seebeck coefficient to increase up to 823 K, resulting in a significantly enhanced PF at high temperatures. In addition, the bipolar contribution to thermal conductivity is effectively suppressed for the Cl-doped samples of Pb0.7Sn0.3Se1- xCl x ( x >= 0.01). We propose that breaking the crystalline mirror symmetry in TCIs could be a new research direction for exploring high performance TE materials. PMID- 29533598 TI - Correction to Impact of Nonideal Nanoparticles on X-ray Photoelectron Spectroscopic Quantitation: An Investigation Using Simulation and Modeling of Gold Nanoparticles. PMID- 29533599 TI - Role of Nitrogen Moieties in N-Doped 3D-Graphene Nanosheets for Oxygen Electroreduction in Acidic and Alkaline Media. AB - This study elucidates the synthesis-structure-property correlations of nitrogen moieties present in nitrogen-functionalized graphene nanomaterials toward oxygen reduction reactions (ORRs) and their electrochemical pathways in acidic and alkaline electrolytes. Porous three-dimensional nitrogen-doped graphene nanosheets (N/3D-GNSs) were fabricated using the sacrificial support method and doped with nitrogen using 10 atom % NH3 under thermal pyrolysis at T = 650, 850, and 1050 degrees C for evaluating the nitrogen species formed under different temperatures. The abundances of the various nitrogen species formed under pyrolytic conditions were evaluated with X-ray photoelectron spectroscopy. Using rotating ring-disk electrode, we analyzed the role played by the nitrogen moieties influencing the electrochemical activity of the N/3D-GNS supports for oxygen reduction reactions (ORRs) in both acidic and alkaline media. It was demonstrated that the concentrations of the nitrogen moieties: graphitic-N, quaternary, hydrogenated-N (hydrogenated nitrogen combined pyrrolic nitrogen and hydrogenated pyridine) and pyridinic-N varied considerably with pyrolysis temperatures. A decrease in graphitic-N content and an increase in the ratio of hydrogenated-N/pyridinic-N significantly improved the activity of the material. The half-wave and onset potentials as well as the current densities and hydrogen peroxide (H2O2)/(HO2-) yields of the N/3D-GNS materials also varied between acidic and alkaline electrolytes but followed the general trend in terms of pyrolysis temperatures and abundance of the nitrogen moieties. Among the synthesized materials, the 3D-graphene nanosheets that were doped with nitrogen at 850 degrees C, optimized to have the highest hydrogenated-N and lowest pyridinic-N as well as better catalyst-ionomer integration, showed the highest ORR performance. This strategy for the tunable synthesis of nitrogen-doped graphene materials with controlled nitrogen functionalization offers a platform for developing active supports or catalytic nanomaterials for fuel cell applications. PMID- 29533600 TI - An Electrochemical Wind Velocity Sensor. AB - Electrochemical interfaces invariably generate unipolar electromotive force because of the unidirectional nature of electrochemical double layers. Herein we show an unprecedented generation of a time varying bipolar electric field between identical half-cell electrodes induced by tailored interfacial migration of magnetic particles. The periodic oscillation of a bipolar electric field is monotonically correlated with velocity-dependent torque, opening new electrochemical pathways targeting velocity monitoring systems. PMID- 29533601 TI - Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C 1027. AB - C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apoprotein and the C-1027 chromophore. The C-1027 chromophore features a nine membered enediyne core appended with three peripheral moieties, including an ( S) 3-chloro-5-hydroxy-beta-tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the ( S)-3-chloro-5-hydroxy-beta-tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide-bond formation, SgcC5 catalyzes ester-bond formation, as demonstrated in vitro, between SgcC2-tethered ( S)-3-chloro-5-hydroxy-beta tyrosine and ( R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate. Here, we report that (i) genes encoding SgcC5 homologues are widespread among both experimentally confirmed and bioinformatically predicted enediyne biosynthetic gene clusters, forming a new clade of condensation enzymes, (ii) SgcC5 shares a similar overall structure with the canonical condensation domains but forms a homodimer in solution, the active site of which is located in a cavity rather than a tunnel typically seen in condensation domains, and (iii) the catalytic histidine of SgcC5 activates the 2-hydroxyl group, while a hydrogen bond network in SgcC5 prefers the R-enantiomer of the acceptor substrate, accounting for the regio- and stereospecific ester-bond formation between SgcC2 tethered ( S)-3-chloro-5-hydroxy-beta-tyrosine and ( R)-1-phenyl-1,2-ethanediol upon acid-base catalysis. These findings expand the catalytic repertoire and reveal new insights into the structure and mechanism of condensation enzymes. PMID- 29533603 TI - Comparative Quantification Method for Glycosylated Products Elongated on beta Xylosides Using a Stable Isotope-Labeled Saccharide Primer. AB - The structures and amounts of glycosaminoglycan (GAG) produced by cells have attracted much interest because GAG biosynthesis activity can change in cellular processes such as disease and differentiation. beta-Xylosides, also called saccharide primers, have been used as artificial acceptors not only to generate GAG oligosaccharides in cells and tissues but also to investigate their biosynthetic pathways. Various analytical methods have been applied to confirm the structure and amounts of GAG oligosaccharides elongated using saccharide primers, yet sample preparation processes such as solid-phase extraction in analysis can cause experimental error and disrupt accurate comparative quantification of glycosylated products. In this study, we developed a new quantification method using a deuterium-labeled saccharide primer. The "heavy" and "light" primers were chemically synthesized, and priming abilities were confirmed by liquid chromatography-tandem mass spectrometry. Relative peak areas of light/heavy products showed good linearity and were well correlated with the theoretical amounts of glycosylated products. Then, as a validation study, we carried out a biosynthesis inhibition assay using known GAG biosynthesis inhibitors. According to the relative quantification using saccharide primers, differences in the mode-of-action among the four GAG biosynthesis inhibitors were dependent on the GAG biosynthetic pathway. Our results indicate that the method will likely forge a new path for comparative glycosaminoglycomics using cultured cells and tissues. PMID- 29533604 TI - Template-Independent Enzymatic Oligonucleotide Synthesis (TiEOS): Its History, Prospects, and Challenges. AB - There is a growing demand for sustainable methods in research and development, where instead of hazardous chemicals, an aqueous medium is chosen to perform biological reactions. In this Perspective, we examine the history and current methodology of using enzymes to generate artificial single-stranded DNA. By using traditional solid-phase phosphoramidite chemistry as a metric, we also explore criteria for the method of template-independent enzymatic oligonucleotide synthesis (TiEOS). As its key component, we delve into the biology of one of the most enigmatic enzymes, terminal deoxynucleotidyl transferase (TdT). As TdT is found to exponentially increase antigen receptor diversity in the vertebrate immune system by adding nucleotides in a template-free manner, researchers have exploited this function as an alternative to the phosphoramidite synthesis method. Though TdT is currently the preferred enzyme for TiEOS, its random nucleotide incorporation presents a barrier in synthesis automation. Taking a closer look at the TiEOS cycle, particularly the coupling step, we find it is comprised of additions > n+1 and deletions. By tapping into the physical and biochemical properties of TdT, we strive to further elucidate its mercurial behavior and offer ways to better optimize TiEOS for production-grade oligonucleotide synthesis. PMID- 29533602 TI - Polyamine Deacetylase Structure and Catalysis: Prokaryotic Acetylpolyamine Amidohydrolase and Eukaryotic HDAC10. AB - Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well defined, only recently has the molecular basis of reversible polyamine acetylation been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized: histone deacetylase 10 (HDAC10) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N8-acetylspermidine deacetylase, and its prokaryotic counterpart, acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa, is a broad-specificity polyamine deacetylase. Similar to the greater family of HDACs, which mainly serve as lysine deacetylases, both enzymes adopt the characteristic arginase-deacetylase fold and employ a Zn2+-activated water molecule for catalysis. In contrast with HDACs, however, the active sites of HDAC10 and APAH are sterically constricted to enforce specificity for long, slender polyamine substrates and exclude bulky peptides and proteins containing acetyl-l-lysine. Crystal structures of APAH and D. rerio HDAC10 reveal that quaternary structure, i.e., dimer assembly, provides the steric constriction that directs the polyamine substrate specificity of APAH, whereas tertiary structure, a unique 310 helix defined by the P(E,A)CE motif, provides the steric constriction that directs the polyamine substrate specificity of HDAC10. Given the recent identification of HDAC10 and spermidine as mediators of autophagy, HDAC10 is rapidly emerging as a biomarker and target for the design of isozyme-selective inhibitors that will suppress autophagic responses to cancer chemotherapy, thereby rendering cancer cells more susceptible to cytotoxic drugs. PMID- 29533605 TI - Direct Measurement of a Biomarker's Native Optimal Frequency with Physical Adsorption Based Immobilization. AB - The optimal frequency (OF) of a biomarker in electrochemical impedance spectroscopy (EIS) is the frequency at which the EIS response best reflects the binding of the biomarker to its molecular recognition element. Commonly, biosensors rely on complicated immobilization chemistry to attach biological molecules to the sensor surface, making the direct study of a biomarker's native OF a challenge. Physical adsorption presents a simple immobilization strategy to study the native biomarker's OF, but its utility is often discouraged due to a loss in biological activity. To directly study a biomarker's native OF and investigate the potential of OF to overcome the limitations of physical adsorption, a combination of EIS and glutaraldehyde-mediated physical adsorption was explored. The experimental sensing platform was prepared by immobilizing either anti-lactoferrin (Lfn) IgG or anti-immunoglobulin E (IgE) onto screen printed carbon electrodes. After characterizing the native OFs of both biomarkers, investigation of the platform's specificity, stability, and performance in complex medium was found to be sufficient. Finally, a paper-based tear sampling component was integrated to transform the testing platform into a prototypical point-of-care dry eye diagnostic. The investigation of native OFs revealed a correlation between the native OFs (57.44 and 371.1 Hz for Lfn and IgE, respectively) and the molecular weight of the antibody-antigen complex. Impedance responses at the native OFs have enabled detection limits of 0.05 mg/mL and 40 ng/mL for Lfn and IgE, respectively, covering the clinically relevant ranges. The native OFs were found to be robust across various testing mediums and conditions. PMID- 29533606 TI - Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer. AB - Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2 oxazoline)s (POx) poly(2-methyl-2-oxazoline- block-2-butyl-2-oxazoline- block-2 methyl-2-oxazoline) (P(MeOx- b-BuOx- b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer. PMID- 29533607 TI - Redox-Active Metallodithiolene Groups Separated by Insulating Tetraphosphinobenzene Spacers. AB - Compounds of the type [(S2C2R2)M(MU-tpbz)M(S2C2R2)] (R = CN, Me, Ph, p-anisyl; M = Ni, Pd, Pt; tpbz = 1,2,4,5-tetrakis(diphenylphosphino)benzene) have been prepared by transmetalation with [(S2C2R2)SnR'2] reagents, by direct displacement of dithiolene ligand from [M(S2C2R2)2] with 0.5 equiv of tpbz, or by salt metathesis using Na2[S2C2(CN)2] in conjunction with X2M(MU-tpbz)MX2 (X = halide). X-ray crystallography reveals a range of topologies (undulating, chair, bowed) for the (S2C2)M(P2C6P2)M(S2C2) core. The [(S2C2R2)M(MU-tpbz)M(S2C2R2)] (R = Me, Ph, p-anisyl) compounds support reversible or quasireversible oxidations corresponding to concurrent oxidation of the dithiolene terminal ligands from ene 1,2-dithiolates to radical monoanions, forming [(-S*SC2R2)M(MU-tpbz)M( S*SC2R2)]2+. The R = Ph and p-anisyl compounds support a second, reversible oxidation of the dithiolene ligands to their alpha-dithione form. In contrast, [(S2C2(CN)2)Ni(tpbz)Ni(S2C2(CN)2)] sustains only reversible, metal-centered reductions. Spectroscopic examination of [(-S*SC2( p-anisyl)2)Ni(MU-tpbz)Ni( S*SC2( p-anisyl)2)]2+ by EPR reveals a near degenerate singlet-triplet ground state, with spectral simulation revealing a remarkably small dipolar coupling constant of 18 * 10-4 cm-1 that is representative of an interspin distance of 11.3 A. This weak interaction is mediated by the rigid tpbz ligand, whose capacity to electronically insulate is an essential quality in the development of molecular-based spintronic devices. PMID- 29533608 TI - Bifunctional Porphyrin-Based Nano-Metal-Organic Frameworks: Catalytic and Chemosensing Studies. AB - The use of 5,10,15,20-tetrakis( p-phenylphosphonic acid)porphyrin (H10TPPA) as a linker in the preparation of porphyrin-based metal-organic frameworks (Por-MOFs) through coordination to lanthanides cations is reported. The resulting unprecedented materials, formulated as [M(H9TPPA)(H2O) x]Cl2. yH2O [ x + y = 7; M3+ = La3+ (1), Yb3+ (2), and Y3+ (3)], prepared using hydrothermal synthesis, were extensively characterized in the solid-state, for both their structure and thermal robustness, using a myriad of solid-state advanced techniques. Materials were evaluated as heterogeneous catalysts in the oxidation of thioanisole by H2O2 and as chemosensors for detection of nitroaromatic compounds (NACs). Nano-Por MOFs 1-3 proved to be effective as heterogeneous catalysts in the sulfoxidation of thioanisole, with Por-MOF 1 exhibiting the best catalytic performance with a conversion of thioanisole of 89% in the first cycle and with a high selectivity for the sulfoxide derivative (90%). The catalyst maintained its activity roughly constant in three consecutive runs. Por-MOFs 1-3 can be employed as chemosensors because of a measured fluorescence quenching up to 70% for nitrobenzene, 1,4 dinitrobenzene, 4-nitrophenol, and phenol, with 2,4,6-trinitrophenol exhibiting a peculiar fluorescence profile. PMID- 29533609 TI - Recent Analytical Techniques Advances in the Carotenoids and Their Derivatives Determination in Various Matrixes. AB - In the present perspective, different approaches to the carotenoids analysis will be discussed providing a brief overview of the most advanced both monodimensional and bidimensional liquid chromatographic methodologies applied to the carotenoids analysis, followed by a discussion on the recents advanced supercritical fluid chromatography * liquid chromatography bidimensional approach with photodiode array and mass spectrometry detection. Moreover a discussion on the online supercritical fluid extraction-supercritical fluid chromatography with tandem mass spectrometry detection applied to the determination of carotenoids and apocarotenoids will also be provided. PMID- 29533610 TI - Microbial Selenate Reduction Driven by a Denitrifying Anaerobic Methane Oxidation Biofilm. AB - Anaerobic oxidation of methane (AOM) plays a crucial role in controlling the flux of methane from anoxic environments. Sulfate-, nitrite-, nitrate-, and iron dependent methane oxidation processes have been considered to be responsible for the AOM activities in anoxic niches. We report that nitrate-reducing AOM microorganisms, enriched in a membrane biofilm bioreactor, are able to couple selenate reduction to AOM. According to ion chromatography, X-ray photoelectron spectroscopy, and long-term bioreactor performance, we reveal that soluble selenate was reduced to nanoparticle elemental selenium. High-throughput 16S rRNA gene sequencing indicates that Candidatus Methanoperedens and Candidatus Methylomirabilis remained the only known methane-oxidizing microorganisms after nitrate was switched to selenate, suggesting that these organisms could couple anaerobic methane oxidation to selenate reduction. Our findings suggest a possible link between the biogeochemical selenium and methane cycles. PMID- 29533611 TI - Microthecaline A, a Quinoline Serrulatane Alkaloid from the Roots of the Australian Desert Plant Eremophila microtheca. AB - Chemical investigation of the roots of the Australian desert plant Eremophila microtheca yielded microthecaline A (1), a novel quinoline-serrulatane natural product. The structure of 1 was determined by spectroscopic analysis, and the absolute configuration was assigned by ECD. Compound 1 exhibited moderate antimalarial activity against Plasmodium falciparum (3D7 strain), with an IC50 of 7.7 MUM. Microthecaline A represents the first quinoline-serrulatane alkaloid to be isolated from Nature. PMID- 29533612 TI - What Do We Know about the Chemistry of Strawberry Aroma? AB - The strawberry, with its unique aroma, is one of the most popular fruits worldwide. The demand for specific knowledge of metabolism in strawberries is increasing. This knowledge is applicable for genetic studies, plant breeding, resistance research, nutritional science, and the processing industry. The molecular basis of strawberry aroma has been studied for more than 80 years. Thus far, hundreds of volatile organic compounds (VOC) have been identified. The qualitative composition of the strawberry volatilome remains controversial though considerable progress has been made during the past several decades. Between 1997 and 2016, 25 significant analytical studies were published. Qualitative VOC data were harmonized and digitized. In total, 979 VOC were identified, 590 of which were found since 1997. However, 659 VOC (67%) were only listed once (single entries). Interestingly, none of the identified compounds were consistently reported in all of the studies analyzed. The present need of data exchange between "omic" technologies requires high quality and robust metabolic data. Such data are unavailable for the strawberry volatilome thus far. This review discusses the divergence of published data regarding both the biological material and the analytical methods. The VOC extraction method is an essential step that restricts interlaboratory comparability. Finally, standardization of sample preparation and data documentation are suggested to improve consistency for VOC quantification and measurement. PMID- 29533614 TI - Diastereoselective Construction of Indole-Bridged Chroman Spirooxindoles through a TfOH-Catalyzed Michael Addition-Inspired Cascade Reaction. AB - The first highly diastereoselective Michael addition/condensation/Friedel-Crafts alkylation cascade reaction of 3-indolyl-substituted oxindoles with ortho hydroxychalcones was established, which afforded a wide range of polycyclic indole-bridged chroman spirooxindoles with novel and complex scaffolds in moderate to excellent yields. PMID- 29533613 TI - Intestinal Anti-Inflammatory Activity of Perillaldehyde. AB - Monoterpenoid perillaldehyde (PA) is the major component in Perilla frutescens leaf essential oil, but its function regarding anti-inflammatory effect is unclear. We explored the anti-inflammatory activity of PA in a dextran sulfate sodium (DSS)-induced colitis mouse model using relief of bodyweight loss (avg. 49.2% mitigation; P = 0.094) and colon damage (avg. 35.3% mitigation; P < 0.05) by administration of PA at a 100 mg/kg dosage. The PA administration resulted in suppression of DSS-induced expression of pro-inflammatory cytokine genes and matrix metalloproteinase-9 in the colon (e.g., avg. 60.6% mitigation for TNF alpha mRNA levels; P < 0.05). These effects were confirmed in macrophage RAW264.7 cells stimulated with lipopolysaccharide (LPS). Application of PA induced cell suppression of LPS-induced expressions of genes and proteins of pro-inflammatory cytokines and induced activation of c-Jun N-terminal kinases (JNKs, p54 and p46; P < 0.05) but not nuclear factor-kappaB p65. The half maximal inhibitory concentration for decreased expression levels of TNF-alpha mRNA was 171.7 MUM. We discuss the in vivo function of PA in amelioration of intestinal inflammation via JNK-mediated cytokine regulation. PMID- 29533615 TI - Palladium-Catalyzed Regioselective C-H Functionalization of Arenes Substituted by Two N-Heterocycles and Application in Late-Stage Functionalization. AB - Reported herein is a Pd-catalyzed regioselective C-H activation method that is used for C-H deuteration, carbonylation, halogenation, and oxidation of arene substrates substituted by two N-heterocycles. When conducted in acetic acid (AcOH), these reactions occur at the five-membered palladacycle sites, whereas they switch to the six-membered palladacycle sites in trifluoroacetic acid (TFA). This controllable regioselective C-H activation is applied for late-stage functionalization of bioactive molecules. A mechanism study indicated that the regioselectivity is achieved by Bronsted acid-Lewis base interactions and electronic effects (in TFA) and the different kinetic stabilities of palladacycle intermediates (in AcOH). PMID- 29533616 TI - Radical Ions of 3-Styryl-quinoxalin-2-one Derivatives Studied by Pulse Radiolysis in Organic Solvents. AB - The absorption-spectral and kinetic behaviors of radical ions and neutral hydrogenated radicals of seven 3-styryl-quinoxalin-2(1 H)-one (3-SQ) derivatives, one without substituents in the styryl moiety, four others with electron-donating (R = -CH3, -OCH3, and -N(CH3)2) or electron-withdrawing (R = -OCF3) substituents in the para position in their benzene ring, and remaining two with double methoxy substituents (-OCH3), however, at different positions (meta/para and ortho/meta) have been studied by UV-vis spectrophotometric pulse radiolysis in neat acetonitrile saturated with argon (Ar) and oxygen (O2) and in 2-propanol saturated with Ar, at room temperature. In acetonitrile solutions, the radical anions (4R-SQ*-) are characterized by two absorption maxima located at lambdamax = 470-490 nm and lambdamax = 510-540 nm, with the respective molar absorption coefficients epsilon470-490 = 8500-13 100 M-1 cm-1 and epsilon510-540 = 6100-10 300 M-1 cm-1, depending on the substituent (R). All 4R-SQ*- decay in acetonitrile via first-order kinetics, with the rate constants in the range (1.2-1.5) * 106 s 1. In 2-propanol solutions, they decay predominantly through protonation by the solvent, forming neutral hydrogenated radicals (4R-SQH*), which are characterized by weak absorption bands with lambdamax = 480-490 nm. Being oxygen-insensitive, the radical cations (4R-SQ*+) are characterized by a strong absorption with lambdamax = 450-630 nm, depending on the substituent (R). They are formed in a charge-transfer reaction between a radical cation derived from acetonitrile (ACN*+) and substituted 3-styryl-quinoxalin-2-one derivatives (4R-SQ) with a pseudo-first-order rate constant k = (2.7-4.7) * 105 s-1 measured in solutions containing 0.1 mM 4R-3-SQ. The Hammett equation plot gave a very small negative slope (rho = -0.08), indicating a very weak influence of the substituents in the benzene ring on the rate of charge-transfer reaction. The decay of 4R-SQ*+ in Ar saturated acetonitrile solutions occurs with a pseudo-first-order rate constant k = (1.6-6.2) * 104 s-1 and, in principle, is not affected by the presence of O2, suggesting charge-spin delocalization over the whole 3-SQ molecule. Most of the radiolytically generated transient spectra are reasonably well-reproduced by semiempirical PM3-ZINDO/S (for 4R-SQ*-) and density functional theory quantum mechanics calculations employing M06-2x hybrid functional together with the def2 TZVP basis set (for 4R-SQ*+). PMID- 29533617 TI - Bis(amino)cyclopropenylidene Catalyzed Rauhut-Currier Reaction between alpha,beta Unsaturated Carbonyl Compounds and para-Quinone Methides. AB - An intermolecular Rauhut-Currier reaction between alpha,beta-unsaturated carbonyl compounds and p-quinone methides has been developed by employing bis(amino)cyclopropenylidene as a catalyst. This protocol allows access to a variety of vinyl diarylmethane derivatives in moderate to good yields. PMID- 29533618 TI - OH Stretching Dynamics in Hydroxide Aqueous Solutions. AB - The concept of ions being either water "structure makers" or water "breakers" seems to be inconsistent with the existence of a critical number of water molecules per ion dictating the properties of an aqueous solution, independent of the ion identity. To investigate this issue, Raman spectra of hydroxide aqueous solutions in the region of the OH stretching mode have been obtained under ambient conditions and at concentrations ranging from extreme dilution to the solubility limit. Spectra have been analyzed with a relatively model-free approach, in terms of a superposition of contributions due to the vibrations of the OH- ions, with two contributions due to the solvent. One of these latter contributions falls at wavenumbers very close to that of the OH- stretching band, sharing with it its concentration dependence of the full width at half maximum (FWHM). The other contribution due to the solvent is very broad, with increasing FWHM with increasing ion concentration. In the light of these observations, an interpretation of the Raman spectra, based on the possibility of distinguishing the self and distinct contributions, is proposed. The present analysis is supported by structural data on the same solutions and puts into evidence relevant structural and dynamical changes occurring when the number of water molecules available per solute is below ~20, irrespective of the ion identity. PMID- 29533619 TI - One-Pot Enantiomeric Synthesis of Thiazole-Containing Amino Acids: Total Synthesis of Venturamides A and B. AB - An effective one-pot procedure for enantiomerical synthesis of thiazole containing amino acid (TCAA) has been established via a cascade disulfide cleavage/thiocarbonylation/intramolecular Staudinger reduction/aza Wittig/oxidation reaction. Starting from the commercially available amino acid building blocks, a number of TCAAs were prepared in good yields and with excellent optical purities. This method bears features of mild reaction conditions, wide substrate adaptability, and good functional group tolerance. The power of this method was also demonstrated through the concise total synthesis of cyclic hexapeptide Venturamides A and B. PMID- 29533620 TI - Ozone-Free Synthesis of Ozonides: Assembling Bicyclic Structures from 1,5 Diketones and Hydrogen Peroxide. AB - Reactions of 1,5-diketones with H2O2 open an ozone-free approach to ozonides. Bridged ozonides are formed readily at room temperature in the presence of strong Bronsted or Lewis acids such as H2SO4, p-TsOH, HBF4, or BF3.Et2O. The expected bridged tetraoxanes, the products of double H2O2 addition, were not detected. This procedure is readily scalable to produce gram quantities of the ozonides. Bridged ozonides are stable and can be useful as building blocks for bioconjugation and further synthetic transformations. Although less stabilized by anomeric interactions than bis-peroxides, ozonides have an intrinsic advantage of having only one weak O-O bond. The role of the synergetic framework of anomeric effects in bis-peroxides is to overcome this intrinsic disadvantage. As the computational data have shown, this is only possible when all anomeric effects in bis-peroxides are activated to their fullest degree. Consequently, the cyclization selectivity is determined by the length of the bridge between the two carbonyl groups of the diketone. The generally large thermodynamic preference for the formation of cyclic bis-peroxides disappears when 1,5-diketones are used as the bis-cyclization precursors. Stereoelectronic analysis suggests that the reason for the bis-peroxide absence is the selective deactivation of anomeric effects in a [3.2.2]tetraoxanonane skeleton by a structural distortion imposed on the tetraoxacyclohexane subunit by the three-carbon bridge. PMID- 29533621 TI - Asymmetric Formal [4 + 2] Annulation of o-Quinone Methides with beta-Keto Acylpyrazoles: A General Approach to Optically Active trans-3,4-Dihydrocoumarins. AB - An asymmetric cascade reaction between beta-keto acylpyrazoles and o-quinone methides in a formal [4 + 2] fashion to access potentially pharmacological active trans-3,4-dihydrocoumarins has been achieved efficiently by using a quinine-based chiral squaramide as the catalyst. The desired products were obtained in high yields with excellent diastereo- and enantioselectivities (up to 96% yield, >19/1 dr and 96% ee) under mild reaction conditions. PMID- 29533622 TI - Enhancing Hybrid Perovskite Detectability in the Deep Ultraviolet Region with Down-Conversion Dual-Phase (CsPbBr3-Cs4PbBr6) Films. AB - Hybrid perovskite photodetectors (PDs) exhibit outstanding performance in the ultraviolet-visible (UV-vis) spectrum but have poor detectability in the deep ultraviolet (DUV) region (200-350 nm). In this work, a novel inorganic-hybrid architecture that incorporates a dual-phase (CsPbBr3-Cs4PbBr6) inorganic perovskite material as a down-conversion window layer and a hybrid perovskite as a light capture layer was prepared to achieve faster, highly sensitive photodetection in the DUV spectrum. A dual-phase inorganic perovskite film coated on the back surface of the photodetector enables strong light absorption and tunes the incident energy into emission bands that are optimized for the perovskite photodetector. The presence of Cs4PbBr6 enhances the capture and down conversion of the incident DUV light. Due to the down-conversion and transport of the DUV photons, a self-driven perovskite photodetector with this composite structure exhibits a fast response time of 7.8/33.6 MUs and a high responsivity of 49.4 mA W-1 at 254 nm without extra power supply. PMID- 29533623 TI - Ultrafast Charge Transfer in Perovskite Nanowire/2D Transition Metal Dichalcogenide Heterostructures. AB - Mixed-dimensional van der Waals (vdW) heterostructures between one-dimensional (1D) perovskite nanowires and two-dimensional (2D) transition metal dichalcogenides (TMDCs) hold great potential for novel optoelectronics and light harvesting applications. However, the ultrafast carrier dynamics between the 1D perovskite nanowires and 2D TMDCs are currently not well understood, which is critical for related optoelectronic applications. Here we demonstrate vdW heterostructures of CsPbBr3 nanowire/monolayer MoS2 and CsPbBr3 nanowire/monolayer WSe2 and further present systematic investigations on their charge transfer dynamics. We show that CsPbBr3/MoS2 and CsPbBr3/WSe2 are type-I and type-II heterostructures, respectively. Both electrons and holes transfer from CsPbBr3 to MoS2 with an efficiency of 71%. As a contrast, holes transfer from CsPbBr3 to WSe2 with a carrier transfer efficiency of 70% and electrons transfer inversely within 7 ps. The ultrafast and efficient charge transfer in the 1D/2D perovskite-TMDC heterostructures suggest great promise in light emission, photodetector, and photovoltaic devices. PMID- 29533624 TI - Quasi-Atomic Bonding Analysis of Xe-Containing Compounds. AB - The origin of bonding in the rare-gas-containing molecules HXeCCH, HXeCCXeH, and HXeOXeH is explored using a quasi-atomic orbital (QUAO) analysis. The QUAOs provide qualitative and quantitative data about bonding through transformations of the density matrix. Bond orders, kinetic bond orders, and the extent of transfer of charge are analyzed. Localized molecular orbitals formed from the QUAOs provide additional insights about the relative polarity of bonds formed by xenon. The analysis suggests significant covalent bonding for Xe-Y (Y = C, O) as well as Xe-H, with both bonds using the same psigma-type orbital on Xe. These covalent interactions are established by substantial charge shifts from Xe to Y as well as to H. Accordingly, a covalent three-center four-electron bond links the atoms H-Xe-Y. On the basis of the analysis, electrostatic interactions do not play a significant role in the Xe-Y or Xe-H bonding. PMID- 29533625 TI - Synthesis and Properties of Energy-Rich Methanofullerenes Containing Norbornadiene and Quadricyclane Moieties. AB - The energy-rich methanofullerenes were synthesized for the first time by the reaction of fullerene C60 with mono- and bisquadricyclane esters of malonic acid. The C-C bond cleavage in the quadricyclane moieties of new hybrid molecules takes place in the presence of catalytic amounts of Cu, Pd, and Pt salts or complexes or SiO2 and is accompanied by heat evolution. PMID- 29533626 TI - Predicting Intersystem Crossing Rates with AIMS-DFT Molecular Dynamics. AB - Accurate prediction of the intersystem crossing rates is important for many different applications in chemistry, physics, and biology. Recently, we implemented the ab initio multiple spawning (AIMS) molecular dynamics method to describe the intersystem crossing processes, where nonradiative transitions between electronic states with different spin multiplicities are mediated by spin orbit coupling. Our original implementation of the direct AIMS dynamics used the complete active space self-consistent field (CASSCF) method to describe multiple coupled electronic states on which multidimensional Gaussian wave packets were propagated. In this work, we improve the computational efficiency and versatility of the AIMS dynamics by interfacing it with the density functional theory (DFT). The new AIMS-DFT and the earlier AIMS-CASSCF implementations are used to investigate the effects of electronic structure methods on the predicted intersystem crossing rate constants and the lowest triplet state lifetime in the GeH2 molecule. We also compare the rates and lifetimes obtained from the AIMS simulations with those predicted by the statistical nonadiabatic transition state theory (NA-TST). In NA-TST, the probabilities of spin transitions are calculated using the Landau-Zener, weak coupling, and Zhu-Nakamura formulas. Convergence of the AIMS rate constants with respect to the simulation time and the number of initial trajectories (Gaussian wave packets) is analyzed. An excellent agreement between AIMS-DFT and AIMS-CASSCF can be explained by cancelation of two effects: higher energy barriers and a stronger spin-orbit coupling in DFT relative to CASSCF. The rate constants obtained with the AIMS-DFT dynamics are about a factor of 2 larger than those predicted by the statistical NA-TST. This is likely due to the importance of the nonlocal interstate transitions missing from the NA-TST description. PMID- 29533627 TI - Above Saddle-Point Regions of Order in a Sea of Chaos in the Vibrational Dynamics of KCN. AB - The dynamical characteristics of a region of regular vibrational motion in the sea of chaos above the saddle point corresponding to the linear C-N-K configuration is examined in detail. To explain the origin of this regularity, the associated phase space structures were characterized using suitably defined Poincare surfaces of section, identifying the different resonances between the stretching and bending modes, as a function of excitation energy. The corresponding topology is elucidated by means of periodic orbit analysis. PMID- 29533628 TI - Transition-Metal-Free Ring Expansion Reactions of Indene-1,3-dione: Synthesis of Functionalized Benzoannulated Seven-Membered Ring Compounds. AB - A novel ring expansion reaction of indene-1,3-dione with alkynyl ketones under transition-metal-free conditions has been developed. This process offers an efficient and direct way to synthesize benzoannulated seven-membered rings or fused-ring compounds through C-C sigma-bond activation. Notable features of the procedure include easily accessible starting materials, good functional group tolerance, and high atom economy. PMID- 29533629 TI - 2-Bromo[6]helicene as a Key Intermediate for [6]Helicene Functionalization. AB - The synthesis of 2-bromo[6]helicene was revised and improved up to 51% yield. Its reactivity was thoroughly investigated, and a library of 17 different carbon, boron, nitrogen, phosphorus, oxygen and sulfur substituted derivatives was prepared. The racemization barrier for 2-bromo[6]helicene was determined, and the usage of enantiomers in the synthesis of optically pure helicenes was rationalized. The three most energy-demanding reactions using enantiomerically pure 2-bromo[6]helicene were tested in order to confirm the predicted enantiomeric excess. PMID- 29533630 TI - Rapid Decoherence Suppresses Charge Recombination in Multi-Layer 2D Halide Perovskites: Time-Domain Ab Initio Analysis. AB - Two-dimensional (2D) Ruddlesden-Popper halide perovskites are appealing candidates for optoelectronics and photovoltaics. Nonradiative electron-hole recombination constitutes a major pathway for charge and energy losses in these materials. Surprisingly, experimental recombination is slower in multilayers than a monolayer, even though multilayer systems have smaller energy gaps and higher frequency phonons that should accelerate the recombination. Focusing on (BA)2(MA) n-1Pb nI3 n+1 with n = 1 and 3, BA = CH3(CH2)3NH3, and MA = CH3NH3, we show that it is the enhancement of elastic electron-phonon scattering that suppresses charge recombination for n = 3, by causing rapid loss of electronic coherence. The scattering is enhanced in the multilayer 2D perovskites because, in contrast to the monolayer, they contain MA cations embedded into the inorganic Pb-I lattice. Although MAs do not contribute directly to electron and hole wave functions, they perturb the Pb-I lattice and create strong electric fields that interact with the charges. The rapid loss of coherence explains long excited state lifetimes that extend into nanoseconds. Both electron-hole recombination and coherence times show excellent agreement with the corresponding lifetime and line width measurements. The simulations rationalize the observed dependence of excited state lifetime in 2D layered halide perovskites on layer thickness and advance our understanding of the atomistic mechanisms underlying charge-phonon dynamics in nanoscale materials. PMID- 29533631 TI - Targeting High Expressed alpha5beta1 Integrin in Liver Metastatic Lesions To Resist Metastasis of Colorectal Cancer by RPM Peptide-Modified Chitosan-Stearic Micelles. AB - Liver metastasis is a leading death cause in colorectal cancer. The pathological differences between orthotopic tumors and metastatic lesions increased the therapeutic difficulty of metastasis. Herein, the alpha5beta1 integrin receptor expression on metastatic cells was first measured, the result showed that metastatic cells expressed the alpha5beta1 integrin higher than that of the original cells from orthotopic tumors. Afterward, RPM peptide-modified chitosan stearic (RPM-CSOSA) was designed based on alpha5beta1 integrin expression. The cytotoxicity and resistance to migration and the invasion ability of the targeting drug delivery system loading doxorubicin (DOX) and curcumin (CUR) were evaluated in vitro. The metastatic inhibition of the targeting drug delivery system was also investigated in HT29 liver metastatic models. The modified RPM peptide could increase the cellular internalization of CSOSA micelles in metastatic tumor cells and endothelial cells mediated by alpha5beta1 integrin. The synergistic effects of RPM-CSOSA/DOX and RPM-CSOSA/CUR could obviously inhibit migratory and invasive abilities of HT29 cells and endothelial cells. Moreover, the RPM-CSOSA/DOX&RPM-CSOSA/CUR could obviously decrease the number of metastatic sites by 86.96%, while CSOSA/DOX&CSOSA/CUR decreased liver metastasis by 66.58% compared with that in the saline group. In conclusion, the RPM peptide modified drug delivery system may provide insights into targeting the metastatic cells overexpressing the alpha5beta1 integrin, and it has the potential to inhibit liver metastasis of colorectal cancer. PMID- 29533633 TI - Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric Addition of Arylboronic Acids to alpha,beta-Unsaturated Cyclic N-Sulfonyl Ketimines. AB - A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging alpha,beta-unsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a ligand-controlled switch in the reaction regioselectivity was attained for the first time. The reactions allow the synthesis of highly valuable alpha,alpha disubstituted chiral allylic amines and enantioenriched 1,4-adducts. Further product transformation provided easy access to various quaternary carbon containing chiral amines and amino acid derivatives bearing multifunctional groups. PMID- 29533632 TI - Asymmetric Modulation on Exchange Field in a Graphene/BiFeO3 Heterostructure by External Magnetic Field. AB - Graphene, having all atoms on its surface, is favorable to extend the functions by introducing the spin-orbit coupling and magnetism through proximity effect. Here, we report the tunable interfacial exchange field produced by proximity coupling in graphene/BiFeO3 heterostructures. The exchange field has a notable dependence with external magnetic field, and it is much larger under negative magnetic field than that under positive magnetic field. For negative external magnetic field, interfacial exchange coupling gives rise to evident spin splitting for N ? 0 Landau levels and a quantum Hall metal state for N = 0 Landau level. Our findings suggest graphene/BiFeO3 heterostructures are promising for spintronics. PMID- 29533634 TI - Multiple Linear Regression Modeling To Predict the Stability of Polymer-Drug Solid Dispersions: Comparison of the Effects of Polymers and Manufacturing Methods on Solid Dispersion Stability. AB - Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two manufacturing techniques, spray-drying and melt extrusion. Each formulation underwent a six-month stability study at accelerated conditions, 40 degrees C and 75% relative humidity (RH). Significant differences in times to crystallization (onset of crystallization) were observed between both the different polymers and the two processing methods. Stability from zero days to over one year was observed. The extensive experimental data set obtained from this stability study was used to build multiple linear regression models to correlate physicochemical properties of the active pharmaceutical ingredients (API) with the stability data. The purpose of these models is to indicate which combination of processing method and polymer carrier is most likely to give a stable solid dispersion. Six quantitative mathematical multiple linear regression based models were produced based on selection of the most influential independent physical and chemical parameters from a set of 33 possible factors, one model for each combination of polymer and processing method, with good predictability of stability. Three general rules are proposed from these models for the formulation development of suitably stable solid dispersions. Namely, increased stability is correlated with increased glass transition temperature ( Tg) of solid dispersions, as well as decreased number of H-bond donors and increased molecular flexibility (such as rotatable bonds and ring count) of the drug molecule. PMID- 29533635 TI - Homoisoflavonoids Are Potent Glucose Transporter 2 (GLUT2) Inhibitors: A Potential Mechanism for the Glucose-Lowering Properties of Polygonatum odoratum. AB - Foods of high carbohydrate content such as sucrose or starch increase postprandial blood glucose concentrations. The glucose absorption system in the intestine comprises two components: sodium-dependent glucose transporter-1 (SGLT1) and glucose transporter 2 (GLUT2). Here five sappanin-type (SAP) homoisoflavonoids were identified as novel potent GLUT2 inhibitors, with three of them isolated from the fibrous roots of Polygonatum odoratum (Mill.) Druce. SAP homoisolflavonoids had a stronger inhibitory effect on 25 mM glucose transport (41.6 +/- 2.5, 50.5 +/- 7.6, 47.5 +/- 1.9, 42.6 +/- 2.4, and 45.7 +/- 4.1% for EA 1, EA-2, EA-3, MOA, and MOB) than flavonoids (19.3 +/- 2.2, 11.5 +/- 3.7, 16.4 +/ 2.4, 5.3 +/- 1.0, 3.7 +/- 2.2, and 18.1 +/- 2.4% for apigenin, luteolin, quercetin, naringenin, hesperetin, and genistein) and phloretin (28.1 +/- 1.6%) at 15 MUM. SAP homoisoflavonoids and SGLT1 inhibitors were found to synergistically inhibit the uptake of glucose using an in vitro model comprising Caco-2 cells. This observed new mechanism of the glucose-lowering action of P. odoratum suggests that SAP homoisoflavonoids and their combination with flavonoid monoglucosides show promise as naturally functional ingredients for inclusion in foods and drinks designed to control postprandial glucose levels. PMID- 29533636 TI - Coupled Yu-Shiba-Rusinov States in Molecular Dimers on NbSe2. AB - Magnetic impurities have a dramatic effect on superconductivity by breaking the time-reversal symmetry and inducing so-called Yu-Shiba-Rusinov (YSR) low energy bound states within the superconducting gap. The spatial extent of YSR states is greatly enhanced in two-dimensional (2D) systems, which should facilitate the formation of coupled states. Here, we observe YSR states on single cobalt phthalocyanine (CoPC) molecules on a 2D superconductor NbSe2 using low temperature scanning tunneling microscopy (STM) and spectroscopy. We use STM lateral manipulation to create controlled CoPc dimers and demonstrate the formation of coupled YSR states. The experimental results are corroborated by theoretical analysis of the coupled states in lattice and continuum models. PMID- 29533637 TI - Chiral Light Design and Detection Inspired by Optical Antenna Theory. AB - Chiral metallic nanostructures can generate evanescent fields which are more highly twisted than circularly polarized light. However, it remains unclear how best to exploit this phenomenon, hindering the optimal utilization of chiral electromagnetic fields. Here, inspired by optical antenna theory, we address this challenge by introducing chiral antenna parameters: the chirality flux efficiency and the chiral antenna aperture. These quantities, which are based on chirality conservation, quantify the generation and dissipation of chiral light. We then present a label-free experimental technique, chirality flux spectroscopy, which measures the chirality flux efficiency, providing valuable information on chiral near fields in the far field. This principle is verified theoretically and experimentally with two-dimensionally chiral coupled nanorod antennas, for which we show that chiral near and far fields are linearly dependent on the magnetoelectric polarizability. This elementary system confirms our concept to quantify chiral electromagnetic fields and paves the way toward broadly tunable chiral optical applications including ultrasensitive detection of molecular chirality or optical information storage and transfer. PMID- 29533638 TI - Polymeric Ion Pumps: Using an Oscillating Stimulus To Drive Solute Transport in Reactive Membranes. AB - The development of membranes that separate molecules on the basis of chemical factors, rather than physical factors, is one promising approach to meeting the demand for membranes that are more selective. In this study, the design of multifunctional, pH-responsive membranes that selectively pump a target solute is detailed. The membranes consist of two functional components: a gate layer made from an amine-functionalized copolymer and a reactive matrix lined by iminodiacetic acid groups that bind divalent cations reversibly. These two chemistries exhibit concurrent changes in the cation binding affinity and gate permeability in response to the pH value of the surrounding solution such that when the membranes are exposed to an oscillating pH, the combination drives a facilitated transport mechanism that pumps ions. In mixed solute systems, calcium permeated through the membrane four times faster than sucrose in the presence of an oscillating pH even though the solutes possess similar hydrodynamic sizes and permeated through the membrane at the same rate when the pH value was constant. The development of polymeric ion pumps was guided by a model that provided several critical insights. First, the solute binding capacity and thickness of the membrane define the asymptotic limit for enhanced selectivity. Second, the maximum enhancement in selectivity is realized in the limit of infinitely rapid oscillations. The multifunctional membranes discussed here provide a platform for the development of processes that can fractionate molecules of similar size but varying chemistry. PMID- 29533639 TI - Palladium-Catalyzed Aerobic Oxidative Coupling of Allylic Alcohols with Anilines in the Synthesis of Nitrogen Heterocycles. AB - We report herein an unprecedented and expedient Pd-catalyzed oxidative coupling of allyl alcohols with anilines to afford beta-amino ketones which are converted into substituted quinolines in a one-pot fashion. The exclusive preference for N alkylation over N-allylation makes this approach unique when compared to those reported in literature. Detailed mechanistic investigations reveal that the conjugate addition pathway was the predominant one over the allylic amination pathway. The notable aspects of the present approach are the use of readily available, bench-stable allyl alcohols and molecular oxygen as the terminal oxidant, in the process dispensing the need for unstable and costly enones. Further, we explored the synthetic utility of beta-amino ketones through an intramolecular alpha-arylation methodology and a one-pot domino annulation, thereby providing rapid access to indolines and quinolines. PMID- 29533640 TI - Graphene Field-Effect Transistor as a High-Throughput Platform to Probe Charge Separation at Donor-Acceptor Interfaces. AB - In organic and low-dimensional materials, electrons and holes are bound together to form excitons. Effective exciton dissociation at interfaces is essential for applications such as photovoltaics and photosensing. Here, we present an interface-sensitive, time-resolved method that utilizes graphene field effect transistor as an electric-field sensor to measure the charge separation dynamics and yield at donor-acceptor interfaces. Compared to other interface-sensitive spectroscopy techniques, our method has a much reduced measurement time and can be easily adapted to different material interfaces. Hence, it can be used as a high throughput screening tool to evaluate the charge separation efficiency in a large number of systems. By using zinc phthalocyanine/fullerene interface, we demonstrate how this method can be used to quantify the charge separation dynamics and yield at a typical organic donor-acceptor interface. PMID- 29533641 TI - Modified Lignin with Anionic Surfactant and Its Application in Controlled Release of Avermectin. AB - Alkali lignin (AL), an anionic polymer, is a byproduct of the paper industry. AL was first modified by quaternization to synthesize quaternized alkali lignin (QAL). The aim of the present study is to reveal the effects of sodium dodecyl benzenesulfonate (SDBS) on the microstructure of QAL. The interaction between SDBS and QAL is studied by means of zeta potential, fluorescence spectrophotometer, and static contact angle measurement. The results indicated that there is an electrostatic interaction and a hydrophobic interaction between QAL and SDBS. The SDBS/QAL complex can self-assemble into lignin-based colloidal spheres (LCSs) in an ethanol/water mixture, which have remarkable avermectin (AVM) encapsulation efficiency and antiphotolysis performance. The cumulative release amount of AVM encapsulated by LCS (LCS@AVM) after 72 h was 77%, and the release was still going on. The release behaviors of LCS@AVM can be controlled by adjusting the ratio (w/w) of LCS to AVM. More than 85% of AVM could be preserved even after 96 h of UV irradiation. LCS showed controlled release and UV-blocking performance for AVM. PMID- 29533643 TI - beta-Lactoglobulin Peptide Fragments Conjugated with Caffeic Acid Displaying Dual Activities for Tyrosinase Inhibition and Antioxidant Effect. AB - The regulation of tyrosinase activity and reactive oxygen species is of great importance for the prevention of dermatological disorders in the fields of medicine and cosmetics. Herein, we report a strategy based on solid-phase peptide chemistry for the synthesis of beta-lactoglobulin peptide fragment/caffeic acid (CA) conjugates (CA-Peps) with dual activities of tyrosinase inhibition and antioxidation. The purity of the prepared conjugates, CA-MHIR, CA-HIRL, and CA HIR, significantly increased to 99%, as acetonide-protected CA was employed in solid-phase coupling reactions on Rink amide resins. The tyrosinase inhibitory activities of all CA-Pep derivatives were higher than the activity of kojic acid, and CA-MHIR exhibited the highest tyrosinase inhibition activity (IC50 = 47.9 MUM). Moreover, CA-Pep derivatives displayed significantly enhanced antioxidant activities in the peroxidation of linoleic acid as compared to the pristine peptide fragments. All CA-Pep derivatives showed no cytotoxicity against B16-F1 melanoma cells. PMID- 29533642 TI - Quantifying Interactions of Nucleobase Atoms with Model Compounds for the Peptide Backbone and Glutamine and Asparagine Side Chains in Water. AB - Alkylureas display hydrocarbon and amide groups, the primary functional groups of proteins. To obtain the thermodynamic information that is needed to analyze interactions of amides and proteins with nucleobases and nucleic acids, we quantify preferential interactions of alkylureas with nucleobases differing in the amount and composition of water-accessible surface area (ASA) by solubility assays. Using an established additive ASA-based analysis, we interpret these thermodynamic results to determine interactions of each alkylurea with five types of nucleobase unified atoms (carbonyl sp2O, amino sp3N, ring sp2N, methyl sp3C, and ring sp2C). All alkylureas interact favorably with nucleobase sp2C and sp3C atoms; these interactions become more favorable with an increasing level of alkylation of urea. Interactions with nucleobase sp2O are most favorable for urea, less favorable for methylurea and ethylurea, and unfavorable for dialkylated ureas. Contributions to overall alkylurea-nucleobase interactions from interactions with each nucleobase atom type are proportional to the ASA of that atom type with proportionality constant (interaction strength) alpha, as observed previously for urea. Trends in alpha-values for interactions of alkylureas with nucleobase atom types parallel those for corresponding amide compound atom types, offset because nucleobase alpha-values are more favorable. Comparisons between ethylated and methylated ureas show interactions of amide compound sp3C with nucleobase sp2C, sp3C, sp2N, and sp3N atoms are favorable while amide sp3C-nucleobase sp2O interactions are unfavorable. Strongly favorable interactions of urea with nucleobase sp2O but weakly favorable interactions with nucleobase sp3N indicate that amide sp2N-nucleobase sp2O and nucleobase sp3N amide sp2O hydrogen bonding (NH...O?C) interactions are favorable while amide sp2N-nucleobase sp3N interactions are unfavorable. These favorable amide nucleobase hydrogen bonding interactions are prevalent in specific protein nucleotide complexes. PMID- 29533644 TI - Modeling Protein S-Aromatic Motifs Reveals Their Structural and Redox Flexibility. AB - S-aromatic motifs are important noncovalent forces for protein stability and function but remain poorly understood. Hence, we performed quantum calculations at the MP2(full)/6-311++G(d,p) level on complexes between Cys (H2S, MeSH) and Met (Me2S) models with models of Phe (benzene, toluene), Trp (indole, 3 methylindole), Tyr (phenol, 4-methylphenol), and His (imidazole, 4 methylimidazole). The most stable gas-phase conformers exhibit binding energies of -2 to -6 kcal/mol, and the S atom lies perpendicular to the ring plane. This reveals preferential interaction with the ring pi-system, except in the imidazoles where S binds edge-on to an N atom. Complexation tunes the gas-phase vertical ionization potentials of the ligands over as much as 1 eV, and strong sigma- or pi-type H-bonding supports charge transfer to the H-bond donor, rendering it more oxidizable. When the S atom acts as an H-bond acceptor (N/O Har...S), calibration of the CHARMM36 force field (by optimizing pair-specific Lennard-Jones parameters) is required. Implementing the optimized parameters in molecular dynamics simulations in bulk water, we find stable S-aromatic complexes with binding free energies of -0.6 to -1.1 kcal/mol at ligand separations up to 8 A. The aqueous S-aromatics exhibit flexible binding conformations, but edge-on conformers are less stable in water. Reflecting this, only 0.3 to 10% of the S indole, S-phenol, and S-imidazole structures are stabilized by N/O-Har...S or S H...Oar/Nar sigma-type H-bonding. The wide range of energies and geometries found for S-aromatic interactions and their tunable redox properties expose the versatility and variability of the S-aromatic motif in proteins and allow us to predict a number of their reported properties. PMID- 29533645 TI - 5,6-Difluorobenzothiazole-Based Conjugated Polymers with Large Band Gaps and Deep Highest Occupied Molecular Orbital Levels. AB - A 5,6-difluorobenzothiazole-based dibromo monomer was successfully synthesized, from which new fluorinated conjugated polymers PF-ffBTz and PFN-ffBTz were prepared via copolymerizations with two fluorene-based diboronic ester monomers. Twisted fluorene-ffBTz backbones enable PF-ffBTz and PFN-ffBTz with large band gaps up to 3.10 eV and deep-lying highest occupied molecular orbital levels down to -6.2 eV. The chemical structures of PF-ffBTz and PFN-ffBTz impart some new functionalities of fluorinated conjugated polymers. PF-ffBTz can show deep blue electroluminescent emission, with high external quantum efficiency of 3.71%. PFN ffBTz, with amino-functionalized side chains on the fluorene unit, can serve as an efficient cathode interlayer in inverted polymer solar cells (PSCs), showing better photovoltaic performances if compared with a ZnO interlayer. In addition, it is found that using an optical filter to cut off the short wavelength section (<=380 nm) of incident light can significantly elevate photostability of PSCs under continuous illumination. PMID- 29533647 TI - Mixing Assisted "Hot Spots" Occupying SERS Strategy for Highly Sensitive In Situ Study. AB - To solve the problem that analyte molecules cannot easily enter "hot spots" on a conventional solid SERS substrate, we developed a mixing-assisted "hot spots" occupying (MAHSO) SERS strategy to improve utilization of "hot spots". Compared with the conventional substrate, the MAHSO substrate enhances the sensitivity of SERS measurement by thousands of times. The MAHSO substrate possesses excellent properties of high enhancement, high uniformity, and long-term stability because the MAHSO substrate is integrated inside an ultrafast microfluidic mixer. The mixer makes analytes and metal colloid homogeneously mixed, and analytes are naturally located in "hot spots", the gaps between adjacent NPs, during the process that NPs deposit on the channel wall. As a multi-inlet device, the MAHSO chip offers a convenient in situ method to study environmental effects on analytes or molecular interactions by flexibly regulating fluid in microchannels and monitoring responses of analytes by SERS spectra. Because all experiments are conducted in aqueous environments, which is similar to the physiological conditions, the MAHSO chip is especially suitable to be applied to study biomolecules. Using this strategy, different conformational changes of the wild type and mutant G150D of protein PMP22-TM4 depending on environmental pH have been observed in situ and analyzed. As a lab-on-a-chip (LoC) device, the MAHSO SERS chip will benefit the field of molecular dynamics, as well as molecule molecule or molecule-surface interactions in the future. PMID- 29533646 TI - Integrated Biosensor for Rapid and Point-of-Care Sepsis Diagnosis. AB - Sepsis is an often fatal condition that arises when the immune response to an infection causes widespread systemic organ injury. A critical unmet need in combating sepsis is the lack of accurate early biomarkers that produce actionable results in busy clinical settings. Here, we report the development of a point-of care platform for rapid sepsis detection. Termed IBS (integrated biosensor for sepsis), our approach leverages (i) the pathophysiological role of cytokine interleukin-3 (IL-3) in early sepsis and (ii) a hybrid magneto-electrochemical sensor for IL-3 detection. The developed platform produces test results within 1 h from native blood samples and detects IL-3 at a sensitivity of <10 pg/mL; this performance is >5-times faster and >10-times more sensitive than conventional enzyme-linked immunoadsorbent assays, the current gold standard. Using clinical samples, we show that elevated plasma IL-3 levels are associated with high organ failure rate and thus greater risk of mortality, confirming the potential of IL-3 as a sepsis diagnostic biomarker. With further system development ( e. g., full automation, data security measures) and rigorous validation studies, the compact and fast IBS could be a practical clinical tool for timely diagnosis and proactive treatment of sepsis. PMID- 29533648 TI - Governing Influence of Thermodynamic and Chemical Equilibria on the Interfacial Properties in Complex Fluids. AB - We propose a comprehensive analysis and a quasi-analytical mathematical formalism to predict the surface tension and contact angles of complex surfactant-infused nanocolloids. The model rests on the foundations of the interaction potentials for the interfacial adsorption-desorption dynamics in complex multicomponent colloids. Surfactant-infused nanoparticle-laden interface problems are difficult to deal with because of the many-body interactions and interfaces involved at the meso-nanoscales. The model is based on the governing role of thermodynamic and chemical equilibrium parameters in modulating the interfacial energies. The influence of parameters such as the presence of surfactants, nanoparticles, and surfactant-capped nanoparticles on interfacial dynamics is revealed by the analysis. Solely based on the knowledge of interfacial properties of independent surfactant solutions and nanocolloids, the same can be deduced for complex surfactant-based nanocolloids through the proposed approach. The model accurately predicts the equilibrium surface tension and contact angle of complex nanocolloids available in the existing literature and present experimental findings. PMID- 29533649 TI - Extensive Evaluation of the Conductor-like Screening Model for Real Solvents Method in Predicting Liquid-Liquid Equilibria in Ternary Systems of Ionic Liquids with Molecular Compounds. AB - A conductor-like screening model for real solvents (COSMO-RS) is nowadays one of the most popular and commonly applied tools for the estimation of thermodynamic properties of complex fluids. The goal of this work is to provide a comprehensive review and analysis of the performance of this approach in calculating liquid liquid equilibrium (LLE) phase diagrams in ternary systems composed of ionic liquid and two molecular compounds belonging to diverse families of chemicals (alkanes, aromatics, S/N-compounds, alcohols, ketones, ethers, carboxylic acid, esters, and water). The predictions are presented for extensive experimental database, including 930 LLE data sets and more than 9000 data points (LLE tie lines) reported for 779 unique ternary mixtures. An impact of the type of molecular binary subsystem on the accuracy of predictions is demonstrated and discussed on the basis of representative examples. The model's capability of capturing qualitative trends in the LLE distribution ratio and selectivity is also checked for a number of structural effects. Comparative analysis of two levels of quantum chemical theory (BP-TZVP-COSMO vs BP-TZVPD-FINE) for the input molecular data for COSMO-RS is presented. Finally, some general recommendations for the applicability of the model are indicated based on the analysis of the global performance as well as on the results obtained for systems relevant from the point of view of important separation problems. PMID- 29533650 TI - Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration. AB - N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice. PMID- 29533651 TI - Coarse-Grain Molecular Dynamics Simulations To Investigate the Bulk Viscosity and Critical Micelle Concentration of the Ionic Surfactant Sodium Dodecyl Sulfate (SDS) in Aqueous Solution. AB - The first critical micelle concentration (CMC) of the ionic surfactant sodium dodecyl sulfate (SDS) in diluted aqueous solution has been determined at room temperature from the investigation of the bulk viscosity, at several concentrations of SDS, by means of coarse-grain molecular dynamics simulations. The coarse-grained model molecules at the mesoscale level are adopted. The bulk viscosity of SDS was calculated at several millimolar concentrations of SDS in water using the MARTINI force field by means of NVT shear Mesocite molecular dynamics. The definition of each bead in the MARTINI force field is established, as well as their radius, volume, and mass. The effect of the size of the simulation box on the obtained CMC has been investigated, as well as the effect of the number of SDS molecules, in the simulations, on the formation of aggregates. The CMC, which was obtained from a graph of the calculated viscosities versus concentration, is in good agreement with the reported experimental data and does not depend on the size of the box used in the simulation. The formation of a spherical micelle-like aggregate is observed, where the dodecyl sulfate tails point inward and the heads point outward the aggregation micelle, in accordance with experimental observations. The advantage of using coarse-grain molecular dynamics is the possibility of treating explicitly charged beads, applying a shear flow for viscosity calculation, and processing much larger spatial and temporal scales than atomistic molecular dynamics can. Furthermore, the CMC of SDS obtained with the coarse-grained model is in much better agreement with the experimental value than the value obtained with atomistic simulations. PMID- 29533652 TI - Orthogonally Protected Diaminoterephthalate Scaffolds: Installation of Two Functional Units at the Chromophore. AB - The 2,5-diaminoterephthalate structural motif is a powerful chromophore with remarkable fluorescence properties. Containing two carboxylate and two amino functions, it defines a colored molecular scaffold which allows for orthogonal functionalization with different functional units. Therefore, different applications in life sciences and materials science could be addressed. In this study, the two amino functions were alkylated by reductive amination with side chains carrying amino (orthogonally protected as Boc or Alloc) and carboxylate functions (orthogonally protected as tBu or allyl ester). After sequential deprotections, functional units were introduced by amidation reactions. As three examples, the chromophore was coupled with retinoic acid and fullerene C60 in order to obtain a triad for studying photoinduced electron transfer processes. Furthermore, cyclooctyne and azide moieties were introduced as functional units, allowing for ligation by click reactions. These two clickable groups were applied in combination with maleimide units which are reactive toward thiol residues. The latter dyes define so-called "turn on" probes, since the fluorescence quantum yields increased by one order of magnitude upon reaction with the molecular target. PMID- 29533653 TI - Three-Dimensional Carbon Current Collector Promises Small Sulfur Molecule Cathode with High Areal Loading for Lithium-Sulfur Batteries. AB - With the high energy density of 2600 W h kg-1, lithium-sulfur (Li-S) batteries have been considered as one of the most promising energy storage systems. However, the serious capacity fading resulting from the shuttle effect hinders its commercial application. Encapsulating small S2-4 molecules into the pores of ultramicroporous carbon (UMC) can eliminate the dissolved polysulfides, thus completely inhibiting the shuttle effect. Nevertheless, the sulfur loading of S2 4/UMC is usually not higher than 1 mg cm-2 because of the limited pore volume of UMC, which is a great challenge for small sulfur cathode. In this paper, by applying ultralight 3D melamine formaldehyde-based carbon foam (MFC) as a current collector, we dramatically enhanced the areal sulfur loading of the S2-4 electrode with good electrochemical performances. The 3D skeleton of MFC can hold massive S2-4/UMC composites and act as a conductive network for the fast transfer of electrons and Li+ ions. Furthermore, it can serve as an electrolyte reservoir to make a sufficient contact between S2-4 and electrolyte, enhancing the utilization of S2-4. With the MFC current collector, the S2-4 electrode reaches an areal sulfur loading of 4.2 mg cm-2 and performs a capacity of 839.8 mA h g-1 as well as a capacity retention of 82.5% after 100 cycles. The 3D MFC current collector provides a new insight for the application of Li-S batteries with high areal small sulfur loading and excellent cycle stability. PMID- 29533654 TI - High Accuracy Ion Mobility Spectrometry for Instrument Calibration. AB - Ion mobility spectrometry (IMS) is widely used to characterize compounds of interest (COIs) based on their reduced mobility ( K0) values. In an attempt to increase the accuracy and agreement of studies, the most recommended method has been to use a reference compound with a known K0 value to calibrate the instrument and calculate COI K0 values from normalized spectra. Researchers are limited by the accuracy of previous K0 value reference measurements on which to base their calibrations. Any inaccuracy in these reference K0 values, typically +/-2%, will propagate through to the calculated K0 value of the COI. For this reason, there is a need to standardize reference K0 values with improved accuracy. Through improvement of the accuracy of reference measurements, a lower degree of error will propagate through new K0 value calculations. The K0 values of the ammonium reactant ion, the potential reference standard dimethyl methylphosphonate (DMMP), and three explosive COIs were characterized at multiple drift gas temperatures, drift gas water contents, and electric field strengths on an accurate ion mobility spectrometry instrument. K0 values reported here are known to +/-0.1% as a result of reducing the error of all instrumental parameters. PMID- 29533655 TI - Biocatalytic Routes to Lactone Monomers for Polymer Production. AB - Monoterpenoids offer potential as biocatalytically derived monomer feedstocks for high-performance renewable polymers. We describe a biocatalytic route to lactone monomers menthide and dihydrocarvide employing Baeyer-Villiger monooxygenases (BVMOs) from Pseudomonas sp. HI-70 (CPDMO) and Rhodococcus sp. Phi1 (CHMOPhi1) as an alternative to organic synthesis. The regioselectivity of dihydrocarvide isomer formation was controlled by site-directed mutagenesis of three key active site residues in CHMOPhi1. A combination of crystal structure determination, molecular dynamics simulations, and mechanistic modeling using density functional theory on a range of models provides insight into the origins of the discrimination of the wild type and a variant CHMOPhi1 for producing different regioisomers of the lactone product. Ring-opening polymerizations of the resultant lactones using mild metal-organic catalysts demonstrate their utility in polymer production. This semisynthetic approach utilizing a biocatalytic step, non-petroleum feedstocks, and mild polymerization catalysts allows access to known and also to previously unreported and potentially novel lactone monomers and polymers. PMID- 29533656 TI - Quantitative Isotope-Dilution High-Resolution-Mass-Spectrometry Analysis of Multiple Intracellular Metabolites in Clostridium autoethanogenum with Uniformly 13C-Labeled Standards Derived from Spirulina. AB - We have investigated the applicability of commercially available lyophilized spirulina ( Arthrospira platensis), a microorganism uniformly labeled with 13C, as a readily accessible source of multiple 13C-labeled metabolites suitable as internal standards for the quantitative determination of intracellular bacterial metabolites. Metabolites of interest were analyzed by hydrophilic-interaction liquid chromatography coupled with high-resolution mass spectrometry. Multiple internal standards obtained from uniformly (U)-13C-labeled extracts from spirulina were used to enable isotope-dilution mass spectrometry (IDMS) in the identification and quantification of intracellular metabolites. Extraction of the intracellular metabolites of Clostridium autoethanogenum using 2:1:1 chloroform/methanol/water was found to be the optimal method in comparison with freeze-thaw, homogenization, and sonication methods. The limits of quantification were <=1 MUM with excellent linearity for all of the calibration curves ( R2 >= 0.99) for 74 metabolites. The precision and accuracy were found to be within relative standard deviations (RSDs) of 15% for 49 of the metabolites and within RSDs of 20% for all of the metabolites. The method was applied to study the effects of feeding different levels of carbon monoxide (as a carbon source) on the central metabolism and Wood-Ljungdahl pathway of C. autoethanogenum grown in continuous culture over 35 days. Using LC-IDMS with U-13C spirulina allowed the successful quantification of 52 metabolites in the samples, including amino acids, carboxylic acids, sugar phosphates, purines, and pyrimidines. The method provided absolute quantitative data on intracellular metabolites that was suitable for computational modeling to understand and optimize the C. autoethanogenum metabolic pathways active in gas fermentation. PMID- 29533657 TI - Scenarios for Demand Growth of Metals in Electricity Generation Technologies, Cars, and Electronic Appliances. AB - This study provides scenarios toward 2050 for the demand of five metals in electricity production, cars, and electronic appliances. The metals considered are copper, tantalum, neodymium, cobalt, and lithium. The study shows how highly technology-specific data on products and material flows can be used in integrated assessment models to assess global resource and metal demand. We use the Shared Socio-economic Pathways as implemented by the IMAGE integrated assessment model as a starting point. This allows us to translate information on the use of electronic appliances, cars, and renewable energy technologies into quantitative data on metal flows, through application of metal content estimates in combination with a dynamic stock model. Results show that total demand for copper, neodymium, and tantalum might increase by a factor of roughly 2 to 3.2, mostly as a result of population and GDP growth. The demand for lithium and cobalt is expected to increase much more, by a factor 10 to more than 20, as a result of future (hybrid) electric car purchases. This means that not just demographics, but also climate policies can strongly increase metal demand. This shows the importance of studying the issues of climate change and resource depletion together, in one modeling framework. PMID- 29533659 TI - Microfluidic Coculture Device for Monitoring of Inflammation-Induced Myocardial Injury Dynamics. AB - Emerging awareness of cardiac macrophages' role in inflammation after myocardial infarction indicates that overabundant proinflammatory macrophages induce accentuated myocardial injury. The investigation of the macrophages cardiomyocytes interaction and inflammation-induced dynamic damage in myocardial infarction, especially in a spatiotemporally controlled manner, remains a huge challenge. Here, we developed an in vitro model using a microfluidic coculture system to mimic inflammatory cardiac injury. To our knowledge, on-chip pathological models focused on inflammation-induced myocardial injury have not been reported. The device consists of two sets of thin interconnecting grooves that isolate heterogeneous cells spatially but maintain their soluble factors communication. The mass transportation is visually characterized, and the complete diffusion reaches equilibrium within 100 s. We investigate the dynamic interaction between the macrophages and the cardiomyocytes in the spatiotemporal controlled microenvironment, mimicking a key aspect of the in vivo pathophysiological process. The results show that the activated macrophages induce time-lapsed apoptotic responses of the cardiac cells and damage mitochondria membrane integrity. The anti-inflammatory and cardio-protective effects of quercetin were explored on the chip. The extent of caspase-3 activation is asynchronous in the individual cardiac cells, suggesting the different apoptosis dynamics. We further demonstrate that the mechanism of activated inflammation is associated with the upregulation of several inflammatory cytokines and NF-kappaB pathway. Thus, the developed microfluidic coculture device provides a useful tool for real-time monitoring of inflammatory response for myocardial disease and holds potential for anti-inflammatory drug screening. PMID- 29533658 TI - Interrogation of Benzomalvin Biosynthesis Using Fungal Artificial Chromosomes with Metabolomic Scoring (FAC-MS): Discovery of a Benzodiazepine Synthase Activity. AB - The benzodiazepine benzomalvin A/D is a fungally derived specialized metabolite and inhibitor of the substance P receptor NK1, biosynthesized by a three-gene nonribosomal peptide synthetase cluster. Here, we utilize fungal artificial chromosomes with metabolomic scoring (FAC-MS) to perform molecular genetic pathway dissection and targeted metabolomics analysis to assign the in vivo role of each domain in the benzomalvin biosynthetic pathway. The use of FAC-MS identified the terminal cyclizing condensation domain as BenY-CT and the internal C-domains as BenZ-C1 and BenZ-C2. Unexpectedly, we also uncovered evidence suggesting BenY-CT or a yet to be identified protein mediates benzodiazepine formation, representing the first reported benzodiazepine synthase enzymatic activity. This work informs understanding of what defines a fungal CT domain and shows how the FAC-MS platform can be used as a tool for in vivo analyses of specialized metabolite biosynthesis and for the discovery and dissection of new enzyme activities. PMID- 29533660 TI - Managing Environmental Liability: An Evaluation of Bonding Requirements for Oil and Gas Wells in the United States. AB - Inactive oil and gas wells present an environmental hazard if not properly plugged. Upon drilling a well, operators are required to post a bond, which ensures that the operator has an incentive to plug and abandon (P&A) at the end of the well's life, and that, if the state is left with the liability of managing "orphaned" wells, it can cover the cost of P&A. Using data from 13 state agencies on their orphaned well plugging expenditures, we provide new estimates of P&A costs in the United States and compare them to bond amounts. Current state bonding requirements are insufficient to cover the average P&A cost of orphan wells in 11 of these 13 states. These should be reviewed and revised where necessary. We also examine the factors influencing P&A costs using detailed data on orphaned wells in Kansas. Given the variability of P&A costs, bonds would be more effective if they varied by factors that are meaningful in explaining P&A costs, such as well depth, location, and proximity to groundwater. State regulators can use the statistical approach developed in this paper to improve bonding requirements and to better predict the P&A costs of their orphaned wells. PMID- 29533661 TI - Broadening the Detection Spectrum of Small Analytes Using a Two-Antibody-Designed Hybrid Immunoassay. AB - The recognition spectrum of immunoassays developed on the basis of class-specific antibodies can include the several nearest analytes but rarely all of the desired representatives of the group. The situation may be sufficiently improved using a hybrid assay combining two antibodies with specificities that complement each other. Two monoclonal antibodies (mAb) with broad but different specificities toward sulfonamides were examined for their binding to a panel of hapten conjugates. mAb-hapten pairs without mutual cross-reactions were identified, and classical direct antigen-coated and mAb-coated ELISAs were developed as formats with referent specificities. Both interactions were combined in a single hybrid assay, which was designed as a one-step double-competitive sandwich-ELISA. For this assay, the intermediate bifunctional reagent mAb(1)-hapten(2) conjugate was synthesized and able to simultaneously bind to hapten(1) and be bound by mAb(2). Formation of a two-mAbs sandwich complex was inhibited by competitors of interaction(1) as well as by competitors of interaction(2). Thus, due to the summation effect, simultaneous determination of analytes recognized by both mAbs was achieved. The hybrid assay can be performed in two reversed arrangements using a coating antigen or coating antibody, the characteristics of which were compared and found to be similar in sensitivity and extended specificity. The suitability of the developed test for the determination of 14 sulfonamides at their maximum residue limit (MRL) concentration was demonstrated using the examples of turkey muscle and milk samples. PMID- 29533662 TI - Macroporous Double-Network Hydrogel for High-Efficiency Solar Steam Generation Under 1 sun Illumination. AB - Solar steam generation is one of the most promising solar-energy-harvesting technologies to address the issue of water shortage. Despite intensive efforts to develop high-efficiency solar steam generation devices, challenges remain in terms of the relatively low solar thermal efficiency, complicated fabrications, high cost, and difficulty in scaling up. Herein, a double-network hydrogel with a porous structure (p-PEGDA-PANi) is demonstrated for the first time as a flexible, recyclable, and efficient photothermal platform for low-cost and scalable solar steam generation. As a novel photothermal platform, the p-PEGDA-PANi involves all necessary properties of efficient broadband solar absorption, exceptional hydrophilicity, low heat conductivity, and porous structure for high-efficiency solar steam generation. As a result, the hydrogel-based solar steam generator exhibits a maximum solar thermal efficiency of 91.5% with an evaporation rate of 1.40 kg m-2 h-1 under 1 sun illumination, which is comparable to state-of-the-art solar steam generation devices. Furthermore, the good durability and environmental stability of the p-PEGDA-PANi hydrogel enables a convenient recycling and reusing process toward real-life applications. The present research not only provides a novel photothermal platform for solar energy harvest but also opens a new avenue for the application of the hydrogel materials in solar steam generation. PMID- 29533663 TI - NNN Pincer Ru(II)-Complex-Catalyzed alpha-Alkylation of Ketones with Alcohols. AB - A series of novel ruthenium(II) complexes supported by a symmetrical NNN ligand were prepared and fully characterized. These complexes exhibited good performance in transfer hydrogenation to form new C-C bonds using alcohols as the alkylating agents, generating water as the only byproduct. A broad range of substrates, including (hetero)aryl- or alkyl-ketones and alcohols, were well tolerated under the optimized conditions. Notably, alpha-substituted methylene ketones were also investigated, which afforded alpha-branched steric hindrance products. A potential application of alpha-alkylation of methylene acetone to synthesize donepezil was demonstrated, which provided the desired product in 83% yield. Finally, this catalytic system could be applied to a one-pot double alkylation procedure with sequential addition of two different alcohols. The current protocol is featured with several characteristics, including a broad substrate scope, low catalyst (0.50 mol %) loadings, and environmental benignity. PMID- 29533664 TI - Computational Modeling of Exciton-Bath Hamiltonians for Light Harvesting 2 and Light Harvesting 3 Complexes of Purple Photosynthetic Bacteria at Room Temperature. AB - Light harvesting 2 (LH2) complex is the primary component of the photosynthetic unit of purple bacteria that is responsible for harvesting and relaying excitons. The electronic absorption line shape of LH2 contains two major bands at 800 and 850 nm wavelength regions. Under low light conditions, some species of purple bacteria replace LH2 with light harvesting 3 (LH3), a variant form with almost the same structure as the former but with distinctively different spectral features. The major difference between the absorption line shapes of LH2 and LH3 is the shift of the 850 nm band of the former to a new 820 nm region. The microscopic origin of this difference has been the subject of some theoretical/computational investigations. However, the genuine molecular level source of such a difference is not clearly understood yet. This work reports a comprehensive computational study of LH2 and LH3 complexes so as to clarify different molecular level features of LH2 and LH3 complexes and to construct simple exciton-bath models with a common form. All-atomistic molecular dynamics simulations of both LH2 and LH3 complexes provide detailed molecular level structural differences of bacteriochlorophylls (BChls) in the two complexes, in particular, in their patterns of hydrogen bonding (HB) and torsional angles of the acetyl group. Time-dependent density functional theory calculation of the excitation energies of BChls for structures sampled from the MD simulations suggests that the observed differences in the HB and torsional angles cannot fully account for the experimentally observed spectral shift of LH3. Potential sources that can explain the actual spectral shift of LH3 are discussed, and their magnitudes are assessed through fitting of experimental line shapes. These results demonstrate the feasibility of developing simple exciton-bath models for both LH2 and LH3, which can be employed for large-scale exciton quantum dynamics in their aggregates. PMID- 29533665 TI - High-Pressure Synthesized Lithium Pentazolate Compound Metastable under Ambient Conditions. AB - Polynitrogen compounds have been actively pursued driven by their potential as ultra-high-performing propellants or explosives. Despite remarkable breakthroughs over the past two decades, the two figures of merit for a compelling material, namely a large fraction of nitrogen by weight and a bulk stability under ambient conditions, have not yet been achieved. We report the synthesis of a lithium pentazolate solid by compressing and laser-heating lithium embedded in molecular N2 around 45 GPa along with its recovery under ambient conditions. The observation by Raman spectroscopy of vibrational modes unique to the cyclo-N5- anion is the signature of the formation of LiN5. Mass spectroscopy experiments confirm the presence of the pentazolate anion in the recovered compound. A monoclinic lattice is obtained from X-ray diffraction measurements and the volume of the LiN5 compound under pressure is in good agreement with the theoretical calculations. PMID- 29533666 TI - Investigation of the Water Adsorption Properties and Structural Stability of MIL 100(Fe) with Different Anions. AB - Investigating metal-organic frameworks (MOFs) as water adsorbents has drawn increasing attention for their potential in energy-related applications such as water production and heat transformation. A specific MOF, MIL-100(Fe), is of particular interest for its large adsorption capacity with the occurrence of water condensation at a relatively low partial pressure. In the synthesis of MIL 100(Fe), depending on the reactants, structures with varying anion terminals (e.g., F-, Cl-, or OH-) on the metal trimer have been reported. In this study, we employed molecular simulations and density functional theory calculations for investigating the water adsorption behaviors and the relative structural stability of MIL-100(Fe) with different anions. We also proposed a possible defective structure and explored its water adsorption properties. The results of this study are in good agreement with the experimental measurements and are in support of the observations reported in the literature. Understanding the spatial configurations and energetics of water molecules in these materials has also shed light on their adsorption mechanism at the atomic level. PMID- 29533669 TI - Elastowetting of Soft Hydrogel Spheres. AB - When a soft hydrogel sphere is placed on a rigid hydrophilic substrate, it undergoes arrested spreading by forming an axisymmetric foot near the contact line, while conserving its global spherical shape. In contrast, liquid water (that constitutes greater than 90% of the hydrogel's volume) spreads into a thin film on the same surface. We study systematically this elastowetting of gel spheres on substrates of different surface energies and find that their contact angle increases as the work of adhesion between the gel and the substrate decreases, as one would observe for drops of pure water-albeit being larger than in the latter case. This difference in the contact angles of gel and water appears to be due to the elastic shear stresses that develop in the gel and oppose its spreading. Indeed, by increasing the elastic modulus of the gel spheres, we find that their contact angle also increases. In addition, the length of the contact foot increases with the work of adhesion and sphere size, while it decreases when the elastic modulus of the gel is increased. We discuss those experimental results in light of a minimal analysis based on energy minimization, volume conservation, and scaling arguments. PMID- 29533668 TI - Biomimetic Targeting of Nanoparticles to Immune Cell Subsets via Cognate Antigen Interactions. AB - Within the body, cellular recognition is mediated in large part by receptor ligand interactions that result from the surface marker expression of the participant cells. In the case of immune cells, these interactions can be highly specific, enabling them to carry out their protective functions in fighting off infection and malignancy. In this work, we demonstrate the biomimetic targeting of antigen-specific immune cell populations by using nanoparticles functionalized with natural membrane derived from cells expressing the cognate antigen. Using red blood cell (RBC)-specific B cells as a model target, it is shown that RBC membrane-coated nanoparticles exhibit enhanced affinity compared with control nanoparticles. The concept is further demonstrated using murine models of alloimmunity and autoimmunity, where B cells elicited against RBCs can be positively labeled using the biomimetic nanoparticles. This strategy for antigen specific immune cell targeting may have utility for the detection and treatment of various autoimmune conditions, and it may additionally have implications for the prevention of immune cell malignancies. PMID- 29533667 TI - Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer. AB - Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical studies, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic cosolvents and by doping of a homopolymer of poly(epsilon-caprolactone), a diblock copolymer composition of poly(ethylene oxide)- block-poly(epsilon-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties. Noninvasive optical imaging was employed to examine the pharmacology and biodistribution of these various nanoparticle formulations in both allografted and autochthonous mouse models of PDAC. In contrast to the results reported with transplanted tumors, spherical micelles as large as 300 nm in diameter were found to extravasate in the autochthonous model, reaching a distance of approximately 20 MUm from the nearest tumor cell clusters. A lipophilic platinum(IV) prodrug of oxaliplatin was further able to achieve a ~7-fold higher peak accumulation and a ~50-fold increase in its retention half-life in pancreatic tumors when delivered with 100 nm long worm-like micelles as when compared to the free drug formulation of oxaliplatin. Through further engineering of nanoparticle properties, as well as by widespread adoption of the autochthonous tumor model for preclinical testing, future therapeutic formulations may further enhance the targeting and penetration of anticancer agents to improve survival outcomes in PDAC. PMID- 29533670 TI - Proteomic and Biochemical Analyses Reveal a Novel Mechanism for Promoting Protein Ubiquitination and Degradation by UFBP1, a Key Component of Ufmylation. AB - Protein post-translational modification by ubiquitin-fold modifier 1, UFM1, regulates many biological processes such as response to endoplasmic reticulum stress and regulation of tumor progression. A recent study has indicated that the UFM1-binding and PCI domain-containing protein 1 (UFBP1) is required for the conjugation of UFM1 to a substrate. However, other biological functions of UFBP1 have not been explored. Here, we use immunoprecipitation and label-free quantitative proteomics to identify UFBP1-interacting proteins in a mammalian cell line. About 80 potential interacting proteins are obtained from MS analyses of three biological replicates. Bioinformatics analyses of these proteins suggest that UFBP1 may participate in the regulation of protein folding, stability, and trafficking. Biochemical experiments discover that UFBP1 expression downregulates the protein level and reduces the stability of several of its interacting proteins, while UFBP1 knockdown increases their protein levels. Protein synthesis inhibition and proteasomal inhibition experiments reveal that UFBP1 promotes their ubiquitination and degradation. Experiments using a model UFBP1-interacting protein ANT3 demonstrate that UFBP1 enhances the interaction between ANT3 and its E3 ligase and thus promotes its ubiquitination and degradation. Our work elucidates a novel molecular mechanism by which UFBP1 regulates protein ubiquitination and degradation. PMID- 29533672 TI - Muscle Strength Is a Poor Screening Test for Predicting Lower Extremity Injuries in Professional Male Soccer Players: A 2-Year Prospective Cohort Study. AB - BACKGROUND: Lower extremity muscle strength tests are commonly used to screen for injury risk in professional soccer. However, there is limited evidence on the ability of such tests in predicting future injuries. PURPOSE: To examine the association between hip and thigh muscle strength and the risk of lower extremity injuries in professional male soccer players. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Professional male soccer players from 14 teams in Qatar underwent a comprehensive strength assessment at the beginning of the 2013/2014 and 2014/2015 seasons. Testing consisted of concentric and eccentric quadriceps and hamstring isokinetic peak torques, eccentric hip adduction and abduction forces, and bilateral isometric adductor force (squeeze test at 45 degrees ). Time-loss injuries and exposure in training and matches were registered prospectively by club medical staff throughout each season. Univariate and multivariate Cox regression analyses were used to calculate hazard ratios (HRs) with 95% CIs. RESULTS: In total, 369 players completed all strength tests and had registered injury and exposure data. Of these, 206 players (55.8%) suffered 538 lower extremity injuries during the 2 seasons; acute muscle injuries were the most frequent. Of the 20 strength measures examined, greater quadriceps concentric peak torque at 300 deg/s (HR, 1.005 [95% CI, 1.00-1.01]; P = .037) was the only strength measure identified as significantly associated with a risk of lower extremity injuries in multivariate analysis. Greater quadriceps concentric peak torque at 60 deg/s (HR, 1.004 [95% CI, 1.00-1.01]; P = .026) was associated with the risk of overuse injuries, and greater bilateral adductor strength adjusted for body weight (HR, 0.75 [95% CI, 0.57-0.97; P = .032) was associated with a lower risk for any knee injury. Receiver operating characteristic curve analyses indicated poor predictive ability of the significant strength variables (area under the curve, 0.45-0.56). CONCLUSION: There was a weak association with the risk of lower extremity injuries for 2 strength variables: greater quadriceps concentric muscle strength at (1) high and (2) low speeds. These associations were too small to identify an "at-risk" player. Therefore, strength testing, as performed in the present study, cannot be recommended as a screening test to predict injuries in professional male soccer. PMID- 29533673 TI - Reply to Johnson: Improve Pulmonary Function Test Reporting. PMID- 29533674 TI - Arthroscopic Rotator Cuff Repair With Graft Augmentation of 3-Dimensional Biological Collagen for Moderate to Large Tears: A Randomized Controlled Study. AB - BACKGROUND: Due to the highly organized tissue and avascular nature of the rotator cuff, rotator cuff tears have limited ability to heal after the tendon is reinserted directly on the greater tubercle of the humerus. Consequently, retears are among the most common complications after rotator cuff repair. Augmentation of rotator cuff repairs with patches has been an active area of research in recent years to reduce retear rate. HYPOTHESIS: Graft augmentation with 3D collagen could prevent retears of the repaired tendon and improve tendon-bone healing in moderate to large rotator cuff tears. STUDY DESIGN: Randomized controlled study; Level of evidence, 2. METHODS: A prospective, randomized controlled study was performed in a consecutive series of 112 patients age 50 to 85 years who underwent rotator cuff repair with the suture-bridge technique (58 patients, control group) or the suture-bridge technique augmented with 3 dimensional (3D) collagen (54 patients, study group). All patients were followed for 28.2 months (range, 24-36 months). Visual analog scale score for pain, University of California Los Angeles (UCLA) shoulder score, and Constant score were determined. Magnetic resonance imaging was performed pre- and postoperatively (at a minimum of 24 months) to evaluate the integrity of the rotator cuff and the retear rate of the repaired tendon. Three patients in each group had biopsies at nearly 24 months after surgery with histological assessment and transmission electron microscopy. RESULTS: A total of 104 patients completed the final follow-up. At the 12-month follow-up, the UCLA shoulder score was 28.1 +/- 1.9 in the study group, which was significantly better than that in the control group (26.9 +/- 2.1, P = .002). The Constant score was also significantly better in the study group (87.1 +/- 3.2) than in the control group (84.9 +/- 4.2, P = .003). However, at the final follow-up, no significant differences were found in the UCLA shoulder scores (29.4 +/- 1.9 in the control group and 30.0 +/- 1.6 in the study group, P = .052) or Constant scores (89.9 +/- 3.2 in the control group and 90.8 +/- 3.5 in the study group, P = .18). In terms of structural integrity, more patients in the study group had a favorable type I retear grade (18/51) than in the control group (10/53) ( P = .06). The postoperative retear rate was 34.0% in the control group and 13.7% in the study group, thus indicating a significantly lower retear rate in the study group ( P = .02). Biopsy specimens of the tendon-bone interface in 6 patients revealed more bone formation and more aligned fibers with larger diameters in the study group than in the control group. No intraoperative or postoperative complications were noted in either group. CONCLUSION: 3D collagen augmentation could provide effective treatment of moderate to large rotator cuff tears, providing substantial functional improvement, and could reduce the retear rate. This technique could also promote new tendon-bone formation, thus exerting a prominent effect on tendon-bone healing. PMID- 29533671 TI - Update in Pulmonary Vascular Disease 2016 and 2017. PMID- 29533676 TI - Improve Pulmonary Function Test Reporting. PMID- 29533675 TI - Flow Cytometry Underestimates and Planimetry Overestimates Alveolar Epithelial Type 2 Cell Expansion after Lung Injury. PMID- 29533678 TI - Autologous Chondrocyte Implantation for Bipolar Chondral Lesions in the Tibiofemoral Compartment. AB - BACKGROUND: Treating bipolar chondral lesions in the tibiofemoral (TF) compartment with cartilage repair procedures is challenging, and a suitable treatment remains unclear. PURPOSE: To evaluate clinical outcomes after autologous chondrocyte implantation (ACI) for the treatment of bipolar chondral lesions in the TF compartment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We evaluated 57 patients who underwent ACI for the treatment of symptomatic bipolar chondral lesions in the TF compartment by a single surgeon between October 1995 and June 2014. One patient did not return for follow-up. Thus, 56 patients (58 knees) were included with a minimum of 2 years' follow-up. A mean of 3.1 lesions per knee were treated, representing a mean total surface area of 16.1 cm2 (range, 3.2-44.5 cm2) per knee. Bipolar lesions were present in the medial compartment (32 knees) and in the lateral compartment (26 knees). Patients were evaluated with the modified Cincinnati Knee Rating Scale, visual analog scale for pain, Western Ontario and McMaster Universities Osteoarthritis Index, and Short Form-36. Patients also answered questions regarding self-rated knee function and satisfaction with the procedure. Standard radiographs were evaluated with the Kellgren-Lawrence grading system. RESULTS: The survival rate was 80% at 5 years and 76% at 10 years. A significantly better survival rate was found in patients with the use of a collagen membrane than periosteum (97% vs 61% at 5 years, respectively; P = .0014). Of 46 knees with retained grafts, all functional scores significantly improved postoperatively, with a very high satisfaction rate (91%) at a mean of 8.3 +/- 5.1 years (range, 2-20 years) after ACI. At last follow-up, 24 of 46 successful knees were radiographically assessed (mean, 5.5 +/- 4.0 years [range, 2.0-18.7 years]) and showed no significant osteoarthritis progression ( P = .3173). Outcomes for 12 patients were considered as failures at a mean of 4.1 years. Of these, 9 patients were converted to partial or total knee arthroplasty at a mean of 4.4 years. Two patients underwent revision ACI at 5 and 17 months. The other 1 patient did not require revision surgery. CONCLUSION: Our study showed that ACI for the treatment of bipolar chondral lesions in the TF compartment provided successful clinical outcomes in patients with retained grafts and possibly prevented or delayed osteoarthritis progression at midterm to long-term follow-up. A collagen membrane is more encouraging than periosteum for bipolar lesions in the TF compartment. While addressing the predisposing factors affecting cartilage repair, ACI could be an adequate salvage procedure for bipolar chondral lesions in the TF compartment for the relatively young arthritic patient who wishes to avoid arthroplasty. PMID- 29533677 TI - The Lung Microbiota of Healthy Mice Are Highly Variable, Cluster by Environment, and Reflect Variation in Baseline Lung Innate Immunity. AB - RATIONALE: The "gut-lung axis" is commonly invoked to explain the microbiome's influence on lung inflammation. Yet the lungs harbor their own microbiome, which is altered in respiratory disease. The relative influence of gut and lung bacteria on lung inflammation is unknown. OBJECTIVES: To determine whether baseline lung immune tone reflects local (lung-lung) or remote (gut-lung) microbe host interactions. METHODS: We compared lung, tongue, and cecal bacteria in 40 healthy, genetically identical, 10-week-old mice, using 16S ribosomal RNA gene quantification and sequencing. We measured inflammatory cytokines, using a multiplex assay of homogenized lung tissue. We compared lung bacteria in healthy mice treated with varied durations of systemic antibiotics. MEASUREMENTS AND MAIN RESULTS: Lung bacterial communities are highly variable among mice, cluster strongly by cage, shipment, and vendor, and are altered by antibiotics in a microbiologically predictable manner. Baseline lung concentrations of two key inflammatory cytokines (IL-1alpha and IL-4) are correlated with the diversity and community composition of lung bacterial communities. Lung concentrations of these inflammatory cytokines correlate more strongly with variation in lung bacterial communities than with that of the gut or mouth. CONCLUSIONS: In the lungs of healthy mice, baseline innate immune tone more strongly reflects local (lung lung) microbe-host interactions than remote (gut-lung) microbe-host interactions. Our results independently confirm the existence and immunologic significance of the murine lung microbiome, even in health. Variation in lung microbiota is likely an important, underappreciated source of experimental and clinical variability. The lung microbiome is an unexplored therapeutic target for the prevention and treatment of inflammatory lung disease. PMID- 29533679 TI - Chronic Obstructive Pulmonary Disease as a Risk Factor for Cardiovascular Disease. A View from the SUMMIT. PMID- 29533681 TI - !HOLA! The Influence of Being Hispanic on Lung Ancestry. PMID- 29533680 TI - Copy number variation in fetal alcohol spectrum disorder. AB - Fetal alcohol spectrum disorder (FASD) is characterized by a combination of neurological, developmental, and congenital defects that may occur as a consequence of prenatal alcohol exposure. Earlier reports showed that large chromosomal anomalies may link to FASD. Here, we examined the prevalence and types of copy number variations (CNVs) in FASD cases previously diagnosed by a multidisciplinary FASD team in sites across Canada. We genotyped 95 children with FASD and 87 age-matched, typically developing controls on the Illumina Human Omni2.5 SNP (single nucleotide polymorphisms) array platform. We compared their CNVs with those of 10 851 population controls to identify rare CNVs (<0.1% frequency), which may include large unbalanced chromosomal abnormalities, that might be relevant to FASD. In 12/95 (13%) of the FASD cases, rare CNVs were found that impact potentially clinically relevant developmental genes, including the CACNA1H involved in epilepsy and autism, the 3q29 deletion disorder, and others. Our results show that a subset of children diagnosed with FASD have chromosomal deletions and duplications that may co-occur or explain the neurodevelopmental impairments in a diagnosed cohort of FASD individuals. Children suspected to have FASD with or without sentinel facial features of fetal alcohol syndrome and neurodevelopmental delays should potentially be evaluated by a clinical geneticist and possibly have genetic investigations as appropriate to exclude other etiologies. PMID- 29533682 TI - Workarounds to Intended Use of Health Information Technology: A Narrative Review of the Human Factors Engineering Literature. AB - Objective To integrate and synthesize insights from recent studies of workarounds to the intended use of health information technology (HIT) by health care professionals. Background Systems are safest when the documentation of how work is done in policies and procedures closely matches what people actually do when they are working. Proactively identifying and managing workarounds to the intended use of technology, including deviations from expected workflows, can improve system safety. Method A narrative review of studies of workarounds with HIT was conducted to identify themes in the literature. Results Three themes were identified: (1) Users circumvented new additional steps in the workflow when using HIT, (2) interdisciplinary team members communicated via HIT in text fields that were intended for other purposes, and (3) locally developed paper-based and manual whiteboard systems were used instead of HIT to support situation awareness of individuals and groups; an example of a locally developed system was handwritten notes about a patient on a piece of paper folded up and carried in a nurse's pocket. Conclusion Workarounds were employed to avoid changes to workflow, enable interdisciplinary communication, coordinate activities, and have real-time portable access to summarized and synthesized information. Application Implications for practice include providing summary overview displays, explicitly supporting role-based communication and coordination through HIT, and reducing the risk to reputation due to electronic monitoring of individual performance. PMID- 29533683 TI - Platelet toll-like receptors are crucial sensors of infectious danger moieties. AB - In addition to their haemostatic role and function in the repair of damaged vascular epithelium, platelets play a defensive role in innate immunity, having the capacity to produce and secrete various anti-infectious factors, as well as cytokines, chemokines and related products, to interact with other immune cells to modulate immune responses to pathogens. Thus, it is now widely acknowledged that platelets participate in inflammatory processes and infection resolution, most notably by expressing and using receptors to bind infectious pathogen moieties and contributing to pathogen clearance. The ability of platelets to sense external danger signals relates to the expression of certain innate immunity receptors, such as toll-like receptors (TLRs), and the activation of efficient cell signalling machinery. TLR engagement triggers platelet response, which results in adapted degranulation according to: the type of TLR engaged, the nature of the ligand and the milieu; together, the TLR-mediated event and other signalling events may be followed by aggregation. Platelets thus use complex tools to mediate a whole range of functions upon sensing danger. By linking the inflammatory and haemostatic platelet response to infection, TLRs play a central role. The extent of the inflammatory response to pathogen clearance is still a debatable issue and is discussed in this short review. PMID- 29533684 TI - Examining Hookah as an Introduction to Nicotine Products among College Students. AB - BACKGROUND: Limited data exist on what young adults report as their first-ever nicotine product; some evidence suggests that they report hookah as their first product smoked. OBJECTIVES: This study reports on the first nicotine product used among undergraduates who had ever tried tobacco, and explores correlates of hookah as that first product. METHODS: Participants included a convenience sample of undergraduate students (n = 1538) at four universities in upstate New York during fall 2013. Descriptive statistics assessed first nicotine product used and prevalence of current use. Logistic regression was used to examine correlates of hookah as the first nicotine product used. RESULTS: Among the 832 students who reported ever use of any nicotine product, 25.4% reported hookah as their first product smoked; only combustible cigarettes (39.5%) were reported more frequently. Among students who ever smoked cigarettes, most reported cigarettes as their introductory product. Among students who never smoked cigarettes, nearly half reported hookah as their introductory product. Among ever nicotine users, current hookah smoking was common (34.9%), and greater than current e-cigarette (25.9%) and current combustible cigarette (26.4%) use. Never users of cigarettes, females, and non-Hispanic African Americans, had higher adjusted odds of reporting hookah as their introductory product. CONCLUSIONS: The results of this study have implications for the identification of risk factors for tobacco initiation, the assessment of tobacco use patterns and behaviors, and the tailoring of tobacco prevention initiatives among youth. Our findings suggest that broadening prevention efforts beyond a focus on combustible cigarettes may be warranted. PMID- 29533685 TI - Mentoring Program for Young Adults with Sickle Cell Disease. AB - Using descriptive case studies, this paper describes a short-term mentoring program using goal attainment scaling for young adults with sickle cell disease (SCD). Two participants received three and seven visits, respectively, before dropping out of the program with no significant change in goal attainment scores. Although the program supported meaningful individualized goals, repeated and cumulative effects of hospitalizations, sickle cell pain episodes, family health issues, unsafe location of residence, and transportation appeared to remain significant barriers for to achieve stated goals. While the value of an individualized, community-based mentoring experience that addresses goal attainment remains unanswered, this project documents the complex and health barriers of young adults living with SCD. PMID- 29533686 TI - Effects of a Multi-Ingredient Energy Supplement on Cognitive Performance and Cerebral-Cortical Activation. AB - This study assessed whether a multi-ingredient energy supplement (MIES) could enhance cerebral-cortical activation and cognitive performance during an attention-switching task. Cerebral-cortical activation was recorded in 24 young adults (12 males, 12 females; 22.8 +/- 3.8 yrs) via electroencephalography (EEG) both at rest and during the attention-switching task before (pretest) and 30 min after (posttest) consumption of a single serving of a MIES (MIES-1), two servings of a MIES (MIES-2), or a placebo (PL) in a double-blinded, randomized crossover experimental design. EEG upper-alpha power was assessed at rest and during the task, wherein d' (Z[hit rate]-Z[false alarm rate]) and median reaction time (RT) for correct responses to targets on attention-hold and attention-switch trials were analyzed. For both d' and RT, the Session (MIES-1, MIES-2, PL) * Time (pretest, posttest) interaction approached statistical significance (p = .07, eta2p = 0.106). Exploring these interactions with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (ps <=.034), suggesting the pretest-to-posttest improvement in sensitivity to task target stimuli (d') and RT increased as a function of supplement dose. With respect to upper-alpha power, the Session * Time interaction was significant (p < .001, eta2p = 0.422). Exploring this interaction with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (p < .001), suggesting pretest-to-posttest increases in cerebral cortical activation were a function of supplement dose. In conclusion, our findings suggest that MIES can increase cerebral-cortical activation and RT during task performance while increasing sensitivity to target stimuli in a dose dependent manner. PMID- 29533687 TI - Assessment of Tear Functions in Patients with Acne Rosacea without Meibomian Gland Dysfunction. AB - PURPOSE: To evaluate the results of tear functions in acne rosacea. METHODS: This prospective study includes 64 eyes of 32 acne rosacea patients without blepharitis and meibomian gland dysfunction and 90 eyes of 45 patients as control group. Tear functions of all were evaluated with ocular surface disease index (OSDI) questionnaire, and measurements of tear osmolarity were performed by using TearLab, Schirmer I tests without anesthesia and fluorescein tear break-up time (TBUT). RESULTS: The mean Schirmer test result was 12.53 +/- 6.54 in study group and 16.21 + 7.52 mm/5 min in control group (p = 0.28). The mean TBUT in study group was 8.21 +/- 4.01 and in control group was 18.03 +/- 6.45 s (p = 0.02). Mean tear osmolarity in study group was 304.77 +/- 15.59and in control group was 275.23 + 28.52 mOsms/L (p = 0.03). Mean OSDI score in study group was 27.51 +/- 16.73 and was 18.15 +/- 7.05 in control group (p = 0.38). CONCLUSIONS: Our study demonstrated lower dry eye tests before the appearance of clinical signs of meibomian gland disease in acne rosacea. PMID- 29533688 TI - Relationship between breastfeeding and asthma prevalence in young children exposed to adverse childhood experiences. AB - OBJECTIVE: To investigate if duration of supplemental breastfeeding is associated with a lower asthma risk and whether adverse childhood experiences (ACEs) early in life influence this relationship in children ages 3 to 5 years. METHODS: Data were from the 2011-2012 National Survey of Children's Health, a nationally representative cross-sectional survey. Modified Poisson regression models were used to estimate incident risk ratios (IRR) for lifetime and current asthma in young children aged 3 to 5 years (n = 15,642). We tested for effect measure modification using stratified analyses. RESULTS: Exclusive breastfeeding for at least 6 months or supplemental breastfeeding for children >=12 months significantly reduced the risk of lifetime asthma prevalence compared to never breastfed children (IRR 0.64; 95% CI: 0.46-0.88, p = 0.007; and IRR 0.68; 95% CI: 0.47-0.99, p = 0.044, respectively), adjusted for covariates. In stratified analyses, breastfeeding reduced the risk of lifetime asthma for children who experienced 1 ACE but not for children who experienced 2 or more ACEs. CONCLUSION: Exclusive breastfeeding for at least 6 months, with and without supplementation, appears to prevent asthma or delay its onset. The protective effect of breastfeeding was attenuated among children who experienced more than 2 ACEs. The known harmful effects that ACEs have on children's health may outweigh the benefits of breastfeeding in reducing the risk of a child developing asthma. Understanding how specific time periods in a child's life may be most affected by exposure to early life adversities, along with the protective effect of breastfeeding against asthma, are important areas of further study. PMID- 29533689 TI - Effects of Arthroscopy for Femoroacetabular Impingement Syndrome on Quality of Life and Economic Outcomes. AB - BACKGROUND: The diagnosis and treatment of femoroacetabular impingement (FAI) have increased steadily within the past decade, and research indicates clinically significant improvements after treatment of FAI with hip arthroscopy. PURPOSE: This study examined the societal and economic impact of hip arthroscopy by high volume surgeons for patients with FAI syndrome aged <50 years with noncontroversial diagnosis and indications for surgery. STUDY DESIGN: Economic and decision analysis; Level of evidence, 2. METHODS: The cost-effectiveness of hip arthroscopy versus nonoperative treatment was evaluated by calculating direct and indirect treatment costs. Direct cost was calculated with Current Procedural Terminology medical codes associated with FAI treatment. Indirect cost was measured with the patient-reported data of 102 patients who underwent arthroscopy and from the reimbursement records of 32,143 individuals between the ages of 16 and 79 years who had information in a private insurance claims data set contained within the PearlDiver Patient Records Database. The indirect economic benefits of hip arthroscopy were inferred through regression analysis to estimate the statistical relationship between functional status and productivity. A simulation based approach was then used to estimate the change in productivity associated with the change in functional status observed in the treatment cohort between baseline and follow-up. To analyze cost-effectiveness, 1-, 2-, and 3-way sensitivity analyses were performed on all variables in the model, and Monte Carlo analysis evaluated the impact of uncertainty in the model assumptions. RESULTS: Analysis of indirect costs identified a statistically significant increase of mean aggregate productivity of $8968 after surgery. Cost effectiveness analysis showed a mean cumulative total 10-year societal savings of $67,418 per patient from hip arthroscopy versus nonoperative treatment. Hip arthroscopy also conferred a gain of 2.03 quality-adjusted life years over this period. The mean cost for hip arthroscopy was estimated at $23,120 +/- $10,279, and the mean cost of nonoperative treatment was estimated at $91,602 +/- $14,675. In 99% of trials, hip arthroscopy was recognized as the preferred cost-effective strategy. CONCLUSION: FAI syndrome produces a substantial economic burden on society that may be reduced through the indirect cost savings and economic benefits from hip arthroscopy. PMID- 29533690 TI - Nurses' Experiences of Assessing Suicide Risk in Specialised Mental Health Outpatient Care in Rural Areas. AB - This study describes nurses' experiences of assessing suicide risk in specialised mental health outpatient care in rural areas in Sweden. We used a qualitative, descriptive design based on twelve interviews that were subjected to qualitative content analysis. The results showed that the nurses felt anguish due to a lack of control. They expressed uncertainty and loneliness, and they struggled with ethical issues and organisational challenges. Having the sole responsibility to assess suicide risk can increase a person's emotional vulnerability and moral stress. Consequently, in order to prevent ill health among these nurses, there is a need for a tolerant work climate and an organisation that provides support to its employees. Assessing suicide risk is a demanding task within mental health outpatient care. Further, nurses operating in rural areas have to initiate and conduct assessments on their own, and they are, together with the physician in charge, also held individually responsible for their assessments. Consequently, it is important to describe nurses' experiences of how they deal with questions concerning suicide risk. Their experiences can foster awareness of the responsibility and the ethical standpoints related to assessing suicide risk, can help outline the need for further education and supervision, and can improve support from co-workers and management. PMID- 29533691 TI - Urinary neutrophil gelatinase-associated lipocalin as a marker for disease activity in lupus nephritis. AB - The neutrophil gelatinase-associated lipocalin (NGAL) has been emerging as a novel biomarker of acute kidney injury while its value in lupus nephritis is uncertain. The aim of this study was to assess urinary NGAL levels as a marker for disease activity in patients with lupus nephritis.This study included 70 systemic lupus erythematosus (SLE) patients; 50 with active lupus nephritis (LN) and 20 without as well as 20 matched controls. The neutrophil gelatinase associated lipocalin (NGAL) in both serum and urine samples was measured by enzyme-linked immunosorbent assay (ELISA). Patients with active LN received standard treatment then assessed for response as well as the value of urinary NGAL (uNGAL). Our results revealed that, The SLE patients with or without LN had an elevated urinary NGAL as compared to controls (p < 0.000) and the mean of uNGAL was (20.67 +/- 5.34),(10.63 +/- 3.53),(5.65 +/- 2.49) respectively. Furthermore,Urinary NGAL levels in LN patients were significantly higher than those in non-LN patients (P < 0.0001). In the ROC curve analysis , the diagnostic performance of uNGAL for discriminating patients with nephritis from those without nephritis showed that the best cutoff value was 13.66 ng/ml ,sensitivity 92%,specificity 75%,area undercurve (0.959) and (P < 0.0001). Measurement of urinary NGAL levels showed an excellent diagnostic performance for discriminating patients with LN from SLE without nephritis. PMID- 29533692 TI - Comparing the effect of pulmonary rehabilitation in patients with uncontrolled and partially controlled asthma. AB - OBJECTIVE: Pulmonary rehabilitation (PR) is an important therapeutic approach in asthmatic patients. Lack of asthma control is associated with high morbidity, poor health outcomes, and decrease in quality of life (QOL). However, there is no clear information about the effectiveness of PR in patients with differing levels of asthma control. This study aimed to compare the efficacy of PR in patients with uncontrolled and partially controlled asthma. METHODS: Before undergoing an 8-week outpatient PR program, patients were classified according to the asthma control test (ACT) as having partially controlled asthma or uncontrolled asthma. Changes in asthma control, exercise capacity, dyspnea perception, pulmonary function tests, arterial blood gas analysis, QOL, and psychological symptoms before and after PR were compared between groups. RESULTS: A total of 49 patients, 21 of whom were in partially controlled and the rest 28 were in uncontrolled asthma, participated in the study. After PR, asthma control perceived dyspnea, exercise capacity, QOL, anxiety, and depression significantly improved in both groups (p < 0.05). When the two groups were compared in terms of the benefits of PR, the improvement in ACT score was significantly greater in patients with uncontrolled asthma than in partially controlled asthma (p < 0.001), whereas the improvements in other parameters were similar between groups (p > 0.05). CONCLUSIONS: Improvement in asthma control is greater in patients with uncontrolled asthma than in patients with partially controlled asthma after PR. Therefore, patients with uncontrolled asthma, in particular, should be given opportunities to benefit from PR programs. PMID- 29533693 TI - Antihypertensive activity of fish protein hydrolysates and its peptides. AB - The rising interest to utilize nutritionally exorbitant fish proteins has instigated research activities in fish waste utilization. The development of newer technologies to utilize fish waste has fostered use of bioactive value added products for specific health benefits. Enzymatically obtained Fish Protein Hydrolysate (FPH) is a rich source of biologically active peptides possessing anti-oxidant, anticancer, antimicrobial and anti-hypertensive activity. Isolating natural remedies to combat alarming negative consequences of synthetic drugs has been the new trend in current research promoting identification of antihypertensive peptides from FPH. In this review, we aim to culminate data available to produce antihypertensive peptides from FPH, its composition and potential to be used as a therapeutic agent. These purified peptides are known to be rich in arginine, valine and leucine. Reports reveal peptides with low molecular weight (<1 kDa) and shorter chain length (<20 amino acids) exhibited higher antihypertensive activity. As these peptides have proven Angiotensin Converting Enzyme - I inhibitory activity in vitro and in vivo, their potential to be used as antihypertensive drugs is outrageous. However, current focus on research in the field of molecular docking is necessary to have improved understanding of interaction of the peptides with the enzyme. PMID- 29533694 TI - Development and validation of a claims-based approach to proxy ECOG performance status across ten tumor groups. AB - AIM: To develop a claims-based prediction model of poor performance status (PS) in commercially insured and Medicare supplemental beneficiaries with cancer. PATIENTS & METHODS: Retrospective analysis was conducted of electronic medical records (EMR) from community oncology practices linked to MarketScan claims. Multivariable logistic regression predicted PS scores from the EMR using claims based diagnostic and procedure codes. RESULTS: The study included 8442 patients diagnosed with cancer from 2007 to 2015. Overall, 8.1% of patients had poor EMR based PS. Bootstrapping results from the final model showed sensitivity and specificity of approximately 75% with a predicted probability cutpoint = 0.078, c statistic = 0.821 and pseudo-R2 = 0.25. CONCLUSION: Patients with poor PS can be identified in claims data. This prediction model enables future studies evaluating cancer treatments and outcomes to account for PS. PMID- 29533695 TI - Labial Incompetence in Mobius Syndrome: LeFort I Impaction Case Report and Review of Management Strategies. AB - Difficulty with speech intelligibility in Mobius syndrome patients due to bilabial incompetence is common yet rarely discussed. We present a patient with Mobius syndrome who underwent counterclockwise LeFort I impaction to improve her labial competence. In addition, we present a literature review of management strategies for labial incompetence correction in Mobius patients. At 7-year follow-up after LeFort 1 impaction, the patient reports improvement in speech intelligibility, specifically regarding the ability to pronounce bilabial consonants. This is the first published report of LeFort I impaction to improve labial competence and bilabial consonant pronunciation in a Mobius syndrome patient. PMID- 29533696 TI - Efficacy of Maxillary Anterior Segmental Distraction Osteogenesis in Patients With Cleft Lip and Palate. AB - OBJECTIVES: To evaluate the effects of maxillary anterior segmental distraction osteogenesis (MASDO) in patients with cleft lip and palate (CLP) and to identify risk factors for increased relapse. DESIGN: A retrospective study. PATIENTS: Thirty-one Japanese patients with CLP who underwent MASDO were eligible for study inclusion. MAIN OUTCOME MEASURES: We evaluated lateral cephalograms obtained before (T1), at 3 months (T2), and at 1 year (T3) after MASDO, and measured changes from T1 to T2 (deltaT1T2), from T2 to T3 (deltaT2T3), and from T1 to T3 (deltaT1T3). We also evaluated the risk factors associated with an increased relapse. RESULTS: Overall (deltaT1T3), MASDO improved retrusion of the maxilla. We measured a significant advancement (6.1 mm) of the anterior maxillary segment in deltaT1T2 (A-McNamara classification) and increases in the overjet and the SNA, ANB, and nasolabial angles. However, skeletal relapse was evident in deltaT2T3, and the median percentage of relapse was 10%. To explore the risk factors, we subdivided patients with a deltaT1T2 of >5 mm into 2 groups based on the percentage of relapse (>15% vs <=15%). There were significant differences between these groups in the vertical positions of the anterior nasal spine and point A, and the angle formed by the SN and palatal planes (SNPP), suggestive of intraoperative counterclockwise rotation of the maxilla. CONCLUSIONS: MASDO is effective for correcting midfacial deficiencies, but counterclockwise rotation of the maxilla during surgery may cause relapse. PMID- 29533698 TI - Evidence-Based Medicine in Otolaryngology, Part 8: Shared Decision Making-Impact, Incentives, and Instruments. AB - In our previous installment, we introduced shared decision making (SDM) as a collaborative process in which patients, families, and clinicians develop a mutually optimized treatment plan when more than 1 reasonable treatment option exists. In this subsequent installment of our Evidence-Based Medicine in Otolaryngology Series, we expand on the topic of SDM, including the related current state of clinical decision making, the impact of SDM on health care utilization and patient satisfaction, the potential role of system and society changes, the experience with SDM as it relates to race and ethnicity, existing financial incentives, and the validated instruments that assess the extent to which SDM occurs. PMID- 29533699 TI - Adverse Events and Time to Diagnosis of In-Office Laryngeal Biopsy Procedures. AB - Objective To examine the adverse events and time to diagnosis of in-office laryngeal biopsy (IOB) procedures. Study Design Retrospective cohort study. Setting Outpatient clinic-tertiary referral medical center. Subjects and Methods A total of 390 IOBs were included in this study. Data on demographic characteristics, outcomes, and complications were collected. Complications were classified as severe-necessitating further intervention or admission-or mild and self-limited. Delay in diagnosis, assessed as a complication of IOB, was calculated as the time from initial examination to final diagnosis. Results Of 390 IOBs, 4 (1%) had complications: epistaxis (n = 2), vocal fold hematoma (n = 1), and aspiration event (n = 1). There were no reports of complications at follow-up. The sensitivity of IOB versus direct laryngoscopy biopsies was 77.8%, and the specificity was 95.1%. When the IOB showed malignancy as a final diagnosis, time to diagnosis was 10.7 days (95% CI, 8.6-12.8). When IOB pathology results changed from benign or carcinoma in situ to malignant (squamous cell carcinoma) by direct laryngoscopy, time to diagnosis was longer: 49.1 days (95% CI, 38.1-60.1) and 36.1 days (95% CI, 15.1-57.1; P < .05), respectively. Conclusions In this cohort, IOBs appear to be free of significant adverse events. IOBs for suspicious laryngeal lesions shorten the time to diagnosis and treatment for the majority of patients; the minority showed a small and insignificant delay. PMID- 29533700 TI - Achieving a Successful Closure of an Anterior Tympanic Membrane Perforation: Evidence-Based Systematic Review. AB - Objectives Surgical repair of a tympanic membrane perforation is a common otologic procedure. However, achieving a successful closure can be challenging, especially if the anterior margin of the tympanic membrane is involved. The aim of this study was to systematically review the literature on evidence published in closure of anterior tympanic membrane perforations. Data Sources The following data sources were searched: Cochrane Central Register of Controlled Trials (1997 to August, 3 2017), MEDLINE (February 1948 to August 3, 2017), and Embase (1975 to August 3, 2017). Data Extraction Two authors independently reviewed titles and abstracts. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta analyses) guidelines were followed. For the purpose of this study, the inclusion criteria were as follows; (1) studies reporting surgical technique for closure of anterior tympanic membrane perforations, (2) primary cases only, (3) articles published in the English language, (4) minimum 6-month follow-up, and (5) recorded pre- and postoperative audiometry. The exclusion criteria were non English language articles, revision surgery, and no audiometric outcomes. Results On initial search, a total of 181 articles were identified (PubMed, n = 136; Cochrane, n = 28; Embase, n = 17). Based on the criteria, 136 articles were excluded. Full text of 45 articles was reviewed, and a further 24 articles were excluded. A total of 21 articles fulfilled the criteria for study inclusion. Conclusions All published evidence is level 4. High-quality controlled studies are required to determine the most effective method for closure of anterior tympanic membrane perforation. PMID- 29533701 TI - Staying Well in a Sea of Harm. AB - Physician psychological wellness is an emergent outcome resulting from dynamic interactions among complex conditions. We may enhance opportunities for physician wellness by applying principles developed to improve another emergent outcome: patient safety. The Safety I approach to patient safety focuses on "what went wrong" and considers humans a liability. Safety II is a powerful complementary approach that focuses on "what went right" and values human creativity. These contrasting perspectives are described in the context of patient safety, but the underlying principles have relevance for physician psychological wellness. We can create conditions that interfere with wellness and conditions that support wellness. We can learn from exploring and reinforcing successes and improving routine processes; together, these approaches may have a greater cumulative positive impact than just addressing problems. In addition to learning from failures, there is much we can learn from success. PMID- 29533702 TI - Adsorption of leather dyes on activated carbon from leather shaving wastes: kinetics, equilibrium and thermodynamics studies. AB - In this work, the adsorption of Acid Black 210 (AB210) and Acid Red 357 (AR357) onto activated carbon prepared from leather shaving wastes (ACLW) was investigated. The activated carbon presented a surface area of 800.4 m2/g with an average pore size of 1.27 nm. The kinetic study showed that the adsorption of both dyes followed the Elovich kinetic model while the AB210 and AR357 isotherm data were well described by the Langmuir and BET models, respectively. Furthermore, the Boyd plot revealed that the adsorption of the leather dyes on activated carbon was mainly governed by film diffusion. The pH had a strong influence on the adsorption, and the higher amounts of dye adsorbed were obtained at pH 2. The obtained activated carbon exhibited a high monolayer adsorption capacity of 573.9 and 204.4 mg/g for AB210 and AR357, respectively. Its high capacity is mainly attributed to its basicity (0.17 mmol/g) and high surface area. Desorption efficiency of the spent activated carbon was found to be 54.3% and 43.0% for AB210 and AR357, respectively. The spontaneity of the process was demonstrated by the negative values of the Gibbs free energy change. PMID- 29533705 TI - Corrigendum. PMID- 29533704 TI - Friends With Health Benefits: The Long-Term Benefits of Early Peer Social Integration for Blood Pressure and Obesity in Midlife. AB - In adults, greater social integration is associated with reduced risk of cardiovascular disease, including hypertension. Social integration earlier in life may be similarly associated with cardiovascular risk. Using a longitudinal sample of 267 Black and White men, we examined whether greater social integration with peers during childhood and adolescence, assessed by parent report, prospectively predicts lower blood pressure and body mass index two decades later in adulthood and whether these effects differ by race, given well-documented racial disparities in hypertension. Boys who were reported by their parents to be more socially integrated with peers evidenced lower blood pressure and body mass index in adulthood, and this effect was not accounted for by body mass index in childhood, childhood socioeconomic status, childhood hostility, childhood physical health, extraversion measured in adolescence, or concurrent adult self reports of social integration. Results did not differ by race, but analyses were not powered to detect interactions of small effect size. PMID- 29533706 TI - Management of Parotid Metastatic Cutaneous Squamous Cell Carcinoma: Regional Recurrence Rates and Survival. AB - Objectives Extent of parotidectomy and neck dissection for metastatic cutaneous squamous cell carcinoma (cSCC) to the parotid is debated. We describe our experience, analyzing outcomes (overall survival and regional recurrence) associated with surgical extent and adjuvant treatment. Study Design A retrospective cohort study of parotidectomy with or without neck dissection for metastatic cSCC. Setting A tertiary referral cancer center in Australia. Subjects and Methods The study group consisted of patients with metastatic cSCC involving the parotid gland who underwent a curative-intent parotidectomy (superficial or total), with or without neck dissection, between 2003 and 2014. Demographic and clinical data, treatment modalities, and outcome parameters were collected from the electronic institutional database. Results Of 78 patients, 65 underwent superficial parotidectomy. Median follow-up was 6.5 years. Sixty-four patients (82%) patients received adjuvant radiotherapy. Cervical lymph nodes were involved in 6 (24%) elective neck dissections. Involved preauricular, facial, external jugular, and occipital nodes occurred in 36.9%. Adjuvant radiotherapy was associated with improved 5-year survival-50% (95% CI, 36%-69%) versus 20% (95% CI, 6%-70%)-and improved 2-year regional control: 89% (95% CI, 67%-100%) versus 40% (95% CI, 14%-100%). The ipsilateral parotid bed recurrence rate was 3.7% for those who received adjuvant radiotherapy and 27% for those who did not receive radiotherapy. Conclusion This study supports surgery plus adjuvant radiotherapy as a standard of care for metastatic cSCC. The low incidence of parotid bed recurrence with this approach suggests that routine elective deep lobe resection may not be required. PMID- 29533703 TI - FUT2 genotype and secretory status are not associated with fecal microbial composition and inferred function in healthy subjects. AB - Heritability analysis of the microbiota has demonstrated the importance of host genotype in defining the human microbiota. The alpha (1,2)-fucosyltransferase 2 encoded by FUT2 is involved in the formation of the H antigen and the SNP, rs601338 is associated with ABO histo-blood group antigen secretion in the intestinal mucosa. Previous studies have provided non replicated results for the association of this polymorphism with the composition and inferred function of intestinal microbiota. We aimed to assess this relationship in a large cohort of 1,190 healthy individuals. Genotyping was performed using the HumanCoreEXOME chip, microbial composition was addressed by 16S rRNA gene sequencing. Firmicutes, Bacteroidetes, and Actinobacteria were the dominant phyla in this cohort. Although we have sufficient power to detect significant associations of FUT2 genotype/ inferred phenotype with the microbiota, our data demonstrate that FUT2 genotype and secretor status is not associated with microbial alpha diversity, microbial composition or inferred microbial function after correction for multiple testing. Thus, FUT2 genotype and inferred phenotype are not associated with human fecal microbial composition and imputed function. PMID- 29533707 TI - A comparison of aerobic granular sludge with conventional and compact biological treatment technologies. AB - The aerobic granular sludge (AGS) technology is growing towards becoming a mature option for new municipal wastewater treatment plants and capacity extensions. A process based on AGS was compared to conventional activated sludge processes (with and without enhanced biological phosphorus removal), an integrated fixed film activated sludge (IFAS) process and a membrane bioreactor (MBR) by estimating the land area demand (footprint), electricity demand and chemicals' consumption. The process alternatives compared included pre-settling, sludge digestion and necessary post-treatment to achieve effluent concentrations of 8 mg/L nitrogen and 0.2 mg/L phosphorus at 7 degrees C. The alternative based on AGS was estimated to have a 40-50% smaller footprint and 23% less electricity requirement than conventional activated sludge. In relation to the other compact treatment options IFAS and MBR, the AGS process had an estimated electricity usage that was 35-70% lower. This suggests a favourable potential for processes based on AGS although more available experience of AGS operation and performance at full scale is desired. PMID- 29533708 TI - Has there been an increase in the frequency with which people who drink in a risky fashion receive advice to cut down on their drinking from 1998 to 2015? AB - BACKGROUND: To assess whether there has been an increase over time in the proportion of people who drink in a risky fashion, who receive expressions of concern about their drinking or advice to cut down. METHODS: Secondary analysis of the Centre for Addiction and Mental Health (CAMH) Monitor population survey, conducted annually in Ontario (participants: 18 or older) and with relevant data available from 1998 to 2015 (N = 48,124). The proportions of participants who drank above weekly low-risk drinking levels (approximated as 15 or more drinks for males and 11 or more for females) who reported receiving expressions of concern about their drinking or advice to cut down were compared between the time periods 1998-2004, 2005-2010, and 2011-2015. Further, proportions were broken down by age group and participant sex. RESULTS: Overall, there were low rates of participants who reported receiving advice about their drinking (16.8% of those drinking above weekly drinking levels) and no evidence of an increase across time, except among males, 34 years and under. Females drinking beyond recommended weekly guidelines were less likely than males to receive advice (11.7% versus 19.3%, respectively; P < .001). Further, older participants drinking beyond weekly guidelines were less likely than younger participants to receive advice (18-34: 16.9%; 35-54: 20.3%; 55 or older: 12.9%; P = .012). CONCLUSIONS: Given that heavy alcohol consumption is a significant contributor to the preventable burden of disease, increased emphasis is merited on finding ways to increase the frequency with which people who drink in a risky fashion receive advice to cut down. PMID- 29533709 TI - Erratum. AB - Grecchi E, Veronese M, Bodini B, et al. Multimodal partial volume correction: Application to [11C]PIB PET/MRI myelin imaging in multiple sclerosis. J Cereb Blood Flow Metab 2017; 37: 3803-3817. Three references in the above article appeared with typesetting coding when published online and in print. The references should have appeared as follows: 8. Aston JAD, Cunningham VJ, Asselin M-C, et al. Positron emission tomography partial volume correction: estimation and algorithms. J Cereb Blood Flow Metab 2002; 22: 1019-1034. 20. Veronese M, Bodini B, Garcia-Lorenzo D, et al. Quantification of [11C]PIB PET for imaging myelin in the human brain: a test-retest reproducibility study in high-resolution research tomography. J Cereb Blood Flow Metab 2015; 35: 1771-1782. 30. Ikoma Y, Edison P, Ramlackhansingh A, et al. Reference region automatic extraction in dynamic [11C]PIB. J Cereb Blood Flow Metab 2013; 33: 1725-1731. PMID- 29533711 TI - Clinical results of a new concept of neurothrombectomy coverage at a remote hospital-"drive the doctor". AB - Background Many tertiary care hospitals cannot provide a continuous thrombectomy service due to the lack of a neurointerventionalist. Aims In this study, we present procedural and clinical results of a new concept in which neuroradiologists of a university hospital provide neurointerventional stroke service to a remote hospital ("drive the doctor"). Methods All consecutive patients with acute ischemic stroke due to large vessel occlusion of the anterior circulation treated with mechanical thrombectomy after hours at a remote hospital (distance of about 100 km) between 2012 and 2016 were analyzed retrospectively. These patients were compared to a group of patients referred to the above mentioned university hospital for MT over a comparable distance ("drip and ship"). Results A total of 60 patients were treated by "drive the doctor" and 66 patients were treated by "drip and ship." Time from onset to imaging was similar in both groups (77 vs. 70 min, P = 0.6847). However, time from imaging to groin puncture was significantly lower in the "drive the doctor" model (112 vs. 232 min, P < 0.0001). Nonetheless, recanalization rate and clinical outcome were similar in both cohorts. Conclusions "Drive the doctor" is a feasible concept of neurothrombectomy coverage at remote hospitals. The presented data suggest that "drive the doctor" is not inferior compared to established stroke concepts such as "drip and ship" regarding recanalization rate and outcome. However, larger and prospective studies are necessary to confirm this finding. PMID- 29533710 TI - A Food-Derived Dietary Supplement Containing a Low Dose of Iron Improved Markers of Iron Status Among Nonanemic Iron-Deficient Women. AB - OBJECTIVE: Iron deficiency is the most common nutrient deficiency in the world. While deficiency can often be resolved through dietary supplementation with iron, adverse events are common and frequently preclude compliance. The objective of this study was to determine whether a food-derived dietary supplement containing a low dose of iron and nutrients that increase iron absorption could resolve iron deficiency with fewer adverse events than reported at higher doses. METHODS: A pilot clinical trial (NCT02683369) was conducted among premenopausal women with nonanemic iron deficiency that was verified by blood screening. Participants consumed a dietary supplement (Blood Builder(r)/Iron Response(r)) once daily for 8 weeks containing 26 mg of iron, vitamin C, folate, and other food-derived nutrients. Primary outcomes were markers of iron status (serum ferritin, hemoglobin, soluble transferrin receptor, total body iron stores) and secondary outcomes were self-reported fatigue and energy. All outcomes were assessed at baseline and 8 weeks. Adverse events were monitored with questionnaires, daily diaries, and contact with a physician. Dependent samples t test and Wilcoxon signed-rank test were used to analyze outcomes. RESULTS: Twenty-three participants enrolled in the study. Iron deficiency was resolved in the sample (mean serum ferritin: baseline = 13.9 MUg/L, 8 weeks = 21.1 MUg/L, p < 0.001). All other markers of iron status, fatigue, and energy also improved during the study (p < 0.04). No adverse events were reported. CONCLUSIONS: While larger and controlled studies are needed to confirm these findings, a food-derived dietary supplement with a low dose of iron and absorption-enhancing nutrients resolved iron deficiency and improved all other markers of iron status without any adverse events. PMID- 29533712 TI - Voice and Swallowing Outcomes of Unilateral Vocal Fold Paralysis: Comparing Younger Adult and Geriatric Patients. AB - Objective To compare voice and swallowing outcomes after treatment in younger adult (<65 years) and geriatric (>=65 years) patients with unilateral vocal fold paralysis (UVFP). Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods The cases of patients presenting to a tertiary voice clinic with UVFP between June 2005 and February 2015 were reviewed. Clinical characteristics and outcomes in a geriatric subset were compared with those in younger adult group. Results A total of 206 patients met our inclusion criteria (n = 110, <65 years; n = 96, >=65 years). Etiology was most commonly iatrogenic (59.2%), and computed tomography led to diagnosis for 62.3% of patients for whom it was obtained. The Voice Handicap Index improved on average by 31.3 points after treatment ( P < .001), with equal improvement between the patient subsets ( P = .71). Swallowing, as objectively assessed by the National Outcomes Measurement System for modified barium swallow, showed a statistically significant improvement in the patient population as a whole (-0.9, P = .02) but was not significantly different within the subgroups (younger, P = .07; geriatric, P = .25). Conclusion Geriatric patients have similar voice and swallowing outcomes as younger adults and should be treated equally aggressive. PMID- 29533713 TI - ActivPALTM determined sedentary behaviour, physical activity and academic achievement in college students. AB - The aim of this study was to examine relationships between activPALTM-determined sedentary behavior (SB) and physical activity (PA) with academic achievement. A total of 120 undergraduates (N = 57 female; 20.6 +/- 2.3 years) participated in the study. Academic achievement was measured as the grade point average obtained from all completed courses. Participants wore on the right tight an activPALTM for 7 days to determine total sedentary time, total number of sedentary breaks, sedentary bouts, standing time, light and moderate-to-vigorous physical activity (MVPA). Separate multiple linear regression models were performed to examine associations between SB variables and academic achievement. Light PA, MVPA, total sedentary time, total standing time, or total number of sedentary breaks were not related to academic achievement. Independently of PA, the amount of time spent in sedentary bouts of 10-20min during weekdays was positively related to academic achievement. Given that college students spend the majority of their workday in environments that encourage prolonged sitting, these data suggest that interruptions in prolonged periods of sitting time every 10-20min via short breaks may optimize cognitive operations associated with academic performance. PMID- 29533714 TI - Assessment of contamination source and quality control approach for polycyclic aromatic hydrocarbons in wood-pressed rapeseed oil. AB - Contamination sources of polycyclic aromatic hydrocarbons (PAHs) in the raw material, oil production and storage processes of wood-pressed rapeseed oil were investigated in this study. The results showed that benzo[a]pyrene (BaP) and PAH4 (sum of BaP, benzo[a]fluoranthene, benzo[b]fluoranthene and chrysene) were unevenly distributed in the kernel (0.56-0.98 and 2.84-8.64 MUg/kg, respectively) and hull (1.53-3.17 and 13.49-22.31 MUg/kg, respectively) of the rapeseed raw materials. The contents of BaP and PAH4 continuously increased during the process of wood-pressed rapeseed oil, ranging from 2.21 to 10.93 and 9.36 to 40.03 MUg/kg, thus demonstrating that a wide range of pollution sources of PAHs existed for the test wood-pressed rapeseed oils. The initial temperature and time of roasting should be controlled at <210 degrees C and <60 min, due to the generation of PAHs in rapeseed by over-roasting. In addition, contact tools and substance such as lubricating oil (from the mill), heat-transfer oil (from roasting machine), rubber gaskets and straws should be properly screened. The BaP and PAH4 of rapeseed placed in the roasting area increased from 0.5 to 2.24 and from 2.08 to 9.03 MUg/kg, respectively. Therefore, roasting fume control and treatment systems are necessary and the roasting section should be strictly isolated from the other stages. Storage can slightly lower the PAHs amounts in the rapeseed oil, which made the contents of BaP and PAH4 decrease from 27.00 to 24.70 and from 138.63 to 117.58 MUg/kg, respectively. Quality control measures of PAHs in wood-pressed rapeseed oil were proposed and implemented, and the final oil products' BaP and PAH4 were kept below 2 and 10 MUg/kg, respectively, which meets the European Commission Regulation No. 835/2011. PMID- 29533715 TI - Differential effects of attentional focus strategies during long-term resistance training. AB - The purpose of this study was to investigate the effects of using an internal versus external focus of attention during resistance training on muscular adaptations. Thirty untrained college-aged men were randomly assigned to an internal focus group (INTERNAL) that focused on contracting the target muscle during training (n = 15) or an external focus group (EXTERNAL) that focused on the outcome of the lift (n = 15). Training for both routines consisted of 3 weekly sessions performed on non-consecutive days for 8 weeks. Subjects performed 4 sets of 8-12 repetitions per exercise. Changes in strength were assessed by six repetition maximum in the biceps curl and isometric maximal voluntary contraction in knee extension and elbow flexion. Changes in muscle thickness for the elbow flexors and quadriceps were assessed by ultrasound. Results show significantly greater increases in elbow flexor thickness in INTERNAL versus EXTERNAL (12.4% vs. 6.9%, respectively); similar changes were noted in quadriceps thickness. Isometric elbow flexion strength was greater for INTERNAL while isometric knee extension strength was greater for EXTERNAL, although neither reached statistical significance. The findings lend support to the use of a mind-muscle connection to enhance muscle hypertrophy. PMID- 29533716 TI - Five-year Clinical Evaluation of a Nanofilled and a Nanohybrid Composite in Class IV Cavities. AB - The purpose of this study was to evaluate a nanofilled and a nanohybrid composite, in combination with manufacturer-recommended etch-and-rinse adhesives, in class IV cavities. Thirty-four patients aged 14-46 years (mean age, 27.1 years) comprised the study group. Twenty-six patients received two class IV restorations and eight patients received four class IV restorations. For each patient, half the number of restorations were performed using a nanohybrid composite (Ceram X duo) and the remaining half used a nanofilled resin composite (Filtek Supreme XT), with two- (XP Bond) and three-step (Scotchbond Multipurpose) etch-and-rinse adhesives, respectively. Two experienced examiners evaluated the restorations for retention, color match, marginal discoloration, wear/loss of anatomic form, caries formation, marginal adaptation, and surface texture to compare the baseline (after placement) and annual recalls over 5 years. The cumulative success rates for the Filtek Supreme XT and Ceram X duo restorations after five years were 86.2% and 89.7%, respectively. Four Filtek Supreme XT and three Ceram X duo restorations failed. There was no statistically significant difference between the nanofilled and nanohybrid composites at any of the evaluation periods for any of the parameters evaluated. Despite the limited number of restorations, all restorations were clinically acceptable regarding retention, color match, marginal discoloration, wear or loss of anatomic form, the formation of caries, marginal adaptation, and surface texture, except the failed restorations. Fracture was the main cause of restoration failure. PMID- 29533717 TI - Does the Use of a "Walking Bleaching" Technique Increase Bone Resorption Markers? AB - OBJECTIVE: This randomized clinical trial evaluated the effect of 35% hydrogen peroxide in comparison with 37% carbamide peroxide in a nonvital bleaching technique of "walking bleaching" (four sessions of treatment) on periodontal markers: nuclear factor kappa B-ligand (RANK-L-process of root resorption marker) and interleukin 1beta (IL-1beta-inflammatory response marker). METHODS AND MATERIALS: Fifty volunteers presenting with discoloration of nonvital teeth and endodontic treatment in good condition participated. Fifty teeth were randomly divided into two study groups according to bleaching gel: HP = 35% hydrogen peroxide (n=25) and 37% carbamide peroxide (n=25). Nonvital bleaching was performed with a walking bleaching technique consisting of four sessions of bleach application. Gingival crevicular fluid samples were taken in order to quantify the RANK-L and IL-1beta levels by enzyme-linked immunosorbent assay. Samples were obtained from six periodontal sites for each bleached tooth: three vestibular and three palatine (mesial, middle, and distal) at seven time periods: baseline, after each of the four sessions of nonvital bleaching, at one week, and at one month after nonvital bleaching. Tooth color variations were analyzed in each session by VITA Bleachedguide 3D-MASTER (DeltaSGU). RESULTS: Significant increments in the RANK-L and IL-1beta levels were detected in each evaluated time compared with baseline ( p<0.05); however, no differences were detected between hydrogen peroxide and carbamide peroxide on increments of the biomarkers studied. The change of color was effective for both nonvital bleaching therapies ( p<0.05). CONCLUSIONS: Nonvital bleaching induced a significant increment in the RANK-L and IL-1beta levels in periodontal tissues around bleached, nonvital teeth. PMID- 29533718 TI - Monolithic Ceramics: Effect of Finishing Techniques on Surface Properties, Bacterial Adhesion and Cell Viability. AB - INTRODUCTION: This study evaluated the morphology, biofilm formation, and viability of human gingival fibroblasts in contact with two monolithic ceramics after two different finishing techniques: polishing or glazing. For this, 92 blocks (4.5 * 4.5 * 1.5 mm) of each ceramic were made using high translucency zirconia partially stabilized by yttrium (YZHT) and lithium silicate reinforced by zirconium (ZLS). METHODS AND MATERIALS: Blocks were sintered and then divided into glazing (g) or polishing (p) surface finish. Surface roughness (Ra and RSm) was evaluated through a contact rugosimeter and profilometry. Specimens were contaminated for heterotypic biofilm formation with Streptococcus mutans, Streptococcus sanguinis and Candida albicans for 16 hours. Biofilm was quantified by counting the colony forming units (CFU/mL) and analyzed by scanning electron microscopy (SEM). Fibroblast viability was evaluated by MTT assay. Surface free energy (SFE) was also determined. Roughness data were evaluated using nonparametric tests, while SFE, MTT and CFU results were evaluated by analysis of variance and Tukey test, and MTT data were also submitted to t-test (all, alpha=0.05). RESULTS: Results showed that polished samples presented a lower high profile mean ( p<0.001); however, YZHTg presented less space between defects ( p=0.0002). SFE showed that YZHT presented higher SFE than ZLS. Profilometry evidenced more homogeneity on polished surfaces. The interaction of finishing technique and microorganisms influenced the CFU ( p=0.00). MTT assay demonstrated initial severe cytotoxic behavior for polished surfaces. SEM images showed homogeneous surfaces, except for glazed YZHT. CONCLUSION: Glazed surfaces have a greater roughness and tend to accumulate more biofilm. Polished surfaces have higher SFE; however, they are temporarily cytotoxic. PMID- 29533719 TI - Viscoelastic Properties of Contemporary Bulk-fill Restoratives: A Dynamic mechanical Analysis. AB - This study investigated the viscoelastic properties of contemporary bulk-fill restoratives in distilled water and artificial saliva using dynamic mechanical analysis. The materials evaluated included a conventional composite (Filtek Z350), two bulk-fill composites (Filtek Bulk-fill and Tetric N Ceram), a bulk fill giomer (Beautifil-Bulk Restorative), and two novel reinforced glass ionomer cements (Zirconomer [ZR] and Equia Forte [EQ]). The glass ionomer materials were also assessed with and without resin coating (Equia Forte Coat). Test specimens 12 * 2 * 2 mm of the various materials were fabricated using customized stainless steel molds. After light polymerization/initial set, the specimens were removed from the molds, finished, measured, and conditioned in distilled water or artificial saliva at 37 degrees C for seven days. The materials (n=10) were then subjected to dynamic mechanical testing in flexure mode at 37 degrees C and a frequency of 0.1 to 10 Hz. Storage modulus, loss modulus, and loss tangent data were subjected to normality testing and statistical analysis using one-way analysis of variance/Dunnett's test and t-test at a significance level of p < 0.05. Mean storage modulus ranged from 3.16 +/- 0.25 to 8.98 +/- 0.44 GPa, while mean loss modulus ranged from 0.24 +/- 0.03 to 0.65 +/- 0.12 GPa for distilled water and artificial saliva. Values for loss tangent ranged from 45.7 +/- 7.33 to 134.2 +/- 12.36 (10-3). Significant differences in storage/loss modulus and loss tangent were observed between the various bulk-fill restoratives and two conditioning mediums. Storage modulus was significantly improved when EQ and ZR was not coated with resin. PMID- 29533720 TI - Impact of Handedness Consistency on Bimanual and Unimanual Continuous Movements. AB - Bimanual coordination is an essential human function requiring efficient interhemispheric communication to produce coordinated movements. Previous research suggests a "bimanual advantage" phenomenon, where completing synchronized bimanual tasks results in less variability than unimanual tasks. Additionally, of hand dominance has been shown to influence coordinated performance. The present study examined the bimanual advantage in individuals with consistent and inconsistent handedness. It was predicted that participants with consistent handedness would not display a bimanual advantage unlike those with inconsistent handedness. Fifty-six young adults completed a finger-tapping paradigm in five conditions: unimanual tapping with either left or right hand, in phase bimanual tapping, and out-of phase bimanual tapping led by either left or right hand. Results were not consistent with the hypothesis that participants with consistent handedness displayed the "bimanual advantage". However, the "bimanual advantage" was not evident for the inconsistent handers when the temporal consistency was measured with either the left or right hand only. Overall, the "bimanual advantage" may be dependent upon consistency of hand preference, as well as the direction of hand dominance. PMID- 29533721 TI - Prediction of Response to Neoadjuvant Chemotherapy and Radiation Therapy with Baseline and Restaging 18F-FDG PET Imaging Biomarkers in Patients with Esophageal Cancer. AB - Purpose To assess the value of baseline and restaging fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) radiomics in predicting pathologic complete response to neoadjuvant chemotherapy and radiation therapy (NCRT) in patients with locally advanced esophageal cancer. Materials and Methods In this retrospective study, 73 patients with histologic analysis confirmed T1/N1-3/M0 or T2-4a/N0-3/M0 esophageal cancer were treated with NCRT followed by surgery (Chemoradiotherapy for Esophageal Cancer followed by Surgery Study regimen) between October 2014 and August 2017. Clinical variables and radiomic features from baseline and restaging 18F-FDG PET were selected by univariable logistic regression and least absolute shrinkage and selection operator. The selected variables were used to fit a multivariable logistic regression model, which was internally validated by using bootstrap resampling with 20 000 replicates. The performance of this model was compared with reference prediction models composed of maximum standardized uptake value metrics, clinical variables, and maximum standardized uptake value at baseline NCRT radiomic features. Outcome was defined as complete versus incomplete pathologic response (tumor regression grade 1 vs 2-5 according to the Mandard classification). Results Pathologic response was complete in 16 patients (21.9%) and incomplete in 57 patients (78.1%). A prediction model combining clinical T-stage and restaging NCRT (post-NCRT) joint maximum (quantifying image orderliness) yielded an optimism-corrected area under the receiver operating characteristics curve of 0.81. Post-NCRT joint maximum was replaceable with five other redundant post-NCRT radiomic features that provided equal model performance. All reference prediction models exhibited substantially lower discriminatory accuracy. Conclusion The combination of clinical T-staging and quantitative assessment of post-NCRT 18F FDG PET orderliness (joint maximum) provided high discriminatory accuracy in predicting pathologic complete response in patients with esophageal cancer. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29533722 TI - Computer-aided Volumetry of Part-Solid Lung Cancers by Using CT: Solid Component Size Predicts Prognosis. AB - Purpose To investigate the relationship between the postoperative prognosis of patients with part-solid non-small cell lung cancer and the solid component size acquired by using three-dimensional (3D) volumetry software on multidetector computed tomographic (CT) images. Materials and Methods A retrospective study by using preoperative multidetector CT data with 0.5-mm section thickness, clinical records, and pathologic reports of 96 patients with primary subsolid non-small cell lung cancer (47 men and 49 women; mean age +/- standard deviation, 66 years +/- 8) were reviewed. Two radiologists measured the two-dimensional (2D) maximal solid size of each nodule on an axial image (hereafter, 2D MSSA), the 3D maximal solid size on multiplanar reconstructed images (hereafter, 3D MSSMPR), and the 3D solid volume of greater than 0 HU (hereafter, 3D SV0HU) within each nodule. The correlations between the postoperative recurrence and the effects of clinical and pathologic characteristics, 2D MSSA, 3D MSSMPR, and 3D SV0HU as prognostic imaging biomarkers were assessed by using a Cox proportional hazards model. Results For the prediction of postoperative recurrence, the area under the receiver operating characteristics curve was 0.796 (95% confidence interval: 0.692, 0.900) for 2D MSSA, 0.776 (95% confidence interval: 0.667, 0.886) for 3D MSSMPR, and 0.835 (95% confidence interval: 0.749, 0.922) for 3D SV0HU. The optimal cutoff value for 3D SV0HU for predicting tumor recurrence was 0.54 cm3, with a sensitivity of 0.933 (95% confidence interval: 0.679, 0.998) and a specificity of 0.716 (95% confidence interval: 0.605, 0.811) for the recurrence. Significant predictive factors for disease-free survival were 3D SV0HU greater than or equal to 0.54 cm3 (hazard ratio, 6.61; P = .001) and lymphatic and/or vascular invasion derived from histopathologic analysis (hazard ratio, 2.96; P = .040). Conclusion The measurement of 3D SV0HU predicted the postoperative prognosis of patients with part-solid lung cancer more accurately than did 2D MSSA and 3D MSSMPR. (c) RSNA, 2018. PMID- 29533723 TI - Dentate Nucleus Signal Intensity Decrease on T1-weighted MR Images after Switching from Gadopentetate Dimeglumine to Gadobutrol. AB - Purpose To determine if the increased dentate nucleus signal intensity following six or more doses of a linear gadolinium-based contrast agent (GBCA) (gadopentetate dimeglumine) changes at follow-up examinations performed with a macrocyclic GBCA (gadobutrol). Materials and Methods This retrospective study included 13 patients with increased dentate nucleus signal intensity following at least six (range, 6-18) gadopentetate dimeglumine administrations who then underwent at least 12 months of follow-up imaging with multiple (range, 3-29) gadobutrol-enhanced magnetic resonance (MR) examinations. Dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios were measured by two radiologists blinded to all patient information, and changes were analyzed by using the paired t test and linear regression. Results The mean dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios increased after gadopentetate dimeglumine administration, from 0.98 +/- 0.03 to 1.10 +/- 0.03 (P < .0001) and from 0.98 +/- 0.030 to 1.09 +/- 0.02 (P < .0001), respectively. With gadobutrol, the mean dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios decreased to 1.03 +/- 0.03 and 1.02 +/- 0.04, respectively (P < .0001). With use of a mixed effects model linear regression allowing for each patient to have a different y intercept, mean dentate nucleus-to-pons and dentate nucleus-to-cerebellar peduncle signal intensity ratios decreased with follow-up time (dentate nucleus to-pons: slope = -0.2% per month [95% confidence interval: -0.0024, -0.0015], R2 = 0.58, P < .0001 for nonzero slope; dentate nucleus-to-cerebellar peduncle: slope = -0.2% per month [95% confidence interval: -0.0024, -0.0015], R2 = 0.61, P < .0001 for nonzero slope). Conclusion Dentate signal intensity increased with at least six gadopentetate dimeglumine-enhanced MR examinations and decreased after switching from a linear (gadopentetate dimeglumine) to a macrocyclic (gadobutrol) GBCA. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29533724 TI - A rapid and efficient method for the isolation of postnatal murine cardiac myocyte and fibroblast cells. AB - The capacity to isolate and study single cardiomyocytes has dramatically enhanced our understanding of the fundamental mechanisms of the heart. Currently, 2 primary methods for the isolation of cardiomyocytes are employed: (i) the neonatal isolation protocol and (ii) the Langendorff isolation method. A major limiting feature of both procedures is the inability to isolate cardiomyocytes between 3 days and 3 weeks after birth. Herein, we report the establishment and validation of a new method for the rapid and efficient isolation of mouse cardiomyocytes, regardless of age. This novel procedure utilizes whole heart perfusion of a trypsin-collagenase Krebs-based buffer through the left ventricle at a high flow rate. Cardiomyocytes can be isolated in significantly less time with a simple, syringe-pump-based apparatus. Typically, we can digest 10-15 hearts per hour. Altogether, we have established an efficient and reproducible method for the rapid isolation of fresh cardiomyocytes from postnatal mouse hearts of any age. PMID- 29533725 TI - Supplement. PMID- 29533726 TI - Immersion with menthol improves recovery between 2 cycling exercises in hot and humid environment. AB - Endurance exercise performance is impaired in a hot and humid environment. This study compared the effects of cold water immersion, with (CMWI) and without (CWI) menthol, on the recovery of cycling performance. Eight heat-acclimatized cyclists (age, 24.1 +/- 4.4 years; mass, 65.3 +/- 5.2 kg) performed 2 randomized sessions, each consisting of a 20-min cycling trial (T1) followed by 10 min of immersion during recovery and then a second 20-min cycling trial (T2). Mean power output and perceived exertion (RPE) were recorded for both trials. Rectal (Trec) and skin temperatures were measured before and immediately after T1, immersion, and T2. Perceived thermal sensation (TS) and comfort were measured immediately after T1 and T2. Power output was significantly improved in T2 compared with T1 in the CMWI condition (+15.6%). Performance did not change in the CWI condition. After immersion, Trec was lower in CWI (-1.17 degrees C) than in CMWI (-0.6 degrees C). TS decreased significantly after immersion in both conditions. This decline was significantly more pronounced in CMWI (5.9 +/- 1 to 3.6 +/- 0.5) than in CWI (5.6 +/- 0.9 to 4.4 +/- 1.2). In CMWI, RPE was significantly higher in T1 (6.57 +/- 0.9) than in T2 (5.14 +/- 1.25). However, there was no difference in TC. This study suggests that menthol immersion probably (i) improves the performance of a repeated 20-min cycling bout, (ii) decreases TS, and (iii) impairs thermoregulation processes. PMID- 29533727 TI - Reduced Orthodontic Tooth Movement in Enpp1 Mutant Mice with Hypercementosis. AB - Previous studies revealed that cementum formation is tightly regulated by inorganic pyrophosphate (PPi), a mineralization inhibitor. Local PPi concentrations are determined by regulators, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which increases PPi concentrations by adenosine triphosphate hydrolysis. Orthodontic forces stimulate alveolar bone remodelling, leading to orthodontic tooth movement (OTM). To better understand how disturbed mineral metabolism and the resulting altered periodontal structures affect OTM, we employed Enpp1 mutant mice that feature reduced PPi and increased cervical cementum in a model of OTM induced by a stretched closed-coil spring ligated between the maxillary left first molar and maxillary incisors. We analyzed tooth movement, osteoclast/odontoclast response, and tooth root resorption by micro-computed tomography, histology, histomorphometry, and immunohistochemistry. Preoperatively, we noted an altered periodontium in Enpp1 mutant mice, with significantly increased periodontal ligament (PDL) volume and thickness, as well as increased PDL-bone/tooth root surface area, compared to wild-type (WT) controls. After 11 d of orthodontic treatment, Enpp1 mutant mice displayed 38% reduced tooth movement versus WT mice. Molar roots in Enpp1 mutant mice exhibited less change in PDL width in compression and tension zones compared to WT mice. Root resorption was noted in both groups with no difference in average depths, but resorption lacunae in Enpp1 mutant mice were almost entirely limited to cementum, with 150% increased cementum resorption and 92% decreased dentin resorption. Osteoclast/odontoclast cells were reduced by 64% in Enpp1 mutant mice, with a predominance of tartrate-resistant acid phosphatase (TRAP) positive cells on root surfaces, compared to WT mice. Increased numbers of TRAP positive cells on root surfaces were associated with robust immunolocalization of osteopontin (OPN) and receptor-activator of NF-kappaB ligand (RANKL). Collectively, reduced response to orthodontic forces, decreased tooth movement, and altered osteoclast/odontoclast distribution suggests Enpp1 loss of function has direct effects on clastic function/recruitment and/or indirect effects on periodontal remodeling via altered periodontal structure or tissue mineralization. PMID- 29533728 TI - Comparison of the first whole genome sequence of 'Haemophilus quentini' with two new strains of 'Haemophilus quentini' and other species of Haemophilus. AB - Comparison of the genome of the Gram negative human pathogen Haemophilus quentini MP1 with other species of Haemophilus revealed that, although it is more closely related to Haemophilus haemolyticus than Haemophilus influenzae, the pathogen is in fact genetically distinct, a finding confirmed by phylogenetic analysis using the H. influenzae multilocus sequence typing genes. Further comparison with two other H. quentini strains recently identified in Canada revealed that these three genomes are more closely related than any other species of Haemophilus; however, there is still some sequence variation. There was no evidence of acquired antimicrobial resistance within the H. quentini MP1 genome nor any mutations within the DNA gyrase or topoisomerase IV genes known to confer resistance to fluoroquinolones, which has been previously identified in other H. quentini isolates. We hope by presenting the annotation and genetic comparison of the H. quentini MP1 genome it will aid the future molecular detection of this potentially emerging pathogen via the identification of unique genes that differentiate it from other species of Haemophilus. PMID- 29533729 TI - Five-Year Survival of Short Single-Tooth Implants (6 mm): A Randomized Controlled Clinical Trial. AB - The aim of the present study was to evaluate whether 6-mm dental implants in the posterior segments of either jaw perform equally well in terms of clinical and radiographic outcomes when compared with 10-mm implants after 5 y of loading. Patients with single-tooth gaps in the posterior area who were scheduled for implant therapy were randomly assigned to a group receiving either a 6- or 10-mm implant. After a healing period of 10 wk, implants were loaded with a screw retained single crown and followed up at yearly intervals. Of 96 patients, 86 could be recalled after 5 y. The implant survival rates amounted to 91% (95% confidence interval: 0.836 to 0.998) for the 6-mm group and 100% for the 10-mm group ( P = 0.036). Median crown-to-implant (C/I) ratios were 1.75 (interquartile range [IQR], 1.50 to 1.90) for the 6-mm group and 1.04 (IQR, 0.95 to 1.15) for the 10-mm group, whereas the median marginal bone levels measured -0.29 mm (IQR, 0.92 to 0.23) for the 6-mm group and -0.15 mm (IQR: -0.93 - 0.41) for the 10-mm group after 5 y. The C/I ratio turned out to be statistically significant ( P < 0.001), whereas marginal bone levels showed no significant difference between the groups. The 6-mm implants exhibited significantly lower survival rates than the 10-mm implants over 5 y, whereas there was no difference between upper and lower jaws in terms of survival ( P = 0.58). Lost implants did not show any sign of marginal bone loss or peri-implant infection previous to loss of osseointegration. High C/I ratio and implant length had no significant effect on marginal bone level changes or technical and biological complications (German Clinical Trials Registry: DRKS00006290). PMID- 29533730 TI - Hyaluronan content and distribution in the rat ventral prostate after castration. AB - Hyaluronan (HA) has been implicated in tissue remodeling, healing, and tumor growth. This study investigated the variation in hyaluronan content, distribution, and metabolism in the rat ventral prostate (VP) in response to androgen deprivation after castration. The mRNA abundance of hyaluronan synthases (Has1-3) and hyaluronidases (Hyal 1-3) were assessed by reverse transcription (RT)-PCR and immunohistochemistry, respectively. The results demonstrated an increased concentration, but an overall reduction in HA content. HA was located in both epithelium and stroma of the prostate of both the noncastrated and castrated animals. Quantitative RT-PCR (qRT-PCR) showed that Has1 and Has2 are major synthases, and that Hyal 1 was the predominant hydrolase expressed in the VP. qRT-PCR also showed that Has1 and Has2 mRNA increased transiently after castration, whereas Has3 mRNA declined markedly. While Hyal 1 mRNA increased slowly up to day 21 after castration, Hyal 2 and Hyal 3 mRNA dropped significantly. CD44 was found in the epithelial cells and in some stromal cells in both hormonal conditions. In conclusion, castration results in increased abundance of Has1 and Has2 mRNA, but is associated with a decrease in the total content of HA, with an increased concentration, and a predominance of short-chain HA molecules. PMID- 29533732 TI - Strain Distribution in the Anterior Inferior Tibiofibular Ligament, Posterior Inferior Tibiofibular Ligament, and Interosseous Membrane Using Digital Image Correlation. AB - BACKGROUND: Ligament repair and augmentation techniques can stabilize syndesmosis injuries. However, little is known about the mechanical behavior of syndesmotic ligaments. The aim of this study was to analyze full-field strain, strain trend under foot rotation, and subregional strain differences of the anterior inferior tibiofibular ligament (AITFL), posterior inferior tibiofibular ligament (PITFL), and interosseous membrane (IOM). METHODS: Eleven fresh-frozen lower limbs were dissected to expose the AITFL, PITFL, and IOM. The foot underwent rotation from 0 degrees to 25 degrees internal and 35 degrees external, with 3 ankle positions (neutral, 15 degrees dorsiflexion, and 25 degrees plantarflexion) and a vertical load of 430 N. Ligament strain was recorded using digital image correlation. RESULTS: The mean strain on the AITFL with 35 degrees external rotation was greater in the proximal portion compared with distal portion in the neutral position ( P = .009) and dorsiflexion ( P = .003). The mean strain in the tibial insertion and midsubstance near tibial insertion were greater when compared with other regions ( P = .018 and P = .009). The subregions of mean strain in the PITFL and IOM groups were not significantly different. The strain trend of AITFL, PITFL, and IOM showed common transformation, just when the foot was externally rotated. CONCLUSION: The findings of this study show that a significantly high strain was observed on the proximal part and the midsubstance near the Chaput tubercle of the AITFL when the ankle was externally rotated. All 3 ligaments resisted the torque in the syndesmosis by external rotation of the foot. CLINICAL RELEVANCE: This study allows for better understanding of the mechanical behavior of the syndesmosis ligaments, which could influence the repair technique and AITFL augmentation techniques. PMID- 29533731 TI - Engineering Vaccines to Reprogram Immunity against Head and Neck Cancer. AB - The recent Food and Drug Administration's approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8+ T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines. PMID- 29533733 TI - DeltaF508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter. AB - The most common cystic fibrosis-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is deletion of phenylalanine at residue 508 (?F508). The ?F508 mutation impairs folding of nucleotide binding domain 1 (NBD1) and interfacial interactions of NBD1 and the membrane spanning domains. Here, we report a domain-targeted screen to identify ?F508-CFTR modulators that act on NBD1. A biochemical screen for DeltaF508-NBD1 cell surface expression was done in Madin-Darby canine kidney cells expressing a chimeric reporter consisting of DeltaF508-NBD1, the CD4 transmembrane domain, and an extracellular horseradish peroxidase (HRP) reporter. Using a luminescence readout of HRP activity, the screen was robust with a Z' factor of 0.7. The screening of ~20,000 synthetic small molecules allowed the identification of compounds from four chemical classes that increased ?F508-NBD1 cell surface expression by up to 4-fold; for comparison, a 12-fold increased cell surface expression was found for a wild-type NBD1 chimera. While the compounds were inactive as correctors of full length DeltaF508-CFTR, several carboxamide-benzothiophenes had potentiator activity with low micromolar EC50. Interestingly, the potentiators did not activate G551D or wild-type CFTR. Our results provide a proof of concept for a cell-based NBD1 domain screen to identify ?F508-CFTR modulators that target the NBD1 domain. PMID- 29533734 TI - Predictive Prognostic Value of Tissue-Based MicroRNA Expression in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-analysis. AB - Oral squamous cell carcinoma (OSCC) is a common type of cancer characterized by a low survival rate, mostly due to local recurrence and metastasis. In view of the importance of predicting tumor behavior in the choice of treatment strategies for OSCC, several studies have attempted to investigate the prognostic value of tissue biomarkers, including microRNA (miRNA). The purpose of this study was to perform a systematic review and meta-analysis to evaluate the relationship between miRNA expression and survival of OSCC patients. Studies were identified by searching on MEDLINE/PubMed, SCOPUS, Web of Science, and Google Scholar. Quality assessment of studies was performed with the Newcastle-Ottawa Scale. Data were collected from cohort studies comparing disease-free survival and overall survival in patients with high miRNA expression compared to those with low expression. A total of 15 studies featuring 1,200 OSCC samples, predominantly from Asia, met the inclusion criteria and were included in the meta-analysis. Poor prognosis correlated with upregulation of 9 miRNAs (miR-21, miR-455-5p, miiR 155-5p, miR-372, miR-373, miR-29b, miR-1246, miR-196a, and miR-181) and downregulation of 7 miRNAs (miR-204, miR-101, miR-32, miR-20a, miR-16, miR-17, and miR-125b). The pooled hazard ratio values (95% confidence interval) related to different miRNA expression for overall survival and disease-free survival were 2.65 (2.07-3.39) and 1.95 (1.28-2.98), respectively. The results of this meta analysis revealed that the expression levels of specific miRNAs can robustly predict prognosis of OSCC patients. PMID- 29533735 TI - Space microgravity drives transdifferentiation of human bone marrow-derived mesenchymal stem cells from osteogenesis to adipogenesis. AB - Bone formation is linked with osteogenic differentiation of mesenchymal stem cells (MSCs) in the bone marrow. Microgravity in spaceflight is known to reduce bone formation. In this study, we used a real microgravity environment of the SJ 10 Recoverable Scientific Satellite to examine the effects of space microgravity on the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs). hMSCs were induced toward osteogenic differentiation for 2 and 7 d in a cell culture device mounted on the SJ-10 satellite. The satellite returned to Earth after going through space experiments in orbit for 12 d, and cell samples were harvested and analyzed for differentiation potentials. The results showed that space microgravity inhibited osteogenic differentiation and resulted in adipogenic differentiation, even under osteogenic induction conditions. Under space microgravity, the expression of 10 genes specific for osteogenesis decreased, including collagen family members, alkaline phosphatase ( ALP), and runt-related transcription factor 2 ( RUNX2), whereas the expression of 4 genes specific for adipogenesis increased, including adipsin ( CFD), leptin ( LEP), CCAAT/enhancer binding protein beta ( CEBPB), and peroxisome proliferator activated receptor-gamma ( PPARG). In the analysis of signaling pathways specific for osteogenesis, we found that the expression and activity of RUNX2 was inhibited, expression of bone morphogenetic protein-2 ( BMP2) and activity of SMAD1/5/9 were decreased, and activity of focal adhesion kinase (FAK) and ERK-1/2 declined significantly under space microgravity. These data indicate that space microgravity plays a dual role by decreasing RUNX2 expression and activity through the BMP2/SMAD and integrin/FAK/ERK pathways. In addition, we found that space microgravity increased p38 MAPK and protein kinase B (AKT) activities, which are important for the promotion of adipogenic differentiation of hMSCs. Space microgravity significantly decreased the expression of Tribbles homolog 3 ( TRIB3), a repressor of adipogenic differentiation. Y15, a specific inhibitor of FAK activity, was used to inhibit the activity of FAK under normal gravity; Y15 decreased protein expression of TRIB3. Therefore, it appears that space microgravity decreased FAK activity and thereby reduced TRIB3 expression and derepressed AKT activity. Under space microgravity, the increase in p38 MAPK activity and the derepression of AKT activity seem to synchronously lead to the activation of the signaling pathway specifically promoting adipogenesis.-Zhang, C., Li, L., Jiang, Y., Wang, C., Geng, B., Wang, Y., Chen, J., Liu, F., Qiu, P., Zhai, G., Chen, P., Quan, R., Wang, J. Space microgravity drives transdifferentiation of human bone marrow-derived mesenchymal stem cells from osteogenesis to adipogenesis. PMID- 29533736 TI - OC-STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up-regulation of permissive fusogen CD9. AB - Cell fusion-mediated formation of multinuclear osteoclasts (OCs) plays a key role in bone resorption. It is reported that 2 unique OC-specific fusogens [ i.e., OC stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP)], and permissive fusogen CD9, are involved in OC fusion. In contrast to DC-STAMP-knockout (KO) mice, which show the osteopetrotic phenotype, OC-STAMP-KO mice show no difference in systemic bone mineral density. Nonetheless, according to the ligature-induced periodontitis model, significantly lower level of bone resorption was found in OC-STAMP-KO mice compared to WT mice. Anti-OC-STAMP-neutralizing mAb down-modulated in vitro: 1) the emergence of large multinuclear tartrate-resistant acid phosphatase-positive cells, 2) pit formation, and 3) mRNA and protein expression of CD9, but not DC-STAMP, in receptor activator of NF-kappaB ligand (RANKL)-stimulated OC precursor cells (OCps). While anti-DC-STAMP-mAb also down-regulated RANKL-induced osteoclastogenesis in vitro, it had no effect on CD9 expression. In our mouse model, systemic administration of anti-OC-STAMP-mAb suppressed the expression of CD9 mRNA, but not DC-STAMP mRNA, in periodontal tissue, along with diminished alveolar bone loss and reduced emergence of CD9+ OCps and tartrate-resistant acid phosphatase-positive multinuclear OCs. The present study demonstrated that OC STAMP partners CD9 to promote periodontal bone destruction by up-regulation of fusion during osteoclastogenesis, suggesting that anti-OC-STAMP-mAb may lead to the development of a novel therapeutic regimen for periodontitis.-Ishii, T., Ruiz Torruella, M., Ikeda, A., Shindo, S., Movila, A., Mawardi, H., Albassam, A., Kayal, R. A., Al-Dharrab, A. A., Egashira, K., Wisitrasameewong, W., Yamamoto, K., Mira, A. I., Sueishi, K., Han, X., Taubman, M. A., Miyamoto, T., Kawai, T. OC STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up-regulation of permissive fusogen CD9. PMID- 29533737 TI - Bcr-Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic-driven mechanism of protein up-regulation. AB - Bcr-Abl (break-point cluster region-abelson), the oncogenic trigger of chronic myelogenous leukemia (CML), has previously been shown to up-regulate the expression and activity of sphingomyelin synthase 1 (SMS1), which contributes to the proliferation of CML cells; however, the mechanism by which this increased expression of SMS1 is mediated remains unknown. In the current study, we show that Bcr-Abl enhances the expression of SMS1 via a 30-fold up-regulation of its transcription. Of most interest, the Bcr-Abl-regulated transcription of SMS1 is initiated from a novel transcription start site (TSS) that is just upstream of the open reading frame. This shift in TSS utilization generates an SMS1 mRNA with a substantially shorter 5' UTR compared with its canonical mRNA. This shorter 5' UTR imparts a 20-fold greater translational efficiency to SMS1 mRNA, which further contributes to the increase of its expression in CML cells. Therefore, our study demonstrates that Bcr-Abl increases SMS1 protein levels via 2 concerted mechanisms: up-regulation of transcription and enhanced translation as a result of the shift in TSS utilization. Remarkably, this is the first time that an oncogene-Bcr-Abl-has been demonstrated to drive such a mechanism that up regulates the expression of a functionally important target gene, SMS1.-Moorthi, S., Burns, T. A., Yu, G.-Q., Luberto, C. Bcr-Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic-driven mechanism of protein up-regulation. PMID- 29533738 TI - Intragastric nutrient infusion reduces motivation for food in male and female rats. AB - The idea that gut-derived satiation signals influence food reward has recently gained traction, but this hypothesis is largely based on studies focused on neural circuitry, not the peripherally released signals. Here, we directly tested the hypothesis that intragastric (IG) nutrient infusion can suppress motivation for food. In a series of experiments, IG sucrose infusion (15 kcal) significantly and reliably reduced operant responding for a sucrose reward on a progressive ratio (PR) schedule. Moreover, food deprivation for 24 h before the test session did not prevent the suppressive effect of nutrients. The suppressive effect of IG sucrose on fixed ratio 5 (FR5) operant responding was also assessed as a comparison. The effect of IG nutrients to reduce motivation was not limited to sucrose; IG Ensure infusion (9.3 kcal) also significantly reduced PR operant responding for sucrose pellets. To verify that these effects were not secondary to the osmotic challenge of concentrated nutrients, we tested IG infusion of noncaloric saline solutions equiosmolar to 40% sucrose or Ensure and found no effect. Finally, we focused on glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) as candidate mediators for the effect of IG nutrients. Pretreatment with exendin-9, a GLP-1 receptor antagonist, delivered intraperitoneally, significantly attenuated the ability of IG nutrients to suppress PR responding and breakpoint in males, but not in females, whereas pretreatment with devazepide, a CCKA receptor antagonist, failed to do so in both sexes. Together, these data support the idea that nutrient-induced satiation signals influence food reward and may implicate GLP-1 in this process. PMID- 29533740 TI - SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption. AB - Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined. PMID- 29533739 TI - beta-Actin shows limited mobility and is required only for supraphysiological insulin-stimulated glucose transport in young adult soleus muscle. AB - Studies in skeletal muscle cell cultures suggest that the cortical actin cytoskeleton is a major requirement for insulin-stimulated glucose transport, implicating the beta-actin isoform, which in many cell types is the main actin isoform. However, it is not clear that beta-actin plays such a role in mature skeletal muscle. Neither dependency of glucose transport on beta-actin nor actin reorganization upon glucose transport have been tested in mature muscle. To investigate the role of beta-actin in fully differentiated muscle, we performed a detailed characterization of wild type and muscle-specific beta-actin knockout (KO) mice. The effects of the beta-actin KO were subtle; however, we confirmed the previously reported decline in running performance of beta-actin KO mice compared with wild type during repeated maximal running tests. We also found insulin-stimulated glucose transport into incubated muscles reduced in soleus but not in extensor digitorum longus muscle of young adult mice. Contraction stimulated glucose transport trended toward the same pattern, but the glucose transport phenotype disappeared in soleus muscles from mature adult mice. No genotype-related differences were found in body composition or glucose tolerance or by indirect calorimetry measurements. To evaluate beta-actin mobility in mature muscle, we electroporated green fluorescent protein (GFP)-beta-actin into flexor digitorum brevis muscle fibers and measured fluorescence recovery after photobleaching. GFP-beta-actin showed limited unstimulated mobility and no changes after insulin stimulation. In conclusion, beta-actin is not required for glucose transport regulation in mature mouse muscle under the majority of the tested conditions. Thus, our work reveals fundamental differences in the role of the cortical beta-actin cytoskeleton in mature muscle compared with cell culture. PMID- 29533742 TI - PlasmidTron: assembling the cause of phenotypes and genotypes from NGS data. AB - Increasingly rich metadata are now being linked to samples that have been whole genome sequenced. However, much of this information is ignored. This is because linking this metadata to genes, or regions of the genome, usually relies on knowing the gene sequence(s) responsible for the particular trait being measured and looking for its presence or absence in that genome. Examples of this would be the spread of antimicrobial resistance genes carried on mobile genetic elements (MGEs). However, although it is possible to routinely identify the resistance gene, identifying the unknown MGE upon which it is carried can be much more difficult if the starting point is short-read whole-genome sequence data. The reason for this is that MGEs are often full of repeats and so assemble poorly, leading to fragmented consensus sequences. Since mobile DNA, which can carry many clinically and ecologically important genes, has a different evolutionary history from the host, its distribution across the host population will, by definition, be independent of the host phylogeny. It is possible to use this phenomenon in a genome-wide association study to identify both the genes associated with the specific trait and also the DNA linked to that gene, for example the flanking sequence of the plasmid vector on which it is encoded, which follows the same patterns of distribution as the marker gene/sequence itself. We present PlasmidTron, which utilizes the phenotypic data normally available in bacterial population studies, such as antibiograms, virulence factors, or geographical information, to identify traits that are likely to be present on DNA that can randomly reassort across defined bacterial populations. It is also possible to use this methodology to associate unknown genes/sequences (e.g. plasmid backbones) with a specific molecular signature or marker (e.g. resistance gene presence or absence) using PlasmidTron. PlasmidTron uses a k-mer-based approach to identify reads associated with a phylogenetically unlinked phenotype. These reads are then assembled de novo to produce contigs in a fast and scalable-to large manner. PlasmidTron is written in Python 3 and is available under the open source licence GNU GPL3 from https://github.com/sanger-pathogens/plasmidtron. PMID- 29533741 TI - Myeloid-specific Acat1 ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity. AB - Macrophages are phagocytes that play important roles in health and diseases. Acyl CoA:cholesterol acyltransferase 1 (ACAT1) converts cellular cholesterol to cholesteryl esters and is expressed in many cell types. Unlike global Acat1 knockout (KO), myeloid-specific Acat1 KO ( Acat1-) does not cause overt abnormalities in mice. Here, we performed analyses in age- and sex-matched Acat1 M/-M and wild-type mice on chow or Western diet and discovered that Acat1-M/-M mice exhibit resistance to Western diet-induced obesity. On both chow and Western diets, Acat1-M/-M mice display decreased adipocyte size and increased insulin sensitivity. When fed with Western diet, Acat1-M/-M mice contain fewer infiltrating macrophages in white adipose tissue (WAT), with significantly diminished inflammatory phenotype. Without Acat1, the Ly6Chi monocytes express reduced levels of integrin-beta1, which plays a key role in the interaction between monocytes and the inflamed endothelium. Adoptive transfer experiment showed that the appearance of leukocytes from Acat1-M/-M mice to the inflamed WAT of wild-type mice is significantly diminished. Under Western diet, Acat1-M/-M causes suppression of multiple proinflammatory genes in WAT. Cell culture experiments show that in RAW 264.7 macrophages, inhibiting ACAT1 with a small molecule ACAT1-specific inhibitor reduces inflammatory responses to lipopolysaccharide. We conclude that under Western diet, blocking ACAT1 in macrophages attenuates inflammation in WAT. Other results show that Acat1-M/-M does not compromise antiviral immune response. Our work reveals that blocking ACAT1 suppresses diet-induced obesity in part by slowing down monocyte infiltration to WAT as well as by reducing the inflammatory responses of adipose tissue macrophages. PMID- 29533743 TI - New genotypes of Liao ning virus (LNV) in Australia exhibit an insect-specific phenotype. AB - Liao ning virus (LNV) was first isolated in 1996 from mosquitoes in China, and has been shown to replicate in selected mammalian cell lines and to cause lethal haemorrhagic disease in experimentally infected mice. The first detection of LNV in Australia was by deep sequencing of mosquito homogenates. We subsequently isolated LNV from mosquitoes of four genera (Culex, Anopheles, Mansonia and Aedes) in New South Wales, Northern Territory, Queensland and Western Australia; the earliest of these Australian isolates were obtained from mosquitoes collected in 1988, predating the first Chinese isolates. Genetic analysis revealed that the Australian LNV isolates formed two new genotypes: one including isolates from eastern and northern Australia, and the second comprising isolates from the south western corner of the continent. In contrast to findings reported for the Chinese LNV isolates, the Australian LNV isolates did not replicate in vertebrate cells in vitro or in vivo, or produce signs of disease in wild-type or immunodeficient mice. A panel of human and animal sera collected from regions where the virus was found in high prevalence also showed no evidence of LNV-specific antibodies. Furthermore, high rates of virus detection in progeny reared from infected adult female mosquitoes, coupled with visualization of the virus within the ovarian follicles by immunohistochemistry, suggest that LNV is transmitted transovarially. Thus, despite relatively minor genomic differences between Chinese and Australian LNV strains, the latter display a characteristic insect specific phenotype. PMID- 29533745 TI - The impact of ERAD on recombinant protein secretion in Pichia pastoris (syn Komagataella spp.). AB - The yeast Pichia pastoris (syn. Komagataella spp.) is a popular cell factory for recombinant protein production. Yeasts in general provide a good starting point for cell factory engineering. They are intrinsically robust and easy to manipulate and cultivate. However, their secretory pathway is not evolutionarily adapted to high loads of secretory protein. In particular, more complex proteins, like the antibody fragment (Fab) used in this study, overwhelm the folding and secretion capacity. This triggers cellular stress responses, which may cause excessive intracellular degradation. Previous results have shown that, in fact, about 60 % of the newly synthesized Fab is intracellularly degraded. Endoplasmic reticulum-associated protein degradation (ERAD) is one possible intracellular degradation pathway for proteins aimed for secretion. We therefore targeted ERAD for cell factory engineering and investigated the impact on recombinant protein secretion in P. pastoris. Three components of the ERAD-L complex, which is involved in the degradation of luminal proteins, and a protein involved in proteasomal degradation, were successfully disrupted in Fab-secreting P. pastoris. Contrary to expectation, the effect on secretion was marginal. In the course of more detailed investigation of the impact of ERAD, we took a closer look at the intracellular variants of the recombinant protein. This enabled us to further zero in on the issue of intracellular Fab degradation and exclude an overshooting ER quality control. We propose that a major fraction of the Fab is actually degraded before entering the secretory pathway. PMID- 29533744 TI - Shiga toxin 2 translocation across intestinal epithelium is linked to virulence of Shiga toxin-producing Escherichia coli in humans. AB - Shiga toxin-producing Escherichia coli (STEC) are characterized by the release of potent Shiga toxins (Stx), which are associated with severe intestinal and renal disease. Although all STEC strains produce Stx, only a few serotypes cause infection in humans. To determine which virulence traits in vitro are linked to human disease in vivo, 13 Stx2a-producing STEC strains of seropathotype (SPT) A or B (associated with severe human intestinal disease and outbreaks) and 6 strains of SPT D or E (rarely or not linked to human disease) were evaluated in a microaerobic human colonic epithelial infection model. All SPT strains demonstrated similar growth, colonization of polarized T84 colon carcinoma cells and Stx release into the medium. In contrast, Stx translocation across the T84 cell monolayer was significantly lower in SPT group DE compared to SPT group AB strains. Further experiments showed that Stx penetration occurred via a transcellular pathway and was independent of bacterial type III secretion and attaching and effacing lesion formation. These results suggest that the extent of Stx transcytosis across the gut epithelium may represent an important indicator of STEC pathogenicity for humans. PMID- 29533746 TI - Transcriptome analysis of a Pseudomonas aeruginosasn-glycerol-3-phosphate dehydrogenase mutant reveals a disruption in bioenergetics. AB - Pseudomonas aeruginosa causes acute and chronic human infections and is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. We previously determined that the sn-glycerol-3-phosphate dehydrogenase encoded by glpD plays a larger role in P. aeruginosa physiology beyond its role in glycerol metabolism. To better understand the effect of a glpD mutation on P. aeruginosa physiology we compared the transcriptomes of P. aeruginosa strain PAO1 and the PAO1DeltaglpD mutant using RNA-seq analysis. We determined that a null mutation of glpD significantly altered amino acid metabolism in P. aeruginosa and affected the production of intermediates that are channelled into the tricarboxylic acid cycle. Moreover, the loss of glpD induced a general stress response mediated by RpoS in P. aeruginosa. Several other phenotypes observed for the P. aeruginosa glpD mutant include increased persister cell formation, reduced extracellular ATP accumulation and increased heat output. Taken together, these findings implicate sn-glycerol-3-phosphate dehydrogenase as a key player in energy metabolism in P. aeruginosa. PMID- 29533747 TI - Azotobacter vinelandii: the source of 100 years of discoveries and many more to come. AB - Azotobacter vinelandii has been studied for over 100 years since its discovery as an aerobic nitrogen-fixing organism. This species has proved useful for the study of many different biological systems, including enzyme kinetics and the genetic code. It has been especially useful in working out the structures and mechanisms of different nitrogenase enzymes, how they can function in oxic environments and the interactions of nitrogen fixation with other aspects of metabolism. Interest in studying A. vinelandii has waned in recent decades, but this bacterium still possesses great potential for new discoveries in many fields and commercial applications. The species is of interest for research because of its genetic pliability and natural competence. Its features of particular interest to industry are its ability to produce multiple valuable polymers - bioplastic and alginate in particular; its nitrogen-fixing prowess, which could reduce the need for synthetic fertilizer in agriculture and industrial fermentations, via coculture; its production of potentially useful enzymes and metabolic pathways; and even its biofuel production abilities. This review summarizes the history and potential for future research using this versatile microbe. PMID- 29533748 TI - Guidelines for prophylaxis of Pneumocystis pneumonia cannot rely solely on CD4 cell count in autoimmune and inflammatory diseases. AB - OBJECTIVES: Guidelines for preventing Pneumocystis pneumonia (PCP) in HIV patients are based on CD4 below 200/mm3. Such cut-off value is suggested to guide prophylaxis in non-HIV conditions (NHIV) especially in autoimmune and inflammatory diseases (AD). We aimed to determine if CD4 could be used to guide PCP prophylaxis in AD. METHODS: CD4 and lymphocyte-count were retrospectively studied in patients diagnosed with PCP between January 2013 and February 2016. RESULTS: 129 patients were included. The median CD4-count was 302/mm3 in AD, which was significantly higher than in HIV patients (19/mm3; p<0.0001). Fifty percent (n=10) of AD patients had CD4 counts greater than 300/mm3. CONCLUSIONS: Prophylaxis for PCP cannot rely solely on CD4-count in NHIV patients especially in AD. PMID- 29533749 TI - Chikungunya virus: a rheumatologist's perspective. AB - Chikungunya virus (CHIKV) is an arthropod-borne alphavirus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It is responsible for a febrile illness, typically accompanied by maculopapular rash and severe, incapacitating arthralgia. The disease, although generally self-limiting, frequently evolves into a long-lasting, debilitating rheumatic disorder, which shares many clinical features with rheumatoid arthritis (RA). The underlying mechanism by which CHIKV induces persistent arthritis remains under investigation, however, currently, attention is drawn to the fact, that chronic chikungunya (CHIK) and RA have many common cellular and cytokine pathways involved in their pathogenesis. Over the past decades, the virus has dispersed unexpectedly from tropical and subtropical regions of Africa and Asia, affecting millions of people worldwide. No licensed vaccine, nor antiviral drug against CHIKV is yet available. Treatment of acute CHIK is symptomatic, whereas in chronic stages, different disease-modifying anti rheumatic drugs (DMARDs) have been used with variable success. Hence, chronic CHIK is an emerging rheumatic condition that rheumatologists have to deal with. This review provides brief insights into the epidemiology, pathogenesis, clinical features and management of Chikungunya disease, with special regard to post chikungunya rheumatic disorder and its relationship with RA. PMID- 29533750 TI - In early arthritis patients, high HAQ at baseline and DAS28 at three months predict suboptimal outcomes at two years: a retrospective cohort study. AB - OBJECTIVES: Early arthritis clinics (EAC) aim to improve rheumatoid arthritis (RA) outcomes by tailoring treatment targeting to remission. Our aim was to analyse disease course and relevant predictors over 2 years in early arthritis; we also assessed the applicability of the "treat-to-target approach" in a real life EAC. METHODS: Patients with early arthritis recruited at the EAC of the University Hospital of Heraklion were followed prospectively according to a follow-up protocol for two years, without implementing a pre-specified treatment protocol, to capture real-life practices. Early predictors of "suboptimal outcomes" (high disease activity or HAQ>1.0 at 2 years) and biologic DMARD (bDMARD) initiation were evaluated with multivariate logistic regression. Intensification of treatment at 3 and 6 months and subsequent long-term outcome were also assessed. RESULTS: 251 patients [RA (n=188), undifferentiated arthritis (n=63)] were included. Although both DAS28 and HAQ at 2 years improved significantly compared to baseline in RA patients [mean (SD) DAS28 and median (IQR) HAQ 3.70 (1.32) and 0.44 (0.75) at 2 years, p<0.001 for both compared to baseline], 43.7% still had moderate and 18.8% high disease activity. The most powerful predictor of suboptimal outcomes or bDMARD initiation in RA was high disease activity at three months (adjusted odds ratio 2.22 and 2.62, respectively). At three and six months 72.8% and 62.4% of patients with medium/high disease activity received treatment intensification, which resulted in significant decrease in disease activity at 2 years (p<0.001 for DeltaDAS28). CONCLUSIONS: DAS28 at three months was the most powerful predictor of suboptimal disease outcome during a 2-year follow-up in early RA. Despite significant DAS reductions, more than 50% of patients have active disease at two years. Failure to fully implement the treat-to-target strategy in our cohort could account for the low remission rates. PMID- 29533751 TI - Comorbidity of PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis) patients: a case control study. AB - OBJECTIVES: To compare the long-term morbidity of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome treated by tonsillectomy (TE) in childhood to that of matched controls. METHODS: We identified 132 PFAPA patients from the medical records treated by TE in 1987-2007 in Oulu University Hospital, Finland. Altogether 119 patients participated the follow-up study and 94 were clinically examined on average 9.0 years after TE. The controls consisted of 230 randomly selected age-, sex-, and birth place matched individuals from the Population Register Center of Finland. The patients and controls completed a detailed questionnaire about their current health and the data were compared. RESULTS: Self-estimated general health was good and growth was normal among PFAPA patients and controls at long-term follow-up. There were no between-group differences in the occurrence of autoimmune or other chronic diseases. Thirty percent of the PFAPA patients and 13% of the controls reported infections as causes of hospital visits during their lifetime (p<0.001). Usage of antibiotics during lifetime was reported by 99% of the PFAPA patients and by 88% of the controls (p= 0.009). Twelve percent of PFAPA patients and 0.4% of the controls reported oral thrush in their history (p=0.003). CONCLUSIONS: The health of the PFAPA patients was as good as that of healthy matched controls. Autoimmune or other chronic diseases were not more prevalent among PFAPA patients treated with TE in childhood than among controls. Respiratory infections and oral thrush were more common among the PFAPA patients than controls. PMID- 29533752 TI - Prevalence and validity of ACR/EULAR remission in four European early rheumatoid arthritis cohorts. AB - OBJECTIVES: In 2011 an ACR/EULAR collaboration developed new remission definitions for RA. In the present study, we evaluated the prevalence and predictive validity of these new ACR/EULAR remission criteria in 4 different European early rheumatoid arthritis cohorts. METHODS: Data from a tot al of 722 patients with early RA were analysed. Presence of remission at 6 months, as defined by one of the 4 proposed ACR/EULAR remission definitions was used to predict good functional and radiological outcome between 1 and 2 years of follow up. RESULTS: Remission rates at 6 months ranged from 2-17% (Boolean definition) between the four cohorts. The level of HAQ and radiological damage varied between cohorts. Patients in remission at 6 months have an increased likelihood of long term good outcome in terms of HAQ stability, but not radiographic stability. The performance of the practice definitions of remission was highly similar to the trial definitions. CRP status seems to add little information to the classification of remission in early RA. CONCLUSIONS: In clinical practice, a minority of patients with early RA achieves remission in the first 6 months of treatment. Remission at 6 months is predictive for good HAQ outcome between year 1 and 2 after inclusion, but not radiographic stability. PMID- 29533753 TI - Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series. AB - OBJECTIVES: B cells play an important role in the initiation and progression of systemic lupus erythematosus (SLE). Accordingly, B cell-targeted therapy has been suggested as a new rational approach for treating lupus. Belimumab, a human monoclonal antibody directed against B lymphocyte stimulator (BLyS), was reported as the first biological treatment effective in reducing mild-to-moderate SLE disease activity by using different scoring systems and endpoints. Conversely clinical trials with rituximab, a chimeric monoclonal antibody directed against the CD20 expressed by B cells, have failed to achieve primary endpoints in spite of a number of reports showing its beneficial effects. Anecdotal reports have described the sequential use of rituximab and belimumab as a more effective treatment than using the individual drugs alone, without compromising safety. METHODS: We report a case series of three patients with active SLE refractory to conventional therapies, who underwent treatment with rituximab followed by belimumab as maintenance therapy. RESULTS: We observed a beneficial effect after sequential treatment with rituximab and belimumab. All patients achieved long standing remission and could reduce or discontinue corticosteroids. Concomitantly, after rituximab administration we observed a rise in BLyS levels, which were dramatically reduced after belimumab introduction. CONCLUSIONS: The modulation of plasma BLyS kinetics in patients undergoing sequential treatment with rituximab and belimumab may represent a possible rationale behind the effectiveness of this combined therapy. PMID- 29533754 TI - Trends in the activity of rheumatoid arthritis as the consequence of treat-to target strategy: eight-year data from 2009 to 2016. AB - OBJECTIVES: To investigate the trends in the activity of rheumatoid arthritis (RA) over the past 8 years and evaluate the value of treat-to target (T2T) strategy in daily practice. METHODS: All the medical records of RA patients from 2009 to 2016 were retrospectively reviewed. Disease activity scores at obtained visits were measured by DAS28-CRP, DAS28-ESR, SDAI and CDAI. To display trends over years, both mean and time-adjusted methods were applied in calculation of annual disease activity and remission rate. Disease activity and remission rate were also compared before and after the year 2011 when application of T2T strategy was initiated in our centre. Furthermore, a sub-cohort study including T2T and non-T2T period groups was conducted with outcome of cumulative percentage of remission and time to achieve first remission during the first year follow-up. RESULTS: In total, 1,001 patients with 6,944 clinical visits were included. Over an eight-year period, significant improvements were witnessed in disease activity and remission rate, measured by all four indices (p<0.0001). More patients achieved lower disease activity and higher remission rates after T2T adherence in 2011 compared to those in the years 2009 and 2010 (p<0.0001). Moreover, sub cohort study revealed that more patients (49.3-73.2% vs. 19.1-34.5%, OR=2.4-3.0) achieved remission with a shorter median time compared with the non-T2T period group (p<0.0001), particularly in DAS28-CRP (21 vs. >52 weeks), DAS28-ESR (37 vs. >52 weeks). CONCLUSIONS: Over the past 8 years, the RA activity has substantially decreased and T2T strategy was directly attributable to the favourable changes in clinical practice. PMID- 29533755 TI - Efficacy and safety of canakinumab in patients with Still's disease: exposure response analysis of pooled systemic juvenile idiopathic arthritis data by age groups. AB - OBJECTIVES: To describe the efficacy, safety, and exposure-response relationship of canakinumab in a subgroup of patients with systemic juvenile idiopathic arthritis (SJIA) aged >=16 years, representative of adult-onset Still's disease (AOSD) patients, and to compare this subgroup with those of children and young adolescents with SJIA by pooling clinical data collected during the development programme of canakinumab. METHODS: Safety and efficacy data on canakinumab treated patients were pooled from 4 SJIA studies (NCT00426218, NCT00886769, NCT00889863, and NCT00891046). In the majority of patients, canakinumab was administered at 4 mg/kg every 4 weeks. Efficacy parameters (adapted American College of Rheumatology [aACR] paediatric and juvenile idiopathic arthritis [JIA] ACR responses), quality of life, C-reactive protein levels, safety, and exposure response relationship were assessed over 12 weeks in 3 age groups (children 2 <12, young adolescents 12-<16 and older adolescents and young adults >=16 years). RESULTS: Efficacy outcomes were analysed in 216 children, 56 young adolescents and 29 older adolescents and young adults. Efficacy parameters across 3 age groups were largely comparable. At Day 15, at least 50% of patients from each age group exhibited aACR >=70 and ACR responses. The safety profile of canakinumab was similar across age groups. One death was reported. CONCLUSIONS: Pooled analyses from SJIA studies indicate that older adolescents and young adults SJIA patients show similar efficacy, safety, and exposure-response relationship on a weight-based dosing regimen as observed in children and adolescent SJIA patients. These analyses suggest that canakinumab may be an effective therapy in young adults with Still's disease. PMID- 29533756 TI - Comprehensive evaluation of finger flexor tendon entheseal soft tissue and bone changes by ultrasound can differentiate psoriatic arthritis and rheumatoid arthritis. AB - OBJECTIVES: To determine whether a detailed sonographic evaluation of the hand flexor tendon compartment could help differentiate between psoriatic arthritis (PsA) and rheumatoid arthritis (RA). METHODS: Thirty-seven patients with PsA, 47 with RA and 10 healthy controls (HC) had flexor tendon (FT) compartment imaging of the dominant hand 2nd to 4th tendons using grey scale (GS) and power Doppler (PD) ultrasound (US) with evaluation for tenosynovitis, peri-tendinous lesions, soft tissue oedema and bony changes at FT insertions. 24/37 PsA and 19/47 RA cases had morning stiffness and 19/37 PsA and 10/47 RA had swollen and/or tender fingers. RESULTS: Tenosynovitis was more common in PsA (25/37) despite higher DAS28 scores in RA (25/37 versus 10/45; p<0.001). Peri-tendinous dermal soft tissue oedema with associated PD signal was evident in one third of PsA patients but in no RA patients (p=0.003). Flexor tendon enthesopathy including new bone formation at the insertional site was significantly more common in PsA (p=0.001). Considering a total inflammatory score per patient summing up the three modifications of the flexor tendon (tenosynovitis, peri-tendinous oedema and insertional enthesophytes) the difference between PsA and RA remained statistically significant (p<0.001). CONCLUSIONS: Our study adds to the growing body of literature that high resolution US of the hand FT compartment may help differentiate between RA and PsA, which needs assessment in the diagnostic setting. PMID- 29533757 TI - Cause-specific mortality in a large population-based cohort of patients with rheumatoid arthritis in Italy. AB - OBJECTIVES: The aim of our study was to investigate cause-specific mortality in rheumatoid arthritis (RA) subjects living in Italy. METHODS: We identified in the electronic archive of the Veneto Region patients aged 20-89 years who were exempt from co-payment for RA in January 2010, and linked them with the archive of causes of deaths of the period 2010-2015. Causes of death were coded according to the International Classification of Diseases, 10th Edition. Standardised mortality ratios (SMRs) with 95% confidence intervals were computed as the ratios between deaths observed in the cohort, and those expected according to age- and gender-specific regional mortality rates. RESULTS: Overall, 16,098 residents diagnosed with RA and aged 20-89 years were enrolled in the cohort. The overall follow-up amounted to 88,599 person-years, with 2,142 registered decedents. The most common causes of death were circulatory diseases (36.6%), neoplasms (24.2%), and respiratory diseases (8.3%). Overall mortality was increased in RA subjects (SMR=1.42, confidence interval 1.36-1.48). Mortality was significantly increased from circulatory (SMR=1.56, 1.45-1.67), respiratory (SMR=1.83, 1.57-2.12), digestive (SMR=1.93, 1.60-2.32), infectious (SMR=2.34, 1.88-2.89), haematological diseases (SMR=3.22, 2.04-4.83), and falls (SMR=1.95, 1.19-3.01). RA was the underlying cause of death in 6.1% of all deaths in the cohort and was mentioned in 25.4% of death certificates. CONCLUSIONS: In our study, a 42% excess risk of death was observed among subjects with RA compared with the general population. Cardiovascular disease is the primary cause of premature death in RA. Adverse effects of therapy and comorbidities should be adequately monitored in RA subjects. PMID- 29533758 TI - Association of TLR7 gene copy number variations with ankylosing spondylitis in a Chinese population: a case control study. AB - OBJECTIVES: To explore the association of TLR7 gene copy number variations (CNVs) with the susceptibility of ankylosing spondylitis (AS). METHODS: The case control study was performed in 649 Chinese Han patients with AS and 628 healthy controls. The copy numbers of TLR7 gene (2 fragments) were measured by AccuCopyTM methods. Chi-square and logistic regression models were performed to investigate the association of TLR7 gene CNVs with AS. Odds ratio (ORs) and 95% confidence intervals (CIs) was calculated to estimate AS risk and the Bonferroni correction was applied owing to multiple testing. RESULTS: The logistic regression analysis showed that one copy was significantly associated with AS susceptibility after Bonferroni correction (for the TLR7_1 fragment: OR=1.458, 95%CI(1.098,1.936), p=0.009; for the TLR7_2 fragment: OR=1.451, 95%CI (1.093,1.927), p=0.010), and this association still exists after adjustment of age and sex (for the TLR7_1 fragment: adjusted OR=2.066, 95%CI (1.318,3.238), p=0.002; for the TLR7_2 fragment: adjusted OR=2.061, 95%CI (1.315,3.230), p=0.002). However, logistic regression analysis stratified by gender showed a higher OR in males (for the TLR7_1 fragment: OR(95%CI)=7.987(3.756,16.983); for the TLR7_2 fragment: OR(95%CI)=7.947(3.738,16.897)) than in females (for the TLR7_1 fragment: OR(95%CI)=0.204(0.080,0.524); for the TLR7_2 fragment: OR(95%CI)=0.204(0.080,0.524)). CONCLUSIONS: We conclude that the lower copy number (=1) of TLR7 gene confers a risk factor for AS susceptibility in males but protective factor in females. PMID- 29533759 TI - Anti-Mullerian hormone receptor type 2 is expressed in gonadotrophs of postpubertal heifers to control gonadotrophin secretion. AB - Preantral and small antral follicles may secret anti-Mullerian hormone (AMH) to control gonadotrophin secretion from ruminant gonadotrophs. The present study investigated whether the main receptor for AMH, AMH receptor type 2 (AMHR2), is expressed in gonadotrophs of postpubertal heifers to control gonadotrophin secretion. Expression of AMHR2 mRNA was detected in anterior pituitaries (APs) of postpubertal heifers using reverse transcription-polymerase chain reaction. An anti-AMHR2 chicken antibody was developed against the extracellular region near the N-terminus of bovine AMHR2. Western blotting using this antibody detected the expression of AMHR2 protein in APs. Immunofluorescence microscopy using the same antibody visualised colocalisation of AMHR2 with gonadotrophin-releasing hormone (GnRH) receptor on the plasma membrane of gonadotrophs. AP cells were cultured for 3.5 days and then treated with increasing concentrations (0, 1, 10, 100, or 1000pgmL-1) of AMH. AMH (10-1000pgmL-1) stimulated (P<0.05) basal FSH secretion. In addition, AMH (100-1000pgmL-1) weakly stimulated (P<0.05) basal LH secretion. AMH (100-1000pgmL-1) inhibited GnRH-induced FSH secretion, but not GnRH-induced LH secretion, in AP cells. In conclusion, AMHR2 is expressed in gonadotrophs of postpubertal heifers to control gonadotrophin secretion. PMID- 29533760 TI - Abnormal extracellular matrix remodelling in the cervix of pregnant relaxin deficient mice is not associated with reduced matrix metalloproteinase expression or activity. AB - Relaxin regulates cervical extracellular matrix (ECM) remodelling during pregnancy by modifying collagen and other ECM molecules by unknown mechanisms. We hypothesised that abnormal collagen remodelling in the cervix of pregnant relaxin deficient (Rln1-/-) mice is due to excessive collagen (Col1a1 and Col3a1) and decreased matrix metalloproteinases (Mmp2, Mmp9, Mmp13 and Mmp7) and oestrogen receptors (Esr1 and Esr2). Quantitative polymerase chain reaction, gelatinase zymography, MMP activity assays and histological staining evaluated changes in ECM in pregnant wildtype (Rln1+/+) and Rln1-/- mice. Cervical Col1a1, Col3a1 and total collagen increased in Rln1-/- mice and were higher at term compared with Rln1+/+ mice. This was not correlated with a decrease in gelatinase (Mmp2, Mmp9) expression or activity, Mmp7 or Mmp13 expression, which were all significantly higher in Rln1-/- mice. In late pregnancy, circulating MMP2 and MMP9 were unchanged. Esr1 expression was highest in Rln1+/+ and Rln1-/- mice in late pregnancy, coinciding with a decrease in Esr2 in Rln1+/+ but not Rln1-/- mice. The relaxin receptor (Rxfp1) decreased slightly in late-pregnant Rln1+/+ mice, but was significantly higher in Rln1-/- mice. In summary, relaxin deficiency results in increased cervical collagen in late pregnancy, which is not explained by a reduction in Mmp expression or activity or decreased Rxfp1. However, an imbalance between Esr1 and Esr2 may be involved. PMID- 29533761 TI - Evaluation of sperm motility with CASA-Mot: which factors may influence our measurements? AB - Computer-aided sperm analysis (CASA) is now routinely used in IVF clinics, animal breeding centres and research laboratories. Although CASA provides a more objective way to evaluate sperm parameters, a significant number of factors can affect these measurements. This paper classifies these factors into four categories: (1) sample and slide (e.g. preincubation time, type of specimen and type of chamber slide); (2) microscope (e.g. light source and microscope stage); (3) hardware and software, including the settings of each system; and (4) user related factors. We review the effects of the different factors in each category on the measurements made and emphasise the need to take measures to standardise evaluations. The take-home message of the present article is that there are several commercial and useful CASA systems, and all are appropriate for routine analysis. Non-commercial systems may also be good choices when the user needs to adapt the device to specific experimental conditions. In both cases (commercial and non-commercial), it is important that standard protocols are put in place for evaluation, as well as methods to validate the system. PMID- 29533762 TI - Extracts of Tectona grandis and Vernonia amygdalina have anti-Toxoplasma and pro inflammatory properties in vitro. AB - Tectona grandis (teak) and Vernonia amygdalina (bitter leaf) are plants used in traditional medicine in West Africa. In this study, we tested ethanolic and hydro ethanolic extracts of bark and leaves of T. grandis and ethanolic extract of leaves of V. amygdalina for their inhibitory effect on Toxoplasma gondii, a protozoan parasite responsible for toxoplasmosis. Ethanolic extract of V. amygdalina leaves had proportional contents of phenols, tannins, flavonoids, and polysaccharides. This extract presented the highest efficacy against T. gondii, the lowest cytotoxicity to mammalian cells, but moderate anti-oxidant activity compared to other plant extracts. Ethanolic extract of T. grandis bark also had elevated anti-T. gondii activity, low cytotoxicity on mammalian cells, and one of the highest anti-oxidant activities. However, the phytochemical content of this extract was not very different from the hydro-ethanolic extract, which had no anti-T. gondii activity. In addition, ethanolic extract of V. amygdalina leaves, but not of T. grandis bark, significantly increased the production of TNF-alpha and NO by antigen-presenting cells. Both extracts had the tendency to decrease expression of major histocompatibility complex molecules at the surface of antigen-presenting cells, while they did not modulate the percentage of apoptotic cells. A study of signalling pathways would help to determine the mechanisms of action of these plant extracts. PMID- 29533763 TI - Evaluation of the inflammatory response to Kudoa septempunctata genotype ST3 isolated from olive flounder (Paralichthys olivaceus) in Caco-2 cells. AB - Kudoa septempunctata (Myxosporea, Multivalvulida) is a parasite of the trunk muscle of cultured olive flounder (Paralichthys olivaceus). We investigated whether K. septempunctata genotype ST3 spores induce cell damage and the secretion of inflammatory mediators in Caco-2 cells, which exhibit characteristics similar to human intestinal epithelial cells. Purified K. septempunctata spores were heated at 95 degrees C for 5 min. Lactate dehydrogenase (LDH) release was measured to determine the efficacy of denaturation. Naive and heated spores, lipopolysaccharide (positive control) and vehicle (negative control) were added to Caco-2 cells. Cells were subjected to the cytotoxic LDH assay and western blot analysis to examine the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. Supernatants were collected to measure nitric oxide (NO) and prostaglandin E2 (PGE2). Most spores were denaturated by heating, and the spore morphology was found to be wrinkled with shell valves and polar capsules. In addition, cytotoxicity and inflammatory mediators, such as NO, PGE2, iNOS, and COX-2, remained unchanged in Caco-2 cells following exposure to naive and heated spores compared with the positive controls. Collectively, the findings of this study imply that spores of K. septempunctata genotype ST3 do not cause inflammation in Caco-2 cells. PMID- 29533765 TI - Contextual predictability shapes signal autonomy. AB - Aligning on a shared system of communication requires senders and receivers reach a balance between simplicity, where there is a pressure for compressed representations, and informativeness, where there is a pressure to be communicatively functional. We investigate the extent to which these two pressures are governed by contextual predictability: the amount of contextual information that a sender can estimate, and therefore exploit, in conveying their intended meaning. In particular, we test the claim that contextual predictability is causally related to signal autonomy: the degree to which a signal can be interpreted in isolation, without recourse to contextual information. Using an asymmetric communication game, where senders and receivers are assigned fixed roles, we manipulate two aspects of the referential context: (i) whether or not a sender shares access to the immediate contextual information used by the receiver in interpreting their utterance; (ii) the extent to which the relevant solution in the immediate referential context is generalisable to the aggregate set of contexts. Our results demonstrate that contextual predictability shapes the degree of signal autonomy: when the context is highly predictable (i.e., the sender has access to the context in which their utterances will be interpreted, and the semantic dimension which discriminates between meanings in context is consistent across communicative episodes), languages develop which rely heavily on the context to reduce uncertainty about the intended meaning. When the context is less predictable, senders favour systems composed of autonomous signals, where all potentially relevant semantic dimensions are explicitly encoded. Taken together, these results suggest that our pragmatic faculty, and how it integrates information from the context in reducing uncertainty, plays a central role in shaping language structure. PMID- 29533766 TI - From 3D Organoids back to 2D Enteroids. AB - In this issue of Developmental Cell, Thorne et al. (2018) describe a simple, scalable method to culture 2D enteroid monolayers that surprisingly recapitulates many of the features of 3D organoid cultures and in vivo intestinal tissue and can be used for high-throughput microscopy-based experiments. PMID- 29533767 TI - APC Moonlights to Prevent Wnt Signalosome Assembly. AB - The scaffold protein APC has a well-known function in ensuring beta-catenin destruction. In this issue of Developmental Cell, Saito-Diaz et al. (2018) uncover another role for APC in Wnt signaling: to prevent clathrin-dependent signalosome formation in the absence of ligand. PMID- 29533768 TI - FOXO3a Provides a Quickstep from Autophagy Inhibition to Apoptosis in Cancer Therapy. AB - FOXO3a, a member of the Forkhead transcription factor family, has roles in apoptosis and autophagy. In this issue of Developmental Cell, Fitzwalter et al. (2018) describe how the blockade of FOXO3a turnover, which normally occurs through autophagy, sensitizes cancer cells to apoptosis through FOXO3a-mediated stimulation of pro-apoptotic PUMA/BBC3 expression. PMID- 29533769 TI - Did Mitochondria Kill the Frog? AB - Genomic divergence can cause reproductive isolation between species. The molecular mechanisms underlying reproductive isolation can thus reveal which genomic features evolve rapidly and become unstable or incompatible in hybrids. In a recent paper in Nature, Gibeaux et al. (2018) report paternal genome instability and metabolic imbalance in hybrids between frog species. PMID- 29533770 TI - Neutrophil Extracellular Traps: The Biology of Chromatin Externalization. AB - Neutrophils are essential to the homeostatic mission of safeguarding host tissues, responding rapidly and diversely to breaches of the host's barriers to infection, and returning tissues to a sterile state. In response to specific stimuli, neutrophils extrude modified chromatin structures decorated with specific cytoplasmic and granular proteins called neutrophil extracellular traps (NETs). Several pathways lead to this unique form of cell death (NETosis). Extracellular chromatin may have evolved to defend eukaryotic organisms against infection, and its release has at least three functions: trapping and killing of microbes, amplifying immune responses, and inducing coagulation. Here we review neutrophil development and heterogeneity with a focus on NETs, NET formation, and their relevance in host defense and disease. PMID- 29533771 TI - Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. AB - Macroautophagy (autophagy) is intimately linked with cell death and allows cells to evade apoptosis. This has prompted clinical trials to combine autophagy inhibitors with other drugs with the aim of increasing the likelihood of cancer cells dying. However, the molecular basis for such effects is unknown. Here, we describe a transcriptional mechanism that connects autophagy to apoptosis. The autophagy-regulating transcription factor, FOXO3a, is itself turned over by basal autophagy creating a potential feedback loop. Increased FOXO3a upon autophagy inhibition stimulates transcription of the pro-apoptotic BBC3/PUMA gene to cause apoptosis sensitization. This mechanism explains how autophagy inhibition can sensitize tumor cells to chemotherapy drugs and allows an autophagy inhibitor to change the action of an MDM2-targeted drug from growth inhibition to apoptosis, reducing tumor burden in vivo. Thus, a link between two processes mediated via a single transcription factor binding site in the genome can be leveraged to improve anti-cancer therapies. PMID- 29533774 TI - Nr2fs Take the Upper Hand in the Upper Jaw. PMID- 29533772 TI - APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. AB - Adenomatous polyposis coli (APC) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting beta catenin degradation downstream of Wnt receptors. Unexpectedly, we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased beta-catenin levels. In contrast, APC2 loss does not promote receptor activation. We show that APC exists in a complex with clathrin and that Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis. Finally, we demonstrate conservation of this mechanism in Drosophila intestinal stem cells. We propose a model in which APC and APC2 function to promote beta-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway. PMID- 29533775 TI - On the relation between body ownership and sense of agency: A link at the level of sensory-related signals. AB - The relation between sense of body ownership and sense of agency is still highly debated. Here we investigated in a large sample of healthy participants the associations between several implicit and explicit indexes of the two senses. Specifically, we examined the correlations between proprioceptive shift (implicit measure) and questionnaire on the subjective experience of ownership (explicit measure) within the rubber hand illusion paradigm (body ownership), and intentional binding (implicit measure), attenuation of the intensity of auditory outcomes of actions (implicit measure) and questionnaire on the subjective experience of authorship (explicit measure) within the Libet's clock paradigm (sense of agency). Our results showed that proprioceptive shift was positively correlated with the attenuation of auditory outcomes. No significant correlations were found between the explicit measures of the two senses. We argue that the individual spatiotemporal constraints subserving the integration of sensory related signals (implicit signature) would be common to both senses, whereas their subjective experience (explicit signature) would rely on additional processes specific for any given sense. PMID- 29533773 TI - PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis. AB - The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/beta-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation injury, genetic ablation of PAF impairs intestinal regeneration along with the severe loss of ISCs and Myc expression. Mechanistically, PAF conditionally occupies and transactivates the c-Myc promoter, which induces the expansion of ISCs/IPCs during intestinal regeneration. In mouse models, PAF knockout inhibits Apc inactivation-driven intestinal tumorigenesis with reduced tumor cell stemness and suppressed Wnt/beta catenin signaling activity, supported by transcriptome profiling. Collectively, our results unveil that the PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells. PMID- 29533776 TI - Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues. AB - Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism. PMID- 29533777 TI - Targeting mRNA Decapping in AML. AB - In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3'-to-5' mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery. PMID- 29533778 TI - ORY-1001: Overcoming the Differentiation Block in AML. AB - In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001-an oral, highly potent and selective covalent small molecule inhibitor of lysine-specific demethylase 1 (LSD1)-in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001. PMID- 29533779 TI - A Non-canonical Polycomb Dependency in Synovial Sarcoma. AB - Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state. PMID- 29533780 TI - Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization. AB - Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype. PMID- 29533781 TI - PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. AB - Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRASG12D induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs. PMID- 29533782 TI - BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency. AB - Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple in vivo models. PMID- 29533783 TI - Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis. AB - Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies. PMID- 29533784 TI - NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma. AB - Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities. PMID- 29533785 TI - Systematic Functional Annotation of Somatic Mutations in Cancer. AB - The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development. PMID- 29533786 TI - Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. AB - Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8+ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-gamma produced by CD8+ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8+ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications. PMID- 29533788 TI - Biomaterial scaffolds for non-invasive focal hyperthermia as a potential tool to ablate metastatic cancer cells. AB - Currently, there are very few therapeutic options for treatment of metastatic disease, as it often remains undetected until the burden of disease is too high. Microporous poly(epsilon-caprolactone) biomaterials have been shown to attract metastasizing breast cancer cells in vivo early in tumor progression. In order to enhance the therapeutic potential of these scaffolds, they were modified such that infiltrating cells could be eliminated with non-invasive focal hyperthermia. Metal disks were incorporated into poly(epsilon-caprolactone) scaffolds to generate heat through electromagnetic induction by an oscillating magnetic field within a radiofrequency coil. Heat generation was modulated by varying the size of the metal disk, the strength of the magnetic field (at a fixed frequency), or the type of metal. When implanted subcutaneously in mice, the modified scaffolds were biocompatible and became properly integrated with the host tissue. Optimal parameters for in vivo heating were identified through a combination of computational modeling and ex vivo characterization to both predict and verify heat transfer dynamics and cell death kinetics during inductive heating. In vivo inductive heating of implanted, tissue-laden composite scaffolds led to tissue necrosis as seen by histological analysis. The ability to thermally ablate captured cells non-invasively using biomaterial scaffolds has the potential to extend the application of focal thermal therapies to disseminated cancers. PMID- 29533787 TI - Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors. AB - KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating DeltaNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies. PMID- 29533789 TI - "Stepwise Extraction" strategy-based injectable bioresponsive composite implant for cancer theranostics. AB - "Smart" bioresponsive materials, which are sensitive to biological signals or pathological abnormalities, are appealing therapeutic platforms for the development of next-generation cancer theranostics. In this work, a novel "stepwise extraction" strategy has been proposed and demonstrated in constructing injectable bioresponsive composite implant, which features unique theranostic responsivenesses to exogenous and external triggers. The as-designed implant exhibits theranostic functions and biodegradability for cancer treatment based on the change of intratumoral microenvironment and the needs of therapeutic process. This "stepwise extraction" process, that is, "solvent extraction", "manganese extraction" and "phosphorus extraction", significantly promoted the biodegradation and disintegration of the bioresponsive implant step by step, accompanied by the corresponding component releases from the PLGA framework and furthermore, accomplished different specific theranostic functions needed at different treatment stages. This is the first demonstration of bioresponsive organic-inorganic hybrid implant with marked theranostic functions and excellent biodegradability by a "stepwise extraction" approach, paving the way to the solutions of unsatisfactory therapeutic efficacy and strong side effects in current cancer therapeutic modalities. PMID- 29533790 TI - Associations of carotid arterial compliance and white matter diffusion metrics during midlife: modulation by sex. AB - Sex differences in cerebral white matter (WM) aging have been debated extensively over the past 2 decades without unequivocal resolution. We aimed to determine if the effects of age and arterial stiffness on WM microstructure differ between sexes. Artery elasticity via carotid artery compliance (CAC) and WM diffusion metrics via diffusion tensor image-derived fractional anisotropy (FA) and mean diffusivity (MD) were measured in 155 (87 females) middle-aged (40-62 years) adults. Males demonstrated poorer water diffusion metrics in WM than women in the corpus callosum body, cingulum, and cingulum (hippocampal). Age and CAC had greater effects on WM water diffusion in males than females in midlife independent of education and cardiovascular risk factors. Sex-moderated age (cingulum FA, cingulum [hippocampal] MD, and uncinate MD, all p < 0.05) and CAC (cingulum FA, p < 0.05) related reductions in regional WM diffusion metrics. CAC mediated age-related associations in regional WM diffusion metrics (cingulum FA, cingulum MD, superior corona radiata MD, and uncinate MD, all p < 0.05) in males but not in females. Age and CAC were associated with WM diffusion metrics independent of cardiovascular risk factors. These associations appear to be stronger in males than in females. PMID- 29533791 TI - Supragingival and subgingival microbiota from patients with poor oral hygiene submitted to radiotherapy for head and neck cancer treatment. AB - OBJECTIVE: This case-control study aimed to evaluate the effects of conventional radiotherapy (RT) on the prevalence and populations of oral microorganisms in head and neck cancer patients who did not receive adequate preventive dental care. It was hypothesized that side effects of radiotherapy could be associated with radiation dose, microbiological aspects, and socioeconomic conditions of the patients. DESIGN: Twenty-eight dentate patients with head and neck cancer submitted to RT were included in the study. Radiation dose received varied from 4320 to 7020 cGy. Patients with the same demographic and health conditions, but no history of cancer or antineoplastic treatment were used as controls. Clinical examinations were carried out before RT, 15-22 days after starting RT, immediately after and 6 months after RT. Supra and subgingival biofilms were collected and cultivated onto selective and non-selective media. Isolates were identified by biochemical and physiological characteristics. Stimulated and unstimulated salivary flow rate and saliva buffer capacity were also determined. RESULTS: Mucositis, dermatitis, xerostomia, dysgeusia, dysphagia and candidiasis were common after starting RT and during the treatment period. Xerostomia was followed by a decrease in salivary pH and buffer capacity, which showed association with the increase of cariogenic cocci and yeast populations, which were also associated with deterioration of hygiene. Candida and family Enterobacteriaceae showed increased prevalence with RT, and were associated with the occurrence of mucositis and xerostomia. CONCLUSIONS: Modifications in oral biofilms of irradiated patients showed association with xerostomia and hygiene conditions, which reinforces the necessity of improving patient compliance to oral health care programs. PMID- 29533792 TI - Removal of dissolved organic matter and control of membrane fouling by a hybrid ferrihydrite-ultrafiltration membrane system. AB - This study investigated the pretreatment effect of ferrihydrite (FH) on the removal of dissolved organic matter (DOM) and membrane fouling control in a hybrid adsorption-ultrafiltration (UF) membrane system. Powdered activated carbon (PAC) was chosen for comparative study, and three surrogates, namely, humic acid (HA), sodium alginate (SA) and bovine serum albumin, were applied in feed water to simulate humic substances, polysaccharides and proteins, respectively. In the hybrid adsorption-membrane system, the impacts of adsorbent cake layers on DOM removal and membrane fouling were systematically investigated. The results demonstrated that FH effectively removed both high-molecular-weight (MW) and low MW HA and SA molecules via ligand exchange and mitigated membrane fouling substantially, regardless of whether FH particles were removed from the feed water before UF. In addition, the large flocs induced by FH and calcium contributed to loose FH layers. In contrast, PAC had almost no capacity to adsorb high-MW DOM molecules due to the microporous structure. And FH was more efficient in removal of DOM and control of membrane fouling than PAC. The different DOM adsorption capacities of FH and PAC lead to different effects on membrane fouling caused by deposition of DOM molecules and cake layers. These results offer guidance for application of hybrid adsorption-membrane filtration systems. PMID- 29533793 TI - Silica nanoparticles promote oxLDL-induced macrophage lipid accumulation and apoptosis via endoplasmic reticulum stress signaling. AB - Oxidized low-density lipoprotein (oxLDL), a marker of hyperlipidemia, plays a pivotal role in the development of atherosclerosis through the induction of macrophage-derived foam cell formation and thereafter apoptosis. Previous studies have indicated that silica nanoparticle (SiNPs) may exert a proatherogenic role, which could induce endothelial dysfunction, and monocytes infiltration. However, little is known about SiNPs' effects on macrophage-derived foam cell formation and apoptosis in the pathogenesis of atherosclerosis. In this study, we investigated the effects of SiNPs and oxLDL coexposure on macrophage-derived lipid metabolism, foam cell and apoptosis by using Raw264.7 cells. As a result, SiNPs enhanced cytotoxicity, apoptosis, and lipid accumulation upon oxLDL stimulation. Furthermore, quantitative determination of the expression levels of genes involved in cholesterol influx or efflux showed significantly up-regulated expressions of CD36 and SRA, whereas down-regulated expressions of ATP-binding cassette A1 (ABCA1), ABCG1, and SRB1 in oxLDL-treated macrophages, especially upon the co-exposure with SiNPs. It indicated that SiNPs promoted lipid accumulation in macrophage cells through not only facilitating cholesterol influx but also inhibiting cholesterol efflux. Endoplasmic reticulum (ER) is specialized for the production, modification, even trafficking of lipids. Interestingly, ER response was triggered upon oxLDL treatment, while SiNPs coexposure augmented the ER stress. Taken together, our results revealed that SiNPs promoted oxLDL-induced macrophage foam cell formation and apoptosis, which may be mediated by ER stress signaling. Thus we propose future researches needed for a better understanding of NPs' toxicity and their interactions with various pathophysiological conditions. PMID- 29533794 TI - Experimental evidence of REE size fraction redistribution during redox variation in wetland soil. AB - The evolution of rare earth element (REE) speciation between reducing and oxidizing conditions in a riparian wetland soil was studied relative to the size fractionation of the solution. In all size fractions obtained from the reduced and oxidized soil solutions, the following analyses were carried out: organic matter (OM) characterization, transmission electron microscopy (TEM) observations as well as major and trace element analyses. Significant REE redistribution and speciation evolution between the various size fractions were observed. Under reducing conditions, the REEs were bound to colloidal and dissolved OM (<2MUm size fractions). By contrast, under oxidizing conditions, they were distributed in particulate (>2MUm size fraction), colloidal (<2MUm size fraction), organic and Fe-enriched fractions. In the particulate size fraction, the REEs were bound to humic and bacterial OM embedding Fe nano-oxides. The resulting REE pattern showed a strong enrichment in heavy REEs (HREEs) in response to REE binding to specific bacterial OM functional groups. In the largest colloidal size fraction (0.2MUm-30kDa), the REEs were bound to humic substances (HS). The lowest colloidal size fraction (<30kDa) is poorly concentrated in the REEs and the REE pattern showed an increase in the middle REEs (MREEs) and heavy REEs (HREEs) corresponding to a low REE loading on HS. A comparison of the REE patterns in the present experimental and field measurements demonstrated that, in riparian wetlands, under a high-water level, reducing conditions are insufficient to allow for the dissolution of the entire Fe nano-oxide pool formed during the oxidative period. Therefore, even under reducing conditions, Fe(III) seems to remain a potential scavenger of REEs. PMID- 29533795 TI - Association of acrylamide hemoglobin biomarkers with obesity, abdominal obesity and overweight in general US population: NHANES 2003-2006. AB - Exposure to chemical contaminants is considered as one of risk factors to the current epidemic of obesity. Acrylamide (AA) is a ubiquitous chemical contaminant in environmental waste, mainstream cigarette smoke and carbohydrate-rich foods, and widely used in industrial manufacturers and cosmetics. Few studies have highlighted the association of daily exposure to AA with obesity-related outcomes. We analyzed data from 8364 participants who aged 20-85years and were recruited in National Health and Nutrition Examination Surveys (NHANES) 2003 2006. We established the model of PROC Survey Logistic regressions via using AA biomarkers in blood, hemoglobin adducts of acrylamide and glycidamide (HbAA and HbGA), as the measure of internal exposure to AA, and assessing obesity, abdominal obesity and overweight with body mass index (BMI) or waist circumference (WC). After the adjustment of sociodemographic variables, lifestyle behaviors, and health-related factors, the ratio of HbGA to HbAA (HbGA/HbAA) was significantly associated with obesity (p for trend<0.0001). The odd ratios (ORs) with 95% confidence intervals (CIs) of HbGA/HbAA across increasing quartiles were 1.740 (1.413-2.144), 2.604 (2.157-3.144), and 2.863 (2.425-3.380) compared with the lowest quartile. HbGA was positively associated with obesity [OR (95% CI): 1.226 (1.041-1.443), 1.283 (1.121-1.468), and 1.398 (1.165-1.679); p for trend=0.0004], while HbAA was inversely associated with obesity [OR (95% CI): 0.839 (0.718-0.980), 0.713 (0.600-0.848), and 0.671 (0.554-0.811); p for trend<0.0001]. Negative associations were found between the sum of HbAA and HbGA (HbAA+HbGA) and the body weight outcomes. Similar associations were also observed between the hemoglobin biomarkers of AA and abdominal obesity as well as overweight. Thus, the hemoglobin adducts of AA as long-term internal exposure biomarkers are strongly associated with obesity-related outcomes in a population of US adults. PMID- 29533796 TI - Sediment dynamics in a large shallow lake characterized by seasonal flood pulse in Southeast Asia. AB - Most of studies on sediment dynamics in stable shallow lakes focused on the resuspension process as it is the dominant process. However, understanding of sediment dynamics in a shallow lake influenced by flood pulse is unclear. We tested a hypothesis that floodplain vegetation plays as a significant role in lessening the intensity of resuspension process in a shallow lake characterized by the flood pulse system. Therefore, this study aimed to investigate sediment dynamics in this type of shallow lake. The target was Tonle Sap Lake (TSL), which is a large shallow lake influenced by a flood pulse system of Mekong River located in Southeast Asia. An extensive and seasonal sampling survey was conducted to measure total suspended solid (TSS) concentrations, sedimentation and resuspension rates in TSL and its 4 floodplain areas. The study revealed that sedimentation process was dominant (TSS ranged: 3-126mgL-1) in the high water period (September-December) while resuspension process was dominant (TSS ranged: 4-652mgL-1) only in the low water period (March-June). In addition, floodplain vegetation reduced the resuspension of sediment (up to 26.3%) in water. The implication of the study showed that resuspension is a seasonally dominant process in shallow lake influenced by the flood pulse system at least for the case of TSL. PMID- 29533797 TI - Oxidative degradation of the antibiotic oxytetracycline by Cu@Fe3O4 core-shell nanoparticles. AB - A core-shell nanostructure composed of zero-valent Cu (core) and Fe3O4 (shell) (Cu@Fe3O4) was prepared by a simple reduction method and was evaluated for the degradation of oxytetracycline (OTC), an antibiotic. The Cu core and the Fe3O4 shell were verified by X-ray diffractometry (XRD) and transmission electron microscopy. The optimal molar ratio of [Cu]/[Fe] (1/1) in Cu@Fe3O4 created an outstanding synergic effect, leading to >99% OTC degradation as well as H2O2 decomposition within 10min at the reaction conditions of 1g/L Cu@Fe3O4, 20mg/L OTC, 20mM H2O2, and pH3.0 (and even at pH9.0). The OTC degradation rate by Cu@Fe3O4 was higher than obtained using single nanoparticle of Cu or Fe3O4. The results of the study using radical scavengers showed that OH is the major reactive oxygen species contributing to the OTC degradation. Finally, good stability, reusability, and magnetic separation were obtained with approximately 97% OTC degradation and no notable change in XRD patterns after the Cu@Fe3O4 catalyst was reused five times. These results demonstrate that Cu@Fe3O4 is a novel prospective candidate for the pharmaceutical and personal care products degradation in the aqueous phase. PMID- 29533798 TI - Vegetation carbon stocks driven by canopy density and forest age in subtropical forest ecosystems. AB - Subtropical forests play an important role in global carbon cycle and in mitigating climate change. Knowledge on the abiotic and biotic driving factors that affect vegetation carbon stocks in subtropical forest ecosystems is needed to take full advantage of the carbon sequestration potential. We used a large scale database from national forest continuous inventory in Zhejiang Province, and combined the Random Forest analysis (RF) and structural equation modeling (SEM) to quantify the contribution of biotic and abiotic driving factors on vegetation carbon stocks, and to evaluate the direct and indirect effects of the main driving factors. The RF model explained 50% of the variation in vegetation carbon stocks; canopy density accounted for 17.9%, and forest age accounted for 7.0%. Moreover, the SEM explained 52% of the variation in vegetation carbon stocks; the value of standardized total effects of canopy density and forest age were 0.469 and 0.327, respectively, suggesting that they were the most crucial driving factors of vegetation carbon stocks. Since the forests in our study were relatively young, the forests had a large potential for carbon sequestration. Overall, our study provided new insights into the sensitivity and potential response of subtropical forest ecosystems carbon cycle to climate change. PMID- 29533799 TI - Ambient volatile organic compounds (VOCs) in Calgary, Alberta: Sources and screening health risk assessment. AB - Exposure to ambient volatile organic compound (VOCs) in urban areas is of interest because of their potential chronic and acute adverse effects to public health. Limited information is available about VOC sources in urban areas in Canada. An investigation of ambient VOCs levels, their potential sources and associated risks to public health was undertaken for the urban core of Alberta's largest city (downtown Calgary) for the period 2010-2015. Twenty-four hour arithmetic and geometric mean concentrations of total VOCs were 42MUg/m3 and 39MUg/m3, respectively and ranged from 16 to 160MUg/m3, with winter levels about two-fold higher than summer. Alkanes (58%) were the most dominant compounds followed by halogenated VOCs (22%) and aromatics (11%). Mean and maximum 24h ambient concentrations of selected VOCs of public health concern were below chronic and acute health risk screening criteria of the United States regulatory agencies and a cancer screening benchmark used in Alberta equivalent to 1 in 100,000 lifetime risk. The Positive matrix factorization (PMF) model revealed nine VOC sources at downtown Calgary, where oil/natural gas extraction/combustion (26%), fuel combustion (20%), traffic sources including gasoline exhaust, diesel exhaust, mixed fugitive emissions (10-15%), and industrial coatings/solvents (12%) were predominant. Other sources included dry cleaning (3.3%), biogenic (3.5%) and a background source (18%). Source-specific health risk values were also estimated. Estimated cancer risks for all sources were below the Alberta cancer screening benchmark, and estimated non-cancer risks for all sources were well below a safe level. PMID- 29533800 TI - A multi-isotopic approach to investigate the influence of land use on nitrate removal in a highly saline lake-aquifer system. AB - Endorheic or closed drainage basins in arid and semi-arid regions are vulnerable to pollution. Nonetheless, in the freshwater-saltwater interface of endorheic saline lakes, oxidation-reduction (redox) reactions can attenuate pollutants such as nitrate (NO3-). This study traces the ways of nitrogen (N) removal in the Petrola lake-aquifer system (central Spain), an endorheic basin contaminated with NO3- (up to 99.2mg/L in groundwater). This basin was declared vulnerable to NO3- pollution in 1998 due to the high anthropogenic pressures (mainly agriculture and wastewaters). Hydrochemical, multi-isotopic (delta18ONO3, delta15NNO3, delta13CDIC, delta18OH2O, and delta2HH2O) and geophysical techniques (electrical resistivity tomography) were applied to identify the main redox processes at the freshwater-saltwater interface. The results showed that the geometry of this interface is influenced by land use, causing spatial variability of nitrogen biogeochemical processes over the basin. In the underlying aquifer, NO3- showed an average concentration of 38.5mg/L (n=73) and was mainly derived from agricultural inputs. Natural attenuation of NO3- was observed in dryland farming areas (up to 72%) and in irrigation areas (up to 66%). In the Petrola Lake, mineralization and organic matter degradation in lake sediment play an important role in NO3- reduction. Our findings are a major step forward in understanding freshwater-saltwater interfaces as reactive zones for NO3- attenuation. We further emphasize the importance of including a land use perspective when studying water quality-environmental relationships in hydrogeological systems dominated by density-driven circulation. PMID- 29533801 TI - An ultra-high surface area mesoporous carbon prepared by a novel MnO-templated method for highly effective adsorption of methylene blue. AB - Mesoporous carbon is considered as the most effective adsorbent for dyes with large molecule diameter. In this study, an ultra-high surface area mesoporous carbon was derived using a kind of new template precursors (manganese salts), i.e. manganese carbonate (MC), manganese oxalate (MO) and manganese acetate (MA). The XRD results demonstrated that after the pyrolysis of the mixture of manganese salts and poly(vinyl alcohol) (PVA) over 500 degrees C, MnO was only the Mn species on carbon and the particle sizes of the generated MnO were in the range of 1.92-15.11 nm, with the lowest value derived from MO. All prepared carbons presented evident mesoporous characteristics, with higher specific surface areas (SBET) at 2138 m2/g, mesopore volume (Vmeso) at 3.56 cm3/g, and mesopore ratios > 95%, together with the lowest and narrowest mesopore size distribution, for the MO-templated sample. The sample had high adsorption capacities for methylene blue, up to 1791 mg/g, and extremely fast adsorption rates with the adsorption equilibrium time within 1 min, which was significantly higher than previous studies. The results demonstrated that the novel MnO-templated method is very promising for the preparation of high surface area mesoporous carbon for highly effective adsorption of methylene blue. PMID- 29533802 TI - Remediation of hydrocarbons polluted water by hydrophobic functionalized cellulose. AB - Remediation of water bodies from petroleum hydrocarbons is of the utmost importance due to health risks related to the high toxicity, mutagenicity and carcinogenicity of the hydrocarbons components that may enter into the food chain. Though several methods were proposed to face up this challenge, they are generally not easily feasible at a contaminated site and quite costly. Here we propose a green, cost-effective technology based on hydrophobized Spanish Broom (SB) cellulose fiber. The natural cellulose fiber was extracted by alkaline digestion of the raw vegetable. The hydrophilic cellulose surface was transformed into a hydrophobic one by the reaction with 4,4'-diphenylmethane diisocyanate (MDI) forming a very stable urethane linkage with the hydroxyl groups of cellulose emerging from the fibers surface. Chemical functionalization was performed with a novel solvent-free technology based on a home-made still reactor were the fiber was kept under vortex stirring and the MDI reactant then spread onto the fiber surface by nebulizing it in form of micrometer-sized droplets. The functionalized fiber, characterized by means of WCA measurements, XPS and ATR FTIR spectroscopy, shows fast adsorption kinetics adsorption capacity as high as 220 mg/g, among the highest ever reported so far in the literature for cellulosic materials. PMID- 29533804 TI - The reduced-risk insecticide azadirachtin poses a toxicological hazard to stingless bee Partamona helleri (Friese, 1900) queens. AB - Large-scale pesticide application poses a major threat to bee biodiversity by causing a decline in bee populations that, in turn, compromises ecosystem maintenance and agricultural productivity. Biopesticides are considered an alternative to synthetic pesticides with a focus on reducing potential detrimental effects to beneficial organisms such as bees. The production of healthy queen stingless bees is essential for the survival and reproduction of hives, although it remains unknown whether biopesticides influence stingless bee reproduction. In the present study, we investigated the effects of the biopesticide azadirachtin on the survival, behavior, morphology, development, and reproduction of queens of the stingless bee Partamona helleri (Friese, 1900). The neonicotinoid imidacloprid was used as a toxic reference standard. Queens were orally exposed in vitro to a contaminated diet (containing azadirachtin and imidacloprid) during development. Azadirachtin resulted in reduced survival, similarly to imidacloprid, altered development time, caused deformations, and reduced the size of the queens' reproductive organs. All of these factors could potentially compromise colony survival. Results from the present study showed azadirachtin posed a toxicological hazard to P. helleri queens. PMID- 29533803 TI - Endocrine activity in an urban river system and the biodegradation of estrogen like endocrine disrupting chemicals through a bio-analytical approach using DRE- and ERE-CALUX bioassays. AB - The Zenne River, crossing the Brussels region (Belgium) is an extremely urbanized river impacted by both domestic and industrial effluents. The objective of this study was to monitor the occurrence and activity of Endocrine Active Substances (EAS) in river water and sediments in the framework of the Environmental Quality Standards Directive (2008/105/EC and 2013/39/EU). Activities were determined using Estrogen and Dioxin Responsive Elements (ERE and DRE) Chemical Activated Luciferase Gene Expression (CALUX) bioassays. A potential contamination source of estrogen active compounds was identified in the river at an industrial area downstream from Brussels with a peak value of 938 pg E2 eq./L water (above the EQS of 0.4 ng/L) and 195 pg E2 eq./g sediment. Estrogens are more abundantly present in the sediments than in the dissolved phase. Principal Component Analysis (PCA) showed high correlations between Suspended Particulate Matter (SPM), Particulate (POC) and Dissolved Organic Carbon (DOC) and estrogenic EAS. The dioxin fractions comply with previous data and all were above the United States Environmental Protection Agency (US EPA) low-level risk, with one (42 pg TCDD eq./g sediment) exceeding the high-level risk value for mammals. The self purifying ability of the Zenne River regarding estrogens was examined with an in vitro biodegradation experiment using the bacterial community naturally present in the river. Hill coefficient and EC50 values (Effective Concentration at 50%) revealed a process of biodegradation in particulate and dissolved phase. The estrogenic activity was decreased by 80%, demonstrating the ability of self purification of estrogenic compounds in the Zenne River. PMID- 29533805 TI - Kinetics and mechanism of OH-initiated atmospheric oxidation of organophosphorus plasticizers: A computational study on tri-p-cresyl phosphate. AB - Understanding the atmospheric fate of organophosphorus plasticizers is important for their environmental risk assessment. However, limited information is available at present. In this study, density functional theory (DFT) calculations were performed to investigate the transformation mechanism and kinetics of tri-p cresyl phosphate (TpCP) initiated by OH. Results show that the initial reactions are dominated by H-abstraction and OH addition to form TpCP-radical, TpCP-OH adducts and aryl phosphodiester. The H-abstraction pathways are more favorable than the OH addition pathways. The TpCP-radical and TpCP-OH adducts can further react with O2 in the atmosphere to finally form benzaldehyde phosphate, hydroxylated TpCP and bicyclic radicals. Based on the transition state theory, the calculated rate constant (kOH) of TpCP with OH at T = 298 K is 1.9 * 10-12 cm3molecule-1s-1 with an atmospheric lifetime of 4.2 days, which demonstrates that gaseous TpCP is atmospherically persistent. This study provides a comprehensive investigation of the OH-initiated oxidation of TpCP, which is useful for understanding its mechanism of transformation and evaluating the risk in atmospheric environment. PMID- 29533806 TI - Ca2+ metabolic disorder and abnormal expression of cardiac troponin involved in fluoride-induced cardiomyocyte damage. AB - Our previous study indicated that excessive fluoride (F) induces ATP5J and ATP5H proactive expression by interfering cardiomyocyte mitochondrial dysfunction in mice. This study aimed to investigate underlying mechanisms of F- induced damage to cardiomyocytes. A total of 100 mg/L F- was added to distilled water to treat Kunming mice for 70 days. Pathological and morphological changes in myocardial tissues were observed under transmission electron microscope and light microscope. Content of ATP and ATP enzyme distributed in cardiomyocytes were determined by fluorescence and ATP enzyme staining. Expression levels of troponin (Tn) C, TnI, TnT and tropomyosin (TPM) were measured by immunofluorescence, western blot, and real-time polymerase chain reaction. Contents of Ca2+ in blood, myocardial cells and faeces were also detected by confocal microscopy and ethylenediaminetetraacetic acid. Using 100 mg/L F- resulted in nuclaer enrichment, the myocardial fibre breakage and mitochondrial lysis. Following mitochondrial structure damage, contents of ATP and ATP enzyme significantly decreased in the fluoride group. Expression levels of TnT and TnI were significantly down-regulated, whereas that of TPM was up-regulated. Content of Ca2+ in cardiomyocytes of fluoride group visibly increased. Interestingly, contents of Ca2+ in blood and faeces decreased. These findings reveal that excessive F ingestion induces Ca2+ metabolic disorder, and an abnormal expression of cardiac Tn are involved in F-induced cardiomyocyte damage. PMID- 29533807 TI - BDD anodic treatment of 6:2 fluorotelomer sulfonate (6:2 FTSA). Evaluation of operating variables and by-product formation. AB - The concerns about the undesired impacts on human health and the environment of long chain perfluorinated alkyl substances (PFASs) have driven industrial initiatives to replace PFASs by shorter chain fluorinated homologues. 6:2 fluorotelomer sulfonic acid (6:2 FTSA) is applied as alternative to PFOS in metal plating and fluoropolymer manufacture. This study reports the electrochemical treatment of aqueous 6:2 FTSA solutions on microcrystalline BDD anodes. Bench scale batch experiments were performed, focused on assessing the effect of the electrolyte and the applied current density (5-600 A m-2) on the removal of 6:2 FTSA, the reduction of total organic carbon (TOC) and the fluoride release. Results showed that at the low range of applied current density (J = 50 A m-2), using NaCl, Na2SO4 and NaClO4, the electrolyte exerted a minimal effect on removal rates. The formation of toxic inorganic chlorine species such as ClO4- was not observed. When using Na2SO4 electrolyte, increasing the applied current density to 350-600 A m-2 promoted a notable enhancement of the 6:2 FTSA removal and defluorination rates, pointing to the positive contribution of electrogenerated secondary oxidants to the overall removal rate. 6:2 FTSA was transformed into shorter-chain PFCAs, and eventually into CO2 and fluoride, as TOC reduction was >90%. Finally, it was demonstrated that diffusion in the liquid phase was controlling the overall kinetic rate, although with moderate improvements due to secondary oxidants at very high current densities. PMID- 29533808 TI - Illumina MiSeq sequencing reveals microbial community in HA process for dyeing wastewater treatment fed with different co-substrates. AB - In present study, a hydrolysis acidification (HA) reactor was used for simulated dyeing wastewater treatment. Co-substrates included starch, glucose, sucrose, yeast extract (YE) and peptone were fed sequentially into the HA reactor to enhance the HA process effects. The performance of the HA reactor and the microbial community structure in HA process were investigated under different co substrates conditions. Results showed that different co-substrates had different influences on the performance of HA reactor. The highest decolorization (50.64%) and COD removal rate (60.73%) of the HA reactor were obtained when sucrose was as the co-substrate. And it found that carbon co-substrates starch, glucose and sucrose exhibited better decolorization and higher COD removal efficiency of the HA reactor than the nitrogen co-substrates YE and peptone. Microbial community structure in the HA process was analyzed by Illumina MiSeq sequencing. Results revealed different co-substrates had different influences on the community structure and microbial diversity in HA process. It was considered that sucrose could enrich the species such as Raoultella, Desulfovibrio, Tolumonas, Clostridium, which might be capable of degrading the dyes. Sucrose was considered to be the best co-substrate of enhancing the HA reactor's performance in this study. This work would provide deep insight into the influence of many different co-substrates on HA reactor performance and microbial communities in HA process. PMID- 29533809 TI - Roles of MSH2 and MSH6 in cadmium-induced G2/M checkpoint arrest in Arabidopsis roots. AB - DNA mismatch repair (MMR) proteins have been implicated in sensing and correcting DNA damage, and in governing cell cycle progression in the presence of structurally anomalous nucleotide lesions induced by different stresses in mammalian cells. Here, Arabidopsis seedlings were grown hydroponically on 0.5 * MS media containing cadmium (Cd) at 0-4.0 mg L-1 for 5 d. Flow cytometry results indicated that Cd stress induced a G2/M cell cycle arrest both in MLH1-, MSH2-, MSH6-deficient, and in WT roots, associated with marked changes of G2/M regulatory genes, including ATM, ATR, SOG1, BRCA1, WEE1, CYCD4; 1, MAD2, CDKA;1, CYCB1; 2 and CYCB1; 1. However, the Cd-induced G2/M phase arrest was markedly diminished in the MSH2- and MSH6-deficient roots, while a lack of MLH1 had no effect on Cd-induced G2 phase arrest relative to that in the wild type roots under the corresponding Cd stress. Expression of the above G2/M regulatory genes was altered in MLH1, MSH2 and MSH6-deficient roots in response to Cd treatment. Furthermore, Cd elicited endoreplication in MSH2- and MSH6-deficient roots, but not in MLH1-deficient Arabidopsis roots. Results suggest that MSH2 and MSH6 may act as direct sensors of Cd-mediated DNA damage. Taken together, we conclude that MSH2 and MSH6, but not MLH1, components of the MMR system are involved in the G2 phase arrest and endoreplication induced by Cd stress in Arabidopsis roots. PMID- 29533810 TI - Phytoremediated marine sediments as suitable peat-free growing media for production of red robin photinia (Photinia x fraseri). AB - Sediments dredged by an industrial port, slightly contaminated by heavy metals and petroleoum hydrocarbons, were phytoremediated and used as peat-free growing media for the red robin photinia (Photinia x fraseri L.). Plants were grown on sediment only (S), sediment mixed with composted pruning residues (S + PR), sediment fertilized with controlled release fertilizers (S + F) and peat-based growing media as control (C). Plant elongation and dry weight, leaf contents of chlorophyll, malondialdehyde (MDA), macronutrients and heavy metals were determined at the end of one growing season. Environmental impact related to the use of sediment-based as compared to peat-based growing media was assessed by the Life Cycle Analysis (LCA). Sediment-based growing media presented significantly higher bulk density, pH and electrical conductivity values, lower C and N contents, and significantly higher total and available P. Red robin photinia grown on S + F growing media showed morphological and chemical parameters similar to those of control plants (C), whereas plants grown on S and S + PR showed lower growth. Leaf concentration of nutrients and heavy metals varied depending on the considered element and growing media, but were all within the common values for ornamental plants, whereas the highest MDA concentrations were found in plants grown on traditional growing media. The LCA indicated the use of sediments as growing media reduced the C footprint of ornamental plant production and the contribute of growing media to the environmental impact per produced plant. We concluded that sediments phytoremediation and use in plant nursery is a practical alternative re-use option for dredged sediments. PMID- 29533811 TI - Fe(II)-regulated moderate pre-oxidation of Microcystis aeruginosa and formation of size-controlled algae flocs for efficient flotation of algae cell and organic matter. AB - The coagulation/flocculation/flotation (C/F/F) process is becoming a popular method for algae-laden water treatment. However, the efficiency of flotation is highly dependent on the ability of the preceding coagulation/flocculation process to form flocculated algae flocs. This study aims to improve the Microcystis aeruginosa flotation efficiency from algae cell and organic matter aspects by applying Fe(II)-regulated pretreatment enhanced Al coagulation process. The ability of the C/F/F process to remove cyanobacterial cells can be enhanced from 8% to 99% at a Fe(II) dose of 30 MUM. The Al dose needed can be reduced by more than half while achieving successful flotation. The introduced Fe(II) after KMnO4 can not only realize moderate pre-oxidation of cyanobacterial cells, but also form in-situ Fe(III). The DOC value can also be decreased significantly due to the formation of in-situ Fe(III), which is more efficient in dissolved organic matter (DOM) removal compared with pre-formed Fe(III). In addition, the gradually hydrolyzed in-situ Fe(III) can facilitate the hydrolysis of Al as a dual coagulant and promote the clustering and cross-linking of Al hydrolyzates, which can enhance the formation of size-controlled algae flocs. Finally, the size controlled algae flocs can be effectively floated by the bubbles released in the flotation process due to the efficient collision and attachment between flocs and bubbles. Therefore, the efficient flotation of algae cell and organic matter can be realized by the Fe(II) regulated moderate pre-oxidation of M. aeruginosa and formation of size-controlled algae flocs. PMID- 29533812 TI - The potential of non-invasive pre- and post-mortem carcass measurements to predict the contribution of carcass components to slaughter yield of guinea pigs. AB - Guinea pig meat consumption is increasing exponentially worldwide. The evaluation of the contribution of carcass components to carcass quality potentially can allow for the estimation of the value added to food animal origin and make research in guinea pigs more practicable. The aim of this study was to propose a methodology for modelling the contribution of different carcass components to the overall carcass quality of guinea pigs by using non-invasive pre- and post mortem carcass measurements. The selection of predictors was developed through correlation analysis and statistical significance; whereas the prediction models were based on Multiple Linear Regression. The prediction results showed higher accuracy in the prediction of carcass component contribution expressed in grams, compared to when expressed as a percentage of carcass quality components. The proposed prediction models can be useful for the guinea pig meat industry and research institutions by using non-invasive and time- and cost-efficient carcass component measuring techniques. PMID- 29533813 TI - A new insight into meat toughness of callipyge lamb loins - The relevance of anti apoptotic systems to decreased proteolysis. AB - The objective of this study was to determine associations of small heat shock proteins (sHSPs) in tenderness development of loins from callipyge and normal genotype lambs. Loins (M. longissimus lumborum) from sixteen lambs across four genotypes were collected throughout 9 days of postmortem aging. The loins from callipyge lambs had more intact desmin and troponin T throughout aging periods, as well as less MU-calpain autolysis and more calpastatin compared to loins from other genotypes (P < 0.05). Delayed onset of apoptosis was found in the callipyge loins indicated by less cytochrome c and more inactive procaspase-3 compared to normal lamb loins (P < 0.05). Less degraded HSP27 was also consistently found in the callipyge loins compared with loins from normal lambs (P < 0.001). The results found up-regulation of anti-apoptotic activities coincided with toughness in callipyge loins, which suggest apoptosis is likely involved in postmortem proteolysis and subsequent meat tenderization. PMID- 29533814 TI - Prediction of pork loin quality using online computer vision system and artificial intelligence model. AB - The objective of this project was to develop a computer vision system (CVS) for objective measurement of pork loin under industry speed requirement. Color images of pork loin samples were acquired using a CVS. Subjective color and marbling scores were determined according to the National Pork Board standards by a trained evaluator. Instrument color measurement and crude fat percentage were used as control measurements. Image features (18 color features; 1 marbling feature; 88 texture features) were extracted from whole pork loin color images. Artificial intelligence prediction model (support vector machine) was established for pork color and marbling quality grades. The results showed that CVS with support vector machine modeling reached the highest prediction accuracy of 92.5% for measured pork color score and 75.0% for measured pork marbling score. This research shows that the proposed artificial intelligence prediction model with CVS can provide an effective tool for predicting color and marbling in the pork industry at online speeds. PMID- 29533815 TI - Prediction of intramuscular fat content and shear force in Texel lamb loins using combinations of different X-ray computed tomography (CT) scanning techniques. AB - Computed tomography (CT) parameters, including spiral computed tomography scanning (SCTS) parameters, intramuscular fat (IMF) and mechanically measured shear force were derived from two previously published studies. Purebred Texel (n = 377) of both sexes, females (n = 206) and intact males (n = 171) were used to investigate the prediction of IMF and shear force in the loin. Two and three dimensional CT density information was available. Accuracies in the prediction of shear force and IMF ranged from R2 0.02 to R2 0.13 and R2 0.51 to R2 0.71 respectively, using combinations of SCTS and CT scan information. The prediction of mechanical shear force could not be achieved at an acceptable level of accuracy employing SCTS information. However, the prediction of IMF in the loin employing information from SCTS and additional information from standard CT scans was successful, providing evidence that the prediction of IMF and related meat eating quality (MEQ) traits for Texel lambs in vivo can be achieved. PMID- 29533816 TI - QM/MM reveals the sequence of substrate binding during OPRT action. AB - Computational investigation of orotate phosphoribosyltransferase (OPRT) action, an enzymatic reaction between phosphoribosyl pyrophosphate (PRPP) and orotic acid (OA) to yield orotidine 5'-monophosphate (OMP), was carried out. Insights into the pathways of the substrate attack step of the reaction were developed under the quantum mechanics/molecular mechanics framework with S. cerevisiae strain as the representative enzyme bearer. Four pathways were proposed for PRPP and OA binding differing in the sequence of PRPP, OA and Mg2+ ion complexation with OPRT. The formation of Mg2+-OPRT complex was accompanied by a small energy change while the largest stabilization was observed for the formation of Mg2+-PRPP complex supporting the experimental observation of Mg2+-PRPP complex as the true substrate for the reaction. Formation of PRPP-OPRT complex was found to be energetically not probable rendering the pathway requiring Mg2+-OA complex not probable. Further, PRPP migration towards the active site was found to be energetically not favoured rendering the pathway involving Mg2+-OA complexation improbable. Migration of OA and Mg2+-PRPP complex towards the active site was found to be energetically probable with a large stabilization of the system when Mg2+-PRPP complex bound to the OA-OPRT complex. This conclusively proved the sequential binding of OA and Mg2+-PRPP complexes during OPRT action. PMID- 29533817 TI - POAP: A GNU parallel based multithreaded pipeline of open babel and AutoDock suite for boosted high throughput virtual screening. AB - High throughput virtual screening plays a crucial role in hit identification during the drug discovery process. With the rapid increase in the chemical libraries, virtual screening process becomes computationally challenging, thereby posing a demand for efficiently parallelized software pipelines. Here we present a GNU Parallel based pipeline-POAP that is programmed to run Open Babel and AutoDock suite under highly optimized parallelization. The ligand preparation module is a unique feature in POAP, as it offers extensive options for geometry optimization, conformer generation, parallelization and also quarantines erroneous datasets for seamless operation. POAP also features multi receptor docking that can be utilized for comparative virtual screening and drug repurposing studies. As demonstrated using different structural datasets, POAP proves to be an efficient pipeline that enables high scalability, seamless operability, dynamic file handling and optimal utilization of CPU's for computationally demanding tasks. POAP is distributed freely under GNU GPL license and can be downloaded at https://github.com/inpacdb/POAP. PMID- 29533818 TI - Culture-free, highly sensitive, quantitative detection of bacteria from minimally processed samples using fluorescence imaging by smartphone. AB - A critical unmet need in the diagnosis of bacterial infections, which remain a major cause of human morbidity and mortality, is the detection of scarce bacterial pathogens in a variety of samples in a rapid and quantitative manner. Herein, we demonstrate smartphone-based detection of Staphylococcus aureus in a culture-free, rapid, quantitative manner from minimally processed liquid samples using aptamer-functionalized fluorescent magnetic nanoparticles. The tagged S. aureus cells were magnetically captured in a detection cassette, and then fluorescence was imaged using a smartphone camera with a light-emitting diode as the excitation source. Our results showed quantitative detection capability with a minimum detectable concentration as low as 10 cfu/ml by counting individual bacteria cells, efficiently capturing S. aureus cells directly from a peanut milk sample within 10 min. When the selectivity of detection was investigated using samples spiked with other pathogenic bacteria, no significant non-specific detection occurred. Furthermore, strains of S. aureus from various origins showed comparable results, ensuring that the approach can be widely adopted. Therefore, the quantitative fluorescence imaging platform on a smartphone could allow on site detection of bacteria, providing great potential assistance during major infectious disease outbreaks in remote and resource-limited settings. PMID- 29533819 TI - Randomized trial of transcranial alternating current stimulation for treatment of auditory hallucinations in schizophrenia. AB - BACKGROUND: Approximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere. METHOD: 22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes. RESULTS: Primary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions. CONCLUSIONS: To our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations. PMID- 29533820 TI - Association of VEGFA variants with altered VEGF secretion and type 2 diabetes: A case-control study. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) contributes to type 2 diabetes (T2DM) pathogenesis, and genetic variations in VEGFA gene were suggested to influence VEGF secretion and T2DM pathogenesis. AIM: To evaluate the association of specific VEGFA variants with altered VEGF levels, and with T2DM among Tunisians. SUBJECTS AND METHODS: A retrospective case-control study, performed on 815 T2DM patients, and 805 healthy controls. VEGF levels were measured by ELISA, genotyping of VEGFA variants was done by allelic exclusion method (real-time PCR). RESULTS: MAF of rs1570360, rs2010963, rs25648, rs833068, rs3025036, and rs3025039 were significantly different between T2DM cases and controls. Increased T2DM risk was associated with rs699947, rs1570360, and rs3025020, while reduced T2DM risk was seen with rs1547651, rs2010963, rs25648, rs3025036, and rs3025039 genotypes, thus assigning T2DM susceptibility and protection, respectively. Reduced VEGF levels were associated with rs833061, rs2010963, and rs3025039 heterozygosity and rs3025036 major allele homozygosity in T2DM cases, while increased VEGF levels were seen in rs833070 homozygous major allele genotype. Both rs699947 and rs1570360 positively, while rs2010963 and rs3025036 negatively correlated with fasting glucose. In addition, rs699947 positively correlated with LDL-cholesterol, and rs3025039 positively correlated with diabetes duration, but negatively with HbA1c and serum triglycerides. Haploview analysis identified Block 1 containing 8 loci, and Block 2 with the remaining 3 loci. Haplotypes ACTGCCGG and AACGGCGA (Block 1) were negatively associated with T2DM, while haplotype CCC was positively and haplotype CGC (Block 2) were negatively associated with T2DM. CONCLUSION: This study confirms the contribution of altered VEGF secretion, resulting from genetic variation in VEGFA gene into T2DM pathogenesis, hence supporting role for VEGFA as T2DM candidate locus. PMID- 29533821 TI - Cognitive disability in adult patients with brain tumors. AB - Cognitive dysfunction is common among patients with intracranial tumors. Most cognitive deficits are subtle, lack specificity, may mimic depression or other neurological disorders and may be recognized in retrospect by the physician. In certain cases, distinguishing between tumor recurrence and cognitive deficits that arise as a consequence of the treatment becomes challenging. Late treatment effects have also become an area of focus as the overall survival and prognosis of patients with brain tumors increases. New data has highlighted the importance of less toxic adjuvant therapies owing to their positive impact on prognosis and quality of life. Various experimental therapies and genetic influences on individual sensitivity towards injury are promising steps towards a better management strategy for cognitive dysfunction. In this literature review, we discuss cognitive dysfunction as a manifestation of intracranial tumors, treatment modalities such as radiotherapy, chemotherapy, surgery and their impact on cognition and patients' quality of life. We also discuss management options for cognitive dysfunction and emerging therapies. PMID- 29533822 TI - Fenton-like oxidation of 4-chlorophenol using H2O2 in situ generated by Zn-Fe CNTs composite. AB - In this paper, a zinc-iron-carbon nanotubes (Zn-Fe-CNTs) composite was prepared, characterized and used to develop a Fenton-like system of Zn-Fe-CNTs/O2 for the degradation of 4-chlorophenol (4-CP), in which H2O2 was generated in situ from zinc-carbon galvanic cells and oxygen in aqueous solution was activated by iron attached on the surface of CNTs to produce .OH radicals for the oxidation of 4 CP. The experimental results showed that the particles of Zn and Fe in Zn-Fe-CNTs composite were adhered to the surface of CNTs, which accelerated the electron transfer process. The BET area of Zn-Fe-CNTs composite was 32.9 m2/g. The contents of Zn and Fe (% w) in the composite were 44.7% and 4.2%, respectively. The removal efficiency of 4-CP and TOC in Zn-Fe-CNTs/O2 system was 90.8% and 52.9%, respectively, with the initial pH of 2.0, O2 flow rate of 800 mL/min, Zn Fe-CNTs dosage of 1.0 g/L, 4-CP concentration of 50 mg/L and reaction time of 20 min. Based on the analysis of the degradation intermediate products with LC-MS and IC, a possible degradation pathway of 4-CP in Zn-Fe-CNTs/O2 system was proposed. PMID- 29533823 TI - Biofilm formation of filamentous fungi Coriolopsis sp. on simple muslin cloth to enhance removal of triphenylmethane dyes. AB - The isolate Coriolopsis sp. (1c3) was cultured on muslin cloth to induce formation of filamentous biofilm. The biofilm and the free-mycelium forms (control) were then used to treat two triphenylmethane dyes; Cotton Blue (CB) and Crystal Violet (CV). The biofilm comprised primarily of a compact mass of mycelium while sparse mycelium network was detected in free-mycelium forms. Results revealed significant decolourization activities by filamentous biofilm of 1c3 for CB (79.6%) and CV (85.1%), compared to free-mycelium forms (72.6 and 58.3%, for CB and CV, respectively). Biodegradation occurred in both biofilm and free-mycelium forms. FTIR spectra revealed that biofilm formation (stacking of mycelium), did not have severe implications to the number and types of functional groups available for dye biosorption. The findings here suggested that formation of biofilm in 1c3 was induced effectively on muslin cloth, leading to enhanced decolourization activities. This technology is simple, feasible and can be adopted and further improved to obtain biofilm to enhance their dye removal efficiency in aqueous solutions. PMID- 29533824 TI - Biomass to levulinic acid: A techno-economic analysis and sustainability of biorefinery processes in Southeast Asia. AB - Aligned with Singapore's commitment to sustainable development and investment in renewable resources, cleaner energy and technology (Sustainable Singapore Blueprint), we report a techno-economic analysis of the biorefinery process in Southeast Asia. The considerations in this study provide an overview of the current and future challenges in the biomass-to-chemical processes with life cycle thinking, linking the land used for agriculture and biomass to the levulinic acid production. 7-8 kg of lignocellulosic feedstock (glucan content 30 35 wt%) from agriculture residues empty fruit bunches (EFB) or rice straw (RS) can be processed to yield 1 kg of levulinic acid. Comparisons of both traditional and "green" alternative solvents and separation techniques for the chemical process were modelled and their relative energy profiles evaluated. Using 2 methyltetrahydrofuran (2-MeTHF) as the process solvent showed to approx. 20 fold less energy demand compared to methyl isobutyl ketone (MIBK) or approx. 180 fold less energy demand compared to direct distillation from aqueous stream. Greenhouse gases emissions of the major operations throughout the supply chain (energy and solvent use, transport, field emissions) were estimated and compared against the impact of deforestation to make space for agriculture purposes. A biorefinery process for the production of 20 ktonne/year of levulinic acid from two different types of lignocellulosic feedstock was hypothesized for different scenarios. In one scenario the chemical plant producing levulinic acid was located in Singapore whereas in other scenarios, its location was placed in a neighboring country, closer to the biomass source. Results from this study show the importance of feedstock choices, as well as the associated plant locations, in the quest for sustainability objectives. PMID- 29533825 TI - Effects of alkali-treated agricultural residues on nitrate removal and N2O reduction of denitrification in unsaturated soil. AB - Lignocellulosic agricultural residues were utilized as denitrification carbon substrates to improve the purification capacity of unsaturated soil and alleviate nitrate pollution of groundwater. In this study, corncob and wheat straw were treated by calcium hydroxide to improve biodegradability and enhance denitrification potential. Calcium hydroxide treatment decreased the contents of lignin (i.e., from 16.7 wt% to 15.2 wt% in corncob and from 21.9 wt% to 20.6 wt% in wheat straw), increased potential biodegradable carbon by 4.4-5.3 times, reached complete nitrate removal 7-14 days earlier and decreased N2O/(N2O+N2) ratios by 85-99%. The results provide an insight into the application of alkali treated agricultural residues as denitrification carbon sources to alleviate nitrate transport to groundwater and reduce potential greenhouse effect. PMID- 29533826 TI - Influential third party on water right conflict: A Game Theory approach to achieve the desired equilibrium (case study: Ilam dam, Iran). AB - Allocating water to organizational stakeholders poses a vital challenge to water managers. Organizations which benefit from water as the primary factor input attempt to achieve their objectives using cost-effective and quick-return strategies, such as increasing the water rights. In such circumstances, lack of water probably results in the conflict. Recognizing the management approaches, organizational priorities, and the stakeholders' influence power can play a dominant role in analyzing the future of such conflicts. In this paper, we analyzed the conflict of water allocation in Ilam dam among organizational stakeholders. We defined the strategies based on the background of the game and organizational objectives. The influence power of stakeholders and the numerical weights of strategies were quantified based on the expert judgment method. The relative priorities of strategies were then calculated for each state of the conflict. We used the GMCR+ model to study the actions of stakeholders. Results suggest that the Jihad Agriculture Organization and the Water and Wastewater Company withdraw more water; hence, there exists no water to meet the environmental water right. In this case, the participation of the third party, such as the Governorship and the Justice can change the future of the conflict, and result in moving to the optimal state. However, results from Inverse GMCR analysis demonstrate that Justice is the most influential third party that can move the conflict towards a desired equilibrium (optimal case). PMID- 29533827 TI - Callitriche cophocarpa biomass as a potential low-cost biosorbent for trivalent chromium. AB - The present study focused on the use of the dry mass of the macrophyte Callitriche cophocarpa as an effective biosorbent for chromium removal from concentrated solutions, typical for industrial effluents. In order to evaluate the usability of C. cophocarpa as the Cr(III) sorbent, its detailed physicochemical characterization has been performed as well as the preliminary adsorption studies. The biosorbent was characterized by specific surface area (SSA), porosity, total organic carbon (TOC), inorganic content as well as the cation exchange capacity (CEC), dominant exchangeable cations and anion exchange capacity (AEC), point of zero charge (pHpzc) and buffering capacity. The effect of the initial chromium concentration, solution pH and co-existing anions on the sorption effectiveness have been investigated. Based on theoretical isotherm models, the maximum adsorption capacity of the dry C. cophocarpa has been determined as 77.1 mg Cr(III)/g. Finally, the strength of Cr-binding onto the plant biomass has been evaluated using the BCR extraction method, stating that chromium was strongly and - under environmental conditions - irreversibly bound to the plant biomass. PMID- 29533828 TI - Conservation Reserve Program effects on floodplain land cover management. AB - Growing populations and industrialized agriculture practices have eradicated much of the United States wetlands along river floodplains. One program available for the restoration of floodplains is the Conservation Reserve Program (CRP). The current research explores the effects CRP land change has on flooding zones, utilizing Flood Modeller and HEC-RAS. Flood Modeller is proven a viable tool for flood modeling within the United States when compared to HEC-RAS. Application of the software is used in the Nodaway River system located in the western halves of Iowa and Missouri to model effects of introducing new forest areas within the region. Flood stage during the conversion first decreases in the early years, before rising to produce greater heights. Flow velocities where CRP land is present are reduced for long-term scopes. Velocity reduction occurs as the Manning's roughness increases due to tree diameter and brush density. Flood zones become more widespread with the implementation of CRP. Future model implementations are recommended to witness the effects of smaller flood recurrence intervals. PMID- 29533829 TI - Kinetic and thermodynamic studies on the adsorption of heavy metals from aqueous solution by melanin nanopigment obtained from marine source: Pseudomonas stutzeri. AB - The difficulty in removal of heavy metals at concentrations below 10 mg/L has led to the exploration of efficient adsorbents for removal of heavy metals. The adsorption capacity of biosynthesized melanin for Mercury (Hg(II)), Chromium (Cr(VI)), Lead (Pb(II)) and Copper (Cu(II)) was investigated at different operating conditions like pH, time, initial concentration and temperature. The heavy metals adsorption process was well illustrated by the Lagergren's pseudo second-order kinetic model and the equilibrium data fitted excellently to Langmuir isotherm. Maximum adsorption capacity obtained from Langmuir isotherm for Hg(II) was 82.4 mg/g, Cr(VI) was 126.9 mg/g, Pb(II) was 147.5 mg/g and Cu(II) was 167.8 mg/g. The thermodynamic parameters revealed that the adsorption of heavy metals on melanin is favorable, spontaneous and endothermic in nature. Binding of heavy metals on melanin surface was proved by Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Photoelectron Spectroscopy (XPS). Contemplating the results, biosynthesized melanin can be a potential adsorbent for efficient removal of Hg(II), Cr(VI), Pb(II) and Cu(II) ions from aqueous solution. PMID- 29533830 TI - Source apportionment of PM2.5 using positive matrix factorization (PMF) at a rural site in Korea. AB - The sources of different pollutants contributing to ambient fine particles (PM2.5) on Daebu Island, Korea, were estimated. Twenty four hour integrated filter samples were collected from May 21-November 1, 2016, and analyzed for organic carbon, elemental carbon, ions, and trace elements. Positive matrix factorization was conducted on the PM2.5 chemical speciation data from the samples to define the pathways and sources of PM2.5 at the sampling site. A total of 80 samples and 24 chemical species were used to run the model and a total of nine sources were identified: secondary sulfate (29.0%), mobile (22.0%), secondary nitrate (13.2%), oil combustion (10.1%), coal combustion (9.4%), aged sea salt (7.9%), soil (5.6%), non-ferrous smelting (1.7%), and industrial activity (1.1%). Conditional probability and potential source contribution functions were then used to determine whether these sources were local or came from pollutants transported over long-range distances. The anthropogenic sources came from local emissions and originated from both industrialized and metropolitan areas, whereas the secondary inorganic aerosols were strongly influenced by the long-range transport of air pollutants from Shandong and Jiangsu provinces in China. PMID- 29533831 TI - In-situ self-assembly of plant polyphenol-coated Fe3O4 particles for oleaginous microalgae harvesting. AB - Plant polyphenol (PP), a natural polymer from the Larix gmelinii, was selected as the surfactant to synthesize Fe3O4. The Fe3O4-PP composite was prepared by in situ self-assembly in solvothermal synthesis, and characterized using FE-SEM, TEM, XRD, FTIR, XPS, TGA, and VSM. The harvesting efficiency of Chlorella vulgaris was investigated under different parameters, including algal organic matter, dosage, and pH. The results showed that the core-shell sphere of Fe3O4-PP (~150 nm) was coated by ~50 nm PP with a saturated magnetization of 40.0 emu/g. The Fe3O4-PP could be directly applied to the culture broth (1.5 g dry cell weight/L, pH = 9.03), achieving 93.0% of harvesting efficiency at 20 g/L. Cells were detached from the harvested aggregates by adjusting pH value to 9.80 and with ultrasonication, which achieved 95.6% of recovery efficiency. The recycled Fe3O4-PP showed high stabilities in surface properties, maintaining more than 87.5% of harvesting efficiency after five recycles. PMID- 29533832 TI - Effects of human management on black carbon sorption/desorption during a water transfer project: Recognizing impacts and identifying mitigation possibilities. AB - Water resources management is an important public concern. In this study, we examined the extent of sorption/desorption of trace pollutants to soil black carbon (BC) in the water level fluctuation zone (WLFZ) of the middle route of the South to North Water Transfer Project in China. In addition, we investigated the main management measures affecting these processes during the project. The results showed that the pseudo second-order model adequately describes the sorption/desorption of phenanthrene on the soil BC in the WLFZ. Water level fluctuation may indirectly influenced BC sorption/desorption by altering water chemistry. Water level residence time had negative effects on BC sorption in short-term experiments (days to months), but the impact gradually diminished with increased residence time. The results suggested that long-term field monitoring of water chemistry is urgent. During the initial period of water transfer, delaying the water supplies as drinking water source or directly irrigating crops could mitigate the adverse impacts. Future research should focus on the water soluble products of BC degradation. The findings of this study should be useful in improving sustainable management of water resources for water transfer projects. PMID- 29533833 TI - Sediment exchange to mitigate pollutant exposure in urban soil. AB - Urban soil is an ongoing source for lead (Pb) and other pollutant exposure. Sources of clean soil that are locally-available, abundant and inexpensive are needed to place a protective cover layer over degraded urban soil to eliminate direct and indirect pollutant exposures. This study evaluates a novel sediment exchange program recently established in New York City (NYC Clean Soil Bank, CSB) and found that direct exchange of surplus sediment extracted from urban construction projects satisfies these criteria. The CSB has high total yield with 4.2 * 105 t of sediment exchanged in five years. Average annual yield (8.5 * 104 t yr-1) would be sufficient to place a 15-cm (6-in.) sediment cover layer over 3.2 * 105 m2 (80 acres) of impacted urban soil or 1380 community gardens. In a case study of sediment exchange to mitigate community garden soil contamination, Pb content in sediment ranged from 2 to 5 mg kg-1. This sediment would reduce surface Pb concentrations more than 98% if it was used to encapsulate soil with Pb content exceeding USEPA residential soil standards (400 mg kg-1). The maximum observed sediment Pb content is a factor of 42 and 71 lower than median surface soil and garden soil in NYC, respectively. All costs (transportation, chemical testing, etc.) in the CSB are paid by the donor indicating that urban sediment exchange could be an ultra-low-cost source for urban soil mitigation. Urban-scale sediment exchange has advantages over existing national- or provincial-scale sediment exchanges because it can retain and upcycle local sediment resources to attain their highest and best use (e.g. lowering pollutant exposure), achieve circular urban materials metabolism, improve livability and maximize urban sustainability. PMID- 29533834 TI - To what extent are midwives adapting antenatal information for pregnant women with intellectual disabilities? A survey of NHS trusts in England. AB - OBJECTIVES: To identify the existing antenatal information provision practices for pregnant women with intellectual disabilities in England. To identify how practices between and within local supervising authorities differed, and if midwives were adapting standard antenatal information for pregnant women with intellectual disabilities, including examples of accessible information being used. STUDY DESIGN: Cross-sectional survey. METHODS: All contact supervisors of midwives from acute trusts with maternity services were accessed via the local supervisor of midwives officers' databases and sent a questionnaire. Quantitative data were collated. Associations between trust size, geographical location, antenatal provision and National Institute for Health and Care Excellence guidelines alongside National policy were examined using Fischer's exact test of association. RESULTS: Contact supervisors of midwives returned a questionnaire on behalf of their trust (74, 53%). The majority worked in maternity units with more than 4000 births a year (50, 66%). Few trusts had a specialist or lead midwife in post for pregnant women with intellectual disabilities (17, 22.9%) but over half (39, 52.7%) reported that their trust had a specialist learning disability nurse in post. Only 28.3% reported availability of post registration training and even fewer (8, 10.8%) had access to written protocols. Less than half reported extra time being offered at the booking (29, 39.1%) or routine antenatal appointments (30, 40.5%). Less than a quarter (17, 22.9%) reported that their trust had routine antenatal written information available in accessible formats. CONCLUSION: Reasonable adjustments to standard antenatal information for pregnant women with intellectual disabilities were not common practice. Most trusts did not have local guidelines in place or offer midwives post registration education to help support them in this requirement. PMID- 29533835 TI - The economic burden of tuberculosis and latent tuberculosis in people living with HIV in Brazil: a cost study from the patient perspective. AB - OBJECTIVE: The objective of this study was to evaluate the direct and indirect costs of tuberculosis (TB) (active and latent TB [LTB]) and HIV co-infection from the patient perspective. STUDY DESIGN: Costing study conducted alongside a pragmatic clinical trial. METHODS: The study was conducted in Brazil in a referral service for HIV/AIDS. We applied a standardised questionnaire to collect data about out-of-pocket expenses and indirect cost. The questionnaire was applied at every patient's appointment in the referral service after TB or LTB diagnosis. We followed all patients' pathways during the prediagnosis period and treatment period. For patients on sickness benefit due to TB/HIV, income loss was calculated as the difference between an employee's wages forgone and the sickness benefit received. The monetary value of the time loss was calculated based on the Brazilian minimum wage/2015. RESULTS: Among 239 people living with HIV recruited in the first year of the trial, 31 patients were included into the costing study, 26 patients who were diagnosed and treated for TB/HIV and five patients who were diagnosed and treated for LTB/HIV. TB/HIV patients incurred higher total costs than LTB/HIV (US$ 1,429 vs US$ 166). The main cost component for TB/HIV was indirect costs, especially income loss (US$ 749). CONCLUSIONS: Public health policies may address ways to prevent high patients' costs through the introduction of more accurate algorithms for TB diagnosis to prevent delays in the diagnosis and treatment. PMID- 29533836 TI - Comparison of student self-debriefing versus instructor debriefing in nursing simulation: A quasi-experimental study. AB - BACKGROUND: Student self-debriefing promotes self-confidence, helps to increase clinical performance, and is a more cost-effective method than is traditional instructor-led debriefing in simulation-based learning. OBJECTIVES: This study compared the effectiveness of debriefing-in terms of the problem-solving process, team effectiveness, debriefing assessment, and debriefing satisfaction-between an experimental group who received both student self-debriefing (SSD) and instructor debriefing (ID) and a control group who received only instructor debriefing. DESIGN: This quasi-experimental study used a pretest-posttest non-equivalent control group design. SETTINGS: Two universities in South Korea. PARTICIPANTS: A convenience sample of 123 senior nursing students. The data were collected between 15 April and 9 June 2016. METHODS: Differences in the problem-solving process, team effectiveness, debriefing assessment, and debriefing satisfaction between the SSD + ID group and the ID-only group were measured. RESULTS: The SSD + ID group showed significant improvements in the problem-solving process (t = 4.32, p < .001) and debriefing satisfaction (t = 3.19, p = .002), but not in debriefing assessment (t = 1.67, p = .097) or team effectiveness (t = 1.84, p = .069) compared to ID-only group. Specifically, as the number of student sessions increased, we observed significant differences in problem-solving ability (F = 9.44, p < .001), debriefing satisfaction (F = 7.78, p < .001), and the subdomains of debriefing assessment: 'maintains an engaging environment' (F = 3.78, p = .025), 'structures the debriefing in an organized way' (F = 4.27, p = .016), and 'helps trainees achieve or sustain future performance' (F = 3.17, p = .045). CONCLUSIONS: Our results can be used to develop guidelines for effective debriefing following simulation in nursing education. Specifically, combining SSD and ID in simulation debriefing and increasing the number of SSD sessions could help improve the problem-solving process and debriefing satisfaction among nursing students. PMID- 29533837 TI - Interprofessional education and collaborative practice: Psychometric analysis of the Readiness for Interprofessional Learning Scale in undergraduate Serbian healthcare student context. AB - BACKGROUND: There is an implicit expectation for medical sciences students to work together effectively as members of health-care team, and interprofessional education is therefore widely accepted. Students' attitudes, which are affected by various factors, have been recognized as the most important predictors of successful implementation of interprofessional education with the aim of developing collaborative practice. The Readiness for Interprofessional Learning Scale has often been used in studies to measure these perspectives. OBJECTIVES: To describe the psychometric properties of the Serbian cross-culturally adapted version of the original Readiness for Interprofessional Learning Scale, to assess the attitudes of undergraduate health science students towards interprofessional education and to evaluate whether a professional group and student characteristics have influence on attitudes towards collaborative practice and shared learning. DESIGN: A descriptive/analytical and comparative cross-sectional study. SETTINGS: Faculty of Medicine in Serbia. PARTICIPANTS: Nursing and medical students after completed first clinical rotations (n = 257). METHODS: The Readiness for Interprofessional Learning Scale for assessing attitudes among students towards interprofessional learning, Professional Identity Questionnaire for Nursing Students for assessing professional identity in nursing students, Professional Nursing Image Survey for assessing attitudes of medical students towards the nursing profession, as well as a socio-demographic questionnaire were the instruments used in this research study. The data were analysed using descriptive and inferential statistics. RESULTS: Exploratory factor analysis on 19 items revealed two-factors accounting for 51.1% of the total variance with the internal reliability alpha = 0.90. The mean total score of the Readiness for Interprofessional Learning Scale was 73.5 (SD = 11.5) indicating that students are ready for interprofessional learning. Nursing students, female students; students in their first years of studies, and those with previously completed education in the field of health care, have been more ready for interprofessional learning and collaborative practice. In the multiple linear regression analysis, gender and assessing professional nursing skills and abilities were significant predictors of medical students' readiness for interprofessional learning, whereas professional identity was for nursing students. CONCLUSION: The Serbian version of the Readiness for Interprofessional Learning Scale has proven to be reliable and valid for the "teamwork, collaboration and shared learning" subscale, while the "role and responsibilities" subscale showed lower stability. The results of this study revealed positive students' attitudes towards interprofessional learning, which is important for Serbia, as a candidate country for European Union membership, and thus making our educational system more inclusive for joining the European Higher Education Area. PMID- 29533838 TI - Morphology of glandular trichomes of Japanese catnip (Schizonepeta tenuifolia Briquet) and developmental dynamics of their secretory activity. AB - Schizonepeta tenuifolia Briquet, commonly known as Japanese catnip, is used for the treatment of colds, headaches, fevers, and skin rashes in traditional Asian medicine (China, Japan and Korea). The volatile oil and its constituents have various demonstrated biological activities, but there is currently limited information regarding the site of biosynthesis. Light microscopy and scanning electron microscopy indicated the presence of three distinct glandular trichome types which, based on their morphological features, are referred to as peltate, capitate and digitiform glandular trichomes. Laser scanning microscopy and 3D reconstruction demonstrated that terpenoid-producing peltate glandular trichomes contain a disk of twelve secretory cells. The oil of peltate glandular trichomes, collected by laser microdissection or using custom-made micropipettes, was demonstrated to contain (-)-pulegone, (+)-menthone and (+)-limonene as major constituents. Digitiform and capitate glandular trichomes did not contain appreciable levels of terpenoid volatiles. The yield of distilled oil from spikes was significantly (44%) higher than that from leaves, while the composition of oils was very similar. Oils collected directly from leaf peltate glandular trichomes over the course of a growing season contained primarily (-)-pulegone (>80% at 32 days after germination) in young plants, while (+)-menthone began to accumulate later (>75% at 80 days after germination), at the expense of (-) pulegone (the levels of (+)-limonene remained fairly stable at 3-5%). The current study establishes the morphological and chemical characteristics of glandular trichome types of S. tenuifolia, and also provides the basis for unraveling the biosynthesis of essential oil in this popular medicinal plant. PMID- 29533839 TI - Radial distribution of wood extractives in European larch Larix decidua by TOF SIMS imaging. AB - Wood extractives in the xylem of European larch Larix decidua were mapped by time of-flight secondary ion mass spectrometry (TOF-SIMS) imaging, which allows the radial distribution of both mineral and lipophilic extractives in the xylem to be scrutinized with high spatial resolution for the first time. Results show that all the components are inhomogeneously distributed across the annual ring. Mineral nutrients including Na+, K+, Ca+, and Cl- ions exhibit no preferential localization between earlywood and latewood, whereas PO3- ion is exclusively present in the ray cells, indicating it may be related to acid phosphatase. Lipophilic extractives were found to be more abundant in the inner secondary xylem. Ion images with 400 nm spatial resolution reveal that fatty acids, triglycerides and phytosterols are co-localized principally in the earlywood within the first annual ring. Resin acids prove to be the main components in the resin canal of the secondary xylem and are distributed in the outer of it. PMID- 29533841 TI - Poly-victimization and trajectories of binge drinking from adolescence to young adulthood among serious juvenile offenders. AB - BACKGROUND: Justice involved youth exposed to multiple forms of victimization (i.e., poly-victimization) may be at risk for long term substance use problems and difficulty in self-regulation, placing them at higher risk of long-term problematic behaviors. This study empirically identifies victimization classifications in a sample of justice involved youth and how long-term binge drinking is related to victimization experiences. We further sought to understand how self-regulatory abilities such as impulse control and emotion regulation effect emergent profiles and binge drinking trajectories. METHODS: Based on a sample of 1354 justice involved youth from 15 to 25 years old, classes of victimization were extracted. Emergent classes were examined in relationship to their binge drinking trajectories using latent growth models. Finally, self regulation was examined as a predictor of binge drinking trajectories across emergent classes. RESULTS: The analyses indicated three classes of victimization: poly-victimized, indirectly victimized, and lowly victimized. Latent growth models revealed that the poly-victimized class had significantly steeper growth in binge drinking as compared to the indirect and low victimized patterns. Impulse and emotional regulation both significantly decelerated binge drinking only for the indirect victimization group. CONCLUSIONS: Findings highlight the need to focus on poly-victimization in understanding binge drinking trajectories as well as the role impulse control and emotional regulation play among justice involved youth. Findings are discussed through the lens of adolescent development, coping strategies, and early traumatic experiences. PMID- 29533840 TI - Association between persistent endocrine-disrupting chemicals (PBDEs, OH-PBDEs, PCBs, and PFASs) and biomarkers of inflammation and cellular aging during pregnancy and postpartum. AB - BACKGROUND: Endocrine-disrupting chemicals (EDCs) can target immune and metabolic pathways. However, few epidemiologic studies have examined the influence of EDCs on measures of inflammation and cellular aging during pregnancy and postpartum. OBJECTIVE: We investigated associations between prenatal exposures to polybrominated diphenyl ethers (PBDEs), hydroxylated PBDE metabolites (OH-PBDEs), polychlorinated biphenyls (PCBs), and per- and polyfluorochemicals (PFASs) with repeated biomarker measurements of inflammation and cellular aging in women during pregnancy and the postpartum period. METHODOLOGY: Overweight or obese pregnant women were recruited from the San Francisco Bay area (n = 103) during their first or second trimester of pregnancy. Blood samples were collected from participants at baseline (median 16 weeks gestation) and at three and nine months postpartum. Serum concentrations of PBDEs, OH-PBDEs, PCBs, and PFASs were measured at baseline. Inflammation biomarkers (interleukin 6 [IL-6], interleukin 10 [IL-10], and tumor necrosis factor [TNF-alpha]) and leukocyte telomere length (LTL), a biomarker of cellular aging, were measured at all three time points. Associations between serum chemical concentrations and repeated measures of IL-6, IL-10, TNF-alpha, and LTL were examined using linear mixed models. We also examined the potential for effect modification by time (visit) and obesity. RESULTS: In adjusted models, we observed positive relationships between PBDEs and pro-inflammatory cytokines (IL-6 and TNF-alpha). A doubling in ?PBDEs was associated with a 15.26% (95% CI 1.24, 31.22) and 3.74% (95% CI -0.19, 7.82) increase in IL-6 and TNF-alpha, respectively. Positive associations were also observed for PFASs and IL-6. A two-fold increase in ?PFASs was associated with a 20.87% (95% CI 3.46, 41.22) increase in IL-6. 5-OHBDE-47 was inversely associated with anti-inflammatory cytokine IL-10. Some EDC-outcome associations, including those of PBDEs with TNF-alpha, were stronger during pregnancy (compared to three or nine months postpartum) and among obese (compared to overweight) women (p interaction <0.05). CONCLUSIONS: These findings suggest that exposure to specific EDCs is associated with increased inflammation among women during pregnancy and the postpartum period. Future studies should replicate these findings in additional study populations and examine the implications of these associations for maternal and child health. PMID- 29533842 TI - pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma. AB - Histone deacetylases (HDACs) are known to be key enzymes in cancer development and progression through their modulation of chromatin structure and the expression and post-translational modification of numerous proteins. Aggressive dedifferentiated tumors, like glioblastoma, frequently overexpress HDACs, while HDAC inhibition can lead to cell cycle arrest, promote cellular differentiation and induce apoptosis. Although multiple HDAC inhibitors, such as quisinostat, are of interest in oncology due to their potent in vitro efficacy, their failure in the clinic as monotherapies against solid tumors has been attributed to poor delivery. Thus, we were motivated to develop quisinostat loaded poly(D,L-lactide) b-methoxy poly(ethylene glycol) nanoparticles (NPs) to test their ability to treat orthotopic glioblastoma. In developing our NP formulation, we identified a novel, pH-driven approach for achieving over 9% (w/w) quisinostat loading. We show quisinostat-loaded NPs maintain drug potency in vitro and effectively slow tumor growth in vivo, leading to a prolonged survival compared to control mice. PMID- 29533843 TI - Influence of stabilizing components on the integrity of antitumor liposomes loaded with lipophilic prodrug in the bilayer. AB - Previously, we proposed a liposomal formulation of melphalan (Mlph)-a chemotherapeutic alkylating agent-incorporated in a fluid lipid bilayer in the form of dioleoylglyceride ester. In this work, we compared the stabilizing effect of different amphiphiles included in the Mlph-liposomes, such as phosphatidylinositol (PI), ganglioside GM1, a conjugate of N-carboxymethyl modified oligoglycine with dioleoylphosphatidylethanolamine (acidic lipopeptide), and polyethylene glycol (2000 Da) conjugated with dipalmitoylphosphatidylethanolamine (PEG-lipid), upon incubation in human serum. Mean hydrodynamic diameter values (86-90 nm) were similar among different liposome samples, while zeta potential values considerably varied. The formulations were incubated in human serum at 37 degrees C for different time intervals up to 24 h. Liposome integrity was evaluated by changes in fluorescence upon leakage of calcein or disruption of Forster resonance energy transfer between donor and acceptor fluorescent lipid probes in the bilayer. The best stabilization of liposomes was achieved upon the addition of ganglioside GM1 or the acidic lipopeptide. Inclusion of 10 mol% PI improved liposome stability only for the first 4 h of incubation. Pegylated liposomal formulations of melphalan lipophilic prodrug with fluid phase bilayer were the least stable, which is probably due to the propensity of the PEG-lipid to exit liposome membranes. Cholesterol-containing bilayers of liquid ordered phase, supplemented with sufficient amounts of the PEG-lipid, showed good stability in serum. PMID- 29533844 TI - The implementation of inertial sensors for the assessment of temporal parameters of gait in the knee arthroplasty population. AB - BACKGROUND: The use of inertial measurement units for the evaluation of temporal parameters of gait has been studied in many populations. However, currently no studies support the use of inertial measurement units for this purpose in the knee arthroplasty population. The objective of the present study was to investigate the agreement between an inertial measurement and camera based system for the assessment of temporal gait parameters in a knee arthroplasty population. METHODS: Sixteen knee arthroplasty patients performed 3 gait trials at a self selected speed along a 6 m walk-way. During the gait trials, gyroscope data from shank-worn inertial measurement units and motion data from optoelectronic cameras were collected simultaneously. A custom-made peak detection algorithm was used to identify gait events from gyroscope data, in order to compute cycle time, stance time and swing time. A marker and coordinate based algorithm was used to calculate temporal gait parameters from kinematical data derived from the camera system. Temporal variables were compared between both methods by calculating intra-class correlation coefficients, mean errors and root mean squared errors. Furthermore, Bland-Altman plots were constructed to assess the agreement between both methods. FINDINGS: Overall good to excellent intra-class correlation values (0.826-0.972) were found. Root mean square errors between both methods ranged from 0.036 to 0.055 s. High levels of agreement were observed for all variables. INTERPRETATION: These findings suggest that inertial measurement units can be used for outside laboratory assessment (e.g. in a hospital environment) of temporal gait parameters in the knee arthroplasty population. PMID- 29533845 TI - RiPP antibiotics: biosynthesis and engineering potential. AB - The threat of antibiotic resistant bacterial infections continues to underscore the need for new treatment options. Historically, small molecule metabolites from microbes have provided a rich source of antibiotic compounds, and as a result, significant effort has been invested in engineering the responsible biosynthetic pathways to generate novel analogs with attractive pharmacological properties. Unfortunately, biosynthetic stringency has limited the capacity of non-ribosomal peptide synthetases and polyketide synthases from producing substantially different analogs in large numbers. Another class of natural products, the ribosomally synthesized and post-translationally modified peptides (RiPPs), have rapidly expanded in recent years with many natively displaying potent antibiotic activity. RiPP biosynthetic pathways are modular and intrinsically tolerant to alternative substrates. Several prominent RiPPs with antibiotic activity will be covered in this review with a focus on their biosynthetic plasticity. While only a few RiPP enzymes have been thoroughly investigated mechanistically, this knowledge has already been harnessed to generate new-to-nature compounds. Through the use of synthetic biology approaches, on-going efforts in RiPP engineering hold great promise in unlocking the potential of this natural product class. PMID- 29533848 TI - Early intervention for personality disorder. AB - Specialized treatments for personality disorder are usually offered late in the course of the disorder, to a small number of help-seeking individuals with entrenched disability. Intervention during the early stages of personality disorder might help to decrease the persistence and/or the severity of personality disorder and to prevent the cascading of secondary psychopathology and psychosocial disability. Research regarding the understanding of and appropriate treatment for early stage personality disorder is growing. However, there is still a lack of clarity in the field about what constitutes early intervention and how it might relate to early intervention for other mental disorders. Also, there is little research on how to design integrated early intervention services suitable for personality and other mental disorders or on the long-term effects of early intervention. PMID- 29533846 TI - Adolescent precursors of young adult drinking motives. AB - INTRODUCTION: Numerous cross-sectional and shorter-term longitudinal studies have supported the role of drinking motives as potent proximal predictors of alcohol phenotypes (e.g., alcohol use, heavy episodic drinking). However, missing from this literature is a focus both on the stability of drinking motives across young adulthood and on adolescent precursors of drinking motives. METHODS: We investigated the adequacy of using a latent trait-state model (LTSM) to investigate three-wave data on social, enhancement, and coping motives for drinking with a community sample of young adults (N = 1004) at the mean ages of 23.8 years, 28.9 years, and 33.5 years. We further investigated adolescent (M age = 16.73 years) predictors of young adult drinking motives using data collected on the sample approximately seven years prior to the first young adult data collection. RESULTS: Findings indicated that all three drinking motives across young adulthood were modeled adequately via the LTSM, and that drinking motives manifested high stability (i.e., rank order) across individuals. Significant common (e.g., being male, alcohol-using peers, stressful life events, boredom susceptibility) and specific (e.g., depressive symptoms for coping motives; heavy episodic drinking for enhancement motives) adolescent precursors of young adult drinking motives were identified. CONCLUSIONS: Common and unique adolescent factors predicted trait-like drinking motives during young adulthood. These findings suggest the utility of intervening during the teen years to prevent or interrupt the development of cognitive motivations that encourage alcohol use for the purpose of affect regulation. PMID- 29533847 TI - The additive effects of depressive symptoms and polysubstance use on HIV risk among gay, bisexual, and other men who have sex with men. AB - INTRODUCTION: Among gay, bisexual, and other men who have sex with men (GBM), collinearity between polysubstance use and mental health concerns has obscured their combined effects on HIV risk with multivariable results often highlighting only one or the other. METHODS: We used mediation and moderation analyses to examine the effects of polysubstance use and depressive symptoms on high-risk sex (i.e., condomless anal sex with serodiscordant/unknown status partner) in a sample of sexually-active GBM, aged >=16 years, recruited in Metro Vancouver using respondent driven sampling. Hospital Anxiety and Depression Scale scores assessed mental health. Alcohol Use Disorder Identification Test scores assessed alcohol disorders. Poly-use of multiple drug types (e.g., stimulants, sedatives, opiates, hallucinogens) was assessed over the previous six months. RESULTS: Among 719 predominantly white (68.0%), gay-identified (80.7%) GBM, alcohol use was not associated with increased prevalence of high-risk sex. Controlling for demographic factors and partner number, an interaction between polysubstance use and depressive symptoms revealed that the combined effects were additively associated with increased odds for high-risk sex. Mediation models showed that polysubstance use partially mediated the relationship between depressive symptoms and high-risk sex. CONCLUSION: An interaction effect between polysubstance use (defined by using 3 or more substances in the past six months) and depressive symptoms (defined by HADS scores) revealed that the combination of these factors was associated with increased risk for high-risk sex - supporting a syndemic understanding of the production of HIV risk. PMID- 29533849 TI - The electrical significance of axon location diversity. AB - The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and maintenance of cellular polarity. Recent experimental and theoretical advances demonstrate that the anatomical site for initiation is remarkably diverse. The AIS location varies not only axially, along the axon, but axons also emerge variably from either the soma or proximal dendrites. Here, we review the evidence that the diversity of AIS and axon location has a substantial impact on the electrical properties and speculate that the anatomical heterogeneity of axon locations expands synaptic integration within cell types and improves information processing in neural circuits. PMID- 29533850 TI - Epidemiology and short-term surgical outcomes of children presenting with cerebellar tumors. AB - OBJECTIVE: Posterior fossa tumor surgery in children poses a significant morbidity and mortality. Large multi-institutional datasets characterizing the epidemiology and morbidity of children undergoing posterior fossa tumor surgery are lacking. The objective of this study is to describe the epidemiology and short term surgical outcomes of children presenting with cerebellar tumors. PATIENTS AND METHODS: A retrospective review of the Kids Inpatient Database (KID) for all hospital discharges in 2012 with a diagnosis of cerebellar tumor (ICD-9 diagnosis code 191.6) was performed and filtered with the ICD-9 procedure code 01.59 (other excision or destruction of lesion or tissue of brain). All children in this cohort were compared with all other children discharged without cerebellar tumors recorded in the database. RESULTS: A total of 461 (1.7/10,000 discharges) children with a diagnosis of cerebellar tumor who had surgical resection of their tumor were discharged during 2012. Compared with the control group, children undergoing cerebellar tumor excision had an increased length of hospital stay (8 vs. 2 days, p < 0.001), discharge to skilled nursing home facilities/home health care (12% vs. 4.6%, p < 0.001), increased hospital charges ($125,747 vs. $14,018, p < 0.001), and mortality (0.87% vs. 0.3%, p = 0.028). Hydrocephalus was treated via external ventriculostomy (EVD) (31%, n = 143) and/or shunt (17%, n = 78), and patients who required an EVD were more likely to receive a shunt (56% vs. 26%, p < 0.001). Mechanical ventilation (7.8%) and ultimately tracheostomy (1.5%) was necessary in few children following cerebellar tumor excision. CONCLUSIONS: As expected, surgical treatment of cerebellar tumors in children may pose significant morbidity. Our exploratory study identifies these patients as a potential high-risk cohort in the United States that may require intensive airway management, treatment of hydrocephalus and long-term nursing support. PMID- 29533851 TI - Preparation of highly dispersed and concentrated aqueous suspensions of nanodiamonds using novel diblock dispersants. AB - HYPOTHESIS: Finding an efficient dispersant for obtaining a good dispersion of 5 nm detonation nanodiamond (DND) is always a challenge. Two newly designed diblock copolymers, both poly(ammonium methacrylate)-block-poly(2-phenoxyethyl acrylate) (PMA-b-PBEA) but with different molar ratios of PMA to PBEA, were proposed to be efficient dispersants in stabilizing the concentrated aqueous suspensions of DND. EXPERIMENTS: The dispersion efficiency of dispersants for DND in aqueous suspensions was studied by the measurements of particle size, sedimentation property, and rheological behavior. The interactions between the added dispersants and DND were identified by the zeta potential and adsorption analyses. Calculations based on Derjaguin-Landau-Verwey-Overbeek (DLVO) theory were conducted for clarifying the dominant parameters relating to the dispersion efficiency of dispersants. FINDINGS: Compared with the commercially popular dispersant ammonium polyacrylate, these two diblock dispersants exhibited superior efficiency in the stabilization of DND suspensions. Using the diblock copolymers as dispersants, good dispersion stability in a DND suspension with an extremely high solid content of 30 wt% was achieved. According to experimental analyses and based on DLVO calculations, a low number of accompanied counter ions, high adsorption capability, and thick PMA-b-PBEA adsorption layer are the main reasons for the extremely high dispersion efficiency of the two new dispersants. PMID- 29533852 TI - Influence of different surfactants on Pickering emulsions stabilized by submicronic silica particles. AB - HYPOTHESIS: Pickering emulsions were prepared using wax and silica submicronic particles (650 nm), as a first step towards the synthesis of Janus particles. Surfactants added to silica particles control the emulsion stability and particles arrangement, i.e. their penetration depth into the wax and their ability to form a monolayer. Thus, a systematic study of surfactants is proposed. EXPERIMENTS: Zeta potential measurements and sedimentation tests are conducted to evaluate interactions of two cationic (CTAB: hexadecyltrimethylammonium bromide and DDAB: didodecyldimethylammonium bromide) and two polymeric surfactants with silica surface. Surfactants affinity for the wax is estimated by contact angle measurements. Emulsions stability is compared to evaluate the ability of particles to stabilize wax droplets. Through microscopic analyses, the penetration depth into the wax is measured as well as the ability to form a monolayer or multilayers/aggregates. FINDINGS: All surfactants modify silica surface properties, but only CTAB and DDAB give stable Pickering emulsions. Because of a better affinity for the wax, DDAB presents the best characteristics for Janus particle synthesis, allowing a larger variation of particles penetration depth into the wax. PMID- 29533853 TI - Room temperature synthesis of water-dispersible Ln3+:CeF3 (Ln = Nd, Tb) nanoparticles with different morphology as bimodal probes for fluorescence and CT imaging. AB - The singular properties of lanthanide-based inorganic nanoparticles (NPs) has raised the attention of the scientific community in biotechnological applications. In particular, those systems with two or more functionalities are especially interesting. In this work, an effective and commercially attractive procedure has been developed that renders uniform, water-dispersible Ln3+:CeF3 (Ln = Tb, Nd) NPs with different shapes and size. The method consists of the homogeneous precipitation, in a mixture of polyol and water, of cations and anions using precursors that allow the controlled release of the latter. The advantages of the reported method are related to the absence of surfactants, dispersing agents or corrosive precursors as well as to the room temperature of the process. The obtained Tb:CeF3 NPs produce an intense emission after excitation through the Ce-Tb energy transfer band located in the UV spectral region, thus being potentially useful as phosphors for in-vitro imaging purposes. On the other hand, the synthesized Nd:CeF3 NPs are good candidates for in-vivo imaging because their excitation and emission wavelengths lie in the biological windows. Finally, the excellent X-ray attenuation efficacy of the Nd:CeF3 NPs is shown, which confers double functionality to this material as both luminescence bioprobe and contrast agent for X-ray computed-tomography. PMID- 29533854 TI - Self-assembly of bacterial amyloid protein nanomaterials on solid surfaces. AB - HYPOTHESIS: Amyloid-forming biofilm proteins of Escherichia coli, namely CsgA and CsgB, can form self-assembled nanofibers on solid surfaces. These proteins can be programmed to form bio-nanomaterials for functional applications. EXPERIMENTS: In this study, the assembly of the CsgA and CsgB protein on solid surfaces was investigated in real time using a quartz crystal microbalance instrument with dissipation monitoring. The assembly kinetics of the CsgA and CsgB proteins in various settings on solid surfaces were investigated. Protein nanowires were investigated using electron microscopy. FINDINGS: CsgA protein polymers and CsgB added CsgA polymers form densely packed biofilm on gold surfaces, whereas CsgB polymers and CsgA-added CsgB polymers form biofilms with high water-holding capacity according to the dissipation data. Electron microscopy images of nanofibers grown on gold surfaces showed that CsgA and CsgB polymers include thicker nanofibers compared to the nanofibers formed by CsgA-CsgB protein combinations. The resulting nano/microstructures were found to have strong fluorescence signals in aqueous environments and in chloroform while conserving the protein nanowire network. PMID- 29533855 TI - FRET based integrated pyrene-AgNPs system for detection of Hg (II) and pyrene dimer: Applications to environmental analysis. AB - The integrated system of pyrene and cetyltrimethyl ammonium bromide (CTAB) capped silver nanoparticles (AgNPs) with a distance (r) of 2.78nm has been developed for the detection of Hg (II) and pyrene dimer. The interaction between pyrene and AgNPs results in the fluorescence quenching of pyrene due to the energy transfer, whose mechanism can be attributed to the Forster Resonance Energy Transfer (FRET) supported by experimental observation and theoretical calculations. The developed probe shows a highly selective and sensitive response towards Hg (II) probably due to the amalgam formation, which results in the fluorescence recovery (90%) of pyrene and color change of solution from yellowish brown to colorless. The addition of Hg (II) may increase the distance between pyrene and AgNPs undergoes the 'FRET OFF' process. This system gives a selective response towards Hg (II) over other competing metal ions. Under the optimal condition, the system offers good linearity between 0.1 and 0.6MUgmL-1 with a detection limit of 62ngmL-1. In addition, the system also provides an effective platform for detection of pyrene in its dimer form even at very low concentrations (10ngmL-1) on the surface of AgNPs. Therefore, it could be used as effective alternatives for the detection of Hg (II) as well as pyrene simultaneously. PMID- 29533856 TI - Motor-evoked potentials reveal functional differences between dominant and non dominant motor cortices during response preparation. AB - Transcranial magnetic stimulation (TMS) of the motor cortex produces motor-evoked potentials (MEPs) in contralateral muscles. The amplitude of these MEPs can be used to measure the excitability of the corticospinal tract during motor planning. In two experiments, we investigated learning-related changes in corticospinal excitability as subjects prepared to respond in a choice reaction time task. Subjects responded with their left or right hand to a left or right arrow, and on some trials the arrow was immediately preceded by a warning cue that signaled which response would be required. TMS was applied to the motor cortex during the warning cues, and MEPs were measured in the dominant or non dominant hand. We observed changes in corticospinal excitability during the warning cue, but these depended on which hand the subject was preparing to respond with, and how experienced they were with the task. When subjects prepared to respond with the non-dominant hand, excitability increased in the non-dominant hemisphere and decreased in the dominant hemisphere. These changes became stronger with task experience, and were accompanied by behavioral improvements in the task. When subjects were preparing a dominant-hand response, the non-dominant hemisphere was suppressed, but this effect disappeared as subjects gained experience with the task. There were no changes in the dominant hemisphere before dominant-hand responses. We conclude that preparing to respond with the non dominant hand involves temporarily reversing an asymmetry in excitability that normally favors the dominant hemisphere, and that this pattern is enhanced by learning during the task. PMID- 29533857 TI - Qualitative and quantitative analysis of furofuran lignans, iridoid glycosides, and phenolic acids in Radix Dipsaci by UHPLC-Q-TOF/MS and UHPLC-PDA. AB - Radix Dipsaci (RD), the dried root of Dipsacus asper, is used in traditional Chinese medicine as a remedy for bone fractures, traumatic hematoma, threatened abortion, and uterine bleeding. A novel ultra high-performance liquid chromatography coupled with quadrupole-time-of-flight tanderm mass spectrometry (UHPLC-Q-TOF/MS) approach was performed to rapidly characterize the chemical constituents of RD. Consequently, 21 compounds, including 12 iridoid glycosides (IGs), 4 furofuran lignans (FLs), and 5 phenolic acids (PAs) were discovered and identified from RD. Among these compounds, 3 IGs were previously unreported. Furthermore, a rapid and reliable UHPLC-DAD-based method was developed. The linearity (R2 > 0.999), repeatability (RSDs < 3.0%), intra-day and inter-day precision (RSDs < 1.6%), recovery (98.9%-102.5%), limits of detection (0.2-2.75 ng), and limits of quantification (0.75-8.5 ng) of the method was validated. The method was successfully applied for the simultaneous determination of 11 compounds in 20 batches of RD collected from various geographical regions in China. Different RD samples exhibited significantly varied contents of 11 analytes, among which IGs and PAs are abundant compounds that could be used as suitable quality markers for RD. The present study provided a useful approach for comprehensively evaluating the chemical composition and quality of RD. PMID- 29533858 TI - Developing a cassette microdosing approach to enhance the throughput of PET imaging agent screening. AB - Cassette dosing is also known as N-in-One dosing: several compounds are simultaneously administrated to a single animal and then the samples are rapidly detected by LC-MS/MS. This approach is a successful strategy to enhance the efficiency of drug discovery and reduce animal usage. However, no report on the utility of the cassette approach in radiotracer discovery has appeared in the literature. This study designed a cassette microdose with LC-MS/MS method to enhance the throughput for screening radiopharmaceutical biodistribution in the rat brain directly. Three unradiolabeled compounds (FPBM FPBM2 and AV-133) were chosen as model drugs administrated intravenously to the rats as a cassette as opposed to discrete study. The rat brain biodistribution data, target localization, the differential uptake ratio (%ID/g) and the brain tissue-specific binding ratio were obtained by the LC-MS/MS analysis. These data matched very well with the values obtained by the standard radioactivity measurements. Moreover, no significant differences between discrete dosing and cassette dosing were observed. By circumventing the need for radiolabeled molecules, this method may be high-throughput and safe for the research and development of new PET imaging agents. The combination of cassette microdosing and LC-MS/MS would be a medium throughput screening tool at an early stage in the discovery/development process of PET imaging agents. PMID- 29533859 TI - Beyond conventional dose-response curves: Sensorgram comparison in SPR allows single concentration activity and similarity assessment. AB - Previously we have introduced two SPR-based assay principles (dual-binding assay and bridging assay), which allow the determination of two out of three possible interaction parameters for bispecific molecules within one assay setup: two individual interactions to both targets, and/or one simultaneous/overall interaction, which potentially reflects the inter-dependency of both individual binding events. However, activity and similarity are determined by comparing report points over a concentration range, which also mirrors the way data is generated by conventional ELISA-based methods So far, binding kinetics have not been specifically considered in generic approaches for activity assessment. Here, we introduce an improved slope-ratio model which, together with a sensorgram comparison based similarity assessment, allows the development of a detailed, USP conformal ligand binding assay using only a single sample concentration. We compare this novel analysis method to the usual concentration-range approach for both SPR-based assay principles and discuss its impact on data quality and increased sample throughput. PMID- 29533860 TI - Quantitation of the anticancer drug abiraterone and its metabolite Delta(4) abiraterone in human plasma using high-resolution mass spectrometry. AB - Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Delta(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer. This study demonstrates the quantitative performance of HRMS and compares the conventional Parallel Reaction Monitoring (PRM) mode of quantitation with the unconventional Full scan MS mode conducted at high resolution (>70,000 resolution). The use of HRMS for quantitation of abiraterone and D4A yielded assays that were linear over a broad concentration range (0.074-509.6 ng/mL for abiraterone; 0.075-59.93 ng/mL for D4A) in both Full scan MS and PRM modes. The assay precision for abiraterone and D4A was below 5% in PRM mode and 7% in Full scan MS mode. Accuracies fell within 98-107% for abiraterone and 104-112% for D4A in PRM mode, and 96-116% for abiraterone and 96-105% for D4A in Full scan MS mode, each meeting the acceptance criteria of FDA approved guidelines for bioanalytical methods The PRM analysis of abiraterone and D4A provided high specificity and reduced background interference, however the Full scan MS detection at a resolution of 70,000 was advantageous in that it required minimal optimization, was simple to implement, yielded comparable quantitative characteristics to PRM and the data is useful for re-analysis. Use of the assays were demonstrated for quantitation of these metabolites in steady state trough level plasma of seventeen (17) patients with mCRPC, demonstrating the inter patient variability of up to 10-fold concentration. PMID- 29533861 TI - Rapid determination of neomycin in biological samples using fluorescent sensor based on quantum dots with doubly selective binding sites. AB - A new analytical method was developed to detect neomycin in complex biological samples using molecularly imprinted polymer to construct an optical sensor. Fluorescent neomycin-imprinted polymers (fMIPs) containing both imprinted cavity and boronate affinity site were synthesized on the surface of silica-modified quantum dots. The fMIPs exhibited high selectivity to neomycin by having two binding sites for the target analyte. Neomycin analogues (competing for imprinted cavity) and D-glucose (competing for the boronate affinity site) did not affect the selectivity of the fMIPs. When combined with a fluorescent microplate reader, the obtained fMIP sensor displayed a linear concentration-dependent fluorescence quenching in response to neomycin in the range of 2-1000 MUg/L, with a limit of detection as 0.16 MUg/L. The fMIP sensor was able to detect trace neomycin in biological samples accurately after simple sample pre-treatment. The sensitivity of the fMIP sensor was higher than HPLC equipped with a fluorescence detector. The fMIP sensor containing the doubly selective binding sites provides a selective, sensitive, accurate, and high through-put approach for neomycin monitoring. PMID- 29533862 TI - Analytical validation of a novel multiplex test for detection of advanced adenoma and colorectal cancer in symptomatic patients. AB - Early detection of colorectal cancer (CRC) is key to reducing associated mortality. Despite the importance of early detection, approximately 40% of individuals in the United States between the ages of 50-75 have never been screened for CRC. The low compliance with colonoscopy and fecal-based screening may be addressed with a non-invasive alternative such as a blood-based test. We describe here the analytical validation of a multiplexed blood-based assay that measures the plasma concentrations of 15 proteins to assess advanced adenoma (AA) and CRC risk in symptomatic patients. The test was developed on an electrochemiluminescent immunoassay platform employing four multi-marker panels, to be implemented in the clinic as a laboratory developed test (LDT). Under the Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP) regulations, a United States-based clinical laboratory utilizing an LDT must establish performance characteristics relating to analytical validity prior to releasing patient test results. This report describes a series of studies demonstrating the precision, accuracy, analytical sensitivity, and analytical specificity for each of the 15 assays, as required by CLIA/CAP. In addition, the report describes studies characterizing each of the assays' dynamic range, parallelism, tolerance to common interfering substances, spike recovery, and stability to sample freeze-thaw cycles. Upon completion of the analytical characterization, a clinical accuracy study was performed to evaluate concordance of AA and CRC classifier model calls using the analytical method intended for use in the clinic. Of 434 symptomatic patient samples tested, the percent agreement with original CRC and AA calls was 87% and 92% respectively. All studies followed CLSI guidelines and met the regulatory requirements for implementation of a new LDT. The results provide the analytical evidence to support the implementation of the novel multi-marker test as a clinical test for evaluating CRC and AA risk in symptomatic individuals. PMID- 29533863 TI - Incidence of and risk factors for clitoral lacerations in a retrospective cohort of more than 14.000 vaginal singleton deliveries. PMID- 29533864 TI - Intramuscular oxytocin administration before vs. after placental delivery for the prevention of postpartum hemorrhage: A randomized controlled prospective trial. AB - OBJECTIVE: Postpartum hemorrhage is still the most significant cause of maternal mortality and morbidity worldwide. Our aim was to evaluate the effect of timing of oxytocin administration on postpartum hemorrhage incidence in parturients with low-risk for postpartum hemorrhage. STUDY DESIGN: A randomized controlled trial was completed on 343 women at a level-three care hospital. In group 1, 10 IU of oxytocin was injected intramuscularly within the first minute following the delivery of the fetus. Group 2 received 10 IU of intramuscular oxytocin immediately following placental delivery. The primary outcome parameters were the incidence of postpartum hemorrhage and the measured blood loss. RESULTS: The rate of postpartum hemorrhage, defined as estimated blood loss >500 mL, did not differ significantly between the two groups (7/172 (4.1%) in group 1 vs. 10/171 (5.8%) in group 2, P = .45). The mean blood loss did not differ significantly between the two groups (192.18 +/- 135.7 in group 1 vs. 198.92 +/- 165.4 mL in group 2, P = .68). The duration of the third stage was significantly shorter in group 1. There were no significant differences between the two groups with respect to the mean changes in hemoglobin and hematocrit, postpartum 24th hour hemoglobin and hematocrit, the additional use of oxytocin, manual expulsion of placenta, curettage, blood transfusion demand, uterine atony, and lengthening of the third stage. CONCLUSION: In a level-three care hospital, timing of intramuscular oxytocin administration did not influence the incidence of postpartum hemorrhage in women with low risk of postpartum hemorrhage. PMID- 29533865 TI - Unconscious priming dissociates 'free choice' from 'spontaneous urge' responses. AB - Advances in neuroscience offer the exciting prospect of understanding 'free' choices - the subject of the free will debate in philosophy. However, while physiological techniques and analysis have progressed rapidly to meet this challenge, task design has not. The challenge is now to develop laboratory tasks that adequately capture 'free' picking or choosing. To isolate 'internally' generated intentions from those impelled by external stimulus, observers are asked to 'choose freely' or to wait for a felt 'urge'. However, no previous work has explicitly distinguished between instructions that refer to 'urges' versus to 'choosing'. The philosopher Alfred Mele (e.g., 2009; 2014) has argued that the distinction is of crucial conceptual importance, but the two have not yet been empirically distinguished. Here, we show that conscious and unconscious, task irrelevant primes, bias observers' binary choices when they are instructed to 'choose freely', not when they 'wait for an urge', underscoring the practical importance of Mele's conceptual distinction. Neuroscience must incorporate this distinction if we are to understand processes underpinning free choice. PMID- 29533866 TI - Aflatoxin B1 exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption. AB - BACKGROUND: Hepatocarcinogenicity of aflatoxin B1 (AFB1) has rarely been studied in populations with hepatitis C virus (HCV) infection and those without hepatitis B virus (HBV) and HCV infection (non-B-non-C). This case-control study nested in a community-based cohort aimed to investigate the HCC risk associated with AFB1 in HCV-infected and non-B-non-C participants. METHODS: Baseline serum AFB1 albumin adduct levels were measured in 100 HCC cases and 1767 controls seronegative for anti-HCV and HBsAg (non-B-non-C), and another 103 HCC cases and 176 controls who were anti-HCV-seropositive and HBsAg-seronegative. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. RESULTS: In 20 years of follow-up, the follow-up time to newly developed HCC was significantly shorter in participants with higher serum AFB1 albumin adduct levels in non-B-non-C (p = 0.0162) and HCV-infected participants (p < 0.0001). Within 8 years of follow-up, HCV infection and AFB1 exposure were independent risk factors for HCC. Elevated serum AFB1-albumin adduct levels were significantly associated with an increased risk of HCC newly developed within 8 years of follow-up in non-B-non-C participants with habitual alcohol consumption [crude OR (95% CI) for high vs. low/undetectable levels, 4.22 (1.16-15.37)] and HCV-infected participants [3.39 (1.31-8.77)], but not in non-B-non-C participants without alcohol drinking habit. AFB1 exposure remained an independent risk predictor for HCV-related HCC after adjustment for other HCC predictors (multivariate-adjusted OR [95% CI], 3.65 [1.32-10.10]). CONCLUSIONS: AFB1 exposure contributes to the development of HCC in participants with significant risk factors for cirrhosis including alcohol and HCV infection. PMID- 29533867 TI - The association between geographic location and incidence of Merkel cell carcinoma in comparison to melanoma: An international assessment. AB - AIM: The aim of this article was to provide worldwide, population-based incidence rates for Merkel cell carcinoma (MCC). METHODS: We included 11,576 cases from 20 countries for time trend analyses (1990-2007) and 11,028 cases (2.5 billion person-years) from 21 countries for the period 2003-2007 extracted from Cancer Incidence in Five Continents. We computed age-standardised incidence rates (World Standard population) per million person years and sex ratios of these rates. We estimated annual percentage changes (EAPCs) of the incidence and studied the association between geographic latitude and MCC incidence. We examined the body site distribution of MCC. FINDINGS: In the majority of populations, the incidence has increased over time (EAPC, men 2.0-21.0%; women 1.6-27.2%). Rate differences between 1995 and 2007 were typically small (men: 0.8-2.2; women: 0.2-1.7). The incidence was relatively stable in some populations (men: U.S. blacks, Japan, Norway, Denmark; women: Denmark, Norway, Sweden). Incidences from 2003 to 2007 were highest in Australia, New Zealand, the United States and Israel among men and in New Zealand, Australia, Ireland and the Netherlands among women. The incidence of MCC and melanoma among white non-Hispanic males in North America was positively associated with living closer to the equator. The proportion of MCC on the head was higher with advanced age. The head was a less likely primary site among blacks as compared with any other ethnicity. INTERPRETATION: Several countries showed increases in MCC incidence among white non-Hispanics over time. Latitude closer to the equator was associated with the MCC incidence in North American men, but barely in women, possibly due to occupational sunlight exposure patterns. PMID- 29533868 TI - Does smoking alter the mutation profile of human papillomavirus-driven head and neck cancers? AB - BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) patients are characterised by a better prognosis than their HPV-negative counterparts. However, this significant survival advantage is not homogeneous and among HPV positive patients those with a smoking history have a significantly increased risk of oncologic failure. The reason why tobacco consumption impacts negatively the prognosis is still elusive. Tobacco might induce additional genetic alterations leading to a more aggressive phenotype. The purpose of this study was to characterise the mutational profile of HPV-positive OPCs by smoking status. We hypothesise a higher frequency of mutations affecting smokers. METHODS: Targeted next-generation sequencing of 39 genes that are recurrently mutated in head and neck cancers (HNCs) caused by tobacco/alcohol consumption was performed in 62 HPV driven OPC cases including smokers and non-smokers. RESULTS: The study population included 37 (60%) non-smokers and 25 (40%) smokers. Twenty (32%) patients had no mutation, 14 (23%) had 1 mutation and 28 (45%) had 2 or more mutations. The most commonly mutated genes regardless of tobacco consumption were PIK3CA (19%), MLL2 (19%), TP53 (8%), FAT 1 (15%), FBXW7 (16%), NOTCH1 (10%) and FGFR3 (10%). Mutation rate was not significantly different in smokers compared with non smokers even when analyses focused on heavy smokers (>20 pack-years vs. <20 pack years). Similarly, there was no significant difference in mutations patterns according to tobacco consumption. CONCLUSION: In HPV-positive patients, smoking does not increase the mutation rate of genes that are recurrently mutated in traditional HNC. Additional studies are warranted to further describe the molecular landscape of HPV-driven OPC according to tobacco consumption. PMID- 29533869 TI - The economic burden of child sexual abuse in the United States. AB - The present study provides an estimate of the U.S. economic impact of child sexual abuse (CSA). Costs of CSA were measured from the societal perspective and include health care costs, productivity losses, child welfare costs, violence/crime costs, special education costs, and suicide death costs. We separately estimated quality-adjusted life year (QALY) losses. For each category, we used the best available secondary data to develop cost per case estimates. All costs were estimated in U.S. dollars and adjusted to the reference year 2015. Estimating 20 new cases of fatal and 40,387 new substantiated cases of nonfatal CSA that occurred in 2015, the lifetime economic burden of CSA is approximately $9.3 billion, the lifetime cost for victims of fatal CSA per female and male victim is on average $1,128,334 and $1,482,933, respectively, and the average lifetime cost for victims of nonfatal CSA is of $282,734 per female victim. For male victims of nonfatal CSA, there was insufficient information on productivity losses, contributing to a lower average estimated lifetime cost of $74,691 per male victim. If we included QALYs, these costs would increase by approximately $40,000 per victim. With the exception of male productivity losses, all estimates were based on robust, replicable incidence-based costing methods. The availability of accurate, up-to-date estimates should contribute to policy analysis, facilitate comparisons with other public health problems, and support future economic evaluations of CSA-specific policy and practice. In particular, we hope the availability of credible and contemporary estimates will support increased attention to primary prevention of CSA. PMID- 29533871 TI - Is the Effect of Postpartum Depression on Mother-Infant Bonding Universal? AB - PURPOSE: Although the negative consequences of maternal depression on infants has been documented in several Western societies, similar studies have not been conducted in Middle-Eastern countries where cultural norms and traditions may differ. The main objective of this study was to determine the risk factors for postpartum depression (PPD) and its relationship to mother -infant bonding in a Lebanese population. METHODS: One hundred and fifty participants were administered the Edinburgh Postpartum Depression Scale (EPDS), and the social support scale at 2-3 days postpartum. At 10-12 weeks mother-infant bonding using the Postpartum Bonding Questionnaire (PBQ) and depression using the Beck Inventory (BDI-II) were assessed during a telephone interview. RESULTS: The prevalence of depression was 19% with an average score of 10.9 +/- 6.02 on the EPDS. At 10-12 weeks 2.7% of the whole sample was depressed with an average score of 18.60 +/- 16.87 on the BDI-II. Risk factors of PPD on the EPDS were; history of alcohol use, complications during pregnancy, not a good marital relationship, baby admitted to an intensive care unit, history of depression and low social support. Risk factors for impaired bonding were age, history of depression, BDI II scores above 20 and low social support. The multiple regression analysis found that impaired bonding was associated with older age, history of depression and low social support, which explained 39% of the variance, F = 7.12, p = 0.02. CONCLUSION: The prevalence of PPD was higher than previously reported at day 2-3 post-delivery, but lower at 10-12 weeks postpartum. Impaired mother- infant bonding was associated older mothers, history of depression, low social support and BDI-II scores above 20 which should alert practitioner to assessing these factors in post-partum mothers. PMID- 29533870 TI - Dynamic stability during split-belt walking and the relationship with step length symmetry. AB - INTRODUCTION: Walking instability is a contributor to falls and other undesired changes in walking performance. We investigated the effect of split-belt treadmill based perturbations on dynamic stability. Furthermore, we examined the relationships for dynamic stability and symmetry during unperturbed and perturbed walking. METHOD: Twenty healthy young adults completed unperturbed and perturbed walking conditions on a split-belt treadmill. The continuous perturbation involved moving the parallel belts at unequal speeds (1.5 m/s: 0.5 m/s). Margins of stability (MoS) and step length symmetry (SYM) were assessed. RESULTS: Stability and symmetry measures each decreased at the onset of the split walking perturbation. Only anterior-posterior (AP) MoS and SYM exhibited adaptive changes. Associations were found primarily for AP MoS with immediate changes in SYM at the onset of split walking, and over the duration of the split walking condition. DISCUSSION: Our findings suggest walking strategies were adapted to maintain dynamic stability when faced with a continuous perturbation. Additionally, dynamic stability was associated with symmetry during perturbed walking. PMID- 29533872 TI - 2-Aryl benzimidazoles: Synthesis, In vitro alpha-amylase inhibitory activity, and molecular docking study. AB - Despite of many diverse biological activities exhibited by benzimidazole scaffold, it is rarely explored for the alpha-amylase inhibitory activity. For that purpose, 2-aryl benzimidazole derivatives 1-45 were synthesized and screened for in vitro alpha-amylase inhibitory activity. Structures of all synthetic compounds were deduced by various spectroscopic techniques. All compounds revealed inhibition potential with IC50 values of 1.48 +/- 0.38-2.99 +/- 0.14 MUM, when compared to the standard acarbose (IC50 = 1.46 +/- 0.26 MUM). Limited SAR suggested that the variation in the inhibitory activities of the compounds are the result of different substitutions on aryl ring. In order to rationalize the binding interactions of most active compounds with the active site of alpha amylase enzyme, in silico study was conducted. PMID- 29533873 TI - Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors. AB - In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (~30-fold) which was confirmed by western blot analysis. It is worth noting that 12a, 12b and 12c displayed highly selective anti-proliferative activity to T-cell leukemia cell lines Jurkat, Molt-4 and neuroblastoma cell line SK-N-BE-(2). Such selective cytotoxicity was also observed in the well-known HDAC8 selective inhibitor PCI 34051 but not in the pan-HDAC inhibitors SAHA and PXD101, indicating that HDAC8 selective inhibitor should have preferable benefit-risk profile in comparison with pan-HDAC inhibitor. Finally, the HDAC8 selectivity of 12a, 12b and 12c was rationalized by molecular docking study. PMID- 29533874 TI - The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease. AB - Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7 methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 MUM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD. PMID- 29533875 TI - Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity. AB - Three out of 16 newly synthesized 1,3-dimethylxanthine derivatives (proxyphylline analogues) exhibited consistencies between antifungal and anticancer properties. Proxyphylline possessing 1-(10H-phenothiazin-10-yl)propan-2-yl (6) and polybrominated benzimidazole (41) or benzotriazole moiety (42) remained selectively cidal against Candida albicans (lg R >= 3 at conc. of 31, 36 and 20 MUM, respectively) however not against normal mammalian Vero cell line in vitro (IC50 >= 280 MUM) and Galleria mellonella in vivo. These compounds also displayed moderate antineoplastic activity against human breast adenocarcinoma (MCF-7) cell line (EC50 = 80 MUM) and high against peripheral blood T lymphoblast (CCRF-CEM) (EC50 = 6.3-6.5 MUM). In addition, 6 and 42 exerted: (1) dual activity against fungal adhesion and damage mature biofilm; (2) necrosis of planktonic cells due to loss of membrane function and of structural integrity; (3) biochemical (inhibition of sessile cell respiration) and morphological changes in cell wall polysaccharide contents. Therefore, leading proxyphylline derivatives can be employed to prevent cancer-associated biofilm Candida infections. PMID- 29533876 TI - Empowering citizens or mining resources? The contested domain of citizen engagement in professional care services. AB - When studying individual attempts to foster citizen engagement, scholars have pointed to the coexistence of competing rationales. Thus far, however, current literature barely elaborates on the socio-political processes through which employees of professional organizations deal with such disparate considerations. To address this gap, this article builds on an ethnographic study, conducted in the Netherlands between 2013 and 2016, of a professional care organization's attempts to engage local citizens in one of its elderly care homes. To investigate how citizen engagement is 'done' in the context of daily organizing, we followed employees as they gradually created and demarcated the scope for such engagement by approaching citizens as either strategic partners (pursuing 'democratic' rationales) or as operational volunteers (pursuing 'instrumental' rationales). In order to deal with such potentially incongruent orientations, we found that employees used discursive strategies to influence the balance that was struck between competing rationales; either through depoliticization-i.e., the downplaying of incongruities and the framing of disparate considerations as being complementary within the pursuit of a shared, overarching goal-or through politicization, i.e., the active challenging of how their colleagues prioritized one consideration over another. By showing how the successful conveyance of such (de)politicized accounts helped employees either defend or redraw the boundaries of what citizen engagement was (not) about, we contribute to extant theorization by (1) developing a processual approach to studying citizen engagement that (2) is sensitive to organizational politics. PMID- 29533877 TI - Fate, morals and rational calculations: Freezing eggs for non-medical reasons in Turkey. AB - This article aims to explore women's decisions to freeze their eggs for non medical reasons in Turkey. It draws on semi-structured interviews conducted with twenty-one women who were either in the process of freezing their eggs, or had completed the process within the previous year. Being highly educated and holding prestigious occupations, on the one hand, and faced with traditional gender norms, on the other, these women are confronted with a challenging decision. When making such a decision to freeze their eggs, women act under the constraints defined by biomedical paradigms, the society they live in, and the future uncertainty of their lives. However, it becomes apparent that women are able to reconcile different kinds of rationalities and concerns in their decisions to freeze eggs. They engage in rational calculations to find a solution to their reproductive concerns; they turn to their own belief systems when dealing with future uncertainty; and they negotiate social norms concerning virginity, while trying to conform to traditional reproductive roles. PMID- 29533879 TI - Audience tuning effects in the context of situated and embodied processes. AB - This review provides an overview of the research on communication and the 'Saying is Believing' paradigm in the context of different perspectives on communication. The process of 'audience tuning' is shaped by a variety of situated factors in contexts that affect the communicators' confidence in their message. The overwhelming common denominator is that the combination of features that create ambiguity yields the optimal condition for the formation of shared realities. I conclude with an argument that the implied invariance of memory processes in shared reality work needs to be more attentive to the regulatory function of memories driving the expression of shared realities. PMID- 29533878 TI - Work and family transitions and the self-rated health of young women in South Africa. AB - Understanding the transition to adulthood has important implications for supporting young adults and understanding the roots of diversity in wellbeing later in life. In South Africa, the end of Apartheid means today's youth are experiencing their transition to adulthood in a changed social and political context which offers opportunities compared to the past but also threats. This paper presents the first national level analysis of the patterning of key transitions (completion of education, entry into the labour force, motherhood and marriage or cohabitation), and the association between the different pathways and health amongst young women. With the use of longitudinal data from the South African National Income Dynamics Study (2008-2015), this paper employs sequence analysis to identify common pathways to adulthood amongst women aged 15-17 years at baseline (n = 429) and logistic regression modelling to examine the association between these pathways and self-rated health. The sequence analysis identified five pathways: 1. 'Non-activity commonly followed by motherhood', 2. 'Pathway from school, motherhood then work', 3. 'Motherhood combined with schooling', 4. 'Motherhood after schooling', and 5. 'Schooling to non-activity'. After controlling for baseline socio-economic and demographic characteristics and health, the regression results show young women who followed pathways characterised by early motherhood and economic inactivity (1, 3 and 4) had poorer self-rated health compared to women whose pathways were characterised by combining motherhood and economic activity (2) and young women who were yet to become economically active or mothers (5). Therefore, policies should seek to prevent adolescent childbearing, support young mothers to continue their educational careers and enable mothers in work and seeking work to balance their work and care responsibilities. Further, the findings highlight the value of taking a holistic approach to health and provide further evidence for the need to consider work-family balance in the development agenda. PMID- 29533881 TI - A workflow for improving estimates of microplastic contamination in marine waters: A case study from North-Western Australia. AB - Plastic pollution is ubiquitous throughout the marine environment, with microplastic (i.e. <5 mm) contamination a global issue of emerging concern. The lack of universally accepted methods for quantifying microplastic contamination, including consistent application of microscopy, photography, an spectroscopy and photography, may result in unrealistic contamination estimates. Here, we present and apply an analysis workflow tailored to quantifying microplastic contamination in marine waters, incorporating stereomicroscopic visual sorting, microscopic photography and attenuated total reflectance (ATR) Fourier transform infrared (FTIR) spectroscopy. The workflow outlines step-by-step processing and associated decision making, thereby reducing bias in plastic identification and improving confidence in contamination estimates. Specific processing steps include (i) the use of a commercial algorithm-based comparison of particle spectra against an extensive commercially curated spectral library, followed by spectral interpretation to establish the chemical composition, (ii) a comparison against a customised contaminant spectral library to eliminate procedural contaminants, and (iii) final assignment of particles as either natural- or anthropogenic-derived materials, based on chemical type, a compare analysis of each particle against other particle spectra, and physical characteristics of particles. Applying this workflow to 54 tow samples collected in marine waters of North-Western Australia visually identified 248 potential anthropogenic particles. Subsequent ATR-FTIR spectroscopy, chemical assignment and visual re-inspection of photographs established 144 (58%) particles to be of anthropogenic origin. Of the original 248 particles, 97 (39%) were ultimately confirmed to be plastics, with 85 of these (34%) classified as microplastics, demonstrating that over 60% of particles may be misidentified as plastics if visual identification is not complemented by spectroscopy. Combined, this tailored analysis workflow outlines a consistent and sequential process to quantify contamination by microplastics and other anthropogenic microparticles in marine waters. Importantly, its application will contribute to more realistic estimates of microplastic contamination in marine waters, informing both ecological risk assessments and experimental concentrations in effect studies. PMID- 29533880 TI - Effects of acclimation on arsenic bioaccumulation and biotransformation in freshwater medaka Oryzias mekongensis after chronic arsenic exposure. AB - Fish can acclimate to chronic arsenic (As) exposure, but the mechanisms of acclimation remain unclear to date. Therefore, this study conducted 28-d chronic inorganic As [As(III) and As(V)] exposures in freshwater medaka (Oryzias mekongensis), examined the As bioaccumulation and biotransformation during exposure, and the As acute toxicity and toxicokinetics after exposure. After chronic As(V) exposure, the 96-h lethal concentration (96-h LC50) of As(V) increased 1.3-fold (from 223 to 286 MUmol/L), indicating that the fish became more tolerant to As(V). The As bioaccumulation in As(V)-exposed fish increased gradually during the initial 21-d exposure period and then decreased at 28 d, indicating that acclimation occurred to regulate the total As levels. Toxicokinetics measurement suggested that As(V) uptake (uptake rate constant, ku) was significantly decreased and As(III) elimination (efflux rate constant, ke1) was significantly increased, both of which could reduce As bioaccumulation. Furthermore, the organic As species became more predominant (50.1-69.3%) in exposed fish, while the inorganic As species were predominant (53.6-56.4%) in the control fish, suggesting that the capability of As biotransformation increased to acclimate inorganic As during chronic exposure. In summary, this study elucidated the acclimation strategies (reduced bioaccumulation and increased biotransformation) of O. mekongensis to counter the ambient As contamination. PMID- 29533882 TI - A hybrid source apportionment strategy using positive matrix factorization (PMF) and molecular marker chemical mass balance (MM-CMB) models. AB - The molecular marker-based chemical mass balance (MM-CMB) method performs well in the source apportionment of organic carbon (OC) but has some difficulty with contributions from primary sources to inorganic secondary ions when apportioning PM2.5 (particles with aerodynamic diameter of 2.5 MUm or less) sources. Positive matrix factorization (PMF) with the input of inorganic and organic tracers can properly estimate the contributions of primary and secondary sources to inorganic secondary ions; however, PMF is unable to apportion several PM2.5 sources with large fractions of organic carbon and few elemental compositions. In this study regarding data collected in 2011 and 2012 at three sites in Wuhan, China, the MM CMB model was used to apportion OC in the PM2.5, and the PMF model was used to apportion the inorganic ions (sulfate, nitrate, and ammonia), dust, and EC. The source contributions of PM2.5 were estimated by reconstructing masses of bulk chemical components that had been apportioned to real-world sources using suitable source apportionment methods. Good performance of this hybrid source apportionment strategy was observed with ten resolved factors, explaining 70-80% of measured PM2.5 mass on average. The hybrid strategy takes the advantages of both models in PM2.5 source apportionment and yields unique source apportionment results for PM2.5 bulk chemical components, which could provide new information for optimizing air quality regulations for the emission abatement of target PM mass and compositions for countries around the world. PMID- 29533883 TI - Validated tools measuring women's satisfaction in breast cancer screening programmes: A systematic review. AB - International guidelines recommend assessing women's satisfaction with breast cancer screening programmes; however, validated tools are needed. A systematic review to identify and evaluate the quality of validated instruments for screening satisfaction, from 01/1965 until 11/2017 was performed. From 3283 individual citations, six instruments were identified. Evaluation of the MammoGraphy Questionnaire using the COSMIN checklist resulted in 'good' to 'excellent' scores in most assessed domains, while the other tools were mostly 'poor'/'fair' quality or did not provide enough information for assessment. Nevertheless, substantial changes in screening processes and programmes have been implemented in recent years. Thus, further development work is needed. PMID- 29533884 TI - Nitrogen removal and recovery from lagoon-pretreated swine wastewater by constructed wetlands under sustainable plant harvesting management. AB - A series of three-stage pilot-scale surface flow constructed wetlands (CWs) planted with Myriophyllum aquaticum were fed with three strengths of lagoon pretreated swine wastewater to study nitrogen (N) removal and recovery under sustainable plant harvesting management. The CWs had mean removal efficiency of 87.7-97.9% for NH4+-N and 85.4-96.1% for total N (TN). The recovered TN mass via multiple harvests of M. aquaticum was greatest (120-222 g N m-2 yr-1) when TN concentrations were 21.8-282 mg L-1. The harvested TN mass accounted for 0.85 100% of the total removal in the different CW units. Based on mass balance estimation, plant uptake, sediment storage, and microbial removal accounted for 13.0-55.0%, 4.9-8.0%, and 33.0-67.5% of TN loading mass, respectively. The results of this study confirm that M. aquaticum is appropriate for the removal and recovery of nutrients in CW systems designed for treating swine wastewater in conjunction with sustainable plant harvesting strategies. PMID- 29533885 TI - A two-stage process facilitating microbial lipid production from N acetylglucosamine by Cryptococcus curvatus cultured under non-sterile conditions. AB - N-acetylglucosamine (GlcNAc), the monomeric constituent of chitin, is rarely studied for lipid production by oleaginous species. This study demonstrated that Cryptococcus curvatus had a great capacity to convert GlcNAc into lipid with high yield using a two-stage production process. Optimal inoculum age and inoculation size strongly improved the two-stage lipid production efficiency. More interestingly, this process rendered superior lipid production under non-sterile condition. The acetate liberated from GlcNAc was consumed timely, while the NH4+ released was rarely assimilated. Lipid titre, lipid content and lipid yield reached 9.9 g/L, 56.9% and 0.23 g/g, respectively, which were significantly higher than those from the conventional process where cell growth and lipid accumulation were coupled. The resulting lipid samples had similar fatty acid compositional profiles to those of vegetable oil, suggesting their potential for biodiesel production. These findings strongly supported the two-stage process as an attractive strategy for better techno-economics of the chitin-to-biodiesel routes. PMID- 29533886 TI - Particle-sparged anaerobic membrane bioreactor with fluidized polyethylene terephthalate beads for domestic wastewater treatment: Modelling approach and fouling control. AB - The study presents a mathematical model developed to better understand and control membrane fouling in a single-staged, anaerobic fluidized bed membrane bioreactor (AFMBR) using polyethylene terephthalate (PET) beads as scouring media. The model was based on combining the anaerobic biological model AM2b and a fouling model applied in membrane filtration. The presented model was validated using experimental data obtained by a laboratory scaled AFMBR reactor run during 250 d under various operational conditions. The combined AM2b and fouling model was able to simulate volatile suspended solids, soluble COD concentration, soluble microbial products concentrations and the methane production rate at steady-state condition with R2 of 95% as well as the trans-membrane pressure with R2 of 99%. The model was able to predict dominant fouling mechanism by assessing fouling resistances caused by cake formation and pore blocking separately. PMID- 29533887 TI - Photocatalytic activity of TiO2/Nb2O5/PANI and TiO2/Nb2O5/RGO as new nanocomposites for degradation of organic pollutants. AB - In this study, highly active titanium dioxide modified by niobium oxide (Nb2O5), polymer (PANI) and reduced graphene oxide (RGO) were successfully prepared. The morphology, structure, surface area and light absorption properties of the present nanocomposites for removal of methylene blue (MB) and methyl orange (MO) were investigated and compared with those of TiO2/Nb2O5 and TiO2 nanoparticles. The characterization techniques such as XRD, FT-IR, UV-vis, SEM, EDX, BET and TEM were employed in order to identify the nanocomposites. Also, photocatalytic properties of TiO2/Nb2O5/PANI and TiO2/Nb2O5/RGO nanocomposites under visible light irradiation were studied. In this way, the obtained results were compared to each other and also compared to TiO2/Nb2O5 and TiO2 nanoparticles. In this context, the chemical oxygen demand (COD) removal follows the photodegradation in observed performance. The results indicate that reduced TiO2/Nb2O5 nanocomposite is effectively modified by graphene oxide to give TiO2/Nb2O5/RGO composite. The TiO2/Nb2O5/RGO exhibits significantly higher photocatalytic activity in degradation of organic dyes under visible light rather than that of TiO2/Nb2O5/PANI, TiO2/Nb2O5 and pure TiO2. PMID- 29533888 TI - Identification of new metabolic pathways in the enantioselective fungicide tebuconazole biodegradation by Bacillus sp. 3B6. AB - The use of triazole fungicides in various fields ranging from agriculture to therapy, can cause long-term undesirable effects on different organisms from various environmental compartments and lead to resistance phenomena (even in humans) due to their extensive use and persistence. Their occurrence in various water bodies has increased and tebuconazole, in particular, is often detected, sometimes in high concentration. Only a few bacterial and fungal strains have been isolated and found to biotransform this fungicide, described as not easily biodegradable. Nevertheless, the knowledge of efficient degrading-strains and metabolites potentially formed could improve bioremediation process and global overview of risk assessment. Therefore, a broad screening of microorganisms, isolated from various environmental compartments or from commercially-available strain collections, allowed us to find six bacterial strains able to biotransform tebuconazole. The most efficient one was studied further: this environmental strain Bacillus sp. 3B6 biotransforms the fungicide enantioselectively (ee = 18%) into two hydroxylated metabolites, one of them being transformed in its turn to alkene by a biotic dehydration reaction. This original enantioselective pathway shows that racemic pesticides should be treated by the environmental risk assessment authorities as a mixture of two compounds because persistence, biodegradation, bioaccumulation and toxicity often show chiral dependence. PMID- 29533889 TI - Reaction condition optimization and degradation pathway in wet oxidation of benzopyrazole revealed by computational and experimental approaches. AB - The nitrogen heterocyclic compounds (NHCs) are very toxic and widely used in many industries, while the treatment of NHCs in wastewater has not attracted enough concern till now. Here we studied the complete degradation of a typical NHCs, benzopyrazole (BP), in wet oxidation. The effects of different operation parameters, such as stirring speed, temperature, reaction time and initial pH, on BP degradation and chemical oxygen demand (COD) removal were studied. BP was totally degraded and the COD removal efficiency achieved 76.7%, after 120 min reaction at 220 degrees C with initial pH 6.5. Meanwhile, 81.7% of the nitrogen from BP was removed from the solution. The toxicity of the BP solution was reduced by 95.2% after wet oxidation at 240 degrees C for 180 min. The influences of coexisted NO3-, CO32-, SO42- and PO43- ions were also investigated. With quantum chemical calculation and intermediates analysis by electrospray ionization mass spectrometry, a very detailed degradation pathway of BP in wet oxidation was proposed. PMID- 29533890 TI - Chlorella vulgaris and Pseudomonas putida interaction modulates phosphate trafficking for reduced arsenic uptake in rice (Oryza sativa L.). AB - Rice grown in arsenic (As) contaminated areas contributes to high dietary exposure of As inducing multiple adverse effects on human health. The As contamination and application of phosphate fertilizers during seedling stage creates a high P and As stress condition. The flooded paddy fields are also conducive for algal growth and microbial activity. The present study proposes potential role of microalgae, Chlorella vulgaris (CHL) and bacteria, Pseudomonas putida (RAR) on rice plant grown under excess As and phosphate (P) conditions. The results show synchronized interaction of CHL + RAR which, reduces As uptake through enhanced P:As and reduced As:biomass ratio by modulating P trafficking. Gene expression analysis of different phosphate transporters exhibited correlation with reduced As uptake and other essential metals. The balancing of reactive oxygen species (ROS), proline accumulation, hormone modulation, and As sequestration in microbial biomass were elucidated as possible mechanisms of As detoxification. The study concludes that RAR and CHL combination mitigates the As stress during P-enriched conditions in rice by: (i) reducing As availability, (ii) modulating the As uptake, and (iii) improving detoxification mechanism of the plant. The study will be important in assessing the role and applicability of P solubilizing biofertilizers in these conditions. PMID- 29533891 TI - Modeling Lung Architecture in the XCAT Series of Phantoms: Physiologically Based Airways, Arteries and Veins. AB - The purpose of this paper was to extend the extended cardiac-torso (XCAT) series of computational phantoms to include a detailed lung architecture including airways and pulmonary vasculature. Eleven XCAT phantoms of varying anatomy were used in this paper. The lung lobes and initial branches of the airways, pulmonary arteries, and veins were previously defined in each XCAT model. These models were extended from the initial branches of the airways and vessels to the level of terminal branches using an anatomically-based volume-filling branching algorithm. This algorithm grew the airway and vasculature branches separately and iteratively without intersecting each other using cylindrical models with diameters estimated by order-based anatomical measurements. Geometrical features of the extended branches were compared with the literature anatomy values to quantitatively evaluate the models. These features include branching angle, length to diameter ratio, daughter to parent diameter ratio, asymmetrical branching pattern, diameter, and length ratios. The XCAT phantoms were then used to simulate CT images to qualitatively compare them with the original phantom images. The proposed growth model produced 46369 +/- 12521 airways, 44737 +/- 11773 arteries, and 39819 +/- 9988 veins to the XCAT phantoms. Furthermore, the growth model was shown to produce asymmetrical airway, artery, and vein networks with geometrical attributes close to morphometry and model based studies. The simulated CT images of the phantoms were judged to be more realistic, including more airways and pulmonary vessels compared with the original phantoms. Future work will seek to add a heterogeneous parenchymal background into the XCAT lungs to make the phantoms even more representative of human anatomy, paving the way towards the use of XCAT models as a tool to virtually evaluate the current and emerging medical imaging technologies. PMID- 29533892 TI - Synthesis of Realistic Simultaneous Positron Emission Tomography and Magnetic Resonance Imaging Data. AB - The investigation of the performance of different positron emission tomography (PET) reconstruction and motion compensation methods requires accurate and realistic representation of the anatomy and motion trajectories as observed in real subjects during acquisitions. The generation of well-controlled clinical datasets is difficult due to the many different clinical protocols, scanner specifications, patient sizes, and physiological variations. Alternatively, computational phantoms can be used to generate large data sets for different disease states, providing a ground truth. Several studies use registration of dynamic images to derive voxel deformations to create moving computational phantoms. These phantoms together with simulation software generate raw data. This paper proposes a method for the synthesis of dynamic PET data using a fast analytic method. This is achieved by incorporating realistic models of respiratory motion into a numerical phantom to generate datasets with continuous and variable motion with magnetic resonance imaging (MRI)-derived motion modeling and high resolution MRI images. In this paper, data sets for two different clinical traces are presented, 18F-FDG and 68Ga-PSMA. This approach incorporates realistic models of respiratory motion to generate temporally and spatially correlated MRI and PET data sets, as those expected to be obtained from simultaneous PET-MRI acquisitions. PMID- 29533893 TI - A DCE-MRI Driven 3-D Reaction-Diffusion Model of Solid Tumor Growth. AB - Predicting tumor growth and its response to therapy remains a major challenge in cancer research and strongly relies on tumor growth models. In this paper, we introduce, calibrate, and verify a novel image-driven reaction-diffusion model of avascular tumor growth. The model allows for proliferation, death and spread of tumor cells, and accounts for nutrient distribution and hypoxia. It is constrained by longitudinal time series of dynamic contrast-enhancement-MRI images. Tumor specific parameters are estimated from two early time points and used to predict the spatio-temporal evolution of the tumor volume and cell densities at later time points. We first test our parameter estimation approach on synthetic data from 15 generated tumors. Our in silico study resulted in small volume errors (<5%) and high Dice overlaps (>97%), showing that model parameters can be successfully recovered and used to accurately predict the tumor growth. Encouraged by these results, we apply our model to seven pre-clinical cases of breast carcinoma. We are able to show promising preliminary results, especially for the estimation for early time points. Processes like angiogenesis and apoptosis should be included to further improve predictions for later time points. PMID- 29533894 TI - Image-Based Reconstruction of Tissue Scatterers Using Beam Steering for Ultrasound Simulation. AB - Numerical simulation of ultrasound images can facilitate the training of sonographers. An efficient and realistic model for the simulation of ultrasonic speckle is the convolution of the ultrasound point-spread function with a distribution of point scatterers. Nevertheless, for a given arbitrary tissue type, a scatterer map that would generate a realistic appearance of that tissue is not known a priori. In this paper, we introduce a principled approach to estimate (reconstruct) such a scatterer map from images, by solving the inverse problem of ultrasound speckle formation, such that images from arbitrary view angles and transducer settings can be generated from those scatterer maps later in simulations. Robust reconstructions are achieved by using multiple measurements of the same tissue with different viewing parameters. For this purpose, a novel use of beam-steering to rapidly and conveniently acquire multiple images of the same scene is proposed. We demonstrate in numerical and physical phantoms and images that the appearance of synthesized images closely match real images for a range of viewing parameters and probe settings. We also present a scene editing scenario exploiting these scatterer representations to create realistic images of augmented anatomy. PMID- 29533895 TI - Adversarial Stain Transfer for Histopathology Image Analysis. AB - It is generally recognized that color information is central to the automatic and visual analysis of histopathology tissue slides. In practice, pathologists rely on color, which reflects the presence of specific tissue components, to establish a diagnosis. Similarly, automatic histopathology image analysis algorithms rely on color or intensity measures to extract tissue features. With the increasing access to digitized histopathology images, color variation and its implications have become a critical issue. These variations are the result of not only a variety of factors involved in the preparation of tissue slides but also in the digitization process itself. Consequently, different strategies have been proposed to alleviate stain-related tissue inconsistencies in automatic image analysis systems. Such techniques generally rely on collecting color statistics to perform color matching across images. In this work, we propose a different approach for stain normalization that we refer to as stain transfer. We design a discriminative image analysis model equipped with a stain normalization component that transfers stains across datasets. Our model comprises a generative network that learns data set-specific staining properties and image-specific color transformations as well as a task-specific network (e.g., classifier or segmentation network). The model is trained end-to-end using a multi-objective cost function. We evaluate the proposed approach in the context of automatic histopathology image analysis on three data sets and two different analysis tasks: tissue segmentation and classification. The proposed method achieves superior results in terms of accuracy and quality of normalized images compared to various baselines. PMID- 29533896 TI - Cross-Modality Image Synthesis via Weakly Coupled and Geometry Co-Regularized Joint Dictionary Learning. AB - Multi-modality medical imaging is increasingly used for comprehensive assessment of complex diseases in either diagnostic examinations or as part of medical research trials. Different imaging modalities provide complementary information about living tissues. However, multi-modal examinations are not always possible due to adversary factors, such as patient discomfort, increased cost, prolonged scanning time, and scanner unavailability. In additionally, in large imaging studies, incomplete records are not uncommon owing to image artifacts, data corruption or data loss, which compromise the potential of multi-modal acquisitions. In this paper, we propose a weakly coupled and geometry co regularized joint dictionary learning method to address the problem of cross modality synthesis while considering the fact that collecting the large amounts of training data is often impractical. Our learning stage requires only a few registered multi-modality image pairs as training data. To employ both paired images and a large set of unpaired data, a cross-modality image matching criterion is proposed. Then, we propose a unified model by integrating such a criterion into the joint dictionary learning and the observed common feature space for associating cross-modality data for the purpose of synthesis. Furthermore, two regularization terms are added to construct robust sparse representations. Our experimental results demonstrate superior performance of the proposed model over state-of-the-art methods. PMID- 29533897 TI - An Overview of Recent Advances in Event-Triggered Consensus of Multiagent Systems. AB - Event-triggered consensus of multiagent systems (MASs) has attracted tremendous attention from both theoretical and practical perspectives due to the fact that it enables all agents eventually to reach an agreement upon a common quantity of interest while significantly alleviating utilization of communication and computation resources. This paper aims to provide an overview of recent advances in event-triggered consensus of MASs. First, a basic framework of multiagent event-triggered operational mechanisms is established. Second, representative results and methodologies reported in the literature are reviewed and some in depth analysis is made on several event-triggered schemes, including event-based sampling schemes, model-based event-triggered schemes, sampled-data-based event triggered schemes, and self-triggered sampling schemes. Third, two examples are outlined to show applicability of event-triggered consensus in power sharing of microgrids and formation control of multirobot systems, respectively. Finally, some challenging issues on event-triggered consensus are proposed for future research. PMID- 29533898 TI - YoTube: Searching Action Proposal Via Recurrent and Static Regression Networks. AB - In this paper, we propose YoTube-a novel deep learning framework for generating action proposals in untrimmed videos, where each action proposal corresponds to a spatial-temporal tube that potentially locates one human action. Most of the existing works generate proposals by clustering low-level features or linking image proposals, which ignore the interplay between long-term temporal context and short-term cues. Different from these works, our method considers the interplay by designing a new recurrent YoTube detector and static YoTube detector. The recurrent YoTube detector sequentially regresses candidate bounding boxes using Recurrent Neural Network learned long-term temporal contexts. The static YoTube detector produces bounding boxes using rich appearance cues in every single frame. To fully exploit the complementary appearance, motion, and temporal context, we train the recurrent and static detector using RGB (Color) and flow information. Moreover, we fuse the corresponding outputs of the detectors to produce accurate and robust proposal boxes and obtain the final action proposals by linking the proposal boxes using dynamic programming with a novel path trimming method. Benefiting from the pipeline of our method, the untrimmed video could be effectively and efficiently handled. Extensive experiments on the challenging UCF-101, UCF-Sports, and JHMDB datasets show superior performance of the proposed method compared with the state of the arts. PMID- 29533899 TI - Diverse Region-Based CNN for Hyperspectral Image Classification. AB - Convolutional neural network (CNN) is of great interest in machine learning and has demonstrated excellent performance in hyperspectral image classification. In this paper, we propose a classification framework, called diverse region-based CNN, which can encode semantic context-aware representation to obtain promising features. With merging a diverse set of discriminative appearance factors, the resulting CNN-based representation exhibits spatial-spectral context sensitivity that is essential for accurate pixel classification. The proposed method exploiting diverse region-based inputs to learn contextual interactional features is expected to have more discriminative power. The joint representation containing rich spectral and spatial information is then fed to a fully connected network and the label of each pixel vector is predicted by a softmax layer. Experimental results with widely used hyperspectral image data sets demonstrate that the proposed method can surpass any other conventional deep learning-based classifiers and other state-of-the-art classifiers. PMID- 29533900 TI - Compression-Dependent Transform-Domain Downward Conversion for Block-Based Image Coding. AB - Transform-domain downward conversion (TDDC) for image coding is usually implemented by discarding some high-frequency components from each transformed block. As a result, a block of fewer coefficients is formed, and a lower compression cost is achieved due to the coding of only a few low-frequency coefficients. In this paper, we focus on the design of a new TDDC-based coding method by using our proposed interpolation-compression directed filtering (ICDF) and error-compensated scalar quantization (ECSQ), leading to the compression dependent TDDC (CDTDDC)-based coding. More specifically, ICDF is first used to convert each macro-block into an coefficient block. Then, this coefficient block is compressed with ECSQ, resulting in a smaller compression distortion for those pixels that locate at some specific positions of a macro-block. We select these positions according to the 4:1 uniform sub-sampling lattice and use the pixels locating at them to reconstruct the whole macro-block through an interpolation. The proposed CDTDDC-based coding can be applied to compress both grayscale and color images. More importantly, when it is used in the color image compression, it offers not only a new solution to reduce the data-size of chrominance components but also a higher compression efficiency. Experimental results demonstrate that applying our proposed CDTDDC-based coding to compress still images can achieve a significant quality gain over the existing compression methods. PMID- 29533901 TI - Robust Single-Image Super-Resolution Based on Adaptive Edge-Preserving Smoothing Regularization. AB - Single-image super-resolution (SR) reconstruction via sparse representation has recently attracted broad interest. It is known that a low-resolution (LR) image is susceptible to noise or blur due to the degradation of the observed image, which would lead to a poor SR performance. In this paper, we propose a novel robust edge-preserving smoothing SR (REPS-SR) method in the framework of sparse representation. An EPS regularization term is designed based on gradient-domain guided filtering to preserve image edges and reduce noise in the reconstructed image. Furthermore, a smoothing-aware factor adaptively determined by the estimation of the noise level of LR images without manual interference is presented to obtain an optimal balance between the data fidelity term and the proposed EPS regularization term. An iterative shrinkage algorithm is used to obtain the SR image results for LR images. The proposed adaptive smoothing-aware scheme makes our method robust to different levels of noise. Experimental results indicate that the proposed method can preserve image edges and reduce noise and outperforms the current state-of-the-art methods for noisy images. PMID- 29533902 TI - Hodgkin lymphoma cell lines: to separate the wheat from the chaff. AB - Characteristic components of Hodgkin lymphoma (HL) tissue are the mono- or multinucleated Hodgkin-Reed-Sternberg (HRS) cells. Given the challenges of isolating these rare malignant cells and the difficulty in culturing cells from patients, many investigators have tried to establish cell lines in efforts to develop cellular tools for in vitro studies. A limited number of HL cell lines exist and have provided valuable insights into HL pathobiology. A literature survey indicated that 35 cell lines derived from HL patients have been published. To determine whether all these alleged HL cell lines hold up to scrutiny, we examined the available data and also put some of these cell lines to the test of hierarchical clustering, providing additional information regarding assignment to cell line type and tissue derivation. Hierarchical clustering separated the bona fide (classical) HL cell lines completely from cell lines derived from other lymphoma categories and proved conclusively that HL cell lines represent a distinct entity, irrespective of the cellular origin of the HRS cells. We conclude by pointing out the need for an intensified search for new cell culture avenues in order to develop a new generation of informative HL cell lines covering more widely the spectrum of HL stages and subtypes. PMID- 29533903 TI - Assessing matrix, interferences and comparability between the Abbott Diagnostics and the Beckman Coulter high-sensitivity cardiac troponin I assays. AB - BACKGROUND: Analytical evaluation of high-sensitivity cardiac troponin (hs-cTn) assays, with particular attention to imprecision, interferences and matrix effects, at normal cTn concentrations, is of utmost importance as many different clinical algorithms use concentration cutoffs <10 ng/L for decision-making. The objective for the present analytical study was to compare the new Beckman Coulter hs-cTnI assay (Access hsTnI) to Abbott's hs-cTnI assay in different matrices and for different interferences, with a focus on concentrations <10 ng/L. METHODS: The limit of blank (LoB) and the limit of detection (LoD) were determined in different matrices for the Beckman hs-cTnI assay. Passing-Bablok regression and difference plots were determined for 200 matched lithium heparin and EDTA plasma samples for the Beckman assay and 200 lithium heparin samples for the Abbott assay. Both EDTA and heparin plasma samples were also evaluated for stability under refrigerated conditions, for endogenous alkaline phosphatase interference and for hemolysis and icterus. RESULTS: The Beckman hs-cTnI assay LoB was 0.5 ng/L with the following range of LoDs=0.8-1.2 ng/L, with EDTA plasma yielding lower concentrations as compared to lithium heparin plasma (mean difference= 14.9%; 95% CI=-16.9 to 12.9). Below 10 ng/L, lithium heparin cTnI results from the Beckman assay were on average 1.1 ng/L (95% CI=0.7 to 1.5) higher than the Abbott results, with no difference between the methods when using EDTA plasma (mean difference =-0.1 ng/L; 95% CI=-0.3 to 0.2). Low cTnI concentrations were less effected by interferences in EDTA plasma. CONCLUSIONS: The Access hsTnI method can reliably detect normal cTnI concentrations with both lithium heparin and EDTA plasma being suitable matrices. PMID- 29533904 TI - Downregulation of tumor-suppressor gene LHX6 in cancer: a systematic review. AB - INTRODUCTION: LIM Homeobox 6 (LHX6) encodes a LIM homeodomain transcription factor, contributes to tissue development and morphogenesis, and is mostly expressed in medial ganglionic eminence and odontogenic mesenchyme. However, it has been reported to play a role in cancer progression. This narrative review summarizes literatures that emphasize the molecular regulation of LHX6 in tumorigenesis. METHODS: In our systematic review, the PubMed database was used for the literature search using the combination of words that included "LHX6" and "cancer". Relevant studies, including in vitro, in vivo experiments, and clinical studies, were analyzed in this review. RESULTS: We found evidences that LHX6 might be important in the inhibition of tumor cell proliferation, growth, invasion, and metastasis through the suppression of Wnt/beta-catenin signaling pathway. Moreover, LHX6 is observed to be downregulated in certain types of cancer due to hypermethylation, thus hindering its tumor suppressing ability. In addition, hypermethylation can also be used to determine the stage of cancer development. CONCLUSION: The downregulation of LHX6 expression might be responsible in promoting cancer progression. Future studies are necessary to investigate the potential of LHX6 as a novel cancer biomarker as well as its therapeutic implications towards certain types of cancer. PMID- 29533905 TI - [Current approaches in the treatment of hyperphosphatemia in chronic kidney disease]. AB - Hyperphosphatemia is a common finding in advanced chronic kidney disease (CKD) and is associated with increased morbidity and mortality. Optimal phosphate control in dialysis patients is a real challenge. In the article, the authors discuss the main phosphate-lowering approaches, such as a change of dietary habits with phosphate restriction and pharmacologic treatment. Several old and new currently available oral phosphate binders are reviewed with their advantages and disadvantages. PMID- 29533906 TI - [Vesicoureteric reflux]. AB - Vesicoureteric reflux (VUR) is defined as the retrograde passage of urine from the bladder into the upper parts of urinary system. The first symptoms may be seen in infancy, but may as well develop during entire life of the patient, in some patients being atypical. A quick diagnosis is of utmost importance since any delay in the treatment can cause many serious complications such as recurrent urinary tract infections (UTI), renal scarring development, hypertension and renal insufficiency. PMID- 29533907 TI - [Spectrum of monoclonal gammopathies]. AB - The monoclonal gammopathies are defined as heterogenous group of diseases characterized by proliferation of a single clone of plasma cells, producing immunoglobulin or light (rarely heavy) chains, which can be detected in blood or urine as monoclonal (M) protein. The most common among them is monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic benign disorder, present in ~ 3% of the population aged >=50 years. However MGUS is a pre malignant condition and may progress to symptomatic multiple myeloma or related malignancies, with annual rate of approximately 1%. The clone may also produce kidney damage, resulting from just the protein M, with different patterns of renal disease. Since the lesions are progressive and may be severe leading to a significant morbidity the term "monoclonal gammopathy of renal significance (MGRS)" has been recently introduced. PMID- 29533908 TI - [MGRS - monoclonal gammopathy of renal significance]. AB - MGRS represents a group of kidney disorders caused by monoclonal gammapathy that is secreted by B cell or plasma cell clone. Kidney biopsy is required in the diagnosis, in the treatment - chemotherapy. When the hematology remision is reached, kidney remision is possible. In case of end-stage kidney disease despite hematologic remission - kidney transplantation may be considered. PMID- 29533909 TI - [Vaccination in chronic kidney disease - guidelines and evidence]. AB - Patients with chronic kidney disease are immunocompromised and deterioration of kidney function builds up the defect of the cellular and humoral immunity. This makes the patients prone to severe life-threatening infections, and results in less effective vaccination. In addition, frequent hospitalizations, immunosuppressive therapy and renal replacement therapy are important risk factors for infection. The review presents recommendations and the evidence for the efficacy of vaccination in different populations of patients with kidney disease. PMID- 29533910 TI - [Approach to recurrent urinary tract infections in women]. AB - Recurrent urinary tract infections (rUTI), defined as >=3 UTI/year or >=2 UTI/half year, are among the most frequent bacterial infections in women and pose a significant clinical challenge to general practitioner. The main risk factors are: sexual activity with different partners, and - in postmenopausal women - urinary incontinence or incomplete voiding. In the article the current treatment and prevention strategies for rUTI are discussed. PMID- 29533911 TI - [Proliferation signal inhibitors in renal transplant recipients]. AB - In the article, the authors discuss proliferation signal inhibitors (PSI), a group of medicines used in immunosuppressive therapy after renal transplantation. They present the mechanism of action of this class, side effects and drug interactions important in clinical practice. In addition, they present the available drugs and their practical application. PMID- 29533912 TI - [New oral hypoglycemic drugs in diabetic kidney disease]. AB - New antidiabetic drugs let optimize the treatment of diabetes. In clinical practice the use of glitazone, incretin drugs (including GLP-1 receptor agonists and DPP-4 dipeptidyl peptidase inhibitors) or glucose-2-cotransporter (SGLT-2) inhibitors is increased. The potential use of these drugs in patients with renal insufficiency is limited both to impaired renal function (and the associated risk of drug or metabolite accumulation in the body), and due to limited clinical data assessing the safety of their use in this group of patients. However, previous experience has allowed us to formulate recommendations for the use of some of the new antidiabetic agents in patients with renal impairment. This provides an opportunity to improve the management of diabetes mellitus and to reduce the complications associated with diabetes (especially cardiovascular disease) in diabetic patients with renal disease. PMID- 29533914 TI - [Systemic lupus erythematosus - news 2017]. AB - Systemic lupus erythematosus is a chronic autoimmune disease with diverse manifestations and clinical course, required multidisciplinary treatment. The etiology, pathogenesis and optimal treatment are still unknown. There are two summaries on SLE, published in 2017, presented below. PMID- 29533913 TI - [Treatment of metabolic acidosis in patients with chronic kidney disease (CKD)]. AB - Metabolic acidosis becoming clinically apparent when glomerular filtration rate (GFR) decreases <30 ml/min/1,73m2. Although usually mild, it can have substantial adverse effects like: impair albumin biosynthesis and glucose metabolism, increase protein catabolism with a decrease of muscle mass, increase bone resorption and inhibition of its formation with growth retardation in children. At present KDIGO (Kidney Disease: Improving Global Outcomes) recommendations support oral sodium bicarbonate supplementation and maintaining HCO3 - concentration >=22 mmol/l in all CKD patients. PMID- 29533915 TI - [Mineralocorticoid receptor antagonists in chronic kidney disease - pros and cons]. AB - Aldosterone takes part in the regulation of body fluid volume, blood pressure and kalemia. In a number of pathological conditions, including chronic kidney disease (CKD), secondary hyperaldosteronism occurs, leading to development of edema, hypervolemia and hypertension. Aldosterone has also a proinflammatory action, leading to heart and blood vessels damage, and is an independent risk factor of death. Some of the research conducted to confirm the expected benefits of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) therapy in CKD patients did not yield positive results, probably due to "aldosterone escape". Mineralocorticoid receptor antagonists (MRA) are being introduced also in the treatment of CKD patients, although the risk of developing hyperkalemia exists. A number of papers suggest a positive influence of MRA on slowing down the progression of renal failure, reduction of cardiovascular risk, and decreasing mortality, with relative safety of treatment, however the data are based on small and heterogenous groups of patients, therefore conclusive information is expected from large trials which are currently being conducted (BARACK D, ALCHEMIST). PMID- 29533916 TI - [Resistant hypertension]. AB - Hypertension is the most common chronic cardiovascular condition, with an increasing prevalence all over the world. Patients with refractory hypertension are the group most at risk for adverse cardiovascular events, but also present a particular diagnostic and therapeutic challenge. The present article reviews the mechanisms of development of resistant hypertension and the possibilities of pharmacological treatment and interventional approaches. PMID- 29533917 TI - [Iron supplementation in chronic kidney disease]. AB - Treatment with iron preparations remains one of the main directions in the treatment of anemia in patients with chronic kidney disease. Intravenous agents, although effective, may have serious adverse effects, while oral iron supplementation may be ineffective due to malabsorption and gastrointestinal side effects. The solution may be modern drugs such as ferric pyrophosphate added to dialysis fluid or liposomal iron without gastrointestinal adverse effects. PMID- 29533918 TI - Intentional overdose of dolutegravir/abacavir/lamivudine (Triumeq) in a 26-year old man. AB - Triumeq is a single-tablet regimen for patients with HIV infection comprising dolutegravir, abacavir and lamivudine. Overdoses with Triumeq have not been reported previously. We present a case of a 26-year-old man who presented to our hospital after intentionally ingesting 30 tablets of Triumeq. An intoxication with Triumeq can lead to several side effects. An overdose of abacavir and lamivudine can cause mitochondrial toxicity and lactic acidosis. An intoxication with dolutegravir appears to be relatively harmless. As Triumeq will be used on a regular basis as treatment for patients with HIV-1 infection, these intoxications are expected to be encountered more often. PMID- 29533919 TI - Finite element modelling and image reconstruction for Lorentz force electrical impedance tomography. AB - OBJECTIVE: We propose a numerical framework to simulate the Lorentz force electrical impedance tomography (LFEIT) measurements on accurate electrode models and an image reconstruction scheme for which data on two pairs of electrodes are sufficient. APPROACH: The adopted finite element-based complete electrode model encompasses the electrode's geometry and contact impedance, accounting for the power losses at the contact interface. For image reconstruction, we suggest an approach based on a modified J-substitution algorithm that requires LFEIT and impedance measurements on two pairs of sensors, essentially necessitating no more than three boundary electrodes. MAIN RESULTS: The results of our simulation study suggest that electrode modelling has a significant impact on the measurements and electrode model inaccuracies may be detrimental to the image reconstruction. For image reconstruction, we suggest an approach based on a modified J-substitution algorithm that requires LFEIT and impedance measurements on two pairs of sensors, essentially necessitating no more than three boundary electrodes. SIGNIFICANCE: This allows for shorter acquisition times, less sonication noise during the acoustic modulation, a simpler measurement setup, and eventually a more succinct and efficient image reconstruction process. PMID- 29533920 TI - Treading on the unknown-the feasibility of a novel approach to investigating the motor control of walking. AB - BACKGROUND AND OBJECTIVE: Walking is a complex human behavior, usually performed in a dynamic environment. Gait parameters are thought to reflect this complexity. Re-StepTM is a therapy system in the form of a computerized shoe, originally developed for the training and rehabilitation of individuals with brain damage. This system may be used as model for studying the complexity that underlies gait. As the first step, we present here the feasibility of the model, after establishing the validity and reliability of stride time and stride-time variability, observed in healthy adults. APPROACH: Fifteen healthy adults participated in this study. To establish concurrent validity, we had five participants walk with the Re-Step on a treadmill equipped with a force plate. To establish inter-rater reliability, we used data from ten participants who walked approximately 300 m with the system. Finally, the stride-time variability of perturbed and unperturbed walks was compared to establish the feasibility of the model. RESULTS: The correlation between the stride times observed with the treadmill and those observed with the Re-Step system was r = 0.971. The interclass correlation coefficient between left and right legs was 1.000 for stride time and 0.827 for its variability. A significant increase (mean difference 0.68%) in stride time variability was observed between unperturbed and perturbed walks. SIGNIFICANCE: The results of this study suggest that stride-time measurements and variability observed in the Re-Step system are valid and reliable and that the model increases the challenge to the control system, thereby making Re-Step useful in the investigation of gait. PMID- 29533921 TI - Symmetry difference electrical impedance tomography-a novel modality for anomaly detection. AB - OBJECTIVE: The theoretical basis, experimental implementation, and proof of concept of a novel electrical impedance tomography (EIT) imaging technique, called symmetry difference EIT, is described. This technique is applicable in situations where there is inherent symmetry in the region being imaged. METHODS: The sample scenario of the human head is used to describe the technique. The head is largely symmetrical across the sagittal plane. A unilateral lesion such as a haemorrhage or region of ischaemia distorts that symmetry. This distortion may be visualised using EIT. Measurement sets from a ring of electrodes placed on the boundary in both clockwise and counter-clockwise orientations are compared to detect the anomaly. Computer simulations featuring a hemispherical model of the head and brain are used initially to demonstrate the theory. Then, a more complex numerical model with anatomically accurate finite element models (FEMs) is used to expand on the concept with a more realistic scenario. Finally, tank experiments are performed with phantom lesions to validate the technique in the real world. RESULTS: Deviations from normal symmetry, due to the presence of lesions, are detectable using this new modality. The ease of detection improves with larger lesions and those far from the plane of symmetry. Quantitative metrics, as well as an image, help to robustly detect and identify both the presence of an abnormality and the cause (haemorrhagic or ischaemic lesion in the scenarios tested) or indeed indicate where no detection is possible. CONCLUSION: Symmetry difference EIT is a valuable new modality that is applicable to cases where the 'normal' features symmetry across a plane. Significantly, a change in the region of interest is not required and hence this technique may be suited to static or quasi-static cases where time difference EIT cannot be used. PMID- 29533922 TI - Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. AB - ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy. PMID- 29533923 TI - Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1. AB - Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with transcriptional changes detectable as early as a week after birth in SCA1-knockin mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1. We found that expanded ATXN1 stimulates the proliferation of postnatal cerebellar stem cells in SCA1 mice. These hyperproliferating stem cells tended to differentiate into GABAergic inhibitory interneurons rather than astrocytes; this significantly increased the GABAergic inhibitory interneuron synaptic connections, disrupting cerebellar Purkinje cell function in a non-cell autonomous manner. We confirmed the increased basket cell-Purkinje cell connectivity in human SCA1 patients. Mutant ATXN1 thus alters the neural circuitry of the developing cerebellum, setting the stage for the later vulnerability of Purkinje cells to SCA1. We propose that other late-onset degenerative diseases may also be rooted in subtle developmental derailments. PMID- 29533924 TI - Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. AB - Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI. PMID- 29533925 TI - Circadian clock component REV-ERBalpha controls homeostatic regulation of pulmonary inflammation. AB - Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBalpha as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV ERBalpha and its paralog REV-ERBbeta in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBalpha plays the dominant role, as deletion of REV-ERBbeta alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBalpha protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole based inverse agonist of REV-ERB, which protects REV-ERBalpha protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBalpha in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBalpha protein couple the core clock to innate immunity. PMID- 29533926 TI - Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy. AB - Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Nav1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Nav1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4 mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction. PMID- 29533928 TI - Validation of Reference Charts for Mid-Trimester Fetal Biometry. AB - OBJECTIVE: The aim of our study was to assess charts proposed for international use in the Intergrowth-21st Project. METHODS: Ultrasound data were collected from 43,923 healthy singleton pregnancies examined at 18-23 weeks of gestation in the Netherlands. Fetal measurements were converted into Z-scores using previous and current Dutch reference charts and Intergrowth charts. The distributions of the Z scores were compared with the expected standard normal distribution. RESULTS: In the Dutch population, Intergrowth curves perform well for head circumference and biparietal diameter, but not for abdominal circumference (AC, Z- score = 0.43) and femur length (FL, Z-score = 0.26). Similar findings have been reported in other European countries. Compared with the population in the Intergrowth study, Dutch women are relatively tall (170 vs. 162 cm) and sturdy (67 vs. 61 kg) with a moderately high BMI. Maternal size, in particular maternal height, is positively correlated with birthweight. CONCLUSIONS: Whilst the establishment of the Intergrowth charts is an important step towards worldwide uniformity, for now locally derived charts still perform better, especially for AC and FL. Results from our validation study indicate that distinction between normal and pathologically small babies may be improved by taking maternal size into account. PMID- 29533927 TI - Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration. AB - The remarkable regeneration capability of skeletal muscle depends on the coordinated proliferation and differentiation of satellite cells (SCs). The self renewal of SCs is critical for long-term maintenance of muscle regeneration potential. Hypoxia profoundly affects the proliferation, differentiation, and self-renewal of cultured myoblasts. However, the physiological relevance of hypoxia and hypoxia signaling in SCs in vivo remains largely unknown. Here, we demonstrate that SCs are in an intrinsic hypoxic state in vivo and express hypoxia-inducible factor 2A (HIF2A). HIF2A promotes the stemness and long-term homeostatic maintenance of SCs by maintaining their quiescence, increasing their self-renewal, and blocking their myogenic differentiation. HIF2A stabilization in SCs cultured under normoxia augments their engraftment potential in regenerative muscle. Conversely, HIF2A ablation leads to the depletion of SCs and their consequent regenerative failure in the long-term. In contrast, transient pharmacological inhibition of HIF2A accelerates muscle regeneration by increasing SC proliferation and differentiation. Mechanistically, HIF2A induces the quiescence and self-renewal of SCs by binding the promoter of the Spry1 gene and activating Spry1 expression. These findings suggest that HIF2A is a pivotal mediator of hypoxia signaling in SCs and may be therapeutically targeted to improve muscle regeneration. PMID- 29533929 TI - Atypical Hemolytic Uremic Syndrome in Children Aged <2 Years. AB - BACKGROUND: There are limited data on infants with atypical hemolytic uremic syndrome (aHUS). The aim of this study was to determine the clinical and laboratory features, and to evaluate treatment modalities and outcomes in infants with aHUS. MATERIALS AND METHODS: Relevant data on patients with onset of aHUS at age <2 years were obtained from the Turkish Pediatric aHUS Registry. RESULTS: Among the 146 patients included in the Registry, 53 (36%) (23 male and 30 female) were enrolled for the study. Age at disease onset was <=1 year in 29 of the patients. In all, 21 (40%) of the patients developed neurological symptoms. Disease-causing mutations were noted in 14 (36%) of the 39 patients in which genetic analysis was performed. Plasma therapy was performed in 42 (79%) patients; eculizumab therapy was administered to treat the first episode of aHUS in 33 (62%) patients and in 5 patients as the first- line therapy. In total, 38 (72%) patients received renal replacement therapy (RRT), 3 (6%) died due to acute illness, and 4 (8%) were discharged from hospital with RRT. Follow-up visit data were available for 46 patients and the median duration was 23 months (range 3-129 months). End-stage renal disease developed only in 1 patient. Proteinuria and hypertension persisted in 17 (37%) and 20 patients (44%) respectively. Eculizumab treatment was continued in 25 of the 39 patients during the follow-up period. CONCLUSION: One-third of the aHUS patients had disease onset during infancy. The prognosis of this life-threatening disease seems to get better with improved treatment modalities. PMID- 29533930 TI - Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling. AB - : Backgroud/Aims: Growing evidence suggests that both cardiomyocyte apoptosis and excessive autophagy exacerbates cardiac dysfunction during myocardial ischemia reperfusion (IR). As a precursor of acetylcholine, choline has been found to protect the heart by repressing ischemic cardiomyocyte apoptosis. However, the relationship between choline and cardiomyocyte autophagy is unclear. The present study aimed to investigate whether autophagy was involved in the cardioprotection of choline during IR. METHODS: Rats were subjected to 30 min reversible ischemia by ligation of left anterior descending coronary artery followed by reperfusion for 2 h. Choline (5 mg/kg, i.v.) alone or along with rapamycin (5 mg/ kg, i.p.) were injected 30 min before ischemia. Transmission electron microscopy, hematoxylin and eosin (HE) and TUNEL staining were conducted to evaluate the effect of choline on cardiac apoptosis and autophagy. Protein levels of autophagic markers including LC3, beclin-1 and p62 as well as Akt and mammalian target of rapamycin (mTOR) were examined by Western blotting. RESULTS: Myocardial IR-induced cardiac apoptosis and accumulation of autophagosomes was attenuated by choline. Choline treatment significantly ameliorated myocardial IR-induced autophagic activity characterized by repression of beclin-1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, and p62 protein abundance. In addition, IR-induced downregulation of p-Akt/mTOR cascade was increased by choline. However, the above functions of choline were abolished by rapamycin. CONCLUSION: These findings suggest that choline plays a protective role against myocardial IR injury by inhibiting excessive autophagy, which might be associated with the activation of Akt/mTOR pathway. This study provides new mechanistic understanding of cardioprotective effect of choline and suggests novel potential therapeutic targets for cardiac IR injury. PMID- 29533931 TI - Sepia Ink Oligopeptide Induces Apoptosis of Lung Cancer Cells via Mitochondrial Pathway. AB - BACKGROUND/AIMS: Our previous study suggested the anti-tumor activity of sepia ink oligopeptide (SIO). Here we sought to investigate the underlying molecular mechanism. METHODS: Cell proliferation was evaluated by cell counting kit-8 (CCK 8) assay. Cell apoptosis was determined by Annexin V/Propidium Iodide (PI) staining. The mitochondria pathway was characterized by quantification of Bcl-2, Bax, Caspase-9 and Cyto-C. The death receptor pathway was analyzed by determinement of Fas, Caspase-8 and NIK. The endoplasmic reticulum (ER)-dependent pathway was determined by measurement the expression of CHOP, Caspase-12, GRP78 and Calpain. The associated gene expression was quantified by RT-PCR and protein level was determined by immunoblotting. RESULTS: We demonstrated treatment with structurally modified SIO (CSIO, 5 uM) significantly inhibited cell proliferation and induced apoptosis in lung cancer cell line A549. The mitochondrial pathway, death receptor pathway and ER stress induced apoptosis were stimulated upon CSIO treatment. The administration with respective inhibitors including midiv-1 (50 uM for 2 h), PDTC (20 uM PDTC for 30 min) and ALLN (20 mM ALLN for 5 h) readily reversed the apoptosis inducing effect of CSIO. CONCLUSION: Our data demonstrates that CSIO is capable of induction apoptosis in lung cancer cell line, which is mediated by all three classical apoptotic pathways. Our results warrant further in vivo investigations of the anti-tumor potential of CSIO. PMID- 29533933 TI - Sanjad-Sakati Syndrome: Oral Health Care. AB - OBJECTIVES: The aim of this report is to describe the orofacial manifestations and dental management of a girl with Sanjad-Sakati syndrome. CLINICAL PRESENTATION AND INTERVENTION: The facial features included microcephaly, thin lips, beaked nose, low set ears, and a retrognathic mandible. An oral examination revealed oligodontia/hypodontia, small dental arches, a high arched palate, and a deep overbite and increased overjet. Oral rehabilitation involved full coverage prosthetic crowns on the upper central incisors, stainless steel crowns on the lower molars, and removable partial prostheses to replace missing teeth. CONCLUSION: Recognition of orofacial features might help in the diagnosis of Sanjad-Sakati syndrome. Dental management of affected patients might be complicated by intellectual, neurological, and endocrine abnormalities. PMID- 29533934 TI - Two N-Linked Glycans Differentially Control Maturation, Trafficking and Proteolysis, but not Activity of the IL-11 Receptor. AB - BACKGROUND/AIMS: The cytokine interleukin-11 (IL-11) has important pro- and anti inflammatory functions. It activates its target cells through binding to the IL 11 receptor (IL-11R), and the IL-11/IL-11R complex recruits a homodimer of glycoprotein 130 (gp130). N-linked glycosylation, a post-translational modification where complex oligosaccharides are attached to the side chain of asparagine residues, is often important for stability, folding and biological function of cytokine receptors. METHODS: We generated different IL-11R mutants via site-directed mutagenesis and analyzed them in different cell lines via Western blot, flow cytometry, confocal microscopy and proliferation assays. RESULTS: In this study, we identified two functional N-glycosylation sites in the D2 domain of the IL-11R at N127 and N194. While mutation of N127Q only slightly affects cell surface expression of the IL-11R, mutation of N194Q broadly prevents IL-11R appearance at the plasma membrane. Accordingly, IL-11R mutants lacking N194 are retained within the ER, whereas the N127 mutant is transported through the Golgi complex to the cell surface, uncovering a differential role of the two N-glycan sequons for IL-11R maturation. Interestingly, IL-11R mutants devoid of one or both N-glycans are still biologically active. Furthermore, the IL 11RN127Q/N194Q mutant shows no inducible shedding by ADAM10, but is rather constitutively released into the supernatant. CONCLUSION: Our results show that the two N-glycosylation sites differentially influence stability and proteolytic processing of the IL-11R, but that N-linked glycosylation is not a prerequisite for IL-11 signaling. PMID- 29533935 TI - Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress. AB - BACKGROUND/AIMS: Hyperuricemia is associated with an increased risk for multiple cardiovascular diseases, but the underlying mechanisms remain largely elusive. Calpain-1 is a protease that is implicated in several pathological conditions that affect the heart. The aim of this current study was to test the effects of uric acid (UA) on cardiomyocyte survival and cardiac function and to investigate the role of calpain-1 in the UA-induced effects in the heart and their underlying mechanisms. METHODS: In vivo, hyperuricemia was induced by oxonic acid (OA) administration in Sprague-Dawley rats for 16 weeks; TUNEL staining was used to identify apoptotic cells. Left ventricular (LV) sections were stained with Sirius Red to evaluate interstitial fibrosis. Cardiac catheterization was performed to evaluate cardiac function. In vitro, cultured H9c2 cells were incubated with different UA concentrations. MTT assays and flow cytometry were used to evaluate cell viability and apoptosis. All related gene expression levels were analyzed by quantitative real-time PCR (qRT-PCR), and all protein expression levels were analyzed by western blotting. RESULTS: Hyperuricemia induction in vivo resulted in cellular apoptosis, interstitial fibrosis and diastolic dysfunction in the rat hearts, as well as increased activation of calpain-1 and endoplasmic reticulum (ER) stress, while allopurinol treatment mitigated the above changes. UA administration in vitro increased apoptosis and decreased H9c2 cell viability in a dose-dependent manner. Increased activation of calpain-1 and ER stress was also observed in the groups with high UA levels. Calpain-1 siRNA and the calpain inhibitor CI-III alleviated UA-induced ER stress and apoptosis, while inhibiting ER stress by tauroursodeoxycholic acid (TUDCA) mitigated UA-induced apoptosis without affecting calpain-1 expression or activity. CONCLUSIONS: These findings suggest that UA induces cardiomyocyte apoptosis through activation of calpain-1 and ER stress. These results may provide new insights into the mechanisms of hyperuricemia-associated cardiovascular risks and hopefully identify new treatment targets. PMID- 29533936 TI - N-Acetyl-Glucosamine Sensitizes Non-Small Cell Lung Cancer Cells to TRAIL-Induced Apoptosis by Activating Death Receptor 5. AB - BACKGROUND/AIMS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-cancer agent due to its selective toxicity. However, many human non-small cell lung cancer (NSCLC) cells are partially resistant to TRAIL, thereby limiting its clinical application. Therefore, there is a need for the development of novel adjuvant therapeutic agents to be used in combination with TRAIL. METHODS: In this study, the effect of N-acetyl-glucosamine (GlcNAc), a type of monosaccharide derived from chitosan, combined with TRAIL was evaluated in vitro and in vivo. Thirty NSCLC clinical samples were used to detect the expression of death receptor (DR) 4 and 5. After GlcNAc and TRAIL co-treatment, DR expression was determined by real-time PCR and western blotting. Cycloheximide was used to detect the protein half-life to further understand the correlation between GlcNAc and the metabolic rate of DR. Non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis was used to detect receptor clustering, and the localization of DR was visualized by immunofluorescence under a confocal microscope. Furthermore, a co-immunoprecipitation assay was performed to analyze the formation of death-inducing signaling complex (DISC). O-linked glycan expression levels were evaluated following DR5 overexpression and RNA interference mediated knockdown. RESULTS: We found that the clinical samples expressed higher levels of DR5 than DR4, and GlcNAc co-treatment improved the effect of TRAIL-induced apoptosis by activating DR5 accumulation and clustering, which in turn recruited the apoptosis-initiating protease caspase-8 to form DISC, and initiated apoptosis. Furthermore, GlcNAc promoted DR5 clustering by improving its O-glycosylation. CONCLUSION: These results uncovered the molecular mechanism by which GlcNAc sensitizes cancer cells to TRAIL-induced apoptosis, thereby highlighting a novel effective agent for TRAIL-mediated NSCLC-targeted therapy. PMID- 29533937 TI - Maternal and Foetal Health Implications of Vitamin D Status during Pregnancy. AB - BACKGROUND: To what extent does the circulating 25-hydroxyvitamin D (25[OH]D) concentration help to meet the physiological needs of humans is an ongoing subject of debate. Remaining unexposed to the sun to reduce melanoma cancer risk, current lifestyle with less out door activities, and increasing obesity rates, which in turn increases the storage of vitamin D in the adipose tissue, are presumably factors that contribute to the substantial upsurge in the prevalence of vitamin D deficiency in humans. Since evidence is lacking regarding the appropriate cut-off points to define vitamin D status during pregnancy, references used to establish the intake recommendations and vitamin D content of prenatal vitamin supplements are quite conservative. SUMMARY: The foetus depends fully on maternal 25(OH)D supply. 25(OH)D readily crosses the placenta and it is activated into 1,25(OH)2D by foetal kidneys. Moreover, 1,25(OH)2D can also be synthesized within the placenta to regulate placental metabolism. The importance of vitamin D during pregnancy for maintaining maternal calcium homeostasis and therefore for foetal bone development is well recognized; major discussions are in progress regarding the potential maternal detrimental effects on pregnancy outcomes, foetal development, and the long-term health of children. Interventional studies have also evaluated the effect of vitamin D for reduction on preterm birth and asthma programming. Key Messages: Clinically, by understanding the effects of vitamin D on perinatal outcomes, we could individualize antenatal counselling regarding vitamin D supplementation to ensure vitamin D repletion without increasing the risk of foetal hypercalcemia. PMID- 29533938 TI - Uniqueness Point Effects during Speech Planning in Adults Who Do and Do Not Stutter. AB - BACKGROUND/AIMS: Previous studies employing a variety of tasks have demonstrated that adults who stutter (AWS) pre-sent with phonological encoding differences compared to adults who do not stutter (AWNS). The present study examined whether atypical preverbal monitoring also influenced AWS performance during one such paradigm - the silent phoneme monitoring task. Specifically, we investigated whether monitoring latencies for AWS were accelerated after the word's uniqueness point - the phoneme that isolates the word from all lexical competitors - as observed for AWNS when monitoring internal and external speech. METHODS: Twenty adults (10 AWS, 10 AWNS) completed a silent phoneme monitoring task using stimuli which contained either (a) early uniqueness points (EUP), (b) late uniqueness points, or (c) no uniqueness point (NUP). Response latency when identifying word final phonemes was measured. RESULTS: AWNS exhibited the expected uniqueness point effect when monitoring internal speech; word-final phonemes were accessed more rapidly for words with EUP than NUP. In contrast, AWS did not differ in the phoneme monitoring speed. That is, AWS did not exhibit the expected uniqueness point effects. CONCLUSION: Findings suggest that inefficient or atypical preverbal monitoring may be present in AWS and support theories that implicate the internal speech monitor as an area of deficit. PMID- 29533939 TI - Sleep-Related Leg Movements in Patients with Transient Ischemic Attack and Controls. AB - BACKGROUND: Periodic leg movements during sleep (PLMS) have been associated with an increased risk for cardiovascular diseases and there is a high prevalence of PLMS found in patients with obstructive sleep apnea syndrome (OSAS). We evaluated patients with transient ischemic attack (TIA) for PLMS and respiratory related leg movements (RRLM), versus a control group without TIA. METHODS: Twenty-five patients with TIA and 34 patients with no vascular diagnosis were referred for polysomnography. Diagnosis of PLMS was made if the periodic leg movement index (PLMI) was >=5 and clinical significant as PLMI >=15. RESULTS: There was no significant difference in PLMI >=5 and >=15 between patients with and without TIA. In the absence of OSAS, 2 out of 5 TIA patients (40%) had a PLMI >=15 compared to 1 of the 19 patients without TIA (5%; p = 0.037). There was no increase in RRLMs when OSAS was present. CONCLUSIONS: TIA patients did not have higher PLMI compared to controls, and in the presence of OSAS, there was no increase in RRLMs compared to patients without TIA. In selective patients, PLMS could be associated with cardiovascular diseases, since PLMS was clinically more often found in the TIA group without OSAS. PMID- 29533940 TI - USP33 is a Biomarker of Disease Recurrence in Papillary Thyroid Carcinoma. AB - BACKGROUND/AIMS: To investigate the clinical significance and functional mechanisms of deubiquitinase USP33 in papillary thyroid carcinoma (PTC). METHODS: Immunohistochemistry staining was conducted to explore the expression of USP33 in PTC tissues and adjacent normal thyroid tissues. Patients' prognosis was evaluated by disease-free survival. The prognostic role of USP33 was tested by univariate and multivariate analyses. To confirm the effect of USP33 in cell proliferation and invasion, overexpression and knockdown of USP33 were performed in two PTC cell lines. Besides, cell cycle, immunoprecipitation, and apoptosis experiments were conducted to further explore the signaling pathways. RESULTS: By analyzing series of 158 PTC tissues, we found that USP33 was down-regulated in tumor tissue compared with normal thyroid tissues, which was closely associated with lymph node metastasis (P<0.001). In particular, univariate and multivariate analyses indicated that USP33 was an independent prognostic biomarker for PTC, low USP33 expression indicated high recurrence risk. Cellular studies with TPC-1 and BCPAP cells demonstrated that USP33 can attenuate the cell capacities of proliferation, migration and invasion. Fluorescence-activated cell sorting experiment found no significant effect of USP33 on cell cycle, whereas the apoptotic caspase proteins were activated by USP33-overexpression. Moreover, the interaction between USP33 and Robo1 protein was identified, and knockdown of Robo1 enhancing the oncogenic effect upon USP33-knockdown, suggesting that USP33 may inhibit tumor progression through Robo1 signaling. CONCLUSIONS: Our data demonstrated that USP33 downregulation in PTC tissues was correlated with poor clinical outcome, which may serve as a novel biomarker and potential therapeutic target. PMID- 29533941 TI - Identification of in vivo Sulci on the External Surface of Eight Adult Chimpanzee Brains: Implications for Interpreting Early Hominin Endocasts. AB - The only direct source of information about hominin brain evolution comes from the fossil record of endocranial casts (endocasts) that reproduce details of the external morphology of the brain imprinted on the walls of the braincase during life. Surface traces of sulci that separate the brain's convolutions (gyri) are reproduced sporadically on early hominin endocasts. Paleoneurologists rely heavily on published descriptions of sulci on brains of great apes, especially chimpanzees (humans' phylogenetically closest living relatives), to guide their identifications of sulci on ape-sized hominin endocasts. However, the few comprehensive descriptions of cortical sulci published for chimpanzees usually relied on post mortem brains, (now) antiquated terminology for some sulci, and photographs or line drawings from limited perspectives (typically right or left lateral views). The shortage of adequate descriptions of chimpanzee sulcal patterns partly explains why the identities of certain sulci on australopithecine endocasts (e.g., the inferior frontal and middle frontal sulci) have been controversial. Here, we provide images of lateral and dorsal surfaces of 16 hemispheres from 4 male and 4 female adult chimpanzee brains that were obtained using in vivo magnetic resonance imaging. Sulci on the exposed surfaces of the frontal, parietal, temporal, and occipital lobes are identified on the images based on their locations, positions relative to each other, and homologies known from comparative studies of cytoarchitecture in primates. These images and sulcal identifications exceed the quantity and quality of previously published illustrations of chimpanzee brains with comprehensively labeled sulci and, thus, provide a larger number of examples for identifying sulci on hominin endocasts than hitherto available. Our findings, even in a small sample like the present one, overturn published claims that australopithecine endocasts reproduce derived configurations of certain sulci in their frontal lobes that never appear on chimpanzee brains. The sulcal patterns in these new images also suggest that changes in two gyri that bridge between the parietal and occipital lobes may have contributed to cortical reorganization in early hominins. It is our hope that these labeled in vivo chimpanzee brains will assist future researchers in identifying sulci on hominin endocasts, which is a necessary first step in the quest to learn how and when the external morphology of the human cerebral cortex evolved from apelike precursors. PMID- 29533942 TI - Biology Explaining Tooth Repair and Regeneration: A Mini-Review. AB - The tooth is an intricate composition of precisely patterned, mineralized matrices and soft tissues. Mineralized tissues include enamel (produced by the epithelial cells called ameloblasts), dentin and cementum (produced by mesenchymal cells called odontoblasts and cementoblasts, respectively), and soft tissues, which include the dental pulp and the periodontal ligament along with the invading nerves and blood vessels. It was perceived for a very long time that teeth primarily serve an esthetical function. In recent years, however, the role of healthy teeth, as well as the impact of oral health on general well-being, became more evident. Tooth loss, caused by tooth decay, congenital malformations (tooth agenesis), trauma, periodontal diseases, or age-related changes, is usually replaced by artificial materials which lack many of the important biological characteristics of the natural tooth. Human teeth have very low to almost absent regeneration potential, due to early loss of cell populations with regenerative capacity, namely stem cells. Significant effort has been made in recent decades to identify and characterize tooth stem cells, and to unravel the developmental programs which these cells follow in order to generate a tooth. PMID- 29533943 TI - High-Concentrate Diet-Induced Change of Cellular Metabolism Leads to Decreases of Immunity and Imbalance of Cellular Activities in Rumen Epithelium. AB - BACKGROUND/AIMS: In animals, the immune and cellular processes of tissue largely depend on the status of local metabolism. However, in the rumen epithelium, how the cellular metabolism affects epithelial immunity, and cellular processes, when the diet is switched from energy-rich to energy-excess status, with regard to animal production and health, have not as yet been reported. METHODS: RNA-seq was applied to compare the biological processes altered by an increase of dietary concentration from 10% to 35% with those altered by an increase of dietary concentration from 35% to 65% (dietary concentrate: the non-grass component in diet, including corn, soya bean meal and additive. High concentrate diet composed of 35% grass, 55% corn, 8% soya bean meal and 2% additive). In addition to the functional analysis of enriched genes in terms of metabolism, the immune system, and cellular process, the highly correlated genes to the enriched metabolism genes were identified, and the function and signaling pathways related to the differentially expressed neighbors were compared among the groups. RESULTS: The variation trends of molar proportions of ruminal SCFAs and those of enriched pathways belonging to metabolism, immune system, and cellular process were altered with the change of diets. With regard to metabolism, lipid metabolism and amino acid metabolism were most affected. According to the correlation analysis, both innate and adaptive immune responses were promoted by the metabolism genes enriched under the 65% concentrate diet. However, the majority of immune responses were suppressed under the 35% concentrate diet. Moreover, the exclusive upregulation of cell growth and dysfunction of cellular transport and catabolism were induced by the metabolism genes enriched under the 65% concentrate diet. On the contrary, a balanced regulation of cellular processes was detected under the 35% concentrate diet. CONCLUSIONS: These results indicated that the alterations of cellular metabolism promote the alterations in cellular immunity, repair, and homeostasis in the rumen epithelium, thereby leading to the switch of concentrate effects from positive to negative with regard to animal production and health. PMID- 29533944 TI - Does Dysbiosis in Intestinal Microbiome Plays a Role in Children with Relapsing Idiopathic Nephrotic Syndrome? PMID- 29533945 TI - Upregulation of Long Non-Coding RNA Small Nucleolar RNA Host Gene 12 Contributes to Cell Growth and Invasion in Cervical Cancer by Acting as a Sponge for MiR-424 5p. AB - BACKGROUND/AIMS: Cervical cancer, which is one of the most aggressive cancers affecting females, has high rates of recurrence and mortality. Small nucleolar RNA host gene 12 (SNHG12) is known to promote the progression of several cancers; however, its exact effects and molecular mechanisms in cervical cancer remain unknown. METHODS: Real-time quantitative PCR was used to determine the expression level of SNHG12 in cervical cancer tissues and cell lines. Loss-of-function assays were performed to examine the effect of SNHG12 on the proliferation, apoptosis, migration and invasion of cervical cancer cells in vitro and tumor growth in vivo. Luciferase experiments were employed to explore the interactions between SNHG12 and miR-424-5p. RESULTS: SNHG12 was found to be abnormally elevated in human cervical cancer tissues compared with paired adjacent normal tissues. Moreover, high SNHG12 expression in tumor tissues was significantly correlated with vascular involvement, lymph node metastasis, advanced FIGO stage and poor prognosis. Furthermore, the knockdown of SNHG12 was found to inhibit proliferation, migration and invasion of cervical cancer cells in vitro, and silencing SNHG12 was shown to suppress tumor growth in a nude mouse model. Mechanistic studies showed that SNHG12 functioned as an endogenous sponge for miR 424-5p, thereby downregulating the expression of miR-424-5p in cervical cancer. Furthermore, the inhibition of miR-424-5p in SNHG12-depleted cells partially reversed the effects on cervical cancer cell apoptosis, adhesion and invasion. CONCLUSION: In summary, our findings suggest that the tumor-promoting role of SNHG12 is to function as a molecular sponge, which negatively regulates miR-424 5p. These findings may provide a potent therapeutic target for cervical cancer. PMID- 29533946 TI - Apparent Diffusion Coefficient Signal Intensity Ratio Predicts the Effect of Revascularization on Ischemic Cerebral Edema. AB - BACKGROUND: Apparent diffusion coefficient (ADC) imaging is a biomarker of cytotoxic injury that predicts edema formation and outcome after ischemic stroke. It therefore has the potential to serve as a "tissue clock" to describe the extent of ischemic injury and potentially predict response to therapy. The goal of this study was to determine the relationship between baseline ADC signal intensity, revascularization, and edema formation. METHODS: We examined the ADC signal intensity ratio (ADCr) of the stroke lesion (defined as the baseline DWI hyperintense region) compared to the contralateral normal hemisphere in 65 subjects from the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy trial. The associations between ADCr, neurologic outcome, and cerebral edema were examined. Finally, we explored the interaction between baseline ADCr and vessel recanalization at day 7 on post-stroke edema. RESULTS: We found that lower initial ADCr was associated with a worse outcome on the modified Rankin Scale (mRS) at 90 days (52.2% of those with ADCr <64% were mRS 5 6 vs. 19.1% with ADCr >=64%, p = 0.006). Those subjects with reconstitution of flow distal to the initial vessel occlusion showed greater normalization of ADCr on follow-up scan (increase in ADCr of 16.4 +/- 2.07 vs. 1.99 +/- 4.33%, p = 0.0039). In those patients with low baseline ADCr, successful revascularization was associated with reduced edema (median swelling volume 164 mL [interquartile range (IQR) 53.3-190 mL] vs. 20.7 mL [IQR 3.20-55.1 mL], p = 0.024). CONCLUSIONS: This study reaffirms the association of ADCr with outcome after stroke, supports the idea that reperfusion may attenuate rather than enhance post-stroke edema, and indicates that the degree of edema with and without revascularization may be predicted by ADCr. PMID- 29533947 TI - Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence. AB - Since the introduction of highly active antiretroviral therapy more than 2 decades ago, HIV-related deaths have dramatically decreased and HIV infection has become a chronic disease. Due to the inability of antiretroviral drugs to eradicate the virus, treatment of HIV infection requires a systemic lifelong therapy. However, even when successfully treated, HIV patients still show increased incidence of age-associated co-morbidities compared with uninfected individuals. Virus- induced immunosenescence, a process characterized by a progressive decline of immune system function, contributes to the premature ageing observed in HIV patients. Although antiretroviral therapy has significantly improved both the quality and length of patient lives, the life expectancy of treated patients is still shorter compared with that of uninfected individuals. In particular, while antiretroviral therapy can contrast some features of HIV-associated immunosenescence, several anti-HIV agents may themselves contribute to other aspects of immune ageing. Moreover, older HIV patients tend to have a worse immunological response to the antiviral therapy. In this review we will examine the available evidence on the role of antiretroviral therapy in the control of the main features regulating immunosenescence. PMID- 29533948 TI - Facing the Unknown: Fear of Progression Could Be a Relevant Psychological Risk Factor for Depressive Mood States among Patients with Multiple Sclerosis. PMID- 29533949 TI - Dysautonomia as Onset Symptom of Myotonic Dystrophy Type 2. AB - Myotonic dystrophy type 2 (DM2) is an autosomal dominant muscular dystrophy caused by the expansion of an intronic tetranucleotide CCTG repeat in CNBP on chromosome 3. As DM1, DM2 is a multisystem disorder affecting, beside the skeletal muscle, various other tissues, including peripheral nerves. Indeed, a subclinical involvement of peripheral nervous system has been described in several cohorts of DM2 patients, whereas DM2 patients manifesting clinical signs and/or symptoms of neuropathy have been only rarely reported. Here, we describe 2 related DM2 patients both of whom displayed an atypical disease onset characterized by dysautonomic symptoms, possibly secondary to peripheral neuropathy. PMID- 29533950 TI - Gut Microbiota Dysbiosis in Children with Relapsing Idiopathic Nephrotic Syndrome. AB - BACKGROUND: While the etiology of idiopathic nephrotic syndrome (idiopathic nephrotic syndrome [INS]; characterized by repeated relapses and comorbid allergic conditions) remains unknown, recent evidence suggests that dysfunction in regulatory T cells (Tregs) plays an important role in the development of INS as well as allergic diseases. We hypothesized that dysbiosis involving decreased butyric acid-producing gut microbiota leads to defective induction and differentiation of peripherally induced Tregs, resulting in INS relapse. METHODS: Study subjects were 12 children with INS, 8 classified as relapsing (R group; median age: 3.0 years) and 4 as non-relapsing (NR group; median age: 4.3 years), and 11 healthy children (HC group; median age: 5.1 years) serving as normal controls. Measurement of microbiota was performed using 16S ribosomal RNA metagenomic analysis, and fecal butyric acid was measured using high performance liquid chromatography. Flow-cytometric analysis of Tregs and CD4-positive (CD4+) cells in peripheral blood was also performed. RESULTS: Metagenomic analysis of gut microbiota using feces showed that the proportion of butyric acid-producing bacteria was significantly lower in R (median 6.36%) than HC (median 18.84%; p = 0.0013), but no different between NR (median 16.71%) and HC (p = 0.29). Fecal organic acid analysis revealed significantly lower butyric acid quantities in R than HC (medians: 0.48 vs. 0.99 mg/g, p = 0.042). Circulating Tregs as a proportion of CD4+ cells were decreased in 75% of R and NR. CONCLUSION: Pediatric relapsing INS patients show gut microbiota dysbiosis, characterized by a decreased proportion of butyric acid-producing bacteria and lower fecal butyric acid quantities, concomitant with reduced circulatory Tregs. PMID- 29533951 TI - An Arabic Version of the Geriatric Depression Scale (30 Items): Psychometric Properties and Some Findings in a Lebanese Elderly Sample. AB - BACKGROUND/AIM: Although the rates of depression and anxiety disorders have been shown to be higher in older people, especially those living in institutional settings, most of this population remains undiagnosed and untreated. The objective is to translate the full-scale Geriatric Depression Scale (30 items, GDS) into Arabic for use in elderly patients in Lebanon, to check its validity and reproducibility in comparison to the original version of the questionnaire, and assess the risk factors associated with depression in the Lebanese geriatric population. METHODS: This case-control study was conducted between June and August 2016 and included 500 patients aged more than 60 years (250 living inside and 250 outside a nursing home). RESULTS: Strongly positive correlations (p < 0.001 for all items of the scale) were found between each item of the scale and the total scale. The mean inter-item correlation for our scale was 0.51, higher than that of the original scale (0.36), with an excellent internal consistency (Cronbach alpha = 0.901). Living in a nursing home, stress, anxiety, being married, age, and the primary level of education would significantly increase depression (beta = 2.211, beta = 0.223, beta = 0.041, beta = 0.902, beta = 0.118, and beta = 3.533, respectively). A normal nutritional status and a university level of education would significantly decrease depression (beta = -0.732; beta = -1.961). CONCLUSION: The Arabic version of the GDS can be used to estimate the severity of depression in the Lebanese elderly population. Periodic screening for anxiety, nutritional status, and stress is also recommended among geriatric people living in Lebanon. PMID- 29533952 TI - Pretreatment Cardiac Vagal Tone Predicts Dropout from and Residual Symptoms after Exposure Therapy in Patients with Panic Disorder and Agoraphobia. PMID- 29533953 TI - Tissue Plasminogen Activator as an Antiangiogenic Agent in Experimental Corneal Neovascularization in Rabbits. AB - AIMS: Anti-vascular endothelial growth factor agents effectively treat age related macular degeneration and myopic choroidal neovascularization (CNV). Tissue plasminogen activator (tPA), a fibrinolytic compound, is used as an adjuvant to displace submacular hemorrhage and to treat type 2 CNV. The purpose of this study was to investigate in in vitro and in vivo experiments the antiangiogenic impact of tPA itself. METHODS: The impact of tPA on the proliferation of human umbilical vein endothelial cells (HUVECs) was assessed by an XTT assay [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide]. A basic fibroblast growth factor-impregnated gelatin hydrogel sheet was implanted into the rabbit cornea to induce corneal neovascularization. Immediately postoperatively, tPA or buffered saline solution (control) was injected intravitreally. RESULTS: The growth and viability of the HUVECs were unaffected by tPA at clinical concentrations. In the control group, the mean lengths of the new vessels were 1.0 +/- 0.41, 1.6 +/- 0.75, and 3.6 +/- 2.1 mm at weeks 1, 2, and 4, respectively. In contrast, tPA significantly (p < 0.01) reduced the corneal neovascularization. CONCLUSION: Although tPA has no direct impact on the vascular endothelial cells in vitro, the fibrinolytic effects of tPA might markedly suppress neovascularization in vivo. PMID- 29533955 TI - Humanized Exposures of a beta-Lactam-beta-Lactamase Inhibitor, Tazobactam, versus Non-beta-Lactam-beta-Lactamase Inhibitor, Avibactam, with or without Colistin, against Acinetobacter baumannii in Murine Thigh and Lung Infection Models. AB - beta-lactam-beta-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including beta-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 ug/mL against AB 25-49 (CS) and 1 and 128 ug/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25-49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25-49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-beta-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the beta-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of beta-lactam-BLIs beyond their primary purpose of beta-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non beta-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model. PMID- 29533957 TI - In utero Partial Exchange Transfusion Combined with in utero Blood Transfusion for Prenatal Management of Twin Anemia-Polycythemia Sequence. AB - Monochorionic twin pregnancies are at risk of unique complications due to placental sharing and vascular connections between placental territories assigned for each twin. Twin anemia-polycythemia sequence (TAPS) is an infrequent but potentially dangerous complication of abnormal placental vascular connections. TAPS occurs due to very-small-caliber (< 1 mm) abnormal placental vascular connections which lead to chronic anemia in the donor twin and polycythemia in the recipient twin. TAPS may occur spontaneously or following fetoscopic laser photocoagulation of communicating placental vessels for twin-twin transfusion syndrome. One of the hallmarks of TAPS is the absence of polyhydramnios and oligohydramnios. The postnatal diagnosis is based on significant hemoglobin discrepancy between the twins. Middle cerebral artery peak systolic velocity Doppler ultrasound allows for the prenatal diagnosis of TAPS. The optimal prenatal treatment and intervention timing has not been established. Here, we report 3 spontaneous TAPS cases diagnosed and managed in the prenatal period with a combination of in utero blood transfusion for the anemic twin (donor) and in utero partial exchange transfusion for the polycythemic twin (recipient). These cases contribute to the limited outcome data of this underutilized method for the management of TAPS. PMID- 29533954 TI - Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-?/STAT3 Signaling in Diabetic Rats. AB - BACKGROUND/AIMS: Protein kinase C(PKC)-epsilon activation is a mechanism of preconditioning cardioprotection but its role in repeated non-invasive limb ischemic preconditioning (rNLIP) mediated cardioprotection against myocardial ischemia/reperfusion (I/R) injury in diabetes is unknown. METHODS: Eight-week streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats were subjected to I/R without or with rNLIP. In vitro, H9C2 cells were cultured with high glucose (HG) and subjected to hypoxia/re-oxygenation (H/R) without or with PKC-epsilon or STAT3 gene knock-down in the absence or presence of remote time hypoxia preconditioning (HPC). RESULTS: Diabetic rats displayed larger post ischemic myocardial infarct size and higher troponin-I release with concomitant cardiac PKC-? overexpression and activation manifested as increased membrane translocation, while phosphorylated STAT3 (p-STAT3) and Akt (p-Akt) were lower compared to non-diabetic rats (all P<0.05). rNLIP reduced infarct size in both non-diabetic and diabetic rats. rNLIP reduced post-ischemic cardiac PKC-? activation in diabetic while increased PKC-? activation in non-diabetic rats, resulting in increased cardiac p-STAT3 and p-Akt. In H9C2 cells, HG increased PKC ? expression and exacerbated post-H/R injury, accompanied with reduced p-STAT3 and p-Akt, which were all reverted by HPC. These HPC protective effects were abolished by either PKC-? or STAT3 gene knock-down, except that PKC-? gene knock down reverted HG and H/R-induced reduction of p-STAT3. CONCLUSION: rNLIP attenuates diabetic heart I/R injury by mitigating HG-induced PKC-? overexpression and, subsequently, activating STAT3. PMID- 29533958 TI - Addressing Racial Disparity in the Progression of Chronic Kidney Disease: Prescribe More Fruits and Vegetables? PMID- 29533959 TI - Efficacy and Safety of Bevacizumab Combined with Mitomycin C or 5-Fluorouracil in Primary Trabeculectomy: A Meta-Analysis of Randomized Clinical Trials. AB - AIM: The objective of this study was to evaluate the efficacy and safety of bevacizumab combined with antimetabolite as an adjunctive therapy in primary trabeculectomy for glaucoma. MATERIALS AND METHODS: PubMed, Cochrane Library, and EMBASE were searched for relevant randomized controlled trials. Efficacy was evaluated by the postoperative mean intraocular pressure (IOP), complete success, and qualified success rates. Safety was evaluated by postoperative complications and surgical interventions. RESULTS: A total of 3 randomized controlled trials were included in the meta-analysis. The primary outcome was postoperative mean IOP at the 12-month follow-up. No significant difference in IOP was found between the bevacizumab + antimetabolite (mitomycin c or 5-fluorouracil) group and the antimetabolite alone group (weighted mean difference -0.27; 95% CI -1.38 to 0.83). There were no significant differences in complete success rates, qualified success rates, postoperative complications, and surgical interventions between the experimental treatment group and the conventional treatment group. CONCLUSIONS: Results of the meta-analysis demonstrated that the combination of bevacizumab (1.25 mg/mL) with a regular concentration of antimetabolite did not show more benefit or harm compared with using antimetabolite alone. Further randomized controlled trials are needed to evaluate the efficacy and safety of bevacizumab combined with lower concentrations and a shorter application time of antimetabolite. PMID- 29533960 TI - The Effect of Improved Dysphagia Care on Outcome in Patients with Acute Stroke: Trends from 8-Year Data of a Large Stroke Register. AB - BACKGROUND: Early dysphagia screening and appropriate management are recommended by current guidelines to reduce complications and case fatality in acute stroke. However, data on the potential benefit of changes in dysphagia care on patient outcome are limited. Our objective was to assess the degree of implementation of dysphagia guidelines and determine the impact of modifications in dysphagia screening and treatment practices on disease complications and outcome in stroke patients over time. METHODS: In this prospective register-based study ("Stroke Register of Northwestern Germany"), all adult stroke patients admitted to 157 participating hospitals between January, 2008 and December, 2015 were included (n = 674,423). Dysphagia incidence upon admission, the proportion of patients receiving a standardized swallowing screening, and the percentage of dysphagic patients being referred to a speech language therapist (SLT) for treatment were obtained per year. Pneumonia rate, modified Rankin Scale (mRS) at discharge, and in-hospital mortality were compared between groups of dysphagic vs. non-dysphagic patients over time. RESULTS: Screening proportions continuously increased from 47.2% in 2008 to 86.6% in 2015. But the proportion diagnosed with dysphagia remained stable with about 19%. The number of dysphagic patients receiving SLT treatment grew from 81.6 up to 87.0%. Pneumonia incidence was higher in dysphagic stroke cases (adjusted OR 5.4 [5.2-5.5], p < 0.001), accompanied by a worse mRS at discharge (adjusted OR for mRS >=3: 3.1 [3.0-3.1], p < 0.001) and higher mortality (adjusted OR 3.1 [3.0-3.2], p < 0.001). The order of magnitude of these end points did not change over time. CONCLUSION: Although advances have been made in dysphagia care, prevalent screening and treatment practices remain insufficient to reduce pneumonia rate, improve functional outcome, and decrease case fatality in dysphagic stroke patients. More research is urgently needed to develop more effective swallowing therapies. PMID- 29533961 TI - First-in-Class Combination Therapy of a Copper(II) Metallo-Phosphorus Dendrimer with Cytotoxic Agents. AB - The metallo-phosphorus dendrimer 1G3-Cu (generation 3 dendrimer bearing 48 conjugated copper(II) on its surface) has antiproliferative activity related to its capacity to activate Bax translocation. In the present study, we evaluate the activity of an association of 1G3-Cu with 5 cytotoxic agents used in chemotherapy having different modes of action. Data show no additive effect with camptothecin and cisplatin, additivity with paclitaxel and MG132, and synergy with doxorubicin. Results suggest that the multivalent Cu-conjugated dendrimer 1G3-Cu (activator of Bax translocation) plays an important role in boosting the clinical impact of Bax accumulation stimulated by the proteasome inhibitor MG132, antimitotic taxanes, and the topo II inhibitor doxorubicin. PMID- 29533963 TI - Usefulness of Plasma Exosomal MicroRNA-451a as a Noninvasive Biomarker for Early Prediction of Recurrence and Prognosis of Non-Small Cell Lung Cancer. AB - OBJECTIVES: The aim of this study was to clarify the usefulness of plasma exosomal microRNA-451a (miR-451a) as a novel biomarker for the early prediction of recurrence and prognosis in non-small cell lung cancer (NSCLC) patients after curative resection. METHODS: Before surgery, plasma samples were collected and exosomal microRNA (miRNA) levels were evaluated. We first profiled specific exosomal miRNAs related to recurrence in 6 NSCLC patients with stage IA cancer by miRNA microarray. We then validated the usefulness of selected miRNAs as biomarkers using the other 285 NSCLC patients. RESULTS: Plasma exosomal miR-451a showed the highest upregulation in the NSCLC patients with recurrence in the miRNA microarray analysis. A significant positive correlation was demonstrated between exosomal miR-451a levels and NSCLC tissue miR-451a levels. Exosomal miR 451a showed a significant association with lymph node metastasis, vascular invasion, and stage. In stage I, II, or III patients, the overall survival (OS) and disease-free survival (DFS) rates among the high-exosomal-miR-451a patients were significantly worse than those among the low-exosomal-miR-451a patients. In Cox multivariate analysis, exosomal miR-451a showed significance for OS and DFS. CONCLUSION: Plasma exosomal miR-451a might serve as a reliable biomarker for the prediction of recurrence and prognosis in NSCLC patients with stage I, II, or III cancer. PMID- 29533962 TI - Antidepressant Use by Class: Association with Major Adverse Cardiac Events in Patients with Coronary Artery Disease. AB - BACKGROUND: To assess use of antidepressants by class in relation to cardiology practice recommendations, and the association of antidepressant use with the occurrence of major adverse cardiovascular events (MACE) including death. METHODS: This is a historical cohort study of all patients who completed cardiac rehabilitation (CR) between 2002 and 2012 in a major CR center. Participants completed the Patient Health Questionnaire (PHQ-9) at the start and end of the program. A linkage system enabled ascertainment of antidepressant use and MACE through 2014. RESULTS: There were 1,694 CR participants, 1,266 (74.7%) of whom completed the PHQ-9 after the program. Depressive symptoms decreased significantly from pre- (4.98 +/- 5.20) to postprogram (3.57 +/- 4.43) (p < 0.001). Overall, 433 (34.2%) participants were on antidepressants, most often selective serotonin reuptake inhibitors (SSRI; n = 299; 23.6%). The proportion of days covered was approximately 70% for all 4 major antidepressant classes; discontinuation rates ranged from 37.3% for tricyclics to 53.2% for serotonin norepinephrine reuptake inhibitors (SNRI). Antidepressant use was significantly associated with lower depressive symptoms after CR (before, 7.33 +/- 5.94 vs. after, 4.69 +/- 4.87; p < 0.001). After a median follow-up of 4.7 years, 264 (20.9%) participants had a MACE. After propensity matching based on pre-CR depressive symptoms among other variables, participants taking tricyclics had significantly more MACE than those not taking tricyclics (HR = 2.46; 95% CI 1.37 4.42), as well as those taking atypicals versus not (HR = 1.59; 95% CI 1.05-2.41) and those on SSRI (HR = 1.45; 95% CI 1.07-1.97). There was no increased risk with use of SNRI (HR = 0.89; 95% CI 0.43-1.82). CONCLUSION: The use of antidepressants was associated with lower depression, but the use of all antidepressants except SNRI was associated with more adverse events. PMID- 29533964 TI - Prelimbic Cortex Deep Brain Stimulation Reduces Binge Size in a Chronic Binge Eating Rat Model. AB - BACKGROUND: Binge eating (BE) involves the consumption of a large amount of food in a short period of time and a loss of control during the binge episode. It is a key feature of the major subtypes of eating disorders like bulimia nervosa, BE disorder, anorexia nervosa binge/purge type. Alterations in the mesocorticolimbic pathway play a crucial role in its pathophysiology. OBJECTIVES: We hypothesized that BE rats receiving deep brain stimulation (DBS) in the prelimbic cortex, a functional analog of the dorsolateral prefrontal cortex in humans, would have a reduced binge size compared with those receiving sham stimulation. METHODS: Eight male Sprague-Dawley rats were implanted with a DBS electrode in the left prelimbic cortex. A protocol which included limited access to a "sweet-fat" diet was used to achieve a chronic BE state in the rats. After reaching a stable binge size, each rat had undergone sham, low-frequency stimulation (60 Hz), and high frequency (130 Hz) stimulation for 3 sessions each, and 2 consecutive treatments were separated by at least 2 empty sessions to allow a washout of the effects. A one-way ANOVA was used for the data analysis. RESULTS: Low-frequency (60 Hz) stimulation of the prelimbic cortex significantly reduced the binge size compared to the sham stimulation (p < 0.0001). High-frequency DBS (130 Hz) had no significant influence on this behavior when compared to sham stimulation (p = 0.9). CONCLUSIONS: This study suggests that low-frequency prelimbic cortex stimulation in BE would be useful for correcting prefrontal hypofunction which is strongly associated with BE and addiction pathogenesis. PMID- 29533965 TI - The Challenges of Translation. PMID- 29533966 TI - Young Brain and Anesthesia: Refusal of Anesthesia Is Not an Option! PMID- 29533967 TI - Anesthesia and Neurodevelopment in Children: Perhaps the End of the Beginning. PMID- 29533968 TI - Eudesmane-Type Sesquiterpene Glycosides from Dictamnus dasycarpus Turcz. AB - Eudesmane-type sesquiterpenes have been reported to exhibit varieties of biological activities. During the process of investigating this kind of natural product from the root bark of Dictamnus dasycarpus Turcz., 13 eudesmane-type sesquiterpene glycosides including six new isolates, named as dictameudesmnosides A1 (1), A2 (2), B (3), C (4), D (5), and E (6), together with seven known ones (7 13), were obtained. Herein, their structures were determined by the analysis of physical data, spectroscopic analysis, and chemical methods. The existence of alpha-configuration glucose units in their structures (1-5, 8) is not very common in natural glycosidic components. Meanwhile, compounds 3-5, 7, and 9-13 displayed TG accumulation inhibitory effects on HepG2 cells. PMID- 29533970 TI - Wearable Smart System for Visually Impaired People. AB - In this paper, we present a wearable smart system to help visually impaired persons (VIPs) walk by themselves through the streets, navigate in public places, and seek assistance. The main components of the system are a microcontroller board, various sensors, cellular communication and GPS modules, and a solar panel. The system employs a set of sensors to track the path and alert the user of obstacles in front of them. The user is alerted by a sound emitted through a buzzer and by vibrations on the wrist, which is helpful when the user has hearing loss or is in a noisy environment. In addition, the system alerts people in the surroundings when the user stumbles over or requires assistance, and the alert, along with the system location, is sent as a phone message to registered mobile phones of family members and caregivers. In addition, the registered phones can be used to retrieve the system location whenever required and activate real-time tracking of the VIP. We tested the system prototype and verified its functionality and effectiveness. The proposed system has more features than other similar systems. We expect it to be a useful tool to improve the quality of life of VIPs. PMID- 29533969 TI - Fraxinellone Attenuates Rheumatoid Inflammation in Mice. AB - This study aimed to evaluate the therapeutic effect of fraxinellone on inflammatory arthritis and identify the underlying mechanisms. Fraxinellone (7.5 mg/kg) or a vehicle control was injected into mice with collagen-induced arthritis (CIA). The severity of arthritis was evaluated clinically and histologically. The differentiation of CD4+ T cells and CD19+ B cells was investigated in the presence of fraxinellone. Osteoclastogenesis after fraxinellone treatment was evaluated by staining with tartrate-resistant acid phosphatase (TRAP) and by measuring the mRNA levels of osteoclastogenesis-related genes. Fraxinellone attenuated the clinical and histologic features of inflammatory arthritis in CIA mice. Fraxinellone suppressed the production of interleukin-17 and the expression of RAR-related orphan receptor gamma t and phospho-signal transducer and activator of transcription 3 in CD4+ T cells. CD19+ B cells showed lower expression of activation-induced cytidine deaminase and B lymphocyte-induced maturation protein-1 after treatment with fraxinellone. The formation of TRAP-positive cells and the expression of osteoclastogenesis-related markers were reduced in the presence of fraxinellone. Inhibition of interleukin 17 and osteoclastogenesis was also observed in experiments using human peripheral mononuclear cells. Fraxinellone alleviated synovial inflammation and osteoclastogenesis in mice. The therapeutic effect of fraxinellone was associated with the inhibition of cellular differentiation and activation. The data suggests that fraxinellone could be a novel treatment for inflammatory arthritis, including rheumatoid arthritis. PMID- 29533971 TI - Respiratory Health Symptoms among Schoolchildren in Relation to Possible Food Related Risk and Protective Factors. AB - Respiratory health outcomes are among the top five causes of child morbidity and mortality around the world. We aimed to investigate possible food-related risk and protective factors for respiratory health outcomes in children. Structured questionnaires completed by primary caregivers of 10-year old children were used to collect information on demographics, socio-economic status, house characteristics and child respiratory health status. Upper (URIs) and Lower (LRIs) respiratory illnesses comprised hay fever, and wheezing, asthma and bronchitis, respectively. Eight hundred questionnaires were distributed, 648 retrieved and 420 completed in full (52.5% response rate). The hay fever 6-month prevalence was 22.4% and wheezing had the highest 6-month prevalence among the LRIs (13.8%). The majority of children ate vegetables (75.5%), fruit (69.3%) and chicken or fish (81.7%) regularly. Nearly half of the children (45.5%) regularly ate processed food. Eating processed food regularly was statistical significantly associated with wheeze (Adjusted Odds Ratio (OR) = 2.65; 95% CI: 1.38-5.08), hay fever (OR = 1.62; 95% CI: 1.09-2.64) and bronchitis (OR = 1.27; 95% CI: 1.06 2.56). The study found an association between regular consumption of processed foods and wheeze, hay fever and bronchitis among 10 year old children. The regular consumption of processed food plays a role in adverse respiratory health effects among children and healthy eating is emphasized. PMID- 29533972 TI - High NOTCH1 mRNA Expression Is Associated with Better Survival in HNSCC. AB - The clinical impact of the expression of NOTCH1 signaling components in squamous cell carcinoma of the pharynx and larynx has only been evaluated in subgroups. The aim of this study was therefore to evaluate NOTCH1 expression in head and neck squamous cell cancer (HNSCC) patient tissue and cell lines. We analyzed tissue from 195 HNSCCs and tissue from 30 normal patients for mRNA expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 using quantitative real-time PCR. Association of expression results and clinical orpathological factors was examined with multivariate Cox regression. NOTCH1 expression was determined in three Human Papilloma Virus (HPV)-positive and nine HPV-negative HNSCC cell lines. High expression of NOTCH1 was associated with better overall survival (p = 0.013) and disease-free survival (p = 0.040). Multivariate Cox regression confirmed the significant influence of NOTCH1 expression on overall survival (p = 0.033) and disease-free survival (p = 0.029). A significant correlation was found between p16 staining and NOTCH1 mRNA expression (correlation coefficient 0.28; p = 0.01). NOTCH1 was expressed at higher levels in HPV-positive HNSCC cell lines compared with HPV-negative cell lines, which was not statistically significant (p = 0.068). We conclude that NOTCH1 expression is associated with overall survival, and that inhibition of NOTCH1 therefore seems less promising. PMID- 29533973 TI - Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer. AB - Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N1-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents. PMID- 29533974 TI - Mood Fluctuation and Psychobiological Instability: The Same Core Functions Are Disrupted by Novel Psychoactive Substances and Established Recreational Drugs. AB - Many novel psychoactive substances (NPS) have entered the recreational drug scene in recent years, yet the problems they cause are similar to those found with established drugs. This article will debate the psychobiological effects of these newer and more traditional substances. It will show how they disrupt the same core psychobiological functions, so damaging well-being in similar ways. Every psychoactive drug causes mood states to fluctuate. Users feel better on-drug, then feel worse off-drug. The strength of these mood fluctuations is closely related to their addiction potential. Cyclical changes can occur with many other core psychobiological functions, such as information processing and psychomotor speed. Hence the list of drug-related impairments can include: homeostatic imbalance, HPA axis disruption, increased stress, altered sleep patterns, neurohormonal changes, modified brain rhythms, neurocognitive impairments, and greater psychiatric vulnerability. Similar patterns of deficit are found with older drugs such as cocaine, nicotine and cannabis, and newer substances such as 3,4-methylenedioxymethamphetamine (MDMA), mephedrone and spice. All psychoactive drugs damage human well-being through similar basic neuropsychobiological mechanisms. PMID- 29533976 TI - Investigation of Differences in Fertility among Progenies from Self-Pollinated Chrysanthemum. AB - Most chrysanthemum cultivars are self-incompatible, so it is very difficult to create pure lines that are important in chrysanthemum breeding and theoretical studies. In our previous study, we obtained a self-compatible chrysanthemum cultivar and its self-pollinated seed set was 56.50%. It was interesting that the seed set of its ten progenies ranged from 0% to 37.23%. Examination of the factors causing the differences in the seed set will lead to an improved understanding of chrysanthemum self-incompatibility, and provide valuable information for creating pure lines. Pollen morphology, pollen germination percentage, pistil receptivity and embryo development were investigated using the in vitro culture method, the paraffin section technique, scanning electron microscopy and transmission electron microscopy. Moreover, RNA sequencing and bioinformatics were applied to analyzing the transcriptomic profiles of mature stigmas and anthers. It was found that the self-pollinated seed set of "Q10-33 11","Q10-33-13","Q10-33-14" and "Q10-33-110" were 37.23%, 26.77%, 7.97% and 0%, respectively. The differences in fertility among four progenies were mainly attributable to differences in pollen germination percentage and pistil receptivity. Failure of the seed set in "Q10-33-110" was possibly due to self incompatibility. In the transcriptomic files, 22 potential stigma S genes and 8 potential pollen S genes were found out. PMID- 29533975 TI - The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets. AB - In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases. PMID- 29533977 TI - Testing of Alignment Parameters for Ancient Samples: Evaluating and Optimizing Mapping Parameters for Ancient Samples Using the TAPAS Tool. AB - High-throughput sequence data retrieved from ancient or other degraded samples has led to unprecedented insights into the evolutionary history of many species, but the analysis of such sequences also poses specific computational challenges. The most commonly used approach involves mapping sequence reads to a reference genome. However, this process becomes increasingly challenging with an elevated genetic distance between target and reference or with the presence of contaminant sequences with high sequence similarity to the target species. The evaluation and testing of mapping efficiency and stringency are thus paramount for the reliable identification and analysis of ancient sequences. In this paper, we present 'TAPAS', (Testing of Alignment Parameters for Ancient Samples), a computational tool that enables the systematic testing of mapping tools for ancient data by simulating sequence data reflecting the properties of an ancient dataset and performing test runs using the mapping software and parameter settings of interest. We showcase TAPAS by using it to assess and improve mapping strategy for a degraded sample from a banded linsang (Prionodon linsang), for which no closely related reference is currently available. This enables a 1.8-fold increase of the number of mapped reads without sacrificing mapping specificity. The increase of mapped reads effectively reduces the need for additional sequencing, thus making more economical use of time, resources, and sample material. PMID- 29533979 TI - Sustained Cytotoxicity of Wogonin on Breast Cancer Cells by Encapsulation in Solid Lipid Nanoparticles. AB - While wogonin has been known to have cytotoxicity against various cancer cells, its bioavailability and cytotoxicity are low due to its low water solubility. Therefore, wogonin-loaded solid lipid nanoparticles were fabricated using a hot melted evaporation technique. The highest solubility of wogonin was observed in stearic acid. Hence, wogonin-loaded solid lipid nanoparticles were composed of stearic acid as the lipid matrix. The physicochemical properties of the wogonin loaded solid lipid nanoparticles were evaluated by dynamic laser scattering and scanning electron microscopy. The wogonin-loaded solid lipid nanoparticles exhibited sustained and controlled release up to 72 h. In addition, it was observed that the wogonin-loaded solid lipid nanoparticles exhibited enhanced cytotoxicity and inhibited poly (ADP-ribose) polymerase in MCF-7 breast cancer cells. Overall, the results indicate that wogonin-loaded solid lipid nanoparticles could be an efficient delivery system for the treatment of breast cancer. PMID- 29533980 TI - Cross-Sectional Associations of Environmental Perception with Leisure-Time Physical Activity and Screen Time among Older Adults. AB - This study investigated associations of perceived environmental factors with leisure-time physical activity (LTPA) and screen time (ST) among older adults. A cross-sectional study was conducted by administering computer-assisted telephone interviews to 1028 older Taiwanese adults in November 2016. Data on personal factors, perceived environmental factors, LTPA, and ST were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine associations of environmental perception with LTPA and ST by using logistic regression analyses. The results showed that after adjusting for potential confounders, older adults who perceived their neighborhood with good access to shops (AS) and to public transportation (AT) were more likely to have sufficient LTPA (AS: OR = 1.64, 95% CI: 1.16-2.32; AT: OR = 1.43; 95% CI, 1.00-2.03) and less likely to have excessive ST (AS: OR = 0.70; 95% CI: 0.50-0.97; AT: OR = 0.64; 95% CI: 0.46 0.90). Different perceived environmental factors were also associated with LTPA and ST, respectively. This study highlights environment perception as a crucial factor for LTPA and ST. These findings suggest that policy makers and physical activity intervention designers should develop both common and individual environmental strategies to improve and increase awareness of the neighborhood environment to promote LTPA and reduce ST among older adults. PMID- 29533978 TI - Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. AB - The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids. PMID- 29533981 TI - Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence. AB - Nano-pulse stimulation (NPS), previously called nsPEFs, induced a vaccine-like effect after ablation of orthotopic N1-S1 hepatocellular carcinoma (HCC), protecting rats from subsequent challenges with N1-S1 cells. To determine immunity, immune cell phenotypes were analyzed in naive, treated and protected rats. NPS provides a positive, post-ablation immuno-therapeutic outcome by alleviating immunosuppressive T regulatory cells (Treg) in the tumor microenvironment (TME), allowing dendritic cell influx and inducing dynamic changes in natural killer cells (NKs), NKT-cells and T-lymphocytes in blood, spleen and liver. NPS induced specific increases in NKs and NKT-cells expressing CD8 and activation receptors CD314-NKG2D and CD161 (NK1.1) in the TME after treatment, as well as some variable changes in CD4+ and CD8+ effector (Tem) and central memory (Tem) lymphocytes in blood and spleen. After orthotopic challenge, CD8+ T-cells were cytotoxic, inducing apoptosis in N1-S1 cells; additionally, in contrast to post-treatment immune responses, CD4+ and CD8+ memory precursor effector cells (MPECs) and short-lived effector cells (SLECs) were present, while still including CD8+ CD161 NK cells, but not involving CD8+ CD314-NKG2D+ NKs. This immunity was N1-S1-specific and was sustained for at least 8 months. NPS vaccinates rats in vivo against HCC by activating innate and adaptive immune memory mechanisms that prevent HCC recurrence. PMID- 29533983 TI - Comparison of Multiple Bioactive Constituents in Different Parts of Eucommia ulmoides Based on UFLC-QTRAP-MS/MS Combined with PCA. AB - Eucommia ulmoides Oilv. (EU), also called Du-zhong, is a classical traditional Chinese medicine. Its bark, leaf, and male flower are all used for medicinal purposes, called Eucommiae Cortex (EC), Eucommiae Folium (EF), and Eucommiae Flos Male (EFM). In order to study the difference in synthesis and the accumulation of metabolites in different parts of EU, a reliable method based on ultra-fast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-QTRAP MS/MS) was developed for the simultaneous determination of a total of 21 constituents, including two lignans, 6 iridoids, 6 penylpropanoids, 6 flavonoids, and one phenol in the samples (EC, EF, and EFM). Furthermore, principal component analysis (PCA) was performed to evaluate and classify the samples according to the contents of these 21 constituents. All of the results demonstrated that the chemical compositions in EC, EF, and EFM were significantly different and the differential constituents (i.e., aucubin, geniposidic acid, chlorogenic acid, pinoresinol-di-O-beta-d-glucopyranoside, geniposide, cryptochlorogenic acid, rutin, and quercetin) were remarkably associated with sample classifications. The research will provide the basic information for revealing the laws of metabolite accumulation in EC, EF, and EFM from the same origin. PMID- 29533982 TI - Use of Placebo in Supplementation Studies-Vitamin D Research Illustrates an Ethical Quandary. AB - History has shown that without explicit and enforced guidelines, even well intentioned researchers can fail to adequately examine the ethical pros and cons of study design choices. One area in which consensus does not yet exist is the use of placebo groups in vitamin supplementation studies. As a prime example, we focus on vitamin D research. We aim to provide an overview of the ethical issues in placebo-controlled studies and guide future discussion about the ethical use of placebo groups. Research in the field of vitamin D shows variation in how placebo groups are used. We outline four types of control groups in use: active control, placebo-control with restrictions on supplementation, placebo-control without supplementation restrictions, and placebo-control with rescue repletion therapy. The first two types highlight discrete ethical issues: active-control trials limit the ability to detect a difference; placebo-control trials that restrict supplementation potentially place subjects at risk of undue harm. The final two, placebo-control without supplementation restrictions or with rescue repletion therapy, offer potential solutions to these ethical challenges. Building on this, guidelines should be established and enforced on the use of placebo in supplementation studies. Furthermore, the field of vitamin D research has the potential to set an example worthy of emulation. PMID- 29533984 TI - Prioritizing Type of Industry through Health Risk Assessment of Occupational Exposure to Dimethylformamide in the Workplace. AB - The purpose of this study was to classify hazards at an industrial level and evaluate the exposure risks of workers exposed to dimethylformamide (DMF) used as a solvent in the workplace and to determine industries that need priority measures in managing DMF exposure. We calculated hazard quotients at an industrial level. The exposure data of DMF in the workplace were obtained from the work environment monitoring program provided by the Korea Occupational Safety and Health Agency. The evaluation was conducted on textile manufacturing, leather manufacturing, chemical manufacturing, pharmaceutical manufacturing, and rubber manufacturing industries, which have many unit work sites handling DMF. The highest central tendency exposure and reasonable maximum exposure were 2.13 and 18.66 mg/m3 for the rubber product manufacturing industry, respectively. A total of 63.8% of workplaces in the textile manufacturing sector had a hazard quotient higher than 1. The highest risk for exposure to DMF is in the rubber and plastic manufacturing industry, and the lowest risk was in the medical materials and pharmaceutical manufacturing sector. Based on this study, effective management of DMF exposure could be achieved by establishing priority management measures for the textile and rubber and plastic product industries. PMID- 29533986 TI - Mobile Phone Dependence, Social Support and Impulsivity in Chinese University Students. AB - This study examined the frequency of mobile phone dependence in Chinese university students and explored its association with social support and impulsivity. Altogether, 909 university students were consecutively recruited from a large university in China. Mobile phone use, mobile phone dependence, impulsivity, and social support were measured with standardized instruments. The frequency of possible mobile phone use and mobile phone dependence was 78.3% and 7.4%, respectively. Multinomial logistic regression analyses revealed that compared with no mobile phone dependence, possible mobile phone dependence was significantly associated with being male (p = 0.04, OR = 0.7, 95% CI: 0.4-0.98), excessive mobile phone use (p < 0.001, OR = 1.2, 95% CI: 1.09-1.2), and impulsivity (p < 0.001, OR = 1.05, 95% CI: 1.03-1.06), while mobile phone dependence was associated with length of weekly phone use (p = 0.01, OR = 2.5, 95% CI: 1.2-5.0), excessive mobile phone use (p < 0.001, OR = 1.3, 95% CI: 1.2 1.4), and impulsivity (p < 0.001, OR = 1.08, 95% CI: 1.05-1.1). The frequency of possible mobile phone dependence and mobile phone dependence was high in this sample of Chinese university students. A significant positive association with impulsivity was found, but not with social support. PMID- 29533985 TI - Antibody-Based Agents in the Management of Antibiotic-Resistant Staphylococcus aureus Diseases. AB - Staphylococcus aureus is a human pathogen that can cause a wide spectrum of diseases, including sepsis, pneumonia, arthritis, and endocarditis. Ineffective treatment of a number of staphylococcal infections with antibiotics is due to the development and spread of antibiotic-resistant strains following decades of antibiotic usage. This has generated renewed interest within the scientific community in alternative therapeutic agents, such as anti-S. aureus antibodies. Although the role of antibodies in the management of S. aureus diseases is controversial, the success of this pathogen in neutralizing humoral immunity clearly indicates that antibodies offer the host extensive protection. In this review, we report an update on efforts to develop antibody-based agents, particularly monoclonal antibodies, and their therapeutic potential in the passive immunization approach to the treatment and prevention of S. aureus infections. PMID- 29533987 TI - The Effect of Tomatine on Gene Expression and Cell Monolayer Integrity in Caco-2. AB - More understanding of the risk-benefit effect of the glycoalkaloid tomatine is required to be able to estimate the role it might play in our diet. In this work, we focused on effects towards intestinal epithelial cells based on a Caco-2 model in order to analyze the influence on the cell monolayer integrity and on the expression levels of genes involved in cholesterol/sterol biosynthesis (LDLR), lipid metabolism (NR2F2), glucose and amino acid uptake (SGLT1, PAT1), cell cycle (PCNA, CDKN1A), apoptosis (CASP-3, BMF, KLF6), tight junctions (CLDN4, OCLN2) and cytokine-mediated signaling (IL-8, IL1beta, TSLP, TNF-alpha). Furthermore, since the bioactivity of the compound might vary in the presence of a food matrix and following digestion, the influence of both pure tomatine and in vitro digested tomatine with and without tomato fruit matrix was studied. The obtained results suggested that concentrations <20 ug/mL of tomatine, either undigested or in vitro digested, do not compromise the viability of Caco-2 cells and stimulate cytokine expression. This effect of tomatine, in vitro digested tomatine or in vitro digested tomatine with tomato matrix differs slightly, probably due to variations of bioactivity or bioavailability of the tomatine. The results lead to the hypothesis that tomatine acts as hormetic compound that can induce beneficial or risk toxic effects whether used in low or high dose. PMID- 29533988 TI - Development and Testing of a Method for Validating Chemical Inactivation of Ebola Virus. AB - Complete inactivation of infectious Ebola virus (EBOV) is required before a sample may be removed from a Biosafety Level 4 laboratory. The United States Federal Select Agent Program regulations require that procedures used to demonstrate chemical inactivation must be validated in-house to confirm complete inactivation. The objective of this study was to develop a method for validating chemical inactivation of EBOV and then demonstrate the effectiveness of several commonly-used inactivation methods. Samples containing infectious EBOV (Zaire ebolavirus) in different matrices were treated, and the sample was diluted to limit the cytopathic effect of the inactivant. The presence of infectious virus was determined by assessing the cytopathic effect in Vero E6 cells. Crucially, this method did not result in a loss of infectivity in control samples, and we were able to detect less than five infectious units of EBOV (Zaire ebolavirus). We found that TRIzol LS reagent and RNA-Bee inactivated EBOV in serum; TRIzol LS reagent inactivated EBOV in clarified cell culture media; TRIzol reagent inactivated EBOV in tissue and infected Vero E6 cells; 10% neutral buffered formalin inactivated EBOV in tissue; and osmium tetroxide vapors inactivated EBOV on transmission electron microscopy grids. The methods described herein are easily performed and can be adapted to validate inactivation of viruses in various matrices and by various chemical methods. PMID- 29533989 TI - The Primary Duct of Bothrops jararaca Glandular Apparatus Secretes Toxins. AB - Despite numerous studies concerning morphology and venom production and secretion in the main venom gland (and some data on the accessory gland) of the venom glandular apparatus of Viperidae snakes, the primary duct has been overlooked. We characterized the primary duct of the Bothrops jararaca snake by morphological analysis, immunohistochemistry and proteomics. The duct has a pseudostratified epithelium with secretory columnar cells with vesicles of various electrondensities, as well as mitochondria-rich, dark, basal, and horizontal cells. Morphological analysis, at different periods after venom extraction, showed that the primary duct has a long cycle of synthesis and secretion, as do the main venom and accessory glands; however, the duct has a mixed mode venom storage, both in the lumen and in secretory vesicles. Mouse anti-B. jararaca venom serum strongly stained the primary duct's epithelium. Subsequent proteomic analysis revealed the synthesis of venom toxins-mainly C-type lectin/C-type lectin-like proteins. We propose that the primary duct's toxin synthesis products complement the final venom bolus. Finally, we hypothesize that the primary duct and the accessory gland (components of the venom glandular apparatus) are part of the evolutionary path from a salivary gland towards the main venom gland. PMID- 29533990 TI - Comparison between Electrocardiographic and Earlobe Pulse Photoplethysmographic Detection for Evaluating Heart Rate Variability in Healthy Subjects in Short- and Long-Term Recordings. AB - Heart rate variability (HRV) is commonly used to assess autonomic functions and responses to environmental stimuli. It is usually derived from electrocardiographic signals; however, in the last few years, photoplethysmography has been successfully used to evaluate beat-to-beat time intervals and to assess changes in the human heart rate under several conditions. The present work describes a simple design of a photoplethysmograph, using a wearable earlobe sensor. Beat-to-beat time intervals were evaluated as the time between subsequent pulses, thus generating a signal representative of heart rate variability, which was compared to RR intervals from classic electrocardiography. Twenty-minute pulse photoplethysmography and ECG recordings were taken simultaneously from 10 healthy individuals. Ten additional subjects were recorded for 24 h. Comparisons were made of raw signals and on time-domain and frequency domain HRV parameters. There were small differences between the inter-beat intervals evaluated with the two techniques. The current findings suggest that our wearable earlobe pulse photoplethysmograph may be suitable for short and long term home measuring and monitoring of HRV parameters. PMID- 29533991 TI - Improving Hydrolysis Characteristics of Xylanases by Site-Directed Mutagenesis in Binding-Site Subsites from Streptomyces L10608. AB - The preparation of oligosaccharides via xylan hydrolysis is an effective way to add value to hemicellulosic material of agricultural waste. The bacterial strain Streptomyces L10608, isolated from soil, contains genes encoding xylanases of glucoside hydrolase family 10/11 (GH10/11), and these have been cloned to catalyze the production of xylooligosaccharide (XOS). To improve the XOS proportion of hydrolysates produced by xylanase, four amino acid residues were substituted by site-directed mutagenesis, and the mutant genes were overexpressed in Escherichia coli. Mutations replaced the codons encoding Asn214 (+2) and Asn86 (-2) by Ala and removed the Ricin B-lectin domain in GH10-xyn, and mutants Y115A (-2) and Y123A (-2) were produced for GH11-xyn. Interestingly, GH10-N86Q had significantly increased hydrolysis of XOS and almost eliminated xylose (X1) to <2.5%, indicating that the -2 binding site of GH10-xyn of L10608 is required for binding with xylotriose (X3). The hydrolytic activity of GH10-N86Q was increased approximately 1.25-fold using beechwood xylan as a substrate and had high affinity for the substrate with a low Km of about 1.85 mg.mL-1. Otherwise, there were no significant differences in enzymatic properties between GH10-N86Q and GH10-xyn. These mutants offer great potential for modification of xylanase with desired XOS hydrolysis. PMID- 29533992 TI - Maternal Residential Proximity to Major Roadways and Pediatric Embryonal Tumors in Offspring. AB - The environmental determinants of pediatric embryonal tumors remain unclear. Because of the growing concern over the impact of exposures to traffic-related air pollution on pediatric cancer, we conducted a population-based study evaluating the impact of maternal residential proximity to major roadways on the risk of pediatric embryonal tumors in offspring. We identified children diagnosed with neuroblastoma, Wilms tumor, retinoblastoma, or hepatoblastoma at <5 years of age from the Texas Cancer Registry and selected unaffected controls from birth certificates. Two residential proximity measures were used: (1) distance to the nearest major roadway, and (2) within 500 m of a major roadway. Logistic regression was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) for each proximity measure on pediatric embryonal tumors. The odds of an embryonal tumor were increased in children born to mothers living within 500 m of a major roadway (aOR = 1.24, 95% CI: 1.00, 1.54). This was consistent for most tumor subtypes, with the strongest associations observed for unilateral retinoblastoma (aOR = 2.57, 95% CI: 1.28, 5.15, for every kilometer closer the mother lived to the nearest major roadway). These findings contribute to the growing evidence that traffic-related air pollution may increase risk for certain pediatric tumors. PMID- 29533993 TI - Nanoparticle-Assisted Metabolomics. AB - Understanding and harnessing the interactions between nanoparticles and biological molecules is at the forefront of applications of nanotechnology to modern biology. Metabolomics has emerged as a prominent player in systems biology as a complement to genomics, transcriptomics and proteomics. Its focus is the systematic study of metabolite identities and concentration changes in living systems. Despite significant progress over the recent past, important challenges in metabolomics remain, such as the deconvolution of the spectra of complex mixtures with strong overlaps, the sensitive detection of metabolites at low abundance, unambiguous identification of known metabolites, structure determination of unknown metabolites and standardized sample preparation for quantitative comparisons. Recent research has demonstrated that some of these challenges can be substantially alleviated with the help of nanoscience. Nanoparticles in particular have found applications in various areas of bioanalytical chemistry and metabolomics. Their chemical surface properties and increased surface-to-volume ratio endows them with a broad range of binding affinities to biomacromolecules and metabolites. The specific interactions of nanoparticles with metabolites or biomacromolecules help, for example, simplify metabolomics spectra, improve the ionization efficiency for mass spectrometry or reveal relationships between spectral signals that belong to the same molecule. Lessons learned from nanoparticle-assisted metabolomics may also benefit other emerging areas, such as nanotoxicity and nanopharmaceutics. PMID- 29533994 TI - Design and Implementation of an RTK-Based Vector Phase Locked Loop. AB - This paper introduces a novel double-differential vector phase-locked loop (DD VPLL) for Global Navigation Satellite Systems (GNSS) that leverages carrier phase position solutions as well as base station measurements in the estimation of rover tracking loop parameters. The use of double differencing alleviates the need for estimating receiver clock dynamics and atmospheric delays; therefore, the navigation filter consists of the baseline dynamic states only. It is shown that using vector processing for carrier phase tracking leads to a significant enhancement in the receiver sensitivity compared to using the conventional scalar based tracking loop (STL) and vector frequency locked loop (VFLL). The sensitivity improvement of 8 to 10 dB compared to STL, and 7 to 8 dB compared to VFLL, is obtained based on the test cases reported in the paper. Also, an increased probability of ambiguity resolution in the proposed method results in better availability for real time kinematic (RTK) applications. PMID- 29533996 TI - Modifications of Au Nanoparticle-Functionalized Graphene for Sensitive Detection of Sulfanilamide. AB - In this paper, we present a simple and feasible electrochemical sensor based on Au nanoparticle-functionalized graphene for the determination of sulfanilamide. Au nanoparticles were deposited on graphene, which acted as a platform to prepare excellent nanocomposites. Attributed to the graphene's large surface area and the Au nanoparticles' strong conductivity, many sulfanilamide molecules were enriched on the sensor surface and the signal response became more sensitive. Under the optimal conditions, the electrochemical sensors could be used for the efficient detection of sulfanilamide. Good linearity was observed in the range of 0.1-1000 MUmol.L-1 and the detection limit was 0.011 MUmol.L-1. Most importantly, the Au nanoparticle-functionalized graphene-modified electrode could be successfully applied for the detection of sulfanilamide in animal meat, and exhibited good stability, acceptable recovery, and offered a promising platform for point-of care detecting in real samples. PMID- 29533995 TI - Using cAMP Sensors to Study Cardiac Nanodomains. AB - 3',5'-cyclic adenosine monophosphate (cAMP) signalling plays a major role in the cardiac myocyte response to extracellular stimulation by hormones and neurotransmitters. In recent years, evidence has accumulated demonstrating that the cAMP response to different extracellular agonists is not uniform: depending on the stimulus, cAMP signals of different amplitudes and kinetics are generated in different subcellular compartments, eliciting defined physiological effects. In this review, we focus on how real-time imaging using fluorescence resonance energy transfer (FRET)-based reporters has provided mechanistic insight into the compartmentalisation of the cAMP signalling pathway and allowed for the precise definition of the regulation and function of subcellular cAMP nanodomains. PMID- 29533997 TI - Long-Term Increase of Radiographic Damage and Disability in Patients with RA in Relation to Disease Duration in the Era of Biologics. Results from the SCQM Cohort. AB - OBJECTIVES: There is little information on the relation between disease duration, disability and radiographic outcome since the introduction of biologics into the therapy of rheumatoid arthritis (RA). No long -term cohort studies have been conducted on this subject so far. To analyse radiographic damage, disability, and disease activity in RA-patients dependent on disease duration in the Swiss national RA cohort (SCQM). METHODS: The primary outcome was the association between the radiographic destruction, assessed by Ratingen scores, and disease duration. All patients with at least one clinical visit were analysed with polynomial and multiple negative binomial models. RESULTS: The disease duration in the 8678 patients with available radiographs analysed ranged between less than 1 and more than 65 years (median 8.3). Disease duration and radiographic destruction were significantly associated with an average increase of Ratingen scores by 8.3% per year. Apart from disease duration, positive rheumatoid factor was the strongest predictor for radiographic destruction. While DAS28-scores remained stable in patients with a disease duration of more than 5 years (median DAS28 2.8), HAQ-DI scores increased continuously by 0.018 for each additional year. CONCLUSION: In this RA cohort, patients show a continuous increase of articular destruction and physical disability in parallel with disease duration. Even when nowadays a satisfactory control of disease activity can be achieved in most patients, RA remains a destructive disease leading to joint destruction and physical disability in many patients. PMID- 29533999 TI - Analysing the Structural Effect of Point Mutations of Cytotoxic Necrotizing Factor 1 (CNF1) on Lu/BCAM Adhesion Glycoprotein Association. AB - Cytotoxic Necrotizing Factor 1 (CNF1) was identified in 1983 as a protein toxin produced by certain pathogenic strains of Escherichia coli. Since then, numerous studies have investigated its particularities. For instance, it is associated with the single chain AB-toxin family, and can be divided into different functional and structural domains, e.g., catalytic and transmembrane domain and interaction sites. A few years ago, the identification of the Lutheran (Lu) adhesion glycoprotein/basal cell adhesion molecule (BCAM) as a cellular receptor for CNF1 provided new insights into the adhesion process of CNF1. Very recently, the Ig-like domain 2 of Lu/BCAM was confirmed as the main interaction site using protein-protein interaction and competition studies with various different mutants. Here, I present in silico approaches that precisely explain the impact of these mutations, leading to a better explanation of these experimental studies. These results can be used in the development of future antitoxin strategies. PMID- 29533998 TI - Randomised Controlled Trial Comparing Daily Versus Depot Vitamin D3 Therapy in 0 16-Year-Old Newly Settled Refugees in Western Australia Over a Period of 40 Weeks. AB - Vitamin D deficiency is highly prevalent in newly settled refugees in Western Australia (WA). If adherence to daily vitamin D therapy is problematic, depot therapy is a therapeutic alternative. The aim of this study was to compare daily versus depot treatment and factors influencing the therapeutic outcome. Newly settled refugees (n = 151) with 25(OH)D levels less than 78 nmol/L were randomised to receive daily or depot vitamin D therapy with eight weekly interval follow up to 40 weeks. Biochemical and clinical parameters were collected at each visit. Generalized Linear Mixed Models (GLMM) examined the longitudinal changes over time controlling for confounders including age, gender, treatment arm, season, country of refuge/origin and sun exposure score. Participants were aged 5.5 months to 16.0 years (75 males, 83 females). Both treatment groups achieved vitamin D sufficiency. The daily treatment group had significantly higher 25(OH)D levels at each visit post baseline and a higher proportion of participants with levels above 50 nmol/L at all time points. Time, treatment group, calcium and sun exposure score were significant predictors of 25(OH)D serum levels. Depot vitamin D therapy is an alternative to daily treatment in this at-risk group of children and adolescents in whom treatment adherence is problematic. PMID- 29534000 TI - Reporting Key Features in Cold-Adapted Bacteria. AB - It is well known that cold environments are predominant over the Earth and there are a great number of reports analyzing bacterial adaptations to cold. Most of these works are focused on characteristics traditionally involved in cold adaptation, such as the structural adjustment of enzymes, maintenance of membrane fluidity, expression of cold shock proteins and presence of compatible solutes. Recent works based mainly on novel "omic" technologies have presented evidence of the presence of other important features to thrive in cold. In this work, we analyze cold-adapted bacteria, looking for strategies involving novel features, and/or activation of non-classical metabolisms for a cold lifestyle. Metabolic traits related to energy generation, compounds and mechanisms involved in stress resistance and cold adaptation, as well as characteristics of the cell envelope, are analyzed in heterotrophic cold-adapted bacteria. In addition, metagenomic, metatranscriptomic and metaproteomic data are used to detect key functions in bacterial communities inhabiting cold environments. PMID- 29534001 TI - The Popeye Domain Containing Genes and Their Function as cAMP Effector Proteins in Striated Muscle. AB - The Popeye domain containing (POPDC) genes encode transmembrane proteins, which are abundantly expressed in striated muscle cells. Hallmarks of the POPDC proteins are the presence of three transmembrane domains and the Popeye domain, which makes up a large part of the cytoplasmic portion of the protein and functions as a cAMP-binding domain. Interestingly, despite the prediction of structural similarity between the Popeye domain and other cAMP binding domains, at the protein sequence level they strongly differ from each other suggesting an independent evolutionary origin of POPDC proteins. Loss-of-function experiments in zebrafish and mouse established an important role of POPDC proteins for cardiac conduction and heart rate adaptation after stress. Loss-of function mutations in patients have been associated with limb-girdle muscular dystrophy and AV-block. These data suggest an important role of these proteins in the maintenance of structure and function of striated muscle cells. PMID- 29534002 TI - Acute Stress and Anxiety in Medical Residents on the Emergency Department Duty. AB - The objectives of this longitudinal study were to compare salivary cortisol release patterns in medical residents and their self-perceived anxiety levels between a regular working day and a day when on call in the emergency department (ED-duty day) and to determine any differences in cortisol release pattern as a function of years of residency or sex. The study included 35 residents (physicians-in-training) of the Granada University Hospital, Granada, Spain. Acute stress was measured on a regular working day and an ED-duty day, evaluating anxiety-state with the Spanish version of the State-Trait Anxiety Inventory. Physiological stress assessment was based on salivary cortisol levels. Cortisol release concentrations were higher on an ED-duty day than on a regular working day, with a significantly increased area under the curve (AUC) (p < 0.006). This difference slightly attenuated with longer residency experience. No gender difference in anxiety levels was observed (p < 0.001). According to these findings, the hypothalamic-pituitary-adrenal axis activity and anxiety levels of medical residents are higher on an ED-duty day than on a regular working day. PMID- 29534003 TI - Energy Absorption Capacity in Natural Fiber Reinforcement Composites Structures. AB - The study of natural fiber reinforcement composite structures has focused the attention of the automobile industry due to the new regulation in relation to the recyclability and the reusability of the materials preserving and/or improving the mechanical characteristics. The influence of different parameters on the material behavior of natural fiber reinforced plastic structures has been investigated, showing the potential for transport application in energy absorbing structures. Two different woven fabrics (twill and hopsack) made of flax fibers as well as a non-woven mat made of a mixture of hemp and kenaf fibers were employed as reinforcing materials. These reinforcing textiles were impregnated with both HD-PE (high-density polyethylen) and PLA (polylactic acid) matrix, using a continuous compression molding press. The impregnated semi-finished laminates (so-called organic sheets) were thermoformed in a second step to half tubes that were assembled through vibration-welding process to cylindric crash absorbers. The specimens were loaded by compression to determine the specific energy absorption capacity. Quasi-static test results were compared to dynamic test data obtained on a catapult arrangement. The differences on the specific energies absorption (SEA) as a function of different parameters, such as the wall thickness, the weave material type, the reinforced textiles, and the matrix used, depending on the velocity rate application were quantified. In the case of quasi static analysis it is observed a 20% increment in the SEA value when wove Hopsack fabric reinforcement is employed. No velocity rate influence from the material was observed on the SEA evaluation at higher speeds used to perform the experiments. The influence of the weave configuration (Hopsack) seems to be more stable against buckling effects at low loading rates with 10% higher SEA values. An increase of SEA level of up to 72% for PLA matrix was observed when compared with HD-PE matrix. PMID- 29534004 TI - Honeybees Tolerate Cyanogenic Glucosides from Clover Nectar and Flowers. AB - Honeybees (Apis mellifera) pollinate flowers and collect nectar from many important crops. White clover (Trifolium repens) is widely grown as a temperate forage crop, and requires honeybee pollination for seed set. In this study, using a quantitative LC-MS (Liquid Chromatography-Mass Spectrometry) assay, we show that the cyanogenic glucosides linamarin and lotaustralin are present in the leaves, sepals, petals, anthers, and nectar of T. repens. Cyanogenic glucosides are generally thought to be defense compounds, releasing toxic hydrogen cyanide upon degradation. However, increasing evidence indicates that plant secondary metabolites found in nectar may protect pollinators from disease or predators. In a laboratory survival study with chronic feeding of secondary metabolites, we show that honeybees can ingest the cyanogenic glucosides linamarin and amygdalin at naturally occurring concentrations with no ill effects, even though they have enzyme activity towards degradation of cyanogenic glucosides. This suggests that honeybees can ingest and tolerate cyanogenic glucosides from flower nectar. Honeybees retain only a portion of ingested cyanogenic glucosides. Whether they detoxify the rest using rhodanese or deposit them in the hive should be the focus of further research. PMID- 29534005 TI - Perceived Benefits and Barriers of a Community-Based Diabetes Prevention and Management Program. AB - This study examined the perceptions of benefits of and barriers to participating in a community-based diabetes program to improve program effectiveness. The Diabetes Prevention and Management (DPM) program was a twenty-two session, 1-year program, modeled after the evidence-based National Diabetes Prevention Program and AADE7 Self-Care Behaviors framework. Community-based participatory research approach was used to culturally tailor the curriculum. Participants included overweight or obese adults with dysglycemia. A benefits and barriers survey was developed to gather information on participants' perception of the program, as well as information on demographics and health literacy levels. Eighty-nine adults participated in the DPM program (73% females; 62% diabetic; 77% had adequate health literacy); 79% of participants completed the benefits and barriers survey. Principal component analysis indicated two components representing benefits (Cronbach's alpha = 0.83) and barriers (alpha = 0.65). The majority perceived high benefits and low barriers to program participation; benefits included helpful interaction with health coach or program leader (73%), improved lifestyle modification (65%) due to the program, and satisfaction with the program (75%). Open-ended questions confirmed themes related to benefits of program participation, suggestion for programmatic improvements as well as barriers to participation. Participant feedback could be used to guide interventions and tailor future program implementation. PMID- 29534006 TI - Research on the Factors Influencing the Measurement Errors of the Discrete Rogowski Coil. AB - An innovative array of magnetic coils (the discrete Rogowski coil-RC) with the advantages of flexible structure, miniaturization and mass producibility is investigated. First, the mutual inductance between the discrete RC and circular and rectangular conductors are calculated using the magnetic vector potential (MVP) method. The results are found to be consistent with those calculated using the finite element method, but the MVP method is simpler and more practical. Then, the influence of conductor section parameters, inclination, and eccentricity on the accuracy of the discrete RC is calculated to provide a reference. Studying the influence of an external current on the discrete RC's interference error reveals optimal values for length, winding density, and position arrangement of the solenoids. It has also found that eccentricity and interference errors decreasing with increasing number of solenoids. Finally, a discrete RC prototype is devised and manufactured. The experimental results show consistent output characteristics, with the calculated sensitivity and mutual inductance of the discrete RC being very close to the experimental results. The influence of an external conductor on the measurement of the discrete RC is analyzed experimentally, and the results show that interference from an external current decreases with increasing distance between the external and measured conductors. PMID- 29534007 TI - Design of Meter-Scale Antenna and Signal Detection System for Underground Magnetic Resonance Sounding in Mines. AB - Magnetic resonance sounding (MRS) is a novel geophysical method to detect groundwater directly. By applying this method to underground projects in mines and tunnels, warning information can be provided on water bodies that are hidden in front prior to excavation and thus reduce the risk of casualties and accidents. However, unlike its application to ground surfaces, the application of MRS to underground environments is constrained by the narrow space, quite weak MRS signal, and complex electromagnetic interferences with high intensities in mines. Focusing on the special requirements of underground MRS (UMRS) detection, this study proposes the use of an antenna with different turn numbers, which employs a separated transmitter and receiver. We designed a stationary coil with stable performance parameters and with a side length of 2 m, a matching circuit based on a Q-switch and a multi-stage broad/narrowband mixed filter that can cancel out most electromagnetic noise. In addition, noises in the pass-band are further eliminated by adopting statistical criteria and harmonic modeling and stacking, all of which together allow weak UMRS signals to be reliably detected. Finally, we conducted a field case study of the UMRS measurement in the Wujiagou Mine in Shanxi Province, China, with known water bodies. Our results show that the method proposed in this study can be used to obtain UMRS signals in narrow mine environments, and the inverted hydrological information generally agrees with the actual situation. Thus, we conclude that the UMRS method proposed in this study can be used for predicting hazardous water bodies at a distance of 7-9 m in front of the wall for underground mining projects. PMID- 29534008 TI - Anti-Inflammatory and Tissue Regenerative Effects of Topical Treatment with Ozonated Olive Oil/Vitamin E Acetate in Balanitis Xerotica Obliterans. AB - Balanitis xerotica obliterans (BXO) is a chronic inflammatory skin disorder, considered the male genital variant of lichen sclerosus. Anti-inflammatory drugs are commonly used in BXO. We evaluated the effects of an innovative formulation of ozonated olive oil with vitamin E acetate (OZOILE(r)) on the inflammatory status and tissue remodeling in male children with BXO. The mRNA transcripts of proteins involved either in inflammation or in dynamics of tissue regeneration were analyzed by quantitative real-time PCR, in foreskins affected by BXO removed from patients untreated or treated with OZOILE(r) cream for 7 days before circumcision. We found a significant reduction in mRNA levels of IL-1beta, TNF alpha, INF-gamma, transglutaminase 2 and NOS2 in foreskins treated with OZOILE(r) in comparison to untreated ones (p < 0.001). No significant differences were observed in NF-kappaB activation in the specimens obtained from treated and untreated patients. Hence, OZOILE(r) treatment up-regulated hypoxia-inducible factor (HIF)-1alpha, vascular endothelial growth factor (VEGF) and E-cadherin gene expression (p < 0.001). The treatment with OZOILE(r) showed effective results in children affected by BXO by reducing the inflammatory process and stimulating mechanisms for tissue regeneration of the foreskin. A randomized clinical trial on a large number of children affected by BXO might be useful to verify the efficacy of topical treatment with OZOILE(r). PMID- 29534009 TI - In Vitro and In Vivo Short-Term Pulmonary Toxicity of Differently Sized Colloidal Amorphous SiO2. AB - In vitro prediction of inflammatory lung effects of well-dispersed nanomaterials is challenging. Here, the in vitro effects of four colloidal amorphous SiO2 nanomaterials that differed only by their primary particle size (9, 15, 30, and 55 nm) were analyzed using the rat NR8383 alveolar macrophage (AM) assay. Data were compared to effects of single doses of 15 nm and 55 nm SiO2 intratracheally instilled in rat lungs. In vitro, all four elicited the release of concentration dependent lactate dehydrogenase, beta-glucuronidase, and tumor necrosis factor alpha, and the two smaller materials also released H2O2. All effects were size dependent. Since the colloidal SiO2 remained well-dispersed in serum-free in vitro conditions, effective particle concentrations reaching the cells were estimated using different models. Evaluating the effective concentration-based in vitro effects using the Decision-making framework for the grouping and testing of nanomaterials, all four nanomaterials were assigned as "active." This assignment and the size dependency of effects were consistent with the outcomes of intratracheal instillation studies and available short-term rat inhalation data for 15 nm SiO2. The study confirms the applicability of the NR8383 AM assay to assessing colloidal SiO2 but underlines the need to estimate and consider the effective concentration of such well-dispersed test materials. PMID- 29534010 TI - Structural Diversity and Biological Activities of Novel Secondary Metabolites from Endophytes. AB - Exploration of structurally novel natural products greatly facilitates the discovery of biologically active pharmacophores that are biologically validated starting points for the development of new drugs. Endophytes that colonize the internal tissues of plant species, have been proven to produce a large number of structurally diverse secondary metabolites. These molecules exhibit remarkable biological activities, including antimicrobial, anticancer, anti-inflammatory and antiviral properties, to name but a few. This review surveys the structurally diverse natural products with new carbon skeletons, unusual ring systems, or rare structural moieties that have been isolated from endophytes between 1996 and 2016. It covers their structures and bioactivities. Biosynthesis and/or total syntheses of some important compounds are also highlighted. Some novel secondary metabolites with marked biological activities might deserve more attention from chemists and biologists in further studies. PMID- 29534012 TI - Ruthenium(eta6,eta1-arene-CH2-NHC) Catalysts for Direct Arylation of 2 Phenylpyridine with (Hetero)Aryl Chlorides in Water. AB - A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N-CH2-arene group. The benzimidazolium halides were readily converted into ruthenium(II)-NHC complexes with the general formula [RuCl2(eta6,eta1-arene-CH2-NHC)]. The structures of all new compounds were characterized by 1H NMR (Nuclear Magnetic Resonance), 13C NMR, FT-IR (Fourier Transform Infrared) spectroscopy and elemental analysis techniques. The single crystal structure of one benzimidazole ruthenium complex, 2b, was determined. The complex is best thought of as containing an octahedrally coordinated Ru center with the arene residue occupying three sites, the remaining sites being occupied by a (carbene)C-Ru bond and two Ru-Cl bonds. The catalytic activity of [RuCl2(eta6,eta1-arene-CH2-NHC)] complexes was evaluated in the direct (hetero)arylation of 2-phenylpyridine with (hetero)aryl chlorides in water as the nontoxic reaction medium. These results show that catalysts 2a and 2b were the best for monoarylation with simple phenyl and tolyl chlorides. For functional aryl chlorides, 2d, 2e, and 2c appeared to be the most efficient. PMID- 29534011 TI - Immunology Guides Skeletal Muscle Regeneration. AB - Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region of interest is exposed. If the extent of trauma surpasses the intrinsic regenerative capacities, signs of fatty degeneration and formation of fibrotic scar tissue can occur, and, consequentially, muscle function deteriorates or is diminished. Despite research efforts to investigate the physiological healing cascade following trauma, our understanding of the early onset of healing and how it potentially determines success or failure is still only fragmentary. This review focuses on the initial physiological pathways following skeletal muscle trauma in comparison to bone and tendon trauma and what conclusions can be drawn from new scientific insights for the development of novel therapeutic strategies. Strategies to support regeneration of muscle tissue after injury are scarce, even though muscle trauma has a high incidence. Based on tissue specific differences, possible clinical treatment options such as local immune-modulatory and cell therapeutic approaches are suggested that aim to support the endogenous regenerative potential of injured muscle tissues. PMID- 29534013 TI - A Novel Hybrid Sequence-Based Model for Identifying Anticancer Peptides. AB - Cancer is a serious health issue worldwide. Traditional treatment methods focus on killing cancer cells by using anticancer drugs or radiation therapy, but the cost of these methods is quite high, and in addition there are side effects. With the discovery of anticancer peptides, great progress has been made in cancer treatment. For the purpose of prompting the application of anticancer peptides in cancer treatment, it is necessary to use computational methods to identify anticancer peptides (ACPs). In this paper, we propose a sequence-based model for identifying ACPs (SAP). In our proposed SAP, the peptide is represented by 400D features or 400D features with g-gap dipeptide features, and then the unrelated features are pruned using the maximum relevance-maximum distance method. The experimental results demonstrate that our model performs better than some existing methods. Furthermore, our model has also been extended to other classifiers, and the performance is stable compared with some state-of-the-art works. PMID- 29534014 TI - Transient Characteristics of a Fluidic Device for Circulatory Jet Flow. AB - In this paper, we report on the design, simulation, and experimental analysis of a miniaturized device that can generate multiple circulated jet flows. The device is actuated by a lead zirconate titanate (PZT) diaphragm. The flows in the device were studied using three-dimensional transient numerical simulation with the programmable open source OpenFOAM and was comparable to the experimental result. Each flow is verified by two hotwires mounted at two positions inside each consisting chamber. The experiment confirmed that the flow was successfully created, and it demonstrated good agreement with the simulation. In addition, a prospective application of the device as an angular rate sensor is also demonstrated. The device is robust, is minimal in size, and can contribute to the development of multi-axis fluidic inertial sensors, fluidic amplifiers, gas mixing, coupling, and analysis. PMID- 29534015 TI - Targeting Hodgkin and Reed-Sternberg Cells with an Inhibitor of Heat-Shock Protein 90: Molecular Pathways of Response and Potential Mechanisms of Resistance. AB - Classical Hodgkin lymphoma (cHL) cells overexpress heat-shock protein 90 (HSP90), an important intracellular signaling hub regulating cell survival, which is emerging as a promising therapeutic target. Here, we report the antitumor effect of celastrol, an anti-inflammatory compound and a recognized HSP90 inhibitor, in Hodgkin and Reed-Sternberg cell lines. Two disparate responses were recorded. In KM-H2 cells, celastrol inhibited cell proliferation, induced G0/G1 arrest, and triggered apoptosis through the activation of caspase-3/7. Conversely, L428 cells exhibited resistance to the compound. A proteomic screening identified a total of 262 differentially expressed proteins in sensitive KM-H2 cells and revealed that celastrol's toxicity involved the suppression of the MAPK/ERK (extracellular signal regulated kinase/mitogen activated protein kinase) pathway. The apoptotic effects were preceded by a decrease in RAS (proto-oncogene protein Ras), p-ERK1/2 (phospho-extracellular signal-regulated Kinase-1/2), and c-Fos (proto-oncogene protein c-Fos) protein levels, as validated by immunoblot analysis. The L428 resistant cells exhibited a marked induction of HSP27 mRNA and protein after celastrol treatment. Our results provide the first evidence that celastrol has antitumor effects in cHL cells through the suppression of the MAPK/ERK pathway. Resistance to celastrol has rarely been described, and our results suggest that in cHL it may be mediated by the upregulation of HSP27. The antitumor properties of celastrol against cHL and whether the disparate responses observed in vitro have clinical correlates deserve further research. PMID- 29534016 TI - CD99: A Cell Surface Protein with an Oncojanus Role in Tumors. AB - The cell surface molecule CD99 has gained interest because of its involvement in regulating cell differentiation and adhesion/migration of immune and tumor cells. However, the molecule plays an intriguing and dual role in different cell types. In particular, it acts as a requirement for cell malignancy or as an oncosuppressor in tumors. In addition, the gene encodes for two different isoforms, which also act in opposition inside the same cell. This review highlights key studies focusing on the dual role of CD99 and its isoforms and discusses major critical issues, challenges, and strategies for overcoming those challenges. The review specifically underscores the properties that make the molecule an attractive therapeutic target and identifies new relationships and areas of study that may be exploited. The elucidation of the spatial and temporal control of the expression of CD99 in normal and tumor cells is required to obtain a full appreciation of this molecule and its signaling. PMID- 29534017 TI - Cellular hnRNP A1 Interacts with Nucleocapsid Protein of Porcine Epidemic Diarrhea Virus and Impairs Viral Replication. AB - The nucleocapsid (N) protein is a major structural component of porcine epidemic diarrhea virus (PEDV), which is predicted to be a multifunctional protein in viral replication. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a cellular protein participating in the splicing of pre-mRNA in the nucleus and translation regulation in the cytoplasm. According to our previous proteomic study about PEDV infection in vivo, hnRNP A1 was thought to be a cellular factor influencing PEDV replication. In this report, PEDV N protein was discovered to colocalize with cellular hnRNP A1 in perinuclear region of PEDV infected cells. Co-immunoprecipitation (CO-IP) results clearly demonstrated that PEDV N protein could bind to human hnRNP A1. Replication of PEDV was inhibited by silencing the expression of hnRNP A1 in CCL-81 cells, suggesting the positive effect of hnRNP A1 on PEDV infection. PMID- 29534018 TI - Eyeing up the Future of the Pupillary Light Reflex in Neurodiagnostics. AB - The pupillary light reflex (PLR) describes the constriction and subsequent dilation of the pupil in response to light as a result of the antagonistic actions of the iris sphincter and dilator muscles. Since these muscles are innervated by the parasympathetic and sympathetic nervous systems, respectively, different parameters of the PLR can be used as indicators for either sympathetic or parasympathetic modulation. Thus, the PLR provides an important metric of autonomic nervous system function that has been exploited for a wide range of clinical applications. Measurement of the PLR using dynamic pupillometry is now an established quantitative, non-invasive tool in assessment of traumatic head injuries. This review examines the more recent application of dynamic pupillometry as a diagnostic tool for a wide range of clinical conditions, varying from neurodegenerative disease to exposure to toxic chemicals, as well as its potential in the non-invasive diagnosis of infectious disease. PMID- 29534019 TI - Combined Subchronic Toxicity of Aluminum (III), Titanium (IV) and Silicon (IV) Oxide Nanoparticles and Its Alleviation with a Complex of Bioprotectors. AB - Stable suspensions of metal/metalloid oxide nanoparticles (MeO-NPs) obtained by laser ablation of 99.99% pure elemental aluminum, titanium or silicon under a layer of deionized water were used separately, or in three binary combinations, or in a ternary combination to induce subchronic intoxications in rats. To this end, the MeO-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks before measuring a large number of functional, biochemical, morphological and cytological indices for the organism's status. In many respects, the Al2O3-NP was found to be the most toxic species alone and the most dangerous component of the combinations studied. Mathematical modeling with the help of the Response Surface Methodology showed that, as well as in the case of any other binary toxic combinations previously investigated by us, the organism's response to a simultaneous exposure to any two of the MeO-NP species under study was characterized by a complex interaction between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which outcome this type was estimated for and on effect and dose levels. With any third MeO-NP species acting in the background, the type of combined toxicity displayed by the other two remained virtually the same or changed significantly, becoming either more or less unfavorable. Various harmful effects produced by the (Al2O3-NP + TiO2-NP + SiO2-NP)-combination, including its genotoxicity, were substantially attenuated by giving the rats per os during the entire exposure period a complex of innocuous bioactive substances expected to increase the organism's antitoxic resistance. PMID- 29534021 TI - Evaluation of Regional Vulnerability to Disasters by People of Ishikawa, Japan: A Cross Sectional Study Using National Health Insurance Data. AB - The 2013 Partial Amendment of the Disaster Countermeasures Basic Law mandated that a roster of vulnerable persons during disasters be created, and further development of evacuation support is expected. In this study, the number of vulnerable people living in target analytical areas are identified in terms of neighborhood units by using the National Health Insurance Database to create a realistic and efficient evacuation support plan. Later, after considering the "vulnerability" of an area to earthquake disaster damage, a quantitative evaluation of the state of the disaster is performed using a principle component analysis that further divided the analytical target areas into neighborhood units to make a detailed determination of the number of disaster-vulnerable persons, the severity of the disaster, etc. The results of the disaster evaluation performed after considering the vulnerability of an area are that 628 disaster vulnerable persons live in areas with a relatively higher disaster evaluation value. PMID- 29534020 TI - Copper-Free 'Click' Chemistry-Based Synthesis and Characterization of Carbonic Anhydrase-IX Anchored Albumin-Paclitaxel Nanoparticles for Targeting Tumor Hypoxia. AB - Triple negative breast cancer (TNBC) is a difficult to treat disease due to the absence of the three unique receptors estrogen, progesterone and herceptin-2 (HER 2). To improve the current therapy and overcome the resistance of TNBC, there is unmet need to develop an effective targeted therapy. In this regard, one of the logical and economical approaches is to develop a tumor hypoxia-targeting drug formulation platform for selective delivery of payload to the drug-resistant and invasive cell population of TNBC tumors. Toward this, we developed a Carbonic Anhydrase IX (CA IX) receptor targeting human serum albumin (HSA) carriers to deliver the potent anticancer drug, Paclitaxel (PTX). We used Acetazolamide (ATZ), a small molecule ligand of CA IX to selectively deliver HSA-PTX in TNBC cells. A novel method of synthesis involving copper free 'click' chemistry (Dibenzocyclooctyl, DBCO) moiety with an azide-labeled reaction partner, known as Strain-Promoted Alkyne Azide Cycloaddition (SPAAC) along with a desolvation method for PTX loading were used in the present study to arrive at the CA IX selective nano-carriers, HSA-PTX-ATZ. The anticancer effect of HSA-PTX-ATZ is higher compared to HSA, PTX and non-targeted HSA-PTX in MDA-MB-231 and MDA-MB-468 cells. The cell killing effect is associated with induction of early and late phases of apoptosis. Overall, our proof-of-concept study shows a promising avenue for hypoxia-targeted drug delivery that can be adapted to several types of cancers. PMID- 29534022 TI - EquiMoves: A Wireless Networked Inertial Measurement System for Objective Examination of Horse Gait. AB - In this paper, we describe and validate the EquiMoves system, which aims to support equine veterinarians in assessing lameness and gait performance in horses. The system works by capturing horse motion from up to eight synchronized wireless inertial measurement units. It can be used in various equine gait modes, and analyzes both upper-body and limb movements. The validation against an optical motion capture system is based on a Bland-Altman analysis that illustrates the agreement between the two systems. The sagittal kinematic results (protraction, retraction, and sagittal range of motion) show limits of agreement of +/- 2.3 degrees and an absolute bias of 0.3 degrees in the worst case. The coronal kinematic results (adduction, abduction, and coronal range of motion) show limits of agreement of - 8.8 and 8.1 degrees, and an absolute bias of 0.4 degrees in the worst case. The worse coronal kinematic results are most likely caused by the optical system setup (depth perception difficulty and suboptimal marker placement). The upper-body symmetry results show no significant bias in the agreement between the two systems; in most cases, the agreement is within +/ 5 mm. On a trial-level basis, the limits of agreement for withers and sacrum are within +/-2 mm, meaning that the system can properly quantify motion asymmetry. Overall, the bias for all symmetry-related results is less than 1 mm, which is important for reproducibility and further comparison to other systems. PMID- 29534023 TI - Internalized Transphobia, Resilience, and Mental Health: Applying the Psychological Mediation Framework to Italian Transgender Individuals. AB - Transgender and gender nonconforming (TGNC) people are a highly-stigmatized population. For this reason, they might internalize society's normative gender attitudes and develop negative mental health outcomes. As an extension of the minority stress model, the psychological mediation framework sheds light on psychological processes through which anti-transgender discrimination might affect mental health. Within this framework, the current study aimed at assessing in 149 TGNC Italian individuals the role of internalized transphobia as a mediator between anti-transgender discrimination and mental health, considering resilience as the individual-level coping mechanism buffering this relationship. The results suggest that both indicators of internalized transphobia (i.e., shame and alienation) mediate the relationship between anti-transgender discrimination and depression, while only alienation mediates the relationship between anti transgender discrimination and anxiety. Furthermore, the results suggest that the indirect relation between anti-transgender discrimination and anxiety through alienation is conditional on low and moderate levels of resilience. Findings have important implications for clinical practice and psycho-social interventions to reduce stigma and stress caused by interpersonal and individual stigma. PMID- 29534025 TI - The Association between Body Mass Index and Health-Related Quality of Life in Treatment-Seeking Arab Adults with Obesity. AB - Few studies have thus far been carried out on Health-Related Quality of Life (HRQoL) and obesity in Arab-speaking countries, an issue that we therefore set out to investigate in this study. HRQoL was assessed by the validated Arabic version of the ORWELL 97 questionnaire in 129 treatment-seeking individuals with obesity referred to the Nutritional and Weight Management Outpatient Clinic at the Department of Nutrition and Dietetics of Beirut Arab University (BAU) in Lebanon, and 129 normal-weight participants of similar age and gender. Participants with obesity, regardless of gender, displayed higher total ORWELL 97 scores when compared with normal-weight controls, indicating that obesity is associated with lower HRQoL. Linear regression analysis showed that a higher body mass index (BMI) is associated with an increase in ORWELL 97 scores, but only among female, not male, participants with obesity (beta = 2.89, 95% confidence interval (CI) = 1.43-4.53, p < 0.001). Moreover, logistic regression analysis showed that a one unit increase in BMI increases the odds of an ORWELL 97 score >= 71.75-considered indicative of a clinically significant impairment of HRQoL-by nearly 23% (odds ratio (OR), 95% CI = 1.23, 1.09-1.40, p < 0.05). If confirmed, our findings should prompt clinicians operating in Arab countries to encourage patients with obesity to initiate and persevere in weight-loss programs at the earliest opportunity. PMID- 29534024 TI - An Update on the Metabolic Roles of Carbonic Anhydrases in the Model Alga Chlamydomonas reinhardtii. AB - Carbonic anhydrases (CAs) are metalloenzymes that are omnipresent in nature. CAs catalyze the basic reaction of the reversible hydration of CO2 to HCO3- and H+ in all living organisms. Photosynthetic organisms contain six evolutionarily different classes of CAs, which are namely: alpha-CAs, beta-CAs, gamma-CAs, delta CAs, zeta-CAs, and theta-CAs. Many of the photosynthetic organisms contain multiple isoforms of each CA family. The model alga Chlamydomonas reinhardtii contains 15 CAs belonging to three different CA gene families. Of these 15 CAs, three belong to the alpha-CA gene family; nine belong to the beta-CA gene family; and three belong to the gamma-CA gene family. The multiple copies of the CAs in each gene family may be due to gene duplications within the particular CA gene family. The CAs of Chlamydomonas reinhardtii are localized in different subcellular compartments of this unicellular alga. The presence of a large number of CAs and their diverse subcellular localization within a single cell suggests the importance of these enzymes in the metabolic and biochemical roles they perform in this unicellular alga. In the present review, we update the information on the molecular biology of all 15 CAs and their metabolic and biochemical roles in Chlamydomonas reinhardtii. We also present a hypothetical model showing the known functions of CAs and predicting the functions of CAs for which precise metabolic roles are yet to be discovered. PMID- 29534026 TI - Molecular Characterization and Overexpression of VpRPW8s from Vitis pseudoreticulata Enhances Resistance to Phytophthora capsici in Nicotiana benthamiana. AB - RPW8 genes are atypical broad-spectrum genes that provide resistance to powdery mildew, downy mildew, the cauliflower mosaic virus in Arabidopsis thaliana, and powdery mildew in tobacco. They play important roles in basal plant pathogen defense. They also provide insights into a novel disease resistance mechanism. In this study, we report on homologous RPW8 genes in Vitis pseudoreticulata. Five VpRPW8 genes were cloned; their Open Reading Frame (ORF) sequences ranged from 1994 base pairs to 2478 base pairs. They were comprised of five exons and four introns and shared 78.66% identity. Their proteins had typical conserved RPW8 and NB-LRR (the nucleotide-binding site and the leucine-rich repeats) domains (except VpRPW8-d, which lacked LRR domains). Prokaryotic expression results were consistent with predicted molecular weights. All five RPW8 genes were located in the cytoplasm. Quantitative real-time PCR (qRT-PCR) analysis showed that VpRPW8s in V. pseudoreticulata were induced by Plasmopara viticola, but nearly only VvRPW8-d genes were induced in Vitis vinifera. Furthermore, a VpRPW8 transgenic tobacco system was established. Overexpressed VpRPW8s enhanced resistance to Phytophthora capsici and VpRPW8s conferred varying degrees of resistance to Ph. capsici in Nicotiana benthamiana. Our study presents novel members of the plant RPW8 family and suggests that VpRPW8s are involved in enhanced resistance to P. viticola and Ph. capsici. PMID- 29534027 TI - Biphasic Scaffolds from Marine Collagens for Regeneration of Osteochondral Defects. AB - BACKGROUND: Collagens of marine origin are applied increasingly as alternatives to mammalian collagens in tissue engineering. The aim of the present study was to develop a biphasic scaffold from exclusively marine collagens supporting both osteogenic and chondrogenic differentiation and to find a suitable setup for in vitro chondrogenic and osteogenic differentiation of human mesenchymal stroma cells (hMSC). METHODS: Biphasic scaffolds from biomimetically mineralized salmon collagen and fibrillized jellyfish collagen were fabricated by joint freeze drying and crosslinking. Different experiments were performed to analyze the influence of cell density and TGF-beta on osteogenic differentiation of the cells in the scaffolds. Gene expression analysis and analysis of cartilage extracellular matrix components were performed and activity of alkaline phosphatase was determined. Furthermore, histological sections of differentiated cells in the biphasic scaffolds were analyzed. RESULTS: Stable biphasic scaffolds from two different marine collagens were prepared. An in vitro setup for osteochondral differentiation was developed involving (1) different seeding densities in the phases; (2) additional application of alginate hydrogel in the chondral part; (3) pre-differentiation and sequential seeding of the scaffolds and (4) osteochondral medium. Spatially separated osteogenic and chondrogenic differentiation of hMSC was achieved in this setup, while osteochondral medium in combination with the biphasic scaffolds alone was not sufficient to reach this ambition. CONCLUSIONS: Biphasic, but monolithic scaffolds from exclusively marine collagens are suitable for the development of osteochondral constructs. PMID- 29534028 TI - Cytotoxic Polyhydroxysteroidal Glycosides from Starfish Culcita novaeguineae. AB - Four new polyhydroxysteroidal glycosides-culcinosides A-D (1, 2, 4, and 7)-along with three known compounds-echinasteroside C (3), linckoside F (5), and linckoside L3 (6)-were isolated from the ethanol extract of starfish Culcita novaeguineae collected from the Xisha Islands of the South China Sea. The structures of new compounds were elucidated through extensive spectroscopic studies and chemical evidence, especially two-dimensional (2D) NMR techniques. The cytotoxicity of the new compounds against human glioblastoma cell lines U87, U251, and SHG44 were evaluated. PMID- 29534029 TI - Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. AB - Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective. PMID- 29534032 TI - Laser Induced Damage of Potassium Dihydrogen Phosphate (KDP) Optical Crystal Machined by Water Dissolution Ultra-Precision Polishing Method. AB - Laser induced damage threshold (LIDT) is an important optical indicator for nonlinear Potassium Dihydrogen Phosphate (KDP) crystal used in high power laser systems. In this study, KDP optical crystals are initially machined with single point diamond turning (SPDT), followed by water dissolution ultra-precision polishing (WDUP) and then tested with 355 nm nanosecond pulsed-lasers. Power spectral density (PSD) analysis shows that WDUP process eliminates the laser detrimental spatial frequencies band of micro-waviness on SPDT machined surface and consequently decreases its modulation effect on the laser beams. The laser test results show that LIDT of WDUP machined crystal improves and its stability has a significant increase by 72.1% compared with that of SPDT. Moreover, a subsequent ultrasonic assisted solvent cleaning process is suggested to have a positive effect on the laser performance of machined KDP crystal. Damage crater investigation indicates that the damage morphologies exhibit highly thermal explosion features of melted cores and brittle fractures of periphery material, which can be described with the classic thermal explosion model. The comparison result demonstrates that damage mechanisms for SPDT and WDUP machined crystal are the same and WDUP process reveals the real bulk laser resistance of KDP optical crystal by removing the micro-waviness and subsurface damage on SPDT machined surface. This improvement of WDUP method makes the LIDT more accurate and will be beneficial to the laser performance of KDP crystal. PMID- 29534030 TI - Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients? AB - The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological samples. This review will highlight the different predictive biomarkers detected by IHC for treatment of lung cancer as well as the present advantages and limitations of this approach. A number of perspectives will be considered. PMID- 29534031 TI - l-Carnitine Supplementation in Recovery after Exercise. AB - Given its pivotal role in fatty acid oxidation and energy metabolism, l-carnitine has been investigated as ergogenic aid for enhancing exercise capacity in the healthy athletic population. Early research indicates its beneficial effects on acute physical performance, such as increased maximum oxygen consumption and higher power output. Later studies point to the positive impact of dietary supplementation with l-carnitine on the recovery process after exercise. It is demonstrated that l-carnitine alleviates muscle injury and reduces markers of cellular damage and free radical formation accompanied by attenuation of muscle soreness. The supplementation-based increase in serum and muscle l-carnitine contents is suggested to enhance blood flow and oxygen supply to the muscle tissue via improved endothelial function thereby reducing hypoxia-induced cellular and biochemical disruptions. Studies in older adults further showed that l-carnitine intake can lead to increased muscle mass accompanied by a decrease in body weight and reduced physical and mental fatigue. Based on current animal studies, a role of l-carnitine in the prevention of age-associated muscle protein degradation and regulation of mitochondrial homeostasis is suggested. PMID- 29534033 TI - Structure/Function Analysis of Cotton-Based Peptide-Cellulose Conjugates: Spatiotemporal/Kinetic Assessment of Protease Aerogels Compared to Nanocrystalline and Paper Cellulose. AB - Nanocellulose has high specific surface area, hydration properties, and ease of derivatization to prepare protease sensors. A Human Neutrophil Elastase sensor designed with a nanocellulose aerogel transducer surface derived from cotton is compared with cotton filter paper, and nanocrystalline cellulose versions of the sensor. X-ray crystallography was employed along with Michaelis-Menten enzyme kinetics, and circular dichroism to contrast the structure/function relations of the peptide-cellulose conjugate conformation to enzyme/substrate binding and turnover rates. The nanocellulosic aerogel was found to have a cellulose II structure. The spatiotemporal relation of crystallite surface to peptide cellulose conformation is discussed in light of observed enzyme kinetics. A higher substrate binding affinity (Km) of elastase was observed with the nanocellulose aerogel and nanocrystalline peptide-cellulose conjugates than with the solution-based elastase substrate. An increased Km observed for the nanocellulosic aerogel sensor yields a higher enzyme efficiency (kcat/Km), attributable to binding of the serine protease to the negatively charged cellulose surface. The effect of crystallite size and beta-turn peptide conformation are related to the peptide-cellulose kinetics. Models demonstrating the orientation of cellulose to peptide O6-hydroxymethyl rotamers of the conjugates at the surface of the cellulose crystal suggest the relative accessibility of the peptide-cellulose conjugates for enzyme active site binding. PMID- 29534034 TI - Thermal Properties of Zeolite-Containing Composites. AB - A zeolite (mordenite)-pore-phenol resin composite and a zeolite-pore-shirasu glass composite were fabricated by hot-pressing. Their thermal conductivities were measured by a laser flash method to determine the thermal conductivity of the monolithic zeolite with the proposed mixing rule. The analysis using composites is useful for a zeolite powder with no sinterability to clarify its thermal properties. At a low porosity <20%, the thermal conductivity of the composite was in excellent agreement with the calculated value for the structure with phenol resin or shirasu glass continuous phase. At a higher porosity above 40%, the measured value approached the calculated value for the structure with pore continuous phase. The thermal conductivity of the monolithic mordenite was evaluated to be 3.63 W/mK and 1.70-2.07 W/mK at room temperature for the zeolite pore-phenol resin composite and the zeolite-pore-shirasu glass composite, respectively. The analyzed thermal conductivities of monolithic mordenite showed a minimum value of 1.23 W/mK at 400 degrees C and increased to 2.51 W/mK at 800 degrees C. PMID- 29534035 TI - A Systematic Underpinning and Framing of the Servicescape: Reflections on Future Challenges in Healthcare Services. AB - Ever since Bitner defined the term "servicescape" as the physical environment in which the service is assembled, several scholars have attempted to better understand the impact of the built environment in the context of different service settings. While servicescape is a topic of increasing academic interest among scholars and practitioners, most studies in the area are dedicated to understanding the built environment of hedonic service. More studies are needed to examine utilitarian servicescape and in this paper, we have focused on the healthcare environment. This study aims to identify the gap in servicescape and healthscape studies by providing a theoretical structure of the current servicescape literature and comprehend the academic differences between hedonic servicescape and utilitarian healthscape studies. After reviewing 44 selected papers based on rigorous criteria, we: (1) framed the servicescape factors; (2) analyzed the servicescape literature from the perspectives of terminologies, research fields, methodologies, and frameworks; and (3) identified the current paths of healthscape research. Through this work, we highlight the significance of adopting different dimensions and factors to evaluate the distinguished service environment by the servicescape type and propose several research agendas for future studies on healthscapes. The research findings can contribute to a deep understanding of healthscapes and can introduce a new viewpoint for interpreting the servicescape in diversified service settings. PMID- 29534036 TI - In Vitro Cocktail Effects of PCB-DL (PCB118) and Bulky PCB (PCB153) with BaP on Adipogenesis and on Expression of Genes Involved in the Establishment of a Pro Inflammatory State. AB - (1) Objective: Highlight the in vitro effects of 3T3-L1 cell exposure to polychlorinated biphenyls (PCB118 and 153) or benzo(a)pyrene (BaP) alone or as a cocktail on adipogenesis (ADG) by focusing on changes in lipid metabolism and inflammatory-related genes expression (INFG) and ADG-related genes expression (ADGG); (2) Results: Treatment from the early stage of cell differentiation by BaP alone or in combination with PCBs decreased the expression of some of the ADGG (PPARgammaGlut-4, FAS, Lipin-1a, Leptin, and Adiponectin). BaP enhanced the INFG, especially MCP-1 and TNFalpha. Co-exposure to BaP and PCB153 showed a synergistic effect on TNFalpha and IL6 expression. Treatment with BaP and PCBs during only the maturation period up-regulated the INFG (IL6, TNFalpha, CXCL-10 & MCP-1). PCB118 alone also enhanced TNFalpha, CXCL-10, and PAI-1 expression. The change in MCP-1 protein expression was in agreement with that of the gene. Finally, the BaP-induced up-regulation of the xenobiotic responsive element (XRE) controlled luciferase activity was impaired by PCB153 but not by PCB118; (3) Conclusion: BaP and PCBs down-regulate a part of ADGG and enhance INFG. The direct regulatory effect of PCBs on both ADGG and INFG is usually rather lower than that of BaP and synergistic or antagonistic cocktail effects are clearly observed. PMID- 29534037 TI - Molecular Cloning and Characterization of Carbonic Anhydrase XII from Pufferfish (Takifugu rubripes). AB - In this study, an 1888-bp carbonic anhydrase XII (CA XII) sequence was cloned from the brain of the pufferfish, Takifugu rubripes. The cloned sequence contained a coding region of 1470-bp, which was predicted to translate into a protein of 490 amino acid residues. The predicted protein showed between 68-56% identity with the large yellow croaker (Larimichthys crocea), tilapia (Oreochromis niloticus), and Asian arowana (Scleropages formosus) CA XII proteins. It also exhibited 36% and 53% identity with human CA II and CA XII, respectively. The cloned sequence contained a 22 amino acid NH2-terminal signal sequence and three Asn-Xaa-Ser/Thr sequons, among which one was potentially glycosylated. Four cysteine residues were also identified (Cys-21, Cys-201, Cys 355, and Cys-358), two of which (Cys-21 and Cys-201) could potentially form a disulfide bond. A 22-amino acid COOH-terminal cytoplasmic tail containing a potential site for phosphorylation by protein kinase A was also found. The cloned sequence might be a transmembrane protein, as predicted from in silico and phylogenetic analyses. The active site analysis of the predicted protein showed that its active site residues were highly conserved with tilapia CA XII protein. Homology modeling of the pufferfish CA XII was done using the crystal structure of the extracellular domain of human carbonic anhydrase XII at 1.55 A resolution as a template. Semi-quantitative reverse transcription (RT)-PCR, quantitative PCR (q-PCR), and in situ hybridization confirmed that pufferfish CA XII is highly expressed in the brain. PMID- 29534038 TI - Social Network Analysis as a Methodological Approach to Explore Health Systems: A Case Study Exploring Support among Senior Managers/Executives in a Hospital Network. AB - Health systems research recognizes the complexity of healthcare, and the interacting and interdependent nature of components of a health system. To better understand such systems, innovative methods are required to depict and analyze their structures. This paper describes social network analysis as a methodology to depict, diagnose, and evaluate health systems and networks therein. Social network analysis is a set of techniques to map, measure, and analyze social relationships between people, teams, and organizations. Through use of a case study exploring support relationships among senior managers in a newly established hospital group, this paper illustrates some of the commonly used network- and node-level metrics in social network analysis, and demonstrates the value of these maps and metrics to understand systems. Network analysis offers a valuable approach to health systems and services researchers as it offers a means to depict activity relevant to network questions of interest, to identify opinion leaders, influencers, clusters in the network, and those individuals serving as bridgers across clusters. The strengths and limitations inherent in the method are discussed, and the applications of social network analysis in health services research are explored. PMID- 29534039 TI - Vinylation of a Secondary Amine Core with Calcium Carbide for Efficient Post Modification and Access to Polymeric Materials. AB - We developed a simple and efficient strategy to access N-vinyl secondary amines of various naturally occurring materials using readily available solid acetylene reagents (calcium carbide, KF, and KOH). Pyrrole, pyrazole, indoles, carbazoles, and diarylamines were successfully vinylated in good yields. Cross-linked and linear polymers were synthesized from N-vinyl carbazoles through free radical and cationic polymerization. Post-modification of olanzapine (an antipsychotic drug substance) was successfully performed. PMID- 29534040 TI - Anti-Inflammatory Polyoxygenated Steroids from the Soft Coral Lobophytum michaelae. AB - Three new polyoxygenated steroids, michosterols A-C (1-3), and four known compounds (4-7) were isolated from the ethyl acetate (EtOAc) extract of the soft coral Lobophytum michaelae, collected off the coast of Taitung. The structures of the new compounds were elucidated on the basis of spectroscopic analyses and comparison of the nuclear magnetic resonance (NMR) data with related steroids. The cytotoxicity of compounds 1-3 against the proliferation of a limited panel of cancer cell lines was assayed. Compound 1 was found to display moderate cytotoxicity against adenocarcinomic human alveolar basal epithelial (A549) cancer cells. It also exhibited potent anti-inflammatory activity by suppressing superoxide anion generation and elastase release in N-formyl-methionyl-leucyl phenylalanine/cytochalasin B (fMLP/CB)-stimulated human neutrophils. Furthermore, 3 could effectively inhibit elastase release, as well. PMID- 29534041 TI - Identification of sucA, Encoding beta-Fructofuranosidase, in Rhizopus microsporus. AB - Rhizopus microsporus NBRC 32995 was found to hydrolyze fructooligosaccharides (FOS), as well as sucrose, almost completely into monosaccharides through the production of sufficient amounts of organic acids, indicating that the complete hydrolysis of FOS was caused by the secretion of beta-fructofuranosidase from fungal cells. Thus, the sucA gene, encoding a beta-fructofuranosidase, was amplified by degenerate PCR, and its complete nucleotide sequence was determined. The total length of the sucA gene was 1590 bp, and the SucA protein of R. microsporus NBRC 32995 belonged to clade VIa, which also contains Rhizopus delemar and is closely related to Saccharomycotina, a subdivision of the Ascomycota. PMID- 29534042 TI - Factors Influencing the Flavour of Bovine Milk and Cheese from Grass Based versus Non-Grass Based Milk Production Systems. AB - There has been a surge in interest in relation to differentiating dairy products derived from pasture versus confined systems. The impact of different forage types on the sensory properties of milk and cheese is complex due to the wide range of on farm and production factors that are potentially involved. The main effect of pasture diet on the sensory properties of bovine milk and cheese is increased yellow intensity correlated to beta-carotene content, which is a possible biomarker for pasture derived dairy products. Pasture grazing also influences fat and fatty acid content which has been implicated with texture perception changes in milk and cheese and increased omega-3 fatty acids. Changes in polyunsaturated fatty acids in milk and cheese due to pasture diets has been suggested may increase susceptibility to lipid oxidation but does not seem to be an issue to due increased antioxidants and the reducing environment of cheese. It appears that pasture derived milk and cheese are easier to discern by trained panellists and consumers than milk derived from conserved or concentrate diets. However, milk pasteurization, inclusion of concentrate in pasture diets, cheese ripening time, have all been linked to reducing pasture dietary effects on sensory perception. Sensory evaluation studies of milk and cheese have, in general, found that untrained assessors who best represent consumers appear less able to discriminate sensory differences than trained assessors and that differences in visual and textural attributes are more likely to be realized than flavour attributes. This suggests that sensory differences due to diet are often subtle. Evidence supports the direct transfer of some volatiles via inhalation or ingestion but more so with indirect transfer post rumen metabolism dietary components. The impact of dietary volatiles on sensory perception of milk and dairy products obviously depends upon their concentration and odour activity, however very little quantitative studies have been carried out to date. Some studies have highlighted potential correlation of pasture with enhanced "barny" or "cowy" sensory attributes and subsequently linked these to accumulation of p cresol from the metabolism of beta-carotene and aromatic amino acids or possibly isoflavones in the rumen. p-Cresol has also been suggested as a potential biomarker for pasture derived dairy products. Other studies have linked terpenes to specific sensory properties in milk and cheese but this only appears to be relevant in milk and cheese derived from unseeded wild pasture where high concentrations accumulate, as their odour threshold is quite high. Toluene also a product of beta-carotene metabolism has been identified as a potential biomarker for pasture derived dairy products but it has little impact on sensory perception due to its high odour threshold. Dimethyl sulfone has been linked to pasture diets and could influence sensory perception as its odour threshold is low. Other studies have linked the presence of maize and legumes (clover) in silage with adverse sensory impacts in milk and cheese. Considerably more research is required to define key dietary related impacts on the flavour of milk and cheese. PMID- 29534043 TI - Case Study of Airborne Pathogen Dispersion Patterns in Emergency Departments with Different Ventilation and Partition Conditions. AB - The prevention of airborne infections in emergency departments is a very important issue. This study investigated the effects of architectural features on airborne pathogen dispersion in emergency departments by using a CFD (computational fluid dynamics) simulation tool. The study included three architectural features as the major variables: increased ventilation rate, inlet and outlet diffuser positions, and partitions between beds. The most effective method for preventing pathogen dispersion and reducing the pathogen concentration was found to be increasing the ventilation rate. Installing partitions between the beds and changing the ventilation system's inlet and outlet diffuser positions contributed only minimally to reducing the concentration of airborne pathogens. PMID- 29534045 TI - Development and Validation of a HPLC-UV Method for Extraction Optimization and Biological Evaluation of Hot-Water and Ethanolic Extracts of Dendropanax morbifera Leaves. AB - Dendropanax morbifera Leveille (Araliaceae) has been used in traditional oriental remedies for cancer, inflammation, diabetes, and thrombosis. However, a validated analytical method, standardization, and optimization of extraction conditions with respect to biological activity have not been reported. In this study, a simple and validated HPLC method for identifying and quantifying active substances in D. morbifera was developed. Hot water and ethanolic D. morbifera leaf extracts from different production regions were prepared and evaluated with regard to their chemical compositions and biological activities. The contents of active compounds such as rutin and chlorogenic acid were determined in four samples collected from different regions. The 80% ethanolic extract showed the best antioxidant activity, phenolic content, reducing power, and xanthine oxidase (XO) inhibitory activity. The validated HPLC method confirmed the presence of chlorogenic acid and rutin in D. morbifera leaf extracts. The antioxidant and XO inhibitory activity of D. morbifera extract could be attributed to the marker compounds. Collectively, these results suggest that D. morbifera leaves could be beneficial for the treatment or prevention of hyperuricemia-related disease, and the validated HPLC method could be a useful tool for the quality control of food or drug formulations containing D. morbifera. PMID- 29534044 TI - Antitumour, Antimicrobial, Antioxidant and Antiacetylcholinesterase Effect of Ganoderma Lucidum Terpenoids and Polysaccharides: A Review. AB - Ganoderma lucidum (Reishi) is a popular medicinal mushroom and has been used in oriental medicine because of its promoting effects on health and life expectancy. G. lucidum contains various compounds with a high grade of biological activty, which increase the immunity and show antitumour, antimicrobial, anti inflammatory, antioxidant and acetylcholinesterase inhibitory activity. Several of these substances belong to the triterpenoids and polysaccharides classes. Proteins, lipids, phenols, sterols, etc. are also present. In the present review, an extensive overview of the presence of antitumour, antimicrobial, antioxidant and antiacetylcholinesterase compounds in G. lucidum extracts will be given, along with an evaluation of their therapeutic effects. PMID- 29534046 TI - A Green Protocol for Microwave-Assisted Extraction of Volatile Oil Terpenes from Pterodon emarginatus Vogel. (Fabaceae). AB - Microwave-assisted extraction of volatile oils (MAE) potentially offers a more efficient and bio-sustainable method than conventional extraction by Clevenger apparatus (CE). This study aimed to optimise the MAE of the volatile oil from Pterodon emarginatus fruits and characterise the volatile compounds. A 23 full factorial central composite design and response surface methodology were used to evaluate the effects of time (min), moisture (%) and microwave power (W) on the extraction yield. The process optimisation was based on the desirability function approach. The reaction time and moisture conditions were standardised in these analyses. The volatile oil composition was analysed by Gas Chromatography/Mass Spectrometry (GC/MS) in order to compare techniques extractions influences. Microwave irradiation showed excellent performance for extraction of the volatile oil from Pterodon emarginatus and there were some advantages in compare to conventional method with respect to the time (14 times), energy (6 times), reagents amounts and waste formation. About chemical composition presents significant differences with the type of extraction. Caryophyllene (25.65%) and trans-alpha-bisabolol (6.24%) were identified as major components in MAE sample while caryophyllene (6.75%) and gamma-elemene (7.02%) are the components with higher relative percentage in CE samples. The microwaves assisted process shown an increase of economic interested compounds present in volatile oil. PMID- 29534048 TI - Cure Cycle Optimization of Rapidly Cured Out-Of-Autoclave Composites. AB - Out-of-autoclave prepreg typically needs a long cure cycle to guarantee good properties as the result of low processing pressure applied. It is essential to reduce the manufacturing time, achieve real cost reduction, and take full advantage of out-of-autoclave process. The focus of this paper is to reduce the cure cycle time and production cost while maintaining high laminate quality. A rapidly cured out-of-autoclave resin and relative prepreg were independently developed. To determine a suitable rapid cure procedure for the developed prepreg, the effect of heating rate, initial cure temperature, dwelling time, and post-cure time on the final laminate quality were evaluated and the factors were then optimized. As a result, a rapid cure procedure was determined. The results showed that the resin infiltration could be completed at the end of the initial cure stage and no obvious void could be seen in the laminate at this time. The laminate could achieve good internal quality using the optimized cure procedure. The mechanical test results showed that the laminates had a fiber volume fraction of 59-60% with a final glass transition temperature of 205 degrees C and excellent mechanical strength especially the flexural properties. PMID- 29534049 TI - Caenorhabditis elegans BRICHOS Domain-Containing Protein C09F5.1 Maintains Thermotolerance and Decreases Cytotoxicity of Abeta42 by Activating the UPR. AB - Caenorhabditis elegans C09F5.1 is a nematode-specific gene that encodes a type II transmembrane protein containing the BRICHOS domain. The gene was isolated as a heat-sensitive mutant, but the function of the protein remained unclear. We examined the expression pattern and subcellular localization of C09F5.1 as well as its roles in thermotolerance and chaperone function. Expression of C09F5.1 under heat shock conditions was induced in a heat shock factor 1 (HSF-1) dependent manner. However, under normal growth conditions, most cells types exposed to mechanical stimuli expressed C09F5.1. Knockdown of C09F5.1 expression or deletion of the N-terminal domain decreased thermotolerance. The BRICHOS domain of C09F5.1 did not exhibit chaperone function unlike those of other proteins containing this domain, but the domain was essential for the proper subcellular localization of the protein. Intact C09F5.1 was localized to the Golgi body, but the N-terminal domain of C09F5.1 (C09F5.1-NTD) was retained in the ER. C09F5.1-NTD delayed paralysis by beta-amyloid (1-42) protein (Abeta42) in Alzheimer's disease model worms (CL4176) and activated the unfolded protein response (UPR) by interacting with Abeta42. An intrinsically disordered region (IDR) located at the N-terminus of C09F5.1 may be responsible for the chaperone function of C09F5.1-NTD. Taken together, the data suggest that C09F5.1 triggers the UPR by interacting with abnormal proteins. PMID- 29534050 TI - Alternative Splicing in the Hippo Pathway-Implications for Disease and Potential Therapeutic Targets. AB - Alternative splicing is a well-studied gene regulatory mechanism that produces biological diversity by allowing the production of multiple protein isoforms from a single gene. An involvement of alternative splicing in the key biological signalling Hippo pathway is emerging and offers new therapeutic avenues. This review discusses examples of alternative splicing in the Hippo pathway, how deregulation of these processes may contribute to disease and whether these processes offer new potential therapeutic targets. PMID- 29534047 TI - Seasonal Reproduction in Vertebrates: Melatonin Synthesis, Binding, and Functionality Using Tinbergen's Four Questions. AB - One of the many functions of melatonin in vertebrates is seasonal reproductive timing. Longer nights in winter correspond to an extended duration of melatonin secretion. The purpose of this review is to discuss melatonin synthesis, receptor subtypes, and function in the context of seasonality across vertebrates. We conclude with Tinbergen's Four Questions to create a comparative framework for future melatonin research in the context of seasonal reproduction. PMID- 29534051 TI - VdPLP, A Patatin-Like Phospholipase in Verticillium dahliae, Is Involved in Cell Wall Integrity and Required for Pathogenicity. AB - The soil-borne ascomycete fungus Verticillium dahliae causes vascular wilt disease and can seriously diminish the yield and quality of important crops. Functional analysis of growth- and pathogenicity-related genes is essential for revealing the pathogenic molecular mechanism of V. dahliae. Phospholipase is an important virulence factor in fungi that hydrolyzes phospholipids into fatty acid and other lipophilic substances and is involved in hyphal development. Thus far, only a few V. dahliae phospholipases have been identified, and their involvement in V. dahliae development and pathogenicity remains unknown. In this study, the function of the patatin-like phospholipase gene in V. dahliae (VdPLP, VDAG_00942) is characterized by generating gene knockout and complementary mutants. Vegetative growth and conidiation of VdPLP deletion mutants (DeltaVdPLP) were significantly reduced compared with wild type and complementary strains, but more microsclerotia formed. The DeltaVdPLP mutants were very sensitive to the cell wall-perturbing agents: calcofluor white (CFW) and Congo red (CR). The transcriptional level of genes related to the cell wall integrity (CWI) pathway and chitin synthesis were downregulated, suggesting that VdPLP has a pivotal role in the CWI pathway and chitin synthesis in V. dahliae. DeltaVdPLP strains were distinctly impaired in in their virulence and ability to colonize Nicotiana benthamiana roots. Our results demonstrate that VdPLP regulates hyphal growth and conidial production and is involved in stabilizing the cell wall, thus mediating the pathogenicity of V. dahliae. PMID- 29534052 TI - Estimation of Fine and Oversize Particle Ratio in a Heterogeneous Compound with Acoustic Emissions. AB - The final phase of powder production typically involves a mixing process where all of the particles are combined and agglomerated with a binder to form a single compound. The traditional means of inspecting the physical properties of the final product involves an inspection of the particle sizes using an offline sieving and weighing process. The main downside of this technique, in addition to being an offline-only measurement procedure, is its inability to characterise large agglomerates of powders due to sieve blockage. This work assesses the feasibility of a real-time monitoring approach using a benchtop test rig and a prototype acoustic-based measurement approach to provide information that can be correlated to product quality and provide the opportunity for future process optimisation. Acoustic emission (AE) was chosen as the sensing method due to its low cost, simple setup process, and ease of implementation. The performance of the proposed method was assessed in a series of experiments where the offline quality check results were compared to the AE-based real-time estimations using data acquired from a benchtop powder free flow rig. A designed time domain based signal processing method was used to extract particle size information from the acquired AE signal and the results show that this technique is capable of estimating the required ratio in the washing powder compound with an average absolute error of 6%. PMID- 29534054 TI - A Comprehensive Review on the Medicinal Plants from the Genus Asphodelus. AB - Abstract: Plant-based systems continue to play an essential role in healthcare, and their use by different cultures has been extensively documented. Asphodelus L. (Asphodelaceae) is a genus of 18 species and of a total of 27 species, sub species and varieties, distributed along the Mediterranean basin, and has been traditionally used for treating several diseases particularly associated with inflammatory and infectious skin disorders. The present study aimed to provide a general review of the available literature on ethnomedical, phytochemical, and biological data related to the genus Asphodelus as a potential source of new compounds with biological activity. Considering phytochemical studies, 1,8 dihydroxyanthracene derivatives, flavonoids, phenolic acids and triterpenoids were the main classes of compounds identified in roots, leaf and seeds which were correlated with their biological activities as anti-microbial, anti-fungal, anti parasitic, cytotoxic, anti-inflammatory or antioxidant agents. PMID- 29534053 TI - Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of The-Art and Current Perspectives. AB - Minimally invasive continuous glucose monitoring (CGM) sensors are wearable medical devices that provide real-time measurement of subcutaneous glucose concentration. This can be of great help in the daily management of diabetes. Most of the commercially available CGM devices have a wire-based sensor, usually placed in the subcutaneous tissue, which measures a "raw" current signal via a glucose-oxidase electrochemical reaction. This electrical signal needs to be translated in real-time to glucose concentration through a calibration process. For such a scope, the first commercialized CGM sensors implemented simple linear regression techniques to fit reference glucose concentration measurements periodically collected by fingerprick. On the one hand, these simple linear techniques required several calibrations per day, with the consequent patient's discomfort. On the other, only a limited accuracy was achieved. This stimulated researchers to propose, over the last decade, more sophisticated algorithms to calibrate CGM sensors, resorting to suitable signal processing, modelling, and machine-learning techniques. This review paper will first contextualize and describe the calibration problem and its implementation in the first generation of CGM sensors, and then present the most recently-proposed calibration algorithms, with a perspective on how these new techniques can influence future CGM products in terms of accuracy improvement and calibration reduction. PMID- 29534055 TI - Evaluation of a Sensor System for Detecting Humans Trapped under Rubble: A Pilot Study. AB - Rapid localization of injured survivors by rescue teams to prevent death is a major issue. In this paper, a sensor system for human rescue including three different types of sensors, a CO2 sensor, a thermal camera, and a microphone, is proposed. The performance of this system in detecting living victims under the rubble has been tested in a high-fidelity simulated disaster area. Results show that the CO2 sensor is useful to effectively reduce the possible concerned area, while the thermal camera can confirm the correct position of the victim. Moreover, it is believed that the use of microphones in connection with other sensors would be of great benefit for the detection of casualties. In this work, an algorithm to recognize voices or suspected human noise under rubble has also been developed and tested. PMID- 29534056 TI - Microporosity and CO2 Capture Properties of Amorphous Silicon Oxynitride Derived from Novel Polyalkoxysilsesquiazanes. AB - Polyalkoxysilsesquiazanes ([ROSi(NH)1.5]n, ROSZ, R = Et, nPr, iPr, nBu, sBu, nHex, sHex, cHex, decahydronaphthyl (DHNp)) were synthesized by ammonolysis at 78 degrees C of alkoxytrichlorosilane (ROSiCl3), which was isolated by distillation as a reaction product of SiCl4 and ROH. The simultaneous thermogravimetric and mass spectrometry analyses of the ROSZs under helium revealed a common decomposition reaction, the cleavage of the oxygen-carbon bond of the RO group to evolve alkene as a main gaseous species formed in-situ, leading to the formation of microporous amorphous Si-O-N at 550 degrees C to 800 degrees C. The microporosity in terms of the peak of the pore size distribution curve located within the micropore size range (<2 nm) and the total micropore volume, as well as the specific surface area (SSA) of the Si-O-N, increased consistently with the molecular size estimated for the alkene formed in-situ during the pyrolysis. The CO2 capture capacity at 0 degrees C of the Si-O-N material increased consistently with its SSA, and an excellent CO2 capture capacity of 3.9 mmol.g-1 at 0 degrees C and CO2 1 atm was achieved for the Si-O N derived from DHNpOSZ having an SSA of 750 m2.g-1. The CO2 capture properties were further discussed based on their temperature dependency, and a surface functional group of the Si-O-N formed in-situ during the polymer/ceramics thermal conversion. PMID- 29534057 TI - Cytokine, C-Reactive Protein, and Heat Shock Protein mRNA Expression Levels in Patients with Active Behcet's Uveitis. AB - BACKGROUND To investigate the gene expression levels of interleukin 10 (IL10), IL18, interferon gamma (IFNG), IFN-gamma receptor (IFNGR), C-reactive protein (CRP), and heat shock protein 70 (HSP70) in patients with active Behcet's uveitis. MATERIAL AND METHODS Forty patients with Behcet's disease diagnosed according to the International Study Group criteria and 30 healthy individuals were included in the study. IL10, IL18, IFNG, IFNGR, CRP, and HSP70 gene expression levels were compared. RESULTS Expression levels of IL18, IFNG, IFNGR, and CRP were significantly higher in patients with active Behcet's uveitis than in control subjects (P<0.01 for all), whereas no significant differences were found in IL10 and HSP70 gene expression levels (P>0.01 for both). CONCLUSIONS IL18, IFNG, IFNGR, and CRP gene expression is significantly increased in active Behcet's uveitis. There was no significant difference between active Behcet's uveitis patients and controls in terms of IL10 and HSP70 gene expression levels. We conclude that drugs prescribed to Behcet's patients with active uveitis downregulate gene expression. PMID- 29534058 TI - Pediatric patients at risk for fever in chemotherapy-induced neutropenia in Bern, Switzerland, 1993-2012. AB - Fever in neutropenia (FN) is the most frequent potentially life threatening complication of chemotherapy for cancer. Prediction of the risk to develop FN during chemotherapy would allow for targeted prophylaxis. This retrospective, single centre cohort study in pediatric patients diagnosed with cancer before 17 years covered two decades, 1993 to 2012. The 583 (73%) of 800 patients diagnosed with cancer who had received chemotherapy were studied here. Data on 2113 observation periods was collected, defined by stable combinations of 11 predefined characteristics potentially associated with FN. They covered 692 years of cumulative chemotherapy exposure time, during which 712 FN episodes were diagnosed, 154 (22%) of them with bacteremia. The risk to develop FN and FN with bacteremia remained stable over time. These data can mainly be used to study FN risks over time and between centers, and to derive or externally validate FN risk prediction rules. PMID- 29534059 TI - Late Maastrichtian pterosaurs from North Africa and mass extinction of Pterosauria at the Cretaceous-Paleogene boundary. AB - Pterosaurs were the first vertebrates to evolve powered flight and the largest animals to ever take wing. The pterosaurs persisted for over 150 million years before disappearing at the end of the Cretaceous, but the patterns of and processes driving their extinction remain unclear. Only a single family, Azhdarchidae, is definitively known from the late Maastrichtian, suggesting a gradual decline in diversity in the Late Cretaceous, with the Cretaceous Paleogene (K-Pg) extinction eliminating a few late-surviving species. However, this apparent pattern may simply reflect poor sampling of fossils. Here, we describe a diverse pterosaur assemblage from the late Maastrichtian of Morocco that includes not only Azhdarchidae but the youngest known Pteranodontidae and Nyctosauridae. With 3 families and at least 7 species present, the assemblage represents the most diverse known Late Cretaceous pterosaur assemblage and dramatically increases the diversity of Maastrichtian pterosaurs. At least 3 families-Pteranodontidae, Nyctosauridae, and Azhdarchidae-persisted into the late Maastrichtian. Late Maastrichtian pterosaurs show increased niche occupation relative to earlier, Santonian-Campanian faunas and successfully outcompeted birds at large sizes. These patterns suggest an abrupt mass extinction of pterosaurs at the K-Pg boundary. PMID- 29534060 TI - Meta-research: Why research on research matters. AB - Meta-research is the study of research itself: its methods, reporting, reproducibility, evaluation, and incentives. Given that science is the key driver of human progress, improving the efficiency of scientific investigation and yielding more credible and more useful research results can translate to major benefits. The research enterprise grows very fast. Both new opportunities for knowledge and innovation and new threats to validity and scientific integrity emerge. Old biases abound, and new ones continuously appear as novel disciplines emerge with different standards and challenges. Meta-research uses an interdisciplinary approach to study, promote, and defend robust science. Major disruptions are likely to happen in the way we pursue scientific investigation, and it is important to ensure that these disruptions are evidence based. PMID- 29534061 TI - Socioeconomic benefit to individuals of achieving 2020 targets for four neglected tropical diseases controlled/eliminated by innovative and intensified disease management: Human African trypanosomiasis, leprosy, visceral leishmaniasis, Chagas disease. AB - BACKGROUND: The control or elimination of neglected tropical diseases (NTDs) has targets defined by the WHO for 2020, reinforced by the 2012 London Declaration. We estimated the economic impact to individuals of meeting these targets for human African trypanosomiasis, leprosy, visceral leishmaniasis and Chagas disease, NTDs controlled or eliminated by innovative and intensified disease management (IDM). METHODS: A systematic literature review identified information on productivity loss and out-of-pocket payments (OPPs) related to these NTDs, which were combined with projections of the number of people suffering from each NTD, country and year for 2011-2020 and 2021-2030. The ideal scenario in which the WHO's 2020 targets are met was compared with a counterfactual scenario that assumed the situation of 1990 stayed unaltered. Economic benefit equaled the difference between the two scenarios. Values are reported in 2005 US$, purchasing power parity-adjusted, discounted at 3% per annum from 2010. Probabilistic sensitivity analyses were used to quantify the degree of uncertainty around the base-case impact estimate. RESULTS: The total global productivity gained for the four IDM-NTDs was I$ 23.1 (I$ 15.9 -I$ 34.0) billion in 2011-2020 and I$ 35.9 (I$ 25.0 -I$ 51.9) billion in 2021-2030 (2.5th and 97.5th percentiles in brackets), corresponding to US$ 10.7 billion (US$ 7.4 -US$ 15.7) and US$ 16.6 billion (US$ 11.6 -US$ 24.0). Reduction in OPPs was I$ 14 billion (US$ 6.7 billion) and I$ 18 billion (US$ 10.4 billion) for the same periods. CONCLUSIONS: We faced important limitations to our work, such as finding no OPPs for leprosy. We had to combine limited data from various sources, heterogeneous background, and of variable quality. Nevertheless, based on conservative assumptions and subsequent uncertainty analyses, we estimate that the benefits of achieving the targets are considerable. Under plausible scenarios, the economic benefits far exceed the necessary investments by endemic country governments and their development partners. Given the higher frequency of NTDs among the poorest households, these investments represent good value for money in the effort to improve well-being, distribute the world's prosperity more equitably and reduce inequity. PMID- 29534062 TI - Early uneven ear input induces long-lasting differences in left-right motor function. AB - How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input. PMID- 29534063 TI - A clinical decision support tool for improving adherence to guidelines on anticoagulant therapy in patients with atrial fibrillation at risk of stroke: A cluster-randomized trial in a Swedish primary care setting (the CDS-AF study). AB - BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains significant undertreatment. The main aim of the current study was to investigate whether a clinical decision support tool (CDS) for stroke prevention integrated in the electronic health record could improve adherence to guidelines for stroke prevention in patients with AF. METHODS AND FINDINGS: We conducted a cluster-randomized trial where all 43 primary care clinics in the county of Ostergotland, Sweden (population 444,347), were randomized to be part of the CDS intervention or to serve as controls. The CDS produced an alert for physicians responsible for patients with AF and at increased risk for thromboembolism (according to the CHA2DS2-VASc algorithm) without anticoagulant therapy. The primary endpoint was adherence to guidelines after 1 year. After randomization, there were 22 and 21 primary care clinics in the CDS and control groups, respectively. There were no significant differences in baseline adherence to guidelines regarding anticoagulant therapy between the 2 groups (CDS group 70.3% [5,186/7,370; 95% CI 62.9%-77.7%], control group 70.0% [4,187/6,009; 95% CI 60.4%-79.6%], p = 0.83). After 12 months, analysis with linear regression with adjustment for primary care clinic size and adherence to guidelines at baseline revealed a significant increase in guideline adherence in the CDS (73.0%, 95% CI 64.6%-81.4%) versus the control group (71.2%, 95% CI 60.8% 81.6%, p = 0.013, with a treatment effect estimate of 0.016 [95% CI 0.003-0.028]; number of patients with AF included in the final analysis 8,292 and 6,508 in the CDS and control group, respectively). Over the study period, there was no difference in the incidence of stroke, transient ischemic attack, or systemic thromboembolism in the CDS group versus the control group (49 [95% CI 43-55] per 1,000 patients with AF in the CDS group compared to 47 [95% CI 39-55] per 1,000 patients with AF in the control group, p = 0.64). Regarding safety, the CDS group had a lower incidence of significant bleeding, with events in 12 (95% CI 9-15) per 1,000 patients with AF compared to 16 (95% CI 12-20) per 1,000 patients with AF in the control group (p = 0.04). Limitations of the study design include that the analysis was carried out in a catchment area with a high baseline adherence rate, and issues regarding reproducibility to other regions. CONCLUSIONS: The present study demonstrates that a CDS can increase guideline adherence for anticoagulant therapy in patients with AF. Even though the observed difference was small, this is the first randomized study to our knowledge indicating beneficial effects with a CDS in patients with AF. TRIAL REGISTRATION: ClinicalTrials.gov NCT02635685. PMID- 29534064 TI - Validation of a genetic risk score for atrial fibrillation: A prospective multicenter cohort study. AB - BACKGROUND: Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF. METHODS AND FINDINGS: Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27-7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF. CONCLUSIONS: Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT01970969. PMID- 29534066 TI - Progression of diabetes, heart disease, and stroke multimorbidity in middle-aged women: A 20-year cohort study. AB - BACKGROUND: The prevalence of diabetes, heart disease, and stroke multimorbidity (co-occurrence of two or three of these conditions) has increased rapidly. Little is known about how the three conditions progress from one to another sequentially through the life course. We aimed to delineate this progression in middle-aged women and to determine the roles of common risk factors in the accumulation of diabetes, heart disease, and stroke multimorbidity. METHODS AND FINDINGS: We used data from 13,714 women aged 45-50 years without a history of any of the three conditions. They were participants in the Australian Longitudinal Study on Women's Health (ALSWH), enrolled in 1996, and surveyed approximately every 3 years to 2016. We characterized the longitudinal progression of the three conditions and multimorbidity. We estimated the accumulation of multimorbidity over 20 years of follow-up and investigated their association with both baseline and time-varying predictors (sociodemographic factors, lifestyle factors, and other chronic conditions). Over 20 years, 2,511 (18.3%) of the women progressed to at least one condition, of whom 1,420 (56.6%) had diabetes, 1,277 (50.9%) had heart disease, and 308 (12.3%) had stroke; 423 (16.8%) had two or three of these conditions. Over a 3-year period, the age-adjusted odds of two or more conditions was approximately twice that of developing one new condition compared to women who did not develop any new conditions. For example, the odds for developing one new condition between Surveys 7 and 8 were 2.29 (95% confidence interval [CI], 1.93-2.72), whereas the odds for developing two or more conditions was 6.51 (95% CI, 3.95-10.75). The onset of stroke was more strongly associated with the progression to the other conditions (i.e., 23.4% [95% CI, 16.3%-32.2%] of women after first onset of stroke progressed to other conditions, whereas the percentages for diabetes and heart disease were 9.9% [95% CI, 7.9%-12.4%] and 11.4% [95% CI, 9.1%-14.4%], respectively). Being separated, divorced, or widowed; being born outside Australia; having difficulty managing on their available income; being overweight or obese; having hypertension; being physically inactive; being a current smoker; and having prior chronic conditions (i.e., mental disorders, asthma, cancer, osteoporosis, and arthritis) were significantly associated with increased odds of accumulation of diabetes, heart disease, and stroke multimorbidity. The main limitations of this study were the use of self reported data and the low number of events. CONCLUSIONS: Stroke was associated with increased risk of progression to diabetes or heart disease. Social inequality, obesity, hypertension, physical inactivity, smoking, or having other chronic conditions were also significantly associated with increased odds of accumulating multimorbidity. Our findings highlight the importance of awareness of the role of diabetes, heart disease, and stroke multimorbidity among middle aged women for clinicians and health-promotion agencies. PMID- 29534065 TI - MicroRNA Signatures for circulating CD133-positive cells in hepatocellular carcinoma with HCV infection. AB - AIM: Molecular characterization of the CD133+ stem cells associated with hepatocarinogensis through identifying the expression patterns of specific microRNAs (miRNAs). METHODS: We investigated the expression pattern of 13 miRNAs in purified CD133+ cells separated from the peripheral blood of healthy volunteers, chronic hepatitis C (CHC), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) patients a long with bone marrow samples from the healthy volunteers and the LC patients using custom miScript miRNA PCR array. RESULTS: The differential expression of the 13 studied miRNAs in CD133+ cells separated from the HCC patients' peripheral blood compared to the controls revealed that miR-602, miR-181b, miR-101, miR-122, miR-192, miR-125a-5p, and miR-221 were significantly up regulated (fold change = 1.8, 1.7, 2, 5.4, 1.6, 2.9 & 1.5 P value = 0.039, 0.0019, 0.0013, 0.0370, 00024, 0.000044 &0.000007 respectively). As for the HCC group compared to the CHC group; miR-602, miR-122, miR-181b, miR 125a-5p, and miR-192 were significantly up regulated (fold change = 13, 3.1, 2.8, 1.6 & 1.56, P value = 0.01, 0.001, 0.000004, 0.002 & 0.007 respectively). Upon comparing the HCC group to the LC group; miR-199a-3p, miR-192, miR-122, miR-181b, miR-224, miR-125a-5p, and miR-885-5p were significantly up regulated (fold change = 5, 6.7, 2.3, 3, 2.5, 4.2 & 39.5 P value = 0.001025, 0.000024, 0.000472, 0.000278, 0.000004, 0.000075 & 0.0000001 respectively) whereas miR-22 was significantly down regulated (fold change = 0.57 P value = 0.00002). Only, miR 192, miR-122, miR-181b and miR-125a-5p were significant common miRNAs in CD133+ cells of the HCC group compared to the other non-malignant groups. CONCLUSION: We identified a miRNA panel comprised of four miRNAs (miR-192, miR-122, miR-181b and miR-125a-5p) that may serve as a molecular tool for characterization of the CD133+ cells associated with different stages of hepatocarinogensis. This panel may aid in developing a new target therapy specific for those CD133+ cells. PMID- 29534067 TI - The importance and challenges of shared decision making in older people with multimorbidity. AB - In a Perspective, Tammy Hoffmann and colleagues discuss medical decision making for elderly patients with multimorbidity. PMID- 29534068 TI - The effect of S100A6 on nuclear translocation of CacyBP/SIP in colon cancer cells. AB - BACKGROUND: Calcyclin Binding Protein/(Siah-1 interacting protein) (CacyBP/SIP) acts as an oncogene in colorectal cancer. The nuclear accumulation of CacyBP/SIP has been linked to the proliferation of cancer cells. It has been reported that intracellular Ca2+ induces the nuclear translocation of CacyBP/SIP. However, the molecular mechanism of CacyBP/SIP nuclear translocation has yet to be elucidated. The purpose of this study was to test whether the Ca2+-dependent binding partner S100 protein is involved in CacyBP/SIP nuclear translocation in colon cancer SW480 cells. METHODS: The subcellular localization of endogenous CacyBP/SIP was observed following the stimulation of ionomycin or BAPTA/AM by immunofluorescence staining in SW480 cells. S100A6 small interfering RNAs (siRNA) were transfected into SW480 cells. Immunoprecipitation assays detected whether S100 protein is relevant to the nuclear translocation of CacyBP/SIP in response to changes in [Ca2+]i. RESULTS: We observed that endogenous CacyBP/SIP is translocated from the cytosol to the nucleus following the elevation of [Ca2+]i by ionomycin in SW480 cells. Co-immunoprecipitation experiments showed that the interaction between S100A6 and CacyBP/SIP was increased simultaneously with elevated Ca2+. Knockdown of S100A6 abolished the Ca2+ effect on the subcellular translocation of CacyBP/SIP. CONCLUSION: Thus, we demonstrated that S100A6 is required for the Ca2+-dependent nuclear translocation of CacyBP/SIP in colon cancer SW480 cells. PMID- 29534069 TI - PRISM: An open source framework for the interactive design of GPU volume rendering shaders. AB - Direct volume rendering has become an essential tool to explore and analyse 3D medical images. Despite several advances in the field, it remains a challenge to produce an image that highlights the anatomy of interest, avoids occlusion of important structures, provides an intuitive perception of shape and depth while retaining sufficient contextual information. Although the computer graphics community has proposed several solutions to address specific visualization problems, the medical imaging community still lacks a general volume rendering implementation that can address a wide variety of visualization use cases while avoiding complexity. In this paper, we propose a new open source framework called the Programmable Ray Integration Shading Model, or PRISM, that implements a complete GPU ray-casting solution where critical parts of the ray integration algorithm can be replaced to produce new volume rendering effects. A graphical user interface allows clinical users to easily experiment with pre-existing rendering effect building blocks drawn from an open database. For programmers, the interface enables real-time editing of the code inside the blocks. We show that in its default mode, the PRISM framework produces images very similar to those produced by a widely-adopted direct volume rendering implementation in VTK at comparable frame rates. More importantly, we demonstrate the flexibility of the framework by showing how several volume rendering techniques can be implemented in PRISM with no more than a few lines of code. Finally, we demonstrate the simplicity of our system in a usability study with 5 medical imaging expert subjects who have none or little experience with volume rendering. The PRISM framework has the potential to greatly accelerate development of volume rendering for medical applications by promoting sharing and enabling faster development iterations and easier collaboration between engineers and clinical personnel. PMID- 29534070 TI - The effects of self-efficacy enhancing program on foot self-care behaviour of older adults with diabetes: A randomised controlled trial in elderly care facility, Peninsular Malaysia. AB - BACKGROUND: Self-care behaviour is essential in preventing diabetes foot problems. This study aimed to evaluate the effectiveness of health education programs based on the self-efficacy theory on foot self-care behaviour for older adults with diabetes. METHODS: A randomised controlled trial was conducted for 12 weeks among older adults with diabetes in elderly care facility in Peninsular Malaysia. Six elderly care facility were randomly allocated by an independent person into two groups (intervention and control). The intervention group (three elderly care facility) received a health education program on foot self-care behaviour while the control group (three elderly care facility) received standard care. Participants were assessed at baseline, and at week-4 and week-12 follow ups. The primary outcome was foot-self-care behaviour. Foot care self-efficacy (efficacy expectation), foot care outcome expectation, knowledge of foot care and quality of life were the secondary outcomes. Data were analysed with Mixed Design Analysis of Variance using the Statistical Package for the Social Sciences version 22.0. RESULTS: 184 respondents were recruited but only 76 met the selection criteria and were included in the analysis. Foot self-care behaviour, foot care self-efficacy (efficacy expectation), foot care outcome expectation and knowledge of foot care improved in the intervention group compared to the control group (p < 0.05). However, some of these improvements did not significantly differ compared to the control group for QoL physical symptoms and QoL psychosocial functioning (p > 0.05). CONCLUSION: The self-efficacy enhancing program improved foot self-care behaviour with respect to the delivered program. It is expected that in the future, the self-efficacy theory can be incorporated into diabetes education to enhance foot self-care behaviour for elderly with diabetes living in other institutional care facilities. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12616000210471. PMID- 29534071 TI - Anthracycline antibiotics derivate mitoxantrone-Destructive sorption and photocatalytic degradation. AB - Nanostructured titanium(IV) oxide was used for the destructive adsorption and photocatalytic degradation of mitoxantrone (MTX), a cytostatic drug from the group of anthracycline antibiotics. During adsorption on a titania dioxide surface, four degradation products of MTX, mitoxantrone dicarboxylic acid, 1,4 dihydroxy-5-((2-((2-hydroxyethyl)amino)ethyl)amino)-8-((2 (methylamino)ethyl)amino)anthracene-9,10-dione, 1,4-dihydroxy-5,8 diiminoanthracene-9,10(5H,8H)-dione and 1,4-dihydroxy-5-imino-8 (methyleneamino)anthracene-9,10(5H,8H)-dione, were identified. In the case of photocatalytic degradation, only one degradation product after 15 min at m/z 472 was identified. This degradation product corresponded to mitoxantrone dicarboxylic acid, and complete mineralization was attained in one hour. Destructive adsorbent manganese(IV) oxide, MnO2, was used only for the destructive adsorption of MTX. Destructive adsorption occurred only for one degradation product, mitoxantrone dicarboxylic acid, against anatase TiO2. PMID- 29534072 TI - A field survey using LAMP assay for detection of Schistosoma mansoni in a low transmission area of schistosomiasis in Umbuzeiro, Brazil: Assessment in human and snail samples. AB - BACKGROUND: In Brazil, schistosomiasis is a parasitic disease of public health relevance, mainly in poor areas where Schistosoma mansoni is the only human species encountered and Biomphalaria straminea is one of the intermediate host snails. A nested-PCR based on a specific mitochondrial S. mansoni minisatellite DNA region has been successfully developed and applied as a reference method in Brazil for S. mansoni detection, mainly in host snails for epidemiological studies. The amplification efficiency of LAMP is known to be higher than PCR. The present work aimed to assess the utility of our previously described SmMIT-LAMP assay for S. mansoni detection in human stool and snail samples in a low transmission area of schistosomiasis in the municipality of Umbuzeiro, Paraiba State, Northeast Region of Brazil. METHODOLOGY/PRINCIPAL FINDINGS: A total of 427 human stool samples were collected during June-July 2016 in the municipality of Umbuzeiro and an overall prevalence of 3.04% (13/427) resulted positive by duplicate Kato-Katz thick smear. A total of 1,175 snails identified as Biomphalaria straminea were collected from 14 breeding sites along the Paraiba riverbank and distributed in 46 pools. DNA from human stool samples and pooled snails was extracted using the phenol/chloroform method. When performing the SmMIT-LAMP assay a total of 49/162 (30.24%) stool samples resulted positive, including 12/13 (92.31%) that were Kato-Katz positive and 37/149 (24.83%) previously Kato-Katz negative. By nested-PCR, only 1/46 pooled DNA snail samples was positive. By SmMIT-LAMP assay, the same sample also resulted positive and an additional one was positive from a different breeding site. Data of human and snail surveys were used to build risk maps of schistosomiasis incidence using kernel density analysis. CONCLUSIONS/SIGNIFICANCE: This is the first study in which a LAMP assay was evaluated in both human stool and snail samples from a low transmission schistosomiasis-endemic area. Our SmMIT-LAMP proved to be much more efficient in detection of S. mansoni in comparison to the 'gold standard' Kato Katz method in human stool samples and the reference molecular nested-PCR in snails. The SmMIT-LAMP has demonstrated to be a useful molecular tool to identify potential foci of transmission in order to build risk maps of schistosomiasis. PMID- 29534073 TI - Deficiency of liver-derived insulin-like growth factor-I (IGF-I) does not interfere with the skin wound healing rate. AB - OBJECTIVE: IGF-I is a growth factor, which is expressed in virtually all tissues. The circulating IGF-I is however derived mainly from the liver. IGF-I promotes wound healing and its levels are decreased in wounds with low regenerative potential such as diabetic wounds. However, the contribution of circulating IGF-I to wound healing is unknown. Here we investigated the role of systemic IGF-I on wound healing rate in mice with deficiency of liver-derived IGF-I (LI-IGF-I-/- mice) during normal (normoglycemic) and impaired wound healing (diabetes). METHODS: LI-IGF-I-/- mice with complete inactivation of the IGF-I gene in the hepatocytes were generated using the Cre/loxP recombination system. This resulted in a 75% reduction of circulating IGF-I. Diabetes was induced with streptozocin in both LI-IGF-I-/- and control mice. Wounds were made on the dorsum of the mice, and the wound healing rate and histology were evaluated. Serum IGF-I and GH were measured by RIA and ELISA respectively. The expression of IGF-I, IGF-II and the IGF-I receptor in the skin were evaluated by qRT-PCR. The local IGF-I protein expression in different cell types of the wounds during wound healing process was analyzed using immunohistochemistry. RESULTS: The wound healing rate was similar in LI-IGF-I-/- mice to that in controls. Diabetes significantly delayed the wound healing rate in both LI-IGF-I-/- and control mice. However, no significant difference was observed between diabetic animals with normal or reduced hepatic IGF-I production. The gene expression of IGF-I, IGF-II and IGF-I receptor in skin was not different between any group of animals tested. Local IGF-I levels in the wounds were similar between of LI-IGF-I-/- and WT mice although a transient reduction of IGF-I expression in leukocytes in the wounds of LI-IGF-I-/- was observed seven days post wounding. CONCLUSION: Deficiency in the liver-derived IGF-I does not affect wound healing in mice, neither in normoglycemic conditions nor in diabetes. PMID- 29534074 TI - Chemokine expression in the early response to injury in human airway epithelial cells. AB - Basal airway epithelial cells (AEC) constitute stem/progenitor cells within the central airways and respond to mucosal injury in an ordered sequence of spreading, migration, proliferation, and differentiation to needed cell types. However, dynamic gene transcription in the early events after mucosal injury has not been studied in AEC. We examined gene expression using microarrays following mechanical injury (MI) in primary human AEC grown in submersion culture to generate basal cells and in the air-liquid interface to generate differentiated AEC (dAEC) that include goblet and ciliated cells. A select group of ~150 genes was in differential expression (DE) within 2-24 hr after MI, and enrichment analysis of these genes showed over-representation of functional categories related to inflammatory cytokines and chemokines. Network-based gene prioritization and network reconstruction using the PINTA heat kernel diffusion algorithm demonstrated highly connected networks that were richer in differentiated AEC compared to basal cells. Similar experiments done in basal AEC collected from asthmatic donor lungs demonstrated substantial changes in DE genes and functional categories related to inflammation compared to basal AEC from normal donors. In dAEC, similar but more modest differences were observed. We demonstrate that the AEC transcription signature after MI identifies genes and pathways that are important to the initiation and perpetuation of airway mucosal inflammation. Gene expression occurs quickly after injury and is more profound in differentiated AEC, and is altered in AEC from asthmatic airways. Our data suggest that the early response to injury is substantially different in asthmatic airways, particularly in basal airway epithelial cells. PMID- 29534075 TI - Association between TERT rs2853669 polymorphism and cancer risk: A meta-analysis of 9,157 cases and 11,073 controls. AB - BACKGROUND: It has been reported that the functional telomerase reverse transcriptase (TERT) rs2853669 polymorphism might contribute to different types of human cancer. However, the association of this mutation with cancer remains controversial. Here, we conducted a meta-analysis to characterize this relationship. MATERIALS AND METHODS/MAIN RESULTS: A systematic search of studies on the association of TERT rs2853669 polymorphism with all types of cancer was conducted in PubMed, Embase and Cochrane Library. The summary odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were used to pool the effect size in a fixed-effects model or a random-effects model where appropriate. A total of 13 articles and 15 case-control studies, including 9,157 cases and 11,073 controls, were included in this meta-analysis. Overall, the pooled results indicated that the rs2853669 polymorphism was significantly associated with increased cancer risk in a homozygote comparison model (CT vs. TT: OR = 1.085, 95% CI: 1.015-1.159, P = 0.016). In the stratified analyses, a significant increased cancer risk was observed in Asian, but not Caucasian patients. A subgroup analysis by cancer type also revealed a significant increase in the risk of lung cancer, but not breast cancer. CONCLUSIONS: The results of this meta analysis suggest that the TERT rs2853669 polymorphism is associated with a significantly increased risk of cancer, particularly lung cancer, in Asian populations. PMID- 29534076 TI - Excess mortality and hospitalizations in transitional-age youths with a long-term disease: A national population-based cohort study. AB - INTRODUCTION: The number of adolescents with a severe chronic disease has increased in high-income countries due to improvements in the prognosis of childhood-onset chronic conditions. The transition from childhood to adulthood is a critical period that may be associated with increased mortality and morbidity. We aimed to estimate the prevalence of adolescents with a long-term disease (LTD) in France and assess their mortality and hospitalization risks relative to the general population. MATERIALS AND METHODS: We extracted a population-based cohort from the French national health insurance database that included 61,119 subjects who reached 14 years of age between 2005 and 2014. LTDs are diagnosed by patients' physicians and then confirmed and registered by a physician of the national health insurance system. We assessed mortality and hospitalizations using data of patients who were between 14 and 21 years-old. RESULTS: Among 14 year-old adolescents, 3.30% (95% confidence interval: 3.16-3.44) had a LTD. Their mortality rate between the ages of 14 and 21 years was 20.9/10,000 person-years (13.7-32.1) versus 1.9 (1.5-2.5) for adolescents without a LTD. Mortality was higher in males than females in youths without a LTD, but not in those with a LTD. We found a similar pattern for the risk of hospitalization for an external cause. The five-year probability of hospitalization was 61.8% among youths with a LTD versus 42.7% for those without. The rate of planned hospitalizations sharply fell at 19 years-of-age among youths with a LTD, whereas the rate of unplanned hospitalizations remained stable. CONCLUSION: The 3% of youths with a LTD have ten-fold higher mortality than those without and a high risk of hospitalization. The decrease in the rate of planned hospitalizations at age 19 among youths with a LTD may indicate differences in medical practice after transfer to adult care or a break in medical care. PMID- 29534077 TI - HIV testing in a South African Emergency Department: A missed opportunity. AB - BACKGROUND: South Africa has the largest HIV epidemic in the world, with 19% of the global number of people living with HIV, 15% of new infections and 11% of AIDS-related deaths. Even though HIV testing is mandated in all hospital-based facilities in South Africa (SA), it is rarely implemented in the Emergency Department (ED). The ED provides episodic care to large volumes of undifferentiated who present with unplanned injury or illness. Thus, the ED may provide an opportunity to capture patients with undiagnosed HIV infection missed by clinic-based screening programs. METHODS AND FINDINGS: In this prospective exploratory study, we implemented the National South African HIV testing guidelines (counselor initiated non-targeted universal screening with rapid point of care testing) for 24-hours a day at Frere Hospital in the Eastern Cape from September 1st to November 30th, 2016. The purpose of our study was to quantify the burden of undiagnosed HIV infection in a South African ED setting. Furthermore, we sought to evaluate the effectiveness of the nationally recommended HIV testing strategy in the ED. All patients who presented for care in the ED during the study period, and who were clinically stable and fully conscious, were eligible to be approached by HIV counseling and testing (HCT) staff to receive a rapid point-of-care HIV test. A total of 2355 of the 9583 (24.6%) patients who presented to the ED for care during the study period were approached by the HCT staff, of whom 1714 (72.8%) accepted HIV testing. There was a high uptake of HIV testing (78.6%) among a predominantly male (58%) patient group who mostly presented with traumatic injuries (70.8%). Four hundred (21.6%) patients were HIV positive, including 115 (6.2%) with newly diagnosed HIV infection. The overall prevalence of HIV infection was twice as high in females (29.8%) compared to males (15.4%). Both sexes had a similar prevalence of newly diagnosed HIV infection (6.0% for all females and 6.4% for all males) in the ED. CONCLUSIONS: Overall there was high HIV testing acceptance by ED patients. A non targeted testing approached revealed a high HIV prevalence with a significant burden of undiagnosed HIV infection in the ED. Unfortunately, a counselor-driven HIV testing approach fell short of meeting the testing needs in this setting, with over 75% of ED patients not approached by HCT staff. PMID- 29534078 TI - The use of the vaccinia virus complement control protein (VCP) in the rat retina. AB - The complement system is highly implicated in both the prevalence and progression of Age-Related Macular Degeneration (AMD). Complement system inhibitors therefore have potential therapeutic value in managing excessive activation of the complement pathways in retinal degenerations. The vaccinia virus complement control protein (VCP) has been shown to be effective as a complement inhibitor in neuroinflammatory models including traumatic brain injury and spinal cord injury. We aimed to investigate the potential of VCP as a therapeutic molecule for retinal degenerations. In this study, we investigated the effect, localisation and delivery of VCP to the rodent retina. Complement inhibition activity of VCP was tested using a hemolytic assay. Photoreceptor cell death, inflammation and retinal stress were assayed to determine if any retinal toxicity was induced by an intravitreal injection of VCP. The effect of VCP was investigated in a model of photo-oxidative retinal degeneration. Localisation of VCP after injection was determined using a fluorescein-tagged form of VCP, as well as immunohistochemistry. Finally, a copolymer resin (Elvax) was trialled for the slow-release delivery of VCP to the retina. We found that a dose equivalent to 20MUg VCP when intravitreally injected into the rat eye did not cause any photoreceptor cell death or immune cell recruitment, but led to an increase in GFAP. In photo-oxidative damaged retinas, there were no differences in photoreceptor loss, retinal stress (Gfap) and inflammation (Ccl2 and C3) between VCP and saline-injected groups; however, Jun expression was reduced in VCP treated retinas. After VCP was injected into the eye, it was taken up in all layers of the retina but was cleared within 1-3 hours of delivery. This study indicates that a method to sustain the delivery of VCP to the retina is necessary to further investigate the effect of VCP as a complement inhibitor for retinal degenerations. PMID- 29534079 TI - Administrative data underestimate acute ischemic stroke events and thrombolysis treatments: Data from a multicenter validation survey in Italy. AB - BACKGROUND: Informing health systems and monitoring hospital performances using administrative data sets, mainly hospital discharge data coded according to International-Classification-Diseases-9edition-Clinical-Modifiers (ICD9-CM), is now commonplace in several countries, but the reliability of diagnostic coding of acute ischemic stroke in the routine practice is uncertain. This study aimed at estimating accuracy of ICD9-CM codes for the identification of acute ischemic stroke and the use of thrombolysis treatment comparing hospital discharge data with medical record review in all the six hospitals of the Florence Area, Italy, through 2015. METHODS: We reviewed the medical records of all the 3915 potential acute stroke events during 2015 across the six hospitals of the Florence Area, Italy. We then estimated sensitivity and Positive Predictive Value of ICD9-CM code-groups 433*1, 434*1 and thrombolysis code 99.10 against medical record review with clinical adjudication. For each false-positive case we obtained the actual diagnosis. For each false-negative case we obtained the primary and secondary ICD9-CM diagnoses. RESULTS: The medical record review identified 1273 acute ischemic stroke events. The hospital discharge records identified 898 among those (true-positive cases),but missed 375 events (false-negative cases), and identified 104 events that were not eventually confirmed as acute ischemic events (false-positive cases). Code-group specific Positive Predictive Value was 85.7% (95%CI,74.6-93.3) for 433*1 and 89.9% (95%CI, 87.8-91.7) for 434*1 codes. Thrombolysis treatment, as identified by ICD9-CM code 99.10, was only documented in 6.0% of acute ischemic stroke events, but was 13.6% in medical record review. CONCLUSIONS: Hospital discharge data were found to be fairly specific but insensitive in the reporting of acute ischemic stroke and thrombolysis, providing misleading indications about both quantity and quality of acute ischemic stroke hospital care. Efforts to improve coding accuracy should precede the use of hospital discharge data to measure hospital performances in acute ischemic stroke care. PMID- 29534080 TI - Analysis of explicit model predictive control for path-following control. AB - In this paper, explicit Model Predictive Control(MPC) is employed for automated lane-keeping systems. MPC has been regarded as the key to handle such constrained systems. However, the massive computational complexity of MPC, which employs online optimization, has been a major drawback that limits the range of its target application to relatively small and/or slow problems. Explicit MPC can reduce this computational burden using a multi-parametric quadratic programming technique(mp-QP). The control objective is to derive an optimal front steering wheel angle at each sampling time so that autonomous vehicles travel along desired paths, including straight, circular, and clothoid parts, at high entry speeds. In terms of the design of the proposed controller, a method of choosing weighting matrices in an optimization problem and the range of horizons for path following control are described through simulations. For the verification of the proposed controller, simulation results obtained using other control methods such as MPC, Linear-Quadratic Regulator(LQR), and driver model are employed, and CarSim, which reflects the features of a vehicle more realistically than MATLAB/Simulink, is used for reliable demonstration. PMID- 29534081 TI - Maternal autonomy and birth registration in India: Who gets counted? AB - This paper examines the effect of maternal socio-economic status in the household, such as their autonomy, ability, freedom and bargaining power, on child birth registration in India using the nationally representative India Human Development Survey-II (IHDS-II), 2011-12. We have estimated a multilevel mixed effects model which accounts for the hierarchical structure of the data and allows us to examine the effects of unobserved 'district' and 'community' characteristics along with individual child level characteristics on probability of birth registration. The results show that between-districts and between individuals differences share a considerably high and an almost equal proportion of the variations in probability of birth registration in India. At individual child level, mother's socio-economic status such as her ability to move around independently and her exposure to outside world, significantly raise the probability of birth registration. More importantly, the marginal effects of the maternal autonomy indicators: mother's ability to move around freely and her control over resources, on birth registration vary across districts in India. Other variables such as institutional birth, mother's antenatal care seeking behaviour, caste, religion, household wealth and parental education are significant determinants of birth registration. PMID- 29534082 TI - Differential transcript abundance in adipose tissue of mature beef cows during feed restriction and realimentation. AB - Feed costs account for over 70% of the annual expenditures in cow/calf production. During the production year the cow uses nutrients to support conceptus growth, milk production, work (grazing and locomotion), and maintenance requirements. The majority of the nutrients are used to support maintenance. Substrate cycling has been identified as one of the major contributors toward energy expenditure associated with maintenance in mature cows. The objective of this study was to determine whether beef cows that differ in the efficiency of weight gain differ in the relative abundance of transcripts for metabolic regulation in adipose tissue. Mature beef cows were subjected to feed restriction followed by ad libitum feed. Adipose tissue from twelve cows with high (n = 6) and low (n = 6) gain based on growth performance during the ad libitum feeding period was evaluated for transcriptome expression differences. A total of 496 genes were differentially expressed and passed Bonferroni correction for the animals with greater gain between restriction and realimentation and 491 genes were differentially expressed among animals with lesser gains between feed restriction and realimentation. Of these two differentially expressed gene lists, 144 genes were common between animals with greater and those with lesser gain. Enriched biological processes included the TCA cycle, oxidative phosphorylation, respiratory electron transport chain and fatty acid metabolic processes. Specific to adipose tissue of low gaining animals was glycolysis and to high gain animals was coenzyme, steroid, cellular amino acid, nitrogen compound metabolic processes, and sensory perception. The oxidative phosphorylation, mitochondrial dysfunction and cholesterol biosynthesis pathways were commonly associated with the high gain animals between feed restriction and realimentation, as well as with the low gaining animals between the two time points. Unique to the high gaining animals were valine degradation and LPS/IL-1 mediated inhibition of RXR function pathways. In this discovery study, genes involved in lipid metabolism, mitochondrial respiration and oxidative phosphorylation pathways appear to be critical to mature cows during times of abundant feed after feed restriction. PMID- 29534083 TI - Verifying the validity and reliability of the Japanese version of the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Scale. AB - BACKGROUND: Pediatric patients, especially in the preverbal stage, cannot self report intensity of pain therefore several validated observational tools, including the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Scale, have been used as a benchmark to evaluate pediatric pain. Unfortunately, this scale is currently unavailable in Japanese, precluding its widespread use in Japanese hospitals. OBJECTIVES: To translate and verify the validity and reliability of the Japanese version of the FLACC Behavioral Scale. METHOD: Back translation was first conducted by eight medical researchers, then an available sample of patients at the University of Tsukuba Pediatric Intensive Care Unit (from May 2017 to August 2017) was enrolled in a clinical study. Two researchers evaluated the validity of the translated FLACC Behavioral Scale by weighted kappa coefficient and intraclass correlation coefficients (ICC). Observational pain was simultaneously measured by the visual analog scale (VAS obs) and reliability was evaluated by correlation analysis. RESULT: The original author approved the translation. For the clinical study, a total of 121 observations were obtained from 24 pediatric patients. Agreement between observers was highly correlated for each of the FLACC categories (Face: kappa = 0.85, Leg: kappa = 0.74, Activity: kappa = 0.89, Cry: kappa = 0.93, Consolability: kappa = 0.93) as well as the total score (Total: kappa = 0.95,). Correlation analysis demonstrated a good criterion validation between the FLACC scale and the VAS obs. (r = 0.96). CONCLUSION: Our Japanese version of the FLACC Behavioral Scale shows high validity and reliability. PMID- 29534085 TI - Cryptanalysis and improvement of a biometrics-based authentication and key agreement scheme for multi-server environments. AB - According to advancements in the wireless technologies, study of biometrics-based multi-server authenticated key agreement schemes has acquired a lot of momentum. Recently, Wang et al. presented a three-factor authentication protocol with key agreement and claimed that their scheme was resistant to several prominent attacks. Unfortunately, this paper indicates that their protocol is still vulnerable to the user impersonation attack, privileged insider attack and server spoofing attack. Furthermore, their protocol cannot provide the perfect forward secrecy. As a remedy of these aforementioned problems, we propose a biometrics based authentication and key agreement scheme for multi-server environments. Compared with various related schemes, our protocol achieves the stronger security and provides more functionality properties. Besides, the proposed protocol shows the satisfactory performances in respect of storage requirement, communication overhead and computational cost. Thus, our protocol is suitable for expert systems and other multi-server architectures. Consequently, the proposed protocol is more appropriate in the distributed networks. PMID- 29534084 TI - Development and characterization of various osteoarthritis models for tissue engineering. AB - Osteoarthritis (OA) is characterized by a progressive loss of articular cartilage, subchondral bone sclerosis and synovial inflammation and is the most common chronic condition worldwide today. However, most treatments have focused on pain relief and OA symptoms. For these reasons, many ongoing studies are currently trying to develop efficient and successful therapies based on its pathology. Animal models that mimic the histopathology and symptoms of OA have a critical role in OA research and make it possible to investigate both secondary osteoarthritic changes due to a precedent event such as traumatic injury and naturally occurring changes for the development of therapeutics which can be tested in preclinical and clinical OA trials. We induced OA in various animal models including rats, rabbits and guinea pigs by chemical, surgical and naturally occurring methods. In particular, the Dunkin-Hartley guinea pig is very attractive as an OA animal model because OA slowly progresses which is similar to human primary OA. Thus, this animal model mimics the pathophysiological process and environment of human primary OA. Besides the spontaneous OA model, anterior cruciate ligament transection (ACLT) with medial meniscectomy and bilateral ovariectomy (OVX) as well as a chemical technique using sodium monoiodoacetate (MIA) were used to induce OA. We found that ACLT in the rat model induced OA changes in the histology and micro-CT image compared to OVX. The osteoarthritic change significantly increased following ACLT surgery in the rabbit model. Furthermore, we identified that OA pathogenic changes occurred in a time dependent manner in spontaneous Dunkin-Hartley guinea pigs. The MIA injection model is a rapid and minimally invasive method for inducing OA in animal models, whereas the spontaneous OA model has a slow and gradual progression of OA similar to human primary OA. We observed that histological OA change was extraordinarily increased at 9 1/2 months in the spontaneous OA model, and thus, the grade was similar with that of the MIA model. Therefore, this study reports on OA pathology using various animal models as well as the spontaneous results naturally occurring in an OA animal model which had developed cartilage lesions and progressive osteoarthritic changes. PMID- 29534086 TI - Refining estimates of availability bias to improve assessments of the conservation status of an endangered dolphin. AB - Estimation of visibility bias is critical to accurately compute abundance of wild populations. The franciscana, Pontoporia blainvillei, is considered the most threatened small cetacean in the southwestern Atlantic Ocean. Aerial surveys are considered the most effective method to estimate abundance of this species, but many existing estimates have been considered unreliable because they lack proper estimation of correction factors for visibility bias. In this study, helicopter surveys were conducted to determine surfacing-diving intervals of franciscanas and to estimate availability for aerial platforms. Fifteen hours were flown and 101 groups of 1 to 7 franciscanas were monitored, resulting in a sample of 248 surface-dive cycles. The mean surfacing interval and diving interval times were 16.10 seconds (SE = 9.74) and 39.77 seconds (SE = 29.06), respectively. Availability was estimated at 0.39 (SE = 0.01), a value 16-46% greater than estimates computed from diving parameters obtained from boats or from land. Generalized mixed-effects models were used to investigate the influence of biological and environmental predictors on the proportion of time franciscana groups are visually available to be seen from an aerial platform. These models revealed that group size was the main factor influencing the proportion at surface. The use of negatively biased estimates of availability results in overestimation of abundance, leads to overly optimistic assessments of extinction probabilities and to potentially ineffective management actions. This study demonstrates that estimates of availability must be computed from suitable platforms to ensure proper conservation decisions are implemented to protect threatened species such as the franciscana. PMID- 29534087 TI - Visual recognition of mirror, video-recorded, and still images in rats. AB - Several recent studies have claimed that rodents have good visual recognition abilities. However, the extent to which rats can recognize other rats and distinguish between males and females using visual information alone remains unclear. In the present study, we investigated the ability of rats to visually recognize mirror, video-recorded, and still images and to discriminate between images of males and females. Rats were tested in a place preference apparatus with a mirror, a video-recorded image of a rat, or a still image of a rat at one end. The data were assessed using t-test with Bonferroni correction. Male and female rats spent significantly more time in the mirror chamber and the video recorded image chamber than in their respective blank chambers (P < 0.05), and male rats also spent more time in the chamber containing a still image. Furthermore, it was found that male rats exhibited significantly more sniffing behavior around the mirror than in the blank chamber (P < 0.05), whereas female rats were no significant differences in the sniffing behaviors in the mirror, moving or still image experiments. Identical results were obtained regardless of whether the rat in the image was the same or opposite sex. These results indicate that rats can process the differences in mirror, video-recorded, and still images as visual information, but are unable to use this information to distinguish between the sexes. PMID- 29534088 TI - Age-dependent changes in metabolic profile of turkey spermatozoa as assessed by NMR analysis. AB - Metabolic profile of fresh turkey spermatozoa at three different reproductive period ages, namely 32, 44 and 56 weeks, was monitored by Nuclear Magnetic Resonance (NMR) spectroscopy and correlated to sperm quality parameters. The age related decrease in sperm quality as indicated by reduction of sperm concentration, sperm mobility and osmotic tolerance was associated to variation in the level of specific water-soluble and liposoluble metabolites. In particular, the highest levels of isoleucine, phenylalanine, leucine, tyrosine and valine were found at 32 weeks of age, whereas aspartate, lactate, creatine, carnitine, acetylcarnitine levels increased during the ageing. Lipid composition also changed during the ageing: diunsaturated fatty acids level increased from 32 to 56 weeks of age, whereas a reduction of polyunsaturated fatty acids content was observed at 56 weeks. The untargeted approach attempts to give a wider picture of metabolic changes occurring in ageing suggesting that the reduction of sperm quality could be due to a progressive deficiency in mitochondrial energy producing systems, as also prompted by the negative correlation found between sperm mobility and the increase in certain mitochondrial metabolites. PMID- 29534089 TI - The prevalence of deranged C-reactive protein and albumin in patients with incurable cancer approaching death. AB - INTRODUCTION: Amongst patients with incurable cancer approaching death, cachexia is common and associated with adverse outcomes. The term cachexia lacks a universally accepted definition and there is no consensus regarding which variables are to be measured. Furthermore, an elevated C-reactive protein is a common clinical challenge in this patient group. This study aims to add to the ongoing discussion regarding the definition of cancer cachexia and to study the role of C-reactive protein and s-albumin in this context. MATERIAL AND METHODS: A 1-year cohort, consisting of 155 cancer patients enrolled in a specialized palliative home care team in the city of Ostersund, Sweden, that were deceased during the year of 2015 was studied. Laboratory measures were studied within 0-30 and 31-60 days prior to death. C-reactive protein >10 mg/L and coinciding s albumin <30 g/L was referred to as "laboratory cachexia". Also, the number of days from the first found "laboratory cachexia" until death was noted. RESULTS: The prevalence of "laboratory cachexia" was 85% 0-30 days prior to death compared to 66% 31-60 days prior to death (p<0.01). The majority of patients (75%) had an onset of "laboratory cachexia" within 0-120 days prior to death, with a median of 47 days. The median values for C-reactive protein and s-albumin within 0-30 days prior to death were 84mg/L and 23g/L respectively. DISCUSSION: Could markedly deranged values of C-reactive protein and s-albumin, such as found in this study, signal a relatively short remaining survival time in patients with incurable cancer and no clinical signs of ongoing infection? The role of "laboratory cachexia" in this context as well as the cut off values for the laboratory measures included may be further discussed. PMID- 29534090 TI - Asymmetric expression level of clock genes in left vs. right nasal mucosa in humans with and without allergies and in rats: Circadian characteristics and possible contribution to nasal cycle. AB - Numerous peripheral tissues possess self-sustaining daily biologic rhythms that are regulated at the molecular level by clock genes such as PER1, PER2, CLOCK, and BMAL1. Physiological function of nasal mucosa exhibits rhythmic variability to a day-night environmental cycle. Nevertheless, little is known of the expression and distribution pattern of clock genes in nasal mucosa. The present study investigates the expression level and distribution pattern of PER1, PER2, CLOCK, and BMAL1 genes in nasal mucosa of healthy controls, allergic rhinitis patients, and normal rats. In human and rat nasal mucosa, the levels of these genes are asymmetrically expressed in nasal mucosa derived from right and left cavities in normal controls, allergic patients, and rat. In human nasal mucosa, the expression levels of these genes were higher in the decongested side than the congested mucosa. In rat nasal mucosa, these clock genes are expressed in a rhythmic circadian manner under the regular light/dark cycles. The expression levels of MUC5AC, a key mucin genes produced in superficial epithelium, are higher in decongested side than that congested side in human nasal mucosa. In rat nasal mucosa, MUC5AC levels showed a circadian rhythm which was associated with different expression levels in nasal mucosa derived from the right and left nasal cavities. Taken together with these results, the present study shows that the clock genes such as PER1, PER2, CLOCK, and BMAL1 are present in human and rat nasal mucosa, and suggest that these clock genes may control the pathophysiological function of nasal mucosa as circadian oscillators and affect the maintenance of the nasal cycle. PMID- 29534091 TI - First aid knowledge, attitude, practice, and associated factors among kindergarten teachers of Lideta sub-city Addis Ababa, Ethiopia. AB - BACKGROUND: Injuries are very common and can occur at any point of time in a day. Unintended injuries in kindergarten children are the most common and need immediate life saving care which is known as first aid. This study aimed to investigate knowledge, attitude, practice, and associated factors of first aid among kindergarten teachers of Lideta sub-city Addis Ababa, Ethiopia. METHOD: A cross-sectional study was conducted among kindergarten teachers. Data was collected using pretested, structured and self-administered questionnaire S1 File. The collected data was entered in to Epi Data version 3.1 software and analyzed using SPSS version 20. Logistic regression analysis was used to identify association between kindergarten teachers' knowledge and attitudes towards first aid and different variables. Odds ratios with 95% CI and p<0.05 were computed to determine the presence of the association. RESULT: One hundred and ninety-four teachers participated in the study with a response rate of 95%. Only 40% of the teachers were knowledgeable and 75% of them had positive attitude for first aid. Eighty percent of teachers encountered with children in need of first aid. Kindergarten teachers older than 35 years [AOR = 4.2, 95%CI: (1.02, 16.9)], five years' experience [AOR = 3.1, 95%CI: (1.2, 7.6)], having previous first aid training [AOR = 3.1, 95%CI: (1.2, 7.7)], source of first aid information and teachers serving in private kindergarten are associated with having knowledge of first aid. Long time experience, type of kindergarten, previous training, and exposure to children in need of first aid were positive association with attitude towards first aid. CONCLUSION: Low first aid knowledge and high positive attitude among kindergarten teachers. Having long time experience, being older age, previous first aid training, and serving in private kindergarten were positively associated with first aid knowledge and positive attitude. Creating awareness and including first aid courses in the kindergarten teachers' curriculum need to be considered. PMID- 29534092 TI - Clinical usefulness of the SAMe-TT2R2 score: A systematic review and simulation meta-analysis. AB - BACKGROUND: Vitamin K antagonist (VKA) therapy is safer and more effective when patients have a high time within the therapeutic range and low international normalised ratio variability. The SAMe-TT2R2 score aims to identify those at risk for poor VKA control. OBJECTIVES: To evaluate the predictive value and clinical usefulness of the SAMe-TT2R2 score to identify those at risk for poor VKA control. METHODS: We performed a systematic review in MEDLINE and Embase for original research papers assessing the SAMe-TT2R2's relation to poor TTR. We performed a meta-analysis where scores >= 2 and >= 3 predicting TTR < 70%. When studies evaluated other cutoffs for TTR or SAMe-TT2R2, they were harmonised by multiple simulations with patient characteristics from the individual studies, if the data were available. RESULTS: 16 studies were identified and used in the meta analysis: 4 and 2 times directly, 8 and 8 times harmonised for scores >= 2 and >= 3, respectively (not all studies provided information about both cutoffs). The sensitivities and specificities were too heterogeneous to pool. The positive likelihood ratios were 1.25 (1.14-1.38) for a score >= 2, and 1.24 (1.09-1.40) for a score >= 3; the negative ones were 0.87 (0.82-0.93) and 0.96 (0.91-1.02), respectively. This shows that the post-test probabilities hardly differ from the prior probability (prevalence). CONCLUSION: The SAMe-TT2R2 score does predict low TTR, but the effect is small. Its effect on individual patients is too limited to be clinically useful. PMID- 29534093 TI - Nitrogen deposition does not affect the impact of shade on Quercus acutissima seedlings. AB - Light and atmospheric nitrogen (N) deposition are among the important environmental factors influencing plant growth and forest regeneration. We used Quercus acutissima, a dominant broadleaf tree species native to the deciduous forests of Northern China, to study the combined effects of light exposure and N addition on leaf physiology and individual plant growth. In the greenhouse, we exposed Quercus acutissima seedlings to one of two light conditions (8% and 80% of full irradiation) and one of three N treatments (0, 6, and 12 g N m-2 y-1). After 87 d, we observed that nitrogen deposition had no significant effects on the seedlings regardless of light exposure. In addition, shade significantly reduced plant height, basal diameter, leaf number, total biomass, gas exchange capacity, and carbohydrate content. In contrast, however, shade significantly increased the amount of photosynthetic pigment, above-ground biomass allocation, and specific leaf area. There was also a hierarchical plasticity among the different seedling characteristics. Compared to traits of growth, biomass, biomass allocation and leaf morphology, the leaf physiology, including photosynthetic pigment, gas exchange, carbohydrate, and PUNE, is more sensitive to light conditions. Among the biomass allocation parameters, the leaf and root mass ratios had a relatively low phenotypic plasticity. The seedlings had high foliar physiological plasticity under various light conditions. Nevertheless, we recommend high irradiance to maintain vigorous seedling growth and, in turn, promote the restoration and reconstruction of vegetation. PMID- 29534094 TI - Genetic variation and diversity in 199 Melilotus accessions based on a combination of 5 DNA sequences. AB - Melilotus is an important genus of legume plants and an herbage with excellent nitrogen fixation; it can tolerate extreme environmental conditions and possesses important medicinal value. However, there is limited genetic information about the genus; thus, we analysed four chloroplast loci (rbcL, matK, psbA-trnH and trnL-F) and one nuclear region (ITS) to determine the genetic diversity of 199 accessions from 18 Melilotus species. The rbcL and matK sequences were highly conserved, whereas the trnL-F and ITS sequences contained variable and parsimony informative sites. In our analyses of the single and combined regions, we calculated the pairwise distance, haplotype and nucleotide diversity and gaps and then constructed phylogenetic trees to assess the genetic diversity, and our results revealed significant variations among the different accessions. The genetic distance values were between zero and nine, and based on the combined regions, the highest frequency value was approximately four. Melilotus showed high haplotype and nucleotide diversity, particularly in the ITS sequences, with values of 0.86 and 0.0087, respectively. The single ITS sequence, psbA-trnH, and the combined matK+rbcL+trnL-F (MRT) and matK+rbcL+psbA-trnH+trnL-F+ITS (MRPTI) regions showed interspecific variation in the gap analysis. Phylogenetic trees calculated using ITS, psbA-trnH and MRPTI sequences indicated distinct genetic relationship in 18 species, and these species could be divided into two groups. By determining the genetic diversity of plants, we can evaluate the genetic relationships among species and accessions, providing a basis for preserving and utilizing the genetic resources of Melilotus. PMID- 29534095 TI - Assessment of dentofacial growth deviation in juvenile idiopathic arthritis: Reliability and validity of three-dimensional morphometric measures. AB - INTRODUCTION: Patients with juvenile idiopathic arthritis (JIA) and involvement of the temporomandibular joint (TMJ) often experience abnormal facial growth. Three-dimensional (3D) assessment of dentofacial growth deviation has become more common with advancement and commercialization of imaging technologies. However, no standardized guidelines exist for interpretation of 3D imaging in patients with JIA. The aim of this study was to propose and validate morphometric measures for the 3D radiographic assessment of dentofacial growth deviation in patients with JIA to enhance: 1) Description of dentofacial growth deviation; 2) Treatment planning; 3) Longitudinal follow-up. METHODS: The study was conducted in a standardized sequential-phased approach involving: 1) Preliminary decision making; 2) Item generation; 3) Test of content-validity; 4) Test of reliability; 5) Test of construct validity; 6) Establishment of final recommendations. RESULTS: Twenty-one morphometric measures were evaluated. Based on results of reliability and validity-testing including subjects with JIA (n = 70) and non-JIA controls (n = 19), seven measures received a "high recommendation" score. Those measures were associated with posterior mandibular height, occlusal cant, mandibular asymmetry, mandibular inclination, and anterior/posterior lower face height. Nine other measures were "moderately recommended" and five received a "somewhat recommendation" score. CONCLUSION: Seven morphometric measures were considered very useful in the 3D assessment of growth deviation in patients with TMJ disease associated with JIA. These variables can be used to standardize the description of dentofacial deformities and to plan corrective interventions. PMID- 29534096 TI - New elephant crisis in Asia-Early warning signs from Myanmar. AB - In the southern Bago Yoma mountain range in Myanmar, Asian elephants are being killed at a disturbing rate. This emerging crisis was identified initially through a telemetry study when 7 of 19 of collared elephants were poached within a year of being fitted with a satellite-GPS collar. Subsequent follow up of ground teams confirmed the human caused death or disappearance of at least 19 elephants, including the seven collared individuals, within a 35 km2 area in less than two years. The carcasses of 40 additional elephants were found in areas located across south-central Myanmar once systematic surveys began by our team and collaborators. In addition to the extreme rate of loss, this study documents the targeting of elephants for their skin instead of the more common ivory, an increasing trend in Myanmar. Intensive research programs focused on other conservation problems identified this issue and are now encouraging local authorities to prioritize anti-poaching efforts and improve conservation policies within the country. Myanmar represents one of the last remaining countries in Asia with substantial wildlands suitable for elephants. Increasing rates of human elephant conflict and poaching events in this country pose a dire threat to the global population. PMID- 29534097 TI - Health-economic outcomes in hospital patients with medical-psychiatric comorbidity: A systematic review and meta-analysis. AB - BACKGROUND: Hospital inpatients often experience medical and psychiatric problems simultaneously. Although this implies a certain relationship between healthcare utilization and costs, this relationship has never been systematically reviewed. OBJECTIVE: The objective is to examine the extent to which medical-psychiatric comorbidities relate to health-economic outcomes in general and in different subgroups. If the relationship is significant, this would give additional reasons to facilitate the search for targeted and effective treatments for this complex population. METHOD: A systematic review in Embase, Medline, Psycinfo, Cochrane, Web of Science and Google Scholar was performed up to August 2016 and included cross-references from included studies. Only peer-reviewed empirical studies examining the impact of inpatient medical-psychiatric comorbidities on three health-economic outcomes (length of stay (LOS), medical costs and rehospitalizations) were included. Study design was not an exclusion criterion, there were no restrictions on publication dates and patients included had to be over 18 years. The examined populations consisted of inpatients with medical psychiatric comorbidities and controls. The controls were inpatients without a comorbid medical or psychiatric disorder. Non-English studies were excluded. RESULTS: From electronic literature databases, 3165 extracted articles were scrutinized on the basis of title and abstract. This resulted in a full-text review of 86 articles: 52 unique studies were included. The review showed that the presence of medical-psychiatric comorbidity was related to increased LOS, higher medical costs and more rehospitalizations. The meta-analysis revealed that patients with comorbid depression had an increased mean LOS of 4.38 days compared to patients without comorbidity (95% CI: 3.07 to 5.68, I2 = 31%). CONCLUSIONS: Medical-psychiatric comorbidity is related to increased LOS, medical costs and rehospitalization; this is also shown for specific subgroups. This study had some limitations; namely, that the studies were very heterogenetic and, in some cases, of poor quality in terms of risk of bias. Nevertheless, the findings remain valid and justify the search for targeted and effective interventions for this complex population. PMID- 29534098 TI - Clusters of anthropometric indicators of body fat associated with maximum oxygen uptake in adolescents. AB - INTRODUCTION: The aim of this study was to evaluate different clusters of anthropometric indicators (body mass index | BMI |, waist circumference | WC |, waist-to-height ratio | WHtR |, triceps skinfold |TR SF|, subscapular skinfold |SE SF|, sum of the triceps and subscapular skinfolds | SigmaTR + SE |, and sum of the triceps, subscapular and suprailiac folds | SigmaTR + SE + SI|) associated with the VO2max levels in adolescents. METHODS: The study included 1,132 adolescents (aged 14-19 years) enrolled in public schools of Sao Jose, Santa Catarina, Brazil, in the 2014 academic year. The dependent variable was the cluster of anthropometric indicators (BMI, WC, WHtR, TR SF, SE SF, SI SF, SigmaTR + SE and SigmaTR + SE + SI) of excess body fat. The independent variable was maximum oxygen uptake (VO2max), estimated by the modified Canadian aerobic fitness test-mCAFT. Control variables were: age, skin color, economic level, maternal education, physical activity and sexual maturation. Multinomial logistic regression was used for associations between the dependent and independent variables. Binary logistic regression was performed to identify the association between adolescents with all anthropometric indicators in excess and independent variables. RESULTS: One in ten adolescents presented all anthropometric indicators of excess body fat. Multinomial regression showed that with each increase of one VO2max unit, the odds of adolescents having three, four, five or more anthropometric indicators of excess body fat decreased by 0.92, 0.85 and 0.73 times, respectively. In the binary regression, this fact was reconfirmed, demonstrating that with each increase of one VO2max unit, the odds of adolescents having simultaneously the eight anthropometric indicators of excess body fat decreased by 0.55. CONCLUSION: It was concluded that with each increase of one VO2max unit, adolescents decreased the odds of simultaneously presenting three or more anthropometric indicators of excess body fat, regardless of biological, economic and lifestyle factors. In addition, the present study identified that one in ten adolescents had all anthropometric indicators of excess body fat. PMID- 29534099 TI - Genetic analysis of zebrafish homologs of human FOXQ1, foxq1a and foxq1b, in innate immune cell development and bacterial host response. AB - FOXQ1 is a member of the forkhead-box transcription factor family that has important functions in development, cancer, aging, and many cellular processes. The role of FOXQ1 in cancer biology has raised intense interest, yet much remains poorly understood. We investigated the possible function of the two zebrafish orthologs (foxq1a and foxq1b) of human FOXQ1 in innate immune cell development and function. We employed CRISPR-Cas9 targeted mutagenesis to create null mutations of foxq1a and foxq1b in zebrafish. Using a combination of molecular, cellular, and embryological approaches, we characterized single and double foxq1a bcz11 and foxq1b bcz18 mutants. This study provides the first genetic mutant analyses of zebrafish foxq1a and foxq1b. Interestingly, we found that foxq1a, but not foxq1b, was transcriptionally regulated during a bacterial response, while the expression of foxq1a was detected in sorted macrophages and upregulated in foxq1a-deficient mutants. However, the transcriptional response to E. coli challenge of foxq1a and foxq1b mutants was not significantly different from that of their wildtype control siblings. Our data shows that foxq1a may have a role in modulating bacterial response, while both foxq1a and foxq1b are not required for the development of macrophages, neutrophils, and microglia. Considering the implicated role of FOXQ1 in a vast number of cancers and biological processes, the foxq1a and foxq1b null mutants from this study provide useful genetic models to further investigate FOXQ1 functions. PMID- 29534100 TI - Analysis of the supply chain and conservation status of sharks (Elasmobranchii: Superorder Selachimorpha) based on fisher knowledge. AB - Increasing fishing effort has caused declines in shark populations worldwide. Understanding biological and ecological characteristics of sharks is essential to effectively implement management measures, but to fully understand drivers of fishing pressure social factors must be considered through multidisciplinary and integrated approaches. The present study aimed to use fisher and trader knowledge to describe the shark catch and product supply chain in Northeastern Brazil, and evaluate perceptions regarding the regional conservation status of shark species. Non-systematic observations and structured individual interviews were conducted with experienced fishers and traders. The demand and economic value of shark fins has reportedly decreased over the last 10 years while the shark meat trade has increased slightly, including a small increase in the average price per kilogram of meat. Several threatened shark species were reportedly often captured off shore and traded at local markets. This reported and observed harvest breaches current Brazilian environmental laws. Fishing communities are aware of population declines of several shark species, but rarely take action to avoid capture of sharks. The continuing capture of sharks is mainly due to a lack of knowledge of environmental laws, lack of enforcement by responsible authorities, and difficulties encountered by fishers in finding alternative income streams. National and regional conservation measures are immediately required to reduce overfishing on shark populations in Northeastern Brazil. Social and economic improvements for poor fishing communities must also be implemented to achieve sustainable fisheries. PMID- 29534102 TI - Differential impact of lytic viruses on prokaryotic morphopopulations in a tropical estuarine system (Cochin estuary, India). AB - Our understanding on the importance of viral lysis in the functioning of tropical estuarine ecosystem is limited. This study examines viral infection of prokaryotes and subsequent lysis of cells belonging to different morphotypes across a salinity gradient in monsoon driven estuarine ecosystem (Cochin estuary, India). High standing stock of viruses and prokaryotes accompanied by lytic infection rates in the euryhaline/mesohaline region of the estuary suggests salinity to have an influential role in driving interactions between prokaryotes and viruses. High prokaryotic mortality rates, up to 42% of prokaryote population in the pre-monsoon season is further substantiated by a high virus to prokaryote ratio (VPR), suggesting that maintenance of a high number of viruses is dependent on the most active fraction of bacterioplankton. Although myoviruses were the dominant viral morphotype (mean = 43%) throughout the study period, there was significant variation among prokaryotic morphotypes susceptible to viral infection. Among them, the viral infected short rod prokaryote morphotype with lower burst estimates (mean = 18 viruses prokaryote-1) was dominant (35%) in the dry seasons whereas a substantial increase in cocci forms (30%) infected by viruses with high burst size (mean = 31 viruses prokaryote-1) was evident during the monsoon season. Such preferential infections of prokaryotic morphopopulations with respect to seasons can have a strong and variable impact on the carbon and energy flow in this tropical ecosystem. PMID- 29534101 TI - Stagnation of histopathological improvement is a predictor of hepatocellular carcinoma development after hepatitis C virus eradication. AB - BACKGROUND: Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients. METHODS: Of 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 +/- 5 and 54 +/- 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and alpha smooth muscle actin (alpha-SMA) was also performed. RESULTS: At baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 +/- 0.6 to 1.0 +/- 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 +/- 0.9 to 2.0 +/- 1.2 (p = 0.2749), during the 97 +/- 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 +/- 7.6% to 7.7 +/- 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and alpha-SMA positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR HCC group. CONCLUSION: Stagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis. PMID- 29534103 TI - Prevalence and correlates of persistent intracellular HIV transcription in individuals on efavirenz versus atazanavir-based regimens: A prospective cohort study. AB - OBJECTIVES: Despite successful virological suppression, HIV transcription frequently persists intracellularly. In this study, we hypothesize that HIV persistent transcription(HIVpt) may affect to a different extent patients on stable efavirenz(EFV) versus atazanavir(ATV)-based regimens. The role of the expression of drug efflux transporters in HIVpt was also investigated. METHODS: We prospectively enrolled 51 virologically suppressed patients on first-line treatment for one year with EFV or ATV combined with emtricitabine and tenofovir and followed them up for one year. Simultaneous ultrasensitive subpopulation staining/hybridization in situ(SUSHI) was performed to identify HIVpt in CD4+ T cells and in the CD4+CD45RO+ T-cell subpopulation. The differential mRNA expression of P-glycoprotein(P-gp/ABCB1) and multidrug resistance-associated protein-1(MRP1/ABCC1) was also evaluated. Univariate logistic regression models were used to evaluate predictors of HIVpt. RESULTS: In the CD4+ T-cell population, HIVpt affected 13/30 of patients on EFV versus 10/21 on ATV. In the CD4+CD45RO+ T-cell population, HIVpt was present in 14/30 of patients on EFV versus 15/21 on ATV. A trend for association was observed between the risk of HIVpt and ATV treatment in the CD4+CD45RO+ T-cell population (OR 2.86, 95% CI 0.87-9.37, p = 0.083). HIVpt status was not associated with loss of virological suppression or CD4 evolution. We found no evidence of differential expression of the drug efflux transporters P-gp and MRP1. CONCLUSIONS: Further study is required to evaluate whether the HIVpt profile in specific cell populations may differ across different antiretroviral regimens and to elucidate the potential clinical impact. PMID- 29534104 TI - Genotyping and spatial analysis of pulmonary tuberculosis and diabetes cases in the state of Veracruz, Mexico. AB - BACKGROUND: Genotyping and georeferencing in tuberculosis (TB) have been used to characterize the distribution of the disease and occurrence of transmission within specific groups and communities. OBJECTIVE: The objective of this study was to test the hypothesis that diabetes mellitus (DM) and pulmonary TB may occur in spatial and molecular aggregations. MATERIAL AND METHODS: Retrospective cohort study of patients with pulmonary TB. The study area included 12 municipalities in the Sanitary Jurisdiction of Orizaba, Veracruz, Mexico. Patients with acid-fast bacilli in sputum smears and/or Mycobacterium tuberculosis in sputum cultures were recruited from 1995 to 2010. Clinical (standardized questionnaire, physical examination, chest X-ray, blood glucose test and HIV test), microbiological, epidemiological, and molecular evaluations were carried out. Patients were considered "genotype-clustered" if two or more isolates from different patients were identified within 12 months of each other and had six or more IS6110 bands in an identical pattern, or < 6 bands with identical IS6110 RFLP patterns and spoligotype with the same spacer oligonucleotides. Residential and health care centers addresses were georeferenced. We used a Jeep hand GPS. The coordinates were transferred from the GPS files to ArcGIS using ArcMap 9.3. We evaluated global spatial aggregation of patients in IS6110-RFLP/ spoligotype clusters using global Moran's I. Since global distribution was not random, we evaluated "hotspots" using Getis-Ord Gi* statistic. Using bivariate and multivariate analysis we analyzed sociodemographic, behavioral, clinic and bacteriological conditions associated with "hotspots". We used STATA(r) v13.1 for all statistical analysis. RESULTS: From 1995 to 2010, 1,370 patients >20 years were diagnosed with pulmonary TB; 33% had DM. The proportion of isolates that were genotyped was 80.7% (n = 1105), of which 31% (n = 342) were grouped in 91 genotype clusters with 2 to 23 patients each; 65.9% of total clusters were small (2 members) involving 35.08% of patients. Twenty three (22.7) percent of cases were classified as recent transmission. Moran's I indicated that distribution of patients in IS6110-RFLP/spoligotype clusters was not random (Moran's I = 0.035468, Z value = 7.0, p = 0.00). Local spatial analysis showed statistically significant spatial aggregation of patients in IS6110-RFLP/spoligotype clusters identifying "hotspots" and "coldspots". GI* statistic showed that the hotspot for spatial clustering was located in Camerino Z. Mendoza municipality; 14.6% (50/342) of patients in genotype clusters were located in a hotspot; of these, 60% (30/50) lived with DM. Using logistic regression the statistically significant variables associated with hotspots were: DM [adjusted Odds Ratio (aOR) 7.04, 95% Confidence interval (CI) 3.03-16.38] and attending the health center in Camerino Z. Mendoza (aOR18.04, 95% CI 7.35-44.28). CONCLUSIONS: The combination of molecular and epidemiological information with geospatial data allowed us to identify the concurrence of molecular clustering and spatial aggregation of patients with DM and TB. This information may be highly useful for TB control programs. PMID- 29534105 TI - Dengue virus in Aedes aegypti and Aedes albopictus in urban areas in the state of Rio Grande do Norte, Brazil: Importance of virological and entomological surveillance. AB - BACKGROUND: Vector control remains the sole effective method to prevent dengue virus (DENV) transmission, although a vaccine for dengue has recently become available and testing of its efficacy and coverage is being performed in multiple places. Entomological surveillance is a key factor in alerting authorities to possible outbreaks, but until now natural DENV infection of mosquito populations has been scarcely used as an early warning system to monitor fluctuating prevalence of infected mosquitoes. The purpose of this study was to determine the burden of adult and larval/pupae of Aedes aegypti and Aedes albopictus with DENV in urban areas in the state of Rio Grande do Norte, Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Immature insect forms (larvae and pupae) were collected from April 2011 to March 2012, whereas the collection of adults was conducted along 3 years: May 2011 to April 2014. Total RNAs of the samples were extracted and the nested reverse transcriptase PCR assay for detecting and typing DENV was performed. Of the 1333 immature insects collected during the study period, 1186 (89%) were A. aegypti and 147 (11%) A. albopictus. DENV-4 was identified in pools of A. aegypti larvae. The rate of DENV infection in immature A. aegypti was expressed as MIR = 3.37. DENV wasnot detected in immature A. albopictus. A total of 1360 adult female mosquitoes of the Aedes genus were captured from May 2011 to April 2014. Of this total, 1293 were A. aegypti (95%) and 67 were A. albopictus (5%). From the 130 pools studied, 27 (20.7%) were positive for DENV. DENV-1 was identified in 2/27 (7.4%) pools; 1of A. albopictus and 1 of A. aegypti. DENV-2 was identified in only 1/27 (3.7%) A. aegypti pools. DENV-4 was the most prevalent, identified in 24/27 (88.8%) of the positive pools, with 19 being of A. aegypti and 5 of A. albopictus pools. The minimum infection rate for adults of the Aedes genus was 19.8, considering both A. aegypti and A. albopictus. CONCLUSIONS/SIGNIFICANCE: This work represents the most complete study to date on the interaction between dengue viruses and Aedes mosquitoes in the State of Rio Grande do Norte, and raises important questions about a possible role of A. albopictus in the transmission of dengue virus in Brazil. PMID- 29534106 TI - A new scheme for strain typing of methicillin-resistant Staphylococcus aureus on the basis of matrix-assisted laser desorption ionization time-of-flight mass spectrometry by using machine learning approach. AB - Methicillin-resistant Staphylococcus aureus (MRSA), one of the most important clinical pathogens, conducts an increasing number of morbidity and mortality in the world. Rapid and accurate strain typing of bacteria would facilitate epidemiological investigation and infection control in near real time. Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry is a rapid and cost-effective tool for presumptive strain typing. To develop robust method for strain typing based on MALDI-TOF spectrum, machine learning (ML) is a promising algorithm for the construction of predictive model. In this study, a strategy of building templates of specific types was used to facilitate generating predictive models of methicillin-resistant Staphylococcus aureus (MRSA) strain typing through various ML methods. The strain types of the isolates were determined through multilocus sequence typing (MLST). The area under the receiver operating characteristic curve (AUC) and the predictive accuracy of the models were compared. ST5, ST59, and ST239 were the major MLST types, and ST45 was the minor type. For binary classification, the AUC values of various ML methods ranged from 0.76 to 0.99 for ST5, ST59, and ST239 types. In multiclass classification, the predictive accuracy of all generated models was more than 0.83. This study has demonstrated that ML methods can serve as a cost-effective and promising tool that provides preliminary strain typing information about major MRSA lineages on the basis of MALDI-TOF spectra. PMID- 29534107 TI - Regulation of FSH expression by differentially expressed miR-186-5p in rat anterior adenohypophyseal cells. AB - Follicle-stimulating hormone (FSH) has key roles in animal reproduction, including spermatogenesis and ovarian maturation. Many factors influence FSH secretion. However, despite the broad functions of microRNAs (miRNAs) via the regulation of target genes, little is known about their roles in FSH secretion. Our previous results suggested that miR-186-5p targets the 3' UTR of FSHb; therefore, we examined whether miR-186-5p could regulate FSH secretion in rat anterior adenohypophyseal cells. miR-186-5p was transfected into rat anterior pituitary cells. The expression of FSHb and the secretion of FSH were examined by RT-qPCR and ELISA. A miR-186-5p mimic decreased the expression of FSHb compared with expression in the control group and decreased FSH secretion. In contrast, both the mRNA levels and secretion of FSH increased in response to miR-186-5p inhibitors. Our results demonstrate that miR-186-5p regulates FSH secretion by directly targeting the FSHb 3' UTR, providing additional functional evidence for the importance of miRNAs in the regulation of animal reproduction. PMID- 29534108 TI - Advances of the reverse lactate threshold test: Non-invasive proposal based on heart rate and effect of previous cycling experience. AB - Our first aim was to compare the anaerobic threshold (AnT) determined by the incremental protocol with the reverse lactate threshold test (RLT), investigating the previous cycling experience effect. Secondarily, an alternative RLT application based on heart rate was proposed. Two groups (12 per group-according to cycling experience) were evaluated on cycle ergometer. The incremental protocol started at 25 W with increments of 25 W at each 3 minutes, and the AnT was calculated by bissegmentation, onset of blood lactate concentration and maximal deviation methods. The RLT was applied in two phases: a) lactate priming segment; and b) reverse segment; the AnT (AnTRLT) was calculated based on a second order polynomial function. The AnT from the RLT was calculated based on the heart rate (AnTRLT-HR) by the second order polynomial function. In regard of the Study 1, most of statistical procedures converged for similarity between the AnT determined from the bissegmentation method and AnTRLT. For 83% of non experienced and 75% of experienced subjects the bias was 4% and 2%, respectively. In Study 2, no difference was found between the AnTRLT and AnTRLT-HR. For 83% of non-experienced and 91% of experienced subjects, the bias between AnTRLT and AnTRLT-HR was similar (i.e. 6%). In summary, the AnT determined by the incremental protocol and RLT are consistent. The AnT can be determined during the RLT via heart rate, improving its applicability. However, future studies are required to improve the agreement between variables. PMID- 29534109 TI - Megacity precipitationsheds reveal tele-connected water security challenges. AB - Urbanization is a global process that has taken billions of people from the rural countryside to concentrated urban centers, adding pressure to existing water resources. Many cities are specifically reliant on renewable freshwater regularly refilled by precipitation, rather than fossil groundwater or desalination. A precipitationshed can be considered the "watershed of the sky" and identifies the origin of precipitation falling in a given region. In this paper, we use this concept to determine the sources of precipitation that supply renewable water in the watersheds of the largest cities of the world. We quantify the sources of precipitation for 29 megacities and analyze their differences between dry and wet years. Our results reveal that 19 of 29 megacities depend for more than a third of their water supply on evaporation from land. We also show that for many of the megacities, the terrestrial dependence is higher in dry years. This high dependence on terrestrial evaporation for their precipitation exposes these cities to potential land-use change that could reduce the evaporation that generates precipitation. Combining indicators of water stress, moisture recycling exposure, economic capacity, vegetation-regulated evaporation, land-use change, and dry-season moisture recycling sensitivity reveals four highly vulnerable megacities (Karachi, Shanghai, Wuhan, and Chongqing). A further six megacities were found to have medium vulnerability with regard to their water supply. We conclude that understanding how upwind landscapes affect downwind municipal water resources could be a key component for understanding the complexity of urban water security. PMID- 29534111 TI - Correction: A Novel Variant in CMAH Is Associated with Blood Type AB in Ragdoll Cats. AB - [This corrects the article DOI: 10.1371/journal.pone.0154973.]. PMID- 29534110 TI - Sodium ion channel alkaloid resistance does not vary with toxicity in aposematic Dendrobates poison frogs: An examination of correlated trait evolution. AB - Spatial heterogeneity in the strength or agents of selection can lead to geographic variation in ecologically important phenotypes. Many dendrobatid frogs sequester alkaloid toxins from their diets and often exhibit fixed mutations at NaV1.4, a voltage-gated sodium ion channel associated with alkaloid toxin resistance. Yet previous studies have noted an absence of resistance mutations in individuals from several species known to sequester alkaloid toxins, suggesting possible intraspecific variation for alkaloid resistance in these species. Toxicity and alkaloid profiles vary substantially between populations in several poison frog species (genus Dendrobates) and are correlated with variation in a suite of related traits such as aposematic coloration. If resistance mutations are costly, due to alterations of channel gating properties, we expect that low toxicity populations will have reduced frequencies and potentially even the loss of resistance alleles. Here, we examine whether intraspecific variation in toxicity in three dendrobatid frogs is associated with intraspecific variation in alleles conferring toxin resistance. Specifically, we examine two species that display marked variation in toxicity throughout their native ranges (Dendrobates pumilio and D. granuliferus) and one species with reduced toxicity in its introduced range (D. auratus). However, we find no evidence for population-level variation in alkaloid resistance at NaV1.4. In fact, contrary to previous studies, we found that alkaloid resistance alleles were not absent in any populations of these species. All three species exhibit fixed alkaloid resistance mutations throughout their ranges, suggesting that these mutations are maintained even when alkaloid sequestration is substantially reduced. PMID- 29534112 TI - How to evaluate sentiment classifiers for Twitter time-ordered data? AB - Social media are becoming an increasingly important source of information about the public mood regarding issues such as elections, Brexit, stock market, etc. In this paper we focus on sentiment classification of Twitter data. Construction of sentiment classifiers is a standard text mining task, but here we address the question of how to properly evaluate them as there is no settled way to do so. Sentiment classes are ordered and unbalanced, and Twitter produces a stream of time-ordered data. The problem we address concerns the procedures used to obtain reliable estimates of performance measures, and whether the temporal ordering of the training and test data matters. We collected a large set of 1.5 million tweets in 13 European languages. We created 138 sentiment models and out-of sample datasets, which are used as a gold standard for evaluations. The corresponding 138 in-sample datasets are used to empirically compare six different estimation procedures: three variants of cross-validation, and three variants of sequential validation (where test set always follows the training set). We find no significant difference between the best cross-validation and sequential validation. However, we observe that all cross-validation variants tend to overestimate the performance, while the sequential methods tend to underestimate it. Standard cross-validation with random selection of examples is significantly worse than the blocked cross-validation, and should not be used to evaluate classifiers in time-ordered data scenarios. PMID- 29534113 TI - Dietary diversity and poverty as risk factors for leprosy in Indonesia: A case control study. AB - BACKGROUND: Poverty has long been considered a risk factor for leprosy and is related to nutritional deficiencies. In this study, we aim to investigate the association between poverty-related diet and nutrition with leprosy. METHODOLOGY/PRINCIPAL FINDINGS: In rural leprosy-endemic areas in Indonesia, we conducted a household-based case-control study using two controls for each case patient (100 recently diagnosed leprosy patients and 200 controls), matched for age and gender. All participants were interviewed to collect information on their demographics, socioeconomic situation, health, and diet. Body mass index, dietary diversity score, as well as anemia and iron micronutrient profiles were also obtained. By means of univariate, block-wise multivariate, and integrated logistic regression analyses, we calculated odds ratios between the variables and the occurrence of leprosy. Unstable income (odds ratio [OR], 5.67; 95% confidence interval [CI], 2.54-12.64; p = 0.000), anemia (OR, 4.01; 95% CI, 2.10-7.64; p = 0.000), and higher household food insecurity (OR, 1.13; 95% CI, 1.06-1.21; p = 0.000) are significantly associated with an increased risk of having leprosy. Meanwhile, higher education (OR, 0.34; 95% CI, 0.15-0.77; p = 0.009) and land ownership (OR, 0.39; 95% CI, 0.18-0.86; p = 0.019) have significant protective associations against leprosy. Although lower dietary diversity, lack of food stock, food shortage, low serum iron, and high ferritin were found more commonly in those with leprosy, the occurrence of leprosy was not significantly associated with iron deficiency (OR, 1.06; 95% CI, 0.10-11.37; p = 0.963). CONCLUSIONS/SIGNIFICANCE: Food poverty is an important risk factor for leprosy susceptibility, yet the mechanisms underlying this association other than nutrient deficiencies still need to be identified. With a stable incidence rate of leprosy despite the implementation of chemoprophylaxis and multidrug therapy, improving dietary diversity through food-based approaches should be initiated and directed toward high-prevalence villages. The possible underlying factors that link poverty to leprosy other than nutrient deficiencies also need to be identified. PMID- 29534114 TI - Teaching medicine with the help of "Dr. House". AB - TV series such as "House MD", "Grey's Anatomy" or "Emergency Room" are well perceived by medical students. Seminars featuring medical TV series such as "House MD" might serve as door-opener to attract medical students to learn more about rare diseases. The TV series "House MD" is troublesome for the main character Dr. House is an excellent diagnostician but at the same time a rather misanthropic person. Therefore, lecturing medicine with the help of "House MD" requires constant evaluation. From 2008 to 2016 we are using the well-known TV series "House MD" continuously to attract medical students and teach them about rare diseases as well as diagnostic strategies. We collected from 213 students a detailed questionnaire assessing their learning experience. 76.6% of our students (n = 157) reported to watching medical dramas on a regular basis. The Dr. House seminar was compared to traditional seminars and our students reported an improved learning effect (69.9%), better concentration (89.7%), higher motivation to participate (88.7%), and more fun (86.7%) (all p<0.001). The students see Dr. House's behavior quite critically. Likert assessment on a 5-point scale identified strong disagreement with Dr. House's interpersonal skills in dealing with his colleagues (median = 1) and patients (median = 1). At the same time, the students strongly agreed with his outstanding diagnostic (median = 5) and therapeutic capabilities (median = 4). Medical students visiting a Dr. House teaching seminar are highly motivated to learn more about rare diseases. They were positively influenced by TV series such as Dr. House to improve their diagnostic and clinical skills. At the same time, they are critical enough not to see Dr. House as a role model for their own personality. Well performed medical TV shows such as Dr. House can successfully be used in an educational setting to motivate medical students to come into seminars to learn more about rare diseases. PMID- 29534115 TI - Gender, time use and overweight and obesity in adults: Results of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - Perceived time constraints have been highlighted in sociological studies as representing a core issue in determining quality of life. The objective of this study was to test the hypothesis that gender inequalities regarding insufficiency of time play a role in the development of overweight and obesity in adults. The study used baseline data (2008-2010) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), which monitors a cohort of 15,105 civil servants of 35 to 74 years of age. Insufficient time for personal care and leisure due to professional and domestic duties, as detailed in a structured questionnaire, comprised the main exposure variable. The outcome variable was overweight/obesity measured according to body mass index. Prevalence ratios were calculated using multinomial logistic regression. A greater proportion of women compared to men reported insufficient time for personal care and leisure (34.5% versus 23.8%, respectively). The prevalence of overweight was greater in men, while obesity was more common in women. Insufficient time for personal care and leisure was associated with overweight (PR = 1.29; 95% CI: 1.04-1.61) and obesity (PR = 1.65; 95% CI: 1.28-2.12) only in women working over 40 hours/week. No significant association was found for males. These results suggest that the length of the working week influences factors underlying weight gain, possibly issues linked to behavior and/or stress mechanisms. The fact that such an association was restricted to women suggests that the results originate from gender inequalities involving relationships between time and health. The findings of this study provide data on which to base public policies aimed at encouraging the redistribution of domestic responsibilities in the direction of gender equity, as well as macrosocial policies such as providing public schools for workers' children. PMID- 29534116 TI - Correction: GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006321.]. PMID- 29534117 TI - A Three-Stage Split-Crest Technique: Case Series of Horizontal Ridge Augmentation in the Atrophic Posterior Mandible. AB - This paper introduces a three-stage split-crest (TSSC) technique for horizontal ridge augmentation in the atrophic posterior mandible. The first stage consists of splitting the ridge. Following a 3- to 4-week healing interval, the second stage consists of expansion of the cortical plate (without elevating the periosteum) and placement of a bone replacement graft material. After 3 to 4 months of healing, the implants are placed. The advantages of this three-stage technique are increased vascularization to the surgical area, a decrease in procedure complications, and improved implant survival rates. An extended treatment time is the main disadvantage. The purpose of this retrospective case series is to review and discuss a new step-by-step surgical procedure of a TSSC technique using a delayed implant placement protocol. The results, advantages, and limitations were also presented. PMID- 29534118 TI - Modulation of Micro RNA Expression and Osteoblast Differentiation by Nanotopography. AB - PURPOSE: This study evaluated the expression pattern of micro RNAs (miRNAs) on a surface with nanotopography compared with a smooth surface (control). MATERIALS AND METHODS: Human mesenchymal stem cells (hMSCs) were plated on different surfaces and compared at 3, 7, and 14 days for alkaline phosphatase (ALP) activity, expression of genes (osterix [OSX], runt-related transcription factor 2 [RUNX2], bone morphogenetic protein 2 [BMP2], and ALP), and expression of miRNAs. Western blot was also used to detect osteogenic proteins (BMP2, OSX, and osteocalcin [OCN]). Scanning electron microscopy of cells plated onto the surfaces was obtained. RESULTS: ALP activity on different surfaces was significantly greater in the nanotopography surface. At day 14, there was a 3.5 fold and a 9-fold increase for the RUNX2 and OSX genes, respectively. BMP2 and ALP also increased by fourfold and sevenfold compared with the control. Protein levels for OSX and BMP2 were also upregulated compared with the control group. Using RNA sequencing technology (RNA-Seq), a total of 117 miRNAs were found to be differentially expressed comparing the control (day 7) with the nanosurface (day 14). Forty-five miRNAs were upregulated, and 72 were downregulated. Several of the miRNAs that were differently expressed regulate osteogenic genes. For example, hsa-miR-135b-5p targets OCN, BSP, RUNX2, COL15A1, and OSX; hsa-miR-122 5p targets OPN; hsa-miR-196a-5p targets BMP4; hsa-miR-26b-5p targets BMP2; and hsa-miR-148b-3p targets OPN. CONCLUSION: Surfaces with nanotopography have the potential to improve the osseointegration response in order to reduce the osseointegration time and also increase bone formation around the implants, improving areas with low bone quality. Within the limitation of this study, nanotopography surfaces affected MSC differentiation to osteoblasts. Several miRNAs were differentially regulated by surface topography. These miRNAs could be related to the differentiation response to help control the osseointegration process. PMID- 29534119 TI - Three-Dimensional Finite Element Analysis on Stress Distribution of Internal Implant-Abutment Engagement Features. AB - PURPOSE: To investigate the stress distribution in an implant-abutment complex with a preloaded abutment screw by comparing implant-abutment engagement features using three-dimensional finite element analysis (FEA). MATERIALS AND METHODS: For FEA modeling, two implants-one with a single (S) engagement system and the other with a double (D) engagement system-were placed in the human mandibular molar region. Two types of abutments (hexagonal, conical) were connected to the implants. Different implant models (a single implant, two parallel implants, and mesial and tilted distal implants with 1-mm bone loss) were assumed. A static axial force and a 45-degree oblique force of 200 N were applied as the sum of vectors to the top of the prosthetic occlusal surface with a preload of 30 Ncm in the abutment screw. The von Mises stresses at the implant-abutment and abutment screw interfaces were measured. RESULTS: In the single implant model, the S conical abutment type exhibited broader stress distribution than the S-hexagonal abutment. In the double engagement system, the stress concentration was high in the lower contact area of the implant-abutment engagement. In the tilted implant model, the stress concentration point was different from that in the parallel implant model because of the difference in the bone level. CONCLUSION: The double engagement system demonstrated a high stress concentration at the lower contact area of the implant-abutment interface. To decrease the stress concentration, the type of engagement features of the implant-abutment connection should be carefully considered. PMID- 29534120 TI - Accuracy of a Template-Guided Implant Surgery System with a CAD/CAM-Based Measurement Method: An In Vitro Study. AB - PURPOSE: The aim of this in vitro study was to evaluate the accuracy of template guided implantation planned with implant-planning software (Implant Studio), comparing computer-aided design/computer-assisted manufacture (CAD/CAM)-based measurements with measurements via cone beam computed tomography (CBCT). MATERIALS AND METHODS: Thirty template-guided implantations were planned and performed on acrylic-resin models. The implant positions were detected with an intraoral scanner, evaluated with CAD quality-control software, and compared with the planned positions in the test group. Preliminary deviations were measured via CBCT in the control group of the first 10 samples and compared with the first 10 samples of the test group. RESULTS: When directly compared, measurements obtained using CBCT (control group) showed a trend toward greater deviations. In the CAD/CAM-based evaluation of the 30 samples, the mean +/- SD deviation of the insertion axis from the planned implant axis was 2.011 +/- 0.855 degrees. The mean deviations of the implant shoulders in the horizontal direction and at the implant apices were 0.725 +/- 0.142 mm and 0.990 +/- 0.244 mm, respectively. In the vertical direction, the mean deviation was 0.541 +/- 0.129 mm. CONCLUSION: CAD/CAM-based measurements are more accurate than CBCT measurements. Therefore, this radiation-free measurement method is a viable diagnostic alternative. Implant planning with planning software and subsequent placement using surgical templates appears to be a reliable and precise therapeutic option in vitro. However, these findings will still have to be supported by in vivo studies. PMID- 29534121 TI - Mouthguard Biomechanics for Protecting Dental Implants from Impact: Experimental and Finite Element Impact Analysis. AB - PURPOSE: The purpose of this study was to evaluate mouthguard shock absorption ability, strain, and stress generation during impact on dental implants placed in the anterior maxilla. The mouthguard material was also characterized. MATERIALS AND METHODS: Sixty experimental models were created and divided into six groups (n = 10): implant type, external hexagon (EH) and Morse taper (MT); without and with two mouthguards (MTG), EVA custom-fitted (Ct-MTG) and standard self-adapted (St-MTG). The Shore A hardness, EVA sheet and mouthguard thickness, and elastic modulus were measured to characterize the mouthguard material. A strain gauge was attached to the palatal surface of the implant abutment, which was subjected to an impact test. Distortion of the abutment and implant was determined after impact from centroid displacements in standardized radiographic images. Two dimensional finite element models were created to represent the six groups and were submitted to nonlinear dynamic impact analysis. The data were statistically analyzed using analysis of variance (ANOVA) and Tukey test (alpha = .05). RESULTS: Ct-MTG resulted in higher Shore A hardness (P < .001). After the heat forming process, the St-MTG maintained the original thickness, but the Ct-MTG thickness had decreased. The elastic modulus of EVA was 18.1 +/- 0.5 MPa. The mouthguard presence reduced strain values significantly (P < .001), particularly for Ct-MTG. There was no significant difference between implant connection types EH and MT (P = .547). CONCLUSION: The external hexagon abutment resulted in higher stress and micro-displacement values. The mouthguard was able to absorb 40% to 46% of the energy caused by the impact on the dental implant. PMID- 29534122 TI - Effects of Screw Configuration on the Preload Force of Implant-Abutment Screws. AB - PURPOSE: The aim of this study was to investigate the effects of tightening torque, screw head angle, and thread number on the preload force of abutment screws. MATERIALS AND METHODS: The test specimens consisted of three self manufactured components (ie, a thread sleeve serving as an implant analog, an abutment analog, and an abutment screw). The abutment screws were fabricated with metric M1.6 external threads. The thread number varied between one and seven threads. The screw head angles were produced in eight varying angles (30 to 180 degrees). A sensor unit simultaneously measured the preload force of the screw and the torsion moment inside the screw shank. The tightening of the screw with the torque wrench was performed in five steps (15 to 35 Ncm). The torque wrench was calibrated before each step. RESULTS: Only the tightening torque and screw head angle affected the resulting preload force of the implant-abutment connection. The thread number had no effect. There was an approximately linear correlation between tightening torque and preload force. CONCLUSION: The tightening torque and screw head angle were the only study parameters that affected the resulting preload force of the abutment screw. The results obtained from this experiment are valid only for a single torque condition. Further investigations are needed that analyze other parameters that affect preload force. Once these parameters are known, it will add value for a strong, but detachable connection between the implant and abutment. Short implants and flat to-flat connections especially will benefit significantly from this knowledge. PMID- 29534123 TI - Comparative Study on the Cutting Effectiveness and Heat Generation of Rotary Instruments Versus Piezoelectric Surgery Tips Using Scanning Electron Microscopy and Thermal Analysis. AB - PURPOSE: The search for optimizing rehabilitation results with the use of osseointegrated implants has led oral surgeons to look for other technologies that can provide better predictability for treatments; however, effectiveness must be considered as well. This study aimed to compare temperature variation during preparation of implant surgical beds using conventional rotary implant burs versus ultrasonic tips and to study perforation effectiveness by analyzing the functional wear of both systems and the influence of such wear on the overheating of cortical bone. MATERIALS AND METHODS: This evaluation was made using thermocouples placed in fresh bovine cortical bone (femur) and connected to a data collector so that the recorded temperatures could provide the thermal behavior of both systems after repeated use of the burs and piezoelectric tips, to compare the wear and the loss of cutting efficiency. Scanning electron microscopy (SEM) was used to compare the topography of both systems' perforations. Biostatistics assays were performed comparing both techniques as well. RESULTS: The collected data and images showed that the wear of the burs and tips did not significantly influence the temperature variation, and the greatest variation occurred in the piezoelectric system for preparations of 13-mm depth. The SEM images show a different surface topography between both systems. While the burs cut the bone, showing a smooth surface, the piezoelectric tips condense the bone and present a rough surface. CONCLUSION: The use of either rotatory burs or piezoelectric tips generates a temperature that does not affect the tissue healing. Burs create a smooth surface, and piezoelectric tips show a more rough and condensed bone surface. The wear of both systems does not have a relevant increase in temperature after the preparation of 30 surgical beds. PMID- 29534124 TI - Effect of Attachment Type on Implant Strain in Maxillary Implant Overdentures: Comparison of Ball, Locator, and Magnet Attachments. Part 2: Palateless Dentures. AB - PURPOSE: Palateless maxillary implant overdentures are often used for patients experiencing problems with a full-palate denture. However, palateless overdentures are reported to be a risk factor for implant complications. The purpose of this study was to examine the strain on implants beneath palateless overdentures with unsplinted attachments under various implant distributions. MATERIALS AND METHODS: A maxillary edentulous model with implants and an experimental palateless overdenture were fabricated. Four strain gauges were attached to each implant, positioned in the anterior, premolar, and molar areas. Three types of unsplinted attachments (ball, locator, and magnet) were set on the implants under various implant distributions. A vertical occlusal load of 98 N was applied through the mandibular complete denture, and the bending strain on the implants was compared using the Kruskal-Wallis test (P = .05). RESULTS: When comparing the strain among different attachments, those using a magnet attachment were the smallest and those using a ball attachment were the greatest, and this difference was significant in most situations (P < .05). When comparing the strain among different implant distributions, the strain on a four-implant distribution was significantly smaller than that on a two-implant distribution in most situations (P < .05), and those using premolar and molar implants recorded the smallest strain. The strain on implants using a locator attachment tended to be midway between those using ball and magnet attachments, regardless of the implant distribution. CONCLUSION: In most implant distributions, magnet attachments decrease the strain on implants more than ball and locator attachments. The most favorable unsplinted attachments for use beneath palateless overdentures to decrease the implant strain are magnet attachments and four implants placed in the premolar and molar areas. PMID- 29534125 TI - MicroSaw and Piezosurgery in Harvesting Mandibular Bone Blocks from the Retromolar Region: A Randomized Split-Mouth Prospective Clinical Trial. AB - PURPOSE: The aim of this randomized prospective split-mouth clinical trial was to evaluate the outcome of bone block harvesting from the retromolar region using the MicroSaw and Piezosurgery. MATERIALS AND METHODS: Fifty-three patients for extensive bilateral bone grafting procedures with or without concomitant implant placement in the maxilla and/or mandible were scheduled. In each patient, bone blocks were harvested in the retromolar area within the external oblique ridge of the mandible. Using a randomized protocol, bone blocks were harvested with the MicroSaw and Piezosurgery either from the right or the left side. Clinical outcome parameters were the comparison of osteotomy time; volume of block graft; and clinical determination of intraoperative complications such as hemorrhage, nerve injury, pain, swelling, and healing of the donor site. RESULTS: The mean osteotomy time for harvesting including luxating a bone block was 5.63 (+/- 1.37) minutes using the MicroSaw and 16.47 (+/- 2.74) minutes using Piezosurgery (P < .05). A mean graft volume of 1.62 (+/- 0.27) cm3 was measured with the MicroSaw and 1.26 (+/- 0.27) cm3 with the piezoelectric surgical device (P < .05). No heavy bleeding at the donor site occurred in any of the cases. Complications due to injury of adjacent teeth or nerve lesion of the mandibular nerve were not observed in any cases. According to a scale, there was little postoperative pain with both instruments, and it decreased within 14 days postoperatively (P > .05). Swelling did not appear significantly different either (P > .05), and none of the donor sites showed primary healing complications. CONCLUSION: The data described in this randomized prospective split-mouth clinical trial indicate that the MicroSaw and Piezosurgery allowed efficient and safe bone block harvesting from the external oblique ridge. Clinically, concerning harvesting time and volume of the grafts, the MicroSaw performed significantly better, whereas pain, swelling, and healing did not appear to be considerably different. Given the improved visibility, precise cut geometries, and the margin of safety afforded by the MicroSaw and Piezosurgery, they are both instruments of choice when harvesting bone from the retromolar area. PMID- 29534126 TI - Accuracy of Navigation-Guided Dental Implant Placement with Screw Versus Hand Template Fixation in the Edentulous Mandible. AB - PURPOSE: Preoperative planning of the implant position as part of a coordinated prosthetic and surgical concept is becoming increasingly important regarding function and esthetics. The aim of this study was to investigate the transmission accuracy of template fixation during surgery in edentulous arches with hand fixation in comparison to intermediary screw fixation. MATERIALS AND METHODS: Preoperatively, 10 implant positions were planned using computed tomography (CT) with the system med3D for implant placement in four mandible models of the Goettingen study model, using a prosthetic diagnostic template. A total of 40 implant insertions were created. For every 20 insertions, the template was temporarily fixed with three screws and compared with the insertion using a hand fixed template. The precision of the transmission was evaluated with and without screw fixation by re-evaluating the preimplant planning with additional CT scanning of the respective models. RESULTS: Compared with the hand-fixed procedure (HFG) in the model situation, there were no significant differences between the deviations of planned and final implant position in the screw-fixed group (FG). According to the study results, the fixed procedure leads to less depth deviation and lateral error of the implant base in relation to the HFG. Within both groups, there were significant differences between the radial deviation tendencies from the implant base to the implant apex (P = .033 for FG and P = .001 for HFG). CONCLUSION: The use of CT-based implant planning succeeds in fixed and hand-fixed surgical procedures with high precision in the atrophic, edentulous mandible model. According to the results of this study, in cases demanding high depth precision, screw-fixation of the template can be helpful. PMID- 29534127 TI - The Effect of Moderately Controlled Type 2 Diabetes on Dental Implant Survival and Peri-implant Bone Loss: A Long-Term Retrospective Study. AB - PURPOSE: The objective of this study was to assess whether long-term implant survival rates and bone loss in patients with moderately controlled type 2 diabetes is similar to the rates reported in the nondiabetic population. MATERIALS AND METHODS: This retrospective observational study utilized patient medical records from a general practitioner's dental office. The records of patients who had moderately controlled type 2 diabetes with hemoglobin A1C (HbA1c) up to 8% and glucose level below 150 mg/dL were reviewed, as patients with HbA1c up to 7% are considered to be well-controlled type 2 diabetes. Follow up data were recorded and analyzed. Inclusion criteria were as follows: partially edentulous patients with missing teeth who were subsequently treated with implant supported prosthetic restorations; patients were at least 18 years of age and demonstrated the ability to maintain oral hygiene. Exclusion criteria were as follows: patients did not present for annual follow-up visits; patients presented with a neglected periodontal status; patient records had incomplete surgical or restorative data or nondiagnostic radiographs; implants with external hexagonal and machined surfaces. All the restorations were cement-retained. Three different implant insertion/placement methods were used: (1) implants immediately inserted following tooth extraction; (2) implants inserted 6 to 8 weeks after tooth extraction to allow for primary healing; and (3) implants inserted 4 to 6 months after tooth extraction. RESULTS: After review of more than 3,256 medical records, 169 patients were identified (with 1,112 implants) who met the inclusion criteria. The mean follow-up time was 8.7 years, with a minimum of 4.9 years. Sixty-seven implants failed, yielding a 94% overall implant survival rate. The overall mean bone loss around the implants was 1.98 (+/- 1.81) mm. Comparable to data published earlier, no statistical significance in survival rate was found between the nondiabetic and diabetic population. The delayed insertion protocol presented the least bone loss, compared with immediate insertion (P = .06), and compared with early insertion (P = .046). CONCLUSION: The results show that implant survival and bone loss levels were comparable to reported outcomes in the nondiabetic population. The delayed insertion protocol presented less bone loss compared with other insertion methods. Likewise, less bone loss was found in implants placed in the posterior region. PMID- 29534128 TI - The Efficacy of an Anatase-Coated Collar Surface in Inhibiting the Bacterial Colonization of Oral Implants: A Pilot Prospective Study in Humans. AB - PURPOSE: The primary prevention of peri-implantitis onset is a key factor in long term implant success, and the evaluation of the antibacterial efficacy of different implant surfaces is fundamental in this way. The aim of this study was to assess if implants with collars coated with anatase were less subjected to bacterial colonization than implants with noncoated collars, and to investigate how implant bacterial colonization varies over time. MATERIALS AND METHODS: Eighteen patients in need of implant-supported rehabilitation were selected to have two adjacent implants placed, one with an anatase-coated collar and one with the collar uncoated. Biofilm samples were collected at four sites around each implant at four different time points. Samples were analyzed through polymerase chain reaction (PCR) to detect and calculate the colonization rate of Aggregactibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Prevotella intermedia. RESULTS: Due to one patient dropout and two nonosseointegrated implants, 32 out of 36 placed implants were followed up for 12 months, and 128 samples for each time point were collected: in total, 512 biofilm samples were analyzed. The type and rate of bacterial colonization were not significantly different between the two groups at all the intervals. However, the anatase-coated collar showed no proliferation of T forsythia. A significant difference in marginal bone level could be observed at the 12-month follow-up only. No significant difference in the other clinical and radiographic indexes was observed. CONCLUSION: In this study, anatase-coated collar implants did not seem to provide significantly different microbiologic outcomes than uncoated collar implants. However, the absence of colonization of the species T forsythia and the slightly smaller peri-implant bone loss at the 12 month follow-up suggest that further investigations on anatase coating are needed. Nevertheless, data on bacterial colonization and crestal bone levels need further investigations to draw meaningful conclusions, due to the statistical power of this pilot study. PMID- 29534129 TI - Lateral Approach to the Maxillary Sinus and Mandibular Canal in Severely Atrophied Posterior Alveolar Bone. AB - PURPOSE: To present a technique to rehabilitate atrophied alveolar ridges in the posterior maxilla and mandible using bone lateral to the maxillary sinus and to the inferior alveolar nerve and to present a retrospective study of the technique. MATERIALS AND METHODS: Severe resorption of the posterior region of the maxilla and mandible was treated following a conservative approach. Patients who presented this bone crest condition that impeded the placement of implants and had an anatomy that allowed the inferior alveolar nerve or the maxillary sinus to be approached laterally were treated. The bone ridge thickness lateral to the maxillary sinus and the inferior alveolar nerve was measured by computed tomography, and implants with a wedge-shaped design were placed in the available bone. A retrospective review of clinical records of these patients, treated between 1998 and 2012 at the Clinest - Clinical Center of Research in Stomatology, was conducted. The studied variables were surgical and prosthetic complications, the implant survival rate, and the difference between the remaining bone ridge measurement in the ridge center and the implant length placed laterally. RESULTS: Fifty-six patients met the inclusion criteria. These patients received 208 implants according to the aforementioned technique. The mean implant length gain was 6.9 mm, varying from 0.5 to 12 mm. The cumulative survival rate was high for both maxillaries. For the implants placed beside the inferior alveolar nerve, none were lost at 2 years, two were lost at 5 years, and four were lost at 10 years. For the implants placed beside the maxillary sinus, only four implants were lost at 10 years. Nerve injuries and surgical/prosthetic complications occurred but were not significant. CONCLUSION: The use of available bone alongside the maxillary sinus and inferior alveolar nerve to place implants is a surgical possibility, and a predictable, safe approach, albeit delicate and experience-dependent. PMID- 29534130 TI - Single-Dose Bioavailability for Prophylactic Coverage in Patients Undergoing Dental Implant Surgery. AB - PURPOSE: The use of antibiotic prophylaxis in dental implant surgery is a routine dental practice to prevent implant failure. Current systematic reviews have yet to confirm the effectiveness of antibiotic treatment at reducing postoperative infection rates in implant procedures. The aim of this study was to quantify amoxicillin plasma levels at the peripheral venous blood and at the surgical implant site in patients undergoing dental treatment. MATERIALS AND METHODS: A prospective study was conducted. Patients undergoing dental implant surgery were selected, and preoperative doses of 1 g of amoxicillin, in the form of an oral tablet, were administered 1 hour prior to implant surgery. The blood samples (1.5 mL) were collected from both the venous and implant sites. Data on the antibiotics were measured using high-pressure liquid chromatography. The quantification method was validated for linearity, selectivity, and detection limits. Statistical analysis of plasma antibiotic was performed, comparing both samples and the age, height, weight, and body mass index (BMI) (Wilcoxon test, P < .05; STATA v.10.0). RESULTS: Thirty-two patients (mean age: 56.28 +/- 12.2 years; range: 31 to 79 years; 20 men) were selected. Both blood samples were taken at a mean 1.16 +/- 0.37 hours after antibiotic intake. The mean amoxicillin concentration at the implant site reached 5 +/- 2.63 MUg/mL (range: 2.04 to 11.18 MUg/mL), while the venous blood level was 4.21 +/- 2.12 MUg/mL (range: 1.6 to 9.98 MUg/mL) (P = .33). No correlations were observed between age, height, weight, and BMI with antibiotic plasma levels. CONCLUSION: These findings demonstrate that plasma concentrations of a prophylactic dose of amoxicillin are higher than the minimum inhibitory concentration needed to prevent the common dental bacteria involved in peri-implantitis and periodontal diseases. PMID- 29534131 TI - Trephine Core Procedure Versus Bone-Added Osteotome Sinus Floor Elevation in the Augmentation of the Sinus Floor: A Comparative Clinical and Radiographic Study. AB - PURPOSE: The aim of this study was to clinically and radiographically compare the trephine core procedure and the bone-added osteotome sinus floor elevation technique in the augmentation of the sinus floor. MATERIALS AND METHODS: A single site in each subject requiring sinus augmentation where the residual bone height was ~4 mm was randomly allocated to either the trephine core procedure or the bone-added osteotome sinus floor elevation technique. Measures of bone fill and bone height were also acquired through scans from cone beam computed tomography obtained before the sinus augmentation procedure (baseline) and before implant placement at approximately 6 months postoperatively. Clinical parameters for healing (early wound healing index), swelling (measurement of preset facial landmarks), and pain (through visual analog scale) were assessed at 1 week and 2 weeks after surgery. The evaluation of bone fill was performed using the digital subtraction technique and morphometric area analysis on the baseline and postoperative scans using two kinds of image processing software. Implants were placed after a healing period of 4 to 6 months, and implant stability quotient values (using SmartPeg Type 49) were recorded immediately after implant placement. RESULTS: While both of the procedures resulted in an increase in bone fill and bone height, there were no significant differences between the techniques. No significant differences were observed between the two groups for implant stability quotient values after implant placement. No significant differences were observed between the two groups for measures of healing, swelling, and pain. CONCLUSION: Based upon this study that compared the trephine core procedure with the bone-added osteotome sinus elevation technique, comparing bone height, bone fill, and primary implant stability, the two procedures appeared to perform in an equivalent fashion. PMID- 29534132 TI - Immediate Loading of Tilted and Axial Posterior Implants in the Edentulous Maxillary Arch: A Retrospective Comparison of 5-Year Outcomes. AB - PURPOSE: The purpose of this study was to retrospectively compare long-term outcomes for immediately loaded tilted and axial implants placed in the posterior region of the edentulous maxillary arch. MATERIALS AND METHODS: Data obtained from a 5-year prospective study designed to assess clinical outcomes following immediate loading of implants with screw-retained fixed restorations in the edentulous maxillary arch were retrospectively reviewed. Where insufficient alveolar bone was available for axial placement of the posterior-most implant on each side of the arch, tilted placement was employed. Implant survival and marginal bone level changes for these tilted and axial posterior implants were compared. RESULTS: Fifty-one subjects received 64 tilted and 38 axial posterior implants. Forty subjects with 53 tilted and 34 axial posterior implants returned for follow-up after 5 years. Five tilted and seven axial implants failed, representing an 89% and 86% survival proportion, respectively. The mean marginal bone loss was 0.79 (SD: 1.42) mm for tilted implants and 0.14 (SD: 0.34) mm for axial implants. The differences in survival proportions and marginal bone loss between axial and tilted implants were not statistically significant. CONCLUSION: Predictable long-term implant rehabilitation may be achieved in the edentulous maxillary arch using posterior tilted implants in combination with immediate loading. PMID- 29534133 TI - Tissue Dimensional Changes in Single-Tooth Immediate Extraction Implant Placement in the Esthetic Zone: A Retrospective Clinical Study. AB - PURPOSE: The aim of this study was to evaluate the buccopalatal volumetric tissue change that occurs following flapless single-tooth immediate extraction placement in the esthetic area and to analyze the role of four different variables. MATERIALS AND METHODS: Patients in need of a single-tooth replacement in the anterior maxillary or mandibular area (premolar to premolar) were recruited for the study. Patients were treated using four different therapeutic modalities: group 1 (healing abutment), group 2 (healing abutment + bone graft), group 3 (provisional restoration), and group 4 (provisional + bone graft). Alginate impressions were taken the day of implant insertion before tooth extraction (T0), at 1 month (T1), at 3 months (T2), and at 6 months (T3). Buccopalatal dimension (BPD) was measured on the study casts at 1, 3, and 5 mm apical to the free gingival margin and compared between T0 and T1 and T2 and T3. RESULTS: Seventy seven patients were included in the study, 29 men and 48 women with a mean age of 54 years (range: 24 to 76 years), and 80 implants were inserted. Thirteen implants were inserted in group 1, 13 in group 2, 20 in group 3, and 34 in group 4. The BPD contraction was more evident for group 1, smaller in group 2 and group 3, and minimal in group 4. Repeated measures analysis of variance (ANOVA) and post hoc tests were used. The data analyzed were considered statistically significant with a level of alpha = .05. The interaction effect P value was numerically zero. CONCLUSION: The results of this study seem to indicate that volumetric tissue changes after immediate extraction placement in the esthetic area can be minimized if a provisional is immediately connected and a bone graft is inserted simultaneously. PMID- 29534134 TI - Crestal Bone Level Around Tissue-Level Implants Restored with Platform Matching and Bone-Level Implants Restored with Platform Switching: A 5-Year Randomized Controlled Trial. AB - PURPOSE: The aim of this randomized clinical trial with a 5-year follow-up was to assess the differences in radiographic levels of peri-implant bone crest between tissue-level implants restored with platform matching (control group) and bone level implants restored with platform switching (test group) in the posterior region. MATERIALS AND METHODS: To assess marginal bone level changes, periapical radiographs were taken at the moment of prosthesis delivery (baseline), at 1 year, and at 5 years after the definitive restoration. RESULTS: One hundred subjects, partially edentulous in the posterior region, were selected for this study. There were 54 men and 46 women between the ages of 25 and 70 years (mean = 50.5 years). A total of 202 implants were assigned to both groups using a randomized procedure (100 implants in the control group and 102 in the test group). The mean marginal bone level (MBL) changes for tissue-level implants restored with platform matching were 0.26 +/- 0.55 mm at baseline to 1 year, 0.34 +/- 0.54 mm at 1 year to 5 years, and 0.61 +/- 0.73 mm at baseline to 5 years. The mean MBL changes for bone-level implants restored with platform switching were -0.03 +/- 0.74 mm at baseline to 1 year, -0.17 +/- 0.67 mm at 1 year to 5 years, and -0.20 +/- 0.75 mm at baseline to 5 years. The mean difference between the two groups was 0.31 mm at baseline to 1 year, 0.53 mm at 1 year to 5 years, and 0.85 mm at baseline to 5 years. There was a statistically significant difference in MBL (P < .001). Both implant systems showed good and similar survival rates (98% for tissue-level implants restored with platform matching and 96.1% for bone-level implants restored with platform switching). CONCLUSION: In this randomized controlled trial, the following observations were made. Radiographic levels of peri-implant bone crest in tissue-level implants restored by platform matching were statistically significant in the three interval times. Meanwhile, MBL changes for bone-level implants restored with platform switching were not statistically significant in the different times studied. Nevertheless, the mean difference between the two groups was statistically significant. PMID- 29534135 TI - Incidence of Peri-implant Diseases on Implants With and Without Laser Microgrooved Collar: A 5-Year Retrospective Study Carried Out in Private Practice Patients. AB - PURPOSE: To retrospectively evaluate the incidence of peri-implant mucositis and peri-implantitis around dental implants with the same body design and surface but different collar surface (laser-microgrooved vs not laser-microgrooved) after 5 years of loading in private practice patients. MATERIALS AND METHODS: The study was carried out on patients at a private dental clinic enrolled in a periodontal maintenance program, who received at least one implant with a laser-microgrooved collar surface and one implant without a laser-microgrooved collar surface. Clinical variables such as plaque, pocket depth, bleeding on probing, suppuration, and radiographic marginal bone loss at > 5 years around implants were investigated. The correlation between the prevalence of peri-implant mucositis/peri-implantitis and biotype, keratinized tissue width, prosthetic connection type, and prosthetic design type was also analyzed. RESULTS: A total of 166 implants in 74 patients were investigated. At the end of the 5-year follow up period, 38 implants presented peri-implant mucositis, accounting for 22.8% of the total, affecting a total of 24 patients (32.4%), while 13 implants (7.8%) in 10 patients (13.5%) were diagnosed with peri-implantitis. Sixteen of 82 laser microgrooved implants (19.5%) and 24 of 84 implants (28.5%) without a laser microgrooved collar presented peri-implant mucositis, while 3 of 82 (3.6%) of laser-microgrooved implants and 10 of 84 (11.9%) implants without a laser microgrooved collar demonstrated peri-implantitis. Differences in implant-based incidence of peri-implant diseases between implants with and without a laser microgrooved collar were statistically significant (P < .05). CONCLUSION: In private practice patients enrolled in a professional, controlled oral hygiene regimen, implants with a laser-microgrooved collar, compared with implants without a laser-microgrooved collar, presented a statistically significantly lower incidence of peri-implant diseases. PMID- 29534136 TI - Immediate Nonsubmerged Custom Root Analog Implants: A Prospective Pilot Clinical Study. AB - PURPOSE: To evaluate the feasibility of a commercially available immediate root analog implant system Replicate (Natural Dental Implants). MATERIALS AND METHODS: Five consecutive patients in need of an implant in the premolar region were recruited for this pilot study. Following clinical examination, a cone beam computed tomography scan was made and the dental impressions digitized. On the basis of the superimposition of these datasets, a three-dimensional (3D) envelope was created for the selected tooth. Subsequently, the tooth root at the prospective implant site was segmented to create a 3D surface, and the obtained mesh data were used as the basis for designing a single-piece root analog implant within the 3D envelope. The designed root analog implant was fabricated using a five-axis computer-aided manufacturing machine. The root analog implants were inserted following flapless minimally invasive root extraction. Following 3 months of uninterrupted healing, definitive restorations were fabricated. Peri implant clinical and radiographic measurements were obtained up to 12 months follow-up. RESULTS: All patients functioned well following 12 months of functional loading. Within one patient, one of the two root analog implants failed early. Peri-implant clinical and radiographic measurements demonstrated a stable situation after 12 months of functional loading. CONCLUSION: A novel digital approach for immediately restoring single teeth using root analog implants was introduced. In the future, long-term evaluation of the root analog implant technique is necessary to evaluate the success and survival of implants that were inserted using this technique. PMID- 29534146 TI - PKC inhibition of sotrastaurin has antitumor activity in diffuse large B-cell lymphoma via regulating the expression of MCT-1. AB - MCT-1 (multiple copies in T-cell lymphoma-1), a novel oncogene, was originally identified in T-cell lymphoma. A recent study has demonstrated that MCT-1 is highly expressed in 85% of diffuse large B-cell lymphomas (DLBCL). PKC (protein kinase C) plays an essential role in signal transduction for multiple biologically active substances for activating cellular functions and proliferation. In this study, we found that the mRNA and protein expression levels of MCT-1 were visibly decreased after knocking down PKC by siRNA in SUDHL 4 and OCI-LY8 DLBCL cell lines. A selective PKC inhibitor, sotrastaurin, effectively inhibited cell proliferation and induced cell apoptosis in a dose- and time-dependent manner. Meanwhile, we also observed that the cell cycle was arrested in the G1 phase in sotrastaurin-treated cells. In addition, MCT-1 was down-regulated in the sotrastaurin treatment group in vivo. Furthermore, we demonstrated that the PKC inhibitor sotrastaurin induced cell apoptosis and cell cycle arrest in DLBCL cells potentially through regulating the expression of MCT 1. Our data suggest that targeting PKC may be a potential therapeutic approach for lymphomas and related malignancies that exhibit high levels of MCT-1 protein. PMID- 29534147 TI - A reassessment of the genome size-invasiveness relationship in reed canarygrass (Phalaris arundinacea). AB - Background and Aims: Genome size is hypothesized to affect invasiveness in plants. Key evidence comes from a previous study of invasive eastern North American populations of the grass Phalaris arundinacea: invasive genotypes with smaller genomes had higher growth rates, and genome sizes were smaller in the invasive vs. native range. This study aimed to re-investigate those patterns by examining a broader range of North American populations and by employing the modern best-practice protocol for plant genome size estimation in addition to the previously used protocol. Methods: Genome sizes were measured using both internal and pseudo-internal standardization protocols for 20 invasive and nine native range accessions of P. arundinacea. After a round of vegetative propagation to reduce maternal environmental effects, growth (stem elongation) rates of these accessions were measured in the greenhouse. Key Results: Using the best-practice protocol, there was no evidence of a correlation between genome size and growth rates (P = 0.704), and no evidence for differences in genome sizes of invasive and native range accessions (P > 0.353). However, using the older genome size estimation protocol, both relationships were significant (reproducing the results of the previous study). Conclusions: Genome size reduction has not driven increased invasiveness in a broad sample of North American P. arundinacea. Further, inappropriate genome size estimation techniques can create spurious correlations between genome size and plant traits such as growth rate. Valid estimation is vital to progress in understanding the potentially widespread effects of genome size on biological processes and patterns. PMID- 29534148 TI - Preterm Birth and Small-for-Gestational Age in Singleton In Vitro Fertilization Births Using Donor Oocytes. AB - We used 2006-2015 US National Assisted Reproductive Technology Surveillance System data to compare preterm birth and fetal growth for livebo n singletons (24 42 week gestation) following donor versus autologous oocyte in vitro fertilization (IVF). Using binary and multinomial logistic regressi n, we computed adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between use of donor oocytes and preterm delivery, small-f r gestational-age (SGA), and large-for-gestational age (LGA), stratified by fresh and thawed embryo status and accounting for maternal characteristics and year of birth. There were 204,855 singleton births from fresh embryo transfers and 106,077 from thawed embryo transfers. Among fresh embryo transfers, donor oocyte births had higher odds of preterm (aOR 1.32, 95% CI 1.27-1.38) and LGA (aOR 1.27, 95% CI 1.21-1.33) but lower odds of SGA (aOR 0.81, 95% CI 0.77-0.85). Among thawed embryo transfers, donor oocyte births had higher odds of preterm (aOR 1.57, 95% CI 1.48-1.65) and SGA (aRR 1.22, 95% CI 1.14-1.31), but lower odds of LGA (aOR 0.87, 95% CI 0.82-0.92). Use of donor oocytes was associated with increased odds of preterm delivery irrespective of embryo status; odds of SGA were increased for donor versus autologous oocyte births among thawed embryo transfers only. PMID- 29534149 TI - Changing Rates of Chronic Pseudomonas aeruginosa Infections in Cystic Fibrosis: A Population-Based Cohort Study. AB - Background: Chronic Pseudomonas aeruginosa lung infection is associated with significant morbidity and mortality in cystic fibrosis (CF). It is not known whether recent advances in care have affected the rates of chronic infection. We aimed to determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF significantly changed over time. Methods: The cohort consisted of individuals with CF followed in the Cystic Fibrosis Foundation Patient Registry aged >=13 years without chronic P. aeruginosa at baseline. Multivariable regression models accounting for within-patient correlation were used to assess the change in rate of developing chronic P. aeruginosa infection between 2003 and 2012. Results: A total of 15504 individuals were followed for a median of 5 (interquartile range, 2-9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < .001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% confidence interval, 0.30-0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified. Conclusions: Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration. PMID- 29534152 TI - NGSphy: phylogenomic simulation of next-generation sequencing data. AB - Motivation: Advances in sequencing technologies have made it feasible to obtain massive datasets for phylogenomic inference, often consisting of large numbers of loci from multiple species and individuals. The phylogenomic analysis of next generation sequencing (NGS) data requires a complex computational pipeline where multiple technical and methodological decisions are necessary that can influence the final tree obtained, like those related to coverage, assembly, mapping, variant calling and/or phasing. Results: To assess the influence of these variables we introduce NGSphy, an open-source tool for the simulation of Illumina reads/read counts obtained from haploid/diploid individual genomes with thousands of independent gene families evolving under a common species tree. In order to resemble real NGS experiments, NGSphy includes multiple options to model sequencing coverage (depth) heterogeneity across species, individuals and loci, including off-target or uncaptured loci. For comprehensive simulations covering multiple evolutionary scenarios, parameter values for the different replicates can be sampled from user-defined statistical distributions. Availability and implementation: Source code, full documentation and tutorials including a 'Getting started' guide are available at http://github.com/merlyescalona/ngsphy. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29534151 TI - A novel computational approach for drug repurposing using systems biology. AB - Motivation: Identification of novel therapeutic effects for existing US Food and Drug Administration (FDA)-approved drugs, drug repurposing, is an approach aimed to dramatically shorten the drug discovery process, which is costly, slow and risky. Several computational approaches use transcriptional data to find potential repurposing candidates. The main hypothesis of such approaches is that if gene expression signature of a particular drug is opposite to the gene expression signature of a disease, that drug may have a potential therapeutic effect on the disease. However, this may not be optimal since it fails to consider the different roles of genes and their dependencies at the system level. Results: We propose a systems biology approach to discover novel therapeutic roles for established drugs that addresses some of the issues in the current approaches. To do so, we use publicly available drug and disease data to build a drug-disease network by considering all interactions between drug targets and disease-related genes in the context of all known signaling pathways. This network is integrated with gene-expression measurements to identify drugs with new desired therapeutic effects based on a system-level analysis method. We compare the proposed approach with the drug repurposing approach proposed by Sirota et al. on four human diseases: idiopathic pulmonary fibrosis, non-small cell lung cancer, prostate cancer and breast cancer. We evaluate the proposed approach based on its ability to re-discover drugs that are already FDA-approved for a given disease. Availability and implementation: The R package DrugDiseaseNet is under review for publication in Bioconductor and is available at https://github.com/azampvd/DrugDiseaseNet. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29534153 TI - ddPCRclust: an R package and Shiny app for automated analysis of multiplexed ddPCR data. AB - Motivation: Droplet digital PCR (ddPCR) is an emerging technology for quantifying DNA. By partitioning the target DNA into ~20 000 droplets, each serving as its own PCR reaction compartment, a very high sensitivity of DNA quantification can be achieved. However, manual analysis of the data is time consuming and algorithms for automated analysis of non-orthogonal, multiplexed ddPCR data are unavailable, presenting a major bottleneck for the advancement of ddPCR transitioning from low-throughput to high-throughput. Results: ddPCRclust is an R package for automated analysis of data from Bio-Rad's droplet digital PCR systems (QX100 and QX200). It can automatically analyze and visualize multiplexed ddPCR experiments with up to four targets per reaction. Results are on par with manual analysis, but only take minutes to compute instead of hours. The accompanying Shiny app ddPCRvis provides easy access to the functionalities of ddPCRclust through a web-browser based GUI. Availability and implementation: R package: https://github.com/bgbrink/ddPCRclust; Interface: https://github.com/bgbrink/ddPCRvis/; Web: https://bibiserv.cebitec.uni bielefeld.de/ddPCRvis/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29534154 TI - Artificial limb representation in amputees. AB - The human brain contains multiple hand-selective areas, in both the sensorimotor and visual systems. Could our brain repurpose neural resources, originally developed for supporting hand function, to represent and control artificial limbs? We studied individuals with congenital or acquired hand-loss (hereafter one-handers) using functional MRI. We show that the more one-handers use an artificial limb (prosthesis) in their everyday life, the stronger visual hand selective areas in the lateral occipitotemporal cortex respond to prosthesis images. This was found even when one-handers were presented with images of active prostheses that share the functionality of the hand but not necessarily its visual features (e.g. a 'hook' prosthesis). Further, we show that daily prosthesis usage determines large-scale inter-network communication across hand selective areas. This was demonstrated by increased resting state functional connectivity between visual and sensorimotor hand-selective areas, proportional to the intensiveness of everyday prosthesis usage. Further analysis revealed a 3 fold coupling between prosthesis activity, visuomotor connectivity and usage, suggesting a possible role for the motor system in shaping use-dependent representation in visual hand-selective areas, and/or vice versa. Moreover, able bodied control participants who routinely observe prosthesis usage (albeit less intensively than the prosthesis users) showed significantly weaker associations between degree of prosthesis observation and visual cortex activity or connectivity. Together, our findings suggest that altered daily motor behaviour facilitates prosthesis-related visual processing and shapes communication across hand-selective areas. This neurophysiological substrate for prosthesis embodiment may inspire rehabilitation approaches to improve usage of existing substitutionary devices and aid implementation of future assistive and augmentative technologies. PMID- 29534155 TI - Disparities in survival after trimodality therapy for esophageal adenocarcinoma. AB - Trimodality therapy with neoadjuvant chemoradiation followed by surgery has emerged as the standard of care for the treatment of locally advanced esophageal cancer. Yet, there is considerable variation in survival within this population. We sought to analyze factors associated with survival after trimodality therapy in esophageal adenocarcinoma. We identified 4,679 patients from the National Cancer Database (NCDB) of the American College of Surgeons who received chemotherapy and radiation prior to surgery for esophageal adenocarcinoma from 2006 to 2013. We excluded patients with stage IV disease and unknown pathological nodal status. We performed regression analyses using a Cox proportional hazards model to identify independent predictors of overall survival. On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins. Insurance status, age, and comorbidity index were also associated with decreased survival. We found that pathologically node-positive patients who received additional adjuvant chemotherapy were associated with improved survival. Compared to private insurance, Medicaid (HR 1.45, CI 1.22-1.73, P < 0.0001), Medicare (HR 1.17, CI 1.04-1.31, P = 0.0082), or having no insurance (HR 1.50, CI 1.17-1.92, P = 0.0012) were all negative predictors of overall survival. In patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with overall survival. In particular, socioeconomic factors relating to access to care are independent predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients. PMID- 29534156 TI - IKBKG (NEMO) 5' Untranslated Splice Mutations Lead to Severe, Chronic Disseminated Mycobacterial Infections. AB - Four patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. Three patients died from disseminated disease. These mutations may be missed by whole exome sequencing. PMID- 29534159 TI - The Art and Science of Vacationing. PMID- 29534158 TI - Sleep Apnea and Heart Failure With a Reduced Ejection Fraction Among Persons Living With Human Immunodeficiency Virus. AB - Background: Sleep apnea (SA) is common and has prognostic significance among broad groups of patients with heart failure (HF). There are no data characterizing the presence, associations, and prognostic significance of SA among persons living with human immunodeficiency virus (PLHIV) with HF. Methods: We conducted a single-center study of PLHIV with HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] <50%) and analyzed the relationship of SA with 30-day HF hospital readmission rate. Results: Our cohort included 1124 individuals admitted with HFrEF; 15% were PLHIV, and 92% were on antiretroviral therapy. SA was noted in 28% of PLHIV and 26% of uninfected controls. Compared to uninfected controls with HFrEF and SA, PLHIV with HFrEF and SA had a lower body mass index, lower LVEF, a higher pulmonary artery systolic pressure (PASP), were more likely to have obstructive rather than central SA (P < .05 for all). In a multivariable model, PASP, low CD4 count, high viral load (VL), and SA parameters (apnea-hypopnea index, CPAP use and duration) were predictors of 30-day HF readmission rate. Each 1-hour increase in CPAP use was associated with a 14% decreased risk of 30-day HF readmission among PLHIV. Conclusions: Compared to uninfected controls, PLHIV were more likely to have obstructive SA than central SA. Apnea severity, low CD4 count, high VL, and cocaine use were positively associated with 30-day HF hospital readmission rate, whereas CPAP use and increased duration of CPAP use conferred protection. PMID- 29534157 TI - The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin. AB - The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration. PMID- 29534160 TI - Prolonged Detection of Zika Virus Nucleic Acid Among Symptomatic Pregnant Women: A Cohort Study. AB - A prospective cohort of women with reverse transcription polymerase chain reaction (RT-PCR) confirmed Zika virus infection aged 18-39 years in Puerto Rico found that pregnant women have about a 3-fold longer estimated median detection of Zika virus RNA in serum, which can increase definitive diagnosis of infection and facilitate timely and appropriate clinical management. PMID- 29534161 TI - ERRATUM FOR "Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update". PMID- 29534162 TI - BRAF and EGFR inhibitors synergize to increase cytotoxic effects and decrease stem cell capacities in BRAF(V600E)-mutant colorectal cancer cells. AB - Mutations in the oncogene BRAF(V600E) are found in ~10% of colorectal cancers (CRCs) and are associated with poor prognosis. However, BRAF(V600E) has a limited response to the small-molecule drug, vemurafenib, a BRAF inhibitor, and BRAF inhibition is thought to cause a feedback activation of EGFR signaling that supports continued proliferation. In this study, we explored the effect of combined use of dabrafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, on BRAF(V600E)-mutant CRC stem cells and its possible mechanisms. Through cell viability analysis, flow cytometry, sphere forming, and western blot analysis, we found that the dabrafenib can synergize with cetuximab to reduce cell viability, induce enhanced apoptotic rates and cell cycle arrest in BRAF(V600E)-mutant HT-29 cells and inhibits stem cell capacities. Further, western blot analysis revealed that PTEN/Src/c-Myc pathway is possibly involved in the synergism between dabrafenib and cetuximab. Overall, our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells. PMID- 29534163 TI - ZFX modulates the growth of human leukemic cells via B4GALT1. PMID- 29534164 TI - Evolution of secondary mitral regurgitation. AB - Aims: Secondary mitral regurgitation (MR) drives adverse remodelling towards late heart failure stages. Little is known about the evolution of MR under guideline directed therapy (GDT) and its relation to cardiac remodelling and outcome. We therefore aimed to assess incidence, impact, and predictors of progressive secondary MR in patients under GDT. Methods and results: We prospectively enrolled 249 patients with chronic heart failure and reduced ejection fraction receiving GDT in this long-term observational study. Of patients with non-severe MR at baseline 81% remained stable whereas 19% had progressive MR. Those patients were more symptomatic (P < 0.001), had higher neurohumoral activation (encompassing various neurohumoral pathways in heart failure, all P < 0.05), larger left atrial size (P = 0.004) and more tricuspid regurgitation (TR, P = 0.02). During a median follow-up of 61 months (IQR 50-72), 61 patients died. Progression of MR conveyed an increased risk of mortality-univariately (HR 2.33; 95% CI 1.34-4.08; P = 0.003), that persisted after multivariate adjustment using a bootstrap-selected confounder model (adjusted HR 2.48; 95% CI 1.40-4.39; P = 0.002). In contrast, regression of MR was not associated with a beneficiary effect on outcome (crude HR 0.84; 95% CI 0.30-2.30; P = 0.73). Conclusions: Every fifth patient with chronic heart failure suffers from MR progression. This entity is associated with a more than two-fold increased risk of death even after careful multivariable adjustment. Symptomatic status, left atrial size, TR, and neurohumoral pathways help to identify patients at risk for progressive secondary MR in an early disease process and open the possibility for closer follow-up and timely intervention. PMID- 29534165 TI - A New Gall Midge Species of Asphondylia (Diptera: Cecidomyiidae) Inducing Flower Galls on Clinopodium nepeta (Lamiaceae) From Europe, Its Phenology, and Associated Fungi. AB - A new gall midge, Asphondylia nepetae sp. n. Viggiani (Diptera: Cecidomyiidae), causing flower gall on Clinopodium nepeta (L.) Kuntze (Lamiaceae), is described from Europe. The morphological characteristics of adult, larvae, and pupa are described and illustrated. Molecular approach (by sequencing 28S-D2, ITS2, and COI) confirmed that A. nepetae is a distinct species. The development of the gall is always associated with the presence of the fungus Botryosphaeria dothidea (Moug.: Fr.) Ces. and De Not. (Botryosphaeriales: Botryosphaeriaceae). The new species can complete several generations per year, on the flowers of the same host plant and its adults emerge from late spring to autumn. Pupae overwinter inside peculiar flower galls in a state of quiescence. The impact of the pest is highly variable with a percentage of flowers infested that ranged between 3 and 57.5% in the sampled years. Insect mortality was, at least in part, due to parasitoids that attack the young stages of the midge. Among them, the dominant species was Sigmophora brevicornis (Panzer) (Chalcidoidea: Eulophidae). PMID- 29534166 TI - Chemical Assay for the Detection of Vertebrate Fecal Metabolites in Adult Blow Flies (Diptera: Calliphoridae). AB - Filth flies are commonly implicated in pathogen transmission routes due to their affinity for vertebrate waste and their synanthropic associations. However, solidifying the link between flies and infected feces in the wild can be difficult, as interpretations made solely from microbial culturing or sequencing methods may represent an incomplete picture of pathogen acquisition. We present an analytical assay using high performance liquid chromatography tandem mass spectrometry (HPLC MS/MS) to detect vertebrate fecal metabolites (urobilinoids) in adult blow fly guts. Proof of concept experiments consisted of controlled feeding in which flies were grouped into three treatments (unfed, exposure to beef liver tissue, and exposure to canine feces; N = 20/treatment) using the black blow fly Phormia regina Meigen (Diptera: Calliphoridae). It was revealed that only feces-related samples exhibited peaks with an m/z of 591 and MS/MS spectra consistent with urobilinoids. These peaks were not seen for beef liver tissue, flies exposed to beef liver tissue, or unfed flies. Samples taken directly from beef liver tissue and from feces of several animals were also tested. To test this assay in wild flies, 216 flies were additionally analyzed to determine whether they had ingested vertebrate feces. About 13% of the wild flies exhibited these same peaks, providing a baseline measure of blow flies collected in urban and residential areas consuming feces from the environment. Overall, this assay can be used for P. regina collected in an applied setting and its integration with microbial culturing and sequencing methods will help to improve its use. PMID- 29534167 TI - Simultaneous laryngopharyngeal pH monitoring (Restech) and conventional esophageal pH monitoring-correlation using a large patient cohort of more than 100 patients with suspected gastroesophageal reflux disease. AB - 24-hour esophageal pH-metry is not designed to detect laryngopharyngeal reflux (LPR). The new laryngopharyngeal pH-monitoring system (Restech) may detect LPR better. There is no established correlation between these two techniques as only small case series exist. The aim of this study is to examine the correlation between the two techniques with a large patient cohort. All patients received a complete diagnostic workup for gastroesophageal reflux including symptom evaluation, endoscopy, 24-hour pH-metry, high resolution manometry, and Restech. Consecutive patients with suspected gastroesophageal reflux and disease-related extra-esophageal symptoms were evaluated using 24-hour laryngopharyngeal and concomitant esophageal pH-monitoring. Subsequently, the relationship between the two techniques was evaluated subdividing the different reflux scenarios into four groups. A total of 101 patients from December 2013 to February 2017 were included. All patients presented extra-esophageal symptoms such as cough, hoarseness, asthma symptoms, and globus sensation. Classical reflux symptoms such as heartburn (71%), regurgitation (60%), retrosternal pain (54%), and dysphagia (32%) were also present. Esophageal 24-hour pH-metry was positive in 66 patients (65%) with a mean DeMeester Score of 66.7 [15-292]. Four different reflux scenarios were detected (group A-D): in 39% of patients with abnormal esophageal pH-metry, Restech evaluation was normal (group A, n = 26, mean DeMeester-score = 57.9 [15-255], mean Ryan score = 2.6 [2-8]). In 23% of patients with normal pH metry (n = 8, group B), Restech evaluation was abnormal (mean DeMeester-score 10.5 [5-13], mean Ryan score 63.5 [27-84]). The remaining groups C and D showed corresponding results. Restech evaluation was positive in 48% of cases in this highly selective patient cohort. As demonstrated by four reflux scenarios, esophageal pH-metry and Restech do not necessarily need to correspond. Especially in patients with borderline abnormal 24-hour pH-metry, Restech may help to support the decision for or against laparoscopic anti-reflux surgery. PMID- 29534168 TI - Progression of secondary mitral regurgitation: from heart failure to valvular heart failure. PMID- 29534169 TI - Erratum to: "No improvements in long-term outcome after coronary artery bypass grafting with arterial grafts as a second conduit: a Swedish nationwide registry study" [Eur J Cardiothorac Surg 2018;53(2):448-454]. PMID- 29534170 TI - Incidence of new-onset left bundle branch block and predictors of new permanent pacemaker following transcatheter aortic valve replacement with the PorticoTM valve. AB - OBJECTIVES: To examine the incidence and timing of new-onset left bundle branch block (LBBB) and new permanent pacemaker implantation (PPI) in patients undergoing transcatheter aortic valve implantation (TAVI) using the repositionable, self-expanding PorticoTM TAVI system (St. Jude Medical, St Paul, MN, USA). Clinical impact and periprocedural factors associated with new PPI were also assessed. METHODS: A total of 198 high-risk patients without pre-existing pacemaker [83.1 +/- 4.7 years, 77.3% women, mean Society of Thoracic Surgeons (STS) 5.8%] from the Pre-CE Mark Portico TAVI system study were prospectively analysed. Twelve-lead electrocardiographic and echocardiographic data were collected prior to, during and after the procedure. Clinical follow-up was performed at 1 year. RESULTS: Transfemoral implantation of the Portico valve was associated with a new PPI rate of 15.2% at 30 days and 16.7% at 1 year. Overall, 53 of the 187 patients without pre-existing LBBB developed new-onset LBBB at 1 year (28.3%); 23 occurred during the procedure. At 30 days, new-onset LBBB spontaneously resolved in 61.0% of patients. New-onset LBBB post-TAVI was not associated with new PPI (P = 0.64); 8 of the 53 patients required new PPI. Multivariable regression analyses revealed pre-existing right bundle branch block (P = 0.004) and aortic annulus diameter (P = 0.001) as independent predictors of new PPI. New PPI at discharge (n = 29) was not associated with increased freedom from all-cause (odds ratio 92.7%, 95% confidence interval 73.7-98.1%; P = 0.49) and cardiovascular (odds ratio 96.6%, 95% confidence interval 77.9-99.5%; P = 0.47) mortality at 1 year. CONCLUSIONS: The Portico TAVI system demonstrated an acceptable rate of new PPI at 1 year without increased mortality risk to patients. New-onset LBBB was common during the procedure, with the majority of events spontaneously resolving by 30 days. No intraprocedural factors were shown to independently predict new PPI. Clinical trial registration number: NCT01493284. PMID- 29534171 TI - Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study. AB - Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21-1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12-1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAPhypertension 5.75 (95% CI 3.5-8.0) and RAPdyslipidaemia 8.16 (95% CI 4.4 11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0-6.6%) of CCS [RR 1.89 (95% CI 1.34-2.66), RAPCVD 7.9 (95% CI 4.1-11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. Conclusion: This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. Clinicaltrials. gov-Nr: NCT02181049. PMID- 29534172 TI - CD36 and lipid metabolism in the evolution of atherosclerosis. AB - Background: CD36 is a multi-functional class B scavenger receptor, which acts as an important modulator of lipid homeostasis and immune responses. Sources of data: This review uses academic articles. Areas of agreement: CD36 is closely related to the development and progression of atherosclerosis. Areas of controversy: Both persistent up-regulation of CD36 and deficiency of CD36 increase the risk for atherosclerosis. Abnormally up-regulated CD36 promotes inflammation, foam cell formation, endothelial apoptosis, macrophage trapping and thrombosis. However, CD36 deficiency also causes dyslipidemia, subclinical inflammation and metabolic disorders, which are established risk factors for atherosclerosis. Growing points: There may be an 'optimal protective window' of CD36 expression. Areas timely for developing research: In addition to traditionally modulating protein functions using gene overexpression or deficiency, the modulation of CD36 function at post-translational levels has recently been suggested to be a potential therapeutic strategy. PMID- 29534173 TI - Midlife Systemic Inflammation is Associated with Frailty in Later Life: The ARIC Study. AB - Background: Evidence suggests systemic inflammation may have a mechanistic role in age-related frailty, yet prospective data is limited. We examined whether systemic inflammation during midlife was associated with late-life frailty within the community-based Atherosclerosis Risk in Communities Study. Methods: Plasma levels of four inflammatory markers (fibrinogen, von Willebrand factor, and Factor VIII, and white blood cell count) were measured during Visit 1 (1987-89; mean age: 52[5]), standardized into z-scores, and combined to create an inflammation composite score. High-sensitivity C-reactive protein (CRP) was measured three (Visit 2, 1990-92) and nine (Visit 4, 1996-99) years later. Frailty was evaluated in 5,760 participants during late life (Visit 5, 2011-13; mean age: 75[5]). Analyses were adjusted for demographic and physiological variables, and midlife medical comorbidity using logistic regression. Results: A one standard deviation increase in midlife inflammation composite score was associated with higher odds of frailty 24 years later (Odds Ratio=1.39, 95% CI: 1.18-1.65). Similarly, each standard deviation increase in Visit 2 CRP (OR=1.24, 1.09-1.40) and Visit 4 CRP (OR=1.35, 1.19-1.53) was associated with a higher odds of frailty 21 and 15 years later. Participants who maintained elevated CRP (>=3 mg/L) at Visits 2 and 4 or transitioned to a state of elevated CRP during this period were more likely to subsequently meet frailty criteria compared to those who maintained low CRP. These associations were stronger among white, compared to African American, participants (p-interactions <.038). Conclusions: Systemic inflammation during midlife may independently promote pathophysiological changes underlying frailty in a subset of the population. PMID- 29534174 TI - BATF2 activates DUSP2 gene expression and up-regulates NF-kappaB activity via phospho-STAT3 dephosphorylation. AB - Growing evidence has revealed that the transcription factor basic leucine zipper transcription factor ATF-like 2 (BATF2) has unique transcriptional activities, including regulating cytokines via TLR signals in macrophages, which affect mortality due to infection and cancer. On the basis of genome-wide analyses using the chromatin immunoprecipitation-sequencing technique, we found that dual specificity phosphatase 2 (Dusp2) had a significantly lower acetyl-histone status in Batf2-/- bone marrow-derived macrophages (BMDMs) compared with wild-type (WT) BMDMs. The phosphatase DUSP2 has been reported to play a critical role in inflammatory responses. Therefore, we evaluated the BATF2 transcriptional activities on the Dusp2 promoter. We found that the DUSP2 and IL-12 p40 expression levels were significantly lower in Batf2-/- BMDMs than in WT controls following their stimulation with TLR7 ligands. Further in vitro studies revealed that phospho-STAT3 was up-regulated and NF-kappaB p50/p65 were down-regulated in Batf2-/- BMDMs compared with their levels in WT controls. Additionally, Th1 immunity was impaired in Batf2-/- mice following their stimulation with TLR7 ligands. We also found that BATF2 interacts with NF-kappaB p65 and promotes DUSP2 expression through the NF-kappaB-binding site in the Dusp2 promoter at -203 to 121. Collectively, our findings suggest that BATF2 activates DUSP2 gene expression and up-regulates NF-kappaB activity via phospho-STAT3 dephosphorylation. PMID- 29534175 TI - Why are there more same-sex than opposite-sex dizygotic twins? AB - STUDY QUESTION: Are there more same-sex (SS) than opposite-sex (OS) pairs among dizygotic twins? SUMMARY ANSWER: In violation of Weinberg's Differential Rule, there are significantly more SS than OS pairs among dizygotic twins in nationally representative samples both in the UK and the USA. WHAT IS KNOWN ALREADY: Since at least 1874, twin researchers have assumed that dizygotic twins were equally likely to be SS or OS (later formalized as Weinberg's Differential Rule). However, recent research on the sex-specific nature of breastmilk suggests that OS twins might be at a developmental disadvantage relative to SS twins. There may therefore be evolutionary selection for the tendency to have SS twins and against the tendency to have OS twins. STUDY DESIGN, SIZE, DURATION: We analyze two population samples (not subject to Lykken's rule of two-thirds): the National Child Development Study in the UK (n = 17 419) from 1958 to present, and the National Longitudinal Study of Adolescent Health in the USA (n = 20 745) from 1994 to present. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a one sample t-test of the proportion of SS dizygotic twins against the theoretical null value of 0.5022. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of SS pairs among dizygotic twins was 0.6043 (t(325) = 3.838, P = 0.00015) in the UK and 0.5739 (t(520) = 3.398, P = 0.00073) in the USA. LIMITATIONS, REASONS FOR CAUTION: Twin type (monozygotic versus dizygotic) was classified by the mother, not by DNA typing, although supplementary data suggest that misclassification was negligible and supplementary analysis shows that potential misclassifications do not change our main conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Weinberg's Differential Rule may be incorrect in its assumption of independence of sexes within dizygotic pairs, and there may be evolutionary selection for SS, and against OS, dizygotic pairs. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 29534176 TI - Donor funding for family planning: levels and trends between 2003 and 2013. AB - The International Conference on Population and Development in 1994 set targets for donor funding to support family planning programmes, and recent initiatives such as FP2020 have renewed focus on the need for adequate funding to rights based family planning. Disbursements supporting family planning disaggregated by donor, recipient country and year are not available for recent years. We estimate international donor funding for family planning in 2003-13, the period covering the introduction of reproductive health targets to the Millennium Development Goals and up to the beginning of FP2020, and compare funding to unmet need for family planning in recipient countries. We used the dataset of donor disbursements to support reproductive, maternal, newborn and child health developed by the Countdown to 2015 based on the Organization for Economic Cooperation and Development Creditor Reporting System. We assessed levels and trends in disbursements supporting family planning in the period 2003-13 and compared this to unmet need for family planning. Between 2003 and 2013, disbursements supporting family planning rose from under $400 m prior to 2008 to $886 m in 2013. More than two thirds of disbursements came from the USA. There was substantial year-on-year variation in disbursement value to some recipient countries. Disbursements have become more concentrated among recipient countries with higher national levels of unmet need for family planning. Annual disbursements of donor funding supporting family planning are far short of projected and estimated levels necessary to address unmet need for family planning. The reimposition of the US Global Gag Rule will precipitate an even greater shortfall if other donors and recipient countries do not find substantial alternative sources of funding. PMID- 29534177 TI - Predictors of ischaemic mitral regurgitation recurrence in patients undergoing combined surgery: additional value of cardiovascular magnetic resonance imaging. AB - OBJECTIVES: We aimed to evaluate (i) the effectiveness of combined surgery (coronary artery bypass grafting with restrictive mitral valve annuloplasty) and (ii) the late gadolinium enhancement cardiovascular magnetic resonance-based predictors of ischaemic mitral regurgitation (IMR) recurrence. METHODS: The prospective analysis included 40 patients with multivessel coronary artery disease, IMR >II degrees and left ventricular (LV) dysfunction undergoing combined surgery. The degree of IMR and LV parameters were assessed preoperatively by transthoracic echocardiography, 3D transoesophageal echocardiography and cardiovascular magnetic resonance and postoperatively by transthoracic echocardiography. The effective mitral valve repair group (n = 30) was defined as having recurrent ischaemic mitral regurgitation (RIMR) <=II degrees at the end of follow-up (25 +/- 11 months). RESULTS: The surgery was effective: freedom from RIMR >II degrees at 1 and 2 years after surgery was 80% and 75%, respectively. Using multivariable logistic regression, 2 independent predictors of RIMR >II degrees were identified: >=3 non-viable LV segments (odds ratio 22, P = 0.027) and >=1 non-viable segment in the LV posterior wall (odds ratio 11, P = 0.026). Using classification trees, the best combinations of cardiovascular magnetic resonance-based and 3D transoesophageal echocardiography based predictors for RIMR >II degrees were (i) posterior mitral valve leaflet angle >40 degrees and LV end-systolic volume index >45 ml/m2 (sensitivity 100%, specificity 89%) and (ii) scar transmurality >68% in the inferior LV wall and EuroSCORE II >8 (sensitivity 83%, specificity 78%). CONCLUSIONS: There is a clear relationship between the amount of non-viable LV segments, especially in the LV posterior and inferior walls, and the recurrence of IMR after the combined surgery. PMID- 29534178 TI - Live birth rates in the first complete IVF cycle among 20 687 women using a freeze-all strategy. AB - STUDY QUESTION: What is the chance of having a child following one complete IVF cycle for patients using a freeze-all strategy? SUMMARY ANSWER: The chance of having a child after the first complete IVF cycle was 50.74% with the freeze-all strategy. WHAT IS KNOWN ALREADY: Several studies have reported on live birth rates (LBRs) based on only the fresh embryo transfer cycle or fresh and frozen thawed embryo transfer cycles. However, the LBR using a freeze-all strategy in IVF is unknown. STUDY DESIGN SIZE AND DURATION: This retrospective cohort study included 20 687 women who started their first IVF cycles using a freeze-all strategy during the period from 1 January 2007, through 31 March 2016, in China. PARTICIPANTS /MATERIALS, SETTING, METHODS: Data on 20 687 women undergoing their first complete cycles using a freeze-all strategy from 2007 to 2016 were analyzed to estimate LBRs. The LBR in a complete cycle was defined as the chance of a live birth from an ovarian stimulation cycle including all subsequent frozen embryo transfers from this stimulation. The relationship between LBR and number of oocyte was explored. MAIN RESULTS AND THE ROLE OF CHANCE: The LBR for the first complete cycle was 50.74% for patients using a freeze-all strategy. By age group, the LBR declined from 63.81% for women under 31 years old to 4.71% for women over 40 years old after the first complete cycle. The LBRs improved as the number of oocytes retrieved increased up to 25 in the freeze-all strategy. LIMITATION AND REASONS FOR CAUTION: This was a retrospective study without a control group. Data on BMI and smoking status were not collected in this database. WIDER IMPLICATIONS OF THE FINDINGS: Our results showed that 50.74% of patients could achieve a live birth after the first complete cycle via a freeze-all strategy. In addition, the LBRs were positively correlated with the number of oocytes retrieved via the freeze-all strategy. These findings are critical for patients and clinicians in making an informed decision to embark on IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.) and the Shanghai Ninth People's Hospital Foundation of China (JYLJ030 to Y.W.). None of the authors have any conflicts of interest to declare. PMID- 29534179 TI - Corrigendum to: 'Barriers to the availability and accessibility of controlled medicines for chronic pain in Africa'. PMID- 29534180 TI - Cohort Profile: The PROspective Quebec (PROQ) Study on Work and Health. PMID- 29534181 TI - The contribution of digestible and metabolizable energy from high-fiber dietary ingredients is not affected by inclusion rate in mixed diets fed to growing pigs. AB - Effects of inclusion rate of fiber-rich ingredients on apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of GE and on the concentration of DE and ME in mixed diets fed to growing pigs were determined. The hypothesis was that increasing the inclusion rate of fiber decreases digestibility of GE, and thus, the contribution of DE and ME from hindgut fermentation because greater concentrations may reduce the ability of microbes to ferment fiber. Twenty ileal-cannulated pigs (BW: 30.64 +/- 2.09 kg) were allotted to a replicated 10 * 4 incomplete Latin Square design with 10 diets and four 26-d periods. There were 2 pigs per diet in each period for a total of 8 replications per diet. A basal diet based on corn and soybean meal (SBM) and a corn-SBM diet with 30% corn starch were formulated. Six additional diets were formulated by replacing 15% or 30% corn starch by 15% or 30% corn germ meal, sugar beet pulp, or wheat middlings, and 2 diets were formulated by including 15% or 30% canola meal in a diet containing corn, SBM, and 30% corn starch. Effects of adding 15% or 30% of each fiber source to experimental diets were analyzed using orthogonal contrasts and t-tests were used to compare inclusion rates within each ingredient. The AID and ATTD of GE and concentration of DE and ME in diets decreased (P < 0.05) with the addition of 15% or 30% canola meal, corn germ meal, sugar beet pulp, or wheat middlings compared with the corn starch diet. However, inclusion rate did not affect the calculated DE and ME or AID and ATTD of GE in any of the ingredients indicating that concentration of DE and ME in ingredients was independent of inclusion rate and utilization of energy from test ingredients was equally efficient between diets with 15% and 30% inclusion. Increased inclusion of fiber in the diet did not influence transit time in the small intestine, but reduced the time of first appearance of digesta in the feces indicating that transit time was reduced in the hindgut of pigs fed high-fiber diets. However, this had no impact on DE and ME or ATTD of GE in test ingredients. In conclusion, fiber reduced the DE and ME in the diet. However, inclusion rate of fiber-rich ingredients in diets did not affect calculated values for DE and ME in feed ingredients indicating that microbial capacity for fermentation of fiber in pigs is not overwhelmed by inclusion of 30% high-fiber ingredients in the diets. PMID- 29534183 TI - Evaluation of coated steroidal implants containing trenbolone acetate and estradiol-17beta on live performance, carcass traits, and sera metabolites in finishing steers. AB - Crossbred beef steers (n = 240; 12 pens/treatment; initial BW = 305 +/- 17.7 kg) were used in a randomized block design feedlot study to evaluate the influence of coated trenbolone acetate (TBA) and estradiol-17beta (E2) implants (Merck Animal Health, Madison, NJ) on gain performance, carcass traits, and sera metabolites. The five treatments were no implant (NI), Revalor-XR on d 0 [200 mg TBA + 20 mg E2 (coated); XR], Revalor-XS on d 0 [200 mg TBA + 40 mg E2 (total): 80 mg TBA + 16 mg E2 (noncoated) and 120 mg TBA + 24 mg E2 (coated); XS], Revalor-200 on d 0 [200 mg TBA + 20 mg E2 (noncoated); E200], or Revalor-200 on d 70 (D200). Interim BW and blood were collected on d 0, 14, 35, 70, 105, 140, and 175 prior to feeding and on d 213 prior to shipping. Following a 24 h clot at 4 degrees C, sera was harvested to quantify circulating E2, IGF-I, NEFA, serum urea-N (SUN), and 17beta-trenbolone (17beta-TbOH). Implanted steers had greater (P <= 0.05) ADG, G:F, and final BW than NI controls. Implants increased (P < 0.05) HCW by 8%, 366 vs. 391, 414, 380, and 396 +/- 6.4 kg, for NI vs. XR, XS, E200, and D200, respectively. The greatest (P <= 0.05) dressing percentage, yield grade, and calculated empty body fat occurred in XS, which had greater (P < 0.05) rib fat than NI, XR, and D200. Marbling scores in NI were greater (P < 0.05) than E200 and D200; steers in XR and XS were intermediate (P > 0.10), not differing from NI, E200, or D200. An implant * day interaction (P <= 0.01) was noted for circulating E2, IGF-I, SUN, and 17beta-TbOH. Implanted steers had elevated (P <= 0.05) sera E2, IGF-I, and 17beta-TbOH, and decreased (P < 0.05) SUN following implantation compared to NI controls. Serum NEFA differed (P < 0.01) over time, but did not differ (P > 0.10) due to implant treatment. These data indicated that the polymer coating applied to the XR implant delayed release of steroidal hormones congruently to D200, with no negative impact on marbling. The greatest dose of E2, contained in XS, provided improvements in gain and carcass weight without detriment to marbling scores compared to NI. PMID- 29534184 TI - GP-diagnosed internalizing and externalizing problems and dropout from secondary school: a cross-sectional study. AB - Background: Dropout from secondary education is a major concern in many Western countries because it is associated with later adverse consequences at the individual and societal level. Efforts have thus been made to identify precursors for dropout. The aim of the study was to examine the risk for not finishing secondary education by age 20 when mental health problems were diagnosed during general practitioner (GP) consultations. Methods: National registries were linked to assess the association between GP-diagnosed internalizing and externalizing problems from the ages of 15-20 years and school dropout in a sample of 63 970 Norwegians, adjusting for health and social background factors. Relative risks (RR) were estimated by Poisson regression. Results: Dropout was bivariately related to both internalizing (RR = 2.2 among girls and 1.7 among boys) and externalizing problems (RR = 2.7 for girls and 2.0 for boys), though the associations were somewhat attenuated in the adjusted analyses. After controlling for somatic comorbidity and parent education level, the absolute risk for not fulfilling secondary education by age 20 was 43% among girls and 60% among boys with internalizing problems and approximately 15% points higher with externalizing problems. The highest absolute risk for dropout was found for boys and girls who have both externalizing and internalizing problems. However, with some overlap in the confidence intervals, the added impact of internalizing problems when added to externalizing problems is uncertain. Conclusions: Intervention for mental health problems by a GP could benefit adolescent education outcomes and mental well-being. PMID- 29534182 TI - Progress in the Management of Primary Aldosteronism. AB - Primary aldosteronism (PA) is now considered as one of leading causes of secondary hypertension, accounting for 5-10% of all hypertensive patients and more strikingly 20% of those with resistant hypertension. Importantly, those with the unilateral disease could be surgically cured when diagnosed appropriately. On the other hand, only a very limited portion of those suspected to have PA has been screened, diagnosed, or treated to date. With current advancement in medical technologies and genetic research, expanding knowledge of PA has been accumulated and recent achievements have also been documented in the care of those with PA. This review is aimed to have focused description on updated topics of the following; importance of PA screening both in the general and specialized settings and careful interpretation of screening data, recent achievements in hormone assays and sampling methods and their clinical relevance, and expanding knowledge on PA genetics. Improvement in workup processes and novel treatment options, as well as better understanding of the PA pathogenesis based on genetic research, might be expected to result in increased cure and better care of the patients. PMID- 29534185 TI - Evaluation of the Xpert HCV Viral Load Finger-Stick Point-of-Care Assay. AB - Point-of-care hepatitis C virus (HCV) RNA testing is advantageous, enabling diagnosis of active infection in a single visit. This study evaluated the sensitivity and specificity of the Xpert HCV Viral Load Finger-Stick assay (Xpert HCV VL FS) for HCV RNA detection (finger-stick) and the Xpert HCV Viral Load assay (plasma) compared with the Abbott RealTime HCV Viral Load assay by venepuncture. Plasma and finger-stick capillary whole-blood samples were collected from participants in an observational cohort in Australia. Of 223 participants enrolled, HCV RNA was detected in 40% of participants (85 of 210) with available Xpert HCV Viral Load testing. Participants receiving HCV therapy were excluded from subsequent analyses (n = 16). Sensitivity of the Xpert HCV Viral Load assay for HCV RNA quantification in plasma collected by venepuncture was 100.0% (95% confidence interval [CI] 96.9%-100.0%) and specificity was 100.0% (95% CI, 94.4%-100.0%). Sensitivity of the Xpert HCV VL FS assay for HCV RNA quantification in samples collected by finger-stick was 100.0% (95% CI, 93.9% 100.0%) and specificity was 100.0% (95% CI, 96.6%-100.0%). The Xpert HCV VL FS test can accurately detect active infection from a finger-stick sample in 1 hour allowing single-visit HCV diagnosis. PMID- 29534186 TI - Early initiation of peritoneal dialysis improves postoperative recovery in children with right ventricular outflow tract obstructive lesions at high risk of fluid overload: a propensity score-matched analysis. AB - OBJECTIVES: Postoperative fluid overload is common in children after cardiac surgery, especially for those with right ventricular outflow tract obstruction, which is associated with poor outcomes. This study was conducted to investigate whether early peritoneal dialysis (PD) was associated with improved outcomes in these children at high risk of fluid overload. METHODS: Between January 2010 and January 2015, a total of 2555 consecutive patients with right ventricular outflow tract obstruction underwent anatomical repair. Using empirical risk evaluation, 219 patients at high risk of fluid overload were identified. A propensity score matching was performed to correct the selection bias and identify the comparable patient groups: the early PD group, in whom PD was initiated within 6 h of admission in paediatric ICU, and the control group, without early PD. The mechanical ventilation time, vasoactive-inotropic score and time to negative fluid balance were compared in 45 matched patient pairs (totally 90). RESULTS: After propensity matching, there were no statistically significant differences between the 2 groups in terms of demographics and preoperative characteristics. The early PD group had shorter mechanical ventilation time [median 49 h, interquartile range (IQR) 31-97 h vs median 76 h, IQR 55-166 h; P < 0.01]; lower vasoactive-inotropic score (median 17, IQR 16-21 vs median 22, IQR 18-26; P < 0.01); shorter duration of inotrope requirement (median 7 days, IQR 6-9 days vs median 8 days, IQR 7-13 days; P < 0.01); shorter time to negative fluid balance (median 20 h, IQR 13-34 h, vs median 48 h, IQR 40-74 h; P < 0.01) and a higher rate of negative fluid balance at 24 h (69% vs 29%, P < 0.01). CONCLUSIONS: When compared with the control group, the early PD group showed shorter mechanical ventilation time, less inotropic requirement and lower time to attain negative fluid balance. On the basis of our empirical risk-evaluation practice, early PD could improve immediate postoperative recovery in children with right ventricular outflow tract obstruction. PMID- 29534187 TI - Impact of PRRSV infection and dietary soybean meal on ileal amino acid digestibility and endogenous amino acid losses in growing pigs. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant disease in the swine industry, and increasing soybean meal (SBM) consumption during this disease challenge may improve performance. Our objectives were to determine the impact of SBM level on apparent total tract (ATTD) and ileal (AID) digestibility during PRRSV infection and to determine ileal basal endogenous losses (BEL) during PRRSV infection. Forty PRRSV negative gilts were fitted with a T-cannula in the distal ileum. Treatments were arranged in a 2 * 2 factorial with high and low SBM (HSBM, 29% vs. LSBM, 10%), with and without PRRSV (n = 6/treatment). The remaining pigs (n = 8/challenge status) were fed a N-free diet. Chromic oxide was used as an indigestible marker. On day post inoculation (dpi) 0, at 47.7 +/- 0.57 kg BW, 20 pigs were inoculated with live PRRSV; 20 control pigs were sham inoculated. Infection was confirmed by serum PCR. Feces were collected at dpi 5 to 6 and dpi 16 to 17, and ileal digesta collected at dpi 7 to 8 and dpi 18 to 19. Feed, feces, and digesta were analyzed for DM, N, and GE. Digesta and feed were analyzed for AA. Data were analyzed in a 2 * 2 + 2 factorial design to determine main effects of diet and PRRSV and their interaction. Data from N-free fed pigs were analyzed separately to determine BEL and hindgut disappearance due to PRRSV infection. All control pigs remained PRRSV negative. There were no interactions for AID of AA; however, HSBM reduced DM, GE, Lys, and Met AID and increased Arg and Gly AID during both collection periods (P < 0.05). At dpi 7 to 8 only, PRRSV reduced DM and GE AID (P < 0.05). At 7 to 8 dpi, BEL of Arg, Ala, and Pro were reduced (P < 0.05) due to PRRSV by 64%, 39%, and 94%, respectively. At dpi 18 to 19, BEL of Thr tended (P = 0.06) to be increased in PRRSV-infected pigs; however, no other differences were observed. Pigs fed LSBM had increased Lys, Met, Thr, Trp, and Pro standardized ileal digestibility (SID), primarily at 7 to 8 dpi. At 7 to 8 dpi, PRRSV reduced Arg, Gly, and Pro SID (P < 0.01), and SID Pro continued to be reduced by 17% at dpi 18 to 19. Compared with HSBM pigs, LSBM reduced hindgut disappearance of DM and GE at dpi 5 to 8 and dpi 16 to 19, while N disappearance was reduced at dpi 5 to 8. There were no differences between control and PRRSV N-free fed pigs. Altogether, SBM inclusion impacts SID of AA and hindgut disappearance of nutrients, regardless of PRRSV. In contrast, there is minimal impact of PRRSV on BEL, and therefore, SID of most AA are not different. PMID- 29534188 TI - Incidence of Unplanned 30-Day Readmissions in Adult Burn Patients in the United States. AB - This study characterizes adult burn readmissions in the United States using a nationally representative hospital inpatient sample. Readmission rates, diagnoses, and risk factors are discussed. We analyzed the 2013 and 2014 Nationwide Readmission Database for adult burn patients. The data were weighted to estimate national 30-day readmission rates. Principal readmission diagnoses were sorted into burn-specific or other readmission categories. We used multivariable logistic regression to assess the effects of patient and hospital stay risk factors on readmissions. An estimated 42,957 U.S. adult burn patients were discharged between January and November of 2013 and 2014. Of these patients, an estimated 3203 had unscheduled readmissions within 30 days (all-cause readmission rate: 7.5%, 95% CI: 6.7-8.2). An estimated 55.4 per cent of unplanned readmissions were for burn-specific principal readmission diagnoses. Burn specific readmission was associated with burn severity and increased with both patient age and the number of comorbidities. Patients whose length of stay was less than 1 day per % total body surface area (%TBSA) burned had higher readmission risk (Adjusted odds ratio = 2.10, 95% CI = 1.48-2.99). The results of logistic regression models were similar for burn-specific readmissions and all cause readmissions. In a nationally representative sample of adult burn patients, 4.1 per cent had unplanned 30-day readmissions for burn-specific reasons; 7.5 per cent were readmitted for any reason. Patient comorbidities and discharge before 1 day per %TBSA from the hospital impact readmission risk. Healthcare providers can use this information to identify at-risk patients, modify their treatment plans, and prevent readmissions. PMID- 29534189 TI - Reoperation for coronary artery stenosis after arterial switch operation. AB - OBJECTIVES: Coronary artery stenosis after an arterial switch operation (ASO) leads to subsequent reoperation. Therefore, we investigated the indications for reoperation and the results of reoperation to suggest methods to improve our management protocol for coronary artery stenosis after an ASO. METHODS: Between September 2003 and December 2016, 86 consecutive patients who underwent an ASO were included in the study. The indications for reoperation, reoperation techniques and postoperative results were investigated. RESULTS: There were 4 in hospital deaths (4.7%). One late death occurred during the median follow-up period of 59.6 months. The 5-year overall survival rate was 94.2%. Seven reoperations were performed in 5 patients due to coronary artery stenosis. The indications for reoperation were severe coronary artery stenosis confirmed by computed tomography (CT) angiography or coronary angiography with or without symptoms. Patients with a coronary artery between the great arteries or a high take-off coronary artery frequently required reoperation due to coronary artery stenosis. None of the patients who underwent unroofing or cut-back angioplasty experienced complications during the median follow-up period of 52.0 months. However, 2 patients who underwent ostioplasty required an additional reoperation due to coronary artery restenosis. CONCLUSIONS: A standardized follow-up protocol including CT angiography or coronary angiography after the ASO is required to address coronary artery stenosis. Good reoperation results were observed using the unroofing and cut-back angioplasty techniques. PMID- 29534190 TI - Susceptibility of the Lesser Mealworm, Alphitobius diaperinus (Coleoptera: Tenebrionidae), From Broiler Farms of Southern Brazil to Insecticides. AB - The lesser mealworm, Alphitobius diaperinus (Panzer, 1797) (Coleoptera: Tenebrionidae), is considered the primary insect pest in broiler farms in Brazil. In this study, we characterized the susceptibility of A. diaperinus populations from broiler farms of southern Brazil to cypermethrin and chlorpyrifos. Larvae and adults of A. diaperinus were exposed to these technical insecticides diluted in acetone in residual bioassays. A geographic variation in the susceptibility of larvae and adults of A. diaperinus to both insecticides was detected. The larval LC50 for cypermethrin ranged from 0.43 to 7.33 ug a.i./cm2. Two populations from Santa Catarina state presented higher resistance ratios of 13.6- and 17-fold. When adults were exposed to cypermethrin, the LC50 ranged from 0.46 to 4.93 ug a.i./cm2, with population SC-3 from Santa Catarina having lower susceptibility (resistance ratio of 10.7-fold). When exposed to chlorpyrifos, A. diaperinus larvae present LC50 values ranging from 0.21 to 4.30 ug a.i./cm2. Larvae from Parana and Santa Catarina (SC-1 population) presented the highest resistance ratios, ranging from 10- to 20-fold. In adults, the LC50 of chlorpyrifos ranged from 0.17 to 5.30 ug a.i./cm2, showing a maximum resistance ratio of 31-fold in a population from Parana state. Based on LC99 values, candidate diagnostic concentrations of 15 and 12 ug a.i./cm2 of cypermethrin and chlorpyrifos, respectively, were also estimated for the resistance monitoring of A. diaperinus in Brazil. The implications of these results in Insect Resistance Management are discussed. PMID- 29534191 TI - Immunoproteasome in the Plasma of Pediatric Patients With Moderate and Major Burns, and Its Correlation With Proteasome and UCHL1 Measured by SPR Imaging Biosensors. AB - The aim of this study was to determine the immunoproteasome concentration in blood plasma of pediatric patients with moderate and major burns and its correlation with circulating proteasome and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) with surface plasmon resonance imaging biosensor. The study population comprised of 30 patients with moderate (n = 21) and severe burns (n = 9), aged 9 months to 14 years. The control group represented 18 healthy, age-matched patients, admitted for herniotomy. Exclusion criteria were as follows: admission to the hospital later than 6 hours after burn, cardiovascular or immunological diseases, and severe preexisting infections. Mean concentrations of immunoproteasome, 20S proteasome, and UCHL1 in the blood plasma of children with burns-4 to 6 hours, 12 hours, 3 days, 5 days, and 7 days after thermal injury were above the levels measured in controls. The immunoproteasome, 20S proteasome, and UCHL1 concentrations in the blood plasma of their patients were highest 12 hours after burn, slowly decreased over time, and on the 5th day still were higher than in controls (P < .05). There was a strong correlation between immunoproteasome and 20S proteasome concentrations 6 hours and 5 days after burn, and moderate correlation 12 hours after burn (P < .05). The immunoproteasome concentration is elevated after burn injury and slowly reaches the normal range during the wound healing process. There is strong correlation between immunoproteasome and 20S proteasome concentrations in the serum of children with moderate and major burns. They did not find such correlation between immunoproteasome and UCHL1 concentrations. Immunoproteasome concentration do not correlate with age or sex. PMID- 29534192 TI - Past and current asbestos exposure and future mesothelioma risks in Britain: The Inhaled Particles Study (TIPS). AB - Background: Occupational and environmental airborne asbestos concentrations are too low and variable for lifetime exposures to be estimated reliably, and building workers and occupants may suffer higher exposure when asbestos in older buildings is disturbed or removed. Mesothelioma risks from current asbestos exposures are therefore not known. Methods: We interviewed and measured asbestos levels in lung samples from 257 patients treated for pneumothorax and 262 with resected lung cancer, recruited in England and Wales. Average lung burdens in British birth cohorts from 1940 to 1992 were estimated for asbestos-exposed workers and the general population. Results: Regression analysis of British mesothelioma death rates and average lung burdens in birth cohorts born before 1965 suggests a lifetime mesothelioma risk of approximately 0.01% per fibre/mg of amphiboles in the lung. In those born since 1965, the average lung burden is ~1 fibre/mg among those with no occupational exposure. Conclusions: The average lifetime mesothelioma risk caused by recent environmental asbestos exposure in Britain will be about 1 in 10 000. The risk is an order of magnitude higher in a subgroup of exposed workers and probably in occupants in the most contaminated buildings. Further data are needed to discover whether asbestos still present in buildings, particularly schools, is a persistent or decreasing hazard to workers who disturb it and to the general population, and whether environmental exposure occurs predominantly in childhood or after beginning work. Similar studies are needed in other countries to estimate continuing environmental and occupational mesothelioma hazards worldwide, including the contribution from chrysotile. PMID- 29534193 TI - Modified Ross-Konno procedure in children: subcoronary implantation technique with Konno incision for annular and subannular hypoplasia. AB - OBJECTIVES: The technique of subcoronary autograft implantation for the Ross procedure has shown excellent durability of aortic valve function in adults. However, its use in children with hypoplastic aortic annulus or multilevel left ventricular outflow tract obstruction (LVOTO) was traditionally precluded. We combined this technique with a Konno incision and evaluated LVOTO relief and durability of the autograft function in growing patients. METHODS: Between January 2012 and January 2017, 13 patients with severe LVOTO and hypoplastic aortic annulus underwent Ross-Konno procedure with subcoronary autograft implantation. The median age at operation was 14 months. Six were infants. Concomitant procedures included resection of endocardial fibroelastosis (n = 9), mitral valvuloplasty (n = 2) and aortic arch repair (n = 1). The Konno incision was enlarged with a patch. The autograft was implanted beneath the ostia of the coronary arteries, retaining external support by the native aortic annulus. RESULTS: A newborn with hypoplastic left heart complex and Turner syndrome died in hospital: early mortality of 7.7%. No residual LVOTO or autograft regurgitation was observed at discharge. At a median follow-up of 20 months, no death had occurred. No catheter or surgical reintervention on the aortic valve or any LVOT site was needed. All peak pressure gradients across the LVOT were <10 mmHg. No autograft regurgitation was detected. CONCLUSIONS: The Ross procedure using subcoronary implantation technique combined with LVOT Konno enlargement is feasible even in patients with multilevel LVOTO and marked size discrepancy between the autograft and native aortic annulus. Longer follow-up is indicated to confirm the expected durability of the autograft function. PMID- 29534194 TI - The essence of appetite: does olfactory receptor variation play a role? AB - Olfactory receptors are G-protein-coupled chemoreceptors expressed on millions of olfactory sensory neurons within the nasal cavity. These receptors detect environmental odorants and signal the brain regarding the location of feed, potential mates, and the presence of possible threats (e.g., predators or chemical toxins). Olfactory receptors also are present in organs outside of the nasal cavity where they bind to molecules such as nutrients and metabolites from the animal's internal environment to elicit physiological responses, including changes in gut motility, ventilation rate, and cellular migration. Recent evidence supports an additional role of olfactory receptors in the regulation of appetite in humans and rodents. In particular, genetic variation among individuals in specific odorant receptor genes has been linked to differences in their feeding behaviors, food choices, and the regulation of energy balance. This review provides a general overview of the olfactory receptors of vertebrates and their genetic variability and provides supporting evidence for a physiological role of olfactory receptors in appetite regulation of livestock. Basic research on olfactory receptors of livestock and their ligands should facilitate the development of novel odorant receptor agonists and identification of specific olfactory receptor variants that may be developed to enhance animal production efficiency. PMID- 29534195 TI - Effects of Sex Steroids on the Spinal Gastrin-Releasing Peptide System Controlling Male Sexual Function in Rats. AB - The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord controls male sexual function in rats. In contrast, in female rats, GRP neurons could scarcely be detected around puberty when circulating ovarian steroid hormones such as estradiol and progesterone levels are increasing. However, little information is available on feminizing or demasculinizing effects of ovarian steroids on the central nervous system in female puberty and adulthood. In this study, to visualize the spinal GRP neurons in vivo, we generated a GRP promoter-Venus transgenic (Tg) rat line and studied the effects of the sex steroid hormones on GRP expression in the rat lumbar cord by examining the Venus fluorescence. In these Tg rats, the sexually dimorphic spinal GRP neurons controlling male sexual function were clearly labeled with Venus fluorescence. As expected, Venus fluorescence in the male lumbar cord was markedly decreased after castration and restored by chronic androgen replacement. Furthermore, androgen induced Venus expression in the spinal cord of adult Tg males was significantly attenuated by chronic treatment with progesterone but not with estradiol. A luciferase assay using a human GRP-promoter construct showed that androgens enhance the spinal GRP system, and more strikingly, that progesterone acts to inhibit the GRP system via an androgen receptor-mediated mechanism. These results demonstrate that circulating androgens may play an important role in the spinal GRP system controlling male sexual function not only in rats but also in humans and that progesterone could be an important feminizing factor in the spinal GRP system in females during pubertal development. PMID- 29534196 TI - Identification of oxidatively modified proteins due to cryopreservation of carp semen. AB - During semen cryopreservation, spermatozoa are exposed to physical and chemical stressors that result in their functional and structural damage. Growing evidence suggests that most cryoinjuries result from oxidative stress accompanying sperm cryopreservation. Elevated amounts of reactive oxygen species (ROS) generated during cryopreservation can react with sperm macromolecules, including proteins. The goal of this study was to investigate the oxidative modifications (measured as carbonylation level changes) of carp spermatozoa proteins triggered by the cryopreservation process. Flow cytometry and computer-assisted sperm analysis were used to evaluate changes in viability, ROS level, and motility of spermatozoa. The spermatozoa proteins that were specifically carbonylated were identified and quantified by Western blotting, in conjunction with 2-dimensional electrophoresis (2D-oxyblot) and matrix-assisted laser desorption/ionization time of-flight/time-of-flight mass spectrometry. Cryopreservation decreased spermatozoa motility (P < 0.01) and viability (P < 0.0001) and significantly increased (P < 0.0001) the number of ROS-positive cells. We identified 25 protein spots, corresponding to 19 proteins, with increases (P < 0.05) in carbonylation level due to freezing/thawing. The identified proteins are involved in motility, metabolism, calcium-ion binding, signal transduction, protein folding, and intracellular transport. The results suggest that carbonylation of flagellar proteins can result in motility disorders and may contribute to the reduced percentage of motile spermatozoa and disturbances in movement trajectory after sperm cryopreservation. Moreover, cryopreservation may contribute to impaired cellular respiration, ATP regeneration, disturbances of Ca2+ turnover, unfolding of cytoplasmic or histone proteins, disturbances of cell signaling and intracellular transport, and reduced membrane stability. Our results contribute to the knowledge concerning cryoinjury and to further development of a modified cryopreservation procedure aimed at minimizing oxidative damage of carp sperm proteins. PMID- 29534197 TI - Using Medicare Claims to Examine Long-term Prostate Cancer Risk of Finasteride in the Prostate Cancer Prevention Trial. AB - Background: Investigators have used administrative claims to better understand cancer outcomes when a research question cannot feasibly be examined within a study. The Prostate Cancer Prevention Trial (PCPT) showed that seven years of finasteride reduced prostate cancer (PC) risk by 25% in men age 55 years or older. However, it was unclear whether the observed reduction in PC for finasteride participants would be maintained after finasteride discontinuation. Methods: We examined PC diagnoses identified by PCPT study records and Medicare claims (finasteride = 9423, placebo = 9457). A Medicare-defined PC diagnosis algorithm was defined using diagnosis and procedure codes. Multivariable Cox regression was used to examine time to PC within prespecified follow-up windows (<6.5, 6.5-7.5, and >7.5 years) using time-dependent covariates interacting with intervention assignment to account for the PCPT protocol-specified end-of-study biopsy at seven years. All statistical tests were two-sided. Results: Median follow-up using the linked database was 16 years. Overall, finasteride arm participants had a 21.1% decrease in the hazard ratio of PC (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.74 to 0.84, P < .001). The beneficial effect of finasteride in reducing the hazard ratio of PC was most pronounced in the first 7.5 years (HR = 0.71, 95% CI = 0.66 to 0.77, P < .001), consistent with the original study findings; after 7.5 years, there was no increased risk of PC for finasteride arm participants (HR = 1.10, 95% CI = 0.96 to 1.26, P = .18). Conclusions: Finasteride provides a substantial reduction in PC through 16 years of follow-up. There was no strong evidence that the benefit of finasteride diminished after the end-of-study follow-up. Utilizing Medicare claims to augment PCPT follow-up illustrates how the novel use of secondary data sources can enhance the ability to detect long-term outcomes from prospective studies. PMID- 29534199 TI - Antibiotic resistance genes show enhanced mobilization through suspended growth and biofilm-based wastewater treatment processes. AB - Wastewater treatment plants (WWTPs) are known to harbor antibiotic resistance genes (ARGs) that are disseminated into the environment via effluent. However, few studies have compared abundance, mobilization and selective pressures for ARGs in WWTPs as a function of variations in secondary treatment bioprocesses. We used shotgun metagenomics to provide a comprehensive analysis of ARG composition, relationship to mobile genetic elements and co-occurrences with antibiotic production genes (APGs) throughout two full-scale municipal WWTPs, one of which employs biofilm-based secondary treatment and another that uses a suspended growth system. Results showed that abundances of ARGs declined by over 90% per genome equivalent in both types of wastewater treatment processes. However, the fractions of ARGs associated with mobile genetic elements increased substantially between influent and effluent in each plant, indicating significant mobilization of ARGs throughout both treatment processes. Strong positive correlations between ARGs and APGs were found for the aminoglycoside antibiotic class in the suspended growth system and for the streptogramin antibiotic class in the biofilm system. The biofilm and suspended growth WWTPs exhibited similarities in ARG abundances, composition and mobilization trends. However, clear differences were observed for within-plant ARG persistence. These findings suggest that both biofilm and suspended growth-based WWTPs may promote genetic mobilization of persistent ARGs that are then disseminated in effluent to receiving water bodies. PMID- 29534198 TI - 18F-FDOPA PET/CT Imaging of MAX-Related Pheochromocytoma. AB - Context: MYC-associated factor X (MAX) has been recently described as a new susceptibility pheochromocytoma (PHEO) gene with a total of ~40 reported cases. At present, no study has specifically described the functional imaging phenotype of MAX-related PHEO. Objective, Patients, and Design: The objective of the present study was to present our experience with contrast-enhanced computed tomography (CT) and 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET)/CT in six consecutive patients (four at the initial diagnosis and two at the follow-up evaluation) with rare, but clinically important, MAX-related PHEOs. In five patients, 18F-FDOPA was also compared with other radiopharmaceutical agents. Results: The patients had five different mutations in the MAX gene that caused disruption of Max/Myc interaction and/or abolished interaction with DNA based on in silico analyses. All but one patient developed bilateral PHEOs during their lifetime. In all cases, 18F-FDOPA PET/CT accurately visualized PHEOs that were often multiple within the same gland or bilaterally and detected more adrenal and extra-adrenal lesions than did CT (per lesion sensitivity, 90.9% vs 52.4% for CT/magnetic resonance imaging). The two PHEOs missed on 18F-FDOPA PET/CT were <1 cm, corresponding to nodular adrenomedullary hyperplasia. 68Ga-DOTA,Tyr3-octreotate PET/CT detected fewer lesions than did 18F-FDOPA PET/CT in one of three patients, and 18F fluorodeoxyglucose PET/CT was only faintly positive in two of four patients with underestimation of extra-adrenal lesions in one patient. Conclusions: MAX-related PHEOs exhibit a marked 18F-FDOPA uptake, a finding that illustrates the common well-differentiated chromaffin pattern of PHEOs associated with activation of kinase signaling pathways. 18F-FDOPA PET/CT should be considered as the first line functional imaging modality for diagnostic or follow-up evaluations for these patients. PMID- 29534200 TI - Pyraclostrobin Impairs Energetic Mitochondrial Metabolism and Productive Performance of Silkworm (Lepidoptera: Bombycidae) Caterpillars. AB - Silkworm cocoon production has been reduced due to a number of problems other than those inherent in sericulture, such as diseases, malnutrition, and inappropriate management. The use of pesticides in areas surrounding mulberry fields can contaminate these plants and consequently harm caterpillars. The aim of this study was to evaluate whether the application of the fungicide pyraclostrobin in mulberry plants interferes with the mitochondrial bioenergetics and the productive performance of silkworms. Mulberry plants were treated with pyraclostrobin (0, 100, 200, and 300 g ha-1). After 30 d of fungicide application, fifth instar caterpillars were fed with leaves from the treated plants. We evaluated in vitro and in vivo mitochondrial bioenergetics of mitochondria from the head and intestines, as well as the feed intake and mortality rate of the caterpillars and the weight of fresh cocoons and cocoons shells. At doses of 50 uM (in vitro) and 200 g ha-1 (in vivo), pyraclostrobin inhibited oxygen consumption in state 3, dissipated membrane potential, and inhibited ATP synthesis in mitochondria. Pyraclostrobin acted as a respiratory chain inhibitor, affecting mitochondrial bioenergetics. The fungicide did not interfere with food consumption but negatively affected mortality rate and weight of cocoons. Mulberry leaves contaminated with pyraclostrobin negatively impact the mitochondrial bioenergetics of silkworms and cocoon production. PMID- 29534201 TI - In vitro activity of amphotericin B-azole combinations against Malassezia pachydermatis strains. AB - Combination therapy has become popular in clinical practice, but limited data on the effects of combinations of antifungal agents is still available for most fungal pathogens. We studied the in vitro response of 30 genetically diverse clinical strains of the basidiomycetous lipophilic yeast Malassezia pachydermatis obtained from cases of canine otitis to several amphotericin B (AMB)-azole combinations. Broth microdilution checkerboard tests revealed that AMB antagonized the effects of itraconazole (ITC) and voriconazole (VRC) in 50% and 6.7% of the strains, respectively, but did not interact with fluconazole or posaconazole (fractional inhibitory concentration index (FICI) values were <4 in all cases). Subsequent Etest-based assays performed for a subset of strains did not confirm the antagonism between AMB and ITC or AMB and VRC. In summary, the results of this study suggest that antagonistic combination effects between AMB and azoles might occur when tested against M. pachydermatis. Nevertheless, as observed for other fungi, different in vitro analyses yielded contrasting results, and the response to AMB-azole combinations was compound- and strain dependant. PMID- 29534202 TI - Structural changes in DNA-binding proteins on complexation. AB - Characterization and prediction of the DNA-biding regions in proteins are essential for our understanding of how proteins recognize/bind DNA. We analyze the unbound (U) and the bound (B) forms of proteins from the protein-DNA docking benchmark that contains 66 binary protein-DNA complexes along with their unbound counterparts. Proteins binding DNA undergo greater structural changes on complexation (in particular, those in the enzyme category) than those involved in protein-protein interactions (PPI). While interface atoms involved in PPI exhibit an increase in their solvent-accessible surface area (ASA) in the bound form in the majority of the cases compared to the unbound interface, protein-DNA interactions indicate increase and decrease in equal measure. In 25% structures, the U form has missing residues which are located in the interface in the B form. The missing atoms contribute more toward the buried surface area compared to other interface atoms. Lys, Gly and Arg are prominent in disordered segments that get ordered in the interface on complexation. In going from U to B, there may be an increase in coil and helical content at the expense of turns and strands. Consideration of flexibility cannot distinguish the interface residues from the surface residues in the U form. PMID- 29534203 TI - Behavioral Variant Frontotemporal Dementia as a Serious Complication of Spontaneous Intracranial Hypotension. AB - BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is a devastating early onset dementia. Symptoms of bvFTD may be caused by spontaneous intracranial hypotension (SIH), a treatable disorder, but no comprehensive study of such patients has been reported. OBJECTIVE: To describe detailed characteristics of a large cohort of patients with SIH and symptoms of bvFTD. METHODS: We identified patients with SIH who met clinical criteria for bvFTD. Patients were compared to a cohort of SIH patients without bvFTD. RESULTS: The mean age for the 21 men and 8 women was 52.9 yr (range, 37-65 yr). All 29 patients with bvFTD symptoms had hypersomnolence. Magnetic resonance imaging showed brain sagging in all patients, cerebrospinal fluid (CSF) opening pressure low in about half of patients, but a spinal CSF leak could not be detected in any patient. All patients underwent epidural blood patching, but 26 patients eventually underwent 1 or more surgical procedures. Overall, a good outcome was obtained in 21 patients (72%); 20 (91%) of 22 patients who had not undergone prior Chiari surgery compared to 1 (14%) of 7 patients who did undergo Chiari surgery (P < .003). Compared to SIH patients without symptoms of bvFTD (n = 547), those with bvFTD symptoms were older, more often male, less often demonstrated CSF leak on spinal imaging, and more often underwent surgery (P < .02). CONCLUSION: bvFTD in SIH is rare and associated with brain sagging and hypersomnolence. Spinal CSF leaks are rarely detected. bvFTD symptoms are often refractory to the usual percutaneous procedures but most patients can be cured. PMID- 29534204 TI - Is 8% O2 more normoxic than 21% O2 for long-term in vitro cultures of human primary term cytotrophoblasts? AB - STUDY QUESTION: Is 8% O2 a better percentage of atmospheric oxygen for long-term cultures of human primary term cytotrophoblasts than the conventional 21% O2 traditionally used in cell culture? SUMMARY ANSWER: Human primary term cytotrophoblasts are able to differentiate into syncytiotrophoblasts under both atmospheric oxygen levels. WHAT IS KNOWN ALREADY: Cell culture is traditionally done under 21% O2, which is equal to a pO2 of ~160 mm Hg. Based on the pO2 measured after instauration of the blood circulation within the placenta, it has been proposed that cytotrophoblasts culture should be under 8% O2, which is equivalent to 60 mm Hg, and that this percentage should be considered as the physiological normoxia for cytotrophoblasts. STUDY, DESIGN, SIZE, DURATION: Cytotrophoblasts were isolated and purified from human term placentas (n > 4). Cells were cultured under 21% O2 and 8% O2 for 12 days. Several cellular parameters were assessed on Days 2, 4, 8 and 12. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placentas were obtained after vaginal or elective cesarean delivery from uncomplicated pregnancies at term (n >= 4). Cell viability was measured by a luminescent assay based on quantitation of the ATP content of living cells. Cell fusion was assessed by quantification of syncytin and e-cadherin mRNA expression by real-time PCR and determination of the fusion index by immunofluorescent microscopy. Trophoblast differentiation was assessed by measuring the expression levels of hCGbeta, inhibin alpha subunit (InhA) and placental growth factor (PlGF) by real-time PCR and ELISA. Finally, the effect of the two oxygen levels on apoptosis and cellular oxidative stress was also investigated by quantifying caspase 3/7 activation, superoxide dismutase 1 (SOD-1) mRNA expression and H2O2 generation. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference between 21% O2 and 8% O2 on cell viability. Cell fusion seemed to be enhanced during the first 4 days when the cells were cultured under 21% O2 compared to 8% O2. The expression level of hCGbeta was equivalent in both oxygen conditions, indicating that there was no difference in trophoblast differentiation. Interestingly, InhA expression was higher under 8% O2, while PlGF expression was inhibited compared to 21% O2. This latter result indicates that 8% O2 may be more hypoxic than normoxic for in vitro culture of primary term cytotrophoblast. This is further corroborated by the fact that 21% O2 did not significantly increase caspase 3/7 activities and the oxidative stress (SOD-1 mRNA expression and H2O2 generation) in our cell cultures. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: The in vitro culture of cytotrophoblasts is artificial and does not reflect the in vivo situation. The cell population is nearly 100% pure, cultured as a monolayer, and the cells bath in a chemically defined culture medium deprived of any oxygen carrier. The oxygen molecules available to the cells are passively dissolved in the medium. The gas dissolution properties of the medium and the cellular consumption rate of oxygen may allow the cells to sustain a wide range of oxygen percentages from 8% to 21%. WIDER IMPLICATIONS OF THE FINDINGS: It is possible to culture human primary term cytotrophoblasts for at least 12 days. The O2 percentage of the air does not negatively affect in vitro cytotrophoblast differentiation. For in vitro culture of cytotrophoblasts, it is not necessary to lower the percentage of atmospheric oxygen to 8%. STUDY FUNDING/COMPETING INTEREST(S): This work was fully supported by 'Fetus for Life' charity. The authors state that there is no conflict of interest to declare regarding the publication of this paper. PMID- 29534205 TI - Bifrontal Craniotomy for Resection of Recurrent Fibrous Dysplasia: 2-Dimensional Operative Video. PMID- 29534206 TI - Systematic review: impact of liver transplantation on employment. AB - Background: The majority of liver transplant recipients survive long term after the procedure. Aim: To assess if this positive outcome is associated with improved employment post-transplant. Methods: A systematic review of publications between 2001 and 2016 was performed. A standard procedure was used to search for suitable publications from two databases (PubMed and EMBASE). Duplicates were removed and abstracts screened by both authors for possible inclusion. Possible suitable publications were obtained and examined for the presence of pre- and post-employment information. Full articles that had this information were reviewed by standard methodology for assessment of bias. Results: A total of 162 individual abstracts were screened. Thirty-five full papers were reviewed and 13 papers included in the detailed review. Risk of bias was considered high due to low response rates, poor assessment of prognostic and confounding factors and varying definitions of employment. Heterogeneous data precluded meta-analysis. Eight studies focused on return to work as a primary outcome and five on quality of life with employment as a secondary outcome. Follow-up varied between 2 and 13 years. Rates of employment fell in all studies assessed. Employment rates ranged from 26 to 80% pre-transplant and 18 to 44% post-transplant. The proportion of those categorized as ill-health retired was 24% greater after orthotopic liver transplantation. Conclusions: Improved survival after liver transplantation was not reflected in a return to employment and retirement was common. Areas for further study include interventions to minimize physical deconditioning, depression associated with lower employment rates and type of work available after transplant. PMID- 29534208 TI - Pituitary apoplexy with a binasal visual field defect. PMID- 29534207 TI - Role of Macrophages and Plasminogen Activator Inhibitor-1 in Delayed Bone Repair in Diabetic Female Mice. AB - Delayed fracture healing is a clinical problem in diabetic patients. However, the mechanisms of diabetic delayed bone repair remain unknown. Here, we investigate the role of macrophages in diabetic delayed bone repair after femoral bone injury in streptozotocin (STZ)-treated and plasminogen activator inhibitor-1 (PAI-1) deficient female mice. STZ treatment significantly decreased the numbers of F4/80 positive cells (macrophages) but not granulocyte-differentiation antigen-1 positive cells (neutrophils) at the damaged site on day 2 after femoral bone injury in mice. It significantly decreased the messenger RNA (mRNA) levels of macrophage colony-stimulating factor, inducible nitric oxide synthase (iNOS), interleukin (IL)-6, and CD206 at the damaged site on day 2 after bone injury. Moreover, STZ treatment attenuated a decrease in the number of hematopoietic stem cells in bone marrow induced by bone injury. On the other hand, PAI-1 deficiency significantly attenuated a decrease in the number of F4/80-positive cells induced by STZ treatment at the damaged site on day 2 after bone injury in mice. PAI-1 deficiency did not affect the mRNA levels of iNOS and IL-6 in F4/80- and CD11b double-positive cells from the bone marrow of the damaged femurs decreased by diabetes in mice. PAI-1 deficiency significantly attenuated the phagocytosis of macrophages at the damaged site suppressed by diabetes. In conclusion, we demonstrated that type 1 diabetes decreases accumulation and phagocytosis of macrophages at the damaged site during early bone repair after femoral bone injury through PAI-1 in female mice. PMID- 29534210 TI - Promoting positive condom use experiences among young black MSM: a randomized controlled trial of a brief, clinic-based intervention. AB - The aim of this study is to determine, among young Black men who have sex with men (YBMSM), the 12-month efficacy of a single-session, clinic-based intervention promoting condom use to enhance sexual pleasure (purpose 1) and the use of condoms from the start-to-finish of anal sex (purpose 2). A pre-test, post-test randomized controlled trial was conducted, using a 12-month period of follow-up observation, in STI clinics. Data from 394 YBMSM completing baseline and 12-month follow-up assessments were analyzed. The experimental condition comprised a one to-one, interactive program (Focus on the Future) designed for tailored delivery. Regarding study purpose 1, in an age-adjusted linear regression model for 277 HIV uninfected men, there was a significant effect of the intervention (Beta=0.13, P =0.036) relative to more favorable sexual experiences when using condoms. Regarding study purpose 2, in an adjusted logistic regression model, for HIV uninfected men, there was a significant effect of the intervention (AOR=0.54, P =0.048) relative to using condoms from start-to-finish of anal sex. Significant effects for HIV-infected men were not observed. A small, but non-significant, effect was observed relative to men's self-report of always using condoms. This single-session program may be a valuable counseling tool for use in conjunction with pre-exposure prophylaxis-related care for HIV-uninfected YBMSM. PMID- 29534209 TI - Poultry rearing on perforated plastic floors and the effect on air quality, growth performance, and carcass injuries - Experiment 2: Heat stress situation. AB - Previously, we reported the effect of rearing conditions (plastic floors and air quality) on carcass injury development of broiler chickens at thermal comfort. In this study, the same rearing conditions were tested at thermal stress. The birds were reared in 2 climatic chambers, and the experiment followed a completely randomized design with one factor, flooring material: wood shaving or perforated plastic. The birds were divided into 16 experimental pens, being 8 females and 8 males. The studied parameters were the same as the previous study (ammonia concentration, carbon dioxide, performance, carcass yield, and variability, and scores of hygiene, gait and chest, and hocks and footpad lesions). Higher ammonia (15 ppm vs. 4 ppm) and carbon dioxide (1,000 ppm vs. 850 ppm) concentration was seen at d 42 for the wood shavings floor as compared to the perforated plastic floor, respectively. Regarding gender, males had better performance than females at 42 d of age on both floor types. Males reared on wood shavings showed a higher meat production (29.049 kg/m2) than females (24.700 kg/m2). There were observed breast lesion incidences of 10.4% (score 1) in males reared on the plastic floor, as well higher incidence of hock injury and footpad dermatitis. Chickens reared on plastic flooring showed better hygiene than chickens reared on wood shavings. Our findings revealed that the use of perforated plastic flooring in a heat stress situation can improve the air quality (less CO2 and NH3 concentration) and bird cleanliness. On the other hand, chickens are more susceptible to develop lesions in the breast, hock, and footpad. We conclude that the use of plastic flooring in heat stress conditions needs more attention, since chickens are more susceptible to develop lesions on the carcass, being a source of pain, impairing bird wellbeing and causing losses in meat production. PMID- 29534211 TI - Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome. AB - Background: Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ~15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ~30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-alpha5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. Methods: To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. Results: In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. Conclusion: We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients. PMID- 29534212 TI - Biochemical, Structural and Physiological Characteristics of Vacuolar H+ Pyrophosphatase. AB - Proton-translocating inorganic pyrophosphatase (H+-PPase) actively translocates protons across membranes coupled with the hydrolysis of inorganic pyrophosphate (PPi). H+-PPase, which is composed of a single protein and uses a simple compound as a substrate, has been recognized as a new type of ion pump in addition to the P-, F- and V-type ion-translocating ATPases. H+- and Na+-PPases are distributed in various organisms including plants, parasitic protozoa, Archaebacteria and bacteria, but are not present in animals or yeast. Vacuolar H+-PPase has dual functions in plant cells: hydrolysis of cytosolic PPi to maintain the levels of PPi, and translocation of protons into vacuoles to maintain the acidity of the vacuolar lumen. Acidification performed with the vacuolar-type H+-ATPase and H+ PPase is essential to maintain acidic conditions, which are necessary for vacuolar hydrolytic enzymes and for supplying energy to secondary active transporters. Recent studies using loss-of-function mutant lines of H+-PPase and complementation lines with soluble PPases have emphasized the physiological importance of the scavenging role of PPi. An overview of the main features of H+ PPases present in the vacuolar membrane is provided in terms of tissue distribution in plants, intracellular localization, structure-function relationship, biochemical potential as a proton pump and functional stability. PMID- 29534213 TI - Palmar and plantar erythema, pulmonary fibrosis and the anti-synthetase syndrome. PMID- 29534214 TI - Short- and long-term outcomes of patients with solid tumours following non surgical intensive care admission. AB - Background: There has been a significant increase in the number of patients presenting with cancer related emergencies and potentially requiring critical care admission. Aim: To analyse the short and long-term outcomes of patients with solid tumours requiring unplanned medical admission to a specialist cancer intensive care unit (ICU). Design: An unplanned cohort study. Methods: A retrospective analysis of patients admitted to a UK specialist tertiary oncology CCU between September 2009 and September 2015. The primary outcome measures were survival to CCU discharge and 1-year survival. Results: 687 patients had an unplanned medical admission. The most frequent primary tumours were lymphoma (22.1%), lung (15.2%) and colorectal (13.0%), and 181 (44.4%) were known to have metastases. The median Acute Physiology and Chronic Health Evaluation (APACHE) II and Intensive Care National Audit and Research Centre (ICNARC) scores were 21 and 17, respectively. ICU mortality was 26.7%, with total hospital mortality of 41.9%. The median survival of the total cohort was 56 days after ICU admission, with 107 patients surviving 365 days. Patients with metastatic disease were almost twice as likely to die within the year following ICU admission compared with their counterparts without metastases. Only pancreatic and lung primaries were shown to have a statistically significant impact on survival at 1 year. Pneumonia carried with it the worst prognosis (cumulative survival 0.11), followed by sepsis (0.25) and non-infective respiratory disease (0.26). Conclusions: The stage and type of cancer appear to have minimal impact on short term ICU outcomes and only confer poorer long-term prognosis related to the disease. PMID- 29534215 TI - Associations between trabecular bone score and vertebral fractures in patients with axial spondyloarthritis. AB - Objectives: To compare trabecular bone scores (TBS) between axial SpA (axSpA) patients with and without vertebral fractures and investigate associations between TBS and vertebral fractures. Methods: Two hundred and fifty-five patients fulfilling the imaging arm of the Assessment of SpondyloArthritis International Society axSpA criteria were enrolled. TBS and BMD were assessed using dual-energy X-ray absorptiometry. Vertebral fracture of the thoracic and lumbar spine was defined according to the Genant criteria. Osteoporosis risk factors, inflammatory markers, DAS and spinal structural damage were also assessed. Univariate logistic regression analysis was performed to identify factors associated with vertebral fractures. Results: There were 31 vertebral fractures in 28/255 axSpA patients (11%). The mean (s.d.) TBS was 1.39 (0.11) and 1.30 (0.13) in patients without and with vertebral fractures, respectively (P < 0.001). BMD in the femoral neck was lower in patients with vertebral fractures (P = 0.027), but BMDs in the lumbar spine and total hip were not. Univariate logistic regression analyses identified old age (?50 years), TNF inhibitor treatment, the presence of syndesmophytes and a low TBS (<1.23) as associated with prevalent vertebral fractures [odds ratio (95% CI): 6.9 (2.0, 24.4), 2.4 (1.0, 5.5), 5.5 (2.2, 13.5) and 5.3 (2.0, 14.1), respectively]. TBS has a better discriminatory value than BMD at the total hip for prediction of vertebral fractures in axSpA patients (P = 0.034). Conclusion: Similar to individuals with primary osteoporosis, axSpA patients with vertebral fractures have a lower TBS. This suggests that TBS has the potential to predict future vertebral fractures in patients with axSpA. PMID- 29534216 TI - Type I Spinal Dural Fistula Treated Using a Minimally Invasive Approach With a 20 mm Nonexpandable Tubular Retractor: 3-Dimensional Operative Video. PMID- 29534217 TI - Now Is the Time to Quickly Eliminate Barriers Along the Hepatitis C Cascade of Care. PMID- 29534218 TI - Intravenous Ketamine Infusion for Complex Regional Pain Syndrome: Survey, Consensus, and a Reference Protocol. AB - Objective: To find and reach a consensus on the usage of ketamine in the treatment of complex regional pain syndrome and to determine a reference protocol for future studies. Design: Three hundred fifty-one medical professionals participated in our survey on practice procedures, with 104 respondents providing information on their usage of ketamine for treating the pain associated with complex regional pain syndrome. Respondents answered questions about inpatient treatment, outpatient treatment, children vs adults, safety, and basic demographic information. An expert group then met to reach a consensus for a reference protocol. Results: There is a difference in how inpatients are treated compared with outpatients, making it necessary to have two different reference protocols. The duration of pain relief varied from one to 10 days to one to six months, with a correlation between the duration of pain relief and total infusion hours per round. Conclusions: The consensus reference protocols are made up of nine recommended topics. Reference protocols need to be validated by extensive research before guidelines can be created. PMID- 29534219 TI - Highly efficient extraction and purification of low-density lipoprotein from hen egg yolk. AB - Low-density lipoprotein (LDL) from hen egg yolk has high nutritional value and plays an important role in the fields of biology, medicine, and materials. To develop fundamental research about LDL, a highly efficient extraction method is necessary. We found that 30% saturated ammonium sulfate can extract more crude LDL than 40% saturation. We selected polyethylene glycol (PEG; nonionic type) to obtain crude LDL. Three factors were employed, namely, degree of polymerization, concentration of PEG, and pH of egg yolk plasma. The optimized condition was 5% PEG 4,000 and plasma pH 6.0, and the best extraction efficiency was 68.1 +/- 0.5 g lipid /100 g DM and 69.9 +/- 2.0% protein. The crude LDL oil of PEG precipitation was very significantly higher (P < 0.01) than ammonium sulfate precipitation (ASP), while there was no significant difference in protein, which indicates that PEG can extract more crude LDL. When ascorbic acid was added, hydrosulfuryl (SH) groups and lipids oxidation degree of crude LDL extracted by PEG (PEG-LDL) was very significantly lower than ASP (P < 0.01). We also obtained both purified LDL and yolk immunoglobulin (IgY) with an appropriate purification column. This paper proposes a highly efficient method to extract LDL with high activity using PEG and ensures co-purification of LDL and IgY. PMID- 29534220 TI - Peripheral arterial disease in Scottish military veterans: a retrospective cohort study of 57 000 veterans and 173 000 matched non-veterans. AB - Background: While traumatic limb loss in military personnel is widely known, the threat posed by peripheral arterial disease (PAD) in those who have served is less well recognized. The aim of our study was to examine the risk of PAD in a Scotland-wide cohort of veterans who served between 1960 and 2012. Methods: Retrospective 30-year cohort study of 56 205 veterans born 1945-85, and 172 741 non-veterans, matched for age, sex and area of residence, using Cox proportional hazard models to examine the association between veteran status, birth cohort, length of service and risk of PAD leading to hospitalization or death. Results: Overall, veterans were at increased risk of PAD compared with non-veterans, unadjusted hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.33-1.60, P < 0.001. The highest risk was in veterans born between 1950 and 1954, HR = 1.76, 95% CI: 1.50-2.07, P < 0.001, and in those with the shortest service (early service leavers), HR = 1.84, 95% CI: 1.49-2.27, P < 0.001. Conclusions: The findings provide evidence for a hidden burden of life- and limb-threatening PAD in older veterans and are consistent with the higher rates of military smoking which have been reported previously. The study emphasizes the need for vascular preventive measures in this group. PMID- 29534221 TI - Relationship between dietary intake and behaviors with oxytocin: a systematic review of studies in adults. AB - Context: Oxytocin plays an important hormonal role in the regulation of feeding and energy intake. Objective: The aims of this review were to 1) determine the effects of dietary intake/behaviors on endogenous oxytocin and 2) examine the effect of exogenous oxytocin on dietary intake/behaviors. Data sources: Published studies up to December 2016 were identified through searches of 5 electronic databases. Data extraction: Eligible studies included those in adults that included a measure related to an individual's diet and a measure of oxytocin and the relationship between the 2 outcomes. Results: Twenty-six studies (n = 912 participants; 77% female) were included. The most common dietary outcomes assessed were alcohol, caffeine, calcium, sodium, fat, and calorie intake. It was found that endogenous oxytocin (n = 13) in nonclinical samples did not change significantly (P > 0.05) through altered diet or behaviors (neutral effect); in contrast, significant (P < 0.05) differences (increases and decreases) were identified in clinical samples. Exogenous oxytocin studies (n = 13) found reduced indices of food intake (positive effect) in clinical and nonclinical samples. Conclusions: Overall, few studies included comprehensive investigation of dietary intakes through the use of validated assessment tools. Dietary intake and behaviors appear to have some influence on oxytocin, with more pronounced effects found with exogenously administered oxytocin. PMID- 29534222 TI - An origin of the immunogenicity of in vitro transcribed RNA. AB - The emergence of RNA-based therapeutics demands robust and economical methods to produce RNA with few byproducts from aberrant activity. While in vitro transcription using the bacteriophage T7 RNA polymerase is one such popular method, its transcripts are known to display an immune-stimulatory activity that is often undesirable and uncontrollable. We here showed that the immune stimulatory activity of T7 transcript is contributed by its aberrant activity to initiate transcription from a promoter-less DNA end. This activity results in the production of an antisense RNA that is fully complementary to the intended sense RNA product, and consequently a long double-stranded RNA (dsRNA) that can robustly stimulate a cytosolic pattern recognition receptor, MDA5. This promoter independent transcriptional activity of the T7 RNA polymerase was observed for a wide range of DNA sequences and lengths, but can be suppressed by altering the transcription reaction with modified nucleotides or by reducing the Mg2+ concentration. The current work thus not only offers a previously unappreciated mechanism by which T7 transcripts stimulate the innate immune system, but also shows that the immune-stimulatory activity can be readily regulated. PMID- 29534223 TI - Impaired IRE1alpha/XBP-1 pathway associated to DNA methylation might contribute to salivary gland dysfunction in Sjogren's syndrome patients. AB - Objectives: Labial salivary glands (LSGs) of SS patients show alterations related to endoplasmic reticulum stress. Glandular dysfunction could be partly the consequence of an altered inositol-requiring enzyme 1alpha (IRE1alpha)/X box binding protein 1 (XBP-1) signalling pathway of the unfolded protein response, which then regulates genes involved in biogenesis of the secretory machinery. This study aimed to determine the expression, promoter methylation and localization of the IRE1alpha/XBP-1 pathway components in LSGs of SS patients and also their expression induced by IFN-gamma in vitro. Methods: IRE1alpha, XBP-1 and glucose-regulated protein 78 (GRP78) mRNA and protein levels were measured by qPCR and western blot, respectively, in LSGs of SS patients (n = 47) and control subjects (n = 37). Methylation of promoters was evaluated by methylation sensitive high resolution melting, localization was analysed by immunofluorescence and induction of the IRE1alpha/XBP-1 pathway components by IFN gamma was evaluated in 3D acini. Results: A significant decrease of IRE1alpha, XBP-1u, XBP-1s, total XBP-1 and GRP78 mRNAs was observed in LSGs of SS patients, which was correlated with increased methylation levels of their respective promoters, and consistently the protein levels for IRE1alpha, XBP-1s and GRP78 were observed to decrease. IFN-gamma decreased the mRNA and protein levels of XBP 1s, IRE1alpha and GRP78, and increased methylation of their promoters. Significant correlations were also found between IRE1alpha/XBP-1 pathway components and clinical parameters. Conclusion: Decreased mRNA levels for IRE1alpha, XBP-1 and GRP78 can be partially explained by hypermethylation of their promoters and is consistent with chronic endoplasmic reticulum stress, which may explain the glandular dysfunction observed in LSGs of SS patients. Additionally, glandular stress signals, including IFN-gamma, could modulate the expression of the IRE1alpha/XBP-1 pathway components. PMID- 29534224 TI - Anti-inflammatory effects of rice bran components. AB - Neuroinflammation has been implicated in the pathology of various psychiatric and neurodegenerative disorders. Accumulating evidence suggests that food components can modulate inflammatory processes, and therefore it could be hypothesized that such nutrients might exhibit therapeutic efficacy against these brain diseases. Rice bran is often discarded as a waste product, although it contains a wide range of potentially useful substances. Several rice fiber components from rice bran have been described as having antiinflammatory properties. This review summarizes the evidence supporting a modulatory effect of rice fiber components on symptoms in several animal models for neuroinflammation. In vitro studies on immune cells and in vivo studies on nutritional intervention in animal models of central and peripheral inflammation are discussed in the context of the potential use of rice fiber components for prevention and treatment of brain diseases in which neuroinflammation is involved. PMID- 29534225 TI - Childhood and Parental Asthma, Future Risk of Bipolar Disorder and Schizophrenia Spectrum Disorders: A Population-Based Cohort Study. AB - Background: Mounting evidence implicates early life and prenatal immune disturbances in the etiology of severe mental illnesses. Asthma is a common illness associated with chronic aberrant immune responses. We aimed to determine if asthma in childhood and parents is associated with bipolar and schizophrenia spectrum disorders. Methods: A cohort study including all children born in Sweden 1973-1995 (N > 2 million) assessing associations between childhood hospitalization for asthma, parental asthma during and pre-pregnancy, and subsequent bipolar and schizophrenia spectrum disorders. Results: Children with hospitalizations for asthma between 11 and 15 years had increased rates of bipolar (adjusted hazard ratio [aHR] = 1.73, 95% confidence interval [CI] = 1.21 2.47) and schizophrenia spectrum disorders (aHR = 1.62, 95% CI = 1.08-2.42). However, there was no association with asthma before aged 11. These results were supported by an analysis of siblings discordant for asthma. We found an association between both maternal and paternal asthma and bipolar disorder (aHR = 1.60, 95% CI = 1.27-2.02, and aHR = 1.44, 95% CI = 1.08-1.93, respectively), but not between parental asthma and schizophrenia spectrum disorders. Conclusions: As far as we are aware, this is the first study to find increased risk of bipolar disorder in children of individuals with asthma. Asthma admissions before aged 11 do not appear to be linked to bipolar or schizophrenia spectrum disorders. Taken together, our results do not suggest a straightforward link between asthma and severe mental illness via neurodevelopmental effects of inflammation, but potentially there is shared genetic vulnerability. This finding has implications for understanding the differential pathogenic mechanisms of bipolar and schizophrenia spectrum disorders. PMID- 29534226 TI - Blue toe syndrome in cutaneous polyarteritis nodosa. PMID- 29534227 TI - Effects of bud-flushing strategies on tree growth. AB - Allocation of carbohydrates between competing organs is fundamental to plant development, growth and productivity. Carbohydrates are synthesized in mature leaves and distributed via the phloem vasculature to developing buds where they are consumed to produce new biomass. The distribution and mass-allocation processes within the plant remain poorly understood and may involve complex feedbacks between different plant functions, with implications for the emergent structure of the plant. Here, we investigate how the order in which dormant buds are flushed affects the development of tree size and reproductive output during the first 20 years of growth in full light and shaded canopy environments. We report the following findings: (i) Bud-flushing strategies strongly affect the temporal dynamics of height, mass and the size of reproduction pool, as well as the resulting architectures. (ii) Bud-flushing strategies affect tree growth by altering the rate of growth and final size of trees. (iii) No single bud-flushing strategy performs best when both the size and allocation for reproduction of the resulting trees are compared. However, we observe that the strategy that optimizes the net carbon gain for the entire tree architecture always results in a high reproduction output. (iv) Branch turnover and meristem regeneration enhance the performance of certain strategies with respect to the measured quantities. These results highlight the importance of employing generic models of architecture (i.e., non-species-specific) to identify general mechanisms of carbon allocation and the spatial distribution of newly formed biomass in growing trees. PMID- 29534229 TI - Ceramide-1-phosphate has protective properties against cyclophosphamide-induced ovarian damage in a mice model of premature ovarian failure. AB - STUDY QUESTION: Is ceramide-1-phosphate (C1P) an ovarian protective agent during alkylating chemotherapy? SUMMARY ANSWER: Local administration of C1P drastically reduces ovarian damage induced by cyclophosphamide (Cy) via protection of follicular reserve, restoration of hormone levels, inhibition of apoptosis and improvement of stromal vasculature, while protecting fertility, oocyte quality and uterine morphology. WHAT IS KNOWN ALREADY: Cancer-directed therapies cause accelerated loss of ovarian reserve and lead to premature ovarian failure (POF). Previous studies have demonstrated that C1P regulates different cellular processes including cell proliferation, cell migration, angiogenesis and apoptosis. This sphingolipid may be capable of modulating vascular development and apoptosis in ovaries affected by chemotherapy. STUDY DESIGN, SIZE, DURATION: The 6-8-week-old mice were weighed and administered either a single intraperitoneal injection of Cy (75 mg/kg) or an equal volume of saline solution only for control mice. Control and Cy mice underwent sham surgery and received an intrabursal injection of saline solution, while Cy + C1P animal groups received 5 MUl C1P, either 0.5 or 1 mM, under the bursa of both ovaries 1 h prior to Cy administration. PARTICIPANTS/MATERIALS, SETTING, METHODS: Animals were euthanized by cervical dislocation or cardiac puncture 2 weeks after surgery for collection of blood orovary and uterus samples, which were cleaned of adhering tissue in culture medium and used for subsequent assays. Ovaries were used for Western blotting or immunohistochemical and/or histological analyses or steroid extraction, as required (n = 5-8 per group). A set of mice (n = 3/group) was destined for oocyte recovery and IVF. Finally, another set (n = 5-6/group) was separated to study fertility parameters. MAIN RESULTS AND THE ROLE OF CHANCE: The number of primordial (P < 0.01), primary (P < 0.05) and preantral follicles (P < 0.05) were decreased in Cy-treated mice compared to control animals, while atretic follicles were increased (P < 0.001). In Cy + C1P mice, the ovaries recovered control numbers of these follicular structures, in both C1P doses studied. Cy affected AMH expression, while it was at least partially recovered when C1P is administered as well. Cy caused an increase in serum FSH concentration (P < 0.01), which was prevented by C1P coadministration (P < 0.01). E2 levels in Cy-treated ovaries decreased significantly compared to control ovaries (P < 0.01), whilst C1P restored E2 levels to those of control ovaries (P < 0.01). Cy increased the expression of BAX (P < 0.01) and decreased the expression of BCLX-L compared to control ovaries (P < 0.01). The ovarian BCLX L:BAX ratio was also lower in Cy-treated mice (P < 0.05). In the Cy + C1P group, the expression levels of BAX, BCLX-L and BCLX-L:BAX ratio were no different than those in control ovaries. In addition, acid sphingomyelinase (A-SMase) expression was higher in Cy-treated ovaries, whilst remaining similar to the control in the Cy + C1P group. Cy increased the apoptotic index (TUNEL-positive follicles/total follicles) in preantral and early antral stages, compared to control ovaries (P < 0.001 and P < 0.01, respectively). C1P protected follicles from this increase. No primordial or primary follicular cells stained for either cleaved caspase-3 or TUNEL when exposed to Cy, therefore, we have found no evidence for follicular reserve depletion in response to Cy being due to apoptosis. Cy caused evident vascular injury, especially in large cortical stromal vessels, and some neovascularization. In the Cy + C1P group, the disruptions in vascular wall continuity were less evident and the number of healthy stromal blood vessels seemed to be restored. In Cy-treated ovaries alpha-SMA-positive cells showed a less uniform distribution around blood vessels. C1P coadministration partially prevented this Cy-induced effect, with a higher presence of alpha-SMA-positive cells surrounding vessels. By H&E staining, Cy-treated mice showed endometrial alterations compared to controls, affecting both epithelial and stromal compartments. However, C1P allowed that the stromal tissue to maintain its loose quality and its glandular branches. Cy-treated animals had significantly lower pregnancy rates and smaller litter sizes compared with control mice (P = 0.013 and P < 0.05, respectively), whereas cotreatment with C1P preserved normal fertility. Furthermore, a higher (P < 0.05) proportion of abnormal oocytes was recovered from Cy-treated mice compared to the control, which was prevented by C1P administration. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The results of this study were generated from an in-vivo animal experimental model, already used by several authors. Further studies on C1P functions in female reproduction in pathological conditions such as chemotherapy-induced ovarian failure and on the safety of use of this sphingolipid are required. WIDER IMPLICATIONS OF THE FINDINGS: The present findings showed that C1P administration prior to Cy might be a promising fertility preservation strategy in female patients who undergo chemotherapy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from ANPCyT (PICT 2015-1117), CONICET (PIP 380), Cancer National Institute (INC) and Roemmers Foundation, Argentina. The authors declare no conflicts of interest. PMID- 29534230 TI - Apparent Range Expansion of Culicoides (Hoffmania) insignis (Diptera: Ceratopogonidae) in the Southeastern United States. AB - Haematophagous biting midges of the genus Culicoides are pests of humans, livestock, and wildlife, and some also serve as vectors of bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) worldwide. In North America, there are only two Culicoides spp. proven to transmit BTV and/or EHDV-Culicoides (Hoffmania) insignis Lutz (Diptera: Ceratopogonidae) and Culicoides (Monoculicoides) sonorensis Wirth and Jones (Diptera: Ceratopogonidae). Culicoides sonorensis is considered the primary vector due to its wide distribution across much of North America, whereas C. insignis has a neotropical distribution historically limited to peninsular Florida. However, Culicoides surveys conducted 2007 to 2015 have detected the presence of C. insignis in five southeastern states (Florida, Georgia, Alabama, Mississippi, and Louisiana), suggesting C. insignis has or is currently experiencing a northwestward range expansion in the southeastern United States. Because C. insignis has a neotropical distribution and is a known vector of BTV serotypes exotic to North America, an expanding range could pose an introduction risk of virus serotypes new to the region and/or increased transmission of circulating endemic serotypes. PMID- 29534228 TI - A three-generation study on the association of tobacco smoking with asthma. AB - Background: Mothers' smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers' smoking may have a similar effect, and biological plausibility that fathers' smoking during adolescence may influence offspring's health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma. Methods: Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged <=51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents' (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Results: Fathers' smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01-2.01] and mothers' smoking during pregnancy (RRR = 1.27, 95% CI: 1.01 1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers' smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17-2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02-1.55). Conclusions: Fathers' smoking during early adolescence and grandmothers' and mothers' smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception. Funding: European Union (Horizon 2020, GA-633212). PMID- 29534231 TI - A SIMPLE NATIONAL INTERCOMPARISON OF RADON IN WATER. AB - Radon-222, a naturally occurring radioactive gas, responsible together with its progeny of around 50% of the average effective dose received by the population, has not been regulated by law until the recent Directive 2013/51 /Euratom. Its transposition into Spanish legislation was made in the recent RD 314/2016, which sets at limit value of 500 Bq l-1 for radon-222 in water for human consumption. Intercomparison exercises, such as those carried out by IPROMA SL and the Laboratory of Environmental Radioactivity of the Cantabria University (LARUC) in November 2015 and December 2016, represent the most useful tool available for detecting problems and taking corrective actions necessary for an efficient measurement by part of the laboratories. The participants in these exercises used three techniques: liquid scintillation counting, gamma spectrometry and desorption followed by ionisation chamber detection. PMID- 29534232 TI - The Biogeography of Deep Time Phylogenetic Reticulation. AB - Most phylogenies are typically represented as purely bifurcating. However, as genomic data have become more common in phylogenetic studies, it is not unusual to find reticulation among terminal lineages or among internal nodes (deep time reticulation; DTR). In these situations, gene flow must have happened in the same or adjacent geographic areas for these DTRs to have occurred and therefore biogeographic reconstruction should provide similar area estimates for parental nodes, provided extinction or dispersal has not eroded these patterns. We examine the phylogeny of the widely distributed New World kingsnakes (Lampropeltis), determine if DTR is present in this group, and estimate the ancestral area for reticulation. Importantly, we develop a new method that uses coalescent simulations in a machine learning framework to show conclusively that this phylogeny is best represented as reticulating at deeper time. Using joint probabilities of ancestral area reconstructions on the bifurcating parental lineages from the reticulating node, we show that this reticulation likely occurred in northwestern Mexico/southwestern US, and subsequently, led to the diversification of the Mexican kingsnakes. This region has been previously identified as an area important for understanding speciation and secondary contact with gene flow in snakes and other squamates. This research shows that phylogenetic reticulation is common, even in well-studied groups, and that the geographic scope of ancient hybridization is recoverable. PMID- 29534233 TI - Multiple-strain Trichophyton mentagrophytes infection in a silver fox (Vulpes vulpes) from a breeding farm. AB - Dermatophyte infections are extremely frequent worldwide, and their epidemiological features and distribution make them one of the most frequent infections all over the world. We identified and analysed multiform T. mentagrophytes strains isolated from a silver fox (Vulpes vulpes) kept on a breeding farm. Identification of dermatophyte strains was carried out traditionally by correlating both the clinical manifestations of the infection with a micro- and macroscopic examination. To confirm the species affiliation fully, molecular differentiation methods were used. DNA was isolated from the dermatophytes with the phenol-chloroform method. The reaction of chitin synthase 1 (chs1) amplification was carried out to confirm the dermatophytes. The phylogenetic analysis was based on the ITS sequences. The polymerase chain reaction melting profile (PCR-MP) procedure was used for differentiation of dermatophyte genomes. Direct analysis of the material sampled from the clinical lesions revealed the presence of arthrospores in the samples collected from all animals with skin lesions. The macromorphology of the colonies obtained from material sampled from the same individual was not homogeneous. The PCR-MP electrophoregram indicated high variability of their genomes. Although the dermatophytes were isolated from one infected fox, no two identical genomic profiles were obtained. The PCR-MP result corresponds with the phenotypic diversity of the isolates. The findings about the multiple dermatophyte infection in one individual complicate any future epidemiology work and other clinical investigation. Previously, using only morphological characteristics, it had been assumed that one fungal isolate per patient could be diagnosed. The novel findings encourage application of the newly developed molecular typing methods in the diagnosis of dermatophytosis. PMID- 29534234 TI - Cost-effectiveness of hydrotherapy versus land-based therapy in patients with musculoskeletal disorders in Singapore. AB - Background: The study evaluated the cost-effectiveness of hydrotherapy versus land-based therapy in patients with musculoskeletal disorders (MSDs) in Singapore. Methods: A decision-analytic model was constructed to compare the cost effectiveness of hydrotherapy to land-based therapy over 3 months from societal perspective. Target population comprised patients with low back pain (LBP), osteoarthritis (OA), rheumatoid arthritis (RA), total hip replacement (THR) and total knee replacement (TKR). Subgroup analyses were carried out to determine the cost-effectiveness of hydrotherapy in individual MSDs. Relative treatment effects were obtained through a systematic review of published data. Results: Compared to land-based therapy, hydrotherapy was associated with an incremental cost effectiveness ratio (ICER) of SGD 27 471 per quality-adjusted life-year (QALY) gained, which was below the willingness-to-pay threshold of SGD 70 000 per QALY (one gross domestic product per capita in Singapore in 2015). For the respective MSDs, hydrotherapy were dominant (more effective and less costly) in THR and TKR, cost-effective for LBP and RA, and not cost-effective for OA. Treatment adherence and cost of hydrotherapy were key drivers to the ICER values. Conclusions: Hydrotherapy was a cost-effective rehabilitation compared to land-based therapy for a population with MSDs in Singapore. However, the benefit of hydrotherapy was not observed in patients with OA. PMID- 29534235 TI - De novo discovery of structural motifs in RNA 3D structures through clustering. AB - As functional components in three-dimensional (3D) conformation of an RNA, the RNA structural motifs provide an easy way to associate the molecular architectures with their biological mechanisms. In the past years, many computational tools have been developed to search motif instances by using the existing knowledge of well-studied families. Recently, with the rapidly increasing number of resolved RNA 3D structures, there is an urgent need to discover novel motifs with the newly presented information. In this work, we classify all the loops in non-redundant RNA 3D structures to detect plausible RNA structural motif families by using a clustering pipeline. Compared with other clustering approaches, our method has two benefits: first, the underlying alignment algorithm is tolerant to the variations in 3D structures. Second, sophisticated downstream analysis has been performed to ensure the clusters are valid and easily applied to further research. The final clustering results contain many interesting new variants of known motif families, such as GNAA tetraloop, kink-turn, sarcin-ricin and T-loop. We have also discovered potential novel functional motifs conserved in ribosomal RNA, sgRNA, SRP RNA, riboswitch and ribozyme. PMID- 29534236 TI - Direct detection of Coccidioides from Arizona soils using CocciENV, a highly sensitive and specific real-time PCR assay. AB - Coccidioides immitis and Coccidioides posadasii are soil fungi endemic to desert regions of the southwestern United States, and the causative agents of valley fever, or coccidioidomycosis. Studies have shown that the distribution of Coccidioides in soils is sporadic and cannot be explained by soil characteristics alone, suggesting that biotic and other abiotic factors should be examined. However, tools to reliably and robustly screen the large number of soils needed to investigate these potential associations have not been available. Thus, we developed a real-time polymerase chain reaction (PCR) assay for testing environmental samples by modifying CocciDx, an assay validated for testing clinical specimens to facilitate coccidioidomycosis diagnosis. For this study, we collected soil samples from previously established locations of C. posadasii in Arizona and new locations in fall 2013 and spring 2014, and screened the extracted DNA with the new assay known as CocciEnv. To verify the presence of Coccidioides in soil using an alternate method, we employed next generation amplicon sequencing targeting the ITS2 region. Results show our modified assay, CocciEnv, is a rapid and robust method for detecting Coccidioides DNA in complex environmental samples. The ability to test a large number of soils for the presence of Coccidioides is a much-needed tool in the understanding of the ecology of the organism and epidemiology of the disease and will greatly improve our understanding of this human pathogen. PMID- 29534237 TI - Microsurgery for Cervicomedullary Tumor: 2-Dimensional Operative Video. PMID- 29534238 TI - Targeting epigenetic DNA and histone modifications to treat kidney disease. AB - Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease. A beneficial in vivo effect over preclinical kidney injury has been reported for drugs that decrease DNA methylation by either inhibiting DNA methylation (e.g. 5 azacytidine and decitabine) or activating DNA demethylation (e.g. hydralazine), decrease histone methylation by inhibiting histone methyltransferases, increase histone acetylation by inhibiting histone deacetylases (HDACs, e.g. valproic acid, vorinostat, entinostat), increase histone crotonylation (crotonate) or interfere with histone modification readers [e.g. inhibits of bromodomain and extra-terminal proteins (BET)]. Most preclinical studies addressed CKD or the AKI to-CKD transition. Crotonate administration protected from nephrotoxic AKI, but evidence is conflicting on DNA methylation inhibitors for preclinical AKI. Several drugs targeting epigenetic regulators are in clinical development or use, most of them for malignancy. The BET inhibitor apabetalone is in Phase 3 trials for atherosclerosis, kidney function being a secondary endpoint, but nephrotoxicity was reported for DNA and HDAC inhibitors. While research into epigenetic modulators may provide novel therapies for kidney disease, caution should be exercised based on the clinical nephrotoxicity of some drugs. PMID- 29534239 TI - Multivariate Pattern Analysis of Genotype-Phenotype Relationships in Schizophrenia. AB - Genetic risk variants for schizophrenia have been linked to many related clinical and biological phenotypes with the hopes of delineating how individual variation across thousands of variants corresponds to the clinical and etiologic heterogeneity within schizophrenia. This has primarily been done using risk score profiling, which aggregates effects across all variants into a single predictor. While effective, this method lacks flexibility in certain domains: risk scores cannot capture nonlinear effects and do not employ any variable selection. We used random forest, an algorithm with this flexibility designed to maximize predictive power, to predict 6 cognitive endophenotypes in a combined sample of psychiatric patients and controls (N = 739) using 77 genetic variants strongly associated with schizophrenia. Tenfold cross-validation was applied to the discovery sample and models were externally validated in an independent sample of similar ancestry (N = 336). Linear approaches, including linear regression and task-specific polygenic risk scores, were employed for comparison. Random forest models for processing speed (P = .019) and visual memory (P = .036) and risk scores developed for verbal (P = .042) and working memory (P = .037) successfully generalized to an independent sample with similar predictive strength and error. As such, we suggest that both methods may be useful for mapping a limited set of predetermined, disease-associated SNPs to related phenotypes. Incorporating random forest and other more flexible algorithms into genotype-phenotype mapping inquiries could contribute to parsing heterogeneity within schizophrenia; such algorithms can perform as well as standard methods and can capture a more comprehensive set of potential relationships. PMID- 29534241 TI - Clinical Features and Outcome of Children with Severe Lower Respiratory Tract Infection Admitted to a Pediatric Intensive Care Unit in South Africa. AB - Aim: Severe acute lower respiratory tract infection (ALRTI) remains an important cause of childhood morbidity and mortality. Methods: This is a 12-month retrospective cohort study of children (0-12 years) admitted to a pediatric intensive care unit (PICU) with ALRTI to investigate risk factors, clinical course and in-hospital survival. Results: In total, 265 patients (median age = 4 months [2-12 months]) were identified. In all,102 (38.5%) had co-morbid disease. Twenty-seven (10.2%) were HIV-infected and 87 (32.8%) were HIV-exposed. In hospital mortality was 34 (12.8%)-24 (9.1%) in PICU and 10 in the wards. Median duration of intensive care unit was 4.0 days (2.0-8.0) and hospital stay was 12.5 days (7.9-28.0). In total, 192 (72.5%) children required invasive ventilation and 42 (15.8%) required inotropic support. Risk factors for mortality included severe malnutrition (odds ratio [OR] = 8.25; 95% confidence interval [CI] = 1.47-46.21), informal housing (OR = 11.87; CI = 1.89-20.81) or inotropic support (OR = 44.35; CI = 8.20-239.92). HIV exposure or infection was associated with a longer duration of hospital stay (OR = 4.41; CI = 2.44-6.39). Conclusion: Severe ALRTI is associated with a high mortality with several factors impacting on in-hospital survival. PMID- 29534240 TI - Sleep disruption as a predictor of quality of life among patients in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS). AB - Study Objectives: Sleep quality is poor among patients with chronic obstructive pulmonary disease (COPD), and studies show that sleep disturbance is associated with low overall quality of life in this population. We evaluated the impact of patient-reported sleep quality and sleep apnea risk on disease-specific and overall quality of life within patients with COPD enrolled in the SPIROMICS study, after accounting for demographics and COPD disease severity. Methods: Baseline data from 1341 participants [892 mild/moderate COPD (FEV1 >= 50% predicted); 449 severe COPD (FEV1 < 50%)] were used to perform three nested (blocks) regression models to predict quality of life (Short Form-12 mental and physical components and St. George's Respiratory Questionnaire). Dependent measures used for the nested regressions included the following: Block1: demographics and smoking history; Block 2: disease severity (forced expiratory volume 1 s; 6 min walk test); Block 3: risk for obstructive sleep apnea (OSA; Berlin questionnaire); and Block 4: sleep quality (Pittsburgh Sleep Quality Index [PSQI]). Results: Over half of participants with COPD reported poor sleep quality (Mean PSQI 6.4 +/- 3.9; 50% with high risk score on the Berlin questionnaire). In all three nested regression models, sleep quality (Block 4) was a significant predictor of poor quality of life, over and above variables included in blocks 1 3. Conclusions: Poor sleep quality represents a potentially modifiable risk factor for poor quality of life in patients with COPD, over and above demographics and smoking history, disease severity, and risk for OSA. Improving sleep quality may be an important target for clinical interventions. Clinical Trial: SPIROMICS. Clinical Trial URL: http://www2.cscc.unc.edu/spiromics/. Clinical Trial Registration: ClinicalTrials.gov NCT01969344. PMID- 29534242 TI - Air-Liquid Interface: Relevant In Vitro Models for Investigating Air Pollutant Induced Pulmonary Toxicity. AB - Air pollution leads to inhalation of several pulmonary stimulants that includes particulate matter, and gaseous substances contributing significantly to the development of chronic lung diseases. However, the pathophysiological mechanism of air pollutant mediated pulmonary toxicity remains unclear. This is primarily due to the lack of efficient test systems, mimicing human inhalation exposure scenarios to air pollutants. The majority of the pulmonary in vitro studies have been conducted using cell lines in submerged cell culture conditions and thereby overlooking the pulmonary physiology. Moreover, submerged cell culture systems lack the possibility to measure effective dose measurements. Particle properties, such as size, surface charge, solubility, transformation, or agglomeration state and chemical properties are altered in solution and are dependent on the composition of cell culture medium. Physiologically relevant in vivo-like in vitro models cultured at air-liquid interface (ALI) is therefore becoming a realistic and efficient tool for lung toxicity testing and cell-cell interaction studies following exposure to aerosolized or gaseous form of air pollutants. Primary bronchial epithelial cells cultured at ALI leads to differentiate into respiratory epithelium consisting of ciliated cells, goblet cells, club cells and basal cells. ALI system is also considered as a feasible approach to implement the "3R principle"-replacement, reduction, and refinement of animal usage in lung toxicity studies. This review discusses the current understanding of relevance, benefits and limitations of the ALI models in comparison to the existing in vitro and in vivo exposure system for testing air pollutants mediated pulmonary toxicity. PMID- 29534243 TI - Cardiovascular vulnerability of childhood cancer survivors: time to progress from risk observation to risk modification. AB - Take home figureModifiers of the association of childhood cancer therapies and excess CV risk observed in adult survivors, together with promising strategies for risk reduction and inherent barriers to achieving reduction in CV risk. CV, cardiovascular; GLS, global longitudinal strain; RT, radiation therapy. PMID- 29534244 TI - Practice Patterns of Providers for the Management of Staphylococcus aureus Bacteremia in Children: Results of an Emerging Infections Network Survey. AB - We conducted a survey of pediatric infectious diseases providers in the Emerging Infections Network regarding the workup and treatment of children with Staphylococcus aureus bacteremia (SAB). We found significant practice variation in the management of children with SAB. These findings emphasize the need for further research to guide best practices. PMID- 29534245 TI - Hyper- and Hypomentalizing in Patients with First-Episode Schizophrenia: fMRI and Behavioral Studies. AB - Background: Historically, research investigating neural correlates of mentalizing deficits in schizophrenia has focused on patients who have been ill for several years with lengthy exposure to medication. Little is known about the neural and behavioral presentations of theory-of-mind deficits in schizophrenia, shortly after the first episode of psychosis. Methods: We investigated social cognition in 17 recently diagnosed first-episode schizophrenia (FES) patients with little or no exposure to antipsychotic medication and 1:1 matched healthy controls. We recorded behavioral and neural responses to the Animated Triangles Task (ATT), which is a nonverbal validated mentalizing task that measures the ascription of intentionality to the movements of objects. Results: FES patients under interpreted social cues and over-interpreted nonsocial cues. These effects were influenced by current intelligence (IQ). Control group and FES neural responses replicated earlier findings in healthy adults. However, a region of anterior medial prefrontal cortex (amPFC) of FES patients showed a different response pattern to that of controls. Unlike healthy controls, patients increased activity in this social cognition region while studying "random" movements of shapes, as compared to the study of movements normally interpreted as "intentional". Conclusions: Mentalizing deficits in FES consists of hypo- and hypermentalizing. The neural pattern of FES patients is consistent with deficits in the ability to switch off mentalizing processes in potentially social contexts, instead increasing them when intentionality is not forthcoming. Overall, results demonstrate complexities of theory of mind deficits in schizophrenia that should be considered when offering social cognitive training programs. PMID- 29534246 TI - Testing vaginal irritation with the Hen's Egg Test-Chorioallantoic Membrane assay AB - The HET-CAM (Hen's Egg Test-Chorioallantoic Membrane) assay is an in vitro alternative to the in vivo Draize rabbit eye test. This qualitative method assesses the irritancy potential of chemicals. The chorioallantoic membrane responds to injury with an inflammatory process similar to that in the rabbit eye's conjunctival tissue. Regarding topical toxicity assessment of medical devices, ISO 10993-10 states that any skin or eye irritant material shall be directly labelled as a potential vaginal irritant without animal testing, suggesting that the irri-tation potentials for the eye and the vaginal epithelia are similar. The aim of this work was to apply the HET-CAM assay to test the irritancy potential of vaginal formulations. Vaginal semisolid medicines and lubricants currently marketed were tested along with the Universal Placebo formulation that has been shown to be clinically safe. Nonoxynol-9 (N-9), a known vaginal irritant, was enrolled as positive control (concentrations ranging from 0.001 to 100% (v/v)). The assay was conducted according to the ICCVAM - Recommended Test Method (NIH Publication No. 10-7553 - 2010). Formulations were then classified according to irritation score (IS), using the analysis methods (A) and (B). The studied vaginal formulations showed low potential for irritation. N-9 was classified as a severe irritant at concentrations above 2%, which is in line with clinical data, envisaging a possible in vitro/in vivo correlation. IS (B) was considered a more detailed classification output. Although still requiring further validation, the HET-CAM assay seems an ideal prospect for in vitro vaginal irritancy testing. PMID- 29534247 TI - Novel Ligands for Platelet Glycoprotein VI. PMID- 29534248 TI - Truncation of ADAMTS13 by Plasmin Enhances Its Activity in Plasma. AB - ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleaves von Willebrand Factor (VWF) multimers to control their thrombogenicity. The fibrinolytic enzyme plasmin can cleave VWF in a similar manner. However, plasmin can also cleave ADAMTS13, which ultimately inactivates it. This leaves the overall role of plasmin in primary haemostasis uncertain.We investigated the combined molecular effects of plasmin on VWF and ADAMTS13. We first identified that plasmin destroys FRETS-VWF73 substrate by cleaving the ADAMTS13 binding region in a buffered system. We next investigated how plasmin affects both VWF and ADAMTS13 under static conditions in plasma by western blotting. We found that globular VWF is largely protected from plasmin cleavage. However, ADAMTS13 is rapidly cleaved under these conditions, suggesting inactivation. Surprisingly, we observed that plasmin enhances ADAMTS13 activity in a modified two-stage FRETS-VWF73 assay that protects FRETS-VWF73 substrate from degradation. In direct binding studies under the same conditions, we found that plasmin generates multiple C-terminally truncated forms of ADAMTS13 with VWF binding capacity. In an effort to seek evidence for this mechanism in vivo, we analysed plasma from patients with systemic amyloidosis, which is hallmarked by a hyperfibrinolytic state. We found that their plasma contained increased levels of C-terminally truncated forms of ADAMTS13, which correlated with their hyperfibrinolytic state.We propose that truncation of ADAMTS13 by plasmin abolishes intramolecular self-association, which improves interaction with unfolded VWF. PMID- 29534249 TI - Cross-evaluation of Pharmacokinetic-Guided Dosing Tools for Factor VIII. AB - BACKGROUND: Patients with severe and moderate haemophilia A are treated prophylactically with factor VIII (FVIII) concentrate. Individualization of prophylaxis can be achieved by pharmacokinetic (PK)-guided dosing. AIM: In this study, the performance of three PK tools (myPKFiT, Web-Accessible Population Pharmacokinetic Service-Hemophilia [WAPPS] and NONMEM) is compared. METHODS: In 39 patients, with severe or moderate haemophilia A, blood samples were collected 4, 24 and 48 hours after administration of 50 IU kg-1 of recombinant FVIII (Advate [n = 30] or Kogenate [n = 9]). FVIII dose, FVIII activity and patient characteristics were entered into the three PK tools. Obtained PK parameters and dosing advises were compared. RESULTS: myPKFiT provided PK parameters for 24 of 30 patients receiving Advate, whereas WAPPS and NONMEM provided estimates for all patients. Half-life was different among the three methods: medians were 12.6 hours (n = 24), 11.2 hours (n = 30) and 13.0 hours (n = 30) for myPKFiT, WAPPS and NONMEM (p < 0.001), respectively. To maintain a FVIII trough level of 0.01 IU mL-1 after 48 hours, doses for myPKFiT and NONMEM were 15.1 and 11.0 IU kg-1 (p < 0.01, n = 11) and for WAPPS and NONMEM were 9.0 and 8.0 IU kg-1 (p < 0.01, n = 23), respectively. In nine patients receiving Kogenate, WAPPS and NONMEM produced different PK-parameter estimates; half-life was 15.0 and 12.3 hours and time to 0.05 IU mL-1 was 69.2 and 60.8 hours, respectively (p < 0.01, n = 9). However, recommended doses to obtain these levels were not different. CONCLUSION: The three evaluated PK tools produced different PK parameters and doses for recombinant FVIII. Haematologists should be aware that recommended doses may be influenced by the choice of PK tool. PMID- 29534250 TI - Third-Generation P2Y12 Inhibitors in East Asian Acute Myocardial Infarction Patients: A Nationwide Prospective Multicentre Study. AB - Third-generation P2Y12 inhibitors (prasugrel, ticagrelor) are recommended in acute myocardial infarction (AMI). We aimed to evaluate the efficacy and safety of third-generation P2Y12 inhibitors in East Asian AMI patients. From the Korean AMI Registry, 9,355 patients who received dual antiplatelet agent (aspirin with clopidogrel [AC], 6,444 [70.5%] patients; aspirin with prasugrel [AP], 1,100 [11.8%] patients; or aspirin with ticagrelor [AT], 1,811 [19.4%] patients) were analysed. In-hospital endpoints were all-cause mortality or bleeding events during admission and 1-year endpoints were major adverse cardiac and cerebrovascular events (MACCE) and major bleeding events. Regarding in-hospital events, AP and AT showed similar all-cause mortality rates but higher bleeding event rates compared with AC. This trend was extended to 1-year endpoints; Cox regression analysis showed that third-generation P2Y12 inhibitors had significantly higher bleeding risk (AP vs. AC: hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.53-2.99; p < 0.001; AT vs. AC: HR, 2.26; 95% CI, 1.73 2.95; p < 0.001). A propensity score matched triplet of 572 patients showed similar 1-year MACCE and higher bleeding events with third-generation P2Y12 inhibitors (2.1 vs. 2.6 vs. 2.1%, p = 0.790 for MACCE and 3.1 vs. 8.0 vs. 8.0%, p < 0.001 for bleeding events, in AC, AP and AT groups, respectively). Inverse probability weighted regression analysis and pooled analysis after randomly imputing missing variables showed consistent results. Collectively, prasugrel and ticagrelor showed similar rates of 1-year MACCE, but a higher rate of bleeding events, compared with clopidogrel in Korean AMI patients. Further studies are warranted to adapt Western guidelines on third-generation P2Y12 inhibitors for East Asians. PMID- 29534251 TI - Somatic/Germinal Mosaicism of a F8 Promoter Deletion Confounds Clinical Predictions in a Family with Haemophilia A: Key Role of Genotype Quantitation. PMID- 29534252 TI - Clinical Evaluation of Free-Breathing Contrast-Enhanced T1w MRI of the Liver using Pseudo Golden Angle Radial k-Space Sampling. AB - PURPOSE: Contrast-enhanced T1-weighted MR imaging of the liver is typically acquired using breath-hold techniques to reduce motion artifacts and to allow for optimal diagnostic image quality. Insufficient breath-holds during MR data collection can cause severe reduction of image quality up to the point of being non-diagnostic. The aim of this study was to evaluate the subjective and objective clinical image quality of a novel free-breathing radial k-space sampling MR technique. MATERIALS AND METHODS: Consent for this study was given by the local IRB committee. 86 patients who underwent both breath-hold (BH) and free breathing (FB) late-phase contrast T1w-FS-FFE liver MRI using conventional BH Cartesian (Cartesian-eTHRIVE) and FB "pseudo golden angle" radial k-space sampling (Radial-eTHRIVE) were included in this retrospective analysis. Subjective analysis comprised 5-point Likert scale ratings (1 = very good; 5 = non-diagnostic) for "artifact impact", "anatomic sharpness", "vessel sharpness", "contrast impression", and "overall diagnostic quality". Relative signal intensities in different ROIs were compared between Cartesian-eTHRIVE and Radial eTHRIVE. For statistical differences paired Wilcoxon test and paired t-test have been performed (p < 0.05). RESULTS: The MR scan time was significantly longer for FB Radial-eTHRIVE (2 min, 54 s) compared to BH Cartesian-eTHRIVE (0 min 15 s). Cartesian-eTHRIVE demonstrated a superior subjective contrast impression and objective measurements revealed an increased lesion-to-liver-contrast for hypointense liver lesions (Hypo-LTLC: 0.33 +/- 0.19 vs. 0.20 +/- 0.11; p = 0.000), while no difference was observed for hyperintense liver lesions (Hyper LTLC). Subjective evaluation showed superior anatomic sharpness ratings by both readers for Radial-eTHRIVE. Most importantly, in a subgroup analysis of patients who were unable to perform adequate breath-holds, free-breathing Radial-eTHRIVE still demonstrated good subjective image quality. CONCLUSION: Free-breathing, radial k-space sampling T1w MRI of the liver delivers high diagnostic image quality, especially in patients who are unable to adequately perform breath-hold maneuvers. Thus, Radial-eTHRIVE can be an important clinical alternative in patients with impaired respiration status. KEY POINTS: . Delayed-phase contrast enhanced MRI of the liver can be robustly performed using a "pseudo golden angle" Radial-eTHRIVE sequence.. . Free-breathing Radial-eTHRIVE yields good diagnostic image quality in case of a high artifact burden in breath-hold Cartesian-eTHRIVE and thus could be used as a "back-up" for patients with impaired respiratory capacity.. . A lower lesion-to-liver-contrast ratio is observed for hypointense liver lesions in free-breathing Radial-eTHRIVE sequence.. CITATION FORMAT: . Hedderich DM, Weiss K, Spiro JE et al. Clinical Evaluation of Free-Breathing Contrast-Enhanced T1w MRI of the Liver using Pseudo Golden Angle Radial k-Space Sampling. Fortschr Rontgenstr 2018; 190: 601 - 609. PMID- 29534253 TI - Dose Reduction and Dose Management in Computed Tomography - State of the Art. AB - BACKGROUND: For years, the number of performed CT examinations has been rising. At the same time, computed tomography became more dose efficient. The aim of this article is to give an overview about the state of the art in dose reduction in CT and to highlight currently available tools in dose management. METHOD: By performing a literature research on Pubmed regarding dose reduction in CT, relevant articles were identified and analyzed. RESULTS AND CONCLUSION: Technical innovations with individual adaptation of tube current and voltage as well as iterative image reconstruction enable a considerable dose reduction with preserved image quality. At the same time, dedicated software tools are able to handle huge amounts of data and allow to optimize existing examination protocols. KEY POINTS: . CT examinations are increasingly performed and contribute considerably to non-natural radiation exposure.. . A correct indication is crucial for each CT examination.. . The examination protocol has to be tailored to the medical question and patient.. . Multiple technical innovations enable considerable dose reduction with constant image quality.. . Dose management with dedicated software tools gains importance.. CITATION FORMAT: . Zinsser D, Marcus R, Othman AE et al. Dose reduction and dose management in computed tomography - State of the art. Fortschr Rontgenstr 2018; 190: 531 - 541. PMID- 29534254 TI - Perioperative Complications of Esophageal Atresia. AB - Current survival rate of infants with esophageal atresia with/without tracheoesophageal fistula (EA/TEF) exceeds 90% and great interest is dedicated to the long-term outcomes and complications. However, perioperative complications represent a significant burden to the EA/TEF infants and a technical challenge for the surgeon. In this review, we will focus on the most frequent perioperative complications specific of EA/TEF to describe their predisposing factors, possible preventive measures, and treatment options. PMID- 29534255 TI - Perioperative Complications Following Surgery for Necrotizing Enterocolitis. AB - Necrotizing enterocolitis (NEC) is a devastating condition that mainly affects premature infants. Advanced cases of NEC require surgical treatment, which in up to 70% of infants is associated with significant perioperative morbidity including anastomosis- or enterostomy-related complications, sepsis, peritonitis, and wound infections. Moreover, the perioperative complications may compromise the long-term gastrointestinal and neurodevelopmental outcome of patients requiring surgery for NEC. PMID- 29534256 TI - Subcutaneoscopic Excision of External Angular Dermoid Cysts: Our Covert Scar Approach in 11 Cases. AB - INTRODUCTION: External angular dermoid cysts, or epidermoid inclusion cysts, are a common subcutaneous tumor of the head and neck. For the majority of these lesions, excision is relatively simple and performed through an incision immediately overlying the mass. Facial lesions in pediatric patients present a unique challenge in that a direct approach carries the potential for visible scar formation. OBJECTIVE: This article aims to detail our experience with subcutaneoscopic excision of external angular dermoid cysts in pediatric patients using endoscopic instrumentation. METHODS: Retrospectively, we reviewed 11 cases, between the ages of 4 months and 3 years with external angular dermoid cysts. An incision is made on the scalp above the hairline, then a tunneled working space is created underneath the skin. 3 mm laparoscopy instruments were then used for providing excellent visualization and precise subcutaneoscopic dissection. RESULTS: There were no complications apparent in any of the 11 cases (except cyst rupture in one case), with mean procedure duration at 61 minutes. Final results at follow-up revealed aesthetically pleasing and well-healed skin incisions, hidden from view behind the hairline. CONCLUSION: The subcutaneoscopic technique utilizing endoscopic instrumentation has the advantage of improved visualization of the cyst, greater precision of dissection, and excellent cosmesis. One disadvantage of this procedure is that this involves learning a new technique while the majority of surgeons are already comfortable with the open approach. Given the safety and efficacy observed for this subcutaneoscopic procedure, this technique can have tremendous possibilities. PMID- 29534257 TI - Therapeutic Perspectives on Chia Seed and Its Oil: A Review. AB - The attraction of novel foods proceeds alongside epidemic cardiovascular disease, diabetes, obesity, and related risk factors. Dieticians have identified chia (Salvia hispanica) as a product with a catalog of potential health benefits relating to these detriments. Chia is currently consumed not only as seeds, but also as oil, which brings about similar effects. Chia seeds and chia seed oil are used mainly as a food commodity and the oil is also used popularly as a dietary ingredient used in various dietary supplements available in the U. S. market. Chia seed is rich in alpha-linolenic acid, the biological precursor to eicosapentaenoic acid, a polyunsaturated fatty acid, and docosahexaenoic acid. Because the body cannot synthesize alpha-linolenic acid, chia has a newfound and instrumental role in diet. However, the inconclusive nature of the scientific community's understanding of its safety warrants further research and appropriate testing. The focus of this work is to summarize dietary health benefits of S. hispanica seed and oil to acknowledge concerns of adverse events from its ingestion, to assess current research in the field, and to highlight the importance of quality compendial standards to support safe use. To achieve this end, a large-scale literature search was partaken on the two well-known databases, PubMed and SciFinder. Hundreds of articles detailing such benefits as decreased blood glucose, decreased waist circumference and weight in overweight adults, and improvements in pruritic skin and endurance in distance runners have been recorded. These benefits must be considered within the appropriate circumstances. PMID- 29534258 TI - Management of Diabetes in the Intrapartum and Postpartum Patient. AB - Achieving maternal euglycemia in women with pregestational and gestational diabetes mellitus is critical to decreasing the risk of neonatal hypoglycemia, as maternal blood glucose levels around the time of delivery are directly related to the risk of hypoglycemia in the neonate. Many institutions use continuous insulin and glucose infusions during the intrapartum period, although practices are widely variable. At Northwestern Memorial Hospital, the "Management of the Perinatal Patient with Diabetes" policy and protocol was developed to improve consistency of management while also allowing individualization appropriate for the patient's specific diabetic needs. This protocol introduced standardized algorithms based on maternal insulin requirements to drive real-time maternal glucose control during labor as well as provided guidelines for postpartum glycemic control. This manuscript describes the development and implementation of this protocol to encourage other institutions to adopt a standardized protocol that allows highly individualized intrapartum care to women with diabetes. PMID- 29534259 TI - Sonographic Diagnosis of Meningoencephalitis in Newborns and Infants. AB - Prenatal, neonatal meningoencephalitis and infections of the brain in older infants are often associated with serious complications which can be diagnosed by sonography through the open fontanelles. Most frequently postmeningitic hydrocephalus and subdural effusions occur. Rarer complications are brain abscesses and ventriculitis which are caused by gram negative bacteria such as E. coli, Serratia marcescens, Proteus and Enterobacter. A serious complication after ventriculitis is the development of compartment hydrocephalus. Multifocal small echogenic lesions scattered all over the brain are suspicious of fungal infections. Stripe-like echogenicities in the basal ganglia of newborns are typical for prenatal infections such as infections with cytomegalovirus, rubella, herpes, toxoplasma gondii and HIV. Late sequelae are intracranial cysts, multifocal encephalomalacia and intracranial calcifications. Color Doppler shows increased perfusion of the brain in the acute phase of the disease. Brain abscesses and infarcts are characterized by decreased or missing perfusion. Spectral Doppler shows increased flow velocities. Increased intracranial pressure causes an increase of the flow velocities in the intracranial part of the internal carotid artery in comparison with the extracranial part. All complications can be diagnosed by ultrasound. Other imaging methods such as MRI are only occasionally necessary. PMID- 29534261 TI - [Multicentric analysis of the use behavior of cochlear implant users]. AB - INTRODUCTION: Novel cochlear implant speech processors are capable of storing data logs. With the help of this information a more individualized patient care can be provided. However, standard data are missing to a greater extent to the individual usage behavior. MATERIALS AND METHODS: In a retrospective study, the use data of 2687 patients were evaluated. All patients had the Nucleus 6 system from Cochlear Ltd. RESULTS: The data allow a normal range to be defined for the duration of use of cochlear implant speech processors. Likewise, the identification of conspicuous usage behavior is possible. PMID- 29534262 TI - [Ophthalmic Genetics: Insights into Actual Methods of Diagnostics, Phenotyping and Therapy]. PMID- 29534260 TI - Two Genetic Variants Associated with Plantar Fascial Disorders. AB - Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5*10-8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others. PMID- 29534263 TI - [Ciliopathies]. AB - Ciliopathies are disorders caused by ciliary dysfunction and can affect an organ system or tissues. Isolated or syndromic retinal dystrophies are the most common ocular manifestation of ciliopathies. The photoreceptor connecting cilium plays a leading role in these ciliopathy-related retinal dystrophies. Dysfunctional photoreceptor cilia cause the most severe type of retinal dystrophy: Leber's congenital amaurosis (LCA). The most common syndromic ciliopathies with an ocular manifestation are Bardet-Biedl syndrome (BBS) and Usher syndrome. Molecular genetic analysis revealed a large number of cilia genes with a high phenotype heterogeneity. Diagnosis of ciliopathies require a multi-disciplinary approach. Causative treatment of ciliopathies is not yet available; therefore, rehabilitative and supportive treatment is mandatory. PMID- 29534264 TI - [The Usher Syndrome, a Human Ciliopathy]. AB - The human Usher syndrome (USH) is a complex, rare disease manifesting in its most common form of inherited deaf-blindness. Due to the heterogeneous manifestation of the clinical symptoms, three clinical types (USH1-3) are distinguished according to the severity of the disease pattern. For a correct diagnosis, in addition to the auditory tests in early newborn screening, ophthalmological examinations and molecular genetic analysis are important. Ten known USH genes encode proteins, which are from heterogeneous protein families, interact in functional protein networks. In the eye and in the ear, USH proteins are expressed primarily in the mechano-sensitive hair cells and the rod and cone photoreceptor cells, respectively. In the hair cells, the USH protein networks are essential for the correct differentiation of the hair bundles as well as for the function of the mechano-electrical transduction complex in the matured cell. In the photoreceptor cells, USH proteins are located in the ciliary region and participate in intracellular transport processes. In addition, a USH protein network is present in the so-called calyceal processes. The lack of calyceal processes and the absence of a prominent visual phenotype in the mouse disqualifies mice as models for studies on the ophthalmic component of USH. While hearing impairments can be compensated with hearing aids and cochlear implants, there is no practical therapy for USH in the eye. Currently, gene-based therapy concepts, such as gene addition, applications of antisense oligonucleotides and TRIDs ("translational readthrough inducing drugs") for the readthrough of nonsense mutations are preclinically evaluated. For USH1B/MYO7A the UshStat gene therapy clinical trial is ongoing. PMID- 29534265 TI - [Retinal Astrocytic Hamartoma in Neurofibromatosis Type 2 - Metaanalysis and a Case Report]. AB - BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic condition with an autosomal dominant pattern of inheritance and incomplete penetrance. It is characterized by multiple benign tumors of the central and peripheral nervous system including astrocytomas, ependymomas, meningeomas, and schwannomas, among which bilateral vestibular schwannomas are the most frequent. Among ocular manifestations of NF2, juvenile subcapsular cataract is the most common followed by epiretinal membranes and combined hamartomas of the retina and retinal pigment epithelium. MATERIALS AND METHODS: Multimodal imaging was performed in a female patient and her data were compared to an overview of published cases with retinal hamartoma in NF2. RESULTS: We report on a case of a 14-year-old girl with genetically confirmed NF2 who presented with bilateral, asymptomatic hyperplasia of glia cells within the ganglion cell and the nerve fibre layer by spectral domain optical coherence tomography (SD-OCT). A metaanalysis of 25 published cases revealed combined hamartomas of the retina and retinal pigment epithelium (CHRRPE) as the most common (16 cases) retinal tumors followed by retinal astrocytic hamartomas (RAH, 7 cases). Retinal hamartomas were most often reported bilaterally and observed prior to the clinical diagnosis of NF2 in 11 of 25 cases. No correlation to sex was observed. Reduced visual acuity, cataracts and epiretinal membranes were the leading ocular manifestations. CONCLUSION: There is a large spectrum of ocular-specific findings in NF2. These are seminal, especially at an early age, enabling an early diagnosis and timely therapy of further tumor manifestations. Retinal astrocytic hamartomas may be very discreet and easily missed on routine examination. Fundus infrared imaging is a useful tool allowing to detect even discreet changes rarely seen by ophthalmoscopy in young children. This allows for a more extensive evaluation by SD-OCT. PMID- 29534266 TI - ? PMID- 29534267 TI - ? PMID- 29534268 TI - Erratum to: Difficult Cases in Robotic Arm-Assisted Total Knee Arthroplasty: A Case Series. PMID- 29534269 TI - Improved Early Postoperative Range of Motion in Total Knee Arthroplasty Using Tranexamic Acid: A Retrospective Analysis. AB - The use of tranexamic acid (TXA) in total knee arthroplasty (TKA) has become common practice. Recent literature has demonstrated a reduction in postoperative knee swelling and drain output while using TXA. Our purpose is to analyze the range of motion (ROM) following TKA in patients who received TXA compared with a control group. We hypothesize that patients treated with TXA will have improved early postoperative ROM when compared with controls. A retrospective chart review was performed for patients who underwent TKA from 2010 to 2012 performed by a single orthopaedic surgeon. Patients were stratified into three cohorts by route of TXA administration including intravenous (IV), topical, and a control group. Dependent variables analyzed included extension, flexion, and total arc ROM on each postoperative day (POD), average ROM across all three postoperative days, as well as pre-to-postoperative differences in ROM. Demographic data were recorded for each patient. A total of 174 patients were included for analysis, 75 controls and 99 receiving TXA. A significant difference was found between the treatment groups and the control for all variables (for each, p <= 0.002). There were no significant differences in ROM between the IV and topical TXA treatment groups (for each, p >= 0.558). A multivariate analysis demonstrated no significant difference between the groups in complication rate or demographic variables. The use of TXA may improve early postoperative ROM following TKA. PMID- 29534270 TI - Intra-articular Alpha-2 Agonists as an Adjunct to Local Anesthetic in Knee Arthroscopy: A Systematic Review and Meta-Analysis. AB - The infiltration of local anesthetic has been shown to reduce postoperative pain in knee arthroscopy. Several studies have shown that the addition of agents such as magnesium and nonsteroidal antiinflammatory drugs (NSAIDs) result in an increased time to first analgesia and overall reduction in pain. The aim of this systematic review and meta-analysis was to determine whether the addition of an alpha-2 agonist (A2A) to intra-articular local anesthetic, results in a reduction in postoperative pain. Four major databases were systematically searched for relevant randomized controlled trials (RCTs) up to July 2017. RCTs containing a control group receiving a local anesthetic and an intervention group receiving the same with the addition of an A2A were included in the review. The included studies were assessed for level of evidence and risk of bias. The data were then analyzed both qualitatively and where appropriate by meta-analysis. We reviewed 12 RCTs including 603 patients. We found that the addition of an A2A resulted in a significant reduction in postoperative pain up to 24 hours. The addition of the A2A increased time to first analgesia request by 258.85 minutes (p < 0.00001). Total 24-hour analgesia consumption was analyzed qualitatively with all included studies showing a significant reduction in total analgesia requirement. Interestingly, none of the studies found an increase in side effects associated with the A2A. This study provides strong evidence for the use of A2As as a means to reduce postoperative pain post arthroscopic knee surgery, without a corresponding increase in side effects. PMID- 29534271 TI - Multiple Ligament Knee Injuries. AB - The posterior cruciate ligament (PCL)-based multiple ligament injury, or dislocated knee, is often part of a multisystem injury complex that not only includes the knee ligaments, but may also include blood vessels, skin, nerves, fractures, and other organ system trauma. These factors must be considered in the scope of treating this complex knee injury. These complex knee ligament injuries can result in significant functional instability for the affected individual. This article will discuss multiple ligament knee injuries evaluation, treatment, and special considerations in the pediatric and adolescent population. PMID- 29534273 TI - Understanding the Limits of Biomechanical Testing. PMID- 29534274 TI - Reduction of the A-Frame Angle of Incline does not Change the Maximum Carpal Joint Extension Angle in Agility Dogs Entering the A-Frame. AB - OBJECTIVE: This article aims to investigate the effect of a decrease in the A frame angle of incline on the highest carpal extension angle in agility dogs. METHODS: Kinematic gait analysis (two-dimensional) measuring carpal extension was performed on 40 dogs entering the A-frame at 3 angles of incline: 40 degrees (standard), 35 degrees and 30 degrees . The highest carpal extension angle from three trials at each incline was examined for a significant effect of A-frame angle with height, body weight and velocity included as covariates. RESULTS: There was no significant effect of A-frame angle on the highest carpal joint extension angle for the first or second limb. The adjusted mean carpal extension angle for the first limb at 40 degrees was 64 degrees [95% confidence interval (CI), 60-68), at 35 degrees was 61 degrees (95% CI, 57-65) and at 30 degrees was 62 degrees (95% CI, 59-65). The raw mean carpal extension angle for all dogs across all A-frame angles for the first limb was 62 degrees (95% CI, 60-64) and the second limb was 61 degrees (95% CI, 59-63). CLINICAL SIGNIFICANCE: Decreasing the A-frame angle of incline from 40 degrees to 30 degrees did not result in reduced carpal extension angles. The failure to find a difference and the narrow CI of the carpal angles may indicate that the physiologic limits of carpal extension were reached at all A-frame angles. PMID- 29534275 TI - Clinical Application of 3D-CISS MRI Sequences for Diagnosis and Surgical Planning of Spinal Arachnoid Diverticula and Adhesions in Dogs. AB - OBJECTIVE: Abnormalities within the spinal arachnoid space are often treated surgically, but they can be challenging to detect with conventional magnetic resonance imaging (MRI) sequences. 3D-CISS sequences are considered superior in evaluating structures surrounded by cerebrospinal fluid (CSF) due to the high signal-to-noise ratio, high contrast-to-noise ratio and intrinsic insensitivity to motion with minimal signal loss due to CSF pulsations. Our objective was to describe findings and advantages in adding 3D-CISS sequences to routine MRI in patients affected by spinal arachnoid diverticula (SAD) or arachnoid adhesions. MATERIAL AND METHODS: This article is a retrospective review of medical records of 19 dogs admitted at Fitzpatrick Referrals between 2013 and 2017 that were diagnosed with SAD and confirmed surgically. Inclusion criterions were the presence of clinical signs compatible with compressive myelopathy and an MRI diagnosis, which included the 3D-CISS sequence. Our database was searched for additional 19 dogs diagnosed with other spinal lesions other than SAD that had the same MR sequences. All MR images were anonymized and evaluated by two assessors. CONCLUSION AND CLINICAL RELEVANCE: 3D-CISS sequence appears to improve confidence in diagnosing and surgical planning (Mann-Whitney U-test: p < 0.0005), delineating SAD from other changes associated with abnormal CSF hydrodynamics and providing more anatomical details than conventional MRI sequences. The clinical data in combination with imaging findings would limit over interpretation, when concurrent pathology within the arachnoid space is present. PMID- 29534276 TI - Canine Vertebral Screw and Rod Fixation System: Design and Mechanical Testing. AB - OBJECTIVES: To develop the canine vertebral screw and rod fixation system (CVSRF) and to compare the biomechanical properties between CVSRF and the screw and polymethylmethacrylate (Screw-PMMA) technique for internal fixation of the vertebral column in dogs. METHODS: The CVSRF consisted of vertebral screws with monoaxial side-loaded head, rods and specific inner screws connecting rod to the screw head. The CVSRF prototype was made from titanium alloy and manufactured by the rapid prototype machine. Vertebrectomy models were simulated by ultra-high molecular-weight polyethylene blocks and tested with the CVSRF system (n = 8) and the Screw-PMMA technique (n = 8). The models were developed according to the American Society for Testing and Materials (ASTM F-1717-04). The biomechanical parameters were the compressive bending yield load, the compressive bending stiffness, the compressive ultimate load and the load displacement curve. RESULTS: The mean values of the compressive bending yield load, compressive bending stiffness and compressive ultimate load of the CVSRF were significantly higher than those of the Screw-PMMA technique (p < 0.01). The load displacement curve of the CVSRF showed higher rigidity and durability than that of the Screw PMMA technique. CLINICAL SIGNIFICANCE: This mechanical study indicated that the CVSRF system can be used for canine vertebral stabilization and the biomechanical properties were better than those for the Screw-PMMA device. PMID- 29534277 TI - Accuracy of Femoral Head and Neck Excision via a Craniolateral Approach or a Ventral Approach. AB - OBJECTIVES: This study aimed to compare the completeness of femoral head and neck removal via a craniolateral approach or a ventral approach when femoral head and neck excision (FHNE) is performed by a novice veterinarian. METHODS: FHNE was performed on both femurs of 10 canine cadavers with each femur randomized by a coin toss to FHNE via the craniolateral or ventral approach. Computed tomography (CT) of the femurs was performed prior to and following FHNE. The volume of bone that should have been removed with an ideal FHNE, the percentage of this volume that remained following FHNE, time to complete the procedure and the number of technical errors were compared between the two groups. RESULTS: No significant difference (p = 0.88) was found in the volume of bone that should have been removed with an ideal ostectomy when using the two approaches (craniolateral 3,814.7 +/- 409.4 mm3; ventral 3,806.2 +/- 479.4 mm3), mean excess residual femoral neck (craniolateral 6.0 +/- 9.6%; ventral 4.8 +/- 6.8%), mean duration of the procedure (craniolateral 19.3 +/- 5.4 minutes; ventral 23.7 +/- 5.6 minutes) or number of technical errors (craniolateral 0/10; ventral 1/10) between the craniolateral and ventral approach groups. CLINICAL RELEVANCE: The completeness of bone removal was not significantly different when FHNE was performed by a novice veterinarian via a craniolateral or ventral approach. PMID- 29534278 TI - Magnetic Resonance Imaging T2 Values of Stifle Articular Cartilage in Normal Beagles. AB - OBJECTIVES: The purpose of this study was to evaluate regional differences of canine stifle articular cartilage using the quantitative magnetic resonance imaging (MRI) technique of T2 mapping. METHODS: Fourteen stifle joints from seven juvenile male Beagle dogs with no evidence or prior history of pelvic limb lameness were imaged ex vivo using standard of care fast spin echo MRI and quantitative T2 mapping protocols. Regions of interest were compared between the femoral, patellar and tibial cartilages, as well as between the lateral and medial femorotibial compartments. Limbs were processed for histology with standard stains to confirm normal cartilage. RESULTS: The average T2 value of femoral trochlear cartilage (37.5 +/- 2.3 ms) was significantly prolonged (p < 0.0001) as compared with the femoral condylar, patellar and tibial condylar cartilages (33.1 +/- 1.5 ms, 32.8 +/- 2.3 ms, and 28.0 +/- 1.7 ms, respectively). When comparing medial and lateral condylar compartments, the lateral femoral condylar cartilage had the longest T2 values (34.8 +/- 2.8 ms), as compared with the medial femoral condylar cartilage (30.9 +/- 1.9 ms) and lateral tibial cartilage (29.1 +/- 2.3 ms), while the medial tibial cartilage had the shortest T2 values (26.7 +/- 2.4 ms). CLINICAL SIGNIFICANCE: As seen in other species, regional differences in T2 values of the canine stifle joint are identified. Understanding normal regions of anticipated prolongation in different joint compartments is needed when using quantitative imaging in models of canine osteoarthritis. PMID- 29534279 TI - A Comparison of Angular Values of the Pelvic Limb with Normal and Medial Patellar Luxation Stifles in Chihuahua Dogs Using Radiography and Computed Tomography. AB - OBJECTIVE: This article aimed to determine and compare the angular values of the pelvic limb in normal and medial patellar luxation (MPL) stifles in Chihuahuas using radiography and computed tomographic (CT) scan, to identify the relationship between pelvic limb angles and severity of MPL. In addition, radiographic and CT images were compared to determine the more suitable method of limb deformity assessment. METHODS: Sixty hindlimbs of Chihuahuas were divided into normal and grade 1, 2, 3 and 4 MPL groups. The pelvic limb angles in frontal and sagittal planes were evaluated on radiography and CT scan. Femoral and tibial torsion angles (FTA and TTA) were evaluated only by CT scan. All angles were compared among normal and MPL stifles and between radiography and CT scan. RESULTS: Based on the CT scan, the mechanical lateral distal femoral angle (mLDFA), anatomical caudal proximal femoral angle (aCdPFA), and TTA were related to the severity of MPL. The mLDFA and TTA were significantly increased (p < 0.05) in grade 4 MPL, while the aCdPFA was significantly decreased in grade 2, 3 and 4 MPL groups. There were significant differences of many angles between radiography and CT scan. CLINICAL SIGNIFICANCE: The angles related to MPL in Chihuahuas are aLDFA, mLDFA, aCdPFA and TTA. Radiography had some limitations for evaluating pelvic limb angles. The caudocranial radiograph is recommended for the assessment of the distal femoral angles, while the craniocaudal radiograph is for the tibial angles. PMID- 29534280 TI - Combined Tibial Plateau Levelling Osteotomy and Tibial Tuberosity Transposition: An Ex Vivo Mechanical Study. AB - OBJECTIVES: The purpose of this study is to compare the load at failure and mode of failure between (1) tibial plateau levelling osteotomy (TPLO) and combined TPLO and tibial tuberosity transposition (TPLO-TTT) (Phase I) and (2) TPLO-TTT and tibial tuberosity transposition (TTT) (Phase II). METHODS: Seven pairs of cadaveric tibiae were tested in each of the Phase I (TPLO vs. TPLO-TTT) and Phase II (TPLO-TTT vs. TTT) experiments. One limb of each pair was randomly assigned to one of two groups for each experimental phase. A tensile force was applied to the patellar ligament until construct failure occurred. RESULTS: There was a significant difference in mean load at failure between TPLO (2092.8 N) and TPLO TTT (1067.8 N), p = 0.004. All TPLO constructs failed by fracture of the tibial crest. The TPLO-TTT constructs failed by cranial displacement of the distal tibial crest. Additionally, the tibial plateau was displaced in the majority of limbs. There was a significant difference in mean load at failure between TPLO TTT (1157.6 N) and TTT (1394.0 N), p = 0.025. The TTT constructs demonstrated a similar mode of failure as TPLO-TTT. CLINICAL SIGNIFICANCE: Although ex vivo mechanical testing does not replicate the postoperative clinical scenario, these results demonstrate reduced construct strength of the combined TPLO-TTT technique compared with TPLO or TTT alone. When performing TPLO-TTT, meticulous technique and implants of adequate strength must be employed to create a robust construct and minimize postoperative tibial crest fixation failure. PMID- 29534281 TI - The Effect of Tibial Plateau Levelling Osteotomy on Stifle Extensor Mechanism Load: A Canine Ex Vivo Study. AB - OBJECTIVE: To evaluate the effect of tibial plateau levelling osteotomy on stifle extensor mechanism load in an ex vivo cruciate-intact canine cadaveric model. STUDY DESIGN: Ex vivo mechanical testing study. ANIMALS: Cadaveric canine pelvic limbs (n = 6). MATERIALS AND METHODS: A 21-mm tibial radial osteotomy was performed on pelvic limbs (n = 6) prior to being mounted into a load-bearing limb press. The proximal tibial segment was incrementally rotated until the anatomical tibial plateau angle had been rotated to at least 1 degrees . The proportional change in stifle extensor mechanism load between the anatomical tibial plateau angle and the neutralized (~6.5 degrees) and over rotated (~1 degrees ) tibial plateau angle was analysed using a one-sample t-test against a null hypothesis of no change. A p-value <=0.05 was considered significant. RESULTS: There was no significant change in the stifle extensor mechanism load from the anatomical tibial plateau angle (308 N [261-355 N]) to the neutralized tibial plateau angle (313 N [254-372 N]; p =.81), or from the anatomical tibial plateau angle to the over-rotated tibial plateau angle (303 N [254-352 N; p = 0.67). CONCLUSION: Tibial plateau levelling osteotomy does not significantly alter stifle extensor mechanism load at either a neutralized or over-rotated tibial plateau angle in our cruciate-intact model. PMID- 29534282 TI - Postoperative Complications Associated with External Skeletal Fixators in Dogs. AB - OBJECTIVES: To quantify and evaluate risks of complications attributable to external skeletal fixator (ESF) usage in dogs. METHODS: A retrospective review of medical records following ESF placement. RESULTS: Case records of 97 dogs were reviewed; fixator-associated complications occurred in 79/97 dogs. Region of ESF placement was significantly associated with complication development (p = 0.005), not complication type (p = 0.086). Complications developed most frequently in the tarsus (9/10), manus (8/9) and humerus (8/9). Superficial pin tract infection and implant failure occurred in 38/97 and 17/97 dogs, respectively. Superficial pin-tract infection occurred frequently in the femur, humerus, radius and ulna and the pes, with implant failure frequent in the tarsus and deep pin-tract infection in the manus and tibia. Transarticular frames were significantly more likely to develop a complication (p = 0.028). Age was significantly associated with complication development (p = 0.029). No associations between breed, sex, weight, fracture type (open or closed), ESF classification and the incidence or type of complications were identified. No associations between, breed, age, sex, weight, fracture type (open or closed), ESF classification and the time to complication development were identified. CLINICAL SIGNIFICANCE: Fixator-associated complications are common in dogs, with the majority of complications related to implant infection. Region and placement of transarticular frames should be carefully considered when selecting stabilization method. PMID- 29534283 TI - Treatment of Osteochondrosis Dissecans of the Canine Stifle Using Synthetic Osteochondral Resurfacing. AB - OBJECTIVE: This article aimed to describe the use and evolution of a synthetic osteochondral resurfacing (SOR) implant in the treatment of osteochondrosis dissecans (OCD) of the femoral condyle and to report the clinical, radiographic, computed tomography and magnetic resonance imaging outcomes of this technique. METHODS: Medical records of dogs that were treated with first-generation (G1) and second-generation (G2) SOR at a single institute were reviewed. Surgical reports and clinical examinations as well as the preoperative, postoperative, and follow-up radiographs, computed tomographic images and magnetic resonance imaging images were reviewed. RESULTS: Fourteen stifles (nine dogs) were included in the study. G1-SOR implants were employed in six stifles of four dogs and G2-SOR implants in eight stifles of five dogs. Osteochondrosis dissecans of the medial femoral condyle was confirmed as the sole pathology in all dogs treated with G1 SOR. Only one of eight OCD lesions was located on the medial condyle in the G2 SOR group with the remaining seven lesions affecting the lateral femoral condyle. At 12 weeks, 13 of 14 stifles displayed implant stability, with no subchondral bone changes or evidence of lucency around any implant. Eight of nine dogs achieved a good-excellent clinical outcome. Complications included one minor surgical site infection and one infective arthritis which required implant removal. CLINICAL SIGNIFICANCE: In this cohort of dogs, both G1-SOR and G2-SOR were successful and repeatable surgical procedures for dogs with OCD of the femoral condyle. PMID- 29534284 TI - Displacement of an Ununited Medial Humeral Condylar Ossification Centre in the Cat. AB - A 2-year-old cat was presented with the complaint of acute-onset non-weight bearing lameness of the right forelimb. When examined, the cat was of short stature and had multiple joint and cartilaginous abnormalities suggestive of chondrodysplasia. The cause of the acute lameness was radiographically identified as a displaced osseous fragment from the medial portion of the right humeral condyle. The features of the osseous fragment were consistent with an ununited medial condylar ossification centre of the distal humerus. Furthermore, a nondisplaced ununited ossified fragment of similar appearance and size was present in the contralateral elbow. Surgical treatment by excision of the displaced fragment resulted in a preinjury level of limb function in the long term outcome evaluation. PMID- 29534285 TI - Big data: breaking new ground in airway research. PMID- 29534286 TI - Clinical Pharmacokinetics and Pharmacodynamics of Etelcalcetide, a Novel Calcimimetic for Treatment of Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease on Hemodialysis. AB - Etelcalcetide, a d-amino acid peptide, is an intravenous calcimimetic approved for the treatment of secondary hyperparathyroidism. Etelcalcetide binds the calcium-sensing receptor and increases its sensitivity to extracellular calcium, thereby decreasing secretion of parathyroid hormone (PTH) by chief cells. Etelcalcetide and its low-molecular-weight transformation products are rapidly cleared by renal excretion in healthy subjects, but clearance is substantially reduced and dependent on hemodialysis in end-stage renal disease. The effective half-life is 3-5 days in patients undergoing hemodialysis 3 times a week. A clinical study using a single microtracer intravenous dose of [14 C]etelcalcetide indicated that 60% of the administered dose was eliminated in dialysate. Etelcalcetide undergoes reversible disulfide exchange with serum albumin to form a serum albumin peptide conjugate that is too large (67 kDa) to be dialyzed, until a subsequent exchange forms etelcalcetide or a low-molecular-weight transformation product. This exchange from albumin is apparent after hemodialysis, when it partially restores etelcalcetide concentrations in plasma. Etelcalcetide has no known risks for drug-drug interactions. In phase 3 studies, 74%-75% of hemodialysis patients with secondary hyperparathyroidism who received etelcalcetide achieved a >30% PTH reduction from baseline versus 8%-10% of patients who received placebo. The pharmacokinetics and pharmacodynamics of etelcalcetide in hemodialysis patients supports a 5-mg starting dose administered after hemodialysis and uptitration in 2.5- or 5-mg increments every 4 weeks to a maximum dose of 15 mg 3 times a week. PMID- 29534287 TI - Model selection for semiparametric marginal mean regression accounting for within cluster subsampling variability and informative cluster size. AB - We propose a model selection criterion for semiparametric marginal mean regression based on generalized estimating equations. The work is motivated by a longitudinal study on the physical frailty outcome in the elderly, where the cluster size, that is, the number of the observed outcomes in each subject, is "informative" in the sense that it is related to the frailty outcome itself. The new proposal, called Resampling Cluster Information Criterion (RCIC), is based on the resampling idea utilized in the within-cluster resampling method (Hoffman, Sen, and Weinberg, 2001, Biometrika 88, 1121-1134) and accommodates informative cluster size. The implementation of RCIC, however, is free of performing actual resampling of the data and hence is computationally convenient. Compared with the existing model selection methods for marginal mean regression, the RCIC method incorporates an additional component accounting for variability of the model over within-cluster subsampling, and leads to remarkable improvements in selecting the correct model, regardless of whether the cluster size is informative or not. Applying the RCIC method to the longitudinal frailty study, we identify being female, old age, low income and life satisfaction, and chronic health conditions as significant risk factors for physical frailty in the elderly. PMID- 29534288 TI - Parenteral Lipid Dose Restriction With Soy Oil, Not Fish Oil, Preserves Retinal Function in Neonatal Piglets. AB - BACKGROUND: A dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (AA) is critical for neonatal retinal development. Both are absent/minimal in parenteral nutrition (PN) using soy-oil emulsions ([SO] Intralipid(r)) traditionally used for neonatal intestinal failure. In contrast, fish-oil emulsions ([FO] Omegaven(r)) are enriched in DHA/AA. The aim of this study was to compare retinal function and fatty acid content in neonatal piglets fed PN with SO or FO. METHODS: Two-5-day-old piglets were randomly allocated to SO (n = 4) or FO (n = 4), provided at equivalent doses (5g/kg/d). After 14 days of PN, retinal function was assessed by electroretinography and retinas were harvested for fatty acid content analysis. Sow-fed piglets served as a reference (REF). RESULTS: Light flash-elicited stoppage of cone and rod dark-currents (a-waves) and the ensuing postsynaptic activation of cone and rod ON bipolar cells (b-waves) were comparable between SO and REF. Responses recorded from FO were subnormal (P <0.001) when compared with both SO and REF. Retinal DHA content was similar in both groups (FO, 14.59% vs SO, 12.22%; P = 0.32); while AA was lower in FO (FO, 6.01% vs SO, 8.21%; P = .001). CONCLUSION: Paradoxically, FO containing more DHA and AA did not preserve retinal function when compared with the same low dose of SO. This may be due to the reduced AA enrichment in the retina with FO treatment. Further investigation into the ideal amounts of DHA and AA for optimal neonatal retinal function is required. PMID- 29534289 TI - Estimating and managing fatigue for our patients: Are we measuring up? PMID- 29534290 TI - Changes in morphology and metabolism enable Mn-oxidizing bacteria from mid oceanic ridge environment to counter metal-induced stress. AB - Mn-oxidizing potential of two metal-tolerant bacterial strains - Halomonas meridiana and Marinobacter algicola isolated from the South West Indian Ridge waters were compared at varying concentrations of Mn (II), i.e., 1, 10, and 100 MUmol and mmol L-1 . Accompanying changes in their morphology and metabolism were also determined. At concentrations >1 mmol L-1 Mn (II), Mn-oxidizing potential of M. algicola was 2-7 times greater than that of H. meridiana. Scanning electron microscopy revealed that exposure to elevated metal content prompted bacterial cells especially those of M. algicola to been enveloped in exopolymeric material and form aggregates. Energy dispersive spectrometric analysis showed that exopolymeric material acts as a nucleation site for Mn deposition and oxide formation which occurs in the form of microspherical aggregates. These features show striking resemblance to biogenically produced Fe-Mn oxide deposits from Lau Basin. Surprisingly, diffractograms of auto-oxidized and bacterially formed Mn oxide showed similarities to the hydrothermal vein mineral Rhodochrosite indicating that it can also be produced biotically. Elongation of cells by up to 4* the original size and distortion in cell shape were evident at Mn (II) concentrations >100 MUmol L-1 . Marked differences in C-substrate utilization by the test strains were also observed in presence of Mn (II). A shift in use of substrates that are readily available in oceanic waters like N-acetyl-d glucosamine to those that can be used under changing redox conditions (d cellobiose) or in the presence of metal ions (d-arabinose, l-asparagine) were observed. These findings highlight the significant role of autochthonous bacteria in transforming reduced metal ions and aiding in the formation of metal oxides. Under natural or laboratory conditions, the mode of bacterially generated Mn oxide tends to remain the same. PMID- 29534291 TI - Nutritional Risk in Emergency-2017: A New Simplified Proposal for a Nutrition Screening Tool. AB - BACKGROUND: There are many nutrition screening tools currently being applied in hospitals to identify risk of malnutrition. However, multivariate statistical models are not usually employed to take into account the importance of each variable included in the instrument's development. OBJECTIVE: To develop and evaluate the concurrent and predictive validities of a new screening tool of nutrition risk. METHODS: A prospective cohort study was developed, in which 4 nutrition screening tools were applied to all patients. Length of stay in hospital and mortality were considered to test the predictive validity, and the concurrent validity was tested by comparing the Nuritional Risk in Emergency (NRE)-2017 to the other tools. RESULTS: A total of 748 patients were included. The final NRE-2017 score was composed of 6 questions (advanced age, metabolic stress of the disease, decreased appetite, changing of food consistency, unintentional weight loss, and muscle mass loss) with answers yes or no. The prevalence of nutrition risk was 50.7% and 38.8% considering the cutoff points 1.0 and 1.5, respectively. The NRE-2017 showed a satisfactory power to indentify risk of malnutrition (area under the curve >0.790 for all analyses). According to the NRE-2017, patients at risk of malnutrition have twice as high relative risk of a very long hospital stay. The hazard ratio for mortality was 2.78 (1.03-7.49) when the cutoff adopted by the NRE-2017 was 1.5 points. CONCLUSION: NRE-2017 is a new, easy-to-apply nutrition screening tool which uses 6 bi-categoric features to detect the risk of malnutrition, and it presented a good concurrent and predictive validity. PMID- 29534292 TI - Prevalence, Evolution, and Risk Factors for Advanced Liver Fibrosis in Adults Undergoing Intestinal Transplantation. AB - INTRODUCTION: Intestinal failure-associated liver disease (IFALD) occurs commonly in intestinal transplant (ITx) candidates receiving parenteral nutrition (PN). The aim of this study is to establish the prevalence and risk factors for advanced liver fibrosis in adults at the time of ITx. METHODS: Retrospective chart review of all ITx was performed in adults between January 2000 and May 2014. Advanced liver fibrosis was defined as stage 3 or stage 4 fibrosis. RESULTS: Fifty-three patients met the inclusion criteria. The mean age was 50.6 +/- 10.9 years, and the majority were female (60.4%) and Caucasian (67.9%). The mean body mass index was 21.7 +/- 3.8 kg/m2 and the median duration of PN was 402 (interquartile range: 529) days. Advanced liver fibrosis at the time of ITx was found in 13 patients (24.5%). The multivariate analysis revealed that female gender and white race were significant predictors of advanced liver fibrosis. A total bilirubin >3.0 mg/dL for > a month prior to ITx was associated with an odds ratio of 8.9 for advanced fibrosis at the time of ITx but did not reach statistical significance (P = 0.055). CONCLUSION: Close to one-quarter of the ITx recipients had advanced liver fibrosis. In the current era of improved PN management, our data suggests that previously reported risk factors for IFALD, such as extreme short gut syndrome and PN duration, may have a lesser impact on development of liver fibrosis. A prolonged duration of bilirubin elevation may be associated with advanced liver fibrosis in patients with IFALD, but this requires validation in a larger cohort. PMID- 29534293 TI - Impact of SMOFLipid on Pulmonary Alveolar Development in Newborn Guinea Pigs. AB - BACKGROUND: Parenteral nutrition (PN) is associated with bronchopulmonary dysplasia in premature infants. In animals, PN leads to alveolar loss following stimulation of apoptosis by oxidative stress (oxidized redox potential). Peroxides and aldehydes generated in PN can induce hypo-alveolarization. The implication of peroxides, which is reduced by light protection, is demonstrated. The implication of aldehydes from omega-6 fatty acids oxidation is expected. The hypothesis is that composition and light exposure of PN influences bronchopulmonary dysplasia development. Since SMOFLipid (SMOF) contains a lower amount of omega-6 fatty acids than Intralipid (IL), the aim was to compare, the impacts of PN compounded with SMOF or IL, photo-protected or not, on alveolar development. MATERIALS AND METHODS: Three-day-old Guinea pigs received PN, photo protected or not, made with SMOF or IL through a jugular vein catheter. After 4 days, lungs were sampled for determinations of redox potential of glutathione, apoptosis (caspase-3, caspase-8, and caspase-9) and alveolarization index (histology: number of intercepts/mm). RESULTS: Compared with IL, SMOF induces a greater oxidation of redox potential (-200 +/- 1 versus [vs] -205 +/- 1 mV), apoptosis (caspase-3: 0.27 +/- 0.04 vs 0.16 +/- 0.02; caspase-9: 0.47 +/- 0.03 vs 0.30 +/- 0.03), and a lower alveolarization index (27.2 +/- 0.8 vs 30.0 +/- 0.9). Photo-protection prevented activation of caspase-9 and was statistically without effect on redox potential, caspase-3, and alveolarization index. CONCLUSION: In our model, SMOF is pro-oxidant and induces hypo-alveolarization following exaggerated apoptosis. These results highlight the need for further studies before introducing SMOFLipid in standard neonatal care. PMID- 29534294 TI - A group sequential test for treatment effect based on the Fine-Gray model. AB - Competing risks endpoints arise when patients can fail therapy from several causes. Analyzing these outcomes allows one to assess directly the benefit of treatment on a primary cause of failure in a clinical trial setting. Regression models can be used in clinical trials to adjust for residual imbalances in patient characteristics, improving the power to detect treatment differences. But, none of the competing risks methods currently available for use in group sequential trials adjust for covariates. We propose a group sequential test for treatment effect that, because it is based on the Fine-Gray model, permits adjustment for covariates. Our derivations show that its sequence of test statistics has an asymptotic distribution with an independent increments structure, which allows standard techniques such as O'Brien-Fleming designs and error spending functions to be employed to meet type I error rate and power specifications. We demonstrate the test in a reanalysis of BMT CTN 0402, a phase III clinical trial that evaluated an experimental treatment for the prevention of adverse outcomes following blood and marrow transplant. Moreover, using a simulation study of randomized group sequential trials, we demonstrate that the proposed method preserves the type I error rate and power at their nominal levels in the presence of influential covariates. PMID- 29534295 TI - The usefulness of electrodiagnostic studies in the diagnosis and management of neuromuscular disorders. AB - INTRODUCTION: This study seeks to evaluate the usefulness of electrodiagnostic (EDX) studies in terms of the patient's diagnosis and subsequent management and to identify patient groups in which EDX is particularly useful. METHODS: The records of new patients referred to a single tertiary hospital EDX laboratory during 1 calendar year were reviewed to determine whether results of EDX studies led to a changed diagnosis and/or management plan. Logistic regression was used to determine whether any factors were associated with changed diagnosis or management. RESULTS: Results of EDX studies led to a change in diagnosis and a confirmation in diagnosis in 51.5% and 46.5% of the cases, respectively. Results of EDX studies led to a change in the management plan in 63.4% of all cases. The diagnosis and management plan were more likely to be changed in older patients and patients referred in hospital. DISCUSSION: EDX studies seem useful for confirming or changing the diagnosis and in guiding management in patients with suspected neuromuscular disorders. Muscle Nerve 58: 191-196, 2018. PMID- 29534296 TI - Estimating individualized treatment rules for ordinal treatments. AB - Precision medicine is an emerging scientific topic for disease treatment and prevention that takes into account individual patient characteristics. It is an important direction for clinical research, and many statistical methods have been proposed recently. One of the primary goals of precision medicine is to obtain an optimal individual treatment rule (ITR), which can help make decisions on treatment selection according to each patient's specific characteristics. Recently, outcome weighted learning (OWL) has been proposed to estimate such an optimal ITR in a binary treatment setting by maximizing the expected clinical outcome. However, for ordinal treatment settings, such as individualized dose finding, it is unclear how to use OWL. In this article, we propose a new technique for estimating ITR with ordinal treatments. In particular, we propose a data duplication technique with a piecewise convex loss function. We establish Fisher consistency for the resulting estimated ITR under certain conditions, and obtain the convergence and risk bound properties. Simulated examples and an application to a dataset from a type 2 diabetes mellitus observational study demonstrate the highly competitive performance of the proposed method compared to existing alternatives. PMID- 29534297 TI - De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. AB - OBJECTIVE: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway. METHODS: We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments. RESULTS: We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2. INTERPRETATION: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794 806. PMID- 29534298 TI - Motivating sample sizes in adaptive Phase I trials via Bayesian posterior credible intervals. AB - In contrast with typical Phase III clinical trials, there is little existing methodology for determining the appropriate numbers of patients to enroll in adaptive Phase I trials. And, as stated by Dennis Lindley in a more general context, "[t]he simple practical question of 'What size of sample should I take' is often posed to a statistician, and it is a question that is embarrassingly difficult to answer." Historically, simulation has been the primary option for determining sample sizes for adaptive Phase I trials, and although useful, can be problematic and time-consuming when a sample size is needed relatively quickly. We propose a computationally fast and simple approach that uses Beta distributions to approximate the posterior distributions of DLT rates of each dose and determines an appropriate sample size through posterior coverage rates. We provide sample sizes produced by our methods for a vast number of realistic Phase I trial settings and demonstrate that our sample sizes are generally larger than those produced by a competing approach that is based upon the nonparametric optimal design. PMID- 29534300 TI - Adaptation of Borrelia burgdorferi to its natural hosts by synonymous codon and amino acid usage. AB - Lyme disease, caused by Borrelia burgdorferi, is a focally endemic tick transmitted zoonotic infection. In this study, the major factors underlying synonymous codon-related amino acid usage in the B. burgdorferi genome and bias in synonymous codon usage of the translation initiation region of coding sequences were analyzed. Additionally, adaptation of B. burgdorferi to several of its hosts was analyzed in the context of synonymous codon usage. Principal component analysis (PCA) revealed that nucleotide content at the third synonymous position of a codon influenced the synonymous codon usage pattern, but the strand specific factor did not influence the synonymous codon usage pattern of B. burgdorferi. In terms of the low GC content of B. burgdorferi coding sequences, the effective number of codons (ENC) showed a significant correlation with GC3 content (at the synonymous position). For the amino acid usage pattern for B. burgdorferi, PCA showed that the strand-specific factor did not contribute to this pattern, while the properties (aromaticity and hydrophobicity) of the amino acids themselves showed strong correlations with this pattern. Under-represented codons, which were frequently selected in the translation initiation region, possibly play roles in regulating gene expression in B. burgdorferi. In terms of co-evolution and synonymous codon usage patterns, adaptation of B. burgdorferi to different intermediate hosts was apparent to different degrees, and the degree of adaptation of this spirochete to wild animals was stronger than that of humans or mice. PMID- 29534299 TI - Getting the best outcomes from epilepsy surgery. AB - Neurosurgery is an underutilized treatment that can potentially cure drug refractory epilepsy. Careful, multidisciplinary presurgical evaluation is vital for selecting patients and to ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guided surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. Ann Neurol 2018;83:676-690. PMID- 29534301 TI - Key HLA-DRB1-DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine. AB - : Approximately 5-10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome-wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. The GWAS identified independent associations of HLA DRB1-DQB1, HLA-DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA-DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1-DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. CONCLUSION: The findings in this study clearly show the importance of HLA-DR-DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018). PMID- 29534302 TI - Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. PMID- 29534303 TI - Orthodontic treatment for prominent upper front teeth (Class II malocclusion) in children and adolescents. AB - BACKGROUND: Prominent upper front teeth are a common problem affecting about a quarter of 12-year-old children in the UK. The condition develops when permanent teeth erupt. These teeth are more likely to be injured and their appearance can cause significant distress. Children are often referred to an orthodontist for treatment with dental braces to reduce the prominence of their teeth. If a child is referred at a young age, the orthodontist is faced with the dilemma of whether to treat the patient early or to wait and provide treatment in adolescence. OBJECTIVES: To assess the effects of orthodontic treatment for prominent upper front teeth initiated when children are seven to 11 years old ('early treatment' in two phases) compared to in adolescence at around 12 to 16 years old ('late treatment' in one phase); to assess the effects of late treatment compared to no treatment; and to assess the effects of different types of orthodontic braces. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 27 September 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 8), MEDLINE Ovid (1946 to 27 September 2017), and Embase Ovid (1980 to 27 September 2017). The US National Institutes of Health Ongoing Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials of orthodontic treatments to correct prominent upper front teeth (Class II malocclusion) in children and adolescents. We included trials that compared early treatment in children (two-phase) with any type of orthodontic braces (removable, fixed, functional) or head-braces versus late treatment in adolescents (one phase) with any type of orthodontic braces or head-braces, and trials that compared any type of orthodontic braces or head-braces versus no treatment or another type of orthodontic brace or appliance (where treatment started at a similar age in the intervention groups).We excluded trials involving participants with a cleft lip or palate, or other craniofacial deformity/syndrome, and trials that recruited patients who had previously received surgical treatment for their Class II malocclusion. DATA COLLECTION AND ANALYSIS: Review authors screened the search results, extracted data and assessed risk of bias independently. We used odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used the fixed effect model for meta-analyses including two or three studies and the random effects model for more than three studies. MAIN RESULTS: We included 27 RCTs based on data from 1251 participants.Three trials compared early treatment with a functional appliance versus late treatment for overjet, ANB and incisal trauma. After phase one of early treatment (i.e. before the other group had received any intervention), there was a reduction in overjet and ANB reduction favouring treatment with a functional appliance; however, when both groups had completed treatment, there was no difference between groups in final overjet (MD 0.21, 95% CI -0.10 to 0.51, P = 0.18; 343 participants) (low-quality evidence) or ANB (MD 0.02, 95% CI -0.47 to 0.43; 347 participants) (moderate-quality evidence). Early treatment with functional appliances reduced the incidence of incisal trauma compared to late treatment (OR 0.56, 95% CI 0.33 to 0.95; 332 participants) (moderate-quality evidence). The difference in the incidence of incisal trauma was clinically important with 30% (51/171) of participants reporting new trauma in the late treatment group compared to only 19% (31/161) of participants who had received early treatment.Two trials compared early treatment using headgear versus late treatment. After phase one of early treatment, headgear had reduced overjet and ANB; however, when both groups had completed treatment, there was no evidence of a difference between groups in overjet (MD -0.22, 95% CI -0.56 to 0.12; 238 participants) (low-quality evidence) or ANB (MD -0.27, 95% CI -0.80 to 0.26; 231 participants) (low-quality evidence). Early (two-phase) treatment with headgear reduced the incidence of incisal trauma (OR 0.45, 95% CI 0.25 to 0.80; 237 participants) (low-quality evidence), with almost half the incidence of new incisal trauma (24/117) compared to the late treatment group (44/120).Seven trials compared late treatment with functional appliances versus no treatment. There was a reduction in final overjet with both fixed functional appliances (MD 5.46 mm, 95% CI -6.63 to -4.28; 2 trials, 61 participants) and removable functional appliances (MD -4.62, 95% CI -5.33 to -3.92; 3 trials, 122 participants) (low-quality evidence). There was no evidence of a difference in final ANB between fixed functional appliances and no treatment (MD -0.53 degrees , 95% CI -1.27 to -0.22; 3 trials, 89 participants) (low-quality evidence), but removable functional appliances seemed to reduce ANB compared to no treatment (MD -2.37 degrees , 95% CI -3.01 to -1.74; 2 trials, 99 participants) (low-quality evidence).Six trials compared orthodontic treatment for adolescents with Twin Block versus other appliances and found no difference in overjet (0.08 mm, 95% CI -0.60 to 0.76; 4 trials, 259 participants) (low-quality evidence). The reduction in ANB favoured treatment with a Twin Block (-0.56 degrees , 95% CI -0.96 to 0.16; 6 trials, 320 participants) (low-quality evidence).Three trials compared orthodontic treatment for adolescents with removable functional appliances versus fixed functional appliances and found a reduction in overjet in favour of fixed appliances (0.74, 95% CI 0.15 to 1.33; two trials, 154 participants) (low-quality evidence), and a reduction in ANB in favour of removable appliances (-1.04 degrees , 95% CI -1.60 to -0.49; 3 trials, 185 participants) (low-quality evidence). AUTHORS' CONCLUSIONS: Evidence of low to moderate quality suggests that providing early orthodontic treatment for children with prominent upper front teeth is more effective for reducing the incidence of incisal trauma than providing one course of orthodontic treatment in adolescence. There appear to be no other advantages of providing early treatment when compared to late treatment. Low-quality evidence suggests that, compared to no treatment, late treatment in adolescence with functional appliances, is effective for reducing the prominence of upper front teeth. PMID- 29534304 TI - Regularized continuous-time Markov Model via elastic net. AB - Continuous-time Markov models are commonly used to analyze longitudinal transitions between multiple disease states in panel data, where participants' disease states are only observed at multiple time points, and the exact state paths between observations are unknown. However, when covariate effects are incorporated and allowed to vary for different transitions, the number of potential parameters to estimate can become large even when the number of covariates is moderate, and traditional maximum likelihood estimation and subset model selection procedures can easily become unstable due to overfitting. We propose a novel regularized continuous-time Markov model with the elastic net penalty, which is capable of simultaneous variable selection and estimation for large number of parameters. We derive an efficient coordinate descent algorithm to solve the penalized optimization problem, which is fully automatic and data driven. We further consider an extension where one of the states is death, and time of death is exactly known but the state path leading to death is unknown. The proposed method is extensively evaluated in a simulation study, and demonstrated in an application to real-world data on airflow limitation state transitions. PMID- 29534305 TI - Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer. AB - BACKGROUND AND OBJECTIVES: Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis. METHODS: We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray. RESULTS: EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes. CONCLUSION: EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy. PMID- 29534306 TI - The hepatic BMAL1/AKT/lipogenesis axis protects against alcoholic liver disease in mice via promoting PPARalpha pathway. AB - : Alcohol liver disease (ALD) is one of the major chronic liver diseases worldwide, ranging from fatty liver, alcoholic hepatitis, cirrhosis, and potentially, hepatocellular carcinoma. Epidemiological studies suggest a potential link between ALD and impaired circadian rhythms, but the role of hepatic circadian proteins in the pathogenesis of ALD remains unknown. Here we show that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect mice from ALD. Ethanol diet-fed mice with liver-specific knockout (Bmal1-LKO) or depletion of Bmal1 develop more severe liver steatosis and injury as well as a simultaneous suppression of both de novo lipogenesis and fatty acid oxidation, which can be rescued by the supplementation of synthetic PPARalpha ligands. Restoring de novo lipogenesis in the liver of Bmal1-LKO mice by constitutively active AKT not only elevates hepatic fatty acid oxidation but also alleviates ethanol-induced fatty liver and liver injury. Furthermore, hepatic over-expression of lipogenic transcription factor ChREBP, but not SREBP 1c, in the liver of Bmal1-LKO mice also increases fatty acid oxidation and partially reduces ethanol-induced fatty liver and liver injury. CONCLUSION: we identified a novel protective role of BMAL1 in hepatocytes against ALD. The protective action of BMAL1 during alcohol consumption depends on its ability to couple ChREBP-induced de novo lipogenesis with PPARalpha-mediated fatty oxidation. (Hepatology 2018). PMID- 29534308 TI - The reality of "ghosts" in authorship of clinical trials in multiple sclerosis. PMID- 29534307 TI - Long-term outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance. AB - : The significance of hepatitis B e-antigen (HBeAg) seroclearance (ESC) in the long term is not well defined. The current study aimed to determine the clinical outcomes, the factors and predictive scores for hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance of a large cohort of patients undergoing ESC. Patients with documented ESC were followed up 3- to 6 monthly. Baseline characteristics and longitudinal laboratory results were recorded. Predictive scores for HCC (HCC-ESC) and HBsAg seroclearance (HBsAg-ESC) were derived from multivariate Cox regression models. A total of 723 patients underwent ESC with a median ESC age and follow-up of 36.0 and 18.3 years, respectively. Only 3.5% and 3.0% had persistently normal alanine aminotransferase (ALT) and HBV DNA <2logs IU/mL, respectively, after ESC. For patients with 100%, 100%-90%, 90%-50%, 50%-10%, 10%-0%, and 0% normal ALT after HBeAg seroclearance, the rate of HCC was 4.3%, 2.2%, 3.6%, 3.9%, 17.3%, and 37.2% at 20 years after ESC, respectively (P < 0.001). At 20 years after ESC, the cumulative incidence of HCC and HBsAg seroclearance was 7.9% and 13.5%, respectively, with an overall survival of 91.5%. ESC age, male sex, cirrhosis, hypoalbuminemia, viral load, and ALT were significant factors for HCC, whereas ESC age, male sex, viral load, and antiviral therapy were significant factors for HBsAg seroclearance. The area under receiver operating characteristics for HCC-ESC and HBsAg-ESC scores to predict HCC and HBsAg seroclearance at 20 years after ESC was 0.92 and 0.74, respectively. CONCLUSION: Male sex, older age at ESC, ALT, and higher level of HBV DNA were associated with higher rates of HCC after ESC. HCC-ESC and HBsAg-ESC predictive scores can determine the likelihood of developing HCC and achieving HBsAg seroclearance. (Hepatology 2018). PMID- 29534309 TI - Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice. AB - OBJECTIVE: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here, we report the neuroreparative effects of myeloablative allogeneic bone marrow transplantation in a humanized murine model of the disease. METHODS: Mice received a transplant of fluorescently tagged sex mismatched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioral motor performance tests. At 6 months post-transplant, mice were euthanized for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a subgroup of transplanted mice also received monthly subcutaneous infusions of the cytokines granulocyte-colony stimulating factor and stem cell factor. RESULTS: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and antioxidant defenses were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells, and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected after cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident. INTERPRETATION: Our data provide proof of concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. Ann Neurol 2018;83:779-793. PMID- 29534311 TI - Tailoring Porous Silicon for Biomedical Applications: From Drug Delivery to Cancer Immunotherapy. AB - In the past two decades, porous silicon (PSi) has attracted increasing attention for its potential biomedical applications. With its controllable geometry, tunable nanoporous structure, large pore volume/high specific surface area, and versatile surface chemistry, PSi shows significant advantages over conventional drug carriers. Here, an overview of recent progress in the use of PSi in drug delivery and cancer immunotherapy is presented. First, an overview of the fabrication of PSi with various geometric structures is provided, with particular focus on how the unique geometry of PSi facilitates its biomedical applications, especially for drug delivery. Second, surface chemistry and modification of PSi are discussed in relation to the strengthening of its performance in drug delivery and bioimaging. Emerging technologies for engineering PSi-based composites are then summarized. Emerging PSi advances in the context of cancer immunotherapy are also highlighted. Overall, very promising research results encourage further exploration of PSi for biomedical applications, particularly in drug delivery and cancer immunotherapy, and future translation of PSi into clinical applications. PMID- 29534312 TI - Computational Screening of New Orthogonal Metal-Free Dipolar Cycloadditions of Mesomeric Betaines. AB - Computational strategies have gained increasing impact in the de novo design of large molecular sets targeted to a desired application. Herein, DFT-assisted theoretical analyses of cycloadditions, involving mesoionic dipoles and strained cycloalkynes, unveil a series of unexplored mesomeric betaines as vastly superior candidates for orthogonal applications. Thus, isosydnones; thiosydnones; and a six-membered homolog, 6-oxo-1,3-oxazinium-4-olate, exhibit enhanced reactivity with respect to sydnone, which is the archetypal mesoionic ring employed so far in orthogonal chemistry. These compounds were found by assessing energy barriers and transition structures, which are largely governed by electron fluxes from dipolarophile to dipole and noncovalent interactions. Charge-transfer analysis also accounts for previous experimental and theoretical results gathered in the literature, and provides a rationale for further substitution variations. The above naked dipoles release only CO2 as a byproduct through retro-Diels-Alder of the resulting cycloadducts. These results should invite practitioners to look at such underestimated dipoles and could also help to minimize the number of experiments. PMID- 29534310 TI - Impact of IFNL4 genotype on Interferon-stimulated Gene Expression during DAA therapy for Hepatitis C. AB - New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, cirrhotic patients receiving a 16 week course of sofosbuvir and ribavirin had a sustained virologic response rate (SVR) of around 50%. In cirrhotic patients, IFNL4 CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon-stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, while the reverse was true for non-CC patients. These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. This article is protected by copyright. All rights reserved. PMID- 29534313 TI - Polymer Nanocomposites with Ultrahigh Energy Density and High Discharge Efficiency by Modulating their Nanostructures in Three Dimensions. AB - Manipulating microstructures of composites in three dimensions has been a long standing challenge. An approach is proposed and demonstrated to fabricate artificial nanocomposites by controlling the 3D distribution and orientation of oxide nanoparticles in a polymer matrix. In addition to possessing much enhanced mechanical properties, these nanocomposites can sustain extremely high voltages up to ~10 kV, exhibiting high dielectric breakdown strength and low leakage current. These nanocomposites show great promise in resolving the paradox between dielectric constant and breakdown strength, leading to ultrahigh electrical energy density (over 2000% higher than that of the bench-mark polymer dielectrics) and discharge efficiency. This approach opens up a new avenue for the design and modulation of nanocomposites. It is adaptable to the roll-to-roll fabrication process and could be employed as a general technique for the mass production of composites with intricate nanostructures, which is otherwise not possible using conventional polymer processing techniques. PMID- 29534314 TI - Stretchable Triboelectric-Photonic Smart Skin for Tactile and Gesture Sensing. AB - Smart skin is expected to be stretchable and tactile for bionic robots as the medium with the ambient environment. Here, a stretchable triboelectric-photonic smart skin (STPS) is reported that enables multidimensional tactile and gesture sensing for a robotic hand. With a grating-structured metal film as the bioinspired skin stripe, the STPS exhibits a tunable aggregation-induced emission in a lateral tensile range of 0-160%. Moreover, the STPS can be used as a triboelectric nanogenerator for vertical pressure sensing with a maximum sensitivity of 34 mV Pa-1 . The pressure sensing characteristics can remain stable in different stretching conditions, which demonstrates a synchronous and independent sensing property for external stimuli with great durability. By integrating on a robotic hand as a conformal covering, the STPS shows multidimensional mechanical sensing abilities for external touch and different gestures with joints bending. This work has first demonstrated a triboelectric photonic coupled multifunctional sensing terminal, which may have great applications in human-machine interaction, soft robots, and artificial intelligence. PMID- 29534315 TI - Template-Directed Synthesis of Titania Nanocages with Four Tetrahedrally Arranged Open Windows. AB - Original titania nanocages are fabricated from sacrificial silica/polystyrene tetrapod-like templates. Here the template synthesis, titania deposition and nanocage development through polystyrene dissolution and subsequent silica etching are described. Discussion about the competitive deposition of titania on the biphasic templates is particularly emphasized. The morphology of the nanocages is investigated by TEM, STEM, EDX mapping and electron tomography. PMID- 29534316 TI - Design and Fabrication of a Hierarchically Structured Scaffold for Tendon-to-Bone Repair. AB - A hierarchically structured scaffold is designed and fabricated for facilitating tendon-to-bone repair. The scaffold is composed of three regions with distinct functions: (i) an array of channels to guide the in-growth of cells and aligned deposition of collagen fibers, as well as integration of the scaffold with the tendon side, (ii) a region with a gradient in mineral composition to facilitate stress transfer between tendon and bone, and (iii) a mineralized inverse opal region to promote the integration of the scaffold with the underlying bone. Cell culture experiments confirm that adipose-derived stromal cells are able to infiltrate and proliferate through the entire thickness of the scaffold without compromised cell viability. The seeded stem cells exhibit directed differentiation into tenocytes and osteoblasts along the mineral gradient as a response to the gradient in Young's modulus. This novel scaffold holds great promise to promote the formation of a functional tendon-to-bone attachment by offering a structurally and compositionally appropriate microenvironment for healing. PMID- 29534317 TI - Tackling Energy Loss for High-Efficiency Organic Solar Cells with Integrated Multiple Strategies. AB - Limited by the various inherent energy losses from multiple channels, organic solar cells show inferior device performance compared to traditional inorganic photovoltaic techniques, such as silicon and CuInGaSe. To alleviate these fundamental limitations, an integrated multiple strategy is implemented including molecular design, interfacial engineering, optical manipulation, and tandem device construction into one cell. Considering the close correlation among these loss channels, a sophisticated quantification of energy-loss reduction is tracked along with each strategy in a perspective to reach rational overall optimum. A novel nonfullerene acceptor, 6TBA, is synthesized to resolve the thermalization and VOC loss, and another small bandgap nonfullerene acceptor, 4TIC, is used in the back sub-cell to alleviate transmission loss. Tandem architecture design significantly reduces the light absorption loss, and compensates carrier dynamics and thermalization loss. Interfacial engineering further reduces energy loss from carrier dynamics in the tandem architecture. As a result of this concerted effort, a very high power conversion efficiency (13.20%) is obtained. A detailed quantitative analysis on the energy losses confirms that the improved device performance stems from these multiple strategies. The results provide a rational way to explore the ultimate device performance through molecular design and device engineering. PMID- 29534318 TI - Molecular-Level Hybridization of Nafion with Quantum Dots for Highly Enhanced Proton Conduction. AB - Nanophase-separated membranes hold promise for fast molecule or ion transfer. However, development and practical application are significantly hindered by both the difficulty of chemical modification and nanophase instability. This can be addressed by organic-inorganic hybridization of functional fillers with a precise distribution in specific nanophase. Here, a molecular-level hybridization for nanophase-separated Nafion using 2-5 nm quantum dots (QDs) as a new smart filler is demonstrated. Two kinds of QDs are prepared and used: hydrophilic polymer-like QDs (PQDs) and hydrophobic graphene oxide QDs (GQDs). Because of selective interactions, QDs offer advantages of matched structural size and automatic recognition with the nanophase. A distinctive synthesis of subordinate-assembly, in which QDs are driven by the self-assembly of Nafion affinity chains, is reported. This results in a precise distribution of QDs in the ionic, or backbone, nanophases of Nafion. The resulting PQDs in the ionic nanophase significantly increase membrane proton conduction and device output-power without loss of mechanical stability. This is difficult to realize with conventional fillers. The GQDs in the backbone nanophase reduce the crystallinity and significantly augment membrane water uptake and swelling capacities. PMID- 29534319 TI - Adipose tissue's rapid response team. PMID- 29534320 TI - Creating Stiff, Tough, and Functional Hydrogel Composites with Low-Melting-Point Alloys. AB - Reinforcing hydrogels with a rigid scaffold is a promising method to greatly expand the mechanical and physical properties of hydrogels. One of the challenges of creating hydrogel composites is the significant stress that occurs due to swelling mismatch between the water-swollen hydrogel matrix and the rigid skeleton in aqueous media. This stress can cause physical deformation (wrinkling, buckling, or fracture), preventing the fabrication of robust composites. Here, a simple yet versatile method is introduced to create "macroscale" hydrogel composites, by utilizing a rigid reinforcing phase that can relieve stress induced deformation. A low-melting-point alloy that can transform from a load bearing solid state to a free-deformable liquid state at relatively low temperature is used as a reinforcing skeleton, which enables the release of any swelling mismatch, regardless of the matrix swelling degree in liquid media. This design can generally provide hydrogels with hybridized functions, including excellent mechanical properties, shape memory, and thermal healing, which are often difficult or impossible to achieve with single-component hydrogel systems. Furthermore, this technique enables controlled electrochemical reactions and channel-structure templating in hydrogel matrices. This work may play an important role in the future design of soft robots, wearable electronics, and biocompatible functional materials. PMID- 29534321 TI - Functional Liquid Crystals towards the Next Generation of Materials. AB - Since the discovery of the liquid-crystalline state in 1888, liquid crystal science has made great advances through fusion with various technologies and disciplines. Recently, new molecular design strategies and new self-assembled structures have been developed as a result of the progress made in synthetic procedures and characterization techniques. Since these liquid crystals exhibit new functions and properties derived from their nanostructures and alignment, a variety of new functions for liquid crystals, such as transport for energy applications, separation for environmental applications, chromism, sensing, electrooptical effects, actuation, and templating have been proposed. This Review presents recent advances of liquid crystals that should contribute to the next generation of materials. PMID- 29534322 TI - Catalytic C-H Trifluoromethoxylation of Arenes and Heteroarenes. AB - The intermolecular C-H trifluoromethoxylation of arenes remains a long-standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a novel trifluoromethoxylating reagent and redox-active catalysts for the direct (hetero)aryl C-H trifluoromethoxylation. Our approach is operationally simple, proceeds at room temperature, uses easy-to-handle reagents, requires only 0.03 mol % of redox-active catalysts, does not need specialized reaction apparatus, and tolerates a wide variety of functional groups and complex structures such as sugars and natural product derivatives. Importantly, both ground-state and photoexcited redox-active catalysts are effective. Detailed computational and experimental studies suggest a unique reaction pathway where photoexcitation of the trifluoromethoxylating reagent releases the OCF3 radical that is trapped by (hetero)arenes. The resulting cyclohexadienyl radicals are oxidized by redox-active catalysts and deprotonated to form the desired products of trifluoromethoxylation. PMID- 29534323 TI - A Simple and Effective Method for Flow Cytometric Study of Lymphoid Malignancies Using Needle Core Biopsy Specimens. AB - OBJECTIVES: We developed a simple and effective rinsing technique (RT) of needle biopsies to produce cell suspensions for flow cytometry (FCM) and evaluated whether the RT is comparable to the conventional tissue cell suspension (TCS) technique. METHODS: We retrieved 93 needle core biopsy cases employing the RT for FCM and 25 needle biopsy cases using TCS for FCM. RESULTS: The diagnostic concordance between the FCM results and the morphologic diagnoses of both groups was compared. The diagnostic concordance was comparable in the RT group (92.6%) to the TCS group (71.4%). Furthermore, the diagnostic concordance in the RT group was associated with number of isolated cells. The diagnostic accuracy increased significantly when the cell number was above 30,000 in the RT group. CONCLUSIONS: The RT for FCM not only maximizes the tissue utilization, but also is a simple and effective method to obtain cell suspension as compared to traditional cell suspension technique. (c) 2018 International Clinical Cytometry Society. PMID- 29534324 TI - A High-Energy-Density Potassium Battery with a Polymer-Gel Electrolyte and a Polyaniline Cathode. AB - A safe, rechargeable potassium battery of high energy density and excellent cycling stability has been developed. The anion component of the electrolyte salt is inserted into a polyaniline cathode upon charging and extracted from it during discharging while the K+ ion of the KPF6 salt is plated/stripped on the potassium metal anode. The use of a p-type polymer cathode increases the cell voltage. By replacing the organic-liquid electrolyte in a glass-fiber separator with a polymer-gel electrolyte of cross-linked poly(methyl methacrylate), a dendrite free potassium anode can be plated/stripped, and the electrode/electrolyte interface is stabilized. The potassium anode wets the polymer, and the cross linked architecture provides small pores of adjustable sizes to stabilize a solid electrolyte interphase formed at the anode/electrolyte interface. This alternative electrolyte/cathode strategy offers a promising new approach to low cost potassium batteries for the stationary storage of electric power. PMID- 29534325 TI - Lithium-Ion Endohedral Fullerene (Li+ @C60 ) Dopants in Stable Perovskite Solar Cells Induce Instant Doping and Anti-Oxidation. AB - Herein, we report use of [Li+ @C60 ]TFSI- as a dopant for spiro-MeOTAD in lead halide perovskite solar cells. This approach gave an air stability nearly 10-fold that of conventional devices using Li+ TFSI- . Such high stability is attributed to the hydrophobic nature of [Li+ @C60 ]TFSI- repelling moisture and absorbing intruding oxygen, thereby protecting the perovskite device from degradation. Furthermore, [Li+ @C60 ]TFSI- could oxidize spiro-MeOTAD without the need for oxygen. The encapsulated devices exhibited outstanding air stability for more than 1000 h while illuminated under ambient conditions. PMID- 29534327 TI - Conjugated Dienyne-Imides as Robust Precursors of 1-Azatrienes for 6pi Electrocyclizations to Furo[2,3-b]dihydropyridine Cores. AB - A novel strategy to generate functionalized 1-azatriene intermediates for 6pi electrocyclizations was developed by using readily accessible dienyne-imides and various terminal olefins under PdII catalysis. Taking advantage of the sequential cooperation between preloaded and incorporated functional handles at 1,3-dien-5 yne skeletons, this method not only enables the selective generation of putative 1-azatrienes but significantly accelerates their thermal 6pi-electrocyclic ring closure processes to a series of highly substituted furo[2,3-b]dihydropyridine derivatives in good yields. PMID- 29534326 TI - Silyl-Phosphino-Carbene Complexes of Uranium(IV). AB - Unprecedented silyl-phosphino-carbene complexes of uranium(IV) are presented, where before all covalent actinide-carbon double bonds were stabilised by phosphorus(V) substituents or restricted to matrix isolation experiments. Conversion of [U(BIPMTMS )(Cl)(MU-Cl)2 Li(THF)2 ] (1, BIPMTMS =C(PPh2 NSiMe3 )2 ) into [U(BIPMTMS )(Cl){CH(Ph)(SiMe3 )}] (2), and addition of [Li{CH(SiMe3 )(PPh2 )}(THF)]/Me2 NCH2 CH2 NMe2 (TMEDA) gave [U{C(SiMe3 )(PPh2 )}(BIPMTMS )(MU Cl)Li(TMEDA)(MU-TMEDA)0.5 ]2 (3) by alpha-hydrogen abstraction. Addition of 2,2,2 cryptand or two equivalents of 4-N,N-dimethylaminopyridine (DMAP) to 3 gave [U{C(SiMe3 )(PPh2 )}(BIPMTMS )(Cl)][Li(2,2,2-cryptand)] (4) or [U{C(SiMe3 )(PPh2 )}(BIPMTMS )(DMAP)2 ] (5). The characterisation data for 3-5 suggest that whilst there is evidence for 3-centre P-C-U pi-bonding character, the U=C double bond component is dominant in each case. These U=C bonds are the closest to a true uranium alkylidene yet outside of matrix isolation experiments. PMID- 29534328 TI - Metal-Organic Framework (MOF) Nanorods, Nanotubes, and Nanowires. AB - New mechanisms for the controlled growth of one-dimensional (1D) metal-organic framework (MOF) nano- and superstructures under size-confinement and surface directing effects have been discovered. Through applying interfacial synthesis templated by track-etched polycarbonate (PCTE) membranes, congruent polycrystalline zeolitic imidazolate framework-8 (ZIF-8) solid nanorods and hollow nanotubes were found to form within 100 nm membrane pores, while single crystalline ZIF-8 nanowires grew inside 30 nm pores, all of which possess large aspect ratios up to 60 and show preferential crystal orientation with the {100} planes aligned parallel to the long axis of the pore. Our findings provide a generalizable method for controlling size, morphology, and lattice orientation of MOF nanomaterials. PMID- 29534329 TI - Late-Stage Functionalization of Drug-Like Molecules Using Diversinates. AB - Late-stage functionalization (LSF) is a powerful method to quickly generate new analogues of a lead structure without resorting to de novo synthesis. We have leveraged Baran Diversinates to carry out late-stage functionalizations on lead structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our functionalization successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, decrease reaction time, and increase reaction yields, we have developed new functionalization conditions involving iron(III) catalysis. Finally, we demonstrate how our LSF reactions using Baran Diversinates can lead to new analogues with improved in vitro DMPK parameters. PMID- 29534330 TI - The Oral Bioavailability of Trans-Resveratrol from a Grapevine-Shoot Extract in Healthy Humans is Significantly Increased by Micellar Solubilization. AB - SCOPE: Grapevine-shoot extract Vineatrol30 contains abundant resveratrol monomers and oligomers with health-promoting potential. However, the oral bioavailability of these compounds in humans is low (?1-2%). The aim of this study was to improve the oral bioavailability of resveratrol from vineatrol by micellar solubilization. METHODS AND RESULTS: Twelve healthy volunteers (six women, six men) randomly ingested a single dose of 500 mg vineatrol (30 mg trans resveratrol, 75 mg trans-epsilon-viniferin) as native powder or liquid micelles. Plasma and urine were collected at baseline and over 24 h after intake. Resveratrol and viniferin were analyzed by HPLC. The area under the plasma concentration-time curve (AUC) and mean maximum plasma trans-resveratrol concentrations were 5.0-fold and 10.6-fold higher, respectively, after micellar supplementation relative to the native powder. However, no detectable amounts of trans-epsilon-viniferin were found in either plasma or urine. The transepithelial permeability of trans-resveratrol and trans-epsilon-viniferin across differentiated Caco-2 monolayers was consistent to the absorbed fractions in vivo. CONCLUSION: The oral bioavailability of trans-resveratrol from the grapevine-shoot extract Vineatrol30 was significantly increased using a liquid micellar formulation, without any treatment-related adverse effects, making it a suitable system for improved supplementation of trans-resveratrol. PMID- 29534331 TI - Reply. PMID- 29534333 TI - Is the T Follicular Regulatory:Follicular Helper T Cell Ratio in Blood a Biomarker for Ectopic Lymphoid Structure Formation in Sjogren's Syndrome? Comment on the Article by Fonseca et al. PMID- 29534332 TI - Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation. AB - OBJECTIVE: Observations of microbial dysbiosis in patients with rheumatoid arthritis (RA) have raised interest in studying microbial-mucosal interactions as a potential trigger of RA. Using the murine collagen-induced arthritis (CIA) model, we undertook this study to test our hypothesis that microbiota modulate immune responses leading to autoimmune arthritis. METHODS: CIA was induced by immunization of mice with type II collagen (CII) in adjuvant on days 0 and 21, with arthritis appearing on days 23 and 24. Intestinal microbiota were profiled by 16S ribosomal RNA sequencing every 7 days during the course of CIA, and intestinal mucosal changes were evaluated on days 14 and 35. Then, microbiota were depleted either early (7 days before immunization) or late (day 21 after immunization) by administration of broad-spectrum antibiotics. Disease severity, autoantibody and systemic cytokine production, and intestinal mucosal responses were monitored in the setting of microbial reduction. RESULTS: Significant dysbiosis and mucosal inflammation occurred early in CIA, prior to visible arthritis, and continued to evolve during the course of disease. Depletion of the microbiota prior to the induction of CIA resulted in an ~40% reduction in disease severity and in significantly reduced levels of serum inflammatory cytokines and anti-CII antibodies. In intestinal tissue, production of interleukin-17A (IL-17A) and IL-22 was delayed. Unexpectedly, microbial depletion during the late phase of CIA resulted in a >50% decrease in disease severity. Anti-CII antibodies were mildly reduced but were significantly impaired in their ability to activate complement, likely due to altered glycosylation profiles. CONCLUSION: These data support a model in which intestinal dysbiosis triggers mucosal immune responses that stimulate T and B cells that are key for the development of inflammatory arthritis. PMID- 29534334 TI - Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl Containing 2,4,6-Trisubstituted Pyrimidine Derivatives as Potential Anti Parkinson Agents. AB - Monoamine oxidase B (MAO-B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl-containing 2,4,6-trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO-B isoform at sub-micromolar concentrations. MVB3 was the most potent MAO-B inhibitor with an IC50 value of 0.38+/-0.02 MUMU, whereas MVB6 (IC50 =0.51+/-0.04 MUMU) and MVB16 (IC50 =0.48+/-0.06 MUMU) were the most selective for MAO-B with a selectivity index of more than 100-fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH-SY5Y cells at concentrations of 25 MUm. MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 MUm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO-B isoform with a dock score of -10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO-B. Thus, propargyl-substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO-B inhibitors for the treatment of Parkinson's disease. PMID- 29534335 TI - Lupus Erythematosus Cell. PMID- 29534337 TI - Differential Clinical Associations of Anti-Nuclear Matrix Protein 2 Autoantibodies in Patients With Idiopathic Inflammatory Myopathies. AB - OBJECTIVE: To investigate the associations between anti-nuclear matrix protein 2 (anti-NXP-2) autoantibody levels and disease activity as well as calcinosis severity in patients with idiopathic inflammatory myopathies (IIMs). METHODS: Serum levels of anti-NXP-2 autoantibodies were determined in 709 patients with IIMs and also serially measured in the patients' sera with an in-house enzyme linked immunosorbent assay using MORC3 recombinant protein. Patients with anti NXP-2 autoantibodies were divided into 2 subgroups: those with and those without calcinosis. Associations of anti-NXP-2 autoantibody levels with organ-specific disease activity (using 10-cm visual analog scale [VAS] scores), serum creatine kinase (CK) levels, and calcinosis severity were investigated in cross-sectional and longitudinal analyses. RESULTS: A cross-sectional analysis of 56 IIM patients with anti-NXP-2 autoantibodies (38 without calcinosis and 18 with calcinosis) showed that in patients without calcinosis, the levels of anti-NXP-2 autoantibodies were positively correlated with the physician's global assessment of disease activity and muscle VAS scores and serum CK levels, whereas no such association was found in patients with calcinosis. Results of the longitudinal study revealed strong correlations of anti-NXP-2 antibody levels with the physician's global assessment and constitutional, cutaneous, gastrointestinal, and muscle VAS scores and serum CK levels in patients without calcinosis, but in patients with calcinosis, only a moderate correlation was observed between anti NXP-2 antibody levels and the physician's global VAS and constitutional VAS scores. Of note, in patients without calcinosis, anti-NXP-2 autoantibodies were found to disappear during periods of clinical remission, but reappeared with disease relapse. No association between anti-NXP-2 antibody levels and the severity of calcinosis was observed. CONCLUSION: These findings indicate that anti-NXP-2 autoantibodies serve as a useful marker for disease activity in patients with IIMs, especially in the absence of calcinosis. The differential associations observed between anti-NXP-2 autoantibody levels and disease activity suggest that there may be a phenotypic difference between patients with and those without calcinosis. PMID- 29534336 TI - Development of a Molecular Signature to Monitor Pharmacodynamic Responses Mediated by In Vivo Administration of Glucocorticoids. AB - OBJECTIVE: To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity. METHODS: Genes modulated by prednisolone were identified from in vitro studies using peripheral blood mononuclear cells from normal healthy volunteers. Using the criteria of a >2-fold change relative to vehicle controls and an adjusted P value cutoff of less than 0.05, 64 up regulated and 18 down-regulated genes were identified. A composite score of the up-regulated genes was generated using a single-sample gene set enrichment analysis algorithm. RESULTS: GC gene signature expression was significantly elevated in peripheral blood leukocytes from normal healthy volunteers following oral administration of prednisolone. Expression of the signature increased in a dose-dependent manner, peaked at 4 hours postadministration, and returned to baseline levels by 48 hours after dosing. Lower expression was detected in normal healthy volunteers who received a partial GC receptor agonist, which is consistent with the reduced transactivation potential of this compound. In cohorts of patients with systemic lupus erythematosus and patients with rheumatoid arthritis, expression of the GC signature was negatively correlated with the percentages of peripheral blood lymphocytes and positively correlated with peripheral blood neutrophil counts, which is consistent with the known biology of the GC receptor. Expression of the signature largely agreed with reported GC use in these populations, although there was significant interpatient variability within the dose cohorts. CONCLUSION: The GC gene signature identified in this study represents a pharmacodynamic marker of GC exposure. PMID- 29534338 TI - 'Massive' metformin overdose. AB - Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old woman presented 5 h after multidrug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol l 1 ) and shock. Despite 3 h of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol l-1 ). Intermittent haemodialysis (IHD) improved acidosis (pH 7.13, lactate 26 mmol l-1 ) but again worsened (pH 6.91, lactate 30 mmol l-1 ) with CVVHDF recommencement. IHD (12 h), CVVHDF (26 h) and vasopressor support for 7 days resulted in survival. Measured metformin concentrations were extremely high with a peak of 292 MUg ml-1 at 8 h postingestion. IHD, but not CVVHDF in this case, was associated with improvement in metabolic acidosis and hyperlactataemia. Pharmacokinetic analysis of metformin concentrations found a reduced apparent oral clearance of 8.2 l h-1 and a half-life of approximately 30 h. During IHD, the apparent oral clearance increased to 22.2 l h-1 with an approximate half-life of 10 h. The impact of prolonged oral absorption from a pharmacobezoar and redistribution of metformin from peripheral sites (including erythrocytes) on the pharmacokinetic profile cannot be determined from the data available. PMID- 29534339 TI - Update on the Health Services Research Doctoral Core Competencies. AB - OBJECTIVE: To present revised core competencies for doctoral programs in health services research (HSR), modalities to deliver these competencies, and suggested methods for assessing mastery of these competencies. DATA SOURCES AND DATA COLLECTION: Core competencies were originally developed in 2005, updated (but unpublished) in 2008, modestly updated for a 2016 HSR workforce conference, and revised based on feedback from attendees. Additional feedback was obtained from doctoral program directors, employer/workforce experts and attendees of presentation on these competencies at the AcademyHealth's June 2017 Annual Research Meeting. PRINCIPAL FINDINGS: The current version (V2.1) competencies include the ethical conduct of research, conceptual models, development of research questions, study designs, data measurement and collection methods, statistical methods for analyzing data, professional collaboration, and knowledge dissemination. These competencies represent a core that defines what HSR researchers should master in order to address the complexities of microsystem to macro-system research that HSR entails. There are opportunities to conduct formal evaluation of newer delivery modalities (e.g., flipped classrooms) and to integrate new Learning Health System Researcher Core Competencies, developed by AHRQ, into the HSR core competencies. CONCLUSIONS: Core competencies in HSR are a continually evolving work in progress because new research questions arise, new methods are developed, and the trans-disciplinary nature of the field leads to new multidisciplinary and team building needs. PMID- 29534341 TI - Gastrointestinal stromal tumour with an unusual presentation as a huge prostatic mass: a case report. PMID- 29534340 TI - Consumption of Fish and Shrimp from Southeast Louisiana Poses No Unacceptable Lifetime Cancer Risks Attributable to High-Priority Polycyclic Aromatic Hydrocarbons. AB - Following oil spills such as the Deepwater Horizon accident (DWH), contamination of seafood resources and possible increased health risks attributable to consumption of seafood in spill areas are major concerns. In this study, locally harvested finfish and shrimp were collected from research participants in southeast Louisiana and analyzed for polycyclic aromatic hydrocarbons (PAHs). PAHs are some of the most important chemicals of concern regarding oil-spill contaminated seafood resources during and following oil spills. Some PAHs are considered carcinogens for risk assessment purposes, and currently, seven of these can be combined in lifetime cancer risk assessments using EPA approaches. Most PAHs were not detected in these samples (minimum detection limits ranged from 1.2 to 2.1 PPB) and of those that were detected, they were generally below 10 PPB. The pattern of detected PAHs suggested that the source of these chemicals in these seafood samples was not a result of direct contact with crude oil. Lifetime cancer risks were assessed using conservative assumptions and models in a probabilistic framework for the seven carcinogenic PAHs. Lifetime health risks modeled using this framework did not exceed a 1/10,000 cancer risk threshold. Conservative, health-protective deterministic estimates of the levels of concern for PAH chemical concentration and seafood intake rates were above the concentrations and intake rates modeled under this probabilistic framework. Taken together, consumption of finfish and shrimp harvested from southeast Louisiana following the DWH does not pose unacceptable lifetime cancer risks from these seven carcinogenic PAHs even for the heaviest possible consumers. PMID- 29534342 TI - Clinical significance of serum transthyretin level in patients with hepatocellular carcinoma. AB - BACKGROUND: Although serum albumin has been reported to be useful as a prognostic biomarker for various malignancies, it is not suitable for prognosis of patients with hepatocellular carcinoma (HCC) due to impaired liver function. We aimed to determine whether serum transthyretin (TTR) level can be used as a novel prognostic biomarker. METHODS: Serum levels of TTR, as well as other nutritional and inflammatory parameters including angiogenic factors, were examined in 25 patients with HCC. RESULTS: The serum TTR levels exhibited a statistically significant inverse correlation with interleukin-6 (r = -0.412, P = 0.041), and showed statistically significant correlations with retinol-binding protein (r = 0.919, P < 0.001) and albumin (r = 0.442, P = 0.027). The patients with TTR <11.4 mg/dL (P = 0.012), those with >=T2 (P = 0.011) and those with a retention rate of indocyanine green after 15 min >=15.5 (P = 0.037) showed poorer prognoses than the counterparts of each parameter. The TTR level <11.4 mg/dL (hazard ratio: 4.837, 95% confidence interval: 1.118-20.926, P = 0.035) and >=T2 (hazard ratio: 5.011, 95% confidence interval: 1.243-20.203, P = 0.023) were independent prognostic factors of HCC patients. CONCLUSION: Serum TTR measurement can be useful for predicting the prognosis of patients with HCC. PMID- 29534343 TI - Weight loss and retroperitoneal mass. PMID- 29534344 TI - How to do lateral retroperitoneoscopic resection of intra-abdominal paraganglioma. PMID- 29534345 TI - Large pulmonary arteriovenous malformation with paradoxical cerebral infarction. PMID- 29534346 TI - Strengthening the Health Care Workforce in Fragile States: Considerations in the Health Care Sector and Beyond. PMID- 29534347 TI - Open transperineal anterior perineal hernia repair. PMID- 29534348 TI - Screening for convergence insufficiency in school-age children. AB - BACKGROUND: Convergence insufficiency (CI) is a common binocular vision disorder which often causes symptoms when doing near work. However, the best screening test for CI is unknown. The purpose of this study was to evaluate the ability of common tests of binocular and accommodative function to identify children with CI in a school screening setting. METHODS: Children aged nine to 14 were invited to participate. Positive fusional vergences, near point of convergence (NPC), accommodative amplitude, accommodative facility, Modified Thorington, and the Convergence Insufficiency Symptom Survey were evaluated. RESULTS: Of the 282 children tested, approximately 20 per cent had 2-3 signs of CI. One half of 2-3 signs of CI and 66 per cent of three signs of CI subjects were symptomatic. Approximately 61 per cent of subjects with symptomatic 2-3 signs of CI had an accompanying low accommodative amplitude. The largest area under the receiver operating characteristic curve was obtained using NPC break measurements. NPC break >= 6 cm for CI and NPC break >= 7 cm for symptomatic CI were the cut points that maximised the sum of sensitivity and specificity. CONCLUSION: NPC break performed best in identifying children with CI. PMID- 29534349 TI - Most effective pain-control procedure for open liver surgery: a network meta analysis. AB - BACKGROUND: To determine the most effective pain-control procedure for open liver surgery through a network meta-analysis and provide a best developing direction in this field. METHODS: PubMed, Embase and Cochrane Library database were searched for randomized controlled trials up to 1 July 2016. We extracted data on post-operative pain score at the 4th-8th hour and 24th hour from studies that compared various pain-control strategies. Network meta-analysis was conducted in Aggregate Data Drug Information System software by evaluating the parametric pain score at rest and on movement. Cumulative probability value was utilized to rank the procedures under examination. The inconsistency would also be tested by node splitting models. RESULTS: Twelve articles containing 661 patients were included. Intrathecal analgesia plus intravenous analgesia played the most effective role in pain controlling at post-operative 4-8 h (both at rest and on movement, P = 0.49 and P = 0.62, respectively) and at post-operative 24 h (both at rest and on movement, P = 0.46 and P = 0.29, respectively). Node-splitting models test revealed that no significant inconsistency existed in this research. CONCLUSIONS: Intrathecal analgesia plus intravenous analgesia revealed the most effective clinical pain-control value for open liver surgery. More importantly, we believed that creating a better comprehensive and systematic combined pain-control procedure should be considered as the developing direction in this field. PMID- 29534350 TI - Complicated appendicitis within an incisional hernia. PMID- 29534351 TI - [Updates on WHO classification of pituitary tumors]. PMID- 29534352 TI - [Clinicopathologic characteristics and prognositic indicators of tonsillar mantle cell lymphoma]. AB - Objective: To investigate clinicopathological features and prognosis of tonsillar mantle cell lymphoma(TMCL). Methods: Clinical data of 25 patients with TMCL at Beijing Friendship Hospital, Capital Medical University from 2002 to 2016 were included. All the cases were reviewed microscopically. Various immunohistochemical stains were performed using the MaxVision two-step method. IgH/CCND1 gene fusion was detected by fluorescent in situ hybridization(FISH). Additionally, randomly selected 40 cases of non-tonsil MCL of the same period were compared. Results: Among all mantle cell lymphomas (MCL), TMCL accounted for 5.6%(25/449). The median age of the patients was 60 years(range: 44-82 years) with a M?F ratio of 5.3 to 1.0. The main symptoms were sore throat and foreign body sensation and patients usually presented with enlargement or mass of tonsil. At the early stage of the disease, 18 cases(72.0%) were clinically misdiagnosed as tonsillitis. Lymph node involvement was present in 76.0%(19/25) of the patients. There were 4 cases(16.0%)with current splenic involvement, 11 cases(44.0%) with pharyngeal focal recidivism, and 3 cases(12.0%) with involvement of other non-lymphoid organs. Morphologically, tonsillar architectures were effaced at various degrees. Eighteen MCL cases showed classical type and 7 cases were blastoid variant. All tumors were positive for CD20 and cyclin D1. 92.0%(23/25) tumors showed weakly positive or positive expression for CD5. FISH test that IgH/CCND1 gene fusion was positive in two CD5 negative classical cases. 18 patients(72.0%) had a median follow-up time of 26 months(range: 6-81 months). The difference of survival rate between stage I-II and stage III-IV patients was not statistically significant(P>0.05). Compared with NTMCL, TMCL was found to have higher proportion of stage I-II disease (chi(2)=12.789, P<0.01), lower the proportion of non-lymphatic organ involvement (chi(2)=8.125, P<0.01), and better prognosis (chi(2)=4.351, P=0.037). Conclusion: The incidence of TMCL is low and prone to be misdiagnosed as tonsillitis. Patients with TMCL are more likely at stage I-II at presentation and the prognosis is better than that of NTMCL. PMID- 29534353 TI - [Langerhans cell sarcoma: a clinicopathologic analysis of four cases]. AB - Objective: To investigate the clinicopathological features, differential diagnosis, and genetic alteration of Langerhans cell sarcoma (LCS). Methods: Four cases of LCS were collected from Fujian Provincial Hospital and Fuzhou General Hospital of Nanjing Military Command of PLA from July 2013 to January 2017. Clinicopathological features and immunophenotype were retrospectively reviewed in four LCS cases combined with genetic mutation analysis of BRAF and ALK. Results: Four cases included 2 women and 2 men with ages from 42 to 79 years (median=59.3 years). The size of the tumors ranged from 2.5-7.8 cm. Histologically, at the low power field, the tumors consisted of highly cellular proliferation in fascicules, whirlpool and diffuse sheets arrangement. The tumor cells were kidney-or horseshoe-shaped to round epithelioid cells or enlarged spindle cells. The neoplastic cells showed cytological atypia, hyperchromatic nuclei with prominent 1 to 2 nucleoli. Multinucleated giant cells were also found. Mitotic activity was approximately (50-70) mitoses/10 HPF. Immunohistochemically, the tumor cells were positive for S-100 protein (4/4), SOX10(3/4), Langerin/CD207(4/4), CD1a(3/4), CD68(3/4), CD163(3/4), and INI-1(4/4). Ki-67 index was 30%-80%. Gene mutation analysis showed that one case had BRAF V600E mutation but none had ALK gene alteration. Conclusions: LCS is a rare tumor with highly malignant potential and distinct morphologic features.The primary treatment for LCS is completely surgical excision and chemotherapy. The prognosis is generally poor. PMID- 29534354 TI - [Primary testicular NK/T cell lymphoma: a clinicopathologic analysis of six cases]. AB - Objective: To evaluate the clinicopathological features, diagnosis and management of primary testicular NK/T cell lymphoma (NKTCL). Methods: Six cases of primary testicular NKTCL at Beijing Friendship Hospital, Capital Medical University from January 2007 to December 2016 were retrospectively analyzed for the morphology, immunephenotype and outcome, and relevant literature was reviewed. Results: The median age of patients at diagnosis was 45 years(range 32-65 years). All patients presented with testicular masses as initial symptoms (6/6), five cases (5/6) were on the right. The lesions were confined to the testis. All patients were classified as Ann Arbor stage I but the tumors exhibited aggressive clinical behavior. Two patients died of the disease within two months, three (3/6) had clinical remission, and one (1/6) was lost to follow-up. Morphologically, the lymphoma cells showed a diffuse growth pattern that largely effaced the interstitial tissues, and surrounded seminiferous tubules in all cases. There was also a prominent angioinvasive pattern, with focal necrosis and karyorrhexis(4/6). Cytologically, the medium-sized neoplastic cells showed scanty to moderate amount of cytoplasm and irregular folded nuclei. The immunophenotype was similar to that of nasal NKTCL: the neoplastic cells were positive for cytoplasmic CD3, CD56, cytotoxic molecules and EBV-encoded small RNA, the loss of CD5 antigen was seen in all cases. Conclusions: Primary testicular NKTCL is extremely rare, highly aggressive and is associated with a poor prognosis. There is no unified standard of treatment. Thus, at the time of diagnosis of testicular lymphoma, NKTCL should be included in the differential diagnosis. PMID- 29534355 TI - [Correlation between C-MYC protein expression and genetic abnormalities in diffuse large B-cell lymphoma]. AB - Objective: To study the correlation between expression of oncogene C-MYC protein and gene abnormality in diffuse large B-cell lymphoma (DLBCL). Methods: The expression of C-MYC protein and gene abnormality were detected by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively, in 42 cases of paraffin-embedded DLBCL. All cases were collected at Department of Pathology, Weifang People's Hospital during January 2015 to October 2016. Results: The positive rate of C-MYC protein expression was 47.6% (20/42) and the rate of abnormal C-MYC gene by FISH was 26.2%(11/42), including translocation (23.8%, 10/42) and gene amplification (2.4%, 1/42). There was a close relationship between the protein expression and gene translocation (chi(2)=11.813; P=0.001) and gene translocation occurred primarily in GCB (chi(2)=4.029; P=0.045). Conclusion: The high expression (>=40%) of C-MYC protein is associated with its gene translocation, suggesting that C-MYC protein detection can be used as a surrogate marker for C-MYC gene translocation in DLBCL. PMID- 29534356 TI - [Clinicopathologic characteristics of Burkitt-like lymphoma with chromosome 11q aberration]. AB - Objective: To analyze clinical, pathological, molecular and genetic characteristics of Burkitt-like lymphoma with chromosome 11q aberration. Methods: A case of Burkitt-like lymphoma with 11q aberration was presented at Beijing Friendship Hospital in November 2016 with detailed clinicopathological features, immunophenotypes, Epstein-Barr virus(EBV) status and molecular genetic characteristics. Results: The patient was a 38-year-old man presenting with the cervical lymphadenopathy. In morphology, the tumor had the similar characteristics of Burkitt lymphoma, including diffuse infiltration of medium to large lymphoid cells, and presence of"starry sky"phenomenon. Immunophenotypically, the tumor cells were positive for CD20, CD10, bcl-6, but negative for bcl-2. MUM-1 showed weak and patchy positivity. Ki-67 index was more than 95%. C-MYC expression was seen in about 50% of tumor cells. EBV in situ hybridization was negative. IgH and IgK genes were clonally rearranged.Fluorescence in situ hybrization detection using MYC break probe was negative but ATM gene amplification on chromosome 11q was detected. The patient did not receive any chemotherapy or radiotherapy and had not recurrence during the 10 months follow-up. Conclusion: Burkitt-like lymphoma with chromosome 11q aberration has similar clinical, morphological and immunological characteristics to classic Burkitt's lymphoma. PMID- 29534357 TI - [Value of immunocytochemistry in differential diagnosis of gastric adenocarcinoma, reactive mesothelial cells and malignant epithelial mesothelioma in metastatic effusion fluid]. AB - Objective: To investigate the diagnostic value of some antibodies in peritoneal fluid of patients with gastric cancer and malignant epithelioid mesothelioma in serous effusion. Methods: One hundred and eighty-two cases of serous effusion were collected at Jilin Cancer Hospital, from July 2012 to July 2016. The expression of GLUT1, CDX2, Villin, calretinin and WT1 was evaluated using SP immunocytochemical technique in peritoneal fluid samples collected from 98 patients with gastric cancer and 74 patients with reactive mesothelial cells. The expression of GLUT1, calretinin and WT1 was also evaluated in serous effusion from 10 patients with mesothelioma. Results: The sensitivity of GLUT1, CDX2 and Villin in adenocarcinoma cells was 91.8%(90/98), 68.4% (67/98) and 88.8%(87/98), respectively. The specificity was 95.9% (71/74), 100.0%(74/74) and 100.0% (74/74), respectively. The sensitivity of calretinin and WT1 for reactive mesothelium was 93.2% (69/74) and 79.7% (59/74), respectively. The specificity was 96.9% (95/98) and 100.0% (98/98), respectively. The sensitivity of GLUT1, calretinin and WT1 for mesothelioma was 9/10, 9/10 and 7/10. The reactivity of GLUT1, CDX2, Villin, calretinin and WT1 showed a significant difference (P<0.01) between adenocarcinoma cells and reactive mesothelium. The reactivity of GLUT1 showed a significant difference (P<0.01) between mesothelioma and reactive mesothelium. Conclusions: The optimal combination is a panel of GLUT1, CDX2, Villin, calretinin and WT1 for differential diagnosis between adenocarcinoma cells and reactive mesothelium in peritoneal fluid of patients with gastric cancer. Whereas GLUT1, calretinin and WT1 is the best for differential diagnosis between reactive mesothelium and mesothelioma in serous effusions. PMID- 29534359 TI - [Clinicopathologic characteristics of pseudomyxoma peritonei]. AB - Objective: To analyze the relationship between clinicopathologic characteristics of pseudomyxoma peritonei (PMP) and its prognosis. Methods: Fifty-two cases of PMP collected from 2012 to 2017 at Beijing Shijitan Hospital, Capital Medical University were reviewed using the diagnostic criteria of WHO 2010. The histopathologic features, including original location, neural invasion and calcification were observed; and the relationship with prognosis was analyzed. Immunohistochemical staining for CK7, CK20 and CDX2 was performed on all cases. ER, PR, and p16 were additionally performed on those without clear origin. Results: Patients' mean age was 52.0 years, and included 29 males and 23 females. Thirty-two cases were derived from appendix; among them, 23 were low grade and 29 were high grade. Signet ring-cells, neural invasion and calcification were detected in 15, 12 and 9 cases respectively. Neural invasion was associated with adverse prognosis (P=0.025) and signet ring cell morphology (P<0.01). Prognosis was not related to gender, age, original location or grade. Conclusion: Neural invasion is not uncommon in PMP and predicts a bad prognosis. PMID- 29534358 TI - [Lipofibromatosis: a clinicopathological analysis of eight cases]. AB - Objective: To investigate the clinicopathological characteristics and differential diagnosis of lipofibromatosis. Methods: The clinicopathological features and immunohistochemical profiles in 8 cases of lipofibromatosis diagnosed at Fudan University Shanghai Cancer Center from January 2008 to June 2017 were studied. Molecular analysis of beta-catenin mutation by Sanger sequencing, NTKR1 and ETV6 rearrangements by FISH were performed. The follow up information was evaluated and the literature was reviewed. Results: There were 4 males and 4 females with a median age of 1.5 years at presentation (range, 3 months-9 years). Tumor arose in the hand (4 cases), foot (2 cases) and trunk (2 cases), manifesting as a painless subcutaneous mass. Two cases were congenital, one with tumor noted at birth and the others shortly after birth. Grossly, the tumors were poorly defined and irregularly shaped, composed predominantly of fatty tissue which was mingled with fibrous element. They ranged from 1 to 5 cm in size (mean, 2.6 cm). Microscopically, they were characterized by variably sized lobules of adipose tissue traversed by fascicles, bundles or trabeculae of proliferative fibroblasts and myofibroblasts, resembling desmoid tumor. In 2 cases, the tumor infiltrated adjacent skeletal muscles. On high power, the spindled fibroblasts and myofibroblasts had a bland appearance with very low mitotic activity (<1/10 HPF). By immunohistochemistry, they showed variable staining of alpha-SMA, MSA, CD34 and CD99, with negativity for beta-catenin, desmin, h-CALD, EMA, ALK, and S-100 protein. Ki-67 index was low (<2%). Molecular analysis showed no mutation of beta-catenin gene (0/3), no NTRK1 gene rearrangement (0/3) and no ETV6 gene rearrangement (0/2). Follow up information was available in 6 patients, revealed local recurrence in two and persistent disease in one. Conclusions: Lipofibromatosis is a special variant of infantile fibromatosis, which has a predilection for the distal portion of the extremities of neonates and infants and characterized by lobules of adipose tissue traversed by demoid tumor-like fibroblasts and myofibroblasts. However, it differs from desmoid tumor by harboring no mutation of beta-catenin gene. Familarity with its clinicopathological characteristics helps the distinction from its morphological mimics. PMID- 29534361 TI - [Expression and prognostic significance of ID3 and TCF3 protein in invasive B cell lymphoma]. PMID- 29534360 TI - [Extensive peritumoral retraction clefts and prognosis in invasive breast carcinomas of no specific type]. AB - Objective: To investigate the effect of extensive retraction clefts (RC, >20% of tumor volume) on prognosis in invasive breast carcinoma of no specific type (IBC NST). Methods: A total of 2 184 cases of IBC-NST diagnosed at the Fourth Hospital of Hebei Medical University from January 2006 to December 2008 were collected. All the cases were diagnosed according to the latest guideline and standard. After excluding cases of shrinkage due to tissue fixation, 483 cases with RC were identified, and the clinical and pathological features were retrospectively analyzed. Results: Among the 483 cases, the mean tumor size was 2.0 cm (range 0.8 to 4.8 cm). Two hundred and thirty-two cases were moderately differentiated (48.0%), 97 were well differentiated (20.1%), 154 were poorly differentiated (31.9%); 382 (79.1%) cases were of stages I and II. A total of 177 cases (36.7%) had lymphatic invasion; nodal metastasis were found in 202 cases (41.8%). Extensive RC was found in 237 of 483 cases (49.1%). Follow-up information was available in 407 patients, and 46 died of breast cancer with survival time from 37 to 103 months. Multivariate analysis of extensive RC showed that tumor size, histological grade and nodal metastasis were risk factors of patients with IBC NST (P<0.05). Lymphatic invasion and nodal metastasis were risk factors for extensive RCs in patients with IBC-NST (P<0.05). There was a high probability of lymph node metastasis in patients of extensive RC without lymphatic invasion, and the difference was statistically significant (P<0.05). Conclusions: Both lymphatic invasion and nodal metastasis are risk factors of extensive RC. The presence of extensive RC in IBC-NST patients is correlated with poor outcome. Tumors with lymphatic invasion are more likely to show extensive RC. PMID- 29534362 TI - [Gender differences with respect to clinicopathologic features and prognosis in solid-pseudopapillary neoplasm of the pancreas]. PMID- 29534363 TI - [Phosphaturic mesenchymal tumor: a clinicopathologic analysis of 7 cases]. PMID- 29534364 TI - [Value of p16/Ki-67 dual-staining immunocytochemistry in cervical cancer screening]. PMID- 29534366 TI - [Cellular blue nevus in lymph node parenchyma: report of a case]. PMID- 29534365 TI - [Comparison of Illumina targeted sequencing and Sanger sequencing in detection of pulmonary adenocarcinoma driver gene mutation]. PMID- 29534367 TI - [Synchronous squamous cell carcinoma of lung and B-cell lymphoma of peritumoural lymph nodes: report of a case]. PMID- 29534368 TI - [Adenocarcinoma arising in heterotopic pancreas of jejunal: report of a case]. PMID- 29534369 TI - [Genetic changes in gynecologic tumors and diagnostic applications]. PMID- 29534370 TI - [The novel role of fatty acid in metabolic control and targeted therapy of diffuse large B-cell lymphoma]. PMID- 29534372 TI - [Research progress on roles of exosomes in propagation of viral diseases]. PMID- 29534371 TI - [Research progress on significance of androgen receptor and epidermal growth factor receptor expression in estrogen receptor-negative and progesterone receptor-negative breast cancer]. PMID- 29534373 TI - [Thinking of neoadjuvant chemotherapy issues of advanced epithelial ovarian cancer]. PMID- 29534374 TI - [Analysis of the difference of serum immunoglobulins, beta2-microglobulin and transferrin in pre-eclampsia and pregnancies complicated with chronic kidney disease]. AB - Objective: To observe and analyze the difference of serum immunoglobulin IgA, IgG, IgM, beta2-microglobulin and transferrin in pre-eclampsia (PE) and pregnancies complicated with chronic kidney disease. Methods: Totally 46(40.0%) pregnancies with PE (PE group), 36(31.3%) pregnancies with chronic kidney disease (chronic kidney disease group) and 33(28.7%) normal pregnancies with normal blood pressure and proteinuria without any complication (control group) delivered in Renji Hospital were recruicted in this study from February 2017 to July 2017. Serum IgA, IgG, IgM, beta2-microglobulin and transferrin levels were detected. Correlation tests were conducted between these indicators and blood pressure, 24 hours proteinuria value and delivery weeks. Results: (1) Comparison of general situation of pregnancies in the 3 groups: there were no significant difference in the age and child bearing history between the 3 groups (all P>0.05), while there was a significant difference in the blood pressure and deliver week (all P<0.01). There was no significant difference in 24 hours proteinuria values between PE group and chronic kidney disease group (Z=-0.187, P=0.852). (2) Comparison of serum immunoglobulin, beta2-microglobulin and transferrin levels in pregnant women with three groups: serum IgA level in chronic kidney disease group was significantly higher than those in PE and control groups [(2.4+/-0.9) vs (1.8+/ 0.9) vs (1.6+/-0.6) g/L; F=9.959, P<0.01]. The serum IgG and IgM values had no significant difference between the 3 groups (all P>0.05). Serum beta2 microglobulin in chronic kidney disease group was significantly higher than those in PE and control groups [(4.0+/-2.6) vs (2.7+/-0.7) vs (2.0+/-0.5) mg/L; F=15.892, P<0.01]. Serum transferrin in chronic kidney disease group was significantly lower than those in PE and control groups [(3.0+/-0.8) vs (3.7+/ 1.1) vs (3.6+/-0.6) g/L; F=6.284, P<0.01]. (3) The correlation between serum immunoglobulin, beta2-microglobulin, transferrin and blood pressure, proteinuria value and delivery weeks in PE group: the blood pressure level was not correlated with serum IgA, beta2-microglobulin and transferrin values in PE group (all P> 0.05). So, 24 hours proteinuria value was positively correlated with beta2 microglobulin (r=0.557, P<0.01), which was negatively correlated with transferrin (r=-0.442, P<0.01) and was not correlated with IgA(r=0.089, P=0.556). There was a negative correlation between delivery weeks and beta2-microglobulin (r=-0.328, P=0.026), and positive correlation with transferrin (r=0.315, P=0.035) and no correlation with IgA (r=-0.169, P=0.260). (4) The correlation between serum immunoglobulin, beta2-microglobulin, transferrin and blood pressure, proteinuria value and delivery weeks in chronic kidney disease group: the blood pressure level was positively correlated with beta2- microglobulin (systolic pressure: r=0.598, P<0.01; diastolic pressure:r=0.557, P<0.01), which was not correlated with IgA and transferrin in chronic kidney disease group (all P>0.05). So, 24 hours proteinuria value was positively correlated with beta2-microglobulin and IgA (r=0.568, r=0.330, both P<0.05), and not correlated with transferrin (r=0.255, P=0.133). Delivery weeks had a negative correlation with beta2 microglobulin (r=-0.574, P<0.01), while it had a positive correlation with transferrin (r=0.369, P=0.027). No correlation was found between delivery weeks and IgA values (r=-0.257, P=0.131). Conclusion: The serum levels of IgA, beta2 microglobulin and transferrin in PE and pregnancies with chronic kidney disease are significantly different, which may provide clinical value for the diagnosis of PE and pregnancies with chronic kidney disease in future. PMID- 29534375 TI - [Clinical analysis of prenatal diagnosis and intervention for primary pleural effusion of 13 cases]. AB - Objective: To optimize the clinical managements of primary fetal hydrothorax (PFHT) fetus by comparing the perinatal survival rate of different prenatal treatments. Methods: Totally 13 fetuses diagnosed with PFHT from July 2009 to December 2015 in the First Affiliated Hospital of Jinan University were collected and received prenatal expectant treatment, thoracocentesis (TC), and thoraco amniotic shunting (TAS), respectively. The perinatal survival rate was compared among the three treatments. Results: Among 13 fetuses of PFHT, pleural effusion was absorbed or remained stable in 2(2/13) cases, and progressed in 11(11/13) cases. Six cases received expectant treatment (2 cases had termination of pregnancy due to progressing effusion, 2 cases had term delivery, and 2 cases had intrauterine death); the perinatal survival rate was 2/6. Six cases received TC (2 cases had term delivery, 2 cases had preterm delivery, and 2 cases had termination of pregnancy due to progressing effusion), the perinatal survival rate was 4/6. One case received TC+TAS (term delivery), the perinatal survival rate was 1/1. The overall perinatal survival rate of prenatal intrauterine intervention was 5/7. Conclusions: The clinical process of PFHT is changeable, and the pleural effusion will progress with gestational age. Intrauterine interventions could improve the perinatal survival rate. PMID- 29534376 TI - [Development and validation of the Chinese version of modified body imgae scale in Chinese population]. AB - Objective: To develop the Chinese version of modified body image scale (MBIS) questionnaires, and to validate them in Chinese population. Methods: The original English MBIS questionnaire was translated into Chinese, following the WHO cross cultural adaptation of health-related quality of life measures. The reliability and validity of the Chinese version of MBIS questionnaires were evaluated in Chinese population, MRKH syndrome patients. Results: Totally 50 patients with MRKH syndrome completed the MBIS and short-form 12-item health survey (SF-12) questionnaires. The Cronbach's alpha of MBIS was 0.741, intraclass correlation coefficients were 0.472-0.815 (P<0.01). MBIS scores were positively correlated with SF-12 scores (Spearman correlation coefficient was-0.409, P<0.01) . Factor analysis showed that MBIS had one common factor. Conclusion: Chinese version of MBIS has high reliability and validity in Chinese population, therefore is suitable for clinic and research. PMID- 29534377 TI - [Analysis of characteristics and influence factors of diagnostic delay of endometriosis]. AB - Objective: To access the influence factors of diagnostic delay of endometriosis. Methods: We designed a questionnaire of diagnostic delay of endometriosis. From February 2014 to February 2016, 400 patients who had dysmenorrhea and diagnosed with endometriosis by surgery in Peking University Third Hospital were surveyed retrospectively. Time and risk factors of diagnostic delay were analyzed. Results: The diagnostic delay of 400 patients was 13.0 years (0.2-43.0 years), 78.5%(314/400) patients thought pain was a normal phenomenon and didn't see the doctor. Patients who suffered dysmenorrhea at menarche experienced longer diagnostic delay than those who had dysmenorrhea after menarche (18.0 vs 4.5 years; Z=191.800, P<0.01) . Patients who suffered aggravating dysmenorrhea experienced shorter delay time than those who suffered stable or relieving dysmenorrhea (11.0 vs 12.5 vs 18.0 years; Z=8.270, P<0.05) , with the difference statistically significant, single factor analysis shows. Severe dysmenorrhea, deep infiltration endometriosis (DIE) , family history of dysmenorrhea or endometriosis, previous surgical history of endometriosis, high stage, with infertility, adenomyoma or other symptoms, could help to shorten diagnostic delay with no significant difference (P>0.05) . By multiple logistic regression analysis, the results shown that whether have dysmenorrhea at menarche and clinical diagnosis time were the independent factors affecting delayed diagnosis (P<0.01) . Conclusions: Diagnostic delay of endometriosis is common and the mean delay time is 13.0 years mainly due to the unawareness of dysmenorrhea. Dysmenorrhea at menarche, clinical diagnosis time and dysmenorrhea intensity are the factors affecting time of diagnostic delay. PMID- 29534378 TI - [S100A7 promotes the metastasis and epithelial-mesenchymal transition on HeLa and CaSki cells]. AB - Objective: To elucidate the impact of over-expression of S100A7 on migration, invasion, proliferation, cell cycle, and epithelial-mesenchymal transition (EMT) in human cervical cancer HeLa and CaSki cells. Methods: (1) Immunohistochemistry of SP was used to examine the expression of S100A7 in 40 cases of squamous cervical cancer tissues and 20 cases of normal cervical tissues. (2) The vectors of pLVX-IRES-Neo-S100A7 and pLVX-IRES-Neo were used to transfect human cervical cancer HeLa and CaSki cells, and the positive clones were screened and identified. Next, transwell migration assay, cell counting kit-8 (CCK-8) assay and fluorescence activating cell sorter (FACS) were used to detect the effect of S100A7-overexpression on the migration, invasion, proliferation and cell cycle of cervical cancer cells. Furthermore, western blot was performed to observe the expression of epithelial marker (E-cadherin) and mesenchymal markers (N-cadherin, vimentin, and fibronectin) of EMT. Results: (1) S100A7 expression was significantly higher in cervical squamous cancer tissues (median 91.6) than that in normal cervical tissues (median 52.1; Z=-2.948, P=0.003) . (2) Stable S100A7 overexpressed cells were established using lentiviral-mediated gene delivery in HeLa and CaSki cells. S100A7 was detected by real-time quantitative reverse transcription PCR, S100A7 mRNA of S100A7-overexpressed cells were 119+/-3 and 177+/-16, increased significantly compared with control groups of median (P<0.01) . Compared with the control cells, the number of S100A7-overexpressed HeLa and CaSki cells that passed the transwell membrane assay were increased significanatly (572+/-51 vs 337+/-25, P<0.01; 100+/-8 vs 41+/-4, P<0.01) .Matrigel invasion assay showed that the number of S100A7-overexpressed HeLa and CaSki cells that passed the transwell membrane were respectively 441+/-15 and 110+/-14, elevated significantly compared with control cells (156+/-21 and 59+/ 7; P<0.05) . However, S100A7 overexpression didn't influence the proliferation and cell cycle progression of HeLa and CaSki cells (P>0.05) . Expression of E cadherin was dramatically decreased, while N-cadherin, vimentin, and fibronectin increased in S100A7-overexpressed cells. Conclusion: S100A7 enhances the migration, invasion and EMT of HeLa cells and CaSki cells, and may be plays an important role in the development of cervical cancer. PMID- 29534380 TI - [The expert consensus of new standard and management of labor(2014):interpretation and statement]. PMID- 29534379 TI - [Effect of S1PR2 inhibition on epithelial ovarian cancer SKOV3 cell proliferation in vitro and in vivo]. AB - Objective: To study the effect and mechanism of S1PR2 inhibition on epithelial ovarian cancer SKOV3 cell proliferation in vitro and in vivo. Methods: (1) A pair of S1PR2 gene small interference RNA (siRNA) , namely si-S1PR2, and a pair of negative control siRNA were designed. Western blot methods were used to detect the silence efficiency of the S1PR2 in the si-S1PR2 group, blank control group and negative control group. (2) Study in vitro: the experiment included three groups, namely si-S1PR2 group, blank control group and negative control group. Cell counting kit-8 (CCK-8) assay was used to detect the proliferation inhibition rates of the transfected cells. The cell cycles of the transfected cells were measured by flow cytometry. Western blot was used to detect the levels of phosph extracellular regulated protein kinase 1/2 (p-ERK1/2) of the transfected cells. (3) Study in vivo:to establish intraperitoneal transplantation models, 8 mice in each group were intraperitoneally injected with 5*10(6) SKOV3 cells. Phosphate buffered saline (PBS) or JTE-013 were administered into mice twice per week starting on day 7 after the injection of the cancer cells. Twenty-eight days after nude mice intraperitoneal injection with JTE-013 or PBS, the mice were sacrificed and the number and the weight of visible tumors were calculated. Results: (1) The results of western blot showed that the relative S1PR2 protein expression levels were 0.24+/-0.04 in the si-S1PR2 group, which was lower than that in the blank control group (1.10+/-0.14, P<0.01) and negative control group (1.07+/-0.13, P<0.01) . (2) The results of CCK-8 assay indicated that after transfected for 24, 48 and 72 hours, the proliferation inhibition rate of si S1PR2 group were respectively (26.6+/-3.3) %, (35.0+/-3.4) %, and (34.0+/-2.8) %, significantly lower than those in the blank control group (all 0; all P<0.01) and negative control group [ (1.7+/-0.9) %, (2.5+/-0.5) %,and (2.4+/-1.1) % respectively; all P<0.01]. The results of flow cytometry showed that the G(0)/G(1) ratio in the si-S1PR2 group [ (70.9+/-2.8) %] was significantly higher than those in the blank control group [ (61.7+/-2.4) %, P<0.01] and negative control group [ (62.1+/-3.3) %, P<0.01]. Western blot showed that the relative expression level of p-ERK1/2 in si-S1PR2 group (0.11+/-0.03) was significantly lower than those in the blank control group [ (0.62+/-0.09) , P<0.01] and negative control group [ (0.68+/-0.09) , P<0.01]. (3)Twenty-eight days after nude mice intraperitoneal injection with JTE-013 or PBS, the tumor number of the control group and JTE-013 group were respectively 15.4+/-4.3 and 8.2+/-3.7, the tumor weight were (0.45+/-0.12) and (0.21+/-0.07) g, respectively. The tumor number and weight in the JTE-013 group were significantly less than those in the control group (all P<0.01) . Conclusions: The growth of ovarian cancer cells could be decreased by S1PR2 inhibition in vitro and in vivo. One of the mechanisms of the growth inhibitory effect is probably that S1PR2 inhibition lower the phosphorylation level of extracellular regulated protein kinase 1/2 (ERK1/2) pathway, which prevent the transformation of ovarian cancer cells from phase G(1) to S. PMID- 29534381 TI - [Sequential treatment of herpes zoster neuralgia]. PMID- 29534382 TI - [Effects and safety of quadratus lumborum block in analgesia after hip arthroplasty]. AB - Objective: To evaluate the efficacy of ultrasound guided quadratus lumborum block combined with non-steroidal anti-inflammatory drugs for postoperative analgesia in patients undergoing total hip arthroplasty. Methods: From January to June 2017, sixty American Society of Anesthesiologists (ASA) physical status I to III patients, aged 55-75 yr, scheduled for total hip arthroplasty, were randomly divided into control group(group N) and quadratus lumborum block (group R). Ultrasound guided quadratus lumborum block was implemented on the affected side at the end of operation.Then 30 ml 0.33% ropivacaine were administrated in group R, while the control group did not receive the same block. A sufentanil patient controlled analgesia pump was connected to the patient. The rest visual analogue score (VAS) were recorded at 0 h(T(0)), 3 h(T(1)), 6 h (T(2)), 12 h(T(3)), 24 h (T(4)), 36 h (T(5)) and 48 h(T(6)) after sugery, the VAS scores on movement were evaluated at T(4), T(5) and T(6) time points.The consumption of sufentanil within each period time were recorded.The maximal flexion and abduction degrees of the hip joint were evaluated at 12, 24, 36 and 48 h after operation. The number of patients for rescue pain relief by intravenous analgesia pump during 24 h and 48 h after surgery were counted in both groups. The postoperative adverse effects and overall satisfaction in the two groups were recorded. Results: The VAS at rest in group R were 0.8+/-0.4, 1.0+/-0.3, 1.2+/-0.5, 2.0+/-0.5, 1.7+/-0.4 , 1.6+/-0.5 at T(1), T(2), T(3), T(4), T(5), T(6) respectively, and those in group N were 3.0+/-0.7, 3.5+/-0.9, 3.8+/-0.9, 3.3+/-1.1, 3.3+/-0.7, 3.0+/-0.7 at the same time points. The VAS at rest were lower in group R than those in control group at all time points (F=203.090, 216.354, 203.956, 35.548, 96.332, 80.577, all P<0.01). The VAS on movement in group R were 2.7+/-0.9, 2.9+/-0.7 , 2.0+/-0.6 at T(4), T(5), T(6) respectively , and those in group N were 6.0+/-1.5, 5.8+/ 1.1, 4.5+/-1.0. The VAS on movement were also lower in group R than those in control group(F=154.561, 143.224, 141.479, all P<0.01). The maximum flexion degrees in group R were (61+/-12)degrees, (64+/-10)degrees, (69+/-15)degrees and(78+/-19)degrees at 12, 24, 36, 48 h after operation, and those were (45+/-11) degrees, (49+/-10)degrees, (52+/-12)degrees and(60+/-14)degrees at the same time points. The maximum flexion degrees in group R were increased more than control group at 12, 24, 36, 48 h after operation(F=34.981, 35.575, 52.106, 41.681, all P<0.01). The abduction degrees in group R were(22+/-6)degrees, (26+/-6)degrees, (27+/-8)degrees and(28+/-7)degrees at 12, 24, 36, 48 h after surgery, and those in group N were (14+/-5) degrees, (17+/-6)degrees, (20+/-6)degrees and(20+/ 5)degrees. The abduction degrees in group R were increased more than those in group N(F=58.974, 33.402, 19.151, 20.575, all P<0.01). The rates of rescue analgesia for pain relief were 10% and 16.7% at 24 h and 48 h after operation respectively in group R, and those were 100% and 100% in group N. Compared to group N, the rates of rescue analgesia for pain relief in group R were significantly decreased (chi(2)=49.091, 42.857, all P<0.01). The incidences of postoperative nausea and vomiting, pruritus in group R were 3.3% and 3.3% respectively, and those in group N were 23.3% and 20.0%. The incidences of nausea and vomiting, pruritus in group R were lower than those in group N (chi(2)=5.192, 4.875, all P<0.01). The overall satisfaction scores in group R (3.7 +/- 1.0 ) were higher than those (1.9+/-0.7) in the group N(t=7.841, P<0.01). Conclusion: The quadratus lumborum block combined with parecoxib sodium for multimodal analgesia after total hip arthroplasty is effective and provides satisfactory analgesia. PMID- 29534383 TI - [Application of continuous serratus plane block with patient-controlled analgesia on postoperation analgesia after thoracoscopic surgery]. AB - Objective: To investigate the application of ultrasound-guided continuous serratus plane block with patient-controlled analgesia on postoperation analgesia after thoracoscopic surgery, and influence on postoperative rehabilitation. Methods: Sixty patients scheduled for thoracoscopic surgery were randomly divided into two groups. PCNA group (n=30) received ultrasound guided continuous serratus plane block with patient-controlled nerve analgesia, with continuous infusion of 0.2% ropivacaine and 30 ml of 0.3% ropivacaine for the first does. PCIA group(n=30) received patient-controlled intravenous analgesia, with continuous infusion of sufentanil. Postoperative visual analogue scale (VAS) and prince henry pain scale (PHPS) were recorded at 1 hour (T(1)), 4 hour (T(2)), 8 hour (T(3)), 24 hour (T(4)), 2 days (T(5)), 3 days (T(6)), 4 days (T(7)), before discharge (T(8)), 30 days (T(9)) after surgery. Adverse reactions and the time of postoperative first out-of-bed activity, passage of gas by anus, bowel movement, chest tube removal, discharge was also recorded. Results: The resting VAS score of T(3), T(4), T(5) in group PCNA and group PCIA were 0(0) vs 0(2.0), 0(0) vs 2.0(2.0), 0(0) vs 0(2.0), the resting VAS score was lower in group PCNA than in group PCIA (Z=-2.524, -3.944, -3.652, P<0.05 or P<0.01). The upper arm activity VAS score of T(2), T(3), T(4), T(5), T(6), T(7) in group PCNA and group PCIA were 0(0) vs 0(2.0), 0(0) vs 2.0(2.5), 0(2.0) vs 2.0(2.0), 0(2.0) vs 2.0(2.0), 0(0) vs 2.0(2.0), 0(0) vs 0(2.0), the upper arm activity VAS score was lower in group PCNA compared with group PCIA (Z=-2.984, -3.915, -4.484, -4.450, -3.422, -2.456, P<0.05 or P<0.01). The coughing VAS score T(3), T(4), T(5), T(6), T(7) in group PCNA and group PCIA were 2.0(2.0) vs 2.0(2.5), 2.0(2.5) vs 4.0(4.0), 2.0(2.5) vs 4.0(4.0), 2.0(2.0) vs 3.0(2.0), 2.0(2.0) vs 2.0(2.0), the coughing VAS score was lower in group PCNA compared with group PCIA (Z=-3.432, -3.410, -2.643, -3.210, 2.746, P<0.05 or P<0.01). The PHPS score was significantly lower in group PCNA at T(3)[1.0(1.3) vs 2.0(2.0)], T(4)[1.0(2.0) vs 3.0(1.0)], T(5)[1.0(1.3) vs 2.0(1.3)], T(6)[1.0(1.3) vs 2.0(2.0)], T(7)[1.0(1.0) vs 1.0(2.0)] compared to group PCIA (Z=-3.149, -3.662, -3.369, -3.681, -2.815, all P<0.01). And the time of out-of-bed activity, passage of gas by anus of the PCNA group were (20.0+/- 6.9)h, ( 16.0+/- 8.0)h, which was advanced more than PCIA group [(23.9+/- 7.1)h, (34.3+/- 13.2)h, t=-2.20, -6.47, all P<0.05]. Furthermore, PCNA group had better sleep quality from the 2nd night to the 4th night , and with lower adverse reactions (all P<0.05). Conclusion: The application of ultrasound-guided continuous serratus plane block after thoracoscopic surgery can reduce postoperative pain and enhance recovery after surgery. PMID- 29534384 TI - [Study of comparing dexmedetomidine and remifentanil for conscious sedation during radiofrequency ablation of hepatocellular carcinoma]. AB - Objective: This study aimed to compare dexmedetomidine with remifentanil for conscious sedation in patients undergoing radiofrequency ablation of hepatocellular carcinoma. Methods: Sixty patients, who were aged 41 to 73 years with American Society of Anesthesiologists (ASA) physical status I-II, and scheduled for elective radiofrequency ablation of hepatocellular carcinoma under conscious sedation in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, from January 2014 to June 2016, were allocated randomly to receive dexmedetomidine maintenance regimen(group D, n=30)or remifentanil maintenance regimen(group R, n=30)by random digital table. Subjects in group D received dexmedetomidine at a loading dose of 0.5 MUg/kg over 10 min followed by 0.2-1.0 MUg.kg(-1).h(-1) infusion until Ramsay sedation scale reached 3-4. Patients in group R received a loading dose of remifentanil 1 MUg/kg followed by remifentanil 4-10 MUg.kg(-1).h(-1) infusion and propofol 1-2 mg.kg(-1).h(-1) infusion until Ramsay sedation scale reached 3-4. Haemodynamic variables, respiratory rate(RR), pulse oxygen saturation (SpO(2))and numeric rating scales(NRS) in each group were collected at entrance(T(0)), puncturing(T(1)), 15 min after beginning of radiofrequency ablation(T(2)), the end of radiofrequency ablation(T(3)) and 30 min after operation(T(4)). Efficacy of anesthesia, incidences of intraoperative respiratory depression, postoperative nausea and vomiting, patient and surgeon satisfaction were evaluated. Results: Compared with group D, the arterial blood pressure and heart rate at T(2) [(92.2+/-15.7)mmHg vs (102.4+/-16.7)mmHg, (69.7+/-15.3) beats/min vs (79.4+/ 17.7) beats/min] and respiratory rate at T(1), T(2) and T(3) [(10.1+/-1.9) breaths/min vs(12.3+/-1.7) breaths/min, (10.8+/-1.5) breaths/min vs(13.6+/-1.6) breaths/min, (13.4+/-1.6) breaths/min vs(14.5+/-1.4)breaths/min] were significantly lower in group R (t=-2.437, -2.271, -4.726, -6.993, -2.834, all P<0.05). With less sulfentanil consumption(23.2+/-8.3)MUg vs( 35.5+/-11.7)MUg, group R got less NRS at T(2) and T(3)(2.4+/-1.1) vs(3.5+/-1.2), (2.4+/-1.3) vs(3.6+/-1.1), and higher NRS at T(4)(3.4+/-1.1) vs( 2.1+/-0.9) than group D(t= 4.696, -3.701, -3.860, 5.010, all P<0.05). Compared with group R, the incidence of intraoperative respiratory depression was significantly lower (23.3% vs 56.7%)and the incidence of inadequate anesthesia(20% vs 0) was significantly higher in group D(chi(2)=5.625, 4.630, both P<0.05). Conclusion: Both dexmedetomidine and remifentanil can be successfully used for conscious sedation in patients undergoing radiofrequency ablation of hepatocellular carcinoma. Remifentanil maintenance regimen provides better intraoperative analgesia and operative condition, while dexmedetomidine is superior to remifentanil in reducing intraoperative respiratory depression and postoperative pain. PMID- 29534385 TI - [Glucose and lipid metabolic disorders in myasthenia gravis patients and its mechanisms]. AB - Objective: To investigate the glucose and lipid metabolic disorders in patients with myasthenia gravis (MG) without glucocorticoid therapy, and the relationships between insulin, insulin resistance, muscle strength, serum levels of osteocalcin, 25-hydroxy vitamin D (25OHD) and glucose and lipid metabolism. Methods: A total of 102 MG patients [(40+/-11) years old, 43 males and 59 females] without glucocorticoid treatment were enrolled in this cross-sectional study. Height, weight and the handgrip of dominant hands were measured. Serum levels of fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 h PBG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-hour postprandial insulin (2 h PINS), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL C) and osteocalcin, 25OHD were detected. Insulin resistance was assessed using homeostasis model assessment of insulin resistance (HOMA-IR). Results: The proportion of impaired fasting glucose or impaired glucose tolerance, type 2 diabetes, dyslipidemia, hyperinsulinemia in male and female were 30.0%, 10.0%, 50.0%, 33.3% and 17.5%, 3.5%, 27.7%, 7.1%, respectively. Serum osteocalcin levels in male and female were 2.8 (1.7, 4.4) MUg/L and 2.3 (1.3, 3.9) MUg/L, respectively. And 25OHD levels in male and female were (93.5+/-34.9) nmol/L and (81.0+/-30.5) nmol/L, respectively. Handgrip of male and female was (37.0+/-9.4) kg and (20.5+/-6.3) kg. After adjusted for age, FINS (r=0.619, P<0.001), 2 h PINS (r=0.640, P<0.001), HOMA-IR (r=0.534, P<0.001) were positively correlated with 2 h PBG, and the handgrip was negatively correlated with TC (r=-0.486, P=0.026), LDL-C (r=-0.485, P=0.026) in male. FINS (r=0.352, P=0.008; r=0.300, P=0.026; r=0.646, P<0.001) and 2 h PINS (r=0.278, P=0.040; r=0.518, P<0.001; r=0.382, P=0.006) and HOMA-IR (r=0.695, P<0.001; r=0.583, P<0.001; r=0.818, P<0.001) were positively correlated with FBG, 2 h PBG, HbA1c, and the handgrip were negatively correlated with FBG (r=-0.424, P=0.016), 2 h PINS (r=-0.345, P=0.034) and positively correlated with HDL-C (r=0.389, P=0.037) in female. There was no association between osteocalcin, 25OHD and glucose and lipid metabolism. Multivariate linear regression analysis also found that there were significant relationships between handgrip, insulin, insulin resistance levels and glucose and lipid metabolic disorders. Conclusion: There was a high proportion of glucose and lipid metabolic disorders in MG patients without glucocorticoid treatment, and the mechanism may be related to insulin resistance induced by muscle weakness. PMID- 29534386 TI - [Surgical treatment of intractable odontoid fracture with atlantoaxial dislocation in children with spinal cord injury]. AB - Objective: To discuss the surgical treatment and its effectiveness of odontoid fracture complicated with atlantoaxial dislocation in children with spinal cord injury. Methods: From January 2010 to December 2014, 10 cases of children under 14 years old, with intractable odontoid fracture with atlantoaxial dislocation were enrolled. The mean duration between injury and admission was 8.5 d (range 1 30 d). The surgery was performed using posterior reduction and internal fixation or anterior release combined with posterior fixation. The medical date including preoperative and postoperative neurological function, degree of reduction and fusion. Results: All cases were followed-up for 12-48 months. The last follow-up X ray and CT examinations showed good reduction and fusion. No fixation failure was observed among all the patients. According to the Frankel, the preoperative neurological function was C in 2 cases, D in 4 cases, and E in 4 cases. At the last follow-up, out of 2 cases with Frankel C improved to D, and the other 8 cases were back to normal. Conclusions: Diagnosis of odontoid fracture complicated with atlantoaxial dislocation is usually delayed in children. One stage posterior reduction and internal fixation or anterior release combined with posterior fixation is an effective and safe surgical procedure for such cases. PMID- 29534387 TI - [Clinical analysis of chronic sternal osteomyelitis with sinus tract after cardiovascular surgery]. AB - Objective: To explore the diagnosis, therapy and prevention method of chronic sternal osteomyelitis with sinus tract after cardiovascular surgery. Methods: A total of 53 patients with chronic sternal sinus tract after cardiovascular surgery between January 2000 and January 2016. After definite diagnosis by contrast fistulography and CT scanning, all the patients received combined modality therapy including debridement, musculocutaneous flap transplantation and intermediate thickness free skin graft transplantation if necessary. Results: One patient died of false aneurysm due to the sternal sinus tract infection, there were no peri-operative death for all the left 52 patients. Forty-five patients had primary healing and 7 patients had secondary healing. All the patients became total recovery within 3-12 weeks after operation and maintained well during the 5 18 months' follow-up. Conclusions: For the patients with chronic sternal osteomyelitis, operative therapy should be performed as soon as possible once the diagnosis is confirmed. Combined modality therapy including debridement, musculocutaneous flap transplantation and intermediate thickness free skin graft transplantation is confirmed to be effective and secure. PMID- 29534388 TI - [Significance of pharyngeal biochemical indexes in the diagnosis of laryngopharyngeal reflux disease]. AB - Objective: To investigate the significance of the detection of pepsin in saliva and the pharyngeal pH monitoring in the diagnosis of laryngopharyngeal reflux disease(LPRD). Methods: A total of 176 patients (140 patients with simple pharyngitis and 36 patients with space-occupying lesions of larynx) who were suspected to have laryngopharyngeal reflux between February and December 2016 were retrospectively reviewed. All the patients were evaluated with reflux symptom index (RSI), reflux finding score (RFS) and 24-hour pharyngeal pH monitoring(Dx-pH). Saliva of patients was collected and the pepsin in the saliva was measured by enzyme-linked immunosorbent assay (ELISA). Results: The positive rate of RSI (RSI>13) and/or RFS (RFS>7) was 56.8% (100/176). The positive rate of pepsin in saliva was 40.9% (72/176) and pepsin in saliva collected at the time of onset of symptom was much higher than that at other time points (P<0.001). The positive rate of pepsin in saliva, Ryan score and the pH<6.0 laryngopharyngeal reflux in space-occupying lesions group [55.6%(20/36), 27.8% (10/36), 69.4%(25/36), respectively] were all higher than simple pharyngitis group [37.1% (52/140), 5.0% (7/140), 50% (70/140), respectively] (P=0.045, P<0.001, P=0.037, respectively). Conclusions: The detection of pepsin in saliva and the pharyngeal pH monitoring reflected different reflux agents, and there was great significance for the diagnosis of LPRD by using two methods together. We found that the weak acid state and consequent pepsin damage played an important role in the occurrence and development of space-occupying lesions of larynx. PMID- 29534389 TI - [Analysis of predictive effect of Androgen receptor on the response to neoadjuvant chemotherapy in breast cancer patients]. AB - Objective: To explore the expression of androgen receptor (AR) in the tissues as well as its association with the clinicopathological factors of primary breast cancer patients treated with neoadjuvant chemotherapy (NAC), and analyze the effect of AR in the prediction of pathologic complete response (PCR) rate. Method: A total of 668 breast cancer patients treated with NAC in Henan Cancer Hospital between March 2014 and June 2017 were retrospectively reviewed. The relationship of AR expression and clinicopathological characteristics was calculated using chi square test. Multivariate analysis using binary Logistic regression was used to analyze correlations of different factors with PCR. Result: All patients were female, with the age of 20-76 years old. AR was detected in 74.6% of tumors, and significantly correlated with hormone receptor (HR), human epidermalgrowth factor receptor-2 (HER-2), Ki-67, CK5/6, epidermal growth factor receptor (EGFR) and molecular subtypes (all P<0.05). Multivariate analysis showed that AR, HR and HER-2 were independent predictors for PCR (all P<0.05). Conclusions: The expressions of AR were more frequently in HR positive breast cancer tissues (86.7%), and lowest in triple-negative breast cancer (TNBC) group (23.2%). AR was independent predictor for PCR. PMID- 29534390 TI - [Factors influencing survival of patients with pancreatic adenocarcinoma after surgical resection]. AB - Objective: To investigate the clinical outcomes and prognostic factors in patients with pancreatic cancer after surgical resection with curative intent and analyze factors affecting 2-year and 5-year survival of patients. Methods: A total of 469 patients with pancreatic adenocarcinoma undergoing curative resection were included in the study, and the clinical data of these patients were analyzed retrospectively. Univariate and multivariate analyses were performed to examine factors affecting prognosis of these patients. The clinicopathological characteristics of patients who survived for <=2 years and >2 years as well as <=5 years and >5 years were compared, respectively. Results: The multivariate analysis showed that lymphovascular invasion (P=0.024), lymph node metastasis (P<0.001), vascular resection (P=0.002), maximum tumor diameter >2 cm (P=0.009), poor differentiation (P<0.001) were negative prognosis factors, but postoperative chemotherapy (P<0.001) was an independent positive prognostic factor. Comparison of the patients who survived for <=2 years and >2 years showed that lymphovascular invasion (P=0.012), lymph node metastasis (P<0.001), vascular resection (P=0.014), maximum tumor diameter>2 cm (P=0.004), poor differentiation (P<0.001), peri-pancreatic fat invasion (P=0.005), absence of postoperative chemotherapy (P<0.001), advanced tumour, node and metastasis (TNM stage) (P<0.001) were associated with 2-year survival. With regard to 5-year survival, lymph node metastasis (P=0.005), poor differentiation (P=0.014) and TNM stage(P=0.025) were associated with it. Conclusions: Our results suggest that lymphovascular invasion, lymph node metastasis, vascular resection, maximum tumor diameter >2 cm, poor differentiation and absence of postoperative chemotherapy were independent negative prognostic factors. Lymph vascular invasion, lymph node metastasis, vascular resection, maximum tumor diameter >2 cm, poor differentiation, peri-pancreatic fat invasion, absence of postoperative chemotherapy, advanced TNM stage were associated with 2-year survival, and lymph node metastasis, degree of differentiation and TNM stage are important prognosis factors affecting long-term survival of patients. PMID- 29534391 TI - [Therapeutic effect and mechanism of carboxyamidotriazole on the pulmonary fibrosis of mice induced by bleomycin]. AB - Objective: To investigate the treatment effect of carboxyamidotriazole (CAI) on bleomycin induced lung fibrosis in mice, and the potential mechanism involved. Methods: A total of 45 mice were divided into three groups randomly. Blank control group (blank group): after a one-time tail vein injection of saline solution 0.2 ml, mice were given polyethylene glycol 400 (PEG-400) 0.1 ml/10 g by gavage once daily for 14 days; the bleomycin group (BLM group): after a one-time tail vein injection of bleomycin 150 mg/kg, mice were given PEG-400 solution 0.1 ml/10 g by gavage once daily for 14 days; CAI group: after a one-time tail vein injection of bleomycin 150 mg/kg, mice were given CAI solution 40 mg/kg by gavage once daily for 14 days. All mice were sacrificed on day 28. Observation index: lung coefficient, survival analysis, pathological section and collagen staining of lung tissue, lung hydroxyproline, Transformation growth factor-beta(1)(TGF beta(1)), gamma-interferon(IFN-gamma), matrix metalloproteinase 9(MMP-9) and tissue inhibitor of matrix metalloproteinasese 1(TIMP-1) content determination in lung homogenate. Results: On day 28 the lung coefficient of mice in BLM group and CAI group was significantly higher than the blank group, and the BLM group was with the highest (all P<0.05). Degree of pulmonary fibrosis in lung tissue pathological specimens (HE staining) was, from heavy to light, BLM group, CAI group, blank group. The content of hydroxyproline in mice lung homogenate was (0.406+/-0.020) MUg/mg in blank group, (0.722+/-0.118) MUg/mg in BLM group, (0.537+/-0.071) MUg/mg CAI group, respectively (all P<0.05). The content of TGF beta(1) in three groups was (15+/-5), (60+/-10), (41+/-10) ng/ml respectively (all P<0.05). The content of IFN-gamma in three groups was (47+/-5), (126+/-24), (194+/-34) pg/ml respectively (all P<0.05). The content of TIMP-1 in three groups was (73+/-6), (369+/-58), (246+/-51) ng/ml respectively (all P<0.05). Comparisons of the content of MMP-9 between each group had no significant difference (P>0.05). Conclusions: CAI can reduce lung injury induced by bleomycin in mice. The mechanism of action is related to the effects of CAI on cytokines such as TGF beta(1), IFN-gamma, MMP-9 and TIMP-1. PMID- 29534392 TI - [Effect of miR-19b on the proliferation and apoptosis of P19CL6 cells during the late-stage of cardiac differentiation]. AB - Objective: To explore the effect of miR-19b on the function of P19CL6 cells and its molecular mechanism. Methods: Overexpression of miR-19b was carried out by transfecting miR-19b plasmid into the P19CL6 cells. MTT assay and flow cytometry were used to determine cell growth and apoptosis, respectively. Western blot was used to detect the expression level of Sox6 in P19CL6 cells. ELISA assay was used to detect the expression levels of apoptosis-related genes (Bax, Bcl-2) in P19CL6 cells at late-stage cardiac differentiation. Further online software TargetScan was used to predict the target genes of miR-19b and verified by dual luciferase reporter assay. Results: Our data showed that overexpression of miR-19b in P19CL6 cells significantly increased the cell growth rates and the apoptosis inhibition rates. The ratio of apoptosis-related proteins (Bax/Bcl-2) was significantly reduced. Results from the TargetScan and dual luciferase reporter showed that Sox6 is the direct target of miR-19b. Conclusions: We conclude that miR-19b might promote cell proliferation and inhibits cell apoptosis during the late-stage of cardiac differentiation by targeting Sox6 expression. PMID- 29534393 TI - [A retrospective study of the treatment of patients hospitalized for asthma exacerbation in China]. AB - Objective: To study the treatment of patients hospitalized for asthma exacerbation in China. Methods: This was a retrospective study and involved patients hospitalized for asthma exacerbation in 29 hospitals throughout China during Jan 2013 to Dec 2014. Information of the demographic features, the severity of the exacerbation, the medicine prescribed during the hospitalization and the use of mechanical ventilation were collected and analyzed. Results: During the study period, there were 3 240 patients hospitalized for asthma exacerbation, and 1 369(42.3%) of them were males 1 871(57.7%)were females. Patients of mild, moderate, severe, and life-threatening exacerbation counted for 41.7%, 37.8%, 19.2% and 1.0%, respectively of the total patients. Of all the patients, 72.6% used bronchodilators by nebulizer, 70.8% used inhaled corticosteroids by nebulizer, 60.5% used intravenous corticosteroids, 17.3% used oral corticosteroids, and 80.5% used antibiotics. The percentages of patients using systemic corticosteroids and antibiotics were higher in patients with more severe exacerbation. In patients with mild exacerbation, there were 74.9% and 52.2% who used antibiotics and systemic corticosteroids, respectively. A total of 73 patients (2.3%) used mechanical ventilation, and 62 of them used noninvasive ventilation, 16 used invasive ventilation, and 5 used both. Conclusions: Nebulizer therapy has been accepted as the main administration route of medicine in the treatment of asthma exacerbation. A large amount of patients used antibiotics and systemic corticosteroids during hospitalization, indicating there may be some overuse of these medicines. PMID- 29534395 TI - [Interpretation of the new 2017 WHO classification of pituitary tumors, and standardization of diagnosis and treatment of pituitary adenomas]. PMID- 29534394 TI - [The significance and role of the 2017 World Health Organization classification of tumors of the pituitary gland]. PMID- 29534396 TI - [The 2017 World Health Organization classification of pituitary adenomas: clinical significance]. PMID- 29534397 TI - [The pathological review of the 2017 World Health Organization classification of tumors of the pituitary gland]. PMID- 29534398 TI - [The application of cortical and subcortical stimulation threshold in identifying the motor pathway and guiding the resection of gliomas in the functional areas]. AB - Objective: This study aimed to analyze the application of cortical and subcortical stimulation threshold in identifying the motor pathway and guiding the resection of gliomas in the functional area, and to illustrate the minimal safe threshold by ROC method. Methods: Fifty-seven patients with gliomas in the functional areas were enrolled in the study at Beijing Tiantan Hospital from 2015 to 2017. Anesthesia was maintained intravenously with propofol 10% and remifentanil. Throughout the resection process, cortical or subcortical stimulation threshold was determined along tumor border using monopolar or bipolar electrodes. The motor pathway was identified and protected from resection according to the stimulation threshold and transcranial MEPs. Minimal threshold in each case was recorded. Results: Total resection was achieved in 32 cases(56.1%), sub-total resection in 22 cases(38.6%), and partial resection in 3 cases(5.3%). Pre-operative motor disability was found in 9 cases. Compared with pre-operative motor scores, 19 exhibited impaired motor functions on day 1 after surgery, 5 had quick recovery by day 7 after surgery, and 7 had late recovery by 3 months after surgery. At 3 months, 7 still had impaired motor function. The frequency of intraoperative seizure was 1.8%(1/57). No other side effect was found during electronic monitoring in the operation. The ROC curve revealed that the minimal safe monopolar subcortical threshold was 5.70 mA for strength deterioration on day 1 and day 7 after surgery. Univariate analysis revealed that decreased transcranial MEPs and minimal subcortical threshold <=5.7 mA were correlated with postoperative strength deterioration. Conclusions: Cortical and subcortical stimulation threshold has its merit in identifying the motor pathway and guiding the resection for tumors within the functional areas. 5.7 mA can be used as the minimal safe threshold to protect the motor pathway from injury. PMID- 29534399 TI - [Microsurgical treatment of temporal cavernous malformation presenting with epilepsy]. AB - Objective: To evaluate the efficacy and safety of microsurgical in the treatment of temporal lobe cerebral cavernous malformation (CCM) with epilepsy. Methods: Temporal lobe CCM patients with epilepsy admitted to our department were collected from January 2010 to September 2016. Locations of the CCM were divided into (1) lateral-lateral to the collateral sulcus; (2) mesial-mesial to the collateral sulcus. In the lateral group, patients were underwent intraoperative electrocorticography (ECoG)-guided resection of lesion and hemosiderin rim. In the medial group, a complete resection of the epileptogenic zone was performed in anterior temporal lobe and hippocampus and (or) amygdala according to lesion and hemosiderin rim. The follow-up period in all patients was at least 1 year. The outcome of epilepsy treatment was evaluated according to the standard Engel scale. Results: Eight patients belong to the lateral group, including 2 males and 6 females, mean age at epilepsy surgery was 35 years old, 100% of patients achieved Engel class I the last follow up. The mesial group had 7 patients, including 4 males and 3 females, mean age at epilepsy surgery was 52 years old, 71.8% of the patients were Engel Class I, 14% were Class II, and 14% were Class III. The patient who was Engel Class III had a posterior temporal venous infarction due to injured the developmental venous anomalies (DVAs). Conclusions: CCM Patients with epilepsy could benefit greatly from complete resection of hemosiderin rim and lesion. The epilepsy prognosis were closely correlated with the location of CCM. Further research is necessary to determine therapeutic strategies of CCMs with associated DVAs. PMID- 29534400 TI - [Changes of platelet aggregability in patients with subcortical ischemic vascular disease]. AB - Objective: To explore the change and value of platelet aggregability(PA)in patients with subcortical ischemic vascular disease (SIVD). Methods: A total of 108 patients with SIVD hospitalized in the Department of Neurology of the First Affiliated Hospital of Anhui Medical University from October 2015 to July 2017 were enrolled as SIVD group and 30 healthy cases were also in cluded as normal controlgroup (NC). According to magnetic resonance imaging(MRI), the SIVD group was further divided into two subtypes: lacunar infarction(LI) (n=31)and leukoaraiosis(LA) (n=77). The severity of LA was further graded according to the Fazekas scale. The maximum aggregation rate of platelets was measured by optical turbidimetry, respectively, using four arachidonic acid (ACA), two adenosine monophosphate (ADP) and collagen (COLL) as inducerin all subjects. The change of PA between the subtypes of SIVD and NC were compared, and the relationship between PA and the severity of LA was analyzed. Results: The level of PA in SIVD was significantly higher than those in NC (P<0.001). In comparison with NC, the level of PA was significantly higher in both LI and LA subgroups(P<0.05). Meanwhile, there was no significant difference between LA group and LI group (P>0.05). Moreover, between LA groups, the PA induced by COLL were significantly different between the LA3 group and the LA1 group (P=0.026). Correlation analysis showed that ageand the level of PA induced by COLL was positively correlated with LA grade (r=0.382, P=0.001; r=0.260, P=0.026). Multivariate logistic regression analysis revealed that after controlling for various factors, when induced by ACA, the risk of SIVD in the highest group (>86.80%) and higher group (82.63% 86.80%) was 13.95 and 3.09 times respectively higher than in the normal group(<82.63%), the differences were statistically significant (P<0.001, P=0.038); when induced by ADP, the risk of SIVD in the highest group (>87.63%) and higher group (82.80%-87.63%) was 20.78 and 5.85 times respectively higher than in the normal group (<82.80%), the differences were statistically significant (P<0.001, P=0.003); When induced by COLL, the risk of SIVD in the highest group (>87.60%) and higher group (83.80%-87.60%)was 28.53 and 9.02 times respectively higher than in the normal group (<83.80%), the differences were statistically significant (P<0.001, P=0.002). Conclusions: The increasedlevel of PA is an independent risk factor of SIVD and closely related with the severity of LA .This study provides a theoretical basis for further understanding of the SIVD's pathogenesis and for the prevention and treatment of SIVD in the clinical practice. PMID- 29534401 TI - [Characteristics of neuromyelitis optica spectrum disorder associated with the area postrema]. AB - Objective: To evaluate the clinical characteristics and the corresponding MRI and laboratory findings in patients with neuromyelitis optica spectrum disorder (NMOSD) associated with area postrema (AP). Methods: The study was a retrospective analysis of data from 120 NMOSD patients, and 18 cases were with AP out of these patients, The clinical presentation, MRI changes, serological markers and treatment outcome were reported. Results: AP occurred in 18 patients (15%, 18/120). AP was the onset symptom in 14 (14/18) patients and 3 days to 7 months (median 40 days) later, optic neuritis or myelitis was involved. One patient presented AP after optic neuritis. Three patients (3/18) had AP and myelitis or optic neuritis simultaneously. AP symptom presented as intractable nausea and vomiting, hiccups. Compared to the patients without AP (n=102), the patients with AP (n=18) had shorter duration and fewer numbers of optic neuritis(P<0.05). There was no statistical difference in sex, onset age, course of disease (relapsing or monophasic) and EDSS scores (P>0.05). The MRI revealed flake or linear lesions in medulla. Twelve patients had cervical cord lesions extending to medulla lesions (12/18). Eleven patients had long cord lesions extending more than 3 spinal cords. The AQP4-antibody did not differ in patients with or without AP (14/18 vs 75/102). The symptom of AP was successfully relieved with methylprednisolone. Conclusion: AP symptoms/signs are common in patients with NMOSD. Vomiting and hiccups can be the first symptoms. The medulla lesions and the lesions extending to upper cervical cord are unique to NMOSD. Awareness of AP presentations is helpful for early diagnosis and proper treatment to prevent further disability. PMID- 29534402 TI - [Multicenter retrospectie analysis on clinical characteristics and pharmaceutical therapy of elderly Patients with chronic heart failure]. AB - Objective: To investigate the clinical characteristics and pharmaceutical therapy of elderly patients with chronic heart failure (CHF). Methods: Using the multi center retrospective cross-sectional survey, we analyzed 1 799 hospitalized patients with CHF as the main cause and NYHA heart function classification II-IV from nine tertiary hospitals of Tianjin during March 2014 to February 2016. According to age, we divided them into non- elderly group(age<65 years), normal elderly group (age >=65-79 years), and the old elderly group(age>=80 years). We analyzed the clinical characteristics and pharmaceutical therapy of different age groups of CHF patients. Results: One thousand seven hundred and ninety-nine patients with CHF, mean age (70+/-13) years old. Elderly patients over 65 accounted for 69.87%; men accounted for 61.53%; the average hospitalization days were 11.33 days, hospitalization days of the old elderly group were significantly prolonged to 13.26 days(P<0.05). With increasing age, the proportion of men, NYHA II and HFrEF patients gradually decreased, the proportion of women, NYHA IV and HFpEF patients gradually increased(all P<0.05). The distribution of HFmrEF in different age groups was not statistically significant(P>0.05), accounting for one third. Etiology and comorbidities: the first eight diseases were coronary heart disease, hypertension, hyperlipidemia, diabetes, pulmonary infection, cerebrovascular disease, renal dysfunction and atrial fibrillation. The ratios of old elderly group with pulmonary infection, cerebrovascular disease, renal dysfunction and atrial fibrillation were significantly higher than the non elderly group( all P<0.05). The numbers of comorbidity in old elderly group and the normal elderly group were higher than the non-elderly group, respectively 3.74, 3.37 and 2.82(all P<0.05). The application rate of beta-blockers and ACEIs in non-elderly group was higher than the other groups (P<0.05). The application rate of ARBs, digitalis, energy metabolites and nitrates in the normal elderly group and the old elderly age group was higher than the non-elderly group (P<0.05). Conclusions: With increasing age, the proportion of men and HFrEF patients with CHF gradually decrease, the proportion of women and HFpEF patients with CHF gradually increase, the proportion of old elderly men and women tend to be equal, HFmrEF maintains the proportion of about 1/3, no change with age. The elderly patients with CHF have more comorbidity, worse heart function, and more serious heart failure.The overall application of anti-HF drugs in elderly CHF patients needs to be improved. PMID- 29534403 TI - [Acute effects of intravenous fasudil with different dosage on patients with congenital heart defects and severe pulmonary arterial hypertension]. AB - Objective: To compare the acute hemodynamic effects of intravenous fasudil with different dosage on patients with congenital heart defects (CHD) and severe pulmonary arterial hypertension (PAH). Methods: Sixty patients (37+/-17 years old) with CHD and PAH were consecutively enrolled. All patients underwent heart catheterization. The patients were randomly divided into two groups: the regular dosage group and the large dosage group. At initiation and 30 min after intravenous fasudil(30 mg and 60 mg respectively), the following hemodynamic parameters were measured and calculated: right atrial pressure(RAP), pulmonary arterypressure(PAP) , systemic artery pressure (SAP), pulmonary capillary wedge pressure(PCWP) , pulmonary vascular resistance(PVR) and systemic vascular resistance( SVR), cardiac index (CI) and artery oxygen saturation (SaO(2)). Results: Compared with pre-medication, both mPAP and PVR tended to reduce significantly in the regular dosage group and the large dosage group: mPAP from (63.7+/-8.6)to (58.3+/-8.5)mmHg(P<0.01) and from (62.9+/-8.8) to(55.1+/-7.8)mmHg (P<0.01), respectively; PVR from(9.9+/-4.3)to (7.7+/-3.9) Wood(P<0. 01) and from (9.5+/-4.9)to(6.1+/-4.8)Wood(P<0.01); CI tended to increase significantly in the two groups: from (2.9+/-0.9) to (3.1+/-1.1) L.min(-1).m(-2)( P<0.05) and from(3.0+/-0.8) to (3.5+/-1.6) L.min(-1).m(-2)( P<0.05), respectively . Compared with the regular dosage group, both mPAP and PVR tended to reduce significantly in the large dosage group: mPAP (8.2+/-1.8) vs (4.2+/-1. 0)mmHg (P<0.05); PVR(3.7+/-1.1) vs (2.1+/-0.8 ) Wood (P<0.05) .Meanwhile , there was no significant difference in CI, SAP, SVR and SaO(2) between the two groups. Conclusion: Fasudil could improve the acute hemodynamic effects of patients with CHD and severe PAH, especially in the large dosage group. PMID- 29534404 TI - [Study on relationship between Set gene expression and clinical manifestations in bone marrow of patients with acute myelogenous leukemia]. AB - Objective: To explore the expression and significance of Set gene in Acute myeloid leukemia (AML) patients , and to analyze its effect for the prognosis of AML. Methods: The level of Set gene expression was detected by real-time PCR in 59 AML patients and 20 heathy people. The mutations in C-kit 8/17 gene, NPM1 gene and FLT3-TKD/ITD gene in 59 AML patients were detected by direct sequencing. Results: The level of Set gene expression[1.41(0.41-3.31)]was significantly higher in 59 AML patients.The expression of Set gene was correlated with the percentage of marrow blasts and CR in AML patients (P=0.040, P<0.001); the CR rate of Set gene high expression group was significantly lower than that of Set gene low expression group(32.1% vs 83.9%, P=0.01). In the intermediate-risk of AML patients with chromosome karyotype analysis, the CR rate of Set gene high expression group and low expression group were 34.8% and 88.9%, and there are significantly different between two groups(P<0.001); univariate and multivariate analysis showed that Set gene high expression group correlated with poor OS[4(2 15)months]and EFS[3(2-13)months])(P=0.021, P=0.017). It suggests that the Set gene maybe one of AML independent poor prognostic marker.The level of Set gene expression did not correlate with sex, age, WBC, HGB, PLT, FAB typing, chromosomal karyotype and NPM1, C-Kit8/17, CEBPa, FLT3-ITD/TKD gene mutations in AML patients(all P>0.05). Conclusions: The level of Set gene expression in bone marrow maybe play an important role in AML. The high expression of Set gene indicates poor prognosis in AML patients. PMID- 29534405 TI - [Expression of anaplastic lymphoma kinase fusion gene in patients with lung sarcomatoid carcinoma and treatment analysis]. AB - Objective: To investigate the expression status of anaplastic lymphoma kinase (ALK) fusion gene in lung sarcomatoid carcinoma (LSC) and the role of ALK inhibitors for treatment. Methods: Total of 84 cases of LSC confirmed by histopathology were detected for ALK fusion gene from January 2011 to December 2014 in the Cancer Hospital of Chinese Academy of Medical Science&Peking Union Medical College and Shandong Zibo Wanjie Cancer Hospital. All patients were primarily treated by the multi-disciplinary mode in combination with chemotherapy or targeted therapy based on surgery. Postoperative adjuvant chemotherapy was given on platinum based two-drug combination regimen. In ALK fusion gene (+ ) patients with recurrence or metastasis, crizotinib target therapy was prefered. Chi-square test was applied for the comparison of 1, 3, 5-year survival rates between the two groups. Results: Eighty-two cases completed the follow-up. ALK fusion gene was found in 9(10.7%) patients. After application of crizotinib, 1 case was evaluated as complete remission, 6 cases as partial response, 2 cases as stable disease; the 1, 3, 5-year survival rate was 100% (9/9), 100% (9/9) and 88.9% (8/9) for the patients with ALK fusion gene, and it was 65.8% (48/73), 15.1% (11/73) and 6.8% (5/73) respectively for patients without ALK fusion gene. There was significant difference in the survival rate between the two groups (chi(2)=1.56, 1.56, 0.83, all P<0.05). Conclusion: ALK fusion gene maybe expressed in LSC patients. Compared with conventional chemotherapy, crizotinib can significantly prolong the survival time of patients with ALK fusion gene. PMID- 29534406 TI - [Predictive value of serum S100B levels in patients with multiple trauma combined delirium for their outcome at intensive care unit discharge]. AB - Objective: To investigate the predictive value of elevated serum S100B level in patients with multiple traumas combined delirium for the clinical prognosis prior to intensive care unit (ICU) discharge. Methods: One hundred seventy-nine patients with multiple traumas diagnosed as delirium after admission over 48 hours to the Department of Critical Care Medicine, People's Hospital Affiliated to Jiangsu University from January 2013 to December 2016 were divided into two groups according to the level of serum S100B measured prior to the ICU discharge: high S100B group (>=0.20 MUg/L, n=53) and low S100B group (<0.20 MUg/L, n=126). The difference of the clinical prognoses between the two groups was evaluated with t or Chi-square test. Results: The patients in high S100B group had a higher ICU readmission rate (18.9% vs 6.3%, chi(2)=6.464, P=0.011). The 30-day mortality was higher for patients in high S100B group than that in low S100B group (5.7% vs 4.0%, chi(2)=0.308, P=0.579). The incidence of adverse outcome was also significantly higher for patients in high S100B group than that in low S100B group (35.8% vs 17.5%, chi(2)=7.144, P=0.008). The sequential organ failure assessment (SOFA) score before ICU discharge was also higher for patients in the high S100B group than that in the low S100B group (3.2+/-1.3 vs 2.4+/-1.1, t=4.204, P=0.000). The duration of ICU stay for patients in high S100B group was significantly longer than that in the low S100B group[(16+/-8) vs (12+/-5) d, t=4.095, P=0.000]. The area under the curve (AUC) of receiver operating characteristics of the S100B was 0.742, 95% CI: 0.574-0.910. The multivariate logistic regression analysis revealed that the odds ratio (95% CI) in the prediction of adverse outcomes by S100B level prior to the ICU discharge was 1.39(1.15-1.53), P=0.009. Conclusion: Elevated serum level of S100B in patients with multiple traumas combined delirium prior to ICU discharge is closely associated with poor clinical prognosis, but it is only a modest predictor that may not be used alone in judgements of clinical treatments for patients. PMID- 29534407 TI - [Application of preset adaptive statistical iterative reconstruction-V in dual enhanced abdominal CT]. AB - Objective: To analyze the effect of preset adaptive statistical iterative reconstruction-V (ASIR-V) on image quality and radiation dose in dual-enhanced abdominal CT and to investigate the optimal ASIR-V in clinic use. Methods: From February 13 to April 30 in 2017, one hundred and eighty patients who received up abdominal CT scan in the First Affiliated Hospital of Zhengzhou University were collected prospectively. All patients underwent arterial phase (AP) and portal venous phase (PVP) enhanced abdominal CT(120 kVp, noise index 10) and were randomly divided into 6 groups according to random number table (A-F, 30 cases in each group). In group A-F, 0-50% preset ASIR-V (an interval of 10%) was applied, respectively. Qualitative parameters (subjective image quality, diagnosis confidence and radiation dose) and quantitative parameters[image noise, CT number and contrast to noise ratio (CNR)]were measured and compared among the groups by using one-way analysis of variance or Kruskal-Wallis H test. Results: The CT dose index volume (CTDIvol) decreased with the increasing of preset ASIR-V. The effective radiation dose (ED) was significant different among groups (F=27.598, P<0.05), and the ED of group B-F dropped by 10.8%, 21.7%, 31.2%, 44.9% and 61.9% respectively when compared with that in group A. Group E showed the optimal image quality (Z=18.675, 27.548, 19.761, all P<0.05) and diagnosis confidence(Z=21.387, 17.693, 22.459, all P<0.05) in plain scan, AP and PVP phases. There was no significant differences in image noise and CT value of liver, pancreas and muscle among groups (F=1.468, 0.337, 0.592, 0.284, all P>0.05). There were significant differences in CNRs in liver and portal vein in PVP phase among the groups (F=3.980, 4.681, both P<0.05). Conclusion: In abdominal CT, 40% preset ASIR-V can provides the best image quality and it can reduce radiation dose for 44.9%. PMID- 29534408 TI - [Chinese expert consensus on tetanus immunization]. AB - Tetanus is an acute specific infection caused by obligate anaerobes, which is still a serious public health problem. Tetanus bacterium is an obligate anaerobic bacterium, widely distributed in nature, which can exist in dust, soil, human or animal excrement. The bacteria invade the body primarily through the skin or mucosal wounds, and most commonly in trauma and burn patients, unclean newborns, and unsafe surgical instruments. Exotoxin produced by tetanus bacteria can cause temporary changes in the central nervous system, manifested as systemic skeletal muscle persistence and paroxysmal spasm, severe cases of laryngospasm, asphyxia, lung infections and organ failure, which is a very serious and potentially fatal disease. This article is an expert consensus on the tetanus immunologic defense, aiming to aid the clinical decision making after open injury. According to epidemiological investigation of tetanus, types of injured population, wound exposure and misunderstandings of immunologic defense, the key measures to prevent tetanus are good wound management and immunization. This statement describes a preventive framework of tetanus immunization, including the tetanus immunization programs of infants, pregnant women, potentially high-risk population, immunodeficiency patients and children born to HIV-infected mothers. This consensus only provides academic guidance, the treatment of the patient must be based on the prevailing medical conditions. PMID- 29534409 TI - [The expert consensus on clinical application of multi-trace elements]. AB - Trace elements are dietary elements which are needed in very minute quantities for the proper growth, development, and physiology of the organism, which play a crucial part in energy metabolism and material transformation. It's generally agreed that trace elements are essential components of parenteral nutrition. These societies for parenteral and enteral nutrition in Europe, the United States and Australia proposed that various trace elements should be provided daily from commencement for all patients receiving parenteral nutrition and published some guidelines on adult trace elements recommendations for parenteral nutrition. This consensus is commissioned by the Chinese Society for Parenteral and Enteral Nutrition, based on the principles of evidence-based medicine. This consensus summarizes the latest available evidence and refers to some recommendations in guidelines both at home and abroad. The detailed evidence-based recommendations include the recommended dose for trace elements supplement of parenteral nutrition by international societies, severe traumatic and perioperative patients, critically ill patients and major burns, cancer patients, liver disease patients, pediatric patients and other parts. The goal is to provide guidance and advice about the supplement of trace elements for patients receiving parenteral nutrition. PMID- 29534410 TI - [Comparison of external fixation with or without limited internal fixation for open knee fractures]. AB - Objective: To explore the characteristics and methods of different fixation methods and prevention of open knee joint fracture. Methods: The data of 86 cases of open knee joint fracture admitted from January 2002 to December 2015 in Department of Orthopaedics, Affiliated Hospital of Chengdu University were analyzed retrospectively.There were 65 males and 21 females aged of 38.6 years. There were 38 cases treated with trans articular external fixation alone, 48 cases were in the trans articular external fixation plus auxiliary limited internal fixation group. All the patients were treated according to the same three stages except for different fixation methods. Observation of external fixation and fracture fixation, fracture healing, wound healing and treatment, treatment and related factors of infection control and knee function recovery. chi(2) test was used to analyze data. Results: Eleven patients had primary wound healing, accounting for 12.8%. Seventy-five patients had two wounds healed, accounting for 87.2%. Only 38 cases of trans articular external fixator group had 31 cases of articular surface reduction, accounting for 81.6%; Five cases of trans articular external fixator assisted limited internal fixation group had 5 cases of poor reduction, accounting for 10.4%; There was significant difference between the two groups (chi(2)=44.132, P<0.05). Take a single cross joint external fixation group, a total of 23 cases of patients with infection, accounted for 60.5% of external fixation group; trans articular external fixation assisted limited internal fixation group there were 30 cases of patients with infection, accounting for the assistance of external fixator and limited internal fixation group 62.5%; There was significant difference between the two groups(chi(2)=0.035, P>0.05). Five cases of fracture nonunion cases of serious infection, patients voluntarily underwent amputation. The Lysholm Knee Scale: In the external fixation group, 23 cases were less than 50 points, accounting for 60.5%, 15 cases were more than 50 points, accounting for 39.5%, external fixation and limited internal fixation group 20 cases were less than 50 points, accounting for 41.7%, 28 cases were more than 50 points, accounting for 58.3%; There was significant difference between the two groups(chi(2)=1.279, P>0.05). Conclusions: Prevention and control of infection is a central link in the treatment of open fracture of the knee. Trans articular external fixator plus limited internal fixation is an important measure to treat open fracture of the knee-joint. PMID- 29534411 TI - [Operative strategy and clinical results of complex four part distal radius fractures by combined palmar and dorsal internal fixation]. AB - Objective: To explore a standard procedure for the treatment of combined dorsal and palmar internal fixation for complex four part distal radius fractures and assess its clinical results. Methods: From May 2009 to October 2016, 38 patients(39 sides)who suffered from complex four part distal radius fractures were performed operatively with open reduction and internal fixation via combined dorsal and palmar approach in Department of Orthopaedic Trauma, Qilu Hospital of Shandong University(Qingdao). The series included 22 males(22 sides) and 16 females(17 sides). Age of the patients was 53.5 years ranging from 25 to 79 years.According to Melone classification, there were 34 sides of type of IV, 5 of type V.According to Frykman classification, there were 15 sides of type VII, 24 sides of type VIII, and all the cases were type C3 according to AO/OTA classification.Preoperatively, the key articular fragments in four part distal radius fractures were identified and the individual fracture patterns from conventional X-ray and CT-scan were analyzed. All the patients were performed combined volar and dorsal fixation.Firstly, a palmar approach which gave access to and fix the palmar-ulnar fragment and the radial styloid fragment was performed.Then a limited dorsal approach across the third extensor compartment which gave access to the dorso-ulnar fragment and a limited dorsal arthrotomy to visualize the radiocarpal joint when necessary were performed.Through dorsal approach, we can address the dorso-ulnar fragment, free intra-articular fragment and direct visualize the joint.Use of a retinacular flap was routinely advocated to help prevent against tendon irritation and rupture.The follow-up control included conventional X-ray, range of motion(ROM), grip strength, and the disabilities of the arm, shoulder and hand index(DASH), as well as the patient rated wrist evaluation(PRWE) score for functional outcome at 6 and 12 months. Results: Thirty-three patients(34 sides) were followed up for at least 12 months.The would healed well in all cases 2 weeks postoperatively, and no soft tissue infections, necrosis or neurovascular complications occurred.All the fractures of 38 cases(39 sides)healed averaged 3.6 months(ranging from 2.5-5.7 months), and no loss of reduction occurred postoperatively.Anatomic reconstruction with a step or gap of <1 mm was achieved in 37 cases(38 sides), Whereas 5 patients were lost to follow-up at 12 months postoperatively.ROM and grip strength were all recovered to over 85% of the unaffected side(exception of the bilateral patient). Median DASH-index and PRWE were 6.5(0-17) and 9.3(0 20)respectively. Conclusion: Combined volar and dorsal approaches allow achieving anatomic reconstruction in complex four part intra-articular distal radius fractures and reveal good functional outcomes at intermediate follow-up. PMID- 29534412 TI - [Revision of Schatzker type VI tibial plateau fracture failure focus on the recovery of lower limb alignment]. AB - Objective: To explore the influence of the lower extremity abnormal alignment and the joint surface, and to explore the surgical skills. Methods: Twenty-two cases of tibial plateau Schatzker VI fracture internal fixation failure revision from January 2012 to January 2017 in Department of Orthopedics, Shanghai 10(th) Hospital.One year follow-up after initial surgery to make sure of failure.Three dimensional CT scan, radiography, infection index, gait analysis, knee joint ROM, femur tibia angle, tibial plateau tibial shaft angle and posterior slope if tibial plateau were observed. The medial approach and bi-planer osteotoma were used.Autogenous iliac bone graft, postoperative fast recovery channel were used.Follow-up point included preoperative and postoperative 7 days, 6 weeks, 3 months, and 6 months.Obvervational index included double lower limbs radiography, knee society score(KSS), complications such as infection, skin necrosis, joint main passive activity, double lower limbs alignment the last follow-up SF-36 scale.Rate was compared by chi(2) test, measurement data using paired sample t test.Correlation was analyzed by Pearson correlation regression testing. Results: Twenty-two patients received follow-up.KSS, more than 21 cases were benign, with good gait.One case was poor, with claudication gait.Not skin necrosis, no deep infection cases, 1 case get blisters 2 days postoperatively, and disappear after 5 days with detumescence and cold therapy.Whether restoring force line affect the KSS significantly(chi(2)=22.000, P=0.000). Knee joint ROM, SF-36 score, KSS and lower limb alignment were improved significantly. In different individual the articular surface and anatomical angle recovered greatly but the posterior slope angle was quite difference which has no correlation with KSS and SF-36 scale(P>0.01). Conclusions: Revision of Schatzker type VI tibial plateau fracture failure should focus on the recovery of lower limb alignment.moderate overcorrect bone cutting and joint surface height can bring benefits to the postoperative knee function.Revision surgery patients have greater psychological pressure, more early psychological intervention is necessary. PMID- 29534413 TI - [Operative treatment of delayed acetabular fractures through combined anterior and Kocher-Langenbeck approaches]. AB - Objective: To discuss the clinical outcomes of treating delayed acetabular fractures by combined anterior and posterior approach. Methods: A retrospective analysis was conducted of 31 delayed acetabular fractures from February 2012 to February 2017 in the First Affiliated Hospital of Chongqing Medical University, including 18 males and 13 females with age of 48.5 years(23 to 67 years) .The injury to the operation time was 35.9 days(22 to 183 days). Of these 31 cases, there were 6 cases of transverse and posterior wall fracture, 8 cases with anterior column+ posterior half transverse fracture, 12 cases with double column fracture and 5 cases of "T" type fracture according to Letournel-Judet classification.All fractures were treated combined anterior and Kocher-Langenbeck approaches, including 13 cases of ilioinguinal approach+ Kocher-Langenbeck(K-L approach), 4 cases of extensile acetabular approach, 7 cases of stoppa approach + K-L approach and 7 cases of side rectus femoris approach.Correlation was analyzed by Pearson correlation regression testing. Results: Follow up to August 2017, all patients were followed up with 36.0 months(from 6 to 55 months). As calculated, the restorational effect was positively with result of the X-ray film and the clinical effect(r=0.823, 0.856; both P<0.05). The evaluation was conducted with Matta's reduction criteria: there were 11 cases classified as anatomic reduction(35.5%), 13 cases as satisfactory reduction(41.9%), and 7 cases as unsatisfactory reduction(22.6%). Excellent and good rate was 77.4%. Functional reductions were categorized by the standard of Matta hip score: 8 excellent cases(25.8%), 11 good cases(35.5%), 8 fail cases(25.8%), and 4 poor cases(12.9%). Conclusion: The treatment of delayed acetabular fracture by combined anterior and posterior approach can fully exposure the anterior and posterior acetabular fcloumns, which is beneficial to the release and fixation of the old acetabular fractures. PMID- 29534414 TI - [Three-dimensional computed tomography analysis and clinical application of sacroiliac screw placement]. AB - Objective: To evaluate the possibility of transverse sacroiliac screw placement in different segments of the sacrum. Methods: Data of 80 pelvic CT scans (slice thickness <=1.0 mm) archived in CT department of the Third Hospital of Hebei Medical University from September 2016 to October 2017 were retrospectively collected. Mimics software was used to rebuild the pelvis three-dimensional model. According to whether the sacral 1(S(1)) segment could place the transverse sacroiliac screws or not, all the sacrums were divided into normal group (n=55) and dysmorphic group (n=25). Simulation the S(1), sacral 2(S(2)) transverse sacroiliac screw placement in 3-Matic software. Analysis whether there was any difference in maximum diameter and length of S(2) transverse sacroiliac screw between the normal group and the dysmorphic group. The pelvic CT data of the dysmorphic group were measured, and the optimal tilt angle and length of the oblique S(1) screw were obtained. The feasibility of transverse sacroiliac screw insertion in sacral 3(S(3)) segment was evaluated.t-test, rank sum test, and chi(2) test was used to analyze data, respectively. Results: In the dysmorphic group, the largest diameter of the S(1) transverse screw was (4.9+/-1.6)mm, and the normal group was (13.6+/-3.6)mm (t=-15.07, P=0.00). In the dysmorphic group, the largest diameter of S(2) transverse screw was (13.8+/-3.0)mm, and was (12.4+/ 2.2)mm in the normal group(t=2.11, P=0.04). There was no significant difference in the length of S(2) transverse sacroiliac screw between the two groups (t=0.47, P=0.64). In the dysmorphic group, the anterior vertebral height of S(1) was (23.1+/-4.0)mm, which was significantly higher than that of the normal group ((14.1+/-4.2)mm)(t=9.01, P=0.00). The angle of S(1)S(2) in the dysmorphic group was 10.9 degrees (3.8 degrees , 17.6 degrees ), which was significantly larger than that of the normal group (2.0 degrees (1.0 degrees , 2.0 degrees ) (Z=-4.03, P=0.00). In the dysmorphic group, the incline angle of the oblique S(1) sacroiliac screw was (35.6+/-6.2) degrees , the anteversion angle was (37.2+/ 4.4) degrees , and the mean screw length was (90.2+/-4.7)mm. In the dysmorphic group, the placement rate of S(3) transverse sacroiliac screw was 48.0%, and that of the normal sacral group was 9.1%. Conclusions: There is often dysmorphic in the sacrum in patients with large S(1) anterior vertebral height and S(1)S(2) angle. Sacral dysmorphic patients with posterior pelvic ring injury may be treated with S(1) pedicle oblique sacroiliac screws. S(3) transverse sacroiliac screws should be carefully placed, especially for the absence of sacral dysmorphic in patients. PMID- 29534415 TI - [Outcome of traditional growing rods for correction of apical vertebra rotation in early-onset scoliosis]. AB - Objective: To evaluate the correction result of traditional dual growing rods on apical vertebral rotation. Methods: This study recruited 19 early-onset scoliosis patients (6 boys and 13 girls) who had received traditional dual growing rods treatment at Department of Spine Surgery, Nanjing Drum Tower Hospital from January 2009 to July 2015. The age at initial surgery was (5.7+/-1.7)years(range, 3 to 9 years). Measurements of primary curve magnitude, height of T(1)-S(1), apical vertebral translation(AVR), apical vertebral body-rib ratio, apical vertebral rotation, thoracic rotation and rib hump were compared between pre operatively, post-operatively, and at latest follow-up, through a paired-t test. Pearson correlation test was used for correlation analysis between parameters. Results: All patients had a follow-up of (49.5+/-12.8)months(range, 24 to 71 months). A total of 111 operative procedures were performed, among which there were 92 lengthening procedures, averagely 4.8 lengthening procedures per patient. The average interval for each lengthening procedure was 10 months. The Cobb angle of primary curve was notably decreased from (66.5+/-13.2) degrees to (35.2+/ 10.9) degrees (t=24.013, P<0.01), and no significant correction loss was found at the latest follow-up ((36.7+/-10.7) degrees )(t=-1.324, P=0.202). In addition, significant correction of AVR, thoracic rotation, apical vertebral translation, apical vertebra body-rib ratio, and rib hump were noted after initial surgery. Whereas, these parameters significant increased during follow-up(all P <0.05) except for thoracic rotation. Pearson correlation analysis showed that the increase of AVR during follow-up significantly correlated with change of apical vertebra translation, apical vertebral body-rib ratio, and rib hump(r=0.652, 0.814, 0.695; all P<0.05). Conclusions: Significant correction of AVR can be achieved after initial surgery in early-onset scoliosis patients treated with traditional dual growing rods. However, such a technique can hardly prevent the deterioration of AVR during follow-up. PMID- 29534416 TI - [Laparoscopic radical antegrade modular pancreatosplenectomy for left-sided pancreatic adenocarcinoma: analysis of 12 cases]. AB - Objective: To evaluate the safety and feasibility of laparoscopic radical antegrade modular pancreatosplenectomy(Lap-RAMPS) for left-sided pancreatic adenocarcinoma. Methods: Clinical data of total 12 patients underwent Lap-RAMPS for left-sided pancreatic adenocarcinoma at Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital from March 2016 to August 2017 were reviewed retrospectively.There were 7 male patients and 5 female patients, with median age of 60.5 years old(47-68 years old). Abdominal enhanced CT, pancreatic MRI, PET-CT were performed on all patients to evaluate the lesion and exclude metastasis.Follow-up were done with out-patient clinic or telephone consultancy until October 2017. Results: All patients underwent pure Lap RAMPS.The medium operative time was 250 minutes(180-445 minutes), and the blood loss was 150 ml(50-500 ml). The medium first flatus time and diet resumption time were 3.0 days(1-5 days) and 3.5 days(1-7 days) respectively.The medium postoperative hospital stay was 9 days(4-18 days). Morbidity occurred in 8 patients with gastric empty delay(n=1), bleeding(n=1), fluid collection(n=3). There was no mortality.The medium overall number of retrived lymph nodes was 15.6 and the positive rate was 41.7%. The R0 rate was 100%.The medium follow-up was 10 months.One patient was diagnosed as liver metastasis after 8 months and accepted chemotherapy.One patient died after 14 months for tumor recurrence and metastasis.Others survived without tumor recurrence or metasitasis. Conclusion: Lap-RAMPS is safe and feasible with accepted oncological outcomes for selected left side pancreatic adenocarcinoma under skilled hands. PMID- 29534417 TI - [End-to-side anastomosis for interrupted aortic arch in neonates and infants]. AB - Objective: To review the early and mid-term results of end-to-side anastomosis technique for interrupted aortic arch in neonates and infants. Methods: Clinic data of 46 patients were diagnosed as interrupted aortic arch in Department of Cardiac Surgery, Guangzhou Women and Children's Medical Center between January 2010 and December 2016 were analyzed retrospectively. Twenty-six cases were neonates. The median age underwent surgery was 23 days (range: 2 days to 8 years). Anatomical subtypes included 36 cases of type A and 10 cases of type B. There was no type C case. The reconstruction of the aortic arch was completed by an extended end-to-side anastomosis technique between the descending aorta and the undersurface of the proximal aortic arch. In 42 patients, all with intracardiac anomalies, had concomitant complete repair of intracardiac anomalies through a median sternotomy. The remaining 4 patients, all without intracardiac anomalies, an end-to-side anastomosis was constructed through a left thoracotomy. During follow-up, aortic arch recurrent obstruction, left ventricular outflow tract obstruction (LVOTO) and tracheal stenosis were focused. Results: There were 3 surgical deaths, with amortality rate of 6.5%. The remaining 43 patients survived after surgery. In 39 of these patients, deep hypothermic cardiac arrest (DHCA) strategy was used for brain protection, and the mean time of DHCA was (16+/-3) minutes. Eight patients underwent delayed sternal closure. The mean mechanical ventilation time and ICU stay time were (3.4+/-1.6) days (range: 2 to 12 days) and (6.4+/-2.7) days (range: 3 to 16 days) respectively. In 16 patients, all with tracheal or bronchial stenosis before surgery, mechanical ventilation was successfully evacuated, and no new airway stenosis occurred. There was no residual pressure difference between upper and lower extremity arterial blood pressure at discharge. Echocardiography showed normal arterial blood flow velocity in aortic arch. At a mean follow-up of (36.2+/-18.9) months (range: 6 months to 7 years), there were two patients lost and one late date. Four patients developed a recurrent stenosis at the aortic arch, of which two were severe, and the other two were mild. In 2 patients, both with mild LVOTO before surgery, no significant increase in the degree of obstruction was found during the follow-up. Two patients developed new mild to moderate LVOTO without clinical symptoms, and continued to follow up. In all patients, the tracheal or bronchial stenosis were extenuated, and there was no new progressive airway stenosis by regular bronchoscopy. Conclusions: The end-to-side anastomosis technique for the reconstruction of the aortic arch achieved excellent early and mid-term results in neonates and infants suffered from interrupted aortic arch. Reducing the anastomotic tension by extensive mobilization is the key to prevent postoperative early complications and late recurrent arch obstruction. PMID- 29534418 TI - [Application of narrow-band imaging flexible ureteroscopy in the diagnosis, treatment and follow-up of upper tract urothelial carcinomas]. AB - Objective: To investigate application value of narrow-band imaging (NBI) flexible ureteroscopy in the diagnosis, treatment and follow-up of upper urinary tract transitional carcinomas (UTUC). Methods: From June 2015 to June 2017, 16 patients of UTUC were treated by flexible ureteroscopy with white light (WLI) and NBI at Department of Urology, Peking University Third Hospital , including 10 females and 6 males. The age of patients ranged from 43 to 84 years (average 68.9 years). There were 54 cases, including 16 cases with first-suspicion of cancer, and 38 cases with known of UTUC as follow-up. Full renal collecting system examination was performed first under WLI and then under NBI by a single urologist, using the URF-V digital flexible ureteroscope. Then number of tumors visualized by WLI and NBI flexible ureteroscopy were imaged, recorded, and then biopsied or subsequently treated by holmium laser resection with pathological examination. The diagnosis results of NBI flexible ureteroscopy were compared with WLI flexible ureteroscopy results. All the patients underwent 2(nd)-look ureteroscopy after 4 to 6 weeks since the first ureteroscopy, and after that follow-up flexible ureteroscopy was every 6 months. Results: All the operations of 54 cases were successful. One case was treated with flexible ureteroscopy and percutaneous nephroscopy to treat the renal pelvis tumors, duo to the multiple and much larger tumors. Subjectively, NBI significantly provided a much clearer view of the tumors, especially their limits and vascular architecture. Objectively, 4 additional tumors (11.5%), as well the extended limits of 3 tumors (8.5%) were detected by NBI when findings by WLI were considered normal. The rate of diagnosis of tumors raised 20.0%. Conclusions: Compared with WLI, NBI flexible ureteroscopy provided even more image of UTUC especially their border between tumor tissue and normal tissue. NBI improved the detection of UTUC over standard WLI with higher rate of diagnosis or lower rate of missed diagnosis. PMID- 29534419 TI - [Clinical features analysis of metanephric adenoma: a series of 16 cases]. AB - Objective: To study the clinical characteristics, image findings, therapeutic method and prognosis of metanephric adenoma. Method: The clinical characteristic, image findings, operation methods and prognosis of 16 metanephric adenoma patients treated at Department of Urology, Peking University First Hospital from January 2004 to March 2016 were analyzed retrospectively. Results: There were 6 male and 10 female patients in the study. The mean age of patients was 33.7 years (ranging from 14 to 83 years). Two patients came to the hospital because of fever, while other 14 patients had no symptoms and found renal tumor by medical examination. One case was found polythemia vera and another 1 case showed mild anemia. Serum creatine of all the cases were in normal range. The tumor of 11 cases were at left side and 5 cases were at right. All patients took urinary tract ultrasound. Fifteen patients took CT examination. Among them, 14 cases were solid mass and 1 case was cystosolid.CT value was (41+/-4) HU. CT scan showed that the tumor was slight enhanced and CT value increased to (77+/-9) HU. Six patients took MRI examination. The MRI showed high or low signal of T1WI or T2WI scans.Tumor size was (4.7+/-3.9)cm (ranging from 1.7 to 17.5 cm). All 16 patients took operation and 11 of them took laparoscopic surgery while the other 5 cases took open surgery. Eleven cases took partial nephrectomy, 4 cases took nephrectomy and 1 case took nephroureterectomy. The surgical procedures were all successful and no complications occured during perioperative period. All cases were all confirmed metanephric adenoma by postoperative pathology and surgery cut edge were all negative. Immunohistochemical study showed that the positive rate of Vimentin, CD57, AE1/AE3, WT1, CK7 and AMACR respectively were 16/16, 15/16, 12/16, 10/16, 3/16 and 2/16. The median follow-up time of 16 cases was 44 months (ranging from 8 to 125 months) and none had recurrence or metastasis.One case died 125 months after surgery because of advanced age(83 years old). Conclusions: Metanephric adenoma is difficult to be diagnosed relying on clinical characteristics and image features. Pathology can help confirm the diagnosis. Partial nephrectomy is the first choice for operation and can achieve good prognosis. But it still needs a regular follow-up. PMID- 29534420 TI - [Implement of multimodal navigation-based virtual reality in the needle biopsy of intracranial eloquent lesions]. AB - Objective: To investigate the clinical value of multimodal navigation-based virtual reality (MNVR) in the needle biopsy of intracranial eloquent lesions. Methods: From January 2016 to January 2017, 20 patients with intracranial deep seated lesions involving eloquent brain areas underwent MNVR-aided needle biopsy at Department of Neurosurgery, People's Liberation Army General Hospital. Preoperatively, MNVR was used to propose and revise the biopsy planning. Intraoperatively, navigation helped trajectory avoid the eloquent structures. Intraoperative MRI (iMRI) was performed to prove the biopsy accuracy and detect the intraoperative complications. Perioperative neurological status, iMRI findings, intraoprative complications, surgical outcome and pathological diagnosis were recorded. Wilcoxon rank-sum test was conducted to compare the preoperative and postoperative neurological scores. Results: MNVR helped revised 45%(9/20) initial biopsy trajectories, which would probably injury the nearby eloquent structures. Navigation helped biopsy trajectories spare the eloquent structures during the operation. No statistical difference was found between postoperative and preoperative neurological status, despite all the lesions were adjacent to eloquent areas. Additionally, 20 patients totally received 21 iMRI scanning. iMRI helped revise incorrect biopsy site in one case and detected intraoperative hemorrhage in another case, both of cases were treated immediately and effectively. No MNVR related adverse events and complications occurred. Conclusions: MNVR-aided needle biopsy of intracranial eloquent lesions is a safe, novel and efficient biopsy modality. This technique is helpful to reduce the incidence of surgery related neurological deficits. PMID- 29534421 TI - [Research advances in anatomical study on the diffusion routs of acute pancreatitis]. AB - The retroperitoneum space comprises anterior pararenal space, perirenal space and posterior pararenal space. Pancreas is a retroperitoneal organ and located in the anterior pararenal space of the retroperitoneum. Left and right sides anterior pararenal space are potentially communicated, which contains many adipose tissues and a little connective tissues. The exacerbation of acute pancreatitis results in the lesion spreading into adjacent area of pancreas in the retroperitoneal space. In addition, the lesion could spread into bare area of stomach, posterior colonic region, subperitoneal space and pelvic retroperitoneal space through the same anatomical space or communicating space. Due to the fascia destruction by pancreatic enzymes or the lesion directly diffuse through the weak fascia, the lesion could also diffuse across fascia to perirenal space, posterior pararenal space, the peritoneal cavity and abdominal wall. Finally, a series of complications are developed. The diffusion paths of acute pancreatitis are complex and diverse. Familiarity with these diffusion paths is useful for determining the severity and guiding therapy. PMID- 29534422 TI - Retraction notice to "Size distribution and sources of 37 toxic species of particulate polycyclic aromatic hydrocarbons during summer and winter in Baoshan suburban area of Shanghai, China" [STOTEN_566-567C (2016) 1519 - 1534]. PMID- 29534423 TI - G Protein alpha Subunit GpaB is Required for Asexual Development, Aflatoxin Biosynthesis and Pathogenicity by Regulating cAMP Signaling in Aspergillus flavus. AB - The heterotrimeric G proteins are critical for signal transduction and function in numerous biological processes including vegetative growth, asexual development and fungal virulence in fungi. Here, we identified four G protein alpha subunits (GanA, GpaB, FadA and GaoC) in the notorious Aflatoxin-producing fungus Aspergillus flavus. GanA, GpaB and FadA have homologues in other fungal species, while GaoC is a novel one. Here, we showed that the loss function of gpaB displayed a defect in conidiophore formation and considerably reduced expression levels of conidia-specific genes brlA and abaA. A decreased viability of cell wall integrity stress and oxidative stress were also found in the ?gpaB mutant. More importantly, aflatoxin (AF) biosynthesis and infection on crop seeds were severely impaired in the gpaB-deficient mutant. Further analyses demonstrated that the intracellular cAMP levels significantly reduced in the gpaB-deficient mutant compared to wildtype strains. Additionally, an alteration of PKA activities in the ?gpaB mutant was also found. Overall, our results indicated that GpaB played diverse roles in asexual sporulation, AF biosynthesis and virulence by regulating cAMP signaling in Aspergillus flavus. PMID- 29534424 TI - Together Forever: Bacterial-Viral Interactions in Infection and Immunity. AB - Most viruses first encounter host cells at mucosal surfaces, which are typically colonized by a complex ecosystem of microbes collectively referred to as the microbiota. Recent studies demonstrate the microbiota plays an important role in mediating host-viral interactions and determining the outcomes of these encounters. This review outlines recently described examples of how bacteria and viruses impact each other particularly during infectious processes. Mechanistically, these effects can be broadly categorized as reflecting direct bacterial-viral interactions and/or involving microbial impacts upon innate and/or adaptive immunity. PMID- 29534425 TI - Potentially Important Therapeutic Interactions between Antibiotics, and a Specially Engineered Emulsion Drug Vehicle Containing Krill-Oil-Based Phospholipids and Omega-3 Fatty Acids. AB - The incidence of antimicrobial resistance (AMR) worldwide is increasing as the pipeline for the development of new chemotherapeutic entities is decreasing. Clearly, overexposure to antibiotics, including excessive dosing, is a key factor that fuels AMR. In fact, most of the new antibacterial agents under development are derivatives of existing classes of antibiotics. Novel approaches involving unique antimicrobial combinations, targets, and/or delivery systems are under intense investigation. An innovative combination of active pharmaceutical ingredients (APIs) consisting of antimicrobial drug(s), krill-oil-based phospholipids, and omega-3 fatty acid triglycerides, that may extend the therapeutic viability of currently effective antibiotics, at least until new chemical entities are introduced, is described. PMID- 29534426 TI - Preparation and Characterization of WS2@SiO2 and WS2@PANI Core-Shell Nanocomposites. AB - Two tungsten disulfide (WS2)-based core-shell nanocomposites were fabricated using readily available reagents and simple procedures. The surface was pre treated with a surfactant couple in a layer-by-layer approach, enabling good dispersion of the WS2 nanostructures in aqueous media and providing a template for the polymerization of a silica (SiO2) shell. After a Stober-like reaction, a conformal silica coating was achieved. Inspired by the resulting nanocomposite, a second one was prepared by reacting the surfactant-modified WS2 nanostructures with aniline and an oxidizing agent in an aqueous medium. Here too, a conformal coating of polyaniline (PANI) was obtained, giving a WS2@PANI nanocomposite. Both nanocomposites were analyzed by electron microscopy, energy dispersive X-ray spectroscopy (EDS) and FTIR, verifying the core-shell structure and the character of shells. The silica shell was amorphous and mesoporous and the surface area of the composite increases with shell thickness. Polyaniline shells slightly differ in their morphologies dependent on the acid used in the polymerization process and are amorphous like the silica shell. Electron paramagnetic resonance (EPR) spectroscopy of the WS2@PANI nanocomposite showed variation between bulk PANI and the PANI shell. These two nanocomposites have great potential to expand the use of transition metals dichalcogenides (TMDCs) for new applications in different fields. PMID- 29534428 TI - EU Regulatory Risk Management of Marine Biotoxins in the Marine Bivalve Mollusc Food-Chain. AB - Food safety risk assessment in the European Union (EU) recognises consumer illness that arises from marine biotoxins as a risk associated with bivalve mollusc consumption. EU food regulations contain various general food safety obligations, which should contribute significantly to managing this risk. EU food regulations additionally impose various specific obligations on both Food Business Operators and Competent Authorities in order to manage the marine biotoxin food safety risk in the bivalve mollusc food-chain. These have a particular focus on the pre-harvest component of the food-chain. A central component of these specific systems is the requirement for ongoing monitoring of phytoplankton and biotoxin concentrations in water and molluscs, respectively. This monitoring explicitly brings a potential outcome of closing production areas delineated by classification to prohibit the harvest of bivalve molluscs as food from those areas when acceptable biotoxin concentrations are exceeded. This review considers the utility of these systems, at conceptual and practical levels, and explores their contribution to an effective regulatory risk management approach. PMID- 29534427 TI - Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells. AB - Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among all the different immunocytes involved in T1D etiopathogenesis, a relevant role of natural killer cells (NKs) is currently emerging. NKs represent the interface between innate and adaptive immunity; they intervene in the defense against infections and present, at the same time, typical features of the adaptive immune cells, such as expansion and generation of memory cells. Several recent studies, performed both in animal models and in human diabetic patients, revealed aberrations in NK cell frequency and functionality in the peripheral blood and in damaged tissues, suggesting their possible redirection towards affected tissues. NKs oscillate from a quiescent to an activated state through a delicate balance of activating and inhibitory signals transduced via surface receptors. Further accurate investigations are needed to elucidate the exact role of NKs in T1D, in order to develop novel immune-based therapies able to reduce the disease risk or delay its onset. PMID- 29534429 TI - Accidents of Electrical and Mechanical Works for Public Sector Projects in Hong Kong. AB - A study on electrical and mechanical (E&M) works-related accidents for public sector projects provided the opportunity to gain a better understanding of the causes of accidents by analyzing the circumstances of all E&M works accidents. The research aims to examine accidents of E&M works which happened in public sector projects. A total of 421 E&M works-related accidents in the "Public Works Programme Construction Site Safety and Environmental Statistics" (PCSES) system were extracted for analysis. Two-step cluster analysis was conducted to classify the E&M accidents into different groups. The results identified three E&M accidents groups: (1) electricians with over 15 years of experience were prone to 'fall of person from height'; (2) electricians with zero to five years of experience were prone to 'slip, trip or fall on same level'; (3) air-conditioning workers with zero to five years of experience were prone to multiple types of accidents. Practical measures were recommended for each specific cluster group to avoid recurrence of similar accidents. The accident analysis would be vital for industry practitioners to enhance the safety performance of public sector projects. This study contributes to filling the knowledge gap of how and why E&M accidents occur and promulgating preventive measures for E&M accidents which have been under researched. PMID- 29534430 TI - Transcriptome Analysis of a Premature Leaf Senescence Mutant of Common Wheat (Triticum aestivum L.). AB - Leaf senescence is an important agronomic trait that affects both crop yield and quality. In this study, we characterized a premature leaf senescence mutant of wheat (Triticum aestivum L.) obtained by ethylmethane sulfonate (EMS) mutagenesis, named m68. Genetic analysis showed that the leaf senescence phenotype of m68 is controlled by a single recessive nuclear gene. We compared the transcriptome of wheat leaves between the wild type (WT) and the m68 mutant at four time points. Differentially expressed gene (DEG) analysis revealed many genes that were closely related to senescence genes. Gene Ontology (GO) enrichment analysis suggested that transcription factors and protein transport genes might function in the beginning of leaf senescence, while genes that were associated with chlorophyll and carbon metabolism might function in the later stage. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the genes that are involved in plant hormone signal transduction were significantly enriched. Through expression pattern clustering of DEGs, we identified 1012 genes that were induced during senescence, and we found that the WRKY family and zinc finger transcription factors might be more important than other transcription factors in the early stage of leaf senescence. These results will not only support further gene cloning and functional analysis of m68, but also facilitate the study of leaf senescence in wheat. PMID- 29534431 TI - Spatiotemporal Variation in Environmental Vibrio cholerae in an Estuary in Southern Coastal Ecuador. AB - Cholera emergence is strongly linked to local environmental and ecological context. The 1991-2004 pandemic emerged in Peru and spread north into Ecuador's El Oro province, making this a key site for potential re-emergence. Machala, El Oro, is a port city of 250,000 inhabitants, near the Peruvian border. Many livelihoods depend on the estuarine system, from fishing for subsistence and trade, to domestic water use. In 2014, we conducted biweekly sampling for 10 months in five estuarine locations, across a gradient of human use, and ranging from inland to ocean. We measured water-specific environmental variables implicated in cholera growth and persistence: pH, temperature, salinity, and algal concentration, and evaluated samples in five months for pathogenic and non pathogenic Vibrio cholerae, by polymerase chain reaction (PCR). We found environmental persistence of pandemic strains O1 and O139, but no evidence for toxigenic strains. Vibrio cholerae presence was coupled to algal and salinity concentration, and sites exhibited considerable seasonal and spatial heterogeneity. This study indicates that environmental conditions in Machala are optimal for cholera re-emergence, with risk peaking during September, and higher risk near urban periphery low-income communities. This highlights a need for surveillance of this coupled cholera-estuarine system to anticipate potential future cholera outbreaks. PMID- 29534432 TI - Influence of Vitamin C on Lymphocytes: An Overview. AB - Vitamin C or ascorbic acid (AA) is implicated in many biological processes and has been proposed as a supplement for various conditions, including cancer. In this review, we discuss the effects of AA on the development and function of lymphocytes. This is important in the light of cancer treatment, as the immune system needs to regenerate following chemotherapy or stem cell transplantation, while cancer patients are often AA-deficient. We focus on lymphocytes, as these white blood cells are the slowest to restore, rendering patients susceptible to often lethal infections. T lymphocytes mediate cellular immunity and have been most extensively studied in the context of AA biology. In vitro studies demonstrate that T cell development requires AA, while AA also enhances T cell proliferation and may influence T cell function. There are limited and opposing data on the effects of AA on B lymphocytes that mediate humoral immunity. However, AA enhances the proliferation of NK cells, a group of cytotoxic innate lymphocytes. The influence of AA on natural killer (NK) cell function is less clear. In summary, an increasing body of evidence indicates that AA positively influences lymphocyte development and function. Since AA is a safe and cheap nutritional supplement, it is worthwhile to further explore its potential benefits for immune reconstitution of cancer patients treated with immunotoxic drugs. PMID- 29534433 TI - Maternal Consumption of Low-Isoflavone Soy Protein Isolate Confers the Increased Predisposition to Alcoholic Liver Injury in Adult Rat Offspring. AB - Offspring of female rats fed either a casein (CAS) diet or a low-isoflavone soy protein isolate (SPI) diet were compared in an animal model of chronic ethanol consumption to investigate whether maternal diet regulates the adaptive responses of offspring to postnatal ethanol exposure and potentially affects the development of liver disease in later life. Female rats were fed either a CAS or an SPI diet before mating, and during pregnancy and lactation. Male offspring from the same litter were pair-fed either a control or ethanol diet for six weeks (CAS/CON, CAS/EtOH, SPI/CON, and SPI/EtOH groups). Serum aminotransferase activities and hepatic inflammatory indicators were higher in the SPI/EtOH group than in the CAS/EtOH group. Ethanol consumption increased serum homocysteine levels, hepatic S-adenosylmethionine:S-adenosylhomocysteine ratio, and hepatic endoplasmic reticulum stress only in offspring of SPI-fed female rats. Total and high-density lipoprotein (HDL) cholesterol levels and mRNA levels of hepatic genes involved in HDL cholesterol assembly were reduced in the SPI group in response to ethanol consumption. In conclusion, offspring of SPI-fed female rats were more susceptible to the later development of alcoholic liver disease than offspring of CAS-fed female rats. Furthermore, maternal SPI consumption altered one-carbon metabolism and cholesterol metabolism of offspring fed an ethanol diet. PMID- 29534434 TI - Key Hormonal Components Regulate Agronomically Important Traits in Barley. AB - The development and growth of plant organs is regulated by phytohormones, which constitute an important area of plant science. The last decade has seen a rapid increase in the unravelling of the pathways by which phytohormones exert their influence. Phytohormones function as signalling molecules that interact through a complex network to control development traits. They integrate metabolic and developmental events and regulate plant responses to biotic and abiotic stress factors. As such, they influence the yield and quality of crops. Recent studies on barley have emphasised the importance of phytohormones in promoting agronomically important traits such as tillering, plant height, leaf blade area and spike/spikelet development. Understanding the mechanisms of how phytohormones interact may help to modify barley architecture and thereby improve its adaptation and yield. To achieve this goal, extensive functional validation analyses are necessary to better understand the complex dynamics of phytohormone interactions and phytohormone networks that underlie the biological processes. The present review summarises the current knowledge on the crosstalk between phytohormones and their roles in barley development. Furthermore, an overview of how phytohormone modulation may help to improve barley plant architecture is also provided. PMID- 29534435 TI - Synthesis and Biological Evaluation of a New Structural Simplified Analogue of cADPR, a Calcium-Mobilizing Secondary Messenger Firstly Isolated from Sea Urchin Eggs. AB - Herein, we reported on the synthesis of cpIPP, which is a new structurally reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca2+-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the "northern" ribose of cADPR was replaced by a pentyl chain and the pyrophosphate moiety by a phophono-phosphate anhydride. The effect of the presence of the new phosphono-phosphate bridge on the intracellular Ca2+ release induced by cpIPP was assessed in PC12 neuronal cells in comparison with the effect of the pyrophosphate bridge of the structurally related cyclic N1 butylinosine diphosphate analogue (cbIDP), which was previously synthesized in our laboratories, and with that of the linear precursor of cpIPP, which, unexpectedly, revealed to be the only one provided with Ca2+ release properties. PMID- 29534436 TI - "French Phage Network"-Third Meeting Report. AB - In its third year of existence, the French Phage Network (Phages.fr) is pursuing its expansion. With more than 25 groups, mostly based in France, working on the various aspects of phage research, the network has increased its visibility, interactivity, and activity. The third meeting of the Phages.fr network, held on November 2017 at the Gif-sur-Yvette Centre National de la Recherche Scientifique (CNRS) campus, was a great opportunity for many young scientists to present their work and interact with more senior scientists, amongst which several were invited from abroad. Here we provide a summary of the work presented at this occasion during the oral presentations and poster sessions. PMID- 29534437 TI - A National County-Level Assessment of U.S. Nursing Facility Characteristics Associated with Long-Term Exposure to Traffic Pollution in Older Adults. AB - Long-term exposure to ambient air pollution increases disease risk in older adults. Nursing facilities located near major roadways potentially expose older adults to traffic pollution. No studies, however, have described the association between nursing facilities and traffic pollution. We obtained data on facility- and census-tract-level characteristics of 15,706 U.S. facilities from the Medicare Nursing Home Compare datasets. We calculated distance to major roadways and traffic density for each facility. In the contiguous U.S. (as of 2014), 345,792 older adults, about 27% of residents in non-hospital facilities, lived within 150 m major roadways (A1 or A2) in 3876 (28% of sampled) facilities. Nationally, for-profit facilities, high-occupancy facilities, and facilities in census tracts with higher percentages of minorities were more likely to have higher exposure to traffic. Counties in Virginia, New York City, and Rhode Island have the highest percent of residents and facilities near major roads. Nationally, over one-quarter of sampled facilities are located near major roadways. Attributes potentially associated with higher exposure to traffic included "for-profit" and "higher minority census tract". Proximity to major roadways may be an important factor to consider in siting nursing facilities. Our results inform potential intervention strategy at both county and facility level. PMID- 29534438 TI - Expression of TXNIP in Cancer Cells and Regulation by 1,25(OH)2D3: Is It Really the Vitamin D3 Upregulated Protein? AB - Thioredoxin-interacting protein (TXNIP) was originally identified in HL-60 cells as the vitamin D3 upregulated protein 1, and is now known to be involved in diverse cellular processes, such as maintenance of glucose homeostasis, redox balance, and apoptosis. Besides the initial characterization, little is known about if and how 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] induces TXNIP expression. We therefore screened multiple cancerous cell lines of different tissue origins, and observed induction, repression, or no change in TXNIP expression in response to 1,25(OH)2D3. In-depth analyses on HL-60 cells revealed a rapid and transient increase in TXNIP mRNA levels by 1,25(OH)2D3 (3-24 h), followed by a clear reduction at later time points. Furthermore, a strong induction in protein levels was observed only after 96 h of 1,25(OH)2D3 treatment. Induction of TXNIP expression by 1,25(OH)2D3 was found to be dependent on the availability of glucose in the culture medium, as well as the presence of a functional glucose transport system, indicating an inter-dependence of 1,25(OH)2D3 actions and glucose-sensing mechanisms. Moreover, the inhibition of de novo protein synthesis by cycloheximide reduced TXNIP half-life in 24 h, but not in 96 h-1,25(OH)2D3 treated HL-60 cells, demonstrating a possible influence of 1,25(OH)2D3 on TXNIP stability in long-term treatment. PMID- 29534439 TI - Preparation of Well-Dispersed Chitosan/Alginate Hollow Multilayered Microcapsules for Enhanced Cellular Internalization. AB - Hollow multilayered capsules have shown massive potential for being used in the biomedical and biotechnology fields, in applications such as cellular internalization, intracellular trafficking, drug delivery, or tissue engineering. In particular, hollow microcapsules, developed by resorting to porous calcium carbonate sacrificial templates, natural-origin building blocks and the prominent Layer-by-Layer (LbL) technology, have attracted increasing attention owing to their key features. However, these microcapsules revealed a great tendency to aggregate, which represents a major hurdle when aiming for cellular internalization and intracellular therapeutics delivery. Herein, we report the preparation of well-dispersed polysaccharide-based hollow multilayered microcapsules by combining the LbL technique with an optimized purification process. Cationic chitosan (CHT) and anionic alginate (ALG) were chosen as the marine origin polysaccharides due to their biocompatibility and structural similarity to the extracellular matrices of living tissues. Moreover, the inexpensive and highly versatile LbL technology was used to fabricate core-shell microparticles and hollow multilayered microcapsules, with precise control over their composition and physicochemical properties, by repeating the alternate deposition of both materials. The microcapsules' synthesis procedure was optimized to extensively reduce their natural aggregation tendency, as shown by the morphological analysis monitored by advanced microscopy techniques. The well dispersed microcapsules showed an enhanced uptake by fibroblasts, opening new perspectives for cellular internalization. PMID- 29534440 TI - Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies. AB - Recently, thioxanthone derivatives were found to protect cells against toxic P glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1-8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 MUM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (-) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1-8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (-) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P gp and highlight the existence of enantioselectivity in the induction mechanism. PMID- 29534441 TI - Strengthening of Aluminum Wires Treated with A206/Alumina Nanocomposites. AB - This study sought to characterize aluminum nanocomposite wires that were fabricated through a cold-rolling process, having potential applications in TIG (tungsten inert gas) welding of aluminum. A206 (Al-4.5Cu-0.25Mg) master nanocomposites with 5 wt % gammaAl2O3 nanoparticles were first manufactured through a hybrid process combining semi-solid mixing and ultrasonic processing. A206/1 wt % gammaAl2O3 nanocomposites were fabricated by diluting the prepared master nanocomposites with a monolithic A206 alloy, which was then added to a pure aluminum melt. The fabricated Al-gammaAl2O3 nanocomposite billet was cold rolled to produce an Al nanocomposite wire with a 1 mm diameter and a transverse area reduction of 96%. Containing different levels of nanocomposites, the fabricated samples were mechanically and electrically characterized. The results demonstrate a significantly higher strength of the aluminum wires with the nanocomposite addition. Further, the addition of alumina nanoparticles affected the wires' electrical conductivity compared with that of pure aluminum and aluminum-copper alloys. The overall properties of the new material demonstrate that these wires could be an appealing alternative for fillers intended for aluminum welding. PMID- 29534442 TI - Food Sources of Energy and Macronutrient Intakes among Infants from 6 to 12 Months of Age: The Growing Up in Singapore Towards Healthy Outcomes (GUSTO) Study. AB - Adequate nutrition during complementary feeding is important for the growth, development and well-being of children. We aim to examine the energy and macronutrient intake composition and their main food sources in a mother offspring cohort study in Singapore. The diets of infants were assessed by 24 h dietary recalls or food diaries collected from mothers when their offspring were 6 (n = 760), 9 (n = 893) and 12 (n = 907) months of age. Food sources of energy and macronutrients were determined using the population proportion methodology. Energy intakes per day (kcal; mean (standard deviation, SD)) of these infants were 640 (158) at 6 months, 675 (173) at 9 months, and 761 (208) at 12 months. Infant formula, breastmilk and infant cereals were the top three food sources of energy and macronutrient intakes in infants through the period 6 to 12 months. Other main energy and carbohydrate sources at 9 and 12 months of age were rice porridge, infant biscuits and fresh fruits, while fish, red meat and eggs were the other main protein and total fat sources. Breast-fed and mixed-fed infants had a more varied diet as compared to formula-fed infants. Formula-fed infants had consistently higher protein and lower total fat consumption compared to those who were breastfed. An understanding of these main food sources during complementary feeding can inform local dietary recommendations and policies. PMID- 29534443 TI - Microbes a Tool for the Remediation of Organotin Pollution Determined by Static Headspace Gas Chromatography-Mass Spectrometry. AB - Tributyltin (TBT) is one of the most toxic anthropogenic compounds introduced into the marine environment. Despite its global ban in 2008, TBT is still a problem of great concern due to its high affinity for particulate matter, providing a direct and potentially persistent route of entry into benthic sediments. Bioremediation strategies may constitute an alternative approach to conventional physicochemical methods, benefiting from the microorganism's potential to metabolize anthropogenic compounds. In this work, a simple, precise and accurate static headspace gas chromatography method was developed to investigate the ability of TBT degrading microbes in sedimentary microcosms over a period of 120 days. The proposed method was validated for linearity, repeatability, accuracy, specificity, limit of detection and limit of quantification. The method was subsequently successfully applied for the detection and quantification of TBT and degradation compounds in sediment samples on day 0, 30, 60, 90 and 120 of the experiment employing the principles of green chemistry. On day 120 the concentration of TBT remaining in the microcosms ranged between 91.91 ng/g wet wt for the least effective microbial inoculant to 52.73 ng/g wet wt for the most effective microbial inoculant from a starting concentration of 100 ng/g wet wt. PMID- 29534444 TI - Protein Supplementation During or Following a Marathon Run Influences Post Exercise Recovery. AB - The effects of protein supplementation on the ratings of energy/fatigue, muscle soreness [ascending (A) and descending (D) stairs], and serum creatine kinase levels following a marathon run were examined. Variables were compared between recreational male and female runners ingesting carbohydrate + protein (CP) during the run (CPDuring, n = 8) versus those that were consuming carbohydrate (CHODuring,n = 8). In a second study, outcomes were compared between subjects who consumed CP or CHO immediately following exercise [CPPost (n = 4) versus CHOPost (n = 4)]. Magnitude-based inferences revealed no meaningful differences between treatments 24 h post-marathon. At 72 h, recovery [Delta(72 hr-Pre)] was likely improved with CPDuring versus CHODuring, respectively, for Physical Energy (+14 +/- 64 vs -74 +/- 70 mm), Mental Fatigue (-52 +/- 59 vs +1 +/- 11 mm), and Soreness-D (+15 +/- 9 vs +21 +/- 70 mm). In addition, recovery at 72 h was likely very likely improved with CPPost versus CHOPost for Physical Fatigue, Mental Energy, and Soreness-A. Thus, protein supplementation did not meaningfully alter recovery during the initial 24 h following a marathon. However, ratings of energy/fatigue and muscle soreness were improved over 72 h when CP was consumed during exercise, or immediately following the marathon. PMID- 29534445 TI - Strengthening Preparedness for Arbovirus Infections in Mediterranean and Black Sea Countries: A Conceptual Framework to Assess Integrated Surveillance in the Context of the One Health Strategy. AB - In the context of One Health, there is presently an effort to integrate surveillance of human, animal, entomological, and environmental sectors. This aims to strengthen the prevention of, and preparedness against, arbovirus infections, also in the light of environmental and climate changes that could increase the risk of transmission. However, criteria to define integrated surveillance, and to compare different systems, still need to be identified and tested. We conducted a scoping review to identify and examine surveillance systems for West Nile virus (WNV), chikungunya virus (CHKV), dengue virus (DENV), and Rift Valley fever virus (RVFV), which involve human, animal, entomological, and environmental sectors. We analyzed findings using a conceptual framework we developed for this purpose. The review highlights that the criteria proposed in the conceptual framework to describe integrated surveillance are consistently reported in the context of studies and programs related to integrated surveillance of the selected arboviral diseases. These criteria can facilitate the identification and description of operationalized One Health surveillance. PMID- 29534448 TI - Measurements by A LEAP-Based Virtual Glove for the Hand Rehabilitation. AB - Hand rehabilitation is fundamental after stroke or surgery. Traditional rehabilitation requires a therapist and implies high costs, stress for the patient, and subjective evaluation of the therapy effectiveness. Alternative approaches, based on mechanical and tracking-based gloves, can be really effective when used in virtual reality (VR) environments. Mechanical devices are often expensive, cumbersome, patient specific and hand specific, while tracking based devices are not affected by these limitations but, especially if based on a single tracking sensor, could suffer from occlusions. In this paper, the implementation of a multi-sensors approach, the Virtual Glove (VG), based on the simultaneous use of two orthogonal LEAP motion controllers, is described. The VG is calibrated and static positioning measurements are compared with those collected with an accurate spatial positioning system. The positioning error is lower than 6 mm in a cylindrical region of interest of radius 10 cm and height 21 cm. Real-time hand tracking measurements are also performed, analysed and reported. Hand tracking measurements show that VG operated in real-time (60 fps), reduced occlusions, and managed two LEAP sensors correctly, without any temporal and spatial discontinuity when skipping from one sensor to the other. A video demonstrating the good performance of VG is also collected and presented in the Supplementary Materials. Results are promising but further work must be done to allow the calculation of the forces exerted by each finger when constrained by mechanical tools (e.g., peg-boards) and for reducing occlusions when grasping these tools. Although the VG is proposed for rehabilitation purposes, it could also be used for tele-operation of tools and robots, and for other VR applications. PMID- 29534447 TI - Selenides and Diselenides: A Review of Their Anticancer and Chemopreventive Activity. AB - Selenium and selenocompounds have attracted the attention and the efforts of scientists worldwide due to their promising potential applications in cancer prevention and/or treatment. Different organic selenocompounds, with diverse functional groups that contain selenium, have been reported to exhibit anticancer and/or chemopreventive activity. Among them, selenocyanates, selenoureas, selenoesters, selenium-containing heterocycles, selenium nanoparticles, selenides and diselenides have been considered in the search for efficiency in prevention and treatment of cancer and other related diseases. In this review, we focus our attention on the potential applications of selenides and diselenides in cancer prevention and treatment that have been reported so far. The around 80 selenides and diselenides selected herein as representative compounds include promising antioxidant, prooxidant, redox-modulating, chemopreventive, anticancer, cytotoxic and radioprotective compounds, among other activities. The aim of this work is to highlight the possibilities that these novel organic selenocompounds can offer in an effort to contribute to inspire medicinal chemists in their search of new promising derivatives. PMID- 29534449 TI - Gold-Catalyzed Addition of beta-Ketoesters to Alkenes: Influence of Electronic and Steric Effects in the Reaction Outcome. AB - The gold-catalyzed intermolecular hydroalkylation of olefins with beta-ketoesters represents a conceptually attractive and useful synthetic tool; however, it has been scarcely applied, remaining a challenge for chemists. The aim of the current study was to investigate the addition of these 1,3-diketo-compounds to alkenes under gold catalysis conditions, in order to establish the electronic and steric effects of the alkenyl substrates in the reaction outcome. The screening of different catalyst systems and diverse olefins enabled defining the alkenyl requirements and the best reaction conditions to efficiently achieve the coupled products. PMID- 29534446 TI - Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection-The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress. AB - Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (mtDNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating mtDNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of mtDNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage. PMID- 29534450 TI - Integrin Activation: Implications for Axon Regeneration. AB - Integrin activation is essential for creating functional transmembrane receptors capable of inducing downstream cellular effects such as cell migration, cell spreading, neurite outgrowth and axon regeneration. Integrins are bidirectional signalling molecules that mediate their effects by 'inside-out' and 'outside-in' signalling. This review will provide a detailed overview of integrin activation focusing on intracellular activation in neurons and discussing direct implications in the regulation of neurite outgrowth and axon regeneration. PMID- 29534452 TI - An Imaging Surface Plasmon Resonance Biosensor Assay for the Detection of T-2 Toxin and Masked T-2 Toxin-3-Glucoside in Wheat. AB - A sensitive, rapid, and reproducible imaging surface plasmon resonance (iSPR) biosensor assay was developed to detect T-2 toxin and T-2 toxin-3-glucoside (T2 G) in wheat. In this competitive assay, an amplification strategy was used after conjugating a secondary antibody (Ab2) with gold nanoparticles. Wheat samples were extracted with a methanol/water mixture (80:20 v/v), then diluted with an equal volume of primary antibody (Ab1) for analysis. Matrix-matched calibration curves were prepared to determine T-2 toxin and T2-G. Recovery studies were conducted at three spiking levels in blank wheat. Mean recoveries ranged from 86 to 90%, with relative standard deviations for repeatability (RSDr) of less than 6%. Limits of detection were 1.2 ng/mL of T-2 toxin and 0.9 ng/mL of T2-G, equivalent to their levels in wheat, of 48 and 36 ug/kg, respectively. The developed iSPR assay was rapid and provided enough sensitivity for the monitoring of T-2 toxin/T2-G in wheat. This is the first iSPR assay useful for detecting the "masked" T2-G in wheat. PMID- 29534451 TI - Stem Cell-Derived Models of Viral Infections in the Gastrointestinal Tract. AB - Studies on the intestinal epithelial response to viral infection have previously been limited by the absence of in vitro human intestinal models that recapitulate the multicellular complexity of the gastrointestinal tract. Recent technological advances have led to the development of "mini-intestine" models, which mimic the diverse cellular nature and physiological activity of the small intestine. Utilizing adult or embryonic intestinal tissue, enteroid and organoid systems, respectively, represent an opportunity to effectively model cellular differentiation, proliferation, and interactions that are specific to the specialized environment of the intestine. Enteroid and organoid systems represent a significant advantage over traditional in vitro methods because they model the structure and function of the small intestine while also maintaining the genetic identity of the host. These more physiologic models also allow for novel approaches to investigate the interaction of enteric viruses with the gastrointestinal tract, making them ideal to study the complexities of host pathogen interactions in this unique cellular environment. This review aims to provide a summary on the use of human enteroid and organoid systems as models to study virus pathogenesis. PMID- 29534453 TI - Fenugreek (Trigonella Foenum-Graecum) Seed Flour and Diosgenin Preserve Endothelium-Dependent Arterial Relaxation in a Rat Model of Early-Stage Metabolic Syndrome. AB - Fenugreek is a common herb possessing several bioactive components including diosgenin. Here, dietary fenugreek seed flour and diosgenin were evaluated on a model of endothelium-dependent vasorelaxation by abdominal aortas isolated from rats receiving high-fat, high-sugar diet (HFHSD). 60 male Wistar rats were randomized into six groups: (i) negative control getting conventional rat feed regimen; (ii) positive control receiving HFHSD; (iii) a test group fed 2 g/kg bw/day fenugreek seed flour (containing 10 mg/kg bw/day diosgenin) + HFHSD; (iv) three test groups fed 1, 10 and 50 mg/kg bw/day diosgenin + HFHSD. Alimentary treatments were carried out for six weeks. The abdominal aortas were isolated, and 2 mm wide rings were sectioned off and mounted at a resting tension of 10 mN in organ baths containing Krebs solution (36 degrees C) exposed to 95% O2 and 5% CO2. After 60-min incubation, a norepinephrine concentration-response (E/c) curve was generated to determine their half-maximal effective concentration (EC50) value. After 60-min wash-out, a pre-contraction with norepinephrine EC50 was made, followed by an acetylcholine E/c curve. Plasma glutathione levels, glutathione-handling enzyme activities and blood antioxidant capacities were also determined. HFHSD significantly decreased the dilatory response to acetylcholine and increased plasma glutathione levels and these effects were significantly reversed by fenugreek seed flour, 10 and 50 mg/kg bw/day diosgenin. Both fenugreek and diosgenin treatments prevent HFHSD-induced endothelial dysfunction and redox changes. As fenugreek treatment was more effective at lower acetylcholine concentrations than diosgenin treatments, components of fenugreek other than diosgenin may contribute to the beneficial effects of dietary fenugreek seed flour. PMID- 29534454 TI - The Comparative Reproducibility and Validity of a Non-Nutritive Sweetener Food Frequency Questionnaire. AB - In order to better assess non-nutritive sweetener (NNS) consumption, measurement tools with greater utility are needed. The objective of this investigation is to determine the reproducibility and validity of a newly developed NNS food frequency questionnaire (NNS-FFQ) that measures five types of NNS (saccharin, aspartame, acesulfame potassium, sucralose and erythritol). Adult participants (n = 123, 56% female, 75% Caucasian, mean age = 36.8 +/- 16.6) completed the NNS-FFQ twice and had 24-h dietary recalls three times over a two-week study period. Reproducibility between two administrations of the NNS-FFQ was assessed via Bland Altman plots, Spearman's correlations (rs) and paired samples t-tests. Bland Altman plots, Cohen's kappa, Spearman's correlations (rs), and paired samples t tests compared NNS intake between the two methods for validity. For reproducibility analyses, Bland-Altman analyses revealed agreement levels above the 95% acceptance level for total NNS (99.2%), erythritol (99.2%), and aspartame (96.7%). Agreement levels for acesulfame potassium (94.3%), saccharin (94.3%), and sucralose (94.3%) were slightly below the acceptable level. For validity analyses, Bland-Altman analyses revealed agreement levels above the 95% acceptance level for total NNS (95.1%), sucralose (95.9%), saccharin (95.9%), and erythritol (95.1%). Agreement levels for aspartame (94.3%) and acesulfame potassium (92.7%) were slightly below the acceptable level. Although less than desirable agreement was found between the methods for aspartame and acesulfame potassium, some variance was expected due to the habitual nature of the NNS-FFQ as compared to the recent intake reported by recalls. Within the context of this constraint, the NNS-FFQ demonstrates acceptable reproducibility and validity. The NNS-FFQ is a brief questionnaire that could be administered among diverse participants at the individual and population levels to measure habitual NNS intake. PMID- 29534455 TI - Dietary Cadmium Intake and Its Effects on Kidneys. AB - Cadmium (Cd) is a food-chain contaminant that has high rates of soil-to-plant transference. This phenomenon makes dietary Cd intake unavoidable. Although long term Cd intake impacts many organ systems, the kidney has long been considered to be a critical target of its toxicity. This review addresses how measurements of Cd intake levels and its effects on kidneys have traditionally been made. These measurements underpin the derivation of our current toxicity threshold limit and tolerable intake levels for Cd. The metal transporters that mediate absorption of Cd in the gastrointestinal tract are summarized together with glomerular filtration of Cd and its sequestration by the kidneys. The contribution of age differences, gender, and smoking status to Cd accumulation in lungs, liver, and kidneys are highlighted. The basis for use of urinary Cd excretion to reflect body burden is discussed together with the use of urinary N-acetyl-beta-d glucosaminidase (NAG) and beta2-microglobulin (beta2-MG) levels to quantify its toxicity. The associations of Cd with the development of chronic kidney disease and hypertension, reduced weight gain, and zinc reabsorption are highlighted. In addition, the review addresses how urinary Cd threshold levels have been derived from human population data and their utility as a warning sign of impending kidney malfunction. PMID- 29534456 TI - Effects of Insect Protein Supplementation during Resistance Training on Changes in Muscle Mass and Strength in Young Men. AB - During prolonged resistance training, protein supplementation is known to promote morphological changes; however, no previous training studies have tested the effect of insect protein isolate in a human trial. The aim of this study was to investigate the potential effect of insect protein as a dietary supplement to increase muscle hypertrophy and strength gains during prolonged resistance training in young men. Eighteen healthy young men performed resistance training four day/week for eight weeks. Subjects were block randomized into two groups consuming either an insect protein isolate or isocaloric carbohydrate supplementation within 1 h after training and pre-sleep on training days. Strength and body composition were measured before and after intervention to detect adaptions to the resistance training. Three-day weighed dietary records were completed before and during intervention. Fat- and bone- free mass (FBFM) improved significantly in both groups (Mean (95% confidence interval (CI))), control group (Con): (2.5 kg (1.5, 3.5) p < 0.01), protein group (Pro): (2.7 kg (1.6, 3.8) p < 0.01) from pre- to post-. Leg and bench press one repetition maximum (1 RM) improved by Con: (42.0 kg (32.0, 52.0) p < 0.01) and (13.8 kg (10.3, 17.2) p < 0.01), Pro: (36.6 kg (27.3, 45.8) p < 0.01) and (8.1 kg (4.5, 11.8) p < 0.01), respectively. No significant differences in body composition and muscle strength improvements were found between groups. In young healthy men, insect protein supplementation did not improve adaptations to eight weeks of resistance training in comparison to carbohydrate supplementation. A high habitual protein intake in both Con and Pro may partly explain our observation of no superior effect of insect protein supplementation. PMID- 29534458 TI - Disease and Treatment-Related Sequelae in Patients with Complex Jugulotympanic Paraganglioma. AB - BACKGROUND: Jugulotympanic paraganglioma (JTP) are benign, high-vascularized lesions that frequently invade the jugular foramen, temporal bone, the upper neck, and the posterior fossa cavity, resulting in a wide variety of clinical symptoms. METHODS: In this retrospective study, we assess the clinical symptoms and discuss the individual multidisciplinary treatment and outcome of 22 patients with JTP. RESULTS: In 12 patients, a hearing deficit was the presenting symptom, whereas pulsatile tinnitus and otalgia were present in six and four patients respectively. Facial nerve involvement was seen in six patients (three HB Grade 1 2 and three HB Grade 4-6). Four patients presented with lower cranial nerve impairment. Rare symptoms were ataxia caused by brainstem compression and papilledema due to cerebral sinus obstruction. A new or worsening of the preoperative facial nerve or lower cranial nerve function occurred in two and four patients respectively. CONCLUSION: The treatment strategy and the surgical approach for JTP should be tailored to the tumor extension and the patient's clinical symptoms. PMID- 29534457 TI - Strengths and Weaknesses of Pre-Clinical Models for Human Melanoma Treatment: Dawn of Dogs' Revolution for Immunotherapy. AB - Despite several therapeutic advances, malignant melanoma still remains a fatal disease for which novel and long-term curative treatments are needed. The successful development of innovative therapies strongly depends on the availability of appropriate pre-clinical models. For this purpose, several mouse models holding the promise to provide insight into molecular biology and clinical behavior of melanoma have been generated. The most relevant ones and their contribution for the advancement of therapeutic approaches for the treatment of human melanoma patients will be here summarized. However, as models, mice do not recapitulate all the features of human melanoma, thus their strengths and weaknesses need to be carefully identified and considered for the translation of the results into the human clinics. In this panorama, the concept of comparative oncology acquires a priceless value. The revolutionary importance of spontaneous canine melanoma as a translational model for the pre-clinical investigation of melanoma progression and treatment will be here discussed, with a special consideration to the development of innovative immunotherapeutic approaches. PMID- 29534459 TI - Astragalus membranaceus Extract Attenuates Inflammation and Oxidative Stress in Intestinal Epithelial Cells via NF-kappaB Activation and Nrf2 Response. AB - Astragalus membranaceus, dried root extract, also known as Astragali radix, is used in traditional Chinese medicine as a tonic remedy. Moreover, it has been reported that Astragalus membranaceus could attenuate intestinal inflammation; however, the underlying mechanism for its anti-inflammatory activity in intestinal epithelial cells (IECs) remains unclear. In this study, we evaluated Astragalus membranaceus extract (5-100 ug/mL) in a model of inflammation and oxidative stress for IECs. We showed that Astragalus membranaceus extract reduced the inflammatory response induced by lipopolysaccharide from E. coli (LPS) plus interferon-gamma (IFN), decreasing tumor necrosis factor-alpha (TNF-alpha) release, cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, nitrotyrosine formation, nuclear factor-kappaB (NF-kappaB) activation, and reactive oxygen species (ROS) release in the non-tumorigenic intestinal epithelial cell line (IEC-6). The antioxidant potential of Astragalus membranaceus extract was also evaluated in a model of hydrogen peroxide (H2O2) induced oxidative stress in IEC-6, indicating that this extract reduced ROS release and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and the expression of antioxidant cytoprotective factors in these cells. The results contributed to clarify the mechanisms involved in Astragalus membranaceus extract-reduced inflammation and highlighted the potential use of this extract as an anti-inflammatory and antioxidant remedy for intestinal diseases. PMID- 29534460 TI - cGMP Signaling in the Cardiovascular System-The Role of Compartmentation and Its Live Cell Imaging. AB - The ubiquitous second messenger 3',5'-cyclic guanosine monophosphate (cGMP) regulates multiple physiologic processes in the cardiovascular system. Its intracellular effects are mediated by stringently controlled subcellular microdomains. In this review, we will illustrate the current techniques available for real-time cGMP measurements with a specific focus on live cell imaging methods. We will also discuss currently accepted and emerging mechanisms of cGMP compartmentation in the cardiovascular system. PMID- 29534461 TI - Assessment of Mycotoxin Exposure in Breastfeeding Mothers with Celiac Disease. AB - OBJECTIVE: To assess the risk of mycotoxin exposure (aflatoxin M1, ochratoxin A, and zearalenone) in celiac disease (CD) breastfeeding mothers and healthy control mothers, as well as in their offspring, by quantifying these contaminants in breast milk. STUDY DESIGN: Thirty-five breastfeeding women with CD on a gluten free diet and 30 healthy breastfeeding controls were recruited. Milk sampling was performed three times per day for three consecutive days. Mycotoxin content was investigated by an analytical method using immunoaffinity column clean-up and high-performance liquid chromatography (HPLC) with fluorometric detection. RESULTS: Aflatoxin M1 (AFM1) was detected in 37% of CD group samples (mean +/- SD = 0.012 +/- 0.011 ng/mL; range = 0.003-0.340 ng/mL). The control group showed lower mean AFM1 concentration levels in 24% of the analyzed samples (0.009 +/- 0.007 ng/mL; range = 0.003-0.067 ng/mL, ANOVA on ranks, p-value < 0.01). Ochratoxin A and zearalenone did not differ in both groups. CONCLUSION: Breast milk AFM1 contamination for both groups is lower than the European safety threshold. However, the estimated exposures of infants from CD mothers and control mothers was much higher (?15 times and ?11 times, respectively) than the threshold set by the joint FAO/WHO Expert Committee on Food Additives (JECFA). Since incongruities exist between JECFA and the European Union standard, a novel regulatory review of the available data on this topic is desirable. Protecting babies from a neglected risk of high AFM1 exposure requires prompt regulatory and food-control policies. PMID- 29534463 TI - Association between Socioeconomic Status and 30-Day and One-Year All-Cause Mortality after Surgery in South Korea. AB - Preoperative socioeconomic status (SES) is associated with outcomes after surgery, although the effect on mortality may vary according to region. This retrospective study evaluated patients who underwent elective surgery at a tertiary hospital from 2011 to 2015 in South Korea. Preoperative SES factors (education, religion, marital status, and occupation) were evaluated for their association with 30-day and one-year all-cause mortality. The final analysis included 80,969 patients who were >=30 years old, with 30-day mortality detected in 339 cases (0.4%) and one-year mortality detected in 2687 cases (3.3%). As compared to never-married patients, those who were married or cohabitating (odds ratio (OR): 0.678, 95% confidence interval (CI): 0.462-0.995) and those divorced or separated (OR: 0.573, 95% CI: 0.359-0.917) had a lower risk of 30-day mortality after surgery. Similarly, the risk of one-year mortality after surgery was lower among married or cohabitating patients (OR: 0.857, 95% CI: 0.746-0.983) than it was for those who had never married. Moreover, as compared to nonreligious patients, Protestant patients had a decreased risk of 30-day mortality after surgery (OR: 0.642, 95% CI: 0.476-0.866). The present study revealed that marital status and religious affiliation are associated with risk of 30-day and one-year all-cause mortality after surgery. PMID- 29534462 TI - Diabetes Mellitus and Ischemic Heart Disease: The Role of Ion Channels. AB - Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels. Ion channels acting in the cross talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients. In particular, some genetic variants for ATP-dependent potassium channels seem to be involved in the determinism of IHD. PMID- 29534464 TI - The GF-3 SAR Data Processor. AB - The Gaofen-3 (GF-3) data processor was developed as a workstation-based GF-3 synthetic aperture radar (SAR) data processing system. The processor consists of two vital subsystems of the GF-3 ground segment, which are referred to as data ingesting subsystem (DIS) and product generation subsystem (PGS). The primary purpose of DIS is to record and catalogue GF-3 raw data with a transferring format, and PGS is to produce slant range or geocoded imagery from the signal data. This paper presents a brief introduction of the GF-3 data processor, including descriptions of the system architecture, the processing algorithms and its output format. PMID- 29534466 TI - All-in-One Gel-Based Electrochromic Devices: Strengths and Recent Developments. AB - Electrochromic devices (ECDs) have aroused great interest because of their potential applicability in displays and smart systems, including windows, rearview mirrors, and helmet visors. In the last decades, different device structures and materials have been proposed to meet the requirements of commercial applications to boost market entry. To this end, employing simple device architectures and achieving a competitive electrolyte are crucial to accomplish easily implementable, high-performance ECDs. The present review outlines devices comprising gel electrolytes as a single electroactive layer ("all-in-one") ECD architecture, highlighting some advantages and opportunities they offer over other electrochromic systems. In this context, gel electrolytes not only overcome the drawbacks of liquid and solid electrolytes, such as liquid's low chemical stability and risk of leaking and soil's slow switching and lack of transparency, but also exhibit further strengths. These include easier processability, suitability for flexible substrates, and improved stabilization of the chemical species involved in redox processes, leading to better cyclability and opening wide possibilities to extend the electrochromic color palette, as discussed herein. Finally, conclusions and outlook are provided. PMID- 29534465 TI - Effect of a Protein Supplement on the Gut Microbiota of Endurance Athletes: A Randomized, Controlled, Double-Blind Pilot Study. AB - Nutritional supplements are popular among athletes to improve performance and physical recovery. Protein supplements fulfill this function by improving performance and increasing muscle mass; however, their effect on other organs or systems is less well known. Diet alterations can induce gut microbiota imbalance, with beneficial or deleterious consequences for the host. To test this, we performed a randomized pilot study in cross-country runners whose diets were complemented with a protein supplement (whey isolate and beef hydrolysate) (n = 12) or maltodextrin (control) (n = 12) for 10 weeks. Microbiota, water content, pH, ammonia, and short-chain fatty acids (SCFAs) were analyzed in fecal samples, whereas malondialdehyde levels (oxidative stress marker) were determined in plasma and urine. Fecal pH, water content, ammonia, and SCFA concentrations did not change, indicating that protein supplementation did not increase the presence of these fermentation-derived metabolites. Similarly, it had no impact on plasma or urine malondialdehyde levels; however, it increased the abundance of the Bacteroidetes phylum and decreased the presence of health-related taxa including Roseburia, Blautia, and Bifidobacterium longum. Thus, long-term protein supplementation may have a negative impact on gut microbiota. Further research is needed to establish the impact of protein supplements on gut microbiota. PMID- 29534467 TI - Expanding the Utilization of Formalin-Fixed, Paraffin-Embedded Archives: Feasibility of miR-Seq for Disease Exploration and Biomarker Development from Biopsies with Clear Cell Renal Cell Carcinoma. AB - Novel predictive tools for clear cell renal cell carcinoma (ccRCC) are urgently needed. MicroRNAs (miRNAs) have been increasingly investigated for their predictive value, and formalin-fixed paraffin-embedded biopsy archives may potentially be a valuable source of miRNA sequencing material, as they remain an underused resource. Core biopsies of both cancerous and adjacent normal tissues were obtained from patients (n = 12) undergoing nephrectomy. After small RNA-seq, several analyses were performed, including classifier evaluation, obesity-related inquiries, survival analysis using publicly available datasets, comparisons to the current literature and ingenuity pathway analyses. In a comparison of tumour vs. normal, 182 miRNAs were found with significant differential expression; miR 155 was of particular interest as it classified all ccRCC samples correctly and correlated well with tumour size (R2 = 0.83); miR-155 also predicted poor survival with hazard ratios of 2.58 and 1.81 in two different TCGA (The Cancer Genome Atlas) datasets in a univariate model. However, in a multivariate Cox regression analysis including age, sex, cancer stage and histological grade, miR 155 was not a statistically significant survival predictor. In conclusion, formalin-fixed paraffin-embedded biopsy tissues are a viable source of miRNA sequencing material. Our results further support a role for miR-155 as a promising cancer classifier and potentially as a therapeutic target in ccRCC that merits further investigation. PMID- 29534468 TI - ARHGAP15 in Human Breast Carcinoma: A Potent Tumor Suppressor Regulated by Androgens. AB - Rho GTPase activating protein 15 (ARHGAP15) is a recently identified GTPase activating protein which enhances intrinsic hydrolysis of GTP-bound Ras-related C3 botulinus toxin substrate (Rac1), resulting in inactivation of Rac1. Although a lot of studies have pointed out the pivotal roles of the Rac1 pathway in the progression of breast carcinomas, the clinical significance of ARHGAP15 has remained largely unknown in human breast carcinomas. Therefore, we immunolocalized ARHGAP15 in one hundred breast carcinoma tissues. ARHGAP15 immunoreactivity was frequently detected in the cytoplasm of carcinoma cells, and was positively correlated with that of Rac1 and androgen receptor labeling index. Furthermore, ARHGAP15 immunoreactivity was significantly correlated with decreased risk of recurrence and improved prognosis, and multivariate analyses demonstrated that ARHGAP15 immunoreactivity was an independent prognostic factor for both disease-free and breast-cancer-specific survival of the patients. In addition, exogenous overexpression of ARHGA15 suppressed cell proliferation and migration of MCF-7 cells and SK-BR-3 cells. On the other hand, ARHGAP15 mRNA was significantly induced by dihydrotestosterone. These findings suggest that ARHGAP15 is an androgen-induced gene and has anti-tumorigenic roles associated with the Rac1 pathway. ARHGAP15 immunoreactivity is therefore considered a potent prognostic factor in human breast carcinomas. PMID- 29534469 TI - In Vitro ADME Properties of Two Novel Antimicrobial Peptoid-Based Compounds as Potential Agents against Canine Pyoderma. AB - Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2, which are effective against the canine skin pathogen Staphylococcus pseudintermedius, the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties. In vitro ADME assays included skin penetration profiles, stability to proteases and liver microsomes, and plasma protein binding. Both B1 and D2 were resistant to proteases and >98% bound to plasma proteins. While half lives in liver microsomes for both were >2 h, peptoid D2 showed higher stability to plasma proteases than the peptide-peptoid hybrid B1 (>2 versus 0.5 h). Both compounds were suitable for administration in an oil-in-water cream formulation (50% release in 8 h), and displayed no skin permeation, in the absence or presence of skin permeability modifiers. Our results indicate that these peptoid based drugs may be suitable as antimicrobials for local treatment of canine superficial pyoderma and that they can overcome the inherent limitations of stability encountered in peptides. PMID- 29534470 TI - Social Frailty Leads to the Development of Physical Frailty among Physically Non Frail Adults: A Four-Year Follow-Up Longitudinal Cohort Study. AB - Social frailty domains may play an important role in preventing physical decline and disability. The aim of this study is to examine the impact of social frailty as a risk factor for the future development of physical frailty among community dwelling older adults who are not yet physically frail. A total of 1226 physically non-frail older adults were analyzed to provide a baseline. Participants completed a longitudinal assessment of their physical frailty 48 months later. Their baseline social frailty was determined based on their responses to five questions, which identified participants who went out less frequently, rarely visited friends, felt less like helping friends or family, lived alone and did not talk to another person every day. Participants with none of these characteristics were considered not to be socially frail; those with one characteristic were considered socially pre-frail; and those with two or more characteristics were considered socially frail. At the four-year follow-up assessment, 24 participants (2.0%) had developed physical frailty and 440 (35.9%) had developed physical pre-frailty. The rates of developing physical frailty and pre-frailty were 1.6% and 34.2%, respectively, in the socially non-frail group; 2.4% and 38.8%, respectively, in the socially pre-frail group; and 6.8% and 54.5%, respectively, in the socially frail group. Participants classified as socially frail at the baseline had an increased risk of developing physical frailty, compared with participants who were not socially frail (OR = 3.93, 95% CI = 1.02-15.15). Participants who were socially frail at the baseline also had an increased risk of developing physical pre-frailty (OR = 2.50, 95% CI = 1.30 4.80). Among independent community-dwelling older adults who are not physically frail, those who are socially frail may be at greater risk of developing physical frailty in the near future. Social frailty may precede (and lead to the development of) physical frailty. PMID- 29534471 TI - Nanoparticle Exposure and Hormetic Dose-Responses: An Update. AB - The concept of hormesis, as an adaptive response of biological systems to moderate environmental challenges, has raised considerable nano-toxicological interests in view of the rapid pace of production and application of even more innovative nanomaterials and the expected increasing likelihood of environmental and human exposure to low-dose concentrations. Therefore, the aim of this review is to provide an update of the current knowledge concerning the biphasic dose responses induced by nanoparticle exposure. The evidence presented confirmed and extended our previous findings, showing that hormesis is a generalized adaptive response which may be further generalized to nanoscale xenobiotic challenges. Nanoparticle physico-chemical properties emerged as possible features affecting biphasic relationships, although the molecular mechanisms underlining such influences remain to be fully understood, especially in experimental settings resembling long-term and low-dose realistic environmental exposure scenarios. Further investigation is necessary to achieve helpful information for a suitable assessment of nanomaterial risks at the low-dose range for both the ecosystem function and the human health. PMID- 29534472 TI - Preliminary Characterization and Bioactivities of Some Impatiens L. Water-Soluble Polysaccharides. AB - Preliminary characterization and bioactivity of water-soluble polysaccharides from four Impatiens species-I. glandulifera Royle, I. parviflora DC., I. balsamina L., and I. noli-tangere L.-were investigated. The yields of polysaccharides range widely from 1.97% for I. parviflora roots to 18.63% for I. balsamina aerial parts. SEC (Size exclusion chromatography) chromatograms show that all samples contained a low molecular weight part that consisted of components of similar molecular weight. The aerial parts and roots of I. balsamina, and I. glandulifera aerial parts had considerable amounts of high molecular weight components up to 2.3 MDa. The sugar composition analysis revealed that Impatiens polysaccharides consisted primarily of galactose, arabinose, rhamnose, mannose, xylose, and glucose. All polysaccharide fractions, except for I. parviflora roots, also contain galacturonic acid. Moreover, in vitro bioactivity of obtained polysaccharides were evaluated. The antioxidant activity was evaluated on the basis of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis-(3-ethyl-benzthia-6-sulfonic acid) (ABTS) radical scavenging assays. The highest antioxidant activity was obtained for I. balsamina aerial parts and I. parviflora roots. Among the tested fractions, only the polysaccharides from I. glandulifera aerial parts were able to significantly decrease the production of IL-8 by 32.7 +/- 10.5%. The results suggest that Impatiens species can be considered as a new source of antioxidants. PMID- 29534474 TI - Production of Micro- and Nanoscale Lignin from Wheat Straw Using Different Precipitation Setups. AB - Micro- and nanosize lignin has recently gained interest due to its improved properties compared to standard lignin available today. As the second most abundant biopolymer after cellulose, lignin is readily available but used for rather low-value applications. Applications for lignin in micro- to nanoscale however, ranging from improvement of mechanical properties of polymer nanocomposites, have bactericidal and antioxidant properties and impregnations to hollow lignin drug carriers for hydrophobic and hydrophilic substances. This research represents a whole biorefinery process chain and compares different precipitation setups to produce submicron lignin particles from lignin containing an organosolv pretreatment extract from wheat straw. A batch precipitation in a stirred vessel was compared with continuous mixing of extract and antisolvent in a T-fitting and mixing in a T-fitting followed by a static mixer. The precipitation in the combination of T-fitting and static mixer with improved precipitation parameters yields the smallest particle size of around 100 nm. Furthermore, drying of particles did not influence the particle sizes negatively by showing decreased particle diameters after the separation process. PMID- 29534473 TI - Peptide Nucleic Acids as a Tool for Site-Specific Gene Editing. AB - Peptide nucleic acids (PNAs) can bind duplex DNA in a sequence-targeted manner, forming a triplex structure capable of inducing DNA repair and producing specific genome modifications. Since the first description of PNA-mediated gene editing in cell free extracts, PNAs have been used to successfully correct human disease causing mutations in cell culture and in vivo in preclinical mouse models. Gene correction via PNAs has resulted in clinically-relevant functional protein restoration and disease improvement, with low off-target genome effects, indicating a strong therapeutic potential for PNAs in the treatment or cure of genetic disorders. This review discusses the progress that has been made in developing PNAs as an effective, targeted agent for gene editing, with an emphasis on recent in vivo, nanoparticle-based strategies. PMID- 29534475 TI - Copycats in Pilot Aircraft-Assisted Suicides after the Germanwings Incident. AB - Aircraft-assisted pilot suicide is a rare but serious phenomenon. The aim of this study was to evaluate changes in pilot aircraft-assisted suicide risks, i.e., a copycat effect, in the U.S. and Germany after the Germanwings 2015 incident in the French Alps. Aircraft-assisted pilot suicides were searched in the U.S. National Transportation Safety Board (NTSB) accident investigation database and in the German Bundestelle fur Flugunfalluntersuchung (BFU) Reports of Investigation database five years before and two years after the deliberate crash of the Germanwings flight into the French Alps in 2015. The relative risk (RR) of the aircraft-assisted pilot suicides was calculated. Two years after the incident, three out of 454 (0.66%) fatal incidents were aircraft-assisted suicides compared with six out of 1292 (0.46%) in the prior five years in the NTSB database. There were no aircraft-assisted pilot suicides in the German database during the two years after or five years prior to the Germanwings crash. The relative aircraft-assisted pilot suicide risk for the U.S. was 1.4 (95% CI 0.3-4.2) which was not statistically significant. Six of the pilots who died by suicide had told someone of their suicidal intentions. We consider changes in the rate to be within a normal variation. Responsible media coverage of aircraft incidents is important due to the large amount of publicity that these events attract. PMID- 29534476 TI - The Burden of COPD Morbidity Attributable to the Interaction between Ambient Air Pollution and Temperature in Chengdu, China. AB - Evidence on the burden of chronic obstructive pulmonary disease (COPD) morbidity attributable to the interaction between ambient air pollution and temperature has been limited. This study aimed to examine the modification effect of temperature on the association of ambient air pollutants (including particulate matter (PM) with aerodynamic diameter <10 MUm (PM10) and <2.5 MUm (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3)) with risk of hospital admissions (HAs) for COPD, as well as the associated morbidity burden in urban areas of Chengdu, China, from 2015 to 2016. Based on the generalized additive model (GAM) with quasi-Poisson link, bivariate response surface model and stratification parametric model were developed to investigate the potential interactions between ambient air pollution and temperature on COPD HAs. We found consistent interactions between ambient air pollutants (PM2.5, PM10 and SO2) and low temperature on COPD HAs, demonstrated by the stronger associations between ambient air pollutants and COPD HAs at low temperatures than at moderate temperatures. Subgroup analyses showed that the elderly (>=80 years) and males were more vulnerable to this interaction. The joint effect of PM and low temperature had the greatest impact on COPD morbidity burden. Using WHO air quality guidelines as reference concentration, about 17.30% (95% CI: 12.39%, 22.19%) and 14.72% (95% CI: 10.38%, 19.06%) of COPD HAs were attributable to PM2.5 and PM10 exposures on low temperature days, respectively. Our findings suggested that low temperature significantly enhanced the effects of PM and SO2 on COPD HAs in urban Chengdu, resulting in increased morbidity burden. This evidence has important implications for developing interventions to reduce the risk effect of COPD morbidity. PMID- 29534477 TI - Experimental Robot Model Adjustments Based on Force-Torque Sensor Information. AB - The computational complexity of humanoid robot balance control is reduced through the application of simplified kinematics and dynamics models. However, these simplifications lead to the introduction of errors that add to other inherent electro-mechanic inaccuracies and affect the robotic system. Linear control systems deal with these inaccuracies if they operate around a specific working point but are less precise if they do not. This work presents a model improvement based on the Linear Inverted Pendulum Model (LIPM) to be applied in a non-linear control system. The aim is to minimize the control error and reduce robot oscillations for multiple working points. The new model, named the Dynamic LIPM (DLIPM), is used to plan the robot behavior with respect to changes in the balance status denoted by the zero moment point (ZMP). Thanks to the use of information from force-torque sensors, an experimental procedure has been applied to characterize the inaccuracies and introduce them into the new model. The experiments consist of balance perturbations similar to those of push-recovery trials, in which step-shaped ZMP variations are produced. The results show that the responses of the robot with respect to balance perturbations are more precise and the mechanical oscillations are reduced without comprising robot dynamics. PMID- 29534478 TI - Safety, Efficacy and Evidence Base for Use of the Subcutaneous Implantable Cardioverter Defibrillator. AB - The trans-venous implantable cardioverter defibrillator (TV-ICD) is effective in treating life-threatening ventricular arrhythmia and reduces mortality in high risk patients. However, there are significant short- and long-term complications that are associated with intravascular leads. These shortcomings are mostly relevant in young patients with long life expectancy and low risk of death from non-arrhythmic causes. Drawbacks of trans-venous leads recently led to the development of the entirely subcutaneous implantable cardioverter defibrillator (S-ICD). The S-ICD does not require vascular access or permanent intravascular defibrillation leads. Therefore, it is expected to overcome many complications associated with conventional ICDs. This review highlights data on safety and efficacy of the S-ICD and is envisioned to help in identifying the role of this device in clinical practice. PMID- 29534479 TI - Communicating Effectively in Pediatric Cancer Care: Translating Evidence into Practice. AB - Effective communication is essential to the practice of pediatric oncology. Clear and empathic delivery of diagnostic and prognostic information positively impacts the ways in which patients and families cope. Honest, compassionate discussions regarding goals of care and hopes for patients approaching end of life can provide healing when other therapies have failed. Effective communication and the positive relationships it fosters also can provide comfort to families grieving the loss of a child. A robust body of evidence demonstrates the benefits of optimal communication for patients, families, and healthcare providers. This review aims to identify key communication skills that healthcare providers can employ throughout the illness journey to provide information, encourage shared decision-making, promote therapeutic alliance, and empathically address end-of life concerns. By reviewing the relevant evidence and providing practical tips for skill development, we strive to help healthcare providers understand the value of effective communication and master these critical skills. PMID- 29534480 TI - Characterization of the Types of Sweeteners Consumed in Honduras. AB - Sweeteners are found in all types of foods, and their high consumption is associated with chronic degenerative diseases, such as diabetes and obesity, among others. A characterization was carried out of food products with sweeteners from the three biggest supermarkets at a national level; they were identified by the list of ingredients and classified according to caloric or non-caloric intake, and pursuant to their country of origin. A statistical interpretation of results was made using descriptive measures such as the number of times the sweeteners were found in the formulation of the products and how many of them were found in a product at the same time. In total, 341 products were evaluated and classified according to the processed food categories of the Pan American Health Organization (PAHO) nutrient profile. The category of beverages had the highest quantity of products with sweeteners, and their consumption by the inhabitants represents a high exposure. Overall, 60.1% of the products evaluated were of US origin; these US exports have a significant impact on the Honduran market. A high-fructose corn syrup caloric sweetener was the one most frequently found in these products; at least 51% are combined with additional sweeteners to increase the sweetening effect. PMID- 29534481 TI - Role of the Short Distance Order in Glass Reactivity. AB - In 2005, our group described for the first time the structural characterization at the atomic scale of bioactive glasses and the influence of the glasses' nanostructure in their reactivity in simulated body fluids. In that study, two bioactive sol-gel glasses with composition 80%SiO2-20%CaO and 80%SiO2-17%CaO 3%P2O5 (in mol-%) were characterized by High-Resolution Transmission Electron Microscopy (HRTEM). Such characterization revealed unknown features of the glasses' structure at the local scale that allowed the understanding of their different in vitro behaviors as a consequence of the presence or absence of P2O5. Since then, the nanostructure of numerous bioactive glasses, including melt prepared, sol-gel derived, and mesoporous glasses, was investigated by HRTEM, Nuclear Magnetic Resonance (NMR) spectroscopy, Molecular Dynamics (MD) simulations, and other experimental techniques. These studies have shown that although glasses are amorphous solids, a certain type of short distance order, which greatly influences the in vitro and in vivo reactivity, is always present. This paper reviews the most significant advances in the understanding of bioactive glasses that took place in the last years as a result of the growing knowledge of the glasses' nanostructure. PMID- 29534482 TI - Assessment of the Baby Friendly Hospital Initiative Implementation in the Eastern Mediterranean Region. AB - The Baby-Friendly Hospital Initiative (BFHI) is a global program for promoting support and protection for breastfeeding. However, its impact on malnutrition, especially in countries of the Eastern Mediterranean region (EMR) that are facing the turmoil of conflict and emergencies, deserves further investigation. Having said that, this paper aims to discuss the status and challenges to BFHI implementation in the EMR countries. Data on BFHI implementation, breastfeeding practices, and nutritional status were collected from countries through structured questionnaires, personal interviews, and databases. The 22 countries of the EMR were categorized as follows: 8 countries in advanced nutrition transition stage (group I), 5 countries in early nutrition transition stage (group II), 4 countries with significant undernutrition (group III), and 5 countries in complex emergency (group IV). The challenges to BFHI implementation were discussed in relation to malnutrition. BFHI was not implemented in 22.7% of EMR countries. Designated Baby-Friendly hospitals totaled 829 (group I: 78.4%, group II: 9.05%; group III: 7.36%; group: IV5.19%). Countries with advanced nutrition transition had the highest implementation of BFHI but the lowest breastfeeding continuity rates. On the other hand, poor nutritional status and emergency states were linked with low BFHI implementation and low exclusive breastfeeding rates but high continuity rates. Early initiation and longer duration of breastfeeding correlated negatively with overweight and obesity (p < 0.001). In countries with emergency states, breastfeeding continues to be the main source of nourishment. However, suboptimal breastfeeding practices prevail because of poor BFHI implementation which consequently leads to malnutrition. Political willpower and community-based initiatives are needed to promote breastfeeding and strengthen BFHI in the region. PMID- 29534483 TI - On the Deployment and Noise Filtering of Vehicular Radar Application for Detection Enhancement in Roads and Tunnels. AB - Recently, radar technology has attracted attention for the realization of an intelligent transportation system (ITS) to monitor, track, and manage vehicle traffic on the roads as well as adaptive cruise control (ACC) and automatic emergency braking (AEB) for driving assistance of vehicles. However, when radar is installed on roads or in tunnels, the detection performance is significantly dependent on the deployment conditions and environment around the radar. In particular, in the case of tunnels, the detection accuracy for a moving vehicle drops sharply owing to the diffuse reflection of radio frequency (RF) signals. In this paper, we propose an optimal deployment condition based on height and tilt angle as well as a noise-filtering scheme for RF signals so that the performance of vehicle detection can be robust against external conditions on roads and in tunnels. To this end, first, we gather and analyze the misrecognition patterns of the radar by tracking a number of randomly selected vehicles on real roads. In order to overcome the limitations, we implement a novel road watch module (RWM) that is easily integrated into a conventional radar system such as Delphi ESR. The proposed system is able to perform real-time distributed data processing of the target vehicles by providing independent queues for each object of information that is incoming from the radar RF. Based on experiments with real roads and tunnels, the proposed scheme shows better performance than the conventional method with respect to the detection accuracy and delay time. The implemented system also provides a user-friendly interface to monitor and manage all traffic on roads and in tunnels. This will accelerate the popularization of future ITS services. PMID- 29534484 TI - Policy Guidelines for Effective Inclusion and Reintegration of People with Chronic Diseases in the Workplace: National and European Perspectives. AB - The increasing prevalence of chronic diseases among the European working age population, as well as the implications for the individual and societal level, underline the need for policy guidelines targeting the effective inclusion of persons with chronic diseases in the workplace. The aim of the present paper was to explore the perspectives of European and National-level stakeholders on existing strategies for work re-integration of persons with chronic diseases, and to provide policy guidelines. A highly-structured interview protocol was distributed to 58 National level stakeholders (policy makers, professionals and employers) from seven European countries. Additionally, 20 European organizations concerned with health-related issues and employment completed an online survey. The findings reveal that employment-related challenges remain largely unaddressed. Both national and European stakeholders considered the existing legislative frameworks inadequate and appraised the co-ordination for the implementation of employment re-integration policies as ineffective. Policies targeting at work re-integration of persons with chronic diseases at European and national level should focus on consistent cooperation among all key stakeholders, awareness raising to staff and management, dissemination of effective strategies, developing research and evaluation standards and establishing monitoring systems on inclusive labour markets. PMID- 29534485 TI - Recombination Events Involving the atp9 Gene Are Associated with Male Sterility of CMS PET2 in Sunflower. AB - Cytoplasmic male sterility (CMS) systems represent ideal mutants to study the role of mitochondria in pollen development. In sunflower, CMS PET2 also has the potential to become an alternative CMS source for commercial sunflower hybrid breeding. CMS PET2 originates from an interspecific cross of H. petiolaris and H. annuus as CMS PET1, but results in a different CMS mechanism. Southern analyses revealed differences for atp6, atp9 and cob between CMS PET2, CMS PET1 and the male-fertile line HA89. A second identical copy of atp6 was present on an additional CMS PET2-specific fragment. In addition, the atp9 gene was duplicated. However, this duplication was followed by an insertion of 271 bp of unknown origin in the 5' coding region of the atp9 gene in CMS PET2, which led to the creation of two unique open reading frames orf288 and orf231. The first 53 bp of orf288 are identical to the 5' end of atp9. Orf231 consists apart from the first 3 bp, being part of the 271-bp-insertion, of the last 228 bp of atp9. These CMS PET2-specific orfs are co-transcribed. All 11 editing sites of the atp9 gene present in orf231 are fully edited. The anther-specific reduction of the co transcript in fertility-restored hybrids supports the involvement in male sterility based on CMS PET2. PMID- 29534486 TI - Human Parainfluenza Virus Type 3 Matrix Protein Reduces Viral RNA Synthesis of HPIV3 by Regulating Inclusion Body Formation. AB - Human parainfluenza virus type 3 is one of the main causes of lower respiratory illness in newborns and infants. The role of the matrix protein (M) in viral budding is extensively studied, but the effect of M on viral replication remains to be determined. Using an HPIV3 minigenome assay, we found that M reduced HPIV3 mingenome-encoded reporter activity even though it had an unspecific effect on the expression of cellular genes. Furthermore, the inhibition effect of M on viral RNA synthesis was proven to be independent of its virus-like particles (VLPs)' release ability. A VLP's defective mutant (ML302A) decreased the expression of minigenome reporter as wild type M did. Using an immunofluorescence assay, we found that M weakened the formation of inclusion bodies (IBs), although it did not co-localize with the IBs. Moreover, using another mutant, ML305A , which is defective in M-nucleoprotein (N) interaction, we found that ML305A had no effect on reporter activity and IB formation as the wild type of M did. Taken together, we conclude that M reduces the replication of HPIV3 and IB formation by M-N interaction. PMID- 29534487 TI - A Pecan-Rich Diet Improves Cardiometabolic Risk Factors in Overweight and Obese Adults: A Randomized Controlled Trial. AB - Evidence from observational and intervention studies has shown a high intake of tree nuts is associated with a reduced risk of cardiovascular disease (CVD), mortality from type 2 diabetes (T2DM), and all-cause mortality. However, there is limited data regarding their effects on indicators of cardiometabolic risk other than hypercholesterolemia, and little is known about the demonstrable health benefits of pecans (Carya illinoensis (Wangenh.) K.Koch). We conducted a randomized, controlled feeding trial to compare the effects of a pecan-rich diet with an isocaloric control diet similar in total fat and fiber content, but absent nuts, on biomarkers related to CVD and T2DM risk in healthy middle-aged and older adults who are overweight or obese with central adiposity. After 4 weeks on a pecan-rich diet, changes in serum insulin, insulin resistance (HOMA IR) and beta cell function (HOMA-beta) were significantly greater than after the control diet (p < 0.05). Pecan consumption also lowered the risk of cardiometabolic disease as indicated by a composite score reflecting changes in clinically relevant markers. Thus, compared to the control diet, the pecan intervention had a concurrent and clinically significant effect on several relevant markers of cardiometabolic risk. PMID- 29534488 TI - Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis. AB - Symptomatic treatment of myasthenia gravis is based on the use of peripherally acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190 fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis. PMID- 29534489 TI - Platforms for Single-Cell Collection and Analysis. AB - Single-cell analysis has become an established method to study cell heterogeneity and for rare cell characterization. Despite the high cost and technical constraints, applications are increasing every year in all fields of biology. Following the trend, there is a tremendous development of tools for single-cell analysis, especially in the RNA sequencing field. Every improvement increases sensitivity and throughput. Collecting a large amount of data also stimulates the development of new approaches for bioinformatic analysis and interpretation. However, the essential requirement for any analysis is the collection of single cells of high quality. The single-cell isolation must be fast, effective, and gentle to maintain the native expression profiles. Classical methods for single cell isolation are micromanipulation, microdissection, and fluorescence-activated cell sorting (FACS). In the last decade several new and highly efficient approaches have been developed, which not just supplement but may fully replace the traditional ones. These new techniques are based on microfluidic chips, droplets, micro-well plates, and automatic collection of cells using capillaries, magnets, an electric field, or a punching probe. In this review we summarize the current methods and developments in this field. We discuss the advantages of the different commercially available platforms and their applicability, and also provide remarks on future developments. PMID- 29534492 TI - A Semi-Analytical Extraction Method for Interface and Bulk Density of States in Metal Oxide Thin-Film Transistors. AB - A semi-analytical extraction method of interface and bulk density of states (DOS) is proposed by using the low-frequency capacitance-voltage characteristics and current-voltage characteristics of indium zinc oxide thin-film transistors (IZO TFTs). In this work, an exponential potential distribution along the depth direction of the active layer is assumed and confirmed by numerical solution of Poisson's equation followed by device simulation. The interface DOS is obtained as a superposition of constant deep states and exponential tail states. Moreover, it is shown that the bulk DOS may be represented by the superposition of exponential deep states and exponential tail states. The extracted values of bulk DOS and interface DOS are further verified by comparing the measured transfer and output characteristics of IZO TFTs with the simulation results by a 2D device simulator ATLAS (Silvaco). As a result, the proposed extraction method may be useful for diagnosing and characterising metal oxide TFTs since it is fast to extract interface and bulk density of states (DOS) simultaneously. PMID- 29534491 TI - Characterization of a Novel Porin-Like Protein, ExtI, from Geobacter sulfurreducens and Its Implication in the Reduction of Selenite and Tellurite. AB - The extI gene in Geobacter sulfurreducens encodes a putative outer membrane channel porin, which resides within a cluster of extHIJKLMNOPQS genes. This cluster is highly conserved across the Geobacteraceae and includes multiple putative c-type cytochromes. In silico analyses of the ExtI sequence, together with Western blot analysis and proteinase protection assays, showed that it is an outer membrane protein. The expression level of ExtI did not respond to changes in osmolality and phosphate starvation. An extI-deficient mutant did not show any significant impact on fumarate or Fe(III) citrate reduction or sensitivity to beta-lactam antibiotics, as compared with those of the wild-type strain. However, extI deficiency resulted in a decreased ability to reduce selenite and tellurite. Heme staining analysis revealed that extI deficiency affects certain heme containing proteins in the outer and inner membranes, which may cause a decrease in the ability to reduce selenite and tellurite. Based on these observations, we discuss possible roles for ExtI in selenite and tellurite reduction in G. sulfurreducens. PMID- 29534490 TI - ATP Release Channels. AB - Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for ATP permeation: anion permeability and a large ion-conducting pore. Currently, five groups of channels are acknowledged as ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs, also known as volume-sensitive outwardly rectifying (VSOR) anion channels), and maxi-anion channels (MACs). Recently, major breakthroughs have been made in the field by molecular identification of CALHM1 as the action potential-dependent ATP-release channel in taste bud cells, LRRC8s as components of VRACs, and SLCO2A1 as a core subunit of MACs. Here, the function and physiological roles of these five groups of ATP release channels are summarized, along with a discussion on the future implications of understanding these channels. PMID- 29534493 TI - Tolerance to Plant Pathogens: Theory and Experimental Evidence. AB - The two major mechanisms of plant defense against pathogens are resistance (the host's ability to limit pathogen multiplication) and tolerance (the host's ability to reduce the effect of infection on its fitness regardless of the level of pathogen multiplication). There is abundant literature on virtually every aspect of plant resistance to pathogens. Although tolerance to plant pathogens is comparatively less understood, studies on this plant defense strategy have led to major insights into its evolution, mechanistic basis and genetic determinants. This review aims at summarizing current theories and experimental evidence on the evolutionary causes and consequences of plant tolerance to pathogens, as well as the existing knowledge on the genetic determinants and mechanisms of tolerance. Our review reveals that (i) in plant-pathogen systems, resistance and tolerance generally coexist, i.e., are not mutually exclusive; (ii) evidence of tolerance polymorphisms is abundant regardless of the pathogen considered; (iii) tolerance is an efficient strategy to reduce the damage on the infected host; and (iv) there is no evidence that tolerance results in increased pathogen multiplication. Taken together, the work discussed in this review indicates that tolerance may be as important as resistance in determining the dynamics of plant-pathogen interactions. Several aspects of plant tolerance to pathogens that still remain unclear and which should be explored in the future, are also outlined. PMID- 29534494 TI - Cytotoxic and Apoptotic Activity of the Novel Harmine Derivative ZC-14 in Sf9 Cells. AB - Harmine, one of the natural beta-carboline alkaloids extracted from Peganum harmala L., exhibits broad spectrum but limited insecticidal ability against many pests. So there is an urgent need to synthesize novel derivatives with high efficiency. In the present study, a new synthetic compound, [1-(2-naphthyl)-3-(2 thioxo-1,3,4-oxadiazol-5-yl) beta-carboline] (ZC-14), showed a strong proliferation inhibition effect against the Spodoptera frugiperda Sf9 cell line in a dose-dependent manner. Simultaneously, apoptosis induced by 7.5 MUg/mL ZC-14 was confirmed with physiological and biochemical evidence, including typical apoptosis characteristics with shrinkage, apoptotic bodies, nuclear condensation/fragmentation, a clear DNA ladder, and a series of apoptotic rates. In addition, mitochondria were confirmed to be involved in apoptosis induced by ZC-14 accompanied with the loss of mitochondrial membrane potential (Deltapsim), the release of cytochrome c from mitochondria into the cytosol and increased expression of cleaved-caspase-3. However, harmine could not induce apoptosis at the same concentration. In summary, these data indicated that compound ZC-14 has a higher cytotoxicity than harmine against Sf9 cells. Besides, it exhibited an anti-proliferative effect in Sf9 cells via inducing apoptosis in which the mitochondrial apoptotic pathway plays a crucial role. PMID- 29534495 TI - Toward Generating More Diagnostic Features from Photoplethysmogram Waveforms. AB - Photoplethysmogram (PPG) signals collected using a pulse oximeter are increasingly being used for screening and diagnosis purposes. Because of the non invasive, cost-effective, and easy-to-use nature of the pulse oximeter, clinicians and biomedical engineers are investigating how PPG signals can help in the management of many medical conditions, especially for global health application. The study of PPG signal analysis is relatively new compared to research in electrocardiogram signals, for instance; however, we anticipate that in the near future blood pressure, cardiac output, and other clinical parameters will be measured from wearable devices that collect PPG signals, based on the signal's vast potential. This article attempts to organize and standardize the names of PPG waveforms to ensure consistent terminologies, thereby helping the rapid developments in this research area, decreasing the disconnect within and among different disciplines, and increasing the number of features generated from PPG waveforms. PMID- 29534497 TI - Citrate- and Succinate-Modified Carbonate Apatite Nanoparticles with Loaded Doxorubicin Exhibit Potent Anticancer Activity against Breast Cancer Cells. AB - Biodegradable inorganic apatite-based particle complex is popular for its pH sensitivity at the endosomal acidic environment to facilitate drug release following cellular uptake. Despite being a powerful anticancer drug, doxorubicin shows severe off-target effects and therefore would need a carrier for the highest effectiveness. We aimed to chemically modify carbonate apatite (CA) with Krebs cycle intermediates, such as citrate and succinate in order to control the growth of the resultant particles to more efficiently carry and transport the anticancer drug into the cancer cells. Citrate- or succinate-modified CA particles were synthesized with different concentrations of sodium citrate or sodium succinate, respectively, in the absence or presence of doxorubicin. The drug loading efficiency of the particles and their cellular uptake were observed by quantifying fluorescence intensity. The average diameter and surface charge of the particles were determined using Zetasizer. Cell viability was assessed by MTT assay. Citrate-modified carbonate apatite (CMCA) exhibited the highest (31.38%) binding affinity for doxorubicin and promoted rapid cellular uptake of the drug, leading to the half-maximal inhibitory concentration 1000 times less than that of the free drug in MCF-7 cells. Hence, CMCA nanoparticles with greater surface area enhance cytotoxicity in different breast cancer cells by enabling higher loading and more efficient cellular uptake of the drug. PMID- 29534496 TI - Liddle Syndrome: Review of the Literature and Description of a New Case. AB - Liddle syndrome is an inherited form of low-renin hypertension, transmitted with an autosomal dominant pattern. The molecular basis of Liddle syndrome resides in germline mutations of the SCNN1A, SCNN1B and SCNN1G genes, encoding the alpha, beta, and gamma-subunits of the epithelial Na+ channel (ENaC), respectively. To date, 31 different causative mutations have been reported in 72 families from four continents. The majority of the substitutions cause an increased expression of the channel at the distal nephron apical membrane, with subsequent enhanced renal sodium reabsorption. The most common clinical presentation of the disease is early onset hypertension, hypokalemia, metabolic alkalosis, suppressed plasma renin activity and low plasma aldosterone. Consequently, treatment of Liddle syndrome is based on the administration of ENaC blockers, amiloride and triamterene. Herein, we discuss the genetic basis, clinical presentation, diagnosis and treatment of Liddle syndrome. Finally, we report a new case in an Italian family, caused by a SCNN1B p.Pro618Leu substitution. PMID- 29534498 TI - The Genus Conradina (Lamiaceae): A Review. AB - Conradina (Lamiaceae) is a small genus of native United States (US) species limited to Florida, Alabama, Mississippi, Tennessee and Kentucky. Three species of Conradina are federally listed as endangered and one is threatened while two are candidates for listing as endangered. The purpose of the present review is to highlight the recent advances in current knowledge on Conradina species and to compile reports of chemical constituents that characterize and differentiate between Conradina species. PMID- 29534499 TI - Research on Flow Field Perception Based on Artificial Lateral Line Sensor System. AB - In nature, the lateral line of fish is a peculiar and important organ for sensing the surrounding hydrodynamic environment, preying, escaping from predators and schooling. In this paper, by imitating the mechanism of fish lateral canal neuromasts, we developed an artificial lateral line system composed of micro pressure sensors. Through hydrodynamic simulations, an optimized sensor structure was obtained and the pressure distribution models of the lateral surface were established in uniform flow and turbulent flow. Carrying out the corresponding underwater experiment, the validity of the numerical simulation method is verified by the comparison between the experimental data and the simulation results. In addition, a variety of effective research methods are proposed and validated for the flow velocity estimation and attitude perception in turbulent flow, respectively and the shape recognition of obstacles is realized by the neural network algorithm. PMID- 29534500 TI - Burden of Severe Fungal Infections in Burkina Faso. AB - Because of the limited access to more powerful diagnostic tools, there is a paucity of data regarding the burden of fungal infections in Burkina Faso. The aim of this study was to estimate the incidence and prevalence of serious fungal infections in this sub-Saharan country. We primarily used the national demographic data and performed a PubMed search to retrieve all published papers on fungal infections from Burkina Faso and its surrounding West African countries. Considering the prevalence of HIV infection (0.8% of the population) and a 3.4% incidence of cryptococcosis in hospitals, it is estimated that 459 patients per year develop cryptococcosis. For pneumocystosis, it is suggested that 1013 new cases occur every year. Taking into account the local TB frequency (population prevalence at 0.052%), we estimate the prevalence of chronic pulmonary aspergillosis at 1120 cases. Severe forms of asthma with fungal sensitization and allergic bronchopulmonary aspergillosis are estimated to affect 7429 and 5628 cases, respectively. Vulvovaginal candidiasis may affect 179,000 women, and almost 1,000,000 children may suffer from tinea capitis. Globally, we estimate that roughly 1.4 million people in Burkina Faso (7.51% of the population) suffer from a serious fungal infection. These data should be used to drive future epidemiological studies, diagnostic approaches, and therapeutic strategies. PMID- 29534501 TI - Oncolytic Adenoviruses in Gastrointestinal Cancers. AB - Gastrointestinal malignancies are challenging cancers with considerable economic and societal impacts on health care systems worldwide. While advances in surgical approaches have provided benefits to a proportion of patients, only modest improvements have been attained in the treatment of patients with advanced disease, resulting in limited improvement in survival rates in these patients. Oncolytic adenoviruses are being developed to address gastrointestinal malignancies. Each platform has evolved to maximize tumor-cell killing potency while minimizing toxicities. Tumor-specific bioengineered adenoviruses using chimeric promoters, prodrug convertase enzymes, lethal genes, tumor suppressor genes, and pseudo-typed capsids can provide the innovations for eventual success of oncolytic virotherapy. This article will review the developments in adenoviral platforms in the context of specific gastrointestinal cancers. From the bench to the implementation of clinical trials, this review aims to highlight advances in the field from its early days to the current state of affairs as it pertains to the application of adenoviral oncolytic therapy to gastrointestinal cancers. PMID- 29534503 TI - Hepatitis B At-Birth Dose Vaccine: An Urgent Call for Implementation in Ghana. AB - Globally, approximately two billion people are infected with the Hepatitis B virus with attributable death estimated at about half a million people annually across the globe. Chronic hepatitis B infection is also an important public health problem in Ghana. The main mode of transmission in endemic regions is the perinatal route. Mother-to-child transmission can be reduced by antiviral therapy especially in the last trimester and adherence to the national immunization schedule. The World Health Organization recommends to add the birth dose vaccine to the current expanded program on immunization (EPI) in all countries but especially for endemic regions. The evidence for the efficacy of the birth dose HBV vaccine is overwhelming and there is an urgent need for its introduction into the current EPI schedule in Ghana. PMID- 29534502 TI - ChREBP-Knockout Mice Show Sucrose Intolerance and Fructose Malabsorption. AB - We have previously reported that 60% sucrose diet-fed ChREBP knockout mice (KO) showed body weight loss resulting in lethality. We aimed to elucidate whether sucrose and fructose metabolism are impaired in KO. Wild-type mice (WT) and KO were fed a diet containing 30% sucrose with/without 0.08% miglitol, an alpha glucosidase inhibitor, and these effects on phenotypes were tested. Furthermore, we compared metabolic changes of oral and peritoneal fructose injection. A thirty percent sucrose diet feeding did not affect phenotypes in KO. However, miglitol induced lethality in 30% sucrose-fed KO. Thirty percent sucrose plus miglitol diet-fed KO showed increased cecal contents, increased fecal lactate contents, increased growth of lactobacillales and Bifidobacterium and decreased growth of clostridium cluster XIVa. ChREBP gene deletion suppressed the mRNA levels of sucrose and fructose related genes. Next, oral fructose injection did not affect plasma glucose levels and liver fructose contents; however, intestinal sucrose and fructose related mRNA levels were increased only in WT. In contrast, peritoneal fructose injection increased plasma glucose levels in both mice; however, the hepatic fructose content in KO was much higher owing to decreased hepatic Khk mRNA expression. Taken together, KO showed sucrose intolerance and fructose malabsorption owing to decreased gene expression. PMID- 29534504 TI - Inhibition of Intracellular ROS Accumulation by Formononetin Attenuates Cisplatin Mediated Apoptosis in LLC-PK1 Cells. AB - Cisplatin is a well-known anticancer drug frequently used for treating solid tumors, including ovarian, testicular, bladder, and cervical tumors. However, usage of cisplatin has been limited because of its adverse effects, particularly nephrotoxicity. Therefore, the present study sought to investigate the protective effect of formononetin against cisplatin-induced cytotoxicity in LLC-PK1 pig kidney epithelial cells as well as the anticancer effect of cisplatin in three different human cervical cancer cell lines, including HeLa, SiHa, and CaSKi cells. We first demonstrated that formononetin strongly prevented cisplatin induced LLC-PK1 cell death. Although formononetin had no anticancer effect, it did not interrupt the anticancer effect of cisplatin in human cervical carcinoma cell lines. Furthermore, the treatment with formononetin reduced reactive oxygen species (ROS) accumulation and chromatin condensation. The percentage of Annexin V-positive cells also increased following cisplatin treatment. Finally, formononetin-inhibited c-Jun N-terminal kinase (JNK) phosphorylation, cleavage of caspase-8 and caspase-3, and the ratio of Bax to Bcl-2 increased with cisplatin. Taken together, these findings suggest that formononetin may be a possible option to prevent nephrotoxicity induced by cisplatin during treatment for cervical cancer. PMID- 29534505 TI - Potential of Cassia alata L. Coupled with Biochar for Heavy Metal Stabilization in Multi-Metal Mine Tailings. AB - To explore the effect of different biochars on Cassia alata L. growth and heavy metal immobilization in multi-metal mine tailings, a 100-day pot experiment was conducted. Three biochars derived from Hibiscus cannabinus core (HB), sewage sludge (SB) and chicken manure (MB), were added to mine tailings at rates of 0.4%, 1% and 3% (w/w). The results showed that the root biomass, shoot biomass, plant height and root length were 1.2-2.8, 1.7-3.2, 1-1.5 and 1.6-3.3 times of those in the control group, respectively. Pb, Zn, Cu, Cd and As contents in the shoot decreased by 63.9-89.5%, 46.9-66.0%, 32.7-62.4%, 40.4-76.4% and 54.9-77.5%, respectively. The biochar significantly increased the pH and decreased the mild acid-soluble Pb and Cu concentrations in the mine tailings. Specifically, SB immobilized Pb and Cu better than MB and HB did, although it did not immobilize As, Zn or Cd. Meanwhile, more attention should be paid to the potential As release as the biochar application rate increases. In conclusion, Cassia alata L. coupled with 3% of SB could be an effective measure for restoring multi-metal mine tailings. This study herein provided a promising ecological restoration technique for future practice of heavy metal stabilization in mine tailings. PMID- 29534507 TI - Carbohydrate Mouth Rinse Fails to Improve Four-Kilometer Cycling Time Trial Performance. AB - We investigated if a carbohydrate (CHO) mouth rinse may attenuate global fatigue and improve 4-km cycling time trial (TT4km) performance. After a preliminary session, cyclists (n = 9) performed a TT4km after a CHO or placebo (PLA) mouth rinse. Mean power output, time, and ratings of perceived exertion (RPE) were recorded throughout the TT4km. Twitch interpolation responses (%VA; voluntary activation and ?Tw; delta peak twitch torque) were compared pre and post TT4km with traditional statistics and effect size (ES) analysis. Time-to-complete the 4 km and mean power output were comparable between CHO (386.4 +/- 28.0 s) and PLA (385.4 +/- 22.4 s). A lower central (p = 0.054) and peripheral (p = 0.02) fatigue in CHO than in PLA were suggested by an extremely-large ES in %VA (manipulation main effect: p = 0.052, d = 1.18; manipulation-by-time interaction effect: p = 0.08, d = 1.00) and an extremely, very-large ES in ?Tw (manipulation main effect: p = 0.07, d = 0.97; time-by-manipulation interaction effect: p = 0.09, d = 0.89). The RPE increased slower in CHO than in PLA (p = 0.051; d = 0.7). The apparent reduction in global fatigue (central and peripheral) and RPESLOPE with only one CHO mouth rinse were not translated into improved TT4km performance. Further tests may be required to verify if these likely differences in global fatigue might represent an edge in the short-lasting cycling time trial performance. PMID- 29534508 TI - Functional Characterization of the alb1 Orthologue Gene in the Ochratoxigenic Fungus Aspergillus carbonarius (AC49 strain). AB - Aspergillus carbonarius, belonging to the group Nigri, is the main species responsible for contamination by ochratoxin A (OTA) in grapes and derivative products. OTA can accumulate in the mycelium and in black conidia of the fungus and released into the matrix. Here, we have deleted in A. carbonarius the alb1 orthologue gene of A. fumigatus, involved in melanin biosynthesis. Three A. carbonarius Deltaalb1 mutants were characterized for morphologic traits and OTA production on different media and temperatures. Deltaalb1 mutants showed a fawn color of conidia associated with a significant reduction of the conidiogenesis and a statistically significant increase (p <= 0.01) of total OTA production as compared to the wild type (WT) strain. The alb1 gene somehow affected OTA partitioning since in Deltaalb1 mutants OTA amount was lower in conidia and was more abundantly secreted into the medium as compared to the WT. On grape berries the Deltaalb1 mutants and the WT caused lesions with similar sizes but OTA amount in berry tissues was higher for the mutants. These results demonstrate that A. carbonarius conidia pigmentation is largely dependent on polyketide biosynthesis. The gene is not directly involved in virulence and its deletion affects morphological features and OTA production in the fungus. PMID- 29534506 TI - Saccharin Increases Fasting Blood Glucose but Not Liver Insulin Resistance in Comparison to a High Fructose-Fed Rat Model. AB - Recent data indicate that artificial sweeteners (AS) may have deleterious effects on glucose metabolism. The purpose of this study was to compare the effects of AS and the effects of a high fructose diet (HFrD) on glucose metabolism and insulin resistance (IR) in Sprague-Dawley (SD) rats. SD rats were fed either regular chow, chow with saccharin (Sac) (0.1 mg/mL) placed in their water, or HFrD for seven weeks. Glucose, insulin, and triglycerides (Tg) levels were measured upon completion. A homeostatic model assessment (HOMA)-IR index was used to determine insulin resistance. The liver was stained to detect signs of a fatty liver. Hepatic mRNA expression of glucose metabolism regulation genes, Srepb-1c (sterol regulatory element binding protein) and ChREB (alpha & beta) (carbohydrate response element binding protein), as well as other glycolytic and lipogenic genes including glucose-6-phosphatase (G6pc), were considered IR markers. Both HFrD and Sac significantly increased fasting blood glucose levels compare to the control (140 +/- 5 and 137 +/- 6 vs. 118 +/- 3 mg/dL, respectively, p < 0.05). However, only HFrD increased insulin secretion (0.99 +/- 0.12 vs. 0.7 +/- 0.1 and 0.6 +/- 0.1 ug/L), Tg levels (420 +/- 43 vs. 152 +/- 20 and 127 +/- 13 mg/dL), and the HOMA-IR index (3.4 +/- 0.4 vs. 2.3 +/- 0.36 and 2.13 +/- 0.3) (HFrD vs. control and sac, p < 0.05). Fatty liver changes were only observed in HFrD fed rats. The expression of ChREB beta, Srepb-1c, and G6pc mRNA were only significantly elevated (between 2-10 times folds, p < 0.05) in HFrD fed rats. Sac may increase fasting blood glucose but has no effect on liver insulin resistance. PMID- 29534509 TI - Effects of Nitric Oxide on Voltage-Gated K+ Currents in Human Cardiac Fibroblasts through the Protein Kinase G and Protein Kinase A Pathways but Not through S Nitrosylation. AB - This study investigated the expression of voltage-gated K+ (KV) channels in human cardiac fibroblasts (HCFs), and the effect of nitric oxide (NO) on the KV currents, and the underlying phosphorylation mechanisms. In reverse transcription polymerase chain reaction, two types of KV channels were detected in HCFs: delayed rectifier K+ channel and transient outward K+ channel. In whole-cell patch-clamp technique, delayed rectifier K+ current (IK) exhibited fast activation and slow inactivation, while transient outward K+ current (Ito) showed fast activation and inactivation kinetics. Both currents were blocked by 4 aminopyridine. An NO donor, S-nitroso-N-acetylpenicillamine (SNAP), increased the amplitude of IK in a concentration-dependent manner with an EC50 value of 26.4 uM, but did not affect Ito. The stimulating effect of SNAP on IK was blocked by pretreatment with 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or by KT5823. 8-bromo-cyclic GMP stimulated the IK. The stimulating effect of SNAP on IK was also blocked by pretreatment with KT5720 or by SQ22536. Forskolin and 8-bromo cyclic AMP each stimulated IK. On the other hand, the stimulating effect of SNAP on IK was not blocked by pretreatment of N-ethylmaleimide or by DL dithiothreitol. Our data suggest that NO enhances IK, but not Ito, among KV currents of HCFs, and the stimulating effect of NO on IK is through the PKG and PKA pathways, not through S-nitrosylation. PMID- 29534510 TI - Effects of Honokiol on CYP450 Activity and Transporter mRNA Expression in Type 2 Diabetic Rats. AB - This study was aimed to clarify the effect of honokiol (Hon) on the activity of Cytochrome P450 (CYP450) enzymes, and the level of mRNA expression of liver and kidney transporters in type 2 diabetic rats induced by high-fat diet and strepotozotocin. Rats were randomly divided into normal control (NC) group, diabetic control (DC) group and Hon groups (n = 6). The activities of hepatic CYP1A2, CYP2E1, CYP2C, CYP2B, CYP3A and CYP4A, and the mRNA expression levels of hepatic and renal transporters, were determined. Compared to the NC group, the activities of CYP1A2, CYP2E1, CYP4A and CYP2C in DC group were increased by 2.36 , 2.10-, 2.55- and 1.86-fold, respectively. The mRNA expression levels of hepatic Oat2, Oatp2b1 and Oatp1a5, and renal Oct1, Octn2, Oatp2b1 and Oatp1a5, were significantly down-regulated, while the mRNA expression levels of hepatic Octn2, Oatp3a1, Oatp1a1 and Mdr2, and renal Oat2, Mrp4 and Bcrp, were significantly upregulated. Compared to the DC group, Hon treatment significantly inhibited the activity of hepatic CYP2E1, CYP4A, 3A and CYP1A2 by 45.6%, 29.2%, 22.7% and 20.7% in Hon high dose group, respectively. Moreover, Hon treatment significantly inhibited the mRNA expression levels of renal Bcrp and Mrp4 by 2.63-fold and 1.54 fold, while significantly upregulated the mRNA expression levels of hepatic Oat2 and Oatp2b1 by 1.52-fold and 1.54-fold in Hon high dose group, respectively. The results suggested that under the diabetes condition, the changes of CYP450 activity and transporter expression inevitably interfere the normal transport, metabolism and efficacy of drugs. The present work firstly reported that Hon treatment ameliorated the abnormal change of hepatic CYP activity (including CYP2E1, CYP4A and CYP1A2) and the transporter mRNA expression (including hepatic Oat2 and Oatp2b1, renal Bcrp and Mrp4) in type 2 diabetic rats induced by high fat diet and strepotozotocin, which are associated with the occurrence and development of diabetes. PMID- 29534511 TI - Protozoan Parasites in Drinking Water: A System Approach for Improved Water, Sanitation and Hygiene in Developing Countries. AB - Improved water, sanitation and hygiene (WASH) are significant in preventing diarrhea morbidity and mortality caused by protozoa in low- and middle-income countries. Due to the intimate and complex relationships between the different WASH components, it is often necessary to improve not just one but all of these components to have sustainable results. The objective of this paper was to review the current state of WASH-related health problems caused by parasitic protozoa by: giving an overview and classification of protozoa and their effect on people's health, discussing different ways to improve accessibility to safe drinking water, sanitation services and personal hygiene behavior; and suggesting an institutional approach to ensure improved WASH. The findings indicate that Giardia and Cryptosporidium are more often identified during waterborne or water washed outbreaks and they are less sensitive than most of the bacteria and viruses to conventional drinking water and wastewater treatment methods. There are various institutions of control and prevention of water-related diseases caused by protozoa in developed countries. Unfortunately, the developing regions do not have comparable systems. Consequently, the institutional and systems approach to WASH is necessary in these countries. PMID- 29534513 TI - Research into Kinect/Inertial Measurement Units Based on Indoor Robots. AB - As indoor mobile navigation suffers from low positioning accuracy and accumulation error, we carried out research into an integrated location system for a robot based on Kinect and an Inertial Measurement Unit (IMU). In this paper, the close-range stereo images are used to calculate the attitude information and the translation amount of the adjacent positions of the robot by means of the absolute orientation algorithm, for improving the calculation accuracy of the robot's movement. Relying on the Kinect visual measurement and the strap-down IMU devices, we also use Kalman filtering to obtain the errors of the position and attitude outputs, in order to seek the optimal estimation and correct the errors. Experimental results show that the proposed method is able to improve the positioning accuracy and stability of the indoor mobile robot. PMID- 29534512 TI - Anthocyanin-Rich Extract from Red Chinese Cabbage Alleviates Vascular Inflammation in Endothelial Cells and Apo E-/- Mice. AB - Anthocyanins, the most prevalent flavonoids in red/purple fruits and vegetables, are known to improve immune responses and reduce chronic disease risks. In this study, the anti-inflammatory activities of an anthocyanin-rich extract from red Chinese cabbage (ArCC) were shown based on its inhibitory effects in cultured endothelial cells and hyperlipidemic apolipoprotein E-deficient mice. ArCC treatment suppressed monocyte adhesion to tumor necrosis factor-alpha-stimulated endothelial cells. This was validated by ArCC's ability to downregulate the expression and transcription of endothelial adhesion molecules, determined by immunoblot and luciferase promoter assays, respectively. The regulation of adhesion molecules was accompanied by transcriptional inhibition of nuclear factor-kappaB, which restricted cytoplasmic localization as shown by immunocytochemistry. Administration of ArCC (150 or 300 mg/kg/day) inhibited aortic inflammation in hyperlipidemic apolipoprotein E-deficient mice, as shown by in vivo imaging. Immunohistochemistry and plasma analysis showed that the aortas from these mice exhibited markedly lower leukocyte infiltration, reduced plaque formation, and lower concentrations of blood inflammatory cytokines than those observed in the control mice. The results suggest that the consumption of anthocyanin-rich red Chinese cabbage is closely correlated with lowering the risk of vascular inflammatory diseases. PMID- 29534514 TI - Integrated Optical Mach-Zehnder Interferometer Based on Organic-Inorganic Hybrids for Photonics-on-a-Chip Biosensing Applications. AB - The development of portable low-cost integrated optics-based biosensors for photonics-on-a-chip devices for real-time diagnosis are of great interest, offering significant advantages over current analytical methods. We report the fabrication and characterization of an optical sensor based on a Mach-Zehnder interferometer to monitor the growing concentration of bacteria in a liquid medium. The device pattern was imprinted on transparent self-patternable organic inorganic di-ureasil hybrid films by direct UV-laser, reducing the complexity and cost production compared with lithographic techniques or three-dimensional (3D) patterning using femtosecond lasers. The sensor performance was evaluated using, as an illustrative example, E. coli cell growth in an aqueous medium. The measured sensitivity (2 * 10-4 RIU) and limit of detection (LOD = 2 * 10-4) are among the best values known for low-refractive index contrast sensors. Furthermore, the di-ureasil hybrid used to produce this biosensor has additional advantages, such as mechanical flexibility, thermal stability, and low insertion losses due to fiber-device refractive index mismatch (~1.49). Therefore, the proposed sensor constitutes a direct, compact, fast, and cost-effective solution for monitoring the concentration of lived-cells. PMID- 29534515 TI - Investigating Patterns for Self-Induced Emotion Recognition from EEG Signals. AB - Most current approaches to emotion recognition are based on neural signals elicited by affective materials such as images, sounds and videos. However, the application of neural patterns in the recognition of self-induced emotions remains uninvestigated. In this study we inferred the patterns and neural signatures of self-induced emotions from electroencephalogram (EEG) signals. The EEG signals of 30 participants were recorded while they watched 18 Chinese movie clips which were intended to elicit six discrete emotions, including joy, neutrality, sadness, disgust, anger and fear. After watching each movie clip the participants were asked to self-induce emotions by recalling a specific scene from each movie. We analyzed the important features, electrode distribution and average neural patterns of different self-induced emotions. Results demonstrated that features related to high-frequency rhythm of EEG signals from electrodes distributed in the bilateral temporal, prefrontal and occipital lobes have outstanding performance in the discrimination of emotions. Moreover, the six discrete categories of self-induced emotion exhibit specific neural patterns and brain topography distributions. We achieved an average accuracy of 87.36% in the discrimination of positive from negative self-induced emotions and 54.52% in the classification of emotions into six discrete categories. Our research will help promote the development of comprehensive endogenous emotion recognition methods. PMID- 29534516 TI - TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice. AB - Although a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5' triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT Gap19 and carbenoxolone in the treatment of this type of chronic liver disease. PMID- 29534518 TI - Nutraceutical or Pharmacological Potential of Moringa oleifera Lam. AB - Moringa oleifera Lam. (M. oleifera), which belongs to the Moringaceae family, is a perennial deciduous tropical tree, and native to the south of the Himalayan Mountains in northern India. M. oleifera is rich in proteins, vitamin A, minerals, essential amino acids, antioxidants, and flavonoids, as well as isothiocyanates. The extracts from M. oleifera exhibit multiple nutraceutical or pharmacological functions including anti-inflammatory, antioxidant, anti-cancer, hepatoprotective, neuroprotective, hypoglycemic, and blood lipid-reducing functions. The beneficial functions of M. oleifera are strongly associated with its phytochemicals such as flavonoids or isothiocyanates with bioactivity. In this review, we summarize the research progress related to the bioactivity and pharmacological mechanisms of M. oleifera in the prevention and treatment of a series of chronic diseases-including inflammatory diseases, neuro-dysfunctional diseases, diabetes, and cancers-which will provide a reference for its potential application in the prevention and treatment of chronic diseases or health promotion. PMID- 29534519 TI - Hyaluronic Acid Decorated Naringenin Nanoparticles: Appraisal of Chemopreventive and Curative Potential for Lung Cancer. AB - Lung carcinoma is the most common cancer in men and second in women (preceded by breast cancer) worldwide. Around 1 in 10 of all cancers diagnosed in men, lung cancer contributed to a total fraction of 20% cancer deaths. Naringenin (NAR) is well known for its chemopreventive properties since ancient times but lacks an appropriate delivery carrier. The objective of present study was to expand the functionality of naringenin loaded poly caprolactone (PCL) nanoparticles in terms of release, chemoprevention and therapeutics. Polymeric nanoparticles such as PCL lack target specificity; hence, surface modification was attempted using layer by layer technique (LBL) to achieve improved and desired delivery as well as target specificity. The designing of Hyaluronic acid (HA) decorated PCL nanoparticles were prepared by utilizing self-assembling LBL technique, where a polycationic layer of a polymer was used as a linker for modification between two polyanionic layers. Additionally, an attempt has been made to strengthen the therapeutic efficacy of PCL nanocarriers by active targeting and overcoming the extracellular matrix associated barriers of tumors using HA targeting cluster determinant 44 receptor (CD44). Cell cytotoxicity study on A549 cells and J774 macrophage cells depicted enhanced anticancer effect of NAR-HA@CH-PCL-NP with safe profile on macrophages. Uptake study on A549 cells advocated enhanced drug uptake by cancer cells. Cell cycle arrest analysis (A549 cell lines) demonstrated the superior cytotoxic effect and active targeting of NAR-HA@CH-PCL-NP. Further chemopreventive treatment with NAR-HA@CH-PCL-NP was found effective in tumor growth inhibitory effect against urethane-induced lung cancer in rat. In conclusion, developed formulation possesses a promising potential as a therapeutic and chemopreventive agent against urethane-induced lung carcinoma in albino wistar rats. PMID- 29534517 TI - The Cells of the Islets of Langerhans. AB - Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-beta islet cells in to insulin-producing beta-cells to replenish beta-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/beta-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of beta-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-beta islet cells to be a reality in humans. We know a fair amount about the biology of beta cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-beta cells, and on human pancreatic islet mass and distribution. PMID- 29534521 TI - Epilepsy Surgery for Skull-Base Temporal Lobe Encephaloceles: Should We Spare the Hippocampus from Resection? AB - The neurosurgical treatment of skull base temporal encephalocele for patients with epilepsy is variable. We describe two adult cases of temporal lobe epilepsy (TLE) with spheno-temporal encephalocele, currently seizure-free for more than two years after anterior temporal lobectomy (ATL) and lesionectomy sparing the hippocampus without long-term intracranial electroencephalogram (EEG) monitoring. Encephaloceles were detected by magnetic resonance imaging (MRI) and confirmed by maxillofacial head computed tomography (CT) scans. Seizures were captured by scalp video-EEG recording. One case underwent intraoperative electrocorticography (ECoG) with pathology demonstrating neuronal heterotopia. We propose that in some patients with skull base temporal encephaloceles, minimal surgical resection of herniated and adjacent temporal cortex (lesionectomy) is sufficient to render seizure freedom. In future cases, where an associated malformation of cortical development is suspected, newer techniques such as minimally invasive EEG monitoring with stereotactic-depth EEG electrodes should be considered to tailor the surrounding margins of the resected epileptogenic zone. PMID- 29534520 TI - mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome. AB - The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cellular growth and metabolism with environmental inputs to ensure that cells grow only under favourable conditions. When active, mTORC1 stimulates biosynthetic pathways including protein, lipid and nucleotide synthesis and inhibits cellular catabolism through repression of the autophagic pathway, thereby promoting cell growth and proliferation. The recruitment of mTORC1 to the lysosomal surface has been shown to be essential for its activation. This finding has significantly enhanced our knowledge of mTORC1 regulation and has focused the attention of the field on the lysosome as a signalling hub which coordinates several homeostatic pathways. The intriguing localisation of mTORC1 to the cellular organelle that plays a crucial role in catabolism enables mTORC1 to feedback to autophagy and lysosomal biogenesis, thus leading mTORC1 to enact precise spatial and temporal control of cell growth. This review will cover the signalling interactions which take place on the surface of lysosomes and the cross-talk which exists between mTORC1 activity and lysosomal function. PMID- 29534522 TI - Regulation of T-Cell Signaling by Post-Translational Modifications in Autoimmune Disease. AB - The adaptive immune system involves antigen-specific host defense mechanisms mediated by T and B cells. In particular, CD4+ T cells play a central role in the elimination of pathogens. Immunological tolerance in the thymus regulates T lymphocytes to avoid self-components, including induction of cell death in immature T cells expressing the self-reactive T-cell receptor repertoire. In the periphery, mature T cells are also regulated by tolerance, e.g., via induction of anergy or regulatory T cells. Thus, T cells strictly control intrinsic signal transduction to prevent excessive responses or self-reactions. If the inhibitory effects of T cells on these mechanisms are disrupted, T cells may incorrectly attack self-components, which can lead to autoimmune disease. The functions of T cells are supported by post-translational modifications, particularly phosphorylation, of signaling molecules, the proper regulation of which is controlled by endogenous mechanisms within the T cells themselves. In recent years, molecular targeted agents against kinases have been developed for treatment of autoimmune diseases. In this review, we discuss T-cell signal transduction in autoimmune disease and provide an overview of acetylation mediated regulation of T-cell signaling pathways. PMID- 29534524 TI - The Impact of Iron Adsorption on the Electronic and Photocatalytic Properties of the Zinc Oxide (0001) Surface: A First-Principles Study. AB - The structural stability, electronic structure, and optical properties of an iron adsorbed ZnO (0001) surface with three high-symmetry adsorption sites are investigated with first-principle calculations on the basis of density functional theory and the Hubbard-U method. It is found that the iron adatom in the H3 adsorption site of ZnO (0001) surface has the lowest adsorption energy of -5.665 eV compared with T4 and Top sites. For the Top site, compared with the pristine ZnO (0001) surface, the absorption peak located at 1.17 eV has a red shift, and the elevation of the absorption coefficient is more pronounced in the visible light region, because the Fe-related levels are introduced in the forbidden band and near the Fermi level. The electrostatic potential computation reveals that the work function of the ZnO (0001) surface is significantly decreased from 2.340 to 1.768 eV when iron is adsorbed on the Top site. Furthermore, the degradation mechanism based on the band structure is analyzed. It can be concluded that the adsorption of iron will promote the separation of photoinduced carriers, thus improving the photocatalytic activity of ZnO (0001) surface. Our study benefits research on the photocatalytic activity of ZnO and the utilization rate of solar energy. PMID- 29534523 TI - Exploring the In Vivo Anti-Inflammatory Actions of Simvastatin-Loaded Porous Microspheres on Inflamed Tenocytes in a Collagenase-Induced Animal Model of Achilles Tendinitis. AB - Tendon rupture induces an inflammatory response characterized by release of pro inflammatory cytokines and impaired tendon performance. This study sought to investigate the therapeutic effects of simvastatin-loaded porous microspheres (SIM/PMSs) on inflamed tenocytes in vitro and collagenase-induced Achilles tendinitis in vivo. The treatment of SIM/PMSs in lipopolysaccharide (LPS)-treated tenocytes reduced the mRNA expressions of pro-inflammatory cytokines (Matrix metalloproteinase-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)). In addition, the local injection of SIM/PMSs into the tendons of collagenase-induced Achilles tendinitis rat models suppressed pro-inflammatory cytokines (MMP-3, COX-2, IL-6, TNF-alpha, and MMP 13). This local treatment also upregulated anti-inflammatory cytokines (IL-4, IL 10, and IL-13). Furthermore, treatment with SIM/PMSs also improved the alignment of collagen fibrils and effectively prevented collagen disruption in a dose dependent manner. Therefore, SIM/PMSs treatment resulted in an incremental increase in the collagen content, stiffness, and tensile strength in tendons. This study suggests that SIM/PMSs have great potential for tendon healing and restoration in Achilles tendinitis. PMID- 29534525 TI - Association between Erythrocyte Membrane Phospholipid Fatty Acids and Sleep Disturbance in Chinese Children and Adolescents. AB - The relationship between circulating fatty acid (FA) composition and childhood sleep disturbance remains largely unclear. We aimed to investigate the association of erythrocyte membrane FA composition with prevalence of sleep disturbance in Chinese children and adolescents. A cross-sectional survey was conducted among 2337 school-aged children and adolescents who completed a clinical assessment in Beijing, China. Presence of sleep disturbance was self reported or parent-reported by questionnaires. Erythrocyte FAs were measured by gas chromatography, and desaturase activities were estimated by FA ratios. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for sleep disturbance across FA quartiles were calculated by a logistical regression model. We found higher proportions of erythrocyte phospholipid 24:0, 24:1n-9, and lower proportions of total n-3 polyunsaturated FA (PUFA), 22:5n-3 and 22:6n-3 in participants with sleep disturbance compared with those without. In the logistical regression models, significant inverse associations were found for total n-3 PUFA, 22:5n-3 and 22:6n-3, the highest versus lowest quartile ORs and 95% CIs were 0.57 (0.40, 0.82), 0.67 (0.47, 0.97) and 0.69 (0.49, 0.96), respectively. For per 1 SD difference of proportion, OR and 95% CI of prevalence of sleep disturbance was 0.91 (0.86, 0.97) for total n-3 PUFA, 0.90 (0.82, 0.98) for 22:5n-3, and 0.92 (0.86, 0.99) for 22:6n-3, respectively. No significant association was found for saturated fatty acids, monounsaturated fatty acids, n-6 polyunsaturated fatty acids or FA ratios. The present study suggested that erythrocyte n-3 PUFAs, especially 22:5n-3 and 22:6n-3, are inversely associated with prevalence of sleep disturbance in Chinese children and adolescents. PMID- 29534526 TI - Peiminine Protects Dopaminergic Neurons from Inflammation-Induced Cell Death by Inhibiting the ERK1/2 and NF-kappaB Signalling Pathways. AB - Neuroinflammation, characterized marked by microglial activation, plays a very important role in the pathogenesis of Parkinson's disease (PD). Upon activation, pro-inflammatory mediators are produced by microglia, triggering excessive inflammatory responses and ultimately damaging dopaminergic neurons. Therefore, the identification of agents that inhibit neuroinflammation may be an effective approach for developing novel treatments for PD. In this study, we sought to investigate whether peiminine protects dopaminergic neurons by inhibiting neuroinflammation. We evaluated the effects of peiminine on behavioural dysfunction, microglial activation and the loss of dopaminergic neurons in a rat model of lipopolysaccharide (LPS)-induced PD. BV-2 cells were pretreated with peiminine for 1 h and then stimulated with LPS for different times. Then, inflammatory responses and the related signalling pathways were analysed. Peiminine markedly attenuated behavioural dysfunction and inhibited the loss of dopaminergic neurons and microglial activation in the LPS-induced PD rat model. In BV-2 cells, peiminine significantly decreased LPS-induced expression of the pro-inflammatory mediators TNF-alpha, IL-6 and IL-1beta, COX-2 and iNOS by inhibiting the phosphorylation of ERK1/2, AKT and NF-kappaB p65. Based on these results demonstrated that peiminine has a role in protecting dopaminergic neurons in the LPS-induced PD rat model by inhibiting neuroinflammation. PMID- 29534527 TI - Geochemical Assessment and Spatial Analysis of Heavy Metals in the Surface Sediments in the Eastern Beibu Gulf: A Reflection on the Industrial Development of the South China Coast. AB - The Beibu Gulf (also named the Gulf of Tonkin), located in the northwest of the South China Sea, is representative of a bay suffering from turbulence and contamination associated with rapid industrialization and urbanization. In this study, we aim to provide the novel baseline levels of heavy metals for the research area. Concentrations of five heavy metals (i.e., Cu, Pb, Zn, Cd and Cr) were determined in surface sediments from 35 sites in the eastern Beibu Gulf. The heavy metal content varied from 6.72 to 25.95 mg/kg for Cu, 16.99 to 57.98 mg/kg for Pb, 73.15 to 112.25 mg/kg for Zn, 0.03 to 0.12 mg/kg for Cd, and 20.69 to 56.47 mg/kg for Cr, respectively. With respect to the Chinese sediment quality criteria, sediments in the eastern Beibu Gulf have not been significantly affected by coastal metal pollutions. The results deduced from the geoaccumulation index (Igeo) showed that the study area has been slightly polluted by Pb, which might be caused by non-point sources. Relatively high concentrations of Cu, Pb and Cd were found around the coastal areas of Guangxi province, the Leizhou Peninsula and the northwest coast of Hainan Island, whereas the highest concentrations of Zn and Cr were found on the northwest coast of Hainan Island. Spatial distribution patterns of the heavy metals showed that bioavailable fractions of Pb were higher than in the residual fractions, while Cu and Cd concentrations in exchangeable and carbonate fractions were relatively higher than those in the bioavailable fractions. Hierarchical clustering analysis suggested that the sampling stations could be separated into three groups with different geographical distributions. Accompanying their similar spatial distribution in the study area, significant correlation coefficients among Cu, Cd and Pb were also found, indicating that these three metals might have had similar sources. Overall, the results indicated that the distribution of these heavy metals in the surface sediments collected from the Beibu Gulf was complex. PMID- 29534528 TI - Development of Dipicolylamine-Modified Cyclodextrins for the Design of Selective Guest-Responsive Receptors for ATP. AB - The construction of supramolecular recognition systems based on specific host guest interactions has been studied in order to design selective chemical sensors. In this study, guest-responsive receptors for ATP have been designed with cyclodextrins (CyDs) as a basic prototype of the turn-on type fluorescent indicator. We synthesized dipicolylamine (DPA)-modified CyD-Cu2+ complexes (Cu.1alpha, Cu.1beta, and Cu.1gamma), and evaluated their recognition capabilities toward phosphoric acid derivatives in water. The UV-Vis absorption and fluorescence spectra revealed that Cu.1beta selectively recognized ATP over other organic and inorganic phosphates, and that beta-CyD had the most suitable cavity size for complexation with ATP. The 1D and 2D NMR analyses suggested that the ATP recognition was based on the host-guest interaction between the adenine moiety of ATP and the CyD cavity, as well as the recognition of phosphoric moieties by the Cu2+-DPA complex site. The specific interactions between the CyD cavity and the nucleobases enabled us to distinguish ATP from other nucleoside triphosphates, such as guanosine triphosphate (GTP), uridine triphosphate (UTP), and cytidine triphosphate (CTP). This study clarified the basic mechanisms of molecular recognition by modified CyDs, and suggested the potential for further application of CyDs in the design of highly selective supramolecular recognition systems for certain molecular targets in water. PMID- 29534529 TI - Functional Analysis of Maize Silk-Specific ZmbZIP25 Promoter. AB - ZmbZIP25 (Zea mays bZIP (basic leucine zipper) transcription factor 25) is a function-unknown protein that belongs to the D group of the bZIP transcription factor family. RNA-seq data showed that the expression of ZmbZIP25 was tissue specific in maize silks, and this specificity was confirmed by RT-PCR (reverse transcription-polymerase chain reaction). In situ RNA hybridization showed that ZmbZIP25 was expressed exclusively in the xylem of maize silks. A 5' RACE (rapid amplification of cDNA ends) assay identified an adenine residue as the transcription start site of the ZmbZIP25 gene. To characterize this silk-specific promoter, we isolated and analyzed a 2450 bp (from -2083 to +367) and a 2600 bp sequence of ZmbZIP25 (from -2083 to +517, the transcription start site was denoted +1). Stable expression assays in Arabidopsis showed that the expression of the reporter gene GUS driven by the 2450 bp ZmbZIP25 5'-flanking fragment occurred exclusively in the papillae of Arabidopsis stigmas. Furthermore, transient expression assays in maize indicated that GUS and GFP expression driven by the 2450 bp ZmbZIP25 5'-flanking sequences occurred only in maize silks and not in other tissues. However, no GUS or GFP expression was driven by the 2600 bp ZmbZIP25 5'-flanking sequences in either stable or transient expression assays. A series of deletion analyses of the 2450 bp ZmbZIP25 5'-flanking sequence was performed in transgenic Arabidopsis plants, and probable elements prediction analysis revealed the possible presence of negative regulatory elements within the 161 bp region from -1117 to -957 that were responsible for the specificity of the ZmbZIP25 5'-flanking sequence. PMID- 29534530 TI - Work Environment, Stress, and Driving Anger: A Structural Equation Model for Predicting Traffic Sanctions of Public Transport Drivers. AB - Public transport is an effective and sustainable alternative to private vehicle usage, also helping to reduce the environmental impact of driving. However, the work environment of public transport operators is full of adverse conditions, which, together with their high mileage, may increase the occurrence of negative safety outcomes such as traffic accidents, often preceded by risky road behaviors enhanced by stress, anger, and difficult operating conditions. The aims of this study were, first, to determine the association between work-related psychosocial factors and individual characteristics of public transport drivers and the rate of traffic sanctions they are subject to; and second, to assess the mediation of driving anger in this relationship. A sample of professional drivers (57.4% city bus, 17.6% taxi, and 25% inter-urban bus male operators) was used for this cross sectional study, responding to a five-section survey including demographic data and driving-related factors, psychosocial work factors including job stress, driving stress, risk predisposition, and driving anger. The results of this study showed significant associations between work-related factors: measures of stress and self-reported rates of traffic fines. Second, it was found that driving anger mediates the associations between driving stress, risk predisposition, and traffic sanctions; and partially mediates the association between driving experience, hourly intensity, and job stress. This study supports the idea that traffic penalties reported by public transport rates are preceded by work related, personality, and other individual factors that, when combined with driving anger, enhance the occurrence of road misbehavior that may affect overall road safety. PMID- 29534531 TI - Comparative Effectiveness of Published Interventions for Elderly Fall Prevention: A Systematic Review and Network Meta-Analysis. AB - BACKGROUND: Falls are a major threat to older adults worldwide. Although various effective interventions have been developed, their comparative effectiveness remains unreported. METHODS: A systematic review and network meta-analysis was conducted to determine the most effective interventions to prevent falls in community-dwelling adults aged 60 and over. Combined odds ratio (OR) and 95% credible interval (95% CrI) were calculated. RESULTS: A total of 49 trials involving 27,740 participants and 9271 fallers were included. Compared to usual care, multifactorial interventions (MFI) demonstrated the greatest efficacy (OR: 0.64, 95% CrI: 0.53 to 0.77) followed by interventions combining education and exercise (EDU + EXC) (OR: 0.65, 95% CrI: 0.38 to 1.00) and interventions combining exercise and hazard assessment and modification (EXC + HAM) (OR: 0.66, 95% CrI: 0.40 to 1.04). The effect of medical care performed the worst (OR: 1.02, 95% CrI: 0.78 to 1.34). Model fit was good, inconsistency was low, and publication bias was considered absent. The overall quality of included trials was high. The pooled odds ratios and ranking probabilities remained relatively stable across all sensitivity analyses. CONCLUSIONS: MFI and exercise appear to be effective to reduce falls among older adults, and should be considered first as service delivery options. Further investigation is necessary to verify effectiveness and suitableness of the strategies to at-risk populations. PMID- 29534532 TI - Characterization of Ageing- and Diet-Related Swine Models of Sarcopenia and Sarcopenic Obesity. AB - Sarcopenia and sarcopenic obesity are currently considered major global threats for health and well-being. However, there is a lack of adequate preclinical models for their study. The present trial evaluated the suitability of aged swine by determining changes in adiposity, fatty acids composition, antioxidant status and lipid peroxidation, development of metabolic disturbances and structural changes in tissues and organs. Iberian sows with clinical evidence of aging related sarcopenia were fed a standard diet fulfilling their maintenance requirements or an obesogenic diet for 100 days. Aging and sarcopenia were related to increased lipid accumulation and cellular dysfunction at both adipose tissue and non-adipose ectopic tissues (liver and pancreas). Obesity concomitant to sarcopenia aggravates the condition by increasing visceral adiposity and causing dyslipidemia, insulin resistance and lipotoxicity in non-adipose tissues. These results support that the Iberian swine model represents certain features of sarcopenia and sarcopenic obesity in humans, paving the way for future research on physiopathology of these conditions and possible therapeutic targets. PMID- 29534533 TI - 3'-UTR Polymorphisms of MTHFR and TS Associated with Osteoporotic Vertebral Compression Fracture Susceptibility in Postmenopausal Women. AB - Postmenopausal osteoporosis is one of the most prominent diseases in postmenopausal women and it is increasing in prevalence with the aging population. Furthermore, osteoporosis and osteoporotic vertebral compression fractures (OVCFs) are related to mortality and decreased quality of life. Therefore, searching for biomarkers that are able to identify postmenopausal women who are at high risk of developing OVCFs is an effective strategy for improving the quality of life of patients and alleviating social and economic burdens. In this study, we investigated methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) gene polymorphisms in postmenopausal women with OVCF. We recruited 301 postmenopausal women and performed genotyping for the presence of MTHFR 2572C>A, 4869C>G and TS 1100C>T, 1170A>G. Genotyping was analyzed using the polymerization chain reaction restriction fragment length polymorphism assay. MTHFR 2572C>A and TS 1100C>T were associated with the prevalence of osteoporosis (MTHFR 2572CC versus CA+AA: odd ratio [OR] adjusted age, hypertention [HTN], and diabetes mellitus [DM] = 0.49, p = 0.012) and the occurrence of OVCFs (MTHFR 2572CC versus CA+AA: OR adjusted age, HTN, and DM = 0.38, p = 0.013; TS 1100CC versus CT+TT: OR adjusted age, HTN, and DM = 0.46, p = 0.02). Our novel finding is the identification of MTHFR and TS genetic variants that decrease susceptibility to OVCFs. Our findings suggest that polymorphisms in the MTHFR and TS genes are associated with susceptibility to osteoporosis and OVCFs in postmenopausal women. PMID- 29534534 TI - Hair as a Biomarker of Long Term Mercury Exposure in Brazilian Amazon: A Systematic Review. AB - Many studies have assessed mercury (Hg) exposure in the Amazonian population. This article performs a literature search of the studies that used hair as a biomarker of Hg exposure in the Brazilian Amazonian population. The search covered the period from 1996 to 2016 and included articles which matched the following criteria: (1) articles related to Hg exposure into Brazilian Amazon; (2) articles that used hair as a biomarker of Hg exposure; (3) articles that used analytical tools to measure the Hg content on hair and (4) articles that presented arithmetic mean and/or minimum and maximum values of Hg. 36 studies were selected. The findings show that most of the studies were performed along margins of important rivers, such as Negro, Tapajos and Madeira. All the population presented mean levels of Hg on hair above 6 ug g-1 and general population, adults, not determined and men presented levels of Hg on hair above 10 ug g-1. The results show that most of the studies were performed by Brazilian institutions/researchers and the majority was performed in the State of Para. The present study identified that Amazonian population has long-term been exposed to Hg. In terms of future perspectives, this study suggests the implementation of a strategic plan for environmental health surveillance in the region in order to promote health and benefit Amazonian population. PMID- 29534536 TI - Lung Cancer Chemopreventive Activity of Patulin Isolated from Penicillium vulpinum. AB - Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-kappaB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-kappaB inhibitors are actively sought after for both cancer chemoprevention and therapy, and fungi represent an interesting unexplored reservoir for such molecules. The aim of the present work was to find naturally occurring lung cancer chemopreventive compounds by investigating the metabolites of Penicillium vulpinum, a fungus that grows naturally on dung. Penicillium vulpinum was cultivated in Potato Dextrose Broth and extracted with ethyl acetate. Bioassay-guided fractionation of this extract was performed by measuring NF-kappaB activity using a HEK293 cell line transfected with an NF-kappaB-driven luciferase reporter gene. The mycotoxin patulin was identified as a nanomolar inhibitor of TNF-alpha-induced NF-kappaB activity. Immunocytochemistry and Western blot analyses revealed that its mechanism of action involved an inhibition of p65 nuclear translocation and was independent from the NF-kappaB inhibitor alpha (IkappaBalpha) degradation process. Enhancing its interest in lung cancer chemoprevention, patulin also exhibited antiproliferative, proapoptotic, and antimigration effects on human lung adenocarcinoma cells through inhibition of the Wnt pathway. PMID- 29534535 TI - Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment. AB - Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-alpha)-mediated reduction of collagen II and decreased TNF-alpha-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-alpha downstream signaling, including I kappa B kinase (IKK)alpha/beta-IkappaBalpha-nuclear factor-kappaB (NF-kappaB) and c-Jun N terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research. PMID- 29534537 TI - Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation. AB - A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel-Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 MUM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro. PMID- 29534539 TI - Prenylated Polyphenols from Broussonetia kazinoki as Inhibitors of Nitric Oxide Production. AB - Excessive nitric oxide (NO) production by macrophages has been involved in inflammatory diseases. Seven polyphenols (1-7) were isolated from Broussonetia kazinoki (B. kazinoki) and investigated as potential inhibitors of NO overproduction in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Among them, four prenylated polyphenols (2-4 and 6) with a catechol moiety efficiently suppressed the LPS-induced high level of NO with IC50 values of less than 6 uM. The compounds 2-4 and 6 also attenuated protein and mRNA levels of inducible nitric oxide synthase (iNOS). Moreover, they suppressed the nuclear factor kappaB (NF-kappaB) activity by inhibiting the degradation of inhibitory-kappaB-alpha (I kappaB-alpha) and the translocation of NF-kappaB into the nucleus in LPS activated macrophages. Taken together, these findings suggest that polyphenols from B. kazinoki might be beneficial for treatment of inflammatory diseases. PMID- 29534538 TI - Recent Advances in Zirconium-89 Chelator Development. AB - The interest in zirconium-89 (89Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a variety of clinical and preclinical applications. However, to be utilized effectively in PET applications it must be stably bound to a targeting ligand, and the most successfully used 89Zr chelator is desferrioxamine B (DFO), which is commercially available as the iron chelator Desferal(r). Despite the prevalence of DFO in 89Zr-immuno-PET applications, the development of new ligands for this radiometal is an active area of research. This review focuses on recent advances in zirconium-89 chelation chemistry and will highlight the rapidly expanding ligand classes that are under investigation as DFO alternatives. PMID- 29534540 TI - New Naphthoquinone Terpenoids from Marine Actinobacterium, Streptomyces sp. CNQ 509. AB - A member of the marine streptomycete clade MAR4, Streptomyces sp. CNQ-509, has genetic potential for the biosynthesis of hybrid isoprenoids and produces several meroterpenoids such as naphterpin, nitropyrrolin and marinophenazine. Our research on the strain CNQ-509 led to the isolation of two new naphterpin derivatives (1 and 2) comprised of naphthoquinone and geranyl moieties along with the known terpenoid, debromomarinone. The two-dimensional structure of these compounds was determined through spectral data analysis using data from NMR, MS and UV spectroscopy. Furthermore, the full structures of 1 and 2 including absolute configurations were unequivocally established by a combination of NMR experiments and chemical modifications. PMID- 29534541 TI - Description of New and Amended Clades of the Genus Photobacterium. AB - Phylogenetic relationships between species in the genus Photobacterium have been poorly studied despite pathogenic and ecological relevance of some of its members. This is the first phylogenetic study that includes new species of Photobacterium (validated or not) that have not been included in any of the previously described clades, using 16S rRNA sequences and multilocus sequence analysis (MLSA) in concatenated sequences of gyrB, gapA, topA, ftsZ and mreB housekeeping genes. Sequence analysis has been implemented using Maximum parsimony (MP), Neighbour-joining (NJ) and Maximum likelihood (ML) treeing methods and the predicted evolutionary relationship between the Photobacterium clades was established on the basis of bootstrap values of >75% for 16S rRNA sequences and MLSA. We have grouped 22 species of the genus Photobacterium into the following 5 clades: Phosphoreum (comprises P. aquimaris, "P. carnosum," P. iliopiscarium, P. kishitanii, P. phosphoreum, "P. piscicola" and "P. toruni"); clade Profundum (composed of P. aestuarii, P. alginatilyticum, P. frigidiphilum, P. indicum, P. jeanii, P. lipolyticum, "P. marinum," and P. profundum); clade Damselae (two subspecies of P. damselae, damselae and piscicida); and two new clades: clade Ganghwense (includes P. aphoticum, P. aquae, P. galatheae, P. ganghwense, P. halotolerans, P. panuliri and P. proteolyticum); and clade Leiognathi (composed by P. angustum, P. leiognathi subsp. leiognathi and "P. leiognathi subsp. mandapamensis"). Two additional clades, Rosenbergii and Swingsii, were formed using a phylogenetic method based on 16S rRNA gene, although they are not confirmed by any MLSA methods. Only P. aplysiae could not be included in none of the established clade, constituting an orphan clade. PMID- 29534542 TI - Influence of InAlN Nanospiral Structures on the Behavior of Reflected Light Polarization. AB - The influence of structural configurations of indium aluminum nitride (InAlN) nanospirals, grown by reactive magnetron sputter epitaxy, on the transformation of light polarization are investigated in terms of varying structural chirality, growth temperatures, titanium nitride (TiN) seed (buffer) layer thickness, nanospiral thickness, and pitch. The handedness of reflected circularly polarized light in the ultraviolet-visible region corresponding to the chirality of nanospirals is demonstrated. A high degree of circular polarization (Pc) value of 0.75 is obtained from a sample consisting of 1.2 MUm InAlN nanospirals grown at 650 degrees C. A film-like structure is formed at temperatures lower than 450 degrees C. At growth temperatures higher than 750 degrees C, less than 0.1 In content is incorporated into the InAlN nanospirals. Both cases reveal very low Pc. A red shift of wavelength at Pc peak is found with increasing nanospiral pitch in the range of 200-300 nm. The Pc decreases to 0.37 for two-turn nanospirals with total length of 0.7 MUm, attributed to insufficient constructive interference. A branch-like structure appears on the surface when the nanospirals are grown longer than 1.2 MUm, which yields a low Pc around 0.5, caused by the excessive scattering of incident light. PMID- 29534543 TI - Validation of a Dietary Screening Tool in a Middle-Aged Appalachian Population. AB - Proactive nutrition screening is an effective public health strategy for identifying and targeting individuals who could benefit from making dietary improvements for primary and secondary prevention of disease. The Dietary Screening Tool (DST) was developed and validated to assess nutritional risk among rural older adults. The purpose of this study was to evaluate the utility and validity of the DST to identify nutritional risk in middle-aged adults. This cross-sectional study in middle-aged adults (45-64 year olds, n = 87) who reside in Appalachia, examined nutritional status using an online health survey, biochemical measures, anthropometry, and three representative 24-h dietary recalls. The Healthy Eating Index (HEI) was calculated to describe overall diet quality. Adults identified by the DST with a nutrition risk had lower HEI scores (50 vs. 64, p < 0.001) and were much more likely to also be considered at dietary risk by the HEI (OR 11.6; 3.2-42.6) when compared to those not at risk. Those at risk had higher energy-adjusted total fat, saturated fat, and added sugar intakes and lower intakes of dietary fiber, and several micronutrients than those classified as not at risk by the DST. Similarly, the at-risk group had significantly lower serum levels of alpha-carotene, beta-carotene, cryptoxanthin, lutein, and zeaxanthin but did not differ in retinol or methylmalonic acid compared with those not at risk. The DST is a valid tool to identify middle-aged adults with nutritional risk. PMID- 29534544 TI - A Comparison of the Effects of Packaging Containing Nano ZnO or Polylysine on the Microbial Purity and Texture of Cod (Gadus morhua) Fillets. AB - Portions of fresh Baltic cod fillets were packed into cellulose boxes (control samples), which were covered with Methyl Hydroxypropyl Celluloses (MHPC) coating with 2% polylysine. The cellulose boxes had square PE films and were enclosed in MHPC coating containing ZnO nanoparticles. The cod fillets were stored at 5 degrees C and examined after 72 h and 144 h storage times. Results obtained in this study showed that the textural parameters of the cod fillets increased, with both Springiness and Cohesiveness found greater after 144 h of storage for all analysed packaging materials. The Gumminess of fillets increased after storage, but the lowest increase was noted in cod samples that were stored in boxes containing PE films with ZnO nanoparticles. It was found that water loss from the cod fillets in these boxes was also lowest. The Adhesiveness of the fish samples stored in boxes devoid of active coatings also increased. In contrast to the packaging material devoid of active coatings, the storage of fillets in active coating boxes resulted in a decrease of adhesiveness. Microbial analysis showed that packaging material containing nano-ZnO was found to be more active against mesophilic and psychotropic bacterial cells than the coatings with polylysine after 72 h and 144 h of storage. PMID- 29534545 TI - Intermittent Fasting with or without Exercise Prevents Weight Gain and Improves Lipids in Diet-Induced Obese Mice. AB - Intermittent fasting (IF) and high intensity interval training (HIIT) are effective lifestyle interventions for improving body composition and overall health. However, the long-term effects of IF and potential synergistic effects of combining IF with exercise are unclear. The purpose of the study was to investigate the long-term effects of IF, with or without HIIT, on body composition and markers of metabolic health in diet-induced obese mice. In a randosmised, controlled design, 8-week-old C57BL/6 mice (males (n = 39) and females (n = 49)) were fed a high fat (HF) and sugar (S) water diet (30% (w/v)) for 24-weeks but were separated into five groups at 12-weeks: (1) 'obese' baseline control (OBC); (2) no intervention (CON); (3) intermittent fasting (IF); (4) high intensity intermittent exercise (HIIT) and (5) combination of dietary and exercise intervention (IF + HIIT). Body composition, strength and blood variables were measured at 0, 10 and/or 12-weeks. Intermittent fasting with or without HIIT resulted in significantly less weight gain, fat mass accumulation and reduced serum low density lipoproteins (LDL) levels compared to HIIT and CON male mice (p < 0.05). The results suggest that IF, with or without HIIT, can be an effective strategy for weight gain prevention despite concurrently consuming a high fat and sugar diet. PMID- 29534547 TI - Genome-Wide Transcriptome Analysis Reveals the Comprehensive Response of Two Susceptible Poplar Sections to Marssonina brunnea Infection. AB - Marssonina leaf spot disease of poplar (MLDP), caused by the hemibiotrophic pathogen Marssonina brunnea, frequently results in damage to many poplar species. In nature, two formae speciales of M. brunnea exist that are susceptible to different poplar subgenera. Marssonina brunnea f. sp. monogermtubi infects poplar hosts from Populus sect. Aigeiros (Aig), while M. brunnea f. sp. multigermtubi always infects poplar hosts from Populus sect. Leuce Duby (Leu). Based on the fungal penetration structures, a comprehensive transcriptomic approach was used to investigate the gene expression patterns of these two poplar subgenera at three crucial infection stages. MLDP significantly altered the expression patterns of many genes involved in mitogen activated protein kinase (MAPKs) and calcium signaling, transcription factors, primary and secondary metabolism, and other processes in both poplar subgenera. However, major differences in gene expression were also observed between the two poplar subgenera. Aig was most responsive at the initial infection stage, while Leu largely interacted with M. brunnea at the necrotrophic phase. Furthermore, the differentially expressed genes (DEGs) involved in pathways related to biotic stress also differed substantially between the two poplar subgenera. Further analysis indicated that the genes involved in cell wall metabolism and phenylpropanoid metabolism were differentially expressed in the progression of the disease. By examining the expression patterns of genes related to the defense against disease, we found that several genes annotated with causing hypersensitive cell death were upregulated at the necrotrophic phase of MLDP, inferring that plant immune response potentially happened at this infection stage. The present research elucidated the potential molecular differences between the two susceptible interaction systems in MLDP and provided novel insight into the temporal regulation of genes during the susceptible response. To the best of our knowledge, this study also constitutes the first to reveal the molecular mechanisms of poplar in response to the transition of hemibiotrophic fungal pathogens from the biotrophic phase to the necrotrophic phase. PMID- 29534548 TI - Comparative Transcriptome Analyses Reveal Potential Mechanisms of Enhanced Drought Tolerance in Transgenic Salvia Miltiorrhiza Plants Expressing AtDREB1A from Arabidopsis. AB - In our previous study, drought-resistant transgenic plants of Salvia miltiorrhiza were produced via overexpression of the transcription factor AtDREB1A. To unravel the molecular mechanisms underpinning elevated drought tolerance in transgenic plants, in the present study we compared the global transcriptional profiles of wild-type (WT) and AtDREB1A-expressing transgenic plants using RNA-sequencing (RNA-seq). Using cluster analysis, we identified 3904 differentially expressed genes (DEGs). Compared with WT plants, 423 unigenes were up-regulated in pRD29A::AtDREB1A-31 before drought treatment, while 936 were down-regulated and 1580 and 1313 unigenes were up- and down-regulated after six days of drought. COG analysis revealed that the 'signal transduction mechanisms' category was highly enriched among these DEGs both before and after drought stress. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation, DEGs associated with "ribosome", "plant hormone signal transduction", photosynthesis", "plant-pathogen interaction", "glycolysis/gluconeogenesis" and "carbon fixation" are hypothesized to perform major functions in drought resistance in AtDREB1A-expressing transgenic plants. Furthermore, the number of DEGs associated with different transcription factors increased significantly after drought stress, especially the AP2/ERF, bZIP and MYB protein families. Taken together, this study substantially expands the transcriptomic information for S. miltiorrhiza and provides valuable clues for elucidating the mechanism of AtDREB1A-mediated drought tolerance in transgenic plants. PMID- 29534546 TI - Applications of Metals for Bone Regeneration. AB - The regeneration of bone tissue is the main purpose of most therapies in dental medicine. For bone regeneration, calcium phosphate (CaP)-based substitute materials based on natural (allo- and xenografts) and synthetic origins (alloplastic materials) are applied for guiding the regeneration processes. The optimal bone substitute has to act as a substrate for bone ingrowth into a defect, as well as resorb in the time frame needed for complete regeneration up to the condition of restitution ad integrum. In this context, the modes of action of CaP-based substitute materials have been frequently investigated, where it has been shown that such materials strongly influence regenerative processes such as osteoblast growth or differentiation and also osteoclastic resorption due to different physicochemical properties of the materials. However, the material characteristics needed for the required ratio between new bone tissue formation and material degradation has not been found, until now. The addition of different substances such as collagen or growth factors and also of different cell types has already been tested but did not allow for sufficient or prompt application. Moreover, metals or metal ions are used differently as a basis or as supplement for different materials in the field of bone regeneration. Moreover, it has already been shown that different metal ions are integral components of bone tissue, playing functional roles in the physiological cellular environment as well as in the course of bone healing. The present review focuses on frequently used metals as integral parts of materials designed for bone regeneration, with the aim to provide an overview of currently existing knowledge about the effects of metals in the field of bone regeneration. PMID- 29534549 TI - Chloroplast Protein Turnover: The Influence of Extraplastidic Processes, Including Autophagy. AB - Most assimilated nutrients in the leaves of land plants are stored in chloroplasts as photosynthetic proteins, where they mediate CO2 assimilation during growth. During senescence or under suboptimal conditions, chloroplast proteins are degraded, and the amino acids released during this process are used to produce young tissues, seeds, or respiratory energy. Protein degradation machineries contribute to the quality control of chloroplasts by removing damaged proteins caused by excess energy from sunlight. Whereas previous studies revealed that chloroplasts contain several types of intraplastidic proteases that likely derived from an endosymbiosed prokaryotic ancestor of chloroplasts, recent reports have demonstrated that multiple extraplastidic pathways also contribute to chloroplast protein turnover in response to specific cues. One such pathway is autophagy, an evolutionarily conserved process that leads to the vacuolar or lysosomal degradation of cytoplasmic components in eukaryotic cells. Here, we describe and contrast the extraplastidic pathways that degrade chloroplasts. This review shows that diverse pathways participate in chloroplast turnover during sugar starvation, senescence, and oxidative stress. Elucidating the mechanisms that regulate these pathways will help decipher the relationship among the diverse pathways mediating chloroplast protein turnover. PMID- 29534550 TI - Identification of Differentially Expressed Genes between Original Breast Cancer and Xenograft Using Machine Learning Algorithms. AB - Breast cancer is one of the most common malignancies in women. Patient-derived tumor xenograft (PDX) model is a cutting-edge approach for drug research on breast cancer. However, PDX still exhibits differences from original human tumors, thereby challenging the molecular understanding of tumorigenesis. In particular, gene expression changes after tissues are transplanted from human to mouse model. In this study, we propose a novel computational method by incorporating several machine learning algorithms, including Monte Carlo feature selection (MCFS), random forest (RF), and rough set-based rule learning, to identify genes with significant expression differences between PDX and original human tumors. First, 831 breast tumors, including 657 PDX and 174 human tumors, were collected. Based on MCFS and RF, 32 genes were then identified to be informative for the prediction of PDX and human tumors and can be used to construct a prediction model. The prediction model exhibits a Matthews coefficient correlation value of 0.777. Seven interpretable interactions within the informative gene were detected based on the rough set-based rule learning. Furthermore, the seven interpretable interactions can be well supported by previous experimental studies. Our study not only presents a method for identifying informative genes with differential expression but also provides insights into the mechanism through which gene expression changes after being transplanted from human tumor into mouse model. This work would be helpful for research and drug development for breast cancer. PMID- 29534551 TI - Raw Data-Based Motion Compensation for High-Resolution Sliding Spotlight Synthetic Aperture Radar. AB - For accurate motion compensation (MOCO) in airborne synthetic aperture radar (SAR) imaging, a high-precision inertial navigation system (INS) is required. However, an INS is not always precise enough or is sometimes not even included in airborne SAR systems. In this paper, a new, raw, data-based range-invariant motion compensation approach, which can effectively extract the displacements in the line-of-sight (LOS) direction, is proposed for high-resolution sliding spotlight SAR mode. In this approach, the sub-aperture radial accelerations of the airborne platform are estimated via a well-developed weighted total least square (WTLS) method considering the time-varying beam direction. The effectiveness of the proposed approach is validated by two airborne sliding spotlight C band SAR raw datasets containing different types of terrain, with a high spatial resolution of about 0.15 m in azimuth. PMID- 29534552 TI - Biosensors for Sustainable Food Engineering: Challenges and Perspectives. AB - Current food production faces tremendous challenges from growing human population, maintaining clean resources and food qualities, and protecting climate and environment. Food sustainability is mostly a cooperative effort resulting in technology development supported by both governments and enterprises. Multiple attempts have been promoted in tackling challenges and enhancing drivers in food production. Biosensors and biosensing technologies with their applications, are being widely applied to tackling top challenges in food production and its sustainability. Consequently, a growing demand in biosensing technologies exists in food sustainability. Microfluidics represents a technological system integrating multiple technologies. Nanomaterials, with its technology in biosensing, is thought to be the most promising tool in dealing with health, energy, and environmental issues closely related to world populations. The demand of point of care (POC) technologies in this area focus on rapid, simple, accurate, portable, and low-cost analytical instruments. This review provides current viewpoints from the literature on biosensing in food production, food processing, safety and security, food packaging and supply chain, food waste processing, food quality assurance, and food engineering. The current understanding of progress, solution, and future challenges, as well as the commercialization of biosensors are summarized. PMID- 29534553 TI - An Efficient Chemoenzymatic Approach towards the Synthesis of Rugulactone. AB - Rugulactone is a natural product isolated from the plant Cryptocarya rugulosa. It has shown very important biological activity as an inhibitor of the nuclear factor kappaB (NF-kappaB) activation pathway. A new chemoenzymatic approach towards the synthesis of rugulactone is presented here. The chirality, induced to the key intermediate by a stereoselective enzymatic reduction utilizing NADPH dependent ketoreductase, is described in detail. PMID- 29534554 TI - Synthesis of O-Amino Sugars and Nucleosides. AB - Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds have attracted increasing research interest because of their easy derivatization through oxime ligation or N oxyamide formation reactions. Various biological applications have been reported for O-amino carbohydrate- and nucleoside-derived compounds. Here, we report our efforts in the design and synthesis of glyco-, glycosyl, nucleoside- and nucleo aminooxy acid derivatives from readily available sugars and amino acids, and their use for the generation of N-oxyamide-linked oligosaccharides, glycopeptides, glycolipids, oligonucleosides and nucleopeptides as novel glycoconjugates or oligonucleotide mimics. Delicate and key points in the synthesis will be emphasized. PMID- 29534555 TI - Improved Labeling of Pancreatic Islets Using Cationic Magnetoliposomes. AB - Pancreatic islets (PIs) transplantation is an alternative approach for the treatment of severe forms of type 1 diabetes (T1D). To monitor the success of transplantation, it is desirable to follow the location of engrafted PIs non invasively. In vivo magnetic resonance imaging (MRI) of transplanted PIs is a feasible cell tracking method; however, this requires labeling with a suitable contrast agent prior to transplantation. We have tested the feasibility of cationic magnetoliposomes (MLs), compared to commercial contrast agents (Endorem and Resovist), by labeling insulinoma cells and freshly isolated rat PIs. It was possible to incorporate Magnetic Ressonance (MR)-detectable amounts of MLs in a shorter time (4 h) when compared to Endorem and Resovist. MLs did not show negative effects on the PIs' viability and functional parameters in vitro. Labeled islets were transplanted in the renal sub-capsular region of healthy mice. Hypointense contrast in MR images due to the labeled PIs was detected in vivo upon transplantation, while MR detection of PIs labeled with Endorem and Resovist was only possible after the addition of transfection agents. These findings indicate that MLs are suitable to image PIs, without affecting their function, which is promising for future longitudinal pre-clinical and clinical studies involving the assessment of PI transplantation. PMID- 29534556 TI - Strengthening Emergency Care Systems to Mitigate Public Health Challenges Arising from Influxes of Individuals with Different Socio-Cultural Backgrounds to a Level One Emergency Center in South East Europe. AB - Emergency center visits are mostly unscheduled, undifferentiated, and unpredictable. A standardized triage process is an opportunity to obtain real time data that paints a picture of the variation in acuity found in emergency centers. This is particularly pertinent as the influx of people seeking asylum or in transit mostly present with emergency care needs or first seek help at an emergency center. Triage not only reduces the risk of missing or losing a patient that may be deteriorating in the waiting room but also enables a time-critical response in the emergency care service provision. As part of a joint emergency care system strengthening and patient safety initiative, the Serbian Ministry of Health in collaboration with the Centre of Excellence in Emergency Medicine (CEEM) introduced a standardized triage process at the Clinical Centre of Serbia (CCS). This paper describes four crucial stages that were considered for the integration of a standardized triage process into acute care pathways. PMID- 29534557 TI - A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma. AB - Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs), which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies. PMID- 29534558 TI - Genome-Wide Analysis of the PYL Gene Family and Identification of PYL Genes That Respond to Abiotic Stress in Brassica napus. AB - Abscisic acid (ABA) is an endogenous phytohormone that plays important roles in the regulation of plant growth, development, and stress responses. The pyrabactin resistance 1-like (PYR/PYL) protein is a core regulatory component of ABA signaling networks in plants. However, no details regarding this family in Brassica napus are available. Here, 46 PYLs were identified in the B. napus genome. Based on phylogenetic analysis, BnPYR1 and BnPYL1-3 belong to subfamily I, BnPYL7-10 belong to subfamily II, and BnPYL4-6 and BnPYL11-13 belong to subfamily III. Analysis of BnPYL conserved motifs showed that every subfamily contained four common motifs. By predicting cis-elements in the promoters, we found that all BnPYL members contained hormone- and stress-related elements and that expression levels of most BnPYLs were relatively higher in seeds at the germination stage than those in other organs or at other developmental stages. Gene Ontology (GO) enrichment showed that BnPYL genes mainly participate in responses to stimuli. To identify crucial PYLs mediating the response to abiotic stress in B. napus, expression changes in 14 BnPYL genes were determined by quantitative real-time RT-PCR after drought, heat, and salinity treatments, and identified BnPYR1-3, BnPYL1-2, and BnPYL7-2 in respond to abiotic stresses. The findings of this study lay a foundation for further investigations of PYL genes in B. napus. PMID- 29534559 TI - Phytoproflex(r): supplementary management of osteoarthrosis: a supplement registry. AB - BACKGROUND: Curcumin is a powerful anti-oxidant that can be used to treat inflammation and pain in chronic conditions such as osteoarthrosis (OA). Phytoproflex(r) is characterized by an innovative delivery system that improves bioavailability of curcuminoids and could be useful in the management of OA. METHODS: This 4-week registry included 56 patients with knee OA treated according to the best standard management for symptomatic OA. On top of that, 24 patients used Phytoproflex(r) supplement preparation (an extract containing boswellic acid 90%, curcumin 20% and valeric acid 0.8%). Patients' control of symptoms and functional capacity were evaluated through the Karnofsky Scale and standardized treadmill test, together with measurement of oxidative stress levels and use of rescue medication. RESULTS: No problems of tolerability or safety were reported among subjects using the supplement. After 4 weeks, patients treated with the supplement reported a significant decrease in pain (P<0.05), and a significant improvement in the fitness scale (P<0.05), indicating that subjects were able to perform normal daily tasks. Less subjects in the supplement group had to use rescue medication (P<0.05), while oxidative stress levels, which were high at inclusion, significantly decreased in both groups (P<0.05). Moreover, the variation in pain-free walking distance and the Karnofsky Scale were significantly more improved (P<0.05) in patients taking the supplement compared to controls. CONCLUSIONS: This preliminary registry study indicates that Phytoproflex(r) can be safely used as an effective, supplementary management in most OA patients. PMID- 29534560 TI - Longevity and Stress Resistant Property of 6-Gingerol from Zingiber officinale Roscoe in Caenorhabditis elegans. AB - In order to discover lifespan-extending compounds made from natural resources, activity-guided fractionation of Zingiber officinale Roscoe (Zingiberaceae) ethanol extract was performed using the Caenorhabditis elegans (C. elegans) model system. The compound 6-gingerol was isolated from the most active ethyl acetate soluble fraction, and showed potent longevity-promoting activity. It also elevated the survival rate of worms against stressful environment including thermal, osmotic, and oxidative conditions. Additionally, 6-gingerol elevated the antioxidant enzyme activities of C. elegans, and showed a dose-depend reduction of intracellular reactive oxygen species (ROS) accumulation in worms. Further studies demonstrated that the increased stress tolerance of 6-gingerol-mediated worms could result from the promotion of stress resistance proteins such as heat shock protein (HSP-16.2) and superoxide dismutase (SOD-3). The lipofuscin levels in 6-gingerol treated intestinal worms were decreased in comparison to the control group. No significant 6-gingerol-related changes, including growth, food intake, reproduction, and movement were noted. These results suggest that 6 gingerol exerted longevity-promoting activities independently of these factors and could extend the human lifespan. PMID- 29534561 TI - From Foldable Open Chains to Shape-Persistent Macrocycles: Synthesis, Impact on 2D Ordering, and Stimulated Self-Assembly. AB - Small molecule self-assembly at surfaces offers an efficient route to highly ordered organic films that can be programmed for a variety of chemical and electronic applications. The success of these materials depends on the ability to program intermolecular interactions to guide precise structural ordering. Toward this objective, we have designed and synthesized a series of bis(triazolo)benzene based pi-conjugated molecules. Our synthesis exploits a last-stage C-C cross coupling reaction to close up zigzag-shaped linear precursors to cyclized products, so that direct side-by-side comparisons can be made for their structure dependent self-assembly behavior at surfaces and response to external stimuli. Indeed, scanning tunneling microscopy (STM) analysis revealed distinct differences as the conformational flexibility of the molecular backbone and the chemical structure of the peripheral groups are varied. Specifically, alkyl chains adsorb and form interdigitated structures, whereas oligo ethylene glycol (OEG) chains remain desorbed and thus shift self-assembly to more densely packed pi-conjugated cores. While the macrocycles self-assemble immediately and spontaneously, their linear precursors exhibit slower self-assembly kinetics, which could be attributed to the difference in the degree of conformational freedom. We also found that perturbation by the STM tip and the addition of cosolutes profoundly impacted the kinetics of self-assembly and surface patterning. This highly unusual behavior highlights the importance of noncovalent interactions that are inherently weak in solution but can be made strong for symmetric and conformationally restricted molecules confined within 2D surfaces. PMID- 29534562 TI - Water-Soluble Redox-Active Cage Hosting Polyoxometalates for Selective Desulfurization Catalysis. AB - Transformations within container-molecules provide a good alternative between traditional homogeneous and heterogeneous catalysis, as the containers themselves can be regarded as single molecular nanomicelles. We report here the designed synthesis of a water-soluble redox-active supramolecular Pd4L2 cage and its application in the encapsulation of aromatic molecules and polyoxometalates (POMs) catalysts. Compared to the previous known Pd6L4 cage, our results show that replacement of two cis-blocked palladium corners with p-xylene bridges through pyridinium bonds formation between the 2,4,6-tri-4-pyridyl-1,3,5-triazine (TPT) ligands not only provides reversible redox-activities for the new Pd4L2 cage, but also realizes the expansion and subdivision of its internal cavity. An increased number of guests, including polyaromatics and POMs, can be accommodated inside the Pd4L2 cage. Moreover, both conversion and product selectivity (sulfoxide over sulfone) have also been much enhanced in the desulfurization reactions catalyzed by the POMs@Pd4L2 host-guest complexes. We expect that further photochromic or photoredox functions are possible taking advantage of this new generation of organo-palladium cage. PMID- 29534564 TI - Novel Theaflavin-Type Chlorogenic Acid Derivatives Identified in Black Tea. AB - Consumption of black tea contributed to many health benefits including the prevention of heart disease and certain types of cancer. However, the chemical composition of black tea has not been fully explored. Most studies have examined different interactions between the four major tea catechins, and limited studies have investigated the interaction between catechins and other components in tea. In the present study, we tested our hypothesis that the ortho-dihydroxyl structure of chlorogenic acid (CGA) could react with the vic-trihydroxy structure of (-)-epigallocatechin 3-gallate (EGCG) and (-)-epigallocatechin (EGC) to generate theaflavin-type of compounds during black tea fermentation. The reaction between CGA and EGCG or EGC was catalyzed by horseradish peroxidase (POD) in the presence of H2O2. Two theaflavin-type compounds EGCG-CGA and EGC-CGA were purified using a Sephadex LH-20 column. Their structures were elucidated on the basis of the analysis of their MS and 1D- and 2D-NMR spectroscopic data. Furthermore, the existence of these two novel compounds was characterized by LC/MS/MS analysis. We also found that EGCG-CGA and EGC-CGA had very similar inhibitory effects on the growth of human colon cancer cells with that of theaflavin 3,3'-digallate. These findings shed light on the interactions between the major bioactive compounds, catechins, and other minor compounds in tea. The confirmation of the presence of this type of reaction in black tea may provide more understanding of the complexity of black tea chemistry. PMID- 29534563 TI - Antibiotic Combinations That Enable One-Step, Targeted Mutagenesis of Chromosomal Genes. AB - Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here, we describe a compound centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain nonessential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway. Guided by this hypothesis, we have identified antibiotic/counterselectable markers to accelerate reverse engineering of two increasingly antibiotic-resistant pathogens, Staphylococcus aureus and Acinetobacter baumannii. For S. aureus, we used wall teichoic acid biosynthesis inhibitors to select for the absence of tarO and for A. baumannii, we used colistin to select for the absence of lpxC. We have obtained desired gene deletions, gene fusions, and promoter swaps in a single plating step with perfect efficiency. Our method can also be adapted to generate markerless deletions of genes using FLP recombinase. The tools described here will accelerate research on two important pathogens, and the concept we outline can be readily adapted to any organism for which a suitable target pathway can be identified. PMID- 29534565 TI - Fabrication and Utilization of Bifunctional Protein/Polysaccharide Coprecipitates for the Independent Codelivery of Two Model Actives from Simple Oil-in-Water Emulsions. AB - Aside from single active microencapsulation, there is growing interest in designing structures for the coencapsulation and codelivery of multiple species. Although currently achievable within solid systems, significant challenges exist in realizing such functionality in liquid formulations. The present study reports on a novel microstructural strategy that enables the coencapsulation and corelease of two actives from oil-in-water emulsions. This is realized through the fabrication of sodium caseinate/chitosan (NaCAS/CS) complexes that in tandem function as encapsulants of one active (hydrophilic) but also as ("Pickering like") stabilizers to emulsion droplets containing a secondary active (hydrophobic). Confocal microscopy confirmed that the two coencapsulated actives occupied distinct emulsion microstructure regions; the hydrophilic active was associated with the NaCAS/CS complexes at the emulsion interface, while the hydrophobic active was present within the oil droplets. Aided by their segregated coencapsulation, the two actives exhibited markedly different corelease behaviors. The hydrophilic active exhibited triggered release that was promoted by changes to pH, which weakened the protein-polysaccharide electrostatic interactions, resulting in particle swelling. The hydrophobic secondary active exhibited sustained release that was impervious to pH and instead controlled by passage across the interfacial barrier. The employed microstructural approach can therefore lead to the segregated coencapsulation and independent corelease of two incompatible actives, thus offering promise for the development of liquid emulsion-based formulations containing multiple actives. PMID- 29534566 TI - Isobutylhydroxyamides from Sichuan Pepper and Their Protective Activity on PC12 Cells Damaged by Corticosterone. AB - The pericarp of Zanthoxylum bungeanum Maxim., commonly known as Sichuan pepper, is a widely used spice to remove fishy odor and add palatable taste. A phytochemical investigation of the 95% ethanol extract of Sichuan pepper resulted in the isolation of 21 isobutylhydroxyamides, including 8 new ones named ZP amides G-N, among which the chiral resolution of racemic ZP-amide A and ZP-amide B was successfully accomplished. The protective activity on corticosterone treated PC12 cells of the isolated isobutylhydroxyamides was also evaluated. The new compounds 3-5 and the known compounds 1, 1a, 2, 2a, 11, and 15 improved the survival rate of PC12 cells. The bioactivity studies disclosed the potential of Sichuan pepper to be developed as new neuroprotective functional food. PMID- 29534567 TI - Synthesis of Hollow Doughnut Shape Mesoporous Silica Nanoparticle: A Case of Self Assembly Composite Templates. AB - The new class of silica nanoparticles with unprecedented structural morphology is synthesized by hydrolysis of tetraethyl orthosilicate (TEOS) in the presence of cetyltrimethylammonium bromide (CTAB), l-arginine, and ammonium metatungstate (AMT) composite template, all in aqueous ethanol. The morphology of the synthesized mesoporous silica nanoparticles (MSNs) can be tuned from a spherical to a hollow doughnut shape through a hollow sphere by controlling the concentration of AMT in the composite template. The formation mechanism of the hollow doughnut shaped MSNs (hd-MSNs) is well-explored by means of zeta potential, high-resolution transmission electron microscopy (HRTEM) with elemental mapping analysis, and X-ray photoelectron spectroscopy. The unique structure of the hd-MSNs as well as their high thermal and mechanical stability is expected to result in their application in shape-selective catalysis, drug delivery, and sensors. PMID- 29534568 TI - Switchable Hydrogel-Gated Organic Field-Effect Transistors. AB - Stimuli-responsive hydrogels represent a class of materials capable of reversibly switching their morphological and physicochemical characteristics. An ultrathin poly(acrylic acid) film (ca. 6 nm) grafted onto the gate of a p-type EGOFET is studied, and the correlation between the swelling state of the hydrogel and the transistor output characteristics is presented. The hydrogel-related swelling process occurring in basic medium causes an increase in threshold voltage due to the abrupt and intense increase of the negative charge density on the gate electrode. The variation of the drain current during the in situ modification of the pH electrolyte allows a quantitative analysis of the hydrogel switching kinetics. This work shows not only the relevance of EGOFET as an analytical tool in the broad sense, i.e., able to follow in real time phase transition processes of stimuli-responsive materials, but also the relevance of using a hydrogel for field-effect-based (bio)detection according to the ability of such material to overcome the well-known Debye length problematics. PMID- 29534569 TI - SnO2 Inverse Opal Composite Film with Low-Angle-Dependent Structural Color and Enhanced Mechanical Strength. AB - Structural colors are attracting considerable attention for their advantages of environmental friendliness and resistance to fading. However, the weak mechanical strength and intrinsic iridescent color restrict their widespread application. This article describes a SnO2 inverse opal composite film with low-angle dependent structural color and enhanced mechanical strength. In the present study, a direct template method was used to prepare SnO2 inverse opals, which were then embedded in polydimethylsiloxane (PDMS). The structural colors of obtained composite films were low-angle-dependent due to light scattering and high effective refractive index. Meanwhile, because of the good physical strength of PDMS, structures of SnO2 inverse opals were provided with effective protection. No specific wavelength shift occurred during stretching, and exhibited excellent cycling stability. All these advantages indicated potential applications in packing and decorating materials. PMID- 29534570 TI - Predicting the Binding Mode of 2-Hydroxypropyl-beta-cyclodextrin to Cholesterol by Means of the MD Simulation and the 3D-RISM-KH Theory. AB - It has been found that a cyclodextrin derivative, 2-hydroxypropyl-beta cyclodextrin (HPbetaCD), has reasonable therapeutic effect on Niemann-Pick disease type C, which is caused by abnormal accumulation of unesterified cholesterol and glycolipids in the lysosomes and shortage of esterified cholesterol in other cellular compartments. We study the binding affinity and mode of HPbetaCD with cholesterol to elucidate the possible mechanism of HPbetaCD for removing cholesterol from the lysosomes. The dominant binding mode of HPbetaCD with cholesterol is found based on the molecular dynamics simulation and a statistical mechanics theory of liquids, or the three-dimensional reference interaction site model theory with Kovalenko-Hirata closure relation. We examine the two types of complexes between HPbetaCD and cholesterol, namely, one-to-one (1:1) and two-to-one (2:1). It is predicted that the 1:1 complex makes two or three types of stable binding mode in solution, in which the betaCD ring tends to be located at the edge of the steroid skeleton. For the 2:1 complex, there are four different types of the complex conceivable, depending on the orientation between the two HPbetaCDs: head-to-head (HH), head-to-tail (HT), tail-to-head (TH), and tail-to-tail (TT). The HT and HH cyclodextrin dimers show higher affinity to cholesterol compared to the other dimers and to all the binding modes of 1:1 complexes. The physical reason why the HT and HH dimers have higher affinity compared to the other complexes is discussed based on the consistency with the 1:1 complex. On the one hand, in case of the HT and HH dimers, the position of each CD in the dimer along the cholesterol chain comes right on or close to one of the positions where a single CD makes a stable complex. On the other hand, one of the CD molecules is located on unstable region along the cholesterol chain, for the case of TH and TT dimers. PMID- 29534571 TI - Responsive Photonic Hydrogel-Based Colorimetric Sensors for Detection of Aldehydes in Aqueous Solution. AB - In this work, we present a fast and efficient strategy for the preparation of responsive photonic hydrogels for aldehyde sensing by combining the self-assembly of monodisperse carbon-encapsulated Fe3O4 nanoparticles (NPs) and in situ photopolymerization of polyacrylamide (PAM) hydrogels. The responsive photonic hydrogels exhibit structural color variation after being treated with formaldehyde aqueous solution, which can be attributed to the chemical reaction between the amide groups in the hydrogels and the formaldehyde. We have also shown that the photonic hydrogels can be used to determine the concentration of formaldehyde and to differentiate aldehydes through a facile reflection spectra shift and color change. This study provides a facile strategy for the visualized determination of aldehyde in aqueous solution. PMID- 29534573 TI - Key Aroma Compounds in Lippia dulcis (Dushi Button). AB - An aroma extract dilution analysis (AEDA) applied on aroma extracts prepared from the edible flower Dushi Button ( Lippia dulcis) resulted in the detection of 34 odor-active compounds. The highest flavor dilution (FD) factors were determined for methyl 2-methylbutanoate, ethyl 2-methylbutanoate, 4-mercapto-4-methyl-2 pentanone, an unknown caramel-like compound, and vanillin. Quantitative measurements performed by application of stable isotope dilution assays (SIDA), followed by a calculation of odor activity values (OAVs), resulted in the revelation of 4-mercapto-4-methyl-2-pentanone, linalool, myrcene, ethyl 2 methylbutanoate, methyl 2-methylbutanoate, and ( Z)-3-hexenal as important contributors to the flavor of Dushi Buttons. PMID- 29534575 TI - Introduction: Oxygen Reduction and Activation in Catalysis. PMID- 29534574 TI - Biotechnological Production of Methyl-Branched Aldehydes. AB - A number of methyl-branched aldehydes impart interesting flavor impressions, and especially 12-methyltridecanal is a highly sought after flavoring compound for savory foods. Its smell is reminiscent of cooked meat and tallow. For the biotechnological production of 12-methyltridecanal, the literature was screened for fungi forming iso-fatty acids. Suitable organisms were identified and successfully grown in submerged cultures. The culture medium was optimized to increase the yields of branched fatty acids. A recombinant carboxylic acid reductase was used to reduce 12-methyltridecanoic acid to 12-methyltridecanal. The efficiency of whole-cell catalysis was compared to that of the purified enzyme preparation. After lipase-catalyzed hydrolysis of the fungal lipid extracts, the released fatty acids were converted to the corresponding aldehydes, including 12-methyltridecanal and 12-methyltetradecanal. PMID- 29534576 TI - Lentivirus-mediated shRNA interference of trefoil factor 3 blocks cell viability, migration and invasion in the papillary thyroid carcinoma cells. AB - Trefoil factor 3 (TFF3), a regulatory protein composed of 59 amino acids, has been suggested to be involved in pathogen- esis, proliferation, invasion, migration and apoptosis in multiple malignant tumors. However, the roles of TFF3 concerning the viability, migration and invasion in papillary thyroid carcinoma cells have not yet been studied. This study aimed to investigate the effect of TFF3 knockdown on a thyroid papillary carcinoma TPC-1 cell line both in vitro and in vivo. In the present study, lentivirus-mediated short hairpin RNA (shRNA) targeting TFF3 plasmids were first constructed and stable TPC-1 cells were obtained while their TFF3 gene was silenced with either shTFF3-TPC-1, or a scrambled shRNA control. TFF3 expression was detected using quantitative real time PCR and western blot analyses. The TPC-1 cell viability was measured by CCK 8 assay and colony formation. The cell migration and invasion were assessed by wound scratch assay and transwell filters. AKT phosphorylation, MMP-9, and BCL-2 expression levels were detected by western blot analyses. Our results showed that TFF3 knockdown significantly inhibits TPC-1 cell viability, migration and invasion. AKT phosphoryla- tion, MMP-9, and BCL-2 levels were all remarkably depressed in TFF3 knockdown TPC-1 cells. Using a thyroid papillary carcinoma xenograft mouse model, we further investigated the effects of TFF3 knockdown in vivo. Significantly delayed xenograft emerging, slower growth rate and lower final tumor weights and volumes were observed in the shTFF3 group as compared to the control group. As expected, the expression levels of MMP-9 and BCL-2 in the xenograft are consistent with those of shTFF3-TPC-1 and shTFF3-TPC-1 cells in vitro. Our results suggest that TFF3 plays a vital role in the viability and oncogenesis of TPC-1 cells and may be a potential target for effective treatment of thyroid papillary carcinoma. PMID- 29534577 TI - The association between LncRNA HOTAIR and cancer lymph node metastasis and distant metastasis: a meta-analysis. AB - HOTAIR has been reported to be associated with development and metastasis in different types of cancer. This meta- analysis collected all relevant articles and explored the correlation of HOTAIR with lymph node metastasis (LNM) and distant metastasis (DM). A literature collection was conducted by searching PubMed, Web of Science, Google Scholar and Cochrane Library (up to Sep 11, 2016). The odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the association with strength. Nineteen studies were included in this study, with a total of 1874 patients. The study objects were all Asians. We found high HOTAIR expression in tumor tissues was significantly correlated with LNM and DM, and analysis showed a pooled OR of 3.18 (95% CI: 2.10-4.81, p<0.00001) and 3.93 (95% CI: 2.39-6.47, p<0.00001), respectively. HOTAIR may serve as a novel diagnostic biomarker for cancer metastasis. PMID- 29534578 TI - Ste20-like kinase is upregulated in glioma and induces glioma invasion. AB - The malignant development and poor prognosis of gliomas are associated with a high degree of invasion and a high recurrence rate. However, the molecular mechanism underlying the invasiveness of glioma remains to be elucidated. Ste20- like kinase (SLK) is one of the members of the Ste20 family, which has been implicated in cellular migration and invasion. In this study, we intended to explore the expression of SLK significantly related to clinicopathologic stages of gliomas. Immunohistochemical staining and western blot analysis demonstrated that SLK was highly expressed in human glioma tissues and cell lines. Kaplan Meier analysis revealed that poor survival was associated with high SLK expression. The inhibition of SLK by RNA interference significantly suppressed the invasion ability of glioma, and on protein level, knock- down of SLK leaded to an up-regulation of E-cadherin and a down-regulation of Vimentin in glioma cells. Collectively, this research shed light on mechanisms of invasion and progression of malignant gliomas and suggested that SLK may be a potential therapeutic strategy for glioma. PMID- 29534579 TI - MicroRNA-30b inhibits non-small cell lung cancer cell growth by targeting the epidermal growth factor receptor. AB - Lung cancer, especially non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality in the world. Both microRNAs and epidermal growth factor receptor (EGFR) are important factors in NSCLC. In our study, the expression of miR-30b in 47 tumor tissues and paired normal tissues of NSCLC were detected by RT-PCR, and we found that miR-30b was down-regulated in NSCLC tumor tissues and was associated with TNM stage, differentiation, and lymph node metastases. Then we investigated the ability of miR-30b to regulate EGFR in several NSCLC cell lines, and found that miR-30b inhibited proliferation, migration and invasion, induced apoptosis and enhanced sensitivity of the NSCLC cells to EGFR tyrosine kinase inhibitors (EGFR-TKIs) by targeting EGFR and repressing EGFR signaling pathways. Overall, these results indicate that miR-30b may be a potential therapeutic target in NSCLC patients. PMID- 29534580 TI - The FBXW7 tumor suppressor inhibits breast cancer proliferation and promotes apoptosis by targeting MTDH for degradation. AB - Metadherin (MTDH) is an oncoprotein and is expressed at high levels in a wide variety of human carcinomas, which represents an important genetic determinant and regulates multiple events in tumorigenesis. MTDH promotes breast cancer cell proliferation and tumorigenesis through the activation of numerous signaling pathways. Currently, the mecha- nism regulating MTDH expression is poorly understood. Here we identified that FBXW7, a component of E3 ubiquitin ligase, targets MTDH for ubiquitin-mediated degradation. Forced overexpression of FBXW7 could decrease the level of MTDH protein, and inhibition of endogenous FBXW7 expression remarkably increases the MTDH protein abundance. More importantly, overexpression of FBXW7 could lead to proliferation arrest and apoptosis in breast cancer cells through targeting MTDH degradation. These data suggest that FBXW7, a tumor suppressor, inhibits breast cancer cell prolifera- tion and promotes apoptosis at least partially through targeting MTDH for proteolysis. This new regulatory mechanism of MTDH by FBXW7 represents a new pathway for malignant phenotype turnover in human breast cancer. PMID- 29534581 TI - Electrochemotherapy with bleomycin and cisplatin enhances cytotoxicity in primary and metastatic uveal melanoma cell lines in vitro. AB - Electrochemotherapy (ECT) enhances responsiveness to cytotoxic drugs in numerous cell lines in vitro. Clinically ECT is widely applied for skin tumor ablation and has shown efficacy in treating non-resectable colorectal liver metastases. There is limited experience of ECT for ocular tumor therapy. We investigated the cytotoxic effect of bleomycin and cisplatin in combination with electroporation on chemoresistant human uveal melanoma (UM) cell lines in vitro. Four UM cell lines (Mel 270, 92-1, OMM-1, OMM-2.5) were treated with electroporation (pulse amplitude 300-1000 V/cm, 8-80 pulses, 100 MUs, 5 Hz) and increasing concentrations of bleomycin and cisplatin (0-7.5 MUg/ml). Cell survival was analyzed by MTT viability assay after 36 hours. UM cell lines were resistant to both bleomycin and cisplatin. In combination with electro- poration, the effects of bleomycin and cisplatin were increased 8-70 fold and 3-15 fold, respectively, in all UM cell lines. At the lowest concentration of bleomycin tested (1 MUg/ml), viability was maximally reduced in all UM cell lines by >=69% with electroporation conditions of 750 V/cm and 20 pulses. All UM cell lines were more resistant to cisplatin; however, electro- poration of 1000 V/cm and 8 pulses resulted in similar reductions in cell viability of 92-1, Mel270 with 2.5 MUg/ml cisplatin, OMM2-5 cells with 5 MUg/ml cisplatin and OMM1 cells with 1 MUg/ml cisplatin. In vitro ECT with bleomycin or cisplatin is more effective than the highest concentration of the antineoplastic drug or electroporation alone, opening new perspectives in primary and metastatic UM treatment. PMID- 29534582 TI - Association between phosphodiesterase type 5 inhibitors use and risk of melanoma: a meta-analysis. AB - This meta-analysis aimed to clarify the actual association between the phosphodiesterase type 5 inhibitors (PDE5-Is) use and the risk of melanoma in erectile dysfunction (ED) patients. A systematic literature search was conducted in online databases in October, 2016 to identify studies focusing on the association between PDE5-Is use and the risk of melanoma. Summarized multivariate adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to assess the strength of associations. A total of six clinical trials containing more than one million participants were included. ED patients using PDE5-Is shared a significant high risk of melanoma (RR=1.12, 95% CI=1.03-1.21, p=0.006). Positive associations were observed in all kinds of prescriptions: single prescription (RR=1.20, 95% CI=1.06-1.35, p=0.003), medium number of prescription (RR=1.15, 95% CI=1.01-1.30, p=0.03), and high number of prescription (RR=1.18, 95% CI=1.05-1.34, P=0.006). Additionally, PDE5-Is were also found to be significantly associated with increased risk of basal cell carcinoma (RR=1.14, 95% CI=1.09-1.19, p<0.00001). Our study indicates that PDE5-Is use could significantly increase the risk of melanoma and basal cell carcinoma. However, the risk of melanoma did not rise significantly with the increased number of prescriptions. Consequently, owing to the lack of information about other potential synergistic factors, it is difficult for us to make a solid conclusion that application of PDE5-Is is the direct cause of increased risk of melanoma. Their relationship needs to be validated by further evidences. PMID- 29534583 TI - Cisplatin binds to pre-miR-200b and impairs its processing to mature microRNA. AB - Cisplatin is an important anticancer drug with a complex mode of action, a variety of possible targets, and numerous resistance mechanisms. While genomic DNA has traditionally been considered to be its most critical anticancer target, several lines of evidence suggest that various RNAs and other biomolecules may play a role in its anticancer mode of action. In this report we demonstrate that cisplatin modifies pre-miR-200b, impairs its processing to mature miRNA, and decreases miR-200b expression in ovarian cancer cells. Considering the role of miR-200b in epithelial-to-mesenchymal transition and cancer chemosensitivity, cisplatin-induced modification of pre-miR-200b and subsequent deregulation of mature miR-200b may, depending on cell context, limit anticancer activity of this important anticancer drug. More gener- ally, precursor miRNAs may be important targets of cisplatin and play a role in this drug's anticancer activity or modulate cell responses to this drug. PMID- 29534584 TI - Tumor suppressor RKIP inhibits prostate cancer cell metastasis and sensitizes prostate cancer cells to docetaxel treatment. AB - Raf kinase inhibitory protein (RKIP) is a well-established metastasis suppressor that is frequently down-regulated in aggressive cancers. However, the impact of RKIP on cancer cell invasion and metastasis in prostate cancer is still elusive. To this end, we overexpressed RKIP in two prostate cancer cell lines. We found that overexpression of RKIP inhibited prostate cancer cells proliferation, migration and invasion. Mechanistically, we found that RKIP overexpression led to down-regula- tion of the NF-kB signaling pathway and inhibition of the epithelial to-mesenchymal transition, which is important step for cancer metastasis. In addition, overexpression of RKIP can promote drug effects of docetaxel on prostate cancer cell lines. In conclusion, overexpression of RKIP significantly inhibits prostate cancer cell migration and metastasis, and overexpression of RKIP could aid prostate cancer treatment and therapy. PMID- 29534585 TI - Urinary fluorescence analysis in diagnosis of bladder cancer. AB - Early diagnosis of bladder cancer is crucial for improvement of cancer specific survival and recurrence rate. We analyzed the possible role of fluorescence urine analysis in bladder cancer diagnosis. The cohort consisted of 20 healthy controls, 40 patients with hematuria and 75 patients with hematuria and histologically proven bladder tumor. Synchronous fluores- cence spectra with a 70 nm wavelength difference were recorded for (1:1-1:128) urine dilutions. Concentration matrices of synchronous spectra (CMSS) were used to classify samples into tested groups. CMSS analysis allowed us to distinguish patients with tumor from patients with hematuria with a sensitivity 55% and specificity 74.7%. This is comparable to the sensitivity and specificity of other non-invasive tests like BTA stat and nmP-22 (Bladder check(r)). Lower fluorescence inten- sity of Imax 280 nm and ratio of 280 nm to 450 nm was found to be associated with the presence of tumor. We have found an association of decreased fluorescence with the stage of the disease. Our data suggest that CMSS urine analysis has a potential role in the non-invasive diagnostic tests for bladder cancer, but it cannot replace the current diagnostic algorithm yet. PMID- 29534586 TI - Identification of biomarkers and potential molecular mechanisms of clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer in adults. The aim of this study is to identify the biomarkers and potential molecular mechanisms of ccRCC. Three gene expression profiles and two miRNA expression profiles were downloaded from GEO database. A total of 330 up regulated differentially expressed genes (DEGs), 545 down-regulated DEGs, 26 up regulated differentially expressed miRNAs (DEMs) and 11 down-regulated DEMs were identified by GEO2R. The gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by KOBAS software. The results showed that GO terms of the up-regulated DEGs were mostly enriched in response to stimulus at BP level, cell periphery at CC level and binding at MF level, while the GO terms of down-regulated DEGs were enriched in single-organism process at BP level, extracellular exosome at CC level and catalytic activity at MF level. As for KEGG pathways, HIF-1 signaling pathway, focal adhesion, PI3K-Akt signaling pathway and metabolic pathways were significantly enriched. Then, protein-protein interaction (PPI) network and miRNA-gene network were constructed and analyzed by Cytoscape. A total of eight DEGs were identified as biomarkers, including VEGFA, PPARA, CCND1, FLT1, CXCL12, FN1, DCN and ERBB4. Expression validation and survival analysis were performed by GEPIA and OncoLnc, respectively. Four biomarkers were verified by quantitative real-time PCR (qPCR) in 786-O cell line and HK-2 cell line. All four genes had the same expression trend as predicted. Our study provides a series of biomarkers and molecular mechanisms for the deeper research of ccRCC. PMID- 29534587 TI - An extensive study of the mechanism of prostate cancer metastasis. AB - The study aimed to identify the pivotal genes and pathways involved in prostate cancer metastasis. Using the expression profile dataset GSE7930, downloaded from the Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) between primary and highly metastatic prostate cell samples were screened, followed by functional analysis and tumor associated genes (TAG) screening. Protein-protein interaction (PPI) network of DEGs was constructed and module analysis was performed. The expression of DEGs and pathway related genes were evaluated by PCR analysis and the migra- tion ability of prostate tumor cells was observed after FABP4-siRNA blocking. Upregulated FABP4 and GK were signifi- cantly enriched in the PPAR signaling pathway, whereas downregulated IGFBP3 and THBS1 were involved in p53 signaling pathway. Among the identified DEGs, 4 downregulated genes (IGFBP3, NPP4B, THBS1, and PCDH1) and 2 upregulated genes (GJA1 and TUSC3) were TAGs. The module was associated with focal adhesion, ECM receptor interaction, p53 signaling, and gap junction pathways with the hub node GJA1. After FABP4 silencing by siRNAs in LNcap and metastatic DU-145 cells, the numbers of migrated cells were all significantly declined. The expressions of IGFBP3, TP53 and PPAR were significantly lower in DU-145 cells than in LNcap cells. In conclusion, FABP4, IGFBP3, THBS1, and GJA1 were determined to be potential markers of prostate cancer cell metastasis, and P53, PPAR and gap junction pathways were found to play important roles in prostate cancer cell metastasis. This study may provide helpful guidelines for clinical management. PMID- 29534588 TI - Change in FGF-2 circulating levels after arterial embolization in patients with bone metastases. AB - Arterial embolization, aimed at the mechanical occlusion of tumor-feeding vessels, represents a satisfactory palliative therapy for bone metastases. In this study, we evaluated if the circulating levels of three factors related to the metastatic process change in response to embolization. Seven patients who underwent embolization of a single skeletal metastasis from carcinomas were analyzed prospectively. Circulating levels of Vascular Endothelial Growth Factor A (VEGF-A), Fibroblast Growth Factor 2 (FGF-2), and Tartrate-Resistant Acid Phosphatase-5b Isoform (TRACP5b) were evaluated before and after embolization at 1, 3, and 6 months. According to morphological and clinical evaluations, all the embolizations were successful. VEGF-A and TRACP5b did not show significant changes after the treatment. On the contrary, FGF-2 signifi- cantly decreased 1 month after the treatment. FGF-2 appears as a promising candidate for monitoring the efficacy of emboli- zation in patients with osteolytic metastases. PMID- 29534589 TI - Mucosal and skin HPV types in tumour-free tonsils and tonsillar tumours. AB - Human papillomavirus (HPV) infection is associated with tonsillar cancer (TC) whose incidence in humans is increasing. Tonsillar tumours are not ordinarily preceded by clinically apparent precancerous lesions, and no markers of the early stage disease are available. Therefore, we evaluated the presence of an active HPV infection also in tumour-free tonsillar tissue. Formalin-fixed paraffin embedded (FFPE) tonsillar specimens from 114 patients with TC and 114 age and gender matched controls were screened for the presence of HPV DNA, expression of HR-HPV E6 mRNA, and p16 overexpression. HPV DNA was identified in 3.5% of tumour free tissues, HR-HPV16 and 58 and LR-HPV111 and 17 were each detected in a single sample. No HR HPV E6 mRNA and p16 overexpression was found. The prevalence of HPV DNA in TC was 69.3%, with HPV16 being the most common (94.9%). Eighty-four percent of HPV16-positive tumours expressed HR HPV E6 mRNA, while no E6 mRNA was present in samples positive for HPV52 and 58. The overexpression of p16 correlated well with HPV DNA in TC, but in tumour-free tonsils no overexpression of p16 was detected.Our data provide further evidence of the etiological role of HPV16 in TC. In tumour-free tissue, the presence of HR-HPVs was rare and silent, as shown by direct and indirect markers. PMID- 29534590 TI - Clinically node-positive bladder cancer: oncological results of induction chemotherapy and consolidative surgery. AB - Patients with clinically node-positive bladder cancer have a poor prognosis, with many receiving only palliative chemo- therapy. We evaluated oncological results in bladder cancer patients with clinically regional and supraregional lymph- adenopathy treated with induction chemotherapy (IC) and consolidative cystectomy. Twenty-five patients with clinically node-positive bladder cancer (including pelvic and retroperitoneal nodes) were treated with 2-4 cycles of IC followed by consolidative cystectomy between 2010 and 2016. Pathologic complete response (pCR) was defined as no residual tumor in the final specimen (ypT0N0).The 3-year cancer-specific (CSS) and recurrence-free survival (RFS) for the whole cohort were 52% and 39%, respectively. The 3-year RFS differed according to volume of nodal metastases, the rates were 56% for minimal nodal disease (cN1) versus 33% for cN2-3 and 0% for cM1 disease (p<0.001). pCR was seen in 7 (28%) patients; 50% in cN1 versus 13% in cN3-M1. pCR associated with 3-year CSS of 80% versus 45% in patients with persistent disease after IC. In conclusion, a multimodal approach to patients with clinically node-positive bladder cancer, consisting of IC followed by consolidative surgery, may achieve long-term survival in selected patients. Better results may be expected in patients with initially minimal nodal burden and complete pathologic response to chemotherapy. Further studies are warranted to improve patient selection for consolidative surgery, especially with supra-regional metastases. PMID- 29534591 TI - Low expression of Cyfip1 may be a potential biomarker in nasopharyngeal carcinoma. AB - Cytoplasmic FMR1 interacting protein 1 (Cyfip1) is a new candidate tumor suppressor gene, which may play an impor- tant role in the occurrence and development of cancers. However, the role of Cyfip1 in nasopharyngeal carcinoma (NPC) remains poorly known. The aim of this study was to investigate the Cyfip1 mRNA expression in NPC and its association with clinicopathological features. The study population comprised 114 Chinese individuals, including 69 NPC tissues and 45 non-cancerous nasopharyngeal tissues. We used real-time fluorescent relatively quantitative PCR to evaluate the Cyfip1 mRNA expression in NPC tissues and non cancerous nasopharyngeal tissues. The expression level of Cyfip1 mRNA was significantly lower in patients with NPC than in the control samples (p=0.001). Furthermore, low expression level of Cyfip1 mRNA was significantly associated with invasive range (T3-T4 vs T1-T2, p=0.001), lymph node metastasis (N1-N3 vs N0, p=0.010), distant metastases (M1 vs M0, p=0.040) and clinical stage (III-IV vs I-II, p<0.001). Our results suggest the association between Cyfip1 mRNA expression and NPC. Detecting the expression of Cyfip1 may provide clinically useful information for diagnosis, progression and treatment methods in NPC. PMID- 29534592 TI - Effect of CALR and JAK2 mutations on the clinical and hematological phenotypes of the disease in patients with myelofibrosis - long-term experience from a single center. AB - Primary myelofibrosis (PMF) is a chronic clonal myeloid disorder. Together with essential thrombocythemia (ET) and polycythemia vera (PV), it belongs to a group of Philadelphia chromosome-negative myeloproliferative neoplasms. An integral part of laboratory tests carried out in this disease group is detecting the presence of mutations in the Janus kinase 2 gene at position 617 (JAK2 V617F) and in the gene encoding for the receptor for thrombopoietin (myeloproliferative leukemia virus oncogene, MPL) found in approximately 60% of PMF patients. The discovery of mutations affecting exon 9 of the calreticulin (CALR) gene was of great benefit to the diagnosis of the diseases in JAK2 V617F and MPL unmutated cases. This is a study of the effect of a mutation in the CALR gene on the clinical course in patients with primary, post-ET and post-PV myelofibrosis. Analysis of 66 patients (54.5% JAK2 V617F; 34.8% CALR; 6.1% MPL; 3.0% triple negative; 1.5% coincidence of CALR and JAK2 V617F) confirmed a different phenotype of the disease in CALR-mutated patients as compared with CALR-unmutated individuals. Those with CALR mutation were significantly younger and had borderline higher platelet counts, less pronounced splenomegaly and less frequent B symptoms at diagnosis. The study suggests that the driver mutation types define variations in the biological basis, clinical manifestations and course of the disease. The presence of CALR mutation has been shown to be an independent prognostic favorable factor. Careful risk stratification of these patients is of great importance to adequate therapeutic decision-making and aids in selecting high-risk patients eligible for allogeneic hematopoietic stem cell transplantation which continues to be the only treatment modality for myelofibrosis having curative potential. PMID- 29534593 TI - Neurotropism as a prognostic factor in cutaneous melanoma patients. AB - Neurotropism is a feature that is encountered rarely in melanoma and is considered to be associated with increased risk of local recurrence. However, its prognostic significance still remains controversial. The objective of this study was to deter- mine the clinical significance of neurotropism in cutaneous melanoma patients. A total of 519 cutaneous melanoma patients were enrolled into this study and their data were analyzed in a retrospective fashion. The melanomas without neurotro- pism (n=496; 95.6%) were larger in number than those with neurotropism (n=23; 4.4%). Compared to non-neurotropic melanomas, neurotropic melanomas were more likely localized in the extremities (p=0.007) and they were more frequently associated with non-superficial spreading histologic subtype (p=0.029), advanced Clark invasion level (IV-V) (p=0.007), thick Breslow depth (p=0.001), high mitotic rate (p=0.041), ulcerated lesions (p<0.001), lymphovascular invasion (p<0.001), and lymph node metastasis (p=0.013). The neurotropic melanomas were significantly associated with both unfavorable relapse free survival (RFS) (p=0.045) and overall survival (OS) (p<0.001). However, neurotropism lost its prognostic signifi- cance in both RFS (p=0.767) and OS (p=0.644) in multivariable analyses. In conclusion, the presence of neurotropism predicts a greater risk for nodal involvement and is associated with worse survival in patients with cutaneous malignant melanoma, on the other hand it is not an independent risk factor when other powerful prognostic variables are considered. PMID- 29534594 TI - Rapid screening test of most frequent BRCA1/BRCA2 pathogenic variants in the NGS era. AB - The average risk of breast cancer in general Slovak population of women is 4-5% and the risk of ovarian cancer is 2%. Probability of breast/ovarian cancer development is higher in individuals carrying a causative germline DNA variant in BRCA1 or BRCA2 gene responsible for hereditary breast/ovarian cancer (HBOC). Although a major proportion of inherited breast/ovarian cancers are due to the mentioned causal mutations, a number of new genes have emerged. Here we describe a rapid, multiplex and comprehensive approach for the detection of pathogenic variants in BRCA1 and BRCA2 genes which most frequently occur in Slovak HBOC population. Analysis comprises the combination of mutation specific methods. Fluorescent PCR amplification followed by fragment analysis for detection of insertions/deletions in exon 11 of BRCA1 gene. Second method is SNaPshot analysis for detection of the most frequent missense and ins/del variants in exons 2, 5, 13, 20 of BRCA1 and exons 11, 23 and 25 of BRCA2 gene. Altogether, we have analyzed 687 samples, 86 (12.5%) in group 1, which fulfilled indication criteria based on the positive family/personal history. Group 2 involved 601 (87.5%) cases, who did not meet the indication criteria and only the screening test was recommended. Using the combined approach, we have identified 47 mutated samples (6.8%), 40 in group 1 (46.5%) and 7 in group 2 (1.1%). However, the presented screening test would not provide complex results of BRCA1/2 gene analysis, it offers testing accessible to a broader spectrum of individuals under the threshold of indication for whole gene analysis. This approach may provide valuable information even in the NGS analysis era. PMID- 29534595 TI - Impact of Tobacco Quitlines on Smoking Cessation in Persons With Mental Illness: A Systematic Review. AB - Persons with mental illness smoke at rates two to four times higher than do persons without mental illness and comprise 30.9% of the U.S. tobacco market. Given the prevalence of mental illness and the known detrimental effects of tobacco, concerted efforts are needed to promote the use of evidence-based treatment options. We conducted a systematic review of studies that examined the impact of tobacco quitline interventions in this population. Results revealed an overall positive impact of cessation services delivered via a tobacco quitline. More research is needed to determine intervention components and patient characteristics that are associated with cessation success. PMID- 29534596 TI - Self-Perceived Mate Value, Facial Attractiveness, and Mate Preferences: Do Desirable Men Want It All? AB - Ten years ago, Buss and Shackelford demonstrated that high mate value (i.e., physically attractive) women held more discerning mate preferences relative to lower mate value women. Since then, researchers have begun to consider the equally important role of men's sexual selectivity in human mate choice. Yet, little research has focused on whether high mate value men are similarly choosy in their mate preferences. In a sample of 139 undergraduate men, relationships between self-perceived mate value as well as female-rated facial attractiveness were examined in relation to men's expressed mate preferences. Results showed that self-perceived mate value was unrelated to men's facial attractiveness as rated by women. Men who believed they were of high mate value were more likely than lower mate value men to prefer to marry at a younger age; to have a spouse who was younger than them; and to have a partner who was sociable, ambitious, high in social status, with good financial prospects, a desire for children, health, good looks, and mutual attraction. Objective male facial attractiveness was generally unrelated to heightened mate preferences, with the exception of heightened preference for similar religious background and good physical health. Findings suggest that men who perceive themselves as high in overall mate value are selective in their mate choice in a manner similar to high mate value women. PMID- 29534597 TI - A Randomized, Controlled Trial of Lottery-Based Financial Incentives to Increase Physical Activity Among Overweight and Obese Adults. AB - PURPOSE: To evaluate the effect of lottery-based financial incentives in increasing physical activity. DESIGN: Randomized, controlled trial. SETTING: University of Pennsylvania Employees. PARTICIPANTS: A total of 209 adults with body mass index >=27. INTERVENTIONS: All participants used smartphones to track activity, were given a goal of 7000 steps per day, and received daily feedback on performance for 26 weeks. Participants randomly assigned to 1 of the 3 intervention arms received a financial incentive for 13 weeks and then were followed for 13 weeks without incentives. Daily lottery incentives were designed as a "higher frequency, smaller reward" (1 in 4 chance of winning $5), "jackpot" (1 in 400 chance of winning $500), or "combined lottery" (18% chance of $5 and 1% chance of $50). MEASURES: Mean proportion of participant days step goals were achieved. ANALYSIS: Multivariate regression. RESULTS: During the intervention, the unadjusted mean proportion of participant days that goal was achieved was 0.26 in the control arm, 0.32 in the higher frequency, smaller reward lottery arm, 0.29 in the jackpot arm, and 0.38 in the combined lottery arm. In adjusted models, only the combined lottery arm was significantly greater than control ( P = .01). The jackpot arm had a significant decline of 0.13 ( P < .001) compared to control. There were no significant differences during follow-up. CONCLUSIONS: Combined lottery incentives were most effective in increasing physical activity. PMID- 29534598 TI - Long-Term Outcomes From Repeated Smoking Cessation Assistance in Routine Primary Care. AB - PURPOSE: To test the association between repeated clinical smoking cessation support and long-term cessation. DESIGN: Retrospective, observational cohort study using structured and free-text data from electronic health records. SETTING: Six diverse health systems in the United States. PARTICIPANTS: Patients aged >=18 years who were smokers in 2007 and had >=1 primary care visit in each of the following 4 years (N = 33 691). MEASURES: Primary exposure was a composite categorical variable (comprised of documentation of smoking cessation medication, counseling, or referral) classifying the proportions of visits for which patients received any cessation assistance (<25% (reference), 25%-49%, 50%-74%, and >=75% of visits). The dependent variable was long-term quit (LTQ; yes/no), defined as no indication of being a current smoker for >=365 days following a visit where nonsmoker or former smoker was indicated. ANALYSIS: Mixed effects logistic regression analysis adjusted for age, sex, race, and comorbidities, with robust standard error estimation to account for within site correlation. RESULTS: Overall, 20% of the cohort achieved LTQ status. Patients with >=75% of visits with any assistance had almost 3 times the odds of achieving LTQ status compared to those with <25% visits with assistance (odds ratio = 2.84; 95% confidence interval: 1.50-5.37). Results were similar for specific assistance types. CONCLUSIONS: These findings provide support for the importance of repeated assistance at primary care visits to increase long-term smoking cessation. PMID- 29534599 TI - Effect of Visitor Perspective on Adoption Decisions at One Animal Shelter. AB - This study investigated the visitor experience at one urban animal shelter. While several previous studies have examined the reasons particular nonhuman animals are chosen by adopters, few have investigated the possible reasons one would visit a shelter and leave without adopting. Over a two-month period, 158 visitors were surveyed after they were finished touring the shelter. One quarter of those exiting the shelter had adopted a pet (companion animal) compared to 11% who had been planning to adopt that day but did not. Almost 20% of survey respondents were just visiting with no plans for pet adoption either that day or in the near future. Being affectionate and friendly were important characteristics sought by potential adopters, although non-adopters reported more frequently than adopters that the animal's reaction to them was important. Shelters should work toward increasing chances for pets to connect and interact with visitors and focus on educating and retaining the interest of those who are not quite ready for a new pet. PMID- 29534600 TI - The long non-coding RNA NEAT1 contributes to extracellular matrix degradation in degenerative human nucleus pulposus cells. AB - Intervertebral disc degeneration is a complex disease involving genetic and environmental factors and multiple cellular processes. The role and expression of the lncRNA NEAT1 were assessed in intervertebral disc degeneration. NEAT1 expression was assessed in degenerative and control nucleus pulposus using RT PCR. Western blotting and RT-PCR were also used to investigate p53 and p21 levels in nucleus pulposus tissues. NEAT1 function in degenerative nucleus pulposus cells was assessed with gain- and loss-of-function experiments. ERK/MAPK signaling was also examined. NEAT1, p53, and p21 were dramatically upregulated in intervertebral disc degeneration. Furthermore, catabolic MMP13 and ADAMTS5 were dysregulated and collagen II and aggrecan were downregulated after NEAT1 overexpression. This effect was reversed by transfection with si-NEAT1 in degenerative nucleus pulposus cells. In addition, NEAT1 was found to affect the activation of the ERK/MAPK pathway. The NEAT1-induced ECM degradation may involve ERK1/2/MAPK signaling. LncRNA NEAT1 may represent a novel molecular target for intervertebral disc degeneration treatment by preventing nucleus pulposus ECM degradation. Impact statement For the first time, our study demonstrates that lncRNA NEAT1 plays a role in the occurrence and development of IDD by participating in extracellular matrix remodeling. This lncRNA regulates catabolic MMP13 and ADAMTS5 and anabolic collagen II and aggrecan by affecting the ERK/MAPK signaling pathway in degenerative human nucleus pulposus (NP) cells. Our research provides a scientific basis for targeting of NEAT1 for the IDD. PMID- 29534601 TI - Carotenoid supplementation and retinoic acid in immunoglobulin A regulation of the gut microbiota dysbiosis. AB - Dysbiosis, a broad spectrum of imbalance of the gut microbiota, may progress to microbiota dysfunction. Dysbiosis is linked to some human diseases, such as inflammation-related disorders and metabolic syndromes. However, the underlying mechanisms of the pathogenesis of dysbiosis remain elusive. Recent findings suggest that the microbiome and gut immune responses, like immunoglobulin A production, play critical roles in the gut homeostasis and function, and the progression of dysbiosis. In the past two decades, much progress has been made in better understanding of production of immunoglobulin A and its association with commensal microbiota. The present minireview summarizes the recent findings in the gut microbiota dysbiosis and dysfunction of immunoglobulin A induced by the imbalance of pathogenic bacteria and commensal microbiota. We also propose the potentials of dietary carotenoids, such as beta-carotene and astaxanthin, in the improvement of the gut immune system maturation and immunoglobulin A production, and the consequent promotion of the gut health. Impact statement The concept of carotenoid metabolism in the gut health has not been well established in the literature. Here, we review and discuss the roles of retinoic acid and carotenoids, including pro-vitamin A carotenoids and xanthophylls in the maturation of the gut immune system and IgA production. This is the first review article about the carotenoid supplements and the metabolites in the regulation of the gut microbiome. We hope this review would provide a new direction for the management of the gut microbiota dysbiosis by application of bioactive carotenoids and the metabolites. PMID- 29534602 TI - Independence, loss, and social identity: Perspectives on driving cessation and dementia. AB - The purpose of this study on driving cessation was to explore the process of coping, decision-making and adaptation through this major life transition. We sought to examine understandings of the emotional responses of drivers and ex drivers with dementia from the perspective of healthcare providers and family caregivers of persons with dementia. Interviews and focus groups were conducted with several key informant groups: healthcare providers who work with patients with dementia and their families ( N = 10), representatives from organizations that provide services and support for persons with dementia ( N = 6), and family caregivers of drivers and former drivers with dementia ( N = 13). Data analysis involved inductive analytic techniques to generate descriptive and analytic themes from the data. The main themes from the analysis involve the: (1) Loss of independence and disruption to identity connected to emotional responses to driving cessation; (2) Experience of driving cessation as one loss within a series of losses related to dementia; (3) Importance of addressing emotional and identity-related effects in supportive responses to driving cessation; and (4) Support for maintained and adapted roles as a strategy to provide meaning and purpose in the context of driving cessation. Driving cessation can represent a significant disruption to identity, and is closely linked to losses, such as independence, within people's broader experiences of grief and loss associated with dementia. The findings suggest the need for supportive responses that address unique emotion and identity-related aspects of driving cessation for people with dementia and their family caregivers. PMID- 29534603 TI - In-home use of personalized music for persons with dementia. AB - Although evidence is mounting that personalized music has beneficial effects for long-term care residents with dementia, little research has examined the effects of personalized music for the majority of persons with dementia living at home. These individuals live at home with care partners who may also benefit from having music that is personalized for their loved one. Using the Music & MemorySM program of personalized playlists delivered via iPod Shuffles(r), the current study examined the effects of the Music & Memory program for persons with dementia by using the Bath Assessment of Subjective Quality of Life in Dementia scale and a Music Listening Experience Scale developed for this study. We also administered three scales that captured care partner experiences. Transcripts of the Bath Assessment of Subjective Quality of Life in Dementia administrations at the beginning of the study and 3 months later, plus interviews about the Music & Memory program, were then analyzed using the interpretive phenomenological analysis method. Themes about the Music & Memory program and life living with dementia for from diagnosed persons and their care partners are discussed. PMID- 29534604 TI - Effect of an Enterococcus faecium probiotic on specific IgA following live Salmonella Enteritidis vaccination of layer chickens. AB - Probiotics and immunization are being widely adopted by the poultry industry with the goal of controlling Salmonella enterica. However, the interaction between these two management protocols has been sparsely studied. The present study aimed to understand the role of an Enterococcus faecium probiotic in the production of salmonella-specific IgA in layers immunized with a live vaccine. Four groups were used: "Control" (no vaccine or probiotic); "Probiotic" (which received an E. faecium product); "Vaccine" (immunized with two doses of a live attenuated S. Enteritidis vaccine); and "Vaccine + probiotic". Faecal salmonella-specific IgA was analysed 7 and 20 days post-vaccination (dpv) boost. At 7 dpv, the "Vaccine" and "Vaccine + probiotic" groups had similar IgA levels. However, at 20 dpv, IgA levels were two times higher in the "Vaccine + probiotic" group compared to the "Vaccine" group. To understand the role of the intestinal microbiota in this finding, bacterial diversity in faeces was analysed by 16S rRNA gene sequencing. The improvement in IgA production in probiotic-treated birds was accompanied by marked changes in the faecal microbiome. Some of the main differences between the "Vaccine" and "Vaccine + probiotic" groups included reduction of Escherichia Shigella and increases in Blautia, Anaerotruncus and Lactobacillus in the latter group. Although no direct causal link can be established from this study design, it is possible that the E. faecium probiotic induces improved antibody production following vaccination via modulation of the intestinal microbiota. PMID- 29534605 TI - The adaptation process of mothers raising a child with complex congenital heart disease. AB - Mothers of children with congenital heart disease (CHD) tend to be concerned about their child's normal life. The majority of these mothers tend to experience negative psychological problems. In this study, the adaptation process of mothers raising a child with complex CHD was investigated based on the sociocultural context of Korea. The data collection was conducted by in-depth interviews and theoretical sampling was performed until the data were saturated. The collected data were analyzed using continuous theoretical comparisons. The results of the present study showed that the core category in the mothers' adaptation process was 'anxiety regarding the future', and the mothers' adaptation process consisted of the impact phase, standing against phase, and accepting phase. In the impact phase, the participants emotionally fluctuated between 'feelings of abandonment' and 'entertaining hope'. In the standing against phase, participants tended to dedicate everything to child-rearing while being affected by 'being encouraged by support' and 'being frustrated by tasks beyond their limits'. In the accepting phase, the subjects attempted to 'accept the child as is', 'resist hard feelings', and 'share hope'. Health-care providers need to develop programs that include information regarding CHD, how to care for a child with CHD, and effective child-rearing behaviors. PMID- 29534606 TI - Playing the game: How young people moderate influences in accommodating asthma in their lives. AB - This article presents moderating influences, one of the sub-core categories from the theory of accommodating interruptions. This theory emerged in the context of young people who have asthma, explaining how they develop behaviours in their everyday lives (Hughes 2014; Hughes et al., 2017). The aim of this research was to develop a theory on the behaviours of young people who have asthma, in relation to the impact of asthma on the lives and the issues affecting them. This research was undertaken using a classic grounded theory approach. Data were collected through in-depth interviews, participant diaries and clinic consultations with young people aged 11-16 years who had asthma for over one year. Moderating influence accounts for how social influences and social culture affect what young people who have asthma wish to achieve and how they want to be perceived by others. Young people moderate influences by their features or attributes in order to meet their own needs. PMID- 29534607 TI - Addressing the selectivity and toxicity of antiviral nucleosides. AB - Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies. PMID- 29534609 TI - The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination. AB - Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of idarucizumab and investigate the influence of idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged idarucizumab increased with increasing idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of idarucizumab was unaffected by dabigatran. In contrast, idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by idarucizumab. Urinary excretion of dabigatran after administration of idarucizumab was delayed, but total dabigatran excreted in urine was unaffected. Idarucizumab and dabigatran were eliminated together via renal pathways. PMID- 29534610 TI - Development of a rapid liquid chromatography tandem mass spectrometry method for the quantitation of serum dexamethasone and its clinical verification. AB - Background Measurement of serum dexamethasone during the overnight dexamethasone suppression test has been recommended to reduce false-positive results when investigating Cushing's syndrome or increasingly commonly found adrenal incidentalomas. Despite this, there remains a paucity of well-validated dexamethasone methods currently available. Here, we describe the development of a rapid and sensitive liquid chromatography tandem mass spectrometry serum dexamethasone assay and verify its utility in a cohort of postmenopausal females. Method Isotopically labelled internal standard was added to samples prior to supported liquid extraction. Extracts were analysed using liquid chromatography tandem mass spectrometry in the positive electrospray ionization mode. Multiple reaction monitoring was used to detect dexamethasone and its corresponding internal standard transitions. Normal healthy postmenopausal women ( n = 95) were recruited and underwent an overnight dexamethasone suppression test, with serum dexamethasone and cortisol measurements at 09:00 after administration of oral dexamethasone 1 mg at 23:00 the night before. Results Mean intra- and inter-assay imprecision were 4.1% and 2.9%, respectively, for dexamethasone concentrations of 1.5, 6.0 and 12.0 nmol/L. Matrix effects were found to be negligible at 106-109% with recovery ranging from 96 to 100%. The limit of quantitation was 0.25 nmol/L, and structural analogue analysis proved the method to be robust against interferences. Applying a serum dexamethasone cut-off of >3.3 nmol/L was associated with a serum cortisol <=50 nmol/L in 84/95 individuals. Conclusion We have developed a sensitive and robust liquid chromatography tandem mass spectrometry method for the quantitation of serum dexamethasone. The method can be used to identify false-positive results during the overnight dexamethasone suppression test or for pharmacokinetic studies. PMID- 29534608 TI - Nucleoside analogs as a rich source of antiviral agents active against arthropod borne flaviviruses. AB - Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations. PMID- 29534611 TI - Surveillance evaluation of the standardization of assay values for serum total 25 hydroxyvitamin D concentration in Japan. AB - Background To assess the vitamin D nutritional status, serum total 25 hydroxyvitamin D (25(OH)D) concentration is measured. We used six automated 25(OH)D immunoassays (AIAs) available in Japan and certified by the Vitamin D Standardization Program (VDSP) at the U.S. Center for Disease Control and Prevention to assess the concordance of the assay results. Methods Serum total 25(OH)D concentrations in SRM 972a and 20 serum samples from patients were determined using three liquid chromatography-tandem mass spectrometry (LC-MS/MS) and six AIAs (pilot study), and an additional 110 serum samples were assessed by the six AIAs (surveillance study). The assay bias from the results of LC-MS/MS by Chiba University or consensus values (i.e. average of six AIAs) was estimated using the procedure described in CLSI document EP09-A3. Results LC-MS/MS at Chiba University could completely separate 25(OH)D2, 25(OH)D3 and 3-epi-25(OH)D3, and the observed values including total 25(OH)D in SRM 972a were all within +/-1.SD of the assigned values. All AIAs produced results greater than +/-3.SD. In the pilot study, four of the six AIAs had an average percentage bias, as estimated by confidence interval (CI), larger than +/-5% (acceptance criterion in CLSI); the bias converged from -6.5% to 3.2% after adjustment by LC-MS/MS. In the surveillance study, 25(OH)D concentrations in AIAs all adjusted to LC-MS/MS converged within +/-5% from consensus values. However, some AIAs showed negative or positive bias from the consensus values. Conclusions Current AIAs in Japan continue to lack standardization. Manufacturers should implement quality assurance strategies so that their values more closely align to those of standard reference material 972a. PMID- 29534612 TI - Identification of a rare haemoglobin variant with a newly reported interference in HbA1c analysis. PMID- 29534614 TI - Analytical evidence to show letters impregnated with novel psychoactive substances are a means of getting drugs to inmates within the UK prison service. AB - Introduction Novel psychotropic substances also known as legal highs are a major concern in UK prisons, fuelling violence and putting a strain on resources for inmates requiring medical treatment for adverse effects. We provide a clinical toxicology service including routine screening for novel psychoactive substances. In 2015, we were approached by Her Majesty Prison Service search dog training team to advise on which novel psychoactive substances to target, and again in 2016 to further provide analytical support to test five letters which the dogs positively identified for novel psychotropic substances during routine searches of prison mail rooms. Here we provide the first analytical confirmation that letters sent to inmates are being used to smuggle novel psychotropic substances into UK prisons. Results Novel psychotropic substances were detected on all five letters and these included the stimulants ethylphenidate, methiopropamine and methoxiphenidaine, the sedative etizolam and the third generation synthetic cannabinoids 5F-AKB-48, AB-FUBINACA, MDMB-CHMICA. Other compounds detected include the class A drug cocaine, class B drug methylphenidate and the cutting agents lignocaine, benzocaine and procaine. Conclusion Novel psychotropic substances smuggled into UK prisons is a major safety and security concern. By analytically confirming letters sent to inmates do contain novel psychotropic substances, we have produced categorical evidence to support anecdotal suggestions that novel psychotropic substances are entering UK prisons in this manner. PMID- 29534613 TI - Evaluation of sample stability for a quantitative faecal immunochemical test and comparison of two sample collection approaches. AB - Background Faecal immunochemical testing is increasingly being used to triage symptomatic patients for suspected colorectal cancer. However, there are limited data on the effect of preanalytical factors on faecal haemoglobin when measured by faecal immunochemical testing. The aim of this work was to evaluate the stability of faecal haemoglobin in faeces and to compare two methods of faecal haemoglobin sampling for faecal immunochemical testing. Methods Six patients provided faeces for faecal haemoglobin measurement which were transferred into specialized collection devices at baseline and at 1, 2, 3 and 7 days after storage at either room temperature or 4 degrees C. A total of 137 patients returned both faeces transferred into the specialized collection device and faeces in a standard collection pot. A quantitative immunoturbidometric method was used to measure faecal haemoglobin and results were compared categorically. Discrepant results were assessed against diagnosis. Results Faecal haemoglobin concentration declined rapidly within a day of storage at room temperature but results remained >=10 MUg Hb/g faeces in 5/6 patients after two days. A faecal haemoglobin result >=10 MUg Hb/g faeces was obtained in 4/6 patients after storage for seven days at 4 degrees C. Results obtained when patients used specialized collection devices were significantly different from results obtained when faeces was transferred into the specialized collection device in the laboratory. Conclusion There is considerable heterogeneity in the sample stability of faecal haemoglobin; therefore, samples should be transferred rapidly into specialized collection devices to prevent false-negative results. Use of collection devices by patients can lead to false-positive results compared with their use in a laboratory. PMID- 29534616 TI - Disease-related expenditures and revision rates in chronic rhinosinusitis patients after endoscopic sinus surgery. AB - AIMS: The objective of this study was to quantify the treatment costs and revision surgery rates in chronic rhinosinusitis (CRS) patients, with and without nasal polyposis (CRSwNP and CRSsNP), who require treatment with endoscopic sinus surgery (ESS). The additive contributions of nasal polyposis (NP) and revision surgery to 1-year costs were a primary focus. MATERIALS AND METHODS: Adults (aged 18-64 years) undergoing ESS for CRS in 2012-2015 were identified within the Blue Health Intelligence database and used to estimate revision rates. Patients with +/-1 year of enrollment around the index ESS were used to estimate 1-year healthcare expenditures. Revision ESS rates were evaluated via Kaplan-Meier and Cox regression models. Disease-related healthcare and pharmacy expenditures were modeled with generalized linear regression to assess the impact of baseline patient characteristics. RESULTS: A total of 86,052 patients underwent ESS for CRS (43.5 +/- 12.4 years; 49.3% male), and a sub-set of 23,542 patients were available for 1-year healthcare expenditure analysis (44.0 +/- 12.1 years; 50.0% male). Revision ESS rates within 1 year were 3.5% in the CRSwNP cohort and 1.6% in the CRSsNP cohort. NP, deviated septum, gender, and region were statistically significant predictors of revision surgery. Mean 1-year treatment expenditures, including the index ESS, were $8,824 for CRSsNP and $11,166 for CRSwNP patients without revision ESS. CRSwNP doubled the risk of revision surgery in the first year after ESS compared with CRSsNP and cost 24% more in the absence of a second procedure. Revision ESS within the first year increased mean 1-year expenditures by $11,150 and $13,139 for CRSsNP and CRSwNP, respectively. LIMITATIONS: The primary limitation was the limited length of follow-up available for estimating revision ESS rates. CONCLUSIONS: In a large commercially insured US population, disease-related expenditures for patients having ESS for CRS are substantial, as are the additive impacts of NP and revision surgery. PMID- 29534617 TI - Celebrating the health literacy skills of parents: A photovoice study. AB - Parents play a vital role in promoting children's health. The parental health literacy skills are important since the decisions they make can have an impact on other family members' health and well-being. Using an assets-based approach, this project aimed to explore the skills parents use to communicate health messages with their children and how they manage their family's health. Six adult parents of children aged 0-16 years old took part in this photovoice study. The thematic analysis suggests that tapping into the creativity of parents through the gamification of health messages and encouraging children's independence are effective ways to promote healthy behaviors. Trusting their instincts and developing good relationships with healthcare providers were also seen as important. However, there is still a need to improve confidence and skills, particularly on how to critically appraise information, especially in this digital age where sources of information are vast and conflicting messages could arise. PMID- 29534619 TI - Genetic characterisation of 19 autosomal STR loci in a population sample from the Southeastern Anatolia Region of Turkey. AB - BACKGROUND: Southeastern Anatolia is the smallest, yet the most densely populated region among the seven major geographic constituents of Turkey. Situated in the Upper Mesopotamia, Southeastern Anatolia was also the northernmost extension of the Fertile Crescent, which is often considered as the earliest cradle of civilisation. AIM: To investigate the autosomal STR polymorphisms associated with a truly representative population sample pool from Southeastern Anatolia. SUBJECTS AND METHODS: Samples from a total of 257 volunteers were analysed by 19 loci autosomal STRs using the commercially available COrDIS Plus Kit. Allele frequencies, statistical parameters of forensic interest and Nei's DA distances with respect to the nearby and distant populations were calculated, besides performing exact tests of population differentiation with the same populations. RESULTS: A combined matching probability of 1.49978 * 10-23 and a combined power of exclusion of 0.999999961 were obtained for the novel Southeastern Anatolian autosomal STR dataset. Furthermore, the Southeastern Anatolia population was found to have close genetic affinities with the other regional populations from Turkey, along with those from an apparent genetic continuum extending from the Near East to Southeastern Europe. CONCLUSIONS: The novel Southeastern Anatolian dataset is expected to be useful in regional forensic genetics investigations and molecular anthropology applications. PMID- 29534618 TI - Investigational CD33-targeted therapeutics for acute myeloid leukemia. AB - INTRODUCTION: There is long-standing interest in drugs targeting the myeloid differentiation antigen CD33 in acute myeloid leukemia (AML). Positive results from randomized trials with the antibody-drug conjugate (ADC) gemtuzumab ozogamicin (GO) validate this approach. Partly stimulated by the success of GO, several CD33-targeted therapeutics are currently in early phase testing. Areas covered: CD33-targeted therapeutics in clinical development include Fc-engineered unconjugated antibodies (BI 836858 [mAb 33.1]), ADCs (SGN-CD33A [vadastuximab talirine], IMGN779), radioimmunoconjugates (225Ac-lintuzumab), bi- and trispecific antibodies (AMG 330, AMG 673, AMV564, 161533 TriKE fusion protein), and chimeric antigen receptor (CAR)-modified immune effector cells. Besides limited data on 225Ac-lintuzumab showing modest single-agent activity, clinical data are so far primarily available for SGN-CD33A. SGN-CD33A has single-agent activity and has shown encouraging results when combined with an azanucleoside or standard chemotherapeutics. However, concerns about toxicity to the liver and normal hematopoietic cells - the latter leading to early termination of a phase 3 trial - have derailed the development of SGN-CD33A, and its future is uncertain. Expert opinion: Early results from a new generation of CD33-targeted therapeutics are anticipated in the next 2-3 years. Undoubtedly, re-approval of GO in 2017 has changed the landscape and rendered clinical development for these agents more challenging. PMID- 29534620 TI - Zika Virus Awareness and Prevention Practices Among University Students in Miami: Fall 2016. AB - In January 2016, the first case of mosquito-borne Zika infection in the mainland United States was confirmed in Miami, Florida. The first locally acquired case was reported 6 months later. Local public health and school officials began warning students of the outbreak on their return to the classroom in August 2016. In November-December 2016, we conducted a survey of students attending a large public university in Miami to determine how well informed they were about Zika. A multistage sampling design was used to contact teaching assistants and ask them for help in recruiting their students. Eligible students had to be 18 years of age or older and enrolled in at least one three-credit course during fall semester. A 25-item questionnaire based on the World Health Organization Zika Knowledge, Attitudes, and Practice Resource Pack was developed, pretested, and approved by the university's institutional review board before it was made available to eligible students through Blackboard Learn or a survey link. About half (50.4%) of the 139 respondents had heard about Zika prior to 2016. Only one student was unaware of Zika before our survey. Most (47.1%) first learned about Zika through television, 18.8% from family or friends, and 15.2% from the Internet, social media, or university e-mail. Two thirds (66.2%) believed Zika could be prevented, 15.1% thought it might be prevented, and 85.7% had taken some precautions. A high level of awareness of the risk of Zika infection was apparent. Most students reported taking steps to avoid exposure to the Zika virus. PMID- 29534621 TI - Actoxumab + bezlotoxumab combination: what promise for Clostridium difficile treatment? AB - INTRODUCTION: Clostridium difficile infection (CDI) is the most common healthcare associated infection worldwide. As standard CDI antibiotic therapies can result in unacceptably high recurrence rates, novel therapeutic strategies for CDI are necessary. A recently emerged immunological therapy is a monoclonal antibody against C. difficile toxin B. Areas covered: In this review, the authors summarize the available pharmacological, preclinical, and clinical data for the CDI treatment based on anti-toxin A (actoxumab) and anti-toxin B (bezlotoxumab) human monoclonal antibodies (HuMabs), and discuss about the potentiality of a therapy that includes HuMab combined administration for CDI. Expert opinion: Although only bezlotoxumab is indicated to reduce recurrence of CDI, experimental studies using a combination of HuMabs actoxumab and bezlotoxumab have shown that bolstering the host immune response against both the C. difficile toxins may be effective in primary and secondary CDI prevention. Besides neutralizing both the key virulence factors, combination of two HuMabs could potentially offer an advantage for a yet to emerge C. difficile strain, which is a steady threat for patients at high risk of CDI. However, as actoxumab development was halted, passive immunotherapy with actoxumab/bezlotoxumab is actually impracticable. Future research will be needed to assess HuMab combination as a therapeutic strategy in clinical and microbiological cure of CDI. PMID- 29534622 TI - Counsellors' practices in donor sperm treatment. AB - When intended parents choose to have donor sperm treatment (DST), this may entail wide-ranging and long-lasting psychosocial implications related to the social parent not having a genetic tie with the child, how to disclose donor-conception and future donor contact. Counselling by qualified professionals is recommended to help intended parents cope with these implications. The objective of this study is to present findings and insights about how counsellors execute their counselling practices. We performed a qualitative study that included 13 counsellors working in the 11 clinics offering DST in the Netherlands. We held a focus group discussion and individual face-to-face semi-structured interviews, which were fully transcribed and analysed using thematic analysis. The counsellors combined screening for eligibility and guidance within one session. They acted according to their individual knowledge and clinical experience and had different opinions on the issues they discussed with intended parents, which resulted in large practice variations. The counsellors were dependent on the admission policies of the clinics, which were mainly limited to regulating access to psychosocial counselling, which also lead to a variety of counselling practices. This means that evidence-based guidelines on counselling in DST need to be developed to provide consistent counselling with less practice variation. PMID- 29534623 TI - Secular trend of head and face shape in adult population of Vojvodina (Serbia). AB - BACKGROUND: Different populations show variation in the pattern of change in craniofacial dimensions over time. Earlier studies of craniofacial traits in the Republic of Serbia were carried out, without any particular reference to secular changes. AIM: The aim of the study is to determine possible changes in craniofacial dimensions among the adult population of Vojvodina (Serbia) during a 33 year period. SUBJECTS AND METHODS: The findings of the study are based on the comparison of data from two cross-sectional surveys. The earlier research was conducted in 1975 (n = 2600) and the second from 2001-2006 (n = 4504). Four craniofacial dimensions and body height were analysed. RESULTS: In terms of the head dimensions, head length in males has increased substantially, while head breadth has decreased in both sexes. The total change in the cephalic index is 0.58 (males) and 0.48 (females) units per decade. Morphological face height has substantially increased, while face breadth has decreased in both sexes over this period. The total change in the facial index per decade is 0.75 units in males and 0.98 in females. CONCLUSION: The results point to a trend of head and face shape remodelling toward a narrower head and more elongated face, consistent with ongoing dolichocephalisation. PMID- 29534624 TI - Bone-anchored prostheses in patients with traumatic bilateral transfemoral amputations: rehabilitation description and outcome in 12 cases treated with the OPRA implant system. AB - PURPOSE: To describe the rehabilitation experience and outcome of treatment with bone-anchored prostheses in individuals with bilateral transfemoral amputations (TFAs) treated in Sweden over a period of 25 years. METHOD: Hospital records were reviewed for all patients with traumatic bilateral TFAs treated until 2015. The use of prostheses, walking aids and wheelchairs was noted. RESULTS: The cohort comprised 12 patients (nine men and three women with a mean age 35 years at treatment) and the median follow-up time was seven years (1-20). At baseline, 9/12 used prostheses and 3/12 did not. The main means of locomotion was in a wheelchair without wearing prostheses (n = 8/12) or in a wheelchair in combination with prosthetic walking supported by walking aids (n = 4/12). All prosthetic users had problems with sitting comfort. At follow-up, 11/12 patients used prostheses, while one did not. The means of locomotion was prosthetic walking in 3/12 cases, a combination of a wheelchair and prosthetic walking in 4/12, a wheelchair while wearing prostheses but not walking in 4/12 and a wheelchair without wearing prostheses in 1/12. Three patients walked unsupported by walking aids. Seven patients had no problem with prosthetic sitting comfort (n = 3 had small problems). CONCLUSIONS: Bone-anchored prostheses in patients with bilateral TFAs resulted in more prosthesis use during everyday locomotion, due hypothetically to improved comfort while wearing prostheses. The results further underline the importance of other assistive devices such as wheelchairs and walking aids used in combination with prostheses in this group of patients facing severe functional limitations. Implications for Rehabilitation This study provides an insight into the details of the rehabilitation and outcome in patients with traumatic bilateral transfemoral amputations treated with bone anchored prostheses in Sweden. The treatment can lead to a large amount of prosthetic use, but most patients will also use a range of assistive devices including full-length prostheses, stubbies, walking aids and wheelchairs after treatment. The importance of sitting in comfort while wearing prostheses should not be underestimated in patients with bilateral transfemoral amputations. PMID- 29534625 TI - Cetuximab for treating non-small cell lung cancer. AB - INTRODUCTION: Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials. Recent data from ongoing trials suggest that more careful selection based on molecular markers may identify good responders. Areas covered: In this article, the authors review the literature concerning basic science studies identifying EGFR as a therapeutic target, pharmacological development of Cetuximab, its pharmacodynamics and pharmacokinetics, and clinical trials on Cetuximab in NSCLC, focusing on recent findings on putative predictive biomarkers. Expert opinion: Cetuximab currently has no role in NSCLC treatment outside of research settings. We argue that failure to identify a predictive biomarker early on has hampered its chances to enter routine practice. Although recent research suggests benefit in highly selected patient subsets, its potential impact is severely dampened by lack of regulatory body approval and the emergence of competitors for the same niches. PMID- 29534626 TI - NF-kappaB signaling pathway-enhanced complement activation mediates renal injury in trichloroethylene-sensitized mice. AB - Both NF-kappaB pathway and complement activation appear to be involved in kidney damage induced by trichloroethylene (TCE). However, any relationship between these two systems has not yet been established. The present study aimed to clarify the role of NF-kappaB in complement activation and renal injury in TCE sensitized BALB/c mice. Mice were sensitized by an initial subcutaneous injection and repeated focal applications of TCE to dorsal skin at specified timepoints. NF kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) was injected (intraperitoneal) before the final two focal TCE challenges. In the experiments, mice had their blood and kidneys collected. Kidney function was evaluated via blood urea nitrogen (BUN) and creatinine (Cr) content; renal histology was examined using transmission electron microscopy (TEM). Kidney levels of phospho p65 were assessed by Western blot and kidney mRNA levels of interleukin (IL) 1beta, IL-6, IL-17, tumor necrosis factor (TNF)-alpha, and p65 by real-time quantitative PCR. Presence of C3 and C5b-9 membrane attack complexes in the kidneys was evaluated via immunohistochemistry. The results showed there was significant swelling, vacuolar degeneration in mitochondria, shrinkage of microvilli, disappearance of brush borders, segmental foot process fusion, and glomerular basement membrane thickening (or disrobing) in kidneys from TCE sensitized mice. In conjunction with these changes, serum BUN and Cr levels were increased and IL-1beta, IL-6, IL-17, and TNFalpha mRNA levels were elevated. Levels of p65 and phospho-p65 protein were also up-regulated, and there was significant C3 and C5b-9 deposition. PDTC pretreatment attenuated TCE-induced up regulation of p65 and its phosphorylation, complement deposition, cytokine release, and renal damage. These results provide the first evidence that NF kappaB pathway has an important role in TCE-induced renal damage mediated by enhanced complement activation in situ. PMID- 29534627 TI - Rheological investigation of high-acyl gellan gum hydrogel and its mixtures with simulated body fluids. AB - Purpose Most of the studies concerning gellan have been focused on its application as a food ingredient, however, gellan is often considered as a candidate for the development of novel pharmaceutical formulations. Taking into account that gellan is ion-sensitive, it can be assumed that its initial mechanical properties can change upon contact with body secretions. Therefore, the aim of the work was to investigate the rheological properties of pure high acyl gellan gum hydrogel (0.4%) and its mixtures with selected simulated body fluids. Methods The rheological investigations were performed on rotational rheometer and included oscillatory temperature, amplitude, and frequency sweeping. The results enabled estimation of the linear viscoelastic regime, calculation of the cross-over points, and percentage of structure recovery. Results In the case of pure hydrogel no evidence of thermosensitivity was observed in the range of 20-40 degrees C. In pH = 1.2 (NaCl/HCl) the hydrogel structure was almost entirely destroyed. Mixing with phosphate buffer (pH = 4.5) resulted in higher gel strength than after dilution with deionized water. The opposite effect was observed in the case of pH = 7.4. The studies performed for the mixture of GG hydrogel and mucin indicated interaction between the components. The hydrogel elasticity increased in the presence of simulated tear, but decreased in simulated saliva and vaginal fluid. Conclusions In this study, it was shown that the stability of a three-dimensional gellan structure may be affected by pH and the presence of mucin which most probably competed with gellan gum in divalent cations binding. The observations presented in this study may be important in terms of potential application of gellan gum as a potential carrier in drug delivery systems. PMID- 29534628 TI - Gemfibrozil has antidepressant effects in mice: Involvement of the hippocampal brain-derived neurotrophic factor system. AB - Major depressive disorder has become one of the most serious neuropsychiatric disorders worldwide. However, currently available antidepressants used in clinical practice are ineffective for a substantial proportion of patients and always have side effects. Besides being a lipid-regulating agent, gemfibrozil is an agonist of peroxisome proliferator-activated receptor-alpha (PPAR-alpha). We investigated the antidepressant effects of gemfibrozil on C57BL/6J mice using the forced swim test (FST) and tail suspension test (TST), as well as the chronic unpredictable mild stress (CUMS) model of depression. The changes in brain derived neurotrophic factor (BDNF) signaling cascade in the brain after CUMS and gemfibrozil treatment were further assessed. Pharmacological inhibitors and lentivirus-expressed short hairpin RNA (shRNA) were also used to clarify the antidepressant mechanisms of gemfibrozil. Gemfibrozil exhibited significant antidepressant actions in the FST and TST without affecting the locomotor activity of mice. Chronic gemfibrozil administration fully reversed CUMS-induced depressive-like behaviors in the FST, TST and sucrose preference test. Gemfibrozil treatment also restored CUMS-induced inhibition of the hippocampal BDNF signaling pathway. Blocking PPAR-alpha and BDNF but not the serotonergic system abolished the antidepressant effects of gemfibrozil on mice. Gemfibrozil produced antidepressant effects in mice by promoting the hippocampal BDNF system. PMID- 29534629 TI - Use of an Anti-Infective Medication Review Process at Hospital Discharge to Identify Medication Errors and Optimize Therapy. AB - BACKGROUND: Medication reconciliation is a major patient safety concern, and the impact of a structured process to evaluate anti-infective agents at hospital discharge warrants further review. OBJECTIVE: The aim of this study was to (1) describe a structured, multidisciplinary approach to review anti-infectives at discharge and (2) measure the impact of a stewardship-initiated antimicrobial review process in identifying and preventing anti-infective-related medication errors (MEs) at discharge. METHODS: A prospective study to evaluate adult patients discharged on anti-infectives was conducted from October 2013 to May 2014. The antimicrobial stewardship program (ASP) classified interventions on anti-infective regimens into predefined ME categories. RESULTS: Forty-five patients who were discharged on 59 anti-infective prescriptions were included in the study. The most common indications for anti-infective regimens at discharge were pneumonia (22%, n = 10), bacteremia (18%, n = 8), and skin and soft tissue infections (16%, n = 7). An ME was identified in 42% (n = 19/45) of anti infective regimens. Seventy percentage of ASP team recommendations were accepted which resulted in an avoidance of MEs in 68% (n = 13/19) of patients with an ME prior to discharge. CONCLUSION: This study describes the outcomes of a stewardship-initiated review process in preventing MEs at discharge. Developing a systematic process for a multidisciplinary ASP team to review all anti-infectives can be a valuable tool in preventing MEs at hospital discharge. PMID- 29534630 TI - Antibiotic Use in the Intensive Care Unit: Optimization and De-Escalation. AB - Appropriate antimicrobial therapy is essential to ensuring positive patient outcomes. Inappropriate or suboptimal utilization of antibiotics can lead to increased length of stay, multidrug-resistant infections, and mortality. Critically ill intensive care patients, particularly those with severe sepsis and septic shock, are at risk of antibiotic failure and secondary infections associated with incorrect antibiotic use. Through the initiation of active empiric antibiotic therapy based upon local susceptibilities, daily evaluation of signs and symptoms of infection and narrowing of antibiotic therapy when feasible, providers can streamline the treatment of common intensive care unit (ICU) infections. Optimizing antibiotic dosing through prolonged infusions can be beneficial in intensive care populations with altered pharmacokinetics. Antimicrobial stewardship teams can assist ICU providers in managing and implementing these tactics. This review will discuss the current literature on antibiotic use in the ICU applying antimicrobial stewardship strategies. Based upon the most recent evidence, ICUs would benefit from employing empiric guidelines for antibiotic use, collecting appropriate specimens and implementing molecular diagnostics, optimizing the dosing of antibiotics, and reducing the duration of total therapy. These strategies for antibiotic use have the potential to enhance patient care while preventing adverse outcomes. PMID- 29534632 TI - Prevalence and Risk of Violent Ideation and Behavior in Serious Mental Illnesses: An Analysis of 63,572 Patient Records. AB - Research has consistently demonstrated that people diagnosed with serious mental illness (SMI) are at increased risk for violent ideation and behavior (VIB) and that this is especially the case for SMI patients with comorbid substance use disorders (SUD). Despite this, what is still largely unknown is the relative prevalence of VIB across diagnostic categories, whether the rates of VIB in SMI groups exceed the rates observed in people with SUD only, and which demographic factors increase the likelihood of VIB under different circumstances for people with SMI. To address these questions, we analyzed the intake records of 63,572 patients diagnosed with SMIs (i.e., schizoaffective disorder, schizophrenia, bipolar disorder, and unipolar depression), substance use disorders, and non-SMI psychiatric disorders. Raw prevalence rates for a combined metric of VIB were established and compared for each group, and a series of logistic regression analyses were performed to estimate how various demographic factors influenced the likelihood of VIB endorsement in each study group. Our results revealed that (a) patients with SMI conditions had higher rates of VIB than both patients with non-SMI psychopathology and those with substance use disorders only; (b) patients with SMI and comorbid substance use pathology were responsible for the majority of VIB within each SMI condition; and (c) men with SMI conditions had higher prevalence rates of VIB than females. In addition, we found that for every SMI diagnosis, comorbid substance use disorders and younger age were related to greater risk for VIB, and where race and gender were found to significantly alter the likelihood of VIB endorsement, African American status and female gender were independently related to greater risk. The implications of these findings and directions for future research are discussed. PMID- 29534631 TI - Synaptic properties of layer VI inverted pyramidal cells in the rodent somatosensory cortex. AB - The properties of specific cortical cell types enable greater understanding of how cortical microcircuits process and transmit sensory, motor, and cognitive information. Previous reports have characterized the intrinsic properties of the inverted pyramidal cell (IPC) where the most prominent dendrite is orientated towards the cortical white matter. Using whole cell patch clamp recordings from rat and mouse somatosensory cortex in conjunction with electric microstimulation of the white matter we characterized the synaptic inputs onto IPCs and the more common upright pyramidal cell (UPC) in the infragranular layers. Both classes of pyramidal cells received monosynaptic glutamatergic input following white matter stimulation, but varied on a number of parameters. Most prominently, UPCs displayed higher amplitude responses and showed greater rates of depression compared to IPCs. These data reinforce the view that IPCs are a separate functional class of cortical neuron. PMID- 29534633 TI - How many single-nucleotide polymorphisms (SNPs) must be tested in order to prove susceptibility to bacterial meningitis in children? Analysis of 11 SNPs in seven genes involved in the immune response and their effect on the susceptibility to bacterial meningitis in children. AB - The aim of this study is to describe the prevalence of single single-nucleotide polymorphisms (SNPs) as well as their combinations in genes encoding proteins involved in the immune response in children with bacterial meningitis. The prospective study group consisted of 39 children with bacterial meningitis and 49 family members surveyed between 2012 and 2016. Eleven SNPs in seven genes involved in immune response were analysed. The mean number of minor frequency alleles (MAF) of studied SNPs was lowest in the control group and highest in patients with pneumococcal meningitis. We found that carrying >=6 MAF of studied SNPs was associated with an increased risk of pneumococcal meningitis. The prevalence of risky variants was noted to be higher in patients with pneumococcal meningitis as compared to the control group. In conclusion, genetic factors are a relevant factor in determining the susceptibility to bacterial meningitis. A statistically significant cumulative effect of mutated variants on increasing the risk of bacterial meningitis was detected. Combining all three SNPs in MBL2 improves the prediction of susceptibility to pneumococcal meningitis. Analysis of risky alleles can help indicate people prone to the disease who are 'gene immunocompromised'. PMID- 29534634 TI - Brachioradialis to extensor pollicis longus transfer to restore thumb extension in seven patients. PMID- 29534635 TI - Reference intervals for hemoglobin and hematocrit in a low-risk pregnancy cohort: implications of racial differences. AB - OBJECTIVE: As anemia in pregnancy is associated with adverse perinatal outcomes, we sought to define the mean and the fifth percentile of Hb and Ht using a contemporary multiethnic large cohort of low-risk pregnancies, and assess potential racial differences. METHODS: We conducted a retrospective cohort study on women who delivered between 1 January 2008 and 31 December 2013 in Reggio Emilia County, Italy. Linear mixed effects models were used to describe changes in mean Hb and Ht, while quantile regression with matrix-design bootstrap defined changes in the fifth percentile of Hb and Ht, controlling for race, maternal age, smoking, and pregnancy number. RESULTS: We analyzed 23,657 hemograms from 7318 pregnancies and 6870 women. Multivariate analysis showed that when compared to Caucasians', African women's mean Hb and Ht were respectively 0.24 (95%CI 0.3 0.17) g/dl and 0.7 (95%CI 0.8-0.5) % lower, while Asian mothers' were 0.11 (95%CI 0.19-0.03) g/dl and 0.3 (95%CI 0.5-0.1) % inferior. Similarly, both African and Asian women had lower fifth Ht percentiles (-1, 95%CI -1.3 to -0.6, and -0.4, 95%CI -0.7 to -0.04) than Caucasians, while African mothers also had lower fifth Hb percentile (0.3, 95%CI 0.5-0.1). The fifth percentile for Hb and Ht were, respectively, 11.3 (95%CI 11-11.5) g/dl and 32.8 (95%CI 32.3-33.4) % in the first trimester, 10.4 (95%CI 10.1-10.6) g/dl and 30.2 (95%CI 29.6-30.8) % in the second trimester, 10.1 (95%CI 9.8-10.3) g/dl and 30.6 (95%CI 30-31.1) % in the third trimester. CONCLUSIONS: We provided contemporary references to define anemia in pregnancy, and we confirmed that even in pregnancy, African and Asian women have lower Hb and Ht than Caucasian. Racial and population-specific references may have significant clinical and public health implication for more accurate disease diagnosis and appropriate treatment. PMID- 29534636 TI - Maternal and fetal effects of chocolate consumption during pregnancy: a systematic review. AB - OBJECTIVES: The purpose of this review is to explore the effects of chocolate consumption during pregnancy on fetus and mother herself. METHODS: Randomized controlled trials/quasi-experimental/observational/controlled before and after studies involving chocolate/cocoa/cacao consumption (irrespective of type or dose, composition, exposure period, and method of administration) among pregnant women/animals; and measuring any outcome (beneficial or harmful) related to fetus or mother after chocolate exposure were included. Databases searched were PubMed, Web of Science and Scopus; between April and May 2017. Risk of bias within each human randomized controlled trial (RCT) and animals' experimental studies was evaluated by "The Cochrane Collaboration's tool" and SYRCLE's tool respectively. RESULTS: Fourteen human studies including a total of 6639 participants and nine animal studies were selected. Outcome variables investigated in human studies were maternal blood pressure, fetal heart rate, and striae gravidarum. Animal studies explored chocolate-induced teratogenicity and fetal metabolic derangements. Ten out of these 23 studies reported chocolate to be "beneficial"; five studies reported adverse effects, whereas eight studies declared chocolate as "neutral". CONCLUSIONS: Maternal chocolate intake has acute stimulatory effects on fetal reactivity and chronic blood pressure reducing effect in mothers. Chocolate is nonteratogenic and does not affect reproductive indices. Metabolic derangements in offsprings born to chocolate fed dams have been reported. Pregnant females must be careful about consumption of cocoa and chocolate. Future studies should be planned, keeping in view heterogeneities identified across the selected studies in this review. PMID- 29534637 TI - Predictors of Trypanosoma lewisi in Rattus norvegicus from Durban, South Africa. AB - This study investigated associations between Trypanosoma lewisi and Xenopsylla cheopis, a common cyclical vector of T. lewisi; Polyplax spinulosa, a reported mechanical vector; and Laelaps echidnina and Laelaps lamborni, 2 rodent mites of Rattus norvegicus in Durban, South Africa. In total, 379 R. norvegicus individuals were live-trapped at 48 sites in 4 locality types around Durban during a 1-yr period. Rats were euthanized, cardiac blood was taken to check for hemoparasites, and ectoparasites were removed for identification. Parasite species richness was higher in pups (2.11) and juveniles (1.02) than adults (0.87). Most rats in the study harbored 1 or 2 of the 5 parasites surveyed. Rats with trypanosomes and fleas were more prevalent in the city center and harbor, where juveniles were most affected. Rats with lice were more prevalent in informal settlements and urban/peri-urban areas, where pups had the highest infestations. There was a significant positive association between rats with fleas and trypanosomes and a negative association between rats with lice and trypanosomes. Location and rat age were significant predictors of T. lewisi, X. cheopis, and P. spinulosa. Mites showed no strong association with trypanosomes. Ectoparasite associations are possibly habitat and life-cycle related. We conclude that Durban's city center, which offers rats harborage, an unsanitary environment, and availability of food, is a high-transmission area for fleas and trypanosomes, and consequently a potential public health risk. PMID- 29534638 TI - Abstracts of invited lectures and oral presentations at ISOBM 2017. PMID- 29534640 TI - Overdue to understand anticoagulation in pulmonary arterial hypertension. PMID- 29534639 TI - Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial. AB - BACKGROUND: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. METHODS: Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. RESULTS: Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. CONCLUSION: The cytokeratin 18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted. PMID- 29534641 TI - The effect of mechanical aspiration of the vertebral body on pulmonary arterial pressure before cement injection in the vertebroplasty procedure. AB - PURPOSE: The aim of this study is to compare the efficacy of the mechanical aspiration technique just prior to cement application in the standard vertebroplasty (VP). METHODS: Forty patients were included in the study. In group A, mechanical aspiration of the cavity was done just before the cement injection and in group B aspiration of vertebral body did not perform, VP was done with the same size cannula, same injection force, same injection speed and same cement viscosity. Pulmonary arterial pressures (PAPs) and blood d-dimer values were recorded preoperatively, 24 h and 3 days after the procedure. The PAP and d-dimer data were statistically compared with Student's t-test. RESULTS: The mean age was 71 (62-87) in A and 70 (64-88) in B. The augmented level was 6.7 in A and 6.9 in B. Cement leakage was present in four in A and six in B. Acute hypotension was observed immediately after cement injection in one patient in A and four patients in B. The preoperative mean PAP in A was 35mm/Hg and elevated to 48 mm/Hg on the first postoperative day and decreased to 42 mm/Hg on the third postoperative day. The mean PAP in B was 36 mm/Hg preoperatively, 71 mm/Hg on the first day, and 58 mm/Hg on the third day ( p < 0.05). The d-dimer values revealed a difference between groups, the PAP values significantly changed between before and after the operation in both groups ( p < 0.005). CONCLUSION: Aspiration of the vertebral body can easily be used to decrease the risk of cement leakage and the migration of fatty particles into the pulmonary circulation. PMID- 29534642 TI - Self-Enhancement and Psychological Adjustment: A Meta-Analytic Review. AB - This article advances the debate about costs and benefits of self-enhancement (the tendency to maintain unrealistically positive self-views) with a comprehensive meta-analytic review (299 samples, N = 126,916). The review considers relations between self-enhancement and personal adjustment (life satisfaction, positive affect, negative affect, depression), and between self enhancement and interpersonal adjustment (informant reports of domain-general social valuation, agency, communion). Self-enhancement was positively related to personal adjustment, and this relation was robust across sex, age, cohort, and culture. Important from a causal perspective, self-enhancement had a positive longitudinal effect on personal adjustment. The relation between self-enhancement and interpersonal adjustment was nuanced. Self-enhancement was positively related to domain-general social valuation at 0, but not long, acquaintance. Communal self-enhancement was positively linked to informant judgments of communion, whereas agentic self-enhancement was linked positively to agency but negatively to communion. Overall, the results suggest that self-enhancement is beneficial for personal adjustment but a mixed blessing for interpersonal adjustment. PMID- 29534643 TI - Increased TLR4 and TREM-1 expression on monocytes and neutrophils in preterm birth: further evidence of a proinflammatory state. AB - OBJECTIVE: Increased inflammation is considered as a risk factor and a promoter of preterm birth (PTB). Monocytes and neutrophils are the main sources of cytokines in the early inflammatory phase. So far, very few studies have indicated CD14/TLR4 and TREM-1 on the monocytes and neutrophils as important targets in PTB. MATERIALS AND METHODS: TLR4 and TREM-1 on CD14+ maternal and cord blood monocytes and neutrophils were detected using flow cytometry in 48 normal term women, 48 PTB with chorioamnionitis (CCA) women, and 40 PTB without CCA women. In the fetal membranes, mRNA and protein levels of the CD14/TLR4-TREM-1 signaling pathway, CD14, TLR4, NF-kappaBp65, and TREM-1 were analyzed by qRT-PCR and western blot. ELISA was further used to detect TLR4 and TREM-1 levels in maternal and cord serums. RESULTS: Compared with the normal term and PTB without CCA women, we found that (1) TLR4 and TREM-1 levels on CD14+ maternal and cord blood monocytes and neutrophils in the PTB with CCA group were elevated (p < .001); (2) the protein and mRNA expressions of CA14, TLR4, NF-kappaBp65, and TREM 1 of the PTB with CCA group were upregulated (p < .001); (3) Maternal and cord serum concentrations of TLR4 and TREM-1 in the PTB with CCA group were greater (p < .001). CONCLUSIONS: The high levels of TLR4 and TREM-1 surface expression were observed on CD14+ maternal and cord blood monocyte and neutrophils, confirming their proinflammatory profiles in PTB with CCA. TLR4 and TREM-1 on monocyte and neutrophils might have a role in infection-related PTB. PMID- 29534644 TI - Insightfulness as a dynamic process in development and treatment: a commentary. AB - This special issue presents a series of conceptually interlinked papers on the construct of insightfulness and its role in child development and intervention. In this commentary, I provide some reflections on the nature of insightfulness from the point of view of developmental and clinical psychology. Four themes are highlighted: (1) the potential role of insightfulness in understanding the parenting mediators of attachment transmission, (2) the role of insightfulness in understanding the connections between early experiences and later social outcomes, (3) the dynamic evolution of insightfulness across development, and (4) the different elements of insightfulness and their distinct contributions to caregiving behavior. PMID- 29534645 TI - The effects of co-witness discussion on confidence and precision in eyewitness memory reports. AB - We examined the influence of co-witness discussion on the metacognitive regulation of memory reports. Participants (N = 92) watched a crime video. Later, a confederate confidently agreed with (gave confirming feedback), disagreed with (gave disconfirming feedback), or gave no feedback (control) regarding participants' answers to questions about the video. Participants who received disconfirming feedback reported fewer fine-grain details than participants in the confirming and control conditions on a subsequent, individual recall test for a different question set. Unexpectedly, this decrease in fine-grain reporting was not accompanied by a decrease in participants' confidence in the accuracy of their fine-grain responses. These results indicate that receiving social comparative feedback about one's memory performance can affect rememberers' metamemorial control decisions, and potentially decrease the level of detail they volunteer in later memory reports. Further research is needed to assess whether these results replicate under different experimental conditions, and to explore the effects of social influences on metamemory. PMID- 29534646 TI - MRI for peripheral artery disease: Introductory physics for vascular physicians. AB - Magnetic resonance imaging (MRI) has advanced significantly in the past decade and provides a safe and non-invasive method of evaluating peripheral artery disease (PAD), with and without using exogenous contrast agents. MRI offers a promising alternative for imaging patients but the complexity of MRI can make it less accessible for physicians to understand or use. This article provides a brief introduction to the technical principles of MRI for physicians who manage PAD patients. We discuss the basic principles of how MRI works and tailor the discussion to how MRI can evaluate anatomic characteristics of peripheral arterial lesions. PMID- 29534648 TI - To Whom Do We Confide Our Secrets? AB - Although prior work has examined secret keeping, no prior work has examined who gets told secrets. Five studies find compassion and assertiveness predict having secrets confided in oneself (as determined by both self- and peer reports), whereas enthusiasm and politeness were associated with having fewer secrets confided. These results bolster suggestions that interpersonal aspects of personality (which can fit a circumplex structure) are driven by distinct causal forces. While both related to agreeableness, compassion (empathy and desire to help) predicts being confided in more, whereas politeness (concern with social norms and social rules) predicts being confided in less. Likewise, while both related to extraversion, assertiveness (having the agency and drive to help) predicts being confided in more, whereas enthusiasm (positive sociality) predicts being confided in less. PMID- 29534647 TI - Implicit and Explicit Racial Attitudes Changed During Black Lives Matter. AB - Lab-based interventions have been ineffective in changing individuals' implicit racial attitudes for more than brief durations, and exposure to high-status Black exemplars like Obama has proven ineffective in shifting societal-level racial attitudes. Antiracist social movements, however, offer a potential societal-level alternative for reducing racial bias. Racial attitudes were examined before and during Black Lives Matter (BLM) and its high points of struggle with 1,369,204 participants from 2009 to 2016. After controlling for changes in participant demographics, overall implicit attitudes were less pro-White during BLM than pre BLM, became increasingly less pro-White across BLM, and were less pro-White during most periods of high BLM struggle. Considering changes in implicit attitudes by participant race, Whites became less implicitly pro-White during BLM, whereas Blacks showed little change. Regarding explicit attitudes, Whites became less pro-White and Blacks became less pro-Black during BLM, each moving toward an egalitarian "no preference" position. PMID- 29534649 TI - Action Dominance: The Performance Effects of Multiple Action Demands and the Benefits of an Inaction Focus. AB - Four experiments uncovered an action dominance error by which people's natural focus on actions hinders appropriate responses to social and nonsocial stimuli. This surprising error comprises higher rates of both omission (misses) and commission (false alarms) when, in responding to action and inaction demands, people have higher numbers of action targets. The action dominance error was verified over four experiments using an analog that required responses to words and to target individuals. Experiments 1 and 2 tested our hypotheses and distinguished the action error effect from the effects of practicing action or inaction responses. Experiment 3 linked the error to the greater cognitive load imposed by the higher proportion of action over inaction targets. Furthermore, Experiment 4 demonstrated that (a) there is a default tendency to pay more attention to action (vs. inaction) targets and (b) shifting focus to inaction targets reduces the action dominance error. PMID- 29534651 TI - Maternal caffeine intake in pregnancy is inversely related to childhood peer problems in Japan: The Kyushu Okinawa Maternal and Child Health Study. AB - OBJECTIVES: The present prebirth cohort study examined the association between maternal caffeine consumption during pregnancy and behavioral problems in Japanese children aged 5 years. METHODS: Subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, and peer problems were assessed using the Japanese parent-report version of the Strengths and Difficulties Questionnaire. Adjustment was made for maternal age, gestation at baseline, region of residence at baseline, number of children at baseline, maternal and paternal education, household income, maternal depressive symptoms during pregnancy, maternal alcohol intake during pregnancy, maternal smoking during pregnancy, child's birth weight, child's sex, breastfeeding duration, and smoking in the household during the first year of life. RESULTS: The contributors of caffeine in the diet during pregnancy were Japanese and Chinese tea (74.8%), coffee (13.0%), black tea (4.4%), confectionaries (4.0%), and soft drinks (3.7%). Higher maternal caffeine consumption during pregnancy was independently associated with a reduced risk of peer problems in the children: the adjusted odds ratios (95% confidence intervals) in the first, second, third, and fourth quartiles of maternal caffeine consumption during pregnancy were 1 (reference), 0.61 (0.35-1.06), 0.52 (0.29-0.91), and 0.51 (0.28-0.91), respectively (P for trend = 0.01). Maternal caffeine intake during pregnancy was not evidently related to the risk of emotional problems, conduct problems, or hyperactivity problems in the children. CONCLUSIONS: Maternal caffeine consumption, mainly from Japanese and Chinese tea, during pregnancy may be preventive against peer problems in Japanese children. PMID- 29534652 TI - The Impact of Absolute CD4 Count and Percentage Discordance on Pneumocystis Jirovecii Pneumonia Prophylaxis in HIV-Infected Patients. AB - Current guidelines suggest that HIV-infected patients should receive chemoprophylaxis against Pneumocystis jirovecii pneumonia (PJP) if they have a cluster determinant 4 (CD4) count <200 cells/mm3 or oropharyngeal candidiasis. Persons with CD4 percentage (CD4%) below 14% should also be considered for prophylaxis. Discordance between CD4 count and CD4% occurs in 16% to 25% of HIV infected patients. Provider compliance with current PJP prophylaxis guidelines when such discordance is present was assessed. Electronic medical records of 429 HIV-infected individuals who had CD4 count and CD4% measured at our clinic were reviewed. CD4 count and percentage discordance was seen in 57 (13%) of 429. Patients with CD4 count >200 but CD4% <14 were significantly less likely to be prescribed PJP prophylaxis compared with those who had CD4 count <200 and CD4% >14 (29% versus 86%; odds ratio = 0.064, 95% confidence interval: 0.0168-0.2436; P < .0001). We emphasize monitoring both the absolute CD4 count and percentage to appropriately guide PJP primary and secondary prophylaxis. PMID- 29534653 TI - Acute Trigeminal Neuralgia Associated with Initiation of Emtricitabine/Tenofovir for HIV Pre-Exposure Prophylaxis. AB - HIV pre-exposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) fixed-dose combination (FTC/TDF) is undergoing rapid scale-up in the United States. While FTC/TDF is typically well tolerated, to our knowledge, cranial nerve pathology associated with FTC/TDF has not been previously described. We report the case of a 35-year-old patient who began FTC/TDF PrEP and developed acute trigeminal neuralgia. The neurologic symptoms resolved after treatment discontinuation and recurred upon rechallenge, resulting in permanent discontinuation of PrEP treatment. PMID- 29534654 TI - Factors Associated with Outcomes of Pre-ART HIV Care. AB - The World Health Organization recommended removing all CD4 requirements for initiation of antiretroviral therapy (ART) in resource-limited settings. We examined the pre-ART period to identify and assess factors associated with outcomes of pre-ART care. Four modes of transition out of pre-ART care were considered. Beta estimates from the competing risks Cox models were used to investigate whether the effects of covariates differed by mode of transition. Median CD4 counts at entry showed no meaningful change over time. Advanced disease progression and presence of opportunistic infections were significant predictors of pre-ART mortality. Men were more likely to die before initiating ART, transfer to another facility, or be lost to follow-up than were women. Removing CD4 thresholds is not likely to substantially reduce program mortality prior to ART initiation unless and until patients enroll earlier in disease progression. Care programs should focus on diagnosis and treatment of opportunistic infections to reduce pre-ART mortality. PMID- 29534655 TI - High Prevalence of Antibiotic-Resistant Otitis Media-Associated Bacterial Flora of Asymptomatic People Living with HIV at Morogoro Hospital, Tanzania. AB - OBJECTIVES: The study aimed to determine the prevalence of otitis media (OM) associated bacterial flora of asymptomatic people living with HIV (PLH) on antiretroviral therapy (ART) and assess antibiotic resistance profiles of the bacteria. METHODOLOGY: Ear secretion specimens were collected by syringe or cotton swabs. Isolated bacteria were subjected to antibiotic sensitivity tests. RESULTS: Of 290 recruited PLH, 81.7% were females and 18.3% males; their CD4+ counts ranged from 0 to 1770. Staphylococcus aureus, Klebsiella pneumonia, and Escherichia coli were the predominant bacteria. High antibiotic resistance was detected on Streptococcus pyogenes and Streptococcus pneumoniae. The prevalence rate of OM-associated bacteria (OAB) was 93.4%, and majority of the bacteria were resistant to multiple antibiotics. Linear association between the prevalence of OAB with both duration of ART and CD4+ counts was observed. CONCLUSION: High prevalence rates of OAB and antibiotic resistance were observed. Negative correlation between CD4+ counts and prevalence of OAB was revealed. PMID- 29534656 TI - Tailored Predictive Formulas for Glomerular Filtration Rate for Early Detection of Deteriorating Renal Function After Pediatric Living-Donor Liver Transplant. AB - OBJECTIVES: In pediatric patients, renal dysfunction after living-donor liver transplant is a major issue that is difficult to evaluate. Recently, predictive equations for Japanese children have been introduced. MATERIALS AND METHODS: We conducted a retrospective study by prospectively collecting data on 26 patients under 16 years old who underwent living-donor liver transplant between June 2004 and March 2015. Serum creatinine and cystatin C levels were measured. Paired t tests and Bland-Altman plots were used to compare the following formulas for estimated glomerular filtration rate: the Schwartz formula and 3 formulas that were matched with Japanese children (polynomial, simple, and cystatin C formulas). RESULTS: Average estimated glomerular filtrations rates (in mL/min/1.73 m2) were 143.46, 122.90, 121.58, and 123.31 using the Schwartz, polynomial, simple, and cystatin C formulas, respectively. The estimated glomerular filtrations rate for biliary atresia was 141.53 +/- 31.37 versus 109.95 +/- 19.52 for other diseases, with significant differences only noted with the cystatin C formula. The formulas tailored for Japanese children showed significantly lower estimated glomerular filtrations rates than those obtained using the Schwartz formula (P < .01). CONCLUSIONS: The use of formulas for measuring estimated glomerular filtrations rates that are based on race may allow early detection of deteriorating renal function. PMID- 29534657 TI - Role of Endoscopic Findings and Biopsies in Renal Transplant Recipients With Gastrointestinal Complications: A Tertiary Care Experience. AB - OBJECTIVES: We investigated the incidence of gastrointestinal disorders requiring endoscopic and histopathologic diagnoses in renal transplant recipients. MATERIALS AND METHODS: In this retrospective analysis, we examined records of patients seen at the Department of Hepato-Gastroenterology and Transplantation Sciences, Sindh Institute of Urology and Trans?lantation (Karachi, Pakistan) from January 2010 to December 2014. Renal transplant recipients with gastrointestinal disorders who required endoscopy, including proctoscopy and upper and lower gastrointestinal endoscopy as per indication, were included. RESULTS: Of 1770 patients included in this study, most were male patients (n = 1517; 85.7%). In this patient group, 1957 endoscopies, including proctoscopies, were performed, which included 1033 esophagogastroduodenoscopies (52.8%), 571 sigmoidoscopies (29.2%), and 107 colonoscopies (5.5%). The most common indications were diarrhea (n = 697; 31.2%) and weight loss (n = 690; 31%). Findings showed esophageal candidiasis in 127 patients (12%); however, biopsy revealed Candida species in 33 patients (34%). Cytomegalovirus and herpes esophagitis were observed in 8 (8.3%) and 5 patients (5.2%). Helicobacter pylori gastritis was seen in 119 patients (15.4%), cytomegalovirus gastritis in 9 patients (1.2%), and gastric lymphoma in 1 patient (0.1%). Duodenal fissuring was the most common pathology observed during endoscopy (396 patients; 33.9%), followed by decreased height of duodenal folds in 157 patients (13.4%), with biopsy showing sprue in 325 patients (37.6%) and giardiasis in 118 patients (13.7%). Lower gastrointestinal endoscopy showed ulcers in 198 patients (24.6%) and polyps in 31 patients (3.9%). Histopathologic examination showed cytomegalovirus colitis in 89 patients (15.5%), amebic colitis in 21 (3.7%), and tuberculosis in 11 (1.9%). CONCLUSIONS: We observed a wide spectrum of pathologic lesions, including opportunistic infections, in endoscopic biopsies from our renal transplant patients. Cytomegalovirus colitis was the most common infection in the lower gastrointestinal tract, whereas giardiasis was the most common in the duodenum. PMID- 29534658 TI - Gene Expression Profile of Toll-Like Receptor/Adaptor/Interferon Regulatory Factor/Cytokine Axis During Liver Regeneration After Partial Ischemia-Reperfusion Injury. AB - OBJECTIVES: Toll-like receptors and downstream signal transduction pathways play pivotal roles in induction of inflammation, which is crucial for liver injury and regeneration. MATERIALS AND METHODS: Using a mouse model of partial hepatic ischemia-reperfusion injury followed by a 28-day time course for liver repair and regeneration, we assessed gene expression levels for Toll-like receptors, myeloid differentiation primary response 88, TIR-domain-containing adapter-inducing interferon-beta, nuclear factor kappaB, interferon regulatory factors, tumor necrosis factor-alpha, and interleukins 1beta and 6 at days 1, 4, 7, 14, and 28 after reperfusion in liver and blood cells by quantitative polymerase chain reaction. RESULTS: Mouse liver was gradually injured until 24 hours after reperfusion, and necrotic areas remained for 7 days. Concurrent with liver necrosis, overexpression of hepatocyte growth factor in blood cells (days 1-14), transient overexpression of cyclin D1 at day 7 in hepatic cells, and overexpression of transforming growth factor-beta1 at days 7 and 14 in blood cells were used to characterize the priming, proliferative, and termination phases of liver regeneration. Liver regeneration was associated with significant up-regulation of Toll-like receptor 4, p65, interferon regulatory factors 1, 3, 9, tumor necrosis factor-alpha, and interleukin 1beta at 24 hours. Liver regeneration was also associated with persistent overexpression of MyD88 (days 1 28) and with delayed TIR-domain-containing adapter-inducing interferon-beta (days 4-28) in hepatic cells. In peripheral blood cells, Toll-like receptor 2 and MyD88 were up-regulated at 24 hours and Toll-like receptor 4 (days 1-14) and interferon regulatory factor 1 (days 1-7) showed persistent overexpression concomitant with interferon regulatory factor 5 (days 7-14); interleukin 1beta (days 1-28) and interleukin 6 (day 4-28) also showed persistent expression. CONCLUSIONS: We depict for the first time a prospective view of cooperative transcriptional activation of Toll-like receptors/adaptors/interferon regulatory factors/cytokines in both liver and blood cells during different phases of liver repair after ischemia-reperfusion injury. PMID- 29534659 TI - Refractory CD20 Positive Cellular Rejection in Living Kidney Transplant: A Case Report and Review of Literature. AB - Transplant is the optimal therapy for patients with end-stage renal disease. Acute cellular rejection refractory to treatment remains a major risk factor for graft loss and poor outcomes. In this study, we describe a 39-year-old man who received a living-related kidney transplant. Two days after transplant, the patient displayed acute deterioration of graft function. Conventional anti rejection therapy was initiated, but graft function did not improve. Biopsy revealed acute cellular rejection (grade IIA), and C4d and HLA antibodies were negative. Immunohistochemistry phenotyping revealed clusters of CD20-positive lymphocytes, with 80% being CD3 positive. Rituximab was prescribed, and graft function improved dramatically. After 1 week, a second graft biopsy was done due to lagging of graft function, shown by serum creatinine of 2.1 mg/dL. Biopsy revealed regenerating acute tubular necrosis with disappearance of the CD20 positive lymphocyte cluster infiltrates. Two year, after transplant, the patient's graft function maintained stable. Phenotyping of the cellular infiltrate is important as it may lead to a proper selection of immunosuppression and consequent improvement of graft outcome. PMID- 29534660 TI - Successful Orthotopic Liver Transplant for Diffuse Biliary Papillomatosis With Malignant Transformation: A Case Report With Long-Term Follow-Up. AB - In patients with biliary papillomatosis, complete resection of the biliary tree (that is, liver transplant along with duodenocephalo-pancreatectomy) is considered the only potential curative treatment, given its diffuse pattern and likelihood of malignant transformation. Nevertheless, such a combined surgical approach can increase patient morbidity and mortality and should be considered only when the distal part of the common bile duct is involved. Here, we avoided duodenocephalo-pancreatectomy in a patient with distal common bile duct free from disease; this approach did not negatively influence survival and appeared to be safer during liver transplant. PMID- 29534661 TI - Management of Plasma Cell-Rich Acute Rejection in Living-Related Kidney Transplant: Role of Proteasome Inhibitor. AB - OBJECTIVES: Plasma cell-rich acute rejection is an aggressive form of acute rejection that occurs late after transplant and is usually resistant to standard antirejection therapy. This study reports the safety, efficacy, and outcomes of plasma cell-rich acute rejection after treatment with bortezomib, a proteasome inhibitor, in 10 patients after a first living-related renal transplant. MATERIALS AND METHODS: Plasma cell-rich acute rejection was diagnosed using the 2007 Banff classification. The treatment protocol for plasma cell-rich acute rejection included methylprednisolone (500 mg/kg), 7 sessions of plasmapheresis, antithymocyte globulin (3-5 mg/kg/day for 10 days), rituximab (2 doses at 375 mg/m2), and bortezomib (1 cycle at 1.3 mg/m2). RESULTS: The mean age of recipients and donors was 23.70 +/- 11.39 and 37.30 +/- 12.82 years, respectively. The mean time to plasma cell-rich acute rejection was 3.1 +/- 2.5 years. The mean serum creatinine level at rejection was 4.8 +/- 2.7 mg/dL. After treatment, serum creatinine decreased to 3.3 +/- 1.8 mg/dL. Serum creatinine levels at 1-year and 2-year follow-up were 3.0 +/- 2.3 and 3.3 +/- 0.9 mg/dL, respectively. There was 1 graft failure due to recurrence of glomerulonephritis/de novo glomerulonephritis. No significant adverse effects were noted in the patients. Bortezomib successfully reverted plasma cell-rich acute rejection and stabilized graft function, with patients showing 2-year graft survival after rejection of 90%. CONCLUSION: Bortezomib-based treatment was successful in reverting plasma cell-rich acute rejection and stabilizing graft function, with graft survival of 90% at 2 years. Further studies with large cohorts and randomized trials with or without bortezomib will help in better evaluation of its efficacy, safety, and outcomes. PMID- 29534662 TI - Primary Bullous Keratopathy in a Patient With Werner Syndrome Treated With Corneal Transplant. AB - Here, we present, to the best of our knowledge, the first case of Werner syndrome with corneal blindness due to bilateral primary bullous keratopathy. Werner syndrome is a rare autosomal recessive disorder characterized by features of premature aging, insulin-dependent diabetes mellitus, osteoporosis, atherosclerosis, hypergonadotrophic hypogonadism, hypertriglyceridemia, scleroderma-like skin changes, and sarcomas. Among ocular manifestations, cataracts, cystoid macular edema, and retinal detachment have been reported. Because these patients show features of premature aging, they have decreased corneal endothelial function and delayed fibroblast growth. To date, there are few reports of wound dehiscence, bleb formation, and bullous keratopathy following surgical insult that have usually occurred after cataract surgery in patients with Werner syndrome. There have been no reports in the literature regarding Werner syndrome presenting with primary corneal decompensation without any inciting factor. Our patient with Werner syndrome had primary bilateral bullous keratopathy and bilateral corneal blindness for 10 years and was eventually rehabilitated by corneal transplant. Hence, this case highlights the importance of early referral of such patients to the ophthalmologist for prompt diagnosis and early treatment so that blindness could be avoided. PMID- 29534663 TI - Recombinant Monoclonal Antibodies for Rabies Post-exposure Prophylaxis. AB - Rabies virus is a prototypical neurotropic virus that causes one of the most dangerous zoonotic diseases in humans. Humanized or fully human monoclonal antibodies (mAb) that neutralize rabies virus would be the basis for powerful post-exposure prophylaxis of rabies in humans, having several significant benefits in comparison with human or equine rabies polyclonal immunoglobulins. The most advanced antibodies should broadly neutralize natural rabies virus isolates, bind with conserved antigenic determinants of the rabies virus glycoprotein, and show high neutralizing potency in assays in vivo. The antibodies should recognize nonoverlapping epitopes if they are used in combination. This review focuses on basic requirements for anti-rabies therapeutic antibodies. The urgency in the search for novel rabies post-exposure prophylaxis and methods of development of anti-rabies human mAb cocktail are discussed. The rabies virus structure and pathways of its penetration into the nervous system are also briefly described. PMID- 29534664 TI - The Role of Interleukin-33 in Pathogenesis of Bronchial Asthma. New Experimental Data. AB - Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and plays an important role in modulating immune system by inducing Th2 immune response via the ST2 membrane receptor. Epithelial cells are the major producers of IL-33. However, IL 33 is also secreted by other cells, e.g., bone marrow cells, dendritic cells, macrophages, and mast cells. IL-33 targets a broad range of cell types bearing the ST2 surface receptor. Many ST2-positive cells, such as Th2 cells, mast cells, basophils, and eosinophils, are involved in the development of allergic bronchial asthma (BA). This suggests that IL-33 directly participates in BA pathogenesis. Currently, the role of IL-33 in pathogenesis of inflammatory disorders, including BA, has been extensively investigated using clinical samples collected from patients, as well as asthma animal models. In particular, numerous studies on blocking IL-33 and its receptor by monoclonal antibodies in asthma mouse model have been performed over the last several years; IL-33- and ST2-deficient transgenic mice have also been generated. In this review, we summarized and analyzed the data on the role of IL-33 in BA pathogenesis and the prospects for creating new treatments for BA. PMID- 29534665 TI - Biotransformation of Progesterone by the Ascomycete Aspergillus niger N402. AB - The ability of the ascomycete Aspergillus niger N402 to transform exogenous progesterone was investigated. We found that this strain has steroid hydroxylating activity and can introduce a hydroxyl group into the progesterone molecule mainly at positions C11(alpha) and C21 with predominant formation of 21 hydroxyprogesterone (deoxycortone). In addition, formation of 6beta,11alpha dihydroxyprogesterone was also observed. Studying the effects of the growth medium composition and temperature on progesterone conversion by A. niger N402 showed that the most intense accumulation of 21-hydroxyprogesterone occurred in minimal synthetic medium at 28 degrees C. Increasing the cultivation temperature to 37 degrees C resulted in almost complete inhibition of the hydroxylase activity in the minimal medium. In the complete medium, a similar increase in temperature inhibited 11alpha-hydroxylase activity and completely suppressed 6beta-hydroxylase activity, but it produced no effect on 21-hydroxylating activity. PMID- 29534666 TI - Modulation of delta-Aminolevulinic Acid Dehydratase Activity by the Sorbitol Induced Osmotic Stress in Maize Leaf Segments. AB - Osmotic stress induced with 1 M sorbitol inhibited delta-aminolevulinic acid dehydratase (ALAD) and aminolevulinic acid (ALA) synthesizing activities in etiolated maize leaf segments during greening; the ALAD activity was inhibited to a greater extent than the ALA synthesis. When the leaves were exposed to light, the ALAD activity increased for the first 8 h, followed by a decrease observed at 16 and 24 h in both sorbitol-treated and untreated leaf tissues. The maximum inhibition of the enzyme activity was observed in the leaf segments incubated with sorbitol for 4 to 8 h. Glutamate increased the ALAD activity in the in vitro enzymatic preparations obtained from the sorbitol-treated leaf segments; sorbitol inhibited the ALAD activity in the preparations from both sorbitol-treated and untreated leaves. It was suggested that sorbitol-induced osmotic stress inhibits the enzyme activity by affecting the ALAD induction during greening and regulating the ALAD steady-state level of ALAD in leaf cells. The protective effect of glutamate on ALAD in the preparations from the sorbitol-treated leaves might be due to its stimulatory effect on the enzyme. PMID- 29534667 TI - Characterization and Mutational Analysis of Two UDP-Galactose 4-Epimerases in Streptococcus pneumoniae TIGR4. AB - Current clinical treatments for pneumococcal infections have many limitations and are faced with many challenges. New capsular polysaccharide structures must be explored to cope with diseases caused by different serotypes of Streptococcus pneumoniae. UDP-galactose 4-epimerase (GalE) is an essential enzyme involved in polysaccharide synthesis. It is an important virulence factor in many bacterial pathogens. In this study, we found that two genes (galEsp1 and galEsp2) are responsible for galactose metabolism in pathogenic S. pneumoniae TIGR4. Both GalESp1 and GalESp2 were shown to catalyze the epimerization of UDP-glucose (UDP Glc)/UDP-galactose (UDP-Gal), but only GalESp2 was shown to catalyze the epimerization of UDP-N-acetylglucosamine (UDP-GlcNAc)/UDP-N-acetylgalactosamine (UDP-GalNAc). Interestingly, GalESp2 had 3-fold higher epimerase activity toward UDP-Glc/UDP-Gal than GalESp1. The biochemical properties of GalESp2 were studied. GalESp2 was stable over a wide range of temperatures, between 30 and 70 degrees C, at pH 8.0. The K86G substitution caused GalESp2 to lose its epimerase activity toward UDP-Glc and UDP-Gal; however, substitution C300Y in GalESp2 resulted in only decreased activity toward UDP-GlcNAc and UDP-GalNAc. These results indicate that the Lys86 residue plays a critical role in the activity and substrate specificity of GalESp2. PMID- 29534668 TI - Adenylyl Cyclase-Associated Protein 1: Structure, Regulation, and Participation in Cellular Processes. AB - This review summarizes information available to date about the structural organization, regulation of functional activity of adenylyl cyclase-associated protein 1 (CAP1), and its participation in cellular processes. Numerous data are generalized on the role of CAP1 in the regulation of actin cytoskeleton and its interactions with many actin-binding proteins. Attention is drawn to the similarity of the structure of CAP1 and its contribution to the remodeling of actin filaments in prokaryotes and eukaryotes, as well as to the difference in the interaction of CAP1 with adenylyl cyclase in these cells. In addition, we discuss the participation of CAP1 in various pathological processes. PMID- 29534669 TI - MicroRNA Sponge Knockdowns miR-483-5p and Upregulates Serum ALT/AST in Transgenic Mice. AB - MicroRNAs are involved in many biological processes. Studying microRNA function requires genetic strategies generating loss-of-function phenotypes, especially in vivo. However, few microRNA loss-of-function models have been reported in mice. Here, we generated several transgenic mouse lines to stably and specifically knockdown miR-483-5p by overexpressing microRNA sponges from CAG promoters. The different levels of expression of microRNA sponges resulted in different levels of mature miR-483-5p, which upregulated serum ALT/AST in these transgenic lines. These results indicate microRNA sponges are effective in mice in vivo, and they can be used in microRNA loss-of-function research. PMID- 29534670 TI - Inhibition of Amyloid Aggregation of Bovine Serum Albumin by Sodium Dodecyl Sulfate at Submicellar Concentrations. AB - Sodium dodecyl sulfate (SDS), as an anionic surfactant, can induce protein conformational changes. Recent investigations demonstrated different effects of SDS on protein amyloid aggregation. In the present study, the effect of SDS on amyloid aggregation of bovine serum albumin (BSA) was evaluated. BSA transformed to beta-sheet-rich amyloid aggregates upon incubation at pH 7.4 and 65 degrees C, as demonstrated by thioflavin T fluorescence, circular dichroism, and transmission electron microscopy. SDS at submicellar concentrations inhibited BSA amyloid aggregation with IC50 of 47.5 uM. The inhibitory effects of structural analogs of SDS on amyloid aggregation of BSA were determined to explore the structure-activity relationship, with results suggesting that both anionic and alkyl moieties of SDS were critical, and that an alkyl moiety with chain length >=10 carbon atoms was essential to amyloid inhibition. We attributed the inhibitory effect of SDS on BSA amyloid aggregation to interactions between the detergent molecule and the fatty acid binding sites on BSA. The bound SDS stabilized BSA, thereby inhibiting protein transformation to amyloid aggregates. This study reports for the first time that the inhibitory effect of SDS on albumin fibrillation is closely related to its alkyl structure. Moreover, the specific binding of SDS to albumin is the main driving force in amyloid inhibition. This study not only provides fresh insight into the role of SDS in amyloid aggregation of serum albumin, but also suggests rational design of novel anti-amyloidogenic reagents based on specific-binding ligands. PMID- 29534671 TI - Interaction between RAD51 and MCM Complex Is Essential for RAD51 Foci Forming in Colon Cancer HCT116 Cells. AB - Colon cancer remains one of the most common digestive system malignancies in the World. This study investigated the possible interaction between RAD51 and minichromosome maintenance proteins (MCMs) in HCT116 cells, which can serve as a model system for forming colon cancer foci. The interaction between RAD51 and MCMs was detected by mass spectrometry. Silenced MCM vectors were transfected into HTC116 cells. The expressions of RAD51 and MCMs were detected using Western blotting. Foci forming and chromatin fraction of RAD51 in HCT116 cells were also analyzed. The results showed that RAD51 directly interacted with MCM2, MCM3, MCM5, and MCM6 in colon cancer HTC116 cells. Suppression of MCM2 or MCM6 by shRNA decreased the chromatin localization of RAD51 in HTC116 cells. Moreover, silenced MCM2 or MCM6 decreased the foci forming of RAD51 in HTC116 cells. Our study suggests that the interaction between MCMs and RAD51 is essential for the chromatin localization and foci forming of RAD51 in HCT116 cell DNA damage recovery, and it may be a theoretical basis for analysis of RAD51 in tumor samples of colon cancer patients. PMID- 29534673 TI - Editorial: Nanoscience Technology: A Smart Tool for Drug Delivery. PMID- 29534672 TI - Isolation of Large Amounts of Highly Pure Mitochondria for "Omics" Studies. AB - Ultracentrifugation on a density gradient remains the only reliable way to obtain highly pure mitochondria preparations. However, it is not readily available for any laboratory and has a serious disadvantage of providing low mitochondria yield, which can be critical when working with limited starting material. Here we describe a combined method for isolation of mitochondria for proteomic studies that includes cell disruption by sonication, differential centrifugation, and magnetic separation. Our method provides remarkable enrichment of mitochondrial proteins as compared to differential centrifugation, magnetic separation, or their combination, and it enables the strongest depletion of cytoplasmic components, as assessed by two-dimensional electrophoresis, mass spectrometry, and Western blot. It also doubles the yield of mitochondria. However, our method should not be used for functional studies as most of the isolated organelles demonstrate disturbed structure in electron microphotographs. PMID- 29534674 TI - Editorial: The Explosion of Biosimilars in Immune Mediated Chronic Inflammatory Diseases. PMID- 29534675 TI - High polymorphism in MHC-DRB genes in golden snub-nosed monkeys reveals balancing selection in small, isolated populations. AB - BACKGROUND: Maintaining variation in immune genes, such as those of the major histocompatibility complex (MHC), is important for individuals in small, isolated populations to resist pathogens and parasites. The golden snub-nosed monkey (Rhinopithecus roxellana), an endangered primate endemic to China, has experienced a rapid reduction in numbers and severe population fragmentation over recent years. For this study, we measured the DRB diversity among 122 monkeys from three populations in the Qinling Mountains, and estimated the relative importance of different agents of selection in maintaining variation of DRB genes. RESULTS: We identified a total of 19 DRB sequences, in which five alleles were novel. We found high DRB variation in R. roxellana and three branches of evidence suggesting that balancing selection has contributed to maintaining MHC polymorphism over the long term in this species: i) different patterns of both genetic diversity and population differentiation were detected at MHC and neutral markers; ii) an excess of non-synonymous substitutions compared to synonymous substitutions at antigen binding sites, and maximum-likelihood-based random-site models, showed significant positive selection; and iii) phylogenetic analyses revealed a pattern of trans-species evolution for DRB genes. CONCLUSIONS: High levels of DRB diversity in these R. roxellana populations may reflect strong selection pressure in this species. Patterns of genetic diversity and population differentiation, positive selection, as well as trans-species evolution, suggest that pathogen-mediated balancing selection has contributed to maintaining MHC polymorphism in R. roxellana over the long term. This study furthers our understanding of the role pathogen-mediated balancing selection has in maintaining variation in MHC genes in small and fragmented populations of free ranging vertebrates. PMID- 29534676 TI - High vaccination coverage is associated with low epidemic level of seasonal influenza in elementary schools: an observational study in Matsumoto City, Japan. AB - BACKGROUND: Influenza virus transmission may be prevented by infection control measures, including vaccination, wearing a mask, gargling with water, and hand washing. It is unclear, however, whether these measures affect influenza epidemics in school settings. METHODS: A prospective epidemiological survey in all public elementary schools in Matsumoto City, Japan, during the 2014/2015 season evaluated the number of diagnosed patients in each school and calculated the reproduction number of schoolchildren. At the end of the prospective survey, a cross-sectional survey evaluated the implementation of infection control measures in these schools. Both results were combined and associations among infection control measures including vaccination, mask wearing, hand washing, water gargling, and epidemic level were evaluated. RESULTS: Of the 13,217 schoolchildren in 29 schools, 2548 were diagnosed with seasonal influenza. A significant negative association was observed between vaccination coverage and reproduction number at each school, but not between other infection control measures and the reproduction number. A regression curve with exponential function was most predictive. At 0% vaccination, the reproduction number was estimated to be 1.39. CONCLUSION: These findings provide evidence that high vaccination coverage was associated with reduced epidemic levels in schools and suggest the need for increased vaccination of schoolchildren. PMID- 29534677 TI - Watchdog - a workflow management system for the distributed analysis of large scale experimental data. AB - BACKGROUND: The development of high-throughput experimental technologies, such as next-generation sequencing, have led to new challenges for handling, analyzing and integrating the resulting large and diverse datasets. Bioinformatical analysis of these data commonly requires a number of mutually dependent steps applied to numerous samples for multiple conditions and replicates. To support these analyses, a number of workflow management systems (WMSs) have been developed to allow automated execution of corresponding analysis workflows. Major advantages of WMSs are the easy reproducibility of results as well as the reusability of workflows or their components. RESULTS: In this article, we present Watchdog, a WMS for the automated analysis of large-scale experimental data. Main features include straightforward processing of replicate data, support for distributed computer systems, customizable error detection and manual intervention into workflow execution. Watchdog is implemented in Java and thus platform-independent and allows easy sharing of workflows and corresponding program modules. It provides a graphical user interface (GUI) for workflow construction using pre-defined modules as well as a helper script for creating new module definitions. Execution of workflows is possible using either the GUI or a command-line interface and a web-interface is provided for monitoring the execution status and intervening in case of errors. To illustrate its potentials on a real-life example, a comprehensive workflow and modules for the analysis of RNA-seq experiments were implemented and are provided with the software in addition to simple test examples. CONCLUSIONS: Watchdog is a powerful and flexible WMS for the analysis of large-scale high-throughput experiments. We believe it will greatly benefit both users with and without programming skills who want to develop and apply bioinformatical workflows with reasonable overhead. The software, example workflows and a comprehensive documentation are freely available at www.bio.ifi.lmu.de/watchdog. PMID- 29534678 TI - Cryoballoon ablation for paroxysmal atrial fibrillation in a case of persistent left superior vena cava. AB - BACKGROUND: Atrial fibrillation (AF) usually originates from pulmonary veins (PVs) but can also be caused by pulmonary veins outside, such as the coronary sinus (CS), the superior vena cava (SVC), and the ligament of Marshall. CASE PRESENTATION: A 69-year-old male with a history of palpitations for 10 years was referred to our institute because of its recurrence for half a day. A dynamic electrocardiogram revealed sinus rhythm (SR) and paroxysmal AF. Echocardiography demonstrated normal cardiac structure, and physical examination results were unremarkable. However, computed tomography angiography (CTA) showed a persistent left superior vena cava (LSVC) but no indication of thrombosis in the left atria. A cryoablation catheter was inserted into the PV. After the PV was successfully isolated, AF was still observed. After cardioversion was synchronized, SR was detected, but AF occurred again in less than a minute. Finally, we observed ectopic atrial electrical activity originating from the LSVC and successfully ablated it. CONCLUSIONS: An LSVC may be a substrate for initiating or perpetuating atrial arrhythmia. Cryoballoon ablation can help treat AF originating from the LSVC. PMID- 29534679 TI - Integrated genomic analysis identifies clinically relevant subtypes of renal clear cell carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC) account for over 80% of renal malignancies. The most common type of RCC can be classified into three subtypes including clear cell, papillary and chromophobe. ccRCC (the Clear Cell Renal Cell Carcinoma) is the most frequent form and shows variations in genetics and behavior. To improve accuracy and personalized care and increase the cure rate of cancer, molecular typing for individuals is necessary. METHODS: We adopted the genome, transcriptome and methylation HMK450 data of ccRCC in The Cancer Genome Atlas Network in this research. Consensus Clustering algorithm was used to cluster the expression data and three subtypes were found. To further validate our results, we analyzed an independent data set and arrived at a consistent conclusion. Next, we characterized the subtype by unifying genomic and clinical dimensions of ccRCC molecular stratification. We also implemented GSEA between the malignant subtype and the other subtypes to explore latent pathway varieties and WGCNA to discover intratumoral gene interaction network. Moreover, the epigenetic state changes between subgroups on methylation data are discovered and Kaplan-Meier survival analysis was performed to delve the relation between specific genes and prognosis. RESULTS: We found a subtype of poor prognosis in clear cell renal cell carcinoma, which is abnormally upregulated in focal adhesions and cytoskeleton related pathways, and the expression of core genes in the pathways are negatively correlated with patient outcomes. CONCLUSIONS: Our work of classification schema could provide an applicable framework of molecular typing to ccRCC patients which has implications to influence treatment decisions, judge biological mechanisms involved in ccRCC tumor progression, and potential future drug discovery. PMID- 29534680 TI - Performance of a brief geriatric evaluation compared to a comprehensive geriatric assessment for detection of geriatric syndromes in family medicine: a prospective diagnostic study. AB - BACKGROUND: Geriatric syndromes are rarely detected in family medicine. Within the AGE program (active geriatric evaluation), a brief assessment tool (BAT) designed for family physicians (FP) was developed and its diagnostic performance estimated by comparison to a comprehensive geriatric assessment. METHODS: This prospective diagnostic study was conducted in four primary care sites in Switzerland. Participants were aged at least 70 years and attending a routine appointment with their physician, without previous documented geriatric assessment. Participants were assessed by their family physicians using the BAT, and by a geriatriciant who performed a comprehensive geriatric assessment within the following two-month period (reference standard). Both the BAT and the full assessment targeted eight geriatric syndromes: cognitive impairment, mood impairment, urinary incontinence, visual impairment, hearing loss, undernutrition, osteoporosis and gait and balance impairment. Diagnostic accuracy of the BAT was estimated in terms of sensitivity, specificity, and predictive values; secondary outcomes were measures of feasibility, in terms of added consultation time and comprehensiveness in applying the BAT items. RESULTS: Prevalence of the geriatric syndromes in participants (N=85, 46 (54.1%) women, mean age 78 years (SD 6))ranged from 30.0% (malnutrition and cognitive impairment) to 71.0% (visual impairment), with a median number of 3 syndromes (IQR 2 to 4) per participant. Sensitivity of the BAT ranged from 25.0% for undernutrition (95%CI 9.8% - 46.7%) to 82.1% for hearing impairment (95%CI 66.5% 92.5%), while specificity ranged from 45.8% for visual impairment (95%CI 25.6 67.2) to 87.7% for undernutrition (76.3% to 94.9%). Finally, most negative predictive values (NPV) were between 73.5% and 84.1%, excluding visual impairment with a NPV of 50.0%. Family physicians reported BAT use as per instructions for 76.7% of the syndromes assessed. CONCLUSIONS: Although the BAT does not replace a comprehensive geriatric assessment, it is a useful and appropriate tool for the FP to screen elderly patients for most geriatric syndromes. TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov on February 20, 2013 ( NCT01816087 ). PMID- 29534681 TI - Increasing incidence of syphilis among patients engaged in HIV care in Alberta, Canada: a retrospective clinic-based cohort study. AB - BACKGROUND: Syphilis is a global health concern disproportionately affecting HIV infected populations. In Alberta, Canada, the incidence of syphilis in the general population has recently doubled with 25% of these infections occurring in HIV-infected patients. The Southern Alberta HIV Clinic (SAC) and Calgary STI Program (CSTI) analyzed the epidemiologic characteristics of incident syphilis infections in our well-defined, HIV-infected population over 11 years. METHODS: Since 2006, as routine practice of both the Southern Alberta Clinic (SAC) and Calgary STI Programs (CSTI), syphilis screening has accompanied HIV viral load measures every four months. All records of patients who, while in HIV care, either converted from being syphilis seronegative to a confirmed seropositive or were re-infected as evidenced by a four-fold increase in rapid plasma reagin (RPR) after past successful treatment, were reviewed. RESULTS: Incident syphilis was identified 249 times in 194 HIV-infected individuals. There were 36 individuals with repeated infections (28.5% of episodes). Following a prior decline in annual incident syphilis rates, the rates have tripled from 8.08/1000 patient-years (95% confidence interval (CI): 4.14-14.75) in 2011, to 27.04 per 1000 person-years (95% CI: 19.45-36.76) in 2016. Half of the syphilis episodes were asymptomatic. Patients diagnosed with syphilis were twice as likely not to be taking ART and had a higher likelihood of having plasma HIV RNA viral loads > 1000 copies/mL (19%). Incident syphilis was seen predominantly in Caucasians (72%, P < 0.001), males (94%, P < 0.001) and men who have sex with men (MSM) as their HIV risk activity (75%, P < 0.001). CONCLUSIONS: We have highlighted the importance of a regular syphilis screening program in HIV-infected individuals demonstrated by increasing rates of incident syphilis in our region. Targeted preventative strategies should be directed towards HIV-infected populations identified at highest risk, including; MSM, prior alcohol abuse, prior recreational drug use and those with prior syphilis diagnoses. PMID- 29534682 TI - Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression. AB - BACKGROUND: Smurf2 E3 ubiquitin ligase physically associates with and regulate the stability of distinct cellular protein substrates. The multi-functional scaffold protein Connector enhancer of kinase suppressor of ras 2 (CNKSR2) plays a key role in regulating cell proliferation, and differentiation through multiple receptor tyrosine kinase pathways. The aim of this study was to investigate whether the interaction between Smurf2 and CNKSR2 has any significant role in the post transcriptional regulation of CNKSR2 expression in breast cancer. METHODS: Here we demonstrate a novel interaction of CNKSR2 with Smurf2 by co immunoprecipitation, indirect immunofluorescence studies, and surface plasmon resonance (SPR) analysis, which can ubiquitinate, but stabilize CNKSR2 by protecting it from proteasome mediated degradation. RESULTS: CNKSR2 protein levels were significantly increased upon forced overexpression of Smurf2, indicating the role of Smurf2 in regulating the stability of CNKSR2. Conversely, Smurf2 knockdown resulted in a marked decrease in the protein level expression of CNKSR2 by facilitating enhanced polyubiquitination and proteasomal degradation and reduced the proliferation and clonogenic survival of MDA-MB-231 breast cancer cell lines. Tissue microarray data from 84 patients with various stages of mammary carcinoma, including (in order of increasing malignant potential) normal, usual hyperplasia, fibrocystic changes, fibroadenoma, carcinoma-in-situ, and invasive ductal carcinoma showed a statistically significant association between Smurf2 and CNKSR2 expression, which is also well correlated with the ER, PR, and HER2 status of the tissue samples. A comparatively high expression of Smurf2 and CNKSR2 was observed when the expression of ER and PR was low, and HER2 was high. Consistently, both Smurf2 and CNKSR2 showed an integrated expression in MCF10 breast progression model cell lines. CONCLUSIONS: Altogether, our findings reveal that Smurf2 is a novel positive regulator of CNKSR2 and suggest that Smurf2 CNKSR2 interaction may serve as a common strategy to control proliferation of human breast cancer cells by modulating CNKSR2 protein stability. PMID- 29534683 TI - Challenges of interpreting epidemiologic surveillance pertussis data with changing diagnostic and immunization practices: the case of the state of Sao Paulo, Brazil. AB - BACKGROUND: A significant increase in pertussis incidence occurred in Brazil, from 2011 to 2014, despite high coverage of childhood immunization with whole cell-pertussis (wP) containing vaccines. This study presents pertussis surveillance data from Sao Paulo state and discusses the challenges to interpret them considering pertussis cyclic epidemic behavior, the introduction of new diagnostic techniques and new vaccination strategies, and enhanced disease awareness during epidemics. METHODS: Observational study including pertussis cases reported to the Surveillance System in Sao Paulo state, from January 2001 to December 2015. Pertussis cases data were retrieved from the National Notifiable Diseases Information System (SINAN) website and from Sao Paulo state Epidemiological Surveillance Center (CVE/SP) database. Vaccination coverage and homogeneity data were collected from the Unified Health System Department of Informatics (DATASUS). We presented cases distribution by year, age group and diagnostic criteria and calculated pertussis incidence rates. The proportions of cases among different age groups were compared using chi-square test for trend. RESULTS: Infants less than 1 year of age were the most affected during the whole period, but the proportions of cases in this age group had a significant decreasing trend, with significant increase in the proportions of cases reported among older age groups (1-4, 5-10 and >=20 years). Cases among infants aged less than 6 months represented >=90% of all cases in children less than 1 year of age in all but 2 years (2012 and 2015). A non-significant decrease in the proportion of cases among infants aged < 2 months was observed in parallel to a significant increase in the proportion of cases in infants aged 6-11 months. CONCLUSIONS: A pertussis outbreak has occurred in a state with universal use of wP vaccine. The disease cyclic behavior has probably had a major role in the increased incidence rates registered in Sao Paulo state, from 2011 to 2014, as well as in the decreased incidence in 2015. Maternal vaccination cannot explain the drop in the number of cases among all age groups, in 2015, as herd protection is not expected, but may have had an impact on the number of cases in infants aged < 2 months. PMID- 29534684 TI - A novel splicing site IRP1 somatic mutation in a patient with pheochromocytoma and JAK2V617F positive polycythemia vera: a case report. AB - BACKGROUND: The role of the hypoxia signaling pathway in the pathogenesis of pheochromocytoma/paraganglioma (PPGL)-polycythemia syndrome has been elucidated. Novel somatic mutations in hypoxia-inducible factor type 2A (HIF2A) and germline mutations in prolyl hydroxylase type 1 and type 2 (PHD1 and PHD2) have been identified to cause upregulation of the hypoxia signaling pathway and its target genes including erythropoietin (EPO) and its receptor (EPOR). However, in a minority of patients presenting with this syndrome, the genetics and molecular pathogenesis remain unexplained. The aim of the present study was to uncover novel genetic causes of PPGL-polycythemia syndrome. CASE PRESENTATION: A female presented with a history of JAK2V617F positive PV, diagnosed in 2007, and right adrenal pheochromocytoma diagnosed and resected in 2011. Her polycythemia symptoms and hematocrit levels continued to worsen from 2007 to 2011, with an increased frequency of phlebotomies. Postoperatively, until early 2013, her hematocrit levels remained normalized. Following this, the hematocrit levels ranged between 46.4 and 48.9% [35-45%]. Tumor tissue from the patient was further tested for mutations in genes related to upregulation of the hypoxia signaling pathway including iron regulatory protein 1 (IRP1), which is a known regulator of HIF-2alpha mRNA translation. Functional studies were performed to investigate the consequences of these mutations, especially their effect on the HIF signaling pathway and EPO. Indel mutations (c.267-1_267delGGinsTA) were discovered at the exon 3 splicing site of IRP1. Minigene construct and splicing site analysis showed that the mutation led to a new splicing site and a frameshift mutation of IRP1, which caused a truncated protein. Fluorescence in situ hybridization analysis demonstrated heterozygous IRP1 deletions in tumor cells. Immunohistochemistry results confirmed the truncated IRP1 and overexpressed HIF 2alpha, EPO and EPOR in tumor cells. CONCLUSIONS: This is the first report which provides direct molecular genetic evidence of association between a somatic IRP1 loss-of-function mutation and PHEO and secondary polycythemia. In patients diagnosed with PHEO/PGL and polycythemia with negative genetic testing for mutations in HIF2A, PHD1/2, and VHL, IRP1 should be considered as a candidate gene. PMID- 29534685 TI - Condom use in combination with ART can reduce HIV incidence and mortality of PLWHA among MSM: a study from Beijing, China. AB - BACKGROUND: Condom use and antiretroviral therapy (ART) are effective means to prevent and control HIV transmission. We aimed to assess the effect of condom use in combination with antiretroviral therapy (ART) on HIV incidence and mortality among men who had sex with men (MSM) in Beijing, China. METHODS: We evaluated the effect of condom use, ART, and the combination of both among people living with HIV/AIDS (PLWHA) of MSM in the Chaoyang District of Beijing using the Asian Epidemic Model (AEM). Evaluation indicators included absolute risk reduction (ARR) and the percentage of relative risk reduction (RRR %). RESULTS: HIV incidence and prevalence declined substantially when condoms were used by MSM in Chaoyang from 2003 to 2013. The ARR of HIV incidence was from 0 to 0.91% and the RRR% was from 0 to 43.93%. The ARR of HIV prevalence was from 0 to 3.79% and the RRR% was from 0 to 31.53%. The HIV mortality rate decreased substantially (ARR from 0 to 1.75%, and RRR% from 0 to 40.03%) when ART was implemented. When condom use combined with ART was implemented in MSM in 2003-2013, HIV incidence declined substantially (ARR from 0 to 0.99%, and RRR% from 0 to 46.11%). HIV prevalence was also reduced with an ARR from 0 to 3.5%, and an RRR% from 0 to 29.88%. The HIV mortality also declined substantially (ARR from - 0.01% to 1.02%, RRR% from - 1.44% to 39.98%). CONCLUSIONS: Among MSM, a combination of condom use and ART reduces both HIV incidence and mortality caused by HIV. Combining these methods results in a more effective prevention and control of HIV. PMID- 29534686 TI - Unexpected presentation of allograft dysfunction triggered by page kidney phenomenon immediately after kidney transplantation: a case report. AB - BACKGROUND: Page kidney phenomenon is caused by strong renal parenchymal compression and leads to renal hypoperfusion and microvascular ischemia, resulting in renal dysfunction and hypertension. Although the development of Page kidney phenomenon in allograft is rare, most of its cases are induced by allograft biopsy or trauma. We observed a case of Page kidney phenomenon that was induced by unusual causes immediately after kidney transplantation. CASE PRESENTATION: A 66-year-old man, whose wife donated a kidney, underwent ABO compatible living kidney transplantation. The allograft had three renal arteries that were trimmed and formed into one piece on the back table, and subsequently, it was anastomosed to the internal iliac artery. Intraoperative Doppler ultrasonography (US) revealed adequate blood flow of each renal artery. Urine output was also observed as soon as allograft blood flow was reperfused. After the surgery, the urine output decreased, and serum creatinine level increased to 6.0 mg/dL. Doppler US did not show evidence of acute rejection, ureteral obstruction, or anastomotic stenosis of the renal arteries. On postoperative day 7, surgical exploration was performed and revealed that the blood flow of each renal artery was adequate but subcapsular hematoma was detected at the upper pole of the allograft. Capsulotomy and hematoma evacuation were performed. Subsequently, urine output increased and serum creatinine level decreased up to 1.7 mg/dL. Allograft sample was obtained 1 h after the transplantation from the lower pole of the allograft. Although the cause of subcapsular bleeding was unclear in this case, a small cyst of the allograft, which might have ruptured during donor nephrectomy, was located in the middle of the hematoma, and oozing around the cyst was observed. CONCLUSIONS: Our case indicated that the small ruptured cyst of the allograft could be the cause of subcapsular hematoma and Page kidney phenomenon. Subcapsular hematoma caused by oozing over time could be difficult to diagnose using Doppler US, and thus, other imaging modalities, such as computed tomography, should be considered. Knowledge of the Page kidney phenomenon in the allograft can lead to early diagnosis and intervention, resulting in better outcomes for recipients with allograft dysfunction. PMID- 29534688 TI - Correction to: Breast cancer subtype discordance: impact on post-recurrence survival and potential treatment options. AB - It has been highlighted that the original manuscript [1] contains a typesetting error regarding the authorship. PMID- 29534687 TI - The SBRT database initiative of the German Society for Radiation Oncology (DEGRO): patterns of care and outcome analysis of stereotactic body radiotherapy (SBRT) for liver oligometastases in 474 patients with 623 metastases. AB - BACKGROUND: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. METHODS: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. RESULTS: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1-4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1-13) and dose per fraction (median: 18.5 Gy; range 3-37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control. CONCLUSION: After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden. PMID- 29534689 TI - Prognostic nutritional index as a predictor of survival in resectable gastric cancer patients with normal preoperative serum carcinoembryonic antigen levels: a propensity score matching analysis. AB - BACKGROUND: An ideal tumor marker should be capable of being detected at any stage of the disease. However, gastric cancer patients do not always have elevated serum carcinoembryonic antigen (CEA) levels, even in advanced cases. Recently, several studies have investigated the associations between preoperative PNI and postoperative long-term outcomes. In this study, we focused on the significance of the prognostic nutritional index (PNI) as a potential predictor of survival in resectable gastric cancer patients with normal preoperative serum CEA levels. METHODS: We retrospectively conducted cohort study to evaluate the PNI as a predictor of survival in 368 resectable gastric cancer patients who underwent potentially curative gastrectomy at our institute between January 2010 and December 2016. We selected 218 patients by propensity score matching to reduce biases due to the different distributions of co-variables among the comparable groups. RESULTS: In the multivariate analysis, pStage (hazard ratio [HR]: 14.003, 95% confidence interval [CI]: 5.033-44.487; p < 0.001), PNI (HR: 2.794, 95% CI: 1.352-6.039; p < 0.001) were identified as independent prognostic factors of CSS in 218 propensity matched gastric cancer patients. The Kaplan Meier analysis demonstrated that low PNI patients had a significantly poorer cancer specific survival (CSS) than high PNI patients (p = 0.008). Among 166 propensity matched gastric cancer patients with normal preoperative serum CEA levels, multivariate analysis demonstrated that pStage (HR: 7.803, 95% CI: 3.015 24.041; p < 0.001) and PNI (HR: 3.078, 95% CI: 1.232-8.707; p = 0.016) were identified as independent prognostic factors of CSS. And Kaplan-Meier analysis demonstrated that low PNI had a significantly poorer CSS than high PNI value (p = 0.011). CONCLUSIONS: This study demonstrates that a low preoperative PNI value is a potential independent risk factor for poorer CSS in patients with gastric cancer, even in those with normal serum CEA levels. PMID- 29534690 TI - ATF-3/miR-590/GOLPH3 signaling pathway regulates proliferation of breast cancer. AB - BACKGROUND: Breast cancer is one of the leading causes of death in women worldwide. Fast growth is the important character of breast cancer, which makes sure the subsequent metastasize and invasion breast cancer. Golgi related genes GOLPH3 has been reported to regulate many kinds of cancers proliferation. However, its upregulator remains largely unknown. miRNA modulate gene expression by post-transcriptional repression to participate in many signaling pathway of breast cancer cell proliferation. miR-590 has been reported to regulate tumorgenesis and could be regulated by its own target ATF-3. But whether miR-590 can be the modulator of Golgi related genes to regulate the breast cancer proliferation is unclear. METHODS: We performed the bioinformatics analysis of survival rate and expression differences of patients using the data of The Cancer Genome Atlas (TCGA).Both of MTS and BrdU assays were used for cell proliferation analysis. Cell cycle was detected by flow cytometry .qRT-PCR was used for detecting the cell cycle related gene expression. Student's t-test or One way anova was used for statistics. RESULTS: We found the upregulation of GOLPH3 in breast cancer samples compared with normal breast tissues, which also was related to the poor prognosis. Overexpression of GOLPH3 significantly promoted proliferation both of MDA-MB-231 cells (ER negative) and MCF-7 cells (ER positive). We further found that miRNA-590-3p could directly target the 3'-UTR of GOLPH3 mRNA to repress its expression. Overexpression of miR-590-3p inhibited the proliferation of MDA-MB-231 and MCF-7 cells. The rescue experiments indicated that overexpression of GOLPH3 significantly resorted the proliferation inhibited by miR-590-3p. We also found that ATF-3 repressed miR-590-3p expression to modulate miR-590/GOLPH3 pathway to regulate breast cancer cells proliferation. CONCLUSIONS: This study not only suggests that the ATF-3/miR-590/GOLPH3 signaling pathway is critically involved in the proliferation of breast cancer cells, but provides a novel therapeutic target and new insight base on epigenetic regulation for future breast cancer diagnosis and clinical treatment. PMID- 29534691 TI - A case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy. AB - BACKGROUND: Ritualistic behaviors are common in obsessive compulsive disorder (OCD), while catatonic stupor occasionally occurs in psychotic or mood disorders. Schizoaffective disorder is a specific mental disorder involving both psychotic and affective symptoms. The syndrome usually represents a specific diagnosis, as in the case of the 10th edition of the International Classification of Diseases (ICD-10) or the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, symptom-based diagnosis can result in misdiagnosis and hinder effective treatment. Few cases of ritualistic behaviors and catatonic stupor associated with schizoaffective disorder have been reported. Risperidone and modified electroconvulsive therapy (MECT) were effective in our case. CASE PRESENTATION: A 35-year-old man with schizoaffective disorder-depression was admitted to the hospital because of ritualistic behaviors, depression, and distrust. At the time of admission, prominent ritualistic behaviors and depression misled us to make the diagnosis of OCD. Sertraline add-on treatment exacerbated the psychotic symptoms, such as pressure of thoughts and delusion of control. In the presence of obvious psychotic symptoms and depression, schizoaffective disorder-depression was diagnosed according to ICD-10. Meanwhile, the patient unfortunately developed catatonic stupor and respiratory infection, which was identified by respiratory symptoms, blood tests, and a chest X-ray. To treat psychotic symptoms, catatonic stupor, and respiratory infection, risperidone, MECT, and ceftriaxone were administered. As a result, we successfully cured the patient with the abovementioned treatment strategies. Eventually, the patient was diagnosed with schizoaffective disorder-depression with ritualistic behaviors and catatonia. Risperidone and MECT therapies were dramatically effective. CONCLUSION: Making a differential diagnosis of mental disorders is a key step in treating disease. Sertraline was not recommended for treating schizoaffective disorder-depression according to our case because it could exacerbate positive symptoms. Controversy remains about whether antipsychotics should be administered for catatonic stupor. However, more case studies will be needed. Risperidone with MECT was beneficial for the patient in our case. PMID- 29534692 TI - Diagnosis and therapeutic monitoring of inborn errors of metabolism in 100,077 newborns from Jining city in China. AB - BACKGROUND: Mandatory newborn screening for metabolic disorders has not been implemented in most parts of China. Newborn mortality and morbidity could be markedly reduced by early diagnosis and treatment of inborn errors of metabolism (IEM). Methods of screening for IEM by tandem mass spectrometry (MS/MS) have been developed, and their advantages include rapid testing, high sensitivity, high specificity, high throughput, and low sample volume (a single dried blood spot). METHODS: Dried blood spots of 100,077 newborns obtained from Jining city in 2014 2015 were screened by MS/MS. The screening results were further confirmed by clinical symptoms and biochemical analysis in combination with the detection of neonatal deficiency in organic acid, amino acid, or fatty acid metabolism and DNA analysis. RESULTS: The percentages of males and females among the 100,077 infants were 54.1% and 45.9%, respectively. Cut-off values were established by utilizing the percentile method. The screening results showed that 98,764 newborns were healthy, and 56 out of the 1313 newborns with suspected IEM were ultimately diagnosed with IEM. Among these 56 newborns, 19 (1:5267) had amino acid metabolism disorders, 26 (1:3849) had organic acid metabolism disorders, and 11 (1:9098) had fatty acid oxidation disorders. In addition, 54 patients with IEM were found to carry mutations, and the other 2 patients had argininemia. CONCLUSIONS: Fifty-six cases of metabolic disorders in Jining were confirmed via newborn screening (NBS) by MS/MS. Early diagnosis and treatment are crucial for the survival and well-being of affected children. A nationwide NBS program using MS/MS is recommended, especially in poor areas of China. PMID- 29534693 TI - Severe eye complications from toxic epidermal necrolysis following initiation of Nevirapine based HAART regimen in a child with HIV infection: a case from Cameroon. AB - BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare life threatening dermatological disorder characterized by extensive epidermal detachment and erosion of mucous membranes. It is typically a side effect of some medications. Nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) is one of the frequently used components of highly active antiretroviral therapy (HAART). Skin rash is its common adverse reaction, usually mild and rarely progressing to TEN. Ophthalmic involvement is common as well but rarely progresses to blindness especially in the pediatric population. CASE PRESENTATION: We report the case of a 3 year 5 month old child diagnosed with HIV who developed TEN 8 days after starting a Nevirapine based HAART regimen. Drug withdrawal and supportive treatment alone were the modalities employed to achieve complete re epithelization of lesions. Patient was lost to follow-up 6 months after being in care and was only seen 3 years later with total loss of vision. CONCLUSION: Blindness, though rare, can be a long-term complication of TEN in children especially with HIV infection. Physicians and patient caregivers should closely monitor these patients, especially during their early stages of treatment amongst others for development of adverse drug reactions. Long-term retention in care is pivotal for identification and prompt management of ocular and other chronic complications, albeit recognizing management challenges in low resourced settings. PMID- 29534694 TI - Predicting the severity of dengue fever in children on admission based on clinical features and laboratory indicators: application of classification tree analysis. AB - BACKGROUND: Dengue fever is a re-emerging viral disease commonly occurring in tropical and subtropical areas. The clinical features and abnormal laboratory test results of dengue infection are similar to those of other febrile illnesses; hence, its accurate and timely diagnosis for providing appropriate treatment is difficult. Delayed diagnosis may be associated with inappropriate treatment and higher risk of death. Early and correct diagnosis can help improve case management and optimise the use of resources such as hospital staff, beds, and intensive care equipment. The goal of this study was to develop a predictive model to characterise dengue severity based on early clinical and laboratory indicators using data mining and statistical tools. METHODS: We retrieved data from a study of febrile illness in children at Angkor Hospital for Children, Cambodia. Of 1225 febrile episodes recorded, 198 patients were confirmed to have dengue. A classification and regression tree (CART) was used to construct a predictive decision tree for severe dengue, while logistic regression analysis was used to independently quantify the significance of each parameter in the decision tree. RESULTS: A decision tree algorithm using haematocrit, Glasgow Coma Score, urine protein, creatinine, and platelet count predicted severe dengue with a sensitivity, specificity, and accuracy of 60.5%, 65% and 64.1%, respectively. CONCLUSIONS: The decision tree we describe, using five simple clinical and laboratory indicators, can be used to predict severe cases of dengue among paediatric patients on admission. This algorithm is potentially useful for guiding a patient-monitoring plan and outpatient management of fever in resource poor settings. PMID- 29534695 TI - Knowledge, attitudes and practices regarding depression among primary health care providers in Fako division, Cameroon. AB - BACKGROUND: Mental health and mental illness are often overlooked in the management of patients in our health services. Depression is a common mental disorder worldwide. Recognising and managing mental illnesses such as depression by primary health care providers (PHCPs) is crucial. This study describes the knowledge, attitudes and practices (KAP) of PHCPs regarding depression in Fako Division. METHODS: A cross-sectional study was conducted among PHCPs (general practitioners, nurses, pharmacy attendants and social workers) in public-owned health facilities in the four health districts in Fako Division. Participants were selected by a consecutive convenience sampling. A structured questionnaire including the Depression Attitude Questionnaire (DAQ) was used to collect information about their socio-demographic characteristics, professional qualifications and KAP about depression. RESULTS: The survey had a response rate of 56.7%. Most of the 226 participants (92.9%) were aware that depression needs medical intervention. Only 1.8% knew a standard tool used to diagnose depression. Two-thirds agreed that majority of the cases of depression encountered originate from recent misfortune. About 66% felt uncomfortable working with depressed patients. Also, 45.1% of PHCPs did not know if psychotropic drugs were available at pharmacies within their health area. Very few (15.2%) reported to have prescribed psychotropic drugs. Less than half (49.1%) of the participants had prior formal training in mental health. CONCLUSION: PHCPs in Fako Division tend to have limited knowledge and poor attitudes regarding depression. Practices towards diagnosis and management of depression tend to be inadequate. There is an urgent need to train PHCPs in mental health in general and depression diagnosis and management in particular. PMID- 29534697 TI - The Pioneers of Nephrology - Professor Gabriel Richet: "I will maintain". AB - Gabriel Richet was one of the great pioneers of European Nephrology. After a pivotal period of work with Jean Hamburger, whom we owe the name of our discipline, Nephrology, he contributed to all aspects of this specialty and was, in particular, a forerunner in dialysis and in the study of interstitial nephropathies.In this passionate and lucid interview, recorded in Paris in 2010, he describes himself as a "lucky man", able to transform folly in happiness. He does not describe himself as an intellectual, but as a warrior, and closes a detailed history of the early days of European Nephrology with a strong statement of the moral stature a physician should have: he underlines, in line with his strong personality, that a physician is a man able to decide, to give orders and to assume their consequences. However, science and care of human beings cannot exist without a heart. "A doctor is someone who decides; when he writes a prescription, this means he prescribes and takes responsibility. Is it possible to give a prescription and decide regardless of compassion?". In his interview, he commented that this last statement is probably not uniformly agreed, but that he'll always defend it, adds freedom as a moral value that a physician should proudly defend: "Unfortunately I know that many do not share my idea, but that's life... I am like the Queen of Holland, whose motto is: I will maintain!". PMID- 29534698 TI - Can knowledge exchange support the implementation of a health-promoting schools approach? Perceived outcomes of knowledge exchange in the COMPASS study. AB - BACKGROUND: Despite the potential population-level impact of a health-promoting schools approach, schools face challenges in implementation, indicating a gap between school health research and practice. Knowledge exchange provides an opportunity to reduce this gap; however, there has been limited evaluation of these initiatives. This research explored researchers' and knowledge users' perceptions of outcomes associated with a knowledge exchange initiative within COMPASS, a longitudinal study of Canadian secondary students and schools. Schools received annual tailored summaries of their students' health behaviours and suggestions for action and were linked with knowledge brokers to support them in taking action to improve student health. METHODS: Qualitative semi-structured interviews were conducted with COMPASS researchers (n = 13), school staff (n = 13), and public health stakeholders (n = 4) to explore their experiences with COMPASS knowledge exchange. Key issues included how knowledge users used school specific findings, perceived outcomes of knowledge exchange, and suggestions for change. RESULTS: Outcomes for both knowledge users and researchers were identified; interestingly, knowledge users attributed more outcomes to using school-specific findings than knowledge brokering. School and public health participants indicated school-specific findings informed their programming and planning. Importantly, knowledge exchange provided a platform for partnerships between researchers, schools, and public health units. Knowledge brokering allowed researchers to gain feedback from knowledge users to enhance the study and a better understanding of the school environment. Interestingly, COMPASS knowledge exchange outcomes aligned with Samdal and Rowling's eight theory-driven implementation components for health-promoting schools. Hence, knowledge exchange may provide a mechanism to help schools implement a health-promoting schools approach. CONCLUSIONS: This research contributes to the limited literature regarding outcomes of knowledge brokering in public health and knowledge exchange in school health research. However, since not all schools engaged in knowledge brokering, and not all schools that engaged discussed these outcomes, further research is needed to determine the amount of engagement required for change and examine the process of COMPASS knowledge brokering to consider how to increase school engagement. PMID- 29534699 TI - Promoting self-management, health literacy and social capital to reduce health inequalities in older adults living in urban disadvantaged areas: protocol of the randomised controlled trial AEQUALIS. AB - BACKGROUND: Older people living in socio-economic deprived urban areas especially suffer the effects of health inequalities but have been insufficiently targeted. Strategies promoted by local primary health care agents might influence health and social behaviours as intermediate social determinants that are modifiable and thus can potentially mitigate health inequalities. Therefore, we aim to develop and assess the effectiveness of a complex intervention based on a community programme that promotes self-management, health literacy and social capital targeting older people from urban socioeconomically disadvantaged areas in order to improve their self-perceived health as an indicator of health inequality reduction. METHODS/DESIGN: Design: A pragmatic multicentre, parallel, randomised controlled trial will be implemented in 16 primary health care centres from six urban areas in neighbourhoods with low-socioeconomic level. TARGET: community dwelling aged 60 years or above who perceive their health as fair or poor. The programme is called "Sentir-nos Be" ("Feeling well") and comprises 12 two-hour sessions held once a week in groups of 12-15 people. Group dynamics are designed to promote mutual support, social participation and new knowledge on health literacy and self-management, resulting in meaningful changes in their daily life that positively affect their health and wellbeing. A sample size of 390 participants, randomised to the intervention or the control group, will be needed to detect a clinically relevant benefit in the primary outcome self-perceived health after 3-month intervention. A follow-up will be conducted at 9 months post intervention. Participants in the control group will receive usual care and remain in a waiting-list to join the programme once the trial ends. A process evaluation will provide greater confidence in the conclusions about the effectiveness of the intervention. Ethics approval: Clinical Investigation Ethics Committee of the IDIAP Jordi Gol (P15/031). Dissemination: Findings will be disseminated through conference presentations and open-access journals. DISCUSSION: The project will promote the implementation of evidence-based intervention procedures in future health policy strategies targeting older people while considering the social aspects of inequality. TRIAL REGISTRATION: NCT02733523 . Retrospectively registered. Date of registration: April 11, 2016. PMID- 29534700 TI - A narrative account of implementation lessons learnt from the dissemination of an up-scaled state-wide child obesity management program in Australia: PEACHTM (Parenting, Eating and Activity for Child Health) Queensland. AB - BACKGROUND: PEACHTMQLD translated the PEACHTM Program, designed to manage overweight/obesity in primary school-aged children, from efficacious RCT and small scale community trial to a larger state-wide program. This paper describes the lessons learnt when upscaling to universal health coverage. METHODS: The 6 month, family-focussed program was delivered in Queensland, Australia from 2013 to 2016. Its implementation was planned by researchers who developed the program and conducted the RCT, and experienced project managers and practitioners across the health continuum. The intervention targeted parents as the agents of change and was delivered via parent-only group sessions. Concurrently, children attended fun, non-competitive activity sessions. Sessions were delivered by facilitators who received standardised training and were employed by a range of service providers. Participants were referred by health professionals or self-referred in response to extensive promotion and marketing. A pilot phase and a quality improvement framework were planned to respond to emerging challenges. RESULTS: Implementation challenges included engagement of the health system; participant recruitment; and engagement. A total of 1513 children (1216 families) enrolled, with 1122 children (919 families) in the face-to-face program (105 groups in 50 unique venues) and 391 children (297 families) in PEACHTM Online. Self-referral generated 68% of enrolments. Unexpected, concurrent and, far-reaching public health system changes contributed to poor program uptake by the sector (only 56 [53%] groups delivered by publicly-funded health organisations) requiring substantial modification of the original implementation plan. Process evaluation during the pilot phase and an ongoing quality improvement framework informed program adaptations that included changing from fortnightly to weekly sessions aligned with school terms, revision of parent materials, modification of eligibility criteria to include healthy weight children and provision of services privately. Comparisons between pilot versus state-wide waves showed comparable prevalence of families not attending any sessions (25% vs 28%) but improved number of sessions attended (median = 5 vs 7) and completion rates (43% vs 56%). CONCLUSIONS: Translating programs developed in the research context to enable implementation at scale is complex and presents substantial challenges. Planning must ensure there is flexibility to accommodate and proactively manage the system changes that are inevitable over time. TRIAL REGISTRATION: ACTRN12617000315314 . This trial was registered retrospectively on 28 February, 2017. PMID- 29534696 TI - Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies. AB - BACKGROUND: Epidemiological studies have clarified the potential associations between regular aspirin use and cancers. However, it remains controversial on whether aspirin use decreases the risk of cancers risks. Therefore, we conducted an updated meta-analysis to assess the associations between aspirin use and cancers. METHODS: The PubMed, Embase, and Web of Science databases were systematically searched up to March 2017 to identify relevant studies. Relative risks (RRs) with 95% confidence intervals (CIs) were used to assess the strength of associations. RESULTS: A total of 218 studies with 309 reports were eligible for this meta-analysis. Aspirin use was associated with a significant decrease in the risk of overall cancer (RR = 0.89, 95% CI: 0.87-0.91), and gastric (RR = 0.75, 95% CI: 0.65-0.86), esophageal (RR = 0.75, 95% CI: 0.62-0.89), colorectal (RR = 0.79, 95% CI: 0.74-0.85), pancreatic (RR = 0.80, 95% CI: 0.68-0.93), ovarian (RR = 0.89, 95% CI: 0.83-0.95), endometrial (RR = 0.92, 95% CI: 0.85 0.99), breast (RR = 0.92, 95% CI: 0.88-0.96), and prostate (RR = 0.94, 95% CI: 0.90-0.99) cancers, as well as small intestine neuroendocrine tumors (RR = 0.17, 95% CI: 0.05-0.58). CONCLUSIONS: These findings suggest that aspirin use is associated with a reduced risk of gastric, esophageal, colorectal, pancreatic, ovarian, endometrial, breast, and prostate cancers, and small intestine neuroendocrine tumors. PMID- 29534701 TI - Recommendations for mRNA analysis of micro-dissected glomerular tufts from paraffin-embedded human kidney biopsy samples. AB - BACKGROUND: Glomeruli are excellent pre-determined natural structures for laser micro-dissection. Compartment-specific glomerular gene expression analysis of formalin-fixed paraffin-embedded renal biopsies could improve research applications. The major challenge for such studies is to obtain good-quality RNA from small amounts of starting material, as applicable for the analysis of glomerular compartments. In this work, we provide data and recommendations for an optimized workflow of glomerular mRNA analysis. RESULTS: With a proper resolution of the camera and screen provided by the next generation of micro-dissection systems, we are able to separate parietal epithelial cells from glomerular tufts. Selected compartment-specific transcripts (WT1 and GLEPP1 for glomerular tuft as well as PAX2 for parietal epithelial cells) seem to be reliable discriminators for these micro-dissected glomerular substructures. Using the phenol-chloroform extraction and hemalaun-stained sections (2 um), high amounts of Bowman's capsule transections (> 300) reveal sufficient RNA concentrations (> 300 ng mRNA) for further analysis. For comparison, in unstained sections from a number of 60 glomerular transections upwards, a minimum amount of 157 ng mRNA with a reasonable mRNA purity [A260/A280 ratio of 1.5 (1.4/1.7) median (25th/75th percentiles)] was reversely transcribed into cDNA. Comparing the effect of input RNA (20, 60, 150 and 300 micro-dissected glomerular transections), transcript expression of POLR2A significantly correlated when 60 and 150 laser micro dissected glomerular transections were used for analysis. There was a lower inter assay coefficient of variability for ADAMTS13, when at least 60 glomerular transections were used. According to the algorithms of geNormPlus and NormFinder, PGK1 and PPIA are more stable glomerular reference transcripts compared to GUSB, GAPDH, POLR2A, RPLPO, TBP, B2M, ACTB, 18SrRNA and HMBS. CONCLUSIONS: Our approach implements compartment-specific glomerular mRNA expression analysis into research applications, even regarding glomerular substructures like parietal epithelial cells. We recommend using of at least 60 micro-dissected unstained glomerular or 300 hemalaun-stained Bowman's capsule transections to obtain sufficient input mRNA for reproducible results. Hereby, the range of RNA concentrations in 60 micro-dissected glomeruli is low and appropriate normalization of Cq values using our suggested reference transcripts (PGK1 and PPIA) allows compensation with respect to different amounts of RNA purity and quantity. PMID- 29534702 TI - Assessment of the societal cost of Taenia solium in Angonia district, Mozambique. AB - BACKGROUND: The zoonotic parasite Taenia solium is endemic in Angonia district, Tete province, Mozambique, though the burden of the disease complex is unknown. METHODS: As part of two cross-sectional studies on human and porcine cysticercosis in the area, unique epidemiological and cost data were collected in Angonia district, Mozambique in 2007. These data provided the basis for the assessment of the societal cost of T. solium in the district, which estimates the impact of the disease on human and pig populations and includes both health and economic approaches in the analysis. RESULTS: Approximately 0.7% (95% Uncertainty Interval (UI), 0.4-0.9) and 0.4% (95% UI, 0.2-0.6) of the total population in the district was estimated to suffer from neurocysticercosis (NCC)-associated epilepsy and headache. The estimated average number of disability-adjusted life years (DALYs) due to NCC-associated epilepsy and headache was 6 (95% UI, 4-8) per thousand persons per year. The total annual costs due to T. solium cysticercosis were estimated at 90,000 USD (95% UI, 39,483-201,463) of which 72% (95% UI, 45 91) were costs linked to human cysticercosis and 28% (95% UI, 9.5-55) to pig production losses. The annual economic burden per NCC-associated epilepsy case in the district amounted to 33 USD (95% UI, 10-76). CONCLUSIONS: In this highly endemic area of Mozambique a large number of individuals suffer from symptoms associated with NCC. Healthy years of life are lost and people are left living with disabilities. Infected pork poses a serious risk to the community and affects the economy of smallholder farmers. Cost for treatment and hospitalization of patients with NCC-associated epilepsy, and lack of productivity and inability of suffering patients to work, further hinder socioeconomic development. Feasible solutions framed within a country specific algorithm and stepwise approaches are needed to control the parasite in the country. PMID- 29534703 TI - A novel quick transendoscopic enteral tubing in mid-gut: technique and training with video. AB - BACKGROUND: This study aimed to evaluate the feasibility, safety, and value of a quick technique for transendoscopic enteral tubing (TET) through mid-gut. METHODS: A prospective interventional study was performed in a single center. A TET tube was inserted into mid-gut through the nasal orifice and fixed on the pylorus wall by one tiny titanium endoscopic clip under anesthesia. The feasibility, safety, success rate, and satisfaction with TET placement were evaluated for enteral nutrition or fecal microbiota transplantation. RESULTS: A total of 86 patients underwent mid-gut TET. The success rate of the TET procedure was 98.8% (85/86). Mean tubing time of the TET procedure was 4.2 +/- 1.9 min. 10 cases of procedure was enough for training of general endoscopist to shorten the procedure time (7.0 min vs 4.0 min, p < 0.05). 97.7% (84/86) of patients were satisfied with the TET placement. Procedure-related and tube-related adverse events were observed in 8.1% (7/86) and 7.0% (6/86) of patients respectively. There were no moderate to severe adverse events during tube extubation. CONCLUSIONS: TET through mid-gut is a novel, convenient, reliable and safe procedure for mid-gut administration with a high degree of patient satisfaction. TRIAL REGISTRATION: This research was retrospectively registered with clinicaltrials.gov. Trial registration date: 29th November 2017. TRIAL REGISTRATION NUMBER: NCT03335982 . PMID- 29534704 TI - The effect of contextual factors on unintentional injury hospitalization: from the Korea National Hospital Discharge Survey. AB - BACKGROUND: It has been suggested that health risks are affected by geographical area, but there are few studies on contextual effects using multilevel analysis, especially regarding unintentional injury. This study investigated trends in unintentional injury hospitalization rates over the past decade in Korea, and also examined community-level risk factors while controlling for individual-level factors. METHODS: Using data from the 2004 to 2013 Korea National Hospital Discharge Survey (KNHDS), trends in age-adjusted injury hospitalization rate were conducted using the Joinpoint Regression Program. Based on the 2013 KNHDS, we collected community-level factors by linking various data sources and selected dominant factors related to injury hospitalization through a stepwise method. Multilevel analysis was performed to assess the community-level factors while controlling for individual-level factors. RESULTS: In 2004, the age-adjusted unintentional injury hospitalization rate was 1570.1 per 100,000 population and increased to 1887.1 per 100,000 population in 2013. The average annual percent change in rate of hospitalizations due to unintentional injury was 2.31% (95% confidence interval: 1.8-2.9). It was somewhat higher for females than for males (3.25% vs. 1.64%, respectively). Both community- and individual-level factors were found to significantly influence unintentional injury hospitalization risk. As community-level risk factors, finance utilization capacity of the local government and neighborhood socioeconomic status, were independently associated with unintentional injury hospitalization after controlling for individual-level factors, and accounted for 19.9% of community-level variation in unintentional injury hospitalization. CONCLUSION: Regional differences must be considered when creating policies and interventions. Further studies are required to evaluate specific factors related to injury mechanism. PMID- 29534705 TI - Diabetes and abnormal glucose regulation in the adult population of Burkina Faso: prevalence and predictors. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) is reportedly growing fast in sub-Saharan Africa. There is however a scarcity of epidemiologic data on DM in Burkina Faso. We carried out a secondary analysis of the first survey conducted in Burkina Faso on a nationally representative sample following the World Health Organization (WHO) Stepwise approach to risk factors Surveillance (STEPS) for non communicable diseases (NCDs) with the aims of identifying the prevalence of NCDs and the prevalence of common risk factors for NCDs. We report here on the prevalence of diabetes and overall abnormal glucose regulation (AGR) and their associated risk factors. METHODS: In the primary study 4800 individuals were randomly sampled using a stratified multistage clusters sampling process. We used fasting capillary whole blood glucose level to define three glucose regulation statuses using WHO's cut-off levels: normal, diabetes and overall abnormal glucose regulation (impaired fasting glucose and diabetes). Appropriate statistical techniques for the analysis of survey data were used to identify the factors associated with diabetes and abnormal glucose regulation fitting a logistic regression model. Analyses were carried out using Stata Version 14 software. RESULTS: The prevalence of DM and AGR were respectively 5.8% (95% CI: 5 6.7) and 9% (95% CI: 8-10.1). Significant risk factors for DM include age (OR = 1.9; P = 0.009 for the age group of 55-64), obesity (OR: 2.6; P = 0.001), former smoke (OR:2; P = 0.03), second-hand smoke (OR = 1.7; P = 0.006) and total cholesterol level (OR: 2.1; P = 0.024). The same predictors were also found significantly associated with AGR. In addition, having an history family diabetes was protective against AGR (OR = 0.5; P = 0.032). CONCLUSION: Diabetes is no longer a rare disease in the adult active population of Burkina Faso. Its burden is significant in both rural and urban areas. Health policies that promote healthy life style are needed to give precedence to the prevention in a context of an under-resourced country. PMID- 29534706 TI - Interventional bronchoscopy in malignant central airway obstruction by extra pulmonary malignancy. AB - BACKGROUND: Interventional bronchoscopy is considered an effective treatment option for malignant central airway obstruction (MCAO). However, there are few reports of interventional bronchoscopy in patients with MCAOs due to extra pulmonary malignancy. Therefore, the objective of this study was to investigate treatment outcomes and prognostic factors for bronchoscopic intervention in patients with MCAO due to extra-pulmonary malignancy. METHODS: We retrospectively analyzed consecutive 98 patients with MCAO due to extra-pulmonary malignancy who underwent interventional bronchoscopy between 2004 and 2014 at Samsung Medical Center (Seoul, Korea). RESULTS: The most common primary site of malignancy was esophageal cancer (37.9%), followed by thyroid cancer (16.3%) and head & neck cancer (10.2%). Bronchoscopic interventions were usually performed using a combination of mechanical debulking (84.7%), stent insertion (70.4%), and laser cauterization (37.8%). Of 98 patients, 76 (77.6%) patients had MCAO due to progression of malignancy, and 42 (42.9%) patients had exhausted all other anti cancer treatment at the time of bronchoscopic intervention. Technical success was achieved in 89.9% of patients, and acute complications and procedure-related deaths occurred in 20.4% and 3.1% of patients, respectively. Reduced survival was associated with MCAO due to cancer other than thyroid cancer or lymphoma, mixed lesions, and not receiving adjuvant treatment after bronchoscopic intervention. CONCLUSIONS: Bronchoscopic intervention could be a safe and effective procedure for MCAO due to end-stage extra-pulmonary malignancies. In addition, we identified possible prognostic factors for poor survival after intervention, which could guide clinicians select candidates that will benefit from bronchoscopic intervention. PMID- 29534708 TI - Feeling good in old age: factors explaining health-related quality of life. AB - BACKGROUND: Sustained growth in longevity raises questions as to why some individuals report a good quality of life in older ages, while others seem to suffer more markedly the effects of natural deterioration. Health-related quality of life (HRQL) is mediated by several easily measurable factors, including socio demographics, morbidity, functional status and lifestyles. This study seeks to further our knowledge of these factors in order to outline a profile of the population at greater risk of poor ageing, and to identify those attributes that might be modified during younger stages of the life course. METHODS: We use nationally representative data for Catalonia (Spain) to explain the HRQL of the population aged 80-plus. Cross-sectional data from 2011 to 2016 were provided by an official face-to-face survey. HRQL was measured using EQ-VAS - the EuroQol-5D visual analogue scale - which summarizes current self-perceived health. Multivariate linear regression was used to identify variables influencing the EQ VAS score. RESULTS: Sociodemographic factors, including being older, female, poorly educated and belonging to a low social class, were related with poor HRQL at advanced ages. The presence of severe mobility problems, pain/discomfort, and anxiety/depression were highly correlated to the HRQL of the elderly, while problems of self-care and with usual activities had a weaker association. CONCLUSIONS: Encouraging the young to stay in education, as well as to adopt healthier lifestyles across the lifespan, might ensure better HRQL when individuals reach old age. More multidisciplinary research is required to understand the multifaceted nature of quality of life in the oldest-old population. PMID- 29534707 TI - Putative salivary protein biomarkers for the diagnosis of oral lichen planus: a case-control study. AB - BACKGROUND: Salivary protein biomarkers for screening and diagnosis of oral lichen planus (OLP) are not well-defined. The objective of this study was to identify putative protein biomarkers for OLP using proteomic approaches. METHODS: Pooled unstimulated whole saliva was collected from five OLP patients and five healthy control participants. Saliva samples were then subjected to two dimensional gel electrophoresis, followed by mass spectrometry to identify putative protein biomarkers. Subsequently, a subset of these putative biomarkers were validated in 24 OLP patients and 24 age-matched healthy control subjects, using an enzyme-linked immunosorbent assay (ELISA). Immunoblotting analyses were then performed in 3 pairs of age- and sex-matched OLP patients and healthy controls to confirm results from the ELISA study. RESULTS: Thirty-one protein spots were identified, corresponding to 20 unique proteins. Notably, fibrinogen fragment D and complement component C3c exhibited increased expression in OLP patients, while cystatin SA exhibited decreased expression in OLP patients, compared with healthy control subjects. ELISA analyses indicated increased expression of fibrinogen fragment D and complement component C3c, and decreased expression of cystatin SA, in the saliva of OLP patients. Statistical differences in the expression of salivary complement C3c were observed between OLP patients and healthy control subjects. Immunoblotting analyses confirmed the results of our ELISA study. CONCLUSION: Complement C3c, fibrinogen fragment D and cystatin SA may serve as salivary biomarkers for screening and/or diagnosis of OLP. PMID- 29534709 TI - Reactive case detection of Plasmodium falciparum in western Kenya highlands: effective in identifying additional cases, yet limited effect on transmission. AB - BACKGROUND: Identifying asymptomatic reservoirs of malaria parasites using index cases as entry points into the community is potentially a cost-effective way towards achieving malaria elimination. METHODS: Within 1 year, 1430 confirmed malaria cases were identified in Marani hospital, western Kenya. Fifty cases were followed up, and 108 index case household members and 612 neighbours within a 100 m radius were screened. As controls, samples were collected from 510 individuals matched with index cases and located at a distance of >= 500 m from them. Infections were diagnosed by microscopy and PCR while simultaneously collecting malaria vectors indoor using pyrethrum spray catches. RESULTS: In the index case and neighbour households, the prevalence of infection was approximately twice as high as in control households (by PCR: index cases households: 28.9%, neighbours: 25.3%, matched controls: 12.9%). In index case households, the indoor vector density (Anopheles gambiae and Anopheles funestus) was higher (0.46 female/house/night) than in neighbouring (0.31 f/h/n) and control houses (0.29 f/h/n). CONCLUSIONS: Screening index case households and neighbours approximately doubles the chance to detect asymptomatic infections compared to randomly selected households. However, even if all cases were followed up, only a small proportion (? 10%) of the asymptomatic reservoir in the population would have been identified. Control programmes need to weigh the increased chance to find cases around index cases vs. the logistical challenges to target this subgroup within the population. PMID- 29534710 TI - Sarcoptes infestation in two miniature pigs with zoonotic transmission - a case report. AB - BACKGROUND: Scabies is a contagious skin disease rarely described in miniature pigs. To the best of the authors' knowledge, a zoonotic transfer from infected pet pigs to humans has not been reported previously. CASE PRESENTATION: This case report describes the infestation with Sarcoptes scabiei mites in two miniature pigs presenting with unusual clinical signs, and disease transmission to a child. Two 7-month-old male castrated miniature pig siblings were examined. Both had developed skin lesions, one animal was presented for neurological signs and emaciation. They were housed together in an indoor- and outdoor enclosure. Dermatological examination revealed a dull, greasy coat with generalized hypotrichosis and multifocal erythema. Microscopic examination of skin scrapings, impression smears of affected skin and ear swabs revealed high numbers of Sarcoptes mites in both animals as well as bacterial overgrowth. A subcutaneous injection of ivermectin 0.3 mg/kg was administered to both animals and repeated after 2 weeks. Both miniature pigs received subcutaneous injections with butafosfan and cyanocobalamin, were washed with a 3% chlorhexidine shampoo and were fed on a well-balanced diet. Pig enclosures were cleaned. The infested child was examined by a physician and an antipruritic cream was prescribed. Both miniature pigs and the child went into clinical remission after treatment. CONCLUSION: Sarcoptic mange is rare or even eradicated in commercial pig farming in many countries but miniature pigs may represent a niche for Sarcoptes scabiei infections. This case report indicates that miniature pigs kept as pets can efficiently transmit zoonotic disease to humans. In addition, these animals may represent a niche for Sarcoptes scabiei infestation in countries where sarcoptic mange in commercial pig farms has been eradicated and could therefore pose, a hazard for specific pathogen free farms. PMID- 29534711 TI - Dynamic network measures reveal the impact of cattle markets and alpine summering on the risk of epidemic outbreaks in the Swiss cattle population. AB - BACKGROUND: Livestock herds are interconnected with each other via an intricate network of transports of animals which represents a potential substrate for the spread of epidemic diseases. We analysed four years (2012-2015) of daily bovine transports to assess the risk of disease transmission and identify times and locations where monitoring would be most effective. Specifically, we investigated how the seasonal dynamics of transport networks, driven by the alpine summering and traditional cattle markets, affect the risk of epidemic outbreaks. RESULTS: We found strong and consistent seasonal variation in several structural network measures as well as in measures for outbreak risk. Analysis of the consequences of excluding markets, dealers and alpine pastures from the network shows that markets contribute much more to the overall outbreak risk than alpine summering. Static descriptors of monthly transport networks were poor predictors of outbreak risk emanating from individual holdings; a dynamic measure, which takes the temporal structure of the network into account, gave better risk estimates. A stochastic simulation suggests that targeted surveillance based on this dynamic network allows a higher detection rate and smaller outbreak size at detection than compared to other sampling schemes. CONCLUSIONS: Dynamic measures based on time-stamped data-the outgoing contact chain-can give better risk estimates and could help to improve surveillance schemes. Using this measure we find evidence that even in a country with intense summering practice, markets continue being the prime risk factor for the spread of contagious diseases. PMID- 29534712 TI - Effect of surface finishing on the colour stability and translucency of dental ceramics. AB - BACKGROUND: The purpose of this study was to investigate the effects of staining solutions and surface finishing on the colour stability and translucency of hybrid ceramic (HC) and resin nanoceramic (RNC) materials. METHODS: Twenty four groups consisting of 10 specimens (240 specimens in total) were created out of HC and RNC, including six groups to be stored in distilled water served as the controls groups. The Vita Enamic technical set, Shofu polishers, medium and fine rubber wheels and Sof-Lex polishing discs were used as polishing instruments. Cola, tea, and coffee were used as staining solutions. The colour differences (?E*) and translucency parameter (TP) were evaluated by a spectrophotometer. Data were analysed by a One-way Analysis of Variance (ANOVA) and Mann-Whitney U test. RESULTS: There was a statistically significant difference between the ?E* values of the HC specimens in the coffee groups and the ?E* values of the other HC groups (p < 0.05). The ?E* values of the RNC specimens in the coffee and tea groups were not different from the specimens in the cola groups (p > 0.05). The TP values of the polished groups were higher than the Sof-Lex groups and the Shofu groups on both HC and RNC materials (p < 0.05). CONCLUSIONS: Increased ?E* values were observed in HC specimens stored in a coffee solution compared to the specimens stored in a tea or cola solution. Both of the RNC specimens stored in coffee and tea had higher ?E* values than the RNC specimens stored in the cola. The TP values of both HC and RNC specimens stored in the coffee solution decreased. PMID- 29534713 TI - Palliative sedation in Germany: factors and treatment practices associated with different sedation rate estimates in palliative and hospice care services. AB - BACKGROUND: Clinical practice of Palliative Sedation (PS) varies between institutions worldwide and sometimes includes problematic practices. Little available research points at different definitions and frameworks which may contribute to uncertainty of healthcare professionals in the application of PS. This analysis investigates what demographic factors and characteristics of treatment practices differ between institutions with high versus low sedation rates estimates in Palliative and Hospice Care in Germany. METHODS: Data sets from 221 organisations from a prior online survey were separated into two sub groups divided by their estimated sedation rate A) lower/equal to 16% (n = 187; 90.8%) and B) higher than 16% (n = 19; 9.2%) for secondary analysis. Demographic factors and characteristics of PS treatment practices between the two groups were compared using T-Tests and Chi2/ Fisher Exact Tests and considered significant (*) at two-sided p < .05. RESULTS: Organisations in group B report that they discuss PS for a higher proportion of patients (38.5%/10.2%, p < 0.000**), rate agitation more often as an indications for PS (78.9%/ 53.5%, p = 0.050*), and are more likely to use Lorazepam (63.2%/ 37.4%, p = 0.047*), Promethazin (26.3%/ 9.6%, p = 0.044*), and (Es-)Ketamin (31.6%/ 12.8%, p = 0.039*) than representatives in group A. Both groups differ significantly in their allocation of three case scenarios to different types of PS. CONCLUSIONS: Both definitions and patterns of clinical practice between palliative and hospice care representatives show divergence, which may be influenced one by another. A comprehensive framework considering conceptual, clinical, ethical, and legal aspects of different definitions of PS could help to better distinguish between different types and nuances of PS. PMID- 29534714 TI - Lumbar spine epidural abscess and facet joint septic arthritis due to Streptococcus agalactiae: a case report. AB - BACKGROUND: Here we report a rare case of lumbar spine epidural abscess and facet joint septic arthritis caused by Streptococcus agalactiae, which had spread to the iliopsoas muscles, leading to urine retention. CASE PRESENTATION: A 68-year old woman with low back pain experienced a sudden onset of bilateral lower limb weakness, it was followed 14 days later by urine retention. At consultation, magnetic resonance imaging and identification of serum beta-hemolytic streptococci provided a diagnosis of Streptococcus agalactiae infection. She was started on antibiotics. Despite diminishing signs of inflammation, preoperative MRI showed an epidural mass at T12-L4 compressing the cord and involving the paravertebral muscles as well. Group B beta-hemolytic streptococci were detected in both urine and blood. Because of bilateral lower limb weakness and urine retention, T12-L4 hemilaminectomy was performed. The L3/L4 intertransverse ligament resected and abscess drained. Histopathology revealed that inflammatory cells had invaded the facet joint. Group B beta-hemolytic streptococci were identified, confirming the diagnosis. The patient continued with the antibiotics postoperatively, and her health rapidly improved. CONCLUSION: Lumbar spine epidural abscess and facet joint septic arthritis caused by Streptococcus agalactiae is a clinical emergency, with significant morbidity and mortality especially with delayed diagnosis. A delay in both diagnosis and aggressive treatment can lead to not only severe neurological deficit but also to septicaemia, multiorgan failure, and even death. PMID- 29534715 TI - Investigating the association between stress, saliva and dental caries: a scoping review. AB - BACKGROUND: This scoping review addressed the question 'what do we know about stress-related changes in saliva and dental caries in general population?' METHODS: The review was conducted using electronic searches via Embase, MEDLINE, PsycINFO, CINAHL and WoS. All published human studies with both observational and experimental designs were included. Two reviewers independently reviewed eligible articles and extracted the data. The studies' quality was assessed using the Effective Public Health Practice Project Quality Assessment Tool. RESULTS: Our search identified 232 reports, of which six were included in this review. All six studies were conducted in children and used salivary cortisol as stress marker. The studies varied by design, types of stressors, children's caries experience, methods of saliva collection. Four studies reported a positive association between saliva cortisol levels and caries (p < 0.05) while the other two reported no association (p > 0.05). The quality of the included studies was weak to moderate. CONCLUSIONS: There is lack of evidence about an association between stress-related changes in saliva and caries. Well-designed longitudinal studies with rigorous measurement technics for stress, saliva and dental caries are necessary. This will help to generate new insights into the multifactorial etiology of caries and provide evidence for a rational method for its control. PMID- 29534716 TI - Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals. AB - BACKGROUND: Clusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the epsilon4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer's disease, and may play additional roles in atherosclerosis pathogenesis. We tested whether genetic variation in CLU was associated with either Alzheimer's disease or atherosclerosis-related diseases. METHODS: We studied individual data on 103,987 participants from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). We genotyped a common CLU variant (rs9331896) and two common APOE variants (rs7412 and rs429358), defining the epsilon2, epsilon3, and epsilon4, alleles in CGPS and CCHS. All individuals in the CGPS and CCHS cohorts were followed from study inclusion to occurrence of event, death, emigration, or until 10 November 2014, whichever came first. Summary consortia data on 258,351 individuals from the International Genomics of Alzheimer's Project (IGAP) and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics and 1000-Genomes-based genome-wide association studies (CARDIoGRAMplusC4D) were used in meta-analyses. RESULTS: In CGPS and CCHS, multifactorially adjusted hazard ratios for Alzheimer's disease, all dementia, vascular dementia, ischemic cerebrovascular disease, and ischemic heart disease were 1.18 (1.07-1.30), 1.09 (1.02-1.17), 0.96 (0.80-1.17), 1.02 (0.97-1.07), and 0.97 (0.93-1.01) per T allele, respectively. Multifactorially adjusted hazard ratios for Alzheimer's disease and all dementia were 2.72 (2.45-3.01) and 2.21 (2.05-2.38) for the APOE E4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the E4 allele) in APOE in predicting Alzheimer's disease or all dementia (P = 0.39 and P = 0.21). In a meta-analysis including consortium data, the overall fixed- and random-effects odds ratios for Alzheimer's disease per T allele were 1.16 (1.13-1.18) (I 2 = 0.0%; P for heterogeneity = 0.89). CONCLUSIONS: A common variant in CLU was associated with a high risk of Alzheimer's disease and all dementia in the general population but not with vascular dementia or ischemic vascular disease. Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative epsilon4 allele, and several subtypes of dementia and atherosclerosis-related endpoints. PMID- 29534717 TI - Genome editing and transcriptional repression in Pseudomonas putida KT2440 via the type II CRISPR system. AB - BACKGROUND: The soil bacterium Pseudomonas putida KT2440 is a "generally recognized as safe"-certified strain with robust property and versatile metabolism. Thus, it is an ideal candidate for synthetic biology, biodegradation, and other biotechnology applications. The known genome editing approaches of Pseudomonas are suboptimal; thus, it is necessary to develop a high efficiency genome editing tool. RESULTS: In this study, we established a fast and convenient CRISPR-Cas9 method in P. putida KT2440. Gene deletion, gene insertion and gene replacement could be achieved within 5 days, and the mutation efficiency reached > 70%. Single nucleotide replacement could be realized, overcoming the limitations of protospacer adjacent motif sequences. We also applied nuclease deficient Cas9 binding at three locations upstream of enhanced green fluorescent protein (eGFP) for transcriptional inhibition, and the expression intensity of eGFP reduced to 28.5, 29.4, and 72.1% of the control level, respectively. Furthermore, based on this CRISPR-Cas9 system, we also constructed a CRISPR-Cpf1 system, which we validated for genome editing in P. putida KT2440. CONCLUSIONS: In this research, we established CRISPR based genome editing and regulation control systems in P. putida KT2440. These fast and efficient approaches will greatly facilitate the application of P. putida KT2440. PMID- 29534718 TI - Ras enhances TGF-beta signaling by decreasing cellular protein levels of its type II receptor negative regulator SPSB1. AB - BACKGROUND: Transformation by oncogene Ras overcomes TGF-beta mediated growth inhibition in epithelial cells. However, it cooperates with each other to mediate epithelial to mesenchymal transition (EMT). The mechanism of how these two pathways interact with each other is controversial. METHODS: Molecular techniques were used to engineer expression plasmids for Ras, SPRY, TGF-beta receptors, type I and II and ubiquitin. Immunoprecipitation and western blots were employed to determine protein-protein interactions, preotein levels, protein phosphorylation while immunofluorecesent staining for molecular co-localization. TGF-beta signalling activities is also determined by its luciferase reporter assay. Trans well assays were used to measure cell migration and invasion. RESULTS: Ras interacts with the SPSB1's SPRY domain to enhance TGF-beta signaling. Ras interacts and colocalizes with the TGF-beta type II receptor's (TbetaRII) negative regulator SPSB1 on the cell membrane, consequently promoting SPSB1 protein degradation via enhanced mono- and di-ubiquitination. Reduced SPSB1 levels result in the stablization of TbetaRII, in turn the increase of receptor levels significantly enhance Smad2/3 phosphorylation and signaling. Importantly, forced expression of SPSB1 in Ras transformed cells suppresses TGF-beta signaling and its mediated migration and invasion. CONCLUSION: Ras positively cooperates with TGF-beta signaling by reducing the cellular protein levels of TbetaRII negative regualtor SPSB1. PMID- 29534719 TI - Formation of chimeric genes with essential functions at the origin of eukaryotes. AB - BACKGROUND: Eukaryotes evolved from the symbiotic association of at least two prokaryotic partners, and a good deal is known about the timings, mechanisms, and dynamics of these evolutionary steps. Recently, it was shown that a new class of nuclear genes, symbiogenetic genes (S-genes), was formed concomitant with endosymbiosis and the subsequent evolution of eukaryotic photosynthetic lineages. Understanding their origins and contributions to eukaryogenesis would provide insights into the ways in which cellular complexity has evolved. RESULTS: Here, we show that chimeric nuclear genes (S-genes), built from prokaryotic domains, are critical for explaining the leap forward in cellular complexity achieved during eukaryogenesis. A total of 282 S-gene families contributed solutions to many of the challenges faced by early eukaryotes, including enhancing the informational machinery, processing spliceosomal introns, tackling genotoxicity within the cell, and ensuring functional protein interactions in a larger, more compartmentalized cell. For hundreds of S-genes, we confirmed the origins of their components (bacterial, archaeal, or generally prokaryotic) by maximum likelihood phylogenies. Remarkably, Bacteria contributed nine-fold more S-genes than Archaea, including a two-fold greater contribution to informational functions. Therefore, there is an additional, large bacterial contribution to the evolution of eukaryotes, implying that fundamental eukaryotic properties do not strictly follow the traditional informational/operational divide for archaeal/bacterial contributions to eukaryogenesis. CONCLUSION: This study demonstrates the extent and process through which prokaryotic fragments from bacterial and archaeal genes inherited during eukaryogenesis underly the creation of novel chimeric genes with important functions. PMID- 29534720 TI - Efficacy and safety of artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Sudan: a systematic review and meta-analysis. AB - BACKGROUND: Malaria is a major public health problem in endemic countries including Sudan, where about 75% of populations are at risk. Due to widespread of chloroquine-resistant strains of Plasmodium falciparum, artemisinin-based combination therapy (ACT) is currently treatment of choice for malaria in the vast majority of malaria-endemic countries. This systematic review and meta analysis is performed to obtain an overall stronger evidence of the outcomes of ACT in the treatment of uncomplicated falciparum malaria from the existing literature in Sudan. METHODS: The preferred reporting items for systematic review and meta-analysis statement were used to select studies to be included in this review. A computerized systematic strategy was adopted to search articles from PubMed, Google Scholar and Science Direct databases. Unpublished materials were also included. Open Meta-Analyst software was used to perform the meta-analysis. Random effects model was used to combine the included studies and the heterogeneity of studies was assessed using Cochrane Q and I2 (chi2 = 73.05, df (19), P < 0.001 and I2 = 73.99). RESULTS: Twenty studies fulfilled the inclusion criteria (ACT in the treatment of uncomplicated falciparum malaria) and were included in the final analysis with a total number of 4070 participants. Malaria treatment outcome was assessed using World Health Organization guidelines. Adequate clinical and parasitological response was used to assess treatment success at the 28th day. Treatment success of all combined studies was 98% [(95% CI 97.2-98.8%), P < 0.001]. Treatment success was higher in malaria patients treated with artemether + lumefantrine (AL) than patients treated with artesunate + sulfadoxine-pyrimethamine (AS + SP) (98.9% (95% CI 98.4-99.4%) vs 97.1% (95% CI 95.5-98.6%), P < 0.001). Eleven studies reported adverse drug reactions (ADRs) to ACT (184 participants out of 3957 (4.65%). The ADRs were mild and resolved spontaneously. There was no severe ADRs or deaths. CONCLUSION: Based on this review, the overall malaria treatment success was high (98%). AL regimen showed higher efficacy compared to AS + SP. The overall regimens were associated with mild low rates ADRs. PMID- 29534721 TI - T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans. AB - BACKGROUND: Shigellosis persists as a public health problem worldwide causing ~ 165,000 deaths every year, of which ~ 55,000 are in children less than 5 years of age. No vaccine against shigellosis is currently licensed. The live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S (S. flexneri 2a; DeltaguaBA, Deltaset, Deltasen) demonstrated to be safe and immunogenic in phase 1 and 2 clinical trials. Earlier reports focused on humoral immunity. However, Shigella is an intracellular pathogen and therefore, T cell mediated immunity (T-CMI) is also expected to play an important role. T-CMI responses after CVD 1208S immunization are the focus of the current study. METHODS: Consenting volunteers were immunized orally (3 doses, 108 CFU/dose, 28 days apart) with CVD 1208S. T CMI to IpaB was assessed using autologous EBV-transformed B-Lymphocytic cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines (IFN-gamma, IL-2, IL-17A and TNF-alpha) and/or expression of the degranulation marker CD107a in 14 volunteers (11 vaccine and 3 placebo recipients). RESULTS: Following the first immunization, T-CMI was detected in CD8 and CD4 T cells obtained from CVD 1208S recipients. Among CD8 T cells, the T effector memory (TEM) and central memory (TCM) subsets were the main cytokine/CD107a producers/expressors. Multifunctional (MF) cells were also detected in CD8 TEM cells. Cells with 2 and 3 functions were the most abundant. Interestingly, TNF alpha appeared to be dominant in CD8 TEM MF cells. In CD4 T cells, TEM responses predominated. Following subsequent immunizations, no booster effect was detected. However, production of cytokines/expression of CD107a was detected in individuals who had previously not responded. After three doses, production of at least one cytokine/CD107a was detected in 8 vaccinees (73%) in CD8 TEM cells and in 10 vaccinees (90%) in CD4 TEM cells. CONCLUSIONS: CVD 1208S induces diverse T-CMI responses, which likely complement the humoral responses in protection from disease. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT01531530). PMID- 29534722 TI - RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. AB - BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly characterized by retinal pigment epithelium (RPE) degeneration with accumulation of abnormal intracellular deposits (lipofuscin) and photoreceptor death. RPE is vital for the retina and integrity of photoreceptors through its phagocytic function which is closely linked to formation of lipofuscin through daily phagocytosis of discarded photoreceptor outer segments (POS). Although phagocytosis has been implicated in AMD, it has not been directly shown to be altered in AMD. RPE phagocytic defect was previously shown to be rescued by subretinal injection of human umbilical tissue derived cells (hUTC) in a rodent model of retinal degeneration (RCS rat) through receptor tyrosine kinase (RTK) ligands and bridge molecules. Here, we examined RPE phagocytic function directly in the RPE from AMD patients and the ability and mechanisms of hUTC to affect phagocytosis in the human RPE. METHODS: Human RPE was isolated from the post-mortem eyes of normal and AMD-affected subjects and cultured. RPE phagocytic function was measured in vitro using isolated POS. The effects of hUTC conditioned media, recombinant RTK ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell derived neurotrophic factor (GDNF), as well as bridge molecules milk-fat-globule EGF-factor 8 (MFG-E8), thrombospondin (TSP)-1, and TSP-2 on phagocytosis were also examined in phagocytosis assays using isolated POS. RNA was isolated from normal and AMD RPE treated with hUTC conditioned media and subjected to transcriptome profiling by RNA-Seq and computational analyses. RESULTS: RPE phagocytosis, while showing a moderate decline with age, was significantly reduced in AMD RPE, more than expected for age. hUTC conditioned media stimulated phagocytosis in the normal human RPE and significantly rescued the phagocytic dysfunction in the AMD RPE. RTK ligands and bridge molecules duplicated the rescue effect. Moreover, multiple molecular pathways involving phagocytosis, apoptosis, oxidative stress, inflammation, immune activation, and cholesterol transport were affected by hUTC in the RPE. CONCLUSIONS: We demonstrated for the first time RPE phagocytic dysfunction in AMD, highlighting its likely importance in AMD, and the ability of hUTC to correct this dysfunction, providing insights into the therapeutic potential of hUTC for AMD. PMID- 29534723 TI - Plumbagin induces RPE cell cycle arrest and apoptosis via p38 MARK and PI3K/AKT/mTOR signaling pathways in PVR. AB - BACKGROUND: This study aimed to explore the effects of plumbagin (PLB) on ARPE-19 cells and underlying mechanism. METHODS: Cultured ARPE-19 cells were treated with various concentrations (0, 5, 15, and 25 MUM) of PLB for 24 h or with 15 MUM PLB for 12, 24 and 48 h. Then cell viability was evaluated by MTT assay and DAPI staining, while apoptosis and cell cycle progression of ARPE cells were assessed by flow cytometric analysis. Furthermore, the level of main regulatory proteins was examinated by Western boltting and the expression of relative mRNA was tested by Real-Time PCR. RESULTS: PLB exhibited potent inducing effects on cell cycle arrest at G2/M phase and apoptosis of ARPE cells via the modulation of Bcl-2 family regulators in a concentration- and time-dependent manner. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways contributing to the anti proliferative activities in ARPE cells. CONCLUSIONS: This is the first report to show that PLB could inhibit the proliferation of RPE cells through down regulation of modulatory signaling pathways. The results open new avenues for the use of PLB in prevention and treatment of proliferative vitreoretinopathy. PMID- 29534725 TI - Elevated whole muscle phosphatidylcholine: phosphatidylethanolamine ratio coincides with reduced SERCA activity in murine overloaded plantaris muscles. AB - BACKGROUND: An increase in phosphatidylcholine:phosphatidylethanolamine (PC:PE) and a decrease in fatty acyl chain length, monounsaturated:polyunsaturated (MUFA:PUFA) fatty acyl ratio reduces SERCA activity in liposomes and in mouse models of obesity and muscular dystrophy. We have previously shown that maximal SERCA activity is significantly reduced in mechanically overloaded (OVL) plantaris, however, whether changes in PC:PE ratio or fatty acyl composition may contribute to the alterations in maximal SERCA activity remain unknown. Here, we tested the hypotheses that in OVL plantaris 1) PC:PE ratio would negatively correlate with maximal SERCA activity and 2) PC fatty acyl chain length (ACL) and/or MUFA:PUFA ratio would positively correlate with maximal SERCA activity. METHODS: To overload plantaris in mice, we transected the soleus and gastrocnemius tendons from one leg, while the contralateral leg underwent a sham surgery. After two weeks, plantaris muscles were extracted, homogenized and processed for SERCA activity and lipid analyses. Specifically, we performed HPTLC densitometry to examine changes in PC, PE, and the ratio of PC:PE. We also performed gas chromatography to assess any potential changes to fatty acyl composition. RESULTS: SERCA activity was significantly reduced in OVL plantaris compared with sham. Coinciding with this, we found a significant increase in PC but not PE in OVL plantaris. In turn, there was an increase in PC:PE but did not reach significance (p = 0.09). However, we found a significant negative correlation between PC:PE and maximal SERCA activity. Fatty acyl composition of PE remained similar between OLV and sham and PC demonstrated higher percent mole fraction of 17:1, 18:1, and ACL compared to sham. In addition, PC ACL, % MUFA, % PUFA, or MUFA:PUFA did not significantly correlate with maximal SERCA activity. CONCLUSIONS: Our results indicate that the phospholipid headgroup PC:PE negatively correlated and could potentially contribute to reductions in SERCA activity seen in functionally overloaded plantaris. In contrast, fatty acyl chain (ACL, % MUFA, % PUFA, MUFA:PUFA) did not correlate with maximal SERCA activity. Future studies will determine whether altering PC:PE with genetic and dietary interventions can influence SERCA activity and ultimately change the physiological outcome in response to muscle overloading. PMID- 29534724 TI - Association of Circulating Transfer RNA fragments with antibody response to Mycoplasma bovis in beef cattle. AB - BACKGROUND: High throughput sequencing allows identification of small non-coding RNAs. Transfer RNA Fragments are a class of small non-coding RNAs, and have been identified as being involved in inhibition of gene expression. Given their role, it is possible they may be involved in mediating the infection-induced defense response in the host. Therefore, the objective of this study was to identify 5' transfer RNA fragments (tRF5s) associated with a serum antibody response to M. bovis in beef cattle. RESULTS: The tRF5s encoding alanine, glutamic acid, glycine, lysine, proline, selenocysteine, threonine, and valine were associated (P < 0.05) with antibody response against M. bovis. tRF5s encoding alanine, glutamine, glutamic acid, glycine, histidine, lysine, proline, selenocysteine, threonine, and valine were associated (P < 0.05) with season, which could be attributed to calf growth. There were interactions (P < 0.05) between antibody response to M. bovis and season for tRF5 encoding selenocysteine (anticodon UGA), proline (anticodon CGG), and glutamine (anticodon TTG). Selenocysteine is a rarely used amino acid that is incorporated into proteins by the opal stop codon (UGA), and its function is not well understood. CONCLUSIONS: Differential expression of tRF5s was identified between ELISA-positive and negative animals. Production of tRF5s may be associated with a host defense mechanism triggered by bacterial infection, or it may provide some advantage to a pathogen during infection of a host. Further studies are needed to establish if tRF5s could be used as a diagnostic marker of chronic exposure. PMID- 29534726 TI - Validation of the adapted Leeds sleep evaluation questionnaire in Ethiopian university students. AB - BACKGROUND: Current evidence supports the applicability of the Leeds Sleep Evaluation Questionnaire (LSEQ) in screening for insomnia. The psychometric properties of the LSEQ have never been investigated in an African population. Therefore, this study aimed to validate the adapted version of the LSEQ-Mizan (LSEQ-M) in Ethiopian university students. METHODS: Of a preliminary sample of 750 (random sampling), 424 students (age = 21.87 +/- 4.13 years and body mass index = 20.84 +/- 3.18 kg/m2) from Mizan-Tepi University, Mizan-Aman, South-west Ethiopia completed the LSEQ-M, the General Anxiety Disorder Scale-7 and a semi structured questionnaire for socio-demographics. Insomnia was screened in accordance with the International Classification of Sleep Disorders as a measure of concurrent validity. RESULTS: Although, individual items showed ceiling and floor effect, the LSEQ-M as a scale did not have these effects. Good internal consistency (Cronbach's alpha of 0.84) and strong internal homogeneity as measured by the correlation coefficient between items scores and the LSEQ-M global score was found. The LSEQ-M showed excellent screening applicability for insomnia with optimal cut-off scores of 52.6 (sensitivity 94%, specificity 80%), and the area under the curve, 0.95 (p < 0.0001). The original 4-Factor model was valid in Ethiopian university students for screening for insomnia. CONCLUSION: The LSEQ-M has excellent psychometric validity in screening for insomnia among Ethiopian university students. PMID- 29534727 TI - Safety studies with the oral rabies virus vaccine strain SPBN GASGAS in the small Indian mongoose (Herpestes auropunctatus). AB - BACKGROUND: Oral vaccination of the small Indian mongoose against rabies has been suggested as a potential tool to eliminate mongoose-mediated rabies on several Caribbean islands. A recently developed oral rabies virus vaccine strain, SPBN GASGAS, has already been shown to be efficacious in this reservoir species. Since, all available oral rabies vaccines are based on replication-competent viruses and vaccine baits are distributed unsupervised in the environment, enhanced safety standards for such vaccine types are required. RESULTS: The results of safety studies, including overdose, repeated doses, dissemination and different routes of administration, in the target species are presented. It was shown that the construct was apathogenic, irrespective of dose and route of administration. Even when it was inoculated directly in the brain, it did not induce rabies infection. Furthermore, the vaccine strain did not spread within the target species after direct oral instillation beyond the site of entry. CONCLUSION: The vaccine strain SPBN GASGAS meets the safety requirements for live rabies virus vaccines in this target species, the small Indian mongoose. PMID- 29534728 TI - Long non-coding RNA MIAT in development and disease: a new player in an old game. AB - BACKGROUND: Long non-coding RNAs (lncRNAs), which are a portion of non-protein coding RNAs (ncRNAs), have manifested a paramount role in the pathophysiology of human diseases, particularly in pathogenesis and progression of disease. Myocardial infarction associated transcript (MIAT), which was recently found to demonstrate aberrant expression in various diseases, such as myocardial infarction, schizophrenia, ischemic stroke, diabetic complications, age-related cataract and cancers, is a novel disease-related lncRNA. This work summarize current evidence regarding the biological functions and underlying mechanisms of lncRNA MIAT during disease development. SHORT CONCLUSION: LncRNA MIAT likely represents a feasible cancer biomarker or therapeutic target. PMID- 29534729 TI - Qualitative approaches to use of the RE-AIM framework: rationale and methods. AB - BACKGROUND: There have been over 430 publications using the RE-AIM model for planning and evaluation of health programs and policies, as well as numerous applications of the model in grant proposals and national programs. Full use of the model includes use of qualitative methods to understand why and how results were obtained on different RE-AIM dimensions, however, recent reviews have revealed that qualitative methods have been used infrequently. Having quantitative and qualitative methods and results iteratively inform each other should enhance understanding and lessons learned. METHODS: Because there have been few published examples of qualitative approaches and methods using RE-AIM for planning or assessment and no guidance on how qualitative approaches can inform these processes, we provide guidance on qualitative methods to address the RE-AIM model and its various dimensions. The intended audience is researchers interested in applying RE-AIM or similar implementation models, but the methods discussed should also be relevant to those in community or clinical settings. RESULTS: We present directions for, examples of, and guidance on how qualitative methods can be used to address each of the five RE-AIM dimensions. Formative qualitative methods can be helpful in planning interventions and designing for dissemination. Summative qualitative methods are useful when used in an iterative, mixed methods approach for understanding how and why different patterns of results occur. CONCLUSIONS: In summary, qualitative and mixed methods approaches to RE-AIM help understand complex situations and results, why and how outcomes were obtained, and contextual factors not easily assessed using quantitative measures. PMID- 29534730 TI - Development of VariLeg, an exoskeleton with variable stiffness actuation: first results and user evaluation from the CYBATHLON 2016. AB - BACKGROUND: Powered exoskeletons are a promising approach to restore the ability to walk after spinal cord injury (SCI). However, current exoskeletons remain limited in their walking speed and ability to support tasks of daily living, such as stair climbing or overcoming ramps. Moreover, training progress for such advanced mobility tasks is rarely reported in literature. The work presented here aims to demonstrate the basic functionality of the VariLeg exoskeleton and its ability to enable people with motor complete SCI to perform mobility tasks of daily life. METHODS: VariLeg is a novel powered lower limb exoskeleton that enables adjustments to the compliance in the leg, with the objective of improving the robustness of walking on uneven terrain. This is achieved by an actuation system with variable mechanical stiffness in the knee joint, which was validated through test bench experiments. The feasibility and usability of the exoskeleton was tested with two paraplegic users with motor complete thoracic lesions at Th4 and Th12. The users trained three times a week, in 60 min sessions over four months with the aim of participating in the CYBATHLON 2016 competition, which served as a field test for the usability of the exoskeleton. The progress on basic walking skills and on advanced mobility tasks such as incline walking and stair climbing is reported. Within this first study, the exoskeleton was used with a constant knee stiffness. RESULTS: Test bench evaluation of the variable stiffness actuation system demonstrate that the stiffness could be rendered with an error lower than 30 Nm/rad. During training with the exoskeleton, both users acquired proficient skills in basic balancing, walking and slalom walking. In advanced mobility tasks, such as climbing ramps and stairs, only basic (needing support) to intermediate (able to perform task independently in 25% of the attempts) skill levels were achieved. After 4 months of training, one user competed at the CYBATHLON 2016 and was able to perform 3 (stand-sit-stand, slalom and tilted path) out of 6 obstacles of the track. No adverse events occurred during the training or the competition. CONCLUSION: Demonstration of the applicability to restore ambulation for people with motor complete SCI was achieved. The CYBATHLON highlighted the importance of training and gaining experience in piloting an exoskeleton, which were just as important as the technical realization of the robot. PMID- 29534731 TI - Adaptation and post-adaptation effects of haptic forces on locomotion in healthy young adults. AB - BACKGROUND: Developing rehabilitation strategies to improve functional walking and postural control in patients is a priority for rehabilitation clinicians and researchers alike. One possible strategy is the use of sensory modalities to elicit adaptive locomotor gait patterns. This study aimed to explore to what extent haptic inputs, in the form of forward-leading tensile forces delivered to the hand, compared to no force, may lead to adaptation and post-adaptation effects on gait parameters, during and after the haptic exposure, respectively. METHODS: Thirteen healthy young individuals were recruited for this study. We developed an innovative system combining virtual reality and haptic tensile forces in the direction of locomotion to simulate walking with a dog. A robotic arm generated forces via an adapted leash to the participant's hand while they walked on a self-paced treadmill immersed in a virtual environment with scene progression synchronized to the treadmill. RESULTS: All participants showed significant increases in instantaneous gait velocity and stride length, with accompanying decreases in double-limb support time (p < 0.05) when walking with a haptic tensile force of either 10 or 20 N, relative to pre-force epoch levels, indicating an adaptation effect. When the 10 or 20 N force was removed, gait measures generally remained changed relative to baseline pre-force levels (p < 0.05), providing evidence of a post-adaptation effect. CONCLUSIONS: Changes in spatiotemporal outcomes provide evidence that both adaptation and post-adaptation effects were present in response to the application and removal of a haptic force. Future studies will investigate whether similar changes in elderly and post-stroke populations can be actualized during steady-state walking. PMID- 29534732 TI - Bedside ultrasound to detect central venous catheter misplacement and associated iatrogenic complications: a systematic review and meta-analysis. AB - BACKGROUND: Insertion of a central venous catheter (CVC) is common practice in critical care medicine. Complications arising from CVC placement are mostly due to a pneumothorax or malposition. Correct position is currently confirmed by chest x-ray, while ultrasonography might be a more suitable option. We performed a meta-analysis of the available studies with the primary aim of synthesizing information regarding detection of CVC-related complications and misplacement using ultrasound (US). METHODS: This is a systematic review and meta-analysis registered at PROSPERO (CRD42016050698). PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched. Articles which reported the diagnostic accuracy of US in detecting the position of CVCs and the mechanical complications associated with insertion were included. Primary outcomes were specificity and sensitivity of US. Secondary outcomes included prevalence of malposition and pneumothorax, feasibility of US examination, and time to perform and interpret both US and chest x-ray. A qualitative assessment was performed using the QUADAS-2 tool. RESULTS: We included 25 studies with a total of 2548 patients and 2602 CVC placements. Analysis yielded a pooled specificity of 98.9 (95% confidence interval (CI): 97.8 99.5) and sensitivity of 68.2 (95% CI: 54.4-79.4). US examination was feasible in 96.8% of the cases. The prevalence of CVC malposition and pneumothorax was 6.8% and 1.1%, respectively. The mean time for US performance was 2.83 min (95% CI: 2.77-2.89 min) min, while chest x-ray performance took 34.7 min (95% CI: 32.6 36.7 min). US was feasible in 97%. Further analyses were performed by defining subgroups based on the different utilized US protocols and on intra-atrial and extra-atrial misplacement. Vascular US combined with transthoracic echocardiography was most accurate. CONCLUSIONS: US is an accurate and feasible diagnostic modality to detect CVC malposition and iatrogenic pneumothorax. Advantages of US over chest x-ray are that it can be performed faster and does not subject patients to radiation. Vascular US combined with transthoracic echocardiography is advised. However, the results need to be interpreted with caution since included studies were often underpowered and had methodological limitations. A large multicenter study investigating optimal US protocol, among other things, is needed. PMID- 29534733 TI - Targeting NMDA receptors in stroke: new hope in neuroprotection. AB - NMDA (N-methyl-d-aspartate) receptors (NMDARs) play a central role in excitotoxic neuronal death caused by ischemic stroke, but NMDAR channel blockers have failed to be translated into clinical stroke treatments. However, recent research on NMDAR-associated signaling complexes has identified important death-signaling pathways linked to NMDARs. This led to the generation of inhibitors that inhibit these pathways downstream from the receptor without necessarily blocking NMDARs. This therapeutic approach may have fewer side effects and/or provide a wider therapeutic window for stroke as compared to the receptor antagonists. In this review, we highlight the key findings in the signaling cascades downstream of NMDARs and the novel promising therapeutics for ischemic stroke. PMID- 29534735 TI - How do people with mood and anxiety disorders perceive and interpret the Drinking Motives Questionnaire? A think-aloud study in a clinical setting. AB - BACKGROUND: Research has identified drinking motives as the final common pathway to alcohol use, and associations between specific drinking motives and drinking patterns have consistently been demonstrated. Data on drinking motives can be used for research, in the planning of prevention strategies and for treatment purposes. The Drinking Motives Questionnaire-Revised (DMQ-R) has become the most used measure of drinking motives. So far, the questionnaire has not been investigated with qualitative methods. The aim of this study was to investigate acceptability, accuracy and usability of the DMQ-R among persons receiving outpatient psychiatric care by studying how responders perceive and interpret the questionnaire. METHOD: A cognitive interviewing technique, the think-aloud method, was used to collect data from 16 non-alcohol dependent patients seeking outpatient psychiatric care (12 women, 4 men). To analyse data, Qualitative Content Analysis was applied in which themes were formed from data only and not from predetermined areas of interest. RESULTS: Overall, acceptability of the DMQ R was high although answers were sometimes given with low accuracy. Responders pointed out that they perceived the questionnaire as non-confrontational and exhaustive. Further, the DMQ-R seemed to launch processes of self-reflection. CONCLUSIONS: Taken together, the results suggest a support for the use of DMQ-R also in the group of psychiatric outpatients. Still, when interpreting the DMQ-R, a certain insecurity of the exactness of answers should be considered. The graphic design should be particularly clear in this group of patients. PMID- 29534734 TI - Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic ischemic brain damage. AB - Our previous studies demonstrated that vitamin A deficiency (VAD) can impair the postnatal cognitive function of rats by damaging the hippocampus. The present study examined the effects of retinoic acid (RA) on apoptosis induced by hypoxic ischemic damage in vivo and in vitro, and investigated the possible signaling pathway involved in the neuroprotective anti-apoptotic effects of RA. Flow cytometry, immunofluorescence staining and behavioral tests were used to evaluate the neuroprotective and anti-apoptotic effects of RA. The protein and mRNA levels of RARalpha, PI3K, Akt, Bad, caspase-3, caspase-8, Bcl-2, Bax, and Bid were measured with western blotting and real-time PCR, respectively. We found impairments in learning and spatial memory in VAD group compared with vitamin A normal (VAN) and vitamin A supplemented (VAS) group. Additionally, we showed that hippocampal apoptosis was weaker in the VAN group than that in VAD group. Relative to the VAD group, the VAN group also had increased mRNA and protein levels of RARalpha and PI3K, and upregulated phosphorylated Akt/Bad levels in vivo. In vitro, excessively low or high RA signaling promoted apoptosis. Furthermore, the effects on apoptosis involved the mitochondrial membrane potential (MMP). These data support the idea that sustained VAD following hypoxic ischemic brain damage (HIBD) inhibits RARalpha, which downregulates the PI3K/Akt/Bad and Bcl-2/Bax pathways and upregulates the caspase-8/Bid pathway to influence the MMP, ultimately producing deficits in learning and spatial memory in adolescence. This suggests that clinical interventions for HIBD should include suitable doses of VA. PMID- 29534736 TI - Prime-boost vaccination targeting prostatic acid phosphatase (PAP) in patients with metastatic castration-resistant prostate cancer (mCRPC) using Sipuleucel-T and a DNA vaccine. AB - BACKGROUND: Prostatic acid phosphatase (PAP) is a prostate tumor antigen, and the target of the only FDA-approved anti-tumor vaccine, sipuleucel-T. We have previously reported in two clinical trials that a DNA vaccine encoding PAP (pTVG HP) could elicit PAP-specific, Th1-biased T cells in patients with PSA-recurrent prostate cancer. In the current pilot trial we sought to evaluate whether this vaccine could augment PAP-specific immunity when used as a booster to immunization with sipuleucel-T in patients with metastatic, castration-resistant prostate cancer (mCRPC). METHODS: Eigthteen patients with mCRPC were randomized to receive sipuleucel-T alone or followed by intradermal immunization with pTVG HP DNA vaccine. Patients were followed for time to progression, and immune monitoring was conducted at defined intervals. RESULTS: Overall, patients were followed for a median of 24 months. 11/18 patients completed treatments as per protocol. No treatment-associated events > grade 2 were observed. Th1-biased PAP specific T-cell responses were detected in 11/18 individuals, and were not statistically different between study arms. Higher titer antibody responses to PAP were detectable in patients who received pTVG-HP booster immunizations. Median time to progression was less than 6 months and not statistically different between study arms. The median overall survival for all patients was 28 months. CONCLUSIONS: These findings suggest that prime-boost vaccination can augment and diversify the type of immunity elicited with anti-tumor vaccination in terms of T cell and humoral immunity. Future studies will explore DNA as priming immunization rather than a booster immunization. TRIAL REGISTRATION: NCT01706458 . PMID- 29534737 TI - Variables influencing wearable sensor outcome estimates in individuals with stroke and incomplete spinal cord injury: a pilot investigation validating two research grade sensors. AB - BACKGROUND: Monitoring physical activity and leveraging wearable sensor technologies to facilitate active living in individuals with neurological impairment has been shown to yield benefits in terms of health and quality of living. In this context, accurate measurement of physical activity estimates from these sensors are vital. However, wearable sensor manufacturers generally only provide standard proprietary algorithms based off of healthy individuals to estimate physical activity metrics which may lead to inaccurate estimates in population with neurological impairment like stroke and incomplete spinal cord injury (iSCI). The main objective of this cross-sectional investigation was to evaluate the validity of physical activity estimates provided by standard proprietary algorithms for individuals with stroke and iSCI. Two research grade wearable sensors used in clinical settings were chosen and the outcome metrics estimated using standard proprietary algorithms were validated against designated golden standard measures (Cosmed K4B2 for energy expenditure and metabolic equivalent and manual tallying for step counts). The influence of sensor location, sensor type and activity characteristics were also studied. METHODS: 28 participants (Healthy (n = 10); incomplete SCI (n = 8); stroke (n = 10)) performed a spectrum of activities in a laboratory setting using two wearable sensors (ActiGraph and Metria-IH1) at different body locations. Manufacturer provided standard proprietary algorithms estimated the step count, energy expenditure (EE) and metabolic equivalent (MET). These estimates were compared with the estimates from gold standard measures. For verifying validity, a series of Kruskal Wallis ANOVA tests (Games-Howell multiple comparison for post-hoc analyses) were conducted to compare the mean rank and absolute agreement of outcome metrics estimated by each of the devices in comparison with the designated gold standard measurements. RESULTS: The sensor type, sensor location, activity characteristics and the population specific condition influences the validity of estimation of physical activity metrics using standard proprietary algorithms. CONCLUSIONS: Implementing population specific customized algorithms accounting for the influences of sensor location, type and activity characteristics for estimating physical activity metrics in individuals with stroke and iSCI could be beneficial. PMID- 29534738 TI - Assessment of performance of the Gail model for predicting breast cancer risk: a systematic review and meta-analysis with trial sequential analysis. AB - BACKGROUND: The Gail model has been widely used and validated with conflicting results. The current study aims to evaluate the performance of different versions of the Gail model by means of systematic review and meta-analysis with trial sequential analysis (TSA). METHODS: Three systematic review and meta-analyses were conducted. Pooled expected-to-observed (E/O) ratio and pooled area under the curve (AUC) were calculated using the DerSimonian and Laird random-effects model. Pooled sensitivity, specificity and diagnostic odds ratio were evaluated by bivariate mixed-effects model. TSA was also conducted to determine whether the evidence was sufficient and conclusive. RESULTS: Gail model 1 accurately predicted breast cancer risk in American women (pooled E/O = 1.03; 95% CI 0.76 1.40). The pooled E/O ratios of Caucasian-American Gail model 2 in American, European and Asian women were 0.98 (95% CI 0.91-1.06), 1.07 (95% CI 0.66-1.74) and 2.29 (95% CI 1.95-2.68), respectively. Additionally, Asian-American Gail model 2 overestimated the risk for Asian women about two times (pooled E/O = 1.82; 95% CI 1.31-2.51). TSA showed that evidence in Asian women was sufficient; nonetheless, the results in American and European women need further verification. The pooled AUCs for Gail model 1 in American and European women and Asian females were 0.55 (95% CI 0.53-0.56) and 0.75 (95% CI 0.63-0.88), respectively, and the pooled AUCs of Caucasian-American Gail model 2 for American, Asian and European females were 0.61 (95% CI 0.59-0.63), 0.55 (95% CI 0.52-0.58) and 0.58 (95% CI 0.55-0.62), respectively. The pooled sensitivity, specificity and diagnostic odds ratio of Gail model 1 were 0.63 (95% CI 0.27 0.89), 0.91 (95% CI 0.87-0.94) and 17.38 (95% CI 2.66-113.70), respectively, and the corresponding indexes of Gail model 2 were 0.35 (95% CI 0.17-0.59), 0.86 (95% CI 0.76-0.92) and 3.38 (95% CI 1.40-8.17), respectively. CONCLUSIONS: The Gail model was more accurate in predicting the incidence of breast cancer in American and European females, while far less useful for individual-level risk prediction. Moreover, the Gail model may overestimate the risk in Asian women and the results were further validated by TSA, which is an addition to the three previous systematic review and meta-analyses. TRIAL REGISTRATION: PROSPERO CRD42016047215 . PMID- 29534739 TI - Comparison of two different combined test strips with fluorescent microspheres or colored microspheres as tracers for rotavirus and adenovirus detection. AB - BACKGROUND: Rotavirus (RV) and enteric adenovirus (AdV) mainly cause infantile infectious gastroenteritis. Several separate test methods for the detection of RV or AdV are currently available, but few tests are able to simultaneously detect both RV and AdV viruses, especially in primary medical institutions. METHODS: The present study was mainly designed to compare the performance of two combined test strips for the detection of RV and AdV: a rotavirus-adenovirus strip with fluorescent microspheres for tracers (FMT); and the CerTest rotavirus-adenovirus blister strip with colored microspheres for tracers (CMT). To test the strips cultures of RV, AdV and from other enteric pathogens were used, in addition to 350 stool specimens from 45 symptomatic patients with gastrointestinal infections. RESULTS: Detection thresholds for RV and AdV cultures using serial dilutions showed that the sensitivity of FMT was significantly higher than that of CMT (both P < 0.05). Specificity evaluation demonstrated that with culture mixtures of Coxsackie (A16), ECHO (type30), and entero- (EV71) viruses there was no detection of cross reaction using the two test strips, i.e., all the results were negative. With regard to the detection of RV in 350 clinical specimens, the total coincidence rate was 92.9%, the positive coincidence rate was 98.2%, and the negative coincidence rate was 90.8%. With regard to AdV detection, the total coincidence rate was 95.4%, the positive coincidence rate was 95.2%, and the negative coincidence rate was 95.5%. CONCLUSIONS: FMT performed better than CMT with regard to the combined detection of RV and AdV. PMID- 29534740 TI - Biomphalaria camerunensis as a viable alternative intermediate host for Schistosoma mansoni in southern Cameroon. AB - BACKGROUND: Intestinal schistosomiasis due to Schistosoma mansoni was mapped in Cameroon in the 1990s and preventive chemotherapy launched since 2005. A situation analysis conducted in 2011 revealed an increase in schistosomiasis transmission, especially in the equatorial part of the country, despite the fact that Biomphalaria pfeifferi, the main intermediate host of this parasite, is now scarce in many foci. Biomphalaria camerunensis, restricted to the equatorial part of the country, is considered as a less suitable host for S. mansoni due to it resistance to the parasite, although exhibiting a better survival than B. pfeifferi. In a context where human migration is quite frequent as a consequence of terrorism, war in neighboring countries, as well as development of hydraulic projects, it seems appropriate to evaluate the current epidemiological role of B. camerunensis to estimate the risk of extension of S. mansoni distribution in Cameroon. To do this, the susceptibility of three B. pfeifferi and five B. camerunensis populations to a strain of S. mansoni was assessed. Juvenile snails (G1) of each population were infected with S. mansoni miracidia, and prepatent period, infection and survival rates of infected snails, as well as cercarial production were recorded and compared between snail species and populations. RESULTS: Compatibility tests were performed on a total of 827 snails: 344 B. pfeifferi and 483 B. camerunensis. Infection rates were quite heterogeneous, higher in B. pfeifferi (61.5%) as compared to B. camerunensis (7.8%) (Chi-square test: chi2 = 258.88, df = 1, P < 0.0001). All the three B. pfeifferi-infected populations were susceptible to S. mansoni. However, among the five B. camerunensis populations tested, four were susceptible to S. mansoni, with 21.9% as the highest infection rate. The prepatent period was, on average, shorter in B. pfeifferi than in B. camerunensis (P < 0.0001), but the cercarial production was significantly higher in B. camerunensis as compared to B. pfeifferi (P < 0.001). CONCLUSION: These findings indicate that B. camerunensis populations might substantially contribute to S. mansoni transmission and dissemination in Cameroon, their low susceptibility being compensated by their high cercariae production. More attention and surveillance towards this species are required to achieve intestinal schistosomiasis elimination in Cameroon. PMID- 29534741 TI - A comprehensive mental health care program for women with polycystic ovary syndrome: protocol for a mixed methods study. AB - BACKGROUND: Psychological health is related to the management of polycystic ovary syndrome (PCOS) and is an essential component of self-efficacy and enjoying a healthy lifestyle. Need assessment and plans to improve the psychological health of these women provides significantly valuable information to design an advantageous intervention program to reach that goal. Therefore, this study will conduct to improve the psychological health for women with PCOS through a designed comprehensive care. METHODS: This is an exploratory mixed method study using consecutive qualitative-quantitative methods, including three consecutive phases. In the first phase, a qualitative study will be conducted to assess their needs and will design a care protocol for improving mental health of women with PCOS. Participants in this phase will select by purposive sampling method and data will collect using semi-structured interviews by taking notes at same time. Data will analyze using conventional content analysis method. At second phase, according the information obtained from previous phase and a literature review a comprehensive program to mental health care will be proposed. Then multidisciplinary team will review and finalize it according to priorities. The third phase will follow a quantitative approach using quasi-experimental study with two groups to measure the effectiveness of this program on the women's psychological health. DISCUSSION: Designing a program based on a qualitative study and a review article and updated evidences can lead to improving of these women's psychological health and quality of life. Consequently, we expect to show that mental health program provided by a multidisciplinary team improves reproductive outcomes while at the same time being cost-effective in women with PCOS. PMID- 29534742 TI - The efficacy and safety of pre-hospital cooling after out-of-hospital cardiac arrest: a systematic review and meta-analysis. AB - BACKGROUND: Mild therapeutic hypothermia (TH), or targeted temperature management, improves survival and neurological outcomes in patients after out-of hospital cardiac arrest (OHCA). International guidelines strongly support initiating TH for all eligible individuals presenting with OHCA; however, the timing of cooling initiation remains uncertain. This systematic review and meta analysis was conducted with all available randomised controlled trials (RCTs) included to explore the efficacy and safety of initiating pre-hospital TH in patients with OHCA. METHODS: The MEDLINE and Cochrane databases were searched from inception to October 2017. Inclusion criteria for full-text review included RCTs comparing pre-hospital TH with no pre-hospital TH after cardiac arrest, patients > 14 years of age with documented cardiac arrest from any rhythm, and outcome data that included survival to hospital discharge and temperature at hospital arrival. Results of retrieved studies were compared through meta analysis using random effects modelling. RESULTS: A total of 10 trials comprising 4220 patients were included. There were no significant differences between the two arms for the primary outcome of neurological recovery (risk ratio [RR] 1.04, 95% CI 0.93-1.15) or the secondary outcome of survival to hospital discharge (RR 1.01, 95% CI 0.92-1.11). However, there was a significantly lower temperature at hospital arrival in patients receiving pre-hospital TH (mean difference - 0.83, 95% CI - 1.03 to - 0.63). Pre-hospital TH significantly increased the risk of re arrest (RR 1.19, 95% CI 1.00 to 1.41). No survival differences were observed among subgroups of patients who received intra-arrest TH vs post-arrest TH or who had shockable vs non-shockable rhythms. CONCLUSIONS: Pre-hospital TH after OHCA effectively decreases body temperature at the time of hospital arrival. However, it does not improve rates of survival with good neurological outcome or overall survival and is associated with increased rates of re-arrest. PMID- 29534743 TI - UGT1A1 gene and neonatal hyperbilirubinemia: a preliminary study from Bengkulu, Indonesia. AB - OBJECTIVE: The genetic involvement in unconjugated neonatal hyperbilirubinemia has been extensively studied. Despite the high incidence of hyperbilirubinemia in Indonesia, studies are lacking. The objective of this study is to elucidate the role of polymorphism in the UGT1A1 in Neonatal Hyperbilirubinemia in Bengkulu, Indonesia. RESULTS: There were 41 neonates enrolled in the study; 30 had a total serum bilirubin level >= 15 mg/dL (hyperbilirubinemia neonates) while 11 has < 15 mg/dL (control neonates). Genetic mutations in Exon 1, UGT1A1*6 (c211g > a) and one in promoter region, UGT1A1*60 (c3279t > g) were determined by polymerase chain reaction-restriction fragment length polymorphism. We found 18 (60%) mutation in exon 1 in hyperbilirubinemia group and 7 (64%) in the control group with an identical allele frequency of 0.3 in both groups. We found heterozygous UGT1A1*60 4 times (13.3%) and homozygous 26 times (86.7%) in the hyperbilirubinemia group, with an identical allele frequency of 0.935 in hyperbilirubinemia and 1 in control group. This study supports the involvement of genetic factors in the development of unconjugated hyperbilirubinemia in Bengkulu population. PMID- 29534744 TI - Impact of nighttime Rapid Response Team activation on outcomes of hospitalized patients with acute deterioration. AB - BACKGROUND: Rapid Response Teams (RRTs) are groups of healthcare providers that are used by many hospitals to respond to acutely deteriorating patients admitted to the wards. We sought to identify outcomes of patients assessed by RRTs outside standard working hours. METHODS: We used a prospectively collected registry from two hospitals within a single tertiary care-level hospital system between May 1, 2012, and May 31, 2016. Patient information, outcomes, and RRT activation information were stored in the hospital data warehouse. Comparisons were made between RRT activation during daytime hours (0800-1659) and nighttime hours (1700 0759). The primary outcome was in-hospital mortality, analyzed using a multivariable logistic regression model. RESULTS: A total of 6023 RRT activations on discrete patients were analyzed, 3367 (55.9%) of which occurred during nighttime hours. Nighttime RRT activation was associated with increased odds of mortality, as compared with daytime RRT activation (adjusted OR 1.34, 95% CI 1.26 1.40, P = 0.02). The time periods associated with the highest odds of mortality were 0600-0700 (adjusted OR 1.30, 95% CI 1.09-1.61) and 2300-2400 (adjusted OR 1.34, 95% CI 1.01-1.56). Daytime RRT activation was associated with increased odds of intensive care unit admission (adjusted OR 1.40, 95% CI 1.31-1.50, P = 0.02). Time from onset of concerning symptoms to RRT activation was shorter among patients assessed during daytime hours (P < 0.001). CONCLUSIONS: Acutely deteriorating ward patients assessed by an RRT at nighttime had a higher risk of in-hospital mortality. This work identifies important shortcomings in health service provision and quality of care outside daytime hours, highlighting an opportunity for quality improvement. PMID- 29534745 TI - Mixed-method analysis of program leader perspectives on the sustainment of multiple child evidence-based practices in a system-driven implementation. AB - BACKGROUND: Understanding program leader perspectives on the sustainment of evidence-based practice (EBP) in community mental health settings is essential to improving implementation. To date, however, much of the literature has focused on direct service provider perspectives on EBP implementation. The aim of this mixed method study was to identify factors associated with the sustainment of multiple EBPs within a system-driven implementation effort in children's mental health services. METHODS: Data were gathered from 186 leaders at 59 agencies within the Los Angeles County Department of Mental Health who were contracted to deliver one of six EBPs within the Prevention and Early Intervention initiative. RESULTS: Multi-level analyses of quantitative survey data (N = 186) revealed a greater probability of leader-reported EBP sustainment in large agencies and when leaders held more positive perceptions toward the EBP. Themes from semi-structured qualitative interviews conducted with a subset of survey participants (n = 47) expanded quantitative findings by providing detail on facilitating conditions in larger agencies and aspects of EBP fit that were perceived to lead to greater sustainment, including perceived fit with client needs, implementation requirements, aspects of the organizational workforce, availability of trainings, and overall therapist attitudes about EBPs. CONCLUSIONS: Findings inform EBP implementation efforts regarding decisions around organizational-level supports and promotion of EBP fit. PMID- 29534746 TI - Left centro-parieto-temporal response to tool-gesture incongruity: an ERP study. AB - BACKGROUND: Action semantics have been investigated in relation to context violation but remain less examined in relation to the meaning of gestures. In the present study, we examined tool-gesture incongruity by event-related potentials (ERPs) and hypothesized that the component N400, a neural index which has been widely used in both linguistic and action semantic congruence, is significant for conditions of incongruence. METHODS: Twenty participants performed a tool-gesture judgment task, in which they were asked to judge whether the tool-gesture pairs were correct or incorrect, for the purpose of conveying functional expression of the tools. Online electroencephalograms and behavioral performances (the accuracy rate and reaction time) were recorded. RESULTS: The ERP analysis showed a left centro-parieto-temporal N300 effect (220-360 ms) for the correct condition. However, the expected N400 (400-550 ms) could not be differentiated between correct/incorrect conditions. After 700 ms, a prominent late negative complex for the correct condition was also found in the left centro-parieto-temporal area. CONCLUSIONS: The neurophysiological findings indicated that the left centro parieto-temporal area is the predominant region contributing to neural processing for tool-gesture incongruity in right-handers. The temporal dynamics of tool gesture incongruity are: (1) firstly enhanced for recognizable tool-gesture using patterns, (2) and require a secondary reanalysis for further examination of the highly complicated visual structures of gestures and tools. The evidence from the tool-gesture incongruity indicated altered brain activities attributable to the N400 in relation to lexical and action semantics. The online interaction between gesture and tool processing provided minimal context violation or anticipation effect, which may explain the missing N400. PMID- 29534747 TI - Composition of sand fly fauna (Diptera: Psychodidae) and detection of Leishmania DNA (Kinetoplastida: Trypanosomatidae) in different ecotopes from a rural settlement in the central Amazon, Brazil. AB - BACKGROUND: Phlebotomine sand flies (Diptera: Psychodidae) are vectors of Leishmania species, the etiological agents of leishmaniasis, which is one of the most important emerging infectious diseases in the Americas. In the state of Amazonas in Brazil, anthropogenic activities encourage the presence of these insects around rural homes. The present study aimed to describe the composition and distribution of sand fly species diversity among the ecotopes (intradomicile, peridomicile and forest) in an area of American cutaneous leishmaniasis transmission and detect natural infection with Leishmania DNA to evaluate which vectors are inside houses and whether the presence of possible vectors represents a hazard of transmission. RESULTS: Phlebotomine sand flies were collected using light traps. A total of 2469 specimens representing 54 species, predominantly females (71.2%), were collected from four sites. Polymerase chain reaction analysis was performed on 670 samples to detect Leishmania DNA. Most of the samples (79.5%) were collected in the forest, with areas closer to rural dwellings yielding a greater abundance of suspected or proven vectors and a larger number of species containing Leishmania DNA. Nyssomyia umbratilis and Bichromomyia flaviscutellata were found near rural homes, and Ny. umbratilis was also found inside homes. Leishmania DNA was detected in different species of sand flies in all ecotopes, including species with no previous record of natural infection. CONCLUSIONS: There is no evidence that vectors of American cutaneous leishmaniasis are becoming established inside homes, but there are sand flies, including Ny. umbratilis and other possible vectors, in environments characterized by a human presence. These species continue to be predominant in the forest but are prevalent in areas closer to ecotopes with a greater human presence. The existence of proven or suspected vectors in this ecotope is due to the structural organization of rural settlements and may represent a hazard of transmission. Although the detection of Leishmania DNA in species that were not previously considered vectors does not mean that they are transmitting the parasite, it does show that the parasite is circulating in ecotopes where these species are found. PMID- 29534748 TI - Piscine orthoreovirus infection in Atlantic salmon (Salmo salar) protects against subsequent challenge with infectious hematopoietic necrosis virus (IHNV). AB - Infectious hematopoietic necrosis virus (IHNV) is endemic in farmed rainbow trout in continental Europe and in various salmonid fish species at the Pacific coast of North America. IHN has never occurred in European Atlantic salmon (Salmo salar) farms, but is considered as a major threat for the European salmon industry. Another virus, Piscine orthoreovirus (PRV), is widespread in the sea phase of Atlantic salmon, and is identified as the causative agent of heart and skeletal muscle inflammation. The aim of this study was to investigate the interactions between a primary PRV infection and a secondary IHNV infection under experimental conditions. A PRV cohabitation challenge was performed with Atlantic salmon. At peak of PRV viremia the fish were challenged by immersion with an IHNV genogroup E isolate. Clinical signs and morbidity were monitored. Target organs were sampled at selected time points to assess viral loads of both pathogens. Antiviral immune response and presence of histopathological findings were also investigated. Whereas the PRV-negative/IHNV positive group suffered significant decrease in survival caused by IHNV, the PRV infected groups did not suffer any morbidity and showed negligible levels of IHNV infection. Antiviral response genes were induced, as measured in spleen samples, from PRV infected fish prior to IHNV challenge. In conclusion, PRV-infection protects Atlantic salmon against IHNV infection and morbidity, most likely by inducing a protective innate antiviral response. PMID- 29534749 TI - Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. AB - Developing drugs that target KRAS, the most frequently mutated oncogene in cancer, has not been successful despite much concerted efforts dedicated towards it in the last thirty years. Considering the key role this driver oncogene plays, the pharmacological drugging of KRAS remains a key challenge for cancer research. In this review, we highlight the emerging experimental strategies for blocking KRAS function and signaling and its direct targeting. We also report on the results in this field of research produced by our group. PMID- 29534750 TI - Fever case management at private health facilities and private pharmacies on the Kenyan coast: analysis of data from two rounds of client exit interviews and mystery client visits. AB - BACKGROUND: Private sector availability and use of malaria rapid diagnostic tests (RDTs) lags behind the public sector in Kenya. Increasing channels through which quality malaria diagnostic services are available can improve access to testing and help meet the target of universal diagnostic testing. Registered pharmacies are currently not permitted to perform blood tests, and evidence of whether malaria RDTs can be used by non-laboratory private providers in line with the national malaria control guidelines is required to inform ongoing policy discussions in Kenya. METHODS: Two rounds of descriptive cross-sectional exit interviews and mystery client surveys were conducted at private health facilities and registered pharmacies in 2014 and 2015, 6 and 18 months into a multi-country project to prime the private sector market for the introduction of RDTs. Data were collected on reported RDT use, medicines received and prescribed, and case management of malaria test-negative mystery clients. Analysis compared outcomes at facilities and pharmacies independently for the two survey rounds. RESULTS: Across two rounds, 534 and 633 clients (including patients) from 130 and 120 outlets were interviewed, and 214 and 250 mystery client visits were completed. Reported testing by any malaria diagnostic test was higher in private health facilities than registered pharmacies in both rounds (2014: 85.6% vs. 60.8%, p < 0.001; 2015: 85.3% vs. 56.3%, p < 0.001). In registered pharmacies, testing by RDT was 52.1% in 2014 and 56.3% in 2015. At least 75% of test-positive patients received artemisinin-based combination therapy (ACT) in both rounds, with no significant difference between outlet types in either round. Provision of any anti-malarial for test-negative patients ranged from 0 to 13.9% across outlet types and rounds. In 2015, mystery clients received the correct (negative) diagnosis and did not receive an anti-malarial in 75.5% of visits to private health facilities and in 78.4% of visits to registered pharmacies. CONCLUSIONS: Non-laboratory staff working in registered pharmacies in Kenya can follow national guidelines for diagnosis with RDTs when provided with the same level of training and supervision as private health facility staff. Performance and compliance to treatment recommendations are comparable to diagnostic testing outcomes recorded in private health facilities. PMID- 29534751 TI - Adipose stromal vascular fraction attenuates TH1 cell-mediated pathology in a model of multiple sclerosis. AB - BACKGROUND: The therapeutic efficacy of adipose-derived stem cells (ASCs) has been investigated for numerous clinical indications, including autoimmune and neurodegenerative diseases. Less is known using the crude adipose product called stromal vascular fraction (SVF) as therapy, although our previous studies demonstrated greater efficacy at late-stage disease compared to ASCs in the experimental autoimmune encephalomyelitis (EAE) mouse, a model of multiple sclerosis. In this study, SVF cells and ASCs were administered during the pathogenic progression, designated as early disease, to elucidate immunomodulatory mechanisms when high immune cell activities associated with autoimmune signaling occur. These implications are essential for clinical translation when considering timing of administration for cell therapies. METHODS: We investigated the effects of SVF cells and ASCs by analyzing the spleens, peripheral blood, and central nervous system tissues throughout the course of EAE disease following administration of SVF cells, ASCs, or vehicle. In vitro, immunomodulatory potentials of SVF cells and ASCs were measured when exposed to EAE-derived splenocytes. RESULTS: Interestingly, treatment with SVF cells and ASCs transiently enhanced the severity of disease directly after administration, substantiating this critical immunomodulatory signaling. More importantly, it was only the EAE mice treated with SVF cells that were able to overcome the advancing pathogenesis and showed improvements by the end of the study. The frequency of lesions in spinal cords following SVF treatment correlated with diminished activities of the T helper type 1 cells, known effector cells of this disease. Co-cultures with splenocytes isolated from EAE mice revealed transcripts of interleukin-10 and transforming growth factor-beta, known promoters of regulatory T cells, that were greatly expressed in SVF cells compared to ASCs, and expression levels of signaling mediators related to effector T cells were insignificant in both SVF cells and ASCs. CONCLUSION: This is the first evidence, to date, to elucidate a mechanism of action of SVF treatment in an inflammatory, autoimmune disease. Our data supports key immunomodulatory signaling between cell therapies and T cells in this T cell mediated disease. Together, treatment with SVF mediated immunomodulatory effects that diminished effector cell activities, promoted regulatory T cells, and reduced neuroinflammation. PMID- 29534752 TI - Teriflunomide promotes oligodendroglial differentiation and myelination. AB - BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of the central nervous system (CNS) which in most cases initially presents with episodes of transient functional deficits (relapsing-remitting MS; RRMS) and eventually develops into a secondary progressive form (SPMS). Aside from neuroimmunological activities, MS is also characterized by neurodegenerative and regenerative processes. The latter involve the restoration of myelin sheaths electrically insulating structures which are the primary targets of autoimmune attacks. Spontaneous endogenous remyelination takes place even in the adult CNS and is primarily mediated by activation, recruitment, and differentiation of resident oligodendroglial precursor cells (OPCs). However, the overall efficiency of remyelination is limited and further declines with disease duration and progression. From a therapeutic standpoint, it is therefore key to understand how oligodendroglial maturation can be modulated pharmacologically. Teriflunomide has been approved as a first-line treatment for RRMS in the USA and the European Union. As the active metabolite of leflunomide, an established disease-modifying anti-rheumatic drug, it mainly acts via an inhibition of de novo pyrimidine synthesis exerting a cytostatic effect on proliferating B and T cells. METHODS: We investigated teriflunomide-dependent effects on primary rat oligodendroglial homeostasis, proliferation, and differentiation related to cellular processes important for myelin repair hence CNS regeneration in vitro. To this end, several cellular parameters, including specific oligodendroglial maturation markers, in vitro myelination, and p53 family member signaling, were examined by means of gene/protein expression analyses. The rate of myelination was determined using neuron-oligodendrocyte co-cultures. RESULTS: Low teriflunomide concentrations resulted in cell cycle exit while higher doses led to decreased cell survival. Short-term teriflunomide pulses can efficiently promote oligodendroglial cell differentiation suggesting that young, immature cells could benefit from such stimulation. In vitro myelination can be boosted by means of an early stimulation window with teriflunomide. p73 signaling is functionally involved in promoting OPC differentiation and myelination. CONCLUSION: Our findings indicate a critical window of opportunity during which regenerative oligodendroglial activities including myelination of CNS axons can be stimulated by teriflunomide. PMID- 29534753 TI - A cross-sectional study on the association between vitamin D levels and caries in the permanent dentition of Korean children. AB - BACKGROUND: A recent study in Canada reported that vitamin D deficiency is associated with dental caries. Because Koreans have been reported to be deficient in vitamin D, we investigated the relationship between dental caries and reduced serum vitamin D levels in Korean children. The purpose of this study was to analyze the relationships between blood vitamin D [25(OH)D] concentrations and dental caries in the permanent dentition of Korean children. METHODS: Data were collected from the Korea National Health and Nutrition Examination Survey performed in 2008-2013. A total of 1688 children (10-12 years of age) were enrolled. Vitamin D intake was measured through analysis of 25-hydroxy vitamin D [25(OH)D] levels. Caries experience in permanent dentition was assessed using the decay-missing-filled teeth (DMFT) index and decayed-missing-filled (DMF) rate. Statistical analyses included complex samples Chi-square tests, complex samples logistic regression analyses, and Pearson's correlations. RESULTS: The group with 25(OH) D levels lower than 50 nmol/L had a higher proportion of children with caries in the permanent dentition and permanent first molar than the group with 25(OH)D levels of 50 nmol/L or more. When external factors, such as sex, were controlled, 25(OH)D levels were not significantly correlated with caries, but were significantly correlated with first molar caries. Children with 25(OH)D levels lower than 50 nmol/L were 1.295 times more likely to have first molar caries than those with 25(OH)D levels of 50 nmol/L or more. Additionally, 25(OH)D levels and DMFT were negatively correlated; however, the degree of correlation was not strong. CONCLUSIONS: The association between 25(OH)D and dental caries is still not clear. However, our findings suggested that vitamin D insufficiency may be a risk factor for dental caries. PMID- 29534754 TI - Early detection of osteoarthritis in rabbits using MRI with a double-contrast agent. AB - BACKGROUND: Articular cartilage degeneration has been evaluated by magnetic resonance imaging (MRI). However, this method has several problems, including its time-consuming nature and the requirement of a high magnetic field or specialized hardware. The purpose of this study was to sequentially assess early degenerative changes in rabbit knee articular cartilage using MRI with a new double-contrast agent. METHODS: We induced osteoarthritis (OA) in the right knee of rabbits by anterior cruciate ligament transection and partial medial meniscectomy. Proton density-weighted images and T2-calculated images were obtained before and after contrast agent injection into the knee. The signal intensity ratio (SIR) values on the proton density-weighted images were calculated by dividing the signal intensity of the articular cartilage by that of joint fluid. Six rabbits were examined using MRI at 2 (designated 2-w OA) and 4 weeks (4-w OA) after the operation. Histological examination was performed 4 weeks after the operation. One rabbit was histologically examined 2 weeks after the operation. The control consisted of six rabbits that were not subjected to the operation. The SIR values, T2 values and the thicknesses of the cartilage of the 2-w OA, 4-w OA and the control before and after contrast agent injection were analyzed. The Mankin score and OARSI (Osteoarthritis Research Society International) score were used for the histological evaluation. RESULTS: Significant differences in the SIR and T2 values of the medial and lateral condyles of the femur were found between the control and the 4-w OA only after contrast agent injection. No significant differences were found in the SIR and T2 values before contrast agent injection between the control, the 2-w OA and 4-w OA. The thickness of the articular cartilage revealed no significant differences. In the histological assessment, the Mankin score and OARSI score sequentially increased from the control to the 4 w OA. CONCLUSION: We evaluated the SIR and T2 values of the knees in a rabbit OA model and a control model using a new double-contrast agent. MRI with this agent enabled OA detection earlier than using conventional MRI. PMID- 29534755 TI - Identification of the cellular components involved in de novo immune hepatitis: a quantitative immunohistochemical analysis. AB - BACKGROUND: Diagnosis of de novo immune hepatitis (dnIH) after liver transplantation relies on biopsy findings, with an abundance of plasma cells (PCs) in the inflammatory infiltrates a hallmark of the disease. Very little is known about what other types of immune cells exist in the infiltrates mainly located in the portal areas of the liver tissue. METHODS: We analyzed the composition of T cells, B cells, PCs, and macrophages in the liver biopsies of 12 patients with dnIH, 9 of them obtained at the time of diagnosis. For comparison, biopsies from 9 patients with chronic rejection (CR) were included in the study. The results were analyzed by a computer-assisted stereology quantification method. RESULTS: The major components of the infiltrates in the portal areas were CD3+ T lymphocytes in both groups, with 36.6% in the dnIH group versus 49.4% in the CR group. CD20+ B lymphocytes represented 14.9% in the dnIH group and 29.1% in the CR group. Macrophage levels were very similar in the dnIH and CR group (19.7% versus 16.8%, respectively). PCs were much less represented in CR biopsies than those from the dnIH group (mean value of 4.7% versus 28.8%). CONCLUSION: In conclusion, the determination of a characteristic cellular profile could be an important tool for a more reliable diagnosis of dnIH, in support of the histological evaluation made by the pathologist, which in most cases is challenging. Recognition of this condition is crucial because it leads to graft failure if left untreated. PMID- 29534756 TI - Implementation of nursing process in clinical settings: the case of three governmental hospitals in Ethiopia, 2017. AB - OBJECTIVE: The purpose of this survey was to evaluate the implementation of the nursing process at three randomly selected governmental hospitals found in Amhara Region North West Ethiopia. RESULT: From the total 338 reviewed documents, 264 (78.1%) have a nursing process format attached with the patient's profile/file, 107 (31.7%) had no nursing diagnosis, 185 (54.7%) of nurses stated their plan of care based on priority, 173 (51.2%) of nurses did not document their interventions based on plan and 179 (53.0%) of nurses did not evaluate their interventions. The overall implementation of nursing process among Felege Hiwot Referal hospital, Debretabor general hospital and Finoteselam general hospitals were 49.12, 68.18, and 69.42% respectively. Nursing professionals shall improve documentation required in implementing the nursing process. Nursing managers (matron, ward heads) shall supervise the overall implementation of nursing process. Hospital nursing services managers (matrons) shall arrange and facilitate case presentations by the nursing staffs which focus on documentation and updates on nursing process. Hospitals need to establish and support nursing process coordinating staff in their institution. PMID- 29534757 TI - A survey of Korean medicine doctors' clinical practice patterns for autism spectrum disorder: preliminary research for clinical practice guidelines. AB - BACKGROUND: The aim of this study was to investigate autism spectrum disorder (ASD) clinical practice patterns of Korean medicine doctors (KMDs) through questionnaire survey. METHODS: Questionnaires on Korean medicine (KM) treatment for ASD were distributed to 255 KMDs on December 5, 2016. The KMDs were psychiatrists, pediatricians, or general practitioners, who treated patients with ASD. The questionnaire covered items on treatment methods, aims of treatment, KM syndrome differentiation, diagnostic tools, and sociodemographic characteristics. Frequency analysis was conducted to describe the participants and their practices. RESULTS: A total 22.4% KMDs (n = 57/255) completed the questionnaires and 54 KMDs (21.2%) matched the inclusion criteria. The KMDs utilized herbal medicine (27.3%), body acupuncture (17.6%), scalp acupuncture (10.7%), moxibustion (6.4%), and Korean medical psychotherapy (5.9%) to treat ASD. The most commonly prescribed herbal medicine was Yukmijihwang-tang. Forty-eight (88.9%) KMDs responded that they used KM syndrome differentiation. 'Organ system, Qi, Blood, Yin, Yang, Fluid and Humor diagnosis' was most frequently used for syndrome differentiation. ASD was mainly diagnosed based on the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) and DSM-5. CONCLUSIONS: The present study demonstrated the current status of KMDs' diagnosis and treatment of ASD. In future clinical trials and clinical practice guidelines, these findings will provide meaningful information on the actual practice patterns of KMDs. PMID- 29534758 TI - TECS: a toxin expression control strategy as a tool for optimization of inducible promoters. AB - BACKGROUND: Transcriptional control of gene expression is a widely utilized regulatory mechanism in synthetic biology, biotechnology and recombinant protein production. It is achieved by utilization of naturally occurring promoters responding to nutrients or chemicals. Despite their regulatory properties, these promoters often possess features which diminish their utility for biotechnology. High basal expression level and low induction ratio can be removed using genetic engineering techniques, although this process is often laborious and time consuming. RESULTS: In order to facilitate optimization process for inducible promoters, we developed a simple method based on a conditional toxin expression which we abbreviate as toxin expression control strategy (TECS). In the presence of sucrose, SacB enzyme from Bacillus subtilis synthesizes levans which cause Eschericha coli cell lysis. However, in the absence of sucrose the enzyme does not affect the growth of the host. We utilized this feature to develop a two-step protocol allowing for efficient selection of inducible promoter variants. Using TECS we were able to modify the well-described pBAD promoter to decrease its leakage while maintaining high activity upon induction. Furthermore, we used the method to test transcriptional interference of lambda phage-derived sequence and optimize it for higher induction levels through random mutagenesis. CONCLUSIONS: We show that TECS is an efficient tool for optimization and development of inducible promoter systems in E. coli. Our strategy is very effective in the selection of promoter variants with improved properties. Its simplicity and short hands-on time make it an attractive method to optimize existing promoters and to construct novel, engineered genetic elements which improve properties of an inducible promoter system. PMID- 29534759 TI - Non-negative discriminative brain functional connectivity for identifying schizophrenia on resting-state fMRI. AB - BACKGROUND: Schizophrenia is a clinical syndrome, and its causes have not been well determined. The objective of this study was to investigate the alteration of brain functional connectivity between schizophrenia and healthy control, and present a practical solution for accurately identifying schizophrenia at single subject level. METHODS: 24 schizophrenia patients and 21 matched healthy subjects were recruited to undergo the resting-state functional magnetic resonance imaging (rs-fMRI) scanning. First, we constructed the brain network by calculating the Pearson correlation coefficient between each pair of the brain regions. Then, this study proposed a novel non-negative discriminant functional connectivity selection method, i.e. non-negative elastic-net based method (N2EN), to extract the alteration of brain functional connectivity between schizophrenia and healthy control. It ranks the significance of the connectivity with a uniform criterion by introducing the non-negative constraint. Finally, kernel discriminant analysis (KDA) is exploited to classify the subjects with the selected discriminant brain connectivity features. RESULTS: The proposed method is applied into schizophrenia classification, and achieves the sensitivity, specificity and accuracy of 100, 90.48 and 95.56%, respectively. Our findings also indicate the alteration of functional network can be used as the biomarks for guiding the schizophrenia diagnosis. The regions of cuneus, superior frontal gyrus, medial, paracentral lobule, calcarine fissure, surrounding cortex, etc. are highly relevant to schizophrenia. CONCLUSIONS: This study provides a method for accurately identifying schizophrenia, which outperforms several state-of-the-art methods, including conventional brain network classification, multi-threshold brain network based classification, frequent sub-graph based brain network classification and support vector machine. Our investigation suggested that the selected discriminant resting-state functional connectivities are meaningful features for classifying schizophrenia and healthy control. PMID- 29534760 TI - Temporal trends of preterm birth in Shenzhen, China: a retrospective study. AB - BACKGROUND: Preterm birth is the leading cause of child mortality under 5 years of age. Temporal trends in preterm birth rates are highly heterogeneous among countries and little information exists for China. To address this data gap, we investigated annual changes in preterm birth incidence rate and explored potential determinants of these changes in Shenzhen, China. METHODS: A total of 1.4 million live births, during 2003-2012, were included from the Shenzhen birth registry. Negative-binominal regression models were used to estimate the annual percent changes in incidence. To identify the potential determinants behind temporal trends, we estimated the contribution of each changing risk factor to changes in rate by calculating the difference in population-attributable risk fraction. RESULTS: Annual preterm birth incidence rates increased by 0.94% (95% CI 0.30%, 1.58%) overall, 3.60% (95% CI 2.73%, 4.48%) for medically induced, and 3.13% (95% CI 1.01%, 5.31%) for preterm premature rupture of membranes, but decreased by 2.34% (95% CI 1.62%, 3.06%) for spontaneous preterm labor. Higher maternal educational attainment (0.20 rate increase), lower proportion of inadequate prenatal care (0.15 rate reduction), more multipara (0.08 rate reduction), decreased proportion of preeclampsia or eclampsia (0.05 rate reduction), and larger proportion of young and older pregnant women (0.04 rate increase) were significant contributors to the overall change over time. Contributions of changing risk factors were different between preterm birth subtypes. CONCLUSIONS: Preterm birth rate in Shenzhen, China increased overall during 2003-2012, although trends varied across three preterm birth subtypes. The rising rates were associated with changes in maternal education and age. PMID- 29534761 TI - Theory-based development of an implementation intervention to increase HPV vaccination in pediatric primary care practices. AB - BACKGROUND: The national guideline for use of the vaccine targeting oncogenic strains of the human papillomavirus (HPV) is an evidence-based practice that is poorly implemented in primary care. Recommendations include completion of the vaccine series before the 13th birthday for girls and boys, giving the first dose at the 11- to 12-year-old check-up visit, concurrent with other recommended vaccines. Interventions to increase implementation of this guideline have had little impact, and opportunities to prevent cancer continue to be missed. METHODS: We used a theory-informed approach to develop a pragmatic intervention for use in primary care settings to increase implementation of the HPV vaccine guideline recommendation. Using a concurrent mixed methods design in 10 primary care practices, we applied the Consolidated Framework for Implementation Research (CFIR) to systematically investigate and characterize factors strongly influencing vaccine use. We then used the Behavior Change Wheel (BCW) and the Theoretical Domains Framework (TDF) to analyze provider behavior and identify behaviors to target for change and behavioral change strategies to include in the intervention. RESULTS: We identified facilitators and barriers to guideline use across the five CFIR domains: most distinguishing factors related to provider characteristics, their perception of the intervention, and their process to deliver the vaccine. Targeted behaviors were for the provider to recommend the HPV vaccine the same way and at the same time as the other adolescent vaccines, to answer parents' questions with confidence, and to implement a vaccine delivery system. To this end, the intervention targeted improving provider's capability (knowledge, communication skills) and motivation (action planning, belief about consequences, social influences) regarding implementing guideline recommendations, and increasing their opportunity to do so (vaccine delivery system). Behavior change strategies included providing information and communication skill training with graded tasks and modeling, feedback of coverage rates, goal setting, and social support. These strategies were combined in an implementation intervention to be delivered using practice facilitation, educational outreach visits, and cyclical small tests of change. CONCLUSIONS: Using CFIR, the BCW and the TDF facilitated the development of a pragmatic, multi component implementation intervention to increase use of the HPV vaccine in the primary care setting. PMID- 29534762 TI - A history of male migration in and out of the Green Sahara. AB - The Sahara was once fertile; a recent study identifies human Y-chromosomal lineages that flourished in this Green Sahara and their relation to present-day populations. PMID- 29534763 TI - A cross-cultural comparison of health-related quality of life and its associated factors among older women in Vietnam and Australia. AB - OBJECTIVE: This study compared health-related quality of life and its associated factors among 305 women in Vietnam and 175 women in Australia aged 60-71. Descriptive analyses, Chi square, independent t-tests, and General Linear Models were used for data analysis. RESULTS: After controlling for socio-demographics, lifestyles, and chronic diseases, older women in Vietnam had lower levels of physical health but similar levels of mental health to those in Australia. In both populations, chronic disease and diet were associated with physical health; physical activity was related to mental health. In Australia, physical activity, exercise, and Body Mass Index were also associated with physical health; age, alcohol consumption, and sleep were also linked with mental health. In Vietnam, age and marital status were also related to physical health; chronic diseases and diet were also correlated with mental health. These findings suggested that interventions developed in Australia targeting the management of diet and physical activity, may be useful for older women in Vietnam. However, future interventions in Vietnam need to be tailored to account for different age groups, marital status, and the number of chronic diseases experienced. Further investigation into the contributions of cultural factors to health-related quality of life is recommended. PMID- 29534764 TI - Online mapping of EMG signals into kinematics by autoencoding. AB - BACKGROUND: In this paper, we propose a nonlinear minimally supervised method based on autoencoding (AEN) of EMG for myocontrol. The proposed method was tested against the state-of-the-art (SOA) control scheme using a Fitts' law approach. METHODS: Seven able-bodied subjects performed a series of target acquisition myoelectric control tasks using the AEN and SOA algorithms for controlling two degrees-of-freedom (radial/ulnar deviation and flexion/extension of the wrist), and their online performance was characterized by six metrics. RESULTS: Both methods allowed a completion rate close to 100%, however AEN outperformed SOA for all other performance metrics, e.g. it allowed to perform the tasks on average in half the time with respect to SOA. Moreover, the amount of information transferred by the proposed method in bit/s was nearly twice the throughput of SOA. CONCLUSIONS: These results show that autoencoders can map EMG signals into kinematics with the potential of providing intuitive and dexterous control of artificial limbs for amputees. PMID- 29534765 TI - Progress of negative symptoms over the initial 5 years of a first episode of psychosis. AB - BACKGROUND: Specialized early intervention (EI) following a first episode of psychosis (FEP) are effective at reducing negative symptoms, although its trajectory warrants systematic assessment. However, findings are equivocal as to whether extended gains are made post 2 years of EI and whether there is additional benefit of extending EI for an additional 3 years. METHODS: Data on 178 FEP patients, from a randomized controlled trial of a 3-year extension of EI service v. transfer to regular care following 2 years of EI service, were used for this report. Repeated measures analysis of variance were conducted separately for the initial 2 years of treatment in an EI service, and for the 3-year post randomization to examine trajectories of negative symptoms over the two periods in the two arms of the study. RESULTS: There were significant improvements in total negative symptoms over the first 2 years of EI F(4.612, 797.905) = 25.263, p < 0.001 and in domains of 'expressivity' and 'motivation'. In the following 3 years, there were further significant improvements in negative symptoms F(4.318, 759.908) = 4.182, p = 0.002 with no difference between groups F(4.318, 759.908) = 1.073, p = 0.371. Changes in negative symptoms over the extension period were driven by expressivity F(4.01, 674.73) = 7.19, p < 0.01, but not motivation F(6.58, 1112.18) = 0.95, p = 0.46. CONCLUSION: Negative symptoms improve significantly over the first 2 years of EI. Subsequent amelioration was largely the result of expressivity. Motivation deficits remained stable. Extended EI offered no advantage over regular care post-randomization. PMID- 29534766 TI - Seasonality and within-subject clustering of rotavirus infections in an eight site birth cohort study. AB - Improving understanding of the pathogen-specific seasonality of enteric infections is critical to informing policy on the timing of preventive measures and to forecast trends in the burden of diarrhoeal disease. Data obtained from active surveillance of cohorts can capture the underlying infection status as transmission occurs in the community. The purpose of this study was to characterise rotavirus seasonality in eight different locations while adjusting for age, calendar time and within-subject clustering of episodes by applying an adapted Serfling model approach to data from a multi-site cohort study. In the Bangladesh and Peru sites, within-subject clustering was high, with more than half of infants who experienced one rotavirus infection going on to experience a second and more than 20% experiencing a third. In the five sites that are in countries that had not introduced the rotavirus vaccine, the model predicted a primary peak in prevalence during the dry season and, in three of these, a secondary peak during the rainy season. The patterns predicted by this approach are broadly congruent with several emerging hypotheses about rotavirus transmission and are consistent for both symptomatic and asymptomatic rotavirus episodes. These findings have practical implications for programme design, but caution should be exercised in deriving inferences about the underlying pathways driving these trends, particularly when extending the approach to other pathogens. PMID- 29534767 TI - Effective International Medical Disaster Relief: A Qualitative Descriptive Study. AB - : Purpose The aim of this study was to assist organizations seeking to develop or improve their medical disaster relief effort by identifying fundamental elements and processes that permeate high-quality, international, medical disaster relief organizations and the teams they deploy. METHODS: A qualitative descriptive design was used. Data were gathered from interviews with key personnel at five international medical response organizations, as well as during field observations conducted at multiple sites in Jordan and Greece, including three refugee camps. Data were then reviewed by the research team and coded to identify patterns, categories, and themes. RESULTS: The results from this qualitative, descriptive design identified three themes which were key characteristics of success found in effective, well-established, international medical disaster relief organizations. These characteristics were first, ensuring an official invitation had been extended and the need for assistance had been identified. Second, the response to that need was done in an effective and sustainable manner. Third, effective organizations strived to obtain high-quality volunteers. CONCLUSION: By following the three key characteristics outlined in this research, organizations are more likely to improve the efficiency and quality of their work. In addition, they will be less likely to impede the overall recovery process. Broby N , Lassetter JH , Williams M , Winters BA . Effective international medical disaster relief: a qualitative descriptive study. Prehosp Disaster Med. 2018;33(2):119-126. PMID- 29534768 TI - Quantifying the impact of mass vaccination programmes on notified cases in the Netherlands. AB - Vaccination programmes are considered a main contributor to the decline of infectious diseases over the 20th century. In recent years, the national vaccination coverage in the Netherlands has been declining, highlighting the need for continuous monitoring and evaluation of vaccination programmes. Our aim was to quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands. We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections. In the first 13 years of mass vaccinations, case notifications declined rapidly with 82.4% (95% credible interval (CI): 74.9-87.6) of notified cases of diphtheria averted, 92.9% (95% CI 85.0-97.2) cases of poliomyelitis, and 79.1% (95% CI 67.1-87.4) cases of mumps. Vaccination of 11-year-old girls against rubella averted 49.9% (95% CI 9.3-73.5) of cases, while universal vaccination averted 68.1% (95% CI 19.4-87.3) of cases. These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands. PMID- 29534769 TI - Incidence and risk factors for healthcare utilisation among patients discharged on outpatient parenteral antimicrobial therapy. AB - Outpatient parenteral antimicrobial therapy (OPAT) programmes facilitate hospital discharge, but patients remain at risk of complications and consequent healthcare utilisation (HCU). Here we elucidated the incidence of and risk factors associated with HCU in OPAT patients. This was a retrospective, single-centre, case-control study of adult patients discharged on OPAT. Cases (n = 63) and controls (n = 126) were patients that did or did not utilise the healthcare system within 60 days. Characteristics associated with HCU in bivariate analysis (P <= 0.2) were included in a multivariable logistic regression model. Variables were retained in the final model if they were independently (P < 0.05) associated with 60-day HCU. Among all study patients, the mean age was 55 +/- 16, 65% were men, and wound infection (22%) and cellulitis (14%) were common diagnoses. The cumulative incidence of 60-day unplanned HCU was 27% with a disproportionately higher incidence in the first 30 days (21%). A statin at discharge (adjusted odds ratios (aOR) 0.23, 95% confidence intervals (CIs) 0.09-0.57), number of prior admissions in past 12 months (aOR 1.48, 95% CIs 1.05-2.10), and a sepsis diagnosis (aOR 4.62, 95% CIs 1.23-17.3) were independently associated with HCU. HCU was most commonly due to non-infection related complications (44%) and worsening primary infection (31%). There are multiple risk factors for HCU in OPAT patients, and formal OPAT clinics may help to risk stratify and target the highest risk groups. PMID- 29534770 TI - Whole-genome sequencing analysis of human bocavirus detected in South Korea. AB - Human bocaviruses (HBoVs) have been detected in human gastrointestinal infections worldwide. In 2005, HBoV was also discovered in infants and children with infections of the lower respiratory tract. Recently, several genotypes of this parvovirus, including HBoV genotype 2 (HBoV2), genotype 3 (HBoV3) and genotype 4 (HBoV4), were discovered and found to be closely related to HBoV. HBoV2 was first detected in stool samples from children in Pakistan, followed by detection in other countries. HBoV3 was detected in Australia and HBoV4 was identified in stool samples from Nigeria, Tunisia and the USA. Recently, HBoV infection has been on the rise throughout the world, particularly in countries neighbouring South Korea; however, there have been very few studies on Korean strains. In this study, we characterised the whole genome and determined the phylogenetic position of CUK-BC20, a new clinical HBoV strain isolated in South Korea. The CUK-BC20 genome of 5184 nucleotides (nt) contains three open-reading frames (ORFs). The genotype of CUK-BC20 is HBoV2, and 98.77% of its nt sequence is identical with those of other HBoVs, namely Rus-Nsc10-N386. Especially, the ORF3 amino acid sequences from positions 212-213 and 454 corresponding to a variable region (VR)1 and VR5, respectively, showed genotype-specific substitutions that distinguished the four HBoV genotypes. As the first whole-genome sequence analysis of HBoV in South Korea, this information will provide a valuable reference for the detection of recombination, tracking of epidemics and development of diagnosis methods for HBoV. PMID- 29534771 TI - Assessment of the accuracy of nutrient calculations of five popular nutrition tracking applications. AB - OBJECTIVE: To assess the accuracy of nutrient intake calculations from leading nutrition tracking applications (apps). DESIGN: Nutrient intake estimates from thirty 24 h dietary recalls collected using Nutrition Data System for Research (NDSR) were compared with intake calculations from these recalls entered by the researcher into five free nutrition tracking apps. Apps were selected from the Apple App Store based on consumer popularity from the list of free 'Health and Fitness' apps classified as a nutrition tracking apps. SUBJECTS: Dietary recall data collected from thirty lower-income adults. RESULTS: Correlations between nutrient intake calculations from NDSR and the nutrition tracking apps ranged from 0.73 to 0.96 for energy and macronutrients. Correlations for the other nutrients examined (Na, total sugars, fibre, cholesterol, saturated fat) ranged from 0.57 to 0.93. For each app, one or more mean nutrient intake calculations were significantly lower than those from NDSR. These differences included total protein (P=0.03), total fat (P=0.005), Na (P=0.02) and cholesterol (P=0.005) for MyFitnessPal; dietary fibre (P=0.04) for Fitbit; total protein (P=0.0004), total fat (P=0.008), Na (P=0.002), sugars (P=0.007), cholesterol (P=0.0006) and saturated fat (P=0.005) for Lose It!; Na (P=0.03) and dietary fibre (P=0.005) for MyPlate; and total fat (P=0.03) for Lifesum. CONCLUSIONS: Findings suggest that nutrient calculations from leading nutrition tracking apps tend to be lower than those from NDSR, a dietary analysis software developed for research purposes. Further research is needed to evaluate the validity of the apps when foods consumed are entered by consumers. PMID- 29534772 TI - Genetic diversity of norovirus in children under 5 years of age with acute gastroenteritis from Angola. AB - Norovirus (NoV) is a major cause of acute gastroenteritis (AGE). In this study, we investigated the genetic diversity of NoV strains identified in children under 5 years of age with AGE in four provinces of Angola. Faecal samples from 343 children were screened for NoV by an in house real-time PCR assay and genotyping was performed by partial capsid gene sequencing. NoV was detected in 17.4% (58/334) of the samples, with high detection rates in children <6 months old (19%) and in children aged 12-24 months (23%). Genotype diversity was large, as demonstrated by the 11 identified genotypes. GII.4 was the predominant genotype (20% of all NoV-positive samples), followed by GII.6 (15%), GI.3 (12%), GII.7 (10%) and by other genotypes to a lesser extent. Two GII.4 variants, New Orleans 2009 and Sydney 2012, were detected and several genetic clusters were observed for genotypes GI.3, GII.6 and GII.7. The present study shows high detection rates and genetic diversity of circulating NoV genotypes in paediatric AGE samples from Angola. This information emphasises the importance of continuous assessment of NoV burden and evolution in the target population. PMID- 29534773 TI - The changing HIV-1 genetic characteristics and transmitted drug resistance among recently infected population in Yunnan, China. AB - Multiple human immunodeficiency virus (HIV)-1 genotypes in China were first discovered in Yunnan Province before disseminating throughout the country. As the HIV-1 epidemic continues to expand in Yunnan, genetic characteristics and transmitted drug resistance (TDR) should be further investigated among the recently infected population. Among 2828 HIV-positive samples newly reported in the first quarter of 2014, 347 were identified as recent infections with BED captured enzyme immunoassay (CEIA). Of them, 291 were successfully genotyped and identified as circulating recombinant form (CRF)08_BC (47.4%), unique recombinant forms (URFs) (18.2%), CRF01_AE (15.8%), CRF07_BC (14.4%), subtype C (2.7%), CRF55_01B (0.7%), subtype B (0.3%) and CRF64_BC (0.3%). CRF08_BC and CRF01_AE were the predominant genotypes among heterosexual and homosexual infections, respectively. CRF08_BC, URFs, CRF01_AE and CRF07_BC expanded with higher prevalence in central and eastern Yunnan. The recent common ancestor of CRF01_AE, CRF07_BC and CRF08_BC dated back to 1983.1, 1992.1 and 1989.5, respectively. The effective population sizes (EPS) for CRF01_AE and CRF07_BC increased exponentially during 1991-1999 and 1994-1999, respectively. The EPS for CRF08_BC underwent two exponential growth phases in 1994-1998 and 2001-2002. Lastly, TDR associated mutations were identified in 1.8% of individuals. These findings not only enhance our understanding of HIV-1 evolution in Yunnan but also have implications for vaccine design and patient management strategies. PMID- 29534774 TI - Outcomes of UTI and bacteriuria caused by ESBL vs. non-ESBL Enterobacteriaceae isolates in pregnancy: a matched case-control study. AB - Infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) have become increasingly prevalent, posing a serious public threat worldwide. It is commonly believed that untreated urinary tract infections (UTI) and asymptomatic bacteriuria (ABU) during pregnancy are associated with poor obstetric outcomes. Currently, there is a paucity of data regarding the outcomes or risk factors of such ESBL-E infections in pregnant women. We conducted a retrospective 1:2 matched case-control study of hospitalised pregnant women with ESBL-E- vs. non-ESBL-producing Enterobacteriaceae-positive urine cultures obtained between 2004 and 2015, and compared risk factors for the development of resistant bacteria, clinical course and outcomes. In total, 87 pregnant women with ESBL-E-positive urine cultures were matched to 174 controls by decade of age, ethnicity and pregnancy trimester. Significant risk factors for acquisition of ESBL-E included prior UTI/ABU episodes (50.6% vs. 26.3%, P < 0.001), previous isolation of ESBL-E in urine cultures (12.6% vs. 0.6%, P < 0.001) and prior antibiotic exposure (71.3% vs. 54%, P = 0.002). Previous hospitalisation, however, was not found to be a risk factor. No significant difference was found in adverse obstetric outcomes. We conclude that prior urinary infections and antibiotic exposure were significant risk factors for the isolation of ESBL-E pathogens from the urine of pregnant women; however, this was not associated with worse obstetric outcomes compared with non-ESBL-E pathogens. PMID- 29534776 TI - Meconium proteins as a source of biomarkers for the assessment of the intrauterine environment of the fetus. AB - Intrauterine environmental factors can be associated with perinatal complications and long-term health outcomes although the underlying mechanisms remain poorly defined. Meconium formed exclusively in utero and passed naturally by a neonate may contain proteins which characterise the intrauterine environment. The aim of the study was proteomic analysis of the composition of meconium proteins and their classification by biological function. Proteomic techniques combining isoelectrofocussing fractionation and LC-MS/MS analysis were used to study the protein composition of a meconium sample obtained by pooling 50 serial meconium portions from 10 healthy full-term neonates. The proteins were classified by function based on the literature search for each protein in the PubMed database. A total of 946 proteins were identified in the meconium, including 430 proteins represented by two or more peptides. When the proteins were classified by their biological function the following were identified: immunoglobulin fragments and enzymatic, neutrophil-derived, structural and fetal intestine-specific proteins. Meconium is a rich source of proteins deposited in the fetal intestine during its development in utero. A better understanding of their specific biological functions in the intrauterine environment may help to identify these proteins which may serve as biomarkers associated with specific clinical conditions/diseases with the possible impact on the fetal development and further health consequences in infants, older children and adults. PMID- 29534775 TI - The importance of serological and molecular analyses for the diagnosis of measles cases and for meeting elimination targets in Turkey from 2007 to 2015. AB - Measles is an important childhood infection targeted to be eliminated by the World Health Organization (WHO). Virus circulation has not been interrupted in the European Region because high vaccination rates could not be achieved among some countries of the WHO European Region including Turkey. The purpose of this study was to evaluate the laboratory findings of measles cases confirmed in the last nine years, to assess the epidemiological data of the cases, to determine the molecular genotyping studies and to emphasise the importance of laboratory based surveillance in measles. From 2007 to 2010, only 18 imported cases were detected in Turkey. However, this number increased with a local outbreak of 111 cases in 2011, followed by another outbreak in 2012 in Istanbul that spread countrywide in the following two years; a total of 8661 laboratory-confirmed measles cases were reported from 2012 to 2015. After ELISA detection of a measles IgM-positive result in serum samples of potential measles cases, RT-PCR was performed with urine or nasopharyngeal swab samples of patients, and amplicons were subjected to sequencing. In the samples of 2010 and 2011, D4 and D9 genotypes were mainly detected; as of 2012, the D8 genotype has gained importance. Although D8 was also identified in 2014, in the same year genotype H1 viruses were detected in Turkey for the first time. Therefore, it is important to perform a genotypic analysis of the virus causing the outbreak, analyse epidemiological connections of the contact, determine the source of the outbreak and plan measures based on this information. PMID- 29534777 TI - Genome-wide association analysis reveals genomic regions on Chromosome 13 affecting litter size and candidate genes for uterine horn length in Erhualian pigs. AB - Litter size has a great impact on the profit of swine producers. Uterine development is an important determinant of reproduction efficiency and could hence affect litter size. Chinese Erhualian pig is one of the most prolific breeds in the world, even though large phenotypic variation in litter size was observed within Erhualian sows. To dissect the genetic basis of the phenotypic variation, we herein conducted genome-wide association studies for total number born and number born alive (NBA) of Erhualian sows. In total, one significant single nucleotide polymorphism (SNP) (P<1.78e-06) and 11 suggestive SNPs (P<3.57e 05) were identified on 10 chromosomes, confirming seven previously reported quantitative trait loci (QTL) and uncovering six QTL for litter size or uterus length. One locus on Sus scrofa chromosome (SSC) 13 (79.28 to 90.43 Mb) harbored a cluster of suggestive SNPs associated with multiparous NBA. The SNP (rs81447100) within this region was confirmed to be significantly (P<0.05) associated with litter size in Erhualian (n=313), Sutai (n=173) and Yorkshire (n=488) populations. Retinol binding protein 2 and retinol binding protein 1 functionally related to the development of uterus were located in a region of 2 Mb around rs81447100. Moreover, four genes related to embryo implantation and development were also detected around other significant SNPs. Taken together, our findings provide a potential marker (rs81447100) for the genetic improvement of litter size not only in Chinese Erhualian pigs but also in European commercial pig breeds like Yorkshire, and would facilitate the final identification of causative variant(s) underlying the effect of SSC13 QTL on litter size. PMID- 29534778 TI - Unmasking the borderline coarctation: the utility of isoproterenol in the paediatric cardiac catheterisation laboratory. AB - BACKGROUND: One indication for intervention in coarctation of the aorta is a peak to-peak gradient >20 mmHg. Gradients may be masked in patients under general anaesthesia and may be higher during exercise. Isoproterenol was given during cardiac catheterisation to simulate a more active physiologic state. OBJECTIVES: We aimed to describe the haemodynamic effects of isoproterenol in patients with coarctation and the impact of intervention on the elicited gradients. METHODS: A retrospective study was performed on two-ventricle patients who underwent cardiac catheterisation for coarctation with isoproterenol testing. RESULTS: 25 patients received isoproterenol before and after intervention. With isoproterenol, the mean diastolic (p=0.0015) and mean arterial (p=0.0065) blood pressures proximal to the coarctation decreased significantly. The mean systolic, diastolic, and mean arterial blood pressures distal to the coarctation decreased significantly (p20 mmHg. Post intervention, the median gradient decreased to 2 (0-29) mmHg, versus baseline, p=0.005, and with isoproterenol it decreased to 8 (0-27) mmHg, versus pre-intervention isoproterenol, p<0.0001. There were significant improvements in the gradients by Doppler (<0.0001) and by blood pressure cuff (p=0.0313). The gradients on isoproterenol best correlated with gradients by blood pressure cuff in the awake state (R2=0.76, p<0.0001). CONCLUSIONS: Isoproterenol can be a useful tool to assess the significance of a coarctation and the effectiveness of an intervention. Percutaneous interventions can effectively reduce the gradients elicited by isoproterenol. PMID- 29534779 TI - Man with back pain and fever. PMID- 29534780 TI - Model of payment should not be the key concern when it comes to emergency department physicians' remuneration. PMID- 29534782 TI - Clinician's Capsules for CJEM 20(2). PMID- 29534781 TI - Finding FOAM and not Froth. PMID- 29534783 TI - One size does not fit all for Canadian trauma systems. PMID- 29534784 TI - CJEM Debate Series: #ChoosingWisely - The Choosing Wisely campaign will not impact physician behaviour and choices. PMID- 29534785 TI - Impact of physician payment mechanism on emergency department operational performance. AB - CLINICIAN'S CAPSULE What is known about the topic? Fee-for-service compensation may motivate physicians to see more patients and improve throughput, or drive excessive testing and referral behaviour that undermine emergency performance. What did this study ask? Does fee-for-service payment reduce emergency wait times, length of stay, and left without being seen rates? What did this study find? We observed an unsustained 24% reduction in time to physician, but no change in length of stay or left without being seen rates. Why does this study matter to clinicians? Fee-for-service compensation may have transient motivational effect but is unlikely to generate system-level improvement. PMID- 29534786 TI - Education scholarship in Canadian emergency medicine: The past, present, and future. PMID- 29534787 TI - Trauma systems and emergency medical services: The missing link for tranexamic acid utilization in major trauma. PMID- 29534788 TI - Implication of transcriptome profiling of spermatozoa for stallion fertility. AB - Poor fertility of breeding stallions is a recognised problem in the equine industry. The aim of the present study was to detect molecular pathways using two groups of stallions that differed in pregnancy rates as well as in the proportion of normal and motile spermatozoa. RNA was isolated from spermatozoa of each stallion and microarray data were analysed to obtain a list of genes for which transcript abundance differed between the groups (P <=0.05, fold change >=1.2). In all, there were 437 differentially expressed (DE) genes between the two groups (P <= 0.05, fold change >=1.2). Next, the DE genes were analysed using Database for Annotation, Visualisation, and Integrated Discovery (DAVID). Finally, ingenuity pathways analysis (IPA) was used to identify top biological functions and significant canonical pathways associated with the DE genes. Analysis using the DAVID database showed significant enrichment in the gene ontology (GO) term 'RNA binding' (P=0.05) and in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway cytokine-cytokine receptor interaction (P=0.02). Furthermore, IPA analysis showed interconnected biological functions and canonical pathways involved in the regulation of spermatogenesis and male fertility. In addition, significantly enriched metabolic pathways were identified. In conclusion, the present study has identified, for the first time, molecular processes in stallion spermatozoa that could be associated with stallion fertility. PMID- 29534789 TI - Radiology reporting of obesity: a survey of patient and clinician attitudes. AB - AIM: To determine whether obesity information obtained via imaging techniques is desirable for clinicians and patients, and to investigate whether it impacts clinical decision-making. MATERIALS AND METHODS: Parallel surveys were designed to assess patient and clinician attitudes to the medical utility and social stigma of reporting obesity on radiology reports performed for other reasons. RESULTS: Where obesity was noted at medical imaging performed for any reason, clinicians and patients strongly agreed that it should be included in the radiology report (5.9 and 5.8, respectively, on a seven-point preference score ranging from strongly disagree [1] to strongly agree [7]). Clinicians and patients indicated a preference for a quantitative report. Clinicians somewhat disagreed and patients disagreed that a radiology report describing obesity would be considered insulting (3 and 2.1, respectively). Clinicians and patients agreed that they would be more likely to discuss overweight/obesity if it was described in a radiology report (5.3 and 6.1 respectively). Clinicians and patients agreed that radiology reports describing obesity would influence future management/behaviour (4.5 and 6.2, respectively). Clinicians strongly disagreed that they would avoid sending patients for scans if obesity was reported (1.3). Patients also disagreed that including such information on a report would result in imaging avoidance (1.9). CONCLUSION: Both clinicians and patients indicate a clear preference for obesity-related information on radiology reports for examinations performed for any reason. Surveyed attitudes suggest including such information is not considered insulting, and is unlikely to result in avoidance of imaging. PMID- 29534790 TI - Microplastics in the environment: Challenges in analytical chemistry - A review. AB - Microplastics can be present in the environment as manufactured microplastics (known as primary microplastics) or resulting from the continuous weathering of plastic litter, which yields progressively smaller plastic fragments (known as secondary microplastics). Herein, we discuss the numerous issues associated with the analysis of microplastics, and to a less extent of nanoplastics, in environmental samples (water, sediments, and biological tissues), from their sampling and sample handling to their identification and quantification. The analytical quality control and quality assurance associated with the validation of analytical methods and use of reference materials for the quantification of microplastics are also discussed, as well as the current challenges within this field of research and possible routes to overcome such limitations. PMID- 29534791 TI - Design considerations for reducing sample loss in microfluidic paper-based analytical devices. AB - The field of microfluidic paper-based analytical devices (MUPADs) is most notably characterized by portable and low-cost analysis; however, struggles to achieve the high sensitivity and low detection limits needs required for many environmental applications hinder widespread adoption of this technology. Loss of analyte to the device material represents an important problem impacting sensitivity. Critically, we found that at least 50% of a Ni(II) sample is lost when being transported down a 30 mm paper channel that is representative of structures commonly found in MUPADs. In this work, we report simple strategies such as adding a waste zone, enlarging the detection zone, and using an elution step to increase device performance. A MUPAD combining the best performing functionalities led to a 78% increase in maximum signal and a 28% increase in sensitivity when transporting Ni(II) samples. Using the optimized MUPAD also led to a 94% increase in maximum signal for Mn(II) samples showing these modifications can be applied more generally. PMID- 29534792 TI - Aptamer-integrated DNA nanoassembly: A simple and sensitive DNA framework to detect cancer cells. AB - The development of powerful techniques to detect cancer cells at early stages plays a notable role in diagnosing and prognosing cancer patients and reducing mortality. This paper reports on a novel functional DNA nanoassembly capable of detecting cancer cells based on structural DNA nanotechnology. DNA nanoassemblies were constructed by the self-assembly of a DNA concatemer to a plenty of sticky ended three-way junctions. While an aptamer moiety guided the nanoassembly to the target cancer cell, the peroxidase-mimicking DNAzymes embedded in the nanoassemblies were used as the sensing element to produce colorimetric signals. As proof-of-concept, as low as 175 cancer cells were detected by the assay, and color change was clearly distinguished by the naked eyes. The proposed system enjoys potential applications for point-of-care cancer diagnosis, with its excellent sensitivity and selectivity. PMID- 29534793 TI - A competitive lateral flow assay for the detection of tenofovir. AB - Proper management of an HIV infection requires that a patient be at least 80-95% adherent to a prescribed drug regimen to avoid poor health outcomes and the development of drug-resistant HIV strains. Clinicians generally monitor adherence habits indirectly through patient self-reporting, pill counting, and electronic drug monitoring. While direct measurement of patient samples like urine for monitoring drug levels is possible, it requires specialized equipment and training that is not readily available in resource-limited settings where the need is greatest. In this work we report the development of an antibody that binds to tenofovir (TFV), a key small molecule drug for both the treatment and prevention of HIV, and a competitive lateral flow assay that uses that antibody to monitor urine samples for the presence of the drug. TFV was conjugated to an immunogenic protein and injected into rabbits to raise polyclonal antibodies sensitive to the drug. The antibodies were verified for TFV-sensitivity by immunoprecipitation and HPLC. A gold nanoparticle-based competitive assay was developed to detect the presence of TFV in urine samples with a sensitivity of 1 MUg mL-1. This TFV assay could be deployed as a point-of-care device for adherence monitoring in resource-limited settings as a low-cost, accurate, and speedy alternative to current methods to better inform changes in treatment. PMID- 29534794 TI - Short-sweep capillary electrophoresis with a selective zinc fluorescence imaging reagent FluoZin-3 for determination of free and metalothionein-2a-bound Zn2+ ions. AB - A capillary electrophoretic (CE) method using a short-sweep approach and laser induced fluorescence (LIF) detection (ShortSweepCE-LIF) was developed for determination of Zn2+ and Cd2+ as complexes with highly selective and sensitive fluorescent probe FluoZin-3. The ShortSweepCE-LIF method, established in this work, can be used for examining competitive Zn2+ and Cd2+ binding properties of metalloproteins or peptides. The parameters including background electrolyte composition, injection pressure and time as well as separation voltage were investigated. Under the optimized conditions, 80 mM HEPES, pH 7.4, with 1.5 MUM FluoZin-3 was used as an electrolyte, hydrodynamic injection was performed at 50 mbar for 5 s, and separation voltage of 25 kV. Limits of detection for Zn2+ and Cd2+ were 4 and 125 nM, respectively. The developed method was demonstrated in a study of interactions between metalothionein-2a isoform and metal ions Zn2+, Co2+ and Cd2+. It was found that FluoZin-3 was able to extract a single Zn2+ ion, while added Co2+ (in surplus) extracted only 2.4 Zn2+ ions, and Cd2+ extracted all 7 Zn2+ ions present in the metalothionein molecule. PMID- 29534795 TI - Biotin-exposure-based immunomagnetic separation coupled with nucleic acid lateral flow biosensor for visibly detecting viable Listeria monocytogenes. AB - Infectious diseases caused by Listeria monocytogenes pose a great threat to public health worldwide. Therefore, a rapid and efficient method for L. monocytogenes detection is needed. In this study, a biotin-exposure-based immunomagnetic separation (IMS) method was developed. That is, biotinylated antibody was first targeted to L. monocytogenes. Then, streptavidin functionalized magnetic nanoparticles were added and anchored onto L. monocytogenes cells indirectly through the strong noncovalent interaction between streptavidin and biotin. Biotin-exposure-based IMS exhibited an excellent capability to enrich L. monocytogenes. Specifically, more than 90% of L. monocytogenes was captured when the bacterial concentration was lower than 104 colony-forming units (CFU)/mL. Importantly, the antibody dosage was reduced by 10 times of that in our previous study, which used antibody direct-conjugated magnetic nanoparticles. Propidium monoazide (PMA) treatment prior to PCR amplification could eliminate the false-positive results from dead bacteria and detected viable L. monocytogenes sensitively and specifically. For viable L.monocytogenes detection, enriched L. monocytogenes was treated with PMA prior to asymmetric PCR amplification. The detection limits of the combined IMS with nucleic acid lateral flow (NALF) biosensor for viable L. monocytogenes detection were 3.5 * 103 CFU/mL in phosphate buffer solution and 3.5 * 104 CFU/g in lettuce samples. The whole assay process of recognizing viable L. monocytogenes was completed within 6 h. The proposed biotin-exposure-mediated IMS combined with a disposable NALF biosensor platform posed no health risk to the end user, and possessed potential applications in the rapid screening and identification of foodborne pathogens. PMID- 29534796 TI - Biomimetic small peptide functionalized affinity monoliths for monoclonal antibody purification. AB - The rapid development of monoclonal antibodies (mAbs) in therapeutic and diagnostic applications has necessitated the advancement of mAbs purification technologies. In this study, a biomimetic small peptide ligand 3,5-di-tert-butyl 4-hydroxybenzoic acid-Arg-Arg-Gly (DAAG) functionalized monolith was fabricated through a metal ion chelation-based multi-step approach. The resulting monolith showed good chromatographic performance. Compared with the Ni2+ based IMAC monolith, the DAAG functionalized monolith exhibited not only excellent specificity but also higher dynamic binding capacity (DBC). The 10% DBC and 50% DBC for hIgG reached as high values as 26.0 and 34.6 mg/mL, respectively, at a ligand density of 8.8 MUmol/mL, due to the high porosity and accessibility of the monolithic matrix. Moreover, the stability of the DAAG functionalized monolith in successive breakthrough experiments indicates that it has a promising potential for long-term use in mAbs purification. Finally, the DAAG functionalized monolith was successfully applied to the purification of trastuzumab or human immunoglobulin G (hIgG) from biological samples. PMID- 29534797 TI - A comparison of fast and reactive pyrolysis with insitu derivatisation of fructose, inulin and Jerusalem artichoke (Helianthus tuberosus). AB - Reactive pyrolysis is a technique that provides mechanistic information by performing pyrolysis of the substrate in a sealed glass capsule at elevated temperature and pressure for relatively long time. This technique has already shown great potential for the analysis of biomass, favouring the formation of only the most thermostable compounds. In this work, both fast and reactive pyrolysis with on-line gas chromatography-mass spectrometry analysis (Py-GC/MS) are used to study fructose, inulin and Jerusalem artichoke tubers (Heliantus tuberosus). Interesting differences were found between the two systems, and became even more evident as the reaction time was increased. The most striking result was the formation of di-fructose dianhydrides (DFAs), a class of compounds with interesting biological activities. DFAs were obtained in high yields from reactive pyrolysis, but not from fast pyrolysis. Hypotheses on the pyrolysis mechanisms were made based upon the composition of the pyrolysates. This work describes for the first time the behaviour of fructans under reactive pyrolysis. PMID- 29534798 TI - Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species. AB - An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity. PMID- 29534799 TI - Solvent-terminated dispersive liquid-liquid microextraction: a tutorial. AB - Solvent-terminated dispersive liquid-liquid microextraction (ST-DLLME) is a special mode of DLLME in which a demulsifying solvent is injected into the cloudy mixture of sample/extractant to break the emulsion and induce phase separation. The demulsification process starts by flocculation of the dispersed microdroplets by Ostwald ripening or coalescence to form larger droplets. Then, the extractant either floats or sinks depending on its density as compared with that for the aqueous sample. The demulsifier should have high surface activity and low surface tension in order to be capable of inducing phase separation. The extraction efficiency in ST-DLLME is controlled by the same experimental variables of normal DLLME (n-DLLME) such as the type and volume of the extractant as well as the disperser. Other parameters such as pH and the temperature of the sample, the stirring rate, the time of extraction and the addition of salt are also important to consider. Along with these factors, the demulsifier type and volume and the demulsification time have to be optimized. By using solvents to terminate the dispersion step in DLLME, the centrifugation process is not necessary. This in turn improves precision, increases throughput, decreases the risk of contamination through human intervention and minimizes the overall analysis time. ST-DLLME has been successfully applied for determination of both inorganic and organic analytes including pesticides and pharmaceuticals in water and biological fluids. Demulsification via solvent injection rather than centrifugation saves energy and makes ST-DLLME easier to automate. These characteristics in addition to the low solvent consumption, the reduced organic waste and the possibility of using water in demulsification bestow green features on ST-DLLME. This tutorial discusses the principle, the practical aspects and the different applications of ST-DLLME. PMID- 29534800 TI - Amplification strategy for sensitive detection of methyltransferase activity based on surface plasma resonance techniques. AB - In this work, a newly developed surface plasma resonance (SPR) system for the sensitive detection of M.SssI activity has been designed based on double signal amplification with DNA chain cyclic reactions and AuNPs. In the absence of M.SssI, hairpin DNA 1 (HP1) can be cleaved into s1 fragments catalyzed by HpaII. The s1 fragments can then trigger a recycling process of hairpin DNA 2 (HP2) hybridization and subsequently release massive s2 and s3 in the solution of Nt.AlwI and HPII. AuNPs-DNA can be captured on gold film by the released s2 and s3 to produce a strong SPR signal. Whereas in the presence of M.SssI, methylated HP1 cannot be cleaved by HpaII, thus produce a weak SPR signal. The SPR signals are dependent on the M.SssI concentration in the range from 0.5 to 50 U/mL. The successful detection of M.SssI activity in clinical serum samples and inhibition of M.SssI using 5-Aza and 5-Aza-dC indicate a great potential of this strategy for building new monitoring platform in bioanalysis and clinical biomedicine. PMID- 29534801 TI - Development of a fast and sensitive method for measuring multiple neonicotinoid insecticide residues in soil and the application in parks and residential areas. AB - A method for simultaneous measure of nine neonicotinoid insecticide residues in soil was developed by using liquid chromatography-tandem mass spectrometry (LC MS/MS) coupled with a quick pretreatment procedure. The soil was extracted with a mixture of acetonitrile and dichloromethane (1:2, v:v) and cleaned up with Primary Secondary Amine (PSA). Matrix-matched standards were prepared to eliminate the interference of the matrix. The LC-MS/MS conditions were optimized to separate the nine neonicotinoids within 6.7 min, and the obtained limits of detection (LODs) and limits of quantification (LOQs) ranged from 0.01 to 0.84 ng g-1 and 0.05-2.79 ng g-1, respectively. Recoveries of the studied neonicotinoids (except for nitenpyram) ranged from 79.41 to 100.20% with relative standard deviations (RSDs) less than 10% at spiked levels of 5 ng mL-1, 100 ng mL-1 and 500 ng mL-1, and RSDs for the interday and intraday method repeatability were less than 9%. The method was applied to measure neonicotinoid residues in soil samples collected from parks (n = 35) and residential areas (n = 33) in Tianjin, China. Seven neonicotinoids were detected, with imidacloprid being the most frequently detected one, followed by acetamiprid and thiamethoxam. The total concentrations of neonicotinoids in soil ranged from 0.27 to 230.76 ng g-1 in parks and 0.23-132.66 ng g-1 in residential areas. PMID- 29534802 TI - Electrical double layer modulation of hybrid room temperature ionic liquid/aqueous buffer interface for enhanced sweat based biosensing. AB - We have investigated the role of kosmotropic anionic moieties and chaotropic cationic moieties of room temperature hydrophilic ionic liquids in enhancing the biosensing performance of affinity based immunochemical biosensors in human sweat. Two ionic liquids, 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM[BF4]) and choline dihydrogen phosphate (Choline[DHP]) were investigated in this study with Choline[DHP] being more kosmotropic in nature having a more protein stabilizing effect based on the hofmeister series. Non-faradaic interfacial charge transfer has been employed as the mechanism for evaluating the formation and the biosensing of capture probe antibodies in room temperature ionic liquids (RTILs)/aqueous human sweat interface. The charge of the ionic moieties were utilized to form compact electrical double layers around the antibodies for enhancing the stability of the antibody capture probes, which was evaluated through zeta potential measurements. The zeta potential measurements indicated stability of antibodies due to electrostatic repulsion of the RTIL charged moieties encompassing the antibodies, thus preventing any aggregation. Here, we report for the first time of non-faradaic electrochemical impedance spectroscopy equivalent circuit model analysis for analyzing and interpreting affinity based biosensing at hybrid electrode/ionic liquid-aqueous sweat buffer interface guided by the choice of the ionic liquid. Interleukin-6 (IL-6) and cortisol two commonly occurring biomarkers in human sweat were evaluated using this method. The limit of detection (LOD) obtained using both ionic liquids for IL-6 was 0.2 pg mL-1 with cross-reactivity studies indicating better performance of IL-6 detection using Choline[DHP] and no response to cross-reactive molecule. The LOD of 0.1 ng/mL was achieved for cortisol and the cross-reactivity studies indicated that cortisol antibody in BMIM[BF4] did not show any signal response to cross-reactive molecules. Furthermore, improved sensitivity and LOD was achieved using ionic liquids as compared to capture probes in aqueous buffer. PMID- 29534803 TI - Tuning of the perylene probe excimer emission with silver nanoparticles. AB - Silver nanoparticles (Ag NPs) enhanced perylene probe excimer emission is reported for the first time. It was observed that strong interactions between the perylene probe and the Ag NPs induced co-aggregation. As a result, a new in situ generated plasmonic absportion band of the Ag NPs at longer wavelength emerged. The monomer emission of the perylene probe was efficiently quenched, and dramatically enhanced probe excimer emission was observed. A remarkable emission enhancement of over 1000 fold was obtained compared to anionic polymers and other nanoparticles. The excimer emission intensity could be finely modulated by the size of the Ag NPs and the functionalities of the perylene probe. The observed Ag NPs enhanced perylene probe excimer emission shows good potential for the development of novel sensing techniques for various bioanalytical applications. PMID- 29534804 TI - Visual detection of cyclobutane pyrimidine dimer DNA damage lesions by Hg2+ and carbon dots. AB - Cyclobutane pyrimidine dimmers (CPDs) and 6-4-[pyrimidine-2'-one] pyrimidine (6-4 PP) are major UV induced DNA damage lesions formed from solar radiation and other sources. CPD lesions are presumably mutagenic and carcinogenic that inhibit polymerases and interfere in DNA replication. An easy and cost effective way for visual detection of these lesions by using fluorescence based method is shown here. Artificial UVA and UVB lights were used for the generation of CPD and 6-4 PPs in selected DNA samples. Binding of Hg2+ ions with DNA before and after induction of CPD and 6-4 PP lesions was evaluated in the presence of highly fluorescent blue emitting carbon dots (CDs). Induction of CPD and 6-4 PPs in DNA causes distortion of DNA structure which hinders the binding of Hg2+ ions to DNA nucleobases. Quenching of fluorescence intensity of CDs by unbound Hg2+ ions was found to be proportional to the amount of CPD and 6-4 PP lesions induced by UV irradiation of DNA samples that offer a biosensing platform for the sensitive detection of CPD lesions in DNA. The fluorescent quenching was visually detectable using hand held UV light without the intervention of any equipment. PMID- 29534805 TI - Bioactivity-guided cut countercurrent chromatography for isolation of lysine specific demethylase 1 inhibitors from Scutellaria baicalensis Georgi. AB - Countercurrent chromatography (CCC) has gradually become a widely used method for preparative separation of bioactive natural molecules. These molecules generally contain distinct scaffolds and characteristics that cannot be readily isolated from plants. While one-dimensional CCC is typically used for the initial purification with insufficiently resolved peaks after locating bioactive components, two-dimensional (2D) or multi-dimensional CCC strategies are employed to improve the resolution of peaks. However, these methods usually present certain disadvantages, such as complicated procedures and increased time consumption, experimental costs, and equipment requirements. Here, a bioactivity guided cut CCC strategy was established to isolate lysine-specific demethylase 1 (LSD1) inhibitors from Scutellaria baicalensis Georgi. Gradient-elution CCC coupled with real-time detection of LSD1 inhibition by the collected fractions was developed. Next, an online-storage recycling CCC mode was designed to enable the active fractions to be stored in coils, and these active fractions were further separated to obtain pure compounds by using sequential recycling elution. In this strategy, active fractions are first identified, and then pure LSD1 inhibitors are isolated in the 2D CCC mode through continuous separation on a single instrument. By using our bioactivity-guided cut CCC strategy, we successfully isolated six natural LSD1 inhibitors from S. baicalensis Georgi, five of which were identified for the first time as natural LSD1 inhibitors. PMID- 29534806 TI - Selectivity of hexaphenylbenzene-based hydrocarbon stationary phase with propeller-like conformation for aromatic and aliphatic isomers. AB - Herein we report a propeller-like hexaphenylbenzene-based hydrocarbon material (denoted as BT) as the stationary phase for capillary gas chromatography (GC). The statically-coated BT capillary column showed a high column efficiency of 4340 plates m-1 and weak polarity. Owing to its unique conformation, pi-electron toroidal delocalization and intrinsic microporosity, the BT stationary phase exhibited interesting selectivity for aromatic compounds over alkanes. Compared with the graphene (G) column, the BT column showed much prolonged retention and high selectivity for aromatic isomers, especially methylnaphthalenes, dimethylnaphthalenes and phenanthrene/anthracene, mainly because of its propeller like conformation with rich intercalation effects. Moreover, it exhibited good column repeatability (intra-day, inter-day) and reproducibility (between-column) with RSD values on the retention times less than 0.08% for intra-day, 0.32% for inter-day and 3.8% for between-column, respectively. Also, it showed good potential for determination of minor isomer impurities in real samples. To the best of our knowledge, this work presents the first example of employing an neat aromatic hydrocarbon material as the GC stationary phase with high selectivity for analytes of a wide ranging polarity. PMID- 29534807 TI - Biomarkers of oxidative stress derived damage to proteins and DNA in human breast milk. AB - Oxidative stress derived biomarkers have been extensively studied for assessing pathological situations in the neonatal period and their usefulness for an early outcome prediction of oxidative stress related diseases in non-invasive biofluids could be demonstrated. This is the first report on a method for the simultaneous detection of a panel of oxidative stress related biomarkers for quantifying damage to proteins and DNA in human breast milk samples. A straightforward sample clean-up procedure using 1.5 mL of milk was developed and extracts were analyzed by ultra-performance liquid chromatography coupled to tandem mass spectrometry. The analytical method was validated and applied to human milk samples from a cohort of mothers of preterm infants, as well as donor human milk samples before and after pasteurization at a human milk bank. The results demonstrate the feasibility of this method for the analysis of a panel of oxidative stress related biomarkers, reporting ranges found in human milk. PMID- 29534808 TI - Investigation of retention of undesirable organic matter from aqueous samples in stopped-flow dialysis procedures for inorganic anions. AB - Sample preparation is a key issue in the analysis of many real samples using ion chromatography (IC). One of the many means of sample preparation that has received considerable attention in recent years is the stopped-flow in-line dialysis approach hyphenated to IC. Using appropriate dialysis membranes undesirable high-molecular weight compounds, colloids and dispersed particulate matter are retained whereas the analyte ions pass through the membrane and are separated and quantified by IC. However, in the many papers about analytical use of in-line dialysis (not only in connection with IC) the retention of undesirable compounds has never been quantified. This study is a first attempt to fil this gap. The breakthrough (BT) of humic acids (HA) and lignin as model compounds often contained in natural water samples was investigated in the stopped-flow dialysis procedure using different dialysis membranes. BT was measured and quantified by UV-absorption in the receiver solution leaving the dialysis cell. The most important factor for retention of undesired compounds is the pore size or the molecular weight cut-off (MWCO) of the dialysis membrane. In addition, the recovery of analytes in acceptable time needs to be considered. The optimized system addresses these two aspects and permits using the proper membrane almost quantitative recovery of several inorganic ions and at the same time almost complete retention of the model interferents. Artificial natural water samples were prepared and analyzed containing a mixture of HA, lignin and a surfactant and a number of anions. In long-term operation no alterations of the dialysis process occurred and no adverse effects in IC separations were observed. PMID- 29534809 TI - Practical Fluid Therapy and Treatment Modalities for Field Conditions for Horses and Foals with Gastrointestinal Problems. AB - With advances in technology and owner education, field management in equine veterinary medicine continues to evolve. Equine gastrointestinal disease is one of the most common types of emergencies evaluated by equine practitioners, and many of these patients can be effectively managed in the field. Although the equine veterinarian must make numerous decisions, fluid therapy, pain management, and antimicrobial use are 3 of the major choices that must be addressed when initiating field treatment of equine gastrointestinal disease. This article addresses the practical use of these 3 treatment categories that are essential to field practice. PMID- 29534810 TI - Advances in Diagnostics and Treatments in Horses and Foals with Gastric and Duodenal Ulcers. AB - Equine gastric ulcer syndrome (EGUS) primarily describes ulceration in the terminal esophagus, nonglandular squamous mucosa, glandular mucosa of the stomach, and proximal duodenum. EGUS is common in all breeds and ages of horses and foals. This article focuses on the current terminology for EGUS, etiologies and pathogenesis for lesions in the nonglandular and glandular stomach, diagnosis, and a comprehensive approach to the treatment and prevention of EGUS in adult horses and foals. PMID- 29534811 TI - Advances in the Diagnosis and Management of Equine Gastrointestinal Diseases. PMID- 29534812 TI - Risk factors for organ space infection after ileal pouch anal anastomosis for chronic ulcerative colitis: An ACS NSQIP analysis. AB - BACKGROUND: Organ space infection (OSI) after ileal pouch anal anastomosis (IPAA) is a devastating complication. The aim of this was study was to determine separately risk factors for OSI after total proctocolectomy (TPC) with IPAA and completion proctectomy (CP) with IPAA. METHODS: 4049 patients with a diagnosis of chronic ulcerative colitis undergoing TPC with IPAA or CP with IPAA between 2005 and 2015 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Primary outcome was an OSI within 30 days of surgery. Multivariable analyses were conducted for the development of OSI after each operation. RESULTS: For TPC with IPAA, urgent surgery (OR: 2.0, p < 0.01) and obesity (OR: 1.6, p < 0.01) were independent risk factors for OSI. Operation length of 275 + minutes (versus <170 min; OR: 2.2, p = 0.02) was predictive of OSI after CP with IPAA. CONCLUSION: Risk factors for OSI differed between the operations. This highlights the importance of the consideration of the physiologic status of the patient when deciding to perform TPC with IPAA or subtotal colectomy with ileostomy initially. PMID- 29534814 TI - LaSalle D. Leffall and mentorship. PMID- 29534813 TI - Discussion of "Higher robotic colorectal surgery volume improves outcomes". PMID- 29534815 TI - Conscious sedation versus rapid sequence intubation for the reduction of native traumatic hip dislocation. AB - BACKGROUND: Traumatic hip dislocations (THD) are a medical emergency. There is debate whether the painful reduction of a dislocated hip should be first attempted using primary conscious sedation (PCS) or primary general anesthesia (PGA) METHODS: All cases of native THD from 2006 to 2015 in the trauma registry of a level 1 trauma center were reviewed. The primary outcome was successful reduction of the THD. RESULTS: 67 patients had a native, meaning not a hip prosthesis, THD. 34 (50.7%) patients had successful PCS, 12 (17.9%) failed PCS and underwent reduction following PGA. 21 (31.3%) underwent PGA. Patients in the PGA group were more severely injured. Time to reduction greater than 6 h was associated with PCS failure (Odds ratio (95% confidence interval) 19.75 (2.06,189.10) p = 0.01). CONCLUSION: Clinicians treating patients with a THD can utilize either PCS or PGA with many patients safely reduced under PCS. However, patients whose hip have been dislocated for more than 6 h are at risk for failure with PCS, and are good candidates for PGA. PMID- 29534816 TI - Increased hospice enrollment and decreased neurosurgical interventions without changes in mortality for older Medicare patients with moderate to severe traumatic brain injury. AB - BACKGROUND: Hospice improves quality and value of end of life care (EOLC), and enrollment has increased for older patients dying from chronic medical conditions. It remains unknown if the same is true for older patients who die after moderate to severe traumatic brain injury (msTBI). METHODS: Subjects included Medicare beneficiaries (>=65 years) who were hospitalized for msTBI from 2005 to 2011. Outcomes included intensity and quality of EOLC for decedents within 30 days of admission, and 30-day mortality for the entire cohort. Logistic regression was used to analyze the association between year of admission, mortality, and EOLC. RESULTS: Among 50,342 older adults, 30-day mortality was 61.2%. Mortality was unchanged over the study period (aOR 0.93 [0.87-1.00], p = 0.06). Additionally, 30-day non-survivors had greater odds of hospice enrollment, lower odds of undergoing neurosurgery, but greater odds of gastrostomy. CONCLUSION: Between 2005 and 2011, hospice enrollment increased, but there was no change in 30-day mortality. PMID- 29534817 TI - LaSalle D. Leffall and disparities in breast cancer. PMID- 29534818 TI - The independent effect of emergency general surgery on outcomes varies depending on case type: A NSQIP outcomes study. AB - BACKGROUND: Emergency general surgery (EGS) is an independent risk factor for morbidity and mortality, and seven procedures account for 80% of the National burden of operative EGS. We aimed to characterize the excess morbidity and mortality attributable to these procedures based on the level of procedural risk. METHODS: Retrospective analysis of the ACS National Surgical Quality Improvement Project (ACS-NSQIP) database. (2005-2014). Seven EGS procedures were stratified as high risk and low risk. Primary outcomes were overall mortality, overall morbidity, major morbidity. Multivariable logistic regression was performed. RESULTS: There were 619,174 patients identified. Comparing EGS to non-EGS in high risk cases the OR for overall mortality was 1.39(1.33,1.45), overall morbidity 1.07 (0.98, 1.16), and major morbidity 1.15(1.03,1,27). In low-risk cases the OR for overall mortality was 1.03 (0.89, 1.19) overall morbidity 1.35 (1.23, 1.48), and major morbidity 2.18(1.90, 2.50). CONCLUSIONS: Using a Nationally representative clinical database we identified significant heterogeneity in the outcomes of EGS depending on procedural risk. Risk stratification and benchmarking strategies need to account for the inherent heterogeneity of EGS. PMID- 29534819 TI - The tale of two stories: Challenges and innovations in breast cancer management. AB - The keynote address The Tale of Two Stories: Challenges and Innovations in Breast Cancer Management presented on March 19-20, 2017 at the celebratory Festschrift Lecture in honor of the great Dr. LaSalle Leffall's on behalf of his impact and contributions to the field of Breast cancer science and treatment as a leader, surgeon, and mentor. This presentation and follow up opinion paper in the field of Breast Disease highlights the challenges that have baffled us and the innovations that have changed and translated into outcomes and those that have not. Where do they parallel and what are the gaps? PMID- 29534820 TI - Determination of finasteride and its metabolite in urine by dispersive liquid liquid microextraction combined with field-enhanced sample stacking and sweeping. AB - The on-line preconcentration technique of field-enhanced sample stacking and sweeping (FESS-sweeping) are combined with dispersive liquid-liquid microextraction (DLLME) to monitor the concentrations of finasteride, which is used in the treatment of androgenetic alopecia, and its metabolite, finasteride carboxylic acid (M3), in urine samples. DLLME is used to concentrate and eliminate the interferences of urine samples and uses chloroform as an extracting solvent and acetonitrile as a disperser solvent. A high conductivity buffer (HCB) was introduced into capillary and then sample plug (90.7% capillary length) was injected into capillary. After applying voltage, the sodium dodecyl sulfate (SDS) swept the analytes from the low conductivity sample solution into HCB. The analytes were concentrated on the field-enhanced sample stacking boundary. The limit of detection for the analytes is 20 ng mL-1. The sensitivity enrichment of finasteride and M3 are 362-fold and 480-fold, respectively, compared with the conventional MEKC method. The on-line preconcentration technique of field enhanced sample stacking and sweeping possess good selectivity because the endogenous steroid did not interfere the detection of finasteride and M3. The analytical technique is applied to investigate the concentrations in urine samples from patients who have been administered finasteride for the treatment of androgenetic alopecia; the amount of M3 detected in 12 h was 72.69 +/- 4.18 MUg. PMID- 29534821 TI - Evaluation of flavour profiles in e-cigarette refill solutions using gas chromatography-tandem mass spectrometry. AB - Many flavour compounds that are present in e-liquids for e-cigarettes are responsible for specific tastes and smoking sensations for users. Data concerning content and specific types of flavours is often limited and unknown to users. The aim of the research was to define and compare flavour profiles of e-liquids with the same group taste from different manufacturers. Gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) was used to separate and identify 90 popular compounds (98, including isomers) of interest. The developed method was validated in terms of accuracy (88-113%) for three spiking levels and the intra day (0.2-13%) and inter-day precision (1-10%). Limits of quantitation were in the range of 10-816 ng/mL, while the matrix effects for 80% of the compounds were at negligible levels. The proposed method is rapid, simple and reliable and uses a green and modern GC-MS/MS technique. Twenty-five samples of five different flavours (tobacco, strawberry, cherry, menthol and apple) from five different producers were analysed, and the determined compounds were categorized and differentiated. The approach proposed in this study allowed for the evaluation of which compounds/group of compounds are responsible for taste and to distinguish common flavour compounds among the investigated brands for each flavour. Furthermore, the presented research can be considered in future toxicological studies. PMID- 29534822 TI - Author's Response. PMID- 29534823 TI - A retrospective multicenter study of the natural history of fetal ovarian cysts. AB - AIM: We investigated the natural history of fetal ovarian cysts to estimate the risk of torsion according to size. METHODS: Cases were identified from 1/1/2000 until 1/1/2015. Data were collected pre- and postnatally on cyst size and sonographic features until an outcome of surgery, torsion, or resolution. Fisher's exact test for categorical data and logistic regression for continuous data were used to test the significance of size on torsion; P value <0.05 was considered significant. RESULTS: 37 patients with unilateral ovarian cysts were included. 12 (32%) resolved spontaneously prenatally, 14 (38%) resolved spontaneously postnatally, 5 (14%) underwent surgery postnatally and 6 (16%) cases underwent torsion. Rate of torsion increased with size from 0% (n=0) in cysts <=20mm to 33% (n=2) in cysts >50mm; however, the overall trend failed to reach statistical significance (P=0.1). Cysts of 0-40mm had a significantly higher rate of spontaneous resolution (90% vs. 44% in >40mm, P=0.003), but the rate of torsion was not significantly different (10% in 0-40mm vs. 25% in >40mm, P=0.26). The median time to postnatal resolution was 10 (5-27) weeks in those treated conservatively. CONCLUSION: Cysts >40mm are significantly less likely to resolve spontaneously; however torsion showed no significant correlation with cyst size. No complications were observed in cysts <20mm. LEVEL OF EVIDENCE: IV, case series with no comparison group. PMID- 29534824 TI - Long-term outcomes for children with very early-onset colitis: Implications for surgical management. AB - PURPOSE: The timing of J-pouch surgery following colectomy for children with very early-onset colitis is controversial, with some advocating early reconstruction and others delaying reconstruction because of fear that the colitis may be owing to Crohn's disease (CD). We sought to determine the long-term incidence of CD in this population and whether there may be clinical features that predict the risk of CD. METHODS: Children with noninfectious colitis diagnosed prior to age 10, who underwent subtotal colectomy and ileostomy from 2000 to 2015, were reviewed. RESULTS: Twenty-five children were identified. Median age at presentation was 5.4years. Four were initially diagnosed with CD (16%), 14 with ulcerative colitis (UC) (56%), and 7 with inflammatory bowel disease unclassified (IBD-U) (28%). Eight eventually had pouch surgery. Five of the children with an initial diagnosis of UC or IBD-U developed findings that changed the diagnosis to CD at a median age of 13.4 (range 10.3 to 16.7) years. None had any indicators of CD at the initial presentation. CONCLUSIONS: Approximately one quarter of patients with very early-onset colitis originally diagnosed as UC or IBD-U had a reclassification in diagnosis to CD over time. J-pouch reconstruction should be delayed until adolescence in children with very early-onset colitis. LEVEL OF EVIDENCE: 2C. PMID- 29534825 TI - Prevalent and Incident Heart Failure in Cardiovascular Outcome Trials of Patients With Type 2 Diabetes. AB - Despite multiple examples of glucose-lowering therapies affecting heart failure (HF) risk, ascertainment of HF data in cardiovascular outcome trials of these medications has not been systematically characterized. In this review, large (n >1,000) published phase III and IV cardiovascular outcome trials evaluating glucose-lowering therapies through June 2017 were identified. Data were abstracted from publications, U.S. Food and Drug Administration advisory committee records, and U.S. Food and Drug Administration labeling documents. Overall, 21 trials including 152,737 patients were evaluated. Rates and definitions of baseline HF and incident HF were inconsistently provided. Baseline ejection fraction data were provided in 3 studies but not specific to patients with HF. No trial reported functional class, ejection fraction, or HF therapy at the time of incident HF diagnosis. HF hospitalization data were available in 15 trials, but only 2 included HF-related events within the primary composite endpoint. This systematic review highlights gaps in HF data capture within cardiovascular outcome trials of glucose-lowering therapies and outlines rationale and strategies for improving HF characterization. PMID- 29534826 TI - Reduction in Percoll volume increases recovery rate of sex-sorted semen of bulls without affecting sperm quality and early embryonic development. AB - The aim of the present study was to evaluate the effects of Percoll volume on recovery rate, sperm quality, and embryo development kinetics in in vitro production of cattle embryos. Straws of conventional and sex-sorted semen were allocated to three different volumes of Percoll: 300 MUL of each Percoll gradient (90%, 60%, and 30%), Control; 100 MUL of each Percoll gradient, P100; and 200 MUL of each Percoll gradient, P200. Sperm quality, fertilization rate, and embryo morpho-kinetic development using time lapse cinematography up to 48 h post insemination were evaluated. For conventionally processed semen, sperm motility, vigor, and recovery rate were greater in the P100 and P200 treatment groups compared to the Control (P < 0.05), whereas reactive oxygen species (ROS) concentrations, lipid peroxidation, and superoxide dismutase enzyme activity were not influenced by treatments. For sex-sorted semen, treatment with P100 increased sperm curvilinear velocity, average path velocity, and amplitude of lateral head displacement (P < 0.05). Recovery rate was greater in the P100 group than Control and P200 groups (P < 0.05), formation of ROS was less in the P100 than Control and P200 groups, and superoxide dismutase enzyme activity was less in the P100 than Control group. Fertilization and cleavage rates, time of first cleavage, and cell number were similar between the P100 and Control groups (P > 0.05). The inclusion of Percoll volumes of 100 MUL resulted in an increased sperm recovery rate without damage to sperm quality or affecting early embryonic development. PMID- 29534827 TI - Effects of immunization against bone morphogenetic protein-15 and growth differentiation factor-9 on ovarian function in mares. AB - Currently there is no contraceptive vaccine that can cause permanent sterility in mares. This study investigates the effect of vaccination against oocyte-specific growth factors, Bone Morphogenetic Protein 15 (BMP-15) and Growth Differentiation Factor 9 (GDF-9), on ovarian function of mares. It was hypothesized that immunization against these growth factors would prevent ovulation and/or accelerate depletion of the oocyte reserve. For this study, 30 mares were randomly assigned to three groups (n = 10/group) and vaccinated with BMP-15 or GDF-9 peptides conjugated to KLH and adjuvant, or a control of phosphate buffered saline and adjuvant. Horses received vaccinations at weeks 0, 6, 12, and 18. Ovarian activity and estrous behavior were evaluated 3 days a week via ultrasonography and interaction with a stallion. The study was initiated on March1, 2016. Upon evaluation of ovulation rate, the GDF-9 group did not have a difference (P = 0.66) in ovulation rate when compared to controls (10.8 and 10.0 ovulations, respectively), but the number of ovulations in the BMP-15 group was less (P = 0.02; 4.9 ovulations). Average follicle size prior to ovulation was less (P < 0.0001) in both treatment groups compared to controls. Estrous behavior was altered in both the BMP-15 and GDF-9 groups compared to controls after the second vaccination (P = 0.05 and 0.03, respectively). Although further research is required to determine the continued effects of vaccination against GDF-9 on ovulation rates, these results indicate that vaccination against BMP-15 and GDF-9 could serve as a contraceptive in wild horse populations. PMID- 29534828 TI - Dose dependence of accelerated repopulation in head and neck cancer: Supporting evidence and clinical implications. AB - BACKGROUND AND PURPOSE: Accelerated repopulation (AR) can compromise tumor control after conventional radiotherapy for fast-growing tumors. Standard AR models assume it begins at a fixed time, with repopulation rates independent of the number of clonogens killed. We investigate the validity and significance of an alternative model where onset-time and rate of AR depend on the number of clonogens killed, and thus on dose and dose-fractionation. MATERIALS AND METHODS: We analyzed tumor control (TCP) from randomized trials for head and neck cancer (HNC, 7283 patients), featuring wide ranges of doses, times, and fractionation schemes. We used the linear-quadratic model with the standard dose-independent AR model, or with an alternative dose-dependent model, where AR onset and rate depend on clonogen killing. RESULTS: The alternative dose-dependent model of AR provides significantly-improved descriptions of a wide range of randomized clinical data, relative to the standard dose-independent model. This preferred model predicts that, for currently-used HNC fractionation schemes, the last 5 fractions do not increase TCP, but simply compensate for increased accelerated repopulation. CONCLUSIONS: The preferred dose-dependent AR model predicts that, for standard fractionation schemes currently used to treat HNC, the final week (5 fractions) could be eliminated without compromising TCP, but resulting in significantly decreased late sequelae due to the lower overall dose. PMID- 29534829 TI - Use of extracranial radiation therapy in metastatic melanoma patients receiving immunotherapy. AB - PURPOSE: Explore the patterns of use of extracranial radiation therapy (RT) in metastatic melanoma patients receiving immunotherapy, its potential association with OS, the impact of the site and timing of RT on clinical outcomes when combined with immunotherapy. MATERIALS AND METHODS: Patients with extracranial metastatic melanoma who received immunotherapy with or without extracranial RT from 2004 to 2013 were obtained from the National Cancer Database. Multivariable Cox regression analysis was used to evaluate factors associated with overall survival (OS). Subset analyses comparing outcomes in patients receiving RT to bone metastases versus soft tissue metastases were also performed. OS was compared using the Kaplan-Meier and log-rank statistics. RESULTS: A total of 1675 patients were identified: 1387 received immunotherapy alone and 288 received immunotherapy plus RT. An increase in the utilization of RT as well as SBRT was noted over time. The rate of RT use was 11.5% (0% with SBRT) in 2004 and gradually rose to 19.8% (27.0% with SBRT) in 2013 (P = 0.04). The median OS was 15.4 vs. 19.4 months in the immunotherapy plus RT and immunotherapy alone groups, respectively (P = 0.02). However, on multivariable analysis, RT was not associated with worse OS. The poor OS in the RT group was confined to the patients who received RT to bone metastases, but not in patients who received RT to soft tissue metastases. In subset analyses of patients irradiated to soft tissue, RT administered at least 30 days before immunotherapy was associated with a higher OS than RT administered within 30 days or 30 days after immunotherapy: median 26.1 months vs. 16.0 months (P = 0.009) vs. 15.4 months (P = 0.004), respectively. CONCLUSIONS: This study demonstrates that extracranial RT plays an increasing role in the management of metastatic melanoma patients in the era of immunotherapy. The site and the timing of RT may have important interaction with immunotherapy, and need to be carefully considered in future clinical trials. PMID- 29534830 TI - Fetal auditory evoked responses to onset of amplitude modulated sounds. A fetal magnetoencephalography (fMEG) study. AB - The human fetal auditory system is functional around the 25th week of gestational age when the thalamocortical connections are established. Fetal magnetoencephalography (fMEG) provides evidence for fetal auditory brain responses to pure tones and syllables. Fifty-five pregnant women between 31 and 40 weeks of gestation were included in the study. Fetal MEG was recorded during the presentation of an amplitude modulated tone (AM) with a carrier frequency of 500 Hz to the maternal abdomen modulated by low modulation rates (MRs) - 2/s and 4/s, middle MR - 8/s and high MRs - 27/s, 42/s, 78/s and 91/s. The aim was to determine whether the fetal brain responds differently to envelope slopes and intensity change at the onset of the AM sounds. A significant decrease of the response latencies of transient event-related responses (ERR) to high and middle MRs in comparison to the low MRs was observed. The highest fetal response rate was achieved by modulation rates of 2/s, 4/s and 27/s (70%, 57%, and 86%, respectively). Additionally, a maturation effect of the ERR (response latency vs. gestational age) was observed only for 4/s MR. The significant difference between the response latencies to low, middle, and high MRs suggests that still before birth the fetal brain processes the sound slopes at the onset in different integration time-windows, depending on the time for the intensity increase or stimulus power density at the onset, which is a prerequisite for language acquisition. PMID- 29534831 TI - Vowel and tone recognition in quiet and in noise among Mandarin-speaking amusics. AB - Music and language are two intricately linked communication modalities in humans. A deficit in music pitch processing as manifested in the condition of congenital amusia has been related to difficulties in lexical tone processing for both tone and non-tonal languages. However, it is still unclear whether amusia also affects the perception of vowel phonemes in quiet and in noise. In this study, we examined vowel-plus-tone identification in quiet and noise conditions among Mandarin-speaking amusics with and without speech tone difficulties (tone agnosics and pure amusics, respectively), and IQ- and age-matched controls. Overall, pure amusics showed vowel and tone identification comparable to the controls in both quiet and noise conditions. Compared to pure amusics and controls, tone agnosics showed deficits in tone perception in both quiet and noise conditions. More importantly, their vowel perception was lower than pure amusics and controls in noise conditions, e.g., at a signal-to-noise ratio of -4 dB, although they showed normal-like performance in quiet and at a signal-to noise ratio of -8 dB. These results suggest that when amusia affected speech tone processing (e.g., tone agnosics), it could also compromise vowel processing in noise. However, amusia alone does not affect tone or vowel perception in Mandarin Chinese either in quiet or in noise. Overall, the current study highlights the necessity of taking heterogeneity within the amusic group into account when considering the related speech deficits in this group. PMID- 29534832 TI - Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A multicenter review. AB - OBJECTIVES: Low grade endometrial stromal sarcoma (LG-ESS) is a rare cancer with an indolent course. We aimed to assess the effectiveness of adjuvant hormonal suppression (HT) with or without oophorectomy (BSO) in prolonging progression free survival (PFS) and overall survival (OS) in patients with LG-ESS. METHODS: We performed a multi-institutional retrospective review of patients treated for low grade LG-ESS from 1985 to 2014. Demographics, treatment and recurrence data were abstracted from medical records. Pathologic diagnosis was confirmed by a gynecologic pathologist. Long-term patient-reported outcomes were obtained via mailed survey. RESULTS: One-hundred-twelve patients underwent surgery for LG-ESS; 59 had postoperative data with a median follow-up of 55months (1-325months). The mean age at diagnosis was 48.5years (22-82years). Forty-nine (61%) had stage I disease. The most common presenting symptoms were abnormal uterine bleeding (38%) and pelvic mass (17%). Seventy-one (63%) patients had BSO at the time of diagnosis. Of the 59 patients with postoperative follow-up information, 49 (73%) underwent BSO, 26 (44%) received HT, 20 (33%) were expectantly managed, and 6 (10%) received chemotherapy, radiation or both. Median PFS for the entire group was 53months and OS was 63months. PFS for those who underwent BSO compared with those who retained their ovaries was 38 vs 11months, p=0.071. PFS for HT vs no HT was 28 vs 23months, p=0.77. CONCLUSIONS: Consistent with prior series, our results support BSO to prolong PFS in LG-ESS but are limited by sample size. Larger studies with more complete follow-up are needed to determine the effect of adjuvant hormonal suppression. PMID- 29534833 TI - Seasonal dynamics of trace elements in sediment and seagrass tissues in the largest Zostera japonica habitat, the Yellow River Estuary, northern China. AB - Trace element accumulation is an anthropogenic threat to seagrass ecosystems, which in turn may affect the health of humans who depend on these ecosystems. Trace element accumulation in seagrass meadows may vary temporally due to, e.g., seasonal patterns in sediment discharge from upstream areas. In addition, when several trace elements are present in sufficiently high concentrations, the risk of seagrass loss due to the cumulative impact of these trace elements is increased. To assess the seasonal variation and cumulative risk of trace element contamination to seagrass meadows, trace element (As, Cd, Cr, Cu, Pb, Hg, Mn and Zn) levels in surface sediment and seagrass tissues were measured in the largest Chinese Zostera japonica habitat, located in the Yellow River Estuary, at three sites and three seasons (fall, spring and summer) in 2014-2015. In all three seasons, trace element accumulation in the sediment exceeded background levels for Cd and Hg. Cumulative risk to Z. japonica habitat in the Yellow River Estuary, from all trace elements together, was assessed as "moderate" in all three seasons examined. Bioaccumulation of trace elements by seagrass tissues was highly variable between seasons and between above-ground and below-ground biomass. The variation in trace element concentration of seagrass tissues was much higher than the variation in trace element concentration of the sediment. In addition, for trace elements which tended to accumulate more in above-ground biomass than below-ground biomass (Cd and Mn), the ratio of above-ground to below ground trace element concentration peaked at times corresponding to high water discharge and high sediment loads in the Yellow River Estuary. Overall, our results suggest that trace element accumulation in the sediment may not vary between seasons, but bioaccumulation in seagrass tissues is highly variable and may respond directly to trace elements in the water column. PMID- 29534834 TI - Immunohistochemical localization of osteoblast activating peptide in the mouse kidney. AB - Osteoblast activating peptide (OBAP) is a newly discovered peptide detected in the rat stomach, which has a major role in osteogenesis. Recently, we revealed its localization in the parietal cells of the rat stomach. There have been no data regarding OBAP expression in the kidney, despite its role in calcium reabsorption in renal tubules. The current study aimed to inspect the expression of OBAP in the kidney of twelve 10-week-old male C3H/HeNJc1 mice using immunohistochemistry, and immunoelectron microscopic localization. The immunohistochemical investigation revealed an OBAP positive reaction mainly in the medulla, which was stronger than the cortex of the kidney and was concentrated in the distal convoluted tubules (DCT), connecting tubules (CT), and the thick limbs of the loop of Henle (HL). Moreover, we clarified that the OBAP was co-distributed with ghrelin and calbindin (markers of the DCT). Interestingly, immunoelectron microscopy demonstrated that OBAP was concentrated in the mitochondrial inner membrane of the DCT and CT. Based on these results, it was concluded that the mitochondria of the DCT, CT, and HL of the mice kidney generate OBAP. Furthermore, our results suggest that OBAP might have a role in the regulation of calcium reabsorption by the renal tubule; however, further investigations are required to clarify this potential role. PMID- 29534835 TI - Erratum to "Is Rapid Recovery Hip and Knee Replacement Possible and Safe in the Octogenarian Patient?" [Journal of Arthroplasty 33 (2018) 316-319]. PMID- 29534836 TI - Global Budget Revenue on a Single Institution's Costs and Outcomes in Patients Undergoing Total Hip Arthroplasty. AB - BACKGROUND: The state of Maryland was granted a waiver by the Center for Medicare and Medicaid Services to implement a Global Budget Revenue (GBR) reimbursement model. This study aims to compare (1) costs of inpatient hospital stays; (2) postacute care costs; (3) lengths of stay (LOS); and (4) discharge disposition who underwent primary total hip arthroplasty at a single Maryland-based orthopedic institution before and after the implementation of GBR. METHODS: The Maryland Center for Medicare and Medicaid Services database was queried to obtain all Medicare patients who underwent total hip arthroplasty at a single institution before and after the implementation of GBR. We compared the differences in costs for the following: inpatient care, the postacute care period, and readmissions. In addition, we evaluated differences in LOS, discharge disposition, and complication rates. RESULTS: There was a significant decrease in inpatient costs ($26,575 vs $23,712), an increase in mean home health costs ($627 vs 1608), and a decrease in mean durable medical equipment costs ($604 vs $82) and LOS (2.92 days vs 2.33 days). There was an increase in discharge to home rates (72.3% vs 78.9%) and a decrease in discharge to acute rehabilitation (4.3% vs 1.8%) CONCLUSION: Under the GBR model, our institution experienced significant cost savings during the inpatient and postacute care episodes. Thus, GBR may serve as a viable solution to reducing costs to Medicare for high-volume arthroplasty institutions with a large Medicare population. Multicentered studies are needed to verify our results. PMID- 29534837 TI - 3D Printing Pharmaceuticals: Drug Development to Frontline Care. AB - 3D printing (3DP) is forecast to be a highly revolutionary technology within the pharmaceutical sector. In particular, the main benefits of 3DP lie in the production of small batches of medicines, each with tailored dosages, shapes, sizes and release characteristics. The manufacture of medicines in this way may finally lead to the concept of personalised medicines becoming a reality. In the shorter term, 3DP could be extended throughout the drug development process, ranging from preclinical development and clinical trials, through to frontline medical care. In this review, we provide a timely perspective on the motivations and potential applications of 3DP pharmaceuticals, as well as a practical viewpoint on how 3DP could be integrated across the pharmaceutical space. PMID- 29534838 TI - Cortactin expression in nasal polyps of Aspirin-Exacerbated Respiratory Disease (AERD) patients. AB - PURPOSE: The term aspirin-exacerbated respiratory disease (AERD) refers to a combination of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and acute respiratory tract reactions to nonsteroidal anti-inflammatory drugs. AERD has now been included among the CRSwNP endotypes, and is considered one of the most aggressive in terms of disease recurrence. Cortactin is a multi-domain protein with a part in several cellular mechanisms involving actin assembly and cytoskeleton arrangement. Cortactin seems to have a role in inflammatory responses and to be implicated in human airway secretion and contraction mechanisms. The novel aim of the present study was to examine cortactin expression in nasal polyps of a consecutive cohort of AERD patients and in nasal mucosa of a control group of patients. MATERIALS AND METHODS: Cortactin expression was assessed immunohistochemically in nasal polyps from 18 consecutive AERD patients who underwent endoscopic sinus surgery and in nasal mucosa of 19 patients without chronic rhinosinusitis. RESULTS: Concomitant allergy was found in 11 AERD patients, most of them male (8 cases; p = 0.02). Cortactin expression in nasal polyps was definitely high (+3) in 17 out of 18 cases, in both epithelial cells (cytoplasmic and membranous immunoreactivity) and activated fibroblasts. A higher cortactin expression was seen in female than in male AERD patients (p = 0.05). CONCLUSIONS: Given this preliminary evidence of cortactin upregulation in the polyps of AERD patients, prospective studies could further investigate the role of cortactin in the biology of AERD, and the potential role of cortactin-targeted approaches in integrated AERD treatments. PMID- 29534840 TI - Atraumatic Clostridial Myonecrosis in an Immunocompromised Host. AB - BACKGROUND: Necrotizing fasciitis is usually associated with a surgical or traumatic wound. Clostridial myonecrosis is an uncommon but deadly infection that can develop in the absence of a wound and is often associated with occult gastrointestinal cancer or immunocompromise, or both. CASE REPORT: We report a case of catastrophic atraumatic Clostridium septicum infection in an immunocompromised host. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians most commonly associate necrotizing fasciitis with superinfection of an open wound. This case reminds physicians that patients with acquired neutropenia can present with spontaneous gas gangrene due to C. septicum. Providers should consider this diagnosis in immunocompromised patients who present with acute onset of severe atraumatic limb pain. PMID- 29534839 TI - Promoter hypomethylation of SKI in autoimmune pancreatitis. AB - The relationship between methylation abnormality and autoimmune pancreatitis (AIP)-a representative IgG4-related disease-has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI. PMID- 29534841 TI - [Alma Ata and family medicine: 40 years of desert crossing]. PMID- 29534842 TI - Strain and Strain Rate: Different Preload Dependence? PMID- 29534843 TI - Left Ventricular Mechanical Dispersion and Global Longitudinal Strain and Ventricular Arrhythmias in Predialysis and Dialysis Patients. AB - BACKGROUND: Patients with advanced chronic kidney disease (CKD) have high risk for sudden cardiac death (SCD) and may benefit from implantable cardioverter defibrillators (ICDs). However, the risk for ICD-related complications is also high in this population. Therefore, there is an unmet need for accurate risk stratification tools to identify patients with CKD at risk for ventricular arrhythmias (VAs), who may benefit from ICD implantation. The aim of this hypothesis-generating study was to investigate the association between left ventricular (LV) mechanical dispersion and LV global longitudinal strain (GLS) measured using two-dimensional speckle-tracking echocardiography and VA and SCD in patients with CKD. METHODS: Patients with CKD stages 3b to 5 (estimated glomerular filtration rate < 45 mL/min/1.73 m2 or on dialysis) were included and were divided into two groups according to the occurrence of VA or SCD during follow-up. LV mechanical dispersion, as a measure of the temporal heterogeneity of the LV deformation, was measured as the SD of time to peak longitudinal strain of 17 LV segments. The ability of LV mechanical dispersion, LV ejection fraction, and LV GLS to discriminate patients with VA or SCD during follow-up was evaluated using receiver operating characteristic curve analysis. RESULTS: Of 250 patients (66% men; mean age, 61 +/- 14 years), 16 (6%) experienced VA or SCD during a median follow-up duration of 28 months (interquartile range, 16-53 months). Using receiver operating characteristic curve analyses, LV GLS (area under the curve = 0.79; 95% CI, 0.68-0.89) and LV mechanical dispersion (area under the curve = 0.71; 95% CI, 0.61-0.82) showed modest discrimination to identify patients at risk for VA or SCD. In contrast, LV ejection fraction showed poor discrimination (area under the curve = 0.60; 95% CI, 0.41-0.78). CONCLUSIONS: LV mechanical dispersion along with LV GLS may be an additional valuable risk marker of VA and SCD in predialysis and dialysis patients. PMID- 29534844 TI - Practice guidelines for the emergency treatment of thrombotic microangiopathy. AB - BACKGROUND AND AIM: The term thrombotic microangiopathy (TMA) involves a heterogeneous group of diseases that can be overwhelming or invalidating, with an acute development, characterised by microangiopathic haemolytic anaemia and thrombocytopaenia. Its management during its initial hours is essential to improving the prognostic of these patients. The aim of this review is to give recommendations about the optimisation of TMA initial treatment and to accelerate the aetiological diagnosis. PATIENTS AND METHODS: We provide a practice guideline based on four steps for the initial management of TMA: diagnosis of suspicion, syndromic confirmation, emergent treatment and complementary tests. RESULTS: The detection of microangiopathic haemolytic anaemia (characterised by elevated reticulocytes, LDH and indirect bilirubin, negative direct Coombs test and schistocytes in peripheral blood), and thrombocytopaenia not explained by other secondary aetiologies confirm the syndromic diagnosis of microangiopathic haemolytic anaemia and thrombocytopaenia (MAHAT). These patients require admission to an Intensive Care Unit to initiate plasma exchange therapy as soon as possible, ideally within the first 4-8hours. Prior to this, samples for ADAMTS13 and complement study should be obtained. Finally, it is important to request the complementary tests necessary to have a correct aetiological diagnosis. CONCLUSIONS: Adherence to the agreed recommendations in this guideline will improve therapeutic results by facilitating cooperation between different specialists involved in TMA management. PMID- 29534845 TI - Patients' and oncologists' views on how oncologists may best address patients' emotions during consultations: An interview study. AB - OBJECTIVE: This qualitative study examines patients' and oncologists' views on how to best address emotions during consultations, and explores oncologists' opinions on their own communication and on strategies to improve oncologists' response to patients' emotions. METHODS: Semi-structured interviews were conducted with 16 cancer patients and 13 oncologists, after watching videotaped consultations illustrating three communication strategies for addressing emotions. RESULTS: Many participants preferred emotion-oriented speech to address patients' emotions; this strategy was assumed to (positively) affect a broad range of outcomes. Nevertheless, some preferred attentive silence or no emotion oriented talk at all. Oncologists and patients had similar views on factors that may hinder oncologists to address emotions. Generally, oncologists mentioned that their response to emotions could be improved; for this, various (educational) strategies were suggested. CONCLUSION: Patients and oncologists generally agree that patients' emotions can best be addressed by empathic, explorative, acknowledging, and supportive statements. Still, differences in preferences exist, thus oncologists need to attune their communication to the individual patient. PRACTICE IMPLICATIONS: The findings can inform medical communication training and encourage oncologists to improve their communication. The regular videotaping of consultations might be a promising method to provide feedback and reflect, thereby improving oncologists' response to patients' emotions. PMID- 29534846 TI - Lung Transplantation in Cystic Fibrosis and the Impact of Extracorporeal Circulation. AB - INTRODUCTION: Lung disease is the major cause of death among cystic fibrosis (CF) patients, affecting 80% of the population. The impact of extracorporeal circulation (ECC) during transplantation has not been fully clarified. This study aimed to evaluate the outcomes of lung transplantation for CF in a single center, and to assess the impact of ECC on survival. METHODS: We performed a retrospective observational study of all trasplanted CF patients in a single center between 1992 and 2011. During this period, 64 lung transplantations for CF were performed. RESULTS: Five- and 10-year survival of trasplanted patients was 56.7% and 41.3%, respectively. Pre-transplantation supplemental oxygen requirements and non-invasive mechanical ventilation (NIMV) do not seem to affect survival (P=.44 and P=.63, respectively). Five- and 10-year survival among patients who did not undergo ECC during transplantation was 75.69% and 49.06%, respectively, while in those did undergo ECC during the procedure, 5- and 10-year survival was 34.14% and 29.87%, respectively (P=.001). PaCO2 is an independent risk factor for the need for ECC. CONCLUSIONS: The survival rates of CF patients undergoing lung transplantation in our hospital are similar to those described in international registries. Survival is lower among patients receiving ECC during the procedure. PaCO2 is a risk factor for the need for ECC during lung transplantation. PMID- 29534847 TI - Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE). AB - Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients. PMID- 29534848 TI - N-terminal Pro B-Type Natriuretic Peptide, High-Sensitivity Cardiac Troponin T, and Hibernating Myocardium in Patients With Ischemic Heart Failure. PMID- 29534849 TI - Capsular serotyping of Haemophilus influenzae by using matrix-associated laser desorption ionization-time of flight mass spectrometry. AB - Haemophilus influenzae is a major pathogenic bacteria causing invasive disease, which is classified into six capsular serotypes (a-f) and non-typeable (NT) strains. Capsular serotyping of H. influenzae is traditionally determined by serological methods and more recently by PCR methods. However, these methods are time-consuming and expensive. In the present study, matrix-associated laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was evaluated as an alternative method for capsular serotyping of H. influenzae clinical strains. We created an in-house database of all six serotypes and NT H. influenzae strains using the main spectrum creation standard method set to the default parameters in MADI-TOF MS. We evaluated the performance of the in-house database using 79 clinical strains already identified by PCR and 58 prospectively collected clinical strains. Measurements were performed using the Bruker MALDI BioTyper system. The peak list was matched against the reference library using the integrated pattern algorithm of the software. The best-matched spectrum was considered the serotyping result. All 137 test strains were correctly identified as H. influenzae using MALDI-TOF MS. The sensitivity and specificity for identification for type b, type e, and type f capsular serotypes and NT H. influenzae using MALDI-TOF MS were 100%/94.3%, 94.7%/97.9%, 97.4%/97.9%, and 85.5%/99.2%, respectively. Our findings indicate that MALDI-TOF MS is a useful alternative method for capsular serotyping of H. influenzae strains. This method is faster and more cost-effective than traditional methods and will therefore be useful for routine applications in clinical laboratories. PMID- 29534850 TI - A successful salvage therapy with daptomycin and linezolid for right-sided infective endocarditis and septic pulmonary embolism caused by methicillin resistant Staphylococcus aureus. AB - Although vancomycin administration is recommended for the treatment of infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA), it is unclear whether an alternative agent, daptomycin, can be used to treat IE with pulmonary complications. A 26-year-old female who had undergone surgical repair of a ventricular septal defect as an early teenager presented with fever, headache, and vomiting. She was admitted to our hospital and diagnosed with right sided IE with septic pulmonary embolism caused by MRSA. Vancomycin, rifampicin, and gentamicin were administered; however, exacerbation of drug eruption due to the antimicrobial agents on the 11th day led us to switch from vancomycin and rifampicin to daptomycin. Furthermore, we included linezolid to treat lung abscesses that accompanied the septic pulmonary embolism. We confirmed negative blood cultures on the 18th day. On the same day, a patch closure for the ventricular septal defect and tricuspid valve replacement were performed. She was discharged on the 65th day with an uneventful postoperative course. This experience suggests that daptomycin and linezolid are effective salvage therapies for right-sided IE caused by MRSA and accompanied by pulmonary complications. PMID- 29534851 TI - A systematic review of the association between a single strenuous event and the development of an inguinal hernia: A medicolegal grey area. AB - BACKGROUND: Inguinal hernia is a common surgical presentation. Evidence for its causation regarding occupational and recreational physical exposures is limited. The aim of this study is to conduct a systematic review objectively evaluating the evidence for a causal link between a single strenuous event and the development of an inguinal hernia. METHOD: A systematic review was carried out in accordance with PRISMA guidelines. PubMed, Ovid Embase, SCOPUS, and Cochrane Library were searched. In addition, the ISRCTN register, ClinicalTrials.gov, ICTR Platform, and EU Clinical Trials Register were searched. Identified publications were collated and both reviewers independently reviewed their contents. FINDINGS: 5508 records were identified, resulting in 5 studies being selected. These 5 studies were all case series. Of 957 patients identified, 1003 hernias were described, of which 983 were inguinal hernias which 255 (26%) were attributed by patients to a single strenuous event. Only two of these studies applied Smith's Criteria (causation of a hernia from a single strenuous event): officially reported, severe pain at the time of the event, no prior history of inguinal hernia, and the diagnosis was made by a doctor within 30 days (preferably 3 days). Only 2 of 54 patients (4%) met all four criteria and so could be considered as having an inguinal hernia relating to a single strenuous event. CONCLUSION: Many patients associate hernias to a single episode, however upon application of more stringent criteria such as Smith's, a much smaller proportion are deemed to be actually attributable to a single strenuous event. PMID- 29534852 TI - WITHDRAWN: Association between TPMT*3C and decreased thiopurine S methyltransferase activity in patients with neuromyelitis optica spectrum disorders in China. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29534853 TI - Isavuconazole: A new broad-spectrum azole. Part 1: In vitro activity. AB - Triazoles compounds are first-line agents for the treatment of invasive fungal diseases. Isavuconazole is the most recent triazole compound, approved in 2015 by the FDA and the EMA to treat invasive aspergillosis and mucormycosis. We reviewed here the in vitro activity of isavuconazole against a vast spectrum of species. Isavuconazole MICs were evaluated using CLSI, EUCAST or Etest methods, with no significant differences between the technics. Low MIC50 and MIC90 (<1MUg/mL) were described for isavuconazole against the majority of Candida spp., except for C. glabrata and C. krusei. In vitro activity against Aspergillus spp. varied according to the species with an overall MIC90 of 1MUg/mL ranging from 0.125MUg/mL (A. fumigatus) to 16MUg/mL (A. niger, A. tubingiensis). As for Aspergillus, the activity of isavuconazole against agents of mucormycosis varies upon genus and species, with an overall MIC90 from 4 (Rhizopus spp.) to 16MUg/mL (Rhizomucor spp. and Mucor spp.). Recently, to help detecting non-wild-type isolates, EUCAST committee has proposed ECOFFs values for C. albicans, C. parapsilosis and C. tropicalis (0.03MUg/mL), for Aspergillus fumigatus (2MUg/mL), A. nidulans (0.25MUg/mL), A. terreus (1MUg/mL), A. flavus (2MUg/mL) and A. niger (4MUg/mL). Moreover, clinical breakpoints (susceptible/resistant) were defined for Aspergillus fumigatus (1MUg/mL), A. nidulans (0.25MUg/mL) and A. terreus (1MUg/mL). Using these breakpoints, isavuconazole showed activity against the vast majority of fungi. PMID- 29534855 TI - Correlates of HIV Testing Among Young Adults in Iran: Findings from a Nationwide Population-Based Survey in 2013. AB - We examined the prevalence and correlates of HIV testing among Iranian young adults. Demographic and behavioral data were collected cross-sectionally. A convenience sample of 19- to 29-year-old young adults (N = 3,246) were recruited from 13 major provinces. Generalized estimating equations models were constructed to identify the correlates of HIV testing. Only 13.6% (n = 443) of the participants had ever tested for HIV. In the multivariable analysis, male sex, married marital status, having extramarital sex, knowing a person living with HIV or who had died of HIV-related diseases, older age, higher education, and higher HIV-related knowledge were positively and significantly associated with HIV testing. Our finding that only about 1 in 7 Iranian young adults had ever tested for HIV was alarming. Interventions aimed at increasing HIV-related knowledge, HIV testing promotion, and identifying the barriers to HIV testing among Iranian young adults remain a public health priority. PMID- 29534856 TI - Delayed sleep phase syndrome and bipolar disorder: Pathogenesis and available common biomarkers. AB - Circadian rhythm disturbances are common in bipolar affective disorder (BD). Delayed sleep-wake phase syndrome (DSWPD) is the most prevalent circadian rhythm sleep-wake disorder (CRSWDs) and is frequently observed in BD. It is unclear whether DSWPD in BD is an independent process or is a consequence of BD. In this hypothetical review, we discuss the overlap between BD and DSWPD and potential common biomarkers for DSWPD and BD. The review will include a discussion of the genetics of DSWPD and BD. Biomarkers elucidating the pathophysiological processes occurring in these two disorders may offer insight into the etiology and prognosis of both conditions. PMID- 29534854 TI - Within-Host Evolution of Human Influenza Virus. AB - The rapid global evolution of influenza virus begins with mutations that arise de novo in individual infections, but little is known about how evolution occurs within hosts. We review recent progress in understanding how and why influenza viruses evolve within human hosts. Advances in deep sequencing make it possible to measure within-host genetic diversity in both acute and chronic influenza infections. Factors like antigenic selection, antiviral treatment, tissue specificity, spatial structure, and multiplicity of infection may affect how influenza viruses evolve within human hosts. Studies of within-host evolution can contribute to our understanding of the evolutionary and epidemiological factors that shape influenza virus's global evolution. PMID- 29534857 TI - IL-33 down-regulates CLDN1 expression through the ERK/STAT3 pathway in keratinocytes. AB - BACKGROUND: Tight junctions (TJs) have important roles in skin barrier function. The TJ protein claudin-1 (CLDN1) is decreased in atopic dermatitis (AD). However, little is known about the mechanism of CLDN1 down-expression. OBJECTIVE: To elucidate the effect of IL-33 on CLDN1 expression in keratinocytes. METHODS: Normal human epidermal keratinocytes (NHEKs) and human skin equivalent models (HSEMs) were cultured in vitro in the presence of IL-33. Production of CLDN1, signal transducer and activator of transcription 3 (STAT3) and Mitogen-activated protein kinases (MAPK) expression were measured by real-time PCR, western blot and immunofluorescence assay. MAPK inhibitors and small interfering RNA were used to confirm the signal pathway of STAT3 and CLDN1. Barrier function was measured by transepithelial electric resistance (TEER) and FITC-dextran flux assays. Electrophoretic Mobility Shift Assay was used to detect STAT3 transcriptional activity. RESULTS: Levels of CLDN1 expression were reduced in the epidermis of AD model mice overexpressing IL-33. IL-33 down-regulated the expression of CLDN1 mRNA and protein in NHEKs and HSEMs. IL-33 attenuated transepithelial electric resistance and induced FITC-dextran flux in NHEKs. The IL-33 suppressed CLDN1 expression was regulated by an extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3). STAT3 suppressed CLDN1 expression by direct binding to the promoters. CONCLUSION: IL-33 may down regulate CLDN1 expression through the ERK/STAT3 pathway in keratinocytes. PMID- 29534858 TI - Enhanced sterilization and healing of cutaneous pseudomonas infection using 5 aminolevulinic acid as a photosensitizer with 410-nm LED light. AB - BACKGROUND: Pseudomonas aeruginosa (PA) frequently develops antibiotic-resistant characteristics, which is clinically problematic. The main reason behind the rise of antibiotic-resistant PA is the extensive use of antibiotics. Therefore, a novel technique is needed to treat PA infections. Photodynamic therapy (PDT) is thought to have the potential to be a non-antibiotic treatment for infections. 5 Aminolevulinic acid (ALA), which works as a photosensitizer after being metabolized into protoporphyrin IX (PpIX) in the heme synthetic pathway, is used for PDT. Thus far, the in vivo effectiveness of PDT using ALA against PA is unknown. OBJECTIVE: In this study, we investigated PDT using ALA both in vitro and in vivo. METHODS AND RESULTS: Although PDT with ALA alone did not show a bactericidal effect on PA, PDT with both ALA and EDTA-2Na had a bactericidal effect in vitro. In in vivo experiments, wounds healed faster in PA-infected mice treated with PDT using both EDTA-2Na and ALA compared to non-PDT. CONCLUSION: These results suggest that PDT with EDTA-2Na and ALA is a potential novel treatment option for PA-infected wounds. PMID- 29534859 TI - Effects of ketamine constant rate infusions on cardiac biomarkers and cardiac function in dogs. AB - OBJECTIVE: To evaluate the effects of ketamine continuous rate infusions (CRI) at two dose rates on cardiovascular function and serum creatine kinase MB isoenzyme (CK-MB) and troponin I in healthy conscious dogs. STUDY DESIGN: Experimental, prospective, crossover, randomized, blinded study. ANIMALS: Eight adult mixed breed dogs, aged 6+/-1 years and weighing 19+/-8.6 kg (mean+/-standard deviation). METHODS: Dogs were administered an intravenous bolus of ketamine (0.5 mg kg-1) followed by a ketamine CRI for 12 hours (20 MUg kg-1 minute-1; treatment TC20 or 40 MUg kg-1 minute-1; treatment TC40). Sedation, heart rate (HR), mean arterial pressure (MAP), electrocardiographic and echocardiographic parameters were evaluated at baseline (T0) and 1 (T1), 2 (T2), 4 (T4), 8 (T8), 12 (T12) and 24 (T24) hours after ketamine infusion started. Serum concentrations of CK-MB and troponin I were measured at baseline and 12, 24 and 48 hours after infusion started. RESULTS: HR increased over the first 4 hours, significantly at T1 in TC20 and at T4 in TC40 when compared with T0 (p < 0.05). MAP was significantly increased at T2 in TC40 when compared with TC20. Behavioral changes, such as stereotypical head movements and twitches, occurred within 4 hours in TC40. There were no significant changes in echocardiographic examinations in any dog when compared with baseline. There were no temporal changes in serum CK-MB activity either within or between treatments (p > 0.05). No troponin I was detected in any sample. CONCLUSIONS AND CLINICAL RELEVANCE: No indication of myocardial injury resulting from ketamine infusion was detected in this study in healthy dogs. Further studies are needed to assess the ketamine infusion effects on antinociception and other organ function not evaluated in the present study. PMID- 29534860 TI - Corrigendum to "A new rat model of neonatal bilirubin encephalopathy (kernicterus)" [J. Pharmacol. Toxicol. Methods 84 (2017) 44-50]. PMID- 29534861 TI - The effect of prior endoscopic correction of vesicoureteral reflux on open ureteral reimplantation: Surgical outcomes and costs. AB - INTRODUCTION: Endoscopic injection of a bulking agent is a common first-line approach to the treatment of vesicoureteral reflux (VUR). While early outcomes are comparable to open ureteroneocystotomy, 5-25% of children will eventually develop recurrent reflux necessitating repeat injections or open ureteral reimplantation. OBJECTIVE: To determine whether prior endoscopic injection of a bulking agent impacts outcomes of subsequent open ureteral reimplantation. STUDY DESIGN: Using a retrospective cohort design, radiographic and clinical outcomes of open ureteral reimplantation were compared between patients with and without prior endoscopic correction of reflux. Surgical and hospitalization data were also compared between groups and a cost comparison was performed to assess differences in healthcare costs between the two cohorts. Units of analysis included total ureters or total patients. For certain variables, subanalysis of unilateral versus bilateral reimplantation was included. RESULTS: A total of 258 patients underwent open reimplantation for VUR between 2007 and 2016 by five pediatric urologists. Final analysis (see Summary Table) included 192 patients with pre-operative and postoperative voiding cystourethrogram (VCUG) and follow up data at a median 4.95 months. Among 317 reimplanted refluxing ureters, radiographic resolution was reached in 26/27 (96.3%) patients with and 279/290 (96.2%) without prior endoscopic treatment (P = 0.981). Clinical success was achieved in 17/17 (100%) patients with and 174/175 (99.4%) without prior endoscopic treatment (P = 0.755). There were no statistically significant differences between duration of surgery or length of hospital stay. There were no statistically significant differences between total charges, total costs, and operating room (OR) costs between groups. DISCUSSION: This study indicated that prior endoscopic injection of a bulking agent did not impact the outcomes or costs of subsequent open ureteroneocystotomy. While prior studies have demonstrated tissue changes associated with injection of a bulking agent, these did not seem to significantly impact the difficulty of later open surgery or the success rates compared to patients who proceeded directly to open correction of reflux. CONCLUSION: Open ureteral reimplantation for recurrent VUR after failed endoscopic injection of a bulking agent was safe and effective, with comparable outcomes and costs to open surgery in patients without prior endoscopic correction. PMID- 29534862 TI - Clinical implications of disappearing colorectal liver metastases have changed in the era of hepatocyte-specific MRI and contrast-enhanced intraoperative ultrasonography. AB - BACKGROUND: Clinical implication of disappearing liver metastases (DLMs) from colorectal cancer after chemotherapy needs to be reviewed in the era of modern imaging studies. METHODS: Between 2010 and 2015, 184 patients underwent curative hepatectomy for colorectal liver metastases following preoperative chemotherapy. The sites of metastases detected on pre-chemotherapy CE-CT were examined post chemotherapy using CE-CT, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), and contrast-enhanced intraoperative ultrasonography (CE-IOUS). DLMs were defined as tumors that disappeared on CE-CT post chemotherapy. The detection rate of DLMs with EOB-MRI and CE-IOUS were assessed, and the outcome of DLMs resected and those left in place were reviewed. RESULTS: A total of 275 DLMs were noted in 59 patients. On EOB-MRI, 71 lesions (26%) were visible and were resected, 92% (65/71) of which contained viable disease. Using CE-IOUS, an additional 94 lesions were identified. A total of 165 DLMs (60%) were identified and resected by sequential use of EOB-MRI and CE-IOUS, 77% (127/165) of which contained viable disease. Of 110 DLMs not identified, 68 were resected, 4% (3/68) of which contained viable disease. Among 42 lesions left in place, 6 (14%) recurred during the median follow-up period of 27 (9-72) months. DISCUSSION: EOB-MRI and CE-IOUS exploration identified clinically relevant DLMs containing viable disease with a high level of accuracy. PMID- 29534863 TI - Representation in the Care Planning Process for Nursing Home Residents With Dementia. AB - OBJECTIVES: Federally mandated assessments of nursing home (NH) residents drive individualized care planning. Residents with cognitive impairment may not be able to meaningfully communicate their care needs and preferences during this process a gap that may be partially addressed by involving surrogates. We describe the prevalence of family participation in the care planning process for long-stay NH residents with varying degrees of cognitive impairment. DESIGN: Retrospective study using administrative data made available as part of an ongoing pragmatic cluster randomized controlled trial. SETTING: A total of 292 NHs from 1 large for profit NH system. PARTICIPANTS: Long-stay NH residents in 2016. MEASUREMENTS: We identified all care planning assessments conducted in 2016 for long-stay NH residents. Cognitive functioning was defined using the Cognitive Function Scale. The Minimum Data Set was used to determine whether a resident, family member, and/or legal guardian participated in the assessment process. Certification and Survey Provider Enhance Reporting system data was used to identify facility-level correlates of family participation. Bivariate and multivariable hierarchical regression results are presented. RESULTS: The analytic sample included 18,552 long-stay NH residents. Family member/representative participation varied by degree of resident cognitive impairment; 8% of residents with no cognitive impairment had family or representative participation in care planning during 2016, compared with 26% of residents with severe impairment. NHs with more social workers had greater family participation in care planning. Available NH characteristics do not explain most of the variation in family participation between NHs (residual intraclass correlation = .57). CONCLUSIONS: Only a minority of family members and surrogates participate in NH care planning, even for residents with severe cognitive impairment. The association between social work staffing and participation suggests family involvement may be a measure of quality improvement capacity. Our findings suggest a lack of voice for a vulnerable population that may have implications on the quality of care received at the end of life. PMID- 29534864 TI - Serum uric acid and progression of diabetic nephropathy in type 1 diabetes. AB - AIMS: Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. METHODS: Post hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3 years (IQR 1.5-3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). RESULTS: Baseline UA was 0.339 mmol/l (SD +/-0.107), GFR 87 ml/min/1.73 m2 (+/-23), geometric mean UAER 1023 mg/24 h (IQR, 631 - 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73 m2 and 4.1 (3.1) ml/min/1.73 m2 in the three lower quartiles of UA, (p = 0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2 = 0.45, p < 0.001). CONCLUSION: Uric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy. PMID- 29534865 TI - The relationship between diabetic risk factors, diabetic complications and salt intake. AB - The relationship between salt and hypertension is the focus of a large amount of research, there are few reviews of the relationship between salt and diabetes, despite the increasing incidence of diabetes. By searching PubMed and the Cochrane Library, we summarized the relationships between diabetic risk factors, diabetic complications and salt intake. The pathophysiological mechanisms underlying the effects of salt on diabetes risk factors and diabetic complications are also discussed. Our findings should assist experts and scholars to understand the current research of salt intake and to pay more attention to the prevention and treatment of related diseases caused by excessive salt intake; guide treatment for patients with diabetes mellitus; and provide a reference for government departments to formulate a reasonable salt restriction policy. We also recommend future research directions. PMID- 29534866 TI - Reply to Kendall et al. PMID- 29534867 TI - Charcoal from anaerobically digested dairy fiber for removal of hydrogen sulfide within biogas. AB - Anaerobically digested fibrous solid (AD fiber) is an abundant material that offers potential to produce value-added products such as biochar. The objective of this paper is to better understand how thermochemical processing conditions affect the capacity of biochars derived from AD fiber to adsorb H2S from biogas. AD fiber was pyrolyzed in an electric tube reactor at temperatures up to 600 degrees C and 60 min. The chars were employed for H2S scrubbing tests from a synthetic biogas. Results showed that the chars' capacity for H2S removal is comparable to that of activated carbon. An additional step consisting of impregnation of the chars with Na2CO3 resulted in an improved capacity for H2S removal. To study the effect of ash, the AD fiber was also subjected to an alternative thermal treatment, hot water extraction (HWE), at 200 degrees C for 60 min. The resulting HWE material showed no removal of H2S from biogas, indicating that the ash and the environment employed for the thermal treatment of AD fiber play an important role in the char's performance for H2S removal. Results also suggest that a portion of the S in the charcoal after the H2S sorption process exists as free or adsorbed S (i.e., not chemically bonded to the charcoal). PMID- 29534868 TI - The impact of surgically placed, intraperitoneal drainage on morbidity and mortality after pancreas resection- A systematic review & meta-analysis. AB - BACKGROUND: Although routinely used, the benefit of surgically placed intraperitoneal drains after pancreas resection is still under debate. To assess the true impact of intraperitoneal drains in pancreas resection, a systematic review with meta-analysis was performed. METHODS: For this, the Preferred Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were conducted and Pubmed/Medline, Embase, Scopus and The Cochrane Library were screened for relevant studies. RESULTS: 8 retrospective and 3 prospective studies were included in the systematic review. No difference was found between patients with or without intraperitoneal drains in mortality (Risk-ratio/RR 0.74, 95% Confidence-interval/CI: 0.47-1.18, p = 0.20), in Grade B/C-postoperative pancreatic fistulas/POPF (RR 1.31, 95%-CI: 0.74-2.32, p = 0.35), in intraabdominal abscesses (RR 0.92, 95%-CI: 0.65-1.30, p = 0.64), in surgical site infection (RR 1.20, 95%-CI: 0.85-1.70, p = 0.30), in delayed gastric emptying (RR 1.11, 95%-CI: 0.65-1.90, p = 0.71), in postoperative haemorrhages (RR 0.92 95% CI: 0.63-1.33, p = 0.65), in reoperations (RR 1.15, 95%-CI: 0.87-1.52, p = 0.33), or in radiological reinterventions (RR 0.95, 95%-CI: 0.69-1.31, p = 0.76). The risk for overall morbidity (RR 1.16, 95%-CI: 1.04-1.29, p = 0.008), of any POPF (RR 2.15, 95%-CI: 1.52-3.04, p < 0.0001) and of readmissions (RR 1.23, 95%-CI: 1.04-1.45, p = 0.01) was increased for patients with intraperitoneal drain compared to patients without following pancreatic resection. CONCLUSION: Regarding the controversial results of the recent prospective, randomized trials this meta-analysis revealed no difference in mortality but an increased risk for postoperative morbidity, POPF and readmissions of patients with intraperitoneal drains after pancreatic resection. Therefore, the indication for intraperitoneal drains should be critically weighed in patients undergoing pancreatic resections. PMID- 29534869 TI - Arthroscopic hip surgery with a microfracture procedure of acetabular full thickness chondral damage. Cohort study with a 3-year follow-up. AB - INTRODUCTION AND PURPOSE: Management of injuries to the articular cartilage is complex and challenging. Our purpose was to assess outcomes of a cohort of patients who underwent hip arthroscopy with full-thickness chondral damage treated with microfracture and compare these outcomes with those from a similar cohort of patients who did not. MATERIAL AND METHODS: We prospectively gathered the data of 31 hips treated with microfracture from January 2009 to January 2016. In the cohort of hips without chondral damage there were 49 hips. All patients were assessed pre- and postoperatively with 4 patient-reported outcome instruments. RESULTS: The mean follow-up was 36.2 months in the cohort of patients with full-thickness chondral damage, and 36.6 months in the cohort of patients without chondral damage. Both groups demonstrated significant improvement in all patient-reported outcome instruments between preoperative and final follow-up. There was no statistically significant difference between both cohorts at final follow-up. DISCUSSION: This study showed that patients undergoing microfracture during hip arthroscopy had significant improvement in all patient-reported outcome instruments during follow-up. The greatest improvement was noted at 6 months postoperatively. Both groups showed no significant difference in final patient-reported outcome instruments scores. PMID- 29534870 TI - Baboon Syndrome Associated with Ampicillin Sulbactam. PMID- 29534871 TI - Fiber-Reinforced Resin Fixed Prostheses on 4 Short Implants in Severely Atrophic Maxillas: 1-Year Results of a Prospective Cohort Study. AB - PURPOSE: The aim of this study was to report on 1-year outcomes of fixed full arch fiber-reinforced resin bridges on short implants in atrophic maxillary jaws. MATERIALS AND METHODS: A prospective cohort study was designed and patients with severely atrophic maxillas, corresponding to Cawood and Howell Classes V and VI, were included. Mesial and distal peri-implant bone levels were assessed on panoramic radiographs that were taken at the time of implant insertion (baseline) and during follow-up visits. RESULTS: Eighteen patients with 72 implants inserted in atrophic maxillary jaws were included in this study. All patients had a follow up visit 1 year after loading. The cumulative 1-year patient-based implant survival rate was 88.8%, and the cumulative 1-year implant-based survival rate was 97.2%. The marginal bone level (MBL) was -0.5 +/- 0.5 mm at the time of loading (n = 72) and -0.8 +/- 0.6 mm (n = 72) after 1 year. The MBL depended substantially on the depth at the time of insertion. No prosthetic failure, such as chipping or fracture, occurred within the first year of loading. CONCLUSION: Prosthetic rehabilitation of atrophic maxillas with prostheses supported by 4 4.0 * 5.0-mm or 3.0- * 8.0-mm implants seems to be a viable and cost-effective treatment option in the short-term. PMID- 29534872 TI - Factors Influencing Postsurgical Diplopia in Orbital Floor Fractures and Prevalence of Other Complications in a Series of Cases. AB - PURPOSE: We conducted a review of orbital fractures treated in our hospital over a period of 4 years. We reviewed several complications of such fractures, especially the relationship of postsurgical diplopia with different presurgical variables: age, gender, type of fracture, fracture area, coronal and sagittal diameter of fracture, fractured floor area, time to surgery, presence of muscle herniation, and presence of muscle entrapment. PATIENTS AND METHODS: Fractures involving the orbital floor remain a controversial issue in terms of surgical treatment and the time from trauma to surgery. Surgical indications are divided into esthetic and functional, and they greatly differ from one medical center to another. We observed that the variables that influence postoperative complications varied in the different studies reviewed. Postsurgical diplopia is one of the most important complications, and its relationship with presurgical variables was the focus of this study. For the purpose of this study, we performed bivariate and multivariate analyses, accepting P < .05 as significant. RESULTS: According to the multivariate analysis, postsurgical diplopia was only associated with trapdoor fractures, regardless of all other variables, especially if these fractures were operated on after 48 hours. In addition, the bivariate analysis showed that fractures involving muscle herniation resulted in less diplopia and a better prognosis if operated on before 48 hours. However, these results were not statistically significant. CONCLUSIONS: Surgery performed within 48 hours of trauma statistically improves fractures with true muscle entrapment and also, fractures with muscle hernation (although in this fractures, the improvement is not statistically significant). PMID- 29534873 TI - Durability of Flexible Ureteroscopes: A Prospective Evaluation of Longevity, the Factors that Affect it, and Damage Mechanisms. AB - BACKGROUND: Flexible ureteroscopy is an established treatment modality for evaluating and treating abnormalities in the upper urinary tract. Reusable ureteroscope (USC) durability is a significant concern. OBJECTIVE: To evaluate the durability of the latest generation of digital and fiber optic reusable flexible USCs and the factors affecting it. DESIGN, SETTING, PARTICIPANTS: Six new flexible USCs from Olympus and Karl Storz were included. The primary endpoint for each USC was its first repair. Data on patient and treatment characteristics, accessory device use, ureteroscopy time, image quality, USC handling, disinfection cycles, type of damage, and deflection loss were collected prospectively. INTERVENTION: Ureteroscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: USC durability was measured as the total number of uses and ureteroscopy time before repair. USC handling and image quality were scored. After every procedure, maximal ventral and dorsal USC deflection were documented on digital images. RESULTS AND LIMITATIONS: A total of 198 procedures were performed. The median number of procedures was 27 (IQR 16-48; 14h) for the six USCs overall, 27 (IQR 20-56; 14h) for the digital USCs, and 24 (range 10-37; 14h) for the fiber optic USCs. Image quality remained high throughout the study for all six USCs. USC handling and the range of deflection remained good under incremental use. Damage to the distal part of the shaft and shaft coating was the most frequent reason for repair, and was related to intraoperative manual forcing. A limitation of this study is its single-center design. CONCLUSIONS: The durability of the latest reusable flexible USCs in the current study was limited to 27 uses (14h). Damage to the flexible shaft was the most important limitation to the durability of the USCs evaluated. Prevention of intraoperative manual forcing of flexible USCs maximizes their overall durability. PATIENT SUMMARY: Current flexible ureteroscopes proved to be durable. Shaft vulnerability was the most important limiting factor affecting durability. PMID- 29534874 TI - A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis. AB - BACKGROUND: Lanosterol demethylase is an enzyme that is essential for fungal growth and catalyzes an early step in the biosynthetic pathway of ergosterol, which is a sterol that is required for fungal cell membrane formation and integrity. Lanosterol demethylase is the molecular target of the class of drugs referred to as "azole antifungals." VT-1161 is a novel, oral, selective inhibitor of fungal lanosterol demethylase and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared with placebo in women with recurrent vulvovaginal candidiasis, which was defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period. STUDY DESIGN: Two hundred fifteen women with a documented history of recurrent vulvovaginal candidiasis and who, at screening, were experiencing an episode of acute vulvovaginal candidiasis (acute vulvovaginal candidiasis; composite vulvovaginal signs and symptoms score of >=3 and a positive potassium hydroxide test for yeast) were enrolled. After treatment of the acute infection with fluconazole, subjects were assigned randomly to 1 of 5 treatment regimens: (1) VT 1161 150 mg once daily for 7 days, then 150 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (2) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 11 weeks, followed by a once-weekly dose of placebo for 12 weeks; (3) VT-1161 150 mg once daily for 7 days, then 150 mg once weekly for 23 weeks; (4) VT-1161 300 mg once daily for 7 days, then 300 mg once weekly for 23 weeks; or (5) a matching placebo regimen for 24 weeks. The primary efficacy outcome was the proportion of subjects with >=1 culture-verified acute vulvovaginal candidiasis episodes through week 48. RESULTS: In the intent-to treat population, the proportion of subjects with >=1 acute vulvovaginal candidiasis episodes ranged from 0-7% across the 4 VT-1161 arms vs 52% in the placebo arm, with all arms achieving statistical significance vs placebo. VT-1161 was well-tolerated with a favorable safety profile, and the incidence of adverse events was lower in all VT-1161 arms compared with placebo. In addition, no patient in any VT-1161 arm discontinued the study early because of an adverse event or laboratory abnormality. There was also no evidence of an adverse effect of VT-1161 on liver function or electrocardiogram recordings. CONCLUSION: In this study, VT-1161 was shown to be efficacious and safe in the treatment of patients with recurrent vulvovaginal candidiasis. These data strongly support further clinical investigation of VT-1161 for the treatment of recurrent vulvovaginal candidiasis. PMID- 29534875 TI - Esculetin suppresses tumor growth and metastasis by targeting Axin2/E-cadherin axis in colorectal cancer. AB - Colorectal cancer (CRC) is the most common malignant disease worldwide due to its metastasis via the epithelial-mesenchymal transition (EMT) process. E-cadherin and Wnt signaling are emerging as potential targets for suppressing the EMT. In this context, Axin2 has been recognized as a negative regulator that inhibits glycogen synthase kinase 3beta (GSK3beta)-mediated degradation of Snail1, a transcriptional repressor of E-cadherin. However, Axin2 can also impede Wnt signaling via beta-catenin degradation. Therefore, Axin2 may serve as either a promoter or suppressor of tumors, and the effects of its inhibition on the cell proliferation and metastasis of CRC require further elucidation. Here, esculetin (ES), a coumarin, was found to have the most potential effects on both beta catenin-responsive transcriptional and E-cadherin promoter activities. ES also showed anti-proliferative and anti-invasive activities in CRC cells. Mechanistically, Axin2 suppression by ES contributed to E-cadherin-mediated Wnt signaling inhibition. Moreover, the ability of ES to inhibit tumor growth and metastasis via Axin2 suppression was further supported in an HCT116-implanted orthotopic mouse model. Collectively, these findings suggest that targeting the Axin2/E-cadherin axis by ES may be an attractive therapeutic strategy for the treatment of metastatic CRC. PMID- 29534876 TI - The role of angiotensin II in cancer metastasis: Potential of renin-angiotensin system blockade as a treatment for cancer metastasis. AB - Hypertension, which often exists as a comorbid condition in cancer patients, is considered as a factor affecting cancer progression. The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is a well-known pressor peptide in RAS. There is also accumulated evidence indicating that Ang II plays a critical role in the metastasis of various cancers by modulating adhesion, migration invasion, proliferation, and angiogenesis. Consistent with this, large epidemiological studies have reported the potential beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and Ang II type 1 receptor blockers (ARBs) against cancer metastasis; however, some of the results remain controversial. Although the precise Ang II-related mechanisms involved in cancer metastasis are not completely clear yet, a number of basic and meta-analytic studies have shown that ACE inhibitors and ARBs reduce the metastatic potential of tumors. In this review, we summarize the relationships among hypertension, RAS, and metastasis as demonstrated in basic and clinical studies. Finally, we discuss the possibility of using RAS inhibitors as anti-metastatic drugs. PMID- 29534877 TI - The protective arm of the renin-angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves. AB - OBJECTIVE: Posterior urethral valve is the most common lower urinary tract obstruction in male children. A high percentage of patients with posterior urethral valve evolve to end-stage renal disease. Previous studies showed that cytokines, chemokines, and components of the renin-angiotensin system contribute to the renal damage in obstructive uropathies. The authors recently found that urine samples from fetuses with posterior urethral valve have increased levels of inflammatory molecules. The aim of this study was to measure renin-angiotensin system molecules and to investigate their correlation with previously detected inflammatory markers in the same urine samples of fetuses with posterior urethral valve. METHODS: Urine samples from 24 fetuses with posterior urethral valve were collected and compared to those from 22 healthy male newborns at the same gestational age (controls). Renin-angiotensin system components levels were measured by enzyme-linked immunosorbent assay. RESULTS: Fetuses with posterior urethral valve presented increased urinary levels of angiotensin (Ang) I, Ang-(1 7) and angiotensin-converting enzyme 2 in comparison with controls. ACE levels were significantly reduced and Ang II levels were similar in fetuses with posterior urethral valve in comparison with controls. CONCLUSIONS: Increased urinary levels of angiotensin-converting enzyme 2 and of Ang-(1-7) in fetuses with posterior urethral valve could represent a regulatory response to the intense inflammatory process triggered by posterior urethral valve. PMID- 29534878 TI - Roundtable discussion: Familial chylomicronemia syndrome: Diagnosis and management. AB - Plasma triglyceride concentrations are normally below 150 mg/dL in the fasting state. However, these lipids can reach values of several thousand mg/dL. Elevations in this range are due to a massive retention of chylomicrons and usually result from multiple genetic variants with superimposed influences such as diabetes and immune disorders. Less commonly, major gene defects in lipoprotein metabolism can be the cause. These may present soon after birth with strong evidence of familial penetrance. The causes of this syndrome have been discussed in a Roundtable published in the most recent issue of this Journal. The polygenic etiology may also have a familial presentation with similar clinical import. The diagnosis and management of these disorders is of importance since they can lead to critical clinical syndromes including death from acute hemorrhagic pancreatitis. The chronic management requires a dedicated medical team and a patient committed to an effective regimen. We are joined in this discussion by Dr P. Barton Duell, University of Oregon Health Sciences Center, and Dr Daniel Gaudet of the Universite de Montreal, Montreal, Quebec. All have had extensive personal experience in the diagnosis and management of patients with familial chylomicronemia. This Roundtable was recorded on November 11, 2017, during a meeting of the National Lipid Association in New Orleans, Louisiana. PMID- 29534879 TI - [Surgical management of deep endometriosis with colorectal involvement: CNGOF-HAS Endometriosis Guidelines]. AB - Deep endometriosis with colorectal involvement is considered one of the most severe forms of the disease due to its impact on patients' quality of life and fertility but also by the difficulties encountered by the clinicians when proposing a therapeutic strategy. Although the literature is very rich, evidence based medicine remains poor explaining the great heterogeneity concerning the management of such patients. Surgery therefore remains a therapeutic option. It improves the intensity of gynecological, digestive and general symptoms and the quality of life. Concerning the surgical approach, it appears that laparoscopy should be the first option; the laparoscopic robot-assisted route can also be proposed. The techniques of rectal shaving, discoid resection and segmental resection are the three techniques used for surgical excision of colorectal endometriosis. The parameters taken into account for the use of either technique are: the surgeon's experience, the depth of infiltration of the lesion within the rectosigmoid wall, the lesion size and circumference, multifocality and the distance of the lesion from the anal margin. In the case of deep endometriosis with colorectal involvement, performing an incomplete surgery increases the rate of pain recurrence and decreases postoperative fertility. In case of surgery for colorectal endometriosis, pregnancy rates are similar to those obtained after ART in non-operated patients. Existing data are insufficient to formally recommend first line surgery or ART in infertile patients with colorectal endometriosis. The surgery for colorectal endometriosis exposes to a risk of postoperative complications and recurrence of which the patients should be informed preoperatively. PMID- 29534880 TI - The impact of changes in radiographic sarcopenia on overall survival in older adults undergoing different treatment pathways for pancreatic cancer. AB - OBJECTIVE: Sarcopenia is associated with poor outcomes in patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC). However, few studies have assessed changes in sarcopenia during multimodality therapy or its effect on overall survival (OS). METHODS: Computed tomography (CT) total psoas area index (TPAI) and weighted average Hounsfield units (HU) were measured at each treatment interval in patients with resectable PDAC. Four cohorts were compared: 1. Neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy ("NSA"; n = 20); 2. surgery plus adjuvant chemotherapy ("SA"; n = 20); 3. neoadjuvant chemotherapy with intent to perform surgery ("Chemotherapy"; n = 24); and 4. treated with palliative intent ("Palliative"; n = 21). RESULTS: Fifty-nine deaths were identified. Median OS was 15.7 months (95% Confidence Interval (CI) 12.7-20.2). Patients who underwent surgery had a higher OS (p < 0.001), with the SA group having a longer OS than the NSA group. Cox regression models identified baseline TPAI (Hazard Ratio (HR) = 0.82; p = 0.04), but not psoas HU, as a significant predictor of OS. The mean decrease in TPAI following neoadjuvant chemotherapy was 0.6 cm2/m2 (p < 0.001; 95% CI -0.8--0.3) and the mean decrease in HU was 2.7 (p = 0.04, 95% CI -5.4--0.1). For patients who underwent surgery (NSA and SA cohorts), a decrease in TPAI was associated with worse OS (HR 0.52; p = 0.05). In contrast, decreased HU was associated with worse OS in patients who did not undergo surgery (HR 0.93; p = 0.01). CONCLUSIONS: In patients who received neoadjuvant chemotherapy, there was a significant decrease in TPAI and HU during treatment. Prospective studies are warranted to assess the impact of TPAI loss and HU changes on clinical outcomes to better individualize treatment pathways based on a patient's fitness. PMID- 29534881 TI - Tumor-promoting cyanotoxin microcystin-LR does not induce procarcinogenic events in adult human liver stem cells. AB - HL1-hT1 cell line represents adult human liver stem cells (LSCs) immortalized with human telomerase reverse transcriptase. In this study, HL1-hT1 cells were found to express mesenchymal markers (vimentin, CD73, CD90/THY-1 and CD105) and an early hepatic endoderm marker FOXA2, while not expressing hepatic progenitor (HNF4A, LGR5, alpha-fetoprotein) or differentiated hepatocyte markers (albumin, transthyretin, connexin 32). In response to microcystin-LR (MC-LR), a time- and concentration-dependent formation of MC-positive protein bands in HL1-hT1 cells was observed. Cellular accumulation of MC-LR occurred most likely via mechanisms independent on organic anion transporting polypeptides (OATPs) or multidrug resistance (MDR) proteins, as indicated (a) by a gene expression analysis of 11 human OATP genes and 4 major MDR genes (MDR1/P-glycoprotein, MRP1, MRP2 and BCRP); (b) by non-significant effects of OATP or MDR1 inhibitors on MC-LR uptake. Accumulation of MC-positive protein bands in HL1-hT1 cells was associated neither with alterations of cell viability and growth, dysregulations of ERK1/2 and p38 kinases, reactive oxygen species formation, induction of double-stranded DNA breaks nor modulations of stress-inducible genes (ATF3, HSP5). It suggests that LSCs might have a selective, MDR1-independent, survival advantage and higher tolerance towards MC-induced cytotoxic, genotoxic or cancer-related events than differentiated adult hepatocytes, fetal hepatocyte or malignant liver cell lines. HL1-hT1 cells provide a valuable in vitro tool for studying effects of toxicants and pharmaceuticals on LSCs, whose important role in the development of chronic toxicities and liver diseases is being increasingly recognized. PMID- 29534882 TI - Investigating the properties of poly (lactic acid)/exfoliated graphene based nanocomposites fabricated by versatile coating approach. AB - In order to overcome the challenges that underlies in dispersion of exfoliated graphene (GR) into poly lactic acid (PLA) matrix by extrusion, a versatile approach is used in this work, where uniform coating of GR over PLA is carried out prior to extrusion of PLA. Effect of melt processing on different graphene loaded composites (PLA-M-0.05GR, PLA-M-0.2GR) is studied. Investigation on the morphology, thermal stability, crystallization property, surface wettability, mechanical property, and dynamic mechanical property of composites are performed. XRD analysis and morphological analysis confirm the formation of well dispersed composite. Thermo-gravimetric analysis and kinetic study reveal significant improvement in thermal stability. Improvement in crystallinity, melting point, crystallization point are found from DSC analysis. Crystallization kinetic study is carried out and nucleation effect of the GR on crystallization of PLA chain is noticed. Hydrophobicity of the PLA composites is increased by the incorporation of graphene. Tensile strength of the composites is noticed to be increased as compared to PLA-M. An improvement of storage modulus for the composites over PLA M is observed by Dynamic mechanical analysis. PMID- 29534883 TI - Hand burns surface area: A rule of thumb. AB - INTRODUCTION: Rapid estimation of acute hand burns is important for communication, standardisation of assessment, rehabilitation and research. Use of an individual's own thumbprint area as a fraction of their total hand surface area was evaluated to assess potential utility in hand burn evaluation. MATERIALS AND METHODS: Ten health professionals used an ink-covered dominant thumb pulp to cover the surfaces of their own non-dominant hand using the contralateral thumb. Thumbprints were assessed on the web spaces, sides of digits and dorsum and palm beyond the distal wrist crease. Hand surface area was estimated using the Banerjee and Sen method, and thumbprint ellipse area calculated to assess correlation. RESULTS: Mean estimated total hand surface area was 390.0cm2+/-SD 51.5 (328.3-469.0), mean thumbprint ellipse area was 5.5cm2+/-SD 1.3 (3.7-8.4), and mean estimated print number was 73.5+/-SD 11.0 (range 53.1-87.8, 95% CI 6.8). The mean observed number of thumbprints on one hand was 80.1+/-SD 5.9 (range 70.0 88.0, 95% CI 3.7), chi2=0.009. The combined mean of digital prints was 42, comprising a mean of two prints each on volar, dorsal, radial and ulnar digit surfaces, except volar middle and ring (3 prints each). Palmar prints were 15 (11 19), dorsal 15 (11-19), ulnar palm border 3, first web space 2, and second, third and fourth web spaces one each. Using the surface of the palm alone, excluding digits, as 0.5% of total body surface area, the area of one thumbprint was approximated as 1/30th of 1%. CONCLUSIONS: We have demonstrated how thumbprint area serves as a simple method for evaluating hand burn surface area. PMID- 29534884 TI - Bridging burn care education with modern technology, an integration with high fidelity human patient simulation. AB - OBJECTIVE: The Advanced Burn Life Support (ABLS) program is a burn-education curriculum nearly 30 years in the making, focusing on the unique challenges of the first 24h of care after burn injury. Our team applied high fidelity human patient simulation (HFHPS) to the established ABLS curriculum. Our hypothesis was that HFHPS would be a feasible, easily replicable, and valuable adjunct to the current curriculum that would enhance learner experience. METHODS: This prospective, evidenced-based practice project was conducted in a single simulation center employing the American Burn Association's ABLS curriculum using HFHPS. Participants managed 7 separate simulated polytrauma and burn scenarios with resultant clinical complications. After training, participants completed written and practical examinations as well as satisfaction surveys. RESULTS: From 2012 to 2013, 71 students participated in this training. Simulation (ABLS-Sim) participants demonstrated a 2.5% increase in written post-test scores compared to traditional ABLS Provider Course (ABLS Live) (p=0.0016). There was no difference in the practical examination when comparing ABLS-Sim versus ABLS Live. Subjectively, 60 (85%) participants completed surveys. The Educational Practice Questionnaire showed best practices rating of 4.5+/-0.7; with importance of learning rated at 4.4+/-0.8. The Simulation Design Scale rating for design was 4.6+/-0.6 with an importance rating of 4.4+/-0.8. Overall Satisfaction and Self Confidence with Learning were 4.4+/-0.7 and 4.5+/-0.7, respectfully. CONCLUSIONS: Integrating HFHPS with the current ABLS curriculum led to higher written exam scores, high levels of confidence, satisfaction, and active learning, and presented an evidenced-based model for education that is easily employable for other facilities nationwide. PMID- 29534885 TI - The efficacy of excision followed by intralesional 5-fluorouracil and triamcinolone acetonide versus excision followed by radiotherapy in the treatment of ear keloids: A randomized control trial. AB - BACKGROUND: The ear is the common site for keloid formation especially in women after ear piercing. Surgery is the main stay of treatment in these lesions but there are large numbers of treatment failures in surgery alone. OBJECTIVE: The objective of this study was to compare the efficacy of post-excision intralesional 5-fluorouracil/triamcinolone acetonide (5-FU/TAC) and post-excision radiotherapy in the treatment of ear keloids. STUDY DESIGN: A randomized controlled trial. SETTING: The study was conducted from May 2014 to January 2015 at Jinnah Burn and Reconstructive Surgery Centre, Allama Iqbal Medical College, Lahore. SUBJECT & METHODOLOGY: After approval from the hospital ethical committee, 60 patients presented in the outpatient department fulfilling the inclusion criteria were selected and randomly assigned in two groups with the help of the random number table. Patients in group A had excision followed by intralesional 5-FU/TAC injections while patients of group B had excision followed by radiotherapy. Patients were assessed at 6 months after completion of treatment for efficacy (no recurrence within 6 months of treatment). RESULTS: In our study total of 60 patients completed the study, with 30 patients in each group. 7 patients (23.34%) in Group-A and 9 patients (30%) in Group-B were males while 23 patients (76.67%) in Group-A and 21 patients (70%) in Group-B were females i.e. male to female ratio is 1:2.75. Mean age was 31.8+6.48years. The comparison of frequency of efficacy in both groups showed that 73.33% (n=22) in Group-A and 43.33% (n=13) in Group-B had efficacy, p value was calculated as 0.01, showing a significant statistical difference. CONCLUSION: Excision and intralesional 5 FU/TAC is an effective treatment for keloids on the ears. PMID- 29534886 TI - Effects of structured home-based exercise program on depression status and quality of life in burn patients. AB - BACKGROUND: Burns can cause life-threatening injuries and severe limitations. This study aimed to evaluate the effects of the structured home-based exercise program on depression status and quality of life in burn patients. MATERIALS AND METHODS: This study was carried out in the Wound and Burn Treatment Department of University of Health Sciences, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul. Thirty burn patients voluntarily participated in this study. Patients' demographic data such as burn area and grade, percentage, type, number of grafts, and duration of hospitalization were recorded. The quality of life was evaluated using the Short Form-36 (SF-36), and depression status was evaluated using Beck Depression Inventory (BDI). The home-based exercise program was defined by the clinical physiotherapist on the day when the patient was discharged. The home-based exercise program was applied for 3 weeks. Evaluations were performed at discharge and repeated after 3 weeks at the end of the exercise program. RESULTS: Of the 30 patients who completed the study (age range, 21-61 years; mean, 34.9+/-12.99 years), 96.7% (n=29) were male and 3.3% (n=1) were female. A statistically significant difference was observed between BDI and SF-36 scores before and after the home-based exercise program (p<0.05). BDI scores decreased after the home-based exercise program, whereas SF-36 scores increased. CONCLUSION: Our study concludes that burn patients who underwent the structured home-based exercise programs attained acceleration of their physical, social, and psychological integrity. Thus, establishing a structured home-based exercise program according to the burn type and clinical course should be continued. PMID- 29534888 TI - Prognostication of superficial Barrett's carcinoma: a Japanese multicenter study. AB - Endoscopic resection (ER) has become the standard therapy for superficial Barrett's carcinoma (BC) in Japan and other countries. Patients undergoing ER sometimes require additional treatment because of recurrence of lymph node metastasis (LNM). We attempted to clarify the histopathologic risk factors for LNM, and the difference between these risk factors for Japanese patients and the conventional risk factors documented for Western patients. This multi-center study included 12 leading institutions belonging to the Japan Research Society for Early Esophageal Cancer and Chromoendoscopy, and was based on a questionnaire designed to gather data on the features of superficial BC cases, except for high grade intraepithelial neoplasia, treated at those institutions. These features were assessed using the standardized pathologic approach employed in Japan, whereby surgically and endoscopically resected specimens are cut into parallel slices 4-5 mm and 2 mm thick, respectively. Seventy-four surgically resected (SR) and 201 ER specimens were analyzed separately. Significant risk factors for LNM were almost the same as conventional risk factors, such as tumor size (cut-off value; 17.5 mm) and depth, vessel infiltration, presence of poorly differentiated components, and the depth (cut-off value; 990 MUm) and width (cut-off value; 4300 MUm) of the submucosal component, in addition to growth pattern (a protruding or flat elevated pattern) and the presence of infiltrative growth. Histopathologic examination revealed that BC cases without invasion to the deep muscularis mucosae (DMM) had almost no risk of LNM. Detailed histopathologic evaluation of thin-slice preparations of ER specimens is considered highly important for prognostication. PMID- 29534887 TI - Antibacterial and remineralizing orthodontic adhesive containing quaternary ammonium resin monomer and amorphous calcium phosphate nanoparticles. AB - OBJECTIVES: To evaluate the bonding performance, antibacterial activity, and remineralization effect on enamel of the orthodontic adhesive containing MAE-DB and NACP. METHODS: Eighty non-carious human premolars were divided into 3 groups: Transbond XT (TB), PEHB + 5% MAE-DB (PD), and PEHB + 40% NACP + 5% MAE-DB (PND). Premolars were bonded with orthodontic brackets, the first subgroup (n = 10) and the second subgroup (n = 10) were subjected to shear bond strength testing after immersed in water for 1 day and in demineralization solution for 28 days respectively and then tested surface roughness, while the third subgroup (n = 6) was used for microhardness evaluation after aged in demineralization solution for 28 days. For each adhesive, fifty disk samples were prepared for antibacterial study. Specimens measuring 12 mm * 2 mm * 2 mm were fabricated for ion release test. RESULTS: Bond strengths were in the order TB = PND > PND = PD for "1-day in water", and in the order TB = PND > PD for "28-days in pH 4 solution". No significant difference in the ARI scores for the three adhesive. Numerous bacteria adhered to TB surface, while PD and PND had minimal bacterial growth and activity. PND showed high levels of Ca and P ions release and enamel hardness. The surface roughness of enamel in PND was much lower than TB and PD and showed no significant difference with the sound, control enamel. CONCLUSION: PND adhesive with 5% MAE-DB and 40% NACP exhibits antibacterial and remineralizing capabilities, and did not adversely affect bond strength compared to commercial adhesive. CLINICAL SIGNIFICANCE: Novel adhesive containing quaternary ammonium monomer and nano-amorphous calcium phosphate represents a promising candidate in combating enamel white spot lesions and even dental caries. PMID- 29534889 TI - Androgen receptor ontogeny in the dorsal hippocampus of male and female rats. PMID- 29534890 TI - Enhanced uptake in 2D- and 3D- lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra- and intracellular environments. AB - In the treatment of lung cancer, there is an urgent need of innovative medicines to optimize pharmacological responses of conventional chemotherapeutics while attenuating side effects. Here, we have exploited some relatively unexplored subtle differences in reduction potential, associated with cancer cell microenvironments in addition to the well-known changes in intracellular redox environment. We report the synthesis and application of novel redox-responsive PLGA (poly(lactic-co-glycolic acid)) -PEG (polyethylene glycol) nanoparticles (RR NPs) programmed to change surface properties when entering tumor microenvironments, thus enhancing cell internalization of the particles and their drug cargo. The new co-polymers, in which PEG and PLGA were linked by 'anchiomeric effector' dithiylethanoate esters, were synthesized by a combination of ring-opening polymerization and Michael addition reactions and employed to prepare NPs. Non redox-responsive nanoparticles (nRR-NPs) based on related PLGA PEG copolymers were also prepared as comparators. Spherical NPs of around 120 nm diameter with a low polydispersity index and negative zeta potential as well as good drug loading of docetaxel were obtained. The NPs showed prolonged stability in relevant simulated biological fluids and a high ability to penetrate an artificial mucus layer due to the presence of the external PEG coating. Stability, FRET and drug release studies in conditions simulating intracellular reductive environments demonstrated a fast disassembly of the external shell of the NPs, thus triggering on-demand drug release. FACS measurements and confocal microscopy showed increased and faster uptake of RR-NPs in both 2D- and 3D- cell culture models of lung cancer compared to nRR-NPs. In particular, the 'designed in' reductive instability of RR-NPs in conditioned cell media, the fast PEG release in the extracellular compartment, as well as a diminution of uptake rate in control experiments where extracellular thiols were neutralized, suggested a partial extracellular release of the PEG fringe that promoted rapid internalization of the residual NPs into cells. Taken together, these results provide further evidence of the effectiveness of PEGylated reducible nanocarriers to permeate mucus layer barriers, and establish a new means to enhance cancer cell uptake of drug carriers by extra-and intra-cellular cleavage of protein- and cell-shielding hydrophilic blocks. PMID- 29534891 TI - Epidemic as a natural process. AB - Mathematical epidemiology is a well-recognized discipline to model infectious diseases. It also provides guidance for public health officials to limit outbreaks. Nevertheless, epidemics take societies by surprise every now and then, for example, when the Ebola virus epidemic raged seemingly unrestrained in Western Africa. We provide insight to this capricious character of nature by describing the epidemic as a natural process, i.e., a phenomenon governed by thermodynamics. Our account, based on statistical mechanics of open systems, clarifies that it is impossible to predict accurately epidemic courses because everything depends on everything else. Nonetheless, the thermodynamic theory yields a comprehensive and analytical view of the epidemic. The tenet subsumes various processes in a scale-free manner from the molecular to the societal levels. The holistic view accentuates overarching procedures in arresting and eradicating epidemics. PMID- 29534892 TI - Pros and cons of different therapeutic antibody formats for recombinant antivenom development. AB - Antibody technologies are being increasingly applied in the field of toxinology. Fuelled by the many advances in immunology, synthetic biology, and antibody research, different approaches and antibody formats are being investigated for the ability to neutralize animal toxins. These different molecular formats each have their own therapeutic characteristics. In this review, we provide an overview of the advances made in the development of toxin-targeting antibodies, and discuss the benefits and drawbacks of different antibody formats in relation to their ability to neutralize toxins, pharmacokinetic features, propensity to cause adverse reactions, formulation, and expression for research and development (R&D) purposes and large-scale manufacturing. A research trend seems to be emerging towards the use of human antibody formats as well as camelid heavy domain antibody fragments due to their compatibility with the human immune system, beneficial therapeutic properties, and the ability to manufacture these molecules cost-effectively. PMID- 29534893 TI - Corrigendum to "A 3D electro-mechanical continuum model for simulating skeletal muscle contraction", J. Theor. Biol. 335 (2013) 108-118. PMID- 29534894 TI - In silico modeling of bone adaptation to rest-inserted loading: Strain energy density versus fluid flow as stimulus. AB - In vivo studies suggest that cyclic and low-magnitude loading can be useful over pharmaceutical drugs in normalizing bone loss as it encourages osteogenesis (i.e. new bone formation) at the sites of elevated strain magnitude. In silico models assumed normal strain or strain energy density (SED) as the stimulus to predict loading-induced osteogenesis, however, these models may have limited success in fitting the in vivo new bone formation at several instances. For example, rest inserted cyclic loading amplifies the new bone formation as compared to continuous-cyclic loading even though similar strain magnitude were induced in both the cases. It is also believed that loading-induced interstitial fluid flow can also be a potential stimulus of osteogenesis. The present study hypothesizes that fluid motion as osteogenic stimulus may explain the afore-mentioned anomalies. Accordingly, this work studies osteogenesis as functions of SED and canalicular fluid motion using an in silico model. Therefore, the new bone formation is considered roughly proportional to stimuli above their osteogenic thresholds. This model attempts to simulate in vivo new bone formation noticed in rest-inserted cantilever loading studies. The model's prediction of site-specific new bone formation improves when fluid flow is considered as the stimulus. It is also noticed that fluid motion as the stimulus closely fits the new bone formation for another in vivo study where the effects of aging on osteogenesis were examined. These attempts to establish fluid flow as a potential osteogenic stimulus can be useful in the prediction of site-specific new bone formation. The findings will ultimately be useful in designing biomechanical interventions such as prophylactic exercises to cure bone loss. PMID- 29534895 TI - In Vitro and In Vivo Characterization of a Preclinical Irradiation-Adapted Model for Ewing Sarcoma. AB - PURPOSE: Radiation therapy (RT) is a viable therapeutic option for Ewing sarcoma (ES) patients. However, little progress has been made to elucidate the mechanisms of radioresistance. This study establishes a novel ES irradiation-adapted model designed to assess molecular and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) alterations secondary to RT. METHODS AND MATERIALS: Radiation adapted cell lines (RACLs) were created in vitro by exposing ES human cell lines to fractionated doses of radiation. Assays to assess migration or invasion potential and RNA expression were performed on the RACLs. Orthotopic intratibial in vivo investigations were performed with irradiation-sensitive and irradiation adapted ES cells to generate tumors. Transplanted mice were imaged using 18F-FDG PET followed by fractionated RT directed at the primary tumor. Mice were monitored for tumor regression and change in metabolic activity using 18F-FDG PET imaging. Protein expression analyses were performed on the RACLs and orthotopic tumors. RESULTS: Exposure to fractionated doses of radiation caused a significant increase in migratory and invasive properties in the RACLs when compared with nonirradiated wild-type ES cells. RACL transcriptomic and proteomic analysis suggests enhanced activation of the mammalian target of rapamycin-AKT pathway when compared with wild-type ES cells. Irradiation-adapted tumors demonstrated significantly less tumor regression (P = .03) than wild-type tumors. Wild-type tumors also had decreased expression of lactate dehydrogenase A protein and significantly lower metabolic activity after RT compared with irradiation-adapted tumors (P = .03). CONCLUSIONS: We developed novel in vitro and in vivo irradiation-adapted ES models. In vitro investigations revealed increased migratory and invasive phenotypes in the RACLs. In vivo investigations demonstrated increased metabolic activity and significantly decreased sensitivity to RT in the irradiation-adapted tumors as demonstrated by growth response curves and 18F-FDG PET activity. Investigations of the RACLs identified possible radiosensitizing-dependent targets in lactate dehydrogenase A and the mammalian target of rapamycin-AKT pathway. PMID- 29534896 TI - Association of 1p/19q Codeletion and Radiation Necrosis in Adult Cranial Gliomas After Proton or Photon Therapy. AB - PURPOSE: To analyze the incidence of and risk factors for clinically significant radiation necrosis (cRN) in adult cranial oligodendrogliomas and astrocytomas treated with proton or photon therapy. METHODS AND MATERIALS: Between 2007 and 2015, 160 patients with grade 2 or 3 oligodendrogliomas (with 1p/19q codeletion, n = 53) or astrocytomas (without 1p/19q codeletion, n = 107) were treated with proton (n = 37) or photon (n = 123) therapy. Clinically significant radiation necrosis (RN) was defined as symptomatic RN or asymptomatic RN that resulted in surgery or bevacizumab administration. The cumulative incidence was calculated using competing risks. Risk factors were identified using Cox proportional hazards. RESULTS: After a median follow-up period of 28.5 months, cRN developed in 18 patients (proton, 6; photon, 12). The 2-year cumulative incidence of cRN for proton and photon therapy was 18.7% (95% confidence interval [CI], 7.5% 33.8%) and 9.7% (95% CI, 5.1%-16%), respectively (P = .16). On multivariate analysis, risk factors for cRN included oligodendroglioma (hazard ratio [HR], 3.57; 95% CI, 1.38-9.25; P = .009) and higher prescription dose (in gray relative biological equivalents [GyRBE]) (HR, 1.30; 95% CI, 1.05-1.61; P = .015). The 2 year cumulative incidence of cRN in oligodendrogliomas and astrocytomas was 24.2% and 6.2%, respectively (P = .01). The relative volume (percentage) of brain receiving 60 GyRBE was a significant dosimetric predictor of cRN in oligodendrogliomas (HR, 1.11; 95% CI, 1.03-1.20; P = .005). CONCLUSIONS: The study showed that 1p/19q codeleted oligodendroglioma was a significant risk factor associated with cRN and the relative volume (percentage) of brain receiving 60 GyRBE was an important dosimetric predictor of cRN for oligodendroglioma patients. There is insufficient evidence at this time to conclude a significant difference in the incidence of cRN between proton and photon therapy. PMID- 29534897 TI - Bioluminescence Tomography Guided Small-Animal Radiation Therapy and Tumor Response Assessment. AB - PURPOSE: The image guided small animal arc radiation treatment platform has adopted onboard cone beam computed tomography and bioluminescence tomography (BLT). We used BLT to guide irradiation delivery and quantitatively assess irradiation-induced tumor response. METHODS AND MATERIALS: BLT was first validated on a tissue-simulating phantom, where the internal chemiluminescent liquid had a constant volume while its luminescence intensity gradually decayed. Then, in vivo experiments were performed on BALB/c mice orthotopically inoculated with 4T1 breast carcinoma cells expressing luciferase. Animals either received radiation treatment (radiation therapy [RT] group, n = 9) or did not (control group, n = 9). BLT was used to guide delivery of a single-fraction 5-Gy radiation dose to the tumor and to evaluate the treatment response. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining was used to evaluate irradiation-induced DNA damage and cell apoptosis. RESULTS: Phantom results showed that BLT not only recovered the constant target volume with <2% deviation but also accurately monitored the decay of the chemiluminescent molecules. For the RT group of animals, there was significant reduction in both the BLT-based tumor volume (21% +/- 10%, P = .001) and bioluminescence intensity (48% +/- 17%, P = .0008). For the control group, a significant increase was detected in the BLT tumor volume (35% +/- 12%, P < .0001) but not the BLT bioluminescence intensity (P = .4). There was a significant difference in the BLT tumor volume between the RT and control groups 7 days after irradiation (P = .03). Regression analysis suggests a strong correlation between the BLT and cone beam computed tomography tumor volume (R2 = 0.93). Analysis using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling staining showed a significant difference in tumor cell apoptosis between the RT and control groups (20.6% +/- 2.9% and 3.2% +/- 1.7%, respectively; P < .05). CONCLUSIONS: BLT onboard the image guided small animal arc radiation treatment platform can be used to accurately guide irradiation delivery and to quantitatively assess treatment response by simultaneously monitoring tumor volume and cancer cell population. PMID- 29534898 TI - Electromagnetic-Guided MLC Tracking Radiation Therapy for Prostate Cancer Patients: Prospective Clinical Trial Results. AB - PURPOSE: To report on the primary and secondary outcomes of a prospective clinical trial of electromagnetic-guided multileaf collimator (MLC) tracking radiation therapy for prostate cancer. METHODS AND MATERIALS: Twenty-eight men with prostate cancer were treated with electromagnetic-guided MLC tracking with volumetric modulated arc therapy. A total of 858 fractions were delivered, with the dose per fraction ranging from 2 to 13.75 Gy. The primary outcome was feasibility, with success determined if >95% of fractions were successfully delivered. The secondary outcomes were (1) the improvement in beam-target geometric alignment, (2) the improvement in dosimetric coverage of the prostate and avoidance of critical structures, and (3) no acute grade >=3 genitourinary or gastrointestinal toxicity. RESULTS: All 858 planned fractions were successfully delivered with MLC tracking, demonstrating the primary outcome of feasibility (P < .001). MLC tracking improved the beam-target geometric alignment from 1.4 to 0.90 mm (root-mean-square error). MLC tracking improved the dosimetric coverage of the prostate and reduced the daily variation in dose to critical structures. No acute grade >=3 genitourinary or gastrointestinal toxicity was observed. CONCLUSIONS: Electromagnetic-guided MLC tracking radiation therapy for prostate cancer is feasible. The patients received improved geometric targeting and delivered dose distributions that were closer to those planned than they would have received without electromagnetic-guided MLC tracking. No significant acute toxicity was observed. PMID- 29534899 TI - Single- and Multi-Fraction Stereotactic Radiosurgery Dose Tolerances of the Optic Pathways. AB - PURPOSE: Dosimetric and clinical predictors of radiation-induced optic nerve/chiasm neuropathy (RION) after single-fraction stereotactic radiosurgery (SRS) or hypofractionated (2-5 fractions) radiosurgery (fSRS) were analyzed from pooled data that were extracted from published reports (PubMed indexed from 1990 to June 2015). This study was undertaken as part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy, investigating normal tissue complication probability (NTCP) after hypofractionated radiation. METHODS AND MATERIALS: Eligible studies described dose delivered to optic nerve/chiasm and provided crude or actuarial toxicity risks, with visual endpoints (ie, loss of visual acuity, alterations in visual fields, and/or blindness/complete vision loss). Studies of patients with optic nerve sheath tumors, optic nerve gliomas, or ocular/uveal melanoma were excluded to obviate direct tumor effects on visual outcomes, as were studies not specifying causes of vision loss (ie, tumor progression vs RION). RESULTS: Thirty four studies (1578 patients) were analyzed. Histologies included pituitary adenoma, cavernous sinus meningioma, craniopharyngioma, and malignant skull base tumors. Prior resection (76% of patients) did not correlate with RION risk (P = .66). Prior irradiation (6% of patients) was associated with a crude 10-fold increased RION risk versus no prior radiation therapy. In patients with no prior radiation therapy receiving SRS/fSRS in 1-5 fractions, optic apparatus maximum point doses resulting in <1% RION risks include 12 Gy in 1 fraction (which is greater than our recommendation of 10 Gy in 1 fraction), 20 Gy in 3 fractions, and 25 Gy in 5 fractions. Omitting multi-fraction data (and thereby eliminating uncertainties associated with dose conversions), a single-fraction dose of 10 Gy was associated with a 1% RION risk. Insufficient details precluded modeling of NTCP risks after prior radiation therapy. CONCLUSIONS: Optic apparatus NTCP and tolerance doses after single- and multi-fraction stereotactic radiosurgery are presented. Additional standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses and better define RION NTCP after SRS/fSRS. PMID- 29534900 TI - Does Prophylactic Radiation Therapy to Avoid Gynecomastia in Patients With Prostate Cancer Increase the Risk of Breast Cancer? AB - PURPOSE: Prostate cancer (PC) patients who undergo antiandrogen monotherapy are offered prophylactic radiation therapy (PRT) to the breast buds to avoid gynecomastia. The aim of the present study was to evaluate whether the risk of breast cancer (BC) in men with PC as their first cancer diagnosis was influenced by PRT. METHODS AND MATERIALS: From the Norwegian Cancer Registry, we collected data from all patients with PC as their first cancer diagnosis from 1997 to 2014. We registered all RT given to the patients in the same period and the occurrence of BC diagnosed >=3 months after the PC diagnosis. The histopathologic diagnoses of all BC cases were collected. Subdistribution hazard ratios for the risk of BC in the PRT and non-PRT groups were estimated. A standardized incidence ratio for BC was calculated by comparing our cohort to the standard male population. RESULTS: We analyzed 59,169 patients with PC, of whom 7864 (13.3%) had received PRT. The median follow-up time was 4 years. Of the 12 men with a diagnosis of BC, 3 had received PRT, and 2 of the 3 were phyllodes tumors. The risk of BC was not significantly different statistically for the patients given PRT compared with the non-PRT group (subdistribution hazard ratio 1.62, 95% confidence interval 0.41-5.62, adjusted for age and time of diagnosis). The standardized incidence ratio was 0.996 (95% confidence interval 0.57-1.75). CONCLUSIONS: In this registry-based study, we did not find an increased risk of BC in PC patients who received PRT. The number of BC cases in our study was low, and the risk of secondary BC after PRT seems to be negligible. The incidence of BC could, however, increase with additional follow-up. Also, 2 patients who had received PRT developed a malignant phyllodes tumor, an extremely rare type of BC associated with gynecomastia. PMID- 29534901 TI - Abscopal Effects With Hypofractionated Schedules Extending Into the Effector Phase of the Tumor-Specific T-Cell Response. AB - PURPOSE: Hypofractionated radiation therapy (hRT) combined with immune checkpoint blockade can induce T-cell-mediated local and abscopal antitumor effects. We had previously observed peak levels of tumor-infiltrating lymphocytes (TILs) between days 5 and 8 after hRT. Because TILs are regarded as radiosensitive, hRT schedules extending into this period might be less immunogenic, prompting us to compare clinically relevant, short and extended schedules with equivalent biologically effective doses combined with anti-programmed cell death 1 (PD1) antibody treatment. METHODS AND MATERIALS: In mice bearing 2 B16-CD133 melanoma tumors, the primary tumor was irradiated with 3 * 9.18 Gy in 3 or 5 days or with 5 * 6.43 Gy in 10 days; an anti-PD1 antibody was given weekly. The mice were monitored for tumor growth and survival. T-cell responses were determined on days 8 and 15 of treatment. The role of regional lymph nodes was studied by administering FTY720, which blocks lymph node egress of activated T cells. Tumor growth measurements after combination treatment using short or extended hRT and control treatment were also performed in the wild-type B16 melanoma and 4T1 breast carcinoma models. RESULTS: In the B16-CD133 model, growth inhibition of irradiated primary and nonirradiated secondary tumors and overall survival were similar with all 3 hRT/anti-PD1 combinations, superior to hRT and anti-PD1 monotherapy, and was strongly dependent on CD8+ T cells. TIL infiltration and local and systemic tumor-specific CD8+ T-cell responses were also similar, regardless of whether short or extended hRT was used. Administration of FTY720 accelerated growth of both primary and secondary tumors, strongly reduced their TIL infiltration, and increased tumor-specific CD8+ T cells in the lymph nodes draining the irradiated tumor. In the 4T1 model, local and abscopal tumor control was also similar, regardless of whether short or extended hRT was used, although the synergy between hRT and anti-PD1 was weaker. No synergies were found in the B16 wild-type model lacking an exogenous antigen. CONCLUSIONS: Our data suggest that combination therapy with hRT schedules extending into the period during which treatment-induced T cells infiltrate the irradiated tumor can provoke local and systemic antitumor effects similar to those with therapy using shorter schedules, if the regional lymph nodes supply sufficient tumor-specific T cells. This has implications for planning clinical RT/immune checkpoint blockade trials. PMID- 29534902 TI - Postmastectomy Radiation Therapy in Women with T1-T2 Tumors and 1 to 3 Positive Lymph Nodes: Analysis of the Breast International Group 02-98 Trial. AB - PURPOSE: To analyze the impact of postmastectomy radiation therapy (PMRT) for patients with T1-T2 tumors and 1 to 3 positive lymph nodes enrolled on the Breast International Group (BIG) 02-98 trial. METHODS AND MATERIALS: The BIG 02-98 trial randomized patients to receive adjuvant anthracycline with or without taxane chemotherapy. Delivery of PMRT was nonrandomized and performed according to institutional preferences. The present analysis was performed on participants with T1-T2 breast cancer and 1 to 3 positive lymph nodes who had undergone mastectomy and axillary nodal dissection. The primary objective of the present study was to examine the effect of PMRT on risk of locoregional recurrence (LRR), breast cancer-specific survival, and overall survival. RESULTS: We identified 684 patients who met the inclusion criteria and were included in the analysis, of whom 337 (49%) had received PMRT. At 10 years, LRR risk was 2.5% in the PMRT group and 6.5% in the no-PMRT group (hazard ratio 0.29, 95% confidence interval 0.12-0.73; P = .005). Lower LRR after PMRT was noted for patients randomized to receive adjuvant chemotherapy with no taxane (10-year LRR: 3.4% vs 9.1%; P = .02). No significant differences in breast cancer-specific survival (84.3% vs 83.9%) or overall survival (81.7% vs 78.3%) were observed according to receipt of PMRT. CONCLUSION: Our analysis of the BIG 02-98 trial shows excellent outcomes in women with T1-T2 tumors and 1 to 3 positive lymph nodes found in axillary dissection. Although PMRT improved LRR in this cohort, the number of events remained low at 10 years. In all groups, 10-year rates of LRR were relatively low compared with historical studies. As such, the use of PMRT in women with 1 to 3 positive nodes should be tailored to individual patient risks. PMID- 29534903 TI - Laboratory evolution reveals regulatory and metabolic trade-offs of glycerol utilization in Saccharomyces cerevisiae. AB - Most microbial species, including model eukaryote Saccharomyces cerevisiae, possess genetic capability to utilize many alternative nutrient sources. Yet, it remains an open question whether these manifest into assimilatory phenotypes. Despite possessing all necessary pathways, S. cerevisiae grows poorly or not at all when glycerol is the sole carbon source. Here we discover, through multiple evolved lineages, genetic determinants underlying glycerol catabolism and the associated fitness trade-offs. Most evolved lineages adapted through mutations in the HOG pathway, but showed hampered osmotolerance. In the other lineages, we find that only three mutations cause the improved phenotype. One of these contributes counter-intuitively by decoupling the TCA cycle from oxidative phosphorylation, and thereby hampers ethanol utilization. Transcriptomics, proteomics and metabolomics analysis of the re-engineered strains affirmed the causality of the three mutations at molecular level. Introduction of these mutations resulted in improved glycerol utilization also in industrial strains. Our findings not only have a direct relevance for improving glycerol-based bioprocesses, but also illustrate how a metabolic pathway can remain unexploited due to fitness trade-offs in other, ecologically important, traits. PMID- 29534904 TI - Variability in invasive mediastinal staging for lung cancer: A multicenter regional study. AB - OBJECTIVE: Prior studies have reported underuse of-but not variability in invasive mediastinal staging in the pretreatment evaluation of patients with lung cancer. We sought to compare rates of invasive mediastinal staging for lung cancer across hospitals participating in a regional quality improvement and research collaborative. METHODS: We conducted a retrospective study (2011-2013) of patients undergoing resected lung cancer from the Surgical Clinical Outcomes and Assessment Program in Washington State. Invasive mediastinal staging included mediastinoscopy and/or endobronchial/esophageal ultrasound-guided nodal aspiration. We used a mixed-effects model to mitigate the influence of small sample sizes at any 1 hospital on rates of invasive staging and to adjust for hospital-level differences in the frequency of clinical stage IA disease. RESULTS: A total of 406 patients (mean age, 68 years; 69% clinical stage IA; and 67% lobectomy) underwent resection at 5 hospitals (4 community and 1 academic). Invasive staging occurred in 66% of patients (95% confidence interval [CI], 61% 71%). CI inspection revealed that 2 hospitals performed invasive staging significantly more often than the overall average (94%, [95% CI, 89%-96%] and 84% [95% CI, 78%-88%]), whereas 2 hospitals performed invasive staging significantly less often than overall average (31% [95% CI, 21%-44%] and 17% [95% CI, 7%-36%]). CONCLUSIONS: Rates of invasive mediastinal staging varied significantly across hospitals providing surgical care for patients with lung cancer. Future studies that aim to understand the reasons underlying variability in care may inform quality improvement initiatives or lead to the development of novel staging algorithms. PMID- 29534905 TI - Oxygenation impairment after total arch replacement with a stented elephant trunk for type-A dissection. AB - OBJECTIVE: To study the risk factors of oxygenation impairment in patients with type-A acute aortic dissection who underwent total arch replacement with a stented elephant trunk. METHODS: In this study, 169 consecutive patients were enrolled who were diagnosed with type-A acute aortic dissection and underwent a total arch replacement procedure at the Qilu Hospital of Shandong University between January 2015 and February 2017. Postoperative oxygenation impairment was defined as arterial oxygen partial pressure/inspired oxygen fraction <= 200 with positive end expiratory pressure >= 5 cm H2O that occurred within 72 hours of surgery. Perioperative clinical characteristics of all patients were collected and univariable analyses were performed. Risk factors associated with oxygenation impairment identified by univariable analyses were included in the multivariable regression analysis. RESULTS: The incidence of postoperative oxygenation impairment was 48.5%. Postoperative oxygenation impairment was associated with prolonged mechanical ventilation time, intensive care unit stay, and hospital stay. Multivariable regression analysis demonstrated that body mass index (odds ratio [OR], 1.204; 95% confidence interval [CI], 1.065-1.361; P = .003), preoperative oxygenation impairment (OR, 9.768; 95% CI, 4.159-22.941; P < .001), preoperative homocysteine (OR, 1.080; 95% CI, 1.006-1.158; P = .032), circulatory arrest time (OR, 1.123; 95% CI, 1.044-1.207; P = .002), and plasma transfusion (OR, 1.002; 95% CI, 1.001-1.003; P = .002) were significantly associated with postoperative oxygenation impairment. CONCLUSIONS: Postoperative oxygenation impairment is a common complication of surgery for type-A acute aortic dissection. Body mass index, preoperative oxygenation impairment, preoperative homocysteine, circulatory arrest time, and plasma transfusion were independent risk factors for oxygenation impairment after a total arch replacement procedure. PMID- 29534907 TI - Discussion. PMID- 29534906 TI - Initial surgical experience following implementation of lung cancer screening at an urban safety net hospital. AB - BACKGROUND: Safety net hospitals provide care mostly to low-income, uninsured, and vulnerable populations, in whom delays in cancer screening are established barriers. Socioeconomic barriers might pose important challenges to the success of a lung cancer screening program at a safety net hospital. We aimed to determine screening follow-up compliance, rates of diagnostic and treatment procedures, and the rate of cancer diagnosis in patients classified as category 4 by the Lung CT Screening Reporting and Data System (Lung-RADS 4). METHODS: We conducted a retrospective review of all patients enrolled in our multidisciplinary lung cancer screening program between March 2015 and July 2016. Demographics, smoking status, Lung-RADS score, and number of diagnostic and therapeutic interventions and cancer diagnoses were captured. RESULTS: A total of 554 patients were screened over a 16-month period. The mean patient age was 63 years (range, 47-85 years), and 60% were male. The majority (92%; 512 of 554) were classified as Lung-RADS 1 to 3, and 8% (42 of 554) were classified as Lung RADS 4. Among the Lung-RADS 4 patients, 98% (41 of 42) completed their recommended follow-up; 29% (12 of 42) underwent a diagnostic procedure, for an overall diagnostic intervention rate of 2% (12 of 554). Eleven of these 12 patients had cancer, and 1 patient had sarcoidosis. The overall rate of surgical resection was 0.9% (5 of 554), and the rate of diagnostic intervention for noncancer diagnosis was 0.1% (1 of 554). CONCLUSIONS: Implementation of a multidisciplinary lung cancer screening program at a safety net hospital is feasible. Compliance with follow-up and interventional recommendations in Lung RADS 4 patients was high despite anticipated social challenges. Overall diagnostic and surgical resection rates and interventions for noncancer diagnosis were low in our initial experience. PMID- 29534908 TI - Discussion. PMID- 29534909 TI - Characterization of the orbital volume in normal population. AB - INTRODUCTION: The aim of the study was to describe the normal orbital volume and its most important relationships with other clinical variables. METHODS: We designed a correlation study and consecutive normal CTs scans were included. Orbital volume and facial anthropometrics were measured and correlated between them. Two independent and blind observers made all the measurements. Uni and multivariate statistical analysis were performed in order to create a predicting model for orbital volume. RESULTS: A total of 199 consecutive patients were included in the study (398 orbits). The mean Orbital Volume (OV) was 24.5 +/- 3.08 cc. Adequate intra and interobserver reliability was observed. There were no differences between the right and left orbit (p=0.73). The male average OV was 24.9 +/- 3.03 cc, the female OV was 23.9 +/- 3.08 cc. Age group analysis demonstrated a slow increase in OV beyond thirty years, but these differences were not significant (p=0.98). Only the age, total facial height, facial width and the interorbital distance were significant and were included in the predictive model of OV. CONCLUSION: We have characterized the normal orbital volume,variations and associations. In order to further advance in the understanding of the clinical implications the abnormal orbital volume must be fully studied. PMID- 29534910 TI - The influence of concomitant medial wall fracture on the results of orbital floor reconstruction. AB - INTRODUCTION: Up to 35% of orbital floor fractures extend to the medial wall. This results in restriction of both abduction and adduction, leading to horizontal diplopia. The greater the defect, the more pronounced the enophthalmos. AIM OF THE STUDY: The aim of the study was to determine the influence of concomitant medial wall defects on enophthalmos and diplopia, and the influence of intraoperative revision on the results of surgical reconstruction in patients with orbital floor fracture. MATERIAL AND METHODS: 78 cases of orbital floor fracture, with or without concomitant medial wall defect, were retrospectively analyzed. Reconstruction surgeries were performed in a similar fashion, but with variation in the alloplastic materials used. Careful investigation of the area was performed during the surgery. RESULTS: Patients with associated medial wall defects had significantly more pronounced enophthalmos than those with isolated floor fracture, with no such difference after the orbital reconstruction. Postoperative vertical diplopia was more common in patients with an associated medial defect. CONCLUSIONS: Associated medial wall defect leads to more severe enophthalmos at presentation. However, if the medial aspect of the orbital wall is revised properly, postoperative outcomes are not inferior to those in cases of isolated floor fracture. PMID- 29534911 TI - Incidence and morphometry of sellar bridges and related foramina in dry skulls: Their significance in middle cranial fossa surgery. AB - PURPOSE: The current study investigated the incidence, morphology and morphometry of the ossified ligaments expanding between petrous bone and posterior clinoid processes and in between the anterior, middle and posterior clinoid processes. Side symmetry, gender dimorphism and age influence were also studied. MATERIALS AND METHODS: A total of 123 adult Greek dry skulls were observed. RESULTS: A caroticoclinoid bar (CCB) was found in 60.2%. Partial CCBs appeared more commonly (36.6%) than complete (23.6%). The caroticoclinoid foramen (CCF) was symmetrical on both sides and genders. An anterior interclinoid, a posterior petroclinoid and a partial posterior interclinoid bar appeared in 19.5%, 6.5% and 2.4%, respectively. Osseous spurs posterolateral to the posterior clinoid process were present in 5.7%. CONCLUSION: The study highlights important morphometric details about osseous bars of the sella region and the related CCF in Greek skulls. Notable differences in the incidence of these bars in Greek individuals compared with findings from other populations highlight the growing awareness of ethnic differences in skull base landmarks. Variations and surgically oriented measurements provided by this study may benefit clinicians involved in the treatment of the middle cranial fossa pathology, enriching understanding of the complicated regional anatomy. Preoperative sellar area mapping is essential, by using computed tomography images, since modification of the surgical approach may be required in cases of severe ossification. PMID- 29534912 TI - Evaluation of condylar resorption rates after orthognathic surgery in class II and III dentofacial deformities: A systematic review. AB - The purpose of this study was to perform a systematic review of morphological alterations in the condyles after orthographic surgery involving a sagittal split ramus osteotomy (SSRO), with or without surgery on the maxilla. Searches were performed on three databases and registered in the PROSPERO. The selected studies fulfilled the criteria established by the following PICO model: (1) population: individuals with skeletal dentofacial deformities (class II or III facial patterns), without asymmetry; (2) intervention: orthognathic surgery for mandibular setback using an SSRO, with or without a Le Fort I osteotomy, and fixed with bicortical screws or plates and screws; (3) comparison: orthognathic surgery for mandibular advancement using an SSRO, with or without a Le Fort I osteotomy, and fixed with plates and screws or bicortical screws; and (4) outcome: condylar resorption rate and relapse. Initially, 1,371 articles were identified and 636 articles were screened after elimination of duplicates, and 6 articles were selected for qualitative analysis based on the inclusion and exclusion criteria. Five studies had data regarding the rate of condylar resorption, varying from 0.0% to 4.2%. In conclusion, condylar resorption and relapses were present in a small percentage of patients studied. PMID- 29534913 TI - Species-specific serine-threonine protein kinase Pkb2 of Bifidobacterium longum subsp. longum: Genetic environment and substrate specificity. AB - The objective of this study was to determine for phosphorylated substrates of the species-specific serine-threonine protein kinase (STPK) Pkb2 from Bifidobacterium longum subsp. longum GT15. Two approaches were employed: analyses of phosphorylated membrane vesicles protein spectra following kinase reactions and analyses of the genes surrounding pkb2. A bioinformatics analysis of the genes surrounding pkb2 found a species-specific gene cluster PFNA in the genomes of 34 different bifidobacterial species. The identified cluster consisted of 5-8 genes depending on the species. The first five genes are characteristic for all considered species. These are the following genes encoding serine-threonine protein kinase (pkb2), fibronectin type III domain-containing protein (fn3), AAA ATPase (aaa-atp), hypothetical protein with DUF58 domain (duf58) and transglutaminase (tgm). The sixth (protein phosphatase, prpC), seventh (hypothetical protein, BLGT_RS02790), and eighth (FHA domain-containing protein, fha) genes are included in this cluster, but they are not found in all species. The operon organization of the PFNA gene cluster was confirmed with transcriptional analysis. AAA-ATPase, which is encoded by a gene of the PFNA gene cluster, was found to be a substrate of the STPK Pkb2. Fourteen AAA-ATPase sites (seven serine, six threonine, and one tyrosine) phosphorylated by STPK Pkb2 were revealed. Analysis of the spectra of phosphorylated membrane vesicles proteins allowed us to identify eleven proteins that were considered as possible Pkb2 substrates. They belong to several functional classes: proteins involved in transcription and translation; proteins of the F1-domain of the FoF1-ATPase; ABC transporters; molecular chaperone GroEL; and glutamine synthase, GlnA1. All identified proteins were considered moonlighting proteins. Three out of 11 proteins (glutamine synthetase GlnA1 and FoF1-ATPase alpha and beta subunits) were selected for further in vitro phosphorylation assays and were shown to be phosphorylated by Pkb2. Four phosphorylated substrates of the species-specific STPK Pkb2 from B. longum subsp. longum GT15 were identified for the first time. They included the moonlighting protein glutamine synthase GlnA, FoF1-ATPase alpha and beta subunits, and the chaperone MoxR family of AAA-ATPase. The ability of bifidobacterial STPK to phosphorylate the substrate on serine, threonine, and tyrosine residues was shown for the first time. PMID- 29534914 TI - Evaluation of the Cepheid(r) Xpert(r)C. difficile binary toxin (BT) diagnostic assay. AB - Strains of Clostridium difficile producing only binary toxin (CDT) are found commonly in animals but not humans. However, human diagnostic tests rarely look for CDT. The Cepheid Xpert C. difficile BT assay detects CDT with equal sensitivity (>=92%) in human and animal faecal samples. PMID- 29534915 TI - Microfluidic devices for sample preparation and rapid detection of foodborne pathogens. AB - Rapid detection of foodborne pathogens at an early stage is imperative for preventing the outbreak of foodborne diseases, known as serious threats to human health. Conventional bacterial culturing methods for foodborne pathogen detection are time consuming, laborious, and with poor pathogen diagnosis competences. This has prompted researchers to call the current status of detection approaches into question and leverage new technologies for superior pathogen sensing outcomes. Novel strategies mainly rely on incorporating all the steps from sample preparation to detection in miniaturized devices for online monitoring of pathogens with high accuracy and sensitivity in a time-saving and cost effective manner. Lab on chip is a blooming area in diagnosis, which exploits different mechanical and biological techniques to detect very low concentrations of pathogens in food samples. This is achieved through streamlining the sample handling and concentrating procedures, which will subsequently reduce human errors and enhance the accuracy of the sensing methods. Integration of sample preparation techniques into these devices can effectively minimize the impact of complex food matrix on pathogen diagnosis and improve the limit of detections. Integration of pathogen capturing bio-receptors on microfluidic devices is a crucial step, which can facilitate recognition abilities in harsh chemical and physical conditions, offering a great commercial benefit to the food manufacturing sector. This article reviews recent advances in current state-of the-art of sample preparation and concentration from food matrices with focus on bacterial capturing methods and sensing technologies, along with their advantages and limitations when integrated into microfluidic devices for online rapid detection of pathogens in foods and food production line. PMID- 29534916 TI - Metoclopramide induced pheochromocytoma crisis. AB - Metoclopramide (MCP) is a commonly used anti-emetic in the emergency department (ED). Its use is generally well tolerated; although infrequent adverse reactions such as extrapyramidal reactions or tardive dyskinesia are reported. However, many ED providers are not familiar with the potentially life-threatening hypertensive emergency that can be precipitated by MCP administration in patients with pheochromocytoma. A previously healthy 36-year-old woman presented to the ED with headache and nausea. She developed acute hypertensive emergency (acute agitation, worsening headache, chest pain and wide complex tachycardia) when her blood pressure (BP) increased to 223/102mmHg (initial BP, 134/86mmHg) after receiving intravenous MCP. Her hospital course was complicated by multi-organ injury, including acute respiratory distress syndrome requiring venous-venous extracorporeal membrane oxygenation, non-ST elevation myocardial infarction, cardiogenic shock, acute liver failure, and oliguric kidney injury requiring continuous renal replacement therapy. CT scan showed previously undiagnosed large right adrenal mass (5.9cm). The diagnosis of pheochromocytoma was confirmed after adrenalectomy. Drug-induced acute pheochromocytoma crisis is a rare event. Early recognition and appropriate blood pressure management with clevidipine, nicardipine, or phentolamine is essential. PMID- 29534917 TI - Acute bilateral retinal artery occlusion causing sudden blindness in 25-year-old patient. AB - A 25-year-old male patient presented to the emergency department with the chief complaint of sudden blindness and was found to have suffered bilateral central retinal artery occlusion (CRAO). This process is most commonly the result of a thrombus or embolus that occludes the retinal artery, and normally presents in a single eye in patients older than 65 who are predisposed to vascular disease. Diagnosis relies most heavily upon funduscopic exam. Potential treatments involve ocular massage, acetazolamide, anterior chamber paracentesis and systemic or local fibrinolysis. Despite these interventions vision is often significantly and permanently impaired. This case underscores the importance of the emergency physician's ability to promptly perform and interpret the funduscopic exam in order to diagnose and evaluate CRAO. PMID- 29534918 TI - Surveillance of carbon monoxide-related incidents - Implications for prevention of related illnesses and injuries, 2005-2014. AB - BACKGROUND: Carbon monoxide (CO) is an insidious gas responsible for approximately 21,000 emergency department visits, 2300 hospitalizations, and 500 deaths in the United States annually. We analyzed 10 combined years of data from two Agency for Toxic Substances and Disease Registry acute hazardous substance release surveillance programs to evaluate CO incident-related injuries. METHODS: Seventeen states participated in these programs during 2005-2014. RESULTS: In those 10years, the states identified 1795 CO incidents. Our analysis focused on 897 CO incidents having injured persons. Of the 3414 CO injured people, 61.0% were classified as general public, 27.7% were employees, 7.6% were students, and 2.2% were first responders. More than 78% of CO injured people required hospital or pre-hospital treatment and 4.3% died. The location for most injured people (39.9%) were homes or apartments, followed by educational facilities (10.0%). Educational services had a high number of people injured per incident (16.3%). The three most common sources of CO were heating, ventilation, and air conditioning systems; generators; and motor vehicles. Equipment failure was the primary contributing factor for most CO incidents. CONCLUSIONS: States have used the data to evaluate trends in CO poisoning and develop targeted public health outreach. Surveillance data are useful for setting new policies or supporting existing policy such as making CO poisoning a reportable condition at the state level and requiring CO alarms in all schools and housing. Public health needs to remain vigilant to the sources and causes of CO to help reduce this injury and death. PMID- 29534919 TI - The association of emergency department administration of sodium bicarbonate after out of hospital cardiac arrest with outcomes. AB - BACKGROUND: Sodium bicarbonate administration is mostly restricted to in-hospital use in Taiwan. This study was conducted to investigate the effect of sodium bicarbonate on outcomes among patients with out-of-hospital cardiac arrest (OHCA). METHODS: This population-based study used a 16-year database to analyze the association between sodium bicarbonate administration for resuscitation in the emergency department (ED) and outcomes. All adult patients with OHCA were identified through diagnostic and procedure codes. The primary outcome was survival to hospital admission and secondary outcome was the rate of death within the first 30days of incidence of cardiac arrest. Cox proportional-hazards regression, logistic regression, and propensity analyses were conducted. RESULTS: Among 5589 total OHCA patients, 15.1% (844) had survival to hospital admission. For all patients, a positive association was noted between sodium bicarbonate administration during resuscitation in the ED and survival to hospital admission (adjusted odds ratio [OR]: 4.47; 95% confidence interval [CI]: 3.82-5.22, p<0.001). In propensity-matched patients, a positive association was also noted (adjusted OR, 4.61; 95% CI: 3.90-5.46, p<0.001). CONCLUSIONS: Among patients with OHCA in Taiwan, administration of sodium bicarbonate during ED resuscitation was significantly associated with an increased rate of survival to hospital admission. PMID- 29534920 TI - Cardiorespiratory responses, nitric oxide production and inflammatory factors in patients with myocardial infarction after rehabilitation. AB - There is evidence that myocardial infarction (MI) patients have an inflammatory process that includes skeletal muscles, and exercise has been reported to reduce some inflammatory markers. The aim of this work was to study NO and some inflammatory markers in quadriceps muscle of MI patients before and after cardiac rehabilitation. Muscle biopsy was obtained in 17 MI patients before and after CR and only once in 11 healthy subjects. Several cardiorespiratory and metabolic parameters were evaluated and skeletal muscle levels of nitric oxide synthases, nitrate, nitrite, nitrotyrosine, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin- 6 (IL-6) and CD154. After CR there was an increase in maximal oxygen consumption (21.2 +/- 1.4 vs 25.7 +/- 2.5 mL/kg/min, P < 0.0001); work load (116.2 +/- 14.9 vs 140 +/- 17 W, P < 0.0001); pulmonary ventilation (59.8 +/- 7,5 vs 73.8 +/- 11.6 L/min, P < 0.0001); anaerobic threshold (53.8% +/- 3.5% vs 60.2% +/- 3.3% of maximal VO2, P < 0.0001), maximal lactatemia (8.1 +/- 1.4 vs 9.3 +/- 1.5 mmol/L, P < 0.0001), and oxygen pulse (11.7 +/- 1.6 vs 14.0 +/- 1.9 mL/pulse, P < 0.0001). CSA of type I fibers increased (4380 +/- 1868 vs 5237 +/- 1530 MUm2, P = 0.02), and nitrate (18.6 +/- 3.04 vs 20.7 +/- 2.0 ng/mg, P < 0.001). There was a negative correlation between BMI, fat%, waist and hip circumferences and NO synthase, nitrite and nitrate after CR. The inflammatory mediators were higher in patients than in control subjects and did not change with CR. TGF-beta correlated directly with nitrite and nitrate and inversely to other inflammatory factors. In conclusion, there is an increase of nitrate post CR, indicating a more effective NO production. TGF-beta was related to anti-inflammatory processes even before CR. PMID- 29534921 TI - Commentary on "The Relationship Between Serum Interleukin-1alpha and Asymptomatic Infrarenal Abdominal Aortic Aneurysm Size, Morphology, and Growth Rates". PMID- 29534922 TI - Transthoracic Ultrasound Imaging of the Descending Thoracic Aorta: Could We, Should We, and Would We? PMID- 29534923 TI - Re: "Comments on a Recent Article on a Prevalent and Disabling Disease". PMID- 29534924 TI - Genetic factors and molecular mechanisms in dry eye disease. AB - Dry eye disease (DED) is a complex condition with a multifactorial etiology that can be difficult to manage successfully. While external factors are modifiable, treatment success is limited if genetic factors contribute to the disease. The purpose of this review is to compile research describing normal and abnormal ocular surface function on a molecular level, appraise genetic studies involving DED or DED-associated diseases, and introduce the basic methods used for conducting genetic epidemiology studies. PMID- 29534925 TI - A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies. AB - A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by 1H NMR, 13C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase. PMID- 29534926 TI - Discovery of N-aryl-N'-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors. AB - A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases. PMID- 29534927 TI - Nano-chemotherapy using cationic liposome that strategically targets the cell membrane potential of pancreatic cancer cells with negative charge. AB - Negatively charged phosphatidylserine (PS) and sialic acid-containing glycosphingolipids (GM1) were observed to be over represented on the cell membranes of pancreatic cancer cells (BxPC-3) as opposed to normal pancreatic cells. Cationic liposomes (CL) were also found to selectively accumulate into the negatively charged cell membranes of BxPC-3 cells and inhibited their growth but have no effect on the viability of normal pancreatic cells. CL induced apoptosis in BxPC-3 cells via activation of caspase-3, -8, and -9 and mitochondrial events and inhibited tumor enlargement in xenograft mouse models of pancreatic cancer. PMID- 29534928 TI - Enantiomeric trans beta-aryl-delta-iodo-gamma-lactones derived from 2,5 dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2. AB - For many years, studies focused on developing new natural or synthetic compounds with antineoplastic activity have attracted the attention of researchers. An interesting group of such compounds seem to be those with both lactone moiety and an aromatic ring which, in addition to antimicrobial or antiviral activity, also exhibit antitumor properties. The study shows antitumor activity of two enantiomeric trans isomers of 5-(1-iodoethyl)-4-(2',5' dimethylphenyl)dihydrofuran-2-one. Our aim was to determine their antitumor activity manifested as an ability to induce apoptosis in selected canine cancer cell lines as well as to evaluate differences in their strength depending on the configuration of their stereogenic centers. The enantiomers (+)-(4R,5S,6R)-1 and (-)-(4S,5R,6S)-2 were found to induce classical caspase-dependent apoptosis through downregulation of the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. Although the mechanism of apoptosis induction was the same for both enantiomers, they differed in their strength, as stronger antineoplastic activity in vitro was exhibited by isomer (+)-(4R,5S,6R)-1. PMID- 29534929 TI - First discovery of a potential carbonate prodrug of NNRTI drug candidate RDEA427 with submicromolar inhibitory activity against HIV-1 K103N/Y181C double mutant strain. AB - In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50 = 0.264 MUM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug. PMID- 29534930 TI - Identification of an aminothiazole series of RORbeta modulators. AB - Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORbeta, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORbeta and RORgamma inverse agonist with no activity towards RORalpha (Fig. 1). To our knowledge, this is one of only two small molecule RORbeta inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORbeta-selective modulators. Herein we describe our SAR optimization efforts that led to a series of potent neutral antagonists of RORbeta. PMID- 29534931 TI - Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction. AB - The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the beta turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a Ki of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity. PMID- 29534932 TI - Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: Involvement of cytokine modulation and neuroprotection. AB - Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether resveratrol, a natural polyphenol that has nootropic effects, could prevent chemobrain and its underlying mechanisms. Mice received three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination, a common chemotherapy regimen, at two day intervals within one week. Resveratrol (50 and 100 mg/kg per day) was orally administered for three weeks, beginning one week before the DAC treatment. Water maze test and manganese-enhanced magnetic resonance imaging were used to evaluate animals' cognitive performance and brain neuronal activity, respectively. Blood and brain tissues were collected for measurement of cytokines, cytokine regulators, and biomarkers for neuroplasticity. DAC treatment produced a striking cognitive impairment. Cotreatment with 100 mg/kg resveratrol ameliorated DAC induced cognitive impairment and decreases in prefrontal and hippocampal neuronal activity. Mice co-treated with both doses of resveratrol displayed significantly lower levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6), but markedly higher levels of the anti inflammatory cytokines IL-4 and IL-10 in several sera and brain tissues than those co-treated with vehicle. Resveratrol modulated the cytokine-regulating pathway peroxisome proliferator activated receptor (PPAR)-gamma/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), and protected against DAC-induced decreases in the expression of the neuroplasticity biomarkers, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), amino acid neurotransmitter receptors, and calmodulin-dependent protein kinase II (CaMKII). These results demonstrate the efficacy of resveratrol in preventing chemobrain and its association with cytokine modulation and neuroprotection. PMID- 29534933 TI - [Use of complementary tests in emergencies and their relation with patient safety incidents]. AB - OBJECTIVE: To analyse the use of complementary tests and their relationship with safety incidents in hospital emergency departments. METHODOLOGY: An analysis was performed on 935 patients seen in the 9 hospital emergency departments. The source of data used for the detection of incidents were: emergency department clinical record and reports, together with face-to-face observation in the department, plus a telephone survey of the patient or family member at one week after the care. Statistical tests used: The Student t test for quantitative variables, Chi squared test for qualitative variables, and the ANOVA test. RESULTS: A peripheral venous catheter was used in 397 patients (42.4% (95% CI; 39.3-45.5%)), with a variability with significant differences between hospitals (P<.01), with a range of use from 37% to 81.8%. It was also observed that in 23.4% (95% CI; 19.2-27.6%) of the cases, the catheter was not used after the first blood draw. Radiological tests were requested for 351 patients, 37.7% (95% CI; 34.6-40.8%), also with significant differences between hospitals (P<.01), ranging from 24.6 to 65, 1%. Incidents were detected in 95 (10.2%) patients (95% CI; 8.3-12.1%) in the all the study centres. A higher proportion of safety incidents have been observed in patients where peripheral venous catheter has been used (12.8%) than in those in whom they had not been used (8.5%) (P=.03), as well as in patients on whom an x-ray was requested (12.8%) compared to those who did not (8.64%) (P=.04). A longer stay was also observed in cases with an incident (mean 248.9minutes) than in those where there were none (mean 164.1minutes) (P<.001). No statistically significant differences were found in the other parameters studied. CONCLUSION: A relationship was observed between the use of a peripheral venous catheter (many of them without use) and radiological tests and the occurrence of safety incidents in the Emergency Departments. PMID- 29534934 TI - Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay. AB - DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L. Combining with radioactive inhibition assay and Surface Plasmon Resonance (SPR) binding assay, we identified compound 3 and its active analogues as novel DOT1L inhibitors with IC50 values range from 7 MUM to 20 MUM in vitro. Together with the analysis of structure activity relationships (SAR) and binding modes of these compounds, we provided clues to assist in the future development of more potent DOT1L inhibitors. Moreover, compounds 3 and 9 effectively inhibited the proliferation of MLL-rearranged leukemia cells MV4-11, which could induce cell cycle arrest and apoptosis. In conclusion, we developed a HTS platform based on AlphaLISA method for screening and discovery of DOT1L novel inhibitor, through which we discovered compound 3 and its analogues as potent DOT1L inhibitors with promising MLL-rearranged leukemia therapeutic application. PMID- 29534935 TI - Synthesis, structure-activity relationships and preliminary mechanism study of N benzylideneaniline derivatives as potential TLR2 inhibitors. AB - Toll-like receptor 2 (TLR2) can recognize pathogen-associated molecular patterns to defense against invading organisms and has been represents an attractive therapeutic target. Until today, none TLR2 small molecule antagonist have been developed in clinical trial. Herein, we designed and synthesized 50 N benzylideneaniline compounds with the help of CADD. And subsequent in vitro studies leading to the optimized compound SMU-A0B13 with most potent inhibitory activity to TLR2 (IC50=18.21 +/- 0.87 MUM). Preliminary mechanism studies indicated that this TLR2 inhibitor can work through the NF-kappaB signaling pathway with high specificity and low toxicity, and can also efficiently downregulate inflammatory cytokines, such as SEAP, TNF-alpha and NO in HEK-Blue hTLR2, human PBMC and Raw 264.7 cell lines. Additionally, the docking situation also indicate SMU-A0B13 can well bind to the TLR2-TIR (PDB: 1FYW) active domain, which probably explains the bioactivity. PMID- 29534936 TI - Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kdelta) inhibitors. AB - In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kdelta inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kdelta inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kdelta isoform selectivity over PI3Kalpha, PI3Kbeta, and PI3Kgamma, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kdelta pocket, which might explain their potent PI3Kdelta inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kdelta inhibitors. PMID- 29534938 TI - Planarian stem cell niche, the challenge for understanding tissue regeneration. AB - Stem cell fate depends on surrounding microenvironment, the so called niche. For this reason, understanding stem cell niche is one of the most challenging target in cell biology field and need to be unraveled with in vivo studies. Planarians offer this unique opportunity, as their stem cells, the neoblasts, are abundant, highly characterized and genetically modifiable by RNA interference in alive animals. However, despite impressive advances have been done in the understanding planarian stem cells and regeneration, only a few information is available in defining signals from differentiated tissues, which affect neoblast stemness and fate. Here, we review on molecular factors that have been found activated in differentiated tissues and directly or indirectly affect neoblast behavior, and we suggest future directions for unravelling this challenge in understanding planarian stem cells. PMID- 29534937 TI - Fluorine-18 labeling of an anti-HER2 VHH using a residualizing prosthetic group via a strain-promoted click reaction: Chemistry and preliminary evaluation. AB - In a previous study, we evaluated a HER2-specific single domain antibody fragment (sdAb) 2Rs15d labeled with 18F via conjugation of a residualizing prosthetic agent that was synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC). In order to potentially increase overall efficiency and decrease the time required for labeling, we now investigate the use of a strain-promoted azide alkyne cycloaddition (SPAAC) between the 2Rs15d sdAb, which had been pre derivatized with an azide-containing residualizing moiety, and an 18F-labeled aza dibenzocyclooctyne derivative. The HER2-targeted sdAb 2Rs15d and a nonspecific sdAb R3B23 were pre-conjugated with a moiety containing both azide- and guanidine functionalities. The thus derivatized sdAbs were radiolabeled with 18F using an 18F-labeled aza-dibenzocyclooctyne derivative ([18F]F-ADIBO) via SPAAC, generating the desired conjugate ([18F]RL-II-sdAb). For comparison, unmodified 2Rs15d was labeled with N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB), the prototypical residualizing agent for radioiodination. Radiochemical purity (RCP), immunoreactive fraction (IRF), HER2-binding affinity and cellular uptake of [18F]RL-II-2Rs15d were assessed in vitro. Paired label biodistribution of [18F]RL-II-2Rs15d and [125I]SGMIB-2Rs15d, and microPET/CT imaging of [18F]RL-II-2Rs15d and the [18F]RL-II-R3B23 control sdAb were performed in nude mice bearing HER2-expressing SKOV-3 xenografts. A radiochemical yield of 23.9 +/- 6.9% (n = 8) was achieved for the SPAAC reaction between [18F]F-ADIBO and azide-modified 2Rs15d and the RCP of the labeled sdAb was >95%. The affinity (Kd) and IRF for the binding of [18F]RL-II-2Rs15d to HER2 were 5.6 +/- 1.3 nM and 73.1 +/- 22.5% (n = 3), respectively. The specific uptake of [18F]RL-II-2Rs15d by HER2-expressing BT474M1 breast carcinoma cells in vitro was 14-17% of the input dose at 1, 2, and 4 h, slightly higher than seen for co-incubated [125I]SGMIB 2Rs15d. The uptake of [18F]RL-II-2Rs15d in SKOV-3 xenografts at 1 h and 2 h p.i. were 5.54 +/- 0.77% ID/g and 6.42 +/- 1.70% ID/g, respectively, slightly higher than those for co-administered [125I]SGMIB-2Rs15d (4.80 +/- 0.78% ID/g and 4.78 +/- 1.39% ID/g). MicroPET/CT imaging with [18F]RL-II-2Rs15d at 1-3 h p.i. clearly delineated SKOV-3 tumors while no significant accumulation of activity in tumor was seen for [18F]RL-II-R3B23. With the exception of kidneys, normal tissue levels for [18F]RL-II-2Rs15d were low and cleared rapidly. To our knowledge, this is the first time SPAAC method has been used to label an sdAb with 18F, especially with residualizing functionality. PMID- 29534939 TI - Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer. AB - BACKGROUND: Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. PATIENTS AND METHODS: Chemotherapy naive mCRPC patients received docetaxel 75 mg/m2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. RESULTS: Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells >=5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. CONCLUSION: The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen. PMID- 29534940 TI - Nivolumab Is a Cost-Effective Second-Line Treatment for Metastatic Renal-Cell Carcinoma. AB - INTRODUCTION: The introduction of active new agents, such as small molecules and checkpoint inhibitors, for the treatment of metastatic renal-cell cancer (mRCC) is associated with a relevant increase in costs, and it is therefore important to strike a balance between the costs of treatment and the added value represented by the improvement of the clinical parameters of interest such as progression free survival (PFS) and overall survival (OS). METHODS: This analysis was conducted to assess the pharmacologic costs of second-line treatments for mRCC and was restricted to pivotal phase 3 randomized controlled trials (RCTs) used as second-line therapy. RESULTS: Our analysis evaluated 4 phase 3 RCTs including a total of 2454 patients. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) reached high scores (grade 5) for the CheckMate 025 trial, medium scores (grade 3) for the RECORD-1 and AXIS trials, and low scores (grade 2) for the INTORSECT trial. When we combined the costs of therapy with the measure of efficacy represented by the PFS and OS, we found that the most relevant increase of costs was associated with the use of nivolumab but that it differed according to the difference in costs in terms of life gained, with the highest costs per week of PFS gained (?11,960) but the lowest cost for month of OS gain (?1772). CONCLUSION: When pharmacologic costs of drugs are combined with the measure of efficacy represented by the OS, nivolumab is a cost effective second-line treatment for patients with mRCC. PMID- 29534942 TI - Revisiting the Prognostic Heterogeneity of AJCC Stage IV Carcinomas of the Upper Urinary Tract. AB - BACKGROUND: Current staging paradigms from the American Joint Committee on Cancer (AJCC) staging system for upper urinary tract carcinomas treat locoregionally advanced (T4 and N+) and metastatic (M1) patients as a single entity (stage IV). The current study proposes a modification of the AJCC staging system where these 2 entities are separated. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (2004-2014) was accessed through SEER*Stat program. Overall survival (OS) analyses according to AJCC and modified staging systems were conducted through Kaplan-Meier analysis. Moreover, cancer-specific survival analysis was conducted through a Cox proportional hazard model. RESULTS: OS was compared according to AJCC and modified AJCC staging systems. The P value for OS trend for both staging systems was < .0001. This was also found when OS was stratified by the site of the primary (renal pelvis vs. ureter) as well as when stratified by the staging approach (pathologic vs. clinical) (P < .0001). Cancer specific Cox proportional hazard analysis (adjusted for age, grade, histology, and surgical treatment) was conducted for both staging systems. Pairwise hazard ratio comparisons between different stage categories for both staging systems were significant (P < .0001). The c index for cancer-specific survival for the AJCC staging system was 0.706 with standard error 0.006 (95% confidence interval, 0.695-0.717), while the c index for cancer-specific survival for the modified AJCC staging system was 0.714 with standard error 0.006 (95% confidence interval, 0.702-0.725). CONCLUSION: Dividing stage IV upper urinary tract carcinomas into locoregionally advanced and metastatic disease subcategories improves the prognostic utility of the staging system compared to the current AJCC staging system. Given the limitations of a SEER-based study, this concept needs to be externally validated in various settings. PMID- 29534941 TI - Predicting Cardiovascular Disease Among Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy: Application of the Framingham Risk Score. AB - BACKGROUND: Testicular cancer survivors (TCSs) are at increased risk of cardiovascular disease (CVD) after cisplatin-based chemotherapy (CBCT). Identifying at-risk survivors would allow early intervention, but risk prediction tools such as the Framingham Risk Score (FRS) have not been applied to TCSs given modern chemotherapy. METHODS: TCSs > 1 year post-CBCT were evaluated. Associations between FRS and clinical, socioeconomic, and lifestyle measures and treatment regimen (4 cycles, etoposide and cisplatin [EP * 4]); 3 or 4 cycles, bleomycin plus EP (BEP * 3, BEP * 4) were analyzed with general linear multivariable models. Controls from the National Health and Nutrition Examination Survey were matched 1:1 to TCSs by age, race, and education with differences in mean FRS evaluated with 2-sided t tests. RESULTS: Of 787 TCSs (median age, 37.3 years; median follow-up, 4.2 years), 284, 342, and 161 received EP * 4, BEP * 3, or BEP * 4, respectively. TCSs had higher median systolic blood pressure (126 vs. 119 mm Hg; P < .001), but fewer were smokers (8.4% vs. 28.2%; P < .001) than controls. In multivariable analysis, no significant differences in FRS between EP * 4, BEP * 3, and BEP * 4 were observed, but less than college education (P < .001) and lack of vigorous exercise (P = .006) were associated with higher FRS. Mean FRS did not differ between TCSs and controls (6.8% vs. 7.3%; P = .67). CONCLUSION: This is the first study to apply the office-based FRS to TCSs. Chemotherapy regimen (BEP * 3 vs. EP * 4) was not associated with FRS, but less educated and less vigorously active patients had higher FRS, and present a high risk subgroup for intense follow-up and counseling. PMID- 29534943 TI - Nitrogen removal performance and microbial community structure in the start-up and substrate inhibition stages of an anammox reactor. AB - In this study, the nitrogen removal performance and microbial community structure were investigated during the start-up, instability, and recovery stages of an anaerobic ammonium oxidation (anammox) reactor loaded with compound carriers (shale ceramsite and suspended ball carrier). The results indicated that the anammox reactor successfully started up on 116th d when the nitrogen loading rate (NLR) reached 0.72 +/- 0.05 kg N m-3 d-1. The anammox reactor ran well with free ammonia (FA) at 13.65 +/- 2.69 mg/L and free nitrous acid (FNA) at 39.49 +/- 10.95 MUg/L, indicating that its tolerance for FA and FNA was higher than that of granular sludge anammox reactors. The anammox system was inhibited when FA and FNA reached 29.65 mg/L and 77.02 MUg/L, respectively. The tolerance of anammox bacteria towards FA and FNA decreased after this inhibition. The nitrogen removal performance could be efficiently recovered by decreasing the influent substrate concentration and increasing the hydraulic retention time (HRT). Candidatus Brocadia and Candidatus Jettenia, two genus-level anammox bacteria, were detected in this reactor using a high-throughput sequencing technique. After high substrate shock, the abundance of Candidatus Brocadia decreased while that of Candidatus Jettenia increased, which might be due to the competition between Candidatus Jettenia and Candidatus Brocadia. The relationships between anammox communities and operational factors were investigated via redundancy analysis (RDA), which showed that FA was the principal factor affecting the microbial community structure during the operation stage. PMID- 29534944 TI - Xylan supplement improves 1,3-propanediol fermentation by Clostridium butyricum. AB - Lignocellulosic biomass as co-substrate enhances the 1,3-propanediol (1,3-PD) production of anaerobic fermenters by increasing their conversion yield from glycerol. To improve 1,3-propanediol (1,3-PD) production by this efficient approach, Clostridium butyricum I5-42 was supplemented with lignocellulosic biomasses (starch free fiber (CPF) from cassava pulp and xylan) as co-substrates. The 1,3-PD production and growth of C. butyricum were considerably higher in glycerol plus CPF and xylan than in glycerol alone, whereas another major polysaccharide (cellulose co-substrate) failed to improve the 1,3-PD production. C. butyricum I5-42 showed no degradation ability on cellulose powder, and only weak activity and slight growth on xylan. However CPF supplemented with xylan strongly enhanced the transcription levels of the major enzymes of 1,3-PD production (glycerol dehydratase, 1,3-propanediol dehydrogenase, and glycerol dehydrogenase). The intracellular redox reactions maintained equal balance in the supplemented media, suggesting that CPF plus xylan promotes 1,3-PD production in the reductive pathway. This promotion is probably mediated by NADH, which is effectively regenerated by small amounts of released oligosaccharides and subsequent activation of the glycerol oxidative pathway. Both supplements also improved the 1,3-PD production at high glycerol concentration. Therefore, supplementation with lignocellulolytic polysaccharides such as xylan can improve the production and productivity of 1,3-PD from glycerol in C. butyricum. Direct supplementation of CPF with xylan in 1,3-PD production has not been previously reported. PMID- 29534945 TI - Aceruloplasminemia and putaminal cavitation. PMID- 29534946 TI - A novel transcranial magnetic stimulator for focal stimulation of rodent brain. PMID- 29534947 TI - Has the question "Number of pulses or number of sessions for rTMS in major depression" been answered adequately? PMID- 29534948 TI - Prolonged neurological deficit following spinal anaesthesia. PMID- 29534949 TI - In reply: steroids, atosiban and pulmonary oedema; are or may be a cause? PMID- 29534950 TI - Incidence and risk factors for chronic pain after elective caesarean delivery under spinal anaesthesia in a Chinese cohort: a prospective study. AB - BACKGROUND: China has one of the highest rates of caesarean delivery in the world. The aim of this study was to investigate the incidence and risk factors for chronic pain after caesarean delivery in a Chinese cohort. METHODS: Patients undergoing elective caesarean delivery with a Pfannenstiel incision under spinal anaesthesia were recruited prospectively at a Chinese tertiary women's hospital. The State Trait Anxiety Inventory was measured before surgery. Postoperative analgesia was provided by intravenous patient-controlled analgesia for 48 hours. Postoperative acute pain scores and analgesic consumption were assessed. After 3, 6 and 12 months, patients were interviewed by telephone regarding whether pain was present, and if present, the intensity, frequency, location and impact of the pain. RESULTS: In total 786 patients completed this study. The incidence of pain at 3, 6 and 12 months was 12.2%, 3.8% and 0.8% respectively. Of patients with pain at 3 months, most patients experienced pain daily (43.7%) or with intervals of a day or more between pain (41.7%), with intensity overall described as mild to moderate. The most common sites of pain were the incision or nearby (56.3%), and the low back (36.4%). Risk factors for pain at 3 months included previous caesarean delivery and higher analgesic consumption at 24 h and 48 h postoperatively. CONCLUSION: Chronic pain after elective caesarean delivery under spinal anaesthesia occurs infrequently, especially in the long-term, in a Chinese population. Patients with a previous caesarean delivery and higher analgesic use were at increased risk. PMID- 29534951 TI - Re: Influence on neonatal outcomes of rocuronium for rapid sequence induction of general anaesthesia for caesarean section. PMID- 29534952 TI - Rocuronium versus suxamethonium for rapid sequence induction of general anaesthesia for caesarean section: influence on neonatal outcomes. PMID- 29534953 TI - Radiographic Predictors of Resectability in Thymic Carcinoma. AB - BACKGROUND: The aim of this study was to assess preoperative computed tomography characteristics of thymic carcinomas and to investigate which features could predict an incomplete surgical resection. A secondary aim was to correlate preoperative imaging features with Masaoka stage. METHODS: In this study, approved by our Institutional Review Board, two readers retrospectively reviewed preoperative computed tomography scans at our tertiary referral oncology center between 1994 and 2014. Imaging features analyzed included tumor morphology, infiltration of surrounding mediastinal fat, loss of surrounding fat plane, degree of contact between tumor and great vessels, and associated pulmonary or pleural abnormality. Surgical and pathologic records were reviewed for completeness of surgical resection and Masaoka stage. RESULTS: Forty-one patients were included, with Masaoka stage I (n = 3), stage II (n = 4), stage III (n = 12), and stage IV (n = 22). Twenty-one patients (51%) had a complete surgical resection. Ten had microscopic residual disease (R1) with involved surgical margins at pathology, and 10 patients had macroscopic residual disease (R2) at surgery. In addition to lesion size, the feature associated with incomplete surgical resection was the degree of tumor contact with adjacent mediastinal vessels on the preoperative computed tomography image (p = 0.038). Many of the more common features associated with incomplete resection were also more likely to be present in patients with late Masaoka stage (III/IV), including infiltration of the mediastinal fat, which was present in all 34 patients with Masaoka stage III/IV compared with 5 patients (71%) with stage I/II (p = 0.03). CONCLUSIONS: Preoperative computed tomography imaging features may help to identify patients at risk for an incomplete surgical resection. PMID- 29534954 TI - Surgery of Hypertrophic Obstructive Cardiomyopathy in Patients With Severe Hypertrophy, Myocardial Fibrosis, and Ventricular Tachycardia. AB - BACKGROUND: In patients with hypertrophic obstructive cardiomyopathy (HOCM) myocardial fibrosis is an independent predictor of adverse outcome. A new technique of HOCM surgical correction in patients with severe hypertrophy and septal myocardial fibrosis has been proposed. METHODS: The excision of the asymmetrical hypertrophied area of the interventricular septum causing obstruction was performed from the conal part of the right ventricle corresponding to the zone of obstruction of the left ventricle (LV). The areas of septal myocardial fibrosis were removed corresponding to the zone of delayed enhancement imaging. Myocardial fibrosis was detected by cardiovascular magnetic resonance. Eleven patients with HOCM with severe hypertrophy, myocardial fibrosis, and episodes of ventricular tachycardia underwent this procedure. Five patients had biventricular obstruction. The follow-up period was 39 +/- 9 months. RESULTS: Ten patients were free of symptoms (New York Heart Association class I) and 1 patient had only mild limitations. The mean echocardiographic gradient in the LV decreased from 88.9 +/- 10.0 to 9.7 +/- 2.1 mm Hg, the mean value of gradient in the right ventricular outflow tract was reduced from 45.2 +/- 4.7 to 3.8 +/- 1.3 mm Hg. Echocardiographically determined septal thickness was reduced from 34.5 +/- 3.8 to 15.5 +/- 1.6 mm. Sinus rhythm without block of His bundle right branch was noted in all patients after the operation. Ventricular tachycardia was not registered. CONCLUSIONS: The benefits of applying the technique include effective surgical treatment of patients with HOCM with severe hypertrophy and biventricular obstruction. It may be an appropriate choice for patients with HOCM with septal myocardial fibrosis. PMID- 29534955 TI - Intramural Metastasis as a Risk Factor for Recurrence in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: The purpose of this study was to assess the clinicopathologic implications of intramural metastasis (IM) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively analyzed 743 patients who underwent esophagectomy. Among these patients, IM was detected in 41 patients (5.5%). The clinicopathologic features of IM and its influence on postoperative recurrence were investigated. RESULTS: In total, 710 male patients and 33 female patients with a mean age of 64.4 +/- 7.7 years were included. The median follow up period was 98.5 months. IM was associated with large tumor size (p < 0.001), advanced T stage (p < 0.001), advanced N stage (p < 0.001), and advanced histologic grade (p < 0.023). IM was detected preoperatively in 51.2% of patients, and the median size of the metastasis was 2.0 cm (range: 0.1 to 6.4 cm). The median distance from the primary tumor to the metastasis was 2.5 cm (range: 0.5 to 21.0 cm); multiple metastases were observed in 46.3% of patients. Multivariable analyses revealed that advanced T stage (p < 0.001), advanced N stage (p < 0.001), and IM presence (p = 0.002) were independent risk factors for recurrence. The 5-year recurrence-free survival was 6.1% for patients with IM and 43.5% for patients without IM (p < 0.001). CONCLUSIONS: IM could be an important prognostic factor, along with anatomic determinants such as the TNM staging system, in patients with ESCC. Effective preoperative evaluation and postoperative surveillance may help improve the outcome of patients with ESCC, particularly when accompanied by IM. PMID- 29534956 TI - Effectiveness of Implemented Interventions on Pathologic Nodal Staging of Non Small Cell Lung Cancer. AB - BACKGROUND: Accurate pathologic nodal staging improves early stage non-small cell lung cancer survival. In an ongoing implementation study, we measured the impact of a surgical lymph node specimen collection kit and a more thorough pathologic gross dissection method on attainment of guideline-recommended pathologic nodal staging quality. METHODS: We prospectively collected data on curative intent non small cell lung cancer resections from 2009 to 2016 from 11 hospitals in four contiguous Dartmouth Hospital referral regions. We categorized patients into four groups based on exposure to the two interventions in our staggered implementation study design. We used chi2 tests to examine the differences in demographic and disease characteristics and surgical quality criteria across implementation groups. RESULTS: Of 2,469 patients, 1,615 (65%) received neither intervention; 167 (7%) received only the pathology intervention; 264 (11%) received only the surgery intervention; and 423 (17%) had both. Rates of nonexamination of lymph nodes reduced sequentially in the order of no intervention, novel dissection, kit, and combined interventions, including nonexamination of any lymph nodes and hilar/intrapulmonary and mediastinal nodes (p < 0.001 for all comparisons). The rates of attainment of National Comprehensive Cancer Network, Commission on Cancer, American Joint Committee on Cancer, and American College of Surgeons Oncology Group guidelines increased significantly in the same sequential order (p < 0.001 for all comparisons). CONCLUSIONS: The combined effect of two interventions to improve pathologic lymph node examination has a greater effect on attainment of a range of surgical quality criteria than either intervention alone. PMID- 29534957 TI - Clinicoradiographic Predictors of Aggressive Biology in Lung Cancer With Ground Glass Components. AB - BACKGROUND: Ground glass opacities pose diagnostic challenges, and even after malignancy is confirmed, prognosis is often unclear. We sought to identify clinicoradiographic features that could predict aggressive tumor biology in lung adenocarcinoma with associated ground glass components. METHODS: A retrospective review of patients with resected lung adenocarcinoma from 2008 to 2013 was performed. Detailed radiographic features were reviewed by two radiologists. Logistic regression was used to identify risks of poor differentiation or a composite outcome of nodal metastases and lymphovascular invasion. RESULTS: In all, 79 patients met criteria for analysis. Larger tumor size (p = 0.04), increasing solid component (p = 0.01), pleural tags (p = 0.03), spiculation (p = 0.01), lobulation (p < 0.05), history of coronary artery disease (p = 0.04), and increasing number of pack-years smoking (p < 0.05) were associated with poorly differentiated tumors. However, after adjustment for size of the solid component, the associations between pleural tags, spiculation, and lobulation with poorly differentiated tumors were negated, whereas number of pack-years and history of coronary artery disease remained statistically significant (p = 0.01 and p = 0.03, respectively). There were no identified clinical or radiographic features associated with lymphovascular invasion/nodal metastasis. CONCLUSIONS: Several radiographic features were associated with aggressive tumor biology, a well-known finding. However, we found that none of these radiographic features remained relevant after we adjusted for the size of the solid component, indicating that radiographic features are not as important as previously believed. Further research will be required to identify reliable markers associated with favorable tumor biology. These studies will ultimately be critical in informing prognosis or guiding extent of resection. PMID- 29534958 TI - StAR protein and steroidogenic enzyme expressions in the rat Harderian gland. AB - The Harderian gland (HG) of the rat (Rattus norvegicus) secretes copious amounts of lipids, such as cholesterol. Here we report a study of the expressions of the StAR protein and key steroidogenic enzymes in the HG of male and female rats. The objective of the present investigation was to ascertain (a) whether the rat HG is involved in steroid production starting with cholesterol, and (b) whether the pattern of gene and protein expressions together with the enzymatic activities display sexual dimorphism. The results demonstrate, for the first time, the expression of StAR gene and protein, and Cyp11a1, Hsd3b1, Hsd17b3, Srd5a1, Srd5a2 and Cyp19a1 genes in the rat HG. StAR mRNA and protein expressions were much greater in males than in females. Immunohistochemical analysis demonstrated a non homogeneous StAR distribution among glandular cells. Hsd17b3 and Cyp19a1 mRNA levels were higher in males than in females, whereas Srd5a1 mRNA levels were higher in females than in males. No significant differences were observed in mRNA levels of Cyp11a1, Hsd3b1 and Srd5a2 between sexes. Furthermore, the in vitro experiments demonstrated a higher 5alpha-reductase activity in the female as compared to the male HG vice versa a higher P450 aro activity in males as compared to females. These results suggest that the Harderian gland can be classified as a steroidogenic tissue because it synthesizes cholesterol, expresses StAR and steroidogenic enzymes involved in both androgen and estrogen synthesis. The dimorphic expression and activity of the steroidogenic enzymes may suggest sex-specific hormonal effects into the HG physiology. PMID- 29534959 TI - The urinary organic acids profile in single large-scale mitochondrial DNA deletion disorders. AB - Single large-scale mitochondrial DNA deletions disorders are classified into three main phenotypes with frequent clinical overlap: Pearson marrow-pancreas syndrome (PMS), Kearns-Sayre syndrome (KSS) and chronic progressive external ophtalmoplegia (PEO). So far, only few anecdotal studies have reported on the urinary organic acids profile in this disease class. In this single-center retrospective study, we performed quantitative evaluation of urinary organic acids in a series of 15 pediatric patients, 7 with PMS and 8 with KSS. PMS patients showed an organic acids profile almost constantly altered, whereas KSS patients frequently presented with normal profiles. Lactate, 3-hydroxybutyrate, 3 hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3 hydroxypropionate, and 3-methylglutaconate represented the most frequent metabolites observed in PMS urine. We also found novel metabolites, 3 methylglutarate, tiglylglycine and 2-methyl-2,3-dihydroxybutyrate, so far never reported in this disease. Interestingly, patients with a disease onset as PMS evolving overtime into KSS phenotype, presented persistent and more pronounced alterations of organic acid signature than in patients with a pure KSS phenotype. Our study shows that the quantitative analysis of urinary organic acid profile represents a helpful tool for the diagnosis of PMS and for the differential diagnosis with other inherited diseases causing abnormal organic acidurias. PMID- 29534960 TI - Applications of mass spectrometry-based targeted and non-targeted lipidomics. AB - Recent advances in mass spectrometry have expanded our knowledge of lipids and lipid metabolic pathways involved in many (patho)physiological events. Targeted and non-targeted lipidomics are powerful analytical strategies with distinct features, and a combination of these two approaches is often employed to maximize the coverage of lipid species detected and quantified in complex biological matrices. This review briefly summarizes the applications of targeted and non targeted lipidomics, mainly focusing on electrospray ionization-liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS), along with recent technical advances in the field. Current limitations and challenges in lipidomics and possible solutions are also discussed. PMID- 29534961 TI - Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-induced apoptosis through upregulation of Bim expression. AB - Inhibition of cathespsin S not only inhibits invasion and angiogenesis, but also induces apoptosis and autophagy in cancer cells. In present study, we revealed that pharmacological inhibitor [Z-FL-COCHO (ZFL)] of cathepsin S up-regulates pro apoptotic protein Bim expression at the posttranslational levels. These effects were not associated with MAPKs and AMPK signal pathways. Interestingly, pretreatment with the chemical chaperones (TUDCA and PBA) and knockdown of protein phosphatase 2A (PP2A) markedly inhibited ZFL-induced Bim upregulation. ZFL enhances oxaliplatin-mediated apoptosis through ER stress-induced Bim upregulation in cancer cells. Collectively, our results suggest that inhibition of cathepsin S-induced Bim upregulation contribute to anti-cancer drug-induced apoptotic cell death in renal carcinoma Caki cells. PMID- 29534962 TI - Barbaloin loaded polydopamine-polylactide-TPGS (PLA-TPGS) nanoparticles against gastric cancer as a targeted drug delivery system: Studies in vitro and in vivo. AB - Gastric cancer is the third leading cause of cancer-associated death worldwide. Although a decrease in its incidence is observed, gastric cancer still poses a major clinical challenge due to poor prognosis and limited treatments. Barbaloin (BBL) is a main medicinal composition of the Chinese traditional medicine aloe vera. BBL has various bioactivities, including anti-oxidant, anti-inflammatory and anti-tumor properties. Polydopamine (pD)-based surface modification is easy to functionalize polymeric nanoparticles (NPs) surfaces with ligands and/or additional polymeric layers. In the present study, BBL-loaded formulations was developed with pD-modified NPs, which was synthesized by polylactide-TPGS (PLA TPGS) (pD-PLA-TPGS/NPs). And galactosamine (Gal) was conjugated on the prepared NPs (Gal-pD-PLA-TPGS/NPs) for targeting the gastric cancer cells. Here, we found that BBL-loaded Gal-pD-PLA-TPGS/NPs showed the highest cellular uptake efficacy in gastric cancer cells. Gal-pD-PLA-TPGS/NPs more significantly reduced the gastric cancer cell viability. Further, greater apoptosis, autophagy and ROS generation was induced by Gal-pD-PLA-TPGS/NPs in gastric cancer cells. Additionally, compared to the other two NPs, Gal-pD-PLA-TPGS/NPs most markedly decreased ATP levels in gastric cancer cells. In vivo, Gal-pD-PLA-TPGS/NPs were specifically targeted to tumor site. Moreover, Gal-pD-PLA-TPGS/NPs exhibited the most anti-tumor effects, as evidenced by the lowest tumor volume and tumor weight. Of note, there was no significant difference was observed in body and liver weight, as well as the histological changes in major organs isolated from each group of mice. Together, the findings indicated that BBL-loaded Gal-pD-PLA TPGS/NPs could be targeted to gastric cancer cells to suppress tumor progression without toxicity. PMID- 29534963 TI - S1P/S1PR3 signaling mediated proliferation of pericytes via Ras/pERK pathway and CAY10444 had beneficial effects on spinal cord injury. AB - Pericytes have long been regarded merely to maintain structural and functional integrity of blood-brain barrier (BBB). Nevertheless, it has also been identified as a component of scar-forming stromal cells after spinal cord injury (SCI). In process of enlargement of spinal cavity after SCI, the number of pericytes increased and outnumbered astrocytes. However, the mechanism of proliferation of pericytes remains unclear. Sphingosine-1-phosphate (S1P) has been reported to play important roles in the formation of glia scar, but previous studies had paid more attention to the astrocytes. The present study aimed to observe the effects of S1P and S1P receptors (S1PRs) on proliferation of pericytes and investigate the underlying mechanism. By double immunostaining, we found that the number of PDGFRbeta-positive pericytes was gradually increased and sealed the cavity, which surrounded by reactive astrocytes. Moreover, the subtype of S1PR3 was found to be induced by SCI and mainly expressed on pericytes. Further, by use of CAY10444, an inhibitor of S1PR3, we showed that S1P/S1PR3 mediated the proliferation of pericytes through Ras/pERK pathway. Moreover, CAY10444 was found to have the effects of enhancing neuronal survival, alleviating glial scar formation, and improving locomotion recovery after SCI. The results suggested that S1P/S1PR3 might be a promising target for clinical therapy for SCI. PMID- 29534964 TI - Inhibiting 6-phosphogluconate dehydrogenase reverses doxorubicin resistance in anaplastic thyroid cancer via inhibiting NADPH-dependent metabolic reprogramming. AB - Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid malignancies and resistant to chemotherapy. Little is known on the underlying mechanisms of ATC resistance to chemotherapy. In our work, we identified that 6 phosphogluconate dehydrogenase (6PGD) is critically involved in the development of ATC resistance to doxorubicin. We found that 6PGD mRNA, protein and enzyme activity levels are significantly upregulated in ATC cells during the prolonged exposure to doxorubicin in a time-dependent manner. 6PGD inhibition by genetic and pharmacological approaches significantly inhibits growth and survival of ATC cells that are highly resistant to doxorubicin. Consistently, 6PGD inhibition also sensitizes ATC cells to doxorubicin treatment. Of note, we observed the decreased level of NADPH, NADH and enzymatic activity of sirtuin-1 in response to 6PGD inhibition in doxorubicin-resistant ATC cells. Lactate level was also reduced by 6PGD inhibition. All these indicate that 6PGD inhibition disrupts metabolic reprogramming in doxorubicin-resistant ATC cells. Our work demonstrates 6PGD activation-mediated resistance in response to doxorubicin and provides an alternative therapeutic strategy to overcome resistance to chemotherapy for ATC treatment. Our findings also highlight the importance of metabolic reprogramming in ATC chemoresistance. PMID- 29534965 TI - Intrinsic attenuation of post-irradiation calcium and ER stress imparts significant radioprotection to lepidopteran insect cells. AB - Sf9 lepidopteran insect cells are 100-200 times more radioresistant than mammalian cells. This distinctive feature thus makes them suitable for studies exploring radioprotective molecular mechanisms. It has been established from previous studies of our group that downstream mitochondrial apoptotic signaling pathways in Sf9 cells are quite similar to mammalian cells, implicating the upstream signaling pathways in their extensive radioresistance. In the present study, intracellular and mitochondrial calcium levels remained unaltered in Sf9 cells in response to radiation, in sharp contrast to human (HEK293T) cells. The isolated mitochondria from Sf9 cells exhibited nearly 1.5 times greater calcium retention capacity than mammalian cells, highlighting their inherent stress resilience. Importantly, UPR/ER stress marker proteins (p-eIF2alpha, GRP4 and SERCA) remained unaltered by radiation and suggested highly attenuated ER and calcium stress. Lack of SERCA induction further corroborates the lack of radiation-induced calcium mobilization in these cells. The expression of CaMKII, an important effector molecule of calcium signaling, did not alter in response to radiation. Inhibiting CaMKII by KN-93 or suppressing CaM by siRNA failed to alter Sf9 cells response to radiation and suggests CaM-CaMKII independent radiation signaling. Therefore, this study suggests that attenuated calcium signaling/ER stress is an important determinant of lepidopteran cell radioresistance. PMID- 29534966 TI - Next-generation sequencing-based miRNA expression analysis in Parp1-deficient embryonic stem cell-derived exosomes. AB - Poly (ADP-ribose) polymerase family, member 1 (Parp1) has pleiotropic and disparate functions in multiple cellular signaling pathways through post translational protein modification. It contributes to the regulation of various cellular processes, including DNA damage repair, cell death, and cell differentiation, genetically or epigenetically. Meanwhile, the functions of Parp1 in intercellular signaling remain to be established. To examine the functions of Parp1 in intercellular signaling, we examined microRNA (miRNA) regulation in exosomes derived from Parp1-deficient (Parp1-/-) embryonic stem (ES) cells. The percentages of miRNAs among total RNAs, including small RNAs such as miRNAs, snRNAs, snoRNAs, tRNAs, exonic RNAs, and intronic RNAs, in Parp1+/+ and Parp1-/- ES cell-derived exosomes were 8.2% and 3.5%, respectively. Overall, 329 distinct miRNAs exhibited >=2-fold changes (118 upregulated; 211 downregulated). The upregulated miRNAs targeted 810 candidate genes, and the downregulated miRNAs targeted 716 candidate genes. Pathway analyses revealed that the upregulated miRNAs were significantly associated with five pathways including MAPK signaling cascades (p < 0.05), indicating that the target genes in these pathways were suppressed in Parp1-/- ES cells. In quantitative analyses of miRNA expression, miR365-3p, let-7a-5p, miR196b-5p, miR203-3p, miR98-5p, and miR146a-5p were increased by >= 2-fold in Parp1-/- ES cell-derived exosomes. Gene ontology enrichment analyses revealed that the upregulated miRNAs were significantly annotated for growth and stress-related cell signaling and cell communication (p < 0.05). Parp1 deficiency in ES cells led to inhibition of cell-cell communication, possibly by intercellular signal transduction, suggesting that Parp1 functions extracellularly by regulating exosomal miRNAs. PMID- 29534967 TI - Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome. AB - Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome. An enrolled subject in this study was a 5-year-old girl carrying a large deletion that included the methyl-CpG-binding domain, transcriptional repression domain, and nuclear localization signal of MECP2. Using the single-cell isolation technique, we found that the two populations of MeCP2-expressing and MeCP2-deficient stem cells kept their MECP2 expression profiles throughout the stages of cell proliferation and neuronal differentiation in vitro. Neurite outgrowth and branching were attenuated in MeCP2-deficient dopaminergic neurons. MeCP2-deficient cells showed reduced mitochondrial membrane potential, ATP production, restricted mitochondrial distribution in neurites, and lower expression of a central mitochondrial fission factor, dynamin-related protein 1 than MeCP2-expressing cells. These data indicated that MeCP2-deficiency dysregulates the expression of mitochondrial factors required for the maturation of dopaminergic neurons. This study also provides insight into the pathogenic mechanism underlying dysfunction of the intracerebral dopaminergic signaling pathway in Rett syndrome. PMID- 29534968 TI - Regulator of G-protein signalling 5 deficiency impairs ventricular remodelling after myocardial infarction by promoting NF-kappaB and MAPK signalling in mice. AB - Regulator of G-protein signalling 5 (RGS5) is, highly expressed in different cell types of the adult human heart, and it is a negative regulator of G protein mediated signalling that inactivates Galpha(q) and Galpha(i) and thereby inhibits many signalling pathways. However, the critical role of RGS5 in the pathology of myocardial infarction (MI) remains unexplored. Here, an in vitro MI model, induced by the permanent ligation of the left anterior descending coronary artery, was used with the isolated hearts of wild type (WT) and RGS5-knockout (KO) mice. Our results showed that the loss of RGS5 decreased the post-MI survival rate and left ventricular (LV) function and increased the infarct size. Additionally, the RGS5 knockout mice exhibited greater inflammation, apoptosis, and ventricular remodelling compared with WT-MI mice. Mechanistically, RGS5 loss activated the pathological response mainly by affecting the NF-kappaB and MAPK signalling pathways. Therefore, our data strongly indicate that RGS5 is a novel modulator of pathological progression after MI that functions NF-kappaB and MAPK signalling. PMID- 29534969 TI - Cefuroxime-associated Kounis syndrome with unique peculiarity in perioperative prophylaxis. AB - Cefuroxime is a broad spectrum antibacterial agent administered in cases of perioperative prophylaxis. Kounis syndrome is defined as the concurrence of anaphylactic events with acute coronary syndromes. Limited data is available for cefuroxime-associated Kounis syndrome in perioperative prophylaxis. We report the case of a 37-year-old woman undergoing bilateral sweat gland resection who presented with Kounis syndrome following cefuroxime infusion for perioperative prophylaxis. The patient had severe symptoms and unique manifestations that never been reported before: pink frothy sputum indicating heart failure, due to severe systolic dysfunction requiring invasive ventilation and intra-aortic balloon counter-pulsation. Cefuroxime-associated Kounis syndrome has several unique and life-threatening peculiarities which broaden our understanding of clinical and laboratory characteristics. It is important for physicians to be aware of possible cardiovascular complications in perioperative cefuroxime prophylaxis. PMID- 29534970 TI - Comparison of contrast sensitivity in beta-thalassemia patients treated by deferoxamine or deferasirox. AB - PURPOSE: To compare contrast sensitivity (CS) in multi-transfused beta thalassemia patients who received deferoxamine with those who received Osveral. METHODS: In this cross sectional study a total of 60 beta-thalassemia patients (30 used deferoxamine and 30 used deferasirox) were regarded as case group and 30 age and sex matched healthy subjects were selected as control group. All subjects had a set of examinations including refraction, visual acuity, Biomicroscopy, ophthalmoscopy and CS. Contrast threshold was assessed with the use of Freiberg visual acuity and contrast test under the mesopic light condition for three frequencies; 1, 5, 15cpd. All data analysis was performed using SPSS, version 17. RESULTS: In visual acuity tests, thalassemic patients did not have any problem. Contrast threshold was higher in thalassemic patients who infuse deferoxamine (1.87+/-0.63, 1.46+/-0.81, and 2.96+/-1.68 in 1, 5, and 15cpd, respectively) than that of those who intake deferasirox (1.74+/-0.80 (P=0.743), 0.99+/-0.74 (P=0.047), and 2.42+/-1.36 (P=0.321) for 1, 5, and 15cpd, respectively), and also than healthy patients (1.33+/-0.58 (P=0.009), 0.95+/-0.68 (P=0.022), and 2.24+/ 1.23 (P=0.135) for 1, 5, and 15cpd, respectively). Comparing those who used deferasirox with healthy subjects, contrast threshold was higher in deferasirox group at all special frequencies (P>0.05). No significant relationship was observed between CS values and duration of transfusion, serum ferritin concentration and dose of chelation therapy (P>0.05). CONCLUSIONS: CS tests can detect visual disturbance in thalassemic patients before the impairment of visual acuity. It is suggested that CS tests be included in their regular eye examination. PMID- 29534971 TI - Obesity metabolic and hormonal disorders associated with obstructive sleep apnea and their impact on the risk of cardiovascular events. AB - OBJECTIVE: To analyze metabolic and hormonal disorders resulting from the association between obesity and obstructive sleep apnea (OSA) syndrome that predispose to cardiovascular diseases and investigate the clinical benefits obtained from treatment approaches for both conditions. METHODS: A literature review between 1997 and 2017 was conducted in the PubMed search database. RESULTS: Obesity is the most important risk factor for OSA, and the progressive increase in its prevalence also affects OSA incidence. In addition, OSA may aggravate weight gain and obesity comorbidities. Both conditions lead to an increase in the risk of cardiovascular events and mortality. The gold standard treatment for moderate to severe OSA is CPAP, but significant reduction in major cardiovascular events was not observed in clinical trials. Body weight reduction appears effective to improve OSA, as long as it is maintained. Lifestyle modifications and drug therapy seem to be the preferred approach to treat obesity, but in severe obesity and moderate to severe OSA, bariatric surgery is probably the most adequate treatment. CONCLUSIONS: Weight control is essential to decrease the risk of cardiovascular events and mortality potentially linked to both obesity and OSA. CPAP seems to treat only OSA without decreasing these risks. Other treatment strategies are lifestyle modifications and drug therapy, which need further investigation as well as bariatric surgery for severe cases. PMID- 29534972 TI - International perspective on management of a patent ductus arteriosus: Lessons learned. AB - Whereas association between a patent ductus arteriosus (PDA) and neonatal morbidities has been well described, consensus has not been reached on whether the relationship is causal, on benefit of (or lack of) treatment, on factors guiding the 'need to treat', and on treatment strategies. Trials to date have primarily focused on the narrow outcome of successful ductal closure. Evidence from several retrospective studies has suggested that management may be modified with increased use of conservative treatment. A paradigm shift has resulted in decreased use of treatments to close the PDA in some centres. This approach cites the lack of demonstrable improvement in short- and long-term respiratory and neurodevelopmental outcomes as an argument. This article reviews current understanding of the wide variation in practice at either institutional, regional, national, or international level. It discusses the potential contributors to variability in diagnostic ascertainment and therapeutic intervention. PMID- 29534973 TI - Lateral but not Medial Hypothalamic AMPK Activation Occurs at the Hypoglycemic Nadir in Insulin-injected Male Rats: Impact of Caudal Dorsomedial Hindbrain Catecholamine Signaling. AB - The hypothalamic energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK), an important regulator of counter-regulatory responses to hypoglycemia, responds to pharmacological manipulation of hindbrain AMPK activity. Dorsomedial hindbrain A2 noradrenergic neurons express hypoglycemia sensitive metabolo-sensory biomarkers, including AMPK. Here, adult male rats were pretreated by intra-caudal fourth ventricular administration of the selective neurotoxin 6-hydroxydopamine (6-OHDA) to determine if catecholamine signaling from the aforesaid site governs hypothalamic AMPK activation during insulin induced hypoglycemia (IIH). Micropunched arcuate (ARH), ventromedial (VMH), paraventricular (PVH), dorsomedial (DMH) nuclei and lateral hypothalamic area (LHA) tissues were obtained at the neutral protamine Hagedorn insulin-induced hypoglycemic nadir, coincident with A2 AMPK activation, for Western blot analysis of AMPK, phospho-AMPK (pAMPK), and relevant metabolic neuropeptides. ARH, VMH, LHA, and DMH norepinephrine levels were altered according to insulin dose; 6-OHDA mediated reversal of these responses was site-specific. IIH elevated LHA and reduced VMH pAMPK protein, profiles that were respectively unchanged or increased by 6-OHDA. PVH and ARH pAMPK was resistant to IIH, but augmented in ARH of neurotoxin- plus insulin-treated rats. ARH neuropeptide Y (NPY) and pro opiomelanocortin (POMC) proteins were correspondingly increased or refractory to IIH; 6-OHDA pretreatment normalized NPY and elevated POMC expression after insulin injection. Results demonstrate site-specific bi-directional adjustments in hypothalamic AMPK reactivity to hypoglycemia. Intensification of ARH/VMH pAMPK by 6-OHDA implies dorsomedial hindbrain improvement of energy balance in those sites during IIH. Neurotoxin-mediated augmentation versus suppression of basal catabolic (ARH POMC/VMH steroidogenic factor-1) or IIH-associated anabolic (ARH NPY) neuropeptide profiles, respectively, may involve local AMPK-dependent against independent mechanisms. PMID- 29534974 TI - Single-unit Activity in the in vitro Entorhinal Cortex During Carbachol-induced Field Oscillations. AB - The muscarinic receptor agonist carbachol (CCh) can induce activity in the theta range (4-15 Hz) in the entorhinal cortex (EC), but the underlying network mechanisms remain unclear. Here, we investigated the interplay between interneurons and principal cells in the EC during CCh-induced theta-like field oscillations in an in vitro brain slice preparation using tetrodes. Field oscillations at 10.1 Hz (IQR = 9.5-10.9 Hz) occurred during bath application of CCh (100 MUM; n = 32 experiments) and were associated with single-unit (n = 189) firing. Interneuron activity increased before principal cell activity at the onset of the oscillations and both interneurons and principal cells fired at specific oscillation phases with interneurons preceding principal cells, suggesting that interneurons modulate principal cell activity during such oscillations. The regularity of occurrence of CCh-induced oscillations was abolished by applying the GABAA receptor antagonist picrotoxin (100 MUM; n = 13). These effects were accompanied by changes in firing with principal cells discharging action potentials before interneurons, along with a loss of preferred firing phase for principal cells in relation to the oscillation peaks. Blocking ionotropic glutamatergic transmission abolished CCh-induced field oscillations (n = 6), suggesting that ionotropic glutamatergic receptor signaling is necessary for their generation. Our results show that neuronal network interactions leading to CCh-induced theta-like field oscillations rest on the close interplay between interneurons and principal cells and that interneurons modulate principal cell activity during such oscillatory activity. Moreover, they underscore the role of ionotropic glutamatergic transmission in this type of oscillations. PMID- 29534975 TI - The Role of Left Dorsolateral Prefrontal Cortex in Language Processing. AB - In addition to the role of left frontotemporal areas in language processing, there is increasing evidence that language comprehension and production require cognitive control and working memory resources involving the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate the role of the left DLPFC in both language comprehension and production. In a double-blind, sham-controlled crossover experiment, thirty-two participants received cathodal or sham transcranial direct current stimulation (tDCS) to the left DLPFC while performing a language comprehension and a language production task. Results showed that cathodal tDCS increases reaction times in the language comprehension task, but decreases naming latencies in the language production task. However, additional analyses revealed that the polarity of tDCS effects was highly correlated across tasks, implying differential individual susceptibility to the effect of tDCS within participants. Overall, our findings demonstrate that left DLPFC is part of the complex cortical network associated with language processing. PMID- 29534976 TI - MicroRNAs in regulatory T cells. PMID- 29534977 TI - MetaGO: Predicting Gene Ontology of Non-homologous Proteins Through Low Resolution Protein Structure Prediction and Protein-Protein Network Mapping. AB - Homology-based transferal remains the major approach to computational protein function annotations, but it becomes increasingly unreliable when the sequence identity between query and template decreases below 30%. We propose a novel pipeline, MetaGO, to deduce Gene Ontology attributes of proteins by combining sequence homology-based annotation with low-resolution structure prediction and comparison, and partner's homology-based protein-protein network mapping. The pipeline was tested on a large-scale set of 1000 non-redundant proteins from the CAFA3 experiment. Under the stringent benchmark conditions where templates with >30% sequence identity to the query are excluded, MetaGO achieves average F measures of 0.487, 0.408, and 0.598, for Molecular Function, Biological Process, and Cellular Component, respectively, which are significantly higher than those achieved by other state-of-the-art function annotations methods. Detailed data analysis shows that the major advantage of the MetaGO lies in the new functional homolog detections from partner's homology-based network mapping and structure based local and global structure alignments, the confidence scores of which can be optimally combined through logistic regression. These data demonstrate the power of using a hybrid model incorporating protein structure and interaction networks to deduce new functional insights beyond traditional sequence homology based referrals, especially for proteins that lack homologous function templates. The MetaGO pipeline is available at http://zhanglab.ccmb.med.umich.edu/MetaGO/. PMID- 29534978 TI - A study of the effects of maternal high fat diet on behavioural responses to acute and repeated administrations of cocaine in rat offspring. AB - Building on previous work in the field, we examined the effect of maternal high fat diet (HFD) during gestation and lactation on the sensitivity of male and female adult offspring to acute and repeated cocaine exposures, and to the expression of cocaine-induced anxiety in the elevated plus maze (EPM). In both male and female offspring, acute injections of cocaine induced a strong locomotor activating effect; repeated injections produced a robust conditioned locomotor response to the context in which they were given cocaine, and heightened activity in response to a subsequent acute challenge of cocaine. Although female offspring of HFD relative to control house chow diet (CHD) dams exhibited a generally elevated level of locomotor activity, this effect was not further enhanced by cocaine administration/s and there were no significant interactions between maternal diet and cocaine in either male or female offspring. Finally, female offspring of HFD relative to CHD dams exhibited enhanced behavioral anxiety in the EPM, an effect that was reversed when the offspring were exposed to cocaine 48 h prior. Although, in contradiction to our hypotheses, the present study failed to demonstrate an effect of maternal diet on the locomotor-activating effects of cocaine, it did replicate all of the established findings upon which its rationale and predictions were based. Thus, we believe that our results provide important context for future studies. PMID- 29534979 TI - Comparative metabolism of tripolide and triptonide using metabolomics. PMID- 29534980 TI - Effects of Paullinia cupana extract on lamotrigine pharmacokinetics in rats: A herb-drug interaction on the gastrointestinal tract with potential clinical impact. AB - Paullinia cupana-containing preparations are being consumed worldwide for weight reduction. As obesity and epilepsy are common comorbidities and lamotrigine (LTG) is a broad-spectrum antiepileptic drug, it is likely to find epilepsy patients taking P. cupana and LTG simultaneously. Thus, this work aimed to investigate the potential interaction between P. cupana extract and LTG in rats. In a study, rats were orally co-administered with a single-dose of P. cupana extract (821 mg/kg) and LTG (10 mg/kg). In another study, rats were orally pre-treated for 14 days with P. cupana extract (821 mg/kg/day) receiving LTG (10 mg/kg, p.o.) on the 15th day. Rats of the respective control groups received the corresponding volume of the extract vehicle. LTG concentrations were determined at several post-dose time points and submitted to a non-compartmental pharmacokinetic analysis. The co administration of P. cupana and LTG induced a significant reduction of LTG Cmax and AUC0-24 and prolonged the mean residence time. However, no significant effects were observed on LTG pharmacokinetics following a 14-day pre-treatment period with the extract. In this study changes in the body weight of rats and in some biochemical parameters were also evaluated. Overall, the results revealed a pharmacokinetic-based herb-drug interaction between P. cupana extract and LTG, mainly after their co-administration. PMID- 29534982 TI - Phenylpropanoids from the fruit of Crataegus pinnatifida exhibit cytotoxicity on hepatic carcinoma cells through apoptosis induction. AB - Eight new phenylpropanoids (1a/1b, 2-4, 5a/5b and 6) including two pairs of enantiomers (1a/1b and 5a/5b), along with a known analogue (7) were isolated from the fruit of Crataegus pinnatifida. Their structures were elucidated using comprehensive spectroscopic methods. Compounds 1a/1b and 5a/5b were separated successfully by chiral chromatographic column. The absolute configurations of enantiomers were determined by comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. The in vitro antitumor activities of the isolates were evaluated against two human hepatocellular carcinoma HepG2 and Hep3B cells. Five compounds (1a/1b, 2-4) exhibited more potent cytotoxicity and their structure-activity relationships were also discussed. Annexin V-FITC/PI staining using flow cytometry was carried out to examine cell apoptosis, and the results showed that compounds 3-4 with the presence of two methoxy groups substituted at C-3' significantly induced apoptosis in HepG2 cells. PMID- 29534981 TI - Lipin deactivation after acetaminophen overdose causes phosphatidic acid accumulation in liver and plasma in mice and humans and enhances liver regeneration. PMID- 29534983 TI - Cutaneous Manifestations of Chronic Vascular Disease. AB - In the contemporary era of medical diagnosis via sophisticated radiographic imaging and/or comprehensive serological testing, a focused physical examination remains paramount in recognizing the cutaneous manifestations of chronic vascular disease. Recognition of the unique cutaneous signs of lymphatic and venous hypertension assists in the diagnosis as well as the staging and classification of both lymphedema and chronic venous insufficiency. Awareness of explicit dermatologic vasomotor manifestations aids not only in the identification of acrocyanosis, Raynaud phenomenon, pernio, and erythromelalgia but also mitigates confusion related to their clinical overlap. Although the clinical signs of peripheral artery disease are not necessarily specific or sensitive, a knowledge of suggestive dermatologic findings is helpful in recognition of severe limb ischemia. A brief review of the epidemiology, etiology, pathogenesis, and therapy of cutaneous related chronic vascular disease follows including an emphasis on characteristic clinical features supported by illustrative photographs. PMID- 29534984 TI - Fibromuscular Dysplasia: Contemporary Concepts and Future Directions. AB - Fibromuscular dyplasia (FMD) is an under-recognized non-atherosclerotic, non inflammatory arteriopathy that occurs most commonly in middle-aged women, but may affect individuals of all age groups. FMD may result in stenosis, aneurysm, dissection, occlusion, or arterial tortuosity. Recently published data demonstrated a genetic association of FMD with a variant in the phosphatase and actin regulator 1 gene (PHACTR1), substantiating that the pathogenesis of this condition has genetic contribution. The renal and extracranial carotid and vertebral arteries are most often involved, although any arterial bed may be affected. Clinical manifestations often reflect the vascular territory affected, and can include hypertension, headaches, pulsatile tinnitus, myocardial infarction, transient ischemic attack and stroke. While the gold standard for diagnostic evaluation of FMD remains catheter-based angiography, noninvasive imaging, including duplex ultrasound, computed tomographic angiography, and magnetic resonance angiography, may be used for diagnosis. Treatment of FMD depends upon symptoms as well as the nature and location of arterial lesions, but may include both medical (blood pressure control, antiplatelet agents) and interventional (angioplasty, stents, coils, surgery) therapies. This contemporary analysis of the literature, combined with our own clinical experience in treating patients with FMD, will highlight pathophysiology, evaluation, management, and common misconceptions in the care of individuals with FMD. PMID- 29534985 TI - Next Generation Endovascular Therapies in Peripheral Artery Disease. AB - Endovascular therapy (EVT) of symptomatic peripheral artery disease (PAD) offers relief of symptoms and enhanced quality of life. Advancements in technique and technology have increased the feasibility and practicality of EVT, which now represents the preferred mode of revascularization over surgical procedures in many centers across the world. In this review, we consider the future of EVT in context of a rapidly expanding population of patients with symptomatic PAD. PMID- 29534986 TI - Peri-Procedural Management of Oral Anticoagulants in the DOAC Era. AB - Peri-procedural management of oral anticoagulants can be complex and confusing for many providers. It involves a careful balance of a patient's thromboembolic risk and bleeding risk. For every patient chronically taking an oral anticoagulant who will be undergoing an elective procedure, a four step approach may be considered when creating a plan for the oral anticoagulant. (1) Does the oral anticoagulant need to stop for the procedure? (2) If yes, when should the oral anticoagulant be stopped pre-procedure? (3) Does the patient require a "bridging" parenteral anticoagulant? (4) When should anticoagulation be re started post procedure? Based on the unique features of warfarin versus the direct oral anticoagulants (DOAC), a unique, personalized plan should be developed and tailored to the individual patient. Anticoagulant specialists, such as anticoagulation clinic pharmacists, may help facilitate this process. PMID- 29534987 TI - Transcriptomic profiling of nematode parasites surviving vaccine exposure. AB - Some nematode species are economically important parasites of livestock, while others are important human pathogens causing some of the most important neglected tropical diseases. In both humans and animals, anthelmintic drug administration is the main control strategy, but the emergence of drug-resistant worms has stimulated the development of alternative control approaches. Among these, vaccination is considered to be a sustainable and cost effective strategy. Currently, Barbervax(r) for the ruminant strongylid Haemonchus contortus is the only registered subunit vaccine for a nematode parasite, although a vaccine for the human hookworm Necator americanus is undergoing clinical trials (HOOKVAC consortium). As both these vaccines comprise a limited number of proteins, there is potential for selection of nematodes with altered sequences or expression of the vaccine antigens. Here we compared the transcriptome of H. contortus populations from sheep vaccinated with Barbervax(r) with worms from control animals. Barbervax(r) antigens are native integral membrane proteins isolated from the brush border of the intestinal cells of the adult parasite and many of those are proteases. Our findings provide no evidence for changes in expression of genes encoding Barbervax(r) antigens in the surviving parasite populations. However, surviving parasites from vaccinated animals showed increased expression of other proteases and regulators of lysosome trafficking, and displayed up regulated lipid storage and defecation abilities that may have circumvented the effect of the vaccine. Implications for other potential vaccines for human and veterinary nematodes are discussed. PMID- 29534988 TI - Genetic diversity and population structure of Theileria parva in South Sudan. AB - Theileria parva is a parasitic protozoan that causes East Coast fever (ECF), an economically important disease of cattle in eastern, central and southern Africa. In South Sudan, ECF is considered a major constraint for livestock development in regions where the disease is endemic. To obtain insights into the dynamics of T. parva in South Sudan, population genetic analysis was performed. Out of the 751 samples included in this study, 178 blood samples were positive for T. parva by species-specific PCR, were collected from cattle from four regions in South Sudan (Bor = 62; Juba = 45; Kajo keji = 41 and Yei = 30) were genotyped using 14 microsatellite markers spanning the four chromosomes. The T. parva Muguga strain was included in the study as a reference. Linkage disequilibrium was evident when populations from the four regions were treated as a single entity, but, when populations were analyzed separately, linkage disequilibrium was observed in Bor, Juba and Kajo keji. Juba region had a higher multiplicity of infection than the other three regions. Principal components analysis revealed a degree of sub structure between isolates from each region, suggesting that populations are partially distinct, with genetic exchange and gene flow being limited between parasites in the four geographically separated populations studied. Panmixia was observed within individual populations. Overall T. parva population genetic analyses of four populations in South Sudan exhibited a low level of genetic exchange between the populations, but a high level of genetic diversity within each population. PMID- 29534989 TI - "That's enough now!": A prospective study of the effects of maternal control on children's snack intake. AB - The aim of this study was to investigate maternal feeding strategies as prospective predictors of young children's snack intake. Participants were 252 mothers of children aged 3-11 years old who completed questionnaire measures of parent feeding strategies (Restriction and Covert Control) and reported on their child's healthy and unhealthy snack intake at two time points separated by three years. Longitudinal regression models showed no prediction of healthy snack food intake. However, Time 1 parental restrictive feeding predicted greater unhealthy snack intake at Time 2, while Time 1 covert feeding strategies predicted lower unhealthy snack intake at Time 2. Structural equation modeling showed that these associations were independent of known covariates that influence children's snack intake (child and parent weight, education level and SES). The results provide longitudinal evidence for the negative impact of restrictive parent feeding strategies on children's snack intake and highlight the importance of dissuading parents from using this type of feeding control. Instead, parents should be encouraged to use more covert feeding strategies that are associated with less unhealthy snack intake over the longer term. PMID- 29534990 TI - Neighborhood characteristics and lifestyle intervention outcomes: Results from the Special Diabetes Program for Indians. AB - Growing evidence reveals various neighborhood conditions are associated with the risk of developing type 2 diabetes. It is unknown, however, whether the effectiveness of diabetes prevention interventions is also influenced by neighborhood characteristics. The purpose of the current study is to examine the impact of neighborhood characteristics on the outcomes of a lifestyle intervention to prevent diabetes in American Indians and Alaska Natives (AI/ANs). Year 2000 US Census Tract data were linked with those from the Special Diabetes Program for Indians Diabetes Prevention Program (SDPI-DP), an evidence-based lifestyle intervention implemented in 36 AI/AN grantee sites across the US. A total of 3394 participants started the intervention between 01/01/2006 and 07/31/2009 and were followed by 07/31/2016. In 2016-2017, data analyses were conducted to evaluate the relationships of neighborhood characteristics with intervention outcomes, controlling for individual level socioeconomic status. AI/ANs from sites located in neighborhoods with higher median household income had 38% lower risk of developing diabetes than those from sites with lower neighborhood income (adjusted hazard ratio = 0.65, 95% CI: 0.47-0.90). Further, those from sites with higher neighborhood concentrations of AI/ANs achieved less BMI reduction and physical activity increase. Meanwhile, participants from sites with higher neighborhood level of vehicle occupancy made more improvement in BMI and diet. Lifestyle intervention effectiveness was not optimal when the intervention was implemented at sites with disadvantaged neighborhood characteristics. Meaningful improvements in socioeconomic and other neighborhood disadvantages of vulnerable populations could be important in stemming the global epidemic of diabetes. PMID- 29534991 TI - Microtubular remodeling and decreased expression of Nav1.5 with enhanced EHD4 in cells from the infarcted heart. AB - : Cardiac Na+ channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the infarcted canine heart. Recent studies show that Nav1.5 cytoskeletal- and endosomal-based membrane trafficking and function are linked to tubulin, microtubular (MT) networks, and Eps15 homology domain containing proteins like EHD4. AIM: Our objective is to understand the relation of tubulin and EHD4 to Nav1.5 channel protein remodeling observed in border zone cells (IZs) when arrhythmias are known to occur; that is, 3-h, 48-h and 5-day post coronary occlusion. MATERIALS METHODS FINDINGS: Our voltage clamp and immunostaining data show that INa density is decreased in the epicardial border zone cells of the 48 h infarcted heart (IZ48h). Immunostaining studies reveal that in post MI cells the cell surface staining of Nav1.5 was reduced and Nav1.5 distribution changed. However, intense co-staining of Nav1.5 and tubulin occurs in core planes and the perinuclear areas in post MI cells. At the same time, there were marked changes in the subcellular location of the EHD4 protein. EHD4 is co-localized with tubulin protein in discrete intracellular "highway" structures. SIGNIFICANCE: The distribution and expression of the three proteins are altered dynamically in post MI cells. In sum, our work illustrates the spatiotemporal complexity of remodeling mechanisms in the post-infarct myocyte. It will be important in future experiments to further explore direct links between MT, EHD proteins, and cell proteins involved in forward trafficking. PMID- 29534992 TI - The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex. AB - AIMS: We have previously identified a chemical scaffold possessing 2 ethoxypropanoic acid (designated as KS15) that directly binds to the C-terminal region of cryptochromes (CRYs: CRY1 and CRY2) and enhances E-box-mediated transcription. However, it is still unclear how KS15 impairs the feedback actions of the CRYs and which chemical moieties are functionally important for its actions. MAIN METHODS: The E-box-mediated transcriptional activities were mainly used to examine the effects of KS15 and its derivatives. Co-immunoprecipitation assays accompanied by immunoblotting were employed to monitor protein-protein associations. We also examined the effects of KS15 and selected derivatives on circadian molecular rhythms in cultured cells. KEY FINDINGS: The present study shows that KS15 inhibits the interaction between CRYs and Brain-Muscle-Arnt-Like protein 1 (BMAL1), thereby impairing the feedback actions of CRYs on E-box dependent transcription by CLOCK:BMAL1 heterodimer, an indispensable transcriptional regulator of the mammalian circadian clock. Subsequent structure activity relationship analyses using a well-designed panel of derivatives identified the structural requirements for the effects of KS15 on CRY-evoked regulation of E-box-mediated transcription. We found that KS15 and several derivatives significantly reduce the amplitude and delayed the phase of molecular circadian rhythms in fibroblast cultures. SIGNIFICANCE: Taken together, our results provide valuable information on the molecular mode-of-action as well as the chemical components of the CRYs inhibitor that pharmacologically impact on the transcriptional activity of the CLOCK:BMAL1 heterodimer. PMID- 29534993 TI - Toxicity of Doxorubicin (Dox) to different experimental organ systems. AB - Doxorubicin (Dox) is a valuable anticancer drug for hematologic and solid tumors. Yet, it can cause multi-organ toxicities in various patients. Since toxicity evaluation is a major criterion to discuss for every experiment, the current mini review focuses on the toxicity of Dox to multiple organs and suggests the most probable mechanism. Though several mechanisms have been suggested, the role of oxidative stress remains elusive among other mechanisms and remains the most probable mechanism for cardiotoxic effect of Dox. PMID- 29534994 TI - Health outcomes for youth with type 1 diabetes at 18 months and 30 months post transition from pediatric to adult care. AB - AIMS: To identify (a) determinants of glycated haemoglobin (HbA1c) at 18 and 30 months following transition in young people with Type 1 diabetes mellitus (T1DM) to a youth-specific diabetes service; and to (b) evaluate the impact of the service on acute admissions with diabetic ketoacidosis (DKA) over a 14-year period. METHODS: An audit of records of youth with T1DM referred from paediatric services to the multidisciplinary transition service at Westmead Hospital, from 2001 to 2012, and followed-up to 2014. RESULTS: Data from 439 adolescents and young adults (Median age: 18) were analysed. The recommended standard of glycaemic control, HbA1c < 7.5% (58 mmol/mol), was achieved by 23% at baseline, 22% at 18-months, and 20% at 30-month. After adjusting for lag time (>3 months) and diabetes duration (>7 years), glycaemic control at first visit predicted subsequent glycaemic control at 18-month and 30-month follow-up. From 2001 to 2014, only 8.6% were lost to follow-up; admissions and readmissions for DKA reduced from 72% (32/47) to 4% (14/340) (p < 0.001). Furthermore, mean length of stay (LOS) significantly decreased from 6.56 to 2.36 days (p < 0.001). CONCLUSIONS: Continuing engagement with the multidisciplinary transition service prevented deterioration in HbA1c following transition. Age-appropriate education and regular follow-up prevents DKA admissions and significantly reduced admission LOS. PMID- 29534995 TI - Statin-induced myopathy SLCO1B1 521T > C is associated with prediabetes, high body mass index and normal lipid profile in Emirati population. AB - BACKGROUND: Statin-induced myopathy has been linked to the C allele of a single nucleotide polymorphism (SNP) (rs4149056) of SLCO1B1 gene. This effect is more significant, but not restricted to simvastatin. Many studies have included European, American, African and Southeast Asian ancestries, but few were carried out on Middle Eastern population. AIM: To detect the prevalence of SLCO1B1 rs4149056 (521T > C) in Emirati population. METHOD: We recruited 282 Emiratis through the UAE National Diabetes and Lifestyle Project. Ethical approval was obtained before the study starts. Besides basic data collection, venous blood samples were collected. Fasting blood glucose, Lipid profile, and insulin levels were measured. Genotyping for rs4149056 (521T > C) was tested in triplicates through Real Time-PCR using TaqMan(r) Drug Metabolism Genotyping Assay. rs2306283 (388A > G) was analyzed for comparison. In addition, presence of minor alleles of both SNPs define stronger association with statin-induced myopathy. RESULTS: The study included 282 individuals, 52.8% were males with median age of 39.5 years. 10% had Diabetes Mellitus and 23% were hypertensive. Median of body mass index (BMI) was 27.68 kg/m2 in males and 28.38 kg/m2 in females. One-hundred ninety seven (69.9%) showed abnormal lipid profile (either increased LDL-cholesterol or triglycerides or both). For rs4149056, C allele was present in 21.3% (2.8% homozygous C and 18.4% heterozygous CT). Although homozygous C genotype prevalence was low, compared with Caucasians (4%) and Africans (0%), C allele was associated with a trend of having higher BMI and abnormal lipid profile. C allele subjects were all pre-diabetics with mean glycated hemoglobin above 6%. Mean BMI in CC, CT, and TT genotypes was 30.91 +/- 4.4, 29.48 +/- 4.2, 27.96 +/- 5.5 kg/m2 respectively, with lack of such a trend observed with the different genotypes of the rs2306283 (used for comparison). Abnormal lipid profile was observed in 7/8(87.5%), 38/52(73.1%) and 152/222(70%) of the CC, CT, and TT genotypes respectively. CONCLUSION: There is lower prevalence of statin-induced myopathy linked C allele of rs4149056 in SLCO1B1 gene in Emirati population, compared to Caucasians and Africans. However, there is a trend of higher glycosylated hemoglobin and BMI associated with normal lipid profile in patients having this allele. PMID- 29534996 TI - Low-sensitivity urine pregnancy testing to assess medical abortion outcome: A systematic review. AB - OBJECTIVE: The objective was to summarize data on the accuracy and acceptability of a strategy for identifying ongoing pregnancy after medical abortion treatment using a low-sensitivity pregnancy test (LSPT). STUDY DESIGN: We searched PubMed to identify studies that evaluated the use of a single posttreatment LSPT for detection of ongoing pregnancy after treatment with mifepristone and misoprostol. We extracted, assessed and summarized data from each study. RESULTS: We found 10 studies that evaluated 6 LSPTs with human chorionic gonadotropin detection thresholds of 1000, 1500 or 2000 mIU/mL. The three earliest studies compared the pregnancy test strategy to standard assessment in the same women; the sensitivity of a positive or invalid LSPT result for detecting ongoing pregnancy ranged from 67% to 100%. Three randomized trials found no significant difference in detection of ongoing pregnancy between the LSPT strategy and routine in-person follow-up. Four noncomparative studies found that of the 12 women who had ongoing pregnancies diagnosed after performing an LSPT, 8 (67%) had positive or invalid LSPT results. Across the 10 studies, 30 of the 59 total ongoing pregnancies (51%) were identified based on symptoms without a positive or invalid LSPT result. Women expressed satisfaction with the LSPT strategy. Risk of bias in the seven later studies was high. CONCLUSIONS: Despite their limitations, most studies showed that the LSPT strategy had moderate sensitivity for identifying ongoing pregnancy and can enable the majority of medical abortion patients to assess treatment outcome at home. However, the LSPT itself had a limited role in the detection of treatment failures in the studies. IMPLICATIONS STATEMENT: The LSPT strategy shows promise for reducing the need for in-person follow-up after medical abortion. A range of home-based options should be validated to meet the varied needs of women and abortion providers in diverse settings. PMID- 29534997 TI - A Phase II, Randomized, Multicenter Study Comparing 10 Months versus 4 Months of Degarelix Therapy in Prolonging the Off Treatment Interval in Men with Localized Prostate Cancer Receiving Intermittent Androgen Deprivation Therapy for Biochemical Recurrence following Radical Local Therapy. AB - PURPOSE: Clinical trials in men initiating intermittent androgen deprivation therapy have used a range of induction durations between 3 and 12 months. We sought to determine whether the duration of induction androgen deprivation therapy would influence the duration of the off treatment interval and the recovery of serum testosterone. MATERIALS AND METHODS: This was a prospective, randomized, open label study. Men with biochemical recurrence after local therapy for prostate cancer and a negative bone scan were randomized to 4 and 10 months of monthly degarelix. The first dose was 240 mg and subsequent doses were 80 mg per month. Quality of life was evaluated by the I-PSS (International Prostate Symptom Score), the PAS-SFI (Problem Assessment Scale of the Sexual Function Index) and the FACT-P (Functional Assessment of Cancer Therapy-Prostate). RESULTS: A total of 90 patients were randomized, including 43 to 4 months and 47 to 10 months of treatment. There was no difference in any relevant baseline laboratory parameter, including prostate specific antigen and testosterone. There was no difference between the 2 treatment groups in time off treatment (HR 1.51, 95% CI 0.60-3.84, p = 0.38). Actuarial median time to testosterone recovery to 8.0 nmol/l or greater was 8.05 months (95% CI 4.34-39.89) in the 10-month treatment arm and 6.24 months (95% CI 5.45-15.90) in the 4-month treatment arm. The log rank test showed no statistical significance between the 2 treatment groups in time to testosterone recovery (p = 0.8392). There was no difference in the testosterone recovery rate between the 2 arms. Men younger than 65 years had a considerably shorter interval off treatment and time to testosterone recovery. There was a lesser adverse effect on quality of life at the end of treatment in the 4-month than in the 10-month arm. CONCLUSIONS: In men with biochemical recurrence who initiated intermittent androgen deprivation therapy with degarelix no difference was observed in the duration of the off treatment interval or the rate of testosterone recovery whether they received 4 or 10 months of induction androgen deprivation therapy. PMID- 29534998 TI - Commonality in the microarchitecture of trabecular bone: A preliminary study. AB - Understanding the relationship between the microstructure and mechanical function of trabecular bone is critical for prediction and prevention of bone fragility fractures. However, a detailed understanding of the structural design of trabecular microarchitecture is still missing. This study hypothesized that there exists a commonality in the underlying probabilistic distributions of microstructural features of trabecular bones, whereas the microstructural differences among individuals are primarily describe by a set of scalar parameters. To test the hypothesis, twenty-three trabecular bone specimens were obtained from two anatomic locations (i.e., femoral neck and vertebral body) and a diverse group of seventeen donors of different age and sex. The number, size, spatial location, and orientation of individual plates and rods in the trabecular bone specimens were determined via volumetric decomposition of 3D MUCT images using the Individual Trabecula Segmentation (ITS) technique. Then, m/n bootstrap Kolmogorov-Smirnov tests were performed to compare the normalized distributions of size, orientation, and spatial arrangement of trabecular plates and rods in the specimens. The results showed that 100% of the twenty-three normalized distributions of each microstructural feature were statistically equivalent irrespective of individual differences among the bone specimens, except the distributions of rod spatial arrangement (<100%). On the other hand, nonparametric Mann-Whitney U tests showed that a set of scalar parameters (i.e., the number, average size, and average nearest neighbor distance of trabecular plates and rods) were statistically different among the individual specimens (p<0.05). Due to the commonality of the underlying distributions, the individual differences in the trabecular microstructure among the specimens seemed to be reflected primarily by changes in the scalar parameters. The above results strongly support the hypothesis of this study and may shed more light on understanding the natural design of trabecular bone microstructures. PMID- 29534999 TI - Diverse signalling of the platelet P2Y1 receptor leads to a dichotomy in platelet function. AB - Platelet P2Y1 receptor signalling via RhoGTPases is necessary for platelet dependent leukocyte recruitment, where no platelet aggregation is observed. We investigated signalling cascades involved in distinct P2Y1-dependent platelet activities in vitro, using specific inhibitors for phospholipase C (PLC) (U73122, to inhibit the canonical pathway), and RhoGTPases: Rac1 (NSC23766) and RhoA (ROCK inhibitor GSK429286). Human platelet rich plasma (for platelet aggregation) or isolated washed platelets (for chemotaxis assays) was treated with U73122, GSK429286 or NSC23766 prior to stimulation with adenosine diphosphate (ADP) or the P2Y1 specific agonist MRS2365. Aggregation, chemotaxis (towards f-MLP), or platelet-induced human neutrophil chemotaxis (PINC) towards macrophage derived chemokine (MDC) was assessed. Molecular docking of ADP and MRS2365 to P2Y1 was analysed using AutoDock Smina followed by GOLD molecular docking in the Accelrys Discovery Studio software. Inhibition of PLC, but not Rac1 or RhoA, suppressed platelet aggregation induced by ADP and MRS2365. In contrast, platelet chemotaxis and PINC, were significantly attenuated by inhibition of platelet Rac1 or RhoA, but not PLC. MRS2365, compared to ADP had a less pronounced effect on P2Y1 induced aggregation, but a similar efficacy to stimulate platelet chemotaxis and PINC, which might be explained by differences in molecular interaction of ADP compared to MRS2365 with the P2Y1 receptor. Platelet P2Y1 receptor activation during inflammation signals through alternate pathways involving Rho GTPases in contrast to canonical P2Y1 receptor induced PLC signalling. This might be explained by selective molecular interactions of ligands within the orthosteric site of the P2Y1 receptor. PMID- 29535000 TI - Pentoxifylline inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures. AB - Pentoxifylline (PTX), a non-specific inhibitor of cAMP phosphodiesterases, is commonly used for treatment of peripheral vascular disorders although its direct action on endothelial cells is not well described. The aim of this study was to determine the influence of PTX on tubule formation and mRNA expression for angiogenesis-related proteins in endothelial cell line C166 and mouse proepicardial explants cultured on collagen. C166 cells and explants were stimulated with proangiogenic cocktail containing bFGF/VEGF-A120/VEGF-A164 and with proangiogenic cocktail enriched with PTX. After stimulation the number and morphology of tubules stained with anti-CD31 antibody was examined under a confocal microscope and expression of mRNA for VEGF-A, VEGF-B, VEGF-C, bFGF, IGF 1, Dll4 and Notch1 was measured with RealTime PCR. In C166 cell line there was no significant difference in tubule formation and mRNA expression, but in proepicardial explants we observed a considerable reduction in tubule number and in mRNA levels for Dll4 and Notch1 after PTX administration. In conclusion, PTX indirectly inhibits angiogenesis in mouse proepicardial explant cultures but has no significant effect on C166 endothelial cell line. PMID- 29535001 TI - 3-(4-Chlorophenylselanyl)-1-methyl-1H-indole, a new selenium compound elicits an antinociceptive and anti-inflammatory effect in mice. AB - Several pathologies, such as pain and inflammation, are modulated by different pathways, making it necessary to develop drugs capable of modulating different pathways. Based on that, we investigated the antinociceptive and anti inflammatory effect of 3-(4-chlorophenylselanyl)-1-methyl-1H-indole (CMI), as well as the systems involved in these actions. This study evaluated the antinociceptive and anti-inflammatory effects of CMI [0.0001-10 mg/kg administered intragastrically (i.g.)] in the formalin, glutamate, hot plate, ear edema induced by croton oil and paw edema induced by formalin tests. In addition, to investigate the mechanism of action, mice were pre-treated with antagonists of adenosinergic, monoaminergic and opioid systems before administration of CMI. The selenium-containing compound decreased the paw licking and biting time in the formalin and glutamate tests, increased the response latency in hot plate test, without ambulatory changes, evaluated in the open field test. CMI was able to reduce both paw and ear edema induced by formalin and croton oil, respectively. Additionally the antinociceptive effect of CMI (0.01 mg/kg) was blocked when mice were pretreated with the antagonists: SCH23390 [D1-receptor antagonist, 0.05 mg/kg, intraperitoneally (i.p.)], WAY100635 (5-HT1A-receptor antagonist, 0.7 mg/kg, i.p.), ondansetron (5-HT3-receptor antagonist, 0.5 mg/kg, i.p.), ketanserin (5-HT2A/2C-receptor antagonist, 0.3 mg/kg, i.p.), naloxone (non selective antagonist 1 mg/kg, i.p.), caffeine (non-selective antagonist, 3 mg/kg, i.p.) and prazosin (alpha1-receptor antagonist, 0.15 mg/kg, i.p). These results demonstrate that the antinociceptive effect of CMI is mediated by monaminergic, opioidergic and adenosinergic modulations and can be a promising molecule capable of modulating different pathways for the treatment of pain and inflammation. PMID- 29535003 TI - Knockout of tissue transglutaminase ameliorates TGFbeta2-induced ocular hypertension: A novel therapeutic target for glaucoma? AB - Glaucoma is a vision threatening optic neuropathy that affects millions of people worldwide. In primary open angle, increased intraocular pressure (IOP) is the main risk factor for the development of this disease. Studies investigating the causes and mechanisms of increased IOP show fibrotic changes in the trabecular meshwork (TM) that are different from those of age-matched controls. Tissue transglutaminase (TGM2), an extracellular matrix (ECM) crosslinking enzyme, covalently crosslinks ECM proteins and causes excessive ECM protein deposition in the TM that could cause increased IOP. Previous literature reports increased expression of TGM2 in glaucomatous eyes compared to controls. We recently have shown that overexpression of TGM2 causes increased ECM crosslinking in the TM, increases IOP, and decreases aqueous humor (AH) outflow facility in mouse eyes. Therefore, we wanted to study the effect of TGM2 knockout (KO) on IOP in TGM2 floxed mice. Ad5.Cre transduction caused partial KO of TGM2, which decreased TGM2 expression in the TM region of mouse eyes. TGM2 KO significantly decreased IOP by itself and also in TGFbeta2 induced ocular hypertensive mice. TGM2 KO also restores the outflow facility in TGFbeta2 transduced eyes. Overall, TGM2 KO rescued the TGFbeta2-induced ocular hypertensive phenotype. Thus, TGM2 may offer potential as a new therapeutic target for glaucoma. PMID- 29535002 TI - Potential phytocompounds for developing breast cancer therapeutics: Nature's healing touch. AB - Breast cancer (BC) is a devastating disease in female around the world causing significant health care burden in both developed and developing countries. In many cases BC has shown resistance to chemotherapy, radiation and hormonal therapy. Development of new, cost effective, affordable treatment method is the need of hour. Chemical compounds isolated from plants are often biologically active and is attracting the attention of scientific community. Different in vitro and in vivo studies have shown a potential role in reducing the risk of cancer metastasis. Large number of phytochemicals are considered to regulate several molecular and metabolic processes like cell cycle regulation, apoptosis activation, angiogenesis and metastatic suppression that can hinders cancer progression. An extensive review of literature has been conducted to underline the key phytochemicals and their mechanism of action. This review article has discussed in detail the regulatory roles of phytochemicals, their analogs and nanoformulations and the probability of using phytochemicals in therapeutic management of BC. Finally, current limitations, challenges and future perspectives of these phytochemicals are also critically discussed. PMID- 29535004 TI - Distribution of pituitary adenylate cyclase-activating polypeptide 2 in zebrafish brain. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multipotent neuropeptide with an amino acid sequence that is well conserved among vertebrates. In teleosts, including zebrafish, the PACAP gene (adcyap1) has been duplicated to yield adcyap1a (coding PACAP1) and adcyap1b (coding PACAP2). This study aims to determine the distribution of these PACAPs and their mRNAs in zebrafish. We generated a zebrafish PACAP2-specific antibody. Using real-time PCR, we observed that adcyap1b mRNA was primarily localized in the brain, with the highest level in the telencephalon, followed by the diencephalon. Using immunostaining of brain tissue samples, PACAP2 immunoreactivity was observed mainly in the telencephalon, hypothalamus, and cerebellum, and the immunopositive fibers formed a line to the habenula. PACAP2-immunopositive cells were observed in the ventral and dorsal regions of the telencephalon and in the hypothalamic nucleus of the diencephalon in the colchicine-injected brain. This distribution of PACAP2 suggests its involvement in higher brain functions in teleosts, such as learning and cognition, as well as instinctive behaviors such as feeding and emotional regulation. PMID- 29535005 TI - Identification of evolutionarily conserved residues required for the bioactivity of a pedal peptide/orcokinin-type neuropeptide. AB - Pedal peptides and orcokinins are structurally related neuropeptides that were first discovered in protostomian invertebrates - mollusks and arthropods, respectively. Recently, pedal peptide/ocokinin (PP/OK)-type neuropeptides were discovered in a deuterostomian phylum, the echinoderms, indicating that the evolutionary origin of this neuropeptide family can be traced back to the common ancestor of bilaterian animals. Sequences comparison of PP/OK-type neuropeptides reveals several conserved residues, including N- and C-terminally located hydrophobic residues that are important for the bioactivity of orcokinin. Here we report the first comprehensive analysis of the structure-activity relationships of a PP/OK-type neuropeptide - starfish myorelaxant peptide (SMP; FGKGGAYDPLSAGFTD) from the starfish Patiria pectinifera (Phylum Echinodermata). Comparison of the bioactivity of SMP with N-terminally and/or C-terminally truncated and alanine-substituted SMP analogs revealed a core peptide (GAYDPLSAGF; SMP(5-14)) that retains the muscle-relaxing activity of SMP, albeit with reduced potency and efficacy. Within this core peptide, alanine-substitution of several residues resulted in complete or partial loss of bioactivity, whilst loss or substitution of the N-terminal phenylalanine residue of SMP also caused a substantial reduction in bioactivity. Furthermore, analysis of the bioactivity of other SMP-like peptides derived from the same precursor as SMP revealed that none of these were more potent/effective than SMP as muscle relaxants. In conclusion, we have identified key residues required for the bioactivity of a PP/OK-type neuropeptide (SMP), including hydrophobic residues located in the N- and C terminal regions that are conserved in PP/OK-type peptides from other phyla as well as core residues that are conserved in echinoderm PP/OK-type peptides. PMID- 29535006 TI - "Big Little Challenges". PMID- 29535007 TI - No Need for Repeat Imaging in Patients with Mild Traumatic Subarachnoid Hemorrhage without Clinical Progression. PMID- 29535008 TI - Syringe Port: A Convenient, Safe, and Cost-Effective Tubular Retractor for Transportal Removal of Deep-Seated Lesions of the Brain. AB - OBJECTIVE: Minimally invasive transportal resection of deep intracranial lesions has become a widely accepted surgical technique. Many disposable, mountable port systems are available in the market for this purpose, like the ViewSite Brain Access System. The objective of this study was to find a cost-effective substitute for these systems. METHODS: Deep-seated brain lesions were treated with a port system made from disposable syringes. The syringe port could be inserted through minicraniotomies placed and planned with navigation. All deep seated lesions like ventricular tumours, colloid cysts, deep-seated gliomas, and basal ganglia hemorrhages were treated with this syringe port system and evaluated for safety, operative site hematomas, and blood loss. RESULTS: 62 patients were operated on during the study period from January 2015 to July 2017, using this innovative syringe port system for deep-seated lesions of the brain. No operative site hematoma or contusions were seen along the port entry site and tract. CONCLUSIONS: Syringe port is a cost-effective and safe alternative to the costly disposable brain port systems, especially for neurosurgical setups in developing countries for minimally invasive transportal resection of deep brain lesions. PMID- 29535009 TI - Sulfated zwitterionic poly(sulfobetaine methacrylate) hydrogels promote complete skin regeneration. AB - : Skin wound healing is a still long-history challenging problem and impeded by the foreign-body reaction including severe inflammation response, poor neovascularization, incomplete re-epithelialization and defective ECM remodeling. Development of biocompatible polymers, in combination with specific drugs or growth factors, has been considered as a promising strategy to treat skin wounds. Significant research efforts have been made to develop poly(ethylene glycol) PEG based polymers for wound healing, however less efforts has been paid to zwitterionic materials, some of which have demonstrated their super low-fouling property in vitro and anti-inflammatory property in vivo. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied them to full-thickness cutaneous wounds in mice. The healing effects of SBMA hydrogels on the wound closure, re-epithelialization ratio, ECM remodeling, angiogenesis, and macrophage responses during wound healing processes were histologically evaluated by in vivo experiments. Collective results indicate that SBMA hydrogels promote full-thickness excisional acute wound regeneration in mice by enhancing angiogenesis, decreasing inflammation response, and modulating macrophage polarization. Consistently, the incorporation of SBMA into PEG hydrogels also improved the overall wound healing efficiency as compared to pure PEG hydrogels. This work demonstrates zwitterionic SBMA hydrogels as promising wound dressings for treating full-thickness excisional skin wounds. STATEMENT OF SIGNIFICANCE: Development of highly effective wound regeneration system is practically important for biomedical applications. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied it to full thickness cutaneous wounds in mice, in comparison with PEG hydrogels as a control. We are the first to examine and reveal the difference between zwitterionic SBMA hydrogels and PEG hydrogels using a full-thickness excisional mice model. Overall, a series of in vivo systematic tests demonstrated that zwitterionic SBMA hydrogels exhibited superior wound healing property in almost all aspects as compared to PEG hydrogels. PMID- 29535010 TI - Technology-assisted risk of bias assessment in systematic reviews requires precise definitions of risk of bias. PMID- 29535011 TI - Translation of Knowledge to Practice-Improving Awareness in NSCLC Molecular Testing. AB - BACKGROUND: Molecular testing in advanced lung cancer is standard in guiding treatment selection. However, population-wide implementation of testing remains a challenge. We developed a knowledge translation intervention to improve understanding among diagnostic specialists about molecular testing and appropriate diagnostic sampling in lung cancer. METHODS: Specialty-specific education programs were developed from existing literature and input from Canadian leaders in lung pathology, respirology, interventional radiology, thoracic surgery, radiation oncology, and medical oncology. The programs, including key messages, review of current data, existing guidelines, group discussion, and participant feedback, were administered at provincial and national specialty meetings. Participant knowledge was assessed before and after the intervention by using anonymous questionnaires. Molecular (EGFR) testing rates in Ontario were also evaluated before and after the intervention period. RESULTS: Ten programs were administered to diagnostic specialists, including respirologists, pathologists, thoracic surgeons, radiologists, radiation oncologists, and medical oncologists, with completion of 255 preintervention and 219 postintervention surveys. At baseline, 30% were unsure of tissue handling methods for molecular testing, 20% chose an incorrect technique, and half were unfamiliar with how to initiate testing. After intervention, specialist knowledge improved regarding tissue handling and appropriate fixation techniques and uncertainty decreased from 30% to 2% (p < 0.001). A 12% increase (relative increase 57%) in molecular (EGFR) testing requests in Ontario was observed over the intervention period (p = 0.0032). CONCLUSIONS: Significant knowledge gaps exist among diagnostic specialists regarding molecular testing and targeted therapy in lung cancer. This initiative significantly improved understanding of the importance and methods of successful molecular testing and correlated with increased testing rates. PMID- 29535012 TI - Identification of a C-type lectin possessing both antibacterial and antiviral activities from red swamp crayfish. AB - C-type lectins are important immune molecules that participate in crustacean defense response. The present work reports a novel C-type lectin (PcLec6) from the red swamp crayfish Procambarus clarkii. PcLec6 encodes a single-peptide protein of 385 amino acids, which include a C-type lectin domain (CTLD) and a serine-rich region. PcLec6 expression in lymph organ and gills was up-regulated after bacterial challenge by Vibrio alginolyticus or white spot syndrome virus (WSSV). Recombinant full-length PcLec6 or its CTLD proteins were used for the functional analyses. Results showed that these two proteins had the capacity to bind to carbohydrates and bacteria. Both the full-length PcLec6 and CTLD facilitated the bacterial clearance, but only full-length PcLec6 protected crayfish from WSSV infection. Furthermore, PcLec6 regulated the expression of ALF genes. These results suggest that PcLec6 is involved in the innate immune response of crayfish against both bacterial and viral pathogens. PMID- 29535013 TI - Effect of individual distal femoral valgus resection in total knee arthroplasty for patients with valgus knee: A retrospective cohort study. AB - BACKGROUND: Proper limb alignment and implant positioning are important for successful total knee arthroplasty (TKA). It remains unknown whether any differences exist in the restoration of limb alignment for valgus knees between fixed and individual femoral valgus correction angle (VCA) for distal femoral resection. METHODS: A total of 63 patients (66 knees) had fixed 4 degrees VCA (fixed group), and 55 patients (59 knees) had individual VCA (individual group). We compared the VCA, mechanical femorotibial (MFT) angle, femoral component angle (alpha), and tibial component angle (beta) between the two groups. RESULTS: There were statistically significant differences in postoperative MFT angle between the two groups (2.0 degrees +/- 1.2 degrees versus 2.8 degrees +/- 1.6 degrees , p < 0.002). A total of 51 (77.3%) patients in the individual group had postoperative alignment deviation within +/-3 degrees compared with that of 32 (54.2%) patients in the fixed group (p = 0.006). We found better postoperative alignment accuracies in the individual group for grade II knee valgus deformities (1.8 degrees +/- 1.2 degrees versus 2.8 degrees +/- 1.5 degrees , p = 0.00). There was a significant difference in alpha angle deviations between the two groups (1.7 degrees +/- 1.3 degrees versus 2.5 degrees +/- 1.8 degrees , p = 0.00). The number of patients with postoperative femoral coronal component alignment deviations within +/-3 degrees in the individual group was higher compared to that in the control group (87.8% versus 67.8%, p = 0.006). CONCLUSIONS: This radiological study showed that individual VCA for distal femoral resection could achieve better postoperative alignment accuracy and fewer outliers of limb and femoral component malalignment in the coronal plane. PMID- 29535014 TI - Clinical effectiveness of treatment of combined upper thoracic spinal stenosis and multilevel cervical spinal stenosis with different posterior decompression surgeries. AB - OBJECTIVE: To explore the clinical effectiveness of various posterior decompression surgeries in the treatment of upper thoracic spinal stenosis combined with multilevel cervical spinal stenosis. METHODS: From January 2010 to December 2015, 22 consecutive patients with combined upper thoracic spinal stenosis and multilevel cervical spinal stenosis were treated with two different approaches of posterior decompression surgeries. In group A with 10 patients, both cervical and thoracic spinal decompression surgeries were performed simultaneously (one-stage surgery); in group B with 8 patients, cervical and thoracic spinal decompression surgeries were performed separately within three months (two-stage surgery). Based on Japanese Orthopedic Association (JOA) scores, improvement rate and extent of neurological function were calculated and the difference was compared between the two groups. RESULTS: There was no significant difference in demographic data between the two groups. However, compared with those of group B, both short-term and long-term improvement rate of neurological function in group A was higher (P < 0.05). In addition, the hospitalization cost was also lower in group A. CONCLUSION: Both one-stage and two-stage posterior decompression surgeries were effective in treating patient with upper thoracic spinal stenosis combined with multilevel cervical spinal stenosis; however, one-stage combined surgery was superior to two-stage surgery. PMID- 29535015 TI - Combined pedicle screw fixation at the fracture vertebrae versus conventional method for thoracolumbar fractures: A meta-analysis. AB - BACKGROUND: Thoracolumbar fractures is a frequent injury occurring in spinal trauma. Outcomes and complications between combined pedicle screw fixation at the fracture vertebrae (AFV) and conventional method cross the fracture vertebrae (CFV) are still controversial. Thus, this study aimed to evaluate differences in outcome variables between these two operative methods. MATERIALS AND METHODS: PubMed, Web of Science, Cochrane Library, EMBASE and CNKI were searched with the terms "thoracolumbar fractures", "posterior", "pedicle screw fixation", and "clinical trial" from Jan 1980 to July 2017. Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted data from eligible studies, with confirmation by cross-checking. The major results and conclusions were concluded, and the different complication rates and functional outcomes were compared. Meta-analysis was performed using RevMan 5.3 software. RESULTS: Eighteen randomized controlled trials involving 1280 patients were eligible. The pooled data revealed that AFV group might be associated with more intraoperative blood loss (MD = 9.84, 95%CI 7.45 to 12.22) and longer operation time (MD = 1.97, 95%CI 0.17 to 3.77) when compared with CFV group. However, AFV group significantly improved visual analogue scale (VAS) (MD = -1.27, 95%CI -1.70 to -0.83), anterior vertebral height (AVH) (MD = 7.58, 95%CI 3.99 to 11.17), short-term Cobb angle (MD = -1.29, 95%CI -2.39 to -0.19), long-term Cobb angle (MD = -4.47, 95%CI -7.30 to -1.63) and loss of long-term correction efficacy (MD = -6.56, 95%CI -7.49 to -5.62) after surgery. Moreover, compared with the CFV group, the AFV group had lower rate of implant failure (MD = 0.16, 95%CI 0.07 to 0.36). Both techniques had similar hospital stay (MD = 0.25, 95%CI -0.52 to 1.03) and postoperative infection (MD = 0.53, 95%CI 0.13 to 2.23). CONCLUSIONS: Though with a more operation time and intraoperative hemorrhage, combined pedicle screw fixation at the fracture veterbrae may be better than traditional fixation cross the fracture level alone for thoracolumbar fractures. PMID- 29535016 TI - Risk factor, early diagnosis and overall survival on outcome of association between pancreatic cancer and diabetes mellitus: Changes and advances, a review. AB - To review literature addressing determination of the risk factor, early diagnosis and overall survival on outcome among patient of pancreatic cancer associated with diabetes mellitus from the perspective of pancreatic surgery. To identify recent guidelines, clinical pathogenesis, pathological classification, screening methodology and advances in surgical management. It identifies those clinical and surgical variables to predict excellent prognosis in respect of life style changes, ongoing advancement in therapeutic and surgical treatment and postoperative follow up. Approximately 85% pancreatic cancer have impaired glucose tolerance and may be associated with diabetes mellitus. Diabetes improves following pancreatic resection. This suggest diabetes is caused by pancreatic cancer. New onset glucose intolerance or DM is an earliest manifestation of pancreatic cancer. Recognition of new onset diabetes as an early manifestation of pancreatic cancer leads to diagnosis of asymptomatic, early stage pancreatic cancer. Thus, helps to aid in better diagnosis and therefore prolonging survival rate. Increasing duration of diabetes mellitus is significantly associated with decreasing risk of pancreatic cancer. Elderly patient with new onset diabetes have high risk of having pancreatic cancer compared to general population. New onset hyperglycemia and diabetes serves as an important screening tool to diagnose asymptomatic pancreatic cancer patient and improves pancreatic cancer related survival. DM in association with pancreatic cancer have reduced overall survival rate and increased mortality. Despite of having dismal prognosis of pancreatic cancer, many studies have concluded the survival rate of 5 years. There exists a bidirectional association between pancreatic cancer and DM is found to be a cause of pancreatic cancer as well as complication. The study on pancreatic cancer and diabetes has offered an interesting field of research based study and surgical practices. PMID- 29535017 TI - Hybrid treatment of tandem, common carotid/innominate artery and ipsilateral carotid bifurcation stenoses by simultaneous, retrograde proximal stenting and eversion carotid endarterectomy: Preliminary results of a case series. AB - BACKGROUND: Tandem stenoses of the internal carotid artery (ICA) and proximal, ipsilateral common carotid artery (CCA) or innominate artery can be treated with a hybrid approach, combining conventional carotid endarterectomy (CEA) and retrograde stenting of the proximal stenosis, through surgical exposure of the carotid bifurcation. The purpose of this study was to evaluate the results of combining eversion CEA with retrograde CCA/innominate artery stenting. MATERIAL AND METHODS: From January 2015 to July 2017, 7 patients, 6 men of a mean age of 72 years (range 59-83 years) underwent simultaneous, retrograde stenting of the proximal CCA/innominate artery and an eversion CEA of the ipsilateral ICA, through surgical exposure of the carotid bifurcation, for severe tandem stenoses. The proximal stenosis involved the left proximal CCA in 4 patients, the proximal innominate artery in 2 patients and the right CCA in one patient. The procedure was performed under general anesthesia in a conventional operating room equipped with a mobile C-arm. A covered, balloon expandable stent was deployed over the proximal stenosis via a 6-F sheath directly introduced into the proximal CCA through the obliquely transected carotid bulb. After removing the sheath, debris were flushed through the carotid bulb and eversion CEA completed the procedure. Study endpoints were: postoperative stroke/mortality rate, cardiac mortality and morbidity, peripheral nerve injury, cervical hematoma, overall late survival, freedom from ipsilateral stroke and patency of arterial reconstruction. RESULTS: No postoperative mortality or neurologic morbidity was observed in any patient. Cervical hematomas and peripheral nerve injuries were likewise absent. At a mean follow-up of 18 months, all the patients were alive, free from neurologic events of new onset and free from restenosis. CONCLUSION: Combined proximal stenting and eversion CEA for tandem lesions seems a valid treatment, with the advantages of eversion CEA over other techniques of carotid bifurcation revascularization. PMID- 29535018 TI - The association of rs11190870 near LBX1 with the susceptibility and severity of AIS, a meta-analysis. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common structural deformity of the spine. Genetics constitute largely to AIS, and the rs11190870 polymorphism has the potential for use in public health and clinical settings as a predictor of AIS risk. The aim of the present meta-analysis was to provide exhaustive evidence to evaluate the association of rs11190870 with the susceptibility and severity of adolescent idiopathic scoliosis (AIS) in multiple ethnic groups and different genders. MATERIALS AND METHODS: The professional databases, including PubMed, Embase, Social Sciences Citation Index, CINAHL, and International Bibliography of the Social Sciences, were searched from 1966 to October 2015. No language restriction was applied. Reference lists of all the selected articles were hand-searched for any additional studies. Three authors independently extracted data from all eligible studies. The data were analyzed by meta-analysis using fixed-effects or random-effects models with mean differences and risk ratios for continuous and dichotomous variables, respectively. RESULTS: Eight studies were included, and the pooled analysis suggested that the T genotype of SNP rs11190870 leads to a higher risk of AIS in multiple ethnic groups regardless of gender (Total:OR, 1.66, 95% CI 1.53, 1.79; I2 = 37.3%, P = 0.000, Female: OR, 1.62, 95% CI 1.50, 1.73; I2 = 26.7%, P = 0.000, Male: OR, 1.79, 95% CI 1.38, 2.20; I2 = 0.00%, P = 0.000). Additionally, the TT and TC genotype had a larger Cobb angle than those with the CC genotype in the overall and female Asian populations. CONCLUSION: A significant association of rs11190870 with AIS was observed in multiple ethnic groups regardless of gender. Additionally, a significant association was found between rs11190870 and curve severity in the overall and female Asian populations. Due to the limited data and clinical heterogeneity, further studies with large sample sizes are required. PMID- 29535020 TI - Molecular insight into drug exporters within the cellular membrane. PMID- 29535019 TI - To free, or not to free: Social reinforcement effects in the social release paradigm with rats. AB - The present research measured social reinforcement in rats, using a social release procedure in which lever presses permitted 10-s access to a familiar social partner. The work requirements for reinforcement increased systematically according to progressive-ratio (PR) schedules. Social and food reinforcement value were compared across blocks of sessions (Experiment 1) and concurrently within the same sessions (Experiment 2). To assess motivational effects, response and reinforcer rates for both reinforcer types were studied under food restriction, social restriction, and combined food and social restriction. Responding was maintained by both reinforcers, albeit at substantially higher levels for food than for social access. Responding for social access decreased to low levels under extinction conditions, demonstrating functional control by the social-reinforcement contingency. Sensitivity to social restriction was seen in some conditions in Experiment 2, in which social reinforcers were earned earlier in the session (at lower food prices) under social restriction than under the other deprivation conditions. Altogether, results are consistent with a social reinforcement conceptualization, and demonstrate an important role for social contact in social release behavior. The study demonstrates a promising set of methods for analyzing and quantifying social reinforcement. PMID- 29535021 TI - Experience of violence from the clients and coping methods among ICU nurses working a hospital in South Korea. AB - PURPOSE: It is difficult to develop a good defense system that can prevent nurses from experiencing physical and verbal violence from patients and families in intensive care units, which are closed spaces. This study aimed to identify intensive care nurses' experience of violence from patients and families and investigate their coping methods, if there are any, in a tertiary hospital in South Korea. METHODS: This study used a mixed methods design utilizing both a survey for collecting quantitative data and individual interviews for a qualitative one. A total of 200 intensive care nurses participated in the survey, with thirty of them taking part in individual interviews. Survey data were analyzed using SPSS 21.0 program, and qualitative data with qualitative content analysis method. RESULTS: In the survey, 99.5% of the nurses reported that they had experienced violence from the patients and 67.5% from their visitors (families or relatives). Verbal violence were reported more than physical ones. They showed moderate or severe responses to violence, scoring an average of 2.98+/-0.63 out of 5. The qualitative data were analyzed to draw 4 themes, 8 categories, and 17 subcategories. The four themes were perception of violence, coping with violence experience, coping resources, and caring mind after violence experience. CONCLUSION: While intensive care nurses experience unpredicted violence from patients and their visitors, they fail to cope well with the experience. The safe working environment of intensive care units is expected to contribute to quality care and an improvement of expertise in nursing. PMID- 29535022 TI - Molecular cloning and expression analysis of ammonium transporters in tea plants (Camellia sinensis (L.) O. Kuntze) under different nitrogen treatments. AB - Ammonium is a major inorganic nitrogen source for tea plant growth and is mainly taken up and transported by ammonium transporters (AMTs). Here, we analyzed the NH4+ uptake kinetics of three tea cultivars, Longjing43 (LJ43), Zhongcha108 (ZC108) and Zhongcha302 (ZC302). The results revealed that ZC302 had a higher NH4+ uptake efficiency than the other two cultivars. The full CDS sequences of three Camellia sinensis ammonium transporter (CsAMT) genes, i.e., CsAMT1.1, CsAMT1.2 and CsAMT3.1, were cloned. Analysis of tissue-specific expression showed that CsAMT1.2 followed a root-specific expression pattern, while transcripts of CsAMT1.1 and CsAMT3.1 were mainly accumulated in leaves. The temporal course experiment on gene expression levels showed CsAMT1.1 and CsAMT3.1 followed a reciprocal expression pattern in leaves as CsAMT1.1 was up-regulated by a short time (2 h, 6 h) nitrogen (N) supply both in the leaves and buds of LJ43 and ZC108; and the expression of CsAMT3.1 in leaves was increased by a long time (72 h) N supply, particularly in ZC302. Therefore, we inferred that CsAMT1.1 and CsAMT3.1 might play important roles in photorespiratory ammonium metabolism. The expression of CsAMT1.2 was extremely high in roots and can be greatly induced by N over a short period of time, especially in ZC302; thus, we concluded CsAMT1.2 might play an important role in ammonium uptake from soils in tea plant roots. PMID- 29535023 TI - E7 oncoprotein of human papillomavirus: Structural dynamics and inhibitor screening study. AB - Human papillomavirus (HPV) has been the primary causative agent of cervical cancer, the most threatening cancer affecting millions of women worldwide. HPV, a small non enveloped DNA virus of high and low risk types contain intrinsically disordered region and it also plays significant role in the development of cervical cancer. HPV E7 contains an ordered Zinc finger motif that binds to pRB and alters its function. It utilizes both disordered N-terminal and structured C terminal regions for cellular transformation. In this study, we have focused extensively on the evolutionary relationships of E7 among various HPV types and generated a 3D homology model of full length HPV 16 E7, since the structure have not been solved till date. We also analysed the stable conformation and atomic flexibility of modelled E7 through molecular dynamics simulation at 100 ns. To understand the disordered based binding sites of E7 oncoprotein, Molecular recognition features (MoRFs) analysis was carried out on the E7 oncoprotein. The validated model was taken forward for the identification of potential lead compounds and the most prominent compounds were selected for the molecular dynamics simulation of the 100 ns for the stability analysis. Overall, this study highlights the holistic E7 regions including important disordered based binding sites analysed through the MoRFs. The potential inhibitor compound that targets the structured C-terminal region of E7 oncoprotein were subjected for the pharmacological properties analysis and further validated for the binding modes of the compounds with the target structure. This study helps in providing a better intuition to develop a potent anti-HPV agent. PMID- 29535024 TI - Excavating chikungunya genome to design B and T cell multi-epitope subunit vaccine using comprehensive immunoinformatics approach to control chikungunya infection. AB - Chikungunya infection has been a cause of countless deaths worldwide. Due to lack of permanent treatment and prevention of this disease, the mortality rate remains very high. Therefore, we followed an immunoinformatics approach for the development of multi-epitope subunit vaccine which is able to elucidate humoral, cell-mediated and innate immune responses inside the host body. Both structural and non-structural proteins of chikungunya virus were utilized for prediction of B-cell and T-cell binding epitopes along with interferon-gamma (IFN-gamma) inducing epitopes. The vaccine construct is composed of beta-defensin as an adjuvant at the N-terminal followed by Cytotoxic T-Lymphocytes (CTL) and Helper T Lymphocyte (HTL) epitopes. The same vaccine construct was also utilized for the prediction of B-cell binding epitopes and IFN-gamma inducing epitopes. This was followed by the 3D model generation, refinement and validation of the vaccine construct. Later on, the interaction of modeled vaccine with the innate immune receptor (TLR-3) was explored by performing molecular docking and molecular dynamics simulation studies. Also to check the efficiency of expression of this vaccine construct in an expression vector, in silico cloning was performed at the final stage of vaccine development. Further, designed multi-epitope subunit vaccine necessitates experimental and clinical investigation to develop as an immunogenic vaccine candidate. PMID- 29535026 TI - Assessment of cerebral blood flow in neonates and infants: A phase-contrast MRI study. AB - Abnormal cerebral blood flow (CBF) is implicated in several neonatal and infant diseases. However, measurement of CBF in this population remains difficult and has not been used in routine clinical MRI. Arterial spin labeling (ASL) methods suffer from both low SNR and poor quantification when applied to very young children. Furthermore, rapid change in brain physiology in this age range makes it difficult to choose sequence parameters such as labeling pulse flip angle and post labeling delay. Phase-contrast (PC) MRI is another approach to measure flow. It provides fast and reliable global CBF assessment, and has great promises in pediatric applications. In this study, we aimed to apply PC-MRI technique for CBF quantification in neonates and infants up to 18 months of age. We first compared several implementations of time-of-flight (TOF) MR angiogram for the visualization of brain's feeding arteries, which provides anatomical information for the positioning of PC-MRI scans. We then measured flow velocity and CBF of the internal carotid artery (ICA) and vertebral artery (VA) in 21 subjects (age 34-114 gestational weeks, 3 females, 18 males), using six encoding velocities (Venc) in each vessel. In ICA, peak arterial flow velocity was 10.2 cm/s at birth and increased to 56.0 cm/s at 18 months old. These values were 4.5-36.3 cm/s, respectively, for VA. CBF after accounting for brain volume revealed a significant (p < 0.001) age-related increase from 13.1 to 84.7 ml/100 g/min within the first 18 months after birth. Based on the peak flow velocity, we provided age-specific recommendations for Venc selection in PC-MRI when one only has time for one scan. The present study used a multi-Venc scheme to determine flow velocities in major feeding arteries of infant brain and may lay a foundation for accurate measurement of whole-brain CBF in this population. PMID- 29535025 TI - Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme. AB - In utero exposure to vinclozolin (VIN), an antiandrogenic fungicide, is linked to multigenerational phenotypic and epigenetic effects. Mechanisms remain unclear. We assessed the role of antiandrogenic activity and DNA sequence context by comparing effects of VIN vs. M2 (metabolite with greater antiandrogenic activity) and wild-type C57BL/6 (B6) mice vs. mice carrying mutations at the previously reported VIN-responsive H19/Igf2 locus. First generation offspring from VIN treated 8nrCG mutant dams exhibited increased body weight and decreased sperm ICR methylation. Second generation pups sired by affected males exhibited decreased neonatal body weight but only when dam was unexposed. Offspring from M2 treatments, B6 dams, 8nrCG sires or additional mutant lines were not similarly affected. Therefore, pup response to VIN over two generations detected here was an 8nrCG-specific maternal effect, independent of antiandrogenic activity. These findings demonstrate that maternal effects and crossing scheme play a major role in multigenerational response to in utero exposures. PMID- 29535027 TI - New waves: Rhythmic electrical field stimulation systematically alters spontaneous slow dynamics across mouse neocortex. AB - The signature rhythm of slow-wave forebrain activity is the large amplitude, slow oscillation (SO: ~1 Hz) made up of alternating synchronous periods of activity and silence at the single cell and network levels. On each wave, the SO originates at a unique location and propagates across the neocortex. Attempts to manipulate SO activity using electrical fields have been shown to entrain cortical networks and enhance memory performance. However, neural activity during this manipulation has remained elusive due to methodological issues in typical electrical recordings. Here we took advantage of voltage-sensitive dye (VSD) imaging in a bilateral cortical preparation of urethane-anesthetized mice to track SO cortical activity and its modulation by sinusoidal electrical field stimulation applied to frontal regions. We show that under spontaneous conditions, the SO propagates in two main opposing directional patterns along an anterior lateral - posterior medial axis, displaying a rich variety of possible trajectories on any given wave. Under rhythmic field stimulation, new propagation patterns emerge, which are not observed under spontaneous conditions, reflecting stimulus-entrained activity with distributed and varied anterior initiation zones and a consistent termination zone in the posterior somatosensory cortex. Furthermore, stimulus-induced activity patterns tend to repeat cycle after cycle, showing higher stereotypy than during spontaneous activity. Our results show that slow electrical field stimulation robustly entrains and alters ongoing slow cortical dynamics during sleep-like states, suggesting a mechanism for targeting specific cortical representations to manipulate memory processes. PMID- 29535028 TI - Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection. AB - BACKGROUND & AIMS: Treatment with direct-acting antiviral (DAA) agents can reduce Model for End-Stage Liver Disease and Child-Pugh-Turcotte (CPT) scores in patients with decompensated cirrhosis caused by hepatitis C virus. However, many of these patients still die or require liver transplantation. We collected data on baseline features of patients and aimed to develop a scoring system to predict response to DAA therapy. METHODS: We performed a retrospective analysis of data from 4 trials on the effects of sofosbuvir-based therapy in patients with hepatitis C virus-associated decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). In these trials, patients were given 12 or 24 weeks of treatment with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin. We collected demographic, clinical, treatment response, and laboratory data from patients and tested their associations with patient outcomes at 36 weeks. The primary outcome was factors associated with reduction of CPT score to class A. RESULTS: The presence of ascites or encephalopathy, serum level of albumin <3.5 g/dL or alanine aminotransferase <60 U/L, and body mass index >25 kg/m2 were associated with an increased risk of not achieving a reduction in CPT to class A, independent of sustained viral response to therapy. Serum level of albumin <2.8 g/dL and abnormal level of bilirubin were associated with an increased risk of liver transplantation or death. We developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated significantly with patient outcomes, which we called the "BE3A score." For patients with scores of 4-5, the hazard ratio for reduction of CPT score to class A was 52.3 (95% confidence interval, 15.2-179.7). CONCLUSIONS: We identified 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated with a reduction of CPT score to class A in patients with hepatitis C virus-associated decompensated cirrhosis receiving DAA therapy. We developed a predictive score using these factors, called the BE3A score, which can be used as a shared decision-making tool, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis. PMID- 29535030 TI - Comprehensive molecular phylogeny of barn owls and relatives (Family: Tytonidae), and their six major Pleistocene radiations. AB - The owl family Tytonidae comprises two genera: Phodilus, limited to the forests of central Africa and South-East Asia, and the ubiquitous Tyto. The genus Tyto is majorly represented by the cosmopolitan Common Barn Owl group, with more than 30 subspecies worldwide. Discrete differences in body size and plumage colouration have led to the classification of this family into many species and subspecies, but the taxonomic status and phylogenetic relationships between taxa remain unclear, and in some groups controversial. Although several previous studies attempted to resolve this problem, they have been limited in their taxonomic and geographical coverage, or have relied on restricted molecular evidence and low sample sizes. Based on the most comprehensive sampling to date (16 out of 17 Tyto species, and one out of three Phodilus species), a multi-locus approach using seven mitochondrial and two nuclear markers, and taking advantage of field data and museum collections available worldwide, our main questions in this study were: (1) what are the phylogenetic relationships and classification status of the whole family; (2) when and where did the most important speciation events occur? We confirm that the Common Barn Owl, Tyto alba is divided into three main evolutionary units: the American Barn Owl, T. furcata; the Western Barn Owl, T. alba; and the Eastern Barn Owl, T. javanica, and suggest a Late Miocene (ca. 6 mya) Australasian and African origin of the group. Our results are supported by fossil age information, given that the most recent common ancestor between the Tytonidae genera Phodilus and Tyto was probably from the Oligocene (ca. 28 mya) of Australasia. We finally reveal six major Pleistocene radiations of Tyto, all resulting in wide-range distributions. PMID- 29535029 TI - Secretion of Hepatitis C Virus Replication Intermediates Reduces Activation of Toll-Like Receptor 3 in Hepatocytes. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) infections most often result in chronic outcomes, although the virus constantly produces replication intermediates, in particular double-stranded RNA (dsRNA), representing potent inducers of innate immunity. We aimed to characterize the fate of HCV dsRNA in hepatocyte cultures to identify mechanisms contributing to viral persistence in presence of an active innate immune response. METHODS: We analyzed hepatocyte based culture models for HCV for induction of innate immunity, secretion of virus positive- or negative-strand RNA, and viral replication using different quantification methods and microscopy techniques. Expression of pattern recognition receptors was reconstituted in hepatoma cells by lentiviral transduction. RESULTS: HCV-infected cells secrete substantial amounts of virus positive- and negative-strand RNAs in extracellular vesicles (EVs), toward the apical and basolateral domain of hepatocytes. Secretion of negative-strand RNA was independent from virus production, and viral RNA secreted in EVs contained higher relative amounts of negative-strands, indicating that mostly virus dsRNA is released. A substantial part of viral replication complexes and dsRNA was found in the endosomal compartment and multivesicular bodies, indicating that secretion of HCV replication intermediates is mediated by the exosomal pathway. Block of vesicle release in HCV-positive cells increased intracellular dsRNA levels and increased activation of toll-like receptor 3, inhibiting HCV replication. CONCLUSIONS: Using hepatocyte-based culture models for HCV, we found a portion of HCV dsRNA intermediates to be released from infected cells in EVs, which reduces activation of toll-like receptor 3. This represents a novel mechanism how HCV evades host immune responses, potentially contributing to viral persistence. PMID- 29535031 TI - Revised classification of the righteye flounders (Teleostei: Pleuronectidae) based on multilocus phylogeny with complete taxon sampling. AB - Members of the family Pleuronectidae are common representatives of the marine benthic fauna inhabiting northern regions of the Atlantic and Pacific oceans. The most recent comprehensive classification of the family, based entirely on morphological synapomorphies, recognized five subfamilies, 23 genera, and 61 extant species. However, several subsequent molecular studies have shown that many synapomorphic characters discovered in the morphological study might represent homoplasies, thereby questioning the reliance on these characters with the warning that they may provide misleading information for testing other morphology-based evolutionary hypotheses. In the present study, we propose a comprehensive taxonomic reassessment of the family Pleuronectidae based on the molecular phylogeny reconstructed from four nuclear and three mitochondrial loci and represented by complete taxon sampling of all but one valid species currently assigned to this family. To check for robustness of the phylogenetic hypothesis, we analyzed the effect of base compositional heterogeneity on phylogenetic signal for each locus and compared six different gene partitioning schemes. The final dataset, comprising 14 partitions and 154 individuals, was used to reconstruct phylogenetic trees in RAxML, MrBayes and BEAST2. Alternative topologies for several questionable nodes were compared using Bayes factors. The topology with the highest marginal likelihood was selected as the final phylogenetic tree for inferring pleuronectid relationships and character evolution. Based on our results, we recognize the Pleuronectidae comprising five subfamilies, 24 genera and 59 species. Our new phylogeny comprises five major monophyletic groups within the family, which we define as the subfamilies within the family: Atheresthinae, Pleuronichthyinae, Microstominae, Hippoglossinae and Pleuronectinae. Taxonomic composition of most of these subfamilies is different from that proposed in previous classifications. We also re-assess hypotheses proposed in earlier studies regarding intra-relationships of species of each lineage. Results of the current study contribute to better understanding of the evolutionary relationships of pleuronectid flatfishes based on molecular evidence, and they also provide the framework towards future comprehensive morphological revision of constituent lineages within the family Pleuronectidae. PMID- 29535032 TI - Dupilumab for hand eczema. PMID- 29535033 TI - Fibrosing Vasculitides: A Heuristic for Investigation. PMID- 29535034 TI - Dermoscopy for the detection and safe extraction of an intracutaneous foreign body. PMID- 29535035 TI - Inflammatory arthritis in pediatric patients with morphea. AB - BACKGROUND: Morphea or localized scleroderma is an inflammatory disorder resulting in fibrosis of the skin and subcutaneous tissues. Joint contractures, arthralgias, and functional compromise are recognized associations of pediatric morphea. The co-existence of inflammatory arthritis and morphea is not well described in the literature. OBJECTIVE: To investigate the relationship between pediatric morphea and inflammatory arthritis with regards to cutaneous, musculoskeletal, and laboratory findings and treatment regimens. METHODS: A systematic retrospective chart review of 53 patients with pediatric morphea was performed and analyzed for morphea subtypes, arthritic joint involvement, serum autoantibodies, and therapeutic interventions. RESULTS: Eleven out of 53 patients had polyarthritis that involved joints unrelated to the site of the cutaneous morphea. These patients were mostly girls with either the linear or generalized subtypes of morphea. Serum levels of antinuclear antibodies were more significantly elevated in patients with arthritis. All children were treated with methotrexate in addition to other systemic or topical immunosuppressive agents. LIMITATIONS: This was a small, single-center retrospective study. CONCLUSION: Pediatric morphea co-existed with inflammatory arthritis in 11 of 53 children. Further understanding and appreciation of this relationship may direct more intensive therapy and musculoskeletal screening. PMID- 29535036 TI - Interactive effects of genetic polymorphisms and childhood adversity on brain morphologic changes in depression. AB - The etiology of depression is characterized by the interplay of genetic and environmental factors and brain structural alteration. Childhood adversity is a major contributing factor in the development of depression. Interactions between childhood adversity and candidate genes for depression could affect brain morphology via the modulation of neurotrophic factors, serotonergic neurotransmission, or the hypothalamus-pituitary-adrenal (HPA) axis, and this pathway may explain the subsequent onset of depression. Childhood adversity is associated with structural changes in the hippocampus, amygdala, anterior cingulate cortex (ACC), and prefrontal cortex (PFC), as well as white matter tracts such as the corpus callosum, cingulum, and uncinate fasciculus. Childhood adversity showed an interaction with the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism, serotonin transporter-linked promoter region (5 HTTLPR), and FK506 binding protein 51 (FKBP5) gene rs1360780 in brain morphologic changes in patients with depression and in a non-clinical population. Individuals with the Met allele of BDNF Val66Met and a history of childhood adversity had reduced volume in the hippocampus and its subfields, amygdala, and PFC and thinner rostral ACC in a study of depressed patients and healthy controls. The S allele of 5-HTTLPR combined with exposure to childhood adversity or a poorer parenting environment was associated with a smaller hippocampal volume and subsequent onset of depression. The FKBP5 gene rs160780 had a significant interaction with childhood adversity in the white matter integrity of brain regions involved in emotion processing. This review identified that imaging genetic studies on childhood adversity may deepen our understanding on the neurobiological background of depression by scrutinizing complicated pathways of genetic factors, early psychosocial environments, and the accompanying morphologic changes in emotion-processing neural circuitry. PMID- 29535038 TI - Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: A meta-analysis. AB - The immune and inflammatory system is involved in the etiology of mood disorders. Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and monocyte/lymphocyte ratio (MLR) are inexpensive and reproducible biomarkers of inflammation. This is the first meta-analysis exploring the role of NLR and PLR in mood disorder. We identified 11 studies according to our inclusion criteria from the main Electronic Databases. Meta-analyses were carried out generating pooled standardized mean differences (SMDs) between index and healthy controls (HC). Heterogeneity was estimated. Relevant sensitivity and meta-regression analyses were conducted. Subjects with bipolar disorder (BD) had higher NLR and PLR as compared with HC (respectively SMD = 0.672; p < 0.001; I2 = 82.4% and SMD = 0.425; p = 0.048; I2 = 86.53%). Heterogeneity-based sensitivity analyses confirmed these findings. Subgroup analysis evidenced an influence of bipolar phase on the overall estimate whit studies including subjects in manic and any bipolar phase showing a significantly higher NLR and PLR as compared with HC whereas the effect was not significant among studies including only euthymic bipolar subjects. Meta-regression showed that age and sex influenced the relationship between BD and NLR but not the relationship between BD and PLR. Meta analysis was not carried out for MLR because our search identified only one study when comparing BD to HC, and only one study when comparing MDD to HC. Subjects with major depressive disorder (MDD) had higher NLR as compared with HC (SMD = 0.670; p = 0.028; I2 = 89.931%). Heterogeneity-based sensitivity analyses and meta-regression confirmed these findings. Our meta-analysis supports the hypothesis that an inflammatory activation occurs in mood disorders and NLR and PLR may be useful to detect this activation. More researches including comparison of NLR, PLR and MLR between different bipolar phases and between BD and MDD are needed. PMID- 29535037 TI - Anterior cingulate activation to implicit threat before and after treatment for pediatric anxiety disorders. AB - BACKGROUND: Research suggests that individuals with anxiety have difficulty ignoring threat distractors when completing tasks with competing stimuli. Studies examining the neural correlates of these emotional processing difficulties in youth anxiety highlight reduced recruitment of regions associated with goal directed attention, such as the anterior cingulate cortex (ACC). In the current study, we examined neural activation during an emotional conflict task in youth with anxiety disorders before and after treatment. METHODS: Twenty-five youth (ages 9-19 years) with generalized, separation, and/or social anxiety disorder and 25 healthy controls underwent 2 functional magnetic resonance imaging scans approximately 13 weeks apart. At each scan, participants completed a task in which they matched shapes in the context of emotional distractors (happy and threatening faces). Between scans, anxious youth were treated with the selective serotonin reuptake inhibitor (SSRI) sertraline or cognitive behavior therapy (CBT). RESULTS: Prior to treatment, anxious youth exhibited reduced activation of the medial prefrontal cortex, encompassing the rostral ACC, when matching shapes in the context of threat distractors relative to healthy controls. Activation in this region increased in anxious youth after treatment, but remained unchanged in the healthy control group. Increases in rostral ACC activation were related to greater reductions in social anxiety and avoidance symptoms following treatment. CONCLUSIONS: Effective treatments for pediatric anxiety may enhance rostral ACC response during attempts to filter out threat-relevant stimuli. Enhanced recruitment of this region may constitute one manner in which CBT and SSRI treatment reduce youth anxiety symptoms, particularly social anxiety and avoidance. PMID- 29535039 TI - Effective deactivation of A549 tumor cells in vitro and in vivo by RGD-decorated chitosan-functionalized single-walled carbon nanotube loading docetaxel. AB - This study aims to construct and evaluate RGD-decorated chitosan (CS) functionalized pH-responsive single-walled carbon nanotube (SWCNT) carriers using docetaxel (DTX) as a model anticancer drug. DTX was loaded onto SWCNT via pi-pi stacking interaction (SWCNT-DTX), followed by the non-covalent conjugation of RGD decorated CS to SWCNT-DTX to prepare RGD-CS-SWCNT-DTX. The RGD-CS-SWCNT-DTX showed significantly higher drug release than the pure drug, giving higher release rate at pH 5.0 (68%) than pH 7.4 (49%). The RGD-CS-SWCNT-DTX could significantly inhibit the growth of A549 tumor cells in vitro, and the uptake amount of A549 cells was obviously higher than that of MCF-7 cells. Meanwhile, the cellular uptake of RGD-CS-SWCNT-DTX was higher than that of CS-SWCNT-DTX in A549 cells, mainly through clathrin and caveolae-mediated endocytosis. The RGD-CS SWCNT-DTX significantly inhibited tumor growth of A549 cell-bearing nude mice through active tumor-targeting ability. Furthermore, no pathological changes were found in tissues and organs. The result demonstrated that RGD-CS-SWCNT-DTX displayed high drug loading, pH-responsive drug release, remarkable antitumor effect in vitro and in vivo, and also good safety to animal body. PMID- 29535040 TI - Correlation of solid dosage porosity and tensile strength with acoustically extracted mechanical properties. AB - Currently, the compressed tablet and its oral administration is the most popular drug delivery modality in medicine. The accurate porosity and tensile strength characterization of a tablet design is vital for predicting its performance such as disintegration, dissolution, and drug-release efficiency upon administration as well as ensuring its mechanical integrity. In current work, a non-destructive contact ultrasonic approach and an associated testing procedure are presented and employed to quantify and relate the acoustically extracted mechanical properties of pharmaceutical compacts to direct porosity and tensile strength measurements. Based on a comprehensive set of experimental data, it is demonstrated how strongly the acoustic wave propagation is modulated and correlated to the tablet porosity and tensile strength of a compact made using spray-dried lactose and microcrystalline cellulose with varying mixture ratios. The effect of mixing ratio on the porosity and tensile strength on the resulting compacts is quantified and, with the acoustic experimental data, mixing ratio is related to the compact ultrasonic characteristics. The ultrasonic techniques provide a rapid, non-destructive means for evaluating compacts in formulation development and manufacturing. The presented approach and data could find critical applications in continuous tablet manufacturing, its real-time quality monitoring, as well as minimizing batch-to-batch quality variations. PMID- 29535041 TI - Amygdala central nucleus modulation of cerebellar learning with a visual conditioned stimulus. AB - Previous studies found that reversible inactivation of the central amygdala (CeA) severely impairs acquisition and retention of cerebellum-dependent eye-blink conditioning (EBC) with an auditory conditioned stimulus (CS). A monosynaptic pathway between the CeA and basilar pontine nuclei (BPN) may be capable of facilitating cerebellar learning. However, given that the CeA projects to the medial auditory thalamus, a critical part of the auditory CS pathway in EBC, the CeA influence on cerebellar learning could be specific to auditory stimuli. Here we examined the generality of CeA facilitation of EBC acquisition and retention in rats using a visual CS. As in our previous studies using an auditory CS, inactivation of the CeA with muscimol severely impaired acquisition and retention of EBC with a visual CS. Extending training to 15 100-trial sessions resulted in acquisition of EBC, indicating that the CeA plays a modulatory role in cerebellar learning and is not part of the necessary neural circuitry for EBC. Tract-tracing experiments verified that axons from the CeA reach both the BPN and medial auditory thalamus (part of the necessary auditory CS pathway), but were not found in the ventral lateral geniculate (part of the necessary visual CS pathway). The neuroanatomical results suggest that the CeA most likely modulates cerebellar learning through its projection to the BPN. The findings of the current study are consistent with the hypothesis that the CeA modulates cerebellar learning by increasing CS-related sensory input to the cerebellar cortex and interpositus nucleus via the BPN. This increase in CS-related input is thought to constitute an increase in attention to the CS during EBC. PMID- 29535042 TI - Behavioral, cellular, and synaptic tagging frameworks. AB - Behavioral tagging is the transformation of a short-term memory induced by a weak experience into a long-term memory through temporal association with a novel experience. This phenomenon was discovered to recapitulate synaptic tagging and capture at the behavioral level. Significant progress has been made in determining the molecular machinery associated with synaptic tagging and capture and behavioral tagging theories. However, the tag setting and recruitment of plasticity-related proteins that occur within the spatiotemporally constrained cell ensemble at the network level (cellular tagging) in the brain where multimodal sensory information is input are just beginning to be understood. Here, we review the evidence for behavioral tagging and the mechanism underlying memory allocation at the network level leading to the overlap of cell ensembles. We also discuss the functional significance of overlapping cell ensembles in association of standard Pavlovian conditioning and distinct memories. Finally, we describe the role of neuronal ensemble overlap in behavioral tagging. PMID- 29535043 TI - Training-induced brain activation and functional connectivity differentiate multi talker and single-talker speech training. AB - In second language acquisition studies, the high talker variability training approach has been frequently used to train participants to learn new speech patterns. However, the neuroplasticity induced by training is poorly understood. In the present study, native English speakers were trained on non-native pitch patterns (linguistic tones from Mandarin Chinese) in multi-talker (N = 16) or single-talker (N = 16) training conditions. We focused on two aspects of multi talker training, voice processing and lexical phonology accessing, and used functional magnetic resonance imaging (fMRI) to measure the brain activation and functional connectivity (FC) of two regions of interest in a tone identification task conducted before and after training, namely the anterior part of the right superior temporal gyrus (aRSTG) and the posterior left superior temporal gyrus (pLSTG). The results showed distinct patterns of associations between neural signals and learning success for multi-talker training. Specifically, post training brain activation in the aRSTG and FC strength between the aRSTG and pLSTG were correlated with learning success in the multi-talker training group but not in the single-talker group. These results suggest that talker variability in the training procedure may enhance neural efficiency in these brain areas and strengthen the cooperation between them. Our findings highlight the brain processing of newly learned speech patterns is influenced by the given training approach. PMID- 29535044 TI - Hippocampal representations as a function of time, subregion, and brain state. AB - How does the hippocampus represent interrelated experiences in memory? We review prominent yet seemingly contradictory theoretical perspectives, which propose that the hippocampus distorts experiential representations to either emphasize their distinctiveness or highlight common elements. These fundamentally different kinds of memory representations may be instantiated in the brain via conjunctive separated codes and adaptively differentiated codes on the one hand, or integrated relational codes on the other. After reviewing empirical support for these different coding schemes within the hippocampus, we outline two organizing principles which may explain the conflicting findings in the literature. First focusing on where the memories are formed and stored, we argue that distinct hippocampal regions represent experiences at multiple levels of abstraction and may transmit them to distinct cortical networks. Then focusing on when memories are formed, we identify several factors that can open and maintain specialized time windows, during which the very same hippocampal network is biased toward one coding scheme over the others. Specifically, we discuss evidence for (1) excitability-mediated integration windows, maintained by persistently elevated CREB levels following encoding of a specific memory, (2) fleeting cholinergically mediated windows favoring memory separation, and (3) sustained dopaminergically mediated windows favoring memory integration. By presenting a broad overview of different hippocampal coding schemes across species, we hope to inspire future empirical and modeling research to consider how factors surrounding memory formation shape the representations in which they are stored. PMID- 29535045 TI - Development of the fear regulation system from early adolescence to young adulthood in female mice. AB - Onset of fear-related disorders such as post-traumatic stress disorder is enhanced from adolescence until adulthood. However, the biological mechanisms underlying this vulnerability remain unclear. Therefore, we investigated contextual fear memory and extinction in 4-, 6-, 8-, 10-, and 15-week-old female mice. We also measured phosphorylation of ERK2 in the medial prefrontal cortex (mPFC) and the dorsal hippocampus following fear conditioning or extinction in 6- and 15-week-old mice. We found that 10- and 15-week-old mice showed stronger fear memory and more resistance to fear extinction than 6-week-old mice. Moreover, 15 week-old mice showed lower ERK2 phosphorylation levels following fear extinction in the mPFC than those 6 weeks old. Our results suggest that female mice acquire strong fear memory and resistance to fear extinction throughout adulthood, which may be related to alteration in ERK2 activation in the mPFC. PMID- 29535046 TI - Photodynamic therapy of Curcuma longa extract stimulated with blue light against Aggregatibacter actinomycetemcomitans. AB - BACKGROUND AND OBJECTIVE: Curcumin, one of an established curcuminoid substances extracted from Curcuma longa, has been used as a photosensitizer (PS) in photodynamic therapy (PDT). Curcuminoid substances has been reported to have benefits in treating dental chronic infection and inflammation diseases, such as chronic periodontitis. The purpose of this study was to find the optimum concentration of Curcuma longa (CL) extract, containing all curcuminoid substances, and the power density of blue light (BL) in photodynamic therapy against periodontally pathogenic bacteria, A. actinomycetemcomitans. METHODS: Antibacterial activity of various concentrations of CL extract against A. actinomycetemcomitans was determined. Exponentially growing bacteria were combined with 2-fold dilution of CL extract solution ranging from 25 to 0.098 MUg/ml. Co-culture bacteria treated with 0.12% chlorhexidine (CHX) served as the positive control. The effect of photostimulation with light emitting diode (LED) 420-480 nm at 16.8 J/cm2 for 1 min on the selected concentration of CL extract was examined. Bacteria viability was determined by plate counting technique. In addition, production of free radicals was tested by electron spin resonance spectroscope (ESR) with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). RESULTS: The antibacterial activity of CL extract was dose dependent. Without BL, 25 MUg/ml CL extract showed 6.03 +/- 0.39 log10A. actinomycetemcomitans. Interestingly, the combination of BL and 0.78 MUg/ml CL extract solution showed complete absence of A. actinomycetemcomitans. Peak signal intensity of hydroxyl radical production was also detected with the combination of BL and CL. CONCLUSIONS: CL extract not only had antimicrobial activity but also could be used as an effective PS when stimulated with BL in PDT. The optimal antibacterial effect of CL extract with BL was equal to the standard oral disinfectant, 0.12% CHX. PMID- 29535047 TI - Design and rational for the precision medicine guided treatment for cancer pain pragmatic clinical trial. AB - INTRODUCTION: Pain is one of the most burdensome symptoms associated with cancer and its treatment, and opioids are the cornerstone of pain management. Opioid therapy is empirically selected, and patients often require adjustments in therapy to effectively alleviate pain or ameliorate adverse drug effects that interfere with quality of life. There are data suggesting CYP2D6 genotype may contribute to inter-patient variability in response to opioids through its effects on opioid metabolism. Therefore, we aim to determine if CYP2D6 genotype guided opioid prescribing results in greater reductions in pain and symptom severity and interference with daily living compared to a conventional prescribing approach in patients with cancer. METHODS: Patients with solid tumors with metastasis and a self-reported pain score >= 4/10 are eligible for enrollment and randomized to a genotype-guided or conventional pain management strategy. For patients in the genotype-guided arm, CYP2D6 genotype information is integrated into opioid prescribing decisions. Patients are asked to complete questionnaires regarding their pain, symptoms, and quality of life at baseline and 2, 4, 6, and 8 weeks after enrollment. The primary endpoint is differential change in pain severity by treatment strategy (genotype-guided versus conventional pain management). Secondary endpoints include change in pain and symptom interference with daily living. CONCLUSION: Pharmacogenetic-guided opioid selection for cancer pain management has potential clinical utility, but current evidence is limited to retrospective and observational studies. Precision Medicine Guided Treatment for Cancer Pain is a pragmatic clinical trial that seeks to determine the utility of CYP2D6 genotype-guided opioid prescribing in patients with cancer. PMID- 29535049 TI - Polychlorinated biphenyl 104 promotes migration of endometrial stromal cells in endometriosis. AB - Polychlorinated biphenyls (PCBs), as part of environmental contaminants, have been proved to be related to endometriosis. This study is to investigate the effect of PCB 104 on cell migration, invasion and resultant gene expression in endometrial stromal cells (ESCs). Fifty-three specimens of eutopic endometrial tissues were collected from twenty-four women with endometriosis (EU-EMS) and twenty-nine women without endometriosis (EU-NON). Both EU-EMS and EU-NON were divided into the PCB 104 exposure group and the control group according to whether they were exposed to PCB 104. Primary cultured ESCs were exposed to PCB 104 at the micro molar doses (2 * 10-3, 0.2 and 1 MUmol/L) and concentrations of 2, 5 and 10 MUmol/L in six-well plates. Cell mobility and proliferation assay were used to evaluate the effects of PCB 104 on the migration, invasion and proliferation of ESCs, and the effect of PCB 104 on actin cytoskeleton was also examined by immunofluorescence. Subsequently, the mRNA levels of related genes including matrix metalloproteinase (MMP) -2, -3, -9, -10, E-cadherin, Snail, Slug and tissue inhibitor of metalloproteinase (TIMP) -2 in ESCs were examined by using real-time PCR, as well as protein levels of MMP-3 and MMP-10 were detected by enzyme-linked immunosorbent assay (ELISA). We explored the role of epidermal growth factor receptor (EGFR) in the expression of MMP-3 and MMP-10 induced by PCB 104. Exposure to PCB 104 significantly increased the migration and invasion of ESCs. The mRNA and protein levels of MMP-3 and MMP-10 in ESCs treated with PCB 104 were higher than that in the control, with a dose- and time-dependent manner in mRNA level, while the expression of MMP-2, MMP-9, TIMP-2, E-cadherin, Snail and Slug did not change significantly. Taken together, PCB 104 promotes migration and invasion of ESCs by inducing the expression of MMP-3 and MMP-10, which may involved the EGFR signalling pathway. PMID- 29535048 TI - SENP2 alleviates CCl4-induced liver fibrosis by promoting activated hepatic stellate cell apoptosis and reversion. AB - SUMOylation and deSUMOylation, a dynamic process, is proved to be involved in various fibrotic diseases. Here, we found SENP2, one of deSUMOylation protease family member, was decreased in CCl4-induced mice fibrotic liver tissues, primary HSCs and restored after spontaneously recovery. In addition, HSC-T6 cells with TGF-beta1 treatment resulted in a significant reduction of SENP2. Ectopic expression of SENP2 hindered cells activation and proliferation induced by TGF beta1 while knockdown of SENP2 showed an opposite effect. Importantly, SENP2 promoted apoptosis of HSC-T6 cells activated by TGF-beta1. Furthermore, restoration of SENP2 was observed in inactivated HSCs after adipogenic differentiation mixture (MDI) treatment. Inadequate SENP2 inhibited the reversion of HSC-T6 cells, featured as aberrant expressions of alpha-SMA and col1a1, two markers of liver fibrosis. It has been reported SENP2 was a suppressant regulator of Wnt/beta-catenin signal pathway. Similarly, we found SENP2 has a negative effect on beta-catenin as well as its downstream genes C-myc and CyclinD1 in liver fibrosis. Collectively, our data indicated SENP2 may be involved in HSCs apoptosis and reversion in liver fibrosis. PMID- 29535051 TI - A national telemedicine network for retinopathy of prematurity screening. AB - PURPOSE: To report the results of retinopathy of prematurity (ROP) screening by a telemedicine system in Chile and evaluate its usefulness for referring patients who require treatment. METHODS: Premature infants at risk of developing ROP from 11 neonatal intensive care units were included. Screening was performed on all infants born at a gestational age of <32 weeks and/or birth weight of <1500 g. A trained nonphysician operator used an imaging system to capture retinal images, which were reviewed by two independent ROP experts. All infants that required treatment were referred for further evaluation. RESULTS: The study included 2,048 eyes of 1,024 premature infants. Mean gestational age was 28.8 +/- 2.2 weeks, and mean birth weight was 1128 +/- 279 g. A total of 5,263 telemedicine examinations were performed and reported. The average number of image sets per patient was 2.6 +/- 2.5. Of the 5,263 images, 4,903 (93%) were recorded to at least the end of zone II; 5,172 (98%) were graded as having good quality, allowing for staging of ROP disease. Forty-two infants (4%) were referred for treatment. Discharged patients with ROP type 2 that regressed did not present with any complications or adverse effects during 6 months' follow-up. CONCLUSIONS: Our study demonstrates the utility of telemedicine screening for ROP with ophthalmologist readers in a developing country. Telemedicine screening was able to detect treatment-requiring ROP. Most of the images had good quality and showed the end of zone II, two variables sufficient to discharge patients. PMID- 29535052 TI - Bruch's membrane opening on optical coherence tomography in pediatric papilledema and pseudopapilledema. PMID- 29535050 TI - TRPA1 and CGRP antagonists counteract vesicant-induced skin injury and inflammation. AB - The skin is highly sensitive to the chemical warfare agent in mustard gas, sulfur mustard (SM) that initiates a delayed injury response characterized by erythema, inflammation and severe vesication (blistering). Although SM poses a continuing threat, used as recently as in the Syrian conflict, no mechanism-based antidotes against SM are available. Recent studies demonstrated that Transient Receptor Potential Ankyrin 1 (TRPA1), a chemosensory cation channel in sensory nerves innervating the skin, is activated by SM and 2-chloroethyl ethyl sulfide (CEES), an SM analog, in vitro, suggesting it may promote vesicant injury. Here, we investigated the effects of TRPA1 inhibitors, and an inhibitor of Calcitonin Gene Related Peptide (CGRP), a neurogenic inflammatory peptide released upon TRPA1 activation, in a CEES-induced mouse ear vesicant model (CEES-MEVM). TRPA1 inhibitors (HC-030031 and A-967079) and a CGRP inhibitor (MK-8825) reduced skin edema, pro-inflammatory cytokines (IL-1beta, CXCL1/KC), MMP-9, a protease implicated in skin damage, and improved histopathological outcomes. These findings suggest that TRPA1 and neurogenic inflammation contribute to the deleterious effects of vesicants in vivo, activated either directly by alkylation, or indirectly, by reactive intermediates or pro-inflammatory mediators. TRPA1 and CGRP inhibitors represent new leads that could be considered for validation and further development in other vesicant injury models. PMID- 29535053 TI - Bruch's membrane opening on optical coherence tomography in pediatric papilledema and pseudopapilledema. PMID- 29535054 TI - Developing and validating a simple and cost-effective strabismus surgery simulator. AB - PURPOSE: To demonstrate that a nonbiologic strabismus surgery simulator is not inferior to a biologic wet lab for teaching the key steps of strabismus surgery. METHODS: A total of 41 medical students were randomly assigned to one of two groups: biologic wet lab or nonbiologic simulator. The students trained according to the group's protocol then participated in a recorded final assessment using a realistic strabismus surgery model. Two independent reviewers, masked to training method, graded the video recordings using three scoring systems: the International Council of Ophthalmology Approved-Ophthalmology Surgical Competency Assessment Rubric for Strabismus Surgery (ICO-OSCAR), the Global Rating Scale of Objective Structured Assessment of Technical Skills (OSATS), and the Alphabetic Summary Scale (ASS). RESULTS: The primary endpoint, total ICO-OSCAR score, was 36.7 +/- 2.2 for the wet lab group and 36.0 +/- 2.7 for the nonbiologic group (difference in means, -0.7; one-sided 95% CI, -2.0, infinity). The lower bound of the one-sided 95% confidence interval for the difference in mean scores was -2.0, which was greater than the a priori noninferiority margin of -5.0 points. The secondary outcome measure, mean total OSATS score and ASS score, revealed no statistical significant differences between training methods (P = 0.73 and P = 0.44, resp.). CONCLUSIONS: The simple, nonbiologic strabismus surgery simulator is not inferior to the biologic wet lab with respect to total ICO-OSCAR score. It is a portable, inexpensive, and effective training tool for novice surgeons. PMID- 29535055 TI - Ethnoracial, Geographic, and Socioeconomic Disparities and Variations in Inflammatory Bowel Disease. PMID- 29535056 TI - A Case of Enteritis Induced by Nivolumab. PMID- 29535057 TI - No Difference in Effectiveness of 8 vs 12 Weeks of Ledipasvir and Sofosbuvir for Treatment of Hepatitis C in Black Patients. AB - BACKGROUND & AIMS: Treatment with the combination of ledipasvir and sofosbuvir for 12 weeks has been approved by the Food and Drug Administration for patients with genotype 1 hepatitis C virus (HCV) infection; some patients can be treated with an 8-week course. Guidelines recommend a 12-week treatment course for black patients, but studies have not compared the effectiveness of 8 vs 12 weeks in black patients who are otherwise eligible for an 8-week treatment regimen. METHODS: We conducted an observational study of Kaiser Permanente Northern California members with HCV genotype 1 infection who were eligible for 8 weeks of treatment with ledipasvir and sofosbuvir (treatment-naive, no cirrhosis, no HIV infection, level of HCV RNA <6 million IU/mL) and were treated for 8 or 12 weeks from October 2014 through December 2016. We used chi2 analyses to compare sustained virologic response 12 weeks after the end of treatment (SVR12) among patients treated for 8 vs 12 weeks, and adjusted Poisson models to identify factors associated with receipt of 12 weeks of therapy among patients eligible for 8 weeks. RESULTS: Of 2653 patients eligible for 8 weeks of treatment with ledipasvir and sofosbuvir, 1958 (73.8%) received 8 weeks of treatment and 695 (26.2%) received 12 weeks; the proportions of patients with SVR12 were 96.3% and 96.3%, respectively (P = .94). Among 435 black patients eligible for the 8-week treatment regimen, there was no difference in the proportions who achieved an SVR12 following 8 vs 12 weeks' treatment (95.6% vs 95.8%; P = .90). Male sex, higher transient elastography or FIB-4 scores, higher INR and level of bilirubin, lower level of albumin, obesity, diabetes, and >=15 alcohol drinks consumed/week were independently associated with receiving 12 weeks of treatment among patients eligible for the 8-week treatment regimen, but were not associated with reduced SVR12 after 8 weeks of treatment. CONCLUSION: In an observational study of patients who received ledipasvir and sofosbuvir treatment for HCV genotype 1 infection, we found that contrary to guidelines, 8-week and 12-week treatment regimens do not result in statistically significant differences in SVR12 in black patients. Patient characteristics were associated with receipt of 12-week regimens among patients eligible for 8 weeks, but were not associated with reduced SVR12 after 8 weeks. Shorter treatment courses might therefore be more widely used without compromising treatment effectiveness. PMID- 29535058 TI - Higher Growth Rate of Branch Duct Intraductal Papillary Mucinous Neoplasms Associates With Worrisome Features. AB - BACKGROUND & AIMS: For patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMNs, cysts), it is a challenge to identify those at high risk for malignant lesions. We sought to identify factors associated with development of pancreatic cancer, focusing on neoplasm growth rate. METHODS: We performed a retrospective study of 189 patients with BD-IPMNs who underwent at least 2 contrast-enhanced cross-sectional imaging studies, 1 year or more apart, at a tertiary referral center from January 2003 through 2013. Patients with cysts that had Fukuoka worrisome or high-risk features were excluded. Two radiologists reviewed all images. Cyst size was recorded at the initial and final imaging studies and growth rate was calculated. We collected patient demographic data, cyst characteristics, and clinical outcomes; univariate logistic regression models were used to determine the odds of developing worrisome features. The primary outcomes were to determine growth rate of low-risk BD-IPMNs and to assess whether cyst growth rate correlates high-risk features of IPMNs. RESULTS: Based on image analyses, cysts were initially a median 11 mm (range, 3-31 mm) and their final size was 12.5 mm (range, 3-42 mm). After a median follow-up time of 56 months (range, 12-163 months), the median cyst growth rate was 0.29 mm/year. Twelve patients developed worrisome features, no patients developed high-risk features, 4 patients had surgical resection, and no cancers developed. The rate of BD-IPMN growth was greater in patients who developed worrisome features than those who did not (2.84 mm/year vs 0.23 mm/year; P < .001). The odds of developing worrisome features increased for each unit (mm) increase in cyst size (odds ratio, 1.149; 95% CI, 1.035-1.276, P = .009). CONCLUSION: In a retrospective analysis of images from patients with BD-IPMN, we found low-risk BD IPMNs to grow at an extremely low rate (less than 0.3 mm/year). BD-IPMNs in only about 6% of patients developed worrisome features, and none developed high-risk features or invasive cancers. BD-IPMNs that developed worrisome features were associated with a significantly higher rate of growth than lesions with low-risk features. Low risk BD-IPMNs that grow more than 2.5 mm/year might require surveillance. PMID- 29535059 TI - Associations of Microscopic Colitis With Other Lymphocytic Disorders of the Gastrointestinal Tract. AB - BACKGROUND & AIMS: Lymphocytic disorders of the upper and lower gastrointestinal tract seem to cluster in patients. We aimed to assess the frequency of comorbid occurrence of lymphocytic disorders in patients with microscopic colitis (MC). METHODS: We collected data from the Miraca Life Sciences Database, a large national electronic repository of histopathologic records of patients throughout the United States. In a population of 228,506 patients who underwent bidirectional endoscopy from January 2008 through July 2016, we studied the comorbid occurrence of celiac disease, duodenal intraepithelial lymphocytosis, lymphocytic gastritis, and lymphocytic esophagitis among 3456 patients with MC. Associations were described in terms of their odds ratios (OR) and 95% CIs. RESULTS: Any type of lymphocytic disorder occurred in 13.7% of patients with MC and 5.9% of patients without MC. The ORs of lymphocytic disorders in patients with MC were: 2.56 (95% CI, 2.32-2.82) for any type of lymphocytic disorder, 3.07 (95% CI, 1.25-7.52) for lymphocytic esophagitis, 15.05 (95% CI, 12.31-18.41) for lymphocytic gastritis, 1.73 (95% CI, 1.53-21.96) for duodenal intraepithelial lymphocytosis, and 6.06 (95% CI, 5.06-7.25) for celiac disease. Comorbidities were more common in patients with lymphocytic than collagenous colitis, with an OR of 1.74 (95% CI, 1.42-2.13). Patients with MC with comorbidities were significantly younger and had a lower proportion of men than patients with MC patients without comorbidities. Diarrhea was the predominant symptoms in all patients MC, irrespective of comorbidities. CONCLUSION: In a retrospective study, we identified lymphocytic disorders of the upper gastrointestinal tract that are significantly more common in patients with than without MC. These associations suggest the existence of an underlying etiology that is common to all lymphocytic disorders and that affects the upper and lower gastrointestinal tract. PMID- 29535060 TI - Endoscopic Ultrasound-guided Specimen Collection and Evaluation Techniques Affect Diagnostic Accuracy. AB - BACKGROUND & AIMS: Outcomes of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) evaluation vary with technique, needles, and methods of specimen evaluation. We performed a direct comparison of diagnostic yields of EUS FNA samples collected using different gauge needles (22- vs 25-gauge), with or without suction. METHODS: We performed a randomized controlled study of 352 patients with suspected pancreatic masses, referred for EUS-FNA at a tertiary referral center. Patients were randomly assigned to 22-gauge needles with or without suction or 25-gauge needles with or without suction. Specimens were evaluated offsite by cell block and rapid onsite cytologic evaluation (ROSE). Final diagnoses were made based on histologic analyses or 12-month follow-up evaluations. The primary outcome was diagnostic adequacy of cell blocks. Secondary outcomes were operating characteristics of ROSE and EUS-FNA, number of passes required for accurate onsite diagnosis, and amount of blood in specimens. RESULTS: The final diagnoses were malignancy (81.5% of patients) and benign disease (17.0% of patients); 1.4% of patients were lost during follow up. Cell block, ROSE, and EUS-FNA led to diagnostic accuracies of 71.9%, 95.5%, and 96.6%, respectively. A 22-gauge needle with suction was associated with more passes for adequate onsite diagnosis (P = .003) and specimens contained more blood (P = .01). Diagnostic accuracy of specimens collected by transduodenal EUS-FNA was lower with 22-gauge needles with suction compared to other techniques (P = .004). CONCLUSION: In a randomized trial of patients undergoing EUS-FNA for pancreatic masses, samples collected with 22-gauge vs 25-gauge needles performed equally well for offsite specimen evaluation. Use of suction appears to increase number of passes needed and specimen bloodiness. Specimen collection techniques should be individualized based on method of evaluation. ClinicalTrials.gov no: NCT02424838. PMID- 29535061 TI - 4-Step Protocol for Disparities in STEMI Care and Outcomes in Women. AB - BACKGROUND: Women with ST-segment elevation myocardial infarction (STEMI) receive suboptimal care and have worse outcomes than men. Whether strategies to reduce STEMI care variability impact disparities in the care and outcomes of women with STEMI is unknown. OBJECTIVES: The study assessed the care and outcomes of men versus women with STEMI before and after implementation of a comprehensive STEMI protocol. METHODS: On July 15, 2014, the authors implemented: 1) emergency department catheterization lab activation; 2) STEMI Safe Handoff Checklist; 3) immediate transfer to an immediately available catheterization lab; and 4) radial first approach to percutaneous coronary intervention (PCI). The authors prospectively studied consecutive patients with STEMI and assessed guideline directed medical therapy (GDMT) before PCI, median door-to-balloon time (D2BT), in-hospital adverse events, and 30-day mortality stratified by sex before (January 1, 2011 to July 14, 2014; control group) and after (July 15, 2014 to December 31, 2016) implementation of the STEMI protocol. RESULTS: Of 1,272 participants (68% men, 32% women), women were older with more comorbidities than men. In the control group, women had less GDMT (77% vs. 69%; p = 0.019) and longer D2BT (median 104 min; [interquartile range (IQR): 79 to 133] min vs. 112 [IQR: 85 to 147] min; p = 0.023). Women had more in-hospital stroke, vascular complications, bleeding, transfusion, and death. In the comprehensive 4-step STEMI protocol, sex disparities in GDMT (84% vs. 80%; p = 0.32), D2BT (89 [IQR: 68 to 106] min vs. 91 [IQR: 68 to 114] min; p = 0.15), and in-hospital adverse events resolved. The absolute sex difference in 30-day mortality decreased from the control group (6.1% higher in women; p = 0.002) to the comprehensive 4-step STEMI protocol (3.2% higher in women; p = 0.090). CONCLUSIONS: A systems-based approach to STEMI care reduces sex disparities and improves STEMI care and outcomes in women. PMID- 29535062 TI - Cocaine and Marijuana Use Among Young Adults With Myocardial Infarction. AB - BACKGROUND: Substance abuse is increasingly prevalent among young adults, but data on cardiovascular outcomes remain limited. OBJECTIVES: The objectives of this study were to assess the prevalence of cocaine and marijuana use in adults with their first myocardial infarction (MI) at <=50 years and to determine its association with long-term outcomes. METHODS: The study retrospectively analyzed records of patients presenting with a type 1 MI at <=50 years at 2 academic hospitals from 2000 to 2016. Substance abuse was determined by review of records for either patient-reported substance abuse during the week before MI or substance detection on toxicology screen. Vital status was identified by the Social Security Administration's Death Master File. Cause of death was adjudicated using electronic health records and death certificates. Cox modeling was performed for survival free from all-cause and cardiovascular death. RESULTS: A total of 2,097 patients had type 1 MI (mean age 44.0 +/- 5.1 years, 19.3% female, 73% white), with median follow-up of 11.2 years (interquartile range: 7.3 to 14.2 years). Use of cocaine and/or marijuana was present in 224 (10.7%) patients; cocaine in 99 (4.7%) patients, and marijuana in 125 (6.0%). Individuals with substance use had significantly lower rates of diabetes (14.7% vs. 20.4%; p = 0.05) and hyperlipidemia (45.7% vs. 60.8%; p < 0.001), but they were significantly more likely to use tobacco (70.3% vs. 49.1%; p < 0.001). The use of cocaine and/or marijuana was associated with significantly higher cardiovascular mortality (hazard ratio: 2.22; 95% confidence interval: 1.27 to 3.70; p = 0.005) and all-cause mortality (hazard ratio: 1.99; 95% confidence interval: 1.35 to 2.97; p = 0.001) after adjusting for baseline covariates. CONCLUSIONS: Cocaine and/or marijuana use is present in 10% of patients with an MI at age <=50 years and is associated with worse all-cause and cardiovascular mortality. These findings reinforce current recommendations for substance use screening among young adults with an MI, and they highlight the need for counseling to prevent future adverse events. PMID- 29535063 TI - Cannabis and Heart Disease: Forward Into the Great Unknown? PMID- 29535064 TI - Short-Term Global Cardiovascular Disease Risk Prediction in Older Adults. AB - BACKGROUND: Current prevention guidelines recommend using the Pooled Cohort Equation (PCE) for 10-year atherosclerotic cardiovascular disease (CVD) risk assessment. However, the PCE has serious limitations in older adults: it excludes heart failure (HF) hospitalization, estimates 10-year risk, which may not be the most relevant time frame, and is not indicated for individuals age >79 years. OBJECTIVES: This study sought to determine whether adding biomarkers to PCE variables improves global CVD (coronary heart disease, stroke, and HF) risk prediction in older adults over a shorter time period. METHODS: Atherosclerosis Risk in Communities study participants without prevalent CVD including HF (n = 4,760; age 75.4 +/- 5.1 years) were followed for incident global CVD events. Adding N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein to the PCE and a "lab model" with the biomarkers, age, race, and gender were assessed for prediction improvement. Area under the receiver operating characteristic curve (AUC) and net reclassification index (NRI) were calculated. RESULTS: Over median follow-up of ~4 years, incident HF was the leading CVD event (n = 193 vs. 118 coronary heart disease and 81 stroke events). Compared to the PCE, each biomarker improved risk prediction. The largest improvement in risk prediction metrics was with the addition of all 3 biomarkers (DeltaAUC 0.103; continuous NRI 0.484). The lab model also performed better than the PCE model (DeltaAUC 0.091, continuous NRI 0.355). CONCLUSIONS: Adding biomarkers to the PCE or a simpler "lab model" improves short-term global CVD risk prediction and may be useful to inform short term preventive strategies in older adults. PMID- 29535065 TI - Smartwatch Algorithm for Automated Detection of Atrial Fibrillation. AB - BACKGROUND: The Kardia Band (KB) is a novel technology that enables patients to record a rhythm strip using an Apple Watch (Apple, Cupertino, California). The band is paired with an app providing automated detection of atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to examine whether the KB could accurately differentiate sinus rhythm (SR) from AF compared with physician interpreted 12-lead electrocardiograms (ECGs) and KB recordings. METHODS: Consecutive patients with AF presenting for cardioversion (CV) were enrolled. Patients underwent pre-CV ECG along with a KB recording. If CV was performed, a post-CV ECG was obtained along with a KB recording. The KB interpretations were compared to physician-reviewed ECGs. The KB recordings were reviewed by blinded electrophysiologists and compared to ECG interpretations. Sensitivity, specificity, and K coefficient were measured. RESULTS: A total of 100 patients were enrolled (age 68 +/- 11 years). Eight patients did not undergo CV as they were found to be in SR. There were 169 simultaneous ECG and KB recordings. Fifty seven were noninterpretable by the KB. Compared with ECG, the KB interpreted AF with 93% sensitivity, 84% specificity, and a K coefficient of 0.77. Physician interpretation of KB recordings demonstrated 99% sensitivity, 83% specificity, and a K coefficient of 0.83. Of the 57 noninterpretable KB recordings, interpreting electrophysiologists diagnosed AF with 100% sensitivity, 80% specificity, and a K coefficient of 0.74. Among 113 cases where KB and physician readings of the same recording were interpretable, agreement was excellent (K coefficient = 0.88). CONCLUSIONS: The KB algorithm for AF detection supported by physician review can accurately differentiate AF from SR. This technology can help screen patients prior to elective CV and avoid unnecessary procedures. PMID- 29535066 TI - Clinical Outcomes of His Bundle Pacing Compared to Right Ventricular Pacing. AB - BACKGROUND: Right ventricular pacing (RVP) is associated with heart failure and increased mortality. His bundle pacing (HBP) is a physiological alternative to RVP. OBJECTIVES: This study sought to evaluate clinical outcomes of HBP compared to RVP. METHODS: All patients requiring initial pacemaker implantation between October 1, 2013, and December 31, 2016, were included in the study. Permanent HBP was attempted in consecutive patients at 1 hospital and RVP at a sister hospital. Implant characteristics, all-cause mortality, heart failure hospitalization (HFH), and upgrades to biventricular pacing (BiVP) were tracked. Primary outcome was the combined endpoint of death, HFH, or upgrade to BiVP. Secondary endpoints were mortality and HFH. RESULTS: HBP was successful in 304 of 332 consecutive patients (92%), whereas 433 patients underwent RVP. The primary endpoint of death, HFH, or upgrade to BiVP was significantly reduced in the HBP group (83 of 332 patients [25%]) compared to RVP (137 of 433 patients [32%]; hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.534 to 0.944; p = 0.02). This difference was observed primarily in patients with ventricular pacing >20% (25% in HBP vs. 36% in RVP; HR: 0.65; 95% CI: 0.456 to 0.927; p = 0.02). The incidence of HFH was significantly reduced in HBP (12.4% vs. 17.6%; HR: 0.63; 95% CI: 0.430 to 0.931; p = 0.02). There was a trend toward reduced mortality in HBP (17.2% vs. 21.4%, respectively; p = 0.06). CONCLUSIONS: Permanent HBP was feasible and safe in a large real-world population requiring permanent pacemakers. His bundle pacing was associated with reduction in the combined endpoint of death, HFH, or upgrade to BiVP compared to RVP in patients requiring permanent pacemakers. PMID- 29535067 TI - Do mothers sound good? A systematic review of the effects of maternal voice exposure on preterm infants' development. AB - Preterm infants are hospitalized in the Neonatal Intensive Care Unit (NICU) and are precociously separated from their mothers. Although developmental care interventions are meant to facilitate mother-infant bonding, physical contact is not always possible. Maternal voice exposure has been proposed as a way to foster maternal closeness and support postnatal bonding. Here we present a systematic review on maternal voice effects on preterm infants' development. Literature search occurred on 4 databases (PubMed, Scopus, Web of Science and CINAHL). Preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines have been adopted and standardized quality appraisal has been carried on. Wide differences emerged in infants' characteristics and maternal voice exposure methods. Inconsistency emerged for physiological outcomes (e.g., heart rate variability, oxygen saturation, number of critical alarm events), whereas a robust pattern of findings emerged for feeding behaviors, as well as cognitive and neurobehavioral development. Maternal voice appears to be a non-noxious intervention, which is consistent with developmental care and which can be embedded in developmental care strategies. PMID- 29535068 TI - A critical review of brain and cognitive reserve in Huntington's disease. AB - The 'reserve' hypothesis posits that the brain undergoes structural and functional reorganisation to actively cope with brain damage or disease. Consistent with passive and active components of 'reserve', the brain moderates its biological substrates (brain reserve) and differentially changes the level of neural activity in tasks-specific networks and/or by recruiting additional non task related brain regions (cognitive reserve) to optimise behavioural performance. How the 'reserve' hypothesis applies in neurodegenerative disorders such as Huntington's disease (HD) remains unknown. We postulate that unless the 'reserve' hypothesis is tested empirically, it is impossible to draw firm conclusions about how task-related neural activity is providing a neuroplastic change in HD and possibly other neurodegenerative disorders. We conclude that there is a pressing need to operationalise cognitive reserve, as well as incorporate different biological substrates into a model of 'reserve'. We suggest that it is important to identify and embed potential neuroprotective modulating factors of 'reserve' in randomised controlled multi-domain non-pharmaceutical interventions to potentially enhance 'reserve' and thus preserve cognitive and psychosocial functioning in HD patients. PMID- 29535069 TI - Residual effects of cannabis use in adolescent and adult brains - A meta-analysis of fMRI studies. AB - While numerous studies have investigated the residual effects of cannabis use on human brain function, results of these studies have been inconsistent. Using meta analytic approaches we summarize the effects of prolonged cannabis exposure on human brain function as measured using task-based functional MRI (fMRI) across studies employing a range of cognitive activation tasks comparing regular cannabis users with non-users. Separate meta-analyses were carried out for studies investigating adult and adolescent cannabis users. Systematic literature search identified 20 manuscripts (13 adult and 7 adolescent studies) meeting study inclusion criteria. Adult analyses compared 530 cannabis users to 580 healthy controls while adolescent analyses compared 219 cannabis users to 224 healthy controls. In adult cannabis users brain activation was increased in the superior and posterior transverse temporal and inferior frontal gyri and decreased in the striate area, insula and middle temporal gyrus. In adolescent cannabis users, activation was increased in the inferior parietal gyrus and putamen compared to healthy controls. Functional alteration in these areas may reflect compensatory neuroadaptive changes in cannabis users. PMID- 29535070 TI - HDAC inhibitors as epigenetic regulators for cancer immunotherapy. AB - In recent years, anti-tumor immunotherapy has shown promising results, and immune oncology is now emerging as the fourth major wave in the treatment of tumors after radiotherapy, chemotherapy and molecular targeted therapy. Understanding the impact of the immune system on neoplastic cells is crucial to improve its effectiveness against cancer. The stratification of patients who might benefit from immunotherapy as well as the personalization of medicine have contributed to the discovery of new immunotherapeutic targets and molecules. In the present review, we discuss the mechanistic role of histone deacetylase inhibitors (HDACi) as potential immunomodulating agents to treat cancer. Our current understanding of the use of HDACi in combination with various immunotherapeutic approaches, such as immunomodulating agents and cancer vaccines, is also addressed. The potential clinical applications of the growing number of novel epigenetic drugs for cancer immunotherapy are widening, and some of these therapies are already in clinical trials. PMID- 29535071 TI - Improving Visual Communication. AB - A tool that creates realtime interactive color maps for scientific visualization helped enhance the dynamics of a major research project for the Climate, Ocean, and Sea Ice Modeling team at Los Alamos National Laboratory. PMID- 29535072 TI - A Taxonomy of Spatial Interaction Patterns and Techniques. AB - This article presents a taxonomy of spatial interaction patterns and techniques and discusses specific examples. PMID- 29535073 TI - ColorMoves: Real-time Interactive Colormap Construction for Scientific Visualization. AB - This article presents ColorMoves, an interactive tool that promotes exploration of scientific data through artist-driven color methods in a unique and transformative way. We discuss the power of contrast in scientific visualization, the design of the ColorMoves tool, and the tools application in several science domains. PMID- 29535074 TI - Efficient C2-Weighting for Image Warping. AB - Handle-driven image warping based on linear blending is widely used in many applications because of its merits on intuitiveness, efficiency, and ease of implementation. In this paper, we develop a method to compute high-quality weights within a closed domain for image warping. The property of C2 continuity in weights is guaranteed by the carefully formulated basis functions. The efficiency of our algorithm is ensured by a closed-form formulation of the computation for weights. The cost of inserting a new handle is only the time to evaluate the distances from the new handle to all other sample points in the domain. A virtual handle insertion algorithm is developed to allow users to freely place handles within the domain while preserving the satisfaction of all expected criteria on weights for linear blending. Experimental examples for real time applications are shown to demonstrate the effectiveness of this method. PMID- 29535075 TI - Parametric Reshaping of Portrait Images for Weight-change. AB - We present an easy-to-use parametric image retouching method for thinning or fattening a face in a single portrait image while maintaining a close similarity to the source image. First, our method reconstructs a 3D face from the input face image using a morphable model. Second, according to the linear regression equation derived from the depth statistics of the soft tissue in the face and the user-set parameters of weight-change degree, we calculate the new positions of the feature points. The Laplacian deformation method is then used for non-feature points in the 3D face model. Our model-based reshaping process can achieve globally consistent editing effects without noticeable artifacts. We seamlessly blend the reshaped face region with the background using image retargeting method based on mesh parametrization. The effectiveness of our algorithm is demonstrated by experiments and user study. PMID- 29535076 TI - 10 Years of MegaMol: The Pain and Gain of Creating Your Own Visualization Framework. AB - This article discusses our experience in creating MegaMol, an open-source visualization framework for large particle-based data. PMID- 29535077 TI - Optimizing Scientist Time through In Situ Visualization and Analysis. AB - In situ processing produces reduced size persistent representations of a simulations state while the simulation is running. The need for in situ visualization and data analysis is usually described in terms of supercomputer size and performance in relation to available storage size. PMID- 29535078 TI - Describing the Process of Adopting Nutrition and Fitness Apps: Behavior Stage Model Approach. AB - BACKGROUND: Although mobile technologies such as smartphone apps are promising means for motivating people to adopt a healthier lifestyle (mHealth apps), previous studies have shown low adoption and continued use rates. Developing the means to address this issue requires further understanding of mHealth app nonusers and adoption processes. This study utilized a stage model approach based on the Precaution Adoption Process Model (PAPM), which proposes that people pass through qualitatively different motivational stages when adopting a behavior. OBJECTIVE: To establish a better understanding of between-stage transitions during app adoption, this study aimed to investigate the adoption process of nutrition and fitness app usage, and the sociodemographic and behavioral characteristics and decision-making style preferences of people at different adoption stages. METHODS: Participants (N=1236) were recruited onsite within the cohort study Konstanz Life Study. Use of mobile devices and nutrition and fitness apps, 5 behavior adoption stages of using nutrition and fitness apps, preference for intuition and deliberation in eating decision-making (E-PID), healthy eating style, sociodemographic variables, and body mass index (BMI) were assessed. RESULTS: Analysis of the 5 behavior adoption stages showed that stage 1 ("unengaged") was the most prevalent motivational stage for both nutrition and fitness app use, with half of the participants stating that they had never thought about using a nutrition app (52.41%, 533/1017), whereas less than one third stated they had never thought about using a fitness app (29.25%, 301/1029). "Unengaged" nonusers (stage 1) showed a higher preference for an intuitive decision-making style when making eating decisions, whereas those who were already "acting" (stage 4) showed a greater preference for a deliberative decision-making style (F4,1012=21.83, P<.001). Furthermore, participants differed widely in their readiness to adopt nutrition and fitness apps, ranging from having "decided to" but not yet begun to act (stage 2; nutrition: 6.88%, 70/1017; fitness: 9.23%, 95/1029) to being "disengaged" following previous adoption (stage 5; nutrition: 13.77%, 140/1017; fitness: 15.06%, 155/1029). CONCLUSIONS: Using a behavior stage model approach to describe the process of adopting nutrition and fitness apps revealed motivational stage differences between nonusers (being "unengaged," having "decided not to act," having "decided to act," and being "disengaged"), which might contribute to a better understanding of the process of adopting mHealth apps and thus inform the future development of digital interventions. This study highlights that new user groups might be better reached by apps designed to address a more intuitive decision-making style. PMID- 29535079 TI - Human Factors and Data Logging Processes With the Use of Advanced Technology for Adults With Type 1 Diabetes: Systematic Integrative Review. AB - BACKGROUND: People with type 1 diabetes (T1D) undertake self-management to prevent short and long-term complications. Advanced technology potentially supports such activities but requires consideration of psychological and behavioral constructs and usability issues. Economic factors and health care provider capacity influence access and uptake of advanced technology. Previous reviews have focused upon clinical outcomes or were descriptive or have synthesized studies on adults with those on children and young people where human factors are different. OBJECTIVE: This review described and examined the relationship between human factors and adherence with technology for data logging processes in adults with T1D. METHODS: A systematic literature search was undertaken by using the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Quality appraisal was undertaken and data were abstracted and categorized into the themes that underpinned the human factor constructs that were examined. RESULTS: A total of 18 studies were included. A total of 6 constructs emerged from the data analysis: the relationship between adherence to data logging and measurable outcomes; satisfaction with the transition to advanced technology for self-management; use of advanced technology and time spent on diabetes-related activities; strategies to mediate the complexities of diabetes and the use of advanced technology; cognition in the wild; and meanings, views, and perspectives from the users of technology. CONCLUSIONS: Increased treatment satisfaction was found on transition from traditional to advanced technology use-insulin pump and continuous glucose monitoring (CGM); the most significant factor was when blood glucose levels were consistently <7.00 mmol/L (P <=.01). Participants spent considerable time on their diabetes self-care. Logging of data was positively correlated with increasing age when using an app that provided meaningful feedback (regression coefficient=55.8 recordings/year; P <=.01). There were benefits of CGM for older people in mediating complexities and fears of hypoglycemia with significant differences in well-being (P <=.001). Qualitative studies explored the contextual use and uptake of technology. The results suggested frustrations with CGM, continuous subcutaneous insulin infusion, calibration of devices, and alarms. Furthermore implications for "body image" and the way in which "significant others" impacted on the behavior and attitude of the individual toward technology use. There were wide variations in the normal use of and interaction with technology across a continuum of sociocultural contexts, which has implications for the way in which future technologies should be designed. Quantitative studies were limited by small sample sizes, making it difficult to generalize findings to other contexts. This was further limited by a sample that was predominantly white, well-controlled, and engaged with self-care. The use of critical appraisal frameworks demonstrated where research into human factors and data logging processes of individuals could be improved. This included engaging people in the design of the technology, especially hard-to-reach or marginalized groups. PMID- 29535080 TI - Improving Internal Medicine Residents' Colorectal Cancer Screening Knowledge Using a Smartphone App: Pilot Study. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer death in the United States. About one in three adults in the United States is not getting the CRC screening as recommended. Internal medicine residents are deficient in CRC screening knowledge. OBJECTIVE: The objective of our study was to assess the improvement in internal medicine residents' CRC screening knowledge via a pilot approach using a smartphone app. METHODS: We designed a questionnaire based on the CRC screening guidelines of the American Cancer Society, American College of Gastroenterology, and US Preventive Services Task Force. We emailed the questionnaire via a SurveyMonkey link to all the residents of an internal medicine department to assess their knowledge of CRC screening guidelines. Then we designed an educational intervention in the form of a smartphone app containing all the knowledge about the CRC screening guidelines. The residents were introduced to the app and asked to download it onto their smartphones. We repeated the survey to test for changes in the residents' knowledge after publication of the smartphone app and compared the responses with the previous survey. We applied the Pearson chi-square test and the Fisher exact test to look for statistical significance. RESULTS: A total of 50 residents completed the first survey and 41 completed the second survey after publication of the app. Areas of CRC screening that showed statistically significant improvement (P<.05) were age at which CRC screening was started in African Americans, preventive tests being ordered first, identification of CRC screening tests, identification of preventive and detection methods, following up positive tests with colonoscopy, follow-up after colonoscopy findings, and CRC surveillance in diseases. CONCLUSIONS: In this modern era of smartphones and gadgets, developing a smartphone-based app or educational tool is a novel idea and can help improve residents' knowledge about CRC screening. PMID- 29535082 TI - Expert Coaching in Weight Loss: Retrospective Analysis. AB - BACKGROUND: Providing coaches as part of a weight management program is a common practice to increase participant engagement and weight loss success. Understanding coach and participant interactions and how these interactions impact weight loss success needs to be further explored for coaching best practices. OBJECTIVE: The purpose of this study was to analyze the coach and participant interaction in a 6-month weight loss intervention administered by Retrofit, a personalized weight management and Web-based disease prevention solution. The study specifically examined the association between different methods of coach-participant interaction and weight loss and tried to understand the level of coaching impact on weight loss outcome. METHODS: A retrospective analysis was performed using 1432 participants enrolled from 2011 to 2016 in the Retrofit weight loss program. Participants were males and females aged 18 years or older with a baseline body mass index of >=25 kg/m2, who also provided at least one weight measurement beyond baseline. First, a detailed analysis of different coach-participant interaction was performed using both intent-to-treat and completer populations. Next, a multiple regression analysis was performed using all measures associated with coach-participant interactions involving expert coaching sessions, live weekly expert-led Web-based classes, and electronic messaging and feedback. Finally, 3 significant predictors (P<.001) were analyzed in depth to reveal the impact on weight loss outcome. RESULTS: Participants in the Retrofit weight loss program lost a mean 5.14% (SE 0.14) of their baseline weight, with 44% (SE 0.01) of participants losing at least 5% of their baseline weight. Multiple regression model (R2=.158, P<.001) identified the following top 3 measures as significant predictors of weight loss at 6 months: expert coaching session attendance (P<.001), live weekly Web-based class attendance (P<.001), and food log feedback days per week (P<.001). Attending 80% of expert coaching sessions, attending 60% of live weekly Web-based classes, and receiving a minimum of 1 food log feedback day per week were associated with clinically significant weight loss. CONCLUSIONS: Participant's one-on-one expert coaching session attendance, live weekly expert-led interactive Web-based class attendance, and the number of food log feedback days per week from expert coach were significant predictors of weight loss in a 6-month intervention. PMID- 29535081 TI - Strengths-Based Behavioral Intervention for Parents of Adolescents With Type 1 Diabetes Using an mHealth App (Type 1 Doing Well): Protocol for a Pilot Randomized Controlled Trial. AB - BACKGROUND: Supportive parent involvement for adolescents' type 1 diabetes (T1D) self-management promotes optimal diabetes outcomes. However, family conflict is common and can interfere with collaborative family teamwork. Few interventions have used explicitly strengths-based approaches to help reinforce desired management behaviors and promote positive family interactions around diabetes care. OBJECTIVE: The aim of this protocol was to describe the development of a new, strengths-based behavioral intervention for parents of adolescents with T1D delivered via a mobile-friendly Web app called Type 1 Doing Well. METHODS: Ten adolescent-parent dyads and 5 diabetes care providers participated in a series of qualitative interviews to inform the design of the app. The 3- to 4-month pilot intervention will involve 82 parents receiving daily prompts to use the app, in which they will mark the diabetes-related strength behaviors (ie, positive attitudes or behaviors related to living with or managing T1D) their teen engaged in that day. Parents will also receive training on how to observe diabetes strengths and how to offer teen-friendly praise via the app. Each week, the app will generate a summary of the teen's most frequent strengths from the previous week based on parent reports, and parents will be encouraged to praise their teen either in person or from a library of reinforcing text messages (short message service, SMS). RESULTS: The major outcomes of this pilot study will include intervention feasibility and satisfaction data. Clinical and behavioral outcomes will include glycemic control, regimen adherence, family relationships and conflict, diabetes burden, and health-related quality of life. CONCLUSIONS: This strengths-based, mobile health (mHealth) intervention aims to help parents increase their awareness of and efforts to support their adolescents' engagement in positive diabetes-related behaviors. If efficacious, this intervention has the potential to reduce the risk of family conflict, enhance collaborative family teamwork, and ultimately improve diabetes outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02877680; https://clinicaltrials.gov/ct2/show/NCT02877680 (Archived by WebCite at http://www.webcitation.org/6xTAMN5k2). PMID- 29535083 TI - Low calorie and low carb diets for weight loss in primary care. PMID- 29535084 TI - Opening the door to grief. PMID- 29535085 TI - Alzheimer's disease research: five minutes with John Hardy. PMID- 29535086 TI - Validity of the Japan Acuity and Triage Scale in adults: a cohort study. AB - OBJECTIVE: The Japan Acuity and Triage Scale (JTAS) was developed based on Canadian Triage and Acuity Scale in 2012 and has been implemented in many Japanese EDs. We assessed the validity of JTAS by examining the association between JTAS triage levels and throughput and clinical outcomes in adult patients. METHODS: We conducted a retrospective analysis of prospectively collected clinical data in the ED of a Japanese tertiary-care hospital. We included self-presenting patients who were >=16 years of age and triaged between June 2013 and May 2014. We assessed the association between the triage level and overall admission and admission to the intensive care units (ICUs) with multivariable logistic regression analysis adjusted with patients' age and the time of visit and ED length of stay using the Kruskal-Wallis rank-sum test. We examined the predictive ability of JTAS for determining overall and ICU admission using receiver operating characteristic curves. RESULTS: We included a total of 27 120 adult patients in our study. The OR for overall admission was greater with a higher triage level compared with the lowest urgency levels. ED length of stay was significantly longer with a higher JTAS level (p<0.001). The OR for ICU admission was greater in JTAS 1 (117.93 (95% CI 69.07 to 201.38)) and JTAS 2 (9.43 (95% CI 13.74 to 29.30)) compared with the lowest urgency levels. The areas under the curve for the predictive ability of JTAS for overall and ICU admission were 0.726 and 0.792, respectively. CONCLUSION: Our study suggests an association of JTAS acuity with overall admission, ICU admission and ED length of stay, thereby demonstrating the predictive validity of JTAS. PMID- 29535087 TI - Impact of Physician Navigators: Looking beyond productivity metrics and silver bullets. PMID- 29535088 TI - Authors' response to 'Impact of physician navigators: looking beyond productivity metrics and silver bullets' by Leung et al. PMID- 29535091 TI - Clinical Outcomes of Plavix and Generic Clopidogrel for Patients Hospitalized With an Acute Coronary Syndrome. AB - BACKGROUND: Clopidogrel is one of the most commonly prescribed medications because of its ability to improve clinical outcomes for a broad range of cardiovascular conditions. After patent protection expired for Plavix in 2012, many healthcare systems adopted generic clopidogrel as a strategy to reduce healthcare costs. METHODS AND RESULTS: We conducted a population-based observational study to determine whether generic clopidogrel was noninferior to Plavix. Patients who were hospitalized with an acute coronary syndrome (ACS) from 2009 to 2014 in Ontario, Canada, >65 years, survived >=7 days after discharge, were eligible for inclusion. The primary outcome was a composite of death and recurrent ACS at 1 year. The noninferiority margin was prespecified at a relative hazard difference of 10%. Inverse propensity of treatment weighting of the propensity score was used to account for differences in baseline characteristics between the treatment groups. The effect of clopidogrel on the hazard of clinical outcomes was estimated using a Cox proportional hazards model within the propensity-weighted cohort using Plavix as a reference. Our study included 24 530 patients with ACS, 12 643 were prescribed Plavix and 11 887 were prescribed generic clopidogrel at hospital discharge. The mean age was 77 years, 57% were men, and 21% had an ST-segment-elevation myocardial infarction. At 1 year, 17.6% of patients prescribed Plavix and 17.9% of patients prescribed clopidogrel experienced the primary outcome (hazard ratio, 1.02; 95% confidence interval, 0.96-1.08; P=0.005 for noninferiority). No significant differences between rates of death, all-cause readmission, ACS, stroke or transient ischemic attack, or bleeding were observed. CONCLUSIONS: Generic clopidogrel was noninferior to Plavix with respect to the composite end point of death and recurrent hospitalization for ACS at 1 year among adults >65 years after an ACS hospitalization. Our findings support generic clopidogrel in ACS, which could lead to substantial healthcare cost savings. PMID- 29535090 TI - Association of Human Immunodeficiency Virus Infection and Risk of Peripheral Artery Disease. AB - BACKGROUND: The effect of human immunodeficiency virus (HIV) on the development of peripheral artery disease (PAD) remains unclear. We investigated whether HIV infection is associated with an increased risk of PAD after adjustment for traditional atherosclerotic risk factors in a large cohort of HIV-infected (HIV+) and demographically similar HIV-uninfected veterans. METHODS: We studied participants in the Veterans Aging Cohort Study from April 1, 2003 through December 31, 2014. We excluded participants with known prior PAD or prevalent cardiovascular disease (myocardial infarction, stroke, coronary heart disease, and congestive heart failure) and analyzed the effect of HIV status on the risk of incident PAD events after adjusting for demographics, PAD risk factors, substance use, CD4 cell count, HIV-1 ribonucleic acid, and antiretroviral therapy. The primary outcome is incident peripheral artery disease events. Secondary outcomes include mortality and amputation in subjects with incident PAD events by HIV infection status, viral load, and CD4 count. RESULTS: Among 91 953 participants, over a median follow up of 9.0 years, there were 7708 incident PAD events. Rates of incident PAD events per 1000 person-years were higher among HIV+ (11.9; 95% confidence interval [CI], 11.5-12.4) than uninfected veterans (9.9; 95% CI, 9.6-10.1). After adjustment for demographics, PAD risk factors, and other covariates, HIV+ veterans had an increased risk of incident PAD events compared with uninfected veterans (hazard ratio [HR], 1.19; 95% CI, 1.13-1.25). This risk was highest among those with time-updated HIV viral load >500 copies/mL (HR, 1.51; 95% CI, 1.38-1.65) and CD4 cell counts <200 cells/mm3 (HR, 1.91; 95% CI, 1.71-2.13). In contrast, HIV+ veterans with time updated CD4 cell count >=500 cells/mm3 had no increased risk of PAD (HR, 1.03; 95% CI, 0.96-1.11). Mortality rates after incident PAD events are high regardless of HIV status. HIV infection did not affect rates of amputation after incident PAD events. CONCLUSIONS: Infection with HIV is associated with a 19% increased risk of PAD beyond that explained by traditional atherosclerotic risk factors. However, for those with sustained CD4 cell counts <200 cells/mm3, the risk of incident PAD events is nearly 2-fold higher whereas for those with sustained CD4 cell counts >=500 cells/mm3 there is no excess risk of incident PAD events compared with uninfected people. PMID- 29535089 TI - Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action. AB - Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action. PMID- 29535092 TI - Ovarian teratoma associated with anti-NMDA (N-methyl D-aspartate) receptor encephalitis. AB - Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a paraneoplastic, immune-mediated encephalopathy with a known association with ovarian teratomas. We present the first case in the UK of a 7-year-old patient presenting with this condition. Having been previously fit and healthy, the patient presented with an acute onset of cognitive disturbances. The initial suspicion was that of an infective encephalopathy; however, the lumbar puncture results were negative. Electroencephalography reported diffuse background slowing, supporting a diagnosis of encephalopathy. Extensive autoimmune screening was done and found to be positive for anti-NMDAR antibodies. A whole body MRI found a right adnexal lesion consistent with ovarian teratoma. At laparoscopy, the right ovary was excised and histology confirmed a mature cystic teratoma with neural tissue. There were no postoperative complications with the patient's neurology recovering progressively at follow-up. PMID- 29535093 TI - An unusual manifestation of olfactory neuroblastoma. AB - A 62-year-old woman presented with an 11-month history of worsening nasal symptoms of rhinorrhoea, anosmia, nasal congestion and intermittent epistaxis. MRI revealed a large mass in the upper nasal vault. Biopsy of the mass revealed an olfactory neuroblastoma. While waiting resection, she acutely developed severe proximal muscle weakness, lethargy and lower extremity oedema. Blood glucose was elevated, and hypokalaemic metabolic alkalosis was noted. Elevated serum cortisol level of 95.7 ug/dL (8.7-22.4 ug/dL) and markedly elevated 24-hour urinary cortisol level of 6962.3 ug/24 hours (4.0-50.0 ug/24 hours) with concurrent adrenocorticotropic hormone (ACTH) level of 171 pg/mL (6-58 pg/mL) were suggestive of an ACTH-dependent source of hypercortisolism. A subsequent positive high-dose dexamethasone suppression test was consistent with ectopic ACTH production. She underwent near-total resection of the right nasal mass followed by radiotherapy, resulting in complete resolution of signs and symptoms of cortisol excess. PMID- 29535094 TI - Coccidioides immitis septic knee arthritis. AB - A 78-year-old man developed right knee pain and swelling without other systemic symptoms. He had travelled frequently to the Central Valley of California. He was diagnosed with coccidioidomycosis based on joint fluid culture. Coccidioidal complement fixation antibody titres were extremely elevated. Arthroscopic debridement and fluconazole therapy did not lead to satisfactory improvement. Subsequent open debridement and change to itraconazole was followed by resolution of clinical signs of infection. PMID- 29535095 TI - Case of Segmental Arterial Mediolysis. AB - Segmental arterial mediolysis (SAM) is a rare, non-inflammatory, vascular condition that predominantly affects medium-sized to large-sized abdominal arteries and can present with haemorrhage into the abdominal cavity. We report the case of a patient with SAM of the coeliac, splenic, renal and gastroduodenal arteries in whom endovascular coil embolisation was successfully used to treat a bleeding gastroduodenal artery pseudoaneurysm. PMID- 29535096 TI - Middle mediastinal schwannoma concealed by asthma and GORD. AB - Neurogenic tumours of the mediastinum in adults occur most often at the posterior mediastinum, majority of which are benign of nerve sheath in origin. A 72-year old woman, known asthmatic, presented with chronic symptoms of hoarseness, dysphagia, chest heaviness, easy fatigability, cough, epigastric pain, feeling of abdominal fullness and choking with food intake and at a supine position. Treated for other disorders, routine chest X-ray incidentally found a homogenous convex radiodensity at the right paratracheal area; mass which was also observed with CT and 18F-fludeoxyglucose-positron emission tomography/CT scan studies. Mediastinoscopy with biopsy showed spindle to plump cells with strong S100 positivity. Thoracoscopic surgery done to completely excise the mass found it to be benign schwannoma. PMID- 29535097 TI - A case of tricuspid valve non-bacterial thrombotic endocarditis presenting as pulmonary embolism in a patient with antiphospholipid antibody syndrome. AB - A 47-year-old woman with a medical history of Raynaud's phenomenon presented with fever, cough and shortness of breath. She was found to have left lower lobe consolidation and pleural effusion and was treated as a case of pneumonia. During the hospital course, her respiratory status worsened, and she was intubated on the third hospital day. To investigate the high A-a gradient, a Computerized Tomographic Pulmonary Embolism (CTPE) study was done which identified a large left lower pulmonary artery embolism. She was also found to have a new murmur, and an echocardiogram demonstrated a large lesion on tricuspid valve. However, multiple sets of her blood cultures came back consistently negative. Alternative diagnoses for culture-negative endocarditis were considered, and a full set of rheumatological workup was done. Laboratory tests were suggestive of antiphospholipid syndrome, hence the diagnosis of tricuspid valve Libman-Sacks endocarditis was made. PMID- 29535098 TI - Resolution of osseous sarcoidosis with steroids. PMID- 29535099 TI - LCAT deficiency as a cause of proteinuria and corneal opacification. PMID- 29535100 TI - Spontaneous thrombosis in an ectatic right coronary artery. PMID- 29535101 TI - Ultrasonographic differentiation of the peripheral choroidal detachment from the circumferential scleral buckle. PMID- 29535102 TI - An optimised pipeline for parallel image-based quantification of gene expression and genotyping after in situ hybridisation. AB - Advances in genome engineering have resulted in the generation of numerous zebrafish mutant lines. A commonly used method to assess gene expression in the mutants is in situ hybridisation (ISH). Because the embryos can be distinguished by genotype after ISH, comparing gene expression between wild-type and mutant siblings can be done blinded and in parallel. Such experimental design reduces the technical variation between samples and minimises the risk of bias. This approach, however, requires an efficient method of genomic DNA extraction from post-ISH fixed zebrafish samples to ascribe phenotype to genotype. Here we describe a method to obtain PCR-quality DNA from 95-100% of zebrafish embryos, suitable for genotyping after ISH. In addition, we provide an image analysis protocol for quantifying gene expression of ISH-probed embryos, adaptable for the analysis of different expression patterns. Finally, we show that intensity-based image analysis enables accurate representation of the variability of gene expression detected by ISH and that it can complement quantitative methods like qRT-PCR. By combining genotyping after ISH and computer-based image analysis, we have established a high-confidence, unbiased methodology to assign gene expression levels to specific genotypes, and applied it to the analysis of molecular phenotypes of newly generated lmo4a mutants. PMID- 29535103 TI - Streamlined histone-based fluorescence lifetime imaging microscopy (FLIM) for studying chromatin organisation. AB - Changes in chromatin structure are key determinants of genomic responses. Thus, methods that enable such measurements are instrumental for investigating genome regulation and function. Here, we report further developments and validation of a streamlined method of histone-based fluorescence lifetime imaging microscopy (FLIM) that robustly detects chromatin compaction states in fixed and live cells, in 2D and 3D. We present a quality-controlled and detailed method that is simpler and faster than previous methods, and uses FLIMfit open-source software. We demonstrate the versatility of this chromatin FLIM through its combination with immunofluorescence and implementation in immortalised and primary cells. We applied this method to investigate the regulation of chromatin organisation after genotoxic stress and provide new insights into the role of ATM in controlling chromatin structure independently of DNA damage. Collectively, we present an adaptable chromatin FLIM method for examining chromatin structure and establish its utility in mammalian cells. PMID- 29535104 TI - Geographic variation in the provider of screening colonoscopy in Canada: a population-based cohort study. AB - BACKGROUND: Screening colonoscopy for the detection of colorectal carcinoma is provided by several specialties. Few studies have assessed geographic variation in the delivery of this care. Our objective was to investigate how geographic and socioeconomic factors affect who provides screening colonoscopy in Canada. METHODS: This was a population-based cohort of all screening colonoscopy procedures performed at publicly funded Canadian health care facilities (excluding those in Quebec) between April 2008 and March 2015. The main outcome of interest was the proportion of colonoscopy procedures performed by surgeons versus gastroenterologists at the neighbourhood level. Predictors of interest included socioeconomic and geographic variables. We used spatial analysis to evaluate significant clustering of practitioner services and multinomial logistic regression to model predictors. RESULTS: We identified 658 113 screening colonoscopy procedures performed by 1886 providers (1169 surgeons and 717 gastroenterologists) over the study period, of which 353 165 (53.7%) were performed by surgeons. A total of 24.2% of neighbourhoods were located within clusters predominantly served by gastroenterologists, and 19.5% were within surgeon clusters; the remainder were in mixed clusters. Rural neighbourhoods had a significantly increased relative risk of being within a surgeon cluster (relative risk [RR] 5.38, 95% confidence interval [CI] 3.48-8.01) compared to mixed clusters and nearly 100 times higher relative risk of being in a surgeon cluster compared to gastroenterologist clusters (RR 98.95, 95% CI 15.3-427.2). Neighbourhoods with the highest socioeconomic status were 1.74 (95% CI 1.14-2.56) times likelier to be in gastroenterologist clusters than in mixed clusters. INTERPRETATION: Surgeons provide a large proportion of colonoscopy procedures in Canada and are essential for access to care, particularly in rural regions. Most Canadians are served relatively equally by surgeons and gastroenterologists. This emphasizes the importance of both specialties to the delivery of colonoscopy care across the country. PMID- 29535105 TI - Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation. AB - Residual antithymocyte globulin (ATG; Thymoglobulin) exposure after allogeneic hematopoietic (stem) cell transplantation (HCT) delays CD4+ T-cell immune reconstitution (CD4+ IR), subsequently increasing morbidity and mortality. This effect seems particularly present after cord blood transplantation (CBT) compared to bone marrow transplantation (BMT). The reason for this is currently unknown. We investigated the effect of active-ATG exposure on CD4+ IR after BMT and CBT in 275 patients (CBT n = 155, BMT n = 120; median age, 7.8 years; range, 0.16-19.2 years) receiving their first allogeneic HCT between January 2008 and September 2016. Multivariate log-rank tests (with correction for covariates) revealed that CD4+ IR was faster after CBT than after BMT with <10 active-ATG * day/mL (P = .018) residual exposure. In contrast, >10 active-ATG * day/mL exposure severely impaired CD4+ IR after CBT (P < .001), but not after BMT (P = .74). To decipher these differences, we performed ATG-binding and ATG-cytotoxicity experiments using cord blood- and bone marrow graft-derived T-cell subsets, B cells, natural killer cells, and monocytes. No differences were observed. Nevertheless, a major covariate in our cohort was Filgrastim treatment (only given after CBT). We found that Filgrastim (granulocyte colony-stimulating factor [G-CSF]) exposure highly increased neutrophil-mediated ATG cytotoxicity (by 40-fold [0.5 vs 20%; P = .002]), which explained the enhanced T-cell clearance after CBT. These findings imply revision of the use (and/or timing) of G-CSF in patients with residual ATG exposure. PMID- 29535107 TI - Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population. AB - OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age <=16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had >=1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services. PMID- 29535108 TI - Point-of-care C-reactive protein at triage for children in the emergency department. PMID- 29535106 TI - Toward dual hematopoietic stem-cell transplantation and solid-organ transplantation for sickle-cell disease. AB - Sickle-cell disease (SCD) leads to recurrent vaso-occlusive crises, chronic end organ damage, and resultant physical, psychological, and social disabilities. Although hematopoietic stem-cell transplantation (HSCT) is potentially curative for SCD, this procedure is associated with well-recognized morbidity and mortality and thus is ideally offered only to patients at high risk of significant complications. However, it is difficult to identify patients at high risk before significant complications have occurred, and once patients experience significant organ damage, they are considered poor candidates for HSCT. In turn, patients who have experienced long-term organ toxicity from SCD such as renal or liver failure may be candidates for solid-organ transplantation (SOT); however, the transplanted organs are at risk of damage by the original disease. Thus, dual HSCT and organ transplantation could simultaneously replace the failing organ and eliminate the underlying disease process. Advances in HSCT conditioning such as reduced-intensity regimens and alternative donor selection may expand both the feasibility of and potential donor pool for transplantation. This review summarizes the current state of HSCT and organ transplantation in SCD and discusses future directions and the clinical feasibility of dual HSCT/SOT. PMID- 29535109 TI - Off-label use of tacrolimus in children with Henoch-Schonlein purpura nephritis: a pilot study. AB - BACKGROUND: Tacrolimus is used off-label in the treatment of Henoch-Schonlein purpura nephritis (HSPN) in children, with limited evidence-based data. Based on clinical empirical experience and mechanism of action, tacrolimus might be promoted as treatment for childhood HSPN. The objectives of this pilot study were to assess its effectiveness and safety, and to explore the potential impact of CYP3A5 genotype. METHODS: Children with HSPN receiving tacrolimus as empirical treatment were included in this prospective, observational study. Effectiveness was classified as complete remission, partial remission or non-response. General safety data analyses during and after study drug exposure included adverse events, reasons for discontinuation, deaths, laboratory data and vital signs. Trough concentration was determined using high-performance liquid chromatography with tandem mass spectrometry. Pharmacogenetic analysis was performed on the CYP3A5 gene. RESULTS: A total of 20 patients with a mean age of 7.5 (SD 2.1) years participated in the whole process of the study. Twelve patients reached complete remission and eight patients reached partial remission at the end of 6 month treatment. No patients discontinued tacrolimus treatment due to adverse events, and no drug-related adverse events were shown to have a causal association with tacrolimus therapy. Dose-adjusted trough concentration was significantly higher in children with CYP3A5*1 allele as compared with patients with CYP3A5*3/*3 genotype (170.7+/-100.9 vs 79.8+/-47.4 (ng/mL)/(mg/kg)). CONCLUSION: This pilot study showed that tacrolimus might be an effective and well-tolerated drug for the treatment of HSPN in children. CYP3A5 polymorphism had a significant impact on tacrolimus concentration. PMID- 29535110 TI - Response to 'When paediatricians and families can't agree'. PMID- 29535111 TI - Feasibility of using touch screen technology for early cognitive assessment in children. AB - OBJECTIVE: To explore the feasibility of using a touch screen assessment tool to measure cognitive capacity in toddlers. DESIGN: 112 typically developing children with a median age of 31 months (IQR: 26-34) interacted with a touch screen cognitive assessment tool. We examined the sensitivity of the tool to age-related changes in cognition by comparing the number of items completed, speed of task completion and accuracy in two age groups; 24-29 months versus 30-36 months. RESULTS: Children aged 30-36 months completed more tasks (median: 18, IQR: 18-18) than those aged 24-29 months (median: 17, IQR: 15-18). Older children also completed two of the three working memory tasks and an object permanence task faster than their younger peers. Children became faster at completing the working memory items with each exposure and registered similar completion times on the hidden object retrieval items, despite task demands being twofold on the second exposure. A novel item required children to integrate what they had learnt on preceding items. The older group was more likely to complete this item and to do so faster than the younger group. CONCLUSIONS: Children as young as 24 months can complete items requiring cognitive engagement on a touch screen device, with no verbal instruction and minimal child-administrator interaction. This paves the way for using touch screen technology for language and administrator independent developmental assessment in toddlers. PMID- 29535112 TI - Latest thinking on antidepressants in children and young people. PMID- 29535113 TI - Elevated platelet counts in a cohort of children with moderate-severe osteogenesis imperfecta suggest that inflammation is present. AB - BACKGROUND: Elevated platelet counts are observed in cancer, autoimmunity and inflammation with concurrent illness. Proinflammatory cytokines are elevated in murine osteogenesis imperfecta (OI) models. We hypothesised that platelet counts might be elevated in children with moderate-severe OI. METHODS: We reviewed the hospital records of 71 children with moderate-severe OI, treated in the Sheffield Children's Hospital's Severe, Complex and Atypical Osteogenesis Imperfecta Highly Specialised Service. Data relating platelet count (below/above average, above upper limit) to prior and concurrent events were summarised as event proportions per child. Additionally, we created platelet SD scores to assess age and time related trends, and relationship with OI type. RESULTS: 1206 platelet counts were recorded. Platelet SD scores were right-shifted by 0.89 SD overall. 49 of 71 (69%) patients had at least one platelet count above the normal range and 246 (20.4%) of all counts were above the upper limit of normal. Of these, 101 (41%) were high despite no confounding factors being present. For the 47 children with data at age less than 2 years, 89 (30.0%) platelet counts were above the upper limit of normal and 39 (44%) had no associated confounding factor. Elevated platelet counts were recorded most often for children with new or existing vertebral fractures. CONCLUSIONS: Raised platelet counts were observed in association with new and healing vertebral fractures, but also (41%-44%) in the absence of identified proinflammatory factors or events. We speculate that these findings are evidence for a proinflammatory component to OI that could be a target for therapeutic intervention. PMID- 29535115 TI - Caloric Restriction as a Therapeutic Approach to Heart Failure: Can Less Be More in (Mice) and Men? PMID- 29535114 TI - Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure. AB - BACKGROUND: Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctional beta-adrenergic receptor signaling, and decreased cardiac inotropic reserve. We tested the effects of a long-term CR diet, started late after myocardial infarction on cardiac function, sympathetic innervation, and beta-adrenergic receptor responsiveness in a rat model of postischemic HF. METHODS AND RESULTS: Adult male rats were randomly assigned to myocardial infarction or sham operation and 4 weeks later were further randomized to a 1 year CR or normal diet. One year of CR resulted in a significant reduction in body weight, heart weight, and heart weight/tibia length ratio when compared with normal diet in HF groups. At the end of the study period, echocardiography and histology revealed that HF animals under the CR diet had ameliorated left ventricular remodeling compared with HF rats fed with normal diet. Invasive hemodynamic showed a significant improvement of cardiac inotropic reserve in CR HF rats compared with HF-normal diet animals. Importantly, CR dietary regimen was associated with a significant increase of cardiac sympathetic innervation and with normalized cardiac beta-adrenergic receptor levels in HF rats when compared with HF rats on the standard diet. CONCLUSIONS: We demonstrate, for the first time, that chronic CR, when started after HF established, can ameliorate cardiac dysfunction and improve inotropic reserve. At the molecular level, we find that chronic CR diet significantly improves sympathetic cardiac innervation and beta adrenergic receptor levels in failing myocardium. PMID- 29535116 TI - How can I safely return to work after maternity leave? PMID- 29535117 TI - Reviewing the literature: choosing a review design. PMID- 29535118 TI - When patients won't leave or families won't let them. PMID- 29535119 TI - Bawa-Garba case: it's the barrel that's the problem. PMID- 29535121 TI - Response to: 'The role of temporal artery biopsy in patients with giant cell arteritis is debated' by Moiseev et al. PMID- 29535120 TI - Identification of calcium pyrophosphate deposition disease (CPPD) by ultrasound: reliability of the OMERACT definitions in an extended set of joints-an international multiobserver study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force. AB - OBJECTIVES: To assess the reliability of the OMERACT ultrasound (US) definitions for the identification of calcium pyrophosphate deposition disease (CPPD) at the metacarpal-phalangeal, triangular fibrocartilage of the wrist (TFC), acromioclavicular (AC) and hip joints. METHODS: A web-based exercise and subsequent patient-based exercise were carried out. A panel of 30 OMERACT members, participated at the web-based exercise by evaluating twice a set of US images for the presence/absence of CPPD. Afterwards, 19 members of the panel met in Siena, Italy, for the patient-based exercise. During the exercise, all sonographers examined twice eight patients for the presence/absence of CPPD at the same joints. Intraoberserver and interobserver kappa values were calculated for both exercises. RESULTS: The web-based exercise yielded high kappa values both in intraobserver and interobserver evaluation for all sites, while in the patient-based exercise, inter-reader agreement was acceptable for the TFC and the AC. TFC reached high interobserver and intraobserver k values in both exercises, ranging from 0.75 to 0.87 (good to excellent agreement). AC reached moderate kappa values, from 0.51 to 0.85 (moderate to excellent agreement) and can readily be used for US CPPD identification. CONCLUSIONS: Based on the results of our exercise, the OMERACT US definitions for the identification of CPPD demonstrated to be reliable when applied to the TFC and AC. Other sites reached good kappa values in the web-based exercise but failed to achieve good reproducibility at the patient-based exercise, meaning the scanning method must be further refined. PMID- 29535122 TI - Additional response to the correspondence: 'Switching from the bio-originators to biosimilar: is it premature to recommend this procedure?' by Cantini and Bennuci. PMID- 29535123 TI - Response to 'Detection of myositis-specific antibodies: additional notes'. PMID- 29535124 TI - Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study. AB - OBJECTIVES: To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). METHODS: We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. RESULTS: This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non biologic disease-modifying antirheumatic drugs. CONCLUSIONS: This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections. PMID- 29535125 TI - A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma. AB - Purpose: The WEE1 tyrosine kinase regulates G2-M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data.Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in gammaH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders.Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740-8. (c)2018 AACR. PMID- 29535126 TI - Exosome-Based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients. AB - Purpose: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third-generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a noninvasive option to detect the mutation; however, sensitivity is low as many patients have too few detectable copies in circulation. Here, we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele-specific qPCR.Experimental Design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a Clinical Laboratory Improvement Amendment laboratory.Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging.Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared with historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing. Clin Cancer Res; 24(12); 2944-50. (c)2018 AACR. PMID- 29535127 TI - TFAP2E Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer. AB - Purpose: A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts.Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU-based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed.Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79-1.87; log-rank P = 0.6]. In stage II-III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU-treated (HR, 0.91; 95% CI, 0.52-1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5-1.54; log-rank P = 0.7).Conclusions:TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. Clin Cancer Res; 24(12); 2820-7. (c)2018 AACR. PMID- 29535128 TI - RIP1-HAT1-SIRT Complex Identification and Targeting in Treatment and Prevention of Cancer. AB - Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(alpha)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention. Clin Cancer Res; 24(12); 2886-900. (c)2018 AACR. PMID- 29535129 TI - Report of the 14th International Conference on Malignant Lymphoma (ICML) Closed Workshop on Future Design of Clinical Trials in Lymphomas. AB - The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop. Clin Cancer Res; 24(13); 2993-8. (c)2018 AACR. PMID- 29535130 TI - p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial. AB - Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial.Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure.Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab (N = 95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01).Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3046-52. (c)2018 AACR. PMID- 29535131 TI - Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo. AB - Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo Here, we have investigated the molecular basis of this activity.Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines.Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i.Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivoClin Cancer Res; 24(12); 2901-12. (c)2018 AACR. PMID- 29535132 TI - Impact of the MitraClip Procedure on Left Atrial Strain and Strain Rate. AB - BACKGROUND: Although reverse remodeling of the left atrium (LA) has been shown after MitraClip placement in degenerative mitral regurgitation (MR), changes in LA strain and strain rate have not been evaluated in these patients or compared with surgical mitral valve repair. METHODS AND RESULTS: We included 87 subjects (mean age 59.7+/-12.3 years) with degenerative MR enrolled in the randomized EVEREST II trial (Endovascular Valve Edge-to-Edge Repair Study II). Baseline peak positive LA strain (epsilon) and strain rates along with longitudinal left ventricular strain (LV epsilon) were compared with 12-month follow-up measures. At 12 months, all 38 mitral valve repair subjects had <=2+ MR, and 31 of the 49 MitraClip had <=2+ MR. Baseline LA strain and strain rate values were similar in MitraClip and mitral valve repair groups. Of the strain rate measures, only peak early diastolic strain rate was consistently decreased in all treatment arms. In patients with reduced baseline LA epsilon, no significant change in LA epsilon occurred in either the MitraClip or mitral valve repair group despite significant MR and LA volume reduction. However, in patients with normal or high baseline epsilon, successful MR reduction by either method resulted in return of LA epsilon to normative values. There was a significant correlation between LA epsilon, LV epsilon values, and change in LA epsilon and LV epsilon over time. CONCLUSIONS: Changes seen in LA epsilon seem to depend on baseline LA and LV function. Changes in LA epsilon after MR reduction may reflect a decrease in LA expansion but may also be influenced by the degree of pre-existing LA dysfunction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00209274. PMID- 29535133 TI - Clip, Slip, and Grip: Impact on Left Atrial Strain. PMID- 29535134 TI - Organoids May Point to Best Therapy. AB - In a recent study, organoids derived from the metastatic tumors of patients with gastrointestinal cancers had a similar response to treatment as the original tumors. Eventually, organoids could become a useful tool for identifying the most effective therapy for each patient. PMID- 29535135 TI - Day-and-Night Closed-Loop Insulin Delivery in a Broad Population of Pregnant Women With Type 1 Diabetes: A Randomized Controlled Crossover Trial. AB - OBJECTIVE: Despite advances in technology, optimal glucose control remains elusive and neonatal complications remain ubiquitous in type 1 diabetes (T1D) pregnancy. Our aim was to examine the safety, efficacy, and longer-term feasibility of day-and-night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We recruited 16 pregnant women (mean [SD]: age 32.8 [5.0] years, T1D duration 19.4 [10.2] years, HbA1c 8.0% [1.1], and BMI 26.6 [4.4] kg/m2) to an open-label, randomized, crossover trial. Participants completed 28 days of closed loop and sensor-augmented pump (SAP) insulin delivery separated by a washout period. Afterward, participants could continue to use the closed-loop system up to 6 weeks postpartum. The primary end point was the proportion of time with glucose levels within the target range (63-140 mg/dL). RESULTS: The proportion of time with glucose levels within target was comparable during closed-loop and SAP insulin delivery (62.3 vs. 60.1% [95% CI -4.1 to 8.3]; P = 0.47). Mean glucose and time spent hyperglycemic >140 mg/dL also did not differ (131.4 vs. 131.4 mg/dL [P = 0.85] and 36.6 vs. 36.1% [P = 0.86], respectively). During closed loop, fewer hypoglycemic episodes occurred (median 8 [range 1-17] vs. 12.5 [1-53] over 28 days; P = 0.04) and less time at <63 mg/dL (1.6 vs. 2.7%; P = 0.02). Hypoglycemia <50 mg/dL (0.24 vs. 0.47%; P = 0.03) and low blood glucose index (1.0 vs. 1.4; P = 0.01) were lower. Less nocturnal hypoglycemia (2300-0700 h) during closed-loop therapy (1.1 vs. 2.7%; P = 0.008) and a trend toward higher overnight time in target (67.7 vs. 60.6%; P = 0.06) were found. CONCLUSIONS: Closed-loop insulin delivery was associated with comparable glucose control and significantly less hypoglycemia than SAP therapy. Larger, longer-duration multicenter trials are now indicated to determine clinical efficacy of closed loop insulin delivery in T1D pregnancy and the impact on neonatal outcomes. PMID- 29535136 TI - Clinical Outcome of Electrophysiologically Guided Ablation for Nonparoxysmal Atrial Fibrillation Using a Novel Real-Time 3-Dimensional Mapping Technique: Results From a Prospective Randomized Trial. AB - BACKGROUND: Clinical outcomes after ablation of persistent atrial fibrillation remain suboptimal. Identification of AF drivers using a novel integrated mapping technique may be crucial to ameliorate the clinical outcome. METHODS AND RESULTS: Persistent AF patients were prospectively enrolled to undergo high-density electrophysiological mapping to identify repetitive-regular activities (RRas) before modified circumferential pulmonary vein (PV) ablation. They have been randomly assigned (1:1 ratio) to ablation of RRa followed by modified circumferential PV ablation (mapping group; n=41) or modified circumferential PV ablation alone (control group; n=40). The primary end point was freedom from arrhythmic recurrences at 1 year. In total, 81 persistent AF patients (74% male; mean age, 61.7+/-10.6 years) underwent mapping/ablation procedure. The regions exhibiting RRa were 479 in 81 patients (5.9+/-2.4 RRa per patient): 232 regions in the mapping group (n=41) and 247 in the control group (n=40). Overall, 185 of 479 (39%) RRas were identified within the PVs, whereas 294 of 479 (61%) in non-PV regions. Mapping-guided ablation resulted in higher arrhythmia termination rate when compared with conventional strategy (25/41, 61% versus 12/40, 30%; P<0.007). Total radiofrequency duration (P=0.38), mapping (P=0.46), and fluoroscopy times (P=0.69) were not significantly different between the groups. No major procedure related adverse events occurred. After 1 year, 73.2% of mapping group patients were free from recurrences versus 50% of control group (P=0.03). CONCLUSIONS: Targeted ablation of regions showing RRa provided an adjunctive benefit in terms of arrhythmia freedom at 1-year follow-up in the treatment of persistent AF. These findings might support a patient-tailored strategy in subjects with nonparoxysmal AF and should be confirmed by additional larger, randomized, multicenter studies. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier NCT02571218. PMID- 29535137 TI - LncKdm2b controls self-renewal of embryonic stem cells via activating expression of transcription factor Zbtb3. AB - Divergent long noncoding RNAs (lncRNAs) represent a major lncRNA biotype in mouse and human genomes. The biological and molecular functions of the divergent lncRNAs remain largely unknown. Here, we show that lncKdm2b, a divergent lncRNA for Kdm2b gene, is conserved among five mammalian species and highly expressed in embryonic stem cells (ESCs) and early embryos. LncKdm2b knockout impairs ESC self renewal and causes early embryonic lethality. LncKdm2b can activate Zbtb3 by promoting the assembly and ATPase activity of Snf2-related CREBBP activator protein (SRCAP) complex in trans Zbtb3 potentiates the ESC self-renewal in a Nanog-dependent manner. Finally, Zbtb3 deficiency impairs the ESC self-renewal and early embryonic development. Therefore, our findings reveal that lncRNAs may represent an additional layer of the regulation of ESC self-renewal and early embryogenesis. PMID- 29535138 TI - Biomarkers of Myocardial Fibrosis: Revealing the Natural History of Fibrogenesis in Fabry Disease Cardiomyopathy. AB - BACKGROUND: Cardiomyopathy is a major determinant of overall Fabry disease (FD) prognosis, with the worst outcomes in patients with myocardial fibrosis. Late gadolinium enhancement is currently the gold standard for evaluation of replacement myocardial fibrosis; however, this event is irreversible, thus identification of biomarkers of earlier diffuse fibrosis is paramount. METHODS AND RESULTS: Type I collagen synthesis and degradation biomarkers (PICP [carboxyterminal propeptide of procollagen type I], ICTP [carboxyterminal telopeptide of type I collagen], and MMP1 [matrix metalloproteinase 1] and MMP2) and markers of bone synthesis and degradation were evaluated (to adjust type I collagen metabolism to bone turnover) in FD patients and controls. FD patients were grouped by cardiomyopathy severity, according to echocardiogram: (1) normal, (2) tissue Doppler abnormalities, (3) left ventricular hypertrophy. A significant increase in PICP and a significant decrease in matrix metalloproteinases were observed in FD patients; even the group with normal echocardiogram had a significant increase in PICP. We also found a significant correlation between left ventricular mass and PICP (rho=0.378, P=0.003) and MMP1 (rho=-0.484, P<0.001). PICP (adjusted for bone turnover) was the better predictor of left ventricular mass in multivariable regression, and its diagnostic accuracy to predict late gadolinium enhancement was also significant. CONCLUSIONS: Collagen type I synthesis is increased in FD cardiomyopathy, even in the earlier stages of the disease, and this profibrotic state has good predictive value for and is likely to be critical to the development of overt left ventricular hypertrophy. Moreover, inhibition of enzymes involved in collagen type I cleavage also seems crucial to myocardial collagen deposition. PMID- 29535139 TI - Preoperative Short-Term Calorie Restriction for Prevention of Acute Kidney Injury After Cardiac Surgery: A Randomized, Controlled, Open-Label, Pilot Trial. AB - BACKGROUND: Acute kidney injury is a frequent complication after cardiac surgery and is associated with adverse outcomes. Although short-term calorie restriction (CR) has proven protective in rodent models of acute kidney injury, similar effects have not yet been demonstrated in humans. METHODS AND RESULTS: CR_KCH (Effect of a Preoperative Calorie Restriction on Renal Function After Cardiac Surgery) is a randomized controlled trial in patients scheduled for cardiac surgery. Patients were randomly assigned to receive either a formula diet containing 60% of the daily energy requirement (CR group) or ad libitum food (control group) for 7 days before surgery. In total, 82 patients were enrolled between April 16, 2012, and February 5, 2015. There was no between-group difference in the primary end point of median serum creatinine increment after 24 hours (control group: 0.0 mg/dL [-0.1 - (+0.2) mg/dL]; CR group: 0.0 mg/dL [-0.2 (+0.2) mg/dL]; P=0.39). CR prevented a rise in median creatinine at 48 hours (control group: +0.1 mg/dL [0.0 - 0.3 mg/dL]; CR group: -0.1 mg/dL [-0.2 - (+0.1) mg/dL]; P=0.03), with most pronounced effects observed in male patients and patients with a body mass index >25. This benefit persisted until discharge: Median creatinine decreased by 0.1 mg/dL (-0.2 - 0.0 mg/dL) in the CR group, whereas it increased by 0.1 mg/dL (0.0 - 0.3 mg/dL; P=0.0006) in the control group. Incidence of acute kidney injury was reduced by 5.8% (41.7% in the CR group compared with 47.5% in the control group). Safety-related events did not differ between groups. CONCLUSIONS: Despite disappointing results with respect to creatinine rise within the first 24 hours, the benefits observed at later time points and the subgroup analyses suggest the protective potential of short-term CR in patients at risk for acute kidney injury, warranting further investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01534364. PMID- 29535140 TI - Elevated Circulating Fibrocytes Is a Marker of Left Atrial Fibrosis and Recurrence of Persistent Atrial Fibrillation. AB - BACKGROUND: In atrial fibrillation (AF), a more extensively fibrotic left atrium (LA) provides a substrate for arrhythmias and increases risk of relapse following ablation. Fibrocytes are bone marrow-derived circulating mesenchymal progenitors that have been identified in the atrium of patients with AF who have valvular diseases. The present study investigates the associations between circulating fibrocytes and LA fibrosis or the prevalence of recurrence after ablation in patients with persistent AF. METHODS AND RESULTS: We measured the proportion, differentiation, and migration of circulating fibrocytes from patients with persistent AF (n=40), those with paroxysmal AF (n=30), and sinus rhythm controls (n=30). LA low-voltage (fibrosis) area was identified by an electroanatomic mapping system, and patients were followed up for 1 year after ablation. The relationship between circulating fibrocyte percentage and LA low-voltage area or recurrence was assessed by multivariate regression analysis. Circulating fibrocyte percentage positively associated with LA low-voltage area in the persistent AF group, and circulating fibrocyte (>=4.05%) was a significant predictor of 1-year recurrence after ablation. Cultured fibrocytes exhibited enhanced potential of differentiation in the persistent AF group (67.58+/-1.54%) versus the paroxysmal AF group (56.67+/-1.52%) and sinus rhythm controls (48.43+/ 1.79%). Furthermore, expression of fibroblast activation markers and cell migratory ability were also elevated in differentiated fibrocytes from patients with persistent AF. Transforming growth factor beta1 and stromal cell-derived factor 1 were elevated in the plasma of patients with persistent AF and were shown to promote fibrocyte differentiation and migration, respectively. CONCLUSIONS: In patients with persistent AF, increased circulating fibrocytes served as a marker of LA fibrosis and recurrence. PMID- 29535142 TI - 65 YEARS OF THE DOUBLE HELIX: Treatment of pituitary tumors with temozolomide: an update. AB - Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance. PMID- 29535141 TI - Predictors and Prognostic Value of Worsening Renal Function During Admission in HFpEF Versus HFrEF: Data From the KorAHF (Korean Acute Heart Failure) Registry. AB - BACKGROUND: Worsening renal function (WRF) is associated with adverse outcomes in patients with heart failure. We investigated the predictors and prognostic value of WRF during admission, in patients with preserved ejection fraction (HFpEF) versus those with reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 5625 patients were enrolled in the KorAHF (Korean Acute Heart Failure) registry. WRF was defined as an absolute increase in creatinine of >=0.3 mg/dL. Transient WRF was defined as recovery of creatinine at discharge, whereas persistent WRF was indicated by a nonrecovered creatinine level. HFpEF and HFrEF were defined as a left ventricle ejection fraction >=50% and <=40%, respectively. Among the total population, WRF occurred in 3101 patients (55.1%). By heart failure subgroup, WRF occurred more frequently in HFrEF (57.0% versus 51.3%; P<0.001 in HFrEF and HFpEF). Prevalence of WRF increased as creatinine clearance decreased in both heart failure subgroups. Among various predictors of WRF, chronic renal failure was the strongest predictor. WRF was an independent predictor of adverse in-hospital outcomes (HFrEF: odds ratio; 2.75; 95% confidence interval, 1.50-5.02; P=0.001; HFpEF: odds ratio, 9.48; 95% confidence interval, 1.19-75.89; P=0.034) and 1-year mortality (HFrEF: hazard ratio, 1.41; 95% confidence interval, 1.12-1.78; P=0.004 versus HFpEF: hazard ratio, 1.72; 95% confidence interval, 1.23-2.42; P=0.002). Transient WRF was a risk factor for 1 year mortality, whereas persistent WRF had no additive risk compared to transient WRF. CONCLUSIONS: In patients with acute heart failure patients, WRF is an independent predictor of adverse in-hospital and follow-up outcomes in both HFrEF and HFpEF, though with a different effect size. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01389843. PMID- 29535143 TI - Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. PMID- 29535144 TI - Minimally symptomatic cerebral amyloid angiopathy-related inflammation: three descriptive case reports. PMID- 29535145 TI - Intensive inpatient rehabilitation for persons with Parkinson's disease: last resort or pre-emptive strike? PMID- 29535146 TI - Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats. AB - Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions. PMID- 29535147 TI - A Host-Pathogen Interaction Screen Identifies ada2 as a Mediator of Candida glabrata Defenses Against Reactive Oxygen Species. AB - Candida glabrata (C. glabrata) forms part of the normal human gut microbiota but can cause life-threatening invasive infections in immune-compromised individuals. C. glabrata displays high resistance to common azole antifungals, which necessitates new treatments. In this investigation, we identified five C. glabrata deletion mutants (?ada2, ?bas1, ?hir3, ?ino2 and ?met31) from a library of 196 transcription factor mutants that were unable to grow and activate an immune response in Drosophila larvae. This highlighted the importance of these transcription factors in C. glabrata infectivity. Further ex vivo investigation into these mutants revealed the requirement of C. glabrata ADA2 for oxidative stress tolerance. We confirmed this observation in vivo whereby growth of the C. glabrata Deltaada2 strain was permitted only in flies with suppressed production of reactive oxygen species (ROS). Conversely, overexpression of ADA2 promoted C. glabrata replication in infected wild type larvae resulting in larval killing. We propose that ADA2 orchestrates the response of C. glabrata against ROS-mediated immune defenses during infection. With the need to find alternative antifungal treatment for C. glabrata infections, genes required for survival in the host environment, such as ADA2, provide promising potential targets. PMID- 29535149 TI - SvABA: genome-wide detection of structural variants and indels by local assembly. AB - Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements. We evaluated SvABA's performance on the NA12878 human genome and in simulated and real cancer genomes. SvABA demonstrates superior sensitivity and specificity across a large spectrum of SVs and substantially improves detection performance for variants in the 20-300 bp range, compared with existing methods. SvABA also identifies complex somatic rearrangements with chains of short (<1000 bp) templated-sequence insertions copied from distant genomic regions. We applied SvABA to 344 cancer genomes from 11 cancer types and found that short templated-sequence insertions occur in ~4% of all somatic rearrangements. Finally, we demonstrate that SvABA can identify sites of viral integration and cancer driver alterations containing medium-sized (50-300 bp) SVs. PMID- 29535148 TI - Identification of General Patterns of Sex-Biased Expression in Daphnia, a Genus with Environmental Sex Determination. AB - Daphnia reproduce by cyclic-parthenogenesis, where phases of asexual reproduction are intermitted by sexual production of diapause stages. This life cycle, together with environmental sex determination, allow the comparison of gene expression between genetically identical males and females. We investigated gene expression differences between males and females in four genotypes of Daphnia magna and compared the results with published data on sex-biased gene expression in two other Daphnia species, each representing one of the major phylogenetic clades within the genus. We found that 42% of all annotated genes showed sex biased expression in D. magna This proportion is similar both to estimates from other Daphnia species as well as from species with genetic sex determination, suggesting that sex-biased expression is not reduced under environmental sex determination. Among 7453 single copy, one-to-one orthologs in the three Daphnia species, 707 consistently showed sex-biased expression and 675 were biased in the same direction in all three species. Hence these genes represent a core-set of genes with consistent sex-differential expression in the genus. A functional analysis identified that several of them are involved in known sex determination pathways. Moreover, 75% were overexpressed in females rather than males, a pattern that appears to be a general feature of sex-biased gene expression in Daphnia. PMID- 29535151 TI - Genetic Reagents for Making Split-GAL4 Lines in Drosophila. AB - The ability to reproducibly target expression of transgenes to small, defined subsets of cells is a key experimental tool for understanding many biological processes. The Drosophila nervous system contains thousands of distinct cell types and it has generally not been possible to limit expression to one or a few cell types when using a single segment of genomic DNA as an enhancer to drive expression. Intersectional methods, in which expression of the transgene only occurs where two different enhancers overlap in their expression patterns, can be used to achieve the desired specificity. This report describes a set of over 2800 transgenic lines for use with the split-GAL4 intersectional method. PMID- 29535150 TI - Evolutionary Rescue over a Fitness Landscape. AB - Evolutionary rescue describes a situation where adaptive evolution prevents the extinction of a population facing a stressing environment. Models of evolutionary rescue could in principle be used to predict the level of stress beyond which extinction becomes likely for species of conservation concern, or, conversely, the treatment levels most likely to limit the emergence of resistant pests or pathogens. Stress levels are known to affect both the rate of population decline (demographic effect) and the speed of adaptation (evolutionary effect), but the latter aspect has received less attention. Here, we address this issue using Fisher's geometric model of adaptation. In this model, the fitness effects of mutations depend both on the genotype and the environment in which they arise. In particular, the model introduces a dependence between the level of stress, the proportion of rescue mutants, and their costs before the onset of stress. We obtain analytic results under a strong-selection-weak-mutation regime, which we compare to simulations. We show that the effect of the environment on evolutionary rescue can be summarized into a single composite parameter quantifying the effective stress level, which is amenable to empirical measurement. We describe a narrow characteristic stress window over which the rescue probability drops from very likely to very unlikely as the level of stress increases. This drop is sharper than in previous models, as a result of the decreasing proportion of stress-resistant mutations as stress increases. We discuss how to test these predictions with rescue experiments across gradients of stress. PMID- 29535152 TI - Mapping the Allosteric Action of Antagonists A740003 and A438079 Reveals a Role for the Left Flipper in Ligand Sensitivity at P2X7 Receptors. AB - P2X7 receptor (P2X7R) activation requires ~100-fold higher concentrations of ATP than other P2X receptor (P2XR) subtypes. Such high levels are found during cellular stress, and P2X7Rs consequently contribute to a range of pathophysiological conditions. We have used chimeric and mutant P2X7Rs, coupled with molecular modeling, to produce a validated model of the binding mode of the subtype-selective antagonist A438079 at an intersubunit allosteric site. Within the allosteric site large effects on antagonist action were found for point mutants of residues F88A, D92A, F95A, and F103A that were conserved or similar between sensitive/insensitive P2XR subtypes, suggesting that these side-chain interactions were not solely responsible for high-affinity antagonist binding. Antagonist sensitivity was increased with mutations that remove the bulk of side chains around the center of the binding pocket, suggesting that the dimensions of the pocket make a significant contribution to selectivity. Chimeric receptors swapping the left flipper (around the orthosteric site) reduced both ATP and antagonist sensitivity. Point mutations within this region highlighted the contribution of a P2X7R-specific aspartic acid residue (D280) that modeling suggests forms a salt bridge with the lower body region of the receptor. The D280A mutant removing this charge increased ATP potency 15-fold providing a new insight into the low ATP sensitivity of the P2X7R. The ortho- and allosteric binding sites form either side of the beta-strand Y291-E301 adjacent to the left flipper. This structural linking may explain the contribution of the left flipper to both agonist and antagonist action. PMID- 29535153 TI - Re: Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study. PMID- 29535154 TI - Formation of COPI-coated vesicles at a glance. AB - The coat protein complex I (COPI) allows the precise sorting of lipids and proteins between Golgi cisternae and retrieval from the Golgi to the ER. This essential role maintains the identity of the early secretory pathway and impinges on key cellular processes, such as protein quality control. In this Cell Science at a Glance and accompanying poster, we illustrate the different stages of COPI coated vesicle formation and revisit decades of research in the context of recent advances in the elucidation of COPI coat structure. By calling attention to an array of questions that have remained unresolved, this review attempts to refocus the perspectives of the field. PMID- 29535155 TI - 2017 Winner: Seth Zimmerman. PMID- 29535156 TI - Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats. AB - Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The current study addressed the efficacy of a heroin vaccine [morphine hapten conjugated to keyhole limpet hemocyanin (M-KLH)] or oxycodone vaccine [oxycodone hapten conjugated to keyhole limpet hemocyanin (OXY-KLH)] for reducing drug distribution to brain after intravenous heroin or oxycodone, or subcutaneous oxycodone. Rats immunized with M-KLH or keyhole limpet hemocyanin (KLH) control received an intravenous bolus dose of 0.26 or 2.6 mg/kg heroin. Vaccination with M-KLH increased retention of heroin and its active metabolites 6-acetylmorphine (6-AM) and morphine in plasma compared with KLH controls, and reduced total opioid (heroin + 6-AM + morphine) distribution to brain but only at the lower heroin dose. Immunization also protected against respiratory depression at the lower heroin dose. Rats immunized with OXY-KLH or KLH control received 0.22 or 2.2 mg/kg oxycodone intravenously, the molar equivalent of the heroin doses. Immunization with OXY-KLH significantly reduced oxycodone distribution to brain after either oxycodone dose, although the magnitude of effect of immunization at the higher oxycodone dose was small (12%). By contrast, vaccination with OXY-KLH was more effective when oxycodone was administered subcutaneously rather than intravenously, reducing oxycodone distribution to brain by 44% after an oxycodone dose of 2.3 mg/kg. Vaccination also reduced oxycodone-induced antinociception. These data suggest that the efficacy of OXY-KLH and M-KLH opioid vaccines is highly dependent upon opioid dose and route of administration. PMID- 29535157 TI - Mainstreamed genetic testing for women with ovarian cancer: first-year experience. AB - BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death for women in the UK. Up to 18% of cases can be attributed to germline mutations in BRCA1 and BRCA2genes. Identifying patients who carry a BRCA mutation provides important information about potential response to treatment and eligibility for therapies such as poly ADP ribose polymerase (PARP) inhibitors. Implementation of systematic genetic testing of patients with ovarian cancer via oncology clinics (mainstreamed genetic testing, MGT) is increasing. METHODS AND RESULTS: This service evaluation reports on the first year of MGT at a tertiary oncology centre in London, UK. In total, 122 patients with high-grade non-mucinous ovarian cancer underwent BRCA germline testing via MGT. Eighteen patients (14.8%) were found to carry a deleterious BRCA1/BRCA2 mutation. Four BRCA carriers did not meet previous criteria for genetic testing and would have been missed. Six BRCA carriers accessed PARP inhibitors post-MGT. Only 22% of patients with a variant of unknown significance (VUS) were referred to clinical genetics services. CONCLUSIONS: MGT appears to be a feasible way of providing BRCA testing to patients with ovarian cancer. Greater clarity of how oncologists use VUS results is needed, as well as further research on psychosocial implications of MGT for patients with ovarian cancer, which may include somatic testing in the future. PMID- 29535158 TI - Association of ambient pollution with inhaler use among patients with COPD: a panel study. AB - BACKGROUND: Studies have linked ambient air pollution to chronic obstructive pulmonary disease (COPD) healthcare encounters. However, the association between air quality and rescue medication use is unknown. OBJECTIVES: We assessed the role of air pollution exposure for increased short-acting beta-2-agonist (SABA) use in patients with COPD through use of remote monitoring technology. METHODS: Participants received a portable electronic inhaler sensor to record the date, time and location for SABA use over a 3-month period. Ambient air pollution data and meteorological data were collected from a centrally located federal monitoring station. Mixed-effects Poisson regression was used to examine the association of daily inhaler use with pollutant levels. Four criteria pollutants (PM2.5, PM10, O3 and NO2), two particulate matter species (elemental carbon (EC) and organic carbon), estimated coarse fraction of PM10 (PM10-2.5) and four multipollutant air quality measures were each examined separately, adjusting for covariates that passed a false discovery rate (FDR) screening. RESULTS: We enrolled 35 patients with COPD (94.3% male and mean age: 66.5+/-8.5) with a mean forced expiratory volume in 1 s (FEV1) % predicted of 44.9+17.2. Participants had a median of 92 observation days (range 52-109). Participants' average SABA inhaler use ranged from 0.4 to 13.1 puffs/day (median 2.8). Controlling for supplemental oxygen use, long-acting anticholinergic use, modified Medical Research Council Dyspnoea Scale and influenza season, an IQR increase in PM10 concentration (8.0 ug/m3) was associated with a 6.6% increase in daily puffs (95% CI 3.5% to 9.9%; FDR <0.001). NO2 and EC concentration were also significantly associated with inhaler use (3.9% and 2.9% per IQR increase, respectively). CONCLUSIONS: Exposure to increased ambient air pollution were associated with a significant increase in SABA use for patients with COPD residing in a low pollution area. PMID- 29535159 TI - Correction to "High N-Acetyltransferase 1 5alpha-androstane-3beta, Expression is Associated with Estrogen Receptor Expression in Breast Tumors, but is not Under Direct Regulation by Estradiol, 17beta-Diol, or Dihydrotestosterone in Breast Cancer Cells". PMID- 29535160 TI - Promyelocytic Leukemia Protein (PML) Requirement for Interferon-induced Global Cellular SUMOylation. AB - We report that interferon (IFN) alpha treatment at short and long periods increases the global cellular SUMOylation and requires the presence of the SUMO E3 ligase promyelocytic leukemia protein (PML), the organizer of PML nuclear bodies (NBs). Several PML isoforms (PMLI-PMLVII) derived from a single PML gene by alternative splicing, share the same N-terminal region but differ in their C terminal sequences. Introducing each of the human PML isoform in PML-negative cells revealed that enhanced SUMOylation in response to IFN is orchestrated by PMLIII and PMLIV. Large-scale proteomics experiments enabled the identification of 558 SUMO sites on 389 proteins, of which 172 sites showed differential regulation upon IFNalpha stimulation, including K49 from UBC9, the sole SUMO E2 protein. Furthermore, IFNalpha induces PML-dependent UBC9 transfer to the nuclear matrix where it colocalizes with PML within the NBs and enhances cellular SUMOylation levels. Our results demonstrate that SUMOylated UBC9 and PML are key players for IFN-increased cellular SUMOylation. PMID- 29535161 TI - IGF1 receptor signaling pathways. AB - Insulin-like growth factors (IGFs) bind specifically to the IGF1 receptor on the cell surface of targeted tissues. Ligand binding to the alpha subunit of the receptor leads to a conformational change in the beta subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src homology collagen (SHC). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain-containing signaling molecules. These include, for example, an 85 kDa regulatory subunit (p85) of phosphatidylinositol 3-kinase (PI 3-kinase), growth factor receptor-bound 2 (GRB2) and SH2-containing protein tyrosine phosphatase 2 (SHP2/Syp). These bindings lead to the activation of downstream signaling pathways, PI 3-kinase pathway and Ras-mitogen-activated protein kinase (MAP kinase) pathway. Activation of these signaling pathways is known to be required for the induction of various bioactivities of IGFs, including cell proliferation, cell differentiation and cell survival. In this review, the well-established IGF1 receptor signaling pathways required for the induction of various bioactivities of IGFs are introduced. In addition, we will discuss how IGF signals are modulated by the other extracellular stimuli or by themselves based on our studies. PMID- 29535163 TI - Pentapeptide Protection of Botrytis-Infected Tomato Plants by Phytosulfokine. PMID- 29535162 TI - Screening for Biologically Annotated Drugs That Trigger Triacylglycerol Accumulation in the Diatom Phaeodactylum. AB - Microalgae are a promising feedstock for the production of triacylglycerol (TAG) for a variety of potential applications, ranging from food and human health to biofuels and green chemistry. However, obtaining high TAG yields is challenging. A phenotypic assay for the accumulation of oil droplets was developed to screen a library of 1,200 drugs, annotated with pharmacology information, to select compounds that trigger TAG accumulation in the diatom Phaeodactylum tricornutum Using this screen, we identified 34 molecules acting in a dose-dependent manner. Previously characterized targets of these compounds include cell division and cell signaling effectors, membrane receptors and transporters, and sterol metabolism. Among the five compounds possibly acting on sterol metabolism, we focused our study on ethynylestradiol, a synthetic form of estrogen that is used in contraceptive pills and known for its ecological impact as an endocrine disruptor. Ethynylestradiol impaired the production of very-long-chain polyunsaturated fatty acids, destabilized the galactolipid versus phospholipid balance, and triggered the recycling of fatty acids from membrane lipids to TAG. The P. tricornutum transcriptomic response to treatment with ethynylestradiol was consistent with the reallocation of carbon from sterols to acetyl-coenzyme A and TAG. The mode of action and catabolism of ethynylestradiol are unknown but might involve several up-regulated cytochrome P450 proteins. A fatty acid elongase, Delta6-ELO-B1, might be involved in the impairment of very-long-chain polyunsaturated fatty acids and fatty acid turnover. This phenotypic screen opens new perspectives for the exploration of novel bioactive molecules, potential target genes, and pathways controlling TAG biosynthesis. It also unraveled the sensitivity of diatoms to endocrine disruptors, highlighting an impact of anthropogenic pollution on phytoplankton. PMID- 29535164 TI - Glycosylation Profile of Immunoglobulin G Is Cross-Sectionally Associated With Cardiovascular Disease Risk Score and Subclinical Atherosclerosis in Two Independent Cohorts. AB - RATIONALE: One measure of protein glycosylation (GlycA) has been reported to predict higher cardiovascular risk by reflecting inflammatory pathways. OBJECTIVE: The main objective of this study is to assess the role of a comprehensive panel of IgG glycosylation traits on traditional risk factors for cardiovascular disease and on presence of subclinical atherosclerosis in addition to GlycA. METHODS AND RESULTS: We measured 76 IgG glycosylation traits in 2970 women (age range, 40-79 years) from the TwinsUK cohort and correlated it to their estimated 10-year atherosclerotic cardiovascular disease risk score and their carotid and femoral plaque measured by ultrasound imaging. Eight IgG glycan traits are associated with the 10-year atherosclerotic cardiovascular disease risk score after adjusting for multiple tests and for individual risk factors-5 with increased risk and 3 with decreased risk. These glycans replicated in 967 women from ORCADES cohort (Orkney Complex Disease Study), and 6 of them were also associated in 845 men. A linear combination of IgG glycans and GlycA is also associated with presence of carotid (odds ratio, 1.55; 95% confidence interval, 1.25-1.93; P=7.5*10-5) and femoral (odds ratio, 1.32; 95% confidence interval, 1.06-1.64; P=0.01) plaque in a subset of women with atherosclerosis data after adjustment for traditional risk factors. One specific glycosylation trait, GP18 the percentage of FA2BG2S1 glycan in total IgG glycans, was negatively correlated with very-low-density lipoprotein and triglyceride levels in serum and with presence of carotid plaque (odds ratio, 0.60; 95% confidence interval, 0.50-0.71; P=5*10-4). CONCLUSIONS: We find molecular pathways linking IgG to arterial lesion formation. Glycosylation traits are independently associated with subclinical atherosclerosis. One specific trait related to the sialylated N-glycan is negatively correlated with cardiovascular disease risk, very-low-density lipoprotein and triglyceride serum levels, and presence of carotid plaque. PMID- 29535166 TI - Maintenance and Breakdown of Glomerular Tuft Architecture. PMID- 29535165 TI - Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation. AB - RATIONALE: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting coexpression gene network analysis on RNA sequencing data from failing human heart, we identified TXNDC5 (thioredoxin domain containing 5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum protein, as a potential novel mediator of cardiac fibrosis, and we completed experiments to test this hypothesis directly. OBJECTIVE: The objective of this study was to determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis. METHODS AND RESULTS: RNA sequencing and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles and in hypertrophied/failing mouse left ventricle. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor beta1 and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under transforming growth factor beta1 stimulation in vitro. Knockdown of TXNDC5 attenuated transforming growth factor beta1-induced hCF activation and ECM protein upregulation independent of SMAD3 (SMAD family member 3), whereas increasing expression of TXNDC5 triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing c-Jun N-terminal kinase activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. Transforming growth factor beta1-induced TXNDC5 upregulation in hCF was dependent on endoplasmic reticulum stress and activating transcription factor 6-mediated transcriptional control. Targeted disruption of Txndc5 in mice (Txndc5-/-) revealed protective effects against isoproterenol-induced cardiac hypertrophy, reduced fibrosis (by ~70%), and markedly improved left ventricle function; post-isoproterenol left ventricular ejection fraction was 59.1+/-1.5 versus 40.1+/-2.5 (P<0.001) in Txndc5-/- versus wild-type mice, respectively. CONCLUSIONS: The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against beta agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure. PMID- 29535167 TI - Insulin-stimulated glucose uptake in skeletal muscle, adipose tissue and liver: a positron emission tomography study. AB - OBJECTIVE: Insulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific. DESIGN AND METHODS: We measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using 18F fluorodeoxyglucose with positron emission tomography (PET) and euglycemic hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort. RESULTS: Skeletal muscle GU less than 33 umol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 umol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging. CONCLUSIONS: We have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender. PMID- 29535169 TI - Bacterial infection and symbiosis. PMID- 29535168 TI - METS-IR, a novel score to evaluate insulin sensitivity, is predictive of visceral adiposity and incident type 2 diabetes. AB - OBJECTIVE: We developed a novel non-insulin-based fasting score to evaluate insulin sensitivity validated against the euglycemic-hyperinsulinemic clamp (EHC). We also evaluated its correlation with ectopic fact accumulation and its capacity to predict incident type 2 diabetes mellitus (T2D). DESIGN AND METHODS: The discovery sample was composed by 125 subjects (57 without and 68 with T2D) that underwent an EHC. We defined METS-IR as Ln((2*G0)+TG0)*BMI)/(Ln(HDL-c)) (G0: fasting glucose, TG0: fasting triglycerides, BMI: body mass index, HDL-c: high density lipoprotein cholesterol), and compared its diagnostic performance against the M-value adjusted by fat-free mass (MFFM) obtained by an EHC. METS-IR was validated in a sample with EHC data, a sample with modified frequently sampled intravenous glucose tolerance test (FSIVGTT) data and a large cohort against HOMA IR. We evaluated the correlation of the score with intrahepatic and intrapancreatic fat measured using magnetic resonance spectroscopy. Subsequently, we evaluated its ability to predict incident T2D cases in a prospective validation cohort of 6144 subjects. RESULTS: METS-IR demonstrated the better correlation with the MFFM (rho = -0.622, P < 0.001) and diagnostic performance to detect impaired insulin sensitivity compared to both EHC (AUC: 0.84, 95% CI: 0.78 0.90) and the SI index obtained from the FSIVGTT (AUC: 0.67, 95% CI: 0.53-0.81). METS-IR significantly correlated with intravisceral, intrahepatic and intrapancreatic fat and fasting insulin levels (P < 0.001). After a two-year follow-up, subjects with METS-IR in the highest quartile (>50.39) had the highest adjusted risk to develop T2D (HR: 3.91, 95% CI: 2.25-6.81). Furthermore, subjects with incident T2D had higher baseline METS-IR compared to healthy controls (50.2 +/- 10.2 vs 44.7 +/- 9.2, P < 0.001). CONCLUSION: METS-IR is a novel score to evaluate cardiometabolic risk in healthy and at-risk subjects and a promising tool for screening of insulin sensitivity. PMID- 29535170 TI - Mechanics of cell division and cytokinesis. PMID- 29535171 TI - Ensuring fidelity of chromosome segregation. PMID- 29535172 TI - Light, space, and time in cancer signaling. PMID- 29535173 TI - The life of a microtubule. PMID- 29535174 TI - Multicellular interactions: regeneration and mechanisms of disease. PMID- 29535175 TI - Organelles in metabolism and stress responses. PMID- 29535176 TI - Organelle morphogenesis, targeting, and distribution. PMID- 29535177 TI - Lipids and proteins mix it up in Philly. PMID- 29535178 TI - Phase shifts in protein folding space: links to stress adaptation and disease. PMID- 29535179 TI - Actin dynamics and function. PMID- 29535180 TI - Fifty years of microtubule sliding in cilia. AB - Motility of cilia (also known as flagella in some eukaryotes) is based on axonemal doublet microtubule sliding that is driven by the dynein molecular motors. Dyneins are organized into intricately patterned inner and outer rows of arms, whose collective activity is to produce inter-microtubule movement. However, to generate a ciliary bend, not all dyneins can be active simultaneously. The switch point model accounts, in part, for how dynein motors are regulated during ciliary movement. On the basis of this model, supported by key direct experimental observations as well as more recent theoretical and structural studies, we are now poised to understand the mechanics of how ciliary dynein coordination controls axonemal bend formation and propagation. PMID- 29535181 TI - Ethical (and epistemological) issues regarding consciousness in cerebral organoids. PMID- 29535182 TI - Reporting suspected abuse or neglect in research involving children. AB - In this article, we explore the ethical issues related to the reporting of suspected abuse or neglect in research involving children. Ethical dilemmas related to reporting child maltreatment are often complex because the rights of children and their adult caregivers may conflict and determinations of abuse or neglect are socially constructed judgments that depend on particular circumstances. We argue that when reporting is legally mandated, investigators must follow the law and report their suspicions to Child Protective Services. When reporting is not legally mandated, investigators still have an ethical obligation to report to help prevent additional maltreatment and allow children to obtain access to services needed to recover from abuse or neglect. We also argue that investigators should include plans and procedures in the research protocol for making reports and training research staff in recognising evidence of child abuse or neglect. Although investigators should report evidence of abuse or neglect that is discovered incidentally, they have no mandate to actively search for such evidence when it is not related to the study's objectives. Investigators should also inform parents and children about their obligations to report suspected abuse or neglect. PMID- 29535183 TI - INSL5 activates multiple signalling pathways and regulates GLP-1 secretion in NCI H716 cells. AB - Insulin-like peptide 5 (INSL5) is a newly discovered gut hormone expressed in colonic enteroendocrine L-cells but little is known about its biological function. Here, we show using RT-qPCR and in situ hybridisation that Insl5 mRNA is highly expressed in the mouse colonic mucosa, colocalised with proglucagon immunoreactivity. In comparison, mRNA for RXFP4 (the cognate receptor for INSL5) is expressed in various mouse tissues, including the intestinal tract. We show that the human enteroendocrine L-cell model NCI-H716 cell line, and goblet-like colorectal cell lines SW1463 and LS513 endogenously express RXFP4. Stimulation of NCI-H716 cells with INSL5 produced phosphorylation of ERK1/2 (Thr202/Tyr204), AKT (Thr308 and Ser473) and S6RP (Ser235/236) and inhibited cAMP production but did not stimulate Ca2+ release. Acute INSL5 treatment had no effect on GLP-1 secretion mediated by carbachol or insulin, but modestly inhibited forskolin stimulated GLP-1 secretion in NCI-H716 cells. However, chronic INSL5 pre treatment (18 h) increased basal GLP-1 secretion and prevented the inhibitory effect of acute INSL5 administration. LS513 cells were found to be unresponsive to INSL5 despite expressing RXFP4 Another enteroendocrine L-cell model, mouse GLUTag cells did not express detectable levels of Rxfp4 and were unresponsive to INSL5. This study provides novel insights into possible autocrine/paracrine roles of INSL5 in the intestinal tract. PMID- 29535184 TI - The invasin D protein from Yersinia pseudotuberculosis selectively binds the Fab region of host antibodies and affects colonization of the intestine. AB - Yersinia pseudotuberculosis is a Gram-negative bacterium and zoonotic pathogen responsible for a wide range of diseases, ranging from mild diarrhea, enterocolitis, lymphatic adenitis to persistent local inflammation. The Y. pseudotuberculosis invasin D (InvD) molecule belongs to the invasin (InvA)-type autotransporter proteins, but its structure and function remain unknown. In this study, we present the first crystal structure of InvD, analyzed its expression and function in a murine infection model, and identified its target molecule in the host. We found that InvD is induced at 37 degrees C and expressed in vivo 2 4 days after infection, indicating that InvD is a virulence factor. During infection, InvD was expressed in all parts of the intestinal tract, but not in deeper lymphoid tissues. The crystal structure of the C-terminal adhesion domain of InvD revealed a distinct Ig-related fold that, apart from the canonical beta sheets, comprises various modifications of and insertions into the Ig-core structure. We identified the Fab fragment of host-derived IgG/IgA antibodies as the target of the adhesion domain. Phage display panning and flow cytometry data further revealed that InvD exhibits a preferential binding specificity toward antibodies with VH3/VK1 variable domains and that it is specifically recruited to a subset of B cells. This finding suggests that InvD modulates Ig functions in the intestine and affects direct interactions with a subset of cell surface exposed B-cell receptors. In summary, our results provide extensive insights into the structure of InvD and its specific interaction with the target molecule in the host. PMID- 29535185 TI - The TatA component of the twin-arginine translocation system locally weakens the cytoplasmic membrane of Escherichia coli upon protein substrate binding. AB - The twin-arginine translocation (Tat) system that comprises the TatA, TatB, and TatC components transports folded proteins across energized membranes of prokaryotes and plant plastids. It is not known, however, how the transport of this protein cargo is achieved. Favored models suggest that the TatA component supports transport by weakening the membrane upon full translocon assembly. Using Escherichia coli as a model organism, we now demonstrate in vivo that the N terminus of TatA can indeed destabilize the membrane, resulting in a lowered membrane energization in growing cells. We found that in full-length TatA, this effect is counterbalanced by its amphipathic helix. Consistent with these observations, the TatA N terminus induced proton leakage in vitro, indicating membrane destabilization. Fluorescence quenching data revealed that substrate binding causes the TatA hinge region and the N-terminal part of the TatA amphipathic helix to move toward the membrane surface. In the presence of TatBC, substrate binding also reduced the exposure of a specific region in the amphipathic helix, indicating a participation of TatBC. Of note, the substrate induced reorientation of the TatA amphipathic helix correlated with detectable membrane weakening. We therefore propose a two-state model in which membrane destabilizing effects of the short TatA membrane anchor are compensated by the membrane-immersed N-terminal part of the amphipathic helix in a resting state. We conclude that substrate binding to TatABC complexes switches the position of the amphipathic helix, which locally weakens the membrane on demand to allow substrate translocation across the membrane. PMID- 29535186 TI - G protein betagamma subunits directly interact with and activate phospholipase Cepsilon. AB - Phospholipase C (PLC) enzymes hydrolyze membrane phosphatidylinositol 4,5 bisphosphate (PIP2) and regulate Ca2+ and protein kinase signaling in virtually all mammalian cell types. Chronic activation of the PLCepsilon isoform downstream of G protein-coupled receptors (GPCRs) contributes to the development of cardiac hypertrophy. We have previously shown that PLCepsilon-catalyzed hydrolysis of Golgi-associated phosphatidylinositol 4-phosphate (PI4P) in cardiac myocytes depends on G protein betagamma subunits released upon stimulation with endothelin 1. PLCepsilon binds and is directly activated by Ras family small GTPases, but whether they directly interact with Gbetagamma has not been demonstrated. To identify PLCepsilon domains that interact with Gbetagamma, here we designed various single substitutions and truncations of WT PLCepsilon and tested them for activation by Gbetagamma in transfected COS-7 cells. Deletion of only a single domain in PLCepsilon was not sufficient to completely block its activation by Gbetagamma, but blocked activation by Ras. Simultaneous deletion of the C terminal RA2 domain and the N-terminal CDC25 and cysteine-rich domains completely abrogated PLCepsilon activation by Gbetagamma, but activation by the GTPase Rho was retained. In vitro reconstitution experiments further revealed that purified Gbetagamma directly interacts with a purified fragment of PLCepsilon (PLCepsilon PH-RA2) and increases PIP2 hydrolysis. Deletion of the RA2 domain decreased Gbetagamma binding and eliminated Gbetagamma stimulation of PIP2 hydrolysis. These results provide first evidence that Gbetagamma directly interacts with PLCepsilon and yield insights into the mechanism by which betagamma subunits activate PLCepsilon. PMID- 29535187 TI - The Hcp-like protein HilE inhibits homodimerization and DNA binding of the virulence-associated transcriptional regulator HilD in Salmonella. AB - HilD is an AraC-like transcriptional regulator that plays a central role in Salmonella virulence. HilD controls the expression of the genes within the Salmonella pathogenicity island 1 (SPI-1) and of several genes located outside SPI-1, which are mainly required for Salmonella invasion of host cells. The expression, amount, and activity of HilD are tightly controlled by the activities of several factors. The HilE protein represses the expression of the SPI-1 genes through its interaction with HilD; however, the mechanism by which HilE affects HilD is unknown. In this study, we used genetic and biochemical assays revealing how HilE controls the transcriptional activity of HilD. We found that HilD needs to assemble in homodimers to induce expression of its target genes. Our results further indicated that HilE individually interacts with each the central and the C-terminal HilD regions, mediating dimerization and DNA binding, respectively. We also observed that these interactions consistently inhibit HilD dimerization and DNA binding. Interestingly, a computational analysis revealed that HilE shares sequence and structural similarities with Hcp proteins, which act as structural components of type 6 secretion systems in Gram-negative bacteria. In conclusion, our results uncover the molecular mechanism by which the Hcp-like protein HilE controls dimerization and DNA binding of the virulence-promoting transcriptional regulator HilD. Our findings may indicate that HilE's activity represents a functional adaptation during the evolution of Salmonella pathogenicity. PMID- 29535188 TI - Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions. AB - Dystrophin, encoded by the DMD gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the DMD gene disrupting the reading frame prevent dystrophin production and result in severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophin's central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin family proteins. However, the effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain, as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exons 45-47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs toward the goal of a successful gene therapy for DMD. PMID- 29535189 TI - Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d. AB - N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes, playing crucial roles in multiple biological processes. m6A is catalyzed by the activity of methyltransferase-like 3 (Mettl3), which depends on additional proteins whose precise functions remain poorly understood. Here we identified Zc3h13 (zinc finger CCCH domain-containing protein 13)/Flacc [Fl(2)d-associated complex component] as a novel interactor of m6A methyltransferase complex components in Drosophila and mice. Like other components of this complex, Flacc controls m6A levels and is involved in sex determination in Drosophila We demonstrate that Flacc promotes m6A deposition by bridging Fl(2)d to the mRNA binding factor Nito. Altogether, our work advances the molecular understanding of conservation and regulation of the m6A machinery. PMID- 29535190 TI - Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification. AB - Cis-regulatory modules (CRMs) are defined by unique combinations of transcription factor-binding sites. Emerging evidence suggests that the number, affinity, and organization of sites play important roles in regulating enhancer output and, ultimately, gene expression. Here, we investigate how the cis-regulatory logic of a tissue-specific CRM responsible for even-skipped (eve) induction during cardiogenesis organizes the competing inputs of two E-twenty-six (ETS) members: the activator Pointed (Pnt) and the repressor Yan. Using a combination of reporter gene assays and CRISPR-Cas9 gene editing, we suggest that Yan and Pnt have distinct syntax preferences. Not only does Yan prefer high-affinity sites, but an overlapping pair of such sites is necessary and sufficient for Yan to tune Eve expression levels in newly specified cardioblasts and block ectopic Eve induction and cell fate specification in surrounding progenitors. Mechanistically, the efficient Yan recruitment promoted by this high-affinity ETS supersite not only biases Yan-Pnt competition at the specific CRM but also organizes Yan-repressive complexes in three dimensions across the eve locus. Taken together, our results uncover a novel mechanism by which differential interpretation of CRM syntax by a competing repressor-activator pair can confer both specificity and robustness to developmental transitions. PMID- 29535191 TI - Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation. AB - Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GABARAPL1 (but not other autophagy genes) and p62, which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of p62 or GABARAPL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce p62 expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions. PMID- 29535192 TI - Transmission of integrin beta7 transmembrane domain topology enables gut lymphoid tissue development. AB - Integrin activation regulates adhesion, extracellular matrix assembly, and cell migration, thereby playing an indispensable role in development and in many pathological processes. A proline mutation in the central integrin beta3 transmembrane domain (TMD) creates a flexible kink that uncouples the topology of the inner half of the TMD from the outer half. In this study, using leukocyte integrin alpha4beta7, which enables development of gut-associated lymphoid tissue (GALT), we examined the biological effect of such a proline mutation and report that it impairs agonist-induced talin-mediated activation of integrin alpha4beta7, thereby inhibiting rolling lymphocyte arrest, a key step in transmigration. Furthermore, the alpha4beta7(L721P) mutation blocks lymphocyte homing to and development of the GALT. These studies show that impairing the ability of an integrin beta TMD to transmit talin-induced TMD topology inhibits agonist-induced physiological integrin activation and biological function in development. PMID- 29535193 TI - Motor axon navigation relies on Fidgetin-like 1-driven microtubule plus end dynamics. AB - During neural circuit assembly, extrinsic signals are integrated into changes in growth cone (GC) cytoskeleton underlying axon guidance decisions. Microtubules (MTs) were shown to play an instructive role in GC steering. However, the numerous actors required for MT remodeling during axon navigation and their precise mode of action are far from being deciphered. Using loss- and gain-of function analyses during zebrafish development, we identify in this study the meiotic clade adenosine triphosphatase Fidgetin-like 1 (Fignl1) as a key GC enriched MT-interacting protein in motor circuit wiring and larval locomotion. We show that Fignl1 controls GC morphology and behavior at intermediate targets by regulating MT plus end dynamics and growth directionality. We further reveal that alternative translation of Fignl1 transcript is a sophisticated mechanism modulating MT dynamics: a full-length isoform regulates MT plus end-tracking protein binding at plus ends, whereas shorter isoforms promote their depolymerization beneath the cell cortex. Our study thus pinpoints Fignl1 as a multifaceted key player in MT remodeling underlying motor circuit connectivity. PMID- 29535194 TI - Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single Cell RNA Sequencing. AB - Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, with one characterized viral reservoir being hematopoietic cells. Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive transcriptome RNA sequencing (RNA-seq) atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistence in vivo is prevalent in diverse tissues. Notably, we find only viral transcripts that resemble gene expression during various stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single-cell RNA-seq and a tractable experimental latency model. In contrast to some current views on latency, we also find no evidence for any highly restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program, albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression.IMPORTANCE Human cytomegalovirus is a prevalent pathogen, infecting most of the population worldwide and establishing lifelong latency in its hosts. Although reactivation from latency causes significant morbidity and mortality in immunocompromised hosts, our molecular understanding of the latent state remains limited. Here, we examine the viral gene expression during natural and experimental latent HCMV infection on a transcriptome-wide level. In contrast to the classical views on herpesvirus latency, we find no evidence for a restricted latency-associated viral gene expression program. Instead, we reveal that latency gene expression largely resembles a late lytic viral profile, albeit at much lower levels of expression. Taken together, our data transform the current view of HCMV persistence and suggest that latency is mainly governed by quantitative rather than qualitative changes in viral gene expression. PMID- 29535195 TI - Predicting the Susceptibility of Meningococcal Serogroup B Isolates to Bactericidal Antibodies Elicited by Bivalent rLP2086, a Novel Prophylactic Vaccine. AB - Bivalent rLP2086 (Trumenba), a vaccine for prevention of Neisseria meningitidis serogroup B (NmB) disease, was licensed for use in adolescents and young adults after it was demonstrated that it elicits antibodies that initiate complement mediated killing of invasive NmB isolates in a serum bactericidal assay with human complement (hSBA). The vaccine consists of two factor H binding proteins (fHBPs) representing divergent subfamilies to ensure broad coverage. Although it is the surrogate of efficacy, an hSBA is not suitable for testing large numbers of strains in local laboratories. Previously, an association between the in vitro fHBP surface expression level and the susceptibility of NmB isolates to killing was observed. Therefore, a flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed and validated by using an antibody that binds to all fHBP variants from both fHBP subfamilies and accurately quantitates the level of fHBP expressed on the cell surface of NmB isolates with mean fluorescence intensity as the readout. Two collections of invasive NmB isolates (n = 1,814, n = 109) were evaluated in the assay, with the smaller set also tested in hSBAs using individual and pooled human serum samples from young adults vaccinated with bivalent rLP2086. From these data, an analysis based on fHBP variant prevalence in the larger 1,814-isolate set showed that >91% of all meningococcal serogroup B isolates expressed sufficient levels of fHBP to be susceptible to bactericidal killing by vaccine-induced antibodies.IMPORTANCE Bivalent rLP2086 (Trumenba) vaccine, composed of two factor H binding proteins (fHBPs), was recently licensed for the prevention of N. meningitidis serogroup B (NmB) disease in individuals 10 to 25 years old in the United States. This study evaluated a large collection of NmB isolates from the United States and Europe by using a flow cytometric MEASURE assay to quantitate the surface expression of the vaccine antigen fHBP. We find that expression levels and the proportion of strains above the level associated with susceptibility in an hSBA are generally consistent across these geographic regions. Thus, the assay can be used to predict which NmB isolates are susceptible to killing in the hSBA and therefore is able to demonstrate an fHBP vaccine-induced bactericidal response. This work significantly advances our understanding of the potential for bivalent rLP2086 to provide broad coverage against diverse invasive-disease-causing NmB isolates. PMID- 29535196 TI - Erratum for Mor et al., "Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids". PMID- 29535197 TI - Serum High-Mobility-Group Box 1 as a Biomarker and a Therapeutic Target during Respiratory Virus Infections. AB - Host-derived "danger-associated molecular patterns" (DAMPs) contribute to innate immune responses and serve as markers of disease progression and severity for inflammatory and infectious diseases. There is accumulating evidence that generation of DAMPs such as oxidized phospholipids and high-mobility-group box 1 (HMGB1) during influenza virus infection leads to acute lung injury (ALI). Treatment of influenza virus-infected mice and cotton rats with the Toll-like receptor 4 (TLR4) antagonist Eritoran blocked DAMP accumulation and ameliorated influenza virus-induced ALI. However, changes in systemic HMGB1 kinetics during the course of influenza virus infection in animal models and humans have yet to establish an association of HMGB1 release with influenza virus infection. To this end, we used the cotton rat model that is permissive to nonadapted strains of influenza A and B viruses, respiratory syncytial virus (RSV), and human rhinoviruses (HRVs). Serum HMGB1 levels were measured by an enzyme-linked immunosorbent assay (ELISA) prior to infection until day 14 or 18 post-infection. Infection with either influenza A or B virus resulted in a robust increase in serum HMGB1 levels that decreased by days 14 to 18. Inoculation with the live attenuated vaccine FluMist resulted in HMGB1 levels that were significantly lower than those with infection with live influenza viruses. RSV and HRVs showed profiles of serum HMGB1 induction that were consistent with their replication and degree of lung pathology in cotton rats. We further showed that therapeutic treatment with Eritoran of cotton rats infected with influenza B virus significantly blunted serum HMGB1 levels and improved lung pathology, without inhibiting virus replication. These findings support the use of drugs that block HMGB1 to combat influenza virus-induced ALI.IMPORTANCE Influenza virus is a common infectious agent causing serious seasonal epidemics, and there is urgent need to develop an alternative treatment modality for influenza virus infection. Recently, host-derived DAMPs, such as oxidized phospholipids and HMGB1, were shown to be generated during influenza virus infection and cause ALI. To establish a clear link between influenza virus infection and HMGB1 as a biomarker, we have systematically analyzed temporal patterns of serum HMGB1 release in cotton rats infected with nonadapted strains of influenza A and B viruses and compared these patterns with a live attenuated influenza vaccine and infection by other respiratory viruses. Towards development of a new therapeutic modality, we show herein that blocking serum HMGB1 levels by Eritoran improves lung pathology in influenza B virus-infected cotton rats. Our study is the first report of systemic HMGB1 as a potential biomarker of severity in respiratory virus infections and confirms that drugs that block virus-induced HMGB1 ameliorate ALI. PMID- 29535198 TI - Antigenic Variation in Streptococcus pneumoniae PspC Promotes Immune Escape in the Presence of Variant-Specific Immunity. AB - Genomic analysis reveals extensive sequence variation and hot spots of recombination in surface proteins of Streptococcus pneumoniae While this phenomenon is commonly attributed to diversifying selection by host immune responses, there is little mechanistic evidence for the hypothesis that diversification of surface protein antigens produces an immune escape benefit during infection with S. pneumoniae Here, we investigate the biological significance of sequence variation within the S. pneumoniae cell wall-associated pneumococcal surface protein C (PspC) protein antigen. Using pspC allelic diversity observed in a large pneumococcal collection, we produced variant specific protein constructs that span the sequence variability within the pspC locus. We show that antibodies raised against these PspC constructs are variant specific and prevent association between PspC and the complement pathway mediator, human factor H. We found that PspC variants differ in their capacity to bind factor H, suggesting that sequence variation within pspC reflects differences in biological function. Finally, in an antibody-dependent opsonophagocytic assay, S. pneumoniae expressing a PspC variant matching the antibody specificity was killed efficiently. In contrast, killing efficacy was not evident against S. pneumoniae expressing mismatched PspC variants. Our data suggest that antigenic variation within the PspC antigen promotes immune evasion and could confer a fitness benefit during infection.IMPORTANCE Loci encoding surface protein antigens in Streptococcus pneumoniae are highly polymorphic. It has become a truism that these polymorphisms are the outcome of selective pressure on S. pneumoniae to escape host immunity. However, there is little mechanistic evidence to support the hypothesis that diversifying protein antigens produces a benefit for the bacteria. Using the highly diverse pspC locus, we have now characterized the functional and immune implications of sequence diversity within the PspC protein. We have characterized the spectrum of biological function among diverse PspC variants and show that pspC sequence diversity reflects functional differences. Further, we show that sequence variation in PspC confers an immune escape benefit in the presence of anti-PspC variant-specific immunity. Overall, the results of our studies provide insights into the functional implications of protein sequence diversity and the role of variant specific immunity in its maintenance. PMID- 29535199 TI - Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils. AB - Carbapenem-resistant Klebsiella pneumoniae is a problem worldwide. A carbapenem resistant K. pneumoniae lineage classified as multilocus sequence type 258 (ST258) is prominent in the health care setting in many regions of the world, including the United States. ST258 strains can be resistant to virtually all clinically useful antibiotics; treatment of infections caused by these organisms is difficult, and mortality is high. As a step toward promoting development of new therapeutics for ST258 infections, we tested the ability of rabbit antibodies specific for ST258 capsule polysaccharide to enhance human serum bactericidal activity and promote phagocytosis and killing of these bacteria by human neutrophils. We first demonstrated that an isogenic wzy deletion strain is significantly more susceptible to killing by human heparinized blood, serum, and neutrophils than a wild-type ST258 strain. Consistent with the importance of capsule as an immune evasion molecule, rabbit immune serum and purified IgG specific for ST258 capsule polysaccharide type 2 (CPS2) enhanced killing by human blood and serum in vitro Moreover, antibodies specific for CPS2 promoted phagocytosis and killing of ST258 by human neutrophils. Collectively, our findings suggest that ST258 CPS2 is a viable target for immunoprophylactics and/or therapeutics.IMPORTANCE Infections caused by carbapenem-resistant K. pneumoniae are difficult to treat, and mortality is high. New prophylactic approaches and/or therapeutic measures are needed to prevent or treat infections caused by these multidrug-resistant bacteria. A strain of carbapenem-resistant K. pneumoniae, classified by multilocus sequence typing as ST258, is present in many regions of the world and is the most prominent carbapenem-resistant K. pneumoniae lineage in the United States. Here we show that rabbit antibodies specific for capsule polysaccharide of ST258 significantly enhance human serum bactericidal activity and promote phagocytosis and killing of this pathogen by human neutrophils. These studies have provided strong support for the idea that development of an immunotherapy (vaccine) for carbapenem-resistant K. pneumoniae infections is feasible and has merit. PMID- 29535200 TI - Characterization of an M-Cluster-Substituted Nitrogenase VFe Protein. AB - The Mo- and V-nitrogenases are two homologous members of the nitrogenase family that are distinguished mainly by the presence of different heterometals (Mo or V) at their respective cofactor sites (M- or V-cluster). However, the V-nitrogenase is ~600-fold more active than its Mo counterpart in reducing CO to hydrocarbons at ambient conditions. Here, we expressed an M-cluster-containing, hybrid V nitrogenase in Azotobacter vinelandii and compared it to its native, V-cluster containing counterpart in order to assess the impact of protein scaffold and cofactor species on the differential reactivities of Mo- and V-nitrogenases toward CO. Housed in the VFe protein component of V-nitrogenase, the M-cluster displayed electron paramagnetic resonance (EPR) features similar to those of the V-cluster and demonstrated an ~100-fold increase in hydrocarbon formation activity from CO reduction, suggesting a significant impact of protein environment on the overall CO-reducing activity of nitrogenase. On the other hand, the M-cluster was still ~6-fold less active than the V-cluster in the same protein scaffold, and it retained its inability to form detectable amounts of methane from CO reduction, illustrating a fine-tuning effect of the cofactor properties on this nitrogenase-catalyzed reaction. Together, these results provided important insights into the two major determinants for the enzymatic activity of CO reduction while establishing a useful framework for further elucidation of the essential catalytic elements for the CO reactivity of nitrogenase.IMPORTANCE This is the first report on the in vivo generation and in vitro characterization of an M-cluster-containing V-nitrogenase hybrid. The "normalization" of the protein scaffold to that of the V-nitrogenase permits a direct comparison between the cofactor species of the Mo- and V-nitrogenases (M- and V-clusters) in CO reduction, whereas the discrepancy between the protein scaffolds of the Mo- and V-nitrogenases (MoFe and VFe proteins) housing the same cofactor (M-cluster) allows for an effective assessment of the impact of the protein environment on the CO reactivity of nitrogenase. The results of this study provide a first look into the "weighted" contributions of protein environment and cofactor properties to the overall activity of CO reduction; more importantly, they establish a useful platform for further investigation of the structural elements attributing to the CO-reducing activity of nitrogenase. PMID- 29535202 TI - Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn's Disease Patients. AB - The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn's disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects' fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects' baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker.IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-alpha) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases. PMID- 29535201 TI - Insights into the Evolution of Host Association through the Isolation and Characterization of a Novel Human Periodontal Pathobiont, Desulfobulbus oralis. AB - The human oral microbiota encompasses representatives of many bacterial lineages that have not yet been cultured. Here we describe the isolation and characterization of previously uncultured Desulfobulbus oralis, the first human associated representative of its genus. As mammalian-associated microbes rarely have free-living close relatives, D. oralis provides opportunities to study how bacteria adapt and evolve within a host. This sulfate-reducing deltaproteobacterium has adapted to the human oral subgingival niche by curtailing its physiological repertoire, losing some biosynthetic abilities and metabolic independence, and by dramatically reducing environmental sensing and signaling capabilities. The genes that enable free-living Desulfobulbus to synthesize the potent neurotoxin methylmercury were also lost by D. oralis, a notably positive outcome of host association. However, horizontal gene acquisitions from other members of the microbiota provided novel mechanisms of interaction with the human host, including toxins like leukotoxin and hemolysins. Proteomic and transcriptomic analysis revealed that most of those factors are actively expressed, including in the subgingival environment, and some are secreted. Similar to other known oral pathobionts, D. oralis can trigger a proinflammatory response in oral epithelial cells, suggesting a direct role in the development of periodontal disease.IMPORTANCE Animal-associated microbiota likely assembled as a result of numerous independent colonization events by free living microbes followed by coevolution with their host and other microbes. Through specific adaptation to various body sites and physiological niches, microbes have a wide range of contributions, from beneficial to disease causing. Desulfobulbus oralis provides insights into genomic and physiological transformations associated with transition from an open environment to a host dependent lifestyle and the emergence of pathogenicity. Through a multifaceted mechanism triggering a proinflammatory response, D. oralis is a novel periodontal pathobiont. Even though culture-independent approaches can provide insights into the potential role of the human microbiome "dark matter," cultivation and experimental characterization remain important to studying the roles of individual organisms in health and disease. PMID- 29535203 TI - Human Memory B Cells Targeting Staphylococcus aureus Exotoxins Are Prevalent with Skin and Soft Tissue Infection. AB - Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. Although S. aureus possesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; and S. aureus isolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or more S. aureus antigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B cell memory or long-lived plasma cells. However, memory B cells reactive with a range of S. aureus antigens were prevalent at both acute-phase and convalescent phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selected S. aureus exotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti-S. aureus memory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses.IMPORTANCE The contribution of B-cell memory and long term antibody responses to host defenses against S. aureus exotoxins remains poorly understood. Our studies confirmed that infection did not commonly lead to enhanced long-term humoral responses. Whereas circulating memory B cells against S. aureus secreted exotoxins were prevalent, they were dominated by cross reactivity with structurally related leucocidin subunits, consistent with recognition of conserved epitopes. These findings also provide the first evidence of a relationship between the reactivity of antistaphylococcal circulating memory B cells and serum antibody levels. In general, infection was not associated with a global defect in B-cell memory for S. aureus secreted factors, and responses were highly dominated by cross-reactivity to structurally related exotoxins, which arguably may alone be suboptimal in providing host defenses. Our studies illuminate aspects of the S. aureus-host relationship that may better inform strategies for the development of an effective protective vaccine. PMID- 29535206 TI - A Comparison of Resident Self-Perception and Pediatric Hospitalist Perceptions of the Supervisory Needs of New Interns. AB - OBJECTIVES: The Association of American Medical Colleges published a list of entrustable professional activities (EPAs) that graduating medical students should be able to perform on day 1 of residency without direct supervision. We sought to explore the perceptions of residents and pediatric hospitalists about the level of supervision new interns need in conducting these EPAs. METHODS: An electronic survey was sent to pediatric hospitalists who supervise interns in a large pediatric residency program in which they were asked to rate the amount of supervision they perceive new interns need when performing 11 EPAs. Another survey was sent to residents in which they were asked how much supervision they needed at the beginning of their intern year when performing the same EPAs. Hospitalist and resident responses were compared. RESULTS: The majority of hospitalists thought new interns could perform only 5 of the 11 EPAs without direct supervision. For 5 of the EPAs, residents' perceptions of their own abilities to perform the EPA independently as interns were significantly greater than the hospitalists' perceptions of interns' abilities. For example, 91% of residents thought they were able to recommend and interpret common diagnostic and screening tests when they were interns without direct supervision, compared with only 30% of attending physicians (P < .001). CONCLUSIONS: Hospitalists and residents in a pediatric residency training program reported that new interns were not consistently able to perform the Association of American Medical Colleges' core EPAs without supervision. Furthermore, residents and pediatric hospitalists perceived new interns' abilities to perform the EPAs without direct supervision significantly differently. PMID- 29535204 TI - Interactions between the Hepatitis C Virus Nonstructural 2 Protein and Host Adaptor Proteins 1 and 4 Orchestrate Virus Release. AB - Hepatitis C virus (HCV) spreads via secreted cell-free particles or direct cell to-cell transmission. Yet, virus-host determinants governing differential intracellular trafficking of cell-free- and cell-to-cell-transmitted virus remain unknown. The host adaptor proteins (APs) AP-1A, AP-1B, and AP-4 traffic in post Golgi compartments, and the latter two are implicated in basolateral sorting. We reported that AP-1A mediates HCV trafficking during release, whereas the endocytic adaptor AP-2 mediates entry and assembly. We demonstrated that the host kinases AAK1 and GAK regulate HCV infection by controlling these clathrin associated APs. Here, we sought to define the roles of AP-4, a clathrin independent adaptor; AP-1A; and AP-1B in HCV infection. We screened for interactions between HCV proteins and the MU subunits of AP-1A, AP-1B, and AP-4 by mammalian cell-based protein fragment complementation assays. The nonstructural 2 (NS2) protein emerged as an interactor of these adaptors in this screening and by coimmunoprecipitations in HCV-infected cells. Two previously unrecognized dileucine-based motifs in the NS2 C terminus mediated AP binding and HCV release. Infectivity and coculture assays demonstrated that while all three adaptors mediate HCV release and cell-free spread, AP-1B and AP-4, but not AP-1A, mediate cell-to-cell spread. Live-cell imaging revealed HCV cotrafficking with AP 1A, AP-1B, and AP-4 and that AP-4 mediates HCV trafficking in a post-Golgi compartment. Lastly, HCV cell-to-cell spread was regulated by AAK1 and GAK and thus susceptible to treatment with AAK1 and GAK inhibitors. These data provide a mechanistic understanding of HCV trafficking in distinct release pathways and reveal a requirement for APs in cell-to-cell viral spread.IMPORTANCE HCV spreads via cell-free infection or cell-to-cell contact that shields it from antibody neutralization, thereby facilitating viral persistence. Yet, factors governing this differential sorting remain unknown. By integrating proteomic, RNA interference, genetic, live-cell imaging, and pharmacological approaches, we uncover differential coopting of host adaptor proteins (APs) to mediate HCV traffic at distinct late steps of the viral life cycle. We reported that AP-1A and AP-2 mediate HCV trafficking during release and assembly, respectively. Here, we demonstrate that dileucine motifs in the NS2 protein mediate AP-1A, AP-1B, and AP-4 binding and cell-free virus release. Moreover, we reveal that AP-4, an adaptor not previously implicated in viral infections, mediates cell-to-cell spread and HCV trafficking. Lastly, we demonstrate cell-to-cell spread regulation by AAK1 and GAK, host kinases controlling APs, and susceptibility to their inhibitors. This study provides mechanistic insights into virus-host determinants that facilitate HCV trafficking, with potential implications for pathogenesis and antiviral agent design. PMID- 29535205 TI - The Biosynthesis of Lipooligosaccharide from Bacteroides thetaiotaomicron. AB - Lipopolysaccharide (LPS), a cell-associated glycolipid that makes up the outer leaflet of the outer membrane of Gram-negative bacteria, is a canonical mediator of microbe-host interactions. The most prevalent Gram-negative gut bacterial taxon, Bacteroides, makes up around 50% of the cells in a typical Western gut; these cells harbor ~300 mg of LPS, making it one of the highest-abundance molecules in the intestine. As a starting point for understanding the biological function of Bacteroides LPS, we have identified genes in Bacteroides thetaiotaomicron VPI 5482 involved in the biosynthesis of its lipid A core and glycan, generated mutants that elaborate altered forms of LPS, and used matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry to interrogate the molecular features of these variants. We demonstrate, inter alia, that the glycan does not appear to have a repeating unit, and so this strain produces lipooligosaccharide (LOS) rather than LPS. This result contrasts with Bacteroides vulgatus ATCC 8482, which by SDS-PAGE analysis appears to produce LPS with a repeating unit. Additionally, our identification of the B. thetaiotaomicron LOS oligosaccharide gene cluster allowed us to identify similar clusters in other Bacteroides species. Our work lays the foundation for developing a structure-function relationship for Bacteroides LPS/LOS in the context of host colonization.IMPORTANCE Much is known about the bacterial species and genes that make up the human microbiome, but remarkably little is known about the molecular mechanisms through which the microbiota influences host biology. A well-known mechanism by which bacteria influence the host centers around lipopolysaccharide (LPS), a component of the Gram-negative bacterial outer membrane. Pathogen-derived LPS is a potent ligand for host receptor Toll-like receptor 4, which plays an important role in sensing bacteria as part of the innate immune response. Puzzlingly, the most common genus of human gut bacteria, Bacteroides, produces LPS but does not elicit a potent proinflammatory response. Previous work showing that Bacteroides LPS differs structurally from pathogen derived LPS suggested the outlines of an explanation. Here, we take the next step, elucidating the biosynthetic pathway for Bacteroides LPS and generating mutants in the process that will be of great use in understanding how this molecule modulates the host immune response. PMID- 29535207 TI - Gain a child, lose a tooth? Using natural experiments to distinguish between fact and fiction. AB - BACKGROUND: Dental diseases are among the most frequent diseases globally and tooth loss imposes a substantial burden on peoples' quality of life. Non experimental evidence suggests that individuals with more children have more missing teeth than individuals with fewer children, but until now there is no causal evidence for or against this. METHODS: Using a Two-Stage Least Squares (2SLS) instrumental variables approach and large-scale cross-sectional data from the Survey of Health, Ageing, and Retirement in Europe (study sample: 34 843 non institutionalised individuals aged 50+ from 14 European countries and Israel; data were collected in 2013), we investigated the causal relationship between the number of biological children and their parents' number of missing natural teeth. Thereby, we exploited random natural variation in family size resulting from (i) the birth of multiples vs singletons, and (ii) the sex composition of the two first-born children (increased likelihood of a third child if the two first-born children have the same sex). RESULTS: 2SLS regressions detected a strong causal relationship between the number of children and teeth for women but not for men when an additional birth occurred after the first two children had the same sex. Women then had an average of 4.27 (95% CI: 1.08 to 7.46) fewer teeth than women without an additional birth whose first two children had different sexes. CONCLUSIONS: This study provides novel evidence for causal links between the number of children and the number of missing teeth. An additional birth might be detrimental to the mother's but not the father's oral health. PMID- 29535208 TI - Matrix elasticity regulates mesenchymal stem cell chemotaxis. AB - Efficient homing of human mesenchymal stem cells (hMSCs) is likely to be dictated by a combination of physical and chemical factors present in the microenvironment. However, crosstalk between the physical and chemical cues remains incompletely understood. Here, we address this question by probing the efficiency of epidermal growth factor (EGF)-induced hMSC chemotaxis on substrates of varying stiffness (3, 30 and 600 kPa) inside a polydimethylsiloxane (PDMS) microfluidic device. Chemotactic speed was found to be the sum of a stiffness dependent component and a chemokine concentration-dependent component. While the stiffness-dependent component scaled inversely with stiffness, the chemotactic component was independent of stiffness. Faster chemotaxis on the softest 3 kPa substrates is attributed to a combination of weaker adhesions and higher protrusion rate. While chemotaxis was mildly sensitive to contractility inhibitors, suppression of chemotaxis upon actin depolymerization demonstrates the role of actin-mediated protrusions in driving chemotaxis. In addition to highlighting the collective influence of physical and chemical cues in chemotactic migration, our results suggest that hMSC homing is more efficient on softer substrates. PMID- 29535209 TI - Identification and characterisation of a cryptic Golgi complex in Naegleria gruberi. AB - Although the Golgi complex has a conserved morphology of flattened stacked cisternae in most eukaryotes, it has lost the stacked organisation in several lineages, raising the question of what range of morphologies is possible for the Golgi. In order to understand this diversity, it is necessary to characterise the Golgi in many different lineages. Here, we identify the Golgi complex in Naegleria, one of the first descriptions of an unstacked Golgi organelle in a non parasitic eukaryote, other than fungi. We provide a comprehensive list of Golgi associated membrane trafficking genes encoded in two species of Naegleria and show that nearly all are expressed in mouse-passaged N. fowleri cells. We then study distribution of the Golgi marker (Ng)CopB by fluorescence in Naegleria gruberi, identifying membranous structures that are disrupted by Brefeldin A treatment, consistent with Golgi localisation. Confocal and immunoelectron microscopy reveals that NgCOPB localises to tubular membranous structures. Our data identify the Golgi organelle for the first time in this major eukaryotic lineage, and provide the rare example of a tubular morphology, representing an important sampling point for the comparative understanding of Golgi organellar diversity.This article has an associated First Person interview with the first author of the paper. PMID- 29535210 TI - Rapid production of pure recombinant actin isoforms in Pichia pastoris. AB - Actins are major eukaryotic cytoskeletal proteins, and they are involved in many important cell functions, including cell division, cell polarity, wound healing and muscle contraction. Despite obvious drawbacks, muscle actin, which is easily purified, is used extensively for biochemical studies of the non-muscle actin cytoskeleton. Here, we report a rapid and cost-effective method to purify heterologous actins expressed in the yeast Pichia pastoris Actin is expressed as a fusion with the actin-binding protein thymosin beta4 and purified by means of an affinity tag introduced in the fusion. Following cleavage of thymosin beta4 and the affinity tag, highly purified functional full-length actin is liberated. We purify actins from Saccharomycescerevisiae and Schizosaccharomycespombe, and the beta- and gamma-isoforms of human actin. We also report a modification of the method that facilitates expression and purification of arginylated actin, a form of actin thought to regulate dendritic actin networks in mammalian cells. The methods we describe can be performed in all laboratories equipped for molecular biology, and should greatly facilitate biochemical and cell biological studies of the actin cytoskeleton. PMID- 29535211 TI - The long tail of molecular alterations in non-small cell lung cancer: a single institution experience of next-generation sequencing in clinical molecular diagnostics. AB - BACKGROUND: Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously. AIMS: To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC. METHODS: A single-institution cohort of 535 non-squamous NSCLC was profiled using a next-generation sequencing panel targeting 22 actionable and cancer-related genes. RESULTS: 441 non-squamous NSCLC (82.4%) harboured at least one gene alteration, including 340 cases (63.6%) with clinically relevant molecular aberrations. Mutations have been detected in all but one gene (FGFR1) of the panel. Recurrent alterations were observed in KRAS, TP53, EGFR, STK11 and MET genes, whereas the remaining genes were mutated in <5% of the cases. Concurrent mutations were detected in 183 tumours (34.2%), mostly impairing KRAS or EGFR in association with TP53 alterations. CONCLUSIONS: The study highlights the feasibility of targeted next-generation sequencing in clinical setting. The majority of NSCLC harboured mutations in clinically relevant genes, thus identifying patients who might benefit from different targeted therapies. PMID- 29535212 TI - Breast cancer histologic grading using digital microscopy: concordance and outcome association. AB - AIMS: Virtual microscopy utilising digital whole slide imaging (WSI) is increasingly used in breast pathology. Histologic grade is one of the strongest prognostic factors in breast cancer (BC). This study aims at investigating the agreement between BC grading using traditional light microscopy (LM) and digital WSI with consideration of reproducibility and impact on outcome prediction. METHODS: A large (n=1675) well-characterised cohort of BC originally graded by LM was re-graded using WSI. Two separate virtual-based grading sessions (V1 and V2) were performed with a 3-month washout period. Outcome was assessed using BC specific and distant metastasis-free survival. RESULTS: The concordance between LM grading and WSI was strong (LM/WSI Cramer's V: V1=0.576, and V2=0.579). The agreement regarding grade components was as follows: tubule formation=0.538, pleomorphism=0.422 and mitosis=0.514. Greatest discordance was observed between adjacent grades, whereas high/low grade discordance was uncommon (1.5%). The intraobserver agreement for the two WSI sessions was substantial for grade (V1/V2 Cramer's V=0.676; kappa=0.648) and grade components (Cramer's V T=0.628, p=0.573 and M=0.580). Grading using both platforms showed strong association with outcome (all p values <0.001). Although mitotic scores assessed using both platforms were strongly associated with outcome, WSI tends to underestimate mitotic counts. CONCLUSIONS: Virtual microscopy is a reliable and reproducible method for assessing BC histologic grade. Regardless of the observer or assessment platform, histologic grade is a significant predictor of outcome. Continuing advances in imaging technology could potentially provide improved performance of WSI BC grading and in particular mitotic count assessment. PMID- 29535213 TI - The liver as an organ at risk for Toxoplasma transmission during transplantation: myth or reality? AB - AIM: Toxoplasmosis following liver transplant with donor-recipient mismatch is rare, but is often life-threatening. However, there are no data on the frequency of cyst carriage in the liver, nor consensual chemoprophylaxis guidelines. This study aimed at describing frequency and localisation of Toxoplasma cysts in the liver in a mouse model of chronic infection to predict the risk in liver transplantation. METHODS: Heart, brain and liver lobes of 21 mice chronically infected with Toxoplasma were collected for DNA extraction and amplification of Toxoplasma gondii rep529 sequence by real-time PCR. RESULTS: Parasite DNA was detected in the liver of 19/21 mice (90.5%), with no preferential anatomical localisation, but with higher parasite loads in the papillary process. Parasite loads in the liver were far lower than in brain and heart. The number of infected lobes was inversely correlated to the total liver weight, but was independent of the brain parasite load and of the parasite strain. CONCLUSIONS: The liver is a frequent site of cyst carriage, confirming that transplantation of an organ from a seropositive donor to seronegative recipient is at high risk for acquired toxoplasmosis. Systematic serological screening prior to transplantation and chemoprophylaxis in patients at risk are fully justified. PMID- 29535214 TI - Short preheating at 41 degrees C leads to a red blood cells count comparable to that in RET channel of Sysmex analysers in samples showing cold agglutination. AB - AIMS: The presence of cold agglutinin in blood samples can cause a spontaneous agglutination of red blood cells (RBCs) when low temperature occurs. This phenomenon causes a spurious lowering of RBC count on the automated haematological analysers that are detected by incongruous values (>=370 g/L) of the mean cellular haemoglobi concentration (MCHC). A preheating at 37 degrees C can remove the RBC agglutination generally resulting in a reliable count. It has been reported that the same result can be reached by using the optical reticulocyte (RET) channel of Sysmex analysers where the RBC count is not influenced by the presence of cold agglutinin. This study aims to evaluate these data in a larger population, with regard to environmental conditions on Sysmex analysers. We have also evaluated the influence of different thermal pretreatments on the RBC count. METHODS: This study was performed on 96 remnants of peripheral blood samples (48 with MCHC in normal range and 48 with MCHC>370 g/L) which have been analysed in different preanalytical conditions on the Sysmex analysers. RESULTS: A preheating of samples at 41 degrees C for 1 min leads to a reversibility of the cold agglutination comparable to the one observed in the RET channel and yields better results compared with 37 degrees C for 2 hours. CONCLUSIONS: None of described procedures assure the complete cold agglutination reversibility in every case. Consequently, since the haematological analysers not yet provide reliable parameters to confirm the complete resolution of agglutination, further verification of RBC count accuracy needs to be performed. PMID- 29535215 TI - Heartbeat: phenotypic heterogeneity of bicuspid aortic valve disease. PMID- 29535216 TI - Response to: 'Screening for atrial fibrillation in hospitalised geriatric patients' by Tavernier et al. PMID- 29535217 TI - Left atrial appendage occlusion in high-risk patients: doing it is better than nothing. PMID- 29535218 TI - The Authors' reply. PMID- 29535219 TI - Visualization of Breast Cancer Metabolism Using Multimodal Nonlinear Optical Microscopy of Cellular Lipids and Redox State. AB - Label-free nonlinear optical microscopy (NLOM) based on two-photon excited fluorescence (TPEF) from cofactors nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD+) is widely used for high-resolution cellular redox imaging. In this work, we combined three label-free NLOM imaging methods to quantitatively characterize breast cancer cells and their relative invasive potential: (i) TPEF optical redox ratio (ORR = FAD+/NADH + FAD+), (ii) coherent Raman scattering of cellular lipids, and (iii) second harmonic generation of extracellular matrix (ECM) collagen. 3D spheroid models of primary mammary epithelial (PME) cells and breast cancer cell lines (T47D and MDA-MB-231) were characterized based on their unique ORR and lipid volume fraction signatures. Treatment with 17beta-estradiol (E2) increased glycolysis in both PME and T47D ER+ breast cancer acini. However, PME cells displayed increased lipid content with no effect on ECM, while T47D cells had decreased lipid storage (P < 0.001) and significant reorganization of collagen. By measuring deuterated lipids synthesized from exogenously administered deuterium-labeled glucose, treatment of T47D cells with E2 increased both lipid synthesis and consumption rates. These results confirm that glucose is a significant source for the cellular synthesis of lipid in glycolytic breast cancer cells, and that the combination of cellular redox and lipid fraction imaging endpoints is a powerful approach with new and complementary information content.Significance: These findings provide unique insight into metabolic processes, revealing correlations between cancer metastasis and cellular redox state, lipid metabolism, and extracellular matrix. Cancer Res; 78(10); 2503-12. (c)2018 AACR. PMID- 29535220 TI - Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis. AB - Inhibin is a heterodimeric TGFbeta family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor specific functions remain unknown. Here, we demonstrate that the alpha subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo Inhibin-induced angiogenesis was abrogated via anti-inhibin alpha antibodies. The endothelial-specific TGFbeta receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically.Significance: Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. Cancer Res; 78(11); 2978-89. (c)2018 AACR. PMID- 29535221 TI - Organelle-Derived Acetyl-CoA Promotes Prostate Cancer Cell Survival, Migration, and Metastasis via Activation of Calmodulin Kinase II. AB - Although emerging evidence suggests a potential role of calcium/calmodulin dependent kinase II (CaMKII) in prostate cancer, its role in prostate cancer tumorigenesis is largely unknown. Here, we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes prostate cancer tumorigenesis. In human prostate cancer specimens, metastatic prostate cancer expressed higher levels of active CaMKII compared with localized prostate cancer. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of prostate cancer metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the beta-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, whereas overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle beta-oxidation and acetyl-CoA transport with cell survival, migration, and prostate cancer metastasis.Significance: This study identifies a cell metabolic pathway that promotes prostate cancer metastasis and suggests prostate cancer may be susceptible to beta-oxidation inhibitors. Cancer Res; 78(10); 2490-502. (c)2018 AACR. PMID- 29535222 TI - Shigellosis outbreak among MSM living with HIV: a case-control study in Taiwan, 2015-2016. AB - OBJECTIVES: Outbreaks of shigellosis among men who have sex with men (MSM) have been reported since the late 1990s. HIV infection is an important risk factor. Since 2014, the global shigellosis epidemic has intensified. Whether chemsex (the use of crystal methamphetamine, gamma-hydroxybutyrate or mephedrone to enhance sex) is a new risk factor has not been previously examined. METHODS: We conducted a population-based, case-control study in Taiwan. Acute shigellosis cases diagnosed during the 2015 outbreak among MSM living with HIV were compared with those without shigellosis. CD4+ counts, plasma viral load (pVL), gonorrhoea, syphilis and amoebiasis records were obtained from the Notifiable Disease Surveillance System database. We invited cases/controls to provide information on illicit drug use and sexual behaviours, using a structured questionnaire. RESULTS: Seventy-five shigellosis cases were compared with 225 controls. High pVL (>100 000 copies/mL; adjusted OR (aOR): 4.9, 95% CI 1.4 to 16.9), gonorrhoea (aOR: 29.4, 95% CI 2.3 to 340.2) and syphilis (aOR: 4.3, 95% CI 1.6 to 11.6) were independent risk factors of shigellosis. Twenty shigellosis cases and 59 controls completed the questionnaire. Oral-to-anal sex (aOR: 15.5, 95% CI 3.6 to 66.7), chemsex (aOR: 5.6, 95% CI 1.4 to 22.7) and poppers use (aOR: 10.9, 95% CI 1.9 to 64.2) within 12 months were independent behavioural risk factors of shigellosis. CONCLUSIONS: Chemsex is a new risk factor for shigellosis among MSM living with HIV, as identified in the 2015-2016 outbreak. Additional risk factors include poppers use, sexual risk behaviours and high pVL. Further studies on chemsex among MSM, which is a rising public health concern, are urgently required. PMID- 29535224 TI - Climate warming enhances snow avalanche risk in the Western Himalayas. AB - Ongoing climate warming has been demonstrated to impact the cryosphere in the Indian Himalayas, with substantial consequences for the risk of disasters, human well-being, and terrestrial ecosystems. Here, we present evidence that the warming observed in recent decades has been accompanied by increased snow avalanche frequency in the Western Indian Himalayas. Using dendrogeomorphic techniques, we reconstruct the longest time series (150 y) of the occurrence and runout distances of snow avalanches that is currently available for the Himalayas. We apply a generalized linear autoregressive moving average model to demonstrate linkages between climate warming and the observed increase in the incidence of snow avalanches. Warming air temperatures in winter and early spring have indeed favored the wetting of snow and the formation of wet snow avalanches, which are now able to reach down to subalpine slopes, where they have high potential to cause damage. These findings contradict the intuitive notion that warming results in less snow, and thus lower avalanche activity, and have major implications for the Western Himalayan region, an area where human pressure is constantly increasing. Specifically, increasing traffic on a steadily expanding road network is calling for an immediate design of risk mitigation strategies and disaster risk policies to enhance climate change adaption in the wider study region. PMID- 29535223 TI - Arabidopsis TSO1 and MYB3R1 form a regulatory module to coordinate cell proliferation with differentiation in shoot and root. AB - Fundamental to plant and animal development is the regulated balance between cell proliferation and differentiation, a process intimately tied to cell cycle regulation. In Arabidopsis, mutations in TSO1, whose animal homolog is LIN54, resulted in severe developmental abnormalities both in shoot and root, including shoot meristem fasciation and reduced root meristematic zone. The molecular mechanism that could explain the tso1 mutant phenotype is absent. Through a genetic screen, we identified 32 suppressors that map to the MYB3R1 gene, encoding a conserved cell cycle regulator. Further analysis indicates that TSO1 transcriptionally represses MYB3R1, and the ectopic MYB3R1 activity mediates the tso1 mutant phenotype. Since animal homologs of TSO1 and MYB3R1 are components of a cell cycle regulatory complex, the DREAM complex, we tested and showed that TSO1 and MYB3R1 coimmunoprecipitated in tobacco leaf cells. Our work reveals a conserved cell cycle regulatory module, consisting of TSO1 and MYB3R1, for proper plant development. PMID- 29535225 TI - Reply to Li Volti et al.: E-cigarette smoke exposure and effect in mice and human cells. PMID- 29535226 TI - Assessment of E-cigarette impact on smokers: The importance of experimental conditions relevant to human consumption. PMID- 29535228 TI - Subannular reconstruction in secondary mitral regurgitation: a meta-analysis. AB - OBJECTIVE: Mitral valve repair using an undersized complete annuloplasty ring in secondary mitral regurgitation with restricted leaflet motion during systole (Carpentier's surgical classification of mitral valve pathology: type IIIb) only inadequately addresses the underlying left ventricular disease. This may lead to an ongoing ventricular remodelling and progressive papillary muscle displacement with increasing leaflet tethering. Several subannular techniques have been proposed to counteract the reoccurrence of mitral regurgitation after mitral valve repair. We aimed to evaluate the potential additive effect of such subannular techniques on the late reoccurrence rate of secondary mitral regurgitation. METHODS: Systematic literature review and meta-analysis were performed on PubMed, Embase and Google Scholar for studies published up to March 2016 and reporting late reoccurrence of mitral regurgitation after mitral valve repair using standard annuloplasty (control group) versus annuloplasty with subannular correction (study group) cohorts. Primary endpoint was late reoccurrence of mitral regurgitation >=2 after surgical mitral valve repair, as defined by follow-up echocardiography. RESULTS: The cumulative number of 1093 patients in 12 included studies served as our study population. A total of 743 patients underwent combined mitral valve repair including annuloplasty and subannular manoeuvre (ie, study group), while the remaining 350 patients underwent an isolated ring annuloplasty (ie, control group). Secondary mitral regurgitation was caused by ischaemic heart disease in 733/743 patients in the study group and 334/350 patients in the control group. Mean echocardiographic follow-up was 42.7+/-13.9 months. Pooled outcome analysis demonstrated that the combination of subannular repair with ring annuloplasty was associated with a significantly lower reoccurrence rate of mitral regurgitation >=2 as compared with annuloplasty alone (OR 0.27, 95% CI 0.19 to 0.38, P=0.0001). CONCLUSION: The combination of subannular reconstruction and mitral valve annuloplasty is associated with a lower late reoccurrence of mitral regurgitation after surgical mitral valve repair, as compared with annuloplasty alone. PMID- 29535229 TI - Late outcomes after the Fontan procedure in patients with single ventricle: a meta-analysis. AB - OBJECTIVE: More patients with Fontan physiology are reaching adulthood. The purpose of this meta-analysis was to evaluate the late outcomes of patients palliated with Fontan procedure and to assess the risk factors for mortality. METHODS: PubMed, Embase and Web of Science were queried to retrieve observational studies of survival in patients following the Fontan procedure with >=5 years of follow-up. A random-effects model was used to determine pooled survival estimates at 5, 10 and 15 years. Meta-regression was used to assess potential moderators for death. RESULTS: Nineteen articles with a total of 5859 patients were included. The weighted mean follow-up time was 8.94+/-2.64 years with overall 8.3% deaths and 1.5% transplants. Pooled survival estimates at 5, 10 and 15 years were 90.7%, 87.2% and 87.5%, respectively; and 88.4%, 85.7% and 84.1%, respectively, for studies that included all three time intervals (n=4). Earliest surgical year included in the study, proportion of atriopulmonary connections versus extracardiac conduit or lateral tunnel, and older age at Fontan were associated with higher rates of death, but ventricular morphology was not. Protein-losing enteropathy, reoperation and pacemaker insertion were reported in 2.1%, 5.6% and 6.8% patients, respectively. CONCLUSIONS: Survival following the Fontan procedure has improved with time and is influenced by Fontan type and age at the time of Fontan. At a mean follow-up of 8.9 years, there was no significant association between survival and ventricular morphology, not taking into account the mortality prior to Fontan. PMID- 29535230 TI - National, regional and global mortality due to alcoholic cardiomyopathy in 2015. AB - OBJECTIVES: (1) A comprehensive mortality assessment of alcoholic cardiomyopathy (ACM) and (2) examination of under-reporting using vital statistics data. METHODS: A modelling study estimated sex-specific mortality rates for each country, which were subsequently aggregated by region and globally. Input data on ACM mortality were obtained from death registries for n=91 countries. For n=99 countries, mortality estimates were predicted using aggregate alcohol data from WHO publications. Descriptive additional analyses illustrated the scope of under reporting. RESULTS: In 2015, there were an estimated 25 997 (95% CI 17 385 to 49 096) global deaths from ACM. This translates into 6.3% (95% CI 4.2% to 11.9%) of all global deaths from cardiomyopathy being caused by alcohol. There were large regional variations with regard to mortality burden. While the majority of ACM deaths were found in Russia (19 749 deaths, 76.0% of all ACM deaths), for about one-third of countries (n=57) less than one ACM death was found. Under-reporting was identified for nearly every second country with civil registration data. Overall, two out of three global ACM deaths might be misclassified. CONCLUSIONS: The variation of ACM mortality burden is greater than for other alcohol attributable diseases, and partly may be the result of stigma and lack of detection. Misclassification of ACM fatalities is a systematic phenomenon, which may be caused by low resources, lacking standards and stigma associated with alcohol-use disorders. Clinical management may be improved by including routine alcohol assessments. This could contribute to decrease misclassifications and to provide the best available treatment for affected patients. PMID- 29535231 TI - Real-Life Observational Studies Provide Actionable Data for Family Medicine. AB - This issue includes several excellent observational studies prompted by physicians' clinical questions. Many people use lots of menthol cough drops-does the menthol overall lengthen the cough duration? When should we intensify treatment of older individuals with diabetes? Do occipital nerve blocks work for acute migraine headaches? Did you know that the plantar fascia can rupture? What happens to those patients with chest pain but low pretest probability for serious cardiac disease who are admitted to the hospital? Acupuncture can work well-for the patients-but how can we incorporate it into the usual pace of the family medicine office? Is it a win-lose situation when medical assistant roles are expanded? How many practice sites do physicians have and does that make a difference in the number or type of health personnel shortage areas? What would you guess on the presence of humor in the medical office-more or less than half of the visits; introduced by doctors or patients; primary care or specialty doctors? PMID- 29535232 TI - Potentially Alarming Trends in the Scope of Practice for Family Physicians. PMID- 29535233 TI - Wide Gap between Preparation and Scope of Practice of Early Career Family Physicians. AB - We found substantial gaps between preparation for, and practice of, early career family physicians in nearly all clinical practice areas. With reported intentions of graduates for a broad scope of practice, gaps between practice and preparation suggest family physicians early in their careers may not be finding opportunities to provide comprehensive care. PMID- 29535234 TI - Menthol Cough Drops: Cause for Concern? AB - BACKGROUND: Over-the-counter (OTC) cough remedies are lightly regulated and their potential side effects may go unrecognized. During 2015, over 282 million cough drops were sold in the United States. A Wisconsin community clinician (RM) made clinical observations suggesting that excessive use of OTC cough drops may exacerbate rather than benefit coughs. The goal of this project was to assess whether menthol in cough drops is related to worse cough symptoms. METHODS: From April 2016 through May 2017, 5 Wisconsin primary care clinics invited adolescent and adult outpatients seeking medical care for an acute or subacute cough to take a voluntary, anonymous, 10-question cough drop use survey that included age, sex, smoking status, cough severity, cough duration, and cough drop use (including type and amount). RESULTS: Of the 548 surveys collected and analyzed, 363 (66.2%) reported using cough drops. Cough drop use was significantly associated with longer duration of cough at presentation (P < .001) but not with overall cough severity (P = .09). Of cough drop users, 269 (90%) reported consuming drops with menthol. Univariate analysis found no statistically significant differences between the menthol and nonmenthol groups for either severity (P = .65) or duration (P = .17). However, significant independent associations were found between cough severity and 1) average menthol dose per cough drop (R = 0.19; P = .007), 2) number of cough drops consumed daily (R = 0.2; P = .002) and 3) total amount of menthol consumed per day (R = 0.21; P = .001) that remained significant (P = .003) after controlling for age, sex, smoking status, season, and clinic site. CONCLUSIONS: Cough severity in some individuals may be negatively influenced by the amount of menthol consumed via cough drops. Clinicians should include cough drop use in history taking of patients with persisting cough illnesses. Further research into potential mechanisms is warranted. PMID- 29535235 TI - Patient-Centered Guidelines for Geriatric Diabetes Care: Potential Missed Opportunities to Avoid Harm. AB - BACKGROUND: Clinicians strive to deliver individualized, patient-centered care. However, these intentions are understudied. This research explores how patient characteristics associated with an high risk-to-benefit ratio with hypoglycemia medications affect decision making by primary care clinicians. METHODS: Using a vignette-based survey, we queried primary care clinicians on their intended management of geriatric patients with diabetes. The patients' ages, disease durations, and comorbidities were systematically varied. Clinicians indicated whether they would intensify glycemic control by adding a second-line hypoglycemia medication. RESULTS: A convenience sample of 336 primary care clinicians completed the survey. Despite the recommendations for HbA1c targets <8% for more complex patients, an 80-year-old woman with an HbA1c of 7.5%, longstanding diabetes, coronary disease, and cognitive impairment and with instrumental activity of daily living dependencies, had a predicted probability of treatment intensification of 35%. Internists were 11% and nurse practitioners were 14% more likely to intensify treatment than family physicians (P < .01). These provider differences remained significant after controlling for geographic differences in treatment intensification. Providers in Florida were more likely to intensify treatment (P < .01). CONCLUSIONS: Primary care clinicians often chose to intensify glycemic control despite individual patient factors that warrant higher glycemic targets based on existing guidelines. This research identifies possible missed opportunities for patient-centered goal setting and raises questions about the influence of training and practice environment on clinical decision making. PMID- 29535236 TI - Delivering Interconception Care During Well-Child Visits: An IMPLICIT Network Study. AB - BACKGROUND: Preterm birth, birth defects, and unintended pregnancy are major sources of infant and maternal morbidity, mortality, and associated resource use in American health care. Interconception Care (ICC) is recommended as a strategy to improve birth outcomes by modifying maternal risks between pregnancies, but no established model currently exists. The Interventions to Minimize Preterm and Low Birth Weight Infants through Continuous Improvement Techniques (IMPLICIT) Network developed and implemented a unique approach to ICC by assessing mothers during their baby's well-child visits (WCVs) up to 24 months. METHODS: Mothers who accompanied their children to WCVs at eleven eastern US family medicine residency programs underwent screening for four risk factors (tobacco use, depression risk, contraception use to avoid unintended pregnancy and prolong interpregnancy interval, and use of a multivitamin with folic acid). Positive screens in women were addressed through brief interventions or referrals to treatment. RESULTS: Mothers accompanied their babies to 92.7% of WCVs. At more than half of WCVs (69.1%), mothers were screened for presence of ICC behavioral risks, although significant practice variation existed. Risk factors were identified at significant rates (tobacco use, 16.2%; depression risk, 8.1%; lack of contraception use, 28.2%; lack of multivitamin use, 45.4%). Women screened positive for 1 or more ICC risk factor at 64.6% of WCVs. Rates of documented interventions for women who screened positive were also substantial (tobacco use, 80.0%; depression risk, 92.8%; lack of contraception use, 76.0%; lack of multivitamin use, 58.2%). CONCLUSION: WCVs provide a reliable point of contact with mothers and a unique opportunity to assess and address behavioral risks for future poor birth outcomes. PMID- 29535237 TI - Greater Occipital Nerve Block for Acute Treatment of Migraine Headache: A Large Retrospective Cohort Study. AB - INTRODUCTION: Greater occipital nerve (GON) blocks are frequently used to treat migraine headaches, although a paucity of supporting clinical evidence exists. The objective of this study was to assess the efficacy of GON block in acute treatment of migraine headache, with a focus on pain relief. METHODS: This retrospective cohort study was undertaken between January 2009 and August 2014 and included patients who underwent at least 1 GON block and attended at least 1 follow-up appointment. Change in the 11-point numeric pain rating scale (NPRS) was used to assess the response to GON block. Response was defined as "minimal" (<30% NPRS point reduction), "moderate" (31-50% NPRS point reduction), or "significant" (>50% NPRS point reduction). RESULTS: A total of 562 patients met inclusion criteria; 423 were women (75%). Mean age was 58.6 +/- 16.7 years. Of these 562, 459 patients (82%) rated their response to GON block as moderate or significant. No statistically significant relationship existed between previous treatment regimens and response to GON block. GON block was equally effective across the different age and sex groups. CONCLUSIONS: Greater occipital block seems to be an effective option for acute management of migraine headache, with promising reductions in pain scores. PMID- 29535238 TI - Retrospective Comparison of Cardiac Testing and Results on Inpatients with Low Pretest Probability Compared with Moderate/High Pretest Probability for Coronary Artery Disease. AB - OBJECTIVE: To determine whether admission, and provocative stress testing of patients who have ruled out for acute coronary syndrome put patients with low risk category for coronary artery disease (CAD) at risk for false-positive provocative stress testing and unnecessary coronary angiogram/imaging. METHODS: A retrospective chart review was performed on patients between 30 and 70 years old, with no pre-existing diagnosis of CAD, admitted to observation or inpatient status chest pain or related complaints. Included patients were categorized based on Duke Clinical Score for pretest probability for CAD into either low-risk group, or moderate/high-risk group. The inpatient course was compared including whether provocative stress testing was performed; results of stress testing; whether patients underwent further coronary imaging; and what the results of the further imaging showed. RESULTS: 543 patients were eligible: 305 low pretest probability, and 238 moderate/high pretest probability. No difference was found in rate of stress testing relative risk (RR) = 1.01 (95% CI, 0.852 to 1.192; P = 0); rate of positive or equivocal stress tests between the 2 groups: RR = 0.653 (95% CI, 0.415 to 1.028; P = .07,). Low-pretest-probability patients had a lower likelihood of positive coronary imaging after stress test, RR = 0.061 (95% CI, 0.004 to 0.957; P = .001). CONCLUSION: Follow-up provocative testing of all patients admitted/observed after emergency department presentation with chest pain is unlikely to find CAD in patients with low pretest probability. Testing all low-probability patients puts them at increased risk for unnecessary invasive confirmatory testing. Further prospective testing is needed to confirm these retrospective results. PMID- 29535227 TI - Effectiveness of new antiplatelets in the prevention of recurrent myocardial infarction. AB - OBJECTIVE: To compare ticagrelor and prasugrel with clopidogrel for recurrent fatal and non-fatal myocardial infarction (reMI) in real-life conditions. METHODS: Case-referent study using the Pharmacoepidemiological General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Cases were patients with reMI from a cohort with index ACS or external to the cohort (same sites). Referents from the cohort, without recurrent event, were matched on index ACS type and date, age and sex with reMI cases. Multivariate conditional logistic regression assessed the OR (95% CI) for reMI associated with ticagrelor and prasugrel vs clopidogrel, adjusted for aspirin use and cardiovascular risk factors. RESULTS: 1047 cases and 2234 matched referents were included. Compared with clopidogrel, ticagrelor and prasugrel were associated with respective ORs of 0.65 (95% CI 0.52 to 0.81) and 0.71 (95% CI 0.53 to 0.96) for reMI occurrence. ORs for ticagrelor and prasugrel vs clopidogrel were: 0.50 (95% CI 0.38 to 0.67) and 0.66 (95% CI 0.45 to 0.95), 0.39 (95% CI 0.24 to 0.62) and 0.44 (95% CI 0.26 to 0.75), 0.63 (95% CI 0.43 to 0.92) and 1.20 (95% CI 0.69 to 2.07), 1.11 (95% CI 0.72 to 1.72) and 0.82 (95% CI 0.44 to 1.54) when index ACS was a first MI, a first ST-elevated MI (STEMI), a first non-STEMI and a recurrent ACS, respectively, and 0.63 (95% CI 0.45 to 0.87) and 0.77 (95% CI 0.41 to 1.45) for patients aged >=70 years. CONCLUSIONS: This real-world study showed a significant reduction of reMI with new antiplatelets compared with clopidogrel, ticagrelor being associated with a greater decrease of risk notably for first, either STEMI or non-STEMI. The larger magnitude of effect may be attributed to potential residual confounding or higher effectiveness compared with efficacy reported in trials (EMA Post Authorisation Study Registry Number EUPAS5905). PMID- 29535239 TI - Barriers and Facilitators to Expanding Roles of Medical Assistants in Patient Centered Medical Homes (PCMHs). AB - BACKGROUND: Many primary care practices participating in patient-centered medical home (PCMH) transformation initiatives are expanding the work roles of their medical assistants (MAs). Little is known about attitudes of MAs or barriers and facilitators to these role changes. METHODS: Secondary data analysis of qualitative cross-case comparison study of 15 New Jersey primary care practices participating in a PCMH project during 2012 to 2013. Observation field notes and in-depth and key informant interviews (with physicians, office managers, staff and care coordinators) were iteratively analyzed using grounded theory. RESULTS: MA roles and responsibilities changed from a mostly reactive role, completing tasks dependent on physician orders during the patient visit and facilitating patient flow through the office, to a more proactive one, conducting previsit planning, engaging in the overall care for patients, and assisting with population management. MAs differed in their attitudes about increased responsibilities, with some welcoming the opportunity to take on expanded roles, others resenting their increased responsibilities, and some expressing insufficient understanding regarding why new tasks and procedures were being implemented. Major barriers to MA role shifts included 1) insufficient understanding of the PCMH concept, 2) lack of time for added responsibilities, 3) additional workload without additional compensation, 4) disparate levels of medical knowledge and training, 5) reluctance of clinicians to delegate tasks, 6) uncertainty in making new workflow changes routine, 7) staff turnover, and 8) change fatigue. MAs were more positive about their role shifts when they 1) understood how their responsibilities fit within broader PCMH practice transformation goals; 2) received formal training in new tasks; 3) had detailed protocols and standing orders; 4) initiated role changes with small, achievable goals; 5) had open communication with clinicians and practice leaders; and 5) received additional compensation or paths to career advancement. CONCLUSIONS: Practice leaders need to be conscious of obstacles when they increase expectations of MAs, and they must be willing to invest time and resources into developing their MA workforce. An environment that allows open dialog with MAs and rewards and compensation that recognizes their increased efforts will help make expansion of MA roles occur more smoothly and efficiently. PMID- 29535240 TI - Critical Factors to Practicing Medical Acupuncture in Family Medicine: Patient and Physician Perspectives. AB - INTRODUCTION: Although an increasing number of physicians are completing medical acupuncture training, only half of those physicians are able to successfully incorporate acupuncture into practice. We conducted a qualitative study to identify the factors and barriers that can enhance and impede physicians' delivery of and patients' engagement in medical acupuncture within the family medicine clinic. METHODS: We conducted interviews with 15 family physicians and 17 patients in a US family medicine clinic that has integrated medical acupuncture into its practice. Audio recordings were transcribed and analyzed by 2 members of the study team in ATLAS.ti, using the constant comparative method. RESULTS: We identified 3 physician themes of factors/barriers that impact delivery/engagement: 1) patients' aversion to needles, 2) time challenges, and 3) access to resources. We identified 3 additional themes from patient interviews: 1) appointment access; 2) wanting noninvasive, no side effects alternative; and 3) openness to anything. DISCUSSION: The factors and barriers reported by physicians/patients help illustrate conditions needed to enhance physicians' ability to provide acupuncture and patients' willingness to engage and sustain it. Participants' experiences help to illustrate strategic approaches to managing these barriers-strategies that can be used by other individuals/institutions to enhance care delivery and patient engagement. PMID- 29535242 TI - A Model for Measuring Ambulatory Access to Care Recovery after Disasters. AB - INTRODUCTION: Although little research has examined impacts of disasters on scheduled ambulatory care services, routine care delivery is important for emergency planning and response because missed or delayed care can lead to more urgent care needs. This article presents potential measures of ambulatory care recovery and resilience and applies the measures to data around a recent disaster. METHODS: We conceptualize "ambulatory care recovery" as the change in median business days to complete appointments that were canceled, and "ambulatory care resiliency" as the change in percentage of completed appointments in time frames before, during, and after disasters. Appointments data from Veterans Affairs (VA) clinics were examined around a category 4 hurricane that affected a coastal area with a substantial veteran population. RESULTS: For the disaster studied, ambulatory care resilience was associated with geographic proximity to the storm's impact. Primary care recovery was longer in locations closest to storm landfall. This research indicates the usefulness of routine appointments data in emergency planning. CONCLUSION: Quantifying care disruptions around disasters is an important step in assessing interventions to improve emergency preparedness and response for clinics. The illustrative example of measures captured the disaster event duration and severity in relation to ambulatory care appointments. PMID- 29535241 TI - Moving Away from the Tip of the Pyramid: Screening and Brief Intervention for Risky Alcohol and Opioid Use in Underserved Patients. AB - PURPOSE: Rates of risky substance use and substance use disorders are high in primary-care practices, yet the adoption of universal screening and brief intervention (SBI) has been slow and uneven. This study aimed to describe SBI related attitudes, practices, and perspectives regarding practice change among medical providers in a minority-majority state. METHODS: We conducted a cross sectional, on-line survey of a practice-based research network of medical providers serving predominantly Hispanic/Latinx and Native American patients in rural and urban settings. The main variables were clinician 1) perspectives on the need to address substance use problems in primary care, 2) current screening and intervention practices, and 3) satisfaction with and willingness to make changes to their practices. RESULTS: Although providers endorsed alcohol and opiate misuse to be significant problems in their practices, only 25% conducted universal screening. Providers reported focusing most of their screening efforts on those with substance use dependence. In general, providers rated importance of and ability to make practice changes moderately high. There was high interest in practice coordination with the community followed by interest in a collaborative care approach. CONCLUSIONS: Providers mainly focus efforts on the relatively few patients at the tip of the pyramid (substance use dependence) rather than on the majority of patients who comprise the middle of the pyramid (risky substance use). Practice change strategies are needed to increase universal screening with a focus on risky substance use, particularly in practices serving racial/ethnic communities. PMID- 29535243 TI - Physician Multisite Practicing: Impact on Access to Care. AB - BACKGROUND: Physician multisite practicing may affect access to care. However, study measuring the degree of multisite practicing is generally lacking. This study aimed to describe physician multisite practicing patterns in Georgia and to assess its impact on access to care. METHODS: Using data from the Georgia Medicaid Management Information System, the American Medical Association Physician Masterfile, and the US Census, mean number of practice sites per physician was calculated. Counts of sites per physician were then modeled in a negative binomial regression. Local differences in spatial accessibility were assessed based on single-site verse multisite practice locations. RESULTS: Among 20,116 physicians (mean age, 49.4 years; 30.5% female) in Georgia, 63.2% reported multiple practice sites. The average practice sites per physician was 3.3 overall, 2.6 for primary care physicians, and 3.6 for other physicians. Younger age, male sex, and practicing in group practice setting were associated with a higher number of practice sites per physician. Spatial accessibility index changed substantially when controlling for multiple practice sites. CONCLUSIONS: Physician multisite practicing was prevalent and affected geographic access to care. More research and investment into health workforce information infrastructure seem warranted to accommodate changing physician practice patterns in data collection and dissemination. PMID- 29535244 TI - Humor During Clinical Practice: Analysis of Recorded Clinical Encounters. AB - OBJECTIVE: Little is known about humor's use in clinical encounters, despite its many potential benefits. We aimed to describe humor during clinical encounters. DESIGN: We analyzed 112 recorded clinical encounters. Two reviewers working independently identified instances of humor, as well as information surrounding the logistics of its use. RESULTS: Of the 112 encounters, 66 (59%) contained 131 instances of humor. Humor was similarly frequent in primary care (36/61, 59%) and in specialty care (30/51, 59%), was more common in gender-concordant interactions (43/63, 68%), and was most common during counseling (81/112, 62%). Patients and clinicians introduced humor similarly (63 vs 66 instances). Typically, humor was about the patient's medical condition (40/131, 31%). DISCUSSION AND CONCLUSION: Humor is used commonly during counseling to discuss the patient's medical condition and to relate to general life events bringing warmth to the medical encounter. The timing and topic of humor and its use by all parties suggests humor plays a role in the social connection between patients and physicians and allows easier discussion of difficult topics. Further research is necessary to establish its impact on clinicians, patients, and outcomes. PMID- 29535245 TI - Evaluation of an Ongoing Diabetes Group Medical Visit in a Family Medicine Practice. AB - PURPOSE: Group medical visits (GMVs), which combine 1-on-1 clinical consultations and group self-management education, have emerged as a promising vehicle for supporting type 2 diabetes management in primary care. However, few evaluations exist of ongoing diabetes GMVs embedded in medical practices. METHODS: This study used a quasi-experimental design to evaluate diabetes GMV at a large family medicine practice. We examined program attendance and attrition, used propensity score matching to create a matched comparison group, and compared participants and the matched group on clinical, process of care, and utilization outcomes. RESULTS: GMV participants (n = 230) attended an average of 1 session. Participants did not differ significantly from the matched comparison group (n = 230) on clinical, process of care or utilization outcomes. CONCLUSIONS: The diabetes GMV was not associated with improvements in outcomes. Further studies should examine diabetes GMV implementation challenges to enhance their effectiveness in everyday practice. PMID- 29535246 TI - Plantar Fascia Rupture: Ultrasound to Facilitate Recognition. AB - Plantar fascia rupture in the absence of previous diagnosis of plantar fasciitis, corticosteroid injection, or injury is a rare occurrence with only 7 case reports in the literature since 1978. This is a case of spontaneous plantar fascia rupture in a 38-year-old active-duty US military member with current considerations in musculoskeletal ultrasound, other radiologic imaging, treatment, and followup of this diagnosis. PMID- 29535247 TI - Moral Distress with Obstacles to Hepatitis C Treatment: A Council of Academic Family Medicine Educational Research Alliance (CERA) Study of Family Medicine Program Directors. AB - BACKGROUND AND OBJECTIVE: To determine whether family medicine program directors (PDs) experienced moral distress due to obstacles to Hepatitis C virus (HCV) treatment, and to explore whether they found those obstacles to be unethical. DESIGN: An omnibus survey by the Council of Academic Family Medicine's Educational Research Alliance was administered to 452 and completed by 273 US based PDs. The survey gauged attitudes and opinions regarding ethical dilemmas in patient access to HCV treatment. RESULTS: Most of the respondents were male. Sixty-four percent of respondents believed that treatment should be an option for all patients regardless of cost. Forty-one percent believed that it was unethical to deny treatment based on past or current substance use, and 38% believed treatment should be offered to patients who were substance abusers. Moral distress was reported by 61% (score >3) of participants when they were unable to offer treatment to patients due to the patient's failure to meet eligibility criteria. In addition, PDs reporting moderate-to-high levels of moral distress were also likely to report the following opinions: 1) treatment should be offered regardless of cost, 2) it is unethical to deny treatment based on past behavior, 3) substance abusers should be offered treatment, 4) it is unethical for medicine to be prohibitively expensive, and 5) Medicaid policy that limits treatment will worsen racial and ethnic disparities. CONCLUSIONS: Currently, important ethical dilemmas exist in the access and delivery of HCV therapy. Although a diversity of opinions is noted, a significant proportion of PDs are concerned about patients' inability to avail equitable care and experience distress. In some cases, this moral distress is in response to, and in conflict with, current guidelines. PMID- 29535248 TI - Revisiting Primary Care's Critical Role in Achieving Health Equity: Pisacano Scholars' Reflections from Starfield Summit II. AB - The second Starfield Summit was held in Portland, Oregon, in April 2017. The Summit addressed the role of primary care in advancing health equity by focusing on 4 key domains: social determinants of health in primary care, vulnerable populations, economics and policy, and social accountability. Invited participants represented an interdisciplinary group of primary care clinicians, researchers, educators, policymakers, community leaders, and trainees. The Pisacano Leadership Foundation was one of the Summit sponsors and held its annual leadership symposium in conjunction with the Summit, enabling several Pisacano Scholars to attend the Summit. After the Summit, a small group of current and former Pisacano Scholars formed a writing group to highlight key themes and implications for action discussed at the Summit. The Summit resonated as a call to action for primary care to move beyond identifying existing health inequities and toward the development of interventions that advance health equity, through education, research, and enhanced community partnerships. In doing so, the Summit aimed to build on the foundational work of Dr. Starfield, challenging us to explore the significant role of primary care in truly achieving health equity. PMID- 29535249 TI - Already 19: Further Reflections on Parenting, Aniridia, and Being a Doctor. AB - The author, a family physician, reflects on raising a daughter with a rare eye disease, aniridia, and learning and memory disabilities as the daughter heads off to college. PMID- 29535250 TI - Please Test My Child for a Cancer Gene, but Don't Tell Her. AB - A 38-year-old woman is diagnosed with Li-Fraumeni syndrome, an autosomal dominant genetic condition that predisposes to a variety of cancers. The woman has an 11 year-old daughter. The geneticist recommends that the child be tested for the Li Fraumeni genetic variant. The mother is concerned about the impact of testing and diagnosis on Karen's psychological well-being. She describes Karen as "highly strung" and as "a worrier." The child has been diagnosed with an anxiety disorder and is managed by a psychologist for counseling. The child is otherwise well. The mother requests that testing be done without disclosing it to the child by adding the test on to routine blood work done for another reason and requests that the results only be revealed if they are positive. Experts in genetics, law, and bioethics discuss whether it is permissible to test the child without her knowledge or assent. PMID- 29535251 TI - Development and Validation of a Novel Pediatric Appendicitis Risk Calculator (pARC). AB - OBJECTIVES: We sought to develop and validate a clinical calculator that can be used to quantify risk for appendicitis on a continuous scale for patients with acute abdominal pain. METHODS: The pediatric appendicitis risk calculator (pARC) was developed and validated through secondary analyses of 3 distinct cohorts. The derivation sample included visits to 9 pediatric emergency departments between March 2009 and April 2010. The validation sample included visits to a single pediatric emergency department from 2003 to 2004 and 2013 to 2015. Variables evaluated were as follows: age, sex, temperature, nausea and/or vomiting, pain duration, pain location, pain with walking, pain migration, guarding, white blood cell count, and absolute neutrophil count. We used stepwise regression to develop and select the best model. Test performance of the pARC was compared with the Pediatric Appendicitis Score (PAS). RESULTS: The derivation sample included 2423 children, 40% of whom had appendicitis. The validation sample included 1426 children, 35% of whom had appendicitis. The final pARC model included the following variables: sex, age, duration of pain, guarding, pain migration, maximal tenderness in the right-lower quadrant, and absolute neutrophil count. In the validation sample, the pARC exhibited near perfect calibration and a high degree of discrimination (area under the curve: 0.85; 95% confidence interval: 0.83 to 0.87) and outperformed the PAS (area under the curve: 0.77; 95% confidence interval: 0.75 to 0.80). By using the pARC, almost half of patients in the validation cohort could be accurately classified as at <15% risk or >=85% risk for appendicitis, whereas only 23% would be identified as having a comparable PAS of <3 or >8. CONCLUSIONS: In our validation cohort of patients with acute abdominal pain, the pARC accurately quantified risk for appendicitis. PMID- 29535253 TI - Pesticides and public health: an analysis of the regulatory approach to assessing the carcinogenicity of glyphosate in the European Union. AB - The present paper scrutinises the European authorities' assessment of the carcinogenic hazard posed by glyphosate based on Regulation (EC) 1272/2008. We use the authorities' own criteria as a benchmark to analyse their weight of evidence (WoE) approach. Therefore, our analysis goes beyond the comparison of the assessments made by the European Food Safety Authority and the International Agency for Research on Cancer published by others. We show that not classifying glyphosate as a carcinogen by the European authorities, including the European Chemicals Agency, appears to be not consistent with, and in some instances, a direct violation of the applicable guidance and guideline documents. In particular, we criticise an arbitrary attenuation by the authorities of the power of statistical analyses; their disregard of existing dose-response relationships; their unjustified claim that the doses used in the mouse carcinogenicity studies were too high and their contention that the carcinogenic effects were not reproducible by focusing on quantitative and neglecting qualitative reproducibility. Further aspects incorrectly used were historical control data, multisite responses and progression of lesions to malignancy. Contrary to the authorities' evaluations, proper application of statistical methods and WoE criteria inevitably leads to the conclusion that glyphosate is 'probably carcinogenic' (corresponding to category 1B in the European Union). PMID- 29535254 TI - Inner Workings: Better sequencing tech may help keep planets clean. PMID- 29535255 TI - Core Concept: Mechanical metamaterials bend the rules of everyday physics. PMID- 29535257 TI - iQOS: evidence of pyrolysis and release of a toxicant from plastic. AB - OBJECTIVE: To evaluate performance of the I quit original smoking (iQOS) heat-not burn system as a function of cleaning and puffing topography, investigate the validity of manufacturer's claims that this device does not burn tobacco and determine if the polymer-film filter is potentially harmful. METHODS: iQOS performance was evaluated using five running conditions incorporating two different cleaning protocols. Heatsticks were visually and stereomicroscopically inspected preuse and postuse to determine the extent of tobacco plug charring (from pyrolysis) and polymer-film filter melting, and to elucidate the effects of cleaning on charring. Gas chromatography-mass spectrometry headspace analysis was conducted on unused polymer-film filters to determine if potentially toxic chemicals are emitted from the filter during heating. RESULTS: For all testing protocols, pressure drop decreased as puff number increased. Changes in testing protocols did not affect aerosol density. Charring due to pyrolysis (a form of organic matter thermochemical decomposition) was observed in the tobacco plug after use. When the manufacturer's cleaning instructions were followed, both charring of the tobacco plug and melting of the polymer-film filter increased. Headspace analysis of the polymer-film filter revealed the release of formaldehyde cyanohydrin at 90 degrees C, which is well below the maximum temperature reached during normal usage. DISCUSSION: Device usage limitations may contribute to decreases in interpuff intervals, potentially increasing user's intake of nicotine and other harmful chemicals. This study found that the tobacco plug does char and that charring increases when the device is not cleaned between heatsticks. Release of formaldehyde cyanohydrin is a concern as it is highly toxic at very low concentrations. PMID- 29535258 TI - Pulmonary Contusion in Mechanically Ventilated Subjects After Severe Trauma. AB - BACKGROUND: Pulmonary contusions are thought to worsen outcomes. We aimed to evaluate the effects of pulmonary contusion on mechanically ventilated trauma subjects with severe thoracic injuries and hypothesized that contusion would not increase morbidity. METHODS: We conducted a single-center, retrospective review of 163 severely injured trauma subjects (injury severity score >= 15) with severe thoracic injury (chest abbreviated injury score >= 3), who required mechanical ventilation for >24 h at a verified Level 1 trauma center. Subject data were analyzed for those with radiographic documentation of pulmonary contusion and those without. Statistical analysis was performed to determine the effects of coexisting pulmonary contusion in severe thoracic trauma. RESULTS: Pulmonary contusion was present in 91 subjects (55.8%), whereas 72 (44.2%) did not have pulmonary contusions. Mean chest abbreviated injury score (3.54 vs 3.47, P = .53) and mean injury severity score (32.6 vs 30.2, P = .12) were similar. There was no difference in mortality (11 [12.1%] vs 9 [12.5%], P > .99) or length of stay (16.29 d vs 17.29 d, P = .60). Frequency of ventilator-associated pneumonia was comparable (43 [47.3%] vs 32 [44.4%], P = .75). Subjects with contusions were more likely to grow methicillin-sensitive Staphylococcus aureus in culture (33 vs 10, P = .004) as opposed to Pseudomonas aeruginosa in culture (6 vs 13, P = .003). CONCLUSIONS: Overall, no significant differences were noted in mortality, length of stay, or pneumonia rates between severely injured trauma subjects with and without pulmonary contusions. PMID- 29535259 TI - High-Frequency Airway Oscillating Device for Respiratory Muscle Training in Subjects With COPD. AB - BACKGROUND: COPD is characterized by expiratory flow limitation, which results in symptomatic dyspnea and reduced exercise capacity. Changes in breathing mechanics mean the respiratory muscles are unable to respond to the ventilatory demands, increasing the sensation of dyspnea. A high-frequency oscillating device has been developed to improve dyspnea in patients with COPD. We conducted a feasibility trial to gain insight into the potential for recruitment, retention, and study design for a future randomized controlled trial. METHODS: Symptomatic subjects with COPD were included on the basis of a Medical Research Council (MRC) score >= 3 and FEV1/FVC < 0.70). Patients were excluded if they received pulmonary rehabilitation within the last 6 months. The intervention employed the device for 8 weeks, 3 times daily. Clinical outcomes included the MRC score, maximal expiratory and inspiratory pressures (PEmax/PImax), the incremental shuttle walk test (ISWT), and the endurance shuttle walk test (ESWT). RESULTS: We successfully recruited 23 subjects with established COPD (65.2% male, mean age 65 +/- 5.03 y, mean % predicted FEV1 43.9 +/- 16, mean FEV1/FVC ratio 0.46 +/- 0.13, and median [interquartile range] MRC 4 [3-5]). There was a significant change in MRC from 4 to 3 pre to post intervention (P = .003). There was a statistically significant difference in PEmaxP < .008 and PImaxP = .044. There were no significant differences observed in the ISWT or ESWT. CONCLUSIONS: This study design appeared feasible to proceed to a clinical effectiveness trial. The use of the device for 8 weeks showed a significant improvement in PEmax, PImax, and reduced symptomatic dyspnea on the MRC dyspnea score. The results of this study should encourage a randomized controlled trial. PMID- 29535260 TI - High-Flow Nasal Cannula in Pediatric Patients: A Survey of Clinical Practice. AB - BACKGROUND: High-flow nasal cannula (HFNC) use has greatly increased in recent years. In non-neonatal pediatric patients, there are limited data available to guide HFNC use, and clinical practice may vary significantly. The goal of this study was to evaluate current HFNC practice by surveying practicing pediatric respiratory therapists. METHODS: A survey instrument was posted on the American Association for Respiratory Care's AARConnect online social media platform in March 2017. Paper versions of the survey were also distributed at the annual Children Hospitals Association meeting. RESULTS: There were 63 responses, of which 98% used HFNC. HFNC was defined as any heated gas delivered by nasal cannula by 49% of respondents, whereas 21% defined HFNC as heated gas delivered via nasal cannula at flow greater than or equal to the patient's inspiratory demand, and 16% defined HFNC as any gas delivered via nasal cannula above predefined thresholds. Initial flow was set per provider orders by 34% of respondents, per respiratory therapist-driven protocol by 28%, per patient weight by 15%, per patient age by 15%; 5% of respondents used other methods. Noninvasive ventilation or CPAP was used by 88% of respondents as the next step for patients who failed HFNC, with 7% opting for intubation and 5% using other interventions. Aerosol therapy was delivered by 75% of respondents during HFNC, with 77% of these respondents delivering aerosol via vibrating mesh nebulizer. During aerosol therapy, 13% of respondents decreased HFNC flow, while 23% removed patients from HFNC. CONCLUSION: There was no consensus on the definition of HFNC, how to set initial flow, or how to make adjustments. Aerosols were delivered by 75% of respondents, predominantly via a vibrating mesh nebulizer placed on the dry side of the humidifier. The definition of HFNC, how to set flow, and aerosolized medication delivery are areas in which more research is needed. PMID- 29535261 TI - p38alpha signaling in Langerhans cells promotes the development of IL-17 producing T cells and psoriasiform skin inflammation. AB - Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38alpha activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38alpha in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell-mediated psoriasiform skin inflammation in mice. The activity of p38alpha in LCs specifically promoted IL-17 production from gammadelta and CD4+ T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion. Inhibition of p38 activity through either pharmacological inhibition or genetic deletion also reduced the severity of established psoriasiform skin inflammation. Together, our findings indicate a critical role for p38alpha signaling in LCs in promoting inflammatory responses in the skin and suggest that targeting p38alpha signaling in LCs may offer an effective therapeutic approach to treat psoriasis. PMID- 29535263 TI - Extension of chemotactic pseudopods by nonadherent human neutrophils does not require or cause calcium bursts. AB - Global bursts in free intracellular calcium (Ca2+) are among the most conspicuous signaling events in immune cells. To test the common view that Ca2+ bursts mediate rearrangement of the actin cytoskeleton in response to the activation of G protein-coupled receptors, we combined single-cell manipulation with fluorescence imaging and monitored the Ca2+ concentration in individual human neutrophils during complement-mediated chemotaxis. By decoupling purely chemotactic pseudopod formation from cell-substrate adhesion, we showed that physiological concentrations of anaphylatoxins, such as C5a, induced nonadherent human neutrophils to form chemotactic pseudopods but did not elicit Ca2+ bursts. By contrast, pathological or supraphysiological concentrations of C5a often triggered Ca2+ bursts, but pseudopod protrusion stalled or reversed in such cases, effectively halting chemotaxis, similar to sepsis-associated neutrophil paralysis. The maximum increase in cell surface area during pseudopod extension in pure chemotaxis was much smaller-by a factor of 8-than the known capacity of adherent human neutrophils to expand their surface. Because the measured rise in cortical tension was not sufficient to account for this difference, we attribute the limited deformability to a reduced ability of the cytoskeleton to generate protrusive force in the absence of cell adhesion. Thus, we hypothesize that Ca2+ bursts in neutrophils control a mechanistic switch between two distinct modes of cytoskeletal organization and dynamics. A key element of this switch appears to be the expedient coordination of adhesion-dependent lock or release events of cytoskeletal membrane anchors. PMID- 29535262 TI - Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors. AB - The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways. We found a previously unknown resistance mechanism to PI3K pathway inhibition that results in AKT rebound activation. In a subset of triple-negative breast cancer cell lines, treatment with a PI3K inhibitor or depletion of PIK3CA expression ultimately promoted AKT reactivation in a manner dependent on the E3 ubiquitin ligase Skp2, the kinases IGF-1R (insulin-like growth factor 1 receptor) and PDK-1 (phosphoinositide-dependent kinase-1), and the cell growth and metabolism regulating complex mTORC2 (mechanistic target of rapamycin complex 2), but was independent of PI3K activity or PIP3 production. Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice. These findings reveal a ubiquitin signaling feedback mechanism by which PI3K inhibitor resistance may emerge in aggressive breast cancer cells. PMID- 29535265 TI - High level of C-type natriuretic peptide induced by hyperandrogen-mediated anovulation in polycystic ovary syndrome mice. AB - Polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, is a complex endocrinopathy that affects the fertility of 9-18% of reproductive-aged women. However, the exact mechanism of PCOS, especially hyperandrogen-induced anovulation, is largely unknown to date. Physiologically, the natriuretic peptide type C/natriuretic peptide receptor 2 (CNP/NPR2) system is essential for sustaining oocyte meiotic arrest until the preovulatory luteinizing hormone (LH) surge. We therefore hypothesized that the CNP/NPR2 system is also involved in PCOS and contributes to arresting oocyte meiosis and ovulation. Here, based on a dehydroepiandrosterone (DHEA)-induced PCOS-like mouse model, persistent high levels of CNP/NPR2 were detected in anovulation ovaries. Meanwhile, oocytes arrested at the germinal vesicle stage correlated with persistent high levels of androgen and estrogen. We further showed that ovulation failure in these mice could be a result of elevated Nppc/Npr2 gene transcription that was directly increased by androgen (AR) and estrogen (ER) receptor signaling. Consistent with this, anovulation was alleviated by administration of either exogenous human chorionic gonadotropin (hCG) or inhibitors of AR or ER to reduce the level of CNP/NPR2. Additionally, the CNP/NPR2 expression pattern in the anovulated follicles was, to some extent, consistent with the clinical expression in PCOS patients. Therefore, our study highlights the important role an overactive CNP/NPR2 system caused by hyperandrogenism in preventing oocytes from maturation and ovulation in PCOS mice. Our findings provide insight into potential mechanisms responsible for infertility in women with PCOS. PMID- 29535264 TI - TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state. AB - Pathogenic T helper 2 (TH2) cells, which produce increased amounts of the cytokines interleukin-5 (IL-5) and IL-13, promote allergic disorders, including asthma. Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial and innate immune cells, stimulates such pathogenic TH2 cell responses. We found that TSLP signaling in mouse CD4+ T cells initiated transcriptional changes associated with TH2 cell programming. IL-4 signaling amplified and stabilized the genomic response of T cells to TSLP, which increased the frequency of T cells producing IL-4, IL-5, and IL-13. Furthermore, the TSLP- and IL-4-programmed TH2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did TH2 cells stimulated with IL-4 alone. TSLP-mediated TH2 cell induction involved distinct molecular pathways, including activation of the transcription factor STAT5 through the kinase JAK2 and repression of the transcription factor BCL6. Mice that received wild-type CD4+ T cells had exacerbated pathogenic TH2 cell responses upon exposure to house dust mites compared to mice that received TSLP receptor-deficient CD4+ T cells. Transient TSLP signaling stably programmed pathogenic potential in memory TH2 cells. In human CD4+ T cells, TSLP and IL-4 promoted the generation of TH2 cells that produced greater amounts of IL-5 and IL-13. Compared to healthy controls, asthmatic children showed enhancement of such T cell responses in peripheral blood. Our data support a sequential cytokine model for pathogenic TH2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases. PMID- 29535266 TI - Prader-Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of miR-425-5p. AB - Gastric cancer (GC) is one of the major global health problems, especially in Asia. Nowadays, long non-coding RNA (lncRNA) has gained significant attention in the current research climate such as carcinogenesis. This research desires to explore the mechanism of Prader-Willi region non-protein coding RNA 1 (PWRN1) on regulating GC process. Differentially expressed lncRNAs in GC tissues were screened out through microarray analysis. The RNA and protein expression level were detected by quantitative real-time PCR (qRT-PCR) and Western blot. Cell proliferation, apoptosis rate, metastasis abilities were respectively determined by cell counting kit 8 (CCK8), flow cytometry, wound healing, and transwell assay. The luciferase reporter system was used to verify the targetting relationships between PWRN1, miR-425-5p, and phosphatase and tensin homolog (PTEN). RNA-binding protein immunoprecipitation (RIP) assay was performed to prove whether PWRN1 acted as a competitive endogenous RNA (ceRNA) of miR-425-5p Tumor xenograft model and immunohistochemistry (IHC) were developed to study the influence of PWRN1 on tumor growth in vivo Microarray analysis determined that PWRN1 was differently expressed between GC tissues and adjacent tissues. qRT-PCR revealed PWRN1 low expression in GC tissues and cells. Up-regulated PWRN1 could reduce proliferation and metastasis and increase apoptosis in GC cells, while miR 425-5p had reverse effects. The RIP assay indicated that PWRN1 may target an oncogene, miR-425-5p The tumor xenograft assay found that up-regulated PWRN1 suppressed the tumor growth. The bioinformatics analysis, luciferase assay, and Western blot indicated that PWRN1 affected PTEN/Akt/MDM2/p53 axis via suppressing miR-425-5p Our findings suggested that PWRN1 functioned as a ceRNA targetting miR 425-5p and suppressed GC development via p53 signaling pathway. PMID- 29535267 TI - Shared and Distinct Rupture Discriminants of Small and Large Intracranial Aneurysms. AB - BACKGROUND AND PURPOSE: Many ruptured intracranial aneurysms (IAs) are small. Clinical presentations suggest that small and large IAs could have different phenotypes. It is unknown if small and large IAs have different characteristics that discriminate rupture. METHODS: We analyzed morphological, hemodynamic, and clinical parameters of 413 retrospectively collected IAs (training cohort; 102 ruptured IAs). Hierarchal cluster analysis was performed to determine a size cutoff to dichotomize the IA population into small and large IAs. We applied multivariate logistic regression to build rupture discrimination models for small IAs, large IAs, and an aggregation of all IAs. We validated the ability of these 3 models to predict rupture status in a second, independently collected cohort of 129 IAs (testing cohort; 14 ruptured IAs). RESULTS: Hierarchal cluster analysis in the training cohort confirmed that small and large IAs are best separated at 5 mm based on morphological and hemodynamic features (area under the curve=0.81). For small IAs (<5 mm), the resulting rupture discrimination model included undulation index, oscillatory shear index, previous subarachnoid hemorrhage, and absence of multiple IAs (area under the curve=0.84; 95% confidence interval, 0.78 0.88), whereas for large IAs (>=5 mm), the model included undulation index, low wall shear stress, previous subarachnoid hemorrhage, and IA location (area under the curve=0.87; 95% confidence interval, 0.82-0.93). The model for the aggregated training cohort retained all the parameters in the size-dichotomized models. Results in the testing cohort showed that the size-dichotomized rupture discrimination model had higher sensitivity (64% versus 29%) and accuracy (77% versus 74%), marginally higher area under the curve (0.75; 95% confidence interval, 0.61-0.88 versus 0.67; 95% confidence interval, 0.52-0.82), and similar specificity (78% versus 80%) compared with the aggregate-based model. CONCLUSIONS: Small (<5 mm) and large (>=5 mm) IAs have different hemodynamic and clinical, but not morphological, rupture discriminants. Size-dichotomized rupture discrimination models performed better than the aggregate model. PMID- 29535269 TI - Oral Care Assessment Tools and Interventions After Stroke. PMID- 29535268 TI - Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). AB - BACKGROUND AND PURPOSE: Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke. METHODS: The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults >=65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V1, left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors. RESULTS: Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V1 (hazard ratio per 1000 MUV*ms 1.04; 95% confidence interval, 1.001-1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT proBNP, 1.09; 95% confidence interval, 1.03-1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67-2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84-1.10). CONCLUSIONS: In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease. PMID- 29535270 TI - Posttreatment National Institutes of Health Stroke Scale Is Superior to the Initial Score or Thrombolysis in Cerebral Ischemia for 3-Month Outcome. AB - BACKGROUND AND PURPOSE: The majority of ischemic stroke patients receiving endovascular recanalization therapy (EVT) experience variable changes of neurological severities during the hyperacute period. We hypothesized that the National Institutes of Health Stroke Scale (NIHSS) score after EVT is a better prognostic factor compared with the initial NIHSS score or revascularization status. METHODS: We identified 566 stroke patients who received EVT at Seoul National University Bundang Hospital between April 2008 and December 2015. We prospectively collected post-EVT NIHSS score, which was measured in the angiography suite by on-duty physicians after completion of EVT. Model 1 included baseline predictors including an initial NIHSS score. In model 2, 3, and 4, revascularization status, post-EVT NIHSS score, or both were additionally included. The discrimination powers for modified Rankin Scale score of 0 to 2 at 3 months were assessed using C statistic, integrated discrimination index, and category-free net reclassification index. RESULTS: The median of initial and post EVT NIHSS score were 14 (9-19) and 11 (5-17) points, respectively (an improvement, 58.8%; no change, 20.7%; deterioration, 20.5%). A modified Rankin Scale score 0 to 2 at 3 months was achieved in 47%. Based on the results of differences among the C statistics, both model 3 and model 4 (C statistics: 0.896 and 0.906) showed significantly increased discrimination power for modified Rankin Scale score 0 to 2 at 3 months than the model 1 or 2 (C statistics: 0.802 and 0.834, P values<0.001 for all comparisons). Model 4 showed significant improvement of both integrated discrimination index and net reclassification index as compared with all other models, but the magnitude of improvement from model 3 to model 4 (integrated discrimination index, 0.021; net reclassification index, 0.322) was modest. CONCLUSIONS: Incorporation of post-EVT NIHSS score conferred better discrimination power to the statistical models for functional recovery. Post-EVT NIHSS score may be an appropriate baseline factor when evaluating an intervention after hyperacute period. PMID- 29535271 TI - Utility-Weighted Modified Rankin Scale as Primary Outcome in Stroke Trials: A Simulation Study. AB - BACKGROUND AND PURPOSE: The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a new patient-centered primary outcome in stroke trials. We aimed to describe utility weights for the mRS health states and to evaluate the statistical efficiency of the UW-mRS to detect treatment effects in stroke intervention trials. METHODS: We used data of the 500 patients enrolled in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Utility values were elicited from the EuroQol Group 5-Dimension Self-Report Questionnaire assessed at 90 days after inclusion, simultaneously with the mRS. Utility weights were determined by averaging the utilities of all patients within each mRS category. We performed simulations to evaluate statistical efficiency. The simulated treatment effect was an odds ratio of 1.65 in favor of the treatment arm, similar for all mRS cutoffs. This treatment effect was analyzed using 3 approaches: linear regression with the UW-mRS as outcome, binary logistic regression with a dichotomized mRS (0 1/2-6, 0-2/3-6, and 0-4/5-6), and proportional odds logistic regression with the ordinal mRS. The statistical power of the 3 approaches was expressed as the proportion of 10 000 simulations that resulted in a statistically significant treatment effect (P<=0.05). RESULTS: The mean utility values (SD) for mRS categories 0 to 6 were: 0.95 (0.08), 0.93 (0.13), 0.83 (0.21), 0.62 (0.27), 0.42 (0.28), 0.11 (0.28), and 0 (0), respectively, but varied substantially between individual patients within each category. The UW-mRS approach was more efficient than the dichotomous approach (power 85% versus 71%) but less efficient than the ordinal approach (power 85% versus 87%). CONCLUSIONS: The UW-mRS as primary outcome does not capture individual variation in utility values and may reduce the statistical power of a randomized trial. PMID- 29535272 TI - Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated those changes by means of a systematic review and meta-analysis. METHODS: We evaluated all population- and hospital based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model. RESULTS: Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval [CI], 20-23); large artery atherosclerosis (23%; 95% CI, 21-25); small artery occlusion (22%; 95% CI, 21-24); other determined cause (3%; 95% CI, 3-3); and undetermined cause (26%; 95% CI, 24-28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26-29) and large artery atherosclerosis in Asians (33%; 95% CI, 31 36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually, P=0.008) and large artery atherosclerosis in Asians (5.7% annually, P<0.001), and a decrease for small artery occlusion in whites (-4.7% annually, P=0.001); there was considerable heterogeneity across all the analyses. CONCLUSIONS: According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS. PMID- 29535273 TI - Cranial Cavernous Malformations: Natural History and Treatment. PMID- 29535274 TI - Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study. AB - BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). METHODS: Summary data on 185 genome-wide lipids associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes. PMID- 29535275 TI - Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases. AB - High structural and sequence similarity within protein families can pose significant challenges to the development of selective inhibitors, especially toward proteolytic enzymes. Such enzymes usually belong to large families of closely similar proteases and may also hydrolyze, with different rates, protein- or peptide-based inhibitors. To address this challenge, we employed a combinatorial yeast surface display library approach complemented with a novel pre-equilibrium, competitive screening strategy for facile assessment of the effects of multiple mutations on inhibitor association rates and binding specificity. As a proof of principle for this combined approach, we utilized this strategy to alter inhibitor/protease association rates and to tailor the selectivity of the amyloid beta-protein precursor Kunitz protease inhibitor domain (APPI) for inhibition of the oncogenic protease mesotrypsin, in the presence of three competing serine proteases, anionic trypsin, cationic trypsin and kallikrein-6. We generated a variant, designated APPIP13W/M17G/I18F/F34V, with up to 30-fold greater specificity relative to the parental APPIM17G/I18F/F34V protein, and 6500- to 230 000-fold improved specificity relative to the wild-type APPI protein in the presence of the other proteases tested. A series of molecular docking simulations suggested a mechanism of interaction that supported the biochemical results. These simulations predicted that the selectivity and specificity are affected by the interaction of the mutated APPI residues with nonconserved enzyme residues located in or near the binding site. Our strategy will facilitate a better understanding of the binding landscape of multispecific proteins and will pave the way for design of new drugs and diagnostic tools targeting proteases and other proteins. PMID- 29535276 TI - Discovery and characterization of a sulfoquinovose mutarotase using kinetic analysis at equilibrium by exchange spectroscopy. AB - Bacterial sulfoglycolytic pathways catabolize sulfoquinovose (SQ), or glycosides thereof, to generate a three-carbon metabolite for primary cellular metabolism and a three-carbon sulfonate that is expelled from the cell. Sulfoglycolytic operons encoding an Embden-Meyerhof-Parnas-like or Entner-Doudoroff (ED)-like pathway harbor an uncharacterized gene (yihR in Escherichia coli; PpSQ1_00415 in Pseudomonas putida) that is up-regulated in the presence of SQ, has been annotated as an aldose-1-epimerase and which may encode an SQ mutarotase. Our sequence analyses and structural modeling confirmed that these proteins possess mutarotase-like active sites with conserved catalytic residues. We overexpressed the homolog from the sulfo-ED operon of Herbaspirillum seropedicaea (HsSQM) and used it to demonstrate SQ mutarotase activity for the first time. This was accomplished using nuclear magnetic resonance exchange spectroscopy, a method that allows the chemical exchange of magnetization between the two SQ anomers at equilibrium. HsSQM also catalyzed the mutarotation of various aldohexoses with an equatorial 2-hydroxy group, including d-galactose, d-glucose, d-glucose-6 phosphate (Glc-6-P), and d-glucuronic acid, but not d-mannose. HsSQM displayed only 5-fold selectivity in terms of efficiency (kcat/KM) for SQ versus the glycolysis intermediate Glc-6-P; however, its proficiency [kuncat/(kcat/KM)] for SQ was 17 000-fold better than for Glc-6-P, revealing that HsSQM preferentially stabilizes the SQ transition state. PMID- 29535277 TI - Cell-cell interactions between monocytes/macrophages and synoviocyte-like cells promote inflammatory cell infiltration mediated by augmentation of MCP-1 production in temporomandibular joint. AB - Many inflammatory cells are known to be home to inflamed temporomandibular joint (TMJ) tissues by stimulation with cytokines and chemokines produced by inflammatory lesions in the TMJ. However, how the inflammatory cells affect the progression of inflammation in TMJ synovial tissues after their homing to inflamed TMJ site is still uncertain. Here, we isolated and cultured TMJ synoviocyte-like cells (TMJSCs) from murine TMJ tissues. We demonstrated that interleukin 1beta (IL-1beta) up-regulated expression of monocyte chemoattractant protein 1 (MCP-1) in TMJSCs. In addition, we found that IL-1beta-treated TMJSCs strongly promoted migratory activity of mouse monocyte/macrophage RAW264.7 cells through secretion of MCP-1. On the other hand, IL-1beta up-regulated expression levels of intracellular adhesion molecule 1 (ICAM-1), a leukocyte adhesion ligand in TMJSCs. In addition, IL-1beta promoted cell-cell adhesion between TMJSCs and RAW264.7 cells. Intriguingly, we also found that cell-cell interactions mediated through soluble factors other than IL-1beta and cell-cell adhesion molecules between IL-1beta-stimulated TMJSCs and RAW264.7 cells synergistically augmented secretion of MCP-1 from these cells. Therefore, these results suggested that the IL-1beta-induced recruitment of monocyte/macrophage lineage cells to inflamed synovial membranes in TMJ was further augmented by the cell-cell interaction induced secretion of MCP-1 from the inflammation site, possibly resulting in prolonged inflammatory responses in TMJ synovial tissue. PMID- 29535278 TI - Regorafenib inhibits tumor progression through suppression of ERK/NF-kappaB activation in hepatocellular carcinoma bearing mice. AB - Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor kappaB (NF-kappaB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro However, the effect of regorafenib on NF-kappaB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-kappaB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK Hep1/luc2) and Hep3B 2.1-7 tumor bearing mice were established and used for the present study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-kappaB p65 (Ser536), phosphorylated AKT, and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-kappaB signaling in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice. PMID- 29535279 TI - Intra-operative periarticular multimodal injection in total knee arthroplasty: a local hospital experience in Hong Kong. AB - INTRODUCTION: Data from a local report revealed the superior outcome of regional anaesthesia and analgesia compared with general anaesthesia and intravenous patient-controlled analgesia in total knee arthroplasty. This retrospective study aimed to assess the efficacy of intra-operative periarticular multimodal injection in improving postoperative pain and reducing morphine consumption with patient-controlled analgesia after total knee arthroplasty in patients with knee osteoarthritis. METHODS: From July 2005 to May 2009, 213 total knee arthroplasties without intra-operative periarticular multimodal injection (control group) were performed at a local hospital. From June 2009 to December 2012, 185 total knee arthroplasties were performed with intra-operative periarticular multimodal injection (cocktail group). The inclusion criteria were osteoarthritis of the knee, single method of anaesthesia (general or neuraxial), simple total knee arthroplasty without any metal augmentation or constraint, and postoperative patient-controlled analgesia. Postoperative patient-controlled morphine doses were compared. RESULTS: A total of 152 total knee arthroplasties were recruited to the cocktail group, and 89 to the control group. Duration of tourniquet application and preoperative knee score did not significantly correlate with morphine consumption by patient-controlled analgesia. Multimodal injection significantly decreased such consumption for 36 h. When injection was separately analysed for general and neuraxial anaesthesia, the effect lasted for 42 h and 24 h, respectively. CONCLUSION: Intra-operative periarticular multimodal injection decreased morphine consumption for up to 42 h postoperatively. PMID- 29535280 TI - [Effects of Aromatherapy on Stress Responses, Autonomic Nervous System Activity and Blood Pressure in the Patients Undergoing Coronary Angiography: A Non Randomized Controlled Trial]. AB - PURPOSE: The purpose of this study was to examine the effects of aromatherapy on stress responses, autonomic nervous system (ANS) activity, and blood pressure in patients hospitalized to receive coronary angiography (CAG). METHODS: A non equivalent control group with a pretest-posttest design was used. The subjects were patients admitted to the day angiography room to receive CAG at E University Hospital (34 in the experimental group and 30 in the control group). The experimental group treatment was inhalation of the aroma oil blended with lavender, ylang-ylang, and neroli at a ratio of 4:2:1 twice before and after CAG. The measurements of stress index, ANS activity, and blood pressure were performed 5 times as follows: at admission, at pre-CAG after treatment I, at post-CAG, 2 hours after treatment II, and 4 hours after treatment II. The data were analyzed using the Mann-Whitney U Test and repeated-measures analysis of variance. RESULTS: Significant interactions in the high frequency of ANS (F=5.58, p=.005) were observed between group and time. Stress index (z=2.14, p=.016), systolic blood pressure (z=4.14, p<.005), and diastolic blood pressure (z=3.28, p=.001) were significantly different between the experimental and control groups after 4 hours of treatment II. CONCLUSION: The findings showed that aromatherapy was not effective before CAG, but was effective after CAG. Therefore, aromatherapy can be used as a nursing intervention for patients receiving CAG. PMID- 29535281 TI - [Development of Job Satisfaction Scale for Clinical Nurses]. AB - PURPOSE: This study was performed to develop the Job Satisfaction Scale for Clinical Nurses (JSS-CN) and verify its validity and reliability. METHODS: A preliminary 42-item version of the JSS-CN was developed through literature reviews and in-depth interviews. The draft scale was developed using thirty-seven items selected following content validity evaluation. Finally, thirty-three items with response options on a 5-point Likert scale were selected based on internal consistency reliability and construct validity. Subsequently, the test-retest reliability and convergent validity of the JSS-CN were verified. RESULTS: Six factors, namely, recognition from the organization and professional achievement, personal maturation through the nursing profession, interpersonal interaction with respect and recognition, accomplishment of accountability as a nurse, display of professional competency, and stability and job worth, were identified, which explained 59.7% of the total variance. The JSS-CN's Cronbach's alpha for the total scale was .95, and the intra-class correlation coefficient was .90. The correlation coefficient between the scores of the JSS-CN and Slavitt's scale was .75, and that between the JSS-CN and job performance was .53. CONCLUSION: Results showed that the JSS-CN has good reliability and validity. Therefore, it is concluded that the JSS-CN could be a useful tool for the measurement of the job satisfaction of clinical nurses in Korea. PMID- 29535282 TI - [Effects of Active Mandibular Exercise for Mouth Opening Limitation Patients after Maxillomandibular Fixation Release: A Non-Randomized Controlled Trial]. AB - PURPOSE: The aim of this study was to evaluate the effects of active mandibular exercise (AME) in patients with limited mouth opening after maxillomandibular fixation (MMF) release. METHODS: The study used a quasi-experimental, nonequivalent control group and a pre test-post test design. Sixty-two patients with Maxillomandibular Fixation Release were assigned to the experimental (n=31) or control group (n=31). The AME was performed in the experimental group for 4 weeks. The exercise AME consisted of maximal mouth opening, lateral excursion and protrusive movement. These movements were repeated ten times a day. After the final exercise of the day, the number of tongue blades used for mouth opening was noted. The effect of AME was evaluated after MMF release at different time intervals: a) immediately, b) after 1 week, c) after 2 weeks, d) after 4 weeks, and e) after 12 weeks. The exercise was assessed using the following criteria: a) mandibular movements, b) pain scores associated with maximal mouth opening, c) discomfort scores associated with range of movement, and d) daily life activities that involve opening the mouth. RESULTS: The experimental group showed significant improvement regarding the range of mandibular movements (maximal mouth opening (F=23.60, p<.001), lateral excursion to the right side (F=5.25, p=.002), lateral excursion to the left side (F=5.97, p=.001), protrusive movement (F=5.51, p=.001)), pain score (F=39.59, p<.001), discomfort score (F=9.38, p<.001). Daily life activities that involve opening the mouth were more favorable compared to those in the control group. CONCLUSION: The AME in patients after MMF release is helpful for increasing mandibular movement range, decreasing pain and discomfort, and improving day life activities that involve opening the mouth. Therefore, AME is highly recommended as an effective nursing intervention. PMID- 29535283 TI - [Development of an Instrument to Assess the Quality of Childbirth Care from the Mother's Perspective]. AB - PURPOSE: This study aimed to develop an instrument to assess the quality of childbirth care from the perspective of a mother after delivery. METHODS: The instrument was developed from a literature review, interviews, and item validation. Thirty-eight items were compiled for the instrument. The data for validity and reliability testing were collected using a questionnaire survey conducted on 270 women who had undergone normal vaginal delivery in Korea and analyzed with descriptive statistics, exploratory factor analysis, and reliability coefficients. RESULTS: The exploratory factor analysis reduced the number of items in the instrument to 28 items that were factored into four subscales: family-centered care, personal care, emotional empowerment, and information provision. With respect to convergence validation, there was positive correlation between this instrument and birth satisfaction scale (r=.34, p<.001). The internal consistency reliability was acceptable (Cronbach's alpha =.96). CONCLUSION: This instrument could be used as a measure of the quality of nursing care for women who have a normal vaginal delivery. PMID- 29535284 TI - [Impact of Uncertainty on the Quality of Life of Young Breast Cancer Patients: Focusing on Mediating Effect of Marital Intimacy]. AB - PURPOSE: The purpose of this study was to examine the mediating effect of marital intimacy on the impact of uncertainty on the quality of life (QoL) of young breast cancer patients. METHODS: This study used a pathway analysis with 154 young breast cancer cases in their early diagnosis stage at a medical center in Korea. Data were collected from November 2016 to February 2017 and analyzed using correlation analysis and pathway analysis. RESULTS: Uncertainty, marital intimacy, and 4 sub-scales of QoL showed a significant correlation. Marital intimacy was directly affected by uncertainty (beta=-.39, p=.013) and 4 sub scales of QoL were also affected by uncertainty. Among the 4 sub-scales of QoL, physical well-being (PWB) (beta=.17, p=.026), social well-being (SWB) (beta=.49, p=.010), and functional well-being (FWB) (beta=.38, p=.009) were affected by marital intimacy but emotional well-being (EWB) was not affected by it. The mediating effect of marital intimacy on the impact of uncertainty on QoL was confirmed. Marital intimacy showed a significant indirect effect on PWB (beta= .07, p=.024), SWB (beta=-.19, p=.008), and FWB (beta=-.15, p=.005), and it means that marital intimacy has a partial mediating effect on the impact of uncertainty on PWB, SWB, and FWB. CONCLUSION: Effects of uncertainty on QoL was mediated by marital intimacy of young breast cancer patients in their early diagnosis stage. It suggests that marital intimacy needs to be considered in providing nursing intervention for young breast cancer patients. PMID- 29535285 TI - [Influential Factors of Complicated Grief of Bereaved Spouses from Cancer Patient]. AB - PURPOSE: The purpose of this study was to investigate variables and construct paths that affect complicated grief. METHODS: Participants in this cross sectional, descriptive study were 164 bereaved spouses of cancer patients at least 12 months before the death. Data were collected from October 2016 to February 2017 using self-report structured questionnaires and were analyzed using IBM SPSS 21.0 and AMOS 20.0. RESULTS: The variables affecting complicated grief of bereaved spouses of cancer patients were the quality of end-of-life care (gamma=.15, p<.001), preparedness for death (beta=-.06, p=.005), and coping with bereavement (beta=-.24, p<.001), whereas the quality of death and dying did not show any effects. Preparedness for death had multiple mediating effects in the relationship between the quality of end-of-life care and complicated grief (z= 2.20, p=.028), and in the relationship between the quality of end-of-life care and coping with bereavement (z=2.11, p=.035). Coping with bereavement had a mediating effect on the relationship between preparedness for death and complicated grief (z=-2.39, p=.017). CONCLUSION: This study revealed that preparedness for death and coping with bereavement play a prominent role in complicated grief. Therefore, it is important to help in preparing for death and enhancing coping with bereavement of spouses providing end-of-life care to cancer patients. In addition, investigating cultural differences in the relationship between the quality of end-of-life care and complicated grief is recommended. PMID- 29535286 TI - [Validity and Reliability of the Korean Version Scale of the Clinical Learning Environment, Supervision and Nurse Teacher Evaluation Scale (CLES+T)]. AB - PURPOSE: This study was conducted to evaluate the validity and reliability of the Korean version of the clinical learning environment, supervision and nurse teacher evaluation scale (CLES+T) that measures the clinical learning environment and the conditions associated with supervision and nurse teachers. METHODS: The English CLES+T was translated into Korean with forward and back translation. Survey data were collected from 434 nursing students who had more than four days of clinical practice in Korean hospitals. Internal consistency reliability and construct validity using confirmatory and exploratory factor analysis were conducted. SPSS 20.0 and AMOS 22.0 programs were used for data analysis. RESULTS: The exploratory factor analysis revealed seven factors for the thirty three-item scale. Confirmatory factor analysis supported good convergent and discriminant validities. The Cronbach's alpha for the overall scale was .94 and for the seven subscales ranged from .78 to .94. CONCLUSION: The findings suggest that the 33 items Korean CLES+T is an appropriate instrument to measure Korean nursing students'clinical learning environment with good validity and reliability. PMID- 29535287 TI - [Threats to Identity: A Grounded Theory Approach on Student Nurses' Experience of Incivility during Clinical Placement]. AB - PURPOSE: This qualitative study aimed to explore the experience of incivility among nursing students. METHODS: Sixteen nursing students who had experienced incivility during their clinical placement were invited for one-on-one interviews until the point of theoretical saturation. The grounded theory approach of Corbin and Strauss was adopted to analyze transcribed interview contents. RESULTS: Incivility occurred in the context of a hierarchical organizational culture, due to nursing students' position as outsiders, non-systematic clinical education, and poor nursing work environment. The experience of incivility was identified as "being mistreated as a marginal person," and nursing students responded to this phenomenon in the following three steps: reality shock, passive action, and submissive acceptance. This process caused students to lose self-esteem and undergo role conflict. Furthermore, nursing students' experience of incivility could eventually lead to workplace bullying in nurses. CONCLUSION: The results of this study suggest that nursing students' experience of incivility can be a process that threatens their identity. It is necessary to develop educational programs and provide appropriate counseling services so that nursing students can actively cope with the incivility. In addition, institutional plans are needed to ensure safe and supportive clinical learning environments. PMID- 29535288 TI - [Structural Equation Model of Health-Related Quality of Life in School Age Children with Asthma]. AB - PURPOSE: This study aimed to construct and test a hypothetical model of the quality of life of school-age children with asthma based on the health-related quality of life model by Wilson and Cleary. METHODS: Data were collected from 205 pairs of pediatric outpatients diagnosed with asthma and their parents in Seoul and Gyeonggi-do from July 2016 to April 2017. The exogenous variables were asthma knowledge, number of accompanying allergic diseases, and social support. The endogenous variables were asthma self-efficacy, asthma symptom control, perceived health status, parental quality of life, and children's quality of life. For data analysis, descriptive statistics, factor analysis, and structural equation modeling were performed. RESULTS: Eighteen of the twenty-four hypotheses selected for the hypothetical model were attentive and supported statistically. Quality of life was explained by asthma self-efficacy, asthma symptom control, perceived health, parental quality of life, and asthma knowledge with 83.5%. CONCLUSION: Strategies for promoting self-efficacy and enforcing asthma knowledge will be helpful for the improvement of health-related quality of life with school-aged asthmatic children. PMID- 29535289 TI - Effects of Parenting Stress and Controlling Parenting Attitudes on Problem Behaviors of Preschool Children: Latent Growth Model Analysis. AB - PURPOSE: This study was conducted to examine the longitudinal effects of parenting stress and parental control attitudes on problem behaviors in preschool children, using a latent growth model. METHODS: Participants were 1,724 pairs of parents and 1,724 preschool children who had completed the panel survey on Korean children (5(th)~7(th) survey panels). RESULTS: An analysis of the multivariate latent growth model of parenting stress, parental control attitudes, and children's problem behaviors suggested that the parents' intercepts for parenting stress influenced their intercepts for parental control attitudes (father: beta=.21, p<.001; mother: beta=.55, p<.001). In addition, the slopes for fathers' parenting stress was the only aspect that affected the slopes for mothers' parental control attitudes (beta=.77, p<.001). Moreover, both the intercepts and slopes of parenting stress and parental control attitudes significantly affected the children's problem behaviors. CONCLUSION: This study is significant as it provides longitudinal evidence of the impact of parenting stress and parental control attitudes on children's problem behaviors. The findings suggest that accurately assessing changes in parenting stress and parental control attitudes and developing intervention programs to reduce them will be effective in reducing problem behaviors in children. PMID- 29535290 TI - Circulating miR-23b as a Novel Biomarker for Early Risk Stratification After ST Elevation Myocardial Infarction. AB - BACKGROUND miR-23b overexpression can promote cardiomyocyte apoptosis and reduce cell growth under hypoxic conditions, suggesting that miR-23b acts as a biomarker for ST-elevation myocardial infarction (STEMI). The aim of this study was to investigate the effect of miR-23b on STEMI patients. MATERIAL AND METHODS We enrolled 80 eligible patients with STEMI and 60 control subjects. Blood samples were obtained at 6 h, 12 h, 24 h, 48 h, 3 days, and 7 days after the onset of symptoms. Another blood sample was collected before and after percutaneous coronary intervention (PCI). The samples were used for real-time quantitative PCR analysis. A Siemens Immulite2000 detector (Germany) was used for cTnI detection, and the serum CK-MB content was detected by electrochemical luminescence method. RESULTS The expression level of miR-23b was increased in patients with STEMI (P<0.05). No significance difference was observed among risk factors, although the clinical data was comparable (P>0.05). The level of miR-23b in STEMI patients after PCI was lower (P<0.05). The ROC curve of plasma miR-23b showed a separation, with an AUC of 0.809 (95%CI, 0.737-0.936, P<0.05), compared to CK-MB with an AUC of 0.753 (95%CI, 0.707-0.896) and cTnI with an AUC of 0.783 (95%CI, 0.723-0.917). CONCLUSIONS The present study reveals that miR-23b is a useful biomarker of STEMI, providing a novel insight for the diagnosis for STEMI. PMID- 29535291 TI - A Case of Low-Grade Primary Cardiac Lymphoma with Pericardial Effusion Diagnosed by Combined 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography (FDG-PET/CT) Imaging and Effusion Cytology. AB - BACKGROUND Primary cardiac lymphoma is rare and can be an aggressive disease, depending on the grade. A case is reported of low-grade primary cardiac lymphoma associated with a pericardial effusion. 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) imaging was useful in the diagnosis and in evaluating the disease activity in this case. CASE REPORT A 72 year-old Japanese woman visited a general practitioner, complaining of dyspnea associated with cardiac tamponade. Pericardiocentesis was performed, and Group V malignant cells were identified by cytology, suspicious for malignant lymphoma. Whole-body FDG-PET/CT scans showed no pleural effusion or lymph node metastasis supporting the diagnosis of primary cardiac lymphoma diagnosed on pericardial effusion. The laboratory investigations showed that levels of serum soluble interleukin-2 (IL-2) receptor (sIL-2R), a diagnostic and prognostic marker for malignant lymphoma, were not elevated (258 U/ml). A six-month follow-up FDG PET/CT scan showed an increased volume of the pericardial effusion and mild but abnormal uptake diffusely in the pericardial space, and the sIL-2R was slightly elevated (860 U/ml). No abnormal FDG accumulation outside the retained pericardial effusion was noted, which was compatible with a clinical picture of low-grade primary cardiac lymphoma, and in a period of watchful waiting during the first two years later, the sIL-2R had reduced to 195 U/ml. CONCLUSIONS This is a rare case of low-grade primary cardiac lymphoma detected in a pericardial effusion, and highlights the utility of the FDG-PET/CT scan as a valuable diagnostic and follow-up modality. PMID- 29535292 TI - Detection of novel astroviruses MLB1 and MLB2 in the sera of febrile Tanzanian children. PMID- 29535294 TI - Addendum: Application of bio-orthogonal proteome labeling to cell transplantation and heterochronic parabiosis. PMID- 29535293 TI - Integrated analysis of human-animal-vector surveillance: West Nile virus infections in Austria, 2015-2016. AB - The results of integrated human and veterinary surveillance for West Nile virus (WNV) infections in Austria during the transmission seasons 2015 and 2016 are shown. Altogether WNV nucleic acid was detected in 21 humans, horses, wild birds and mosquito pools. In detail: in four human clinical cases [two cases of West Nile fever (WNF) and two cases of West Nile neuroinvasive disease (WNND)]; eight blood donors [among 145,541 tested donations], of which three remained asymptomatic and five subsequently developed mild WNF; two horses with WNND, of which one recovered and one had to be euthanized; two wild birds [one goshawk and one falcon, both succumbed to WNND]; and five Culex pipiens mosquito pools. Compared to previous years the number of infections increased remarkably. All infections were recorded in the city of Vienna and neighboring regions of Lower Austria. Sixteen coding-complete WNV sequences were established which were closely related to each other and to other Austrian, Czech and Italian viruses, all belonging to the Central/Southern European cluster of WNV sublineage 2d. However, several genetically slightly different WNV strains seem to co-circulate in the same area, as demonstrated by phylogenetic analysis. Based on detailed sequence analysis, all newly discovered Austrian WNV strains had the potential to cause neurological disease, but no correlation was found between severity of disease and the analyzed genetic virulence/neuroinvasiveness markers. Results of integrated human-animal-vector surveillance presented in this paper provide a comprehensive description of WNV activity in the region and will facilitate proactive public health measures to prevent or mitigate potential outbreaks. PMID- 29535295 TI - A four-year survey (2011-2014) of West Nile virus infection in humans, mosquitoes and birds, including the 2012 meningoencephalitis outbreak in Tunisia. AB - A West Nile virus (WNV) outbreak occurred in Tunisia between mid-July and December 2012. To assess the epidemiological features of the WNV transmission cycle, human cerebrospinal fluid samples from patients with suspected cases (n = 79), Culex pipiens mosquitoes (n = 583) and serum specimens from domestic and migratory birds (n = 70) were collected for 4 years (2011-2014) in the Tunisian Sahel region. Viral testing was performed by polymerase chain reaction (PCR). The WNV genome was detected in 7 patients (8.8%), 4 Culex pipiens pools, and a domestic mallard (Anas platyrhynchos). All PCR-positive samples were from the Monastir region. Phylogenetic analysis revealed that two different WNV strain groups circulated, and isolates from the reservoir (bird), vector (Culex pipiens), and dead-end hosts (humans) were closely related. The Monastir region is a hot-spot for WNV infection, and the reiterative presence of WNV over the years has increased the risk of viral reemergence in Tunisia, which highlights the need for more enhanced and effective WNV surveillance in humans with public awareness campaigns strengthened by monitoring mosquitoes and maintaining avian surveillance for early detection of WNV circulation. PMID- 29535297 TI - Warm Arctic episodes linked with increased frequency of extreme winter weather in the United States. AB - Recent boreal winters have exhibited a large-scale seesaw temperature pattern characterized by an unusually warm Arctic and cold continents. Whether there is any physical link between Arctic variability and Northern Hemisphere (NH) extreme weather is an active area of research. Using a recently developed index of severe winter weather, we show that the occurrence of severe winter weather in the United States is significantly related to anomalies in pan-Arctic geopotential heights and temperatures. As the Arctic transitions from a relatively cold state to a warmer one, the frequency of severe winter weather in mid-latitudes increases through the transition. However, this relationship is strongest in the eastern US and mixed to even opposite along the western US. We also show that during mid-winter to late-winter of recent decades, when the Arctic warming trend is greatest and extends into the upper troposphere and lower stratosphere, severe winter weather-including both cold spells and heavy snows-became more frequent in the eastern United States. PMID- 29535296 TI - Comparison of the pathogenic potential of highly pathogenic avian influenza (HPAI) H5N6, and H5N8 viruses isolated in South Korea during the 2016-2017 winter season. AB - Highly pathogenic avian influenza (HPAI) A(H5N6) and A(H5N8) virus infections resulted in the culling of more than 37 million poultry in the Republic of Korea during the 2016/17 winter season. Here we characterize two representative viruses, A/Environment/Korea/W541/2016 [Em/W541(H5N6)] and A/Common Teal/Korea/W555/2017 [CT/W555(H5N8)], and evaluate their zoonotic potential in various animal models. Both Em/W541(H5N6) and CT /W555(H5N8) are novel reassortants derived from various gene pools of wild bird viruses present in migratory waterfowl arising from eastern China. Despite strong preferential binding to avian virus-type receptors, the viruses were able to grow in human respiratory tract tissues. Em/W541(H5N6) was found to be highly pathogenic in both chickens and ducks, while CT/W555(H5N8) caused lethal infections in chickens but did not induce remarkable clinical illness in ducks. In mice, both viruses appeared to be moderately pathogenic and displayed limited tissue tropism relative to HPAI H5N1 viruses. Em/W541(H5N6) replicated to moderate levels in the upper respiratory tract of ferrets and was detected in the lungs, brain, spleen, liver, and colon. Unexpectedly, two of three ferrets in direct contact with Em/W541(H5N6)-infected animals shed virus and seroconverted at 14 dpi. CT/W555(H5N8) was less pathogenic than the H5N6 virus in ferrets and no transmission was detected. Given the co-circulation of different, phenotypically distinct, subtypes of HPAI H5Nx viruses for the first time in South Korea, detailed virologic investigations are imperative given the capacity of these viruses to evolve and cause human infections. PMID- 29535298 TI - Analysis of global prevalence of antibiotic resistance in Acinetobacter baumannii infections disclosed a faster increase in OECD countries. AB - Acinetobacter baumannii is one of the most challenging nosocomial pathogens due to the emergence and widespread of antibiotic resistance. We aimed to provide the first analysis of global prevalence of antibiotic resistance in A. baumannii infections, by synthesizing data and knowledge through a systematic review. We searched studies reporting antibiotic resistance in A. baumannii infections using the Medline, Embase, Web of Science, and Cochrane databases from January 2000 to December 2016. Studies were eligible if they investigated and reported antibiotic resistance in A. baumannii infections with inpatients or outpatients in hospital. Our investigation showed a high prevalence of resistance to the common prescribed antibiotics in A. baumannii infections in both OECD (Organization for Economic Co operation and Development) and non-OECD countries. Strikingly, though OECD countries have substantially lower pooled prevalence of resistance compared to non-OECD countries based on the data during 2006-2016, a further investigation in a time scale disclosed a faster increase in OECD countries during the past 11 years, and currently both of them have a comparable prevalence of resistance (2011-2016). Tigecycline and colistin are still active but their resistances are expected to become common if the preventative measures are not taken. Antibiotic resistance in A. baumannii infection developed fast and is a crisis for both OECD and non-OECD countries. A "post-antibiotic era" for A. baumannii infection is expected in the next 10-20 years without immediate actions from pharmaceutical companies and governments. PMID- 29535299 TI - Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms. AB - We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment. PMID- 29535300 TI - Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling. AB - Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts. PMID- 29535301 TI - Rapid rise of the ESBL and mcr-1 genes in Escherichia coli of chicken origin in China, 2008-2014. AB - Extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) strains are emerging around the world as a source of resistance to beta-lactam antibiotics such as ampicillin, cefotaxime, and ceftazidime. mcr-1 is a novel plasmid mediated gene conferring resistance to colistin. The aim of this study was to investigate the prevalence of ESBL-EC mcr-1 of chicken origin in the different provinces of China during 2008-2014. Overall, 341 of 821 isolates were determined to be ESBL-EC strains, and the proportion of ESBL-positive strains almost doubled from 2008 to 2014. The findings of our study revealed regional differences, with significantly more ESBL-EC isolates from stockbreeding in concentrated poultry industry areas in Shandong than from the other four provinces. The ESBL type analysis showed that blaCTX-M was the most prevalent ESBL-encoding gene (92.7%). In total, twelve subtypes of CTX-M genes were detected, among which, blaCTX-M-55 (34.3%) and blaCTX-M-65 (17.9%) were the major identified genotypes. In addition, blaTEM and pAmpC genes were carried by 86.0% and 8.5% of isolates, respectively. In this study, we also observed 44 E. coli isolates with multiple ST types (ST46, ST1286, ST10, ST29, ST101, and ST354) carrying mcr-1, and the majority of mcr-1 carrying plasmids were IncI2. The whole-genome sequencing analysis indicated the co-existence of blaCTX-M and mcr-1 in ESBL-EC of both animal and human origin, and phylogenetic analysis further revealed their close relationship, especially several isolates sharing a small number of SNPs, which suggested the increasing trend of co-existence and transmission of ESBL and mcr-1 in both clinical medicine and veterinary medicine. PMID- 29535302 TI - New insights into chikungunya virus emergence and spread from Southeast Asia. PMID- 29535303 TI - Author Correction: Nuclear lamin A/C harnesses the perinuclear apical actin cables to protect nuclear morphology. AB - In the original version of this Article, the affiliation details for Arghavan Louhghalam were incorrectly given as 'Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA', and it should have been given as 'Department of Civil and Environmental Engineering, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA'. Furthermore, an incorrect grant number, R1610512, was acknowledged. The correct grant number is NRF-2016R1C1B2015018. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29535304 TI - Functionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell. AB - G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in a broad range of physiological responses and disease states. Activated GPCRs can undergo agonist-induced phosphorylation by G protein receptor kinases (GRKs) and second messenger-dependent protein kinases such as protein kinase A (PKA). Here, we characterize spatially segregated subpopulations of beta2-adrenergic receptor (beta2AR) undergoing selective phosphorylation by GRKs or PKA in a single cell. GRKs primarily label monomeric beta2ARs that undergo endocytosis, whereas PKA modifies dimeric beta2ARs that remain at the cell surface. In hippocampal neurons, PKA-phosphorylated beta2ARs are enriched in dendrites, whereas GRK-phosphorylated beta2ARs accumulate in soma, being excluded from dendrites in a neuron maturation-dependent manner. Moreover, we show that PKA phosphorylated beta2ARs are necessary to augment the activity of L-type calcium channel. Collectively, these findings provide evidence that functionally distinct subpopulations of this prototypical GPCR exist in a single cell. PMID- 29535305 TI - Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination. AB - The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin's surface. Here, we reveal an unexpected role for the vertebrate cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential. PMID- 29535306 TI - Role of monkeys in the sylvatic cycle of chikungunya virus in Senegal. AB - Arboviruses spillover into humans either as a one-step jump from a reservoir host species into humans or as a two-step jump from the reservoir to an amplification host species and thence to humans. Little is known about arbovirus transmission dynamics in reservoir and amplification hosts. Here we elucidate the role of monkeys in the sylvatic, enzootic cycle of chikungunya virus (CHIKV) in the region around Kedougou, Senegal. Over 3 years, 737 monkeys were captured, aged using anthropometry and dentition, and tested for exposure to CHIKV by detection of neutralizing antibodies. Infant monkeys were positive for CHIKV even when the virus was not detected in a concurrent survey of mosquitoes and when population immunity was too high for monkeys alone to support continuous transmission. We conclude that monkeys in this region serve as amplification hosts of CHIKV. Additional efforts are needed to identify other hosts capable of supporting continuous circulation. PMID- 29535307 TI - Structure-based design of chimeric antigens for multivalent protein vaccines. AB - There is an urgent need to develop vaccines against pathogenic bacteria. However, this is often hindered by antigenic diversity and difficulties encountered manufacturing membrane proteins. Here we show how to use structure-based design to develop chimeric antigens (ChAs) for subunit vaccines. ChAs are generated against serogroup B Neisseria meningitidis (MenB), the predominant cause of meningococcal disease in wealthy countries. MenB ChAs exploit factor H binding protein (fHbp) as a molecular scaffold to display the immunogenic VR2 epitope from the integral membrane protein PorA. Structural analyses demonstrate fHbp is correctly folded and the PorA VR2 epitope adopts an immunogenic conformation. In mice, immunisation with ChAs generates fHbp and PorA antibodies that recognise the antigens expressed by clinical MenB isolates; these antibody responses correlate with protection against meningococcal disease. Application of ChAs is therefore a potentially powerful approach to develop multivalent subunit vaccines, which can be tailored to circumvent pathogen diversity. PMID- 29535308 TI - Scalable WDM phase regeneration in a single phase-sensitive amplifier through optical time lenses. AB - Optical data regeneration is attractive, due to its potential to increase transmission reach and data throughput in communication systems, and several interesting proposals have been made. However, efficient and scalable solutions for regeneration of multiple parallel wavelength channels have been elusive, constituting a key challenge, which must be overcome for optical regeneration to have any prospect of being adapted in actual communication systems. Here we report a scalable wavelength-division multiplexing (WDM) regeneration scheme for phase only regeneration, which satisfies the multichannel requirement, using a set of optical time-lens-based Fourier processors combined with a single phase sensitive amplifier (PSA). We describe the concept theoretically, and experimentally demonstrate simultaneous regeneration of 16 WDM channels with 50 GHz spacing, each carrying 10-Gbit/s DPSK phase-modulated data. The proposed scheme relies on ultrafast broadband optical processing and is inherently scalable in modulation speed and channel number. PMID- 29535309 TI - Structural change as a key component for agricultural non-CO2 mitigation efforts. AB - Agriculture is the single largest source of anthropogenic non-carbon dioxide (non CO2) emissions. Reaching the climate target of the Paris Agreement will require significant emission reductions across sectors by 2030 and continued efforts thereafter. Here we show that the economic potential of non-CO2 emissions reductions from agriculture is up to four times as high as previously estimated. In fact, we find that agriculture could achieve already at a carbon price of 25 $/tCO2eq non-CO2 reductions of around 1 GtCO2eq/year by 2030 mainly through the adoption of technical and structural mitigation options. At 100 $/tCO2eq agriculture could even provide non-CO2 reductions of 2.6 GtCO2eq/year in 2050 including demand side efforts. Immediate action to favor the widespread adoption of technical options in developed countries together with productivity increases through structural changes in developing countries is needed to move agriculture on track with a 2 degrees C climate stabilization pathway. PMID- 29535310 TI - Author Correction: Restoration of patterned vision with an engineered photoactivatable G protein-coupled receptor. AB - Kevin J. Cao and Richard H. Kramer, who developed extended release with beta cyclodextrin, were inadvertently omitted from the author list and author contributions section of this Article. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29535311 TI - Publisher Correction: Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells. AB - The original PDF version of this Article contained errors in the spelling of Luiz Carlos Caires-Junior, Uira Souto Melo, Bruno Henrique Silva Araujo, Alessandra Soares-Schanoski, Murilo Sena Amaral, Kayque Alves Telles-Silva, Vanessa van der Linden, Helio van der Linden, Joao Ricardo Mendes de Oliveira, Nivia Maria Rodrigues Arrais, Joanna Goes Castro Meira, Ana Jovina Barreto Bispo, Esper Abrao Cavalheiro, and Robert Andreata-Santos, which were incorrectly given as Luiz Carlos de Caires Jr., UiraSouto Melo, Bruno Silva Henrique Araujo, Alessandra Soares Schanoski, MuriloSena Amaral, Kayque Telles Alves Silva, Vanessa Van der Linden, Helio Van der Linden, Joao Mendes Ricardo de Oliveira, Nivia Rodrigues Maria Arrais, Joanna Castro Goes Meira, Ana JovinaBarreto Bispo, EsperAbrao Cavalheiro, and Robert Andreata Santos. Furthermore, in both the PDF and HTML versions of the Article, the top panel of Fig. 3e was incorrectly labeled '10608 1' and should have been '10608-4', and financial support from CAPES and DECIT-MS was inadvertently omitted from the Acknowledgements section. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29535312 TI - GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network. AB - GATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss-of function despite a dearth of information regarding their effect on disease course or their mechanistic impact on the breast cancer transcriptional network. Here, we address molecular and clinical features associated with GATA3 mutations. A novel classification scheme defines distinct clinical features for patients bearing breast tumors with mutations in the second GATA3 zinc-finger (ZnFn2). An engineered ZnFn2 mutant cell line by CRISPR-Cas9 reveals that mutation of one allele of the GATA3 second zinc finger (ZnFn2) leads to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor. At other loci, associated with epithelial to mesenchymal transition, gain of binding correlates with increased gene expression. These results demonstrate that not all GATA3 mutations are equivalent and that ZnFn2 mutations impact breast cancer through gain and loss-of function. PMID- 29535313 TI - Large sub-clonal variation in Phytophthora infestans from recent severe late blight epidemics in India. AB - The population structure of the Phytophthora infestans populations that caused the recent 2013-14 late blight epidemic in eastern India (EI) and northeastern India (NEI) was examined. The data provide new baseline information for populations of P. infestans in India. A migrant European 13_A2 genotype was responsible for the 2013-14 epidemic, replacing the existing populations. Mutations have generated substantial sub-clonal variation with 24 multi-locus genotypes (MLGs) found, of which 19 were unique variants not yet reported elsewhere globally. Samples from West Bengal were the most diverse and grouped alongside MLGs found in Europe, the UK and from neighbouring Bangladesh but were not linked directly to most samples from south India. The pathogen population was broadly more aggressive on potato than on tomato and resistant to the fungicide metalaxyl. Pathogen population diversity was higher in regions around the international borders with Bangladesh and Nepal. Overall, the multiple shared MLGs suggested genetic contributions from UK and Europe in addition to a sub structure based on the geographical location within India. Our data indicate the need for improved phytosanitary procedures and continuous surveillance to prevent the further introduction of aggressive lineages of P. infestans into the country. PMID- 29535314 TI - Benchmarking common quantification strategies for large-scale phosphoproteomics. AB - Comprehensive mass spectrometry (MS)-based proteomics is now feasible, but reproducible quantification remains challenging, especially for post translational modifications such as phosphorylation. Here, we compare the most popular quantification techniques for global phosphoproteomics: label-free quantification (LFQ), stable isotope labeling by amino acids in cell culture (SILAC) and MS2- and MS3-measured tandem mass tags (TMT). In a mixed species comparison with fixed phosphopeptide ratios, we find LFQ and SILAC to be the most accurate techniques. MS2-based TMT yields the highest precision but lowest accuracy due to ratio compression, which MS3-based TMT can partly rescue. However, MS2-based TMT outperforms MS3-based TMT when analyzing phosphoproteome changes in the DNA damage response, since its higher precision and larger identification numbers allow detection of a greater number of significantly regulated phosphopeptides. Finally, we utilize the TMT multiplexing capabilities to develop an algorithm for determining phosphorylation site stoichiometry, showing that such applications benefit from the high accuracy of MS3-based TMT. PMID- 29535315 TI - A Unified Approach to Nonlinear Transformation Materials. AB - The advances in geometric approaches to optical devices due to transformation optics has led to the development of cloaks, concentrators, and other devices. It has also been shown that transformation optics can be used to gravitational fields from general relativity. However, the technique is currently constrained to linear devices, as a consistent approach to nonlinearity (including both the case of a nonlinear background medium and a nonlinear transformation) remains an open question. Here we show that nonlinearity can be incorporated into transformation optics in a consistent way. We use this to illustrate a number of novel effects, including cloaking an optical soliton, modeling nonlinear solutions to Einstein's field equations, controlling transport in a Debye solid, and developing a set of constitutive to relations for relativistic cloaks in arbitrary nonlinear backgrounds. PMID- 29535316 TI - Thermally Tunable Ultra-wideband Metamaterial Absorbers based on Three dimensional Water-substrate construction. AB - Distilled water has frequency dispersive characteristic and high value of imaginary part in permittivity, which can be seen as a good candidate of broadband metamaterial absorbers(MAs) in microwave. Here, an interesting idea based on the combination of water-substrate and metallic metamaterial in the three-dimensional construction is proposed, which can achieve outstanding broadband absorption. As a proof, the distilled water is filled into the dielectric reservoir as ultra-thin water-substrate, and then the water-substrates are arranged on the metal backplane periodically as three-dimensional water substrate array(TWA). Simulation shows that the TWA achieves broadband absorption with the efficiency more than 90% from 8.3 to 21.0 GHz. Then, the trigonal metallic fishbone structure is introduced here between the water-substrate and the dielectric reservoir periodically as three-dimensional water-substrate metamaterial absorber(TWMA). The proposed TWMA could achieve ultra-broadband absorption from 2.6 to 16.8 GHz, which has increase by 64.8% in relative absorption bandwidth. Meanwhile, due to the participation of distilled water, the thermally tunable property also deserves to be discussed here. In view of the outstanding performance, it is worth to expect a wide range of applications to emerge inspired from the proposed construction. PMID- 29535317 TI - Freely suspended perforated polymer nanomembranes for protein separations. AB - Selective removal of nanometer-sized compounds such as proteins from fluids is an often challenging task in many scientific and industrial areas. Addressing such tasks with highly efficient and selective membranes is desirable since commonly used chromatographic approaches are expensive and difficult to scale up. Nanomembranes, molecularly thin separation layers, have been predicted and shown to possess outstanding properties but in spite ultra-fast diffusion times and high-resolution separation, to date they generally lack either of two crucial characteristics: compatibility with biological fluids and low-cost production. Here we report the fast and easy fabrication of highly crosslinked polymer membranes based on a thermoset resin (poly[(o-cresyl glycidyl ether)-co formaldehyde (PCGF) cured with branched polyethyleneimine (PEI)) with nanoscale perforations of 25 nm diameter. During spin casting, microphase separation of a polylactide-co-glycolide induces the formation of nanometer sized domains that serve as templates for perforations which penetrate the 80 nm thick membranes. Ultrathin perforated nanomembranes can be freely suspended on the cm scale, exhibit high mechanical strength, low surface energies and a sharp permeability cutoff at a hydrodynamic diameter of 10 nm suitable for protein separations. PMID- 29535318 TI - Publisher Correction: Statistical modeling of RNA structure profiling experiments enables parsimonious reconstruction of structure landscapes. AB - The originally published version of this Article contained an error in Figure 2, due to a typesetting error. Panels d and e were positioned such that the locations of the mutations in panel d did not align correctly with the corresponding nucleotides in the reactivity profile in panel e. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29535319 TI - A meta-analysis of birth-origin effects on reproduction in diverse captive environments. AB - Successfully establishing captive breeding programs is a priority across diverse industries to address food security, demand for ethical laboratory research animals, and prevent extinction. Differences in reproductive success due to birth origin may threaten the long-term sustainability of captive breeding. Our meta analysis examining 115 effect sizes from 44 species of invertebrates, fish, birds, and mammals shows that, overall, captive-born animals have a 42% decreased odds of reproductive success in captivity compared to their wild-born counterparts. The largest effects are seen in commercial aquaculture, relative to conservation or laboratory settings, and offspring survival and offspring quality were the most sensitive traits. Although a somewhat weaker trend, reproductive success in conservation and laboratory research breeding programs is also in a negative direction for captive-born animals. Our study provides the foundation for future investigation of non-genetic and genetic drivers of change in captivity, and reveals areas for the urgent improvement of captive breeding. PMID- 29535320 TI - Theory of isolated magnetic skyrmions: From fundamentals to room temperature applications. AB - Magnetic skyrmions are topological quasiparticles of great interest for data storage applications because of their small size, high stability, and ease of manipulation via electric current. However, although models exist for some limiting cases, there is no universal theory capable of accurately describing the structure and energetics of all skyrmions. The main barrier is the complexity of non-local stray field interactions, which are usually included through crude approximations. Here we present an accurate analytical framework to treat isolated skyrmions in any material, assuming only a circularly-symmetric 360 degrees domain wall profile and a homogeneous magnetization profile in the out of-plane direction. We establish the first rigorous criteria to distinguish stray field from DMI skyrmions, resolving a major dispute in the community. We discover new phases, such as bi-stability, a phenomenon unknown in magnetism so far. We predict materials for sub-10 nm zero field room temperature stable skyrmions suitable for applications. Finally, we derive analytical equations to describe current-driven dynamics, find a topological damping, and show how to engineer materials in which compact skyrmions can be driven at velocities >1000 m/s. PMID- 29535321 TI - Sharing of photobionts in sympatric populations of Thamnolia and Cetraria lichens: evidence from high-throughput sequencing. AB - In this study, we explored the diversity of green algal symbionts (photobionts) in sympatric populations of the cosmopolitan lichen-forming fungi Thamnolia and Cetraria. We sequenced with both Sanger and Ion Torrent High-Throughput Sequencing technologies the photobiont ITS-region of 30 lichen thalli from two islands: Iceland and Oland. While Sanger recovered just one photobiont genotype from each thallus, the Ion Torrent data recovered 10-18 OTUs for each pool of 5 lichen thalli, suggesting that individual lichens can contain heterogeneous photobiont populations. Both methods showed evidence for photobiont sharing between Thamnolia and Cetraria on Iceland. In contrast, our data suggest that on Oland the two mycobionts associate with distinct photobiont communities, with few shared OTUs revealed by Ion Torrent sequencing. Furthermore, by comparing our sequences with public data, we identified closely related photobionts from geographically distant localities. Taken together, we suggest that the photobiont composition in Thamnolia and Cetraria results from both photobiont-mycobiont codispersal and local acquisition during mycobiont establishment and/or lichen growth. We hypothesize that this is a successful strategy for lichens to be flexible in the use of the most adapted photobiont for the environment. PMID- 29535322 TI - Author Correction: Non-Invasive whole-body detection of complement activation using radionuclide imaging in a mouse model of myocardial ischaemia-reperfusion injury. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29535323 TI - Uniaxial strain control of spin-polarization in multicomponent nematic order of BaFe2As2. AB - The iron-based high temperature superconductors exhibit a rich phase diagram reflecting a complex interplay between spin, lattice, and orbital degrees of freedom. The nematic state observed in these compounds epitomizes this complexity, by entangling a real-space anisotropy in the spin fluctuation spectrum with ferro-orbital order and an orthorhombic lattice distortion. A subtle and less-explored facet of the interplay between these degrees of freedom arises from the sizable spin-orbit coupling present in these systems, which translates anisotropies in real space into anisotropies in spin space. We present nuclear magnetic resonance studies, which reveal that the magnetic fluctuation spectrum in the paramagnetic phase of BaFe2As2 acquires an anisotropic response in spin-space upon application of a tetragonal symmetry-breaking strain field. Our results unveil an internal spin structure of the nematic order parameter, indicating that electronic nematic materials may offer a route to magneto mechanical control. PMID- 29535324 TI - The Boring Billion, a slingshot for Complex Life on Earth. AB - The period 1800 to 800 Ma ("Boring Billion") is believed to mark a delay in the evolution of complex life, primarily due to low levels of oxygen in the atmosphere. Earlier studies highlight the remarkably flat C, Cr isotopes and low trace element trends during the so-called stasis, caused by prolonged nutrient, climatic, atmospheric and tectonic stability. In contrast, we suggest a first order variability of bio-essential trace element availability in the oceans by combining systematic sampling of the Proterozoic rock record with sensitive geochemical analyses of marine pyrite by LA-ICP-MS technique. We also recall that several critical biological evolutionary events, such as the appearance of eukaryotes, origin of multicellularity & sexual reproduction, and the first major diversification of eukaryotes (crown group) occurred during this period. Therefore, it appears possible that the period of low nutrient trace elements (1800-1400 Ma) caused evolutionary pressures which became an essential trigger for promoting biological innovations in the eukaryotic domain. Later periods of stress-free conditions, with relatively high nutrient trace element concentration, facilitated diversification. We propose that the "Boring Billion" was a period of sequential stepwise evolution and diversification of complex eukaryotes, triggering evolutionary pathways that made possible the later rise of micro-metazoans and their macroscopic counterparts. PMID- 29535325 TI - Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters Slc16a2 (Mct8) and Slc16a10 (Mct10). AB - Transmembrane proteins that mediate the cellular uptake or efflux of thyroid hormone potentially provide a key level of control over neurodevelopment. In humans, defects in one such protein, solute carrier SLC16A2 (MCT8) are associated with psychomotor retardation. Other proteins that transport the active form of thyroid hormone triiodothyronine (T3) or its precursor thyroxine (T4) have been identified in vitro but the wider significance of such transporters in vivo is unclear. The development of the auditory system requires thyroid hormone and the cochlea is a primary target tissue. We have proposed that the compartmental anatomy of the cochlea would necessitate transport mechanisms to convey blood borne hormone to target tissues. We report hearing loss in mice with mutations in Slc16a2 and a related gene Slc16a10 (Mct10, Tat1). Deficiency of both transporters results in retarded development of the sensory epithelium similar to impairment caused by hypothyroidism, compounded with a progressive degeneration of cochlear hair cells and loss of endocochlear potential. Administration of T3 largely restores the development of the sensory epithelium and limited auditory function, indicating the T3-sensitivity of defects in the sensory epithelium. The results indicate a necessity for thyroid hormone transporters in cochlear development and function. PMID- 29535326 TI - Effects of Phytase Transgenic Maize on the Physiological and Biochemical Responses and the Gut Microflora Functional Diversity of Ostrinia furnacalis. AB - Transgenic maize hybrids that express the Aspergillus niger phyA2 gene could significantly improve phosphorus bioavailability to poultry and livestock. However, little information has been reported about the effects of phytase transgenic maize on the Asian corn borer (ACB), Ostrinia furnacalis (Guenee). This study provides valuable information about the physiological, biochemical and gut microflora functional diversity changes of ACBs fed phytase transgenic maize. The weights, survival rates, in vivo protein contents, activities of two detoxification enzymes and three antioxidant enzymes of ACBs fed phytase transgenic maize exhibited no significant differences to those fed non-transgenic maize. Functional diversities of the gut microflora communities of ACBs were not affected by different fodder treatments, but significant differences were observed between different generations of ACBs. Our study provides useful information about the biochemical responses and gut microflora community functional diversities of ACBs fed phytase transgenic maize firstly and the results will help to assess the potential effects of phytase transgenic maize on other target and non-target arthropods in the future. PMID- 29535327 TI - Plasma IL-23 and IL-5 as surrogate markers of lesion metabolic activity in patients with hepatic alveolar echinococcosis. AB - Fluorodeoxyglucose (FDG) uptake by alveolar echinococcosis (AE) liver lesions is a signal of their metabolic activity and of disease progression. In order to find a surrogate marker for this status, we investigated whether parameters of the peripheral and/or periparasitic immune responses were associated with metabolic activity in a prospective case-control study of 30 AE patients and 22 healthy controls. Levels of 18 cytokines and chemokines, representative of innate and adaptive immune responses, were assessed in plasma and peripheral cells of two groups of patients with (MAAE) and without (MIAE) metabolically active lesions, and in the liver of MAAE patients. Mixed cytokine profile was observed in the peripheral blood of AE patients, with a predominance of Th2, Th17 and Treg responses. Among the detected markers only plasma IL-5 and IL-23, more elevated in MAAE patients, were found discriminant. Discrimination between MAAE and MIAE patients obtained by using IL-23 was improved when IL-5 was used in combination. The combination of elevated levels of IL-5 and IL-23 is significantly associated with FDG uptake at PET scan. It offers a new tool for the follow-up of AE patients which could substitute to FDG-PET whenever non-available to assess disease progression. PMID- 29535328 TI - Use of quercetin in animal feed: effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken. AB - Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co administered enrofloxacin or other similar antimicrobials. PMID- 29535329 TI - Statistically derived asymmetric membrane potentials from alpha-helical and beta barrel membrane proteins. AB - Modeling membrane protein (MP) folding, insertion, association and their interactions with other proteins, lipids, and drugs requires accurate transfer free energies (TFEs). Various TFE scales have been derived to quantify the energy required or released to insert an amino acid or protein into the membrane. Experimental measurement of TFEs is challenging, and only few scales were extended to depth-dependent energetic profiles. Statistical approaches can be used to derive such potentials; however, this requires a sufficient number of MP structures. Furthermore, MPs are tightly coupled to bilayers that are heterogeneous in terms of lipid composition, asymmetry, and protein content between organisms and organelles. Here we derived asymmetric implicit membrane potentials from beta-barrel and alpha-helical MPs and use them to predict topology, depth and orientation of proteins in the membrane. Our data confirm the 'charge-outside' and 'positive-inside' rules for beta-barrels and alpha-helical proteins, respectively. We find that the beta-barrel profiles have greater asymmetry than the ones from alpha-helical proteins, as a result of the different membrane architecture of gram-negative bacterial outer membranes and the existence of lipopolysaccharide in the outer leaflet. Our data further suggest that pore-facing residues in beta-barrels have a larger contribution to membrane insertion and stability than previously suggested. PMID- 29535330 TI - Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents. AB - Several MRI contrast agent clinical formulations are now known to leave deposits of the heavy metal gadolinium in the brain, bones, and other organs of patients. This persistent biological accumulation of gadolinium has been recently recognized as a deleterious outcome in patients administered Gd-based contrast agents (GBCAs) for MRI, prompting the European Medicines Agency to recommend discontinuing the use of over half of the GBCAs currently approved for clinical applications. To address this problem, we find that the orally-available metal decorporation agent 3,4,3-LI(1,2-HOPO) demonstrates superior efficacy at chelating and removing Gd from the body compared to diethylenetriaminepentaacetic acid, a ligand commonly used in the United States in the GBCA Gadopentetate (Magnevist). Using the radiotracer 153Gd to obtain precise biodistribution data, the results herein, supported by speciation simulations, suggest that the prophylactic or post-hoc therapeutic use of 3,4,3-LI(1,2-HOPO) may provide a means to mitigate Gd retention in patients requiring contrast-enhanced MRI. PMID- 29535331 TI - Author Correction: TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513 G>A mutation. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29535333 TI - Atlantic deep water circulation during the last interglacial. AB - Understanding how the Atlantic Meridional Overturning Circulation (AMOC) evolved during crucial past geological periods is important in order to decipher the interplay between ocean dynamics and global climate change. Previous research, based on geological proxies, has provided invaluable insights into past AMOC changes. However, the causes of the changes in water mass distributions in the Atlantic during different periods remain mostly elusive. Using a state-of-the-art Earth system model, we show that the bulk of NCW in the deep South Atlantic Ocean below 4000 m migrated from the western basins at 125 ka to the eastern basins at 115 ka, though the AMOC strength is only slightly reduced. These changes are consistent with proxy records, and it is mainly due to more penetration of the AABW at depth at 115 ka, as a result of a larger density of AABW formed at 115 ka. Our results show that depth changes in regional deep water pathways can result in large local changes, while the overall AMOC structure hardly changes. Future research should thus be careful when interpreting single proxy records in terms of large-scale AMOC changes, and considering variability of water-mass distributions on sub-basin scale would give more comprehensive interpretations of sediment records. PMID- 29535332 TI - Rare human Caspase-6-R65W and Caspase-6-G66R variants identify a novel regulatory region of Caspase-6 activity. AB - The cysteine protease Caspase-6 (Casp6) is a potential therapeutic target of Alzheimer Disease (AD) and age-dependent cognitive impairment. To assess if Casp6 is essential to human health, we investigated the effect of CASP6 variants sequenced from healthy humans on Casp6 activity. Here, we report the effects of two rare Casp6 amino acid polymorphisms, R65W and G66R, on the catalytic function and structure of Casp6. The G66R substitution eliminated and R65W substitution significantly reduced Casp6 catalytic activity through impaired substrate binding. In contrast to wild-type Casp6, both Casp6 variants were unstable and inactive in transfected mammalian cells. In addition, Casp6-G66R acted as a dominant negative inhibitor of wild-type Casp6. The R65W and G66R substitutions caused perturbations in substrate recognition and active site organization as revealed by molecular dynamics simulations. Our results suggest that full Casp6 activity may not be essential for healthy humans and support the use of Casp6 inhibitors against Casp6-dependent neurodegeneration in age-dependent cognitive impairment and AD. Furthermore, this work illustrates that studying natural single amino acid polymorphisms of enzyme drug targets is a promising approach to uncover previously uncharacterized regulatory sites important for enzyme activity. PMID- 29535334 TI - Organ-specific responses during brain death: increased aerobic metabolism in the liver and anaerobic metabolism with decreased perfusion in the kidneys. AB - Hepatic and renal energy status prior to transplantation correlates with graft survival. However, effects of brain death (BD) on organ-specific energy status are largely unknown. We studied metabolism, perfusion, oxygen consumption, and mitochondrial function in the liver and kidneys following BD. BD was induced in mechanically-ventilated rats, inflating an epidurally-placed Fogarty-catheter, with sham-operated rats as controls. A 9.4T-preclinical MRI system measured hourly oxygen availability (BOLD-related R2*) and perfusion (T1-weighted). After 4 hrs, tissue was collected, mitochondria isolated and assessed with high resolution respirometry. Quantitative proteomics, qPCR, and biochemistry was performed on stored tissue/plasma. Following BD, the liver increased glycolytic gene expression (Pfk-1) with decreased glycogen stores, while the kidneys increased anaerobic- (Ldha) and decreased gluconeogenic-related gene expression (Pck-1). Hepatic oxygen consumption increased, while renal perfusion decreased. ATP levels dropped in both organs while mitochondrial respiration and complex I/ATP synthase activity were unaffected. In conclusion, the liver responds to increased metabolic demands during BD, enhancing aerobic metabolism with functional mitochondria. The kidneys shift towards anaerobic energy production while renal perfusion decreases. Our findings highlight the need for an organ specific approach to assess and optimise graft quality prior to transplantation, to optimise hepatic metabolic conditions and improve renal perfusion while supporting cellular detoxification. PMID- 29535335 TI - Thermal conductivity reduction in silicon fishbone nanowires. AB - Semiconductor nanowires are potential building blocks for future thermoelectrics because of their low thermal conductivity. Recent theoretical works suggest that thermal conductivity of nanowires can be further reduced by additional constrictions, pillars or wings. Here, we experimentally study heat conduction in silicon nanowires with periodic wings, called fishbone nanowires. We find that like in pristine nanowires, the nanowire cross-section controls thermal conductivity of fishbone nanowires. However, the periodic wings further reduce the thermal conductivity. Whereas an increase in the wing width only slightly affects the thermal conductivity, an increase in the wing depth clearly reduces thermal conductivity, and this reduction is stronger in the structures with narrower nanowires. Our experimental data is supported by the Callaway-Holland model, finite element modelling and phonon transport simulations. PMID- 29535336 TI - Tissue Phenomics for prognostic biomarker discovery in low- and intermediate-risk prostate cancer. AB - Tissue Phenomics is the discipline of mining tissue images to identify patterns that are related to clinical outcome providing potential prognostic and predictive value. This involves the discovery process from assay development, image analysis, and data mining to the final interpretation and validation of the findings. Importantly, this process is not linear but allows backward steps and optimization loops over multiple sub-processes. We provide a detailed description of the Tissue Phenomics methodology while exemplifying each step on the application of prostate cancer recurrence prediction. In particular, we automatically identified tissue-based biomarkers having significant prognostic value for low- and intermediate-risk prostate cancer patients (Gleason scores 6 7b) after radical prostatectomy. We found that promising phenes were related to CD8(+) and CD68(+) cells in the microenvironment of cancerous glands in combination with the local micro-vascularization. Recurrence prediction based on the selected phenes yielded accuracies up to 83% thereby clearly outperforming prediction based on the Gleason score. Moreover, we compared different machine learning algorithms to combine the most relevant phenes resulting in increased accuracies of 88% for tumor progression prediction. These findings will be of potential use for future prognostic tests for prostate cancer patients and provide a proof-of-principle of the Tissue Phenomics approach. PMID- 29535337 TI - Effects of temperature, moisture, and metal salt content on dielectric properties of rice bran associated with radio frequency heating. AB - Dielectric heating including microwave (MW) and radio frequency (RF) energy has been regarded as alternative thermal treatments for food processing. To develop effective rice bran (RB) stabilization treatments based on RF and MW heating, dielectric properties (DPs) with dielectric constant (epsilon') and loss factor (epsilon") of RB samples at frequencies (10-3000 MHz), temperatures (25-100 degrees C), moisture content (MC, 10.36-24.69% w.b.) and three metal salt levels (0.05-2.00%) were determined by an open-ended coaxial probe and impedance analyzer. Results indicated that both epsilon' and epsilon" of RB samples increased with increasing temperature and MC. The increase rate was greater at higher temperature and moisture levels than at lower levels, especially at frequencies lower than 300 MHz. Cubic order models were developed to best fit the relationship between DPs of RB samples and temperature/MC at five frequencies with R2 greater than 0.994. Both epsilon" and RF heating rate of RB samples increased significantly with added NaCl (2%), KCl (1%) and Na6O18P6 (2%). The obtained data are useful in developing computer models and simulating dielectric heating for RB stabilization and may also provide theoretical basis for synergistic stabilization of RB under combined dielectric heating with metal salts. PMID- 29535338 TI - Renormalization of the critical exponent for the shear modulus of magnetoactive elastomers. AB - It is shown that the critical exponent for the effective shear modulus of a composite medium where a compliant polymer matrix is filled with ferromagnetic particles may significantly depend on the external magnetic field. The physical consequence of this dependence is the critical behavior of the relative magnetorheological effect. PMID- 29535339 TI - Identification and characterization of evolutionarily conserved alternative splicing events in a mangrove genus Sonneratia. AB - Alternative splicing (AS), which produces multiple mRNA transcripts from a single gene, plays crucial roles in plant growth, development and environmental stress responses. Functional significances of conserved AS events among congeneric species have not been well characterized. In this study, we performed transcriptome sequencing to characterize AS events in four common species of Sonneratia, a mangrove genus excellently adaptive to intertidal zones. 7,248 to 12,623 AS events were identified in approximately 25% to 35% expressed genes in the roots of the four species. The frequency of AS events in Sonneratia was associated with genomic features, including gene expression level and intron/exon number and length. Among the four species, 1,355 evolutionarily conserved AS (ECAS) events were identified from 1,170 genes. Compared with non-ECAS events, ECAS events are of shorter length and less possibility to introduce premature stop codons (PTCs) and frameshifts. Functional annotations of the genes containing ECAS events showed that four of the 26 enriched Gene Ontology (GO) terms are involved in proton transport, signal transduction and carbon metabolism, and 60 genes from another three GO terms are implicated in responses to osmotic, oxidative and heat stresses, which may contribute to the adaptation of Sonneratia species to harsh intertidal environments. PMID- 29535341 TI - Universal scaling-law for flow resistance over canopies with complex morphology. AB - Flow resistance caused by vegetation is a key parameter to properly assess flood management and river restoration. However, quantifying the friction factor or any of its alternative metrics, e.g. the drag coefficient, in canopies with complex geometry has proven elusive. We explore the effect of canopy morphology on vegetated channels flow structure and resistance by treating the canopy as a porous medium characterized by an effective permeability, a property that describes the ease with which water can flow through the canopy layer. We employ a two-domain model for flow over and within the canopy, which couples the log-law in the free layer to the Darcy-Brinkman equation in the vegetated layer. We validate the model analytical solutions for the average velocity profile within and above the canopy, the volumetric discharge and the friction factor against data collected across a wide range of canopy morphologies encountered in riverine systems. Results indicate agreement between model predictions and data for both simple and complex plant morphologies. For low submergence canopies, we find a universal scaling law that relates friction factor with canopy permeability and a rescaled bulk Reynolds number. This provides a valuable tool to assess habitats sustainability associated with hydro-dynamical conditions. PMID- 29535340 TI - Exploring the effects of anodal and cathodal high definition transcranial direct current stimulation targeting the dorsal anterior cingulate cortex. AB - The dorsal anterior cingulate cortex (dACC) has been identified as a core region affected by many disorders, representing a promising target for neuromodulation. High Definition-transcranial Direct Current Stimulation (HD-tDCS) is a non invasive neuromodulation technique that has already shown promising outcomes and has been tested to engage deeper structures. This study investigates whether it is possible to modulate dACC activity using anodal and cathodal HD-tDCS. Furthermore, it examines what effects anodal and cathodal HD-tDCS targeting dACC have on cognitive and emotional processing. Forty-five healthy subjects were randomly assigned to 1 of 3 groups: anodal, cathodal, and sham. Resting-state electroencephalography (rsEEG) and a cognitive and emotional Counting Stroop task were administered before and after HD-tDCS. RsEEG showed changes: anodal HD-tDCS showed significant increase in beta frequency band activity in dACC, while cathodal HD-tDCS led to significant increase in activity at dorsal and rostral ACC in the theta frequency band. Behavioral changes were also found after anodal HD-tDCS in the cognitive Counting Stroop for incongruent trials and after cathodal HD-tDCS in the emotional Counting Stroop for emotional trials. This study demonstrated that HD-tDCS is able to modulate dACC activity, suggesting that it has the potential to be used as a treatment tool. PMID- 29535342 TI - Ultrasound-enhanced electrospinning. AB - Electrospinning is commonly used to produce polymeric nanofibers. Potential applications for such fibers include novel drug delivery systems, tissue engineering scaffolds, and filters. Electrospinning, however, has shortcomings such as needle clogging and limited ability to control the fiber-properties in a non-chemical manner. This study reports on an orifice-less technique that employs high-intensity focused ultrasound, i.e. ultrasound-enhanced electrospinning. Ultrasound bursts were used to generate a liquid protrusion with a Taylor cone from the surface of a polymer solution of polyethylene oxide. When the polymer was charged with a high negative voltage, nanofibers jetted off from the tip of the protrusion landed on an electrically grounded target held at a constant distance from the tip. Controlling the ultrasound characteristics permitted physical modification of the nanofiber topography at will without using supplemental chemical intervention. Possible applications of tailor-made fibers generated by ultrasound-enhanced electrospinning include pharmaceutical controlled-release applications and biomedical scaffolds with spatial gradients in fiber thickness and mechanical properties. PMID- 29535343 TI - Unveiling new interdependencies between significant DNA methylation sites, gene expression profiles and glioma patients survival. AB - In order to find clinically useful prognostic markers for glioma patients' survival, we employed Monte Carlo Feature Selection and Interdependencies Discovery (MCFS-ID) algorithm on DNA methylation (HumanMethylation450 platform) and RNA-seq datasets from The Cancer Genome Atlas (TCGA) for 88 patients observed until death. The input features were ranked according to their importance in predicting patients' longer (400+ days) or shorter (<=400 days) survival without prior classification of the patients. Interestingly, out of the 65 most important features found, 63 are methylation sites, and only two mRNAs. Moreover, 61 out of the 63 methylation sites are among those detected by the 450 k array technology, while being absent in the HumanMethylation27. The most important methylation feature (cg15072976) overlaps with the RE1 Silencing Transcription Factor (REST) binding site, and was confirmed to intersect with the REST binding motif in human U87 glioma cells. Six additional methylation sites from the top 63 overlap with REST sites. We found that the methylation status of the cg15072976 site affects transcription factor binding in U87 cells in gel shift assay. The cg15072976 methylation status discriminates <=400 and 400+ patients in an independent dataset from TCGA and shows positive association with survival time as evidenced by Kaplan-Meier plots. PMID- 29535344 TI - Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated. Two compounds (15 and 17) displayed higher inhibitory activity towards BChE with IC50 values of 6.23 MUM and 3.57 MUM, and a good antioxidant activity with EC50 values 14.9 MUM and 16.7 MUM, respectively. The same compounds further exhibited selective inhibitory activity against BChE over AChE. Computational studies were used to compare protein binding pockets and evaluate the interaction fingerprints of the compound. Molecular simulations showed a conserved protein residue interaction network between the compounds, resulting in similar interaction energy values. Thus, combination of biochemical and computational approaches could represent rational guidelines for further structural modification of these hydroxy-benzofuran derivatives as future drugs for treatment of AD. PMID- 29535345 TI - Bio-derived three-dimensional hierarchical carbon-graphene-TiO2 as electrode for supercapacitors. AB - This paper reports a novel loofah-derived hierarchical scaffold to obtain three dimensional biocarbon-graphene-TiO2 (BC-G-TiO2) composite materials as electrodes for supercapacitors. The loofah scaffold was first loaded with G and TiO2 by immersing, squeezing, and loosening into the mixed solution of graphene oxide and titania, and then carbonized at 900 degrees C to form the BC-G-TiO2 composite. The synergistic effects of the naturally hierarchical biocarbon structure, graphene, and TiO2 nanoparticles on the electrochemical properties are analyzed. The biocarbon provides a high interconnection and an easy accessibility surface for the electrolyte. Graphene bridged the BC and TiO2 nanoparticles, improved the conductivity of the BC-G-TiO2 composite, and increased the electron transfer efficiency. TiO2 nanoparticles also contributed to the pesudocapacitance and electrochemical stability. PMID- 29535346 TI - Azolla along a phosphorus gradient: biphasic growth response linked to diazotroph traits and phosphorus-induced iron chlorosis. AB - Azolla spp., a water fern often used for phytoremediation, is a strong phosphorus (P) accumulator due to its high growth rate and N2 fixing symbionts (diazotrophs). It is known that plant growth is stimulated by P, but the nature of the interactive response of both symbionts along a P gradient, and related changes in growth-limiting factors, are unclear. We determined growth, and N and P sequestration rates of Azolla filiculoides in N-free water at different P concentrations. The growth response appeared to be biphasic and highest at levels >=10 P umol l-1. Diazotrophic N sequestration increased upon P addition, and rates were three times higher at high P than at low P. At 10 umol P l-1, N sequestration rates reached its maximum and A. filiculoides growth became saturated. Due to luxury consumption, P sequestration rates increased until 50 umol P l-1. At higher P concentrations (>=50 umol l-1), however, chlorosis occurred that seems to be caused by iron- (Fe-), and not by N-deficiency. We demonstrate that traits of the complete symbiosis in relation to P and Fe availability determine plant performance, stressing the role of nutrient stoichiometry. The results are discussed regarding Azolla's potential use in a bio-based economy. PMID- 29535347 TI - Direct coupling of detergent purified human mGlu5 receptor to the heterotrimeric G proteins Gq and Gs. AB - The metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) that modulate synaptic activity and plasticity throughout the mammalian brain. Signal transduction is initiated by glutamate binding to the venus flytrap domains (VFT), which initiates a conformational change that is transmitted to the conserved heptahelical domains (7TM) and results ultimately in the activation of intracellular G proteins. While both mGlu1 and mGlu5 activate Galphaq G-proteins, they also increase intracellular cAMP concentration through an unknown mechanism. To study directly the G protein coupling properties of the human mGlu5 receptor homodimer, we purified the full-length receptor, which required careful optimisation of the expression, N-glycosylation and purification. We successfully purified functional mGlu5 that activated the heterotrimeric G protein Gq. The high-affinity agonist-PAM VU0424465 also activated the purified receptor in the absence of an orthosteric agonist. In addition, it was found that purified mGlu5 was capable of activating the G protein Gs either upon stimulation with VU0424465 or glutamate, although the later induced a much weaker response. Our findings provide important mechanistic insights into mGlu5 G protein-dependent activity and selectivity. PMID- 29535348 TI - Global warming in the context of 2000 years of Australian alpine temperature and snow cover. AB - Annual resolution reconstructions of alpine temperatures are rare, particularly for the Southern Hemisphere, while no snow cover reconstructions exist. These records are essential to place in context the impact of anthropogenic global warming against historical major natural climate events such as the Roman Warm Period (RWP), Medieval Climate Anomaly (MCA) and Little Ice Age (LIA). Here we show for a marginal alpine region of Australia using a carbon isotope speleothem reconstruction, warming over the past five decades has experienced equivalent magnitude of temperature change and snow cover decline to the RWP and MCA. The current rate of warming is unmatched for the past 2000 years and seasonal snow cover is at a minimum. On scales of several decades, mean maximum temperatures have undergone considerable change ~ +/- 0.8 degrees C highlighting local scale susceptibility to rapid temperature change, evidence of which is often masked in regional to hemisphere scale temperature reconstructions. PMID- 29535349 TI - The dynamics of TGF-beta in dental pulp, odontoblasts and dentin. AB - Transforming growth factor-beta (TGF-beta) is critical for cell proliferation and differentiation in dental pulp. Here, we show the dynamic mechanisms of TGF-beta in porcine dental pulp, odontoblasts and dentin. The mRNA of latent TGF-beta1 and TGF-beta3 is predominantly expressed in odontoblasts, whereas the mRNA expression level of latent TGF-beta2 is high in dental pulp. TGF-beta1 is a major isoform of TGF-beta, and latent TGF-beta1, synthesized in dental pulp, is primarily activated by matrix metalloproteinase 11 (MMP11). Activated TGF-beta1 enhances the mRNA expression levels of MMP20 and full-length dentin sialophosphoprotein (DSPP) in dental pulp cells, coinciding with the induction of odontoblast differentiation. Latent TGF-beta1 synthesized in odontoblasts is primarily activated by MMP2 and MMP20 in both odontoblasts and dentin. The activity level of TGF-beta1 was reduced in the dentin of MMP20 null mice, although the amount of latent TGF-beta1 expression did not change between wild-type and MMP20 null mice. TGF-beta1 activity was reduced with the degradation of DSPP-derived proteins that occurs with ageing. We propose that to exert its multiple biological functions, TGF-beta1 is involved in a complicated dynamic interaction with matrix metalloproteinases (MMPs) and/or DSPP-derived proteins present in dental pulp, odontoblasts and dentin. PMID- 29535350 TI - TGF-beta1 promotes cell barrier function upon maturation of corneal endothelial cells. AB - Human corneal endothelial cells (HCECs) easily become fibroblastic-like when cultured, rendering them unsuitable for tissue engineering of the cornea. Transforming growth factor beta (TGF-beta) could be a key factor in this phenomenon; however, TGF-beta is also known to maintain the endothelium in a quiescent state in vivo. This work aimed to compare the effects of TGF-beta1 on the phenotype of HCECs during the proliferation and maturation phases. Our results show that addition of TGF-beta1 during the active proliferation phase produced fibroblastic HCECs and loss of the cell junction markers ZO-1 and n cadherin, independent from the presence of epidermal growth factor (EGF). By contrast, addition of TGF-beta1 in maturation media containing few mitogens led to an endothelial phenotype and functional cell junctions as HCECs developed a high trans-endothelial resistance. Furthermore, addition of AG-1478, an epithelial growth factor receptor inhibitor, enhanced the gain of the endothelial phenotype and cell barrier function. Overall, these results show that TGF-beta1 can be used to promote the formation of a typical leaky endothelial barrier during the maturation phase of cultured HCECs. A two-phase culture of HCECs using distinct proliferation and maturation media could also be key for developing ideal HCEC culture conditions. PMID- 29535351 TI - Fully Printed Wearable Vital Sensor for Human Pulse Rate Monitoring using Ferroelectric Polymer. AB - The ability to monitor subtle changes in vital and arterial signals using flexible devices attached to the human skin can be valuable for the detection of various health conditions such as cardiovascular disease. Conventional Si device technologies are being utilised in traditional clinical systems; however, its fabrication is not easy owing to the difficulties in adapting to conventional processes. Here, we present the development of a fully printed, wearable, ferroelectric-polymer vital sensor for monitoring the human pulse wave/rate on the skin. This vital sensor is compact, thin, sufficiently flexible, and conforms to the skin while providing high pressure sensitivity, fast response time, superior operational stability, and excellent mechanical fatigue properties. Moreover, the vital sensor is connected to a communication amplifier circuit for monitoring the pulse waves with a wireless sensing system. This sensor system can realise the development of new healthcare devices for wearable sensor applications. PMID- 29535352 TI - Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo. AB - Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampus in vivo. PMID- 29535353 TI - Structural insights into positive and negative allosteric regulation of a G protein-coupled receptor through protein-lipid interactions. AB - Lipids are becoming known as essential allosteric modulators of G protein-coupled receptor (GPCRs). However, how they exert their effects on GPCR conformation at the atomic level is still unclear. In light of recent experimental data, we have performed several long-timescale molecular dynamics (MD) simulations, totalling 24 MUs, to rigorously map allosteric modulation and conformational changes in the beta2 adrenergic receptor (beta2AR) that occur as a result of interactions with three different phospholipids. In particular, we identify different sequential mechanisms behind receptor activation and deactivation, respectively, mediated by specific lipid interactions with key receptor regions. We show that net negatively charged lipids stabilize an active-like state of beta2AR that is able to dock Gsalpha protein. Clustering of anionic lipids around the receptor with local distortion of membrane thickness is also apparent. On the other hand, net neutral zwitterionic lipids inactivate the receptor, generating either fully inactive or intermediate states, with kinetics depending on lipid headgroup charge distribution and hydrophobicity. These chemical differences alter membrane thickness and density, which differentially destabilize the beta2AR active state through lateral compression effects. PMID- 29535354 TI - Fluorescent polydopamine nanoparticles as a probe for zebrafish sensory hair cells targeted in vivo imaging. AB - Fluorescent polydopamine nanoparticles (FPNPs) are prepared via the ethylenediamine (EDA)-induced degradation of as-prepared non-fluorescent polydopamine (PDA) and used for targeted bioimaging. The reductive treatment of PDA in the presence of EDA yields fluorescent precipitates, inspiring us to seek various biological approaches to preparing FPNPs with excellent optical and biocompatible properties. Moreover, we firstly found that FPNPs selectively label neuromast hair cells in the lateral line of zebrafish, their applications as a reliable fluorescent indicator to investigate the neuromast hair cells, to in turn determine the viability of hair cells, was demonstrated. FPNPs also provided a minimal toxicity enable to assay the number of functional hair cells per neuromast in live animals as development proceeds. Upon combined incubation with TO-PRO-3, a well-established hair cell marker, all hair cells that were rapidly labeled with FPNPs were observed to be also completely labeled with the TO-PRO-3, labeling hair cells in neuromasts positioned in the supraorbital, otic and occipital lateral line as well as in posterior lateral line of living zebrafish larvae. Their potential efficacy for biological applications was demonstrated by their excellent optical and biocompatible properties, offering new opportunities in cancer research, real-time monitoring of stem cell transplantation and other cell-based therapies. PMID- 29535355 TI - High-throughput fecundity measurements in Drosophila. AB - Fecundity is probably the most frequently studied fitness component in Drosophila. Nevertheless, currently used methods to measure fecundity are not well-suited for large-scale experiments, with many populations being assayed in parallel. Here we present a standardized pipeline to measure fecundity in many Drosophila population samples with substantially reduced hand on times. Using a high-contrast medium for egg laying, we developed a Java plug-in for ImageJ to quantify the number of eggs by image processing. We show that our method is fast and provides reliable egg counts. PMID- 29535356 TI - Enhanced features of Dictyoglomus turgidum Cellulase A engineered with carbohydrate binding module 11 from Clostridium thermocellum. AB - Lignocellulosic biomass (LCB) is a low-cost and abundant source of fermentable sugars. Enzymatic hydrolysis is one of the main ways to obtain sugars from biomass, but most of the polysaccharide-degrading enzymes are poorly efficient on LCB and cellulases with higher performances are required. In this study, we designed a chimeric protein by adding the carbohydrate binding module (CBM) of the cellulosomal enzyme CtLic26A-Cel5E (endoglucanase H or CelH) from Clostridium (Ruminiclostridium) thermocellum to the C-terminus of Dtur CelA, an interesting hyperthermostable endoglucanase from Dictyoglomus turgidum. The activity and binding rate of both native and chimeric enzyme were evaluated on soluble and insoluble polysaccharides. The addition of a CBM resulted in a cellulase with enhanced stability at extreme pHs, higher affinity and activity on insoluble cellulose. PMID- 29535357 TI - In Vivo Small Molecule Delivery to the Optic Nerve in a Rodent Model. AB - Small molecule delivery to the optic nerve would allow for exploration of molecular and cellular pathways involved in normal physiology and optic neuropathies such as glaucoma, and provide a tool for screening therapeutics in animal models. We report a novel surgical method for small molecule drug delivery to the optic nerve head (ONH) in a rodent model. In proof-of-principle experiments, we delivered cytochalasin D (Cyt D; a filamentous actin inhibitor) to the junction of the superior optic nerve and globe in rats to target the actin rich astrocytic cytoskeleton of the ONH. Cyt D delivery was quantified by liquid chromatography and mass spectrometry of isolated optic nerve tissue. One day after Cyt D delivery, anterior ONH filamentous actin bundle content was significantly reduced as assessed by fluorescent-tagged phalloidin labeling, relative to sham delivery. Anterior ONH nuclear counts and axon-specific beta-3 tubulin levels, as well as peripapillary retinal ganglion cell layer nuclear counts were not significantly altered after Cyt D delivery relative to sham delivery. Lastly, the surgical delivery technique caused minimal observable axon degeneration up to 10 days post-surgery. This small molecule delivery technique provides a new approach to studying optic neuropathies in in vivo rodent models. PMID- 29535358 TI - A Possible Role of Dust in Resolving the Holocene Temperature Conundrum. AB - Climate models generally fail to produce a warmer (by as much as 0.5 degrees C) early to mid-Holocene than the pre-industrial in the global annual temperature, which has been termed the Holocene temperature conundrum. Here we use a fully coupled atmosphere-ocean general circulation model to test whether the conundrum can be partially resolved by considering the fact that atmospheric dust loading was much reduced during the early to mid-Holocene. Our experiments show that the global annual mean surface temperature increases by 0.30 degrees C and 0.23 degrees C for the mid-Holocene (6 ka) and early Holocene (9 ka), respectively, if the dust is completely removed. The temperature increase scales almost linearly with the fraction of dust being removed, with the 50% dust reduction experiment for the 6 ka being the only one deviating from the linear trend. The indirect effect of dust, which is highly uncertain and is not included in the model, may further enhance the warming. Therefore, the neglect of dust reduction in the Holocene in climate models could contribute significantly to the model-data discrepancy, especially in the Northern Hemisphere. PMID- 29535359 TI - Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression. AB - Eya genes encode a unique family of multifunctional proteins that serve as transcriptional co-activators and as haloacid dehalogenase-family Tyr phosphatases. Intriguingly, the N-terminal domain of Eyas, which does not share sequence similarity to any known phosphatases, contains a separable Ser/Thr phosphatase activity. Here, we demonstrate that the Ser/Thr phosphatase activity of Eya is not intrinsic, but arises from its direct interaction with the protein phosphatase 2A (PP2A)-B55alpha holoenzyme. Importantly, Eya3 alters the regulation of c-Myc by PP2A, increasing c-Myc stability by enabling PP2A-B55alpha to dephosphorylate pT58, in direct contrast to the previously described PP2A B56alpha-mediated dephosphorylation of pS62 and c-Myc destabilization. Furthermore, Eya3 and PP2A-B55alpha promote metastasis in a xenograft model of breast cancer, opposing the canonical tumor suppressive function of PP2A B56alpha. Our study identifies Eya3 as a regulator of PP2A, a major cellular Ser/Thr phosphatase, and uncovers a mechanism of controlling the stability of a critical oncogene, c-Myc. PMID- 29535361 TI - Herpesviruses possess conserved proteins for interaction with Nedd4 family ubiquitin E3 ligases. AB - Nedd4 is a family of ubiquitin E3 ligases that regulate numerous cellular processes. In this report, we showed that alpha- and beta-herpesviruses have membrane proteins that regulate the function of the Nedd4 family members. Although the homology search score was quite low, UL56 of herpes simplex virus type 1 and 2, ORF0 of varicella-zoster virus, UL42 of human cytomegalovirus, and U24 of human herpesvirus 6A, 6B, and 7 all possess at least one PPxY (PY) motif in their cytoplasmic domain, and are able to bind with Itch, a member of the Nedd4 family. These viral proteins altered the localization of Itch and decreased Itch expression in co-expressing cells. In addition, these viral proteins reduced the production of retrovirus vectors through the regulation of the Nedd4 family of proteins. U24, but not the other proteins, effectively reduced CD3epsilon expression on the T cell surface. These viral molecules are thought to contribute to the specific function of each virus through the regulation of Nedd4 family activity. PMID- 29535360 TI - miR200-regulated CXCL12beta promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. AB - High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25+FOXP3+ T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12beta) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12beta expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12alpha. Thus, our data highlight the differential regulation of the CXCL12alpha and CXCL12beta isoforms in HGSOC, and reveal a CXCL12beta associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC. PMID- 29535362 TI - Recovery from supercooling, freezing, and cryopreservation stress in larvae of the drosophilid fly, Chymomyza costata. AB - Physiological adjustments accompanying insect cold acclimation prior to cold stress have been relatively well explored. In contrast, recovery from cold stress received much less attention. Here we report on recovery of drosophilid fly larvae (Chymomyza costata) from three different levels of cold stress: supercooling to -10 degrees C, freezing at -30 degrees C, and cryopreservation at -196 degrees C. Analysis of larval CO2 production suggested that recovery from all three cold stresses requires access to additional energy reserves to support cold-injury repair processes. Metabolomic profiling (targeting 41 metabolites using mass spectrometry) and custom microarray analysis (targeting 1,124 candidate mRNA sequences) indicated that additional energy was needed to: clear by-products of anaerobic metabolism, deal with oxidative stress, re-fold partially denatured proteins, and remove damaged proteins, complexes and/or organelles. Metabolomic and transcriptomic recovery profiles were closely similar in supercooled and frozen larvae, most of which successfully repaired the cold injury and metamorphosed into adults. In contrast, the majority of cryopreseved larvae failed to proceed in ontogenesis, showed specific metabolic perturbations suggesting impaired mitochondrial function, and failed to up-regulate a set of 116 specific genes potentially linked to repair of cold injury. PMID- 29535363 TI - Transcriptomic analysis of transgressive segregants revealed the central role of photosynthetic capacity and efficiency in biomass accumulation in sugarcane. AB - Sugarcane is among the most efficient crops in converting solar energy into chemical energy. However, due to its complex genome structure and inheritance, the genetic and molecular basis of biomass yield in sugarcane is still largely unknown. We created an F2 segregating population by crossing S. officinarum and S. spontaneum and evaluated the biomass yield of the F2 individuals. The F2 individuals exhibited clear transgressive segregation in biomass yield. We sequenced transcriptomes of source and sink tissues from 12 selected extreme segregants to explore the molecular basis of high biomass yield for future breeding of high-yielding energy canes. Among the 103,664 assembled unigenes, 10,115 and 728 showed significant differential expression patterns between the two extreme segregating groups in the top visible dewlap leaf and the 9th culm internode, respectively. The most enriched functional categories were photosynthesis and fermentation in the high-biomass and the low-biomass groups, respectively. Our results revealed that high-biomass yield was mainly determined by assimilation of carbon in source tissues. The high-level expression of fermentative genes in the low-biomass group was likely induced by their low energy status. Group-specific expression alleles which can be applied in the development of new high-yielding energy cane varieties via molecular breeding were identified. PMID- 29535364 TI - A pantropically introduced tree is followed by specific ectomycorrhizal symbionts due to pseudo-vertical transmission. AB - Global trade increases plant introductions, but joint introduction of associated microbes is overlooked. We analyzed the ectomycorrhizal fungi of a Caribbean beach tree, seagrape (Coccoloba uvifera, Polygonacaeae), introduced pantropically to stabilize coastal soils and produce edible fruits. Seagrape displays a limited symbiont diversity in the Caribbean. In five regions of introduction (Brazil, Japan, Malaysia, Reunion and Senegal), molecular barcoding showed that seagrape mostly or exclusively associates with Scleroderma species (Basidiomycota) that were hitherto only known from Caribbean seagrape stands. An unknown Scleroderma species dominates in Brazil, Japan and Malaysia, while Scleroderma bermudense exclusively occurs in Reunion and Senegal. Population genetics analysis of S. bermudense did not detect any demographic bottleneck associated with a possible founder effect, but fungal populations from regions where seagrape is introduced are little differentiated from the Caribbean ones, separated by thousands of kilometers, consistently with relatively recent introduction. Moreover, dry seagrape fruits carry Scleroderma spores, probably because, when drying on beach sand, they aggregate spores from the spore bank accumulated by semi-hypogeous Scleroderma sporocarps. Aggregated spores inoculate seedlings, and their abundance may limit the founder effect after seagrape introduction. This rare pseudo-vertical transmission of mycorrhizal fungi likely contributed to efficient and repeated seagrape/Scleroderma co-introductions. PMID- 29535365 TI - Macular Choroidal Small-Vessel Layer, Sattler's Layer and Haller's Layer Thicknesses: The Beijing Eye Study. AB - To study macular choroidal layer thickness, 3187 study participants from the population-based Beijing Eye Study underwent spectral-domain optical coherence tomography with enhanced depth imaging for thickness measurements of the macular small-vessel layer, including the choriocapillaris, medium-sized choroidal vessel layer (Sattler's layer) and large choroidal vessel layer (Haller's layer). In multivariate analysis, greater thickness of all three choroidal layers was associated (all P < 0.05) with higher prevalence of age-related macular degeneration (AMD) (except for geographic atrophy), while it was not significantly (all P > 0.05) associated with the prevalence of open-angle glaucoma or diabetic retinopathy. There was a tendency (0.07 > P > 0.02) toward thinner choroidal layers in chronic angle-closure glaucoma. The ratio of small vessel layer thickness to total choroidal thickness increased (P < 0.001; multivariate analysis) with older age and longer axial length, while the ratios of Sattler's layer and Haller's layer thickness to total choroidal thickness decreased. A higher ratio of small-vessel layer thickness to total choroidal thickness was significantly associated with a lower prevalence of AMD (early type, intermediate type, late geographic type). Axial elongation-associated and aging-associated choroidal thinning affected Haller's and Sattler's layers more markedly than the small-vessel layer. Non-exudative and exudative AMD, except for geographic atrophy, was associated with slightly increased choroidal thickness. PMID- 29535366 TI - In tendons, differing physiological requirements lead to functionally distinct nanostructures. AB - The collagen-based tissues of animals are hierarchical structures: even tendon, the simplest collagenous tissue, has seven to eight levels of hierarchy. Tailoring tissue structure to match physiological function can occur at many different levels. We wanted to know if the control of tissue architecture to achieve function extends down to the nanoscale level of the individual, cable like collagen fibrils. Using tendons from young adult bovine forelimbs, we performed stress-strain experiments on single collagen fibrils extracted from tendons with positional function, and tendons with energy storing function. Collagen fibrils from the two tendon types, which have known differences in intermolecular crosslinking, showed numerous differences in their responses to elongation. Unlike those from positional tendons, fibrils from energy storing tendons showed high strain stiffening and resistance to disruption in both molecular packing and conformation, helping to explain how these high stress tissues withstand millions of loading cycles with little reparative remodeling. Functional differences in load-bearing tissues are accompanied by important differences in nanoscale collagen fibril structure. PMID- 29535367 TI - Author Correction: A Study on Image Quality in Polarization-Resolved Second Harmonic Generation Microscopy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29535368 TI - High planktonic diversity in mountain lakes contains similar contributions of autotrophic, heterotrophic and parasitic eukaryotic life forms. AB - A rich eukaryotic planktonic community exists in high-mountain lakes despite the diluted, oligotrophic and cold, harsh prevailing conditions. Attempts of an overarching appraisal have been traditionally hampered by observational limitations of small, colorless, and soft eukaryotes. We aimed to uncover the regional eukaryotic biodiversity of a mountain lakes district to obtain general conclusions on diversity patterns, dominance, geographic diversification, and food-web players common to oligotrophic worldwide distributed freshwater systems. An unprecedented survey of 227 high-altitude lakes comprising large environmental gradients was carried out using Illumina massive tag sequencing of the 18S rRNA gene. We observed a large Chrysophyceae dominance in richness, abundance and novelty, and unveiled an unexpected richness in heterotrophic phagotrophs and parasites. In particular, Cercozoa and Chytridiomycota showed diversity features similar to the dominant autotrophic groups. The prominent beta-dispersion shown by parasites suggests highly specific interactions and a relevant role in food webs. Interestingly, the freshwater Pyrenean metacommunity contained more diverse specific populations than its closest marine oligotrophic equivalent, with consistently higher beta-diversity. The relevance of unseen groups opens new perspectives for the better understanding of planktonic food webs. Mountain lakes, with remarkable environmental idiosyncrasies, may be suitable environments for the genetic diversification of microscopic eukaryotic life forms. PMID- 29535369 TI - Multi-scale X-ray computed tomography to detect and localize metal-based nanomaterials in lung tissues of in vivo exposed mice. AB - In this methodological study, we demonstrated the relevance of 3D imaging performed at various scales for the ex vivo detection and location of cerium oxide nanomaterials (CeO2-NMs) in mouse lung. X-ray micro-computed tomography (micro-CT) with a voxel size from 14 um to 1 um (micro-CT) was combined with X ray nano-computed tomography with a voxel size of 63 nm (nano-CT). An optimized protocol was proposed to facilitate the sample preparation, to minimize the experimental artifacts and to optimize the contrast of soft tissues exposed to metal-based nanomaterials (NMs). 3D imaging of the NMs biodistribution in lung tissues was consolidated by combining a vast variety of techniques in a correlative approach: histological observations, 2D chemical mapping and speciation analysis were performed for an unambiguous detection of NMs. This original methodological approach was developed following a worst-case scenario of exposure, i.e. high dose of exposure with administration via intra-tracheal instillation. Results highlighted both (i) the non-uniform distribution of CeO2 NMs within the entire lung lobe (using large field-of-view micro-CT) and (ii) the detection of CeO2-NMs down to the individual cell scale, e.g. macrophage scale (using nano-CT with a voxel size of 63 nm). PMID- 29535371 TI - The severity of ankylosing spondylitis and responses to anti-tumour necrosis factor biologics are not influenced by the tumour necrosis factor receptor polymorphism incriminated in multiple sclerosis. AB - Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693 GG homozygotes actually had significantly worse BASDAI (mean 4.2, 95% CI: 4-4.5) than AA homozygotes (mean 3.8, 95% CI: 3.7-4) in both the unadjusted (difference = 0.4, p = 0.006) and adjusted analyses (difference = 0.2-0.5, p = 0.002-0.04 depending on the adjustment model). We found no evidence that rs1900693 predicted functional status (BASFI) or global disease scores (BAS-G), and it exerted no influence on either the intention to treat with or efficacy of anti-TNF treatment. PMID- 29535370 TI - Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2). AB - Herpes simplex virus type 2 (HSV-2) is an incurable viral infection with severity ranging from asymptomatic to frequent recurrences. The viral shedding rate has been shown as a reproducible HSV-2 severity end point that correlates with lesion rates. We used a genome-wide association study (GWAS) to investigate the role of common human genetic variation in HSV-2 severity. We performed a GWAS on 223 HSV 2-positive participants of European ancestry. Severity was measured by viral shedding rate, as defined by the percent of days PCR+ for HSV-2 DNA over at least 30 days. Analyses were performed under linear regression models, adjusted for age, sex, and ancestry. There were no genome-wide significant (p < 5E-08) associations with HSV-2 viral shedding rate. The top nonsignificant SNP (rs75932292, p = 6.77E-08) associated with HSV-2 viral shedding was intergenic, with the nearest known biologically interesting gene (ABCA1) ~130 kbp downstream. Several other SNPs approaching significance were in or near genes with viral or neurological associations, including four SNPs in KIF1B. The current study is the first comprehensive genome-wide investigation of human genetic variation in virologic severity of established HSV-2 infection. However, no significant associations were observed with HSV-2 virologic severity, leaving the exact role of human variation in HSV-2 severity unclear. PMID- 29535372 TI - Surgically induced astigmatism following trabeculectomy. AB - PURPOSE: Surgically induced astigmatism (SIA) has attracted much interest in recent times because changes in corneal astigmatism can lead to decreased uncorrected visual acuity and patient discomfort. This study aimed to evaluate SIA and to identify factors correlated therewith after trabeculectomy. METHODS: We retrospectively reviewed medical charts of patients who were treated with trabeculectomy at 120 degrees meridian (superotemporal area on right eye and superonasal area on left eye) by the same surgeon. Preoperative keratometric data were compared with data collected from 2 months to 12 months postoperatively. SIA was evaluated using Naeser's polar value analysis. RESULTS: Using Naeser's method, DeltaKP(120) was calculated as 0.7 +/- 0.7 (0.82@104 degrees ), which indicates a with-the-rule change. After surgery, the combined mean polar values changed significantly (Hotelling T2 = 22.47; p < 0.001). Multivariate analysis of variance indicated that postoperative intraocular pressure and location of surgery were independent factors that were significantly associated with SIA (p = 0.002 and 0.03, respectively). CONCLUSIONS: Trabeculectomy at the 120 degrees meridian was not astigmatically neutral. In addition, the SIA after trabeculectomy appears to be greater in eyes with low postoperative intraocular pressure and a superonasal surgical wound rather than a superotemporal wound. PMID- 29535373 TI - Propeller flaps in eyelid reconstruction. AB - PURPOSE: Propeller flaps are island flaps that reach the recipient site through an axial rotation. The flap has a subcutaneous pedicle on which it pivots, thereby resembling a helicopter propeller. We present our series of propeller flaps for the reconstruction of large eyelid defects. METHODS: This is a retrospective review of the clinical case notes of eight patients that underwent tumour excision with reconstruction with a cutaneous propeller flap supplied by a non-perforator orbicularis pedicle between July and December 2016. RESULTS: Propeller flaps were used in the reconstruction of five lower lid defects (size range 19 * 5 mm to 25 * 8 mm), one medial canthus defect (13 mm diameter), one complete upper lid defect (42 * 19 mm diameter) and one lid sparing extenteration defect. The flaps were recruited from nasolabial, lateral canthal, temple or medial upper cheek skin. Post-operatively one case had 'trapdooring' which required flap revision at 4 months and one had persistent oedema that settled without intervention. CONCLUSIONS: The reconstruction of large eyelid defects is challenging in part because of the paucity of locally available skin. Propeller flaps are a paradigm shift in periocular reconstruction in which the subcutaneous pedicle enables the recruitment of large and highly mobile skin flaps from a wide area of regional tissue. PMID- 29535374 TI - AAV-mediated NT-3 overexpression protects cochleae against noise-induced synaptopathy. AB - The synapse between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) has been identified as a sensitive structure to noise-induced damage in the mammalian cochlea. Since this synapse provides the major information pathway from the cochlea to the auditory brain, it is important to maintain its integrity. Neurotrophin-3 (NT-3) has been known to play an important role in the development and the functional maintenance of this synapse. Application of exogenous NT-3, or overexpression of this gene in a transgenic animal model, have shown the value to protect this synapse from noise-induced damage. In the present study, NT-3 overexpression was induced by cochlear gene transfection before noise exposure via the use of an adeno-associated viral (AAV) vector. We found that such an overexpression provided a significant synaptic protection against a noise exposure that caused massive damage to the synapses, likely due to it promoting the repair of the synapse after the initial damage. PMID- 29535375 TI - MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. AB - Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer's disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 +/- 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN. The volume of AAV2-BDNF (3 * 108 vg/ul) infusion linearly correlated with the number of BDNF labeled cells and the volume (mm3) of BDNF immunoreactivity in the entorhinal cortex. BDNF is normally trafficked to the hippocampus from the entorhinal cortex; in these experiments, we also found that BDNF immunoreactivity was elevated in the hippocampus following therapeutic BDNF vector delivery to the entorhinal cortex, achieving growth factor distribution through key memory circuits. These findings indicate that MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorhinal cortex and the hippocampus. These methods are adaptable to human clinical trials. PMID- 29535376 TI - Wing bone geometry reveals active flight in Archaeopteryx. AB - Archaeopteryx is an iconic fossil taxon with feathered wings from the Late Jurassic of Germany that occupies a crucial position for understanding the early evolution of avian flight. After over 150 years of study, its mosaic anatomy unifying characters of both non-flying dinosaurs and flying birds has remained challenging to interpret in a locomotory context. Here, we compare new data from three Archaeopteryx specimens obtained through phase-contrast synchrotron microtomography to a representative sample of archosaurs employing a diverse array of locomotory strategies. Our analyses reveal that the architecture of Archaeopteryx's wing bones consistently exhibits a combination of cross-sectional geometric properties uniquely shared with volant birds, particularly those occasionally utilising short-distance flapping. We therefore interpret that Archaeopteryx actively employed wing flapping to take to the air through a more anterodorsally posteroventrally oriented flight stroke than used by modern birds. This unexpected outcome implies that avian powered flight must have originated before the latest Jurassic. PMID- 29535378 TI - Author Correction: Identification of Aspergillus fumigatus UDP-Galactopyranose Mutase Inhibitors. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29535377 TI - Bioimpedance-defined overhydration predicts survival in end stage kidney failure (ESKF): systematic review and subgroup meta-analysis. AB - Both overhydration and comorbidity predict mortality in end-stage kidney failure (ESKF) but it is not clear whether these are independent of one another. We undertook a systematic review of studies reporting outcomes in adult dialysis patients in which comorbidity and overhydration, quantified by whole body bioimpedance (BI), were reported. PubMed, EMBASE, PsychInfo and the Cochrane trial database were searched (1990-2017). Independent reviewers appraised studies including methodological quality (assessed using QUIPS). Primary outcome was mortality, with secondary outcomes including hospitalisation and cardiovascular events. Of 4028 citations identified, 46 matched inclusion criteria (42 cohorts; 60790 patients; 8187 deaths; 95% haemodialysis/5% peritoneal dialysis). BI measures included phase angle/BI vector (41%), overhydration index (39%) and extra:intracellular water ratio (20%). 38 of 42 cohorts had multivariable survival analyses (MVSA) adjusting for age (92%), gender (66%), diabetes (63%), albumin (58%), inflammation (CRP/IL6-37%), non-BI nutritional markers (24%) and echocardiographic data (8%). BI-defined overhydration (BI-OH) independently predicted mortality in 32 observational cohorts. Meta-analysis revealed overhydration >15% (HR 2.28, 95% CI 1.56-3.34, P < 0.001) and a 1-degree decrease in phase angle (HR 1.74, 95% CI 1.37-2.21, P < 0.001) predicted mortality. BI-OH predicts mortality in dialysis patients independent of the influence of comorbidity. PMID- 29535380 TI - Conventional dendritic cells are required for the cross-presentation of leukemia specific antigen in a model of AML relapse post-BMT. PMID- 29535381 TI - Protective environment for hematopoietic cell transplant (HSCT) recipients: The Infectious Diseases Working Party EBMT analysis of global recommendations on health-care facilities. AB - International guidelines on protective environment for HSCT recipients proposed a set of 10 global recommendations in 2009 on protective environment (GRPE) concerning hospital room design and ventilation. The EBMT Infectious Diseases Working Party undertook a survey on the status on protective environment for HSCT recipients with the aim of surveying current practices and their agreement with GRPE recommendations. The questionnaire consisted of 37 questions divided into 5 sections about filtration, air changes, maintenance, and the protective environment in rooms and the surrounding unit. Overall, 177 centres (response rate 33%) from 36 countries responded, indicating that 99.4% of patient rooms were equipped with HEPA filters, but only 48.6% of the centre's staff were aware of, and could confirm, regular replacement of filters based on manufacturers' recommendations. Well-sealed rooms were used in terms of windows (70.6%), ceilings (35%), and plumbing pipes (51.4%). The sensor monitors in the patient room used to determine when the HEPA filters require changing were installed only in 18.1% of centres. Only 1 centre fulfilled all 10 GRPE recommendations, while 62 centres fulfilled the 3 level "A" recommendations. In conclusion, HEPA filtered rooms are available in almost all centres, while fewer centres fulfilled other requirements. Knowledge on the details and maintenance of protective environments in the HSCT setting was inadequate, reflecting a lack of communication between the health personnel involved, hospital infection control and the hospital maintenance services. PMID- 29535379 TI - Molecular basis of an agarose metabolic pathway acquired by a human intestinal symbiont. AB - In red algae, the most abundant principal cell wall polysaccharides are mixed galactan agars, of which agarose is a common component. While bioconversion of agarose is predominantly catalyzed by bacteria that live in the oceans, agarases have been discovered in microorganisms that inhabit diverse terrestrial ecosystems, including human intestines. Here we comprehensively define the structure-function relationship of the agarolytic pathway from the human intestinal bacterium Bacteroides uniformis (Bu) NP1. Using recombinant agarases from Bu NP1 to completely depolymerize agarose, we demonstrate that a non agarolytic Bu strain can grow on GAL released from agarose. This relationship underscores that rare nutrient utilization by intestinal bacteria is facilitated by the acquisition of highly specific enzymes that unlock inaccessible carbohydrate resources contained within unusual polysaccharides. Intriguingly, the agarolytic pathway is differentially distributed throughout geographically distinct human microbiomes, reflecting a complex historical context for agarose consumption by human beings. PMID- 29535382 TI - Single centre results of targeted busulphan, fludarabine and serotherapy conditioning in haematopoietic stem cell transplantation for haemophagocytic lymphohistiocytosis. PMID- 29535383 TI - A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis. AB - The Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ. We further show that the Hippo pathway is a critical mediator of VEGF-induced angiogenesis and tumor vasculogenic mimicry. Thus, our work offers a biosensor tool for the study of the Hippo pathway and suggests a role for Hippo signaling in regulating blood vessel formation in physiological and pathological settings. PMID- 29535384 TI - Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer. AB - Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle checkpoints, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification. PMID- 29535385 TI - Dual effect of PEG-PE micelle over the oligomerization and fibrillation of human islet amyloid polypeptide. AB - The oligomerization and fibrillation of human islet amyloid polypeptide (hIAPP) play a central role in the pathogenesis of type 2 diabetes. Strategies for remodelling the formation of hIAPP oligomers and fibrils have promising application potential in type 2 diabetes therapy. Herein, we demonstrated that PEG-PE micelle could inhibit hIAPP oligomerization and fibrillation through blocking the hydrophobic interaction and the conformational change from random coil to beta-sheet structures of hIAPP. In addition, we also found that PEG-PE micelle could remodel the preformed hIAPP fibrils allowing the formation of short fibrils and co-aggregates. Taken together, PEG-PE micelle could rescue hIAPP induced cytotoxicity by decreasing the content of hIAPP oligomers and fibrils that are related to the oxidative stress and cell membrane permeability. This study could be beneficial for the design and development of antiamyloidogenic agents. PMID- 29535386 TI - Highly efficient heritable targeted deletions of gene clusters and non-coding regulatory regions in Arabidopsis using CRISPR/Cas9. AB - Genome editing using CRISPR/Cas9 is considered the best instrument for genome engineering in plants. This methodology is based on the nuclease activity of Cas9 that is guided to specific genome sequences by single guide RNAs (sgRNAs) thus enabling researchers to engineer simple mutations or large chromosomal deletions. Current methodologies for targeted genome editing in plants using CRISPR/Cas9 are however largely inefficient, mostly due to low Cas9 activity, variable sgRNA efficiency and low heritability of genetic lesions. Here, we describe a newly developed strategy to enhance CRISPR/Cas9 efficiency in Arabidopsis thaliana focusing on the design of novel binary vectors (pUbiCAS9-Red and pEciCAS9-Red), the selection of highly efficient sgRNAs, and the use of direct plant regeneration from induced cell cultures. Our work demonstrates that by combining these three independent developments, heritable targeted chromosomal deletions of large gene clusters and intergenic regulatory sequences can be engineered at a high efficiency. Our results demonstrate that this improved CRISPR/Cas9 methodology can provide a fast, efficient and cost-effective tool to engineer targeted heritable chromosomal deletions, which will be instrumental for future high-throughput functional genomics studies in plants. PMID- 29535387 TI - Publisher Correction: Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid. AB - In the original version of this Article, extraneous text not belonging to the article was accidentally appended to end of the first paragraph of the discussion. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 29535389 TI - Combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase 4 inhibitor in type 2 diabetes: a systematic review with meta-analysis. AB - Sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors have complementary mode of action. For the meta-analysis comparing the efficacy and safety between SGLT2 inhibitor plus DPP4 inhibitor (SGLT2i/DPP4i) and placebo plus DPP4 inhibitor (PCB/DPP4i) in patients with type 2 diabetes mellitus (T2DM), we selected randomized controlled trials from electronic databases by predefined criteria. The primary outcome of interest was the change in glycated hemoglobin A1c (HbA1c) from baseline. Of 605 potentially relevant studies, 7 eligible RCTs comprising 2,082 patients were included.SGLT2i/DPP4i showed a greater reduction in HbA1c (weighted mean difference -0.6%, 95% CI -0.7 to -0.5%), fasting plasma glucose, 2 h postprandial plasma glucose, and body weight compared to PCB/DPP4i. The risk of hypoglycemia increased in SGLT2i/DPP4i compared to that in PCB/DPP4i only when insulin or sulfonylureas were included as a background therapy. The risk of urinary tract infection was not increased in SGLT2i/DPP4i; however, the risk of genital infection increased upon adding SGLT2 inhibitors to pre-existing DPP4 inhibitors. In conclusion, compared to PCB/DPP4i, SGLT2i/DPP4i achieved better glycemic control and greater weight reduction without increasing the risk of hypoglycemia and urinary tract infection in patients with inadequately controlled T2DM. PMID- 29535390 TI - Publisher Correction: Magnetic field enhancement of organic photovoltaic cells performance. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29535388 TI - Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. AB - Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors. PMID- 29535392 TI - Prevalence of the single-nucleotide polymorphism rs11554137 (IDH1105GGT) in brain tumors of a cohort of Italian patients. AB - IDH mutational status is required for proper diagnosis according to the WHO criteria revised in 2016. The single nucleotide polymorphism (SNP) rs11554137 (IDH1105GGT) at codon 105 of IDH1 has been reported in patients with several tumor types, including those with glioma. The aim of this study is to investigate the prevalence of IDH1105GGT in a cohort of brain tumors, and its association with clinicopathologic features and IDH1 and IDH2 missense mutations. Exon 4 of IDH1 and IDH2 was analyzed in a series of brain tumors classified according to current WHO criteria. DNA from control individuals was analyzed to infer the prevalence of IDH1105GGT in the reference population. Analysis was performed using next generation sequencing. IDH1105GGT was three times more frequent in patients with tumors (44/293 cases, 15.0%) vs. population controls (6/109, 5.5%) (p = 0.0102). IDH1105GGT was more frequent in grade III tumors (26.1%) compared to grade II (10.9%, p = 0.038) and grade IV tumors (13.7%, p = 0.041). IDH1 105GGT was more frequent in grade II and III tumors without an IDH tumor missense mutation (43.8%) than in those with (11.5%, p = 0.005). The IDH1105GGT SNP likely represents an important genetic marker, worthy of additional investigation to better understand the clinical and biological features of IDH-WT infiltrating gliomas. PMID- 29535391 TI - Molecular typing of Mycobacterium kansasii using pulsed-field gel electrophoresis and a newly designed variable-number tandem repeat analysis. AB - Molecular epidemiological studies of Mycobacterium kansasii are hampered by the lack of highly-discriminatory genotyping modalities. The purpose of this study was to design a new, high-resolution fingerprinting method for M. kansasii. Complete genome sequence of the M. kansasii ATCC 12478 reference strain was searched for satellite-like repetitive DNA elements comprising tandem repeats. A total of 24 variable-number tandem repeat (VNTR) loci were identified with potential discriminatory capacity. Of these, 17 were used to study polymorphism among 67 M. kansasii strains representing six subtypes (I-VI). The results of VNTR typing were compared with those of pulsed-field gel electrophoresis (PFGE) with AsnI digestion. Six VNTRs i.e. (VNTR 1, 2, 8, 14, 20 and 23) allow to differentiate analyzed strains with the same discriminatory capacities as use of a 17-loci panel. VNTR typing and PFGE in conjunction revealed 45 distinct patterns, including 11 clusters with 33 isolates and 34 unique patterns. The Hunter-Gaston's discriminatory index was 0.95 and 0.66 for PFGE and VNTR typing respectively, and 0.97 for the two methods combined. In conclusion, this study delivers a new typing scheme, based on VNTR polymorphism, and recommends it as a first-line test prior to PFGE analysis in a two-step typing strategy for M. kansasii. PMID- 29535393 TI - Finite Dimension: A Mathematical Tool to Analise Glycans. AB - There is a need to develop widely applicable tools to understand glycan organization, diversity and structure. We present a graph-theoretical study of a large sample of glycans in terms of finite dimension, a new metric which is an adaptation to finite sets of the classical Hausdorff "fractal" dimension. Every glycan in the sample is encoded, via finite dimension, as a point of Glycan Space, a new notion introduced in this paper. Two major outcomes were found: (a) the existence of universal bounds that restrict the universe of possible glycans and show, for instance, that the graphs of glycans are a very special type of chemical graph, and (b) how Glycan Space is related to biological domains associated to the analysed glycans. In addition, we discuss briefly how this encoding may help to improve search in glycan databases. PMID- 29535394 TI - Chemical composition and hepatoprotective effect of free phenolic extract from barley during malting process. AB - In this study, No.Ganpi4 of barley was steeped and malted to investigate the changes of phenolic compounds during malting process. The free phenolic extract from raw barley (FPEB) was analyzed by HPLC and predominant compounds were (+) catechin, protocatechuate and quercetin. The FPEB was evaluated for hepatoprotective effect in vivo and in vitro. Intragastric administration of FPEB (100, 200 and 400 mg/kg/bw) to mice significantly weakened the effects of hepatic damage induced by CCl4 toxicity on serum markers, including serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, total cholesterol and total triglycerides. FPEB administration also increased the hepatic levels of antioxidant enzymes, such as superoxide dismutase, catalase and glutathione peroxidase. Histopathological examinations further confirmed that FPEB could protect the liver from CCl4-induced damage. In vitro, the experimental results demonstrated that FPEB could reduce BRL hepatocyte apoptosis and damage induced by CCl4. These results suggest that FPEB exerts an effective protection for hepatic injury, and barley has the potential as a functional food to prevent hepatic injury. PMID- 29535395 TI - Systematic review and network meta-analysis of treatment strategies for asymptomatic carotid disease. AB - We aim to perform a systematic review and meta-analysis to investigate outcomes of treatment strategies for asymptomatic carotid disease. We searched electronic bibliographic sources (MEDLINE, EMBASE, CINAHL and CENTRAL) to identify randomised controlled trials (RCT) reporting comparative outcomes of carotid endarterectomy (CEA), carotid stenting (CAS) and best medical therapy (BMT) in asymptomatic carotid disease. We performed pairwise meta-analysis applying random or fixed-effects models and reported the results as the odds ratio (OR) or risk difference (RD) and 95% confidence interval (CI). We also performed a network meta-analysis and obtained a hierarchy of the competing interventions using rankograms and the surface under the cumulative ranking curve and mean ranks. Stroke and death within 30 days and during follow up were the primary outcome endpoints. Eleven RCTs were identified reporting a total of 8,954 patients. Compared to BMT, CEA reduces the odds of long-term mortality (OR 0.70, 95% CI 0.43, 1.12) and ipsilateral stroke (OR 0.59 95% CI 0.50, 0.71). Network meta analyses league table demonstrated that BMT is superior to CEA and CAS in terms of perioperative stroke risk and mortality. CEA is the preferred method to reduce the long-term risk of ipsilateral stroke and mortality for patients with asymptomatic carotid disease. PMID- 29535396 TI - Development and validation of the Canine Reward Responsiveness Scale -Examining individual differences in reward responsiveness of the domestic dog. AB - Although there is ample data indicating that reward processing plays an important role in human psychopathologies and pharmaco- and psychotherapy treatment response, the corresponding animal-model research needs to be extended to models whose motivational and social dispositions are better generalizable than those of the traditional models. Accordingly, our aim was to develop and assess the reliability and validity of an owner-report rating scale of reward responsiveness in domestic dogs (N = 2149) and then to examine individual differences in reward responsiveness. Responsiveness was categorisable by reward type (ball/toy and food) and exhibited individual variability manifesting in age- and breed-related differences. Rating scale scores were associated with behavioural observation of reward processing, indicating evidence of convergent validity. Ball/toy and food reward responsiveness were associated with owner-rated hyperactivity-impulsivity' inattention and with differences in training, indicating evidence of concurrent validity. Extreme (vs. average) reward responsiveness was also predicted by dogs' hyperactivity-impulsivity and inattention' and extreme responsiveness was associated with increased likelihood of physical health and/or social problems. These findings are informative with regard to the dog as an animal model for various human behavioural and cognitive functions' and also for the dog in its own right as they are relevant to training and welfare. PMID- 29535397 TI - Drosophila Ubiquitin C-Terminal Hydrolase Knockdown Model of Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Many factors have been shown to contribute to its pathogenesis including genetic and environmental factors. Ubiquitin C-terminal hydrolase L1 (UCHL1) is also known to be involved in the pathogenesis of PD. We herein modeled the study of UCHL1 in Drosophila melanogaster and investigated its functions in PD. The specific knockdown of the Drosophila ortholog of UCHL1 (dUCH) in dopaminergic neurons (DA neurons) led to the underdevelopment and/or degeneration of these neurons, specifically in DL1 DA neuron cluster in the larval brain lobe and PPM2, PPM3, PPL2ab, and VUM DA neuron clusters in the adult brain. These defects were followed by a shortage of dopamine in the brain, which subsequently resulted in locomotor dysfunction. The degeneration of DA neurons in dUCH knockdown adult brain, which occurred progressively and severely during the course of aging, mimics the epidemiology of PD. DA neuron and locomotor defects were rescued when dUCH knockdown flies were treated with vitamin C, a well-known antioxidant. These results suggest that dUCH knockdown fly is a promising model for studying the pathogenesis and epidemiology of PD as well as the screening of potential antioxidants for PD therapeutics. PMID- 29535398 TI - Trichostatin A inhibits the activation of Hepatic stellate cells by Increasing C/EBP-alpha Acetylation in vivo and in vitro. AB - Reversal of activated hepatic stellate cells (HSCs) to a quiescent state and apoptosis of activated HSCs are key elements in the reversion of hepatic fibrosis. CCAAT/enhancer binding protein alpha (C/EBP-alpha) has been shown to inhibit HSC activation and promote its apoptosis. This study aims to investigate how C/EBP-alpha acetylation affects the fate of activated HSCs. Effects of a histone deacetylation inhibitor trichostatin A (TSA) on HSC activation were evaluated in a mouse model of liver fibrosis caused by carbon tetrachloride (CCl4) intoxication. TSA was found to ameliorate CCl4-induced hepatic fibrosis and improve liver function through increasing the protein level and enhancing C/EBP-alpha acetylation in the mouse liver. C/EBP-alpha acetylation was determined in HSC lines in the presence or absence of TSA, and the lysine residue K276 was identified as a main acetylation site in C/EBP-alpha protein. C/EBP alpha acetylation increased its stability and protein level, and inhibited HSC activation. The present study demonstrated that C/EBP-alpha acetylation increases the protein level by inhibiting its ubiquitination-mediated degradation, and may be involved in the fate of activated HSCs. Use of TSA may confer an option in minimizing hepatic fibrosis by suppressing HSC activation, a key process in the initiation and progression of hepatic fibrosis. PMID- 29535399 TI - Hybrid setup for stable magnetic fields enabling robust quantum control. AB - Well controlled and highly stable magnetic fields are desired for a wide range of applications in physical research, including quantum metrology, sensing, information processing, and simulation. Here we introduce a low-cost hybrid assembly of rare-earth magnets and magnetic field coils to generate a field strength of [Formula: see text]10.9 mT with a calculated spatial variation of less than 10-6 within a diameter of spherical volume of 150 MUm. We characterise its tuneability and stability performance using a single Mg+ atom confined in a radio-frequency surface-electrode trap under ultra-high vacuum conditions. The strength of the field can be tuned with a relative precision of <=2 * 10-5 and we find a passive temporal stability of our setup of better than 1.0 * 10-4 over the course of one hour. Slow drifts on time scales of a few minutes are actively stabilised by adjusting electric currents in the magnetic field coils. In this way, we observe coherence times of electronic superposition states of greater than six seconds using a first-order field insensitive (clock) transition. In a first application, we demonstrate sensing of magnetic fields with amplitudes of >=0.2 MUT oscillating at [Formula: see text]2pi * 60 MHz. Our approach can be implemented in compact and robust applications with strict power and load requirements. PMID- 29535400 TI - Author Correction: Electroporation of mice zygotes with dual guide RNA/Cas9 complexes for simple and efficient cloning-free genome editing. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29535401 TI - 100- kyr cyclicity in volcanic ash emplacement: evidence from a 1.1 Myr tephra record from the NW Pacific. AB - It is a longstanding observation that the frequency of volcanism periodically changes at times of global climate change. The existence of causal links between volcanism and Earth's climate remains highly controversial, partly because most related studies only cover one glacial cycle. Longer records are available from marine sediment profiles in which the distribution of tephras records frequency changes of explosive arc volcanism with high resolution and time precision. Here we show that tephras of IODP Hole U1437B (northwest Pacific) record a cyclicity of explosive volcanism within the last 1.1 Myr. A spectral analysis of the dataset yields a statistically significant spectral peak at the ~100 kyr period, which dominates the global climate cycles since the Middle Pleistocene. A time domain analysis of the entire eruption and delta18O record of benthic foraminifera as climate/sea level proxy shows that volcanism peaks after the glacial maximum and ~13 +/- 2 kyr before the delta18O minimum right at the glacial/interglacial transition. The correlation is especially good for the last 0.7 Myr. For the period 0.7-1.1 Ma, during the Middle Pleistocene Transition (MPT), the correlation is weaker, since the 100 kyr periodicity in the delta18O record diminishes, while the tephra record maintains its strong 100 kyr periodicity. PMID- 29535402 TI - Unsupervised Segmentation of Greenhouse Plant Images Based on Statistical Method. AB - Complicated image scene of the agricultural greenhouse plant images makes it very difficult to obtain precise manual labeling, leading to the hardship of getting the accurate training set of the conditional random field (CRF). Considering this problem, this paper proposed an unsupervised conditional random field image segmentation algorithm ULCRF (Unsupervised Learning Conditional Random Field), which can perform fast unsupervised segmentation of greenhouse plant images, and further the plant organs in the image, i.e. fruits, leaves and stems, are segmented. The main idea of this algorithm is to calculate the unary potential, namely the initial label of the Dense CRF, by the unsupervised learning model LDA (Latent Dirichlet Allocation). In view of the ever-changing image features at different stages of fruit growth, a multi-resolution ULCRF is proposed to improve the accuracy of image segmentation in the middle stage and late stage of the fruit growth. An image is down-sampled twice to obtain three layers of different resolution images, and the features of each layer are interrelated with each other. Experiment results show that the proposed method can segment greenhouse plant images in an unsupervised method automatically and obtain a high segmentation accuracy together with a high extraction precision of the fruit part. PMID- 29535403 TI - Metabolic response to amylose-rich wheat-based rusks in overweight individuals. AB - BACKGROUND/OBJECTIVES: The amylose-amylopectin ratio influences starch properties. A higher amylose content is associated with slower starch digestion thus reducing the postprandial plasma glucose response and improving the overall postprandial metabolism. So far, limited evidence is available on the metabolic effect of wheat-based foods rich in amylose. This randomised controlled study investigated the acute metabolic effects of amylose-rich wheat-based rusks in overweight subjects focusing on potential mechanisms. SUBJECTS/METHODS: Ten overweight subjects consumed in random order two test meals differing only in the carbohydrate source: rusks prepared with amylose-rich wheat flour (ARR) or conventional wheat flour (control). Blood samples were taken at fasting and over 4 h after the meal. Satiety and intestinal fermentation were evaluated by VAS and H2-breath test, respectively. RESULTS: ARR reduced plasma glucose response during the first two hours after the meal and the desire to eat, and increased breath hydrogen concentration at 4 h (p < 0.05 for all). Moreover, according to computational models, the ARR slightly reduced intestinal glucose absorption in the first hour after the meal and increased the overall postprandial insulin sensitivity. CONCLUSIONS: Rusks made with amylose-rich flour could be useful for improving postprandial glucose metabolism and reduce the desire to eat, thus possibly contributing to the prevention and treatment of overweight/obesity, impaired glucose tolerance or diabetes. PMID- 29535404 TI - Dietary patterns are associated with attention-deficit/hyperactivity disorder (ADHD) symptoms among preschoolers in mainland China. AB - BACKGROUND/OBJECTIVES: To identify the major dietary patterns among preschoolers and assess the relation of major dietary patterns to attention deficit/hyperactivity disorder (ADHD). SUBJECTS/METHODS: A cross-sectional survey was conducted comprising a large sample of 14,912 children aged 3-6 years old in Ma'anshan city of Anhui Province in China. A semi-quantitative food frequency questionnaire and the 10-item Chinese version of the Conners' abbreviated symptom questionnaire were administered to assess usual dietary intakes and ADHD. Social demographic information was also collected. Major dietary patterns were identified by principal components analysis. Logistic regression was employed to explore the association of dietary patterns with ADHD. RESULTS: Five dietary patterns were identified explaining 47.96% of the total diet variation. The "processed" dietary component was the principal pattern that explained the higher percentage of variability, 24.69%. After controlling for potential confounders, preschoolers in the top quintile of the "processed" (odds ratio (OR) = 1.56, 95% confidence interval (CI): 1.31-1.86) and "snack" (OR = 1.76, 95% CI = 1.49-2.07) dietary pattern score had greater odds for having ADHD symptoms compared with those in the lowest quintile. Lowest scores on the "vegetarian" were associated with significantly a higher likelihood of indications of ADHD symptoms (OR = 0.67, 95% CI = 0.56-0.79). CONCLUSIONS: This study showed that preschoolers tend to choose unhealthy dietary pattern in Ma'anshan, China. "Processed" and "snack" dietary patterns were significantly and positively correlated with ADHD symptoms, while "vegetarian" dietary patterns were negatively correlated with ADHD symptoms. PMID- 29535405 TI - Empirically derived dietary habits are associated with irritable bowel syndrome. AB - BACKGROUND/OBJECTIVES: The associations between empirically derived dietary habits and irritable bowel syndrome (IBS) have not been investigated. This study aimed to assess the relationship between empirically derived dietary habits and IBS in a large population of Iranian adults. SUBJECTS/METHODS: In a cross sectional study, dietary habits of 4763 adults were assessed in three domains, "meal pattern", "eating rate" and "intra-meal fluid intake". We used latent class analysis to identify classes of dietary habits. IBS was defined based on ROME III criteria. RESULTS: IBS was prevalent in 20.3% (n = 966) of the study population. Two distinct classes of meal patterns: "regular" and "irregular", three classes of eating rates: "moderate", "moderate-to-slow" and "moderate-to-fast" and two classes of fluid ingestion with meals: "moderate" and "heavy intra-meal drinking" were identified. After adjustment for confounders, "heavy intra-meal fluid intake" was protectively associated with IBS (OR = 0.79; 95% CI:0.64-0.96). When potential confounders were considered, "meal pattern" and "eating rate" were not significantly associated with IBS in the whole population. After adjustment for confounders, women with "irregular meal pattern" had a 30% greater risk of having IBS, compared with those with "regular meal pattern" (OR = 1.30; 95% CI:1.02 1.67). Overweight participants with "fast eating rate" were 70% more likely to have IBS, compared to those with "moderate eating rate" (OR = 1.70; 95% CI:1.13 2.55). "Irregular meal pattern" was related to frequency and severity of abdominal pain. CONCLUSIONS: We found a significant association between heavy intra-meal fluid intake" and IBS. More large-scale prospective studies are needed to affirm this association. PMID- 29535406 TI - From fat cells through an obesity theory. PMID- 29535407 TI - Size Exclusion Chromatography Method for Purification of Nicotinamide Mononucleotide (NMN) from Bacterial Cells. AB - Over 12% of the world's health resources are spent on treating diabetes, as high blood glucose is the third cause of mortality worldwide. Insulin resistance is the basis of the most common form of diabetes: type 2 diabetes. Recent animal studies report successful attempts at reversing type 2 diabetes by the administering of the NAD+ precursor nicotinamide mononucleotide (NMN). However, the current high price of this molecule urges for more efficient and cost effective production methods. This work proposes a method for purifying NMN by Size Exclusion Chromatography (SEC) on silica with a covalently attached coating of poly(2-hydroxyethyl aspartamide) (PolyHEA) stationary phase using an isocratic elution with a denaturing mobile phase (50 mM formic acid) from a complex molecular mixture such as a fermentation broth. The eluted peaks were identified by UV-Vis analysis and confirmed with ESI+ mass spectrometry and a HPLC reversed phase method. The proposed SEC method is simple, patent-free, directly applicable for industrial production with a minimum scale up effort. The need for multiple chromatographic steps is eliminated and the lysate filtration and clarification steps are simplified. Substantial reduction in NMN production costs and increased purity of NMN to the level suitable for usage in humans are expected. PMID- 29535408 TI - Selection of reference genes for miRNA qRT-PCR under abiotic stress in grapevine. AB - Grapevine is among the fruit crops with high economic value, and because of the economic losses caused by abiotic stresses, the stress resistance of Vitis vinifera has become an increasingly important research area. Among the mechanisms responding to environmental stresses, the role of miRNA has received much attention recently. qRT-PCR is a powerful method for miRNA quantitation, but the accuracy of the method strongly depends on the appropriate reference genes. To determine the most suitable reference genes for grapevine miRNA qRT-PCR, 15 genes were chosen as candidate reference genes. After eliminating 6 candidate reference genes with unsatisfactory amplification efficiency, the expression stability of the remaining candidate reference genes under salinity, cold and drought was analysed using four algorithms, geNorm, NormFinder, deltaCt and Bestkeeper. The results indicated that U6 snRNA was the most suitable reference gene under salinity and cold stresses; whereas miR168 was the best for drought stress. The best reference gene sets for salinity, cold and drought stresses were miR160e + miR164a, miR160e + miR168 and ACT + UBQ + GAPDH, respectively. The selected reference genes or gene sets were verified using miR319 or miR408 as the target gene. PMID- 29535410 TI - Effects of root pruning radius and time on yield of tuberous roots and resource allocation in a crop of Helianthus tuberosus L. AB - The production of tuberous roots is usually reduced by vigorous vegetative growth because of the competition for resource between the vegetative parts and reproductive organs. In this study, we conducted root pruning to examine the vigorous vegetative growth by regulating root growth, subsequently limiting vegetative growth and improving tuber yield. Compared with the control, stem, tuber, and root biomasses were all improved, whereas both flower and leaf biomasses were increased. Tuber biomass was improved by 23.48% to 50.32%, with the largest tuber biomass obtained at root cutting radius 4/5 R. With delayed root cutting time, tuber and root biomasses increased first and then decreased. The largest tuber biomass was obtained at 65 seedling stage. With a delay in root cutting time, the trend line of aboveground, underground, and total biomasses changed gradually. However, whereas underground and total biomasses showed a gradually increasing, aboveground biomass showed a decreasing. The values of stem leaf and shoot-root ratios under different root cutting were higher than those of the control. With a delay in root cutting time, stem-leaf ratio showed an initial increase and then decreased with largest value being obtained at 80 seedling stage, whereas the largest shoot-root ratio was obtained at 115 seedling stage. PMID- 29535409 TI - The role of combining medroxyprogesterone 17-acetate with human menopausal gonadotropin in mouse ovarian follicular development. AB - Medroxyprogesterone 17-acetate (MPA) combined with human menopausal gonadotropin (hMG) has been effectively used for ovarian stimulation in clinical practice. However, the molecular mechanism of MPA + hMG treatment in follicular development is poorly described. Here we performed a study to investigate the impact of MPA + hMG on ovarian stimulation utilizing a mouse model in vivo. Forty female BALB/C mice were randomly divided into four groups of 10 each and treated during ciestrus stage and continued for 5 days: control group, MPA group, hMG group, and MPA + hMG group. Morphological and molecular biology methods were used for detecting serum hormones and ovarian function. MPA + hMG group exhibited increasing follicle stimulating hormone (FSH), antral follicle, FSH receptor (FSHR) and phosphorylated mammal target of rapamycin (p-mTOR), and decreasing luteinizing hormone (LH), estradiol (E2), progesterone (P), corpus luteum, phosphoinositide 3-kinase (PI3K), Akt and mTOR compared with control group. In contrast, MPA + hMG group showed reduced FSH, LH, E2, P, corpus luteum, LH receptor (LHR), and activated PI3K,/Akt/mTOR pathway compared with hMG group (P < 0.05). Collectively, these data definitively established that MPA plus hMG may modulate the hormone, hormone receptor and PI3K/Akt/mTOR signaling pathway to influence follicular development in the mouse ovary. Our study provides overwhelming support for MPA + hMG as an effective treatment for infertility in women. PMID- 29535411 TI - Minor hysteresis patterns with a rounded/sharpened reversing behavior in ferromagnetic multilayer. AB - Hysteresis of ferromagnetic system exhibits a fundamental stimulus-response behavior, thereby casting all the important macromagnetic system parameters such as coercivity, nucleation field, saturation magnetization, and hysteresis loss. Recently, increasing attention has been paid to exploration of relatively less understood minor loop behavior, since faster operation of magnetic devices is inevitably accompanied by minor hysteresis behavior from cycling among unsaturated ferromagnetic states. Here, we report our microscopic investigation of unusual minor hysteresis loop behavior, represented by rounded or sharpened response of minor hysteresis loop of (CoFeB/Pd)4 multilayer film. It is observed that rounded and sharpened response in the minor hysteresis response could be manifested under proper conditions. The minor loop behavior has been systematically investigated by direct microscopic magnetic domain observation using magneto-optical Kerr microscopy. The rounded response of magnetization at the reversing external field along the minor hysteresis curve, so far neglected or considered as one of 'unusual' behaviors, has been found to be elaborately controllable by tuning the reversing field strength and the field sweep rate for multilayers with low repeat numbers. Variable roundedness of the minor hysteresis loop is understandable based on the analysis of magnetic domain dynamics such as domain nucleation and the domain wall velocity. PMID- 29535412 TI - The Impact of Alkaliphilic Biofilm Formation on the Release and Retention of Carbon Isotopes from Nuclear Reactor Graphite. AB - 14C is an important consideration within safety assessments for proposed geological disposal facilities for radioactive wastes, since it is capable of re entering the biosphere through the generation of 14C bearing gases. The irradiation of graphite moderators in the UK gas-cooled nuclear power stations has led to the generation of a significant volume of 14C-containing intermediate level wastes. Some of this 14C is present as a carbonaceous deposit on channel wall surfaces. Within this study, the potential of biofilm growth upon irradiated and 13C doped graphite at alkaline pH was investigated. Complex biofilms were established on both active and simulant samples. High throughput sequencing showed the biofilms to be dominated by Alcaligenes sp at pH 9.5 and Dietzia sp at pH 11.0. Surface characterisation revealed that the biofilms were limited to growth upon the graphite surface with no penetration of the deeper porosity. Biofilm formation resulted in the generation of a low porosity surface layer without the removal or modification of the surface deposits or the release of the associated 14C/13C. Our results indicated that biofilm formation upon irradiated graphite is likely to occur at the pH values studied, without any additional release of the associated 14C. PMID- 29535413 TI - Tailoring light delivery for optogenetics by modal demultiplexing in tapered optical fibers. AB - Optogenetic control of neural activity in deep brain regions ideally requires precise and flexible light delivery with non-invasive devices. To this end, Tapered Optical Fibers (TFs) represent a versatile tool that can deliver light over either large brain volumes or spatially confined sub-regions, while being sensibly smaller than flat-cleaved optical fibers. In this work, we report on the possibility of further extending light emission length along the taper in the range 0.4 mm-3.0 mm by increasing the numerical aperture of the TFs to NA = 0.66. We investigated the dependence between the input angle of light (thetain) and the output position along the taper, finding that for thetain > 10 degrees this relationship is linear. This mode-division demultiplexing property of the taper was confirmed with a ray tracing model and characterized for 473 nm and 561 nm light in quasi-transparent solution and in brain slices, with the two wavelengths used to illuminate simultaneously two different regions of the brain using only one waveguide. The results presented in this manuscript can guide neuroscientists to design their optogenetic experiments on the base of this mode-division demultiplexing approach, providing a tool that potentially allow for dynamic targeting of regions with diverse extension, from the mouse VTA up to the macaque visual cortex. PMID- 29535414 TI - Acute pancreatitis with long-term celecoxib vs. ibuprofen or naproxen: data from the PRECISION trial. PMID- 29535415 TI - Response to Alkhatib and Alasadi. PMID- 29535416 TI - Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. AB - OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55 2.18], p = 1.85 * 10-12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30-2.13], p = 5.13 * 10-05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care. PMID- 29535417 TI - Childhood body mass index and risk of inflammatory bowel disease in adulthood: a population-based cohort study. AB - BACKGROUND: The increasing incidence of inflammatory bowel disease (IBD) in western countries has led to the hypothesis that obesity-related inflammation could play a role in the etiology of IBD. However, this hypothesis lacks confirmation in studies of individuals prior to the typical onset of IBD in young adulthood. METHODS: In a cohort of 316,799 individuals from the Copenhagen School Health Records Register (CSHRR), we examined whether BMI at ages 7 through 13 years was associated with later IBD. Linking the CSHRR to the Danish National Patient Register, we identified cases of Crohn's disease (CD) and ulcerative colitis (UC) diagnosed during follow-up. Cox regression was used to estimate the hazard ratios (HR) with 95% confidence intervals. RESULTS: During 10 million person-years of follow-up, 1500 individuals were diagnosed with CD and 2732 with UC. At all examined ages, a 1 unit increase in BMI z-score was associated with a significantly decreased risk of UC (HRs = 0.9) and with a significantly increased risk of CD when diagnosed before age 30 (HRs = 1.2). We observed no associations between changes in BMI z-score between 7 and 13 years and later risk of CD or UC. CONCLUSION: We found a direct association between childhood BMI and CD diagnosed before 30 years of age, and an inverse association between childhood BMI and UC irrespective of age. Our results support the previous hypotheses of obesity being a risk factor for CD, and suggest that childhood underweight might be a risk factor for UC. PMID- 29535418 TI - Seasonally varying footprint of climate change on precipitation in the Middle East. AB - Climate change is expected to alter precipitation patterns; however, the amplitude of the change may broadly differ across seasons. Combining different seasons may mask contrasting climate change signals in individual seasons, leading to weakened signals and misleading impact results. A realistic assessment of future climate change is of great importance for arid regions, which are more vulnerable to any change in extreme events as their infrastructure is less experienced or not well adapted for extreme conditions. Our results show that climate change signals and associated uncertainties over the Middle East region remarkably vary with seasons. The region is identified as a climate change hotspot where rare extreme precipitation events are expected to intensify for all seasons, with a "highest increase in autumn, lowest increase in spring" pattern which switches to the "increase in autumn, decrease in spring" pattern for less extreme precipitation. This pattern is also held for mean precipitation, violating the "wet gets wetter, dry gets drier" paradigm. PMID- 29535419 TI - DEAD-box helicase 27 promotes colorectal cancer growth and metastasis and predicts poor survival in CRC patients. AB - Copy number alterations (CNAs) are crucial for colorectal cancer (CRC) development. In this study, DEAD box polypeptide 27 (DDX27) was identified to be highly amplified in both TCGA CRC (474/615) and primary CRC (47/103), which was positively correlated with its mRNA overexpression. High DDX27 mRNA (N = 199) and protein expression (N = 260) predicted poor survival in CRC patients. Ectopic expression of DDX27 increased CRC cells proliferation, migration and invasion, but suppressed apoptosis. Conversely, silencing of DDX27 exerted opposite effects in vitro and significantly inhibited murine xenograft tumor growth and lung metastasis in vivo. Up-regulation of DDX27 enhanced and prolonged TNF-alpha mediated NF-kappaB signaling. Nucleophosmin (NPM1) was identified as a binding partner of DDX27. DDX27 increased nuclear NPM1 and NF-kappaB-p65 interaction to enhance DNA binding activity of NF-kappaB. Silencing NPM1 abrogated DDX27 activating NF-kappaB signaling and its tumor-promoting function. Together, DDX27 is overexpressed and plays a pivotal oncogenic role in CRC. PMID- 29535420 TI - LncFZD6 initiates Wnt/beta-catenin and liver TIC self-renewal through BRG1 mediated FZD6 transcriptional activation. AB - Liver tumor-initiating cells (TICs), the drivers for liver tumorigenesis, accounts for liver tumor initiation, metastasis, drug resistance and relapse. Wnt/beta-catenin signaling pathway emerges as a critical modulator in liver TIC self-renewal. However, the molecular mechanism of Wnt/beta-catenin initiation in liver tumorigenesis and liver TICs is still elusive. Here, we examined the expression pattern of 10 Wnt receptors (FZD1-FZD10), and found only FZD6 is overexpressed along with liver tumorigenesis. What's more, a divergent lncRNA of FZD6, termed lncFZD6, is also highly expressed in liver cancer and liver TICs. LncFZD6 drives liver TIC self-renewal and tumor initiation capacity through FZD6 dependent manner. LncFZD6 interacts with BRG1-embedded SWI/SNF complex and recruits it to FZD6 promoter, and thus drives the transcriptional initiation of FZD6 by chromatin remodeling. WNT5A, a ligand of FZD6, is highly expressed in liver non-TICs and drives the self-renewal of liver TICs through lncFZD6-BRG1 FZD6-dependent manner. Through FZD6 transcriptional regulation in cis, lncFZD6 activates Wnt/beta-catenin signaling in liver TICs. LncFZD6-BRG1-Wnt5A/beta catenin pathway can serve as a target for liver TIC elimination. Altogether, lncFZD6 promotes Wnt/beta-catenin activation and liver TIC self-renewal through BRG1-dependent FZD6 expression. PMID- 29535421 TI - Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-kappaB signaling pathway. AB - During tumor development, stromal cells are co-opted to the tumor milieu and provide favorable conditions for the tumor. Hypoxia stimulates cancer cells to acquire a more malignant phenotype via activation of hypoxia-inducible factor 1 (HIF-1). Given that cancer cells and astrocytes in glioblastomas coexist in a hypoxic microenvironment, we examined whether astrocytes affect the adaptation of glioblastoma cells to hypoxia. Immunoblotting, reporter assays, quantitative RT PCR, and chromatin immunoprecipitation were performed to evaluate HIF-1 signaling in glioblastoma cells. Astrocyte-derived chemokine C-C motif ligand 20 (CCL20) was identified using cytokine arrays, and its role in glioblastoma development was evaluated in orthotopic xenografts. Astrocytes augmented HIF-1alpha expression in glioblastoma cells under hypoxia. The expression of HIF-1 downstream genes, cancer colony formation, and Matrigel invasion of glioblastoma cells were stimulated by conditioned medium from astrocytes pre-exposed to hypoxia. CCL20 was secreted in a hypoxia-dependent manner from astrocytes and busted the hypoxic induction of HIF-1alpha in glioblastoma cells. Mechanistically, the CCL20/CCR6 signaling pathway upregulates HIF-1alpha by stimulating nuclear factor kappa B-driven transactivation of the HIF1A gene. Compared with the control tumors, CCR6-deficient glioblastoma xenografts grew more slowly, with poor vascularization, and expressed lower levels of HIF-1alpha and its downstream proteins. Furthermore, CCR6 expression was correlated with HIF 1alpha expression in GEO and TCGA datasets from human glioblastoma tissues. These results suggest that glioblastoma cells adapt well to hypoxic stress by virtue of CCL20 derived from neighboring astrocytes. PMID- 29535423 TI - JNK and Yorkie drive tumor progression by generating polyploid giant cells in Drosophila. AB - Epithelial cancer tissues often possess polyploid giant cells, which are thought to be highly oncogenic. However, the mechanisms by which polyploid giant cells are generated in tumor tissues and how such cells contribute to tumor progression remain elusive. We previously noticed in Drosophila imaginal epithelium that cells mutant for the endocytic gene rab5 exhibit enlarged nuclei. Here we find that mutations in endocytic 'neoplastic tumor-suppressor' genes, such as rab5, vps25, erupted, or avalanche result in generation of polyploid giant cells. Genetic analyses on rab5-defective cells reveal that cooperative activation of JNK and Yorkie generates polyploid giant cells via endoreplication. Mechanistically, Yorkie-mediated upregulation of Diap1 cooperates with JNK to downregulate the G2/M cyclin CycB, thereby inducing endoreplication. Interestingly, malignant tumors induced by Ras activation and cell polarity defect also consist of polyploid giant cells, which are generated by JNK and Yorkie-mediated downregulation of CycB. Strikingly, elimination of polyploid giant cells from such malignant tumors by blocking endoreplication strongly suppressed tumor growth and metastatic behavior. Our observations suggest that JNK and Yorkie, two oncogenic proteins activated in many types of human cancers, cooperatively drive tumor progression by generating oncogenic polyploid giant cells. PMID- 29535422 TI - The HER4-YAP1 axis promotes trastuzumab resistance in HER2-positive gastric cancer by inducing epithelial and mesenchymal transition. AB - Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer. PMID- 29535424 TI - Comprehensive genomic profiling of neuroendocrine bladder cancer pinpoints molecular origin and potential therapeutics. AB - Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin. We identified pervasive age-related and APOBEC-mediated mutagenesis patterns, and one patient displayed a somatic fingerprint attributable to aristolochic acid exposure, an established etiology of urothelial cell carcinoma. Deep RNA sequencing revealed dysregulated tumorigenic pathways and novel fusion transcripts, including a targetable in frame PVT1-ERBB2 variant associated with aberrant expression of ERBB2 gene (encoding HER2 receptor). Furthermore, we provided preliminary evidence that combined TP53 and RB1 depletion favored lineage switching from oncogene-addicted urothelial cancer cells to neuroendocrine-like tumor cells, and resulted in decreased response to targeted agents. Together, these data present the first high-resolution genomic portrait of neuroendocrine bladder cancer, which holds important implications for the biological understanding and rational treatment of this deadly disease. PMID- 29535425 TI - Second malignancies in patients with myeloproliferative neoplasms: a population based cohort study of 9379 patients. AB - To determine the risk of a wide range of second malignancies in patients with myeloproliferative neoplasms (MPNs), we conducted a large population-based study and compared the results to matched controls. From national Swedish registers, 9379 patients with MPNs diagnosed between 1973 and 2009, and 35,682 matched controls were identified as well as information on second malignancies, with follow-up until 2010. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated using Cox regression and a flexible parametric model. There was a significantly increased risk of any non-hematologic cancer with HR of 1.6 (95% CI: 1.5-1.7). The HRs for non-melanoma skin cancer was 2.8 (2.4-3.3), kidney cancer 2.8 (2.0-4.0), brain cancer 2.8 (1.9-4.2), endocrine cancers 2.5 (1.6 3.8), malignant melanoma 1.9 (1.4-2.7), pancreas cancer 1.8 (1.2-2.6), lung cancer 1.7 (1.4-2.2), and head and neck cancer 1.7 (1.2-2.6). The HR of second malignancies was similar across all MPN subtypes, sex, and calendar periods of MPN diagnosis. The risk of developing a hematologic malignancy was also significantly increased; the HR for acute myeloid leukemia was 46.0 (32.6-64.9) and for lymphoma 2.6 (2.0-3.3). In conclusion, our study provides robust population-based support of an increased cancer risk in MPN patients. PMID- 29535426 TI - Mutant IL-7Ralpha and mutant NRas are sufficient to induce murine T cell acute lymphoblastic leukemia. PMID- 29535428 TI - Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation. AB - Activating mutations in NT5C2, a gene encoding cytosolic purine 5'-nucleotidase (cN-II), confer chemoresistance in relapsed acute lymphoblastic leukemia. Here we show that all mutants became independent of allosteric effects of ATP and thus constitutively active. Structural mapping of mutations described in patients demonstrates that 90% of leukemia-specific allelles directly affect two regulatory hotspots within the cN-II molecule-the helix A region: residues 355 365, and the intersubunit interface: helix B (232-242) and flexible interhelical loop L (400-418). Furthermore, analysis of hetero-oligomeric complexes combining wild-type (WT) and mutant subunits showed that the activation is transmitted from the mutated to the WT subunit. This intersubunit interaction forms structural basis of hyperactive NT5C2 in drug-resistant leukemia in which heterozygous NT5C2 mutation gave rise to hetero-tetramer mutant and WT proteins. This enabled us to define criteria to aid the prediction of NT5C2 drug resistance mutations in leukemia. PMID- 29535427 TI - Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? AB - Multiple myeloma (MM) is a malignant plasma cell (PC) disorder, characterized by a complex interactive network of tumour cells and the bone marrow (BM) stromal microenvironment, contributing to MM cell survival, proliferation and chemoresistance. Mesenchymal stem cells (MSCs) represent the predominant stem cell population of the bone marrow stroma, capable of differentiating into multiple cell lineages, including fibroblasts, adipocytes, chondrocytes and osteoblasts. MSCs can migrate towards primary tumours and metastatic sites, implying that these cells might modulate tumour growth and metastasis. However, this issue remains controversial and is not well understood. Interestingly, several recent studies have shown functional abnormalities of MM patient-derived MSCs indicating that MSCs are not just by-standers in the BM microenvironment but rather active players in the pathophysiology of this disease. It appears that the complex interaction of MSCs and MM cells is critical for MM development and disease outcome. This review will focus on the current understanding of the biological role of MSCs in MM as well as the potential utility of MSC-based therapies in this malignancy. PMID- 29535429 TI - SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. AB - Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia-pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L's normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation's effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers. PMID- 29535430 TI - Granulomonocytic progenitors are key target cells of azacytidine in higher risk myelodysplastic syndromes and acute myeloid leukemia. PMID- 29535431 TI - U2AF1 mutation types in primary myelofibrosis: phenotypic and prognostic distinctions. PMID- 29535432 TI - Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts. PMID- 29535435 TI - Taenia saginata Infection Diagnosed Based on the Number of Uterine Branches Observed During Capsule Endoscopy. PMID- 29535433 TI - Photoinduced Topological Phase Transitions in Topological Magnon Insulators. AB - Topological magnon insulators are the bosonic analogs of electronic topological insulators. They are manifested in magnetic materials with topologically nontrivial magnon bands as realized experimentally in a quasi-two-dimensional (quasi-2D) kagome ferromagnet Cu(1-3, bdc), and they also possess protected magnon edge modes. These topological magnetic materials can transport heat as well as spin currents, hence they can be useful for spintronic applications. Moreover, as magnons are charge-neutral spin-1 bosonic quasiparticles with a magnetic dipole moment, topological magnon materials can also interact with electromagnetic fields through the Aharonov-Casher effect. In this report, we study photoinduced topological phase transitions in intrinsic topological magnon insulators in the kagome ferromagnets. Using magnonic Floquet-Bloch theory, we show that by varying the light intensity, periodically driven intrinsic topological magnetic materials can be manipulated into different topological phases with different sign of the Berry curvatures and the thermal Hall conductivity. We further show that, under certain conditions, periodically driven gapped topological magnon insulators can also be tuned to synthetic gapless topological magnon semimetals with Dirac-Weyl magnon cones. We envision that this work will pave the way for interesting new potential practical applications in topological magnetic materials. PMID- 29535436 TI - Another RESIN for Pouchitis: Chronic Pouchitis With Erosion Secondary to Sodium Polystyrene Sulfonate Crystals. PMID- 29535437 TI - Reply to "Definition of Small for Gestational Age and Low Birthweight". PMID- 29535438 TI - Small For Gestational Age and Low Birthweight: Distinct Entities. PMID- 29535439 TI - Continuing Medical Education Questions: March 2018: Long-Term Safety of In Utero Exposure to Anti-TNFalpha Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study. PMID- 29535440 TI - Continuing Medical Education Questions: March 2018: Severity And Outcomes Of Upper Gastrointestinal Bleeding With Bloody Vs. Coffee-Grounds Hematemesis. PMID- 29535441 TI - Combined Endoscopic-Percutaneous Biliary Restoration Following Severe Bile Duct Injury During Cholecystectomy. PMID- 29535442 TI - Benefit of Treatment With Sebelipase-Alfa in a 63-Year-Old Patient With Advanced Liver and Atherosclerotic Disease Due to Lysosomal Acid Lipase Deficiency (LAL D). PMID- 29535443 TI - The North American Consensus on Breath Testing: The Controversial Diagnostic Role of Lactulose in SIBO. PMID- 29535445 TI - Reply to Satta et al. PMID- 29535444 TI - Past Time for Doctors to Lessen their Dependence on Corticosteroids in the Treatment of IBD. AB - Corticosteroids and antibodies to tumor necrosis factor (anti-TNF) are mainstays of treatment of acutely active IBD and while anti-TNF therapy is indicated for maintenance therapy, chronic corticosteroid therapy is associated with known significant risks. Nonetheless, chronic or recurrent corticosteroid treatment in IBD is common. In this edition of the journal Lewis et al. use Medicaid and Medicare databases to contrast adverse outcomes in persons with IBD and either corticosteroid or anti-TNF use. Compared to high dose corticosteroid use, anti TNF therapy is associated with less risk for death in Crohn's disease but no statistical difference in death outcomes in ulcerative colitis. The adverse effects of corticosteroids are well known yet vigilance is still required to ensure their use is limited to the short term. PMID- 29535446 TI - Tubular immaturity causes erythropoietin-deficiency anemia of prematurity in preterm neonates. AB - Kidneys are physiologically hypoxic due to huge oxygen consumption for tubular reabsorption. The physiological hypoxia makes the kidney an appropriate organ for sensitively detecting oxygen levels and producing erythropoietin (EPO). In preterm neonates, immature kidneys cannot produce sufficient EPO, which results in anemia of prematurity (AOP). The cause of EPO insufficiency in AOP has been unclear, therefore current therapeutic options are transfusion and injection of recombinant human EPO. This report shows that the cause of insufficient EPO production in AOP is elevated renal oxygen levels due to poor oxygen consumption by immature tubules. Neonatal mice with AOP showed low tubular transporter expression and elevated renal oxygen levels compared with those without AOP. Enhancing transporter expression in AOP mice induced renal hypoxia and EPO production. In preterm neonates, red blood cell counts, hemoglobin levels, and hematocrit levels correlated with tubular function, but not with serum creatinine, gestational age, or birth weight. Furthermore, pharmacological upregulation of hypoxia signaling ameliorated AOP in mice. These data suggest that tubular maturation with increased oxygen consumption is required for renal EPO production. PMID- 29535447 TI - Does playing violent video games cause aggression? A longitudinal intervention study. AB - It is a widespread concern that violent video games promote aggression, reduce pro-social behaviour, increase impulsivity and interfere with cognition as well as mood in its players. Previous experimental studies have focussed on short-term effects of violent video gameplay on aggression, yet there are reasons to believe that these effects are mostly the result of priming. In contrast, the present study is the first to investigate the effects of long-term violent video gameplay using a large battery of tests spanning questionnaires, behavioural measures of aggression, sexist attitudes, empathy and interpersonal competencies, impulsivity related constructs (such as sensation seeking, boredom proneness, risk taking, delay discounting), mental health (depressivity, anxiety) as well as executive control functions, before and after 2 months of gameplay. Our participants played the violent video game Grand Theft Auto V, the non-violent video game The Sims 3 or no game at all for 2 months on a daily basis. No significant changes were observed, neither when comparing the group playing a violent video game to a group playing a non-violent game, nor to a passive control group. Also, no effects were observed between baseline and posttest directly after the intervention, nor between baseline and a follow-up assessment 2 months after the intervention period had ended. The present results thus provide strong evidence against the frequently debated negative effects of playing violent video games in adults and will therefore help to communicate a more realistic scientific perspective on the effects of violent video gaming. PMID- 29535448 TI - Reply to 'Eukaryote lateral gene transfer is Lamarckian'. PMID- 29535449 TI - Eukaryote lateral gene transfer is Lamarckian. PMID- 29535450 TI - A model of neglect during postnatal life heightens obesity-induced hypertension and is linked to a greater metabolic compromise in female mice. AB - : .: Exposure to early life stress (ELS) is associated with behavioral-related alterations, increases in body mass index and higher systolic blood pressure in humans. Postnatal maternal separation and early weaning (MSEW) is a mouse model of neglect characterized by a long-term dysregulation of the neuroendocrine system. OBJECTIVES: Given the contribution of adrenal-derived hormones to the development of obesity, we hypothesized that exposure to MSEW could contribute to the worsening of cardiometabolic function in response to chronic high-fat diet (HF) feeding by promoting adipose tissue expansion and insulin resistance. SUBJECTS: MSEW was performed in C57BL/6 mice from postnatal days 2-16 and weaned at postnatal day 17. Undisturbed litters weaned at postnatal day 21 served as the control (C) group. At the weaning day, mice were placed on a low-fat diet (LF) or HF for 16 weeks. RESULTS: When fed a LF, male and female mice exposed to MSEW display similar body weight but increased fat mass compared to controls. However, when fed a HF, only female MSEW mice display increased body weight, fat mass, and adipocyte hypertrophy compared with controls. Also, female MSEW mice display evidence of an early onset of cardiometabolic risk factors, including hyperinsulinemia, glucose intolerance, and hypercholesterolemia. Yet, both male and female MSEW mice fed a HF show increased blood pressure compared with controls. CONCLUSIONS: This study shows that MSEW promotes a sex-specific dysregulation of the adipose tissue expansion and glucose homeostasis that precedes the development of obesity-induced hypertension. PMID- 29535451 TI - Effect of combined naltrexone and bupropion therapy on the brain's functional connectivity. AB - BACKGROUND: The control of food intake in environments with easy access to highly rewarding foods is challenging to most modern societies. The combination of sustained release (SR) naltrexone and SR bupropion (NB32) has been used in weight loss and obesity management. However, the effects of NB32 on the brain circuits implicated in the regulation of food intake are unknown. Here we used functional connectivity density (FCD) mapping to evaluate the effects of NB32 on resting brain FC. METHODS: Thirty-six healthy women underwent magnetic resonance imaging (MRI) before and after 4-week treatment with NB32 (n = 16) or with placebo (n = 20). In each imaging visit, a 5-min resting-state functional MRI scan was conducted after 15 h of fasting. The FC of brain regions showing significant group effects on FCD were subsequently assessed using seed-voxel correlation analyses. We characterized the associations between FCD measures and craving control scores in the Control of Eating Questionnaire. RESULTS: After NB32 treatment, the group showed lower local and global FCD than the placebo group in the right superior parietal cortex and lower local FCD in the left middle frontal gyrus. Seed-voxel correlation analysis for the right superior parietal cortex seed demonstrated higher positive FC with the dorsal anterior cingulate gyrus (ACC), bilateral insula, and left superior parietal gyrus and stronger negative FC with right inferior frontal gyrus and right superior parietal cortices for the NB32 than the placebo group. Further, the NB32 group showed a significant correlation between local FCD change after treatment in left middle frontal gyrus and craving control scores (r = 0.519, p = 0.039). CONCLUSIONS: NB32 treatment decreased local and global FCD in superior parietal cortex and increased its connectivity with ACC (involved with saliency attribution), insula (interoception), and decreased local FCD in the medial prefrontal cortex (craving), which might underlie NB32 improved control over eating behaviors. ClinicalTrails.gov: NCT00711. PMID- 29535452 TI - ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1, and PGC-1alpha deacetylation. AB - BACKGROUND AND AIMS: Uncorrected obesity contributes to cardiac remodeling and contractile dysfunction although the underlying mechanism remains poorly understood. Mitochondrial aldehyde dehydrogenase (ALDH2) is a mitochondrial enzyme with some promises in a number of cardiovascular diseases. This study was designed to evaluate the impact of ALDH2 on cardiac remodeling and contractile property in high fat diet-induced obesity. METHODS: Wild-type (WT) and ALDH2 transgenic mice were fed low (10% calorie from fat) or high (45% calorie from fat) fat diet for 5 months prior to the assessment of cardiac geometry and function using echocardiography, IonOptix system, Lectin, and Masson Trichrome staining. Western blot analysis was employed to evaluate autophagy, CaM kinase II, PGC-1alpha, histone H3K9 methyltransferase SUV39H, and Sirt-1. RESULTS: Our data revealed that high fat diet intake promoted weight gain, cardiac remodeling (hypertrophy and interstitial fibrosis, p < 0.0001) and contractile dysfunction (reduced fractional shortening (p < 0.0001), cardiomyocyte function (p < 0.0001), and intracellular Ca2+ handling (p = 0.0346)), mitochondrial injury (elevated O2- levels, suppressed PGC-1alpha, and enhanced PGC-1alpha acetylation, p < 0.0001), elevated SUV39H, suppressed Sirt1, autophagy and phosphorylation of AMPK and CaM kinase II, the effects of which were negated by ALDH2 (p <= 0.0162). In vitro incubation of the ALDH2 activator Alda-1 rescued against palmitic acid-induced changes in cardiomyocyte function, the effect of which was nullified by the Sirt 1 inhibitor nicotinamide and the CaM kinase II inhibitor KN-93 (p < 0.0001). The SUV39H inhibitor chaetocin mimicked Alda-1-induced protection again palmitic acid (p < 0.0001). Examination in overweight human revealed an inverse correlation between diastolic cardiac function and ALDH2 gene mutation (p < 0.05). CONCLUSIONS: Taken together, these data suggest that ALDH2 serves as an indispensable factor against cardiac anomalies in diet-induced obesity through a mechanism related to autophagy regulation and facilitation of the SUV39H-Sirt1 dependent PGC-1alpha deacetylation. PMID- 29535453 TI - Smoking habit from the paternal line and grand-child's overweight or obesity status in early childhood: prospective findings from the lifeways cross generation cohort study. AB - BACKGROUND/OBJECTIVES: The role of smoking from the paternal line during the pre conception period on grand-child's overweight/obesity and associated underlying pathways are uncertain. We examined whether the smoking status from the paternal line was associated with the grand-child's higher weight at birth, and overweight or obesity at 5 and 9 years of age. The grandparental smoking effect from the maternal line was also explored. SUBJECTS/METHODS: Participants were fathers and grandparents and grand-children from the Lifeways Cross Generational Cohort (N = 1021 for the analysis at birth; N = 562 and N = 284 for the analysis at 5 and 9 years, respectively). Paternal and grandparental smoking was defined as smoking versus non-smoking. Children's weight categories compared were high versus normal weight at birth, and overweight/obesity versus normal weight (based on BMI and waist circumference) at age of five and nine years. Logistic regression models were used to estimate the crude and adjusted associations. RESULTS: After adjustment for several child and parental factors, at age five there was an association between paternal smoking and offspring's overweight/obesity based on BMI (Adjusted Odds Ratio (AOR), and 95%CI: 1.76, 1.14-2.71, p-value: 0.010), most marked for boys (AOR: 2.05, 1.06-3.96, p-value: 0.032). These associations remained when confined to the children sample with biological fathers only (overall sample, AOR: 1.92, 1.22-3.02, p-value: 0.005; son, AOR: 2.09, 1.06-4.11, p-value: 0.033). At age 9, the paternal grandmothers' smoking was positively associated with their grandchild's overweight/obesity status based on waist circumference (AOR: 3.29, 1.29-8.37), and especially with that of her granddaughter (AOR: 3.44, 1.11-10.69). These associations remained when analysing only the children sample with biological fathers (overall sample, AOR: 3.22,1.25 8.29, p-value: 0.016; granddaughter, AOR: 3.55, 1.13-11.15, p-value: 0.030). CONCLUSION: The smoking habit from the paternal line is associated with grand children's adiposity measures during their early childhood, which might be epigenetically transmitted through male-germline cells. PMID- 29535454 TI - Essential hypertension: the specialist as part of therapeutic intervention. PMID- 29535455 TI - Comparison of pulse wave velocity and pulse pressure amplification in association with target organ damage in community-dwelling elderly: The Northern Shanghai Study. AB - This study aimed to investigate the discrepancy between pulse wave velocity (PWV) and pulse pressure amplification (PPA) in association with hypertensive target organ damage (TOD) in the elderly. From June 2014 to August 2015, 1599 participants aged >65 years old from communities located in northern Shanghai were recruited. Carotid-femoral pulse wave velocity (cfPWV), peripheral blood pressure (BP), central BP and other TOD indicators, including the ratio of the early ventricular filling velocity (E) to the peak velocity of the tissue Doppler velocity of septal mitral annulus (E/Ea), left ventricular mass index (LVMI), carotid intima-medium thickness (CIMT), estimated glomerular filtration rate (eGFR), and urinary albumin-creatinine ratio (ACR), were determined for each participant. PPA was defined as the peripheral-to-central pulse pressure ratio. In multivariable linear regression analysis, cfPWV was significantly associated with CIMT (beta = 12.83 +/- 4.28 MUm per SD; P = 0.003) and eGFR (beta = -1.85 +/ 0.69 ml/min/1.73 m2 per SD; P = 0.007), whereas PPA was significantly associated with E/Ea (beta = -0.25 +/- 0.10 per SD; P = 0.01) and LVMI (beta = -3.00 +/- 0.78 g/m2 per SD; P < 0.001). Similarly, in multivariable logistic regression analysis, cfPWV was significantly associated with arterial plaque (odds ratio [OR], 1.21 [95% confidence interval [CI], 1.05-1.39]; P = 0.007), peripheral artery disease (OR, 1.22 [95% CI, 1.06-1.42]; P = 0.007), chronic kidney diseases (OR, 1.24 [95% CI, 1.01-1.54]; P = 0.04) and microalbuminuria (OR, 1.21 [95% CI, 1.07-1.37]; P = 0.002), while PPA was tightly associated with left ventricular hypertrophy (OR, 0.85 [95% CI, 0.72-0.99]; P = 0.04) and diastolic dysfunction (OR, 0.78 [95% CI, 0.64-0.96]; P = 0.02). In conclusion, cfPWV is a vessel related and renal-related biomarker, while PPA is a cardiac-related biomarker in community-based elderly. PMID- 29535456 TI - Higher blood pressure during light exercise is associated with increased left ventricular mass index in normotensive subjects. AB - An exaggerated blood pressure response during an exercise test reflects a future risk of hypertension and is related to increased left ventricular mass (LVM) in hypertensive patients. However, whether this relationship exists in normotensive subjects is not known. We enrolled 7923 health normotensive screening volunteers. Systolic blood pressure (SBP) at stage 1 of the exercise test was used as an indicator of the exercise BP response. Two-dimensional echocardiography was used to obtain the LVM index. Exercise SBP was significantly correlated with the LVM index (r = 0.11, P < 0.001). Higher exercise SBP at stage 1 was associated with an increased LVM index after adjusting for age, sex, body mass index, hemoglobin, SBP at rest, and peak oxygen consumption (P < 0.001). Higher SBP during low intensity exercise was associated with an increased LVM index in normotensive subjects. PMID- 29535457 TI - Gastrointestinal cancer: Organoids predict clinical responses. PMID- 29535458 TI - Dennis L Murphy, MD. PMID- 29535459 TI - Larry J Seidman. PMID- 29535460 TI - Pamela Sklar. PMID- 29535461 TI - Population Ageing and the Elderly. PMID- 29535462 TI - MESSAGE FROM THE GENERAL SECRETARY, INDIAN PSYCHIATRIC SOCIETY. PMID- 29535463 TI - Clinical Practice Guidelines for Elderly. PMID- 29535464 TI - MESSAGE FROM THE INDIAN PSYCHIATRIC SOCIETY TASK FORCE ON CLINICAL PRACTICE GUIDELINES. PMID- 29535465 TI - PREAMBLE OF THE CLINICAL PRACTICE GUIDELINES FOR ELDERLY. PMID- 29535466 TI - The Geropsychiatric Interview- Assessment and Diagnosis. PMID- 29535467 TI - Clinical Practice Guidelines for Management of Dementia. PMID- 29535468 TI - Clinical Practice Guidelines for Management of Delirium in Elderly. PMID- 29535469 TI - Clinical Practice Guidelines for Management of Depression in Elderly. PMID- 29535470 TI - Clinical Practice Guideline for Management of Psychoses in Elderly. PMID- 29535471 TI - Clinical practice guidelines for Geriatric Anxiety Disorders. PMID- 29535472 TI - Clinical Practice Guideline on Management of Sleep Disorders in the Elderly. PMID- 29535474 TI - Clinical Practice Guidelines for addressing the Rehabilitation Needs of Elderly in the Indian context. PMID- 29535473 TI - Clinical Practice Guidelines for management of Sexual Disorders in Elderly. PMID- 29535475 TI - Second Foundation - A New Medical School for Northern Ireland? PMID- 29535478 TI - Punishment Attacks in Post-Ceasefire Northern Ireland: An Emergency Department Perspective. AB - Northern Ireland (NI) has been in a post-conflict state for over twenty years. However, injuries sustained during paramilitary Punishment Attacks (PA) remain a common hospital presentation. The aim of this study was to compare the current province-wide frequency and cost with data collected from the same unit in 1994, the end of the so called, "Troubles". A ten month retrospective emergency chart analysis from all assault and gunshot wound (GSW) attendances to the Emergency Department, Royal Victoria Hospital Belfast (RVH) in 2012 was carried out. Age, sex, injury type, treatment outcome and associated cost of PA was documented. During the study period we recorded a total of thirty two PAs. Twenty seven were the result of gunshot wounds (GSWs), while five were assaults (punishment beatings). Seventeen required admission for definitive management. Nine cases required orthopaedic intervention, two required plastic surgery, two required maxillofacial input and one case required vascular surgery. All but two of those involved were male. Mean age of individuals admitted was 27.47. Total cost of patients both admitted and managed in the Emergency Department (ED) amounted to L91,362. On comparison with 1994, there are more PA presentations. Due to changing wound characteristics and evolving management overall cost is however less. PMID- 29535477 TI - Hyponatraemia in Hospitalised Adults: a Guide for the Junior Doctor. AB - Hyponatraemia is common and often a source of confusion for junior doctors. It is infrequently dangerous, but when it is, is a medical emergency and requires urgent treatment to avoid life-threatening cerebral oedema. Treatment of acute hyponatraemia is also potentially hazardous; it is therefore important to be able to recognise when urgent management is not indicated, and to investigate appropriately. This paper focuses on these issues, which are most likely to be the cause of consternation for the junior doctor. Recommendations are largely based on the 2014 joint European clinical practice guidance for management of hyponatraemia; the 2010 GAIN (N Ireland) guidance and 2013 American guidance are also referenced. PMID- 29535479 TI - The use of Collagenase Clostridium Histolyticum in the management of Dupuytren's contracture-outcomes of a pilot study in a District General Hospital setting. AB - Introduction: Collagenase Clostridium Histolyticum (CCH) is a recognised treatment option for adult patients presenting with Dupuytren's contracture (DC). Patients and Methods: Twenty male patients with established DC were treated using CCH. The average metacarpophalangeal (MCP) joint and proximal interphalangeal joint (PIP) contractures pre-treatment were 520 (range, 0 - 750) and 350 (range, 0 - 840) respectively. The average DASH score pre-treatment was 24.2 points (range, 0 - 68.2 points). Patients were reviewed at lmonth, 3months and at an average of 23 months (17 to 27 months). Results: MCP joint contractures significantly improved compared to pre-treatment and the improvement was maintained at latest follow up. PIP joint contractures did significantly improve but to a lesser degree and there was no significant improvement compared to pre treatment beyond 3months. A trend for MCP and PIP joint contracture recurrence was observed at latest follow up but did not reach statistical significance. DASH scores significantly improved from pre-treatment and the improvement was maintained at latest follow up. At 3months, the average patient satisfaction score was 9.5 (range, 6 - 10), which decreased to 8.6 (range, 6 - 10) at latest follow up. We estimated a potential cost saving of approximately L70,000 by treating 20 patients using CCH compared to inpatient operative fasciectomy. Conclusion: CCH is a useful option in the management of DC in appropriately selected patients. Cost-effectiveness in the treatment of DC should be carefully considered. PMID- 29535480 TI - An Imperfect Peace: Trends In Paramilitary Related Violence 20 Years After The Northern Ireland Ceasefires. AB - Background: The 1994 Northern Ireland ceasefire heralded a new beginning for the region after 30-years of violence. In the 20-years following the cessation of hostilities, paramilitary punishment attacks continue to occur in breach of the ceasefire. The aim of this study was to review trends in these attacks over the 20-years and their impact on orthopaedic services. Methods: We conducted a retrospective review of patients admitted under orthopaedic services following paramilitary assault across Northern Ireland over the last 20-years. The frequency of assaults, demographics of the victim population, injury pattern and weapons used was determined. Data on the total number of attacks was obtained from the Police Service for Northern Ireland (PSNI). Results: 3691 paramilitary style attacks occurred between 1994 and 2014 despite bilateral ceasefires. The overwhelming majority of attacks are on males, however females and children as young as 12 have been victims. Prior to 1994, penetrating trauma predominated (62% vs 38%), with blunt trauma more common post ceasefire (60% vs 40%). 33% of those injured required orthopaedic treatment. The type of weapon used in these assaults has changed primarily from ballistic to non-ballistic devices. Conclusions: We present data of paramilitary related trauma presenting to orthopaedic services across Northern Ireland in the 20-years since the conclusion of hostilities following the negotiated 1994 ceasefire. Many assaults continue to occur despite being in breach of the ceasefire. The frequency of these assaults is however, declining. The type of weapons used has changed resulting in less ballistic trauma and more blunt trauma. The injury pattern associated with blunt trauma has significant long-term morbidity and potentially a greater financial burden on the health service. Implications: 20-years of peace in Northern Ireland has had a hugely positive impact on the political and financial stability of the region. Unfortunately, continued violence represents a significant burden on the health service resources and causes potential long-term changes to victim's lives. PMID- 29535481 TI - All-Terrain Vehicle(ATV) Injuries - An Institutional Review Over 6 Years. AB - Objective: Quad bike or all-terrain vehicle (ATV) related injuries are a significant cause of trauma and may present with severe or fatal injuries. Most of the literature describing ATV related injuries come from North America and Australasia and data from the United Kingdom is scarce despite a high prevalence of ATV use. The aim of this study was to describe our single centre experience with ATV injuries over a 6-year period from 2010 to 2015. Materials and Methods: This is a cohort analysis of 65 patients who presented with ATV related injuries in South West Acute Hospital, UK between 2010 and 2015. Results: 65 patients had ATV injuries. 34 (52%) patients were children between 0 - 17 years of age. 88% (n=57) patients were ejected from the ATV, six got trapped underneath and two had collisions. "Ejection" as a mechanism of injury was significantly more common than the other mechanisms (p<0.0001). Compliance with helmet use was low at 16% (n=10). Extremity (48%) and head and face trauma (43%) were the most common injuries. One (1.5%) patient died while 3 (4.6%) patients had major morbidity. Conclusion: ATV injuries are an important cause of trauma admissions and carry a significant risk of morbidity and mortality. Extremity and head trauma are the most common injuries resulting from ATV accidents. More than 50% of the injured are children. Compliance with helmet use is low and calls for legislation and public awareness strategies to reduce the impact of ATV accidents on health care. PMID- 29535482 TI - Faecal Microbiota Transplantation for Clostridium Difficile - a local perspective. AB - Clostridium Difficile represents one of the major challenges of the antimicrobial era with associated significant morbidity. Treatment options are limited to a number of specific antibiotics with significant failure rates. Faecal Microbiota Transplantation has been recognised as a possible treatment option when standard therapy fails. We report a local case of Clostridium Difficile Infection ultimately requiring Faecal Microbiota Transplantation with good success. While no formal service providing the treatment is available within Northern Ireland it is a feasible treatment option for Clostridium Difficile Infection. PMID- 29535483 TI - "Showercap" Sign: Spontaneous Uterine Rupture in a Primiparous Woman. AB - A 32-year-old primiparous woman presented with severe abdominal pain at 21 weeks' gestation. Background history of laparoscopy for chronic pelvic pain and a spontaneous miscarriage was noted. On examination, she was peritonitic and tachycardic with low grade fever and anemia. MRI abdomen demonstrated a uterine rupture with a large cap of clotted blood overlying the uterine fundus with the appearance of a "shower cap" and large volume haemoperitoneum, the presumptive diagnosis was uterine rupture with placental extrusion. Emergency laparotomy confirmed a two litre haemoperitoneum due to a 3cm defect at the uterine fundus through which a portion of placenta and membrane were extruding. Hysterotomy and delivery of the non-viable fetus was performed. The defect was repaired. It is important to remember that there are many causes of acute abdominal pain in pregnant patients, obstetric and other. Uterine rupture is a rare but life threatening cause. An underlying risk factor is usually identified. PMID- 29535484 TI - Severe Burns in World War II. PMID- 29535485 TI - Widening Participation To The Medical Course At Queens University Belfast. AB - The United Kingdom Clinical Aptitude Test (UKCAT) was introduced to assist in identification of applicants from all levels of society with the appropriate characteristics to become good doctors. Evidence that the UKCAT has achieved such widened participation (WP) in applicants to medical school remains elusive. One of the limitations to WP investigation has been that data on socioeconomic status of applicants to medical schools has been obtained through voluntary submission on application to UKCAT and up to 30% of applications offered either none or only limited information. In this study of local applicants (451 from Northern Ireland) to Queens University Belfast (QUB) for 2012, socioeconomic data was ascertained through post code analysis. These data were utilized to investigate the relationship between affluence, application to the medical school and UKCAT score. Our study has shown that for NI applicants to QUB medical school, postcode /socioeconomic back ground accounts for only 3 percent of UK CAT score variation. We have also shown that our admissions process is largely independent of socioeconomic background. However we have demonstrated that the socioeconomic profile of applicants from Northern Ireland to QUB medical school is such that even if every applicant to QUB in 2012 were offered a place in the medical school the number of applicants from least affluent areas would increase by only 9. In conclusion efforts to achieve meaningful WP must be directed at raising aspirations for a career in Medicine within the community. PMID- 29535486 TI - PRE-OPERATIVE CARBAMAZEPINE-INDUCED HYPONATRAEMIA: SHOULD WE ACCEPT A RESET HYPO OSMOLAR BASELINE AND PROCEED WITH SURGERY? PMID- 29535487 TI - HOW CONFIDENT AND PREPARED ARE CORE MEDICAL TRAINEES IN THE UK TO PROCEED TO THE REGISTRAR LEVEL: THE TRAINEES' PERSPECTIVES. PMID- 29535488 TI - A PILOT OF THE USE OF VOICE RECOGNITION SOFTWARE IN AN ENDOCRINE OUTPATIENT CLINIC. PMID- 29535489 TI - 'THE USE OF THYROID ULTRASOUND BY NON-RADIOLOGISTS FOR THE ASSESSMENT OF THYROID NODULES'. PMID- 29535490 TI - ERRATUM. AB - [This corrects the article on p. 15 in vol. 86, PMID: 28298707.]. PMID- 29535491 TI - The Importance of Holistic Care at the End of Life. PMID- 29535492 TI - Curiositas (Neurology). PMID- 29535493 TI - DIAGNOSIS DIZZY? PMID- 29535494 TI - CAN WE PREVENT PSYCHOSIS? INNOVATIVE SERVICE OFFERS NEW HOPE. PMID- 29535495 TI - THE SUCCESS OF INTRAVITREAL INJECTIONS. PMID- 29535496 TI - So you want to be a Mohs surgeon? PMID- 29535497 TI - Corrigendum to "Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis". AB - [This corrects the article DOI: 10.1155/2016/1320365.]. PMID- 29535498 TI - Reference values for anterior chamber morphometrics with swept-source optical coherence tomography in a Caucasian population. AB - Purpose: The aim of this study is to generate reference values for anterior chamber morphometrics to facilitate the interpretation of anterior chamber images acquired with swept-source optical coherence tomography (SS-OCT) in a Caucasian population. Materials and methods: Non-glaucomatous Caucasian subjects, who were newly referred to the outpatient department of the University Eye Clinic Maastricht UMC+, were asked to undergo anterior segment assessment with SS-OCT imaging prior to routine eye examination (including visual acuity and refractive error measurements, Goldmann applanation tonometry, slit lamp examination and funduscopy). Results: A total of 647 Caucasian subjects, aged 40-80 years, were included. Mean age (+/- standard deviation) was 61.7+/-10.3 years, and 294 were male (45%). Mean refractive error was -0.63+/-3.17 D. OCT images and measurements were obtained in all cases. The mean temporal trabecular iris angle at 500 um (TIA500) was 27.04 degrees +/-12.04 degrees , the mean nasal TIA500 was 27.43 degrees +/-11.75 degrees , the mean anterior chamber depth (ACD) was 2.75+/-0.39 mm and the mean lens vault (LV) was 0.44+/-0.30 mm. A smaller temporal TIA500, shallower ACD and higher LV were found in female and hyperopic subjects. Conclusion: Reference values for anterior chamber morphometrics in Caucasians were generated, quantified and presented. These values offer tools for the interpretation of anterior segment images of Caucasians and differentiation between presumed mechanisms of angle closure. PMID- 29535499 TI - Correlation between glycemic control and peripapillary retinal nerve fiber layer thickness in Saudi type II diabetics. AB - Objective: To evaluate the effect of diabetes mellitus (DM), diabetic retinopathy, and degree of glycemic control (glycosylated hemoglobin [HbA1c]) on peripapillary retinal nerve fiber layer thickness (RNFLT) using optical coherence tomography. Methods: The study included 126 eyes of healthy controls (n=32) and diabetics patients (n=31), whose ages ranged from 40 to 70 years. The diabetic group was divided into: Subgroup 1: with HbA1c <7% and Subgroup 2: with HbA1c >=7%. All patients underwent full ophthalmic examination. HbA1c level was obtained with the A1cNow+ system and the peripapillary RNFLT was measured using 3D-OCT 2000 Topcon (360-degree circular scan with 3.4 mm diameter centered on optic disc). Results: The obtained data demonstrates significant decrease in peripapillary RNFLT in superior and inferior quadrants of the right eye (p=0.000 and p=0.039, respectively), and in superior quadrant of the left eye (p=0.002) with impairment of glycemic control. Pearson's correlation test showed significant negative correlation of RNFLT with HbA1c in the superior quadrant in both eyes. Conclusion: Impairment of glycemic control affects the peripapillary RNFLT mainly in the superior quadrant. This thickness also tends to decrease with long-standing DM, use of DM medications, and development of diabetic retinopathy. The measurement of peripapillary RNFLT may become a useful method to monitor early retinal changes in diabetic patients. PMID- 29535500 TI - Flicker electroretinograms of eyes with cataract recorded with RETeval system before and after mydriasis. AB - Purpose: The aim of this study is to determine the effect of pupil size of eyes with cataracts on the flicker electroretinograms (ERGs) elicited and recorded with the RETeval system. Patients and methods: Forty-one eyes of 41 patients (mean age, 76.5+/-7.3 years) that had grade 2 nuclear or cortical cataract without any other abnormalities were studied. Flicker ERGs were recorded before and after mydriatic drops instillation. The ERGs were elicited by the white light delivered at the frequency of 28.3 Hz and intensities of 2, 8, and 32 Td-s. The amplitudes and the implicit times of the flicker ERGs before and after mydriasis were compared. Results: There were no significant differences between the amplitudes before and after mydriasis (P=0.35, 2 Td-s; P=0.31, 8 Td-s; P=0.50, 32 Td-s). There were also no significant differences between the implicit times before and after mydriasis (P=0.86, 2 Td-s; P=0.98, 8 Td-s; P=0.95, 32 Td-s). The mean amplitudes and implicit times of the nuclear and cortical cataracts groups before the mydriasis were also not significantly different from those after mydriasis for all stimulus intensities. Conclusion: The lack of significant differences in the amplitudes and the implicit times of the flicker ERG of cataractous eyes before and after mydriasis indicated that the RETeval flicker ERGs in cataractous eyes is less affected by the pupil diameter. With our earlier study, it was assumed that the effect of cataracts on the RETeval flicker ERGs was due to the opacity of the crystalline lens, and the influence of the cataract would not be reduced or increased by mydriasis. PMID- 29535501 TI - Integration of microRNA-mRNA profiles and pathway analysis of plant isoquinoline alkaloid berberine in SGC-7901 gastric cancers cells. AB - Purpose: Berberine (BBR) is a traditional Chinese medicine normally used for gastroenteritis, and recent research found that it could fight against tumors. In this study, we focused on integrating miRNA sequencing and RNA sequencing of SGC 7901 gastric cancer cells treated by BBR to elucidate their underlying mechanisms. Materials and methods: WST-1 assay and flow cytometry were used to check the effects of BBR on SGC-7901. miRNA sequencing and RNA sequencing were used to establish the miRNA and mRNA profiles of BBR-treated SGC-7901. Results: The results showed that BBR could inhibit the proliferation of SGC-7901 cells and induce G1 arrest in cell cycle phase and apoptosis. A total of 1,960 upregulated genes and 4,837 downregulated genes were identified in the RNA sequencing and 347 upregulated and 93 downregulated miRNAs in the miRNA sequencing. A total of 78 novel miRNAs were also found. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that the genes were related to pathways in cancer and metabolism. We also analyzed the miRNA-mRNA network of genes grouped into cell cycle, apoptosis, inflammation, metabolism, cell junction, acetylization process, TGF-beta pathway, and Wnt signaling pathway. Conclusion: BBR could inhibit the proliferation of SGC-7901 cells and induce apoptosis. Integrated analysis of microRNA-mRNA profiles is a promising approach to validate gene expression patterns associated with malignant phenotype and study the mechanisms of anticancer. PMID- 29535502 TI - Magnesium: does it reduce ischemia/reperfusion injury in an adnexal torsion rat model? AB - Aim: The aim of the present study was to assess the protective effects of magnesium sulfate (MgSO4) on ischemia/reperfusion (I/R) induced ovarian damage in a rat ovarian torsion model. Methods: Forty-two female Sprague Dawley rats were included in the study. They were divided into six groups as Group 1, sham; Group 2, bilateral ovarian torsion; Group 3, bilateral ovarian torsion-detorsion; Group 4, MgSO4-sham; Group 5, MgSO4-bilateral ovarian torsion; Group 6, bilateral ovarian torsion-MgSO4-detorsion. Both torsion and detorsion periods lasted 3 hours. In Groups 4, 5 and 6, MgSO4 (600 mg/kg) was administered by intraperitoneal route 30 minutes before sham operation, torsion and detorsion, respectively. At the end of the study period, both ovaries were removed. One of the ovaries was used for histopathological analyses and the other for biochemical analyses. Results: In the torsion-detorsion group, all the histopathological scores were higher compared to the sham and torsion only group (p<0.05). Administration of MgSO4 only caused significant decrease in the inflammatory cell scores of the torsion-detorsion group (p<0.05). MgSO4, whether given before torsion or before detorsion, suppressed malondialdehyde levels when compared to the untreated groups (p<0.01 and p<0.001, respectively). Glutathione peroxidase activities were significantly higher in the MgSO4 applied torsion and detorsion groups than Groups 2 and 3 (p<0.05, for both). Administration of MgSO4 also caused an increase in glutathione levels in the torsion and detorsion groups compared to the torsion only and detorsion only groups (p<0.05, for both). Also, total oxidant status levels decreased in the MgSO4 applied torsion and detorsion groups compared to the untreated corresponding ones (p<0.01 and p<0.001, respectively). MgSO4 significantly decreased the Oxidative Stress Index levels in the torsion-detorsion group compared to Group 2 (p<0.001). Conclusion: Histopathological and biochemical analysis revealed that prophylactic treatment with MgSO4 reduces the changes observed in I/R injury in a rat model. PMID- 29535503 TI - Risk factors for calcineurin inhibitor nephrotoxicity after renal transplantation: a systematic review and meta-analysis. AB - Background: Nephrotoxicity of calcineurin inhibitors (CNIs) is the major concern for long-term allograft survival despite its predominant role in current immunosuppressive regime after renal transplantation. CNI nephrotoxicity is multifactorial with demographic, environmental, and pharmacogenetic flexibility, whereas studies indicating risk factors for CNI nephrotoxicity obtained incomplete or conflicting results. Methods: A systematic review and meta-analysis of risk factors for CNI nephrotoxicity was performed on all retrieved studies through a comprehensive research of network database. Data were analyzed by Review Manager 5.2 with heterogeneity assessed using the Cochrane Q and I2 tests. CNI nephrotoxicity was primarily indicated with protocol biopsy or index-based clinical diagnosis, and the secondary outcome was defined as delayed graft function. Results: Twelve observational studies containing a total of 2,849 cases were identified. Donor age (odds ratio [OR], 1.01; 95% CI, 1.01-1.03; p=0.02), recipient zero-time arteriosclerosis (OR, 1.44; 95% CI, 1.04-1.99; p=0.03), and CYP3A5*3/*3 genotype (OR, 2.80; 95% CI, 2.63-2.98; p=0.00) were confirmed as risk factors for CNI nephrotoxicity. Subgroup and sensitivity analysis claimed donor age as a significant contributor in Asian and Caucasian areas. Conclusion: Older donor age, recipient zero-time arteriosclerosis, and CYP3A5*3/*3 genotype might add up the risk for CNI nephrotoxicity, which could be interpreted into a robust biomarker system. PMID- 29535504 TI - Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation. AB - Introduction: Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants. Materials and methods: This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX 019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with >=7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study. Results: Baseline characteristics were comparable between treatment sequences. For HTX-019, mean (percent coefficient of variation) area under the curve (AUC) from time 0 to time of last measurable plasma concentration (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and plasma concentration at 12 h (C12 h) for HTX-019 were 43,729 h*ng/mL (32.7), 45,460 h*ng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 h*ng/mL (32.0), 46,163 h*ng/mL (36.6), and 1,022 ng/mL (28.5). Also, 90% CIs (94.186-101.354) were within bioequivalence bounds (80%-125%). Within 1 h following infusion start, one (1%) HTX-019 recipient reported one TEAE, while 20 (20%) fosaprepitant recipients reported 32 TEAEs. Dyspnea occurred in three fosaprepitant recipients (at <1 min in two subjects and at 18 min in one subject, considered study drug related) and one HTX-019 recipient (at 120 h, associated with a respiratory tract infection and considered not related to the study drug). No severe TEAEs, serious adverse events, or deaths occurred; all TEAEs resolved. Conclusion: HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis. PMID- 29535505 TI - Efficacy of atorvastatin on the prevention of contrast-induced acute kidney injury: a meta-analysis. AB - Background: Results of studies on the efficacy of atorvastatin pretreatment on reducing the prevalence of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) have been controversial. Objective: We undertook a meta analysis to evaluate the efficacy of atorvastatin on contrast-induced nephropathy (CIN) after CAG or PCI. Materials and methods: We undertook a systematic search of electronic databases (PubMed, Embase, and the Cochrane Library) up to June 2017. A meta-analysis was carried out including randomized controlled trials (RCTs) that compared atorvastatin pretreatment with pretreatment with a low-dose statin or placebo for CIAKI prevention in patients undergoing CAG. The main endpoint was CIN prevalence. Results: Nine RCTs were included in our meta analysis. Atorvastatin pretreatment reduced the prevalence of CIN significantly (odds ratio [OR] 0.46; 95% confidence interval [95% CI] 0.27-0.79; p=0.004). The benefit of high-dose atorvastatin pretreatment was consistent when compared with the control group (OR 0.45; 95% CI 0.21-0.95; p=0.04). Conclusion: At high doses, atorvastatin pretreatment was associated with a significant reduction in the prevalence of CIAKI in patients undergoing CAG. Pretreatment with high-dose atorvastatin could be employed to prevent CIAKI. PMID- 29535506 TI - Written reflection in an eHealth intervention for adults with type 2 diabetes mellitus: a qualitative study. AB - Background: Individuals with type 2 diabetes mellitus (T2DM) are responsible for the daily decisions and actions necessary to manage their disease, which makes self-management the cornerstone of diabetes care. Many patients do not reach recommended treatment goals, and thus it is important to develop and evaluate innovative interventions that facilitate optimal motivation for adequate self management of T2DM. Objective: The aim of the current study was to explore how adults with T2DM experience using reflection sheets to stimulate written reflection in the context of the Guided Self-Determination (GSD) eHealth intervention and how written reflection might affect their motivation for self management of T2DM. Methods: We used a qualitative design in which data were collected through individual interviews. The sample consisted of 10 patients who completed the GSD eHealth intervention, and data were analyzed using qualitative content analysis. Results: The qualitative content analysis yielded 2 main themes. We labeled the first theme as "Written reflection affects awareness and commitment in diabetes self-management", which reflects 2 subthemes, namely, "Writing creates space and time for autonomous reflection" and "Writing influences individuals' focus in diabetes self-management". We labeled the second theme as "Written reflection is perceived as inapplicable in diabetes self management", which reflects 2 subthemes, namely, "Responding in writing is difficult" and "The timing of the writing is inappropriate". Conclusion: Our findings indicate that written reflection in the context of the GSD eHealth intervention may be conducive to motivation for diabetes self-management for some patients. However, it seems that in-person consultation with the diabetes nurse may be necessary to achieve the full potential benefit of the GSD as an eHealth intervention. We advocate further development and examination of the GSD as a "blended" approach, especially for those who consider written reflection to be difficult or unfamiliar. PMID- 29535507 TI - Cultural adaptation and validation of patient decision aids: a scoping review. AB - In order to promote self-determination, patients have to be actively involved with their care providers in health-care decision making, especially when such decisions involve personal preferences. Decision aids (DAs) are tools that can contribute to patient-centered decision-making processes. To benefit from previous fieldwork and avoid duplicating developmental efforts and producing many similar DAs, the adaptation of existing DAs to new cultural contexts is a resource-saving option. However, there are no guidelines on how to culturally adapt and validate DAs. This study aimed to identify and document existing procedures for the cultural adaptation and validation of patient DAs. A scoping review examined studies conducting cultural adaptation and/or validation of patient DAs. The following databases were searched in February 2016: CINAHL, EMBASE, Medline (Ovid), PASCAL, PsychINFO, and PubMed. From the 13 studies selected, 11 main procedures were identified: appraisal of the original DA, assessment of the new cultural context, translation, linguistic adaptation, cultural adaptation, usability testing, exploration of DA acceptability, test retest reliability, content validity, construct validity, and criterion validity. A conceptual synthesis of these studies suggests there are four phases in the adaptation/validation process of DAs aimed at: 1) exploring the original DA and the new cultural context, 2) adapting the original DA to the new cultural context, 3) lab testing the preliminary version of the adapted DA, and 4) field testing the adapted DA in a real use context. By facilitating the adaptation and broader implementation of DAs, patients may ultimately be empowered in decision making processes. PMID- 29535508 TI - Transcutaneous electrical nerve stimulation and placebo analgesia: is the effect the same for young and older individuals? AB - Purpose: Placebo analgesia refers to a perceived reduction in pain intensity following the administration of a simulated or otherwise medically ineffective treatment. Previous studies have shown that many factors can influence the magnitude of placebo analgesia. However, few investigations have examined the effect of age on placebo analgesia, and none have done it in the context of electrotherapeutic interventions. The objective of this study is to compare the placebo response induced by sham transcutaneous electrical nerve stimulation (TENS) between young and older individuals, using an experimental heat-pain paradigm. Patients and methods: Twenty-two young (21-39 years) and 22 older (58 76 years) healthy adults participated in this comparative study. Experimental heat pain was evoked with a thermode (2-min stimulation at a constant individually adjusted temperature) applied on the lumbar region. Participants were asked to evaluate the intensity of their pain using a computerized visual analog scale. Experimental pain was induced before and after an unconditioned placebo intervention (placebo TENS) applied for 25 min. Results: In young individuals, no significant pain reductions were noted, whereas in older individuals, a statistically significant pain reduction was observed after the placebo stimulation (P<0.01). Between-group analyses revealed that placebo analgesia was greater in older individuals (40% pain reduction) compared with young individuals (15% pain reduction) (P<0.05). However, sham TENS increased heat-pain thresholds in the young group (P<0.01), but not in the older group (P=0.43). Conclusion: Our results indicate that placebo analgesia is influenced by age, with older individuals showing larger placebo analgesia than young adults. Although these results should be confirmed in clinical pain populations, the current observations bear potentially important consequences for the design of future placebo-controlled trials and for healthcare professionals working with elderly patients. PMID- 29535509 TI - Health status, health behaviors, and the ability to perform everyday activities in Poles aged >=65 years staying in their home environment. AB - Background: The incidence of chronic diseases increases with age; about 73% of people who are aged >=60 years suffer from at least 1 chronic disease, and among those older than 70 years, chronic diseases afflict more than >84% of the population. According to epidemiological data, at least 4 chronic disease types coexist in senior citizens, causing their disability. These are mainly cardiovascular diseases; motor system diseases; ophthalmological, auditory, neurological, and mental diseases; and mental impairment. They worsen or limit self-dependence in everyday activities. The process begins with complex activities and advances with age. At first, functional performance deficits are discreet; then, they may gradually lead to complete dependence on other people or institutions. Objective: This study aimed to assess the relationship between diseases and health behaviors, as well as the everyday functioning of people aged >=65 years staying in their home environment. Methods: The research involved 504 elderly people. The inclusion criteria were age (>=65 years) and staying in one's own home environment. The direct interview technique was applied, as well as use of proprietary interview questionnaire and standardized tools used in geriatrics: Barthel scale, measuring performance in everyday activities, and the Instrumental Activities of Daily Living scale, assessing complex everyday activities. Results: The most frequent disease among the responders was arterial hypertension (77.58%), followed by degenerative joint disease (62.10%), and circulatory failure (43.23%). Lower functional performance was associated with circulatory failure, cerebral stroke, atherosclerosis, Alzheimer's disease, diabetes, Parkinson's disease, degenerative joint disease, and bronchial asthma. Performance worsening significantly influenced the frequency of hospitalizations, with a mean score of 4.31 per person. Medical rehabilitation was practiced by 18.65% of the responders. Conclusion: Circulatory failure, cerebral stroke, atherosclerosis, bronchial asthma, diabetes, degenerative joint disease, Parkinson's disease, and Alzheimer's disease negatively affect functional performance in elderly people. Hospitalization rates increase with lowering independence in everyday functioning. Future research is needed with regard to the relationship between the practiced rehabilitation and independence in everyday functioning of the elderly. PMID- 29535510 TI - Gene-expression changes in knee-joint tissues with aging and menopause: implications for the joint as an organ. AB - Background: When considering the "joint as an organ", the tissues in a joint act as complementary components of an organ, and the "set point" is the cellular activity for homeostasis of the joint tissues. Even in the absence of injury, joint tissues have adaptive responses to processes, like aging and menopause, which result in changes to the set point. Purpose: The purpose of this study in a preclinical model was to investigate age-related and menopause-related changes in knee-joint tissues with the hypothesis that tissues will change in unique ways that reflect their differing contributions to maintaining joint function (as measured by joint laxity) and the differing processes of aging and menopause. Methods: Rabbit knee-joint tissues from three groups were evaluated: young adult (gene expression, n=8; joint laxity, n=7; water content, n=8), aging adult (gene expression, n=6; joint laxity, n=7; water content, n=5), and menopausal adult (gene expression, n=8; joint laxity, n=7; water content, n=8). Surgical menopause was induced with ovariohysterectomy surgery and gene expression was assessed using reverse-transcription quantitative polymerase chain reaction. Results: Aging resulted in changes to 37 of the 150 gene-tissue combinations evaluated, and menopause resulted in changes to 39 of the 150. Despite the similar number of changes, only eleven changes were the same in both aging and menopause. No differences in joint laxity were detected comparing young adult rabbits with aging adult rabbits or with menopausal adult rabbits. Conclusion: Aging and menopause affected the gene-expression patterns of the tissues of the knee joint differently, suggesting unique changes to the set point of the knee. Interestingly, aging and menopause did not affect knee-joint laxity, suggesting that joint function was maintained, despite changes in gene expression. Taken together, these findings support the theory of the joint as an organ where the tissues of the joint adapt to maintain joint function. PMID- 29535511 TI - Reduced MBD2 expression enhances airway inflammation in bronchial epithelium in COPD. AB - Background: Chronic obstructive pulmonary disease (COPD) is a common inflammatory lung disease characterized by inflammatory cells activation and production of inflammatory mediators. Methyl-CpG-binding domain protein 2 (MBD2) plays an important role in diverse immunological disorders by regulating immune cell functions, such as differentiation and mediator secretion. However, the role of MBD2 in COPD remains unknown. Methods: MBD2 protein expression in lung tissues of patients with COPD and cigarette smoke (CS)-exposed mice were evaluated by Western blot and immunohistochemistry. The role of MBD2 in cigarette smoke extract (CSE)-induction of inflammatory mediator expression in the human bronchial epithelial (HBE) cell line was assessed by silencing MBD2 expression in vitro. The involvement of signaling pathways in mediation of inflammation was tested with signaling inhibitors. Results: Compared with controls, MBD2 expression was distinctly reduced in the bronchial epithelium of both patients with COPD and CS-exposed mice. Moreover, MBD2 expression was decreased in HBE after CSE stimulation in vitro. Moreover, MBD2 knockdown enhanced interleukin (IL)-6 and IL-8 expression in HBE in the presence and absence of CSE treatment by the ERK signaling pathway. Conclusion: MBD2 protein expression was reduced in the airway epithelium of COPD. In HBE, this reduced expression was associated with increased levels of IL-6 and IL-8 mediated by the ERK pathway. These results suggest that MBD2 could contribute to chronic airway inflammation in COPD. PMID- 29535512 TI - The relationship between exercise capacity and different functional markers in pulmonary rehabilitation for COPD. AB - Rationale: The relationship of functional parameters such as lung mechanics, chest kinematics, metabolism and peripheral and respiratory muscle function with the level of exercise tolerance remains a controversial subject. While it has been previously shown that pulmonary rehabilitation is capable of improving exercise tolerance in patients afflicted by COPD, as expressed by values of 6 minute walking test (6MWT), the degree of contribution to this change by each of the aforementioned parameters remains unclear. Aims: To investigate the correlation between changes in exercise capacity and other functional markers following pulmonary rehabilitation in COPD and to determine which parameters are more closely related to improvements of exercise tolerance. Materials and methods: Three hundred and twenty-seven patients with COPD (with average, 95% CI for forced expiratory volume in the first second [FEV1]: 45% [25%-83%] predicted, age: 64 [48-80] years, and BMI: 27 [13.5-40.4] kg/m2) participated in this study. Thirty percent of the patients had pulmonary hypertension as comorbidity. Patients underwent a pulmonary rehabilitation program with 20-30 minutes sessions two to three times per day for 4 weeks. The program was composed of chest wall stretching, controlled breathing exercises, and a personalized training schedule for cycling and treadmill use. Measurements of 6MWT, lung function, chest wall expansion, grip strength, maximal inspiratory pressure, and breath holding time were taken. The Body mass index, airflow Obstruction, Dyspnea and Exercise capacity (BODE-index), body mass index [BMI], FEV1, 6MWT, modified Medical Research Dyspnea Scale score, and an alternative scale score (for BMI, FEV1, 6MWT, and COPD Assessment Test) were calculated. Results: Rehabilitation resulted in a generalized improvement in 6MWT among patients (average: 360 [95% CI: 178 543 m] vs average: 420 [95% CI: 238-601 m], p<0.05). Improvements in exercise tolerance were found to be most closely associated with changes in composite BODE index (R2=-0.6), Alternative Scale (R2=-0.56), dyspnea score (modified Medical Research Dyspnea Scale R2=-0.54), and health status (COPD Assessment Test R2= 0.4, p<0.05). In addition, improvements in exercise tolerance were found to moderately correlate with improvements in inspiratory vital capacity (IVC, R2=0.34, p<0.05). Post-rehabilitation changes in IVC displayed a connection with grip strength (R2=0.6) and chest expansion (R2=0.48). Conclusion: Enhancements in exercise tolerance had correlation with changes in IVC, BODE-index, and the new Alternative Scale. However, comprehensive assessment needs to include considerations of chest kinematics and peripheral and respiratory muscle function as well. PMID- 29535513 TI - Effect of the economic crisis on the use of health and home care services among Spanish COPD patients. AB - Background: Chronic obstructive pulmonary disease (COPD) is a major cause of disability and death worldwide. Consequently, COPD patients are frequent users of health and social resources. Therefore, they are highly vulnerable to decreases in investment in healthcare services. We aimed to describe the utilization of health and home care services among Spanish COPD patients during the economic crisis to identify factors independently associated with changes in the utilization of these services and to study the time trends from 2009 to 2014. Methods: We used data from the European Health Interview Surveys for Spain (EHSS) conducted between 2009/2010 (n=22,188) and 2014 (n=22,842). We included responses from adults with COPD aged 40 years or over. Dependent variables included self reported hospitalizations during the previous year, general practitioner (GP) visits during the last 4 weeks, other health care services used during the previous year (nursing, rehabilitation, and psychological services), and home care services use during the previous year. Independent variables included demographic and socioeconomic characteristics, health status variables, and lifestyles. Results: We identified 1,328 and 1,008 COPD patients from EHSS 2009 and EHSS 2014, respectively. We observed a significant increase in non-GP services use (30.6% in 2009 vs 39.11% in 2014; p<0.001). No changes were found for hospitalizations, GP visits, and home care services use over time. Multivariable models showed that associated factors with a higher use included any chronic comorbidity and worse self-rated health. Physical activity was a strong predictor of fewer hospitalizations and less home care service use. Female sex was associated with significantly fewer hospitalizations (OR 0.72; 95% CI 0.58-0.89). Conclusion: We found an increase in the use of non-GP services (nursing, rehabilitation, and psychological) but not in other health and home care services. The only differences in hospitalizations were observed according to sex. Therefore, the effect of the economic crisis, if any, seems to have been of small magnitude. PMID- 29535514 TI - The effect of environmental factors on the differential expression of miRNAs in patients with chronic obstructive pulmonary disease: a pilot clinical study. AB - Objective: The objective of the study was to analyze the effect of environmental factors on the differential expression of microRNAs in the peripheral blood of migratory and local patients in northern People's Republic of China and on clinical symptoms of local patients in northern People's Republic of China with COPD. Methods: A total of 118 patients in the northern region and 8 migratory patients were enrolled in this prospective study. We collected general information. Blood samples were collected from 9 patients in the Beijing group, from 8 patients in the migratory group and from 9 healthy control subjects. After extracting the total RNA from these 3 groups, serum miRNA was identified by Solexa sequencing. We collected COPD assessment test (CAT) and Modified British Medical Research Council (mMRC) scores at different levels of air pollution and also collected the number of exacerbations over the year prior to the baseline and in the year preceding the follow-up. Results: In total 9 miRNAs were differentially expressed. When air quality index (AQI) >100, the CAT and mMRC scores at baseline were significantly higher than those when the AQI <=100 (P<0.001). When AQI >100, the follow-up CAT and mMRC scores were significantly higher than those when AQI <=100 (P<0.001). Follow-up mMRC scores were significantly higher than baseline scores (P=0.04). When AQI <=100, the baseline CAT score of the group with fewer symptoms was 6.50 (4.00-8.75). However, when AQI >100, the baseline CAT score of this fewer symptoms group was 10.00 (6.25 12.00). The median CAT score was close to 10. When AQI <=100, the follow-up CAT score of the fewer symptoms group was 8.00 (4.25-12.00). However, when AQI >100, the follow-up CAT score of the fewer symptoms group was 9.50 (6.00-16.75). The median CAT score was close to 10. Conclusion: Environmental factors may cause differential expression of miRNAs in the peripheral blood of migratory and local patients in northern People's Republic of China. Air pollution may aggravate clinical symptoms of patients with COPD. PMID- 29535515 TI - Home noninvasive ventilatory support for patients with chronic obstructive pulmonary disease: patient selection and perspectives. AB - Long-term or home mechanical noninvasive ventilation (Home-NIV) has become a well established form of therapy over the last few decades for chronic hypercapnic COPD patients in European countries. However, meta-analyses and clinical guidelines do not recommend Home-NIV for COPD patients on a routine basis. In particular, there is ongoing debate about Home-NIV in chronic hypercapnic COPD regarding the overall effects, the most favorable treatment strategy, the selection of eligible patients, and the time point at which it is prescribed. The current review focuses on specific aspects of patient selection and discusses the various scientific as well as clinical-guided perspectives on Home-NIV in patients suffering from chronic hypercapnic COPD. In addition, special attention will be given to the topic of ventilator settings and interfaces. PMID- 29535516 TI - Relationship between the presence of bronchiectasis and acute exacerbation in Thai COPD patients. AB - Background: The prevalence rate of bronchiectasis in COPD is variable. Coexisting bronchiectasis and COPD may influence COPD severity and exacerbation. Objective: We investigated whether bronchiectasis is associated with frequent or severe COPD exacerbation. Lower airway bacterial and mycobacterial infections are a possible mechanism for bronchiectasis. Materials and methods: A cross-sectional study was conducted in 2013-2014. COPD exacerbations and hospitalizations were reviewed. Spirometry and CT were performed. COPD symptoms were assessed by using the COPD assessment test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Sputum inductions were performed and specimens were sent for microbiology. Results: We recruited 72 patients. Global Initiative for Chronic Obstructive Lung Disease (GOLD) A, B, C, and D, were noted in 20%, 27.1%, 14.3%, and 38.6% of the patients, respectively. Frequent exacerbations (>=2) and/or >=1 hospitalization in the previous year were observed in 40.3% of patients. Median mMRC of COPD with frequent and non-frequent exacerbations was 1.0 (range 1-2) and 2.0 (range 1-3), (p=0.002), respectively. Median CAT of COPD with frequent and non-frequent exacerbations was 20.5 (3-37) and 11.0 (2-32), (p=0.004), respectively. CT detected bronchiectasis was observed in 47.2% of patients. Median mMRC of COPD with and without bronchiectasis was 1.0 (0-4) and 1.0 (0-4) (p=0.22), respectively. Median CAT of COPD with and without bronchiectasis was 16.2 (95% CI: 12.9-19.6) and 13.0 (3-37), (p=0.49), respectively. The lower post bronchodilator forced expiratory volume in 1 second (FEV1) of COPD with frequent exacerbations than those without was noted (p=0.007). The post-bronchodilator forced expiratory volume at 1 second percent in patients with and without bronchiectasis was not different (p=0.91). After adjusting for gender, severity of airflow obstruction, severity of COPD symptoms, the odds ratio for bronchiectasis with frequent and/or severe exacerbation was 4.99 (95% CI: 1.31 18.94), (p=0.018). Neither bacterial nor mycobacterial airway infection was associated with bronchiectasis or frequent exacerbation. Conclusions: Bronchiectasis is common in Thai COPD. It was associated with frequent exacerbation or hospitalization. Mycobacterial tuberculosis in COPD patients with bronchiectasis was uncommon. PMID- 29535517 TI - The effects of repeated Toll-like receptors 2 and 4 stimulation in COPD alveolar macrophages. AB - Background: COPD is a progressive inflammatory airway disease characterized by increased numbers of alveolar macrophages in the lungs. Bacterial colonization of the lungs is a common feature in COPD and can promote inflammation through continual and repeated Toll-like receptor (TLR) stimulation. We have studied the response of COPD alveolar macrophages to repetitive stimulation with TLR2 and TLR4 ligands. We investigated the effect of sequential stimulation with different ligands to determine whether this results in tolerance or amplification of the immune response. Methods: We stimulated alveolar macrophages from COPD patients (n=9) and smokers (n=8) with the TLR4 agonist lipopolysaccharide (LPS) or the TLR2 agonist Pam3CSK4 for 24 hours before restimulating again for 24 hours. Cytokine protein release and gene expression were investigated. Results: Repetitive stimulation of COPD and smokers macrophages with LPS for both 24-hour periods caused a reduction in tumor necrosis factor alpha, CCL5, and IL-10 production compared to cells that were not exposed initially to LPS. IL-6 and CXCL8 production were not significantly altered following repetitive LPS stimulation. The same pattern was observed for repeated stimulation with Pam3CSK4. Using COPD macrophages, LPS followed by Pam3CSK4 stimulation increased the levels of all cytokines compared to media followed by Pam3CSK4. Conclusion: TLR tolerance in COPD alveolar macrophages occurs after repetitive stimulation with the same TLR ligand, but this only occurs for selected cytokines. CXCL8 production is not reduced after repetitive TLR stimulation with the same ligand; this may be an important mechanism for the increased CXCL8 levels that have been observed in COPD. We showed that TLR4 stimulation followed by TLR2 stimulation does not cause tolerance, but enhances cytokine production. This may be a relevant mechanism by which bacteria cause excessive inflammation in COPD patients. PMID- 29535518 TI - Noninvasive visualization of early osteoarthritic cartilage using targeted nanosomes in a destabilization of the medial meniscus mouse model. AB - Background: Early stage osteoarthritis (OA) is clinically asymptomatic due to the avascular and the aneural nature of the cartilage tissue. Nevertheless, early detection of cartilage tissue is critical in order to impede the progression of OA. Hence, in order to develop effective preventive therapy for OA, diagnosis in the early stages is necessary. Methods: To achieve this goal, we have developed targeted, fluorescent nanosomes conjugated with monoclonal anti-type II collagen antibodies (MabCII) for diagnosis of early OA. The MabCII-coated nanosomes (targeted-nanosomes) bind to the damaged cartilage explants in vitro and in vivo in an OA mouse model that mimics early stage OA. The OA mouse model was induced by destabilization of the medial meniscus (DMM) in 9-10 weeks old C57Bl/6 mice. Results: The targeted-nanosomes enhanced the binding specificity to the cartilage tissue according to the severity of damage. Conclusion: We show that MabCII nanosomes can precisely detect early stage OA in the DMM mouse model. Thus, MabCII-nanosomes have the potential to be used as a non-invasive method for diagnosing the early osteoarthritic lesions. PMID- 29535519 TI - Colon-targeted delivery of cyclosporine A using dual-functional Eudragit(r) FS30D/PLGA nanoparticles ameliorates murine experimental colitis. AB - Background: Colon-targeted oral nanoparticles (NPs) have emerged as an ideal, safe, and effective therapy for ulcerative colitis (UC) owing to their ability to selectively accumulate in inflamed colonic mucosa. Cyclosporine A (CSA), an immunosuppressive agent, has long been used as rescue therapy in severe steroid refractory UC. In this study, we developed CSA-loaded dual-functional polymeric NPs composed of Eudragit(r) FS30D as a pH-sensitive polymer for targeted delivery to the inflamed colon, and poly(lactic-co-glycolic acid) (PLGA) as a sustained release polymer. Methods: CSA-loaded Eudragit FS30D nanoparticles (ENPs), PLGA nanoparticles (PNPs), and Eudragit FS30D/PLGA nanoparticles (E/PNPs) were prepared using the oil-in-water emulsion method. Scanning electron microscope images and zeta size data showed successful preparation of CSA-loaded NPs. Results: PNPs exhibited a burst drug release of >60% at pH 1.2 (stomach pH) in 0.5 h, which can lead to unwanted systemic absorption and side effects. ENPs effectively inhibited the burst drug release at pH 1.2 and 6.8 (proximal small intestine pH); however, nearly 100% of the CSA in ENPs was released rapidly at pH 7.4 (ileum-colon pH) owing to complete NP dissolution. In contrast to single functional PNPs and ENPs, the dual-functional E/PNPs minimized burst drug release (only 18%) at pH 1.2 and 6.8, and generated a sustained release at pH 7.4 thereafter. Importantly, in distribution studies in the gastrointestinal tracts of mice, E/PNPs significantly improved CSA distribution to the colon compared with PNPs or ENPs. In a mouse model of colitis, E/PNP treatment improved weight loss and colon length, and decreased rectal bleeding, spleen weight, histological scoring, myeloperoxidase activity, macrophage infiltration, and expression of proinflammatory cytokines compared with PNPs or ENPs. Conclusion: Overall, this work confirms the benefits of CSA-loaded E/PNPs for efficiently delivering CSA to the colon, suggesting their potential for UC therapy. PMID- 29535520 TI - Targeted delivery of anti-miR-155 by functionalized mesoporous silica nanoparticles for colorectal cancer therapy. AB - Introduction: MicroRNA-155 (miR-155) is an oncogenic microRNA, which is upregulated in many human cancers including colorectal cancer (CRC). Overexpression of miR-155 has been found to regulate several cancer-related pathways, and therefore, targeting miR-155 may be an effective strategy for cancer therapy. However, effective and safe delivery of anti-miR-155 to tumors remains challenging for the clinical applications of anti-miR-155-based therapeutics. Methods: In this study, we explored the expression of miR-155 and the transcription factor nuclear factor kappa B (NF-kappaB) in CRC tissues and cell lines, and the possible relationship between miR-155 and NF-kappaB. We further report on anti-miR-155-loaded mesoporous silica nanoparticles (MSNs) modified with polymerized dopamine (PDA) and AS1411 aptamer (MSNs-anti-miR 155@PDA-Apt) for the targeted treatment of CRC. Results: Results showed that miR 155 is overexpressed in CRC tissues and cell lines, and there is a positive feedback loop between NF-kappaB and miR-155. Compared to the control groups, MSNs anti-miR-155@PDA-Apt could efficiently downregulate miR-155 expression in SW480 cells and achieve significantly high targeting efficiency and enhanced therapeutic effects in both in vivo and in vitro experiments. Furthermore, inhibition of miR-155 by MSNs-anti-miR-155@PDA-Apt can enhance the sensitivity of SW480 to 5-fluorouracil chemotherapy. Conclusion: Thus, our results suggested that MSNs-anti-miR-155@PDA-Apt is a promising nanoformulation for CRC treatment. PMID- 29535521 TI - The evaluation of zinc and copper content in tooth enamel without any pathological changes - an in vitro study. AB - Objectives: The objectives of the study were to evaluate the content of copper and zinc in individual layers of tooth enamel and to analyze the relationships between the study minerals in individual layers of tooth enamel. Patients and methods: Fifteen human permanent teeth were cut off every 150 MUm alongside the labial surface. Acid biopsy of each layer was performed. The zinc content was determined using the air-acetylene flame method. The copper content was determined using the electrothermal technique with argon. Results: The mean zinc concentrations increased significantly starting from the outer enamel surface, with the maximum concentration in the 150-300 MUm layer. The mean copper concentrations increased substantially from the outer enamel surface to a depth of 150 MUm, and then a slight downward trend of this mineral levels was seen, down to a depth of 450 MUm. Strong positive correlation was found between the zinc and copper concentrations at depths of 150-300, 450-600 and 600-750 MUm. Conclusion: The levels of zinc and copper in the outer enamel layers may have an effect on the increased content of unipolar minerals at deeper enamel layers. The content of the study elements determined may reflect the process of mineralization and maturation of enamel in the pre-eruption period.